PMID- 22421611 TI - 16S rRNA gene sequence analysis of a Brucella melitensis infection misidentified as Bergeyella zoohelcum. AB - Misidentification of Brucella species from clinical specimens using commercial bacterial identification systems is a recurring problem. An isolate from a bacterimic patient was identified as Bergeyella zoohelcum by MicroScan Walk-Away (Siemens Healthcare Diagnostics Inc., West Sacramento, CA, USA) and as Brucella melitensis by Vitek 2 system (bioMerieux Inc., Durham, NC, USA). Because of this identification ambiguity by the two automated bacterial identification systems we performed 16S rRNA sequencing and serotyping of the isolate and confirmed it as a Brucella spp. Combining the sequence data with the Vitek 2 system data we conclude that the infection was caused by B. melitensis. PMID- 22421612 TI - Double trouble: a case of von Recklinghausen's disease with coexistent lepromatous leprosy. AB - Leprosy (or Hansen disease) is a tropical disease which affects the skin and nerves leading to deformities and disabilities. Von Recklinghausen's disease (neurofibromatosis 1) is a well-recognized genetic disorder with both cutaneous and systemic manifestations. Lesions of neurofibromatosis may be mistaken for nodules of lepromatous leprosy and vice versa. Occurrence of both von Recklinghausen's disease and lepromatous leprosy together is very rare. Since cutaneous nodules can also occur in neurofibromatosis, lepromatous leprosy can be easily missed. The presence of lepromatous leprosy in a patient with von Recklinghausen's disease is unique and poses certain diagnostic dilemmas which are discussed in this report. PMID- 22421613 TI - Plasmodium falciparum malaria, bilateral sixth cranial nerve palsy and delayed cerebellar ataxia. AB - We describe the case of a 14-year-old Caucasian male, a resident in the Democratic Republic of the Congo, who was observed in Portugal with severe Plasmodium falciparum malaria with high-level parasitemia and severe thrombocytopenia. The course was complicated by bilateral sixth cranial nerve palsy during acute malaria, followed by the appearance of delayed cerebellar ataxia during the recovery phase. This occurred after successful treatment with quinine plus doxycycline over seven days. Different levels of thrombocytopenia and C-reactive protein were observed during both neurologic events in the presence of HRP-2 positive tests for Plasmodium falciparum antigen. The patient recovered completely after three months. PMID- 22421614 TI - Study of microbial keratitis in central India. PMID- 22421615 TI - Facing the challenges of hepatitis B management in a developing country. PMID- 22421616 TI - A probable association between HTLV-1 and endemic mycosis in Latin America. PMID- 22421617 TI - 3-D illustration of network orientations of interstitial cells of Cajal subgroups in human colon as revealed by deep-tissue imaging with optical clearing. AB - Morphological changes of interstitial cells of Cajal (ICC) have been proposed to characterize motility disorders. However, a global view of the network orientations of ICC subgroups has not been established to illustrate their three dimensional (3-D) architectures in the human colon. In this research, we integrate c-kit immunostaining, 3-D microscopy with optical clearing, and image rendering to present the location-dependent network orientations with high definition. Full-depth colonic tissues were obtained from colectomies performed for nonobstructing carcinoma. Specimens of colon wall were prepared away from the tumor site. C-kit and nuclear fluorescent staining were used to identify the ICC processes and cell body. Optical clearing was used to generate transparent colon specimens, which led to panoramic visualization of the fluorescence-labeled ICC networks at the myenteric plexus (ICC-MY), longitudinal (ICC-LM) and circular (ICC-CM) muscles, and submucosal boundary (ICC-SM) up to 300 MUm in depth via confocal microscopy with subcellular level resolution. We observed four distinct network patterns: 1) periganglionic ICC-MY that connect with ICC-LM and ICC-CM, 2) plexuses of ICC-LM within the longitudinal muscle and extending toward the serosa, 3) repetitive and organized ICC-CM layers running parallel to the circular muscle axis and extending toward the submucosa, and 4) a condensed ICC SM layer lining the submucosal border. Among the four patterns, the orderly aligned ICC-CM layers provide an appropriate target for quantitation. Our results demonstrate the location-dependent network orientations of ICC subgroups and suggest a practical approach for in-depth imaging and quantitative analysis of ICC in the human colon specimen. PMID- 22421618 TI - Review: Experimental models for Barrett's esophagus and esophageal adenocarcinoma. AB - Several different cell culture systems and laboratory animal models have been used over the years to study Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Most of the existing models have key differences with the human esophagus and complex pathogenesis of disease. None of the models offers an ideal system for the complex study of environmental exposure, genetic risk, and prevention strategies. In fact, different model systems may be required to answer different specific research questions about the pathogenesis of BE and EAC. Given the high mortality associated with EAC and the fact that current screening strategies miss most cases of EAC, advances in basic and translational science related to esophageal injury, repair, and carcinogenesis are clearly needed. This review describes several of the existing and potential model systems for BE and EAC with their benefits and disadvantages. PMID- 22421619 TI - Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure. AB - In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo. PMID- 22421620 TI - Serpin B1 protects colonic epithelial cell via blockage of neutrophil elastase activity and its expression is enhanced in patients with ulcerative colitis. AB - Serpin B1 is a monocyte neutrophil elastase (NE) inhibitor and is one of the most efficient inhibitors of NE. In the present study, we investigated the role of serpin B1 in the pathogenesis of ulcerative colitis by using clinical samples and an experimental model. The colonic expression of serpin B1 was determined by real time polymerase chain reaction (PCR), Western blot analysis, and immunohistological studies in both normal and inflamed mucosa from patients with ulcerative colitis. Serpin B1 mRNA expression was determined by real-time PCR in the mouse dextran sodium sulfate (DSS)-induced colitis model. Young adult mouse colonic epithelial (YAMC) cells were used to determine the role of serpin B1. Serpin B1 gene transfected YAMC cells were treated with H(2)O(2) to measure cell viability. The expression of NE was determined in YAMC cells treated with H(2)O(2). NE-silenced YAMC cells were also treated with H(2)O(2) and then measured for viability. Upregulated expression of serpin B1 in colonic mucosa was confirmed from patients with active ulcerative colitis. Immunohistochemical studies showed that serpin B1 expression was localized not only in inflammatory infiltration cells but also in epithelial cells. Serpin B1 mRNA expression was also increased in colonic mucosa of mouse DSS-induced colitis. Serpin B1 transfected YAMC cells were resistant against the treatment of H(2)O(2). H(2)O(2) treatment significantly induced NE in YAMC cells, and NE-silenced YAMC cells were also resistant against the treatment of H(2)O(2). These results suggest that serpin B1 may be a novel marker of active ulcerative colitis and may play an important role in the pathogenesis of inflammatory bowel disease. PMID- 22421621 TI - In pursuit of scientific excellence: sex matters. PMID- 22421622 TI - Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection. AB - Intestinal adaptation is an important compensatory response to massive small bowel resection (SBR) and occurs because of a proliferative stimulus to crypt enterocytes by poorly understood mechanisms. Recent studies suggest the enteric nervous system (ENS) influences enterocyte proliferation. We, therefore, sought to determine whether ENS dysfunction alters resection-induced adaptation responses. Ret+/- mice with abnormal ENS function and wild-type (WT) littermates underwent sham surgery or 50% SBR. After 7 days, ileal morphology, enterocyte proliferation, apoptosis, and selected signaling proteins were characterized. Crypt depth and villus height were equivalent at baseline in WT and Ret+/- mice. In contrast after SBR, Ret+/- mice had longer villi (Ret+/- 426.7 +/- 46.0 MUm vs. WT 306.5 +/- 7.7 MUm, P < 0.001) and deeper crypts (Ret+/- 119 +/- 3.4 MUm vs. WT 82.4 +/- 3.1 MUm, P < 0.001) than WT. Crypt enterocyte proliferation was higher in Ret+/- (48.8 +/- 1.3%) than WT (39.9 +/- 2.1%; P < 0.001) after resection, but apoptosis rates were similar. Remnant bowel of Ret+/- mice also had higher levels of glucagon-like peptide 2 (6.2-fold, P = 0.005) and amphiregulin (4.6-fold, P < 0.001) mRNA after SBR, but serum glucagon-like peptide 2 protein levels were equal in WT and Ret+/- mice, and there was no evidence of increased c-Fos nuclear localization in submucosal neurons. Western blot confirmed higher crypt epidermal growth factor receptor (EGFR) protein levels (1.44-fold; P < 0.001) and more phosphorylated EGFR (2-fold; P = 0.003) in Ret+/- than WT mice after SBR. These data suggest that Ret heterozygosity enhances intestinal adaptation after massive SBR, likely via enhanced EGFR signaling. Reducing Ret activity or altering ENS function may provide a novel strategy to enhance adaptation attenuating morbidity in patients with short bowel syndrome. PMID- 22421623 TI - Comparative effectiveness of focused shock wave therapy of different intensity levels and radial shock wave therapy for treating plantar fasciitis: a systematic review and network meta-analysis. AB - OBJECTIVES: To compare the effectiveness of focused shock wave (FSW) therapy of different intensity levels and a new alternative, radial shock wave (RSW) for managing plantar fasciitis. DATA SOURCES: Electronic databases including MEDLINE and PubMed were searched from January 1996 to June 2011. STUDY SELECTION: Randomized controlled trials comparing shock wave and placebo therapy were included. Two reviewers independently scrutinized eligible articles, and disagreement was resolved by discussion. Literature searching identified 93 nonduplicate citations, of which 12 trials comprising 1431 participants were included. DATA EXTRACTION: Information, such as patient characteristics, shock wave intensity, and outcome measures, was extracted by 1 reviewer and checked by another. Both reviewers assessed the trials' quality by using the Jadad scale. DATA SYNTHESIS: FSW therapy of different intensity ranges was treated as 3 subgroups, whereas studies using RSW therapy were regarded as a separate group. The success rates of treatment and pain reduction magnitudes were used as the outcomes. The traditional meta-analysis showed that medium and high-intensity FSW therapy had reliably higher success rates and pain reduction than the placebo, while the effectiveness of low-intensity FSW therapy and RSW therapy appeared less convincing because of very large confidence intervals. After employing network meta-analysis, the probability of being the best therapy was the highest in RSW therapy, followed by low-, medium-, or high-intensity FSW therapy. The meta-regression indicated that the success rate of FSW therapy was not related to its intensity, whereas elevated energy efflux densities tended to relieve pain more. CONCLUSIONS: Setting the highest and mostly tolerable energy output within medium intensity ranges is the ideal option when applying FSW therapy on plantar fasciitis. RSW therapy is considered an appropriate alternative because of its lower price and probably better effectiveness. PMID- 22421624 TI - Ottawa panel evidence-based clinical practice guidelines for aerobic walking programs in the management of osteoarthritis. AB - OBJECTIVE: To update the Evidence-Based Clinical Practice Guidelines (EBCPGs) on aerobic walking programs for the management of osteoarthritis (OA) of the knee. DATA SOURCES: A literature search was conducted using the electronic databases MEDLINE, PubMed, and the Cochrane Library for all studies related to aerobic walking programs for OA from 1966 until February 2011. STUDY SELECTION: The literature search found 719 potential records, and 10 full-text articles were included according to the selection criteria. The Ottawa Methods Group established the inclusion and exclusion criteria regarding the characteristics of the population, by selecting adults of 40 years old and older who were diagnosed with OA of the knee. DATA EXTRACTION: Two reviewers independently extracted important information from each selected study using standardized data extraction forms, such as the interventions, comparisons, outcomes, time period of the effect measured, and study design. The statistical analysis was reported using the Cochrane collaboration methods. An improvement of 15% or more relative to a control group contributes to the achievement of a statistically significant and clinically relevant progress. A specific grading system for recommendations, created by the Ottawa Panel, used a level system (level I for randomized controlled studies and level II for nonrandomized articles). The strength of the evidence of the recommendations was graded using a system with letters: A, B, C+, C, D, D+, or D-. DATA SYNTHESIS: Evidence from 7 high-quality studies demonstrated that facility, hospital, and home-based aerobic walking programs with other therapies are effective interventions in the shorter term for the management of patients with OA to improve stiffness, strength, mobility, and endurance. CONCLUSIONS: The greatest improvements were found in pain, quality of life, and functional status (grades A, B, or C+). A common limitation inherent to the EBCPGs is the heterogeneity of studies included with regards to the characteristics of the population, the interventions, the comparators, the outcomes, the period of time, and the study design. It is strongly recommended to use the Cochrane Risk of Bias Summary assessment to evaluate the methodologic quality of the studies and to consider avenues for future research on how aerobic walking programs would be beneficial in the management of OA of the hip. PMID- 22421625 TI - Lung volume recruitment slows pulmonary function decline in Duchenne muscular dystrophy. AB - OBJECTIVE: To evaluate the long-term effect on measures of forced vital capacity (FVC) before and after the introduction of regular lung volume recruitment (LVR) maneuvers (breath-stacking) in individuals with Duchenne muscular dystrophy (DMD). DESIGN: Retrospective cohort study of pulmonary function data, including FVC, cough peak flow (CPF), maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP). Data were collected for 33 months prior to and 45 months after LVR introduction. SETTING: Ambulatory care in a tertiary level regional rehabilitation center in Canada. PARTICIPANTS: All individuals (N=22) with DMD (mean age +/- SD, 19.6+/-2.4y), who were prescribed LVR and reported adherence with therapy. INTERVENTIONS: Introduction of regular LVR (breath stacking); 3 to 5 maximal lung inflations (maximum insufflation capacity [MIC]) using a hand-held resuscitation bag and mouthpiece, twice daily. MAIN OUTCOME MEASURES: Measures included the rate of decline of FVC in percent-predicted, before and after the introduction of regular LVR. Changes in maximum pressures (MIP, MEP), MIC, and cough peak flows were also measured. RESULTS: At LVR initiation, FVC was 21.8+/-16.9 percent-predicted, and cough peak flows were <270L/min (144.8+/-106.9L/min). Annual decline of FVC was 4.7 percent-predicted a year before LVR and 0.5 percent-predicted a year after LVR initiation. The difference, 4.2 percent-predicted a year (95% confidence interval, 3.5-4.9; P<.000), represents an 89% improvement in the annual rate of FVC decline. CONCLUSIONS: The rate of FVC decline in DMD patients improves dramatically with initiation of regular LVR. PMID- 22421626 TI - Relations between 6 minute walking distance and 10 meter walking speed in patients with multiple sclerosis and stroke. AB - OBJECTIVE: To investigate the relationship between a short walking test and a long walking test in patients with walking disability due to multiple sclerosis (MS) or stroke. DESIGN: Cross-sectional observational study. SETTING: University hospital and sport science department. PARTICIPANTS: Patients with MS (n=38), patients with stroke (n=48), and healthy subjects (n=46). Patients were participants in other clinical trials. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Walking speed in a 10m walk test and a 6 minute walk test was compared. RESULTS: Despite differences in absolute walking speed between long and short tests, strong correlations were found between both the tests in patients with MS (r=.95) and in patients with stroke (r=.94), whereas a more moderate correlation was found in healthy controls (r=.69-.70). CONCLUSIONS: Our findings show that walking speeds of a short walking test and a long walking test are strongly correlated in both patients with MS and patients with stroke, whereas correlations in healthy subjects are weaker. PMID- 22421627 TI - Responses of the less affected arm to bilateral upper limb task training in early rehabilitation after stroke: a randomized controlled trial. AB - OBJECTIVES: To investigate effects of bilateral training (BT) on ipsilesional arm dexterity and activity limitation; to explore clinical and demographic factors that influence training effects; and to explore relationships between contralesional and ipsilesional recovery. DESIGN: Single-blind randomized controlled trial with outcome assessment at baseline, postintervention (6 wk), and follow-up (18 wk). SETTING: Inpatient acute and rehabilitation hospitals. PARTICIPANTS: Participants were randomized to a BT group in which training involved the ipsilesional and contralesional arms (n=56) or control training involving the contralesional arm only (n=50). INTERVENTIONS: Supervised BT or control training for 20 minutes on weekdays over a 6-week period using a standardized program. MAIN OUTCOME MEASURES: Upper limb activity limitation: Action Research Arm Test; and dexterity: Nine-Hole Peg Test (9HPT). RESULTS: Lower baseline scores were found for the ipsilesional arm on both measures compared with published normative values. The BT group demonstrated significantly greater change in dexterity (P=.03) during the intervention phase at 0 to 6 weeks (.06+/-.07pegs/s) compared with the control group (.02+/-.02pegs/s). The effect was lost for overall recovery at 0 to 18 weeks (P=.93). Younger participants (age<=68y) performed the 9HPT faster at baseline than older participants (P=.04) and demonstrated greater overall recovery with BT than older participants (P=.04). There was no significant correlation between ipsilesional and contralesional recovery. CONCLUSIONS: The study suggests that BT may lead to clinically small improvements in ipsilesional performance of fine, rapid dexterity tasks. Younger participants responded better to BT. There was no relationship between contralesional and ipsilesional recovery, suggesting that different causes and recovery mechanisms may exist. PMID- 22421628 TI - Is smokeless tobacco use becoming more common among U.S. male smokers? Trends in Alaska. AB - INTRODUCTION: The tobacco industry has promoted the use of smokeless tobacco (SLT) to smokers as a substitution for cigarettes when smoking is not possible, and some smokers are using SLT this way. However, few publications have examined recent trends in dual cigarette and SLT use (dual use) over time in the U.S. MATERIALS AND METHODS: We examined trends in the use of SLT among current, former and never cigarette smokers using data on adult (aged 18+ years) males (n=16,590) from the 1996-2008 Alaska Behavioral Risk Factor Surveillance System (BRFSS). We also examined trends from 2004 to 2008 in cigarette consumption among dual users. RESULTS: Between 1996 and 2008, the overall prevalence of current SLT use and prevalence of current smoking among Alaskan men did not significantly change over time (p-value from age-adjusted models p=.63, p=.09, respectively). When we examined trends in SLT use by smoking status, we found that the prevalence of current SLT use remained unchanged between 1996 and 2008 among former and never smokers, but almost doubled among current smokers (age-adjusted p=.004). Between 2004 and 2008, cigarette consumption remained steady among current smokers who did not use SLT, but significantly decreased among dual users (age-adjusted p<.001). CONCLUSIONS: Our findings suggest that male smokers in Alaska are increasingly likely to use SLT, but do not appear to be switching to SLT use exclusively. We recommend that other state tobacco control programs examine trends in dual use to confirm our findings, and for programs to continue encouraging cessation of all tobacco products. PMID- 22421629 TI - The effects of neonatal paternal deprivation on pair bonding, NAcc dopamine receptor mRNA expression and serum corticosterone in mandarin voles. AB - High levels of paternal care are important for the development of social behavior in monogamous rodents. However, the effects of paternal care on the formation of pair bonding and underlying neuroendocrine mechanisms, especially the involvements of dopamine system and corticosterone, are not well understood. We investigated effects of paternal deprivation on pair bonding in mandarin voles (Microtus mandarinus), a socially monogamous rodent. Paternal deprivation was found to inhibit the formation of pair bonding in females according to partner preference tests (PPT). Paternal deprivation also reduced body contact behavior and increased aggression in males and females in PPT. During social interaction tests (SIT), paternal deprivation was found to reduce investigative and aggressive behaviors but increase body contact and self-grooming in females, and reduce staring, aggression, body contact and self-grooming in males when interacting with the opposite sex. Paternal deprivation reduced the expression of dopamine 1-type receptor (D1R) mRNA and dopamine 2-type receptor (D2R) mRNA in the nucleus accumbens of female offspring in later life, but enhanced mRNA expression of these two dopamine receptors in males. After three days of cohabitation the expression of D1R mRNA and D2R mRNA was negatively correlated for voles reared by two parents, but positively correlated in paternally deprived animals. Paternal deprivation reduced serum corticosterone levels in females but had the opposite effect in males. Three days of cohabitation did not alter corticosterone levels of PD females, but reduced it in PC females. Our results provide substantial evidence that paternal deprivation inhibits the formation of pair bonding in female mandarin voles and alters social behavior later in life. These behavioral variations were possibly associated with sex-specific alterations in the expression of two types of dopamine receptors and serum corticosterone levels induced by paternal deprivation. PMID- 22421630 TI - Next-generation sequencing to identify genetic causes of cardiomyopathies. AB - PURPOSE OF REVIEW: This review examines the application of next-generation sequencing (NGS) technologies in the identification of the causation of nonsyndromic genetic cardiomyopathies. RECENT FINDINGS: NGS sequencing of the entire genetic coding sequence (the exome) has successfully identified five novel genes and causative variants for cardiomyopathies without previously known cause within the last 12 months. Continual rapidly decreasing costs of NGS will shortly allow cost-effective sequencing of the entire genomes of affected individuals and their relatives to include noncoding and regulatory variant discovery and epigenetic profiling. Despite this rapid technological progress with sequencing, analysis of these large data sets remains challenging, particularly for assigning causality to novel rare variants identified in DNA samples from patients with cardiomyopathy. SUMMARY: NGS technologies are rapidly moving to identify novel rare variants in patients with cardiomyopathy, but assigning pathogenicity to these novel variants remains challenging. PMID- 22421631 TI - Nebivolol withdrawal results in blood pressure returning toward pretreatment levels, but without rebound symptoms: phase IV randomized trial. AB - Rapid withdrawal of antihypertensive drugs may lead to blood pressure (BP) increase above pretreatment values or symptoms such as palpitations, chest pain, and tremor. This phase IV trial assessed the consequences of abrupt and stepwise withdrawal of nebivolol, a beta(1)-selective blocker, in individuals with stage I II hypertension. After a 4- to 5-week placebo washout phase and 12-week single blind nebivolol treatment (10-40 mg/day, titrated based on BP response), participants achieving BP control (systolic BP [SBP]/diastolic BP [DBP] <140/90 mm Hg) or response (SBP decrease >=10 mm Hg or DBP decrease >=5 mm Hg) entered a 4-week, randomized, double-blind phase of continued nebivolol treatment (n = 102) or withdrawal to placebo (n = 105). Primary and secondary efficacy measures were changes in mean sitting DBP and SBP, respectively, analyzed using an analysis of covariance model. Safety and tolerability were also assessed. In the withdrawal phase, nebivolol and placebo groups demonstrated mean DBP increases of 1.8 and 7.7 mm Hg, respectively (P < .001), and SBP increases of 3.5 and 7.6 mm Hg (P = .011). Twenty-three (22.5%) nebivolol-treated and 18 (17.1%) placebo-treated participants experienced a treatment-emergent adverse event. No adverse events associated with beta-blocker withdrawal and considered causally related to nebivolol were reported. Nebivolol withdrawal resulted in a mean BP increase near pretreatment levels and was not associated with rebound hypertension. PMID- 22421632 TI - Sialic acid reduction in the saliva of streptozotocin induced diabetic rats. AB - OBJECTIVE: Diabetes causes changes in the salivary glands and in the composition of saliva, as well as symptoms such as dry mouth and hyposalivation. Therefore, this study aimed at investigating changes in salivary secretion and composition, in response to parasympathetic stimuli, in diabetic rats induced with streptozotocin. DESIGN: Diabetes was induced by a single intraperitoneal injection of streptozotocin. Thirty days after diabetes induction, the animals were anaesthetized and salivation was stimulated by an intraperitoneal injection of Pilocarpine (0.6mg/kg body weight) dissolved in distilled water. Saliva was collected for 40min and immediately stored at -80 degrees C until analysis. The salivary flow rate, amount of total protein, amylase and peroxidase activities, and free and total sialic acid contents were measured. RESULTS: Salivary flow rate was reduced in the diabetic group (p<0.05). Moreover, increases in total protein amount and in amylase and peroxidase activities were observed in diabetic animals. No difference was observed for free sialic acid content between groups. On the other hand, a significantly decrease in the total sialic acid content was observed in the diabetic group (p<0.05). CONCLUSIONS: Our findings suggest that a decrease in sialic acid in the saliva of diabetic animals can be related to xerostomia reported by diabetic patients. However, further clinical trials are needed to verify if the decrease in sialic acid also occurs in human saliva. PMID- 22421633 TI - Molecular cloning and characterization of a cytochrome P450 in sanguinarine biosynthesis from Eschscholzia californica cells. AB - Benzophenanthridine alkaloids, such as sanguinarine, are produced from reticuline, a common intermediate in benzylisoquinoline alkaloid biosynthesis, via protopine. Four cytochrome P450s are involved in the biosynthesis of sanguinarine from reticuline; i.e. cheilanthifoline synthase (CYP719A5; EC 1.14.21.2.), stylopine synthase (CYP719A2/A3; EC 1.14.21.1.), N-methylstylopine hydroxylase (MSH) and protopine 6-hydroxylase (P6H; EC 1.14.13.55.). In this study, a cDNA of P6H was isolated from cultured Eschscholzia californica cells, based on an integrated analysis of metabolites and transcript expression profiles of transgenic cells with Coptis japonica scoulerine-9-O-methyltransferase. Using the full-length candidate cDNA for P6H (CYP82N2v2), recombinant protein was produced in Saccharomyces cerevisiae for characterization. The microsomal fraction containing recombinant CYP82N2v2 showed typical reduced CO-difference spectra of P450, and production of dihydrosanguinarine and dihydrochelerythrine from protopine and allocryptopine, respectively. Further characterization of the substrate-specificity of CYP82N2v2 indicated that 6-hydroxylation played a role in the reaction. PMID- 22421634 TI - The differences between aromatizable and non-aromatizable androgens in relation to body composition and metabolic syndrome risk factors in men. AB - The relationships between the parameters of metabolic syndrome and non aromatizable metabolites of testosterone have been discussed in literature. Some papers describe these metabolites as one of the possible causes of male-type obesity. On the contrary, other studies show a protective influence of dihydrotestosterone on visceral obesity. The aim of this study to analyse the relationship between anthropometric parameters, lipid spectrum, glycemia and the level of endogenous testosterone and dihydrotestosterone, and to compare the effects of these androgens. Our population-based study involved 232 healthy men ranging from 20 to 78 years with BMI 18 to 39 kg/m(2). Serum testosterone, dihydrotestosterone and sex hormone binding globulin SHBG levels, lipid spectrum, glucose metabolism parameters were measured and the oral glucose tolerance test was carried out in all subjects. Their anthropometric parameters (weight, height, waist, hips, waist-to-hip ratio, 14 skin folds) and body composition parameters were determined and calculated by the Antropo program. Multiple regression analysis showed a correlation between hormonal levels, esp. of testosterone and dihydrotestosterone, and the anthropometric data, lipid spectrum and parameters of glucose regulation. Low testosterone and/or dihydrotestosterone was correlated to a higher body-mass index, fat content, waist diameter, total-, HDL-, LDL cholesterol and triglycerides, fasting glucose, insulin resistance and lower muscle and bone mass. In addition, statistical analysis using multivariate regression with reduction in dimensionality did not discover any striking difference between aromatizable and non-aromatizable androgens in their association to lipid and glucose metabolism parameters in healthy, normosthenic men. In conclusion, the association of endogenous testosterone and dihydrotestosterone to anthropometric data, lipid spectrum and insulin sensitivity are of the same quality; however, the effect of the circulating levels of dihydrotestosterone is quantitatively smaller. PMID- 22421635 TI - Biomaterials in regenerative medicine: engineering to recapitulate the natural. AB - The functional significance of the extracellular matrix (ECM) has generally been defined in terms of the provision of a structural support for cell adhesion and the establishment of tissue physical integrity. Recent evidence has, however, led to a paradigm shift according to which the ECM is increasingly recognised to exert a profound influence on cell behaviour, including gene expression, migration and the maintenance of functional homeostasis. The objective of this focussed review is to highlight selected observations underpinning this conclusion. Finally, we discuss the implications of these findings for regenerative medicine in the specific context of developing the 'next generation' of advanced wound care devices for the clinical management of recalcitrant chronic wounds. PMID- 22421636 TI - Bioelectrochemical regulation accelerates facultatively syntrophic proteolysis. AB - Bioelectrochemical systems can affect microbial metabolism by controlling the redox potential. We constructed bioelectrochemical cultures of the proteolytic bacterium, Coprothermobacter proteolyticus strain CT-1, both as a single-culture and as a co-culture with the hydrogenotrophic methanogen, Methanothermobacter thermautotrophicus strain ?H, to investigate the influences of bioelectrochemical regulation on facultatively syntrophic proteolysis. The co-culture and single culture were cultivated at 55 degrees C with an anaerobic medium containing casein as the carbon source. The working electrode potential of the bioelectrochemical system was controlled at -0.8V (vs. Ag/AgCl) for bioelectrochemical cultures and was not controlled for non-bioelectrochemical cultures. The cell densities of hydrogenotrophic methanogen and methane production in the bioelectrochemical co-culture were 3.6 and 1.5 times higher than those in the non-bioelectrochemical co-culture after 7 days of cultivation, respectively. Contrastingly, the cell density of Coprothermobacter sp. in the bioelectrochemical co-culture was only 1.3 times higher than that in the non bioelectrochemical co-culture. The protein decomposition rates were nearly proportional to the cell density of Coprothermobacter sp. in the all types of cultures. These results indicate that bioelectrochemical regulation, particularly, affected the carbon fixation of the hydrogenotrophic methanogen and that facultatively syntrophic proteolysis was accelerated as a result of hydrogen consumption by the methanogens growing well in bioelectrochemical co-cultures. PMID- 22421637 TI - Predictors of right ventricle dysfunction after anterior myocardial infarction. AB - BACKGROUND: Regardless significant therapeutic advances, mortality and morbidity after myocardial infarction (MI) are still high. For a long time, the importance of right ventricle (RV) function has been neglected. Recently, RV dysfunction has also been associated with poor outcomes in the setting of heart failure. The shape, location, and contraction conditions make the RV chamber assessment technically challenging. METHODS: Our study identified clinical characteristics and left ventricle (LV) echocardiographic data performed 3-5 days after MI that could be associated with RV dysfunction (RV fractional area change [FAC] < 35%) 6 months after MI. RESULTS: The RV dysfunction group consisted of 11 patients (RV FAC 29.4% +/- 5.2) and the no RV dysfunction group of 71 patients (RV FAC 43.7% +/- 5.1); (P < 0.001). Both groups presented the same baseline clinical characteristics. Left atrium (LA), interventricular septum (IVS), and left ventricular posterior wall (LVPW) were larger in RV dysfunction than in no RV dysfunction. Conversely, E wave deceleration time (EDT) was lower in RV dysfunction when compared with no RV dysfunction. Left atrium(adj) (adjusted by gender, age, infarct size, and body mass index) (odds ratio [OR], 1.22; confidence interval [CI], 1.016-1.47; P = 0.032), interventricular septum(adj) (OR, 1.49; CI, 1.01-2.23; P = 0.044), and E wave deceleration time(adj) (OR, 0.98; CI, 0.97-0.98; P = 0.029) assessed soon after MI predicted RV failure after 6-months. CONCLUSIONS: LV diastolic dysfunction, resulting from anterior MI and assessed 3-5 days after the event, may play an important role in predicting RV dysfunction 6 months later. PMID- 22421638 TI - Gender-related differences in left ventricular mass in nonhypertensive young adults: it's not all about size. PMID- 22421639 TI - Fragrance material review on 2-phenylpropyl acetate. AB - A toxicologic and dermatologic review of 2-phenylpropyl acetate when used as a fragrance ingredient is presented. 2-Phenylpropyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand alone document. Available data for 2-phenylpropyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances. PMID- 22421640 TI - Update on cutaneous lupus erythematosus. PMID- 22421641 TI - Skin health in Bangladesh: an overview. PMID- 22421642 TI - Morphea: evidence-based recommendations for treatment. AB - Morphea is a rare fibrosing disorder of the skin. Evidence-based treatment strategies in morphea are lacking. This review summarizes the available data on morphea treatment and provides therapeutic strategies based on morphea subtypes. The Cochrane Library, Medline and Embase from inception until May of 2011 were searched using the key words "morphea" and "morphea treatment." Reference lists of the resultant articles, as well as relevant reviews, were also searched. This review focuses on randomized controlled trials, prospective interventional trials without controls and retrospective reviews with greater than five subjects. PMID- 22421643 TI - Oatmeal in dermatology: a brief review. AB - The purpose of this review is to gather and summarize in vitro, in vivo, and clinical trials on oatmeal preparations and their uses in dermatology. Literature searches have been carried out to collect in vivo and in vitro studies as well as clinical trials on this subject. The results suggest that oatmeal possesses antioxidant and anti-inflammatory properties and its administration is effective on a variety of dermatologic inflammatory diseases such as pruritus, atopic dermatitis, acneiform eruptions, and viral infections. Additionally, oatmeal plays a role in cosmetics preparations and skin protection against ultraviolet rays. Although some promising results citing the use of oatmeal to treat numerous dermatologic conditions have been found, the complete efficacy of oatmeal has not been sufficiently explored. This paper proposes accurate and useful information concerning the use of oatmeal in clinical practice to dermatologists. PMID- 22421644 TI - The safety and efficacy of a combined diode laser and bipolar radiofrequency compared with combined infrared light and bipolar radiofrequency for skin rejuvenation. AB - BACKGROUND: As the demand for noninvasive procedures for skin rejuvenation is increasing, combined diode laser and radiofrequency and combined infrared and radiofrequency devices have recently emerged. AIM: To compare Polaris WRA(TM), a combination device of diode light and RF, and ReFirme ST(TM), a combination device of infrared and bipolar RF, in terms of safety and efficacy on skin rejuvenation. METHODS: Fourteen Korean volunteers of skin type II-IV, with facial laxity and periorbital rhytids, received three treatments at 3-week intervals with combined diode laser and bipolar radiofrequency (laser fluence 30 J/cm2, RF fluence 90 J/cm3) on the right half of their faces and combined infrared light and bipolar radiofrequency (RF fluence 120 J/cm3) on the left half of their faces. Clinical photos of front and bilateral sides of the subjects' faces were taken at baseline and at 6, 9, 12 weeks after the treatment initiation. The investigators' and the subjects' global assessments were performed. RESULTS: There is no statistically significant difference in the overall outcome between Polaris WRA(TM) and Refirme ST(TM) based on pre- and post-treatment objective measurements. Polaris WRA(TM) was more effective than Refirme ST(TM) at reducing wrinkles when therapeutic results of the two appliances were compared based on the patient satisfaction measurements. After the treatment with both instruments, histological increase in the production and rearrangement of collagen fibers at the dermal layer was observed. The density of the collagen fibers was more increased with the Polaris WRA(TM)-treated facial area than that of Refirme ST(TM). Treatment was generally well tolerated, and there was no serious complication. CONCLUSION: In this study, both the lasers appeared to be safe, and effective methods for treating skin laxity and facial wrinkles. Combined diode laser and radiofrequency was more effective than combined infrared and radiofrequency at reducing wrinkles and pores when the therapeutic results of both the appliances were compared. PMID- 22421645 TI - Hand eczema: correlation of morphologic patterns, atopy, contact sensitization and disease severity. AB - BACKGROUND: Hand eczema is a common distressing condition aggravated by a number of endogenous and exogenous factors. Various morphological forms of hand eczema have been described, but categorization into one of them is not always possible. AIMS: To study the morphological patterns of hand eczema, relationship of atopy with hand eczema, and the implications of contact sensitization with respect to severity and diagnosis of hand eczema. METHODS: Hundred consecutive patients of hand eczema attending the contact dermatitis clinic of the institute were recruited over a two year period from 2004-05. Objective assessment was done using hand eczema severity index (HECSI) and all the patients were patch tested using Indian standard series. RESULTS: Unspecified type of hand eczema with no definite morphologic picture was seen in 62% followed by pompholyx in 14%. Hand eczema severity was not found to be statistically associated with age, sex, and atopic status of the patient. Positive patch test to one or more allergen was present in 65% of patients. The most common allergens were potassium dichromate (25%), fragrance mix (16%), nickel sulphate (14%), and PPD (13%). There was no significant correlation between patch test positivity and hand eczema severity or atopic status of the patient. Among the morphological patterns pompholyx was strongly associated with an atopic status (P=0.004). CONCLUSIONS: Hand eczema was seen twice more commonly in men. Atopic and non-atopic patients of hand eczema had no difference in the severity of disease. Contact sensitivity to different allergens did not correlate with increased eczema severity. PMID- 22421646 TI - Ultrathin split-thickness skin grafting followed by narrowband UVB therapy for stable vitiligo: an effective and cosmetically satisfying treatment option. AB - BACKGROUND: Different surgical techniques in the form of tissue or cellular grafting procedures are used alone or in combination with narrowband UVB (NBUVB) to treat stable vitiligo resistant to medical treatment. AIM: To evaluate the cosmetic results obtained with ultrathin split-thickness skin grafts followed by NBUVB therapy in resistant, stable vitiligo. METHODS: Forty patients of stable vitiligo were treated with ultrathin split-thickness grafting and the patients were then put on NBUVB therapy. The results obtained were analyzed by the extent of repigmentation achieved as well as the final cosmetic outcome at the recipient as well as donor sites. RESULTS: The first evidence of repigmentation was seen in the second week after starting NBUVB. On objective assessment, more than 90% repigmentation was seen in 83% of patients and the overall cosmetic results at the recipient site were graded as good to excellent in 90% patients at the end of NBUVB treatment. Perigraft halo of depigmentation was seen in six patients (15%) on the recipient site. Hypertrophic scarring was observed in two patients at the donor site. CONCLUSIONS: Ultrathin split-thickness skin grafting, when combined with NBUVB therapy, leads to better cosmetic outcome with faster onset of repigmentation in resistant stable vitiligo. PMID- 22421647 TI - A comparative study on efficacy of high and low fluence Q-switched Nd:YAG laser and glycolic acid peel in melasma. AB - BACKGROUND: Melasma is acquired symmetric hypermelanosis characterized by light to-deep brown pigmentation over cheeks, forehead, upper lip, and nose. Treatment of this condition is difficult and associated with high recurrence rates. With the advent of newer therapies, there is interest in the use of glycolic acid peels and Q-switched Nd:YAG laser (QSNYL) in high and low fluence for this disorder. AIMS: To compare the therapeutic efficacy of low fluence QSNYL, high fluence QSNYL, and glycolic acid peel in melasma in three study groups of 25 patients each. METHODS: Seventy-five Indian patients diagnosed as melasma were included. These patients were randomly divided in three groups (Group A = 25 patients of melasma treated with low-fluence QSNYL at weekly intervals, Group B = 25 patients of melasma treated with glycolic acid peel at 2 weeks intervals, Group C = 25 patients of melasma treated with high-fluence QSNYL at 2 weeks intervals). Study period and follow-up period was of 12 weeks each. Out of the 75 patients included, 21 patients in Group A, 19 patients in Group B, and 20 patients in Group C completed the study. Response to treatment was assessed using melasma area and severity index score. RESULTS: Significant improvement was recorded in all the three groups. The improvement was statistically highly significant in Group A as compared to Group C (P<0.005), significant in Group A as compared to Group B (P<0.05), and also in Group B when compared to Group C (P<0.05). Low-fluence QSNYL was associated with least side effects. CONCLUSIONS: This study shows the efficacy of low-fluence QSNYL and glycolic acid peel in melasma. These could be an effective treatment options compared to conventional methods for the treatment of melasma. PMID- 22421648 TI - Efficacy of topical photodynamic therapy for keratoacanthomas: a case-series of four patients. AB - Topical photodynamic therapy (PDT) is an excellent treatment option for various non-melanoma skin cancers and precancerous lesions, including actinic keratosis, Bowen's disease, and basal cell carcinoma. The clinical use of PDT includes a broad range of neoplastic, inflammatory, and infectious skin diseases. There is also anecdotal evidence suggesting the efficacy of PDT for the treatment of keratoacanthomas (KA). We report a case-series of four patients with solitary KA confirmed by histology, treated with topical PDT with methylaminolevulinic acid (MAL) cream. After three sessions of PDT, the lesions completely disappeared. There was no evidence of recurrence and excellent cosmetic outcome was achieved after three years of follow-up. Topical photodynamic therapy with MAL can be a therapeutic alternative for KA with good clinical and cosmetic outcomes. PMID- 22421649 TI - Drug-induced hypersensitivity syndrome with human herpesvirus-6 reactivation. AB - A 45-year-old man, on carbamazepine for the past 3 months, was referred as a case of atypical measles. On examination, he had high-grade fever, generalized itchy rash, cough, vomiting and jaundice. A provisional diagnosis of drug hypersensitivity syndrome to carbamazepine was made with a differential diagnosis of viral exanthema with systemic complications. Laboratory investigations revealed leukocytosis with eosnophilia and elevated liver enzymes. Real-time multiplex polymerase chain reaction (PCR) on throat swab and blood was suggestive of human herpesvirus-6 (HHV-6). Measles was ruled out by PCR and serology. The diagnosis of drug-induced hypersensitivity syndrome (DIHS) was confirmed, which could explain all the features manifested by the patient. HHV-6 infects almost all humans by age 2 years. It infects and replicates in CD4 T lymphocytes and establishes latency in human peripheral blood monocytes or macrophages and early bone marrow progenitors. In DIHS, allergic reaction to the causative drug stimulates T cells, which leads to reactivation of the herpesvirus genome. DIHS is treated by withdrawal of the culprit drug and administration of systemic steroids. Our patient responded well to steroids and HHV-6 was negative on repeat real-time multiplex PCR at the end of treatment. PMID- 22421650 TI - A family of Bart-Pumphrey syndrome. AB - Bart-Pumphrey syndrome (BPS) is an autosomal-dominant disorder characterized by hearing loss, leukonychia, knuckle pads and palmoplantar keratoderma. Two mutations in the extracellular domain of GBJ2 are resposible for this syndrome. To date, less than 10 case reports or clinical series about BPS have been published in the literature. Hearing loss and knuckle pads are the more commonly seen findings of this syndrome. Three generations and six family members with variable findings of knuckle pads, leukonychia, hearing loss and palmoplantar hyperkeratosis were presented in this report. We want to emphasize that dermatogists must be alert during the evaluation of these findings because some findings of this disorder may be vague or absent. PMID- 22421651 TI - Familial atrophia maculosa varioliformis cutis: first case report from the Indian subcontinent with pedigree analysis. AB - Familial atrophia maculosa varioliformis cutis is a very rare disorder with less than 28 cases being reported in the literature worldwide and remains a mystery both as far as genetics and the virtue of its pathogenesis is concerned. We present a case of mother and son, both having this disorder with presentations unique in terms of sites involved and try to draw a five generations pedigree chart for the same. We further support its inheritance pattern as autosomal dominant. Also, we propose oral isotretinoin as an effective treatment modality for the same. PMID- 22421652 TI - A case of subungual exostosis. PMID- 22421653 TI - Are Q-switched lasers for Nevus of Ota really effective in pigmented skin? PMID- 22421654 TI - Is cholinergic urticaria a seasonal disorder in some patients? PMID- 22421655 TI - Prevalence of autoantibodies in patients with pemphigus. PMID- 22421656 TI - A case of granular cell tumor with an interesting clinical course. PMID- 22421657 TI - Genital squamous cell carcinoma presenting with multicentric ulcers: an unusual manifestation of skin malignancy. PMID- 22421658 TI - Rhabdomyolysis associated with roxithromycin hypersensitivity syndrome. PMID- 22421659 TI - A case of herpes gestationis: follow-up study of autoantibodies using enzyme linked immunosorbent assay and immunoblotting. PMID- 22421660 TI - Hyperhidrosis of face and scalp: repeated successful treatment with botulinum toxin type A. PMID- 22421661 TI - A rare case of multiple genital and perianal melanoacanthomas. PMID- 22421662 TI - Multiple subcutaneous angiomyxolipomas associated with olecranon bursa cyst: a rare presentation of a rare entity. PMID- 22421663 TI - Named cells in dermatology. PMID- 22421664 TI - Eberconazole--pharmacological and clinical review. PMID- 22421665 TI - The eminent Indian leprosy researcher--Dr. C. K. Job. PMID- 22421666 TI - Lobulated mass on the back of the scalp. PMID- 22421668 TI - Spectrum of purpura fulminans: report of three classical prototypes and review of management strategies. AB - Purpura fulminans is a rare syndrome of intravascular thrombosis and hemorrhagic infarction of the skin that is rapidly progressive and is accompanied by vascular collapse and disseminated intravascular coagulation. It usually occurs in children, but this syndrome has also been noted in adults. The three forms of this disease are classified by the triggering mechanisms. We describe three classical cases of purpura fulminans of the three classical prototypes treated at our center and their varied clinical outcomes. We also describe a case of acute infectious purpura fulminans secondary to systemic leptospirosis which to our best knowledge is the first reported case in world literature. The various treatment options for purpura fulminans have also been reviewed. PMID- 22421669 TI - Bardet-Biedl syndrome: a rare case report from North India. AB - The Bardet-Biedl syndrome (BBS) is a rare ciliopathic human autosomal-recessive disorder, affecting multiple organ systems. Less than 15 cases have been reported from India. The authors present a classical case of BBS presenting to dermatology outpatient with hypogonadism and features such as marked central obesity, retinal dystrophy, polydactyly, structural renal abnormalities and mental retardation, along with a brief review of the literature. This case exemplifies the need for multidisciplinary management in such cases. PMID- 22421670 TI - Patient-physician relationship in patients with psoriasis. PMID- 22421671 TI - Fusarial onychomycosis among gardeners: a report of two cases. PMID- 22421672 TI - An unusual case of multiple erythematous nodules with ulcerative lesion. PMID- 22421673 TI - Hidradenitis suppurativa involving the preauricular region: an unusual location. PMID- 22421674 TI - Pulmonary and cutaneous sarcoidosis in a treated case of renal tuberculosis. PMID- 22421675 TI - Delleman syndrome: report of a case in an adolescent boy. PMID- 22421676 TI - Linear IgA bullous dermatosis induced by ampicillin/sulbactam. PMID- 22421677 TI - Plasma cell vulvitis: a vulvar itching dilemma. PMID- 22421678 TI - Cutaneous combined desmoplastic melanoma. PMID- 22421679 TI - A rare cause of oral papillomatous lesions: Cowden syndrome. PMID- 22421680 TI - Reddish-brown plaque on the left buttock. PMID- 22421681 TI - Indium(III) catalysed substrate selective hydrothiolation of terminal alkynes. AB - In(OTf)(3) is reported as the first catalyst having the ability to selectively catalyse both Markovnikov and anti-Markovnikov hydrothiolation of terminal alkynes under identical reaction conditions depending upon the nature of the thiol employed. PMID- 22421682 TI - Age-related changes in intramuscular and subcutaneous fat content and fatty acid composition in growing pigs using longitudinal data. AB - The evolution of intramuscular fat (IMF) and subcutaneous backfat (SB) content and fatty acid composition with age was investigated. A repeated sampling scheme (n=517) for longissimus dorsi (LM) and SB specimens was performed from 160 to 220 days on 216 purebred Duroc barrows. IMF content increased linearly with age at a rate of 0.05%/day, with major compositional changes occurring in C18:1 and C18.2, which increased and decreased by around 4%, respectively. Backfat thickness increase rate declined with age, showing similar compositional changes to IMF but halved in magnitude. Fat content itself also influenced fat composition. At a fixed age, both saturated (SFA) (C16:0) and monounsaturated (MUFA) (C18:1) increased with IMF but only SFA (C16:0 and C18:0) with SB. Aging mostly affected MUFA while fatness SFA. A delay in age at slaughter will enhance IMF and C18:1 in relation to overall fatness but at expense of decreasing body and loin growth rate. PMID- 22421683 TI - Effect of solvent to sample ratio on total lipid extracted and fatty acid composition in meat products within different fat content. AB - The effect of solvent to sample ratio on total extracted lipids and fatty acid (FA) composition in meat products with different fat contents was evaluated. Total lipids were extracted according to the Folch et al. (1957) method, using a 20:1 ratio of chloroform:methanol (2:1, v/v) to sample (A), and also testing the solvent:sample ratio of 10:1 (B). Higher amounts of total lipids and total FA from neutral lipids were obtained using the A ratio, which could be due to an insufficient chloroform:dry-weight sample proportion which could be insufficient for solubilizing the total amount of lipids. In the polar lipid fraction, the total amount of FA was higher using the B rather than the A ratio, which may be caused by the higher volume of added water when using A than B. When studying the FA composition of different lipid fractions, the volume of both the solvent and the water for total lipid extraction should be considered. PMID- 22421684 TI - Detection of antiphospholipid antibodies by automated chemiluminescence assay. AB - The laboratory diagnosis of antiphospholipid antibody syndrome (APS) requires the demonstration of antiphospholipid antibodies (aPL) by lupus anticoagulant (LAC) measured through coagulation assays, anticardiolipin IgG or IgM antibodies (aCL) and/or anti-beta2-glycoprotein I IgG or IgM antibodies (anti-beta2-GPI), usually detected by ELISA. In this study we tested aCL by a new automated system using the chemiluminescence principle. Our results showed that, while almost all the sera from APS patients, positive for IgG aCL and anti-beta2-GPI by ELISA, were also positive for IgG aCl by chemiluminescence, only 30.13% of patients without clinical manifestations of APS, but positive for aCL and persistently negative for anti-beta2-GPI (by ELISA) and LA, confirmed the positive test by chemiluminescence. This difference was highly significant (p<0.0001). Interestingly, this test also prompted to identify 20% of patients positive for LA, but persistently negative for both aCL and anti-beta2-GPI IgG (ELISA). Thus, the new technology of automated chemiluminescence assay for measuring aPL may represent an useful tool to identify "true" APS patients. PMID- 22421685 TI - The place of race and racism in cultural competence: what can we learn from the English experience about the narratives of evidence and argument? AB - This paper outlines the history of workforce strategies for providing mental health care to "black and ethnic minorities" in England. Universal mental health policies failed to deliver equity in care, and thus specific policies were launched to address ethnic inequalities in care experiences and outcomes. The emphasis on race equality rather than cultural complexity led to widespread acceptance of the need for change. The policy implementation was delivered in accord with multiple regional and national narratives of how to reduce inequalities. As changes in clinical practice and services were encouraged, resistance emerged in various forms from clinicians and policy leaders. In the absence of commitment and then dispute about forms of evidence, divergent policy and clinical narratives fuelled a shift of attention away from services to silence issues of race equality. The process itself represents a defence against the pain of acknowledging systemic inequities whilst rebutting perceived criticism. We draw on historical, psychoanalytic, and learning theory in order to understand these processes and the multiple narratives that compete for dominance. The place of race, ethnicity, and culture in history and their representation in unconscious and conscious thought are investigated to reveal why cultural competence training is not simply an educational intervention. Tackling inequities requires personal development and the emergence and containment of primitive anxieties, hostilities, and fears. In this paper we describe the experience in England of moving from narratives of cultural sensitivity and cultural competence, to race equality and cultural capability, and ultimately to cultural consultation as a process. Given the need to apprehend narratives in care practice, especially at times of disputed evidence, cultural consultation processes may be an appropriate paradigm to address intersectional inequalities. PMID- 22421686 TI - Religious competence as cultural competence. AB - Definitions of cultural competence often refer to the need to be aware and attentive to the religious and spiritual needs and orientations of patients. However, the institution of psychiatry maintains an ambivalent attitude to the incorporation of religion and spirituality into psychiatric practice. This is despite the fact that many patients, especially those from underserved and underprivileged minority backgrounds, are devotedly religious and find much solace and support in their religiosity. I use the case of mental health of African Americans as an extended example to support the argument that psychiatric services must become more closely attuned to religious matters. I suggest ways in which this can be achieved. Attention to religion can aid in the development of culturally competent and accessible services, which in turn, may increase engagement and service satisfaction among religious populations. PMID- 22421687 TI - The management of dislocated intraocular lenses. PMID- 22421688 TI - National estimates of seroincidence and seroprevalence for herpes simplex virus type 1 and type 2 among US military adults aged 18 to 29 years. AB - BACKGROUND: While population-based seroprevalence studies of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are widespread, seroincidence studies are largely limited to select or high-risk populations. The US military offers a potential population to derive national seroincidence rate estimates for young adults (ages 18-29). METHODS: We used banked, longitudinal serum specimens collected in a cohort of 1094 military personnel aged 18 to 30 years who served between 1989 and 2005 to estimate national HSV-1 and HSV-2 seroincidence and seroprevalence for the young, adult military population, weighted according to the US Census. Serum was tested with indirect ELISA (enzyme-linked immunosorbent assay). RESULTS: Estimated national seroincidence rates for the US young, adult military population were 9.1 per 100 person-years (95% confidence interval: 4.6 13.5) for HSV-1 and 6.2 (95% confidence interval: 3.1-9.3) for HSV-2. Female sex and black race were associated with significantly higher HSV-2 seroconversion rates. Our estimated HSV1/2 seroprevalences were comparable to US national data provided by National Health and Nutrition Examination Surveys' serosurveys except for non-Hispanic blacks and Hispanics. CONCLUSION: Although these US 2000 Census weighted estimates of HSV-1 and HSV-2 seroincidence apply only to young, military adults, they nonetheless supply, to our knowledge, the only national figures that might be used to predict US national HSV1/2 seroincidence in young adults. Thus, we believe that our findings in this military population can be used to inform the planning of HSV-1 and 2 prevention measures in the general, young-adult US population. PMID- 22421689 TI - Recreational drug use: an emerging concern among venue-based male sex workers in China. AB - A 2009 survey of 418 venue-based male commercial sex workers in Shenzhen, China revealed that 19.9% used recreational drugs. Consistent condom use by drug users was lower than that by nonusers. HIV, syphilis, and herpes simplex virus 2 prevalences were higher among drug users. Prevention programs need to address drug use among male commercial sex workers in China. PMID- 22421690 TI - Periodical antibiotic treatment for the control of gonococcal and chlamydial infections among sex workers in Benin and Ghana: a cluster-randomized placebo controlled trial. AB - BACKGROUND: In resource-poor settings, control of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) among female sex workers (FSWs) is difficult. We sought to determine whether periodical antibiotic treatment (PAT) might be effective in controlling these infections among West African FSWs. Secondary objectives were to determine the impact of PAT on human immunodeficiency virus (HIV) incidence among FSWs and on NG/CT prevalence among their clients. METHODS: Cluster-randomized, double-blind, placebo-controlled trial among FSW communities in Benin and Ghana. Within each of 9 pairs of clusters of FSW communities, one was allocated to receive, during 9 months, a monthly antibiotic (alternatively ciprofloxacin or azithromycin, n = 296 FSWs) and the other a placebo (n = 340 FSWs). Prevalence of NG/CT infections was measured at 3-month intervals using the polymerase chain reaction. HIV status was determined at the beginning and at the end of the study. RESULTS: After adjusting for age, HIV status, duration of prostitution, price per intercourse and condom use, and accounting for prevalence at enrollment and cluster-pairing effect, prevalence ratios (intervention vs. placebo) of NG infection were 0.77 (P = NS), 1.07 (P = NS), and 0.49 (P = 0.05) at the first, second, and third follow-up visits, respectively. PAT neither reduced significantly CT prevalence or HIV incidence among FSWs nor NG/CT prevalence among their clients. CONCLUSION: The only beneficial impact of PAT was on the prevalence of gonococcal infections among FSWs 9 months after the beginning of the intervention. Although PAT could be more effective in other circumstances, for instance, in the early stages of a program for FSWs, it can not be recommended at present as a routine strategy to control cervical infections among FSWs. PMID- 22421691 TI - Estimation of the burden of disease and costs of genital Chlamydia trachomatis infection in Canada. AB - BACKGROUND: Rates of Chlamydia trachomatis (CT) infection in Canada have been increasing since the mid-1990s. We sought to estimate the burden of CT in this population. METHODS: We developed an age- and sex-structured mathematical model parameterized to reproduce trends in CT prevalence between 1991 and 2009 in the Canadian population aged 10 to 39 years. Costs were identified, measured, and valued using a modified societal perspective and converted to year 2009 Canadian dollars. Cost-effectiveness of the implemented policy of enhanced screening for asymptomatic infections was estimated by comparison with model-projected trends in the absence of increased screening. Main outcome measures were current net cost and burden of illness attributable to CT infection, and incremental cost effectiveness ratios. RESULTS: Under base case model assumptions, there was a trend of increasing detection of CT cases (due to increases in screening), despite an underlying stabilization of actual CT infections. Average estimated costs associated with CT infection over this period were $51.4 million per year. Costs of screening and treatment of asymptomatic infections as a proportion of total CT costs were estimated to have increased over time, whereas costs of long term sequelae associated with untreated infections declined over the same period. Compared with no change in screening, enhanced screening was estimated to be highly cost-effective, with an incremental cost-effectiveness ratio of $2910 per quality-adjusted life year. CONCLUSIONS: Despite increases in screening, the economic burden of CT in Canada remains high. Further investigation of trends in chlamydia-associated complications is required to better understand the impact of screening on incidence. PMID- 22421692 TI - High annual syphilis testing rates among gay men in Australia, but insufficient retesting. AB - INTRODUCTION: Since 2000, infectious syphilis notifications have increased substantially among Australian gay men. We describe testing at a frequency lower than guidelines recommend. METHODS: We examined data from a cross-sectional survey of gay men in 5 Australian cities in 2010. We used logistic regression to identify correlates of no lifetime syphilis test among HIV-uninfected men and <2 tests per year in HIV-infected men and higher-risk HIV-uninfected men. RESULTS: Of 6329 HIV-uninfected men, 65% reported a syphilis test in the past year, and 86% in their lifetime, and factors associated with no lifetime syphilis test were lower social engagement with gay men, older age, fewer sexual partners, no anal sex with casual partners, and not being aware syphilis could be asymptomatic. Among higher-risk HIV-uninfected men (>10 partners in the past 6 months), factors associated with <2 syphilis tests in the past year were nonmetropolitan residence, older age, no anal sex or unprotected anal intercourse with casual partners, not aware syphilis could be acquired through oral sex, and testing at a nonregular general practitioner. Of the 580 HIV-infected, 87% reported a syphilis test in the past year, and 96% in their lifetime, and factors associated with <2 syphilis tests in the past year were unprotected anal intercourse with HIV uninfected casual partner and recruitment from social or sex-on-premises venues. CONCLUSIONS: Our analysis showed high lifetime and annual syphilis testing rates in Australian gay men, but low retesting rates. We identified factors associated with less frequent syphilis testing rates among Australian gay men to assist in developing targeted screening strategies. PMID- 22421693 TI - The effect of medical male circumcision on urogenital Mycoplasma genitalium among men in Kisumu, Kenya. AB - BACKGROUND: We determined the prevalence of urethral Mycoplasma genitalium (MG) infection and whether infection was associated with circumcision status among men enrolled in the randomized trial of medical male circumcision to prevent HIV acquisition in Kisumu, Kenya. METHODS: MG and Trichomonas vaginalis were detected in first void urine by APTIMA transcription-mediated amplification assay. first void urine and urethral swabs were assessed for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) by polymerase chain reaction assay. Herpes simplex virus type 2 antibodies were detected by IgG ELISA. Multivariable logistic regression identified factors associated with MG infection. RESULTS: Specimens were collected between July and September 2010, and 52 (9.9%; 95% confidence interval [CI]: 7.3%-12.4%) MG infections were detected among 526 men. N. gonorrhoeae and T. vaginalis were not associated with MG. CT coinfection was 5.8% in MG-infected men, and 0.8% among MG-uninfected men (P = 0.02). MG infection was predominantly asymptomatic (98%). The prevalence of MG was 13.4% in uncircumcised men versus 8.2% in circumcised men (P = 0.06). Being circumcised nearly halved the odds of MG (adjusted odds ratio [aQR] = 0.54; 95% CI: 0.29-0.99), adjusted for other variables significant at the P < 0.05 level: herpes simplex virus type 2 infection (aOR = 2.05; 95% CI: 1.05-4.00), CT infection (aOR = 2.69; 95% CI: 1.44-5.02), and washing the penis <=1 hour after sex (aOR = 0.47; 95% CI: 0.24 0.95). CONCLUSIONS: MG infection was reduced among men who were circumcised, adding to the benefits of male circumcision in preventing several sexually transmitted infections. PMID- 22421694 TI - When they break up and get back together: length of adolescent romantic relationships and partner concurrency. AB - BACKGROUND: Sex partner concurrency is an important risk factor for sexually transmitted infection transmission. Understanding how adolescents conceptualize the length of their relationships when they break up and get back together is essential to the assessment of concurrency. METHODS: A prospective cohort of 392 late adolescents and emerging adults, aged 14 to 19 years at baseline, were recruited from 2 clinics in Baltimore, MD and interviewed semiannually for 3 years. At each interview, participants were asked to report on all of their sexual partners in the previous 6 months, the length of relationship, and whether they thought their partner had other sex partners. For relationships that had broken up and gotten back together, reports of length of the relationship were compared before and after the breakup. Random effects logistic regression was used to examine the association between length of relationship and both breakup and partner concurrency. RESULTS: For relationships that ended and subsequently got back together, participants considered the length of relationship to include the period when they were broken up. Longer relationships were at increased odds of both having broken up and gotten back together (odds ratio [OR] = 1.04, 95% confidence interval [CI]: 1.02, 1.05) and of partner concurrency (OR = 1.03, 95% CI: 1.02, 1.04). The magnitude of the odds of concurrency was greater for relationships that had broken up and gotten back together (OR = 1.07, 95% CI: 1.02, 1.11). CONCLUSIONS: Findings from this study emphasize the need for an improved understanding of the association between the temporal dynamics of late adolescent and emerging adult romantic relationships and concurrency. PMID- 22421695 TI - Low rate of syphilis screening among high-risk emergency department patients tested for gonorrhea and chlamydia infections. AB - BACKGROUND: Implementing national recommendations for syphilis screening is not feasible in the emergency department (ED) setting. The purpose of this study was to determine the syphilis screening rate among ED patients tested for gonorrhea and chlamydia (GC/CT) and the syphilis prevalence among those who were tested. METHODS: A 1-year retrospective cohort study in an urban ED. At the time of this study, there were no explicit syphilis screening guidelines and testing was at the discretion of the treating physician. We determined the proportion of all GC/CT-tested patients who also underwent syphilis screening and the prevalence of syphilis among this group. Predictors of syphilis screening among patients tested for GC/CT were identified. RESULTS: GC/CT tests were performed in 3951 (4.7%) of the 83,988 ED visits, of which 332 (8.4%) were reactive. The mean age of GC/CT tested patients was 22.6 +/- 12 years, most were female (67%), black (47%), and English speaking (74%). Syphilis screening was completed in 1218 (31%) of the GC/CT-tested patients, 17 tests (1.4%) were reactive, which included 8 (0.7%) unique patients with newly diagnosed syphilis. In multivariable analysis, the following variables were predictive of syphilis screening: empirical GC/CT treatment (odds ratio [OR]: 1.9, 95% confidence interval [CI]: 1.6-2.3), evaluation in the low acuity section of the ED (OR: 1.8, 95% CI: 1.4-2.3), a reactive GC/CT test (OR: 1.3, 95% CI: 1.0-1.6), and age <=25 years (OR: 1.2, 95% CI: 1.0-1.4). CONCLUSION: Among ED patients tested for GC/CT, less than one-third were screened for syphilis. Failure to screen these patients likely resulted in missed opportunities for syphilis diagnosis. PMID- 22421696 TI - The performance of cerebrospinal fluid treponemal-specific antibody tests in neurosyphilis: a systematic review. AB - BACKGROUND: No single laboratory test is both sensitive and specific to diagnose neurosyphilis. Several major clinical guidelines suggest that negative cerebrospinal fluid (CSF) treponemal-specific antibody tests rule out the diagnosis of neurosyphilis. Our aim was to systematically review the literature and describe the performance of treponemal-specific CSF antibody tests when diagnosing neurosyphilis. METHODS: Two reviewers independently assessed studies published in electronic databases, trial registries, and bibliographies for content and quality. Entry criteria included the assessment of treponemal specific CSF tests currently used in clinical practice, and the use of standard criteria for both diagnosis and exclusion of neurosyphilis. The primary outcomes were sensitivity, specificity, and negative predictive values of treponemal specific CSF antibody tests. RESULTS: Of 141 unique citations, 18 studies were included in the systematic review. Due to significant heterogeneity among studies, we were unable to generate pooled summary statistics. Seven different treponemal-specific tests were assessed. Of those, 13 studies evaluated the CSF FTA-ABS (fluorescent treponemal antibody-absorbed) and 9 evaluated the CSF fluorescent treponemal antibody. The performance estimates of these tests were highly variable and depended on the choice of negative and positive controls. No single test had perfect sensitivity, thus the negative predictive value was dependant on the specificity of the test and the prevalence (i.e., pretest probability) of neurosyphilis: the higher the prevalence, the lower the negative predictive value. Few studies included HIV-infected persons. CONCLUSIONS: A negative CSF-treponemal-specific antibody test may not exclude the diagnosis of neurosyphilis when the clinical suspicion for neurosyphilis is high. PMID- 22421697 TI - Treponemal tests for neurosyphilis--less accurate than what we thought? PMID- 22421698 TI - Incidence, prevalence, and epidemiology of herpes simplex virus-2 in HIV-1 positive and HIV-1-negative adolescents. AB - BACKGROUND: Several studies have assessed risk factors associated with herpes simplex virus-2 (HSV-2) prevalence in adults; however, few have focused on HSV-2 incidence, particularly in adolescents. The objective of this study was to determine HSV-2 prevalence and incidence and associated risk factors in a HIV-1 positive and at risk HIV-1-negative adolescent population. METHODS: Sera were tested for HSV-2 antibodies in 518 adolescents in the Reaching for Excellence in Adolescent Care and Health cohort at baseline and again at the final follow-up visit. Prevalence at baseline and incidence (per person years) of HSV-2 infection were calculated. Furthermore, among HIV-1-positive individuals, a subgroup analysis was performed to assess risk factors for HSV-2 infection. Conditional logistic regression was used to estimate odds ratios and P values for associations between CD4+ T-cell (CD4+) count, HIV-1 viral load (VL), and HSV-2 acquisition, adjusting for antiretroviral therapy use, other sexually transmitted infections, gender, race, and number of sexual partners. RESULTS: At baseline, 179 (35%) subjects were HSV-2 positive, with an additional 47 (16%) new cases being identified during a median follow-up time of 1.95 years and an incidence rate of 7.35 cases per 100 person years. Several risk factors were associated with HSV-2 prevalence (being female, non-Hispanic, uncertainty of sexual preference, and HIV-1 positive) and incidence (using drugs, alcohol, and number of new sexual partners). Among HIV-1 positives, an increase in CD4+ count by 50 cell/mm(3) (odds ratio, 1.17; 95% CI, 1.04-1.31, P = 0.008) was associated with HSV-2 acquisition. CONCLUSIONS: The high prevalence and incidence of HSV-2 infection among adolescents, compared with the general population at this age group suggests a critical need for screening and preventive programs among this targeted group. PMID- 22421699 TI - Prevalence and determinants of recent HIV testing among sexually active men who have sex with men in the St. Louis metropolitan area, Missouri, 2008. AB - BACKGROUND: New human immunodeficiency virus (HIV) diagnoses in the St. Louis metropolitan area, MO, occur predominantly among men who have sex with men (MSM). The Centers for Disease Control and Prevention recommends HIV testing at least annually for sexually active MSM. We examined prevalence and factors associated with recent HIV testing among MSM in the St. Louis area. METHODS: The 2008 National HIV Behavioral Surveillance system recruited men in 21 US metropolitan areas through venue-based, time-space sampling. Men were interviewed for behavioral risks and testing history. The analysis included men in St. Louis who had engaged in male-male sex during the previous year and excluded men who had tested HIV-positive >12 months before the interviews. Factors associated with testing during the previous 12 months were identified using log-binomial regression. RESULTS: Among 339 MSM, 198 (58%) had been tested during the previous 12 months. MSM were more likely to have been tested if they were black (adjusted prevalence ratio [APR]: 1.6; 95% confidence interval [CI]: 1.0-2.5); had visited a health care provider during the previous 12 months (APR: 1.6; 95% CI: 1.3-2.1); or had ever disclosed same-sex attractions or male-male sex to health care providers (APR: 1.6; 95% CI: 1.2-2.0). Of the 141 men who were untested within 12 months, 89 (63%) attributed not testing to perceived low risk. CONCLUSIONS: Nearly half of sexually active MSM in this analysis had not been tested for HIV during the previous year. Annual visits to health care providers during which sexual risk is discussed are likely to promote testing among MSM. PMID- 22421700 TI - Sexual transmission behaviors and serodiscordant partnerships among HIV-positive men who have sex with men in Asia. AB - We described sexual transmission behaviors and serodiscordant partnerships among an online sample of HIV-positive men who have sex with men (N = 416) in Asia. High rates of unprotected anal intercourse (74.8%), serodiscordant partnerships (68.5%), and unprotected sex within serodiscordant partnerships (~60.0%) were reported. Increased number of partners, meeting partners on the Internet, drug use before sex, and not knowing one's viral load were associated with unprotected anal intercourse. Efforts to develop and scale up biomedical and behavioral interventions for HIV-positive men who have sex with men in Asia are needed. PMID- 22421701 TI - Emergence and characterization of Neisseria gonorrhoeae isolates with decreased susceptibilities to ceftriaxone and cefixime in Canada: 2001-2010. AB - BACKGROUND: Globally, Neisseria gonorrhoeae antimicrobial resistance has been increasing, and in particular, reports of isolates with reduced susceptibility to third-generation cephalosporins have surfaced. We examined the phenotypic and genetic characteristics of 155 N. gonorrhoeae isolates with decreased susceptibilities to third-generation cephalosporins isolated in Canada between 2001 and mid-2010. METHODS: Minimum inhibitory concentrations (MICs) were determined by agar dilution on N. gonorrhoeae isolates, and those displaying elevated MICs to cefixime (MIC = 0.25 MUg/mL and 0.5 MUg/mL) and ceftriaxone (MIC = 0.125 MUg/mL and 0.25 MUg/mL) were examined using N. gonorrhoeae multiantigen sequence typing (NG-MAST) and sequencing of resistance determinants associated with decreased cephalosporin susceptibilities (penA, mtrR, ponA, porB1b (penB alteration). RESULTS: Between 2001 and 2010, there has been a shift in the modal MICs from 0.016 to 0.125 MUg/mL for cefixime and from 0.016 to 0.063 MUg/mL for ceftriaxone. Thirty-seven different sequence types (STs) were identified among the isolates using N. gonorrhoeae multiantigen sequence typing; ST3158, ST225, and ST1407 were most prevalent at 25.9%, 19.4%, and 14.8%, respectively. The penA mosaic was present in 60% of the isolates, with the most common penA mosaic types XXXII and X identified at 51.0% and 7.7%, respectively, whereas the nonmosaic penA type XII was identified in 36.8% of the isolates. CONCLUSIONS: In Canada, N. gonorrhoeae isolates with decreased susceptibilities to third-generation cephalosporins have increased over the years. The alterations in penA, mtrR, and porB1b (penB alteration) are important determinants identified in these isolates. The most common STs identified among these Canadian isolates have also been reported worldwide. PMID- 22421702 TI - Amantadine-induced myoclonus in a patient with progressive supranuclear palsy. AB - Progressive supranuclear palsy (PSP) is a tauopathy that generally results in a hypokinetic disorder. Treatment is largely symptomatic, with some small studies indicating a benefit with dopaminergic therapy. Myoclonus is a hyperkinetic disorder that can be seen as part of later stage Parkinson's disease and in multiple system atrophy, but is rarely seen in PSP. Here we report a case of myoclonus precipitated by amantadine in a patient with PSP. PMID- 22421703 TI - A fluorinated quinuclidine benzamide named LMA 10203 acts as an agonist of insect nicotinic acetylcholine receptors. AB - In the present study, we take advantage of the fact that cockroach dorsal unpaired median neurons express different nicotinic acetylcholine receptor subtypes to demonstrate that simple quinuclidine benzamides such as the 2 fluorinated benzamide LMA 10203, could act as an agonist of cockroach alpha bungarotoxin-insensitive nicotinic acetylcholine receptor subtype, called nAChR2. Indeed, 1 mM LMA 10203 induced ionic currents which were partially blocked by 0.5 MUM alpha-bungarotoxin and methyllycaconitine and completely blocked by 5 MUM mecamylamine. Moreover, the current-voltage curve revealed that the ionic current induced by LMA 10203 increased from -30 mV to +20 mV confirming that it acted as an agonist of alpha-bungarotoxin-insensitive nAChR2. In addition, 1 mM LMA 10203 induced a depolarization of the sixth abdominal ganglion and this neuroexcitatory activity was completely blocked by 5 MUM mecamylamine. These data suggest that nAChR2 was also expressed at the postsynaptic level on the synapse between the cercal afferent nerve and the giant interneurons. Interestingly, despite LMA 10203 being an agonist of cockroach nicotinic receptors, it had a poor insecticidal activity. We conclude that LMA 10203 could be used as an interesting compound to identify specific insect nAChR subtypes. PMID- 22421704 TI - Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity. AB - Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity. PMID- 22421705 TI - Long-term changes in handgrip strength in men and women--accounting the effect of right censoring due to death. AB - BACKGROUND: Age-related decline in muscle strength is among of the most important factors in the aging process leading to disability. This study examines age related changes in handgrip strength through a 22-year follow-up in men and women. Because handgrip strength is associated with mortality, this study also accounts for the selection effect of right censoring by comparing the estimates of handgrip strength decline based either on only the handgrip strength data or on the data of both the handgrip strength and survival times. METHODS: Data are from 1,890 men and women aged 30 years or more at baseline participating in the population-based Mini-Finland Health Examination Survey (1978-1980) with repeated handgrip strength measurement in 2000-2001. RESULTS: In men aged 31-41 years, the annual decrease in handgrip strength was approximately 3.5 Newtons (N). After that, the decrease accelerated and stabilized around the age of 75 years, being approximately 7.3 N per year. In women, respectively, prior to 45 years, the annual decrease was approximately 2 N and after age 80 years approximately 4 N per year. The estimates for the handgrip strength decline were more pronounced when the right censoring due to death was accounted for, especially for persons aged 65 years and older. CONCLUSIONS: Our work confirms that the right censoring, which depends on the outcome of interest, should be accounted for in analyses. PMID- 22421706 TI - Muscle strength in older community-dwelling men is related to type of milk feeding in infancy. AB - BACKGROUND: There is a growing literature that links greater duration and exclusivity of breastfeeding to beneficial effects on adult health outcomes. Muscle growth in the neonatal period may be very sensitive to variations in early nutrition, but little is known about long-term effects of infant feeding on muscle strength. METHODS: In 2,983 community-dwelling older men and women born 1931-1939, we examined the relationship between their type of milk feeding in infancy and their muscle strength in adult life. Information about milk feeding for each participant was abstracted from their infant record; grip strength was measured using a Jamar dynamometer. RESULTS: Sixty percent (1,783) of the participants were breastfed only, 31% (926) were breast- and bottle-fed, and 9% (274) were bottle-fed only. There were no differences in type of milk feeding between men and women or according to social class at birth. Among the men studied, grip strength was related to the type of milk feeding, such that greater exposure to breast milk in infancy was associated with greater grip strength in adult life (p = .023). This association remained after adjustment for the effects of a range of confounding influences (birthweight, infant growth, height, age at measurement, adult diet, and level of physical activity). In contrast, the type of milk feeding in infancy was not related to grip strength among the women studied (p = .807). CONCLUSIONS: These data suggest that in men, differences in nutritional exposure in the early postnatal period may have lifelong implications for muscle strength. PMID- 22421707 TI - Carboxylic acid functionalized ortho-linked oxacalix[2]benzene[2]pyrazine: synthesis, structure, hydrogen bond and metal directed self-assembly. AB - Cyclooligomerization of 2,6-dichloropyrazine 4 and benzyl 2,3-dihydroxybenzoate 5 under microwave irradiation resulted in a racemic pair of ester functionalized ortho-linked oxacalix[2]benzene[2]pyrazine 6, which was further transformed to the corresponding racemic carboxylic acid functionalized ortho-linked oxacalix[2]benzene[2]pyrazine 3. Both enantiomers of 3 adopt 1,3-alternate conformations with their two carboxylic acid groups pointing to opposite directions in the solid state. Enantiomers of 3 form a step-like one-dimensional supramolecular polymer via intermolecular hydrogen bond interactions between the carboxylic acids for crystals obtained in methanol. No hydrogen bonds were formed between the carboxylic acids for crystals of 3 obtained in pyridine and aqueous guanidine solutions; instead, intermolecular hydrogen bonds between the carboxylic acid groups of 3 and pyridine, as well as guanidinium ions were formed. Under metal-mediated self-assembly conditions, the pyrazinyl nitrogen atoms in 3 interacted with transition metal ions, such as Ag(I), Cu(II) and Zn(II), and resulted in the formation of four new metal-containing supramolecular complexes. Metallomacrocycles 7, 8 and 9 were formed by reactions of 3 with Ag(I) or Cu(II) ions by bridging two ligands 3 in the equatorial region via M-N coordination bonds. A one-dimensional coordination polymer 10 was generated by reaction between ligand 3 and Zn(II) ions, and a cage-based structure is presented in 10 by bridging of the cyclophane units by Zn(2+) ions via Zn-N and Zn-O bonds. PMID- 22421708 TI - Cone-beam computed tomography as an adjunct to performance of percutaneous cementoplasty of the acetabulum. AB - Acetabuloplasty is a valuable palliative adjunct for the treatment of patients with painful metastatic disease to the pelvis in selected cases. We report the case of a 45-year-old woman with morbid obesity and with breast carcinoma who was technically difficult to treat under fluoroscopic guidance due to very poor visualization secondary to her body habitus. It was possible to perform radiofrequency ablation and acetabuloplasty with the use of cone-beam computed tomography for guidance. PMID- 22421709 TI - Selection of symptomatic patients with Crohn's disease for abdominopelvic computed tomography: role of serum C-reactive protein. AB - BACKGROUND: Results of previous studies have shown that repeated abdominopelvic computed tomography (CT) examinations can lead to substantial cumulative diagnostic radiation exposure in patients with Crohn's disease (CD). Improved selection of patients referred for CT will reduce unnecessary radiation exposure. This study examines if serum C-reactive protein (CRP) concentration predicts which symptomatic patients with CD are likely to have significant disease activity or disease complications (such as abscess) detected on abdominopelvic CT. METHODS: All abdominopelvic CTs performed on patients with CD at a tertiary referral centre during the period June 2003 to June 2008 were identified. CT findings were coded by a pair of independent blinded senior radiologists for (i) small bowel luminal disease, (ii) large bowel luminal disease, (iii) mesenteric inflammatory changes, (iv) penetrating disease (fistulas, abscess, or phlegmon), (v) acute disease complications (obstruction or perforation), and (vi) acute non CD findings. Imaging findings were correlated with serum CRP checked within 14 days before imaging. The reference range for CRP was defined as 0-5 mg/L. RESULTS: A total of 147 patients with symptomatic CD had a CRP assay performed within 14 days before undergoing abdominopelvic CT. The median time from CRP assay to imaging was 2 days (interquartile range, 0-6 days). Median CRP before imaging was 24 mg/L (interquartile range, 6-88 mg/L). CT was normal in 34 of 147 case (23.1%). Patients with normal CRP (n = 36) were significantly less likely to have penetrating disease (odds ratio [OR], 0.04 [95% confidence interval {CI}, 0.01-0.7]; P < .001) or large bowel luminal disease (OR, 0.3 [95% CI, 0.1-0.8]; P < .05). Normal CRP excluded penetrating disease with a sensitivity of 1.0 (95% CI, 0.87-1.0). CRP levels did not correlate with the presence of small bowel luminal disease (n = 82), mesenteric inflammatory changes (n = 68), or acute disease complications (n = 10). CONCLUSION: Symptomatic patients with CD and normal serum CRP are unlikely to have evidence of abscess, fistulating disease, or large bowel luminal disease detected on abdominopelvic CT. However, abdominopelvic CT may demonstrate evidence of clinically significant non penetrating CD or complications, including perforation and acute obstruction, regardless of serum CRP concentration. PMID- 22421710 TI - Enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones. AB - Two approaches have been developed for the enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones to form a quaternary carbon centre using (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol as the chiral ligand. Good yields and high enantioselectivities (80-91% ee) were achieved with a range of alkyl aryl ketones in a convenient one-pot protocol using ethyl iododifluoroacetate and diethylzinc to form the difluorinated Reformatsky reagent homogeneously. In the traditional two-step Reformatsky reaction using the preformed Reformatsky reagent generated from ethyl iododifluoroacetate and zinc dust, good yields and good enantioselectivities (75-84% ee) were also obtained. PMID- 22421711 TI - Clinical implications of HBsAg quantification in patients with chronic hepatitis B. AB - Quantification of serum hepatitis B surface antigen (HBsAg) helps the management of patients with chronic hepatitis B virus (HBV) infection. Median HBsAg levels differ significantly during the natural history of HBV infection, progressively declining from immune tolerance to inactive phase. The combination of an HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL at a single time point accurately identifies true inactive carriers. During antiviral treatment, HBsAg levels decline more rapidly in patients under peg-interferon (Peg-IFN) than in those under nucleos(t)ide analogues (NUC), and in responders to peg-IFN compared to non responders suggesting that a response-guided therapy in both HBeAg-positive and negative patients treated with Peg-IFN could improve to cost-effectiveness of this therapeutic approach. Given the low rates of HBsAg clearance on NUC therapy, new studies to test whether Peg-IFN and NUC combination fosters HBsAg decline in long-term responders to NUC, are being explored. PMID- 22421712 TI - Therapeutic applications of octreotide in pediatric patients. AB - BACKGROUND/AIM: We report our experience with the use of octreotide as primary or adjunctive therapy in children with various gastrointestinal disorders. PATIENTS AND METHODS: A pharmacy database identified patients who received octreotide for gastrointestinal diseases. Indications for octreotide use, dosing, effectiveness, and adverse events were evaluated by chart review. RESULTS: A total of 21 patients (12 males), aged 1 month to 13 years, were evaluated. Eleven received octreotide for massive gastrointestinal bleeding caused by portal hypertension induced lesions (n=7), typhlitis (1), Meckel's diverticulum (1), and indefinite source (2). Blood transfusion requirements were reduced from 23 +/- 9 mL/kg (mean +/- SD) to 8 +/- 15 mL/kg (P<0.01). Four patients with pancreatic pseudocyst and/or ascites received octreotide over 14.0 +/- 5.7 days in 2 patients. In 3 children, pancreatic pseudocyst resolved in 12 +/- 2 days and pancreatic ascites resolved in 7 days in 2. Three patients with chylothorax received octreotide for 14 +/- 7 days with complete resolution in each. Two infants with chronic diarrhea received octreotide over 11 +/- 4.2 months. Stool output decreased from 85 +/- 21 mL/kg/day to 28 +/- 18 mL/kg/day, 3 months after initiation of octreotide. The child with dumping syndrome responded to octreotide in a week. Adverse events developed in 4 patients: Q-T interval prolongation and ventricular fibrillation, hyperglycemia, growth hormone deficiency, and hypertension. CONCLUSION: Octreotide provides a valuable addition to the therapeutic armamentum of the pediatric gastroenterologist for a wide variety of disorders. Serious adverse events may occur and patients must be closely monitored. PMID- 22421713 TI - Percutaneous endoscopic gastrostomy tube placement for end-stage palliation of malignant gastrointestinal obstructions. AB - BACKGROUND/AIM: Decompression of malignant gastrointestinal obstructions is an uncommon indication for percutaneous endoscopic gastrostomy (PEG) tubes. The purpose of this study is to determine the efficacy of venting PEG tubes in relieving nausea and vomiting and assessing complications associated with tube placement. PATIENTS AND METHODS: This study is a retrospective chart review of patients with PEG tubes placed to decompress malignant gastrointestinal obstructions between January 2005 and September 2010 by the gastroenterology service at our institute. Patient demographics, symptom relief, procedural complications, diet tolerability and home palliation were reviewed. RESULTS: Seven PEG tubes were inserted to decompress malignant gastrointestinal obstructions. The mean patient age was 62 years (range 37-82 years). The underlying primary malignancies were small intestine (1), appendiceal (1), pancreatic (2), and colon (3) cancer. Gastric outlet obstruction was present in 3 (43%) patients while small bowel obstruction occurred in 4 (57%) patients. There was relief of nausea and vomiting in 6 (86%) patients. Procedural complications were present in 1 (14%) patient and involved superficial cellulitis followed by peristomal leakage. Patients with gastric outlet obstruction continued to have limited oral intake while patients with small bowel obstruction tolerated varying degrees of oral nutrition. Six (86%) patients were discharged home after PEG tube placement, but only 2 (33%) were able to undergo end-stage palliation at home without re-admission for hospital palliation. CONCLUSIONS: Venting PEG tubes significantly reduce the symptoms of nausea and vomiting in patients with metastatic gastrointestinal obstruction due to primary gastrointestinal malignancies. Complications associated with tube placement were minimal. PMID- 22421714 TI - Unusual, metastatic, or neuroendocrine tumor of the pancreas: a diagnosis with endoscopic ultrasound-guided fine-needle aspiration and immunohistochemistry. AB - BACKGROUND/AIM: To determine the yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in combination with immunostains in diagnosing unusual solid pancreatic masses (USPM) in comparison with pancreatic adenocarcinoma (ACP). PATIENTS AND METHODS: All EUS-FNA of solid pancreatic masses performed with a 22-gauge needle were included. Data on clinical presentations, mass characteristics, presence of pancreatitis, yield of tissue, and final diagnosis were compared between the two groups. On site cytopathology was provided and additional passes were requested to perform immunostains. RESULTS: Two hundred and twenty-nine cases with either adenocarcinoma or USPM were included. The median age of the cohort was 65 years. ACP (210/229, 92%) accounted for the majority of the cases. The USPM included neuroendocrine (NET) masses (n=13), metastatic renal carcinoma (n=3), metastatic melanoma (n=1), lymphoma (n=1), and malignant fibrous histiocytoma (n=1). Subjects with ACP were significantly more likely to present with loss of weight (P=0.02) or obstructive jaundice (P<0.001). Subjects with ACP were more likely to have suspicious/atypical FNA biopsy results as compared with USPM (10% vs 0%). The sensitivity of EUS-FNA with immunostains was 93% in ACP as compared with 100% in USPM. Diagnostic accuracy was higher in USPM as compared with ACP (100% vs 93%). CONCLUSIONS: EUS-FNA using a 22-gauge needle with immunostains has excellent diagnostic yield in patients with USPMs, which is comparable if not superior to the yield in pancreatic adenocarcinoma. PMID- 22421715 TI - The possible role of selenium concentration in hepatitis B and C patients. AB - BACKGROUND/AIM: The compelling evidence reported that selenium is an essential trace mineral for human beings. Selenium plays a pivotal role in the restoration of immune functions. High rates of hepatitis B and C are present in Pakistan. Epidemiologic surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as viral infection. The present study was designed to evaluate the concentration of selenium in the serum of patients suffering from hepatitis B and C. PATIENTS AND METHODS: In this cross sectional descriptive analytical study, serum selenium concentration of 150 patients suffering from hepatitis B and C, along with 26 healthy controls, was determined by atomic absorption spectrophotometer equipped with hydride generation system, model Analytic Jena (Vario III). RESULTS: The mean and standard deviation of serum selenium concentration observed in male and female patients with hepatitis C were 101.60 +/- 0.55 and 77.43 +/- 0.47 MU g/L, respectively, whereas the mean and standard deviation of serum selenium concentration observed in male and female patients with hepatitis B were 107.58 +/- 0.44 and 137.8 +/- 0.36 MUg/L. Analysis of t test showed significant difference between C and B (P<0.001) patients in serum selenium concentration, when compared with the control. CONCLUSION: The obtained results indicate that serum selenium concentration of hepatitis B and C patients is less than serum selenium concentration of healthy individuals. However, serum selenium decline is relative to severity of disease. Based on findings of this study, it is proposed that selenium should be supplemented in such patients in order to optimize nutritional support and to get better treatment response. PMID- 22421716 TI - Role of gum chewing on the duration of postoperative ileus following ileostomy closure done for typhoid ileal perforation: a prospective randomized trial. AB - BACKGROUND/AIM: There is ample evidence in the recent literature that gum chewing after elective colonic anastomosis decreases postoperative ileus (POI). But there are very few studies on small bowel anastomosis done in relaparotomy cases. This study aimed to evaluate the effect of gum chewing on the duration of POI following small bowel anastomosis performed for the closure of intestinal stoma, made as temporary diversion in the selected cases of typhoid perforation peritonitis. PATIENTS AND METHODS: Hundred patients undergoing elective small bowel anastomosis for the closure of stoma were randomly assigned to the study group (n=50) and the control group (n=50). The study group patients chewed gum thrice a day for 1 h each time starting 6 h after the surgery until the passage of first flatus. The control group patients had standard postoperative treatment. RESULTS: Study and control group patients were comparable at inclusion. The mean time for the appearance of bowel sounds as well as the passage of first flatus was significantly shorter in the study group (P=0.040, P=0.006). The feeling of hunger was also experienced earlier in study group cases (P=0.004). The postoperative hospital stay was shorter in the study group, but the difference was not significant (P=0.059). CONCLUSIONS: The cases of relaparotomy requiring additional adhesiolysis and small bowel anastomosis for stoma closure are benefited by postoperative gum chewing. PMID- 22421717 TI - Early recurrence of pancreatic cancer after resection and during adjuvant chemotherapy. AB - BACKGROUND/AIM: Adjuvant chemotherapy for 6 months is the current standard of care after potentially curative resection of pancreatic cancer and yields an overall survival of 15-20 months. Early tumor recurrence before or during adjuvant chemotherapy has not been evaluated so far. These patients may not benefit from adjuvant treatment. PATIENTS AND METHODS: Thirty-five patients with resection of ductal pancreatic carcinoma and adjuvant chemotherapy with gemcitabine were analyzed between 2005 and 2007. All patients had a computed tomography (CT) scan before and during adjuvant chemotherapy after 2-3 months, 12/35 patients had a histologically confirmed R1 resection. Recurrence of pancreatic cancer was determined by CT scan and the clinical course. RESULTS: Median survival of 35 patients with resected pancreatic cancer was 19.7 months, and the 2-year survival was 44%. Thirteen (37%) of the 35 patients analyzed with a CT scan showed tumor recurrence during adjuvant chemotherapy. Overall survival of patients with tumor recurrence was 9.3 months with a 2-year survival rate of 13%, whereas median overall survival of patients without early relapse was 26.3 months (P<0.001). Local recurrence of pancreatic cancer occurred in 38% (5/13); 46% (6/13) of patients developed distant metastasis, and 38% (5/13) developed lymph node metastasis. Early tumor recurrence during or adjuvant chemotherapy did not correlate with R status (R1 vs R0, P=0.69), whereas histologically confirmed lymph node invasion (pN0 vs pN1) and grading showed a statistically significant correlation with early relapse (P<0.05). CONCLUSION: A significant fraction of patients with resected pancreatic cancer have early relapse during adjuvant chemotherapy, especially those with lymph node metastasis. Radiologic examinations prior to and during adjuvant chemotherapy will help to identify patients with tumor recurrence who are unlikely to benefit from adjuvant treatment and will need individualized palliative chemotherapy. PMID- 22421718 TI - Complicated jejunal diverticulitis: a challenging diagnosis and difficult therapy. AB - BACKGROUND/AIM: In contrast to diverticulosis of the colon, jejunal diverticulosis is a rare entity that often becomes clinically relevant only after exacerbations occur. The variety of symptoms and low incidence make this disease a difficult differential diagnosis. PATIENTS AND METHODS: Data from all patients who were treated in our surgical department for complicated jejunal diverticulitis, that is, gastrointestinal hemorrhage or a diverticula perforation were collected prospectively over a 6-year period (January 2004 to January 2010) and analyzed retrospectively. RESULTS: The median age among the 9 patients was 82 years (range: 54-87). Except for 2 cases (elective operation for a status postjejunal peridiverticulitis and a re-perforation of a diverticula in a patient s/p segment resection with free perforation), the diagnosis could only be confirmed with an exploratory laparotomy. Perforation was observed in 5 patients, one of which was a retroperitoneal perforation. The retroperitoneal perforation was associated with transanal hemorrhage. Hemodynamically relevant transanal hemorrhage requiring transfusion were the reason for an exploratory laparotomy in 2 further cases. In one patient, the hemorrhage was the result of a systemic vasculitis with resultant gastrointestinal involvement. A singular jejunal diverticulum caused an adhesive ileus in one patient. The extent of jejunal diverticulosis varied between a singular diverticulum to complete jejunal involvement. A tangential, transverse excision of the diverticulum was carried out in 3 patients. The indication for segment resection was made in the case of a perforation with associated peritonitis (n=4) as well as the presence of 5 or more diverticula (n=2). Histological analysis revealed chronic pandiverticulitis in all patients. Median operating time amounted to 142 minutes (range: 65-210) and the median in-hospital stay was 12 days (range: 5-45). Lethality was 0%. Major complications included secondary wound closure after s/p repeated lavage and bilateral pleural effusions in one case. Signs of malabsorption as the result of a short bowel syndrome were not observed. Minor complications included protracted intestinal atony in 2 cases and pneumonia in one case. Median follow up was 6 months (range: 1-18). CONCLUSION: Complicated jejunal diverticulitis often remains elusive preoperatively due to its unspecific clinical presentation. A definitive diagnosis can often only be made intraoperatively. The resection of all diverticula and/or the complete diverticula-laden segment is the goal in chronic cases. The operative approach chosen (tangential, transverse excision vs segment resection) should be based on the extent of the jejunal diverticulosis as well as the intraoperative findings. PMID- 22421719 TI - Regional variation in prevalence of overweight and obesity in Saudi children and adolescents. AB - BACKGROUND/AIMS: There are limited data on regional variation of overweight and obesity in the Kingdom of Saudi Arabia. Therefore, the aim of this report is to explore the magnitude of these variation in order to focus preventive programs to regional needs. SETTING AND DESIGN: Community-based multistage random sample of representative cohort from each region. PATIENTS AND METHODS: the study sample was cross-sectional, representative of healthy children and adolescents from 2 to 17 years of age. Body mass index (BMI) was calculated according to the formula (weight/height2). The 2000 center for disease control reference was used for the calculation of prevalence of overweight and obesity defined as the proportion of children and adolescents whose BMI for age was above 85 th and 95 th percentiles respectively, for Northern, Southwestern and Central regions of the Kingdom. Chi square test was used to assess the difference in prevalence between regions and a P value of <0.05 was considered significant. RESULTS: The sample size was 3525, 3413 and 4174 from 2-17 years of age in the Central, Southwestern and Northern regions respectively. The overall prevalence of overweight was 21%, 13.4% and 20.1%, that of obesity was 9.3%, 6% and 9.1% in the Central, Southwestern and Northern regions respectively indicating a significantly-lower prevalence in the Southwestern compared to other regions (P<0.0001). CONCLUSIONS: This report revealed significant regional variations important to consider in planning preventive and therapeutic programs tailored to the needs of each region. PMID- 22421720 TI - Clinical predictors of fulminant colitis in patients with Clostridium difficile infection. AB - BACKGROUND/AIM: Clostridium difficile infection (CDI) can affect up to 8% of hospitalized patients. Twenty-five percent CDI patients may develop C. difficile associated diarrhea (CDAD) and 1-3% may progress to fulminant C. difficile colitis (FCDC). Once developed, FCDC has higher rates of complications and mortality. PATIENTS AND METHODS: A 10-year retrospective review of FCDC patients who underwent colectomy was performed and compared with randomly selected age- and sex-matched non-fulminant CDAD patients at our institution. FCDC (n=18) and CDAD (n=49) groups were defined clinically, radiologically, and pathologically. Univariate analysis was performed using Chi-square and Student's t test followed by multivariate logistic regression to compute independent predictors. RESULTS: FCDC patients were significantly older (77 +/- 13 years), presented with triad of abdominal pain (89%), diarrhea (72%), and distention (39%); 28% had prior CDI and had greater hemodynamic instability. In contrast, CDAD patients were comparatively younger (65 +/- 20 years), presented with only 1 or 2 of these 3 symptoms and only 5% had prior CDI. No significant difference was noted between the 2 groups in terms of comorbid conditions, use of antibiotics, or proton pump inhibitor. Leukocytosis was significantly higher in FCDC patients (18.6 +/- 15.8/mm3 vs 10.7 +/- 5.2/mm3; P=0.04) and further increased until the point of surgery. Use of antiperistaltic medications was higher in FCDC than CDAD group (56% vs 22%; P=0.01). CONCLUSIONS: Our data suggest several clinical and laboratory features in CDI patients, which may be indicative of FCDC. These include old age (>70 years), prior CDI, clinical triad of increasing abdominal pain, distention and diarrhea, profound leukocytosis (>18,000/mm3), hemodynamic instability, and use of antiperistaltic medications. PMID- 22421721 TI - Hepatic metastasis from adrenocortical carcinoma fifteen years after primary resection. AB - We report the case of a 73-year-old man who presented with an asymptomatic hepatic mass during investigation of mild chronic obstructive pulmonary disease by a plain chest radiograph, followed by ultrasonography, which revealed a solitary hepatic lesion measuring 7.1 cm * 6.5 cm * 5.8 cm in dimension. Fine- needle aspiration of the mass revealed malignant cells compatible with hepatocellular carcinoma. Interestingly, the patient had a left adrenalectomy and complete left nephrectomy in 1987, for a non-functioning left adrenocortical carcinoma (ACC). The ACC was diagnosed as stage two, with no evidence of local invasion or distant metastases. No adjuvant therapy was recommended postoperatively. After a five-year follow-up, there was no evidence of ACC recurrence and the patient was declared cured from his ACC. The patient underwent a complete segmental resection of the right lobe of the liver successfully. The final diagnosis of the mass was a well-differentiated metastatic adrenocortical carcinoma. PMID- 22421722 TI - Non-familial double malignancy of the colon and ampulla of Vater: a case report and review of literature. AB - Apart from their association in familial and hereditary cancer syndromes, sporadic double malignancies of the gastrointestinal tract involving the ampulla of Vater and colon are extremely rare. Although synchronous resection of the two by adding a colectomy to a pancreaticoduodenctomy can be accomplished with minimal increase in the surgical morbidity, a few patients, however, are best managed by a staged resection. We report a case of sporadic double malignancy of the ampulla of Vater and right colon who despite the best attempts continued to bleed and remained malnourished and was successfully managed by staged right hemicolectomy followed by a pancreaticoduodenectomy. PMID- 22421723 TI - Efficacy of colchicine in the treatment of mesenteric panniculitis in a young patient. AB - Mesenteric panniculitis (MP) is a rare inflammatory and fibrotic disease of the mesentery of unknown etiology. It has various clinical and radiological manifestations, posing a diagnostic challenge for clinicians. Its diagnosis is indicated via radiologic imaging and is usually confirmed via peritoneal biopsies. We describe a case of a patient with histopathologically proven MP, in which steroid dependence was successfully managed with colchicine. PMID- 22421724 TI - Massive diffuse intraperitoneal multicystic mass in an infant. Botryoid rhabdomyosarcoma (RMS). PMID- 22421725 TI - Megaesophagus in the pediatric age group: a diagnostic dilemma. H-type tracheoesophageal fistula (H-type TEF). PMID- 22421731 TI - Local contamination in relation to population genetic diversity and resilience of an arctic marine amphipod. AB - The objective of this study was to investigate whether populations inhabiting a contaminated environment are affected in terms of decreased genetic diversity due to selection of tolerant genotypes and if such effect carries a cost. Marine arctic amphipod populations (Orchomenella pinguis) were collected from sites within a contaminated fjord, as well as from sites outside the fjord on the west coast of Greenland over three years (2006-2008). Impacts on genetic diversity, effects on resilience such as development of tolerance and cost were determined. AFLP-analysis was used to explore within and between population genetic diversity, and exposure studies were performed where the populations were subjected to known and unknown stressors to assess resilience. Populations collected at three contaminated sites all had reduced genetic diversity in 2007 compared to populations outside the fjord. This pattern was different in 2008 as all contaminated site populations increased in diversity, whereas a decrease in diversity occurred at the outer sites. However, tolerance, but even more so, cost, was related to contamination exposure in 2008, in spite of the shift in genetic diversity. We suggest that contamination rapidly induces effects that can be captured as tolerance and associated cost, whereas effects on genetic diversity can be difficult to separate from recent migration events that dilute eventual decreases in diversity due to contamination pressure. As long as impacted populations can be influenced by migration events that increase the genetic diversity and add health to an affected population, populations in contaminated areas may have enhanced probability of survival. PMID- 22421733 TI - Anti-Mullerian hormone is highly expressed and secreted from cumulus granulosa cells of stimulated preovulatory immature and atretic oocytes. AB - This study investigated anti-Mullerian hormone (AMH) expression and secretion from cumulus granulosa cells (GC) and steroidogenesis in follicular fluids (FF) with relation to oocyte maturational stages and fertilization capacity in large preovulatory follicles. This prospective study included 53 ovulatory women undergoing intracytoplasmic sperm injection. FF and cumulus GC from 140 large preovulatory follicles were individually obtained during oocyte retrieval. Main outcome measures were oocyte maturation, fertilization and embryo quality. FF were assayed for AMH, progesterone, 17beta-oestradiol and testosterone. Cumulus GC were assayed for AMH mRNA expression. AMH mRNA expression and secretion in cumulus GC in preovulatory follicles containing germinal-vesicle (GV) and metaphase-I (MI) oocytes were significantly higher than follicles containing MII oocytes (P<0.01 and P<0.0001, respectively). In addition, FF AMH concentrations from atretic oocytes were significantly higher than from MII oocytes. No correlation was found between AMH expression and secretion to fertilization or embryo quality. FF of MI and GV oocytes had higher concentrations of testosterone and lower progesterone/oestradiol ratios than MII oocytes, and FF of atretic oocytes contained higher testosterone concentrations than FF of MII oocytes. AMH is highly expressed in and secreted from cumulus GC of preovulatory follicles containing premature and atretic oocytes. Anti-Mullerian hormone (AMH) is produced in the female exclusively by granulosa cells. AMH has recently been shown to be one of the most important markers of ovarian reserve and it is highly associated with ovarian follicular development. This study investigates AMH expression and secretion from cumulus granulosa cells (GC) and steroidogenesis in the follicular fluids (FF) with relation to oocyte maturational stages, and fertilization capacity in large preovulatory follicles. We conducted a prospective study with 53 ovulatory women undergoing intracytoplasmic sperm injection. FF and cumulus GC from 140 large preovulatory follicles were individually obtained during oocyte retrieval. The main outcome measures were oocyte maturation, fertilization and embryo quality. FF were assayed for AMH, progesterone, 17beta-oestradiol and testosterone. Cumulus GC were assayed for AMH mRNA expression. AMH mRNA expression in cumulus GC and AMH concentrations in FF of preovulatory follicles containing premature oocytes (germinal vesicle (GV) and metaphase I (MI)) were significantly higher than preovulatory follicles containing mature oocytes (MII oocytes). In addition, FF AMH concentrations of atretic oocytes were significantly higher than FF AMH of MII oocytes. No correlation was found between AMH expression and secretion for fertilization or embryo quality. FF of preovulatory MI and GV oocytes had higher levels of testosterone and lower progesterone/oestradiol ratios than MII oocytes, and FF of atretic oocytes contained higher testosterone levels than FF of MII oocytes. This study shows that AMH is highly expressed in and secreted from cumulus GC of preovulatory follicles containing premature and atretic oocytes. PMID- 22421730 TI - Endogenous viruses: insights into viral evolution and impact on host biology. AB - Recent studies have uncovered myriad viral sequences that are integrated or 'endogenized' in the genomes of various eukaryotes. Surprisingly, it appears that not just retroviruses but almost all types of viruses can become endogenous. We review how these genomic 'fossils' offer fresh insights into the origin, evolutionary dynamics and structural evolution of viruses, which are giving rise to the burgeoning field of palaeovirology. We also examine the multitude of ways through which endogenous viruses have influenced, for better or worse, the biology of their hosts. We argue that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses. PMID- 22421734 TI - Neuromuscular electrical stimulation for intensive care unit-acquired weakness: protocol and methodological implications for a randomized, sham-controlled, phase II trial. AB - BACKGROUND: As the population ages and critical care advances, a growing number of survivors of critical illness will be at risk for intensive care unit (ICU) acquired weakness. Bed rest, which is common in the ICU, causes adverse effects, including muscle weakness. Consequently, patients need ICU-based interventions focused on the muscular system. Although emerging evidence supports the benefits of early rehabilitation during mechanical ventilation, additional therapies may be beneficial. Neuromuscular electrical stimulation (NMES), which can provide some muscular activity even very early during critical illness, is a promising modality for patients in the ICU. OBJECTIVE: The objectives of this article are to discuss the implications of bed rest for patients with critical illness, summarize recent studies of early rehabilitation and NMES in the ICU, and describe a protocol for a randomized, phase II pilot study of NMES in patients receiving mechanical ventilation. DESIGN: The study was a randomized, sham controlled, concealed, phase II pilot study with caregivers and outcome assessors blinded to the treatment allocation. SETTING: The study setting will be a medical ICU. PARTICIPANTS: The study participants will be patients who are receiving mechanical ventilation for 1 day or more, who are expected to stay in the ICU for an additional 2 days or more, and who meet no exclusion criteria. INTERVENTION: The intervention will be NMES (versus a sham [control] intervention) applied to the quadriceps, tibialis anterior, and gastrocnemius muscles for 60 minutes per day. MEASUREMENTS: Lower-extremity muscle strength at hospital discharge will be the primary outcome measure. LIMITATIONS: Muscle strength is a surrogate measure, not a patient-centered outcome. The assessments will not include laboratory, genetic, or histological measures aimed at a mechanistic understanding of NMES. The optimal duration or dose of NMES is unclear. CONCLUSIONS: If NMES is beneficial, the results of the study will help advance research aimed at reducing the burden of muscular weakness and physical disability in survivors of critical illness. PMID- 22421735 TI - Retraining postural responses with exercises emphasizing speed poststroke. AB - BACKGROUND: Postural responses are impaired after stroke, with reduced or delayed muscle activity in the paretic leg muscles. OBJECTIVE: The efficacy of exercises emphasizing speed of movement in modifying postural responses to perturbations that were not practiced was investigated. DESIGN: This was a dual cohort design. METHODS: A convenience sample of 32 individuals with hemiparesis poststroke (mean number of weeks poststroke=11.3, SD=4.1) who were recruited upon discharge from an inpatient rehabilitation hospital and a control group of age- and sex-matched individuals who were healthy (n=32) performed a single session of exercise emphasizing speed of movement. To assess postural responses to internal perturbation, unilateral arm raise and load drop tasks were performed before exercises (pre-exercise), immediately after exercises (post-exercise), and 15 minutes after exercises (retention). The time to burst peak and area of the biceps femoris muscle (BF) electromyographic (EMG) activity in the arm raise task was measured with the arm acceleration and velocity of the center of pressure (COP) excursion. For the load drop task, the anticipatory EMG deactivation area of the BF was calculated. In both tasks, the vertical ground reaction forces were recorded for each leg separately. RESULTS: Before exercise, EMG and force platform measures were smaller in the stroke group than in the control group. After exercise, the paretic BF time to burst peak decreased, the paretic BF EMG area increased, and the COP velocity increased in the arm raise task, as did the paretic BF anticipatory EMG deactivation area in the load drop task. The stroke group was weight bearing more symmetrically after exercises. Most changes were retained 15 minutes after the exercises. LIMITATIONS: The retention period was short, and there was no control group of individuals with stroke. CONCLUSIONS: The results of this efficacy study demonstrated that fast movement exercises improved postural responses to perturbations that were not practiced. PMID- 22421736 TI - Interaction of feedback frequency and task difficulty in children's motor skill learning. AB - BACKGROUND: Providing adults with knowledge of results (KR) after each practice trial (100% KR) usually is found to be detrimental to motor skill learning compared with conditions in which feedback is less frequently provided. The effect of 100% KR on children's learning is less clear, with research showing that children with cerebral palsy benefit from less frequent KR, whereas children with typical development do not. OBJECTIVE: This study was designed to examine the interaction of KR frequency and task complexity on the acquisition, retention, and transfer of a novel throwing skill in fourth- and fifth-grade children with typical development. DESIGN: This was an observational study. METHODS: Children threw beanbags for accuracy at an unseen target while walking or while standing still. These 2 levels of task complexity were crossed with 2 frequencies (33% and 100%) of KR provision. Following practice, retention tests without feedback were performed 5 minutes later and then 1 week later along with transfer tests to assess the generalizability of learning. RESULTS: Analyses revealed that learning was improved on the easy version of the task when a 33% KR frequency was provided during practice. In contrast, in the difficult version, learning was facilitated by provision of a 100% KR frequency during practice. CONCLUSIONS: Structuring practice conditions for children should take into account task complexity and feedback frequency in determining the cognitive challenge necessary for optimal skill learning. More generally, the findings suggest that practitioners teaching motor skills should design practice conditions in accordance with the cognitive processing capacity of the learner. PMID- 22421737 TI - Cardiac remodeling is not modulated by overexpression of muscle LIM protein (MLP). AB - Muscle LIM protein (MLP) has been proposed to be a central player in the pathogenesis of heart muscle disease. In line with this notion, the homozygous loss of MLP results in cardiac hypertrophy and dilated cardiomyopathy. Moreover, MLP is induced in several models of cardiac hypertrophy such as aortic banding and myocardial infarction. We thus hypothesized that overexpression of MLP might change the hypertrophic response to cardiac stress. In order to answer the question whether MLP modulates cardiac hypertrophy in vivo, we generated a novel transgenic mouse model with cardiac-specific overexpression of MLP. Three independent transgenic lines did not show a pathological phenotype under baseline conditions. Specifically, contractile function and heart weight to body weight ratios at different ages were normal. Next, the transgenic animals were challenged with pressure overload due to aortic constriction. Surprisingly, transgenic mice developed cardiac hypertrophy to the same extent as their wild type littermates. Moreover, neither contractile dysfunction nor pathological gene expression in response to pressure overload were differentially affected by MLP overexpression. Finally, in a milder in vivo model of hypertrophy induced by chronic infusion of angiotensin-II, cardiac mass and hypertrophic gene expression were again identical in MLP transgenic mice and controls. Taken together, we provide evidence that cardiac overexpression of MLP does not modulate the heart's response to various forms of pathological stress. PMID- 22421738 TI - Investigating the benefit of adding a vena cava filter to anticoagulation with fondaparinux sodium in patients with cancer and venous thromboembolism in a prospective randomized clinical trial. AB - BACKGROUND: The benefit of adding a vena cava filter to anticoagulation in treating cancer patients with venous thromboembolism remains controversial. We initiated this study as the first prospectively randomized trial to evaluate the addition of a vena cava filter placement to anticoagulation with the factor Xa inhibitor fondaparinux sodium in patients with cancer. METHODS: Sixty-four patients with deep vein thrombosis (86 %) and/or pulmonary embolism (55 %) were randomly assigned to receive anticoagulation with fondaparinux sodium with or without a vena cava filter. Endpoints included rates of complications by treatment arm, recurrent thromboembolism, complete resolution of thromboembolism, and survival rates. RESULTS: No patient had a recurrent deep vein thrombosis; two (3 %) patients had new pulmonary emboli, one in each randomized cohort. Major bleeding occurred in three patients (5 %). Two patients on the vena cava filter arm (7 %) had complications from the filter. Median survivals were 493 days in the anticoagulation only arm and 266 days for anticoagulation + vena cava filter (p < 0.57). Complete resolution of venous thromboembolism occurred in 51 % of patients within 8 weeks of initiating anticoagulation. CONCLUSIONS: No advantage was found for placement of a vena cava filter in addition to anticoagulation with fondaparinux sodium in terms of safety, recurrent thrombosis, recurrent pulmonary embolism, or survival in this prospective randomized trial evaluating anticoagulation plus a vena cava filter in cancer patients. Favorable complete resolution rates of thrombosis were observed on both study arms. PMID- 22421740 TI - Stripping voltammetry study of ultra-trace toxic metal ions on highly selectively adsorptive porous magnesium oxide nanoflowers. AB - We have demonstrated highly selective and sensitive detection of Pb(II) and Cd(II) using a highly selective adsorptive porous magnesium oxide (MgO) nanoflowers. The MgO nanoflower-modified glassy carbon electrode was electrochemically characterized using cyclic voltammetry; and the anodic stripping voltammetric performance of bound Pb(II) and Cd(II) was evaluated using square wave anodic stripping voltammetry (SWASV) analysis. The MgO nanoflower modified electrode exhibited excellent sensing performance toward Pb(II) and Cd(II) that was never observed previously at bismuth (Bi)-based electrodes. Simultaneous additions of Pb(II) and Cd(II) were investigated in the linear range from 3.3 to 22 nM for Pb(II) and 40 to 140 nM for Cd(II), and detection limits of 2.1 pM and 81 pM were obtained, respectively. Some foreign ions, such as Cu(II), Zn(II) and Cr(III) do not interfere with the detection of Pb(II) and Cd(II). To the best of our knowledge, this is the first example of a highly adsorptive metal oxide with hierarchical micro/nanostructure that allows the detection of both Pb(II) and Cd(II) ions. PMID- 22421739 TI - Effects of a Rhodiola rosea L. extract on the acquisition, expression, extinction, and reinstatement of morphine-induced conditioned place preference in mice. AB - RATIONALE: Opioid addiction is a chronic, recurrent brain disease that is characterised by compulsive drug seeking and a high rate of relapse even after long periods of abstinence. Prevention of relapse is the primary goal of addiction treatment and is still the major limitation in drug therapy. OBJECTIVES: The present study investigated the effects of a Rhodiola rosea L. hydroalcoholic extract (RHO), a well-known traditional oriental medicine, on establishment and reinstatement of morphine-induced conditioned place preference (CPP) in mice. METHODS: CPP was induced by intraperitoneal injection of morphine (10 mg/kg) as an 8-day conditioning schedule. The effects of RHO on the rewarding properties of morphine were tested in mice receiving oral administration of RHO (10, 15, and 20 mg/kg) 60 min prior to each morphine injection (acquisition) or prior to the CPP test on day 9 (expression). Once established, CPP was extinguished by repeated testing, during which conditioned mice were injected daily with different doses of RHO. Finally, the efficacy of RHO in blocking reinstatement of CPP provoked by priming injections and physical stress was also evaluated. RESULTS: RHO administration showed dose dependency for prevention of establishment of CPP and was effective in facilitating extinction of morphine induced CPP. RHO suppressed both priming- and stress-induced reinstatement of CPP in a dose-dependent manner. CONCLUSIONS: In conclusion, as RHO was effective for reducing craving and vulnerability to relapse, it might be a very effective natural remedy for the treatment of opioid addiction. PMID- 22421741 TI - Multidrug resistant tuberculosis diagnosed by synovial fluid analysis. AB - Tuberculosis remains a major public health problem worldwide. HIV co-infection is contributing to an increased incidence of the disease, particularly that caused by multidrug resistant strains of Mycobacterium tuberculosis (MT). We describe an HIV-infected patient with pleural and lymph node tuberculosis diagnosed by pleural effusion characteristics and biopsy specimens, without MT identification, that further presented with knee-joint involvement. Arthrocentesis allowed MT isolation and drug susceptibility testing, resulting in a diagnosis of multidrug resistant tuberculosis and an appropriate treatment regimen. MT identification and drug susceptibility tests are very important, especially for HIV co-infected patients. PMID- 22421742 TI - Giant metal-organic frameworks with bulky scaffolds: from microporous to mesoporous functional materials. AB - New concepts on the design and synthesis of crystalline metal-organic frameworks (MOFs) have made them a subject of considerable interest in the growing field of materials science. By creating larger cavity sizes by a nearly infinite combination of metal nodes and organic linkers, many innovative characteristics of microporous MOFs have been revealed. The primary goal of this perspective article is to highlight the frontiers in the development of giant MOFs that are deliberately constructed from metallated or metal-free bulky scaffolds. Incorporating these types of distinct bulky ligands into giant MOFs may lead to MOFs with a large cavity size, intriguing properties and new framework topology. Emerging applications of these materials in catalysis, adsorption, and sensors are also discussed. PMID- 22421743 TI - Carbon-gold core-shell structures: formation of shells consisting of gold nanoparticles. AB - Carbon spheres were obtained via the Stober method using phenolic resin followed by carbonization. Spherical carbon-gold core-shell particles were fabricated by deposition of gold nanoparticles on the modified surface of carbon spheres. PMID- 22421745 TI - A randomized study of pharmacokinetics, efficacy, and safety of 2 raltegravir plus atazanavir strategies in ART-treated adults. AB - BACKGROUND: New antiretroviral drug classes provide opportunities to explore novel regimens. METHODS: HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (Cmin) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up. RESULTS: Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C(min) [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C(min) [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable. CONCLUSIONS: In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h. PMID- 22421747 TI - Patient attrition between diagnosis with HIV in pregnancy-related services and long-term HIV care and treatment services in Kenya: a retrospective study. AB - BACKGROUND: There has been little attention, until recently, to linking women who test HIV positive in pregnancy-related services to long-term HIV care and treatment services. METHODS: A retrospective review of routine hospital data was carried out in 2 hospitals in Kenya. Associations between available demographic information and uptake of HIV-related services within 6 months of HIV diagnosis in pregnancy-related services were assessed using logistic regression. Kaplan Meier survival analysis was used to assess time between HIV diagnosis and registration at the HIV clinic. Referrals between pregnancy-related and HIV related services were observed. RESULTS: At Naivasha hospital, the proportion of women registering at the HIV clinic within 6 months was 17.2% (153 of 892); at Gilgil hospital, it was 35.4% (84 of 237). Highly active antiretroviral therapy (HAART) was initiated by 40% and 27% of known eligible women in Naivasha and Gilgil, respectively. Non-systematic registration of clients on first contact at the HIV clinic, and restricted availability of services due to costs and opening hours were observed. In Naivasha, year, attendance at multiple pregnancy-related visits, and attendance at antenatal care in Naivasha hospital were associated with registration at the HIV clinic. In Gilgil, year, attendance at multiple pregnancy-related visits, and women being in their first pregnancy were associated with the outcome. CONCLUSIONS: Only 4% of women estimated to need HAART for their own care initiated HAART within 6 months of HIV diagnosis. Challenges associated with providing longitudinal care are especially evident in the context of high population mobility. Innovation in service delivery is required to improve uptake of services. PMID- 22421746 TI - HIV replication, inflammation, and the effect of starting antiretroviral therapy on plasma asymmetric dimethylarginine, a novel marker of endothelial dysfunction. AB - BACKGROUND: HIV infection is associated with premature development of cardiovascular disease. Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce cardiovascular disease risk. METHODS: A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40 ligand (sCD40L), and P-selectin levels. RESULTS: At study entry, median (interquartile range) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) MUg/mL, 251 (135-696) MUmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n = 114), participants randomized to immediate ART (n = 134) had 10.3% lower ADMA levels (P = 0.003) at 12 months; treatment differences in sCD40L (95% confidence interval: -17% to 44%; P = 0.53) and P-selectin (95% confidence interval: -10% to 10%; P = 0.95) were not significant. The difference in ADMA for those assigned immediate ART compared with those assigned ART deferral was greater among younger patients and those with higher levels of high-sensitivity C-reactive protein and D-dimer (P <= 0.05 for interaction for both) but not HIV RNA level at baseline (P = 0.51). DISCUSSION: ART initiation leads to declines in ADMA levels, a marker of nitric oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that upregulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research. PMID- 22421748 TI - Sexual risk behaviors, circumcision status, and preexisting immunity to adenovirus type 5 among men who have sex with men participating in a randomized HIV-1 vaccine efficacy trial: step study. AB - BACKGROUND: The Step Study found that men who had sex with men (MSM) who received an adenovirus type 5 (Ad5) vector-based vaccine and were uncircumcised or had prior Ad5 immunity, had a higher HIV incidence than MSM who received placebo. We investigated whether differences in HIV exposure, measured by reported sexual risk behaviors, may explain the increased risk. METHODS: Among 1764 MSM in the trial, 726 were uncircumcised, 994 had prior Ad5 immunity, and 563 were both uncircumcised and had prior Ad5 immunity. Analyses compared sexual risk behaviors and perceived treatment assignment among vaccine and placebo recipients, determined risk factors for HIV acquisition, and examined the role of insertive anal intercourse in HIV risk among uncircumcised men. RESULTS: Few sexual risk behaviors were significantly higher in vaccine versus placebo recipients at baseline or during follow-up. Among uncircumcised men, vaccine recipients at baseline were more likely to report unprotected insertive anal intercourse with HIV-negative partners (24.9% vs. 18.1%; P = 0.03). Among uncircumcised men who had prior Ad5 immunity, vaccine recipients were more likely to report unprotected insertive anal intercourse with partners of unknown HIV status (46.0% vs. 37.8%; P = 0.05). Vaccine recipients remained at higher risk of HIV infection compared with placebo recipients (hazard ratio = 2.8; 95% confidence interval, 1.2-6.8) controlling for potential confounders. CONCLUSIONS: These analyses do not support a behavioral explanation for the increased HIV infection rates observed among uncircumcised men in the Step Study. Identifying biologic mechanisms to explain the increased risk is a priority . PMID- 22421749 TI - Training mouse pathologists: ten years of workshops on the Pathology of Mouse Models of Human Disease. PMID- 22421750 TI - Regulatory forum opinion piece: obligatory microscopic examination of intermediate dose groups in non-rodent toxicity studies--is it necessary? AB - In non-rodent toxicity studies supporting pharmaceutical or chemical product registration, the value of histopathology evaluation of all tissues from all animals from all dose groups is an ongoing discussion topic among pathologists. This manuscript documents an examination of this topic through a retrospective review of internal nonclinical study data from non-rodent toxicity studies performed at three pharmaceutical companies (Abbott Laboratories, Eli Lilly, and Pfizer, Inc.) and an informal survey of the current practices within the toxicological pathology community. The retrospective review of 325 non-rodent studies in which all organs in all dose groups were examined revealed no evidence that risk assessment would have changed if only the control and high-dose animals and target organs only in intermediate dose groups had been examined. One study had target tissues in a lower-dose group that were not identified in the high dose group; however, there was no impact on the overall study interpretation. The recently revised European Medicines Agency guideline regarding repeated-dose toxicity studies encourages the examination of all tissues at all dose levels in non-rodent studies. In conclusion, the evaluation of all tissues from all animals may not be justified as a routine practice; however, regulatory guidance with input from toxicologic pathologists will influence these policy decisions. PMID- 22421751 TI - Predictors of survival in sepsis: what is the best inflammatory marker to measure? AB - PURPOSE OF REVIEW: Sepsis is relevant due to its high morbidity and mortality. For both sepsis diagnosis and outcome prediction many biomarkers have been described in the literature. Most of these markers are objects of scientific interest rather than being introduced into daily clinical practice. However, due to their unspecific character and their insufficient predictive value for the individual person, research focus is still on new aspects in sepsis-related biomarkers. RECENT FINDINGS: Beyond the widely used acute-phase proteins C reactive protein (CRP) and procalcitonin (PCT), many new molecules have been studied deriving from different organs or cells affected, due to the systemic nature of sepsis. Cytokines, coagulation factors/characteristics, vasoactive hormones, and several others have been recently proved to be relevant in sepsis syndrome and probably useful for outcome prediction. However, single time point measurements may be less predictive than consideration of the time-dependent course of parameters. Clinical decision just based on a biomarker is still not feasible because of the huge inter-individual differences in the inflammatory response. SUMMARY: Many biomarkers display relevant correlation with the clinical outcome of patients with severe sepsis and septic shock. Consideration of their time courses may be more reliable than absolute levels. Clinical decision should not be based only on biomarkers but organ dysfunctions, for example, should also be taken into account. PMID- 22421752 TI - Managing possible antibiotic allergy in children. AB - PURPOSE OF REVIEW: In children, allergic reactions to antibiotic are rare and several recent publications confirmed that they are clearly overdiagnosed, representing a major public health problem. Highlighting the most recent literature, the present review addresses the management of children with a possible antibiotic allergy. RECENT FINDINGS: In diagnosis of antibiotic allergy, the patient's history is central although not sufficient. In case of suspicion of an allergy, the child should be referred to an allergist in order to perform a complete allergy workup, based on carefully selected diagnostic tests depending on whether an immediate or a nonimmediate reaction is suspected. The antigen challenge test remains the gold standard and has gained in importance, particularly in children presenting a benign rash while taking antibiotic treatment. However, this test potentially exposes individuals to a significant risk of severe reaction and has relevant cost and is time consuming. Several new diagnostic tools are currently under investigation and provide promising results. SUMMARY: Accurate diagnosis of antibiotic allergy is important not only to prevent serious or even life-threatening reactions, but also to avoid unnecessary drug restriction associated with increased resistance and health costs. PMID- 22421753 TI - The function of neutrophils in sepsis. AB - PURPOSE OF REVIEW: Neutrophils are an essential arm of the innate immune response. In patients with sepsis, reprogramming of neutrophil occurs, manifest by impaired recruitment of neutrophils to sites of infection, abnormal accumulation of neutrophils to remote sites, and dysregulation of neutrophil effector responses. This review examines the mechanisms underlying dysregulated neutrophil trafficking and function during sepsis. RECENT FINDINGS: Mechanisms governing neutrophil function in sepsis are complex. Bacterial products, cytokines/chemokines, leukotrienes, and immunomodulatory hormones can modulate neutrophil migratory responses during sepsis via induction of cytoskeletal changes, disruption of polymorphonuclear leukocyte (PMN)-endothelial cell interactions, and alterations in G-protein-coupled receptor expression or signaling. Impaired chemotactic responses and alterations in neutrophil function can occur as a result of dysregulated PMN G-protein-coupled receptor and Toll like receptor expression and/or signaling. As sepsis evolves, neutrophil gene expression is altered, leading to suppression of proinflammatory and immunomodulatory genes, as well as decreased production of reactive oxygen species. Neutrophil extracellular traps are produced to contain and kill invading pathogens, but can paradoxically promote further tissue damage. SUMMARY: Neutrophil migration is a coordinated process that is altered at multiple stages during sepsis. In combination with impaired neutrophil function, these alterations culminate in defective innate immunity in septic patients. Defining the mechanisms involved and strategies to interrupt these deleterious responses requires further investigation. PMID- 22421754 TI - Unsolved problems in the approach to pediatric community-acquired pneumonia. AB - PURPOSE OF REVIEW: This review discusses unsolved problems concerning pediatric community-acquired pneumonia (CAP) and identifies the areas of research that need to be developed. RECENT FINDINGS: Diagnosing pediatric CAP and the required hospitalization are difficult problems especially in the presence of mild signs and symptoms. It is frequently not possible to identify the cause of this disease, and this explains why antibiotics are unnecessarily prescribed in some cases. The treatment recommendations for severe CAP are better defined than those for mild and moderate CAP. SUMMARY: It is possible to prepare recommendations for most of the problems that emerge in severe cases of pediatric CAP even though its cause can also be difficult to identify. However, the recommended approach to mild or moderate cases is always based on mainly moderate or poor quality evidence. There is an urgent need for further studies aimed at defining first line and second-line antibiotic therapy for mild and moderate CAP. In the absence of new data, it is necessary to be aware that a substantial number of patients will not be optimally treated. PMID- 22421755 TI - New fluoride-promoted hypoiodite-catalytic oxidative cycloetherification to aromatic spiroketals. AB - A new catalytic application of hypoiodite reagents generated in situ from iodide ions is found, which succeeded in the synthesis of bisbenzannelated spiroketal cores for the first time. Fluoride was proven to be obligatory for this spiroketalization, which is the first fluoride-promoted oxidative cycloetherification to aromatic spiroketals. PMID- 22421756 TI - [The importance of psycho-oncology]. AB - Cancer patients not only exhibit physical care problems, but also have various psychological, social, and existential problems which cause stress that can induce psychological disorders. Psychological distress causes suffering in patients and negatively impacts their treatment. Therefore, appropriate interventions are required. Family caregivers also suffer from mental and physical burdens that cause poor health, leading them to being called "second order patients," and necessitating their own treatment and care. Thus, cancer treatment involves biological and humanistic approaches. Psycho-oncology deals with the humanistic aspects of cancer treatment to help reduce the psychological burden of patients. Bereavement is one of the most stressful events that a family experiences. Intervention is sometimes needed for mental, physical, and social reactions to grief in the family. Bereavement care, "postvention," is considered effective for reducing the family's stress. PMID- 22421757 TI - [Borderline resectable pancreatic cancer - a definition and effective treatment strategy]. AB - The survival benefit of extended surgery for advanced pancreatic cancer has been denied by four randomized controlled trials. However, there still is confusion and conflict over the definition and effective treatment strategy for so-called locally advanced or borderline resectable pancreatic cancer. Although there are a number of reports that showed outcomes of preoperative chemotherapy or chemoradiotherapy for this disease, the definitions and treatment regimens described in these studies vary. Moreover, all of the studies were Phase I / II trials or retrospective analysis, and there is no Phase III trial currently focused on this issue. It is urgently necessary to establish an international consensus on the definition of borderline resectable pancreatic cancer. The usefulness of neoadjuvant treatment for this disease should also be elucidated in future clinical trials. In this review article, we discuss the current understanding and definition of borderline resectable pancreatic cancer, and the value of neoadjuvant treatment strategy for treating it. PMID- 22421758 TI - [Radiological evaluation of pancreatic ductal adenocarcinoma]. AB - Curative resection is one of the key treatments that influences the survival of pancreatic ductal adenocarcinoma patients. For curative resection, and to avoid unnecessary resection, it is important to diagnose and find the stage of pancreatic carcinoma correctly. CTis the most widely available and most validated imaging modality for this purpose. In this article, we reviewed the effective CTprotocols for detecting pancreatic carcinoma and the CTimaging findings of pancreatic carcinoma that will effect the resectability of the tumor. We also reviewed advantages and disadvantages of other imaging modalities, and imaging findings of some pancreatic carcinomas other than ductal adenocarcinoma. PMID- 22421759 TI - [Pancreatic ductal carcinoma concomitant with intraductal papillaly mucinous neoplasm]. AB - IPMN is a slow-growing tumor and has a good prognosis, but is very often associated with a high incidence of pancreatic ductalcarcinoma(DC). Unlike IPMN, DC progresses rapidly, and has a poor prognosis. However, DC concomitant with IPMN has a better prognosis than DC without IPMN. The reason for the good prognosis of the former is undetermined, but perhaps it is the early detection of DC or its not so malignant behavior. It is important to thoroughly examine the entire pancreas for the potentialco -occurrence of DC in patients with IPMN. PMID- 22421760 TI - [Laparoscopic surgery for pancreatic cancer]. AB - Laparoscopic distal pancreatectomy is currently in widespread use because of its technical simplicity, although laparoscopic pancreaticoduodenectomy is practiced in only a limited number of surgical institutions due to the associated technical difficulties especially at reconstruction. The indication for the treatment of pancreatic cancer by a laparoscopic procedure remains controversial. Because pancreatic cancer is already advanced at the time of diagnosis in many cases, it requires a difficult radical operation in terms of lymphadenectomy with nerves plexus in laparoscopic surgery. The oncologic clearance of pancreatic resection may be achievable by laparoscopic surgery, although longer follow-up and larger series of treatment are still needed. PMID- 22421761 TI - [Systemic chemotherapy and chemoradiotherapy for advanced pancreatic cancer]. AB - Currently, we are able to use S-1 with gemcitabine and erlotinib, as well as gemcitabine alone, as first-line therapy for advanced pancreatic cancer. In addition, a clinical trial of FOLFIRINOX is underway in Japan. On the other hand, chemoradiotherapy is considered to be one of the treatments of choice for locally advanced pancreatic cancer. This review summarizes current knowledge about non surgical treatment for advanced pancreatic cancer, mainly based on the results of recent clinical trials. PMID- 22421762 TI - [Multidisciplinary therapy for pancreatic cancer - clinical impact for preoperative therapy and peptide vaccine therapy]. AB - Pancreatic cancer survival is poor for those with high-grade malignancy, so multidisciplinary therapy is required for pancreatic cancer patients. Borderline resectable pancreatic cancer patients, according to the National Comprehensive Cancer Net- work(NCCN), have a high incidence of R1/2 resection, which demonstrates poor survival. It is thought that not only postoperative therapy but also preoperative therapy is essential to improve the survival of advanced pancreatic cancer patients. Preoperative chemoradiotherapy leads to R0 resection, resulting in improved survival of borderline resectable pancreatic cancer patients. Metastatic disease survival might be improved by intensive chemotherapy, and super-responder chemotherapy might be performed for resection, which means the new concept of adjuvant chemotherapy. On the other hand, antigenspecific CD8-positive CTL is generated by stimulation of peptide. Three clinical trials are on-going using OCV-101, OCV-105, and OTS-102, respectively. The development of a peptide vaccine used as a medicine is anticipated. PMID- 22421763 TI - [The importance of p53 and ras mutation as predictive markers for adjuvant chemotherapy in non-small-cell lung cancer]. AB - OBJECTIVE: A previous large, randomized, control trial(JBR.10)revealed that adjuvant chemotherapy with cisplatin(CDDP) and vinorelbine(VNR)was effective for non-small-cell lung cancer(NSCLC). It was also reported that adjuvant chemotherapy was not effective for p53-negative or K-ras mutation-positive patients. To clarify whether p53 and ras statuses are true predictive markers for chemotherapy with cisplatin, chemosensitivity was examined using an in vitro drug sensitivity assay. MATERIALS AND METHODS: Surgically resected fresh tumor specimens obtained from 27 patients at our institute with NSCLC were used for this study. Histoculture Drug Response Assay(HDRA)was applied to evaluate the chemosensitivity of CDDP and VNR in these specimens. p53 expression was evaluated by immunohistochemistry, and K-ras mutation by direct sequencing. RESULT: Four of the 27 patients were positive for K-ras mutation. The inhibition rate of CDDP was 54+/-5% for K-ras mutation positive-patients, and 50+/-13% for negative-patients. There was no significant difference between these two groups. p53 overexpression was observed in 14 patients, but not in 13 patients. The inhibition rate of CDDP was 50+/-12% for p53- overexpressed patients, and 50+/-12% for patients not overexpressed. The inhibition rate of VNR was 36+/-17% for p53- overexpressed patients, and 33+/-14%for patients not overexpressed. As for 8 adenocarcinoma patients, the inhibition rate of CDDP of p53-overexpressed patients(59+/-8%)was significantly(p=0. 018)higher than that of patients not overexpressed (45+/-9%). p53 overexpression may be a predictive marker for chemotherapy using CDDP in lung adenocarcinoma. CONCLUSION: p53 overexpression may be a possible predictive marker for adjuvant chemotherapy using CDDP in NSCLC. PMID- 22421764 TI - [Alternate-day oral therapy with S-1 for adjuvant chemotherapy of gastric cancer]. AB - Postoperative adjuvant chemotherapy with S-1 is a standard treatment for several digestive cancers. We conducted alter- nate-day oral therapy as postoperative adjuvant chemotherapy with S-1, for 31 patients with pathological stage II / IIIgastric cancer for whom radical resection had been performed. We examined the effects, the rate of compliance with all of the dosing instructions, cancer recurrence, and the survival rate with S-1 by the administration method for 31 cases. Twenty-eight patients(90. 3%)could be administered S-1 for one year. Those with side effects were admitted in 4 cases(13%). Those with side effects of grade 3 or more were not admitted. The 3-year survival rate was obtained; stage II 91%, and stage III 67% in gastric cancer. Four patients had recurrences at; the rate of 13%. In conclusion, the number of side effects was decreased, and a high rate of compliance with all dosing instructions was achieved in alternate-day oral therapy with S-1, compared with the daily oral method. This method can be a safe and useful way to administer S-1 oral therapy. PMID- 22421765 TI - [Oral capecitabine as postoperative adjuvant chemotherapy in stage III colon cancer patients]. AB - Capecitabine(Xeloda(r))has been a global standard drug for the treatment of colon cancer since large randomized controlled trials demonstrated its efficacy and safety in treating patients suffering from the disease. Few studies have been conducted to assess the effects of oral capecitabine treatment on Japanese patients. Therefore, we conducted this study to evaluate oral capecitabine as postoperative adjuvant chemotherapy in 50 patients who underwent surgery for stage III colon cancer at our department. Patients received an 8 courses treatment with capecitabine during the study, and the incidence of adverse events, treatment completion rate, and treatment compliance were assessed. Adverse events were reported in a total of 46 patients(92%). The most common adverse event was hand foot syndrome(HFS), reported in 39 patients(78%), whereas bone-marrow toxicity and diarrhea were reported in as few as 2(4%)and 3(6%)patients, respectively. Both these events were mild in severity, and no patients required hospitalization, nor were they associated with treatment related deaths. The median treatment duration was 8 courses ranging from 3 to 8 courses, and the 8 courses treatment completion rate was 96%. The relative dose intensity, which was used as a treatment compliance index, is expressed as the actual dose taken by the patient divided by the dose planned at baseline. The median and mean of the relative dose intensity were 100%(ranging from 37% to 100%)and 93%, respectively. The results of this study showed that the safety profile of oral capecitabine therapy was generally favorable, with a lower incidence and lesser severity of life-threatening bone-marrow toxicity and diarrhea, although the treatment is still associated with frequent HFS. This is the great advantage of capecitabine when it is used as postoperative adjuvant chemotherapy for gastrointestinal cancer. Indeed, a satisfactory treatment completion rate was achieved in this study while maintaining a sufficient dose and treating HFS, by reducing the dose, interrupting treatment, or providing appropriate corrective measures. PMID- 22421766 TI - [High incidence-rate of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy (FEC100)]. AB - BACKGROUND: Oral mucositis is a frequent complication, but is poorly studied among patients with solid tumors. The purpose of this study is to clarify the incidence rate of oral mucositis in Japanese breast cancer patients receiving anthracycline-based chemotherapy(FEC100). METHODS: From June 2007 to July 2008, 61 breast cancer patients eligible for this study received anthracycline-based chemotherapy(FEC100: 5-FU 500mg/m / / 2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)at National Kyushu Cancer Center and Iwate Medical University Hospital. The incidence rate and grade of oral mucositis were evaluated in these patients. RESULTS: The cumulative incidence of oral mucositis was about 50%. Episodes of oral mucositis were more common during courses with febrile neutropenia than during courses without it(75. 0% vs 44. 9%, p=0. 12). The reduction of oral mucositis was only 13. 6% after administering the steroidal ointment and/or mouthwash, including sodium azulene sulfonate. CONCLUSIONS: New methods are needed to prevent and treat oral mucositis in patients receiving anthracycline- based chemotherapy(FEC100). PMID- 22421767 TI - [Survey on oncologists-provided information on treatment-related infertility to breast cancer patients]. AB - PURPOSE: Treatment-related infertility is an important issue facing breast cancer survivors of childbearing age. A previous study at the National Cancer Center Hospital between 2000 and 2004 analyzed 136 postoperative breast cancer patients under 40 years old, and found that only 7% of them had been provided with information on fertility-related issues by their treating physicians. However, the way in which information is shared may have changed, given the recent publication of national and international guidelines on fertility issues in cancer patients, and we hypothesized that there will be an increase in the percentage of cases in which information about fertility-related issues is provided. METHODS: We retrospectively analyzed patients 40 years old or younger who underwent surgery for primary breast cancer in this hospital between 2007 and 2009. We assessed patients' and oncologists' backgrounds, pathological stage, treatment plans, and whether or not oncologists provided explanations regarding fertility-related issues. RESULTS: One hundred cases were analyzed. Five percent, 15%, and 80%of patients were < 30, 30-35, and $gt;35 years old, respectively. Sixty-one percent of patients had partners, while 29%had prior deliveries. Information on fertility-related issues was provided to 56% of patients. Significant factors influencing whether information was provided were patients' reproductive history (odds ratio(OR): 5. 717, 95% confidence interval(CI): 1.752- 18.66, p=0. 004) and recommended treatment(OR: 24.22, CI: 3.150-186. 2, p=0. 017). By contrast, oncologists' background( specialty, gender, and duration of career as a physician)was not significant. The frequency with which treatment plans were changed did not correlate statistically with the provision of information on fertility-related issues. CONCLUSIONS: Information on treatment related infertility is now provided much more frequently than in the past. We should encourage both patients and medical professionals to increase their awareness about this important issue. PMID- 22421768 TI - [Three-day-type transdermal fentanyl patch conversion by rapid titration method with short-acting oral oxycodone for cancer pain]. AB - This study compared the efficacy and safety of a 3-day-type transdermal fentanyl patch conversion by the rapid titration method to short-acting oral oxycodone for cancer pain.We evaluated seven hospitalized cancer patients who had moderate to severe cancer pain.Pain intensity was rated using an 11-point(0-10)numerical rating scale(NRS).All 7 patients initially reported their pain intensity at rest as NRS>=4 during treatment by Non-Steroidal Anti-Inflammatory Drugs(NSAIDs).Short - acting oral oxycodone(OxiNorm(r))5 mg was administered to all patients.One hour after short-acting oral oxycodone was administered, pain assessment was carried out using NRS by the author.Short -acting oral oxycodone was administered four times a day periodically, and as a rescue dose.If the total daily dose of short acting oral oxycodone was stable for 2 days, we switched to the 3-day-type transdermal fentanyl patch.The optimal dosage of the 3-day-type transdermal fentanyl patch was determined by titration of short-acting oral oxycodone.All 7 patients reported mild levels(NRS<=2)of cancer pain for 2 days.No serious side effects were reported.The 3-day-type transdermal fentanyl patch conversion by the rapid titration method with short-acting oral oxycodone can be accomplished safely and effectively for patients with moderate cancer pain. PMID- 22421769 TI - [Assessment of health-related quality of life in cancer outpatients treated with chemotherapy]. AB - PURPOSE: Few studies have been conducted to elucidate the health-related quality of life(HR-QOL)of cancer outpatients treated with chemotherapy. In this study, we attempted to determine the physical and psychological distress of cancer outpatients treated with chemotherapy. METHODS: Two-hundred and ninety-six outpatients with various malignancies, including malignant lymphoma, and esophageal, gastric, pancreatic, colon, lung, breast, ovarian, uterine and skin cancers, were investigated using the Japanese version of the M. D. Anderson symptom inventory from March through June 2010 in Tokyo Medical University Hospital. RESULTS: The results of the survey questionnaire indicated that 59 patients suffered from fatigue, 56 experienced numbness or tingling, 48 felt drowsy, 39 had low moods, 40 felt distressed, 38 had no appetite, 38 had dry mouth, 37 were in pain, 37 had disturbed sleep, 31 had shortness of breath, 24 had nausea, 17 suffered from vomiting, and 13 patients had memory problems. Furthermore, these symptoms interfered with work(65 patients), walking(56 patients), mood(52 patients), life enjoyment(49 patients), general activity(49 patients), and relationships with other people(42 patients). Medications prescribed for HR-QOL control were non-steroidal anti-inflammatory drugs(93 patients), morphine(32 patients), and adjuvant analgesics(47 patients). CONCLUSION: The present findings may help in the development of management strategies for physical and psychological distress, and improve HR-QOL of cancer outpatients treated with chemotherapy. PMID- 22421770 TI - [Assessment of psychological distress in cancer outpatients treated with chemotherapy]. AB - PURPOSE: Few studies have been conducted to elucidate the psychological distress of cancer outpatients being treated with chemotherapy. In this study, we attempted to determine the types of psychological distress endured by cancer outpatients being treated with chemotherapy. METHODS: We investigated 194 outpatients with various malignancies, including hematological, esophageal, gastric, pancreatic, colon, lung, breast, ovarian, uterine and skin cancers, using the Japanese version of the Self-Rating Depression Scale, from June through December 2010, in our hospital. RESULTS: The results of the survey questionnaire indicated suspected adjustment disorders in 84 patients(43. 3%)and major depression in 14 patients(7. 2%). Medications prescribed for psychological distress were antianxiety drugs(18 patients: 9. 3%), antidepressant drugs(2 patients: 1. 0%), and sleeping pills(50 patients: 25. 8%). CONCLUSION: Our findings may be useful for the development of management strategies for psychological distress, and we suggest that there is a need for improvement in the quality of life of cancer outpatients being treated with chemotherapy. PMID- 22421771 TI - [A case of advanced lung adenocarcinoma with cavity formation shrunken by bevacizumab added on the 3rd course of 6th-line chemotherapy]. AB - A 65-year-old man was pointed out to have an abnormal lung shadow by chest radiograph in a medical examination in 2007. An extensive examination diagnosed him as a case of advanced lung adenocarcinoma. He was treated by chemotherapy up to the 5th-line(cisplatin+docetaxel->CPT-11+S-1->amrubicin >gemcitabine+vinorelbine->pemetrexed), and the evaluation after the 5th-line treatment revealed disease progression. As he still maintained good performance status, the 6th- line treatment with carboplatin(AUC6, day 1)+paclitaxe(l 200mg/m2, day 1)(Q3W)was administered in March, 2010. The tumor size had been increasing slightly after 2 courses of chemotherapy, although it was within the range of stable disease. Therefore, bevacizumab(15mg/kg, day 1)was added after the 3rd course of treatment, and the tumor began shrinking obviously with cavity formation. Although the positioning of bevacizumab has not been established after 2nd-line treatment for advanced non-small cell lung carcinoma, we experienced a case of good tumor response by adding the bevacizumab in the middle of the 6th line chemotherapy. PMID- 22421772 TI - [A case of adenocarcinoma of the lung with malignant pleural effusion in elderly patient treated effectively by pemetrexed and carboplatin]. AB - An 83-year-old male with left chest pain and dyspnea was referred to our hospital. A left upper lung tumor(f3. 6 cm in diameter)and pleural effusion in enhanced thoracic CT with suspicion of malignant pleural effusion were pointed out in June, 2009. There were no swelling lymph nodes and distant metastases by various imaging methods. The diagnosis of pleuritis carcinomatosa was obtained by Video-Assisted Thoracic Surgery(VATS). Intraoperative intrapleural hypotonic treatment was given at the same time. Cytology specimens revealed adenocarcinoma. We diagnosed Stage IV(cT2aN0M1a)adenocarcino- ma of the lung, and treated the patient with pemetrexed(PEM)/carboplatin(CBDCA)chemotherapy. He received 4 courses of chemotherapy. Thereafter, the pleural effusion improved, and the tumor lesion disappeared. There was no abnormal accumulation of fluorodeoxyglucose(FDG)in the positron emission tomography CT(PET-CT)scan, and he was doing well without any sign of recurrence twenty-two months after treatment. This was a rare case of adenocarcinoma of the lung with malignant pleural effusion treated effectively by PEM/CBDCA chemotherapy, a safe treatment for an elderly patient. PMID- 22421773 TI - [A case of elderly advanced squamous cell lung carcinoma successfully treated with nedaplatin and S-1 combination chemotherapy]. AB - A 7 4-year-old male was referred to our hospital for an abnormal chest shadow pointed out by a medical examination. A chest computed tomography revealed a tumor shadow 39 X 32mm in size in his left upper lobe in January, 2010. Pathological examination of biopsy specimens showed squamous cell carcinoma of the lung. Although there was no distant metastasis, multiple metastases to mediastinal lymph nodes was noted. He was diagnosed as Stage III A(cT2aN2M0). Considering his age and the histology of the disease, systemic chemotherapy with nedaplatin and S-1 was performed. The diameter of the primary lesion was decreased from 39mm to 18mm after 4 courses of chemotherapy, and was considered as partial response (PR)according to the RECIST criteria. The adverse events were grade 2 appetite loss, grade 3 neutropenia, and grade 2 thrombocytopenia. Recently, various new agents for treating non-squamous cell lung carcinoma have been developed, but there has been little progress in the treatment of squamous cell lung carcinoma. We experienced a patient with advanced squamous cell lung carcinoma who responded with CDGP/S-1 combination chemotherapy. We are now conducting a phase I / II clinical study to verify the usefulness of this regimen against advanced squamous cell lung carcinoma. PMID- 22421774 TI - [A case of bronchioloalveolar carcinoma successfully treated with low-dose, alternate-day administration of erlotinib]. AB - Erlotinib is a selective epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor, which shows favorable antitumor activity against chemorefractory lung carcinoma, especially with EGFR gene mutations. We experienced a case in which oxy- genation and performance status improved in with low-dose erlotinib of 100mg/day administered every other day incidental- ly, although a dose of erlotinib 150mg/day daily is encouraged by the RECIST guideline. A 77-year-old male was diagnosed with bronchioloalveolar carcinoma(BAC)and given first-line combination chemotherapy of carboplatin and pemetrexed. However, antitumor activity was not satisfactory. His performance status(PS)was scored as 2 and home oxygen therapy (HOT)was introduced. As second-line chemotherapy, erlotinib was administered 100mg/day daily. However, the patient took the medication every other day at his own discretion, due to severe eruption and itching sensation. Since this case is classified as a nonmeasurable lesion according to the RECIST guideline, it was difficult to measure antitumor activity by tumor size. But improvement of oxygenation, with a performance status score of 0 and normalization of serum CEA level suggested that erlonitib administration of 100mg/day every other day showed antitumor activity. PMID- 22421775 TI - [A case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy]. AB - We report a case of breast cancer in a 58-year-old female patient. In 2005, she was hospitalized for therapy of left breast cancer. The tumor observed was accompanied by invasion of the skin and ribs. At the same time, multiple liver and bone metastases were also observed(solid tubular adenocarcinoma, ER(+), PgR(+/-), HER2(3+), T4NxM1, stage IV). She was started on radiation therapy and chemotherapy(paclitaxel+trastuzumab). While the liver and bone metastases remained unchanged, the primary focus became noticeably smaller. In the course of follow-up visits, we began to administer her paclitaxel biweekly. This treatment, however, worsened her liver metastases and led us to switch to combination chemotherapy with vinorelbine and capecitabine. After 6 courses of the therapy, her liver metastases disappeared and her tumor marker levels became normal. The combination chemotherapy was continued for 1 year and then followed by 18 months of chemotherapy with capecitabine alone until recurrence of liver metastases was observed. Capecitabine along with cyclophosphamide was orally administered, bringing her tumor marker levels down to the normal range again. After approximately 6 years from the start of treatment, the patient is still alive. PMID- 22421776 TI - [A case of recurrent breast cancer with brain metastases successfully treated with vinorelbine and anastrozole after multiple chemo-endocrine therapies]. AB - We report a case of recurrent hormone receptor-positive breast cancer with brain metastases that showed good response to vinorelbine(VNR)and anastrozole(ANA). A 49-year-old woman with a history of left breast cancer had initially undergone modified radical mastectomy, but was diagnosed with lung metastases 8 years postoperatively. Despite treatment with docetaxel and tamoxifen, multiple brain metastases were detected 10 years postoperatively. To achieve prompt improvement of neurological symptoms, surgical resection was performed for two large brain foci. Stereotactic radiosurgery using a gamma- knife was applied for the remaining multiple brain metastases. Histological examination identified the brain tumors as estrogen receptor-positive, HER2-negative metastatic breast cancer. Despite the use of cyclophosphamide, adriamycin and 5- fluorouracil(CAF therapy)and capecitabine, brain metastases recurred twice along with pleuritis carcinomatosis and bone metastasis. In addition to gamma-knife re-treatment, therapy was started with VNR and ANA. All metastatic sites including brain showed a good response to therapy with few adverse reactions, and no recurrence has been observed over 3 years. PMID- 22421777 TI - [Remarkable improvement in a patient with metastatic and locally advanced HER2 positive breast cancer treated with trastuzumab plus vinorelbine]. AB - A 39-year-old premenopausal nulliparous woman presented with severe pain in her right breast, bleeding and pus-like discharge, and a deep ulcer approximately 18 cm in diameter.Contralateral breast metastasis, bilateral axillary lymph node metastases, and multiple lung and bone metastases were detected on computed tomography.Five years previously she had undergone surgery for ovarian cancer and had prematurely discontinued adjuvant chemotherapy because of side effects. Following the administration of pain control, the patient received trastuzumab(Tr)plus vinorelbine(VNR)for her breast cancer as first-line therapy to avoid hair loss.The ulcer on her right chest wall underwent complete epithelialization and the patient's performance status improved from 3 to 0.The pus-like discharge, pain, bleeding, and odor from the breast resolved completely, and 5 months later, her quality of life had improved.The lung metastases also resolved completely.No adverse affects, including hematotoxicity and hair loss, were seen until treatment failure 12.5 months later. Second-line and third-line treatments were performed, but brain metastases developed, and the patient's overall condition deteriorated because of the development of ileus of unknown etiology.She died 21 months later.The patient received all therapies on an outpatient basis. Combination therapy using Tr and VNR is superior in safety and tolerability, and has been considered an option for first-line treatment of metastatic, locally advanced HER2-positive breast cancer. PMID- 22421778 TI - [A case of stage IVb cervical carcinoma in which survival was prolonged by two different chemotherapies and CCRT]. AB - Pulmonary metastasis from primary cervical carcinoma is rare, with an incidence of 4.16-7.7%. Chemotherapy is the most common treatment; however, the overall prognosis is poor. This case report describes a complete response to CCRT and TC therapy of cervical carcinoma metastatic to the lung. The patient, a 57-year-old woman, was initially diagnosed with FIGO clinical Stage IVb cervical carcinoma with lung metastasis, after presenting with vaginal bleeding. She had a 90 pack/year smoking history. She was initially treated with systemic chemotherapy(TC therapy: PTX, CBDCA 1 course)followed by concurrent chemoradiotherapy(CCRT)with weekly CDDP2 0mg/m2. She had a complete response of her pelvic disease as well as a decrease in the size of metastatic lesions. Following CCRT, she was scheduled to continue TC therapy, but was only able to complete two courses secondary to a myocardial infarction. A lung biopsy at that time showed no evidence of malignancy, and the patient has remained without any evidence of disease for the past six years. PMID- 22421779 TI - [A case of advanced gastric cancer responding to S-1 therapy, leading to pathologically complete response]. AB - Our patient was a 74-year-old man with abdominal pain. A gastrofiberscope revealed type 2 advanced gastric cancer. An abdominal computed tomography(CT)demonstrated liver and lymph node metastases. The No. 8a lymph node was 7 cm in diameter, and it invaded the head of the pancreas. Since a curative operation was deemed impossible, S-1 was administered orally for 28 consecutive days with a 14-day interval. After 2 courses of monotherapy, CT showed that metastatic lymph nodes were reduced and that liver metastases had mostly disappeared. After 8 courses, the primary lesion was scarred and the lymph node metastases were remarkably reduced. Therefore, we conducted distal gastrectomy and lymph node resection (D2). Histological findings revealed that there were no cancer cells in either the primary tumor or the lymph nodes, meaning that the resected lesions were Grade 3 in pathology. This rare case showed that S-1 monotherapy enabled curative surgery of unresectable gastric cancer with pathological CR. PMID- 22421780 TI - [A case of S-1-resistant resected advanced gastric cancer with para-aortic lymph node recurrence responding to bi-weekly CPT-11 and CDDP]. AB - A 64-year-old man with advanced gastric cancer who underwent a curative total gastrectomy(LM, Less, Type 3, 70*55 mm, por1>tub2>sig, pT3(ss), med, INF b, ly3, v3, pN3b(41/61), pPM0, pDM0, pT3N3bM0, Stage III B)followed by adjuvant chemotherapy(paclitaxel+S-1)a year ago, revealed an increasing level of serum CEA and para-aortic lymphnode (#16b1)recurrence on abdominal CT. He was given chemotherapy with low-dose weekday CDDP+S-1 for the recurrence, after which he failed to respond. Thereafter, he received 2nd-line chemotherapy with bi-weekly CPT-11+CDDP as a S-1- refractory regimen. 3 courses of the regimen reduced the serum CEA level accompanied by grade 3 of anemia. After recovery from the adverse event, another 4 courses at a 20% lower dosage for safety were administered. Complete response to the lymphnode was ensured on the abdominal CT with a reduced serum CEA level into the normal range. The patient has no signs of recurrence and has survived in fair condition for more than 5 years after the surgery. The combination treatment of biweekly CPT-11+CDDP can be a worthwhile regimen for patient with S-1-refractory recurrence of the resected advanced gastric cancer. PMID- 22421781 TI - [A case of gastric cancer treated with modified docetaxel, cisplatin and 5 fluorouracil(mDCF)with ingestion inability]. AB - The standard regimen of S-1 and cisplatin is not adaptable for patients with gastric cancer with an ingestion inability. A 74- year-old man was revealed to have unresectable gastric cancer with severe pyloric stenosis(cT4, cN3, cH1, cP0, cStage IV). He was treated with systemic chemotherapy using modified docetaxel, cisplatin and 5-fluorouracil(mDCF). He had manageable neutropenia(grade 3 and 4)during his treatment. CT findings after 3 courses showed reduced primary tumor and metastatic lesions. A curative operation was performed based on the effective response with downstaging. Palliative surgery was considered before receiving chemotherapy. mDCF therapy is one of the recommended options for gastric cancer with an ingestion inability. PMID- 22421782 TI - [A case of successful S-1 alternate-day administration for far-advanced remnant gastric cancer]. AB - A 81-year-old man presented with anemia. He received a distal gastrectomy for gastric ulcer as a 40-year-old, and was also diagnosed with prostate cancer with bone metastasis as an 80-year-old. He has been undergoing treatment with anti androgen therapy. Gastrointestinal endoscopic examination showed advanced gastric cancer, which was diagnosed as poorly differentiated adenocarcinoma. Computed tomography(CT)showed enlarged para-aortic lymph nodes. The clinical Stage was IV: cT3, N3, M1. He was treated with oral S-1 alternate-day administration of 100mg/day. The tumor in his remnant stomach shrunk in size by 3 months after beginning S-1 administration, and an endoscopic examination revealed a scar, but no cancer cells were found in a biopsy specimen of the scar tissue. Furthermore, CT scan showed that the swollen para-aortic lymph nodes were obviously reduced in size. As a result, we diagnosed this as a partial response to chemotherapy with S 1 alternate-day administration. No adverse events during the treatment were due to S-1 administration. His quality of life and poor food intake remarkably improved. S-1 alternate-day therapy demonstrated efficacy and tolerable toxicity even for a patient who was elderly and /or with poor performance status. S-1 can be managed safely on an outpatient basis without side effects for a long duration, and has been superior in terms of continuity of treatment. PMID- 22421783 TI - [Marked response to oral administration of UFT and leucovorin for liver metastases from colon cancer in an elderly patient]. AB - A83 -year-old man was admitted to our hospital for the treatment of advanced ascending colon cancer with liver metastases. He had initially undergone an ileocecal resection for ascending colon cancer. Subsequently, we started oral administration of UFT/LV(UFT 400mg/day, LV 75 mg/day, and 4 weeks of therapy followed by a week suspension of treatment). After 3 courses, his tumors responded well to treatment, and CT showed marked regression of liver metastases. After 10 courses, liver metastases had almost disappeared. Two years passed without any adverse events since UFT/LV therapy was started. These findings suggest that UFT/LV therapy is very safe and effective for elderly patients with unresectable colorectal cancer. PMID- 22421784 TI - [A case of resected rectal cancer with hepatic node and multiple liver metastases effectively treated by preoperative modified FOLFOX6 and sLV5FU2 chemotherapy]. AB - A 55-year-old male had complained of melena.Colonoscopy revealed a type 2 tumor at the rectum.CT demonstrated hepatic lymph nodes and multiple liver metastases(stage IV).Low anterior resection was performed(tub2, RsRa, circ, type 2, pSS, pN1, sH3, cHN1, sP0, cM0: fstage IV).The patient was treated with mFOLFOX6 and sLV5FU2 after operation.CT revealed a partial response after 14 courses of systemic chemotherapy.sLV5 FU2 therapy was converted to capecitabine because he experienced bone marrow suppression.CT showed that the liver metastases had enlarged but the hepatic lymph nodes disappeared.Right portal vein embolization was performed.After 4 weeks, right hepatectomy and hepatic lymph node dissection were performed.Preoperative chemotherapy with mFOLFOX6 seems beneficial as a neoadjuvant chemotherapy for hepatic lymph node-positive advanced colorectal cancer. PMID- 22421785 TI - [A case of pancreatic cancer with liver metastasis controlled effectively by chemotherapy based on chemosensitivity test and stereotactic body radiotherapy]. AB - A 5 5-year-old woman was admitted to our hospital for pancreatic cancer with liver metastasis. We performed pancreatoduodenectomy, D2 dissection, and partial liver resection. Tissue from a resected liver metastasis was submitted to a chemosensitivity test. Based on the test results, we performed systemic chemotherapy with paclitaxel and hepatic artery infusion with gemcitabine for lung and liver metastasis after surgery. Furthermore, we added stereotactic body radiation therapy(SBRT)(48 Gy/4 Fr)for 3 liver metastases that showed enlargement after chemotherapy. Effective control of recurrent tumors was possible for 2 years and 5 month, and she maintained normal daily activities. She died of peritoneal dissemination 3 years and one month after surgery. Combined modality therapy with anticancer agents based on a chemosensitivity test and SBRT may be one useful therapy for pancreatic cancer with distant metastases. PMID- 22421786 TI - Integration of B cell responses through Toll-like receptors and antigen receptors. AB - Unlike other immune cells, B cells express both an antigen-specific B cell receptor (BCR) and Toll-like receptors (TLRs). Dual BCR and TLR engagement can fine-tune functional B cell responses, directly linking cell-intrinsic innate and adaptive immune programmes. Although most data regarding B cell-specific functions of the TLR signalling pathway have been obtained in mice, the discovery of patients with a deficiency in this pathway has recently provided an insight into human B cell responses. Here, we highlight the importance of the integration of signalling pathways downstream of BCRs and TLRs in modulating B cell function, focusing when possible on B cell-intrinsic roles. PMID- 22421787 TI - The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. AB - How the immune system remembers a previous encounter with a pathogen and responds more efficiently to a subsequent encounter has been one of the central enigmas for immunologists for over a century. The identification of pathogen-specific memory lymphocytes that arise after an infection provided a cellular basis for immunological memory. But the molecular mechanisms of immunological memory remain only partially understood. The emerging evidence suggests that epigenetic changes have a key role in controlling the distinct transcriptional profiles of memory lymphocytes and thus in shaping their function. In this Review, we summarize the recent progress that has been made in assessing the differential gene expression and chromatin modifications in memory CD4(+) and CD8(+) T cells, and we present our current understanding of the molecular basis of memory T cell function. PMID- 22421789 TI - Synthesis of tetrasubstituted alkenes via metathesis. AB - Fully substituted olefin generation via metathesis is presented. Catalyst development, optimization of reaction conditions and substrate screening are included. In addition, asymmetric alkene metathesis, the cross metathesis reaction for this transformation and its application in natural products will be discussed. PMID- 22421790 TI - Synthesis of azanucleosides through regioselective ring-opening of epoxides catalyzed by sulphated zirconia under microwave and solvent-free conditions. AB - New azanucleosides were obtained using sulphated zirconia (ZS) as catalyst in the nucleophilic oxirane ring opening reaction of 1-allyl-3-(oxiran-2-ylmethyl) pyrimidine-2,4(1H,3H)-dione and 1-allyl-5-methyl-3-(oxiran-2-ylmethyl)-pyrimidine 2,4(1H,3H)-dione, with (S)-prolinol. The new templates were obtained with good yields following a route which exploits the reactivity of epoxides in the presence of sulphated zirconia as catalyst. The key step was carried out using microwave and solvent-free conditions and proceeds with high selectivity. PMID- 22421791 TI - Oxime esters of 2,6-diazaanthracene-9,10-dione and 4,5-diazafluoren-9-one as photo-induced DNA-cleaving agents. AB - Two series of oxime esters containing the 2,6-diazaanthracene-9,10-dione bis-(O benzoyloxime) and 4,5-diazafluoren-9-one O-9-benzoyloxime moieties have been synthesized and tested as photo-induced DNA cleaving agents. All these compounds were found to cleave DNA upon irradiation with 312 nm UV light. The structure activity relationship of these molecules for DNA cleavage was established. A plausible reaction mechanism is also proposed. PMID- 22421792 TI - Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes. AB - An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals--drugs, pesticides, and environmental pollutants- interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D 13C and 1D 15N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D 13C-NMR and 15N-NMR spectra caused an increase in the tenfold cross validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR techniques, providing an independent estimator that can increase confidence in a structure-activity assessment. When modeling was applied to hazardous environmental chemicals, it was found that up to 20% of them may be substrates and up to 10% of them may be inhibitors of the CYP3A4 and CYP2D6 isoforms. The developed models provide a rare opportunity for the environmental health branch of the public health service to extrapolate to hazardous chemicals directly from human clinical data. Therefore, the pharmacological and environmental health branches are both expected to benefit from these reported models. PMID- 22421793 TI - Modeling chemical interaction profiles: II. Molecular docking, spectral data activity relationship, and structure-activity relationship models for potent and weak inhibitors of cytochrome P450 CYP3A4 isozyme. AB - Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2-3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak inhibitors of CYP3A4 were used to train the models. Using these models, a synthetic majority rules consensus classifier was implemented, while the confidence of estimation was assigned following the percent agreement strategy. The classifier was applied to a testing set of 120 inhibitors not included in the development of the models. Five compounds of the test set, including known strong inhibitors dalfopristin and tioconazole, were classified as probable potent inhibitors of CYP3A4. Other known strong inhibitors, such as lopinavir, oltipraz, quercetin, raloxifene, and troglitazone, were among 18 compounds classified as plausible potent inhibitors of CYP3A4. The consensus estimation of inhibition potency is expected to aid in the nomination of pharmaceuticals, dietary supplements, environmental pollutants, and occupational and other chemicals for in-depth evaluation of the CYP3A4 inhibitory activity. It may serve also as an estimate of chemical interactions via CYP3A4 metabolic pharmacokinetic pathways occurring through polypharmacy and nutritional and environmental exposures to chemical mixtures. PMID- 22421794 TI - How medical students' behaviors and attitudes affect the impact of a brief curriculum on nutrition counseling. AB - OBJECTIVE: To evaluate a nutrition curriculum and explore the influence of medical students' own nutrition practices on its impact. METHODS: An anonymous survey was given to first-year medical students attending a required course immediately prior to and 2 weeks after a 2-hour interactive nutrition curriculum intervention in a large private urban medical school in New York, New York. Main outcomes included self-reported nutrition counseling confidence, ability to assess diet, and nutrition knowledge measured using 4-point Likert scales. RESULTS: One hundred eleven students completed surveys pre-curriculum (69%) and 121 completed them post-curriculum (75%). The authors found overall pre-post differences in dietary assessment ability (2.65 vs 3.05, P < .001) and counseling confidence (1.86 vs 2.22, P < .001). In addition to the curricular impact, students' nutrition-related behaviors and attitudes were positively associated with outcomes. CONCLUSIONS AND IMPLICATIONS: A nutrition curriculum for medical students improves students' nutrition counseling-related confidence, knowledge, and skills even when controlling for personal nutrition-related behaviors. PMID- 22421795 TI - Diastereoselective generation of triple-stranded helicates induced by gem dimethyl groups on a linker. AB - The diastereoselectivity of the self-assembly of bis(dipyrromethene) ligands with trivalent metals was improved by introducing gem-dimethyl groups to the linker. PMID- 22421796 TI - Silver triflate-copper(II) acetate cooperative catalysis in a cascade reaction for concise synthesis of 2-carbonyl H-pyrazolo[5,1-a]isoquinolines. AB - A cascade reaction of N'-(2-alkynylbenzylidene)hydrazide with allenoate in the presence of dioxygen co-catalyzed by silver triflate and copper(II) acetate under mild conditions is described, which provides an efficient approach to 2-carbonyl H-pyrazolo[5,1-a]isoquinolines. PMID- 22421797 TI - Evolutions of microbial degradation pathways for parent xenobiotic and for its metabolites follow different schemes. AB - BACKGROUND AND PURPOSES: The pathways used by microorganisms for the metabolism of every xenobiotic substrate are specific. The catabolism of a xenobiotic goes through a series of intermediate steps and lower intermediates (metabolites) appear in sequence. The structure of the metabolites can be similar to the parents due to kinship. The purposes of this study were to examine if the degradation pathways that were developed for a parent xenobiotic are effective to degrade the parent's lower metabolites, and if the reverse is true. MATERIALS AND METHODS: The xenobiotic substrates, 2,4-dichlorophenoxyacetic acid (2,4-D, the parent xenobiotic) and its metabolite 2,4-dichlorophenol (2,4-DCP), were independently subjected to acclimation and degradation tests by the biomasses of mixed-culture activated sludge and a pure culture of Arthrobacter sp. RESULTS: Activated sludge and Arthrobacter sp. that were acclimated to 2,4-D effectively degraded 2,4-D and the lower metabolites of 2,4-D, typically 2,4-DCP. During the degradation of 2,4-D, accumulations of the lower metabolites of 2,4-D were not found. The degradation pathways acquired from acclimation to 2,4-D are effective for all the metabolites of 2,4-D. However, pathways acquired from acclimation to 2,4-DCP are not effective in the degradation of the parent 2,4-D. CONCLUSIONS: Microorganisms acclimated to 2,4-D evolve their degradation pathways by a scheme that is different from the scheme the microorganisms employ when they are acclimated to the metabolites of 2,4-D. PMID- 22421798 TI - Response to W. Kramer: The human sex odds at birth after the atmospheric atomic bomb tests, after Chernobyl, and in the vicinity of nuclear facilities: comment (doi:10.1007/s11356-011-0644-8). AB - INTRODUCTION: This paper is in response to criticism of our article "The human sex odds at birth after the atmospheric atomic bomb tests, after Chernobyl, and in the vicinity of nuclear facilities" published in Environ Sci Pollut Res 18(5):697-707, 2011. METHODS: Our findings and methods concerning the disturbed human sex odds at birth have been criticized in this journal for being artifacts of data mining, that the concept of statistical significance was misunderstood, and that confounding factors have not been accounted for. Here, we show that this criticism has no basis. We applied well-established statistical methods to large official data sets, and confounding is less important at the level of secular sex odds trends in aggregated annual figures from countries or continents. RESULTS AND CONCLUSIONS: Moreover, our results are strengthened by recent findings concerning increased infant death sex odds in Germany and increased Down syndrome prevalence at birth across Europe after Chernobyl. Prompted by our studies, an official investigation in Lower Saxony, Germany, by the "Niedersachsisches Landesgesundheitsamt (NLGA)" confirmed our observation of severely escalated sex odds within 40 km distance from the nuclear storage site in Gorleben, Germany. PMID- 22421799 TI - Survey of phthalates, alkylphenols, bisphenol A and herbicides in Spanish source waters intended for bottling. AB - BACKGROUND, AIM AND SCOPE: Groundwaters and source waters are exposed to environmental pollution due to agricultural and industrial activities that can enhance the leaching of organic contaminants. Pesticides are among the most widely studied compounds in groundwater, but little information is available on the presence of phthalates, alkylphenols and bisphenol A. These compounds are used in pesticide formulations and represent an emerging family of contaminants due to their widespread environmental presence and endocrine-disrupting properties. Knowledge on the occurrence of contaminants in source waters intended for bottling is important for sanitary and regulatory purposes. So the aim of the present study was to evaluate the presence of phthalates, alkylphenols, triazines, chloroacetamides and bisphenol A throughout 131 Spanish water sources intended for bottling. Waters studied were spring waters and boreholes which have a protection diameter to minimize environmental contamination. MATERIALS AND METHODS: Waters were solid-phase extracted (SPE) and analysed by gas chromatography coupled to mass spectrometry (GC-MS). Quality control analysis comprising recovery studies, blank analysis and limits of detection were performed. RESULTS AND DISCUSSION: Using SPE and GC-MS, the 21 target compounds were satisfactorily recovered (77-124 %) and limits of quantification were between 0.0004 and 0.029 MUg/L for pesticides, while for alkylphenols, bisphenol A and phthalates the limits of quantification were from 0.0018 MUg/L for octylphenol to 0.970 MUg/L for bis(2-ethylhexyl) phthalate. Among the 21 compounds analysed, only 9 were detected at levels between 0.002 and 1.115 MUg/L. Compounds identified were triazine herbicides, alkylphenols, bisphenol A and two phthalates. Spring waters or shallow boreholes were the sites more vulnerable to contaminants. Eighty-five percent of the samples did not contain any of the target compounds. CONCLUSIONS: Target compounds were detected in a very low concentration and only in very few samples. This indicates the good quality of source waters intended for bottling and the effectiveness of the protection measures adopted in Spain. None of the samples analysed exceeded the maximum legislated levels for drinking water both in Spain and in the European Union. PMID- 22421800 TI - Effect directed analysis and mixture effects of estrogenic compounds in a sediment of the river Elbe. AB - INTRODUCTION: Endocrine disrupting chemicals (EDCs) are present in the environment and can have serious effects on humans and wildlife. For the establishment of environmental quality guidelines and regulation of EDCs, a better understanding and knowledge of the occurrence and the behavior of environmental EDCs is necessary. The aim of the present study was to comprehensively identify substances that are responsible for the estrogenic effect of an environmental sediment sample taken from the river Elbe/Germany. DISCUSSION: The estrogenic effect of the organic sediment extract was determined using the yeast-estrogen-screen (YES). The sample was fractionated by liquid chromatography (LC) for effect directed analysis. The composition of estrogen active fractions was further investigated by gas chromatography-mass spectrometry and high-resolution LC-MS analysis. The composition of the environmental sample was rebuilt with pure compounds in order to assess the partition of estrogenic activity caused by the identified compounds. The organic sediment extract showed an estrogenic potential of 1.9 +/- 0.4 ng/g ethinylestradiol equivalents in the sediment. The most prominent contaminants with an estrogenic potential were 17beta-estradiol, estrone, and 4-iso-nonylphenols, but other xenoestrogens like bisphenol A and stigmasterol could be found as well. A rebuild of the sample was measured in the YES in order to investigate mixture effects. About 67 % of the observed estrogenic effect in the sediment extract could be explained by a mixture which contained all identified compounds. Chlorophene (o-benzyl-p chlorophenol)-a widely used antiseptic that was also identified in the sediment extract-has xenoestrogenic properties in the YES that are in the range of other xenoestrogens like 4-n-nonylphenol. This is the first report on chlorophene acting as a xenoestrogen. PMID- 22421801 TI - Magnetic beads-based electrochemiluminescence immunosensor for determination of cancer markers using quantum dot functionalized PtRu alloys as labels. AB - A novel electrochemiluminescence (ECL) immunosensor for sensitive detection of human chorionic gonadotrophin antigen (HCG-Ag) was constructed using CdTe quantum dot functionalized nanoporous PtRu alloys (QDs@PtRu) as labels for signal amplification. In this paper, nanoporous PtRu alloy was employed as the carrier for immobilization of CdTe QDs and antibodies. Primary monoclonal antibody to alfa-HCG antigen (McAb(1)) was immobilized onto the surface of chitosan coated Fe(3)O(4) magnetic nanoparticles (Fe(3)O(4)/CS MNPs) by glutaraldehyde (GA) as coupling agent. Then McAb(1) could be easily separated and assembled on the surface of indium tin oxide glass (ITO) owing to their excellent magnetic properties with external magnetic forces holding the MNPs. Due to signal amplification from the high loading of CdTe QDs, 4.67-fold enhancements in ECL signal for HCG-Ag detection was achieved compared to the unamplified method (single QDs as labels). Under optimal conditions, a wide detection range (0.005~50 ng mL(-1)) and low detection limit (0.8 pg mL(-1)) were achieved through the sandwich-type immunosensor. The novel immunosensor showed high sensitivity and selectivity, excellent stability, and good reproducibility, and thus has great potential for clinical detection of HCG-Ag. In particular, this approach presents a novel class of combining bifunctional nanomaterials with preferable ECL properties and excellent magnetism, which suggests considerable potential in a wide range of applications for bioassays. PMID- 22421802 TI - Synthesis and properties of thienopyrrole based heteroacenes- indolodibenzothienopyrrole and dicarbazolodithienopyrrole. AB - We report the syntheses and properties of thienopyrrole based unsymmetrical and extended heteroacenes, which are isoelectronic with heptacene (30pi) and nonacene (38pi), respectively. Optical and electrochemical properties of these seven and nine rings fused systems are studied. The optoelectronic properties of the syn and anti-isomers of the unsymmetrical heteroacenes are also compared. The influence of the position of the heteroatoms in the fused corona, upon the optical and electrochemical properties, is rationalized based on the contributions from the benzenoid vs. quinonoid-type structures of these molecules. PMID- 22421803 TI - Immune-neuroendocrine integration at the adrenal gland: cytokine control of the adrenomedullary transcriptome. AB - The bovine chromaffin cell represents an ideal model for the study of cell signaling to gene expression by first messengers. An abundance of GPCR, ionotropic, and growth factor receptors are expressed on these cells, and they can be obtained and studied as an abundant highly enriched cell population; importantly, this is true of no other postmitotic neuroendocrine or neuronal cell type. Chromaffin cells have now been shown to bear receptors for cytokines whose expression in the circulation is highly elevated in inflammation, including tumor necrosis factor, interferon, interleukin-1, and interleukin-6. The use of bovine specific microarrays, and various biochemical measurements in this highly homogenous cell preparation reveals unique cohorts of distinct genes regulated by cytokines in chromaffin cells, via signaling pathways that are in some cases uniquely neuroendocrine. The transcriptomic signatures of cytokine signaling in chromaffin cells suggest that the adrenal medulla may integrate neuronal, hormonal, and immune signaling during inflammation, through induction of paracrine factors that signal to both adrenal cortex and sensory afferents of the adrenal gland, and autocrine factors, which determine the duration and type of paracrine secretory signaling that occurs in either acute or chronic inflammatory conditions. PMID- 22421804 TI - Genetic association of SLC2A14 polymorphism with Alzheimer's disease in a Han Chinese population. AB - Glucose uptake and metabolism are impaired in Alzheimer's disease (AD) brain, which appear to be a cause, rather than a consequence of neurodegeneration. Recently, the gene of the 14th isoform of subfamily A of solute carrier family 2 (SLC2A14), encoding glucose transporter 14 (GLUT14), was identified for the association in vivo with AD pathology of Tau, and rs10845990 within SLC2A14 showed association with AD in Caucasians. In order to evaluate the involvement of the SLC2A14 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (597 LOAD cases and 605 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.015, allele P = 0.039). The G-carrying genotype (GT + GG) individuals showed a 1.41-fold increased risk compared with the TT genotype carriers (odds ratio (OR) = 1.41, 95 % confidence interval (CI) = 1.11-1.79, P = 0.005, Power = 83.6 %). After stratification by ApoE epsilon4-carrying status, rs10845990 polymorphism was only significantly associated with LOAD in non-ApoE epsilon4 allele carriers (P < 0.001). Multivariate logistic regression analysis also conferred this positive association between the SNP rs10845990 and LOAD in the dominant and additive model after adjustment for age, gender, and the ApoE epsilon4 carrier status. These results suggested that SLC2A14 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population. PMID- 22421805 TI - Challenges to treatment of leukemia in HIV-positive children. AB - We describe the challenges to treatment of leukemia in three cases of human immunodeficiency virus (HIV)-infected children with multiple infections and complications. Two of the three patients had acute myeloid leukemia and the other one acute lymphoblastic leukemia. Two of the patients were known with HIV infection; the third was diagnosed on admission. All patients received antiretroviral therapy with standard doses of lamivudine, stavudine and efavirenz or lopinavir/retonavir. All three were diagnosed with Mycobacterium tuberculosis on one or more occasions: pulmonary or miliary involvement or tuberculous meningitis. One patient developed spinal paraplegia and needed an urgent laminectomy. Later he recovered almost completely. The interaction between antiretroviral and antituberculosis treatments combined with chemotherapy, antibiotics and supportive care is not known. Despite the severity and the complexity of several associated diseases, the outcome of the patients was rewarding and encouraging. PMID- 22421806 TI - Hydrogen-bonded network of hydration water around model solutes. AB - Clustering of water molecules in the hydration shells of spherical structureless solutes was studied in dependence on thermodynamic state, solute radius R(sp) and strength U(0) of water-solute interaction. Two qualitatively different clustering states of hydration water have been found: an "ordered" state with a hydrogen bonded (H-bonded) network, which includes most of the hydration water, and a "disordered" state with small H-bonded clusters of hydration water. The transition from the ordered to disordered state occurs upon increasing temperature and decreasing pressure. This percolation transition is rounded due to the finite solute size and occurs in some temperature (pressure) interval. A finite-size scaling was applied to determine the transition temperature T(infinity) in the limit R(sp)->infinity. Strengthening of the water-solute interaction strongly enhances the stability of the ordered state: the transition temperature increases by about 35 degrees C, when U(0) decreases by 1 kcal mol( 1). At T > T(infinity) and fixed U(0), the stability of the H-bonded water network increases upon decreasing solute size. PMID- 22421807 TI - Are there education differentials in disability and mortality transitions and active life expectancy among Japanese older adults? Findings from a 10-year prospective cohort study. AB - OBJECTIVES: To investigate the robust education-health association found in Western developed nations in the Japanese context. We examined disability and mortality transitions and computed active life expectancy (ALE) by educational attainment for a cohort of Japanese adults aged 65+ years. METHOD: Nationally representative data from the Nihon University Japanese Longitudinal Study of Aging over a 10-year period in Japan (1999, 2001, 2003, 2006, and 2009) were used (N = 4,968). Disability was measured by difficulties in performing daily activities. A multistate life table method was employed using an interpolated Markov chain approach. RESULTS: There is little effect of education on disability and mortality transitions. Except for transiting from an active to inactive state (disability incidence), the other health transitions, including to mortality, are not statistically significant. ALE computations show that Japanese men and women with more education can expect more years of remaining life and active life. DISCUSSION: The robust education-health relationship found in Western societies does not seem applicable in Japan. We discuss the casual mechanisms addressed in the literature in relation to Japan's relatively egalitarian society and specific characteristics. PMID- 22421808 TI - Formal education level versus self-rated literacy as predictors of cognitive aging. AB - OBJECTIVES: To compare the prediction of cognitive functioning by formal education and self-rated literacy and the differences in prediction across younger and older cohorts. METHOD: Data on 28,535 respondents were drawn from a cross-sectional representative sample of community-dwelling older individuals (>=50), participating in the Survey of Health, Ageing, and Retirement in Europe. Education level was classified according to the International Standard Classification of Education 1997 (ISCED-1997) self-rated literacy was determined by having respondents rate their reading and writing on 1-5 scales. Cognitive functioning was measured by verbal recall, word fluency, and arithmetic ability. RESULTS: Structural equation modeling demonstrated that self-rated literacy was more strongly associated with cognitive functioning than was education level, with or without additional exogenous variables (age, sex, household income, medical conditions, activities of daily living, reading eyesight, and country). The association between education level and cognitive functioning was weaker in older than in younger age groups, whereas the association between self-rated literacy and cognitive functioning showed the opposite trend. DISCUSSION: Self rated literacy was found to be a better predictor of late-life cognitive functioning than was the level of formal education. The results have implications for studies of age-related differences in which education level is taken into account. PMID- 22421809 TI - The effect of coresidence with an adult child on depressive symptoms among older widowed women in South Korea: an instrumental variables estimation. AB - OBJECTIVES: To estimate the causal effect of coresidence with an adult child on depressive symptoms among older widowed women in South Korea. METHOD: Data from the first (2006) and second (2008) waves of the Korea Longitudinal Study of Ageing were used. The analysis was restricted to widowed women aged >=65 years with at least one living child (N = 2,446). We used an instrumental variables (IVs) estimation exploiting two child characteristics as IVs (the number of sons and whether the eldest child is a daughter). Specification tests for IVs showed that these instruments predict the probability of an older widowed woman's coresidence with an adult child but do not directly affect depressive symptoms. RESULTS: Our IV two-stage least-squares estimator suggested that coresidence with an adult child has a protective effect on depressive symptoms among older widowed women in South Korea. Coresidence was found to be endogenous in our statistical model of depressive symptoms. DISCUSSION: The IV estimation method can be a useful approach to addressing the potential endogeneity between intergenerational coresidence and elderly health. Rapidly decreasing rates of intergenerational coresidence may raise public health concerns among older widowed women in South Korea. PMID- 22421810 TI - Migrant selection and the health of U.S. immigrants from the former Soviet Union. AB - Few prior studies have investigated the health of U.S. immigrants from the former Soviet Union (FSU). Utilizing data from the 2000 U.S. census and the 2000-2007 National Health Interview Survey (NIHS), we compare levels of disability of FSU immigrants with U.S.-born whites (ages 50-84). Our findings suggest an "epidemiologic paradox" in that FSU immigrants possess higher levels of education compared with U.S.-born whites, but report considerably higher disability with and without adjustment for education. Nonetheless, FSU immigrants report lower levels of smoking and heavy alcohol use compared with U.S.-born whites. We further investigate disability by period of arrival among FSU immigrants. Changes in Soviet emigration policies conceivably altered the level of health selectivity among emigres. We find evidence that FSU immigrants who emigrated during a period when a permission to emigrate was hard to obtain (1970-1986) displayed less disability compared with those who emigrated when these restrictions were less stringent (1987-2000). Finally, we compare disability among Russian-born U.S. immigrants with that of those residing in Russia as a direct test of health selectivity. We find that Russian immigrants report lower levels of disability compared with Russians in Russia, suggesting that they are positively selected for health despite their poor health relative to U.S.-born whites. PMID- 22421811 TI - Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. AB - OBJECTIVE: The modest association between radiographic joint damage and pain in osteoarthritis (OA) has led to the suggestion of facilitated central pain processing. This study evaluated the importance of ongoing tissue pathology in the maintenance of enhanced central pain processing. METHODS: Pain assessment was performed on 48 patients with symptomatic knee OA and 21 sex- and age-matched pain-free healthy control subjects. Twenty of the OA patients subsequently underwent total knee replacement surgery and were reassessed. Pressure-pain thresholds (PPTs) were recorded using a pressure algometer (both over and distant from the knee) and a double-chamber inflatable cuff mounted around the calf. Spatial summation was assessed by relating PPTs using the dual- and single chamber cuff. Conditioned pain modulation (CPM) was assessed by recording the increase in PPT in response to experimental arm pain. RESULTS: PPTs at the knee and at sites away from the knee were reduced in OA patients as compared with healthy pain-free control subjects (P < 0.0001). Cuff PPTs were decreased in OA patients as compared with the healthy controls (P < 0.05), who also exhibited a greater degree of spatial summation (P < 0.05). Whereas an elevation of PPTs was noted in the healthy controls in response to experimental arm pain (P < 0.0001), no such CPM was observed in the OA patients. Following joint replacement in the OA patients, there was a reduction in the widespread mechanical hyperesthesia, along with normalization of spatial summation ratios and restoration of CPM. CONCLUSION: The widespread hyperesthesia and enhanced spatial summation observed in OA patients imply sensitized central pain mechanisms together with the loss of CPM. Normalization of the results following joint replacement implies that these central pain processes are maintained by peripheral input. PMID- 22421812 TI - Primary central nervous system vasculitis: pathology and mechanisms. AB - Primary vasculitis of the central nervous system (PCNSV) is a rare and diagnostically challenging form of vasculitis limited to the brain and/or spinal cord. It is a complex and often severe disease with multifaceted clinical and pathological appearances, suggesting multiple disease subtypes and the potential existence of multiple etiologic pathways. We describe in detail the clinical, imaging, and neuropathological findings of PCNSV summarizing literature data and our observations from a cohort of 131 patients diagnosed at Mayo Clinic over a 25 year period (1983-2007). Unlike systemic vasculitis, little is known regarding PCNSV pathogenesis and the involved immunological mechanisms. Increased recognition of the disease spectrum and in-depth characterization of its histopathologic and immunological phenotype will be critical to eventually understanding the underlying derangements and mechanisms driving PCNSV. Improved understanding of the pathogenetic mechanisms of the disease may also help determine whether the different histologic patterns and clinical subsets represent more than one disease and ultimately may permit development of novel diagnostic and therapeutic strategies for it. PMID- 22421813 TI - Ectomycorrhizal fungal communities associated with Masson pine (Pinus massoniana Lamb.) in Pb-Zn mine sites of central south China. AB - To advance our understanding of ectomycorrhizal fungal communities in mining areas, the diversity and composition of ectomycorrhizal fungi associated with Masson pine (Pinus massoniana Lamb.) and soil chemistry were investigated in Taolin lead-zinc (Pb-Zn) mine tailings (TLT), two fragmented forest patches in a Huayuan Pb-Zn mineland (HY1 and HY2), and a non-polluted forest in Taolin in central south China. Ectomycorrhizal fungal species were identified by morphotyping and sequence analyses of the internally transcribed spacer regions of ribosomal DNA. The two study sites in the Huayuan mineland (HY1 and HY2) were significantly different in soil Pb, Zn, and cadmium (Cd) concentrations, but no significant difference was observed in ectomycorrhizal colonization, ectomycorrhizal fungal richness, diversity, or rank-abundance. In addition, the similarity of ectomycorrhizal fungal communities between HY1 and HY2 was quite high (Sorensen similarity index = 0.47). Thus, the concentration of heavy metals may not be determining factors in the structure of these communities. In the tailings, however, significantly lower ectomycorrhizal colonization and ectomycorrhizal fungal richness were observed. The amounts of Pb and Zn in the tailing sand were higher than the non-polluted forest but far lower than in HY1. Thus, these heavy metals did not account for the reduced colonization and ectomycorrhizal fungal richness in TLT. The ectomycorrhizal fungal community in TLT was dominated by four pioneer species (Rhizopogon buenoi, Tomentella ellisii, Inocybe curvipes, and Suillus granulatus), which collectively accounted for 93.2 % of root tip colonization. The immature soil conditions in tailing (low N and P, sand texture, and lack of organic matter) may only allow certain pioneer ectomycorrhizal fungal species to colonize the site. When soil samples from four sites were combined, we found that the occurrences of major ectomycorrhizal fungal taxa were not clearly related to the concentrations of Pb, Zn, and Cd. In conclusion, our results suggest that ectomycorrhizal fungal communities in mining areas are not necessarily affected by heavy metals themselves but could be largely determined by soil maturity. PMID- 22421814 TI - Haworforbins A-C, new phenolics from Haworthia cymbiformis. AB - Two new isocoumarin glucosides, haworforbins A (1) and B (2), and a new chromone, haworforbin C (3), have been isolated from Haworthia cymbiformis. Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Haworforbin C (3) exhibited moderate inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cell line. PMID- 22421815 TI - Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. AB - BACKGROUND: The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6 MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6 MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability. AIM: This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL. PMID- 22421816 TI - Sorption of small molecule vapours by single crystals of [Pt{4' (Ph)trpy}(NCS)]SbF6 where trpy = 2,2':6',2''-terpyridine: a porous material with a structure stabilised by extended pi-pi interactions. AB - Treatment of [Pt{4'-(Ph)trpy}Cl]SbF(6) with AgSCN in a metathesis reaction in refluxing acetonitrile affords, after work-up, single crystals of [Pt{4' (Ph)trpy}(NCS)]SbF(6).CH(3)CN, where trpy is 2,2':6',2''-terpyridine. These crystals lose solvent to give single crystals of [Pt{4'-(Ph)trpy}(NCS)]SbF(6) (1). An X-ray crystal structure determination of 1 shows that the SCN(-) ion is N bound and that the cation as a whole is approximately planar. Compound 1 is porous with "empty" channels that corkscrew through the crystal: this crystal structure is stabilised by extended pi-pi interactions between the planar cations. When a single crystal of 1 is exposed to vapours of acetonitrile the vapours are sorbed without loss of single crystallinity, as confirmed by crystal structure determinations of 1 and 1.CH(3)CN using the same single crystal. Similarly, single crystals of 1 sorb vapours of methanol without loss of single crystallinity, as confirmed by a crystal structure determination of 1.CH(3)OH. We also report the crystal structure of 1.(CH(3))(2)CO; however, in this case the single crystal was grown directly from acetone. Compound 1 and its solvates are all yellow. Nevertheless, there are differences between the emission spectra recorded for 1 and its solvates in the solid state. Thus, whereas 1 exhibits very weak multiple emission from (3)MLCT (MLCT = metal-to-ligand charge transfer) and excimeric (3)pi-pi* excited states, 1.CH(3)CN and 1.(CH(3))(2)CO both exhibit more intense (3)MLCT emission; and the emission by 1.CH(3)OH is complicated by the presence of metallophilic interactions in the crystal. We discuss the role of the solvent in causing these differences. PMID- 22421817 TI - Statin label changes. PMID- 22421818 TI - Extended-release exenatide (Bydureon) for type 2 diabetes. PMID- 22421819 TI - Nitroglycerin ointment (Rectiv) for anal fissure. PMID- 22421821 TI - Analytical techniques for the detection of alpha-amino-beta-methylaminopropionic acid. AB - The non-protein amino acid L-alpha-amino-beta-methylaminopropionic acid (BMAA) has been linked to several neurodegenerative diseases. Its presence in trace amounts in complex sample such as bacterial, plant and mammalian tissue extracts and hydrolyzates makes analysis a complicated process requiring good analytical technique. There are conflicting reports in the literature regarding the presence or absence of BMAA in key samples, but the absence of standardized or validated methods makes comparison of the disparate findings difficult to compare. This critical review will summarize the historic and recent literature, and provide suggestions for improving the methods currently in practice. PMID- 22421822 TI - Sphenoidal-clival neoformation: an endoscopic approach. AB - The cranial base has distinct embryologic origins. The anterior cranial base is derived solely from the neural crest, similar to other facial bones, whereas the posterior cranial base is formed by the paraxial mesoderm. Both these parts also develop and grow with distinct features. Unlike other craniofacial bones that are mostly formed through intramembraneous ossification, the cranial base is formed through endochondral ossification, in which a cartilage plate, known as the chondrocranium, is formed first and soon replaced by bones. Individual bones are then connected by cartilaginous structures, termed synchondroses, which are morphologically similar to long-bone growth plates.These processes justify the presence of a disembryogenic cyst in the sphenoid bone. The authors present a case of a clival-sphenoidal region neoformation treated with a transnasal endoscopic approach. PMID- 22421823 TI - Pseudoaneurysm of the facial artery after the injection of local anesthetics. AB - Generally, a true aneurysm is a dilatation of the vessel wall, whereas a pseudoaneurysm (PA) is a weakening or rent in a vessel wall, with contained rupture into the surrounding tissues. In the face, PAs of the facial artery are an extremely rare development after penetrating or blunt trauma. A 31-year-old woman presented with nontender, palpable, and firm lump that had been steadily increasing in size over a 4-week period. Examination confirmed a firm and spherical swelling in the left mandibular area, which was nonpulsatile. The patient presented with a mass on the upper part of her left chin 6 months after the injection of local anesthetics for dental treatment. After the procedure, a hematoma developed over the injection site, and it was treated with local ice. This case is unique in that the lesion seen using computed tomography and ultrasonography scanning had an unusual presentation. Ultrasonography revealed thrombi within the tumor, and color Doppler examination showed blood moving in the perivascular mass. During the operation via intraoral incision, a lesion was found as a dilation of the muscular branch of the facial artery. The facial artery was exposed, isolated, and tied off with a 2-0 white silk ligature. Histopathologic analysis determined that the content of the fragile cystic lesion was an organized thrombus and hematoma. As with any penetrating facial injury, local anesthetics can damage vessels and produce a PA. Therefore, we present a rare case of false facial artery aneurysm with no associated risk factors, which was nonpulsatile on presentation. PMID- 22421824 TI - Combining platelet-rich plasma and tissue-engineered skin in the treatment of large skin wound. AB - The objective of the study was to observe the effects of tissue-engineered skin in combination with platelet-rich plasma (PRP) and other preparations on the repair of large skin wound on nude mice.We first prepared PRP from venous blood by density-gradient centrifugation. Large skin wounds were created surgically on the dorsal part of nude mice. The wounds were then treated with either artificial skin, tissue-engineered skin, tissue-engineered skin combined with basic fibroblast growth factor, tissue-engineered skin combined with epidermal growth factor, or tissue-engineered skin combined with PRP. Tissue specimens were collected at different time intervals after surgery. Hematoxylin-eosin and periodic acid-Schiff staining and immunohistochemistry were performed to assess the rate of wound healing.Macroscopic observations, hematoxylin-eosin/periodic acid-Schiff staining, and immunohistochemistry revealed that the wounds treated with tissue-engineered skin in combination with PRP showed the most satisfactory wound recovery, among the 5 groups. PMID- 22421825 TI - Reconstruction for defects of the lower lip after tumor ablation. AB - BACKGROUND: The lip carcinoma, which frequently affects the lower lip, is one of the most common cancers of the head and neck region composing 25% to 30% of all oral cancers. The accepted method of therapy for lip cancer is surgical excision and reconstruction. The repair should satisfy 2 fundamental requirements: to achieve appropriate aesthetic quality and to conserve labial function. Currently, a wide range of reconstructive procedures have been developed. OBJECTIVE: The objective of the study was to summarize the clinical experience of reconstruction for lower lip defects to facilitate the selection of a proper reconstructive strategy for different conditions in clinical practice. METHODS: We performed a retrospective analysis of 43 patients who had undergone a standardized reconstructive approach based on the literature published and our own experience over the past 4 years. RESULTS: Over an average period of 7.5 months' follow-up, recurrences or major complications did not happen, and most patients were satisfied with their functional and aesthetical outcome. Focusing on the location and the width of the defects of lower lip, a table has been exhibited to orient the surgeons to select a suitable reconstructive procedure for each patient. CONCLUSIONS: Successful reconstruction of all defects can be attained, if as many surgical procedures as possible have been mastered, and a more proper means used. PMID- 22421826 TI - Effect of number and geometry of resorbable screws on biomechanical stability of in vitro model with sagittal split ramus osteotomy. AB - The purpose of this study was to investigate the effect of the number and the geometry of resorbable screws (RSs; Inion CPS System; Inion Ltd, Tampere, Finland) on the biomechanical stability of the in vitro model with sagittal split ramus osteotomy. The sagittal split ramus osteotomy polyurethane hemimandible (Synbone, Malans, Switzerland) was fixed by 7 osteosynthesis methods after 5 mm advancement of the distal segment (n = 5 for each method): 1TP (1 titanium miniplate and 4 screws), 3RL (3 RSs with linear configuration at the retromolar area [RMA]), 2R1B (2 RSs at RMA and 1 RS at the mandibular body [MB]), 2R1A (2 RSs at the RMA and 1 RS at the mandibular angle [MA]), 3R1B (3 RSs at RMA and 1 RS at the MB), 3R1A (3 RSs at RMA and 1 RS at the MA), and 3R1A1B (3 RSs at the RMA, 1 RS at the MA, and 1 RS at the MB). Values of linear compressive load were measured at 1- to 5-mm displacement of the lower first molar with a 1-mm interval and were statistically analyzed. From 1- to 5-mm displacement, there were significant differences in load values among groups (P < 0.05, P < 0.01, P < 0.01, P < 0.001, and P < 0.001, respectively). When the amount of displacement was increased, the difference in load values between 1TP, 3RL, and 2R1B became significantly prominent. There was a significant difference in total load values according to number and geometry of RSs (P < 0.001). All kinds of geometry with more than 3 RSs were more rigid than 1TP. The 3R1A1B method showed better biomechanical stability than 1TP, 3RL, and 2R1B. In 3 RS and 4 RS groups, fixation in MA (2R1A, 3R1A) exhibited a tendency of better stability than fixation in MB (2R1B, 3R1B). Fixation with 2R1A could provide better biomechanical stability than 1TP and similar rigidity with 3R1A1B. PMID- 22421827 TI - Intranasal approach for manipulating the depressor septi nasi. AB - A hyperactivated depressor septi nasi is an important factor contributing to nasal tip drooping. Although many studies have examined this, its treatment remains controversial. This study presents a surgical intervention based on an anatomic study.Ten fresh cadavers with large noses were used for the anatomic study. Between April 2008 and September 2010, 20 patients underwent surgical intervention for hyperactivated depressor septi nasi.In all of the cadaver dissections, the depressor septi nasi was present, although it was difficult to identify the muscle clearly in 6 of the cadavers. We found that the depressor septi nasi in the other 4 cadavers consisted of 3 fascicles. The medial fascicles were divided into superficial and deep fibers. Both the deep and superficial fibers were inserted into the dermocartilaginous ligament in the nearby nasal tip. After the superficial fibers were interdigitated with the orbicularis oris, they originated from the alveolar bone. The deep fibers originated at the anterior nasal spine. The intermediate fascicles inserted to the footplates of the medial crus and caudal septum. After interdigitating with the medial fascicles and orbicularis oris, they also originated from the alveolar bone. The drooping nasal tips were improved in all cases using an intranasal approach to manipulate the depressor septi nasi. No specific complication was seen. Surgical intervention of a hyperactivated depressor septi nasi using an intranasal approach was a useful method for correcting a drooping nasal tip. PMID- 22421828 TI - Improved correction of supraorbital rim deformity in craniosynostosis by the "tilt" procedure. AB - Orbital rim deficits are a feature of metopic, unilateral coronal, and bilateral coronal craniosynostosis. Several procedures have been developed to address this issue, but relapse to the preoperative hypoplastic deformity and stunted growth of the fronto-orbital region are common. The authors describe a technique modification of the conventional lateral canthal advancement referred to as the orbital rim "tilt" procedure, which aims to preserve inferior bony support for the orbital rim and create projection with optimal proclination of the fronto orbital complex. PMID- 22421829 TI - Spring-mediated cranioplasty in patients with multiple-suture synostosis and cloverleaf skull deformity. AB - The concept of using implantable springs in craniofacial surgery was developed to dynamically remodel the cranium at the postoperative period. Springs have been shown as an effective treatment modality especially for single-suture synostosis patients and had several advantages over traditional techniques. This report presents 2 patients with cloverleaf skull and 1 patient with multiple-suture synostosis, with severe lacunae, who showed signs of increased intracranial pressure. Decompression and reconstruction were performed using implantable springs after Pi craniectomy. In all patients, lacunae disappeared and calvarial bones ossified almost completely. The shape of the patients' cranium improved as well. Implantable springs could be a useful addition to the armamentarium of every craniofacial surgeon. PMID- 22421830 TI - Validation of the GILLS score for tongue-lip adhesion in Robin sequence patients. AB - BACKGROUND: The GILLS score consists of gastroesophageal reflux disease, preoperative intubation, late surgical intervention, low birth weight, and syndromic diagnosis. The purpose of this study was to test the validity of the GILLS score in predicting success of tongue-lip adhesion (TLA) in managing Robin sequence. MATERIALS AND METHODS: Infants with Robin sequence were included in the study if they had a TLA for airway compromise subsequent to formulation of the GILLS scoring system, that is, they were not included in the original GILLS analysis. The patients were prospectively considered based on the presence of the 5 factors that constitute the GILLS score. A score of <= 2 predicts success of TLA. RESULTS: Twenty patients met the inclusion criteria. Tongue-lip adhesion managed the compromised airway in 18 (90%) of 20 patients. Overall, the GILLS score had a sensitivity of 83%, specificity of 50%, positive predictive value of 94%, and negative predictive value of 25%. CONCLUSIONS: The GILLS score accurately predicts a successful outcome for TLA in infants with Robin sequence. For infants with a score of 2 or less, TLA is the procedure of choice. Infants with a GILLS score of 3 or greater were 5 times more likely to fail TLA than those with a score of 2 or less. In these patients, other methods of managing the airway should be considered. PMID- 22421831 TI - Clinical evaluation of obstructive sleep apnea in children. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is often found in children affected by congenital or acquired craniomaxillomandibular malformations. This disease carries different levels of risk, ranging from attention problems at school to growth problems and serious disorders, such as cor pulmonale or sudden infant death. The examination that is most commonly used to evaluate the severity of OSAS is polysomnography, and the therapeutic course is often determined by the disease state. Considering the discrepancy between clinical history and polysomnographic findings, we felt the need to identify an instrument for evaluating OSA to be used as a support for polysomnography. MATERIALS AND METHODS: This study was carried out on pediatric patients affected by congenital or acquired craniomaxillofacial malformations. We selected 34 pediatric patients, including 15 boys and 19 girls, aged between 1 and 16 years, with a mean age of 7.3 years. The study consisted of individuation of common clinical history data obtained from each patient and associating those data with the level of OSA severity identified by polysomnography. We were able to isolate certain symptoms and signs that can be predictive of OSA from research in the literature and our clinical experience with pediatric patients. In the clinic, we have found that the clinical history, given by the parents, often differs significantly from the instrumental findings obtained with polysomnography. From the previously expressed considerations and comparison of clinical history data and questionnaires, we have extracted the most significant questions for our questionnaire, which are present in the literature but formulated for adults. RESULTS AND CONCLUSIONS: The obstructive airway child test was found to be a very efficient method to evaluate and diagnose OSA. In all patients, it consistently revealed the pathology and never underestimated OSA severity. The examination focuses on clinical signs and symptoms because, in our opinion, clinical history, reported by the parents, can be more accurate than any instrumental examination. PMID- 22421832 TI - Need for revision surgery after alveolar cleft repair. AB - The study assessed the need for revision surgery and the relating factors in alveolar cleft autogenous bone grafting in patients with complete cleft. It was a retrospective study carried out in 2009. The medical records of the 54 patients with alveolar cleft who underwent autogenous bone grafting in the maxillofacial department in Shariati Hospital from 2005 to 2008 were studied. The patients' age, sex, cleft type, age at palatal and alveolar clefts repair, tooth missing, surgery turn, and presence of orthodontic treatment were assessed. The patients' alveolar bone height was evaluated from their postoperative and follow-up panoramic radiographs. In general, 41% (n = 22) of patients needed revision surgery. Among all patients, 20 (37%) had secondary bone grafting and 34 (63%) had tertiary bone grafting. For 77% of the secondary unilateral clefts and 71% of bilateral ones, the remaining bone was at least three-fourths of the normal. Logistic regression model controlling for grafting time, surgery turn, orthodontic supervision, and age at palatal cleft closure showed that orthodontic treatment is associated with a lower need for revision surgery (odds ratio = 0.3; 95% confidence interval, 0.1-1.0). In conclusion, although alveolar cleft bone grafting is necessary for the reconstruction of the complete clefts, all these patients must be under the supervision of orthodontists to benefit from the surgical treatment. PMID- 22421833 TI - Human bone morphogenetic protein 2-transduced mesenchymal stem cells improve bone regeneration in a model of mandible distraction surgery. AB - BACKGROUND: Bone morphogenetic proteins (BMPs) are actively involved in ossification, and BMP-2 participates throughout the entire process. Gene therapy for bone regeneration using adenovirus-expressing BMPs has been successful in small mammals, but it has not been satisfactory in large mammals. METHODS: We generated a 3-component implant (3C graft) comprising autologous mesenchymal stem cells (MSCs), ex vivo transduced with an adenovirus vector-expressing BMP-2 and embedded in a demineralized human bone matrix (DBM). RESULTS: In vitro studies demonstrated vector-induced osteogenesis; osteoblast population and mineralization of the extracellular matrix were greater in the vector-transduced cultures than in the controls (nontransduced MSCs stimulated with osteogenic media were used as positive controls, and nontransduced MSCs served as a negative control). The 3-component grafts were used to fill osteotomies created by bone distraction surgery in mongrel dogs. Control groups comprised dogs with bone distraction alone and dogs with nontransduced MSC grafts. The radiography follow up, performed 10 weeks after distraction, demonstrated a remarkable reduction in the consolidation period compared with controls. Postmortem mandibles submitted for anatomic and histologic analyses showed improved remodeling and bone maturation in the 3C-grafted dogs. Inflammatory infiltrates were not observed in any of the treated areas, and no liver toxicity was detected. CONCLUSIONS: We demonstrated acceleration of osteogenesis in a dog model for bone distraction by using an implant of BMP-2 modified MSCs. These results are helpful for future clinical trials of mandible bone distraction. PMID- 22421834 TI - Novel model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2. Part II. AB - BACKGROUND: Animal models of bone reconstruction have shown recombinant human bone morphogenetic protein 2 (rhBMP-2) to be an effective therapy in the acute calvarial defect wound. The purpose of this study was to compare the effectiveness of rhBMP-2 in a rabbit model of an unfavorable scarred calvarial wound with the criterion standard of autograft. METHODS: Nineteen adult New Zealand white rabbits underwent subtotal calvariectomy. After 6 weeks of healing and normal scar formation, these animals underwent reoperation for scar debridement and assignment to 1 of 4 therapeutic groups. Animals were assigned to an empty control group (no treatment, n = 3), vehicle control group (neutral buffered solution on an absorbable collagen sponge [ACS], n = 3), surgical control group (cryopreserved autograft, n = 3), or an experimental treatment group (rhBMP-2 on an ACS, n = 10). All animals underwent computed tomography imaging at 0, 2, 4, and 6 weeks after secondary reconstructive surgery. At 6 weeks, all animals were killed, and the defects were examined histologically. Percentage of healing of each defect was determined, and a 4 * 3 mixed-model analysis of variance was performed on healing as a function of time and therapy. RESULTS: Based on measures of defect radiopacity, the treatment group (rhBMP 2/ACS) and surgical control group (autograft) were statistically equivalent with 98% and 83% healing, respectively, at 6 weeks. The empty control and vehicle control groups were inferior to the treatment group (rhBMP-2/ACS) and surgical control (autograft) groups at each timepoint (P < 0.05). Histologically, bone in the surgical control (autograft) group was less trabecular and less cellular than the bone formed in the experimental treatment group (rhBMP-2/ACS). CONCLUSIONS: Compared with historical controls, rhBMP-2 therapy was as effective in reconstructing calvarial defects in the unfavorable scarred wound as in the acute favorable calvarial wound. When compared with cryopreserved autograft, rhBMP-2 regenerated bone showed equal defect coverage and similar bone thickness with varying bony architecture. PMID- 22421835 TI - Coordinated events: FGF signaling and other related pathways in palatogenesis. AB - Cleft palate is a common craniofacial anomaly that is costly to both patients and the health care system. Investigation of each stage of palate development enhances understanding of this anomaly. Although the exact molecular signaling mechanisms that contribute to palatogenesis remain elusive, multiple pathways, such as fibroblast growth factor (FGF) signaling, have been recognized as important contributors. Alterations in FGF signaling have previously been implicated in palatal clefting. The current review discusses FGF signaling and the major signaling mediators affecting FGF signaling during each stage of palatogenesis. PMID- 22421836 TI - Use of intraoral miniplates to control postoperative occlusion after high condylectomy for the treatment of condylar hyperplasia. AB - Mandibular condylar hyperplasia is a rare disorder, characterized by unilateral mandibular overgrowth with overeruption of the dentition on the affected side. Although the etiology is unclear, multiple surgical techniques have been described to correct the associated mandibular bone, occlusal, and soft tissue deformities. Often a condylectomy, to arrest mandibular growth, is combined with various orthognathic procedures to restore occlusion and facial harmony. Here we report our technique of isolated high condylectomy with simultaneous intraoral placement of maxillary and mandibular miniplates. Each plate has an intraoral extension that allows our orthodontists to develop vertical force vectors to intrude the maxillary and mandibular molar segments. Using this combined surgical and orthodontic technique, we were able to postoperatively control the occlusal cant, restore the dental midline, improve facial aesthetics, and resolve the patient's contralateral temporomandibular joint dysfunction without concomitant orthognathic surgery. As a result of our findings, we are currently using, and would recommend, this technique for patients requiring surgical-orthodontic intervention for other conditions. PMID- 22421837 TI - Maintenance of certification: unilateral cleft lip repair. AB - Cleft lip repair is arguably one of the defining procedures in the field of plastic surgery. The results may be dramatic both visually and emotionally. The variety of techniques of cleft lip repair is well described in the literature, in part because of its inherent difficulty to master. The following article reviews the history of cleft lip repair and attempts to make clear the techniques of the rotation-advancement-type repair. PMID- 22421838 TI - Volumetric analysis of anterior versus posterior cranial vault expansion in patients with syndromic craniosynostosis. AB - BACKGROUND: Syndromic craniosynostosis is associated with a high incidence of elevated intracranial pressure. The most common treatment paradigm is to perform anterior cranial vault reconstruction in infancy followed later by possible expansion of the posterior cranial vault and midface advancement. Recently, however, posterior cranial vault expansion has been advocated as an initial step in treatment. We sought to quantify volumetric changes with anterior versus posterior cranial vault surgery in these patients. MATERIALS AND METHODS: We reviewed patients with syndromic brachycephalic craniosynostosis treated in our unit from 2002 to 2009 with existing preoperative fine-cut computed tomographic scans. Using computer software (Analyze; Mayo Clinic, Rochester, MN) and computed tomographic data, the senior author simulated both anterior and posterior cranial vault expansions. Expansion was simulated with a series of translational advancements of the separated segments. Volumetric data were compared for each simulated procedure. RESULTS: Thirteen patients underwent simulated cranial vault reconstructions. At 2, 10, and 20 mm of anterior advancement, the mean increase in intracranial volume was 1.8%, 8.8%, and 17.7%, respectively, whereas posterior advancements achieved 2.4%, 11.9%, and 23.9%, respectively. On average, posterior cranial vault reconstruction created 35% more relative expansion than anterior expansion at equivalent degrees of advancement (P < 0.001). In all simulations, posterior cranial vault reconstruction created greater intracranial volume changes than anterior reconstructions. CONCLUSIONS: This simulation demonstrates that, in syndromic brachycephalic craniosynostosis, posterior cranial vault advancement achieves approximately 35% greater intracranial volume expansion compared with equivalent degrees of anterior cranial vault advancement. This may help guide decisions in treatment sequencing of patients with syndromic craniosynostosis. PMID- 22421839 TI - Effect of immersion cleansing in color stability and hardness of soft denture reliners. AB - Hygienic care of removable prostheses is important, and denture cleansers selected must be efficient and maintain the physicomechanical properties of soft reliners. Microwave energy has been reported to increase the sanitation effectiveness of denture cleansers. The purpose of the study was to evaluate hardness and color stability of some visible light polymerized and autopolymerized soft reliners after exposure in different denture-cleansing treatments. Six soft denture reliners (2 autopolymerized silicones, 1 autopolymerized acrylic, and 3 visible light polymerized ones) were exposed to 4 cleansing treatments (Corega Whitening, Polident 5-Minute, Corega Whitening + microwaving, Polident 5-Minute + microwaving). Hardness was measured with a Shore A durometer, and color changes were evaluated by a tristimulus colorimeter. The results were subjected to 2-way analysis of variance and Scheffe test for post hoc comparisons at a confidence level of alpha = 0.05. Sofreliner showed the smallest hardness change, and LightLiner the greatest. Versasoft and Sofreliner seem to have the lowest color change for every cleansing treatment examined, whereas LightLiner and Eversoft presented the greatest. Silicone-based materials demonstrated the smallest changes in both hardness and color, either when using water or with any of the other cleansing treatments. PMID- 22421840 TI - Distraction osteogenesis for tracheostomy dependent children with severe micrognathia. AB - Obstructive sleep apnea (OSA) in pediatric populations is often associated with congenital craniofacial malformations resulting in decreased pharyngeal airway, which in severe cases leads to tracheostomy dependence. The purpose of this study was to use distraction osteogenesis to improve the airway and decannulate the tracheostomy. This study involved 11 OSA tracheostomy-dependent patients (age range, 4 months to 6 years) who underwent bilateral distraction in the mandibular body using extraoral distraction devices. Following a latency period of 4 days, gradual distraction at a rate of 1 mm/d was performed followed by a consolidation period of 10 weeks. Three-dimensional computed tomography reconstruction of the face and neck before and after the mandibular lengthening aided in quantitative volumetric evaluation of mandibular volume and airway volume. The results demonstrated mandibular elongation of a mean of 30 mm on each side, an increase in mandibular volume by an average of 29.19%, and increase in pharyngeal airway by an average of 70.53%. Two to 3 months following the last lengthening, all 11 patients were decannulated with improvement of signs and symptoms of OSA and elimination of oxygen requirement. Mean follow-up was 2.0 years. The oxygen saturation level rose to more than 95%, and the apnea index respiratory disturbance index was less than 2 episodes per hour for all patients. Bilateral mandibular distraction is a useful method in younger children to decannulate permanent tracheostomy expanding the hypoplastic mandible and concomitantly advance the base of tongue and hyoid bone increasing the pharyngeal airway. PMID- 22421841 TI - Change in brow position after upper blepharoplasty or levator advancement. AB - Brow position after blepharoplasty is somewhat controversial. Some authors insist that brow position remains unchanged after surgery. On the other hand, there is also an opinion that brow position changes after surgery.We evaluate the influence of upper blepharoplasty or correction of ptosis on brow position in East Asians. Sixty patients (120 eyes) who underwent upper blepharoplasty or levator advancement were evaluated for change in brow position. Marginal reflex distance 1, brow height from medial canthus, upper eyelid margin on midpupillary level, lateral canthus, and brow height from the center of the pupil were measured before surgery and 6 months after surgery. The distance between the upper lid margin and the brow was shortened after upper blepharoplasty or levator advancement, which could cause brow depression. Change in brow height was greater after levator advancement than after blepharoplasty. These findings might be helpful for the prediction of brow position after surgery. Our study also implies that the possibility of a change in postoperative brow position change should be explained to patients before surgery, particularly ptosis patients. PMID- 22421842 TI - A novel craniofacial osteogenesis distraction system enabling control of distraction distance and vector for the treatment of syndromic craniosynostosis. AB - BACKGROUND: Distraction osteogenesis is now an important clinical tool in craniofacial surgery. However, controlling the distance and vector of distraction in infants with syndromic craniosynostosis with good repeatability is a task that still proves difficult today. We have developed a new facial osteogenesis distraction system that combines the advantages of external and internal distraction devices to enable control of both the distraction distance and vector. This article describes the method and short-term results of this system. METHODS: Our distraction system uses both a conventional external distraction device and a newly developed internal distraction device. Postoperative control of the distraction vector is performed using the external device, whereas control of distraction distance is done with the adjustable-angle internal device. This system was used for 2 patients with Crouzon syndrome. RESULTS: The system enabled control of lengthening distance and vector, and no complications occurred during the procedures. CONCLUSIONS: We developed a facial distraction system leveraging the advantages of external and internal distraction devices, which we then used to successfully control both lengthening distance and vector. The system would be particularly indicated in patients with severe scarring due to multiple follow-up surgeries and in patients requiring distraction of 20 mm or more. Aligning the periorbital profile at 5 to 6 years old caused the maxilla to rotate counterclockwise, and we consider that a procedure combining Le Fort III osteotomy with Le Fort I and II osteotomies is required to prevent these rotations. PMID- 22421843 TI - Ear concha. AB - This article classifies man's ear concha to defined shape groups where the concha is the hollow area next to the ear canal. Quantitative results about the ear concha shapes as well as their classification into 36 defined shape groups are also reported. This quantitative survey is an additional step in analyzing the shape of face parts, where, in a article published in The Journal of Craniofacial Surgery (2011;22:1-4), nose shapes were analyzed quantitatively and classified into 14 shapes. It should be noted that in Google, under the subject, "Tamir the Journal of Craniofacial Surgery," the survey about noses is mentioned about 120 times! To the best of the author's knowledge, the quantitative approach on the shapes of ear concha has never been implemented before. The results are based on 2425 pictures of real ears. The major results are as follows: (1) The author succeeded in classifying all subjects' ear concha into 36 groups as demonstrated in a figure (numbers in the bottom left of each image are the absolute number of concha of a certain type; those in the bottom right indicate the percentage). (2) The most widespread concha is number 29, which appeared 393 times and is 16.2% of the total number. The less widespread shape is number 34, which appeared only once (0.04% of the total). In addition to the numerical results, the subjects were evaluated with respect to a human's ear--anatomy, shapes, and relation to a human's character. PMID- 22421844 TI - Removal of a low-velocity projectile from the base of the sphenoid sinus using navigation-guided endoscopy. AB - PURPOSE: A patient surviving after a metal projectile penetrates the sphenoid sinus is unusual. Removing a foreign object from this region is challenging because of the difficult access and proximity to delicate structures. The use of navigation-guided endoscopy makes the manipulation of the surgical instruments near delicate structures safer, and the procedure is minimally invasive. RESULTS: A computed tomographic scan of brain showed the projectile located at the base of the left sphenoid sinus. To prevent infection and irritation and avoid secondary surgical damage, navigation-guided endoscopy was used to remove the bullet. Using the BRAINLAB navigation system, the movement of the endoscope could be followed on the screen, and the tip could be navigated into close contact with the projectile. The bullet could be located, without being visible through the endoscope, making the incision and removal of the bony wall of the sinus minimal; it was removed without complications. Intraoperative navigation of endoscopes is very useful because it enables the surgeon to correlate the visual information through the endoscope with the localization of the instruments seen on the navigation screen. Patient safety and reinforced self-confidence of surgeons are advantages of this procedure. Reduced operative time may not always occur because of a lack of experience with the navigation system. CONCLUSIONS: When there are no vascular or neurologic complications, a minimally invasive treatment using nasal navigation-guided endoscopic removal can limit the potential surgical damage. PMID- 22421845 TI - Postoperative stability of 2-jaw surgery with clockwise rotation of the occlusal plane. AB - OBJECTIVE: The objective of this study was to investigate the skeletal stability after Le Fort I osteotomy with clockwise rotation and bilateral sagittal split osteotomy. MATERIALS AND METHODS: The sample consisted of 31 young Korean patients who were treated with Le Fort I osteotomy with clockwise rotation and setback bilateral sagittal split osteotomy. The lateral cephalographs were obtained before surgery (T1), right after surgery (T2), and on an average of 6.23 months after the operation (T3). The horizontal and vertical relations of landmarks to the reference line and soft tissue changes were evaluated. RESULT: During the T2 - T1 period, there was superior and anterior movement of the posterior part (PNS, UMD) and advancement and impaction of the anterior part (ANS, A point, UIE) of the maxilla. The mandible was moved superiorly and posteriorly. During the T3 - T2 period, maxillary segment showed counterclockwise rotational relapse. The posterior part was relatively stable especially in the vertical position and the anterior part moved in the posterior and superior directions. Mandibular landmarks showed forward relapse in the horizontal aspect and superior relapse in the vertical aspect. The posterior part (PNS and UMD) showed a significantly higher stability rate (>70%) in the vertical aspect and the anterior part of the maxilla (ANS, A point) demonstrated a significantly lower value (<30%) in the vertical aspect. According to the skeletal changes, the soft tissue of the lower facial profile is rotated clockwise. CONCLUSIONS: Two jaw surgeries involving clockwise rotation of the occlusal plane showed stable results especially in the maxillary posterior landmarks. The clockwise rotational movement can be beneficial to increase skeletal stability and facial aesthetics in Asians. PMID- 22421846 TI - Sagittal maxillary growth pattern in unilateral cleft lip and palate patients with unrepaired cleft palate. AB - OBJECTIVE: The objective of the study was to examine the sagittal maxillary growth pattern during the mixed and permanent dentition in unilateral cleft lip and palate (UCLP) patients with unrepaired cleft palate. PATIENTS AND METHODS: A total of 30 nonsyndromic UCLP patients with unrepaired cleft palate were included, 15 of whom were in mixed dentition and 15 in permanent dentition.Cephalograms were analyzed and compared in the patients with UCLP who have operatively undergone repair with both the lip and palate as well as normal subjects. RESULTS: The UCLP patients with unrepaired cleft palate in mixed dentition showed decreased anterior-posterior length of the maxilla. The UCLP patients with unrepaired cleft palate in permanent dentition demonstrated an almost normal maxillary growth. The operated-on patients both in mixed and permanent dentitions showed maxillary retrusion as well as decreased maxillary length. CONCLUSIONS: There appears that there may be the potential normal maxillary growth in UCLP patients, and early surgical repair of the cleft palate may affect sagittal maxillary growth pattern in patients with cleft. PMID- 22421847 TI - Ethmoid sinus osteoma associated with blow-out fracture. AB - Osteoma is a benign tumor that is composed of compact or cancellous bone. It is the most common benign neoplasm of the paranasal sinus, and ethmoid sinuses are the second most common sites of paranasal sinus osteoma. The symptoms of ethmoid sinus osteoma can give rise to various kinds and extent of symptoms. In symptomatic cases, surgical management is necessary, but appropriate surgical approach to the ethmoid sinus is not clearly established. We describe 2 male patients with a diagnosis of blow-out fractures after trauma; ethmoid sinus osteoma on preoperative computed tomography scans was coincidentally found, and the surgical correction was done simultaneously. The purpose of this article was to present the successful surgical removal of ethmoid osteoma through lamina papyracea and transcaruncular approach, resulting in both successful surgical correction and good cosmetic outcome. PMID- 22421848 TI - Intraoral approach to zygomatic fracture: modified technique for infraorbital rim fixation. AB - The intraoral approach to zygomatic fracture treatment was introduced by Keen in 1909. This technique allows both an adequate visualization of the zygomaticomaxillary buttress and intraoral reduction of zygomatic arch fractures. Similar techniques have been published over the last 30 years. The aim of this study was to describe a modification of the Keen technique that promotes adequate visualization of the infraorbital rim and permits reduction and fixation of this region in cases of zygomatic fractures. The present technique has several advantages such as that (a) only 1 incision is necessary to approach the zygomaticomaxillary buttress and infraorbital rim, (b) it optimizes surgical time, and (c) it avoids periorbital scars. PMID- 22421849 TI - Repair of a submucous cleft palate by W-pushback and levator repositioning without incision to the nasal mucosa. AB - The author created an innovative method of W-pushback and levator repositioning without having to make an incision to the nasal mucosa for submucous cleft palate repair.The W-shaped mucoperiosteal flap is outlined where the 2 peaks of W are the alveolar processes of both canine teeth and the midpoint of W is the anterior limit of the cleft notch of the hard palate. A short incision, medial to and behind the maxillary tuberosity and curved forward onto the palate and extended forward just medial to the alveolar process, is joined by a second incision from the apex of the cleft to the region of the canine tooth. The W-shaped mucoperiosteal flap is raised until the midline notch of the hard palate is exposed. The nasal mucosa and abnormally inserted levator veli palatini muscle to the posterior border of the hard palate bone are detached. By leaving the nasal mucosa intact, the detached levator veli palatini muscle is approximated at the midline and so the zona pellucida is obliterated. The cleft uvulas are cut in half and closed. The approximated W-flap is joined to the small anterior flap by 1 or more sutures (the W-pushback).Three patients were operated on with this technique without serious complications.The author believes that this method can make the levator sling and increase the length of the soft palate without making an incision to the nasal mucosa. PMID- 22421850 TI - Split, temporalis muscle flap for repair of recalcitrant cerebrospinal fluid leaks of the anterior cranial fossa. AB - Cerebrospinal fluid repair after dural disruption is critical in preventing morbidity and mortality in trauma and cancer patients. Among reconstructive options, coverage with the temporalis muscle has been a staple in many surgeons' armamentarium. However, the donor-site morbidity has been a major drawback in the use of this technique. Here, we present our method of split, temporalis harvest for anterior cranial base reconstruction, which seeks to regain dural integrity, while maintaining aesthetic and functional elements of the donor site. We present 2 patients, demonstrating the ease of harvest, fulfillment of both cosmetic and reconstructive goals, widespread applicability, and versatility of our split, temporalis muscle flap. PMID- 22421851 TI - Treatment of frontal sinus fracture using bioabsorbable mesh plates. AB - Accurate reduction and stable fixation are important in the treatment of frontal sinus fracture. Usually, metal plates and screws were used because of easy handling and delicate fixation. However, palpability and possibility for secondary operation for plate removal were shortcomings. For improving these problems, we used absorbable mesh plate for fixation of reduced frontal bones.In this study, 14 patients with frontal sinus fracture were treated by open reduction and rigid fixation using absorbable mesh plates. Mean follow-up period was 17.6 months. Considering anterior and posterior table involvement, nasofrontal duct injury, and concomitant neurosurgical problems, additional surgical procedures including degloving sinus mucosa, cranialization, and obliteration of nasofrontal duct were also conducted.There was no remarkable early and late postoperative complication. Aesthetic results were also satisfactory. Absorbable mesh plates were easy to mold and convenient for screw fixation. Moreover, there was no necessity of secondary operation for removal of plates.We believe that absorbable mesh plates might be a useful material for fixation instead of metal plates and screws especially in mild to moderate degree of frontal bone fractures. PMID- 22421852 TI - Morphology of the zygomaticus minor and its relationship with the orbicularis oculi muscle. AB - The aim of this study was to examine in detail the anatomic variations in the orbicularis oculi muscle (OOc) and relationship of the zygomaticus minor muscle (ZMi) with the OOc, thereby providing an anatomic basis for explaining facial animation and attachment to the periorbital muscle. Sixty-one hemifaces from embalmed Korean adult cadavers (34 males, 27 females; age range, 45-85 years; mean age, 62.6 years) were used in this study. The prevalence of cases in which the ZMi did not run straight from the upper lip, rather running straight to the corner of the levator labii superioris, was 36.1% (22/61), because the origin of ZMi covered the inferior border of the OOc. The prevalence of mixing of the belly of the orbital part of the outer edge of the OOc with the ZMi was 88.5%, and that of blending of the ZMi band into the lower inner corner of the OOc was 55.7%. The area of blending of the OOc and ZMi was located 17.8 mm down from the Frankfort plane and 8.9 mm lateral to the vertical line between the lateral canthus and the Frankfort plane in the lateral part of the OOc. At this position, the mixed belly extends medially for a distance of 16 mm. This research has identified the exact location where the ZMi and OOc blend and determined the relationship between the ZMi and the suborbicularis oculi fat. This result will be given as basic data for understanding facial expressions and for performing composite rhytidectomy. PMID- 22421853 TI - Regenerative medicine: implications for craniofacial surgery. AB - Craniofacial reconstruction of cases with complex anatomy challenges surgeons. The recently emerging field of tissue engineering and regenerative medicine has resulted in a variety of novel therapeutic concepts particularly in the craniofacial area. However, researchers still face significant problems when translating scientific concepts from the bench to the bedside. Reconstruction procedures depend on sustainability, aesthetic outcome, and functionality. Tissue engineering approaches yield powerful tools for long-term satisfying results enabling customized reconstruction and supporting natural healing processes. In conclusion, further advances of tissue-engineered reconstruction need multidisciplinary research to create complex tissue structures and make satisfactory outcomes clinically achievable for most patients. This review highlights clinical advances in the field and gives an overview about current scientific concepts. PMID- 22421854 TI - Straight and angulated abutments in platform switching: influence of loading on bone stress by three-dimensional finite element analysis. AB - PURPOSE: In view of reports in the literature on the benefits achieved with the use of platform switching, described as the use of an implant with a larger diameter than the abutment diameter, the goal being to prevent the (previously) normal bone loss down to the first thread that occurs around most implants, thus enhancing soft tissue aesthetics and stability and the need for implant inclination due to bone anatomy in some cases, the aim of this study was to evaluate bone stress distribution on peri-implant bone, by using three dimensional finite element analysis to simulate the influence of implants with different abutment angulations (0 and 15 degrees) in platform switching. METHODS: Four mathematical models of an implant-supported central incisor were created with varying abutment angulations: straight abutment (S1 and S2) and angulated abutment at 15 degrees (A1 and A2), submitted to 2 loading conditions (100 N): S1 and A1-oblique loading (45 degrees) and S2 and A2-axial loading, parallel to the long axis of the implant. Maximum (sigmamax) and minimum (sigmamin) principal stress values were obtained for cortical and trabecular bone. RESULTS: Models S1 and A1 showed higher sigmamax in cortical and trabecular bone when compared with S2 and A2. The highest sigmamax values (in MPa) in the cortical bone were found in S1 (28.5), followed by A1 (25.7), S2 (11.6), and A2 (5.15). For the trabecular bone, the highest sigmamax values were found in S1 (7.53), followed by A1 (2.87), S2 (2.85), and A2 (1.47). CONCLUSIONS: Implants with straight abutments generated the highest stress values in bone. In addition, this effect was potentiated when the load was applied obliquely. PMID- 22421855 TI - Factors related to blood loss during fronto-orbital advancement. AB - BACKGROUND: Blood loss during fronto-orbital advancement (FOA) remains a significant potential source of morbidity. This study explored variables that might correlate with calculated blood loss (CBL) during this procedure. METHODS: The authors reviewed infants with craniosynostosis who underwent primary FOA (1997-2009). Patient demographics, operative time, and mean arterial pressure (MAP) were recorded. Serial MAPs were averaged for a MAPmean and subtracted from preoperative baseline to calculate MAP%decrease. This provided indicators of both absolute and relative hypotension, respectively. Calculated blood loss was based on preoperative/postoperative hemoglobin values and transfusion volumes and accounted for hemodilutional effects. RESULTS: Ninety infants underwent FOA at an average age of 10.7 +/- 12.9 months and mean weight of 9.0 +/- 7.0 kg. Average operative time was 4.2 hours, and intraoperative MAP was 56.1 mm Hg, 22.6% lower than baseline. Mean CBL was 259.3 mL, or 39.3% of estimated blood volume, negatively correlating with surgical age (r = -0.033, P < 0.05) and positively trending with operative time (r = 0.55, P < 0.05). Absolute hypotension was associated with greater blood loss, as demonstrated by an inverse relationship between CBL and MAPmean (r = -0.19, P < 0.05). From the perspective of relative hypotension, no association was found between CBL and MAP%decrease. CONCLUSIONS: Greater operative efficiency and deferring operative correction to a later age may diminish blood loss during FOA. The study results also raise serious concerns regarding the hemodynamic benefits of controlled systemic hypotension. PMID- 22421856 TI - Risk factors for death in elderly patients with facial fractures secondary to falls. AB - BACKGROUND: Craniomaxillofacial trauma is associated with severe injuries and disability. There are no recent reports analyzing the demographics of facial trauma in elderly patients. Our objective was to review the demographics, outcomes, and risk factors associated with death in elderly patients with facial fractures in a single-institution level I trauma center. METHODS: We performed a retrospective review of the University of Pittsburgh Medical Center Trauma Registry from January 1999 to December 2008 in an institutional review board approved protocol. The search query included all types of craniofacial trauma using International Classification of Diseases, Ninth Revision coding. A chi test was used for analyzing categorical data. Continuous data were analyzed using unpaired t-test or analysis of variance. Logistic regressions were done to determine odds ratio (OR) for death. P = 0.05 was deemed significant. RESULTS: A total of 16,528 patients with facial trauma were identified. Of these, 4536 patients had falls. Among the falls, 1020 patients had facial fractures. Finally, 460 patients were younger than 65 years, and 560 were older than 65 years. The variable with the highest odds for mortality in patients with facial fractures was intensive care unit admission (OR, 13.1), followed by acute renal failure (OR, 10.3), medical history of myocardial infarction (OR, 5.1), coagulopathy (OR, 4.78), age older than 65 years (OR, 4.13), acute respiratory failure (OR, 3.55), Abbreviated Injury Scale score greater than 3 at the head (OR, 3.5), congestive heart failure (OR, 2.64), history of cardiac surgery (OR, 2.4), and vault skull fracture (OR, 2.35). CONCLUSIONS: Craniofacial trauma is a serious condition in the elderly. Associated injuries are demonstrated to have a deleterious effect on survival. Recognition of these risk factors is likely to promote the development of preventive measurements to decrease fatal outcomes. PMID- 22421857 TI - Two- and three-dimensional models for the visualization of jaw tumors based on CT MRI image fusion. AB - PURPOSE: The objective of this study was to demonstrate the feasibility of two- and three-dimensional (2D and 3D) models based on computed tomography-magnetic resonance imaging (CT-MRI) image fusion for the visualization of jaw tumors. METHODS: Seven patients with proved jaw tumors were involved in this study. Both preoperative CT and MRI image data were acquired in DICOM format and imported into Surgicase CMF software, respectively. Then, the structures of interest, including tumor, muscle, and vascular, and so on, were segmented based on different thresholds and reconstructed in 3D texture. Finally, CT-MRI image fusion was semiautomatically performed to obtain the fused 2D images and 3D models for the visualization of jaw tumors. The qualities of the fused 2D images and 3D models together with their potential applications in surgical management of jaw tumors were qualitatively assessed. Besides, the importance of this imaging technique in terms of training junior surgeons was also discussed in detail. RESULTS: Computed tomography-MRI image fusion clearly showed the relationship between tumors and adjacent structures. The qualitative assessment of fused images was satisfied. CONCLUSIONS: Although there are some limitations, the 2D images and 3D models based on CT-MRI image fusion can provide a powerful tool for the visualization of jaw tumors. It may offer surgeons an assisted tool for the subject-specific preoperative planning, surgical simulation, and intraoperative guidance for jaw tumors. Furthermore, it also may offer valuable 2D and 3D models for training junior surgeons or provide a useful tool for surgeons to communicate well with patients. PMID- 22421858 TI - Major donor area complication after a mandibular reconstruction with an osseous fibular free flap: pseudo-compartment syndrome. AB - The popularity of the fibular free flap in mandibular reconstructions is persisting, and major donor area complications rarely occur after fibular free flap operations. Still, we have observed a pseudo-compartment syndrome in a 52 year-old patient on the 12th postoperative day after a mandibular reconstruction with a fibular free flap. When an obstruction in the deep venous system (deep vein thrombosis) was observed in the Doppler ultrasound-guided imaging, the patient has been taken to the operating room for an emergency surgery and the donor area has been completely reopened (in the manner of a fasciotomy). After this procedure, the circulation in the foot appeared to return to normal. The exposed muscles of the patient, who was started on a low-molecular-weight heparin treatment for the deep vein thrombosis, have been closed with skin grafts on the 10th day. No functional loss was observed during the 2-month follow-up period. PMID- 22421859 TI - Outcomes in computer-assisted surgical simulation for orthognathic surgery. AB - Orthognathic surgery is a powerful tool to address skeletal discrepancies of the jaws; however, the model surgery and splint fabrication necessary to successfully complete this surgery are laborious and time consuming. Previous studies have described the utility of computer-assisted surgical simulation (CASS) to eliminate the need for plaster cast model surgery. This article evaluates the implementation of a CASS system for treatment planning and splint fabrication in a series of 11 orthognathic surgery patients. All patients were treatment planned using a CASS system for computer-simulated osteotomies and splint fabrication. As a safety measure, traditional model surgery and splint fabrication were also performed on all cases. Each case was evaluated for accuracy of cephalometric analysis, splint accuracy, splint durability, and ease of treatment planning. All splints fit as well, or better, than those fabricated using traditional methods. In 2 cases, occlusal cants were detected by the CASS system that were undetected by traditional cephalometric analysis and physical examination. In 1 case, the skeletal midline identified on the computed tomographic scan was incongruent with the soft tissue clinical midline of the face, and this discrepancy was recognized and compensated for by correlation of the physical examination and preoperative clinical photos.In this series of 11 patients, the CASS system proved to be an effective mechanism to treatment plan cases and prepare surgical splints for patients undergoing orthognathic surgery. PMID- 22421860 TI - Malignant chondroid syringoma with central nervous system involvement. AB - Malignant chondroid syringoma is a mixed cutaneous tumor, with epithelial and mesenchymal components, which compromises principally the trunk and extremities. This lesion is quite rare, with few cases related in the literature and no publications demonstrating its involvement of the central nervous system. Histologically, owing to its mixed origin, it represents a lesion that is difficult to recognize, often being confused with basocellular carcinoma. We report the case of a female patient, carrier of malignant chondroid syringoma in the occipital region, with invasion of the central nervous system, who was submitted to surgical excision of the lesion at our service. We also made a brief revision of the literature on the theme. PMID- 22421861 TI - Navigation-guided resection for a tenosynovial giant cell tumor involving the temporomandibular joint and skull base. AB - Tenosynovial giant cell tumor is a very rare, benign lesion from the synovium. It seldom happens in the temporomandibular joint area and skull base that is difficult to resect and reconstruct. We present a case treated with computer assisted navigation to help mark the tumor boundaries, protect vital structures, and facilitate the reconstruction process. Follow-up at 6 months after surgery showed no tumor recurrent and good temporomandibular joint function. PMID- 22421862 TI - Management of delayed infection after insertion of bioresorbable plates at the infraorbital rim. AB - Delayed infections after use of absorbable plates in the infraorbital region have been documented in various reports. We report 2 cases of infections at the infraorbital rim after fixation with absorbable plates: one was managed with surgical removal and one was managed with conservative treatment. We recommend that, before treatment, computed tomographic scans and cultures be obtained whenever possible. The presence of maxillary sinusitis is the single most important factor in choosing surgical removal of the plates, but the patient should be fully informed about the possibility of postoperative ectropion. PMID- 22421863 TI - Preemptive analgesic effect of low doses of celecoxib is superior to low doses of traditional nonsteroidal anti-inflammatory drugs. AB - PURPOSE: The purpose of the study was to compare the preemptive analgesic effect of celecoxib, a cyclooxygenase 2 inhibitor, with a traditional nonsteroidal anti inflammatory drug, ibuprofen, in patients after minor oral surgery procedures. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled, prospective clinical trial was conducted over an 8-month period. Participants were randomly allocated to receive a standard oral dose of 200 mg celecoxib, 400 mg ibuprofen, or a placebo containing lactose, preemptively 1 h before surgery. Using a patient diary, patients recorded pain intensity, pain relief, and global evaluations throughout the 24-hour period after dosing. The overall analgesic effect, onset of action, peak effect, and duration of effect were evaluated, with the primary end point being total pain relief over 8 hours. The safety profile was assessed on the basis of physical findings and spontaneous reports of adverse experiences. RESULTS: The results showed that compared with ibuprofen, celecoxib had superior analgesic effects on all measures of analgesic efficacy, including overall analgesic effect (total pain relief over 8 hours: 18.1 vs 12.2, P < 0.001), time to onset of effect (30 vs 60 minutes, P = 0.003), peak pain relief (score, 2.7 vs 2.4, P < 0.05), and duration of effect (>24 vs 7.0 hours, P < 0.001). The safety profile was similar across all treatment groups. CONCLUSIONS: This is the first reported study that demonstrates the superior analgesic effect of celecoxib, for the release of acute postoperative pain following surgery, when compared with the traditional nonsteroidal anti-inflammatory drug, ibuprofen. There was no safety compromise when celecoxib was used in lower doses to provide analgesia for patients who need minor surgery. PMID- 22421864 TI - Ultrasound-guided simultaneous irrigation and drainage of facial abscess. AB - The establishment of drainage and the elimination of the origin of infection are essential procedures for successful management of odontogenic infections. Irrigation and aspiration are considered as the 2 main procedures for the treatment of facial space infections; we invented a new method named simultaneous irrigation and aspiration. The simultaneous irrigation and aspiration method is significantly less painful and less invasive compared with the standard surgical incision and drainage. This method was thought to be useful for managing facial infections if proper patient selection is performed. PMID- 22421865 TI - DELFI: a new orbital conformer in the management of enucleated patients. AB - Anophthalmia and micro-orbitism due to infections, traumatic events, and oncologic disease can occur both in adulthood and in childhood. After restoring the volume of the socket surgically or using an expander, concurrent forniceal expansion with expanding conformer should be maintained. We created a new type of conformer that is possible to fit even in very reduced or very irregularly shaped socket. It is formed by 3 acrylic portions connected by metallic clumps that represent an intrinsic mechanism of expansion. The 3 acrylic portions could be modeled on the shape of the individual patient socket while the metal elements allow a thrust in 3 directions. The positioning of this conformer does not need any surgical treatment and it is possible to fit it in an ambulatory manner; it is shaped on the individual patient and is then available in most cases that occur. PMID- 22421866 TI - Endoscopic thyroidectomy for bilateral thyroid diseases: safety and effectiveness. AB - BACKGROUND: The aim of this study was to assess the safety and efficacy of endoscopic thyroidectomy (ET) for bilateral thyroid diseases. METHODS: From March 2001 to January 2011, we performed a retrospective review of 30 cases of ET via breast approach for bilateral thyroid diseases. We rendered 50 cases of unilateral ET (group 2) and another 30 cases of open thyroidectomy for bilateral thyroid diseases (group 3) as control groups. Comparison between groups 1 and 2 and groups 1 and 3 in perioperative details and follow-up was reviewed. RESULTS: The patients in group 1 required longer operating time, more intraoperative blood loss, more amount of drainage, and longer postoperative hospital stay compared with group 2. Compared with group 3, the patients in group 1 were associated with more operating time but less estimated blood loss, less amount of drainage, and shorter postoperative drainage stay. In group 1, 5 cases have temporary postoperative complications but completed resolution. No recurrence occurred, and all patients were satisfied with their excellent overall cosmesis and the surgical outcome of the procedure. CONCLUSIONS: Endoscopic thyroidectomy is a safe and feasible procedure for bilateral thyroid disease with a good prognosis. PMID- 22421867 TI - Adjacent flaps for lower lip reconstruction after mucocele resection. AB - Mucocele forms because of salivary gland mucous extravasation or retention and is usually related to trauma in the area of the lower lip. It is a common benign lesion in the oral region. Although there are many conservative treatments such as the creation of a pouch (marsupialization), freezing (cryosurgery), micromarsupialization, and CO2 laser vaporization, surgical resection is the most commonly used means. Generally speaking, an elliptic incision was made to fully enucleate the lesion along with the overlying mucosa and the affected glands, then direct suturing is adequate. However, in some cases, direct suturing could cause lower lip deformity, and adjacent flaps for lower lip reconstruction after mucocele resection might be quite necessary. Based on our experience, adjacent mucosal flaps could be used when lesions were close to or even break through the vermilion border or their diameters were much more than 1 cm. A-T advancement flaps and transposition flaps were the mostly applied ones. Follow-up showed that all patients realized primary healing after 1 week postoperatively with satisfactory lower lip appearance, and there was no sign of increasing incidence of relapse. PMID- 22421868 TI - Novel splint allowing concurrent midface and occlusal control during orotracheal intubation. AB - Occlusal splints are used in craniomaxillofacial surgery to control the dental bearing bony structures of the midface and mandible. They are created to guide the mobile bone segments into position based on the ideal or planned dental and facial relationships. For conventional orthognathic cases and maxillofacial trauma scenarios involving the dentition, a nasal endotracheal tube is required, allowing the teeth to be closed into intermaxillary fixation. However, in situations where access to the nasal cavity is required, such as concurrent rhinoplasty, or when higher osteotomies involving the midface are performed requiring advancement or manipulation of the nasal region, the nasal tube needs to be converted into an oral tube (J Clin Anesth 2011;23:342). This requires time and inconvenience and is a potentially dangerous maneuver in the setting of existing surgical edema, fluids, and manipulation. We report on a novel oral splint design allowing for both intermaxillary fixation to be established using an oral endotracheal tube while allowing for manipulation of the midface via the nasal cavity and not requiring a tube change intraoperatively. PMID- 22421869 TI - Inversion of the flap at the lower ear and restoration of the flap at postauricular skin for reconstruction of the earlobe. AB - We describe a technique for reconstruction of the earlobe. This technique is to reconstruct the earlobe by inversing the flap at the lower ear and restoring the flap at postauricular skin. Although there are many procedures that aim to reconstruct the earlobe naturally, the aesthetic results of using our method are better because the scar tissue that remains behind the ear is hidden. PMID- 22421870 TI - Transsutural distraction osteogenesis versus osteotemy distraction osteogenesis. AB - BACKGROUND: The technique of transsutural distraction osteogenesis (TSDO) rendered a new and minimally invasive alternative for midfacial advancement. Many topics addressed the osteotomy distraction of the midface; we know less, however, about the destiny of the advanced midface by transsutural distraction. METHODS: Long-term results of 20 patients with midfacial hypoplasia treated by either TSDO or osteotomy distraction osteogenesis (ODO) were investigated clinically, cephalometrically, and statistically. The follow-up period ranged from 4 to 10 years, and radiographic analysis, inpatient duration, whole length of treatment, times of outpatient treatment, and surgical morbidity were assessed. RESULTS: Nine patients were treated by the technique of TSDO, with a mean follow-up of 5.2 years (range, 4-8 years), and 11 by Le Fort III osteotomy distraction, with a mean follow-up of 6.4 years (range, 4-10 years). In TSDO group, the mean angle of SNA was 74.4 degrees preoperatively, 81.6 degrees immediately after distraction, 81.7 degrees at 6 months postoperatively, and 81.8 degrees in 4- to 8-year postoperative period. In ODO group, the mean angle of SNA was 74.0 degrees preoperatively, 85.3 degrees immediately after distraction, 83.2 degrees at 6 months postoperatively, and 83.1 degrees in 4- to 10-year postoperative period. In TSDO group, the mean advancement of anterior nasal spine-pterygomaxillary fissure length was 5.5 mm immediately after distraction, 0.03 mm at 6 months postoperatively, and 0.4 mm in 4- to 8-year postoperative period, resulting in no statistically significant retrusion; in ODO group, the mean advancement of anterior nasal spinepterygomaxillary fissure length was 12.2 mm immediately after distraction, which decreased 2.5 mm at 6 months postoperatively and 2.5 mm in 4- to 10-year postoperative period, resulting in retrusion rate of about 20%. The patients in ODO group had longer inpatient duration, and 1 patient had an inharmonious forward movement manifested nasal root prominence and medial canthal alteration. Those in group TSDO had a longer process of treatment and more times of outpatient manipulation. CONCLUSIONS: The technique of TSDO is effective, minimally invasive, and aesthetically optimal for early correction of midfacial hypoplasia of the growing children, and the technique of ODO can be used successfully for hypoplastic midface of the adults. The most postoperative retrusion appeared in the first 6 months, and no statistically significant retrusion occurred in growing patients. PMID- 22421871 TI - Computational fluid dynamics study of the inspiratory upper airway and clinical severity of obstructive sleep apnea. AB - The apnea-hypopnea index (AHI) is a widely accepted measure for the severity of obstructive sleep apnea (OSA). Current methods to determine AHI fail to provide anatomic information for treatment decisions. In this report, we studied three dimensional models of upper airways acquired by computed tomographic scanning with geometric measurements and computational fluid dynamics (CFD) analysis and evaluated the correlations with AHI.Participants had CT scans of their upper airways after standard polysomnography studies. Three-dimensional surface models of upper airways were generated for cross-sectional area measurements of the choanae (ACH) and the smallest cross-sectional area (Amin). Computational fluid dynamic analysis was then performed by using this three-dimensional model. Pressure differences required to set tidal volume during inspiration (DeltaPmin INSP) and expiration (DeltaPmax-EXP) and minimum negative pressure produced in the level of ACH (Pmin-INSP at ACH) and Amin (Pmin-INSP at Amin) were calculated. Correlations of these parameters and the body mass index with AHI were analyzed. Statistical differences between groups of different AHI ranges were also compared.The pressure distribution simulated by CFD demonstrated abrupt pressure drops in Amin level, and this phenomenon was more significant in severe OSA. All parameters except ACH and Pmin-INSP at Amin significantly correlated with the AHI, and there were significant statistical differences between the OSA groups and the normal group. The results indicate that, in our study group, the geometry of pharyngeal airway and its CFD simulation correlate well with AHI. This model may be further applied for clinical evaluation. PMID- 22421872 TI - Osteochondroma of the mandibular condyle: surgical excision followed by occlusal stabilization. AB - Osteochondroma of the mandibular condyle in adults can be treated by surgical excision, condylectomy followed by costochondral graft or orthognathic surgery. Such complex treatment plan may not be appropriate for patients with old age, affected with chronic osteochondroma of the condyle. In this clinical report, we present a patient with osteochondroma of the condyle treated by surgical excision. The patient's postoperative occlusion was a contraindication for orthognathic surgery because of the severe abrasion of the teeth and the chronic compensation of the dentition to the deviated mandible. Surgical excision of the lesion was carried out under general anesthesia, and the remaining condylar head was salvaged as much as possible. No graft materials or posthodontic condyle reconstruction was carried out. Because there was no occlusal stop to secure the mandible in a centric relation position of the condyle, a stabilization splint was delivered to position the condyle in a relatively stable position. The stability of the condyle position was evaluated by follow-up cone beam computed tomographic scans of the pathologic and the contralateral condyle, along with clinical factors such as occlusal contact points and mandible movements assayed by ARCUSdigma (KaVo). After significant condylar position was achieved, full prosthodontic reconstruction was performed to both the patient's and the dentist's satisfaction. PMID- 22421873 TI - Epidemiological trends of traumatic optic nerve injuries in the largest Canadian adult trauma center. AB - BACKGROUND: There has been a paucity of information on the epidemiology of traumatic optic neuropathy (TON). This study documents epidemiology of TON over 2 decades in the largest level I adult trauma center in Canada. METHODS: Data on all the trauma patients admitted to Sunnybrook Health Sciences Centre from 1986 to 2007 were collected in a prospective database. The aggregate data on optic nerve injuries including demographic data, etiology, Injury Severity Score (ISS), and associated head and facial injuries were recorded. These were analyzed using univariate and multivariate techniques to summarize the association of different variables with TON. RESULTS: During the study period, 0.4% of all trauma patients had TON. The respective demographics for TON group were as follows: male, 76%; median for age, 33.5 years; length of hospital stay, 14 days; ISS, 32; and case fatality, 14%. About two thirds of patients with TON had associated significant head injuries. Conversely, 2.3% of patients with head injury had TON. The relative incidence of TON per year has remained variable from 0% to 1.2%. Motorized vehicle accidents remained the main etiology of TON (63%), but fall had the highest relative frequency leading to TON. In univariate analysis, both ISS and significant head injury were associated with TON. In multivariate analysis, TON was associated with only nasoethmoid complex fractures and significant head injury. CONCLUSIONS: These data provide useful information on the frequency and etiologies of TON. It also highlights the importance of studies on better diagnostic tools for TON. PMID- 22421874 TI - Cellular microbiology: EPEC puts actin on the Map. PMID- 22421875 TI - Parasite physiology: Plasmodium gets the PK4 blood test. PMID- 22421876 TI - Bacterial secretion: Highly sprung secretion. PMID- 22421877 TI - Modulating immunity as a therapy for bacterial infections. AB - Despite our efforts to halt the increase and spread of antimicrobial resistance, bacteria continue to become less susceptible to antimicrobial drugs over time, and rates of discovery for new antibiotics are declining. Thus, it is essential to explore new paradigms for anti-infective therapy. One promising approach involves host-directed immunomodulatory therapies, whereby natural mechanisms in the host are exploited to enhance therapeutic benefit. The objective is to initiate or enhance protective antimicrobial immunity while limiting inflammation induced tissue injury. A range of potential immune modulators have been proposed, including innate defence regulator peptides and agonists of innate immune components such as Toll-like receptors and NOD-like receptors. PMID- 22421878 TI - Bacterial RNA thermometers: molecular zippers and switches. AB - Bacteria use complex strategies to coordinate temperature-dependent gene expression. Many genes encoding heat shock proteins and virulence factors are regulated by temperature-sensing RNA sequences, known as RNA thermometers (RNATs), in their mRNAs. For these genes, the 5' untranslated region of the mRNA folds into a structure that blocks ribosome access at low temperatures. Increasing the temperature gradually shifts the equilibrium between the closed and open conformations towards the open structure in a zipper-like manner, thereby increasing the efficiency of translation initiation. Here, we review the known molecular principles of RNAT action and the hierarchical RNAT cascade in Escherichia coli. We also discuss RNA-based thermosensors located upstream of cold shock and other genes, translation of which preferentially occurs at low temperatures and which thus operate through a different, more switch-like mechanism. Finally, we consider the potential biotechnological applications of natural and synthetic RNATs. PMID- 22421879 TI - The rise of the Enterococcus: beyond vancomycin resistance. AB - The genus Enterococcus includes some of the most important nosocomial multidrug resistant organisms, and these pathogens usually affect patients who are debilitated by other, concurrent illnesses and undergoing prolonged hospitalization. This Review discusses the factors involved in the changing epidemiology of enterococcal infections, with an emphasis on Enterococcus faecium as an emergent and challenging nosocomial problem. The effects of antibiotics on the gut microbiota and on colonization with vancomycin-resistant enterococci are highlighted, including how enterococci benefit from the antibiotic-mediated eradication of gram-negative members of the gut microbiota. Analyses of enterococcal genomes indicate that there are certain genetic lineages, including an E. faecium clade of ancient origin, with the ability to succeed in the hospital environment, and the possible virulence determinants that are found in these genetic lineages are discussed. Finally, we review the most important mechanisms of resistance to the antibiotics that are used to treat vancomycin resistant enterococci. PMID- 22421881 TI - Nickel-catalyzed C-P coupling of aryl mesylates and tosylates with H(O)PR1R2. AB - A method was developed for the nickel-catalyzed phosphonylation of aryl mesylates and tosylates with H(O)PR(1)R(2). To the best of our knowledge, this is the first example of nickel-catalyzed C-P coupling of aryl mesylates and tosylates. Most of the substrates gave moderate to good yields under our catalytic system. PMID- 22421883 TI - Major air leak at H1N1 swine flu presentation in childhood. PMID- 22421880 TI - The structural biology of HIV-1: mechanistic and therapeutic insights. AB - Three-dimensional molecular structures can provide detailed information on biological mechanisms and, for cases in which the molecular function affects human health, can significantly aid in the development of therapeutic interventions. For almost 25 years, key components of the lentivirus HIV-1, including the envelope glycoproteins, the capsid and the replication enzymes reverse transcriptase, integrase and protease, have been scrutinized to near atomic-scale resolution. Moreover, structural analyses of the interactions between viral and host cell components have yielded key insights into the mechanisms of viral entry, chromosomal integration, transcription and egress from cells. Here, we review recent advances in HIV-1 structural biology, focusing on the molecular mechanisms of viral replication and on the development of new therapeutics. PMID- 22421884 TI - A general and reversible phase transfer strategy enabling nucleotides modified high-quality water-soluble nanocrystals. AB - We report a facile and general phase transfer strategy using nucleotides or nucleosides as phase transfer reagents to render a wide variety of nanomaterials transferring from organic phase to aqueous phase or vice versa, while preserving their intrinsic physicochemical features. PMID- 22421885 TI - Statistical methods for the analysis of time-location sampling data. AB - Time-location sampling (TLS) is useful for collecting information on a hard-to reach population (such as men who have sex with men [MSM]) by sampling locations where persons of interest can be found, and then sampling those who attend. These studies have typically been analyzed as a simple random sample (SRS) from the population of interest. If this population is the source population, as we assume here, such an analysis is likely to be biased, because it ignores possible associations between outcomes of interest and frequency of attendance at the locations sampled, and is likely to underestimate the uncertainty in the estimates, as a result of ignoring both the clustering within locations and the variation in the probability of sampling among members of the population who attend sampling locations. We propose that TLS data be analyzed as a two-stage sample survey using a simple weighting procedure based on the inverse of the approximate probability that a person was sampled and using sample survey analysis software to estimate the standard errors of estimates (to account for the effects of clustering within the first stage [locations] and variation in the weights). We use data from the Young Men's Survey Phase II, a study of MSM, to show that, compared with an analysis assuming a SRS, weighting can affect point prevalence estimates and estimates of associations and that weighting and clustering can substantially increase estimates of standard errors. We describe data on location attendance that would yield improved estimates of weights. We comment on the advantages and disadvantages of TLS and respondent-driven sampling. PMID- 22421886 TI - Nitrogen starvation, salt and heat stress in coffee (Coffea arabica L.): identification and validation of new genes for qPCR normalization. AB - Abiotic stresses are among the most important factors that affect food production. One important step to face these environmental challenges is the transcriptional modulation. Quantitative real-time PCR is a rapid, sensitive, and reliable method for the detection of mRNAs and it has become a powerful tool to mitigate plant stress tolerance; however, suitable reference genes are required for data normalization. Reference genes for coffee plants during nitrogen starvation, salinity and heat stress have not yet been reported. We evaluated the expression stability of ten candidate reference genes using geNorm PLUS, NormFinder, and BestKeeper softwares, in plants submitted to nitrogen starvation, salt and heat stress. EF1, EF1alpha, GAPDH, MDH, and UBQ10 were ranked as the most stable genes in all stresses and software analyses, while RPL39 and RPII were classified as the less reliable references. For reference gene validation, the transcriptional pattern of a Coffea non-symbiotic hemoglobin (CaHb1) was analyzed using the two new recommended and the most unstable gene references for normalization. The most unstable gene may lead to incorrect interpretation of CaHb1 transcriptional analysis. Here, we recommend two new reference genes in Coffea for use in data normalization in abiotic stresses: MDH and EF1. PMID- 22421887 TI - Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis. AB - Organometallic analogues of chloroquine show promise as new antimalarial agents capable of overcoming resistance to the parent drug chloroquine. Here, the synthesis and characterization of three new cymantrene (CpMn(CO)(3)) and cyrhetrene (CpRe(CO)(3)) 4-aminoquinoline conjugates with either an amine or amide linker are reported. The antimalarial activity of the new organometallic conjugates N-(2-(7-chloroquinolin-4-ylamino)ethyl)-4-cymantrenylbutanamide (3), N (2-(7-chloroquinolin-4-ylamino)ethyl)-4-cyrhetrenylbutanamide (4) and N-(7 chloroquinolin-4-yl)-N'-(cymantrenylmethyl)ethane-1,2-diamine (6) was evaluated against a chloroquine-sensitive (CQS) and a chloroquine-resistant strain (CQR) of the malaria parasite Plasmodium falciparum. The cymantrene complex with an amine linker (6) showed good activity against the CQS strain but was inactive against the CQR strain. In contrast, cymantrene and cyrhetrene compounds with an amide linker were active against both the CQS and the CQR strain. In addition, the antibacterial, anti-trypanosomal and anti-leishmanial activity of the compounds was evaluated. Compound 6 showed submicromolar activity against Trypanosoma brucei at a concentration where the toxicity to normal human cells is low. No significant effect was noticed on the exchange of manganese for rhenium in the CpM(CO)(3) moiety in any of the biological assays. PMID- 22421888 TI - Role of cellular oxidative stress and cytochrome c in the pathogenesis of psoriasis. AB - Oxidative-free radicals and apoptosis have linked to chronic skin diseases. Higher levels of oxidative radicals and the release of mitochondrial cytochrome c may have a role in the pathogenesis of psoriasis. We investigated the possible role of cellular oxidative stress and release of cytochrome c of mitochondria in the pathogenesis of psoriasis. Disease severity was assessed by psoriasis area severity index score (PASI) of 55 psoriasis patients, they grouped as mild (11), moderate (20) and severe (24), also 20 healthy individuals used as controls. All groups were subjected for serum malondialdehyde (MDA), nitric oxide (NO.), superoxide dismutase (SOD), catalase (CAT), total antioxidant status (TAS) and serum cytochrome c concentrations. We found that, (1) Severity wise increase in MDA and NO., and decrease in SOD, CAT and TAS levels in all patients with different degrees of psoriasis; (2) PASI showed positive correlation with the increase in MDA and NO., and negatively with decreased SOD, CAT and TAS levels; (3) significant increase in cytochrome c level was observed among psoriasis patients which showed negative correlation to MDA and NO. levels in mild and positively with moderate and severe groups. The release of mitochondrial cytochrome c indicates the induction of apoptosis mediated via oxidative stress which ultimately plays role in the pathogenesis of psoriasis. PMID- 22421889 TI - Reynolds numbers exhibit dramatic influence on directionality of movement of self propelled systems. AB - Self-propelled artificial objects are at the current forefront of research. We demonstrate here that the motion directionality of millimetre sized self propelled objects is highly dependent on the Reynolds numbers (Re) of the systems, with emphasis on the "intermediate" Re region (1-600). Our findings have strong implication on the motion controllability and predictability of these independent self-propelled systems. PMID- 22421890 TI - Expert's comment concerning Grand Rounds case entitled "Fusionless posterior hemivertebra resection in a 2-year-old child with 16 years follow-up" (by D. Jeszenszky, T. F. Fekete, F. S. Kleinstueck, D. Haschtmann, L. Bognar). PMID- 22421891 TI - Human mesenchymal stem cells and biomaterials interaction: a promising synergy to improve spine fusion. AB - PURPOSE: Spine fusion is the gold standard treatment in degenerative and traumatic spine diseases. The bone regenerative medicine needs (i) in vitro functionally active osteoblasts, and/or (ii) the in vivo induction of the tissue. The bone tissue engineering seems to be a very promising approach for the effectiveness of orthopedic surgical procedures, clinical applications are often hampered by the limited availability of bone allograft or substitutes. New biomaterials have been recently developed for the orthopedic applications. The main characteristics of these scaffolds are the ability to induce the bone tissue formation by generating an appropriate environment for (i) the cell growth and (ii) recruiting precursor bone cells for the proliferation and differentiation. A new prototype of biomaterials known as "bioceramics" may own these features. Bioceramics are bone substitutes mainly composed of calcium and phosphate complex salt derivatives. METHODS: In this study, the characteristics bioceramics bone substitutes have been tested with human mesenchymal stem cells obtained from the bone marrow of adult orthopedic patients. RESULTS: These cellular models can be employed to characterize in vitro the behavior of different biomaterials, which are used as bone void fillers or three-dimensional scaffolds. CONCLUSIONS: Human mesenchymal stem cells in combination with biomaterials seem to be good alternative to the autologous or allogenic bone fusion in spine surgery. The cellular model used in our study is a useful tool for investigating cytocompatibility and biological features of HA-derived scaffolds. PMID- 22421892 TI - One-step synthesis of fluorescein modified nano-carbon for Pd(II) detection via fluorescence quenching. AB - Carbon black (CB) nanoparticles modified with fluorescein, a highly fluorescent molecule, were prepared using a facile and efficient methodology. Simply stirring CB in aqueous solution containing fluorescein resulted in the strong physisorption of fluorescein onto the CB surface. The resulting Fluorescein/CB was then characterised by means of X-ray photoelectron spectroscopy (XPS), cyclic voltammetry (CV), fluorescence microscopy and fluorescence spectroscopy. The optimum experimental conditions for fluorescence of Fluorescein/CB viz. fluorescence excitation and emission wavelengths, O(2) removal and the amount of Fluorescein/CB used, were investigated. The Fluorescein/CB was used as a fluorescent probe for the sensitive detection of Pd(II) in water, based on fluorescence quenching. The results demonstrated that the fluorescence intensity of Fluorescein/CB decreased with increasing Pd(II) concentration, and the fluorescence quenching process could be described by the Stern-Volmer equation. The limit of detection (LOD) for the fluorescence quenching of Fluorescein/CB by Pd(II) in aqueous solution was found to be 1.07 MUM (based on 3sigma). Last, approaches were studied for the removal of Fe(III) which interferes with the fluorescence quenching of Fluorescein/CB. Complexation of Fe(III) with salicylic acid was used to enhance and control the selectivity of Fluorescein/CB sensor towards Pd(II) in the presence of Fe(III). PMID- 22421893 TI - Association between FTO variant and change in body weight and its interaction with dietary factors: the DiOGenes study. AB - Although FTO is an established obesity-susceptibility locus, it remains unknown whether it influences weight change in adult life and whether diet attenuates this association. Therefore, we investigated the association of FTO-rs9939609 with changes in weight and waist circumference (WC) during 6.8 years follow-up in a large-scale prospective study and examined whether these associations were modified by dietary energy percentage from fat, protein, carbohydrate, or glycemic index (GI). This study comprised data from five countries of European Prospective Investigation into Cancer and Nutrition (EPIC) and was designed as a case-cohort study for weight gain. Analyses included 11,091 individuals, of whom 5,584 were cases (age (SD), 47.6 (7.5) years), defined as those with the greatest unexplained annual weight gain during follow-up and 5,507 were noncases (48.0 (7.3) years), who were compared in our case-noncase (CNC) analyses. Furthermore, 6,566 individuals (47.9 (7.3) years) selected from the total sample (all noncases and 1,059 cases) formed the random subcohort (RSC), used for continuous trait analyses. Interactions were tested by including interaction terms in the models. In the RSC-analyses, FTO-rs9939609 was associated with BMI (beta (SE), 0.17 (0.08) kg.m(-2)/allele; P = 0.034) and WC (0.47 (0.21) cm/allele; P = 0.026) at baseline, but not with weight change (5.55 (12.5) g.year(-1)/allele; P = 0.66) during follow up. In the CNC-analysis, FTO-rs9939609 was associated with increased risk of being a weight-gainer (OR: 1.1; P = 0.045). We observed no interaction between FTO-rs9939609 and dietary fat, protein and carbohydrate, and GI on BMI and WC at baseline or on change in weight and WC. FTO-rs9939609 is associated with BMI and WC at baseline, but association with weight gain is weak and only observed for extreme gain. Dietary factors did not influence the associations. PMID- 22421894 TI - HCV core-induced nonobese hepatic steatosis is associated with hypoadiponectinemia and is ameliorated by adiponectin administration. AB - Obesity-related hepatic steatosis is commonly associated with central fat accumulation and alterations in adipocytokine secretion; however, the connection between nonobese hepatic steatosis and adipocytokines remains unclear. We aim to investigate this connection using an animal model of conditional hepatitis C virus (HCV) core-transgenic mice. Double transgenic mice (DTM) with doxycycline (dox)-regulated hepatic overexpression of the HCV core protein were fed standard rodent chow ad libitum following 1 month of a dox-rich diet. The mice exhibited nonobese hepatic steatosis at 2 months of age. The levels of leptin and adiponectin were assessed in 2-month-old DTM (i.e., HCV core-tetracycline transactivator (tTA)) and single transgenic mice (STM; i.e., tTA). The total fat mass and the body fat distribution of the mice were evaluated using dual-energy X ray absorptiometry (DEXA) and magnetic resonance imaging (MRI). Microarray analyses and quantitative real-time PCR were conducted using RNA obtained from the visceral fat of paired DTM and STM. Adiponectin was administered intraperitoneally to the 2-month-old DTM. No significant differences of the various fat components were noted between the DTM and STM. Leptin mRNA was downregulated in the visceral fat of DTM (P = 0.011), and serum adiponectin protein levels were reduced in the DTM compared with those in the STM (P = 0.035). Adiponectin treatment also significantly ameliorated hepatic steatosis in the DTM compared to the controls (P = 0.024). In conclusion, HCV core-induced nonobese hepatic steatosis is associated with downregulation of the leptin gene in visceral fat and concurrent hypoadiponectinemia; however, these effects may be ameliorated by adiponectin treatment. PMID- 22421895 TI - Air-displacement plethysmography pediatric option in 2-6 years old using the four compartment model as a criterion method. AB - The objective of this study was to determine the accuracy, precision, bias, and reliability of percent fat (%fat) determined by air-displacement plethysmography (ADP) with the pediatric option against the four-compartment model in 31 children (4.1 +/- 1.2 years, 103.3 +/- 10.2 cm, 17.5 +/- 3.4 kg). %Fat was determined by (BOD POD Body Composition System; COSMED USA, Concord, CA) with the pediatric option. Total body water (TBW) was determined by isotope dilution ((2)H(2)O; 0.2 g/kg) while bone mineral was determined by dual-energy X-ray absorptiometry (DXA) (Lunar iDXA v13.31; GE, Fairfield, CT and analyzed using enCore 2010 software). The four-compartment model by Lohman was used as the criterion measure of %fat. The regression for %fat by ADP vs. %fat by the four-compartment model did not deviate from the line of identity where: y = 0.849(x) + 4.291. ADP explained 75.2% of the variance in %fat by the four-compartment model while the standard error of the estimate (SEE) was 2.09 %fat. The Bland-Altman analysis showed %fat by ADP did not exhibit any bias across the range of fatness (r = 0.04; P = 0.81). The reliability of ADP was assessed by the coefficient of variation (CV), within subject SD, and Cronbach's alpha. The CV was 3.5%, within-subject SD was 0.9%, and Cronbach's alpha was 0.95. In conclusion, ADP with the pediatric option is accurate, precise, reliable, and without bias in estimating %fat in children 2-6 years old. PMID- 22421896 TI - Parent predictors of child weight change in family based behavioral obesity treatment. AB - Family based behavioral treatment for overweight and obese children includes parenting skills targeting the modification of child eating and activity change. The purpose of this study was to examine parenting skills and parent weight change as predictors of child weight change in a sample of 80 parent/child dyads who were enrolled in a family based behavioral weight loss program for childhood obesity. Eighty overweight and obese children and their parents who enrolled in treatment in two sites were included in the study. Variables included those related to parent modeling (parent BMI), home food environment, parenting (parent and child report), and demographics. Results suggested that parent BMI change was a significant predictor of child weight, in that a reduction of 1 BMI unit in the parent was associated with a 0.255 reduction in child BMI. None of the other variables were significant in the final model. This study is consistent with other research showing that parent weight change is a key contributor to child weight change in behavioral treatment for childhood obesity. Researchers and clinicians should focus on encouraging parents to lose weight to assist their overweight and obese child in weight management. PMID- 22421897 TI - BMI predicts emotion-driven impulsivity and cognitive inflexibility in adolescents with excess weight. AB - Adolescent obesity is increasingly viewed as a brain-related dysfunction, whereby reward-driven urges for pleasurable foods "hijack" response selection systems, such that behavioral control progressively shifts from impulsivity to compulsivity. In this study, we aimed to examine the link between personality factors (sensitivity to reward (SR) and punishment (SP), BMI, and outcome measures of impulsivity vs. flexibility in--otherwise healthy--excessive weight adolescents. Sixty-three adolescents (aged 12-17) classified as obese (n = 26), overweight (n = 16), or normal weight (n = 21) participated in the study. We used psychometric assessments of the SR and SP motivational systems, impulsivity (using the UPPS-P scale), and neurocognitive measures with discriminant validity to dissociate inhibition vs. flexibility deficits (using the process-approach version of the Stroop test). We tested the relative contribution of age, SR/SP, and BMI on estimates of impulsivity and inhibition vs. switching performance using multistep hierarchical regression models. BMI significantly predicted elevations in emotion-driven impulsivity (positive and negative urgency) and inferior flexibility performance in adolescents with excess weight--exceeding the predictive capacity of SR and SP. SR was the main predictor of elevations in sensation seeking and lack of premeditation. These findings demonstrate that increases in BMI are specifically associated with elevations in emotion-driven impulsivity and cognitive inflexibility, supporting a dimensional path in which adolescents with excess weight increase their proneness to overindulge when under strong affective states, and their difficulties to switch or reverse habitual behavioral patterns. PMID- 22421898 TI - Is there a better way to monitor abstinence among substance abusers awaiting transplantation? AB - PURPOSE OF REVIEW: Conventional biomarkers are poor measures of ongoing abstinence. Due to short and variable windows of detection, the chances that an active substance user will be detected during the 6-month waiting period depend on the testing method and the drug. Herein we discuss hair testing as an alternative matrix for monitoring abstinence. Issues and obstacles related to adoption of a more uniform testing protocol are identified. RECENT FINDINGS: Hair testing is a powerful matrix with the capacity to detect drugs for up to 90 days. Seemingly a logical choice for use in situations in which continuous abstinence is required, it mostly has been employed in Europe with forensic populations such as alcoholics seeking drivers license reinstatement. Only two studies have been conducted in transplant patients. In both, hair testing detected more active users than other modalities. SUMMARY: Use of conventional biomarkers results in variable rates of drug detection, raising questions about fairness of the selection process. Hair analysis significantly increases detection rates. Programs adopting hair analysis should be prepared for more patients to be disqualified during the 6-month waiting period, but those testing negative at baseline could, theoretically, proceed with transplantation sooner. Selection of more optimal candidates also could improve outcomes. PMID- 22421899 TI - Current world literature. PMID- 22421901 TI - Dural mast cell degranulation is a putative mechanism for headache induced by PACAP-38. AB - BACKGROUND: Pituitary adenylate cyclase activating peptide-38 (PACAP-38) has been shown to induce migraine in migraineurs, whereas the related peptide vasoactive intestinal peptide (VIP) does not. In the present study we examine the hypothesis that PACAP-38 and its truncated version PACAP-27 but not VIP cause degranulation of mast cells in peritoneum and in dura mater. METHODS: The degranulatory effects of PACAP-38, PACAP-27 and VIP were investigated by measuring the amount of N acetyl-beta-hexosaminidase released from isolated peritoneal mast cells and from dura mater attached to the skull of the rat in vitro. In peritoneal mast cells N truncated fragments of PACAP-38 (PACAP(6-38), PACAP(16-38) and PACAP(28-38)) were also studied. To investigate transduction pathways involved in mast cell degranulation induced by PACAP-38, PACAP-27 and VIP, the phospholipase C inhibitor U-73122 and the adenylate cyclase inhibitor SQ 22536 were used. RESULTS: The peptides induced degranulation of isolated peritoneal mast cells of the rat with the following order of potency: PACAP-38 = PACAP(6-38) = PACAP(16 38) " PACAP-27 = VIP = PACAP(28-38). In the dura mater we found that 10(-5) M PACAP-38 was significantly more potent in inducing mast cell degranulation than the same concentration of PACAP-27 or VIP. Inhibition of intracellular mechanisms demonstrated that PACAP-38-induced degranulation is mediated by the phospholipase C pathway. Selective blockade of the PAC(1) receptor did not attenuate degranulation. CONCLUSION: These findings correlate with clinical studies and support the hypothesis that mast cell degranulation is involved in PACAP-induced migraine. PACAP-38 has a much stronger degranulatory effect on rat peritoneal and dural mast cells than VIP and PACAP-27. The difference in potency between PACAP 38- and PACAP-27/VIP-induced peritoneal mast cell degranulation is probably not related to the PAC(1) receptor but is caused by a difference in efficacy on phospholipase C. PMID- 22421902 TI - Migraine-triggered hemifacial spasm: three new cases. AB - BACKGROUND: The occurrence of hemifacial spasm (HFS) during an episode of migraine has been seldom reported. Here we describe three new cases presenting with HFS in association with migraine attacks. CASE RESULTS: Three patients (one woman and two men, aged 31-36 years) developed HFS in close temporal relationship with migraine headaches. All of them started having the muscle spasms after pain onset. Two of them had electromyographic evidence of facial nerve damage, and continued having HFS once the pain abated. CONCLUSIONS: Migraine attacks may be associated with HFS. The appearance of HFS could be related to migraine activity. A mechanism of central hyperexcitability in connection with nociceptive inputs on the trigeminal nucleus caudalis and/or a dilation of vessels compressing the facial nerve at the root exit zone could lead to the development of HFS in predisposed patients. 'Migraine-triggered hemifacial spasm' could possibly be regarded as a complication of migraine. PMID- 22421904 TI - Triplet state of 4-methoxybenzyl alcohol chemisorbed on silica nanoparticles. AB - The knowledge of photochemical kinetics in colloidal systems is important in understanding environmental photochemistry on dispersed solid surfaces. As model materials for the chemically sorbed organic compounds present in natural environments, modified silica nanoparticles (NPs) were obtained here by condensation of the silanol groups of fumed silica nanoparticles with 4 methoxybenzyl alcohol. These particles were characterized by different techniques. To evaluate their toxicity, the inhibition of the natural luminescence emission of the marine bacterium Vibrio fischeri in suspensions of the particles was measured. Laser flash-photolysis experiments (lambda(exc) = 266 nm) performed with NP suspensions in acetonitrile-aqueous phosphate buffer mixtures showed the formation of the lowest triplet excited state of the chemisorbed organic groups (lambda(max) = 390 nm). DFT calculations of the absorption spectrum of this radical support the assignment. From the calculated triplet energy, a thermodynamically favorable energy transfer from these triplet states to oxygen to yield singlet molecular oxygen is predicted. A value of 0.09 was measured for the quantum yield of singlet molecular oxygen generation by air saturated suspensions of the nanoparticles in the mixture of solvents acetonitrile-aqueous phosphate buffer. The quantum yield of singlet molecular oxygen generation by the free 4-methoxybenzyl alcohol in the same solvent is 0.31. PMID- 22421905 TI - Amlodipine enhances amelioration of vascular insulin resistance, oxidative stress, and metabolic disorders by candesartan in metabolic syndrome rats. AB - BACKGROUND: The pharmacological advantage of combination of an angiotensin receptor blocker (ARB) and a calcium-channel blocker (CCB) is not fully defined. This study was undertaken to elucidate the potential benefit of their combination in metabolic syndrome. METHODS: SHR/NDmcr-cp (SHRcp), a rat model of human metabolic syndrome, were divided into four groups, and were administered (i) vehicle, (ii) candesartan (an ARB) 0.3 mg/kg/day, (iii) amlodipine (a CCB) 3 mg/kg/day, and (iv) candesartan 0.3 mg/kg/day plus amlodipine 3 mg/kg/day, for 4 weeks. RESULTS: Candesartan, amlodipine, or their combination significantly ameliorated the impairment of vascular endothelium-dependent relaxation with acetylcholine in SHRcp. However, the impairment of insulin-induced vasodilation in SHRcp was partially improved by candesartan alone, but not by amlodipine alone. Interestingly, amlodipine added to candesartan synergistically enhanced the improvement of impaired insulin-induced vasodilation by candesartan, indicating the synergistic improvement of vascular insulin resistance by the combination of these drugs. Candesartan alone, but not amlodipine alone, significantly attenuated vascular superoxide and NADPH oxidase subunit p22phox in SHRcp. Amlodipine added to candesartan synergistically enhanced the reduction of vascular p22phox levels and superoxide by candesartan in SHRcp, suggesting the association of vascular insulin resistance with oxidative stress. Furthermore, the combination of candesartan with amlodipine synergistically decreased the increase in visceral adipocyte size, serum free-fatty acid, and tumor necrosis factor-alpha in SHRcp. CONCLUSIONS: ARB and CCB combination synergistically ameliorated vascular insulin resistance in metabolic syndrome, being associated with the synergistic attenuation of vascular oxidative stress and metabolic disorders. PMID- 22421906 TI - Red wine polyphenols do not lower peripheral or central blood pressure in high normal blood pressure and hypertension. AB - BACKGROUND: Epidemiological data suggest that modest red wine consumption may reduce cardiovascular disease risk. Red wine polyphenols improved human endothelial vascular function and reduced blood pressure (BP) in animal studies, but the results of human intervention studies investigating the effect of red wine polyphenols on BP are inconsistent. The objective was to investigate whether polyphenols extracted from red wine reduce peripheral and central BP in subjects with high-normal BP or grade 1 hypertension. METHODS: In a double-blind, placebo controlled three-period crossover trial, we assigned 61 subjects (mean age 61.4 +/- 8.4 years) with office systolic BP 135 +/- 9 mm Hg and diastolic BP 82 +/- 8 mm Hg to dairy drinks containing either placebo, 280 mg red wine polyphenols, or 560 mg red wine polyphenols. After each 4-week intervention period, office and 24 h ambulatory BP measurements, and central hemodynamic measurements derived from continuous finger BP recordings were assessed. RESULTS: Polyphenol treatment did not significantly affect 24-h BP: systolic/diastolic BP was 143 +/- 2/84 +/- 1 mm Hg after placebo, 143 +/- 2/84 +/- 1 mm Hg after 280 mg/day of red wine polyphenols, and 142 +/- 2/83 +/- 1 mm Hg after 560 mg/day. Neither dose of polyphenol treatment changed office or central BP, aortic augmentation index (AIx) or pulse wave reflection index. CONCLUSIONS: Intake of red wine polyphenols in two different dosages for 4 weeks did not decrease peripheral or central BP in subjects with a high normal or grade 1 hypertension. Our findings do not support the hypothesis that polyphenols account for the suggested cardiovascular benefits of red wine consumption by lowering BP. PMID- 22421907 TI - Independent association of cognitive dysfunction with cardiac hypertrophy irrespective of 24-h or sleep blood pressure in older hypertensives. AB - BACKGROUND: Our aim was to assess whether cardiac hypertrophy is associated with cognitive function independently of office, 24-h, or sleep blood pressure (BP) levels in older hypertensive patients treated with antihypertensive medications. METHODS: In this cross-sectional study, we recruited 443 hypertensive patients aged over 60 years (mean age: 73.0 years; 41% men) who were ambulatory, lived independently, and were without clinically overt dementia. They underwent measurements of 24-h BP monitoring, echocardiographic left ventricular mass index (LVMI), and cognitive function (mini-mental state examination, MMSE). RESULTS: MMSE score was inversely associated with office, 24-h, awake, and sleep systolic BP (SBP) (each, P < 0.05). There was a close association between MMSE score and LVMI (rho = -0.32; P < 0.001). Using multiple logistic regression analysis including numerous covariates (i.e., age, sex, obesity, current smoking, educational level, duration of antihypertensive medications, renal dysfunction, statin use, and previous history of cardiovascular disease), the odds ratio (OR) for the presence of cognitive dysfunction, defined as the lowest quartile of MMSE score (median MMSE score: 23 points; n = 115), was estimated; the presence of cardiac hypertrophy (LVMI >=125 kg/m(2) in men and >=110 kg/m(2) in women) as well as uncontrolled 24-h BP (mean 24-h SBP/diastolic BP (DBP) >=130/80 mm Hg) or sleep BP (mean sleep SBP/DBP >=120/70 mm Hg), but not uncontrolled office BP (mean office SBP/DBP >=140/90 mm Hg), were independently associated with cognitive dysfunction (all P < 0.05). CONCLUSIONS: Among older hypertensive patients with antihypertensive medications, those who had echocardiographically determined cardiac hypertrophy may be at high risk for cognitive dysfunction, irrespective of their office BP and 24-h BP levels. PMID- 22421908 TI - Effect of endurance exercise training and curcumin intake on central arterial hemodynamics in postmenopausal women: pilot study. AB - BACKGROUND: Lifestyle modification (i.e., regular physical activity and diet) is effective in preventing the age-related increase in cardiovascular disease risks. Potential therapeutic effects of curcumin (diferuloylmethane) have been confirmed on various diseases, including cancer and Alzheimer's disease, but the effects of curcumin have not been tested on central arterial hemodynamics. The aim of this pilot study was to test the hypothesis that the regular endurance exercise combined with daily curcumin ingestion lowers the age-related increase in left ventricular (LV) afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women using a randomized, double-blind, placebo-controlled, parallel manner. METHODS: Forty-five women were randomly assigned to four interventions: "placebo ingestion" (n = 11), "curcumin ingestion" (n = 11), "exercise training with placebo ingestion" (n = 11), or "exercise training with curcumin ingestion" (n = 12). Curcumin or placebo pills (150 mg/day) were administered for 8 weeks. Aortic blood pressure (BP) and augmentation index (AIx), an index of LV afterload, were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms. RESULTS: There were no significant differences in baseline hemodynamic variables among four groups. After the interventions, brachial systolic BP (SBP) significantly decreased in both exercise-trained groups (P < 0.05 for both), whereas aortic SBP significantly decreased only in the combined-treatment (e.g., exercise and curcumin) group (P < 0.05). Heart rate (HR) corrected aortic AIx significantly decreases only in the combined-treatment group. CONCLUSIONS: These findings suggest that regular endurance exercise combined with daily curcumin ingestion may reduce LV afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women. PMID- 22421909 TI - [Early diagnosis in Alzheimer's disease protects competence]. PMID- 22421910 TI - The science of interruption. PMID- 22421911 TI - Development of an evidence-based framework of factors contributing to patient safety incidents in hospital settings: a systematic review. AB - OBJECTIVE: The aim of this systematic review was to develop a 'contributory factors framework' from a synthesis of empirical work which summarises factors contributing to patient safety incidents in hospital settings. DESIGN: A mixed methods systematic review of the literature was conducted. DATA SOURCES: Electronic databases (Medline, PsycInfo, ISI Web of knowledge, CINAHL and EMBASE), article reference lists, patient safety websites, registered study databases and author contacts. ELIGIBILITY CRITERIA: Studies were included that reported data from primary research in secondary care aiming to identify the contributory factors to error or threats to patient safety. RESULTS: 1502 potential articles were identified. 95 papers (representing 83 studies) which met the inclusion criteria were included, and 1676 contributory factors extracted. Initial coding of contributory factors by two independent reviewers resulted in 20 domains (eg, team factors, supervision and leadership). Each contributory factor was then coded by two reviewers to one of these 20 domains. The majority of studies identified active failures (errors and violations) as factors contributing to patient safety incidents. Individual factors, communication, and equipment and supplies were the other most frequently reported factors within the existing evidence base. CONCLUSIONS: This review has culminated in an empirically based framework of the factors contributing to patient safety incidents. This framework has the potential to be applied across hospital settings to improve the identification and prevention of factors that cause harm to patients. PMID- 22421912 TI - Development and evaluation of a 3-day patient safety curriculum to advance knowledge, self-efficacy and system thinking among medical students. AB - PURPOSE: To develop a patient safety curriculum and evaluate its impact on medical students' safety knowledge, self-efficacy and system thinking. METHODS: This study reports on curriculum development and evaluation of a 3-day, clinically oriented patient safety intersession that was implemented at the Johns Hopkins School of Medicine in January 2011. Using simulation, skills demonstrations, small group exercises and case studies, this intersession focuses on improving students' teamwork and communication skills and system-based thinking while teaching on the causes of preventable harm and evidence-based strategies for harm prevention. One hundred and twenty students participated in this intersession as part of their required second year curriculum. A pre-post assessment of students' safety knowledge, self-efficacy in safety skills and system-based thinking was conducted. Student satisfaction data were also collected. RESULTS: Students' safety knowledge scores significantly improved (mean +19% points; 95% CI 17.0 to 21.6; p<0.01). Composite system thinking scores increased from a mean pre-intersession score of 60.1 to a post-intersession score of 67.6 (p<0.01). Students had statistically significant increases in self efficacy for all taught communication and safety skills. Participant satisfaction with the intersession was high. CONCLUSIONS: The patient safety intersession resulted in increased knowledge, system-based thinking, and self-efficacy scores among students. Similar intersessions can be implemented at medical, nursing, pharmacy and other allied health schools separately or jointly as part of required school curricula. Further study of the long-term impact of such education on knowledge, skills, attitudes and behaviours of students is warranted. PMID- 22421913 TI - Do some trusts deliver a consistently better experience for patients? An analysis of patient experience across acute care surveys in English NHS trusts. AB - INTRODUCTION: Data were used from inpatient, outpatient and accident and emergency surveys in acute trusts in England to examine consistency in patient reported experience across services, and factors associated with systematic variations in performance. METHODS: Standardised mean scores for six domains of patient experience were constructed for each survey for 145 non-specialist acute trusts. Hierarchical cluster analysis was used to investigate whether and how trust performance clusters. Multilevel regression analysis was used to determine trust characteristics associated with performance. RESULTS: Cluster analysis identified three groups: trusts that performed consistently above (30 trusts) or below (six trusts) average, and those with mixed performance. All the poor performing trusts were in London, none were foundation trusts or teaching hospitals, and they had the highest mean deprivation score and the lowest proportion of white inpatients and response rates. Foundation and teaching status, and the proportion of white inpatients, were positively associated with performance; deprivation and response rates showed less consistent positive associations. No regional effects were apparent after adjusting for independent variables. CONCLUSION: The results have significant implications for quality improvement in the NHS. The finding that some NHS providers consistently perform better than others suggests that there are system-wide determinants of patient experience and the potential for learning from innovators. However, there is room for improvement overall. Given the large samples of these surveys, the messages could also have relevance for healthcare systems elsewhere. PMID- 22421914 TI - A process-analysis microsystem based on density gradient centrifugation and its application in the study of the galvanic replacement mechanism of Ag nanoplates with HAuCl4. AB - Density gradient ultracentrifuge separation has been employed as a process analysis microsystem combining a microreactor and a separator. As a paradigm, intermediates formed after tens of seconds in the galvanic replacement of Ag nanoplates in high concentrated AuCl(4)(-) solution are captured, providing evidence of the mechanism of the reaction, which is difficult to obtain in other ways. PMID- 22421915 TI - Use of adult day care centers: do they offset utilization of health care services? AB - PURPOSE: Based on the medical offset effect, the goal of the study was to examine the extent to which users and nonusers of adult day care centers (ADCC) differ in frequency of use of out-patient health services (visits to specialists) and in patient health services (number of hospital admissions, length of hospitalizations, and visits to emergency departments). DESIGN AND METHODS: A case-control study was used with a sample of 800 respondents, of whom 400 were users of 13 day care centers in the southern region of Israel and 400 were nonusers, matched by age, gender, and active family physician. Data collection included face-to-face interviews using a structured questionnaire. Data on health care service utilization were drawn from the central computerized data of one of the health care organizations in Israel. RESULTS: Although users of ADCC significantly differed from nonusers in socioeconomic characteristics, they did not significantly differ from nonusers in the magnitude of health care services' utilization. Utilization of health care services was rather connected with morbidity rather than with use of ADCC. Therefore, no offset effect was found. IMPLICATIONS: The current form of ADCC in Israel focuses mainly on meeting social needs of the participants and therefore do not meet the their actual health needs. Therefore, inclusion of health services within ADCC may have an offset effect, but this necessitates further examination. PMID- 22421916 TI - Impact on seniors of the patient-centered medical home: evidence from a pilot study. AB - PURPOSE: To assess the impact on health care cost and quality among seniors of a patient-centered medical home (PCMH) pilot at Group Health Cooperative, an integrated health care system in Washington State. DESIGN AND METHODS: A prospective before-and-after evaluation of the experience of seniors receiving primary care services at 1 pilot clinic compared with seniors enrolled at the remaining 19 primary care clinics owned and operated by Group Health. Analyses of secondary data on quality and cost were conducted for 1,947 seniors in the PCMH clinic and 39,396 seniors in the 19 control clinics. Patient experience with care was based on survey data collected from 487 seniors in the PCMH clinic and of 668 in 2 specific control clinics that were selected for their similarities in organization and patient composition to the pilot clinic. RESULTS: After adjusting for baseline, seniors in the PCMH clinic reported higher ratings than controls on 3 of 7 patient experience scales. Seniors in the PCMH clinic had significantly greater quality outcomes over time, but this difference was not significant relative to control. PCMH patients used more e-mail, phone, and specialist visits but fewer emergency services and inpatient admissions for ambulatory care sensitive conditions. At 1 and 2 years, the PCMH and control clinics did not differ significantly in overall costs. IMPLICATIONS: A PCMH redesign can be associated with improvements in patient experience and quality without increasing overall cost. PMID- 22421917 TI - Hand-assisted positioning and contact pressure control for motion compensated robotized transcranial magnetic stimulation. AB - PURPOSE: In Transcranial Magnetic Stimulation (TMS), the principle of magnetic induction is used to stimulate the brain non-invasively. Currently, robotic TMS systems are developed to guarantee precise coil placement on the head and in this way achieve the repeatability of stimulation results. However, usability concerns such as the complicated coil positioning are still unsolved for motion compensated robotized TMS. In this paper, we demonstrate the integration of a force-torque control into a robotic TMS system to improve usability, safety, and precision. METHODS: We integrated a force-torque sensor between robot effector and TMS coil. Coil calibration and gravity compensation have been developed. Based on them, we have implemented hand-assisted positioning for easy and fast coil placement. Furthermore, we have enhanced the existing motion compensation algorithms with a contact pressure control. RESULTS: The positioning time for an experienced user decreased up to 40% with the help of hand-assisted positioning in comparison with not hand-assisted robotized positioning. It also enabled an inexperienced user to use the system safely. CONCLUSION: Integration of a force torque control into the motion compensated robotized TMS system greatly enhances system's usability, which is a prerequisite for integration in the clinical workflow and clinical acceptance. PMID- 22421918 TI - Streptomyces manipurensis sp. nov., a novel actinomycete isolated from a limestone deposit site in Manipur, India. AB - A novel actinobacterium, designated MBRL 201(T), was isolated from a sample collected from a limestone quarry at Hundung, Manipur, India. The strain was characterized using polyphasic taxonomy. Comparison of the 16S rRNA gene sequence of strain MBRL 201(T) and other Streptomyces species showed sequence similarities ranging from 93.0 to 99.6 % and strain MBRL 201(T) showed closest similarities to Streptomyces virginiae NBRC 12827(T) (99.6 %) and Streptomyces cinnamonensis NBRC 15873(T) (99.6 %). The DNA relatedness between MBRL 201(T) and the type strains of S. virginiae NBRC 12827(T) and S. cinnamonensis NBRC 15873(T) were 44.5 and 35.6 % respectively. Strain MBRL 201(T) contained LL: -diaminopimelic acid (A(2)pm) as the diagnostic diamino acid, with glucose as the main sugar, while small amounts of galactose, glucose, mannose, rhamnose, ribose and xylose were also present in cell-wall hydrolysates. The major fatty acids identified were anteiso-C(15:0) (38.9 %), iso-C(15:0) (19.9 %) and anteiso-C(17:1) (14.7 %). The predominant menaquinones detected were MK-9(H(6)) and MK-9(H(8)), while the polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositolmannosides, with other unknown phospholipids and lipids. The G+C content of the genomic DNA was 72.9 %. The phenotypic and genotypic data showed that strain MBRL 201(T) merits recognition as a representative of a novel species of the genus Streptomyces. It is proposed that the isolate should be classified in the genus Streptomyces as a novel species, Streptomyces manipurensis sp. nov. The type strain is MBRL 201(T) (=DSM 42029(T) = JCM 17351(T)). PMID- 22421919 TI - Uncovertebral hypertrophy is a significant risk factor for the occurrence of heterotopic ossification after cervical disc replacement: survivorship analysis of Bryan disc for single-level cervical arthroplasty. AB - OBJECTIVES: The purpose of this study is to investigate the incidence of heterotopic ossification (HO) in the Bryan cervical arthroplasty group and to identify associations between preoperative factors and the development of HO. METHODS: We performed a retrospective review of clinical and radiological data on patients who underwent single-level cervical arthroplasty with Bryan prosthesis between January 2005 and September 2007. Patients were postoperatively followed up at 1, 3, 6, 12 months and every year thereafter. The clinical assessment was conducted using Odom's criteria. The presence of HO was evaluated on the basis of X-ray at each time-point according to the McAfee classification. In this study, we focused on survivorship of Bryan prosthesis for single-level arthroplasty. The occurrence of ROM-affecting HO was defined as a functional failure and was used as an endpoint for determining survivorship. RESULTS: Through the analysis of 19 cases of Bryan disc arthroplasty for cervical radiculopathy and/or myelopathy, we revealed that ROM-affecting HO occurs in as many as 36.8% of cases and found that 37% of patients had ROM-affecting HO within 24 months following surgery. The overall survival time to the occurrence of ROM-affecting HO was 36.4 +/- 4.4 months. Survival time of the prosthesis in the patient group without preoperative uncovertebral hypertrophy was significantly longer than that in the patient group with preoperative uncovertebral hypertrophy (47.2 months vs 25.5 months, p = 0.02). Cox regression proportional hazard analysis illustrated that preoperative uncovertebral hypertrophy was determined as a significant risk factor for the occurrence of ROM-affecting HO (hazard ratio = 12.30; 95% confidential interval = 1.10-137.03; p = 0.04). CONCLUSION: These findings suggest that the condition of the uncovertebral joint must be evaluated in preoperative planning for Bryan cervical arthroplasty. PMID- 22421920 TI - Jan Mikulicz-Radecki (1850-1905): a fundamental contributor to world surgery; surgeon of the head, neck, and esophagus. AB - We present some of many valuable and unique achievements of Jan Mikulicz-Radecki with special regard to his contribution to laryngology. He constructed esophagogastroscope, and was one of the first to perform endoscopy of esophagus and ventricle. He published several papers describing new approaches to maxillary sinus through inferior meatus, surgical management of tonsillar cancer via lateral pharyngotomy, correction of post-traumatic nasal deformations, and the use of iodophorm in healing wounds. Among Mikulicz's many celebrated scientific achievements, the most important remains the development of asepsis and creation of a surgical school, which was a modernized continuation of Langenbeck-Billroth achievements. PMID- 22421921 TI - Health-related quality of life after tonsillotomy versus tonsillectomy in young adults: 6 years postsurgery follow-up. AB - The indication for tonsil surgery is tonsillitis or obstructive symptoms due to tonsillar hypertrophy, associated with morbidity affecting health related quality of life (HRQL). Surgery performed is either tonsillectomy (TE) or partial intra capsular tonsillectomy/tonsillotomy (TT). TT is associated with fewer postoperative complications and rapid recovery, but with risk for regrowth of tonsillar tissue and return of sleep disordered breathing (SDB) or infections. The aim of this study was to investigate the long-term effects of TT and TE in young adults relating to HRQL and well-being as consequence of obstructive symptoms or ENT-infections after 6 years versus effect after 1 year. Young adults with symptoms of tonsillar hyperplasia were randomized to TE (44) or TT (32). Patients were assessed prior to surgery and 1 and 6 years postoperatively. Short Form 36 and the EuroQul Visual Analog Scale evaluated HRQL. Questionnaire was used to explore well-being, obstruction symptoms and infections. Patient BMI was calculated. Six years after surgery, 91 % of young adults (TE39/TT29) reported persisting benefits in well-being, reduced obstructive problems and fewer infections. Some patients in both groups reported a slight increase in snoring compared to 1 year after surgery, but still less than before surgery. Obesity was more frequent among those snoring. Both TT and TE in young adults yielded HRQL improvements and reduction in symptoms defining SDB persisting through 6 years postsurgery. Results indicated that both surgical methods were equally effective. Findings favor choice of TT due to lesser postoperative morbidity. PMID- 22421922 TI - Rac1 is a possible link between obesity and oxidative stress in Chinese overweight adolescents. AB - Enhanced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the monocytes occurred in metabolic syndrome, hypertension, diabetes and obese patients in adults. However, whether NADPH oxidase is involved in the oxidative stress of overweight adolescents without comorbidities is still unclear. This study aimed to identify whether and how NADPH oxidase plays a crucial role in overweight adolescents. The study was performed in 93 overweight adolescents and 31 normal weight controls. Moreover, 87 overweight adolescents were enrolled in weight-loss program. Demographics characteristics, anthropometrics, composition and clinical characteristics were analyzed. Oxidative stress indexes including the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in plasma and the expression of NADPH oxidase in the monocytes were examined. Overweight adolescents showed a higher oxidative stress state, as indicated by decreased SOD activity and elevated MDA level (P < 0.01). Furthermore, increased NADPH oxidase activity in the monocytes was accompanied by Rac1 upregulation. A significant positive bivariate correlation was found between Rac1 expression and MDA (r = 0.289). There also was a significant positive bivariate correlation between Rac1 expression and obesity-related indexes including BMI (r = 0.227) and percentage of trunk fat (r = 0.233). Data from weight-loss program reinforced the results. Partial correlation analysis indicated that obesity-induced oxidative stress and Rac1 expression is a consequence of aberrant glucose-lipid metabolism in overweight adolescents. In conclusion, we provided novel data showing that NADPH oxidase in the monocytes was highly activated by enhancing Rac1 expression in Chinese overweight adolescents and Rac1 may act as a link between obesity and oxidative stress in overweight adolescents. PMID- 22421923 TI - Associations of variants in FTO and near MC4R with obesity traits in South Asian Indians. AB - Recent genome-wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity-related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity- and type 2 diabetes (T2DM)-related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity-related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist-hip ratio. Consistent associations were observed for adipose tissue specific measurements such as skinfold thickness reinforcing the association with obesity-related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity-related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity-related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian "thin-fat" phenotype. PMID- 22421924 TI - The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin. AB - Oxyntomodulin (OXM) is a peptide secreted postprandially from the L-cells of the gut that has a weak affinity for both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Peripheral administration of OXM in humans and rodents causes weight loss reducing food intake and increasing energy expenditure. It has been suggested that OXM modulates energy intake solely through GLP1R agonism. Because glucagon decreases food intake in rodents and humans, we examined whether activation of the GCGR is involved in the body weight lowering effects of OXM. We identified an equipotent GLP1R-selective peptide agonist that differs from OXM by only one residue (Q3->E, OXMQ3E), but has no significant GCGR agonist activity in vitro and ~100-fold reduced ability to stimulate liver glycogenolysis. Chronic treatment of obese mice with OXM and OXMQ3E demonstrated that OXM exhibits superior weight loss and lipid-lowering efficacy, and antihyperglycemic activity that is comparable to the corresponding GLP1R-selective agonist. Studies in Glp1r(-/-) mice and coadministration of OXM and a GCGR antagonist revealed that the antiobesity effect of OXM requires activation of both GLP1R and GCGR. Our data provide new insight into the mechanism of action of OXM and suggest that activation of GCGR is involved in the body weight-lowering action of OXM. PMID- 22421926 TI - Acute exercise and training alter blood lipid and lipoprotein profiles differently in overweight and obese men and women. AB - Our purpose was to elucidate effects of acute exercise and training on blood lipids-lipoproteins, and high-sensitivity C-reactive protein (hsCRP) in overweight/obese men (n = 10) and women (n = 8); age, BMI, body fat percentage, and VO(2)max were (mean +/- SEM): 45 +/- 2.5 years, 31.9 +/- 1.4 kg.m(-2), 41.1 +/- 1.5%, and 25.2 +/- 1.3 mlO(2).kg(-1).min(-1). Before exercise training subjects performed an acute exercise session on a treadmill (70% VO(2)max, 400 kcal energy expenditure), followed by 12 weeks of endurance exercise training (land-based or aquatic-based treadmill): 3 sessions.week(-1), progressing to 500 kcal.session(-1) during which subjects maintained accustomed dietary habits. After training, the acute exercise session was repeated. Blood samples, obtained immediately before and 24 h after acute exercise sessions, were analyzed for serum lipids, lipoproteins, and hsCRP adjusted for plasma volume shifts. Exercise training increased VO(2)max (+3.67 mlO(2).kg(-1).min(-1), P < 0.001) and reduced body weight (-2.7 kg, P < 0.01). Training increased high-density lipoprotein (HDL) and HDL(2b)-cholesterol (HDL-C) concentrations (+3.7 and +2.4 mg.dl(-1), P < 0.05) and particle numbers (+588 and +206 nmol.l(-1), P < 0.05) in men. In women despite no change in total HDL-C, subfractions shifted from HDL(3)-C (-3.2, P < 0.01) to HDL(2b)-C (+3.5, P < 0.05) and HDL(2a)-C (+2.2 mg.dl(-1), P < 0.05), with increased HDL(2b) particle number (+313 nmol.l(-1), P < 0.05). Training reduced LDL(3) concentration and particle number in women (-1.6 mg.dl(-1) and -16 nmol.l(-1), P < 0.05). Acute exercise reduced the total cholesterol (TC): HDL-C ratio in men (-0.16, P < 0.01) and increased hsCRP in all subjects (+0.05 mg.dl( 1), P < 0.05), regardless of training. Training did not affect acute exercise responses. Our data support the efficacy of endurance training, without dietary intervention, to elicit beneficial changes in blood lipids-lipoproteins in obese men and women. PMID- 22421925 TI - From metabolic normality to cardiometabolic risk factors in subjects with obesity. AB - The aim of the study was to evaluate the 3 years incidence of cardiometabolic risk factors, such as impaired fasting glucose, reduced high-density lipoprotein (HDL)-cholesterol, increased plasma triglycerides or blood pressure as well as impaired glucose tolerance in overweight or obese (ow/ob) and normal body weight (nbw) subjects metabolically normal at baseline. Subjects from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study were analyzed. We analyzed 284 nbw and 152 ow/ob subjects who, at baseline, did not show any of the above-mentioned cardiometabolic risk factors. At 3 years, these parameters were re-evaluated. Intima-media thickness (IMT) of the common carotid artery (CCA) was echographically measured. At follow-up, the incidence of one or more cardiometabolic risk factors was 57.2% in ow/ob vs. 31.7% in nbw (P < 0.0001). After adjustment for age, sex, menopause status, lifestyle parameters, insulin sensitivity, and fasting insulinemia, BMI remained significantly linked to the development of one or more cardiometabolic risk factors (P = 0.02). An increased BMI at follow-up was significantly associated with the development of cardiometabolic alterations, in both nbw and ow/ob groups (P = 0.04). Ow/ob subjects who, at 3 years follow-up, remained metabolically normal, showed a less favourable cardiometabolic profile, when compared to nbw counterparts. In ow/ob metabolically normal males and females, intima-media of the common carotid at follow-up was thicker than in nbw (P = 0.03 for males, P = 0.04 for females). In conclusion, metabolically normal obese subjects show a higher incidence of cardiometabolic risk factors, in a short follow-up period. Weight gain is significantly associated with the development of these factors, in both nbw and ow/ob subjects. PMID- 22421927 TI - Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. AB - The BLOOM-DM (Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus) study evaluated efficacy and safety of lorcaserin for weight loss in patients with type 2 diabetes. Secondary objectives included evaluations of glycemic control, lipids, blood pressure, and quality of life. This 1-year, randomized, placebo-controlled trial enrolled 604 patients 1:1:1 to placebo, lorcaserin 10 mg once daily (QD) or lorcaserin 10 mg twice daily (BID). Patients were treated with metformin, a sulfonylurea (SFU) or both; had glycated hemoglobin (HbA(1c)) 7-10%; were 18-65 years old; and had BMI 27-45 kg/m(2). Patients received diet and exercise counseling. Safety monitoring included serial echocardiograms. Mean (+/- SD) age was 52.7 +/- 8.7; 54.2% were women; 60.5% were white, 20.9% were African American, and 13.8% were Hispanic. Mean (+/- SD) weight was 103.6 +/- 17.8 kg; BMI was 36.0 +/- 4.5 kg/m(2). Most patients (91.7%) took metformin; 50.2% took a SFU. More patients lost >=5% body weight with lorcaserin BID (37.5%; P < 0.001) or lorcaserin QD (44.7%; P < 0.001) vs. placebo (16.1%; modified intent to treat (MITT)/last observation carried forward (LOCF)). Least square mean (+/- SEM) weight change was -4.5 +/- 0.35% with lorcaserin BID and -5.0 +/- 0.5% with lorcaserin QD vs. -1.5 +/- 0.36% with placebo (P < 0.001 for each). HbA(1c) decreased 0.9 +/- 0.06 with lorcaserin BID, 1.0 +/- 0.09 with lorcaserin QD, and 0.4 +/- 0.06 with placebo (P < 0.001 for each); fasting glucose decreased 27.4 +/- 2.5 mg/dl, -28.4 +/- 3.8 mg/dl, and 11.9 +/- 2.5 mg/dl, respectively (P < 0.001 for each). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin BID, 10.5% on lorcaserin QD, and 6.3% on placebo. Common adverse events were headache, back pain, nasopharyngitis, and nausea. Lorcaserin was associated with significant weight loss and improvement in glycemic control in patients with type 2 diabetes. PMID- 22421928 TI - CCN3: a novel anti-fibrotic treatment in end-stage renal disease? AB - Fibrosis is a major cause of end-stage renal disease (ESRD) a progressive loss in renal function that occurs over a period of months or years, is characterized by a decreased capability of the kidneys to excrete waste products. There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. Plasma levels of CCN2, a fibrogenic agent, is a predictor of ESRD and mortality in patients with type 1 diabetic nephropathy. CCN3 has been hypothesized to have antagonistic effects to CCN2 both in vitro and in vivo, including in cultured mesangial cells. In a recent study, van Roeyen and colleagues (Am J Pathol in press, 2012) showed that in vivo overexpression of CCN3 in a model of anti-Thy1.1-induced experimental glomerulonephritis resulted in decreased albuminuria, glomerulosclerosis and reduced cortical collagen type I accumulation. CCN3 enhanced angiogenesis yes suppressed mesangial cell proliferation. Thus CCN3 protein may represent a novel therapeutic approach to help repair glomerular endothelial damage and mesangioproliferative changes and hence prevent renal failure, glomerulosclerosis and tubulointerstitial fibrosis. PMID- 22421929 TI - Enhanced fluorescent chemosensor for Ag+ in absolute aqueous solution and living cells: an experimental and theoretical study. AB - Rosamine derivative RC-1, bearing macrocyclic ligand [15]aneNO(2)S(2) as receptor, was synthesized as an enhanced fluorescent chemosensor for Ag(+) in absolute aqueous solution. The fluorescence images in living cells show the potential application of RC-1. The difference of fluorescence enhancement process after binding with Ag(+)/Hg(2+) in acetonitrile/water solution was first proved by theoretical calculations. PMID- 22421930 TI - Osseous metastases of gastro-enteropancreatic neuroendocrine tumours. Diagnostic value of intra-therapeutic 177Lu-octreotate imaging in comparison with bone scintigraphy. AB - AIM: Peptide receptor radionuclide therapy with 177Lu-octreotate is an effective treatment option for metastatic gastroenteropancreatic neuroendocrine tumors (GEP NET) and allows intratherapeutic imaging through a 177Lu-octreotate scan (LuS). The diagnostic value of this treatment scan is not yet established. This study aims to compare the sensitivity of LuS and bone scintigraphy (BS) regarding bone metastases and investigate potential implications of functional imaging results. PATIENTS, METHODS: We retrospectively analyzed 29 consecutive GEP NET patients with bone metastases and baseline BS treated with 177Lu-octreotate. A semi quantitative scoring system was used for the comparative evaluation. Treatment outcome (time-to-progression of bone metastases) was correlated with the intra individual imaging discrepancy (Kaplan-Meyer curves, log-rank test, p < 0.05). RESULTS: In 19 of 29 patients (65.5%) LuS was superior (LuS > BS), whereas in 10 patients (34.5%) both modalities were comparable. BS showed no additional (LuS negative) metastatic bone lesions in our cohort. None of the investigated baseline characteristics was associated with imaging discrepancy. On the other hand, functional imaging discrepancy had no impact on treatment response (p = 0.43) or time-to-progression (p = 0.92). CONCLUSIONS: Intra-therapeutic 177Lu octreotate imaging is superior over bone scintigraphy for detection of bone metastases in GEP NET. BS may help to distinguish osseous from non-osseous localization. The presence of an osteoblastic correlate in BS seems to have no impact on therapeutic outcome. PMID- 22421931 TI - Gamma-ray thermoluminescence measurements: a record of fallout deposition in Hiroshima? AB - In certain Hiroshima neighborhoods, radiation measurements using thermoluminescence dosimetry (TLD) exceed what can be explained by the initial gamma-ray doses and uncertainties from the Dosimetry System 2002 (DS02). This problem was not previously recognized as being isolated to certain parts of that city. The ratio between TLD measurements and DS02 dose calculations for gamma rays appear to grow larger than unity up to more than three with increasing ground range, but closer examination shows the excess TLD dose (0.1, 0.2, or possibly up to 0.8 Gray) is correlated with certain neighborhoods and could be due to radioactive fallout. At Nagasaki, the TLD measurements do not show this same excess, probably because there were no TLD measurements taken more than 800 m downwind (eastward) from the Nagasaki hypocenter, so that any small excess TLD dose was masked by larger initial gamma-ray doses of 25-80 Gray in the few downwind samples. The DS02 Report had noted many measurements lower than the DS02 calculation for several Nagasaki TLD samples, independent of ground range. This was explained as being the result of previously unaccounted urban shielding which was observed from Nagasaki pre-bomb aerial photos. However, the Hiroshima excess TLD dose issue was not resolved. If the excess TLD doses at Hiroshima are an indication of fallout, it may be possible to use additional TLD studies to make better estimates of the locations and radiation doses to survivors from the fallout after the bombings at both cities. PMID- 22421932 TI - [18F]FDG-PET/CT in patients affected by retroperitoneal fibrosis: a bicentric experience. AB - PURPOSE: The aim of our study was to assess the feasibility and usefulness of 2 [(18)F]-fluoro-2-deoxy-D: -glucose positron emission tomography computed tomography ([(18)F]FDG-PET/CT) in patients affected by retroperitoneal fibrosis. MATERIALS AND METHODS: We retrospectively evaluated 25 patients studied in two centers: 18 underwent [(18)F]FDG-PET/CT as initial evaluation, three during follow-up, three during steroid therapy, and one to re-evaluate the disease. Among the group who underwent initial evaluation, ten underwent a second [(18)F]FDG-PET/CT after steroid therapy. RESULTS: [(18)F]FDG-PET/CT was positive in 18 patients and negative in seven. Among the ten patients who underwent a second study after steroid therapy, six showed complete metabolic response, three partial response, and one no significant maximum standardized uptake value (SUV(max)) reduction. CONCLUSION: Our preliminary results show that [(18)F]FDG PET/CT is feasible and suitable for evaluating retroperitoneal fibrosis and is useful in assessing therapy response. Larger studies are desirable to confirm these findings and to determine the appropriate position of [(18)F]FDG-PET/CT in the diagnostic flow chart for this disease. PMID- 22421933 TI - The Peabody Treatment Progress Battery: history and methods for developing a comprehensive measurement battery for youth mental health. AB - There is increased need for comprehensive, flexible, and evidence-based approaches to measuring the process and outcomes of youth mental health treatment. This paper introduces a special issue dedicated to the Peabody Treatment Progress Battery (PTPB), a battery of measures created to meet this need. The PTPB is an integrated set of brief, reliable, and valid instruments that can be administered efficiently at low cost and can provide systematic feedback for use in treatment planning. It includes eleven measures completed by youth, caregivers, and/or clinicians that assess clinically-relevant constructs such as symptom severity, therapeutic alliance, life satisfaction, motivation for treatment, hope, treatment expectations, caregiver strain, and service satisfaction. This introductory article describes the rationale for the PTPB and its development and evaluation, detailing the specific analytic approaches utilized by the different papers in the special issue and a description of the study and samples from which the participants were taken. PMID- 22421934 TI - A survey of procedural sedation and analgesia practices in pediatric oncology centers in India. AB - OBJECTIVE: Repeated lumbar punctures (LP) and bone marrow aspirations (BMA) are part of childhood cancer management. Adequate sedation and analgesia for these procedures in a safe environment is desirable. We evaluate current practice related to this in pediatric oncology centers in India. METHODS: Clinicians attending the 2nd Annual India Pediatric Oncology Initiative meeting at New Delhi in February 2010 were invited to complete a questionnaire. Questionnaires were also sent by email to the remaining major pediatric oncology centers not represented at the meeting. Responses for LP and BMA were separately collated and variability by type of hospital and patient caseload was assessed. RESULTS: Responses were obtained from 26 of 32 centers (81%) approached. A median of 3 personnel (mostly pediatric residents and nurses) were present during the procedures. Some form of sedation and analgesia was used for LP and BMA in 88.5% and 100% centers respectively. However, use of systemic sedation and analgesia (usually midazolam +/- ketamine) for LP and BMA in >=75% patients was seen in 47.8% and 61.6% centers respectively. General anesthesia was not used in any center. Additional restraint was commonly used and its use was significantly more in public hospitals (p = 0.01). Monitoring was usually done by observation of vital signs, with use of pulse-oximetry in less than half of the centers. CONCLUSIONS: There is varied use of sedation and analgesia for LP and BMA in pediatric oncology centers in India. Further research is needed to identify the reasons for this. Availability of resources is likely to be a factor. PMID- 22421935 TI - Retinoblastoma: an overview. AB - Retinoblastoma, the most common intraocular malignancy of childhood arises due to mutation of the retinoblastoma gene on chromosome 13q14. In the hereditary setting this mutation is present in all germ line cells and can occur as early as during development; however it requires a mandatory second "hit" or mutation of the remaining allele for retinoblastoma to develop. The non-hereditary form arises from spontaneous mutation affecting both alleles in a somatic cell of the retina. The tumor may present with leucocoria or strabismus. The diagnosis is best made by an ophthalmologist who examines the patient under sedation. Although tissue biopsy is not routinely performed, imaging studies like ultrasound and MRI scan can serve as useful adjuncts to help in establishing the diagnosis and also aid in staging. Group A tumors are smaller than 3 mm while group B tumors are >3 mm or those located in the macula. Groups C and D tumors are associated with localized and diffuse vitreous seeds respectively. Group E tumors occupy >50% of the globe and are generally not salvagable. Despite the fact that great advances have been made in the treatment of retinoblastoma in the last two decades, a large number patients undergo procedures associated with significant morbidity such as enucleation. We recommend large multi institutional studies using newer therapeutic models and targeting novel pathways to improve the outcome in advanced stage retinoblastoma. PMID- 22421936 TI - Study of urinary tract infection and bacteriuria in neonatal sepsis. AB - OBJECTIVE: To determine magnitude of Urinary tract infection (UTI) in neonatal sepsis and to evaluate bacteriuria as indicator of neonatal urinary tract infection for use in resource limited settings. METHODS: This prospective study of 200 neonates was conducted in NICU of MVJ Medical College and Research Hospital. Two hundred neonates were included in the study. There were 130 term (93 boys, 37 girls) and 70 pre-term neonates (47 boys, 23 girls). Early onset sepsis group comprised of 109 neonates and late onset sepsis group comprised of 91 neonates. RESULTS: The overall magnitude of UTI was 6%. The urine culture positivity in the early onset sepsis group was 1.83% and in the late onset group was 10.98% (p <0.05). Urine culture positivity in proven sepsis was 6.32% and in suspected sepsis group was 5.78%. The sensitivity of bacteriuria in neonatal UTI was 91.6% and specificity was 97.8%. CONCLUSIONS: Magnitude of UTI in neonatal sepsis is 6%, with urine culture positivity in late onset sepsis being much higher than in early onset sepsis. Bacteriuria has good sensitivity and specificity in resource limited settings in detecting septic neonates with UTI. PMID- 22421937 TI - Copper(II) complexes of quinoline polyazamacrocyclic scorpiand-type ligands: X ray, equilibrium and kinetic studies. AB - The formation of Cu(II) complexes with two isomeric quinoline-containing scorpiand-type ligands has been studied. The ligands have a tetraazapyridinophane core appended with an ethylamino tail including 2-quinoline (L1) or 4-quinoline (L2) functionalities. Potentiometric studies indicate the formation of stable CuL(2+) species with both ligands, the L1 complex being 3-4 log units more stable than the L2 complex. The crystal structure of [Cu(L1)](ClO(4))(2).H(2)O shows that the coordination geometry around the Cu(2+) ions is distorted octahedral with significant axial elongation; the four Cu-N distances in the equatorial plane vary from 1.976 to 2.183 A, while the axial distances are of 2.276 and 2.309 A. The lower stability of the CuL2(2+) complex and its capability of forming protonated and hydroxo complexes suggest a penta-dentate coordination of the ligand, in agreement with the type of substitution at the quinoline ring. Kinetic studies on complex formation can be interpreted by considering that initial coordination of L1 and L2 takes place through the nitrogen atom in the quinoline ring. This is followed by coordination of the remaining nitrogen atoms, in a process that is faster in the L1 complex probably because substitution at the quinoline ring facilitates the reorganization. Kinetic studies on complex decomposition provide clear evidence on the occurrence of the molecular motion typical of scorpiands in the case of the L2 complex, for which decomposition starts with a very fast process (sub-millisecond timescale) that involves a shift in the absorption band from 643 to 690 nm. PMID- 22421938 TI - Treatment of established lesions caused by high-risk human papilloma virus using a synthetic vaccine. AB - Here, we review a novel vaccine modality, characterized by the administration of long (23 to 45 amino acids) synthetic peptides in incomplete Freund's adjuvant (mineral oil based, Montanide ISA-51), delivered subcutaneously. Such vaccines were first demonstrated to be much more potent in preclinical T-cell response induction and tumor therapy experiments than were short major histocompatibility complex class I-binding peptides. Nevertheless, a recent study has shown the clinical efficacy of an anchor-modified short gp100 peptide in melanoma patients. We now review the evidence and mode of action of a long peptide vaccine consisting of 13 overlapping peptides, together covering the entire length of the 2 oncogenic proteins E6 and E7 of high-risk human papilloma virus type 16 (HPV16), causing complete regression of all lesions and eradicating virus in 9 of 20 women with high-grade vulvar intraepithelial neoplasia. The nature and strength of the vaccine-induced T-cell response correlated significantly with the clinical response. This vaccine promises to be of use not only in patients with premalignant lesions caused by high-risk HPV16 but also in malignant tumors caused by this virus, including HPV16-positive cervical cancer, vulvar cancer, anal cancer, and head and neck cancer. PMID- 22421939 TI - Recruitment of natural killer cells in advanced stages of endogenously arising B cell lymphoma: implications for therapeutic cell transfer. AB - During inflammation and in transplantable tumor models, natural killer (NK) cells are recruited to pathologic tissues and activated to produce proinflammatory cytokines favoring adaptive immune responses of the T-helper type 1 (Th1) type. Interferon (IFN)-gamma is needed to induce chemokines that attract NK cells in transplanted tumors. Nothing, however, is known on NK-cell migration in spontaneous tumors. As effective recruitment is a prerequisite for therapeutic NK cell transfer, we investigated the cytokine milieu and the mechanisms that are instrumental for NK-cell accumulation in an endogenous tumor model. We make use of lambda-myc transgenic mice that harbor the c-myc oncogene and develop spontaneous B-cell lymphoma. In contrast to lymphomas induced by tumor cell injection, virtually no IFN-gamma produced by NK or by other cells was present in the tumor environment, particularly in advanced stages. Dendritic cells showed an impaired expression of interleukin-12, which is suggestive of deficient Th1 priming. The IFN-gamma-dependent chemokines CXCL9 and CXCL10 were pivotal for NK cell migration in the endogenous lymphoma model. Although IFN-gamma was absent in late tumor stages, there was still expression of CXCL9 and CXCL10 with an ongoing influx of NK cells. The results demonstrate that transplantable tumor models do not reflect the situation as found in endogenously arising neoplasia, because in the latter, effective Th1 and cytotoxic T-lymphocyte responses are presumably not induced because of impaired IFN-gamma production. The data also suggest that CXCL9 and CXCL10 production and NK-cell migration become independent of IFN-gamma during tumor progression, and therefore support approaches of adoptive NK-cell transfer that hold promise for treatment of cancer. PMID- 22421940 TI - Optimization of antitumor immunotherapy mediated by type III secretion system based live attenuated bacterial vectors. AB - Recently, due to their effective ability to deliver antigen to antigen-presenting cells in vivo, type III secretion system-based attenuated bacterial vectors have increasingly attracted attention for their potential interest in cancer vaccine development. We have previously developed live attenuated Pseudomonas aeruginosa type III secretion system-based vectors to deliver in vivo tumor antigens. In this work, we improved the performance of these bacterial vectors through several approaches in different murine cancer models involving non-self-antigens or self antigens. First, by modulating injection frequency and interval, bacterial vaccination-activated immune response could be enhanced and the in vivo therapeutic efficacy of bacterial vaccines could be improved. The optimized vaccination scheme induced long-lasting CD8+ T cells' response. Second, a dual antigen delivery pattern was successfully applied in our bacterial vectors. Compared with a single antigen delivery vector, biantigen delivery vectors demonstrated several advantages including better tumor rejection efficiency, simplicity of use, and safety. Third, 1 more attenuated mutant-CHA-OAL strain that is totally avirulent in mice was further adapted to grow in a chemically defined medium to comply with current good manufacturing processes. The poor infectivity of this new strain could be overcome by vaccinations at multiple loci, yielding an efficiently improved vaccination performance. Taken together, our results highlight the potential of our live attenuated P. aeruginosa vectors for applications in relevant clinical trials. PMID- 22421941 TI - A novel HLA-A2-restricted CTL epitope of tumor-associated antigen L6 can inhibit tumor growth in vivo. AB - Vaccines utilizing cytotoxic T lymphocyte (CTL) epitopes are promising for the treatment of cancer and chronic infectious diseases. Tumor-associated antigen L6 (TAL6) is overexpressed in some epithelial cancer cells. In this report, we detected TAL6 expression in breast cancer tissue using quantitative reverse transcriptase-polymerase chain reaction. We found that >80% of breast tumor tissue highly expressed TAL6 compared with adjacent normal breast tissue. To identify CTL epitopes from TAL6, we synthesized 18 peptides for HLA-A2-binding assay based on the MHC-binding motif using 4 computer prediction programs. Positive binders identified by ELISA were immunized in HLA-A2 transgenic (A2 Tg) mice. Two peptides, peptide 2 and peptide 5, induced T-cell responses in A2 Tg mice. To confirm whether these peptides could be processed and presented to induce T-cell responses in vivo, A2 Tg mice were immunized with plasmid DNA encoding TAL6. We found that both peptides 2 and 5 stimulated splenocytes from TAL6-immunized mice to secrete interferon-gamma. However, only peptide 5 could induce expression of the cytolytic molecule CD107a on CD8+ T cells after immunization. Furthermore, peptide 5-immunized A2 Tg mice could inhibit the growth of TAL6-positive tumors (EL4/TAL6/HLA-A2) in A2 Tg mice but not in wild type mice. These results demonstrate that the TAL6-derived CTL epitope could induce HLA-A2-restricted immunity against TAL6-expressing tumor cells. PMID- 22421942 TI - 5-Fluorouracil and interferon-alpha immunochemotherapy enhances immunogenicity of murine pancreatic cancer through upregulation of NKG2D ligands and MHC class I. AB - Pancreatic cancer has the poorest prognosis of all gastrointestinal cancers, driving the need for new therapeutic approaches. Adjuvant 5-fluorouacil (5-FU) chemotherapy proved effective in increasing the survival of patients with resected tumors. Furthermore, the addition of interferon alpha (IFN-alpha) immunotherapy to 5-FU has shown encouraging clinical results. The aim of this study was to determine the relevance of different immune cell populations, namely natural killer (NK) cells, CD8 T cells, and dendritic cells, in the anticancer immune response mediated by the combination therapy using an orthotopic mouse model of pancreatic carcinoma and to get more insight into the underlying mechanisms of action. Depleting CD8 T cells, NK cells, or dendritic cells significantly reduced the anticancer effects mediated by the combination therapy. Tumors of mice treated with 5-FU+IFN-alpha harbored higher numbers of infiltrating NK cells in comparison with control mice. In addition, NK cells isolated from these mice showed enhanced cytotoxicity against Panc02 pancreatic cancer cells. Furthermore, 5-FU+IFN-alpha treatment increased the expression of major histocompatibility complex class I and NKG2D ligands on Panc02 cells that could be a potential key for enhancing the immunogenicity of tumors. Understanding how this combination therapy enhances the immunogenicity of pancreatic tumors in our model may provide potential predictive biomarkers. This will allow to evaluate the efficacy of this immunochemotherapy more effectively in future clinical trials and to identify patients who will benefit most from it. PMID- 22421943 TI - EBV Latency II-derived peptides induce a specific CD4+ cytotoxic T-cell activity and not a CD4+ regulatory T-cell response. AB - Epstein-Barr virus (EBV) is associated with several malignant diseases that can be distinguished by their patterns of viral latent gene expression. We developed here an original peptidic approach to favor the induction of a specific CD4+ T cell response against EBV latency II malignancies (Hodgkin's lymphoma, nasopharyngeal carcinoma, T/NK lymphoma). Previously, we selected 6 peptides derived from EBV nuclear antigen-1, latency membrane proteins (LMP)-1, and LMP-2 highly promiscuous for major histocompatibility complex class II molecules and showed their ability to induce interferon-gamma-secreting CD4+ T cells. We confirmed here that all peptides used in cocktail are recognized by human CD4+ memory T cells from healthy donors, inducing a broad T-helper (Th)1 cytokine secretion interferon-gamma, interleukin-2. Furthermore, we have generated EBV specific CD4+ T-cell lines and proved their cytotoxic potential, not only on original models expressing latency II antigens (EBV-transformed T cell or monocyte), but also on lymphoblastoid cell lines expressing latency III antigens (lymphoblastoid cell lines). In addition, granzyme B enzyme-linked immunospot assays suggested that a part of this specific cytotoxic activity could be linked to the granule lytic pathway. Very importantly, we have showed that neither phenotypical changes nor functional activities of CD4+CD25+CD127(low)-regulatory T cells were observed in response to EBV+ peptides, avoiding any risk of aggravation of the preexisting immunosuppressive environment reported in EBV associated malignancies. In conclusion, our promiscuous peptide cocktail could be used safely in immunotherapeutic approaches against EBV latency II malignancies, mainly to prevent relapse in high-risk patients further to classic treatments. PMID- 22421944 TI - Silencing of the TGF-beta1 gene increases the immunogenicity of cells from human ovarian carcinoma. AB - Cells from many tumors produce transforming growth factor (TGF)-beta which facilitates their escape from control by the immune system. We previously reported that nonimmunogenic cells from either of 2 transplantable mouse tumors became effective as therapeutic tumor vaccines after lentivirus-mediated shRNA interference to "silence" the TGF-beta1 gene. We now show that cells from in vitro cultured human ovarian carcinomas (OvC) make large amounts of TGF-beta1 and that this can be prevented by "silencing" the TGF-beta1 gene. We further show that in vitro sensitization of peripheral blood mononuclear cells in the presence of either mitomycin-treated OvC cells whose TGF-beta1 gene was silenced or in vitro matured dendritic cells that had been pulsed with homogenates from OvC cells with silenced TGF-beta1 generated a stronger Th1/Tc1 immune response to the respective wild-type OvC and also to the OvC antigens mesothelin and HE4 as measured by ELIspot assays. The percentage of interferon-gamma and tumor necrosis factor-alpha-producing CD4+ and CD8+ T cells increased while there were fewer cells expressing markers characteristic for regulatory T cells or myeloid-derived suppressor cells. Similar results were obtained when peripheral blood mononuclear cells from a patient with OvC were sensitized to dendritic cells pulsed with homogenate from autologous TGF-beta1-silenced tumor cells, and a cytolytic lymphocyte response was generated to autologous OvC cells. Our results support clinical evaluation of TGF-beta1-silenced tumor vaccines for immunotherapy of OvC. PMID- 22421945 TI - Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. AB - CD40, a member of the tumor necrosis factor receptor superfamily, is broadly expressed on antigen-presenting cells and other cells, including fibroblasts and endothelial cells. Binding of CD40 and its natural ligand CD40L (CD154) triggers cytokine secretion, and increased expression of costimulatory molecules is required for T-cell activation and proliferation. However, to our knowledge, the use of agonistic antibodies to CD40 to boost adoptively transferred T cells in vivo has not been investigated. The purpose of this study was to determine whether anti-CD40 monoclonal antibody (mAb) in combination with interleukin (IL) 2 could improve the efficacy of in vitro-activated T cells to enhance antitumor activity. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without anti-CD40 mAb. In this model, the combination of anti-CD40 mAb with IL-2 led to expansion of adoptively transferred T cells and induced a more robust antitumor response. Furthermore, the expression of CD40 on bone marrow-derived cells and the presence of CD80/CD86 in the host were required for the expansion of adoptively transferred T cells. The use of neutralizing mAb to IL-12 provided direct evidence that enhanced IL-12 secretion induced by anti-CD40 mAb was crucial for the expansion of adoptively transferred T cells. Collectively, these findings provide a rationale to evaluate the potential application of anti-CD40 mAb in adoptive T-cell therapy for cancer. PMID- 22421946 TI - Simplified method of the growth of human tumor infiltrating lymphocytes in gas permeable flasks to numbers needed for patient treatment. AB - Adoptive cell therapy of metastatic melanoma with autologous tumor infiltrating lymphocytes (TIL) is clinically effective, but TIL production can be challenging. Here we describe a simplified method for initial TIL culture and rapid expansion in gas-permeable flasks. TIL were initially cultured from tumor digests and fragments in 40 mL capacity flasks with a 10 cm2 gas-permeable silicone bottom, G Rex10. A TIL rapid expansion protocol (REP) was developed using 500 mL capacity flasks with a 100 cm2 gas-permeable silicone bottom, G-Rex100. TIL growth was successfully initiated in G-Rex10 flasks from tumor digests from 13 of 14 patients and from tumor fragments in all 11 tumor samples tested. TIL could then be expanded to 8-10*109 cells in a 2-step REP that began by seeding 5*106 TIL into a G-Rex100 flask, followed by expansion at day 7 into 3 G-Rex100 flasks. To obtain the 30-60*109 cells used for patient treatment, we seeded 6 G-Rex100 flasks with 5*106 cells and expanded into 18 G-Rex100 flasks. Large-scale TIL REP in gas-permeable flasks requires approximately 9-10 L of media, about 3-4 times less than other methods. In conclusion, TIL initiation and REP in gas-permeable G Rex flasks require fewer total vessels, less media, less incubator space, and less labor than initiation and REP in 24-well plates, tissue culture flasks, and bags. TIL culture in G-Rex flasks will facilitate the production of TIL at the numbers required for patient treatment at most cell processing laboratories. PMID- 22421947 TI - Adoptive immunotherapy with CMV-specific cytotoxic T lymphocytes for stem cell transplant patients with refractory CMV infections. AB - Adoptive immunotherapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTL) is an effective strategy for preventing and treating viral reactivation after allogeneic stem cell transplantation (SCT). We have shown previously that CMV CTL can be generated in 1 to 2 weeks by stimulating donor lymphocytes with peptide mixes derived from full-length pp65 and IE1. We conducted a multi-institutional study of CMV-specific CTL for patients with persistent or anti-viral-resistant CMV infections after allogeneic SCT, to determine the safety, feasibility, and immunologic effects of this approach. We were successful in stimulating CTL from 10/10 donors with pooled CMV overlapping peptide mixes. Five of the 7 subjects who met infusion criteria had new onset CMV specific CTL activity detected within 4 to 6 weeks after infusion. Of the 2 subjects who did not have immunologic responses after infusion, 1 received CTL with a low viability after thawing, and the other patient received cyclosporine A and systemic corticosteroids at the time of the infusion, achieving only a low, transient increase (10%) in pp65-specific activity. There was no graft-versus host disease attributable to these infusions. These findings indicate that the infusion of CTL stimulated over 1 to 2 weeks with overlapping CMV peptides can result in virus-specific immune reconstitution in SCT recipients, without exacerbations of graft-versus-host disease. PMID- 22421948 TI - Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. AB - BACKGROUND: Patients with type II diabetes mellitus (DM) have an increased risk of adenomatous colorectal (CRC) polyps and CRC cancer. The use of the anti hyperglycemic agent metformin is associated with a reduced incidence of cancer related deaths. METHODS: We retrospectively evaluated the medical records of 4758 patients seen at a single institution and determined that 424 patients were identified by their physicians as having type II DM and CRC cancer. Data were subsequently acquired determining the subject's age, body mass index (BMI), and disease date of diagnosis, stage, site of cancer, treatment, and survival. RESULTS: Patients with type II DM and CRC cancer treated with metformin as one of their diabetic medications had a survival of 76.9 months (95% CI=61.4-102.4) as compared with 56.9 months in those patients not treated with metformin (95% CI=44.8-68.8), P=0.048. By using a multivariable Cox regression model adjusted for age, sex, race, BMI, and initial stage of disease, we demonstrated that type II diabetic patients treated with metformin had a 30% improvement in overall survival (OS) when compared with diabetic patients treated with other diabetic agents. CONCLUSION: Colorectal cancer patients with DM treated with metformin as part of their diabetic therapy appear to have a superior OS. PMID- 22421949 TI - Synthesis of injectable and cohesive nano hydroxyapatite scaffolds. AB - Biomimetically synthesized nanosized hydroxyapatite particles have been converted into an injectable paste using a neutral phosphate buffer. Synthesized system manifested a self setting behavior at 37 degrees C in 20 min and revealed a macroporous self assembled microstructure. Stability of the injectable hydroxyapatite has been confirmed in aqueous medium as well as in human blood. Effect of ball milling was also studied on the stability of the system. PMID- 22421951 TI - Facile synthesis of 2-alkyl/aryloxy-2H-azirines and their application in the synthesis of pyrroles. AB - Free carbenes generated from alpha-diazo oxime ethers by photolysis undergo facile N-O insertion to afford 2-alkyl/aryloxy-2H-azirines in good to excellent yields. This method allowed for the development of a tandem reaction for pyrrole synthesis via 1,3-dipolar cycloaddition. PMID- 22421950 TI - Local inhibition of angiogenesis by halofuginone coated silicone materials. AB - Anti-angiogenic therapy is a promising approach for the treatment of increased angiogenesis in certain diseases. We aimed to investigate the local anti angiogenic effect of silicone implants coated with Halofuginone, an angiogenesis inhibitor that inhibits synthesis of collagen-type-I and matrix metalloproteinases. The degree of angiogenesis was observed after implantation of surface modified Halofuginone eluting silicone implants into a submuscular pocket in rats over a period of 3 months. Subsequently, key mediators of angiogenesis (TGF-beta-1, bFGF, COL1A1, MMP-2, MMP-9, VEGF and PDGF) were established by immunohistological staining and RT-PCR and statistically evaluated. In comparison to uncoated silicone implants, Halofuginone eluting silicone implants lead to a significant local decrease of angiogenesis. Halofuginone eluting hybrid surface silicone implants have a significant local anti-angiogenic effect by down regulating the expression activity of key mediators of angiogenesis. PMID- 22421952 TI - Use of methoxy polyethylene glycol-epoetin beta in stage 3, 4 or 5 non-dialysis chronic kidney disease. AB - BACKGROUND: Methoxy polyethylene glycol-epoetin beta (PEG-EPO) is indicated for the treatment of anaemia due to chronic kidney disease. Its long half-life allows it to be administered once per month in maintenance therapy. OBJECTIVE: To evaluate the use, effectiveness and cost of PEG-EPO in a group of pre-dialysis chronic renal failure patients. METHOD: Retrospective observational study in pre dialysis patients who began treatment with PEG-EPO between May 2008 and February 2009. The following data were gathered: age, sex, haemoglobin levels (Hb) and erythropoiesis-stimulating agent (ESA) dose and frequency. The follow-up period was 12 months. RESULTS: We included 198 patients. Mean Hb upon starting PEG-EPO in patients who had received no prior treatment was 10.8g/l, and 11.6g/l at 90 days (P<.0001). In patients previously treated with ESA, mean Hb before starting PEG-EPO treatment was 11.2g/l, and 11.4g/l at 12 months (P=.846). Hb values were higher than 12g/l (P<.0001) after 12 months of treatment in 25% of patients; of these, 45% had values above 13g/l. We observed doses 39% lower than those indicated on the drug leaflet, resulting in a reduction in the originally expected theoretical costs. CONCLUSIONS: The doses of PEG-EPO administered to patients with a prior history of ESA treatment were lower than those indicated by the drug leaflet, and Hb remained stable after 12 months of treatment. A large portion of the patients had levels above the 13g/l threshold. PMID- 22421953 TI - Membranous glomerulonephritis, psoriasis and etanercept. A chance or causal association? AB - Psoriasis is a cutaneous disease with systemic involvement. Tissue damage is considered to be immune-mediated, and etanercept currently provides effective treatment. Kidney injury arising from this condition has not yet been fully explained in the literature. We present a case of membranous nephropathy with C1q deposits followed by development of psoriasis. In this article we will review the possible association between these conditions and the response to this biological molecule. PMID- 22421954 TI - [Interventional therapy of pulmonary emphysema]. PMID- 22421955 TI - A simple colorimetric detection of DNA methylation. AB - In this work, we describe a simple colorimetric method to detect DNA methylation. Adenomatous polyposis coli (APC) with a small CpG region containing methylated cytosine (methylated APC) was synthesized and tested. Methylated APC was first captured and enriched by anti-5-methylcytosine monoclonal antibody conjugated magnetic microspheres (MMPs). Then a probe partly complementary to the APC sequence was added, resulting in the formation of DNA duplexes. The microsphere captured probe was then released by heat denaturation and added into unmodified gold nanoparticle (AuNP) solution. Colorimetric detection was performed by salt induced aggregation. The limit of detection is 80 fmol. Semi-quantitative analysis was done with a UV/Vis spectrophotometer by recording the absorbance of AuNP solution at 520 nm. Thus, this method provides a simple, rapid and quantitative tool for DNA methylation detection. PMID- 22421956 TI - Elevated plasma homocysteine levels in patients with multiple sclerosis are associated with male gender. AB - Elevated homocysteine (Hcy) levels exert several neurotoxic actions and vascular dysfunctions that may be involved in pathogenesis and progression of multiple sclerosis (MS). The effective role of Hcy in MS however remains to be determined. The aim of this work was to compare plasma Hcy levels in MS patients and neurological disease controls (NDC) and to evaluate their relationships with clinical and demographic variables. In this cross-sectional study, we examined plasma Hcy levels in 217 patients with MS [53 clinically isolated syndromes (CIS) suggestive of MS, 134 relapsing remitting (RR), 23 secondary progressive (SP) and seven primary progressive (PP) MS], recruited among patients attending a tertiary clinical center in southern Italy and in 219 age/sex-matched controls. Median Hcy levels were slightly higher in MS patients compared to NDC (9.1 MUmol/l; range, 3.4-35.9 vs. 8.6, range 3.5-27.4; p = 0.02). Median Hcy concentrations were increased in males more than in females in the MS population (10.4 vs. 8.4; p < 0.0001), whereas no differences across genders were found in NDC (9.1 vs. 8.5). Hcy levels were higher in male MS patients compared to the male NDC patients (p = 0.001). Patients with CIS had lower Hcy (7.5 MUmol/l; p = 0.004) compared to patients with RR (9.5 MUmol/l), SP (10.1 MUmol/l) and PP (9.9 MUmol/l). Median Hcy concentration was higher in patients with disease duration longer than 22 months (9.7 vs. 8.6 MUmol/l; p = 0.02). Plasma Hcy levels are increased in patients with definite MS. Higher Hcy levels are associated with male sex, suggesting a role of Hcy in neurodegenerative processes of MS, which are prominent in male patients. PMID- 22421957 TI - Effects of the anion salt nature on the rate constants of the aqueous proton exchange reactions. AB - The proton-transfer ground-state rate constants of the xanthenic dye 9-[1-(2 methyl-4-methoxyphenyl)]-6-hydroxy-3H-xanthen-3-one (TG-II), recovered by Fluorescence Lifetime Correlation Spectroscopy (FLCS), have proven to be useful to quantitatively reflect specific cation effects in aqueous solutions (J. M. Paredes, L. Crovetto, A. Orte, J. M. Alvarez-Pez and E. M. Talavera, Phys. Chem. Chem. Phys., 2011, 13, 1685-1694). Since these phenomena are more sensitive to anions than to cations, in this paper we have accounted for the influence of salts with the sodium cation in common, and the anion classified according to the empirical Hofmeister series, on the proton transfer rate constants of TG-II. We demonstrate that the presence of ions accelerates the rate of the ground-state proton-exchange reaction in the same order than ions that affect ion solvation in water. The combination of FLCS with a fluorophore undergoing proton transfer reactions in the ground state, along with the desirable feature of a pseudo-dark state when the dye is protonated, allows one unique direct determination of kinetic rate constants of the proton exchange chemical reaction. PMID- 22421958 TI - Stoichiometry of the slow I(ks) potassium channel in human embryonic stem cell derived myocytes. AB - The delayed rectifier I(ks) potassium channel is composed of alpha-(KCNQ1) and beta-(KCNE1) subunits. The stoichiometry of I(ks) channels is a matter of some debate. Recently some investigators proposed that the number of KCNE1 subunits per KCNQ1 tetramer could be vary from one to four depending on the relative expression of these two genes. Here we review our previous study of biophysical properties of I(ks) in human embryonic stem cell-derived cardiomyocytes (hESC CMs) showed that I(ks) in hESC-CMs is a coassembly channel with a stoichiometry other than 1:1, which could be further modulated by additional KCNE1. PMID- 22421960 TI - Hemangioendothelioma: a rare case of a primary intracardiac tumor. AB - Kaposiform hemangioendothelioma (KH) is a rare tumor of vascular origin that commonly affects the cutaneous tissues of the extremities. It can, however, affect the abdomen, thorax, head, or neck. Compared with juvenile hemangiomas, which tend to regress, KH tumors are locally aggressive and usually persist. Associated morbidity and mortality rates range from 12 to 30 % and typically are related to either compressive effects on surrounding vital structures or effects of the Kasabach-Merritt phenomenon [10, 11, 13]. To our knowledge, this report is the first to describe KH presenting as a primary intracardiac tumor. PMID- 22421959 TI - Calsequestrin mutations and catecholaminergic polymorphic ventricular tachycardia. AB - Cardiac calsequestrin (Casq2) is the major Ca2+ binding protein in the sarcoplasmic reticulum, which is the principle Ca2+ storage organelle of cardiac muscle. During the last decade, experimental studies have provided new concepts on the role of Casq2 in the regulation of cardiac muscle Ca2+ handling. Furthermore, mutations in the gene encoding for cardiac calsequestrin, CASQ2, cause a rare but severe form of catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we review the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to CPVT caused by CASQ2 mutations. We also describe the clinical aspects of CPVT and provide an update of its contemporary clinical management. PMID- 22421961 TI - A novel totivirus-like virus isolated from bat guano. AB - Previous metagenomic analysis indicated that numerous insect viruses exist in bat guano. In this study, we isolated a novel double-stranded RNA virus, a tentative member of the family Totiviridae, designated Tianjin totivirus (ToV-TJ), from bat feces. The virus is an icosahedral particle with a diameter of 40-43 nm, and it causes cytopathic effect in Sf9, Hz, and C6/36 cell lines. Full-length genomic sequence analysis showed that ToV-TJ shares high similarity with the totivirus OMRV-AK4, which was recently isolated from mosquitoes in Japan. The full-length genome of the ToV-TJ was 7611 bp and contained two predicted non-overlapping open reading frames (ORFs): ORF1, encoding the capsid protein (CP), and ORF2, encoding an RNA-dependent RNA polymerase. Bioassay of ToV-TJ by feeding on the larvae of Spodoptera exigua and Helicoverpa armigera (Hubner) suggests that this virus is not infectious for these two larvae in vivo. Sequences similar to that of ToV-TJ have been detected in bat feces sampled in Yunnan and Hainan Provinces, suggesting that this virus is widely distributed. PMID- 22421962 TI - Characterization and analysis of the full-length genome of a strain of the European QX-like genotype of infectious bronchitis virus. AB - In recent years, strains of infectious bronchitis virus belonging to the QX-like genotype have been causing huge economic losses in commercial chicken flocks in different countries in Europe. In order to expand the knowledge of the molecular features of these viruses, we have sequenced and characterized the complete genome of European QX-like IBV strain CK/SWE/0658946/10, which was isolated in 2010 in Sweden. The genome is 27664 nucleotides in length, comprising six genes and 5' and 3' untranslated regions. The ORF1a, spike and nucleocapsid genes were under strong positive selective pressure that resulted in genetic diversity in relation to classical IBV isolates. The full-length genome of the CK/SWE/0658946/10 strain has the highest nucleotide sequence identity (93.18%) to ITA/90254/2005 and the lowest nucleotide identity (89.10%) to strain CQ04-1. Phylogenetic analysis of partial S1 gene sequences of IBV strains showed that the European QX-like genotype comprises strains that have been predominantly circulating in this continent for the past decade. PMID- 22421963 TI - How apoptotic cells aid in the removal of their own cold dead bodies. AB - Apoptotic cell clearance facilitates the removal of aged, damaged, infected or dangerous cells although minimizing perturbation of surrounding tissues, and is a vital process in the development and homeostasis of multicellular organisms. Importantly, failure to correctly execute programmed cell death and subsequent corpse clearance is broadly associated with chronic inflammatory and/or autoimmune diseases such as systemic lupus erythematosus. Apoptotic cells develop dramatic morphological changes including contraction, membrane blebbing and apoptotic body formation, which were among the first and most readily identifiable features of cellular suicide. However, understanding the purpose of apoptotic cell morphological changes has proven to be elusive, and recent studies have made somewhat surprising, and occasionally opposing, conclusions about the contribution of blebbing to phagocytic clearance and prevention of inflammatory/autoimmune disease. We review the evidence indicating how apoptotic blebs actively promote corpse recognition, uptake, and generation of auto reactive antibodies. PMID- 22421964 TI - dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8. AB - Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-alpha (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors of the TNFR superfamily, but instead is physically associated to TLR3. The recruitment of caspase-8 to TLR3 requires RIP1, and is negatively modulated by cellular inhibitor of apoptosis protein (cIAP)2-TNF receptor-associated factor (TRAF)2 TNFR-associated death domain (TRADD) ubiquitin ligase complex, which regulates RIP1 ubiquitination. Intriguingly, unlike Fas- or TRAILR-dependent death signaling, caspase-8 recruitment and activation within the TLR3 death-signaling complex appears not to be stringently dependent on Fas-associated with death domain (FADD). Our findings uncover a novel aspect of the molecular mechanisms involved during apoptosis induced by the innate immune receptor TLR3 in cancer cells. PMID- 22421965 TI - Actin reorganization as the molecular basis for the regulation of apoptosis in gastrointestinal epithelial cells. AB - The gastrointestinal (GI) epithelium is a rapidly renewing tissue in which apoptosis represents part of the overall homeostatic process. Regulation of apoptosis in the GI epithelium is complex with a precise relationship between cell position and apoptosis. Apoptosis occurs spontaneously and in response to radiation and cytotoxic drugs at the base of the crypts. By contrast, the villus epithelial cells are extremely resistant to apoptosis. The molecular mechanism underlying this loss of function of villus epithelial cells to undergo apoptosis shortly after their exit from the crypt is unknown. In this study we demonstrate for the first time, that deletion of two homologous actin-binding proteins, villin and gelsolin renders villus epithelial cells extremely sensitive to apoptosis. Ultrastructural analysis of the villin-gelsolin(-/-) double-knockout mice shows an abnormal accumulation of damaged mitochondria demonstrating that villin and gelsolin function on an early step in the apoptotic signaling at the level of the mitochondria. A characterization of functional and ligand-binding mutants demonstrate that regulated changes in actin dynamics determined by the actin severing activities of villin and gelsolin are required to maintain cellular homeostasis. Our study provides a molecular basis for the regulation of apoptosis in the GI epithelium and identifies cell biological mechanisms that couple changes in actin dynamics to apoptotic cell death. PMID- 22421966 TI - Cell death research, on an island girt by sea. PMID- 22421967 TI - Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. AB - 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a master regulator of glycolysis by its ability to synthesize fructose-2,6-bisphosphate, a potent allosteric activator of 6-phosphofructo-1-kinase. Being a substrate of the E3 ubiquitin ligase anaphase-promoting complex-Cdh1 (APC(Cdh1)), PFKFB3 is targeted to proteasomal degradation in neurons. Here, we show that activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) stabilized PFKFB3 protein in cortical neurons. Expressed PFKFB3 was found to be mainly localized in the nucleus, where it is subjected to degradation; however, expression of PFKFB3 lacking the APC(Cdh1)-targeting KEN motif, or following NMDAR stimulation, promoted accumulation of PFKFB3 and its release from the nucleus to the cytosol through an excess Cdh1-inhibitable process. NMDAR-mediated increase in PFKFB3 yielded neurons having a higher glycolysis and lower pentose-phosphate pathway (PPP); this led to oxidative stress and apoptotic neuronal death that was counteracted by overexpressing glucose-6-phosphate dehydrogenase, the rate limiting enzyme of the PPP. Furthermore, expression of the mutant form of PFKFB3 lacking the KEN motif was sufficient to trigger oxidative stress and apoptotic death of neurons. These results reveal that, by inhibition of APC(Cdh1), glutamate receptors activation stabilizes PFKFB3 thus switching neuronal metabolism leading to oxidative damage and neurodegeneration. PMID- 22421968 TI - TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death. AB - TP53INP1 (tumor protein 53-induced nuclear protein 1) is a tumor suppressor, whose expression is downregulated in cancers from different organs. It was described as a p53 target gene involved in cell death, cell-cycle arrest and cellular migration. In this work, we show that TP53INP1 is also able to interact with ATG8-family proteins and to induce autophagy-dependent cell death. In agreement with this finding, we observe that TP53INP1, which is mainly nuclear, relocalizes in autophagosomes during autophagy where it is eventually degraded. TP53INP1-LC3 interaction occurs via a functional LC3-interacting region (LIR). Inactivating mutations of this sequence abolish TP53INP1-LC3 interaction, relocalize TP53INP1 in autophagosomes and decrease TP53INP1 ability to trigger cell death. Interestingly, TP53INP1 binds to ATG8-family proteins with higher affinity than p62, suggesting that it could partially displace p62 from autophagosomes, modifying thereby their composition. Moreover, silencing the expression of autophagy related genes (ATG5 or Beclin-1) or inhibiting caspase activity significantly decreases cell death induced by TP53INP1. These data indicate that cell death observed after TP53INP1-LC3 interaction depends on both autophagy and caspase activity. We conclude that TP53INP1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy. PMID- 22421969 TI - Mesenchymal stem cells: a double-edged sword in regulating immune responses. AB - Mesenchymal stem cells (MSCs) have been employed successfully to treat various immune disorders in animal models and clinical settings. Our previous studies have shown that MSCs can become highly immunosuppressive upon stimulation by inflammatory cytokines, an effect exerted through the concerted action of chemokines and nitric oxide (NO). Here, we show that MSCs can also enhance immune responses. This immune-promoting effect occurred when proinflammatory cytokines were inadequate to elicit sufficient NO production. When inducible nitric oxide synthase (iNOS) production was inhibited or genetically ablated, MSCs strongly enhance T-cell proliferation in vitro and the delayed-type hypersensitivity response in vivo. Furthermore, iNOS(-/-) MSCs significantly inhibited melanoma growth. It is likely that in the absence of NO, chemokines act to promote immune responses. Indeed, in CCR5(-/-)CXCR3(-/-) mice, the immune-promoting effect of iNOS(-/-) MSCs is greatly diminished. Thus, NO acts as a switch in MSC-mediated immunomodulation. More importantly, the dual effect on immune reactions was also observed in human MSCs, in which indoleamine 2,3-dioxygenase (IDO) acts as a switch. This study provides novel information about the pathophysiological roles of MSCs. PMID- 22421970 TI - Modulated expression of genes associated with NO signal transduction contributes to the cholesterol-lowering effect of electro-acupuncture. AB - Electro-acupuncture (EA) at Fenglong acupoint (ST40) can lower the levels of serum cholesterol and triacylglycerols. To study the hepatic genes responsible for the cholesterol-lowering effect of EA, suppression subtractive hybridization combined with the switch mechanism at the 5'-end of RNA template cDNA synthesis and long-distance PCR were employed using hepatic tissues from hypercholesterolemia and EA-treated mice. 68 % of the identified genes are involved in metabolism, immune response, and signal transduction pathways. Real time PCR and western blot indicate that EA at ST40 induces the expression of nNOS and Mt1, two genes involved in NO signal transduction. EA treatment for hypercholesterolemia thus involves the modulation of several biological pathways and provides a physiological link between NO signal transduction and the cholesterol-lowering effect of EA. PMID- 22421971 TI - Pre-treatment of Pinus radiata substrates by basidiomycetes fungi to enhance enzymatic hydrolysis. AB - Pre-treatment is important step prior to enzymatic hydrolysis of ligno-cellulosic biomass in order to obtain renewable carbon source ca. glucose. Pinus radiata biomass including wood blocks, wood chips and steam exploded wood (SEW) were used to investigate the effect of fungal pre-treatment on glucose yield. Comparison was made using one white-rot fungus (Trametes versicolor) and three brown-rot fungi (Coniophora puteana, Antrodia xantha and Oligoporus placenta). This is the first study where SEW was treated with basidiomycetes and subsequent enzymatic hydrolysis gave 5 g glucose/l which is an order of magnitude greater compared to control biomass (0.5 g glucose/l). This enhanced glucose yield is due to the novel pre-treatment sequence used in this study. PMID- 22421972 TI - A fully human CD19/CD3 bi-specific antibody triggers potent and specific cytotoxicity by unstimulated T lymphocytes against non-Hodgkin's lymphoma. AB - The use of a bi-specific antibody (BsAb) is an attractive and specific approach to cancer therapy. We have constructed a fully human recombinant single chain Fv BsAb against CD19 and CD3 that was an effective treatment in an animal model of non-Hodgkin's lymphoma (NHL). The CD19/CD3 BsAb was expressed in CHO cells and purified by Ni-column chromatography. Flow cytometry revealed that the CD19/CD3 BsAb specifically bound to both CD19 and CD3-positive cells. In vitro, the CD19/CD3 BsAb could stimulate T cell proliferation and induce the lysis of cultured Raji cells in the presence of unstimulated T lymphocytes. In vivo, the CD19/CD3 BsAb efficiently inhibited tumour growth in SCID mice of NHL, and the survival time of the mice was significantly prolonged. Therefore, our CD19/CD3 BsAb is a useful tool that could be a suitable candidate for treatment of NHL. PMID- 22421973 TI - Comparison of glucose/xylose co-fermentation by recombinant Zymomonas mobilis under different genetic and environmental conditions. AB - Three xylose-fermenting recombinant Zymomonas mobilis strains containing different Peno-talB/tktA operon terminators were engineered. Each showed similar levels of foreign protein expression and xylose fermentation performance. Strain CP4-P2-1 was further used to compare the glucose/xylose co-fermentation under various cultivation environments to improve the efficiency of the process. Optimal co-fermentation was achieved at 30-34 degrees C and pH 5.5 using xylose grown preculture cells giving 20.5 g ethanol/l, ethanol productivity of 0.43 g/l h and ethanol yield of 0.44 g/g at 48 h. Adverse culture conditions mainly influenced the efficiency of xylose fermentation but not glucose fermentation. The key factors affecting co-fermentation were also explored at the molecular level. This study provides valuable insights into the effective harnessing of biomass resources. PMID- 22421974 TI - Construction of a human scFv antibody library with VH regions randomized and its application. AB - A non-immunized human single chain variable fragment (scFv) library containing 2.5 * 10(7) individual clones was constructed from antibody variable region genes of 200 non-immunized donors. ScFv gene repertories were generated by randomly combining rearranged variable regions of heavy chain (VH) and natural occurring light chain (VL) using overlapping extension PCR (OE-PCR). Five recombinant protein antigens from different species were successfully used to select specific binders. Phage ELISA showed that the recombinant phage particle could specifically bind to non-structural protein 1 of Avian influenza virus. This method can therefore efficiently generate a phage antibody library. PMID- 22421975 TI - A novel microbial fuel cell and photobioreactor system for continuous domestic wastewater treatment and bioelectricity generation. AB - A system containing a sequential anode-cathode configuration microbial fuel cell and a photobioreactor was developed for continuous treatment of wastewater and electricity generation. Wastewater was treated by the fuel cell to decrease the chemical oxygen demand (COD), phosphorus and nitrogen and to produce electricity. The effluent from the cathode compartment of the cell was continuously fed to an external photobioreactor to remove the remaining P and N using microalgae. Alone, the fuel cell generated a maximum power of 20.3 W/m(3) and achieved removal of 85 % COD, 58 % total phosphorus (TP) and 91 % NH(4) (+)-N. When coupled with the photobioreactor, the system removed 92 % TP and 99 % NH(4) (+)-N. These results demonstrate both the effectiveness and the potential application of the coupled system to continuously treat domestic wastewater and simultaneously generate electricity. PMID- 22421976 TI - Immobilization of Pholiota adiposa xylanase onto SiO2 nanoparticles and its application for production of xylooligosaccharides. AB - Enhanced yields of different lignocellulases were obtained under statistically optimized parameters using Pholiota adiposa. The k (cat) value (4,261 s(-1)) of purified xylanase under standard assay conditions was the highest value ever reported. On covalent immobilization of the crude xylanase preparation onto functionalized silicon oxide nanoparticles, 66 % of the loaded enzyme was retained on the particle. Immobilized enzyme gave 45 % higher concentrations of xylooligosaccharides compared to the free enzyme. After 17 cycles, the immobilized enzyme retained 97 % of the original activity, demonstrating its prospects for the synthesis of xylooligosaccharides in industrial applications. PMID- 22421977 TI - Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National Health and Nutrition Examination Survey III. AB - BACKGROUND: Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals. METHODOLOGY: We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0<= HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex. PRINCIPAL FINDINGS: Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences. CONCLUSIONS: Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility. Given the increasing prevalence of obesity, further research is urgently needed to develop interventions to prevent sarcopenic obesity and its metabolic consequences. PMID- 22421978 TI - Detection of synovitis in the hands of patients with rheumatologic disorders: diagnostic performance of optical imaging in comparison with magnetic resonance imaging. AB - OBJECTIVE: To prospectively compare an indocyanine green (ICG)-enhanced optical imaging system with contrast-enhanced magnetic resonance imaging (MRI) for the detection of synovitis in the hands of patients with rheumatologic disorders. METHODS: Forty-five patients (30 women [67%], mean +/- SD age 52.6 +/- 13.4 years) in whom there was a clinical suspicion of an inflammatory arthropathy were examined with a commercially available device for ICG-enhanced optical imaging as well as by contrast-enhanced 3T MRI as the standard of reference. Three independent readers graded the degree of synovitis in the carpal, metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints of both hands (1,350 joints), using a 4-point ordinate scale (0 = no synovitis, 1 = mild, 2 = moderate, 3 = severe). Statistical analyses were performed using a logistic generalized estimating equation approach. Agreement of optical imaging ratings made by the different readers was estimated with a weighted kappa coefficient. RESULTS: When MRI was used as the standard of reference, optical imaging showed a sensitivity of 39.6% (95% confidence interval [95% CI] 31.1 48.7%), a specificity of 85.2% (95% CI 79.5-89.5%), and accuracy of 67.0% (95% CI 61.4-72.1%) for the detection of synovitis in patients with arthritis. Diagnostic accuracy was especially limited in the setting of mild synovitis, while it was substantially better in patients with severely inflamed joints. Moderate interreader and intrareader agreement was observed. CONCLUSION: The evaluated ICG enhanced optical imaging system showed limitations for the detection of inflamed joints of the hand in comparison with MRI. PMID- 22421979 TI - ZnS nanoparticle gels for remediation of Pb2+ and Hg2+ polluted water. AB - ZnS nanoparticle (NP) gel networks were used as cation exchange materials for the removal of Pb(2+) and Hg(2+) from aqueous solutions. First, the suitability of the gel as a remediation material was studied by analyzing the mechanism of the cation exchange reaction. ZnS NP gels can exchange with other divalent cations (Pb(2+), Hg(2+)) under mild reaction conditions. The speed of the reaction is influenced by the reduction potential of the incoming cation. The ZnS aerogels can remove Pb(2+) and Hg(2+) from aqueous solutions with a wide range of initial concentrations. For initial Pb(2+) concentrations of 100 ppb, the Pb(2+) concentration can be reduced below the action limit established by the EPA (15 ppb). Under thermodynamically forcing conditions, the water remediation capacity of the ZnS NP aerogels was determined to be 14.2 mmol Pb(2+)/ g ZnS aerogel, which is the highest value reported to date. PMID- 22421980 TI - Seasonal distribution, source investigation and vertical profile of phenolic endocrine disrupting compounds in Dianchi Lake, China. AB - Phenolic endocrine disrupting compounds, including nonylphenol-di-ethoxylate (NP2EO), nonylphenol-mono-ethoxylate (NP1EO), 4-nonylphenol (4-NP), bisphenol A (BPA), 4-cumylphenol (4-CP) and 4-tert-octylphenol (4-t-OP), were investigated in water, surface sediment and sediment cores in Dianchi Lake to track their seasonal distributions, pollution sources and historical trends. The concentrations of NP2EO, NP1EO, 4-NP, BPA, 4-CP and 4-t-OP were up to 295.14, 448.48, 45.28, 530.33, 8.96 and 21.37 ng L(-1) in water, and up to 297.11, 809.63, 4.58, 166.87, 3.62 and 40.69 ng g(-1) dry weight in surface sediment, respectively. Except BPA in water, concentrations of all the other phenolic compounds in both of the matrices were higher in January than in July, 2011. The concentrations decreased significantly with an increase in distance from the sampling locations which were adjacent to the urban areas (Kunming City, Chenggong City and Jinning City). The pollution of phenolic EDCs came mainly from industry, agriculture and daily life. The relationships between the concentrations of target compounds and the six water quality parameters were evaluated. There were significant positive correlations between concentrations of phenolic compounds in water and in surface sediment. For sediment cores, three clearly separated maxima occurred in segments 0-5 cm (the late 2000s), 5-10 cm (the early and mid of 2000s) and 20-25 cm (the mid of 1980s), respectively. NP2EO, NP1EO and BPA were the three dominant compounds in the lake. PMID- 22421981 TI - Diabetic nephropathy but not HbA1c is predictive for frequent complications of Charcot feet - long-term follow-up of 164 consecutive patients with 195 acute Charcot feet. AB - AIMS: To investigate the clinical characteristics, treatment and long-term outcome of patients with acute Charcot feet (CF). METHODS: Single-center retrospective analysis. Treatment of CF: stage-dependent immobilization/weight off therapy, orthopaedic/adjusted shoes, foot surgery. 164 consecutive participants (type 1 vs. type 2 diabetes): 12 vs. 150, non-diabetic peripheral neuropathy: n=2, presented with 195 (17 vs. 176) CF. Mean follow-up: 4.7 +/- 2.5 (range 2.2-9.8) vs. 5.4 +/- 2.9 (range 0.8-18.8) years, vital at follow-up: 100 vs. 88%. RESULTS: Baseline characteristics: age: 43.7 +/- 10.9 vs. 57.9 +/- 8.9 years (p<0.001), male gender: 66.7 vs. 77.3%, diabetes duration: 19.2 +/- 9.1 vs. 13 +/- 8.6 years (p=0.018), GHb: 8.1 +/- 2.4 vs. 7.6 +/- 1.6%, BMI: 24 +/- 5.3 vs. 33.7 +/- 6.5 kg/m2 (p<0.001), Levine 1: 18.2 vs. 7.4%, Levine 2: 45.5 vs. 65.9%, Sanders 2: 58.3 vs. 68.5%, Sanders 3: 33.3 vs. 45%. THERAPY: immobilization for 6 +/- 4.2 vs. 5.4 +/- 4.5 months, orthopaedic/adjusted shoes: 27.3 vs. 20.5%, foot surgery: 11.8 vs. 18.2%. Major complications: 50 vs. 56% (rocker bottom deformities: 23.5 vs. 46.3%, foot ulcerations: 17.6 vs. 24.6%, CF amputations: 0 vs. 6%), not CF amputations: 16.7 vs. 15.3%, second episodes of CF: 41.6 vs. 18.3% after 5-132 months. Diabetic nephropathy was associated with an increase, intensive antihypertensive therapy with a decrease of complications. CONCLUSIONS: Patients with CF are middle-aged, overweight males with type 2 diabetes above 10 years. Patients with type 1 diabetes are younger, have normal BMI and longer diabetes duration. Major complications and second episodes of CF are frequent. Diabetic nephropathy could be a risk factor for CF related complications. The awareness for CF must be improved.The study was conducted due to the Declaration of Helsinki. PMID- 22421982 TI - Seronegative myasthenia gravis and Graves' disease. Is there a link? AB - Graves' disease (GD) and myasthenia gravis (MG) are common autoimmune diseases but their coexistence is very rare. They may possibly share the same pathogenetic mechanisms. Recent research has shown the involvement of autoantibodies, lymphocytes, cytokines and chemokines in the pathogenesis of MG and GD. It appears that Th17 cell lineage is involved in autoimmune thyroid disease (AITD) and seems to be key factor in the development of both MG and GD.A 34-year-old male with seronegative myasthenia gravis due to thymic hyperplasia was diagnosed with also GD and opthalmopathy. Several diagnostic and therapeutic issues regarding the relevant literature are discussed. PMID- 22421983 TI - Metabolic effects of short-term GLP-1 treatment in insulin resistant heart failure patients. AB - We studied the metabolic effects of 48-h GLP-1 treatment in insulin resistant heart failure patients.In a randomized placebo-controlled double-blinded cross over study, 11 non-diabetic HF patients with IHD received 48-h GLP-1 and placebo infusion. We applied OGTT, hyperinsulinemic clamp, indirect calorimetry, forearm, and tracer methods.7 insulin resistant HF (EF 28%+/-2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body protein turnover (p=0.08) but did not cause muscle wasting. No significant changes in circulating levels of insulin, glucagon, free fatty acids or insulin sensitivity were detected.GLP-1 treatment decreased glucose levels and increased glucose tolerance in insulin resistant HF patients with IHD. Hypoglycemia was common and may limit the use of GLP-1 in these patients. Insulin sensitivity, lipid-, and protein metabolism remained unchanged.Data were collected at the examinational laboratories of Department of Endocrinology and Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. PMID- 22421984 TI - Effects of sex and age on serum 1,5-anhydroglucitol in nondiabetic subjects. AB - The aim of this study was to demonstrate the effects of sex and age on serum levels of 1,5-AG in nondiabetic subjects.A total of 1 134 nondiabetic subjects aged 16-96 years with HbA1c less than 6.8% were recruited and divided into 4 HbA1c groups (Q1: HbA1c<=5.3; Q2: 5.4-5.8; Q3: 5.9-6.3; and Q4: 6.4-6.8 [%]). 38 elderly subjects (65 years or older) in the Q3 and Q4 groups (13 men and 25 women) underwent a 75-g oral glucose tolerance test (OGTT).The Q4 group had significantly lower 1,5-AG levels than did the Q1 group among nonelderly males, nonelderly females, and elderly men. In elderly women, 1,5-AG levels did not differ among the 4 HbA1c groups. In both nonelderly and elderly subjects, the 1,5 AG level of the Q1 group was significantly higher in males than in females. Stepwise multivariate regression analysis showed that age was significantly associated with 1,5-AG level in both sexes. HbA1c was significantly associated with the 1,5-AG level in males, while there was no significant association between HbA1c and the 1,5-AG level in females. In the elderly OGTT group, although the glucose levels of both sexes during OGTT were identical, the mean urinary glucose levels and the percentages of subjects with glucosuria were significantly higher in elderly men than in elderly women.Serum 1,5-AG levels were significantly associated with age and sex. The sensitivity of the 1,5-AG level for identifying postprandial hyperglycemia in elderly women with near normoglycemia is less reliable because they have a higher renal threshold for glucose. PMID- 22421985 TI - Genotoxicity evaluation in severe or mild diabetic pregnancy in laboratory animals. AB - This study aimed to evaluate the genotoxicity (DNA damage levels) in lymphocyte samples from pregnant Wistar rats with severe or mild diabetes and in whole blood samples from their newborns. Wistar female rats (1 and 90 days of age) and male rats (approximately 90 days of age) were used. The experiment consisted of 2 experimental groups (n=8 animals/group): 1) rats with severe diabetes, 2) rats with mild diabetes. For mild diabetes induction, the rats received streptozotocin (STZ) subcutaneously (100 mg/kg body weight) at day of birth, and those showing glycemia from 120 to 300 mg/dL in their adult life were included. For induction of severe diabetes, adult rats received 40 mg/kg STZ (intravenous route), and those showing glycemia > 300 mg/dL were included. At day 21 of pregnancy, the rats were anesthetized and euthanized for removal of maternal and fetal blood samples for determination of the oxidative DNA damage by applying Endo III and Fpg using the comet assay. Thus, the rats with mild diabetes and their offspring showed higher Fpg-sensitive sites, reflecting the damage resulting from hyperglycemia. The rats with severe diabetes and their offspring showed higher oxidative DNA damage detected by Fpg and Endo III-sensitive sites, showing general repercussions related to diabetes. The enzymatic treatment for DNA damage evidenced that the maternal repercussions of diabetes are associated with oxidative DNA damage of their newborn, which was not reflected using only the analysis of DNA damage free of the enzymes. PMID- 22421986 TI - Differential diagnosis of hyperandrogenism in women with polycystic ovary syndrome. AB - According to the Androgen Excess and Polycystic Ovary Syndrome Society (AE&PCOS), the main feature of PCOS is clinical hyperandrogenism or laboratory hyperandrogenaemia. Therefore, in diagnosing PCOS one must always exclude other causes of androgen excess. In a woman with hyperandrogenism, the diagnosis of PCOS can usually be made according to the patient's history and careful clinical examination. Signs of mild hyperandrogenaemia usually start after the menarche and cycles continue to be anovulatory in adult life. Non-classical congenital adrenal hyperplasia (NCCAH) can be another cause of hyperandrogenism with oligomenorrhea. This can be diagnosed in a patient with elevated basal or ACTH stimulated serum 17OH-progesterone (17-OHP) levels or in a case of a significant decrease in serum testosterone (TST) and dehydroepiandrosterone sulphate (DHEA-S) in a two day dexamethasone suppression test. Cushing's disease (ACTH producing pituitary adenoma) is a rare cause of hyperandrogenaemia in women with recent onset of hyperandrogenism. However, it must always be taken into the consideration in a patient with accompanying signs of hypercortisolism. It can usually be excluded by performing an overnight dexamethasone suppression test or the measurement of 24 h urinary free cortisol levels. Severe signs of hyperandrogenism which lead to virilization should always lead to the exclusion of androgen secreting tumors of ovarian or adrenal origin. These are very rare but should be always taken into the account in a patient with recent onset of severe signs of androgen excess and very high serum androgen levels. Mild signs of hyperandrogenaemia in a woman with recent oligomenorrhea should always lead to the exclusion of hyperprolactinaemia. PMID- 22421987 TI - Nanoscale charge distribution and energy band modification in defect-patterned graphene. AB - Defects were introduced precisely to exfoliated graphene (G) sheets on a SiO(2)/n(+) Si substrate to modulate the local energy band structure and the electron pathway using solution-phase oxidation followed by thermal reduction. The resulting nanoscale charge distribution and band gap modification were investigated by electrostatic force microscopy and spectroscopy. A transition phase with coexisting submicron-sized metallic and insulating regions in the moderately oxidized monolayer graphene were visualized and measured directly. It was determined that the delocalization of electrons/holes in a graphene "island" is confined by the surrounding defective C-O matrix, which acts as an energy barrier for mobile charge carriers. In contrast to the irreversible structural variations caused by the oxidation process, the electrical properties of graphene can be restored by annealing. The defect-patterned graphene and graphene oxide heterojunctions were further characterized by electrical transport measurement. PMID- 22421988 TI - Number of lymph nodes evaluated: prognostic value in pancreatic adenocarcinoma. AB - INTRODUCTION: The impact of the number of lymph node (LN) evaluated pathologically on accurate staging is unknown. Our primary aim was to determine a minimum number of evaluated LN needed to provide accurate staging of pancreatic cancer. METHODS: Four hundred ninety-nine patients underwent a curative pancreatectomy for pancreatic adenocarcinoma cancer from 1981-2007. The probability of understaging a patient as N0 was estimated based on the number of LN evaluated. The prognostic value of LN ratio (LNR) was assessed. RESULTS: Survival for node-negative (pN0) patients with <11 LN examined was worse than for pN0 patients with >=11 LNs with a hazard ratio (95 % CI) of 1.33 (1.1-1.7, p = 0.01) with 3-year survivals of 32 vs. 50%, respectively. Three-year survival for pN1 patients with <11 nodes evaluated was similar to pN1 patients with >=11 nodes (25 vs. 30%). LNR >= 0.17 predicted worse survival with hazard ratio of 1.76 (1.3 2.4, p = 0.001) than LNR < 0.17; 3-year survivals were 37 vs. 19%. CONCLUSION: Patients with "N0" disease with <11 LN evaluated pathologically have worse survival, suggesting that metastatic nodes were missed by evaluating too few nodes. For pN1 patients, LNR stratifies survival of patient cohorts more accurately. Adequate staging of pancreatic cancer requires pathologic evaluation of >=11 LNs. PMID- 22421989 TI - Preschool children dietary patterns and associated factors. AB - OBJECTIVES: To identify dietary patterns in pre-school children and to investigate its determinants. METHODS: Cross-sectional study nested in a cohort born between 2004 and 2005 in the municipality of Diamantina, state of Minas Gerais, Brazil. The instrument used to explore the dietary patterns was a frequency questionnaire for food consumption. Factor analysis was used for the identification of the dietary patterns. The study also assessed personal and socioeconomic data and anthropometric measurements of 232 preschoolers in the period between July 2009 and July 2010. The determinants of food patterns were identified by logistic regression. RESULTS: Three patterns were obtained, which were called: "mixed diet," "snack," and "unhealthy." The children of mothers with low education are more likely (odds ratio - OR = 3.80; confidence interval 95% - 95%CI = 1.90-7.60) to consume food from the "mixed diet" pattern, and less likely (OR = 0.31; 95%CI = 0.15-0.61) to consume food from the "snack" pattern, while those with higher per capita income are more likely to consume food from the "unhealthy" pattern (OR = 2.43; 95%CI = 1.13-5.24). CONCLUSION: Three dietary patterns were identified in the studied population, which were determined by the level of maternal education and per capita income. PMID- 22421990 TI - Effect of antenatal growth and prematurity on brain white matter: diffusion tensor study. AB - BACKGROUND: White matter maturation is characterised by increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD). Contradictory results have been published on the effect of premature birth on white matter maturation at term-equivalent age. OBJECTIVE: To assess the association of gestational age and low birth-weight-for-gestational-age (z-score) with white matter maturation. MATERIALS AND METHODS: Infants (n = 76, 53 males) born at different gestational ages were imaged at term-equivalent age. Gestational age and birth weight z-score were used as continuous variables and the effect on diffusion parameters was assessed. Brain maturation was studied using regions-of-interest analysis in several white matter areas. RESULTS: Gestational age showed no significant effect on white matter maturation at term-equivalent age. Children with low birth weight z-score had lower FA in the genu and splenium of the corpus callosum (regression, P = 0.012 and P = 0.032; correlation, P = 0.009 and P = 0.006, respectively), and higher MD in the splenium of the corpus callosum (regression, P = 0.002; correlation, P = 0.0004) compared to children whose birth weight was appropriate for gestational age. CONCLUSION: Children with low birth weight relative to gestational age show delay and/or anomaly in white matter maturation at term equivalent age. PMID- 22421991 TI - Computational study of the adsorption and dissociation of phenol on Pt and Rh surfaces. AB - The adsorption of phenol on flat and stepped Pt and Rh surfaces and the dissociation of hydrogen from the hydroxyl group of phenol on Pt(111) and Rh(111) were studied by density functional calculations. On both Pt(111) and Rh(111), phenol adsorbs with the aromatic ring parallel to the surface and the hydroxyl group tilted away from the surface. Furthermore, adsorption on stepped surfaces was concluded to be unfavourable compared to the (111) surfaces due to the repulsion of the hydroxyl group from the step edges. Transition state calculations revealed that the reaction barriers, associated with the dissociation of phenol into phenoxy, are almost identical on Pt and Rh. Furthermore, the oxygen in the dissociated phenol is strongly attracted by Rh(111), while it is repelled by Pt(111). PMID- 22421992 TI - [The future of public health research in Germany]. PMID- 22421993 TI - Electrochemiluminescent detection of mucin 1 protein and MCF-7 cancer cells based on the resonance energy transfer. AB - A novel sensing strategy for sensitive detection of mucin 1 protein (MUC1) and MCF-7 cells based on electrochemiluminescence (ECL) resonance energy transfer (ERET) from bis(2,2'-bipyridine)-(5-aminophenanthroline)ruthenium(II) (Ru1) to graphene oxide (GO) was proposed. The MUC1 aptamer was covalently combined with Ru1 (Ru1-aptamer) using aqueous carbodiimide coupling chemistry. Due to the strong noncovalent interaction between the Ru1-aptamer and GO, the ECL of Ru1 was efficiently quenched because of the ERET. In the presence of a target MUC1 protein, the binding between the Ru1-aptamer and MUC1 disturbed the interaction between the Ru1-aptamer and GO. These interactions led to the release of the Ru1 aptamer from GO, and resulted in the restoration of Ru1 ECL. This was shown to detect MUC1 protein sensitively in a linear range from 64.9 to 1036.8 nM with a detection limit of 40 nM. With further application in the detection of MCF-7 cells, the presented method could respond at concentrations as low as 30 cancer cells per mL. By substituting the aptamer and the corresponding target, this method could be conveniently extended for the sensitive detection of other biomolecules. PMID- 22421994 TI - Orofacial features of hypohidrotic ectodermal dysplasia. AB - Hypohidrotic ectodermal dysplasia (HED) is a type of genodermatosis characterized by the abnormal development of sweat glands, teeth, and hair. The most prevalent form of HED is X-linked hypohidrotic ectodermal dysplasia (XLHED), which is associated with mutations in the EDA gene. The aim of this case report was to describe a family with XLHED with emphasis on differences in orofacial features between members. Family members were systematically evaluated to characterize the pattern of inheritance and clinical features. Dental examination included evaluation of agenesis and abnormal teeth structure. The pedigree of the last seven generations of the family was constructed. Clinical examination and medical history revealed five males affected by HED and nine female as heterozygous carriers. The males exhibited the classic phenotype of XLHED, with dental abnormalities, hypohydrosis, and craniofacial dysmorphologies. The heterozygous carriers of the X-linked gene defect principally exhibited dental agenesis of the lateral maxillary incisors. Careful clinical examination, including dental evaluation, is an important way to detect heterozygous carriers of X-linked HED. Heterozygous parents of patients with HED may also show some features of the disorder. The identification of female carriers results in genetic counseling being offered to affected families, as well as providing adequate treatment as necessary and long-term follow-up of these patients. PMID- 22421995 TI - Spindle cell epulis in an 8-month-old child: a histologic variant of congenital granular cell epulis? AB - A case of an epulis in an 8-month-old boy is reported. The tumor was localized on the mandibular alveolar ridge and, according to the parents, was a recurrence of a congenital tumor excised when the boy was 2 months old. Microscopically, it was composed of many spindled or ovoid cells with vesicular nuclei and non-granular eosinophilic cytoplasm, and covered by acanthotic parakeratinized squamous epithelium with broad rete pegs. Immunohistochemically, the spindled and ovoid cells were intensely positive for vimentin and neuron-specific enolase, and negative for S-100 protein. The final diagnosis was spindle cell epulis. The possible correlation of this lesion with congenital granular cell epulis is discussed. PMID- 22421996 TI - Management of ocular surface exposure. PMID- 22421997 TI - Retinoblastoma: direct chemotherapeutic drug delivery into the vitreous cavity. PMID- 22421998 TI - Tie1 deficiency induces endothelial-mesenchymal transition. AB - Endothelial-mesenchymal transition (EndMT) has a significant role in embryonic heart formation and in various pathologies. However, the molecular mechanisms that regulate EndMT induction remain to be elucidated. We show that suppression of receptor tyrosine kinase Tie1 but not Tie2 induces human endothelial cells to undergo EndMT and that Slug deficiency reverts this process. We find that Erk1/2, Erk5 and Akt cascades control Slug promoter activity induced by Tie1 deficiency. Interestingly, EndMT is present in human pancreatic tumour. We propose that EndMT associated with Tie1 downregulation participates in the pathological development of stroma observed in tumours. PMID- 22421999 TI - Replicates and repeats--what is the difference and is it significant? A brief discussion of statistics and experimental design. PMID- 22422000 TI - Get your fingers out of p53's way! PMID- 22422001 TI - A new class of SUMO proteases. PMID- 22422002 TI - Wildlife forensics. Genomics has become a powerful tool to inform conservation measures. PMID- 22422003 TI - To hype, or not to(o) hype. Communication of science is often tarnished by sensationalization, for which both scientists and the media are responsible. PMID- 22422005 TI - Metastatic signet ring colon cancer in a Caribbean young adult and review of the literature. AB - Colorectal cancer is the third most common neoplasm diagnosed in the USA, with less than 3% of patients younger than 40 years. Although most of the literature indicates that younger patients present with a higher stage and grade of cancer, mortality is not clearly correlated. Furthermore, the literature pertaining to colorectal cancer in the nonwhite youth is limited. In this case report, we report a case of aggressive colorectal cancer metastasizing in a young Afro Caribbean woman with no known risk factors. The aim of this report is to raise awareness of this entity in the younger population, particularly in Afro Caribbeans, which remains a highly understudied group compared with the rest of the US population. PMID- 22422004 TI - Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. AB - Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics--streptomycin and vancomycin--and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the 'hygiene hypothesis', our data support a neonatal, microbiota-driven, specific increase in susceptibility to experimental murine allergic asthma. PMID- 22422006 TI - Operative treatment of femoral neck osteochondroma through a digastric approach in a pediatric patient: a case report and review of the literature. AB - A digastric approach has been used successfully to treat adult patients with femoral neck osteochondromas; however, to our knowledge, this has not been described in pediatric patients with open proximal femur growth plates. A case of femoral neck osteochondroma in an 11-year-old boy is presented and treatment using a digastric approach is described. No intraoperative femoral neck fracture or postoperative avascular necrosis occurred. There is no recurrence of the tumor at the 7-year follow-up. Surgical hip dislocation through a digastric approach provides adequate exposure of the femoral neck for osteochondroma resection and this technique should be considered for such circumstances. PMID- 22422007 TI - Congenital insensitivity to pain with anhidrosis: a case report of a 33-year-old patient. AB - Congenital insensitivity to pain with anhidrosis is a type IV hereditary sensory and autonomic neuropathy, presenting early in life. This disorder results from defective neural crest differentiation with loss of the first-order afferent system, which is responsible for sensations of pain and temperature; a neuronal loss in the sympathetic ganglia is also present. A case of a 33-year-old patient with congenital insensitivity to pain with anhidrosis is presented. From the time of birth, he did not sweat and did not respond to painful stimuli, although unexplained bouts of fever were often observed in infancy; an extensive workup during childhood helped establish the diagnosis. Throughout childhood and adulthood, the patient presented multiple infections and fractures in various sites of his body, growth disturbances, and avascular necrosis, and Charcot arthropathies and joint dislocations mainly affected his elbow and hip joint. At the final follow-up, at the age of 33 years, he was found to be obese, with a limited social life. A Charcot elbow restricted the activity of his left upper limb, and the dislocated hips combined with the instability of the ankle joints limited the ambulation distance. A specific treatment protocol has not been established in the literature; the main principles that can be applied in patients with normal intelligence include training programs to prevent self mutilation and accidental injuries and an early diagnosis and treatment of the infections. PMID- 22422008 TI - Development of dye-sensitized solar cells composed of liquid crystal embedded, electrospun poly(vinylidene fluoride-co-hexafluoropropylene) nanofibers as polymer gel electrolytes. AB - In order to overcome the problems associated with the use of liquid electrolytes in dye-sensitized solar cells (DSSCs), a new system composed of liquid crystal embedded, polymer electrolytes has been developed. For this purpose, three types of DSSCs have been fabricated. The cells contain electrospun poly(vinylidene fluoride-co-hexafluoropropylene) (e-PVdF-co-HFP) polymer gel electrolyte, with and without doping with the liquid crystal E7 and with a liquid electrolyte. The morphologies of the newly prepared DSSCs were explored using field emission scanning electron microscopy (FE-SEM). Analysis of the FE-SEM images indicate that the DSSC composed of E7 embedded on e-PVdF-co-HFP polymer gel electrolyte has a greatly regular morphology with an average diameter. The ionic conductivity of E7 embedded on e-PVdF-co-HFP polymer gel electrolyte was found to be 2.9 * 10( 3) S/cm at room temperature, a value that is 37% higher than that of e-PVdF-co HFP polymer gel electrolyte. The DCCS containing the E7 embedded, e-PVdF-co-HFP polymer gel electrolyte was observed to possess a much higher power conversion efficiency (PCE = 6.82%) than that of an e-PVdF-co-HFP nanofiber (6.35%). In addition, DSSCs parameters of the E7 embedded, e-PVdF-co-HFP polymer gel electrolyte (V(oc) = 0.72 V, J(sc) = 14.62 mA/cm(2), FF = 64.8%, and PCE = 6.82% at 1 sun intensity) are comparable to those of a liquid electrolyte (V(oc) = 0.75 V, J(sc) = 14.71 mA/cm(2), FF = 64.9%, and PCE = 7.17%, both at a 1 sun intensity). PMID- 22422009 TI - Occupational respiratory and skin diseases among Finnish machinists: findings of a large clinical study. AB - PURPOSE: Machinists are exposed to many sensitizing and irritant substances, but no previous study has assessed the occurrence of clinically verified occupational diseases in an unselected large workforce of machinists. Our aim was to study the occurrence of clinically verified occupational respiratory and skin diseases cross-sectionally in a large sample of machinists in southern Finland. METHODS: A computer-assisted telephone interview on occupational exposures and health was carried out in a sample of 961 machining workers from 64 metalworking companies. Of these, 757 (79%) answered the interview. A total of 245 subjects reported work related respiratory or skin symptoms and were invited to clinical examinations; 138 of these underwent a clinical interview and examination by an occupational health physician. On the basis of this examination, 32 subjects were further examined at the Finnish Institute of Occupational Health (FIOH) for occupational skin or respiratory diseases. RESULTS: One case of occupational asthma (OA) and seven cases of occupational dermatoses (OD) were diagnosed, giving a prevalence of 0.13% (95% CI 0-0.39) for OA, and 0.92% (95% CI 0.24-1.16) for OD. The OA was induced by the patient's own MWF. Additional five cases of newly diagnosed non occupational asthma (0.79%, 95% CI = 0.16-1.42) were detected. No cases of occupational rhinitis or COPD were diagnosed. The dermatoses diagnoses consisted of four cases of allergic contact dermatitis and three cases of irritant contact dermatitis. The most common causes of the ODs were MWFs. CONCLUSION: This large clinical study of machinists representing metalworking in South Finland showed a prevalence of 0.13% of OA and 0.92% of OD. This relatively low occurrence of occupational diseases may reflect the strict Finnish criteria for the diagnosis of these occupational diseases and the relatively good level of occupational hygiene in machining workshops in Finland. Reported respiratory and skin symptoms were common, and these milder conditions may be linked to irritant rather than sensitizing exposures. PMID- 22422010 TI - Carbon dioxide (CO2) demand-controlled ventilation in university computer classrooms and possible effects on headache, fatigue and perceived indoor environment: an intervention study. AB - PURPOSE: To study the effects of a CO(2) demand-controlled ventilation system (variable flow) in computer classrooms on perceived air quality and sick building syndrome. METHODS: University students (27% women) participated in a blinded study. Two classrooms had variable flow (mean 5.56 ac/h); two others had constant ventilation flow (mean 5.07 ac/h). After one week, ventilation conditions were shifted. The students reported symptoms/perceptions during the last hour on rating scales. Temperature, air humidity, CO(2), PM10 and number concentration of particles were measured simultaneously. Cat (Fel d 1), dog (Can f 1), horse (Equ cx) and house dust mites (Der f 1 and Der p 1) allergens were measured in dust. Those participating twice in the same classroom (N = 61) were analysed longitudinally. RESULTS: Mean CO(2) was 784 ppm (9% of time >1,000 ppm) with variable flow and 809 ppm with constant flow conditions (25% of time >1,000 ppm). Mean temperature (22.6 degrees C), PM10 (18 MUg/m(3)) and number concentration (1,860 pt/cm(3)) were unchanged. The median levels of cat, dog, horse and Der f 1 allergens were 10,400 ng/g, 4,900 ng/g, 13,700 U/ng and 260 ng/g dust, respectively. There were slightly less headache (p = 0.003), tiredness (p = 0.007) and improved perceived air quality (p = 0.02) with variable flow. CONCLUSIONS: Use of a CO(2)-controlled ventilation system, reducing elevated levels of CO(2), may slightly reduce headache and tiredness and improve perceived air quality. The high levels of pet allergens, due to track in of allergens from the home and possible accumulation due to electrostatic forces, illustrate a need for improved cleaning. PMID- 22422011 TI - Iron, brain and neuropsychiatric problem. PMID- 22422012 TI - Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. AB - OBJECTIVE: To evaluate the association of progressive multifocal leukoencephalopathy (PML) with immunosuppressive therapy for autoimmune rheumatic diseases (ARDs). METHODS: A Freedom of Information Act request was submitted for all cases of PML within the Food and Drug Administration Adverse Event Reporting System database. ARD cases were selected for further analysis. RESULTS: A total of 34 confirmed cases of PML in the setting of ARDs were identified: 17 had systemic lupus erythematosus, 10 had rheumatoid arthritis, 4 had vasculitis, and 3 had dermatomyositis. Fifteen of these patients were treated with one or more biologic agents: 14 received rituximab (RTX), 6 received anti-tumor necrosis factor (anti-TNF) therapy (5 treated with anti-TNF agent prior to RTX). Four RTX treated patients were not receiving additional immunosuppressive therapy at the time of PML onset, other than an antimalarial drug and/or low-dose glucocorticoids; all others who were receiving a biologic agent were also receiving one or more synthetic disease-modifying agents. All but 1 patient receiving a biologic agent had at least 1 potential confounding factor for the diagnosis of PML. The remaining 19 confirmed cases of PML among ARD patients were treated with synthetic disease-modifying antirheumatic drugs only, 14 of whom had received an alkylating agent. CONCLUSION: PML has been reported in patients with ARD treated with various immunosuppressive agents. The limitations of this study preclude definitive attribution of causality. While the paucity of confirmed cases recently exposed to anti-TNF therapy suggests a causal relationship is unlikely, a specific signal is emerging with regard to rituximab and PML. Although this is a rare adverse event associated with RTX therapy, the devastating nature of PML mandates continued vigilance, particularly in patients with current or prior exposure to an alkylating agent. PMID- 22422013 TI - A water soluble Cu(I)-NHC for CuAAC ligation of unprotected peptides under open air conditions. AB - A reducing agent-free version of CuAAC able to operate under open air conditions is reported. A readily-synthesizable, hydrophilic and highly stable Cu(I)-NHC allows the clean ligations of unprotected peptides comprising sensitive side chains, at millimolar concentrations. PMID- 22422014 TI - Changes in racial-ethnic disparities in use and adequacy of mental health care in the United States, 1990-2003. AB - OBJECTIVE: This study examined changes in white-black and white-Latino disparities in the use of any mental health care and minimally adequate mental health care. METHODS: Using data from the 1990–1992 National Comorbidity Survey (NCS) and the 2001–2003 National Comorbidity Survey Replication (NCS-R), this study examined changes by race-ethnicity in use of mental health care among individuals age 18 to 54 with a 12-month mood or anxiety disorder. The sample consisted of 1,198 NCS respondents and 929 NCS-R respondents. Changes in disparities were estimated in the use of any mental health care in the general medical sector, the specialty mental health sector, and in total. Changes in disparities were also estimated in the use of minimally adequate mental health care (in total only). RESULTS: Disparities in the use of any mental health care increased over time, particularly between non-Latino whites and non-Latino blacks in the general medical sector and between non-Latino whites and Latinos in the specialty mental health sector. Disparities in the use of minimally adequate mental health care persisted between whites and blacks over time but were not detected between whites and Latinos in either period. CONCLUSIONS: The findings of greater racial-ethnic disparities in the general medical and specialty mental health sectors indicate that more targeted policies and programs are needed to increase use of mental health care in these health sectors among persons from racial-ethnic minority groups. The persistence of white-black disparities in the use of minimally adequate mental health care warrants further examination. PMID- 22422015 TI - Change in mental health service use after offering youth-specific versus adult programs to transition-age youths. AB - OBJECTIVES: This study examined changes in service use associated with providing age-specific services for youths in their transitional years, ages 18-24. METHODS: A quasi-experimental, difference-in-difference design with propensity score weighting was used to compare mental health service utilization (use of outpatient, inpatient, emergency, and justice system services) among 931 youths enrolled in outpatient programs specifically for transition-age youths and 1,574 youths enrolled in standard adult outpatient programs in San Diego County, California, from July 2004 through December 2009. RESULTS: Among youths enrolled in outpatient programs geared toward youths of transitional age, the mean number of annual outpatient mental health visits increased by 12.2 (p<.001) compared with youths enrolled in standard adult outpatient programs. CONCLUSIONS: Compared with traditional adult outpatient mental health programs, age-specific programs were associated with an increased use of outpatient mental health services. Future research is needed to assess the effectiveness of age-specific programs for transition-age youths and how use of these programs relates to improved clinical, educational, and vocational outcomes over time. PMID- 22422016 TI - Major depressive disorder with psychosis-like symptoms among Latinos. AB - OBJECTIVE: The lifetime prevalence of psychosis-like symptoms among Latinos living in the United States is 9.5%, and up to 27% of Latinos with major depressive disorder also experience psychosis-like symptoms. Yet clinicians remain uncertain about the nature and clinical implications of these putative psychotic symptoms, and there is no consensus about treatment strategies. The authors conducted a review of the literature to examine the epidemiology, clinical features, and significance of psychosis-like symptoms among Latinos, particularly when such symptoms present with major depressive disorder, and the strategies to treat them. METHODS: A search of the National Library of Medicine was conducted for all articles published through February 2011 by using the keywords "Hispanic" and "Latino" with "depression and psychotic," with "idiom of distress," and with "psychotic." RESULTS: A total of 37 articles were reviewed. In clinical settings, the prevalence of psychosis-like symptoms among cross sections of Latino patients ranged from 22% to 46% and was even higher among Latino veterans. Psychosis-like symptoms were associated with higher medical and psychiatric comorbidity and greater suicidality, functional impairment, and utilization of services. The authors describe the types of psychosis-like symptoms experienced by Latinos and propose criteria for the differential diagnosis of such symptoms and typical psychotic features. CONCLUSIONS: Clinicians treating depressed Latinos are often confronted with the clinical dilemma of whether to augment antidepressants with an antipsychotic. The authors argue that atypical psychotic symptoms experienced by Latinos with major depressive disorder are nonpsychotic manifestations and that antipsychotic medication should be delayed unless treatment of depression fails to address the psychosis-like symptoms. PMID- 22422017 TI - Racial-ethnic differences in referral source, diagnosis, and length of stay in inpatient substance abuse treatment. AB - OBJECTIVE: Racial-ethnic differences in referral source, diagnosis, and length of stay in substance abuse treatment were examined. METHODS: Data from 495 African Americans, 492 Hispanics, and 497 non-Hispanic whites were analyzed. RESULTS: Hispanics were less likely than whites to be referred by crisis services; African Americans were more likely than other groups to be referred from criminal justice settings. At admission Hispanics and African Americans were more likely to have a drug use disorder, and whites were more likely to have an alcohol use disorder. Both African Americans and Hispanics were more likely than whites to have a cluster B personality disorder diagnosis at discharge. African Americans had longer stays than other groups. CONCLUSIONS: The findings could be used to design interventions to reduce disparities in inpatient substance abuse treatment. PMID- 22422018 TI - Recent trends in the treatment of posttraumatic stress disorder and other mental disorders in the VHA. AB - OBJECTIVE: This study proposed to evaluate Veterans Health Administration (VHA) specialty mental health care workload for treating posttraumatic stress disorder (PTSD) and other mental disorders between 2005 and 2010 in comparison with results from 1997 to 2005. The 2005-2010 time frame represents a period of increased utilization of services by recently returning veterans and of program expansion within VHA. METHODS: VHA administrative databases were queried for all veterans receiving specialty mental health treatment annually between 2005 and 2010. Veterans were categorized by military service era (WWII or Korea, Vietnam, post-Vietnam, Persian Gulf War [including operations in Iraq and Afghanistan], and peacetime or other), diagnosis (PTSD or a non-PTSD mental disorder), and deployment to Iraq or Afghanistan. RESULTS: The total number of veterans served per year increased by 623,326 (117.6%) between 1997 and 2010. Veterans with PTSD increased at a greater rate since 2005 compared with veterans with other mental disorders. Vietnam veterans constituted a majority of all veterans treated for PTSD or for other mental disorders, and the number of Vietnam veterans treated for PTSD continues to grow. The number of visits per veteran with PTSD increased between 2006 and 2010, reversing previous trends. The rate of increase has been highest for Iraq and Afghanistan veterans. CONCLUSIONS: Both the number treated and treatment intensity have increased for veterans with PTSD who served in current conflicts, which might be expected, and in the Vietnam era, now 30 years past. A reversal of past declines in treatment intensity coincides with an increase in PTSD treatment funding and program expansion since 2005. PMID- 22422019 TI - Uranium oxide and other airborne particles deposited on cypress leaves close to a nuclear facility. AB - Enhanced activity of actinides and some decay products has been reported for the leaves of cypress trees (Chamaecyparis nootkatensis) at the edge of the Malvesi uranium-processing facility, southwestern France. The enhanced activity is due to the release of actinides via the smokestacks and from artificial ponds inside the facility. This study was conducted to characterize airborne particulate matter deposited on the leaf surfaces and to investigate whether or not radioactive particles may be identified. Air-dried leaf samples were examined by scanning electron microscopy, in combination with energy-dispersive X-ray spectrometry. The samples were scanned systematically in both secondary and backscattered electron modes. Particles ranging in size from <200 nm to ~40 MUm were found on most portions of the adaxial leaf surface, but they are especially abundant at the boundary between facial and lateral leaves. The majority of the analyzed particles could be attributed to five principal classes: carbonates, silicates, sulfates, oxides/hydroxides, and halides. In addition, other types of particles were found, including Fe alloys; scheelite-group phases; phosphates; sulfides; and fly ash spheres. Similar particles were also observed on the surface of a wheat sample used for comparison. Of special interest are U-rich particles, which were observed on the cypress leaves only and which were identified as U oxides, except for one particle, which was a U-oxide-fluoride. These U-rich particles were released into the atmosphere by the nuclear facility prior to their deposition on the leaf surfaces. As most of the U-rich particles are <2.5 MUm across, they are respirable. Once inhaled, particles containing alpha-emitting isotopes represent a potentially long-term source of ionizing radiation inside the lungs and thus, pose a threat to the health of people living nearby. PMID- 22422020 TI - HIV status should also be documented in patients with tuberculosis-associated symmetrical peripheral gangrene. PMID- 22422021 TI - Oral involvement in sarcoidosis: report of 12 cases. AB - AIM: To assess the clinical features, treatment and outcome of oral sarcoidosis and to determine whether oral involvement is associated with a particular clinical phenotype of sarcoidosis. DESIGN: Multicentric retrospective study. METHODS: Retrospective chart review. Each patient was matched with four controls. RESULTS: Twelve patients (9 women, 3 men) were identified. Their median age at sarcoidosis diagnosis was 38 years. Oral involvement was the first clinical evidence of sarcoidosis in seven cases and was a relapse symptom in five cases. Clinical presentations were nodules (n = 7) or ulcers (n = 5) and were mostly solitary. The tongue was the commonest site affected (n = 4), followed by lips (n = 3), oral mucosa (n = 2), palate (n = 2) and gingiva (n = 1). Patients with oral sarcoidosis were significantly younger and had more frequent lacrimal or salivary glands and upper airway tract clinical involvement than the controls; increased angiotensin-converting enzyme was less frequent in oral sarcoidosis. Multiple treatments of oral sarcoidosis were used: no treatment (n = 3), surgery (n = 2), corticosteroids (n = 7), hydroxychloroquine (n = 3), methotrexate (n = 2), doxycycline (n = 1). Methotrexate was efficient in one patient, hydroxychloroquine showed benefit in only 1 out of 3 patients. Three patients presented oral relapses. After a mean follow-up of 6 years, 10 patients experienced a complete (n = 7) or partial (n = 3) remission of oral sarcoidosis; stability was observed in the remaining two cases. CONCLUSION: Although oral manifestations of sarcoidosis are unusual, physicians should be aware that this specific localization is frequently the first manifestation of the disease. Treatment modalities range from observation in asymptomatic patients to immunosuppressants for severe involvement. PMID- 22422022 TI - CT fluoroscopy-guided vertebral augmentation with a radiofrequency-induced, high viscosity bone cement (StabiliT((r))): technical results and polymethylmethacrylate leakages in 25 patients. AB - OBJECTIVE: To assess the technical results of CT fluoroscopy-guided, radiofrequency-induced vertebral augmentation (StabiliT(r)) in terms of vertebral height restoration and polymethylmethacrylate (PMMA) leakages, occurring in 25 individual patients with vertebral compression fractures and osteolysis. MATERIALS AND METHODS: From 07/2010 to 08/2011, 25 patients (16 women, nine men; age 71 +/- 14; range 41-89) with painful vertebral compression fractures due to osteoporosis (n = 19), metastases (n = 2) or multiple myeloma (n = 4) underwent vertebral augmentation with a radiofrequency-activated, high-viscosity polymethylmethacrylate (PMMA) bone cement (StabiliT(r) Vertebral Augmentation system; DFINE Europe GmbH, Mannheim) under local anesthesia. Thirty-four vertebrae (Th5-L5) were treated in 27 sessions under CT fluoroscopy guidance (128 row CT, Somatom Definition AS, Siemens, Erlangen) using a unilateral access and a cavity-creating osteotome prior to remote-controlled, hydraulically driven cement injection. 1/2/3 levels were treated in 21/5/1 session(s). Vertebral height change in the midsagittal plane (anterior, midvertebral, posterior endplate distance) and PMMA leaks were retrospectively evaluated using the postinterventional CT. RESULTS: All patients were successfully treated in the first session. Mean (MV +/- SD) procedure time and amount of injected PMMA were 56 +/- 14 min and 4.5 +/- 1.4 ml, respectively. Mean anterior/midvertebral/posterior height gain was +7.1/+9.7/+0.4%. Small local vertebral leaks were observed in 18/34 vertebrae (53%) without any clinical sequelae. No major complications occurred. CONCLUSIONS: CT fluoroscopy-guided, RF induced vertebral augmentation with a high-viscosity bone cement (StabiliT(r)) was safe and technically successful in all patients. Using a hydraulic cement injection technique, a moderate restoration of anterior and midvertebral height was seen while the system was not markedly superior to standard vertebroplasty regarding the frequency of minor asymptomatic PMMA leaks. PMID- 22422023 TI - Can MR imaging challenge the commonly accepted theory of the pathogenesis of solitary enchondroma of long bone? AB - OBJECTIVE: It has been widely postulated that enchondromas arise from cartilage remnants that have been displaced from the growth plate into the metaphysis. However, this theory remains unproven. Based on the common occurrence of enchondromas on routine knee MR imaging (2.9 %), one would expect to find displaced cartilage in the metaphysis of skeletally immature individuals on routine knee MR examinations if the above theory was to be supported. MATERIALS AND METHODS: The electronic databases of a specialist orthopedic hospital and children's hospital were searched for skeletally immature patients who underwent MR imaging of the knee for a variety of indications. Individuals with Ollier disease or hereditary multiple exostoses were excluded. The MR images were subsequently reviewed by a musculoskeletal radiologist for evidence of displaced cartilage into the metaphysis. RESULTS: We reviewed 240 MR examinations of the knee that were performed in 209 patients. There were 125 MR studies in male and 115 MR examinations in female patients (age range: 5 months-16 years; median age: 13 years). In 97.1 %, the growth plates around the knee demonstrated a regular appearance. Seven cases (2.9 %) in six patients showed cartilage extension from the growth plate into the metaphysis, which remained in continuity with the growth plate. There were no cases of displaced cartilage into the metaphysis on MRI. CONCLUSIONS: Our study challenges the widely believed theory that enchondromas arise from displaced growth plate remnants. PMID- 22422024 TI - The irreversible formation of palladium carbide during hydrogenation of 1-pentyne over silica-supported palladium nanoparticles: in situ Pd K and L3 edge XAS. AB - The catalytically active phase of silica-supported palladium catalysts in the selective and non-selective hydrogenation of 1-pentyne was determined using in situ X-ray absorption spectroscopy at the Pd K and L(3) edges. Upon exposure to alkyne, a palladium carbide-like phase rapidly forms, which prevents hydrogen to diffuse into the bulk of the nano-sized particles. Both selective and non selective hydrogenation occur over carbided particles. The palladium carbide-like phase is stable under reaction conditions and only partially decomposes under high hydrogen partial pressure. Non-selective hydrogenation to pentane is not indicative of hydride formation. The palladium carbide phase was detected in the EXAFS analysis and the K edge XANES showed representative features. PMID- 22422025 TI - An efficient and simple method for site-selective modification of O6-methyl-2' deoxyguanosine in DNA. AB - O(6)-Methyl-2'-deoxyguanosine (O(6)-Me-dG) is a mutagenic nucleotide in DNA. O(6) Me-dG in DNA was rapidly and selectively modified by a functionality transfer reaction using the ODN incorporating 6-S-functionalized thioguanosine. Subsequent labelling of O(6)-Me-dG with the fluorescent FAM or biotin group via click chemistry has permitted the sensitive and selective detection of O(6)-Me-dG in DNA. PMID- 22422026 TI - Fluorine ions-mediated morphology control of anatase TiO2 with enhanced photocatalytic activity. AB - This review briefly summarizes recent advances in fluorine ions-mediated morphology control of anatase TiO(2) in the forms of nanotube arrays, nanosheets with high-energy facets, and hollow spheres. The correlations between the enhanced photocatalytic activity and structural and morphological modifications of anatase TiO(2) by fluorine ions are addressed. PMID- 22422027 TI - Functionalization and reduction of graphene oxide with p-phenylene diamine for electrically conductive and thermally stable polystyrene composites. AB - A facile and efficient approach was developed to simultaneously functionalize and reduce graphene oxide (GO) with p-phenylene diamine (PPD) by simple refluxing. This was possible by the nucleophilic substitution reaction of epoxide groups of GO with amine groups of PPD aided by NH(3) solution. As a consequence, electrical conductivity of GO-PPD increased to 2.1 * 10(2) S/m, which was nearly 9 orders of magnitude higher than that of GO. Additionally, after the incorporation of GO-PPD in polystyrene (PS), the composites exhibited a sharp transition from electrically insulating to conducting behavior with a low percolation threshold of ~0.34 vol %, which was attributed to the improved dispersion and the reduction of GO-PPD. Thermal stability of the PS/GO-PPD composite was also ~8 degrees C higher than that of PS. PMID- 22422028 TI - Mechanical determinants of 100-m sprint running performance. AB - Sprint mechanics and field 100-m performances were tested in 13 subjects including 9 non-specialists, 3 French national-level sprinters and a world-class sprinter, to further study the mechanical factors associated with sprint performance. 6-s sprints performed on an instrumented treadmill allowed continuous recording of step kinematics, ground reaction forces (GRF), and belt velocity and computation of mechanical power output and linear force-velocity relationships. An index of the force application technique was computed as the slope of the linear relationship between the decrease in the ratio of horizontal to-resultant GRF and the increase in velocity. Mechanical power output was positively correlated to mean 100-m speed (P < 0.01), as was the theoretical maximal velocity production capability (P < 0.011), whereas the theoretical maximal force production capability was not. The ability to apply the resultant force backward during acceleration was positively correlated to 100-m performance (r (s) > 0.683; P < 0.018), but the magnitude of resultant force was not (P = 0.16). Step frequency, contact and swing time were significantly correlated to acceleration and 100-m performance (positively for the former, negatively for the two latter, all P < 0.05), whereas aerial time and step length were not (all P > 0.21). Last, anthropometric data of body mass index and lower-limb-to-height ratio showed no significant correlation with 100-m performance. We concluded that the main mechanical determinants of 100-m performance were (1) a "velocity oriented" force-velocity profile, likely explained by (2) a higher ability to apply the resultant GRF vector with a forward orientation over the acceleration, and (3) a higher step frequency resulting from a shorter contact time. PMID- 22422029 TI - Neurobiology of repression: a hypothetical interpretation. AB - Freud lived in a time when technology was incapable of explaining the biological correlates of the mental processes he described in psychoanalytic theory. During the last two decades, advances in neuroimaging methods and neuroscience have provided new insights for understanding mind-brain collaboration. Neurobiological underpinnings of psychoanalytical concepts have been an area of interest in recent years. This paper will suggest a new hypothesis for neurobiology of repression. This hypothesis will be discussed with the help of our knowledge about neurobiological mechanisms underlying perception of the emotional significance of an event, memory formation of an emotionally arousing stimulus, role of prefrontal cortex in modulation of subcortical information, neural mechanisms of suppression and molecular mechanisms of memory erasure. We suggest that dorsolateral prefrontal cortex, and especially its caudal part plays a major role for repression of childhood traumatic events. Possible molecular mechanism of memory erasure in repression is long term depression of glutamatergic neurotransmission between prefrontal cortex- thalamus- limbic system. PMID- 22422030 TI - A novel compound heterozygous mutation in the BEST1 gene causes autosomal recessive Best vitelliform macular dystrophy. AB - PURPOSE: To determine the genetic basis of early onset autosomal recessive Best vitelliform macular dystrophy (arBVMD) in a family with three affected children. DESIGN: Clinical and family-based genetic study. METHODS: Seven subjects making up a family with three children affected by Best vitelliform macular dystrophy were studied. Standard ophthalmic exam with dilated ophthalmoscopy and imaging were performed in each individual. The eleven exons of BEST1 were directly sequenced. RESULTS: All three affected children have the clinical characteristic features of Best vitelliform macular dystrophy: large macular vitelliform lesions, scattered vitelliform lesions along the arcades and in the peripheral retina, and an accumulation of serous retinal fluid. A novel compound heterozygous mutation in the BEST1 gene was found in the three affected individuals (L41P and I201T). The unaffected parents and children only harbor one heterozygous mutation. CONCLUSION: arBVMD can be caused by the compound heterozygous mutation L41P and I201T in the BEST1 gene. PMID- 22422031 TI - Vitreo-papillary adhesion as a prognostic factor in pseudo- and lamellar macular holes. AB - PURPOSE: To determine the incidence of vitreopapillary adhesion (VPA) and to investigate its value as a prognostic factor in the surgical outcome of pseudo- (PMH) and lamellar macular holes (LMH). METHODS: A total of 76 consecutive patients, diagnosed with PMH (41 eyes) or LMH (35 eyes) were included. Eyes with VPA were alternatively assigned to the surgical or control group. Surgery consisted of a 25G vitrectomy and internal limiting membrane peeling with blue dye staining. There were six visits: baseline, the day of surgery, and 1, 3, 6, and 9 post-operative months. Main outcome measures were the incidence of VPA and changes in the outer retinal layers and visual acuity. RESULTS: VPA was found in 27% (11/41) of patients with PMH and 37% (13/35) with LMH (P=0.03). In presence of VPA, the best-corrected visual acuity (BCVA) improved in the surgery group from 32 +/- 8 to 47 +/- 8 letters, whereas the control group went from 34 +/- 7 to 31 +/- 8 letters. The difference in letters between the surgery and control groups was statistically significant for both distance (P=0.032) and near (P=0.04) vision. Intra-retinal cysts were significantly correlated with a poor functional prognosis (P=0.01). We found the presence of focal damage to the outer retinal layers in LMH and PMH. CONCLUSION: VPA is more frequent in the presence of LMH vsPMH. It significantly influences the tangential forces at the vitreoretinal interface, exacerbating anatomical changes, and worsening the functional prognosis. Functional difference between the surgical and control groups was statistically significant for distant and near vision in presence of VPA. PMID- 22422032 TI - Re 'Isolated eyelid edema in Melkersson-Rosenthal syndrome: a case series'. PMID- 22422033 TI - Implantation and explantation of an active epiretinal visual prosthesis: 2-year follow-up data from the EPIRET3 prospective clinical trial. AB - PURPOSE: The EPIRET3 retinal prosthesis was implanted in six volunteers legally blind from retinitis pigmentosa (RP) and removed after 4 weeks. Two years later, these subjects were re-examined to investigate ocular side effects and potential changes to quality of life. METHODS: Vision-related quality of life was recorded using the NEI-VFQ-25 questionnaire. Clinical data including interval history, visual acuity, and intraocular pressure were obtained. Anterior and posterior segments of the study eyes were examined and photographed; this included fluorescein angiography and optical coherence tomography (OCT). RESULTS: Data from five patients could be analysed. Life-quality score was consistent with results obtained at baseline. No unexpected structural alteration could be found in the study eyes. A moderate epiretinal gliosis was present in areas where the epiretinal stimulator had been fixated using retinal tacks. Angiography revealed no leakage or neovascularisation; OCT showed no generalised increase of central retinal thickness. CONCLUSIONS: Vision-related quality of life is low in patients suffering from end-stage RP. No further deterioration of life quality could however be detected within our monitoring period. Surgery was well tolerated by both patients and their eyes, without adverse events occurring during the follow up period. Epiretinal gliosis is known to occur with retinal tacks, but seems of no major concern to the integrity of the study eyes. However, it may potentially interfere with functional aspects of active implants. Hence, alternative, possibly biochemical, fixation methods merit further research. PMID- 22422034 TI - Ocular lymphoma with extrascleral extension as primary manifestation of Richter syndrome. PMID- 22422036 TI - Conditional activation of beta-catenin signaling in mice leads to severe defects in intervertebral disc tissue. AB - OBJECTIVE: The incidence of low back pain is extremely high and is often linked to intervertebral disc (IVD) degeneration. The mechanism of this disease is currently unknown. This study was undertaken to investigate the role of beta catenin signaling in IVD tissue function. METHODS: beta-catenin protein levels were measured by immunohistochemical analysis of disc samples obtained from patients with disc degeneration and from normal subjects. To generate beta catenin conditional activation (cAct) mice, Col2a1-CreER(T2) -transgenic mice were bred with beta-catenin(fx(Ex3)/fx(Ex3)) mice. Changes in disc tissue morphology and function were examined by micro-computed tomography, histologic analysis, and real-time polymerase chain reaction assays. RESULTS: beta-catenin protein was up-regulated in disc tissue samples from patients with disc degeneration. To assess the effects of increased beta-catenin levels on disc tissue, we generated beta-catenin cAct mice. Overexpression of beta-catenin in disc cells led to extensive osteophyte formation in 3- and 6-month-old beta catenin cAct mice, which were associated with significant changes in the cells and extracellular matrix of disc tissue and growth plate. Gene expression analysis demonstrated that activation of beta-catenin enhanced runt-related transcription factor 2-dependent Mmp13 and Adamts5 expression. Moreover, genetic ablation of Mmp13 or Adamts5 on the beta-catenin cAct background, or treatment of beta-catenin cAct mice with a specific matrix metalloproteinase 13 inhibitor, ameliorated the mutant phenotype. CONCLUSION: Our findings indicate that the beta catenin signaling pathway plays a critical role in disc tissue function. PMID- 22422037 TI - Neointimal tissue characteristics following sirolimus-eluting stent implantation: OCT quantitative tissue property analysis. AB - The neointimal tissue characteristics inside sirolimus-eluting stent (SES) were evaluated by optical coherence tomography (OCT) according to follow-up duration. One hundred and thirty-three Optical coherence tomography was performed in 96 patients with 143 SES which were retrospectively included and divided into 2 groups according to follow-up duration: Group 1, <24 months (98 stents in 71 patients); Group 2, >24 months (35 stents in 25 patients). The neointimal tissue coverage pattern and characteristics were studied using a new OCT analysis system which can quantitatively analyze tissue property by measuring attenuation, backscatter and signal intensity in the region of interest. Using these parameters, a multivariable logistic regression model was constructed to divide neointima into homogenous or heterogeneous type. We defined homogeneous nointima as neointimal tissue having uniform optical properties and does not showing focal variations in backscattering pattern and heterogeneous neointima as neointimal tissue with focally changing optical properties and showing various backscattering patterns. The average time between stent implantation and follow up OCT imaging was 1.2 years in Group 1 and 3.2 years in Group 2. The number of neointima covered cross-sections, neointimal thickness, and neointimal area increased significantly with the length of follow-up duration after SES implantation (P < 0.01). The incidence of heterogeneous neointima was higher in Group 2 than in Group 1 (P < 0.01). Heterogeneous neointima was associated with higher incidence of microvessels (P = 0.0023) and lipid rich plaque (P = 0.0015) compared with homogeneous neointima. The neointimal tissue characteristics may change over time after SES implantation. The incidence of heterogeneous pattern was higher in the SES group with longer follow-up duration. Microvessels and lipid rich plaques were more frequently observed in neointima with heterogeneous pattern. Neointimal heterogeneity could be an important factor for the late stability of SES. PMID- 22422038 TI - The as-prepared gold cluster-based fluorescent sensor for the selective detection of As(III) ions in aqueous solution. AB - Water-soluble fluorescent gold clusters (AuCs) have been successfully synthesized by a wet-chemical approach at room temperature using a dipeptide l-cysteinyl-l cysteine. We have followed the core-etching mechanism for the synthesis of the gold clusters. Clusters show the excitation maximum at 300 nm and the emission maximum at 410 nm. These gold clusters show interesting fluorescent properties including large Stoke's shift (110 nm), with a quantum yield of 41.3%, and photochemical stability. Transmission electron microscopic analysis shows that most of these particles are <1.5 nm. These clusters have been applied successfully to develop the new fluorescent sensor for the selective and ultra sensitive detection of As(III) ions in the presence of other bivalent and trivalent metal ions in aqueous solution with a lower detection limit of 53.7 nM and this is far below the permissible limit (133 nM) of arsenic in drinking water permitted by WHO and USEPA. These gold clusters also show semiconducting behavior. PMID- 22422039 TI - Acoustically enriching, large-depth aquatic sampler. AB - In marine biology, it is useful to collect water samples when exploring the distribution and diversity of microbial communities in underwater environments. In order to provide, e.g., a miniaturized submersible explorer with the capability of collecting microorganisms, a compact sample enrichment system has been developed. The sampler is 30 mm long, 15 mm wide, and just a few millimetres thick. Integrated in a multilayer steel, polyimide and glass construction is a microfluidic channel with piezoelectric transducers, where microorganism and particle samples are collected and enriched, using acoustic radiation forces for gentle and labelless trapping. High-pressure, latchable valves, using paraffin as the actuation material, at each end of the microfluidic channel keep the collected sample pristine. A funnel structure raised above the surface of the device directs water into the microfluidic channel as the vehicle propels itself or when there is a flow across its hull. The valves proved leak proof to a pressure of 2.1 MPa for 19 hours and momentary pressures of 12.5 MPa, corresponding to an ocean depth of more than 1200 metres. By reactivating the latching mechanism, small leakages through the valves could be remedied, which could thus increase the leak-less operational time. Fluorescent particles, 1.9 MUm in diameter, were successfully trapped in the microfluidic channel at flow rates up to 15 MUl min(-1), corresponding to an 18.5 cm s(-1) external flow rate of the sampler. In addition, liquid-suspended GFP-marked yeast cells were successfully trapped. PMID- 22422040 TI - Predictors of employment among cancer survivors after medical rehabilitation--a prospective study. AB - OBJECTIVES: This study aimed to (i) investigate cancer survivor's employment status one year after the completion of a medical rehabilitation program and (ii) identify demographic, cancer, and psychosocial, treatment-, and work-related predictors of return to work (RTW) and time until RTW. METHODS: A total of 1520 eligible patients were consecutively recruited on average 11 months post diagnosis and assessed at the beginning (t(0)) (N=1148) and end of rehabilitation (t(1)) (N=1060) and 12 months after rehabilitation (t(2)) (N=750). Participants completed validated measures assessing functional impairments, pain, anxiety, depression, quality of life, social support, and work-related characteristics including work ability, sick leave absence, job requirements, work satisfaction, self-perceived employer accommodation, and perceived job loss. Physicians estimated the degree of cancer-entity-specific functional impairment. RESULTS: In a mean time of six weeks after rehabilitation, 568 patients (76%) had returned to work. The multivariate hierarchical logistic regression analysis indicated that baseline RTW intention [odds ratio (OR) 6.22, 95% confidence interval (95% CI) 1.98-19.51], perceived employer accommodation (OR 1.93, 95% CI 0.33-0.99), high job requirements (OR=1.84, 95% CI 1.02-3.30), cancer recurrence or progression (OR=0.27, 95% CI 0.12 - 0.63), baseline sick leave absence (OR=0.26, 95% CI 0.09 0.77), and problematic social interactions (OR=0.58, 95% CI 0.33-0.99) emerged as significant predictors for RTW. The explained variance of the total model was Nagelkerke's R2=0.59 (P<0.001). CONCLUSION: Our findings emphasize the high relevance of motivational factors. Occupational motivation and skepticism towards returning to work should be carefully assessed at the planning of the rehabilitation program. PMID- 22422041 TI - Improved anatomic visualization of a glomus caroticum tumour within the carotic bifurcation with combined 68Ga-DOTATATE PET/MRI. PMID- 22422042 TI - SPET/CT imaging in radionuclide cisternography to detect cerebrospinal fluid leakage in spontaneous intracranial hypotension associated with SLE. PMID- 22422043 TI - A carbon-rich ruthenium decorated dysprosium single molecule magnet. AB - The association of a carbon-rich ruthenium complex with an anisotropic dysprosium ion leads to a unique complex showing SMM behaviour with multiple relaxation processes. PMID- 22422044 TI - A fluorescent sensor for selective detection of cyanide using mesoporous graphitic carbon(IV) nitride. AB - A turn-on fluorescence sensor, Cu(2+)-c-mpg-C(3)N(4), was developed for detection of CN(-) in aqueous solution by simply mixing cubic mesoporous graphitic carbon nitride (c-mpg-C(3)N(4)) and aqueous solution of Cu(NO(3))(2). The highly sensitive detection of CN(-) with a detection limit of 80 nM is not only possible in aqueous solution but also in human blood serum. PMID- 22422045 TI - S-nitrosylation of c-Src via NMDAR-nNOS module promotes c-Src activation and NR2A phosphorylation in cerebral ischemia/reperfusion. AB - Previous studies suggested that activated c-Src promote the tyrosine phosphorylation of NMDA receptor subunit NR2A, and thus aggravate the injury induced by transient cerebral ischemia/reperfusion (I/R) in rat hippocampus CA1 region. In this study, we examined the effect of nitric oxide (NO) on the activation of c-Src and the tyrosine phosphorylation of NMDA receptor NR2A subunit. The results show that S-nitrosylation and the phosphorylation of c-Src were induced after cerebral I/R in rats, and administration of nNOS inhibitor 7 NI, nNOS antisense oligonucleotides and exogenous NO donor sodium nitroprusside diminished the increased S-nitrosylation and phosphorylation of c-Src during cerebral I/R. The cysteine residues of c-Src modified by S-nitrosylation are Cys489, Cys498, and Cys500. On the other hand, NMDAR antagonist MK-801 could attenuate the S-nitrosylation and activation of c-Src. Taken together, the S nitrosylation of c-Src is provoked by NO derived from endogenous nNOS, which is activated by Ca(2+) influx from NMDA receptors, and promotes the auto phosphorylation at tyrosines and further phosphorylates NR2A. The molecular mechanism we outlined here is a novel postsynaptic NMDAR-nNOS/c-Src-mediated signaling amplification, the 'NMDAR-nNOS -> NO -> SNO-c-Src -> p-c-Src -> NMDAR nNOS' cycle, which presents the possibility as a potential therapeutic target for stroke treatment. PMID- 22422047 TI - Large-scale production of PMMA/SWCNT composites based on SWCNT modified with PMMA. AB - In this work, a two-step method consisting of in situ polymerization of polymethyl methacrylate (PMMA) in the presence of single-walled carbon nanotubes (SWCNT), followed by the redispersion of the resulting compound in dimethylformamide (DMF), was used to fabricate SWCNT modified with PMMA (SWCNT PMMA). Raman spectroscopy revealed that PMMA was merely wrapped around the SWCNT when raw SWCNT or purified SWCNT were used as the starting material. However, PMMA was covalently bonded to SWCNT when acid treated SWCNT (SWCNT-COOH) was used as the starting material. SWCNT-PMMA compounds were further diluted in pure PMMA by conventional melt compounding at large scale (several kilograms) to obtain transparent composites containing 0.09 wt % SWCNT. The micro- and nano-dispersion of the SWCNT in the composites were analyzed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The thermal and mechanical properties of the composites were determined by thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), tensile testing, and Charpy impact testing. At the the low SWCNT loading studied, the tensile properties remain unchanged, whereas the impact strength improves by 20%. PMID- 22422046 TI - Identification of a major enzyme for the synthesis and hydrolysis of cyclic ADP ribose in amphibian cells and evolutional conservation of the enzyme from human to invertebrate. AB - Cyclic ADP-ribose (cADPR), a metabolite of NAD(+), is known to function as a second messenger for intracellular Ca(2+) mobilization in various vertebrate and invertebrate tissues. In this study, we isolated two Xenopus laevis cDNAs (frog cd38 and cd157 cDNAs) homologous to the one encoding the human cADPR-metabolizing enzyme CD38. Frog CD38 and CD157 are 298-amino acid proteins with 35.9 and 27.2 % identity to human CD38 and CD157, respectively. Transfection of expression vectors for frog CD38 and CD157 into COS-7 cells revealed that frog CD38 had NAD(+) glycohydrolase, ADP-ribosyl cyclase (ARC), and cADPR hydrolase activities, and that frog CD157 had no enzymatic activity under physiological conditions. In addition, when recombinant CD38 and frog brain homogenate were electrophoresed on an SDS-polyacrylamide gel, ARC of the brain homogenate migrated to the same position in the gel as that of frog CD38, suggesting that frog CD38 is the major enzyme responsible for cADPR metabolism in amphibian cells. The frog cd38 gene consists of eight exons and is ubiquitously expressed in various tissues. These findings provide evidence for the existence of the CD38-cADPR signaling system in frog cells and suggest that the CD38-cADPR signaling system is conserved during vertebrate evolution. PMID- 22422048 TI - Gis predictive mapping of terrestrial gamma radiation in the Northern State, Sudan. AB - This study presents the evaluation of absorbed dose in air due to gamma-emitting nuclides from (238)U and (232)Th series, (40)K and (137)Cs and the corresponding geographical information system (GIS) predictive mapping for the Northern State. Activity concentration of (238)U, (232)Th , (40)K and (137)Cs in soil samples collected from different locations have been measured using high-resolution gamma spectrometry. On average, activity concentrations were 19+/-4 ((238)U), 47+/-11 ((232)Th), 317+/-65 ((40)K) and 2.26 Bq kg(-1) for (137)Cs. Absorbed dose rate in air at a height of 1 m above ground surface was calculated using seven sets of dose rate conversion factors (DRCFs) and the corresponding annual effective dose was estimated. On average, the values obtained fall within a narrow range of 44 and 53 nGy h(-1), indicating that the variation in absorbed dose rate is insignificant for different DRCFs. The corresponding annual effective dose ranged from 53 to 65 uSv y(-1). Using GIS, prediction maps for concentrations of (238)U, (232)Th, (40)K and (137)Cs were produced. Also, a map for absorbed dose rate in air at a height of 1 m above the ground level was produced, which showed a trend of increasing from the west towards south-east of the State. PMID- 22422049 TI - Exploring concordance and discordance for return of incidental findings from clinical sequencing. AB - PURPOSE: The aim of this study was to explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing. METHODS: Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole-genome sequencing. For most conditions, the specialists independently considered three molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants are known to be pathogenic), and a missense variant predicted in silico to be pathogenic. RESULTS: On average, for adults and children, respectively, each specialist selected 83.5 and 79.0 conditions or genes of 99 in the known pathogenic mutation categories, 57.0 and 53.5 of 72 in the truncating variant categories, and 33.4 and 29.7 of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes. CONCLUSION: Specialists were highly concordant for the return of findings for 64 conditions or genes if discovered incidentally during whole-exome sequencing or whole-genome sequencing.Genet Med 2012:14(4):405-410. PMID- 22422050 TI - Broadening research consent in the era of genome-informed medicine. AB - Genetic variant associations and advances in research technologies are generating an unprecedented volume of genomic data. Whole-genome sequencing will introduce even greater depth to current data sets and will propel medical research and development. Yet as one area of biomedical research evolves, another stagnates: informed consent. As presently employed, informed consent is not entirely attuned to the era of whole-genome sequencing. The greatest value of genomic data lays in its accessibility over time; the current model of informed consent restricts the use of data and does not readily accommodate prospective basic and clinical research, a priori research, or opportunities to act upon incidental findings. It also disengages the research participant from the discovery process, discouraging the provision of research results that may have clinical value to that individual. A revisited informed consent approach-the Informed Cohort Oversight Board (ICOB)-has been proven successful at consenting individuals to a model which facilitates the simultaneous construction of longitudinal data with the return of results to participants as scientific knowledge and technology allows. The opportunity to sequence once and consult often is cost-effective, encourages scientific innovation, and provides the opportunity to quickly translate genomics into better clinical care. PMID- 22422051 TI - Template synthesis of SnO2/alpha-Fe2O3 nanotube array for 3D lithium ion battery anode with large areal capacity. AB - Electrodes with three-dimensional (3D) nanostructure are expected to improve the energy and power densities per footprint area of lithium ion microbatteries. Herein, we report a large-scale synthesis of a SnO(2)/alpha-Fe(2)O(3) composite nanotube array on a stainless steel substrate via a ZnO nanowire array as an in situ sacrificial template without using any strong acid or alkali. Importantly, both SnO(2) and alpha-Fe(2)O(3) contribute to the lithium storage, and the hybridization of SnO(2) and alpha-Fe(2)O(3) into an integrated nanotube structure provides them with an elegant synergistic effect when participating in electrochemical reactions. Large areal capacities and good rate capability are demonstrated for such a composite nanotube array. Particularly noteworthy is that the areal capacities (e.g. 1.289 mAh cm(-2) at a current rate of 0.1 mA cm(-2)) are much larger than those of many previous thin-film/3D microbattery electrodes. Our work suggests the possibility of further improving the areal capacity/energy density of 3D microelectrodes by designing ordered hybrid nanostructure arrays. PMID- 22422052 TI - Piezoelectricity of bone and electrical callus. PMID- 22422053 TI - Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines. AB - Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 (IL-3)-dependent murine cell lines like Ba/F3, resulting in loss of IL-3 dependence. Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia (AML) cell lines, despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients. We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death, involving Bax/Bcl2 modulation. Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs, shown here using the HL-60 leukemic cell line. Flt3 expression was investigated in two cellular model systems, the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line, and proliferation was reduced in both systems. HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl 2. Furthermore, we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent. Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines. PMID- 22422054 TI - Impact of cross-calibration methods on the interpretation of a treatment comparison study using 2 depression scales. AB - BACKGROUND: Many questionnaires assessing depressive symptoms are available. Most of these questionnaires are constructed based on classical test theory, making comparisons of individual scores difficult. Item response theory (IRT) allows the comparison of scores from different instruments. In this study, the impact of IRT based cross-calibration methods on the results of a treatment outcome study was evaluated using 2 instruments. METHODS: Data collected during admission and discharge procedures from 1066 inpatients in 2 psychosomatic clinics using different depression measures were analyzed. To achieve comparability across the applied depression measures, we used an IRT-based conversion table to transform scores from one instrument's scale to the other. Latent trait values were also estimated using different instruments in each clinic. We compared these methods to the traditional approach of using the same instrument in both clinics and examined their effects on the statistical analyses. RESULTS: There was no substantial change in the interpretation of the study results when different instruments were used. However, F values, P values, and effect sizes in the analysis of variance changed significantly. This might be attributed to differences in the content or measurement properties of the instruments. Interestingly, no difference was observed between use of transformed sum scores and latent trait values. CONCLUSIONS: IRT cross-calibration methods are a convenient way to enhance the comparability of questionnaire data in applied clinical settings but seem not to be able to overcome differences in measurement properties of the instruments. As these differences can lead to biased results, there is a need for further research into more advanced techniques. PMID- 22422055 TI - Gender and the use of Veterans Health Administration homeless services programs among Iraq/Afghanistan veterans. AB - BACKGROUND: Female Veterans comprise 12% of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans, the largest proportion of women to serve of any prior cohort. We sought to determine the sex-specific risk of using a Veterans Health Administration (VHA) homeless program among OEF/OIF Veterans and to identify factors associated with increased risk of program use for women compared with men. METHODS: We included OEF/OIF Veterans with at least 1 VHA clinical visit between October 1, 2001, and September 30, 2009. The study's outcome was the time to first use of a VHA homeless program. Cox proportional-hazards regression was used to estimate the relative risk of using a homeless program by sex, adjusting for relevant sociodemographic and clinical variables. Exploratory analyses examined interactions between sex and all covariates. RESULTS: Of 445,319 Veterans, 7431 (1.7%) used a VHA homeless program, of which 961 were females (1.8%), and 6470 were males (1.7%) during a median follow-up period of 3.20 years. Women were as likely as men to use a homeless program (adjusted hazard ratio, 1.02; 95% confidence interval, 0.95-1.09); median time to first use was similar for female and male Veterans (1.88 vs. 1.88 y, respectively, P=0.53). In exploratory analyses, we found increased risk of program use for women compared with men for the following subgroups: ages 26-35 years, 100% service connected disability rating, posttraumatic stress disorder diagnosis, and northeast location. CONCLUSIONS: Overall, there was no substantial difference in the sex-specific risk of using a VHA homeless program. In light of this finding, VHA homeless programs must be prepared to recognize and address the unique needs of female OEF/OIF Veterans. PMID- 22422056 TI - Evaluating the effect of hospital and insurance type on the risk of 1-year mortality of very low birth weight infants: controlling for selection bias. AB - OBJECTIVES: We examined the effect of hospital type and medical coverage on the risk of 1-year mortality of very low birth weight (VLBW) infants while adjusting for possible selection bias. METHODS: The study population was limited to singleton live birth infants having birth weight between 500 and 1500 g with no congenital anomalies who were born in Arkansas hospitals between 2001 and 2007. Propensity score (PS) matching and PS covariate adjustment were used to mitigate selection bias. In addition, a conventional multivariable logistic regression model was used for comparison purposes. RESULTS: Generally, all 3 analytical approaches provided consistent results in terms of the estimated relative risk, absolute risk reduction, and the number needed to treat. Using the PS matching method, VLBW infants delivered at a hospital with a neonatal intensive care unit (NICU) were associated with a 35% relative decrease (95% bootstrap confidence interval, 18.5%-48.9%) in the risk of 1-year mortality as compared with those infants delivered at non-NICU hospitals. Furthermore, our results showed that on average, 16 VLBW infants (95% bootstrap confidence interval, 11-32), would need to be delivered at a hospital with an NICU to prevent 1 additional death at 1 year. However, there was not a difference in the risk of 1-year mortality between VLBW infants born to Medicaid-insured versus non-Medicaid-insured women. CONCLUSIONS: Estimated relative risk of infant mortality was significantly lower for births that occurred in hospitals with an NICU; therefore, greater efforts should be made to deliver VLBW neonates in an NICU hospital. PMID- 22422057 TI - Usual source of care and the quality of medical care experiences: a cross sectional survey of patients from a Taiwanese community. PMID- 22422058 TI - Antioxidant-substituted tetrapyrazinoporphyrazine as a fluorescent sensor for basic anions. AB - Tetrapyrazinoporphyrazine substituted at its periphery with eight antioxidant 3,5 di-t-butyl-4-hydroxyphenyl groups behaves as a turn-on fluorescent sensor for fluoride anions. Conversely, the precursor antioxidant-substituted 1,2 phthalonitrile was found to act in turn-off mode suggesting that the origin of the phenomenon lies at the phenolate-substituted 1,4-pyrazinyl moiety. PMID- 22422059 TI - Glyco-macroligand microarray with controlled orientation and glycan density. AB - We report a new type of glycan microarray, namely, oriented and density controlled glyco-macroligand microarray based on end-point immobilization of glycopolymer that was accompanied with boronic acid (BA) ligands in different sizes as detachable "temporary molecular spacers". Briefly, an O-cyanate chain end functionalized lactose-containing glycopolymer was pre-complexed with polyacrylamide-BA, lysozyme-BA, and bovine serum albumin (BSA)-BA conjugates as macromolecular spacers first and then immobilized onto an amine-functionalized glass slide via isourea bond formation both at pH 10.3, respectively. Subsequently, the macromolecular spacers were detached from the immobilized glycopolymers at pH 7.4 so as to afford the oriented and density controlled glycopolymer microarrays. The spaced glycopolymer microarray showed enhanced lectin (Arachis hypogaea) binding compared to a non-spaced one. Among them, the polyacrylamide-BA spaced glycopolymer showed the highest level of lectin binding compared to lysozyme-BA- and BSA-BA-spaced glycopolymers. Furthermore, SPR results confirmed the same trend of density-dependent lectin binding as the glycoarray. This glyco-macroligand microarray platform permits variations of glycan density in the polymer, glycopolymer density and its orientation on the microarray surface and thus will provide a versatile tool for profiling glycan recognition for both basic biological research and practical applications. PMID- 22422060 TI - Magnetic resonance imaging in transient global amnesia: lessons learned from 198 cases. AB - PURPOSE: Patients with transient global amnesia (TGA) present with a characteristic clinical syndrome although other differential diagnoses have to be considered. Diffusion-weighted imaging (DWI) represents a highly specific diagnostic tool in the context of TGA; however, standard clinical DWI often fails to detect the small characteristic hippocampal lesions. The diagnostic success of DWI sequences in TGA patients was analyzed with respect to slice thickness and time interval between symptom onset. METHODS: Magnetic resonance imaging (MRI) studies of 198 patients with clinically diagnosed TGA were retrospectively analyzed. All DWI studies were grouped according to the slice thickness applied (3 mm, 5 mm and 6 mm). The three groups were assessed for group-specific detection rates of hippocampal lesions with diffusion restriction. In addition the detection rates were evaluated with respect to the time interval between TGA symptom onset and MRI examination. RESULTS: A significant increase in detection rates (about 8.4% per mm) was found when thinner slices were acquired (44.7% for 3 mm, 27.1% for 5 mm and 19.6% for 6 mm slice thickness). The detection rate was highest (up to 80%) when MRI was performed 2 days after TGA symptom onset. CONCLUSIONS: The MRI protocol in patients with TGA should include a DWI sequence with a slice thickness of 3 mm or less. The examination should be performed on day 2 after symptom onset to fully exploit the diagnostic value of DWI which represents a sensitive and specific diagnostic tool for patients with TGA. PMID- 22422061 TI - Role of porcine reproductive and respiratory syndrome virus nucleocapsid protein in induction of interleukin-10 and regulatory T-lymphocytes (Treg). AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection induces interleukin (IL)-10 production and increased numbers of PRRSV-specific regulatory T-lymphocytes in infected pigs. In the present study, the roles of the nucleocapsid (N) protein in induction of IL-10 and CD4(+)CD25(+)Foxp3(+) lymphocytes (T(reg)) were investigated. Transfection of porcine monocyte-derived dendritic cells (MoDCs) and pulmonary alveolar macrophages (PAMs) with a plasmid encoding N protein resulted in significant upregulation of IL-10 gene expression in the gene-transfected cells. Structural conformation, but not nuclear localization, of the expressed N protein was indicated to be essential for the ability to induce IL-10. Furthermore, the presence of recombinant N proteins in cultured PBMCs increased the number of IL-10-producing lymphocytes. Strong induction of IL-10-producing cells and T(reg) was observed when using N protein pulsed MoDCs, suggesting an important role of MoDCs in induction of IL-10 and T(reg) by the N protein. Neutralization of IL-10 by addition of an anti-IL-10 antibody in the culture system resulted in marked reduction of PRRSV-induced T(reg) in the cultured PBMCs. Together, the data demonstrate the immunomodulatory properties of the PRRSV N protein and the linkage between IL-10 production and development of PRRSV-induced T(reg). Our results reveal an immunomodulatory function of the PRRSV N protein that may contribute to the unique immunological outcome observed following PRRSV infection. PMID- 22422062 TI - Low pathogenic H7 subtype avian influenza viruses isolated from domestic ducks in South Korea and the close association with isolates of wild birds. AB - We characterized low pathogenic avian influenza (LPAI) viruses of the H7 subtype that were isolated from domestic ducks and wild birds in South Korea from 2008 to 2011. A total of 20 H7 viruses were collected from live-bird markets (LBMs), duck farms and wild-bird habitats using avian influenza (AI) surveillance and epidemiological approaches. A phylogenetic analysis of the H7 viruses that were isolated from domestic ducks and wild birds demonstrated that they were separated into 12 genotypes (A-D and Wb-1-8, respectively), indicating genetic diversity. These H7 viruses were related to the recently isolated Eurasian LPAI H7 viruses and various influenza viruses that are circulating in Asia, including southern China and South Korea. The same genotype was not found between domestic poultry and wild-bird isolates; however, most of the H7 viruses in poultry (genotypes B and C) were closely related to the H7 virus isolated from a wild bird (genotype Wb-3). Animal-challenge studies revealed that certain H7 AI viruses replicated well only in chickens or ducks depending on the genotype, indicating that the pathogenicity of H7 viruses has the potential to be altered due to multiple reassortments, and these viruses can potentially expand their host range. Our results are evidence of abundant and frequent reassortment between H7 viruses in poultry and wild birds and emphasize the continuing need to monitor the evolutionary genetics of the influenza virus in poultry and wild birds. PMID- 22422063 TI - Genetic and phylogenetic characterization of genome segments 2 and 6 of bluetongue virus isolates in Japan from 1985 to 2008. AB - This study conducted genetic and phylogenetic analyses of genome segments 2 and 6 (Seg-2 and Seg-6), which encode serotype-specific structural proteins of the outer capsid, of bluetongue virus (BTV) isolated in Japan from 1985 to 2008. The Japanese strains of BTV were clearly sorted into six groups by several genetic characteristics of Seg-2, including segment length, ORF length and 5'- and 3' terminal sequences, and were identified as serotypes 2, 3, 9, 12, 16 and 21 by phylogenetic comparisons with Seg-2 of reference and field strains of serotypes 1 24. In contrast, phylogenetic comparisons of Seg-6 also revealed some variations among the Japanese strains and partial correlations of the serotypes between the Japanese strains and the reference or field strains. Thus, the results revealed that at least six serotypes of BTV were isolated in Japan and that there were some variations in the genetic and phylogenetic characteristics of Seg-2 and Seg 6 among the Japanese strains, suggesting that BTV of several different origins has appeared sporadically in Japan. These data will be beneficial for understanding BTV epidemiology and taking better control measures against bluetongue in Japan and its neighbouring countries in the Asia-Pacific region. PMID- 22422064 TI - Tomato RNA polymerase II interacts with the rod-like conformation of the left terminal domain of the potato spindle tuber viroid positive RNA genome. AB - Potato spindle tuber viroid (PSTVd) is a small, single-stranded, circular, non coding RNA pathogen. Host DNA-dependent RNA polymerase II (RNAP II) was proposed to be critical for its replication, but no interaction site for RNAP II on the PSTVd RNA genome was identified. Using a co-immunoprecipitation strategy involving a mAb specific for the conserved heptapeptide (i.e. YSPTSPS) located at the carboxy-terminal domain of the largest subunit of RNAP II, we established the interaction of tomato RNAP II with PSTVd RNA and showed that RNAP II associates with the left terminal domain of PSTVd (+) RNA. RNAP II did not interact with any of several PSTVd (-) RNAs tested. Deletion and site-directed mutagenesis of a shortened model PSTVd (+) RNA fragment were used to identify the role of specific nucleotides and structural motifs in this interaction. Our results provide evidence for the interaction of a RNAP II complex from a natural host with the rod-like conformation of the left terminal domain of PSTVd (+) RNA. PMID- 22422065 TI - Genetic analysis of a novel nidovirus from fathead minnows. AB - A bacilliform virus was isolated from diseased fathead minnows (Pimephales promelas). Analysis of the complete genome coding for the polyprotein (pp1ab), spike (S), membrane (M) and nucleocapsid (N) proteins revealed that the virus was most like white bream virus (WBV), another bacilliform virus isolated from white bream (Blicca bjoerkna L.) and the type species of the genus Bafinivirus within the order Nidovirales. In addition to similar gene order and size, alignment of deduced amino acid sequences of the pp1ab, M, N and S proteins of the fathead minnow nidovirus (FHMNV) with those of WBV showed 46, 44, 39 and 15 % identities, respectively. Phylogenetic analysis using the conserved helicase domain of the replicase showed FHMNV was distinct from WBV, yet the closest relative identified to date. Thus, FHMNV appears to represent a second species in the genus Bafinivirus. A PCR assay was developed for the identification of future FHMNV like isolates. PMID- 22422066 TI - A third gyrovirus species in human faeces. AB - Until 2011 the genus Gyrovirus in the family Circoviridae consisted of a single virus (Chicken anemia virus or CAV) causing a common immunosuppressive disease in chickens when a second gyrovirus (HGyV) was reported on the skin of 4 % of healthy humans. HGyV is very closely related to a recently described chicken gyrovirus, AGV2, suggesting that they belong to the same viral species. During a viral metagenomic analysis of 100 human faeces from children with diarrhoea in Chile we identified multiple known human pathogens (adenoviruses, enteroviruses, astroviruses, sapoviruses, noroviruses, parechoviruses and rotaviruses) and a novel gyrovirus species we named GyV3 sharing <63 % similarity with other gyrovirus proteins with evidence of recombination with CAV in its UTR. Gyroviridae consensus PCR revealed a high prevalence of CAV DNA in diarrhoea and normal faeces from Chilean children and faeces of USA cats and dogs, which may reflect consumption of CAV-infected/vaccinated chickens. Whether GyV3 can infect humans and/or chickens requires further studies. PMID- 22422067 TI - Evidence for an endogenous papillomavirus-like element in the platypus genome. AB - Papillomaviruses (PVs) infect a wide range of vertebrates and have diversified into multiple genetic types, some of which have serious consequences for human health. Although PVs have to date only been characterized as exogenous viral forms, here we report the observation of an endogenous viral element (EPVLoa) in the genome of the platypus (Ornithorhynchus anatinus) that is related to PVs. Further data mining for endogenous PV-like elements is therefore warranted. PMID- 22422069 TI - Role of PET/CT in the functional imaging of endocrine pancreatic tumors. AB - Endocrine pancreatic tumors (EPTs) are a heterogeneous group of neoplasms with variable clinical and biological features and prognosis, ranging from very slow growing tumors to highly aggressive and very malignant ones. As other neuroendocrine tumors, EPTs are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. The more widespread use of hybrid machines, i.e., positron emission tomography/computed tomography (PET/CT), allows to perform imaging with high resolution and high diagnostic accuracy especially for small lesions, and to correlate anatomic location with function. The recent WHO recommendations for classification and prognostic factors help the selection of tracers likely to show a positive image on PET; therefore, tracers exploiting specific metabolic patterns ((18)F-DOPA and (11)C-5-HTP) or specific receptor expression ((68)Ga-DOTA-peptides) are suited to well-differentiated tumors, while the use of (18)F-FDG is preferred for poorly-differentiated neoplasms with high proliferative activity and loss of neuroendocrine features. In differentiated EPTs, (11)C-5-HTP performs better than (18)F-DOPA even though its use is hampered by its complex production and limited availability and experience; (68)Ga peptides are indicated for all type of gastroenteropancreatic (GEP) neuroendocrine tumors, regardless of their functional activity. In addition, (68)Ga-DOTA-peptides play a distinctive role in planning peptide receptor radionuclide therapy. PMID- 22422068 TI - Deployment of the human immunodeficiency virus type 1 protein arsenal: combating the host to enhance viral transcription and providing targets for therapeutic development. AB - Despite the success of highly active antiretroviral therapy in combating human immunodeficiency virus type 1 (HIV-1) infection, the virus still persists in viral reservoirs, often in a state of transcriptional silence. This review focuses on the HIV-1 protein and regulatory machinery and how expanding knowledge of the function of individual HIV-1-coded proteins has provided valuable insights into understanding HIV transcriptional regulation in selected susceptible cell types. Historically, Tat has been the most studied primary transactivator protein, but emerging knowledge of HIV-1 transcriptional regulation in cells of the monocyte-macrophage lineage has more recently established that a number of the HIV-1 accessory proteins like Vpr may directly or indirectly regulate the transcriptional process. The viral proteins Nef and matrix play important roles in modulating the cellular activation pathways to facilitate viral replication. These observations highlight the cross talk between the HIV-1 transcriptional machinery and cellular activation pathways. The review also discusses the proposed transcriptional regulation mechanisms that intersect with the pathways regulated by microRNAs and how development of the knowledge of chromatin biology has enhanced our understanding of key protein-protein and protein-DNA interactions that form the HIV-1 transcriptome. Finally, we discuss the potential pharmacological approaches to target viral persistence and enhance effective transcription to purge the virus in cellular reservoirs, especially within the central nervous system, and the novel therapeutics that are currently in various stages of development to achieve a much superior prognosis for the HIV-1-infected population. PMID- 22422075 TI - Mortality predictive indexes for the community-dwelling elderly US population. AB - BACKGROUND: Few predictive indexes for long-term mortality have been developed for community-dwelling elderly populations. Parsimonious predictive indexes are important decision-making tools for clinicians, policy makers, and epidemiologists. OBJECTIVE: To develop 1-, 5-, and 10-year mortality predictive indexes for nationally representative community-dwelling elderly people. DESIGN: Cohort study. SETTING: The Second Longitudinal Study of Aging (LSOA II). PARTICIPANTS: Nationally representative civilian community-dwelling persons at least 70 years old. We randomly selected 60% of the sample for prediction development and used the remaining 40% for validation. MAIN MEASURES: Sociodemographics, impairments, and medical diagnoses were collected from the LSOA II baseline interviews. Instrumental activities of daily living (IADLs) stages were derived to measure functional status. All-cause mortality was obtained from the LSOA II Linked Mortality Public-use File. RESULTS: The analyses included 7,373 sample persons with complete data, among which mortality rates were 3.7%, 23.3%, and 49.8% for 1, 5, and 10 years, respectively. Four, eight, and ten predictors were identified for 1-, 5-, and 10-year mortality, respectively, in multiple logistic regression models to create three predictive indexes. Age, sex, coronary artery disease, and IADL stages were the most essential predictors for all three indexes. C-statistics of the three indexes were 0.72, 0.74, and 0.75 in the development cohort and 0.72, 0.72, and 0.74 in the validation cohort for 1-, 5-, and 10-year mortality, respectively. Five risk groups were defined based on the scores. CONCLUSIONS: The 1-, 5-, and 10-year mortality indexes include parsimonious predictor sets maximizing ease of mortality prediction in community settings. Thus, they may provide valuable information for prognosis of elderly patients and guide the comparison of alternative interventions. Including IADL stage as a predictor yields simplified mortality prediction when detailed disease information is not available. PMID- 22422076 TI - [Direct and indirect costs of fractures due to osteoporosis in Austria]. AB - OBJECTIVES: We examined the financial burden of osteoporosis in Austria. METHODS: We took both direct and indirect costs into consideration. Direct costs encompass medical costs such as expenses for pharmaceuticals, inpatient and outpatient medical care costs, as well as other medical services (e.g., occupational therapies). Non-medical direct costs include transportation costs and medical devices (e.g., wheel chairs or crutches). Indirect costs refer to costs of productivity losses due to absence of work. Moreover, we included costs for early retirement and opportunity costs of informal care provided by family members. While there exist similar studies for other countries, this is the first comprehensive study for Austria. For our analysis, we combined data of official statistics, expert estimates as well as unique patient surveys that are currently conducted in the course of an international osteoporotic fracture study in Austria. RESULTS: Our estimation of the total annual costs in the year 2008 imposed by osteoporosis in Austria is 707.4 million ?. The largest fraction of this amount is incurred by acute hospital treatment. Another significant figure, accounting for 29% of total costs, is the opportunity cost of informal care. CONCLUSIONS: The financial burden of osteoporosis in Austria is substantial. Economic evaluations of preventive and therapeutic interventions for the specific context of Austria are needed to inform health policy decision makers. PMID- 22422077 TI - Enabling and disabling polo-like kinase 1 inhibition through chemical genetics. AB - Polo-like kinase 1 (Plk1) is a core regulator of cell division and an emerging target for cancer therapy. Pharmacologic inhibitors of Plk1 exist but affect other kinases, complicating their in vivo validation. To address this, we examined effects of two structurally unrelated Plk1 inhibitors (BI-2536 and TAL) against isogenic human cell lines that solely express wildtype (wt) or analogue sensitive (as) Plk1 alleles. Unexpectedly, Plk1(as) cells displayed profound biochemical and functional resistance to both inhibitors. Cells that co-express Plk1(wt) and Plk1(as) exhibit loss-of-function phenotypes only when both kinase alleles are inhibited. Resistance to BI-2536 is linked to an intragenic suppressor mutation (C67V) that restores an otherwise invariant valine to the kinase active site. Structural modeling demonstrates that this mutation not only enables Plk1(as) to function in vivo but also occludes BI-2536 from the ATP binding pocket. Our results reveal the molecular basis of Plk inhibitor selectivity and a potential mechanism for tumor cell resistance. PMID- 22422078 TI - Design of main-chain polymers of chiral imidazolidinone for asymmetric organocatalysis application. AB - Main-chain polymers of chiral imidazolidinone were successfully synthesized by reaction of chiral imidazolidinone dimers with disulfonic acid. Chiral imidazolidinones were incorporated into the main-chain of the polymer by ionic bonding. These polymers could be used as polymeric chiral organocatalysts for asymmetric Diels-Alder reactions. PMID- 22422079 TI - Can augmentation index be used as an accurate tool in the diagnosis of peripheral obstructive arterial disease? AB - BACKGROUND: The use of radial augmentation index (rAI) as an indicator of vascular disease was investigated in the vascular imaging laboratory in a regional hospital. AIMS: The aim of this study was to investigate whether a correlation exists between ankle-brachial pressure index (ABPI) and rAI in normal subjects, patients with peripheral obstructive arterial disease, and diabetic patients. METHODS: A group of 46 patients and 14 controls had ABPI and rAI measured and factors affecting AI were assessed. RESULTS: rAI was found to have a negative correlation with ABPI (Spearman's rho = -0.513, p < 0.01). There was significant increase in the rAI scores of diabetic patients compared to normal patients (normal median was 64% lower than diabetic median, p < 0.01) and in peripheral obstructive vascular disease patients compared to normal (normal median 69% lower, p < 0.001). Of the various affecting factors, age stood out with rAI having a positive correlation to age (Spearman's rho = 0.68, p < 0.01). CONCLUSIONS: The augmentation index appears be a significant indicator of cardiovascular disease and may be a useful tool in the diagnosis of vascular pathology. PMID- 22422080 TI - Preparation and structural control of metal coordination-assisted supramolecular architectures of porphyrins. Nanocubes to microrods. AB - We have successfully prepared metal coordination-assisted porphyrin assemblies such as nanocubes, nanorods and microrods by controlling the synthetic conditions. The internal structures and lifetimes of the excited states are also quantitatively discussed. PMID- 22422082 TI - Clinical and microbiological effects of ozone nano-bubble water irrigation as an adjunct to mechanical subgingival debridement in periodontitis patients in a randomized controlled trial. AB - AIM: Ozone nano-bubble water (NBW3) seems to be suitable as an adjunct to periodontal treatment owing to its potent antimicrobial effects, high level of safety, and long storage stability. The aim of the present study was to evaluate the clinical and microbiological effects of NBW3 irrigation as an adjunct to subgingival debridement for periodontal treatment. METHODS: Twenty-two subjects were randomly assigned to one of the two treatment groups: full-mouth mechanical debridement with tap water (WATER) or full-mouth mechanical debridement with NBW3 (NBW3). Clinical examination was performed at baseline and 4 and 8 weeks after treatment. Microbiological examination was carried out just before and after treatment and at 1 and 8 weeks posttreatment. RESULTS: There were significant improvements in all clinical parameters after 4 weeks in both groups. The reduction in the probing pocket depth and the clinical attachment gain after 4 and 8 weeks in the NBW3 group were significantly greater than those in the WATER group. Moreover, only the NBW3 group showed statistically significant reductions in the mean total number of bacteria in subgingival plaque over the study period. CONCLUSIONS: The present study suggests that subgingival irrigation with NBW3 may be a valuable adjunct to periodontal treatment. CLINICAL RELEVANCE: This study verified the potential of new antimicrobial agent, MNW3, as an adjunct to periodontal treatment. PMID- 22422083 TI - [Pathological staging and response evaluation of rectal carcinoma]. AB - The application of so-called neoadjuvant therapy may induce changes in tumor tissues that have to be determined concerning the degree of severity (regression grading) and which also influence pathological staging. The extent of morphological changes (response) to be evaluated ranges from carcinomas showing no damage at all to complete disappearance of carcinomas. More than ten different systems of regression grading have been published in order to assess the dimension of morphological changes in a semiquantitative manner. PMID- 22422084 TI - Long-term survival of salivary streptococci on dental devices made of ethylene vinyl acetate. AB - Bacterial infection associated with the use of medical or dental devices is a serious concern. Although devices made of ethylene vinyl acetate (EVA) are often used in the oral cavity, there are no established standards for their storage. We investigated bacterial survival on EVA sheets under various storage conditions to establish a standard for hygienic storage of such dental devices. Bacterial counts were evaluated, which showed a significant decrease after washing with sterilized water, mechanical brushing and rinsing, and using Mouthguard Cleaner as compared to untreated samples. In addition, no bacteria were detected on samples stored 2 days or longer in a ventilated environment, whereas they were detected for up to 14 days on samples without any cleaning stored in a closed environment. Bacterial counts for the untreated samples gradually declined, while surviving bacteria on samples treated with sterilized water and mechanical brushing showed a rapid decrease. Additionally, bacterial identification using polymerase chain reaction (PCR) revealed that Streptococcus oralis was dominantly detected on salivary samples after 14 days of storage among both two subjects. For effective hygienic storage of dental devices made of EVA, washing with sterilized water is important to remove absorbed salivary compounds along with storage in a ventilated environment. PMID- 22422085 TI - Prevalence of Enterococcus faecalis in saliva and filled root canals of teeth associated with apical periodontitis. AB - To investigate the prevalence of Enterococcus faecalis in saliva and filled root canals of patients requiring endodontic retreatment for apical periodontitis. Patients with apical periodontitis who were referred for endodontic retreatment were examined. The type and quality of the restoration, symptoms, quality of obturation were recorded. During retreatment, an oral rinse sample and root canal sample were cultured using brain-heart infusion agar and bile esculinazide agar to select for E. faecalis. The 16S rRNA technique was used to identify E. faecalis. A total of 32 women and 22 men (mean age: 38 years; s.d.: 11 years) and 58 teeth were studied. The prevalence of E. faecalis was 19% in the saliva and 38% in the root canals. The odds that root canals harbored E. faecalis were increased if the saliva habored this bacterium (odds ratio=9.7; 95% confidence interval=1.8-51.6; P<0.05). Teeth with unsatisfactory root obturation had more cultivable bacterial species in root canals than teeth with satisfactory root obturation (P<0.05). E. faecalis is more common in root canals of teeth with apical periodontitis than in saliva. The prevalence of E. faecalis in root canals is associated with the presence of E. faecalis in saliva. PMID- 22422086 TI - Laser capture microdissection enables cellular and molecular studies of tooth root development. AB - Epithelial-mesenchymal interactions (EMIs) are critical for tooth development. Molecular mechanisms mediating these interactions in root formation is not well understood. Laser capture microdissection (LCM) and subsequent microarray analyses enable large scale in situ molecular and cellular studies of root formation but to date have been hindered by technical challenges of gaining intact histological sections of non-decalcified mineralized teeth or jaws with well-preserved RNA. Here,we describe a new method to overcome this obstacle that permits LCM of dental epithelia,adjacent mesenchyme,odontoblasts and cementoblasts from mouse incisors and molars during root development. Using this method,we obtained RNA samples of high quality and successfully performed microarray analyses. Robust differences in gene expression,as well as genes not previously associated with root formation,were identified. Comparison of gene expression data from microarray with real-time reverse transcriptase polymerase chain reaction (RT-PCR) supported our findings. These genes include known markers of dental epithelia,mesenchyme,cementoblasts and odontoblasts,as well as novel genes such as those in the fibulin family. In conclusion,our new approach in tissue preparation enables LCM collection of intact cells with well-preserved RNA allowing subsequent gene expression analyses using microarray and RT-PCR to define key regulators of tooth root development. PMID- 22422087 TI - Hypertonicity augments bullfrog taste nerve responses to inorganic salts. AB - The tonicity of taste stimulating solutions has been usually ignored, though taste substances themselves yielded the tonicity. We investigated the effect of hypertonicity on bullfrog taste nerve responses to inorganic salts by adding nonelectrolytes such as urea and sucrose that elicited no taste nerve responses. Here, we show that hypertonicity alters bullfrog taste nerve-response magnitude and firing pattern. The addition of urea or sucrose enhances the taste nerve response magnitude to NaCl and shifts the concentration-response curve to the left. The effect of hypertonicity on responses to CaCl(2) is bimodal; hypertonicity suppresses CaCl(2) responses at concentrations less than ~30 mM and enhances them at concentrations greater than ~30 mM. The hypertonicity also enhances response magnitude to other monovalent salts. The extent of the enhancing effects depends on the difference between the mobility of the cation and anion in the salt. We quantitatively suggest that both the enhancing and suppressing effects result from the magnitude and direction of local circuit currents generated by diffusion potentials across tight junctions surrounding taste receptor cells. PMID- 22422088 TI - Interaction between breeding habitat and elevation affects prevalence but not infection intensity of Batrachochytrium dendrobatidis in Brazilian anuran assemblages. AB - Chytridiomycosis, an infectious disease of amphibians, is caused by the fungus Batrachochytrium dendrobatidis (Bd) and has been linked to declining amphibian populations worldwide. The susceptibility of amphibians to chytridiomycosis induced population declines is potentially influenced by many factors, including environmental characteristics, differences among host species and the growth of the pathogen itself. We investigated the effects of elevation and breeding habitat on Bd prevalence and individual infection intensity (zoospore loads) in 3 anuran assemblages of the Atlantic Coastal Forest of Brazil. Bd infection intensity was strongly influenced by elevation and breeding habitat, but we found no evidence of an interaction between those 2 variables in explaining the number of zoospores sampled from individual frogs. In contrast, Bd infection odds were predicted by elevation and by an interaction between elevation and breeding habitat, such that frogs had a higher probability of Bd infection in lotic habitats at low elevations. Our results indicate that Bd persists across a wide variety of habitats and elevations in the Atlantic Coastal Forest. Prevalence and infection intensity of Bd are highest at high elevations where overall environmental conditions for Bd are most favorable. In addition, at low elevations amphibian host habitat choice is also an important determinant of infection. Our study highlights the need to investigate interacting variables of host ecology and the environment simultaneously. PMID- 22422089 TI - Evaluation of a filtration-based method for detecting Batrachochytrium dendrobatidis in natural bodies of water. AB - Infectious diseases are emerging as a significant threat to wildlife. The resulting increased effort to monitor wildlife diseases is driving the development of innovative pathogen monitoring techniques, including many polymerase chain reaction (PCR)-based diagnostics. Despite the utility of these PCR-based techniques, there is still much to be learned about their ability to accurately detect target pathogens in nature. We assessed the diagnostic sensitivity of a PCR-based water filtration technique to detect the directly transmitted aquatic fungal pathogen Batrachochytrium dendrobatidis (Bd) by comparing the results of 4 repeated filter sampling events from 20 ponds to those of skin swabs from ca. 60 boreal chorus frogs Pseudacris maculata from each pond. Filters failed to detect Bd in 31 to 77% of the swab-positive ponds, depending on the time of sampling. However, after 3 repeated sampling events, filtration of small volumes of water (ca. 600 ml) correctly identified 94% of the ponds that tested Bd positive with swabbing, with the highest rates of detection occurring after breeding but before larvae reached metamorphosis. Our results are a case study demonstrating the importance of timing and resampling for the detection of an aquatic microbial pathogen, Bd, from water. This will be a useful technique for monitoring Bd, but additional data are needed to test the degree to which our findings are species or population specific. Future studies need to examine the sensitivity of this technique in other habitats and species that host Bd. These studies will aid in the development of cost-effective monitoring regimes for Bd and potentially other aquatic pathogens. PMID- 22422090 TI - Broth medium for the successful culture of the fish pathogen Piscirickettsia salmonis . AB - Piscirickettsiosis or salmonid rickettsial septicaemia (SRS) caused by Piscirickettsia salmonis constitutes one of the main problems in farmed salmonid and marine fishes. Since the first reports of the disease, it has been successfully isolated and maintained in eukaryotic cell--culture systems, but these systems are time-consuming, the media are costly, and eliminating heavily contaminated host cell debris is difficult. In this report, we describe a marine based broth supplemented with L-cysteine, named AUSTRAL-SRS broth, that facilitates superior growth of P. salmonis strains. Strains reached an optical density of approximately 1.8 when absorbance was measured at 600 nm after 6 d incubation at 18 degrees C. Several passages (n = 6) did not alter the culture kinetics. We report for the first time the purification of DNA, lipopolysaccharide (LPS) and whole membrane protein obtained from P. salmonis grown in this liquid medium, and thus provide a suitable platform to simplify the preparation of P. salmonis cells for genetic and serological studies. Moreover, the results of the cytopathic effect test showed that P. salmonis grown in AUSTRAL-SRS broth maintained their virulence properties, inducing apoptosis after 3 d. This makes the medium a good candidate for the successful growth of P. salmonis and an excellent basis for the development of low cost vaccines. PMID- 22422091 TI - Kidney pathology and parasite intensity in rainbow trout Oncorhynchus mykiss surviving proliferative kidney disease: time course and influence of temperature. AB - Proliferative kidney disease (PKD) is an endoparasitic disease of salmonids caused by the myxozoan parasite Tetracapsuloides bryosalmonae. We recently described the development of the disease from initial infection until manifestation of clinical disease signs in rainbow trout held at 2 water temperatures, 12 and 18 degrees C. The aim of the present study is to investigate whether (1) infected fish surviving the clinical phase would recover from renal pathological changes, (2) whether they would be able to reduce the parasite load in the kidneys, and (3) whether water temperatures would influence renal recovery and parasite clearance. At 18 degrees C, fish showed a gradual recovery of normal kidney morphology which was associated with a decline in parasite numbers and infection prevalence. Fish kept at 12 degrees C initially showed an enhancement of kidney lesions before recovery of normal kidney morphology took place. The decrease in renal parasite load was retarded compared to 18 degrees C. The results from the present study provide evidence that rainbow trout surviving the clinical phase of PKD are able to (1) fully restore renal structure, and (2) significantly reduce renal parasite loads, although 100% clearance was not achieved within the experimental period of this study. Water temperature influences the rate but not the outcome of the recovery process. PMID- 22422092 TI - Metazoan parasites on the gills of the skipjack tuna Katsuwonus pelamis (Osteichthyes: Scombridae) from the Alboran Sea (western Mediterranean Sea). AB - The gills of 31 skipjack tuna Katsuwonus pelamis (L.) caught in the Alboran Sea (western Mediterranean Sea) were examined for metazoan parasites, and the gills of 4 specimens from the Balearic Sea (also western Mediterranean Sea) were analysed for comparative purposes. Nine -species of parasites were found, including 8 didymozoid trematodes (Atalostrophion cf. bio-varium, Didymocylindrus filiformis, Didymocylindrus simplex, Didymocystis reniformis, Didymoproblema fusiforme, Didymozoon longicolle, Koellikeria sp. and Lobatozoum multisacculatum) and 1 caligid copepod (Caligus bonito). Koellikeria sp. and L. multisacculatum were not recorded in the Balearic Sea. Most of the parasites (79.2% of all specimens) were didymozoids. Didymozoon longicolle was the dominant species; A. cf. biovarium, D. simplex, D. fusiforme and L. multisacculatum are reported from the Mediterranean Sea for the first time. No correlation was found between the intensity of infection of any parasite species and host size or sex. Most of the parasites, particularly didymozoids, showed a high site-specificity. Significant differences were found between the parasite assemblages of K. pelamis from the Alboran Sea and from the Atlantic Ocean. D. fusiforme, D. longicolle and L. multisacculatum are suggested as potential tags to follow skipjack tuna migrations between the Atlantic Ocean and Mediterranean Sea. PMID- 22422093 TI - Azumiobodo hoyamushi gen. nov. et sp. nov. (Euglenozoa, Kinetoplastea, Neobodonida): a pathogenic kinetoplastid causing the soft tunic syndrome in ascidian aquaculture. AB - We used morphological and genetic analyses to investigate a pathogenic kinetoplastid isolated from a diseased edible ascidian Halocynthia roretzi with soft tunic syndrome. The morphological characteristics of the kinetoplastid are similar to those in the order Neobodonida in the subclass Metakinetoplastida. However, the presence of unique globular bodies distinguishes this kinetoplastid from the other polykinetoplastic genera (i.e. Cruzella, Dimastigella and Rhynchobodo) in this order. These globular bodies are cytoplasmic inclusions without an outer delimiting membrane and are composed of a homologous granular matrix containing electron-dense bands. A phylogenetic tree based on 18S rRNA gene sequences also indicated that the kinetoplastid belongs to the order Neobodonida, although it forms an independent clade in this order. From these results, we propose a new genus in the order Neobodonida, i.e. Azumiobodo gen. nov., and Azumiobodo hoyamushi as the type species for the genus. PMID- 22422094 TI - Skeletal structure and progression of growth anomalies in Porites australiensis in Okinawa, Japan. AB - Growth anomalies (GAs), one of the diseases recently reported for scleractinian corals, are characterized by an abnormal skeletal structure and reduced zooxanthella density. The pathological characteristics of GAs were studied in colonies of Porites australiensis on a reef in Kayo, Okinawa, Japan. Corallites in the GA region lost the skeletal architecture characteristic of P. australiensis, and polyp density had decreased in the GAs due to enlargement of both calices and the coenosteum. The gross productivity of isolated GA samples was lower than in healthy samples and decreased to almost 0 within 11 d after isolation. However, when GA samples were brought into contact with healthy looking samples from the same colony, they fused and both the GA and healthy regions grew. Healthy samples fused with GA samples grew more slowly than those fused with healthy samples. For in situ GAs surrounded by healthy tissue, tissue death usually started at the center of the GA, probably due to a deficiency in the translocated energy supply from the surrounding tissue. The total area of the GA region and the dead area increased at a rate of 5.3 +/- 2.9 cm2 yr-1. These results suggest that GA regions are maintained by energy supplies from surrounding healthy tissues and that GAs may have a negative impact on host corals. PMID- 22422095 TI - Fast quantitative PCR, locked nucleic acid probes and reduced volume reactions are effective tools for detecting Batrachochytrium dendrobatidis DNA. AB - The fungal pathogen Batrachochytrium dendrobatidis threatens amphibian populations around the world. The ability to detect this pathogen on infected animals and in the environment is critical for understanding and controlling this pandemic. We tested several advances in quantitative PCR (qPCR) techniques to detect B. dendrobatidis DNA. We used a fast PCR thermocycler and enzymes that reduced the volume and the duration of the reaction. We also compared a conventional TaqMan minor groove binding (MGB) probe to an identical locked nucleic acid (LNA) counterpart. The fast qPCR reaction had a high degree of sensitivity to B. dendrobatidis DNA. The LNA probe was effective for detecting B. dendrobatidis DNA and produced results -similar to those of the MGB probe. The modifications that we tested can improve the cost, time efficiency and specificity of quantitative PCR as a tool for detecting pathogen DNA. PMID- 22422096 TI - First detection of piscine reovirus (PRV) in marine fish species. AB - Heart and skeletal muscle inflammation (HSMI) is a disease that affects farmed Atlantic salmon Salmo salar L. several months after the fish have been transferred to seawater. Recently, a new virus called piscine reovirus (PRV) was identified in Atlantic salmon from an outbreak of HSMI and in experimentally challenged fish. PRV is associated with the development of HSMI, and has until now only been detected in Atlantic salmon. This study investigates whether the virus is also present in wild fish populations that may serve as vectors for the virus. The virus was found in few of the analyzed samples so there is probably a more complex relationship that involves several carriers and virus -reservoirs. PMID- 22422097 TI - Structural characterization of electrodeposited copper hexacyanoferrate films by using a spectroscopic multi-technique approach. AB - A deep structural investigation predominantly by X-ray spectroscopic techniques is conducted on films of copper hexacyanoferrate (CuHCF) deposited under different conditions, aimed at establishing structure-properties relationships. We show that the potentiodynamic electrosynthesis of CuHCF on carbon-based surfaces produces a highly disordered material, with a variable amount of Prussian Blue (PB). The subsequent Cu(2+) intercalation induces the partial conversion of PB into CuHCF, which explains the improved electrocatalytic properties after the intercalation process. Both Cu and Fe K-edge data have been recorded. For the sample with the lower amount of PB, we could perform a multiple edge data analysis to determine the local atomic environment around both metal centres using the same set of structural parameters. The presence of high multiplicity Cu-N-C-Fe linear chains has allowed us to determine accurately the local environment of Fe while fitting the Cu K-edge data only. Using this approach we have retrieved structural information around Fe for those samples in which the concomitant presence of PB would have made impossible the analysis of the Fe K-edge. The Fe-C, C-N and Cu-N bond distances have been found in agreement with those of the bulk structures, but higher values of [Fe(CN)(6)] vacancies for the building blocks have been evidenced, reaching a value of ~45% in one sample. XANES, Raman and SEM data agree with the model proposed for each studied electrode. PMID- 22422098 TI - Nuclear medicine imaging in tuberculosis using commercially available radiopharmaceuticals. AB - In this paper, data available on nuclear medicine imaging using commercially available radiopharmaceuticals for the differentiation, staging, and prediction or assessment of the response to treatment in tuberculosis (TB) are reviewed. Limited available studies suggest that single photon emission computed tomography (SPECT) using either 201Tl, 99mTc-sestamibi, or 99mTc-tetrofosmin is accurate (>=85%) and has a high negative predictive value (>=90%) for the differentiation of TB from carcinoma in patients presenting with a solitary pulmonary nodule (SPN). The criteria for detection of TB on 201Tl SPECT are nondepiction of the suspicious lesion in the delayed image or a negative retention index [washout on the delayed images (3-4 h postinjection) vs. the early image (5-15 min postinjection)] and a comparable-to-background uptake on 99mTc-sestamibi or 99mTc tetrofosmin SPECT. Another SPECT tracer of potential interest for the differentiation of TB from malignant SPN that warrants further exploration, is N isopropyl-p-[123I]iodoamphetamine (123I-IMP). In contrast, 18F-fluorodeoxyglucose (18F-FDG) PET is unable to differentiate malignancy from TB and thus cannot be used as a tool to reduce futile biopsy/thoracotomy in these patients. A limited number of studies have reported on the potential of nuclear medicine imaging in assessment of the extent of disease in patients with extrapulmonary TB using 67Ga citrate SPECT and 18F-FDG PET, respectively. 67Ga-citrate SPECT was shown to be as sensitive as bone scintigraphy for the detection of bone infection and was found to be complementary to computed tomography (CT) imaging. 18F-FDG PET was found to be significantly more efficient when compared with CT, respectively, in over half of patients for the identification of sites of lymph node involvement that were missed by CT and often the only sites of extrapulmonary TB identified. Unfortunately, 18F-FDG PET findings did not lead to alterations in treatment planning in any of the patients under study. Additional studies confirming these findings are urgently required. Similar to the setting of SPN, 18F-FDG PET cannot differentiate malignant lymph node involvement from lymph node involvement by TB. These results and the recent findings of Demura and colleagues using 18F-FDG PET further suggest that nuclear medicine imaging techniques could be used for the evaluation of therapeutic response. Prospective studies, focusing on specific subgroups of patients in whom such an imaging approach might be clinically relevant, for example in multidrug-resistant TB patients, are warranted. In acquired immunodeficiency syndrome patients, 67Ga scintigraphy proved to be a reliable and sensitive method for the primary detection and follow-up of opportunistic pneumonias, including TB. Combining 201Tl scintigraphy with 67Ga scintigraphy was shown to increase the specificity for both pulmonary and extrapulmonary TB, which is a 67Ga(+) and 201Tl(-) mismatch pattern in acquired immunodeficiency syndrome patients that is specific for mycobacterial infections. Finally, the results obtained using both SPECT and PET indicate that nuclear medicine could be an important noninvasive method for the determination of disease activity, detection of extrapulmonary TB, and determination of response to therapy. PMID- 22422099 TI - Hypoxia assessed by 18F-fluoromisonidazole positron emission tomography in newly diagnosed gliomas. AB - OBJECTIVE: The aim of this study was to evaluate the degree of hypoxia in newly diagnosed gliomas using 18F-fluoromisonidazole (FMISO) PET and to compare the results with tumor grade. METHODS: A total of 30 patients with newly diagnosed gliomas were examined using FMISO PET. Grading of the tumor was performed according to the WHO classification. The FMISO PET images were scaled to the venous blood concentration of FMISO activity to produce tumor-to-blood (T/B) values. Hypoxia was defined as a region with a T/B ratio of at least 1.2, and the maximum T/B (T/Bmax) value was calculated by region-of-interest analysis. RESULTS: There was a correlation between FMISO uptake and glioma grade, with all low-grade gliomas (grades I and II) demonstrating no hypoxia and all high-grade gliomas (grades III and IV) showing hypoxia. The mean T/Bmax in grade IV gliomas was significantly higher than that in grade III gliomas (P<0.02). CONCLUSION: FMISO PET is a potential tracer in the assessment of noninvasive tumor grading in newly diagnosed gliomas. PMID- 22422100 TI - How has the management of medullary thyroid carcinoma changed with the advent of 18F-FDG and non-18F-FDG PET radiopharmaceuticals. AB - Medullary thyroid cancer (MTC) arises from parafollicular C cells and is an elusive tumor to image. It occurs as a sporadic neoplasm in 70-80% of cases and is hereditary in 20-30% because of germline mutations of the rearranged during transfection proto-oncogene. Successful disease management relies on accurate staging. Tumor secretory biomarkers are highly sensitive to a disease; however, despite a wide variety of radiopharmaceuticals for molecular imaging that take advantage of hybrid SPECT/CT and PET/CT fusion imaging, imaging of MTC is still problematic. After initial surgical resection, the limited sensitivity of localization of small locoregional disease and the inability to detect early liver metastases hamper the success of later surgical approaches. F fluorodeoxyglucose PET has been used to detect MTC recurrences with modest success and may be best suited for only a small subset of more biologically aggressive MTCs. Recent developments in PET imaging with novel radiopharmaceuticals targeting specific cellular processes of MTC offer increased sensitivity for identifying recurrence, assessing prognosis, and guiding selection of optimal therapies. PMID- 22422101 TI - A comprehensive understanding of melting temperature of nanowire, nanotube and bulk counterpart. AB - Surface energies of nanostructures are of considerable interest, and thermodynamic methods have provided valuable insight into the physics and chemistry of these systems. Although the effect of surface energy on melting behaviors of nanostructures has been widely investigated in theoretical calculations and simulations, from the thermodynamics at the nanometer scale point of view, the comprehensive understanding of the fundamental physical and chemical issues involved in nanostructures' melting is still lacking. For instance, nanostructures with negative curvature, such as nanotubes, show different melting behaviors compared with the nanostructures with positive curvature such as nanowires, and both nanotubes and nanowires exhibit abnormal melting temperature compared with that of the bulk counterparts. Herein, we put forward a general model to elucidate the melting temperature of the nanostructures with positive and negative curvatures based on the surface energy at the nanometer. Further, the surface mean square relative atomic displacement (MSRD) of these nanostructures has been studied from the perspective of the size dependent cohesive energy consideration, which can provide the atomic understanding of the nanostructures' melting. Theoretical analyses indicate that both melting temperatures of the nanostructures with the positive and negative curvatures decrease with decreasing dimensionality, and the surface MSRDs show different size effects in the systems with the positive and negative curvatures, respectively. The melting temperature of the surface with the negative curvature is higher than that of the surface with the positive curvature, and both melting temperatures are smaller than that of the bulk counterpart when the size of nanostructures is less than a threshold value. The unique melting behaviors of nanostructures are attributed to the size- and curvature-dependent surface energy of nanostructures. These results provide new insight into the fundamental understanding of the melting temperature of nanostructures. PMID- 22422102 TI - Prostate Cancer Chemoprevention Targeting High Risk Populations: Model for Trial Design and Outcome Measures. AB - Inspite of the large number of promising nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in high risk cohorts are required to inform design of phase II clinical trials. Additionally, a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must be utilized to evaluate effectiveness in these trials. The goal of this paper is to provide a model, using a systematic approach for evaluating the safety, effectiveness and mechanism of action of a well characterized nutrient-derived agent-isoflavones - in a phase II clinical trial for prostate cancer (CaP) chemoprevention, targeting a population of African American (AA) and Caucasian men. Based on our previous observations, we hypothesize that the effects of isoflavones on prostate carcinogenesis are mainly mediated through the down regulation of androgen receptor (AR) and AR activity in AA men is higher due to its shorter length of Glutamine repeats in its N-terminus. We thus believe that isoflavones will exert a stronger protective effect for CaP in AA men and cause a higher activation of FOXO factors and their target genes. The aim of the study is to evaluate the comparative effectiveness of the study agent and placebo, in addition to a comparison of the effectiveness and safety in African American men compared to Caucasian men treated with this agent. PMID- 22422103 TI - Extended survival observed in adoptive activated T lymphocyte immunotherapy for advanced lung cancer: results of a multicenter historical cohort study. AB - PURPOSE: To clarify the long-term effect of immunotherapy, the effect of adoptive activated T lymphocyte immunotherapy on advanced lung cancer was evaluated in terms of survival time. In addition, the performance status of cancer patients under immunotherapy was examined. EXPERIMENTAL DESIGN: Over 5 * 10(9) alpha-beta T lymphocytes cultured ex vivo with an immobilized anti-CD3 antibody and interleukin-2 were injected intravenously into patients, once every 2 weeks for 3 months or longer. Follow-up of these patients was carried out using clinical records and by telephone interview questionnaire. Patients undergoing immunotherapy in immunotherapy clinics and those undergoing other anticancer therapies without immunotherapy in seven hospitals in Tokyo were enrolled in this study. Data were analyzed by a third-party statistician. Performance status was studied on another series of various cancer patients who underwent immunotherapy. RESULTS: The overall median survival time of the patients with the best supportive care, which was obtained using Kaplan-Meier's model, was 5.6 months, and those with immunotherapy alone, chemotherapy alone, and immuno-chemotherapy were 12.5, 15.7, and 20.8 months, respectively. Using Cox' proportional hazard model, we examined the possible factors on survival time by univariate analysis. Then, the patients were stratified by gender and histological type for multivariate analysis. Significantly low hazard ratios were observed for immunotherapy and radiotherapy in males with squamous cancer; for chemotherapy and radiotherapy in male with adenocarcinoma; and for immunotherapy in females with adenocarcinoma. Addition of immunotherapy to chemotherapy resulted in a statistically significant decrease in hazard ratio in females with adenocarcinoma. Studies on the performance status (PS), determined according to the European Cooperative Oncology Group criteria, revealed a continuous high level of PS under immunotherapy until around 2 months before death, in contrast to the gradual increase of tumor marker level. CONCLUSIONS: The effectiveness of immunotherapy on advanced lung cancer is limited but may extend life span under certain conditions. Immunotherapy itself provided no clinical benefit by itself as compared with chemotherapy, but a significant additive effect of immunotherapy on chemotherapy was observed in females with adenocarcinoma. Moreover, immunotherapy can maintain good quality of life of the patients until near the time of death. PMID- 22422104 TI - The influence of informal caregivers on adherence in COPD patients. AB - BACKGROUND: Contributions of informal caregivers to adherence among chronic obstructive pulmonary disease (COPD) patients remain understudied. PURPOSE: This study aims to evaluate the association between caregiver presence and adherence to medical recommendations among COPD patients. METHODS: Three hundred and seventy-four COPD patients were asked whether they had a caregiver. Medication adherence was assessed using pharmacy refill data. Smoking status was based on patient self-report. One-way ANOVAs and chi-square analyses were performed controlling for age and number of illnesses. RESULTS: Compared with the "no caregiver" group, antihypertensive medications adherence was higher in the "spousal caregiver" (0.68 vs. 0.81; 95% CI=0.04 and 0.22) and "non-spousal caregiver" (0.68 vs. 0.80; 95% CI=0.03 and 0.22) groups; long-acting beta agonist adherence was higher in the "spousal caregiver" group (0.60 vs.0.80; 95% CI=0.05 and 0.43). Patients in the "spousal caregiver" group had fewer current smokers compared with the "no caregiver" (chi(2)=16.08; p<0.001) and "non-spousal caregiver" (chi(2)=5.07; p<0.05) groups; those in the "non-spousal caregiver" group reported fewer smokers than the "no caregiver" group (chi(2)=4.54; p<0.05). CONCLUSIONS: Caregivers, especially spouses, may improve adherence in COPD. Future interventions may target patients without caregivers to optimize COPD management. PMID- 22422105 TI - Chronic beta2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice. AB - Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the beta(2)-agonist epinephrine more in the young. Although epinephrine and beta(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the beta(2)-blocking drug ICI 118551. In contrast, exercise combined with the beta(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and beta(2) agonist had stopped. To test whether beta(2)-agonist alone was effective, the animals that had received beta(2)-blockade were then given beta(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The beta(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although beta(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake. PMID- 22422106 TI - Selective domain stabilization as a strategy to reduce human serum albumin-human granulocyte colony stimulating factor aggregation rate. AB - Therapeutic proteins must be generally formulated to reduce unwanted aggregation. Fusion proteins, which comprise domains assembled from separate proteins, may require unique formulation strategies in order to maximize their stability. A fusion protein of human serum albumin (HSA) and human granulocyte colony stimulating factor (GCSF; HSA-GCSF) was used as a model to test the hypothesis that formulations that increase the thermodynamic conformational stability of the least stable domain of a fusion protein will stabilize the entire fusion protein against aggregation. Conformational stability of HSA-GCSF was modulated by addition of octanoic acid, which was previously shown to increase the conformational stability of HSA, the least stable domain. Contrary to our hypothesis, increased conformational stability of the HSA domain did not result in increased resistance to aggregation of HSA-GCSF. These results for HSA-GCSF were also compared with similar studies conducted previously on a therapeutic protein formed by the fusion of HSA and human growth hormone (hGH; HSA-hGH). PMID- 22422108 TI - Fluorescence photobleaching to evaluate flow velocity and hydrodynamic dispersion in nanoslits. AB - Velocity measurement is a key issue when studying flows below the micron scale, due to the lack of sensitivity of conventional detection techniques. We present an approach based on fluorescence photobleaching to evaluate flow velocity at the nanoscale by direct visualization. Solutions containing a fluorescent dye are injected into nanoslits. A photobleached line, created through laser beam illumination, moves through the channel due to the fluid flow. The velocity and effective diffusion coefficient are calculated from the temporal data of the line position and width respectively. The measurable velocity range is only limited by the diffusion rate of the fluorescent dye for low velocities and by the apparition of Taylor dispersion for high velocities. By controlling the pressure drop and measuring the velocity, we determine the fluid viscosity. The photobleached line spreads in time due to molecular diffusion and Taylor hydrodynamic dispersion. By taking into account the finite spatial and temporal extensions of the bleaching under flow, we determine the effective diffusion coefficient, which we find to be in good agreement with the expression of the two dimensional Taylor-Aris dispersion coefficient. Finally we analyze and discuss the role of the finite width of the rectangular slit on hydrodynamic dispersion. PMID- 22422107 TI - The conundrum of iron in multiple sclerosis--time for an individualised approach. AB - Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome--some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations. PMID- 22422109 TI - Large volume variation of an anisotropic graphene nanosheet electrochemical mechanical actuator under low voltage stimulation. AB - Large volume variation of electrode materials is important for actuator design. A graphene nanosheet membrane of paralleled structure could provide large volume variation as high as 98% by controlling its interspace distance through ionic liquid pre-expanding treatment. PMID- 22422110 TI - DBU-catalyzed tandem additions of electron-deficient 1,3-conjugated enynes with 2 aminomalonates: a facile access to highly substituted 2-pyrrolines. AB - An efficient, metal free approach to highly substituted 2-pyrrolines by DBU catalyzed tandem additions (a formal [3+2] cycloaddition) of electron-deficient 1,3-conjugated enynes and 2-aminomalonates under mild conditions was developed. PMID- 22422112 TI - Analysis of variance: variably complex. PMID- 22422113 TI - Training one type of striated muscle to counteract failure of another type. PMID- 22422114 TI - Prenatal stress and hippocampal BDNF expression: a fading imperative. PMID- 22422115 TI - Triggering of cardiac arrhythmic events in long QT syndrome: lessons from funny bunnies. PMID- 22422116 TI - Ion channels in patho-physiology. PMID- 22422117 TI - Feasibility and acceptability of gentamicin in the Uniject prefilled injection system for community-based treatment of possible neonatal sepsis: the experience of female community health volunteers in Nepal. AB - OBJECTIVE: Explore feasibility and acceptability of gentamicin in the Uniject prefilled injection system, in combination with oral cotrimoxazole-p and an appropriate newborn weighing scale, for treatment of possible neonatal sepsis when administered in the community by female community health volunteers. STUDY DESIGN: In a community-based program in Nepal, 45 volunteers recorded 422 live births. Among these, 82 infants were identified as having possible severe bacterial infection. In all, 67 of these infants were treated with gentamicin in Uniject and 15 were referred to the health facility. Mixed methods were used to collect data about Uniject performance, acceptability and safety. RESULT: Volunteers successfully treated 67 infants with gentamicin in Uniject. Gentamicin in Uniject performed well and was acceptable. CONCLUSION: Gentamicin in Uniject, in combination with cotrimoxazole-p and an appropriate newborn weighing scale, is a feasible and acceptable option for treatment of possible neonatal sepsis in the community by female community health volunteers. PMID- 22422118 TI - Neonatal outcomes are associated with latency after preterm premature rupture of membranes. AB - OBJECTIVE: To determine factors associated with latency time to birth after preterm premature rupture of membranes (PPROM) and the impact on neonatal outcomes. STUDY DESIGN: Data on singleton pregnancies with PPROM (n=1535 infants) were prospectively collected in a computerized perinatal/neonatal database at a tertiary care perinatal center. Latency was characterized as <=72h versus >72 h after PPROM. RESULT: The percentage of women with latency to birth >72 h decreased from 67% in very preterm (gestational age (GA) 25 to 28 weeks) to 10% in late preterm women (GA 33 to 36 weeks). PPROM women with latency <=72 h were more likely to have pregnancy-induced hypertension and birth weight <3%; PPROM women with latency >72 h were more likely to have received steroids and develop clinical chorioamnionitis. PPROM <32 weeks GA with latency <=72 h was associated with a two-fold higher incidence of severe neonatal morbidity, while PPROM between 29 to 34 weeks GA and latency <=72 h was associated with a higher incidence of moderate neonatal morbidity. CONCLUSION: A latency period >72 h was associated with a decreased incidence of adverse neonatal outcomes up to 32 weeks GA for severe and 34 weeks GA for moderate morbidity indices. PMID- 22422120 TI - [Psoriasis]. PMID- 22422121 TI - [Cutaneous leishmaniasis as travelers' disease. Clinical presentation, diagnostics and therapy]. AB - Leishmaniasis is a disease with worldwide increasing incidence, which in Germany is almost exclusively observed in patients who have travelled to classical endemic regions such as the Mediterranean basin. Cause of the disease is an infection with protozoan parasites of the genus Leishmania, which are transmitted by sand flies and replicate intracellularly within mammalian hosts. Depending on the inoculated parasite (sub-) species and the immune status of the host, a local cutaneous, diffuse cutaneous, mucocutaneous or visceral form of leishmaniasis will develop. Cutaneous leishmaniasis, which frequently appears only weeks after the bite of a sand fly, starts with the formation of a papule, which subsequently can turn into a skin ulcer. The latter may heal spontaneously after months leaving behind a scar or persist as chronic, non-healing cutaneous leishmaniasis. If cutaneous leishmaniasis is suspected, a sterile skin biopsy followed by appropriate diagnostic measures in a specialized laboratory to identify the pathogen should be performed. For the decision on the type of therapy, several clinical parameters (e.g. number and localization of lesions, immune status) and, most importantly, the underlying parasite (sub-) species need to be considered. Therapy can consist of a variety of topical measures or systemic drug treatment. A modern and safe vaccine does not yet exist. PMID- 22422124 TI - Human achaete-scute homolog-1 expression in neuroendocrine breast carcinoma. AB - Neuroendocrine (NE) breast carcinoma is defined by morphological features similar to those of NE tumors of other organs and NE marker expression in at least 50 % of neoplastic cells. However, a NE morphology may be observed even in breast carcinomas lacking NE markers. Human achaete-scute homolog-1 (hASH-1) is a transcription factor that plays a key role in the regulation of mammalian neural and NE cell development and has been identified in several human NE tumors. The aim of this study was to investigate hASH-1 expression in human breast cancers. hASH-1 expression was evaluated in 482 consecutive non-NE invasive breast carcinomas, in a series of 84 breast cancers with >50 % NE marker expression (high NE differentiation) and 21 carcinomas with NE histology but negative or focally (<50 %) positive for NE markers (low NE differentiation). hASH-1 protein was evaluated by a specific monoclonal antibody using immunohistochemistry and gene expression by real-time polymerase chain reaction. None of the non-NE invasive breast carcinomas expressed hASH-1 at any levels. hASH-1 was expressed in tumor cell nuclei of 63 and 38 % of cases with high and low NE differentiation, respectively. Strong correlation with protein and gene expression levels was observed (p < 0.0001). hASH-1 expression was correlated to a low mitotic count (p = 0.02) and a low Ki67 proliferative index (p = 0.0062). hASH-1 expression occurs in breast cancers with NE differentiation regardless of the extent of the NE cell population, and it is restricted to a subset of tumor cells having a low proliferative potential. PMID- 22422125 TI - Using community surveillance data to differentiate between emerging and endemic amphibian diseases. AB - We analyzed submission data from a wildlife care group during amphibian disease surveillance in Queensland, Australia. Between January 1999 and December 2004, 877 white-lipped tree frogs Litoria infrafrenata were classified according to origin, season and presenting category. At least 69% originated from urban Cairns, significantly more than from rural and remote areas. Total submissions increased during the early and late dry seasons compared with the early wet season. Frogs most commonly presented each year with injury, followed by 'other', sparganosis and irreversible emaciation of unknown aetiology. This is the first report of Spirometra erinacei infection in this species. A high prevalence (28%) of visible S. erinacei infection was found in emaciated frogs, but this was not statistically different from that in non-emaciated diseased frogs (25%). However, 14 emaciated specimens that were necropsied all had heavy S. erinacei infections, and the odds of visible sparganosis were statistically greater in emaciated frogs compared with injured, non-diseased frogs. We provide a detailed case definition for a new endemic disease manifesting as irreversible emaciation, for which S. erinacei may be the primary aetiological agent. The lack of significant spatial or temporal patterns in case presentation suggests that this is not a currently emerging disease. We show that community wildlife groups can play a valuable role in monitoring disease trends, particularly in urban areas, but identify a number of limitations associated with passive syndromic surveillance. We conclude that it is critical that professionals be involved in establishing syndromic case definitions, diagnostic pathology, complementary active disease surveillance, and data analysis and interpretation in all wildlife disease investigations. PMID- 22422126 TI - Treatment of amphibians infected with chytrid fungus: learning from failed trials with itraconazole, antimicrobial peptides, bacteria, and heat therapy. AB - Amphibian conservation goals depend on effective disease-treatment protocols. Desirable protocols are species, life stage, and context specific, but currently few treatment options exist for amphibians infected with the chytrid fungus Batrachochytrium dendrobatidis (Bd). Treatment options, at present, include antifungal drugs and heat therapy, but risks of toxicity and side-effects make these options untenable in some cases. Here, we report on the comparison of several novel treatments with a more generally accepted antifungal treatment in experimental scientific trials to treat Bd-infected frogs including Alytes obstetricans tadpoles and metamorphs, Bufo bufo and Limnodynastes peronii metamorphs, and Lithobates pipiens and Rana muscosa adults. The experimental treatments included commercial antifungal products (itraconazole, mandipropamid, steriplantN, and PIP Pond Plus), antimicrobial skin peptides from the Bd resistant Pelophylax esculentus, microbial treatments (Pedobacter cryoconitis), and heat therapy (35 degrees C for 24 h). None of the new experimental treatments were considered successful in terms of improving survival; however, these results may advance future research by indicating the limits and potential of the various protocols. Caution in the use of itraconazole is warranted because of observed toxicity in metamorphic and adult frogs, even at low concentrations. Results suggest that rather than focusing on a single cure-all, diverse lines of research may provide multiple options for treating Bd infection in amphibians. Learning from 'failed treatments' is essential for the timely achievement of conservation goals and one of the primary aims for a publicly accessible treatment database under development. PMID- 22422127 TI - Oral and cloacal microflora of wild crocodiles Crocodylus acutus and C. moreletii in the Mexican Caribbean. AB - Bacterial cultures and chemical analyses were performed from cloacal and oral swabs taken from 43 American crocodiles Crocodylus acutus and 28 Morelet's crocodiles C. moreletii captured in Quintana Roo State, Mexico. We recovered 47 bacterial species (28 genera and 14 families) from all samples with 51.1% of these belonging to the family Enterobacteriaceae. Fourteen species (29.8%) were detected in both crocodile species and 18 (38.3%) and 15 (31.9%) species were only detected in American and Morelet's crocodiles, respectively. We recovered 35 bacterial species from all oral samples, of which 9 (25.8%) were detected in both crocodile species. From all cloacal samples, we recovered 21 bacterial species, of which 8 (38.1%) were detected in both crocodile species. The most commonly isolated bacteria in cloacal samples were Aeromonas hydrophila and Escherichia coli, whereas in oral samples the most common bacteria were A. hydrophila and Arcanobacterium pyogenes. The bacteria isolated represent a potential threat to crocodile health during conditions of stress and a threat to human health through crocodile bites, crocodile meat consumption or carrying out activities in crocodile habitat. We especially warn about the presence of Salmonella arizonae and S. typhi, which cause enteritis and septicemia in crocodiles and salmonellosis and typhoid fever in humans. The risk of bacterial contamination from crocodiles to humans could increase in the future because of the accelerated destruction of crocodile habitat, which could lead to an augmentation of human crocodile interactions. Information on bacterial diversity reported here could help in the choice of antibacterial products in case of infections that are of crocodile origin. PMID- 22422128 TI - Systemic iridovirus from threespine stickleback Gasterosteus aculeatus represents a new megalocytivirus species (family Iridoviridae). AB - Megalocytiviruses have been associated with epizootics resulting in significant economic losses in public aquaria and food-fish and ornamental fish industries, as well as threatening wild fish stocks. The present report describes characteristics of the first megalocytivirus from a wild temperate North American fish, the threespine stickleback Gasterosteus aculeatus. Moribund and dead fish sampled after transfer to quarantine for an aquarium exhibit had amphophilic to basophilic intracytoplasmic inclusions (histopathology) and icosahedral virions (transmission electron microscopy) consistent with an iridovirus infection. Phylogenetic analyses of the major capsid, ATPase, and DNA polymerase genes confirmed the virus as the first known member of the genus Megalocytivirus (family Iridoviridae) from a gasterosteid fish. The unique biologic and genetic properties of this virus are sufficient to establish a new Megalocytivirus species to be formally known as the threespine stickleback iridovirus (TSIV). The threespine stickleback is widely distributed throughout the northern hemisphere in both freshwater and estuarine environments. The presence of megalocytiviruses with broad host specificity and detrimental economic and ecologic impacts among such a widely dispersed fish species indicates the need for sampling of other stickleback populations as well as other North American sympatric marine and freshwater ichthyofauna. PMID- 22422129 TI - Antimicrobial susceptibility of Francisella noatunensis subsp. noatunensis strains isolated from Atlantic cod Gadus morhua in Norway. AB - A total of 30 isolates of Francisella noatunensis subsp. noatunensis isolated from Atlantic cod Gadus morhua L. were tested for susceptibility, in the form of minimal inhibitory concentration (MIC) values, against the following antibacterial agents: flumequine, oxolinic acid, ciprofloxacin, florfenicol, oxytetracycline, erythromycin, streptomycin sulphate, trimetoprim/sulphadiazine and rifampin. All the isolates had a low susceptibility to oxytetracycline, trimetoprim/sulphadiazine (Tribrissen(r)), erythromycin, ciprofloxacin and streptomycin with MIC values of 64, 64 to 128, 16, 8 and 32 to 128 ug ml-1, respectively. The strains were, on the other hand, susceptible to florfenicol, oxolinic acid, flumequine and rifampin with MIC values of 0.5, 0.25, 0.25 and 0.25 to 1 ug ml-1, respectively. PMID- 22422130 TI - Fate of Francisella noatunensis, a pathogen of Atlantic cod Gadus morhua, in blue mussels Mytilus edulis. AB - Francisellosis, caused by the bacterium Francisella noatunensis, is one of the most severe diseases affecting farmed cod, and has caused great economic loss for the cod farming industry in Norway. We studied the fate of F. noatunensis in the marine environment, focusing on the role of blue mussels. In experimental challenges, waterborne F. noatunensis was rapidly filtered by the blue mussel and transported to the digestive diverticulae. The bacteria passed through the entire digestive system. Intraperitoneal injection of cod with suspensions prepared from faeces collected from challenged mussels resulted in the development of francisellosis in the recipients, demonstrating that some bacteria were alive and infective when shed in mussel faeces. Bacterial clearance from the mussels was relatively fast, and no evidence was found, suggesting that the bacterium is capable of persisting or multiplying in the mussel tissues. A cohabitation experiment with cod and mussels previously exposed to F. noatunensis did not lead to infection in cod. A direct transmission from contaminated mussels to cod was thus not demonstrated; however, faeces particles with infective bacteria may play a role in the transmission of the bacterium in marine food chains. PMID- 22422131 TI - Influence of disseminated neoplasia, trematode infections and gametogenesis on surfacing and mortality in the cockle Cerastoderma edule. AB - Cerastoderma edule is a widely distributed bivalve mollusc, commercially exploited throughout Europe and is also an important food source for birds and crustaceans. Recently, mass surfacing and mortalities of cockles have been observed and reported at sites in Ireland and elsewhere, particularly in the summer months. One such site is Flaxfort Strand, Courtmacsherry Bay, County Cork, Ireland, an important feeding area used by many seabirds during the summer months. For the past few years large numbers of surfaced cockles have been observed at the site in a moribund condition. Samples of cockles from this area were collected over the summer months and their health status assessed. Cockles that had surfaced (moribund) and those still buried in the sediment were quantified and screened: sex, gonadal maturity and size class of cockles were also determined. Disseminated neoplasia and trematodes were observed in screened cockles. The most significant finding during the study was that mortalities and surfacing of cockles was related to a greater incidence of disseminated neoplasia. No neoplasia was observed in the smallest and largest size classes. There was a significantly higher prevalence of neoplasia in moribund cockles than in buried cockles, whereas in both groups a similar concentration of trematode metacercariae was observed in the screened tissues. Also, most of the cockles that had surfaced were either in the process of spawning or were spent. Overall a much larger percentage of moribund cockles exhibited both trematode infections plus neoplasia compared with buried cockles. A combination of the presence of neoplasia and trematodes, along with stress related to spawning, may immunocompromise the cockless, causing the animals to surface and become moribund. PMID- 22422132 TI - Invasive crayfish and crayfish plague on the move: first detection of the plague agent Aphanomyces astaci in the Romanian Danube. AB - Native European crayfish, such as Astacus leptodactylus, are threatened, among other factors, by the crayfish plague agent Aphanomyces astaci, dispersed by invasive North American crayfish. Two of these invaders, Pacifastacus leniusculus and Orconectes limosus, have extended their distribution in the River Danube catchment; the latter was detected for the first time in Romania in 2008. We monitored, at monthly intervals for over 2 yr, occurrence of native A. leptodactylus and invasive O. limosus at 6 sites on the Romanian Danube and checked for the invasive species in 4 of its tributaries. Between January 2009 and March 2011, the relative abundances of O. limosus steadily increased with time, while the native A. leptodactylus dramatically decreased in abundance. O. limosus expanded downstream at a rate of ca. 15 km yr-1; in August 2011, it was already present in the upper 105 km of the Romanian Danube. An agent-specific real-time PCR analyses demonstrated the presence of A. astaci DNA in at least 32% of the analysed invasive (n = 71) and 41% of the native (n = 49) crayfish coexisting in the Danube. Furthermore, A. astaci was also detected in A. leptodactylus captured about 70 km downstream of the O. limosus invasion front (at the time of sampling). Assuming a steady rate of expansion, O. limosus may invade the sensitive Danube delta area in the mid-2060s, even without long distance dispersal. The crayfish plague agent, however, may reach the delta substantially earlier, through dispersal downstream among populations of native crayfish. PMID- 22422133 TI - Living an unfamiliar body: the significance of the long-term influence of bodily changes on the perception of self after stroke. AB - The aim of this study is to illuminate the significance of the long-term influence of bodily changes on the perception of self after stroke by means of narrative interviews with 23 stroke survivors. A phenomenological-hermeneutic approach inspired by the philosophy of Merleau-Ponty and Ricoeur is the methodological framework. Zahavi's understanding of the embodied self and Leder's concept of dys-appearance along with earlier research on identity guide the comprehensive understanding of the theme. The meaning of bodily changes after stroke can be understood as living with an altered perception of self. Stroke survivors perceive their bodies as fragile, unfamiliar and unreliable and tend to objectify them. The weak and discomforting body that 'cannot' demands constant, comprehensive awareness to keep itself in play. These long-term and often permanent consequences of bodily weakness may turn stroke survivors' intentionality inwards, away from external activities and projects and relationships with others. Negative judgements from others are added to lost roles and positions and threaten the vulnerable self. Stroke survivors try to regain familiarity with their body by their life-long project of testing its boundaries. Mastering important tasks helps them strengthen their self-concept. Health care workers should be aware of the embodied self and engage in long-term dialogues with stroke survivors to strengthen positive perceptions of body and self. More research is needed to understand destructive post-stroke phenomena such as fatigue and pain and to find effective methods to help stroke survivors regain wholeness of body and self. PMID- 22422134 TI - Don't let the bedbugs bite: the Cimicidae debacle and the denial of healthcare and social justice. AB - Although bedbug infestation is not a new public health problem, it is one that is becoming more alarming among healthcare professionals, public health officials, and ethicists given the magnitude of patients who may be denied treatment, or who are unable to access treatment, especially those underserved populations living in low income housing. Efforts to quarantine and eradicate Cimicidae have been and should be made, but such efforts require costly interventions. The alternative, however, can further exacerbate the already growing problems of injustice, i.e., unfair treatment of patients, inaccessibility of needed resources. In the following paper, I examine the ramifications of denying access to medical care, among other healthcare justice dilemmas surrounding bedbug infestations. I also explore the value of health, and how healthcare professionals and public officials often feel as though bedbugs are not a priority because they, themselves, are not diseases, regardless of the fact they cause physical and mental problems that affect a person's health. I propose recommendations for improving the health and well-being of those vulnerable populations who are facing a difficult and growing public health problem that is currently being ignored in medical and public health ethics literature, regardless of increased media attention and unusual habitats of localized infestations, e.g., Statue of Liberty, New York City. PMID- 22422135 TI - EGFR and KRAS mutational analysis and their correlation to survival in pancreatic and periampullary cancer. AB - OBJECTIVES: Pancreatic and periampullary cancers have a high incidence of activating KRAS mutations. The aim of this study was to determine the incidence of KRAS and EGFR mutations in pancreatic and periampullary cancers and their relationship with survival. METHODS: One hundred patients undergoing pancreaticoduodenectomy or pancreatic biopsy for cancer were recruited. Samples of formalin-fixed paraffin-embedded or fresh pancreatic tissue were obtained. EGFR was analyzed by DNA sequencing of exons 18 to 21. KRAS was analyzed by pyrosequencing of codons 12, 13, and 61. RESULTS: EGFR mutations were found in 2 (2.3%) of 88 assessable cases. One in exon 18 (c.1966C>T, p.Q710X) and 1 in exon 19 (c.2066A>G, p.E734G). A synonymous single-nucleotide polymorphism in exon 20 (c.2361G>A, p.Q787) was identified in 57 (67.8%) of 84 patients studied. Twenty eight (41.2%) of 68 cases harbored a point mutation in KRAS codon 12 (26 cases) and codon 61 (2 cases). The overall median survival was 308 days (range, 7-2623 days). The presence of KRAS point mutations did not significantly alter median survival time (22.8 vs 28.1 months, P = 0.88). CONCLUSIONS: EGFR somatic mutations are rare in pancreatobiliary malignancies. KRAS mutations are less common than previous reports and do not correlate with survival. PMID- 22422136 TI - Hepatitis B virus status and risk of pancreatic ductal adenocarcinoma: a case control study from China. AB - OBJECTIVES: This study was to assess the role of hepatitis B virus (HBV) infection in pancreatic ductal adenocarcinoma (PDAC) risk using a hospital-based case-control design. METHODS: Patients with pathologically confirmed PDAC (943) and 1128 matched controls were recruited from 2 hospitals. We evaluated the associations between risk of PDAC and age, sex, history of diabetes mellitus (DM), etc. In addition, we examined the interactive effects of HBV status and known risk factors for pancreatic cancer. RESULTS: Chronic hepatitis B and inactive hepatitis B surface antigen (HBsAg) carrier state (HBsAg positive) had a significantly increased risk of pancreatic cancer, with an adjusted odds ratio of 1.60 (95% confidence interval [CI], 1.15-2.24). Furthermore, significant interactions were detected between a history of DM and chronic hepatitis B and inactive HBsAg positive, but not with antibodies to hepatitis B core antigen (anti-HBc) positive/antibodies to HBsAg (anti-HBs) negative, with an adjusted odds ratio of 5.42 (95% CI, 2.76-10.64), compared with those who were HBsAg negative/anti-HBc negative without a history of DM. CONCLUSIONS: These results suggest that HBsAg-positive or anti-HBc-positive/anti-HBs-negative patients have an increased risk for PDAC independent of other risk factors. Significant interactions were found between a history of DM and chronic HBV infection for PDAC risk. PMID- 22422137 TI - Different incretin responses after pancreatoduodenectomy and distal pancreatectomy. AB - OBJECTIVES: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known as incretins to stimulate insulin secretion. The aims of this study were to investigate the postoperative beta-cell function and hormonal responses of GLP-1 and GIP after pancreatoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: Oral glucose tolerance tests were performed in 34 patients (20 PD and 14 DP) before and 1 month after operation. The changes in the serum glucose and insulin concentrations, homeostasis model assessment of insulin resistance, and pancreatic beta-cell function (BCF) were analyzed. GLP-1 and GIP were also measured. RESULTS: There was no patient with postoperative deterioration of glucose tolerance after PD, whereas impairment of glucose metabolism was observed after DP. Homeostasis model assessment of insulin resistance decreased after PD, whereas those after DP showed no change. The postoperative BCF were lower than preoperative values in both groups. GLP-1 increased after DP but not after PD, whereas GIP decreased after PD but not after DP. CONCLUSIONS: The changes in glucose metabolism and incretin responses were different between PD and DP. The increased level of GLP-1 after DP might reflect the relatively insufficient BCF; and thus, perioperative administration of GLP-1 might improve the diabetic condition after DP. PMID- 22422138 TI - Comparison of health-related quality of life in patients with neuroendocrine tumors with quality of life in the general US population. AB - OBJECTIVE: The objective of this study was to evaluate the health-related quality of life (HRQL) burden of patients with neuroendocrine tumor (NET) and associations with demographic and clinical factors. METHODS: Patients with NET were invited to participate in an online, anonymous survey consisting of 2 standardized HRQL measures, SF-36 and PROMIS-29, and a set of demographic and disease-related questions. General linear models were used to evaluate the associations between HRQL and demographic and clinical characteristics. RESULTS: A total of 663 patients participated. These patients with NET demonstrated worse HRQL scores compared to the general population and to a sample of mixed cancer patients and survivors. Patients with current NET (tumor not surgically removed or came back after surgery), carcinoid syndrome, or an increased number of bowel movements or flushing episodes experience worsened HRQL compared to patients with NET without those characteristics after adjustment for other clinical and demographic variables. CONCLUSIONS: Patients with NET reported worse HRQL scores compared to the general population. NET-related symptoms such as diarrhea and flushing were associated with reduced quality of life in this cross-sectional study. Optimal management of NET and carcinoid syndrome may significantly improve HRQL among patients with NETs. PMID- 22422139 TI - Utility of nuclear magnetic resonance spectroscopy for pancreatic cancer studies. AB - OBJECTIVES: The aims of this study were (1) to determine nuclear magnetic resonance spectroscopic characteristics and metabolite profiles of serum samples from patients with pancreatic cancer compared with noncancerous control samples and (2) to ascertain if the accuracy of metabolite identification by 1D spectra can be improved upon by confirmation of spin-system assignment using more sophisticated experiments. METHODS: Nuclear magnetic resonance spectra, including 1D, total correlation spectroscopy, and heteronuclear multiple/single quantum coherence, were obtained from serum samples from patients with pancreatic cancer and control subjects and used to determine serum levels of a range of metabolites. RESULTS: The data show that total choline (P = 0.03), taurine (P = 0.03), and glucose plus triglycerides (P = 0.01) are significantly higher in cancer versus control samples. Also detected were species that could not be individually identified and that were designated UCM (unresolved complex matter). Levels of UCM are significantly higher in subjects with cancer, being almost double those of control samples. CONCLUSIONS: Although metabolites such as lactate, taurine, glucose, choline, and triglycerides can be determined from 1D spectra, accuracy is improved by confirmation of spin-system assignment with total correlation spectroscopy and heteronuclear multiple/single quantum coherence spectral analysis. In addition, we introduce a new metric, UCM, which is at higher concentrations in cancer compared with control samples. PMID- 22422140 TI - Understanding disintegrant action by visualization. AB - The aim of this study was to utilize high-speed video imaging for understanding the disintegrability of compacts and disintegrant action upon wetting. High-speed video imaging was used to visualize the disintegration of compacts and effect of wetting on free disintegrant particles. Acquired images were processed using MATLAB, and changes in the compact area and instantaneous motion of compacted particles on contact with water were analyzed. The capillary action of compacts was also determined for various disintegrants. Finally, the breakdown behavior of compacts prepared with selected disintegrants was analyzed at different compression forces to evaluate recovery of compaction strain. Water-insoluble inert diluent, dicalcium phosphate, was used as a comparator. The results from this visualization study provided an in-depth understanding of the disintegrant behavior of free and compacted disintegrant particles upon wetting. The mechanisms of swelling, capillary action, disruption of particle-particle bonds and strain recovery were successfully monitored by video imaging. The disintegration of compacts containing crospovidone appeared to be less influenced by swelling or wicking action. The influence of compression force on the disintegration of selected disintegrants confirmed that strain recovery is the dominant mechanism for the disintegrant action of crospovidone. PMID- 22422141 TI - Regulating DNA translocation through functionalized soft nanopores. AB - Nanopores have emerged as promising next-generation devices for DNA sequencing technology. The two major challenges in such devices are: (i) find an efficient way to raise the DNA capture rate prior to funnelling a nanopore, and (ii) reduce the translocation velocity inside it so that single base resolution can be attained efficiently. To achieve these, a novel soft nanopore comprising a solid state nanopore and a functionalized soft layer is proposed to regulate the DNA electrokinetic translocation. We show that, in addition to the presence of an electroosmotic flow (EOF), which reduces the DNA translocation velocity, counterion concentration polarization (CP) occurs near the entrance of the nanopore. The latter establishes an enrichment of the counterion concentration field, thereby electrostatically enhancing the capture rate. The dependence of the ionic current on the bulk salt concentration, the soft layer properties, and the length of the nanopore are investigated. We show that if the salt concentration is low, the ionic current depends largely upon the length of the nanopore, and the density of the fixed charge of the soft layer, but not upon its degree of softness. On the other hand, if it is high, ionic current blockade always occurs, regardless of the levels of the other parameters. The proposed soft nanopore is capable of enhancing the performance of DNA translocation while maintaining its basic signature of the ionic current at high salt concentration. The results gathered provide the necessary information for designing devices used in DNA sequencing. PMID- 22422142 TI - Bioactive glass enhances bone ingrowth into the porous titanium coating on orthopaedic implants. AB - PURPOSE: The aim of the study was to verify the ability of nanoparticulate bioactive glass (BAG) to infiltrate into the porous titanium (Ti) layer on Ti based implants to promote osseointegration. METHODS: The porous titanium layer on Ti-based implants was impregnated with nanoparticulate BAG. The implants without or with BAG were implanted bilaterally in tibial holes of ten New Zealand white rabbits. The rabbits were sacrificed after ten weeks for examinations. Beside histological examination, EDXS analysis of polished cross-sections of explanted implants was also performed with the aim to quantitatively evaluate the bone-to pore contact and bone-in-pore ratio. RESULTS: After ten weeks, EDXS analyses of cross-sections of the explanted implants confirmed that bioactive glass was fully resorbed and that the pores throughout the thickness of the porous titanium layer were to a large extent filled with a new bone. In the absence of bioactive glass, only the outer part of the porous layer was filled with bone. The implants without BAG in the porous Ti-layer exhibited similar bone-to-pore contact, while significant improvement of bone ingrowth into the pores was observed for the implants with BAG (38%), as opposed to those without it (22%). CONCLUSION: This study confirmed that the nanoparticulate bioactive glass within the porous titanium surface layer on implants promotes osseointegration and stimulates the formation of bone within the pores. PMID- 22422143 TI - Mesh-integrated microdroplet array for simultaneous merging and storage of single cell droplets. AB - We constructed a mesh-grid integrated microwell array which enables easy trapping and consistent addition of droplets. The grid acts as a microchannel structure to guide droplets into the microwells underneath, and also provides open access for additional manipulation in a high-throughput manner. Each droplet in the array forms a stable environment of pico-litre volume to implement a single-cell-based assay. PMID- 22422144 TI - [Ocular decompression retinopathy after combined deep sclerectomy and trabeculotomy]. PMID- 22422145 TI - [Pseudophakic cystoid macular oedema]. AB - Pseudophakic cystoid macular oedema is still a relevant clinical disease entity although major progress in modern cataract surgery has been made within the last decades. The relevance is attributed to the large number of cases that are performed each year. Even after uneventful surgery, a pseudophakic cystoid macular oedema can develop and may lead to severe and lasting visual impairments. In respect to the pathophysiology, four consecutive steps have to be considered: (i) surgical procedure-related induction and release of various inflammation mediators into the anterior chamber; (ii) removal of the physiological lens barrier between the anterior and posterior segments of the eye, leading consecutively to an increase in diffusion rate in either direction; (iii) local action of the inflammation mediators towards the macular area; and (iv) increased vitreoretinal traction due to the anteriorly oriented drive of the vitreous. To prevent the development of a pseudophakic cystoid macular oedema, systemic and ocular pathologies should be treated consequently prior to surgery. Furthermore, an individual risk profile of each patient needs to be evaluated to define the best pre- and postsurgical medical treatment. A less traumatic surgical approach can help to prevent macular oedema development additionally. The diagnosis is made by performing biomicroscopy, fluorescence angiography and optical coherence tomography as well as by evaluating the patients' major complaints. Standard operation procedures or recommended guidelines by the specialised eye associations to prevent and treat pseudophakic cystoid macular oedema are not available up to date. A synopsis of recommendations in the literature suggests a step-wise treatment regimen, including topical medical treatment on the one hand and a surgical approach on the other hand as well as a combination of both, if needed. Topical medical treatment options include the use of non-steroidal, corticosteroid and/or carbonic anhydrase inhibitor eye drops. Surgical interventions include pars plana vitrectomy. PMID- 22422146 TI - A homochiral diamond framework constructed from Fe(III) and Mn(II) oxo-clusters supported by Sb(III) tartrate scaffolds. AB - A homochiral diamond framework was obtained by using a secondary building unit (SBU) comprising an oxo-cluster containing 4Fe(III) and 3Mn(II) ions supported by Sb(3)O tartrate scaffolds. A fully protonated tetratopic cation, tetrakis(4 pyridyloxymethylene)methane (TPOM), acts as a template to arrange the clusters on a diamond lattice. PMID- 22422147 TI - A flexible DNA modification approach towards construction of gold nanoparticle assemblies. AB - A flexible strategy for the preparation of nanostructures of gold nanoparticles (AuNPs) through DNA directed assembly has been proposed. This strategy would greatly enhance the stability, precision and flexibility in the construction of DNA-base structural and functional devices, and promote the development of DNA nanotechnology. PMID- 22422148 TI - Analysis of the subcomponents and cortical terminations of the perisylvian superior longitudinal fasciculus: a fiber dissection and DTI tractography study. AB - The anatomy of the perisylvian component of the superior longitudinal fasciculus (SLF) has recently been reviewed by numerous diffusion tensor imaging tractography (DTI) studies. However, little is known about the exact cortical terminations of this tract. The aim of the present work is to isolate the different subcomponents of this tract with fiber dissection and DTI tractography, and to identify the exact cortical connections. Twelve postmortem human hemispheres (6 right and 6 left) were dissected using the cortex-sparing fiber dissection. In addition, three healthy brains were analyzed using DTI-based tractography software. The different components of the perisylvian SLF were isolated and the fibers were followed until the cortical terminations. Three segments of the perisylvian SLF were identified: (1) anterior segment, connecting the supramarginal gyrus and superior temporal gyrus with the precentral gyrus, (2) posterior segment, connecting the posterior portion of the middle temporal gyrus with the angular gyrus, and (3) long segment of the arcuate fasciculus that connects the middle and inferior temporal gyri with the precentral gyrus and posterior portion of the inferior and middle frontal gyri. In the present study, three different components of the perisylvian SLF were identified. For the first time, our dissections revealed that each component was connected to a specific cortical area within the frontal, parietal and temporal lobes. By accurately depicting not only the trajectory but also cortical connections of this bundle, it is possible to develop new insights into the putative functional role of this tract. PMID- 22422149 TI - Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein. AB - Huntington's disease (HD) is a genetically neurodegenerative disease, affecting the central nervous system and leading to mental and motor dysfunctions. To date, there is no cure for HD; as a result, HD patients gradually suffer devastating symptoms, such as chorea, weight loss, depression and mood swings, until death. According to previous studies, the exon 1 region of the huntingtin (HTT) gene with expanded CAG trinucleotide repeats plays a critical role in causing HD. In vitro studies using exon 1 of HTT fused with green fluorescent protein (GFP) gene have facilitated discovering several mechanisms of HD. However, whether this chimera construct exerts similar functions in vivo is still not clear. Here, we report the generation of transgenic mice carrying GFP fused with mutant HTT exon 1 containing 84 CAG trinucleotide repeats, and the evaluation of phenotypes via molecular, neuropathological and behavioral analyses. Results show that these transgenic mice not only displayed neuropathological characteristics, observed either by green fluorescent signals or by immunohistochemical staining, but also progressively developed pathological and behavioral symptoms of HD. Most interestingly, these transgenic mice showed significantly differential expression levels of nuclear aggregates between cortex and striatum regions, highly mimicking selective expression of mutant HTT in HD patients. To the best of our knowledge, this is the first report showing different nuclear diffusion profiling in mouse models with transgenic mice carrying the exon 1 region of mutant HTT. Our model will be beneficial for tracing the expression of mutant HTT and accelerating the understanding of selective pathological progression in HD. PMID- 22422151 TI - Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer. AB - Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment. PMID- 22422152 TI - High-sensitivity troponin assays and clinical decisions. PMID- 22422153 TI - Selecting clinical quality indicators for laboratory medicine. AB - BACKGROUND: Quality in laboratory medicine is often described as doing the right test at the right time for the right person. Laboratory processes currently operate under the oversight of an accreditation body which gives confidence that the process is good. However, there are aspects of quality that are not measured by these processes. These are largely focused on ensuring that the most clinically appropriate test is performed and interpreted correctly. METHODS: Clinical quality indicators were selected through a two-phase process. Firstly, a series of focus groups of clinical scientists were held with the aim of developing a list of quality indicators. These were subsequently ranked in order by an expert panel of primary and secondary care physicians. RESULTS: The 10 top indicators included the communication of critical results, comprehensive education to all users and adequate quality assurance for point-of-care testing. Laboratories should ensure their tests are used to national standards, that they have clinical utility, are calibrated to national standards and have long-term stability for chronic disease management. Laboratories should have error logs and demonstrate evidence of measures introduced to reduce chances of similar future errors. Laboratories should make a formal scientific evaluation of analytical quality. CONCLUSIONS: This paper describes the process of selection of quality indicators for laboratory medicine that have been validated sequentially by deliverers and users of the service. They now need to be converted into measureable variables related to outcome and validated in practice. PMID- 22422155 TI - Role of sentinel lymphadenectomy in thin cutaneous melanomas with positive deep margins on initial biopsy. AB - INTRODUCTION: Breslow thickness (BRES) on initial melanoma biopsy determines need for sentinel lymph node (SLN) biopsy. In presence of positive deep margins, BRES is indeterminate. We hypothesized that thin (BRES <0.76 mm) melanomas with positive deep margins and thicker melanomas (BRES 0.76-2.0 mm) have statistically similar risk of SLN metastasis. METHODS: Retrospective review was performed of adult patients undergoing wide excision plus SLN biopsy for melanoma from 01/2004 to 05/2010. Group 1 (BRES <0.76 mm and positive deep margins) was compared to Group 2 (BRES 0.76-2.0 mm, regardless of margin status). Primary outcome was presence of SLN metastasis. RESULTS: 260 patients were eligible, 72 (28%) in Group 1 and 188 (72%) in Group 2. Average age was 57 years, with 120 (46%) females. SLNs were positive in 6/72 (8.3%) patients in Group 1 and 17/188 (9.0%) patients in Group 2 (P=0.86). The two groups were not statistically different by multivariate analysis (P=0.49). In multivariate model, Clark's level IV (P=0.009) was only predictive factor of SLN metastasis. CONCLUSIONS: Melanoma patients with thin BRES but positive deep margins carry risk of SLN metastasis similar to patients with thicker melanomas. Positive deep margins should be considered in decision to perform SLN biopsy. Clark's level IV was significantly associated with SLN metastasis. PMID- 22422156 TI - Overexpressed mutant optineurin(E50K) induces retinal ganglion cells apoptosis via the mitochondrial pathway. AB - Mutations in the coding region of the OPTN gene are associated with certain glaucomas. Although the function of the optineurin protein is yet to be elucidated, the most common mutation, E50K, is associated with a severe phenotype. Plasmids expressing wild-type Optineurin (WT) and mutant Optineurin(E50K) were transfected into RGC-5 and monitored by immunofluorescence staining and western blotting. The mutant Optineurin(E50K) induced the death of retinal ganglion cells by generation of reactive oxygen species accompanied disruption of mitochondrial transmembrane potential, down-regulation of bcl-2, and up-regulation of bax, which led to the release of cytochrome C from the mitochondria into the cytosol, which, in turn, resulted in the activation of caspase-9 and caspase-3, indicating that mutant Optineurin(E50K) acquired the ability to induce cell death through the mitochondrial caspase-dependent cell death pathway. PMID- 22422157 TI - Vitamin D receptor gene variability as a factor influencing bone mineral density in pediatric patients. AB - To determine the relationship between the polymorphism of vitamin D receptor gene and the bone mineral density in children. The study group consisted of 395 children aged 6-18 years. All patients underwent genotyping using the PCR-RFLP method within polymorphic loci BsmI (rs1544410), FokI (rs2228570), ApaI (rs7975232) and Taq I (rs731236) of the VDR gene. The BMD (g/cm(2), Z score) and BMC (g, Z score) by DXA method, as well as Z scores of the BUA, SOS and Stiffness ultrasound parameters were evaluated. Based on densitometry results, children were divided into 3 groups: I-Z score +/- 1.0; II-Z score from -1.1 to -2.0; and III-Z score <= -2.1. A control group numbering 294 children was used for the purpose of allele frequency comparisons. The occurrence of studied polymorphism alleles in the control group did not significantly differ from the values expected according to the Hardy-Weinberg equilibrium (p values: 0.1224 for BsmI; 0.5958 for TaqI; 0.0817 for ApaI; and 0.8901 for FokI). Allele a ApaI carrier status in group III children was associated with an increased BMD (x = 0.8 vs 0.69, p = 0.0296) and BMC value (x = 28.76 vs 22.14, p = 0.0565) in spine projection results, Stiffness (x = -1.12 vs -1.91, p = 0.0347) and SOS (x = -1.43 vs -2.27, p = 0.0319) ultrasound parameters. In group II, significantly increased SOS values (-1.13 vs -1.73, p = 0.0378) were noted in f (FokI) carriers. The presence of aa ApaI and ff FokI polymorphisms favours a higher bone mass and better bone structure (decreased bone mass loss) in the analysed group. PMID- 22422158 TI - Endothelial nitric oxide synthase intron 4 VNTR gene polymorphisms in European and African populations. AB - Endogenous nitric oxide (NO) is a molecule synthesized by endothelium nitric oxide synthase encoded by the ecNOS gene that plays an important role in regulating the systemic, cardiac and pulmonary circulation. Impairment in NO synthesis has been associated to many cardiovascular disorders, including coronary artery disease and hypertension. We investigated the frequency of the intron 4 VNTR ecNOS gene polymorphism in an Ivorian and an Italian population. The frequencies of the ecNOSb/b, ecNOSa/b and ecNOSa/a genotypes were 0.422, 0.476, and 0.102, respectively, for the Ivorian sample, and 0.712, 0.269, and 0.019, respectively, for the Italian population. The frequencies of ecNOS4b and ecNOS4a alleles were 0.660 and 0.340, respectively, for the Ivorian group, and 0.847 and 0.153, respectively, for the studied Italian population. Genotype frequencies were in Hardy-Weinberg equilibrium in both populations. The Ivorian population showed a significantly higher frequency of the ecNOS4a allele compared to other African and non-African populations, while the Italian sample confirmed the high genetic homogeneity of this polymorphism among Europeans. The maldistribution of endothelial ecNOS polymorphisms between populations could be the results of differential exposure to selection pressures in Africa and during the out-of-Africa expansion. PMID- 22422160 TI - [A brief instrument for the assessment of childhood abuse and neglect: the childhood trauma screener (CTS)]. AB - OBJECTIVE: There is a lack of a psychometrically sound screening questionnaire that assesses important dimensions of traumatic experiences during childhood and adolescence in a time-efficient way. Based on the German version of the "Childhood Trauma Questionnaire" (CTQ, 28 items) we developed a five-item self report childhood trauma screener (CTS) that covers sexual, emotional and physical abuse and emotional and physical neglect. METHOD: The data set of the SHIP-LEGEND study (n = 1668) was used to extract five items of the CTQ that optimally covered the five dimensions and showed a high correlation with the total score. In two validation samples (clinical sample [n = 211] and subjects from the BiDirect study [n = 288]) the psychometric properties of the CTS were evaluated. RESULTS: The correlations between the five CTS Items and the corresponding dimensions from the CTQ were r = 0.55 to 0.87 (p < 0.0001) within the clinical sample. Furthermore, we found high correlations (r = 0.88; p < 0.0001) with the total CTQ score. The internal consistency was 0.757 (Cronbachs alpha). CONCLUSION: The CTS is a reliable, valid and economic screener for the retrospective assessment of adverse childhood experiences especially in large epidemiological studies. PMID- 22422161 TI - [Wish to change smoking behaviour among staff and patients of a psychiatric hospital]. AB - Objective To examine smoking behaviour and motivation to reach abstinence among staff and patients of a psychiatric hospital.Methods In two due day surveys all in-patients and staff of the Centre for Psychiatry Weissenau were interviewed by a questionnaire.Results The response rate was 78.5 %. 442 (48 %) out of 933 subjects (523 patients, 410 staff) were smokers. Patients were smoking more frequently than staff (58 % vs. 34 %) and were more severely nicotine-dependent. Significant gender differences were observed with regard to prevalence and nicotin dependence. 57 % said they wanted to stop smoking and 34 % would appreciate therapeutic offers. There were no significant differences between patients and staff.Conclusions Psychiatric patients are as motivated as staff for offers about smoking cessation. There is a need for therapeutic offers. PMID- 22422162 TI - [Dialectical Behavior Therapy (DBT) in a patient with factitious disorder: therapist's and patient's perspective]. AB - OBJECTIVE: Presentation of the disorder model and inpatient psychotherapy of a patient with factitious disorder as seen from the therapist's and patient's perspective. METHOD: Case report including the patient's own notations. RESULTS: The description of her motives by the patient facilitated a concise planning of therapy and its successful progression. CONCLUSIONS: The factitious disorder is based on learning experiences and is maintained, among other things, by the care of the medical personnel. Principles and interventions of DBT could successfully be employed. PMID- 22422163 TI - [Indication decision in preliminary talks of a psychiatric day hospital]. AB - OBJECTIVE: The aim of this study is to assess relevant patient- and therapist associated traits for indication decision for a psychiatric day hospital. METHODS: Therapeutic assessments concerning emotional experience, initial working relationship and disorder-related criteria were investigated after 155 preliminary talks at one day hospital. RESULTS: A higher patient's motivation and a current symptomatology predict a positive indication outcome. Patients who do not start treatment although a positive indication are significantly less motivated, a personality disorder is suspected more likely and the quality of the working relationship tends to be worse than in the admitted patients. CONCLUSIONS: Preliminary talks have a selective function concerning the indication for day hospital treatment. PMID- 22422164 TI - A new thiophene substituted isoindigo based copolymer for high performance ambipolar transistors. AB - A novel thiophene substituted isoindigo and its copolymer with benzothiadiazole have been synthesized. The polymer with low lying LUMO energy levels exhibits excellent ambipolar behavior in field effect transistors with both hole and electron mobilities recorded over 0.1 cm(2) V(-1) s(-1). PMID- 22422165 TI - Procalcitonin: a useful biomarker to discriminate infection after cardiopulmonary bypass in children. AB - OBJECTIVE: To determine whether procalcitonin discriminates between postcardiopulmonary bypass inflammatory syndrome and infectious complication in children better than does C-reactive protein. DESIGN: Prospective study of children admitted to the intensive care unit after cardiopulmonary bypass. PATIENTS: Classified according to a diagnosis of systemic inflammatory response syndrome and bacterial infection or systemic inflammatory response syndrome but no bacterial infection. Two hundred thirty-one cases were recruited. MEASUREMENT AND MAIN RESULTS: Procalcitonin, C-reactive protein, and leukocyte count were measured daily from surgery until day 3. Twenty-two patients were infected (9.5%). Significant differences were detected in the procalcitonin values of the infected group vs. the noninfected group, especially at day 2 (p = .000). There were no differences in the C-reactive protein values. The optimal cutoff for procalcitonin was >2 ng/mL at day 1 and above 4 ng/mL at the day 2. There was a greater sensitivity and specificity than with C-reactive protein as an infection predictor. CONCLUSION: Procalcitonin is useful in the diagnosis of bacterial infection after cardiopulmonary bypass. Because procalcitonin kinetics are different in postcardiopulmonary bypass patients, the cutoff to diagnose infection should be different from the normal cutoff. PMID- 22422166 TI - Glasgow Coma Scale as a predictor for hemocoagulative disorders after blunt pediatric traumatic brain injury. AB - OBJECTIVE: Coagulopathy is a complication of traumatic brain injury and its presence after injury has been identified as a risk factor for prognosis. It was our aim to determine whether neurologic findings reflected by Glasgow Coma Scale at initial resuscitation can predict hemocoagulative disorders resulting from traumatic brain injury that may aggravate clinical sequelae and outcome in children. DESIGN: A retrospective analysis of 200 datasets from children with blunt, isolated traumatic brain injury documented in the Trauma Registry of the Deutsche Gesellschaft fur Unfallchirurgie was conducted. Inclusion criteria were primary admission, age <14 yrs, and sustained isolated blunt traumatic brain injury. SETTING: Trauma Registry of the Deutsche Gesellschaft fur Unfallchirurgie affiliated trauma centers in Germany. PATIENTS: : Two hundred datasets of children (age <14 yrs) with blunt isolated traumatic brain injury were analyzed: children were subdivided into two groups according to Glasgow Coma Scale at the scene (Glasgow Coma Scale <= 8 vs. Glasgow Coma Scale >8) and reviewed for coagulation abnormalities upon emergency room admission and outcome. MEASUREMENT AND MAIN RESULTS: Fifty-one percent (n = 102 of 200) of children had Glasgow Coma Scale >8 and 49% (n = 98 of 200) had Glasgow Coma Scale <= 8 at the scene. The incidence of coagulopathy at admission was higher in children with Glasgow Coma Scale <= 8 compared to children with Glasgow Coma Scale >8: 44% (n = 31 of 71) vs. 14% (n = 11 of 79) (p < .001). Multivariate logistic regression revealed that Glasgow Coma Scale <= 8 at scene was associated with coagulopathy at admission (odds ratio 3.378, p = .009) and stepwise regression identified Glasgow Coma Scale <= 8 as an independent risk factor for coagulopathy. Mortality in children with Glasgow Coma Scale <= 8 at scene was substantially higher with the presence of coagulation abnormalities at admission compared to children in which coagulopathy was absent (51.6%, n = 16 of 31 vs. 5% n = 2 of 40). CONCLUSIONS: Glasgow Coma Scale <= 8 at scene in children with isolated traumatic brain injury is associated with increased risk for coagulopathy and mortality. These results may guide laboratory testing, management, and blood bank resources in acute pediatric trauma care. PMID- 22422167 TI - Noble-metal-free carbon nanotube-Cd0.1Zn0.9S composites for high visible-light photocatalytic H2-production performance. AB - Visible light photocatalytic H(2) production from water splitting using solar light is of great importance from the viewpoint of solar energy conversion and storage. In this study, a novel visible-light-driven photocatalyst multiwalled carbon nanotube modified Cd(0.1)Zn(0.9)S solid solution (CNT/Cd(0.1)Zn(0.9)S) was prepared by a simple hydrothermal method. The prepared samples exhibited enhanced photocatalytic H(2)-production activity under visible light. CNT content had a great influence on photocatalytic activity and an optimum amount of CNT was determined to be ca. 0.25 wt%, at which the CNT/Cd(0.1)Zn(0.9)S displayed the highest photocatalytic activity under visible light, giving an H(2)-production rate of 78.2 MUmol h(-1) with an apparent quantum efficiency (QE) of 7.9% at 420 nm, even without any noble metal cocatalysts, exceeding that of pure Cd(0.1)Zn(0.9)S by more than 3.3 times. The enhanced photocatalytic activity was due to CNT as an excellent electron acceptor and transporter, thus reducing the recombination of charge carriers and enhancing the photocatalytic activity. Furthermore, the prepared sample was photostable and no photocorrosion was observed after photocatalytic recycling. Our findings demonstrated that CNT/Cd(0.1)Zn(0.9)S composites were a promising candidate for the development of high-performance photocatalysts in photocatalytic H(2) production. This work not only shows a possibility for the utilization of low cost CNT as a substitute for noble metals (such as Pt) in the photocatalytic H(2)-production but also for the first time shows a significant enhancement in the H(2)-production activity by using metal-free carbon materials as effective co-catalysts. PMID- 22422168 TI - How to manage acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL is changing, from the worst among AML as it used to be, to currently the best. The application of all-trans-retinoic acid (ATRA) to the induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a new treatment option because of their targeting mechanisms, milder toxicities and improvements of long term outcomes; this combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL, particularly the novel approaches to newly diagnosed patients and the handling of side effects of treatment and relapse treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment. PMID- 22422169 TI - Super long-term highly active and selective hydroformylation in a room temperature-solidifiable guanidinium ionic liquid with a polyether tag. AB - Here we report a novel room temperature-solidifiable guanidinium methanesulfonate with a polyether tag and its use in Rh-catalysed biphasic hydroformylation of higher olefins. This novel ionic liquid can efficiently immobilize the Rh-TPPTS catalyst and render super long-term high activity and chemoselectivity, and no significant loss of activity, selectivity or Rh was observed after thirty-five cycles. PMID- 22422170 TI - Rapid screening of antibiotic toxicity in an automated microdroplet system. AB - We report an automated microfluidic platform for 'digitally' screening the composition space of droplets containing cocktails of small molecules and demonstrate the features of this system by studying epistatic interactions between antibiotics and Escherichia coli ATCC 25922. This system has several key characteristics: (i) it uses small (<100 MUL) samples of liquids and suspensions of bacteria that are introduced directly into the chip; (ii) it generates a sequence of droplets with compositions, including reagents and bacterial cell suspensions that are programmed by the user; (iii) it exports the sequence of droplets to an external segment of tubing that is subsequently disconnected for incubation and storage; and (iv) after incubation of bacteria in droplets, the droplets are injected into a second device equipped with an in-line fiber optic spectrophotometer that measures cell growth. The system generates and fuses droplets with precise (<1% in standard deviation) control of liquid volumes and of the concentrations of input substrates. We demonstrate the application of this technology in determining the minimum inhibitory concentration and pair-wise interactions of ampicillin, tetracycline, and chloramphenicol against E. coli. The experiments consumed small volumes of reagents and required minutes to create the droplets and several hours for their incubation and analysis. PMID- 22422171 TI - Combining early postoperative parathyroid hormone and serum calcium levels allows for an efficacious selective post-thyroidectomy supplementation treatment. AB - BACKGROUND: Optimal treatment protocol to prevent symptomatic hypocalcemia following total thyroidectomy is still matter of debate. We prospectively evaluated the efficacy of a selective supplementation protocol based on both early postoperative intact parathyroid hormone (iPTH) and serum calcium levels. METHODS: Two hundred thirty consecutive patients were divided in three different groups of treatment according to iPTH levels 4 h after total thyroidectomy (4 h iPTH) and serum calcium levels in the first postoperative day (1PO-Ca): group A (4 h-iPTH > 10 pg/ml, 1PO-Ca >= 8.5 mg/dl), no treatment; group B (4 h-iPTH > 10 pg/ml, 1PO-Ca < 8.5 mg/dl), oral calcium (OC) 3 g per day; and group C (4 h-iPTH <= 10 pg/ml), OC 3 g + calcitriol (VD) 1 MUg per day. Development of biochemical and/or symptomatic hypocalcemia was evaluated. RESULTS: Fifty-nine patients (25.6%) had subnormal 4 h-iPTH levels (<=10 pg/ml) (group C). Among patients with normal 4 h-iPTH levels, 25 (10.9%) had subnormal 1PO-Ca (<8.5 mg/dl) (group B). The remaining 146 patients (63.5%) had normal 4 h-iPTH and 1PO-Ca levels (group A). One patient in group A, 2 in group B, and 18 in group C developed biochemical hypocalcemia. Only one patient in group C experienced major symptoms. Treatment was discontinued within 1 month in all the patients in group B. At a mean follow up of 303 days, five patients in group C were still under supplementation treatment. CONCLUSION: The proposed supplementation protocol seems efficacious in preventing symptomatic hypocalcemia. It could allow a safe and early discharge of most patients, thus avoiding the constraints and the costs of routine supplementation. PMID- 22422172 TI - Verification of early removal of the chest tube after absorbable mesh-based pneumostasis subsequent to video-assisted major lung resection for cancer. AB - BACKGROUND: We previously reported that the combined use of absorbable mesh and fibrin glue is superior to the use of fibrin glue alone to stop intraoperative air leaks. However, concern remains about whether mesh-based pneumostasis can induce the recurrence of air leaks after chest tube removal. METHODS: We reviewed our prospective database of selected patients (n = 206) who underwent video assisted major lung resection for cancer. Exclusion criteria included simultaneous combined resection, induction radiotherapy, entire intrathoracic adhesion, or a history of prior ipsilateral thoracotomy. We sealed any intraoperative air leaks with absorbable mesh and fibrin glue and then carried out prophylactic chest-tube drainage for 1 day. RESULTS: Intraoperative air leaks were detected in 133 (65%) patients. Overall, air leaks were not detected postoperatively in 186 (91%) patients, allowing chest tube removal on the day after the operation. The mean length of time for chest tube drainage was 1.2 days. A prolonged air leak (>7 days) was observed in one (0.5%) patient, and this leak resolved by itself. After chest tube removal, an air leak recurred in six (2.9%) patients during the 30 day follow-up period, necessitating chest tube reinsertion. Although the recurrence was observed more frequently after segmentectomy than after lobectomy (p = 0.04), the recurrence was not observed more frequently in patients who had an intraoperative air leak than in patients who did not (p = 0.3). CONCLUSION: Early removal of the chest tube after pneumostasis with absorbable mesh is verified in selected patients who underwent video-assisted major lung resection for cancer. However, further attempts should be made to prevent air leaks after anatomical segmentectomy. PMID- 22422173 TI - Assessment of swallowing function impairment in patients with benign goiters and impact of thyroidectomy: a case control study. AB - BACKGROUND: Swallowing-related quality of life (QoL) in patients with benign thyroid goiters is not much studied. The aim of this study was to assess swallowing function impairment in patients with benign goiters, compare it to a control population, and also find the impact of thyroidectomy and various factors on the outcome of swallowing function. METHODS: We performed a prospective case control study from September 2009 to September 2011 which consisted of 124 patients who were to undergo primary thyroid surgery and 100 age- and sex-matched controls. A translated and validated modified swallowing quality-of-life (SWAL QOL) questionnaire was used to assess patients' perception of dysphagia. Presurgery scores of patients and controls and pre- and postsurgery scores (>6 months after surgery) of patients were compared. RESULTS: The mean age of males and females in the control and patient groups were 37.7 vs. 39.5 years and 37.4 vs. 39.8 years, respectively. Twelve patients (9.7%) complained of dysphasia at presentation. Sixty-three patients (50.8%) underwent total thyroidectomy and 61 (49.2%) had hemithyroidectomy at the time of initial evaluation, 75, 23.4, and 1.6% of patients were euthyroid, hyperthyroid, and hypothyroid, respectively. Presurgery scores of patients in all of the 11 domains of the SWAL-QOL were lower compared to those of controls. Comparing separately with the matched controls, females had significant differences in nine domains (except for sleep and fatigue) of the SWAL-QOL questionnaire but males did not. Postoperatively, both male and female patients showed significant improvement in the scores of all the domains. Female gender, hyperthyroidism, thyroid nodularity, retrosternal extension, procedure, and weight of the resected specimen were the factors associated with significant improvement in various domains. CONCLUSION: Dysphagia seems to be an underestimated problem in patients with benign goiters. Uncomplicated thyroidectomy results in significant improvement in swallowing related QoL irrespective of patient profile and extent of thyroidectomy. PMID- 22422175 TI - Pseudo-partial likelihood for proportional hazards models with biased-sampling data. AB - We obtain a pseudo-partial likelihood for proportional hazards models with biased sampling data by embedding the biased-sampling data into left-truncated data. The log pseudo-partial likelihood of the biased-sampling data is the expectation of the log partial likelihood of the left-truncated data conditioned on the observed data. In addition, asymptotic properties of the estimator that maximize the pseudo-partial likelihood are derived. Applications to length-biased data, biased samples with right censoring and proportional hazards models with missing covariates are discussed. PMID- 22422174 TI - Practical considerations for conducting ecotoxicity test methods with manufactured nanomaterials: what have we learnt so far? AB - This review paper reports the consensus of a technical workshop hosted by the European network, NanoImpactNet (NIN). The workshop aimed to review the collective experience of working at the bench with manufactured nanomaterials (MNMs), and to recommend modifications to existing experimental methods and OECD protocols. Current procedures for cleaning glassware are appropriate for most MNMs, although interference with electrodes may occur. Maintaining exposure is more difficult with MNMs compared to conventional chemicals. A metal salt control is recommended for experiments with metallic MNMs that may release free metal ions. Dispersing agents should be avoided, but if they must be used, then natural or synthetic dispersing agents are possible, and dispersion controls essential. Time constraints and technology gaps indicate that full characterisation of test media during ecotoxicity tests is currently not practical. Details of electron microscopy, dark-field microscopy, a range of spectroscopic methods (EDX, XRD, XANES, EXAFS), light scattering techniques (DLS, SLS) and chromatography are discussed. The development of user-friendly software to predict particle behaviour in test media according to DLVO theory is in progress, and simple optical methods are available to estimate the settling behaviour of suspensions during experiments. However, for soil matrices such simple approaches may not be applicable. Alternatively, a Critical Body Residue approach may be taken in which body concentrations in organisms are related to effects, and toxicity thresholds derived. For microbial assays, the cell wall is a formidable barrier to MNMs and end points that rely on the test substance penetrating the cell may be insensitive. Instead assays based on the cell envelope should be developed for MNMs. In algal growth tests, the abiotic factors that promote particle aggregation in the media (e.g. ionic strength) are also important in providing nutrients, and manipulation of the media to control the dispersion may also inhibit growth. Controls to quantify shading effects, and precise details of lighting regimes, shaking or mixing should be reported in algal tests. Photosynthesis may be more sensitive than traditional growth end points for algae and plants. Tests with invertebrates should consider non-chemical toxicity from particle adherence to the organisms. The use of semi-static exposure methods with fish can reduce the logistical issues of waste water disposal and facilitate aspects of animal husbandry relevant to MMNs. There are concerns that the existing bioaccumulation tests are conceptually flawed for MNMs and that new test(s) are required. In vitro testing strategies, as exemplified by genotoxicity assays, can be modified for MNMs, but the risk of false negatives in some assays is highlighted. In conclusion, most protocols will require some modifications and recommendations are made to aid the researcher at the bench. PMID- 22422177 TI - Severity of leukoaraiosis in large vessel atherosclerotic disease. AB - BACKGROUND AND PURPOSE: The severity of white matter hyperintensity, or leukoaraiosis, is a marker of cerebrovascular disease. In stroke, WMH burden is strongly linked to lacunar infarction; however, impaired cerebral perfusion due to extracranial or intracranial atherosclerosis may also contribute to WMH burden. We sought to determine whether WMH burden is associated with extracranial or intracranial stenosis in patients with AIS. MATERIALS AND METHODS: Patients with AIS with admission head/neck CTA and brain MR imaging were included in this analysis. "Extracranial stenosis" was defined as >50% stenosis in the extracranial ICA, and "intracranial," as >50% stenosis in either the middle, anterior, or posterior cerebral arteries on CTA, on either side. WMHV was determined by using a validated semiautomated protocol. Multiple regression was used to assess the relationship between WMHV and extracranial/intracranial atherosclerosis. RESULTS: Of 201 subjects, 51 (25.4%) had extracranial and 63 (31.5%) had intracranial stenosis. Mean age was 62 +/- 15 years; 36% were women. Mean WMHV was 12.87 cm(3) in the extracranial and 8.59 cm(3) in the intracranial stenosis groups. In univariate analysis, age (P < .0001), SBP and DBP (P = .004), and HTN (P = .0003) were associated with WMHV. Extracranial stenosis was associated with greater WMHV after adjustment for intracranial stenosis (P = .04). In multivariate analysis including extracranial stenosis, only age (P < .0001) and HTN (P = .03) demonstrated independent effects on WMHV. CONCLUSIONS: In our cohort of patients with AIS, age and HTN were the strongest determinants of the WMHV severity. Future studies are warranted to unravel further association between WMHV and cerebral vessel atherosclerosis. PMID- 22422178 TI - Brain tissue oxygen monitoring to assess reperfusion after intra-arterial treatment of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a retrospective study. AB - BACKGROUND AND PURPOSE: Cerebral vasospasm resistant to medical management frequently requires intra-arterial spasmolysis. Angiographic resolution of vasospasm does not provide physiologic data on the adequacy of reperfusion. We recorded pre- and postspasmolysis PbO(2) data in the endovascular suite to determine whether this physiologic parameter could be used to determine when successful reperfusion was established. MATERIALS AND METHODS: Eight patients with 10 Licox monitors and cerebral vasospasm underwent intra-arterial spasmolysis. Pre- and postspasmolytic PbO(2) was recorded for comparison. Other physiologic parameters, such as CPP, ICP, SaO(2), and Fio(2), were also recorded. RESULTS: Mean prespasmolysis PbO(2) recordings were 35.2 and 27.3 for the mild-to moderate and moderate-to-severe vasospasm group, respectively. Mean postspasmolysis PbO(2) increased to 40.3 and 38.4, respectively, which was statistically significant (P < .05) for both groups. In 100% of instances in the moderate-to-severe group and 83% of instances in mild-to-moderate group, the mean PbO(2) increased after spasmolysis and correlated with improvement in angiographic vasospasm. Other physiologic parameters, such as CPP, ICP, SaO(2), and Fio(2), did not show any statistically significant difference before and after spasmolysis. CONCLUSIONS: PbO(2) monitoring provides the interventionalist with an objective physiologic parameter to determine adequate spasmolysis. Further investigation is needed to establish target PbO(2) rates indicative of adequate reperfusion, which can be used in the endovascular suite. PMID- 22422179 TI - Intravascular frequency-domain optical coherence tomography assessment of atherosclerosis and stent-vessel interactions in human carotid arteries. AB - BACKGROUND AND PURPOSE: Carotid artery-related stroke is largely an embolic disease that has been correlated with inflammation, plaque rupture, and thrombus formation in "vulnerable" atherosclerotic plaque. Nevertheless, current guidelines for carotid revascularization in asymptomatic patients rely on the calculation of stenosis for risk assessment, a parameter that has been viewed with increasing skepticism. Intravascular OCT is an imaging technique that offers high axial resolution (10 MUm), allowing an unprecedented micron-level assessment of human carotid plaque morphology. This observational article reports the first successful use of the newest iteration of this technology, FDOCT without balloon occlusion to assess human carotid artery disease and carotid stent-vessel interaction in vivo. MATERIALS AND METHODS: Four patients with asymptomatic carotid artery disease and ambiguous noninvasive and/or angiographic data underwent carotid FDOCT to assess risk and to formulate a treatment strategy. RESULTS: Findings include the unexpected demonstration of TCFAs, plaque rupture, thrombus, inflammation, and marked tissue prolapse through stent struts in patients without high-risk factors by conventional criteria, as well as low-risk features in a patient with a high-risk noninvasive study. The procedures were performed without safety issues or special accommodations for vessel occlusion. CONCLUSIONS: The present study demonstrates the technical feasibility of FDOCT in cervical carotid arteries. As such, this technology holds the promise of not only clarifying ambiguous data in individual patients but of providing data that might call for a future paradigm shift in the assessment of asymptomatic carotid artery disease. PMID- 22422180 TI - Review of 2 decades of aneurysm-recurrence literature, part 1: reducing recurrence after endovascular coiling. AB - SUMMARY: Angiographic recurrence following endovascular therapy is an indirect measure of the potential for hemorrhage. Because patients and physicians consider recurrence to be a suboptimal outcome with some chance of future hemorrhage, much effort has been expended to reduce the incidence of recurrence. The literature regarding aneurysm recurrence following endovascular therapy, spanning 2 decades, is extensive. We will review and summarize the effort to reduce recurrence following endovascular treatment of cerebral aneurysms. PMID- 22422181 TI - Differentiation of pyogenic brain abscesses from necrotic glioblastomas with use of susceptibility-weighted imaging. AB - BACKGROUND AND PURPOSE: A common imaging finding in brain abscess and necrotic glioblastoma is a T2 hypointense margin. The features of this hypointense rim on SWI have not been previously described, to our knowledge. We aimed to differentiate abscesses from glioblastomas by assessing the morphology of their lesion margin by using SWI. MATERIALS AND METHODS: T2WI and SWI were performed in 12 abscesses and 20 rim-enhancing glioblastomas. On T2WI and SWI, the prevalence and the border types (complete versus incomplete) of hypointense rims were qualitatively assessed. On SWI, the contour (smooth versus irregular) and the location of hypointense rims relative to the contrast-enhancing rims as well as the prevalence of the "dual rim sign," defined as 2 concentric rims at lesion margins with the outer one being hypointense and the inner one hyperintense relative to cavity contents, were also analyzed. RESULTS: Prevalence and the border types of the hypointense rims on T2WI were not different between abscesses and glioblastomas. On SWI, there were significantly more hypointense rims that were complete (P < .001) and smooth (P < .001), having the same location as the contrast-enhancing rims (P < .001) for abscesses. A dual rim sign was present in 9 of 12 abscesses but absent in all glioblastomas (P < .001). CONCLUSIONS: SWI may be helpful in differentiating pyogenic abscesses from necrotic glioblastomas. The dual rim sign is the most specific imaging feature distinguishing the 2. PMID- 22422182 TI - Review of 2 decades of aneurysm-recurrence literature, part 2: Managing recurrence after endovascular coiling. AB - Cerebral aneurysms are treated to prevent hemorrhage or rehemorrhage. Angiographic recurrences following endovascular therapy have been a problem since the advent of this treatment technique, even though posttreatment hemorrhage remains rare. Notwithstanding its unclear clinical significance, angiographic recurrence remains not only a prime focus in the literature but also frequently leads to potentially risky retreatments. The literature regarding aneurysm recurrence following endovascular therapy, spanning 2 decades, is immense and immensely confusing. We review the topic of recurrence following endovascular treatment of cerebral aneurysms in an effort to distill it down to fundamental material relevant to clinical practice. PMID- 22422183 TI - Correlation of perfusion parameters with genes related to angiogenesis regulation in glioblastoma: a feasibility study. AB - BACKGROUND AND PURPOSE: Integration of imaging and genomic data is critical for a better understanding of gliomas, particularly considering the increasing focus on the use of imaging biomarkers for patient survival and treatment response. The purpose of this study was to correlate CBV and PS measured by using PCT with the genes regulating angiogenesis in GBM. MATERIALS AND METHODS: Eighteen patients with WHO grade IV gliomas underwent pretreatment PCT and measurement of CBV and PS values from enhancing tumor. Tumor specimens were analyzed by TCGA by using Human Gene Expression Microarrays and were interrogated for correlation between CBV and PS estimates across the genome. We used the GO biologic process pathways for angiogenesis regulation to select genes of interest. RESULTS: We observed expression levels for 92 angiogenesis-associated genes (332 probes), 19 of which had significant correlation with PS and 9 of which had significant correlation with CBV (P < .05). Proangiogenic genes such as TNFRSF1A (PS = 0.53, P = .024), HIF1A (PS = 0.62, P = .0065), KDR (CBV = 0.60, P = .0084; PS = 0.59, P = .0097), TIE1 (CBV = 0.54, P = .022; PS = 0.49, P = .039), and TIE2/TEK (CBV = 0.58, P = .012) showed a significant positive correlation; whereas antiangiogenic genes such as VASH2 (PS = -0.72, P = .00011) showed a significant inverse correlation. CONCLUSIONS: Our findings are provocative, with some of the proangiogenic genes showing a positive correlation and some of the antiangiogenic genes showing an inverse correlation with tumor perfusion parameters, suggesting a molecular basis for these imaging biomarkers; however, this should be confirmed in a larger patient population. PMID- 22422184 TI - Unprotected carotid artery stenting in symptomatic patients with high-grade stenosis: results and long-term follow-up in a single-center experience. AB - BACKGROUND AND PURPOSE: The use of cerebral protection during CAS is an extended practice. Paradoxically it is open to question because it can lead to potential embolic complications. The aim of this study was to evaluate the safety and efficacy of CASWPD in patients with severe symptomatic carotid artery stenosis. MATERIALS AND METHODS: A prospective study was performed including 210 consecutive patients (201 symptomatic and 9 asymptomatic) with carotid artery stenosis >70%. All patients were treated by CASWPD. Angiographic results and neurologic complications were recorded during the procedure and within 30 days after it. All patients underwent clinical evaluation and Doppler sonography follow-up at 3, 6, and 12 months after the procedure. RESULTS: Two hundred twenty carotid arteries were treated. The average degree of stenosis was 88.9%. The procedure was successfully completed in 212 (96.4%) arteries. After stent placement, 98.6% of arteries showed no residual stenosis or <30%. Balloon angioplasty dilation before stent placement was performed in 16% of cases. During the 30-day periprocedural period, there were 3 major complications (1.4%), including 1 disabling ischemic stroke, 1 acute stent thrombosis, and 1 MI. The last 2 patients died from these complications. At 1-year follow-up 24 (12.8%) restenoses, 2 new ipsilateral strokes, 1 contralateral stroke, and 5 deaths (2.7%) had occurred. None of these deaths were related to the initial stroke. CONCLUSIONS: In our study, unprotected stent placement in symptomatic patients with severe carotid artery stenosis has demonstrated a low incidence of complications. We believe that this is due to the reduction of maneuvering and manipulation through the stenosis and to the protective effect of the stent placement before angioplasty balloon dilation. PMID- 22422185 TI - The benefits of beauty. PMID- 22422186 TI - Gray matter pathology in MS: a 3-year longitudinal study in a pediatric population. AB - BACKGROUND AND PURPOSE: GM pathology is considered a major determinant of disability in MS, but the comprehension of its origin and progression rate is limited by the uncertainty of dating the biologic disease onset. Thus, we planned a longitudinal study aimed at analyzing and comparing cortical pathology in pediatric and adult MS patients at clinical onset. MATERIALS AND METHODS: Within 12 months from clinical onset, 35 patients with cMS and 57 with aMS were included in a longitudinal study. At T0, GMf and CL number and volume were analyzed. Percentages of Delta-GMf and number of new CLs were assessed every year for 3 years (T1-T3). Twenty-eight age- and sex-matched NCs constituted the reference population. RESULTS: At T0, GMf did not differ between cMS and NC (P = .18), while it was lower in patients with aMS compared with both NCs (P < .001) and patients with cMS (P < .001). The number of patients with CLs, as well as CL number and volume, were higher in patients with aMS than in those with cMS (P < .001). At T3, Delta-GMf was higher in both patients with cMS (1.6% +/- 0.5%; range 0.7%-3.4%; P < .001) and aMS (1.6% +/- 0.6%; range 0.6%-3.4%; P < .001) compared with NCs (0.7% +/- 0.2%; range 0.4%-1.1%), whereas no difference was observed between patients with cMS and aMS (P = .93). Delta-GMf significantly correlated with increased CL volume (cMS: r = 0.46; aMS: r = 0.48) and with the appearance of new CLs (cMS: r = 0.51; aMS: r = 0.49). CONCLUSIONS: Our findings suggest that focal (CLs) and diffuse (atrophy) GM damage are strictly associated with the biologic onset of MS, and proceed linearly and partly independently of WM pathology. PMID- 22422187 TI - MR imaging of papilledema and visual pathways: effects of increased intracranial pressure and pathophysiologic mechanisms. AB - Papilledema, defined as swelling of the optic disc, frequently occurs in the setting of increased ICP and in a variety of medical conditions, including pseudotumor cerebri, sinus thrombosis, intracerebral hemorrhage, frontal lobe neoplasms, and Chiari malformation. Noninvasive imaging of the ON is possible by using MR imaging, with a variety of findings occurring in the setting of papilledema, including flattening of the posterior sclera, protrusion of the optic disc, widening of the ONS, and tortuosity of the ON. Early recognition of papilledema and elevated ICP is of paramount importance for ensuring restoration of vision. Newer advanced MR imaging techniques such as fMRI and DTI may prove useful in the future to assess the potential effects of papilledema on retinal and visual pathway integrity. PMID- 22422188 TI - Assessment of platelet inhibition by point-of-care testing in neuroendovascular procedures. AB - Antiplatelet agents are an important component of the preventive strategies currently used in clinical practice to minimize the risk of thromboembolic events during and after endovascular procedures. Because of the variability in the response to antiplatelet agents, measuring the degree of platelet inhibition may help identify and properly treat poor responders. POC testing is defined as diagnostic testing at or near the site of patient care. Knowledge of the specifics of these devices among practicing neurointerventionalists is relatively limited. In this article, the different POC devices available are presented, and their clinical utility in relation to endovascular procedures is discussed. PMID- 22422189 TI - Challenges of the anatomy and diffusion tensor tractography of the Meyer loop. AB - This review addresses the complex and often controversial anatomy of the anterior bundle of the OR, also known as the Meyer loop. Before the advent of MR imaging, 2 main types of studies attempted to ascertain the "safe" distance for anterior temporal lobe resection to avoid postsurgical VFDs. There were those based first on postoperative VFD correlation and second on anatomic dissection studies. In the past decade, noninvasive diffusion MR imaging-based tractography techniques have been developed in an attempt to elucidate white matter connectivity. Although many of these techniques are still experimental, there are some clinical situations for which they may prove to be very helpful if properly performed and validated. The motivation for this review was to improve the outcome of patients with TLE undergoing temporal lobectomy: Would having anatomic information about the OR available to the neurosurgeon decrease the risk of postsurgical VFDs? PMID- 22422190 TI - Multimodal imaging of reversible cerebral vasoconstriction syndrome: a series of 6 cases. AB - RCVS is a clinical condition of recurrent severe headaches that may be associated with ischemic or hemorrhagic stroke and that is defined by the presence of segmental vasoconstriction in multiple cerebral arteries. The angiographic appearance resembles vasculitis, except that the abnormalities resolve during the course of several months. Because the treatment of RCVS differs from that for vasculitis, radiologists must understand the clinical and radiologic features so as to better guide imaging algorithms and facilitate diagnosis. We present a series of 6 cases of RCVS that highlight the imaging features across multiple modalities. PMID- 22422191 TI - Prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes in Austria. AB - Mortality of cardiovascular diseases in patients with type 1 diabetes is increased 2- to 20-fold compared to non-diabetic individuals. In young adults with type 1 diabetes, cardiovascular events are more often the cause of premature death than nephropathy. The aim of this study was to evaluate the prevalence and extent of cardiovascular risk factors in children and adolescents with type 1 diabetes in Austria. In a cross sectional study data of children with type 1 diabetes <18 years of age treated at the Children's department of the University Hospitals of Vienna and Graz were collected. We recorded body mass index, waist circumference, blood pressure, HbA1c, triglycerides, total cholesterol, high density lipoprotein cholesterol and low-density lipoprotein cholesterol according to age, sex, age at manifestation, diabetes duration, and insulin requirement. From 264 patients (49.4% male) complete data were available. Of all patients, 76.1% had one or more risk factors, 20.8% had two or more, 10.2% had three or more, and 4.9% had four or more risk factors. Insufficient glycemic control was the most frequent risk factor, present in 60.6% of our patients, followed by elevated triglycerides (22.7%) and increased body mass index (20.1%). Higher prevalence of risk factors was correlated with increasing age, diabetes duration, HbA1c, and insulin requirement. In conclusion, children and adolescents with type 1 diabetes have a much higher prevalence of cardiovascular risk factors compared to non-diabetic individuals. To prevent future cardiovascular events, achieving the best possible glycemic control, early detection of further risk factors, and adequate intervention are highly important. PMID- 22422192 TI - Clinical practice : coeliac disease. AB - Coeliac disease (CD) is an immune-mediated systemic condition elicited by gluten and related prolamines in genetically predisposed individuals and characterised by gluten-induced symptoms and signs, specific antibodies, a specific human leukocyte antigen (HLA) type and enteropathy. The risk of coeliac disease is increased in first-degree relatives, certain syndromes including Down syndrome and autoimmune disorders. It is thought to occur in 1 in 100-200 individuals, but still only one in four cases is diagnosed. Small-bowel biopsy is no longer deemed necessary in a subgroup of patients, i.e. when all of the following are present: typical symptoms or signs, high titres of and transglutaminase antibodies, endomysial antibodies, and HLA-type DQ2 or DQ8. In all other cases, small-bowel biopsy remains mandatory for a correct diagnosis. Therapy consists of a strictly gluten-free diet. This should result in complete disappearance of symptoms and of serological markers. Adequate follow-up is considered essential. CONCLUSION: Although small-bowel biopsy may be omitted in a minority of patients, small-bowel biopsy is essential for a correct diagnosis of CD in all other cases. Diagnostic work-up should be completed before treatment with gluten-free diet instituted. PMID- 22422193 TI - Assigning Brassica microsatellite markers to the nine C-genome chromosomes using Brassica rapa var. trilocularis-B. oleracea var. alboglabra monosomic alien addition lines. AB - Brassica rapa var. trilocularis-B. oleracea var. alboglabra monosomic alien addition lines (MAALs) were used to assign simple sequence repeat (SSR) markers to the nine C-genome chromosomes. A total of 64 SSR markers specific to single C chromosomes were identified. The number of specific markers for each chromosome varied from two (C3) to ten (C4, C7 and C9), where the designation of the chromosomes was according to Cheng et al. (Genome 38:313-319, 1995). Seventeen additional SSRs, which were duplicated on 2-5 C-chromosomes, were also identified. Using the SSR markers assigned to the previously developed eight MAALs and recently obtained aneuploid plants, a new Brassica rapa-B. oleracea var. alboglabra MAAL carrying the alien chromosome C7 was identified and developed. The application of reported genetically mapped SSR markers on the nine MAALs contributed to the determination of the correspondence between numerical C genome cytological (Cheng et al. in Genome 38:313-319, 1995) and linkage group designations. This correspondence facilitates the integration of C-genome genetic information that has been generated based on the two designation systems and accordingly increases our knowledge about each chromosome. The present study is a significant contribution to genetic linkage analysis of SSR markers and important agronomic traits in B. oleracea and to the potential use of the MAALs in plant breeding. PMID- 22422194 TI - Synthesis of high-quality carbon nanodots from hydrophilic compounds: role of functional groups. AB - A simple one-pot hydrothermal approach has been demonstrated for the preparation of highly water soluble and photoluminescent carbon nanodots (C-dots) from low cost organic compounds. We found that the compounds incorporating amino and carboxylic acid groups are suitable for the preparation of highly photoluminescent and water-soluble C-dots. PMID- 22422195 TI - High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. AB - BACKGROUND: CX3CL1 is the only CX3C chemokine that can chemoattract T cells, natural killer (NK) cells, and dendritic cells (DCs). The role of CX3CL1 in breast carcinoma remains unknown. METHODS: Immunohistochemical staining for CX3CL1, CD8, CD57, and CD1a was performed on 204 breast carcinoma specimens using tissue microarray blocks to determine whether CX3CL1 expression correlated with a good prognosis and antitumor immunity. RESULTS: The number of stromal CD8+ T cells, intratumoral CD1a+ DCs, and stromal CD57+ NK cells were significantly increased in the high CX3CL1 expression group compared with those in the low CX3CL1expression group. Patients with high CX3CL1 expression had a significantly better disease-free and overall survival than those with low CX3CL1 expression (P=0.002 and P<0.001, respectively). CX3CL1 expression was identified as one of the independent prognostic factors for disease-free and overall survival (P=0.046 and P=0.010, respectively). CONCLUSION: The expression of CX3CL1 by tumor cells appears to enhance the recruitment of CD8+ T cells, CD57+ NK cells, and CD1a+ DCs, thereby bringing about a better prognosis in breast carcinoma. CX3CL1 is a new prognostic biomarker and may be a novel candidate for development of a more effective therapeutic strategy for breast carcinoma. PMID- 22422197 TI - The time-averaged inflammatory disease activity estimates the progression of erosions in MRI of the sacroiliac joints in ankylosing spondylitis. AB - A method to estimate the individual ankylosing spondylitis (AS) patient radiological progression of semi-quantitative magnetic resonance imaging (MRI) changes in the sacroiliac joints has not been described yet, which this study examines. Inflammatory disease activity and MRIs of the sacroiliac joints of 38 patients with recent onset established AS were analyzed at baseline and during follow-up. Sacroiliac MRIs were semi-quantitatively assessed using a modification of the "Spondylarthritis Research Consortium of Canada" (SPARCC) method. In each patient, the annual inflammatory disease activity was estimated by the time averaged C-reactive protein (CRP; mg/l), calculated as the area under the curve. The mean (SD) CRP decreased from 1.3 (1.8) at baseline to 0.5 (0.6) at follow-up MRI (p < 0.04), which has been performed after a mean (SD) disease course of 2.8 (1.5) years. The mean (SD) annual increase (?) of SPARCC score from baseline to follow-up MRI was 0.4 (0.4). Baseline individual SPARCC sub-score for bone marrow edema did not statistically significantly correlate with individual ?SPARCC sub score for erosions (p = N.S.). The individual AS patient correlation between annual time-averaged inflammatory disease activity and each annual ?SPARCC sub scores was only statistically significant for erosions (p < 0.01; r = 0.71). Our results show that bone marrow edema and contrast-medium enhancement at baseline do not relate to the progression of erosions but the calculation of the individual patient annual time-averaged inflammatory disease activity allows to estimate the annual progression of erosions in sacroiliac MRIs of patients with AS. PMID- 22422196 TI - Risk of hip fracture with hip or knee osteoarthritis: a systematic review. AB - Osteoarthritis (OA) and hip fracture are two common musculoskeletal disorders associated with substantial societal and personal burden. The objective of this systematic review was to determine the association between hip or knee OA and risk of hip fractures in people aged 45 years and older as compared to people aged 45 years and older who do not have OA. We searched CINAHL, Cochrane Database of Systematic Reviews, Embase, OVID Medline, PUBMED, and SCOPUS for studies published up to July 2010 and conducted forward searches of included studies using Web of Science. Two reviewers independently screened articles for inclusion, extracted data, and evaluated the risk of bias of included studies using the Newcastle-Ottawa Scale. Eleven articles were included. Three investigated individuals with knee OA, two included adults with knee or hip OA, and six investigated adults with hip OA. We did not combine the hip OA or the knee OA studies in a meta-analysis due to the heterogeneity in: study populations and covariates adjusted for in estimates of association. Hip OA may be related to a decreased risk of hip fracture when considering crude estimates of association or estimates of association adjusted for a limited number of covariates, although not all studies found support for the presence of this association. The association between knee OA and hip fracture remains unclear. The presence of OA in the hip or knee should not act as an indication that assessment for hip fracture risk is unnecessary. PMID- 22422198 TI - Electroplated porous polypyrrole nanostructures patterned by colloidal lithography for drug-delivery applications. AB - Porous nanostructures of polypyrrole (Ppy) were fabricated using colloidal lithography and electrochemical techniques for potential applications in drug delivery. A sequential fabrication method was developed and optimized to maximize the coverage of the Ppy nanostructures and to obtain a homogeneous layer over the substrate. This was realized by masking with electrophoretically-assembled polystyrene (PS) nanospheres and then electroplating. Drug/biomolecule adsorption and the release characteristics for the porous nanostructures of Ppy were investigated using rhodamine B (Rh-B). Rh-B is an easily detectable small hydrophobic molecule that is used as a model for many drugs or biological substances. The porous Ppy nanostructures with an enhanced surface area exhibited higher Rh-B loading capacity than bulk planar films of Ppy. Moreover, tunability of surface morphology for further applications (e.g., sensing, cell adhesion) was demonstrated. PMID- 22422199 TI - The clinical significance of serum soluble Fas and p53 protein in breast cancer patients: comparison with serum CA 15-3. AB - Serum sFas and p53 protein have been observed in breast cancer patients, but their clinical usefulness for diagnosis and therapy monitoring has not been clarified. The aim of this study was to compare the clinical utility of serum sFas and p53 protein with that of serum CA 15-3 as the most commonly used breast cancer tumor marker. Serum samples were taken from 35 normal healthy controls and 35 breast cancer patients before surgery, after 2 weeks of surgery and after six cycles of FAC chemotherapy. Serum sFas and p53 protein levels were measured using ELISA kits. Serum CA 15-3 levels were determined using IRMA kit. Mean Serum levels of sFas and CA 15-3 were significantly elevated while p53 protein was significantly declined in breast cancer patients than controls. Serum p53 protein showed the greatest significant area under the ROC curve (84.3%) followed by sFas (80.5%), then CA 15-3 (78%). The sensitivity, specificity and cut-off value for diagnosing breast cancer patients were 84.2%, 82.6% and 2.88 U/ml for p53 protein, 83.3%, 68.2% and 497.3 pg/ml for sFas and 45.8%, 100% and 23 U/ml for CA15-3. Surgical removal of breast resulted in a significant decline in serum sFas level with no effect on serum p53 protein and CA 15-3 levels. Six cycles of chemotherapy resulted in a significant elevation in serum sFas level with no effect on serum p53 protein and CA 15-3 levels. sFas was significantly correlated with tumor grade. It could be concluded that although serum p53 protein is superior to sFas and CA15-3 for diagnosis of breast cancer patients, only sFas is useful for monitoring the response of breast cancer patients to surgery and chemotherapy if the effect of systemic inflammatory reactions is excluded. PMID- 22422201 TI - Inherited leukoencephalopathies. PMID- 22422202 TI - Biogenesis and significance of central nervous system myelin. AB - The central nervous system is composed of neurons and glia cells. Although neurons have long been considered the functionally important cells, an ever expanding body of research has revealed many critical functions of neuroglia. Among these, the myelin sheath elaborated by oligodendrocytes acts as a dynamic partner to the axons it enwraps and can no longer be considered as an inert membrane. In addition to its best known roles of providing insulation and optimizing conduction velocity, myelination modulates the maturation, survival, and regenerative capacity of axons through trophic support and signaling molecules. Myelin is produced through a complex process involving cell differentiation, biosynthesis of specialized lipids and proteins, interaction with environmental signals, and coordinated changes in cell morphology. Understanding the pathophysiology of primary myelin disorders, and the challenges faced in treating them, is facilitated through understanding of the structure, function, and generation/regeneration of myelin. PMID- 22422203 TI - Assessment of normal myelination with magnetic resonance imaging. AB - White matter myelination is essential to postnatal neurologic maturation and can be accurately evaluated by magnetic resonance imaging (MRI). Accordingly, MRI pulse sequences should be optimized for detection of myelin in young children. T1 weighted images are most useful during the first year of life. These demonstrate myelin-related white matter hyperintensity consequent to increasing cholesterol and galactocerebroside within myelin membranes. T2-weighted images are most useful in later stages of myelination, during which time elaboration of myelin leads to reduction in brain water content with associated T2 hypointensity. Additional information regarding the status of myelination can be obtained from T2-weighted fluid attenuation inversion recovery (FLAIR) and diffusion tensor imaging (DTI) pulse sequences. Clinically useful milestones for assessment of myelination across all these MRI pulse sequences are available as guidelines to image interpretation. Evaluation of myelination status using a combination of T1- and T2-weighted images should be routine in the interpretation of all pediatric brain MRI exams. PMID- 22422204 TI - Leukoencephalopathies associated with macrocephaly. AB - Macrocephaly, enlarged head size, can be seen in a wide range of conditions including hydrocephalus and genetic syndromes. Benign familial macrocephaly may be seen in multiple generations and is not associated with neurologic concerns. When macrocephaly is seen in conjunction with abnormal white matter on neuroimaging, specific genetic leukoencephalopathies should be considered, including Alexander's disease, Canavan's disease, childhood ataxia with central hypomyelination/ vanishing white matter disease (CACH/VWMD), glutaric aciduria type I, L2-hydroxyglutaric aciduria, and megalencephalic leukoencephalopathy with subcortical cysts (MLC). PMID- 22422205 TI - Peroxisomal leukoencephalopathy. AB - Peroxisomal leukoencephalopathies include diseases belonging to the Zellweger spectrum and the rhizomelic chondrodysplasia punctata spectrum, as well as some single enzyme defects of peroxisomal beta-oxidation. The authors present information on the clinical and diagnostic approach, and the characteristics of brain magnetic resonance imaging (MRI) in these diseases. MRIs of patients belonging to the Zellweger spectrum may show developmental anomalies and regressive changes consisting of abnormal cerebral white matter. Involvement of the central white matter of the cerebellar hemispheres is frequently seen. The leukoencephalopathy is progressive, with or without peripheral nerve involvement, in patients with a prolonged course of the disease. MRI characteristics in the severe phenotype of rhizomelic chondrodysplasia punctata include supratentorial white matter abnormalities, with a parietooccipital predominance. Demyelinative lesions are the hallmark of the cerebral form of X-linked adrenoleukodystrophy and may appear in a similar way in patients with adrenomyeloneuropathy progressing to a cerebral form. The diagnosis of a peroxisomal disorder can be determined by a battery of biochemical assays in blood and/or urine, and should be confirmed in cultured fibroblasts and DNA analysis. Treatment of the peroxisomal leukoencephalopathies is largely symptomatic, except for boys affected by the cerebral form of X-linked adrenoleukodystrophy in whom a bone marrow/hematopoietic stem cell transplant can be lifesaving, at least in the early stages of the disease. PMID- 22422206 TI - Lysosomal disorders associated with leukoencephalopathy. AB - Metachromatic leukodystrophy and Krabbe's disease are among the most widely recognized causes of leukodystrophy. However, white matter changes have been described in several other lysosomal storage disorders. These conditions are summarized and those associated with hypomyelination are reviewed in more detail. PMID- 22422207 TI - Mitochondrial syndromes with leukoencephalopathies. AB - White matter involvement has recently been recognized as a common feature in patients with multisystem mitochondrial disorders that may be caused by molecular defects in either the mitochondrial genome or the nuclear genes. It was first realized in classical mitochondrial syndromes associated with mitochondrial DNA (mtDNA) mutations, such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Leigh's disease, and Kearns-Sayre's syndrome. Deficiencies in respiratory chain complexes I, II, IV, and V often cause Leigh's disease; most of them are due to nuclear defects that may lead to severe early onset leukoencephalopathies. Defects in a group of nuclear genes involved in the maintenance of mtDNA integrity may also affect the white matter; for example, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) caused by thymidine phosphorylase deficiency, Navajo neurohepatopathy (NNH) due to MPV17 mutations, and Alpers syndrome due to defects in DNA polymerase gamma (POLG). More recently, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) has been reported to be caused by autosomal recessive mutations in a mitochondrial aspartyl-tRNA synthetase, DARS2 gene. A patient with leukoencephalopathy and neurologic complications in addition to a multisystem involvement warrants a complete evaluation for mitochondrial disorders. A definite diagnosis may be achieved by molecular analysis of candidate genes based on the biochemical, clinical, and imaging results. PMID- 22422208 TI - Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders. AB - The purpose of this article is to present contemporary information on the clinical and molecular diagnosis and the treatment of Pelizaeus-Merzbacher's disease (PMD) and related leukodystrophies. Various types of mutations of the X linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. A diffuse pattern of hypomyelination is seen on magnetic resonance imaging (MRI) of PMD/SPG2 patients. A similar constellation of signs and pattern of hypomyelination lead to the autosomal recessive disease called Pelizaeus-Merzbacher-like disease 1 (PMLD1) and the less severe spastic paraplegia 44 (SPG44), caused by mutations of the gap junction protein, gamma-2 gene (GJC2), formerly known as the gap junction protein, alpha 12 gene (GJA12). Magnetic resonance spectroscopy (MRS) and brainstem auditory evoked potentials (BAEP) may assist with differential clinical diagnosis of PMD and PMLD1. Supportive therapy for patients with PMD/SPG2 and PMLD1/SPG44 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices. PMID- 22422209 TI - Leukoencephalopathies associated with disorders of cobalamin and folate metabolism. AB - Disorders of cobalamin and folate intracellular metabolism that result in defective remethylation of homocysteine to methionine are associated with leukodystrophy, whereas disorders of cobalamin transport generally are not. Cobalamin derivatives are needed for only two reactions in man; remethylation of homocysteine to methionine, with methylcobalamin as a cofactor for methionine synthase, and the conversion of methylmalonyl-coenzyme A to succinyl coenzyme A by methylmalonyl-CoA mutase, with adenosylcobalamin as a cofactor. Mutations at various metabolic steps affect the synthesis of adenosylcobalamin (CblA, CblB, and CblD2), methylcobalamin (CblE, CblG, and CblD1), or both of these (CblF, CblD, and CblC). The most common disorder of folate metabolism, 5,10 methylenetetrahydrofolate deficiency, also affects remethylation and presents with leukodystrophy. Pathways of cobalamin and folate metabolism intersect at one site, methionine synthase. Patients with the remethylating disorders present acutely or chronically with significant neurologic, hematologic, vascular, and other symptoms. Circulating levels of cobalamin and folate are usually normal in these disorders, and initial diagnosis is aided by measurement of homocysteine and methylmalonic acid in blood or urine, together with hematologic tests. Current diagnosis is often by newborn screening. These disorders all show autosomal recessive inheritance, and all are treatable, although with variable outcome. PMID- 22422210 TI - Recognition and diagnosis of neuro-ichthyotic syndromes. AB - The combination of neurologic disease and ichthyosis defines a heterogeneous group of rare inherited disorders that present in infancy through early adulthood. Although affected patients share the cutaneous feature of ichthyosis, there is variability in the nature and severity of neurologic disease. Impaired cognition, spasticity, sensorineural deafness, visual impairment, and/or seizures are the primary neurologic findings. Most of these disorders are caused by genetic defects in lipid metabolism, glycoprotein synthesis, or intracellular vesicle trafficking. The clinical features of some of the neuro-ichthyoses are distinct enough to allow their clinical recognition, but confirmatory biochemical or genetic tests are necessary for accurate diagnosis. Treatment of the ichthyosis is largely symptomatic, and except for Refsum's disease, there are no effective pathogenesis-based therapies for the neurologic disease. PMID- 22422211 TI - Leukoencephalopathies in adulthood. AB - The understanding of the genetic basis of late-onset leukoencephalopathies has continued to increase in recent years. The most commonly presenting leukoencephalopathies in adulthood can be late-onset manifestations of metabolic pathways. The understanding of these diagnoses is crucial to the evaluation of adult patients presenting with leukoencephalopathies. The authors provide an overview of the common leukoencephalopathies in adulthood, the current understanding of the pathology, and genetics of these disorders with typical imaging findings. When available, treatment options will be discussed. PMID- 22422212 TI - A new method of accurate hand- and arm-tracking for small primates. AB - The investigation of grasping movements in cortical motor areas depends heavily on the measurement of hand kinematics. Currently used methods for small primates need either a large number of sensors or provide insufficient accuracy. Here, we present both a novel glove based on electromagnetic tracking sensors that can operate at a rate of 100 Hz and a new modeling method that allows to monitor 27 degrees of freedom (DOF) of the hand and arm using only seven sensors. A rhesus macaque was trained to wear the glove while performing precision and power grips during a delayed grasping task in the dark without noticeable hindrance. During five recording sessions all 27 joint angles and their positions could be tracked reliably. Furthermore, the field generator did not interfere with electrophysiological recordings below 1 kHz and did not affect single-cell separation. Measurements with the glove proved to be accurate during static and dynamic testing (mean absolute error below 2 degrees and 3 degrees , respectively). This makes the glove a suitable solution for characterizing electrophysiological signals with respect to hand grasping and in particular for brain-machine interface applications. PMID- 22422213 TI - Phosphorus sorption-desorption behaviour of river bed sediments in the Abshineh river, Hamedan, Iran, related to their composition. AB - Phosphorus (P) sorption by sediments may play a vital role in buffering P concentration in the overlying water column. To characterize P sorption desorption in the river bed sediments, 17 bed sediment samples collected from Abshineh river, in a semi arid region, Hamedan, western Iran were studied through a batch experiment and related to sediment composition. The sorbed fraction ranged from 4.4% to 5.4% and from 38.5% to 86.0% of sorption maxima when 20 and 1,500 mg P kg(-1), respectively, was added to the sediment samples. Phosphorus sorption curves were well fitted to the Langmuir model. Zero equilibrium P concentration ranged from 0.10 to 0.51 mg P l(-1) and varied with sediment characteristics. Phosphorus desorption differed strongly among the studied bed sediments and ranged from 10.8% to 80.2% when 1,500 mg P kg(-1) was added. The results of the geochemical modelling indicated that even under low P addition (2 mg l(-1)), the solutions are mainly saturated with respect to hydroxyapatite and beta-tricalcium phosphate minerals and undersaturated with respect to other Ca and Mg minerals, whereas under higher P addition (150 mg l(-1)), most Ca-P solid phases, except the most soluble mineral (brushite), will likely precipitate. A Langmuir sorption maximum was positively correlated with carbonate calcium. Estimated P retention capacity of the bed sediments are generally lower and zero equilibrium P concentration values higher in upstream sites than at the downstream sites, suggesting that sediments in upstream and downstream may act as source and sink of P, respectively. PMID- 22422214 TI - Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroaryl bromides. AB - A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer. PMID- 22422215 TI - Conformational relaxation dynamics of a poly(N-isopropylacrylamide) aqueous solution measured using the laser temperature jump transient grating method. AB - We observed phase transition and phase relaxation processes of a poly(N isopropylacrylamide) (PNIPAM) aqueous solution using the heterodyne transient grating (HD-TG) method combined with the laser temperature jump technique. The sample temperature was instantaneously raised by about 1.0 K after irradiation of a pump pulse to crystal violet (CV) molecules for heating, and the phase transition was induced for the sample with an initial temperature just below the lower critical solution temperature (LCST); the following phase relaxation dynamics was observed. Turbidity relaxation was observed in both the turbidity and HD-TG responses, while another relaxation process was observed only in the HD TG response, namely via the refractive index change. It is suggested that this response is due to formation of globule molecules or their assemblies since they would have nothing to do with turbidity change but would affect the refractive index, which is dependent on the molar volume of a chemical species. Furthermore, the grating spacing dependence of the HD-TG responses suggests that the response was caused by the counter propagating diffusion of the coil molecules as a reactant species and the globule molecules as a product species and the lifetime of the globule molecules ranged from 1.5 to 5 seconds. Thus, we conclude that the turbidity reflects the dynamics of aggregate conditions, not molecular conditions. The coil and globule sizes were estimated from the obtained diffusion coefficient. The sizes of the coil molecules did not change at the initial temperatures below the LCST but increased sharply as it approaches LCST. We propose that the coil-state molecules associate due to hydrophobic interaction when the initial temperature was higher than LCST minus 0.5 K and that the globule-state molecules generated from the coil-state molecules showed a similar trend in temperature. The phase transition was also induced by heating under a microscope, and the relaxation process was followed using the fluorescence peak shift of a fluorescent molecule-labeled PNIPAM. The result also supports the existence of a globule molecule or its assembly remains for several seconds in the phase relaxation. PMID- 22422216 TI - About the manuscript Arica et al. PMID- 22422217 TI - Characterization of a microfluidic in vitro model of the blood-brain barrier (MUBBB). AB - The blood-brain barrier (BBB), a unique selective barrier for the central nervous system (CNS), hinders the passage of most compounds to the CNS, complicating drug development. Innovative in vitro models of the BBB can provide useful insights into its role in CNS disease progression and drug delivery. Static transwell models lack fluidic shear stress, while the conventional dynamic in vitro BBB lacks a thin dual cell layer interface. To address both limitations, we developed a microfluidic blood-brain barrier (MUBBB) which closely mimics the in vivo BBB with a dynamic environment and a comparatively thin culture membrane (10 MUm). To test validity of the fabricated BBB model, MUBBBs were cultured with b.End3 endothelial cells, both with and without co-cultured C8-D1A astrocytes, and their key properties were tested with optical imaging, trans-endothelial electrical resistance (TEER), and permeability assays. The resultant imaging of ZO-1 revealed clearly expressed tight junctions in b.End3 cells, Live/Dead assays indicated high cell viability, and astrocytic morphology of C8-D1A cells were confirmed by ESEM and GFAP immunostains. By day 3 of endothelial culture, TEER levels typically exceeded 250 Omega cm(2) in MUBBB co-cultures, and 25 Omega cm(2) for transwell co-cultures. Instantaneous transient drop in TEER in response to histamine exposure was observed in real-time, followed by recovery, implying stability of the fabricated MUBBB model. Resultant permeability coefficients were comparable to previous BBB models, and were significantly increased at higher pH (>10). These results demonstrate that the developed MUBBB system is a valid model for some studies of BBB function and drug delivery. PMID- 22422218 TI - A systematic review of clinical studies on hereditary factors in pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: There is growing evidence that pelvic organ prolapse (POP) is at least partly caused by underlying hereditary risk factors. The aim of our study was to provide a systematic literature review and meta-analysis of clinical studies on family history of POP as a risk factor for POP in individual women. METHODS: The databases PubMed and Embase were searched. Clinical studies reporting on family history of POP in relation to POP in individual women were included. RESULTS: Sixteen studies were included, of which eight enabled us to calculate a pooled odds ratio (OR). The pooled OR of POP in case of a positive family history of POP was 2.58 (95 % confidence interval 2.12-3.15). CONCLUSIONS: Women with POP are substantially more likely to have family members with the same condition compared to women without POP. This strengthens the hypothesis that genetic predisposition plays an important role in the development of POP. PMID- 22422219 TI - The role of serum C-reactive protein in women with lower urinary tract symptoms. AB - INTRODUCTION AND HYPOTHESIS: Some lower urinary tract dysfunction (LUTD) subtypes may be associated with low-grade inflammation. This study aimed to investigate the role of serum C-reactive protein (CRP) levels in women with lower urinary tract symptoms (LUTS). METHODS: A total of 197 consecutive women with non-stress urinary incontinence (non-SUI) LUTS and 18 healthy women without LUTS (normal controls) were enrolled. LUTS include urinary storage, voiding, and post micturition symptoms. Patients with previous bladder or urethral surgery, active urinary tract infections, or possible neurogenic lesions were excluded. Serum CRP levels were measured before any treatment was given. Patients were stratified to LUTD subgroups based on a 3-day voiding diary, uroflowmetry, and selective videourodynamic studies. RESULTS: Median CRP levels were significantly higher in women with overactive bladder (OAB) wet (i.e., with urgency incontinence, n = 30, 0.12 mg/dl) than those in women with bladder oversensitivity (n = 68, 0.075 mg/dl, P = 0.008) and the control group (0.055 mg/dl, P = 0.032). Further analysis revealed that body mass index and maximum flow rate were two independent factors that affected CRP levels. The area under the receiver-operating characteristic curve for using CRP to predict OAB wet was 0.55, and the most predictive cutoff point for CRP was 0.15 mg/dl (sensitivity 43.5 %, specificity 72.7 %). CONCLUSIONS: High serum CRP levels were found in women with OAB wet, and they were related to lower maximum urinary flow rates and higher body mass indices in non-SUI LUTD. However, serum CRP is not a suitable biomarker for discriminating between subtypes of non-SUI LUTD. PMID- 22422220 TI - A Russian renaissance? PMID- 22422221 TI - The shared burden. PMID- 22422222 TI - Final say. PMID- 22422223 TI - Two nations divided by a common purpose. PMID- 22422235 TI - Putin promises science boost. PMID- 22422237 TI - Spacecraft aims to expose violent hearts of galaxies. PMID- 22422236 TI - Forecasters look back in time. PMID- 22422238 TI - Water under pressure. PMID- 22422239 TI - China's budget backs science. PMID- 22422240 TI - Japan fails to settle University dispute. PMID- 22422242 TI - The split brain: a tale of two halves. PMID- 22422243 TI - Plant biotechnology: make it a decaf. PMID- 22422244 TI - Drug research: plug the real brain drain. PMID- 22422245 TI - Drug research: a plan for mental illness. PMID- 22422250 TI - Turing: beyond the original concept. PMID- 22422251 TI - Alcohol control: be sparing with international laws. PMID- 22422252 TI - Turing: brain model still incomplete. PMID- 22422253 TI - Animal models: ads against chimp research criticized. PMID- 22422254 TI - Turing: Colossus computer revisited. PMID- 22422255 TI - Organic chemistry: catalysis in tight spaces. PMID- 22422256 TI - Electronics: inside story of ferroelectric memories. PMID- 22422257 TI - Developmental biology: a brainy background. PMID- 22422258 TI - Genetics: broken giant linked to heart failure. PMID- 22422259 TI - Condensed-matter physics: a duo of graphene mimics. PMID- 22422260 TI - Biochemistry: favouring the unfavoured. PMID- 22422261 TI - Gene expression: transcription initiation unwrapped. PMID- 22422262 TI - Ancient deuterostome origins of vertebrate brain signalling centres. AB - Neuroectodermal signalling centres induce and pattern many novel vertebrate brain structures but are absent, or divergent, in invertebrate chordates. This has led to the idea that signalling-centre genetic programs were first assembled in stem vertebrates and potentially drove morphological innovations of the brain. However, this scenario presumes that extant cephalochordates accurately represent ancestral chordate characters, which has not been tested using close chordate outgroups. Here we report that genetic programs homologous to three vertebrate signalling centres-the anterior neural ridge, zona limitans intrathalamica and isthmic organizer-are present in the hemichordate Saccoglossus kowalevskii. Fgf8/17/18 (a single gene homologous to vertebrate Fgf8, Fgf17 and Fgf18), sfrp1/5, hh and wnt1 are expressed in vertebrate-like arrangements in hemichordate ectoderm, and homologous genetic mechanisms regulate ectodermal patterning in both animals. We propose that these genetic programs were components of an unexpectedly complex, ancient genetic regulatory scaffold for deuterostome body patterning that degenerated in amphioxus and ascidians, but was retained to pattern divergent structures in hemichordates and vertebrates. PMID- 22422263 TI - Creating, moving and merging Dirac points with a Fermi gas in a tunable honeycomb lattice. AB - Dirac points are central to many phenomena in condensed-matter physics, from massless electrons in graphene to the emergence of conducting edge states in topological insulators. At a Dirac point, two energy bands intersect linearly and the electrons behave as relativistic Dirac fermions. In solids, the rigid structure of the material determines the mass and velocity of the electrons, as well as their interactions. A different, highly flexible means of studying condensed-matter phenomena is to create model systems using ultracold atoms trapped in the periodic potential of interfering laser beams. Here we report the creation of Dirac points with adjustable properties in a tunable honeycomb optical lattice. Using momentum-resolved interband transitions, we observe a minimum bandgap inside the Brillouin zone at the positions of the two Dirac points. We exploit the unique tunability of our lattice potential to adjust the effective mass of the Dirac fermions by breaking inversion symmetry. Moreover, changing the lattice anisotropy allows us to change the positions of the Dirac points inside the Brillouin zone. When the anisotropy exceeds a critical limit, the two Dirac points merge and annihilate each other-a situation that has recently attracted considerable theoretical interest but that is extremely challenging to observe in solids. We map out this topological transition in lattice parameter space and find excellent agreement with ab initio calculations. Our results not only pave the way to model materials in which the topology of the band structure is crucial, but also provide an avenue to exploring many-body phases resulting from the interplay of complex lattice geometries with interactions. PMID- 22422264 TI - Designer Dirac fermions and topological phases in molecular graphene. AB - The observation of massless Dirac fermions in monolayer graphene has generated a new area of science and technology seeking to harness charge carriers that behave relativistically within solid-state materials. Both massless and massive Dirac fermions have been studied and proposed in a growing class of Dirac materials that includes bilayer graphene, surface states of topological insulators and iron based high-temperature superconductors. Because the accessibility of this physics is predicated on the synthesis of new materials, the quest for Dirac quasi particles has expanded to artificial systems such as lattices comprising ultracold atoms. Here we report the emergence of Dirac fermions in a fully tunable condensed-matter system-molecular graphene-assembled by atomic manipulation of carbon monoxide molecules over a conventional two-dimensional electron system at a copper surface. Using low-temperature scanning tunnelling microscopy and spectroscopy, we embed the symmetries underlying the two dimensional Dirac equation into electron lattices, and then visualize and shape the resulting ground states. These experiments show the existence within the system of linearly dispersing, massless quasi-particles accompanied by a density of states characteristic of graphene. We then tune the quantum tunnelling between lattice sites locally to adjust the phase accrual of propagating electrons. Spatial texturing of lattice distortions produces atomically sharp p-n and p-n-p junction devices with two-dimensional control of Dirac fermion density and the power to endow Dirac particles with mass. Moreover, we apply scalar and vector potentials locally and globally to engender topologically distinct ground states and, ultimately, embedded gauge fields, wherein Dirac electrons react to 'pseudo' electric and magnetic fields present in their reference frame but absent from the laboratory frame. We demonstrate that Landau levels created by these gauge fields can be taken to the relativistic magnetic quantum limit, which has so far been inaccessible in natural graphene. Molecular graphene provides a versatile means of synthesizing exotic topological electronic phases in condensed matter using tailored nanostructures. PMID- 22422265 TI - DNA-based self-assembly of chiral plasmonic nanostructures with tailored optical response. AB - Matter structured on a length scale comparable to or smaller than the wavelength of light can exhibit unusual optical properties. Particularly promising components for such materials are metal nanostructures, where structural alterations provide a straightforward means of tailoring their surface plasmon resonances and hence their interaction with light. But the top-down fabrication of plasmonic materials with controlled optical responses in the visible spectral range remains challenging, because lithographic methods are limited in resolution and in their ability to generate genuinely three-dimensional architectures. Molecular self-assembly provides an alternative bottom-up fabrication route not restricted by these limitations, and DNA- and peptide-directed assembly have proved to be viable methods for the controlled arrangement of metal nanoparticles in complex and also chiral geometries. Here we show that DNA origami enables the high-yield production of plasmonic structures that contain nanoparticles arranged in nanometre-scale helices. We find, in agreement with theoretical predictions, that the structures in solution exhibit defined circular dichroism and optical rotatory dispersion effects at visible wavelengths that originate from the collective plasmon-plasmon interactions of the nanoparticles positioned with an accuracy better than two nanometres. Circular dichroism effects in the visible part of the spectrum have been achieved by exploiting the chiral morphology of organic molecules and the plasmonic properties of nanoparticles, or even without precise control over the spatial configuration of the nanoparticles. In contrast, the optical response of our nanoparticle assemblies is rationally designed and tunable in handedness, colour and intensity-in accordance with our theoretical model. PMID- 22422266 TI - Asymmetric spiroacetalization catalysed by confined Bronsted acids. AB - Acetals are molecular substructures that contain two oxygen-carbon single bonds at the same carbon atom, and are used in cells to construct carbohydrates and numerous other molecules. A distinctive subgroup are spiroacetals, acetals joining two rings, which occur in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles. Despite numerous methods for the catalytic asymmetric formation of other commonly occurring stereocentres, there are few approaches that exclusively target the chiral acetal centre and none for spiroacetals. Here we report the design and synthesis of confined Bronsted acids based on a C(2)-symmetric imidodiphosphoric acid motif, enabling a catalytic enantioselective spiroacetalization reaction. These rationally constructed Bronsted acids possess an extremely sterically demanding chiral microenvironment, with a single catalytically relevant and geometrically constrained bifunctional active site. Our catalyst design is expected to be of broad utility in catalytic asymmetric reactions involving small and structurally or functionally unbiased substrates. PMID- 22422269 TI - Low radiation dose non-contrast cardiac CT: is it of value in the evaluation of mechanical aortic valve. AB - BACKGROUND: Prosthetic bileaflet mechanical valve function has been traditionally evaluated using echocardiography and fluoroscopy. Multidetector computed tomography (MDCT) is a novel technique for cardiac evaluation. PURPOSE: To evaluate bileaflet mechanical aortic valves using a low-milliampere (mA), non contrast MDCT protocol with a limited scan range. MATERIAL AND METHODS: Forty patients with a bileaflet mechanical aortic valve were evaluated using a non contrast, low-mA, ECG-gated 64 MDCT protocol with a limited scan range. MDCT findings of opening and closing valve angles were correlated to fluoroscopy and echocardiography. Also, the valve visibility was evaluated on MDCT and fluoroscopy according to a 3-point grading scale. RESULTS: The visualization score with the MDCT was significantly superior to the fluoroscopy (3 vs. 2.7). A strong correlation was noted between the opening (r = 0.82) and closing (r = 0.96) valve angles with MDCT and fluoroscopy without a statistically significant difference (P = 0.31 and 0.16, respectively). The mean effective radiation dose of the suggested protocol was 4 +/- 0.5 mSv. Five valves were evaluated using transesophageal echocardiography because the valves were difficult to evaluate with transthoracic echocardiography, and all of these valves were evaluated optimally with MDCT. A high-pressure gradient was noted in nine valves, and the MDCT showed that seven of these valves inadequately opened, and two valves opened well, which resulted in patient valve mismatch. Incomplete valve closure was noted in five valves, and the echocardiography showed significant transvalvular regurgitation in all five valves. CONCLUSION: MDCT can provide a precise measurement of valve function and can potentially evaluate high-pressure gradients and transvalvular regurgitation. PMID- 22422267 TI - Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. AB - The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens. Understanding how pathogen specific immunity is elicited while avoiding inappropriate responses to the background of innocuous antigens is essential for understanding and treating intestinal infections and inflammatory diseases. The ingestion of protein antigen can induce oral tolerance, which is mediated in part by a subset of intestinal dendritic cells (DCs) that promote the development of regulatory T cells. The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c(+) CD11b(+) MHCII(+) cells) comprised of two predominant subsets: CD103(+) CX(3)CR1(-) DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells, and CD103(-) CX(3)CR1(+) DCs (with features of macrophages), which promote tumour necrosis factor-alpha (TNF-alpha) production, colitis, and the development of T(H)17 T cells. However, the mechanisms by which different intestinal LP-DC subsets capture luminal antigens in vivo remains largely unexplored. Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103(+) LP-DCs. The preferential delivery of antigens to DCs with tolerogenic properties implies a key role for this GC function in intestinal immune homeostasis. PMID- 22422270 TI - T2* relaxometry mapping of the uterine zones. AB - BACKGROUND: Previous literature demonstrated that the T2* value of the uterine junctional zone was lower than that of peripheral myometrium by using BOLD MR imaging. We expect T2* mapping image may add more information to T2-weighted images of the uterine myometrium. PURPOSE: To evaluate whether T2* mapping software would reproduce the result of previous report, and to apply the software to benign uterine diseases. MATERIAL AND METHODS: Five healthy volunteers and 19 patients clinically suspected of having benign pelvic disease were imaged using a 1.5T MR system. All women were of reproductive age, and all provided informed consent. Sagittal T2* images using a multishot EPI sequence were obtained. T2* values were calculated and color T2* maps reconstructed using a T2* fitting tool. RESULTS: The uterine zones could be identified in all 24 examinations on the T2* maps. In addition, a thin "4th zone" was seen between the endometrium and the JZ (junctional zone) in 19 of 24 examinations. The T2* value of JZ was significantly lower than that of peripheral myometrium (PM) (P < 0.001). No significant difference in the T2* value of the JZ or of PM was noted between normal uterus and uterus with leiomyomas and/or adenomyosis. CONCLUSION: A quantitative T2* map can easily be obtained using the PRIDE software T2* fitting tool, and the software reproduces the result from previous report. T2* value of the junctional zone was lower than that of peripheral myometrium regardless of having benign myometrial diseases. PMID- 22422271 TI - Expression of estrogen receptors in gastric cancer and their clinical significance. AB - BACKGROUNDS AND OBJECTIVES: The male predominance of gastric cancer suggests that female sex hormones may have a protective effect against gastric cancer. We evaluated the expression of estrogen receptors in gastric cancer tissue and cells and the clinical significance of ER-beta expression in gastric cancer. METHOD: ER alpha, ER-beta proteins extracted from normal stomach, gastric cancer tissues, and cultured gastric cancer cells (KATO-III, mkn28, mkn45, and mkn74) were assessed by Western blot analysis. The clinical significance of ER-beta was explored using tissue microarray methods and immunohistochemical staining of specimens from 148 gastric cancers. RESULTS: Both ER-alpha and beta protein expression were noted in normal and gastric cancer tissues. However, in cultured gastric cells, only ER-beta was noted in mkn28 and mkn74. Of 148 gastric cancers, 67 (45.3%) were ER-beta positive. The ER-beta positive group was associated with lower tumor stage, Lauren's intestinal type, negative perineural invasion, and free of recurrence. The ER-beta positive group had a better 3-year survival compared with the negative group in survival analysis. CONCLUSION: Our results suggest that the presence of ER-beta in gastric cancer could have a protective effect against invasiveness of gastric cancer. Further studies are needed to clarify the role of ER-beta in gastric cancers. PMID- 22422273 TI - Emergence of multidrug-resistant NDM-1-producing Gram-negative bacteria in Bangladesh. AB - The main objective of this study was to investigate the prevalence of bla (NDM-1) in Gram-negative bacteria in Bangladesh. In October 2010 at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) laboratories, 1,816 consecutive clinical samples were tested for imipenem-resistant Gram-negative organisms. Imipenem-resistant isolates were tested for the bla (NDM-1) gene. Among 403 isolates, 14 (3.5 %) were positive for bla (NDM-1), and the predominant species were Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli. All bla (NDM-1)-positive isolates were resistant to multiple antibiotics. Among beta-lactamase genes, bla (CTX-M-1-group) was detected in ten isolates (eight bla (CTX-M-15)), bla (OXA-1-group) in six, bla (TEM) in nine, bla (SHV) in seven, and bla (VIM) and bla (CMY) in two isolates each. The 16S rRNA methylase gene, armA, was detected in five K. pneumoniae isolates and in one E. coli isolate. rmtB and rmtC were detected in a Citrobacter freundii and two K. pneumoniae isolates, respectively. qnr genes were detected in two K. pneumoniae isolates (one qnrB and one qnrS) and in an E. coli isolate (qnrA). Transferable plasmids (60-100 MDa) carrying bla (NDM-1) were detected in 7 of the 11 plasmid containing isolates. Pulsed-field gel electrophoresis (PFGE) analysis grouped K. pneumoniae isolates into three clusters, while E. coli isolates differed significantly from each other. This study reports that approximately 3.5 % of Gram-negative clinical isolates in Bangladesh are NDM-1-producing. PMID- 22422274 TI - Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. AB - Certain guidelines for the prevention of ventilator-associated pneumonia (VAP) recommend oral care with chlorhexidine, but none refer to the use of a toothbrush for oral hygiene. The role of toothbrush use has received scant attention. Thus, the objective of this study was to compare the incidence of VAP in critical care patients receiving oral care with and without manual brushing of the teeth. This was a randomized clinical trial developed in a 24-bed medical-surgical intensive care unit (ICU). Patients undergoing invasive mechanical ventilation for than 24 h were included. Patients were randomly assigned to receive oral care with or without toothbrushing. All patients received oral care with 0.12 % chlorhexidine digluconate. Tracheal aspirate samples were obtained during endotracheal intubation, then twice a week, and, finally, on extubation. There were no significant differences between the two groups of patients in the baseline characteristics. We found no statistically significant differences between the groups regarding the incidence of VAP (21 of 217 [9.7 %] with toothbrushing vs. 24 of 219 [11.0 %] without toothbrushing; odds ratio [OR] = 0.87, 95 % confidence interval [CI] = 0.469-1.615; p = 0.75). Adding manual toothbrushing to chlorhexidine oral care does not help to prevent VAP in critical care patients on mechanical ventilation. PMID- 22422275 TI - Stability of sputter-deposited gold nanoparticles in imidazolium ionic liquids. AB - The stability of gold nanoparticles synthesised by sputter deposition has been studied in situ in 1-butyl-3-methylimidazolium ionic liquids with bis(trifluoromethylsulfonyl)imide, tetrafluoroborate, hexafluorophosphate and dicyanamide anions with UV-VIS absorption spectroscopy and transmission electron microscopy. Besides the growth of the gold nanoparticles, two other processes were observed after sputtering, namely aggregation and sedimentation of these nanoparticles. To model the absorption spectra of the sputtered gold nanoparticles, generalized multiparticle Mie calculations were performed. These theoretical calculations confirm the increase in absorbance at longer wavelength for larger aggregates and are in agreement with the experimental observations. It was found that the kinetics of aggregation and sedimentation scale with the viscosity of the ionic liquid. Small amounts of water were found to have a large detrimental influence on the stability of the colloidal suspensions of the gold nanoparticles in ionic liquids. From the large discrepancy between the theoretical and the experimentally observed stability of the NPs, it was concluded that structural forces stabilize the gold nanoparticles. This was also borne out by AFM measurements. PMID- 22422276 TI - N,N-Dimethylformamide-stabilized gold nanoclusters as a catalyst for the reduction of 4-nitrophenol. AB - In this study, we investigated the catalytic properties of N,N-dimethylformamide (DMF)-stabilized gold nanoclusters (AuNCs) in the reduction of 4-nitrophenol (PNP) to 4-aminophenol by NaBH(4), a well known model reaction to be catalyzed by metal surfaces. The DMF-stabilized AuNCs were prepared in DMF by a surfactant free method. The DMF-stabilized AuNCs showed high catalytic activity even when used in small quantities (~10(-7) g). The pseudo-first-order rate constant (k(app)) and activation energy were estimated to be 3 * 10(-3) s(-1) and 31 kJ mol(-1), respectively, with 1.0 MUM of the gold catalyst at 298 K. The catalytic activity of the DMF-stabilized AuNCs was strongly influenced by the layer of adsorbed DMF on the Au NCs. This layer of adsorbed DMF prohibited the reactants from penetrating to the surface of the AuNCs via the diffusion at the beginning of the reaction, resulting in an induction time (t(0)) before PNP reduction began. Restructuring of the DMF layer (essentially a form of activation) was the key to achieving high catalytic activity. In addition, atomically monodisperse Au(25)(SG)(18)NCs (SG: glutathione) showed higher catalytic activity in the PNP reduction (k(app) = 8 * 10(-3) s(-1)) even with a low catalyst concentration (1.0 MUM), and there was no induction time (t(0)) in spite of the strongly binding ligand glutathione. This suggested that the catalytically active surface sites of the Au(25)(SG)(18)NCs were not sterically hindered, possibly because of the unique core-shell-like structure of the NCs. Retaining these open sites on AuNCs may be the key to making the NCs effective catalysts. PMID- 22422277 TI - Multifunctional stable fluorescent magnetic nanoparticles. AB - Because of their multifunctionality and unique magnetic properties, superparamagnetic iron oxide nanoparticles (SPIONs) have been recognized as very promising materials for various biomedical applications. The main difficulty with the use of SPIONs as multimodal bioimaging agents is their lack of fluorescence. Since cells can act as extremely efficient filters for the elution of surface bound fluorescent tags with nanoparticles, the surface loaded fluorescence dyes significantly decay after a short period of time. Here, for the first time, we introduce novel, engineered multimodal SPIONs with a permanent fluorescence capability, the study of which can lead to a deeper understanding of biological processes at the biomolecular level, greatly influencing molecular diagnostics, imaging and therapeutic applications. PMID- 22422278 TI - Colorimetric detection of trace water in tetrahydrofuran using N,N'-substituted oxoporphyrinogens. AB - Oxoporphyrinogens (OxPs) bind water molecules at pyrrolic NH and quinonoid carbonyl groups leading to visible colour changes due to variation in the pi electronic structure of OxPs. Introduction of hydrophilic substituents at two pyrrole NH groups improves sensitivity to H(2)O, and one OxP derivative is a colorimetric indicator of trace H(2)O (~50 ppm) in THF. PMID- 22422279 TI - Fuzzy control with amplitude/pulse-width modulation of nerve electrical stimulation for muscle force control. AB - The main goal of this study was to study the performance of fuzzy logic controllers combined with simplified hybrid amplitude/pulse-width (AM/PW) modulation to regulate muscle force via nerve electrical stimulation. The recruitment curves with AM/PW and AM modulations were constructed for the calf muscles of rabbits. Integrated with the modulation methods, a proportional integral-derivative (PID) and three fuzzy logic controllers were designed and applied for the electrical stimulation of tibial nerves to control the ankle torque under isometric conditions. The performance of the two modulation methods combined with the four controllers was compared when the ankle was fixed at three positions for both in vivo experiments and model simulations using a nonlinear muscle model. For the animal experiments, AM/PW modulation performed better than AM modulation alone. The fuzzy PI controller performed marginally better and was resistant to external noises, though it tended to have a larger overshoot. The performance of the controllers had a similar trend in the three different joint positions, and the simulation results with the nonlinear model matched the experimental results well. In conclusion, AM/PW modulation improved controller performance, while the contribution of fuzzy logic was only marginal. PMID- 22422280 TI - [Intra- and interrater variability of sonographic investigations of patella and achilles tendons]. AB - BACKGROUND: Clinical examinations of tendon disorders routinely include ultrasound examinations, despite the fact that availability of data concerning validity criteria of these measurements are limited. The present study therefore aims to evaluate the reliability of measurements of Achilles- and Patella tendon diameter and in the detection of structural adaptations. MATERIALS AND METHODS: In 14 healthy, recreationally active subjects both asymptomatic Achilles (AT) and patella tendons (PT) were measured twice by two examiners in a test-retest design. Besides the detection of anteroposterior (a.p.-) and mediolateral (m.l.-) diameters, areas of hypoechogenicity and neovascularisation were registered. Data were analysed descriptively with calculation of test-retest variability (TRV), intraclass-correlation coefficient (ICC) and Bland and Altman's plots with bias and 95 % limits of agreement (LOA). RESULTS: Intra- and interrater differences of AT- and PT-a.p.-diameter varied from 0.2 - 1.2 mm, those of AT- and PT-m.l diameter from 0.7 - 5.1 mm. Areas of hypoechogenicity were visible in 24 % of the tendons, while 15 % showed neovascularisations. Intrarater AT-a.p. -diameters showed sparse deviations (TRV 4.5 - 7.4 %; ICC 0.60 - 0.84; bias -0.05 - 0.07 mm; LOA -0.6 - 0.5 to -1.1 - 1.0 mm), while interrater AT- and PT-m.l.-diameters were highly variable (TRV 13.7 - 19.7 %; ICC 0.11 - 0.20; bias -1.4 - 4.3 mm; LOA -5.5 - 2.7 to -10.5 - 1.9 mm). CONCLUSION: Our results suggest that the measurement of AT- and PT-a.p. -diameters is a reliable parameter. In contrast, reproducibility of AT- and PT-m.l.-diameters is questionable. The study corroborates the presence of hypoechogenicity and neovascularisation in asymptomatic tendons. PMID- 22422281 TI - [Quantified TDI elastography of the patellar tendon in athletes]. AB - BACKGROUND: TDI elastosonography allows, in contrast to conventional methods, a quantitative-numerical evaluation of the quality of a tendon on the basis of so called strain scores. Previous studies on elastosonography were mainly based on qualitative methods, which only allow for a graduated colour and optical-visual representation. The aim of this study was to assess the strain scores of non symptomatic compared to symptomatic patellar tendons in order to estimate reference values. Furthermore, the correlation between the neovascularisation apparent in power Doppler sonography and the magnitude of the strain scores was investigated. METHODS: In total n = 75 athletes aged 33.2 +/- 12.7 years were included in the study, with the ligamentum patellae diagnosed in n = 37 as being clinical non-symptomatic and in n = 38 as being symptomatic. After a detailed anamnesis and a clinical examination, all subjects underwent a conventional B mode, a Dynaflow power Doppler and a TDI elastosonography of the ligamentum patellae using the Aplio MX (Toshiba Medical Systems, Corp.) in the longitudinal and cross-section planes, respectively. RESULTS: The strain scores of the non symptomatic ligamentum patellae in the longitudinal section were on average 0.070 (+/- 0.039) depending on the measuring field. The symptomatic tendons showed significantly higher values in the longitudinal section with an average of 0.137 (+/- 0.052). Similar values were evident in the cross-section. In 58 % of the symptomatic tendons neovascularisation was detected. A correlation between the duration of the medical history and the presence of neovascularisation was thereby verified. CONCLUSIONS: The presented results show that TDI elastosonography in the hands of an experienced examiner is an appropriate method for quantifying the quality of the patellar tendon and gives additional information beyond that of B-mode, power Doppler sonography and MRI. To what extent the strain scores of the TDI elastosonography in addition to conventional sonography can influence the choice of the therapeutic procedure must be evaluated by conducting further studies. PMID- 22422282 TI - [Visualisation of bioabsorbable suture anchors with digital projection radiography and magnetic resonance imaging]. AB - BACKGROUND: During the last few years bioabsorbable suture anchors have become widely established along side metallic suture anchors in orthopaedic surgery. However, there are still some difficulties in evaluating the postoperative situation after implanting bioabsorbable suture anchors. The aim of this study was to examine the visualisation of bioabsorbable suture anchors with digital projection radiography and magnetic resonance imaging. MATERIALS AND METHODS: Ten Mitek-Anchor-Panalok(r) suture anchors made of polylactic acid were implanted in an ex-vivo animal study design. After implantation the specimens were examined with digital projection radiography and MRI. The analysis was performed with regard to the bony defects and the anchor material itself. RESULTS: With digital projection radiography and MRI, it was possible to detect the bony defects after implantation of the anchors. The anchor material could not be visualised. CONCLUSION: The results of this study demonstrate that neither digital projection radiography nor MRI is well suited for the detection of the bioabsorbable suture anchors in the postoperative situation. Whereas the bony defects can be well described, the anchors cannot be directly visualised. The visualisation of bioabsorbable anchors remains a clinical problem in orthopaedic surgery. PMID- 22422283 TI - [Therapy of acute ankle sprain: one-year results of primary conservative treatment]. AB - INTRODUCTION AND AIM: Ankle sprains (supination-eversion injury) have a high incidence. Conservative treatment is generally the method of choice. This study is intended to evaluate the 1-year results of a standardised treatment protocol. MATERIAL AND METHODS: A total of 416 patients who had suffered an ankle sprain were included into this study. All of them had undergone primary conservative treatment. A total of 66 of them (15.9 %) had undergone operative treatment within one year after injury. The indications for operation were persistent pain, swelling or persistent instability. In 33 patients an arthroscopy for evaluation of the joint and debridement was used. In the case of a persistent instability 22 ligament augmentations (Kuner periostal flap) and 11 peroneus tenodesis (Watson Jones) were performed. The evaluation was done by using the AOFAS score ("Ankle Hindfoot Scale" of the American Orthopedic Foot and Ankle Society). RESULTS: A 1 year follow-up was possible in 96.4 % of the patients. The mean AOFAS score was 77.1 +/- 10.5 points after conservative treatment. Those patients who needed an arthroscopic debridement had a slightly better outcome (AOFAS score 79.5 +/- 10.2 points). Patients who had undergone stabilisation operations tended to have the best outcome (p = 0.093). The AOFAS score was 79.6 +/- 15.4 points in patients after periostal flap augmentation, respectively, 83.0 +/- 7.4 points after peroneus tenodesis. CONCLUSIONS: The results confirm the benefit of conservative treatment in acute ankle sprain. Even so about 15 - 20 % of the patients still suffer from persistent pain, swelling or instability. The indication for operative intervention should be made relatively broadly. Most of these patients profit from the operation. Above all, after ankle sprain patients need a continuous re-evaluation by a specialised centre during the first post-injury year. PMID- 22422284 TI - [Risk factors for accidents during sports while serving in German armed forces]. AB - In the German Armed Forces sports activities should bring the benefits of good health and trained fitness which are the hallmarks of sportsmen. In order to achieve this aim it is important to avoid accidents which negate the benefit of sports. Until today there appear to be no studies in existence which demonstrate the risk factors of sports activities undertaken while in military service. Equivalent studies on civilian sport activities are scarcely comparable. To find out risk factors for accidents with any period of recovery we followed sports accidents while on duty in a German barracks with 4,300 soldiers over a two-year period. Additionally we asked about the time needed for recovery from each accident, parameters of lifestyle, the body mass index and the possibility of a nightshift before each accident. We examined a minimum of 410 accidents. We found associations between the accidents studied and particular risk factors, including doing sports more than two times a week, being active in a fitness or sports club, having the accident together with another sportsman and doing a nightshift before the day of the accident. Bad ground conditions contributed to a large number of accidents. A body mass index of 25 and higher had a significantly prolonged time for recovery. To avoid accidents, sport and ground conditions should be adapted to each other. In addition, overweight people are not only compromised for cardiovascular and neurological diseases but also have a higher risk of needing a prolonged time for recovery, thus it is important that overweight should be avoided and not only just be treated. PMID- 22422285 TI - [Analysis and evaluation of the health status of physical education teachers focusing on dance teachers]. AB - INTRODUCTION: A dance teacher teaches in various professional and amateur genres. The physical load depends on the target group and is partly submaximal or even higher. The only tool of dance teachers is their own body. There are only few other tools to facilitate such work. Therefore, keeping the body in a good health status is of great significance. Up to the present, there have been little or no data on the health status of persons teaching dance. The aim of this study is to examine the health status of persons who teach dance in order to initiate a data base for the development of further projects with a preventive medical focus. METHODS: A total of 165 (f: 154, m: 11) average aged (46.1 years) dance teachers in Germany responded to a cross-section questionnaire survey. RESULTS: Teaching dance is for 96.6 % "the job of their dreams". Of all dance teachers 89.4 % continue to work while in pain and 85.5 % cannot afford a "longer down-time". 78.2 % state that they have paused due to a work-related disease, although 56.9 % of the respondents consider their occupation to be the cause for a disease with the answer only, seldom (44.4 %) or never (12.5 %). 4.5 % consult a medical doctor only after the self-treatment has failed. The lower extremity is the most common anatomic region in acute injuries (57.6 %) as well as in chronic complaints (58.3 %). The causes are multiple and comprise physical as well as psychic factors such as a high pressure of expectation (64.8 %) or a tight schedule/time table (43 %). 29 % of all dance teachers suffer from internal and 58 % from orthopaedic complaints. 43.1 % of them state that these complaints result from their occupation. 80.5 % make an acute injury responsible for compulsary breaks. DISCUSSION: The discrepancies between the self-perception and the findings of this investigation clearly show that the psychic and physical load in this occupation should not be underestimated. Here, further research on the social, psychic and physical health status of dance teachers is required. The results of this investigation warrant further research in the field of activity of the variable and up to now unprotected dance teacher profession in Germany. PMID- 22422286 TI - Survival of ovarian somatic cells during sex change in the protogynous wrasse, Halichoeres trimaculatus. AB - The three-spot wrasse (Halichoeres trimaculatus), which inhabits the coral reefs of Okinawa, changes sex from female to male. Sex change in this species is controlled by a social system. Oocytes disappear completely from the ovary, and male germ cells and somatic cells comprising testicular tissue arise a new during the sex change process. However, little is known of the fate and origin of the gonadal tissue-forming cells during sex change. In particular, the fate of ovarian somatic cells has not been determined, although the ovarian tissue regresses histologically. To approach this question, we analyzed apoptosis and cell proliferation in the sex-changing gonads. Unexpectedly, we found that few apoptotic somatic cells were present during sex change, suggesting that ovarian somatic cells might survive during the regression of the ovarian tissue. On the other hand, cell proliferation was detected in many granulosa cells surrounding the degenerating oocytes, a few epithelial cells covering ovigerous lamella and a few somatic cells associated with gonial germ cells at an early stage of sex change. Then, we found that proliferative ovarian somatic cells remained in the gonads late in the sex change process. Based on these results, we concluded that some functional somatic cells of the ovary are reused as testicular somatic cells during the gonadal sex change in the three-spot wrasse. PMID- 22422287 TI - Sequence analysis of 5' regulatory regions of the Machado-Joseph disease gene (ATXN3). AB - Machado-Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)(n) expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5' regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5' untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5' UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant. PMID- 22422290 TI - Retracted article. Monoaminergic and nitriergic modulation for antidepressant like activity of naringin in unstressed and acute immobilization-induced stressed mice. PMID- 22422289 TI - Bilateral common carotid artery ligation transiently changes brain lipid metabolism in rats. AB - Brain lipid metabolism was studied in rats following permanent bilateral common carotid artery ligation (BCCL), a model for chronic cerebral hypoperfusion. Unesterified (free) fatty acids (uFA) and acyl-CoA concentrations were measured 6 h, 24 h, and 7 days after BCCL or sham surgery, in high energy-microwaved brain. In BCCL compared to sham rats, cytosolic phospholipase A(2) (cPLA(2)) immunoreactivity in piriform cortex, and concentrations of total uFA and arachidonoyl-CoA, an intermediate for arachidonic acid reincorporation into phospholipids, were increased only at 6 h. At 24 h, immunoreactivity for secretory phospholipase A(2) (sPLA(2)), which may regulate blood flow, was increased near cortical and hippocampal blood vessels. BCCL did not affect levels of brain IB(4)+ microglia, glial fibrillary acidic protein (GFAP)+ astrocytes, cyclooxygenase-2 (COX-2) immunoreactivity at any time, but increased cPLA(2) immunoreactivity in one region at 6 h. Thus, BCCL affected brain lipid metabolism transiently, likely because of compensatory sPLA(2)-mediated vasodilation, without producing evidence of neuroinflammation. PMID- 22422291 TI - Investigation on the vibrational and structural properties of a self-structured bridged silsesquioxane. AB - The crystalline structure of ureidopyrimidinone-based silane (UPY) has been determined. The local and long range order structuring of the bridged silsesquioxane (MUPY) resulting from the sol-gel hydrolysis-condensation of the former precursor has been investigated by MFTIR (Mid Fourier Transform InfraRed) combined with DFT (Density Functional Theory) and XRD (X-ray diffraction) studies. These studies showed that a long range structuring exists within the organic fragments with the transcription of the DDAA (Donor-Donor-Acceptor Acceptor) H-bonding array from UPY to MUPY whereas a disordered siloxane network was revealed in the hybrid material. PMID- 22422292 TI - Neem cake: chemical composition and larvicidal activity on Asian tiger mosquito. AB - New pesticides based on natural products are urgently needed, in consideration of their environmental care and lower collateral effects. Neem oil, the main product obtained from Azadiractha indica A. Juss, commonly known as neem tree, is mainly used in medical devices, cosmetics and soaps, as well as important insecticide. Manufacturing of neem oil first includes the collection of the neem seeds as raw material used for the extraction. Neem cake is the waste by-product remaining after extraction processes. The quality of the oil, as that of the cake, strictly depends from the quality of seeds as well as from the type of extraction processes used, which strongly influences the chemical composition of the product. Currently, the different types of commercial neem cake on the market are roughly identified as oiled and deoiled cake, but several other differences can be detected. The differences are relevant and must be determined, to obtain the necessary correlation between chemical constitution and larvicidal activities. Six different batches of neem cake, marketed by several Indian and European companies, were analyzed by HPLC and HPTLC, and their fingerprints compared, obtaining information about the different compositions, focusing in particular on nortriterpenes, considered as the main active components of neem oil. Therefore, the chemical composition of each cake was connected with the biological activitiy, i.e., the effects of the extracts of the six neem cakes were tested on eggs and larvae of Aedes albopictus (Stegomyia albopicta) (Diptera: Culicidae), commonly known as Asian tiger mosquito. The results confirmed the previously reported larvicide effects of neem cake that, however, can now be related to the chemical composition, in particular with nortriterpenes, allowing in that way to discriminate between the quality of the various marketed products, as potential domestic insecticides. PMID- 22422293 TI - Efficacy of rBm86 against Rhipicephalus (Boophilus) microplus (IVRI-I line) and Hyalomma anatolicum anatolicum (IVRI-II line) infestations on bovine calves. AB - With an aim to evaluate the protective potentiality of rBm86 against Rhipicephalus (Boophilus) microplus Indian Veterinary Research Institute (IVRI)-I line and Hyalomma anatolicum anatolicum IVRI-II line infestations on crossbred (Bos indicus * Bos taurus) calves, 20 animals of 3 months of age were randomly divided in to four equal groups and maintained in tick-proof conditions. Animals of groups 1 and 2 were immunized with 2 ml of rBm86 (100 MUg)-based vaccine (procured from Revetmex S.A. de C.V, Mexico City, Mexico) thrice at 30 days interval. Animals of groups 3 and 4 were kept as negative control and inoculated with PBS only. Each animal of group 1 and 3 was challenged with 7-day-old 50 unfed adults of H. anatolicum anatolicum (1:1, male and female), and each animal of groups 2 and 4 was challenged with 6-8-day-old R. (B.) microplus larvae obtained from 50 mg of eggs, on 17th day of the last immunization. The efficacy of rBm86 against tick infestations was determined as percentage reduction in number of adults dropped (DT%), engorged body weight (DR%), egg masses (DO%), and immunogen efficacy (E%). The calculated data were 11.8, 10.8, 15.0, and 25.1 %, respectively, for DT, DR, DO, and E% against H. anatolicum anatolicum infestation, while in the case of R. (B.) microplus infestation, the corresponding data were 6.4, 11.24, 40.7, and 44.5 %, respectively. The results indicated partial effectiveness of rBm86 antigen(s) in imparting protection against homologous and heterologous challenge infestations of Indian ticks. The results indicated identification of more effective antigen(s) for the development of vaccine against economically important tick species in India. PMID- 22422294 TI - Osmoregulatory strategies in natural populations of the black-chinned tilapia Sarotherodon melanotheron exposed to extreme salinities in West African estuaries. AB - The effect of salinity was studied in natural populations of the black-chinned tilapia (Sarotherodon melanotheron) from West Africa. This euryhaline species colonizes nearly all coastal environments from bays to lagoons characterized by salinities ranging from fresh water to hypersaline water over 100 0/00. Individuals were sampled during the dry season at several locations characterized by different levels of salinity (3-102 0/00). Their osmotic status and their gills were analyzed. The branchial mitochondria-rich cells (MRC), localized at the basis of the filaments and along the lamellae in fish taken from the saline stations, showed a wide plasticity with significant differences in their number and size. The most striking results were a significant larger area (~3x) and a higher number (~55x) of MRC at high salinity (102 0/00) compared to low salinity (3 0/00). The major ion transporters and channels were localized by immunocytochemistry and different expression patterns have been recorded between stations. Despite an increased Na+/K+-ATPase (NKA) alpha-subunit expression and NKA activity, pointing to an increased monovalent ion excretion, a severe osmotic imbalance was recorded in animals living in hypersaline environments. PMID- 22422295 TI - Multimodality evaluation of cardiac sarcoidosis. PMID- 22422296 TI - Effusive-constrictive pericarditis. AB - Effusive-constrictive pericarditis (ECP) is an increasingly recognized clinical syndrome. It has been best characterized in patients with tamponade who continue to have elevated intracardiac pressure after the removal of pericardial fluid. The disorder is due to pericardial inflammation causing constriction in conjunction with the presence of pericardial fluid under pressure. The etiology is diverse with similar causes to constrictive pericarditis and the condition is more prevalent with certain etiologies such as tuberculous pericarditis. The diagnosis is most accurately made using simultaneous intrapericardial and right atrial pressure measurements with pericardiocentesis, although non-invasive Doppler hemodynamic assessment can assess residual hemodynamic findings of constriction following pericardiocentesis. The clinical presentation has considerable overlap with other pericardial syndromes and as yet there are no biomarkers or non-invasive findings that can accurately predict the condition. Identifying patients with ECP therefore requires a certain index of clinical suspicion at the outset, and in practice, a proportion of patients may be identified once there is objective evidence for persistent atrial pressure elevation after pericardiocentesis. Although a significant number of patients will require pericardiectomy, a proportion of patients have a predominantly inflammatory and reversible pericardial reaction and may improve with the treatment of the underlying cause and the use of anti-inflammatory medications. Patients should therefore be observed for the improvement on these treatments for a period, whenever possible, before advocating pericardiectomy. Imaging modalities identifying ongoing pericardial inflammation such as contrast-enhanced magnetic resonance imaging or nuclear imaging may identify those subsets more likely to respond to medical therapies. Pericardiectomy, if necessary, requires removal of the visceral pericardium. PMID- 22422297 TI - Anionic [4+3] heteroannulation of 2-azidoacrylates: a modular synthesis of 2 benzazepin-1-ones. AB - 2-Azidoacrylates undergo [4+3] annulation with phthalides under anionic conditions at low temperatures to furnish 5-hydroxy-2-benzazepinones, the formation of which represents a new concept for the construction of azepines as well as a new reactivity of 2-azidoacrylates. PMID- 22422298 TI - Manifold sensitivity improvement of swelling-based sensors. AB - The sensitivity of swelling-based gold core-organic shell nanoparticle vapor sensors is improved manifold by cooling sensors below ambient temperature. This is due to the reduced volatility of the analyte. Sensitivity to a particular analyte scales with temperature like that of analyte's saturated vapor pressure, thus allowing quantitative prediction of sensitivity enhancement. We believe our conclusions apply to all swelling-based sensors. PMID- 22422299 TI - The use of the microplate alamar blue assay (MABA) to assess the susceptibility of Mycobacterium lepraemurium to anti-leprosy and other drugs. AB - Although murine leprosy is no longer a common illness, our understanding of the biology of this disease is incomplete. One particular example of this concerns the etiologic agent Mycobacterium lepraemurium (MLM). MLM is a fastidious microorganism that is difficult to grow in axenic media; in a way, this has hampered attempts to thoroughly study its physiological and metabolic characteristics. MLM is an obligate intracellular bacillus that invades macrophages and replicates profusely with a generation time that oscillates between 0.5 and 11 days. In the present study, we have successfully maintained MLM alive for more than 12 days in vitro, providing us with an opportunity to study its susceptibility to several anti-leprosy agents and other drugs. To achieve this, we used a fluorescence reduction assay of alamar blue (a resazurin) in a microplate format (microplate-alamar-blue-assay; MABA), which is a highly sensitive, practical, and inexpensive method for assaying cell viability. We found that MLM was highly susceptible to clofazimine and rifampicin and was less susceptible to streptomycin, thiacetazone, kanamycin, dapsone, and ethionamide, in that order. MLM was not susceptible to four plant triterpenoids (oleanolic acid, neolignan-c, sitosterol, and ursolic acid) for which bactericidal activity has been reported in M. tuberculosis. Because the MABA has high sensitivity, it can be used to monitor the activity of microorganisms that are difficult to cultivate (such as M. lepraemurium), in response to various drugs, thus offering a method to complement the study of murine leprosy, about which many questions remain unanswered. PMID- 22422300 TI - Effects of hepatitis C virus infection on the pharmacokinetics of ritonavir boosted atazanavir in HIV-1-infected patients. AB - Most antiretrovirals are metabolized in the liver, and overexposure could be more common in human immunodeficiency virus (HIV)-infected patients with hepatic impairment. Careful monitoring of potential drug-related liver injury in clinical practice is necessary. The aim of our study was to analyze the trough concentrations (C (trough)) of atazanavir (ATV) in the plasma of HIV/hepatitis C virus (HCV)-co-infected patients and to compare the values with those of a HIV infected control population. C (trough) values (22-26 h after last intake) of atazanavir, following the administration of atazanavir/ritonavir 300/100 mg once daily as part of antiretroviral therapy, were assessed by HPLC. We also collected data on dosing of atazanavir, and on demographic (age, gender, and ethnicity), physiological (weight and body mass index), and clinical parameters (CD4+ cell count, HIV-RNA viremia, co-medication, and hepatitis C co-infection). A total of 28 Caucasian HIV-infected adults were studied, of whom 13 were HIV/HCV co infected. No baseline characteristics differed between the two cohorts, except statistically significant differences regarding ALT, AST, and total bilirubin. The median (range) plasma ATV C (trough) levels were 0.62 (0.05-3.22) MUg/ml in HIV patients and 0.32 (0.04-3.37) MUg/ml in HIV/HCV patients. Thus, there was no significant difference in plasma trough levels of atazanavir in the two cohorts. In our patients with mild impairment of hepatic function caused by HCV infection, atazanavir C (trough) was comparable in HIV-infected and HIV/HCV-co-infected patients. PMID- 22422301 TI - Systematic analysis of genotype-specific drug responses in cancer. AB - A systematic understanding of genotype-specific sensitivity or resistance to anticancer agents is required to provide improved patient therapy. The availability of an expansive panel of annotated cancer cell lines enables comparative surveys of associations between genotypes and compounds of various target classes. Thus, one can better predict the optimal treatment for a specific tumor. Here, we present a statistical framework, cell line enrichment analysis (CLEA), to associate the response of anticancer agents with major cancer genotypes. Multilevel omics data, including transcriptome, proteome and phosphatome data, were integrated with drug data based on the genotypic classification of cancer cell lines. The results reproduced known patterns of compound sensitivity associated with particular genotypes. In addition, this approach reveals multiple unexpected associations between compounds and mutational genotypes. The mutational genotypes led to unique protein activation and gene expression signatures, which provided a mechanistic understanding of their functional effects. Furthermore, CLEA maps revealed interconnections between TP53 mutations and other mutations in the context of drug responses. The TP53 mutational status appears to play a dominant role in determining clustering patterns of gene and protein expression profiles for major cancer genotypes. This study provides a framework for the integrative analysis of mutations, drug responses and omics data in cancers. PMID- 22422302 TI - Complex polymer brush gradients based on nanolithography and surface-initiated polymerization. AB - Confined surface gradients consisting of polymer brushes have great potential in various applications such as microfluidic devices, sensors, and biophysical research. Among the available fabrication approaches, nanolithographies combined with self-assembled monolayers and surface-initiated polymerization have became powerful tools to engineer confined gradients or predefined complex gradients on the nanometre size. In this tutorial review, we mainly highlight the research progress of the fabrication of confined polymer brush gradients by using electron beam, laser, and probe-based nanolithographies and the physical base for these approaches. The application of these polymer brush gradients in biomedical research is also addressed. PMID- 22422303 TI - Prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in healthy Hungarian men over 50 years of age: the HunMen Study. AB - This study reports a high prevalence of hypovitaminosis D and low bone mineral density (BMD) in a healthy Hungarian male cohort over 50 years of age. Men with 25-hydroxyvitamin D levels of <75 nmol/L had a significantly higher 10-year hip and major osteoporotic fracture probability using the country-specific fracture risk assessment (FRAX) algorithm. INTRODUCTION: The aim of this study is to characterize the prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in healthy Hungarian men over 50 years of age. METHODS: We determined levels of 25-hydroxyvitamin D (25-OH-D), PTH, osteocalcin (OC), C-terminal telopeptides of type-I collagen (CTX-I), procollagen type 1 amino-terminal propeptide (PINP), BMD at L1-L4 (LS) and femur neck (FN), daily dietary calcium intake, and the 10-year probability of hip fracture and a major osteoporotic fracture using the country-specific FRAX algorithm in 206 randomly selected ambulatory men. RESULTS: The mean (range) age of the volunteers was 60 (51-81) years. The prevalence of hypovitaminosis D (25-OH-D, <75 nmol/L) was 52.9%. The prevalence of low (T-score < -1.0) BMD at the FN and LS was 45% and 35.4%, respectively. The mean (range) FRAX hip fracture and FRAX major osteoporotic fracture was 0.8% (0-9.4%) and 3.8% (1.7-16%), respectively. On comparing the vitamin D sufficient to the insufficient group, there was a statistically significant difference between the FRAX hip fracture and FRAX major osteoporotic fracture indexes. There was significant seasonal variation in the vitamin D levels; the lowest levels were measured in winter and the highest in summer. CONCLUSIONS: A high prevalence of hypovitaminosis D and low BMD were observed in the studied Hungarian male population. This is the first study reporting higher 10-year hip and major osteoporotic fracture probability using the country-specific FRAX algorithm in individuals with hypovitaminosis D. PMID- 22422304 TI - Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency. AB - Treatment of vitamin D deficiency for 3 months with oral cholecalciferol 5,000 IU daily was more effective than 2,000 IU daily in achieving optimal serum 25 hydroxyvitamin D (25OHD) concentrations. Optimal 25OHD serum level calculated to be 63.8 nmol/L. All parameters of muscle strength improved following administration of cholecalciferol for 3 months. INTRODUCTION: The aim of this study was to determine the optimal dose of cholecalciferol required to achieve target serum 25OHD level >= 75 nmol/L and its relationship to both bone turnover and muscle strength. METHODS: Thirty deficient patients (serum 25OHD <= 50 nmol/L) were randomly assigned into two groups-i.e. 2,000 and 5,000 IU/day. Data were collected at baseline, at 2 and 3 months post-therapy: (a) clinical demographics, (b) dietary calcium recall, (c) physical tests of muscle function and (d) biochemistry. Statistical analysis used paired student t test and analysis of variance. Regression analysis was used to determine relationship between serum 25OHD and parathyroid hormone (PTH). RESULTS: Twenty-six (87%) patients completed 3 months of therapy. The percent increase in serum 25OHD (compared to baseline) was 82.7% in 2,000-IU group and 219.5% in 5,000-IU group. All participants (100%) achieved a serum 25OHD concentration >50 nmol/L; only 5 subjects (45.4%) in 2,000-IU group compared to 14 subjects (93.3%) in 5,000-IU group achieved final 25OHD concentration >= 75 nmol/L (p < 0.01). In the regression analysis, the reflexion point at which the PTH level increased above the normal range was calculated to be 63.8 nmol/L 25OHD. All parameters of muscle strength showed trends in improvements following the administration of both the 2,000 and 5,000 IU doses. No patient reported untoward side effects and no patient developed hypercalcaemia. CONCLUSION: Treatment for 3 months with oral cholecalciferol 5,000 IU daily may be more effective than 2,000 IU daily in achieving optimal serum 25OHD concentrations in vitamin D-deficient patients. PMID- 22422305 TI - Life expectancy following diagnosis of a vertebral compression fracture. AB - SUMMARY: The life expectancy of vertebral compression fracture (VCF) patients was evaluated as a function of their treatment. Compared to non-operated patients, the kyphoplasty and vertebroplasty patient cohort had 115% and 44% greater adjusted life expectancy, respectively. Kyphoplasty patients had a 34% greater adjusted life expectancy than vertebroplasty patients. INTRODUCTION: Balloon kyphoplasty and vertebroplasty are minimally invasive procedures for the treatment of painful VCFs. This comparative effectiveness study characterized the life expectancy of VCF patients as a function of their treatment. METHODS: Life expectancy of VCF patients in the 100% U.S. Medicare dataset (2005-2008) was estimated using a parametric Weibull survival model (adjusted for comorbidities), and compared between operated and non-operated patients as well as between kyphoplasty and vertebroplasty patients. A total of 858,978 patients with a newly diagnosed VCF were identified, including 119,253 kyphoplasty patients (13.9%) and 63,693 vertebroplasty patients (7.4%). RESULTS: Adjusted life expectancy was 85% greater for operated than non-operated patients (p < 0.001; 95% confidence interval: 82-89%). Compared to non-operated patients, the kyphoplasty and vertebroplasty patient cohort had 115% (p < 0.001; 95% confidence interval: 111 119%) and 44% (p < 0.001; 95% confidence interval: 42-47%) greater adjusted life expectancy, respectively. Kyphoplasty patients had a 34% greater adjusted life expectancy than vertebroplasty patients (p < 0.001; 95% confidence interval: 31 36%). Across all gender-age groups, the median life expectancy predicted by the parametric Weibull model was 2.2-7.3 years greater for operated than non-operated patients. CONCLUSIONS: Statistically significant and substantial differences in life expectancy were observed between the treated and non-treated cohorts in the Medicare population. Among the treated cohorts, patients in the vertebroplasty group experienced less of a survival benefit than those who received kyphoplasty. The results will be a useful basis for future cost effectiveness studies of VCF treatments for the Medicare population. PMID- 22422306 TI - Effects of climbing on core strength and mobility in adults. AB - The objective of this study was to examine the impact of an indoor climbing training and detraining program on core/handgrip strength and trunk mobility in men and women. 28 young sedentary adults participated in this study and were assigned to an intervention (30+/-3 years) or a control (29+/-2 years) group. The intervention group participated in 8 weeks (2 times/week) of indoor climbing training, followed by 8 weeks of detraining. Tests included the measurement of maximal isometric strength (MIS) of the trunk flexors/extensors, the assessment of trunk mobility in the sagittal (SAP) and the coronal (CRP) plane as well as testing of handgrip strength. After training, significant improvements were observed in MIS of the trunk flexors/extensors (~19-22%, all p<0.01), in trunk mobility in SAP/CRP (~14-19%, all p<0.01), and in handgrip strength (~5%, p<0.01). During detraining, MIS (~12-13%, all p<0.01) and trunk mobility (~7-10%, all p<0.01) deteriorated significantly, whereas handgrip strength remained. This indoor climbing training program conducted in sedentary adults proved to be feasible (i. e., attendance rate of 89.4%) and effective. It is suggested that indoor climbing should be permanently conducted to maintain the observed improvements in core muscle strength and trunk mobility. PMID- 22422307 TI - Short term rehabilitation and ankle instability. AB - Chronic ankle instability (CAI) after ankle sprains has been shown to cause foot and ankle disability. Although rehabilitation programs for patients with CAI have been performed in related studies, few researchers have studied overall performance including pain, balance, and isokinetic torque. The purpose of this study was to determine if a short-term rehabilitation program that addressed range of motion (ROM), functional muscular performance, and neuromuscular control, can improve the foot/ankle disability index (FADI), FADI-Sport, ROM, star excursion balance test (SEBT), and isokinetic torque for patients with CAI. Prior to the experiment, we investigated the principal injury site through an administered questionnaire on 236 potential participants, and selected 18 male subjects aged between 21 and 23 years. 9 subjects (rehabilitation group, RG) with unilateral CAI took part in the rehabilitation program for 4 weeks, whereas 9 subjects (control group, CG) did not participate in that program. The results were as follows; the RG significantly increased FADI, FADI-Sport scores, and ROM on the injured limb compared with the CG. Also, the RG had greater SEBT reaches and improvements in isokinetic torque compared with the CG. In conclusion, these results demonstrate that a short-term rehabilitation program can improve functional limitations in patients with CAI. PMID- 22422308 TI - Ecological validity of the Yo-Yo SFIE2 test. AB - The present study investigated the movement pattern of Portuguese top-level futsal referees (n=16) during competitive games and the ecological validity of the new Yo-Yo Sideways-Forwards Intermittent Endurance level 2 test (Yo-Yo SFIE2). Total distance covered (TD), high-intensity running (HIR), sprinting (SPR), and sideways running (Sw) during matches were 5.78+/-0.24 (+/-SEM), 0.77+/ 0.08, 0.17+/-0.02 and 1.61+/-0.28 km, respectively, with peak 5-min values of 0.50+/-0.02, 0.12+/-0.01, 0.05+/-0.01 and 0.20+/-0.02 km, respectively. TD, HIR and Sw decreased by 30% (p<0.001), 43% and 60% (p<0.01), respectively from the first to the last 10-min period. Yo-Yo SFIE2 performance was 1205+/-107 (625 2015) m and showed large correlations with match-values and peak 5-min values for HIR (r=0.58 and 0.68, p<0.01) and SPR (r=0.56 and 0.57, p<0.05). Yo-Yo SFIE2 HR after 4 min [95+/-1 (87-99) % HRpeak] showed a nearly perfect inverse correlation with Yo-Yo SFIE2 performance (r= -0.90, p<0.001) and large inverse correlations (p<0.05) with match-values and peak 5-min values for HIR (r= -0.55 and -0.71) and SPR (r= -0.57 and -0.55). In conclusion, the Yo-Yo SFIE2 test is movement specific for top-level futsal referees as high-intensity running and sideways running are important parts of their match activity profile, and maximal and sub maximal versions of the Yo-Yo SFIE2 test correlates with certain aspects of the physical match performance of top-level futsal referees. PMID- 22422309 TI - 3-min all-out exercise test for running. AB - A 3-min all-out exercise test (3 MT) estimates critical power and the curvature constant for cycle ergometry validly; however, the mode of running has not been studied. We examined the efficacy of a running 3 MT, using global positioning sensor data, to predict outdoor racing performance. Women distance runners (n=14) were tested at preseason within a month prior to competing officially in either short or middle distance races. Critical speed (CS) (4.46+/-0.41 m/s) estimated from the 3 MT did not differ (p>0.05) from the mean speed of gas exchange threshold and maximum oxygen uptake (50%Delta), as derived from a custom treadmill graded exercise test (4.55+/-0.24 m/s). Runners with higher curvature constants (D'), estimated from the 3 MT, raced at higher speeds above CS (R2 ranging 0.63-0.99). Race speeds for 800 m exceeded the speed for 150 s of all-out running, rendering 800 m estimates less accurate. Conversely, predicted times for the other distances yielded strong intraclass correlations (alpha) and low coefficients of variation (%) values (alpha=0.74/1.7% and alpha=0.87/2.1%, for 1 600 and 5 000 m, respectively). Use of the running 3 MT for performances ranging ~2.5-18 min is recommended. PMID- 22422310 TI - Shoulder rotational properties of throwing athletes. AB - Throwing arm injuries are common and often related to the shoulder external and internal rotation. Quantitative assessment may provide new insights to physical assessment and options for treatment. After having signed IRB approved consents and filled out injury questionnaires, 96 baseball pitchers were examined on both shoulders using a custom-made wireless device. The resistance onset angle (ROA), end-point angle (EPA), shoulder rotational flexibility (SRF) in both external and internal rotation, and rotational ranges of motion (ROM) of both shoulders were determined. About 34% of subjects had surgeries on their throwing arm. Another 15% of subjects had throwing arm injuries that did not require surgical treatments. The throwing arm had significantly lower internal ROA, EPA and SRF, but significantly higher external ROA, EPA and SRF than the non-throwing arm. There were significant differences in shoulder rotational properties among groups with different surgery locations. Subjects with shoulder surgeries had greater internal rotation flexibility of their throwing arm than those with surgeries on the elbow. Throwers with injury and surgery history had significantly different shoulder rotational properties. Abnormal shoulder rotational properties may be related to throwing arm injuries. A better understanding of their relationship may lead us to effective preventive measures of throwing arm injuries. PMID- 22422311 TI - Kinematic analysis of soccer players in shuttle running. AB - The intermittent shuttle running test is mainly used within soccer to assess aerobic power. For this reason we studied kinematic parameters and heart rate at both an increasing speed, [Yo-Yo Endurance Lv 1 (Y1)] and at constant velocity [95% maximal aerobic velocity (MAV(95%))]. 12 soccer players were selected for this study. A high-speed digital camera (210 Hz) was used to record motion; Dartfish5.5Pro was used to perform 2D video analysis and heart rate was also recorded and computed during the test. The parameters considered (baseline measures with respect to the end of each test) in this study were: step length (SL), contact time (CT) and heart rate (HR). SL: 40% in Y1 and -22% in MAV(95%). CT: -31% in Y1 and 29% in MAV(95%). HR: increased 96% in Y1 and 17% in MAV(95%). These results highlight 2 different neuromechanical strategies adopted under fatigued conditions. In light of the clear changes of the CT in MAV(95%) (29%) and with respect to the moderate changes in HR (17%) it is clear that the CT is the most important parameter, as it experiences greater adaptations associated with neuromuscular patterns, under a fatigued condition as opposed to HR. PMID- 22422312 TI - Morphology-controlled synthesis of ZnO replicas with photonic structures from butterfly (Papilio paris) wing scales for tunable optical properties. AB - ZnO replicas with photonic structures were fabricated from Papilio paris butterfly wing scales and their tunable optical properties were studied. Through modification of the fabrication method, the reticular porous network structure was successfully replicated from dark black (DB) wing scales. The DB wing scale replicas exhibit a photonic band gap (PBG) in the visible region, which overlaps with the visible emission range of ZnO. Both DB and GB (greenish-blue) wing scale replicas can work as one-dimensional diffraction gratings in optical diffraction experiments, whose spot distances can be tuned by different periodic sizes of butterfly wing structure. Moreover, the ZnO DB wing scale replicas exhibit improved photoluminescence (PL) spectra with reduced visible emission and enhanced UV emission, which can both be attributed to the existence of a PBG produced by the reticular porous network structure in DB wing scales. These results can be very helpful in the research of applications of ZnO materials in UV lasing and optical diffraction devices. PMID- 22422313 TI - Inducibility of chemical defenses in Norway spruce bark is correlated with unsuccessful mass attacks by the spruce bark beetle. AB - Secondary attraction to aggregation pheromones plays a central role in the host colonization behavior of the European spruce bark beetle Ips typographus. However, it is largely unknown how the beetles pioneering an attack locate suitable host trees, and eventually accept or reject them. To find possible biomarkers for host choice by I. typographus, we analyzed the chemistry of 58 Norway spruce (Picea abies) trees that were subsequently either (1) successfully attacked and killed, (2) unsuccessfully attacked, or (3) left unattacked. The trees were sampled before the main beetle flight in a natural Norway spruce dominated forest. No pheromones were used to attract beetles to the experimental trees. To test the trees' defense potential, each tree was treated in a local area with the defense hormone methyl jasmonate (MeJ), and treated and untreated bark were analyzed for 66 different compounds, including terpenes, phenolics and alkaloids. The chemistry of MeJ-treated bark correlated strongly with the success of I. typographus attack, revealing major chemical differences between killed trees and unsuccessfully attacked trees. Surviving trees produced significantly higher amounts of most of the 39 analyzed mono-, sesqui-, and diterpenes and of 4 of 20 phenolics. Alkaloids showed no clear pattern. Differences in untreated bark were less pronounced, where only 1,8-cineole and (-)-limonene were significantly higher in unsuccessfully attacked trees. Our results show that the potential of individual P. abies trees for inducing defense compounds upon I. typographus attack may partly determine tree resistance to this bark beetle by inhibiting its mass attack. PMID- 22422314 TI - Topological analysis and interactive visualization of biological networks and protein structures. AB - Computational analysis and interactive visualization of biological networks and protein structures are common tasks for gaining insight into biological processes. This protocol describes three workflows based on the NetworkAnalyzer and RINalyzer plug-ins for Cytoscape, a popular software platform for networks. NetworkAnalyzer has become a standard Cytoscape tool for comprehensive network topology analysis. In addition, RINalyzer provides methods for exploring residue interaction networks derived from protein structures. The first workflow uses NetworkAnalyzer to perform a topological analysis of biological networks. The second workflow applies RINalyzer to study protein structure and function and to compute network centrality measures. The third workflow combines NetworkAnalyzer and RINalyzer to compare residue networks. The full protocol can be completed in ~2 h. PMID- 22422315 TI - Oxime-based linker libraries as a general approach for the rapid generation and screening of multidentate inhibitors. AB - The described oxime-based library protocol provides detailed procedures for the linkage of aminooxy functionality with aldehyde building blocks that result in the generation of libraries of multidentate inhibitors. Synthesis of inhibitors for protein tyrosine phosphatases (PTPs) and antagonists directed against the human tumor susceptibility gene 101 (TSG101) are shown as examples. Three steps are involved: (i) the design and synthesis of aminooxy platforms; (ii) tethering with aldehydes to form oxime-based linkages with sufficient purity; and (iii) direct in vitro biological evaluation of oxime products without purification. Each coupling reaction is (i) performed in capped microtubes at room temperature (20-23 degrees C); (ii) diluted for inhibitory evaluation; and (iii) screened with targets in microplates to provide IC(50) or K(d) values. The synthesis of the aminooxy platforms takes 3-5 d; tethering with the aldehydes takes 24 h; and inhibition assay of enzymes and protein-protein interactions takes 30 min and 2 h, respectively. PMID- 22422316 TI - Arrayed cellular microenvironments for identifying culture and differentiation conditions for stem, primary and rare cell populations. AB - During the development of an organism, cells are exposed to a myriad of signals, structural components and scaffolds, which collectively make up the cellular microenvironment. The majority of current developmental biology studies examine the effect of individual or small subsets of molecules and parameters on cellular behavior, and they consequently fail to explore the complexity of factors to which cells are exposed. Here we describe a technology, referred to as arrayed cellular microenvironments (ACMEs), that allows for a high-throughput examination of the effects of multiple extracellular components in a combinatorial manner on any cell type of interest. We will specifically focus on the application of this technology to human pluripotent stem cells (hPSCs), a population of cells with tremendous therapeutic potential, and one for which growth and differentiation conditions are poorly characterized and far from defined and optimized. A standard ACME screen uses the technologies previously applied to the manufacture and analysis of DNA microarrays, requires standard cell-culture facilities and can be performed from beginning to end within 5-10 days. PMID- 22422317 TI - Generation of induced pluripotent stem cells from a small amount of human peripheral blood using a combination of activated T cells and Sendai virus. AB - Induced pluripotent stem cells (iPSCs) have become important cell sources for genetic disease models, and they have the potential to be cell sources for future clinical therapies. However, invasive tissue sampling reduces the number of candidates who consent to donate cells for iPSC generation. In addition, integrated transgenes can potentially insert at inappropriate points in the genome, and in turn have a direct oncogenic effect. Technical modifications using a combination of activated T cells and a temperature-sensitive mutant of Sendai virus (SeV) can avoid invasive tissue sampling and residual transgene issues in generating iPSCs. Such advances may increase the number of consenting patients for cell donations. Here we present a detailed protocol for the generation of iPSCs from a small amount of human peripheral blood using a combination of activated T cells and mutant SeV encoding human OCT3/4, SOX2, KLF4 and c-MYC; T cell-derived iPSCs can be generated within 1 month of blood sampling. PMID- 22422318 TI - A practical method to predict physical stability of amorphous solid dispersions. AB - PURPOSE: To predict the crystallization time of amorphous solid dispersions by controlling the combined effect of temperature and moisture content. METHODS: The authors exposed amorphous samples of spray-dried API and Hydroxypropylmethylcellulose Phtalate to various temperature and humidity conditions below and above the glass transition temperature (Tg) until crystallization of the API was observed. The crystallization of API was detected by XRPD, while the T ( g ) and the water absorption by the amorphous dispersion are quantified by mDSC and water sorption analysis. RESULTS: Extrapolation of the data obtained at a temperature above T ( g ) to conditions below T ( g ) gives only a qualitative trend. By contrast, in conditions below T ( g ) the logarithm of onset of crystallization time was shown to vary linearly with the T ( g ) /T ratio. A statistical analysis shows that the data obtained in the highest temperature/humidity conditions, for which the onset of crystallization is below 3 months, can be extrapolated over 15 months. CONCLUSIONS: The proposed methodology can be used as a stress program to predict long-term stability from a relatively short observation period and to design appropriate temperature and humidity conditions for long-term storage to prevent crystallization. PMID- 22422319 TI - Solubility at the molecular level: development of a critical aggregation concentration (CAC) assay for estimating compound monomer solubility. AB - PURPOSE: In drug discovery research the formation of soluble compound aggregates is a major cause of false positives, false negatives, and distorted values in High-Throughput Screening assays that measure either binding or functional activity. These aggregation-based artifacts lead to serious distortions in the SAR which are critical to successful lead optimization. In this work we introduce a new approach by which the "critical aggregation concentration" (CAC) is determined, thereby overcoming limitations inherent to traditional solubility methods and enabling estimation of small molecule monomer solubility. METHODS: The theoretical and experimental basis of a new confocal Static Light Scattering plate reader assay is presented. RESULTS: Tests conducted with model systems, commercial compounds, and Abbott library compounds show that the CAC assay can measure aqueous monomer solubilities reproducibly and reliably, achieving a sensitivity of ~0.2 MUm, which is an improvement of approximately two orders of magnitude over nephelometry. CONCLUSIONS: Determination of compound monomer solubilities in a screening format is possible for the first time with the cSLS CAC methodology. It is currently in routine use in Abbott's drug discovery program, and has enabled identification of many compound induced artifacts in binding or activity assays that are missed by traditional kinetic solubility measurements. PMID- 22422320 TI - Assessment of the lateral diffusion and penetration of topically applied drugs in humans using a novel concentric tape stripping design. AB - PURPOSE: To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique. METHOD: Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin. RESULTS: CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3 mins ranged between 83.0 and 92.9 % and decreased to between 64.5 and 66.9 % at 3 h. IBU recovery further decreased to 47.7 +/- 5.6 % at 6 h, correlating with greater in vitro penetration relative to CAF and HC. CONCLUSION: Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time. PMID- 22422321 TI - Pharmacokinetic/pharmacodynamic modeling of methylprednisolone effects on iNOS mRNA expression and nitric oxide during LPS-induced inflammation in rats. AB - PURPOSE: Increased expression of inducible nitric oxide synthase (iNOS) resulting in nitric oxide elevation represents an important component of inflammatory responses. We assess the effects of methylprednisolone (MPL) on these processes during endotoxin-induced acute inflammation and provide a mechanism-based model to quantitatively describe them. METHODS: Male Lewis rats were dosed with lipopolysaccharide (50 MUg/kg LPS) alone or with methylprednisolone (10 and 50 mg/kg) and sacrificed at different time points. Plasma MPL, lung iNOS mRNA expression, plasma nitric oxide (NO) and other physiological factors were measured. Sodium nitrate (750 MUmole/kg) was given to a separate cohort of rats to assess NO disposition kinetics. PK-PD modeling was performed with ADAPT 5. RESULTS: Disposition kinetics of plasma MPL and NO showed bi-exponential decline and were described by two-compartment models. LPS increased expression of iNOS mRNA in lung and increased plasma NO, while MPL dosing palliated this increase in a dose-dependent manner. These effects were well captured using tandem indirect response and precursor-pool models. CONCLUSION: The model provides a quantitative assessment of the suppression of NO production by MPL and shows that the major effects are at the transcriptional level by reducing expression of iNOS mRNA. PMID- 22422322 TI - A non-invasive, low-cost study design to determine the release profile of colon drug delivery systems: a feasibility study. AB - PURPOSE: Conventional bioavailability testing of dosage forms based on plasma concentration-time graphs of two products in a two-period, crossover-design, is not applicable to topical treatment of intestinal segments. We introduce an isotope dual-label approach ((13)C- and (15)N(2)-urea) for colon drug delivery systems that can be performed in a one-day, non-invasive study-design. METHODS: Four healthy volunteers took an uncoated or a ColoPulse-capsule containing (13)C urea and an uncoated capsule containing (15)N(2)-urea. In case of colon-release (13)C-urea is fermented and (13)C detected as breath (13)CO(2). Absorbed (13)C urea and (15)N-urea are detected in urine. RESULTS: C and (15)N in urine released from uncoated capsules showed a ratio of 1.01 +/- 0.06. The (13)C/(15)N-recovery ratio after intake of a ColoPulse-capsule was constant and lower >12 h post-dose (median 0.22, range 0.13-0.48). The (13)C/(15)N-ratio in a single urine sample at t >= 12 h predicted the 24 h non-fermented fraction (13)C of <26 %. Breath (13)CO(2) indicated delayed (>3 h) release and a fermented fraction (13)C >54 %. CONCLUSIONS: Breath and urine (13)C and (15)N data describe the release-profile and local bioavailability of a colon delivery device. This allows non-invasive bioavailability studies for evaluation of colon-specific drug delivery systems without radioactive exposure and with increased power and strongly reduced costs. PMID- 22422323 TI - Pancreatitis in the setting of the metabolic syndrome. AB - There is paucity of literature on the relation of obesity with recurrent and chronic pancreatitis. We recorded the clinical details and the outcome of five patients with recurrent pancreatitis who had components of the metabolic syndrome. Their age ranged from 8 to 20 years. All five patients had acanthosis nigricans. Body mass index (BMI) could not be evaluated as these patients lost weight following episodes of pancreatitis. Three patients had two or more first degree relatives who had diabetes mellitus. Only one patient had severe necrotizing pancreatitis. Coexisting liver disease was seen in two patients. Elevated serum cholesterol levels and moderately elevated serum triglycerides along with elevated serum amylase levels observed in these patients suggest possibility of a different mechanism from that of hypertriglyceridemia-related pancreatitis. Evaluation of pancreatic steatosis should be considered in patients with pancreatitis in the setting of metabolic syndrome. PMID- 22422324 TI - Binder-free Ge nanoparticles-carbon hybrids for anode materials of advanced lithium batteries with high capacity and rate capability. AB - We present a facile synthetic route toward binder-free, highly-dispersed Ge nanoparticles in carbon matrices using one-step pyrolysis of self-assembled Ge polymer hybrids. 3-Dimensionally arranged Ge-carbon exhibits remarkably enhanced cycling properties and rate capability compared with carbon sheathed Ge lacking organization. PMID- 22422325 TI - Pediatric and young adult patients and oncofertility. AB - OPINION STATEMENT: With improving survival rates for pediatric and young adult cancer patients, considerations regarding the long-term effects of therapy have become more important. Cancer therapies are known to pose reproductive risks, though the effects may be unpredictable. All at-risk patients should have a discussion about potential treatment-related infertility before the onset of cancer therapy, and should be offered appropriate fertility preservation options. Embryo and sperm cryopreservation are considered standard therapy, though oocyte cryopreservation is gaining acceptance. Ovarian tissue cryopreservation, while still experimental, is showing great promise. It is the only option currently available to prepubertal girls. No fertility preservation options exist for prepubertal boys though some institutions may offer experimental testicular tissue cryopreservation. PMID- 22422326 TI - Coagulopathies and thrombosis: usual and unusual causes and associations, part VI. PMID- 22422327 TI - Tissue factor pathway inhibitor: new insights into an old inhibitor. AB - Blood coagulation in vivo is triggered by the tissue factor (TF) pathway. The major physiological regulator of this pathway is tissue factor pathway inhibitor (TFPI), a Kunitz-type inhibitor that regulates the activity of the TF-factor VIIa complex in a factor Xa-dependent manner, thus controlling the generation of thrombin and ultimately, fibrin. Although some of the in vivo and in vitro effects of TFPI have been described for nearly a century, the bulk of the research that has elucidated the physiology of this inhibitor has only occurred in the past 25 years. Despite this, many questions remain. This review will highlight the recent advances in knowledge related to TFPI, with an emphasis on new insights into its physiology, association with disease, and possible use as a therapeutic anticoagulant. PMID- 22422328 TI - Evaluating heparin-induced thrombocytopenia: the old and the new. AB - Heparin-induced thrombocytopenia (HIT) is a rare but potentially serious complication of heparin use. Prompt diagnosis is crucial and requires the integration of clinical assessment and laboratory testing. Pretest clinical scoring systems (i.e., 4 Ts) have been established. Immunoassays can detect the presence of antibodies directed toward heparin-platelet factor 4 (H-PF4) complexes, but provide no information about their ability to activate platelets. A low clinical score, when combined with a negative immunoassay result obviates the need for further testing. However, immunoassays and 4 Ts scores have only modest specificity. Functional testing (serotonin release assay or heparin induced platelet activation) remain important in confirming the presence of pathogenic H-PF4 antibodies, but are technically demanding to perform and limited in guiding clinical decisions in the acute setting. This review evaluates current immuno- and functional assays available in the laboratory diagnosis of HIT, and describes recent attempts to improve the specificity of enzyme immunoassays, including adopting an immunoglobulin G-specific assay and raising the optical density value cutoff for a positive result. The importance of donor selection and newer functional assays, including flow cytometry-based assays, are also discussed. A current approach to integrating clinical scoring, immunoassays, and functional testing for HIT is also outlined. PMID- 22422329 TI - Prophylaxis for venous thromboembolism: a great global divide between expert guidelines and clinical practice? AB - Our understanding of development and prevention of venous thromboembolism (VTE) has improved dramatically since Virchow described the triad of stasis, hypercoagulability, and endothelial dysfunction during the mid-1800s. A full arsenal of effective pharmacological and mechanical methods can help prevent VTE and many professional organizations have provided extensive evidence-based statements for VTE prophylaxis. Disappointingly, however, VTE has remained the major preventable cause of hospital death. Adherence rate to clinical guidelines is undesirably low. Many real-world patients have also been excluded from VTE prevention trials and hence practice guidelines recommendations. The comprehensive and repetitious formats of many available guidelines also limit their readability and applicability by nonthrombosis specialists. Moreover, some patients suffer from VTE despite complying with the contemporary prophylaxis regimens. Besides, significant heterogeneity exists in thromboprophylaxis practice and pitfalls between different countries. Last but not the least; although many at-risk patients are underprophylaxed, there is evidence to suggest that overprophylaxis (i.e., prescription of thromboprophylaxis in low-risk patients) comprises another important problem. We review the thromboprophylaxis practice and pitfalls around the world and provide recommendations on how the major obstacles can be overcome. PMID- 22422330 TI - Exposure to high altitude: a risk factor for venous thromboembolism? AB - There are several genetic and acquired risk factors for venous thromboembolism. Exposure to high altitude (HA), either during air travel, ascension of mountains, or while engaging in sports activities, has been observed to result in a hypercoagulable state, thus predisposing to thromboembolic events. Although several previous studies have suggested that conditions present at HAs contribute to establish a prothrombotic milieu, published reports are contradictory and the exact underlying mechanism remains poorly understood. Results from HA studies also show that environmental conditions at HA such as hypoxia, dehydration, hemoconcentration, low temperature, use of constrictive clothing as well as enforced stasis due to severe weather, would support the occurrence of thrombotic disorders. The three leading factors of Virchow triad, that is, venous stasis, hypercoagulability, and vessel-wall injury, all appear to be present at HA. In synthesis, the large list of environmental variables suggests that a single cause of HA-induced thromboembolic disorders (TED) may not exist, so that this peculiar phenomenon should be seen as a complex or multifactorial trait. Further investigation is needed to understand the risk of TED at HA as well as the possible underlying mechanisms. PMID- 22422331 TI - Coffee intake and cardiovascular disease: virtue does not take center stage. AB - Coffee is one of the most popular and heavily consumed beverages worldwide, despite the many different methods of preparation and presentation. The results of several epidemiological studies are suggestive for the existence of a U-shaped relationship between coffee consumption and both cardiovascular events and mortality, whereby a lower risk seems associated with low (i.e., less than one cup per day) or high (i.e., more than or equal to four cups per day) coffee intake, whereas a higher risk is reported for intermediate consumption (i.e., two to four cups per day). Most benefits are evident in individuals with a rapid caffeine metabolizer genotype and a low baseline cardiovascular risk. Benefits have also been differentially associated with consumption of decaffeinated coffee, filtered coffee, coffee consumption during lunchtime or dinner, and when coffee is produced in the Italian style (i.e., by espresso or moka). The leading favorable effects have been attributed to various compounds present in coffee. Thus, chlorogenic acids would be effective in decreasing blood pressure, systemic inflammation, risk of type 2 diabetes, and platelet aggregation, whereas caffeine intake has instead been associated with decreased body weight, as well as with increased flow-mediated dilatation and fibrinolysis. PMID- 22422332 TI - Determination of rivaroxaban in human plasma samples. AB - Rivaroxaban is one of the novel oral direct factor Xa inhibitors, which is effective in preventing thromboembolic complications at fixed doses (i.e., once daily), without the need for dose adjustment according to laboratory monitoring. Nearly 60% of rivaroxaban is cleared from circulation by glomerular filtration, 30% of which is excreted as active drug. Therefore, as renal elimination plays a pivotal role in the metabolism of this drug, impairment of renal function may be important during anticoagulation with rivaroxaban over long periods of time. The assessment of the anticoagulant effect/concentration of rivaroxaban may thus be useful in special patient populations such as in the elderly and eldest, during acute diseases with concurrent dehydration, before surgery, during bleeding or thrombotic episodes, or to verify adherence to therapy. Rivaroxaban prolongs prothrombin time in a dose-dependent, linear fashion. Activated partial thromboplastin time (APTT) is also prolonged, but in an exponential manner. Substantial differences in test results might be generated by different thromboplastin and APTT reagents. One-step prothrombin-induced clotting time assay is sensitive to low concentrations of rivaroxaban. Chromogenic substrate assays specific for factor Xa are also sensitive to rivaroxaban. Several initiatives are currently ongoing to standardize the various methods to determine rivaroxaban in human plasma samples, some of which will be summarized in this article along with the dose-dependent effects of rivaroxaban on relevant coagulation parameters. Therefore, although rivaroxaban prolongs all coagulation assays used to assess the anticoagulant effects of most anticoagulants, the most specific assay cannot be identified at present. Moreover, clinical trials are needed to determine the relationship of assay results with bleeding or thrombotic complications. PMID- 22422333 TI - Atherothrombosis in von Willebrand disease: an analysis of the literature and implications for clinical management. AB - In spite of coagulation impairment, people with congenital bleeding disorders can still develop atherosclerosis and its thrombotic complications. This issue has been particularly addressed in recent years as an increasing number of such patients now reach an elderly age and have to confront age-related comorbidities, including cardiovascular diseases, and as a consequence, challenges concerning the management of concomitant bleeding and atherothrombotic risk. Von Willebrand disease (VWD), caused by quantitative and/or functional defects of von Willebrand factor (VWF), is the most common congenital bleeding disorder, with an estimated prevalence in the general population of 1 to 2%, although clinically significant VWD is much less common. Despite the high population impact of VWD and increasing knowledge of the pathophysiological role of VWF in atherothrombosis, data concerning atherosclerosis and its vascular complications in VWD patients are rather limited, and even more scarce when clinical management is considered. The relevance of this association is certainly underestimated and, possibly, contributes to bleeding complications observed in patients on antithrombotic treatment or undergoing invasive cardiovascular procedures. This review will analyze the available literature data and discuss the implications for management of VWD patients with atherothrombosis, in the light of the information of bleeding risk in the general population and of recent, growing data from hemophilia patients. PMID- 22422334 TI - High platelet reactivity and antiplatelet therapy resistance. AB - The term resistance has been applied to interindividual variability in platelet reactivity during antiplatelet therapy or to thrombosis despite appropriate therapy. In particular "aspirin resistance" and "clopidogrel resistance" have been the subject of intense investigation for their association with poor cardiovascular outcomes. Several mechanisms have been investigated including resistance arising from poor bioavailability, especially in clopidogrel therapy as resulting from a loss of function variant in hepatic metabolism required for prodrug activation. A limitation of studies linking on-treatment reactivity and clinical outcome is that they have been performed in high-risk patients with recent atherothrombotic disease. On-treatment platelet reactivity correlates with acuity of recent atherothrombosis, and variability in pretreatment platelet function predicts on-treatment platelet function for both aspirin and clopidogrel. It is therefore likely that high on-treatment platelet function at the time of testing may often result from underlying platelet hyperreactivity related to acute atherothrombosis, rather than true pharmacological resistance. The association of high on-treatment platelet reactivity with poor clinical outcomes may therefore be attributed to variability in underlying burden of disease instead of, or in addition to, pharmacological resistance to antiplatelet therapy. PMID- 22422335 TI - Hemostatic properties of the lymph: relationships with occlusion and thrombosis. AB - Lymphatic thrombosis is a rare occurrence, and although its frequency is likely underestimated, its burden remains substantially lower than that of venous or arterial thrombosis. Current evidence suggests that despite measurable levels of fibrinogen, von Willebrand factor and other coagulation factors in the lymph, fibrin generation is substantially inhibited under physiological conditions, essentially making the lymph a hypocoagulable biological fluid. Although factor VIIa-tissue factor-catalyzed activation of factor X is possible in the lymph, fibrin generation is largely counteracted by the unavailability of cell surface anionic phospholipids such as those physiologically present on blood platelets, combined with only low levels of coagulation factors, and the strong inhibitory activity of heparin, antithrombin, and tissue factor pathway inhibitor. Enhanced fibrinolytic activity further contributes to reduce the development and growth of lymph clots. Nevertheless, lymphatic thrombosis is occasionally detected, especially in the thoracic duct, axillary, or inguinal lymphatics. Pathogenetic mechanisms are supported by the release of thromboplastin substances from the injured lymphatic endothelium accompanied by chronic obstruction of lymph flow in the presence of a hypercoagulable milieu, thereby mirroring the Virchow triad that otherwise characterizes venous thrombosis. In theory, any source of lymphatic vessel occlusion, such as internal obliteration, external compression, or increased lymphatic pressure, might predispose to localized lymphatic thrombosis. The leading pathologies that can trigger thrombosis in the lymphatic vessels include cancer (due to external compression, neoplastic obliteration of the lymphatic lumen by metastatic cells, or lymphatic dysfunction after lymph node dissection), infections (especially lymphatic filariasis or sustained by Chlamydia trachomatis, Mycobacterium tuberculosis, Treponema pallidum, or Streptococcus pyogenes), congestive heart failure, chronic edema and inflammation of the distal lower limb, complications of central venous catheterization, coronary artery bypass grafting, thoracic outlet syndrome, and amyloidosis. PMID- 22422336 TI - Degradation of troponin I in serum or plasma: mechanisms, and analytical and clinical implications. AB - A prolonged myocardial ischemia, which results from a total deprivation of blood supply to an area of cardiac muscle for an appreciable period of time, is the leading mechanism responsible for acute myocardial infarction (AMI). The irreversible injury of myocardiocytes and the subsequent release of a variety of intracellular components into blood is the cornerstone of the diagnosis of AMI. Cardiac troponins are advocated as the biochemical gold standards among the various biomarkers of plaque instability, plaque rupture, ischemia, reversible cellular injury, and early and late necrosis (i.e., irreversible injury). The assessment of cardiac troponins in the diagnostic approach of patients with chest pain presents, however, some specific challenges due to the complex mechanisms of release from the injured myocardium, as well as to the enzymatic degradation by cardiac and extracardiac proteases (i.e., calpains, caspases, cathepsin L, and gelatinase A) that might alter the immunoreactivity (and thus laboratory detection) of the molecules. These two aspects will be discussed in this article, with specific focus on cardiac troponin I, as a variety of immunoassays based on antibodies which recognize different epitopes on the molecule is available for the measurement of this important cardiac biomarker. PMID- 22422337 TI - The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism. AB - Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT. PMID- 22422338 TI - Risk factors associated with self-injurious behaviors in children and adolescents with autism spectrum disorders. AB - While self-injurious behaviors (SIB) can cause significant morbidity for children with autism spectrum disorders (ASD), little is known about its associated risk factors. We assessed 7 factors that may influence self-injury in a large cohort of children with ASD: (a) atypical sensory processing; (b) impaired cognitive ability; (c) abnormal functional communication; (d) abnormal social functioning; (e) age; (f) the need for sameness; (g) rituals and compulsions. Half (52.3%, n = 126) of the children (n = 241, aged 2-19 years) demonstrated SIB. Abnormal sensory processing was the strongest single predictor of self-injury followed by sameness, impaired cognitive ability and social functioning. Since atypical sensory processing and sameness have a greater relative impact on SIB, treatment approaches that focus on these factors may be beneficial in reducing self-harm in children with ASD. PMID- 22422339 TI - The effect of gestational age on symptom severity in children with autism spectrum disorder. AB - Between 2006 and 2010, two research-validated instruments, Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were filled out online by 4,188 mothers of Autism Spectrum Disorder (ASD) children, aged 4-21, as part of voluntary parental participation in a large web-based registry. Univariate and multivariate linear regression analysis (adjusted for child's sex, ability to verbalize, categorical IQ score, and fetal growth rate) demonstrated significantly higher SCQ and SRS scores for ASD children of both preterm (<37 weeks) and post-term (>42 weeks) gestational age (GA) compared to ASD children of normal GA, thus indicating that both preterm and post-term children manifest increased ASD symptomatology. Normal GA at birth appears to mitigate the severity of autistic social impairment in ASD children. PMID- 22422340 TI - Inflammatory responses induced by fluoride and arsenic at toxic concentration in rabbit aorta. AB - Epidemiological and experimental studies have demonstrated the atherogenic effects of environmental toxicant arsenic and fluoride. Inflammatory mechanism plays an important role in the pathogenesis of atherosclerosis. The aim of the present study is to determine the effect of chronic exposure to arsenic and fluoride alone or combined on inflammatory response in rabbit aorta. We analyzed the expression of genes involved in leukocyte adhesion [P-selectin (P-sel) and vascular cell adhesion molecule-1(VCAM-1)], recruitment and transendothelial migration of leukocyte [interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1)] and those involved in pro-inflammatory cytokines [interleukin-6 (IL-6)]. We found that fluoride and arsenic alone or combined increased the expression of VCAM-1, P-sel, MCP-1, IL-8, and IL-6 at the RNA and protein levels. The gene expressions of inflammatory-related molecules were attenuated when co-exposure to the two toxicants compared with just one of them. We also examined the lipid profile of rabbits exposed to fluoride and (or) arsenic. The results showed that fluoride slightly increased the serum lipids but arsenic decreased serum triglyceride. We showed that inflammatory responses but not lipid metabolic disorder may play a crucial role in the mechanism of the cardiovascular toxicity of arsenic and fluoride. PMID- 22422341 TI - Characterization of the role of protein-cysteine residues in the binding with sodium arsenite. AB - To better characterize the interaction of protein-cysteines with sodium arsenite, arsenic-binding proteins were identified from the arsenic-resistant Chinese hamster ovary cell line SA7 using a p-aminophenylarsine oxide (PAO)-agarose matrix in combination with proteomic techniques. Twenty of the isolated arsenic binding proteins were further peptide-mapped by MALDI-Q-TOF-MS. The binding capacity of PAO-agarose-retained proteins was then verified by re-applying Escherichia coli overexpressed recombinant proteins with various numbers of cysteine residues onto the PAO-agarose matrix. The results showed that recombinant heat shock protein 27 (HSP27, with one cysteine residue), reticulocalbin-3 (RCN3, with no cysteine residue), galectin-1 (GAL1, with six cysteine residues), but not peroxiredoxin 6 (Prdx6, with one cysteine residue but not retained by the PAO-agarose matrix), were bound to the PAO-agarose matrix. The six free cysteine residues in GAL1 were individually or double-mutated to alanine by means of site-directed mutagenesis and subjected to CD and ICP-MS analysis. The binding capacity of GAL1 for sodium arsenite was significantly attenuated in C16A, C88A and all double mutant clones. Taken together, our current data suggest that the cysteine residues in GAL1 may play a critical role in the binding of arsenic, but that in the case of RCN3 and Prdx6, this interaction may be mediated by other factors. PMID- 22422342 TI - In vivo visualisation of nanoparticle entry into central nervous system tissue. AB - Because the potential neurotoxicity of nanoparticles is a significant issue, characterisation of nanoparticle entry into the brain is essential. Here, we describe an in vivo confocal neuroimaging method (ICON) of visualising the entry of fluorescent particles into the parenchyma of the central nervous system (CNS) in live animals using the retina as a model. Rats received intravenous injections of fluorescence-labelled polybutyl cyanoacrylate nanoparticles that had been synthesised by a standard miniemulsion polymerisation process. We performed live recording with ICON from before and up to 9 days after particle injection and took photomicrographs of the retina. In addition, selective retrograde labelling of the retinal ganglion cells was achieved by stereotaxic injection of a fluorescent dye into the superior colliculus. Using ICON, we observed vascular kinetics of nanoparticles (wash-in within seconds), their passage to the retina parenchyma (within minutes) and their distribution (mainly cellular) under in vivo conditions. For the detection of cell loss--which is important for the evaluation of toxic effects--in another experiment, we semi-quantitatively analysed the selectively labelled retinal neurons. Our results suggest that the dye per se does not lead to neuronal death. With ICON, it is possible to study nanoparticle kinetics in the retina as a model of the blood-brain barrier. Imaging data can be acquired within seconds after the injection, and the long term fate of cellular uptake can be followed for many days to study the cellular/extracellular distribution of the nanoparticles. ICON is thus an effective and meaningful tool to investigate nanoparticle/CNS interactions. PMID- 22422343 TI - A walk around the A3-coupling. AB - In recent years, the transition-metal catalyzed three-component coupling of an aldehyde, an alkyne and an amine, commonly called A(3)-coupling, has been established as a convenient and general approach towards propargylamines. Furthermore, the A(3)-coupling has found a broad application as a key step in the construction of various nitrogen-containing heterocycles, biologically active compounds and natural products. Several interesting modifications of the A(3) coupling as well as different tandem reactions involving A(3)-coupling have been developed. This tutorial review aims to highlight the current achievements in the field of A(3)-couplings and related transformations. PMID- 22422344 TI - Radiotolerance of phosphatases of a Serratia sp.: potential for the use of this organism in the biomineralization of wastes containing radionuclides. AB - Aqueous wastes from nuclear fuel reprocessing present special problems of radiotoxicity of the active species. Cells of Serratia sp. were found previously to accumulate high levels of hydrogen uranyl phosphate (HUP) via the activity of a phosphatase enzyme. Uranium is of relatively low radiotoxicity whereas radionuclide fission products such as (90)Sr and (137)Cs are highly radiotoxic. These radionuclides can be co-crystallized, held within the bio-HUP "host" lattice on the bacterial cells and thereby removed from contaminated solution, depending on continued phosphatase activity. Radiostability tests using a commercial (60)Co gamma-source showed that while cell viability and activity of purified phosphatase were lost within a few hours on irradiation, whole-cell phosphatase retained 80% of the initial activity, even after loss of cell culturability, which was increased to 100% by the incorporation of mercaptoethanol as an example radioprotectant, beyond an accumulated dose of >1.3 MGy. Using this co-crystallization approach (without mercaptoethanol) (137)Cs(+) and (85)Sr(2+) were removed from a simulated waste selectively against a 33-fold excess of Na(+). PMID- 22422345 TI - Simultaneous determination of four shanzhiside methylester derivatives in rabbit plasma by liquid chromatography/tandem mass spectrometry. AB - A simple and sensitive high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for simultaneous determination of shanzhiside methylester and its three derivatives in rabbit plasma. The method showed good linearity and no endogenous material interfered with the marked compounds and internal standard (IS) capatol peaks. Samples were processed by acetonitrile precipitation. Chromatography was performed using a C18 column (150 * 3.9 mm i.d., 4 um). The mobile phase consisted of methanol and water (60:40, v/v) during a total run time of 7 min. The main mass parent ions and daughter ions pairs (m/z) for monitoring were: shanzhiside methylester, 429.0/267.4; 8-O-acetyl shanzhiside methylester, 470.9/411.3; loganin, 413.2/251.4; phloyoside II, 479.2/281.3; and IS 385.2/203.3. Finally, the method was applied to a pharmacokinetic study of rabbits following intravenous administration of iridoid glycosides extracted from traditional herb Lamiophlomis rotata. PMID- 22422346 TI - Spontaneous cervical epidural hematoma associated with thunderclap headache. PMID- 22422347 TI - Primary headache in the elderly in South-East Asia. AB - Headache aetiology and presentation are considerably different in elderly individuals. However, literature on headache characteristics among Asians is limited. The objective of this study was to evaluate the headache characteristics among elderly in an outpatient clinic setting in Malaysia, a South-East Asian country with diverse ethnicity. In this prospective cross-sectional study, patients presenting with headache to Neurology and Primary Care Clinics of University Malaya Medical Centre between February 2010 and July 2010 were included. Data for consecutive eligible adult patients were entered in a prospective headache registry. International Headache Criteria II (ICHD-II) were used to classify various headache subtypes. Patients with headache due to intracranial space occupying lesions were excluded. Patient were divided into two age groups-elderly (55 years and above) and younger (less than 55 years of age). Of the 175 screened patients, 165 were included in the study-70 in elderly age group and 95 in younger group. Tension-type headache was the commonest subtype (45.7 %) among the elderly while Migraine without aura (54.7 %) was more common in young adults. More elderly patients suffered from chronic daily headache as compared to younger patients (47.1 vs. 28.4 %; p = 0.015). Headache subtypes and frequency differ considerably among elderly South East Asian patients. PMID- 22422348 TI - Unusual high dose of tacrolimus in liver transplant patient, a case report. AB - CASE: We describe the case of a liver transplant patient who had great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. The patient was homozygous for the CYP3A5*3 allele. However, the respective donor carried the wild-type CYP3A5*1/*1 genotype. Regarding ABCB1 SNPs at exon 21 and 26, the patient showed the 2677GT and 3435CC genotypes. For the corresponding donor we observed the 2677GG and 3435CC wild-type genotypes. One, two and three weeks after transplantation the patient received daily 0.219, 0.287 and 0.273 mg/kg of tacrolimus, respectively. However, the corresponding tacrolimus trough blood levels were of 4.6, 5.6 and 6.1 ng/mL. The tacrolimus target level of 10.4 ng/mL was finally reached after 1 month of therapy. During the entire period of observation the kidney showed no sign of damage. No other signs of toxicity were reported except for the occurrence of an isolated systolic hypertension. CONCLUSIONS: CYP3A5 genotyping may represent a useful tool to better evaluate the appropriate initial dose of tacrolimus for patients carrying a liver with the CYP3A5*1/*1 genotype. PMID- 22422349 TI - Levosimendan does not improve cardiac output or blood pressure in a rodent model of propranolol toxicity when administered using various dosing regimens. AB - BACKGROUND: Levosimendan (CAS: 141505-33-1) is a myocardial calcium sensitizer that improves myocardial contractility in various forms of heart failure. It produces a moderate improvement in cardiac output (CO) without an improvement in blood pressure (BP) in verapamil and metoprolol poisoned rodents. AIM: To assess the effect of various levosimendan dosing regimens on hemodynamics in a rodent model of propranolol poisoning. METHOD: Male Wistar rats (350-450 g) were anesthetized, ventilated, and instrumented to record BP, heart rate (HR), and CO. Propranolol was infused continually. When BP dropped to 50% of baseline rats received 1 of 7 treatments: (1) 0.9% saline (control), (2) levosimendan 36 MUg/kg loading dose then 0.6 MUg/kg per min, (3) levosimendan 0.6 MUg/kg per min, (4) epinephrine 0.5 MUg/kg per min, (5) levosimendan 70 MUg/kg loading dose then 1.2 MUg/kg per min, (6) levosimendan 1.2 MUg/kg per min, and (7) levosimendan 70 MUg/kg loading dose alone. Hemodynamics were recorded every 10 minutes for 70 minutes. Cardiac output, mean arterial pressure, and HR for each group were compared with control. RESULTS: All groups had comparable baseline and maximal toxicity hemodynamics prior to initiation of treatment. Levosimendan did not improve CO or BP with any dosing regimen. Blood pressure tended to be lower than control for all doses of levosimendan. Epinephrine significantly improved BP but not CO compared to all other treatment groups. Survival did not differ between groups. CONCLUSIONS: Unlike in verapamil and metoprolol poisoning models, levosimendan did not improve CO or survival in propranolol poisoning. Epinephrine improved BP, but not CO, suggesting that its actions were due to peripheral vasoconstriction. PMID- 22422350 TI - Design and synthesis of screening libraries based on the muurolane natural product scaffold. AB - The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D(5.5), hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC(50) values ranging from 14 to 33 MUM. PMID- 22422351 TI - Estimation of extracellular fluid volume in children. AB - BACKGROUND: Many equations have been developed to estimate various body fluid volumes from height and weight, but few have been developed for children. The aim of this study was to compare four height/weight formulae for estimating extracellular fluid volume (eECV) in children against measured extracellular fluid volume (mECV). METHODS: The mECV was obtained from plasma Cr-51-EDTA clearance data used for routine measurement of glomerular filtration rate (GFR) in two groups of children (n=182 and 69, respectively). eECV obtained using the formulae of Abraham et al. (Clin J Am Assoc Nephrol 6:741-747, 2011) and Friis Hansen (Pediatrics 28:169-181, 1961) were compared with mECV in both patient groups. The formulae of Bird et al. (J Nucl Med 44:1037-1043, 2003) and of Peters (Nucl Med Commun 32:375-380, 2011) were originally based on groups 1 and 2, respectively, so the eECV from them was compared with the mECV in groups 2 and 1, respectively. RESULTS: The eECV from the Friis-Hansen formula underestimated the mECV in larger children. Biases (mean differences between eECV and mECV) from the Bird (0.146 l) and Peters (0.029 l) formulae were not significantly different from zero, but those from the Abraham formula was higher than zero (0.694 and 0.588 l in groups 1 and 2; p<0.001). Precisions (standard deviations of the biases) of these three formulae were similar, ranging from 0.731 l (Peters) to 0.878 l (Abraham, group 2; p>0.1). CONCLUSION: The formulae of Bird, Peters and Abraham have similar precisions. The higher bias of the Abraham formula is probably due to the higher values of mECV on which their formula was based. The Friis-Hansen formula no longer has a place. PMID- 22422352 TI - [What are the reasons for patient preference? A comparison between oral and subcutaneous administration]. AB - BACKGROUND: Today there are different subcutaneous and three oral applicable medications for prevention of venous thromboembolism after knee and hip replacement. It is a general opinion that patients will prefer oral administration. However, until today there has been no study that analysed patient preferences and motives for deciding on the kind of administration. These data would be of interest since the consideration of patient preferences could improve adherence. The present study analysed patient preferences regarding oral or subcutaneous administration of medication after elective hip or knee replacement surgery. The results will have implications for clinical practice and for decision-making concerning the kind of administration. MATERIAL AND METHODS: This prospective, multi-centric, observational study was conducted in six emergency hospitals and six rehabilitation hospitals. 178 current hip and knee replacement patients undergoing thromboprophylaxis and at least one further oral medication were interviewed. Subjective assessment data of patients were collected on study-specific questionnaires (epidemiological data, amount and background of general oral medication, details on subcutaneous thromboprophylaxis, preference of administration, causes for preference). RESULTS: 71.91 % of the interviewed patients preferred the daily intake of a tablet, whereas only 14.61 % favoured the daily subcutaneous injection. Main causes for the preference of oral administration were easier (86.6 % of nominations) and less complex (73.1 % of nominations) handling. 70.9 % reported that one more oral application would be unproblematic. Painlessness of oral administration was relevant for 65.7 %. Causes for preferring subcutaneous administration were "safety" (55.3 % of nominations) and an assumption of a generally better effectivity of subcutaneous (47.4 % of nominations) administration. Subjective discomfort induced by subcutaneus administration increased with the time interval since surgery. Less than 5 % of patients prefer subcutaneous administration due to the high volume of their existing oral medication. CONCLUSION: Patient approval of oral administration is governed by practical and comfort issues. In general, patients on existing oral medications are uncritical concerning a temporary additional oral medication. The clear discomfort measured in association with subcutaneous administration supports the idea that the oral route will have advantages for patient adherence. In particular this is of relevance with increasing time interval since surgery. Patients who have a very high volume of oral medications will probably profit from subcutaneous administration. The main reasons that patients gave for the preference of subcutaneous administration are based on incorrect knowledge. Therefore it is necessary to improve patient education concerning the existing alternatives for thromboprophylaxis. PMID- 22422353 TI - [Subsequent treatment following proximal femoral fracture - who, when, where? Assessment of the current situation in Germany]. AB - BACKGROUND: Geriatric fractures are an increasing challenge for the German health care system. While the acute care for patients with proximal femoral fractures is already standardised, differences remain in the further treatment and rehabilitation. A survey was conducted in cooperation with the section of geriatric trauma (AG Alterstraumatologie) of the German Association of Trauma Surgery (DGU) to point out existing problems in this group of patients. MATERIAL AND METHODS: In October/November 2010 an electronic questionnaire, assessing the medical care for patients after proximal femoral fracture, was sent to 1080 medical directors of trauma and orthopaedic surgery departments in Germany. RESULTS: 339 (31.4 %) departments participated. The analysis revealed that 57 % of the hospitals had cooperation agreements with aftercare hospitals. 37 % of all hospitals had problems in finding a rehabilitation hospital. The initiation of a rehabilitation procedure is almost exclusively based on the doctors' decision. Influence of employees with other professions is marginal. Mobility and Barthel index before the release from the acute care hospital are major factors in the decision making. CONCLUSION: The questionnaire confirms that there are problems in the aftercare service of geriatric patients all around Germany. A further improvement of collaboration between acute and aftercare hospitals is required. PMID- 22422354 TI - Thymidylate synthase mRNA levels in plasma and tumor as potential predictive biomarkers for raltitrexed sensitivity in gastric cancer. AB - Different chemotherapeutic agents currently available are effective only in certain subsets of patients. Predictive biomarkers will be helpful in choosing those agents and can improve the clinical efficiency by a more personalized chemotherapeutic approach. Raltitrexed is a novel water-soluble quinazoline folate analogue and can improve the efficiency of gastric cancer treatment, but its predictive biomarker remains unclear. The aim of our study was to investigate the role of plasma and tumor thymidylate synthase (TS) mRNA levels as predictive biomarkers for raltitrexed in gastric cancer. In total, 125 freshly removed gastric tumor specimens and corresponding blood samples before surgery were collected. Raltitrexed sensitivity was determined by histoculture drug response assay procedures. TS mRNA levels in tumor and plasma were determined by quantitative reverse transcription polymerase chain reaction. Plasma TS mRNA level in cancer patients was significantly higher than in healthy subjects (p = 0.009) and was significantly correlated with TS mRNA level in tumor tissues (r = 0.665, p < 0.001). Tumor and plasma TS mRNA expression levels were significantly lower in raltitrexed-sensitive group than in resistant group (p = 0.007 and 0.013, respectively). The sensitivity and accuracy of raltitrexed sensitivity prediction based on plasma TS mRNA levels were 82 and 60%, respectively, whereas the prediction based on tumor TS mRNA reached 70% sensitivity and 68% accuracy. These results indicate that TS mRNA level in plasma can mirror tumor TS mRNA level, and both of them can be used to predict raltitrexed sensitivity in gastric cancer. PMID- 22422355 TI - Commentary: a sociologist's view on community genetics. AB - This commentary illustrates and discusses potential research directions for sociologists and anthropologists interested in the field of community genetics and its emerging networks of individuals genetically at risk. Community genetics the application of medical genetics in community settings for the benefit of individuals-also involves social issues of lay-professional misunderstandings (and more recently also the different perspectives of various expert communities), stigmatization, discrimination, and medicalization. Focusing on a socio-anthropological perspective regarding the views and disagreements surrounding the definition and scope of community genetics, I overview several epistemological, methodological, and practical contributions that such perspective can offer to the study of community genetics. PMID- 22422356 TI - The importance and value of EQA for diagnostic genetic laboratories. AB - Quality control in a laboratory setting requires the establishment of effective training, standard operating procedures, internal quality control, validation of tests and external quality assessment (EQA). A structured quality management system subject to regular internal and external audits will minimise the error rate. EQA, therefore, gives assurance, both to patients and referring clinicians, that the diagnostic laboratory is competent to produce results that are reliable and accurate. EQA is educational and aims to improve and validate the overall quality of genetic service to the user. Regular EQA assessment compares laboratory performance against set standards and also allows comparison between laboratories. Sometimes EQA can also help to define good standards (best practice), although this does depend on the type of EQA test. EQA interprets best practice standards (=quality) into a numerical score (=quantity). While international bodies or professional organisations set these standards, EQA is able to assess whether these standards are met, with any omissions resulting in a reduction in the total score. Although EQA has an educational role rather than a punitive role, critical errors affecting clinical management will result in a laboratory receiving a poor performance categorisation. Accurate analysis and interpretation are essential quality parameters that require extensive knowledge of the aetiology of genetic abnormalities/disease and risk factors. Training of staff in interpretation of the results together with a comprehensive means of reporting normal and abnormal genetic results underpins the diagnostic service to the patient. Poor-performing laboratories are, therefore, encouraged to review their internal processes. EQA schemes that have been established for many years have seen improvements in the analytical and reporting content over time, thereby improving the quality of diagnostic service available to patients. PMID- 22422357 TI - How obedience of marriage rules may counteract genetic drift. AB - Marriage rules are a common component of many human societies. Since these rules, translated into mating patterns, would imply inbreeding, the question arises as to their long-term population genetic effects. We show by simulation that continuous unilateral or bilateral cross-cousin mating, reflecting the most common form of prescribed marriage, increases homozygosity but at the same time slows down considerably the loss of gene diversity due to genetic drift. For X chromosomal genes, this effect is more pronounced if marriage, translated into mating, is matrilateral rather than patrilateral. Although the maintenance of gene diversity, in principle, could have conferred a selective advantage to the initiation of marriage rules, the mechanisms driving such a move are difficult to perceive. We therefore conclude that the possible preservation of gene diversity through marriage rule-induced inbreeding is a by-product, not the source, of a cultural invention that instead rested on foresight and strategic thinking. PMID- 22422358 TI - Scope of definitions of genetic testing: evidence from a EuroGentest survey. AB - Genetic testing is a term used in different settings, often with very different meanings. There are only very few studies published about the various possible definitions of "genetic testing", and evidence is lacking from its use in professional practise. The need for precise definitions is particularly felt when producing legislation, policy recommendations or professional guidelines. EuroGentest Unit 3 (Clinical, Community and Public Health Genetics) had, as one of its objectives, to analyse definitions of "genetic testing" and propose consensus working definitions, if possible. To assess what was meant when using this term, in each individual professional context, a questionnaire was developed to evaluate if a consensus definition was desirable and achievable and what items or information should be included in the scope of such a definition. The questionnaire was sent to all EuroGentest partners and other registered users of its website; 135 answers were received, a response rate of 22%. The need for a consensus definition was acknowledged by the vast majority, although there was much less concordance about the possibility of attaining one. Clinical geneticists were the most supportive for context-dependent definitions. Conflicting perspectives arose, however, when discussing the inclusion of some type of tests, material or technology used. At issue seemed to be the distinction between the concepts of genetic material-based testing and genetic information. PMID- 22422359 TI - Assessing the risks and benefits of diagnosing genetic conditions with variable phenotypes through population screening: Klinefelter syndrome as an example. AB - Consideration of postnatal population-based genetic screening programs is becoming increasingly common. Assessing the medical and psychosocial impacts of this can be particularly complex for genetic conditions with variable phenotypes, especially when outcomes may be more related to quality of life rather than reducing physical morbidity and mortality. In this article, we present a framework for assessing these impacts, by comparing diagnosis and non-diagnosis at different age points. We use the example of Klinefelter syndrome, a common yet frequently under-diagnosed genetic condition for which interventions are available. This framework can be used to supplement established screening guidelines and inform decision-making. PMID- 22422360 TI - Recent advances in the epidemiologic investigation of risk factors for asthma: a review of the 2011 literature. AB - The present review aims to identify and summarize epidemiologic investigations published during 2011 on the environmental risk factors for asthma. Potentially eligible papers were identified by a MEDLINE search. In total, 1,130 items were retrieved. Based on a broad definition of environment, the following topics were included: obesity, diet, vitamin D, air pollution, farming environment, and social factors. Some of the more relevant contributions included evidence that 1) obesity precedes asthma, 2) fruit consumption is longitudinally associated with a lower risk of asthma and atopy, 3) a comprehensive statewide smoking ban was followed by a reduction in hospital admissions for asthma, 4) asthma is one of the diseases showing the largest burdens due to environmental tobacco smoke, 5) traffic-related urban air pollution is associated with bronchial inflammation as measured by fractional exhaled nitric oxide and uncontrolled asthma, 6) aeroallergens and desert dust may contribute to the short-term effects of air pollution and asthma, and 7) maternal exposure to air pollution before and during pregnancy may alter the immune competence in offspring. PMID- 22422361 TI - Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. AB - STUDY OBJECTIVE: To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT (QTc) interval. DESIGN: Randomized, partial-blind, placebo-controlled, single-dose, 3-period, balanced crossover study. SETTING: Clinical research unit. SUBJECTS: Forty-two healthy subjects were randomized; of these subjects, 38 completed the study, three withdrew early because of protocol violations, and one was lost to follow-up. INTERVENTION: Subjects were randomized to receive three single doses of the following treatments: dolutegravir 250-mg suspension, moxifloxacin 400-mg tablet, and placebo suspension; each treatment was separated by a 14-day washout period. Treatment with the dolutegravir and placebo suspension was blinded, whereas treatment with moxifloxacin was open label. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetic exposure at a supratherapeutic dose of dolutegravir 250 mg was 2 4 times higher than the pharmacokinetic exposure at clinically relevant dosages (50 mg once or twice/day). The upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QTc interval (DeltaDeltaQTcF) using Fridericia's formula was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with moxifloxacin, a positive control for QT-interval prolongation. The maximum DeltaDeltaQTcF values for dolutegravir and moxifloxacin were observed at 4 hours: 1.99 msec (90% CI -0.55-4.53 msec) and 9.58 msec (90% CI 7.05-12.11 msec), respectively. CONCLUSION: This pharmacokinetic pharmacodynamic model demonstrates no relationship between dolutegravir plasma concentration and DeltaDeltaQTcF. Furthermore, a supratherapeutic dose of dolutegravir was generally well tolerated without any serious or severe adverse events. As such, dolutegravir does not affect cardiac repolarization. PMID- 22422362 TI - High-pressure phase transition of Bi2Fe4O9. AB - The high-pressure behaviour of Bi2Fe4O9 was analysed by in situ powder and single crystal x-ray diffraction and Raman spectroscopy. Pressures up to 34.3(8) GPa were generated using the diamond anvil cell technique. A reversible phase transition is observed at approximately 6.89(6) GPa and the high-pressure structure is stable up to 26.3(1) GPa. At higher pressures the onset of amorphization is observed. The crystal structures were refined from single crystal data at ambient pressure and pressures of 4.49(2), 6.46(2), 7.26(2) and 9.4(1) GPa. The high-pressure structure is isotypic to the high-pressure structure of Bi2Ga4O9. The lower phase transition pressure of Bi2Fe4O9 with respect to that of Bi2Ga4O9 (16 GPa) confirms the previously proposed strong influence of cation substitution on the high-pressure stability and the misfit of Ga3+ and Fe3+ in tetrahedral coordination at high pressure. A fit of a second order Birch-Murnaghan equation of state to the p-V data results in K0 = 74(3) GPa for the low-pressure phase and K0 = 79(2) GPa for the high-pressure phase. The mode Gruneisen parameters were obtained from Raman-spectroscopic measurements. PMID- 22422363 TI - Variable electric fields for high throughput electroporation protocol design in curvilinear coordinates. AB - The mathematical solution to the electric field equation in cylindrical coordinates, has suggested to us a new experimental methodology and device for reducing experimental effort in designing electroporation protocols. Using a new cylindrical electroporation system, we show, with an Escherichia coli cell model, how key electroporation parameters emerge precisely from single experiments rather than through interpolation from numerous experiments in the conventional Cartesian electroporation system. PMID- 22422364 TI - Chemical transformations supported by the [Re6(MU3-Se)8]2+ cluster core. AB - This Perspective article discusses three interesting chemical transformations promoted by the octahedral [Re(6)(MU(3)-Se)(8)](2+) cluster core. These include (1) nucleophilic addition of alcohols to cluster-bound nitrile(s) to produce imino ester complexes; (2) synthesis of cluster-imine complexes with geometric specificity by reacting cluster nitrile solvates with organic azides; and (3) preparation and reactivity studies of carbonyl complexes of the cluster. We found that cluster-bound nitrile ligands were activated toward nucleophilic attack by methanol or ethanol, affording predominantly the Z-configured cluster-imino ester complexes, for which a mechanism evoking bifurcated hydrogen bonding interactions involving both the alcohol OH group and two nearest Se atoms of the cluster core was proposed. When reacted with organic azides, cluster-bound nitrile ligands were displaced and cluster-imine complexes were obtained, presumably through the formation of the corresponding cluster-azide complexes, followed by their photodecomposition. Lastly, cluster complexes featuring all-terminal carbonyl ligands were synthesized. Back-bonding interactions were verified, both experimentally and by computational studies. Their thermal and photo-stabilities were also evaluated, so was their reactivity toward methyl lithium for the eventual making of cluster-carbene catalysts. These findings, together with those by others, portend an exciting, new direction in the chemistry of solid-state type transition metal clusters. PMID- 22422365 TI - Hierarchical supramolecular structuring and dynamical properties of water soluble polyethylene glycol-perylene self-assemblies. AB - The structural and dynamical properties of dilute aqueous solutions of poly(ethylene glycol)-perylene diimides (PEG(n)-PDI) have been investigated by means of static and dynamic light scattering, TEM microscopy, and small-angle X ray scattering experiments. The amphiphilic PEG(n)-PDI molecules first self assemble into stable and compact primary stacks of a few units of planar PDI through hydrophobic and pi-pi interactions. These primary stacks subsequently arrange in large and globular aggregates of typically 100-250 nm via weak PEG chain interpenetration. Surprisingly, the scattered electric field autocorrelation function g((1))(q,t) measured by dynamic light scattering evolves over very long periods of times (several months) and up to a bimodal distribution. The fast relaxation mechanism is associated to the diffusion of free primary stacks, whereas the slower relaxation still indicates the presence of large self-assemblies. Kinetic experiments show that the large supramolecular aggregates slowly release the free primary stacks whose proportion increases with time. This dissociation depends on several parameters such as PEG side chain length, total concentration, and shaking. PMID- 22422366 TI - Bilateral simultaneous breast reconstruction with SGAP flaps. AB - BACKGROUND: Two work-horse approaches to postmastectomy breast reconstruction are the deep inferior epigastric perforator flap and the superior gluteal artery perforator (SGAP) flap [and its variation, the lateral septocutaneous superior gluteal artery perforator flap]. Our purpose was fourfold: 1) to analyze our experience with the SGAP flaps for simultaneous bilateral breast reconstruction; 2) to analyze our experience with lateral septocutaneous superior gluteal artery perforator flaps for that procedure; 3) to compare our results with those in the literature; and 4) to highlight the importance of preoperative three-dimensional computed tomographic angiography. METHODS: A retrospective chart review was completed for 23 patients who underwent breast reconstruction between December 2005 and January 2010 via an SGAP flap (46 flaps). We reviewed flap weight, ischemia time, length of stay, overall flap survival, fat necrosis development, and emergency re-exploration. RESULTS: Mean weights were 571.2 +/- 222.0 g (range 186-1,117 g) and 568.0 +/- 237.5 g (range 209-1,115 g) for the left and right buttock flap, respectively. Mean ischemia time was 129.1 +/- 15.7 and 177.7 +/- 24.7 minutes for the first and second flap, respectively. Mean hospital stay was 5.3 +/- 2.5 days. All flaps survived. Fat necrosis developed in five flaps (10.8%), and emergency re-exploration was required in three patients (three flaps). CONCLUSIONS: When harvesting abdominal tissue is a poor option, the SGAP flap is an efficacious procedure for patients desiring autologous breast reconstruction, and bilateral procedures can be performed simultaneously. PMID- 22422367 TI - Understanding the mechanism of cellulose dissolution in 1-butyl-3 methylimidazolium chloride ionic liquid via quantum chemistry calculations and molecular dynamics simulations. AB - While N,N'-dialkylimidazolium ionic liquids (ILs) have been well-established as effective solvents for dissolution and processing of cellulose, the detailed mechanism at the molecular level still remains unclear. In this work, we present a combined quantum chemistry and molecular dynamics simulation study on how the ILs dissolve cellulose. On the basis of calculations on 1-butyl-3 methylimidazolium chloride, one of the most effective ILs dissolving cellulose, we further studied the molecular behavior of cellulose models (i.e. cellulose oligomers with degrees of polymerization n = 2, 4, and 6) in the IL, including the structural features and hydrogen bonding patterns. The collected data indicate that both chloride anions and imidazolium cations of the IL interact with the oligomer via hydrogen bonds. However, the anions occupy the first coordination shell of the oligomer, and the strength and number of hydrogen bonds and the interaction energy between anions and the oligomer are much larger than those between cations and the oligomer. It is observed that the intramolecular hydrogen bond in the oligomer is broken under the combined effect of anions and cations. The present results emphasize that the chloride anions play a critically important role and the imidazolium cations also present a remarkable contribution in the cellulose dissolution. This point of view is different from previous one that only underlines the importance of the chloride anions in the cellulose dissolution. The present results improve our understanding for the cellulose dissolution in imidazolium chloride ILs. PMID- 22422368 TI - Neuromuscular disorders: Troponin activator improves muscle function. PMID- 22422371 TI - Neurological disorders: A class of its own. PMID- 22422374 TI - Nitrogen-doped porous carbon nanofiber webs as anodes for lithium ion batteries with a superhigh capacity and rate capability. AB - Nitrogen-doped carbon nanofiber webs (CNFWs) with high surface areas are successfully prepared by carbonization-activation of polypyrrole nanofiber webs with KOH. The as-obtained CNFWs exhibit a superhigh reversible capacity of 943 mAh g(-1) at a current density of 2 A g(-1) even after 600 cycles, which is ascribed to the novel porous nanostructure and high-level nitrogen doping. PMID- 22422375 TI - Familial occurrence of the VATER/VACTERL association. AB - The acronym VATER/VACTERL association is used to describe the non-random co occurrence of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheo-esophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We report a familial case of VATER/VACTERL association in which both the index case and her maternal uncle displayed four major component features of the disorder. A systematic literature search identified 12 previously described familial cases. However, on comparison, both members fulfilled the diagnostic criteria for VATER/VACTERL association only in one instance, and ours is the second such report. Although, a SNP array-based analysis identified no causal genomic alteration, the findings in the present family suggest that genetic factors are implicated in the development of the disorder. PMID- 22422377 TI - Efficient intracellular delivery of camptothecin by silica/titania hollow nanoparticles. AB - Silica/titania hollow nanoparticles (HNPs) with 50 nm were fabricated by using the dissolution and redeposition method and modified with anti-[human epidermal growth factor receptor 2] monoclonal antibody (herceptin), and their application as camptothecin (CPT) delivery agents to human breast cancer SK-BR-3 cells was investigated. Although the diameter of herceptin-modified HNPs (HER-HNP) is smaller than that of other reported mesoporous silica nanoparticles, the extensive hollow cavity of HNPs (ca. 30 nm) allowed the loading of a large amount of CPT. CPT-loaded HER-HNP (HER-HNP-CPT) did not release CPT in phosphate buffered saline over a period of 24 h, however, HER-HNP-CPT in a hydrophobic solvent released its entire load of CPT. In addition, HER-HNPs were efficiently internalized owing to their herceptin conjugation and optimized size. To evaluate in vitro antitumor efficacy, apoptosis/necrosis and viability of HER-HNP-CPT treated cells were investigated. When the cells were treated with HER-HNP-CPT for 30 min, a few apoptotic cells were observed. After 24 h, the viability of HER-HNP CPT-treated SK-BR-3 decreased to 60 %, which revealed highly efficient chemotherapy. However, CPT loaded into HNP or HER-HNP had no significant effects on the viability of macrophages. Judging from these data, HER-HNPs are very suitable for application in anticancer therapy. A HER-HNP-CPT drug delivery system offers a new direction for a hydrophobic anticancer drug carrier and can be expanded to practical applications with further studies. PMID- 22422378 TI - A ZFN/piggyBac step closer to autologous liver cell therapy. PMID- 22422379 TI - Evaluation of two minimal-preparation regimes for CT colonography: optimising image quality and patient acceptability. AB - OBJECTIVE: To compare a 2 day bowel preparation regime of barium, iodine and a mild stimulant laxative with a 1 day iodine-only regime for CT colonography (CTC). METHODS: 100 consecutive patients underwent CTC. The first 50 patients (Regime 1) ingested 1 bisacodyl tablet twice a day 3 days before CTC and 1 dose each of 50 ml of barium and 20 ml of iodinated contrast per day starting 2 days before CTC. The second 50 patients (Regime 2) ingested 3 doses of iodinated contrast over 24 h prior to CTC. Volumes of residual stool and fluid, and the effectiveness of stool and fluid tagging, were graded according to methods established by Taylor et al (Taylor S, Slaker A, Burling D, Tam E, Greenhalgh R, Gartner L, et al. CT colonography: optimisation, diagnostic performance and patient acceptability of reduced-laxative regimens using barium-based faecal tagging. Eur Radiol 2008; 18: 32-42). A 3 day low-residue diet was taken by both cohorts. Questionnaires rating the side-effects and burden of the bowel preparation were compared to a control cohort of patients undergoing barium enema. RESULTS: The proportion of colons producing none/scattered stool (score 1) was 90.3% with Regime 1 and 65.0% with Regime 2 (p<0.005). Any residual stool was significantly better tagged with Regime 1 (score 5), with 91.7% of Regime 1 exhibiting optimum tagging vs 71.3% of Regime 2 (p<0.05). No significant differences in side-effects between the bowel preparation regimes for CTC were elicited. Bowel preparation for barium enema was tolerated significantly worse than both of the CTC bowel preparation regimes. CONCLUSION: Regime 1, containing a 3 day preparation of a mild laxative, barium and iodine, produced a significantly better prepared colon, with no difference in patient acceptability. PMID- 22422380 TI - Development of a highly efficient implanted thermal ablation device: in vivo experiment in rat liver. AB - OBJECTIVES: To evaluate an implanted thermal ablation device that can be heated with high efficiency using a resonant circuit as the implant. METHODS: 16 rats were used. The implants, adjusted at a resonance frequency of 4 MHz, were fixed on the surface of the liver of rats under laparotomy. In 14 of 16 rats, an alternating magnetic field (AMF) was applied for 6 min with an output of 300 W from outside the body using a ferrite core applicator. The implant temperature during AMF exposure was measured. The 14 rats were divided into 5 groups, depending on time from AMF application until they were sacrificed (1 h, 1 day, 3 days, 7 days and 1 month after application). Two rats not exposed to AMF were used as controls. Livers were removed and evaluated; the cross-sectional area and width of the ablated region were measured. RESULTS: During AMF exposure, the implant temperature rose to 127.8+/-39.3 degrees C (mean+/-standard deviation). The cross-sectional area of the ablated region was largest after 1 day and tended to decrease with time. The widths of the ablated region were 4.87+/-0.22 mm, 4.15+/-0.36 mm, 3.67+/-0.58 mm and 3.24+/-0.16 mm in the 1 day, 3 day, 7 day and 1 month groups, respectively. No significant differences (p<0.05) were seen in either cross-sectional area or width of the ablated region. CONCLUSION: Sufficient heat for ablation was obtained in vivo using a newly developed implanted thermal ablation device. This device may be a new option for thermal ablation therapy. PMID- 22422381 TI - Clinico-radiological spectrum of bilateral temporal lobe hyperintensity: a retrospective review. AB - Bilateral temporal lobe hyperintensity (BTH) is a commonly encountered MRI finding in a wide spectrum of clinical conditions and often poses a diagnostic challenge to the radiologist. The purpose of this paper is to elucidate several diseases that manifest as BTH on MRI, based on a retrospective review of cranial MRI of 65 cases seen in our institution between October 2007 and September 2010. We found BTH in different clinical scenarios that included infective diseases (herpes simplex virus, congenital cytomegalovirus infection), epileptic syndrome (mesial temporal sclerosis), neurodegenerative disorders (Alzheimer's disease, frontotemporal dementia, Type 1 myotonic dystrophy), neoplastic conditions (gliomatosis cerebri), metabolic disorders (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, Wilson's disease, hyperammonemia), dysmyelinating disease (megalencephalic leukoencephalopathy with subcortical cysts), and vascular (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and paraneoplastic (limbic encephalitis) disorders. The conventional MRI findings with advanced MRI such as diffusion weighted imaging, susceptibility-weighted imaging and MR spectroscopy along with laboratory results are potentially helpful in distinguishing the different clinical conditions and thus affect the early diagnosis and clinical outcome. PMID- 22422382 TI - Comparison of the underestimation rate in cases with ductal carcinoma in situ at ultrasound-guided core biopsy: 14-gauge automated core-needle biopsy vs 8- or 11 gauge vacuum-assisted biopsy. AB - OBJECTIVE: The objective of this study was to compare the underestimation rate of invasive carcinoma in cases with ductal carcinoma in situ (DCIS) at percutaneous ultrasound-guided core biopsies of breast lesions between 14-gauge automated core needle biopsy (ACNB) and 8- or 11-gauge vacuum-assisted biopsy (VAB), and to determine the relationship between the lesion type (mass or microcalcification on radiological findings) and the DCIS underestimation rate. METHODS: We retrospectively reviewed imaging-guided biopsies of breast lesions performed from February 2003 to August 2008. 194 lesions were diagnosed as DCIS at ultrasound guided core biopsy: 138 lesions in 132 patients by 14-gauge ACNB, and 56 lesions in 56 patients by 8- or 11-gauge VAB. The histological results of the core biopsy samples were correlated with surgical specimens. The clinical and radiological findings were also reviewed. The histological DCIS underestimation rates were compared between the two groups and were analysed for differences according to the clinical and radiological characteristics of the lesions. RESULTS: The DCIS underestimation rate was 47.8% (66/138) for 14-gauge ACNB and 16.1% (9/56) for VAB (p<0.001). According to the lesion type on sonography, DCIS underestimation was 43.4% (63/145) in masses (47.6% using ACNB and 15.8% using VAB; p=0.012) and 24.5% (12/49) in microcalcifications (50.0% using ACNB and 16.2% using VAB; p=0.047). CONCLUSION: The underestimation rate of invasive carcinoma in cases with DCIS at ultrasound-guided core biopsies was significantly higher for ACNB than for VAB. Furthermore, this difference does not change according to the lesion type on ultrasound. Therefore, ultrasound-guided VAB can be a useful method for the diagnosis of DCIS lesions presented as either mass or microcalcification. PMID- 22422383 TI - CT and MR cholangiography: advantages and pitfalls in perioperative evaluation of biliary tree. AB - Recent developments in imaging technology have enabled CT and MR cholangiopancreatography (MRCP) to provide minimally invasive alternatives to endoscopic retrograde cholangiopancreatography for the pre- and post-operative assessment of biliary disease. This article describes anatomical variants of the biliary tree with surgical significance, followed by comparison of CT and MR cholangiographies. Drip infusion cholangiography with CT (DIC-CT) enables high resolution three-dimensional anatomical representation of very small bile ducts (e.g. aberrant branches, the caudate branch and the cystic duct), which are potential causes of surgical complications. The disadvantages of DIC-CT include the possibility of adverse reactions to biliary contrast media and insufficient depiction of bile ducts caused by liver dysfunction or obstructive jaundice. Conventional MRCP is a standard, non-invasive method for evaluating the biliary tree. MRCP provides useful information, especially regarding the extrahepatic bile ducts and dilated intrahepatic bile ducts. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRCP may facilitate the evaluation of biliary structure and excretory function. Understanding the characteristics of each type of cholangiography is important to ensure sufficient perioperative evaluation of the biliary system. PMID- 22422384 TI - Consideration of optimal isodose surface selection for target coverage in micro multileaf collimator-based stereotactic radiotherapy for large cystic brain metastases: comparison of 90%, 80% and 70% isodose surface-based planning. AB - OBJECTIVE: This study aims to compare dynamic conformal arc (DCA) plans based on different-percentage isodose surfaces (IDSs), normalised to 100% at the isocentre, for target coverage (TC; dose prescription) in stereotactic radiotherapy for large cystic brain metastases. METHODS: The DCA plans were generated for 15 targets (5 spherical models and 10 metastatic brain lesions) based on 90%, 80% and 70% IDSs for dose prescription to attain >=99% TC values using the Novalis Tx platform. These plans were optimised mainly by leaf margin and/or collimator angle adjustment, while similar arc arrangements were used. RESULTS: TC values were equivalent among the three plans. Conformity index values were similar between the 80% and 70% plans, while they were worse in the 90% plans. Mean doses (D(mean)) of the interior 3 mm rind structure were highest in the 70% plans, followed by the 80% plans and lowest in the 90% plans. D(mean) of the exterior 3 mm rind structure and the ratio of 50%/100% isodose volumes (Paddick's gradient index values) were highest in the 90% plans, followed by 80% and lowest in the 70% plans. CONCLUSIONS: These results suggest that the 70% IDS plans might be beneficial for both tumour control and reducing toxicity to surrounding normal tissue if appropriate dose conformity and precise treatment set-up are ensured. The 90% IDS plans are unfavourable in view of inferior dose gradient outside the target and should be limited to cases in which the target dose homogeneity is given the highest priority. PMID- 22422385 TI - Multiple-electrode radiofrequency ablations using Octopus(r) electrodes in an in vivo porcine liver model. AB - OBJECTIVES: The objective of this study was to determine the in vivo efficacy of radiofrequency ablation (RFA) in porcine liver using Octopus(r) electrodes for creating a large coagulation compared with RFA using clustered electrodes. METHODS: A total of 39 coagulations were created using a 200-W generator and clustered electrodes or Octopus electrodes during laparotomy in 19 pigs. Radiofrequency was applied to the livers using four protocols: (1) Group A-1, monopolar mode using a clustered electrode (n=11); (2) Group A-2, monopolar mode using an Octopus electrode (n=11); (3) Group B-1, consecutive monopolar mode using three, clustered electrodes (n=8); and (4) Group B-2, switching monopolar mode using two Octopus electrodes (n=9). The energy efficiency, shape, diameters (D) and volume (V) of the coagulation volume were compared in each of the two groups. RESULTS: The mean maximum D and V of the coagulations in Group A-2 (4.7 cm and 33.1 cm(3), respectively) were significantly larger than those in Group A 1 (4.1 cm and 20.3 cm(3), respectively) (p<0.05). Furthermore, the mean minimum D, maximum D and V of the coagulations in Group B-2 were significantly larger than those in Group B-1, i.e. 5.3 vs 4.0 cm, 6.6 vs 4.9 cm and 66.9 vs 30.2 cm(3), respectively (p<0.05). The energy efficiencies were also significantly higher in Groups A-2 and B-2 than in Groups A-1 and B-1 (p<0.05). CONCLUSION: The Octopus electrodes were more efficient for creating a large ablation zone than clustered electrodes, and the efficacy of RFA with Octopus electrodes can be amplified in the switching monopolar mode. PMID- 22422386 TI - Music during interventional radiological procedures, effect on sedation, pain and anxiety: a randomised controlled trial. AB - OBJECTIVE: To assess the effects of playing patient-selected music during interventional procedures on (1) the doses of sedation and analgesia and (2) anxiety levels. METHODS: Patients undergoing interventional radiological procedures were randomised to either the intervention (music) or the control (no music) group. Patients in the intervention group had music of their choice played via headphones during the procedure. The primary outcomes were reductions in the doses of drugs for sedation (midazolam) and analgesia (fentanyl). Anxiety levels were assessed both before and after the procedure using the validated State Anxiety Inventory. Mean pulse rate and average of mean blood pressures were also recorded before and during the procedures as surrogate indicators of anxiety levels. RESULTS: 100 patients were randomised in a 1:1 ratio. There were 58 males and 42 females, with a mean age of 58 years. Sedation was required in 21 (42%) patients in the music group compared with 30 (60%) patients in the control group (p=0.046). The mean [standard deviation (SD)] midazolam dose was 2.1 mg (2.3 mg) in the control group and 1.3 mg (2.2 mg) in the music group (p=0.027). The mean (SD) fentanyl dose was 29 mg (40 mg) in the control group and 18 mg (34 mg) in the music group (p=0.055). There was no significant effect of music on the change from baseline in anxiety levels (p=0.74), pulse rate (p=0.56) or blood pressure (p=0.34). CONCLUSION: Sedation requirements are significantly reduced by playing self-selected music to the patient during interventional radiology procedures. By lowering sedation during interventional radiology, music makes the procedure safer. It also contributes favourably to the overall patient experience. PMID- 22422387 TI - Pathological correlation with diffusion restriction on diffusion-weighted imaging in patients with pathological complete response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results. AB - OBJECTIVE: The objective of this study was to assess causative pathological factors associated with diffusion restriction on diffusion-weighted imaging (DWI) in patients who achieved pathological complete response (pCR) after treatment with neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer. METHODS: In total, 43 patients with locally advanced rectal cancer (>=T3 or lymph node positive) who underwent neoadjuvant CRT, subsequent surgery and ultimately achieved pCR were enrolled. All patients underwent pre- and post-CRT 3.0 T rectal MRI with DWI. Two radiologists blinded to pathological staging reviewed pre- and post-CRT 3.0 T rectal MRI for the presence of diffusion restriction in the corresponding tumour areas on post-CRT DWI, with a third radiologist arbitrating any disagreement. The consensus of these findings was then correlated with pathological data such as intramural mucin and the degree of proctitis and mural fibrosis seen on surgical specimen. Additionally, the pre-CRT tumour volume was measured to define the effect of this variable on the degree of radiation proctitis and fibrosis, as well as the presence of intramural mucin. RESULTS: Diffusion restriction occurred in 18 subjects (41.9%), while 25 subjects remained diffusion restriction-free (58.1%). The diffusion restriction group tended to have more severe proctitis and mural fibrosis when compared with non-diffusion restriction group (p<0.001). Intramural mucin was also more common in the diffusion restriction group (p=0.052). Higher pre-CRT tumour volumes were significantly predictive of the degree of proctitis (p=0.0247) and fibrosis (p=0.0445), but not the presence of intramural mucin (p=0.0944). Proctitis and mural fibrosis severity were also identified as independent pathological risk factors for diffusion restriction on multivariate analysis (p=0.0073 and 0.0011, respectively). CONCLUSION: Both radiation-induced proctitis and fibrosis were significant and independent predictors of diffusion restriction in patients achieving pCR after treatment with neoadjuvant CRT for locally advanced rectal cancer, and pre-CRT tumour volume significantly affects both variables. PMID- 22422388 TI - MRI of the small-bowel: how to differentiate primary neoplasms and mimickers. AB - MRI of the gastrointestinal tract is gaining clinical acceptance and is increasingly used to evaluate patients with suspected small-bowel diseases. MRI may be performed with enterography or enteroclysis, both of which combine the advantages of cross-sectional imaging with those of conventional enteroclysis. In this paper, MRI features of primary small-bowel neoplasms, the most important signs for differential diagnosis and the diseases that can be considered as mimickers of small-bowel neoplasms, are discussed. PMID- 22422389 TI - Ultraselective transcatheter infusion of epirubicin in water-in-oil-in-water emulsion for small hepatocellular carcinoma. AB - OBJECTIVE: We have previously reported the clinical efficacy of water-in-oil-in water (W/O/W) emulsions, particularly for non-selective transcatheter arterial infusion (TAI) therapy. W/O/W emulsions limit damage to normal hepatic parenchyma, because of their minimal embolic effect on peripheral arteries and slow release of anticancer agent. The purpose of this study was to evaluate the safety and effectiveness of ultraselective TAI (UTI) of a W/O/W emulsion for hepatocellular carcinoma (HCC). METHODS: 11 patients with Stage I-III small HCCs (<5 cm) underwent UTI with a W/O/W emulsion at our institute. Response was assessed using the Response Evaluation Criteria in Solid Tumors. Disease-free survival time was estimated using the Kaplan-Meier method. RESULTS: All 10 patients, excluding a patient who underwent a hepatectomy after UTI, achieved complete response. The 6, 12 and 30 month cumulative disease-free survival rates for the 10 patients were 100%, 90% and 60%, respectively. The patient who underwent hepatectomy after UTI developed complete necrosis of the HCC and peritumoral non-tumorous liver parenchyma. CONCLUSION: UTI therapy using a W/O/W emulsion for patients with small HCCs results in a good local response. PMID- 22422390 TI - Comparison between chest digital tomosynthesis and CT as a screening method to detect artificial pulmonary nodules: a phantom study. AB - OBJECTIVES: The objective of this study was to evaluate the imaging capabilities of chest digital tomosynthesis (DT) as a screening method for the detection of artificial pulmonary nodules, and to compare its efficiency with that of CT. METHODS: DT and CT were used to detect artificial pulmonary nodules (5 mm and 8 mm in diameter, ground-glass opacities) placed in a chest phantom. Using a three dimensional filtered back-projection algorithm at acquisition angles of 8 degrees , 20 degrees , 30 degrees and 40 degrees , DT images of the desired layer thicknesses were reconstructed from the image data acquired during a single tomographic scan. Both standard and sharp CT reconstruction kernels were used, and the detectability index (DI) valves computed for both the DT scan acquisition angles and CT reconstruction kernel types were considered. For the observer study, we examined 50 samples of artificial pulmonary nodules using both DT and CT imaging. On the basis of evaluations made by five thoracic radiologists, a jackknife free-response receiver operating characteristic (JAFROC) study was performed to compare and assess the differences in detection accuracy between CT and DT imaging. RESULTS: For each increased acquisition angle, DI obtained by DT imaging was similar to that obtained by CT imaging. The difference in the observer-averaged JAFROC figure of merit for the five readings was 0.0363 (95% confidence interval: -0.18, 0.26; F=0.101; p=0.75). CONCLUSION: With the advantages of a decreased radiation dose and the practical accessibility of examination, DT may be a useful alternative to CT for the detection of artificial pulmonary nodules. PMID- 22422391 TI - Cerebral CT angiography using a small volume of concentrated contrast material with a test injection method: optimal scan delay for quantitative and qualitative performance. AB - OBJECTIVES: The objective of this study was to determine the optimal scan delay quantitatively and qualitatively in cerebral CT angiography (CTA) with a test injection method at the circle of Willis (cW). METHODS: 66 consecutive patients suspected of having unruptured intracranial aneurysms underwent CTA using 40 ml of 370 mg iodine ml(-1) contrast material (CM). After the time until CM arrival at the cW (T(cW)) was calculated, scan delay was divided into three groups according to T(cW) and scan duration (SD) between the second cervical vertebra and cW as follows: [(T(cW)+6)-SD] in 21 patients (Group A); [(T(cW)+8)-SD] in 23 patients (Group B); and [(T(cW)+10)-SD] in 22 patients (Group C). Arterial and venous attenuation in the intracranial vessels was measured. Mean attenuation values were compared quantitatively. The arterial enhancement and venous overlap at the cW and above the cW were qualitatively compared among the three groups. RESULTS: Mean arterial attenuation in Groups B and C was significantly higher than that in Group A. Mean venous attenuation in Group C was significantly higher than those in Groups A and B. Arterial enhancement above the cW showed a significant difference between Groups A and C, and at the cW between Groups A and B, and Groups A and C. There was a significant difference in venous overlap among the three groups, except for that at the cW between Groups B and C. CONCLUSIONS: Setting scan delay as [(T(cW)+8)-SD] s can produce the best performance both quantitatively and qualitatively. PMID- 22422392 TI - Liver T1rho MRI measurement in healthy human subjects at 3 T: a preliminary study with a two-dimensional fast-field echo sequence. AB - OBJECTIVES: The aim of this study was to explore the technical feasibility of T(1)rho MRI for the liver, and to determine the normal range of liver T(1)rho in healthy subjects at clinical 3 T. METHODS: There were 15 healthy volunteers. Three representative axial slices were selected to cut through the upper, middle and lower liver. A rotary echo spin-lock pulse was implemented in a two dimensional fast-field echo sequence. Spin-lock frequency was 500 Hz, and the spin-lock times of 1, 10, 20, 30, 40 and 50 ms were used for T(1)rho mapping. The images were acquired slice by slice during breath-holding. Regions of interest (ROIs; n=5) were manually placed on each slice of the liver parenchyma region, excluding artefacts and vessels. The mean value of these ROIs (n=15) was regarded as the liver T(1)rho value for the subject. Six subjects were scanned once at fasting status; six subjects were scanned once 2 h post meal; three subjects were scanned twice at fasting status; and seven subjects were scanned twice 2 h post meal. RESULTS: When two readers measured the same 10 data sets, the interreader reproducibility (ICC: intraclass correlation coefficient) was 0.955. With the 10 subjects scanned twice, the ICC for scan-rescan reproducibility was 0.764. There was no significant difference for the liver T(1)rho value at the fasting status (43.08+/-1.41 ms) and post-meal status (42.97+/-2.38 ms, p=0.867). Pooling together all the 32 scans in this study, the normal liver T(1)rho value ranged from 38.6 to 48.3 ms (mean 43.0 ms, median 42.6 ms). CONCLUSION: It is feasible to obtain consistent liver T(1)rho measurement for human subjects at 3 T. PMID- 22422393 TI - Evaluation of weather-based rice yield models in India. AB - The objective of this study was to compare two different rice simulation models- standalone (Decision Support System for Agrotechnology Transfer [DSSAT]) and web based (SImulation Model for RIce-Weather relations [SIMRIW])--with agrometeorological data and agronomic parameters for estimation of rice crop production in southern semi-arid tropics of India. Studies were carried out on the BPT5204 rice variety to evaluate two crop simulation models. Long-term experiments were conducted in a research farm of Acharya N G Ranga Agricultural University (ANGRAU), Hyderabad, India. Initially, the results were obtained using 4 years (1994-1997) of data with weather parameters from a local weather station to evaluate DSSAT simulated results with observed values. Linear regression models used for the purpose showed a close relationship between DSSAT and observed yield. Subsequently, yield comparisons were also carried out with SIMRIW and DSSAT, and validated with actual observed values. Realizing the correlation coefficient values of SIMRIW simulation values in acceptable limits, further rice experiments in monsoon (Kharif) and post-monsoon (Rabi) agricultural seasons (2009, 2010 and 2011) were carried out with a location-specific distributed sensor network system. These proximal systems help to simulate dry weight, leaf area index and potential yield by the Java based SIMRIW on a daily/weekly/monthly/seasonal basis. These dynamic parameters are useful to the farming community for necessary decision making in a ubiquitous manner. However, SIMRIW requires fine tuning for better results/decision making. PMID- 22422394 TI - Bargaining and the provision of health services. AB - We model and compare the bargaining process between a purchaser of health services, such as a health authority, and a provider (the hospital) in three plausible scenarios: (a) activity bargaining: the purchaser sets the price and activity (number of patients treated) is bargained between the purchaser and the provider; (b) price bargaining: the price is bargained between the purchaser and the provider, but activity is chosen unilaterally by the provider; (c) efficient bargaining: price and activity are simultaneously bargained between the purchaser and the provider. We show that: (1) if the bargaining power of the purchaser is high (low), efficient bargaining leads to higher (lower) activity and purchaser's utility, and lower (higher) prices and provider's utility compared to price bargaining. (2) In activity bargaining, prices are lowest, the purchaser's utility is highest and the provider's utility is lowest; activity is generally lowest, but higher than in price bargaining for high bargaining power of the purchaser. (3) If the purchaser has higher bargaining power, this reduces prices and activity in price bargaining, it reduces prices but increases activity in activity bargaining, and it reduces prices but has no effect on activity in efficient bargaining. PMID- 22422395 TI - Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle. AB - The functional role of the voltage-gated K(+) (K(V)) channels in human detrusor smooth muscle (DSM) is largely unexplored. Here, we provide molecular, electrophysiological, and functional evidence for the expression of K(V)2.1, K(V)2.2, and the electrically silent K(V)9.3 subunits in human DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of K(V)2.1, K(V)2.2, and K(V)4.2 homotetrameric channels and of K(V)2.1/9.3 heterotetrameric channels, was used to examine the role of these channels in human DSM function. Human DSM tissues were obtained during open bladder surgeries from patients without a history of overactive bladder. Freshly isolated human DSM cells were studied using RT-PCR, immunocytochemistry, live-cell Ca(2+) imaging, and the perforated whole cell patch-clamp technique. Isometric DSM tension recordings of human DSM isolated strips were conducted using tissue baths. RT-PCR experiments showed mRNA expression of K(V)2.1, K(V)2.2, and K(V)9.3 (but not K(V)4.2) channel subunits in human isolated DSM cells. K(V)2.1 and K(V)2.2 protein expression was confirmed by Western blot analysis and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the voltage step-induced K(V) current in freshly isolated human DSM cells. ScTx1 (100 nM) significantly increased the intracellular Ca(2+) level in DSM cells. In human DSM isolated strips, ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude and muscle force, and enhanced the amplitude of the electrical field stimulation-induced contractions within the range of 3.5-30 Hz stimulation frequencies. These findings reveal that ScTx1-sensitive K(V)2-containing channels are key regulators of human DSM excitability and contractility and may represent new targets for pharmacological or genetic intervention for bladder dysfunction. PMID- 22422396 TI - Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels. AB - Overactive bladder syndrome is frequently associated with increased detrusor smooth muscle (DSM) contractility. We tested the hypothesis that pharmacological activation of the large-conductance voltage- and Ca(2+)-activated K(+) (BK) channel with NS-1619, a selective BK channel opener, reduces the excitability and contractility of human DSM. We used the amphotericin-perforated whole cell patch clamp technique on freshly isolated human DSM cells, live-cell Ca(2+) imaging, and isometric DSM tension recordings of human DSM strips obtained from open bladder surgeries. NS-1619 (30 MUM) significantly increased the amplitude of the voltage step-induced whole cell BK currents, and this effect was abolished by pretreatment with 200 nM iberiotoxin (IBTX), a selective BK channel inhibitor. In current-clamp mode, NS-1619 (30 MUM) significantly hyperpolarized the resting membrane potential, and the hyperpolarization was reversed by IBTX (200 nM). NS 1619 (30 MUM) significantly decreased the intracellular Ca(2+) level in isolated human DSM cells. BK channel activation with NS-1619 (30 MUM) significantly inhibited the amplitude, muscle force, frequency, duration, and tone of the spontaneous phasic and pharmacologically induced DSM contractions from human DSM isolated strips. IBTX (200 nM) suppressed the inhibitory effects of NS-1619 on spontaneous contractions. The amplitude of electrical field stimulation (0.5-50 Hz)-induced contractions was significantly reduced by NS-1619 (30 MUM). Our data suggest that pharmacological activation of BK channels could represent a novel treatment option to control bladder dysfunction in humans. PMID- 22422397 TI - Caveolin-1, antiapoptosis signaling, and anchorage-independent cell growth. Focus on "Caveolin-1 regulates Mcl-1 stability and anoikis in lung carcinoma cells". PMID- 22422399 TI - In pursuit of scientific excellence: sex matters. PMID- 22422398 TI - Gating of connexin 43 gap junctions by a cytoplasmic loop calmodulin binding domain. AB - Calmodulin (CaM) binding sites were recently identified on the cytoplasmic loop (CL) of at least three alpha-subfamily connexins (Cx43, Cx44, Cx50), while Cx40 does not have this putative CaM binding domain. The purpose of this study was to examine the functional relevance of the putative Cx43 CaM binding site on the Ca(2+)-dependent regulation of gap junction proteins formed by Cx43 and Cx40. Dual whole cell patch-clamp experiments were performed on stable murine Neuro-2a cells expressing Cx43 or Cx40. Addition of ionomycin to increase external Ca(2+) influx reduced Cx43 gap junction conductance (G(j)) by 95%, while increasing cytosolic Ca(2+) concentration threefold. By contrast, Cx40 G(j) declined by <20%. The Ca(2+)-induced decline in Cx43 G(j) was prevented by pretreatment with calmidazolium or reversed by the addition of 10 mM EGTA to Ca(2+)-free extracellular solution, if Ca(2+) chelation was commenced before complete uncoupling, after which g(j) was only 60% recoverable. The Cx43 CL(136-158) mimetic peptide, but not the scrambled control peptide, or Ca(2+)/CaM-dependent kinase II 290-309 inhibitory peptide also prevented the Ca(2+)/CaM-dependent decline of Cx43 G(j). Cx43 gap junction channel open probability decreased to zero without reductions in the current amplitudes during external Ca(2+)/ionomycin perfusion. We conclude that Cx43 gap junctions are gated closed by a Ca(2+)/CaM-dependent mechanism involving the carboxyl-terminal quarter of the connexin CL domain. This study provides the first evidence of intrinsic differences in the Ca(2+) regulatory properties of Cx43 and Cx40. PMID- 22422402 TI - Molecular diagnostics: are we there yet? PMID- 22422400 TI - Single nucleotide polymorphisms in the matrix metalloproteinase gene family and the frequency and duration of gastroesophageal reflux disease influence the risk of esophageal adenocarcinoma. AB - The matrix metalloproteinase (MMP) family of proteins mediates various cellular pathways, including apoptosis and angiogenesis. Polymorphisms of MMP genes are associated with increased esophageal adenocarcinoma (EAC) risk. Gastroesophageal reflux disease (GERD) is an established EAC risk factor. We examined whether MMP polymorphism-EAC risk is modified by GERD. In total, 309 EAC patients and 279 frequency-matched healthy controls underwent MMP1 1G/2G, MMP3 6A/5A, MMP12 -82A/G and MMP12 1082A/G genotyping. Questionnaires collected GERD history. EAC risk was analyzed using logistic regression, adjusted for key covariates and stratified by GERD. Joint effects models explored GERD severity and duration, whereas additional models explored genotype-GERD interactions in EAC risk. We determined that each MMP1 and MMP3 minor (variant) allele was independently associated with increased EAC risk (adjusted odds ratio (AOR) 3.2, 95% confidence interval (CI) 2.0-5.1, p < 0.001 and AOR 1.8, 95% CI 1.1-2.7, p = 0.01, respectively) only among those with GERD but not in GERD-free individuals (all p = nonsignificant). There were significant interactions between the MMP1 variants and the presence of GERD (p = 0.002) and between MMP3 variants and GERD (p = 0.04). There was an equally strong interaction between cumulative GERD severity and MMP1 (p = 0.002). The AOR of each variant allele was 14.9 (95% CI 1.6-136) for individuals with severe GERD, 1.7 (95% CI 1.0-2.7) for mild-moderate GERD and 0.98 (95% CI 0.7 1.4) for those without GERD. This was further reflected in separate analyses of frequency and duration of GERD. In conclusion, MMP1 1G/2G (and possibly MMP3 6A/5A) polymorphisms alter EAC risk differentially for GERD and GERD-free individuals. PMID- 22422403 TI - Leveling the playing field: bringing development of biomarkers and molecular diagnostics up to the standards for drug development. AB - Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts. PMID- 22422404 TI - Impact of preanalytic factors on the design and application of integral biomarkers for directing patient therapy. AB - Molecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. PMID- 22422405 TI - Bridging the gap: moving predictive and prognostic assays from research to clinical use. AB - The development of clinically useful molecular diagnostics requires validation of clinical assay performance and achievement of clinical qualification in clinical trials. As discussed elsewhere in this Focus section on molecular diagnostics, validation of assay performance must be rigorous, especially when the assay will be used to guide treatment decisions. Here we review some of the problems associated with assay development, especially for academic investigators. These include lack of expertise and resources for analytical validation, lack of experience in designing projects for a specific clinical use, lack of specimens from appropriate patient groups, and lack of access to Clinical Laboratory Improvement Amendments-certified laboratories. In addition, financial support for assay validation has lagged behind financial support for marker discovery or drug development, even though the molecular diagnostic may be considered necessary for the successful use of the companion therapeutic. The National Cancer Institute supports a large number of clinical trials and a significant effort in drug development. In order to address some of these barriers for predictive and prognostic assays that will be used in clinical trials to select patients for a particular treatment, stratify patients into molecularly defined subgroups, or choose between treatments for molecularly defined tumors, the National Cancer Institute has begun a pilot program designed to lessen barriers to the development of validated prognostic and predictive assays. PMID- 22422406 TI - Development and use of integral assays in clinical trials. AB - Clinical trials that include integral biomarkers to determine eligibility, assign treatment, or assess outcome must employ robust assays to measure the molecular analyte of interest. The decision to develop a biomarker assay into a test suitable for use in humans should be driven by clinical need, that is, there should be a clear clinical purpose for undertaking the test development. Supporting in vitro or in vivo research on the ability of the marker to distinguish subgroups of patients with a given characteristic is necessary. The magnitude of the difference in treatment effect expected with use of the marker should be sufficient to support differential treatment prescription for marker positive and -negative patients. Analytical and clinical validation of the marker assay should be completed before the clinical trial is initiated to ensure that the assay is stable enough for clinical use throughout the trial. Clinical use of the assay requires that it be performed in a Clinical Laboratory Improvement Amendments-accredited laboratory, and the need to apply for an Investigational Device Exemption from the U.S. Food and Drug Administration should be considered. In this article we elaborate on the steps required to get a biomarker assay ready for use as an integral component of a clinical trial and give an example of the use of an integral assay in a phase III trial. PMID- 22422407 TI - Lessons learned from the investigational device exemption review of Children's Oncology Group trial AAML1031. AB - The U.S. Food and Drug Administration is now exerting its regulatory authority over the use of molecular diagnostics and related assays for medical decision making in clinical trials, by performing pre-Investigational Device Exemption reviews in all phases of clinical trials. In this review, we assess the analytical performance of the assay for the diagnostic, and consider how that performance affects the diagnostic and the patient and their risks and benefits from treatment. We also discuss the process involved in the first review of a new Children's Oncology Group phase III trial in acute myelogenous leukemia. The lessons learned and recommendations for how to prepare for and incorporate this new level of regulatory review into the protocol development process are presented. PMID- 22422408 TI - Biomarker discovery, development, and implementation in France: a report from the French National Cancer Institute and cooperative groups. AB - Biomarkers are increasingly changing the medical practice in oncology. One of the major challenges in the field of personalized medicine or biologically adapted therapies is to ensure a rapid and extensive implementation of emerging biomarkers as soon as proof of their medical usefulness is obtained. A special program has been developed in France to facilitate the assessment and use of biomarkers. The French National Cancer Institute has set up a total of 28 laboratories in public hospitals to perform biomarker testing for clinical use. This program is enabling all patients who present with cancer to receive free testing for biomarkers, such as K-Ras, epidermal growth factor receptor, c-Kit, and Braf mutations. Funding for these laboratories comes from the French Ministry of Health. The future of these laboratories includes the development of DNA arrays and multiplex technologies for clinical use. Toward that end, the French National Cancer Institute is financing several large clinical trials that several large clinical trials are currently evaluating the feasibility and medical utility of DNA arrays and next-generation sequencing in the context of academic centers. The programs are being run by cooperative groups. PMID- 22422410 TI - Anxiety in predicting suicide-related symptom of typhoon disaster victims: a one year follow-up study in southern Taiwan. AB - The aim of this study was to screen those at high risk of psychological distress in areas affected by typhoon Morakot, which hit Taiwan on August 7th, 2009. Screening was conducted a year later to assess the changes in psychiatric symptoms and investigate the factors which may be predictive of psychological distress and suicide ideation. One-hundred and fifty-two participants were collected at the first screening and 125 a year later. The five-item Brief Symptom Rating Scale was used to measure the level of psychological distress. Our results showed the prevalence of psychological distress immediately post-disaster was 2.4% and increased to 4.0% the next year. The level of anxiety post-disaster could predict continuous psychological distress and the development of suicidal ideation a year later. Traumatic events prior to the typhoon were not associated with the level of psychological distress a year after the disaster. Difference was found in the level of hostility immediately post-disaster and a year later. Our follow-up study found anxiety was the only indicator which predicted psychological distress a year later, and hostility was a transient state which was lower a year after the disaster. Policy-makers and future programs should focus on high anxiety cases post-disaster to prevent mental symptom and suicide ideation development. PMID- 22422411 TI - [Child and adolescent psychiatry and the municipality]. PMID- 22422409 TI - PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. AB - PURPOSE: We sought to determine whether phosphoinositide 3-kinase (PI3K) pathway mutation or activation state and rapamycin-induced feedback loop activation of Akt is associated with rapamycin sensitivity or resistance. EXPERIMENTAL DESIGN: Cancer cell lines were tested for rapamycin sensitivity, Akt phosphorylation, and mTOR target inhibition. Mice injected with breast or neuroendocrine cancer cells and patients with neuroendocrine tumor (NET) were treated with rapalogs and Akt phosphorylation was assessed. RESULTS: Thirty-one cell lines were rapamycin sensitive (RS) and 12 were relatively rapamycin resistant (RR; IC(50) > 100 nmol/L). Cells with PIK3CA and/or PTEN mutations were more likely to be RS (P = 0.0123). Akt phosphorylation (S473 and T308) was significantly higher in RS cells (P < 0.0001). Rapamycin led to a significantly greater pathway inhibition and greater increase in p-Akt T308 (P < 0.0001) and p-Akt S473 (P = 0.0009) in RS cells. Rapamycin and everolimus significantly increased Akt phosphorylation but inhibited growth in an in vivo NET model (BON). In patients with NETs treated with everolimus and octreotide, progression-free survival correlated with p-Akt T308 in pretreatment (R = 0.4762, P = 0.0533) and on-treatment tumor biopsies (R = 0.6041, P = 0.0102). Patients who had a documented partial response were more likely to have an increase in p-Akt T308 with treatment compared with nonresponders (P = 0.0146). CONCLUSION: PIK3CA/PTEN genomic aberrations and high p-Akt levels are associated with rapamycin sensitivity in vitro. Rapamycin mediated Akt activation is greater in RS cells, with a similar observation in patients with clinical responses on exploratory biomarker analysis; thus feedback loop activation of Akt is not a marker of resistance but rather may function as an indicator of rapamycin activity. PMID- 22422412 TI - [International psychiatric top research by Dutch or Flemish institutes]. PMID- 22422413 TI - [Determinants of seclusion in a psychiatric institution: a naturalistic and exploratory study]. AB - BACKGROUND: Seclusion of a psychiatric patient is a multifactorial process in which patient, staff and ward variables all play a role. So far, few studies have investigated to what extent these variables in combination can be the determinants of seclusion. AIM: To investigate, in a multivariate study, what influence certain patient, staff and ward variables had on the decision to seclude a psychiatric patient and to use the findings to support specific interventions which could reduce the total number of seclusions in our institution. METHOD: We based our study on 78 secluded patients and 96 similar control-patients (not secluded at that time) and we collected data from these patients with regard to some quantified patient, staff and ward variables. In this retrospective cross-sectional study we performed a multivariate logistic regression analysis on the data. This enabled us to study associative links but not causal links. RESULTS: Seclusion was found to be a multifactorial process which revealed significant associations with several patients variables (nosie variables irritability and motor retardation) and one staff variable (subjective feeling of safety among nursing staff on the day of the patient's seclusion). We also found many more non-significant associations. CONCLUSION: Interventions that might reduce the number of seclusions (in our institution) should perhaps be directed towards the irritability and motor retardation of the patient and towards feelings of safety among the nursing staff. PMID- 22422414 TI - [Research of seclusion: well begun, but still half done]. PMID- 22422415 TI - [Antidepressants and the risk of bleeding]. AB - BACKGROUND: By blocking the serotonin transporter system antidepressants can, in theory, result in bleedings. However, we do not yet know how great the risk of bleeding is and what the clinical implications are. AIM: To assess how great the risk of bleeding is and what the clinical implications are. METHOD: Using keywords 'antidepressants' and 'bleeding' we searched the relevant literature up to March 2011 to find out what the risk of bleeding were for users of antidepressants. RESULTS: 34 studies met our selection criteria. Most studies reported upper gastrointestinal bleeding and hemorrhagic cerebrovascular accidents (CVA). Antidepressants with high serotonin affinity can slightly increase the risk of upper gastrointestinal bleeding. Antidepressants do not increase the risk for hemorrhagic CVA. Very little information is available about other types of bleeding. CONCLUSION: Our systematic review of the literature shows that antidepressants are relatively safe as far as bleeding is concerned. Precautions can be taken in the case of high risk patients. PMID- 22422416 TI - [Signs and significance of a tick-bite: psychiatric disorders associated with Lyme disease]. AB - BACKGROUND: In view of the increased prevalence of Lyme disease and the increased attention given to the disease in the media, psychiatrists are more likely to be confronted with patients with psychiatric disorders that may be linked to Lyme disease. AIM: To present an overview of some diagnostic problems and psychiatric disorders that can occur in the context of Lyme disease. METHOD: The literature was reviewed systematically with the help of Medline and Embase for the period 1990-October 2010 and relevant articles were studied that were mentioned in the reference lists of the articles selected. RESULTS: The most frequently discussed psychiatric disorders associated with Lyme disease are depressive and psychotic disorders and cognitive impairment with memory and concentration disorders. Medically unexplained symptoms can be attributed to hitherto unrecognised Lyme disease. The fear of contracting Lyme disease can in itself lead to psychiatric decompensation. CONCLUSION: Further investigations into borrelia-infection are indicated in case of atypical psychiatric disorders and/or an atypical response to treatment and when the anamnesis and/or physical examination are suggestive of Lyme disease. PMID- 22422417 TI - [Behavioural standard or coercive measure? Some considerations regarding the special issue on ROM]. AB - BACKGROUND: The cost of mental health care has possibly risen more than costs in other sectors of health care in the Netherlands. In an attempt to control the rising costs, new policies have been implemented that include the introduction of selective financial penalties for those in need of mental health care as well as the start of performance-based mental health care reimbursement. In order to achieve the latter goal, a nation-wide large-scale data collection was introduced based on clinical routine outcome monitoring (ROM) data, with a view to using these data for benchmarking. AIM: Closer inspection of the benchmarking efforts in terms of scientific validity. METHOD: Qualitative review and analysis. RESULTS: Analysis shows that the type of ROM data that is collected in the Netherlands is valid for tracking the outcomes of individual patients, but unsuitable for performance comparisons between institutions for reasons of case mix, instrument-mix, bias and lack of sensitivity. CONCLUSION: Attempts to introduce benchmarking based on rom will probably have a negative impact on the practice of mental health care in the Netherlands. More input from mental health professionals and scientists is required in order to identify more rational and efficient ways of spending scarce resources. PMID- 22422418 TI - [Transparancy mental health care improved by ROM and benchmarking]. PMID- 22422419 TI - [Care for addicted, pregnant women: justification for pressure and coercion]. AB - BACKGROUND: The care of addicted, pregnant women and the protection of the newborn child and its future wellbeing have long been issues of considerable concern and require further attention. AIM: To reflect upon current practice and to consider whether it is justified, and to draw up an agenda for further ethical discussion and research. METHOD: We performed an ethical analysis on the basis of criteria for pressure and coercion. RESULTS: Measures involving pressure or coercion constitute an infringement of the pregnant woman's freedom of action to make personal choices. This requires a more explicit moral justification than is actually provided in the current practice. CONCLUSION: A moral justification needs to be more firmly based on the proportionality and the subsidiarity of specific forms of pressure and coercion. The routine application for prenatal supervision by a guardian seems to be at odds with these conditions. A major problem is that according to Dutch law coercive measures (that are in the interests of the child) cannot be taken within the first 24 weeks of a pregnancy. PMID- 22422420 TI - [The new curriculum for the University Training Course in Psychiatry in South Limburg and for the Mental Health Services in Eindhoven]. AB - BACKGROUND: The curriculum for the Academic Training Course in Psychiatry in South- Limburg (UOP-ZL) needed to be modernised. There were widely differing views about the purpose and function of psychiatry and about the structure of the curriculum. Trainees failed to attend regularly because of their daily duties. AIM: Following discussion about the need for modernisation of the course in Psychiatry (HOOP), the UOP-ZL curriculum was thoroughly revised and updated. METHOD: Further development of HOOP, a careful study of the teaching material and discussion among members of UOP-ZL and the Mental Health Service in Eindhoven, led to the development of more unified views about psychiatry and produced the ingredients for a revised curriculum for training in psychiatry. RESULTS: In the early stages of their course, trainees are introduced to some basic principles; these include understanding the mechanisms for dimensions of affect, motivation, salience and cognition from a biological, cognitive and ecological perspective, and perceiving the relationship between these factors and normal and abnormal behaviour. The course is a mix of problem based learning and interactive classroom teaching and is delivered by clinical and scientific experts. Every two weeks the trainees in each year-group are given a whole day 'free' (i.e. free of normal duties) when they are required to attend classed and lectures. CONCLUSION: The two main results of the new curriculum are: diagnosis-related teaching has been replaced by an approach based on explanatory mechanisms for dimensional psychopathology and dysfunction, and the tuition provided is both problem-based and interactive and is given by expert teachers. PMID- 22422421 TI - [Anti- NMDA- receptor encephalitis; a neuropsychiatric illness requiring further study]. AB - We describe the case of a 17-year-old girl with anti-NMDA-receptor encephalitis. She had the characteristic psychiatric symptoms such as hallucinations, delirious and bizarre behaviour, and catatonic symptoms. She later also displayed neurological symptoms such as epileptic seizures, dyskinesias and sensitivity disturbances. After treatment with corticosteroids and immunoglobulins patient recovered completely. Potentially lethal symptoms can arise from the autonomic dysregulation. The incidence of this disorder has not yet been established. The catatonic features should be treated adequately with high doses of benzodiazepines. Because patients usually present with psychiatric symptoms, treatment often starts in a psychiatric setting. In view of the serious somatic complications it is desirable that the patient be treated in a general hospital. Early diagnosis and treatment are very important because the chances of recovery are thereby enhanced. PMID- 22422422 TI - [Treatment of clozapine-induced tachycardia with propranolol complicated by psoriasis]. AB - A 25-year-old male developed sinus tachycardia after given clozapine for treatment-resistant psychosis in schizophrenia. The tachycardia was treated successfully with propranolol for several weeks. The patient developed skin eruptions, later diagnosed as psoriasis. Propranolol is known to be capable of causing, evoking or aggravating psoriasis. Several other drugs commonly used in psychiatric practice are also known to cause psoriasis. Doctors need to be aware to the possible side effects of such drugs because they can jeopardise the patient's wellbeing and reduce the efficacy of psychiatric treatment. PMID- 22422423 TI - [Reaction on 'seven views on mental disorder' (1)]. PMID- 22422424 TI - [Reaction on 'seven views on mental disorder' (2)]. PMID- 22422425 TI - [Response to 'ADD psychosis: treatment with antipsychotics and methylphenidate?']. PMID- 22422426 TI - A turning point for Alzheimer's disease? AB - Despite an archive of over 73,000 research papers published in the last two decades on the subject of Alzheimer's disease (AD), little clinical progress has been made relative to how people get sporadic AD and what can be done to help them avoid it. This review spotlights strategic steps that could be a turning point in the dramatic lowering of Alzheimer prevalence. The main strategy includes application of four pillars of prevention: 1) early identification of AD vascular risk factors; 2) early detection of AD vascular risk factors; 3) early intervention of AD vascular risk factors based on evidence-based medical decisions; 4) patient follow-up to assess and modify interventions as needed. Tandem to these four pillars of prevention, a proactive lifestyle consisting of a healthy diet coupled to physical and mental activity should be applied as part of any therapeutic intervention. We are persuaded by mounting and compelling evidence that AD is a multifactorial disorder kindled by vascular risk factors that generate chronic brain hypoperfusion (CBH) during advanced aging. A pathobiological cascade of biochemical events in the presence of CBH that leads to oxidative stress and neurodegeneration appears to involve multiple biofactors including micronutrients, trace metals, lipids, and pro-oxidants, as reviewed in this special issue of BioFactors. Modulation of these biofactors may help prevent or control incipient AD. (c) 2012 International Union of Biochemistry and Molecular Biology, Inc. PMID- 22422427 TI - A review of exenatide: optimizing glycemic control and associated cardiovascular risk factors in type 2 diabetes. AB - Type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for the development of cardiovascular disease. With an increasing prevalence of obesity, this risk has increased further. Management of T2DM in obese patients is particularly challenging as treatment with the majority of glucose-lowering agents results in weight gain. Thus, the development of a therapeutic option which could improve glycemic control without weight gain or hypoglycemia, such as the glucagon-like peptide-1 (GLP-1) analog exenatide, is a welcome addition to the currently available therapies in the management of T2DM. With recognition and better understanding of the role of incretin hormones in T2DM, exenatide was developed and introduced into clinical practice in 2005. Both randomized controlled trials and retrospective observational studies have shown that treatment with exenatide not only improves glycemic control, with a low risk of hypoglycemia, but also results in concurrent weight loss and the additional benefit of improvement in cardiovascular risk factors. This article will provide an overview of both short- and long-acting exenatide in the management of T2DM and associated cardiovascular risk factors. PMID- 22422428 TI - Treatment of dementia patients with fracture of the proximal femur in a specialized geriatric care unit compared to conventional geriatric care. AB - To prove the efficiency of a specialized geriatric ward (cognitive geriatric unit, CGU) for patients with a fracture of the proximal femur and additional dementia, we conducted a matched-pair analysis comparing 96 patients with fracture of the proximal femur and additional dementia matched for age, sex, surgical treatment and the degree of cognitive impairment by MMSE score. A total of 48 patients were treated in the CGU, offering extended geriatric assessment, special education of staff, and architecture appropriate for patients with cognitive decline. Target criteria were a gain in the Barthel index and Tinetti score, the length of stay, new admissions to nursing home, the frequency of neuroleptic, antidepressant, and antidementive medication, and the number of specified clinical diagnoses for the dementia syndrome. Length of stay was significantly longer in the CGU. The increase of the Tinetti score was significantly higher in the patients in the CGU, regardless of the length of stay (analysis of covariance: treatment (CGU/non-CGU): F(1/93) = 9.421, p = 0.003; covariate (length of stay): F(1/93) = 3.452, p = 0.066, eta(2) = 3.6%). In the intervention group, the number of definite diagnoses concerning the dementia syndrome was also higher. Comparison of drug treatment and the percentage of new admission to a nursing home did not differ between groups. Treatment in a specialized, "cognitive geriatric unit" seems to result in better mobility of demented patients with proximal fractures of the femur. PMID- 22422429 TI - Potential role of metabolomic approaches for Chinese medicine syndromes and herbal medicine. AB - Systems biology has significantly increased in recent years. Its method and design resemble those of traditional Chinese medicine (TCM), which is a unique medical system that assisted the ancient Chinese in dealing with disease. The technology platforms of systems biology, especially metabolomics, could provide more rapid, direct, concise and effective methods for disease research. In particular, metabolomics could provide useful tools for exploring the essence of Chinese medicine syndromes (CMS) disease, facilitating personalized TCM. Moreover, metabolomics has the potential to enable mapping of early biochemical changes in disease and hence provide an opportunity to develop predictive biomarkers that can trigger earlier interventions. A future hope for the metabonomic approach is the identification of biomarkers that are able to highlight individuals likely to suffer from disease and enable early diagnosis of the disease or the identification of those at risk, and it will help to understand CMS and modernize TCM. In this review, we focus on the key role of robust metabolomic approaches as an aid for traditional herbal medicine; particular attention will be paid to the past successes in applications of metabonomics to contribute to low-molecular-weight metabolites (biomarkers) discovery in TCM research. PMID- 22422430 TI - Hierarchical and multifunctional three-dimensional network of carbon nanotubes for microfluidic applications. AB - Three-Dimensional network of carbon nanotubes: The 3D network of CNTs have hierarchical structures comprised of interconnected SWNTs between Si pillars in microfluidic channels. The Al(2)O(3) coated 3D networks were used for size different nanoparticles filtration and streptavidin capturing in very diluted solution. The 3D network of SWNTs systems will provide a robust multifuncitonal platform for a variety of biomedical and environmental applications. PMID- 22422431 TI - ortho-Phenylene oligomers with terminal push-pull substitution. AB - ortho-Phenylenes are an emerging class of helical oligomers and polymers. We have synthesized a series of push-pull-substituted o-phenylene oligomers (dimethylamino/nitro) up to the octamer. Conformational analysis of the hexamer using a combination of low-temperature NMR spectroscopy and ab initio predictions of (1)H NMR chemical shifts indicates that, like other o-phenylenes, they exist as compact helices in solution. However, the substituents are found to have a significant effect on their conformational behavior: the nitro-functionalized terminus is 3-fold more likely to twist out of the helix. Protonation of the dimethylamino group favors the helical conformer. UV/vis spectroscopy indicates that the direct charge-transfer interaction between the push-pull substituents attenuates quickly compared to other conjugated systems, with no significant charge-transfer band for oligomers longer than the trimer. On protonation of the dimethylamino group, significant bathochromic shifts with increasing oligomer length are observed: the effective conjugation length is 9 repeat units, more than twice that of the parent oligomer. This behavior may be rationalized through examination of the frontier molecular orbitals of these compounds, which exhibit greater delocalization after protonation, as shown by DFT calculations. PMID- 22422432 TI - A magnetoencephalographic study of face processing: M170, gamma-band oscillations and source localization. AB - EEG studies suggested that the N170 ERP and Gamma-band responses to faces reflect early and later stages of a multiple-level face-perception mechanism, respectively. However, these conclusions should be considered cautiously because EEG-recorded Gamma may be contaminated by noncephalic activity such as microsaccades. Moreover, EEG studies of Gamma cannot easily reveal its intracranial sources. Here we recorded MEG rather than EEG, assessed the sources of the M170 and Gamma oscillations using beamformer, and explored the sensitivity of these neural manifestations to global, featural and configural information in faces. The M170 was larger in response to faces and face components than in response to watches. Scrambling the configuration of the inner components of the face even if presented without the face contour reduced and delayed the M170. The amplitude of MEG Gamma oscillations (30-70 Hz) was higher than baseline during an epoch between 230-570 ms from stimulus onset and was particularly sensitive to the configuration of the stimuli, regardless of their category. However, in the lower part of this frequency range (30-40 Hz) only physiognomic stimuli elevated the MEG above baseline. Both the M170 and Gamma were generated in a posterior ventral network including the fusiform, inferior-occipital and lingual gyri, all in the right hemisphere. The generation of Gamma involved additional sources in the visual system, bilaterally. We suggest that the evoked M170 manifests a face perception mechanism based on the global characteristics of face, whereas the induced Gamma oscillations are associated with the integration of visual input into a pre-existent coherent perceptual representation. PMID- 22422433 TI - Light white oils exhibit low tissue accumulation potential and minimal toxicity in F344 rats. AB - Female F344 rats were fed diets containing 0.02%, 0.2%, or 2.0% white mineral oil for 90 days. There were no gross or microscopic differences in target organs at the 0.02% level. In the higher-dose groups, relative liver and mesenteric lymph node (MLN) weights were increased, and MLN inflammation was observed. At the 2% level, there was very limited evidence of microgranuloma formation in the liver but at a lower incidence and at lesser severity than has been reported in studies of C22-C25 oils. Analysis of liver extracts from treated rats revealed that C15 C20 constituents were underrepresented by comparison to their corresponding concentrations in the test oil. These results provide evidence that although hydrocarbons with carbon numbers < C20 are absorbed, they are not preferentially retained and do not contribute to inflammatory processes in liver. PMID- 22422434 TI - Comparison of the repeated dose toxicity of isomers of dinitrotoluene. AB - Dinitrotoluene (DNT) is a nitroaromatic explosive used in propellant mixtures and in the production of plastics. Isomers of DNT were administered daily via oral gavage to male Sprague-Dawley rats for 14 days to determine the subacute toxicity of individual isomers of DNT. The 3,5-DNT isomer was the most toxic isomer, inducing weight loss and mortality within 3 days. Cyanosis and anemia were observed for all isomers. Exposure to 2,4-, 2,6-, and 3,5-DNT resulted in decreased testes mass and degenerative histopathological changes. Increased splenic mass was observed for 2,4-, 2,6-, and 2,5-DNT. Extramedullary hematopoiesis of the spleen was noted for all isomers, while lymphoid hyperplasia of the spleen was noted for all isomers except 2,5-DNT. Increased liver mass was observed for 2,3-DNT and 3,4-DNT. Hepatocellular lesions were observed for 2,6 DNT and 2,4-DNT. Neurotoxic effects were noted for 3,4-DNT, 2,4-DNT, and 3,5-DNT. PMID- 22422435 TI - "Squaring the clusters": a Mn(III)4Ni(II)4 molecular square from nickel(II) induced structural transformation of a Mn(II/III/IV)12 cage. AB - A Mn(III)(4)Ni(II)(4) molecular square exhibiting slow magnetization relaxation has been prepared from the reaction of a Mn(II)(4)Mn(III)(6)Mn(IV)(2) cluster and a simple Ni(II) source. PMID- 22422436 TI - Preliminary evaluation of biplane correlation (BCI) stereographic imaging for lung nodule detection. AB - A biplane correlation (BCI) imaging system obtains images that can be viewed in stereo, thereby minimizing overlapping structures. This study investigated whether using stereoscopic visualization provides superior lung nodule detection compared to standard postero-anterior (PA) image display. Images were acquired at two oblique views of +/-3 degrees as well as at a standard PA position from 60 patients. Images were processed using optimal parameters and displayed on a stereoscopic display. The PA image was viewed in the standard format, while the oblique views were paired to provide a stereoscopic view of the subject. A preliminary observer study was performed with four radiologists who viewed and scored the PA image then viewed and scored the BCI stereoscopic image. The BCI stereoscopic viewing of lung nodules resulted in 71 % sensitivity and 0.31 positive predictive value (PPV) index compared to PA results of 86 % sensitivity and 0.26 PPV index. The sensitivity for lung nodule detection with the BCI stereoscopic system was reduced by 15 %; however, the total number of false positives reported was reduced by 35 % resulting in an improved PPV index of 20 %. The preliminary results indicate observer dependency in terms of relative advantage of either system in the detection of lung nodules, but overall equivalency of the two methods with promising potential for BCI as an adjunct diagnostic technique. PMID- 22422437 TI - A review and critical analysis of professional societies' guidelines for pharmacologic management of type 2 diabetes mellitus. AB - The development of clinical practice guidelines (CPGs), which are promulgated by various sponsoring organizations to provide direction to clinicians for management of complex problems, generally adhere to a set of key principles. To reassure the users of their scientific and ethical validity, these include the use of a system to rate the quality of evidence on which the guideline is based and the divulgence of any conflicts of interest (COI) among members of the panel developing the guidelines. I analyzed the CPGs for pharmacologic management of patients with type 2 diabetes written by the two US professional societies that developed such guidelines (American Association of Clinical Endocrinologists [AACE] and the American Diabetes Association/European Association for the Study of Diabetes [ADA/EASD]) to assess their adherence to these principles of guideline development and to compare them with regard to simplicity, consideration of costs, and peer review status. To put the existence of COIs in these guidelines into context, I also reviewed the COIs from government-sponsored panels that developed diabetes CPGs. The results of this analysis suggest that both the AACE and ADA/EASD guidelines should be regarded as consensus documents rather than true CPGs, since neither guideline employed evidence grading. COI was extremely common among the members of both CPG panels from professional organizations, as well in the CPG panels with government sponsorship. In addition, the nature and extent of external peer review of these guidelines is unclear. Given these limitations, the AACE and ADA/EASD CPGs for diabetes management should be regarded as advisory at best, rather than prescriptive or authoritative, especially in view of their noncompliance with key principles of guideline development. PMID- 22422438 TI - Primary repair of crush nerve injuries by means of biological tubulization with muscle-vein-combined grafts. AB - Despite extensive research and surgical innovation, the treatment of peripheral nerve injuries remains a complex issue, particularly in nonsharp lesions. The aim of this study was to assess the clinical outcome in a group of 16 patients who underwent, in emergency, a primary repair for crush injury of sensory and mixed nerves of the upper limb with biological tubulization, namely, the muscle-vein combined graft. The segments involved were sensory digital nerves in eight cases and mixed nerves in another eight cases (four median nerves and four ulnar nerves). The length of nerve defect ranged from 0.5 to 4 cm (mean 1.9 cm). Fifteen of 16 patients showed some degree of functional recovery. Six patients showed diminished light touch (3.61), six had protective sensation (4.31), and three showed loss of protective sensation (4.56) using Semmes-Weinstein monofilament test. All the patients who underwent digital nerve repair had favorable results graded as S4 in one case, S3+ in six cases, and S3 in one case. With respect to mixed nerve repair, we observed two S4, two S3+, two S3, one S2, and one S0 sensory recovery. Less favorable results were observed for motor function with three M4, one M3, two M2, and two M0 recoveries. Altogether, the results of this retrospective study demonstrates that tubulization nerve repair in emergency, in case of short nerve gaps, may restore the continuity of the nerve avoiding secondary nerve grafting. This technique preserves donor nerve and, in case of failure, does not preclude a delayed repair with a nerve graft. PMID- 22422439 TI - The Italian version of the Fear-Avoidance Beliefs Questionnaire (FABQ-I): cross cultural adaptation, factor analysis, reliability, validity, and sensitivity to change. AB - STUDY DESIGN: Evaluation of the psychometric properties of a translated and culturally adapted questionnaire. OBJECTIVE: Translating, culturally adapting, and validating the Italian version of the Fear-Avoidance Beliefs Questionnaire (FABQ-I) to allow its use with Italian-speaking patients with low-back pain (LBP). SUMMARY OF BACKGROUND DATA: Growing attention is being given to standardized outcome measures to improve interventions for LBP. A translated form of the FABQ has never been validated in Italian patients with LBP. METHODS: The FABQ-I questionnaire was developed by means of forward-backward translation, a final review by an expert committee, and a test of the prefinal version to establish its correspondence with the original English version. The psychometric testing included factor analysis, reliability by internal consistency (Cronbach alpha) and test-retest reliability (intraclass coefficient correlation), convergent validity by comparing FABQ-I with the Italian version of the Tampa Scale of Kinesiophobia (TSK-I), and discriminant validity by comparing FABQ-I with a visual analogue scale, the Roland Morris Disability Questionnaire, and the Hospital Anxiety and Depression Scale (Pearson correlation). RESULTS: It took 4 months to develop a shared version of the FABQ-I. The questionnaire was administered to 180 subjects and proved to be acceptable. Factor analysis revealed a 2-factor, 12-item solution (57% of explained variance). The questionnaire showed good internal consistency (alpha = 0.822) and high test retest reliability (intraclass coefficient correlation = 0.869). Convergent validity showed a moderate correlation with TSK-I (r = 0.440), and discriminant validity showed moderate-poor correlations with a visual analogue scale (r = 0.335), Roland Morris Disability Questionnaire (r = 0.414), and Hospital Anxiety and Depression Scale (r = 0.258 for the Anxiety score and r = 0.246 for the Depression score). The results of the psychometric analyses of the subscales were similar to those of the scale as a whole. CONCLUSION: The FABQ outcome measure was successfully translated into Italian and proved to have a good factorial structure and psychometric properties that replicated the results of other existing versions. Its use is recommended for research purposes. PMID- 22422440 TI - Osteosarcoma of the mobile spine. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: Our goal was to assess whether en bloc resection had an impact on survival. SUMMARY OF BACKGROUND DATA: Osteogenic sarcoma occurs rarely in the mobile spine, but when it does, the prognosis is poor. Wide resection is recommended for osteogenic sarcoma of the extremities, but wide resection is difficult and often dangerous in the spine. The goal of this study was to examine whether en bloc removal of osteogenic sarcomas in the mobile spine improves survival. METHODS: We performed a retrospective review of all cases of high-grade, osteogenic sarcoma of the mobile spine treated with high-dose methotrexate and adrimaycin-based chemotherapy between 1985 through 2005. There were 9 male patients and 8 female patients. Patients were followed for a median of 38 months or until death, and surviving patients were followed for a minimum of 6.4 years. Patients were grouped on the basis of whether they underwent en bloc spondylectomy. The Enneking stage and Weinstein, Boriani, and Biagini stage, as well as the pre- and postoperative Frankel grades, were collected on all patients. Local recurrence and metastasis data were collected for all patients. Overall survival was calculated using Kaplan-Meier methods with the log rank test utilized to evaluate the effect of en bloc resection on survival. RESULTS: Twelve (71%) of 17 patients with osteogenic sarcoma of the mobile spine died. Median disease-specific survival for the entire cohort was 38.1 months (standard error 29.6; 95% confidence interval 0-96). Nine patients underwent en bloc resection. Median overall survival for patients after en bloc resection was 77.3 months (standard error 62; 95% confidence interval 96) versus 17 months (standard error 6.5; 95% confidence interval 4-29.6) (P = 0.09). Eleven (65%) of 17 patients developed pulmonary metastasis, and 9 of those 11 died from their disease (P = 0.04). Six (35%) patients developed a local recurrence, and all 6 died from their disease (P = 0.07). CONCLUSION: Osteogenic sarcoma of the mobile spine presents a significant challenge, and most patients die from their disease in spite of aggressive surgery and chemotherapy. Metastastic disease is associated with a worse prognosis. There is a trend toward improved survival with en bloc resection when compared with intralesional resection. Osteogenic sarcoma of the mobile spine is rare and historically has a very poor prognosis. We reviewed our cases of osteogenic sarcoma of the mobile spine to assess whether modern en bloc resection improved survival. Survival remains poor, but there is a trend toward improved survival with en bloc resection. PMID- 22422441 TI - Fatal pulmonary embolism: when the cause is not a thrombus. AB - STUDY DESIGN: We report a case of pulmonary embolism of polymethylmethacrylate material after percutaneous vertebroplasty. OBJECTIVE: To describe a severe vertebroplasty complication, the pulmonary embolism, which proved to be fatal in a patient with many chronic disabilities. SUMMARY OF BACKGROUND DATA: Until 2007, the literature noted that the risk of embolism of polymethylmethacrylate after a percutaneous vertebroplasty counted a small number of pulmonary cement embolism and a smaller number of fatal consequences. The most recent research revealed that the risk of a pulmonary cement embolism ranges from 3.5% to 23% for osteoporotic compression fractures. METHODS: This study is a case report of an 80 year-old patient with multiple medical comorbid factors, chronic obstructive pulmonary disease, mild renal failure, osteoporosis, and hepatic cirrhosis. Symptoms of pulmonary embolism developed 1 month after a percutaneous vertebroplasty. An echocardiography report suggested that the cement infiltrated the right atrium and the right pulmonary artery, and this was confirmed by a computed tomographic scan. As the therapy with oxygen and low-molecular-weight heparin failed to solve the thrombus, the patient required a surgical tricuspid annuloplasty and the extirpation of the right atrial and right pulmonary masses. RESULTS: The course of the operation was complicated by pulmonary infection, and the patient ultimately succumbed to infection/respiratory failure. CONCLUSION: The presence of intravascular/intracardiac foreign bodies is underreported in literature, but it is quite common in clinical practice. We need to discuss the choice of some non-risk-free interventions such as vertebroplasty in older patients already affected by multiple main disabilities. PMID- 22422442 TI - Spontaneous clinical and radiological resolution of vertebral sarcoidosis: a case report. AB - STUDY DESIGN: Case report of occult presentation of asymptomatic vertebral sarcoidosis. OBJECTIVE: To illustrate a case of vertebral sarcoidosis with occult presentation and subsequent spontaneous resolution. SUMMARY OF BACKGROUND DATA: Vertebral sarcoidosis is an uncommon disorder characterized by noncaseating granulomatous infiltration of the spine. It most commonly affects the thoracic spine. The disc spaces are usually preserved; clinical presentation and imaging characteristics are variable. METHODS: Case presentation and report. RESULTS: A 41-year-old man with classic pulmonary sarcoidosis presented after a work-related back injury. Magnetic resonance injury of his spine demonstrated multiple enhancing lesions throughout the thoracic and lumbar vertebrae. Classic granulomas were identified on subsequently obtained core biopsy specimens, and the diagnosis of vertebral sarcoidosis was made. CONCLUSION: To our knowledge, this is the first case of concomitant pulmonary and asymptomatic vertebral sarcoidosis with spontaneous resolution of the vertebral manifestations without definitive treatment. A broad differential diagnosis should be entertained for new enhancing spine lesions including noninfectious inflammatory diseases such as sarcoidosis. PMID- 22422443 TI - Light-induced dynamics in conjugated bis(terpyridine) ligands--a case study toward photoactive coordination polymers. AB - Terpyridine coordination compounds have recently revealed their potential toward optoelectronic applications, which are based on (i) their excellent charge transfer properties or (ii) intriguing luminescence properties of the systems, depending on their design. This article features recent work in dissecting the photophysical properties of such materials by investigating the photoinduced processes in individual molecular fragments. The article starts considering the terpyridine ligands themselves before discussing the impact of metal coordination. After shedding light into the interplay of different electronic states in the terpyridine complexes, first results of a single-molecule fluorescence study are presented, which allow for correlation of the overall luminescence properties with the structure of the polymer. PMID- 22422444 TI - O-Linked glycome and proteome of high-molecular-mass proteins in human ovarian cancer ascites: Identification of sulfation, disialic acid and O-linked fucose. AB - The O-linked glycosylation of the main acidic high-molecular-weight glycoprotein from ascites fluid from patients with ovarian cancer were analyzed. The O-linked oligosaccharides were shown to consist of mainly highly sialylated core 1 and 2 structures with a smaller amount of sulfated core 2 structures. These structures were shown to be able to be further extended into small keratan sulfate (KS)-type oligosaccharides with up to four N-acetyllactosamine units. Proteomic studies of the acidic fraction of ascites fluid from patients with ovarian cancer showed that this fraction was enriched in proteoglycans. Among them, lumican, agrin, versican and dystroglycans were potential candidates, with threonine- and serine rich domains that could carry a significant amount of O-linked glycosylation, including also the O-linked KS. Glycomic analysis using liquid chromatography (LC)-tandem mass spectrometry (MS/MS) also showed that the disialic acid NeuAc NeuAc- was frequently found as the terminating structure on the O-linked core 1 and 2 oligosaccharides from one ascites sample. Also, a small amount of the epidermal growth factor (EGF)-associated O-linked fucose structure Gal-GlcNAc Fucitol was detected with and without sialic acid in the LC-MS/MS analysis. Candidate proteins containing O-linked fucose were suggested to be proteoglycan type molecules containing the O-linked fucose EGF consensus domain. PMID- 22422445 TI - Everolimus-eluting versus sirolimus-eluting stents: an updated meta-analysis of randomized trials. AB - BACKGROUND: Everolimus-eluting stents (EES; Xience V) are among the most commonly used newer generation drug-eluting stents in clinical practice and have clearly proven superiority over paclitaxel-eluting stents. Nevertheless, the relative merits of EES against the previous gold-standard sirolimus-eluting stent (SES; Cypher) have been less extensively assessed. We aimed to compare the clinical outcomes of EES with SES in patients with coronary artery disease undergoing percutaneous coronary intervention. METHODS AND RESULTS: We identified eight eligible randomized trials comparing EES with SES including 11,167 patients. The primary endpoint was the incidence of major adverse cardiac events (MACE). Secondary endpoints were target lesion revascularization (TLR) and the composite of definite and probable stent thrombosis. The follow-up ranged from 9 to 36 months. No heterogeneity across the trials was observed regarding the selected endpoints. There was no difference in risk of MACE (HR 0.91 [0.79-1.04]; p = 0.15), TLR (HR 0.86 [0.72-1.04]; p = 0.12) and the composite of definite and probable stent thrombosis (HR 0.84 [0.54-1.29], p = 0.42). The risk of definite stent thrombosis was significantly lower in patients receiving EES (HR 0.49 [0.27 to 0.91]; p = 0.02). CONCLUSION: Using the largest available dataset of patients treated in randomized trials, the present meta-analysis demonstrated that the use of EES versus SES was associated with comparable incidence of overall clinical events. However, EES may be associated with a lower risk of definite stent thrombosis. PMID- 22422446 TI - CFD simulation of mixing for high-solids anaerobic digestion. AB - A computational fluid dynamics (CFD) model that simulates mechanical mixing for high-solids anaerobic digestion was developed. Numerical simulations of mixing manure slurry which exhibits non-Newtonian pseudo-plastic fluid behavior were performed for six designs: (i) one helical ribbon impeller; (ii) one anchor impeller; (iii) one curtain-type impeller; (iv) three counterflow (CF-2) impellers; (v) two modified high solidity (MHS 3/39 degrees ) impellers; and (vi) two pitched blade turbine impellers. The CFD model was validated against measurements for mixing a Herschel-Bulkley fluid by ribbon and anchor impellers. Based on mixing time with respect to mixing energy level, three impeller types (ribbon, CF-2, and MHS 3/39 degrees ) stand out when agitating highly viscous fluids, of these mixing with two MHS 3/39 degrees impellers requires the lowest power input to homogenize the manure slurry. A comparison of digestion material demonstrates that the mixing energy varies with manure type and total solids concentration to obtain a given mixing time. Moreover, an in-depth discussion about the CFD strategy, the influences of flow regime and impeller type on mixing characteristics, and the intrinsic relation between mixing and flow field is included. PMID- 22422447 TI - Is epidemiology ready for epigenetics? PMID- 22422448 TI - Cohort profile: The peri/post-natal epigenetic twins study. PMID- 22422449 TI - Associations with early-life socio-economic position in adult DNA methylation. AB - BACKGROUND: Disadvantaged socio-economic position (SEP) in childhood is associated with increased adult mortality and morbidity. We aimed to establish whether childhood SEP was associated with differential methylation of adult DNA. METHODS: Forty adult males from the 1958 British Birth Cohort Study were selected from SEP extremes in both early childhood and mid-adulthood. We performed genome wide methylation analysis on blood DNA taken at 45 years using MeDIP (methylated DNA immunoprecipitation). We mapped in triplicate the methylation state of promoters of approximately 20,000 genes and 400 microRNAs. Probe methylation scores were averaged across triplicates and differential methylation between groups of individuals was determined. Differentially methylated promoter sites of selected genes were validated using pyrosequencing of bisulfite-converted DNA. RESULTS: Variably methylated probes (9112 from n = 223,359 on the microarray) corresponded to 6176 gene promoters with at least one variable probe. Unsupervised hierarchical clustering of probes obtained from the 500 most variable promoters revealed a cluster enriched with high SEP individuals confirming that SEP differences contribute to overall epigenetic variation. Methylation levels for 1252 gene promoters were associated with childhood SEP vs 545 promoters for adulthood SEP. Functionally, associations with childhood SEP appear in promoters of genes enriched in key cell signalling pathways. The differentially methylated promoters associated with SEP cluster in megabase-sized regions of the genome. CONCLUSIONS: Adult blood DNA methylation profiles show more associations with childhood SEP than adult SEP. Organization of these associations across the genome suggests a well-defined epigenetic pattern linked to early socio-economic environment. PMID- 22422450 TI - Adult global DNA methylation in relation to pre-natal nutrition. AB - BACKGROUND: Exposure to a pre-natal famine environment has been associated with a persistent decrease in DNA methylation of the IGF2 gene, although study findings on other loci have been highly variable. There have been no studies to date of the relation between pre-natal famine and overall global DNA methylation in adulthood. METHODS: Our study population includes 350 births with pre-natal exposure to the Dutch famine of 1944-45 selected from three birth clinics, 290 births from these clinics born before or after the famine as unexposed time controls and 307 same-sex siblings of either birth group as unexposed family controls. All study subjects were interviewed and underwent a medical examination at a mean age of 58 years when blood samples were also collected. As measures of genomic DNA methylation, we analysed two repetitive elements, LINE-1 (long interspersed nucleotide element 1) and Sat2 (Satellite 2 DNA sequence) by pyrosequencing and MethyLight, respectively, and overall genomic DNA methylation using the Luminometric methylation assay (LUMA). RESULTS: Mean DNA methylation by LUMA was 75.2% [standard deviation (SD) 4.7], by LINE-1 was 77.1% (SD 2.5) and by Sat2 was 122.2 (SD 56.2). Pre-natal famine exposure was associated with negligible changes in all three assays {LUMA: -0.16% [95% confidence interval (95% CI) -0.49 to 0.81], P = 0.63; LINE-1: -0.05 % (95% CI -0.33 to 0.22), P = 0.70; and Sat2: -0.51% (95% CI -7.38 to 6.36), P = 0.88} relative to unexposed controls, adjusting for age at examination and within family clustering. CONCLUSION: Our results show no relation between overall global DNA methylation in adults and pre-natal famine exposure. Further work should focus on selected regions in the genome that may be differentially methylated in response to changes in early life exposures and predict adult health outcomes. PMID- 22422451 TI - Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. AB - The burgeoning interest in the field of epigenetics has precipitated the need to develop approaches to strengthen causal inference when considering the role of epigenetic mediators of environmental exposures on disease risk. Epigenetic markers, like any other molecular biomarker, are vulnerable to confounding and reverse causation. Here, we present a strategy, based on the well-established framework of Mendelian randomization, to interrogate the causal relationships between exposure, DNA methylation and outcome. The two-step approach first uses a genetic proxy for the exposure of interest to assess the causal relationship between exposure and methylation. A second step then utilizes a genetic proxy for DNA methylation to interrogate the causal relationship between DNA methylation and outcome. The rationale, origins, methodology, advantages and limitations of this novel strategy are presented. PMID- 22422452 TI - DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. AB - BACKGROUND: Gestational age at birth strongly predicts neonatal, adolescent and adult morbidity and mortality through mostly unknown mechanisms. Identification of specific genes that are undergoing regulatory change prior to birth, such as through changes in DNA methylation, would increase our understanding of developmental changes occurring during the third trimester and consequences of pre-term birth (PTB). METHODS: We performed a genome-wide analysis of DNA methylation (using microarrays, specifically CHARM 2.0) in 141 newborns collected in Baltimore, MD, using novel statistical methodology to identify genomic regions associated with gestational age at birth. Bisulphite pyrosequencing was used to validate significant differentially methylated regions (DMRs), and real-time PCR was performed to assess functional significance of differential methylation in a subset of newborns. RESULTS: We identified three DMRs at genome-wide significance levels adjacent to the NFIX, RAPGEF2 and MSRB3 genes. All three regions were validated by pyrosequencing, and RAGPEF2 also showed an inverse correlation between DNA methylation levels and gene expression levels. Although the three DMRs appear very dynamic with gestational age in our newborn sample, adult DNA methylation levels at these regions are stable and of equal or greater magnitude than the oldest neonate, directionally consistent with the gestational age results. CONCLUSIONS: We have identified three differentially methylated regions associated with gestational age at birth. All three nearby genes play important roles in the development of several organs, including skeletal muscle, brain and haematopoietic system. Therefore, they may provide initial insight into the basis of PTB's negative health outcomes. The genome-wide custom DNA methylation array technology and novel statistical methods employed in this study could constitute a model for epidemiologic studies of epigenetic variation. PMID- 22422453 TI - Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. AB - BACKGROUND: During the past 5 years, high-throughput technologies have been successfully used by epidemiology studies, but almost all have focused on sequence variation through genome-wide association studies (GWAS). Today, the study of other genomic events is becoming more common in large-scale epidemiological studies. Many of these, unlike the single-nucleotide polymorphism studied in GWAS, are continuous measures. In this context, the exercise of searching for regions of interest for disease is akin to the problems described in the statistical 'bump hunting' literature. METHODS: New statistical challenges arise when the measurements are continuous rather than categorical, when they are measured with uncertainty, and when both biological signal, and measurement errors are characterized by spatial correlation along the genome. Perhaps the most challenging complication is that continuous genomic data from large studies are measured throughout long periods, making them susceptible to 'batch effects'. An example that combines all three characteristics is genome-wide DNA methylation measurements. Here, we present a data analysis pipeline that effectively models measurement error, removes batch effects, detects regions of interest and attaches statistical uncertainty to identified regions. RESULTS: We illustrate the usefulness of our approach by detecting genomic regions of DNA methylation associated with a continuous trait in a well-characterized population of newborns. Additionally, we show that addressing unexplained heterogeneity like batch effects reduces the number of false-positive regions. CONCLUSIONS: Our framework offers a comprehensive yet flexible approach for identifying genomic regions of biological interest in large epidemiological studies using quantitative high-throughput methods. PMID- 22422454 TI - Global LINE-1 DNA methylation is associated with blood glycaemic and lipid profiles. AB - BACKGROUND: Patterns of DNA methylation change with age and these changes are believed to be associated with the development of common complex diseases. The hypothesis that Long Interspersed Nucleotide Element 1 (LINE-1) DNA methylation (an index of global DNA methylation) is associated with biomarkers of metabolic health was investigated in this study. METHODS: Global LINE-1 DNA methylation was quantified by pyrosequencing in blood-derived DNA samples from 228 individuals, aged 49-51 years, from the Newcastle Thousand Families Study (NTFS). Associations between log-transformed LINE-1 DNA methylation levels and anthropometric and blood biochemical measurements, including triglycerides, total cholesterol, low density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, fasting glucose and insulin secretion and resistance were examined. RESULTS: Linear regression, after adjustment for sex, demonstrated positive associations between log-transformed LINE-1 DNA methylation and fasting glucose {coefficient 2.80 [95% confidence interval (CI) 0.39-5.22]}, total cholesterol [4.76 (95% CI 1.43 8.10)], triglycerides [3.83 (95% CI 1.30-6.37)] and LDL-cholesterol [5.38 (95% CI 2.12-8.64)] concentrations. A negative association was observed between log transformed LINE-1 methylation and both HDL cholesterol concentration [-1.43 (95% CI -2.38 to -0.48)] and HDL:LDL ratio [-1.06 (95% CI -1.76 to -0.36)]. These coefficients reflect the millimoles per litre change in biochemical measurements per unit increase in log-transformed LINE-1 methylation. CONCLUSIONS: These novel associations between global LINE-1 DNA methylation and blood glycaemic and lipid profiles highlight a potential role for epigenetic biomarkers as predictors of metabolic disease and may be relevant to future diagnosis, prevention and treatment of this group of disorders. Further work is required to establish the role of confounding and reverse causation in the observed associations. PMID- 22422455 TI - Plasticity, robustness, development and evolution. PMID- 22422456 TI - Plasticity and robustness in development and evolution. PMID- 22422457 TI - Why evolution needs development, and medicine needs evolution. PMID- 22422458 TI - A critical appraisal of the predictive adaptive response hypothesis. PMID- 22422459 TI - Epigenesis for epidemiologists: does evo-devo have implications for population health research and practice? PMID- 22422460 TI - Something old, something new, something false but much that's true. PMID- 22422461 TI - Parenting practices and intergenerational associations in cognitive ability. AB - BACKGROUND: Cognitive ability is an important contributor to life chances, with implications for cycles of advantage or disadvantage across generations. Parenting practices are known to influence offspring cognitive development, but the extent to which these mediate intergenerational continuities and discontinuities in cognitive ability has not been adequately studied. METHODS: We used factor analysis to derive summary measures of parenting practices, and regression analyses and path modelling to test associations between these and cognitive function at age 8 years in 1690 first offspring of the British 1946 birth cohort. Analyses allowed for direct and indirect effects of parental original and achieved social circumstances, educational attainment and own childhood cognitive ability. Additional covariates were provided by indicators of parental physical and mental health. RESULTS: Regression analyses revealed that three aspects of parenting, intellectual home environment, parental aspiration and cognitive stimulation, were positively and independently associated with offspring childhood cognitive ability, whereas coercive discipline was negatively and independently associated. Path modelling was appropriate for intellectual environment, which also revealed direct and indirect effects of parental cognitive ability and educational and occupational attainment on offspring cognitive ability. CONCLUSION: Parenting practices, particularly provision of an intellectual environment, were directly associated with offspring cognitive development. These data add to the relatively few studies that examine intergenerational continuity and discontinuity in cognitive ability. PMID- 22422464 TI - Does sexual function survey in Denmark offer any support for male circumcision having an adverse effect? PMID- 22422466 TI - Improved two-stage tests for stratified phase II cancer clinical trials. AB - In a single-arm, two-stage, phase II cancer clinical trial for efficacy screening of cytotoxic agents, a common primary endpoint is a binary (yes/no) patient response to treatment. Usually, fixed decision boundaries are used in binomial tests to determine whether the study treatment is promising enough to be studied in a large-scale, randomized phase III trial. We may know in advance that the patient response distribution for a phase II clinical trial will be heterogeneous, making it advisable to stratify patients into subgroups, each with a different prognosis. In this case, fixed decision boundaries may be inappropriate. In this article, we propose two-stage tests based on the Neyman Pearson lemma. The proposed test statistic is a linear combination of the observed number of responders in each stratum. The test allows adjustment of the decision boundaries to the observed numbers of patients in each stratum and permits sample sizes to be increased adaptively after the originally planned number of patients is observed at each of the two stages. Our numerical results show that the proposed test is more powerful than an existing test in many cases. Finally, we present an application to a Children's Oncology Group phase II clinical trial in patients who relapsed after initial treatment for neuroblastoma. PMID- 22422467 TI - Human mesenchymal stem cells are recruited to injured liver in a beta1-integrin and CD44 dependent manner. AB - Human bone marrow mesenchymal stem cells (hMSCs) have shown benefit in clinical trials of patients with liver disease. Efficient delivery of cells to target organs is critical to improving their effectiveness. This requires an understanding of the mechanisms governing cellular engraftment into the liver. Binding of hMSCs to normal/injured liver tissue, purified extracellular matrices, and human hepatic sinusoidal endothelial cells (HSECs) were quantified in static and flow conditions. To define the mechanisms underpinning hMSC interactions, neutralizing adhesion molecule antibodies were used. Fluorescently labelled hMSCs were infused intraportally into CCl(4) -injured mice with and without neutralizing antibodies. hMSCs expressed high levels of CD29/beta1-integrin and CD44. Using liver tissue binding assays, hMSC adhesion was greatest in diseased human liver versus normal liver (32.2 cells/field versus 20.5 cells/field [P = 0.048]). Neutralizing antibodies against CD29 and CD44 reduced hMSC binding to diseased liver by 34% and 35%, respectively (P = 0.05). hMSCs rolled at 528 MUm/second on HSECs in flow assays. This rolling was abolished by CD29 blockade on hMSCs and vascular cell adhesion molecule-1 (VCAM-1) blockade on HSECs. Firm adhesion to HSECs was reduced by CD29 (55% [P = 0.002]) and CD44 (51% [P = 0.04]) blockade. Neutralizing antibodies to CD29 and CD44 reduced hepatic engraftment of hMSCs in murine liver from 4.45 cells/field to 2.88 cells/field (P = 0.025) and 2.35 cells/field (P = 0.03), respectively. hMSCs expressed modest levels of chemokine receptors including CCR4, CCR5, and CXCR3, but these made little contribution to hMSC adhesion in this setting. CONCLUSION: hMSCs bind preferentially to injured liver. Rolling of hMSCs is regulated by CD29/VCAM-1, whereas CD29/CD44 interactions with VCAM-1, fibronectin, and hyaluronan on HSECs determine firm adhesion both in vitro and in vivo as demonstrated using a murine model of liver injury. PMID- 22422468 TI - Reactivation of human polyomavirus JC in patients affected by psoriasis vulgaris and psoriatic arthritis and treated with biological drugs: preliminary results. AB - Psoriasis vulgaris (PsV) and psoriatic arthritis (PSA) are inter-related heritable inflammatory skin diseases. Psoriatic lesions develop as a result of abnormal immune responses, hyperproliferation and altered differentiation of keratinocytes, and a notable subset of psoriatic patients develops PsA, characterized by joints inflammation. Recently, biological drugs were introduced to treat these diseases. However, this therapy has already been associated with the development of serious life-threatening infections, such as the reactivation of human polyomavirus JC (JCV), responsible for the progressive multifocal leukoencephalopathy (PML), a lethal demyelinating disease caused by oligodendrocytes lytic infection. Therefore, the aims of our study were the investigation of the possible JCV reactivation in PsV and PsA patients treated with adalimumab, etanercept, and methotrexate, performing quantitative real-time PCR in sera and skin biopsies at the time of recruitment (T0) and after 3 (T3) and 6 (T6) months of treatment, and the sequencing analysis of the JCV non-coding control region (NCCR). We found JCV DNA in 5/15 PsV patients and in 2/15 PsA patients and JCV NCCR sequence analysis always showed a structure similar to non pathogenic CY archetype, with random occurrence of a few irrelevant point mutations. Nevertheless the poor number of patients analyzed, our preliminary data can pave the way for taking into account that the follow-up of JCV DNA detection and the JCV NCCR sequence analysis in psoriatic patients may be important to evaluate the risk of PML onset, considering that patients affected by autoimmune diseases and treated with biologics continue to rise. PMID- 22422469 TI - Modulation of hepatic drug metabolizing enzymes by dietary doses of thymoquinone in female New Zealand White rabbits. AB - Herbal medicines can affect drug metabolizing enzymes. Therefore the effect of thymoquinone (TQ), the active ingredient of black seeds, was examined on rabbit liver drug metabolizing enzymes. Two groups of New Zealand female rabbits received TQ at 10 and 20 mg/kg/day orally and a control group of six animals each were killed after 8 weeks. Blood and livers were harvested and the activity of cytochrome P450 (CYP) and phase II enzymes in the microsomal and cytosolic preparations were measured by HPLC and ELISA methods. The liver enzymes ALT/AST and albumin were similar in the three groups. CYP1A2, CYP3A4, but not CYP2E1, were significantly diminished by TQ treatment. Of the phase II enzymes, glutathione-S-transferase (GST) and glutathione peroxidase (GPx) were significantly induced by the high TQ dose, while the total glutathione levels were unaffected. Glutathione reductase (GR), on the other hand, was significantly induced in the two experimental groups. Thymoquinone has differential effects on CYP and phase II enzymes. Inhibition of some CYP enzyme activities may lead to a hazardous herb-drug interaction. Induction of GR activity may explain the salutatory effect of the black seeds in inhibiting the generation of bioactive metabolites known to promote carcinogenesis and oxidative cell damage. PMID- 22422470 TI - Comparison of male chimeric mice generated from microinjection of JM8.N4 embryonic stem cells into C57BL/6J and C57BL/6NTac blastocysts. AB - To identify ways to improve the efficiency of generating chimeric mice via microinjection of blastocysts with ES cells, we compared production and performance of ES-cell derived chimeric mice using blastocysts from two closely related and commonly used sub-strains of C57BL/6. Chimeras were produced by injection of the same JM8.N4 (C57BL/6NTac) derived ES cell line into blastocysts of mixed sex from either C57BL/6J (B6J) or C57BL/6NTac (B6NTac) mice. Similar efficiency of production and sex-conversion of chimeric animals was observed with each strain of blastocyst. However, B6J chimeric males had fewer developmental abnormalities involving urogenital and reproductive tissues (1/12, 8%) compared with B6NTac chimeric males (7/9, 78%). The low sample size did not permit determination of statistical significance for many parameters. However, in each category analyzed the B6J-derived chimeric males performed as well, or better, than their B6NTac counterparts. Twelve of 14 (86%) B6J male chimeras were fertile compared with 6 of 11 (55%) B6NTac male chimeras. Ten of 12 (83%) B6J chimeric males sired more than 1 litter compared with only 3 of 6 (50%) B6NTac chimeras. B6J male chimeras produced more litters per productive mating (3.42 +/- 1.73, n = 12) compared to B6NTac chimeras (2.17 +/- 1.33, n = 6). Finally, a greater ratio of germline transmitting chimeric males was obtained using B6J blastocysts (9/14; 64%) compared with chimeras produced using B6NTac blastocysts (4/11; 36%). Use of B6J host blastocysts for microinjection of ES cells may offer improvements over blastocysts from B6NTac and possibly other sub-strains of C57BL/6 mice. PMID- 22422471 TI - Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse. AB - Recent advances in systems genetics and integrative functional genomics have greatly improved the study of complex neurological and behavioral traits. The methods developed for the integrated characterization of new, high-resolution mouse genetic reference populations and systems genetics enable behavioral geneticists an unprecedented opportunity to address questions of the molecular basis of neurological and psychiatric disorders and their comorbidities. Integrative genomics augment these strategies by enabling rapid informatics assisted candidate gene prioritization, cross-species translation, and mechanistic comparison across related disorders from a wealth of existing data in mouse and other model organisms. Ultimately, through these complementary approaches, finding the mechanisms and sources of genetic variation underlying complex neurobehavioral disease related traits is becoming tractable. Furthermore, these methods enable categorization of neurobehavioral disorders through their underlying biological basis. Together, these model organism-based approaches can lead to a refinement of diagnostic categories and targeted treatment of neurological and psychiatric disease. PMID- 22422473 TI - Large-area 2D periodic crystalline silicon nanodome arrays on nanoimprinted glass exhibiting photonic band structure effects. AB - Two-dimensional silicon nanodome arrays are prepared on large areas up to 50 cm2 exhibiting photonic band structure effects in the near-infrared and visible wavelength region by downscaling a recently developed fabrication method based on nanoimprint-patterned glass, high-rate electron-beam evaporation of silicon, self organized solid phase crystallization and wet-chemical etching. The silicon nanodomes, arranged in square lattice geometry with 300 nm lattice constant, are optically characterized by angular resolved reflection measurements, allowing the partial determination of the photonic band structure. This experimentally determined band structure agrees well with the outcome of three-dimensional optical finite-element simulations. A 16% photonic bandgap is predicted for an optimized geometry of the silicon nanodome arrays. By variation of the duration of the selective etching step, the geometry as well as the optical properties of the periodic silicon nanodome arrays can be controlled systematically. PMID- 22422472 TI - Alternative approaches to modeling hereditary dystonias. AB - Dystonia is a movement disorder characterized by involuntary muscle contractions resulting in abnormal postures. Although common in the clinic, the etiology of dystonia remains unclear. Most dystonias are idiopathic and are not associated with clear pathological brain abnormalities. Attempts to genetically model these dystonias in rodents have failed to replicate dystonic symptoms. This is at odds with the fact that rodents can exhibit dystonia. Because of this discrepancy, it is necessary to consider alternative approaches to generate phenotypically and genotypically faithful models of dystonia. Conditional knockout of dystonia related genes is 1 technique that may prove useful for modeling genetic dystonias. Lentiviral-mediated small or short hairpin RNA (shRNA) knockdown of particular genes is another approach. Finally, in cases in which the function of a dystonia-related gene is well-known, pharmacological blockade of the protein product can be used. Such an approach was successfully implemented in the case of rapid-onset dystonia parkinsonism, DYT12. This (DYT12) is a hereditary dystonia caused by mutations in the alpha3 isoform of the sodium potassium adenosine triphosphatase (ATPase) pump (sodium pump), which partially hampers its physiological function. It was found that partial selective pharmacological block of the sodium pumps in the cerebellum and basal ganglia of mice recapitulates all of the salient features of DYT12, including dystonia and parkinsonism induced by stress. This DYT12 model is unique in that it faithfully replicates human symptoms of DYT12, while targeting the genetic cause of this disorder. Acute disruption of proteins implicated in dystonia may prove a generally fruitful method to model dystonia in rodents. PMID- 22422474 TI - Measurement of autophagic activity in mammalian cells. AB - Macroautophagy (referred to herein as autophagy) is a process in which cells engulf portions of cytoplasm in double-membrane vesicles called autophagosomes. These autophagosomes can also capture protein oligomers associated with neurodegenerative diseases, infectious agents (like bacteria), and even organelles (like mitochondria). Autophagosomes are transported along microtubules towards the microtubule organizing center of cells, where the lysosomes are clustered. After fusion and content exchange with lysosomes, the autophagosome cargo is degraded by lysosomal hydrolases. This unit describes some of the core autophagy assays that are in common use, including LC3 immunoblotting, light microscopy analyses of different stages of autophagy, electron microscopy, and an assay of autophagy substrate accumulation. Autophagy assays should generally not be performed alone, but should be accompanied by complementary assays to enable robust interpretations. PMID- 22422475 TI - Analysis of polarized membrane traffic in hepatocytes and hepatic cell lines. AB - The protocols described in this unit were developed to monitor membrane traffic in cultured cell monolayers that display hepatic polarity. In general, the assays are designed to visualize and/or quantitate membrane trafficking by monitoring the fates of antibodies bound to specific membrane proteins. We first describe how to infect cells with recombinant adenovirus, the preferred method for introducing exogenous genes into hepatic cells. We next provide a morphological assay to monitor basolateral to apical transcytosis. In a supporting protocol, we describe how to visualize apical recycling and/or retention. In an additional supporting protocol, we provide a semi-quantitative method to measure the relative extents of apical delivery. Finally, we describe quantitative assays to measure basolateral internalization and recycling. The methods presented in this unit provide a relatively simple, yet powerful approach to examining hepatic membrane traffic. PMID- 22422476 TI - Analysis of nonsense-mediated mRNA decay in Saccharomyces cerevisiae. AB - Nonsense-mediated mRNA decay is a highly conserved pathway that degrades mRNAs with premature termination codons. These mRNAs include mRNAs transcribed from nonsense or frameshift alleles as well as wild-type mRNA with signals that direct ribosomes to terminate prematurely. This unit describes techniques to monitor steady-state mRNA levels, decay rates, and structural features of mRNAs targeted by this pathway, as well as in vivo analysis of nonsense suppression and allosuppression in the yeast Saccharomyces cerevisiae. Protocols for the structural features of mRNA include analysis of cap status, 5' and 3' untranslated region (UTR) lengths, and poly(A) tail length. PMID- 22422477 TI - Temperature sensing and in vivo imaging by molybdenum sensitized visible upconversion luminescence of rare-earth oxides. AB - A novel high excited state energy transfer pathway to overcome the phonon quenching effect in rare-earth (RE) oxide upconversion (UC) materials is reported. In Er(Tm)-Yb oxide systems, an extraordinary enhancement of UC luminescence efficiency with four orders of magnitude is realized by Mo co doping. The RE oxides with significant UC efficiency are successfully utilized for temperature sensing and in vivo imaging. PMID- 22422478 TI - Closure of the patent ductus arteriosus with the new duct occluder II additional sizes device. AB - OBJECTIVE: The objective of this study was to evaluate the technical feasibility, safety, and efficacy of the new device Amplatzer duct occluder II additional sizes (ADO II AS) for closure of patent ductus arteriosus (PDA). BACKGROUND: Transcatheter device closure is the standard care for PDA. Currently available technology is not designed for closure of small PDA in young children. METHODS: From April to July 2011, seven children (five females, median age 1.5 years, median weight 11.4 kg) underwent PDA closure with the ADO II AS. Six had isolated PDA, one had PDA associated with preductal coarctation. We evaluated early and short-term results. RESULTS: All but one PDA was closed via an antegrade approach. Mean fluoroscopy and procedural times were 8.0 +/- 3.9 and 49.8 +/- 27.9 min, respectively. No complications occurred. Immediate trivial residual shunt was present in one patient. In all devices, the retention disks laid flat against the walls of the pulmonary artery and aorta, without protrusion into the vessel lumen. The echocardiography performed after 24 hr did not show any residual shunt. At a median follow-up of 2 months, the PDAs were completely occluded without obstruction of the pulmonary arteries or aorta. CONCLUSIONS: The new device ADO II AS was safely deployed with complete resolution of the PDA shunt. The lower profile and symmetry of this device allows for venous or arterial approach and smaller delivery catheter size. The ADO II AS might be a preferable alternative for closure of small-moderate PDAs. PMID- 22422479 TI - A man for single molecules. PMID- 22422482 TI - Radiofrequency ablation after breast lumpectomy added to extend intraoperative margins in the treatment of breast cancer (ABLATE): a single-institution experience. AB - BACKGROUND: Breast-conserving surgery is often preferred to treat early-stage breast cancer. This method aims to minimize repeat excision and local recurrence rates. The ABLATE Registry expands this to multiple centers with a total accrual goal of 250. This video illustrates an intraoperative radiofrequency ablation (RFA) technique. METHODS: Sixteen women with a mean age of 65 years underwent RFA after lumpectomy. The RFA probe was deployed 1 cm circumferentially in the cavity and maintained at 100 degrees C for 15 min. The ablation zone was monitored with color-flow ultrasound. Patients returned 2 weeks later to complete the Subjective Cosmetic Scale and the European Organisation for Research and Treatment of Cancer Body Image Scale. RESULTS: At a mean follow-up of 3.9 months, there were no local recurrences. Two-week cosmesis scores were excellent (n = 9) or good (n = 5). CONCLUSIONS: Our initial experience is encouraging. Continued national accrual will permit evaluation of reduction in repeat excision and local recurrence rate, as well as potentially reduce requirements for adjuvant radiation. PMID- 22422483 TI - Quadriplegia secondary to cervical spondylotic myelopathy-a rare complication of head and neck surgery. AB - BACKGROUND: Free tissue reconstruction after ablation of head and neck malignancy often requires extensive cervical manipulation, which may exacerbate preexisting cervical spondylosis and result in progression to cervical myelopathy. We present a rare case of postoperative quadriplegia caused by cervical spondylotic myelopathy after head and neck reconstruction. METHODS AND RESULTS: A 63-year-old man without a history of cervical spondylosis underwent resection of a gingivo buccal squamous cell carcinoma with immediate reconstruction with free fibula osteocutaneous flap. On postoperative day 4, the patient was found to have quadriplegia. MRI demonstrated severe cervical myelopathy. Decompressive laminectomy was performed. The patient underwent an extensive rehabilitation program but only realized moderate improvement. CONCLUSION: Cervical spondylotic myelopathy is a rare but disastrous complication of head and neck surgery. We hypothesize that it is potentially avoidable with heightened awareness of this disease entity, preoperative identification of patients at risk, and prophylactic interventions PMID- 22422484 TI - Judging roughness by sight--a 7-Tesla fMRI study on responsivity of the primary somatosensory cortex during observed touch of self and others. AB - Observing another person being touched activates our own somatosensory system. Whether the primary somatosensory cortex (S1) is also activated during the observation of passive touch, and which subregions of S1 are responsible for self and other-related observed touch is currently unclear. In our study, we first aimed to clarify whether observing passive touch without any action component can robustly increase activity in S1. Secondly, we investigated whether S1 activity only increases when touch of others is observed, or also when touch of one's own body is observed. We were particularly interested in which subregions of S1 are responsible for either process. We used functional magnetic resonance imaging at 7 Tesla to measure S1 activity changes when participants observed videos of their own or another's hand in either egocentric or allocentric perspective being touched by different pieces of sandpaper. Participants were required to judge the roughness of the different sandpaper surfaces. Our results clearly show that S1 activity does increase in response to observing passive touch, and that activity changes are localized in posterior but not in anterior parts of S1. Importantly, activity increases in S1 were particularly related to observing another person being touched. Self-related observed touch, in contrast, caused no significant activity changes within S1. We therefore assume that posterior but not anterior S1 is part of a system for sharing tactile experiences with others. PMID- 22422485 TI - Genetic variants modify susceptibility to leukemia in infants: a Children's Oncology Group report. AB - BACKGROUND: The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE. PROCEDURE: We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements. RESULTS: Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633). CONCLUSION: IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy. PMID- 22422486 TI - Oleuropein, chief constituent of olive leaf extract, prevents the development of morphine antinociceptive tolerance through inhibition of morphine-induced L-type calcium channel overexpression. AB - It has been shown that blockade of L-type calcium channels could abolish the development of opioid-induced antinociceptive tolerance. Here, the antitolerant effects of olive leaf extract (OLE) and its main component, oleuropein, which have a calcium channel blocker property were determined. Adult male Wistar rats were injected with morphine (20 mg/kg, i.p.) for 8 days to induce antinociceptive tolerance. Then OLE (50-200 mg/kg i.g.) and oleuropein (1-10 mg/kg i.p.) were injected concomitantly with morphine. The tail-flick test was used to assess the nociceptive threshold. The dorsal half of the lumbar spinal cord was assayed for the expression of L-type calcium channel using semiquantitative RT-PCR. The results showed that OLE (200 mg/kg) completely prevented morphine tolerance development. In addition, oleuropein in dose of 10 mg/kg, but not in 5 mg/kg, prevented the development of morphine antinociceptive tolerance. In addition, a significant increase in the mRNA levels of calcium channel (43.9%) was observed in the lumbar spinal cord of tolerant animals, which was reversed by effective of dose OLE. In conclusion, the results indicate that olive leaf extract has a potential antitolerant property against the chronic usage of morphine and that its main component, oleuropein, is responsible for such effect. PMID- 22422487 TI - Time-dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long-Term Safety (REAL) database. METHODS: We analyzed 727 RA patients who had started either infliximab or etanercept (the anti-TNF group; 1,480.1 patient-years [PY]) and 571 RA patients who had started conventional nonbiologic disease-modifying antirheumatic drugs (the unexposed group; 1,104.1 PY) at the time of enrollment in the REAL. We assessed the occurrence of SIs within a 3-year observation period, including the period after switching to other TNF antagonists, and all SIs, unlimited to the first one in each patient as reported in other studies, to evaluate the real safety of TNF antagonists in daily practice. RESULTS: The incidence rate of SIs per 100 PY was 5.54 (95% confidence interval [95% CI] 4.44-6.84) in the anti-TNF group and 2.72 (95% CI 1.87-3.83) in the unexposed group. Poisson regression analysis revealed that the relative risk (RR) of continuous use of TNF antagonists for SIs after adjusting for baseline and time-dependent covariates was significantly elevated both overall (1.97, 95% CI 1.25-3.19) and for the first year (2.40, 95% CI 1.20-5.03), but not for the second and third years combined (1.38, 95% CI 0.80-2.43). The adjusted RR for SIs of etanercept compared to infliximab was not significantly elevated. CONCLUSION: Continuous anti-TNF therapy was significantly associated with increased risks for developing SIs during, but not after, the first year. PMID- 22422488 TI - L-Theanine extends lifespan of adult Caenorhabditis elegans. AB - PURPOSE: Compounds that delay aging in model organisms may be of significant interest to anti-aging medicine, since these substances potentially provide pharmaceutical approaches to promote healthy lifespan in humans. We here aimed to test whether pharmaceutical concentrations of L-theanine, a putative anti-cancer, anti-obesity, blood pressure-lowering, and neuroprotective compound contained in green tea (Camellia sinensis), are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. METHODS: Adult C. elegans roundworms were maintained on agar plates, were fed E. coli strain OP50 bacteria, and L-theanine was applied to agar to test (1) whether it may increase survival upon paraquat exposure and (2) whether it may promote longevity by quantifying survival in the presence and absence of the compound. RESULTS: L-Theanine increases survival of C. elegans in the presence of paraquat at a concentration of 1 micromolar. L-theanine extends C. elegans lifespan when applied at concentrations of 100 nM, as well as 1 and 10 micromolar. CONCLUSIONS: In the model organism C. elegans, L-theanine is capable of promoting paraquat resistance and longevity suggesting that this compound may as well promote healthy lifespan in mammals and possibly humans. PMID- 22422489 TI - Construct validity of the modified numeric rating scale of patient global assessment in psoriatic arthritis. AB - OBJECTIVE: The construct validity of the patient global health assessment (PGA) in psoriatic arthritis (PsA) has not been analyzed, despite its common use. We evaluated the construct validity of a numeric rating scale (NRS) of the PGA in PsA. METHODS: Patients with PsA who fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria were recruited at a tertiary referral center. Demographic data were collected and PGA data were determined from administration of an 11-point NRS (0 to 10 points representing best to worst status). Convergent and discriminant validity were evaluated by correlation between PGA and clinical variables. Patients were grouped as having severe disease based on Disease Activity Score 28-joint count (DAS28) > 5.1, Health Assessment Questionnaire (HAQ) > 1.0, walking with aids, and social welfare-dependent. Patients were grouped as being in remission by DAS28 < 2.6 and the Minimal Disease Activity Criteria. Known-group validity of PGA was evaluated. RESULTS: A total of 125 patients (52% men) were studied. Convergent validity revealed strong correlations of PGA with pain score, HAQ, and DAS28; and weak correlations with skin severity score, physician's global assessment and morning stiffness. In multivariate analysis, PGA was associated with pain, physical function, mental function, and skin severity score. PGA distinguished different levels of severity well, as determined by comparison with different known groups with large effect sizes. CONCLUSION: Judged on an NRS, the PGA had good construct validity and satisfactorily distinguished all levels of severity in PsA. PMID- 22422490 TI - Hepatitis B virus-associated antigen deposition in renal tissue from patients with systemic lupus erythematosus. AB - OBJECTIVE: To determine the significance of hepatitis B virus (HBV)-associated antigen deposition in renal tissue from patients with systemic lupus erythematosus (SLE). METHODS: The medical records of 166 inpatients with lupus nephritis and 384 controls without SLE were analyzed retrospectively. Patients with SLE were classified as positive or negative depending on whether HBV associated antigen deposition was detected in renal biopsies. RESULTS: HBV associated antigen deposition was mainly detected in renal tissue from patients with SLE (50.6%), primary renal glomerular disease (20.8%), and allergic purpura (21.7%). It was not detected in renal tissue from patients with diabetic nephropathy, hypertensive nephrosclerosis, thin basement membrane nephropathy, or Alport syndrome. Hepatitis B surface antigen and core antigen were deposited in the mesangial region and vascular loops. The positive group had a significantly higher frequency of IgG, IgA, and IgM deposition than the negative group (53.6% vs 30.5%; p < 0.01). There was no significant difference in the types of lupus nephritis observed between the 2 groups. CONCLUSION: There was a high prevalence of HBV-associated antigen deposition in renal tissue of patients with SLE by indirect immunofluorescence, which may result mainly from the cross-reactivity with deposited immunoglobulins. PMID- 22422491 TI - Clinical features of late-onset ankylosing spondylitis: comparison with early onset disease. AB - OBJECTIVE: Ankylosing spondylitis (AS) is generally observed in young patients but can occur later in life or in persons >= 50 years of age. Our objective was to characterize the clinical features of late-onset AS in a large multicenter national cohort. METHODS: We studied late-onset AS in the National Registry of Spondyloarthritis of the Spanish Society of Rheumatology (REGISPONSER database) cohort (n = 1257), of whom 3.5% had onset at age >= 50 years versus a control group with onset at < 50 years. RESULTS: There were no differences between late onset and early-onset AS according to sex and family history of spondyloarthropathies. Patients in the late-onset group more often showed involvement of the cervical spine (22.7% vs 9.7%; p = 0.03) and arthritis of the upper (13.6% vs 3.0%; p = 0.002) and lower limbs (27.3% vs 15.2%; p = 0.03) as first manifestations than did patients in the early-onset group. A higher percentage of mixed forms (axial and peripheral joint disease) during the course of the disease was also recorded in the late-onset group (50% vs 24%; p = 0.0001). CONCLUSION: Our study suggests that age at onset of AS affects the patients' presenting clinical form. Arthritis of the upper limbs requires a differential diagnosis with other conditions frequent in patients over 50 years of age, such as rheumatoid arthritis or crystal-induced arthropathy. PMID- 22422492 TI - Patient-reported outcomes in polymyalgia rheumatica. AB - OBJECTIVE: To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR). METHODS: The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS). RESULTS: At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness. CONCLUSION: PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR. PMID- 22422493 TI - Hepatic steatosis and disease activity in subjects with psoriatic arthritis receiving tumor necrosis factor-alpha blockers. AB - OBJECTIVE: Little is known about tumor necrosis factor-alpha (TNF-alpha) blockers, disease activity, and liver steatosis (hepatic steatosis; HS) in subjects with psoriatic arthritis (PsA). We prospectively evaluated changes in HS during treatment with TNF-alpha blockers. METHODS: In 48 patients with PsA who had evidence of HS before the beginning of TNF-alpha blocker treatment, an ultrasound followup examination was performed after a 12-month treatment period with TNF-alpha blockers. All subjects were stratified according to minimal disease activity (MDA) or not (n-MDA), during treatment with TNF-alpha blockers. Changes in grade of HS were evaluated in parallel in 42 controls with HS and without PsA. RESULTS: At baseline, no significant difference in HS score was found between PsA subjects and controls (HS scores 1.46 +/- 0.65 vs 1.62 +/- 0.66, respectively; p = 0.249). At 12-month followup, a worsening HS score was found in 20 (41.7%) patients with PsA and in 6 (14.3%) controls (p = 0.005). Overall, the grade of HS worsening was higher in patients with PsA (0.37 +/- 0.70) than in controls (0.09 +/- 0.43; p = 0.028). A significantly lower prevalence of worsening HS was found among patients with PsA with MDA, compared with n-MDA subjects (16.7% vs 66.7%, respectively; p = 0.001). Laboratory measures of liver function behaved similarly. The risk of worsening HS in patients with PsA who had MDA was similar to that in controls (HR 1.20, 95% CI 0.34-4.33, p = 0.77), and higher in patients who did not have MDA (HR 4.46, 95% CI 1.73-11.47, p = 0.001, regression analysis). CONCLUSION: Compared with patients with MDA, those with active disease after 12-month treatment with TNF alpha blockers exhibited significantly higher incidence of worsening liver steatosis. PMID- 22422494 TI - Smoking, smoking cessation, and disease activity in a large cohort of patients with rheumatoid arthritis. AB - OBJECTIVE: While cigarette smoking is the best-studied environmental factor contributing to rheumatoid arthritis (RA), no study to date has examined the influence of smoking cessation on disease activity. We examined this relationship in an observational cohort of patients with RA in the United States. METHODS: Patients enrolled in the Consortium of Rheumatology Researchers of North America registry (CORRONA) were stratified into never, former, and current smokers at enrollment. Current smokers were further stratified into continued and ceased smoking groups during their followup in the registry. The primary outcome was change in Clinical Disease Activity Index (CDAI) at last visit in a multivariate, random-effects regression model accounting for multiple timepoints. RESULTS: At last visit, there was no significant change in CDAI between ceased smokers and continued smokers (coefficient -0.00091, SE 0.0033, p = 0.7834). The study did confirm prior cross-sectional studies that current smokers have worse disease activity than former or never smokers. CONCLUSION: In the short term, smoking cessation did not appear to influence change in disease activity over time. PMID- 22422495 TI - Clinical, functional, and radiographic differences among juvenile-onset, adult onset, and late-onset ankylosing spondylitis. AB - OBJECTIVE: The aim of our study was to compare the clinical, functional, and radiographic outcomes at different ages of onset in patients with ankylosing spondylitis (AS). METHODS: A total of 546 patients were enrolled consecutively and classified into 3 groups based on their age at symptom onset: (1) juvenile onset AS (age <= 16 years; JoAS); (2) adult-onset AS (> 16 but < 40 years; AoAS); and (3) late-onset AS (>= 40 years; LoAS). We compared the differences among the 3 groups. OR for disease outcomes were calculated and adjusted for sex, HLA-B27, and disease duration. RESULTS: There were 67 patients (12.3%) with JoAS, 460 (84.2%) with AoAS, and 19 (3.5%) with LoAS. Male sex and HLA-B27 were associated with a younger age at onset (p < 0.001). Compared to patients with AoAS, patients with JoAS were more likely to present with peripheral arthritis, while patients with JoAS and LoAS were less likely to have back pain at the onset of AS (p < 0.05). After controlling for multiple covariates, JoAS was found to be associated with a worse functional outcome and global assessment, and a high serum immunoglobulin A level (p < 0.05). Patients with JoAS had less lumbar spinal radiographic severity (p < 0.05). There were no statistical differences in clinical or functional outcome between the LoAS and AoAS groups. None of the LoAS patients had radiographic hip involvement. CONCLUSION: Sex and HLA-B27 are significantly associated with age at onset of AS. Both JoAS and LoAS have their distinctive symptoms/signs at onset and different disease outcomes. PMID- 22422496 TI - Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis. AB - OBJECTIVE: Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk. METHODS: Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and meta analysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry. RESULTS: Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12-1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15-1.54) and TT genotype p = 0.00046; OR 2.02 (1.36-2.98)]. CONCLUSION: We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype. PMID- 22422497 TI - How do physicians weigh benefits and risks associated with treatments in patients with osteoarthritis in the United Kingdom? AB - OBJECTIVE: To quantify the relative importance that UK physicians attach to the benefits and risks of current drugs when making treatment decisions for patients with osteoarthritis (OA). METHODS: Physicians treating at least 10 patients with OA per month completed an online discrete-choice experiment survey and answered 12 treatment-choice questions comparing medication profiles. Medication profiles were defined by 4 benefits (reduction in ambulatory pain, resting pain, stiffness, and difficulty doing daily activities) and 3 treatment-related risks [bleeding ulcer, stroke, and myocardial infarction (MI)]. Each physician made medication choices for 3 of 9 hypothetical patients (varied by age, history of MI, hypertension, and history of gastrointestinal bleeding). Importance weights were estimated using a random-parameters logit model. Treatment-related risks physicians were willing to accept in exchange for various reductions in ambulatory and resting pain also were calculated. RESULTS: The final sample was 475. A reduction in ambulatory pain from 75 mm to 25 mm (1.6 units) was 1.1 times as important as an increase in MI risk from 0% to 1.5% (1.5 units). The greatest importance was for eliminating a 3% treatment-related risk of MI or stroke. On average, physicians were willing to accept an increase in bleeding ulcer risk of 0.7% (95% CI 0.4%-1.7%) for a reduction in ambulatory pain of 75 mm to 50 mm. CONCLUSION: When presented with well-known benefits and risks of OA treatments, physicians placed greater importance on the risks than on the analgesic properties of the drug. This has implications for the reporting of the results of clinical research to physicians. PMID- 22422498 TI - Apoptosis as a mechanism of action of tumor necrosis factor antagonists in rheumatoid arthritis. AB - Tumor necrosis factor (TNF) antagonists are drugs developed to block endogenous TNF, an essential proinflammatory molecule with a central role in the pathogenesis of rheumatoid arthritis (RA). Although extensive studies have been performed concerning the mode of action of TNF-blocking agents, there are still many unresolved questions and potential differences between different TNF blocking drugs. One unresolved issue is to what extent apoptosis is affected by TNF blockade in RA. We provide an overview of studies that have investigated the proapoptotic effect of different anti-TNF drugs in RA, searching for a unified interpretation of somewhat contradictory data. PMID- 22422499 TI - Systemic sclerosis fibroblasts show specific alterations of interferon-gamma and tumor necrosis factor-alpha-induced modulation of interleukin 6 and chemokine ligand 2. AB - OBJECTIVE: We evaluated the effect of interferon-gamma (IFN-gamma) and/or tumor necrosis factor-alpha (TNF-alpha) on the secretion of prototype proinflammatory cytokine interleukin 6 (IL-6), compared to T-helper 1 [Th1; chemokine (C-X-C motif) ligand 10 (CXCL10)] or Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines, in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease. METHODS: Fibroblast cultures from 5 SSc patients (disease duration < 2 yrs) and 5 healthy controls were evaluated for the production of IL-6, CXCL10, and CCL2 at the basal level and after stimulation with IFN-gamma and/or TNF-alpha. RESULTS: SSc fibroblasts basally produced higher levels of IL-6 than controls, while no difference was observed about CCL2 and CXCL10. TNF-alpha was able to dose-dependently induce IL-6 and CCL2 secretion in SSc, but not in control fibroblasts. By stimulation with increasing doses of IFN gamma, SSc fibroblasts were induced to secrete CCL2 and CXCL10, while no effect was observed on IL-6. The combination of IFN-gamma and TNF-alpha induced a strong secretion of IL-6 and CCL2 in SSc fibroblasts but not in controls. In contrast, the synergistic effect of IFN-gamma and TNF-alpha on CXCL10 secretion was similar in SSc fibroblasts and in controls. CONCLUSION: SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, CXCL10, and CCL2 under the influence of IFN-gamma and/or TNF-alpha. SSc fibroblasts are more active than controls in the secretion of IL-6 at baseline, and in the production of IL-6 and CCL2 under the combined IFN-gamma/TNF-alpha stimulation. PMID- 22422500 TI - Risk of gastrointestinal events in patients with rheumatoid arthritis after withdrawal of rofecoxib. AB - OBJECTIVE: To examine the incidence of gastrointestinal (GI) events in patients with rheumatoid arthritis (RA) after the removal of rofecoxib from the market. METHODS: Residents of British Columbia with a diagnosis of RA who were chronic users of cyclooxygenase 2 (COX-2) inhibitors or nonselective nonsteroidal antiinflammatory drugs (nsNSAID) as of September 30, 2004, were included. We studied the risk of GI events using incidence rates and adjusted HR from Cox proportional hazards regression using time-dependent covariates. RESULTS: The cohort comprised 4266 patients with a mean age of 60 years and over 72% women, of which 2034 (48%) were classified as COX-2 inhibitor users and 2232 (52%) as chronic nsNSAID users as of September 30, 2004. The 2 groups were well balanced on baseline covariates except for comorbid conditions. In the year following rofecoxib withdrawal, 174 patients (5.5%) experienced 1 or more GI events, defined as a GI-related physician visit or hospitalization. There was no statistically significant increase in the risk of a GI event between those classified as a COX-2 inhibitor or nsNSAID user at the time of withdrawal (HR 1.03, 95% CI 0.69-1.54). Considering the drug exposure at the time of the event, there was no increased risk of GI events associated with the use of either COX-2 inhibitors or nsNSAID, or with the use of oral corticosteroids, low-dose aspirin, or clopidogrel, after adjustment for potential confounders. CONCLUSION: In this cohort, withdrawal of rofecoxib did not result in a significant increase in GI events among patients with RA. PMID- 22422501 TI - Levels of plasma-soluble triggering receptor expressed on myeloid cells-1 (sTREM 1) are correlated with disease activity in rheumatoid arthritis. AB - OBJECTIVE: To determine whether levels of plasma-soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are elevated in patients with rheumatoid arthritis (RA) and whether levels are correlated with disease activity and other variables. METHODS: Our study included 71 patients with RA and 50 age- and sex matched healthy controls. Clinical characteristics and laboratory measures, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and 28 joint Disease Activity Score (DAS28) were assessed. Plasma levels of sTREM-1 and tumor necrosis factor-alpha (TNF-alpha) were measured by ELISA. RESULTS: Patients with RA had significantly higher plasma sTREM-1 levels than healthy controls (170.10 +/- 84.71 pg/ml vs 97.41 +/- 40.64 pg/ml; p < 0.001). In patients with RA, plasma sTREM-1 levels were found to be correlated with DAS28, ESR, CRP, white blood cell counts, neutrophil counts, and plasma TNF-alpha levels (r = 0.329, p = 0.005; r = 0.241, p = 0.043; r = 0.314, p < 0.001; r = 0.261, p = 0.028; r = 0.278, p = 0.019; and r = 0.313, p = 0.009, respectively). Plasma sTREM-1 levels in patients with active disease status (DAS28 > 3.2) were significantly higher than in those with low disease status (DAS28 <= 3.2; 208.89 +/- 100.14 pg/ml vs 150.29 +/- 68.70 pg/ml; p = 0.005). CONCLUSION: Patients with RA had higher plasma sTREM-1 levels than healthy controls, and plasma sTREM-1 levels were correlated with disease activity measures, suggesting that plasma sTREM-1 could play a role in the inflammatory process associated with TNF-alpha, and that it may be a useful disease activity marker in RA. PMID- 22422502 TI - Sequential design of phase II-III cancer trials. AB - Although traditional phase II cancer trials are usually single arm, with tumor response as endpoint, and phase III trials are randomized and incorporate interim analyses with progression-free survival or other failure time as endpoint, this paper proposes a new approach that seamlessly expands a randomized phase II study of response rate into a randomized phase III study of time to failure. This approach is based on advances in group sequential designs and joint modeling of the response rate and time to event. The joint modeling is reflected in the primary and secondary objectives of the trial, and the sequential design allows the trial to adapt to increase in information on response and survival patterns during the course of the trial and to stop early either for conclusive evidence on efficacy of the experimental treatment or for the futility in continuing the trial to demonstrate it, on the basis of the data collected so far. PMID- 22422503 TI - Prevention for college students who suffer alcohol-induced blackouts could deter high-cost emergency department visits. AB - Fifty percent of college students who drink report alcohol-induced blackouts, and alcohol abusers in general put a heavy burden on the medical care system. Using data drawn from a randomized, controlled alcohol intervention trial at five university sites, our study quantified the costs of visits to emergency departments by college students who experienced blackouts from drinking alcohol. Of 954 students in the study, 52 percent of males and 50 percent of females at the outset of the study had experienced an alcohol-induced blackout in the past year. Of 404 emergency department visits among the study participants over a two year observation period, about one in eight were associated with blackout drinking. Injuries ranged from broken bones to head and brain injuries requiring computed tomography. We calculate that on a large university campus having more than 40,000 students, blackout-associated emergency department visit costs would range from $469,000 to $546,000 per year. We conclude that blackouts are a strong predictor of emergency department visits for college drinkers and that prevention efforts aimed at students with a history of blackouts might reduce injuries and emergency department costs. PMID- 22422504 TI - Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy. AB - Glycogen storage disease type Ia (GSD-Ia), which is characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by deficiencies in the endoplasmic reticulum (ER)-associated glucose-6 phosphatase-alpha (G6Pase-alpha or G6PC) that hydrolyzes glucose-6-phosphate (G6P) to glucose. G6Pase-alpha activity depends on the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the ER lumen. The functional coupling of G6Pase-alpha and G6PT maintains interprandial glucose homeostasis. We have shown previously that gene therapy mediated by AAV-GPE, an adeno-associated virus (AAV) vector expressing G6Pase-alpha directed by the human G6PC promoter/enhancer (GPE), completely normalizes hepatic G6Pase-alpha deficiency in GSD-Ia (G6pc(-/-) ) mice for at least 24 weeks. However, a recent study showed that within 78 weeks of gene deletion, all mice lacking G6Pase-alpha in the liver develop HCA. We now show that gene therapy mediated by AAV-GPE maintains efficacy for at least 70-90 weeks for mice expressing more than 3% of wild-type hepatic G6Pase-alpha activity. The treated mice displayed normal hepatic fat storage, had normal blood metabolite and glucose tolerance profiles, had reduced fasting blood insulin levels, maintained normoglycemia over a 24-hour fast, and had no evidence of hepatic abnormalities. After a 24-hour fast, hepatic G6PT messenger RNA levels in G6pc(-/-) mice receiving gene therapy were markedly increased. Because G6PT transport is the rate-limiting step in microsomal G6P metabolism, this may explain why the treated G6pc(-/-) mice could sustain prolonged fasts. The low fasting blood insulin levels and lack of hepatic steatosis may explain the absence of HCA. CONCLUSION: These results confirm that AAV-GPE-mediated gene transfer corrects hepatic G6Pase-alpha deficiency in murine GSD-Ia and prevents chronic HCA formation. PMID- 22422505 TI - Eosinophilic esophagitis: allergic contribution, testing, and management. AB - Both basic science and clinical data indicate a strong role for allergy as a cause of eosinophilic esophagitis. As a result, one of the desired goals of therapy is identification and elimination of food antigens that trigger the allergic inflammatory pathway. Traditional methods for identification of causative food antigens include induction of symptoms with exposure to the antigen, demonstration of serum IgE antibodies against antigens and induction of immediate (IgE) or delayed (Th2) reactions against dermal instillation of antigens. Although some data support the use of these tests in patients with eosinophilic esophagitis, they are limited in this disease. This limitation results from an inability to provoke recognizable symptoms and a lack of concordance between allergies identified in the skin and the blood with the antigens that trigger esophageal disease. As a result, allergy therapy in eosinophilic esophagitis consists of global elimination of food antigens with an elemental diet or exclusion of the most common antigens. As compliance is difficult with these strategies, the mainstay of allergy therapy in eosinophilic esophagitis has become the use of medications that blunt the allergic pathway such as steroids with a future aimed toward more specific inhibitors of this pathway in eosinophilic esophagitis specifically. PMID- 22422506 TI - How does knowledge from translational research impact our clinical care of pediatric inflammatory bowel disease patients? AB - Recent translational studies have provided new insights into pathogenesis, disease behavior, and treatment responses in pediatric Inflammatory Bowel Disease (IBD). Registry studies have identified distinct clinical phenotypes with increasing age of onset; this has led to a revision of the clinical phenotyping system, now termed the Paris classification system. It is recognized that there are infantile (age <2 years), very early onset (VEO, age 2-10), and early onset (EO, age 10-17) forms of disease. Rare genetic mutations affecting anti-microbial and anti-inflammatory pathways have been discovered in infantile and VEO forms, while genetic pathways identified in EO disease have been similar to adult-onset IBD. Genetic and serologic patterns measured soon after diagnosis have been shown to be associated with more aggressive stricturing behavior; these patterns may now be used clinically to help predict disease course. More recently, clinical and genetic models have been developed that, if validated, could be used to predict treatment responses. PMID- 22422507 TI - The natural history of radiographic knee osteoarthritis: a fourteen-year population-based cohort study. AB - OBJECTIVE: To establish the natural history of radiographic knee osteoarthritis (OA) over 14 years in a community-based cohort. METHODS: We examined women from the Chingford Women's Study, a community-based cohort followed up for more than 14 years. We selected women for whom bilateral radiographs of the knees (with the legs in full extension) were obtained at approximately 5-year intervals. Radiographs were scored for OA in a blinded manner, using Kellgren/Lawrence (K/L) grades. Descriptive statistics and odds ratios (ORs) were used to compare the incidence, worsening, and progression of radiographic knee OA. RESULTS: A complete radiography series was available for 561 of the original 1,003 subjects enrolled in the study. The median age of these subjects at baseline was 53 years (interquartile range 48-58 years). At baseline, 13.7% of the subjects had radiographic knee OA (K/L grade>=2) in at least one knee, and the prevalence increased to 47.8% by year 15. The annual cumulative incidence of radiographic knee OA was 2.3% between baseline and year 15. The annual rates of disease progression and worsening between baseline and year 15 were 2.8% and 3.0%, respectively. Subjects with a K/L grade of 1 at baseline were more likely to experience worsening by year 15 compared with subjects with a baseline grade of 0 (OR 4.5, 95% confidence interval 2.7-7.4). CONCLUSION: This is the longest natural history study of radiographic knee OA to date. The results showed relatively low rates for the incidence and progression of radiographic knee OA; more than half of all subjects had no radiographic evidence of knee OA over a 15 year period of time. Subjects with a baseline K/L grade of 1 were more likely than subjects with other baseline K/L grades to experience worsening of knee OA. PMID- 22422508 TI - GRP78/BiP is a novel downstream target of IGF-1 receptor mediated signaling. AB - Glucose regulated protein 78/immunoglobulin binding protein (GRP78/BiP) is an endoplasmic reticulum (ER) chaperone protein and master regulator of the unfolded protein response (UPR). The response of GRP78 to overt pharmacologically induced ER stress is well established, whereas the modulation of GRP78 to physiologic changes is less characterized. In this study, we examined the regulation of GRP78 in response to reduced IGF-1 growth factor signaling, a common consequence of calorie restriction (CR). ER chaperone protein expression was quantified in cell lysates prepared from the livers of calorie restricted (CR) and ad libitum fed mice, as well as MEFs grown in normal medium or serum starved. The requirement of IGF-1 signaling on GRP78 expression was studied using MEFs with IGF-1 receptor overexpression (R+) or deletion (R-), and the regulatory mechanism was examined using mTORC1 and PI3K inhibitors, as well as R- cells with knockdown of transcription factor FOXO1 compared to shRNA control. We observed a 40% reduction in GRP78 protein expression in CR mice and in serum-starved MEF cells. R- cells had drastically reduced AKT phosphorylation and exhibited lower levels of ER chaperones, in particular 80% less GRP78. Despite an 80% reduction in GRP78 expression, R- cells were not under chronic ER stress, but were fully capable of activating the UPR. Neither forced expression of FOXO1-AAA nor knockdown of FOXO1 in R- cells affected GRP78 expression. In conclusion, we report that IGF-1 receptor signaling regulates GRP78 expression via the PI3K/AKT/mTORC1 axis independent of the canonical UPR and FOXO1. PMID- 22422509 TI - Strategies of adaptation of Staphylococcus epidermidis to hospital and community: amplification and diversification of SCCmec. AB - OBJECTIVES: Staphylococcus epidermidis is a harmless commensal, but it can become a human pathogen, mainly in the hospital environment. In order to clarify strategies used by these bacteria to adapt to the hospital environment, we compared the population structure and staphylococcal cassette chromosome mec (SCCmec) content of S. epidermidis from the community and hospital. METHODS: S. epidermidis were collected from nasal swabs of both healthy military draftees (192 isolates) and patients (94 isolates) recovered in the same time period and geographical region. S. epidermidis were characterized by PFGE, multilocus sequence typing and SCCmec typing. RESULTS: Clonal complex 5 was predominant in the hospital (100%) and the community (58%), but some clonal types were specific to each environment and others were found in both (C/H clones). The methicillin resistant S. epidermidis (MRSE) colonization rate in the community was very low (7%) when compared with the hospital (30%; P < 0.05). Community-associated MRSE carried mostly SCCmec IV and V [Simpson's index of diversity (SID) = 57.52%; 95% CI 38.35-76.69], whereas hospital-associated MRSE carried 17 SCCmec structures (SID = 82.67%; 95% CI 77.38-87.96). Isolates of the same PFGE type had a much higher number of different SCCmec types when collected in the hospital than in the community. CONCLUSIONS: Our data suggest that the S. epidermidis population is composed of hospital-associated clonal types, community-associated clonal types and types that are able to survive in both environments. Moreover, adaptation to the hospital environment in S. epidermidis appears to promote an increase in the frequency and diversification of SCCmec. PMID- 22422510 TI - Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions: another single center retrospective adds clarity or controversy? PMID- 22422511 TI - Protective role of zinc during aluminum-induced hepatotoxicity. AB - The study was carried out to assess the role of zinc (Zn) in mitigating the biochemical alterations induced by aluminum (Al) in rat liver. Rats were divided into four groups: normal control, Al treated (AlCl3, 100 mg/kg b.wt./day), Zn treated (ZnSO4, 227 mg/L drinking water), and combined Al + Zn treated. Al and zinc treatments were given for a total duration of 2 months. Al treatment caused a significant increase in the activity of alkaline phosphatase (ALP), but decreased aspartate aminotransferase (AST) and alanine aminotranferase (ALT) activities, which showed the reverse trend following Zn supplementation. Levels of lipid peroxidation (LPx) and activities of catalase and glutathione-S transferase (GST) were significantly decreased following Al treatment, which, however, were increased significantly in Zn co-treated rats. Further Al exposure showed a significant increase in reduced glutathione (GSH) content as well as activities, of superoxide dismutase (SOD) and glutathione reductase (GR). However, Zn supplementation to Al-treated rats brought down the raised levels of reduced (GSH) and SOD to within normal limits, but caused no effect on GR activity. Furthermore, Al treatment also resulted in alterations in liver histoarchitecture with disruption of hepatic cords and increased vacuolization, which were close to normal following Zn supplementation. The present study reveals that Zn is effective in attenuating the liver damage inflicted by Al toxicity. PMID- 22422512 TI - Episodic autobiographical memory in amnestic mild cognitive impairment: what are the neural correlates? AB - Autobiographical memory in amnestic Mild Cognitive Impairment (aMCI) is characterized by impaired retrieval of episodic memories, but relatively preserved personal semantic knowledge. This study aimed to identify (via FDG-PET) the neural substrates of impaired episodic specificity of autobiographical memories in 35 aMCI patients compared with 24 healthy elderly controls. Significant correlations between regional cerebral activity and the proportion of episodic details in autobiographical memories from two life periods were found in specific regions of an autobiographical brain network. In aMCI patients, more than in controls, specifically episodic memories from early adulthood were associated with metabolic activity in the cuneus and in parietal regions. We hypothesized that variable retrieval of episodic autobiographical memories in our aMCI patients would be related to their variable capacity to reactivate specific sensory-perceptual and contextual details of early adulthood events linked to reduced (occipito-parietal) visual imagery and less efficient (parietal) attentional processes. For recent memories (last year), a correlation emerged between the proportion of episodic details and activity in lateral temporal regions and the temporo-parietal junction. Accordingly, variable episodic memory for recent events may be related to the efficiency of controlled search through general events likely to provide cues for the retrieval of episodic details and to the ability to establish a self perspective favouring recollection. PMID- 22422513 TI - Anastomotic failure with a ring anastomotic coupler due to disengagement of its rings. PMID- 22422514 TI - Photochemical preparation of sub-wavelength heterogeneous laser-induced periodic surface structures. AB - Laser-induced periodic surface structures (LIPSS) are a phenomenon caused by interaction of light with solid surfaces. We present a photochemical concept which uses LIPSS-related light intensity patterns for the generation of heterogeneous nanostructures. The process facilitates arbitrary combinations of substrate and LIPSS-pattern materials. An efficient method for the generation of organometallic hybrid-nanowire arrays on porous anodic aluminum oxide is demonstrated. PMID- 22422515 TI - Initial experience using a bipolar radiofrequency ablation device for hemostasis during thyroidectomy. AB - BACKGROUND: The purpose of this study was to evaluate a novel bipolar radiofrequency ablation (BRFA) device using nanotechnology for division of all named vessels during thyroidectomy. METHODS: All thyroidectomies from January 2008 to July 2010 at a single institution used the BRFA device (EnSeal, Ethicon Endo-Surgery, Cincinnati, OH) for hemostasis. Clinicopathologic data and complications were recorded and compared with existing literature using other energy devices. RESULTS: Fifty-eight thyroidectomies were performed. Mean age was 54.7 years, and mean operating room time was 81 minutes. The average estimated blood loss was 46 mL. Ninety percent of patients were discharged in <23 hours. There were no hemorrhages. There was 1 recurrent laryngeal nerve (RLN) injury, and 1 case of transient hypocalcemia. CONCLUSION: This first small series using the BRFA device reveals initial safety and effectiveness for thyroid hemostasis, and warrants further study. The minimal thermal spread inherent in this device may make it an attractive option when structures such as the RLN may be near the zone of hemostasis. PMID- 22422516 TI - Genetic evaluation of IS900 partial sequence of Mycobacterium avium subsp. paratuberculosis Brazilian isolates from bovine milk. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of paratuberculosis. Insertion sequence IS900 is used for the identification of MAP. The objective of this study was to verify the genetic conservation of IS900 sequences in raw milk samples. To evaluate genetic conservation, 206 quarter milk samples and 16 bulk-tank milk samples were collected. DNA extraction and IS900 PCR were performed in all samples. Six samples amplified the expected fragment. To confirm the identity of the amplified fragments, PCR products were cloned and sequenced. The resulting sequences were compared with other MAP sequences from GenBank, and it was possible to identify eight polymorphic regions and to form five distinct haplotypes. The number of mutations in each haplotype was verified. IS900 sequence is a very well-conserved sequence that could be used as tool for the molecular detection of this agent and epidemiological purposes. The results showed the first genetic analysis on Brazilian isolates of MAP. PMID- 22422517 TI - Neuroprotective effect of vitamin E isoforms against chronic alcohol-induced peripheral neurotoxicity: possible involvement of oxidative-nitrodative stress. AB - Small-fiber painful peripheral neuropathy is one of the long-term complications of alcohol for which there is no reliable successful therapy available. The precise mechanisms by which chronic alcohol consumption produces peripheral nerve fiber damage and loss remain unclear. Emerging data from clinical and preclinical studies suggest that increased oxidative-nitrodative stress mediated release of proinflammatory cytokines from damaged neural tissues may play a central role in the pathogenesis of alcoholic neuropathy. The present study investigated the effect of both the isoforms of vitamin E (alpha-tocopherol and tocotrienol) against chronic alcohol-induced peripheral neuropathy in rats. Ethanol treated rats showed a significant decrease in paw-withdrawal threshold in both Randall Selitto and von-Frey hair tests along with a significant reduction in tail flick latency in the tail-immersion test. A decreased pain threshold was associated with significant alterations in oxidative-nitrodative stress markers and an increase in proinflammatory cytokines (TNF-alpha and IL-1beta). The 4-week treatment with tocotrienol significantly ameliorated behavioral, biochemical and molecular alterations in alcohol treated rats. However, alpha-tocopherol failed to produce any protective effect. The results of the present study suggest that oxidative-nitrodative stress mediated cytokine signaling may be responsible for alcohol-induced peripheral neurotoxicity and tocotrienol treatment might be beneficial in chronic alcoholics exhibiting neuropathy. PMID- 22422518 TI - A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance. AB - The kinetics of hepatitis B surface antigen (HBsAg) levels preceding spontaneous HBsAg seroclearance has not been fully investigated. The kinetics of HBsAg and hepatitis B virus (HBV) DNA of 203 treatment-naive, hepatitis B e antigen (HBeAg) negative patients with spontaneous HBsAg seroclearance were compared with 203 age and sex-matched HBeAg-negative controls. Serum samples at 3 years, 2 years, 1 year, and 6 months before HBsAg seroclearance and at the time of HBsAg loss were tested. Median HBsAg levels at these respective time points before HBsAg seroclearance were 23.5, 3.51, 0.524, and 0.146 IU/mL. For all time points, patients with HBsAg seroclearance had significantly lower median HBsAg and HBV DNA levels, compared to those of the controls (all P < 0.001). Median HBsAg and HBV DNA levels declined significantly until HBsAg seroclearance (P < 0.001). Although median HBsAg levels also decreased significantly with time (P = 0.006) in controls, median HBV DNA levels remained similar (P = 0.414). Serum HBsAg levels, followed by HBsAg log reduction, were the best predictors of HBsAg seroclearance, with an area under the receiving operator characteristic (AUROC) of 0.833 (95% confidence interval [CI]: 0.792-0.873) and 0.803 (95% CI: 0.755 0.849), respectively. The optimal cut-off HBsAg level and HBsAg reduction to predict HBsAg seroclearance were <200 IU/mL (sensitivity, 84.2%; specificity, 73.4%) and 0.5 log IU/mL/year (sensitivity, 62.8%; specificity, 88.7%), respectively. For patients with HBsAg levels >= 200 IU/mL, an annual 0.5-log reduction was highly predictive of subsequent HBsAg seroclearance (AUROC, 0.867; 95% CI: 0.778-0.956). CONCLUSION: To conclude, serum HBsAg <200 IU/mL and 0.5-log reduction in HBsAg were predictive of HBsAg seroclearance within 3 years of follow-up. These parameters may serve as good indicators for the consideration of treatment duration and cessation for chronic hepatitis B. PMID- 22422519 TI - Role of non-specific DNA in reducing coding DNA requirement for transient gene expression with CHO and HEK-293E cells. AB - Transient gene expression (TGE) is a rapid method for the production of recombinant proteins in mammalian cells. While the TGE volumetric productivity has improved significantly over the past decade, the amount of plasmid DNA (pDNA) needed for transfection remains very high. Here, we examined the use of non specific (filler) DNA to partially replace the transgene-bearing plasmid DNA (coding pDNA) in transfections of Chinese hamster ovary (CHO) and human embryo kidney (HEK-293E) cells. When the optimal amount of coding pDNA for either host was reduced by 67% and replaced with filler DNA, the recombinant protein yield decreased by only 25% relative to the yield in control transfections. Filler DNA did not affect the cellular uptake or intracellular stability of coding pDNA, but its presence lead to increases of the percentage of transfected cells and the steady-state level of transgene mRNA compared to control transfections. Studies of the physicochemical properties of DNA-polyethyleneimine (PEI) complexes with or without filler DNA did not reveal any differences in their size or surface charge. The results suggest that filler DNA allows the coding pDNA to be distributed over a greater number of DNA-PEI complexes, leading to a higher percentage of transfected cells. The co-assembly of filler DNA and coding pDNA within complexes may also allow the latter to be more efficiently utilized by the cell's transcription machinery, resulting in a higher level of transgene mRNA. PMID- 22422520 TI - Recent developments in enediyne chemistry. AB - The enediynes are known for highly potent anticancer, antimicrobial, as well as cytotoxic activities. The discovery of enediynes from natural sources was achieved in late 1980s. They are presently of high interest, because they exert their biological action due to their ability to form a diradical, which abstracts H-atoms from the DNA backbone, thus causing cell death. Nowadays, the major works are dedicated to the syntheses of enediynes. This review covers recent developments in enediyne chemistry of the last few decades. It is subdivided in six chapters dealing with the discussion of the chemistry and biological significances of enediynes, and the factors responsible for a better activation of enediynes and potent biological evaluations. PMID- 22422521 TI - The production of multiple small peptaibol families by single 14-module Peptide synthetases in Trichoderma/Hypocrea. AB - The most common sequences of peptaibiotics are 11-residue peptaibols found widely distributed in the genus Trichoderma/Hypocrea. Frequently associated are 14 residue peptaibols sharing partial sequence identity. Genome sequencing projects of three Trichoderma strains of the major clades reveal the presence of up to three types of nonribosomal peptide synthetases with 7, 14, or 18-20 amino acid adding modules. Here, we provide evidence that the 14-module NRPS type found in T. virens, T. reesei (teleomorph Hypocrea jecorina), and T. atroviride produces both 11- and 14-residue peptaibols based on the disruption of the respective NRPS gene of T. reesei, and bioinformatic analysis of their amino acid-activating domains and modules. The sequences of these peptides may be predicted from the gene sequences and have been confirmed by analysis of families of 11- and 14 residue peptaibols from the strain 618, termed hypojecorins A (23 sequences determined, 4 new) and B (3 sequences determined, 2 new), and the recently established trichovirins A from T. virens. The distribution of 11- and 14-residue products is strain-specific and depends on growth conditions as well. Possible mechanisms of module skipping are discussed. PMID- 22422522 TI - Synthesis and evaluation of 6-aza-2'-deoxyuridine monophosphate analogs as inhibitors of thymidylate synthases, and as substrates or inhibitors of thymidine monophosphate kinase in Mycobacterium tuberculosis. AB - A series of 5-substituted analogs of 6-aza-2'-deoxyuridine 5'-monophosphate, 6 aza-dUMP, has been synthesized and evaluated as potential inhibitors of the two mycobacterial thymidylate synthases (i.e., a flavin-dependent thymidylate synthase, ThyX, and a classical thymidylate synthase, ThyA). Replacement of C(6) of the natural substrate dUMP by a N-atom in 6-aza-dUMP 1a led to a derivative with weak ThyX inhibitory activity (33% inhibition at 50 MUM). Introduction of alkyl and aryl groups at C(5) of 1a resulted in complete loss of inhibitory activity, whereas the attachment of a 3-(octanamido)prop-1-ynyl side chain in derivative 3 retained the weak level of mycobacterial ThyX inhibition (40% inhibition at 50 MUM). None of the synthesized derivatives displayed any significant inhibitory activity against mycobacterial ThyA. The compounds have also been evaluated as potential inhibitors of mycobacterial thymidine monophosphate kinase (TMPKmt). None of the derivatives showed any significant TMPKmt inhibition. However, replacement of C(6) of the natural substrate (dTMP) by a N-atom furnished 6-aza-dTMP (1b), which still was recognized as a substrate by TMPKmt. PMID- 22422523 TI - Synthesis and in vitro inhibition properties of siRNA conjugates carrying acridine and quindoline moieties. AB - The synthesis of RNA molecules carrying acridine or quindoline residues at their 3'- and 5'-termini is reported. These conjugates are fully characterized by MALDI TOF mass spectrometry. Modified siRNA duplexes carrying acridine or quindoline moieties were evaluated for inhibition of the tumor necrosis factor. The conjugates showed inhibitory properties similar to those of unmodified RNA duplexes in HeLa cells transfected with oligofectamine. The fluorescent properties of acridine derivatives allow direct observation of the cytoplasmatic distribution of modified siRNA inside the cells. PMID- 22422524 TI - Antifeedant activity of fatty acid esters and phytosterols from Echium wildpretii. AB - Crude extracts and fractions from Echium wildpretii H. Pearson ex Hook. f. subsp. wildpretii (Boraginaceae) have been tested against insect species Spodoptera littoralis, Leptinotarsa decemlineata, and the aphids Myzus persicae, Diuraphis noxia, Metopolophium dirhodum, Rhopalosiphum maidis, and Rhopalosiphum padi. The EtOH extract and the lipid and steroidal fractions of E. wildpretii exhibited significant antifeedant activities against the aphids and L. decemlineata. Two bioactive mixtures composed of fatty acid esters and n-alkanes were obtained from the lipid fraction. The bioguided fractionation of the steroidal fraction resulted in the isolation of glutinol, beta-sitosterol, (3beta,7alpha)-stigmast-5 ene-3,7-diol, and (3beta,7alpha)-7-methoxystigmast-5-en-3-ol. The latter two compounds exhibited potent antifeedant activities against L. decemlineata indicating that the presence of an O-bearing C(7) was responsible for the activities of these molecules. PMID- 22422525 TI - Chemical and morphological diversity in wild populations of Mentha longifolia in Israel. AB - Populations of Mentha longifolia, an endangered species in Israel, were tested for essential oil composition and conservational ability. In 2002-2003, 25 wild populations country-wide were tested, indicating population divergence into two chemotypes. Chemotype A was characterized by high levels of menthone and pulegone, and chemotype B by high levels of piperitenone oxide and piperitone oxide. Chemotype A was more abundant (22 of 25 populations) than chemotype B (11 of 25 populations). However, a chemotype/population interaction was not recorded (P > 0.05). In spring 2003, seven of the 25 wild populations were resampled, propagated, and cultivated at the Newe Ya'ar campus. Then, in 2004, the propagated plants were tested for essential oil composition. The propagated plants maintained the essential oil composition as well as the chemotype frequency distribution of the original wild population from which they were obtained. Since a chemotype/population interaction was not recorded, and the cultivated plants displayed the wild population essential oil composition, it can be concluded that i) the chemotype diversity is genetically based, and ii) the M. longifolia populations sampled can be horticulturally conserved. PMID- 22422526 TI - N(3)-protection of thymidine with Boc for an easy synthetic access to sugar alkylated nucleoside analogs. AB - The use of Boc as a nucleobase-protecting group in the synthesis of sugar modified thymidine analogs is reported. Boc was easily inserted at N(3) by a simple and high-yielding reaction and found to be stable to standard treatments for the removal of Ac and (t) BuMe(2) Si (TBDMS) groups, as well as to ZnBr(2) mediated 4,4'-dimethoxytrityl (DMTr) deprotection. Boc Protection proved to be completely resistant to the strong basic conditions required to regioselectively achieve O-alkylation, therefore, providing synthetic access to a variety of sugar alkylated nucleoside analogs. To demonstrate the feasibility of this approach, two 3'-O-alkylated thymidine analogs have been synthesized in high overall yields and fully characterized. PMID- 22422527 TI - Essential oil composition and antimicrobial activity of wild and cultivated Moroccan Achillea ageratum L.: a rare and threatened medicinal species. AB - The essential oils of leaves and flowers of the wild and cultivated Moroccan Achillea ageratum L., a rare and threatened medicinal species, were examined by GC/MS, and their chemical compositions were compared. At least nine components were identified in both wild and cultivated A. ageratum oils, representing more than 95% of the oils. Artemisyl acetate (62.34-78.79%), yomogi alcohol (4.89 12.40%), santolina alcohol (4.86-11.77%), and artemisia alcohol (3.36-7.04%) were the major compounds. Terpene-alcohol proportion was higher in wild A. ageratum than in cultivated A. ageratum. The antibacterial analysis showed that both oils presented high activity against all the studied Gram-positive strains in a range of MIC values from 2.55 to 7.02 mg/ml, but they appeared not effective against the tested Gram-negative ones (MIC values 20.40-41.10 mg/ml). They also exhibited remarkable antifungal activities against Candida species with MIC values ranging from 5.83 to 8.42 mg/ml. From these results, it was concluded that domestication of this threatened medicinal species using clonal propagation did not significantly affect its chemical composition and consequently its antimicrobial properties. PMID- 22422528 TI - Understanding How H-NOX (Heme Nitric Oxide/Oxygen) domain works needs first clarifying how diatomic gases are relocated inside this sensing protein. A molecular-mechanics approach. AB - H-NOX (Heme Nitric Oxide/Oxygen) domain has widespread occurrence, either standalone or associated with functional proteins, sending signals for functions that span from modulating vasodilation and neurotransmission with humans to competition and symbiosis with bacteria. Understanding how H-NOX works, and possibly intervening on degeneration for health purposes, needs first clarifying how diatomic gases are relocated through this protein in relation to the deeply buried heme. To this end, a biased form of molecular dynamics, i.e., Random Accelaration Molecular Dynamics (RAMD), is used by applying a randomly oriented tiny force to heme-dissociated CO of Nostoc sp. H-NOX, while changing randomly the direction of the force, if CO travels less than specified for the evaluated block. The result is that a large area of the protein, comprising amino acids from serine 44 to leucine 67 along two adjacent helices, offers a broad portal to CO from the surrounding medium to the deeply buried heme. Most traffic is concentrated through a channel lined by tyrosine 49, valine 52, and leucine 67. This modifies the picture drawn from mapping Xe cavities on pressurizing Nostoc sp. H-NOX with Xe gas. What is the main pathway with Xe-cavity mapping becomes a minor pathway with RAMD, and vice versa. The reason is that the fluctuating protein under MD creates clefts for CO slipping through, as it is expected to occur in nature. PMID- 22422529 TI - Composition and antibacterial activity of the essential oils of four commercial grades of Omani luban, the oleo-gum resin of Boswellia sacra FLUECK. AB - The essential oil compositions of four botanically certified and commercially available samples of Omani lubans (oleo-gum resins of Boswellia sacra Flueck.), locally known as Hoojri, Najdi, Shathari, and Shaabi in Jibali Arabic, obtained from plants growing in four different geographic locations of the Dhofar region of Oman, were analyzed by GC-FID, GC/MS, and (13) C-NMR spectroscopy. The market price of these four grades of lubans differed considerably, according to their color, clump size, and texture. However, this study revealed that Hoojri, the first grade luban, and Shaabi, the fourth grade luban, which greatly differed in their price, closely resembled each other in their essential oil composition, yield, and physicochemical characteristics, except the color and texture. The composition, yield, and specific rotation of the oils of Najdi and Shathari, the second and the third grade lubans, respectively, were different from those of Hoojri and Shaabi, but they both had high limonene contents. Najdi oil was different from the other three oils in terms of its high myrcene content. alpha Pinene was the principal component in all the oils and can be considered as a chemotaxonomical marker that confirms the botanical and geographical source of the resins. All the oils showed pronounced activity against a panel of bacteria, and the trend in their bioactivity and their mode of action are discussed. PMID- 22422530 TI - Defensive sesquiterpenes from Senecio candidans and S. magellanicus, and their structure-activity relationships. AB - Eleven eremophilanolides, 1-3 and 6-13, and two eremophilanes, 24 and 25, were isolated from Senecio candidans and S. magellanicus from the Magallanes Region (Chile). Compounds 2, 3, 9, and 10 have not been previously reported as natural products. Their structures were established by NMR spectroscopic analysis and chemical transformations. The X-ray analysis of compounds 11, 13, and 17 were also performed. Different semisynthetic analogs from eremophilanolide 11 were generated to carry out a structure-activity relationship study. Their possible plant defensive role was tested against herbivorous insects (Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae) and plants (Lactuca sativa). Additionally, their effects on insect (Sf9) and mammalian (CHO) cell lines were tested. PMID- 22422531 TI - Antifungal Activity of the Essential Oils of Callitris neocaledonica and C. sulcata Heartwood (Cupressaceae). AB - Mortality due to fungal infections has increased substantially, becoming a worldwide problem in public health. As a contribution to the discovery of new antifungal agents, the properties of the heartwood essential oils of two trees growing in New Caledonia, Callitris neocaledonica and C. sulcata (Cupressaceae) were investigated. The essential oils extracted by hydrodistillation were characterized by GC-FID and GC/MS analyses. From C. neocaledonica oil, 31 constituents were identified, representing 97.0% of the total oil composition, which was mainly constituted by oxygenated sesquiterpenes (88%). Among them, guaiol (1; 30.2%), bulnesol (2; 12.5%), alpha-eudesmol (3; 10.5%), beta-eudesmol (4; 10.5%), gamma-eudesmol (10.2%), and elemol (4.9%) predominated. The chemical composition of C. sulcata oil, from which 39 constituents were identified (96.8% of the total oil composition), showed some similarities with that of C. neocaledonica oil. The major constituents were also oxygenated sesquiterpenes, accounting for 78.5% of the oil, amongst them, mainly compounds 1 (16.1%), 3 and 4 (9.7% each), as well as 2 (7.4%). The antifungal activity of the oils against clinical isolates of four dermatophytic fungi (Trichophyton mentagrophytes, T. rubrum, Microsporum canis, and M. gypseum) and six yeasts (Candida albicans, C. parapsilosis, C. glabrata, C. krusei, Cryptococcus neoformans, and Cryptococcus gattii) was tested by determining minimum inhibitory concentrations (MICs) using the microdilution method. The best antifungal activities of the C. neocaledonica and C. sulcata oils were obtained against C. krusei (MICs of 3.9 and 0.975 MUg/ml, resp.). These MIC values were similar to those of the reference drugs itraconazole and fluconazole (1.0 and 0.5 mg/ml, resp.). The oils were also subjected to a screening for their possible DPPH(.) (2,2-diphenyl-1 picrylhydrazyl) radical-scavenging activity. C. neocaledonica essential oil was more active than C. sulcata oil (93.3 vs. 32.2% DPPH(.) scavenged at 250 MUg/ml). PMID- 22422532 TI - New verticillane diterpenoids from Cespitularia taeniata. AB - Chemical investigation of Cespitularia taeniata has led to the isolation of three new verticillanes, cespitulins E-G (1-3, resp.). The structures of these compounds were elucidated by spectroscopic analysis, especially HR-MS and 2D-NMR techniques. Compound 1 possesses a rare norverticillane skeleton with two adjacent OH groups at C(5) and C(6), while the seco-compound 2 with an aldehyde group at C(9) results from an unusual bond cleavage between C(9) and C(10). Pharmacological studies revealed that compound 3 exhibited significant activities on superoxide-anion generation and elastase release by human neutrophils in response to FMLP/CB. A plausible biogenetic pathway for compound 2 is also discussed. PMID- 22422533 TI - Comparative chemical composition of the essential oils obtained by microwave assisted hydrodistillation and hydrodistillation from Agrimonia pilosa LEDEB. Collected in three different regions of China. AB - Conventional hydrodistillation (HD) and microwave-assisted hydrodistillation (MAHD) were performed to obtain the volatile oils of Agrimonia pilosa Ledeb. harvested in three different regions of China, which were subsequently characterized by GC-FID and GC/MS analyses. Compared with HD, MAHD was advantageous in terms of energy savings and extraction time (60 vs. 240 min for MAHD and HD, resp.). The chemical composition varied among the different oils obtained, and the variations in the contents of the main constituents of the oils were irregular. Hence, these variations affected both the quantity and composition of the oils. The oil yields (0.15-0.21%) were affected by the method of extraction and the region of harvest, with the maximum amount of oil obtained by MAHD for the plants collected in Hubei (HB) and the minimum yield obtained by HD for the plants from Zhejing (ZJ). Hexadecanoic acid constituted the major compound of the essential oils, with the highest content found in the oil obtained by HD for plants from HB (41.18%) and the lowest one found in the oil obtained by MAHD from plants from ZJ (11.83%). Microwave irradiation did not adversely affect the composition of the essential oils. The findings show that MAHD is a modern, green, and fast technology. PMID- 22422534 TI - Cancer proteomics. AB - Cancer presents high mortality and morbidity globally, largely due to its complex and heterogenous nature, and lack of biomarkers for early diagnosis. A proteomics study of cancer aims to identify and characterize functional proteins that drive the transformation of malignancy, and to discover biomarkers to detect early stage cancer, predict prognosis, determine therapy efficacy, identify novel drug targets, and ultimately develop personalized medicine. The various sources of human samples such as cell lines, tissues, and plasma/serum are probed by a plethora of proteomics tools to discover novel biomarkers and elucidate mechanisms of tumorigenesis. Innovative proteomics technologies and strategies have been designed for protein identification, quantitation, fractionation, and enrichment to delve deeper into the oncoproteome. In addition, there is the need for high-throughput methods for biomarker validation, and integration of the various platforms of oncoproteome data to fully comprehend cancer biology. PMID- 22422535 TI - Effect of vitamin D repletion on urinary calcium excretion among kidney stone formers. AB - BACKGROUND AND OBJECTIVES: Despite the important role of vitamin D in maintaining bone health, many clinicians are reluctant to treat vitamin D deficiency in kidney stone formers because of the theoretical risk of increasing urinary calcium excretion. This study examined the effect of vitamin D repletion on urinary calcium excretion among stone formers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants (n=29) were recruited from urology clinics affiliated with New York Presbyterian Hospital. Enrollment criteria included a history of nephrolithiasis, urinary calcium excretion between 150 and 400 mg/d, and a serum 25-hydroxyvitamin D level <30 ng/ml. Participants were given oral ergocalciferol (50,000 IU/wk) for 8 weeks. Serum and 24-hour urine tests were repeated after 8 weeks. RESULTS: Levels of 25-hydroxyvitamin D increased significantly after vitamin D repletion (17+/-6 and 35+/-10 ng/ml, P<0.001), but mean 24-hour urinary calcium excretion did not change (257+/-54 and 255+/-88 mg/d at baseline and follow-up, respectively, P=0.91). However, 11 participants had an increase in urinary calcium excretion >=20 mg/d; these participants also had an increase in urine sodium excretion, likely reflecting dietary variability. No participant experienced adverse effects from vitamin D, including hypercalcemia. CONCLUSIONS: Among stone formers with vitamin D deficiency, a limited course of vitamin D repletion does not seem to increase mean urinary calcium excretion, although a subset of individuals may have an increase. These data suggest that vitamin D therapy, if indicated, should not be withheld solely on the basis of stone disease, but 24-hour urinary calcium excretion should be monitored after repletion. PMID- 22422536 TI - Estimating baseline kidney function in hospitalized patients with impaired kidney function. AB - BACKGROUND AND OBJECTIVES: Inaccurate determination of baseline kidney function can misclassify acute kidney injury (AKI) and affect the study of AKI-related outcomes. No consensus exists on how to optimally determine baseline kidney function when multiple preadmission creatinine measurements are available. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The accuracy of commonly used methods for estimating baseline serum creatinine was compared with that of a reference standard adjudicated by a panel of board-certified nephrologists in 379 patients with AKI or CKD admitted to a tertiary referral center. RESULTS: Agreement between estimating methods and the reference standard was highest when using creatinine values measured 7-365 days before admission. During this interval, the intraclass correlation coefficient (ICC) for the mean outpatient serum creatinine level (0.91 [95% confidence interval (CI), 0.88-0.92]) was higher than the most recent outpatient (ICC, 0.84 [95% CI, 0.80-0.88]; P<0.001) and the nadir outpatient (ICC, 0.83 [95% CI, 0.76-0.87; P<0.001) serum creatinine. Using the final creatinine value from a prior inpatient admission increased the ICC of the most recent outpatient creatinine method (0.88 [95% CI, 0.85-0.91]). Performance of all methods declined or was unchanged when the time interval was broadened to 2 years or included serum creatinine measured within a week of admission. CONCLUSIONS: The mean outpatient serum creatinine measured within a year of hospitalization most closely approximates nephrologist adjudicated serum creatinine values. PMID- 22422537 TI - Decision support and CKD: not there yet. PMID- 22422539 TI - Pedometer-assessed physical activity in children and young adults with CKD. AB - BACKGROUND AND OBJECTIVES: Data on physical activity are limited in children with CKD. The objectives of this study were to measure the level and correlates of physical activity in children and young adults with CKD and to determine the association of physical activity with physical performance and physical functioning. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Physical activity was measured for 7 days using pedometers; physical performance was measured by the 6 minute walk distance (6MWD) and physical functioning with the PedsQL 4.0. RESULTS: Study participants were 44 patients 7-20 years of age who had CKD stage 1-4 (n=12), had ESRD and were undergoing dialysis (n=7), or had undergone kidney transplantation (n=25). Participants were very sedentary; they walked 6218 (interquartile range, 3637, 9829) steps per day, considerably less than recommended. Physical activity did not differ among participants in the CKD stage 1-4, ESRD, and transplant groups. Females were less active than males (P<0.01), and physical activity was 44% lower among young adults (18-20 years) than younger participants (P<0.05). Physical activity was associated positively with maternal education and hemoglobin concentration and inversely with body mass index. Respective 6MWD in males and females was 2 and approximately 4 SDs below expected. Low levels of physical activity were associated with poor physical performance and physical functioning, after adjustment for age, sex, and body mass index. CONCLUSIONS: In most participants with CKD, physical activity was considerably below recommended levels. Future studies are needed to determine whether increasing physical activity can improve physical performance and physical functioning. PMID- 22422540 TI - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. AB - BACKGROUND AND OBJECTIVES: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed. RESULTS: Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression. CONCLUSIONS: Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations. PMID- 22422538 TI - Effects of six versus three times per week hemodialysis on physical performance, health, and functioning: Frequent Hemodialysis Network (FHN) randomized trials. AB - BACKGROUND AND OBJECTIVES: Relatively little is known about the effects of hemodialysis frequency on the disability of patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined changes in physical performance and self-reported physical health and functioning among subjects randomized to frequent (six times per week) compared with conventional (three times per week) hemodialysis in both the Frequent Hemodialysis Network daily (n=245) and nocturnal (n=87) trials. The main outcome measures were adjusted change in scores over 12 months on the short physical performance battery (SPPB), RAND 36-item health survey physical health composite (PHC), and physical functioning subscale (PF) based on the intention to treat principle. RESULTS: Overall scores for SPPB, PHC, and PF were poor relative to population norms and in line with other studies in ESRD. In the Daily Trial, subjects randomized to frequent compared with conventional in-center hemodialysis experienced no significant change in SPPB (adjusted mean change of -0.20+/-0.19 versus -0.41+/-0.21, P=0.45) but experienced significant improvement in PHC (3.4+/-0.8 versus 0.4+/-0.8, P=0.009) and a relatively large change in PF that did not reach statistical significance. In the Nocturnal Trial, there were no significant differences among subjects randomized to frequent compared with conventional hemodialysis in SPPB (adjusted mean change of -0.92+/-0.44 versus -0.41+/-0.43, P=0.41), PHC (2.7+/-1.4 versus 2.1+/-1.5, P=0.75), or PF (-3.1+/-3.5 versus 1.1+/-3.6, P=0.40). CONCLUSIONS: Frequent in-center hemodialysis compared with conventional in-center hemodialysis improved self-reported physical health and functioning but had no significant effect on objective physical performance. There were no significant effects of frequent nocturnal hemodialysis on the same physical metrics. PMID- 22422541 TI - Systemic sclerosis disease modification clinical trials design: quo vadis? PMID- 22422542 TI - Relevance of the primary lesion in the prognosis of metastatic cutaneous squamous cell carcinoma. AB - BACKGROUND: It remains unclear how primary tumor factors impact on prognosis in patients with nodal metastasis in head and neck cutaneous squamous cell carcinoma (SCC). The purpose of this study was to assess whether primary tumor characteristics are independent prognostic factors. METHODS: Patients treated for metastatic cutaneous SCC from 1978 to 2010 were identified (n = 239). A proportional hazards model was used to assess the effect of primary tumor variables. RESULTS: On multivariable analysis, tumor differentiation (hazard ratio [HR], 0.2; 95% confidence interval [CI], 0.1-0.8; p = .03) was found to be significantly associated with disease-specific survival (DSS), unlike margin status (p = .23), tumor size (p = .21), and thickness (p = .11). Patient, treatment, and nodal factors were confirmed to be important predictors of survival. CONCLUSION: This article suggests that pathological features of the primary lesion bear little importance in the presence of established nodal metastasis, other than tumor differentiation. It validates the grouping of T1-3N1 as stage III under the current American Joint Committee on Cancer (AJCC) TNM staging system. PMID- 22422543 TI - Effects of carbofuran and deltamethrin on acetylcholinesterase activity in brain and muscle of the common carp. AB - This work investigated the effect from exposure to insecticides carbofuran and deltamethrin on acetylcholinesterase (AChE) activity in the brain and muscle of common carp (Cyprinus carpio). Both pesticides were evaluated through two separate experiments, and carp were exposed in a semi-static system to three different concentrations of carbofuran (10, 50, and 100 MUg/L) and deltamethrin (0.08, 0.4, and 0.8 MUg/L) during a month with sampling times at 0, 4, 15, and 30 days (n = 7 from each aquarium). AChE activity was significantly inhibited in both organs of carps exposed to carbofuran at all sampling times depending on dose and time, reaching inhibition values of 73.5 and 67.1%, in brain and muscle tissues respectively, after 30 days with the highest concentration. On the contrary, AChE activity was not significantly affected after deltamethrin exposure at all concentrations and times of the assay. This study shows that the measurement of brain and muscle AChE activity in Cyprinus carpio is a useful biomarker of carbamates exposure and/or effects, but has no application with pyrethroids. PMID- 22422544 TI - Symptomatic right ventricular ischemia secondary to a critical stenosis in a nondominant right coronary artery. AB - Stable angina pectoris owing to isolated right ventricular ischemia from a critical stenosis in a nondominant right coronary artery is a rare entity and documentation of isolated right ventricular ischemia even rarer. We present a case of isolated right ventricular ischemia documented by fractional flow reserve (FFR) and resolution of symptoms after percutaneous coronary intervention. PMID- 22422545 TI - Thumb reconstruction with a wrap-around free flap in hand radiation injury. AB - We describe a patient with hand radiation injury that was caused by (192)Ir radiation source exposure. The cutaneous symptoms that appear after local radiation exposure follow a certain time pattern consisting of the prodromal, manifestation, subacute, chronic, and late stages. Although the clinical characteristics of each stage are well known, limited cases of photographic demonstrations to the progressive local radiation reaction have been reported. We demonstrate characteristics of serial necrotic changes in the fingers after radiation exposure in photographs. Initially, blisters, mild erythema, and swelling were present in the exposed fingers. However, at 3 years postexposure, total necrosis, severe flexion deformity, and bony exposure were present in the exposed fingers. For restoration of hand function, we performed a transmetacarpal, metacarpophalangeal, and transphalangeal amputation of the second, third, and fourth fingers, respectively. After debridement of the necrotic thumb tissue, a wrap-around free flap from the hallux was performed for thumb reconstruction. At 2 years postoperatively, the free flap survived well and graft bone union had occurred. The patient's hand function had improved such that he could grip a large object using the reconstructed thumb and the fifth finger. PMID- 22422546 TI - Impact of scale space search on age- and gender-related changes in MRI-based cortical morphometry. AB - In magnetic resonance imaging based brain morphometry, Gaussian smoothing is often applied to increase the signal-to-noise ratio and to increase the detection power of statistical parametric maps. However, most existing studies used a single smoothing filter without adequately justifying their choices. In this article, we want to determine the extent for which performing a morphometry analysis using multiple smoothing filters, namely conducting a scale space search, improves or decreases the detection power. We first compared scale space search with single-filter analysis through a simulated population study. The multiple comparisons in our four-dimensional scale space searches were corrected for using a unified P-value approach. Our results illustrate that, compared with a single-filter analysis, a scale space search analysis can properly capture the variations in analysis results caused by variations in smoothing, and more importantly, it can obviously increase the sensitivity for detecting brain morphometric changes. We also show that the cost of an increased critical threshold for conducting a scale space search is very small. In the second experiment, we investigated age and gender effects on cortical volume, thickness, and surface area in 104 normal subjects using scale space search. The obtained results provide a perspective of scale space theory on the morphological changes with age and gender. These results suggest that, in exploratory studies of aging, gender, and disease, conducting a scale space search is essential, if we are to produce a complete description of the structural changes or abnormalities associated with these dimensions. PMID- 22422547 TI - RKIP and cytotrophoblast motility. PMID- 22422549 TI - Clinical trials in chronic myeloid leukemia. AB - The introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) has substantially improved the outcome of CML patients. Despite the positive results, problems and questions remained. This was the rationale to setup trials for treatment optimization, where imatinib was administered in higher dose and/or in combination with other therapy but where also new and potentially more efficacious second-generation TKI, nilotinib and dasatinib, were investigated. This review summarizes data of recently published first-line studies with the standard treatment imatinib 400 mg as one study arm. Results of randomized comparisons to higher-dose imatinib treatment, nilotinib or dasatinib are discussed. With regard to outcome interpretation, general aspects on statistical issues and endpoint definitions are put into focus. Considering decidedly increased longevity thanks to TKI treatment, future research should include the evaluation of the quality of life (QoL). Relating also to QoL, safe ways of drug discontinuation need to be investigated. PMID- 22422550 TI - Antibody therapy for acute lymphoblastic leukemia. AB - Advances in chemotherapy administration have made acute lymphoblastic leukemia (ALL) a curable disease; however, most patients will relapse, despite readily attaining a complete remission. Treatment of relapse has shown dismal results with little advances made in the recent decades. Antigenic-directed therapy of ALL can complement cytotoxic chemotherapy and has shown encouraging results. This review will evaluate four antigens in ALL (CD20, CD22, CD52, and CD19) and therapeutic strategies to target them. We will review the clinical and preclinical data surrounding rituximab, epratuzumab, inotuzumab ozogamicin, alemtuzumab, blinatumomab, and chimeric antigen receptor-modified T-cell therapy. PMID- 22422551 TI - Early interactions of Edwardsiella ictaluri, with Pangasianodon catfish and its invasive ability in cell lines. AB - Commercial Pangasianodon catfish production is heavily impacted by Bacillary Necrosis of Pangasius (BNP) caused by Edwardsiella ictaluri. This study aimed to investigate the early bacterium-host interactions following immersion challenge and to compare the retrieved data with the invasion ability of the used isolates in fish cell lines. Firstly, Pangasianodon hypophthalmus fingerlings were challenged via immersion using E. ictaluri isolate HO2 or 223. At different times post inoculation, fish were sacrificed and gill and internal organ samples were taken for bacteriological, histological and immunohistochemical evaluation. The bacterial load was higher for fish inoculated with isolate HO2 compared with 223. Histological and immunohistochemical analysis revealed multifocal necrotic areas in kidney, spleen and liver of HO2 inoculated fish at 72 h post inoculation with short rod-shaped immunoperoxidase positive bacteria clustered inside cells respectively. Bacteria especially were present in the gills and intestinal tract of HO2 inoculated fish, suggesting the gastrointestinal tract and gills act as portals of entry. Following, the ability of HO2, 223 and four additional isolates to invade a Chinook salmon embryo cell line, a fat head minnow cell line and a rainbow trout liver cell line was tested. All E. ictaluri isolates were invasive in all cell lines albeit at different degrees. Isolate HO2 was highly invasive in all cell lines with a significantly higher invasion capacity than isolate 223 in the Chinook salmon embryo cell line. A correlation between in vivo virulence and in vitro invasiveness hence is suggested although further studies are needed to confirm this hypothesis. PMID- 22422552 TI - Quercetin, quercetin glycosides and taxifolin differ in their ability to induce AhR activation and CYP1A1 expression in HepG2 cells. AB - The natural flavonoid quercetin is a low affinity ligand of the aryl hydrocarbon receptor (AhR), a transcription factor regulating the expression of cytochrome P450 (CYP) 1A enzymes. This study examined the ability of quercetin, isoquercitrin (quercetin-3-O-glucoside), rutin (quercetin-3-O-rutinoside) and taxifolin (dihydroquercetin) to activate AhR and to induce CYP1A1 expression in human hepatoma HepG2 cells. Gene reporter assays showed that quercetin significantly activated AhR and triggered CYP1A1 transcription after 24 h exposure. These effects were, however, much lower than those of 2,3,7,8 tetrachlorodibenzo-p-dioxin, a prototypical AhR ligand. Quercetin also induced a significant increase in CYP1A1 mRNA levels together with a moderate increase in the level of CYP1A1 activity. In contrast, isoquercitrin and rutin had negligible effects on AhR activity and CYP1A1 expression. Taxifolin at the highest concentration tested (50 um) produced a mild non-significant increase in AhR activity and CYP1A1 transcription. Taxifolin also significantly increased CYP1A1 mRNA expression, but this effect was approximately 15 times weaker than that of quercetin and was not accompanied by induction of CYP1A1 activity. It is concluded that quercetin, but not its 3-O-glycosides isoquercitrin and rutin, induces AhR activation and CYP1A1 expression in HepG2 cells and that the CYP1A1 inducing activity of taxifolin has a low toxicological potential. PMID- 22422553 TI - Protein-based stable isotope probing (protein-SIP) in functional metaproteomics. AB - The community phenotype as the sum of molecular functions of organisms living in consortia strongly depends on interactions within these communities. Therefore, the analyses of the most significant molecules in terms of the phenotype, the proteins, have to be performed on samples without disrupting the meta-species environment. Due to the increasing genomic information, proteins provide insights into a potential molecular function and the phylogenetic structure of the community. Unfortunately, the lists of identified proteins are often based first on the technical capacity of the used methods or instruments, and second on the interpretation of them by the assignment of molecular functions to proteins in databases. Especially in non-model organisms the functions of many proteins are often not known and an increasing number of studies indicate a significant amount of uncertainty. To decrease the dependency on assumptions and to enable functional insights by metaproteome approaches, the metabolic labeling from an isotopically labeled substrate can be used. Since the metabolites deriving from the substrate are very rarely species-specific, the incorporation of the stable isotope into proteins can be used as a surrogate marker for metabolic activity. The degree of incorporation can be determined accurately on the peptide level by mass spectrometry; additionally, the peptide sequence provides information on the metabolic active species. Thereby, protein-stable isotope probing (protein-SIP) adds functional information to metaproteome approaches. The classical metaproteome approaches will be reviewed with an emphasis on their attempts towards functional interpretation. The gain from functional insights into metaproteomics by using metabolic labeling of stable isotopes of carbon, nitrogen, and sulfur is reviewed with a focus on the techniques of measurement, calculation of incorporation and data processing. PMID- 22422554 TI - Mitochondria-targeting photoacoustic therapy using single-walled carbon nanotubes. AB - In vitro photoacoustic therapy using modified single-walled carbon nanotubes (SWNTs) as "bomb" agents is a newly reported approach for cancer. Herein, a mitochondria-targeting photoacoustic modality using unmodified SWNTs and its in vitro and in vivo antitumor effect are reported. Unmodified SWNTs can be taken up into cancer cells due to a higher mitochondrial transmembrane potential in cancerous cells than normal cells. Under the irradiation of a 1064 nm pulse laser, 79.4% of cancer cells with intracellular SWNTs die within 20 s, while 82.3% of normal cells without SWNTs remain alive. This modality kills cancer cells mainly by triggering cell apoptosis that initiates from mitochondrial damage, through the depolarization of mitochondria and the subsequent release of cytochrome c after photoacoustic therapy. It is very effective in suppressing tumor growth by selectively destroying tumor tissue without causing epidermis injury. Taken together, these discoveries provide a new method using mitochondria localized SWNTs as photoacoustic transducers for cancer treatment. PMID- 22422555 TI - Structured three-dimensional co-culture of mesenchymal stem cells with meniscus cells promotes meniscal phenotype without hypertrophy. AB - Menisci play a crucial role in weight distribution, load bearing, shock absorption, lubrication, and nutrition of articular cartilage within the knee joint. Damage to the meniscus typically does not heal spontaneously due to its partial avascular nature. Partial or complete meniscectomy is a common clinical treatment of the defective meniscus. However, this procedure ultimately leads to osteoarthritis due to increased mechanical stress to the articular cartilage. Meniscus tissue engineering offers a promising solution for partial or complete meniscus deficiency. Mesenchymal stem cells (MSC) have the potential to differentiate into meniscal fibrochondrocyte as well as deliver trophic effects to the differentiated cells. This study tested the feasibility of using MSC co cultured with mature meniscal cells (MC) for meniscus tissue engineering. Structured cell pellets were created using MC and MSC at varying ratios (100:0, 75:25, 50:50, 25:75, and 0:100) and cultured with or without transforming growth factor-beta 3 supplemented chondrogenic media for 21 days. The meniscal and hypertrophic gene expression, gross appearance and structure of the pellets, meniscus extracellular matrix (ECM), histology and immunohistochemistry of proteoglycan and collagen were evaluated. Co-culture of MC with MSC at 75:25 demonstrated highest levels of collagen type I and glycosaminoglycans (GAG) production, as well as the lowest levels of hypertrophic genes, such as COL10A1 and MMP13. All co-culture conditions showed better meniscus ECM production and hypertrophic inhibition as compared to MSC culture alone. The collagen fiber bundles observed in the co-cultures are important to produce heterogenic ECM structure of meniscus. In conclusion, co-culturing MC and MSC is a feasible and efficient approach to engineer meniscus tissue with enhanced ECM production without hypertrophy. PMID- 22422556 TI - Ultrasonographic hand features in systemic sclerosis and correlates with clinical, biologic, and radiographic findings. AB - OBJECTIVE: To investigate ultrasonographic (US) hand features in systemic sclerosis (SSc) patients and their relationship with clinical, biologic, and radiographic data. METHODS: Fifty-two consecutive SSc patients were included in a cross-sectional observational study together with 24 rheumatoid arthritis (RA) patients enrolled as controls. All patients underwent clinical examination, including tender and swollen joint counts, measurement of disability indices, and hand/wrist radiographs. US was performed on the hand and wrist joints and was aimed at the detection of synovitis, tenosynovitis, and calcinosis. RESULTS: Synovitis and tenosynovitis were more frequently detected with US in SSc patients (46% and 27%, respectively) than with clinical examination (15% and 6%, respectively; P < 0.01 for both comparisons). Fifty-seven percent of patients had inflammatory synovitis (mostly Doppler grade 1), and tenosynovitis was either inflammatory or fibrotic. Calcifications were observed using US and radiographs in 40% and 36% of SSc patients, respectively (P = 0.8). As compared to RA, US features specific to SSc were sclerosing tenosynovitis (P < 0.01) and soft tissue calcifications (P = 0.01). CONCLUSION: Our study confirms that articular involvement in SSc is underestimated by a single clinical examination. It is characterized by mild inflammatory changes and the specific findings include sclerotic US aspects together with calcinosis. Further prospective studies are warranted to evaluate the predictive value of these findings and determine whether they should be considered for adapting a therapeutic strategy. PMID- 22422557 TI - Multielectron redox chemistry of a neutral, NIR-active, indigo-pillared Re(I) based triangular metalloprism. AB - Self-assembled, hexarhenium(I), triangular metalloprism compound [{(CO)(3)Re(MU 2)Re(CO)(3)}(3)(MU(3)-1)(2)] (3) featuring three bis-chelating pillarlike indigo dianions (MU-2), each of which connects two fac-Re(CO)(3) cores, which are interconnected by a tritopic N donor, that is, a 2,4,6-tris(4-pyridyl)-1,3,5 triazine (MU(3)-1, tPyTz) ligand, has been synthesized in high yield and characterized. Metalloprism 3 exhibits a strong absorption in the near-infrared (NIR) region. The reversible, multielectron redox properties of the electrogenerated 3(n) species, where n=3+, 0, 3-, 4-, 5-, 8-, in the visible and especially in the NIR region were investigated in THF solution by cyclic voltammetry (CV), chronocoulometry, EPR spectroscopy, and thin-layer UV/Vis/NIR spectroelectrochemistry (SEC). Stepwise, site-specific electrochemical reductions lead to the formation of a series of highly stable ion (radical) species in which electrons associated with MU-2 or MU(3)-1 components of the molecule can be clearly distinguished. An EPR investigation revealed interaction of unpaired electrons with the metal nuclei ((185,187)Re, I=5/2) in the reduced intermediates. The framework has C(2) symmetry, and accidental degeneracies suffice. Detailed theoretical calculations by structure-based DFT confirm that the triply degenerate HOMO has >=70% indigo character with a sizable dpi-Re character, while the LUMO is dominated by the triply degenerate indigo ligands, and the LUMO+1 by doubly degenerate tPyTz ligands. A comparison of 3 and previously reported 2,2'-bis-benzimidazolate- (BiBzlm) or alkoxy-pillared Re(I) metalloprisms indicates a very low switching potential with a potential window of less than 1 V and reversibly accessible optical properties with higher stability of the intermediates. The properties exhibited by 3 appear to be due to the slight tuning of the bridging ligand from N,N(-) to N,O(-). PMID- 22422558 TI - Effect of an interdisciplinary rehabilitation program on quality of life in patients with head and neck cancer: review of clinical experience. AB - BACKGROUND: Patients with head and neck cancer experience complex posttreatment challenges. In a preliminary uncontrolled study, we evaluated the extent to which they can benefit from an interdisciplinary rehabilitation program. METHODS: Twenty-seven patients completed an 8-week nutrition-rehabilitation program. Six minute walk distance (6MWD), body weight, symptom burden, distress, and quality of life were assessed at baseline and at the end of the program. RESULTS: Patients improved their mean 6MWD by 59 m (effect size = 0.8), and 78% of patients either maintained or increased their body weight. They also reported a clinically meaningful reduction in severity of insomnia, pain, weakness, anorexia, shortness of breath, depression and distress, and improvement in quality of life (effect sizes = 0.6-0.9). However, they reported no change in symptom interference with function. CONCLUSION: An interdisciplinary rehabilitation program may be beneficial to patients with head and neck cancer after treatment, but its effects should be evaluated in a controlled trial. PMID- 22422559 TI - Tissue-specific copper accumulation, zinc levels, induction, and purification of metallothionein in freshwater crab Sinopotamon henanense exposed to subacute waterborne copper. AB - Copper (Cu) is one of the most important essential metals for crustaceans, buttoxic in excess. Metallothioneins (MT) are a family of low molecular weight, cysteine-rich, metal-binding proteins, which play important roles in metal homeostasis, detoxification, and cytoprotection. In the present study, Sinopotamon henanense were exposed to 0 (controls), 2.86, and 14.3 mg L(-1) waterborne Cu, Cu accumulation, zinc (Zn) levels and MT induction in gills and hepatopancreas were determined with Cd/Hemoglobin saturation assay and atomic absorption spectrophotometry method. Results showed that Cu accumulation and MT levels were both tissue-specific and revealed some time-dependent and dose dependent, respectively. The highest Cu accumulations of 82.10 +/- 16.38 MUg g( 1) w wt were observed in the gill after 15 days of 14.3 mg L(-1) Cu exposure, the peak MT induction of 136.16 +/- 19.39 MUg g(-1) w wt were observed in the hepatopancreas after 3 day of 14.3 mg L(-1) Cu exposure.In addition, the essential metal homeostasis of Zn was disturbed in some ways by subacute Cu exposure. The calculated ratios of actual Cu to theoretical maximum metal bound by MT indicating that the hepatopancreas had much greater Cu-binding potentials than the gills. Positive correlation were shown between MT induction and Cu accumulation both in hepatopancreas and gills, indicating that MT induction in S. henanense can be considered as a biomarker for subacute waterborne Cu pollution. Furthermore, the Cu induced MT (CuMT) from S. henanense was purified using acetone precipitation (50-80%), followed by gel filtration chromatography and anion exchange chromatography. SDS-PAGE and time-of-flight mass spectrometry analysis showed that S. henanense CuMT possess two isoforms and both mainly existed as monomer and dimmer forms. These present studies will be helpful to increase the database information of heavy metal-induced MT in terms of crustaceans. PMID- 22422560 TI - Anatomic variables contributing to a higher periprocedural incidence of stroke and TIA in carotid artery stenting: single center experience of 833 consecutive cases. AB - OBJECTIVES: This study was conducted to identify patient-related variables that are associated with a higher rate of neurological adverse events during carotid artery stenting (CAS). BACKGROUND: CAS is considered as an alternative treatment for patients with carotid artery stenosis. Despite technical advancements and increase of operator experience, periprocedural neurologic complications cannot completely be prevented. Case selection based on anatomical criteria and other patient characteristics could improve the outcome after CAS. METHODS: Between 2006 and 2009, 833 CAS procedures were performed in 751 consecutive patients under cerebral protection. The influence of patient characteristics, procedural details, and the anatomy of the supraaortic vessels on the incidence of major in hospital adverse events was assessed. RESULTS: Successful CAS was performed in 99.2% of the procedures. The in-hospital death and stroke rate was 2.0% (1 major stroke, 10 minor strokes, and 7 deaths). Octogenarians had a fourfold higher death and stroke rate than patients younger than 80 years old. There was an increased risk of stroke and death in patients with critical aortic stenosis. Presence of a bovine arch, tortous common carotid artery (CCA) and angulated distal internal carotid artery were associated with a higher risk of stroke and transient ischemic attack. A recently developed scoring system for anatomic suitability correlates well with the periprocedural neurological outcome in this case series. CONCLUSIONS: Anatomical conditions and octogenarian age were associated with an increased rate of neurologic adverse events during CAS. Our findings support a newly proposed scoring system for anatomic suitability to identify patients at high risk for CAS. PMID- 22422561 TI - Dialectical behavior therapy in an intensive outpatient program with a mixed diagnostic sample. AB - OBJECTIVES: Intensive outpatient programs (IOPs) have become increasingly common for treating highly distressed patients, and a burgeoning number of IOPs are based on, or informed by, dialectical behavior therapy (DBT). The goal of the present study was to evaluate the effectiveness of DBT in a community mental health center IOP for patients with heterogeneous diagnoses. METHOD: Using a within-subjects design, we examined changes in depression, anxiety, mindfulness, and hope during DBT treatment in a community mental health center in the Midwestern United States. The final sample comprised 56 participants (59% female) ranging in age from 18 to 73 years, with a mean age of 36.8 years (standard deviation = 13.7). The majority of participants (80%) met criteria for a mood disorder, just over half met criteria for an anxiety disorder, and 20% met criteria for comorbid substance abuse or dependence. Over half met criteria for more than one diagnosis. Length of treatment varied based on the needs of the individual patient; treatment ranged from 2 to 16 weeks, with an average stay of 6 weeks. RESULTS: Depression and anxiety scores decreased significantly and hope scores increased significantly over the course of treatment (all p's < .001). Mindfulness scores did not increase significantly, although changes did occur in the predicted direction. In addition, the extent to which hope and mindfulness increased over the course of treatment predicted final depression and anxiety scores after controlling for baseline symptom levels. CONCLUSIONS: Results suggest that this DBT-informed intervention was effective in reducing depression and anxiety and increasing hope. Because of the move away from inpatient hospitalizations over the last few decades, it is incumbent on the field to find alternative ways to treat patients in need of more acute, intensive care. Moreover, these treatments must be cost effective, as many of these patients have limited financial resources. Group therapy formats might provide an appropriate and needed bridge for this coverage gap. The results of this study suggest that a DBT-informed IOP might be an amenable treatment for this population. PMID- 22422562 TI - Testing a model of research intention among U.K. clinical psychologists: a logistic regression analysis. AB - OBJECTIVES: Previous research highlights barriers to clinical psychologists conducting research, but has rarely examined U.K. clinical psychologists. The study investigated U.K. clinical psychologists' self-reported research output and tested part of a theoretical model of factors influencing their intention to conduct research. METHODS: Questionnaires were mailed to 1,300 U.K. clinical psychologists. RESULTS: Three hundred and seventy-four questionnaires were returned (29% response-rate). This study replicated in a U.K. sample the finding that the modal number of publications was zero, highlighted in a number of U.K. and U.S. studies. Research intention was bimodally distributed, and logistic regression classified 78% of cases successfully. Outcome expectations, perceived behavioral control and normative beliefs mediated between research training environment and intention. CONCLUSIONS: Further research should explore how research is negotiated in clinical roles, and this issue should be incorporated into prequalification training. PMID- 22422563 TI - Cognitive processes mediate the relation between mindfulness and social anxiety within a clinical sample. AB - OBJECTIVES: The researchers investigated the relation between mindfulness and social anxiety symptoms, and examined whether this relation is mediated by cognitive appraisals commonly associated with social anxiety. PARTICIPANTS: Ninety-eight individuals diagnosed with social phobia. DESIGN: Using a cross sectional design, ordinary least squares regression and bootstrapping mediation analyses were used to test the study hypotheses. RESULTS: Mindfulness was negatively related to symptoms of social anxiety. This relation was partially mediated by cognitive appraisals about the likelihood and cost of a negative social outcome. CONCLUSION: Further research using a longitudinal design and other measures of mindfulness is needed to replicate these findings and further explicate the mechanism by which mindfulness might be associated with negative cognitive appraisals. PMID- 22422564 TI - Insights into bone metabolism of avian embryos in ovo via 3D and 4D 18F-fluoride positron emission tomography. AB - PURPOSE: The chick embryo is a well-known economical in vivo model system and is widely applied in preclinical research, e.g., bone development studies. It is therefore surprising that no studies concerning the application of (18)F-fluoride microPET to bone metabolism have been reported so far. This may be due to motion artifacts or the lack of convenient tracer injection sites. METHODS: We resolved the above problems using a combination of sample preparation, anesthesia, microPET imaging, and computational processing, and describe a convenient way of visualizing three- and four- dimensional features of bone metabolism in living chick embryos. RESULTS: The application of (18)F-fluoride microPET facilitates repeat measurements, highly reproducible and motion-artifact-free skeletal imaging, and provides quantitative measurements of in ovo metabolic activities in the bones of developing chick. During microPET measurement, radio tracer was injected intravascularly using a custom-made catheter system, allowing us to additionally investigate early time points in tracer kinetics and uptake. CONCLUSIONS: Our results show that bone metabolism in living chick embryos can be reproducibly studied and quantified in ovo, even for multiple tracer injections over a longer time period. The use of dynamic (18)F-fluoride microPET imaging made it possible to visualize and analyze even small bone structures with excellent quality. Moreover, as our data are comparable to data from corresponding rodent experiments, the use of embryonated chicken eggs is a convenient and economical alternative to other animal models. PMID- 22422565 TI - Gemcitabine and vinorelbine chemotherapy for refractory or relapsing aggressive non-Hodgkin lymphoma. PMID- 22422566 TI - Protective effect and potential mechanism of Ginkgo biloba extract EGb 761 on STZ induced neuropathic pain in rats. AB - Diabetes induced neuropathic pain is recognized as one of the most difficult types of pain to treat with conventional analgaesics. EGb 761 is a standardized extract of Ginkgo biloba that has analgaesic and antiinflammatory properties and modulatory effects on key pain-related molecules. We examined the effect of EGb 761 on streptozotocin (STZ)-induced neuropathic pain behaviours and assessed its mechanism of action. Streptozotocin (20 mg/kg i.p for 5 days) was administered to induce experimental diabetes. Pain hypersensitivity to radiant heat was measured using the Dynamic Plantar Aesthesiometer to test the pain threshold. Diabetic rats exhibited mechanical allodynia and thermal hyperanalgaesia after the third week of STZ injection and concomitantly increased thiobarbituric acid reactive substance and nitric oxide concentration. The antioxidant enzymes level of superoxide dismutase and catalase was markedly reduced in STZ-diabetic rats (p < 0.05). Systemic administration of EGb 761 (25, 50 and 100 mg/kg), starting after the third week following STZ injection, dose-dependently reversed STZ-induced thermal hyperanalgaesia and mechanical allodynia. Moreover, it reduced oxidonitrosative stress and concomitantly restored the level of antioxidant enzymes (p < 0.05) as compared with untreated diabetic rats. These results suggest that EGb 761 attenuated STZ-induced neuropathic pain behaviours by inhibiting oxidative and nitrosative stress and may constitute a new approach for treatment of painful diabetic neuropathy. PMID- 22422567 TI - Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: the role of diabetes mellitus. AB - The risk of hepatic fibrosis and cirrhosis in hereditary hemochromatosis relates to the degree of iron loading, but iron alone does not explain the variability in disease penetrance. This study sought to identify clinical cofactors that increase the risk of progressive liver disease. We identified 291 patients from our database who were homozygous for the C282Y mutation in HFE and had undergone a liver biopsy with quantification of hepatic iron concentration (HIC) and fibrosis staging. Data were collected from a retrospective chart review, including age, gender, alcohol consumption, medical therapy, smoking history, metabolic risk factors, mobilizable iron, and laboratory results. Male gender, excess alcohol consumption, HIC, and the presence of diabetes were independently associated with increasing fibrosis stage in multivariate analysis. Of these, the presence of diabetes showed the strongest association (odds ratio, 7.32; P = 0.03). The presence of steatosis was associated with higher fibrosis scores, but this was of borderline statistical significance. Risk factors for hepatic steatosis were male gender, impaired glucose tolerance, and increased body mass index. CONCLUSION: The presence of diabetes was associated with more severe hepatic fibrosis independent of iron loading, male gender, and alcohol consumption. The mechanism for this association is unknown and deserves further evaluation; however, it is possible that diabetes produces an additional hepatic oxidative injury from hyperglycemia. Thus, management of such cofactors in patients with hemochromatosis is important to reduce the risk of liver injury and fibrosis. PMID- 22422568 TI - Fabrication of lipid tubules with embedded quantum dots by membrane tubulation protein. AB - The first one-dimensional (1D) assembly of low-toxicity CuInS(2) /ZnS quantum dots (QDs) embedded in lipid nanotubules, formed from liposomes using the Amphiphysin-BAR (Bin-Amphiphysin-Rvs domain of human amphiphysin) protein to elongate the structure, is reported. The QD-containing lipid nanotubules display a high aspect ratio of ~500:1 (~40 nm diameter and 20 MUm length) and are stable for more than 20 h. Furthermore, this methodology is extended to the assembly of various nanoparticle species within 1D lipid nanotubules, and includes materials such as CdSe and Au. Encapsulation within the hydrophobic core of the bilayer makes these materials highly biocompatible. The developed methodology and materials with these unique characteristics could be useful for various applications in nanobiotechnology and nanomedicine. PMID- 22422570 TI - Human mesenchymal stem cell position within scaffolds influences cell fate during dynamic culture. AB - Cell-based tissue engineering is limited by the size of cell-containing constructs that can be successfully cultured in vitro. This limit is largely a result of the slow diffusion of molecules such as oxygen into the interior of three-dimensional scaffolds in static culture. Bioreactor culture has been shown to overcome these limits. In this study we utilize a tubular perfusion system (TPS) bioreactor for the three-dimensional dynamic culture of human mesenchymal stem cells (hMSCs) in spherical alginate bead scaffolds. The goal of this study is to examine the effect of shear stress in the system and then quantify the proliferation and differentiation of hMSCs in different radial annuli of the scaffold. Shear stress was shown to have a temporal effect on hMSC osteoblastic differentiation with a strong correlation of shear stress, osteopontin, and bone morphogenic protein-2 occurring on day 21, and weaker correlation occurring at early timepoints. Further results revealed an approximate 2.5-fold increase in cell number in the inner annulus of TPS cultured constructs as compared to statically cultured constructs after 21 days. This result demonstrated a nutrient transfer limitation in static culture which can be mitigated by dynamic culture. A significant increase (P < 0.05) in mineralization in the inner and outer annuli of bioreactor cultured 4 mm scaffolds occurred on day 21 with 79 +/- 29% and 53 +/- 25% mineralization area, respectively, compared to 6 +/- 4% and 19 +/- 6% mineralization area, respectively, in inner and outer annuli of 4 mm statically cultured scaffolds. Surprising lower mineralization area was observed in 2 mm bioreactor cultured beads which had the highest levels of proliferation. These results may demonstrate a relationship between scaffold position and stem cell fate. In addition the decreased proliferation and matrix production in statically cultured scaffolds compared to bioreactor cultured constructs demonstrate the need for bioreactor systems and the effectiveness of the TPS bioreactor in promoting hMSC proliferation and differentiation in three-dimensional scaffolds. PMID- 22422572 TI - Inhibition of Candida albicans yeast-hyphal transition and biofilm formation by Solidago virgaurea water extracts. AB - Xerostomia is a decrease of saliva secretion, which can unbalance the oral microflora, mainly to the benefit of Candida albicans. The aim of the present study was to find a plant extract that could create an unfavourable environment for Candida, and would, therefore, be appropriate for use in a dry-mouth daily care mouthwash. Water extract from the herbaceous plant Solidago virgaurea (Goldenrod) was selected due to its saponin content (plant detergents). Saponin concentrations reached 0.7 and 0.95 mg ml(-1) in S. virgaurea subsp. virgaurea and S. virgaurea subsp. alpestris extracts, respectively. C. albicans was grown in liquid medium and cells were counted by microscopic examination after 0, 4 and 24 h of incubation. Solidago extracts did not inhibit the growth of C. albicans (four strains), Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus mutans, Streptococcus salivarius or Enterococcus faecalis. When inocula were incubated with Solidago extract for 4 and 24 h, we observed a decrease in Candida yeast-hyphal transition. Candida biofilms were then prepared in microtitre plates and treated with plant extracts at 0 h, to estimate biofilm formation, or at 18 h to estimate the effect of the saponin on pre-formed biofilms. Biofilm formation and pre-formed biofilms were both strongly inhibited. In conclusion, the S. virgaurea extract was efficient against two key virulence factors of C. albicans: the yeast-hyphal transition phase and biofilm formation. PMID- 22422571 TI - Head and neck squamous cell carcinoma in pregnant women. AB - BACKGROUND: The aim of this study was to investigate oral cancer in pregnant women, a rare but therapeutically challenging patient subset. METHODS: After institutional review board approval, an EMERSE search was used to identify all women treated at the University of Michigan from 1998 to 2010 with head and neck squamous cell carcinoma (HNSCC) during pregnancy. This identified 4 patients with tongue cancer. Biomarkers and human papillomavirus (HPV) were assessed by immunohistochemistry and multiplex PCR/mass spectrometry, respectively. RESULTS: Two patients responded well to therapy and are alive more than 10 years after diagnosis; 2 patients died of disease. All tumors overexpressed EGFR and Bcl-xL, 3 of 4 overexpressed c-Met, both tumors that progressed overexpressed p53. All tumors were negative for HPV, p16, estrogen receptor, progesterone receptor, and HER-2. CONCLUSIONS: Biomarkers of aggressive tumors (high EGFR, c-Met; high Bcl xL-low p53) did not correlate with outcome. Additional studies are needed to determine whether perineural invasion, delay in diagnosis, and p53 overexpression are factors in poor survival. PMID- 22422573 TI - Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo. AB - We investigated the molecular basis of the tolerance of Candida albicans biofilms to antifungals using the miconazole as a model compound, and translated the resulting data to other antifungals. Sessile cells of C. albicans Deltaefg1, lacking the transcription factor Efg1, showed increased susceptibility to miconazole, amphotericin B and caspofungin, whereas these sessile cells were equally resistant to fluconazole. The increased sensitivity to miconazole was, at least, partly due to an increased accumulation of miconazole in the cells as compared to wild-type or reintegrant Deltaefg1(EFG1) sessile cells. By using a rat biofilm model, we further confirmed the role of Efg1 in the tolerance of C. albicans biofilms to miconazole when grown in vivo. PMID- 22422574 TI - Risk factors associated with kanamycin-resistant tuberculosis in a Beijing tuberculosis referral hospital. AB - The rapidly increasing number of multidrug-resistant tuberculosis (MDR-TB) cases worldwide underlines the necessity for the rational use of key second-line drugs such as kanamycin. In this study, we determined the prevalence of, and risk factors associated with, kanamycin-resistant tuberculosis (TB) in 309 Hospital, Beijing, China, with the aim of providing information for better case management in order to minimize further development of extensively drug-resistant TB (XDR TB). Drug susceptibility testing results and clinical data were retrospectively analysed for hospitalized TB patients for whom such data were available in 309 Hospital for the period 1997-2009. Univariate and multivariate analyses were used to determine the risk factors associated with kanamycin-resistant TB. During 1997 2009, 553 (14.4 %) of 3843 tested Mycobacterium tuberculosis isolates from hospitalized TB patients were kanamycin-resistant. The increasing trend of resistance to kanamycin was reversed since 2000. The independent risk factors associated with kanamycin-resistant TB included living in urban areas [adjusted odds ratio (OR) = 1.89], being retreated for repeat cases (adjusted OR = 1.60), being smear-positive for acid-fast bacilli at admission to the hospital (adjusted OR = 1.39), having ofloxacin-resistant (adjusted OR = 1.61) or para aminosalicylic acid-resistant TB (adjusted OR = 1.47), having MDR-TB (adjusted OR = 5.10), having MDR-TB plus ofloxacin resistance (adjusted OR = 4.27) and having poly-resistant TB (adjusted OR = 3.94). The remaining rate of kanamycin resistance is still high despite the reversal of the increasing trend during the past decade. Surveillance of kanamycin resistance, especially among high-risk populations, should be continued to closely monitor trends so that appropriate action can be taken. PMID- 22422575 TI - 1H,89Y HMQC and further NMR spectroscopic and X-ray diffraction investigations on yttrium-containing complexes exhibiting various nuclearities. AB - 2D (1)H,(89)Y heteronuclear shift correlation through scalar coupling has been applied to the chemical-shift determination of a set of yttrium complexes with various nuclearities. This method allowed the determination of (89)Y NMR data in a short period of time. Multinuclear NMR spectroscopy as function of temperature, PGSE NMR-diffusion experiments, heteronuclear NOE measurements, and X-ray crystallography were applied to determine the structures of [Y(5)(OH)(5)(L Val)(4)(Ph(2)acac)(6)] (1) (Ph(2)acac=dibenzoylmethanide, L-Val=L-valine), [Y(2)(OTf)(3)] (3), and [Y(2)(4)(OTf)(5)] (5) (2: [(S)P{N(Me)N=C(H)Py}(3)], 4: [B{N(Me)N=C(H)Py}(4)](-)) in solution and in the solid state. The structures found in the solid state are retained in solution, where averaged structures were observed. NMR diffusion measurements helped us to understand the nuclearity of compounds 3 and 5 in solution. (1)H,(19)F HOESY and (19)F,(19)F EXSY data revealed that the anions are specifically located in particular regions of space, which nicely correlated with the geometries found in the X-ray structures. PMID- 22422576 TI - Dysregulation of the autonomic nervous system and its association with the presence and intensity of chronic widespread pain. AB - OBJECTIVE: To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP. METHODS: Cross-sectional data were obtained from 1,574 subjects (healthy controls as well as persons with depressive and anxiety disorders) participating in The Netherlands Study of Depression and Anxiety. The Chronic Pain Grade was used to assess pain intensity and pain-related disability. Heart rate (HR), SD of the normal-to-normal interval (SDNN), the preejection period (PEP), and respiratory sinus arrhythmia (RSA) were used to assess the ANS. Logistic regression analyses and linear regression analyses were conducted with adjustment for potential confounders. RESULTS: No differences in HR, PEP, SDNN, or RSA values were found between CWP subjects and controls after adjustment for confounders. However, lower SDNN and lower RSA were associated with higher pain intensity in subjects with CWP. CONCLUSION: Lower parasympathetic activity, as assessed with SDNN and RSA, is associated with higher pain intensity in subjects with CWP. This large and well-controlled study does not provide evidence for an association between dysregulation of the ANS and the presence of CWP. PMID- 22422577 TI - Prevalence and echocardiographic features of iatrogenic atrial septal defect after catheter-based mitral valve repair with the MitraClip system. AB - OBJECTIVES: Review the prevalence, echocardiographic features and potential predictors of iatrogenic ASD (iASD) created with the MitraClip guiding catheter. BACKGROUND: Catheter-based repair of mitral regurgitation (MR) with the MitraClip device (Abbott Vascular, Menlo Park, CA), is performed through a 22-French transseptal guiding catheter. The echocardiographic prevalence of iASDs after the MitraClip procedure has not been reported. METHODS: Thirty subjects undergoing MitraClip repair during the roll-in phase of the EVEREST II randomized trial who had baseline, 30 day, 6 and 12 month transthoracic echocardiograms (TTEs) available for review were included. Patients who underwent surgery for MR within the first 12 months were excluded. Residual iASD size, right ventricular (RV) size, left atrial (LA) volume, and tricuspid/MR grade were quantified. RESULTS: iASDs were found at 12 months in 8 patients (27%) with a mean diameter of 6.6 +/- 3.1 mm. Subjects with iASD at 12 months had more residual MR, increased TR and a trend toward larger LA volumes than non-iASD patients. 83% of non-ASD patients were free from MR > 2+ at 12 mos. vs. 38% of those with iASD (p=0.016). There were no other significant associations between clinical and echocardiographic variables and the persistence of iASD. CONCLUSIONS: After MitraClip repair, persistent iASDs occur at a rate comparable to reports after other transseptal interventional procedures and do not appear hemodynamically significant. Patients with persistent iASDs had less MR reduction at 12-months and a trend toward larger LA volumes, suggesting that increased LA pressure may be a mechanism for persistent iASD. PMID- 22422578 TI - CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. AB - The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle invasive (T2-4) tumours. CDKN2A copy number was determined by multiplex ligation dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p < 0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan-Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation. PMID- 22422579 TI - Protection by cilostazol against amyloid-beta(1-40)-induced suppression of viability and neurite elongation through activation of CK2alpha in HT22 mouse hippocampal cells. AB - Amyloid-beta peptide (Abeta) deposits in the brain are critical in the neurotoxicity induced by Abeta. This study elucidates the underlying signaling pathway by which cilostazol protects HT22 neuronal cells from Abeta(1-40) (3-30 MUM)-induced deterioration of cell proliferation, viability, and neurite elongation. Cilostazol rescued HT22 cells from the apoptotic cell death induced by Abeta toxicity through the downregulation of phosphorylated p53 (Ser15), Bax, and caspase-3 and the upregulation of Bcl-2 expression, which improved neuronal cell proliferation and viability. Furthermore, Abeta(1-40) suppressed both phosphorylated CK2alpha protein expression and CK2 activity in the cytosol; these were concentration dependently recovered by cilostazol (3-30 MUM). Cilostazol significantly increased the levels of GSK-3beta phosphorylation at Ser9 and beta catenin phosphorylation at Ser675 in the cytosol and nucleus. Cilostazol effects were reversed by KT5720 (1 MUM, PKA inhibitor) and TBCA (40 MUM, inhibitor of CK2) and CK2alpha knockdown by siRNA transfection. Likewise, Abeta-stimulated GSK 3beta phosphorylation at Tyr 216 was decreased by cilostazol in the control but not in the CK2alpha siRNA-transfected cells. Furthermore, the Abeta (10 MUM) induced suppression of neurite elongation was recovered by cilostazol; this recovery was attenuated by inhibitors such as KT5720 and TBCA and blocked by CK2alpha knockdown. In conclusion, increased cAMP-dependent protein kinase-linked CK2alpha activation underlies the pharmacological effects of cilostazol in downregulating p53 phosphorylation at Ser15 and upregulating GSK-3beta phosphorylation at Ser9/beta-catenin phosphorylation at Ser675, thereby suppressing Abeta(1-40)-induced neurotoxicity and improving neurite elongation. PMID- 22422580 TI - Elevated serum cystatin C in severe OSA younger men without complications. AB - PURPOSE: Serum cystatin C is a promising new biomarker of glomerular filtration rate and cardiovascular events, but few studies focused on serum cystatin C levels in obstructive sleep apnea (OSA) patients. The aim of our study was to evaluate the association between serum cystatin C and OSA in younger men (<=40 years old of age) without complications. METHODS: We prospectively recruited consecutive participants without comorbidities who underwent polysomnography. Fasting blood samples were obtained from all subjects for biological profile measurements. Statistical analysis was used to evaluate the relationship between serum cystatin C and other parameters. RESULTS: The population consisted of 98 subjects (mean age = 32.5 years, mean body mass index = 27.93 kg/m(2)) that were divided according to polysomnographic finding into control group (n = 23), mild (n = 15), moderate (n = 24), and severe (n = 36) OSA group. Compared with the control group, patients with severe OSA were significantly heavier (body mass index, 29.69 +/- 3.81 vs. 26.42 +/- 3.10) and presented significantly higher levels of high sensitive C-reactive protein (hsCRP) (1.10 +/- 0.28 vs. 0.88 +/- 0.20 mg/l) and serum cystatin C (0.87 +/- 0.12 vs. 0.74 +/- 0.10 mg/l) (p < 0.05 for all comparisons). Cystatin C was correlated with Apnea Hypopnea Index (AHI), Oxygen Desaturation Index, hsCRP, creatinine, and estimated glomerular filtration rate (r = 0.319, 0.279, 0.321, 0.233, -0.241, p = 0.001, 0.005, 0.001, 0.021, 0.017, respectively). After adjustment for confounding factors, AHI was significantly and positively associated with serum cystatin C levels (beta = 0.284, p = 0.007). CONCLUSIONS: Our finding indicated that serum cystatin C was associated with the severity of OSA in younger men. Further study is needed to find out whether OSA patients with increased serum cystatin C levels are prone to subclinical cardiovascular and renal diseases. PMID- 22422581 TI - The undisclosed role of disturbed sleep and hypoxia on metabolism: the importance of upper airways pathology. PMID- 22422582 TI - Non-native aggregation of recombinant human granulocyte-colony stimulating factor under simulated process stress conditions. AB - Effective inhibition of protein aggregation is a major goal in biopharmaceutical production processes optimized for product quality. To examine the characteristics of process-stress-dependent aggregation of human granulocyte colony-stimulating factor (G-CSF), we applied controlled stirring and bubble aeration to a recombinant non-glycosylated preparation of the protein produced in Escherichia coli. We characterized the resulting denaturation in a time-resolved manner using probes for G-CSF conformation and size in both solution and the precipitate. G-CSF was precipitated rapidly from solutions that were aerated or stirred; only small amounts of soluble aggregates were found. Exposed hydrophobic surfaces were a characteristic of both soluble and insoluble G-CSF aggregates. Using confocal laser scanning microscopy, the aggregates presented mainly a circular shape. Their size varied according to incubation time and stress applied. The native intramolecular disulfide bonds in the insoluble G-CSF aggregates were largely disrupted as shown by mass spectrometry. New disulfide bonds formed during aggregation. All involved Cys(18) , which is the only free cysteine in G-CSF; one of them had an intermolecular Cys(18(A)) -Cys(18(B)) crosslink. Stabilization strategies can involve external addition of thiols and extensive reduction of surface exposition during processing. PMID- 22422583 TI - Beyond reasonable doubt: who is the culprit in lipotoxicity in NAFLD/NASH? PMID- 22422584 TI - Fed-batch microbioreactor platform for scale down and analysis of a plasmid DNA production process. AB - The rising costs of bioprocess research and development emphasize the need for high-throughput, low-cost alternatives to bench-scale bioreactors for process development. In particular, there is a need for platforms that can go beyond simple batch growth of the organism of interest to include more advanced monitoring, control, and operation schemes such as fed-batch or continuous. We have developed a 1-mL microbioreactor capable of monitoring and control of dissolved oxygen, pH, and temperature. Optical density can also be measured online for continuous monitoring of cell growth. To test our microbioreactor platform, we used production of a plasmid DNA vaccine vector (pVAX1-GFP) in Escherichia coli via a fed-batch temperature-inducible process as a model system. We demonstrated that our platform can accurately predict growth, glycerol and acetate concentrations, as well as plasmid copy number and quality obtained in a bench-scale bioreactor. The predictive abilities of the micro-scale system were robust over a range of feed rates as long as key process parameters, such as dissolved oxygen, were kept constant across scales. We have highlighted plasmid DNA production as a potential application for our microbioreactor, but the device has broad utility for microbial process development in other industries as well. PMID- 22422585 TI - Effect of Sutherlandia frutescens on the lipid metabolism in an insulin resistant rat model and 3T3-L1 adipocytes. AB - High fat diet induced insulin resistance correlates with dyslipidaemia and ectopic fat deposits in skeletal muscle and liver. The effects of Sutherlandia frutescens, an antidiabetic medicinal plant, on lipid metabolism were evaluated in an insulin resistant (IR) rat model and in 3 T3-preadipocytes. Wistar rats received normal diet (ND) or high fat diet (HFD). After the onset of IR in the HFD group, the rats were subdivided into two subgroups, which either continued with HFD or were treated with 50 mg S. frutescens/kg BW/day and HFD (HFD + SF). After 4 weeks, the HFD + SF rats had a significantly lower body weight than the HFD rats (p < 0.05). Blood plasma analysis showed a decrease in insulin, free fatty acids and triglycerides. Related changes in lipid parameters were observed in the liver, skeletal muscle and adipose tissue. To investigate the effects of S. frutescens on adipose tissue, 3 T3-L1 cells were used as a model. Treatment with S. frutescens led to a decrease in triglyceride accumulation, whilst glucose consumption and lactate production were increased (p < 0.05). These results indicate that S. frutescens directly affects mitochondrial activity and lipid biosynthesis in adipose tissue and provide a mechanism by which S. frutescens can restore insulin sensitivity by modulating fatty acid biosynthesis. PMID- 22422586 TI - Tupisteroide A-C, three new polyhydroxylated steroidal constituents from the roots of Tupistra chinensis. AB - Three new steroidal compounds with polyhydroxy groups, tupisteroide A-C (1-3), were obtained from the roots of Tupistra chinensis, together with one known compound (4) that was isolated from this plant for the first time. The structures of tupisteroide A-C were determined on the basis of one- and two-dimensional NMR spectroscopy, including (1) H-(1) H Correlation Spectroscopy, Heteronuclear Multiple Bond Correlation, and Heteronuclear Single Quantum Coherence experiments. The isolated compounds were evaluated for their cytotoxic activities against A549, HepG2, and CaSki cancer cell lines in vitro. Among them, compounds 1, 2, and 4 did not show significant inhibitory activity, but compound 3 showed cytotoxicity against A549 cancer cell lines with IC(50) values of 25.0 MUM. PMID- 22422587 TI - Characterising the myocardial interstitial space: the clinical relevance of non invasive imaging. AB - The myocardial interstitial or extracellular space exists as a complex and dynamic environment, vital for normal cardiac structure and function. The physiological pathways for normal control of collagen turnover, and the pathological development of fibrosis are beginning to be understood, as are their relationships to cardiac remodelling and adverse outcomes. Emerging non-invasive imaging techniques (echocardiography, cardiovascular magnetic resonance, positron emission tomography) may allow a clearer understanding and measurement of these processes in vivo. Preliminary results are exciting, spanning valvular and congenital heart disease, cardiomyopathy and rarer diseases such as amyloid. In this review, such developments and research directions are explored, including the rapid developments in cardiovascular magnetic resonance T1 mapping and its use with contrast to derive extracellular volume. The authors present a state-of the-art assessment of the strengths and weaknesses of each modality, and distil a framework to equip the reader with an understanding of the technical issues useful for the interpretation of emerging clinical studies. PMID- 22422588 TI - Implantable cardioverter defibrillators: risks accompany the life-saving benefits. AB - Sudden cardiac arrest is the one of the most common causes of death in developed countries and accounts for between 180,000 and over 450,000 per year in the USA. Antiarrhythmic drug approaches to prevention of sudden cardiac death have been resoundingly ineffective. The implantable cardioverter defibrillator (ICD) constitutes one of the most important and well validated therapeutic advances in modern cardiovascular medicine. Consequently, ICD use has increased exponentially, although implementation has been quite variable geographically and with respect to other measures. In view of the expanded use of ICDs, the potential shortcomings and risks of ICD therapy have attracted attention. This commentary summarises the weaknesses, disadvantages and risks of the ICD in a balanced fashion in light of their proven life-saving benefits. PMID- 22422589 TI - Long-term outcomes of percutaneous coronary intervention versus coronary artery bypass grafting for unprotected left main coronary bifurcation disease in the drug-eluting stent era. AB - OBJECTIVES: There are limited data on long-term outcomes (i.e., beyond 4 years) for patients with unprotected left main bifurcation disease who underwent percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) in the drug-eluting stent (DES) era. This study therefore compared the treatment effects of PCI and CABG in unprotected left main bifurcation disease. METHODS: 865 patients with unprotected left main bifurcation disease treated with either PCI using DES (n=556) or CABG (n=309) were evaluated between May 2003 and December 2009. PCI-treated patients were further categorised into simple stenting (n=360) or complex stenting (n=196). RESULTS: Median follow-up was 4.2 years (IQR 2.9-5.2 years). After adjusting covariates with multivariate Cox hazard regression model and inverse probability of treatment weighting, the long-term cumulative rates of death (HR 0.95; 95% CI 0.62 to 1.45) or composite of death, Q wave myocardial infarction, or stroke (HR 0.97, 95% CI 0.64 to 1.48) were not significantly different for patients undergoing PCI or CABG except for target vessel revascularisation (TVR) (HR 4.42, 95% CI 2.39 to 8.18). The complex stenting group had similar long-term clinical outcomes compared with the simple stenting group except for TVR (HR 1.94, 95% CI 1.22 to 3.10). In further analysis with propensity score matching, overall findings were consistent. CONCLUSIONS: In patients with unprotected left main bifurcation disease, PCI using DES provides similar long-term (up to 5.2 years) clinical outcomes except for TVR compared with CABG. Complex and simple stenting yielded similar outcomes except for a higher TVR rate in complex stenting. PMID- 22422590 TI - Amiodarone induced interatrial electrical dissociation mimics restored sinus rhythm in patient with persistent left atrial flutter. PMID- 22422591 TI - Plasma asymmetric dimethylarginine and mortality in patients with acute decompensation of chronic heart failure. AB - OBJECTIVES: To investigate the prognostic value of circulating levels of asymmetric dimethylarginine (ADMA) in patients with acute decompensation of (New York Heart Association (NYHA) class III/IV) chronic heart failure and reduced left ventricular ejection fraction. DESIGN: Single-centre prospective observational study. SETTING: Tertiary referral centre. PATIENTS: A total of 651 consecutive and eligible hospitalised patients were studied. Patients were divided into four groups according to the quartiles of circulating levels of ADMA upon presentation. MAIN OUTCOME MEASURES: Incidence of in-hospital (or 7-day in the case of prolonged hospitalisation), 31-day and 1-year cardiac mortality were the pre-specified study end points. RESULTS: Cumulative rates of in-hospital, 31 day and 1-year cardiac mortality were 10.6%, 18.7% and 36.4%, respectively. There was a gradual increased risk of in-hospital (p(for trend)=0.011), 31-day (p(for trend)=0.044) and 1-year (p(for trend)<0.001) mortality with increasing ADMA quartiles. After adjustment for possible confounders, patients at the highest ADMA quartile were at significantly higher risk for in-hospital (p=0.042), 31-day (p=0.032) and 1-year (p<0.001) mortality than those in the lowest quartile. CONCLUSIONS: According to the present results, an elevated circulating level of ADMA is a strong independent predictor of short-term and long-term mortality in patients with acute decompensation of NYHA class III/IV chronic heart failure and reduced left ventricular ejection fraction. ADMA levels upon presentation may confer enhanced risk stratification in this setting. PMID- 22422592 TI - Calcium carbonate-gold nanocluster hybrid spheres: synthesis and versatile application in immunoassays. AB - Fluorescent gold nanoclusters (AuNCs) were incorporated into porous calcium carbonate spheres through electrostatic interaction. The resulting CaCO(3)/AuNCs hybrid material exhibited interesting properties, such as porous structure, excellent biocompatibility, good water solubility, and degradability. These properties make the CaCO(3)/AuNCs hybrid material a promising template to assemble horseradish peroxidase/antibody conjugates (HRP-Ab(2)). By using CaCO(3)/AuNCs/HRP-Ab(2) bioconjugates as probes, a versatile immunosensor was developed for fluorescent and electrochemical detection of the cancer biomarker neuron-specific enolase (NSE). The detection limits of the sensor were 2.0 and 0.1 pg mL(-1) for fluorescent and electrochemical detection, respectively. The immunosensor shows high sensitivity and offers an alternative strategy for the detection of other proteins and DNA. PMID- 22422593 TI - Current treatments of isolated articular cartilage lesions of the knee achieve similar outcomes. AB - BACKGROUND: Many surgical techniques, including microfracture, periosteal and perichondral grafts, chondrocyte transplantation, and osteochondral grafts, have been studied in an attempt to restore damaged articular cartilage. However, there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee. QUESTIONS/PURPOSES: We compared postoperative functional outcomes, followup MRI appearance, and arthroscopic examination after microfracture (MF), osteochondral autograft transplantation (OAT), or autologous chondrocyte implantation (ACI). METHODS: We prospectively investigated 30 knees with MF, 22 with OAT, and 18 with ACI. Minimum followup was 3 years (mean, 5 years; range, 3-10 years). We included only patients with isolated cartilage defects and without other knee injuries. The three procedures were compared in terms of function using the Lysholm knee evaluation scale, Tegner activity scale, and Hospital for Special Surgery (HSS) score; modified Outerbridge cartilage grades using MRI; and International Cartilage Repair Society (ICRS) repair grade using arthroscopy. RESULTS: All three procedures showed improvement in functional scores. There were no differences in functional scores and postoperative MRI grades among the groups. Arthroscopy at 1 year showed excellent or good results in 80% after MF, 82% after OAT, and 80% after ACI. Our study did not show a clear benefit of either ACI or OAT over MF. CONCLUSIONS: Owing to a lack of superiority of any one treatment, we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22422594 TI - Cardiac valve replacement in patients with antiphospholipid syndrome. AB - OBJECTIVE: To analyze the results of cardiac valve replacement in a multicenter cohort of patients with antiphospholipid syndrome (APS) and to identify prognostic factors of poor outcome. METHODS: We performed a retrospective analysis of clinical manifestations (cardiac involvement and APS characteristics), operative and early postoperative courses, and long-term followup. All of the patients fulfilled the Sapporo criteria for APS. Logistic regression analyses were performed to identify those variables associated with adverse outcomes. RESULTS: Between 1981 and 2008, 33 valvular replacements were carried out in 32 patients with APS. The mean +/- SD age at the time of surgery was 43.09 +/- 14.08 years. Thirty patients were women. Primary APS was present in 21 patients. The median followup time after surgery was 33.5 months (range 0-192 months). The mitral valve was the most frequently replaced (22 of 33). Mechanical valve replacement was performed in 23 patients (71.9%). The mortality rate was 12.5% (1 cardiogenic shock, 1 septic shock, 1 following renal transplantation, and 1 hemorrhagic stroke). Fourteen patients experienced 20 complications (8 major bleeding, 5 thrombotic events, 2 valvular deteriorations, 2 third-degree atrioventricular block, 1 endocarditis, 1 cardiac tamponade, and 1 cardiac failure). Fifty percent of the patients had an uneventful outcome. CONCLUSION: Morbidity and mortality were high in APS patients undergoing valve replacement surgery. Most complications were related to thrombosis and bleeding. Anticoagulation must be carefully monitored to prevent hemorrhagic and thrombotic complications. PMID- 22422595 TI - Amplatzer vascular plug for transcatheter closure of persistent unligated vertical vein after repair of infracardiac total anomalous pulmonary venous connection. AB - Repair of total anomalous pulmonary venous connection (TAPVC) involves anastomosing the pulmonary venous confluence with the left atrium and ligating the vertical vein. Sometimes, the vertical vein needs to be left open as a pop off with the idea that it will close over time. Infrequently an unligated vertical vein may remain patent after repair of infaracardiac TAPVC leading to hemodynamic instability. We report an infant in whom an unligated vertical vein remained patent after the repair of infracardiac TAPVC and caused hemodynamically significant left-to-right shunting. A successful transcatheter closure of persistent patent unligated vertical vein was performed using the Amplatzer Vascular Plug-I device. PMID- 22422596 TI - Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation. AB - To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.02-0.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX 93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentration-time curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt. PMID- 22422597 TI - Jugular and vagal paragangliomas: Systematic study of management with surgery and radiotherapy. AB - BACKGROUND: The definitive treatment for head and neck paraganglioma (PG) is surgical excision. Unfortunately, surgery, particularly of vagal paraganglioma (VPG; "glomus vagale") and foramen jugulare ("glomus jugulare") tumors, may be complicated by injuries to the lower cranial nerves, a high price to pay for treatment for a benign tumor. Alternatively these tumors may be followed without treatment, or irradiated. The purpose of this review was to compare the existing evidence concerning the efficacy and safety of surgery, external beam radiotherapy (EBRT), and stereotactic radiosurgery (SRS), for jugular paragangliomas (JPGs) and VPGs. METHODS: Relevant articles were reviewed using strict criteria for systematic searches. Forty-one surgical studies met the criteria which included 1310 patients. Twenty articles including 461 patients treated with EBRT, and 14 radiosurgery studies comprising 261 patients were also evaluated. Results were compared between treatment modalities using analysis of variance (ANOVA) tests. RESULTS: A total of 1084 patients with JPGs and 226 VPGs were treated with different surgical procedures. Long-term control of the disease was achieved in 78.2% and 93.3% of patients, respectively. A total of 715 patients with JPG were treated with radiotherapy: 461 with EBRT and 254 with SRS. Control of the disease with both methods was obtained in 89.1% and 93.7% of the patients, respectively. The treatment outcomes of a JPG treated with surgery or radiotherapy were compared. Tumor control failure, major complication rates, and the number of cranial nerve palsies after treatment were significantly higher in surgical than in radiotherapy series. The results of SRS and EBRT in JPGs were compared and no significant differences were observed in tumor control. Because only 1 article reported on the treatment of 10 VPGs with radiotherapy, no comparisons with surgery could be made. Nevertheless, the vagus nerve was functionally preserved in only 11 of 254 surgically treated patients (4.3%). CONCLUSION: There is evidence that EBRT and SRS offer a similar chance of tumor control with lower risks of morbidity compared with surgery in patients with JPGs. Although the evidence is based on retrospective studies, these results suggest that surgery should be considered only for selected cases, but the decision should be individual for every patient. PMID- 22422598 TI - Diffusion-based extraction of DMSO from a cell suspension in a three stream, vertical microchannel. AB - Cells are routinely cryopreserved for investigative and therapeutic applications. The most common cryoprotective agent (CPA), dimethyl sulfoxide (DMSO), is toxic, and must be removed before cells can be used. This study uses a microfluidic device in which three streams flow vertically in parallel through a rectangular channel 500 um in depth. Two wash streams flow on either side of a DMSO-laden cell stream, allowing DMSO to diffuse into the wash and be removed, and the washed sample to be collected. The ability of the device to extract DMSO from a cell stream was investigated for sample flow rates from 0.5 to 4.0 mL/min (Pe = 1,263-10,100). Recovery of cells from the device was investigated using Jurkat cells (lymphoblasts) in suspensions ranging from 0.5% to 15% cells by volume. Cell recovery was >95% for all conditions investigated, while DMSO removal comparable to a previously developed two-stream device was achieved in either one quarter the device length, or at four times the flow rate. The high cell recovery is a ~25% improvement over standard cell washing techniques, and high flow rates achieved are uncommon among microfluidic devices, allowing for processing of clinically relevant cell populations. PMID- 22422599 TI - Spontaneous firing and evoked responses of spinal nociceptive neurons are attenuated by blockade of P2X3 and P2X2/3 receptors in inflamed rats. AB - P2X3 and P2X2/3 receptors are selectively expressed on primary afferent nociceptors and have been implicated in modulating nociception in different models of pathological pain, including inflammatory pain. In an effort to delineate further the role of P2X3 receptors (homomeric and heteromeric) in the modulation of nociceptive transmission after a chronic inflammation injury, A 317491, a potent and selective P2X3-P2X2/3 antagonist, was administered to CFA inflamed rats in order to examine its effects on responses of spinal dorsal horn neurons to mechanical and thermal stimulation. Systemic injection of A-317491 (30 MUmol/kg, i.v.) reduced the responses of wide-dynamic-range (WDR) and nociceptive specific (NS) neurons to both high-intensity mechanical (pinch) and heat (49 degrees C) stimulation. A-317491 also decreased low-intensity (10 g von Frey hair) mechanically evoked activity of WDR neurons but did not alter WDR neuronal responses to cold stimulation (5 degrees C). Spontaneous firing of WDR neurons in CFA-inflamed rats was also significantly attenuated by A-317491 injection. By using immunohistochemistry, P2X3 receptors were demonstrated to be enhanced in lamina II of the spinal dorsal horn after inflammation. In summary, blockade of P2X3 and P2X2/3 receptors dampens mechanical- and heat-related signaling, as well as nonevoked activity of key classes of spinal nociceptive neurons in inflamed animals. These data suggest that P2X3 and/or P2X2/3 receptors have a broad contribution to somatosensory/nociceptive transmission in rats with a chronic inflammatory injury and are consistent with previous behavioral data demonstrating antiallodynic and antihyperalgesic effects of receptor antagonists. PMID- 22422600 TI - Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs. AB - The effectiveness of human bone marrow mesenchymal stem cell (hBMSC) transplantation to treat acute and chronic liver injury has been demonstrated in animal models and in a few nonrandomized clinical trials. However, no studies have investigated hBMSC transplantation in the treatment of fulminant hepatic failure (FHF), especially in large animal (pig) models. The aim of this study was to demonstrate the safety, effectiveness, and underlying mechanism of hBMSC transplantation for treating FHF in pigs through the intraportal route. Human BMSCs (3 * 10(7) ) were transplanted into pigs with FHF via the intraportal route or peripheral vein immediately after D-galactosamine injection, and a sham group underwent intraportal transplantation (IPT) without cells (IPT, peripheral vein transplantation [PVT], and control groups, respectively, n = 15 per group). All of the animals in the PVT and control groups died of FHF within 96 hours. In contrast, 13 of 15 animals in the IPT group achieved long-term survival (>6 months). Immunohistochemistry demonstrated that transplanted hBMSC-derived hepatocytes in surviving animals were widely distributed in the hepatic lobules and the liver parenchyma from weeks 2 to 10. Thirty percent of the hepatocytes were hBMSC-derived. However, the number of transplanted cells decreased significantly at week 15. Only a few single cells were scattered in the regenerated liver lobules at week 20, and the liver tissues exhibited a nearly normal structure. CONCLUSION: Immediate IPT of hBMSCs is a safe and effective treatment for FHF. The transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation into hepatocytes during the initial stage of FHF. This method can possibly be used in future clinical therapy. PMID- 22422601 TI - A protein-stabilizing technology for enhanced antibody stability and antibody binding profiles in a microchip array. AB - The stability of therapeutic antibodies during downstream processing and storage is important for functionality and quality. To determine functional antibody performance, the UNIchip(r) high-density protein microarray with 384 recombinant antigenic targets was developed; this allows characterization of antibody specificity by generating standardized quantitative binding profiles. In this study, we used UNIchip(r) to test the efficacy of a novel protein stabilizing and protecting solution (SPS) to preserve the binding specificity and binding strength of a therapeutic anti-TNF-alpha antibody (Adalimumab; Humira). Our results show that reconstituted SPS-formulated and lyophilized Adalimumab elicits significantly less off-target activity after reconstitution and preserves binding strength even after six weeks of storage at 40 degrees C compared with Adalimumab that underwent the same treatment with the original formulation. By means of UNIchip(r) , we were able to confirm the protein stabilizing effects of SPS as shown by preserved antibody functionality. PMID- 22422602 TI - Transferring 'graduates' from adult to older adult mental health services - a comparison of two services in the Midlands. PMID- 22422603 TI - Activity in older people with and without a major depressive disorder. PMID- 22422604 TI - A case of primary progressive aphasia associated with depression. PMID- 22422605 TI - Antibacterial and antimycobacterial lignans and flavonoids from Larrea tridentata. AB - Three lignans and four flavonoids were isolated and characterized from Larrea tridentata and compounds were tested against 16 bacterial species/strains. Results showed that: dihydroguaiaretic acid (1) had activity towards methicillin resistant (MR) Staphylococcus aureus (minimum inhibitory concentration (MIC) 50 ug/mL) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MIC 12.5-50 ug/mL); 4-epi-larreatricin (2) was active against Enterobacter cloacae (MIC 12.5 ug/mL), as well as sensitive (MIC 50 ug/mL) and MDR strains of M. tuberculosis (MIC 25 ug/mL). 3'-Demethoxy-6-O-demethylisoguaiacin (3) displayed activity against sensitive and resistant S. aureus (MIC 25 ug/mL), Enterococcus faecalis (MIC 12.5 ug/mL), Escherichia coli (MIC 50 ug/mL), E. cloacae (MIC 12.5 ug/mL) and MDR strains of M. tuberculosis (MIC 12.5 ug/mL). 5,4'-Dihydroxy 3,7,8,3'-tetramethoxyflavone (4) and 5,4'-dihydroxy-3,7,8-trimethoxyflavone (5) were active against M. tuberculosis MDR strains having MIC values of 25 and 25-50 ug/mL, respectively, while 5,4'-dihydroxy-7-methoxyflavone (6) was active against S. aureus (MIC 50 ug/mL) and E. faecalis (MIC 50 ug/mL). We concluded that lignan 3 is the main compound responsible for the antibacterial activity of L. tridentata. Lignans 1 and 2 as well as flavonoid 6 contribute with some degree of antibacterial activity. On the other hand, compounds 1, 2, 3, 4 and 5 contributed to the antimycobacterial activity found in L. tridentata. PMID- 22422606 TI - Remarkable sensitivity of the electrochemical reduction of benzophenone to proton availability in ionic liquids. AB - The reduction of benzophenone was investigated in five different ionic liquids by using transient cyclic voltammetry, near steady-state voltammetry, and numerical simulation. Two reversible, well-resolved one-electron-reduction processes were observed in dry (<=20 ppm water, ca. 1 mM)) 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([Bmpyrd][NTf(2)]) and 1-butyl-1 methylpiperidinium bis(trifluoromethylsulfonyl)imide ([Bmpipd][NTf(2)]), which did not contain any readily available proton source. Upon addition of water, the second process became chemically irreversible and shifted to a more positive potential by approximately 600 mV; moreover, the two reduction processes merged into a single two-electron proton-coupled process when about 0.6 M H(2)O was present. This large dependence of potential on water content, which was not observed in molecular solvents (electrolyte), was explained by a reaction mechanism that incorporated protonation and hydrogen-bonding interactions of the benzophenone dianion with as many as seven water molecules. In the three imidazolium-based ionic liquids used herein, the first benzophenone-reduction process was again reversible, whilst the second reduction process became chemically irreversible owing to the availability of the C2-H imidazolium protons in these ionic liquids. The reversible potentials for benzophenone reduction were remarkably independent of the identity of the ionic liquids, thereby implying either weak interactions with the ionic liquids or relatively insignificant differences in the levels of ion-pairing. Thus, the magnitude of the separation of the potentials of the reversible first and irreversible second reduction processes mainly reflected the proton availability from either the ionic liquid itself or from adventitious water. Consequently, voltammetric reduction of benzophenone provides a sensitive tool for the determination of proton availability in ionic liquids. PMID- 22422607 TI - A multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in bifurcation lesions treated with a single-stenting technique: six-month angiographic and 12-month clinical results of the drug-eluting balloon in bifurcations trial. AB - BACKGROUND: Percutaneous treatment of coronary bifurcation lesions remains hampered by suboptimal results, mainly in the side branch (SB), even with the use of drug-eluting stents (DES). Paclitaxel drug-eluting balloons (DEB) could provide an attractive alternative to treat bifurcations in combination with a provisional T-stenting technique in order to minimize SB restenosis. We compared angiographic and clinical outcomes of a provisional T-stenting technique with a DEB plus bare-metal stent (BMS) versus BMS versus paclitaxel DES. METHODS: In this randomized, international, multicenter, single-blinded 3-arm study, 117 patients with coronary bifurcation lesions underwent treatment with: (A) DEB in both main branch (MB) and SB and BMS in MB; (B) BMS in MB and regular balloon angioplasty in SB; or (C) paclitaxel DES in MB and regular balloon in SB. All patients underwent provisional T-stenting with an identical stent platform in the MB. Paclitaxel was the drug for elution in groups A and C. The primary endpoint was 6-month angiographic late luminal loss. Secondary end points were 6-month binary restenosis and 12-month major adverse cardiac events (MACE: death, myocardial infarction, target vessel revascularization). RESULTS: The procedure was successful in all cases. Late luminal loss, measured respectively in the proximal MB, distal MB and SB was 0.58 +/- 0.65, 0.41 +/- 0.60, and 0.19 +/- 0.66 mm in group A; 0.60 +/- 0.65, 0.49 +/- 0.85, and 0.21 +/- 0.57 mm in group B; and 0.13 +/- 0.45, 0.19 +/- 0.64, and 0.11 +/- 0.43 mm in group C (P = 0.001). Binary restenosis rates per bifurcation and MACE rates were 24.2%, 28.6%, and 15% (P = 0.45) and 20%, 29.7%, and 17.5% (P = 0.40) in groups A, B, and C, respectively. CONCLUSIONS: Pretreatment of both MB and SB with DEB failed to show angiographic and clinical superiority over conventional BMS, using a provisional T-stenting technique. Moreover DES showed superior angiographic results than DEB and BMS. PMID- 22422608 TI - Ginkgolide B reduces neuronal cell apoptosis in the traumatic rat brain: possible involvement of toll-like receptor 4 and nuclear factor kappa B pathway. AB - Ginkgolide B (GB) has been demonstrated to have a variety of pharmacological actions. Accumulating evidence indicates that GB may exert a protective effect on brain injury. The study was designed to investigate the influence of GB on toll like receptor 4 (TLR-4) and nuclear factor kappaB (NF-kappaB)-dependent inflammatory responses and neuronal cell apoptosis after traumatic brain injury (TBI). Wistar rats were subjected to 5, 10 and 20 mg/kg GB daily for 5 days, intraperitoneally, following TBI. Rats were sacrificed at hour 2, 6 and 12, as well as day 1, 2, 3 and 5 after TBI. The administration of 10 and 20 mg/kg GB could significantly (least-significant difference test: p < 0.05) suppress gene expressions of TLR-4 and NF-kappaB, lessen concentrations of tumour necrosis factor alpha, interleukin-1beta and interleukin-6, as well as reduce the number of apoptotic neuronal cells in traumatic rat brain tissues, but the administration of 5 mg/kg GB did not (p > 0.05). However, a clear concentration response relationship was not found. Thus, GB may inhibit TLR-4 and NF-kappaB dependent inflammatory responses, and furthermore lessen neuronal cell apoptosis after TBI, which may support the use of GB for the treatment of TBI. PMID- 22422609 TI - Temperature-dependent formation and transformation of mesostructures in water ionic liquid mixtures. AB - The temperature-dependent formation and transformation of mesostructures in binary mixtures of the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim(+)][BF(4)(-)]) and water are characterized. Through addition of nitroxide radicals as paramagnetic spin probes, the temperature dependence of the solution structure can be assessed by using electron paramagnetic resonance (EPR) spectroscopy from typical solutes' points of view. Additionally, the phase behavior on cooling and reheating is probed by differential scanning calorimetry (DSC). Thermal hysteresis and memory effects are observed, and DSC is used to identify the crystallization and thawing of ice as the pertinent phase transition. The EPR data of the nitroxide radicals before and after freezing and thawing reveal a transformation of the mesostructures, probably triggered by the crystallization of water pools to ice. A more polar state results after thawing, thereby suggesting a rupture and dissolution of the ordered IL-rich mesostructures. If the thawed solutions are not agitated, the system relaxes very slowly, that is, at room temperature with a time constant of approximately 90 h, to its equilibrium state of mesophase-separated IL-rich and bulk-like water regions. PMID- 22422610 TI - Overexpression of the nuclear factor-kappa B (p65) in association with local failure in patients with head and neck carcinoma undergong radiotherapy or chemoradiotherapy. AB - BACKGROUND: The aim of this study was to evaluate nuclear factor-kappa B (NF kappaB) expression as a biologic marker to predict local control in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy or chemoradiotherapy. METHODS: The mRNA expression levels of the NF-kappaB family genes were determined with real-time-polymerase chain reaction in 77 patients with HNSCC treated with radiotherapy or chemoradiotherapy. RESULTS: The mRNA NF kappaB (p65) expression in pretreatment tumors was significantly related to local control (p = .03). The 5-year local recurrence-free survival rate in patients with low-level NF-kappaB (p65) expression (n = 42) was 79.9%, and in patients with a high level of expression it was 42.1% (p = .001). In a multivariate analysis, the mRNA NF-kappaB (p65) expression level was the only variable related to local control of the tumor. CONCLUSION: Expression of the NF-kappaB (p65) gene may be a radiosensitivity marker for patients with a HNSCC. PMID- 22422611 TI - Non-enzymatic palladium recovery on microbial and synthetic surfaces. AB - The use of microorganisms as support for reduction of dissolved Pd(II) to immobilized Pd(0) nanoparticles is an environmentally friendly approach for Pd recovery from waste. To better understand and engineer Pd(0) nanoparticle synthesis, one has to consider the mechanisms by which Pd(II) is reduced on microbial surfaces. Escherichia coli, Shewanella oneidensis, and Pseudomonas putida were used as model organisms in order to elucidate the role of microbial cells in Pd(II) reduction under acidic conditions. Pd(II) was reduced by formate under acidic conditions, and the process occurred substantially faster in the presence of cells as compared to cell-free controls. We found no difference between native (untreated) and autoclaved cells, and could demonstrate that even a non-enzymatic protein (bovine serum albumin) stimulated Pd(II) reduction as efficiently as bacterial cells. Amine groups readily interact with Pd(II), and to specifically test their role in surface-assisted Pd(II) reduction by formate, we replaced bacterial cells with polystyrene microparticles functionalized with amine or carboxyl groups. Amine-functionalized microparticles had the same effect on Pd(II) reduction as bacterial cells, and the effect could be hampered if the amine groups were blocked by acetylation. The interaction with amine groups was confirmed by infrared spectroscopy on whole cells and amine-functionalized microparticles. In conclusion, bio-supported Pd(II) reduction on microbial surfaces is possibly mediated by a non-enzymatic mechanism. We therefore suggest the use of amine-rich biomaterials rather than intact cells for Pd bio-recovery from waste. PMID- 22422612 TI - Neural correlates of cognitive ability. AB - The challenge to neuroscientists working on intelligence is to discover what neural structures and mechanisms are at the basis of such a complex and variegated capability. Several psychologists agree on the view that behavioral flexibility is a good measure of intelligence, resulting in the appearance of novel solutions that are not part of the animal's normal behavior. This article tries to indicate how the supposed differences in intelligence between species can be related to brain properties and suggests that the best neural indicators may be the ones that convey more information processing capacity to the brain, i.e., high conduction velocity of fibers and small distances between neurons, associated with a high number of neurons and an adequate level of connectivity. The neural bases of human intelligence have been investigated by means of anatomical, neurophysiological, and neuropsychological methods. These investigations have led to two important findings that are briefly discussed: the parietofrontal integration theory of intelligence, which assumes that a distributed network of cortical areas having its main nodes in the frontal and parietal lobes constitutes a probable substrate for smart behavior, and the neural efficiency hypothesis, according to which intelligent people process information more efficiently, showing weaker neural activations in a smaller number of areas than less intelligent people. PMID- 22422613 TI - Nonspecific predictors of weight gain in the early stages of outpatient cognitive behavioral therapy for adults with anorexia nervosa: Replication and extension. AB - OBJECTIVE: This study extends previous work, examining psychological factors that influence the level of weight gain across the first 20 sessions of cognitive behavioral therapy (CBT) for anorexia nervosa. METHOD: Thirty-two patients with anorexia nervosa (mean body mass index (BMI) = 16.0; SD = 1.11) completed measures of eating attitudes and comorbid axis 1 pathology at the outset of CBT, and their weight gain was measured at the 6th and 20th sessions of the therapy. RESULTS: Unhealthy eating attitudes at the start of therapy were associated with slower weight gain across the first 20 sessions of CBT. In contrast, higher levels of pretreatment axis 1 pathology were associated with slower weight gain only after the 6th session. The axis 1 features that moderated weight gain over 20 sessions of CBT were broader than those that had previously been shown to predict weight gain over the first 10 CBT sessions. DISCUSSION: During CBT for anorexia nervosa, weight gain might be enhanced by addressing a range of aspects of axis 1 pathology (e.g., depression, hostility, and features of anxiety). However, the approach is likely to be less important at first than directly addressing eating pathology and overvalued ideas about eating, shape, and weight. PMID- 22422614 TI - Association of metals and proteasome activity in erythrocytes of prostate cancer patients and controls. AB - Information is lacking on the effects toxic environmental metals may have on the 26S proteasome. The proteasome is a primary vehicle for selective degradation of damaged proteins in a cell and due to its role in cell proliferation, inhibition of the proteasome has become a target for cancer therapy. Metals are essential to the proteasome's normal function and have been used within proteasome-inhibiting complexes for cancer therapy. This study evaluated the association of erythrocyte metal levels and proteasome chymotrypsin-like (CT-like) activity in age- and race matched prostate cancer cases (n=61) and controls (n=61). Erythrocyte metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). CT-like activity was measured by proteasome activity assay using a fluorogenic peptide substrate. Among cases, significant correlations between individual toxic metals were observed (r(arsenic-cadmium)=0.49, p<0.001; r(arsenic-lead)=0.26, p=0.04, r(cadmium-lead) 0.53, p<0.001), but there were no significant associations between metals and CT-like activity. In contrast, within controls there were no significant associations between metals, however, copper and lead levels were significantly associated with CT-like activity. The associations between copper and lead and proteasome activity (r(copper-CT-like)=-0.28, p=0.002 ; r(lead-CT like)=0.23, p=0.011) remained significant in multivariable models that included all of the metals. These findings suggest that biologically essential metals and toxic metals may affect proteasome activity in healthy controls and, further, show that prostate cancer cases and controls differ in associations between metals and proteasome activity in erythrocytes. More research on toxic metals and the proteasome in prostate cancer is warranted. PMID- 22422615 TI - Examining carer stress in dementia: the role of subtype diagnosis and neuropsychiatric symptoms. AB - INTRODUCTION: Caring for people with dementia incurs significant stress for carers. Stress has been related to the duration of caring role, the number of weekly hours provided and severity of cognitive impairment. What remains less clear is the impact of neuropsychiatric symptoms and subtype of dementia on carer stress and this study aimed to examine these. METHODS: Dementia carers were recruited for people with a range of dementia subtypes. Carers were interviewed using the Neuropsychiatric Inventory with the Carer Distress Scale. Cognitive fluctuations were assessed using the Dementia Cognitive Fluctuations Scale. All patients were also examined with The Cambridge Assessment for mental disorders in the elderly. RESULTS: Dementia diagnostic subtype, the presence of cognitive fluctuations and some neuropsychiatric symptoms (psychosis and mood disturbance) did predict carer stress (all at p < 0.01) but age, gender and severity of cognitive impairment did not (all p > 0.33). Carers of people with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) experienced more stress than those caring for patients with Alzheimer's disease and vascular dementia. Carer stress was associated with higher levels of psychosis, mood disturbances, daytime sleep and cognitive fluctuations in the person with dementia. CONCLUSIONS: This study identified the significant impact on carers of providing care for people with DLB and PDD dementia subtypes and also highlighted the significant impact of providing care for patients with high levels of psychosis, mood disturbances and cognitive fluctuations. PMID- 22422616 TI - Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. AB - OBJECTIVE: To investigate the association of anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy with HLA class I and II antigens. METHODS: HLA antigens were determined in 1) 20 white and 8 African American anti-HMGCR patients, 2) 487 white and 167 African American controls, and 3) 51 white subjects with mild self-limited statin intolerance. RESULTS: White anti-HMGCR patients had a higher frequency of the combination HLA-DR11, DQA5, and DQB7 than controls or statin-intolerant subjects (70% versus 17%; odds ratio [OR] 11.7 [95% confidence interval (95% CI) 4.0-35.3], P = 4.1 * 10(-7) and 70% versus 21%; OR 8.3 [95% CI 2.2-33.9], P = 5.4 * 10(-4) , respectively). This combination was not increased in African American anti-HMGCR subjects compared to controls (13% versus 3%; OR 4.6 [95% CI 0.2-53.3], P = 0.2). However, DR11 was increased in African American anti-HMGCR patients compared to controls (88% versus 21%; OR 26.4 [95% CI 3.1-590.3], P = 0.0002). High-resolution mapping showed that 95% with DR11 had DRB1*11:01. DQA1 and DQB6 were less frequent in white anti-HMGCR positive patients compared to controls (25% versus 65%; OR 0.2 [95% CI 0.1-0.5], P = 5.5 * 10(-4) and 0% versus 45%; OR 0.0 [95% CI 0.0-0.3], P = 2.1 * 10(-5) , respectively). DRB11 was not associated with particular disease features. CONCLUSION: DRB1*11:01 is associated with an increased risk of anti-HMGCR myopathy in whites and African Americans. These findings suggest a mechanistic link between statin exposure, increased HMGCR expression, and the possible presentation of HMGCR-derived peptide(s) by DRB1*11:01. PMID- 22422617 TI - Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells. AB - The pro-fibrotic connective tissue growth factor (CTGF) has been linked to the development and progression of diabetic vascular and renal disease. We recently reported that low-density lipoproteins (LDL) induced expression of CTGF in aortic endothelial cells. However, the molecular mechanisms are not fully defined. Here, we have studied the mechanism by which LDL regulates CTGF expression in renal mesangial cells. In these cells, treatment with pertussis toxin abolished LDL stimulated activation of ERK1/2 and c-Jun N-terminal kinase (JNK), indicating the involvement of heterotrimeric G proteins in LDL signaling. Treatment with LDL promoted activation and translocation of endogenous sphingosine kinase 1 (SK1) from the cytosol to the plasma membrane concomitant with production of sphingosine-1-phosphate (S1P). Pretreating cells with SK inhibitor, dimethylsphinogsine or down-regulation of SK1 and SK2 revealed that LDL-dependent activation of ERK1/2 and JNK is mediated by SK1. Using a green fluorescent protein-tagged S1P1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that LDL induced S1P receptor activation. Pretreating cells with S1P1/S1P3 receptor antagonist VPC23019 significantly inhibited activation of ERK1/2 and JNK by LDL, suggesting that LDL elicits G protein-dependent activation of ERK1/2 and JNK by stimulating SK1 dependent transactivation of S1P receptors. Furthermore, S1P stimulation induced expression of CTGF in a dose-dependent manner that was markedly inhibited by blocking the ERK1/2 and JNK signaling pathways. LDL-induced CTGF expression was pertussis toxin sensitive and inhibited by dimethylsphinogsine down-regulation of SK1 and VPC23019 treatment. Our data suggest that SK1-dependent S1P receptor transactivation is upstream of ERK1/2 and JNK and that all three steps are required for LDL-regulated expression of CTGF in mesangial cells. PMID- 22422618 TI - Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis. AB - Runx2, a runt-related transcriptional factor family member, is involved in the regulation of osteoblast differentiation. Interestingly, it is abundant in growth arrested 3T3-L1 preadipocytes and was dramatically down-regulated during adipocyte differentiation. Knockdown of Runx2 expression promoted 3T3-L1 adipocyte differentiation, whereas overexpression inhibited adipocyte differentiation and promoted the trans-differentiation of 3T3-L1 preadipocytes to bone cells. Runx2 was down-regulated specifically by dexamethasone (DEX). Only type I Runx2 was expressed in 3T3-L1 preadipocytes. Using luciferase assay and chromatin immunoprecipitation-quantitative PCR analysis, it was found that DEX repressed this type of Runx2 at the transcriptional level through direct binding of the glucocorticoid receptor (GR) to a GR-binding element in the Runx2 P2 promoter. Further studies indicated that GR recruited histone deacetylase 1 to the Runx2 P2 promoter which then mediated the deacetylation of histone H4 and down-regulated Runx2 expression. Runx2 might play its repressive role through the induction of p27 expression, which blocked 3T3-L1 adipocyte differentiation by inhibiting mitotic clonal expansion. Taken together, we identified Runx2 as a new downstream target of DEX and explored a new pathway between DEX, Runx2, and p27 which contributed to the mechanism of the 3T3-L1 adipocyte differentiation. PMID- 22422619 TI - Palladium-catalyzed intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides. AB - Give me a ring? An efficient approach has been developed for the intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides catalyzed by palladium (see scheme). From a synthetic viewpoint, this method is highly attractive because the catalyst loading is low, the optimized reaction conditions are mild, and the substrate scope is broad. PMID- 22422620 TI - Negative effects of curcumin on liver injury induced by alcohol. AB - Curcumin is known for its antiinflammatory and antifibrotic properties in liver damage. However, the negative effects of curcumin on alcoholic liver damage are seldom reported. In this study, both advantageous and disadvantageous functions of curcumin on alcoholic liver injury were observed. In order to determine the effects of curcumin on liver fibrosis induced by alcohol, 5% ethanol and/or curcumin (1 * 10(-3) or 1 * 10(-4) m) were injected intravenously in mice. Hematoxylin-eosin staining was performed to determine the value of liver injury by optical density analyses. Liver histology was evaluated by an experienced hepatopathologist blinded to the type of treatment received by the animals. Ethanol accelerates serum levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), liver injury, production of tumor necrosis factor alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and nuclear factor kappa B (NF-kappaB) during 5% ethanol-induced liver injury. 1 * 10(-3) m curcumin accelerates liver injury and liver cellular edema during only 5% ethanol induced liver injury evolution, whereas 1 * 10(-4) m curcumin does not lead to (or protect) alcoholic liver injury. Therefore, it is suggested that curcumin may have dual effects on alcoholic liver injury depending on its concentration. PMID- 22422621 TI - Prognostic indicators of foot-related disability in patients with rheumatoid arthritis: results of a prospective three-year study. AB - OBJECTIVE: To determine the prevalence and natural history of foot-related disability in patients with rheumatoid arthritis (RA). A secondary aim was to identify explanatory variables, including forefoot bursae, that are either associated with or predictive of disabling foot complications in patients with RA. METHODS: A longitudinal prospective cohort study recruited patients with RA from a rheumatology outpatient clinic. Data were collected at baseline (n = 149) and 1-year (n = 120) and 3-year followup (n = 60). Patient-reported disabling foot complications were evaluated using the subscales of the Foot Impairment Score (FIS): foot impairment/footwear restriction (FIS(IF)) and activity limitation/participation restriction (FIS(AP)). Explanatory variables investigated included ultrasound-detectable forefoot pathology and markers of disease activity. RESULTS: Disabling foot complications were highly prevalent on all occasions. Changes in foot impairment and activity limitation were significantly associated with fluctuations in disease activity (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR]: r = 0.455, P < 0.0001; ESR: r = -0.356, P = 0.008 and DAS28-ESR: r = 0.433, P = 0.001; ESR: r = -0.439, P = 0.001 for the FIS(IF) and FIS(AP), respectively), and approaching a significant association with changes in forefoot bursae (FIS(IF): r = 0.255, P = 0.063 and FIS(AP): r = 0.255, P = 0.063). The presence of disease duration and forefoot bursae was a significant prognostic indicator of foot impairment (P = 0.009 and P = 0.012, respectively), explaining 16% of score variability in the final regression model. Disease duration, forefoot bursae, and erosion presence were identified as significant prognostic indicators of activity limitation (P = 0.002, P = 0.006, and P = 0.019, respectively), explaining 35% of score variability in the final regression model. CONCLUSION: Despite advances in disease management, patients report disability associated with foot problems. Forefoot bursae should be considered for targeted therapy. PMID- 22422622 TI - Endothelial cell surface expression of protein disulfide isomerase activates beta1 and beta3 integrins and facilitates dengue virus infection. AB - Infection with dengue virus (DENV) causes diseases ranging from mild dengue fever to severe hemorrhage or shock syndrome. DENV infection of endothelial cells may cause cell apoptosis or vascular leakage and result in clinical illness of hemorrhage. However, the endothelial cell molecules involved in DENV infection and the mechanisms governing virus-cell interactions are still uncertain. Since protein disulfide isomerase (PDI) reducing function at the cell surface was shown to be required for entry of certain viruses and bacteria, we explored the role of PDI expressed on endothelial cell surface in DENV infection. Using siRNA to knock down PDI, DENV infection was reduced which could be reversed by treating cells with a reducing agent Tris(2-carboxyethyl)phosphine hydrochloride (TCEP). DENV induced PDI surface expression was mediated through the Lys-Asp-Glu-Leu (KDEL) receptor-Src family kinase signal pathway. Furthermore, cell surface PDI colocalized with beta1 and beta3 integrins after DENV infection, and the activation of integrins was blocked by PDI inhibition. Finally, blockade of PDI inhibited DENV entry into endothelial cells. Our findings suggest a novel mechanism whereby surface PDI which causes integrin activation is involved in DENV entry, and DENV infection further increases PDI surface expression at later time points. These findings may have implications for anti-DENV drug design. PMID- 22422625 TI - Chemo-enzymatic assembly of clickable cellulose surfaces via multivalent polysaccharides. AB - The chemist's guide to the galactosyl unit: A chemo-enzymatic process is developed for the multivalent functionalization of cellulose surfaces via regioselective oxidation of heteropolysaccharides with galactose 6-oxidase. Reductive amination, surface sorption, and click chemistry enable the assembly of (bio)chemically active cellulose surfaces for applications ranging from functional biocomposites to in vitro diagnostics. PMID- 22422626 TI - The art of fluorescence imaging with chemical sensors. AB - Fluorescence imaging techniques involving chemical sensors are essential tools in many fields of science and technology because they enable the visualization of parameters which exhibit no intrinsic color or fluorescence, for example, oxygen, pH value, CO(2), H(2)O(2), Ca(2+), or temperature, to name just a few. This Review aims to highlight the state of the art of fluorescence sensing and imaging, starting from a comprehensive overview of the basic functional principles of fluorescent probes (or indicators) and the design of sensor materials. The focus is directed towards the progress made in the development of multiple sensors and methods for their signal read out. Imaging methods involving optical sensors are applied in quite diverse scientific areas, such as medical research, aerodynamics, and marine research. PMID- 22422627 TI - Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. AB - The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-beta1. The expression of alpha-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription polymerase chain reaction, and the expression of alpha-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-beta1 pathway was evaluated by western blot analysis. In TGF-beta1-induced NPDFs, berberine significantly inhibited the expression of alpha-SMA and collagen type I mRNA and reduced alpha SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and alpha SMA in TGF-beta1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. PMID- 22422628 TI - Quercetin in elimination of tumor initiating stem-like and mesenchymal transformation property in head and neck cancer. AB - BACKGROUND: Previously, we enriched a subpopulation of head and neck cancer derived tumor initiating cells (HNC-TICs) presented high tumorigenic, chemo radioresistant, and coupled with epithelial-mesenchymal transition (EMT) properties. The purpose of this study was to investigate the therapeutic effect and molecular mechanisms of quercetin on HNC-TICs. METHOD: ALDH1 activity of head and neck cancer cells with quercetin treatment was assessed by the Aldefluor assay flow cytometry analysis. Self-renewal, invasiveness, and EMT capability of HNC-TICs with different doses of quercetin was presented. RESULTS: We first observed that the treatment of quercetin significantly downregulated the ALDH1 activity of head and neck cancer cells in a dose-dependent manner (p < .05). Moreover, quercetin reduced self-renewal property and stemness signatures expression in head and neck cancer-derived sphere cells. The migration ability of head and neck cancer-derived sphere cells was lessened under quercetin treatment partially due to the decreased productions of Twist, N-cadherin, and vimentin. CONCLUSION: Quercetin suppressing HNC-TICs characteristics may therefore be valuable therapeutics clinically in combination with standard treatment modalities. PMID- 22422629 TI - Perinuclear positioning of the inactive human cystic fibrosis gene depends on CTCF, A-type lamins and an active histone deacetylase. AB - The nuclear positioning of mammalian genes often correlates with their functional state. For instance, the human cystic fibrosis transmembrane conductance regulator (CFTR) gene associates with the nuclear periphery in its inactive state, but occupies interior positions when active. It is not understood how nuclear gene positioning is determined. Here, we investigated trichostatin A (TSA)-induced repositioning of CFTR in order to address molecular mechanisms controlling gene positioning. Treatment with the histone deacetylase (HDAC) inhibitor TSA induced increased histone acetylation and CFTR repositioning towards the interior within 20 min. When CFTR localized in the nuclear interior (either after TSA treatment or when the gene was active) consistent histone H3 hyperacetylation was observed at a CTCF site close to the CFTR promoter. Knockdown experiments revealed that CTCF was essential for perinuclear CFTR positioning and both, CTCF knockdown as well as TSA treatment had similar and CFTR-specific effects on radial positioning. Furthermore, knockdown experiments revealed that also A-type lamins were required for the perinuclear positioning of CFTR. Together, the results showed that CTCF, A-type lamins and an active HDAC were essential for perinuclear positioning of CFTR and these components acted on a CTCF site adjacent to the CFTR promoter. The results are consistent with the idea that CTCF bound close to the CFTR promoter, A-type lamins and an active HDAC form a complex at the nuclear periphery, which becomes disrupted upon inhibition of the HDAC, leading to the observed release of CFTR. PMID- 22422630 TI - Visualization of coronary plaque in arterial remodeling using a new 40-MHz intravascular ultrasound imaging system. AB - OBJECTIVES: The aim of this study was to characterize coronary plaque in target lesions with vessel remodeling using iMap-intravascular ultrasound (IVUS). BACKGROUND: The relationship between the plaque component and vessel remodeling remains to be elucidated. iMAP-IVUS is an imaging system that can be used to assess the plaque composition by radiofrequency signals from 40 MHz IVUS. METHODS: IVUS examinations were performed for the de novo target vessels of 146 stable angina pectoris patients (174 vessels). The patients were divided into two groups: including a nonpositive remodeling group (non-PR, remodeling index <= 1.0, 125 vessels) and a positive remodeling group (PR, remodeling index > 1.0, 49 vessels). RESULTS: The percent plaque burden in the PR group were lager than those in the non-PR group (79.05% vs. 74.36%, P < 0.01). Attenuation plaques were more frequently observed in PR group (40.8% vs. 12.1%, P < 0.0001). The percentages of lipidic and necrotic relative areas at the minimum lumen sites were greater in the PR group than in the non-PR group (7.22% vs. 6.03%, P <0.05 and 22.08% vs. 14.71%, P < 0.001, respectively), and the percentage of the fibrotic area was smaller (54.82% vs. 61.42%, P < 0.05). In addition, a positive linear correlation was observed between the remodeling index and either the lipidic or necrotic area (r = 0.37, P <0.0001 and r = 0.35, P < 0.0001, respectively). CONCLUSIONS: The coronary plaque characteristics in PR patients showed increased lipidic and necrotic areas and the degree of coronary remodeling correlated with the lipidic and necrotic plaque area. (c) 2012 Wiley Periodicals, Inc. PMID- 22422632 TI - Dermatitis Herpetiformis: Rare Cutaneous Manifestation of Colon Adenocarcinoma. PMID- 22422633 TI - Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces. AB - The discovery of small-molecule drugs aimed at disrupting protein-protein associations is expected to lead to promising therapeutic strategies. The small molecule binds to the target protein thus replacing its natural protein partner. Noteworthy, structural analysis of complexes between successful disruptive small molecules and their target proteins has suggested the possibility that such ligands might somehow mimic the binding behavior of the protein they replace. In these cases, the molecules show a spatial and "chemical" (i.e., hydrophobicity) similarity with the residues of the partner protein involved in the protein protein complex interface. However, other disruptive small molecules do not seem to show such spatial and chemical correspondence with the replaced protein. In turn, recent progress in the understanding of protein-protein interactions and binding hot spots has revealed the main role of intermolecular wrapping interactions: three-body cooperative correlations in which nonpolar groups in the partner protein promote dehydration of a two-body electrostatic interaction of the other protein. Hence, in the present work, we study some successful complexes between already discovered small disruptive drug-like molecules and their target proteins already reported in the literature and we compare them with the complexes between such proteins and their natural protein partners. Our results show that the small molecules do in fact mimic to a great extent the wrapping behavior of the protein they replace. Thus, by revealing the replacement the small molecule performs of relevant wrapping interactions, we convey precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug-design endeavors. PMID- 22422634 TI - Disease modification and other trials in systemic sclerosis have come a long way, but have to go further. PMID- 22422631 TI - American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. AB - An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections. PMID- 22422635 TI - Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes. AB - STUDY OBJECTIVE: To investigate potential drug-drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers. DESIGN: Two, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials. SETTING: Clinical research unit. PARTICIPANTS: Fifty-four healthy adult volunteers were enrolled in the two drug-drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox-Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine. INTERVENTION: In the first drug-drug interaction study, 36 participants received a single oral dose of clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17-22, with a single dose of clobazam 10 mg coadministered on day 22, to study the effects of CYP3A4 or CYP2C19 inhibition, respectively, on clobazam and its active metabolite N-desmethylclobazam (N-CLB). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and clobazam 40 mg/day on days 4-19, to study clobazam's effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4. MEASUREMENTS AND MAIN RESULTS: In the first DDI study, coadministration of ketoconazole (a CYP3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity (AUC(0 infinity) ) 54% and decreased clobazam's maximum plasma concentration (C(max) ) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for N-CLB to a lesser degree. The CYP2C19 inhibitor omeprazole increased AUC(0-infinity) and C(max) of N-CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, N-CLB has 3-4 times greater exposure than clobazam. In the second DDI study, no clinically significant drug-drug interactions were observed between clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1-hydroxymidazolam metabolite, however, decreased by 27% and increased 4-fold, respectively. Clobazam increased dextromethorphan (CYP2D6) AUC(0-infinity) by 95% and C(max) by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP3A4 or CYP2C19, or inhibit CYP2C19, had negligible effects on clobazam or N-CLB. Clobazam did not affect valproic acid or lamotrigine exposures. CONCLUSION: These findings suggest no clinically meaningful drug-drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox-Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment. PMID- 22422636 TI - Telescopic catheter-in-long sheath and parallel to a stiff guide wire technique for complex pulmonary artery anatomy. AB - Selective catheterization and procedures in pulmonary arteries may be very challenging. We developed a technique in which an extra-stiff guide wire was placed in a pulmonary artery. Across it a long sheath was placed proximally or controlateral to the lesion to be treated. An angiographic catheter was then placed parallel to the guide wire in a telescopic way within the long sheath. This system facilitated greater stability, allowing fine tuning of catheter position to reach and treat the target lesion. Here, we present five cases in whom this technique was used; a patient with multiple arteriovenous fistulas in a difficult to reach area and four subjects with complex pulmonary artery stenoses. PMID- 22422637 TI - Inhibition of Cu-amyloid-beta by using bifunctional peptides with beta-sheet breaker and chelator moieties. AB - Breaking the mold: Inhibition of toxic amyloid-beta (Abeta) aggregates and disruption of Cu-Abeta with subsequent redox-silencing of Cu have been considered promising strategies against Alzheimer's disease. The design and proof of concept of simple peptides containing a Cu-chelating/redox-silencing unit and an Abeta aggregation inhibition unit (beta-sheet breaker) is described (see scheme). PMID- 22422638 TI - Arynes and cyclohexyne in natural product synthesis. AB - This Minireview highlights recent advances in the field of aryne and cyclohexyne chemistry that have allowed the extraordinary reactivity of these entities to be harnessed during the course of natural product syntheses. The syntheses presented rely on the use of these reactive species in chemoselective transformations and follow unprecedented synthetic strategies that are inspiring for the practitioners of synthetic organic chemistry. PMID- 22422639 TI - Inhibitory activities of compounds from the twigs of Garcinia hombroniana Pierre on human low-density lipoprotein (LDL) oxidation and platelet aggregation. AB - The methanol extract of the twigs of Garcinia hombroniana, which showed strong LDL antioxidation and antiplatelet aggregation activities, was subjected to column chromatography to obtain 3,5,3',5'-tetrahydroxy-4-methoxybenzophenone, 1,7 dihydroxyxanthone and eight triterpenoids, garcihombronane B, D, E and F, friedelin, glutin-5-en-3beta-ol, stigmasterol and lupeol. The structures of the compounds were elucidated by spectroscopic methods. The compounds were evaluated for their ability to inhibit copper-mediated LDL oxidation and arachidonic acid (AA)-, adenosine diphosphate (ADP)-, collagen-induced platelet aggregation in vitro. Among the compounds tested, 3,5,3',5'-tetrahydroxy-4-methoxybenzophenone and 1,7-dihydroxyxanthone showed strong inhibitory activity on LDL oxidation with half-maximal inhibitory concentration (IC(50)) values of 6.6 and 1.7 uM, respectively. 3,5,3',5'-Tetrahydroxy-4-methoxybenzophenone exhibited strong activity on AA-, ADP- and collagen-induced platelet aggregation with IC(50) values of 53.6, 125.7 and 178.6 uM, respectively, while 1,7 dihydroxyxanthone showed significant and selective inhibitory activity against ADP-induced aggregation with IC(50) value of 5.7 uM. Of the triterpenoids tested, garcihombronane B showed moderate activity against LDL oxidation and garcihombronane D and F showed selective inhibition on ADP-induced platelet aggregation. PMID- 22422640 TI - SPARC/SFN interaction, suppresses type I collagen in dermal fibroblasts. AB - We previously suggested that keratinocyte releasable factors might modulate the wound healing process by regulating the expression of key extracellular matrix components such as collagenase (matrix metalloproteinase-1) and type I collagen in fibroblasts. The first one, we called it keratinocyte-derived anti-fibrogenic factor (KDAF), identified as stratifin (SFN) also named 14-3-3sigma, revealing a strong collagenase activity. However, the second factor, which we named keratinocyte-derived collagen-inhibiting factor(s) (KD-CIF) that has shown to control the synthesis of type I collagen, was not known. Upon conducting a series of systematic protein purification methods followed by mass spectroscopy, two proteins: secreted protein acidic rich in cystein (SPARC) and SFN were identified in keratinocyte-conditioned media. Using co-immunoprecipitation and 3D modeling, we determined that SFN and SPARC form a complex thereby controlling the type I collagen synthesis and expression in fibroblasts. The levels of these proteins in fibrotic tissues (animal and human) were also evaluated and a differential expression of these proteins between normal and fibrotic tissue confirmed their potential role in development of fibrotic condition. In conclusion, this study describes for the first time an interaction between SPARC and SFN that may have implications for the regulation of matrix deposition and prevention of dermal fibrotic conditions such as hypertrophic scars and keloid. PMID- 22422641 TI - An intermolecular heterobimetallic system for photocatalytic water reduction. AB - Teamwork: A new intermolecular heterobimetallic system for photocatalytic water reduction, consisting of a photosensitizer of the type [Ru(bpy)(2)(L)](PF(6))(2) (L=bidentate ligand), a dichloro palladium complex PdCl(2)(L) serving as the water reduction catalyst, and triethyl amine as electron donor, is presented. Variations of the ligand as well as of the palladium source results in a significant improvement of the performance of the catalyst system. PMID- 22422642 TI - Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network. AB - OBJECTIVE: To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme. BACKGROUND: Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism. METHODS: Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score. RESULTS: The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362,809 patients and 792,665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90-1.66). There were 1449 renal dysfunction events among 272,099 patients and 574,584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58-1.44). There were 1434 hepatic dysfunction events among 367,612 patients and 815,945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45-1.31). CONCLUSIONS: Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4 substrate with CYP3A4 inhibitor concomitancy. PMID- 22422643 TI - Transgenic Xenopus laevis with the ef1-alpha promoter as an experimental tool for amphibian retinal regeneration study. AB - Complete retinal regeneration occurs after the removal of the whole tissue in mature Xenopus laevis, as well as in the newt. Here, we produced F1 and F2 lines of transgenic X. laevis containing an EGFP gene under a translation elongation factor 1-alpha (ef1-alpha) promoter and investigated how the gene is reactivated in retinal pigmented epithelial (RPE) cells when the neural retina (NR) is removed. The results showed that EGFP expression is reduced in the adult ocular tissues of nonmanipulated transgenic animals, and EGFP-expressing cells are occasionally found heterogeneously in the lens, NR and RPE tissues. During retinal regeneration, the EGFP gene is reactivated in the RPE and ciliary marginal cells. Transgenic animals were also used for a transplant study because of the genetic marker of the donor tissue. Transplanted RPE clearly transdifferentiated to regenerate the retina in the ocular chamber. This study is, to our knowledge, the first report of a transgenic study of amphibian retinal regeneration, and the approach is promising for future molecular analyses. PMID- 22422644 TI - The role of domain: domain interactions versus domain: water interactions in the coarse-grained simulations of the E1P to E2P transitions in Ca-ATPase (SERCA). AB - SERCA is an important model system for understanding the molecular details of conformational change in membrane transport systems. This reflects the large number of solved X-ray structures and the equally large database of mutations that have been assayed. In this computational study, we provide a molecular dynamics description of the conformational changes during the E1P -> E2P transitions. This set of states further changes with insertion mutants in the A M3 linker region. These mutants were experimentally shown to lead to significant shifts in rates between the E1P -> E2P states. Using the population shift framework and dynamic importance sampling method along with coarse-grained representations of the protein, lipid, and water, we suggest why these changes are found. The calculations sample on intermediates and suggest that changes in interactions, individual helix interactions, and water behavior are key elements in the molecular compositions that underlie shifts in kinetics. In particular, as the insertion length grows, it attracts more water and disrupts domain interactions, creating changes as well at the sites of key helix interactions between the A-Domain and the P-Domain. This provides a conceptual picture that aids understanding of the experimental results. PMID- 22422645 TI - Critical aortic stenosis in a patient with a large saccular abdominal aortic aneurysm: simultaneous transcatheter aortic valve implantation and drive-by endovascular aortic aneurysm repair. AB - Elderly patients with aortic stenosis are often deemed too high risk, and consequently turned down for conventional surgery. Transcatheter aortic valve implantation (TAVI) is a safe and an increasingly attractive option in this group of patients. Although TAVI has been shown to be successful and safe, the cardiovascular assessment of other co-morbidities in this susceptible group of patients is critical to ensuring good clinical outcomes. The presence of a saccular abdominal aortic aneurysm (AAA) in our patient was an example of an important co-morbidity which could have a significant impact on the outcome of TAVI, if not managed appropriately. The increased systolic pressure post successful TAVI will result in an increased strain within the wall of the saccular AAA with an increased risk of rupture. Therefore, a timely management strategy for the AAA was necessary. We believe that we report the first case of simultaneous TAVI and endovascular aneurysm repair (EVAR). The patient underwent uncomplicated transfemoral TAVI immediately followed by successful drive-by percutaneous EVAR delivered over the same superstiff guidewire via the transfemoral route. Our case highlights the importance of a detailed assessment in all patients before consideration for TAVI, and the multi-disciplinary team and a management strategy for both pathologies tailored to the patient. The case demonstrates the versatility of trans-catheter techniques which has enabled the treatment of aortic stenosis and abdominal AAA in a single procedure. PMID- 22422646 TI - One-pot three-component highly selective synthesis of homoallylboronates by using metal-free catalysis. PMID- 22422647 TI - "Tamed" silylium ions: versatile in catalysis. PMID- 22422648 TI - New antifungal compounds from Aspergillus terreus isolated from desert soil. AB - Two new butyrolactone I derivatives: 3-[3-hydroxy-4-(3-methyl-but-2-enyl)-phenyl] 5-(-4-hydroxybenzyl)-4-methyl-dihydrofuran-2(3H)-one (1) and (Z)-3-[3-hydroxy-4 (3-methyl-but-2-enyl)-phenyl]-5-(-4-hydroxybenzylidene)-4-methyl-dihydrofuran 2(3H)-one (2), in addition to the previously described (S)-methyl-4-hydroxy-2-[4 hydroxy-3-(3-methyl-but-2-enyl)-benzyl]-3-(4-hydroxy-phenyl)-5-oxo-2,5-dihydro furan-2-carboxylic acid methyl ester (3), were identified from a strain of Aspergillus terreus Thom (Trichocomaceae) isolated from desert soil. The antifungal activities of both intra- and extracellular metabolites of A. terreus grown on yeast extract sucrose and malt extract media were determined. Only the secondary metabolites of A. terreus grown on yeast extract sucrose medium were active against Aspergillus fumigatus RCMB 002008. The antifungal activity of A. terreus was attributed to the presence of the compounds (1) and (2), whose minimum inhibitory concentrations (MIC) against A. fumigatus were found to be 32.00 and 16.00 ug/mL respectively. Structure elucidation was carried out using UV spectrometry, electrospray ionization mass spectrometry (ESIMS), high resolution electron impact (HREIMS) spectrometry, (1)H- and (13) C-NMR, proton proton correlation spectroscopy ((1)H-(1)H Cosy), distortionless enhancement by polarization transfer (DEPT), heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlations (HMBC) spectroscopy. PMID- 22422649 TI - Mangiferin aglycone attenuates radiation-induced damage on human intestinal epithelial cells. AB - Recent studies suggest that mangiferin aglycone (norathyriol) has great potential as a novel radioprotector without any known toxic side effects. In this study, we assessed the protective effects of mangiferin aglycone against radiation-induced injuries on normal human intestinal epithelial cells (HIECs), while using mangiferin as a reference compound. The in vitro experiments showed that pretreatment of either mangiferin aglycone or mangiferin could inhibit cytotoxic effects of ionizing irradiation (IR) on HIECs. Cellular changes were estimated by measuring cell viability, clonogenic surviving rate, and apoptotic rate. Compared to mangiferin, we found mangiferin aglycone had greater radioprotective effects of mangiferin aglycone on HIECs. It has been demonstrated that the cytotoxicity of ionizing radiation relates to its capacity to induce DNA damage. In view of this, we monitored DNA double-strand breaks (DSBs) using gammaH2AX foci formation to test whether mangiferin aglycone and mangiferin could modulate genotoxic effects of radiation. It shows that mangiferin aglycone could eliminate 46.8% of the total DSBs of the cells exposed to 2 Gy IR, which is significantly better than mangiferin. Complementing earlier results from our group, it appears possible to conclude that mangiferin aglycone presents potential useful effects on IR-induced damage and may be a better radioprotective agent than mangiferin therapeutically. PMID- 22422650 TI - Magnetic resonance chemical exchange saturation transfer imaging and nanotechnology. AB - Chemical exchange saturation transfer (CEST) agents and paramagnetic CEST (PARACEST) agents display bound water signals that exchange protons with the bulk water. CEST magnetic resonance imaging (MRI) relies on exchangeable protons that resonate at a chemical shift that is distinguishable from the bulk water signal. In some cases, paramagnetic chelates are utilized to shift the bound water frequency further away from the bulk water. Radiofrequency prepulses applied at the appropriate frequency can saturate the exchangeable protons, which transfer into the bulk water pool and lead to reduced equilibrium magnetization. Therefore, CEST and PARACEST agents allow the image contrast to be switched 'on' and 'off' by simply changing the pulse sequence parameters. One of the main limitations with this approach is the inherent insensitivity of MRI to CEST and PARACEST agents. Nanoscale carriers have been developed to improve the limit of detection for these agents, demonstrating the feasibility of in vivo molecular or cellular MRI based on CEST or PARACEST contrast. These carriers have been based on a number of different nanoparticle constructs, such as liposomes, dendrimers, polymers, adenovirus particles, and perfluorocarbon nanoparticles. The unique MRI properties of CEST and PARACEST nanoparticle systems have spawned research into an array of potential medical applications. PMID- 22422651 TI - New loop diuretic prescriptions may be an acute risk factor for falls in the nursing home. AB - PURPOSE: Although chronic use of diuretics has been implicated as a risk factor for falls, it is unknown whether changes in diuretic drugs are associated with an acutely elevated risk of falls. We evaluated the relationship between change in a diuretic prescription (new prescription or increased dose) and the occurrence of documented falls among nursing home residents. METHODS: Participants of the cohort were 1785 long-term care residents of two large nursing homes (2005-2010; Boston, MA). A self-matched, case-crossover analysis was used to examine whether there is an acutely increased risk of falling in the day following a diuretic drug change compared with days without a diuretic drug change. Odds ratios with 95% confidence intervals were calculated using conditional logistic regression models. RESULTS: During a mean follow-up of 8.4 months, 1181 participants experienced an incident fall. Nine participants experienced a diuretic change on the day before the fall. The odds of falling one day following a change in a diuretic was elevated (OR = 2.08; 95% CI = 0.89, 4.86). The association was stronger and reached nominal statistical significance when loop diuretics were examined separately (OR = 2.46; 95% CI = 1.02, 5.92). We estimated that, for every 271 loop diuretic drug changes, one excess fall occurred. CONCLUSIONS: Nursing home residents are at an increased risk of falls in the day following a new prescription or increased dose of a loop diuretic drug. Extra precautions should be taken immediately following a loop diuretic drug change in an effort to prevent falls. PMID- 22422652 TI - Fhos encodes a Drosophila Formin-like protein participating in autophagic programmed cell death. AB - Larval tissues undergo programmed cell death (PCD) during Drosophila metamorphosis. PCD is triggered in a stage and tissue-specific fashion in response to ecdysone pulses. The understanding of how ecdysone induces the stage and tissue-specificity of cell death remains obscure. Several steroid-regulated primary response genes have been shown to act as key regulators of cellular responses to ecdysone by inducing a cascade of transcriptional regulation of late responsive genes. In this article, the authors identify Fhos as a gene that is required for Drosophila larval salivary gland destruction. Animals with a P element mutation in Fhos possess persistent larval salivary glands, and precise excisions of this P-element insertion resulted in reversion of this salivary gland mutant phenotype. Fhos encodes the Drosophila homolog of mammalian Formin Fhos. Fhos is differentially transcribed during development and responds to ecdysone in a method that is similar to other cell death genes. Similarly to what has been shown for its mammalian counterpart, FHOS protein is translocated to the nucleus at later stages of cell death. Fhos mutants posses disrupted actin cytoskeleton dynamics in persistent salivary glands. Together, our data indicate that Fhos is a new ecdysone-regulated gene that is crucial for changes in the actin cytoskeleton during salivary gland elimination in Drosophila. PMID- 22422653 TI - Solution NMR structure of the ribosomal protein RP-L35Ae from Pyrococcus furiosus. AB - The ribosome consists of small and large subunits each composed of dozens of proteins and RNA molecules. However, the functions of many of the individual protomers within the ribosome are still unknown. In this article, we describe the solution NMR structure of the ribosomal protein RP-L35Ae from the archaeon Pyrococcus furiosus. RP-L35Ae is buried within the large subunit of the ribosome and belongs to Pfam protein domain family PF01247, which is highly conserved in eukaryotes, present in a few archaeal genomes, but absent in bacteria. The protein adopts a six-stranded anti-parallel beta-barrel analogous to the "tRNA binding motif" fold. The structure of the P. furiosus RP-L35Ae presented in this article constitutes the first structural representative from this protein domain family. PMID- 22422654 TI - Friable but treatable: coronary artery dissections in Ehlers-Danlos syndrome. AB - Vascular Ehlers-Danlos syndrome is a rare connective tissue disorder associated with arterial dissection or rupture. Percutaneous coronary intervention (PCI) is often critical in patients with this syndrome because their coronary arteries are prone to dissection, enhancing the risk of stent borders dissection when conventional stent deployment pressures are used. Coronary artery bypass graft (CABG) treatment for these patients may also raise concerns because the left internal mammary artery is probably friable. Therefore, coronary artery revascularization in vascular Ehlers-Danlos syndrome either using PCI or CABG is challenging due to the arteries friability. A small number of cases have been published describing the friability of the vessels and associated complications; nevertheless, the optimum treatment remains unclear. We report the case of a 54 year-old woman treated successfully with PCI and CABG in two different acute coronary syndrome episodes, in which specific technical issues related to both procedures were decisive. PMID- 22422655 TI - Making sense of the global health crisis: policy narratives, conflict, and global health governance. AB - Health has become a policy issue of global concern. Worried that the unstructured, polycentric, and pluralist nature of global health governance is undermining the ability to serve emergent global public health interests, some commentators are calling for a more systematic institutional response to the "global health crisis." Yet global health is a complex and uncertain policy issue. This article uses narrative analysis to explore how actors deal with these complexities and how uncertainties affect global health governance. By comparing three narratives in terms of their basic assumptions, the way they define problems as well as the solutions they propose, the analysis shows how the unstructured pluralism of global health policy making creates a wide scope of policy conflict over the global health crisis. This wide scope of conflict enables effective policy-oriented learning about global health issues. The article also shows how exclusionary patterns of cooperation and competition are emerging in health policy making at the global level. These patterns threaten effective learning by risking both polarization of the policy debate and unanticipated consequences of health policy. Avoiding these pitfalls, the analysis suggests, means creating global health governance regimes that promote openness and responsiveness in deliberation about the global health crisis. PMID- 22422658 TI - Asymmetric hydrolytic kinetic resolution with recyclable macrocyclic Co(III) salen complexes: a practical strategy in the preparation of (R)-mexiletine and (S)-propranolol. AB - A chiral cobalt(III) complex (1e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47% with respect to the epoxides, 53% with respect to the diols) and high enantioselectivity (ee>99% for the epoxides, up to 96% for the diols) were achieved in 2.5-16 h. The Co(III) macrocyclic salen complex (1e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol. PMID- 22422659 TI - Visualization of inflammation using (19) F-magnetic resonance imaging and perfluorocarbons. AB - Inflammation plays a central pathophysiological role in a large number of diseases. While conventional magnetic resonance imaging (MRI) can depict gross tissue alterations due to proton changes, specific visualization of inflammation is an unmet task in clinical medicine. (19) F/(1) H MRI is a novel technology that allows tracking of stem and immune cells in experimental disease models after labelling with perfluorocarbon (PFC) emulsions. (19) F markers such as PFC compounds provide a unique signal in vivo due to the negligible (19) F background signal of the body. Concomitant acquisition of (1) H images places the labelled cells into their anatomical context. This novel imaging technique has been applied to monitor immune cell responses in myocardial infarction, pneumonia, bacterial abscess formation, peripheral nerve injury, and rejection of donor organs after transplantation. Upon systemic application PFC nanoparticles are preferentially phagozytosed by circulating monocytes/macrophages and, thus, the fluorine signal in inflamed organs mainly reflects macrophage infiltration. Moreover, attenuation of the inflammatory response after immunosuppressive or antibiotic treatments could be depicted based on (19) F/(1) H-MRI. Compared to other organ systems (19) F-MRI of neuroinflammation is still challenging, mainly because of lack in sensitivity. In focal cerebral ischemia early application of PFCs revealed ongoing thrombotic vessel occlusion rather than cell migration indicating that timing of contrast agent application is critical. Current restrictions of (19) F/(1) H-MRI in sensitivity may be overcome by improved imaging hardware, imaging sequences and reconstruction techniques, as well as improved label development and cell labelling procedures in the future. PMID- 22422660 TI - Furanodiene enhances tamoxifen-induced growth inhibitory activity of ERa-positive breast cancer cells in a PPARgamma independent manner. AB - Herbal plants are enriched with compounds with a wide range of biological activities. Furanodiene is a sesquiterpene isolated from Rhizoma Curcumae. Growing evidence shows furanodiene exhibits diversified activities of hepatoprotection, anti-inflammation, anti-angiogenesis, and anti-tumor. However, its biological activities against breast cancer have not been deeply understood, and its potential as an anti-breast cancer agent combined with tamoxifen (TAM) has not been evaluated so far. This study describes the combined effects of furanodiene and TAM in human breast cancer cells in vitro. The results showed that ERa-negative MDA-MB-231 cells were much more sensitive than ERa-positive MCF 7 cells to the growth inhibition due to furanodiene. Combined administration of furanodiene and TAM led to marked increase in growth inhibition, cell cycle arrest and pro-apoptotic activity in ERa-positive cells compared to individual agent, and enhanced the down-regulation of p-cyclin D1, cyclin D1, CDK2, CDK6, p Rb, Rb and p-p44, and the up-regulation of p27, Bax and Bad, but did not show increased cytotoxicity in ERa-negative MCF-10A non-tumorigenic breast epithelial cells. Co-incubation induced the typical PARP cleavage or caspase 9 cleavages compared to individual agent. In addition, PPARgamma activity inhibition by its antagonist T0070907 did not significantly reverse the enhanced effect of furanodiene and TAM suggesting that anti-cancer properties of combination were PPARgamma independent. Our data indicated that furanodiene could enhance the growth inhibitory and pro-apoptotic activity of TAM by inducing cell cycle arrest and cell apoptosis via CDKs-cyclins and mitochondria-caspases-dependent, and PPARgamma-independent signaling pathways in breast cancer cells, without contributions to the cytotoxicity of TAM. PMID- 22422661 TI - Acute effect of high-dose isoflavones from Pueraria lobata (Willd.) Ohwi on lipid and bone metabolism in ovariectomized mice. AB - We investigated the acute metabolic effects of isoflavones from Pueraria lobata (Willd.) Ohwi (IPL) in ovariectomized (OVX) mice. After 4 weeks of IPL feeding at 500 mg/day/kg body weight (OVX500), plasma 17beta-estradiol concentrations were significantly higher (+25%, p < 0.05), whereas plasma triglyceride levels were significantly lower in OVX mice (-15%, p < 0.05) compared with controls. Abdominal adipose tissue weight was marginally reduced in IPL-fed groups compared with OVX controls and the plasma levels of liver enzymes were unchanged. In addition, IPL significantly inhibited the reduction of bone mineral density in the femurs of OVX mice (OVX200, +22%; OVX500, +26%; p < 0.05) compared with controls after 4 weeks of IPL feeding. In quantitative polymerase chain reaction analysis the expression of aromatase was significantly suppressed and SULT1E1 was increased by IPL feeding, showing that IPL feeding may not alter the risk for breast cancer in mice. Our results suggest that IPL could ameliorate menopausal symptoms in mice. Further studies will confirm the effects of IPL in humans. PMID- 22422662 TI - Formation of single-chain polymer nanoparticles in water through host-guest interactions. PMID- 22422663 TI - Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma. AB - The histologic presence of macrophages (tumor-associated macrophages, TAMs) and neutrophils (tumor-associated neutrophils, TANs) has been linked to poor clinical outcomes for solid tumors. The exact mechanism for this association with worsened prognosis is unclear. It has been theorized that TAMs are immunomodulated to an alternatively activated state and promote tumor progression. Similarly, TANs have been shown to promote angiogenesis and tumor detachment. TAMs and TANs were characterized for activation state and production of prometastatic mediators in an immunocompetent murine model of pancreatic adenocarcinoma. Specimens from liver metastases were evaluated by immunofluorescence and immunoblotting. TAMS have upregulated expression of CD206 and CD163 markers of alternative activation, (4.14 +/- 0.55-fold and 7.36 +/- 1.13-fold over control, respectively, P < 0.001) but do not have increased expression of classically activated macrophage markers CCR2 and CCR5. TAMs also express oncostatin M (OSM). We found that TANs, not TAMs, predominantly produce matrix metalloproteinase-9 (MMP-9) in this metastatic tumor microenvironment, while MMP-2 production is pan-tumoral. Moreover, increased expression of VEGF colocalized with TAMs as opposed to TANs. TAMs and TANs may act as distinct effector cells, with TAMs phenotypically exhibiting alternative activation and releasing OSM and VEGF. TANs are localized at the invasive front of the metastasis, where they colocalize with MMP-9. Improved understanding of these interactions may lead to targeted therapies for pancreas adenocarcinoma. PMID- 22422664 TI - Cardiac sympathetic activation in patients with pulmonary arterial hypertension. AB - Patients with congestive heart failure (CHF) due to left ventricular (LV) dysfunction have sympathetic activation specifically directed to the myocardium. Although pulmonary arterial hypertension (PAH) is associated with increased systemic sympathetic activity, its impact on sympathetic drive to ventricular myocardium is unknown. Fifteen patients with PAH (9 women; 54 +/- 12 years) were studied: 10 with idiopathic PAH and 5 with a connective tissue disorder. We measured hemodynamics, as well as radiolabeled and endogenous concentrations of arterial and coronary sinus norepinephrine (NE). These measures were repeated after inhaled nitric oxide (NO). Measurement of transcardiac NE concentrations and the cardiac extraction of radiolabeled NE allowed calculation of the corrected transcardiac gradient of NE (CTCG of NE). Comparative data were collected from 15 patients (9 women: 55 +/- 12 yr) with normal LV function and 15 patients with CHF (10 women; 53 +/- 12 yr). PAH patients had elevated arterial NE concentrations compared with those with normal LV function but were similar to those with CHF. The CTCG of NE was higher in those with PAH than in the normal LV group (3.6 +/- 2.2 vs. 1.5 +/- 0.9 pmol/ml; P < 0.01) but similar to that seen in those with CHF (3.3 +/- 1.4; P = NS). Inhaled NO, which reduced pulmonary artery pressure and increased cardiac output, had no effect on cardiac sympathetic activity. Therefore, cardiac sympathetic activation occurs in PAH. The mechanism of this activation remains uncertain but does not involve elevations in left heart filling pressure. PMID- 22422666 TI - In pursuit of scientific excellence: sex matters. PMID- 22422665 TI - In utero glucocorticoid exposure reduces fetal skeletal muscle mass in rats independent of effects on maternal nutrition. AB - Maternal stress and undernutrition can occur together and expose the fetus to high glucocorticoid (GLC) levels during this vulnerable period. To determine the consequences of GLC exposure on fetal skeletal muscle independently of maternal food intake, groups of timed-pregnant Sprague-Dawley rats (n = 7/group) were studied: ad libitum food intake (control, CON); ad libitum food intake with 1 mg dexamethasone/l drinking water from embryonic day (ED)13 to ED21 (DEX); pair-fed (PF) to DEX from ED13 to ED21. On ED22, dams were injected with [(3)H]phenylalanine for measurements of fetal leg muscle and diaphragm fractional protein synthesis rates (FSR). Fetal muscles were analyzed for protein and RNA contents, [(3)H]phenylalanine incorporation, and MuRF1 and atrogin-1 (MAFbx) mRNA expression. Fetal liver tyrosine aminotransferase (TAT) expression was quantified to assess fetal exposure to GLCs. DEX treatment reduced maternal food intake by 13% (P < 0.001) and significantly reduced placental mass relative to CON and PF dams. Liver TAT expression was elevated only in DEX fetuses (P < 0.01). DEX muscle protein masses were 56% and 70% than those of CON (P < 0.01) and PF (P < 0.05) fetuses, respectively; PF muscles were 80% of CON (P < 0.01). Muscle FSR decreased by 35% in DEX fetuses (P < 0.001) but were not different between PF and CON. Only atrogin-1 expression was increased in DEX fetus muscles. We conclude that high maternal GLC levels and inadequate maternal food intake impair fetal skeletal muscle growth, most likely through different mechanisms. When combined, the effects of decreased maternal intake and maternal GLC intake on fetal muscle growth are additive. PMID- 22422667 TI - Humoral regulation of heart rate during digestion in pythons (Python molurus and Python regius). AB - Pythons exhibit a doubling of heart rate when metabolism increases several times during digestion. Pythons, therefore, represent a promising model organism to study autonomic cardiovascular regulation during the postprandial state, and previous studies show that the postprandial tachycardia is governed by a release of vagal tone as well as a pronounced stimulation from nonadrenergic, noncholinergic (NANC) factors. Here we show that infusion of plasma from digesting donor pythons elicit a marked tachycardia in fasting snakes, demonstrating that the NANC factor resides in the blood. Injections of the gastrin and cholecystokinin receptor antagonist proglumide had no effect on double-blocked heart rate or blood pressure. Histamine has been recognized as a NANC factor in the early postprandial period in pythons, but the mechanism of its release has not been identified. Mast cells represent the largest repository of histamine in vertebrates, and it has been speculated that mast cells release histamine during digestion. Treatment with the mast cell stabilizer cromolyn significantly reduced postprandial heart rate in pythons compared with an untreated group but did not affect double-blocked heart rate. While this study indicates that histamine induces postprandial tachycardia in pythons, its release during digestion is not stimulated by gastrin or cholecystokinin nor is its release from mast cells a stimulant of postprandial tachycardia. PMID- 22422668 TI - Effects of priming exercise on the speed of adjustment of muscle oxidative metabolism at the onset of moderate-intensity step transitions in older adults. AB - Aging is associated with a functional decline of the oxidative metabolism due to progressive limitations of both O(2) delivery and utilization. Priming exercise (PE) increases the speed of adjustment of oxidative metabolism during successive moderate-intensity transitions. We tested the hypothesis that such improvement is due to a better matching of O(2) delivery to utilization within the working muscles. In 21 healthy older adults (65.7 +/- 5 yr), we measured contemporaneously noninvasive indexes of the overall speed of adjustment of the oxidative metabolism (i.e., pulmonary Vo(2) kinetics), of the bulk O(2) delivery (i.e., cardiac output), and of the rate of muscle deoxygenation (i.e., deoxygenated hemoglobin, HHb) during moderate-intensity step transitions, either with (ModB) or without (ModA) prior PE. The local matching of O(2) delivery to utilization was evaluated by the DeltaHHb/DeltaVo(2) ratio index. The overall speed of adjustment of the Vo(2) kinetics was significantly increased in ModB compared with ModA (P < 0.05). On the contrary, the kinetics of cardiac output was unaffected by PE. At the muscle level, ModB was associated with a significant reduction of the "overshoot" in the DeltaHHb/DeltaVo(2) ratio compared with ModA (P < 0.05), suggesting an improved O(2) delivery. Our data are compatible with the hypothesis that, in older adults, PE, prior to moderate-intensity exercise, beneficially affects the speed of adjustment of oxidative metabolism due to an acute improvement of the local matching of O(2) delivery to utilization. PMID- 22422669 TI - Vascular perfusion limits mesenteric lymph flow during anaphylactic hypotension in rats. AB - To determine fluid extravasation in the splanchnic vascular bed during anaphylactic hypotension, the mesenteric lymph flow (Q(lym)) was measured in anesthetized rats sensitized with ovalbumin, along with the systemic arterial pressure (P(sa)) and portal venous pressure (P(pv)). When the antigen was injected into the sensitized rats (n = 10), P(sa) decreased from 125 +/- 4 to 37 +/- 2 mmHg at 10 min with a gradual recovery, whereas P(pv) increased by 16 mmHg at 2 min and returned to the baseline at 10 min. Q(lym) increased 3.3-fold from the baseline of 0.023 +/- 0.002 g/min to the peak levels of 0.075 +/- 0.009 g/min at 2 min and returned to the baseline within 12 min. The lymph protein concentrations increased after antigen, a finding indicating increased vascular permeability. To determine the role of the P(pv) increase in the antigen-induced increase in Q(lym), P(pv) of the nonsensitized rats (n = 10) was mechanically elevated in a manner similar to that of the sensitized rats by compressing the portal vein near the hepatic hilus. Unexpectedly, P(pv) elevation alone produced a similar increase in Q(lym), with the peak comparable to that of the sensitized rats. This finding aroused a question why the antigen-induced increase in Q(lym) was limited despite the presence of increased vascular permeability. Thus the changes in splanchnic vascular surface area were assessed by measuring the mesenteric arterial flow. The mesenteric arterial flow was decreased much more in the sensitized rats (75%; n = 5) than the nonsensitized P(pv) elevated rats (50%; n = 5). In conclusion, mesenteric lymph flow increases transiently after antigen presumably due to increased capillary pressure of the splanchnic vascular bed via downstream P(pv) elevation and perfusion and increased vascular permeability in anesthetized rats. However, this increased extravasation is subsequently limited by decreases in vascular surface area and filtration pressure. PMID- 22422670 TI - Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise. AB - In a previous report (Schier et al., Am J Physiol Regul Integr Comp Physiol 301: R1557-R1568, 2011), we demonstrated with a new behavioral procedure that rats exhibit stimulus-bound suppression of intake in response to an intraduodenal (ID) bitter tastant predicting subsequent malaise. With the use of the same modified taste aversion procedure, the present experiments evaluated whether the sweet taste properties of ID stimuli are likewise detected and encoded. Thirsty rats licked at sipper spouts for hypotonic NaCl for 30 min and received brief (first 6 min) yoked ID infusions of either the same NaCl or an isomolar lithium chloride (LiCl) solution in each session. An intestinal taste cue was mixed directly into the LiCl infusate for aversion training. Results showed that rats failed to detect intestinal sweet taste alone (20 mM Sucralose) but clearly suppressed licking in response to a nutritive sweet taste stimulus (234 mM sucrose) in the intestine that had been repeatedly paired with LiCl. Rats trained with ID sucrose in LiCl subsequently generalized responding to ID Sucralose alone at test. Replicating this, rats trained with ID Sucralose in compound with 80 mM Polycose rapidly suppressed licking to the 20 mM Sucralose alone in a later test. Furthermore, ID sweet taste signaling did not support the rapid negative feedback of sucrose or Polycose on intake when their digestion and transport were blocked. Together, these results suggest that other signaling pathways and/or transporters engaged by caloric carbohydrate stimuli potentiate detection of sweet taste signals in the intestine. PMID- 22422671 TI - Body image predicts quality of life in men with prostate cancer. AB - OBJECTIVE: Most men diagnosed with prostate cancer in the USA will survive. Of the many aspects of survivorship affected by prostate cancer, body image receives limited attention despite some indication that it may be important to men with the disease. The present study investigated how body image changes over time and the relations between changes in body image and quality of life (QOL) in men with prostate cancer. METHODS: In a longitudinal design, patients (N = 74) completed questionnaires before treatment (T1) and at 1 month (T2) and 2 years (T3) following treatment completion. RESULTS: Growth curve modeling indicated that there was no significant change over time in group-level body image scores. However, hormone treatment was associated with a negative trajectory of change over 2 years. Also, analysis of individual difference scores indicated that >=50% of patients demonstrated change of at least 0.5 standard deviation between time points. Hierarchical regression indicated that change in body image between T1 and T2 was significantly associated with change in QOL between T1 and T3, while controlling for demographic variables, treatment, treatment-related functioning, and general and treatment-specific positive expectations. In predicting change in body image between T1 and T2, treatment-specific positive expectation was the only significant predictor. CONCLUSIONS: The present study demonstrates that body image is an important component of the prostate cancer experience. Findings suggest that body image has a meaningful association with QOL among prostate cancer survivors. PMID- 22422672 TI - Not all types of acute kidney injury are equal in the setting of liver transplantation. PMID- 22422673 TI - Palladium-catalyzed carbonylative Heck reaction of aryl bromides with vinyl ethers to 3-alkoxy alkenones and pyrazoles. AB - Three COming together: The first carbonylative Heck coupling reaction of aryl bromides and vinyl ethers leading to 1-aryl-3-alkoxy-2-propen-1-ones has been established (see scheme). Based on this coupling methodology, a novel one-pot synthesis of aryl-substituted pyrazoles was also realized. PMID- 22422674 TI - Intracoronary ECG ST-segment recovery during primary percutaneous intervention for ST-segment myocardial infarction: insights from a cardiac MRI study. AB - BACKGROUND: ST-segment-resolution (STR) on surface electrocardiogram (ECG) is a good surrogate for myocardial reperfusion in patients with acute ST-segment elevation-myocardial-infarction (STEMI). We sort to determine the optimal criteria of measuring STR on intracoronary-ECG (IC-ECG) for prediction of myocardial injury evaluated by cardiac MRI (CMR). METHODS: Measurements of IC-ECG ST-segments were performed at baseline, immediately after (early) and 15 min (late) after achieving TIMI-3 flow during primary-PCI. The degree of ST-segment shift from baseline noted upon the IC-ECG was divided into four groups: (group 1) ST-segment-resolution >1 mm, (group 2) <30% resolution, (group 3) >50% resolution, (group 4) >70% resolution at both early and late time points. Patients had CMR at days 3 and 90 postprimary-PCI. RESULTS: Fifty two patients (aged 60 +/- 11 years; 43 males) were evaluated. Early intracoronary-ECG ST segment resolution (early IC-STR >1 mm) correlated with smaller scar mass (P = 0.003), nonviable myocardial mass (P < 0.001), and microvascular obstruction (MVO) (P = 0.004) on CMR at day 3. Ejection fraction (EF) was also better at day 3 (P = 0.026) and 90 (P = 0.039). Patients with poor early IC-STR (IC-STR <30%) conversely is associated with larger scar mass (P = 0.017), nonviable myocardial mass (P = 0.01), and MVO (P = 0.021) at day 3. This was also associated with worse EF at day 90 (P = 0.044). Neither group 3 or 4, or the late measurements of late IC-STR correlated with CMR markers of myocardial injury. CONCLUSION: The degree of early IC-STR (defined by IC-STR > 1 mm or <30%) successfully predicts myocardial damage following primary-PCI for an acute STEMI. Further studies are required to investigate its potential utility. PMID- 22422675 TI - Protective effects of fermented Citrus unshiu peel extract against ultraviolet-A induced photoageing in human dermal fibrobolasts. AB - The aqueous extracts of Citrus unshiu peel containing flavonoid glycosides was used as co-substrate with Schizophyllum commune mycelia producing beta glucosidase and its biological activities were studied. beta-glucosidase-produced S. commune mycelia converted the glycosides (narirutin and hesperidin) into aglycones (naringenin and hesperetin). The photoprotective potential of fermented C. unshiu peel extract with S. commune (S-CPE) was tested in human dermal fibroblasts (HDFs) exposed to UVA. It was revealed that S-CPE had an inhibitory effect on human interstitial collagenase (matrix metalloproteinase, MMP-1) expression in UVA-irradiated HDFs. The treatment of UVA-irradiated HDFs with S CPE resulted in a dose-dependent decrease in the expression level of MMP-1 mRNA. The UVA irradiation raised the proportion of senescence-associated beta galactosidase (SA-beta-gal) positive cells in comparison with the normal control group. The treatment of UVA-irradiated HDFs with S-CPE was shown to decrease the level of SA-beta-gal (by approximately 45% at an S-CPE concentration 0.1%, w/v) compared with the UVA-irradiated HDFs. It was found that S-CPE containing hesperetin has notable collagen biosynthetic activity for fibroblasts, indicating that S-CPE can be promising cosmetic ingredients. PMID- 22422676 TI - 3rd International Consultation on Incontinence--Research Society 2011. PMID- 22422678 TI - Determination of febuxostat in human plasma using ultra-performance liquid chromatography tandem mass spectrometry. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of febuxostat in human plasma. The liquid-liquid extraction technique was used for the extraction of febuxostat from human plasma using trandolapril as the internal standard (IS). Chromatography was performed on a ultra-performance liquid chromatography (UPLC) BEH C18, 50 mm X 2.1 mm, 1.7 um particle size column, with the mobile phase consisting of 0.1% formic acid and acetonitrile (in a 25:75 ratio), followed by detection using mass spectrometry. The method involves a simple reversed isocratic chromatography condition and mass spectrometry detection, which enables detection at sub-microgram levels. The method was validated and the lower limit of quantification for febuxostat was found to be 0.075 ug/ml. The mean recovery for febuxostat ranged from 100.9 to 106.5%. This method increased the sensitivity and selectivity; resulting in high-throughput analysis of febuxostat using commercially available IS for pharmacokinetic, bioavailability, and bioequivalence studies, with a chromatographic run time of 1.5 min only. PMID- 22422677 TI - Mouse genetic and phenotypic resources for human genetics. AB - The use of model organisms to provide information on gene function has proved to be a powerful approach to our understanding of both human disease and fundamental mammalian biology. Large-scale community projects using mice, based on forward and reverse genetics, and now the pan-genomic phenotyping efforts of the International Mouse Phenotyping Consortium, are generating resources on an unprecedented scale, which will be extremely valuable to human genetics and medicine. We discuss the nature and availability of data, mice and embryonic stem cells from these large-scale programmes, the use of these resources to help prioritize and validate candidate genes in human genetic association studies, and how they can improve our understanding of the underlying pathobiology of human disease. PMID- 22422679 TI - Evaluation of the impact of HIV serostatus, tobacco smoking and CD4 counts on epidermoid anal cancer survival. AB - Tobacco smoking and HIV infection increase the risk of epidermoid anal cancer (EAC). No published studies have examined smoking and EAC outcomes, and the literature is discrepant regarding outcomes of HIV-positive patients with EAC. The goal of this study was to examine smoking history, HIV status and outcomes in EAC patients. We conducted a retrospective analysis of adults with invasive EAC treated in the University of Washington hospital system from 1 January 1994 to 31 December 2008. Sixty-three patients were included. Forty-seven patients (75%) had primary chemoradiation, of whom 42 (89%) completed therapy. Two patients (3%) received radiotherapy alone. Fourteen patients (22%) underwent primary surgery, of whom 11 (79%) underwent tumour excision and three (21%) abdominoperineal resection (APR). We analysed smoking history, HIV status and CD4 count (>= 200 cells/MUL/<200 cells/MUL for HIV-positive patients) versus outcomes. Forty-five patients (71%) were in remission, and 44 (70%) were alive at last follow-up. Overall survival was significantly better for never-smokers than for ever smokers. There were no differences in outcomes according to HIV status or CD4 counts. Patients with anal cancer who smoke have worse overall survival than non smoking patients. HIV infection does not appear to affect anal cancer outcomes. PMID- 22422680 TI - Use of the Internet for home testing for Chlamydia trachomatis in Sweden: who are the users? AB - Sweden was the first country to introduce online Chlamydia trachomatis testing for both men and women and this article provides information about the user characteristics and which risk groups are reached with this method. During the years 2005-2007 a questionnaire was administered with a response rate of 86% (n = 6025) (62.5% women, 37.5% men). Over 60% of respondents were aged below 26 years and single. The average years of education for men and women was 14 (range 9.0 26.0). The mean Internet usage time was 22.4 hours/week among men and 15.5 hours/week among women. Only 22% men and 34% women had tested themselves for C. trachomatis at clinics previously. Respondents reported a higher frequency of previous sexually transmitted infections (STIs) compared with other Internet users (i.e. C. trachomatis: men 19%, women 24%). Eighty percent of online test users had engaged in sex with >= 2 partners without a condom during the previous year. Online C. trachomatis test users are mostly young people with high sexual risk behaviour. PMID- 22422681 TI - Declining sexually transmitted infections among female sex workers: the results of an HIV and sexually transmitted infection prevention strategy in Honduras, 2006-08. AB - In 2006, we implemented an HIV and sexually transmitted infection (STI) prevention programme for female sex workers (FSWs) in three Honduran cities. All FSW attending STI clinics underwent regular examinations and STI testing. Information on condom use with different partners was collected at each visit. After three years, we detected a significant decline in the prevalence of syphilis from 2.3% at the first screening to 0.0% at the third screening (P = 0.05), and of chlamydia, from 6.1% to 3.3% (P = 0.01). No changes were observed in the prevalence of gonorrhoea or trichomoniasis. The cumulative HIV prevalence remained constant (P = 0.44). Reports of condom use with clients increased from 93.8% to 98.9% (P < 0.001). The implementation of an HIV/STI prevention programme in FSW has contributed to increases in condom use with clients and the reduction in syphilis and chlamydia prevalence. The intervention should be strengthened and considered as part of a national health policy strategy. PMID- 22422682 TI - Predictors of antiretroviral treatment-associated tuberculosis in Ethiopia: a nested case-control study. AB - Little is known about the predictors of antiretroviral treatment (ART)-associated tuberculosis (TB) in developing nations. The objective of this study was to determine predictors of ART-associated TB in adults with HIV infection at Jimma University Hospital, Ethiopia. A nested case-control study was conducted in October 2009. The study population consisted of adults with HIV infection (aged >14 years) who developed active TB in the first six months since ART initiation and controls that did not develop active TB. Data were collected using a structured and pretested questionnaire. Cox proportions hazards analysis was done to determine predictors of ART-associated TB. A total of 357 patients (119 cases and 238 controls) participated in the study. After six months of follow-up, cumulative incidence of ART-associated TB was 5.2% (123/2355). Forty (33.6%) cases were lost to follow-up after they developed ART-associated TB and 11 (9.2%) died. Fifty-one (21.4%) controls interrupted ART and 11 (4.6%) died. A CD4 lymphocyte count increase >0.5/MUL/day (adjusted hazard ratio [AHR] = 19.80, 95% confidence interval [CI]: 9.52, 41.12, P < 0.001), a base-line CD4 lymphocyte count <200 cells/MUL (AHR = 9.59, 95% CI: 2.36, 39.04, P = 0.002), World Health Organization (WHO) clinical stage 3 or 4 (AHR = 3.04, 95% CI: 1.62, 5.69, P < 0.001), night sweats during ART initiation (AHR = 1.53, 95% CI: 1.06, 2.21, P < 0.001) and high ART adherence (AHR = 1.30, 95% CI: 1.13, 1.50, P < 0.001) were independent predictors of ART-associated TB. HIV-infected adults with these risk factors should be followed cautiously for the development of ART-associated TB. Good ART adherence and a good immunological response during ART were associated with ART-associated TB, most likely because of an immune reconstitution inflammatory syndrome unmasking the TB. PMID- 22422683 TI - Patients accessing HIV treatment via sexual health services: what are the risks of the dual case-note system? AB - In many British hospitals, HIV-positive patients access care via genitourinary (GU) medicine services. As a result of National Health Service (NHS) legislation, such patients may have information concerning HIV treatment filed separately from their general clinical records. We sought to evaluate accuracy of medication records of patients with both GU medicine and general hospital case-notes, and to assess clinical risk arising from incorrect or incomplete recording. In this retrospective review, 156 episodes of care from 100 HIV-positive patients with separate HIV case-notes were evaluated for accuracy of medication recording, when paired with clinical notes from attendances in other hospital departments. Discrepancies were observed in 52.6% of care episodes; significant discrepancies were apparent in 7.8%. The dual case-note system represents significant risk to patient care. We recommend that hospitals that continue to operate this system urgently consider amalgamation of HIV care records into hospital case sheets, in line with current national standards. PMID- 22422684 TI - Longitudinal assessment of cardiac diastolic function in HIV-infected patients. AB - Asymptomatic isolated diastolic dysfunction (DD), with normal left ventricular systolic function, may be the first indication of underlying cardiac disease in HIV-negative populations. We previously reported a high prevalence (37%) of DD among asymptomatic HIV-infected patients at low risk for AIDS and cardiovascular disease (CVD). We performed a longitudinal assessment of interval echocardiographic changes in this cohort over a four-year period. Repeat transthoracic echocardiograms (TTEs) utilized standard techniques. Sixty (of the original 91) HIV-infected patients, predominately men, underwent repeat TTE (median follow-up 3.7 years, interquartile range [IQR] 3.5, 4.0). Cohort characteristics (median; IQR) include age 42.0 (36.5, 46.0) years, HIV duration 16.4 years (8.1, 18.9), current CD4 count 572.0 cells/mm(3) (436.5, 839.0), antiretroviral therapy (ART) duration 8.1 years (4.8, 13.4) and Framingham risk score 1.0 (0.0, 2.0). DD was observed in 28/60 patients on re-evaluation (47%, 95% confidence interval [CI] 34%, 60%); 31% (11/36) of patients had new onset DD for an overall incidence of 8.2/100 person-years. On follow-up, subjects with DD were older, had a trend towards higher body mass index, hypertension and longer duration of HIV infection compared with subjects without DD. We confirmed a high prevalence of DD (47%) in asymptomatic HIV-infected patients at low risk for AIDS and CVD. PMID- 22422685 TI - Incidence of major clinical outcomes in a cohort of Ugandan and Zimbabwean women with HIV-1 infection followed from seroconversion. AB - We conducted a prospective cohort study of 306 HIV-1-infected women, followed from seroconversion for median 6.4 years in Uganda (UG) and Zimbabwe (ZM) to describe the incidence of major clinical outcomes (MCOs), defined as World Health Organization stage 4 conditions and any tuberculosis (TB). In Uganda, 19 MCOs occurred in 13 participants at median 4.6 years and a median CD4 count of 213 cells/mm(3). In Zimbabwe, 29 MCOs occurred in 27 participants at median 4.0 years (P < 0.001 versus UG) and median CD4 count of 219 cells/mm(3) (P = 0.83 versus UG). MCO incidence was not statistically different (UG: 2.82 cases/100 person years versus ZM: 2.45; P = 0.64) except for TB (UG: 0.59 versus ZM: 2.02 cases/100 person-years; P = 0.02). This significant difference in TB incidence is primarily due to a TB screening and isoniazid prevention therapy programme that was implemented in Uganda, but not in Zimbabwe, highlighting the importance of integrated TB screening and treatment within HIV programmes. PMID- 22422686 TI - Sexual assault and coincident alcohol use in attendees at a genitourinary medicine clinic in the south of England. AB - To investigate the relationship between alcohol consumption and the experience of sexual assault, either as victim or perpetrator, among genitourinary (GU) medicine department attendees in Portsmouth, UK, we carried out a cross-sectional survey of consecutive patients attending the walk-in service when a researcher was available. Self-completed questionnaires were used and anonymized data were collected from 1186 participants (response rate 34%). Responses showed that 15.6% of female and 3.7% of male participants had ever being sexually assaulted. Women who reported sexual assault drank more on a heavy night out than those who did not report sexual assault (mean 21.3 versus 17.0 units, P = 0.041). Over half of the victims had been drinking prior to the relevant assault. Twenty-seven participants (2.3%) admitted to having sex with a person who was not fully willing. Of these, 59% had been drinking prior to the assault, and the majority believed alcohol had contributed to the assault. Any strategies aiming to reduce the incidence of sexual assault must address hazardous drinking as a high priority. PMID- 22422687 TI - Evaluation of HIV-1 resistance to antiretroviral drugs among 150 patients after six months of therapeutic interruption. AB - Most of the antiretroviral (ARV) studies in Brazil have been reported in treatment-experienced and naive patients rather than in the setting of treatment interruption (TI). In this study, we analysed reasons given for TI and resistance mutations occurring in 150 HIV-1-infected patients who underwent TI. Of the patients analysed, 110 (73.3%) experienced TI following medical advice, while the remaining patients stopped antiretroviral therapy (ART) of their own accord. The main justifications for TI were: ARV-related toxicities (38.7%), good laboratory parameters (30%) and poor adherence (20%). DNA sequencing of the partial pol gene was successful in 137 (91.3%) patients, of whom 38 (27.7%) presented mutations conferring ARV resistance. A higher viral load prior to TI correlated with drug resistance (P < 0.05). Our results demonstrate that there are diverse rationales for TI and that detection of resistant strains during TI most likely indicates a fitter virus than the wild type. High viral loads coupled with unprotected sex in this group could increase the likelihood of transmission of drug-resistant virus. Thus, treating physicians should be alerted to this problem when the use of ARVs is interrupted. PMID- 22422688 TI - Efficacy and safety of ceftriaxone for uncomplicated gonorrhoea: a meta-analysis of randomized controlled trials. AB - We conducted a systematic review and meta-analysis of ceftriaxone for treatment of uncomplicated gonorrhoea compared with four other antibiotics. Thirteen randomized controlled trials (RCTs) totalling treatment of 2557 patients with uncomplicated gonorrhoea were included. Statistically significant differences were observed in side-effects, which were increased after ceftriaxone 250 mg versus cefotaxime 500 mg (odds ratio [OR] 1.87; 95% confidence interval [CI] 1.14 3.08). Cure rates of ceftriaxone 250 mg were significantly better than cefixime 400 mg (OR 1.77; 95% CI 1.11-2.80) as was ceftriaxone 125 mg versus spectinomycin 2 g (OR 3.44; 95% CI 1.08-10.90). There was no statistically significant difference between ceftriaxone 250 mg and cefixime 800 mg in cure rates (OR 1.39; 95% CI 0.92-2.10) or adverse effects (OR 1.29, 95% CI 0.58-2.84) for treating uncomplicated gonorrhoea. The cure rate after ceftriaxone 250 mg was not significantly different from that after spectinomycin 2 g (OR 1.96; 95% CI 1.00 3.87). In conclusion, this meta-analysis revealed that 250 mg ceftriaxone had a higher efficacy than 400 mg cefixime for uncomplicated gonorrhoea. Also, ceftriaxone 125 mg is a better choice than spectinomycin 2 g for patients with uncomplicated gonorrhoea, but ceftriaxone had higher side-effect rates than cefotaxime. In the current era further randomized controlled clinical trials of ceftriaxone for uncomplicated gonorrhoea are warranted. PMID- 22422689 TI - A tale of two audits: closing the feedback loop on clearance rates of anogenital warts at three months. AB - Our management of anogenital warts was audited. By case-note review 95% were clear of original warts by three months (assuming wart clearance if patients stopped attending). However, by confirmed outcome (documented in case-notes or verified by telephone) only 81% were clear. The main reason for failure was inconsistent patient attendance. Subsequently, clinic staff were advised to emphasize the importance of regular treatment. A second audit was performed after 12 months. By case-note review 127/134 (95%) had achieved wart clearance, but by confirmed outcome only 74/89 (83%) were clear (P = 0.004). More men (89%) achieved clearance than women (80%). Again, the main reason for failure was inconsistent attendance. There are few data of outcomes in clinical practice at three months. Auditable outcome measures should be challenging yet achievable. Perhaps 90% clearance at three months is not achievable in clinical practice when allowing for the evidence base and patient choice. Is it time to revise the standard? PMID- 22422690 TI - Managing vaccines: defining the remit of primary care and specialist HIV clinics in the delivery of immunization to individuals with HIV infection. AB - The British HIV Association (BHIVA) has published guidelines for immunization of HIV-infected adults. A chart review of 200 HIV-infected patients diagnosed was conducted to determine shortcomings in previous practice and determine which vaccines should routinely be given in specialist HIV clinics and which might be able to be delegated to primary care clinics. Data were collected on administration of three categories of vaccinations: (1) vaccines used in all individuals with chronic disease (pneumococcal, influenza, swine flu H1N1); (2) targeted vaccinations used in non-immune individuals with HIV who are at risk of exposure (hepatitis A and hepatitis B); (3) routine vaccines traditionally delivered to the whole population (measles/mumps/rubella [MMR], diphtheria/tetanus/pertussis and meningitis C/ACWY). Pneumococcal vaccine was delivered to 54% of eligible patients, 52% of eligible individuals completed a full hepatitis B programme of vaccination and 21% (42/200) were naturally immune; hepatitis A vaccine was delivered to 36% of eligible individuals. With increasing demands on resources, it seems likely that HIV services will have to harness resources of primary care in vaccine programmes in relation to routine vaccines. By improving communication between primary and secondary care mistakes with live vaccination decisions could be avoided; HIV services should continue to perform targeted and chronic disease vaccines, i.e. for category 1 and category 2 vaccines. PMID- 22422691 TI - Early invasive squamous cell carcinoma of the penis presenting in a 39-year-old man. AB - Penile cancer, albeit an uncommon malignancy, commonly affects men aged between 50 and 70 years, often with a history of predisposing factors such as Bowen's disease or leukoplakia. We describe a case of early invasive squamous cell carcinoma of the penis in a 39-year-old man with no history of predisposing factors, treated by a partial glansectomy. PMID- 22422692 TI - Tuberculous syringomyelia in an HIV-infected patient: a case report. AB - A 37-year-old HIV-positive Gambian woman presented with spastic weakness of the right leg six years after receiving treatment for tuberculous meningitis (TBM). Magnetic resonance imaging (MRI) of the spine showed a multiloculated syrinx in the thoracic spinal cord extending from the T2 to the T11 level. Syringomyelia and syringobulbia have been reported as complications of TBM. We describe the first case of syringomyelia as an uncommon late complication of treated TBM in the setting of HIV infection. Early recognition of this rare entity may avoid irreversible neurological sequelae. PMID- 22422693 TI - Brachial plexus neuritis in the context of acute HIV seroconversion illness: a case report. AB - We report an unusual case of bilateral brachial plexus neuritis occurring during the seroconversion stage of an HIV infection in a 45-year-old man. Brachial plexus neuritis is thought to be an immune mediated inflammatory reaction resulting in acute onset of shoulder pain followed by muscle weakness and wasting. There is often a history of viral illness, diagnosis is clinical, and treatment is supportive. Many sufferers are left with residual defects. Clinicians should consider the possibility of HIV infection when managing a patient with brachial plexus neuritis. PMID- 22422694 TI - Bilateral brachial neuritis secondary to varicella reactivation in an HIV positive man. AB - We present the case of a 48-year-old HIV-positive man, who developed acute onset of pain in both upper limbs associated with proximal weakness and distal paraesthesia. Eight weeks prior to this presentation he had had varicella zoster affecting his right S1 dermatome. CD4 count was 355 cells/mm(3) and he was antiretroviral therapy (ART) naive. Power was 0/5 proximally and 4/5 distally in the upper limbs. Reflexes were absent and there was sensory loss in the C5, C6 and T1 dermatomes. Cerebrospinal fluid (CSF) examination showed a lymphocytosis with low glucose; however, CSF Mycobacterium tuberculosis (TB), and herpes simplex virus polymerase chain reaction (HSV PCR) were negative as was syphilis serology. Electromyography showed marked motor axonal loss. Magnetic resonance imaging (MRI) did not show any cervical spinal lesion. Varicella zoster virus (VZV) PCR was positive in the CSF. He was treated with high-dose intravenous aciclovir with good resolution of his syndrome over time and was commenced on ART. We believe this to be the first case report of varicella reactivation causing bilateral neuralgic amyotrophy in an HIV-positive patient. PMID- 22422695 TI - An unusual haematological presentation of the immune reconstitution inflammatory syndrome. AB - We describe the case of a newly diagnosed HIV-1-positive man who was noted to have asymptomatic HIV-related idiopathic (immune) thrombocytopaenic purpura. On commencing antiretroviral therapy we believe he experienced an uncommon immune reconstitution phenomenon resulting in the rapid worsening of his thrombocytopenia, requiring steroid therapy which stabilized his platelet levels. PMID- 22422696 TI - The perils of relying on anti-hepatitis B total core antibody in screening individuals infected with HIV. AB - Co-infection with HIV and hepatitis B virus (HBV) has serious long-term consequences. We describe a case of an HIV-infected heterosexual black African man with a delayed diagnosis of HBV infection. Baseline HBV screening was performed using a sequential testing algorithm starting with a total core antibody (anti-HBc) test, which was negative. He had no evidence of immunity against HBV and subsequently received three unsuccessful courses of HBV vaccination. He had mild but persistent elevation of liver enzymes over a five year period despite maintaining full suppression of HIV replication on efavirenz, lamivudine and zidovudine; the latter was changed to abacavir due to lipoatrophy. Further testing revealed e-antibody positive chronic HBV infection with undetectable anti-HBc reactivity. High-grade HBV viraemia associated with L180M and M240V drug-resistance mutations was confirmed. He was subsequently switched to a tenofovir-based regimen, which achieved HBV suppression. Adopting effective HBV screening strategies in HIV-infected patients is recommended. PMID- 22422697 TI - The prevalence of selected high-risk human papillomavirus infections among female sex workers in Dhaka, Bangladesh. PMID- 22422698 TI - 1,4-Bis(diarylamino)-2,5-bis(4-cyanophenylethenyl)benzenes: fluorophores exhibiting efficient red and near-infrared emissions in solid state. PMID- 22422699 TI - Prevention of de novo hepatitis B with adefovir dipivoxil in recipients of liver grafts from hepatitis B core antibody-positive donors. AB - Lamivudine has been shown to prevent de novo hepatitis B virus (HBV) infections in liver transplantation (LT) patients receiving hepatitis B core antibody positive (HBcAb(+)) grafts, but it may produce long-term resistance. Adefovir dipivoxil (ADV) might be effective in preventing de novo hepatitis and resistance. A single-center, prospective trial was conducted with 16 adults (10 men and 6 women, mean age = 54 +/- 11 years) who underwent LT with HBcAb(+) grafts between September 2007 and October 2009. After LT, patients were given ADV [10 mg daily (adjusted for renal function)]. No hepatitis B immune globulin was administered. At LT, all graft recipients were hepatitis B surface antigen negative (HBsAg(-)), 38% were surface antibody-positive (HBsAb(+)), and 50% were HBcAb(+). The median follow-up after LT was 1.8 years (range = 1.0-2.6 years). All recipients had undetectable HBV DNA (<40 IU/mL) after LT until the end of follow-up. One recipient (6%) who was HBsAb(-) and HBcAb(-) before LT became HBsAg(+) after 52 weeks. One recipient was switched from ADV to entecavir for chronic renal insufficiency, and 19% of the patients had renal dose adjustments. There was a nonsignificant trend of increasing creatinine levels over time (1.2 mg/dL at LT, 1.3 mg/dL 1 year after LT, and 2.0 mg/dL 2 years after LT, P = 0.27). A comparison with a control cohort of LT recipients with hepatitis C virus who did not receive ADV showed no difference in the creatinine levels at LT or 1 year after LT. In conclusion, ADV prophylaxis prevents HBV replication in recipients of HBcAb(+) livers but does not fully protect recipients from de novo HBV. Long-term follow-up is needed to better determine the risk of de novo infection. PMID- 22422700 TI - A new trick of INPP4A: decreased expression of INPP4A in patients with temporal lobe epilepsy and pilocarpine-induced rat model. AB - Inositol polyphosphate phosphatase 4 A (INPP4A), a phosphoinositides phosphatase, is highly expressed in the central nervous system and plays a role in glutamate excitotoxicity and cell proliferation. Our aim was to investigate the expression of INPP4A in patients with temporal lobe epilepsy (TLE) and in a rat model of epilepsy. We assessed the expression of INPP4A in the temporal neocortex from 20 TLE patients. The result showed that INPP4A expression was significantly lower in TLE patients than in controls. To validate the results found in TLE patients, we assessed the expression of INPP4A in rat model. Rat epilepsy was induced by lithium-pilocarpine. Expression of INPP4A of rat models was assessed by immunohistochemistry, immunofluorescence, and Western blotting. INPP4A was expressed in the membrane and cytoplasm of neurons. In the hippocampus and neocortex of epileptic rats, INPP4A expression was first downregulated at the 24 h after seizures and maintained decreased levels at 72 h, 7 days, 14 days, 30 days, and 60 days, respectively. These results suggest that a decreased expression of INPP4A in the brain may be associated with TLE. PMID- 22422701 TI - Early beneficial effects of drug-eluting stents in vein grafts wane during long term follow-up: a case-control study. AB - OBJECTIVES: The aim of the study was to compare outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in saphenous vein graft (SVG) interventions in a case-control study with a long-term follow-up. BACKGROUND: Safety and efficacy of DES in SVG interventions are still controversial. METHODS: We performed a multicenter registry assessing clinical outcomes with DES vs. BMS. We included 311 patients (239 men, age 68 +/- 8 years) who underwent percutaneous coronary interventions (PCI) of SVG lesions with DES (n = 138) or BMS (n = 173) with a 2-year follow-up. RESULTS: The two groups were similar for age, sex, main risk factors, incidence of diabetes, use of IIb/IIIa antagonists, use of aspiration devices or filters, number of stents, and total stent length. Overall, at 9 months follow-up incidence of major adverse cardiac events (MACE) and target vessel revascularization (TVR) were significantly lower in the DES group compared with the BMS group (10.9% vs. 22.0%, P = 0.014 and 8.7% vs. 19.1% in DES and BMS respectively, P = 0.015), while there was no significant difference in incidence of myocardial infarction (5.1% vs. 5.2%, P = 0.96) or death (2.2% vs. 4%, respectively, P = 0.54). However, at 24-month follow-up incidence of MACE was 29.7% in the DES group and 37.0% in BMS group (P = 0.29); incidence of TVR (23.2% vs. 28.9% P = 0.39), myocardial infarction (9.4% vs. 9.2%), death (7.2% vs. 6.9%) were also similar in the two groups. CONCLUSIONS: Although DES appear safe, our findings suggest that the early benefit of DES in SVG may rapidly wane during long-term follow-up. PMID- 22422702 TI - Representation of rare diseases in health information systems: the Orphanet approach to serve a wide range of end users. AB - Rare disorders are scarcely represented in international classifications and therefore invisible in information systems. One of the major needs in health information systems and for research is to share and/or to integrate data coming from heterogeneous sources with diverse reference terminologies. ORPHANET (www.orpha.net) is a multilingual information portal on rare diseases and orphan drugs. Orphanet information system is supported by a relational database built around the concept of rare disorders. Representation of rare diseases in Orphanet encompasses levels of increasing complexity: lexical (multilingual terminology), nosological (multihierarchical classifications), relational (annotations epidemiological data-and classes of objects-genes, manifestations, and orphan drugs-integrated in a relational database), and interoperational (semantic interoperability). Rare disorders are mapped to International Classification of Diseases (10th version), SNOMED CT, MeSH, MedDRA, and UMLS. Genes are cross referenced with HGNC, UniProt, OMIM, and Genatlas. A suite of tools allow for extraction of massive datasets giving different views that can be used in bioinformatics to answer complex questions, intended to serve the needs of researchers and the pharmaceutical industry in developing medicinal products for rare diseases. An ontology is under development. The Orphanet nomenclature is at the crossroads of scientific data repositories and of clinical terminology standards, and is suitable to be used as a standard terminology. PMID- 22422703 TI - Double C-H functionalization in sequential order: direct synthesis of polycyclic compounds by a palladium-catalyzed C-H alkenylation-arylation cascade. AB - Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)(2)] and PCy(3).HBF(4) in the presence of Cs(2)CO(3) in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring. PMID- 22422704 TI - Is overactive bladder in children and adults the same condition? ICI-RS 2011. AB - AIM: To report the debate on the relationship between overactive bladder (OAB) in children and adults during the ICI-RS meeting in 2010. METHODS: Literature supporting or being against the theory that OAB in children and adults represents the same condition has been reviewed and debated. RESULTS: Growing evidence is showing a strong link between urinary symptoms in childhood, such as nocturnal enuresis (NE) and OAB symptoms, and OAB in adulthood. Behavioral and environmental factors may have an important role in predisposed subjects. Studies on familial and genetic factors have been reported. CONCLUSION: It might be inappropriate to state that OAB in children and adults represents the same condition. However, epidemiological and genetic findings demonstrate a strong link between OAB symptoms in these two different ages of life. Predisposing factors and behavioral and/or environmental elements may lead to OAB occurrence in adults. PMID- 22422705 TI - Effects of anthocyanin-rich tea "Sunrouge" on dextran sodium sulfate-induced colitis in mice. AB - Sunrouge, an anthocyanin-rich tea, has similar levels of catechins as "Yabukita," the most popular green tea cultivar consumed in Japan. Green tea polyphenols (GTPs) have attracted interest due to their potent antioxidative activities combined with a lack of side effects in humans at normal consumption levels. However, we previously reported that high doses (0.5 and 1%) of dietary GTPs can result in deterioration of colitis and failed to prevent colon carcinogenesis in inflamed colons. In the present study, we determined the inhibitory effects of Sunrouge on colitis in dextran sodium sulfate (DSS)-treated and untreated control mice. Five-week-old female ICR mice were administered a single dose of Yabukita or Sunrouge (extracts in 1 mL distilled water) via a stomach tube for 3 weeks. After 1 week of treatment, the mice were divided into four groups (two Yabukita and two Sunrouge groups) and given drinking water with or without 3% DSS for 2 weeks, then they were euthanized. Those treated with DSS developed watery diarrhea and bloody stools, and showed body weight loss, spleen hypertrophy, and shortening of the colon, as well as deteriorations in survival rate, liver function, colon mucosal interleukin-1beta level and expression of phase II detoxification enzyme mRNA. Sunrouge improved these DSS-induced symptoms, at least in part, whereas Yabukita showed either no effect or adverse effects in regard to some those parameters. It is suggested that the differences between Yabukita and Sunrouge on DSS-induced colitis might be due to the high levels of anthocyanins found in Sunrouge tea. PMID- 22422706 TI - Control of MCAK degradation and removal from centromeres. AB - Mitotic centromere associated kinesin (MCAK) is a kinesin related protein with the ability to stimulate microtubule depolymerization. It is found at spindle poles, where it may be involved in poleward microtubule flux, and at kinetochores and centromeres where it plays a role in correcting chromosome alignment errors. Its microtubule depolymerase activity and recruitment to centromeres is regulated by phosphorylation, but little is known about how MCAK is maintained at appropriate levels. We previously reported that MCAK accumulates during the cell cycle and is then degraded during mitosis. Using proteomic analysis, we have now identified a new phosphorylation site on MCAK that is responsible for its degradation. Mutation of the site to prevent phosphorylation prolonged the stability of the protein beyond the metaphase to anaphase transition and into the subsequent cell cycle whereas a phosphomimetic mutation accelerated degradation. Unexpectedly, the mutation that prevented phosphorylation also inhibited the removal of MCAK from centromeres causing it to remain attached throughout the cell cycle. Even low expression of phosphorylation-resistant MCAK delayed mitosis and interfered with cell division. Mitotic defects were also observed by overexpressing a green fluorescent protein-tagged version of wild-type MCAK that similarly escaped degradation and accumulated to toxic levels, but did not remain associated with kinetochores during interphase. The results demonstrate that degradation is an important mechanism for controlling the activity of MCAK. PMID- 22422707 TI - Material transfer and polarity reversal in contact charging. AB - In touch: the outcome of contact electrification between dielectrics depends not only on the transfer of charge but also on the transfer of material. Although only minute quantities of materials are being exchanged during contact, they can reverse the polarity of dielectrics. The reported results corroborate the mosaic model and suggest that the observations are because of the mechanical softness/hardness of the materials. PMID- 22422708 TI - Hemodynamics-compliant reconstruction of the right hepatic vein for adult living donor liver transplantation with a right liver graft. AB - Secure reconstruction of the right hepatic vein (RHV) is essential for the successful implantation of a right liver graft during living donor liver transplantation (LDLT). To develop reliable surgical techniques for RHV reconstruction, we performed 3 concurrent studies: a simulation study using a fluid dynamics experimental model and a computational simulation model; an observational study analyzing the hemodynamic changes during radiological interventions for RHV stenosis; and a prospective clinical study establishing hemodynamics-compliant surgical techniques. The simplified fluid dynamics experimental model revealed that actually measured outflow volumes were very similar to theoretical values derived from a fluid dynamics formula. The computational simulation model showed that outflow decreases were nearly linearly correlated with the degree of stenosis when it exceeded 50%. The clinical observational study revealed that mild (<=50%), moderate (50%-75%), and severe RHV stenoses (>=75%) had mean pressure gradients of 2.5 +/- 1.0, 6.6 +/- 2.3, and 9.6 +/- 2.8 mm Hg, respectively. The prospective clinical study was performed for patients who underwent RHV reconstruction with RHV angle blunting and inferior vena cava enlargement (n = 274); a historical control group of patients who underwent reconstruction by other methods (n = 225) was also used. RHV stenting within 2 weeks and 1 year was necessary for 1 patient (0.4%) and 5 patients (1.8%) in the study group, respectively, and for 9 patients (4.0%) and 21 patients (9.1%) in the control group, respectively (P < 0.01). The mean cephalocaudal length of patulous RHV anastomoses was greater in the study group versus the control group (P < 0.001). In conclusion, our modified RHV reconstruction technique significantly reduces the risk of RHV stenosis. We thus suggest the routine or selective use of this technique as a part of graft standardization for LDLT using a right liver graft. PMID- 22422709 TI - Role of embolic protection devices in ostial saphenous vein graft lesions. AB - BACKGROUND: Although embolic protection devices (EPDs) have been shown to be beneficial in saphenous vein graft (SVG) lesions, their role in the subgroup of ostial SVG lesions has received limited study. METHODS: The coronary angiograms and procedural outcomes of 109 patients undergoing stenting of 113 ostial SVG lesions were retrospectively reviewed to determine the frequency of EPD use and the periprocedural outcomes. RESULTS: Ninety-eight (87%) of the 113 lesions were suitable for EPD use, that was used in 70 lesions (71%). A Filterwire (Boston Scientific) or a SPIDER (ev3) filter were used in 54 (77%) and 16 (23%) of lesions, respectively. Difficulty retrieving the filter post stenting was encountered in eight lesions (11%) and led to stent thrombosis causing cardiac arrest in one patient (1%). Angiographic success was achieved in 111 (98%) of 113 lesions. CONCLUSIONS: EPDs can be utilized in the majority of ostial SVG lesions, but in 11% of cases filter retrieval can be challenging and may rarely (in approximately 1%) lead to a significant complication. PMID- 22422710 TI - Functional parcellation of the inferior frontal and midcingulate cortices in a flanker-stop-change paradigm. AB - Conflict monitoring and motor inhibition are engaged in the performance of complex tasks. The midcingulate cortex (MCC) has been suggested to detect conflicts, whereas the right inferior frontal cortex (IFC) seems to be of relevance for the inhibition process. The current experiment investigates the neural underpinnings of their interplay via a modified flanker paradigm. Conflict was manipulated by the congruency of flanking stimuli relative to a target (congruent vs. incongruent) and motor inhibition by a within-trial response change of the initiated response (keep response vs. stop-change). We used event related functional magnetic resonance imaging, decomposition with high model order ICA, and single trial analysis to derive a functional parcellation of the whole-brain data. Results demonstrate the segmentation of the MCC into anterior and posterior subregions, and of the IFC into the pars opercularis, pars triangularis, and pars orbitalis. The pars opercularis and pars triangularis of the right IFC constituted the foundation of inhibition-related networks. With high conflict on incongruent trials, activity in the posterior MCC network, as well as in one right IFC network was observed. Stop-change trials modulated both the MCC as well as networks covering extended parts of the IFC. Whereas conflict processing and inhibition most often are studied separately, this study provides a synopsis of functionally coupled brain regions acting in concert to enable an optimal performance in situations involving interference and inhibition. PMID- 22422712 TI - n-Type reduced graphene oxide field-effect transistors (FETs) from photoactive metal oxides. AB - Graphene is of considerable interest as a next-generation semiconductor material to serve as a possible substitute for silicon. For real device applications with complete circuits, effective n-type graphene field effect transistors (FETs) capable of operating even under atmospheric conditions are necessary. In this study, we investigated n-type reduced graphene oxide (rGO) FETs of photoactive metal oxides, such as TiO(2) and ZnO. These metal oxide doped FETs showed slight n-type electric properties without irradiation. Under UV light these photoactive materials readily generated electrons and holes, and the generated electrons easily transferred to graphene channels. As a result, the graphene FET showed strong n-type electric behavior and its drain current was increased. These n doping effects showed saturation curves and slowly returned back to their original state in darkness. Finally, the n-type rGO FET was also highly stable in air due to the use of highly resistant metal oxides and robust graphene as a channel. PMID- 22422711 TI - The chemical complexity of cellular microtubules: tubulin post-translational modification enzymes and their roles in tuning microtubule functions. AB - Cellular microtubules are marked by abundant and evolutionarily conserved post translational modifications that have the potential to tune their functions. This review focuses on the astonishing chemical complexity introduced in the tubulin heterodimer at the post-translational level and summarizes the recent advances in identifying the enzymes responsible for these modifications and deciphering the consequences of tubulin's chemical diversity on the function of molecular motors and microtubule associated proteins. PMID- 22422713 TI - Mesoporosity of zeolite Y: quantitative three-dimensional study by image analysis of electron tomograms. PMID- 22422714 TI - Vascular pressure monitorization for necessity of vascular augmentation in a rat extended abdominal perforator flap model. AB - In case blood perfusion compromises, vascular enhancement with arterial supercharge or venous superdrainage can increase viability of the flap. In this study, vascular pressure monitorization was used in a rat extended abdominal perforator flap model to reveal intraoperative vascular compromise and the need for vascular augmentation. A rat abdominal perforator flap was designed, which was based on the right second cranial perforator of epigastric artery. Vascular pressures of the flap were monitored continuously for 60 min, by catheters placed in the right superficial inferior epigastric artery and vein. Forty rats were divided into four experimental groups, as follows: group 1 (n = 10, no vascular augmentation), group II (n = 10, arterial supercharge), group III (n = 10, venous superdrainage), and group IV (n = 10, arterial and venous augmentation). Arterial supercharge and/or venous superdrainage were performed by using the left superficial inferior epigastric artery and vein. After the rats were sacrificed on the 7th day, total flap area and necrotic regions were evaluated. Mean arterial blood pressure was found significantly lower (P < 0.05) and mean venous blood pressure was measured significantly higher (P < 0.05) in group I than the groups II, III, and IV. Flap survival area was also larger in the groups II, III, and IV than the group I (P < 0.05). The results of this experimental study demonstrate that arterial insufficiency and venous congestion are almost always present in the rat extended abdominal perforator flap model, similar to deep inferior epigastric perforator flap. When such an extended perforator flap is used, arterial and venous pressure monitorization may be considered as a tool to support intraoperative clinical findings to reveal the need of vascular augmentation and ascertain flap viability. PMID- 22422715 TI - Vitamin E in aging, dementia, and Alzheimer's disease. AB - Since its discovery, vitamin E has been extensively researched by a large number of investigators in an attempt to fully understand its role in a variety of pathophysiological contexts. The vast majority of published work has focused on vitamin E's antioxidant properties, which is why it is well known as a lipophilic antioxidant that protects membranes from being oxidatively damaged by free radicals. However, several lines of investigation have recently revealed that vitamin E has biological roles unrelated to its antioxidant properties. Among these roles, vitamin E has been described as: a regulator of signal transduction, gene expression, and redox sensor. In parallel with the discovery of novels cellular functions of vitamin E, the introduction of the free radical theory of brain aging has propelled a renewed interest in this vitamin. Most of the resulting work has been based on the postulate that, by preventing and/or minimizing the oxidative stress-dependent brain damage, vitamin E could be used as therapeutic approach. In this article, we will consider the existing literature regarding the biological properties of vitamin E and the potential therapeutic and/or preventative roles that this natural dietary factor plays in brain aging, cognition, and Alzheimer's dementia. PMID- 22422716 TI - Stability criteria for the outcomes of statistical tests to assess drug effectiveness with a single study. AB - At least two adequate and well-controlled clinical studies are usually required to support effectiveness of a certain treatment. In some circumstances, however, a single study providing strong results may be sufficient. Some statistical stability criteria for assessing whether a single study provides very persuasive results are known. A new criterion is introduced, and it is based on the conservative estimation of the reproducibility probability in addition to the possibility of performing statistical tests by referring directly to the reproducibility probability estimate. These stability criteria are compared numerically and conceptually. This work aims to help both regulatory agencies and pharmaceutical companies to decide if the results of a single study may be sufficient to establish effectiveness. PMID- 22422717 TI - Somatosensory mechanical response and digit somatotopy within cortical areas of the postcentral gyrus in humans: an MEG study. AB - Somatosensory evoked fields in response to compression (termed as Co) and decompression (termed as De) of glabrous skin (D1, thumb; D2, index finger; D5, little finger) were recorded. Although estimated equivalent current dipoles (ECDs) following stimulation of D1 and D5 were larger, but not significantly larger, in decompression than in compression, those of D2 were significantly larger (P = 0.035). The ECDs were located in the postcentral gyrus in the order of D5De, D2De, and D1De medially, posteriorly, and superiorly in decompression but not in compression (z-value, F = 2.692, P = 0.031). The average distance of ECDs between D1 and D5 was longer in decompression (12.8 +/- 1.6 mm) than in compression (9.1 +/- 1.6 mm). Our data suggest that the cortical response for the commonly used digit D2 is functionally different from those for other digits (D1 and D5) that the somatotopic variability is greater in compression. PMID- 22422718 TI - Catalytic enantiospecific [3+2] annulation of aminocyclopropanes with ketones. AB - An almost familiar ring: The first enantiospecific [3+2] annulation of donor acceptor aminocyclopropanes with ketones is reported (see scheme; Phth=phthaloyl). The reaction is catalysed by tin(IV) chloride (5 mol %) at -78 degrees C and gives aminotetrahydrofurans bearing a quaternary C5 atom in high yield, diastereoselectivity and enantiospecificity (see scheme). PMID- 22422719 TI - Stabilization of actin filaments prevents germinal vesicle breakdown and affects microtubule organization in Xenopus oocytes. AB - In Xenopus oocytes, extremely giant nuclei, termed germinal vesicles, contain a large amount of actin filaments most likely for mechanical integrity. Here, we show that microinjection of phalloidin, an F-actin-stabilizing drug, prevents the germinal vesicle breakdown (GVBD) in oocytes treated with progesterone. These nuclei remained for more 12 h after control oocytes underwent GVBD. Immunostaining showed significant elevation of actin in the remaining nuclei and many actin filament bundles in the cytoplasm. Furthermore, microtubules formed unusual structures in both nuclei and cytoplasm of phalloidin-injected oocytes stimulated by progesterone. Cytoplasmic microtubule arrays and intranuclear microtubules initially formed in phalloidin-injected oocytes as control oocytes exhibited white maturation spots; these structures gradually disappeared and finally converged upon intranuclear short bundles when control oocytes completed maturation. In contrast, treatment of oocytes with jasplakinolide, a cell membrane-permeable actin filament-stabilizing drug, did not affect GVBD. This drug preferentially induced accumulation of actin filaments at the cortex without any increase in cytoplasmic actin staining. Based on these results, intranuclear and cytoplasmic actin filament dynamics appear to be required for the completion of GVBD and critically involved in the regulation of microtubule assembly during oocyte maturation in Xenopus laevis. PMID- 22422720 TI - Left recurrent laryngeal nerve palsy secondary to left pulmonary artery stent in a child. AB - We report a 10-year-old girl who developed persistent hoarseness after stent placement for the treatment of left pulmonary artery stenosis. Laryngoscopy performed 21 months after stent placement revealed left vocal cord paralysis, presumed secondary to compression of the left recurrent laryngeal nerve by the stent. Pediatric cardiologists should be reminded of this possible rare complication after stent placement. PMID- 22422721 TI - A heteromeric snake toxin and the molecular details of pain perception. PMID- 22422722 TI - Adaptive blinded sample size adjustment for comparing two normal means--a mostly Bayesian approach. AB - Adaptive sample size redetermination (SSR) for clinical trials consists of examining early subsets of on-trial data to adjust prior estimates of statistical parameters and sample size requirements. Blinded SSR, in particular, while in use already, seems poised to proliferate even further because it obviates many logistical complications of unblinded methods and it generally introduces little or no statistical or operational bias. On the other hand, current blinded SSR methods offer little to no new information about the treatment effect (TE); the obvious resulting problem is that the TE estimate scientists might simply 'plug in' to the sample size formulae could be severely wrong. This paper proposes a blinded SSR method that formally synthesizes sample data with prior knowledge about the TE and the within-treatment variance. It evaluates the method in terms of the type 1 error rate, the bias of the estimated TE, and the average deviation from the targeted power. The method is shown to reduce this average deviation, in comparison with another established method, over a range of situations. The paper illustrates the use of the proposed method with an example. PMID- 22422723 TI - The direct effects of inattention and hyperactivity/impulsivity on peer problems and mediating roles of prosocial and conduct problem behaviors in a community sample of children. AB - OBJECTIVE: This study tested whether children's symptoms of inattention and hyperactivity/impulsivity were associated with peer problems and whether these associations were mediated by conduct problems and prosocial behaviors. METHOD: A community sample of 500 children, including 245 boys and 255 girls, who ranged in age from 6 to 9 years (M = 7.6, SD = 0.91) were recruited. Teachers' report of children's inattention, hyperactivity/impulsivity, conduct problems, prosocial behaviors, and peer problems was collected. RESULTS: Symptoms of inattention and hyperactivity/impulsivity were significantly positively associated with peer problems. Conduct problems were associated with more peer problems and prosocial behaviors with less peer problems. Conduct problems and prosocial behaviors partially mediated the association between hyperactivity/impulsivity and peer problems and fully mediated the inattention-peer problems association. CONCLUSION: Findings show that prosocial behaviors and conduct problems are important variables that account for some of the negative impact of symptoms of inattention and hyperactivity/impulsivity on peer functioning. PMID- 22422724 TI - Neural changes when actions change: adaptation of strong and weak expectations. AB - Repeated experiences with an event create the expectation that subsequent events will expose an analog structure. These spontaneous expectations rely on an internal model of the event that results from learning. But what happens when events change? Do experience-based internal models get adapted instantaneously, or is model adaptation a function of the solidity of, i.e., familiarity with, the corresponding internal model? The present fMRI study investigated the effects of model solidity on model adaptation in an action observation paradigm. Subjects were made acquainted with a set of action movies that displayed an altered script when encountered again in the scanning session. We found model adaptation to result in an attenuation of the premotor-parietal network for action observation. Model solidity was found to modulate activation in the parahippocampal gyrus and the anterior cerebellar lobules, where increased solidity correlated with activity increase. Finally, the comparison between early and late stages of learning indicated an effect of model solidity on adaptation rate. This contrast revealed the involvement of a fronto-mesial network of Brodmann area 10 and the ACC in those states of learning that were signified by high model solidity, no matter if the memorized original or the altered action model was the more solid component. Findings suggest that the revision of an internal model is dependent on its familiarity. Unwarranted adaptations, but also perseverations may thus be prevented. PMID- 22422725 TI - Bonding in a borylene complex investigated by photoionization and dissociative photoionization. AB - The borylene complex [(OC)(5)Cr=B=N(SiMe(3))(2)] has been investigated by using threshold photoelectron-photoion coincidence spectroscopy with synchrotron radiation. The ionization energy of the parent complex and the 0 K appearance energies of the sequential CO loss channels have been determined. The derived bond-dissociation energies are used to discuss bonding and energetics in this compound. PMID- 22422726 TI - Developmental expression and cardiac transcriptional regulation of Myh7b, a third myosin heavy chain in the vertebrate heart. AB - The mammalian heart expresses two myosin heavy chain (MYH) genes (Myh6 and Myh7), which are major components of the thick filaments of the sarcomere. We have determined that a third MYH, MYH7B, is also expressed in the myocardium. Developmental analysis shows Myh7b expression in cardiac and skeletal muscle of Xenopus, chick and mouse embryos, and in smooth muscle tissues during later stages of mouse embryogenesis. Myh7b is also expressed in the adult human heart. The promoter region of the Myh7b gene shows remarkable similarity between diverse species, suggesting that transcriptional control mechanisms have been conserved. Using luciferase reporter analysis in rat cardiomyocytes, it can be shown that MEF2, GATA, and E-box regulatory elements are essential for efficient expression of the Myh7b gene. In addition two conserved elements that do not correspond to consensus binding sites for known transcription factors are also essential for full transcriptional activity of the Myh7b reporter. Finally, the Myh7b gene shows a transcriptional response similar to Myh6 in response to cardiac hypertrophy. PMID- 22422727 TI - "Good enough" medicine: noninferiority clinical trials and the management of fever and neutropenia. PMID- 22422728 TI - Safety and efficacy of balloon pulmonary valvuloplasty: a multicenter experience. AB - BACKGROUND: Balloon pulmonary valvuloplasty (BPV) is the treatment of choice for patients with pulmonary valve stenosis (PS); however, safety and efficacy outcomes are lacking in the current era. METHODS: Demographic, procedural, and adverse event (AE) data were prospectively collected using a multicenter registry (C3PO) and cases performed between 02/07 and 06/10 at eight institutions. The registry was queried for cases of isolated BPV. Multivariable models were built to determine risk factors for procedure failure and adverse outcomes. RESULTS: 211 cases were included (45%, <1 month). Procedural success was achieved in 91% procedures, being defined as one or more of the following: post-BPV peak systolic valvar gradient to < 25 mm Hg (88%), decrease in gradient by 50% (79%), or reduction of RV/systemic pressure ratio by 50% (45%). Procedural success was more common in neonates, when compared to older patients (96% vs. 87%, P = 0.03). Risk factors for procedural failure included moderate or severe pulmonary valve thickening (OR 2.9, CI 1-8.3), and presence of supravalve PS (OR 9.6, CI 2.7 33.8). Low severity AEs (levels 1-2) occurred in 9% of patients and higher severity AEs (levels 3-5) occurred in 3% of patient; there were no deaths. Risk factors for any AE (levels 1-5) were age below 1 month (OR 3.5, CI 1.3-8.9), as well as operator experience of less than 10 years (OR 3.8, CI 1.5-9.9). CONCLUSIONS: Procedural success is common and AEs, especially higher severity AEs, are rare for BPV in patients with isolated PS. Results have improved considerably when compared to historical data. PMID- 22422729 TI - Enantioselective 5-endo-dig carbocyclization of beta-ketoesters with internal alkynes employing a four-component catalyst system. PMID- 22422730 TI - Thieno[3,4-b]thiophene-based organic dyes for dye-sensitized solar cells. AB - New dipolar sensitizers containing an ethyl thieno[3,4-b]thiophene-2-carboxylate (ETTC) entity in the conjugated spacer have been synthesized in two isomeric forms. These compounds were used as the sensitizers of n-type dye-sensitized solar cells (DSSCs). The best conversion efficiency (5.31%) reaches approximately 70% of the N719-based (7.41%) DSSC fabricated and measured under similar conditions. The ETTC-containing compounds exhibit a bathochromic shift of the absorption compared to their thiophene congeners due to the quinoid effect, however, charge-trapping at the ester group of ETTC was found to jeopardize the electron injection and lower the cell efficiency. Charge trapping is alleviated as the ester group of ETTC is replaced with a hydrogen atom, as evidenced from the theoretical computation. PMID- 22422731 TI - Rituximab or a second anti-tumor necrosis factor therapy for rheumatoid arthritis patients who have failed their first anti-tumor necrosis factor therapy? Comparative analysis from the British Society for Rheumatology Biologics Register. AB - OBJECTIVE: To compare the effectiveness of rituximab (RTX) or a second anti-tumor necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) patients who had failed their first anti-TNF and switched to either RTX or a second anti-TNF, in routine clinical practice. METHODS: RA patients were registered with the British Society for Rheumatology Biologics Register. Response to treatment 6 months after switching was assessed using European League Against Rheumatism (EULAR) criteria and improvements in a Health Assessment Questionnaire (HAQ) score (0.22 unit or more). Regression analyses were used to compare EULAR response and improvement in HAQ score between the 2 groups, adjusting for propensity scores. RESULTS: In total, 1,328 patients were included in the analysis of EULAR response, and 937 patients were included in the analysis of HAQ scores. Six months after switching, 54.8% of patients who switched to RTX were EULAR responders compared to 47.3% of those who switched to a second anti-TNF. A total of 38.4% of RTX patients achieved a clinically important improvement in HAQ score compared to 29.6% in anti-TNF patients. After adjustment using propensity scores, patients who switched to RTX were significantly more likely to achieve EULAR response (odds ratio [OR] 1.31; 95% confidence interval [95% CI] 1.02, 1.69) compared to those who switched to an alternative anti-TNF. RTX patients were also significantly more likely to achieve improvements in HAQ score (OR 1.49; 95% CI 1.07, 2.08). CONCLUSION: The results suggest that switching to RTX may be of more benefit than switching to an alternative anti-TNF therapy after failing the first anti-TNF therapy in RA patients. PMID- 22422734 TI - Quantum-dot-tagged reduced graphene oxide nanocomposites for bright fluorescence bioimaging and photothermal therapy monitored in situ. AB - Quantum-dot-tagged reduced graphene oxide (QD-rGO) nanocomposites (left) internalized into targeted tumor cells display bright fluorescence from the QDs (right); by absorbing NIR radiation incident on the rGO and converting it into heat, they also cause simultaneous cell death and fluorescence reduction (bottom). The nanocomposite is thus capable of tumor imaging, photothermal therapy and in situ monitoring of treatment in progress. PMID- 22422735 TI - Right versus left transradial approach for coronary catheterization in octogenarian patients. AB - OBJECTIVES: The aim of the study was to evaluate if the left radial approach (LRA) confers any additional advantage compared to the right radial approach (RRA) in octogenarian patients who undergo a coronary diagnostic procedure. BACKGROUND: Octogenarians, an increasing segment of patients in our society, present a higher risk of access-site complications related to invasive coronary catheterization. Transradial approach has been shown to be an effective alternative to reduce vascular complications. Although some studies have suggested that elderly people might benefit from a LRA, the advantages of using the left or right radial access remain not clear. METHODS: One hundred octogenarian patients undergoing a transradial coronary angiogram with normal Allen test and without previous history of coronary artery by-pass grafting were randomized to either LRA (n = 50) or RRA (n = 50). The primary end-points of the study were procedural and fluoroscopy times. RESULTS: Mean age was 82.6 years (80 88) and 59% were males. Procedural and fluoroscopy times were similar among study groups. Crossover was required in two patients (4%) with RRA and five patients (10%) with LRA (P = 0.24). Subclavian tortuosity was more frequent in the right side (32% vs. 6% in the left side; P = 0.002) but this difference did not translate into longer procedural or fluoroscopy times or higher cross-over, procedural difficulty or wire manipulation. CONCLUSIONS: In our series of octogenarian patients, the LRA was a valid alternative for diagnostic procedures but its usage was not associated with a significant reduction in procedural and fluoroscopy times compared to the RRA. PMID- 22422736 TI - Clinical significance of pulmonary nodules detected by CT and Not CXR in patients treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and -5: a report from the Children's Oncology Group. AB - BACKGROUND: Metastatic lung disease in Wilms tumor (WT) patients was traditionally identified by chest radiograph (CXR). It is unclear whether patients with small lesions, detectable only by computed tomography ("CT-only" lesions), require the more intensive therapy, including doxorubicin and lung irradiation, given to patients with metastases detectable by CXR. PROCEDURES: This study involved 417 patients with favorable histology WT and isolated lung metastases (detected by CXR or CT) who were registered on National Wilms tumor Study (NWTS)-4 or -5. Outcomes by method of detection (CXR vs. CT-only), use of lung radiation, and 2- or 3-drug chemotherapy (dactinomycin and vincristine +/- doxorubicin) were determined and compared using the log-rank test. RESULTS: There were 231 patients with lung lesions detected by CXR and 186 by CT-only. Of the patients with CT-only nodules, 37 received only 2 drugs and 101 did not receive lung radiation. Five-year event-free survival (EFS) was greater for patients receiving three drugs (including doxorubicin) with or without lung radiation than for those receiving two drugs (80% vs. 56%; P = 0.004). There was no difference seen in 5-year overall survival (OS) between the 3- and 2-drug subsets (87% vs. 86%; P = 0.91). There were no significant differences in EFS (82% vs. 72%; P = 0.13) or OS (91% vs. 83%; P = 0.46) for patients with CT-only nodules whether they received lung radiation or not. CONCLUSIONS: Our results suggest that patients with CT-only lung lesions may have improved EFS but not OS from the addition of doxorubicin but do not appear to benefit from pulmonary radiation. PMID- 22422737 TI - Identifying generic predictors of outcome in patients presenting to primary care with nonspinal musculoskeletal pain. AB - OBJECTIVE: To identify which generic prognostic factors, such as pain intensity, levels of disability, and psychological factors, are most strongly associated with outcome from musculoskeletal pain, regardless of the location of pain. We tested the hypothesis that pain location does not add predictive value to these generic prognostic models, and that such prognostic factors are equally important across different pain locations. METHODS: Data from a prospective observational cohort of primary care patients with acute (n = 413) and chronic (n = 414) nonspinal musculoskeletal pain were used to develop predictive models. The analysis was carried out in 3 steps: derivation of predictive models including generic factors only, investigation of the added predictive value of pain location, and investigation of effect modification by pain location. RESULTS: Generic factors predicted outcome over different time periods (3 months and 12 months) and for both acute and chronic musculoskeletal pain (area under the receiver operating characteristic curve 0.73-0.75). The most consistent predictors of poor outcome were having had the same complaint in the previous year (odds ratio range 2.03-3.46), a lower level of education, lower scores on the Short Form 36 vitality subscale, using pain medication at baseline, and being bothered by the complaint more often in the past 3 months. Pain location variables only slightly improved the predictive ability of the models over generic factors and were inconsistent across the models. CONCLUSION: Generic factors appear to play an important role in the prognosis of acute and chronic nonspinal musculoskeletal pain, regardless of the location of pain. PMID- 22422738 TI - Excimer laser with adjunctive balloon angioplasty and heparin-coated self expanding stent grafts for the treatment of femoropopliteal artery in-stent restenosis: twelve-month results from the SALVAGE study. AB - OBJECTIVES: The aim of the study is to evaluate the safety and effectiveness of treating femoropopliteal in-stent restenosis (ISR) with debulking with excimer laser followed by implantation of a VIABAHN endoprosthesis. BACKGROUND: The optimal treatment strategy for femoropopliteal ISR is unclear. METHODS: The SALVAGE study is a multicenter prospective registry involving nine US centers. Patients with femoropopliteal ISR with moderate to severe intermittent claudication or critical limb ischemia (Rutherford categories 2-5) and an ankle brachial index (ABI) =0.8 were treated with excimer laser and the VIABAHN endoprosthesis. The primary efficacy endpoint is primary patency at 12 months as measured by duplex ultrasonography. The primary safety endpoint is the major adverse event (MAE) rate at 30 days. RESULTS: Twenty-seven patients were enrolled. The mean lesion length was 20.7 +/- 10.3 cm. The majority of lesions were TASC (TASC I) C and D (81.4%). All lesions were pretreated with excimer laser and percutaneous transluminal angioplasty (PTA) prior to VIABAHN implantation. Technical success was achieved in 100% of cases. There were no MAE at 30 days. Primary patency at 12 months was 48%. The ankle brachial index increased from 0.58 +/- 0.24 at baseline to 0.90 +/- 0.17 at 12 months. There was improvement in all quality-of-life parameters. The 12-month TLR rate was 17.4%. CONCLUSIONS: The strategy of excimer laser atherectomy and PTA followed by implantation of a self-expanding stent graft for the treatment of femoropopliteal ISR is safe and associated with high procedural success. Primary patency rate at 12-months was suboptimal; however, the TLR rate was low. PMID- 22422739 TI - Ambulatory care connections of Medicaid-insured children with sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD) requires coordinated ambulatory care from generalists and hematologists. We examined when children with SCD establish ambulatory care connections, whether these connections are maintained, and how these connections are used before and after hospitalizations. PROCEDURE: We conducted a retrospective cohort study of Medicaid-insured Maryland children with SCD from 2002 to 2008. For children enrolled from birth, time to first, second, and third generalist and first hematologist visits was plotted. For all children, we analyzed ambulatory visits by age group, by emergency department (ED) and hospital use, and before and after hospitalizations. RESULTS: The overall study cohort comprised 851 children; 178 provided data from birth. Ambulatory care connections to generalists were made rapidly; connections to hematologists occurred more slowly, if at all (38% of children had not seen a hematologist by age 2 years). Visits with generalists decreased as patients aged, as did visits with hematologists (54% of children in the 12-17 year age group had no hematology visits in 2 years). Children with higher numbers of ED visits or hospitalizations also had higher numbers of ambulatory visits (generalist and hematologist). Most children had visits with neither generalists nor hematologists in the 30 days before and after hospitalizations. CONCLUSIONS: Medicaid-insured children with SCD rapidly connect with generalists after birth; connections to hematologists occur more slowly. The observation that connections to generalists and hematologists diminish with time and are infrequently used around hospitalizations suggests that the ambulatory care of many Medicaid-insured children with SCD may be inadequate. PMID- 22422740 TI - CT myocardial perfusion: a step towards quantification. PMID- 22422741 TI - Prognostication or identification of palliative needs in advanced heart failure: where should the focus lie? PMID- 22422742 TI - Sudden cardiac death and inherited channelopathy: the basic electrophysiology of the myocyte and myocardium in ion channel disease. AB - Mutations involving cardiac ion channels result in abnormal action potential formation or propagation, leading to cardiac arrhythmias. Despite the large impact on society of sudden cardiac death resulting from such arrhythmias, understanding of the underlying cellular mechanism is poor and clinical risk stratification and treatment consequently limited. Basic research using molecular techniques, as well as animal models, has proved extremely useful in improving our knowledge of inherited arrhythmogenic syndromes. This offers the practitioner tools to accurately diagnose rare disorders and provides novel markers for risk assessment and a basis for new strategies of treatment. PMID- 22422743 TI - Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation. AB - OBJECTIVE: To assess the cost-effectiveness of dabigatran etexilate, a new oral anticoagulant, versus warfarin and other alternatives for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation (AF). METHODS: A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin, aspirin or no therapy. Two patient cohorts with AF (starting age of <80 and >=80 years) were considered separately, in line with the UK labelled indication. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost effectiveness ratios (ICERs). RESULTS: Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years. Larger differences were observed comparing dabigatran etexilate with aspirin or no therapy. For patients initiating treatment at ages <80 and >=80 years, the ICERs for dabigatran etexilate were L4831 and L7090/QALY gained versus warfarin with a probability of cost-effectiveness at L20 000/QALY gained of 98% and 63%, respectively. For the patient cohort starting treatment at ages <80 years, the ICER versus aspirin was L3457/QALY gained and dabigatran etexilate was dominant (ie, was less costly and more effective) compared with no therapy. These results were robust in sensitivity analyses. CONCLUSIONS: This economic evaluation suggests that the use of dabigatran etexilate as a first-line treatment for the prevention of stroke and systemic embolism is likely to be cost-effective in eligible UK patients with AF. PMID- 22422744 TI - Identifying community based chronic heart failure patients in the last year of life: a comparison of the Gold Standards Framework Prognostic Indicator Guide and the Seattle Heart Failure Model. AB - OBJECTIVE: To assess the clinical utility of the Gold Standards Framework Prognostic Indicator Guide (GSF) and the Seattle Heart Failure Model (SHF) to identify patients with chronic heart failure (CHF) in the last year of life. DESIGN, SETTING AND PATIENTS: An observational cohort study of 138 community based ambulatory patients with New York Heart Association (NYHA) class III and IV CHF managed by a specialist heart failure nursing team. MAIN OUTCOME MEASURES: 12 month mortality, and sensitivity and specificity of GSF and SHF. RESULTS: 138 CHF patients with NYHA class III and IV symptoms were identified from a population of 368 ambulatory CHF patients. 119 (86%) met GSF criteria for end of life care. The SHF model identified six (4.3%) patients with a predicted life expectancy of 1 year or less. At the 12 month follow-up, 43 (31%) patients had died. The sensitivity and specificity for GSF and SHF in predicting death were 83% and 22%, and 12% and 99%, respectively. Receiver operator characteristic analysis of SHF revealed a C index of 0.68+/-0.05 (95% CI 0.58 to 0.77). Chronic kidney disease (serum creatinine >=140 MUmol/l) was a strong univariate predictor of 12 month mortality, with a sensitivity of 56% and specificity of 72%. CONCLUSIONS: Neither the GSF nor the SHF accurately predicted which patients were in the last year of life. The poor prognostic ability of these models highlights one of the barriers to providing timely palliative care in CHF. PMID- 22422745 TI - Positron emission tomography measurements of myocardial blood flow: assessing coronary circulatory function and clinical implications. PMID- 22422746 TI - Conflict of interest policies and disclosure requirements among European Society of Cardiology National Cardiovascular Journals. AB - Disclosure of potential conflicts of interest (COI) is used by biomedical journals to guarantee credibility and transparency of the scientific process. COI disclosure, however, is not systematically nor consistently dealt with by journals. Recent joint editorial efforts paved the way towards the implementation of uniform vehicles for COI disclosure. This paper provides a comprehensive editorial perspective on classical COI-related issues. New insights into current COI policies and practices among European Society of Cardiology national cardiovascular journals, as derived from a cross-sectional survey using a standardised questionnaire, are discussed. PMID- 22422747 TI - The early and mid-term fate of the axillary artery following axillary artery cut down and cardiac catheterization in infants and young children. AB - OBJECTIVES: To study the early and mid-term vascular complications of axillary artery catheterization in children <2 years by clinical and ultrasound examination. BACKGROUND: Femoral arterial access for cardiac catheterization in young children is associated with significant morbidity. Early complications of axillary artery catheterization have been reported but no long-term vascular follow-up data are available. METHODS: Prospective case-control study using standard vascular ultrasound techniques to examine the upper limbs in study participants (n = 10). RESULTS: In total, 23% of axillary artery catheterizarions (56 procedures in 54 patients) resulted in acute arterial insufficiency requiring heparin. Of the survivors under follow-up (n = 33), none had symptoms of chronic arterial insufficiency. At a median follow-up of 8 years postprocedure, three out of the ten study participants had a weak brachial pulse in the test arm but no significant difference in arm measurements. Color Doppler revealed occlusion of the axillary artery in the test arm with collateralization in three patients. The brachial peak systolic velocity (V(max)) was significantly lower in the test arm than the control arm of all the patients with a mean difference of 30 cm/sec (P = 0.007). CONCLUSION: Our study is the first to examine the long-term vascular sequelae of axillary artery catheterization using ultrasound examination and highlights the importance of careful surveillance of vascular access sites. Although axillary artery cut-down for cardiac catheterization in infants and young children does not appear to result in clinical signs of chronic arterial insufficiency, we demonstrate clear evidence of flow abnormalities on vascular ultrasound which are of uncertain long-term significance. PMID- 22422752 TI - A genomic approach to bacterial taxonomy: an examination and proposed reclassification of species within the genus Neisseria. AB - In common with other bacterial taxa, members of the genus Neisseria are classified using a range of phenotypic and biochemical approaches, which are not entirely satisfactory in assigning isolates to species groups. Recently, there has been increasing interest in using nucleotide sequences for bacterial typing and taxonomy, but to date, no broadly accepted alternative to conventional methods is available. Here, the taxonomic relationships of 55 representative members of the genus Neisseria have been analysed using whole-genome sequence data. As genetic material belonging to the accessory genome is widely shared among different taxa but not present in all isolates, this analysis indexed nucleotide sequence variation within sets of genes, specifically protein-coding genes that were present and directly comparable in all isolates. Variation in these genes identified seven species groups, which were robust to the choice of genes and phylogenetic clustering methods used. The groupings were largely, but not completely, congruent with current species designations, with some minor changes in nomenclature and the reassignment of a few isolates necessary. In particular, these data showed that isolates classified as Neisseria polysaccharea are polyphyletic and probably include more than one taxonomically distinct organism. The seven groups could be reliably and rapidly generated with sequence variation within the 53 ribosomal protein subunit (rps) genes, further demonstrating that ribosomal multilocus sequence typing (rMLST) is a practicable and powerful means of characterizing bacteria at all levels, from domain to strain. PMID- 22422753 TI - Multiple leptospiral sphingomyelinases (or are there?). AB - Culture supernatants of leptospiral pathogens have long been known to haemolyse erythrocytes. This property is due, at least in part, to sphingomyelinase activity. Indeed, genome sequencing reveals that pathogenic Leptospira species are richly endowed with sphingomyelinase homologues: five genes have been annotated to encode sphingomyelinases in Leptospira interrogans. Such redundancy suggests that this class of genes is likely to benefit leptospiral pathogens in their interactions with the mammalian host. Surprisingly, sequence comparison with bacterial sphingomyelinases for which the crystal structures are known reveals that only one of the leptospiral homologues has the active site amino acid residues required for enzymic activity. Based on studies of other bacterial toxins, we propose that leptospiral sphingomyelinase homologues, irrespective of their catalytic activity, may possess additional molecular functions that benefit the spirochaete. Potential secretion pathways and roles in pathogenesis are discussed, including nutrient acquisition, dissemination, haemorrhage and immune evasion. Although leptospiral sphingomyelinase-like proteins are best known for their cytolytic properties, we believe that a better understanding of their biological role requires the examination of their sublytic properties as well. PMID- 22422754 TI - The fimbriae activator MatA switches off motility in Escherichia coli by repression of the flagellar master operon flhDC. AB - Flagella provide advantages to Escherichia coli by facilitating taxis towards nutrients and away from unfavourable niches. On the other hand, flagellation is an energy sink to the bacterial cell, and flagella also stimulate host innate inflammatory responses against infecting bacteria. The flagellar assembly pathway is ordered and under a complex regulatory circuit that involves three classes of temporally regulated promoters as well as the flagellar master regulator FlhD(4)C(2). We report here that transcription of the flhDC operon from the class 1 promoter is under negative regulation by MatA, a key activator of the common mat (or ecp) fimbria operon that enhances biofilm formation by E. coli. Ectopic expression of MatA completely precluded motility and flagellar synthesis in the meningitis-associated E. coli isolate IHE 3034. Northern blotting, analysis of chromosomal promoter-lacZ fusions and electrophoretic mobility shift assays revealed an interaction between MatA and the flhDC promoter region that apparently repressed flagellum biosynthesis. However, inactivation of matA in the chromosome of IHE 3034 had only a minor effect on flagellation, which underlines the complexity of regulatory signals that promote flagellation in E. coli. We propose that the opposite regulatory actions of MatA on mat and on flhDC promoters advance the adaptation of E. coli from a planktonic to an adhesive lifestyle. PMID- 22422755 TI - Functions of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system effectors. AB - Salmonella enterica serovars cause severe disease in humans, such as gastroenteritis and typhoid fever. The bacteria are able to invade and replicate within host cells, including epithelial cells and macrophages. Pathogenesis of Salmonella is facilitated by a type III secretion system (T3SS) encoded by genes of Salmonella pathogenicity island 2 (SPI-2). Intracellular replication occurs in a specialized membrane compartment, the Salmonella-containing vacuole (SCV), and depends on translocation of approximately 30 effector proteins via the SPI-2 T3SS into the host endomembrane system and cytoplasm. In this review we discuss the many different functions of these effectors, which range from maintaining the integrity of the SCV and its juxtanuclear location, to interference with the host cytoskeleton and immune signalling. PMID- 22422756 TI - Ageing in Escherichia coli requires damage by an extrinsic agent. AB - Evidence for ageing in symmetrically dividing bacteria such as Escherichia coli has historically been conflicting. Early work found weak or no evidence. More recent studies found convincing evidence, but negative results are still encountered. Because bacterial ageing is believed to result from non-genetic (e.g. oxidative) damage, we tested the possibility that the negative outcomes resulted from the lack of an extrinsic damage agent. We found that streptomycin, which produces mistranslated proteins that are more vulnerable to oxidation, was able to induce both damage and ageing in bacterial populations. A dosage effect relating the level of damage to the concentration of streptomycin was observed. Our results explain the previous inconsistencies, because all studies that failed to find evidence for bacterial ageing did not use a damage agent. However, all studies that succeeded in finding evidence utilized fluorescent proteins as a visual marker. We suggest that ageing in those studies was induced by the harmful effects of an extrinsic factor, such as the proteins themselves or the excitation light. Thus, all of the earlier studies can be reconciled and bacterial ageing is a real phenomenon. However, the study and observation of bacterial ageing require the addition of an extrinsic damage agent. PMID- 22422757 TI - Racial differences in dementia care among nursing home residents. AB - OBJECTIVES: This article aims to describe potential racial differences in dementia care among nursing home residents with dementia. METHODS: Using data from the 2004 National Nursing Home Survey (NNHS) in regression models, the authors examine whether non-Whites are less likely than Whites to receive special dementia care--defined as receiving special dementia care services or being in a dementia special care unit (SCU)--and whether this difference derives from differences in resident or facility characteristics. RESULTS: The authors find that non-Whites are 4.3 percentage points less likely than Whites to receive special dementia care. DISCUSSION: The fact that non-Whites are more likely to rely on Medicaid and less likely to pay out of pocket for nursing home care explains part but not all of the difference. Most of the difference is due to the fact that non-Whites reside in facilities that are less likely to have special dementia care services or dementia care units, particularly for-profit facilities and those in the South. PMID- 22422758 TI - Loneliness as a risk factor for hypertension in later life. AB - OBJECTIVE: The present study aims to determine the impact of loneliness on hypertension in later life. METHOD: Data for this study are derived from a sample of 1,880 older Malaysians via a cross-sectional survey entitled "Patterns of Social Relationships and Psychological Well-Being Among Older Persons in Peninsular Malaysia." Loneliness is assessed by the PGCMS item, "How much do you feel lonely?" Data analysis is carried out using the Statistical Package for Social Sciences (SPSS) version 19.0. RESULTS: Nearly one third of respondents report high level of loneliness. The overall prevalence of hypertension is 39% (95% CI=36.9-41.3). Logistic regression, controlling for sociodemographic factors and several chronic medical conditions, shows that loneliness significantly increases likelihood of hypertension in later life (OR=1.31, p<=.05, 95% CI=1.04 1.66). DISCUSSION: The results show loneliness as a major risk factor for hypertension and call for health care professionals to be aware of the negative physiological effects of loneliness in old age. PMID- 22422760 TI - Effect of a fall prevention program on balance maintenance using a quasi experimental design in real-world settings. AB - OBJECTIVES: To examine the effect of a fall prevention program offered under real world conditions on balance maintenance several months after the program. To explore the program's impact on falls. METHOD: A quasi-experimental study was conducted among community-dwelling seniors, with pre- and postintervention measures of balance performance and self-reported falls. Ten community-based organizations offered the intervention (98 participants) and 7 recruited participants to the study's control arm (102 participants). An earlier study examined balance immediately after the 12-week program. The present study focuses on the 12-month effect. Linear regression (balance) and negative binomial regression (falls) procedures were performed.falls. RESULTS: During the 12-month study period, experimental participants improved and maintained their balance as reflected by their scores on three performance tests. There was no evidence of an effect on falls.falls. DISCUSSION: Structured group exercise programs offered in community-based settings can maintain selected components of balance for several months after the program's end. PMID- 22422759 TI - Modifying measures based on differential item functioning (DIF) impact analyses. AB - OBJECTIVE: Measure modification can impact comparability of scores across groups and settings. Changes in items can affect the percent admitting to a symptom. METHODS: Using item response theory (IRT) methods, well-calibrated items can be used interchangeably, and the exact same item does not have to be administered to each respondent, theoretically permitting wider latitude in terms of modification. RESULTS: Recommendations regarding modifications vary, depending on the use of the measure. In the context of research, adjustments can be made at the analytic level by freeing and fixing parameters based on findings of differential item functioning (DIF). The consequences of DIF for clinical decision making depend on whether or not the patient's performance level approaches the scale decision cutpoint. High-stakes testing may require item removal or separate calibrations to ensure accurate assessment. DISCUSSION: Guidelines for modification based on DIF analyses and illustrations of the impact of adjustments are presented. PMID- 22422761 TI - Self-reported functional status among the old-old: a comparison of two Israeli cohorts. AB - OBJECTIVES: To examine differences in functional status among two successive cohorts. METHOD: The study was a comparative analysis of Jewish respondents aged 75 to 94 from two nationwide random samples: the Cross-Sectional and Longitudinal Aging Study (1989-1992; N = 1,200) and the Survey of Health, Ageing, and Retirement in Europe (2005-2006; N = 379). Self-reported functional limitation and disability were compared by means of logistic regressions and MANCOVA, controlling for age, gender, origin, education, marital status, income, self rated health, and home care receipt. RESULTS: Reported functional limitation decreased in the later cohort (SHARE-Israel), but activities of daily living (ADL) and instrumental activities of daily living (IADL) disability increased. Receipt of home care moderated these effects. ADL and IADL disability increased among home care-receiving respondents in the later cohort whereas functional limitation decreased among respondents not in receipt of home care. DISCUSSION: The findings suggest that different measures used to assess the disablement process capture different aspects and that contextual factors influence how older people rate their own functional capacity. PMID- 22422762 TI - Validity and reliability of the short physical performance battery in two diverse older adult populations in Quebec and Brazil. AB - OBJECTIVES: To assess the validity and reliability of the Short Physical Performance Battery (SPPB) in adults 65 to 74 years old, capable in all basic activities of daily living (ADL), in Quebec and Brazil. METHODS: Participants were recruited in St. Bruno (Quebec) by local advertisements (n = 60) and in Santa Cruz (Brazil) by random sampling (n = 64). The SPPB includes tests of gait, balance, and lower-limb strength. Disability status was categorized as intact mobility, limited mobility, and difficulty in any of ADL. RESULTS: There was a graded decrease in mean SPPB scores with increasing limitation of lower limbs, disability, and poor health. Using the test-retest reliability the authors evaluated the intraclass correlation coefficient, which was high in both samples: .89 (95% CI: 0.83, 0.93) in St. Bruno and .83 in Santa Cruz (95% CI: 0.73, 0.89). DISCUSSION: This study provides evidence for the validity and reliability of SPPB in diverse populations. PMID- 22422763 TI - Inferring species trees directly from biallelic genetic markers: bypassing gene trees in a full coalescent analysis. AB - The multispecies coalescent provides an elegant theoretical framework for estimating species trees and species demographics from genetic markers. However, practical applications of the multispecies coalescent model are limited by the need to integrate or sample over all gene trees possible for each genetic marker. Here we describe a polynomial-time algorithm that computes the likelihood of a species tree directly from the markers under a finite-sites model of mutation effectively integrating over all possible gene trees. The method applies to independent (unlinked) biallelic markers such as well-spaced single nucleotide polymorphisms, and we have implemented it in SNAPP, a Markov chain Monte Carlo sampler for inferring species trees, divergence dates, and population sizes. We report results from simulation experiments and from an analysis of 1997 amplified fragment length polymorphism loci in 69 individuals sampled from six species of Ourisia (New Zealand native foxglove). PMID- 22422764 TI - Accession-specific haplotypes of the internal transcribed spacer region in Arabidopsis thaliana--a means for barcoding populations. AB - Eukaryote genomes contain multiple copies of nuclear ribosomal DNA (nrDNA) harboring both highly conserved and variable regions. This has made nrDNA the most popular genetic marker for phylogenetic studies and the region of choice for barcoding projects. Furthermore, many scientists believe that all copies of nrDNA within one nucleus are practically identical due to concerted evolution. Here, we investigate the model plant species Arabidopsis thaliana for intragenomic variation of the internal transcribed spacer (ITS) region of nrDNA. Based on a modified deep sequencing approach, we provide a comprehensive list of ITS polymorphisms present in the two most widely used accessions of A. thaliana-Col-0 and Ler. Interestingly, we found that some polymorphisms are shared between these genetically very distinct accessions. On the other hand, the high number of accession-specific polymorphisms shows that each accession can be clearly and easily characterized by its specific ITS polymorphism patterns and haplotypes. Network analysis based on the detected haplotypes demonstrates that the study of ITS polymorphism patterns and haplotypes is an extremely powerful tool for population genetics. Using the methods proposed here, it will now be possible to extend the traditionally species-bound barcoding concept to populations. PMID- 22422765 TI - Modern taurine cattle descended from small number of near-eastern founders. AB - Archaeozoological and genetic data indicate that taurine cattle were first domesticated from local wild ox (aurochs) in the Near East some 10,500 years ago. However, while modern mitochondrial DNA (mtDNA) variation indicates early Holocene founding event(s), a lack of ancient DNA data from the region of origin, variation in mutation rate estimates, and limited application of appropriate inference methodologies have resulted in uncertainty on the number of animals first domesticated. A large number would be expected if cattle domestication was a technologically straightforward and unexacting region-wide phenomenon, while a smaller number would be consistent with a more complex and challenging process. We report mtDNA sequences from 15 Neolithic to Iron Age Iranian domestic cattle and, in conjunction with modern data, use serial coalescent simulation and approximate Bayesian computation to estimate that around 80 female aurochs were initially domesticated. Such a low number is consistent with archaeological data indicating that initial domestication took place in a restricted area and suggests the process was constrained by the difficulty of sustained managing and breeding of the wild progenitors of domestic cattle. PMID- 22422766 TI - The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is caused by mutation of the Survival Motor Neurons 1 (SMN1) gene and is characterized by degeneration of spinal motor neurons. The severity of SMA is primarily influenced by the copy number of the SMN2 gene. Additional modifier genes that lie outside the SMA locus exist and one gene that could modify SMA is the Zinc Finger Protein (ZPR1) gene. To test the significance of ZPR1 downregulation in SMA, we examined the effect of reduced ZPR1 expression in mice with mild and severe SMA. We report that the reduced ZPR1 expression causes increase in the loss of motor neurons, hypermyelination in phrenic nerves, increase in respiratory distress and disease severity and reduces the lifespan of SMA mice. The deficiency of SMN-containing sub-nuclear bodies correlates with the severity of SMA. ZPR1 is required for the accumulation of SMN in sub-nuclear bodies. Further, we report that ZPR1 overexpression increases levels of SMN and promotes accumulation of SMN in sub-nuclear bodies in SMA patient fibroblasts. ZPR1 stimulates neurite growth and rescues axonal growth defects in SMN-deficient spinal cord neurons from SMA mice. These data suggest that the severity of disease correlates negatively with ZPR1 levels and ZPR1 may be a protective modifier of SMA. PMID- 22422767 TI - Identification of 70 calcium-sensing receptor mutations in hyper- and hypo calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. AB - The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca(2+))-binding sites. To elucidate the structure-function relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 A of one or more of the predicted Ca(2+) binding sites, particularly at the VFTD cleft, which is the principal site of Ca(2+) binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca(2+) by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca(2+) binding and the function of the CaSR. PMID- 22422768 TI - Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans. PMID- 22422769 TI - DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. AB - Disrupted-In-Schizophrenia 1 (DISC1), a strong genetic candidate for psychiatric illness, encodes a multicompartmentalized molecular scaffold that regulates interacting proteins with key roles in neurodevelopment and plasticity. Missense DISC1 variants are associated with the risk of mental illness and with brain abnormalities in healthy carriers, but the underlying mechanisms are unclear. We examined the effect of rare and common DISC1 amino acid substitutions on subcellular targeting. We report that both the rare putatively causal variant 37W and the common variant 607F independently disrupt DISC1 nuclear targeting in a dominant-negative fashion, predicting that DISC1 nuclear expression is impaired in 37W and 607F carriers. In the nucleus, DISC1 interacts with the transcription factor Activating Transcription Factor 4 (ATF4), which is involved in the regulation of cellular stress responses, emotional behaviour and memory consolidation. At basal cAMP levels, wild-type DISC1 inhibits the transcriptional activity of ATF4, an effect that is weakened by both 37W and 607F independently, most likely as a consequence of their defective nuclear targeting. The common variant 607F additionally reduces DISC1/ATF4 interaction, which likely contributes to its weakened inhibitory effect. We also demonstrate that DISC1 modulates transcriptional responses to endoplasmic reticulum stress, and that this modulatory effect is ablated by 37W and 607F. By showing that DISC1 amino acid substitutions associated with psychiatric illness affect its regulatory function in ATF4-mediated transcription, our study highlights a potential mechanism by which these variants may impact on transcriptional events mediating cognition, emotional reactivity and stress responses, all processes of direct relevance to psychiatric illness. PMID- 22422770 TI - Commentaries on viewpoint: epigenetic regulation of the ACE gene might be more relevant to endurance physiology than the I/D polymorphism. PMID- 22422771 TI - Last word on viewpoint: epigenetic regulation of the ACE gene might be more relevant to endurance physiology than the I/D polymorphism. PMID- 22422772 TI - Postural effects of vestibular-mediated sympathetic activation. PMID- 22422774 TI - Sarcoid flexor tenosynovitis in the hand. PMID- 22422775 TI - Segmental palmar cordectomy with McCash open wound under local anaesthesia. PMID- 22422776 TI - The maximum distal and ulnar position of a fixed-angle volar plate to avoid intra articular penetration: a cadaver study. PMID- 22422777 TI - GnRH-agonist versus GnRH-antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study. AB - BACKGROUND: In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist, and if so, to what extent the progesterone rise affects the probability of pregnancy. METHODS: Overall 190 patients were randomized: 94 in the GnRH agonist group and 96 in the GnRH-antagonist group. The GnRH-agonist long protocol started on Day 21 of the preceding cycle with intranasal buserelin (600 mg per day). The GnRH-antagonist protocol started on Day 6 of the stimulation with ganirelix or cetrorelix (each 0.25 mg). All blood samples were analysed with the Elecsys analyzer. An intention-to-treat analysis was applied. RESULTS: A progesterone rise >1.5 ng/ml was noticed in 23.0% of the antagonist group, comparable with 24.1% incidence within the agonist group. Per patient randomized, delivery rates were also comparable: 28.1% in the antagonist group and 24.5% in the agonist group (odds ratio = 1.21, 95% confidence interval: 0.63-2.31, P= 0.56). However, there was a reduction in delivery rates when progesterone exceeded the threshold of 1.5 ng/ml, both in the agonist group (9.5 versus 31.8%, P= 0.03) and in the antagonist group (14.3 versus 34.3%, P= 0.07). CONCLUSIONS: Although the incidence of a progesterone rise was similar between the two analogues, our findings reconfirm previous observations that insufficient progesterone control (>1.5 ng/ml) on the day of ovulation triggering is related to poor delivery rates in both protocols. The current study has shown that the reproductive outcomes with the two GnRH analogues are comparable. Possible modes of action to circumvent late follicular progesterone rise should be explored. TRIAL REGISTRATION NUMBER: NCT01191710. PMID- 22422778 TI - The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. AB - BACKGROUND: This study aimed to calculate costs and health-related quality of life of women with endometriosis-associated symptoms treated in referral centres. METHODS: A prospective, multi-centre, questionnaire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries. The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008. The main outcome measures were health care costs, costs of productivity loss, total costs and quality-adjusted life years. Predictors of costs were identified using regression analysis. RESULTS: Data analysis of 909 women demonstrated that the average annual total cost per woman was ?9579 (95% confidence interval ?8559-?10 599). Costs of productivity loss of ?6298 per woman were double the health care costs of ?3113 per woman. Health care costs were mainly due to surgery (29%), monitoring tests (19%) and hospitalization (18%) and physician visits (16%). Endometriosis-associated symptoms generated 0.809 quality adjusted life years per woman. Decreased quality of life was the most important predictor of direct health care and total costs. Costs were greater with increasing severity of endometriosis, presence of pelvic pain, presence of infertility and a higher number of years since diagnosis. CONCLUSIONS: Our study invited women to report resource use based on endometriosis-associated symptoms only, rather than drawing on a control population of women without endometriosis. Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases (diabetes, Crohn's disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life. PMID- 22422779 TI - Death and the coroner: some reflections on current practice and proposed reforms. PMID- 22422780 TI - 'Appropriate' medical treatment: what's in a word? AB - Following the amendments in the 2007 Act, there were several revisions made focusing largely on community treatment orders and deprivation of liberty of persons lacking capacity. One of the amendments included a requirement that 'appropriate treatment' be 'available' for compulsion to be imposed in a variety of contexts, most notably admission for treatment under section 3. The definition of appropriate medical treatment within the Act appears largely circular, and therefore of little assistance. The Code of Practice provides some guidance but does little to add to the statutory language. In terms of jurisprudence, there are three reported cases concerning the provision. These cases are analysed and their significance is discussed in an attempt to formulate a clearer definition for appropriate medical treatment. PMID- 22422781 TI - The second professional and detention renewal: an exploration of a generic statutory role. AB - The amended Mental Health Act of 2007 introduced the generic statutory role of the second professional in the renewal of authority for detention, with the purpose of providing an additional safeguard for patients. Completed detention renewals from a National Health Service (NHS) Trust were systematically collected over 12 months (n = 47). Second professionals identified on Form H5 were requested to return a questionnaire designed to explore the role and the eligibility, knowledge base and attitudes of those fulfilling it, in comparison to the requirements as described in the code of practice and in relation to the stated purpose of the role. Twenty-eight second professionals completed questionnaires, giving a response rate of 60%. Several factors were identified which appeared to conspire against the notion that the aim of the role had been achieved in a meaningful way. The reasons underlying this included tokenistic statutory paperwork and a clear lack of specific training. Training needs identified included increasing legal knowledge and raising awareness of the ethical issues associated with a statutory role with a responsible nature. The findings challenge the assumption of readiness in those being asked to act in the generic statutory role of the second professional and highlight the potential for difficulties in the process of moving towards a cultural change of distributed responsibility in psychiatry, both in terms of the introduction of generic statutory roles in the absence of training and also with relevance to the changing nature of traditionally defined professional roles as suggested by new ways of working. PMID- 22422782 TI - The utility of Y-STR profiling in four-, six- and eight-day postcoital vaginal swabs. AB - Y-STR profiles using the Promega PowerPlex((r)) Y system were attempted on multiple vaginal swabs collected at four, six and eight days after intercourse from female partners of 11 couples. At four days postcoitus, full composite profiles (where swabs yielded confirmed alleles at all 11 loci) were obtained for five of the 11 couples and 78% of all possible alleles summed for all couples were confirmed (able to be duplicated in different swabs). Results for composite profiles for all couples taken at six days after intercourse showed that 53% of all alleles summed for all couples were confirmed. Only one couple yielded a full composite profile at six days after intercourse. Composite profiles from swabs taken at eight days after intercourse for all couples confirmed only 44% of all possible alleles summed for all couples. At eight days postcoitus, no couple yielded a full composite profile and the largest number of confirmed alleles for any couple was eight. However, one of 44 individual swabs taken from all couples combined at eight days postcoitus yielded a 10-locus profile. Composite partial profiles from the eight-day postcoital set with confirmed results at a minimum of five loci (8 of 11 couples) yielded haplotype frequencies from 0.000323 to 0.125862 using the Y chromosome haplotype reference database, suggesting that meaningful Y-STR information can still be obtained at much extended postcoital intervals. PMID- 22422783 TI - Using sound of target impact for acoustic reconstructions of shooting events. AB - The sound of a bullet hitting a target is sometimes discernable in an audio recording of a shooting event and can be used to determine the distance from shooter to target. This paper provides an example where the microphone is adjacent to the shooter and presents the simple mathematics needed in cases where the microphone is adjacent to the target. Spectrograms of the sound of bullet impact on a human-sized animal are also presented. PMID- 22422784 TI - Locational characteristics of the increasing number of forensic autopsy cases in Kyoto, Japan. AB - In Japan, the definition of unnatural death is not prescribed in law. However, a legal judgment recently defined unnatural death as all deaths, excluding natural deaths and deaths from diseases. Legally, unnatural deaths must be reported to the police. In the case of a reported death being considered as suspicious by the police, a forensic autopsy is required. The number of autopsies and the autopsy rate in Japan and Kyoto has increased over the last 10 years. Using data collected from 221 autopsy cases between 2008 and 2010 in Kyoto, Japan, the characteristics of locations where autopsy cases were discovered were analysed to identify reasons for the increase in autopsy numbers. It was found that factors including amount of human interaction and socioeconomic factors may help to explain the statistically significant correlations found. PMID- 22422785 TI - The epidemiology of homicide in Italy by season, day of the week and time of day. AB - Circadian and seasonal rhythms have an impact on the risk of violent death in humans, with more evidence available in suicide than in homicide. This study set out to investigate the pattern of deaths by homicide in Italy, taking into account the month, the day of the week and the time of day when the homicidal incident happened. Data based on official statistics on deaths by homicide (n = 3894) from 2003 to 2008 were analysed by spectral analysis and circular statistics techniques based on the Rayleigh test. Homicides showed seasonal distribution with a bimodal pattern, with summer (July and August) and winter (December and January) peaks over the other seasons. Homicides also peaked on Sundays and Mondays and were at their highest at night-time (00:00 to 5:59 hours). These rhythms in homicide victimization could be accounted for by social factors - within the framework of the routine activity theory - by psychological factors, including those leading to domestic violence, and by biological factors, including those impacting on impulse dyscontrol. The identification of risk or protective factors involved in the victim's surviving or succumbing to an assault might be important for the prevention of the worst outcome of injury at large, suicides and accidents included. PMID- 22422786 TI - Pontomedullary lacerations in pedestrians: an autopsy study. AB - It is common that injuries to the head are among the most frequent injuries found in pedestrian accidents, and can constitute a serious, if not fatal, threat. Brainstem lesions have only occasionally been reported in pedestrian injuries. The aim of this study has been to determine the frequency of brainstem pontomedullary lacerations (PMLs) among fatally injured pedestrians, the frequency of concomitant cranial, facial and cervical spine injuries in such cases, as well as to establish their possible underlying mechanism. In this work, PML was present in a significant number of fatally injured pedestrians from a sample of 50 out of 360 cases with head injuries (14%). When observed alone, the most frequent head impact areas were the chin, lateral and frontal (chi(2) = 14.200, df = 4, P = 0.007) in the subgroup with PML. Hinge fractures were most often seen in this subgroup (25 cases), followed by the absence of skull base fractures (chi(2) = 26.320, df = 3, P < 0.01). There are several possible mechanisms of PML in these cases. Impact to the chin, with or without a skull base fracture, could lead to this fatal injury due to impact force transmission. Additionally, lateral head impacts, the most frequent in pedestrians, with subsequent hinge fractures, PML and fronto-posterior hyperextension of the head that is associated with upper-spine fractures, may be possible mechanisms of brainstem injury in fatally injured pedestrians. PMID- 22422787 TI - Retrospective analysis of anaesthesia-related deaths during a 12-year period: looking at the data from a forensic point of view. AB - Anaesthesia-related death is one of the most complex events to be studied in forensic pathology because of its rarity and its doubtful presentation. Particularly, the difficulties in assessing the cause of deaths in such circumstances are underlined. A scale must be considered in order to determine the causal role of anaesthesia in the process leading to death. Indeed, beyond deaths exclusively explained by anaesthetic care, there are deaths that are not anaesthesia-related and deaths explained by surgery and co-morbidities in which the role of anaesthetic care has to be carefully investigated. A retrospective analysis of 3138 autopsies is presented with the aim of better understanding the patho-physiological process of anaesthesia-related mortality and to determine the causal role of anaesthesiological care in the process leading to death, thus assessing the real incidence of deaths due to anaesthesia (0.16%). In the present study, the number of deaths generically anaesthesia-related (33 cases) accounts for 2.06% of autopsies due to medical malpractice claims and 1.05% of all autopsies. The number of deaths totally related to anaesthesic care is rather low with 0.32% of autopsies due to medical malpractice claims and 0.16% of all autopsies. Anaesthesia-related deaths were due to lack of or delay in intubation (2 cases), acute cardio-respiratory failure (2 cases) and anaesthetic-induced hepatotoxicity (1 case). The importance of a careful forensic investigation (clinical and familial history, medical records, complete autopsy and toxicology), which can lead to a clear understanding of anaesthesia-related deaths, is also stressed. PMID- 22422788 TI - Left-sided ventricular cardiomyopathy with minimal right ventricular involvement. AB - Left-sided ventricular arrhythmogenic cardiomyopathy is rare and represents a rather different expression of the arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC). Among sudden cardiac deaths, ARVC plays a significant role. ARVC is considered as a cardiomyopathy of unknown aetiology that primarily involves the right ventricle (RV) and is characterized by progressive replacement of myocytes by fibro-fatty tissue, complicating a spectrum of arrhythmias. Predominant ARVC with left ventricular (LV) involvement is also reported. The LV variant of arrhythmogenic cardiomyopathy with minimal or no RV involvement is rare. A 31-year-old previously healthy young man, without a significant family history, was found dead in bed. Autopsy revealed an enlarged heart and asymmetrical LV hypertrophy with widely patent coronary arteries. LV myocardium demonstrated evidence of prominent epicardial fibro-fatty tissue that is predominantly fatty in nature and infiltrates into the myocardium. Microscopy of the LV free wall showed fibro-fatty tissue infiltration into the epicardial aspect of the LV that extends well into the mid-myocardium. A moderate to marked degree of interstitial fibrous tissue deposition was noted about adipocytes and cardiomyocytes. There was no evidence of chronic ischaemic changes or of significant myofibre disarray. The RV showed minimal fibro-fatty infiltration with normal myocytes. This report highlights a rare case which confirms previous observations that the LV variant of arrhythmogenic cardiomyopathy could occur with minimal or no involvement of the RV. Further studies are required in this context to elicit the spectrum and the exact nature of this disease. PMID- 22422789 TI - Imprudent blow, catastrophic consequence: a case of commotio cordis associated with violence. AB - Commotio cordis is a rare and catastrophic mechano-electric feedback syndrome, and it is especially apt to occur in male children, adolescents and youths during sports activities. The authors present a case of unexpected sudden death due to commotio cordis associated with violence. In a house of detention, a 19-year-old boy was punched and kicked in the face, neck and chest during a fight with another suspect in their ward. Unfortunately, his precordium was the major injured region. The victim turned pale, then lost the ability to resist and lost consciousness immediately. When the emergency medical personnel arrived, the victim was found in a condition of cardiac and respiratory arrest and he was pronounced dead at the scene without cardiopulmonary resuscitation. Both autopsy signs and forensic morphology were in accord with the criteria for commotio cordis diagnosis, showing no cardiac or other organic fatal lesions and no underlying cardiac diseases; moreover, the toxicological screening was negative for alcohol, drug and common toxicants. In the present case, the whole fight was seen by some witnesses in their ward, and it was recorded by the monitoring unit. Based on the statements of the witnesses and the monitoring videotape, combined with the forensic pathological and toxicological examinations, all the testimonies supported the conclusion that the cause of death was commotio cordis. PMID- 22422791 TI - Posttraumatic growth, coping strategies, and psychological distress in adolescent survivors of cancer. AB - Only recently have researchers begun to empirically examine positive outcomes such as posttraumatic growth in adolescent cancer. This article examines associations between posttraumatic growth, coping strategies, and psychological distress in adolescent cancer survivors. Adolescents who finished cancer treatment 2 to 10 years prior (N = 31) completed self-report measures of posttraumatic growth, coping, symptomatology, and disease-related characteristics. Younger age at diagnosis and less use of avoidant coping strategies predicted lower levels of psychological distress. Adolescents' beliefs that they were more likely to relapse and the use of more acceptance coping strategies predicted higher levels of posttraumatic growth. Adolescent cancer survivors may be capable of experiencing posttraumatic growth. Those who believe they are more prone to relapse and use more acceptance coping strategies are likely to have higher levels of posttraumatic growth. As health care professionals encourage adolescent cancer survivors to use fewer avoidant coping strategies, they can also encourage survivors to use more acceptance coping strategies. PMID- 22422792 TI - Pharmaceutical thrombosis prophylaxis, bleeding complications and thromboembolism in a national cohort of hysterectomy for benign disease. AB - BACKGROUND: Pharmaceutical thrombosis prophylaxis (PTP) with low-molecular-weight heparin (LMWH) is highly effective in preventing venous thromboembolic events (VTEs) and fatal pulmonary embolism. Important risk factors for VTEs are surgery and immobilization, along with malignancy. Many studies involving gynaecological malignancies show no increased risk for bleeding complications with PTP. Little is known about the PTP-associated risk for bleeding complications with hysterectomy for benign disease, or about current VTE incidence in the less invasive hysterectomy methods. METHODS: Our observational prospective national 1 year cohort from 1 January to 31 December 2006 in 53 hospitals represented 79.4% (5297 of 6645) of hysterectomies performed for benign cause in Finland in 2006. We evaluated PTP use and VTE incidence. Operative and post-operative bleeding complications were analysed with logistic regression adjusted for confounders: age, BMI, experience of the gynaecological surgeon, hospital type, indication for hysterectomy, uterine weight, operative haemorrhage, concomitant surgery, adhesiolysis and antibiotic prophylaxis. RESULTS: Hysterectomies were performed by three main approaches: 2345 vaginal hysterectomies (VHs, 44%), of which 1433 were for uterine prolapse and 912 for other indications, 1679 laparoscopic hysterectomies (LHs, 32%) and 1255 abdominal hysterectomies (AHs, 24%). PTP was given to 64.8% of patients (3420 of 5279) and was identified as LMWH in 3313 patients (97%); 107 left unidentified. By type of hysterectomy, PTP was given in VH for uterine prolapse to 73.2% of patients, VH for other indication to 51.6%, in LH to 59.4% and in AH to 71.9%. For all hysterectomies analysed together, PTP doubled the odds for post-operative haemorrhage or haematoma. By type of hysterectomy, PTP associated with post-operative haemorrhage or haematoma in VH for prolapse [2.7% of PTP given, versus 0.8% of no PTP; odds ratio (OR): 4.82, 95% confidence interval (CI): 1.38-16.83]; and in AH (3.1% versus 1.4%; OR: 2.87, 95% CI: 1.03-7.98), and in AH also with post-operative transfusion (3.1% versus 1.4%; OR: 3.34, 95% CI: 1.41-7.88). For LH and VH for indications other than prolapse, the effect of PTP on post-operative haemorrhage was non-significant. For VH, the risk for post-operative haemorrhage fell with age. Operative mean haemorrhage with all hysterectomy types, and operative bleeding complications in AH and VH also fell with age. Obesity increased haemorrhage and operative bleeding complications for LH and VH, whereas post-operative bleeding complications were less for the obese in AH. VTEs were 6 of 5279 (0.1%): two PEs each occurred after AH and VH, and two deep venous thromboses after LH. CONCLUSIONS: With a relatively wide PTP coverage (64.8%), VTEs were rare (0.1%). All affected had received PTP. Analysis of efficacy, meaning interpretation of how many VTEs or deaths were prevented, cannot be done from our observational study but related to safety in hysterectomy for benign disease, PTP associated with post-operative bleeding complications with AH and with VH for prolapse. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov protocol (NCT00744172). PMID- 22422793 TI - The clinical features and management of perineal endometriosis with anal sphincter involvement: a clinical analysis of 31 cases. AB - BACKGROUND: The aim of this study was to investigate the appropriate measures for diagnosing and treating perineal endometriosis (PEM) with anal sphincter involvement. METHODS: Between January 1992 and April 2011, the clinical features, diagnosis and management of 31 patients who were diagnosed with PEM with anal sphincter involvement at the Peking Union Medical College Hospital were retrospectively analyzed using their clinical records. A range of 6-78 months of outpatient follow-up after surgery were conducted for these 31 patients but was extended by telephone interviews with 29 patients conducted in December 2011. RESULTS: All 31 patients had a history of vaginal delivery. The level of serum CA(125) was elevated in only 2 (6.5%) cases. All cases received surgical treatment, which included narrow excision (NE, close to the edge of the endometrioma) with primary sphincteroplasty (PSp) for 30 cases and incomplete excision (IE) for 1 case. Of the 30 cases in the NE group, 20 (66.7%) received hormone therapy preoperatively. Up until December 2011, there was one recurrence (3.6%) of PEM in the NE group. PEM relapse occurred in the IE patient 6 years after the initial IE surgery. Perineal abscesses were found in one patient post operatively. No complaint of dyspareunia and no fecal incontinence episodes were observed during follow-up. CONCLUSIONS: Based on our own experience, NE and PSp may be indicated for the treatment of PEM with anal sphincter involvement. PMID- 22422794 TI - Effect of foam sclerotherapy on healing and long-term recurrence in chronic venous leg ulcers. AB - INTRODUCTION: The ESCHAR trial showed that superficial venous surgery and compression in chronic venous ulceration achieved a 24-week healing rate of 65% and 12-month recurrence rate of 12%. Foam sclerotherapy treatment is an alternative to surgery. The aim of this study is to assess the effect of foam sclerotherapy on ulcer healing and recurrence in chronic venous leg ulcers. METHODS: Chronic venous leg ulcers (CEAP [clinical, aetiological, anatomical and pathological elements] 5 and CEAP 6) with superficial venous reflux were treated between March 2006 and June 2011 with ultrasound-guided foam sclerotherapy and compression.Venous duplex was performed on all legs before and after treatment. Twenty-four-week ulcer healing and one- and four-year ulcer recurrence rates were calculated using Kaplan-Meier survival analysis. RESULTS: Two hundred legs (186 patients) with chronic venous ulcers (CEAP 5: n 1/4 163 and CEAP 6: n 1/4 37) were treated with foam sclerotherapy. Complete occlusion was achieved in 185/200 (92.5%) limbs, short segment occlusion in 14/200 (7%) limbs and one leg segment failed to occlude. One patient suffered an asymptomatic non-occlusive deep vein thrombosis (DVT) diagnosed on duplex scan at one week and one presented with an occlusive DVT three weeks following a normal scan at one week. One patient developed an asymptomatic occlusive DVT at two weeks following a non-occlusive DVT diagnosed on initial one-week scan. Eighteen patients were lost to follow-up (3 moved away and 15 died of unrelated causes). The 24-week healing rate was 71.1% and one- and four-year recurrence rates were 4.7% and 28.1%, respectively. CONCLUSION: Foam sclerotherapy is effective in abolition of superficial venous reflux and may contribute to similar ulcer healing and long-term recurrence rates to superficial venous surgery. Foam sclerotherapy is an attractive alternative to surgery in this group of patients. PMID- 22422795 TI - Intra-arterial injection, a rare but serious complication of sclerotherapy. AB - Intra-arterial injections represent the most feared complication of sclerotherapy for varicose veins. We present a case of an inadvertent intra-arterial injection of polidocanol at the left medial calf in a 59-year-old woman with subsequent arterial occlusions of the posterior tibial artery and foot arteries. Despite several therapeutic interventions, lower-limb amputation could not be prevented. We conducted a PubMed search for articles reporting arterial complications related to sclerotherapy, in order to evaluate aetiology, clinical presentation, therapeutic management and outcome of sclerotherapy-associated intra-arterial injections during the past 50 years. Intra-arterial injection of a sclerosing solution was reported in 63 cases, mostly after injection near the ankle region or the distal medial calf. Clinical presentation was frequently characterized by immediate pain during injection and distal ischaemia with subsequent tissue loss. Despite several treatment approaches, amputation could not be prevented in 31 cases (52.5%). The pathophysiology of arterial complications related to intra arterial injection and advisable therapeutic interventions are discussed. Inadvertent intra-arterial injection represents a limb-threatening complication of sclerotherapy. Target-oriented and prompt therapy seems inevitable in order to reduce the risk of permanent tissue loss and amputation. PMID- 22422796 TI - Differential effects of mild therapeutic exercise during a period of inactivity on power generation in soleus type I single fibers with age. AB - The purpose of this study was to investigate the effects of mild therapeutic exercise (treadmill) in preventing the inactivity-induced alterations in contractile properties (e.g., power, force, and velocity) of type I soleus single fibers in three different age groups. Young adult (5- to 12-mo-old), middle-aged (24- to 31-mo-old), and old (32- to 40-mo-old) F344BNF1 rats were randomly assigned to three experimental groups: weight-bearing control (CON), non-weight bearing (NWB), and NWB with exercise (NWBX). NWB rats were hindlimb suspended for 2 wk, representing inactivity. The NWBX rats were hindlimb suspended for 2 wk and received therapeutic exercise on a treadmill four times a day for 15 min each. Peak power and isometric maximal force were reduced following hindlimb suspension (HS) in all three age groups. HS decreased fiber diameter in young adult and old rats (-21 and -12%, respectively). Specific tension (isometric maximal force/cross-sectional area) was significantly reduced in both the middle-aged ( 36%) and old (-23%) rats. The effects of the mild therapeutic exercise program on fiber diameter and contractile properties were age specific. Mild treadmill therapeutic exercise attenuated the HS-induced reduction in fiber diameter (+17%, 93% level of CON group) and peak power (MUN.fiber length.s(-1)) (+46%, 63% level of CON group) in young adult rats. In the middle-aged animals, this exercise protocol improved peak power (+60%, 100% level of CON group) and normalized power (kN.m(-2).fiber length.s(-1)) (+45%, 108% level of CON group). Interestingly, treadmill exercise resulted in a further reduction in shortening velocity (-42%, 67% level of CON group) and specific tension (-29%, 55% level of CON group) in the old animals. These results suggest that mild treadmill exercise is beneficial in attenuating and preventing inactivity-induced decline in peak power of type I soleus single fibers in young adult and middle-aged animals, respectively. However, this exercise program does not prevent the HS-induced decline in muscle function in the old animals. PMID- 22422797 TI - Effect of hyperoxic exposure during early development on neurotrophin expression in the carotid body and nucleus tractus solitarii. AB - Synaptic activity can modify expression of neurotrophins, which influence the development of neuronal circuits. In the newborn rat, early hyperoxia silences the synaptic activity and input from the carotid body, impairing the development and function of chemoreceptors. The purpose of this study was to determine whether early hyperoxic exposure, sufficient to induce hypoplasia of the carotid body and decrease the number of chemoafferents, would also modify neurotrophin expression within the nucleus tractus solitarii (nTS). Rat pups were exposed to hyperoxia (fraction of inspired oxygen 0.60) or normoxia until 7 or 14 days of postnatal development (PND). In the carotid body, hyperoxia decreased brain derived neurotrophic factor (BDNF) protein expression by 93% (P = 0.04) after a 7 day exposure, followed by a decrease in retrogradely labeled chemoafferents by 55% (P = 0.004) within the petrosal ganglion at 14 days. Return to normoxia for 1 wk after a 14-day hyperoxic exposure did not reverse this effect. In the nTS, hyperoxia for 7 days: 1) decreased BDNF gene expression by 67% and protein expression by 18%; 2) attenuated upregulation of BDNF mRNA levels in response to acute hypoxia; and 3) upregulated p75 neurotrophic receptor, truncated tropomyosin kinase B (inactive receptor), and cleaved caspase-3. These effects were not observed in the locus coeruleus (LC). Hyperoxia for 14 days also decreased tyrosine hydroxylase levels by 18% (P = 0.04) in nTS but not in the LC. In conclusion, hyperoxic exposure during early PND reduces neurotrophin levels in the carotid body and the nTS and shifts the balance of neurotrophic support from prosurvival to proapoptotic in the nTS, the primary brain stem site for central integration of sensory and autonomic inputs. PMID- 22422798 TI - In pursuit of scientific excellence: sex matters. PMID- 22422799 TI - Impact of chronic exercise training on the blood pressure response to orthostatic stimulation. AB - Exercise training elicits morphological adaptations in the left ventricle (LV) and large-conduit arteries that are specific to the type of training performed (i.e., endurance vs. resistance exercise). We investigated whether the mode of chronic exercise training, and the associated cardiovascular adaptations, influence the blood pressure responses to orthostatic stimulation in 30 young healthy men (10 sedentary, 10 endurance trained, and 10 resistance trained). The endurance-trained group had a significantly larger LV end-diastolic volume normalized by body surface area (vs. sedentary and resistance-trained groups), whereas the resistance-trained group had a significantly higher LV wall thickness and aortic pulse wave velocity (PWV) compared with the endurance-trained group. In response to 60 degrees head-up tilt (HUT), mean arterial pressure (MAP) rose in the resistance-trained group (+6.5 +/- 1.6 mmHg, P < 0.05) but did not change significantly in sedentary and the endurance-trained groups. Systolic blood pressure (SBP) decreased in endurance-trained group (-8.3 +/- 2.4 mmHg, P < 0.05) but did not significantly change in sedentary and resistance-trained groups. A forward stepwise multiple regression analysis revealed that LV wall thickness and aortic PWV were significantly and independently associated with the MAP response to HUT, explaining ~41% of its variability (R(2) =0.414, P < 0.001). Likewise, aortic PWV and the corresponding HUT-mediated change in stroke volume were significantly and independently associated with the SBP response to HUT, explaining ~52% of its variability (R(2) = 0.519, P < 0.0001). Furthermore, the change in stroke volume significantly correlated with LV wall thickness (r = 0.39, P < 0.01). These results indicate that chronic resistance and endurance exercise training differentially affect the BP response to HUT, and that this appears to be associated with training-induced morphological adaptations of the LV and large-conduit arteries. PMID- 22422800 TI - Hypoxia recruits intrapulmonary arteriovenous pathways in intact rats but not isolated rat lungs. AB - Intrapulmonary arteriovenous anastomoses (IPAVS) directly connect the arterial and venous circulations in the lung, bypassing the capillary network. Here, we used solid, latex microspheres and isolated rat lung and intact, spontaneously breathing rat models to test the hypothesis that IPAVS are recruited by alveolar hypoxia. We found that hypoxia recruits IPAVS in the intact rat, but not the isolated lung. IPAVS are at least 70 MUm in the rat and, interestingly, appear to be recruited when the mixed venous Po(2) falls below 22 mmHg. These data provide evidence that large-diameter, direct arteriovenous connections exist in the lung and are recruitable by hypoxia in the intact animal. PMID- 22422801 TI - Total-body creatine pool size and skeletal muscle mass determination by creatine (methyl-D3) dilution in rats. AB - There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-(methyl-d(3)) (D(3)-creatinine) in urine after a defined oral tracer dose of D(3)-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D(3) creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D(3)-creatine in muscle and D(3)-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D(3)-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D(3)-creatine (<1 mg/rat) was >99% bioavailable with 0.2-1.2% urinary spillage. Isotopic steady state was achieved within 24-48 h. Creatine pool size calculated from urinary D(3)-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass (r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D(3)-creatine followed by the measurement of D(3)-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass. PMID- 22422802 TI - Pathophysiology of Q waves in II, III, avF in systemic lupus erythematosus. Evaluation using cardiovascular magnetic resonance imaging. AB - OBJECTIVES: To investigate the pathophysiology of Q waves in II, III, avF in systemic lupus erythematosus (SLE) by cardiovascular magnetic resonance (CMR). METHODS: Inflammation evaluation by CMR using T2, early (EGE) and late gadolinium enhanced images (LGE) was performed in 20 SLE patients with mild cardiac symptoms and Q in leads II, III, avF of ECG. Their results were compared with 20 SLE patients with the same symptoms and normal ECG. RESULTS: In both groups, T2, EGE and left ventricular ejection fraction were normal. However, in 3/20 with Q in II, III, avF, CMR revealed lesions indicative of acute myocarditis. In the rest of them, CMR documented transmural LGE, due to past inferior myocardial infarction in 4/20 and epicardial LGE due to past myocarditis in 8/20 (4/8 in the inferior and 4/8 in the lateral wall of left ventricle). No LGE was found in 5/20 and the Q was attributed to the position of the heart. In 3/20 with normal ECG, CMR detected past myocarditis in 2/3 and myocardial infarction in 1/3. Coronary angiography assessed coronary artery disease in all SLE with evidence of myocardial infarction and normal coronaries in 9/10 patients with past myocarditis. CONCLUSION: Q in II, III, avF in SLE may indicate myocardial infarction, acute or past inflammation or be a positional finding. The lack of Q does not exclude the possibility of infarction or inflammation. CMR is the best tool to reveal the pathophysiology of Q waves in SLE and guide treatment of heart involvement in these patients. PMID- 22422803 TI - Culture shapes electrocortical responses during emotion suppression. AB - Previous work has shown that emotional control is highly valued in Asian culture. However, little is known about how this cultural value might influence emotional processing. Here, we hypothesized that Asians are 'culturally trained' to down regulate emotional processing when required to suppress emotional expressions. Such down-regulation, however, is unlikely for European Americans because their culture values emotional expression (vs control) more. To test these predictions, we adopted the parietal late positive potential (LPP) of the event-related potential as an objective indicator of emotional processing. Both Asian and European Americans were exposed to either unpleasant or neutral pictures while instructed to either attend or suppress expression of emotions. Both groups showed an equally pronounced parietal positivity ~600 ms post-stimulus. As predicted, however, Asians subsequently showed a significant decrease of the parietal LPP in the suppression (vs attend) condition. The initial positivity completely disappeared 2000 ms post-stimulus. In contrast, for European Americans the parietal LPP suppression effect was completely absent although there was an early occurring, sustained increase in frontal positivity in the suppression (vs attend) condition. Implications for culture and emotion research are discussed. PMID- 22422804 TI - Transient and sustained neural responses to death-related linguistic cues. AB - Recent research showed that perception of death-related vs death-unrelated linguistic cues produced increased frontoparietal activity but decreased insular activity. This study investigated (i) whether the increased frontoparietal and decreased insular activities are, respectively, associated with transient trial specific processes of death-related linguistic cues and sustained death-related thought during death-relevance judgments on linguistic cues and (ii) whether the neural activity underlying death-related thought can predict individuals' dispositional death anxiety. Participants were presented with death related/unrelated words, life-related/unrelated words, and negative valence/neutral words in separate sessions. Participants were scanned using functional magnetic resonance imaging while performing death-relevance, life relevance, and valence judgments on the words, respectively. The contrast of death-related vs death-unrelated words during death-relevance judgments revealed transient increased activity in the left inferior parietal lobule, the right frontal eye field, and the right superior parietal lobule. The contrast of death relevance judgments vs life-relevance/valence judgments showed decreased activity in the bilateral insula. The sustained insular activity was correlated with dispositional death anxiety, but only in those with weak transient frontoparietal responses to death-related words. Our results dissociate the transient and sustained neural responses to death-related linguistic cues and suggest that the combination of the transient and sustained neural activities can predict dispositional death anxiety. PMID- 22422805 TI - Adverse reactions to metal debris: histopathological features of periprosthetic soft tissue reactions seen in association with failed metal on metal hip arthroplasties. AB - AIM: To describe the histopathology of localised adverse reactions to metal debris (ARMD) seen in association with failed metal on metal (MoM) hip arthroplasties. The nature of aseptic lymphocytic vasculitis associated lesion (ALVAL) is investigated. METHODS: Periprosthetic soft tissues biopsied at time of revision from failed MoM hip arthroplasties from January 2007 to March 2011 were analysed. The inflammatory cell response was categorised into perivascular lymphocytic cuffing (ALVAL), lymphoid aggregate formation with or without germinal centres, metallosis characterised by sheets of macrophages with intracytoplasmic metallic debris and well-defined granulomas. RESULTS: 123 patient samples were analysed, 36 males (29.2%) and 87 females (70.8%). Three cases showing complete tissue necrosis were excluded. Patients were reviewed between 3.27 to 69.6 months postarthroplasty, with an average of 30.92 months. 103 cases (85.8%) showed ALVAL, 18 cases also showed well-defined granulomas. Of the 103 cases with ALVAL, 60 cases also showed a diffuse chronic lymphocytic synovitis, and 40 cases showed lymphoid aggregates with germinal centres. 17 cases (14.2%) showed pure metallosis. Small vessels showing ALVAL expressed peripheral node addressin. CONCLUSIONS: ARMD is a spectrum of changes comprising of pure metallosis, ALVAL and granulomatous inflammation. ALVAL, a distinctive inflammatory response seen in ARMD, is a precursor of lymphoid neogenesis. Lymphoid neogenesis documented in a variety of chronic inflammatory conditions most probably contributes to tissue necrosis and prosthetic failure seen in MoM hip arthroplasties. The role of vascular changes in contributing to necrosis is unclear at this stage. PMID- 22422806 TI - Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. AB - BACKGROUND: Forkhead Box P1 (FOXP1) has been described as both a tumour suppressor candidate and a potential oncogene. The aim of this study is to identify new prognostic biomarkers and therapeutic target structures for the diagnosis and treatment of hepatocellular carcinoma (HCC). METHODS: The expression of FOXP1 mRNA in HCC was characterised using real-time PCR and 20 pairs of fresh frozen HCC tissues and corresponding non-cancerous tissues. FOXP1 protein expression in HCC was confirmed using immunohistochemistry on a tissue microarray chip. Finally, FOXP1 expression was correlated with conventional clinicopathological features of HCC and patient outcome. RESULTS: The expression of FOXP1 mRNA and protein in HCC cells was much higher than in normal hepatic cells (Z=2.315, p=0.021 and chi(2)=28.071, 95% CI 0.233 to 0.480, p<0.001, individually). The comparison of clinicopathological characteristics and immunohistochemistry by chi(2) test analysis showed that the high expression of FOXP1 in HCC was related to large tumour diameter (chi(2)=6.210, p=0.013), high serum alpha-fetoprotein levels (chi(2)=6.920, p=0.031) and later stage grouping with tumour node metastasis classification (chi(2)=6.714, p=0.035). Kaplan-Meier survival and Cox regression analysis showed that high FOXP1 expression (HR=2.182, 95% CI 1.146 to 4.154, p=0.018) and regional lymph node metastasis (HR=2.326, 95% CI 1.037 to 5.217, p=0.041) were independent prognosis factors. CONCLUSIONS: From this investigation the authors elucidated for the first time that the correlation of high FOXP1 expression correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for HCC. These results also support a role for FOXP1 as an oncogene in HCC. PMID- 22422807 TI - Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: We aimed to investigate the regional distribution of grey matter (GM) and white matter (WM) atrophy in patients with relapsing-remitting (RR) MS and their relationship with gender, clinical findings, and T2 lesions. METHODS: Clinical and magnetic resonance imaging assessments were obtained from 78 patients with RRMS and 88 controls. GM and WM atrophy were estimated using voxel based morphometry (SPM8). RESULTS: Patients with RRMS experienced atrophy of the deep GM nuclei, and several cortical regions mainly located in the fronto parietal lobes. WM atrophy involved posterior regions of the brain, including the cerebellum and brainstem. Compared with men, affected women showed atrophy of several WM tracts, while gender did not impact GM atrophy. Disease duration > 5 years was associated with atrophy of the thalami and inferior frontal gyrus, while WM atrophy was already prominent in patients with disease duration <= 5 years. Expanded Disability Status Scale score > 3.0 was associated with diffuse WM atrophy and basal ganglia and precentral gyrus atrophy. T2 lesions were marginally associated to focal atrophy. DISCUSSION: In RRMS, GM and WM atrophy have distinct patterns of regional distribution, with a sparing of GM infratentorial regions. Gender, disease duration and disability affect differently the topography of GM/WM atrophy, while T2 lesions play a modest role. PMID- 22422809 TI - Do HSCs divide asymmetrically? PMID- 22422808 TI - Time-patterns of annualized relapse rates in randomized placebo-controlled clinical trials in relapsing multiple sclerosis: a systematic review and meta analysis. AB - BACKGROUND: Although it is known that the annualized relapse rate (ARR) in patients with multiple sclerosis (MS) changes as disease progresses, in the design and analysis of trials in relapsing multiple sclerosis (RMS) constant ARRs are assumed. OBJECTIVES: This paper aims to assess time-patterns of trial ARR by conducting a systematic review of randomized, placebo-controlled trials in RMS. METHODS: A systematic literature search was conducted by searching PubMed for randomized, placebo-controlled trials in RMS. In meta-analyses the following comparisons of trial ARR were carried out for the placebo controls and active treatment arms: months 1-6 vs. months 7-12, and months 1-12 vs. months 13-24. RESULTS: A total of 52 trials was identified. Out of these, information on the time-dependence of trial ARR could be extracted from 13 trials. The ARR was by 25% (p = 0.0005) and 40% (p < 0.0001) higher in months 1-12 compared with months 13-24 for placebo and active treatments, respectively. Consequently, the treatment effects were by 13% (p = 0.23) larger in the second year compared with the first year. Within the first year of follow-up the ARR was by 4% (p = 0.75) and 23% (p = 0.06) higher in months 1-6 compared with months 7-12 for placebo controls and active arms, respectively. CONCLUSIONS: Trial ARR decreases during a trial in RMS, which is in line with epidemiological findings and has implications for design and analysis of future trials. The observed decrease in trial ARR might be at least partially explained by regression to the mean. Individual patient data analyses are warranted. PMID- 22422810 TI - Human FcgammaRIIA at center stage. PMID- 22422811 TI - Public health comes to immune deficiency. PMID- 22422812 TI - Thrombosis risk in purely obstetric APS. PMID- 22422813 TI - Equal-opportunity treatment of EBV-PTLD. PMID- 22422814 TI - Natural revenge over cytomegalovirus. PMID- 22422815 TI - Angiogenesis is controlled by miR-27b associated with endothelial tip cells. PMID- 22422816 TI - Unverifiable publications in otolaryngology residency applications. AB - OBJECTIVE: To determine the prevalence of unverifiable ("ghost") publications in applications to an otolaryngology residency program through the Electronic Residency Application Service (ERAS), correlate with applicant characteristics, and determine if incidence changed after the addition of PubMed (PMID) numbers in 2008. STUDY DESIGN AND SETTING: Cross-sectional study of residency applications before and after inclusion of PMID numbers at an academic otolaryngology program. SUBJECTS AND METHODS: Applications for 2007 and 2008 were reviewed. Publications were verified against Medline, Google Scholar, PubMed, ISI Web of Science, and Google. Ghost publications were defined as journals, books, abstracts, or posters that could not be verified as presented, published, or including the applicant author. RESULTS: In total, 489 applications were reviewed: 243 before PMID numbers were requested and 246 after. Of 2300 listed publications, 125 (5%) were not actual publications and 460 (20%) were in pending status. Forty-five percent (775/1715) could not be verified: 660 of 953 (69%) abstracts/posters, 18 of 47 (38%) chapters, and 97 of 715 (14%) journal articles. Abstracts/posters and book chapters were hardest to verify. The proportion of overall reported publications that could be verified was lower following the addition of PMID to the ERAS application (P = .0003), and the proportion of verifiable journal articles was unchanged from 86.0% to 86.9% (P = .62). Unlike previous findings, gender and medical school ranking were not associated with ghost publications. CONCLUSION: A substantial number of publications, especially book chapters and posters/abstracts, listed on otolaryngology residency applications could not be verified. The addition of the PMID to applications did not reduce the number of ghost journal publications. PMID- 22422819 TI - Monoclonal B-cell lymphocytosis: right track or red herring? AB - Monoclonal B-cell lymphocytosis (MBL), a newly recognized entity found in approximately 3% of normal persons, precedes chronic lymphocytic leukemia. However, MBLs progress into overt malignancy only in a very minor portion of cases, thus raising the clinical concern of whether and how we can discriminate at diagnosis which rare cases will evolve into a fully fledged tumor. Understanding the molecular/biologic features underlying the risk of progression may significantly modify our strategies for correctly managing B-cell premalignant states. MBL cells bear the same chromosomal abnormalities of chronic lymphocytic leukemia. Genome-wide sequencing and animal models indicate that genetic abnormalities disrupting the control of cell growth and survival cooperate with microenvironment-triggered events, mainly represented by antigen mediated B-cell receptor and coreceptor stimulation, to trigger and fuel clonal expansion. The initial functional activation of survival/proliferation pathways may later become subsidized by autonomous genetic abnormalities (eg, a single mutation) affecting the same or parallel critical signaling pathway(s). PMID- 22422820 TI - Concomitant inactivation of Rb and E2f8 in hematopoietic stem cells synergizes to induce severe anemia. AB - The retinoblastoma (Rb) tumor suppressor plays important roles in regulating hematopoiesis, particularly erythropoiesis. In an effort to understand whether Rb function can be mediated by E2F transcription factors in a BM-derived hematopoietic system in mice, we uncovered a functional synergy between Rb and E2F8 to promote erythropoiesis and to prevent anemia. Specifically, whereas Mx1 Cre-mediated inactivation of Rb or E2f8 in hematopoietic stem cells only led to mild erythropoietic defects, concomitant inactivation of both genes resulted in marked ineffective erythropoiesis and mild hemolysis, leading to severe anemia despite the presence of enhanced extramedullary erythropoiesis. Interestingly, although ineffective erythropoiesis was already present in the RbDelta/Delta mice and exacerbated in the RbDelta/Delta;E2f8Delta/Delta mice, hemolysis was exclusively manifested in the double-knockout mice. Using an adoptive transfer system and an erythroid-specific knockout system, we have shown that the synergy of Rb and E2f8 deficiency in triggering severe anemia is intrinsic to the erythroid lineage. Surprisingly, concomitant inactivation of Rb and E2f7, a close family member of E2f8, did not substantially worsen the erythropoietic defect resulted from Rb deficiency. The results of the present study reveal the specificity of E2F8 in mediating Rb function in erythropoiesis and suggest critical and overlapping roles of Rb and E2f8 in maintaining normal erythropoiesis and in preventing hemolysis. PMID- 22422821 TI - Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields. AB - The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF-enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization. Peripheral sympathetic nerve neurons express the G-CSF receptor and ex vivo stimulation of peripheral sympathetic nerve neurons with G-CSF reduced NE reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. Based on these data, we investigated the NE reuptake inhibitor desipramine in HSPC mobilization. Whereas desipramine did not by itself elicit circulating HSPCs, it increased G-CSF-triggered mobilization efficiency significantly and rescued mobilization in a model mimicking "poor mobilizers." Therefore, these data suggest that blockade of NE reuptake may be a novel therapeutic target to increase stem cell yield in patients. PMID- 22422822 TI - Intra-individual variation in G2 chromosomal radiosensitivity. AB - Intra-individual variation in G(2) chromosomal radiosensitivity was examined by repeatedly taking blood samples from two individuals. Two healthy female volunteers provided a total of 44 blood samples, Donor 1 gave 28 samples in four time periods between 2001 and 2006 and Donor 2 gave 16 samples in two of the same time periods. Lymphocytes were cultured for 72 h prior to irradiation with 0.5 Gy, 300 kV X-rays. Colcemid was added 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Donor 1 exhibited significant intra-individual variation in G(2) chromosomal radiosensitivity for two of the four time periods. Variation was not significant for Period 1 (13 samples, P = 0.111) and Period 2 (six samples, P = 0.311) but was significant for Period 3 (two samples, P = 0.030) and Period 4 (seven samples, P = 0.005). Significant intra-individual variation was observed for both time periods involving Donor 2, these being Period 2 (nine samples, P = 0.002) and Period 4 (seven samples, P < 0.001). The combined data from all time periods exhibited a significant intra-individual variation for Donor 1 (P < 0.001) and Donor 2 (P < 0.001). These findings led to the conclusion that too much reliance should not be placed on the result from a single sample when assessing individual radiosensitivity status. PMID- 22422823 TI - Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. AB - Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms)>=very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1 year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442). PMID- 22422824 TI - Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine. AB - The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230. PMID- 22422825 TI - The DEAH-box helicase RHAU is an essential gene and critical for mouse hematopoiesis. AB - The DEAH helicase RHAU (alias DHX36, G4R1) is the only helicase shown to have G quadruplex (G4)-RNA resolvase activity and the major source of G4-DNA resolvase activity. Previous report showed RHAU mRNA expression to be elevated in human lymphoid and CD34(+) BM cells, suggesting a potential role in hematopoiesis. Here, we generated a conditional knockout of the RHAU gene in mice. Germ line deletion of RHAU led to embryonic lethality. We then targeted the RHAU gene specifically in the hematopoiesis system, using a Cre-inducible system in which an optimized variant of Cre recombinase was expressed under the control of the Vav1 promoter. RHAU deletion in hematopoietic system caused hemolytic anemia and differentiation defect at the proerythroblast stage. The partial differentiation block of proerythroblasts was because of a proliferation defect. Transcriptome analysis of RHAU knockout proerythroblasts showed that a statistically significant portion of the deregulated genes contain G4 motifs in their promoters. This suggests that RHAU may play a role in the regulation of gene expression that relies on its G4 resolvase activity. PMID- 22422826 TI - Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. AB - We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479. PMID- 22422827 TI - Liver hyperplasia after tamoxifen induction of Myc in a transgenic medaka model. AB - Myc is a global transcriptional regulator and one of the most frequently overexpressed oncoproteins in human tumors. It is well established that activation of Myc leads to enhanced cell proliferation but can also lead to increased apoptosis. The use of animal models expressing deregulated levels of Myc has helped to both elucidate its function in normal cells and give insight into how Myc initiates and maintains tumorigenesis. Analyses of the medaka (Oryzias latipes) genome uncovered the unexpected presence of two Myc gene copies in this teleost species. Comparison of these Myc versions to other vertebrate species revealed that one gene, myc17, differs by the loss of some conserved regulatory protein motifs present in all other known Myc genes. To investigate how such differences might affect the basic biological functions of Myc, we generated a tamoxifen-inducible in vivo model utilizing a natural, fish-specific Myc gene. Using this model we show that, when activated, Myc17 leads to increased proliferation and to apoptosis in a dose-dependent manner, similar to human Myc. We have also shown that long-term Myc17 activation triggers liver hyperplasia in adult fish, allowing this newly established transgenic medaka model to be used to study the transition from hyperplasia to liver cancer and to identify Myc-induced tumorigenesis modifiers. PMID- 22422828 TI - High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney. AB - Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO) promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens) or partially resistant (DIOres) to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways. PMID- 22422829 TI - Exploring molecular genetics of bladder cancer: lessons learned from mouse models. AB - Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies worldwide, causing considerable morbidity and mortality. It is unusual among the epithelial carcinomas because tumorigenesis can occur by two distinct pathways: low-grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS, whereas high-grade, muscle-invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma (RB). Over the past 20 years, a plethora of genetically engineered mouse (GEM) models of UCC have been developed, containing deletions or mutations of key tumour suppressor genes or oncogenes. In this review, we provide an up-to-date summary of these GEM models, analyse their flaws and weaknesses, discuss how they have advanced our understanding of UCC at the molecular level, and comment on their translational potential. We also highlight recent studies supporting a role for dysregulated Wnt signalling in UCC and the development of mouse models that recapitulate this dysregulation. PMID- 22422830 TI - Diabetes clinical trials: helped or hindered by the current shift in regulatory requirements? AB - Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs. PMID- 22422831 TI - Polymyositis. PMID- 22422832 TI - Credibility of claims of subgroup effects in randomised controlled trials: systematic review. AB - OBJECTIVE: To investigate the credibility of authors' claims of subgroup effects using a representative sample of recently published randomised controlled trials. DESIGN: Systematic review. DATA SOURCE: Core clinical journals, as defined by the National Library of Medicine, in Medline. STUDY SELECTION: Randomised controlled trials published in 2007. Using prespecified criteria, teams of trained reviewers independently judged whether authors claimed subgroup effects and the strength of their claims. Reviewers assessed each of these claims against 10 predefined criteria, developed through a search of existing criteria and a consensus process. RESULTS: Of 207 randomised controlled trials reporting subgroup analyses, 64 (31%) made claims for the primary outcome. Of those, 20 were strong claims and 28 claims of a likely effect. Authors included subgroup variables measured at baseline in 60 (94%) trials, used subgroup variable as a stratification factor at randomisation in 13 (20%), clearly prespecified their hypotheses in 26 (41%), correctly prespecified direction in 4 (6%), tested a small number of hypotheses in 28 (44%), carried out a test of interaction that proved statistically significant in 6 (9%), documented replication of a subgroup effect with previous related studies in 21 (33%), identified consistency of a subgroup effect across related outcomes in 19 (30%), and provided a compelling indirect evidence for the effect in 14 (22%). In the 19 trials making more than one claim, only one (5%) checked the independence of the interaction. Of the 64 claims, 54 (84%) met four or fewer of the 10 criteria. For strong claims, more than 50% failed each of the individual criteria, and only three (15%) met more than five criteria. CONCLUSION: Authors often claim subgroup effects in their trial report. However, the credibility of subgroup effects, even when claims are strong, is usually low. Users of the information should treat claims that fail to meet most criteria with scepticism. Trial researchers should report the conduct of subgroup analyses and provide sufficient evidence when claiming a subgroup effect or suggesting a possible effect. PMID- 22422833 TI - New guidance for troponin assays. PMID- 22422834 TI - Subgroup analyses. PMID- 22422835 TI - Scientists speak out against activists' pressure preventing animal imports. PMID- 22422836 TI - CORECLUST: identification of the conserved CRM grammar together with prediction of gene regulation. AB - Identification of transcriptional regulatory regions and tracing their internal organization are important for understanding the eukaryotic cell machinery. Cis regulatory modules (CRMs) of higher eukaryotes are believed to possess a regulatory 'grammar', or preferred arrangement of binding sites, that is crucial for proper regulation and thus tends to be evolutionarily conserved. Here, we present a method CORECLUST (COnservative REgulatory CLUster STructure) that predicts CRMs based on a set of positional weight matrices. Given regulatory regions of orthologous and/or co-regulated genes, CORECLUST constructs a CRM model by revealing the conserved rules that describe the relative location of binding sites. The constructed model may be consequently used for the genome-wide prediction of similar CRMs, and thus detection of co-regulated genes, and for the investigation of the regulatory grammar of the system. Compared with related methods, CORECLUST shows better performance at identification of CRMs conferring muscle-specific gene expression in vertebrates and early-developmental CRMs in Drosophila. PMID- 22422837 TI - Rapid hierarchical assembly of medium-size DNA cassettes. AB - Synthetic biology applications call for efficient methods to generate large gene cassettes that encode complex gene circuits in order to avoid simultaneous delivery of multiple plasmids encoding individual genes. Multiple methods have been proposed to achieve this goal. Here, we describe a novel protocol that allows one-step cloning of up to four gene-size DNA fragments, followed by a second assembly of these concatenated sequences into large circular DNA. The protocols described here comprise a simple, cheap and fast solution for routine construction of cassettes with up to 10 gene-size components. PMID- 22422838 TI - The CDK5 repressor CDK5RAP1 is a methylthiotransferase acting on nuclear and mitochondrial RNA. AB - The unusual cyclin-dependent protein kinase 5 (CDK5) was discovered based on its sequence homology to cell cycle regulating CDKs. CDK5 was found to be active in brain tissues, where it is not involved in cell cycle regulation but in the regulation of neuronal cell differentiation and neurocytoskeleton dynamics. An aberrant regulation of CDK5 leads to the development of various neurodegenerative diseases including Alzheimer's disease. Although CDK5 is not regulated by cyclins, its activity does depend on the association with a protein activator and the presence or absence of further inhibitory factors. Recently, CDK5RAP1 was discovered to inhibit the active CDK5 kinase. Here, we show that CDK5RAP1 is a radical SAM enzyme, which postsynthetically converts the RNA modification N6 isopentenyladenosine (i(6)A) into 2-methylthio-N6-isopentenyladenosine (ms(2)i(6)A). This conversion is surprisingly not limited to mitochondrial tRNA, where the modification was known to exist. Instead, CDK5RAP1 introduces the modification also into nuclear RNA species establishing a link between postsynthetic kinase-based protein modification and postsynthetic RNA modification. PMID- 22422839 TI - Bacillus subtilis genome editing using ssDNA with short homology regions. AB - In this study, we developed a simple and efficient Bacillus subtilis genome editing method in which targeted gene(s) could be inactivated by single-stranded PCR product(s) flanked by short homology regions and in-frame deletion could be achieved by incubating the transformants at 42 degrees C. In this process, homologous recombination (HR) was promoted by the lambda beta protein synthesized under the control of promoter P(RM) in the lambda cI857 P(RM)-P(R) promoter system on a temperature sensitive plasmid pWY121. Promoter P(R) drove the expression of the recombinase gene cre at 42 degrees C for excising the floxed (lox sites flanked) disruption cassette that contained a bleomycin resistance marker and a heat inducible counter-selectable marker (hewl, encoding hen egg white lysozyme). Then, we amplified the single-stranded disruption cassette using the primers that carried 70 nt homology extensions corresponding to the regions flanking the target gene. By transforming the respective PCR products into the B. subtilis that harbored pWY121 and incubating the resultant mutants at 42 degrees C, we knocked out multiple genes in the same genetic background with no marker left. This process is simple and efficient and can be widely applied to large scale genome analysis of recalcitrant Bacillus species. PMID- 22422840 TI - Critical amino acids in Escherichia coli UmuC responsible for sugar discrimination and base-substitution fidelity. AB - The active form of Escherichia coli DNA polymerase V responsible for damage induced mutagenesis is a multiprotein complex (UmuD'(2)C-RecA-ATP), called pol V Mut. Optimal activity of pol V Mut in vitro is observed on an SSB-coated single stranded circular DNA template in the presence of the beta/gamma complex and a transactivated RecA nucleoprotein filament, RecA*. Remarkably, under these conditions, wild-type pol V Mut efficiently incorporates ribonucleotides into DNA. A Y11A substitution in the 'steric gate' of UmuC further reduces pol V sugar selectivity and converts pol V Mut into a primer-dependent RNA polymerase that is capable of synthesizing long RNAs with a processivity comparable to that of DNA synthesis. Despite such properties, Y11A only promotes low levels of spontaneous mutagenesis in vivo. While the Y11F substitution has a minimal effect on sugar selectivity, it results in an increase in spontaneous mutagenesis. In comparison, an F10L substitution increases sugar selectivity and the overall fidelity of pol V Mut. Molecular modeling analysis reveals that the branched side-chain of L10 impinges on the benzene ring of Y11 so as to constrict its movement and as a consequence, firmly closes the steric gate, which in wild-type enzyme fails to guard against ribonucleoside triphosphates incorporation with sufficient stringency. PMID- 22422841 TI - Unveiling combinatorial regulation through the combination of ChIP information and in silico cis-regulatory module detection. AB - Computationally retrieving biologically relevant cis-regulatory modules (CRMs) is not straightforward. Because of the large number of candidates and the imperfection of the screening methods, many spurious CRMs are detected that are as high scoring as the biologically true ones. Using ChIP-information allows not only to reduce the regions in which the binding sites of the assayed transcription factor (TF) should be located, but also allows restricting the valid CRMs to those that contain the assayed TF (here referred to as applying CRM detection in a query-based mode). In this study, we show that exploiting ChIP information in a query-based way makes in silico CRM detection a much more feasible endeavor. To be able to handle the large datasets, the query-based setting and other specificities proper to CRM detection on ChIP-Seq based data, we developed a novel powerful CRM detection method 'CPModule'. By applying it on a well-studied ChIP-Seq data set involved in self-renewal of mouse embryonic stem cells, we demonstrate how our tool can recover combinatorial regulation of five known TFs that are key in the self-renewal of mouse embryonic stem cells. Additionally, we make a number of new predictions on combinatorial regulation of these five key TFs with other TFs documented in TRANSFAC. PMID- 22422842 TI - siRNAs targeted to certain polyadenylation sites promote specific, RISC independent degradation of messenger RNAs. AB - While most siRNAs induce sequence-specific target mRNA cleavage and degradation in a process mediated by Ago2/RNA-induced silencing complex (RISC), certain siRNAs have also been demonstrated to direct target RNA reduction through deadenylation and subsequent degradation of target transcripts in a process which involves Ago1/RISC and P-bodies. In the current study, we present data suggesting that a third class of siRNA exist, which are capable of promoting target RNA reduction that is independent of both Ago and RISC. These siRNAs bind the target messenger RNA at the polyA signal and are capable of redirecting a small amount of polyadenylation to downstream polyA sites when present, however, the majority of the activity appears to be due to inhibition of polyadenylation or deadenylation of the transcript, followed by exosomal degradation of the immature mRNA. PMID- 22422843 TI - High-throughput single-molecule analysis of DNA-protein interactions by tethered particle motion. AB - Tethered particle motion (TPM) monitors the variations in the effective length of a single DNA molecule by tracking the Brownian motion of a bead tethered to a support by the DNA molecule. Providing information about DNA conformations in real time, this technique enables a refined characterization of DNA-protein interactions. To increase the output of this powerful but time-consuming single molecule assay, we have developed a biochip for the simultaneous acquisition of data from more than 500 single DNA molecules. The controlled positioning of individual DNA molecules is achieved by self-assembly on nanoscale arrays fabricated through a standard microcontact printing method. We demonstrate the capacity of our biochip to study biological processes by applying our method to explore the enzymatic activity of the T7 bacteriophage exonuclease. Our single molecule observations shed new light on its behaviour that had only been examined in bulk assays previously and, more specifically, on its processivity. PMID- 22422844 TI - Real-time assay for testing components of protein synthesis. AB - We present a flexible, real-time-coupled transcription-translation assay that involves the continuous monitoring of fluorescent Emerald GFP formation. Along with numerical simulation of a reaction kinetics model, the assay permits quantitative estimation of the effects on full-length protein synthesis of various additions, subtractions or substitutions to the protein synthesis machinery. Since the assay uses continuous fluorescence monitoring, it is much simpler and more rapid than other assays of protein synthesis and is compatible with high-throughput formats. Straightforward alterations of the assay permit determination of (i) the fraction of ribosomes in a cell-free protein synthesis kit that is active in full-length protein synthesis and (ii) the relative activities in supporting protein synthesis of modified (e.g. mutated, fluorescent labeled) exogenous components (ribosomes, amino acid-specific tRNAs) that replace the corresponding endogenous components. Ribosomes containing fluorescent-labeled L11 and tRNAs labeled with fluorophores in the D-loop retain substantial activity. In the latter case, the extent of activity loss correlates with a combination of steric bulk and hydrophobicity of the fluorophore. PMID- 22422845 TI - Molecular testing for infectious diseases should be done in the clinical microbiology laboratory. AB - Over the past decade, there has been an explosion in the use of molecular tests to diagnose and manage infectious diseases. HIV is a prime example of an infectious agent whose diagnosis at least in the acute stage, susceptibility testing, and management are all dependent on molecular diagnostics. The ability to accurately diagnose a plethora of respiratory pathogens quickly, simply, and relatively inexpensively compared to traditional methods is becoming a reality. Direct sequencing and microarray analysis holds great promise for directly detecting a wide variety of organisms from clinical specimens. The question is where this testing should be done in the clinical laboratory. There are at least four models that have emerged: Molecular infectious disease testing as an arm of the clinical microbiology laboratory. Molecular infectious disease testing done in a central molecular pathology laboratory under the leadership of a clinical microbiologist. Molecular infectious disease testing done in a central molecular pathology laboratory under the leadership of an individual whose primary interest is in another area of molecular pathology. Molecular infectious disease testing sent to a reference laboratory and not done on site or within the institution's health care system. We have asked three individuals who have thought about this very complex issue to share their rationale for supporting one of these models. Frederick Nolte is the Director of Clinical Laboratories and Director of Molecular Pathology at the Medical University of South Carolina, is active in and held several positions of responsibility in AMP (Association of Molecular Pathology) and is Chair of the CLSI's Area Committee for Molecular Methods, Alex McAdam is the Director of the Infectious Diseases Diagnostic Division at Children's Hospital Boston and an editor of this journal, and his colleague, Nima Mosammaparast, is the Assistant Director of the Infectious Diseases Diagnostic Laboratory at Children's Hospital Boston. PMID- 22422846 TI - Development and evaluation of a genus-specific, probe-based, internal-process controlled real-time PCR assay for sensitive and specific detection of Blastocystis spp. AB - Blastocystis is a common intestinal parasite of unsettled clinical significance, which is not easily detected by standard parasitological methods. The genus comprises at least 13 subtypes (STs) (which likely represent separate species), 9 of which have been found in humans. Recent data indicate that at least one of the subtypes is associated with intestinal disease. A quantitative TaqMan 5' nuclease real-time PCR (TaqMan PCR) including an internal process control (IPC) was developed for the detection of Blastocystis and shown to be applicable to genomic DNAs extracted directly from feces. The assay enabled successful amplification of DNAs from all relevant subtypes within the genus (ST1 to ST9). For assay evaluation, 153 samples previously tested by xenic in vitro culture (XIVC) were screened by the TaqMan assay. A total of 49/51 samples positive by XIVC and 13/102 samples negative by XIVC were positive by the TaqMan assay; samples positive by the TaqMan assay and negative by XIVC were subsequently tested by conventional PCR, and amplicons could be identified to the subtype level by sequencing in 69% of the cases. Compared to the TaqMan assay, XIVC had a sensitivity of 79%. This is the first time that a genus-specific, probe-based, internal-process-controlled real-time PCR assay for the detection Blastocystis has been introduced. PMID- 22422847 TI - Simultaneous identification of 29 prevalent invasive pneumococcal serotypes or pairs of serotypes by hybridization-ligation PCR. AB - A hybridization-ligation PCR assay was developed for the simultaneous detection and identification of 21 pneumococcal serotypes and 8 pairs of serotypes in the same serogroup: 1, 2, 3, 4, 5, 6A, 6B, 6C-6D, 7F-7A, 8, 9A-9V, 9N-9L, 11A, 14, 15B-15C, 16F, 17F, 18B-18C, 19A, 19F, 20, 21, 22A-22F, 23A, 23B, 23F, 28A-28F, 35B and 38. This novel assay was validated with 185 serotyped pneumococcal invasive clinical isolates and 57 culture-negative pleural fluids previously typed by real-time PCR. PMID- 22422848 TI - Direct detection of Mycobacterium tuberculosis complex in clinical samples by a molecular method based on GenoQuick technology. AB - Several molecular systems for direct detection of Mycobacterium tuberculosis complex (MTBC) have recently been developed. The GenoQuick MTB assay (GQ-MTB) used in this study detected 82 of the 96 (85.4%) samples with MTBC, including 50 of 64 (78.1%) samples with negative acid-fast bacillus smears. Fifteen samples containing nontuberculous mycobacteria were also studied: 13 were GQ-MTB negative, one was positive, and one was indeterminate. GQ-MTB showed good effectiveness for the direct detection of MTBC from clinical samples. PMID- 22422849 TI - Association between beta-lactamase-encoding bla(OXA-51) variants and DiversiLab rep-PCR-based typing of Acinetobacter baumannii isolates. AB - This study investigated the correlation between bla(OXA-51) variants and Acinetobacter baumannii worldwide clonal lineages 1 to 8 (WW1 to -8). The bla(OXA 51-like) genes of 102 A. baumannii isolates were sequenced. Using DiversiLab repetitive-sequence-based PCR (rep-PCR) typing, 92 of these isolates had previously been assigned to WW1 to -8 and 10 were unclustered. Clustering of DNA sequences was performed using the neighbor-joining method and the Jukes-Cantor phylogenetic correction. bla(OXA-51) variants were in good correlation with DiversiLab-defined clonal lineages. Sequence-based typing of bla(OXA-51) variants has the potential to be applied for epidemiologic characterization of A. baumannii and to identify worldwide clonal lineages 1 to 8. PMID- 22422850 TI - Frequency of microbiologically correct antibiotic therapy increased by infectious disease consultations and microbiological results. AB - In a prospective observational study of bacteremic patients we ascertained the influence of different parts of culture results on the correctness of empirical antibiotic therapy. Ninety-three bacteremic patients requiring antibiotic treatment were included. Patients who had consultations with an infectious disease consultation service before they became bacteremic received microbiologically correct empirical antibiotic therapy more often than those who did not have such consultations (75% versus 53%; P = 0.03). As a direct result of Gram staining, 92% of all patients received microbiologically correct antibiotic therapy. PMID- 22422851 TI - HIV-1 proviral DNA loads (as determined by quantitative PCR) in patients subjected to structured treatment interruption after antiretroviral therapy failure. AB - The impact of Structured Treatment Interruption (STI) in peripheral blood mononuclear cell (PBMC) proviral reservoirs in 41 highly active antiretroviral therapy (HAART)-treated viremic individuals at baseline and 12 weeks after STI was determined using quantitative PCR (qPCR). Viral load increased 0.7 log(10) and CD4 decreased 97.5 cells/mm(3) after 12 weeks. A total of 28 of the 41 individuals showed an increased proviral load, 19 with a statistically significant increase above 10%. An increase in active viral replication is an important factor in the replenishment of the proviral reservoir even for short time periods. PMID- 22422852 TI - Comparison of seven tests for high-grade cervical intraepithelial neoplasia in women with abnormal smears: the Predictors 2 study. AB - High-risk human papillomavirus (HPV) DNA/RNA testing provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). Several new HPV tests are now available for this purpose, and a direct comparison of their properties is needed. Seven tests were evaluated with samples in liquid PreservCyt transport medium from 1,099 women referred for colposcopy: the Hybrid Capture 2 (Qiagen), Cobas (Roche), PreTect HPV-Proofer (NorChip), Aptima HPV (Gen-Probe), and Abbott RealTime assays, the BD HPV test, and CINtec p16(INK4a) cytology (mtm laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology found on either the biopsy or the treatment specimen after central review. Three hundred fifty-nine women (32.7%) had CIN grade 2+ (CIN2+), with 224 (20.4%) having CIN3+. For detection of CIN2+, Hybrid Capture 2 had 96.3% sensitivity, 19.5% specificity, and 37.4% PPV. Cobas had 95.2% sensitivity, 24.0% specificity, and 37.6% PPV. The BD HPV test had 95.0% sensitivity, 24.2% specificity, and 37.8% PPV. Abbott RealTime had 93.3% sensitivity, 27.3% specificity, and 38.2% PPV. Aptima had 95.3% sensitivity, 28.8% specificity, and 39.3% PPV. PreTect HPV-Proofer had 74.1% sensitivity, 70.8% specificity, and 55.4% PPV. CINtec p16(INK4a) cytology had 85.7% sensitivity, 54.7% specificity, and 49.1% PPV. Cytology of a specimen taken at colposcopy (mild dyskaryosis or worse) had 88.9% sensitivity, 58.1% specificity, and 50.7% PPV. Our study confirms that, in a referral setting, HPV testing by a number of different tests provides high sensitivity for high-grade disease. Further work is needed to confirm these findings in a routine screening setting. PMID- 22422853 TI - Trends and characteristics of culture-confirmed Staphylococcus aureus infections in a large U.S. integrated health care organization. AB - Infections due to Staphylococcus aureus present a significant health problem in the United States. Between 1990 and 2005, there was a dramatic increase in community-associated methicillin-resistant S. aureus (MRSA), but recent reports suggest that MRSA may be declining. We retrospectively identified S. aureus isolates (n = 133,450) that were obtained from patients in a large integrated health plan between 1 January 1998 and 31 December 2009. Trends over time in MRSA were analyzed, and demographic risk factors for MRSA versus methicillin susceptible S. aureus (MSSA) were identified. The percentage of S. aureus isolates that were MRSA increased from 9% to 20% between 1998 and 2001 and from 25% to 49% between 2002 and 2005 and decreased from 49% to 43% between 2006 and 2009. The increase in MRSA was seen in blood and in other bacteriological specimens and occurred in all age and race/ethnicity groups, though it was most pronounced in persons aged 18 to <50 years and African-Americans. Hospital onset infections were the most likely to be MRSA (odds ratio [OR], 1.58; confidence interval [CI], 1.46 to 1.70, compared to community-associated cases), but the largest increase in MRSA was in community-associated infections. Isolates from African-Americans (OR, 1.73; CI, 1.64 to 1.82) and Hispanics (OR, 1.11; CI, 1.06 to 1.16) were more likely to be MRSA than those from whites. After substantial increases between 1998 and 2005 in the proportion of S. aureus isolates that were MRSA, the proportion decreased between 2006 and 2009. Hospital onset S. aureus infections are disproportionately MRSA, as are those among African-Americans. PMID- 22422854 TI - The small membrane filter method of microscopy to diagnose pulmonary tuberculosis. AB - We modified microscopy for acid-fast bacilli to diagnose tuberculosis (TB) using small membrane filters (SMFs) after special processing and prefiltration. With the first specimen obtained from each of 335 persons suspected of having TB, the sensitivity of the new SMF method using fluorescence microscopy (FM) was 89% (95% confidence interval [CI]: 80%, 95%). This was significantly better (P = 0.0001) than the sensitivity of routine FM of centrifuged specimens of 60% (95% CI: 49%, 71%) or that of direct sputum smears of 56% (95% CI: 40%, 72%). PMID- 22422855 TI - Validation of the MycAssay Pneumocystis kit for detection of Pneumocystis jirovecii in bronchoalveolar lavage specimens by comparison to a laboratory standard of direct immunofluorescence microscopy, real-time PCR, or conventional PCR. AB - Pneumocystis jirovecii pneumonia is a significant cause of morbidity and mortality in AIDS patients as well as those with non-HIV immunosuppressive diseases. To aid diagnosis, the commercial MycAssay Pneumocystis real-time PCR assay (Myconostica, Ltd., Manchester, United Kingdom) targeting the mitochondrial ribosomal large subunit (mtLSU) has been developed to detect P. jirovecii in bronchoalveolar lavage (BAL) specimens. Here, we validated this assay against a laboratory standard of direct immunofluorescence microscopy, a cdc2 real-time PCR assay, or conventional PCR and sequencing of mtLSU. While more sensitive than any of these three assays analyzed individually, the MycAssay Pneumocystis assay demonstrated 100% sensitivity, 100% specificity, a 100% negative predictive value, and a 100% positive predictive value for detecting the presence of P. jirovecii in BAL specimens compared to the laboratory standard. Of note, two samples with positive cycle threshold (C(T)) values according to the MycAssay Pneumocystis assay lacked exponential amplification curves and thus were deemed negative. Also negative according to the laboratory standard, these samples highlight the importance of examining the amplification curves, in addition to noting the C(T) values, when interpreting positive results. Comparison of the MycAssay Pneumocystis assay to a laboratory standard establishes this assay to be a highly sensitive and specific method for the detection of P. jirovecii in bronchoalveolar lavage specimens. The approach may also be useful for the clinical laboratory validation of other sensitive real-time PCR assays. PMID- 22422856 TI - Standardized one-step real-time reverse transcription-PCR assay for universal detection and quantification of hepatitis delta virus from clinical samples in the presence of a heterologous internal-control RNA. AB - As for other chronic viral diseases, quantification of hepatitis delta virus (HDV) loads may be useful for patient management. We describe a one-step quantitative reverse transcription-PCR assay that is reliable and automatable and meets the regulatory authorities' standards for accurate quantification of the major HDV genotypes. It includes an internal control and uses in vitro transcribed RNAs as standards. Its linearity range is 500 to 1.7 * 10(11) copies/ml, its sensitivity is around 150 copies/ml, its repeatability is around 15%, and its reproducibility is below 0.25 log(10) copies/ml. PMID- 22422857 TI - Molecular subtyping of Treponema pallidum during a local syphilis epidemic in men who have sex with men in Melbourne, Australia. AB - Treponema pallidum is the causative agent of syphilis, a sexually transmitted infection of significant public health importance. Since 2000 there has been a marked increase in the number of cases of syphilis infections notified in Victoria, Australia, with the majority of cases occurring in men who have sex with men (MSM) and the highest incidence being in HIV-infected MSM. The molecular subtyping method described by Pillay et al. (A. Pillay et al., Sex. Transm. Dis. 25:408-414, 1998) has been used in this study to determine the diversity of T. pallidum subtypes circulating locally and to look for any relationship between T. pallidum subtypes and HIV status over a 6-year period (2004 to 2009). Treponema pallidum DNA was detected in 303 patient specimens (n = 3,652), and full subtyping profiles were obtained from 90 of these (from 88 patients). A total of 11 T. pallidum subtypes were identified: types 14e (28, 31.1%), 14d (15, 16.7%), 14k (13, 14.4%), 14p (12, 13.3%), 14i (7, 7.8%) 14b (6, 6.7%), 14l (5, 5.6%), and 12i, 13b, 13i, and 13e (1 each, 1.1%). This study showed a similar level of variation among circulating T. pallidum strains compared with that in other studies using the same methodology. A different mix of strains and different predominating strains have been found at each geographical study location, with type 14e emerging as the predominant local strain in Victoria. There was no detectable trend between T. pallidum subtypes and the specimen collection site or stage of syphilis (where known), nor was there any relationship between particular strains and HIV status. PMID- 22422858 TI - A new loop-mediated isothermal amplification method for rapid, simple, and sensitive detection of Leptospira spp. in urine. AB - We developed a new loop-mediated isothermal amplification (LAMP) method to detect rrs, a 16S rRNA gene of pathogenic Leptospira spp. in urine. The method enables detection of two leptospiral cells per reaction mixture following boiling of urine specimens. The sensitivity of this method is higher than that of culture or of flaB nested PCR. PMID- 22422859 TI - Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. AB - MicroRNAs regulate gene expression through deadenylation, repression, and messenger RNA (mRNA) decay. However, the contribution of each mechanism in non steady-state situations remains unclear. We monitored the impact of miR-430 on ribosome occupancy of endogenous mRNAs in wild-type and dicer mutant zebrafish embryos and found that miR-430 reduces the number of ribosomes on target mRNAs before causing mRNA decay. Translational repression occurs before complete deadenylation, and disrupting deadenylation with use of an internal polyadenylate tail did not block target repression. Lastly, we observed that ribosome density along the length of the message remains constant, suggesting that translational repression occurs by reducing the rate of initiation rather than affecting elongation or causing ribosomal drop-off. These results show that miR-430 regulates translation initiation before inducing mRNA decay during zebrafish development. PMID- 22422860 TI - The coexistence of superconductivity and topological order in the Bi2Se3 thin films. AB - Three-dimensional topological insulators (TIs) are characterized by their nontrivial surface states, in which electrons have their spin locked at a right angle to their momentum under the protection of time-reversal symmetry. The topologically ordered phase in TIs does not break any symmetry. The interplay between topological order and symmetry breaking, such as that observed in superconductivity, can lead to new quantum phenomena and devices. We fabricated a superconducting TI/superconductor heterostructure by growing dibismuth triselenide (Bi(2)Se(3)) thin films on superconductor niobium diselenide substrate. Using scanning tunneling microscopy and angle-resolved photoemission spectroscopy, we observed the superconducting gap at the Bi(2)Se(3) surface in the regime of Bi(2)Se(3) film thickness where topological surface states form. This observation lays the groundwork for experimentally realizing Majorana fermions in condensed matter physics. PMID- 22422861 TI - ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C. AB - The endosomal sorting complex required for transport (ESCRT) machinery plays an evolutionarily conserved role in cytokinetic abscission, the final step of cell division where daughter cells are physically separated. Here, we show that charged multivesicular body (MVB) protein 4C (CHMP4C), a human ESCRT-III subunit, is involved in abscission timing. This function correlated with its differential spatiotemporal distribution during late stages of cytokinesis. Accordingly, CHMP4C functioned in the Aurora B-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage. CHMP4C engaged the chromosomal passenger complex (CPC) via interaction with Borealin, which suggested a model whereby CHMP4C inhibits abscission upon phosphorylation by Aurora B. Thus, the ESCRT machinery may protect against genetic damage by coordinating midbody resolution with the abscission checkpoint. PMID- 22422862 TI - A fine-scale chimpanzee genetic map from population sequencing. AB - To study the evolution of recombination rates in apes, we developed methodology to construct a fine-scale genetic map from high-throughput sequence data from 10 Western chimpanzees, Pan troglodytes verus. Compared to the human genetic map, broad-scale recombination rates tend to be conserved, but with exceptions, particularly in regions of chromosomal rearrangements and around the site of ancestral fusion in human chromosome 2. At fine scales, chimpanzee recombination is dominated by hotspots, which show no overlap with those of humans even though rates are similarly elevated around CpG islands and decreased within genes. The hotspot-specifying protein PRDM9 shows extensive variation among Western chimpanzees, and there is little evidence that any sequence motifs are enriched in hotspots. The contrasting locations of hotspots provide a natural experiment, which demonstrates the impact of recombination on base composition. PMID- 22422863 TI - Second hospital courts partnership deal with private sector company. PMID- 22422864 TI - AstraZeneca takes legal action to delay generic quietiapine in US. PMID- 22422865 TI - Access to healthcare is highest in Massachusetts, lowest in Texas, finds scorecard. PMID- 22422866 TI - ARB protects podocytes from HIV-1 nephropathy independently of podocyte AT1. AB - BACKGROUND: Angiotensin I-converting enzyme inhibitors and angiotensin receptor blockers protect podocytes more effectively than other anti-hypertensive drugs. Transgenic rats overexpressing angiotensin II Type 1 (AT1) receptor selectively in podocytes have been shown to develop glomerulosclerosis. The prevailing hypothesis is that angiotensin II has a capacity of directly acting on the AT1 receptor of podocytes to induce injury. We therefore investigated the mechanism of reno-protective effect of AT1 receptor in a mouse model of HIV-1 nephropathy. METHODS: We generated transgenic mice carrying the HIV-1 gene (control/HIV-1) or both HIV-1 gene and podocyte-selectively nullified AT1 gene (AT1KO/HIV-1). In these mice, we measured urinary protein or albumin excretion and performed histological analysis. RESULTS: At 8 months of age, AT1KO/HIV-1 (n = 13) and control/HIV-1 (n = 15) mice were statistically indistinguishable with respect to urinary albumin/creatinine ratio (median 2.5 versus 9.1 mg/mg), glomerulosclerosis (median 0.63 versus 0.45 on 0-4 scale) and downregulation of nephrin (median 6.90 versus 7.02 on 0-8 scale). In contrast to the observed lack of effect of podocyte-specific AT1KO, systemic AT1 inhibition with AT1 blocker (ARB) significantly attenuated proteinuria and glomerulosclerosis in HIV-1 mice. CONCLUSION: These results indicate that the protective effect of ARB is mediated through its receptors on cells other than podocytes, such as efferent arteriolar smooth muscle cells. PMID- 22422867 TI - Preemptive renal transplant candidate survival, access to care, and renal function at listing. AB - BACKGROUND: Preemptive transplantation is associated with better survival and transplant outcomes than transplantation after dialysis has been started. The purpose of this study is to examine associations between candidate characteristics, likelihood of preemptive transplant, candidate survival and renal function (RF) at the time of listing. METHODS: We looked at 57 677 solitary renal transplant candidates from the Scientific Registry of Transplant Recipients database listed prior to dialysis from 2000 to 2009. Using multivariable models, we measured associations between candidate characteristics, likelihood of preemptive transplantation, candidate survival and RF at listing. RESULTS: Candidates with higher RF at listing were more likely to be male, Caucasian, diabetic, be a prior transplant recipient and have more education. Higher RF at listing was strongly associated with greater likelihood of receipt of preemptive transplant [adjusted odds ratio = 1.45, 95% confidence interval (CI) 1.38-1.51] and conferred a significant survival advantage [adjusted hazards ratio = 0.84, 95% CI 0.79-0.89, per 5 mL/min/1.73 m(2)]. CONCLUSIONS: Patient characteristics associated with higher RF at listing suggest differences in access to care. Given that higher RF at the time of listing was also significantly associated with greater likelihood of preemptive transplantation and better survival prior to transplantation, our results suggest that listing at higher levels of RF may improve transplant candidate outcomes. PMID- 22422868 TI - The impact of regulatory T cells in acute rejection. PMID- 22422869 TI - Prediction of glomerular filtration rate from serum concentration of cystatin C: comparison of two analytical methods. AB - BACKGROUND: The aim of this study was to compare two methods used to measure serum cystatin C (Cys) and their accuracy to predict glomerular filtration rate (GFR). METHODS: Three hundred and sixty-seven adult chronic kidney disease (CKD) patients with different functional impairments participated in this study. GFR was determined as the renal clearance of 99mTc-DTPA. Serum concentrations of cystatin C (SCys) were determined with an immunonephelometric method and with an immunoturbidimetric method. RESULTS: A very high linear correlation was found between the two measurements of SCys (r=0.929). The mean difference of SCysTurb SCysNeph was 0.02+/-0.43 mg/L (not significant). A high logarithmic correlation was also found between SCys and GFR (r was 0.919 for SCysNeph and 0.937 for SCysTurb). By means of multiple regression analysis, we developed formulae to predict GFR from SCysNeph, SCysTurb and SCr. For comparison, GFR was predicted using published formulae. A good agreement was found between predicted GFR and measured GFR. The results showed that the accuracy of SCysNeph, SCysTurb and SCr and of the different prediction formulae were quite similar. CONCLUSIONS: The immunoturbidimetric method seems adequate to measure SCys and to predict GFR and its impairment in CKD, at least similar to the immunonephelometric method. The accuracy of SCys and of derived formulae was not higher than that of SCr and SCr based formulae. PMID- 22422870 TI - White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. AB - OBJECTIVES: To summarise evidence on the association between white rice consumption and risk of type 2 diabetes and to quantify the potential dose response relation. DESIGN: Meta-analysis of prospective cohort studies. DATA SOURCES: Searches of Medline and Embase databases for articles published up to January 2012 using keywords that included both rice intake and diabetes; further searches of references of included original studies. STUDY SELECTION: Included studies were prospective cohort studies that reported risk estimates for type 2 diabetes by rice intake levels. DATA SYNTHESIS: Relative risks were pooled using a random effects model; dose-response relations were evaluated using data from all rice intake categories in each study. RESULTS: Four articles were identified that included seven distinct prospective cohort analyses in Asian and Western populations for this study. A total of 13,284 incident cases of type 2 diabetes were ascertained among 352,384 participants with follow-up periods ranging from 4 to 22 years. Asian (Chinese and Japanese) populations had much higher white rice consumption levels than did Western populations (average intake levels were three to four servings/day versus one to two servings/week). The pooled relative risk was 1.55 (95% confidence interval 1.20 to 2.01) comparing the highest with the lowest category of white rice intake in Asian populations, whereas the corresponding relative risk was 1.12 (0.94 to 1.33) in Western populations (P for interaction=0.038). In the total population, the dose-response meta-analysis indicated that for each serving per day increment of white rice intake, the relative risk of type 2 diabetes was 1.11 (1.08 to 1.14) (P for linear trend<0.001). CONCLUSION: Higher consumption of white rice is associated with a significantly increased risk of type 2 diabetes, especially in Asian (Chinese and Japanese) populations. PMID- 22422871 TI - Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: cohort study. AB - OBJECTIVE: To assess the relation between troponin concentration, assay precision, and clinical outcomes in patients with suspected acute coronary syndrome. DESIGN: Cohort study. SETTING: Tertiary centre in Scotland. PARTICIPANTS: 2092 consecutive patients admitted with suspected acute coronary syndrome were stratified with a sensitive troponin I assay into three groups (<0.012, 0.012-0.049, and >=0.050 ug/L) based on the 99th centile for troponin concentration (0.012 ug/L; coefficient of variation 20.8%) and the diagnostic threshold (0.050 ug/L; 7.2%). MAIN OUTCOME MEASURE: One year survival without events (recurrent myocardial infarction, death) in patients grouped by troponin concentration. RESULTS: Troponin I concentrations were <0.012 ug/L in 988 patients (47%), 0.012-0.049 ug/L in 352 patients (17%), and >=0.050 ug/L in 752 patients (36%). Adoption of the 99th centile would increase the number of people receiving a diagnosis of myocardial infarction from 752 to 1104: a relative increase of 47%. At one year, patients with troponin concentrations of 0.012 0.049 ug/L were more likely to be dead or readmitted with recurrent myocardial infarction than those with troponin concentrations <0.012 ug/L (13% v 3%, P<0.001; odds ratio 4.7, 95% confidence interval 2.9 to 7.9). Compared with troponin >=0.050 ug/L, patients with troponin 0.012-0.049 ug/L had a higher risk profile but were less likely to have a diagnosis of, or be investigated and treated for, acute coronary syndrome. CONCLUSION: Lowering the diagnostic threshold to the 99th centile and accepting greater assay imprecision would identify more patients with acute coronary syndrome at risk of recurrent myocardial infarction and death but would increase the diagnosis of myocardial infarction by 47%. It remains to be established whether reclassification of these patients and treatment for myocardial infarction would improve outcome. PMID- 22422872 TI - Association between low functional health literacy and mortality in older adults: longitudinal cohort study. AB - OBJECTIVE: To investigate the association between low functional health literacy (ability to read and understand basic health related information) and mortality in older adults. DESIGN: Population based longitudinal cohort study based on a stratified random sample of households. SETTING: England. PARTICIPANTS: 7857 adults aged 52 or more who participated in the second wave (2004-5) of the English Longitudinal Study of Ageing and survived more than 12 months after interview. Participants completed a brief four item test of functional health literacy, which assessed understanding of written instructions for taking an aspirin tablet. MAIN OUTCOME MEASURE: Time to death, based on all cause mortality through October 2009. RESULTS: Health literacy was categorised as high (maximum score, 67.2%), medium (one error, 20.3%), or low (more than one error, 12.5%). During follow-up (mean 5.3 years) 621 deaths occurred: 321 (6.1%) in the high health literacy category, 143 (9.0%) in the medium category, and 157 (16.0%) in the low category. After adjusting for personal characteristics, socioeconomic position, baseline health, and health behaviours, the hazard ratio for all cause mortality for participants with low health literacy was 1.40 (95% confidence interval 1.15 to 1.72) and with medium health literacy was 1.15 (0.94 to 1.41) compared with participants with high health literacy. Further adjustment for cognitive ability reduced the hazard ratio for low health literacy to 1.26 (1.02 to 1.55). CONCLUSIONS: A third of older adults in England have difficulties reading and understanding basic health related written information. Poorer understanding is associated with higher mortality. The limited health literacy capabilities within this population have implications for the design and delivery of health related services for older adults in England. PMID- 22422873 TI - White rice and risk of type 2 diabetes. PMID- 22422874 TI - Surgical results and staging of non-small cell lung cancer with interlobar pleural invasion. AB - The aim of this study was to compare the survival rates of non-small cell lung cancer (NSCLC) with interlobar pleural invasion (IPI) with that of patients with other T2 and T3 diseases according to the seventh TNM staging system. One thousand and one patients with pathologic T2 and T3 NSCLC (according to the seventh staging criteria) treated between 1980 and 2004 were retrospectively evaluated. Among these, 682 patients were pathologically staged as T2 without IPI (T2 group), 25 as T2 with IPI (IPI group) and 294 as T3 (T3 group). The 5-year survival rate for the T2, IPI and T3 groups were 52.0, 31.1 and 36.3%, respectively. In patients without nodal involvement, the 5-year survival rates of the T2N0, IPIN0 and T3N0 groups were 60.9, 40.0 and 45.9%, respectively. The survival rate was significantly different between the T3N0 and T2N0 groups (P < 0.001) and between the IPIN0 and T2N0 (P = 0.020) groups. There was no significant difference in the survival rate between the IPIN0 and T3N0 groups (P = 0.644). In patients without nodal involvement, the survival of NSCLC with IPI is similar to that of the T3 disease. PMID- 22422875 TI - Candidal mediastinitis successfully treated using vacuum-assisted closure following open-heart surgery. AB - Deep sternal wound infections (DSWIs) are an uncommon but serious complication after open-heart surgery. The reported incidence of DSWIs due to Candida albicans is 0.4%, but these infections have an extremely high mortality of 56%. We herein report a rare case of a 79-year old woman who suffered from Candidal DSWI after repeated open-heart surgeries. We treated her with negative pressure wound therapy (NPWT). This is the rare case report that provides evidence that NPWT is a safe and suitable technique for the management of Candidal DSWIs. PMID- 22422876 TI - Does off-pump coronary artery bypass surgery have a beneficial effect on mortality in patients with left ventricular dysfunction? AB - A best evidence topic was written according to a structured protocol. The question addressed was whether off-pump coronary artery bypass surgery (OPCAB) offered any beneficial effect on mortality when compared with on-pump coronary artery bypass surgery (ONCAB) in patients with left ventricular dysfunction (LVD). A total of 491 papers were found using the reported searches of which 17 represented the best evidence. The authors, date, journal, study type, outcome measures and results are tabulated. The 17 studies (only containing patients with LVD) comprised of one prospective randomized trial, one meta-analysis and 15 retrospective studies. The prospective trial associated the OPCAB technique with significantly lower in-hospital mortality. By comprising of seven studies and 1512 patients, the meta-analysis showed no significant difference in terms of operative mortality. Of the retrospective studies, all 15 compared short-term mortality (<30-day) of which four showed significantly lower mortality in the OPCAB group. Nine of the studies compared mid-term mortality (30 days to 5 years) with no significant difference detected and three of the studies compared long term mortality (>5 years) with no significant difference detected. We conclude that there is limited evidence to associate the OPCAB technique with improved short-term mortality. The majority of the studies suffered from significant limitations such as containing data from operations carried out prior to the year 2000, a period when off-pump surgery was in its infancy. They frequently contained major differences in baseline characteristics with no specific inclusion/exclusion criteria, description of handling of patients converted from off-pump to bypass or reporting of myocardial viability and concomitant mitral regurgitation. Nine studies reported completeness of revascularization of which eight associated the OPCAB group with a poorer degree of revascularization making comparisons less valid. The lack of high-quality data indicates that prospective randomized trials are needed. The CRISP Trial ('Coronary artery grafting in high risk patients randomized to off-pump or on-pump surgery') has recently been halted due to recruitment difficulties. The CORONARY ('Coronary artery bypass surgery off- or on-pump revascularization study') trial is a large international multicentre randomized study that is recruiting well and is likely to provide valuable information in the near future. PMID- 22422877 TI - Surgical treatment of a pulmonary artery aneurysm due to a regurgitant quadricuspid pulmonary valve. AB - We report the case of a patient with a pulmonary artery (PA) aneurysm secondary to a regurgitant quadricuspid pulmonary valve, in which both lesions were successfully repaired. The patient, a 16-year old boy, was known to have had pulmonary regurgitation and progressive dilation of the PA for years. He was operated on when he developed symptoms of effort, a dilated right ventricle and a PA of 55 mm. The quadricuspid pulmonary valve was an intraoperative finding. It had a dilated annulus, two normal cusps, a third with a 'sparrow-nest' configuration and the fourth was severely hypoplastic (which explained the valve regurgitation). The valve was repaired through tricuspidisation of the quadricuspid pulmonary valve (annular plication at the level of the hypoplastic cusp, freeing of excedentary tissue from the 'sparrow-nest' cusp and its reattachment to the plicated annulus). The aneurysm was treated through a reduction pulmonary arterioplasty. Early assessment showed the minimal regurgitation of the valve and a normal diameter PA. The outcome was uneventful, with a stable correction after 44 months of follow-up. To our knowledge, this is the first repair of a quadricuspid pulmonary valve, through tricuspidisation. PMID- 22422878 TI - p110delta phosphoinositide 3-kinase represses IgE switch by potentiating BCL6 expression. AB - PI3Ks are key signaling enzymes required for triggering many immunological functions. In B lymphocytes, PI3K signaling is required for Ag-induced proliferation and robust production of most Ab isotypes. Paradoxically, PI3K was found to have a negatively regulatory function regarding Ab class switch recombination, and blockade of PI3K can strongly potentiate IgE switch. In this article, we explore the mechanisms of this unexpected negative regulatory function of PI3K regarding IgE. We demonstrate that p110delta PI3K selectively regulates IgE switch in a B cell-intrinsic manner by controlling germline transcription of the IgE promoter (epsilonGLT). Although p110delta can regulate transcription of activation-induced cytidine deaminase via Akt, repression of epsilonGLT and IgE switch is not dependent on Akt signaling. Inhibition of p110delta, but not Akt, leads to reduced expression of transcriptional repressor B cell lymphoma 6 (BCL6) and concomitant upregulation of epsilonGLT and other BCL6-target genes. p110delta inhibitor treatment strikingly alters the balance between BCL6 and IRF4 (a transcription factor that antagonizes BCL6), leading to increased IRF4 and decreased BCL6 expression levels in germinal center B cells. Ectopic expression of BCL6 can partially overcome the elevated epsilonGLTs and potentiated IgE switching in p110delta-inhibited B cells. To our knowledge, these results provide the first evidence that p110delta PI3K signaling regulates BCL6 expression and indicate that PI3K promotes the germinal center B cell program and selectively represses IgE switch by maintaining sufficient levels of BCL6. PMID- 22422879 TI - Nonplasmacytoid, high IFN-alpha-producing, bone marrow dendritic cells. AB - Plasmacytoid dendritic cells (pDC) are the producers of type I IFNs in response to TLR9 ligands. However, we have found that when bone marrow is depleted of pDC, the IFN-alpha produced in response to TLR9 ligands is not fully removed. We assign the source of this non-pDC IFN-alpha as a newly described DC type. It displays the high IFN-alpha producing activity of pDC but to a more limited range of viruses. Unlike pDC, the novel DC display high T cell stimulation capacity. Moreover, unlike mouse pDC, they are matured with GM-CSF and are less prone to apoptosis upon activation stimuli, including viruses. We propose that these DC constitute a novel bone marrow inflammatory DC type, ideally geared to linking innate and adaptive immune responses in bone marrow via their potent IFN-alpha production and high T cell stimulatory capacity. PMID- 22422880 TI - Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells, and B cells does not prevent graft-versus-host disease induction. AB - The efficacy of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD). Host hematopoietic APCs are important initiators of GVHD, making them logical targets for GVHD prevention. Conventional dendritic cells (DCs) are key APCs for T cell responses in other models of T cell immunity, and they are sufficient for GVHD induction. However, we report in this article that in two polyclonal GVHD models in which host hematopoietic APCs are essential, GVHD was not decreased when recipient conventional DCs were inducibly or constitutively deleted. Additional profound depletion of plasmacytoid DCs and B cells, with or without partial depletion of CD11b(+) cells, also did not ameliorate GVHD. These data indicate that, in contrast with pathogen models, there is a surprising redundancy as to which host cells can initiate GVHD. Alternatively, very low numbers of targeted APCs were sufficient. We hypothesize the difference in APC requirements in pathogen and GVHD models relates to the availability of target Ags. In antipathogen responses, specialized APCs are uniquely equipped to acquire and present exogenous Ags, whereas in GVHD, all host cells directly present alloantigens. These studies make it unlikely that reagent based host APC depletion will prevent GVHD in the clinic. PMID- 22422881 TI - Antigen-independent induction of Tim-3 expression on human T cells by the common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 is associated with proliferation and is dependent on the phosphoinositide 3-kinase pathway. AB - T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of a subset of CD8(+) and Th1 CD4(+) T cells. Elevated expression of Tim-3 on virus-specific T cells during chronic viral infections, such as HIV-1, hepatitis B virus, and hepatitis C virus, positively correlates with viral load. Tim-3(+) cytotoxic T cells are dysfunctional and are unable to secrete effector cytokines, such as IFN-gamma and TNF-alpha. In this study, we examined potential inducers of Tim-3 on primary human T cells. Direct HIV-1 infection of CD4(+) T cells, or LPS, found to be elevated in HIV-1 infection, did not induce Tim-3 on T cells. Tim-3 was induced by the common gamma-chain (gammac) cytokines IL-2, IL-7, IL-15, and IL-21 but not IL-4, in an Ag-independent manner and was upregulated on primary T cells in response to TCR/CD28 costimulation, as well as gammac cytokine stimulation with successive divisions. gammac cytokine-induced Tim-3 was found on naive, effector, and memory subsets of T cells. Tim-3(+) primary T cells were more prone to apoptosis, particularly upon treatment with galectin-9, a Tim-3 ligand, after cytokine withdrawal. The upregulation of Tim-3 could be blocked by the addition of a PI3K inhibitor, LY 294002. Thus, Tim-3 can be induced via TCR/CD28 costimulation and/or gammac cytokines, likely through the PI3K pathway. PMID- 22422882 TI - Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. AB - The contribution of individual molecular aberrations to the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease that affects multiple organs, is often difficult to evaluate because of the presence of abundant confounding factors. To assess the effect of increased expression of the phosphatase protein phosphatase 2A (PP2A) in T cells, as recorded in SLE patients, we generated a transgenic mouse that overexpresses the PP2Ac subunit in T cells. The transgenic mouse displays a heightened susceptibility to immune mediated glomerulonephritis in the absence of other immune defects. CD4(+) T cells produce increased amounts of IL-17 while the number of neutrophils in the peripheral blood is increased. IL-17 neutralization abrogated the development of glomerulonephritis. We conclude that increased PP2Ac expression participates in SLE pathogenesis by promoting inflammation through unchecked IL-17 production and facilitating the development of end-organ damage. PMID- 22422883 TI - Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection. AB - We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9(+/+)) and TLR-deficient (TLR9(-/-)) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b(+) dendritic cells (DCs), 2) the induction of IFN-gamma and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4(+) and CD8(+) T cells, CD11b(+) lung DCs, and exudate macrophages at week 3. The significance of CCL7 induction downstream of TLR9 signaling was investigated by determining whether CCL7 reconstitution would improve immunological parameters in C. neoformans-infected TLR9(-/-) mice. Early reconstitution with CCL7 1) improved accumulation and activation of CD11b(+) DCs at week 1, 2) restored early IFN-gamma production in the lungs, and 3) restored the accumulation of major effector cell subsets. CCL7 administration abolished the difference in lung fungal burdens between TLR9(+/+) and TLR9(-/-) mice at week 3; however, significant reduction of fungal burdens between PBS- and CCL7 treated mice has not been observed, suggesting that additional mechanism(s) apart from early CCL7 induction contribute to optimal fungal clearance in TLR9(+/+) mice. Collectively, we show that TLR9 signaling during the afferent phase contributes to the development of protective immunity by promoting the early induction of CCL7 and IFN-gamma and the subsequent early recruitment and activation of DCs and additional effector cells in mice with cryptococcal pneumonia. PMID- 22422884 TI - The fusion protein of IFN-alpha and apolipoprotein A-I crosses the blood-brain barrier by a saturable transport mechanism. AB - IFN-alpha is widely used for the treatment of chronic viral hepatitis and malignancies. However, systemic IFN-alpha treatment causes severe neuropsychiatric complications in humans, including depression, anxiety, and cognitive impairments. We have previously reported that the fusion protein formed by IFN-alpha and apolipoprotein A-I (IA) circulates bound to high-density lipoproteins (HDLs) and exhibits liver targeting, increased half-life, enhanced immunostimulatory activity, and reduced cytotoxicity. As the transport of HDLs across the blood-brain barrier is a highly complex and regulated process, in this study, we examine the effects of IA on the brain. Determination of IFN-alpha in brain and serum after hydrodynamic administration of different doses of a plasmid encoding IFN-alpha or IA showed that IA penetrated into the brain by a saturable transport mechanism. Thus, at high serum levels of the transgenes, the induction of IFN-sensitive genes and the number of phospho-STAT1(+) cell nuclei in the brain were substantially higher with IFN-alpha than with IA. This was associated with attenuation of neurodepression in mice given IA, as manifested by shorter immobility time in the tail suspension test. However, when given low doses of rIFN-alpha or the same antiviral units of HDLs containing IA, the induction of IFN-stimulated genes in the brain was significantly greater with the latter. In conclusion, IA crosses the blood-brain barrier not by diffusion, as is the case of IFN-alpha, but by a facilitated saturable transport mechanism. Thus, linkage to apolipoprotein A-I may serve to modulate the effects of IFN-alpha on the CNS. PMID- 22422885 TI - L-tryptophan-kynurenine pathway metabolites regulate type I IFNs of acute viral myocarditis in mice. AB - The activity of IDO that catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn) increases after diseases caused by different infectious agents. Previously, we demonstrated that IDO has an important immunomodulatory function in immune-related diseases. However, the pathophysiological role of IDO following acute viral infection is not fully understood. To investigate the role of IDO in the l-Trp-Kyn pathway during acute viral myocarditis, mice were infected with encephalomyocarditis virus, which induces acute myocarditis. We used IDO deficient (IDO(-/-)) mice and mice treated with 1-methyl-d,l-Trp (1-MT), an inhibitor of IDO, to study the importance of Trp-Kyn pathway metabolites. Postinfection with encephalomyocarditis virus infection, the serum levels of Kyn increased, whereas those of Trp decreased, and IDO activity increased in the spleen and heart. The survival rate of IDO(-/-) or 1-MT-treated mice was significantly greater than that of IDO(+/+) mice. Indeed, the viral load was suppressed in the IDO(-/-) or 1-MT-treated mice. Furthermore, the levels of type I IFNs in IDO(-/-) mice and IDO(-/-) bone marrow-transplanted IDO(+/+) mice were significantly higher than those in IDO(+/+) mice, and treatment of IDO(-/-) mice with Kyn metabolites eliminated the effects of IDO(-/-) on the improved survival rates. These results suggest that IDO has an important role in acute viral myocarditis. Specifically, IDO increases the accumulation of Kyn pathway metabolites, which suppress type I IFNs production and enhance viral replication. We concluded that inhibition of the Trp-Kyn pathway ameliorates acute viral myocarditis. PMID- 22422886 TI - CD27 stimulation promotes the frequency of IL-7 receptor-expressing memory precursors and prevents IL-12-mediated loss of CD8(+) T cell memory in the absence of CD4(+) T cell help. AB - Fully functional CD8(+) T cell memory is highly dependent upon CD4(+) T cell support. CD4(+) T cells play a critical role in inducing the expression of CD70, the ligand for CD27, on dendritic cells. In this study, we demonstrate that CD27 stimulation during primary CD8(+) T cell responses regulates the ability to mount secondary CD8(+) T cell responses. CD27 stimulation during vaccinia and dendritic cell immunization controls the expression of the IL-7R (CD127), which has been shown to be necessary for memory CD8(+) T cell survival. Furthermore, CD27 stimulation during primary CD8(+) T cell responses to vaccinia virus restrained the late expression on memory precursor cells of cytokine receptors that support terminal differentiation. The formation of CD8(+) T cell memory precursors and secondary CD8(+) T cell responses was restored in the absence of CD27 costimulation when endogenous IL-12 was not available. Similarly, the lesion in CD8(+) T cell memory that occurs in the absence of CD4(+) T cells did not occur in mice lacking IL-12. These data indicate that CD4(+) T cell help and, by extension, CD27 stimulation support CD8(+) T cell memory by modulating the expression of cytokine receptors that influence the differentiation and survival of memory CD8(+) T cells. PMID- 22422887 TI - Complement component C1q regulates macrophage expression of Mer tyrosine kinase to promote clearance of apoptotic cells. AB - Failure to efficiently clear apoptotic cells is linked to defects in development and the onset of autoimmunity. Complement component C1q is required for efficient engulfment of apoptotic cells in mice and humans; however, the molecular mechanisms leading to C1q-dependent engulfment are not fully understood. In this study, we used primary mouse macrophages to identify and characterize a novel molecular mechanism for macrophage-mediated C1q-dependent engulfment of apoptotic cells. We found that macrophage activation with C1q resulted in cycloheximide sensitive enhanced engulfment, indicating a requirement for de novo protein synthesis. To investigate the cycloheximide-sensitive pathway, C1q-elicited macrophage transcripts were identified by microarray. C1q triggered the expression of Mer tyrosine kinase (Mer) and the Mer ligand growth arrest-specific 6: a receptor-ligand pair that mediates clearance of apoptotic cells. Full-length native C1q, and not the collagen-like tail or heat-denatured protein, stimulated Mer expression. This novel pathway is specific to C1q because mannose-binding lectin, a related collectin, failed to upregulate Mer expression and function. Soluble Mer-Fc fusion protein inhibited C1q-dependent engulfment of apoptotic cells, indicating a requirement for Mer. Moreover, Mer-deficient macrophages failed to respond to C1q with enhanced engulfment. Our results suggest that C1q elicits a macrophage phenotype specifically tailored for apoptotic cell clearance, and these data are consistent with the established requirement for C1q in prevention of autoimmunity. PMID- 22422888 TI - Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. AB - Genetic polymorphisms of IFN regulatory factor 5 (IRF5) are associated with an increased risk of lupus in humans. In this study, we examined the role of IRF5 in the pathogenesis of pristane-induced lupus in mice. The pathological response to pristane in IRF5(-/-) mice shared many features with type I IFN receptor (IFNAR)( /-) and TLR7(-/-) mice: production of anti-Sm/RNP autoantibodies, glomerulonephritis, generation of Ly6C(hi) monocytes, and IFN-I production all were greatly attenuated. Lymphocyte activation following pristane injection was greatly diminished in IRF5(-/-) mice, and Th cell differentiation was deviated from Th1 in wild-type mice toward Th2 in IRF5(-/-) mice. Th cell development was skewed similarly in TLR7(-/-) or IFNAR(-/-) mice, suggesting that IRF5 alters T cell activation and differentiation by affecting cytokine production. Indeed, production of IFN-I, IL-12, and IL-23 in response to pristane was markedly decreased, whereas IL-4 increased. Unexpectedly, plasmacytoid dendritic cells (pDC) were not recruited to the site of inflammation in IRF5(-/-) or MyD88(-/-) mice, but were recruited normally in IFNAR(-/-) and TLR7(-/-) mice. In striking contrast to wild-type mice, pristane did not stimulate local expression of CCL19 and CCL21 in IRF5(-/-) mice, suggesting that IRF5 regulates chemokine-mediated pDC migration independently of its effects on IFN-I. Collectively, these data indicate that altered production of IFN-I and other cytokines in IRF5(-/-) mice prevents pristane from inducing lupus pathology by broadly affecting T and B lymphocyte activation/differentiation. Additionally, we uncovered a new, IFN-I independent role of IRF5 in regulating chemokines involved in the homing of pDCs and certain lymphocyte subsets. PMID- 22422890 TI - Lymphohistiocytosis in the brain: recognition of a potentially reversible aspect of primary HLH. PMID- 22422889 TI - Cognitive function and retinal and ischemic brain changes: the Women's Health Initiative. AB - OBJECTIVE: To examine the association between retinopathy and cognitive decline or brain lesions and volumes in older women. METHODS: This study included 511 women aged 65 and older who were simultaneously enrolled in the Women's Health Initiative Memory Study and the Sight Examination Study. In this analysis, we examined the link between retinopathy, assessed using fundus photography (2000 2002), cognitive performance over time assessed by the modified Mini-Mental State Examination (3MSE) (1996-2007), and white matter hyperintensities and lacunar infarcts in the basal ganglia. RESULTS: Presence of retinopathy was associated with poorer 3MSE scores (mean difference = 1.01, SE: 0.43) (p = 0.019) over a 10 year follow-up period and greater ischemic volumes in the total brain (47% larger, p = 0.04) and the parietal lobe (68% larger, p = 0.01) but not with measures of regional brain atrophy. CONCLUSIONS: The correspondence we found between retinopathy and cognitive impairment, along with larger ischemic lesion volumes, strengthens existing evidence that retinopathy as a marker of small vessel disease is a risk factor for cerebrovascular disease that may influence cognitive performance and related brain changes. Retinopathy may be useful as a clinical tool if it can be shown to be an early marker related to neurologic outcomes. PMID- 22422891 TI - Lateralized central facilitation of trigeminal nociception in cluster headache. AB - OBJECTIVE: To investigate whether central facilitation of trigeminal pain processing is part of the pathophysiology of cluster headache (CH). METHODS: Sixty-six patients with CH (18 episodic CH inside bout, 28 episodic CH outside bout, 20 chronic CH) according to the International Classification of Headache Disorders-II classification, as well as 30 healthy controls, were investigated in a case-control study using simultaneous recordings of the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1). RESULTS: nBR latency ratio (headache side/nonheadache side) was decreased in all CH patients independent from CH subtype compared with healthy controls indicating central facilitation at brainstem level. Area under the curve ratio was increased in patients with episodic CH inside bout only. PREP showed decreased N2 latency ratio in patients with chronic CH indicating central facilitation at supraspinal (thalamic or cortical) level. CONCLUSIONS: Asymmetric facilitation of trigeminal nociceptive processing predominantly on brainstem level was detected in patients with CH. This alteration is most pronounced in the acute pain phase of the disease, but appears to persist in remission periods. Only chronic CH patients show additional changes of PREP prompting to supraspinal changes of pain processing related to the chronic state of disease in regard to neuronal plasticity, which exceeds changes observed in episodic CH. PMID- 22422892 TI - Recurrent stroke on imaging and presumed paradoxical embolism: a cross-sectional analysis. AB - OBJECTIVE: To identify whether factors supporting a diagnosis of paradoxical embolism (i.e., venous thrombosis or Valsalva maneuver) are associated with radiologic markers of recurrent strokes in patients with patent foramen ovale (PFO) and cryptogenic stroke (CS). Such clinical indicators of paradoxical embolism are commonly viewed as risk factors for CS recurrence, but precise risk estimates are lacking. METHODS: Data from the prospective Tufts PFO Registry collected at the time of the index CS were analyzed. We defined the following radiologic markers of stroke recurrence: 1) strokes of different radiologic ages and 2) silent strokes (detected on MRI but without symptoms preceding the index event). We examined the association between the radiologic endpoints and the clinical indicators of paradoxical embolism with multivariate logistic regression models, adjusting for age and gender. RESULTS: Data were available for 224 subjects. Strokes of different radiologic ages were not associated with the thrombosis-predisposing conditions (1.2 [95% confidence interval 0.5-2.7]), the Valsalva maneuver (1.3 [0.6-3.1]), or the presence of either of these factors. No statistically significant association was found in subgroups stratified by anatomic location of the index stroke or for the outcome of silent strokes. CONCLUSIONS: Our negative findings do not lend support to using the presence of clinical indicators of paradoxical embolism as an indication for percutaneous PFO closure. Factors that support a paradoxical embolism mechanism may be different from those that predict paradoxical embolism recurrence. Further investigations with clinical follow-up and larger sample sizes are needed to reach more precise estimates for the associations examined. PMID- 22422893 TI - Is brain health in the eye of the beholder? PMID- 22422894 TI - Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors. AB - OBJECTIVE: To determine the effect of treatment gaps on the risk of institutionalization or death among community-dwelling elderly patients treated with cholinesterase inhibitors (ChIs). METHODS: A survival analysis was conducted among a cohort of community-dwelling elderly patients (age 66+) newly treated with ChIs identified in the Quebec drug claims databases (Regie de l'Assurance Maladie du Quebec [RAMQ]) between January 1, 2000, and December 31, 2007. Treatment nonpersistence during the year following ChI initiation was defined as treatment discontinuation or gaps of at least 6 weeks. To account for reverse causality, Cox proportional hazard modeling was conducted only among patients who did not discontinue treatment, in order to assess the association between treatment nonpersistence and institutionalization or death. RESULTS: Among the 24,394 elderly ChI users, 4,108 (16.8) experienced a treatment gap during the year following ChI treatment initiation while 596 (2.4%) discontinued their treatment within the first 3 months (early stoppers) and 4,038 (16.6%) after 3 months of treatment (late stoppers). Of all treated patients, 4,409 (18.1%) were institutionalized or died during follow-up. In patients who did not stop their treatment, the risk of institutionalization or death appeared lower in patients who experienced a treatment gap (hazard ratio 0.91; 95% confidence interval 0.86 0.96). CONCLUSIONS: Our results suggest that, contrary to what was previously reported in clinical trials, treatment gaps do not compromise the outcome of patients treated with ChIs in a real-life setting. PMID- 22422895 TI - The minimum prevalence of CADASIL in northeast England. PMID- 22422896 TI - CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. AB - OBJECTIVES: To differentiate onset of CNS involvement in primary hemophagocytic lymphohistiocytosis (HLH) from that of other CNS inflammatory diseases and to identify early symptoms linked to abnormal cognitive outcome. METHODS: Forty-six children with primary HLH who had neurologic evaluation within 2 weeks and brain MRI within 6 months of diagnosis were included. Initial symptoms, CSF study, brain MRI, and neurologic outcome were assessed. Brain MRIs were compared with those of 44 children with acute disseminated encephalomyelitis (ADEM). RESULTS: At disease onset, 29 children (63%) had neurologic symptoms and 7 (15%) had microcephaly. Twenty-three (50%) children had abnormal CSF study, but only 15 (33%) had abnormal brain MRI. The latter showed that patients with HLH, unlike patients with ADEM, had symmetric periventricular lesions, without thalamic and brainstem involvement and with infrequent hyposignal intensity on T1. At the end of follow-up (3.6 +/- 3.6 years), 17 of the 28 (61%) surviving patients had normal neurologic status, 5 (18%) had a severe neurologic outcome, and 6 (21%) had mild cognitive difficulties. Abnormal neurologic outcome was not influenced by age or type of genetic defect, but by the presence of neurologic symptoms, MRI lesions, or abnormal CSF study at onset. Early clinical and MRI symptoms may regress after treatment. CONCLUSION: Neurologic symptoms are frequent at the onset of primary HLH and are mostly associated with abnormal CSF findings, but with normal brain MRI. In cases of abnormal brain MRI, the observed lesions differ from those of ADEM. PMID- 22422898 TI - Gastric antral vascular ectasia in a patient with GIST after treatment with imatinib: case report and literature review. AB - Imatinib mesylate is a receptor kinase inhibitor approved by the Food and Drug Administration for the treatment of malignant metastatic and/or unresectable gastrointestinal stromal tumors and chronic myelogenous leukemia. Although imatinib is generally well tolerated, certain adverse drug reactions are common. These include gastrointestinal side-effects such as diarrhea, nausea and vomiting, as well as hematological side-effects and other miscellaneous side effects such as fatigue, edema, dermatitis and dyspnea. We present a previously unreported adverse effect of imatinib, gastric antral vascular ectasia, in a 74 year-old woman with gastrointestinal stromal tumor in remission treated with adjuvant imatinib. Endoscopy performed prior to starting imatinib showed normal gastric mucosa, but 8 months after starting imatinib showed diffuse gastric inflammation. Repeat endoscopy 1 month after discontinuing imatinib showed significant improvement in gastric inflammation. PMID- 22422897 TI - A comparison of nine scales to detect depression in Parkinson disease: which scale to use? AB - OBJECTIVE: The Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study compared the psychometric properties of 9 depression scales to provide guidance on scale selection in Parkinson disease (PD). METHODS: Patients with PD (n = 229) from community-based neurology practices completed 6 self report scales (Beck Depression Inventory [BDI]-II, Center for Epidemiologic Studies Depression Rating Scale-Revised [CESD-R], 30-item Geriatric Depression Scale [GDS-30], Inventory of Depressive Symptoms-Patient [IDS-SR], Patient Health Questionnaire-9 [PHQ-9], and Unified Parkinson's Disease Rating Scale [UPDRS] Part I) and were administered 3 clinician-rated scales (17-item Hamilton Depression Rating Scale [HAM-D-17], Inventory of Depressive Symptoms-Clinician [IDS-C], and Montgomery-Asberg Depression Rating Scale [MADRS] and a psychiatric interview. DSM-IV-TR diagnoses were established by an expert panel blinded to the self-reported rating scale data. Receiver operating characteristic curves were used to estimate the area under the curve (AUC) of each scale. RESULTS: All scales performed better than chance (AUC 0.75-0.85). Sensitivity ranged from 0.66 to 0.85 and specificity ranged from 0.60 to 0.88. The UPDRS Depression item had a smaller AUC than the BDI-II, HAM-D-17, IDS-C, and MADRS. The CESD-R also had a smaller AUC than the MADRS. The remaining AUCs were statistically similar. CONCLUSIONS: The GDS-30 may be the most efficient depression screening scale to use in PD because of its brevity, favorable psychometric properties, and lack of copyright protection. However, all scales studied, except for the UPDRS Depression, are valid screening tools when PD-specific cutoff scores are used. PMID- 22422899 TI - Phase II study of intensive post-remission chemotherapy and stem cell transplantation for adult acute lymphoblastic leukemia and lymphoblastic lymphoma: Japan Clinical Oncology Group Study, JCOG9402. AB - OBJECTIVE: To evaluate the efficacy and safety of intensive post-remission chemotherapy for untreated patients aged 15-69 years with adult acute lymphoblastic leukemia and lymphoblastic lymphoma in a multicenter Phase II study. METHODS: The chemotherapy regimen consisted of induction, post-remission and maintenance for 2 years. The primary endpoint was 5-year progression-free survival, and secondary endpoints included complete remission rate, overall survival and adverse events. Among 115 patients enrolled, 108 eligible patients [median age, 33.5 years (range, 15-69)] including 96 acute lymphoblastic leukemia and 12 lymphoblastic lymphoma were assessed. Other major characteristics were male 50%, T-cell phenotype 21%, Philadelphia chromosome 22%, B-symptom+ 35% and performance status 2/3 22%. RESULTS: Eighty-seven patients achieved complete remission (81%; 95% confidence interval 72-88%), while five (5%) died during the chemotherapy protocol. The median overall survival and progression-free survival were 1.8 years (95% confidence interval, 1.5-2.6) and 1.2 years (95% confidence interval, 0.8-1.6), respectively. Their 5-year overall survival and progression free survival were 29 and 28%, respectively. The 5-year overall survival of 31 patients who underwent allogeneic (n = 19) or autologous (n = 12) stem cell transplantation during first complete response was 51%. Major non-hematologic toxicities of Grade 3 or greater were infections (21%) and pulmonary complications (6%). When compared with the investigators' previous Phase II trials, JCOG9402 improved progression-free survival and overall survival when compared with JCOG8702; however, it did not show improvement when compared with JCOG9004. CONCLUSIONS: Although the intensified induction and post-remission chemotherapy was feasible and 28% of the patients with adult acute lymphoblastic leukemia or lymphoblastic lymphoma achieved long-term progression-free survival, JCOG9402 did not show improvement. PMID- 22422900 TI - Physician-scientists: the bridge between medicine and science. PMID- 22422901 TI - Inhaled dry powder mannitol: a solution for cystic fibrosis. PMID- 22422902 TI - Monitoring for tuberculosis drug hepatotoxicity: moving from opinion to evidence. PMID- 22422903 TI - New treatments for idiopathic pulmonary fibrosis, empyema, and chronic obstructive pulmonary disease. PMID- 22422904 TI - Endobronchial erosion of vascular embolic coil. PMID- 22422905 TI - Joint effect of single-nucleotide polymorphisms and smoking exposure in chronic obstructive pulmonary disease risk. PMID- 22422906 TI - Learning from the learning effect in the six-minute-walk test. PMID- 22422907 TI - Prediction of fraction of inspired oxygen to achieve a desired arterial partial pressure of oxygen. PMID- 22422908 TI - From disease heterogeneity through patient endotype to "microtype": the future for chronic obstructive pulmonary disease research? PMID- 22422909 TI - Histopathological lung changes in children due to biomass fuel. PMID- 22422910 TI - Reversible cystic lesions of Pneumocystis jirovecii pneumonia. PMID- 22422911 TI - The ESC White Paper sets standards for conflicts of interest. PMID- 22422912 TI - Secondary stroke prevention: patent foramen ovale, aortic plaque, and carotid stenosis. AB - Stroke is the most debilitating cardiovascular event. It has a variety of causes that may be present simultaneously. In young or otherwise healthy people, the search for a patent foramen ovale (PFO) has become standard. In stroke of the elderly, atherosclerosis and atrial fibrillation are in the foreground but the PFO should not be ignored. The risk of a PFO-related stroke over time is controversial and so is its prevention by device closure. The association of proximal aortic plaques in arteries subtending the brain and stroke is considered strong, ignoring that it is as putative as that of the PFO. Statins can prevent progression of such plaques. Antiplatelet agents in asymptomatic and surgical endarterectomy in symptomatic patients or highly ulcerated lesions are the treatment of choice. Stenting with protection devices was shown competitive in selected patients. PMID- 22422913 TI - Introduction and evaluation of a 'pre-ART care' service in Swaziland: an operational research study. AB - OBJECTIVE: To implement and evaluate a formal pre-antiretroviral therapy (ART) care service at a district hospital in Swaziland. DESIGN: Operational research. SETTING: District hospital in Southern Africa. PARTICIPANTS: 1171 patients with a previous diagnosis of HIV. A baseline patient group consisted of the first 200 patients using the service. Two follow-up groups were defined: group 1 was all patients recruited from April to June 2009 and group 2 was 200 patients recruited in February 2010. INTERVENTION: Introduction of pre-ART care-a package of interventions, including counselling; regular review; clinical staging; timely initiation of ART; social and psychological support; and prevention and management of opportunistic infections, such as tuberculosis. PRIMARY AND SECONDARY OUTCOME MEASURES: Proportion of patients assessed for ART eligibility, proportion of eligible patients who were started on ART and proportion receiving defined evidence-based interventions (including prophylactic co-trimoxazole and tuberculosis screening). RESULTS: Following the implementation of the pre-ART service, the proportion of patients receiving defined interventions increased; the proportion of patient being assessed for ART eligibility significantly increased (baseline: 59%, group 1: 64%, group 2: 76%; p=0.001); the proportion of ART-eligible patients starting treatment increased (baseline: 53%, group 1: 81%, group: 2, 81%; p<0.001) and the median time between patients being declared eligible for ART and initiation of treatment significantly decreased (baseline: 61 days, group 1: 39 days, group 2: 14 days; p<0.001). CONCLUSIONS: This intervention was part of a shift in the model of care from a fragmented acute care model to a more comprehensive service. The introduction of structured pre ART was associated with significant improvements in the assessment, management and timeliness of initiation of treatment for patients with HIV. PMID- 22422914 TI - Presymptomatic cerebral blood flow changes in CHMP2B mutation carriers of familial frontotemporal dementia (FTD-3), measured with MRI. AB - OBJECTIVES: To assess functional changes measured by cerebral blood flow (CBF) in the presymptomatic stage of frontotemporal dementia linked to chromosome 3 (FTD 3) caused by a truncating mutation in CHMP2B. DESIGN: Case-control study. SETTING: A memory clinic and tertiary referrals centre for dementia and inherited neurodegenerative disorders. PARTICIPANTS: The authors included 11 presymptomatic CHMP2B mutation carriers and seven first-degree-related family non-carriers. Participants were MRI scanned twice with an interval of 15 months. PRIMARY AND SECONDARY OUTCOME MEASURES: Local functional changes in brain tissue perfusion were measured as CBF with two different MR techniques, gradient echo (GRE) and spin echo (SE), focusing on CBF in all cerebral vessels (GRE) and cerebral capillaries (SE), respectively. As planned, data analysis included co registration of perfusion images to structural T1 images. Perfusion data were then extracted from seven regions-of-interest, normalised to white matter and statistically compared between carriers and non-carriers. RESULTS: For SE, contrasts between carriers and non-carriers showed significant differences in temporal, occipital and parietal lobes and in hippocampus. There was no evidence of changes from baseline to follow-up. For GRE, there were no significant differences between carriers and non-carriers. CONCLUSIONS: Significantly decreased CBF was found in presymptomatic CHMP2B mutation carriers in occipital and parietal lobes. Comparing SE with GRE, data indicate that FTD-3 vascular pathology might primarily affect brain capillaries. PMID- 22422915 TI - A serial qualitative interview study of infant feeding experiences: idealism meets realism. AB - OBJECTIVE: To investigate the infant feeding experiences of women and their significant others from pregnancy until 6 months after birth to establish what would make a difference. DESIGN: Qualitative serial interview study. SETTING: Two health boards in Scotland. PARTICIPANTS: 72 of 541 invited pregnant women volunteered. 220 interviews approximately every 4 weeks with 36 women, 26 partners, eight maternal mothers, one sister and two health professionals took place. RESULTS: The overarching theme was a clash between overt or covert infant feeding idealism and the reality experienced. This is manifest as pivotal points where families perceive that the only solution that will restore family well being is to stop breast feeding or introduce solids. Immediate family well-being is the overriding goal rather than theoretical longer term health benefits. Feeding education is perceived as unrealistic, overly technical and rules based which can undermine women's confidence. Unanimously families would prefer the balance to shift away from antenatal theory towards more help immediately after birth and at 3-4 months when solids are being considered. Family-orientated interactive discussions are valued above breastfeeding-centred checklist style encounters. CONCLUSIONS: Adopting idealistic global policy goals like exclusive breast feeding until 6 months as individual goals for women is unhelpful. More achievable incremental goals are recommended. Using a proactive family-centred narrative approach to feeding care might enable pivotal points to be anticipated and resolved. More attention to the diverse values, meanings and emotions around infant feeding within families could help to reconcile health ideals with reality. PMID- 22422916 TI - A question-answer pair (QAP) database integrated with websites to answer complex questions submitted to the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS): a descriptive study. AB - OBJECTIVE: To assess a question-answer pair (QAP) database integrated with websites developed for drug information centres to answer complex questions effectively. DESIGN: Descriptive study with comparison of two subsequent 6-year periods (1995-2000 and 2001-2006). SETTING: The Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS). PARTICIPANTS: A randomised sample of QAPs from the RELIS database. PRIMARY OUTCOME MEASURE: Answer time in days compared with Mann-Whitney U test. SECONDARY OUTCOME MEASURE: Number of drugs involved (one, two, three or more), complexity (judgemental and/or patient related or not) and literature search (none, simple or advanced) compared with chi(2) tests. RESULTS: 842 QAPs (312 from 1995 to 2000 and 530 from 2001 to 2006) were compared. The fraction of judgemental and patient-related questions increased (66%-75% and 54%-72%, respectively, p<0.01). Number of drugs and literature search (>50% advanced) was similar in the two periods, but the fraction of answers referring to the RELIS database increased (13%-31%, p<0.01). Median answer time was reduced from 2 days to 1 (p<0.01), although the fraction of complex questions increased from the first to the second period. Furthermore, the mean number of questions per employee per year increased from 66 to 89 from the first to the second period. CONCLUSIONS: The authors conclude that RELIS has a potential to efficiently answer complex questions. The model is of relevance for organisation of drug information centres. PMID- 22422917 TI - Non-response in a nationwide follow-up postal survey in Finland: a register-based mortality analysis of respondents and non-respondents of the Health and Social Support (HeSSup) Study. AB - OBJECTIVE: To examine difference in mortality between postal survey non respondents and respondents. DESIGN: A prospective cohort study with baseline survey in 1998 and comprehensive linkage to national mortality registers until 2005, the Health and Social Support study. SETTING: A population-based postal survey of the working-aged population in Finland in 1998. PARTICIPANTS: The original random sample comprised 64 797 working-aged individuals in Finland (20 24, 30-34, 40-44, 50-54 years of age; 32 059 women and 32 716 men), yielding 25 898 (40.0%) responses in the baseline postal survey in 1998. PRIMARY OUTCOME MEASURE: Registry-based primary causes of death encoded with the International Classification of Diseases (ICD-10). RESULTS: In women, HR for total mortality was 1.75 (95% CI 1.40 to 2.19) times higher among the non-respondents compared with the respondents. In men, non-response was associated with a 1.41-fold (1.21 1.65) excess risk of total mortality. Non-response associated in certain age groups with deaths due to diseases in women and with deaths due to external causes in men. The most prominent excess mortality was seen for total mortality for both genders and for mortality due to external causes among men. CONCLUSIONS: Postal surveys result in slight underestimation of illness prevalence. PMID- 22422918 TI - Governance of preventive Health Intervention and On time Verification of its Efficiency: the GIOVE Study. AB - OBJECTIVES: The GIOVE Study was aimed to the achievement of allocative efficiency of the budget allocated to the prevention of human papillomavirus (HPV)-induced diseases. An ex-ante determination of the most efficient allocation of resources between screening and multicohort quadrivalent immunisation programmes was followed by the ex-post assessment of the allocative efficiency actually achieved after a 12-month period. DESIGN: A bound optimisation model was developed to determine the ex-ante allocative efficiency of resources. The alternatives compared were the screening programme alone and the quadrivalent immunisation with access to screening. A sensitivity analysis was carried out to assess the uncertainty associated with the main inputs of the model. Subsequently, a cohort of girls with a complete recorded vaccination history were enrolled in an observational retrospective study for 18 months to ensure full compliance with the recommended schedule of vaccination (0, 2, 6 months) within a 12-month time horizon. SETTING: Basilicata region, in the south of Italy. PARTICIPANTS: 12 848 girls aged 12, 15, 18 or 25 years. INTERVENTION: Immunisation with quadrivalent anti-HPV vaccine. OUTCOME MEASURES: The vaccination coverage rate was considered to be the indicator of the best achievable benefit, given the budgetary constraints. RESULTS: Assuming a vaccine price of ?100 per dose, a vaccination coverage rate of 59.6% was required for the most effective allocation of resources. The optimal rate of coverage was initially in favour of the multicohort strategy of vaccination against HPV (72.8%+/-2%). When the price paid for the quadrivalent vaccine dropped to ?85 per dose, the most efficient coverage rate (69.5%) shifted closer to the immunisation rate actually achieved during the 12-month observation period. CONCLUSIONS: The bound optimisation model demonstrated to be a useful approach to the ex-ante allocation and the ex-post assessment of the resources allocated to the implementation of a multicohort quadrivalent anti-HPV vaccination programme. PMID- 22422919 TI - Job strain among blue-collar and white-collar employees as a determinant of total mortality: a 28-year population-based follow-up. AB - OBJECTIVES: To investigate the effect of job demand, job control and job strain on total mortality among white-collar and blue-collar employees working in the public sector. DESIGN: 28-year prospective population-based follow-up. SETTING: Several municipals in Finland. PARTICIPANTS: 5731 public sector employees from the Finnish Longitudinal Study on Municipal Employees Study aged 44-58 years at baseline. OUTCOMES: Total mortality from 1981 to 2009 among individuals with complete data on job strain in midlife, categorised according to job demand and job control: high job strain (high job demands and low job control), active job (high job demand and high job control), passive job (low job demand and low job control) and low job strain (low job demand and high job control). RESULTS: 1836 persons died during the follow-up. Low job control among men increased (age adjusted HR 1.26, 95% CI 1.12 to 1.42) and high job demand among women decreased the risk for total mortality HR 0.82 (95% CI 0.71 to 0.95). Adjustment for occupational group, lifestyle and health factors attenuated the association for men. In the analyses stratified by occupational group, high job strain increased the risk of mortality among white-collar men (HR 1.52, 95% CI 1.09 to 2.13) and passive job among blue-collar men (HR 1.28, 95% CI 1.05 to 1.47) compared with men with low job strain. Adjustment for lifestyle and health factors attenuated the risks. Among white-collar women having an active job decreased the risk for mortality (HR 0.78, 95% CI 0.60 to 1.00). CONCLUSION: The impact of job strain on mortality was different according to gender and occupational group among middle aged public sector employees. PMID- 22422920 TI - Seasonal Influenza Vaccine Effectiveness in the community (SIVE): protocol for a cohort study exploiting a unique national linked data set. AB - INTRODUCTION: Seasonal influenza vaccination is recommended for all individuals aged 65 years and over and in individuals younger than 65 years with comorbidities. There is good evidence of vaccine effectiveness (VE) in young healthy individuals but less robust evidence for effectiveness in the populations targeted for influenza vaccination. Undertaking a randomised controlled trial to assess VE is now impractical due to the presence of national vaccination programmes. Quasi-experimental designs offer the potential to advance the evidence base in such scenarios, and the authors have therefore been commissioned to undertake a naturalistic national evaluation of seasonal influenza VE by using data derived from linkage of a number of Scottish health databases. The aim of this study is to examine the effectiveness of the seasonal influenza vaccination in the Scottish population. METHODS AND ANALYSIS: A cohort study design will be used pooling data over nine seasons. A primary care database covering 4% of the Scottish population for the period 2000-2009 has been linked to the national database of hospital admissions and the death register and is being linked to the Health Protection Scotland virology database. The primary outcome is VE measured in terms of rate of hospital admissions due to respiratory illness. Multivariable regression will be used to produce estimates of VE adjusted for confounders. The major challenge of this approach is addressing the strong effect of confounding due to vaccinated individuals being systematically different from unvaccinated individuals. Analyses using propensity scores and instrumental variables will be undertaken, and the effect of an unknown confounder will be modelled in a sensitivity analysis to assess the robustness of the estimates. ETHICS AND DISSEMINATION: The West of Scotland Research Ethics Committee has classified this project as surveillance. The study findings will be disseminated in peer-reviewed publications and presented at international conferences. PMID- 22422921 TI - Study protocol: a cross-sectional survey of seasonal affective disorder in Danish populations with and without severe visual impairments. AB - INTRODUCTION: People with seasonal affective disorder (SAD) experience recurrent seasonal fluctuations in energy, mood and appetite. Retinal light exposure is suggested to play an important role in the pathogenesis and treatment of SAD. The aim of the study is to determine the prevalence of SAD in persons with severe visual impairments or blindness and to compare the results to a control group without visual impairments. Moreover, the authors wish to investigate whether SAD is correlated to the degree of impairment or to the diagnosis. METHODS AND ANALYSIS: 2781 persons with visual impairments ranging from total blindness to Snellen visual acuity 6/60 receive information letter and questionnaire by post. Completed questionnaires can be returned by post, email or telephone. For each respondent, all eye-related diagnoses will be obtained from national registries. Normally sighted and demographically matched control respondents will be contacted in a similar manner the subsequent winter season. The Seasonal Pattern Assessment Questionnaire rates seasonal variation within the six items: sleep, appetite, social activity, mood, energy and body weight. The Seasonal Pattern Assessment Questionnaire yields a Global Seasonal Score and a prevalence of SAD. Outcomes from the two groups will be compared. Moreover, outcomes from subgroups of the visually impaired population will be compared. ETHICS AND DISSEMINATION: The study is approved by the Danish Data Protection Agency. Results will be published in a relevant scientific journal and be communicated to respondents and relevant institutions through cooperation with the Danish Association of the Blind. PMID- 22422922 TI - Biomarkers of oxidative stress and risk of developing colorectal cancer: a cohort nested case-control study in the European Prospective Investigation Into Cancer and Nutrition. AB - Oxidative stress has been shown to play an important role in carcinogenesis, but prospective evidence for an association between biomarkers of oxidative stress and colorectal cancer (CRC) risk is limited. The authors investigated the association between prediagnostic serum levels of oxidative stress indicators (i.e., reactive oxygen metabolites (ROM) and ferric reducing ability of plasma (FRAP)) and CRC risk. This was examined in a nested case-control study (1,064 CRC cases, 1,064 matched controls) in the European Prospective Investigation Into Cancer and Nutrition cohort (1992-2003). Incidence rate ratios and 95% confidence intervals were calculated using conditional logistic regression analyses. ROM were associated with overall CRC risk (highest tertile vs. lowest: adjusted incidence rate ratio (IRR(adj)) = 1.91, 95% confidence interval (CI): 1.47, 2.48), proximal (IRR(adj) = 1.89, 95% CI: 1.06, 3.36) and distal (IRR(adj) = 2.31, 95% CI: 1.37, 3.89) colon cancer, and rectal cancer (IRR(adj) = 1.69, 95% CI: 1.05, 2.72). When results were stratified by tertile of follow-up time, the association remained significant only in participants with less than 2.63 years of follow-up (IRR(adj) = 2.28, 95% CI: 1.78, 2.94; P-heterogeneity < 0.01). FRAP was not associated with CRC risk. In conclusion, prediagnostic serum ROM levels were associated with increased risk of CRC. However, this association was seen only in subjects with relatively short follow-up, suggesting that the association results from production of reactive oxygen species by preclinical tumors. PMID- 22422923 TI - Adjusting for partial verification or workup bias in meta-analyses of diagnostic accuracy studies. AB - A key requirement in the design of diagnostic accuracy studies is that all study participants receive both the test under evaluation and the reference standard test. For a variety of practical and ethical reasons, sometimes only a proportion of patients receive the reference standard, which can bias the accuracy estimates. Numerous methods have been described for correcting this partial verification bias or workup bias in individual studies. In this article, the authors describe a Bayesian method for obtaining adjusted results from a diagnostic meta-analysis when partial verification or workup bias is present in a subset of the primary studies. The method corrects for verification bias without having to exclude primary studies with verification bias, thus preserving the main advantages of a meta-analysis: increased precision and better generalizability. The results of this method are compared with the existing methods for dealing with verification bias in diagnostic meta-analyses. For illustration, the authors use empirical data from a systematic review of studies of the accuracy of the immunohistochemistry test for diagnosis of human epidermal growth factor receptor 2 status in breast cancer patients. PMID- 22422924 TI - Alveolar macrophages in diabetes: friends or foes? AB - AMs constitute an important bridge between innate and adaptive immunity. AMs patrol the lungs against pathogens, remove senescent cells, and help repair tissue. AM function is altered in many diseases, including DM, where AM abnormal immune responses may worsen infections or lead to exacerbation of inflammatory reactions. In vivo experimental models have greatly contributed to our knowledge of AM function. Studies have shown that during hyperglycemic states, the phagocytic function of AMs and the expression of adhesion molecules may be altered, interfering with the recruitment of immune cells to the inflammatory site. Insulin treatment seems to recover the normal function of impaired AMs. However, much research is still needed to characterize AMs and to better understand their role in inflammation and infection, particularly in diabetic patients. In this review, we attempt to explore recently accumulated knowledge about AM function and how this function is deficient in DM. Additionally, AM polarization is compared briefly with that of T cells, and this may interfere with how immune response is driven. This review discusses how impaired AMs lead to an aberrant immune response that contributes to worsening infection and autoimmunity, opening up discussion for future work in the field. PMID- 22422925 TI - Glycyrrhizin and isoliquiritigenin suppress the LPS sensor toll-like receptor 4/MD-2 complex signaling in a different manner. AB - Recent evidences suggest that the extracts of plant products are able to modulate innate immune responses. A saponin GL and a chalcone ILG are representative components of Glycyrrhiza uralensis, which attenuate inflammatory responses mediated by TLRs. Here, we show that GL and ILG suppress different steps of the LPS sensor TLR4/MD-2 complex signaling at the receptor level. Extract of G. uralensis suppressed IL-6 and TNF-alpha production induced by lipid A moiety of LPS in RAW264.7 cells. Among various G. uralensis-related components of saponins and flavanones/chalcones, GL and ILG could suppress IL-6 production induced by lipid A in dose-dependent manners in RAW264.7 cells. Furthermore, elevation of plasma TNF-alpha in LPS-injected mice was attenuated by passive administration of GL or ILG. GL and ILG inhibited lipid A-induced NF-kappaB activation in Ba/F3 cells expressing TLR4/MD-2 and CD14 and BMMs. These components also inhibited activation of MAPKs, including JNK, p38, and ERK in BMMs. In addition, GL and ILG inhibited NF-kappaB activation and IL-6 production induced by paclitaxel, a nonbacterial TLR4 ligand. Interestingly, GL attenuated the formation of the LPS TLR4/MD-2 complexes, resulting in inhibition of homodimerization of TLR4. Although ILG did not affect LPS binding to TLR4/MD-2, it could inhibit LPS induced TLR4 homodimerization. These results imply that GL and ILG modulate the TLR4/MD-2 complex at the receptor level, leading to suppress LPS-induced activation of signaling cascades and cytokine production, but their effects are exerted at different steps of TLR4/MD-2 signaling. PMID- 22422926 TI - Factors influencing exposure to secondhand smoke in preschool children living with smoking mothers. AB - INTRODUCTION: The health effects on young children of exposure to secondhand smoke (SHS) are well described. Recent work suggests that over one quarter of school-aged children in Scotland are regularly exposed to SHS in the home. The study was designed to describe SHS exposure in preschool children whose mothers smoked and identify factors that influence exposure. METHODS: Smoking mothers with at least one child aged 1-5 years were recruited to the Reducing Families' Exposure to Secondhand Smoke in the Home study. Concentrations of airborne particulate matter less than 2.5 MUm in size (PM(2.5)) in the home were measured together with child's salivary cotinine. Demographics including age, accommodation type, socioeconomic status, and number of cigarettes smoked at home were recorded. RESULTS: Data were collected from 54 homes. In 89% of the homes, concentrations of PM(2.5) exceeded health-based guidance values at some point of the day. Household PM(2.5) concentrations were highest during the evening hours of 6 p.m. to midnight. Younger children had higher salivary cotinine concentrations than older children, and the geometric mean of salivary cotinine was 2.36 ng/ml. Household smoking restrictions and maternal confidence in enforcing smoking restrictions in their own home were strongly associated with child's SHS exposure. CONCLUSIONS: Preschool children's exposure to SHS in homes where the mother smokes is considerable. Interventions and policy development to increase parental awareness of the health effects of SHS and provide parents with the confidence to implement smoke-free households are required to reduce the SHS exposure of preschool age children. PMID- 22422927 TI - The natural course of nicotine dependence symptoms among adolescent smokers. AB - INTRODUCTION: Few studies have investigated the natural course of nicotine dependence prospectively from the earliest experiences with smoking. METHODS: Drawing on a cohort of 9th- and 10th-grade adolescents followed over 48 months, survival analyses were conducted to evaluate the cumulative probability, following smoking initiation, for the development of nicotine dependence symptoms. RESULTS: Although each nicotine dependence symptom was significantly more prevalent among adolescents who had smoked more than 100 cigarettes by the end of the follow-up assessment, 20% of adolescents smoking fewer than 100 cigarettes reported experiencing "smoking to relieve restlessness and irritability" and "smoking a lot more now to be satisfied compared to when first smoked." Nicotine dependence symptoms were also reported before reaching 100 cigarettes for a substantial number of adolescents (between 9.4% and 58.8% for individual symptoms). Endorsement of nicotine dependence symptoms prospectively predicted past-week smoking (odds ratios [ORs] between 3.18 and 14.62 for significant symptoms) and past-month daily smoking (significant symptoms' ORs between 3.52 and 10.68) at the 48-month assessment even when controlling for amount of previous smoking. CONCLUSIONS: The present study adds to the growing body of literature on the natural course of nicotine dependence from earliest experiences with smoking by showing that symptoms of nicotine dependence may develop soon after initiation and/or at low levels of smoking. Our findings suggest that novice adolescent smokers should not be neglected in smoking cessation intervention and that screening and effective intervention for early emerging symptoms among adolescent smokers may be an important target in preventing chronic smoking. PMID- 22422928 TI - The risk of adverse cardiovascular events from varenicline balanced against the benefits in mortality from smoking cessation. PMID- 22422929 TI - Prevalence of video game use, cigarette smoking, and acceptability of a video game-based smoking cessation intervention among online adults. AB - INTRODUCTION: Video games may serve as an ideal platform for developing and implementing technology-based contingency management (CM) interventions for smoking cessation as they can be used to address a number of barriers to the utilization of CM (e.g., replacing monetary rewards with virtual game-based rewards). However, little is known about the relationship between video game playing and cigarette smoking. The current study determined the prevalence of video game use, video game practices, and the acceptability of a video game-based CM intervention for smoking cessation among adult smokers and nonsmokers, including health care professionals. METHODS: In an online survey, participants (N = 499) answered questions regarding their cigarette smoking and video game playing practices. Participants also reported if they believed a video game-based CM intervention could motivate smokers to quit and if they would recommend such an intervention. RESULTS: Nearly half of the participants surveyed reported smoking cigarettes, and among smokers, 74.5% reported playing video games. Video game playing was more prevalent in smokers than nonsmokers, and smokers reported playing more recently, for longer durations each week, and were more likely to play social games than nonsmokers. Most participants (63.7%), including those who worked as health care professionals, believed that a video game-based CM intervention would motivate smokers to quit and would recommend such an intervention to someone trying to quit (67.9%). CONCLUSIONS: Our findings suggest that delivering technology-based smoking cessation interventions via video games has the potential to reach substantial numbers of smokers and that most smokers, nonsmokers, and health care professionals endorsed this approach. PMID- 22422930 TI - Fulminant hyperacute rejection after unilateral lung transplantation. AB - Hyperacute rejection (HAR) is a well-known complication in renal and cardiac transplantation, but rare in lung recipients. We present a case of HAR of the lung graft with a fatal outcome of a male patient with preformed class II anti HLA antibodies. PMID- 22422931 TI - T2-T3 sympathectomy versus sympathicotomy for essential palmar hyperhidrosis: comparison of effects on cardio-respiratory function. AB - OBJECTIVES: The aim of this study was to determine cardio-respiratory changes after endothoracic sympathetic denervation and their correlation with the extent of denervation. METHODS: A total of 45 patients with essential palmar hyperhidrosis were randomized into two groups: the conventional group (CG; 23 patients) and the simplified group (SG; 22 patients). In the CG, excision of T2 and T3 ganglia was performed, whereas in the SG only separation of the sympathetic chain was performed at the same level. Patients underwent respiratory and cardiovascular exercise tests before, at 2 weeks and again at 6 months after the procedure. The postoperative values were then compared with the preoperative values to assess the statistical difference. RESULTS: Twenty-one patients in each group completed the study. In the SG, forced expiratory volume in 1 s (FEV 1; P < 0.01) and forced vital capacity (FVC; P < 0.01) were significantly reduced at 2 weeks, but returned to similar baseline values 6 months after the procedure. No significant cardiac changes were observed. In the CG, both FEV 1 and FVC were significantly reduced at 2 weeks (P < 0.01) and at 6 months after operation (P < 0.05). A significant reduction in forced expiratory flow between 25 and 75% of vital capacity (P < 0.01) and a relevant increase in airway resistance (P < 0.05) during the entire postoperative course were also observed. Heart rates at rest and at peak exercise were significantly reduced at 2 weeks (P < 0.01) and significantly decreased 6 months after the procedure (P < 0.05). No other changes were registered. The cardio-respiratory alterations remained at a sub-clinical level; all patients completed the exercise test without symptoms. CONCLUSION: Sympathectomy may result in a disturbance of bronchomotor tone and cardiac function. Such changes remained at a sub-clinical level and seemed directly correlated with the extension of denervation. PMID- 22422932 TI - Identification of acetabular labral pathological changes in asymptomatic volunteers using optimized, noncontrast 1.5-T magnetic resonance imaging. AB - BACKGROUND: Acetabular labral tears as a source of potential hip pain have received a great deal of attention in recent literature. The gold standard for identifying acetabular labral tears is hip arthroscopy, but recent advances in optimized, noncontrast magnetic resonance imaging (MRI) have proven effectiveness in identifying intra-articular hip pathological changes without the invasive nature of hip arthroscopy or gadolinium-enhanced arthrography. There are little data in the literature on imaging results in an asymptomatic population. PURPOSE: The objective of this study was to use an optimized, noncontrast 1.5-T MRI protocol to identify hip abnormalities, including paralabral cysts, in asymptomatic volunteers. STUDY DESIGN: Case series (prevalence); Level of evidence, 4. METHODS: In this study, 42 hips in asymptomatic patients with an average age of 34 years (range, 27-43 years) were prospectively imaged with optimized, noncontrast 1.5-T MRI scans. Two fellowship-trained musculoskeletal radiologists interpreted the scans at 2 different points in time and commented on the presence of labral abnormalities including paralabral cysts. The results were analyzed for both interobserver and intraobserver reliability. RESULTS: Acetabular paralabral cysts were identified in 11 of 42 (26.2%) and 9 of 42 (21.4%) hips by the 2 respective radiologists, with an interobserver reliability of 90.5% (kappa = .74) and intraobserver reliability of 95.2% (kappa = .87). In addition, acetabular labral tears were identified in 36 of 42 (85.7%) and 34 of 42 (80.9%) hips, with an interobserver reliability of 90.5% (kappa = .70) and intraobserver reliability of 95.2% (kappa = .83). CONCLUSION: Utilizing an optimized, noncontrast 1.5-T MRI protocol, we report the previously undescribed prevalence of acetabular labral pathological abnormalities and paralabral cysts in a young, asymptomatic population. This emphasizes the importance of correlating patient symptoms with history and physical examination when evaluating patients with hip pain and radiographic abnormalities as defined by MRI criteria. These data demonstrate that labral tears can occur without symptoms. PMID- 22422933 TI - Hyphal surface architecture and cell morphology of Trichoderma reesei. AB - The filamentous fungus Trichoderma reesei which is known to secrete high amounts of cellulolytic enzymes was found to produce a massive amount of fibrous material at the outer surface of the cell wall as observed by ultrahigh-resolution low voltage scanning electron microscopy. Using transmission electron microscopy, the cell wall ornamentation of the hyper-cellulosic mutant PC-3-7 was found to be less massive and much thinner than for QM9414. A significant amount of fibrous material was produced in Avicel-grown cultures that were less abundant in glucose grown cultures and Avicel was occasionally found entangled within the cell wall associated fibrous layer. PMID- 22422934 TI - Local root apex hypoxia induces NO-mediated hypoxic acclimation of the entire root. AB - Roots are very sensitive to hypoxia and adapt effectively to a reduced availability of oxygen in the soil. However, the site of the root where oxygen availability is sensed and how roots acclimate to hypoxia remain unclear. In this study, we found that the root apex transition zone plays central roles in both sensing and adapting to root hypoxia. The exposure of cells of the root apex to hypoxia is sufficient to achieve hypoxic acclimation of the entire root; particularly relevant in this respect is that, of the entire root apex, the transition zone cells show the highest demand for oxygen and also emit the largest amount of nitric oxide (NO). Local root apex-specific oxygen deprivation dramatically inhibits the oxygen influx peak in the transition zone and simultaneously stimulates a local increase in NO emission. The hypoxia-induced efflux of NO is strictly associated with the transition zone and is essential for hypoxic acclimation of the entire root. PMID- 22422935 TI - Ef7 encodes an ELF3-like protein and promotes rice flowering by negatively regulating the floral repressor gene Ghd7 under both short- and long-day conditions. AB - Much progress has been made in our understanding of photoperiodic flowering of rice and the mechanisms underlying short-day (SD) promotion and long-day (LD) repression of floral induction. In this study, we identified and characterized the Ef7 gene, one of the rice orthologs of Arabidopsis EARLY FLOWERING 3 (ELF3). The ef7 mutant HS276, which was induced by gamma-irradiation of the japonica rice cultivar 'Gimbozu', flowers late under both SD and LD conditions. Expression analyses of flowering time-related genes demonstrated that Ef7 negatively regulates the expression of Ghd7, which is a repressor of the photoperiodic control of rice flowering, and consequently up-regulates the expression of the downstream Ehd1 and FT-like genes under both SD and LD conditions. Genetic analyses with a non-functional Ghd7 allele provided further evidence that the delayed flowering of ef7 is mediated through the Ghd7 pathway. The analysis of light-induced expression of Ghd7 revealed that the ef7 mutant was more sensitive to red light than the wild-type plant, but the gate of Ghd7 expression was unchanged. Thus, our results show that Ef7 functions as a floral promoter by repressing Ghd7 expression under both SD and LD conditions. PMID- 22422936 TI - Shedding light on melanocyte pathobiology in vivo. AB - Cutaneous malignant melanoma is rapidly increasing in the developed world and continues to be a challenge in the clinic. Although extensive epidemiologic evidence points to solar UV as the major risk factor for melanoma, there is a significant gap in our knowledge about how this most ubiquitous environmental carcinogen interacts with the largest organ of the mammalian body (skin) at the microenvironmental and molecular level. We review some recent advances that have started to close this gap. PMID- 22422938 TI - Reconsidering the paradigm of cancer immunotherapy by computationally aided real time personalization. AB - Although therapeutic vaccination often induces markers of tumor-specific immunity, therapeutic responses remain rare. An improved understanding of patient specific dynamic interactions of immunity and tumor progression, combined with personalized application of immune therapeutics would increase the efficacy of immunotherapy. Here, we developed a method to predict and enhance the individual response to immunotherapy by using personalized mathematical models, constructed in the early phase of treatment. Our approach includes an iterative real-time in treatment evaluation of patient-specific parameters from the accruing clinical data, construction of personalized models and their validation, model-based simulation of subsequent response to ongoing therapy, and suggestion of potentially more effective patient-specific modified treatment. Using a mathematical model of prostate cancer immunotherapy, we applied our model to data obtained in a clinical investigation of an allogeneic whole-cell therapeutic prostate cancer vaccine. Personalized models for the patients who responded to treatment were derived and validated by data collected before treatment and during its early phase. Simulations, based on personalized models, suggested that an increase in vaccine dose and administration frequency would stabilize the disease in most patients. Together, our findings suggest that application of our method could facilitate development of a new paradigm for studies of in-treatment personalization of the immune agent administration regimens (P-trials), with treatment modifications restricted to an approved range, resulting in more efficacious immunotherapies. PMID- 22422937 TI - Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. AB - Age is a major risk factor for the development of cancer. Senescent fibroblasts, which accumulate with age, secrete protumorigenic factors collectively referred to as the senescence-associated secretory phenotype (SASP). Here, we examined the molecular mechanisms that control SASP activation, focusing on the known SASP factor osteopontin (OPN). We found that expression of the canonical SASP members interleukin (IL)-6 and IL-8, but not OPN, were dependent upon a persistent DNA damage response (DDR) as evidenced by ATM and NF-kappaB activation. Treatment with several histone deacetylase (HDAC) inhibitors robustly activated SASP in the absence of DNA breaks, suggesting that DDR-dependent SASP activation occurs in response to chromatin remodeling rather than physical breaks in DNA. In the setting of HDAC inhibition, IL-6 and IL-8 expression remained dependent upon ATM and NF-kappaB, while OPN expression remained independent of these factors. Further analysis revealed that HDAC1 inhibition was sufficient to induce OPN expression, which is interesting given that loss of HDAC1 expression correlates with increased OPN expression within the stromal compartment of invasive breast cancers. Importantly, fibroblasts treated with HDAC inhibitors promoted tumor growth in vivo. Our findings therefore indicate that HDAC modulation plays an important role in stromal cell activation, with important implications for the use of HDAC inhibitors in the treatment of cancer. PMID- 22422939 TI - In vivo quantification of cell coupling in plants with different phloem-loading strategies. AB - Uptake of photoassimilates into the leaf phloem is the key step in carbon partitioning and phloem transport. Symplasmic and apoplasmic loading strategies have been defined in different plant taxa based on the abundance of plasmodesmata between mesophyll and phloem. For apoplasmic loading to occur, an absence of plasmodesmata is a sufficient but not a necessary criterion, as passage of molecules through plasmodesmata might well be blocked or restricted. Here, we present a noninvasive, whole-plant approach to test symplasmic coupling and quantify the intercellular flux of small molecules using photoactivation microscopy. Quantification of coupling between all cells along the prephloem pathways of the apoplasmic loader Vicia faba and Nicotiana tabacum showed, to our knowledge for the first time in vivo, that small solutes like sucrose can diffuse through plasmodesmata up to the phloem sieve element companion cell complex (SECCC). As expected, the SECCC was found to be symplasmically isolated for small solutes. In contrast, the prephloem pathway of the symplasmic loader Cucurbita maxima was found to be well coupled with the SECCC. Phloem loading in gymnosperms is not well understood, due to a profoundly different leaf anatomy and a scarcity of molecular data compared with angiosperms. A cell-coupling analysis for Pinus sylvestris showed high symplasmic coupling along the entire prephloem pathway, comprising at least seven cell border interfaces between mesophyll and sieve elements. Cell coupling together with measurements of leaf sap osmolality indicate a passive symplasmic loading type. Similarities and differences of this loading type with that of angiosperm trees are discussed. PMID- 22422940 TI - Osmosensitive changes of carbohydrate metabolism in response to cellulose biosynthesis inhibition. AB - Cellulose is the most abundant biopolymer in the world, the main load-bearing element in plant cell walls, and represents a major sink for carbon fixed during photosynthesis. Previous work has shown that photosynthetic activity is partially regulated by carbohydrate sinks. However, the coordination of cellulose biosynthesis with carbohydrate metabolism and photosynthesis is not well understood. Here, we demonstrate that cellulose biosynthesis inhibition (CBI) leads to reductions in transcript levels of genes involved in photosynthesis, the Calvin cycle, and starch degradation in Arabidopsis (Arabidopsis thaliana) seedlings. In parallel, we show that CBI induces changes in carbohydrate distribution and influences Rubisco activase levels. We find that the effects of CBI on gene expression and carbohydrate metabolism can be neutralized by osmotic support in a concentration-dependent manner. However, osmotic support does not suppress CBI-induced metabolic changes in seedlings impaired in mechanoperception (mid1 complementing activity1 [mca1]) and osmoperception (cytokinin receptor1 [cre1]) or reactive oxygen species production (respiratory burst oxidase homolog DF [rbohDF]). These results show that carbohydrate metabolism is responsive to changes in cellulose biosynthesis activity and turgor pressure. The data suggest that MCA1, CRE1, and RBOHDF-derived reactive oxygen species are involved in the regulation of osmosensitive metabolic changes. The evidence presented here supports the notion that cellulose and carbohydrate metabolism may be coordinated via an osmosensitive mechanism. PMID- 22422944 TI - Extracorporeal photopheresis as a curative treatment strategy in non epidermotropic T-cell lymphoma and large granular lymphocyte leukemia. AB - BACKGROUND: To evaluate the efficacy of extracorporeal photopheresis (ECP) in noncutaneous T-cell lymphoma and large granular lymphocytes leukemia (LGL). PATIENTS AND METHODS: We have treated 12 refractory/relapsed patients. Six peripheral T-cell lymphoma (PTCL), one T-lymphoblastic lymphoma and five LGL with blood involvement received six biweekly leukapheresis as induction phase, followed by one course a week for 4 weeks as consolidation and one course of maintenance per month for responders until progression/relapse or disappearance of the peripheral clone. RESULTS: Six patients responded to phototherapy. Two PTCL and two LGL achieved a complete response (CR) and two other PTCL a partial response. The median duration of CR was 117 months (45-150 months) for these four patients. The peripheral clone followed by flow cytometry decreased in all six responders. Two patients with a complete disappearance of the peripheral clone have not relapsed. CONCLUSIONS: As for cutaneous T-cell lymphoma, ECP therefore to be efficient for PTCL and LGL. Early decrease and disappearance of the peripheral clone were the indicators of clinical response and nonrelapse, respectively. PMID- 22422945 TI - Open access--pass the buck. PMID- 22422950 TI - Particle physics. Key neutrino measurement signals China's rise. PMID- 22422951 TI - Drug discovery. New institute aims to help academics make medicines. PMID- 22422952 TI - Archaeology. Critics assail notion that Europeans settled Americas. PMID- 22422941 TI - Dynamic nucleotide-binding site and leucine-rich repeat-encoding genes in the grass family. AB - The proper use of resistance genes (R genes) requires a comprehensive understanding of their genomics and evolution. We analyzed genes encoding nucleotide-binding sites and leucine-rich repeats in the genomes of rice (Oryza sativa), maize (Zea mays), sorghum (Sorghum bicolor), and Brachypodium distachyon. Frequent deletions and translocations of R genes generated prevalent presence/absence polymorphism between different accessions/species. The deletions were caused by unequal crossover, homologous repair, nonhomologous repair, or other unknown mechanisms. R gene loci identified from different genomes were mapped onto the chromosomes of rice cv Nipponbare using comparative genomics, resulting in an integrated map of 495 R loci. Sequence analysis of R genes from the partially sequenced genomes of an African rice cultivar and 10 wild accessions suggested that there are many additional R gene lineages in the AA genome of Oryza. The R genes with chimeric structures (termed type I R genes) are diverse in different rice accessions but only account for 5.8% of all R genes in the Nipponbare genome. In contrast, the vast majority of R genes in the rice genome are type II R genes, which are highly conserved in different accessions. Surprisingly, pseudogene-causing mutations in some type II lineages are often conserved, indicating that their conservations were not due to their functions. Functional R genes cloned from rice so far have more type II R genes than type I R genes, but type I R genes are predicted to contribute considerable diversity in wild species. Type I R genes tend to reduce the microsynteny of their flanking regions significantly more than type II R genes, and their flanking regions have slightly but significantly lower G/C content than those of type II R genes. PMID- 22422954 TI - Environmental policy. Something fishy? NOAA economics study makes waves. PMID- 22422953 TI - Infectious disease. HIV prevention and cure insights come from failure and success. PMID- 22422955 TI - Toxicology. Heart-stopping revelation about how Chinese mushroom kills. PMID- 22422957 TI - Newsmaker interview: Hunter Rawlings III. On teaching, tuition, and talent. Interview by Jeffrey Mervis. PMID- 22422956 TI - Mental health care. Who needs psychiatrists? PMID- 22422958 TI - Add ecology to the pre-medical curriculum. PMID- 22422959 TI - IEG's role in evaluating climate financing. PMID- 22422962 TI - Comment on "Widespread RNA and DNA sequence differences in the human transcriptome". AB - Li et al. (Research Articles, 1 July 2011, p. 53; published online 19 May 2011) reported large numbers of differences between DNA and messenger RNA in human cells, indicating unprecedented levels of RNA editing, and including sequence changes not produced by any of the known RNA editing mechanisms. However, common sources of systematic errors in high-throughput sequencing technology, which were not properly accounted for in this study, explain most of the claimed differences. PMID- 22422963 TI - Comment on "Widespread RNA and DNA sequence differences in the human transcriptome". AB - Li et al. (Research Articles, 1 July 2011, p. 53; published online 19 May 2011) reported more than 10,000 mismatches between messenger RNA and DNA sequences from the same individuals, which they attributed to previously unrecognized mechanisms of gene regulation. We found that at least 88% of these sequence mismatches can likely be explained by technical artifacts such as errors in mapping sequencing reads to a reference genome, sequencing errors, and genetic variation. PMID- 22422964 TI - Comment on "Widespread RNA and DNA sequence differences in the human transcriptome". AB - Li et al. (Research Articles, 1 July 2011, p. 53; published online 19 May 2011) reported widespread differences between the RNA and DNA sequences of the same human cells, including all 12 possible mismatch types. Before accepting such a fundamental claim, a deeper analysis of the sequencing data is required to discern true differences between RNA and DNA from potential artifacts. PMID- 22422966 TI - Science and government. Navigating the anthropocene: improving Earth system governance. PMID- 22422967 TI - Cell biology. Membrane bending tug of war. PMID- 22422968 TI - Physiology. She said no, pass me a beer. PMID- 22422969 TI - Geophysics. Monitoring volcanoes. PMID- 22422970 TI - Applied physics. Valuing reversible energy storage. PMID- 22422972 TI - Chemistry. Getting molecular electrons into motion. PMID- 22422971 TI - AIDS/HIV. HIV interplay with SAMHD1. PMID- 22422973 TI - Retrospective. Norton Zinder (1928-2012). PMID- 22422974 TI - Human evolution out of Africa: the role of refugia and climate change. AB - Although an African origin of the modern human species is generally accepted, the evolutionary processes involved in the speciation, geographical spread, and eventual extinction of archaic humans outside of Africa are much debated. An additional complexity has been the recent evidence of limited interbreeding between modern humans and the Neandertals and Denisovans. Modern human migrations and interactions began during the buildup to the Last Glacial Maximum, starting about 100,000 years ago. By examining the history of other organisms through glacial cycles, valuable models for evolutionary biogeography can be formulated. According to one such model, the adoption of a new refugium by a subgroup of a species may lead to important evolutionary changes. PMID- 22422975 TI - The fern sporangium: a unique catapult. AB - Various plants and fungi have evolved ingenious devices to disperse their spores. One such mechanism is the cavitation-triggered catapult of fern sporangia. The spherical sporangia enclosing the spores are equipped with a row of 12 to 13 specialized cells, the annulus. When dehydrating, these cells induce a dramatic change of curvature in the sporangium, which is released abruptly after the cavitation of the annulus cells. The entire ejection process is reminiscent of human-made catapults with one notable exception: The sporangia lack the crossbar that arrests the catapult arm in its returning motion. We show that much of the sophistication and efficiency of the ejection mechanism lies in the two very different time scales associated with the annulus closure. PMID- 22422976 TI - Ultrastrong coupling of the cyclotron transition of a 2D electron gas to a THz metamaterial. AB - Artificial cavity photon resonators with ultrastrong light-matter interactions are attracting interest both in semiconductor and superconducting systems because of the possibility of manipulating the cavity quantum electrodynamic ground state with controllable physical properties. We report here experiments showing ultrastrong light-matter coupling in a terahertz (THz) metamaterial where the cyclotron transition of a high-mobility two-dimensional electron gas (2DEG) is coupled to the photonic modes of an array of electronic split-ring resonators. We observe a normalized coupling ratio, Omega/omega(c) = 0.58, between the vacuum Rabi frequency, Omega, and the cyclotron frequency, omega(c). Our system appears to be scalable in frequency and could be brought to the microwave spectral range with the potential of strongly controlling the magnetotransport properties of a high-mobility 2DEG. PMID- 22422977 TI - Laser scribing of high-performance and flexible graphene-based electrochemical capacitors. AB - Although electrochemical capacitors (ECs), also known as supercapacitors or ultracapacitors, charge and discharge faster than batteries, they are still limited by low energy densities and slow rate capabilities. We used a standard LightScribe DVD optical drive to do the direct laser reduction of graphite oxide films to graphene. The produced films are mechanically robust, show high electrical conductivity (1738 siemens per meter) and specific surface area (1520 square meters per gram), and can thus be used directly as EC electrodes without the need for binders or current collectors, as is the case for conventional ECs. Devices made with these electrodes exhibit ultrahigh energy density values in different electrolytes while maintaining the high power density and excellent cycle stability of ECs. Moreover, these ECs maintain excellent electrochemical attributes under high mechanical stress and thus hold promise for high-power, flexible electronics. PMID- 22422978 TI - Scaling hetero-epitaxy from layers to three-dimensional crystals. AB - Quantum structures made from epitaxial semiconductor layers have revolutionized our understanding of low-dimensional systems and are used for ultrafast transistors, semiconductor lasers, and detectors. Strain induced by different lattice parameters and thermal properties offers additional degrees of freedom for tailoring materials, but often at the expense of dislocation generation, wafer bowing, and cracks. We eliminated these drawbacks by fast, low-temperature epitaxial growth of Ge and SiGe crystals onto micrometer-scale tall pillars etched into Si(001) substrates. Faceted crystals were shown to be strain- and defect-free by x-ray diffraction, electron microscopy, and defect etching. They formed space-filling arrays up to tens of micrometers in height by a mechanism of self-limited lateral growth. The mechanism is explained by reduced surface diffusion and flux shielding by nearest-neighbor crystals. PMID- 22422979 TI - A change in the geodynamics of continental growth 3 billion years ago. AB - Models for the growth of continental crust rely on knowing the balance between the generation of new crust and the reworking of old crust throughout Earth's history. The oxygen isotopic composition of zircons, for which uranium-lead and hafnium isotopic data provide age constraints, is a key archive of crustal reworking. We identified systematic variations in hafnium and oxygen isotopes in zircons of different ages that reveal the relative proportions of reworked crust and of new crust through time. Growth of continental crust appears to have been a continuous process, albeit at variable rates. A marked decrease in the rate of crustal growth at ~3 billion years ago may be linked to the onset of subduction driven plate tectonics. PMID- 22422980 TI - The multielectron ionization dynamics underlying attosecond strong-field spectroscopies. AB - Subcycle strong-field ionization (SFI) underlies many emerging spectroscopic probes of atomic or molecular attosecond electronic dynamics. Extending methods such as attosecond high harmonic generation spectroscopy to complex polyatomic molecules requires an understanding of multielectronic excitations, already hinted at by theoretical modeling of experiments on atoms, diatomics, and triatomics. Here, we present a direct method which, independent of theory, experimentally probes the participation of multiple electronic continua in the SFI dynamics of polyatomic molecules. We use saturated (n-butane) and unsaturated (1,3-butadiene) linear hydrocarbons to show how subcycle SFI of polyatomics can be directly resolved into its distinct electronic-continuum channels by above threshold ionization photoelectron spectroscopy. Our approach makes use of photoelectron-photofragment coincidences, suiting broad classes of polyatomic molecules. PMID- 22422981 TI - Climatic niche shifts are rare among terrestrial plant invaders. AB - The assumption that climatic niche requirements of invasive species are conserved between their native and invaded ranges is key to predicting the risk of invasion. However, this assumption has been challenged recently by evidence of niche shifts in some species. Here, we report the first large-scale test of niche conservatism for 50 terrestrial plant invaders between Eurasia, North America, and Australia. We show that when analog climates are compared between regions, fewer than 15% of species have more than 10% of their invaded distribution outside their native climatic niche. These findings reveal that substantial niche shifts are rare in terrestrial plant invaders, providing support for an appropriate use of ecological niche models for the prediction of both biological invasions and responses to climate change. PMID- 22422982 TI - The path from beta-carotene to carlactone, a strigolactone-like plant hormone. AB - Strigolactones, phytohormones with diverse signaling activities, have a common structure consisting of two lactones connected by an enol-ether bridge. Strigolactones derive from carotenoids via a pathway involving the carotenoid cleavage dioxygenases 7 and 8 (CCD7 and CCD8) and the iron-binding protein D27. We show that D27 is a beta-carotene isomerase that converts all-trans-beta carotene into 9-cis-beta-carotene, which is cleaved by CCD7 into a 9-cis configured aldehyde. CCD8 incorporates three oxygens into 9-cis-beta-apo-10' carotenal and performs molecular rearrangement, linking carotenoids with strigolactones and producing carlactone, a compound with strigolactone-like biological activities. Knowledge of the structure of carlactone will be crucial for understanding the biology of strigolactones and may have applications in combating parasitic weeds. PMID- 22422983 TI - Sexual deprivation increases ethanol intake in Drosophila. AB - The brain's reward systems reinforce behaviors required for species survival, including sex, food consumption, and social interaction. Drugs of abuse co-opt these neural pathways, which can lead to addiction. Here, we used Drosophila melanogaster to investigate the relationship between natural and drug rewards. In males, mating increased, whereas sexual deprivation reduced, neuropeptide F (NPF) levels. Activation or inhibition of the NPF system in turn reduced or enhanced ethanol preference. These results thus link sexual experience, NPF system activity, and ethanol consumption. Artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF-NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly. PMID- 22422984 TI - SNARE proteins: one to fuse and three to keep the nascent fusion pore open. AB - Neurotransmitters are released through nascent fusion pores, which ordinarily dilate after bilayer fusion, preventing consistent biochemical studies. We used lipid bilayer nanodiscs as fusion partners; their rigid protein framework prevents dilation and reveals properties of the fusion pore induced by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor). We found that although only one SNARE per nanodisc is required for maximum rates of bilayer fusion, efficient release of content on the physiologically relevant time scale of synaptic transmission apparently requires three or more SNARE complexes (SNAREpins) and the native transmembrane domain of vesicle-associated membrane protein 2 (VAMP2). We suggest that several SNAREpins simultaneously zippering their SNARE transmembrane helices within the freshly fused bilayers provide a radial force that prevents the nascent pore from resealing during synchronous neurotransmitter release. PMID- 22422985 TI - Decoding in the absence of a codon by tmRNA and SmpB in the ribosome. AB - In bacteria, ribosomes stalled at the end of truncated messages are rescued by transfer-messenger RNA (tmRNA), a bifunctional molecule that acts as both a transfer RNA (tRNA) and a messenger RNA (mRNA), and SmpB, a small protein that works in concert with tmRNA. Here, we present the crystal structure of a tmRNA fragment, SmpB and elongation factor Tu bound to the ribosome at 3.2 angstroms resolution. The structure shows how SmpB plays the role of both the anticodon loop of tRNA and portions of mRNA to facilitate decoding in the absence of an mRNA codon in the A site of the ribosome and explains why the tmRNA-SmpB system does not interfere with normal translation. PMID- 22422986 TI - Structural basis for the rescue of stalled ribosomes: structure of YaeJ bound to the ribosome. AB - In bacteria, the hybrid transfer-messenger RNA (tmRNA) rescues ribosomes stalled on defective messenger RNAs (mRNAs). However, certain gram-negative bacteria have evolved proteins that are capable of rescuing stalled ribosomes in a tmRNA independent manner. Here, we report a 3.2 angstrom-resolution crystal structure of the rescue factor YaeJ bound to the Thermus thermophilus 70S ribosome in complex with the initiator tRNA(i)(fMet) and a short mRNA. The structure reveals that the C-terminal tail of YaeJ functions as a sensor to discriminate between stalled and actively translating ribosomes by binding in the mRNA entry channel downstream of the A site between the head and shoulder of the 30S subunit. This allows the N-terminal globular domain to sample different conformations, so that its conserved GGQ motif is optimally positioned to catalyze the hydrolysis of peptidyl-tRNA. This structure gives insights into the mechanism of YaeJ function and provides a basis for understanding how it rescues stalled ribosomes. PMID- 22422989 TI - Acetylation: a novel link between double-strand break repair and autophagy. AB - Histone deacetylase (HDAC) inhibitors are clinically relevant because they are used as anticancer drugs. Recent evidence sheds light on an intriguing connection among the DNA damage response (DDR), protein acetylation, and autophagy. HDAC inhibitors have been shown to counteract key steps in the cellular response to double-strand break formation by affecting checkpoint activation, homologous recombination-mediated repair of DNA lesions, and stability of crucial enzymes involved in resection of DNA ends. The degradation of the resection factors depends on autophagy, which plays a detrimental role when cells are in a hyperacetylated state and experience treatment with radiomimetic anticancer drugs. Future work will be required to further investigate the mechanisms underlying the link between acetylation, autophagy, and the DDR, as well as the significance of mTORC1 inhibitors, which are potent inducers of autophagy that are now used in cancer treatment. PMID- 22422988 TI - Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. AB - How breast cancer cells respond to the stress of endocrine therapies determines whether they will acquire a resistant phenotype or execute a cell-death pathway. After a survival signal is successfully executed, a cell must decide whether it should replicate. How these cell-fate decisions are regulated is unclear, but evidence suggests that the signals that determine these outcomes are highly integrated. Central to the final cell-fate decision is signaling from the unfolded protein response, which can be activated following the sensing of stress within the endoplasmic reticulum. The duration of the response to stress is partly mediated by the duration of inositol-requiring enzyme-1 activation following its release from heat shock protein A5. The resulting signals appear to use several B-cell lymphoma-2 family members to both suppress apoptosis and activate autophagy. Changes in metabolism induced by cellular stress are key components of this regulatory system, and further adaptation of the metabolome is affected in response to stress. Here we describe the unfolded protein response, autophagy, and apoptosis, and how the regulation of these processes is integrated. Central topologic features of the signaling network that integrate cell-fate regulation and decision execution are discussed. PMID- 22422990 TI - Dietary cadmium exposure and risk of postmenopausal breast cancer: a population based prospective cohort study. AB - The ubiquitous food contaminant cadmium has features of an estrogen mimetic that may promote the development of estrogen-dependent malignancies, such as breast cancer. However, no prospective studies of cadmium exposure and breast cancer risk have been reported. We examined the association between dietary cadmium exposure (at baseline, 1987) and the risk of overall and estrogen receptor (ER) defined (ER(+) or ER(-)) breast cancer within a population-based prospective cohort of 55,987 postmenopausal women. During an average of 12.2 years of follow up, 2,112 incident cases of invasive breast cancer were ascertained (1,626 ER(+) and 290 ER(-)). After adjusting for confounders, including consumption of whole grains and vegetables (which account for 40% of the dietary exposure, but also contain putative anticarcinogenic phytochemicals), dietary cadmium intake was positively associated with overall breast cancer tumors, comparing the highest tertile with the lowest [rate ratio (RR), 1.21; 95% confidence interval (CI), 1.07-1.36; P(trend) = 0.02]. Among lean and normal weight women, statistically significant associations were observed for all tumors (RR, 1.27; 95% CI, 1.07 1.50) and for ER(+) tumors (RR, 1.25; 95% CI, 1.03-1.52) and similar, but not statistically significant associations were found for ER(-) tumors (RR, 1.22; 95% CI, 0.76-1.93). The risk of breast cancer increased with increasing cadmium exposure similarly within each tertile of whole grain/vegetable consumption and decreased with increasing consumption of whole grain/vegetables within each tertile of cadmium exposure (P(interaction) = 0.73). Overall, these results suggest a role for dietary cadmium in postmenopausal breast cancer development. PMID- 22422991 TI - A model for personalized in vivo analysis of human immune responsiveness. AB - Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34(+) cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele-matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (T(regs)), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34(+) cell donor, but the T cell phenotypes were more predominantly "naive" than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural T(regs) intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This "personalized immune" mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well. PMID- 22422992 TI - Data-driven prediction of drug effects and interactions. AB - Adverse drug events remain a leading cause of morbidity and mortality around the world. Many adverse events are not detected during clinical trials before a drug receives approval for use in the clinic. Fortunately, as part of postmarketing surveillance, regulatory agencies and other institutions maintain large collections of adverse event reports, and these databases present an opportunity to study drug effects from patient population data. However, confounding factors such as concomitant medications, patient demographics, patient medical histories, and reasons for prescribing a drug often are uncharacterized in spontaneous reporting systems, and these omissions can limit the use of quantitative signal detection methods used in the analysis of such data. Here, we present an adaptive data-driven approach for correcting these factors in cases for which the covariates are unknown or unmeasured and combine this approach with existing methods to improve analyses of drug effects using three test data sets. We also present a comprehensive database of drug effects (Offsides) and a database of drug-drug interaction side effects (Twosides). To demonstrate the biological use of these new resources, we used them to identify drug targets, predict drug indications, and discover drug class interactions. We then corroborated 47 (P < 0.0001) of the drug class interactions using an independent analysis of electronic medical records. Our analysis suggests that combined treatment with selective serotonin reuptake inhibitors and thiazides is associated with significantly increased incidence of prolonged QT intervals. We conclude that confounding effects from covariates in observational clinical data can be controlled in data analyses and thus improve the detection and prediction of adverse drug effects and interactions. PMID- 22422993 TI - Structure-guided design of a high-affinity platelet integrin alphaIIbbeta3 receptor antagonist that disrupts Mg2+ binding to the MIDAS. AB - An integrin found on platelets, alpha(IIb)beta(3) mediates platelet aggregation, and alpha(IIb)beta(3) antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg(2+)) located in the beta subunit metal ion-dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the alpha(IIb) subunit and a carboxyl group that coordinates the MIDAS Mg(2+) in the beta(3) subunits. They induce conformational changes in the beta(3) subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of alpha(IIb)beta(3) (RUC-1) that binds exclusively to the alpha(IIb) subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a ~100-fold higher affinity. RUC-2 does not induce major conformational changes in beta(3) as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2-alpha(IIb)beta(3) headpiece complex in 1 mM calcium ion (Ca(2+))/5 mM Mg(2+) at 2.6 A revealed that RUC-2 binds to alpha(IIb) the way RUC-1 does, but in addition, it binds to the beta(3) MIDAS residue glutamic acid 220, thus displacing Mg(2+) from the MIDAS. When the Mg(2+) concentration was increased to 20 mM, however, Mg(2+) was identified in the MIDAS and RUC-2 was absent. RUC-2's ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg(2+) concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other alpha(IIb)beta(3) antagonists and may offer advantages as a therapeutic agent. PMID- 22422994 TI - Treating human autoimmunity: current practice and future prospects. AB - Autoimmune diseases are caused by immune cells attacking the host tissues they are supposed to protect. Recent advances suggest that maintaining a balance of effector and regulatory immune function is critical for avoiding autoimmunity. New therapies, including costimulation blockade, regulatory T cell therapy, antigen-specific immunotherapy, and manipulating the interleukin-2 pathway, attempt to restore this balance. This review discusses these advances as well as the challenges that must be overcome to target these therapies to patients suffering from autoimmune disease while avoiding the pitfalls of general immunosuppression. PMID- 22422995 TI - Belief in the dangerousness of people with mental disorders: a review. AB - BACKGROUND: The scientific literature on stigma has been confused because there are multiple components of stigma with different correlates. In order to help make sense of this confusion, the present review focuses on research on one of the most commonly measured components - belief in dangerousness. METHOD AND RESULTS: The review examines: measurement of belief in dangerousness; prevalence of belief in dangerousness; characteristics of people who believe in dangerousness; experiences associated with belief in dangerousness; characteristics of people that elicit belief in dangerousness; the effects of psychiatric labelling; the effects of causal explanations; interventions to reduce belief in dangerousness; and effects on help-seeking. CONCLUSION: It is concluded that future research needs to focus on rigorous evaluation of interventions to reduce belief in dangerousness and the impact of this belief on people affected by mental disorders. PMID- 22422996 TI - Revisiting the role of spike afterhyperpolarization and spike threshold in motoneuron current-frequency gain. AB - The relationship between synaptic or injecting input level and firing rate is an important metric to characterize neuron input-output dynamics. In this study, we examine two long-held, but never validated, assumptions in the "algebraic summation of afterhyperpolarization" theory, which explains how firing rate varies with input (typically referred to as input current-frequency modulation or "F-I gain"). In the theory, the afterhyperpolarizations themselves, along with spike threshold, were assumed constant. That is, whereas they were central concepts in the theory, they were not included in any feedback loops, wherein they could both affect and be affected by firing rate. We performed intracellular recordings from spinal motoneurons in the adult cat to determine whether F-I gain correlates with the afterhyperpolarization and/or spike threshold. We observe that the afterhyperpolarization does indeed appear to be out of the F-I gain mechanism loop, and thus that original assumption holds. However, the presented experimental evidence indicates that the spike threshold appears to be in the loop. That is, spike threshold variation associated with input correlates with F I gain. We present an extension to the original theory, which explains the F-I gain experimental correlations. PMID- 22422998 TI - Changes in interhemispheric inhibition from active to resting primary motor cortex during a fine-motor manipulation task. AB - The effect of performance of a sensorimotor task on the interhemispheric inhibition (IHI) induced from the active primary motor cortex (M1) to the resting M1 was examined in 10 right-handed subjects. Transcranial magnetic stimulation (TMS) was performed to produce motor evoked potentials (MEP) in the resting right (Rt)-first dorsal interosseous (FDI). For the paired-TMS paradigm, a conditioning stimulus (CS) was delivered to the Rt-M1, and its intensity was adjusted from 0.6 to 1.4 times the resting motor threshold of the MEP in the left (Lt)-FDI in 0.2 steps. The test stimulus was delivered to the Lt-M1, and its intensity was adjusted to evoke similar MEP amplitudes in the Rt-FDI among the task conditions. The interstimulus interval was fixed at 10 ms. As a sensorimotor task, a fine motor manipulation (FM) task (using chopsticks to pick up, transport, and release glass balls) was adopted. In addition, an isometric abduction (IA) task was also performed as a control task. These tasks were carried out with the left hand. The IHI from the active to the resting M1 observed during the FM task was markedly increased compared with that induced during the IA task, and this effect was not dependent on the MEP amplitude evoked in the active Lt-FDI by the CS. The present findings suggest that the increased IHI from the active to the resting M1 observed during the FM task was linked to reductions in the activity of the ipsilateral intracortical inhibitory circuit, as we reported previously. PMID- 22422997 TI - Ability of primary auditory cortical neurons to detect amplitude modulation with rate and temporal codes: neurometric analysis. AB - Amplitude modulation (AM) is a common feature of natural sounds, and its detection is biologically important. Even though most sounds are not fully modulated, the majority of physiological studies have focused on fully modulated (100% modulation depth) sounds. We presented AM noise at a range of modulation depths to awake macaque monkeys while recording from neurons in primary auditory cortex (A1). The ability of neurons to detect partial AM with rate and temporal codes was assessed with signal detection methods. On average, single-cell synchrony was as or more sensitive than spike count in modulation detection. Cells are less sensitive to modulation depth if tested away from their best modulation frequency, particularly for temporal measures. Mean neural modulation detection thresholds in A1 are not as sensitive as behavioral thresholds, but with phase locking the most sensitive neurons are more sensitive, suggesting that for temporal measures the lower-envelope principle cannot account for thresholds. Three methods of preanalysis pooling of spike trains (multiunit, similar to convergence from a cortical column; within cell, similar to convergence of cells with matched response properties; across cell, similar to indiscriminate convergence of cells) all result in an increase in neural sensitivity to modulation depth for both temporal and rate codes. For the across-cell method, pooling of a few dozen cells can result in detection thresholds that approximate those of the behaving animal. With synchrony measures, indiscriminate pooling results in sensitive detection of modulation frequencies between 20 and 60 Hz, suggesting that differences in AM response phase are minor in A1. PMID- 22422999 TI - The relationship between voltage-sensitive dye imaging signals and spiking activity of neural populations in primate V1. AB - Voltage-sensitive dye imaging (VSDI) is a powerful technique for measuring neural population responses from a large cortical region simultaneously with millisecond temporal resolution and columnar spatial resolution. However, the relationship between the average VSDI signal and the average spiking activity of neural populations is largely unknown. To better understand this relationship, we compared visual responses measured from V1 of behaving monkeys using VSDI and single-unit electrophysiology. We found large and systematic differences between position and orientation tuning properties obtained with these two techniques. We then determined that a simple computational model could explain these tuning differences. This model, together with our experimental results, allowed us to estimate the quantitative relationship between the average VSDI signal and local spiking activity. We found that this relationship is similar to the previously reported nonlinear relationship between average membrane potential and spike rate in single V1 neurons, suggesting that VSDI signals are dominated by subthreshold synaptic activity. This model, together with the VSDI measured maps for spatial position (retinotopy) and orientation, also allowed us to estimate the spatial integration area over which neural responses contribute to the VSDI signal at a given location. We found that the VSDI-integration area is consistent with a Gaussian envelope with a space constant of ~230 MUm. Finally, we show how this model and estimated parameters can be used to predict the pattern of population responses at the level of spiking activity from VSDI responses. PMID- 22423000 TI - Motor unit recruitment strategies and muscle properties determine the influence of synaptic noise on force steadiness. AB - Motoneurons receive synaptic inputs from tens of thousands of connections that cause membrane potential to fluctuate continuously (synaptic noise), which introduces variability in discharge times of action potentials. We hypothesized that the influence of synaptic noise on force steadiness during voluntary contractions is limited to low muscle forces. The hypothesis was examined with an analytical description of transduction of motor unit spike trains into muscle force, a computational model of motor unit recruitment and rate coding, and experimental analysis of interspike interval variability during steady contractions with the abductor digiti minimi muscle. Simulations varied contraction force, level of synaptic noise, size of motor unit population, recruitment range, twitch contraction times, and level of motor unit short-term synchronization. Consistent with the analytical derivations, simulations and experimental data showed that force variability at target forces above a threshold was primarily due to low-frequency oscillations in neural drive, whereas the influence of synaptic noise was almost completely attenuated by two low-pass filters, one related to convolution of motoneuron spike trains with motor unit twitches (temporal summation) and the other attributable to summation of single motor unit forces (spatial summation). The threshold force above which synaptic noise ceased to influence force steadiness depended on recruitment range, size of motor unit population, and muscle contractile properties. This threshold was low (<10% of maximal force) for typical values of these parameters. Results indicate that motor unit recruitment and muscle properties of a typical muscle are tuned to limit the influence of synaptic noise on force steadiness to low forces and that the inability to produce a constant force during stronger contractions is mainly attributable to the common low-frequency oscillations in motoneuron discharge rates. PMID- 22423002 TI - Object representation and distance encoding in three-dimensional environments by a neural circuit in the visual system of the blowfly. AB - Three motion-sensitive key elements of a neural circuit, presumably involved in processing object and distance information, were analyzed with optic flow sequences as experienced by blowflies in a three-dimensional environment. This optic flow is largely shaped by the blowfly's saccadic flight and gaze strategy, which separates translational flight segments from fast saccadic rotations. By modifying this naturalistic optic flow, all three analyzed neurons could be shown to respond during the intersaccadic intervals not only to nearby objects but also to changes in the distance to background structures. In the presence of strong background motion, the three types of neuron differ in their sensitivity for object motion. Object-induced response increments are largest in FD1, a neuron long known to respond better to moving objects than to spatially extended motion patterns, but weakest in VCH, a neuron that integrates wide-field motion from both eyes and, by inhibiting the FD1 cell, is responsible for its object preference. Small but significant object-induced response increments are present in HS cells, which serve both as a major input neuron of VCH and as output neurons of the visual system. In both HS and FD1, intersaccadic background responses decrease with increasing distance to the animal, although much more prominently in FD1. This strong dependence of FD1 on background distance is concluded to be the consequence of the activity of VCH that dramatically increases its activity and, thus, its inhibitory strength with increasing distance. PMID- 22423001 TI - The influence of surround suppression on adaptation effects in primary visual cortex. AB - Adaptation, the prolonged presentation of stimuli, has been used to probe mechanisms of visual processing in physiological, imaging, and perceptual studies. Previous neurophysiological studies have measured adaptation effects by using stimuli tailored to evoke robust responses in individual neurons. This approach provides an incomplete view of how an adapter alters the representation of sensory stimuli by a population of neurons with diverse functional properties. We implanted microelectrode arrays in primary visual cortex (V1) of macaque monkeys and measured orientation tuning and contrast sensitivity in populations of neurons before and after prolonged adaptation. Whereas previous studies in V1 have reported that adaptation causes stimulus-specific suppression of responsivity and repulsive shifts in tuning preference, we have found that adaptation can also lead to response facilitation and shifts in tuning toward the adapter. To explain this range of effects, we have proposed and tested a simple model that employs stimulus-specific suppression in both the receptive field and the spatial surround. The predicted effects on tuning depend on the relative drive provided by the adapter to these two receptive field components. Our data reveal that adaptation can have a much richer repertoire of effects on neuronal responsivity and tuning than previously considered and suggest an intimate mechanistic relationship between spatial and temporal contextual effects. PMID- 22423003 TI - Motion clouds: model-based stimulus synthesis of natural-like random textures for the study of motion perception. AB - Choosing an appropriate set of stimuli is essential to characterize the response of a sensory system to a particular functional dimension, such as the eye movement following the motion of a visual scene. Here, we describe a framework to generate random texture movies with controlled information content, i.e., Motion Clouds. These stimuli are defined using a generative model that is based on controlled experimental parametrization. We show that Motion Clouds correspond to dense mixing of localized moving gratings with random positions. Their global envelope is similar to natural-like stimulation with an approximate full-field translation corresponding to a retinal slip. We describe the construction of these stimuli mathematically and propose an open-source Python-based implementation. Examples of the use of this framework are shown. We also propose extensions to other modalities such as color vision, touch, and audition. PMID- 22423004 TI - Innovations in motoneuron synchrony drive rapid temporal modulations in vertebrate acoustic signaling. AB - Rapid temporal modulation of acoustic signals among several vertebrate lineages has recently been shown to depend on the actions of superfast muscles. We hypothesized that such fast events, known to require synchronous activation of muscle fibers, would rely on motoneuronal properties adapted to generating a highly synchronous output to sonic muscles. Using intracellular in vivo recordings, we identified a suite of premotor network inputs and intrinsic motoneuronal properties synchronizing the oscillatory-like, simultaneous activation of superfast muscles at high gamma frequencies in fish. Motoneurons lacked spontaneous activity, firing synchronously only at the frequency of premotor excitatory input. Population-level motoneuronal output generated a spike like, vocal nerve volley that directly determines muscle contraction rate and, in turn, natural call frequency. In the absence of vocal output, motoneurons showed low excitability and a weak afterhyperpolarization, leading to rapid accommodation in firing rate. By contrast, vocal activity was accompanied by a prominent afterhyperpolarization, indicating a dependency on network activity. Local injection of a GABA(A) receptor antagonist demonstrated the necessity of electrophysiologically and immunohistochemically confirmed inhibitory GABAergic input for motoneuronal synchrony and vocalization. Numerous transneuronally labeled motoneurons following single-cell neurobiotin injection together with electrophysiological collision experiments confirmed gap junctional coupling, known to contribute to synchronous activity in other neural networks. Motoneuronal synchrony at the premotor input frequency was maintained during differential recruitment of variably sized motoneurons. Differential motoneuron recruitment led, however, to amplitude modulation (AM) of vocal output and, hence, natural call AM. In summary, motoneuronal intrinsic properties, in particular low excitability, predisposed vocal motoneurons to the synchronizing influences of premotor inputs to translate a temporal input code into a coincident and extremely synchronous, but variable-amplitude, output code. We propose an analogous suite of neuronal properties as a key innovation underlying similarly rapid acoustic events observed among amphibians, reptiles, birds, and mammals. PMID- 22423005 TI - Similar muscles contribute to horizontal and vertical acceleration of center of mass in forward and backward walking: implications for neural control. AB - Leg kinematics during backward walking (BW) are very similar to the time-reversed kinematics during forward walking (FW). This suggests that the underlying muscle activation pattern could originate from a simple time reversal, as well. Experimental electromyography studies have confirmed that this is the case for some muscles. Furthermore, it has been hypothesized that muscles showing a time reversal should also exhibit a reversal in function [from accelerating the body center of mass (COM) to decelerating]. However, this has not yet been verified in simulation studies. In the present study, forward simulations were used to study the effects of muscles on the acceleration of COM in FW and BW. We found that a reversal in function was indeed present in the muscle control of the horizontal movement of COM (e.g., tibialis anterior and gastrocnemius). In contrast, muscles' antigravity contributions maintained their function for both directions of movement. An important outcome of the present study is therefore that similar muscles can be used to achieve opposite functional demands at the level of control of the COM when walking direction is reversed. However, some muscles showed direction-specific contributions (i.e., dorsiflexors). We concluded that the changes in muscle contributions imply that a simple time reversal would be insufficient to produce BW from FW. We therefore propose that BW utilizes extra elements, presumably supraspinal, in addition to a common spinal drive. These additions are needed for propulsion and require a partial reconfiguration of lower level common networks. PMID- 22423006 TI - NMDAR antagonist action in thalamus imposes delta oscillations on the hippocampus. AB - Work on schizophrenia demonstrates the involvement of the hippocampus in the disease and points specifically to hyperactivity of CA1. Many symptoms of schizophrenia can be mimicked by N-methyl-d-aspartate receptor (NMDAR) antagonist; notably, delta frequency oscillations in the awake state are enhanced in schizophrenia, an abnormality that can be mimicked by NMDAR antagonist action in the thalamus. Given that CA1 receives input from the nucleus reuniens of the thalamus, we sought to determine whether an NMDAR antagonist in the thalamus can affect hippocampal processes. We found that a systemic NMDAR antagonist (ketamine; 50 mg/kg) increased the firing rate of cells in the reuniens and CA1 in awake rats. Furthermore, ketamine increased the power of delta oscillations in both structures. The thalamic origin of the change in hippocampal properties was demonstrated in three ways: 1) oscillations in the two structures were coherent; 2) the hippocampal changes induced by systematic ketamine were reduced by thalamic injection of muscimol; and 3) the hippocampal changes could be induced by local injection of ketamine into the thalamus. Lower doses of ketamine (20 mg/kg) did not evoke delta oscillations but did increase hippocampal gamma power, an effect not dependent on the thalamus. There are thus at least two mechanisms for ketamine action on the hippocampus: a low-dose mechanism that affects gamma through a nonthalamic mechanism and a high-dose mechanism that increases CA1 activity and delta oscillations as a result of input from the thalamus. Both mechanisms may be important in producing symptoms of schizophrenia. PMID- 22423007 TI - Orbitofrontal cortical activity during repeated free choice. AB - Neurons in the orbitofrontal cortex (OFC) have been shown to encode subjective values, suggesting a role in preference-based decision-making, although the precise relation to choice behavior is unclear. In a repeated two-choice task, subjective values of each choice can account for aggregate choice behavior, which is the overall likelihood of choosing one option over the other. Individual choices, however, are impossible to predict with knowledge of relative subjective values alone. In this study we investigated the role of internal factors in choice behavior with a simple but novel free-choice task and simultaneous recording from individual neurons in nonhuman primate OFC. We found that, first, the observed sequences of choice behavior included periods of exceptionally long runs of each of two available options and periods of frequent switching. Neither a satiety-based mechanism nor a random selection process could explain the observed choice behavior. Second, OFC neurons encode important features of the choice behavior. These features include activity selective for exceptionally long runs of a given choice (stay selectivity) as well as activity selective for switches between choices (switch selectivity). These results suggest that OFC neural activity, in addition to encoding subjective values on a long timescale that is sensitive to satiety, also encodes a signal that fluctuates on a shorter timescale and thereby reflects some of the statistically improbable aspects of free-choice behavior. PMID- 22423008 TI - A population-based study of hepatitis D virus as potential risk factor for hepatocellular carcinoma. AB - Hepatitis D virus (HDV) is dependent on the presence of hepatitis B virus (HBV) for transmission and replication because of its inability to produce its own coat. It remains unclear whether HDV infection increases the risk of hepatocellular carcinoma. Using the Swedish Hospital Discharge Register and Outpatient Registry, we identified 9160 patients with chronic HBV infection between 1997 and 2008, of whom 327 had chronic HDV infection and 323 had acute HDV infection. Standardized incidence ratios (SIRs) were calculated for these patients compared with the general population. The risk of hepatocellular carcinoma was greatly increased in patients with HBV and HDV (SIR = 137.17, 95% confidence interval [CI] = 62.19 to 261.51). The risk of hepatocellular carcinoma among patients with HBV and HDV was increased (SIR = 6.11, 95% CI = 2.77 to 11.65) when patients with chronic HBV infection alone were used as the reference population. Similar results were observed for patients with chronic HDV infection (SIR = 99.26, 95% CI = 42.39 to 196.55). Our findings indicate that HDV is a strong risk factor for hepatocellular carcinoma. PMID- 22423009 TI - Impact of reduced tobacco smoking on lung cancer mortality in the United States during 1975-2000. AB - BACKGROUND: Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975-2000. METHODS: A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975-2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General's first report on Smoking and Health in 1964. RESULTS: Approximately 795,851 US lung cancer deaths were averted during the period 1975-2000: 552,574 among men and 243,277 among women. In the year 2000 alone, approximately 70,218 lung cancer deaths were averted: 44,135 among men and 26,083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975-2000, 38% of the lung cancer deaths that could have been averted in 1991-2000, and 44% of lung cancer deaths that could have been averted in 2000. CONCLUSIONS: Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease. PMID- 22423010 TI - Association of established smoking among adolescents with timing of exposure to smoking depicted in movies. AB - BACKGROUND: It is not known whether exposure to smoking depicted in movies carries greater influence during early or late adolescence. We aimed to quantify the independent relative contribution to established smoking of exposure to smoking depicted in movies during both early and late adolescence. METHODS: We prospectively assessed 2049 nonsmoking students recruited from 14 randomly selected public schools in New Hampshire and Vermont. At baseline enrollment, students aged 10-14 years completed a written survey to determine personal, family, and sociodemographic characteristics and exposure to depictions of smoking in the movies (early exposure). Seven years later, we conducted follow-up telephone interviews to ascertain follow-up exposure to movie smoking (late exposure) and smoking behavior. We used multiple regression models to assess associations between early and late exposure and development of established smoking. RESULTS: One-sixth (17.3%) of the sample progressed to established smoking. In analyses that controlled for covariates and included early and late exposure in the same model, we found that students in the highest quartile for early exposure had 73% greater risk of established smoking than those in the lowest quartile for early exposure (27.8% vs 8.6%; relative risk for Q4 vs Q1 = 1.73, 95% confidence interval = 1.14 to 2.62). However, late exposure to depictions of smoking in movies was not statistically significantly associated with established smoking (22.1% vs 14.0%; relative risk for Q4 vs Q1 = 1.13, 95% confidence interval = 0.89 to 1.44). Whereas 31.6% of established smoking was attributable to early exposure, only an additional 5.3% was attributable to late exposure. CONCLUSIONS: Early exposure to smoking depicted in movies is associated with established smoking among adolescents. Educational and policy-related interventions should focus on minimizing early exposure to smoking depicted in movies. PMID- 22423011 TI - The 795 thousand and ending a century of tobacco. PMID- 22423012 TI - Is the albumin retrieval hypothesis a paradigm shift for nephrology? PMID- 22423013 TI - Intensive hemodialysis: back to the beginning? PMID- 22423014 TI - The eternal (nocturnal) quest for better dialysis outcomes. PMID- 22423015 TI - Balint groups: a tool for personal and professional resilience. PMID- 22423016 TI - Religion in primary care: let's talk about it. PMID- 22423018 TI - World Health Organization position on breastfeeding. PMID- 22423019 TI - Screening for abdominal aortic aneurysm. PMID- 22423020 TI - Human papillomavirus vaccine and pregnancy. AB - QUESTION A: patient of mine who recently learned she was 6 weeks pregnant had received the recombinant human papillomavirus (HPV) quadrivalent vaccine at 4 weeks of gestation. She is quite worried about how this will affect her baby. What is known about the safety of the HPV vaccine during pregnancy? ANSWER: The HPV vaccine is generally not recommended for use in pregnant women. However, theoretically, because it is not a live vaccine, it is not expected to be associated with an increased risk. Also, information from the manufacturer's pregnancy registry and phase 3 clinical trials does not indicate an increased risk of fetal malformations or other adverse effects due to the vaccine. PMID- 22423021 TI - Effectiveness of rotavirus vaccine in preventing severe acute gastroenteritis in children. AB - QUESTION: As rotavirus vaccines enter the scheduled immunization programs in Canada, more and more of the children younger than 1 year of age in my practice are receiving rotavirus vaccines. Is there evidence that rotavirus vaccines are effective in preventing acute gastroenteritis complications such as dehydration and hospitalization? ANSWER: To reduce the burden of illness of rotavirus-induced gastroenteritis, 2 orally administered rotavirus vaccines were licensed in recent years. Large studies documented the safety profiles of these vaccines and several provinces introduced a vaccine as part of their immunization program. Recent data from developed and developing countries suggest that the rotavirus vaccine is substantially reducing morbidity and mortality among children. Initial clinical trials are now being supported by effectiveness data from field studies, showing a 70% to 100% reduction in emergency department visits and hospitalizations of children with rotavirus acute gastroenteritis. PMID- 22423022 TI - Dermacase. Can you identify this condition? Inflammatory linear verrucous epidermal nevus. PMID- 22423023 TI - Ophthaproblem. Can you identify this condition? Choroidal metastasis. PMID- 22423024 TI - You and your EMR: the research perspective: part 3. Answering practice-level questions. PMID- 22423025 TI - The last C: centred in family medicine. PMID- 22423026 TI - There's no place like home. PMID- 22423027 TI - Focusing on generalism. PMID- 22423028 TI - Diagnoses of anxiety and depression in clinical-scenario patients: survey of Saskatchewan family physicians. AB - OBJECTIVE: To investigate family physicians' differential diagnoses of clinical scenario patients presenting with symptoms of either generalized anxiety disorder (GAD) or a major depressive episode (MDE). DESIGN: Cross-sectional survey. SETTING: Saskatchewan. PARTICIPANTS: A total of 331 family physicians practising in Saskatchewan as of December 2007. MAIN OUTCOME MEASURES: Type and number of physicians' differential diagnoses for a GAD-scenario patient and an MDE-scenario patient. RESULTS: The survey response rate was 49.7% (331 of 666 surveys returned). Most physicians suggested a diagnosis of anxiety (82.5%) for the GAD scenario patient and a diagnosis of depression (84.2%) for the MDE-scenario patient. In descending order, the 5 most frequent differential diagnoses for the GAD-scenario patient were anxiety, hyperthyroidism, depression, panic disorder or attack, and bipolar disorder. The 5 most frequent differential diagnoses for the MDE-scenario patient were depression, anxiety, hypothyroidism, irritable bowel syndrome, and anemia. Neither a diagnosis of anxiety nor a diagnosis of depression was associated with physicians' personal attributes (sex, age, and years in practice) or organizational setting (number of total patient visits per week, private office or clinic, solo practice, Internet access, and rural practice setting). However, physicians in solo practice suggested fewer differential diagnoses for the GAD-scenario patient than those in group practice; physicians in practice 30 years or longer suggested fewer differential diagnoses for the MDE-scenario patient than those in practice fewer than 10 years. On average, physicians suggested 3 differential diagnoses for each of the scenarios. CONCLUSION: Most family physicians recognize depression and anxiety in patients presenting with symptoms of these disorders and consider an average of 3 differential diagnoses in each of these cases. PMID- 22423029 TI - Treatment and follow-up of anxiety and depression in clinical-scenario patients: survey of Saskatchewan family physicians. AB - OBJECTIVE: To explore family physicians' recommendations for treatment of, and number of weeks to first follow-up visit for, clinical-scenario patients presenting with symptoms of either a major depressive episode (MDE) or generalized anxiety disorder (GAD), as well as physicians' perceived barriers to optimal care for these patients. DESIGN: Cross-sectional survey. SETTING: Saskatchewan. PARTICIPANTS: A total of 331 family physicians practising in Saskatchewan as of December 2007. MAIN OUTCOME MEASURES: Type of treatment and number of weeks to first follow-up visit recommended for clinical-scenario patients, as well as family physicians' barriers to providing optimal care. RESULTS: The response rate was 49.7% (331 of 666 surveys returned). Most physicians recommended treatment of the GAD-scenario patient (93.7%) and the MDE scenario patient (90.1%). Most physicians recommended immediate (65.6%) rather than delayed (28.1%) treatment of the GAD-scenario patient, and immediate (55.6%) rather than delayed (34.5%) treatment of the MDE-scenario patient. Pharmacotherapy alone (26.3%) was the most commonly recommended immediate treatment of the GAD-scenario patient; combination pharmacotherapy and counseling (15.8%) was the most commonly recommended immediate treatment of the MDE-scenario patient. Most physicians recommended that the first follow-up visit occur within 2 weeks for the GAD (79.4%) and the MDE (82.5%) clinical-scenario patients. Physicians were more likely to identify themselves rather than patients and the health care system as barriers to providing optimal care to the GAD (39.4%) and the MDE (39.8%) clinical-scenario patients. CONCLUSION: Most family physicians recommend immediate treatment and early follow-up for patients presenting with symptoms of GAD or MDE. Physician-related barriers outweigh patient and health system barriers to providing optimal care to patients with common psychiatric disorders. PMID- 22423030 TI - Applying justice and commitment constructs to patient-health care provider relationships. AB - OBJECTIVE: To examine patients' experiences of fairness and commitment in the health care context with an emphasis on primary care providers. DESIGN: Qualitative, semistructured, individual interviews were used to gather evidence for the justice and commitment frameworks across a variety of settings with an emphasis on primary care relationships. SETTING: Rural, urban, and semiurban communities in Nova Scotia. PARTICIPANTS: Patients (ages ranged from 19 to 80 years) with varying health care needs and views on their health care providers. METHODS: Participants were recruited through a variety of means, including posters in practice settings and communication with administrative staff in clinics. Individual interviews were conducted and were audiotaped and transcribed verbatim. A modified grounded theory approach was used to interpret the data. MAIN FINDINGS: Current conceptualizations of justice (distributive, procedural, interpersonal, informational) and commitment (affective, normative, continuance) capture important elements of patient-health care provider interactions and relationships. CONCLUSION: Justice and commitment frameworks developed in other contexts encompass important dimensions of the patient-health care provider relationship with some exceptions. For example, commonly understood subcomponents of justice (eg, procedural consistency) might require modification to apply fully to patient-health care provider relationships. Moreover, the results suggest that factors outside the patient-health care provider dyad (eg, familial connections) might also influence the patient's commitment to his or her health care provider. PMID- 22423031 TI - Just the FACS or stalking the elusive circulating endothelial progenitor cell. PMID- 22423032 TI - MiRrored regulation of KLF2 and KLF4. PMID- 22423033 TI - Vascular dysfunction even after 20 years in children exposed to passive smoking: alarming results and need for awareness. PMID- 22423034 TI - Role of adenosine in response to vascular inflammation. PMID- 22423035 TI - Adenosine signaling: good or bad in erectile function? AB - The erectile status of penile tissue is governed largely by the tone of cavernosal smooth muscle cells, which is determined by the balance of vascular relaxants and constrictors. Vascular relaxants play a key role in regulating the tone of cavernosal smooth muscle and thus the initiation and maintenance of penile erection. Early studies drew attention to the potential role of adenosine signaling in this process. However, the serendipitous discovery of the effect of sildenafil on erectile physiology drew more attention toward nitric oxide (NO) as a vasodilator in the process of penile erection, and a recently discovered, unexpected erectile phenotype of adenosine deaminase-deficient mice reemphasizes the importance of adenosine as a key regulatory of erectile status. Adenosine, like NO, is a potent and short-lived vasorelaxant that functions via cyclic nucleotide second messenger signaling to promote smooth muscle relaxation. Recent studies reviewed here show that adenosine functions to relax the corpus cavernosum and promote penile erection. Excess adenosine in penile tissue contributes to the disorder called priapism, and impaired adenosine signaling is associated with erectile dysfunction. More recent research summarized in this review reveals that adenosine functions as a key endogenous vasodilator in the initiation and maintenance of normal penile erection. This new insight highlights adenosine signaling pathways operating in penile tissue as significant therapeutic targets for the treatment of erectile disorders. PMID- 22423036 TI - Regulation of cardiovascular development by adenosine and adenosine-mediated embryo protection. AB - Few signaling molecules have as much potential to influence the developing mammal as the nucleoside adenosine. Adenosine levels increase rapidly with tissue hypoxia and inflammation. Adenosine antagonists include the methylxanthines caffeine and theophylline. The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (A1AR, A2aAR, A2bAR, and A3AR). We examined how adenosine acts via A1ARs to influence embryo development. Transgenic mice were studied along with embryo cultures. Embryos lacking A1ARs were markedly growth retarded following intrauterine hypoxia exposure. Studies of mice selectively lacking A1AR in the heart identify the heart as a key site of adenosine's embryo-protective effects. Studies of isolated embryos showed that adenosine plays a key role in modulating embryo cardiac function, especially in the setting of hypoxia. When pregnant mice were treated during embryogenesis with the adenosine antagonist caffeine, adult mice had abnormal heart function. Adenosine acts via A1ARs to play an essential role in protecting the embryo against intrauterine stress, and adenosine antagonists, including caffeine, may be an unwelcome exposure for the embryo. PMID- 22423037 TI - Regulation of neutrophil function by adenosine. AB - Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all 4 adenosine receptor subtypes. At low concentrations, adenosine can act via the A(1) and A(3) adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A(2A) and A(2B) receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and noninfectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function. PMID- 22423038 TI - Regulation of macrophage function by adenosine. AB - Following its release into the extracellular space in response to metabolic disturbances, the endogenous nucleoside adenosine exerts a range of immunomodulatory effects and cells of the mononuclear phagocyte system are among its major targets. Adenosine governs mononuclear phagocyte functions via 4 G protein-coupled cell membrane receptors, which are denoted A(1), A(2A), A(2B), and A(3) receptors. Adenosine promotes osteoclast differentiation via A(1) receptors and alters monocyte to dendritic cell differentiation through A(2B) receptors. Adenosine downregulates classical macrophage activation mainly through A(2A) receptors. In contrast A(2B) receptor activation upregulates alternative macrophage activation. Adenosine promotes angiogenesis, which is mediated by inducing the production of vascular endothelial growth factor by mononuclear phagocytes through A(2A), A(2B), and A(3) receptors. By regulating mononuclear phagocyte function adenosine dictates the course of inflammatory and vascular diseases and cancer. PMID- 22423039 TI - A2 adenosine receptors and vascular pathologies. AB - Cardiovascular disease, a leading cause of death and morbidity, is regulated, among various factors, by inflammation. The level of the metabolite adenosine is augmented under stress, including inflammatory, hypoxic, or injurious events. Adenosine has been shown to affect various physiological and pathological processes, largely through 1 or more of its 4 types of receptors: the A1 and A3 adenylyl cyclase inhibitory receptors and the A2A and A2B adenylyl cyclase stimulatory receptors. This article focuses on reviewing common and distinct effects of the 2 A2-type adenosine receptors on vascular disease and the mechanisms involved. Understanding the pathogenesis of vascular disease mediated by these receptors is important to the development of therapeutics and to the prevention and management of disease. PMID- 22423040 TI - Regulation of foam cells by adenosine. AB - Macrophages rely on reverse cholesterol transport mechanisms to rid themselves of excess cholesterol. By reducing accumulation of cholesterol in the artery wall, reverse cholesterol transport slows or prevents development of atherosclerosis. In stable macrophages, efflux mechanisms balance influx mechanisms, and accumulating lipids do not overwhelm the cell. Under atherogenic conditions, inflow of cholesterol exceeds outflow, and the cell is ultimately transformed into a foam cell, the prototypical cell in the atherosclerotic plaque. Adenosine is an endogenous purine nucleoside released from metabolically active cells by facilitated diffusion and generated extracellularly from adenine nucleotides. Under stress conditions, such as hypoxia, a depressed cellular energy state leads to an acute increase in the extracellular concentration of adenosine. Extracellular adenosine interacts with 1 or more of a family of G protein-coupled receptors (A(1), A(2A), A(2B), and A(3)) to modulate the function of nearly all cells and tissues. Modulation of adenosine signaling participates in regulation of reverse cholesterol transport. Of particular note for the development of atherosclerosis, activation of A(2A) receptors dramatically inhibits inflammation and protects against tissue injury. Potent antiatherosclerotic effects of A(2A) receptor stimulation include inhibition of macrophage foam cell transformation and upregulation of the reverse cholesterol transport proteins cholesterol 27 hydroxylase and ATP binding cassette transporter A1. Thus, A(2A) receptor agonists may correct or prevent the adverse effects of inflammatory processes on cellular cholesterol homeostasis. This review focuses on the importance of extracellular adenosine acting at specific receptors as a regulatory mechanism to control the formation of foam cells under conditions of lipid loading. PMID- 22423042 TI - Role of cystic fibrosis transmembrane conductance regulator in patients with chronic sinopulmonary disease. AB - BACKGROUND: Previous studies report a high frequency of mutations in the cystic fibrosis (CF) transmembrane conductance regulator gene (CFTR) in patients with idiopathic bronchiectasis. However, most studies have based their findings on preselected patient groups or have performed limited testing for CF transmembrane conductance regulator (CFTR) dysfunction. The objective of our study was to evaluate the prevalence of CFTR gene mutations and/or CFTR-related ion channel abnormalities among subjects with idiopathic chronic sinopulmonary disease and the prevalence of CF or a CFTR-related disorder in this population. METHODS: We evaluated 72 prospectively enrolled patients from 1995 to 2005 at the Hospital for Sick Children and St. Michael's Hospital with idiopathic chronic sinopulmonary disease for evidence of CFTR-mediated abnormalities. We performed CFTR genotyping and assessed CFTR function using sweat testing and nasal potential difference testing. The results were compared with data from healthy control subjects, CF heterozygotes, and patients with CF. RESULTS: The CFTR functional tests in idiopathic sinopulmonary patients showed a continuous spectrum, ranging from normal to values typically seen in individuals with CF. Forty-eight patients (66%) demonstrated CFTR mutations and/or abnormalities of CFTR function. Twenty-two (31%) fulfilled criteria for a diagnosis of CF and 26 (36%) for a CFTR-related disorder with a strong female preponderance. Functional tests, more than genotyping, were instrumental in establishing a CF diagnosis. Clinical features failed to distinguish subjects with CF from those with CFTR related or idiopathic disease. CONCLUSIONS: The high prevalence of CF and CFTR dysfunction among patients with idiopathic chronic sinopulmonary disease underscores the need for extensive diagnostic evaluation for CF. PMID- 22423043 TI - Encouraging pulmonary outcome for surviving, neurologically intact, extremely premature infants in the postsurfactant era. AB - OBJECTIVE: The aim of this study was to determine the long-term pulmonary outcome of extreme prematurity at a single tertiary-care center from 1997 to 2001 in the postsurfactant era. METHODS: We assessed symptoms, exhaled nitric oxide, spirometry, methacholine challenge (provocative concentration of methacholine required to decrease FEV1 by 20% [PC(20)]), lung volumes, diffusion, and cardiopulmonary exercise tolerance. RESULTS: Of 279 infants born, 192 survived to discharge, and 79 of these developed bronchopulmonary dysplasia (BPD) (65 mild, 12 moderate, two severe). We studied a subgroup of 53 neurologically intact preterm subjects aged 10 +/- 1.5 years (28 with BPD [born, 26.2 +/- 1.4 weeks; birth weight, 821 +/- 164 g] and 25 without BPD [born, 27.2 +/- 1 weeks; birth weight, 1,050 +/- 181 g]) and compared them with 23 term control subjects. Of the BPD cases, 21 were mild, seven were moderate, and none was severe; 77.4% of subjects received antenatal steroids, and 83% received postnatal surfactant. Sixty percent of the preterm subjects wheezed at age < 2 years compared with 13% of the control subjects (P < .001), but only 13% wheezed in the past year compared with 0% of control subjects (not significant). For preterm and control subjects, respectively (mean +/- SD), FEV1 % predicted was 85% +/- 10% and 94% +/ 10% (P < .001), with limited reversibility; residual volume/total lung capacity was 29.3% +/- 5.5% and 25% +/- 8% (P < .05); diffusing capacity/alveolar volume was 89.6% +/- 9.2% and 97% +/- 10% (P < .005); and PC(20) was 6.5 +/- 5.8 mg/mL and 11.7 +/- 5.5 mg/mL (P < .001). PC(20) was < 4 mg/mL in 49% of preterm subjects despite normal exhaled nitric oxide. Most measurements were similar in premature subjects with and without BPD. Peak oxygen consumption and breathing reserve were normal, but % predicted maximal load (measured in Watts) was 69% +/- 15% for subjects with BPD compared with 88% +/- 23% for subjects without and 86% +/- 20% for control subjects (P < .01). CONCLUSIONS: Pulmonary outcome was encouraging at mid-childhood for neurologically intact survivors in the postsurfactant era. Despite mechanical ventilation and oxygen therapy, most had no or mild BPD. Changes found probably reflect the hypoplastic lungs of prematurity. PMID- 22423044 TI - Industrial methodology for process verification in research (IMPROVER): toward systems biology verification. AB - MOTIVATION: Analyses and algorithmic predictions based on high-throughput data are essential for the success of systems biology in academic and industrial settings. Organizations, such as companies and academic consortia, conduct large multi-year scientific studies that entail the collection and analysis of thousands of individual experiments, often over many physical sites and with internal and outsourced components. To extract maximum value, the interested parties need to verify the accuracy and reproducibility of data and methods before the initiation of such large multi-year studies. However, systematic and well-established verification procedures do not exist for automated collection and analysis workflows in systems biology which could lead to inaccurate conclusions. RESULTS: We present here, a review of the current state of systems biology verification and a detailed methodology to address its shortcomings. This methodology named 'Industrial Methodology for Process Verification in Research' or IMPROVER, consists on evaluating a research program by dividing a workflow into smaller building blocks that are individually verified. The verification of each building block can be done internally by members of the research program or externally by 'crowd-sourcing' to an interested community. www.sbvimprover.com IMPLEMENTATION: This methodology could become the preferred choice to verify systems biology research workflows that are becoming increasingly complex and sophisticated in industrial and academic settings. PMID- 22423045 TI - The Rhox5 homeobox gene regulates the region-specific expression of its paralogs in the rodent epididymis. AB - The mechanisms by which the region-specific expression patterns of clustered genes evolve are poorly understood. The epididymis is an ideal organ to examine this, as it is a highly segmented tissue that differs significantly in structure between closely related species. Here we examined this issue through analysis of the rapidly evolving X-linked reproductive homeobox (Rhox) gene cluster, the largest known homeobox gene cluster in metazoans. In the mouse, we found that most Rhox genes are expressed primarily in the caput region of the epididymis, a site where sperm mature and begin acquiring forward motility. This region specific expression pattern depends, in part, on the founding member of the Rhox cluster--Rhox5--as targeted mutation of Rhox5 greatly diminishes the expression of several other family members in the caput region. In the rat, Rhox5 expression switches from the caput to the site of sperm storage: the cauda. All Rhox genes under the control of Rhox5 in the mouse epididymis display a concomitant change in their regional expression in the rat epididymis. Our results lead us to propose that widespread changes in the region-specific expression pattern of genes over evolutionary time can be the result of alterations of one or only a few master regulatory genes. PMID- 22423046 TI - Wild-derived inbred mice no longer ART-resistant. PMID- 22423047 TI - Differential and gonad stage-dependent roles of kisspeptin1 and kisspeptin2 in reproduction in the modern teleosts, morone species. AB - Kisspeptin is an important regulator of reproduction in many vertebrates. The involvement of the two kisspeptins, Kiss1 and Kiss2, and their receptors, Gpr54-1 and Gpr54-2, in controlling reproduction was studied in the brains of the modern teleosts, striped and hybrid basses. In situ hybridization and laser capture microdissection followed by quantitative RT (QRT)-PCR detected coexpression of kiss1 and kiss2 in the hypothalamic nucleus of the lateral recess. Neurons expressing gpr54-1 and gpr54-2 were detected in several brain regions. In the preoptic area, gpr54-2 was colocalized in GnRH1 neurons while gpr54-1 was expressed in cells attached to GnRH1 fibers, indicating two different modes of GnRH1 regulation. The expression of all four genes was measured in the brains of males and females at different life stages using QRT-PCR. The levels of kiss1 and gpr54-1 mRNA, the latter being expressed in minute levels, were consistently lower than those of kiss2 and gpr54-2. While neither gene's expression increased at prepuberty, all were dramatically elevated in mature females. The levels of kiss2 mRNA increased also in mature males. Kiss1 peptide was less potent than Kiss2 in elevating plasma luteinizing hormone levels and in up-regulating gnrh1 and gpr54-2 expression in prepubertal hybrid bass in vivo. In contrast, during recrudescence, Kiss1 was more potent than Kiss2 in inducing luteinizing hormone release, and Kiss2 down-regulated gnrh1 and gpr54-2 expression. This is the first report in fish to demonstrate the alternating actions and the importance of both neuropeptides for reproduction. The organization of the kisspeptin system suggests a transitional evolutionary state between early to late evolving vertebrates. PMID- 22423048 TI - Early expression of pregnancy-specific glycoprotein 22 (PSG22) by trophoblast cells modulates angiogenesis in mice. AB - Mouse and human pregnancy-specific glycoproteins (PSG) are known to exert immunomodulatory functions during pregnancy by inducing maternal leukocytes to secrete anti-inflammatory cytokines that promote a tolerogenic decidual microenvironment. Many such anti-inflammatory mediators also function as proangiogenic factors, which, along with the reported association of murine PSG with the uterine vasculature, suggest that PSG may contribute to the vascular adaptations necessary for successful implantation and placental development. We observed that PSG22 is strongly expressed around the embryonic crypt on Gestation Day 5.5, indicating that trophoblast giant cells are the main source of PSG22 during the early stages of pregnancy. PSG22 treatment up-regulated the secretion of transforming growth factor beta 1 and vascular endothelial growth factor A (VEGFA) in murine macrophages, uterine dendritic cells, and natural killer cells. A possible role of PSGs in uteroplacental angiogenesis is further supported by the finding that incubation of endothelial cells with PSG22 resulted in the formation of tubes in the presence and absence of VEGFA. We determined that PSG22, like human PSG1 and murine PSG17 and PSG23, binds to the heparan sulfate chains in syndecans. Therefore, our findings indicate that despite the independent evolution and expansion of human and rodent PSG, members in both families have conserved functions that include their ability to induce anti inflammatory cytokines and proangiogenic factors as well as to induce the formation of capillary structures by endothelial cells. In summary, our results indicate that PSG22, the most abundant PSG expressed during mouse early pregnancy, is likely a major contributor to the establishment of a successful pregnancy. PMID- 22423049 TI - Fibroblast growth factor 8b causes progressive stromal and epithelial changes in the epididymis and degeneration of the seminiferous epithelium in the testis of transgenic mice. AB - Transgenic (Tg) mice expressing human fibroblast growth factor 8b (FGF8-b) under the probasin promoter (Tg [Pbsn-FGF8] L2-L5Elo; hereafter referred to as FGF8-b Tg) were shown to produce FGF8-b at high levels in the prostate and epididymis and at lower levels in the testis. The present study examined the effects of FGF8 b expression on the epididymis and testis. In old (age, >6 mo) FGF8-b-Tg mice, epididymides were frequently enlarged, with epithelial and stromal hypercellularity progressing upon aging to epithelial dysplasia and malignant transformation of stroma. In addition, oligospermia, dilatation of the duct, and inflammation were frequently observed in the epididymides. In association with the epididymal changes, some FGF8-b-Tg mice presented a degenerative seminiferous epithelium of the testis. Consistent with this observation, infertile males were found in two FGF8-b-Tg mouse lines. Masson trichrome staining and immunohistochemical analysis of smooth muscle actin, laminin, and androgen receptor revealed that changes in the epididymal stroma closely resembled those previously found in the prostates of the FGF8-b-Tg mice. Genes previously found to be upregulated in the prostate of FGF8-b-Tg mice, such as osteopontin (Spp1) connective tissue growth factor (Ctgf), apolipoprotein D (Apod), and FGF receptor 1c (Fgfr1-c), were also upregulated in the epididymides, suggesting that similar molecular mechanisms were active in both tissues. However, unlike in the prostate, the changes in the epididymal epithelium of the FGF8-b-Tg mice did not progress into invasive carcinoma. The results suggest that prolonged and enhanced FGF signaling induces dramatic changes in the epididymis and testis that lead to infertility in a portion of the FGF8-b-Tg males. PMID- 22423050 TI - Neuroendocrine control of FSH secretion: IV. Hypothalamic control of pituitary FSH-regulatory proteins and their relationship to changes in FSH synthesis and secretion. AB - The current dogma is that the differential regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and secretion is modulated by gonadotropin-releasing hormone (GnRH) pulse frequency and by changes in inhibins, activins, and follistatins both at the pituitary and at the peripheral level. To date no studies have looked at the overlapping function of these regulators in a combined setting. We tested the hypothesis that changes in GnRH pulse frequency alter the relative abundance of these regulators at the pituitary and peripheral levels in a manner consistent with changes in pituitary and circulating concentrations of FSH; that is, an increase in FSH will be accompanied by increased stimulatory input (activin) and/or reduced follistatin and inhibin. Ovariectomized ewes were subjected to a combination hypothalamic pituitary disconnection (HPD)-hypophyseal portal blood collection procedure. Hypophyseal portal and jugular blood samples were collected for a 6-h period from non-HPD ewes, HPD ewes, or HPD ewes administered GnRH hourly or every 3 h for 4 days. In the absence of endogenous hypothalamic and ovarian hormones that regulate gonadotropin secretion, 3-hourly pulses of GnRH increased pituitary content of FSH more than hourly GnRH, although these differences were not evident in the peripheral circulation. The results failed to support the hypothesis in that the preferential increase of pituitary content of FSH by the lower GnRH pulse frequency could be explained by changes in the pituitary content of inhibin A, follistatin, or activin B. Perhaps the effects of GnRH pulse frequency on FSH is due to changes in the balance of free versus bound amounts of these FSH regulatory proteins or to the involvement of other regulators not monitored in this study. PMID- 22423051 TI - Effect of the anti-oxidant tempol on fetal growth in a mouse model of fetal growth restriction. AB - Fetal growth restriction (FGR) greatly increases the risk of perinatal morbidity and mortality and is associated with increased uterine artery resistance and levels of oxidative stress. There are currently no available treatments for this condition. The hypothesis that the antioxidant 4-hydroxy-2,2,6,6 tetramethylpiperidin-1-oxyl (Tempol) would improve uterine artery function and rescue fetal growth was tested in a mouse model of FGR, using the endothelial nitric oxide synthase knockout mouse (Nos3(-/-)). Pregnant Nos3(-/-) and control C57BL/6J mice were treated with the superoxide dismutase-mimetic Tempol (1 mmol/L) or vehicle from Gestational Day 12.5 to 18.5. Tempol treatment significantly increased pup weight (P < 0.05) and crown-rump length (P < 0.01) in C57BL/6J and Nos3(-/-) mice. Uterine artery resistance was increased in Nos3(-/-) mice (P < 0.05); Tempol significantly increased end diastolic velocity in Nos3(-/ ) mice (P < 0.05). Superoxide production in uterine arteries did not differ between C57BL/6J and Nos3(-/-) mice but was significantly increased in placentas from Nos3(-/-) mice (P < 0.05). This was not reduced by Tempol treatment. Placental System A activity was reduced in Nos3(-/-) mice (P < 0.01); this was not improved by treatment with Tempol. Treatment of Nos3(-/-) mice with Tempol, however, was associated with reduced vascular density in the placental bed (P < 0.05). This study demonstrated that treatment with the antioxidant Tempol is able to improve fetal growth in a mouse model of FGR. This was associated with an increase in uterine artery blood flow velocity but not an improvement in uterine artery function or placental System A activity. PMID- 22423052 TI - Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice. AB - To understand mechanisms underlying acquisition of pluripotency, it is critical to identify cells that can be converted to pluripotent stem cells. For this purpose, we focused on unipotent primordial germ cells (PGCs), which can be reprogrammed into pluripotent embryonic germ (EG) cells under defined conditions. Treatment of PGCs with combinations of signaling inhibitors, including inhibitors of MAP2K (MEK), GSK3B (GSK-3beta), and TGFB (TGFbeta) type 1 receptors, induced cells to enter a pluripotent state at a high frequency (12.1%) by Day 10 of culture. When we employed fluorescence-activated cell sorting to monitor conversion of candidate cells to a pluripotent state, we observed a cell cycle shift to S phase, indicating enrichment of pluripotent cells, during the early phase of EG formation. Transcriptome analysis revealed that PGCs retained expression of some pluripotent stem cell-associated genes, such as Pou5f1 and Sox2, during EG cell formation. On the other hand, PGCs lost their germ lineage characteristics and acquired expression of pluripotent stem cell markers, such as Klf4 and Eras. The overall gene expression profiles revealed by this system provide novel insight into how pluripotency is acquired in germ-committed cells. PMID- 22423053 TI - Contribution of maternal NODAL to term pregnancy. PMID- 22423054 TI - Cell-specific and temporal aspects of gene expression in the chicken oviduct at different stages of the laying cycle. AB - Egg formation and embryonic development occur as the yolk passes through the magnum, isthmus, and shell gland of the oviduct before oviposition in hens. The present study identified candidate genes associated with secretory function of the chicken oviduct after ovulation and contributing to egg formation and oviposition. Hens (n = 5 per time point) were euthanized to recover the reproductive tract when the egg was in the magnum (3 h after ovulation) and the shell gland (20 h after ovulation). Total RNA was extracted from each segment of the oviducts and subjected to Affymetrix chicken GeneChip analysis. Quantitative PCR and in situ hybridization analyses of selected genes confirmed the validity of the gene expression patterns detected using microarray analysis. In particular, ACP1, CALB1, CYP26A1, PENK, RCAN1 and SPP1 expression increased significantly in the shell gland between 3 h and 20 h postovulation, whereas only RCNA1 expression increased significantly in the magnum between 3 h and 20 h postovulation. Results of the high-throughput analysis revealed cell-specific and temporal changes in gene expression in the oviduct at 3 h and 20 h postovulation in laying hens provide novel insight into changes at the molecular and cellular levels of candidate genes related to formation of the egg and oviposition. PMID- 22423055 TI - Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macular oedema. AB - PURPOSE: To determine the relationship between retinal ischaemia and the presence of macular oedema (DMO) in patients with diabetic retinopathy (DR) using ultra widefield fluorescein angiography (UWFA) imaging. METHODS: A retrospective review of 122 eyes of 70 treatment-naive diabetic patients who underwent diagnostic UWFA using the Optos 200Tx imaging system. Two independent, masked graders quantified the area of retinal ischaemia. Based on clinical examination and optical coherence tomography (OCT), each patient was given a binary classification as either having DMO or no DMO. McNemar's test (with Yates' correction as indicated) and a two-sample test of proportions were used to determine the relationship between DMO and ischaemia for binary and proportional data, respectively. Linear and logistic models were constructed using generalised estimating equations to test relationships between independent variables, covariates and outcomes while controlling for inter-eye correlation, age, gender, haemoglobin A1c, mean arterial pressure and dependence on insulin. RESULTS: Seventy-six eyes (62%) exhibited areas of retinal ischaemia. There was a significant direct correlation between DMO and peripheral retinal ischaemia as seen on UWFA (p<0.001). In addition, patients with retinal ischaemia had 3.75 times increased odds of having DMO compared with those without retinal ischaemia (CI 1.26 to 11.13, p<0.02). CONCLUSION: Retinal ischaemia is significantly correlated with DMO in treatment naive patients with DR. UWFA is a useful tool for detecting peripheral retinal ischaemia, which may have direct implications in the diagnosis, follow-up and treatment such as targeted peripheral photocoagulation. PMID- 22423056 TI - Sex differences in outcomes following isolated coronary artery bypass graft surgery in Australian patients: analysis of the Australasian Society of Cardiac and Thoracic Surgeons cardiac surgery database. AB - OBJECTIVES: Women undergoing isolated coronary artery bypass graft (CABG) surgery have been previously shown to be at an independently increased risk for post operative morbidity and mortality. The current study evaluates the impact of sex as an independent risk factor for early and late morbidity and mortality following isolated CABG surgery. METHODS: Data obtained between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program was retrospectively analysed. Demographic, operative data and post-operative complications were compared between male and female patients using chi-square and t-tests. Long-term survival analysis was performed using Kaplan-Meier survival curves and the log-rank test. Independent risk factors for short- and long-term mortality were identified using binary logistic and Cox regression, respectively. RESULTS: CABG surgery was undertaken in 21 534 patients at 18 Australian institutions; 22.2% were female. Female patients were generally older (mean age, 68 vs. 65 years, P < 0.001) and presented more often with congestive heart failure (P < 0.001), hypertension (P < 0.001), diabetes mellitus (P < 0.001) and cerebrovascular disease (P < 0.001). Women demonstrated a greater 30-day mortality (2.2% vs. 1.5%, P < 0.001) on univariate analysis but not on multivariate analysis (P = 0.638). Similarly, women demonstrated a greater late mortality than men on univariate analysis (P = 0.006) but not on multivariate analysis (P = 0.093). Women had a decreased risk of early complications including new renal failure (P = 0.001) and deep sternal wound infection (P = 0.017) but were more likely to require red blood cell transfusion (P < 0.001). CONCLUSIONS: Female patients undergoing isolated CABG surgery have a greater 30-day mortality which may be accounted for by a poorer pre-operative risk factor profile. Further investigation is required into the reasons for differential outcome after CABG based on sex. PMID- 22423057 TI - Competitive flow and arterial graft a word of caution. PMID- 22423058 TI - Transcranial Doppler-detected cerebral embolic load during transcatheter aortic valve implantation. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) is an alternative to surgery for high-risk patients with severe aortic valve stenosis. Periprocedural stroke is reported at an incidence up to 10%. Magnetic resonance imaging studies have identified new onset of clinically silent ischaemic cerebral lesions more frequently (68-84%). So far, few data are available about cerebral embolism during TAVI. The aim of this study was to determine the frequency of high intensity transient signals (HITS) and to explore differences in the HITS pattern between transfemoral and transapical access and between self-expanding (SE) and balloon-expandable (BE) deployment technique. METHODS: Transcranial Doppler (TCD) ultrasound recordings of 44 patients undergoing TAVI (age 78 +/- 6 years; logistic EuroSCORE 28 +/- 15%; transfemoral access, n = 32; transapical access, n = 12; SE, n = 27; BE, n = 17) were analysed for HITS during the following intervals: (i) instrumentation prior to valvuloplasty, (ii) balloon valvuloplasty, (iii) prosthesis deployment (DP) and (iv) post-implantation (PI) including any re-dilatation episodes. The total procedural load of HITS and HITS frequency in procedural intervals were compared between different access routes and DP techniques. Periprocedural neurocognitive impairment was assessed clinically and by the confusion assessment method (CAM) prior to TAVI and on post procedural days 1 and 4-6. RESULTS: TCD recordings demonstrated the occurrence of HITS in all patients. DP was associated with the highest load of HITS. Access route did not significantly influence the total burden of periprocedural HITS. During procedures using the SE type, a slightly larger total load of HITS was observed than with the BE type (P = 0.024). This was mainly due to more HITS during the DP (P = 0.027) and the PI interval (P = 0.002). No incidence of delirium was detected by CAM ratings. Two patients suffered a new onset of stroke within the 2 weeks following the procedure. In-hospital death and 30-day mortality were 0/44. CONCLUSIONS: HITS are observed during all procedural intervals in TAVI. The embolic events appear to peak during DP. In our series, the overall cerebral embolic load did not differ between the transfemoral and the transapical access route. TCD monitoring in TAVI is useful to identify periods and manipulations associated with an increased cerebral embolic load and may help to further enhance the safety of this procedure. PMID- 22423059 TI - Action point: intraoperative lymph node staging. PMID- 22423060 TI - False-positivity of mediastinal lymph nodes has negative effect on survival in potentially resectable non-small cell lung cancer. AB - OBJECTIVES: It has been shown that increased metabolic activity of primary tumour has a negative effect on survival in non-small cell lung cancer (NSCLC) staged with positron emission tomography integrated computed tomography (PET/CT). We hypothesized that an increased metabolic activity of mediastinal lymph nodes would have worse survival even if it is false. METHODS: Three hundred and twenty eight consecutive patients with NSCLC histology were imaged with PET/CT within 90 days of surgery between September 2005 and March 2009. Patients who had neoadjuvant chemotherapy (n = 22), patients with prior history of NSCLC (n = 9) or other malignancies within 5 years (n = 11) were excluded from the study. Patients with negative mediastinoscopy underwent resection. Pathological results were revised according to the seventh tumor-node-metastasis staging system. Kaplan-Meier test was used for survival. Log-rank and Cox analyses were used for comparisons. RESULTS: A total of 286 patients (262 male; mean age: 58.5 years) were evaluated. There were 22 (6.7%) operative deaths and none of the patients were lost to follow-up. The median follow-up in the remaining 264 patients was 26 months (range, 2-61 months). Tumour size, nodal spread and stage were all strongly associated with survival from NSCLC (P < 0.001). There were 63 true positive, 65 false-positive (FP), 152 true-negative (TN) and six false-negative findings on mediastinal staging after PET/CT. The maximum standardized uptake value of primary tumour was significantly higher in FP patients than in TN patients (P = 0.012). After excluding pN2-positive patients, TN patients had better survival than FP patients (P = 0.006). Multivariate analysis showed that false-positivity of mediastinal lymph nodes was independently associated with worse survival (hazard ratio = 0.63; P = 0.02). There were 146 patients with pT1 4, pN0 treated with R0 surgical resection. Disease-free survival and overall survival were also significantly better for TN patients in completely resected group (P = 0.009 versus 0.016). CONCLUSIONS: We have shown that false-positivity of mediastinal lymph nodes had yielded worse survival in surgically staged or resected NSCLC patients staged with PET/CT. This result may help to allocate patients with potentially poor prognosis for considered additional therapy. PMID- 22423061 TI - Pulmonary artery banding as 'open end' palliation of systemic right ventricles: an interim analysis. AB - OBJECTIVES: A morphological right ventricle (RV) is not ideally suited for the long-term maintenance of the systemic circulation. The aim of this analysis was to evaluate the intermediate results and outcome of pulmonary artery banding (PAB) in an open-ended strategy. METHODS: This is a retrospective review of patients with systemic RVs who had undergone PAB in our institution from April 1985 to January 2011. PAB was placed in 5 patients late after the Senning operation and in 15 patients with corrected transposition; of whom, 6 had a large ventricular septal defect. RESULTS: PAB was performed at a median age of 4.3 years (range: 0.9-14.9), median follow-up of 86 months (range: 0.5-379). All 20 patients are alive and are being followed up. Tricuspid regurgitation (TR), RV function and dilation showed no deterioration after banding (P = 0.9). Ninety per cent (18/20) have adequate ongoing palliation with PAB. One patient underwent a double-switch operation and one received an additional bidirectional Glenn shunt. A dilatable band was redilated with improvement in percutaneous saturation and in another the procedure was abandoned due to development of transient atrioventricular block. Functional class remained either unchanged or improved. CONCLUSIONS: PAB was performed with no mortality and low morbidity. PAB in these heterogeneous patients provides true 'open ended palliation' by allowing left ventricular training in those going for anatomical repair, stabilizing or improving RV function and TR in others, thereby delaying surgery. It can also be left in place as long-term palliation. The addition of a dilatable band allows manipulation of pulmonary flows, but longer follow-up is required to provide data on best management strategies for these complex patients. PMID- 22423062 TI - Modulation of monocyte chemoattractant protein-1 expression by ischaemic preconditioning in a lung autotransplant model. AB - OBJECTIVES: Monocyte chemoattractant protein-1 (MCP-1) is believed to play a crucial role in lung ischaemia-reperfusion injury (LIRI). Ischaemic preconditioning (IP) has been shown to protect several organs from ischaemia reperfusion (IR) injury, although less is known about IP's effect on MCP-1 modulation. The objective of this study was to investigate IP's effect on MCP-1 expression in lung tissue and its relationship with oxidative stress and proinflammatory cytokine production in an experimental LIRI model. METHODS: Two groups (IP and control groups) of seven large white pigs underwent a lung autotransplant (left pneumonectomy, ex situ superior lobectomy and lower lobe reimplantation). Before pneumonectomy was performed in the study group, IP was induced with two cycles of 5 min of left pulmonary artery occlusion with a 5 min interval of reperfusion between the two occlusions. Blood samples and lung biopsies were obtained at prepneumonectomy (PPn), at prereperfusion (PRp) and up to 30 min after reperfusion of the implanted lobe (Rp-10' and Rp-30'). Haemodynamic and blood-gas measurements, evaluation of oxidative stress in lung tissue and MCP-1, tumour necrosis factor-alpha (TNF-alpha) and IL-1 protein and mRNA measurements in lung tissue were performed. Nonparametric tests were used to compare differences between groups. Data are expressed as mean +/- SEM. RESULTS: In control lungs, MCP-1 protein levels were found to be higher at PRp, Rp-10' and Rp-30' than at PPn (0.59 +/- 0.1 vs. 0.21 +/- 0.05, 0.47 +/- 0.01 vs. 0.21 +/- 0.05 and 0.56 +/- 0.01 vs. 0.21 +/- 0.05, respectively; P < 0.05). These differences were not evident in the IP group. MCP-1 levels at PRp, Rp-10' and Rp 30' were significantly higher in the control group than in the IP group (0.59 +/- 0.1 vs. 0.15 +/- 0.02, 0.47 +/- 0.01 vs. 0.13 +/- 0.01 and 0.56 +/- 0.01 vs. 0.27 +/- 0.01, respectively; P < 0.05). MCP-1, TNF-alpha and IL-1 mRNA expressions were lower at PRp, Rp-10' and Rp-30' (control vs. IP group, P < 0.05) when IP was carried out. Lipid peroxidation metabolites and myeloperoxidase activity increase in lung tissue were prevented by IP. CONCLUSIONS: In this model, LIRI induced the expression of MCP-1 and the proinflammatory proteins TNF-alpha and IL-1 in control lungs. IP significantly reduced the expression of these chemokines and cytokines. These features may explain the reduction of oxidative stress observed with IP. PMID- 22423063 TI - Intracardiac varix of the left atrium. AB - A 68-year-old female patient with a history of hyperlipidaemia and fatty liver was referred for evaluation of an incidentally detected asymptomatic cardiac mass. Computed tomographic scan imaging showed a large calcified mass in the left atrium. Echocardiography revealed a 2.4 1.5 cm, well-circumscribed, round, high echoic mass with severe calcification and low mobility attached to the lower rim of the fossa ovalis. The cardiac mass along with part of the fossa ovalis and left atrial wall were excised. Histological diagnosis was compatible with intracardiac varix. PMID- 22423064 TI - The spectrum of double-outlet right atrium including hearts with three atrioventricular valves. AB - Double-outlet right atrium (DORA) is characterized by simultaneous right atrial emptying into both ventricles. Ventriculoatrial septal malalignment is the cardinal morphological feature. Three cases are presented to depict two major types of DORA-DORA with a malaligned atrial septum and DORA with a malaligned ventricular septum. We describe two subtypes of each form of DORA: DORA with a malaligned atrial septum presents with either a common atrioventricular (AV) junction (guarded by a common AV valve) or with a single AV junction (due to the absence of the left AV junction). DORA with a malaligned ventricular septum may be associated with a right ventricle (RV) that is adequate for biventricular repair or a severely hypoplastic RV not compatible with biventricular repair. DORA with a malaligned ventricular septum is closely related to typical straddling of the tricuspid valve. Peculiarly, DORA with a malaligned ventricular septum presents three AV valves at the AV junction and is associated with an abnormal disposition of the AV conduction axis. Clear understanding of the morphology of these lesions is important in preventing a surgical misadventure at the crux of the heart. PMID- 22423065 TI - Delayed syndrome of thoracic insufficiency: a consequence of non-rigid reconstruction of a large chest wall defect. PMID- 22423066 TI - Multiple bilateral intraparenchymal pulmonary artery aneurysms. PMID- 22423067 TI - Coronary pseudoaneurysm secondary to blunt chest trauma. PMID- 22423068 TI - Penetrating chest wound with twisted steel. PMID- 22423069 TI - Left atrial appendage perforation during interventional occluder implantation. PMID- 22423070 TI - Angiofibroma in the right atrium and inferior vena cava. PMID- 22423071 TI - Results of ring annuloplasty for mitral regurgitation due to cardiomyopathy. PMID- 22423072 TI - Comparison of small and enlarged aortic roots. PMID- 22423074 TI - Post-intubation membranous trachitis after endotracheal intubation. PMID- 22423075 TI - The EuroSCORE: are we contributing to its overprediction of mortality in cardiac surgery nowadays? PMID- 22423076 TI - How important is the size of the mitral ring? PMID- 22423078 TI - Issues related to increased systemic perfusion pressure during cardiopulmonary bypass and its safety. PMID- 22423081 TI - Subtle changes in renal function are associated with differences in late survival following adult cardiac surgery. AB - OBJECTIVES: To determine the predictors of post-operative renal function following adult cardiac surgery, and to assess the influence of this on late survival. METHODS: Prospectively collected data were analysed on 8032 patients who underwent coronary artery bypass grafting, valve surgery or combined procedures from 1 January 1998 until 31 December 2008, who did not require preoperative renal replacement therapy. The estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease formula accounting for ethnicity pre-operatively, post-operatively on the fourth post operative day, and the post-operative nadir based upon the peak post-operative creatinine within 30 days of surgery. Late survival data were obtained from the UK Central Cardiac Audit Database (CCAD). Appropriate frailty analyses were conducted in R and model fit was compared using Aikaike's Information Criterion. Initial analysis intended to determine predictors of post-operative renal function including pre-operative eGFR, EuroSCORE and surgical procedure including the operative procedure and bypass time. Further analysis examined its influence on late survival. RESULTS: Median follow-up was 72 months (IQR 48-105) during which there were 904 late deaths. The most powerful predictor of the day 4 eGFR was the pre-operative eGFR but other factors contributed including increasing EuroSCORE and bypass time. The pre-operative eGFR was shown to be a strong and independent predictor of late outcome (P = 0.0001, HR 0.497 95%CI 0.434-564); however, model fit was significantly improved using the day 4 eGFR (P = 0.0001, HR 0.43 95%CI 0.385-0.482). No specific change in individual renal function was identified as a predictor of adverse late survival, and neither the pre-operative nor day 4 eGFR was predictive of the nadir of renal function. CONCLUSIONS: Subtle early changes in renal function at the time of surgery are powerful predictors of adverse late outcome and can be predicted by pre-operative renal function. PMID- 22423082 TI - Does the cardioplegic solution have an effect on early outcomes following heart transplantation? AB - OBJECTIVE: The choice of cardioplegic solution for myocardial preservation in heart transplantation (HT) remains debated. We analysed our experience with three different cardioplegic solutions in adult HT performed during past 5 years, in terms of non-immunological intraoperative biventricular graft failure (BVF) and in-hospital mortality. METHODS: A total of 133 patients underwent HT at our hospital from January 2006 to December 2010. Patients were divided into three groups, according to the solution adopted in the donor: HTK-Custodiol (n = 61), Celsior (n = 38) and St Thomas (n = 34). For each patient, solution was chosen according to surgeon's preference. RESULTS: Recipient and donor mean age was 48.2 +/- 12.7 and 43.8 +/- 13.6 years, respectively. Twenty-four patients (18.0%) were in Status 1 at the transplant. The mean ischaemic time was 187.9 +/- 52.6 min. Intraoperative BVF was observed in 18 cases (13.5%). Patients with BVF, and their respective donors, were older than the other patients (patients: 53.3 vs 47.4 years, P = 0.06; donors: 49.4 vs 42.9 years, P 0.06), and experienced significantly higher in-hospital mortality (47.3 vs 7.8%, P = 0.0001). The combination of patients aged 60 years or older with donors aged 60 years or older carried a mortality of 66.6% (6 out of 9). The three groups of patients did not differ significantly in terms of preoperative and intraoperative features and outcomes, including biventricular graft failure and death. At multivariate analysis, predictors of in-hospital death were a combination of both a recipient and a donor aged >= 60 years (OR 27.9), intraoperative BVF (OR 14.8) and previous cardiac surgery (OR 13.0). Cardioplegic solution did not predict mortality. CONCLUSIONS: We did not observe a significant effect of the kind of cardioplegic solution on the early HT outcomes. The combination between both a recipient and a donor aged >= 60 years, reoperation and BVF are strong predictors of in-hospital death. PMID- 22423083 TI - Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury. AB - Spinal injury disrupts connections between the brain and spinal cord, causing life-long paralysis. Most spinal injuries are incomplete, leaving spared neural pathways to motor neurons that initiate and coordinate movement. One therapeutic strategy to induce functional motor recovery is to harness plasticity in these spared neural pathways. Chronic intermittent hypoxia (CIH) (72 episodes per night, 7 nights) increases synaptic strength in crossed spinal synaptic pathways to phrenic motoneurons below a C2 spinal hemisection. However, CIH also causes morbidity (e.g., high blood pressure, hippocampal apoptosis), rendering it unsuitable as a therapeutic approach to chronic spinal injury. Less severe protocols of repetitive acute intermittent hypoxia may elicit plasticity without associated morbidity. Here we demonstrate that daily acute intermittent hypoxia (dAIH; 10 episodes per day, 7 d) induces motor plasticity in respiratory and nonrespiratory motor behaviors without evidence for associated morbidity. dAIH induces plasticity in spared, spinal pathways to respiratory and nonrespiratory motor neurons, improving respiratory and nonrespiratory (forelimb) motor function in rats with chronic cervical injuries. Functional improvements were persistent and were mirrored by neurochemical changes in proteins that contribute to respiratory motor plasticity after intermittent hypoxia (BDNF and TrkB) within both respiratory and nonrespiratory motor nuclei. Collectively, these studies demonstrate that repetitive acute intermittent hypoxia may be an effective and non-invasive means of improving function in multiple motor systems after chronic spinal injury. PMID- 22423084 TI - The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. AB - Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing. PMID- 22423085 TI - The cost of accumulating evidence in perceptual decision making. AB - Decision making often involves the accumulation of information over time, but acquiring information typically comes at a cost. Little is known about the cost incurred by animals and humans for acquiring additional information from sensory variables due, for instance, to attentional efforts. Through a novel integration of diffusion models and dynamic programming, we were able to estimate the cost of making additional observations per unit of time from two monkeys and six humans in a reaction time (RT) random-dot motion discrimination task. Surprisingly, we find that the cost is neither zero nor constant over time, but for the animals and humans features a brief period in which it is constant but increases thereafter. In addition, we show that our theory accurately matches the observed reaction time distributions for each stimulus condition, the time-dependent choice accuracy both conditional on stimulus strength and independent of it, and choice accuracy and mean reaction times as a function of stimulus strength. The theory also correctly predicts that urgency signals in the brain should be independent of the difficulty, or stimulus strength, at each trial. PMID- 22423086 TI - Microstimulation of the monkey superior colliculus induces pupil dilation without evoking saccades. AB - The orienting reflex is initiated by a salient stimulus and facilitates quick, appropriate action. It involves a rapid shift of the eyes, head, and attention and other physiological responses such as changes in heart rate and transient pupil dilation. The SC is a critical structure in the midbrain that selects incoming stimuli based on saliency and relevance to coordinate orienting behaviors, particularly gaze shifts, but its causal role in pupil dilation remains poorly understood in mammals. Here, we examined the role of the primate SC in the control of pupil dynamics. While requiring monkeys to keep their gaze fixed, we delivered weak electrical microstimulation to the SC, so that saccadic eye movements were not evoked. Pupil size increased transiently after microstimulation of the intermediate SC layers (SCi) and the size of evoked pupil dilation was larger on a dim versus bright background. In contrast, microstimulation of the superficial SC layers did not cause pupil dilation. Thus, the SCi is directly involved not only in shifts of gaze and attention, but also in pupil dilation as part of the orienting reflex, and the function of pupil dilation may be related to increasing visual sensitivity. The shared neural mechanisms suggest that pupil dilation may be associated with covert attention. PMID- 22423087 TI - Spike resonance properties in hippocampal O-LM cells are dependent on refractory dynamics. AB - During a wide variety of behaviors, hippocampal field potentials show significant power in the theta (4-12 Hz) frequency range and individual neurons commonly phase-lock with the 4-12 Hz field potential. The underlying cellular and network mechanisms that generate the theta rhythm, however, are poorly understood. Oriens lacunosum moleculare (O-LM) interneurons have been implicated as crucial contributors to generating theta in local hippocampal circuits because of their unique axonal projections, slow synaptic kinetics and the fact that spikes are phase-locked to theta field potentials in vivo. We performed experiments in brain slice preparations from Long-Evans rats to investigate the ability of O-LM cells to generate phase-locked spike output in response to artificial synaptic inputs. We find that O-LM cells do not respond with any preference in spike output at theta frequencies when injected with broadband artificial synaptic inputs. However, when presented with frequency-modulated inputs, O-LM spike output shows the ability to phase-lock well to theta-modulated inputs, despite their strong low-pass profiles of subthreshold membrane impedance. This result was dependent on spike refractory dynamics and could be controlled by real-time manipulation of the postspike afterhyperpolarization. Finally, we show that the ability of O-LM cells to phase-lock well to theta-rich inputs is independent of the h-current, a membrane mechanism often implicated in the generation of theta frequency activity. PMID- 22423088 TI - Early activation of microglia triggers long-lasting impairment of adult neurogenesis in the olfactory bulb. AB - Microglia, the innate immune cells of the brain, engulf and eliminate cellular debris during brain injury and disease. Recent observations have extended their roles to the healthy brain, but the functional impact of activated microglia on neural plasticity has so far been elusive. To explore this issue, we investigated the role of microglia in the function of the adult olfactory bulb network in which both sensory afferents and local microcircuits are continuously molded by the arrival of adult-born neurons. We show here that the adult olfactory bulb hosts a large population of resident microglial cells. Deafferentation of the olfactory bulb resulted in a transient activation of microglia and a concomitant reduction of adult olfactory bulb neurogenesis. One day after sensory deafferentation, microglial cells proliferate in the olfactory bulb, and their numbers peaked at day 3, and reversed at day 7 after lesion. Similar lesions performed on immunodeficient mice demonstrate that the both innate and adaptive lymphocyte responses are dispensable for the lesion-induced microglial proliferation and activation. In contrast, when mice were treated with an antiinflammatory drug to prevent microglial activation, olfactory deafferentation did not reduce adult neurogenesis, showing that activated microglial cells per se, and not the lack of sensory experience, relates to the survival of adult-born neurons. We conclude that the status of the resident microglia in the olfactory bulb is an important factor directly regulating the survival of immature adult born neurons. PMID- 22423089 TI - A neuronal model of predictive coding accounting for the mismatch negativity. AB - The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spiking excitatory and inhibitory neurons interconnected in a layered cortical architecture with distinct input, predictive, and prediction error units. A spike timing dependent learning rule, relying upon NMDA receptor synaptic transmission, allows the network to adjust its internal predictions and use a memory of the recent past inputs to anticipate on future stimuli based on transition statistics. We demonstrate that this simple architecture can account for the major empirical properties of the MMN. These include a frequency-dependent response to rare deviants, a response to unexpected repeats in alternating sequences (ABABAA...), a lack of consideration of the global sequence context, a response to sound omission, and a sensitivity of the MMN to NMDA receptor antagonists. Novel predictions are presented, and a new magnetoencephalography experiment in healthy human subjects is presented that validates our key hypothesis: the MMN results from active cortical prediction rather than passive synaptic habituation. PMID- 22423090 TI - Local visual energy mechanisms revealed by detection of global patterns. AB - A central goal of visual neuroscience is to relate the selectivity of individual neurons to perceptual judgments, such as detection of a visual pattern at low contrast or in noise. Since neurons in early areas of visual cortex carry information only about a local patch of the image, detection of global patterns must entail spatial pooling over many such neurons. Physiological methods provide access to local detection mechanisms at the single-neuron level but do not reveal how neural responses are combined to determine the perceptual decision. Behavioral methods provide access to perceptual judgments of a global stimulus but typically do not reveal the selectivity of the individual neurons underlying detection. Here we show how the existence of a nonlinearity in spatial pooling does allow properties of these early mechanisms to be estimated from behavioral responses to global stimuli. As an example, we consider detection of large-field sinusoidal gratings in noise. Based on human behavioral data, we estimate the length and width tuning of the local detection mechanisms and show that it is roughly consistent with the tuning of individual neurons in primary visual cortex of primate. We also show that a local energy model of pooling based on these estimated receptive fields is much more predictive of human judgments than competing models, such as probability summation. In addition to revealing underlying properties of early detection and spatial integration mechanisms in human cortex, our findings open a window on new methods for relating system-level perceptual judgments to neuron-level processing. PMID- 22423091 TI - Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1. AB - The Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1) is a protein complex containing the schizophrenia susceptibility factor dysbindin, which is encoded by the gene DTNBP1. However, mechanisms engaged by dysbindin defining schizophrenia susceptibility pathways have not been quantitatively elucidated. Here, we discovered prevalent and novel cellular roles of the BLOC-1 complex in neuronal cells by performing large-scale Stable Isotopic Labeling of Cells in Culture (SILAC) quantitative proteomics combined with genetic analyses in dysbindin-null mice (Mus musculus) and the genome of schizophrenia patients. We identified 24 proteins that associate with the BLOC-1 complex, many of which were altered in content/distribution in cells or tissues deficient in BLOC-1. New findings include BLOC-1 interactions with the COG complex, a Golgi apparatus tether, and antioxidant enzymes peroxiredoxins 1-2. Importantly, loci encoding eight of the 24 proteins are affected by genomic copy number variation in schizophrenia patients. Thus, our quantitative proteomic studies expand the functional repertoire of the BLOC-1 complex and provide insight into putative molecular pathways of schizophrenia susceptibility. PMID- 22423092 TI - Functional features of trans-differentiated hair cells mediated by Atoh1 reveals a primordial mechanism. AB - Evolution has transformed a simple ear with few vestibular maculae into a complex three-dimensional structure consisting of nine distinct endorgans. It is debatable whether the sensory epithelia underwent progressive segregation or emerged from distinct sensory patches. To address these uncertainties we examined the morphological and functional phenotype of trans-differentiated rat hair cells to reveal their primitive or endorgan-specific origins. Additionally, it is uncertain how Atoh1-mediated trans-differentiated hair cells trigger the processes that establish their neural ranking from the vestibulocochlear ganglia. We have demonstrated that the morphology and functional expression of ionic currents in trans-differentiated hair cells resemble those of "ancestral" hair cells, even at the lesser epithelia ridge aspects of the cochlea. The structures of stereociliary bundles of trans-differentiated hair cells were in keeping with cells in the vestibule. Functionally, the transient expression of Na+ and I(h) currents initiates and promotes evoked spikes. Additionally, Ca2+ current was expressed and underwent developmental changes. These events correlate well with the innervation of ectopic hair cells. New "born" hair cells at the abneural aspects of the cochlea are innervated by spiral ganglion neurons, presumably under the tropic influence of chemoattractants. The disappearance of inward currents coincides well with the attenuation of evoked electrical activity, remarkably recapitulating the development of hair cells. Ectopic hair cells underwent stepwise changes in the magnitude and kinetics of transducer currents. We propose that Atoh1 mediates trans-differentiation of morphological and functional "ancestral" hair cells that are likely to undergo diversification in an endorgan-specific manner. PMID- 22423093 TI - Multisensory decision-making in rats and humans. AB - We report a novel multisensory decision task designed to encourage subjects to combine information across both time and sensory modalities. We presented subjects, humans and rats, with multisensory event streams, consisting of a series of brief auditory and/or visual events. Subjects made judgments about whether the event rate of these streams was high or low. We have three main findings. First, we report that subjects can combine multisensory information over time to improve judgments about whether a fluctuating rate is high or low. Importantly, the improvement we observed was frequently close to, or better than, the statistically optimal prediction. Second, we found that subjects showed a clear multisensory enhancement both when the inputs in each modality were redundant and when they provided independent evidence about the rate. This latter finding suggests a model where event rates are estimated separately for each modality and fused at a later stage. Finally, because a similar multisensory enhancement was observed in both humans and rats, we conclude that the ability to optimally exploit sequentially presented multisensory information is not restricted to a particular species. PMID- 22423095 TI - Action of the noradrenergic system on adult-born cells is required for olfactory learning in mice. AB - We have previously shown that an experience-driven improvement in olfactory discrimination (perceptual learning) requires the addition of newborn neurons in the olfactory bulb (OB). Despite this advance, the mechanisms which govern the selective survival of newborn OB neurons following learning remain largely unknown. We propose that activity of the noradrenergic system is a critical mediator providing a top-down signal to control the selective survival of newly born cells and support perceptual learning. In adult mice, we used pharmacological means to manipulate the noradrenergic system and neurogenesis and to assess their individual and additive effects on behavioral performance on a perceptual learning task. We then looked at the effects of these manipulations on regional survival of adult-born cells in the OB. Finally, using confocal imaging and electrophysiology, we investigated potential mechanisms by which noradrenaline could directly influence the survival of adult-born cells. Consistent with our hypotheses, direct manipulation of noradrenergic transmission significantly effect on adult-born cell survival and perceptual learning. Specifically, learning required both the presence of adult-born cell and noradrenaline. Finally, we provide a mechanistic link between these effects by showing that adult-born neurons receive noradrenergic projections and are responsive to noradrenaline. Based upon these data we argue that noradrenergic transmission is a key mechanism selecting adult-born neurons during learning and demonstrate that top-down neuromodulation acts on adult-born neuron survival to modulate learning performance. PMID- 22423094 TI - Dorsoventral differences in intrinsic properties in developing CA1 pyramidal cells. AB - The dorsoventral and developmental gradients of entorhinal layer II cell grid properties correlate with their resonance properties and with their hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel current characteristics. We investigated whether such correlation existed in rat hippocampal CA1 pyramidal cells, where place fields also show spatial and temporal gradients. Resonance was absent during the first postnatal week, and emerged during the second week. Resonance was stronger in dorsal than ventral cells, in accord with HCN current properties. Resonance responded to cAMP in ventral but not in dorsal cells. The dorsoventral distribution of HCN1 and HCN2 subunits and of the auxiliary protein tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b) could account for these differences between dorsal and ventral cells. The analogous distribution of the intrinsic properties of entorhinal stellate and hippocampal cells suggests the existence of general rules of organization among structures that process complementary features of the environment. PMID- 22423096 TI - Agrin-signaling is necessary for the integration of newly generated neurons in the adult olfactory bulb. AB - In the adult forebrain, new interneurons are continuously generated and integrated into the existing circuitry of the olfactory bulb (OB). In an attempt to identify signals that regulate this synaptic integration process, we found strong expression of agrin in adult generated neuronal precursors that arrive in the olfactory bulb after their generation in the subventricular zone. While the agrin receptor components MuSK and Lrp4 were below detection level in neuron populations that represent synaptic targets for the new interneurons, the alternative receptor alpha3-Na(+)K(+)-ATPase was strongly expressed in mitral cells. Using a transplantation approach, we demonstrate that agrin-deficient interneuron precursors migrate correctly into the OB. However, in contrast to wild-type neurons, which form synapses and survive for prolonged periods, mutant neurons do not mature and are rapidly eliminated. Using in vivo brain electroporation of the olfactory system, we show that the transmembrane form of agrin alone is sufficient to mediate integration and demonstrate that excess transmembrane agrin increases the number of dendritic spines. Last, we provide in vivo evidence that an interaction between agrin and alpha3-Na(+)K(+)-ATPase is of functional importance in this system. PMID- 22423098 TI - Synaptotagmin 1 is necessary for the Ca2+ dependence of clathrin-mediated endocytosis. AB - The role of Ca2+ in synaptic vesicle endocytosis remains uncertain due to the diversity in various preparations where several forms of endocytosis may contribute variably in different conditions. Although recent studies have demonstrated that Ca2+ is important for clathrin-mediated endocytosis (CME), the mechanistic role of Ca2+ in CME remains to be elucidated. By monitoring CME of single vesicles in mouse chromaffin cells with cell-attached capacitance measurements that offer millisecond time resolution, we demonstrate that the dynamics of vesicle fission during CME is Ca2+ dependent but becomes Ca2+ independent in synaptotagmin 1 (Syt1) knock-out cells. Our results thus suggest that Syt1 is necessary for the Ca2+ dependence of CME. PMID- 22423097 TI - Lost in transition: aging-related changes in executive control by the medial prefrontal cortex. AB - Neural correlates of aging in the medial prefrontal cortex (mPFC) were studied using an operant delayed response task. The task used blocks of trials with memory-guided (delayed alternation) and visually-guided (stimulus-response) responding. Older rats (24 months) performed at a slow pace compared with younger rats (6 months). They wasted time engaged in nonessential behaviors (e.g., licking on spouts beyond the period of reward delivery) and were slow to respond at the end of the delay period. Aged mPFC neurons showed normal spatial processing. They differed from neurons in younger rats by having reduced modulations by imperative stimuli indicating reward availability and reduced activity associated with response latencies for reward collection. Older rats showed reduced sensitivity to imperative stimuli at three levels of neural activity: reduced fractions of neurons with changes in firing rate around the stimulus, reduced correlation over neurons at the time of the stimulus as measured with analysis of population activity, and reduced amplitudes of event related fluctuations in intracortical field potentials at the time of the imperative stimulus. Our findings suggest that aging alters the encoding of time sensitive information and impairs the ability of prefrontal networks to keep subjects "on task." PMID- 22423099 TI - Corticomuscular coherence is tuned to the spontaneous rhythmicity of speech at 2 3 Hz. AB - Human speech features rhythmicity that frames distinctive, fine-grained speech patterns. Speech can thus be counted among rhythmic motor behaviors that generally manifest characteristic spontaneous rates. However, the critical neural evidence for tuning of articulatory control to a spontaneous rate of speech has not been uncovered. The present study examined the spontaneous rhythmicity in speech production and its relationship to cortex-muscle neurocommunication, which is essential for speech control. Our MEG results show that, during articulation, coherent oscillatory coupling between the mouth sensorimotor cortex and the mouth muscles is strongest at the frequency of spontaneous rhythmicity of speech at 2-3 Hz, which is also the typical rate of word production. Corticomuscular coherence, a measure of efficient cortex-muscle neurocommunication, thus reveals behaviorally relevant oscillatory tuning for spoken language. PMID- 22423100 TI - Neuronal encoding of subjective value in dorsal and ventral anterior cingulate cortex. AB - We examined the activity of individual cells in the primate anterior cingulate cortex during an economic choice task. In the experiments, monkeys chose between different juices offered in variables amounts and subjective values were inferred from the animals' choices. We analyzed neuronal firing rates in relation to a large number of behaviorally relevant variables. We report three main results. First, there were robust differences between the dorsal bank (ACCd) and the ventral bank (ACCv) of the cingulate sulcus. Specifically, neurons in ACCd but not in ACCv were modulated by the movement direction. Furthermore, neurons in ACCd were most active before movement initiation, whereas neurons in ACCv were most active after juice delivery. Second, neurons in both areas encoded the identity and the subjective value of the juice chosen by the animal. In contrast, neither region encoded the value of individual offers. Third, the population of value-encoding neurons in both ACCd and ACCv underwent range adaptation. With respect to economic choice, it is interesting to compare these areas with the orbitofrontal cortex (OFC), previously examined. While neurons in OFC encoded both pre-decision and post-decision variables, neurons in ACCd and ACCv only encoded post-decision variables. Moreover, the encoding of the choice outcome (chosen value and chosen juice) in ACCd and ACCv trailed that found in OFC. These observations indicate that economic decisions (i.e., value comparisons) take place upstream of ACCd and ACCv. The coexistence of choice outcome and movement signals in ACCd suggests that this area constitutes a gateway through which the choice system informs motor systems. PMID- 22423101 TI - Lateral hypothalamic orexin/hypocretin neurons that project to ventral tegmental area are differentially activated with morphine preference. AB - Orexin (or hypocretin) is synthesized exclusively in dorsomedial, perifornical, and lateral hypothalamus (LH). These neurons are implicated in several functions, including reward processing. We examined the ventral tegmental area (VTA) as a possible site of orexin action for drug preference during protracted morphine abstinence, and studied functional topography of orexin projections to VTA. Male Sprague Dawley rats were used to investigate whether orexin cells that project to VTA exhibit Fos activation with morphine conditioned place preference (CPP), and whether these cells exhibit increased Fos with morphine CPP during protracted abstinence. Unilateral injections of a retrograde tracer (WGA-Au, 350-400 nl) were made into the VTA or a nonreward area, locus ceruleus, and morphine or placebo pellets were implanted for 14 d. Approximately 2 weeks after pellet removal (post dependence), CPP conditioning and testing were conducted. Triple labeling for WGA-Au, Fos, and orexin revealed that the percentage of VTA projecting orexin neurons Fos activated on the CPP test day significantly increased in post-dependent (vs nondependent) rats, and was exclusive to LH orexin neurons (not dorsomedial or perifornical). Post-dependent animals showed a positive correlation between CPP scores and percentages of Fos-activated, caudal VTA-projecting LH orexin cells. Unlike afferents to caudal VTA, percentages of rostral VTA-projecting, LH orexin cells that were Fos activated showed a positive correlation with CPP only in nondependent animals. Fos in LC-projecting orexin cells was not correlated with CPP in any group. These results indicate that VTA is a heterogeneous and functionally significant target of orexin neurons for morphine reward during protracted abstinence. PMID- 22423102 TI - Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory motor defects are a consequence, not a cause, of motor neuron dysfunction. AB - The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction. PMID- 22423103 TI - Neural activity in cortical area V4 underlies fine disparity discrimination. AB - Primates are capable of discriminating depth with remarkable precision using binocular disparity. Neurons in area V4 are selective for relative disparity, which is the crucial visual cue for discrimination of fine disparity. Here, we investigated the contribution of V4 neurons to fine disparity discrimination. Monkeys discriminated whether the center disk of a dynamic random-dot stereogram was in front of or behind its surrounding annulus. We first behaviorally tested the reference frame of the disparity representation used for performing this task. After learning the task with a set of surround disparities, the monkey generalized its responses to untrained surround disparities, indicating that the perceptual decisions were generated from a disparity representation in a relative frame of reference. We then recorded single-unit responses from V4 while the monkeys performed the task. On average, neuronal thresholds were higher than the behavioral thresholds. The most sensitive neurons reached thresholds as low as the psychophysical thresholds. For subthreshold disparities, the monkeys made frequent errors. The variable decisions were predictable from the fluctuation in the neuronal responses. The predictions were based on a decision model in which each V4 neuron transmits the evidence for the disparity it prefers. We finally altered the disparity representation artificially by means of microstimulation to V4. The decisions were systematically biased when microstimulation boosted the V4 responses. The bias was toward the direction predicted from the decision model. We suggest that disparity signals carried by V4 neurons underlie precise discrimination of fine stereoscopic depth. PMID- 22423104 TI - Deletion of ecto-5'-nucleotidase (CD73) reveals direct action potential-dependent adenosine release. AB - Purinergic signaling is a highly complex system of extracellular communication involved in many physiological and pathological functions in the mammalian brain. Its complexity stems from the multitude of purine receptor subtypes and endogenous purine receptor ligands (including ATP, ADP, UTP, UDP, and adenosine). Potentially all of these ligands could be directly released, and some could also arise from extracellular metabolism. A widely held consensus is that, except under pathological conditions, extracellular adenosine arises only from ectoATPase-mediated metabolism of previously released ATP. Here, we have used mice that lack the CD73 gene (encoding ecto-5'-nucleotidase that converts AMP to adenosine) to test whether action potential-dependent adenosine release in the cerebellum depends on prior ATP release. Surprisingly, we have uncovered two parallel pathways of adenosine release: one that is indirect via glutamate receptor-dependent release of ATP and a second of equal amplitude that has no dependence on prior release of ATP and thus represents the direct release of adenosine. This component of adenosine release is blocked by bafilomycin and modulated by mGlu4 receptor activation, strongly supporting adenosine release by exocytosis from parallel fibers. Our findings are a major step in understanding the mechanisms of adenosine release and are likely to have implications for all aspects of physiology where adenosine plays a key modulatory role. PMID- 22423105 TI - Spatial firing correlates of physiologically distinct cell types of the rat dentate gyrus. AB - The dentate gyrus (DG) occupies a key position in information flow through the hippocampus. Its principal cell, the granule cell, has spatially selective place fields. However, the behavioral correlates of cells located in the hilus of the rat dentate gyrus are unknown. We report here that cells below the granule layer show spatially selective firing that consists of multiple subfields. Other cells recorded from the DG had single place fields. Compared with cells with multiple fields, cells with single fields fired at lower rates during sleep were less bursty, and were more likely to be recorded simultaneously with large populations of neurons that were active during sleep and silent during behavior. We propose that cells with single fields are likely to be mature granule cells that use sparse encoding to potentially disambiguate input patterns. Furthermore, we hypothesize that cells with multiple fields might be cells of the hilus or newborn granule cells. These data are the first demonstration, based on physiological criteria, that single- and multiple-field cells constitute at least two distinct cell classes in the DG. Because of the heterogeneity of firing correlates and cell types in the DG, understanding which cell types correspond to which firing patterns, and how these correlates change with behavioral state and between different environments, are critical questions for testing long-standing computational theories that the DG performs a pattern separation function using a very sparse coding strategy. PMID- 22423106 TI - Prolonged disynaptic inhibition in the cortex mediated by slow, non-alpha7 nicotinic excitation of a specific subset of cortical interneurons. AB - Cholinergic activation of nicotinic receptors in the cortex plays a critical role in arousal, attention, and learning. Here we demonstrate that cholinergic axons from the basal forebrain of mice excite a specific subset of cortical interneurons via a remarkably slow, non-alpha7 nicotinic receptor-mediated conductance. In turn, these inhibitory cells generate a delayed and prolonged wave of disynaptic inhibition in neighboring cortical neurons, altering the spatiotemporal pattern of inhibition in cortical circuits. PMID- 22423107 TI - Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum. AB - Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder affecting both the peripheral nervous system and CNS. However, the precise role of KCC3 in the maintenance of ion homeostasis in the nervous system and the pathogenic mechanisms leading to HMSN/ACC remain unclear. We established two Slc12a6 Cre/LoxP transgenic mouse lines expressing C-terminal truncated KCC3 in either a neuron-specific or ubiquitous fashion. Our results suggest that neuronal KCC3 expression is crucial for axon volume control. We also demonstrate that the neuropathic features of HMSN/ACC are predominantly due to a neuronal KCC3 deficit, while the auditory impairment is due to loss of non neuronal KCC3 expression. Furthermore, we demonstrate that KCC3 plays an essential role in inflammatory pain pathways. Finally, we observed hypoplasia of the corpus callosum in both mouse mutants and a marked decrease in axonal tracts serving the auditory cortex in only the general deletion mutant. Together, these results establish KCC3 as an important player in both central and peripheral nervous system maintenance. PMID- 22423108 TI - ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. AB - Both sporadic and autosomal dominant forms of Parkinson's disease (PD) have been causally linked to mutations in leucine-rich repeat kinase 2 (LRRK2), a large protein with multiple domains. The kinase domain plays an important role in LRRK2 mediated toxicity. Although a number of investigations have focused on LRRK2 kinase activity, less is known about the GTPase function of LRRK2. The activity of GTPases is regulated by GTPase activating proteins (GAPs) and GTP exchange factors. Here, we identify ArfGAP1 as the first GAP for LRRK2. ArfGAP1 binds LRRK2 predominantly via the WD40 and kinase domain of LRRK2, and it increases LRRK2 GTPase activity and regulates LRRK2 toxicity both in vitro and in vivo in Drosophila melanogaster. Unexpectedly, ArfGAP1 is an LRRK2 kinase substrate whose GAP activity is inhibited by LRRK2, whereas wild-type and G2019S LRRK2 autophosphorylation and kinase activity are significantly reduced in the presence of ArfGAP1. Overexpressed ArfGAP1 exhibits toxicity that is reduced by LRRK2 both in vitro and in vivo. Delta64-ArfGAP1, a dominant-negative ArfGAP1, and shRNA knockdown of ArfGAP1 reduce LRRK2 toxicity. Thus, LRRK2 and ArfGAP1 reciprocally regulate the activity of each other. Our results provide insight into the basic pathobiology of LRRK2 and indicate an important role for the GTPase domain and ArfGAP1 in LRRK2-mediated toxicity. These data suggest that agents targeted toward regulation of LRRK2 GTP hydrolysis might be therapeutic agents for the treatment of PD. PMID- 22423109 TI - Are extrasynaptic GABAA receptors important targets for sedative/hypnotic drugs? AB - High-affinity extrasynaptic GABA(A) receptors are persistently activated by the low ambient GABA levels that are known to be present in extracellular space. The resulting tonic conductance generates a form of shunting inhibition that is capable of altering cellular and network behavior. It has been suggested that this tonic inhibition will be enhanced by neurosteroids, antiepileptics, and sedative/hypnotic drugs. However, we show that the ability of sedative/hypnotic drugs to enhance tonic inhibition in the mouse cerebellum will critically depend on ambient GABA levels. For example, we show that the intravenous anesthetic propofol enhances tonic inhibition only when ambient GABA levels are <100 nm. More surprisingly, the actions of the sleep-promoting drug 4,5,6,7 tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP) are attenuated at ambient GABA levels of just 20 nm. In contrast, our data suggest that neurosteroid enhancement of tonic inhibition will be greater at high ambient GABA concentrations. We present a model that takes into account realistic estimates of ambient GABA levels and predicted extrasynaptic GABA(A) receptor numbers when considering the ability of sedative/hypnotic drugs to enhance tonic inhibition. These issues will be important when considering drug strategies designed to target extrasynaptic GABA(A) receptors in the treatment of sleep disorders and other neurological conditions. PMID- 22423110 TI - In vivo nerve-macrophage interactions following peripheral nerve injury. AB - In vertebrates, the peripheral nervous system has retained its regenerative capacity, enabling severed axons to reconnect with their original synaptic targets. While it is well documented that a favorable environment is critical for nerve regeneration, the complex cellular interactions between injured nerves with cells in their environment, as well as the functional significance of these interactions, have not been determined in vivo and in real time. Here we provide the first minute-by-minute account of cellular interactions between laser transected motor nerves and macrophages in live intact zebrafish. We show that macrophages arrive at the lesion site long before axon fragmentation, much earlier than previously thought. Moreover, we find that axon fragmentation triggers macrophage invasion into the nerve to engulf axonal debris, and that delaying nerve fragmentation in a Wld(s) model does not alter macrophage recruitment but induces a previously unknown 'nerve scanning' behavior, suggesting that macrophage recruitment and subsequent nerve invasion are controlled by separate mechanisms. Finally, we demonstrate that macrophage recruitment, thought to be dependent on Schwann cell-derived signals, occurs independently of Schwann cells. Thus, live cell imaging defines novel cellular and functional interactions between injured nerves and immune cells. PMID- 22423111 TI - Activation of NMDA receptors upregulates a disintegrin and metalloproteinase 10 via a Wnt/MAPK signaling pathway. AB - A disintegrin and metalloproteinase 10 (ADAM10) is the constitutive alpha secretase that governs the nonamyloidogenic pathway of beta-amyloid precursor protein processing and is an attractive drug target for treating Alzheimer's disease. To date, little is known about the mechanism by which ADAM10 is regulated in neurons. Using mouse primary cortical neurons, we show here that NMDA receptor (NMDAR) activation led to upregulation of the genes encoding ADAM10 and beta-catenin proteins. Interestingly, the ADAM10 upregulation was abolished by inhibitors of Wnt/beta-catenin signaling. Conversely, activation of the Wnt/beta-catenin signaling pathway by recombinant Wnt3a stimulated ADAM10 expression. We further showed that both the NMDAR- and Wnt3a-induced ADAM10 upregulation was blocked by ERK inhibitors. We suggest that the NMDARs control ADAM10 expression via a Wnt/MAPK signaling pathway. PMID- 22423112 TI - The interaction between cell adhesion molecule L1, matrix metalloproteinase 14, and adenine nucleotide translocator at the plasma membrane regulates L1-mediated neurite outgrowth of murine cerebellar neurons. AB - We have identified the adenine nucleotide translocator (ANT) isoforms ANT1 and ANT2 that are present in the plasma membrane of mouse cerebellar neurons as novel binding partners of the cell adhesion molecule L1. The direct interaction between ANT and L1 is mediated by sites within the fibronectin type III domains of L1 and the first and third extracellular loops of the ANT proteins. We also show that L1 interacts with the ANT binding partner matrix metalloprotease 14 (MMP14) and that the ANT proteins bind directly to the L1 interaction partner glyceraldehyde-3 phosphate dehydrogenase (GAPDH). Moreover, we provide evidence that the functional interplay between L1, ANT proteins, MMP14, and GAPDH at the plasma membrane mediates L1-induced neurite outgrowth of cerebellar neurons. Disruption of this interplay by ANT inhibitors, ANT-derived synthetic peptides, and/or function-blocking MMP14 and ANT antibodies leads to alterations in L1-dependent neurite outgrowth. Stimulation of L1-mediated signaling in cerebellar neurons triggers transient ATP secretion via ANT proteins and leads to transient src family-dependent tyrosine phosphorylation of L1, ANT1, ANT2, and MMP14. Thus, our results indicate that plasma membrane-localized ANT1 and ANT2 regulate L1 mediated neurite outgrowth in conjunction with MMP14. PMID- 22423113 TI - TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice. AB - Accumulating evidence suggests that neuroimmune interactions contribute to pathological pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca2+-permeable cation channel that acts as a sensor for reactive oxygen species. TRPM2 is expressed abundantly in immune cells and is important in inflammatory processes. The results of the present study show that TRPM2 plays a crucial role in inflammatory and neuropathic pain. While wild-type and TRPM2 knock-out mice showed no difference in their basal sensitivity to mechanical and thermal stimulation, nocifensive behaviors in the formalin test were reduced in TRPM2 knock-out mice. In carrageenan-induced inflammatory pain and sciatic nerve injury-induced neuropathic pain models, mechanical allodynia and thermal hyperalgesia were attenuated in TRPM2 knock-out mice. Carrageenan-induced inflammation and sciatic nerve injury increased the expression of TRPM2 mRNA in the inflamed paw and around the injured sciatic nerve, respectively. TRPM2 deficiency diminished the infiltration of neutrophils and the production of chemokine (C-X-C motif) ligand-2 (CXCL2), a major chemokine that recruits neutrophils, but did not alter the recruitment of F4/80-positive macrophages in the inflamed paw or around the injured sciatic nerve. Microglial activation after nerve injury was suppressed in the spinal cord of TRPM2 knock-out mice. Furthermore, CXCL2 production and inducible nitric oxide synthase induction were diminished in cultured macrophages and microglia derived from TRPM2 knock-out mice. Together, these results suggest that TRPM2 expressed in macrophages and microglia aggravates peripheral and spinal pronociceptive inflammatory responses and contributes to the pathogenesis of inflammatory and neuropathic pain. PMID- 22423114 TI - Categorical speech processing in Broca's area: an fMRI study using multivariate pattern-based analysis. AB - Although much effort has been directed toward understanding the neural basis of speech processing, the neural processes involved in the categorical perception of speech have been relatively less studied, and many questions remain open. In this functional magnetic resonance imaging (fMRI) study, we probed the cortical regions mediating categorical speech perception using an advanced brain-mapping technique, whole-brain multivariate pattern-based analysis (MVPA). Normal healthy human subjects (native English speakers) were scanned while they listened to 10 consonant-vowel syllables along the /ba/-/da/ continuum. Outside of the scanner, individuals' own category boundaries were measured to divide the fMRI data into /ba/ and /da/ conditions per subject. The whole-brain MVPA revealed that Broca's area and the left pre-supplementary motor area evoked distinct neural activity patterns between the two perceptual categories (/ba/ vs /da/). Broca's area was also found when the same analysis was applied to another dataset (Raizada and Poldrack, 2007), which previously yielded the supramarginal gyrus using a univariate adaptation-fMRI paradigm. The consistent MVPA findings from two independent datasets strongly indicate that Broca's area participates in categorical speech perception, with a possible role of translating speech signals into articulatory codes. The difference in results between univariate and multivariate pattern-based analyses of the same data suggest that processes in different cortical areas along the dorsal speech perception stream are distributed on different spatial scales. PMID- 22423115 TI - Does the human dorsal stream really process a category for tools? AB - Previously, Almeida et al. (2008) used a technique called Continuous Flash Suppression to show that human dorsal stream cortical areas specifically responded to a "tool category." Here, we used the same technique to clarify what attributes of tools are processed in the dorsal stream. We examined surface attributes and shape. A significant priming effect was found when we removed surface attributes by using line drawings instead of photographs. In a second experiment, we manipulated shape and we found that there were no significant priming effects when we used nonelongated tool pictures as tool prime stimuli. To better clarify the effect of shape attributes on priming effects, we conducted a further experiment using elongated stick-like rectangles as prime stimuli and found that elongated shapes significantly shortened the reaction time to the tool pictures as target stimuli. Additionally, when elongated vegetables were used as prime stimuli, the reaction time to the tool pictures as target stimuli was also significantly shortened, but there was no effect when stubby vegetables were used. Finally, when we controlled for orientation by presenting rotated elongated stick-like rectangles, diamond shapes, and cut circles as prime stimuli, we found that rectangles replicated the same significant priming effect as previous experiments, but the others did not. These results suggest that the dorsal stream processes elongated shapes but does not process the tool category specifically. PMID- 22423116 TI - Additional risk of hypertension and smoking for aneurysms in people with a family history of subarachnoid haemorrhage. AB - BACKGROUND: Smoking and hypertension increase the risk of aneurismal subarachnoid haemorrhage (SAH) two to threefold whereas a familial predisposition increases the risk sixfold. We assessed the additional risk of smoking and hypertension for the presence of an intracranial aneurysm (IA) in first-degree relatives of patients with familial SAH. METHODS: We studied first-degree relatives of patients with familial SAH who were screened for the presence of aneurysms. RRs with corresponding 95% CIs for the risk of IA were calculated for smoking and hypertension. RESULTS: The RRs were 1.5 (95% CI 0.7 to 3.2) for smoking, 1.9 (95% CI 1.0 to 3.7) for hypertension and 2.7 (95% CI 1.4 to 5.3) for smoking plus hypertension. The increased RR for hypertension was found in both women and men, but the increased RR for smoking was found in women only. CONCLUSION: The extent of the increased risk of smoking and hypertension for the presence of IA in first degree relatives of patients with familial SAH is similar to that in patients without familial predisposition. Risk factor profiles should be included in future genetic studies. PMID- 22423117 TI - Depression: an inflammatory illness? AB - Major depressive disorder (MDD) is associated with significant morbidity and mortality. Findings from preclinical and clinical studies suggest that psychiatric illnesses, particularly MDD, are associated with inflammatory processes. While it is unlikely that MDD is a primary 'inflammatory' disorder, there is now evidence to suggest that inflammation may play a subtle role in the pathophysiology of MDD. Most of the evidence that links inflammation to MDD comes from three observations: (a) one-third of those with major depression show elevated peripheral inflammatory biomarkers, even in the absence of a medical illness; (b) inflammatory illnesses are associated with greater rates of MDD; and (c) patients treated with cytokines are at greater risk of developing major depressive illness. We now know that the brain is not an immune privileged organ. Inflammatory mediators have been found to affect various substrates thought to be important in the aetiopathogenesis of MDD, including altered monoamine and glutamate neurotransmission, glucocorticoid receptor resistance and adult hippocampal neurogenesis. At a higher level, inflammation is thought to affect brain signalling patterns, cognition and the production of a constellation of symptoms, termed 'sickness behaviour'. Inflammation may therefore play a role in the aetiology of depression, at least in a 'cohort' of vulnerable individuals. Inflammation may not only act as a precipitating factor that pushes a person into depression but also a perpetuating factor that may pose an obstacle to recovery. More importantly, inflammatory markers may aid in the diagnosis and prediction of treatment response, leading to the possibility of tailored treatments, thereby allowing stratification of what remains a heterogenous disorder. PMID- 22423118 TI - Update on the pathophysiology and management of idiopathic intracranial hypertension. AB - Idiopathic intracranial hypertension is a disease of unknown aetiology, typically affecting young obese women, producing a syndrome of increased intracranial pressure without identifiable cause. Despite a large number of hypotheses and publications over the past decade, the aetiology is still unknown. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue and cerebral venous abnormalities are areas of active study regarding the pathophysiology of idiopathic intracranial hypertension. There continues to be no evidence based consensus or formal guidelines regarding management and treatment of the disease. Treatment studies show that the diagnostic lumbar puncture is a valuable intervention beyond its diagnostic importance, and that weight management is critical. However, many questions remain regarding the efficacy of acetazolamide, CSF shunting procedures and cerebral transverse venous sinus stenting. PMID- 22423119 TI - Viruses associated with pneumonia in adults. AB - Viral pneumonia, which is typically associated with disease in childhood, is increasingly recognized as causing problems in adults. Certain viruses, such as influenza virus, can attack fully immunocompetent adults, but many viruses take advantage of more-vulnerable patients. The latter include patients receiving immunosuppressive therapy and elderly subjects, particularly those residing in long-term care facilities. The range of viruses producing pneumonia in adults includes common agents, such as varicella-zoster virus and influenza virus, as well as respiratory syncytial virus, human metapneumovirus, adenoviruses, picornaviruses, and coronaviruses. The roles played by other agents, such as rhinoviruses and human bocaviruses, in pneumonia are still under study. While therapy for most of theses agents, at least in adults, has not yet been fully clarified, it is reasonable to assume antivirals may work in certain situations if they are introduced early enough in the course of infection. PMID- 22423120 TI - High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study. AB - BACKGROUND: Gram-negative bacteria susceptible only to colistin (COS) are emerging causes of severe nosocomial infections, reviving interest in the use of colistin. However, consensus on the most effective way to administer colistin has not yet been reached. METHODS: All patients who had sepsis due to COS gram negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded. RESULTS: Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment. CONCLUSIONS: Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity. PMID- 22423121 TI - Burden and transmission of zoonotic foodborne disease in a rural community in Mexico. AB - BACKGROUND: The foodborne transmission and human health impact of Salmonella and Campylobacter infections have rarely been evaluated at the population level in highly endemic settings. METHODS: A prospective 15-month cohort study of 127 infants and 119 elderly people was combined with animal and food surveillance to determine the incidence and severity of Salmonella and Campylobacter gastroenteritis in a comparatively prosperous rural community in Mexico. RESULTS: Salmonella and Campylobacter were isolated in up to 75% and 57%, respectively, of raw retail meat and in up to 4.5% of ready-to-eat foods. Rates of acute gastroenteritis of any etiology in infants and elderly people were, respectively, 2.1 and 0.7 episodes per person per year. The annual incidence density rate of Salmonella gastroenteritis was 17.8 per 100 infants and 7.9 per 100 elderly people; the rate of Campylobacter gastroenteritis was 11.7 per 100 infants and 0 per 100 elderly people. Pulsed-field gel electrophoresis analysis yielded multiple clusters of human, meat, and/or animal Salmonella and Campylobacter isolates with indistinguishable patterns. On average, gastroenteritis episodes with these pathogens lasted 3 days in infants and 2 days in elderly people. Medical attention was sought in 44% of diarrheal episodes in infants and in 26% of diarrheal episodes in elderly people; none required hospitalization. Infants with multidrug-resistant Salmonella gastroenteritis had a higher frequency of bloody stools and medical visits (50% vs 11%; odds ratio, 8.5; P = .04) than those with more susceptible strains. CONCLUSIONS: In this relatively advantaged Mexican rural community, the human health impact of a food chain heavily contaminated with Salmonella and Campylobacter was of low magnitude. PMID- 22423122 TI - Editorial commentary: Closing the loop--a colistin clinical study to confirm dosing recommendations from PK/PD modeling. PMID- 22423123 TI - Site of extrapulmonary tuberculosis is associated with HIV infection. AB - BACKGROUND: In the United States, the proportion of patients with extrapulmonary tuberculosis (EPTB) has increased relative to cases of pulmonary tuberculosis. Patients with central nervous system (CNS)/meningeal and disseminated EPTB and those with human immunodeficiency virus (HIV)/AIDS have increased mortality. The purpose of our study was to determine risk factors associated with particular types of EPTB. METHODS: We retrospectively reviewed 320 cases of EPTB from 1995 2007 at a single urban US public hospital. Medical records were reviewed to determine site of EPTB and patient demographic and clinical characteristics. Multivariable logistic regression analyses were performed to determine independent associations between patient characteristics and site of disease. RESULTS: Patients were predominantly male (67%), African American (82%), and US born (76%). Mean age was 40 years (range 18-89). The most common sites of EPTB were lymphatic (28%), disseminated (23%), and CNS/meningeal (22%) disease. One hundred fifty-four (48.1%) were HIV-infected, 40% had concomitant pulmonary tuberculosis, and 14.7% died within 12 months of EPTB diagnosis. Multivariable analysis demonstrated that HIV-infected patients were less likely to have pleural (adjusted odds ratio [AOR] 0.3; 95% confidence interval [CI] .2, .6) as site of EPTB disease than HIV-uninfected patients. Among patients with EPTB and HIV infection, patients with CD4 lymphocyte cell count <100 were more likely to have severe forms of EPTB (CNS/meningeal and/or disseminated) (AOR 1.6; 95% CI, 1.0, 2.4). CONCLUSIONS: Among patients hospitalized with EPTB, patients coinfected with HIV and low CD4 counts were more likely to have CNS/meningeal and disseminated disease. Care for similar patients should include consideration of these forms of EPTB since they carry a high risk of death. PMID- 22423124 TI - Poorer immunologic outcome on treatment among patients infected with HIV-1 non-B subtypes compared with subtype B in Singapore. PMID- 22423125 TI - H5N1 avian influenza in children. AB - BACKGROUND: Avian influenza continues to pose a threat to humans and maintains the potential for greater transmissibility. Understanding the clinical presentation and prognosis in children will help guide effective diagnosis and treatment. METHODS: A global patient registry was created to enable systematic collection of clinical, exposure, treatment, and outcomes data on confirmed cases of H5N1. Bivariate and multivariate statistical tools were used to describe clinical presentation and evaluate factors prognostic of survival. RESULTS: Data were available from 13 countries on 193 children <18 years who were confirmed as having been infected with H5N1; 35.2% of cases were from Egypt. The case fatality rate (CFR) for children was 48.7%, with Egypt having a very low pediatric CFR. Overall, children aged <=5 years had the lowest CFR and were brought to hospitals more quickly and treated sooner than older children. Children who presented for medical care with a complaint of rhinorrhea had a 76% reduction in the likelihood of death compared with those who presented without rhinorrhea, even after statistical adjustment for age, having been infected in Egypt, and oseltamivir treatment (P = .02). Delayed initiation of treatment with oseltamivir increases the likelihood of death, with an overall 75% increase in the adjusted odds ratio for death for each day of delay. CONCLUSIONS: The presence of rhinorrhea appears to indicate a better prognosis for children with H5N1, with most patients surviving regardless of age, country, or treatment. For individuals treated with oseltamivir, early initiation of treatment substantially enhances the chance of survival. PMID- 22423126 TI - Editorial commentary: Accounting for pertussis. PMID- 22423127 TI - Unexpectedly limited durability of immunity following acellular pertussis vaccination in preadolescents in a North American outbreak. AB - BACKGROUND: Despite widespread childhood vaccination against Bordetella pertussis, disease remains prevalent. It has been suggested that acellular vaccine may be less effective than previously believed. During a large outbreak, we examined the incidence of pertussis and effectiveness of vaccination in a well vaccinated, well-defined community. METHODS: Our center provides care to 135 000 patients, 40% of the population of Marin County, California. A total of 171 patients tested positive for B. pertussis from 1 March to 31 October 2010 by polymerase chain reaction (PCR). Electronic medical records were reviewed for demographic characteristics and vaccination status. RESULTS: We identified 171 cases of clinical pertussis, 132 of which were in pediatric patients. There was a notable increase in cases among patients aged 8-12 years. The rate of testing peaked among infants but remained relatively constant across ages until 12 years. The rate of positive tests was low for ages 0-6 years and increased among preadolescents, peaking among those aged 12 years. The vaccination rate among PCR positive preadolescents were approximately equal to that of controls. The vaccine effectiveness was 41%, 24%, and 79% for children aged 2-7 years, 8-12 years, 13 18 years, respectively. CONCLUSIONS: Our data suggests that the current schedule of acellular pertussis vaccine doses is insufficient to prevent outbreaks of pertussis. We noted a markedly increased rate of disease from ages 8-12 years, proportionate to the interval since the last scheduled vaccine. Stable rates of testing ruled out selection bias. The possibility of earlier or more numerous booster doses of acellular pertussis vaccine either as part of routine immunization or for outbreak control should be entertained. PMID- 22423128 TI - Rhabdomyolysis in a patient treated with linezolid for extensively drug-resistant tuberculosis. PMID- 22423129 TI - Failure to radiologically confirm community-acquired pneumonia means antibiotic overtreatment. PMID- 22423132 TI - Typhoid fever outbreak associated with frozen mamey pulp imported from Guatemala to the western United States, 2010. AB - BACKGROUND: Fifty-four outbreaks of domestically acquired typhoid fever were reported between 1960 and 1999. In 2010, the Southern Nevada Health District detected an outbreak of typhoid fever among persons who had not recently travelled abroad. METHODS: We conducted a case-control study to examine the relationship between illness and exposures. A case was defined as illness with the outbreak strain of Salmonella serotype Typhi, as determined by pulsed-field gel electrophoresis (PFGE), with onset during 2010. Controls were matched by neighborhood, age, and sex. Bivariate and multivariate statistical analyses were completed using logistic regression. Traceback investigation was completed. RESULTS: We identified 12 cases in 3 states with onset from 15 April 2010 to 4 September 2010. The median age of case patients was 18 years (range, 4-48 years), 8 (67%) were female, and 11 (92%) were Hispanic. Nine (82%) were hospitalized; none died. Consumption of frozen mamey pulp in a fruit shake was reported by 6 of 8 case patients (75%) and none of the 33 controls (matched odds ratio, 33.9; 95% confidence interval, 4.9). Traceback investigations implicated 2 brands of frozen mamey pulp from a single manufacturer in Guatemala, which was also implicated in a 1998-1999 outbreak of typhoid fever in Florida. CONCLUSIONS: Reporting of individual cases of typhoid fever and subtyping of isolates by PFGE resulted in rapid detection of an outbreak associated with a ready-to-eat frozen food imported from a typhoid-endemic region. Improvements in food manufacturing practices and monitoring will prevent additional outbreaks. PMID- 22423133 TI - HIV-infected ugandan adults taking antiretroviral therapy with CD4 counts >200 cells/MUL who discontinue cotrimoxazole prophylaxis have increased risk of malaria and diarrhea. AB - BACKGROUND: Cotrimoxazole prophylaxis prolongs survival and prevents opportunistic infections, malaria, and diarrhea in persons infected with human immunodeficiency virus (HIV). Many countries recommend that individuals taking antiretroviral therapy (ART) discontinue cotrimoxazole when CD4 counts are >200 cells/MUL. However, this practice has not been evaluated in sub-Saharan Africa. METHODS: Patients in the Home-Based AIDS Care program in eastern Uganda initiated ART if they had a CD4 cell count <=250 cells/MUL or World Health Organization stage III or IV HIV disease. In the program's fourth year, patients with CD4 counts >200 cells/MUL were randomly assigned, by household, to continue or discontinue cotrimoxazole. Consenting participants were followed for episodes of malaria and diarrhea. RESULTS: At randomization, 836 eligible patients had been receiving ART for a mean of 3.7 years, with a median CD4 count of 489 cells/MUL; 94% had a viral load <400 copies/mL. Among those continuing (n = 452) vs discontinuing (n = 384) cotrimoxazole, 0.4 vs 12.2%, respectively, had at least 1 episode of malaria (P < .001), and 14% vs 25%, respectively, had at least 1 episode of diarrhea (P < .001). Compared to those remaining on cotrimoxazole, patients who discontinued had a relative risk of malaria of 32.5 (95% confidence interval [CI], 8.6-275.0; P < .001) and of diarrhea of 1.8 (95% CI, 1.3-2.4; P < .001). CONCLUSIONS: HIV-infected adults on ART with CD4 counts >200 cells/MUL who live in a malaria-endemic area of sub-Saharan Africa and who abruptly discontinue cotrimoxazole prophylaxis have an increased incidence of malaria and diarrhea compared with those who continue prophylaxis. Clinical Trials Registration. NCT00119093. PMID- 22423134 TI - Impact of pneumococcal conjugate vaccination on otitis media: a systematic review. AB - Acute otitis media (AOM) is a leading cause of visits to physicians and of antibiotic prescriptions for young children. We systematically reviewed studies on all-cause AOM episodes and physician visits in which impact was attributed to pneumococcal conjugate vaccines, either as efficacy or effectiveness. Of 18 relevant publications found, most used the 7-valent pneumococcal conjugate vaccine (7vCRM). The efficacy of 7vCRM against all-cause AOM episodes or visits was 0%-9% in randomized trials and 17%-23% in nonrandomized trials. In observational database studies, physician visits for AOM were already declining in the 3-5 years before 7vCRM introduction (mean change, -15%; range, +14% to 24%) and continued to decline afterward (mean, -19%; range, +7% to -48%). This vaccine provides some protection against OM, but other factors have also contributed to the recent decline in OM incidence. Future effectiveness studies should thus use better-controlled methods to estimate the true impact of vaccination on AOM. PMID- 22423135 TI - Septic shock attributed to Candida infection: importance of empiric therapy and source control. AB - BACKGROUND: Delayed treatment of candidemia has previously been shown to be an important determinant of patient outcome. However, septic shock attributed to Candida infection and its determinants of outcome have not been previously evaluated in a large patient population. METHODS: A retrospective cohort study of hospitalized patients with septic shock and blood cultures positive for Candida species was conducted at Barnes-Jewish Hospital, a 1250-bed urban teaching hospital (January 2002-December 2010). RESULTS: Two hundred twenty-four consecutive patients with septic shock and a positive blood culture for Candida species were identified. Death during hospitalization occurred among 155 (63.5%) patients. The hospital mortality rate for patients having adequate source control and antifungal therapy administered within 24 hours of the onset of shock was 52.8% (n = 142), compared to a mortality rate of 97.6% (n = 82) in patients who did not have these goals attained (P < .001). Multivariate logistic regression analysis demonstrated that delayed antifungal treatment (adjusted odds ratio [AOR], 33.75; 95% confidence interval [CI], 9.65-118.04; P = .005) and failure to achieve timely source control (AOR, 77.40; 95% CI, 21.52-278.38; P = .001) were independently associated with a greater risk of hospital mortality. CONCLUSIONS: The risk of death is exceptionally high among patients with septic shock attributed to Candida infection. Efforts aimed at timely source control and antifungal treatment are likely to be associated with improved clinical outcomes. PMID- 22423136 TI - Baseline platelet count and creatinine clearance rate predict the outcome of neutropenia-related invasive aspergillosis. AB - BACKGROUND: Invasive aspergillosis (IA) is a life-threatening infection for immunocompromised patients. Improvement in IA outcome has been hampered by lack of early prognostic factors, namely, those available before starting chemotherapy (baseline) or early in the course of IA (nonbaseline). We hypothesized that prognostic factors can be identified before chemotherapy, <=7 days from the first positive serum Aspergillus galactomannan index (s-GMI). METHODS: We analyzed 98 patients with multiple myeloma who developed neutropenia-related IA and had a positive s-GMI. Three response criteria were used: kinetics of s-GMI, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definitions, and 6-week survival. Baseline and nonbaseline variables were analyzed separately. RESULTS: Independent response predictors at baseline were a platelet count >=65,000 platelets/mm(3) (odds ratio [OR], 1.009; 95% confidence interval [CI], 1.001-1.017; P = .03) by s-GMI kinetics, and a platelet count >=65,000 platelets/mm(3) (OR, 1.009; 95% CI, 1.002 1.017; P = .01) and a creatinine clearance rate >=53 mL/min (OR, 1.024; 95% CI, 1.006-1.042; P = .009) by EORTC/MSG criteria, with response rates of 83% and 28% when both variables were above or below these cutoffs, respectively (P < .001). Only baseline creatinine clearance rate >=53 mL/min predicted 6-week survival (P = .003). Normalization of the s-GMI <=7 days after the first positive s-GMI and neutrophil recovery were the nonbaseline factors associated with positive outcomes. CONCLUSIONS: Two simple, inexpensive to measure, widely available, and routinely collected prechemotherapy values, platelet count and creatinine clearance rate, predict IA outcome and stratify patients into low-, intermediate , and high-risk categories, while early evaluation of s-GMI allows timely treatment modification. These findings may improve patient outcomes by optimizing management strategies for this serious infection and may prove valuable in designing clinical trials of interventions to improve IA outcomes. PMID- 22423137 TI - Vitamin D deficiency is associated with silent coronary artery disease in cardiovascularly asymptomatic African Americans with HIV infection. AB - BACKGROUND: Growing evidence suggests that vitamin D deficiency Is associated with clinical coronary artery disease (CAD). The relationship between vitamin D deficiency and subclinical CAD in HIV-infected individuals is not well characterized. METHODS: Computed tomographic (CT) coronary angiography was performed using contrast-enhanced 64-slice multidetector CT imaging, and vitamin D levels and the presence of traditional and novel risk factor for CAD were obtained in 674 HIV-infected African American (AA) participants aged 25-54 years in Baltimore, MD, without symptoms/clinical evidence of CAD. RESULTS: The prevalence of vitamin D deficiency (25-hydroxy vitamin D <10 ng/mL) was 20.0% (95% confidence interval [CI], 16.9-23.1). Significant (>=50%) coronary stenosis was present in 64 (9.5%) of 674 participants. Multiple logistic regression analysis revealed that male gender (adjusted odds ratio [OR], 2.19; 95% CI, 1.17 4.10), diastolic BP >=85 mmHg (adjusted OR: 1.94, 95% CI: 1.02 -3.68), low density lipoprotein cholesterol >=100 mg/dL (adjusted OR, 1.95; 95% CI, 1.13 3.36), cocaine use for >=15 years (adjusted OR, 1.77; 95% CI, 1.01-3.10), use of antiretroviral therapies for >=6 months (adjusted OR, 2.26; 95% CI, 1.17-4.36), year of enrollment after 2005 (adjusted ORs for 2006-2007, 2008-2009, and 2010 were 0.32 [95% CI, 0.13-0.76], 0.26 [95% CI, 0.12-0.56], and 0.32 (95% CI, 0.15 0.65], respectively), and vitamin D deficiency (adjusted OR, 2.28; 95% CI, 1.23 4.21) were independently associated with significant coronary stenosis. CONCLUSIONS: Both vitamin D deficiency and silent CAD are prevalent in HIV infected AAs. In addition to management of traditional CAD risk factors and substance abuse, vitamin D deficiency should be evaluated in HIV-infected AAs. These data support the conduct of a prospective trial of vitamin D in this high risk patient population. PMID- 22423138 TI - Is ritual cleansing a missing link between fatal infection and brain-eating amoebae? PMID- 22423140 TI - Use of Internet search data to monitor impact of rotavirus vaccination in the United States. AB - Google-based Internet query share (IQS) for rotavirus search terms correlated well with US rotavirus laboratory detections from 2004 to 2010 (r = 0.88; P < .001), capturing the reduction observed during postvaccine years (2008-2010). IQS analysis could become an inexpensive and reliable supplement for monitoring the impact of rotavirus vaccination in the United States. PMID- 22423139 TI - Increased risk of noninfluenza respiratory virus infections associated with receipt of inactivated influenza vaccine. AB - We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses. PMID- 22423141 TI - An image-based model of atrial muscular architecture: effects of structural anisotropy on electrical activation. AB - BACKGROUND: Computer models that capture key features of the heterogeneous myofiber architecture of right and left atria and interatrial septum provide a means of investigating the mechanisms responsible for atrial arrhythmia. The data necessary to implement such models have not previously been available. The aims of this study were to characterize surface geometry and myofiber architecture throughout the atrial chambers and to investigate the effects of this structure on atrial activation. METHODS AND RESULTS: Atrial surface geometry and myofiber orientations were reconstructed in 3D at 50*50*50-MUm(3) resolution from serial images acquired throughout the sheep atrial chambers. Myofiber orientations were determined by Eigen-analysis of the structure tensor. These data have been incorporated into an anatomic model that provides the first quantitative representation of myofiber architecture throughout the atrial chambers. By simulating activation on this 3D structure, we have confirmed the roles of specialized myofiber tracts such as the crista terminalis, pectinate muscles, and the Bachman bundle on the spread of activation from the sinus node. We also demonstrate how the complex myocyte arrangement in the posterior left atrium contributes to activation time dispersion adjacent to the pulmonary veins and increased vulnerability to rhythm disturbance generated by ectopic stimuli originating in the pulmonary vein sleeves. CONCLUSIONS: We have developed a structurally detailed, image-based model of atrial anatomy that provides deeper understanding of the role that myocyte architecture plays in normal and abnormal atrial electric function. PMID- 22423142 TI - Correlation between signal-averaged ECG and the histologic evaluation of the myocardial substrate in right ventricular outflow tract arrhythmias. AB - BACKGROUND: The differential diagnosis between idiopathic and cardiomyopathy related right ventricular outflow tract (RVOT) ventricular arrhythmias (VAs) is crucial. Signal-averaged ECG (SAECG) abnormalities are frequent in cardiomyopathy related RVOT-VAs, although their pathophysiologic basis and diagnostic value in this setting are undefined. We tested the association between SAECG and the myocardial substrate underlying RVOT-VAs. METHODS AND RESULTS: Twenty-four consecutive patients (median age, 50 years [42-59]; 12 men) with RVOT-VAs (10 with frequent [>1000/24 hours] premature ventricular contractions, 14 with ventricular tachycardias) underwent SAECG with 40-Hz filtering and electroanatomic mapping (EAM) with EAM-guided biopsy for characterization of the RVOT-VAs substrate. A filtered averaged QRS (fQRS) was obtained and analyzed for fQRS duration, low amplitude signal duration<40 mV (LAS40), and root-mean-square voltage in the last 40 ms of the QRS (RMS40). Standard definition of EAM scar was used. EAM-guided biopsy diagnosed ARVC in 11 (46%), myocarditis in 8 (33%), and idiopathic RVOT-VAs in 5 (21%) patients. Patients with cardiomyopathy-related RVOT-VAs had >=1 EAM scar (median, 2 [1-2]; all with RVOT scar). EAM of patients with idiopathic RVOT-VAs was normal. Patients with cardiomyopathy-related RVOT VAs had significantly longer fQRS (106 ms [92-132] versus 83 ms [82-84], P=0.01) and LAS40 (39 ms [36-51] versus 19 ms [18-21], P=0.02), and lower RMS40 (18 uV [9 26] versus 33 uV [32-33], P=0.04). A significant linear correlation was found between the extension (cm2) of the RVOT scar and all 3 SAECG parameters (rs=0.76, P<0.001 for the fQRSd; rs=0.73, P<0.001 for the LAS40; and rs=-0.72, P<0.001 for the RMS40). Using the established 2 of 3 criteria (ie, late potentials), SAECG diagnosed cardiomyopathy-related RVOT-VAs with high positive (100%) but low negative (38%) predictive values and missed 7 of 9 (78%) patients with RVOT scar<8 cm2. CONCLUSIONS: In patients with RVOT-VAs, abnormal SAECG parameters reflect the presence of extensive cardiomyopathic involvement of the RVOT. However, a negative SAECG does not reliably rule out cardiomyopathy-related RVOT VAs in the presence of a small RVOT scar. PMID- 22423143 TI - Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families. AB - BACKGROUND: Carotid intima-media thickness (CIMT) is a subclinical measure for atherosclerosis. Previously, we have mapped quantitative trait loci (QTLs) for CIMT to chromosomes 7p (maximum logarithm of odds=3.1) and to 14q (maximum logarithm of odds=2.3). We sought to identify the underlying genetic variants within those QTLs. METHODS AND RESULTS: Using the 100 extended Dominican Republican (DR) families (N=1312) used in the original linkage study, we fine mapped the QTLs with 2031 tagging single nucleotide polymorphisms (SNPs). Promising SNPs in the family data set were examined in an independent population based subcohort comprised of DR individuals (N=553) from the Northern Manhattan Study. Among the families, evidence for association (P<0.001) was found in multiple genes (ANLN, AOAH, FOXN3, CCDC88C, PRiMA1, and an intergenic SNP rs1667498), with the strongest association at PRiMA1 (P=0.00007, corrected P=0.047). Additional analyses revealed that the association at these loci, except PRiMA1, was highly significant (P=0.00004~0.00092) in families with evidence for linkage, but not in the rest of families (P=0.13~0.80) and the population-based cohort, suggesting the genetic effects at these SNPs are limited to a subgroup of families. In contrast, the association at PRiMA1 was significant in both families with and without evidence for linkage (P=0.002 and 0.019, respectively) and the population-based subcohort (P=0.047), supporting a robust association. CONCLUSIONS: We identified several candidate genes for CIMT in DR families. Some of the genes manifest genetic effects within a specific subgroup and others were generalized to all groups. Future studies are needed to further evaluate the contribution of these genes to atherosclerosis. PMID- 22423144 TI - Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. AB - BACKGROUND: The limitations of serum testosterone and estradiol (E(2)) measurements using non-extraction platform immunoassays (IAs) are widely recognized. Switching to more specific mass spectrometry (MS)-based methods has been advocated, but directly comparative data on the two methods are scarce. METHODS: We compared serum testosterone and E(2) measurements in a large sample of middle-aged/elderly men using a common platform IA and a gas chromatography (GC)-MS method, in order to assess their limitations and advantages, and to diagnose male hypogonadism. Of subjects from the European Male Aging Study (n=3174; age 40-79 years), peripheral serum testosterone and E(2) were analyzed using established commercial platform IAs (Roche Diagnostics E170) and in-house GC-MS methods. RESULTS: Over a broad concentration range, serum testosterone concentration measured by IA and MS showed high correlation (R=0.93, P<0.001), which was less robust in the hypogonadal range (<11 nmol/l; R=0.72, P<0.001). The IA/MS correlation was weaker in E(2) measurements (R=0.32, P<0.001, at E(2) <40.8 pmol/l, and R=0.74, P<0.001, at E(2) >40.8 pmol/l). Using MS as the comparator method, IA ascertained low testosterone compatible with hypogonadism (<11 nmol/l), with 75% sensitivity and 96.3% specificity. The same parameters with IA for the detection of low E(2) (<40.7 pmol/l) were 13.3 and 99.3%, and for high E(2) (>120 pmol/l) 88.4 and 88.6%. CONCLUSION: A validated platform IA is sufficient to detect subnormal testosterone concentrations in the diagnosis of male hypogonadism. The IA used for E(2) measurements showed poor correlation with MS and may only be suitable for the detection of high E(2) in men. PMID- 22423145 TI - Compound prism design principles, I. AB - Prisms have been needlessly neglected as components used in modern optical design. In optical throughput, stray light, flexibility, and in their ability to be used in direct-view geometry, they excel over gratings. Here we show that even their well-known weak dispersion relative to gratings has been overrated by designing doublet and double Amici direct-vision compound prisms that have 14 degrees and 23 degrees of dispersion across the visible spectrum, equivalent to 800 and 1300 lines/mm gratings. By taking advantage of the multiple degrees of freedom available in a compound prism design, we also show prisms whose angular dispersion shows improved linearity in wavelength. In order to achieve these designs, we exploit the well-behaved nature of prism design space to write customized algorithms that optimize directly in the nonlinear design space. Using these algorithms, we showcase a number of prism designs that illustrate a performance and flexibility that goes beyond what has often been considered possible with prisms. PMID- 22423146 TI - Compound prism design principles, II: triplet and Janssen prisms. AB - Continuing the work of the first paper in this series [Appl. Opt. 50, 4998-5011 (2011)], we extend our design methods to compound prisms composed of three independent elements. The increased degrees of freedom of these asymmetric prisms allow designers to achieve greatly improved dispersion linearity. They also, however, require a more careful tailoring of the merit function to achieve design targets, and so we present several new operands for manipulating the compound prisms' design algorithm. We show that with asymmetric triplet prisms, one can linearize the angular dispersion such that the spectral sampling rate varies by no more than 4% across the entire visible spectral range. Doing this, however, requires large prisms and causes beam compression. By adding a beam compression penalty to the merit function, we show that one can compromise between dispersion linearity and beam compression in order to produce practical systems. For prisms that do not deviate the beam, we show that Janssen prisms provide a form that maintains the degrees of freedom of the triplet and that are capable of up to 32 degrees of dispersion across the visible spectral range. Finally, in order to showcase some of the design flexibility of three-element prisms, we also show how to design for higher-order spectral dispersion to create a two-dimensional spectrum. PMID- 22423147 TI - Compound prism design principles, III: linear-in-wavenumber and optical coherence tomography prisms. AB - We extend the work of the first two papers in this series [Appl. Opt. 50, 4998 5011 (2011), Appl. Opt. 50, 5012-5022 (2011)] to design compound prisms for linear-in-wavenumber dispersion, especially for application in spectral domain optical coherence tomography (OCT). These dispersive prism designs are believed to be the first to meet the requirements of high resolution OCT systems in direct view geometry, where they can be used to shrink system size, to improve light throughput, to reduce stray light, and to reduce errors resulting from interpolating between wavelength- and wavenumber-sampled domains. We show prism designs that can be used for thermal sources or for wideband superluminescent diodes centered around wavelengths 850, 900, 1300, and 1375 nm. PMID- 22423148 TI - Influence of the Electrolyte Film Thickness on Charge Dynamics of Ionic Liquids in Ionic Electroactive Devices. AB - Developing advanced ionic electroactive devices such as ionic actuators and supercapacitors requires the understanding of ionic diffusion and drifting processes, which depend on the distances over which the ions travel, in these systems. The charge dynamics of [C(4)mim][PF(6)] ionic liquid films and Aquivion membranes with 40 wt% [C(2)mim][TfO] were investigated over a broad film thickness (d) range. It was found that the double layer charging time tau(DL) follows the classic model tau(DL) = lambda(D)d/(2D) very well, where D is the diffusion coefficient and lambda(D) the Debye length. In the longer time regimes (t ? tau(DL)) where diffusion dominates, the charge dynamics become voltage dependent. For low applied voltage, the later stage charge process seems to follow the d(2) dependence. However, at high voltages (> 0.5 V) in which significant device responses occur, the charging process does not show d(2) dependence so that tau(diff) = d(2)/(4D), corresponding to the ion diffusion from the bulk region, was not observed. PMID- 22423149 TI - Multidirectional left ventricular performance detected with three-dimensional speckle-tracking strain in patients with chronic right ventricular pacing and preserved ejection fraction. AB - AIMS: Although right ventricular (RV) pacing has a detrimental effect on global left ventricular (LV) function even in some patients with preserved ejection fraction (EF), its mechanism remains unclear. METHODS AND RESULTS: We studied 116 subjects; 56 patients with RV pacing and preserved EF (all >=50%), 30 EF-matched controls, and 30 heart failure (HF) patients with RV pacing and reduced EF (all <=35%). Radial, circumferential, and longitudinal dyssynchrony and function were quantified as standard deviations of the time-to-peak strain and global peak strain from all 16 LV segments using three-dimensional (3D) speckle-tracking strain. The degree of radial and circumferential dyssynchrony and function were similar for patients with RV pacing and preserved EF and controls. However, patients with RV pacing and preserved EF showed a greater longitudinal dyssynchrony of 46 +/- 14 vs. 31 +/- 9 ms (P < 0.01) and lower global longitudinal strain at 25 +/- 4 vs. 34 +/- 7% compared with controls (P < 0.001). Furthermore, longitudinal strain at the apical level was significantly lower than that at the mid- and basal level (20 +/- 4 vs. 27 +/- 5 and 26 +/- 5%, P < 0.001), and longitudinal dyssynchrony at the apical level was significantly larger than at the mid- and basal level (44 +/- 19 vs. 36 +/- 20 and 32 +/- 15 ms, P < 0.05) in patients with RV pacing and preserved EF. In contrast, HF patients with RV pacing and reduced EF showed greater radial, circumferential, and longitudinal dyssynchrony, and lower global radial, circumferential, and longitudinal strain than did controls (all P < 0.001). CONCLUSION: Three dimensional speckle-tracking strain was found to be useful for evaluating early subtle changes associated with chronic RV pacing, and may thus play a clinical role in predicting future global LV dysfunction. PMID- 22423150 TI - Identification of "ever-cropped" land (1984-2010) using Landsat annual maximum NDVI image composites: Southwestern Kansas case study. AB - A time series of 230 intra- and inter-annual Landsat Thematic Mapper images was used to identify land that was ever cropped during the years 1984 through 2010 for a five county region in southwestern Kansas. Annual maximum Normalized Difference Vegetation Index (NDVI) image composites (NDVI(ann-max)) were used to evaluate the inter-annual dynamics of cropped and non-cropped land. Three feature images were derived from the 27-year NDVI(ann-max) image time series and used in the classification: 1) maximum NDVI value that occurred over the entire 27 year time span (NDVI(max)), 2) standard deviation of the annual maximum NDVI values for all years (NDVI(sd)), and 3) standard deviation of the annual maximum NDVI values for years 1984-1986 (NDVI(sd84-86)) to improve Conservation Reserve Program land discrimination.Results of the classification were compared to three reference data sets: County-level USDA Census records (1982-2007) and two digital land cover maps (Kansas 2005 and USGS Trends Program maps (1986-2000)). Area of ever-cropped land for the five counties was on average 11.8 % higher than the area estimated from Census records. Overall agreement between the ever-cropped land map and the 2005 Kansas map was 91.9% and 97.2% for the Trends maps. Converting the intra-annual Landsat data set to a single annual maximum NDVI image composite considerably reduced the data set size, eliminated clouds and cloud-shadow affects, yet maintained information important for discriminating cropped land. Our results suggest that Landsat annual maximum NDVI image composites will be useful for characterizing land use and land cover change for many applications. PMID- 22423151 TI - Facile synthesis of 2,3,5,6-tetrabromo-4-methyl-nitrocyclohexa-2,5-dien-1-one, a mild nitration reagent. AB - Nitrocylcohexadienones have been applied as nitration reagents for mild, mono nitrating reactions. The original synthesis of 2,3,5,6-tetrabromo-4-methyl-4 nitrocylcohexa-2,5-dien-1-one appeared to be difficult to pursue due to both the solvent system and reaction conditions. Therefore, we applied a modified solvent system and optimized the reaction conditions to prepare the dienone at 0 degrees C, eventually overcome the difficulties. PMID- 22423153 TI - Multidrug-resistant tuberculosis today. PMID- 22423154 TI - Maternal mortality and human rights: landmark decision by United Nations human rights body. PMID- 22423155 TI - Public health round-up. PMID- 22423156 TI - The health-care challenges posed by population ageing. AB - Shrinking fertility rates and longer lives are changing the demographic landscape of countries worldwide, challenging not only the way we think about how to fund care for older people, but attitudes to ageing itself. PMID- 22423157 TI - Fixing fistula. AB - While new clinical management guidelines promise better treatment outcomes for women with obstetric fistula, more needs to be done to prevent this debilitating condition in the first place. PMID- 22423158 TI - From population control to human rights. Interview by Sarah Cumberland. PMID- 22423159 TI - Prioritizing risk factors to identify preventive interventions for economic assessment. AB - OBJECTIVE: To explore a risk factor approach for identifying preventive interventions that require more in-depth economic assessment, including cost effectiveness analyses. METHODS: A three-step approach was employed to: (i) identify the risk factors that contribute most substantially to disability adjusted life years (DALYs); (ii) re-rank these risk factors based on the availability of effective preventive interventions warranting further cost effectiveness analysis (and in some instances on evidence from existing cost effectiveness analyses); and (iii) re-rank these risk factors in accordance with their relative contribution to health inequalities. Health inequalities between the Maori and non-Maori populations in New Zealand were used by way of illustration. FINDINGS: Seven of the top 10 risk factors prioritized for research on preventive interventions in New Zealand were also among the 10 risk factors most highly ranked as contributing to DALYs in high-income countries of the World Health Organization's Western Pacific Region. The final list of priority risk factors included tobacco use; alcohol use; high blood pressure; high blood cholesterol; overweight/obesity, and physical inactivity. All of these factors contributed to health inequalities. Effective interventions for preventing all of them are available, and for each risk factor there is at least one documented cost-saving preventive intervention. CONCLUSION: The straightforward approach to prioritizing risk factors described in this paper may be applicable in many countries, and even in those countries that lack the capacity to perform additional cost-effectiveness analyses, this approach will still make it possible to determine which cost-effective interventions should be implemented in the short run. PMID- 22423160 TI - The tyranny of distance: maternity waiting homes and access to birthing facilities in rural Timor-Leste. AB - OBJECTIVE: To examine the impact of maternity waiting homes on the use of facility-based birthing services for women in two remote districts of Timor Leste. METHODS: A before-and-after study design was used to compare the number of facility-based births in women who lived at different distances (0-5, 6-25, 26-50 and > 50 km) from the health centre before and after implementation of maternity waiting homes. Routine data were collected from health centre records at the end of 2007; they included 249 births in Same, Manufahi district, and 1986 births in Lospalos, Lautem district. Population data were used to estimate the percentage of women in each distance category who were accessing facility-based care. FINDINGS: Most facility-based births in Same (80%) and Lospalos (62%) were among women who lived within 5 km of the health centre. There was no significant increase in the number of facility-based births among women in more remote areas following implementation of the maternity waiting homes. The percentage of births in the population that occurred in a health facility was low for both Manufahi district (9%) and Lautem district (17%), and use decreased markedly as distance between a woman's residence and the health facilities increased. CONCLUSION: The maternity waiting homes in Timor-Leste did not improve access to facility-based delivery for women in remote areas. The methods for distance analysis presented in this paper provide a framework that could be used by other countries seeking to evaluate maternity waiting homes. PMID- 22423161 TI - A systems approach to improving maternal health in the Philippines. AB - OBJECTIVE: To examine the impact of health-system-wide improvements on maternal health outcomes in the Philippines. METHODS: A retrospective longitudinal controlled study was used to compare a province that fast tracked the implementation of health system reforms with other provinces in the same region that introduced reforms less systematically and intensively between 2006 and 2009. FINDINGS: The early reform province quickly upgraded facilities in the tertiary and first level referral hospitals; other provinces had just begun reforms by the end of the study period. The early reform province had created 871 women's health teams by the end of 2009, compared with 391 teams in the only other province that reported such teams. The amount of maternal-health-care benefits paid by the Philippine Health Insurance Corporation in the early reform province grew by approximately 45%; in the other provinces, the next largest increase was 16%. The facility-based delivery rate increased by 44 percentage points in the early reform province, compared with 9-24 percentage points in the other provinces. Between 2006 and 2009, the actual number of maternal deaths in the early reform province fell from 42 to 18, and the maternal mortality ratio from 254 to 114. Smaller declines in maternal deaths over this period were seen in Camarines Norte (from 12 to 11) and Camarines Sur (from 26- to 23). The remaining three provinces reported increases in maternal deaths. CONCLUSION: Making health-system-wide reforms to improve maternal health has positive synergistic effects. PMID- 22423162 TI - Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007-2010. AB - OBJECTIVE: To present a global update of drug-resistant tuberculosis (TB) and explore trends in 1994-2010. METHODS: Data on drug resistance among new and previously treated TB patients, as reported by countries to the World Health Organization, were analysed. Such data are collected through surveys of a representative sample of TB patients or surveillance systems based on routine drug susceptibility testing. Associations between multidrug-resistant TB (MDR-TB) and human immunodeficiency virus (HIV) infection and sex were explored through logistic regression. FINDINGS: In 2007-2010, 80 countries and 8 territories reported surveillance data. MDR-TB among new and previously treated cases was highest in the Russian Federation (Murmansk oblast, 28.9%) and the Republic of Moldova (65.1%), respectively. In three former Soviet Union countries and South Africa, more than 10% of the cases of MDR-TB were extensively drug-resistant. Globally, in 1994 to 2010 multidrug resistance was observed in 3.4% (95% confidence interval, CI: 1.9-5.0) of all new TB cases and in 19.8% (95% CI: 14.4 25.1) of previously treated TB cases. No overall associations between MDR-TB and HIV infection (odds ratio, OR: 1.4; 95% CI: 0.7-3.0) or sex (OR: 1.1; 95% CI: 0.8 1.4) were found. Between 1994 and 2010, MDR-TB rates in the general population increased in Botswana, Peru, the Republic of Korea and declined in Estonia, Latvia and the United States of America. CONCLUSION: The highest global rates of MDR-TB ever reported were documented in 2009 and 2010. Trends in MDR-TB are still unclear in most settings. Better surveillance or survey data are required, especially from Africa and India. PMID- 22423163 TI - Female genital cutting: current practices and beliefs in western Africa. AB - OBJECTIVE: To conduct a cross-national comparative study of the prevalence and correlates of female genital cutting (FGC) practices and beliefs in western Africa. METHODS: Data from women who responded to the Multiple Indicator Cluster Surveys between 2005 and 2007 were used to estimate the frequencies of ever having been circumcised, having had a daughter circumcised, and believing that FGC practices should continue. Weighted logistic regression using data for each country was performed to determine the independent correlates of each outcome. FINDINGS: The prevalence of FGC was high overall but varied substantially across countries in western Africa. In Sierra Leone, Gambia, Burkina Faso and Mauritania, the prevalence of FGC was 94%, 79%, 74% and 72%, respectively, whereas in Ghana, Niger and Togo prevalence was less than 6%. Older age and being Muslim were generally associated with increased odds of FGC, and higher education was associated with lower odds of FGC. The association between FGC and wealth varied considerably. Burkina Faso was the only country in our study that experienced a dramatic reduction in FGC prevalence from women (74%) to their daughters (25%); only 14.2% of the women surveyed in that country said that they believe the practice should continue. CONCLUSION: The prevalence of FGC in western Africa remains high overall but varies substantially across countries. Given the broad range of experiences, successful strategies from countries where FGC is declining may provide useful examples for high-prevalence countries seeking to reduce their own FGC practices. PMID- 22423164 TI - Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether cotrimoxazole reduces mortality in adults receiving antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in low- and middle-income countries through a systematic review and meta-analysis. METHODS: PubMed and Embase were searched for randomized controlled trials and prospective and retrospective cohort studies that compared mortality or morbidity in HIV-infected individuals aged >= 13 years on cotrimoxazole and ART and on ART alone. The Newcastle-Ottawa Quality Assessment Scale was used to assess selection, confounding and measurement bias. Publication bias was assessed using Egger's and Begg's tests. Sensitivity analysis was performed because the I squared statistic indicated substantial heterogeneity in study results. A random effects model was used for meta-analysis. FINDINGS: Nine studies were included. Begg and Egger P-values for the seven that reported the effect of cotrimoxazole on mortality were 0.29 and 0.49, respectively, suggesting no publication bias. The I-squared statistic was 93.2%, indicating high heterogeneity in study results. The sensitivity analysis showed that neither the follow-up duration nor the percentage of individuals with World Health Organization stage 3 or 4 HIV disease at baseline explained the heterogeneity. The summary estimate of the effect of cotrimoxazole on the incidence rate of death was 0.42 (95% confidence interval: 0.29-0.61). Since most studies followed participants for less than 1 year, it was not possible to determine whether cotrimoxazole can be stopped safely after ART-induced immune reconstitution. CONCLUSION: Cotrimoxazole significantly increased survival in HIV-infected adults on ART. Further research is needed to determine the optimum duration of cotrimoxazole treatment in these patients. PMID- 22423165 TI - Prevalence and determinants of common perinatal mental disorders in women in low- and lower-middle-income countries: a systematic review. AB - OBJECTIVE: To review the evidence about the prevalence and determinants of non psychotic common perinatal mental disorders (CPMDs) in World Bank categorized low and lower-middle-income countries. METHODS: Major databases were searched systematically for English-language publications on the prevalence of non psychotic CPMDs and on their risk factors and determinants. All study designs were included. FINDINGS: Thirteen papers covering 17 low- and lower-middle-income countries provided findings for pregnant women, and 34, for women who had just given birth. Data on disorders in the antenatal period were available for 9 (8%) countries, and on disorders in the postnatal period, for 17 (15%). Weighted mean prevalence was 15.6% (95% confidence interval, CI: 15.4-15.9) antenatally and 19.8% (19.5-20.0) postnatally. Risk factors were: socioeconomic disadvantage (odds ratio [OR] range: 2.1-13.2); unintended pregnancy (1.6-8.8); being younger (2.1-5.4); being unmarried (3.4-5.8); lacking intimate partner empathy and support (2.0-9.4); having hostile in-laws (2.1-4.4); experiencing intimate partner violence (2.11-6.75); having insufficient emotional and practical support (2.8-6.1); in some settings, giving birth to a female (1.8-2.6), and having a history of mental health problems (5.1-5.6). Protective factors were: having more education (relative risk: 0.5; P = 0.03); having a permanent job (OR: 0.64; 95% CI: 0.4-1.0); being of the ethnic majority (OR: 0.2; 95% CI: 0.1-0.8) and having a kind, trustworthy intimate partner (OR: 0.52; 95% CI: 0.3-0.9). CONCLUSION: CPMDs are more prevalent in low- and lower-middle-income countries, particularly among poorer women with gender-based risks or a psychiatric history. PMID- 22423166 TI - Reduced death rates from cyclones in Bangladesh: what more needs to be done? AB - Tropical storms, such as cyclones, hurricanes and typhoons, present major threats to coastal communities. Around two million people worldwide have died and millions have been injured over the past two centuries as a result of tropical storms. Bangladesh is especially vulnerable to tropical cyclones, with around 718 000 deaths from them in the past 50 years. However, cyclone-related mortality in Bangladesh has declined by more than 100-fold over the past 40 years, from 500 000 deaths in 1970 to 4234 in 2007. The main factors responsible for these reduced fatalities and injuries are improved defensive measures, including early warning systems, cyclone shelters, evacuation plans, coastal embankments, reforestation schemes and increased awareness and communication. Although warning systems have been improved, evacuation before a cyclone remains a challenge, with major problems caused by illiteracy, lack of awareness and poor communication. Despite the potential risks of climate change and tropical storms, little empirical knowledge exists on how to develop effective strategies to reduce or mitigate the effects of cyclones. This paper summarizes the most recent data and outlines the strategy adopted in Bangladesh. It offers guidance on how similar strategies can be adopted by other countries vulnerable to tropical storms. Further research is needed to enable countries to limit the risks that cyclones present to public health. PMID- 22423167 TI - The Influence of Union Instability and Union Quality on Children's Aggressive Behavior. AB - We investigate whether mother's poor union quality attenuates the association between union instability and young children's behavioral adjustment. Using data from three waves of the Fragile Families and Child Wellbeing Study to consider children born to married or cohabiting mothers (N=1,730), we determine that children who have experienced poor union quality between mothers and their partners have higher predicted aggressive behavior scores at age 3, regardless of whether they have experienced union transitions, compared to children who have experienced high-quality, stable unions. Children who have experienced instability in the context of higher-quality unions and relatively less acrimonious dissolutions are similar to children raised in high-quality stable unions in terms of predicted aggressive behavior scores. PMID- 22423168 TI - Learning How to Ask: Reflections on Engaging American Indian Research Participants. PMID- 22423169 TI - Management of oesophageal coins in children. AB - OBJECTIVE: Is a watch and wait approach safe in asymptomatic patients presenting to the emergency department with a confirmed oesophageal coin on x-ray? METHODS: A retrospective case note review for children <16 years attending with a confirmed oesophageal coin on x-ray over a 7-year period (1 January 2004 to 31 December 2010). RESULTS: 89% (33/37) of coins in asymptomatic patients, who were conservatively managed, had passed spontaneously on repeat chest x-ray up to 18 h later. No patient who was discharged with a middle or lower oesophageal coin required a GA and no child who was treated conservatively developed any complications. CONCLUSION: In the UK asymptomatic children, with no history of tracheal or oesophageal disease and a confirmed oesophageal coin on x-ray should undergo a period of observation up to 18 h. This can be safely undertaken at home, followed by a repeat x-ray in the emergency department. PMID- 22423170 TI - Semiparametric Stochastic Modeling of the Rate Function in Longitudinal Studies. AB - In longitudinal biomedical studies, there is often interest in the rate functions, which describe the functional rates of change of biomarker profiles. This paper proposes a semiparametric approach to model these functions as the realizations of stochastic processes defined by stochastic differential equations. These processes are dependent on the covariates of interest and vary around a specified parametric function. An efficient Markov chain Monte Carlo algorithm is developed for inference. The proposed method is compared with several existing methods in terms of goodness-of-fit and more importantly the ability to forecast future functional data in a simulation study. The proposed methodology is applied to prostate-specific antigen profiles for illustration. Supplementary materials for this paper are available online. PMID- 22423171 TI - Coexistence of Obesity and Anemia in Older Mexican Adults. AB - INTRODUCTION: Developing countries in Latin America (LA) are experiencing rapid aging as a result of advances in medical interventions. This rapid aging has not occurred with comparable improvements in standards of living. Chronic conditions are becoming highly prevalent while exposure to infectious communicable diseases is very common. This unique situation where communicable and non-communicable diseases coexist in the presence of low socioeconomic status place countries in LA in a unique epidemiological situation. Mexico presents a very good example where the impact of this situation on health warrants further analysis. METHODS: We use data from the Mexican National Health and Nutrition Survey (ENSANut 2006), a cross-sectional study representative of all urban and rural areas of Mexico. A total of 5,605 adults older than 60 years of age with valid values for Body Mass Index and Hemoglobin were analyzed. We first included a descriptive analysis of the coexistence of anemia and obesity by age, gender and characteristics of the living environment. We reported the weighted percentages for each covariate by each of four nutritional condition categories (obese and anemic, only-obese, only anemic, not obese and not anemic). We used multinomial logit regressions to determine the association of socioeconomic characteristics, health status and the living environment with the presence of the three nutritional condition categories. RESULTS: In the ENSANut cohort 10.3% of older adults are anemic, 25.0% are obese and 2.6% are both anemic and obese. Approximately 62% has neither anemia nor obesity. Within the 38% that fall in the three nutritional condition categories, the co-existence of obesity & anemia appears to be associated with metropolitan area residence, living alone, being male, having relatively high wealth, and reporting two or more chronic health conditions. Analyzing the effect of the covariates to distinguish between outcome categories, living environment, age, gender, wealth, and smoking show a significant effect when comparing across the three nutritional categories. CONCLUSIONS: Older Mexican adults with both obesity & anemia have a different profile compared to that of adults with only one of the conditions. Future studies need to do a careful clinical evaluation of this group and design clinical interventions to avoid complications. Additionally, social support initiatives that target specific groups of older adults according to their health and social needs must be established. PMID- 22423172 TI - Parental Child-Rearing Strategies Influence Self-Regulation, Socio-Emotional Adjustment, and Psychopathology in Early Adulthood: Evidence from a Retrospective Cohort Study. AB - This study examined the association between recollected parental child-rearing strategies and individual differences in self-regulation, socio-emotional adjustment, and psychopathology in early adulthood. Undergraduate participants (N = 286) completed the EMBU - a measure of retrospective accounts of their parents' child-rearing behaviors - as well as self-report measures of self-regulation and socio-emotional adjustment across the domains of eating disorder symptoms, physically risky behavior, interpersonal problems, personal financial problems, and academic maladjustment. A subset of participants also completed the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF). Parental warmth was found to be related to overall better self-regulation and improved interpersonal and academic adjustment. In contrast, both parental rejection and overcontrol were found to be related to general deficits in self-regulation as well as adjustment difficulties and psychopathology. Parental rejection was most closely related to internalizing clinical presentations like anxiety, depression, and somatization, whereas overcontrol was most aligned with increased hypomanic activation and psychoticism. Mediation analyses demonstrated that the relationships between parental child-rearing strategies and socio-emotional adjustment and psychopathology were partially mediated by self-regulation. Future directions are suggested, including basic and translational research related to better understanding the roles of parental child-rearing and self-regulation in the development of internalizing symptoms, activation, and psychotic symptoms. PMID- 22423173 TI - Psychometric Study of the Occupational Self Assessment with Adolescents After Infectious Mononucleosis. AB - This study examined the psychometric characteristics of the Occupational Self Assessment (OSA) which measures clients' perceptions of their own competence and the value they assign to occupations. Two hundred and ninety-six adolescents with acute mononucleosis completed the OSA along with the Fatigue Scale, the Checklist of Infectious Symptoms, the Child Health Questionnaire, and the Perceived Stress Scale. Results indicated that OSA items coalesced to capture the intended constructs that the rating scales functioned as intended and that over 90% of adolescents were validly measured. The OSA showed adequate sensitivity and was stable over time. As expected, the OSA measures of competence were moderately associated with infectious symptoms, fatigue severity, health status, and stress while the measure of values was not and both measures were not associated with age, gender, or ethnicity. Finally, as expected, adolescents who had not recovered from mononucleosis after 12 months showed lower measures on the competence scale while still attaching the same value/importance to occupational participation when compared to recovered adolescents. PMID- 22423174 TI - Spline Confidence Bands for Functional Derivatives. AB - We develop in this paper a new procedure to construct simultaneous confidence bands for derivatives of mean curves in functional data analysis. The technique involves polynomial splines that provide an approximation to the derivatives of the mean functions, the covariance functions and the associated eigenfunctions. We show that the proposed procedure has desirable statistical properties. In particular, we first show that the proposed estimators of derivatives of the mean curves are semiparametrically efficient. Second, we establish consistency results for derivatives of covariance functions and their eigenfunctions. Most importantly, we show that the proposed spline confidence bands are asymptotically efficient as if all random trajectories were observed with no error. Finally, the confidence band procedure is illustrated through numerical simulation studies and a real life example. PMID- 22423175 TI - Analysis of Pressure Variations in a Low-Pressure Nickel-Hydrogen Battery - Part 1. AB - A low pressure nickel-hydrogen battery using either a metal hydride or gaseous hydrogen for H(2) storage has been developed for use in implantable neuroprosthetic devices. In this paper, pressure variations inside the cell for the gaseous hydrogen version are analyzed and correlated with oxygen evolution side reaction at the end of charging, the recombination of oxygen with hydrogen during charging and a subsequent rest period, and the self-discharge of the nickel electrode. About 70% of the recombination occurred simultaneously with oxygen evolution during charging and the remaining oxygen recombined with hydrogen during the 1(st) hour after charging. Self-discharge of the cell varies linearly with hydrogen pressure at a given state of charge and increased with increasing battery charge levels. The coulometric efficiency calculated based on analysis of the pressure-time data agreed well with the efficiency calculated based on the current-time data. Pressure variations in the battery are simulated accurately to predict coulometric efficiency and the state of charge of the cell, factors of extreme importance for a battery intended for implantation within the human body. PMID- 22423176 TI - Placement of Accelerometers for High Sensing Resolution in Micromanipulation. AB - High sensing resolution is required in sensing of surgical instrument motion in micromanipulation tasks. Accelerometers can be employed to sense physiological motion of the instrument during micromanipulation. Various configurations of accelerometer placement had been introduced in the past to sense motion of a rigid-body such as a surgical instrument. Placement (location and orientation) of accelerometers fixed in the instrument plays a significant role in achieving high sensing resolution. However, there is no literature or work on the effect of placement of accelerometers on sensing resolution. In this paper, an approach of placement of accelerometers within an available space to obtain highest possible sensing resolution in sensing of rigid-body motion in micromanipulation tasks is proposed. Superiority of the proposed placement approach is shown in sensing of a microsurgical instrument angular motion by comparing sensing resolutions achieved as a result of employing the configuration following the proposed approach and the existing configurations. Apart from achieving high sensing resolution, and design simplicity, the proposed placement approach also provides flexibility in placing accelerometers; hence it is especially useful in applications with limited available space to mount accelerometers. PMID- 22423177 TI - A Micro Motion Sensing System for Micromanipulation Tasks. AB - An optical-based motion sensing system has been developed for real-time sensing of instrument motion in micromanipulation. The main components of the system consist of a pair of position sensitive detectors (PSD), lenses, an infrared (IR) diode that illuminates the workspace of the system, a non-reflective intraocular shaft, and a white reflective ball attached at the end of the shaft. The system calculates 3D displacement of the ball inside the workspace using the centroid position of the IR rays that are reflected from the ball and strike the PSDs. In order to eliminate inherent nonlinearity of the system, calibration using a feedforward neural network is proposed and presented. Handling of different ambient light and environment light conditions not to affect the system accuracy is described. Analyses of the whole optical system and effect of instrument orientation on the system accuracy are presented. Sensing resolution, dynamic accuracies at a few different frequencies, and static accuracies at a few different orientations of the instrument are reported. The system and the analyses are useful in assessing performance of hand-held microsurgical instruments and operator performance in micromanipulation tasks. PMID- 22423178 TI - Cancer patient navigator tasks across the cancer care continuum. AB - Cancer patient navigation (PN) programs have been shown to increase access to and utilization of cancer care for poor and underserved individuals. Despite mounting evidence of its value, cancer patient navigation is not universally understood or provided. We describe five PN programs and the range of tasks their navigators provide across the cancer care continuum (education and outreach, screening, diagnosis and staging, treatment, survivorship, and end-of-life). Tasks are organized by their potential to make cancer services understandable, available, accessible, affordable, appropriate, and accountable. Although navigators perform similar tasks across the five programs, their specific approaches reflect differences in community culture, context, program setting, and funding. Task lists can inform the development of programs, job descriptions, training, and evaluation. They also may be useful in the move to certify navigators and establish mechanisms for reimbursement for navigation services. PMID- 22423179 TI - Delayed postural control during self-generated perturbations in the frail older adults. AB - PURPOSE: The aim of this study was to investigate the coordination between posture and movement in pathological aging (frailty) in comparison with normal aging, with the hypothesis that in pathological aging, postural control evolves towards a more reactive mode for which the perturbation induced by the movement is not anticipated and leads to delayed and late postural adjustments. METHODS: Elderly subjects performed rapid focal arm-raising movements towards a target, from an upright standing position in two stimuli conditions: simple reaction time and choice reaction time (CRT). Hand and center of pressure (CoP) kinematics were compared between a control group and a frail group of the same age. RESULTS: In frail individuals, the entire movement was impaired and slowed down. In addition, postural adjustments that classically precede and accompany the focal arm movement were delayed and reduced, especially in the CRT condition in which the motor prediction is more limited. Finally, a correlation between the time to CoP maximal velocity and the timed up- and-go score was observed. CONCLUSION: In these patients, it was concluded that the control of the CoP displacement evolved from a proactive mode in which the perturbation associated with the arm movement is anticipated toward a more reactive mode in which the perturbation is compensated by late and delayed adjustments. PMID- 22423180 TI - Myocardial infarction in patients over 90 years of age. AB - BACKGROUND: The aim of this study was to examine the trend in increasing life expectancy in relation to heart attack and cardiac catheterization. METHODS: A retrospective study of very elderly patients over 90 years of age (study group) and between 70 and 79 years of age (control group) with myocardial infarction and acute coronary syndrome who underwent coronary angiography was conducted. RESULTS: A total of 1100 cardiac catheterizations were performed in the cardiac catheterization laboratory of Vinzentius-Hospital in Landau, Germany from 2007 to 2011. The number of coronary angiographies performed in patients aged over 90 years and those aged 70-79 years was 36 and 354, respectively, during this same time period. No increase in the number of evidence-based therapy for coronary heart disease by cardiac catheterization was observed in the very elderly patients over this time period. CONCLUSION: An increase in the number of patients aged over 90 years and a rise in heart attacks, as evaluated by coronary angiography, could not be found in this study. PMID- 22423181 TI - Cervical cancer screening in primary health care setting in Sudan: a comparative study of visual inspection with acetic acid and Pap smear. AB - OBJECTIVE: To determine the feasibility of visual inspection with the use of acetic acid (VIA) as a screening method for cervical cancer, an alternative to the Pap smear used in primary health care setting in Sudan, and to compare sensitivity, specificity, positive and negative predictive values, and histological diagnosis of positive cases of both tests. METHODS: A cross sectional study of 934 asymptomatic women living in Khartoum, Sudan, was conducted during 2009-2010. A semi-structured questionnaire containing socio economic and reproductive variables was used to collect data from each participant. Methods of screening used were VIA and conventional Pap smear, followed by colposcopy and biopsy for confirmation of the positive results of both screening tests. RESULTS: The tests identified altogether 119 (12.7%) positive women. VIA detected significantly more positive women than Pap smear (7.6% versus 5.1%; P = 0.004), with an overlap between the two screening tests in 19% of positive results. There was no significant difference between VIA and Pap smear findings and sociodemographic and reproductive factors among screened women. Use of colposcopy and biopsy for positive women confirmed that 88/119 (73.9%) were positive for cervical intraepithelial neoplasia. VIA had higher sensitivity than Pap smear (74.2% versus 72.9%; P = 0.05) respectively. Out of 88 confirmed positive cases, 22 (25.0%) cases were invasive cervical cancer in stage 1, of which 19 versus three were detected by VIA and Pap smear respectively (P = 0.001). VIA had higher sensitivity and lower specificity than Pap smear (60.2% versus 47.7%) and (41.9% versus 83.8%) respectively. The combination of VIA/Pap has better sensitivity and specificity than each independent test (82.6% and 92.2%). CONCLUSION: The findings of this study showed that VIA has higher sensitivity and lower specificity compared to Pap smear, but a combination of both tests has greater sensitivity and specificity than each test independently. It indicates that VIA is useful for screening of cervical cancer in the primary health care setting in Sudan, but positive results need to be confirmed by colposcopy and biopsy. PMID- 22423182 TI - Role of notch signaling in osteoimmunology--from the standpoint of osteoclast differentiation. AB - The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Osteoimmunology comprises the interplay between the immune system and bone metabolism. Osteoclasts, cells that resorb bone, play a crucial role in bone metabolism. In this review, we discuss the role of Notch signaling in osteoimmunology that is crucial for physiological bone remodeling (such as in orthodontic tooth movement, where bone remodeling is in balance) and undue non-physiological Notch signaling which results in pathological bone remodeling (such as in rheumatoid arthritis and periodontitis, where bone remodeling is out of balance) from the point view of osteoclast differentiation. A proposal is made that Notch signaling not only controls immune system reaction but also interferes with osteoclast differentiation involved in the bone remodeling process. Therefore, Notch signaling could be a promising therapeutic target at conditions that cross link the immune system with the skeletal system. PMID- 22423184 TI - Dental age in patients with impacted maxillary canines related to the position of the impacted teeth. PMID- 22423185 TI - Treatment timing of MARA and fixed appliance therapy of Class II malocclusion. AB - The objective of this study is to evaluate the effect of timing on Mandibular Anterior Repositioning Appliance (MARA) and fixed appliance treatment of Class II malocclusion in a prospective clinical trial. The treated sample consisted of 51 consecutively treated patients at prepubertal (n = 21), pubertal (n = 15), and postpubertal (n = 15) stages of development. Control groups for the three treated groups were generated from growth data of untreated Class II subjects. Lateral cephalograms were digitized and superimposed via cephalometric software at T1 (pre-treatment) and T2 (after comprehensive treatment). The T1-T2 changes in the treated groups were compared to those in their corresponding control groups with Mann-Whitney tests with Bonferroni correction. Mandibular elongation was greater at the pubertal stage (Co-Gn +2.6 mm, with respect to controls). Headgear effect on the maxilla was greater in the pre-peak sample (Co-A -1.9 mm, with respect to controls). Dentoalveolar compensations (proclination of lower incisors, extrusion and mesialization of lower molars, and reduction in the overbite) were significant in the pre-peak and post-peak groups. Optimal timing for Class II treatment with MARA appliance is at the pubertal growth spurt, with enhanced mandibular skeletal changes and minimal dentoalveolar compensations. PMID- 22423186 TI - A new species of Habralictus Moure from Dominica, Lesser Antilles (Hymenoptera, Halictidae). AB - A new species of Habralictus Moure (Apoidea, Halictidae) is described from the island of Dominica, Habralictus gonzalezisp. n. The species is distinguished from other West Indian Habralictus and a key is provided to the West Indian Habralictus. Brief comments on the genus Habralictus and bee species of Dominica are provided. PMID- 22423187 TI - Description of a new species of the leafhopper genus Zyginella Low from Southwest China (Hemiptera, Cicadellidae, Typhlocybinae). AB - A new species, Zyginella menghaiensissp. n. (Hemiptera: Cicadellidae: Typhlocybinae: Zyginellini), is described from Chinaand a key to species of Zyginella from China is provided. PMID- 22423188 TI - A new genus of oak gallwasp, Coffeikokkos Pujade-Villar & Melika, gen. n., with a description of a new species from Costa Rica (Hymenoptera, Cynipidae). AB - A new genus of oak gallwasp, Coffeikokkos Pujade-Villar & Melika, gen. n., is described from Costa Rica. Diagnostic characters and generic limits of the new genus are discussed in detail. The new genus includes Coffeikokkos copeyensis Pujade-Villar & Melika, sp. n., which induces galls on stems of Quercus bumelioides, an endemic oak to Costa Rica, Honduras and Panama. The new species and galls are described and illustrated. PMID- 22423189 TI - A new species of Andean semiaquatic lizard of the genus Potamites (Sauria, Gymnophtalmidae) from southern Peru. AB - We describe a new lizard species of the genus Potamites from the montane forests of the Cordillera de Vilcabamba (Cusco region) and Apurimac River valley (Ayacucho region), between 1500 and 2000 meters of elevation, in southern Peru. The new species is distinguishable from all other species of the genus mainly by having highly keeled scattered scales on dorsum and females lacking femoral pores. PMID- 22423190 TI - Two new and rare mountain door-snails (Gastropoda, Pulmonata, Clausiliidae) from high mountain areas in Macedonia. AB - Two species of Clausiliidaeare described as new to science. Euxinella alpinellasp. n. is the fourth species within genus Euxinella Nordsieck, 1973, and Vestia lazaroviisp. n. is the second species of genus Vestia recorded from the Republic of Macedonia. In both species, the clausilium apparatus shows a high degree of variation. PMID- 22423191 TI - On the spider genus Amaurobius (Araneae, Amaurobiidae) in India and Nepal. AB - A new species, Amaurobius koponenisp. n., is described from Himachal Pradesh on the basis of a male specimen. A key to all five genera of Amaurobiidae that occur in Asia is provided. Four species from India and Nepal incorrectly assigned to Amaurobius are transferred to three genera of Titanoecidae: Anuvinda milloti (Hubert, 1973), comb. n., Pandava andhraca (Patel & Reddy, 1990), comb. n., Pandava nathabhaii (Patel & Patel, 1975), comb. n., and Titanoeca sharmai (Bastawade, 2008), comb. n. PMID- 22423192 TI - A pair of new sister species of Loneura (Psocodea, 'Psocoptera', Ptiloneuridae) from Valle del Cauca, Colombia, representing a new infrageneric group. AB - Two sister species of Loneura, from Valle del Cauca, Colombia, are here described and illustrated. They constitute a new species group that modifies the scheme of classification, proposed earlier for the genus by Garcia Aldrete et al. (2011b). The new group is characterized by having the central sclerite of the male hypandrium with four posterior projections. A key to the males of Group II is included. The types are deposited in the Entomological Museum of the Universidad del Valle. Colombia may prove to be the most species rich area for Loneura. PMID- 22423193 TI - A new species of spider fly in the genus Sabroskya Schlinger from Malawi, with a key to Acrocerinae world genera (Diptera, Acroceridae). AB - In this paper we diagnose the genus Sabroskya Schlinger, 1960 and describe Sabroskya schlingerisp. n. from Malawi. We also provide dichotomous keys to species of Sabroskya and to world genera of the subfamily Acrocerinae, both extant and extinct. PMID- 22423194 TI - New taxa of terrestrial molluscs from Turkey (Gastropoda, Pristilomatidae, Enidae, Hygromiidae, Helicidae). AB - This paper reports on results of several collecting trips of the authors in Turkey. In the course of this research, a long-lasting question was addressed. It could be proven that the nominal species Bulimus frivaldskyi L. Pfeiffer, 1847 is closely related to Meijeriella canaliculata Bank, 1985, and thus this species is shifted from the genus Ena Turton, 1831, to the genus Meijeriella Bank, 1985. Meijeriella canaliculata Bank, 1985, could be recorded from Turkey for the first time. The nomenclatural situation of the species Euchondrus septemdentatus (Roth, 1839) vs. its replacement name Euchondrus borealis (Mousson, 1874) is discussed. A new arrangement of the species formely comprised in the genus Zebrina Held, 1837 is presented, and the genera Rhabdoena Kobelt & Moellendorff, 1902, and Leucomastus A. Wagner, 1927 are re-established. The following species and subspecies new to science could be described: Vitrea gosteliisp. n. (Pristilomatidae), Turanena demirsoyisp. n., Euchondrus paucidentatussp. n., Rhabdoena gosteliisp. n. (all Enidae), Metafruticicola kizildagensissp. n. (Hygromiidae), and Assyriella thospitis menkhorstissp. n. (Helicidae). For several other species, new distribution records are listed. PMID- 22423195 TI - Contribution to knowledge of the genus Chydaeus in Xizang Autonomous Region [Tibet] and Yunnan Province, China (Coleoptera, Carabidae, Harpalini). AB - Five new species of the genus Chydaeus Chaudoir, 1854 are described from China: Chydaeus fugongensissp. n. (Shibali, Fugong County, Yunnan Province), Chydaeus gutangensissp. n. (Gutang, Medog County, Xizang Autonomous Region [Tibet]), Chydaeus hanmiensissp. n. (Hanmi, Medog County, Xizang Autonomous Region [Tibet]), Chydaeus asetosussp. n. (NE of Fugong, Yunnan Province), and Chydaeus baoshanensissp. n. (N of Baoshan, Yunnan Province). Taxonomic and faunistic notes on eleven other species occurring in Xizang and Yunnan are also provided. Chydaeus shunichii Ito, 2006 is re-described, based on specimens from Lushui County, Yunnan. Chydaeus kumei Ito, 1992 is treated as a subspecies of Chydaeus andrewesi Schauberger, 1932 [NEW STATUS]. The taxonomic status of Chydaeus guangxiensis Ito, 2006 is discussed. The following taxa are recorded from China for the first time: Chydaeus obtusicollis Schauberger, 1932 (Xizang and Yunnan), Chydaeus malaisei Kataev & Schmidt, 2006 (Yunnan), Chydaeus semenowi (Tschitscherine, 1899) (Xizang and Yunnan), Chydaeus andrewesi andrewesi Schauberger, 1932 (Xizang and Yunnan), Chydaeus andrewesi kumei Ito (Yunnan), Chydaeus bedeli interjectus Kataev & Schmidt, 2002 (Xizang), and Chydaeus bedeli vietnamensis Kataev & Schmidt, 2002 (Yunnan). PMID- 22423196 TI - Detecting intra-fraction motion in patients undergoing radiation treatment using a low-cost wireless accelerometer. AB - The utility of a novel, high-precision, non-intrusive, wireless, accelerometer based patient orientation monitoring system (APOMS) in determining orientation change in patients undergoing radiation treatment is reported here. Using this system a small wireless accelerometer sensor is placed on a patient's skin, broadcasting its orientation to the receiving station connected to a PC in the control area. A threshold-based algorithm is developed to identify the exact amount of the patient's head orientation change. Through real-time measurements, an audible alarm can alert the radiation therapist if the user-defined orientation threshold is violated. Our results indicate that, in spite of its low cost and simplicity, the APOMS is highly sensitive and offers accurate measurements. Furthermore, the APOMS is patient friendly, vendor neutral, and requires minimal user training. The versatile architecture of the APOMS makes it potentially suitable for variety of applications, including study of correlation between external and internal markers during Image-Guided Radiation Therapy (IGRT), with no major changes in hardware setup or algorithm. PMID- 22423197 TI - Preparation, Characterization and Sensitive Gas Sensing of Conductive Core-sheath TiO(2)-PEDOT Nanocables. AB - Conductive core-sheath TiO(2)-PEDOT nanocables were prepared using electrospun TiO(2) nanofibers as template, followed by vapor phase polymerization of EDOT. Various techniques were employed to characterize the sample. The results reveal that the TiO(2) core has an average diameter of ~78 nm while the PEDOT sheath has a uniform thickness of ~6 nm. The as-prepared TiO(2)-PEDOT nanocables display a fast and reversible response to gaseous NO(2) and NH(3) with a limit of detection as low as 7 ppb and 675 ppb (S/N=3), respectively. This study provides a route for the synthesis of conductive nanostructures which show excellent performance for sensing applications. PMID- 22423198 TI - A geometric modelling approach to determining the best sensing coverage for 3 dimensional acoustic target tracking in wireless sensor networks. AB - Existing 3-dimensional acoustic target tracking methods that use wired/wireless networked sensor nodes to track targets based on four sensing coverage do not always compute the feasible spatio-temporal information of target objects. To investigate this discrepancy in a formal setting, we propose a geometric model of the target tracking problem alongside its equivalent geometric dual model that is easier to solve. We then study and prove some properties of dual model by exploiting its relationship with algebra. Based on these properties, we propose a four coverage axis line method based on four sensing coverage and prove that four sensing coverage always yields two dual correct answers; usually one of them is infeasible. By showing that the feasible answer can be only sometimes identified by using a simple time test method such as the one proposed by ourselves, we prove that four sensing coverage fails to always yield the feasible spatio temporal information of a target object. We further prove that five sensing coverage always gives the feasible position of a target object under certain conditions that are discussed in this paper. We propose three extensions to four coverage axis line method, namely, five coverage extent point method, five coverage extended axis lines method, and five coverage redundant axis lines method. Computation and time complexities of all four proposed methods are equal in the worst cases as well as on average being equal to Theta(1) each. Proposed methods and proved facts about capabilities of sensing coverage degree in this paper can be used in all other methods of acoustic target tracking like Bayesian filtering methods. PMID- 22423199 TI - Sensing a changing world. PMID- 22423200 TI - Research of DOA Estimation Based on Single MEMS Vector Hydrophone. AB - The MEMS vector hydrophone is a novel acoustic sensor with a "four-beam-cilia" structure. Based on the MEMS vector hydrophone with this structure, the paper studies the method of estimated direction of arrival (DOA). According to various research papers, many algorithms can be applied to vector hydrophones. The beam forming approach and bar graph approach are described in detail. Laboratory tests by means of the a standing-wave tube are performed to validate the theoretical results. Both the theoretical analysis and the results of tests prove that the proposed MEMS vector hydrophone possesses the desired directional function. PMID- 22423202 TI - An overview on wireless sensor networks technology and evolution. AB - Wireless sensor networks (WSNs) enable new applications and require non conventional paradigms for protocol design due to several constraints. Owing to the requirement for low device complexity together with low energy consumption (i.e., long network lifetime), a proper balance between communication and signal/data processing capabilities must be found. This motivates a huge effort in research activities, standardization process, and industrial investments on this field since the last decade. This survey paper aims at reporting an overview of WSNs technologies, main applications and standards, features in WSNs design, and evolutions. In particular, some peculiar applications, such as those based on environmental monitoring, are discussed and design strategies highlighted; a case study based on a real implementation is also reported. Trends and possible evolutions are traced. Emphasis is given to the IEEE 802.15.4 technology, which enables many applications of WSNs. Some example of performance characteristics of 802.15.4-based networks are shown and discussed as a function of the size of the WSN and the data type to be exchanged among nodes. PMID- 22423203 TI - Primary cilia: highly sophisticated biological sensors. AB - Primary cilia, thin hair-like structures protruding from the apical surface of most mammalian cells, have gained the attention of many researchers over the past decade. Primary cilia are microtubule-filled sensory organelles that are enclosed within the ciliary membrane. They originate at the cell surface from the mother centriole that becomes the mature basal body. In this review, we will discuss recent literatures on the roles of cilia as sophisticated sensory organelles. With particular emphasis on vascular endothelia and renal epithelia, the mechanosensory role of cilia in sensing fluid shear stress will be discussed. Also highlighted is the ciliary involvement in cell cycle regulation, development, cell signaling and cancer. Finally, primary cilia-related disorders will be briefly described. PMID- 22423204 TI - REMOTE, a Wireless Sensor Network Based System to Monitor Rowing Performance. AB - In this paper, we take a hard look at the performance of REMOTE, a sensor network based application that provides a detailed picture of a boat movement, individual rower performance, or his/her performance compared with other crew members. The application analyzes data gathered with a WSN strategically deployed over a boat to obtain information on the boat and oar movements. Functionalities of REMOTE are compared to those of RowX [1] outdoor instrument, a commercial wired sensor instrument designed for similar purposes. This study demonstrates that with smart geometrical configuration of the sensors, rotation and translation of the oars and boat can be obtained. Three different tests are performed: laboratory calibration allows us to become familiar with the accelerometer readings and validate the theory, ergometer tests which help us to set the acquisition parameters, and on boat tests shows the application potential of this technologies in sports. PMID- 22423205 TI - Ion-sensitive field-effect transistor for biological sensing. AB - In recent years there has been great progress in applying FET-type biosensors for highly sensitive biological detection. Among them, the ISFET (ion-sensitive field effect transistor) is one of the most intriguing approaches in electrical biosensing technology. Here, we review some of the main advances in this field over the past few years, explore its application prospects, and discuss the main issues, approaches, and challenges, with the aim of stimulating a broader interest in developing ISFET-based biosensors and extending their applications for reliable and sensitive analysis of various biomolecules such as DNA, proteins, enzymes, and cells. PMID- 22423206 TI - Semiconductor quantum dots in chemical sensors and biosensors. AB - Quantum dots are nanometre-scale semiconductor crystals with unique optical properties that are advantageous for the development of novel chemical sensors and biosensors. The surface chemistry of luminescent quantum dots has encouraged the development of multiple probes based on linked recognition molecules such as peptides, nucleic acids or small-molecule ligands. This review overviews the design of sensitive and selective nanoprobes, ranging from the type of target molecules to the optical transduction scheme. Representative examples of quantum dot-based optical sensors from this fast-moving field have been selected and are discussed towards the most promising directions for future research. PMID- 22423207 TI - A hybrid adaptive routing algorithm for event-driven wireless sensor networks. AB - Routing is a basic function in wireless sensor networks (WSNs). For these networks, routing algorithms depend on the characteristics of the applications and, consequently, there is no self-contained algorithm suitable for every case. In some scenarios, the network behavior (traffic load) may vary a lot, such as an event-driven application, favoring different algorithms at different instants. This work presents a hybrid and adaptive algorithm for routing in WSNs, called Multi-MAF, that adapts its behavior autonomously in response to the variation of network conditions. In particular, the proposed algorithm applies both reactive and proactive strategies for routing infrastructure creation, and uses an event detection estimation model to change between the strategies and save energy. To show the advantages of the proposed approach, it is evaluated through simulations. Comparisons with independent reactive and proactive algorithms show improvements on energy consumption. PMID- 22423209 TI - Chalcogenide glass optical waveguides for infrared biosensing. AB - Due to the remarkable properties of chalcogenide (Chg) glasses, Chg optical waveguides should play a significant role in the development of optical biosensors. This paper describes the fabrication and properties of chalcogenide fibres and planar waveguides. Using optical fibre transparent in the mid-infrared spectral range we have developed a biosensor that can collect information on whole metabolism alterations, rapidly and in situ. Thanks to this sensor it is possible to collect infrared spectra by remote spectroscopy, by simple contact with the sample. In this way, we tried to determine spectral modifications due, on the one hand, to cerebral metabolism alterations caused by a transient focal ischemia in the rat brain and, in the other hand, starvation in the mouse liver. We also applied a microdialysis method, a well known technique for in vivo brain metabolism studies, as reference. In the field of integrated microsensors, reactive ion etching was used to pattern rib waveguides between 2 and 300 MUm wide. This technique was used to fabricate Y optical junctions for optical interconnections on chalcogenide amorphous films, which can potentially increase the sensitivity and stability of an optical micro-sensor. The first tests were also carried out to functionalise the Chg planar waveguides with the aim of using them as (bio)sensors. PMID- 22423211 TI - The pH Response and Sensing Mechanism of n-Type ZnO/Electrolyte Interfaces. AB - Ever since the discovery of the pH-sensing properties of ZnO crystals, researchers have been exploring their potential in electrochemical applications. The recent expansion and availability of chemical modification methods has made it possible to generate a new class of electrochemically active ZnO nanorods. This reduction in size of ZnO (to a nanocrystalline form) using new growth techniques is essentially an example of the nanotechnology fabrication principle. The availability of these ZnO nanorods opens up an entire new and exciting research direction in the field of electrochemical sensing. This review covers the latest advances and mechanism of pH-sensing using ZnO nanorods, with an emphasis on the nano-interface mechanism. We discuss methods for calculating the effect of surface states on pH-sensing at a ZnO/electrolyte interface. All of these current research topics aim to explain the mechanism of pH-sensing using a ZnO bulk- or nano-scale single crystal. An important goal of these investigations is the translation of these nanotechnology-modified nanorods into potential novel applications. PMID- 22423212 TI - Platform for a hydrocarbon exhaust gas sensor utilizing a pumping cell and a conductometric sensor. AB - Very often, high-temperature operated gas sensors are cross-sensitive to oxygen and/or they cannot be operated in oxygen-deficient (rich) atmospheres. For instance, some metal oxides like Ga(2)O(3) or doped SrTiO(3) are excellent materials for conductometric hydrocarbon detection in the rough atmosphere of automotive exhausts, but have to be operated preferably at a constant oxygen concentration. We propose a modular sensor platform that combines a conductometric two-sensor-setup with an electrochemical pumping cell made of YSZ to establish a constant oxygen concentration in the ambient of the conductometric sensor film. In this paper, the platform is introduced, the two-sensor-setup is integrated into this new design, and sensing performance is characterized. Such a platform can be used for other sensor principles as well. PMID- 22423213 TI - Detecting proteins in highly autofluorescent cells using quantum dot antibody conjugates. AB - We have applied quantum dot (Qdot) antibody conjugates as a biomolecular probe for cellular proteins important in biogeochemical cycling in the sea. Conventional immunological methods have been hampered by the strong autofluorescence found in cyanobacteria cells. Qdot conjugates provide an ideal alternative for studies that require long-term imaging of cells such as detection of low abundance cellular antigens by fluorescence microscopy. The advantage of Qdot labeled probes over conventional immunological methods is the photostability of the probe. Phycoerythrin bleaches in cyanobacterial cells under prolonged UV or blue light excitation, which means that the semiconducting nanocrystal probe, the Qdot, can yield a strong fluorescent signal without interference from cellular pigments. PMID- 22423214 TI - Understanding Goals of Care Statements and Preferences among Patients and Their Surrogates in the Medical ICU. AB - BACKGROUND: Treatment decisions should be based on patients' goals of care to provide an ethical, patient-centered framework for decision-making. OBJECTIVES: The purpose of this study is to improve our understanding about how patients' and surrogates' goals of care are communicated and interpreted in an MICU. METHODS: One hundred patients admitted to an MICU, or their surrogates, responded to an open-ended question about goals of care for their hospitalization followed by a closed-ended question regarding their most important goal of care. Investigators interpreted participants' open-ended responses and compared these interpretations with participants' closed-ended, most-important-goal selections. RESULTS: Investigators' interpretations of participants' open-ended goals of care responses matched participants' closed-ended most important goal of care in only 28 of 100 cases. However, there was good inter-rater reliability between investigators in their interpretation of participants' open-ended responses, with agreement in 78 of 100 cases. CONCLUSIONS: Clinicians should be cautious in interpreting patients' or surrogates' responses to open-ended questions about goals of care. A shared understanding of goals of care may be facilitated by alternating open-ended and closed-ended questions to clarify patients' or surrogates' responses. PMID- 22423215 TI - Montessori-Based Activities as a Trans-Generational Interface for Persons with Dementia and Preschool Children. AB - Montessori-based activities for persons with dementia have been used to successfully provide opportunities for programming between older adults and preschool children in shared site. intergenerational care programs. Such intergenerational programming allows older adults with dementia to fulfill roles of teacher or mentor to younger children or as collaborative workmates for persons with more advanced dementia while providing children with positive one-on one interactions with older adults. We review several studies using this approach, describe characteristics of the programs, participants and results obtained and provide recommendations for those interested in extending this line of work. PMID- 22423218 TI - All-d-Enantiomer of beta-Amyloid Peptide Forms Ion Channels in Lipid Bilayers. AB - Alzheimer's disease (AD) is the most common type of senile dementia in aging populations. Amyloid beta (Abeta)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Abeta-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Abeta binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Abeta peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Abeta effects even in the absence of receptor-peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Abeta isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Abeta isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Abeta isomer channels, and the d-isomer channel conductance is blocked by Zn(2+), a known blocker of l-Abeta isomer channels. MD simulations further verify formation of beta-barrel-like Abeta channels with d- and l isomers, illustrating that both d- and l-Abeta barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca(2+) leaking, unregulated channels in AD, and suggest that Abeta toxicity is mediated through a receptor-independent, nonstereoselective mechanism. PMID- 22423219 TI - Effect of network architecture on synchronization and entrainment properties of the circadian oscillations in the suprachiasmatic nucleus. AB - In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus constitutes the central circadian pacemaker. The SCN receives light signals from the retina and controls peripheral circadian clocks (located in the cortex, the pineal gland, the liver, the kidney, the heart, etc.). This hierarchical organization of the circadian system ensures the proper timing of physiological processes. In each SCN neuron, interconnected transcriptional and translational feedback loops enable the circadian expression of the clock genes. Although all the neurons have the same genotype, the oscillations of individual cells are highly heterogeneous in dispersed cell culture: many cells present damped oscillations and the period of the oscillations varies from cell to cell. In addition, the neurotransmitters that ensure the intercellular coupling, and thereby the synchronization of the cellular rhythms, differ between the two main regions of the SCN. In this work, a mathematical model that accounts for this heterogeneous organization of the SCN is presented and used to study the implication of the SCN network topology on synchronization and entrainment properties. The results show that oscillations with larger amplitude can be obtained with scale-free networks, in contrast to random and local connections. Networks with the small-world property such as the scale-free networks used in this work can adapt faster to a delay or advance in the light/dark cycle (jet lag). Interestingly a certain level of cellular heterogeneity is not detrimental to synchronization performances, but on the contrary helps resynchronization after jet lag. When coupling two networks with different topologies that mimic the two regions of the SCN, efficient filtering of pulse-like perturbations in the entrainment pattern is observed. These results suggest that the complex and heterogeneous architecture of the SCN decreases the sensitivity of the network to short entrainment perturbations while, at the same time, improving its adaptation abilities to long term changes. PMID- 22423220 TI - Mechanistic basis of branch-site selection in filamentous bacteria. AB - Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed. PMID- 22423221 TI - A meta-analysis and genome-wide association study of platelet count and mean platelet volume in african americans. AB - Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5*10(-8) of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1*10(-9)), 7q11 (rs13236689, CD36, p = 2.8*10(-9)), 10q21 (rs7896518, JMJD1C, p = 2.3*10(-12)), 11q13 (rs477895, BAD, p = 4.9*10(-8)), and 20q13 (rs151361, SLMO2, p = 9.4*10(-9)). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5*10(-8), two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis. PMID- 22423222 TI - Integrating recent data in managing adverse events in the treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a major cause of cancer-related morbidity and mortality worldwide. In the United States, HCC is the main cause of death in patients with cirrhosis, and the incidence of this malignancy is on the rise. Because HCC is associated with a particularly poor prognosis, emphasis is placed on surveillance of high-risk patients. Early detection allows a greater chance of diagnosing HCC before it has spread, thus increasing the chances that the patient can be potentially cured with surgical techniques such as resection and transplantation. However, most cases of HCC are not diagnosed until at least some of the cancer has spread or multiple nodules exist. For these patients, treatment options include percutaneous and transarterial ablation, as well as systemic chemotherapy. Systemic therapy is now considered the standard of care for patients with advanced tumors. Traditional treatment was based on cytotoxic chemotherapeutic agents, such as doxorubicin. This approach was associated with minimal benefit and a high rate of toxicity. Recently, targeted agents have proven more effective and safer in this setting. The oral multikinase inhibitor sorafenib is now approved for the treatment of unresectable HCC and is currently the only approved agent for advanced HCC. In order to maximize the benefit of sorafenib and other investigational agents for patients with advanced disease, effective interventions have been designed to mitigate their associated adverse events, such as hand-foot skin reactions and hypertension. PMID- 22423223 TI - Periarticular bone changes in osteoarthritis. PMID- 22423224 TI - Industry Perspective on OA. PMID- 22423225 TI - Estimation of lipid peroxidation induced by hydrogen peroxide in cultured human lymphocytes. AB - Malondialdehyde (MDA) is used for the estimation of damage by reactive oxygen species. MDA is a major reactive aldehyde resulting from the peroxidation of biological membranes. The most common method used to assess MDA production is the thiobarbituric acid (TBARS) assay. However, the value of this method is curbed by low specificity and has been criticized for its use in human studies. In the present study we have used an alternative method for the estimation of MDA production i.e. reaction of MDA with a chromogenic agent 1-methyl-2-phenylindole at 45 degrees C. The paper describes the method of preparing standards for the estimation of MDA (lipid peroxidation) after the treatment with an oxidative stress inducing agent hydrogen peroxide (H(2)O(2)). In the present study, the treatments of 1, 5, 10, 20, 50, 100, 150 and 200 MUM of H(2)O(2) induced significant increase in lipid peroxidation as compared to the untreated ones. The results suggest that the present method can be used to measure the lipid peroxidation in cultured human peripheral blood lymphocytes and is specific for MDA estimation. PMID- 22423226 TI - No Evidence for the In Vivo Induction of Genomic Instability by Low Doses of CS Gamma Rays in Bone Marrow Cells of BALB/CJ and C57BL/6J Mice. AB - In spite of extensive research, assessment of potential health risks associated with exposure to low-dose (<= 0.1 Gy) radiation is still challenging. We evaluated the in vivo induction of genomic instability, expressed as late occurring chromosome aberrations, in bone-marrow cells of two strains of mouse with different genetic background, i.e. the radiosensitive BALB/cJ and the radioresistant C57BL/6J strains following a whole-body exposure to varying doses of (137)Cs gamma rays (0, 0.05, 0.1, and 1.0 Gy). A total of five mice per dose per strain were sacrificed at various times post-irradiation up to 6 months for sample collections. Three-color fluorescence in situ hybridization for mouse chromosomes 1, 2, and 3 was used for the analysis of stable-aberrations in metaphase-cells. All other visible gross structural-abnormalities involving non painted-chromosomes were also evaluated on the same metaphase-cells used for scoring the stable-aberrations of painted-chromosomes. Our new data demonstrated in bone-marrow cells from both strains that low doses of low LET-radiation (as low as 0.05 Gy) are incapable of inducing genomic instability but are capable of reducing specific aberration-types below the spontaneous rate with time post irradiation. However, the results showed the induction of genomic instability by 1.0 Gy of (137)Cs gamma rays in the radiosensitive strain only. PMID- 22423227 TI - Are some neurons hypersensitive to metallic nanoparticles? AB - Engineered metallic nanomaterial particles (MENAP) represent a significant breakthrough in developing new products for use by consumers and industry. Skin application (e.g., via creams and sprays containing nanoparticles) may provide a key route of potential intake of MENAP and can lead to retrograde transport from nerve endings in the skin to the somatosensory neurons in dorsal root ganglia (DRG). This paper uses a novel theoretical model (stochastic threshold microdose [STM] model) to characterize survival of DRG neurons exposed in cell culture replicates to copper nanoparticles, based on published data. Cell death via autophagy is assumed here to occur as a result of the uptake (called hits) of the nanoparticles by mitochondria. Theoretical results are presented for the existence of a hypersensitive fraction (about 20%) of neurons that are killed in significant numbers when on average > 1 hit to the at-risk mitochondria occurs. Further, most hypersensitive neurons appear to be killed by a cumulative exposure of about 2,000 micromolar-hours and the remaining resistant cells may have dysfunctional mitochondria. Based on these theoretical findings, it is predicted that repeated exposure (e.g., over years) of the skin of humans to MENAP could lead to significant nervous system damage and related morbidity. PMID- 22423228 TI - Cancer mortality, state mean elevations, and other selected predictors. AB - This ecological inquiry compares cancer mortality rates in the U.S. to the predictor of natural background radiation (via land elevation means) along with eight other predictors thought to be associated with cancer mortality. Age adjusted cancer mortality in 2006 was compared to the predictors of mean land elevation, percent of smokers, educational attainment, percent of population without health insurance, income, obesity, health perception, physical activity, and diet. Among the six predictors considered appropriate for multiple linear regression, three were found to be statistically significant; from strongest to weakest, these three were: smoking, land elevation, and educational attainment. The predictors of smoking and educational attainment have long been considered associated with cancer mortality. The finding that the predictor of land elevation / natural background radiation is inversely related to cancer mortality is another piece of evidence supporting the theory of radiation hormesis. In this study, land elevation / natural background radiation ranked second in predictive strength regarding cancer mortality, behind smoking and ahead of educational attainment. Since this is an ecological inquiry, no causal inferences can be made. PMID- 22423229 TI - The sandpile model: optimal stress and hormesis. AB - The sandpile model (developed by chaos theorists) is an elegant visual metaphor for the cumulative impact of environmental stressors on complex adaptive systems an impact that is paradoxical by virtue of the fact that the grains of sand being steadily added to the gradually evolving sandpile are the occasion for both its disruption and its repair. As a result, complex adaptive systems are continuously refashioning themselves at ever-higher levels of complexity and integration - not just in spite of "stressful" input from the outside but by way of it. Stressful input is therefore inherently neither bad ("poison") nor good ("medication"). Rather, it will be how well the system (be it sandpile or living system) is able to process, integrate, and adapt to the stressful input that will make of it either a growth-disrupting (sandpile-destabilizing) event or a growth promoting (sandpile-restabilizing) opportunity. Too much stress - "traumatic stress" - will be too overwhelming for the system to manage, triggering instead devastating breakdown. Too little stress will provide too little impetus for transformation and growth, serving instead simply to reinforce the system's status quo. But just the right amount of stress - "optimal stress" - will provoke recovery by activating the system's innate capacity to heal itself. PMID- 22423230 TI - Interspecies Chemical Signals Released into the Environment May Create Xenohormetic, Hormetic and Cytostatic Selective Forces that Drive the Ecosystemic Evolution of Longevity Regulation Mechanisms. AB - Various organisms (i.e., bacteria, fungi, plants and animals) within an ecosystem can synthesize and release into the environment certain longevity-extending small molecules. Here we hypothesize that these interspecies chemical signals can create xenohormetic, hormetic and cytostatic selective forces driving the ecosystemic evolution of longevity regulation mechanisms. In our hypothesis, following their release into the environment by one species of the organisms composing an ecosystem, such small molecules can activate anti-aging processes and/or inhibit pro-aging processes in other species within the ecosystem. The organisms that possess the most effective (as compared to their counterparts of the same species) mechanisms for sensing the chemical signals produced and released by other species and for responding to such signals by undergoing certain hormetic and/or cytostatic life-extending changes to their metabolism and physiology are expected to live longer then their counterparts within the ecosystem. Thus, the ability of a species of the organisms composing an ecosystem to undergo life-extending metabolic or physiological changes in response to hormetic or cytostatic chemical compounds released to the ecosystem by other species: 1) increases its chances of survival; 2) creates selective forces aimed at maintaining such ability; and 3) enables the evolution of longevity regulation mechanisms. PMID- 22423231 TI - Hormetic signaling patterns. AB - Organisms are perpetually facing noxious insults but exhibit surprising diverse reaction patterns. Depending on the strength, frequency and quality of the stress stimuli biological systems may react with increased vitality, future stress resistance or with injury and degeneration. Whereas a multitude of such specific stress responses has been observed in diverse biological systems the underlying molecular mechanisms are mainly unknown. These knowledge restrictions urge the exploration of specific molecular signaling reactions controlling the ambivalent responses of cells and organisms to noxious effects. The adaptive responses of signaling networks to defined stress stimuli need to be investigated in a time and dose-resolved manner in cellular and organismic models. Anticipated results are expected to significantly advance the understanding of the molecular signatures of stress responses and may also promote ongoing efforts for the effective use of the organism's preventive and regenerative potentials in modern medicine. PMID- 22423232 TI - Hormesis and the salk polio vaccine. AB - The production of the Salk vaccine polio virus by monkey kidney cells was generated using the synthetic tissue culture medium, Mixture 199. In this paper's retrospective assessment of this process, it was discovered that Mixture 199 was modified by the addition of ethanol to optimize animal cell survival based on experimentation that revealed a hormetic-like biphasic response relationship. This hormesis-based optimization procedure was then applied to all uses of Mixture 199 and modifications of it, including its application to the Salk polio vaccine during preliminary testing and in its subsequent major societal treatment programs. PMID- 22423233 TI - Lanthanum Element Induced Imbalance of Mineral Nutrients, HSP 70 Production and DNA-Protein Crosslink, Leading to Hormetic Response of Cell Cycle Progression in Root Tips of Vicia faba L. seedlings. AB - The effects and mechanisms of rare earth elements on plant growth have not been extensively characterized. In the current study, Vicia faba L. seedlings were cultivated in lanthanum (La)-containing solutions for 10 days to investigate the possible effects and mechanisms of La on cell proliferation and root lengthening in roots. The results showed that increasing La levels resulted in abnormal calcium (Ca), Ferrum (Fe) or Potassium (K) contents in the roots. Flow cytometry analysis revealed G1/S and S/G2 arrests in response to La treatments in the root tips. Heat shock protein 70 (HSP 70) production showed a U-shaped dose response to increasing La levels. Consistent with its role in cell cycle regulation, HSP 70 fluctuated in parallel with the S-phase ratios and proliferation index. Furthermore, DNA-protein crosslinks (DPCs) enhanced at higher La concentrations, perhaps involved in blocking cell progression. Taken together, these data provide important insights into the hormetic effects and mechanisms of REE(s) on plant cell proliferation and growth. PMID- 22423234 TI - Time-dependent beneficial effect of chronic polyphenol treatment with catechin on endothelial dysfunction in aging mice. AB - A controlled redox environment is essential for vascular cell maturation and function. During aging, an imbalance occurs, leading to endothelial dysfunction. We hypothesized that, according to the concept of hormesis, exposure to physiologic oxidative stress during the maturation phase of the endothelium will activate protective pathways involved in stress resistance. C57Bl/6 mice were treated with the polyphenol catechin for the last 3 (post-maturation) or 9 months prior study at 12 months of age. Endothelial dysfunction, assessed by acetylcholine-induced dilations of isolated renal arteries, was present at 12 months (P<0.05). Only the 3-month treatment with catechin fully prevented the decline in efficacy and sensitivity to acetylcholine (P<0.05). Splenocytes adhesion to the native endothelium, expression of CD18 and shedding of CD62L and PSGL-1 augmented in 12 months old mice (P<0.05): only 3-month catechin fully normalized adhesion and prevented the expression of adhesion molecules on splenocytes (P<0.05). Aging was associated with vascular gene alterations, which were prevented by 3-month catechin treatment (P<0.05). In contrast, 9-month catechin further increased COX-2, p22(phox) and reduced MnSOD (P<0.05). In conclusion, we demonstrate a pivotal role of cellular redox equilibrium: exposure to physiologic oxidative stress during the maturation phase of the endothelium is essential for its function. PMID- 22423235 TI - A Review of Vibro-acoustography and its Applications in Medicine. AB - In recent years, several new techniques based on the radiation force of ultrasound have been developed. Vibro-acoustography is a speckle-free ultrasound based imaging modality that can visualize normal and abnormal soft tissue through mapping the acoustic response of the object to a harmonic radiation force induced by ultrasound. In vibro-acoustography, the ultrasound energy is converted from high ultrasound frequencies to a low acoustic frequency (acoustic emission) that is often two orders of magnitude smaller than the ultrasound frequency. The acoustic emission is normally detected by a hydrophone. In medical imaging, vibroacoustography has been tested on breast, prostate, arteries, liver, and thyroid. These studies have shown that vibro-acoustic data can be used for quantitative evaluation of elastic properties. This paper presents an overview of vibro-acoustography and its applications in the areas of biomedicine. PMID- 22423236 TI - COMBATing Breast Cancer Conference 2011 -Stories of Success and Failure. PMID- 22423237 TI - Histopathologically proven autoimmune pancreatitis mimicking neuroendocrine tumor or pancreatic cancer. AB - Autoimmune pancreatitis (AIP) can be difficult to distinguish from pancreatic cancer. We report a case of histopathologically proven AIP mimicking neuroendocrine tumor (NET) or pancreatic cancer in a 53-year-old man. He was referred to our hospital for further evaluation of a pancreatic mass detected on ultrasonography at a medical check-up. Abdominal ultrasonography showed a 15-mm hypoechoic mass located in the pancreatic body. Computed tomography revealed a tumor without any contrast enhancement, and magnetic resonance imaging demonstrated the mass to be hyperintense on diffusion-weighted image. Endoscopic retrograde cholangiopancreatography revealed slight dilatation of a branch of the pancreatic duct without stricture of the main pancreatic duct. The common bile duct seemed intact. Under suspicion of a non-functioning NET or malignant neoplasm, laparotomy was performed. At laparotomy, an elastic firm and well circumscribed mass was found suggestive of a non-functioning NET, thus enucleation was performed. Histopathologically, the lesion corresponded to AIP. PMID- 22423238 TI - Unusual presentation of localized gastric mucosa-associated lymphoid tissue lymphoma mimicking poorly differentiated gastric adenocarcinoma. AB - The risk of misdiagnosing neoplastic cells typically infiltrating an epithelium forming a lymphoepithelial lesion as poorly differentiated gastric cancer in endoscopic biopsies, particularly in low-grade mucosa-associated lymphoid tissue (MALT) lymphomas, is described. A 76-year-old woman was referred for management of a poorly differentiated gastric adenocarcinoma. Diagnostic endoscopy in our unit showed a 2 cm raised, submucosal lesion with central erosion in the upper body of the stomach, but repeat biopsies of the lesion were interpreted as inflamed gastric mucosa and negative for malignancy. Systematic gastric biopsies to rule out any foci of MALT lymphoma changes were also negative. Therefore, endoscopic submucosal dissection was performed to obtain an accurate specimen. Histology revealed centrocyte-like cells and a lymphoepithelial lesion invading into the mucosa with obliteration of the gastric glands, which was initially interpreted as poorly differentiated adenocarcinoma. PMID- 22423239 TI - Advanced gastric neuroendocrine carcinoma with an adenocarcinoma component. AB - In the present study, we observed that the adenocarcinoma component in the mucosa was continuous with neuroendocrine carcinoma (NEC) in the deeper layers; this suggests the normal course of NEC carcinogenesis at the histological level. A 72 year-old man was admitted to our hospital with a chief complaint of tarry stools. Endoscopic examination of the upper gastrointestinal tract revealed a 2-cm tumor, with a deep central depression, surrounded by a smooth elevated area, in the middle of the stomach body. A biopsy showed that the tumor was a moderately differentiated gastric adenocarcinoma. The patient underwent total gastrectomy and standard lymph node dissection. The resected tumor was a 3.5 * 2.5 cm type 2 lesion. It comprised two elements at the histological level: (i) a moderately differentiated adenocarcinoma in the superficial portion of the mucous membrane layer, and (ii) NEC-like cells with dark, round nuclei and scant cytoplasm, presenting a solid and trabecular pattern, in the submucosal and muscularis propria layers. Immunohistochemical findings showed that the NEC-like cells were diffusely positive for chromogranin A, synaptophysin, neural cell adhesion molecule, and neuron-specific enolase, but were negative for carcinoembryonic antigen. The Ki-67 labeling index was 95%. The final pathological diagnosis was gastric NEC with an adenocarcinoma component and a high cellular proliferative potential. PMID- 22423240 TI - An isolated neurofibromal polyp of the colon. AB - Solitary neurofibromal colonic polyps are a rare entity, particularly outside the setting of neurofibromatosis type 1. The clinical significance of such lesions has not yet been established. Though typically benign tumors, neurofibromas have been reported to undergo malignant transformation, with an increased risk of malignancy when associated with neurofibromatosis. In this case report, we present the rare case of a man found to have an isolated colonic neurofibroma without any personal/family history or clinical features of neurofibromatosis. A 59-year-old man with a history of dyslipidemia and degenerative joint disease presented for a routine screening colonoscopy. The colonoscopy revealed no abnormalities except a 3 mm transverse colon polyp and another 4 mm polyp in the descending colon. Biopsy results showed the descending colonic polyp to be a tubular adenoma; however, multiple levels of the 3 mm transverse colon polyp revealed interlacing bundles of spindle cells extending into the lamina propria with comma-shaped nuclei consistent with findings seen in neurofibroma. Isolated colonic neurofibromas are rare and understudied. While they are usually benign, they may undergo malignant transformation, especially when associated with neurofibromatosis. Thus, patients presenting with isolated neurofibromas should be followed for development of neurofibromatosis and malignancies. PMID- 22423241 TI - An inflammatory fibroid polyp in the hepatic flexure of the colon treated with argon plasma coagulation, endoscopic clipping and polypectomy. AB - Inflammatory fibroid polyp (IFP) is a rare benign polypoid lesion of the gastrointestinal tract. Most IFPs occur in the stomach and colonic occurrence is very rare. Histologically IFP is characterized by a mixture of numerous small vessels, fibroblasts and edematous connective tissue associated with marked inflammatory infiltration by eosinophils. We present a rare case of a pedunculated IFP in the hepatic flexure of the colon treated successfully with a combination of argon plasma coagulation, endoclipping and polypectomy. A 74-year old asymptomatic female underwent a screening colonoscopy in our hospital. A 12 mm pedunculated polyp was found at the hepatic flexure of the colon. After saline injection, we attempted to remove the polyp with a hot snare. However the polyp stalk was extremely difficult to resect despite several attempts with the hot snare. We placed an endoclip at the base of the stalk and then applied argon plasma coagulation at 1.0 l/min and 40 W. After these measures we were able to resect the stalk and the polyp was retrieved. Histologically the polyp was located in the submucosa of the gastrointestinal tract. Proliferation of spindle cells and infiltration of inflammatory cells such as plasma cells and eosinophils were observed. The spindle cells were positive for CD34 and S100 but negative for c-kit and muscle markers. These findings are consistent with a histopathological diagnosis of IFP. PMID- 22423242 TI - Acute liver dysfunction in the course of norovirus gastroenteritis. AB - A 48-year-old female with abdominal pain and malaise who showed delayed symptom of acute gastroenteritis came to see us. Her illness was diagnosed as norovirus infection, but liver dysfunction accompanied this gastroenteritis. We investigated the pathogenesis of this hepatitis for all causes including drugs, but we could not detect norovirus infection. The liver damage improved shortly in course of the gastroenteritis. She recovered completely within 2 weeks without any damage left. Norovirus-induced liver dysfunction is not known, and there is no report in the literature. We report, for the first time, the case of liver dysfunction with norovirus gastroenteritis. PMID- 22423243 TI - Dual microcatheter retrograde transvenous obliteration of gastric varices: coil embolization as a substitute for balloon occlusion. AB - Dual microcatheter retrograde transvenous obliteration (DMRTO) of gastric varices enables dual microcatheters to be advanced to the gastric varices themselves or to a site adjacent to the varices. The sclerosing agent is infused through the first microcatheter following coil embolization of the outflow vessels through the second microcatheter, which is placed several centimeters back from the varices. We present two cases of gastric varices in whom balloon-occluded retrograde transvenous obliteration failed, because of angulated gastrosubphrenic shunt in case 1 and a tortuous and elongated gastrorenal shunt in case 2. DMRTO successfully achieved eradication of the gastric varices in both cases. PMID- 22423244 TI - Calcium channel blockers and esophageal sclerosis: should we expect exacerbation of interstitial lung disease? AB - Esophageal sclerosis is the most common visceral manifestation of systemic sclerosis, resulting in impaired esophageal clearance and retention of ingested food; in addition, co-existence of lung fibrosis with esophageal scleroderma is not uncommon. Both the progression of generalized connective tissue disorders and the damaging effect of chronic aspiration due to esophageal dysmotility appear to be involved in this procedure of interstitial fibrosis. Nifedipine is a widely prescribed calcium antagonist in a significant percentage of rheumatologic patients suffering from Raynaud syndrome, in order to inhibit peripheral vasospasm. Nevertheless, blocking calcium channels has proven to contribute to exacerbation of gastroesophageal reflux, which consequently can lead to chronic aspiration. We describe the case of severe exacerbation of interstitial lung disease in a 76-year-old female with esophageal sclerosis who was treated with oral nifedipine for Raynaud syndrome. PMID- 22423245 TI - Adult Intussusception Caused by Descending Colon Cancer during Chemotherapy of Stomach Cancer Recurrence. AB - Intussusception in adults is uncommon, and it is rare in the descending colon because of its fixation to the retroperitoneum. We herein describe a case of intussusception caused by descending colon cancer. A 74-year-old man was admitted to our hospital for treatment of vomiting and abdominal pain. He had undergone chemotherapy for lymph node recurrence of stomach cancer for about 4 years. Computed tomography revealed a 'target mass' with a tumor in the descending colon. We diagnosed his illness as intussusception of a descending colon tumor and performed emergency laparotomy. Conservative resection was performed following anastomosis after reduction of the intussusception. The tumor was pathologically diagnosed as poorly differentiated adenocarcinoma with neuroendocrine features. To the best of our knowledge, this is the first report of an intussusception caused by descending colon cancer incidentally diagnosed during chemotherapy for stomach cancer recurrence. PMID- 22423246 TI - Hypotension due to Chemotherapy in a Patient with Small Cell Lung Cancer and Lambert-Eaton Myasthenic Syndrome Undergoing Hemodialysis: A First Case Report. AB - We present the first case of small cell lung cancer with Lambert-Eaton myasthenic syndrome during hemodialysis (HD). A 72-year-old male patient receiving HD experienced progressive muscle weakness. He was diagnosed with small cell lung cancer with Lambert-Eaton myasthenic syndrome due to an increased serum level of anti-voltage-gated calcium channel antibody and aspiration cytology on endobronchial ultrasonography for the swelling of a subcarinal lymph node. He received chemotherapy consisting of carboplatin (300 mg/m(2)) and etoposide (50 mg/m(2)), to which he had a partial response. However, the second therapy course could not be administered because of the unexpected development of severe hematological adverse events, which also prevented him from undergoing further HD. This case indicates that caution should be taken when using chemotherapy for such patients because of hypotension due to chemotherapy, with which it is impossible to undergo HD. PMID- 22423247 TI - Reduction in Circulating Tumor Cell Count following Therapy with nab-Paclitaxel plus Carboplatin in a Patient with Leptomeningeal Carcinomatosis from Breast Cancer. AB - This case study reports on a 56-year-old woman with breast adenocarcinoma and leptomeningeal metastases. After initial chemotherapy with a dose-dense regimen of doxorubicin/cyclophosphamide followed by 3 cycles of docetaxel (100 mg/m(2)), a lumpectomy was performed that revealed invasive ductal carcinoma with lymph node involvement. Because of the extent of the disease, she underwent a mastectomy. Two months after the completion of initial chemotherapy, leptomeningeal metastases were detected on December 13, 2006. After completion of whole-brain radiation therapy, she received systemic chemotherapy with a novel albumin-bound 130-nm formulation of paclitaxel (nab(r)-paclitaxel) at 100 mg/m(2) combined with carboplatin AUC = 6, both given weekly. Clinical response was prompt, with a reduction in the circulating tumor cell (CTC) count from 63 before treatment to 2 after the first treatment cycle. While undergoing treatment with nab-paclitaxel plus carboplatin, she reported an improvement in neurologic symptoms, including a decrease in headaches, improved cognition and balance, and an overall improved quality of life. Before the third treatment cycle, she had a CTC count of 2. Without treatment, the median survival of patients diagnosed with leptomeningeal metastases is 4-6 weeks. However, this patient survived for 4 months after the diagnosis of leptomeningeal carcinomatosis. Treatment was discontinued because of complications of urosepsis, and the patient died on April 7, 2007. Our case shows that additional treatment with weekly nab-paclitaxel combined with carboplatin (AUC6) can prolong life for some patients with leptomeningeal carcinomatosis from breast cancer. PMID- 22423248 TI - Detection of asymptomatic cardiac metastasis and successful salvage chemotherapy comprising a prednisone, Etoposide, procarbazine, and cyclophosphamide regimen in an elderly Japanese patient suffering from a delayed recurrence of diffuse large B-cell lymphoma. AB - We report a case of facial diffuse large B-cell lymphoma (DLBCL) associated with recurrent metastasis in the heart and other sites in a 76-year-old Japanese woman. Initially, she developed DLBCL in her left upper eyelid that spread into the left orbit (Ann Arbor classification stage I). The lesion went into clinical regression after 4 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy followed by radiotherapy. More than 3 years later, the lymphoma recurred in her facial skin, together with metastases in the mediastinal lymph nodes and the heart; the tumor in the heart was successfully detected by PET/CT and cardiac MRI. To treat the recurrent lesions, we performed a salvage chemotherapy regimen comprising prednisone, etoposide, procarbazine, and cyclophosphamide, which successfully induced tumor regression. PMID- 22423249 TI - Polyaspartamide Vesicle induced by Metallic Nanoparticles. AB - Polymer vesicles are being extensively studied to emulate self-assembly in biological systems and also use them in a variety of biological and industrial applications. This study demonstrates a novel strategy to prepare polymer vesicles in a pure aqueous medium by driving the micelle-to-vesicle transition with metallic nanoparticles. We synthesized poly(2-amino-2-hydroxyethyl aspartamide) (PAHA) substituted with octadecyl chains, which could form micelle like self-aggregates in the aqueous medium and chemically bind with platinum precursors. Then, in situ polymerization of Pt nanoparticles within the PAHA self aggregates generated polymer vesicles that possess nanoparticles within bilayers, because of the increase of the hydrophilic mass ratio to total mass of PAHA, f (w). This new strategy to prepare polymer vesicles would greatly serve to facilitate the control of self-assembly and ultimately improve the functionality of a wide array of polymer vesicles. PMID- 22423250 TI - Cancer in older patients: an analysis of elderly oncology. AB - Is it possible to define when someone is elderly? The worldwide population is growing not only in number but also in age; it is estimated that the population will increase to around 750 million by 2021. Two thirds of cancer occurs in the over 65 age groups. With an increasing elderly population, it can be derived that cancer will become a more prevalent condition. The burden of cancer on the medical profession will be even more apparent than before. In addition the elderly age group has different needs compared with younger oncology patients; there can be no 'rule of thumb' with the management of elderly illness. Factors such as frailty are significant when treating cancer in the older patients. The assessment of quality of life in older patients with cancer is also an important factor. Is it best for a patient to enjoy life as it is with cancer or aim for increased life expectancy by undertaking treatment with the threat of morbidity however severe during that period? The volume of scientific evidence currently available to support all the issues in geriatric oncology is greatly limited; almost all treatments designed for oncology are being tested in randomized clinical trials preferentially using younger cohorts of patients. Changes need to be made in order to further this field of medicine. Geriatric oncology is no longer a palliative field, as a healthy active life can now be expected by some older patients. The burden of oncology in the elderly will need to take a modern approach regarding the management of these patients. PMID- 22423251 TI - Companion diagnostics: changing patient management. AB - At the European Multidisciplinary Cancer Congress (EMCC), held in Stockholm in September 2011, a recurring theme in many of the workshops was personalised medicine, including the latest developments in prognostic and predictive biomarkers. Such markers, it is hoped, will enable clinicians to use available resources to best effects-by offering treatments to only those patients most likely to benefit, or by avoiding treatments that are likely to cause toxicities with limited benefit. The emergence of novel diagnostic tools that can distinguish subsets of patients with different response to treatment is likely to result in a paradigm shift in the way in which we manage cancer in the future. This report focuses on some of the key developments and challenges in providing a truly individualised approach to therapy, as presented at EMCC 2011. PMID- 22423252 TI - Aspirin for the older person: report of a meeting at the Royal Society of Medicine, London, 3rd November 2011. AB - On November 23rd 2011, the Aspirin Foundation held a meeting at the Royal Society of Medicine in London to review current thinking on the potential role of aspirin in preventing cardiovascular disease and reducing the risk of cancer in older people. The meeting was supported by Bayer Pharma AG and Novacyl. PMID- 22423254 TI - Effect of cardiac resynchronization therapy on beat-to-beat T-wave amplitude variability. AB - AIMS: T-wave amplitude variability (TAV) is a promising non-invasive predictor of arrhythmic events in patients with dilated cardiomyopathy. We aimed to evaluate the effect of cardiac resynchronization therapy (CRT) on native TAV, its relation with left ventricular (LV) reverse remodelling and the occurrence of ventricular tachyarrhythmias (VTs). METHODS AND RESULTS: In this prospective study, we included 40 heart failure patients with left bundle branch block in sinus rhythm (25 male; 16 with ischaemic aetiology; aged 62.7 +/- 9.5 years; New York Heart Association class II-IV). Echocardiographic parameters and TAV were evaluated at baseline and 6 months after implantation of CRT device combined with an implantable cardioverter-defibrillator. T-wave amplitude variability was determined by a 20-min high-resolution electrocardiogram Holter recording during native conduction. After TAV assessment, patients were monitored for 15.7 +/- 5.2 months for the occurrence of VTs. Decrease in median TAV [from 40.45 MUV (24.75 56.00) to 28.15 MUV (20.93-37.95), P = 0.004] was observed after 6 months of CRT. However, decrease of median TAV was only noticed in patients with LV reverse remodelling [46.9 MUV (27.5-70.0) to 25.8 MUV (20.2-32.4), P < 0.001] and in patients without VTs [40.5 MUV (27.5-55.9) to 24.4 MUV (17.1-31.5), P < 0.001]. Native median TAV > 35.4 uV after 6 months of CRT had an 83% sensitivity and 93% specificity for predicting the occurrence of VTs. CONCLUSIONS: Decrease of TAV after CRT is associated with LV reverse remodelling and indicates a reduction of the intrinsic arrhythmogenic substrate. Median TAV after CRT had a good predicting value for VT occurrence in long-term follow-up. PMID- 22423255 TI - The need for standardization of time- and frequency-domain analysis of body surface electrocardiograms for assessment of the atrial fibrillation substrate. PMID- 22423256 TI - Reduced connexin40 protein expression in the right atrial appendage of patients bearing the minor connexin40 allele (-44 G --> A). AB - AIMS: The occurrence of connexin40 (Cx40) minor polymorphism (-44 G -> A) was increased in patients with idiopathic atrial fibrillation (AF), although its effect on atrial Cx40 protein expression is unknown. We aimed to evaluate whether alterations in Cx40 are directly linked to the development of AF, we studied the effect of this polymorphism on Cx40 expression and distribution in patients without any history of AF and in patients who developed post-operative AF. METHODS AND RESULTS: Hundred and eight patients (mean age 67 +/- 9 years), without a history of AF or conditions that predispose to AF, were included. During heart surgery, 10 cc blood was collected for DNA genotyping and the right atrial appendage was partly excised. Ten patients (9%) were homozygous for the minor allele (AA, Group 1), 30 (28%) were heterozygous (AG, Group 2), and 68 (63%) were non-carriers (GG, Group 3). Ten age- and sex-matched tissue samples per group were analysed for Cx40 expression by: (i) real-time quantitative polymerase chain reaction (Q-PCR), (ii) western blotting, and (iii) immunohistochemistry on cryosections. Real-time quantitative polymerase chain reaction showed no significant differences of Cx40 mRNA among the groups. Western blot analysis, however, revealed a reduction in Cx40 protein in Groups 1 (-36.4%) and 2 (-39.5%) as compared with Group 3. Immunohistochemistry confirmed this reduction but indicated an unaltered subcellular distribution of the remaining Cx40. Incidence of post-operative AF (28%) was age-dependent but unrelated to the presence of the polymorphism or fibrosis. CONCLUSION: Presence of the Cx40 minor allele (-44 G -> A) results in a uniform down-regulation of right atrial appendage Cx40 protein which was not significantly related to development of post operative AF. PMID- 22423257 TI - Fine needle aspiration at endoscopic ultrasound with a novel side-port needle: a pilot experience. AB - BACKGROUND: Diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) varies relating to the equipment used and the site targeted. Multiple needle passes are usually required to obtain a diagnosis. A new needle incorporating a side port carries a theoretical advantage regarding acquisition of cytological material. METHODS: To demonstrate the safety and efficacy of the Olympus side-port needle across a spectrum of indications for EUS FNA, a prospective collection of 16 consecutive cases was undertaken at a tertiary gastroenterology referral centre in metropolitan Sydney, Australia. EUS FNA was performed with the novel Olympus side-port needle. EUS FNA was otherwise performed in the conventional fashion. The number of needle passes required for diagnosis, number of passes total, diagnosis on cytology and conclusive diagnosis were recorded. RESULTS: Diagnostic material was obtained at the first pass in 56.2% of patients. Mean number of passes required to reach a diagnosis was 2.1. Diagnosis was made on first pass in 62.5% of solid non-lymph-node lesions. The diagnosis was reached in 94%. CONCLUSIONS: The novel side-port needle is safe and effective; further evaluation with a prospective randomized trial is warranted. PMID- 22423258 TI - EUS-guided drainage and stent placement for postoperative intra-abdominal and pelvic fluid collections in oncological surgery. AB - OBJECTIVES: The objective of this study was to evaluate the role and benefits of endoscopic ultrasonography (EUS) in the management of postoperative intra abdominal fluid collections after attempted curative surgery for abdominal cancer. METHODS: The authors retrospectively analysed the Endobase from 1 July 2007 to 30 January 2011 for patients with a postoperative intra-abdominal fluid collection who had undergone EUS-guided drainage and the placement of a stent. The data analysed included the demographics, type of surgery and clinical indications of each patient as well as their clinical and radiological findings. RESULTS: Six patients (three men and three women; mean age, 61.8 years [range, 38 78 years]) with intra-abdominal and pelvic fluid collections after abdominal surgery for cancer had undergone EUS-guided internal drainage. All procedures had been performed using linear EUS guidance and 8-Fr stent drainage catheters ('one step device', Giovannini, NWOA system Needle-Wire, Cook). The collection types included perigastric abscess (n = 3), perigastric hematoma and rectal hematoma (n = 1), perirectal biloma (n = 1), and perirectal abscess (n = 1). Patients had undergone the following types of surgery: lower-anterior rectal resection (n = 2), Whipple's duodenopancreatectomy type (n = 1), total gastrectomy (n = 1), splenectomy (n = 1), and distal pancreatectomy (n = 1). The number of stents inserted for each collection was one (five patients) and two (one patient). CONCLUSIONS: EUS-guided drainage and stenting provide another option for the management of postoperative collections. It allows access to areas that are difficult to reach with the CT-guided approach and it can be performed accurately, efficiently and safely. In addition to this, the internal nature of the drainage offers patients more comfort. PMID- 22423259 TI - The challenge of Helicobacter pylori resistance to antibiotics: the comeback of bismuth-based quadruple therapy. AB - A proton-pump inhibitor (PPI), clarithromycin-based, triple therapy has been the recommended treatment for Helicobacter pylori eradication for the past 15 years. Due to a steady increase in H. pylori resistance to clarithromycin, this triple clarithromycin-based treatment has become progressively less efficacious. Several approaches are available to address this situation: one is to test for clarithromycin resistance so that this triple clarithromycin-based regimen is given only to those who will benefit; a second is to prescribe the drugs sequentially, beginning with amoxicillin and a PPI followed by clarithromycin and metronidazole, again with a PPI or the four drugs prescribed concomitantly; a third alternative is to use bismuth-based quadruple therapy, PPI plus a standardized three-in-one capsule, bismuth subcitrate potassium, metronidazole, and tetracycline (BMT, sold under licence as Pylera(r)). The advantages of these different approaches are reviewed, including the relevance of BMT three-in-one capsule in clinical practice. PMID- 22423260 TI - Efficacy and safety of the probiotic Saccharomyces boulardii for the prevention and therapy of gastrointestinal disorders. AB - Several clinical trials and experimental studies strongly suggest a place for Saccharomyces boulardii as a biotherapeutic agent for the prevention and treatment of several gastrointestinal diseases. S. boulardii mediates responses resembling the protective effects of the normal healthy gut flora. The multiple mechanisms of action of S. boulardii and its properties may explain its efficacy and beneficial effects in acute and chronic gastrointestinal diseases that have been confirmed by clinical trials. Caution should be taken in patients with risk factors for adverse events. This review discusses the evidence for efficacy and safety of S. boulardii as a probiotic for the prevention and therapy of gastrointestinal disorders in humans. PMID- 22423261 TI - Endoscopic management of nonampullary duodenal polyps. AB - Duodenal polyps are a rare finding in patients presenting for gastroscopy, being found in 0.3-4.6% of cases. The majority of patients are asymptomatic. The most common lesions necessitating removal are duodenal adenomas which should be differentiated from other mucosal lesions such as ectopic gastric mucosa, and submucosal lesions such as carcinoids and gastrointestinal stromal tumours (GISTs). Adenomas can occur sporadically or as part of a polyposis syndrome. Both groups carry malignant potential but this is higher in patients with a polyposis syndrome. The majority of sporadic duodenal adenomas are flat or sessile and occur in the second part of the duodenum. Historically duodenal adenomas have been managed by radical surgery, which carried significant mortality and morbidity, or more conservative local surgical excision which resulted in high local recurrence rates. There is growing evidence for the use of endoscopic mucosal resection (EMR) techniques for treatment of sporadic nonampullary duodenal adenomas, with good outcomes and low complication rates. Endoscopic submucosal dissection (ESD) carries greater risk of complications and should be reserved for experts in this technique. Patients with sporadic duodenal adenomas carry an increased risk of colonic neoplasia and should be offered colonoscopy. The impact of endoscopic resection on the course of polyposis syndromes such as familial adenomatous polyposis (FAP) needs further study. PMID- 22423262 TI - Efficacy and safety of telaprevir in patients with genotype 1 hepatitis C infection. AB - Chronic hepatitis C infection represents a significant and growing health problem worldwide. Patients with genotype 1 hepatitis C respond poorly to the current standard of care, pegylated interferon and ribavirin, which is frequently associated with unpleasant side effects. Consequently new agents with improved efficacy and tolerability are needed. The efficacy and safety of the direct acting antiviral agent telaprevir in the treatment of genotype 1 hepatitis C infection have been demonstrated in a number of clinical trials. The addition of telaprevir to standard therapy considerably improves response rates and allows response-guided shortening of treatment duration in a substantial number of treatment-naive patients. Side effects associated with telaprevir therapy include rash, anaemia, gastrointestinal disturbance and anorectal discomfort. Telaprevir resistant variants have been identified in patients who have failed telaprevir containing therapy, and whether selection of these variants will compromise future therapeutic options is currently unknown. The efficacy and safety of telaprevir in the treatment of the most challenging patients, including those with recurrent hepatitis C following liver transplantation and those co-infected with HIV, remains to be established. PMID- 22423263 TI - Ipilimumab: its potential in non-small cell lung cancer. AB - Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, enterocolitis, and hyperthyroidism. These adverse events may be improved with high-dose glucocorticoids and may be correlated with tumor response. Phase III studies are ongoing. Future studies may investigate ipilimumab in the management of early stage lung cancer. Strategies for potential translational research studies are also discussed to identify prognostic and predictive biomarkers for the use of ipilimumab in the treatment of patients with NSCLC. PMID- 22423264 TI - Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls. AB - The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers. PMID- 22423265 TI - The potential for BRAF V600 inhibitors in advanced cutaneous melanoma: rationale and latest evidence. AB - Historically, patients with advanced cutaneous melanoma have a poor prognosis and limited treatment options. The discovery of selective v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation as an oncogenic mutation in cutaneous melanoma and the importance of the mitogen-activated protein kinase (MAPK) pathway in its tumourigenesis have changed the treatment paradigm for melanoma. Selective BRAF inhibitors and now MEK inhibitors have demonstrated response rates far higher than standard chemotherapeutic options and we review the phase I-III results for these agents in this article. The understanding of mechanisms of resistance that may occur upstream, downstream, at the BRAF level or bypassing the MAPK pathway provides a platform for rational drug development and combination therapies. PMID- 22423266 TI - Therapeutic strategy in unresectable metastatic colorectal cancer. AB - While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials. PMID- 22423267 TI - (How) does 1,3,5-triethylbenzene scaffolding work? Analyzing the abilities of 1,3,5-triethylbenzene- and 1,3,5-trimethylbenzene-based scaffolds to preorganize the binding elements of supramolecular hosts and to improve binding of targets. AB - 1,3,5-triethylbenzenes have been widely used as supramolecular templates to organize molecular-recognition elements. It is believed that the steric-gearing effect of the 1,3,5-triethylbenzene template directs the binding elements toward the same face of the central ring, hence increasing the binding affinity. At the same time the 1,3,5-trimethylbenzene scaffold, without steric-gearing effects, has also been found to improve the binding affinities of hosts compared to the unsubstituted analogues. By studying experimental data from the literature and the Cambridge Structural Database, as well as by conducting computational studies of representative structures, we concluded that the steric gearing offered by the ethyl groups confers some energetic advantage over the methyl groups, but the size of this advantage can be small and is dependent on the groups involved. PMID- 22423268 TI - Binding of group 15 and group 16 oxides by a concave host containing an isophthalamide unit. AB - A bi-macrocycle with an incorporated isophthalamide substructure was synthesized by double amide formation between an isophthaloyl dichloride and two equivalents of a bis(alkenyloxy)aniline, followed by ring-closing metathesis and hydrogenation. In contrast to many related isophthalamides, the concave host exhibits a better binding for oxides, such as DMSO or pyridine-N-oxide, than for halide anions. A general method for a quick estimation of the strength of binding derived from only a few data points is presented and gives an estimated K(ass) of pyridine-N-oxide of ca. 40 M(-1), NMR titration confirms 25 M(-1). PMID- 22423269 TI - Regioselectivity in the multicomponent reaction of 5-aminopyrazoles, cyclic 1,3 diketones and dimethylformamide dimethylacetal under controlled microwave heating. AB - The multicomponent reaction of 5-aminopyrazole derivatives with cyclic 1,3 dicarbonyl compounds and dimethylformamide dimethylacetal (DMFDMA) in DMF at 150 degrees C under controlled microwave heating afforded regioselectively 8,9 dihydropyrazolo[1,5-a]quinazolin-6(7H)-ones 6 rather than the corresponding dihydropyrazolo[5,1-b]quinazolin-8(5H)-ones 4. PMID- 22423270 TI - Imidazole as a parent pi-conjugated backbone in charge-transfer chromophores. AB - Research activities in the field of imidazole-derived push-pull systems featuring intramolecular charge transfer (ICT) are reviewed. Design, synthetic pathways, linear and nonlinear optical properties, electrochemistry, structure-property relationships, and the prospective application of such D-pi-A organic materials are described. This review focuses on Y-shaped imidazoles, bi- and diimidazoles, benzimidazoles, bis(benzimidazoles), imidazole-4,5-dicarbonitriles, and imidazole derived chromophores chemically bound to a polymer chain. PMID- 22423271 TI - On the control of secondary carbanion structure utilising ligand effects during directed metallation. AB - N,N-Diisopropyl-2-propylbenzamide 6-H undergoes lateral deprotonation by t-BuLi in the presence of the Lewis base PMDTA (N,N,N',N",N" pentamethyldiethylenetriamine) to give a benzyllithium 6-Li(l).PMDTA that incorporates a trigonal planar secondary carbanion. In the solid state, the amide directing group and the PMDTA additive work together to abstract the metal ion from the deprotonated alpha-C of the propyl group (4.107(4) A). A short distance of 1.376(3) A is observed between the deprotonated carbon centre and a planar aromatic system that shows a pattern of bond lengths which contrasts with that reported for related tertiary carbanion systems. Analogous benzylic deprotonation is seen if 6-H is treated with t-BuLi in the presence of diglyme to give 6 Li(l).DGME. X-ray crystallography now shows that the metal ion more closely approaches the tertiary carbanion (2.418(6) A) but that the planarity of the deprotonated carbon centre and the bonding pattern in the organic anion seen in the PMDTA complex are retained. DFT analysis corroborates both the short distance between aromatic ring and carbanion centre and the unperturbed nature of aromaticity in 6-Li(l).L (L = Lewis base). The observation of two structure-types for the carbanion in solution is explained theoretically and by NMR spectroscopy in terms of cis and trans isomerism imparted by partial double bond character in the arene-(alpha-C) bond. PMID- 22423272 TI - A general and facile one-pot process of isothiocyanates from amines under aqueous conditions. AB - A general and facile one-pot protocol for the preparation of a broad range of alkyl and aryl isothiocyanates has been developed from their corresponding primary amines under aqueous conditions. This synthetic process involves an in situ generation of a dithiocarbamate salt from the amine substrate by reacting with CS(2) followed by elimination to form the isothiocyanate product with cyanuric acid as the desulfurylation reagent. The choice of solvent is of decisive importance for the successful formation of the dithiocarbamate salt particularly for highly electron-deficient substrates. This novel and economical method is suitable for scale-up activities. PMID- 22423273 TI - Fluorescent hexaaryl- and hexa-heteroaryl[3]radialenes: Synthesis, structures, and properties. AB - The syntheses of three new [3]radialenes - hexakis(3,5-dimethylpyrazolyl)-, hexakis(3-cyanophenyl)-, and hexakis(3,4-dicyanophenyl)[3]radialene (1-3) - are reported. Compound 3 is obtained in five steps with an excellent yield of 76% in the key step. Compared to that, the respective steps of the syntheses of 1 and 2 result in lower yields. All compounds adopt a double bladed propeller conformation in solution. Compound 3 is considerably more electron deficient than previously reported hexaaryl[3]radialenes, with reduction potentials of -0.06 and -0.45 V in CH(2)Cl(2). The compounds mostly display red fluorescence with large Stokes shifts. PMID- 22423274 TI - Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model. AB - For the condensation of anions such as phosphate and ADP to form ATP and water, nature employs sophisticated supramolecular systems to overcome coulomb repulsion and activation barriers. For an attempt to create a simple, analogous chemical system, the dimerization of vanadate is probably the simplest model. We have investigated Zn-benzylcyclene which favors the dimerization thermodynamically as shown by NMR titration. Moreover, EXSY NMR experiments reveal that the vanadate dimer is also kinetically stabilized with respect to hydrolysis by complexation with Zn-cyclene. PMID- 22423275 TI - On the mechanism of action of gated molecular baskets: The synchronicity of the revolving motion of gates and in/out trafficking of guests. AB - We used dynamic (1)H NMR spectroscopic methods to examine the kinetics and thermodynamics of CH(3)CCl(3) (2) entering and leaving the gated molecular basket 1. We found that the encapsulation is first-order in basket 1 and guest 2, while the decomplexation is zeroth-order in the guest. Importantly, the interchange mechanism in which a molecule of CH(3)CCl(3) directly displaces the entrapped CH(3)CCl(3) was not observed. Furthermore, the examination of the additivity of free energies characterizing the encapsulation process led to us to deduce that the revolving motion of the gates and in/out trafficking of guests is synchronized, yet still a function of the affinity of the guest for occupying the basket: Specifically, the greater the affinity of the guest for occupying the basket, the less effective the gates are in "sweeping" the guest as the gates undergo their revolving motion. PMID- 22423276 TI - Synthesis of highly functionalized beta-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines. AB - A rapid and simple procedure was devised for the synthesis of multifunctionalized cyclic beta-amino esters and gamma-amino alcohols via the 1,3-dipolar cycloaddition of nitrile oxides to beta-aminocyclopentenecarboxylates. The opening of the isoxazoline reductive ring to the corresponding highly functionalized 2-aminocyclopentanecarboxylates occurred stereoselectively with good yields. PMID- 22423277 TI - Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy. AB - Heating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the alpha-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde - which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions - or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine. PMID- 22423278 TI - Computational evidence for intramolecular hydrogen bonding and nonbonding X...O interactions in 2'-haloflavonols. AB - The conformational isomerism and stereoelectronic interactions present in 2' haloflavonols were computationally analyzed. On the basis of the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis, the conformer stabilities of 2'-haloflavonols were found to be dictated mainly by a C=O...H-O intramolecular hydrogen bond, but an unusual C-F...H-O hydrogen-bond and intramolecular C-X...O nonbonding interactions are also present in such compounds. PMID- 22423279 TI - Progress in liquid crystal chemistry II. PMID- 22423280 TI - Improved syntheses of high hole mobility phthalocyanines: A case of steric assistance in the cyclo-oligomerisation of phthalonitriles. AB - It has been shown that the base-initiated cyclo-oligomerisation of phthalonitriles is favoured by bulky alpha-substituents making it possible to obtain the metal-free phthalocyanine directly and in high yield. The phthalocyanine with eight alpha-isoheptyl substituents gives a high time-of flight hole mobility of 0.14 cm(2).V(-1).s(-1) within the temperature range of the columnar hexagonal phase, that is 169-189 degrees C. PMID- 22423281 TI - Laterally substituted symmetric and nonsymmetric salicylideneimine-based bent core mesogens. AB - Bent-core mesogens have gained considerable importance due to their ability to form new mesophases with unusual properties. Relationships between the chemical structure of bent-core molecules and the type and physical properties of the formed mesophases are relatively unknown in detail and differ strongly from those known for calamitic liquid crystals. In this paper symmetric and nonsymmetric five-ring salicylideneaniline-based bent-core mesogens are presented, and the effect of lateral substituents attached at the outer phenyl rings (F, Cl, Br) or the central phenyl ring (CH(3)) on the liquid-crystalline behaviour and on the physical properties is studied. Corresponding benzylideneaniline-based compounds were additionally prepared in order to study the influence of the intramolecular hydrogen bond. The occurring mesophases were investigated by differential scanning calorimetry, polarising microscopy, X-ray diffraction and dielectric and electro-optical measurements. The paper reports on new findings with respect to the structure-property relationships of bent-core mesogens. On one hand, the disruptive effect of laterally substituted halogen atoms, F, Cl and Br, on the mesophase behaviour of three isomeric series was much lower than expected. On the other hand, an increase of the clearing temperature by 34 K was observed, caused by small lateral substituents. The electro-optical behaviour, especially the type of polar switching and corresponding molecular movements, is sensitive to variations in the molecular structure. PMID- 22423282 TI - The interplay of configuration and conformation in helical perylenequinones: Insights from chirality induction in liquid crystals and calculations. AB - The chirality transfer in liquid crystals induced by two helical perylenequinones (namely, the natural compounds cercosporin and phleichrome) was investigated by integrating measurements of helical twisting power with a conformational analysis by DFT calculations and with the prediction of their twisting ability by the surface-chirality method. The two quasi-enantiomeric derivatives induce oppositely handed cholesteric phases when introduced as dopants in nematic solvents. We evaluated the role of the different conformations of the chiral hydroxyalkyl side chains in determining the helical twisting power: They were found to affect the strength of the chirality transfer, although the handedness of the induced cholesteric phase is essentially determined by the axial chirality (helicity) of the core of the perylenequinones. PMID- 22423283 TI - Efficient oxidation of oleanolic acid derivatives using magnesium bis(monoperoxyphthalate) hexahydrate (MMPP): A convenient 2-step procedure towards 12-oxo-28-carboxylic acid derivatives. AB - A new, straightforward and high yielding procedure to convert oleanolic acid derivatives into the corresponding delta-hydroxy-gamma-lactones, by using the convenient oxidizing agent magnesium bis(monoperoxyphthalate) hexahydrate (MMPP) in refluxing acetonitrile, is reported. In addition, a two-step procedure for the preparation of oleanolic 12-oxo-28-carboxylic acid derivatives directly from Delta(12)-oleananes, without the need for an intermediary work-up, and keeping the same reaction solvent in both steps, is described as applied to the synthesis of 3,12-dioxoolean-28-oic acid. PMID- 22423284 TI - Carbamate derivatives and sesquiterpenoids from the South China Sea gorgonian Melitodes squamata. AB - Five carbamate derivatives, obtucarbamates C and D (1, 2), dimethyl ((carbonylbis(azanediyl))bis(2-methyl-5,1-phenylene))dicarbamate (3), obtucarbamates A and B (4, 5), and four aromadendrane-type sesquiterpenoids, (+) 4beta-N-methenetauryl-10beta-methoxy-1beta,5alpha,6beta,7beta-aromadendrane (6), (-)-4beta-N-methenetauryl-10beta-methoxy-1beta,5beta,6alpha,7alpha-aromadendrane (7), (-)-4alpha,10beta-aromadendranediol (8), (+)-4beta,10beta-aromadendranediol (9) were obtained from the South China Sea gorgonian coral Melitodes squamata Nutting. Compounds 1, 2, 6, and 7 were new, and their structures were established by spectroscopic analyses. Compounds 6 and 7 contained a taurine group that was rarely found in marine natural compounds, and 7 showed moderate antibacterial activity. The possible biosynthesis routes of 1-5 were conjectured. PMID- 22423285 TI - Efficient, highly diastereoselective MS 4 A-promoted one-pot, three-component synthesis of 2,6-disubstituted-4-tosyloxytetrahydropyrans via Prins cyclization. AB - A simple, efficient and highly diastereoselective one-pot three-component synthesis of functionalized 2,6-disubstituted-4-tosyloxytetrahydropyrans was performed. The synthesis features an optimized Prins cyclization in which an aromatic homoallylic alcohol, an aromatic/aliphatic aldehyde, and p toluenesulfonic acid (catalyst and reagent) are reacted in the presence of molecular sieves (MS) 4 A at reflux in dichloromethane to afford excellent yields (72-96%) within short reaction times (20-90 min). The MS 4 A-promoted synthesis proved to be versatile enough to provide an array of symmetrical and unsymmetrical tetrahydropyran derivatives in economical manner. Furthermore, cleavage of the 4-tosyl group under mild conditions afforded 4 hydroxytetrahydropyran in excellent yields (95-96%). PMID- 22423286 TI - Biocatalytic hydroxylation of n-butane with in situ cofactor regeneration at low temperature and under normal pressure. AB - The hydroxylation of n-alkanes, which proceeds in the presence of a P450 monooxygenase advantageously at temperatures significantly below room temperature, is described. In addition, an enzymatic hydroxylation of the "liquid gas" n-butane with in situ cofactor regeneration, which does not require high pressure conditions, was developed. The resulting 2-butanol was obtained as the only regioisomer, at a product concentration of 0.16 g/L. PMID- 22423287 TI - A concise synthesis of 3-(1-alkenyl)isoindolin-1-ones and 5-(1-alkenyl)pyrrol-2 ones by the intermolecular coupling reactions of N-acyliminium ions with unactivated olefins. AB - A concise synthesis of 3-(1-alkenyl)isoindolin-1-ones and 5-(1-alkenyl)pyrrol-2 ones has been achieved by the coupling reactions of N-acyliminium ions produced from 3-hydroxyisoindol-1-ones or 5-hydroxy-1-pyrrol-2-ones with unactivated olefins in the presence of BF(3).OEt(2) at room temperature. For most of the olefins, the reactions afforded the C(sp3)-C(sp2) cross-coupling products, but for the alpha-methylstyrene and 1-hexene, the C(sp3)-C(sp3) cross-coupling products were obtained. PMID- 22423288 TI - Fifty years of oxacalix[3]arenes: A review. AB - Hexahomotrioxacalix[3]arenes, commonly called oxacalix[3]arenes, were first reported in 1962. Since then, their chemistry has been expanded to include numerous derivatives and complexes. This review describes the syntheses of the parent compounds, their derivatives, and their complexation behaviour towards cations. Extraction data are presented, as are crystal structures of the macrocycles and their complexes with guest species. Applications in fields as diverse as ion selective electrode modifiers, fluorescence sensors, fullerene separations and biomimetic chemistry are described. PMID- 22423289 TI - Ion-exchange-resin-catalyzed adamantylation of phenol derivatives with adamantanols: Developing a clean process for synthesis of 2-(1-adamantyl)-4 bromophenol, a key intermediate of adapalene. AB - A clean process has been developed for the synthesis of 2-adamantylphenol derivatives through adamantylation of substituted phenols with adamantanols catalyzed by commercially available and recyclable ion-exchange sulfonic acid resin in acetic acid. The sole byproduct of the adamantylation reaction, namely water, could be converted into the solvent acetic acid by addition of a slight excess of acetic anhydride during the work-up procedure, making the process waste free except for regeneration of the ion-exchange resin, and facilitating the recycling of the resin catalyst. The ion-exchange sulfonic acid resin catalyst could be readily recycled by filtration and directly reused at least ten times without a significant loss of activity. The key intermediate of adapalene, 2-(1 adamantyl)-4-bromophenol, could be produced by means of this waste-free process. PMID- 22423291 TI - A ferrocene redox-active triazolium macrocycle that binds and senses chloride. AB - A ferrocene bis(triazole) macrocycle was synthesised in good yield by the Eglinton coupling of an acyclic bis(alkyne) precursor and characterised in the solid state by X-ray crystallography. Alkylation gives the corresponding triazolium macrocycle, which binds chloride and benzoate strongly in CD(3)CN solution through favourable charge-assisted C-H...anion interactions, as evidenced by (1)H NMR titration experiments. Preliminary electrochemical studies reveal that the redox-active macrocycle is capable of sensing chloride in CH(3)CN solution. PMID- 22423290 TI - Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes. AB - A series of di-, tri- and tetravalent axles and wheels for the synthesis of pseudorotaxanes bearing the tetralactam macrocycle/diamide axle binding motif was prepared. Starting from iodinated monovalent precursors, Sonogashira cross coupling reactions were utilized to couple the binding sites to appropriate spacer groups. Through this "Lego" or "toolbox" approach, the convergent synthesis of host and guests with a well-defined number of the binding sites is possible. In addition, the spatial arrangement of the binding sites can be controlled through the quite rigid connections between linker and binding sites. Although a quantitative assessment of binding strengths was not possible by NMR titration experiments, typical and significant shifts of the signals of the diamide moiety indicate qualitatively the formation of pseudorotaxanes from the axle and wheel precursors. PMID- 22423292 TI - Double N-arylation reaction of polyhalogenated 4,4'-bipyridines. Expedious synthesis of functionalized 2,7-diazacarbazoles. AB - Unusual 2,7-diazacarbazoles were prepared in one step from readily available tetra-halogenated 4,4'-bipyridines by using a double N-arylation reaction in the presence of the Pd-XPhos catalyst system. Moderate to good yields were obtained in this site-selective Buchwald-Hartwig double amination. The functionalization of these tricyclic derivatives was performed by using Pd-catalyzed cross-coupling reactions such as the Stille and Suzuki couplings. Two compounds were analyzed by X-ray diffraction and show pi-pi stacking involving the diazacarbazole moieties and the phenyl rings of functionalized groups. PMID- 22423293 TI - Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity. AB - A halogenmethylsulfonyl moiety is incorporated in numerous active herbicides and fungicides. The synthesis of tribromomethyl phenyl sulfone derivatives as novel potential pesticides is reported. The title sulfone was obtained by following three different synthetic routes, starting from 4-chlorothiophenol or 4 halogenphenyl methyl sulfone. Products of its subsequent nitration were subjected to the S(N)Ar reactions with ammonia, amines, hydrazines and phenolates to give 2 nitroaniline, 2-nitrophenylhydrazine and diphenyl ether derivatives. Reduction of the nitro group of 4-tribromomethylsulfonyl-2-nitroaniline yielded the corresponding o-phenylenediamine substrate for preparation of structurally varied benzimidazoles. PMID- 22423294 TI - Synthesis, solid-state fluorescence properties, and computational analysis of novel 2-aminobenzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides. AB - New fluorescent compounds, benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides (3a-g), 2-amino-4-methylsulfanylbenzo[4,5]thieno[3,2-d]pyrimidine (6), and 2-amino-4 methylsulfanyl-7-methoxybenzo[4,5]furo[3,2-d]pyrimidine (7), were synthesized in good yields from heterocyclic ketene dithioacetals (1a-c) and guanidine carbonate (2a) or (S)-methylisothiourea sulfate (2b) in pyridine under reflux. Among the fused pyrimidine derivatives, compound 3c, which has an amino group at the 2 position and a benzylamino group at the 4-position of the pyrimidine ring, showed the strongest solid-state fluorescence. The absorption and emission properties of the compounds were quantitatively reproduced by a series of ab initio quantum chemical calculations. PMID- 22423295 TI - Synthesis of oleophilic electron-rich phenylhydrazines. AB - Phenylhydrazines 1 substituted with two or three long-chain alkyl, alkoxy or alkylsulfanyl groups were successfully prepared by acid-induced removal of the Boc group in hydrazides 2. The reaction is carried out with 5 equivalents of TfOH in CF(3)CH(2)OH/CH(2)Cl(2) at -40 degrees C for 1.5 min. Under these conditions, the deprotected hydrazine 1 is fully protonated, which increases its stability in the reaction medium. The hydrazines were isolated in 60-86% yields and purities >90%. The hydrazides 2 were obtained in 43-71% yields from aryl bromides 5, which were lithiated with t-BuLi and subsequently reacted with di-tert-butyl azodicarboxylate (DTBAD). PMID- 22423296 TI - Conserved and species-specific oxylipin pathways in the wound-activated chemical defense of the noninvasive red alga Gracilaria chilensis and the invasive Gracilaria vermiculophylla. AB - Chemical defense of the invasive red alga Gracilaria vermiculophylla has been studied and compared to that of the noninvasive but related Gracilaria chilensis. Both species rely on a wound-activated chemical defense that makes them less attractive to the herbivorous sea snail Echinolittorina peruviana. The chemical stress response of both species was monitored by LC-ESIMS-based metabolic profiling and revealed commonalities and differences. Both algae rely on a rapid lipoxygenase mediated transformation of arachidonic acid to known and novel oxylipins. Common products are 7,8-dihydroxyeicosatetraenoic acid and a novel eicosanoid with an unusual gamma-lactone moiety. Several prostaglandins were predominantly formed by the invasive species. The role of some of these metabolites was investigated by surveying the attachment of E. peruviana on artificial food containing the respective oxylipins. Both algae species are defended against this general herbivore by 7,8-dihydroxyeicosatetraenoic acid, whereas the prostaglandins and the novel oxylipins were inactive at naturally occurring concentrations. The role of different oxylipins in the invasive potential of Gracilaria spp. is discussed. PMID- 22423297 TI - The volatiles of pathogenic and nonpathogenic mycobacteria and related bacteria. AB - Volatiles released by pathogenic and nonpathogenic mycobacteria, as well as by mycobacteria-related Nocardia spp., were analyzed. Bacteria were cultivated on solid and in liquid media, and headspace samples were collected at various times during the bacterial lifecycle to elucidate the conditions giving optimal volatile emission. Emitted volatiles were collected by using closed-loop stripping analysis (CLSA) and were analyzed by gas-chromatography-mass spectrometry. A wide range of compounds was produced, although the absolute amount was small. Nevertheless, characteristic bouquets of compounds could be identified. Predominantly aromatic compounds and fatty-acid derivatives were released by pathogenic/nonpathogenic mycobacteria, while the two Nocardia spp. (N. asteroides and N. africana) emitted the sesquiterpene aciphyllene. Pathogenic Mycobacterium tuberculosis strains grown on agar plates produced a distinct bouquet with different volatiles, while liquid cultures produce less compounds but sometimes an earlier onset of volatile production because of their steeper growth curves under this conditions. This behavior differentiates M. tuberculosis from other mycobacteria, which generally produced fewer compounds in seemingly lower amounts. Knowledge of the production of volatiles by M. tuberculosis can facilitate the rational design of alternative and faster diagnostic measures for tuberculosis. PMID- 22423298 TI - Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis. AB - The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors has been developed. Reaction monitoring was achieved by using an inline ReactIR flow cell, which allows fast and convenient optimization of reaction parameters. The reductions proceeded well, and the desired products were isolated in high yields and with excellent enantioselectivities. PMID- 22423299 TI - Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones. AB - A core 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-one scaffold is elaborated at C-3(Me) by base-mediated aldol condensation to give new 3-alkenyl-4,5,6,7 tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural products. PMID- 22423300 TI - Self-assembly of Ru(4) and Ru(8) assemblies by coordination using organometallic Ru(II)(2) precursors: Synthesis, characterization and properties. AB - Coordination-driven self-assembly of binuclear half-sandwich p-cymene ruthenium(II) complexes [Ru(2)(MU-eta(4)-C(2)O(4))(MeOH)(2)(eta(6)-p cymene)(2)](O(3)SCF(3))(2) (1a) or [Ru(2)(MU-eta(4)-N,N' diphenyloxamidato)(MeOH)(2)(eta(6)-p-cymene)(2)](O(3)SCF(3))(2) (1b) separately with an imidazole-based tetratopic donor L in methanol affords two tetranuclear metallamacrocycles 2a and 2b, respectively. Conversely, the similar combination of L with 2,5-dihydroxy-1,4-benzoquinonato (dhbq) bridged binuclear complex [Ru(2)(MU-eta(4)-C(6)H(2)O(4))(MeOH)(2)(eta(6)-p-cymene)(2)](O(3)SCF(3))(2) (1c) in 1:2 molar ratio resulted in an octanuclear macrocyclic cage 2c. All the self assembled macrocycles 2a-2c were isolated as their triflate salts in high yields and were characterized fully by multinuclear ((1)H, (13)C and (19)F) NMR, infrared (IR) and electrospray ionization mass spectrometry (ESIMS). In addition, the molecular structure of macrocycle 2a was established unequivocally by single crystal X-ray diffraction analysis and adopts a tetranuclear rectangular geometry with the dimensions of 5.53 A * 12.39 A. Furthermore, the photo- and electrochemical properties of these newly synthesized assemblies have been studied by using UV-vis absorption and cyclic voltammetry analysis. PMID- 22423301 TI - Dioxane dibromide mediated bromination of substituted coumarins under solvent free conditions. AB - An efficient solvent-free protocol for regioselective bromination of substituted coumarins has been developed by using dioxane dibromide as the solid brominating agent. The efficacy of the solvent-free protocol has been established. The effects of the electronic nature and location of the substituents on the outcome of the reaction have been rationalized with a proposed mechanism. PMID- 22423302 TI - Reduction of benzylic alcohols and alpha-hydroxycarbonyl compounds by hydriodic acid in a biphasic reaction medium. AB - The synthetic protocol for the reduction of alcohols to hydrocarbons by using hydriodic acid, first described by Kiliani more than 140 years ago, was improved to be more applicable to organic synthesis. Instead of a strongly acidic, aqueous solution, a biphasic toluene-water reaction medium was used, which allowed the conversion of primary, secondary and tertiary benzylic alcohols, in good yields and short reaction times, into the corresponding hydrocarbons. Red phosphorous was used as the stoichiometric reducing agent. Keto, ester, amide or ether groups are tolerated, and catalytic amounts of hydriodic acid (0.2 equiv) in the presence of 0.6 equiv phosphorous are sufficient to achieve conversion. PMID- 22423303 TI - Principles of hand fracture management. AB - The hand is essential in humans for physical manipulation of their surrounding environment. Allowing the ability to grasp, and differentiated from other animals by an opposing thumb, the main functions include both fine and gross motor skills as well as being a key tool for sensing and understanding the immediate surroundings of their owner. Hand fractures are the most common fractures presenting at both accident and emergency and within orthopaedic clinics. Appropriate evaluation at first presentation, as well as during their management, can significantly prevent both morbidity and disability to a patient. These decisions are dependant on a wide range of factors including age, hand dominance, occupation and co-morbidities.A fracture is best described as a soft tissue injury with an associated bony injury. Despite this being the case, this paper intends to deal mainly with the bone injury and aims to discuss both the timing, as well as the methods available, of hand fracture management. PMID- 22423304 TI - The future of rheumatoid arthritis and hand surgery - combining evolutionary pharmacology and surgical technique. AB - Rheumatoid arthritis is a systemic autoimmune disease of uncertain aetiology, which is characterized primarily by synovial inflammation with secondary skeletal destructions.Rheumatoid Arthritis is diagnosed by the presence of four of the seven diagnostic criteria, defined by The American College of Rheumatology.Approximately half a million adults in the United Kingdom suffer from rheumatoid arthritis with an age prevalence between the second and fourth decades of life; annually approximately 20,000 new cases are diagnosed.The management of Rheumatoid Arthritis is complex; in the initial phase of the disease it primarily depends on pharmacological management. With disease progression, surgical input to correct deformity comes to play an increasingly important role. The treatment of this condition is also intimately coupled with input from both the occupational therapists and physiotherapy. PMID- 22423305 TI - A systematic review of dynamometry and its role in hand trauma assessment. AB - The dynamometer was developed by American neurologists and came into general use in the late 19th century. It is still used in various ways as a diagnostic and prognostic tool in clinical settings. In this systematic review we assessed in detail the different uses of dynamometry, its reliability, different dynamometers used and the influence of rater experience by bringing together and evaluating all published literature in this field. It was found that dynamometry is applied in a wide range of medical conditions. Furthermore, the great majority of studies reported acceptable to high reliability of dynamometry. Jamar mechanical dynamometer was used most often in the studies reviewed. There were mixed results concerning the effect of rater experience. The factors influencing the results of dynamometry were identified as age, gender, body weight, grip strength, BMI, non/dominant hand, assessing upper/lower limbs, rater and patient's strength and the distance from the joint where the dynamometer is placed. This review provides an understanding of the relevance and significance of dynamometry which should serve as a starting point to guide its use in hand trauma assessment. On the basis of our findings, we suggest that hand dynamometry has a great potential, and could be used more often in clinical practice. PMID- 22423306 TI - Adherence and Risk Behaviour in Patients with HIV Infection Receiving Antiretroviral Therapy in Bangkok. AB - It could be postulated that due to lifestyle factors, patients with poor antiretroviral therapy (ART) adherence may also have risky sexual behaviour potentially leading to HIV transmission. There are limited data regarding unprotected sex risk and ART adherence in resource limited settings and our study set out to investigate these in an HIV clinic in Bangkok. Patients completed an anonymous questionnaire regarding their relationship details, ART adherence, sexual behaviour, alcohol and drug use and HIV transmission beliefs. Laboratory findings and medical history were also collected. Unprotected sex risk (USR) was defined as inconsistent condom use with a partner of negative or unknown HIV status. Five hundred and twelve patients completed the questionnaire. Fifty seven per cent of patients reported having taken ARV >95% of the time in the last month and 58% had been sexually active in the previous 30 days. Only 27 patients (5%) were classified as having USR in our cohort. Multivariate analysis showed USR was associated with female gender (OR 2.9, 95% CI 1.2-7.0, p0.02) but not with adherence, age, type or number of partners, recreational drug or alcohol use nor beliefs about HIV transmission whilst taking ART. Levels of USR in this resource limited setting were reassuringly low and not associated with poor ART adherence; as all USR patients had undetectable viral loads onward HIV transmission risk is likely to be low but not negligible. Nonetheless condom negotiation techniques, particularly in women, may be useful in this group. PMID- 22423307 TI - Pediatric cerebellar hemorrhagic glioblastoma multiforme. AB - We report the case of an 11 year old boy who presented with nausea, vomiting and ataxia. He was evaluated with computed tomography (CT) and magnetic resonance imaging (MRI). Imaging demonstrated minimal enhancement and hemorrhage of a cerebellar mass. Cerebellar glioblastoma multiforme (GBM) is extremely rare in the cerebellum at any age but especially in children. The atypical findings of minimal enhancement, cerebellar location and hemorrhagic presentation combine to make the prospective diagnosis of GBM a difficult one. This rare combination of findings has not been previously reported. PMID- 22423308 TI - Vitamin D and Brain Imaging in the Elderly: Should we Expect Some Lesions Specifically Related to Hypovitaminosis D? AB - Hypovitaminosis D is associated with cognitive decline in the elderly, but the issue of causality remains unresolved. Definitive evidence would include the visualization of brain lesions resulting from hypovitaminosis D. The aim of the present article is to determine, through a literature review, the location and nature of possible brain disorders in hypovitaminosis D. We found limited brain imaging data, which reported ischemic infarcts and white matter hyperintensities in hypovitaminosis D, though did not provide their specific location or report any focal atrophy. Based on the finding of executive dysfunctions (i.e., mental shifting and information updating impairments) in the presence of hypovitaminosis D, we suggest that hypovitaminosis D is associated with a dysfunction of the frontal-subcortical neuronal circuits, particularly the dorsolateral circuit. Further imaging studies are required to corroborate this assumption and to determine whether hypovitaminosis D results in degenerative and / or vascular lesions. PMID- 22423309 TI - Predation by bears drives senescence in natural populations of salmon. AB - Classic evolutionary theory predicts that populations experiencing higher rates of environmentally caused ("extrinsic") mortality should senesce more rapidly, but this theory usually neglects plausible relationships between an individual's senescent condition and its susceptibility to extrinsic mortality. We tested for the evolutionary importance of this condition dependence by comparing senescence rates among natural populations of sockeye salmon (Oncorhynchus nerka) subject to varying degrees of predation by brown bears (Ursus arctos). We related senescence rates in six populations to (1) the overall rate of extrinsic mortality, and (2) the degree of condition dependence in this mortality. Senescence rates were determined by modeling the mortality of individually-tagged breeding salmon at each site. The overall rate of extrinsic mortality was estimated as the long-term average of the annual percentage of salmon killed by bears. The degree of condition dependence was estimated as the extent to which bears killed salmon that exhibited varying degrees of senescence. We found that the degree of condition dependence in extrinsic mortality was very important in driving senescence: populations where bears selectively killed fish showing advanced senescence were those that senesced least rapidly. The overall rate of extrinsic mortality also contributed to among-population variation in senescence-but to a lesser extent. Condition-dependent susceptibility to extrinsic mortality should be incorporated more often into theoretical models and should be explicitly tested in natural populations. PMID- 22423310 TI - The impact of the unstructured contacts component in influenza pandemic modeling. AB - BACKGROUND: Individual based models have become a valuable tool for modeling the spatiotemporal dynamics of epidemics, e.g. influenza pandemic, and for evaluating the effectiveness of intervention strategies. While specific contacts among individuals into diverse environments (family, school/workplace) can be modeled in a standard way by employing available socio-demographic data, all the other (unstructured) contacts can be dealt with by adopting very different approaches. This can be achieved for instance by employing distance-based models or by choosing unstructured contacts in the local communities or by employing commuting data. METHODS/RESULTS: Here we show how diverse choices can lead to different model outputs and thus to a different evaluation of the effectiveness of the containment/mitigation strategies. Sensitivity analysis has been conducted for different values of the first generation index G(0), which is the average number of secondary infections generated by the first infectious individual in a completely susceptible population and by varying the seeding municipality. Among the different considered models, attack rate ranges from 19.1% to 25.7% for G(0) = 1.1, from 47.8% to 50.7% for G(0) = 1.4 and from 62.4% to 67.8% for G(0) = 1.7. Differences of about 15 to 20 days in the peak day have been observed. As regards spatial diffusion, a difference of about 100 days to cover 200 km for different values of G(0) has been observed. CONCLUSION: To reduce uncertainty in the models it is thus important to employ data, which start being available, on contacts on neglected but important activities (leisure time, sport mall, restaurants, etc.) and time-use data for improving the characterization of the unstructured contacts. Moreover, all the possible effects of different assumptions should be considered for taking public health decisions: not only sensitivity analysis to various model parameters should be performed, but intervention options should be based on the analysis and comparison of different modeling choices. PMID- 22423311 TI - Female chimpanzees use copulation calls flexibly to prevent social competition. AB - The adaptive function of copulation calls in female primates has been debated for years. One influential idea is that copulation calls are a sexually selected trait, which enables females to advertise their receptive state to males. Male male competition ensues and females benefit by getting better mating partners and higher quality offspring. We analysed the copulation calling behaviour of wild female chimpanzees (Pan troglodytes schweinfurthii) at Budongo Forest, Uganda, but found no support for the male-male competition hypothesis. Hormone analysis showed that the calling behaviour of copulating females was unrelated to their fertile period and likelihood of conception. Instead, females called significantly more while with high-ranking males, but suppressed their calls if high-ranking females were nearby. Copulation calling may therefore be one potential strategy employed by female chimpanzees to advertise receptivity to high-ranked males, confuse paternity and secure future support from these socially important individuals. Competition between females can be dangerously high in wild chimpanzees, and our results indicate that females use their copulation calls strategically to minimise the risks associated with such competition. PMID- 22423312 TI - Identifying Canadian freshwater fishes through DNA barcodes. AB - BACKGROUND: DNA barcoding aims to provide an efficient method for species-level identifications using an array of species specific molecular tags derived from the 5' region of the mitochondrial cytochrome c oxidase I (COI) gene. The efficiency of the method hinges on the degree of sequence divergence among species and species-level identifications are relatively straightforward when the average genetic distance among individuals within a species does not exceed the average genetic distance between sister species. Fishes constitute a highly diverse group of vertebrates that exhibit deep phenotypic changes during development. In this context, the identification of fish species is challenging and DNA barcoding provide new perspectives in ecology and systematics of fishes. Here we examined the degree to which DNA barcoding discriminate freshwater fish species from the well-known Canadian fauna, which currently encompasses nearly 200 species, some which are of high economic value like salmons and sturgeons. METHODOLOGY/PRINCIPAL FINDINGS: We bi-directionally sequenced the standard 652 bp "barcode" region of COI for 1360 individuals belonging to 190 of the 203 Canadian freshwater fish species (95%). Most species were represented by multiple individuals (7.6 on average), the majority of which were retained as voucher specimens. The average genetic distance was 27 fold higher between species than within species, as K2P distance estimates averaged 8.3% among congeners and only 0.3% among concpecifics. However, shared polymorphism between sister-species was detected in 15 species (8% of the cases). The distribution of K2P distance between individuals and species overlapped and identifications were only possible to species group using DNA barcodes in these cases. Conversely, deep hidden genetic divergence was revealed within two species, suggesting the presence of cryptic species. CONCLUSIONS/SIGNIFICANCE: The present study evidenced that freshwater fish species can be efficiently identified through the use of DNA barcoding, especially the species complex of small-sized species, and that the present COI library can be used for subsequent applications in ecology and systematics. PMID- 22423313 TI - A triad of lys12, lys41, arg78 spatial domain, a novel identified heparin binding site on tat protein, facilitates tat-driven cell adhesion. AB - Tat protein, released by HIV-infected cells, has a battery of important biological effects leading to distinct AIDS-associated pathologies. Cell surface heparan sulfate protoglycans (HSPGs) have been accepted as endogenous Tat receptors, and the Tat basic domain has been identified as the heparin binding site. However, findings that deletion or substitution of the basic domain inhibits but does not completely eliminate Tat-heparin interactions suggest that the basic domain is not the sole Tat heparin binding site. In the current study, an approach integrating computational modeling, mutagenesis, biophysical and cell based assays was used to elucidate a novel, high affinity heparin-binding site: a Lys12, Lys41, Arg78 (KKR) spatial domain. This domain was also found to facilitate Tat-driven beta1 integrin activation, producing subsequent SLK cell adhesion in an HSPG-dependent manner, but was not involved in Tat internalization. The identification of this new heparin binding site may foster further insight into the nature of Tat-heparin interactions and subsequent biological functions, facilitating the rational design of new therapeutics against Tat-mediated pathological events. PMID- 22423315 TI - A local maximal inequality under uniform entropy. AB - We derive an upper bound for the mean of the supremum of the empirical process indexed by a class of functions that are known to have variance bounded by a small constant delta. The bound is expressed in the uniform entropy integral of the class at delta. The bound yields a rate of convergence of minimum contrast estimators when applied to the modulus of continuity of the contrast functions. PMID- 22423316 TI - CT and MR imaging patterns for pancreatic carcinoma invading the extrapancreatic neural plexus (Part I): Anatomy, imaging of the extrapancreatic nerve. AB - Pancreatic carcinoma is an extremely high-grade malignant tumor with fast development and high mortality. The incidence of pancreatic carcinoma continues to increase. Peripancreatic invasion and metastasis are the main characteristics and important prognostic factors in pancreatic carcinoma, especially invasion into the nervous system; pancreatic nerve innervation includes the intrapancreatic and extrapancreatic nerves. A strong grasp of pancreatic nerve innervation may contribute to our understanding of pancreatic pain modalities and the metastatic routes for pancreatic carcinomas. Computed tomography (CT) and magnetic resonance imaging (MRI) are helpful techniques for depicting the anatomy of extrapancreatic nerve innervation. The purpose of the present work is to show and describe the anatomy of the extrapancreatic neural plexus and to elucidate its characteristics using CT and MRI, drawing on our own previous work and the research findings of others. PMID- 22423317 TI - Health care reform in the USA: Recommendations from USA and non-USA radiologists. AB - AIM: To compare the opinions and recommendations of imaging specialists from United States (USA) and non-USA developed nations for USA health care reform. METHODS: A survey was emailed out to 18 imaging specialists from 17 non-USA developed nation countries and 14 radiologists within the USA regarding health care reform. The questionnaire contained the following questions: what are the strengths of your health care system, what problems are present in your nation's health care system, and what recommendations do you have for health care reform in the USA. USA and non-USA radiologists received the same questionnaire. RESULTS: Strengths of the USA health care system include high quality care, autonomy, and access to timely care. Twelve of 14 (86%) USA radiologists identified medicolegal action as a major problem in their health care system and felt that medicolegal reform was a critical aspect of health care reform. None of the non-USA radiologists identified medicolegal aspects as a problem in their own country nor identified it as a subject for USA health care reform. Eleven of 14 (79%) USA radiologists and 16/18 (89%) non-USA radiologists identified universal health care coverage as an important recommendation for reform. CONCLUSION: Without full universal coverage, meaningful health care reform will likely require medicolegal reform as an early and important aspect of improved and efficient health care. PMID- 22423318 TI - Initial assessment of chest X-ray in thoracic trauma patients: Awareness of specific injuries. AB - AIM: To compare the reported injuries on initial assessment of the chest X-ray (CXR) in thoracic trauma patients to a second read performed by a dedicated trauma radiologist. METHODS: By retrospective analysis of a prospective database, 712 patients with an injury to the chest admitted to the University Medical Center Utrecht were studied. All patients with a CXR were included in the study. Every CXR was re-evaluated by a trauma radiologist, who was blinded for the initial results. The findings of the trauma radiologist regarding rib fractures, pneumothoraces, hemothoraces and lung contusions were compared with the initial reports from the trauma team, derived from the original patient files. RESULTS: A total of 516 patients with both thorax trauma and an initial CXR were included in the study. After re-evaluation of the initial CXR significantly more lung contusions (53.3% vs 34.1%, P < 0.001), hemothoraces (17.8% vs 11.0%, P < 0.001) and pneumothoraces (34.4% vs 26.4%, P < 0.001) were detected. During initial assessment significantly more rib fractures were reported (69.8% vs 62.3%, P < 0.001). CONCLUSION: During the initial assessment of a CXR from trauma patients in the emergency department, a significant number of treatment-dictating injuries are missed. More awareness for these specific injuries is needed. PMID- 22423319 TI - Primary lymphoma of the liver - A complex diagnosis. AB - A 59-year-old woman presented with the clinical symptoms and radiologic investigations of a liver lesion suspect of metastasis. However, postoperative histopathology revealed a primary hepatic lymphoma (PHL). The case of a patient with a solitary PHL, which was treated by resection and subsequent chemotherapy, will be discussed with a short overview of the literature. PMID- 22423320 TI - Diagnostic challenge of lipomatous uterine tumors in three patients. AB - Lipomatous uterine tumors are uncommon benign neoplasms, with incidence ranging from 0.03% to 0.2%. They can generally be subdivided into two types: pure or mixed lipomas. A third group of malignant neoplasm has been proposed, which is liposarcoma; however, this is very rare. In this article, we report three patients having lipomatous uterine tumors, including one uterine lipoma and two uterine lipoleiomyomas. All our patients are postmenopausal women, which is the typical presenting age group. They did not have any symptoms and the tumors were only found incidentally on imaging. However, in some patients, symptoms may uncommonly occur. If symptoms occur, these are similar to those of leiomyoma. We illustrate the imaging features of the tumors in our patients with ultrasound, computed tomography (CT) scan and magnetic resonance imaging (MRI). The tumor typically appears as a well-defined homogenously hyperechoic lesion on ultrasound. It shows fat density on CT scan and signal intensity of fat on MRI. MRI is the modality of choice because of its multiplanar capability and its ability to demonstrate fat component of the lesion, as illustrated in our cases. We also discuss the importance of differentiating lipomatous uterine tumors from other lesions, especially ovarian teratoma which requires surgical intervention. Despite the rarity and the common asymptomatic nature of the tumors, we believe that this series of three cases demonstrates a review of a rare tumor which provides important knowledge for patient management. PMID- 22423321 TI - Statistical laws governing fluctuations in word use from word birth to word death. AB - We analyze the dynamic properties of 10(7) words recorded in English, Spanish and Hebrew over the period 1800-2008 in order to gain insight into the coevolution of language and culture. We report language independent patterns useful as benchmarks for theoretical models of language evolution. A significantly decreasing (increasing) trend in the birth (death) rate of words indicates a recent shift in the selection laws governing word use. For new words, we observe a peak in the growth-rate fluctuations around 40 years after introduction, consistent with the typical entry time into standard dictionaries and the human generational timescale. Pronounced changes in the dynamics of language during periods of war shows that word correlations, occurring across time and between words, are largely influenced by coevolutionary social, technological, and political factors. We quantify cultural memory by analyzing the long-term correlations in the use of individual words using detrended fluctuation analysis. PMID- 22423322 TI - Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity. AB - It is well known that natural products are a rich source of compounds for applications in medicine, pharmacy, and biology. However, the exact molecular mechanisms of natural agents in human health have not been clearly defined. Here, we demonstrate for the first time that the polyphenolic phytoalexin resveratrol promotes expression and activity of Argonaute2 (Ago2), a central RNA interference (RNAi) component, which thereby inhibits breast cancer stem-like cell characteristics by increasing the expression of a number of tumour-suppressive miRNAs, including miR-16, -141, -143, and -200c. Most importantly, resveratrol induced Ago2 resulted in a long-term gene silencing response. We also found that pterostilbene, which is a natural dimethylated resveratrol analogue, is capable of mediating Ago2-dependent anti-cancer activity in a manner mechanistically similar to that of resveratrol. These findings suggest that the dietary intake of natural products contributes to the prevention and treatment of diseases by regulating the RNAi pathway. PMID- 22423323 TI - Little and large: body size and genetic clines in a New Zealand gecko (Woodworthia maculata) along a coastal transect. AB - Clinal variation can result from primary differentiation or secondary contact and determining which of these two processes is responsible for the existence of a cline is not a trivial problem. Samples from a coastal transect of New Zealand geckos (Woodworthia maculata) identified for the first time a body size cline 7 10 km wide. The larger geckos are almost twice the mass of the small adult geckos. Clines in allele and haplotype frequency were found at two of the four genetic loci examined. Estimated width of the morphological cline was concordant with neither the narrower mtDNA cline (3-7 m) nor the wider nuclear cline (RAG-2; 34-42 km), and cline centers were not coincident. Although the body size cline is narrow compared to the entire range of the species, it is 2-3 orders of magnitude greater than estimates of dispersal distance per generation for these geckos. No evidence of assortative mating, nor of hybrid disadvantage was identified, thus there is little evidence to infer that endogenous selection is maintaining a hybrid zone. We cannot distinguish secondary contact from primary origin of this body size cline but conclude that secondary contact is likely due to the occurrence of mtDNA haplotypes from three distinct clades within the coastal transect and the presence of two frequency clines within this region. PMID- 22423324 TI - Expression of nitrous oxide reductase from Pseudomonas stutzeri in transgenic tobacco roots using the root-specific rolD promoter from Agrobacterium rhizogenes. AB - The nitrous oxide (N(2)O) reduction pathway from a soil bacterium, Pseudomonas stutzeri, was engineered in plants to reduce N(2)O emissions. As a proof of principle, transgenic plants expressing nitrous oxide reductase (N(2)OR) from P. stutzeri, encoded by the nosZ gene, and other transgenic plants expressing N(2)OR along with the more complete operon from P. stutzeri, encoded by nosFLZDY, were generated. Gene constructs were engineered under the control of a root-specific promoter and with a secretion signal peptide. Expression and rhizosecretion of the transgene protein were achieved, and N(2)OR from transgenic Nicotiana tabacum proved functional using the methyl viologen assay. Transgenic plant line 1.10 showed the highest specific activity of 16.7 umol N(2)O reduced min(-1) g(-1) root protein. Another event, plant line 1.9, also demonstrated high specific activity of N(2)OR, 13.2 umol N(2)O reduced min(-1) g(-1) root protein. The availability now of these transgenic seed stocks may enable canopy studies in field test plots to monitor whole rhizosphere N flux. By incorporating one bacterial gene into genetically modified organism (GMO) crops (e.g., cotton, corn, and soybean) in this way, it may be possible to reduce the atmospheric concentration of N(2)O that has continued to increase linearly (about 0.26% year( 1)) over the past half-century. PMID- 22423325 TI - Role of recent and old riverine barriers in fine-scale population genetic structure of Geoffroy's tamarin (Saguinus geoffroyi) in the Panama Canal watershed. AB - The role of physical barriers in promoting population divergence and genetic structuring is well known. While it is well established that animals can show genetic structuring at small spatial scales, less well-resolved is how the timing of the appearance of barriers affects population structure. This study uses the Panama Canal watershed as a test of the effects of old and recent riverine barriers in creating population structure in Saguinus geoffroyi, a small cooperatively breeding Neotropical primate. Mitochondrial sequences and microsatellite genotypes from three sampling localities revealed genetic structure across the Chagres River and the Panama Canal, suggesting that both waterways act as barriers to gene flow. F-statistics and exact tests of population differentiation suggest population structure on either side of both riverine barriers. Genetic differentiation across the Canal, however, was less than observed across the Chagres. Accordingly, Bayesian clustering algorithms detected between two and three populations, with localities across the older Chagres River always assigned as distinct populations. While conclusions represent a preliminary assessment of genetic structure of S. geoffroyi, this study adds to the evidence indicating that riverine barriers create genetic structure across a wide variety of taxa in the Panama Canal watershed and highlights the potential of this study area for discerning modern from historical influences on observed patterns of population genetic structure. PMID- 22423326 TI - Reef fish hybridization: lessons learnt from butterflyfishes (genus Chaetodon). AB - Natural hybridization is widespread among coral reef fishes. However, the ecological promoters and evolutionary consequences of reef fish hybridization have not been thoroughly evaluated. Butterflyfishes form a high number of hybrids and represent an appropriate group to investigate hybridization in reef fishes. This study provides a rare test of terrestrially derived hybridization theory in the marine environment by examining hybridization between Chaetodon trifasciatus and C. lunulatus at Christmas Island. Overlapping spatial and dietary ecologies enable heterospecific encounters. Nonassortative mating and local rarity of both parent species appear to permit heterospecific breeding pair formation. Microsatellite loci and mtDNA confirmed the status of hybrids, which displayed the lowest genetic diversity in the sample and used a reduced suite of resources, suggesting decreased adaptability. Maternal contribution to hybridization was unidirectional, and no introgression was detected, suggesting limited, localized evolutionary consequences of hybridization.Comparisons to other reef fish hybridization studies revealed that different evolutionary consequences emerge, despite being promoted by similar factors, possibly due to the magnitude of genetic distance between hybridizing species. This study highlights the need for further enquiry aimed at evaluating the importance and long-term consequences of reef fish hybridization. PMID- 22423327 TI - Population genomics of resource exploitation: insights from gene expression profiles of two Daphnia ecotypes fed alternate resources. AB - Consumer-resource interactions are a central issue in evolutionary and community ecology because they play important roles in selection and population regulation. Most consumers encounter resource variation at multiple scales, and respond through phenotypic plasticity in the short term or evolutionary divergence in the long term. The key traits for these responses may influence resource acquisition, assimilation, and/or allocation. To identify relevant candidate genes, we experimentally assayed genome-wide gene expression in pond and lake Daphnia ecotypes exposed to alternate resource environments. One was a simple, high quality laboratory diet, Ankistrodesmus falcatus. The other was the complex natural seston from a large lake. In temporary ponds, Daphnia generally experience high-quality, abundant resources, whereas lakes provide low-quality, seasonally shifting resources that are chronically limiting. For both ecotypes, we used replicate clones drawn from a number of separate populations. Fourteen genes were differentially regulated with respect to resources, including genes involved in gut processes, resource allocation, and activities with no obvious connection to resource exploitation. Three genes were differentially regulated in both ecotypes; the others may play a role in ecological divergence. Genes clearly linked to gut processes include two peritrophic matrix proteins, a Niemann-Pick type C2 gene, and a chymotrypsin. A pancreatic lipase, an epoxide hydrolase, a neuroparsin, and an UDP-dependent glucuronyltransferase are potentially involved in resource allocation through effects on energy processing and storage or hormone pathways. We performed quantitative rt-PCR for eight genes in independent samples of three clones of each of the two ecotypes. Though these largely confirmed observed differential regulation, some genes' expression was highly variable among clones. Our results demonstrate the value of matching the level of biological replication in genome-wide assays to the question, as it gave us insight into ecotype-level responses at ecological and evolutionary scales despite substantial variation within ecotypes. PMID- 22423328 TI - Can balancing selection on MHC loci counteract genetic drift in small fragmented populations of black grouse? AB - The ability of natural populations to adapt to new environmental conditions is crucial for their survival and partly determined by the standing genetic variation in each population. Populations with higher genetic diversity are more likely to contain individuals that are better adapted to new circumstances than populations with lower genetic diversity. Here, we use both neutral and major histocompatibility complex (MHC) markers to test whether small and highly fragmented populations hold lower genetic diversity than large ones. We use black grouse as it is distributed across Europe and found in populations with varying degrees of isolation and size. We sampled 11 different populations; five continuous, three isolated, and three small and isolated. We tested patterns of genetic variation in these populations using three different types of genetic markers: nine microsatellites and 21 single nucleotide polymorphisms (SNPs) which both were found to be neutral, and two functional MHC genes that are presumably under selection. The small isolated populations displayed significantly lower neutral genetic diversity compared to continuous populations. A similar trend, but not as pronounced, was found for genotypes at MHC class II loci. Populations were less divergent at MHC genes compared to neutral markers. Measures of genetic diversity and population genetic structure were positively correlated among microsatellites and SNPs, but none of them were correlated to MHC when comparing all populations. Our results suggest that balancing selection at MHC loci does not counteract the power of genetic drift when populations get small and fragmented. PMID- 22423329 TI - A species assemblage approach to comparative phylogeography of birds in southern Australia. AB - We present a novel approach to investigating the divergence history of biomes and their component species using single-locus data prior to investing in multilocus data. We use coalescent-based hierarchical approximate Bayesian computation (HABC) methods (MsBayes) to estimate the number and timing of discrete divergences across a putative barrier and to assign species to their appropriate period of co-divergence. We then apply a coalescent-based full Bayesian model of divergence (IMa) to suites of species shown to have simultaneously diverged. The full Bayesian model results in reduced credibility intervals around divergence times and allows other parameters associated with divergence to be summarized across species assemblages. We apply this approach to 10 bird species that are wholly or patchily discontinuous in semi-arid habitats between Australia's southwest (SW) and southeast (SE) mesic zones. There was substantial support for up to three discrete periods of divergence. HABC indicates that two species wholly restricted to more mesic habitats diverged earliest, between 594,382 and 3,417,699 years ago, three species from semi-arid habitats diverged between 0 and 1,508,049 years ago, and four diverged more recently, between 0 and 396,843 years ago. Eight species were assigned to three periods of co-divergence with confidence. For full Bayesian analyses, we accounted for uncertainty in the two remaining species by analyzing all possible suites of species. Estimates of divergence times from full Bayesian divergence models ranged between 429,105 and 2,006,355; 67,172 and 663,837; and 24,607 and 171,085 for the earliest, middle, and most recent periods of co-divergence, respectively. This single-locus approach uses the power of multitaxa coalescent analyses as an efficient means of generating a foundation for further, targeted research using multilocus and genomic tools applied to an understudied biome. PMID- 22423330 TI - Climate change and the decline of a once common bird. AB - Climate change is predicted to negatively impact wildlife through a variety of mechanisms including retraction of range. We used data from the North American Breeding Bird Survey and regional and global climate indices to examine the effects of climate change on the breeding distribution of the Rusty Blackbird (Euphagus carolinus), a formerly common species that is rapidly declining. We found that the range of the Rusty Blackbird retracted northward by 143 km since the 1960s and that the probability of local extinction was highest at the southern range margin. Furthermore, we found that the mean breeding latitude of the Rusty Blackbird was significant and positively correlated with the Pacific Decadal Oscillation with a lag of six years. Because the annual distribution of the Rusty Blackbird is affected by annual weather patterns produced by the Pacific Decadal Oscillation, our results support the hypothesis that directional climate change over the past 40 years is contributing to the decline of the Rusty Blackbird. Our study is the first to implicate climate change, acting through range retraction, in a major decline of a formerly common bird species. PMID- 22423331 TI - Increased divergence but reduced variation on the Z chromosome relative to autosomes in Ficedula flycatchers: differential introgression or the faster-Z effect? AB - Recent multilocus studies of congeneric birds have shown a pattern of elevated interspecific divergence on the Z chromosome compared to the autosomes. In contrast, intraspecifically, birds exhibit less polymorphism on the Z chromosome relative to the autosomes. We show that the four black-and-white Ficedula flycatcher species show greater genetic divergence on the Z chromosome than on the autosomes, and that the ratios of intraspecific polymorphism at Z-linked versus autosomal markers are below the neutral expectation of 75%. In all species pairs, we found more fixed substitutions and fewer shared polymorphisms on the Z chromosome than on the autosomes. Finally, using isolation with migration (IMa) models we estimated gene flow among the four closely related flycatcher species. The results suggest that different pattern of evolution of Z chromosomes and autosomes is best explained by the faster-Z hypothesis, since the estimated long term gene flow parameters were close to zero in all comparisons. PMID- 22423332 TI - Evolution of reproductive morphology among recently diverged taxa in the Drosophila mojavensis species cluster. AB - The morphological evolution of sexual traits informs studies of speciation due to the potential role of these characters in reproductive isolation. In the current study, we quantified and compared genitalic variation within the Drosophila mojavensis species cluster to infer the mode of evolution of the male aedeagus. This system is ideal for such studies due to the opportunity to test and compare levels of variation along a divergence continuum at various taxonomic levels within the group. Shape variation was quantified using elliptic Fourier descriptors and compared among the four D. mojavensis host races, and between D. mojavensis and its sister species Drosophila arizonae. Aedeagus shape was diagnostic for D. arizonae, and among three of the four D. mojavensis subspecies. In each of these cases, there was less variation within subspecies than among subspecies, which is consistent with the pattern predicted if genitalia are evolving according to a punctuated change model, and are involved with mate recognition. However, aedeagus shape in Drosophila mojavensis sonorensis was highly variable and broadly overlapping with the other three subspecies, suggesting aedeagus evolution in this subspecies is more complex and subject to additional evolutionary factors. These results are interpreted and discussed in the context of selection on mate recognition systems and the potential for failed copulation. PMID- 22423333 TI - Identity and relationships of the Arboreal Caatinga among other floristic units of seasonally dry tropical forests (SDTFs) of north-eastern and Central Brazil. AB - The tree species composition of seasonally dry tropical forests (SDTF) in north eastern and central Brazil is analyzed to address the following hypotheses: (1) variations in species composition are related to both environment (climate and substrate) and spatial proximity; (2) SDTF floristic units may be recognized based on peculiar composition and environment; and (3) the Arboreal Caatinga, a deciduous forest occurring along the hinterland borders of the Caatinga Domain, is one of these units and its flora is more strongly related to the caatinga vegetation than to outlying forests. The study region is framed by the Brazilian coastline, 50th meridian west and 21st parallel south, including the Caatinga Domain and extensions into the Atlantic Forest and Cerrado Domains. Multivariate and geostatistic analyses were performed on a database containing 16,226 occurrence records of 1332 tree species in 187 georeferenced SDTF areas and respective environmental variables. Tree species composition varied significantly with both environmental variables and spatial proximity. Eight SDTF floristic units were recognized in the region, including the Arboreal Caatinga. In terms of species composition, its tree flora showed a stronger link with that of the Cerrado Dry Forest Enclaves. On the other hand, in terms of species frequency across sample areas, the links were stronger with two other units: Rock Outcrops Caatinga and Agreste and Brejo Dry Forests. There is a role for niche-based control of tree species composition across the SDTFs of the region determined primarily by the availability of ground water across time and secondarily by the amount of soil mineral nutrients. Spatial proximity also contributes significantly to the floristic cohesion of SDTF units suggesting a highly dispersal-limited tree flora. These units should be given the status of eco regions to help driving the conservation policy regarding the protection of their biodiversity. PMID- 22423334 TI - Evaluation of experimental genetic management in reintroduced bighorn sheep. AB - Positive demographic responses have been reported in several species where the immigration or supplementation of genetically distinct individuals into wild populations has resulted in a genetic rescue effect. However, rarely have researchers incorporated what could be considerable risk of outbreeding depression into planning for genetic management programs. We assess the genetic effects of an experiment in genetic management involving replicate populations of California bighorn sheep (Ovis canadensis californiana) in Oregon, USA, which previously experienced poor productivity and numerical declines. In the experiment, two declining populations were supplemented with ewes from a more genetically diverse population of California bighorn sheep in Nevada. We incorporated analysis of genetic samples representing both experimental populations prior to supplementation, samples from the supplemented individuals, and samples collected from both experimental populations approximately one generation after supplementation. We used genetic analyses to assess the integration of supplemented and resident populations by identifying interpopulation hybrids. Further, we incorporated demographic simulations to assess the risk of outbreeding depression as a result of the experimental augmentation. Finally, we used data from microsatellites and mitochondrial sequences to determine if genetic management increased genetic diversity in the experimental populations. Our analyses demonstrated the success of genetic management by documenting interpopulation hybrids, identifying no evidence for outbreeding depression as a result of contact between the genetically distinct supplemented and resident populations, and by identifying increased population level metrics of genetic diversity in postsupplementation populations compared with presupplementation levels. PMID- 22423335 TI - Persistence of self-recruitment and patterns of larval connectivity in a marine protected area network. AB - The use of marine protected area (MPA) networks to sustain fisheries and conserve biodiversity is predicated on two critical yet rarely tested assumptions. Individual MPAs must produce sufficient larvae that settle within that reserve's boundaries to maintain local populations while simultaneously supplying larvae to other MPA nodes in the network that might otherwise suffer local extinction. Here, we use genetic parentage analysis to demonstrate that patterns of self recruitment of two reef fishes (Amphiprion percula and Chaetodon vagabundus) in an MPA in Kimbe Bay, Papua New Guinea, were remarkably consistent over several years. However, dispersal from this reserve to two other nodes in an MPA network varied between species and through time. The stability of our estimates of self recruitment suggests that even small MPAs may be self-sustaining. However, our results caution against applying optimization strategies to MPA network design without accounting for variable connectivity among species and over time. PMID- 22423338 TI - A Study of Needle Image Artifact Localization in Confirmation Imaging of MRI guided Robotic Prostate Biopsy. AB - Recently several systems for magnetic resonance image (MRI) guided needle placement in the prostate have been reported. In comparison to conventional ultrasound-guided needle placement in the prostate, these MRI-guided systems promise improved targeting accuracy for prostate intervention procedures including biopsy, fiducial marker insertion, injection and focal therapy. In MRI guided needle interventions, after a needle is inserted, the needle position is often confirmed with a volumetric MRI scan. Commonly used titanium needles are not directly visible in an MR image, but they generate a susceptibility artifact in the immediate neighborhood of the needle. This paper reports the results of a quantitative study of the relation between the true position of titanium biopsy needle and the corresponding needle artifact position in MR images. The titanium needle artifact was found to be displaced 0.38 mm and 0.32 mm shift in scanner's frequency and phase encoding direction, respectively. The artifact at the tip of the titanium needle was observed to bend toward the scanner's B(0) magnetic field direction. PMID- 22423336 TI - Possible effects of global environmental changes on Antarctic benthos: a synthesis across five major taxa. AB - Because of the unique conditions that exist around the Antarctic continent, Southern Ocean (SO) ecosystems are very susceptible to the growing impact of global climate change and other anthropogenic influences. Consequently, there is an urgent need to understand how SO marine life will cope with expected future changes in the environment. Studies of Antarctic organisms have shown that individual species and higher taxa display different degrees of sensitivity to environmental shifts, making it difficult to predict overall community or ecosystem responses. This emphasizes the need for an improved understanding of the Antarctic benthic ecosystem response to global climate change using a multitaxon approach with consideration of different levels of biological organization. Here, we provide a synthesis of the ability of five important Antarctic benthic taxa (Foraminifera, Nematoda, Amphipoda, Isopoda, and Echinoidea) to cope with changes in the environment (temperature, pH, ice cover, ice scouring, food quantity, and quality) that are linked to climatic changes. Responses from individual to the taxon-specific community level to these drivers will vary with taxon but will include local species extinctions, invasions of warmer-water species, shifts in diversity, dominance, and trophic group composition, all with likely consequences for ecosystem functioning. Limitations in our current knowledge and understanding of climate change effects on the different levels are discussed. PMID- 22423339 TI - Magnesium and the acute physician. AB - Magnesium deficiency, and to a lesser extent magnesium excess, is commonly encountered in patients admitted to the Acute Medical Unit. It is important that acute physicians are able to identify those at risk of these states and initiate appropriate investigation and treatment. This article aims to provide the reader with a sound understanding of magnesium physiology and its effect at a cellular level. The causes, symptoms and treatment of magnesium disorders are discussed along with a review of evidence regarding the therapeutic use of magnesium. PMID- 22423340 TI - ECG dispersion mapping predicts clinical deterioration, measured by increase in the Simple Clinical Score. AB - OBJECTIVE: ECG dispersion mapping (ECG-DM) is a novel technique that reports abnormal ECG microalternations. We report the ability of ECG-DM to predict clinical deterioration of acutely ill medical patients, as measured by an increase in the Simple Clinical Score (SCS) the day after admission to hospital. METHODS: 453 acutely ill medical patients (mean age 69.7 +/- 14.0 years) had the SCS recorded and ECGDM performed immediately after admission to hospital. RESULTS: 46 patients had an SCS increase 20.8 +/- 7.6 hours after admission. Abnormal micro-alternations during left ventricular re-polarization had the highest association with SCS increase (p=0.0005). Logistic regression showed that only nursing home residence and abnormal micro-alternations during re polarization of the left ventricle were independent predictors of SCS increase with an odds ratio of 2.84 and 3.01, respectively. CONCLUSION: ECG-DM changes during left ventricular re-polarization are independent predictors of clinical deterioration the day after hospital admission. PMID- 22423341 TI - Improving the safety of patient transfer from AMU using a written checklist. AB - Unsafe patient transfers are one of the top reasons for incident reporting in hospitals. Criteria guiding safe transfer have been issued by the NHS Litigation Authority. To meet this standard, a "transfer check list" was redesigned for all patients leaving the Acute Medical Unit (AMU) in the Heartlands Hospital. Following the introduction of the checklist two full audit cycles were conducted. The first cycle highlighted an extremely poor uptake of the checklist. After interventions to educate nursing staff and raise awareness of the issues at the regular staff meetings, re-audit demonstrated significant improvement in completion rate. Subsequent monitoring indicates continued improvement, with compliance up to 95% for completion of the transfer checklist on AMU. Incident reporting relating to transfer has also decreased significantly. PMID- 22423342 TI - Where do AMU nurses perceive their educational needs? Results of the 20:10 project. AB - Our aim was to identify the perceived educational needs of nurses working in acute medicine to enable development of a training curriculum specifically for this staff group. METHODS: Post-graduate nurses from North Wales were invited to list 20 conditions and 10 skills for which they felt under prepared for their work in acute medicine. A workshop was then organized, attended by acute medicine nurses, medical colleagues and educationalists from two local universities to discuss initial data. RESULTS: Nurses identified particular needs for education around presenting symptoms with perceived deficits in knowledge or training. We found a heavy emphasis on respiratory and cardiac conditions. There was considerable overlap with frequent diagnostic categories from non-surgical hospital discharges and with priorities for training of junior doctors. Skills were often those traditionally associated with medical staff or care of patients with critical illnesses. CONCLUSION: The 20:10 project represents the first attempt to map educational needs of nursing staff on the Acute Medical Units of a large University Health Board using self-reported needs. The identified needs will support professional development, create incentives for recruitment and guide University postgraduate developments and commissioning. PMID- 22423343 TI - A hot bath to calm what ails you: the Cannabis Hyperemesis Syndrome. AB - The Cannabis Hyperemesis Syndrome (CHS) defines a recently described paradoxical association between recurrent vomiting episodes, daily cannabis excess and symptomatic relief with a hot bath or shower. Importantly, symptom resolution only occurs with cessation of cannabis use. We describe a case of CHS which had resulted in repeated hospital admissions. As cannabis use is common, it is important for both patients and Acute Physicians to be aware of this increasingly recognised condition. PMID- 22423344 TI - Endogenous endophthalmitis and liver abscesses. AB - We present a case of endogenous endophthalmitis secondary to liver abscesses, in a patient with no previous medical comorbidities or risk factors for immunosuppression. The patient presented with acute painless loss of vision and feeling generally unwell. Investigations revealed Streptococcus anginosus constellatus bacteraemia, and evidence of diverticular disease that likely predisposed to the liver abscesses. Due to prompt diagnosis and administration of antibiotics, the patient had a good visual outcome. This case highlights the importance of being aware of endogenous endophthalmitis, as early diagnosis and prompt administration of antibiotics will optimise visual outcomes. PMID- 22423345 TI - A young patient with heart failure: picture quiz question. AB - Case report A 28 year old gentleman presented after an episode of collapse with loss of consciousness. He gave a history of non-specific malaise and myalgia over the previous 7 days, with fever, a generalised rash and a non productive cough. He developed progressive shortness of breath with sharp, pleuritic chest pain that was unresponsive to antibiotics in the community. PMID- 22423348 TI - The patient presenting with acute hemiparesis. AB - Acute hemiparesis is a common cause of presentation to hospital. In the majority of cases the cause is acute stroke, which is ischaemic in 80% of cases. This article aims to provide the reader with a practical approach to the initial management of suspected stroke.The problem-based format highlights some of the specific questions raised in the 2009 curriculum for training in Acute Internal Medicine, with reference to recent guidance from the National Institute for Health and Clinical Excellence (NICE). PMID- 22423349 TI - Haemoptysis: diagnosis and treatment. AB - Haemoptysis is a common symptom in clinical practice, which requires further investigation. Fortunately, massive haemoptysis only accounts for a small proportion of these episodes. It is a medical emergency that carries a high mortality rate. There are no agreed management guidelines. This review discusses proposed methods of resuscitation as well as outlining a diagnostic algorithm and discusses treatments including bronchial artery embolization, endobronchial therapy, surgery and medical therapies. PMID- 22423350 TI - Viewpoint: norovirus outbreak on the AMU: a lesson in shared clinical leadership. AB - Three times a year, the first Wednesday of the month heralds a changeover of junior doctors within our hospital. This year, the first Wednesday in December provided a different kind of challenge. The voice on the phone confirmed the words that no one wanted to hear: "You have three confirmed cases of Norovirus and you have to close to new admissions". PMID- 22423352 TI - Striatal functional alteration during incentive anticipation in pediatric anxiety disorders. AB - OBJECTIVE: Behavioral inhibition is an early childhood temperament recently associated with altered striatal response in adolescence to incentives of increasing magnitudes. Since early childhood behavioral inhibition is also associated with risk for adolescent social phobia, a similar pattern of striatal activation may manifest in social phobia. The present study compares striatal function in healthy adolescents, adolescents with social phobia, and adolescents with generalized anxiety disorder. METHOD: Blood-oxygen-level-dependent signal in striatal regions was examined in 58 medication-free adolescents-14 with social phobia, 18 with generalized anxiety disorder but not social phobia, and 26 with no psychiatric disorder-matched on sex, age, puberty, IQ, and socioeconomic status. During functional magnetic resonance imaging, participants responded to incentive cues depicting potential monetary gains or losses of varying magnitudes. RESULTS: While anticipating incentives of increasing magnitude, adolescents with social phobia showed increasingly heightened caudate and putamen activation at a level greater than that seen in the healthy comparison and generalized anxiety disorder groups. The generalized anxiety disorder group showed a unique valence-specific putamen response relative to the healthy comparison or social phobia group. Both patient groups displayed more complex patterns in the nucleus accumbens than in the caudate or putamen. CONCLUSIONS: Caudate and putamen hypersensitivity to incentives of increasing magnitudes characterizes adolescent social phobia, relative to activation in this region in adolescents with generalized anxiety disorder as well as healthy adolescents. Thus, these findings resemble the pattern previously found in adolescents with early childhood behavioral inhibition, thereby implicating similar neural responses to anticipation of incentives in both early childhood behavioral inhibition and adolescent social phobia. PMID- 22423353 TI - Attention bias modification treatment for pediatric anxiety disorders: a randomized controlled trial. AB - OBJECTIVE: While attention bias modification (ABM) is a promising novel treatment for anxiety disorders, clinical trial data remain restricted to adults. The authors examined whether ABM induces greater reductions in pediatric anxiety symptoms and symptom severity than multiple control training interventions. METHOD: From a target sample of 186 treatment-seeking children at a hospital based child anxiety clinic, 40 patients with an ongoing anxiety disorder who met all inclusion criteria were enrolled in the study. Children were randomly assigned to one of three conditions: ABM designed to shift attention away from threat; placebo attention training using stimuli identical to those in the ABM condition; and placebo attention training using only neutral stimuli. All participants completed four weekly 480-trial sessions (1,920 total trials). Before and after the attention training sessions, children's clinical status was determined via semistructured interviews and questionnaires. Reduction in the number of anxiety symptoms and their severity was compared across the three groups. RESULTS: Change in the number of anxiety symptoms and their severity differed across the three conditions. This reflected significant reductions in the number of anxiety symptoms and symptom severity in the ABM condition but not in the placebo attention training or placebo-neutral condition. CONCLUSIONS: ABM, compared with two control conditions, reduces pediatric anxiety symptoms and severity. Further study of efficacy and underlying mechanisms is warranted. PMID- 22423354 TI - Acute nonlymphocytic leukemia presenting with pancytopenia. PMID- 22423355 TI - Retraction. PMID- 22423356 TI - About the European Journal of Pain. PMID- 22423357 TI - Proceeding of a Conference "Integrative Neural Systems Underlying Vital Aerodigestive Tract Functions", June 17-19, 2010, Madison, Wisconsin. PMID- 22423358 TI - Resolution-adapted recombination of structural features significantly improves sampling in restraint-guided structure calculation. AB - Recent work has shown that NMR structures can be determined by integrating sparse NMR data with structure prediction methods such as Rosetta. The experimental data serve to guide the search for the lowest energy state towards the deep minimum at the native state which is frequently missed in Rosetta de novo structure calculations. However, as the protein size increases, sampling again becomes limiting; for example, the standard Rosetta protocol involving Monte Carlo fragment insertion starting from an extended chain fails to converge for proteins over 150 amino acids even with guidance from chemical shifts (CS-Rosetta) and other NMR data. The primary limitation of this protocol--that every folding trajectory is completely independent of every other--was recently overcome with the development of a new approach involving resolution-adapted structural recombination (RASREC). Here we describe the RASREC approach in detail and compare it to standard CS-Rosetta. We show that the improved sampling of RASREC is essential in obtaining accurate structures over a benchmark set of 11 proteins in the 15-25 kDa size range using chemical shifts, backbone RDCs and HN-HN NOE data; in a number of cases the improved sampling methodology makes a larger contribution than incorporation of additional experimental data. Experimental data are invaluable for guiding sampling to the vicinity of the global energy minimum, but for larger proteins, the standard Rosetta fold-from-extended-chain protocol does not converge on the native minimum even with experimental data and the more powerful RASREC approach is necessary to converge to accurate solutions. PMID- 22423359 TI - Identification of the bile salt binding site on IpaD from Shigella flexneri and the influence of ligand binding on IpaD structure. AB - Type III secretion (TTS) is an essential virulence factor for Shigella flexneri, the causative agent of shigellosis. The Shigella TTS apparatus (TTSA) is an elegant nanomachine that is composed of a basal body, an external needle to deliver effectors into human cells, and a needle tip complex that controls secretion activation. IpaD is at the tip of the nascent TTSA needle where it controls the first step of TTS activation. The bile salt deoxycholate (DOC) binds to IpaD to induce recruitment of the translocator protein IpaB into the maturing tip complex. We recently used spectroscopic analyses to show that IpaD undergoes a structural rearrangement that accompanies binding to DOC. Here, we report a crystal structure of IpaD with DOC bound and test the importance of the residues that make up the DOC binding pocket on IpaD function. IpaD binds DOC at the interface between helices alpha3 and alpha7, with concomitant movement in the orientation of helix alpha7 relative to its position in unbound IpaD. When the IpaD residues involved in DOC binding are mutated, some are found to lead to altered invasion and secretion phenotypes. These findings suggest that adoption of a DOC bound structural state for IpaD primes the Shigella TTSA for contact with host cells. The data presented here and in the studies leading up to this work provide the foundation for developing a model of the first step in Shigella TTS activation. PMID- 22423361 TI - [A mutation suppressing a sumoylation site in the MITF transcriptional regulator predisposes to melanoma and renal carcinoma]. PMID- 22423360 TI - The N-terminal domains of SOCS proteins: a conserved region in the disordered N termini of SOCS4 and 5. AB - Suppressors of cytokine signaling (SOCS) proteins function as negative regulators of cytokine signaling and are involved in fine tuning the immune response. The structure and role of the SH2 domains and C-terminal SOCS box motifs of the SOCS proteins are well characterized, but the long N-terminal domains of SOCS4-7 remain poorly understood. Here, we present bioinformatic analyses of the N terminal domains of the mammalian SOCS proteins, which indicate that these domains of SOCS4, 5, 6, and 7 are largely disordered. We have also identified a conserved region of about 70 residues in the N-terminal domains of SOCS4 and 5 that is predicted to be more ordered than the surrounding sequence. The conservation of this region can be traced as far back as lower vertebrates. As conserved regions with increased structural propensity that are located within long disordered regions often contain molecular recognition motifs, we expressed the N-terminal conserved region of mouse SOCS4 for further analysis. This region, mSOCS486-155, has been characterized by circular dichroism and nuclear magnetic resonance spectroscopy, both of which indicate that it is predominantly unstructured in aqueous solution, although it becomes helical in the presence of trifluoroethanol. The high degree of sequence conservation of this region across different species and between SOCS4 and SOCS5 nonetheless implies that it has an important functional role, and presumably this region adopts a more ordered conformation in complex with its partners. The recombinant protein will be a valuable tool in identifying these partners and defining the structures of these complexes. PMID- 22423362 TI - Core needle biopsy from a small retroperitoneal lymphoma guided by image-fusion and electromagnetic needle tracking. PMID- 22423363 TI - Structural analysis of Escherichia coli C5 protein. PMID- 22423364 TI - Proceedings of the VIIth International Conference on Boar Semen Preservation honoring Vernon George Pursel, 14-17 August 2011, Bonn, Germany. PMID- 22423365 TI - Proceedings of the Satellite Workshop on Comparative Genomics, Research in Computational Molecular Biology (RECOMB-CG), March 28-31, 2011, Vancouver, Canada. PMID- 22423366 TI - [Comparison of efficacy of pegylated interferon alfa-2a or interferon alfa-2b combination therapy with nucleus(t)ide analogues in HBeAg positive chronic hepatitis B patients]. PMID- 22423367 TI - [Variation and significance of CD4+CD25+ regulatory T cells in chronic hepatitis B patients complicated with hepatic steatosis]. PMID- 22423368 TI - [Hepatitis B virus(HBV)subgenotypes and mutations in core promoter and precore/core in Xinjiang Uighur]. PMID- 22423369 TI - [Clinical observation of Qianggan capsule in the treatment of non-alcoholic of non-alcoholic fatty liver fibrosis]. PMID- 22423370 TI - [Analysis of clinical correlated factors of primary carcinoma of the liver with and without cirrhosis]. PMID- 22423371 TI - [The role of CTGF in mediating hepatocytes epithelial-to-mesenchymal transition and hepatic fibrogenesis]. PMID- 22423372 TI - [Autonomic dysfunction in liver cirrhosis]. PMID- 22423373 TI - Cutaneous lymphocyte antigen and alpha4beta7 T-lymphocyte responses are associated with peanut allergy and tolerance in children. AB - BACKGROUND: It is unclear whether the initial route of allergen exposure in early life could influence the subsequent development of allergy, with cutaneous sensitization leading to peanut allergy (PA), and tolerance induced by oral exposure. The skin- and gastrointestinal (GI)-homing markers, cutaneous lymphocyte antigen (CLA) and alpha4beta7 integrin, are used to determine whether the state of PA correlates with peanut-specific CLA responses, with tolerance associated with predominant alpha4beta7 responses. METHODS: CLA+ and alpha4beta7+ memory T cells were isolated and cultured with peanut extract to assess their proliferation. Stimulation indices were compared in peanut allergic and non allergic (NA) groups, and peanut-specific cytokine production was measured. RESULTS: In peanut allergic patients, peanut-specific proliferation predominates in the skin-homing CLA+ subset, whilst peanut-tolerant groups have a mixed CLA/alpha4beta7 response (P = 0.008). Comparison with a control food antigen (ovalbumin) showed that these differences are allergen specific. Cytokine responses showed trends towards Th1 skewing in the GI-homing alpha4beta7+ cells of peanut-tolerant groups and Th2 skewing in the skin-homing CLA+ cells of peanut allergic patients. CONCLUSION: The predominance of the CLA+ response to peanut in peanut allergic patients is consistent with the hypothesis that allergic sensitization occurs through the skin. The predominant alpha4beta7+ response in peanut-tolerant groups suggests that allergen exposure through the GI tract induces tolerance. PMID- 22423374 TI - Immunotherapy with oligomannose-coated liposomes ameliorates allergic symptoms in a murine food allergy model. AB - BACKGROUND: Allergen-specific immunotherapy has been anticipated to be a disease modifying therapy for food allergies. We previously reported that CD8(+) regulatory T cells may prevent antigen-sensitized mice from developing allergic diarrhea. Because oligomannose-coated liposomes (OML) have been shown to induce MHC class I-restricted CD8(+) T cell responses, we analyzed the adjuvant activities of OML for inducing regulatory CD8(+) T cells and mucosal tolerogenic responses in allergen-sensitized mice. METHODS: The BALB/c mice that were previously sensitized to ovalbumin (OVA) were intranasally immunized with OVA encased in OML (OVA-OML) or OVA-encased in non-coated liposomes (OVA-NL). We assessed allergic diarrhea induced by oral OVA administration, OVA-specific immunoglobulin production, and cytokine production in the intestines and mesenteric lymph nodes (MLNs). RESULTS: Intranasal immunization with OVA-OML, but not OVA-NL, suppressed the development of allergic diarrhea. This was associated with in vitro Ag-induced IL-10 production and the in vivo expansion of CD8(+) CD28(-) and CD4(+) CD25(+) Foxp3(+) T cell populations among mesenteric lymph node mononuclear cells, and was significantly ablated by anti-SIGNR1 or anti-CR3 mAbs. Up-regulation of serum OVA-specific IgE was suppressed, whereas OVA specific IgG1, IgG2a, and soluble IgA production were enhanced by intranasal administration of OVA-OML. Adoptive transfer of CD8(+) CD28(-) T cells but not CD28(+) CD8(+) T cells from the MLNs of OVA-OML-treated mice ameliorated the development of diarrhea. CONCLUSION: These results suggest that intranasal immunization with Ag-encased OML may be an effective immunotherapy for food allergies, as it induces a subset of regulatory CD8(+) T cells as well as CD4(+) CD25(+) Foxp3(+) T cell and modulates humoral immune responses in allergen sensitized mice. PMID- 22423375 TI - Bilateral optic atrophy. PMID- 22423376 TI - A monofocal pontine lesion. PMID- 22423378 TI - Enhancers in the spotlight. PMID- 22423377 TI - Comorbid impulse control disorder in bipolar disorder: the role of antidepressants. PMID- 22423379 TI - Sperm histones are organized to carry epigenetic clues into the zygote . PMID- 22423380 TI - Closed-loop stimulation: the future of surgical therapy of brain disorders? PMID- 22423381 TI - Does secretion of aberrant tau underlie lesion spread in tauopathies? PMID- 22423382 TI - New gene for ALS-FTD. PMID- 22423383 TI - Effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on retinal vascularity in diabetic rats. AB - BACKGROUND: The aim of the present study is to investigate the effectiveness of terutroban, a selective antagonist of the thromboxane/prostaglandin endoperoxide receptor, in preventing retinal ischaemia in a model of diabetes in rats. METHODS: Experimental diabetes was induced with streptozotocin. Rats were distributed into five groups (n = 20): (1) non-diabetic rats, (2) rats with diabetes (DR) treated with vehicle, (3) DR treated with aspirin (2 mg/kg/day p.o.), (4) DR treated with terutroban (5 mg/kg/day p.o.), (5) DR treated with terutroban (30 mg/kg/day p.o.). The follow-up period was 3 months. The main assessment was the percentage of retinal surface covered with vessels permeable to peroxidase. Platelet aggregation, aortic prostacyclin and nitric oxide production, plasma levels of lipid peroxides (thiobarbituric-acid-reactive substances) and 3-nitrotyrosine and serum levels of IL-6 were evaluated. RESULTS: Diabetes induced a reduction in retinal vascularity (76.9%), aortic prostacyclin (37.8%) and nitric oxide production (35.0%), and increased platelet aggregation, lipid peroxides, 3-nitrotyrosine. When compared with vehicle-treated DR, terutroban increased the percentage of retinal surface covered by PVPP (38% for terutroban-5 and 61% for terutroban-30), aortic prostacyclin (188% for terutroban 5 and 146% for terutroban-30) and nitric oxide production (320% for terutroban-5 and 390% for terutroban-30). Moreover, terutroban reduced platelet reactivity (27.8-95.1%, according to the inducer), lipid peroxides (60.7% for terutroban-5 and 50.0% for terutroban-30), 3-nitrotyrosine (43.8% for terutroban-5 and 36.8% for terutroban-30) and IL-6 concentration (18.0% for terutroban-30). The effect of terutroban in retinal, nitrosative and aortic parameters was significantly higher than that of aspirin. CONCLUSIONS: Terutroban significantly protected retinal vascularity from ischaemia in experimental diabetes, and this result could be attributed not only to its antiplatelet/antithrombotic activities but also to its vascular properties. PMID- 22423384 TI - Imipramine treatment reverses depressive-like behavior in alloxan-diabetic rats. AB - BACKGROUND: A growing body of evidence has shown an association between diabetes and depression, as well a role of brain-derived neurotrophic factor (BDNF) in diabetes and depression. The present study was designed to evaluate the behavioural and molecular effects of the anti-depressant imipramine in diabetic rats. METHODS: To this aim, after induction of diabetes by alloxan (150 mg/kg), Wistar rats were treated with imipramine (30 mg/kg) once a day for 14 days and then subjected to behavioural tests. BDNF was then assessed in the prefrontal cortex, hippocampus and amygdala. RESULTS: In diabetic rats treated with saline, we observed an increase in the immobility time, compared with control rats treated with saline. Treatment with imipramine decreased the immobility time in nondiabetic and diabetic rats, compared with both nondiabetic and diabetic rats treated with saline. In the open-field test, it was observed that treatment with imipramine reduced the number of crossings the diabetic rats performed, compared with nondiabetic rats treated with saline. The number of rearings did not alter in any of the groups. Diabetic rats injected with saline did not show altered BDNF levels in the prefrontal cortex, hippocampus or amygdala, but interestingly, the treatment with imipramine in diabetic animals increased BDNF levels in the prefrontal cortex. CONCLUSIONS: In conclusion, this study demonstartes a link between diabetes and depression in rats and that imipramine exerted antidepressant effects in diabetic animals. PMID- 22423385 TI - Erratum to ''Characterization of the regulatory roles of the SUMO. AB - BACKGROUND: Type 1 diabetes is a multi-factorial autoimmune disease that results from the destruction of insulin-producing beta cells of the pancreas; both genetic and environmental factors are thought to contribute to its development. Recently, a novel gene encoding small ubiquitin-like modifier protein 4 (SUMO4) was cloned and a single nucleotide substitution (M55V) was found to be strongly associated with type 1 diabetes. SUMO4 was shown to interact with IkappaBalpha and inhibit NFkappaB transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify IkappaBalpha by sumoylation, and so lead to activation of NFkappaB and transcription of genes implicated in the development of type 1 diabetes. However, the effects of sumoylation on immune cells are poorly understood. METHODS: Human SUMO1, 2, 3, 4 and mouse SUMO2 (mSUMO2) were cloned and overexpressed in T and B cells using retroviral transduction. We then investigated whether SUMO overexpression affected their functions in vitro. To study the function of mSUMO2 in vivo, we made transgenic mice overexpressing mSUMO2 in T cells and pancreatic beta cells and compared them with transgenic mice expressing a super-repressor of NFkappaB (a dominant negative form of NFkappaB, IkappaBalphaDeltaN) in T cells. Diabetes was induced in the two groups of mice by i.p. injection of streptozotocin. RESULTS: Human SUMO1, 2, 3, 4 and mSUMO2 were all found to negatively regulate the transcriptional activity of T and B cells. Supporting this idea, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines unlike T cells from the IkappaBalphaDeltaN mice. However, transgenic mice overexpressing mSUMO2 had the same susceptibility to diabetes as wild type whereas the mice overexpressing IkappaBalphaDeltaN Tg were completely protected against diabetes. CONCLUSION: These results indicate that at least in T cells, whereas NFkappaB has pro apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NFkappaB and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type. PMID- 22423386 TI - Clinical profiles and long-term outcomes of patients with pancreatic ductal adenocarcinoma and diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) is considered to be a possible risk factor and/or a manifestation of pancreatic ductal adenocarcinoma (PDAC). This study is aimed at analysing the potential association of diabetes mellitus with the development and pathogenic degrees of PDAC and post-surgical survival of Chinese Han PDAC patients. METHODS: A total of 1123 patients with PDAC were recruited and included 256 patients with diabetes mellitus within 2 years (new-onset) and 62 patients with diabetes mellitus >= 2 years (long-standing). Additional 466 patients with type 2 diabetes mellitus were included in this study. Their clinical characteristics and long-term outcomes were analysed. RESULTS: In comparison with patients with type 2 diabetes mellitus alone, PDAC patients with new-onset diabetes mellitus had an older onset age of diabetes mellitus and lower body mass index (BMI). Among PDAC cases, patients with new-onset diabetes mellitus were associated with neural invasion, poor tumour differentiation and shorter post-surgical survival. However, more than half of these patients became euglycemic after surgical resection of tumours. CONCLUSIONS: PDAC patients developed new-onset diabetes mellitus at an older age, and they had shorter post surgical survival. The underlying mechanisms by which comorbid diabetes mellitus affect the clinical profiles and outcomes of PDAC patients deserve further researches. PMID- 22423387 TI - Low-profile psychiatric hospitals in high-profile neighborhoods. PMID- 22423388 TI - Demonstrate your value to retain, add case management staff. AB - Some hospitals are eliminating case management positions as a budget-cutting initiative, in part because the hospital leadership doesn't understand the value case management brings to the table. - Market your department to senior management. - Describe the case management role and contribution to the revenue cycle. - Present data that is relevant to the hospital administration. - Create reports that are short and to the point. PMID- 22423389 TI - Keep reports short and to the point. PMID- 22423390 TI - Denials drop when CMs, MDs act as a team. AB - A study at Good Samaritan Hospital in Dayton, OH, determined that denial rates are lowest when case managers (CMs) and physicians collaborate on patient status. - Study analyzed denials during three different arrangements for determining patient status. - Biggest number of denials occurred when physicians acted alone. - When CMs set status, denials dropped in 7 of 10 DRGs with 2% or more denials. PMID- 22423391 TI - Collaboration eliminates sepsis readmissions. AB - St. Anthony's Hospital and Pinellas Point Nursing and Rehabilitation, both in St. Petersburg, FL, collaborated on a project to reduce sepsis readmissions after a study of heart failure patients showed that many were readmitted with sepsis. - Multidisciplinary committee from both facilities met to develop a sepsis protocol. - Hospital standardized information, tests, and lab values it sends with transferred patients. - Nursing facility screens patients for sepsis on every shift for 15 days. -Team developed a protocol for when patients show signs and symptoms of sepsis. PMID- 22423392 TI - ED navigators steer patients to appropriate providers. AB - At Presbyterian Healthcare Services in Albuquerque, NM, emergency department navigators refer patients with minor ailments to primary care providers or urgent care centers. All patients are triaged by nurse in ED. - Appropriate patients are sent to the hospital's Lean Track area where they are evaluated by a physician or mid-level provider. - Patients who can safely be treated in 12-24 hours are referred to the navigator, who obtains an appointment for them with a primary care provider or urgent care center. PMID- 22423393 TI - Readmission project aims to smooth transitions. AB - WellStar Health System in suburban Atlanta partners with post-acute providers to improve transitions in care and reduce readmissions. - Staff holds regular meeting with post-acute providers. -Team collaborates on smoothing transitions. - CMs work with facilities to take back patients after ED visits. -Transition coach follows patients after discharge. PMID- 22423394 TI - ED appointment-setting helps manage surges. PMID- 22423395 TI - The power of listening. PMID- 22423396 TI - Pharmaceuticals and medical devices: business practices. PMID- 22423397 TI - The 4th International Consensus Conference: Primary Systemic Treatment in the Management of Operable Breast Cancer: Toward the Rapid Assessment of Therapy Efficacy, 2010, Cremona, Italy. PMID- 22423398 TI - [One hundred books which built up neurology (61): "Selected Writings of John Hughlings Jackson" (1931-1932)]. PMID- 22423399 TI - Complex systems, evolution, and animal models. PMID- 22423401 TI - Gynecological laparoscopic surgery. PMID- 22423400 TI - Laser applications for treatment of the genitourinary tract, including the genitalia, urinary tract, bladder, prostate, kidneys, and related structures. PMID- 22423402 TI - Coil occlusion of aneurysms. PMID- 22423403 TI - Rheumatology. PMID- 22423405 TI - [Thoughts on the Physiological Society of Japan]. PMID- 22423404 TI - Neurotology. PMID- 22423406 TI - [Thoughts on modern physiology--Fukushima and principle of life]. PMID- 22423407 TI - Center of Cleft lip-Cleft palate and Craniofacial Deformities, Khon Kaen University in association with "Tawanchai project" and faculty of medicine Khon Kaen University. Foreword. PMID- 22423408 TI - Comparison of a clinical method with two radiographic methods for assessing quality of alveolar bone grafts. AB - The aim of the present study was to test the agreement between a new developed clinical examination method and two commonly used radiographic scales (Bergland and Chelsea) for assessing alveolar bone graft outcomes in the cleft lip and palate patients. This new clinical method consisted of: (1) Probing depth for the teeth adjacent to the cleft and (2) Residual defects at the bone graft site. Two trained examiners examined the subjects in the present study. The inter- and intra-reliability tests of the two clinical criteria and the two radiographic scales produced the excellent agreement level of Kappa values (0.85-1.00). Comparison of the "acceptable-unacceptable" proportions between clinical and radiographic examination methods using McNemar's Chi-square showed non significant differences (p-values 0.317-1.00), and good level Kappa values (0.68 0.77). It is suggested that the new clinical examination method could be used as an alternative screening tool for alveolar bone graft assessment. PMID- 22423409 TI - Prediction of final treatment for class III malocclusion of patients with oral clefts. AB - OBJECTIVE: To evaluate the value of predicted treatment plans interpreted from a previously developed Formula for Orthodontics and Surgery Prediction (FOSP) in patients with cleft lip and/or palate (CLP). MATERIAL AND METHOD: Orthodontic treatment records were collected of 105 non-syndromic CLP patients between the ages of 5 and 29 years, having Class III malocclusions of varying severity. Three cephalometric values from pre-treatment lateral cephalometric radiographs were determined for use with the FOSP. A receiver operating curve (ROC) was used to identify the optimal cut-off score for classifying predicted treatment needs, whether orthodontics alone or orthognathic surgery. The clinical merit of using the FOSP was determined by comparing predicted plans with actual treatments. RESULTS: The predictive value using a cut-off score of 0.6475 from the FOSP-for recommending the final treatment provided--was correctly classified for 79 subjects (75.2%). Sensitivity and specificity of the FOSP for prediction of the need for orthognathic surgery were 68.1% (52.9%-80.9%) and 81.0% (68.6%-90.1%), respectively. CONCLUSION: The FOSP can be used for early treatment prediction and counseling, and for more objectively specifying the type of orthodontic treatment for CLP patients. Other sources of information-such as evaluation of psychological and socioeconomic status, and patient's wishes-are still necessary for finalizing the treatment plan. PMID- 22423410 TI - Comparison of the modified Huddart/Bodenham and GOSLON yardstick methods for assessing outcomes following primary surgery for unilateral cleft lip and palate. AB - OBJECTIVE: To test the measure of agreement between the modified Huddart/Bodenham scoring system and the GOSLON Yardstick for assessing the dental occlusions of patients with unilateral complete cleft lip and palate (UCLP) and to test the time taken for each assessment. MATERIAL AND METHOD: 60 sets of study models of 8 10-year-old UCLP patients who attended the Department of Orthodontics at the Faculty of Dentistry, Khon Kean University were evaluated. All subjects had undergone their cleft lip and palate repairs, but no alveolar bone grafts or any orthodontic treatment were done. The judgments of two trained examiners were used to place the modified Huddart/Bodenham score for each set of models into one of 5 categories corresponding to the GOSLON ratings to test for agreement between the two methods. The strength of agreement of ratings was analyzed by weighted kappa statistics. A paired t-test was carried out to compare the time taken in assessment with each index. RESULTS: There was good agreement between the two methods with a kappa value of 0.73. The GOSLON assessment took significantly less time than the modified Huddart/Bodenham assessment. CONCLUSION: The modified Huddart/Bodenham scoring system can be used as an alternative to the more commonly used GOSLON Yardstick for diagnostic purposes. Although the numerical scoring system takes more time, it provides more information about the sites of occlusal discrepancy than does the GOSLON Yardstick. PMID- 22423411 TI - The final orthodontic treatment outcome evaluation in patients with cleft lip and palate at Khon Kaen University Cleft Lip and Palate Center: a pilot study. AB - The primary objective of the present study was to use the Peer Assessment Rating (PAR) Index to assess the outcome of the final phase of treatment in cleft lip and palate patients with orthodontic treatment alone and with orthognathic surgery. A secondary objective was to determine the improvement in the occlusion of the two treatment alternatives. The study sample consisted of 27 patients who received orthodontic treatment alone and 7 patients who received orthodontic treatment combined with orthognathic surgery were evaluated. The results showed that the orthognathic surgery group had greater PAR scores pre-treatment than did the orthodontic treatment alone group. Post-treatment and improvement of PAR scores were similar for both groups. Two subjects in orthodontic treatment alone group had excellent improvement whereas other cases presented less but still desired improvement. For the orthognathic surgery group, all cases demonstrated great improvement in malocclusion. PMID- 22423412 TI - Speech and language therapy model for children with cleft lip/palate in Lao People's Democratic Republic. AB - BACKGROUND: Surgical treatment can reduces disfigurement for children with cleft lip/palate (CLP); however, most children have persistent speech and language problems especially if speech and language services are not available in underserviced and/or developing regions and countries. Children in such areas cannot reach appropriate and timely speech therapy services. OBJECTIVE: To establish a speech and language therapy model in Lao People's Democratic Republic (Lao PDR), by combining the principles of Community-Based Rehabilitation (CBR), Primary Health Care (PHC) and institutional medical approaches. MATERIAL AND METHOD: Participatory workshops during which a speech and language therapy model would be developed. RESULTS: A speech and language therapy model for children with CLP in Lao PDR was established based upon the existing healthcare system and regional context. CONCLUSION: A speech and language therapy model should be implemented among children with CLP in Lao PDR as well as other developing countries where there is a paucity of speech and language therapy services. PMID- 22423413 TI - Cost effectiveness of speech camps for children with cleft palate in Thailand. AB - Most mobile cleft lip and palate (CLP) surgical units and international missions developing countries generally address surgical issues that reduce the physical abnormalities of the people. Stigmatization persists as speech therapy for most patients is delayed (or they get none at all) due to a shortage of speech and language pathologists. OBJECTIVE: To estimate cost effectiveness of speech camps. MATERIAL AND METHOD: The 4-day speech camp and 1-day follow-up session were established based on the Community-Based Model for Speech Disorders for Children with Cleft Lip/Palate. Twelve children with CLP (age ranged 3 years 6 months-13 years) attended a 4-day speech camp and a 1-day follow-up session (6 months later) for remediation of their articulation disorders. Estimation of both the expense and duration for both speech camp and follow-up session were compared to those for getting speech services from the nearest speech center. RESULTS: Both a 4-day speech camp and a 1-day follow-up session significantly reduced the number of articulation defects. The average combined cost of a speech camp and the follow-up session was 13,623.04 baht/child (or $US 412.82/child at an exchange rate of 33 baht = $US 1) and spent only 6 months. For getting speech services from speech center, cost would be 129,112.08 baht/child ($US 3,912.49) and spend approximately 4-5 years to get the same number of speech services as received speech camp and 1-day follow-up session. This represents a savings of more than a million baht ( 1,386,252.46 or $US 42,007) over against the cost of providing speech therapy over a longer period in a hospital setting for 12 children. Moreover, children with CLP had no longer compensatory articulation defects that cause complicated speech problems and CONCLUSION: Speech camp and follow-up session provided cost effectiveness for problem-solving in the case of lack of speech services for children with CLP in Thailand. PMID- 22423414 TI - Satisfaction of speech and treatment for children with cleft lip/palate in Lao People's Democratic Republic. AB - BACKGROUND: Surgical treatment and speech therapy for people with cleft lip and palate (CLP) in the Lao People's Democratic Republic (Lao PDR) are either limited or not available in some areas. There continue to be patients needing surgical correction for abnormalities but they are past the age when surgery would be appropriate. Moreover, they have not been given speech services or received integrative multidisciplinary diagnosis and treatment. OBJECTIVE: To explore satisfaction on speech and treatment outcomes, as well as the further treatment needs for CLP in Lao PDR. MATERIAL AND METHOD: A literature review was undertaken and a background conducted on the problems of services for CLP in Lao PDR. A questionnaire was then developed to explore the magnitude of effects on speech and treatment outcomes as well as further treatment needs for CLP. RESULTS: Average scoring of children with CLP speech and configuration indicated that they have the least satisfaction with articulation and figure of lips. The majority of caregivers and patients agreed that correction of articulation defects was the aspect of their care most needing further treatment. CONCLUSION: Satisfaction with speech and treatment outcomes was critical issues in Lao PDR requiring development of an appropriate therapy model for children with CLP. PMID- 22423415 TI - A qualitative study of health-related quality of life and psychosocial adjustments of Thai adolescents with repaired cleft lips and palates. AB - OBJECTIVE: The purposes of the present study were (1) to study the meaning of Health-Related Quality of Life (HRQoL) from the insider's perspective and (2) to explore the relevant psychosocial adjustments involved in the HRQoL of Thai 12-to 17-year-old adolescents with repaired cleft lip and cleft palate (CLP). MATERIAL AND METHOD: The study included a sample of 18 adolescents with non-syndromic repaired CLP and 6 parents of these adolescents. The participants were recruited from an orthodontic clinic in the Faculty of Dentistry, Mahidol University, and all were in-depth interviewed. RESULTS: HRQoL can be categorized into four domains: physical symptoms,functional limitations, emotional well-being and social well-being. In the affected group they were striking differences in psychological assets, psychosocial resources and socioeconomic disparities. The majority of these participants were well-adjusted and able to cope with the adversities they experienced as a result of their conditions; hence it was noted that, participants with consistent support from parents,friends and professionals were likely to have a positive health status and satisfaction with treatment. CONCLUSION: These findings have important implications in measuring a multidimensional HRQoL construct, and will enhance issues regarding adaptation strategies which have an impact on HRQoL of adolescents with CLP. PMID- 22423416 TI - Study of care for patients with cleft lip/palate (CLP) in Lao People's Democratic Republic. AB - OBJECTIVE: The objectives of the study were to determine basic information, understand health-related problems and examine problem-solving strategies among patients with cleft lip/palate (CLP) residing in Lao People's Democratic Republic (PDR). MATERIAL AND METHOD: This was a cross-sectional, descriptive study. The research team interviewed 24 patients with CLP who underwent surgery at the Khammouan Hospital between October 16-20, 2010 and their caregivers. A questionnaire was developed by the research team to collect information on demographics, health-related problems and problem-solving strategies. Content validity was reviewed by five experts. RESULTS: Sixty-two percent (15/24) of the patients were boys with an average age of 6.3 years. Fifty percent of the patients had both a cleft lip and cleft palate. Heredity played a major role in causing the CLP among the majority of patients (58%). Most of caregivers resided in either Khammouan (33%) and Bolikhamxai Province (33%). With respect to the caregivers, their average age was 36 years, 50% were fathers and mothers, 87% had a family income lower than one million Kip/month (124 USD); all were satisfied with the treatment provided, 96% had sufficient knowledge for helping or publicizing the proper treatment to other patients and 87% knew of the healthcare resources for patients with CLP (i.e., Khammouan Hospital provides free-of-charge surgery). The caregivers also understood the need for regular, life-long follow up care of cleft lip. However, 87% of the caregivers did not know the causes of CLP, 75% did not know that the patients with ridges cleft must have a ridges bone graft surgery, while 66% did not know about post operative care, wound care, audiometry and speech therapy. CONCLUSION: Although timely receipt of primary cleft surgery is essential to the physical and psychosocial well-being of patients with CLP, those residing in Lao PDR did not receive surgery until the age of 6 years. The main reasons for this are the lack of awareness regarding diagnosis and treatment, limited availability of health services, and insufficient financial resources; therefore, both technical and financial support from external stakeholders is crucial. The establishment of a local medical infrastructure, training local surgeons and free access are also critical for the development of a sustainable and effective multidisciplinary management program for patients with CLP and their families. PMID- 22423417 TI - Early dental arch relationships as treatment outcome in children with complete unilateral cleft lip and palate in northeastern Thailand. AB - The objective of the present study was to evaluate the dental arch relationships of children with complete unilateral cleft lip and palate (UCLP) as an early surgical repair outcome in the Northeastern part of Thailand. The study used a 5 year study model of 46 complete UCLP, non consecutive, patients whose primary repair had been performed at Khon Kaen University. The outcome of dental arch relationships was assessed using the 5-Year-Olds' Index. Agreement of rating was assessed with weighted kappa statistics; both the intra- and inter-examiner agreements were high, indicating good reproducibility. The results indicated that the surgical outcome was graded as poor and very poor for 60% of patients and excellent, good, or fair for 40% of patients. This result was also poor compared with other overseas reports. PMID- 22423418 TI - Revision rates of alveolar bone grafting in unilateral cleft lip and palate patients with and without orthodontic preparation. AB - The main purpose of the present study was to compare the revision rates of alveolar bone grafting in cleft lip and palate (CLP) patients with and without orthodontic preparation. The dental record of 101 patients with unilateral cleft lip and palate were examined. Details were recorded of general characteristic, the need for revision, intraoral condition prior to surgery, surgical procedure and the cause of revision. The revision rates were 11.9% and 20.6% in orthodontic preparation and non-orthodontic preparation groups, respectively. The Fisher's exact test showed that there was no difference in the revision rate between both groups. Intraoral conditions prior to grafting and different surgical procedures did not affect the success of alveolar bone grafting. PMID- 22423419 TI - Long-term outcomes of surgical management in the patients with facial congenital melanocytic nevi. AB - BACKGROUND: The challenges of management of facial congenital melanocytic nevi (CMN) are the balance of the risk of malignant transformation, surgical management and the long-term evaluation of the functional and cosmetic outcomes. OBJECTIVE: To present information on the long-term surgical management outcomes of patients with facial CMN, which may be applicable for future clinical and surgical approaches for these lesions. MATERIAL AND METHOD: A follow-up study was performed of patients with facial CMN that were clinically evaluated by the author at Srinagarind Hospital, Khon Kaen University, between 1993 and 2011. The clinical records, photographs, surgical managements and outcomes were analyzed. RESULTS: Among the 20 patients assessed, the female-to-male ratio was 2.33 to 1 with one patient being a twin. Most (95%) had a single and ten a large CMN. The surgical treatments of these lesions included: serial excision, excision with full thickness skin grafts, excision with composite graft, excision with local and regional flaps, and excision with tissue expanders and flap. The long-term outcome revealed that no patient's condition changed or developed into melanoma. Most of the patients had an acceptable cosmetic and functional outcome. One patient had a hypertrophic scar on the face, one a mild ectropion of the lower eyelid and 2 hyperpigmentation of the skin-grafted area. CONCLUSION: The author presents a number of surgical techniques that may be used for decision-making in surgical management of each CMN. For the most part, analysis of the characteristics of the CMN, comprehensive evaluation of the anatomic composition of the defects and application of good reconstructive methods will provide acceptable long-term surgical outcomes and reduce the psychological impact to parents and patients. Early surgical removal of large CMNs is recommended and long-term follow-up until adulthood are the two essentials. PMID- 22423420 TI - Study of care for patients with cleft lip/palate (CLP) in the Lao People's Democratic Republic: health provider's perspective. AB - OBJECTIVE: The objectives of the present study included learning basic information on the problems among, and problem-solving for, the persons caring for patients with cleft lip/palate (CLP) in Lao People's Democratic Republic (PDR). MATERIAL AND METHOD: This was a cross-sectional, descriptive study done by completing a questionnaire during an interview. The sample group comprised physicians, anesthetists, nurses and public health officers a total of 34 persons from eight hospitals who attended a workshop at the Khammouan Hospital (October 16-20, 2010). The questionnaires were approved by 5 assessors and had a Cronbach's alpha of 0.89. General demographic information was collected as well as knowledge and understanding vis-a-vis the care of pediatric patients with CLP at Khammouan Hospital, in Lao People's Democratic Republic (PDR). RESULTS: Twenty of the public health officers surveyed were females. The average age of the officers was approximately 40 years. Sixteen of the officers were nurses from Khammouan Hospital. The survey of public health officers' taking care of patients with CLP revealed that (a) 19 were trained at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand (b) 23 had experience in caring for patients with CLP (c) 17 had a medical specialist at the center (d) 4 had sufficient officers at the center and (e) 13 had a good understanding of a multidisciplinary team approach to the care of patients with CLP while the majority (21) had either a poor understanding (13) or none at all (8). The survey of medical personnel's understanding in regard to the care of patients with CLP was moderate (x = 3.08, SD = 0.99). CONCLUSION: The problems of taking care of patients with CLP include lack of personnel (specifically professors to teach) knowledge, medical equipment and financial support. The solution lies in help from the government and overseas organizations for in- and out-bound training and grants. PMID- 22423421 TI - Challenges in evaluation, management and outcome of the patients with Treacher Collins Syndrome. AB - BACKGROUND: The challenges for management of Treacher Collins Syndrome (TCS) are the analysis of deformities and staged soft tissue and bony reconstruction. OBJECTIVE: To present clinical and radiologic findings, the evaluation methods and the concept of staged reconstruction for patients with TCS. MATERIAL AND METHOD: The authors reviewed the clinical and radiologic findings, the evaluation methods, the staged reconstruction and early surgical outcome of three patients with TCS treated at Srinagarind Hospital, between 1994 and RESULTS: One patient underwent evaluation by CT scan for planning, reconstruction of the zygoma and orbit, correction of the lower eyelid coloboma, bilateral staged ear reconstruction with costal cartilage. At the age of 8 years, he had acceptable initial outcome with planned middle ear management and staged facial reconstruction. Palatoplasties of a cleft palate were performed in two patients, CONCLUSION: TCS is a rare craniofacial deformity but poses challenges in evaluation, management and reconstructive surgery. The development of Craniofacial Center and interdisciplinary management is important for provision proper evaluation, initial management and longitudinal care, including appropriate timing for staged reconstruction of bone, ear and soft tissue reconstruction in patients with TCS. This treatment should be tailored and balanced with the functional and psychological needs of patient and his/her family. In developing countries, funding from other resources, including the not for-profit foundations, is needed in order to increase patients' accessibility, and improve the quality of the entire treatment program. PMID- 22423422 TI - Pierre Robin sequence: challenges in the evaluation, management and the role of early distraction osteogenesis. AB - BACKGROUND: The challenges for the management of Pierre Robin Sequence (PRS) are the evaluation and management of airway and feeding difficulty from glossoptosis and associated cleft palate. OBJECTIVE: To present the clinical findings, management, outcome and the role of early distraction osteogenesis in patients with PRS. MATERIAL AND METHOD: The medical records were reviewed of patients with PRS seen and managed by the authors at Srinagarind Hospital, Khon Kaen University between 2001 and 2011. RESULTS: Fifteen patients with PRS were seen and managed. The female-to male ratio was 1.8 to 1 (9 girls, 5 boys). All of the patients presented with a small mandible, retrodisplaced tongue and upper airway difficulty. One patient had cleft lip only and one patient had cleft lip with cleft palate. Patients were primarily from the provinces of Khon Kaen and Mahasarakham. Conservative management was successful in 12 patients while the 3 with tracheostomy required distraction osteogenesis and the tracheostomy was subsequently successfully decanualated. At the last follow-up, most of the patients had proper catch-up and mandibular growth. CONCLUSION: Primary management of airway insufficiency in patients with PRS can be managed in a prone position with or without nasopharyngeal airway, prolonged intubation, tongue-lip adhesion, mandibular distraction osteogenesis and tracheostomy. The present study confirmed that proper conservative management can be used to manage most of the patients with PRS. However, early mandibular distraction should be considered when (a) indicated in patients with respiratory insufficiency to avoid tracheostomies or (b) successfully decannulating tracheostomies. Interdisciplinary team management is needed to ensure proper evaluation, improve care and optimum outcome. PMID- 22423423 TI - Craniofacial microsomia: goals of treatment, staged reconstruction and long-term outcome. AB - BACKGROUND: Craniofacial microsomia (CFM) is a complex congenital condition and includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches. OBJECTIVE: to present a review of the clinical presentations, assessment, treatment and outcome of the patients with CFM who were treated by the authors in Srinagarind hospital, Khon Kaen University. MATERIAL AND METHOD: Medical records were reviewed of patients with CFM, seen and managed by the authors at Srinagarind Hospital between 1993 and 2011; for an analysis of the clinical and radiologic assessments, treatments and outcomes. RESULTS: There were 23 patients (14 males and 9 females), 4 of whom had bilateral deformities, 19 unilateral deformities, and 1 syndromic CFM. The clinical presentation ranged from microtia to more severe deformities involving the mandible, zygoma and maxilla. Surgical treatments included: correction of macrostomia, distraction osteogenesis, staged ear reconstruction, orbit-maxillary mandibular surgery, soft tissue reconstruction with dermis fat graft, vascularized free tissue transfer, cleft lip-cleft lip nose repair and palatoplasty. Most of the patients were satisfied with the medical treatment and many patients were still in the growing skeletal age and had staged reconstruction planned. CONCLUSION: The goals of treatment for CFM are to (a) manage respiratory insufficiency and feeding problems (b) maximize hearing and communication (c) improve facial symmetry and proper facial growth and (d) optimize dental occlusion. These patients require staged reconstruction and coordinated care by an experienced multidisciplinary craniofacial team in order to ensure a thorough, comprehensive assessment of the nature and extent of the problems and to provide better treatment planning and long-term outcome adapted to the respective anatomic and functional deformities of each patient, and the needs of their family and other involved stakeholders. PMID- 22423424 TI - Home visit patients and family with cleft lip and palate. AB - BACKGROUND: The operating process for cleft care, requires continuity of care involving a multidisciplinary team. When the patient goes to hospital to receive surgery, parents and family feel nervous about their children and need to know how to take care of their children afterwards. Some patients will have operations into their teenage years. The scar on their face will give them low self esteem and feelings of isolation. Patients and family need information and encouragement. Home visit should be a good process to convey information and encourage patients and family. OBJECTIVE: Of this project were to convey information and encourage patients and family and to evaluate patients/family problems and needs as well as to promote networking. MATERIAL AND METHOD: A team meeting took place to decide about the families to be visited. After selection the family nurse coordinator contacted them by telephone, as well as contacting the primary care unit near to the family and then travelled to visit the family. The collected data was by questionnaire, observation and in-depth interview. RESULTS: 2 families were visited before and after operation, 8 families were visited 2-3 days after operation. The families have better knowledge, more confidence and can take better care of their children. Unfortunately health care professionals in primary care unit were too busy to join with the team. CONCLUSION: Home visit is a good process to convey information and find patients and family problems/needs because they are more relaxed than in hospital, so can better understand and talk more easily. The families are happy to see the home visit team and are more confident to take care of their children after visit. PMID- 22423425 TI - Nursing care system development for patients with cleft lip-palate and craniofacial deformities in Srinagarind Hospital: pre-post operation. AB - BACKGROUND: Cleft lip and palate are the most common craniofacial anomalies. Srinagarind Hospital has 150-200 cases each year. The operating process of care requires continuity of care involving a multidisciplinary team. When the patients go to hospital to have operation, pain, limited activity and food are very different from normal life. During pre and post operative care nurses who work continuously and closely with the patients should have knowledge, experience and ability to take excellent care of their patients and families. This can prevent complications and help their decision process, decrease parents stress and encourage better co-operation. OBJECTIVE: To develop a nursing care system for patients with cleft lip-palate undergoing operation. MATERIAL AND METHOD: This is an action research divided into 3 phases. Phase 1, situation review: review of nursing care process by interview, focus group, observation and nursing documents. Phase 2, nursing system management: developing guidelines, composing nursing manual, handbook for parents, VCD for patients and family and story telling. Following that announcement and implementation. Phase 3: evaluation. RESULT: The authors found that guidelines, nursing manual, handbook for parents, VCD for patients and family and story telling are appropriate and have good utilization, but the pictures in handbook for parents and storytelling were not clear, too small and not attractive. CONCLUSION: Nursing manual for giving information about pre-post operative care, handbook for parents, story telling and VCD about pre-post operative care provide optimal care for patients and family with cleft lip and palate, but need to evaluate further the nursing outcome after this nursing system development. PMID- 22423426 TI - Postoperative pain in patients with cleft lip and palate in Srinagarind Hospital. AB - BACKGROUND: Srinagarind Hospital has about 150-200 cases of patients with cleft lip and cleft palate each year. The operating process requires continuity of care involving a multidisciplinary team. When the patients go to hospital to undergo operation, pain is one of the most important symptoms to try and control effectively. During pre and post operative care nurses who work continuously and closely with the patients are the best persons to assist with pain relief. They need to have knowledge, experience and ability to take excellent care about pain control as well as having to have continuing assessment and selection of pain measurement tool. They can then better help to relieve patients pain, decrease parents stress and encourage better cooperation. OBJECTIVE: To the present study pain score level in patients with cleft lip cleft palate during the 24 hour period after operation. MATERIAL AND METHOD: This is the retrospective descriptive study. Data was collected from medical records. 86 Medical records of the patients with cleft lip cleft palate who were admitted in 3c ward between January to December 2010. Medical Records were purposively selected for the study and recorded with a data collection form. RESULT: 39% of patients after cheiloplasty and 55.6% of patients after palatoplasty received painkillers before leaving operating room, 29.29% of patients after cheilopalsty and 15.50% of patients after palatoplasty had severe pain immediately in ward. 48.8% of patients after cheiloplasty have moderate to severe pain at the 4th hour. Pain score was less when longer time after operation. Only 7.3% have pain after the 16th hour and pain finish after the 20th hour after operation. 51.1% in patients after palatoplasty have moderate to very severe pain at the 4th hour and 15.6% have moderate to very severe pain still occurring until the 24th hour. CONCLUSION: Some of the patients with cleft lip and palate after operation received painkillers before leaving operating room. Pain score immediately at ward is severe to very severe pain. 22.09% of patients after cheiloplasty and palatoplasy have moderate to severe pain at the 4th hour. For patients after cheiloplasty pain will continue until the 16th hour after operation, but patients after palatoplasty pain will continue more than 24 hours. PMID- 22423427 TI - Quality of life in patients with cleft lip and palate after operation. AB - BACKGROUND: Cleft lip and cleft palate are the most common craniofacial anomalies. Srinagarind Hospital has 150-200 cases each year. The operating process of care, requires continuity of care involving a multidisciplinary team. When the patients go to hospital for an operation they experience pain, limited activity and also food is very different from normal life. When attending school they suffer speech articulation problems and feel shy and isolated, which has a detrimental affect on their life style and quality of life. OBJECTIVE: The main purpose of the study is to the present study quality of life in patients with cleft lip and palate after operation. MATERIAL AND METHOD: The present study is descriptive research using qualitative and quantitative approaches. The studied population were patients age 8-18 years old who were admitted at 3C Ward and Outpatient Department, Srinagarind Hospital. 33 patients were interviewed for the quantitative approach. Guideline for in-depth interview with 15 patients were used for the qualitative approach. Quantitative data were analyzed and presented in frequency, percentage and standard deviation. The qualitative data were analyzed through content analysis. RESULTS: Patients consider their QOL is high level, but in detail they still worry about self concept psychological well being. From indept interview patients would like to get further treatment to minimize their scar as soon as possible. CONCLUSION: Patients consider their quality of life as high level, but they would like to get further treatment. PMID- 22423428 TI - Frontoethmoidal meningoencephalocele: challenges and the Tawanchai center's long term integrated management. AB - BACKGROUND: The challenges for the management of patients with fronto-ethmoidal meningoencephalocele (FEEM) include: classification, assessment and analysis of the deformities, craniofacial reconstruction and long-term management. OBJECTIVE: To present experience of the Tawanchai Craniofacial Center of long-term integrated management and outcome of patients with FEEM. MATERIAL AND METHOD: Medical records were reviewed of 32 patients with FEEM treated by the authors between 1993 and 2011 at the Tawanchai Center, Srinagarind Hospital; the referral center for Northeast Thailand. RESULTS: Geographic Information System (GIS) analysis was used to examine the incidence and pattern of referrals to our Center. Most of the patients had the nasoethmoidal type (12 patients) followed by the combined naso-ethmoidal/-orbital type (8 patients). The surgical procedures included craniofacial reconstruction with medial canthopexy, orbital translocation, external repair and nasal reconstruction. Ultimately, most patients were satisfied with their remedied facial appearance. The Center's interdisciplinary protocol for the care of patients with FEEM was established. CONCLUSION: Experience demonstrated that a craniofacial center with interdisciplinary management was necessary to provide proper, early and longitudinal care and to achieve optimum outcomes for the patients with FEEM. In each case, the surgical outcome depended on the severity and classification of the deformities and the extent of associated brain anomalies. Nevertheless, in every case the final measurement should be done at the age of complete skeletal maturity. Funding from a number of sources, including the Foundation, is needed to ensure patients' access to treatment and follow-up and for the Craniofacial Cleft Center to improve the quality of treatment and programing. PMID- 22423429 TI - The dollars and sense of on-site medical clinics: regulatory and practical considerations for employers. PMID- 22423430 TI - Weaving with the world: Winnicott's re-imagining of reality. AB - For Winnicott, at the root of psychic life is primary creativity from which meaningfulness emerges spontaneously. One non-psychoanalytic source of Winnicott's view can be found in the work of the English romantic poets Wordsworth and Coleridge. Winnicott discovered in these poets kindred spirits who deepened his appreciation of the delicate area between what is perceived and what conceived. The author suggests one way to read Winnicott's theory of primary creativity is as a re-imagining of what it means to have contact with reality. For Winnicott, the emphasis is less on conflict between pleasure and reality and more on contrast between two different kinds of relationship with reality as it becomes increasingly external. PMID- 22423431 TI - Significant increase in communication among psychoanalysts working within different theoretical and cultural traditions. PMID- 22423432 TI - A particular form of paternal identification in women. PMID- 22423433 TI - Paternal identification in women: a dialogue between Jay Greenberg and Marilia Aisenstein. PMID- 22423434 TI - Witnessing across time: accessing the present from the past and the past from the present. AB - We are used to the idea that trauma in the past interrupts our capacity to grasp the present. But present or recent trauma can have a similar dissociative effect on our capacity to experience the more distant past. Contemporary trauma can rob the past of its goodness, leaving one feeling as if the past is gone, dead, separated from the present. The vitalization of the present by the past or the past by the present requires that experiences be linked across time. These links are created, in both directions, via categories of experience characterized by shared affect (Modell 1990, 2006). Such categories are created, in turn, by metaphor; and the construction of these metaphors across time requires that one be able to occupy self-states in both the past and the present that can then bear witness to one another. Trauma can result in the dissociation of these self states from one another, leading to a disconnection of present and past. PMID- 22423435 TI - Karl Abraham's revolution of 1916: from sensual sucking to the oral-aggressive wish of destruction. AB - The author argues that "The First Pregenital Stage of the Libido" (Abraham 1916 1917) expounds a new conception of orality, i.e., of purposeful oral aggression directed against an object during the first stage of psychic development. This conception is shown to be contrary to Freud's view of orality as elaborated in Three Essays on the Theory of Sexuality (1905), as well as in other writings of late 1914 and 1915. Abraham's conception ignores fundamental dimensions of Freud's thinking during these years, namely, the difference between autoerotism/narcissism and object love, on the one hand, and also between the leading role of sexuality and the secondary role of aggression, on the other. Thus, Abraham's thinking represents a basic theoretical change that had far reaching consequences for psychoanalytic practice. PMID- 22423436 TI - Reversible perspective and splitting in time. AB - The element of time--the experience of it and the defensive use of it--is explored in conjunction with the use of reversible perspective as a psychotic defense. Clinical material from a long analysis illustrates how a psychotic patient used the reversible perspective, with its static splitting, to abolish the experience of time. When he improved and the reversible perspective became less effective for him, he replaced it with a more dynamic splitting mechanism using time gaps. With further improvement, the patient began to experience the passage of time, and along with it the excruciating pain of separation, envy, and loss. PMID- 22423437 TI - Pregnancy, thirdness, and the aesthetics of catastrophe in Heinrich von Kleist. AB - In documenting his own personal crisis of faith in Enlightenment rationalism through letters and essays, Kleist exposes the epistemological fissures in its edifice. This paper explores in psychoanalytic terms the dilemmas associated with knowing and not knowing, and the relationship between self and other, revealed by these texts. Kleist's literary work goes beyond expressing this crisis of knowledge to enact a kind of solution to it, not resolving the contradictions that are central in his world but presenting them aesthetically, intact and precariously balanced. More specifically, a pregnancy conceived without the knowledge of the mother-to-be--in his novella "The Marquise of O" (1807a)- suggests a modification of the psychoanalytic third to include within it the catastrophe that it also mitigates. PMID- 22423438 TI - Listening to the psychic consequences of Nazism in psychoanalytic patients. PMID- 22423439 TI - The adolescent's discourse: new forms of civilization's discontents. PMID- 22423440 TI - [Still continuing to believe]. PMID- 22423444 TI - [Paranoid psychoses]. PMID- 22423445 TI - [Paranoia and persecution]. AB - The idea of paranoia has existed since Antiquity, but it was only in the 19th centurythat psychiatrists became interested in it and sought to describe it. Delusion and the feeling of persecution are common in all paranoiacs. The origins of the disease can be found in the patient's psychic structure. Establishing and maintaining contact with a caregiver is one way of helping the patient. PMID- 22423446 TI - [Sensitive paranoia, concepts and a clinical case study]. AB - Sensitive paranoia, classified by Ernst Kretschmer, is a combination of a paranoid disorder with solitude and mental distress. Sensitive paranoiacs, often depressive and anxious, perceive themselves as being excluded from society while at the same time cultivating a resentment towards it. They also constantly put themselves down. Group therapy can help these patients to find appeasement in their social life. PMID- 22423447 TI - [Paranoid delusions and homicides inside or outside the family]. AB - Paranoia is a mental pathology which severely complicates interpersonal relationships. Its mechanisms and its delusional themes often mean that paranoid subjects have strained, or even violent relations inside and/or outside their family. These difficuIt relationships can sometimes even lead to serious assaults without causing death or more rarely result in homicides with frequent pre incident indicators. PMID- 22423448 TI - [Erotomania, adapting to the engendered dangerousness]. AB - Erotomania is a dangerous pathology which is based up on the three stages of hope, pique and rancour. In the relationship, it implies the personal commitment of the therapist who must proceed with great care. Reducing, or eliminating this dangerousness is one aim but must not constitute the only goal. PMID- 22423449 TI - [The vigilante, a romantic figure according to paranoid logic]. AB - When patients "transform" themselves into vigilantes, they respond only to their own law and logic. In two examples taken from fiction, "vigilante" characters have experienced an initial trauma.What is the situation in daily clinical practice and how can we open the treatment door for patients suffering from paranoia? PMID- 22423450 TI - [Bibliography]. PMID- 22423451 TI - [Therapeutic gites in child psychiatry]. AB - Therapeutic gites in child psychiatry. A therapeutic stay in a gite is a project led by a multidisciplinary team. It enables children to experiment with the notion of pleasure and to develop their level of socialisation, their personality and their independence, outside the family environment. For caregivers, it provides a rich source of clinical material and strengthens the team dynamics. PMID- 22423452 TI - [Therapeutic activities for adolescents in crisis]. AB - The treatment of adolescents in crisis can be based around therapeutic activities. Professionals organise and lead workshops. These workshops can help professionals gain a better understanding of the patients and find suitable answers. PMID- 22423453 TI - [Jean-Martin Charcot]. PMID- 22423454 TI - Advances in health promotion for adolescents and young adults. Preface. PMID- 22423455 TI - Critical junctures: assuring healthy outcomes for adolescents in the new millennium. AB - Adolescence represents one of the key transitional periods in the life course. During adolescence, individuals are particularly sensitive to environmental or contextual inputs and undergo tremendous physical, social, emotional, and cognitive growth and development, developing habits, behavior patterns, and relationships that influence their lifelong health outcomes. This article provides an overview of the current status of adolescent health in the United States, key examples of areas in which health improvements have been achieved over the past decade, and recent developments in adolescent health policy, including opportunities within health care reform and other federal efforts, that should serve to improve adolescent health over the next decade. PMID- 22423456 TI - The economic impact of adolescent health promotion policies and programs. AB - Adolescence is a critical period in the human lifecycle, a time of rapid physical and socioemotional growth and a time when individuals establish lifestyle habits and health behaviors that often endure into and have lasting effects in adulthood. Adolescent health promotion programs play a critical role in helping youth establish healthy lifestyles. In this article, we present a socio ecological model as a framework for identifying effective policy and program areas that have a positive impact on adolescent health behaviors. Our discussion focuses on 4 key areas: reproductive health; obesity prevention; mental health and substance use, including smoking; and injury and violence prevention. We proceed with an overview of the current status of state-led adolescent health promotion policies and programs from a newly created policy database and then examine the evidence on the cost of preventable adolescent health problems and the cost-effectiveness of health promotion programs and policies. We conclude by discussing the threat posed to adolescent health promotion services and state-led policy initiatives by proposed and implemented federal and state-level budget cuts and examine the possible health and economic repercussions of reducing or eliminating these programs. PMID- 22423457 TI - Social marketing: an underutilized tool for promoting adolescent health. AB - Social marketing applies some of the same principles used in commercial marketing for the analysis, planning, execution, and evaluation of programs designed to motivate voluntary behavioral change. It relies on consumer research for understanding the people they hope to change, including their values, aspirations, fears, lifestyle, and factors that motivate and deter them from adopting desired behaviors. Social marketing has been applied in public health settings since the 1980s for promoting such behaviors as safer sex, hypertension and cholesterol control, reduced occurrence of alcohol-impaired driving, improved utilization of public health prevention and screening services, and enactment of better school nutrition policies in schools. Although most evidence for social marketing's utility comes from interventions directed at adult audiences, its application with adolescents may help to address issues that have been challenging or unresponsive to health behavior change specialists. This article describes the basic tenets of social marketing as a behavior change process, identifies its previously successful applications with adolescent audience segments, and offers both lessons learned and projected future applications that employ emerging communication technologies. PMID- 22423458 TI - Enhancing resilience among young people: the role of communities and asset building approaches to intervention. AB - Adolescent development is a complex, interactive process that involves individuals, families, peer groups, institutions, and communities. Resilience is a process reflecting one's ability to respond positively to the multitude of risks inherent in growth and development. This article focuses on strategies for enhancing resilience and health outcomes among young people. We explore the conditions under which young people, their families, and community institutions promote positive health outcomes. We review emerging issues with an emphasis on building social capital and cohesion to foster resilience through family and community relationships and resources. We provide examples of evidence-based interventions, including those with demonstrated cost-effectiveness. Informed by these data, we make recommendations for the practice of adolescent medicine and further research focused on physician involvement in strengthening family and community resilience and social capital to improve the lives of young people. PMID- 22423459 TI - Employment and training programs: a context for reaching out of school youth with mental health and other health programs. AB - Youth who have dropped out of school engage in risky health behaviors and have limited access to health care. It is difficult for health experts to develop programs that successfully reach this population. Employment and training programs for youth who have dropped out are a potential venue for addressing the many health needs of these youth. This article reviews the history of such programs and the available evidence about their health services and health outcomes. It also describes the development of a mental health intervention in an employment and training program in Baltimore and the lessons learned from that experience. PMID- 22423460 TI - Resilience in action: an evidence-informed, theoretically driven approach to building strengths in an office-based setting. AB - Positive Youth Development and resilience-based strategies designed to develop youth capabilities are promising means to reduce risky behaviors. This article focuses on applying a strengths-based approach in a health setting. It is anchored in behavioral models that propose that people make health-promoting decisions when they possess enough information to wish to change, motivation to drive them toward change, and the skill sets to take action toward and then maintain healthier behaviors. It considers how our interactions will benefit when we (1) form a trustworthy connection and health-promoting partnership, (2) use a behavioral screen that addresses risk in the context of existing strengths, (3) elicit strengths as well as challenges, (4) facilitate youth to derive their own solutions, and (5) offer teens positive coping strategies. PMID- 22423461 TI - Delivering adolescent preventive services in an office setting. AB - Adolescence has long been recognized as a vulnerable period. Although several major medical professional organizations have published adolescent preventive care guidelines, regional and national surveys of youth, providers, and medical records all suggest many gaps exist in the delivery of recommended preventive services. In this article, we review the development of adolescent preventive health guidelines, describe current rates of preventive health screening and counseling, and explore barriers to delivery of preventive care for this age group. We present resources and practical suggestions to help the reader create an adolescent-friendly environment and to facilitate preventive health care delivery in your practice. PMID- 22423462 TI - Innovative approaches to using new media and technology in health promotion for adolescents and young adults. AB - Over the past decade, new technology and media have changed the way we communicate, access information, and share content with one another. Most 12- to 17-year-olds now own cell phones, and most adolescents and young adults spend several hours per day on computers and cell phones. The American Academy of Pediatrics now encourages all pediatricians to increase their knowledge of new media and technology. This article details technology access among adolescents and young adults, highlights several current and potential innovative applications for new technology and social networking in health promotion, and discusses issues to consider as practitioners move toward integrating new media into clinical and health education settings. PMID- 22423463 TI - We have the evidence to enhance adolescent sexual and reproductive health--do we have the will? AB - The negative outcomes of early childbearing and sexually transmitted infections (STIs), including HIV/AIDS, threaten the health of adolescents more than any other age group. Ensuring the sexual and reproductive health of the more than 1.5 billion young people aged 10 to 25 around the world is central to global health. Country-level indicators show dramatic variations in sexual risk. Percentages of those who engage in sexual intercourse range from less than 1% of females in Pakistan to 54% of males in Cuba. Divergent rates of early pregnancy and STIs between countries and regions parallel variations in sexual behaviors, including age of sexual debut; number of partners; and use of contraception, including condoms. To understand these variations, many factors affecting the sexual and reproductive health of young people around the world such as age of marriage, norms and expectations around sexual behavior, gender inequities, and educational and economic opportunities must be considered. PMID- 22423464 TI - Health promotion with adolescent and young adult males: an empowerment approach. AB - Adolescent and young adult males, especially those who are economically and socially marginalized, need greater access to "male-friendly" health services. Engaging young males in health education and clinical services is challenging but feasible and is of vital importance not only for young men, but also their families, their communities, and the nation. Health and social service providers can play vital roles in promoting the health and well-being of young men by developing mutually respectful collaborations that break down the silos separating medical, educational, juvenile justice, social service, and other systems. We present the interdisciplinary clinic- and community-based initiatives developed by Columbia University Mailman School of Public Health and New York Presbyterian Hospital that connect young males to clinical and health education services and empower them to choose behaviors that promote their health. We describe our "empowerment approach" to working with young men that recognizes the powerful influence of gender on utilization of health services, emphasizes the importance of a strengths-based perspective, and reframes the context of help seeking from passive participation to active engagement. PMID- 22423465 TI - Youth empowerment solutions for violence prevention. AB - The limited success of youth violence prevention interventions suggests that effective prevention needs to address causes at multiple levels of analysis and empower youth in developing and implementing prevention programs. In this article, we review published studies of youth violence prevention efforts that engage youth in developing or implementing violence prevention activities. The reviewed studies suggest the promise of youth empowerment strategies and the need for systematic outcome studies of empowerment programs. After reviewing empowerment theory applied to youth violence prevention programs, we present a case study of the Youth Empowerment Solutions (YES) for Peaceful Communities program. YES engages middle-school youth in an after-school and summer program that includes a culturally tailored character development curriculum and empowers the youth to plan and implement community improvement projects with assistance from adult neighborhood advocates. The case study focuses on outcome evaluation results and presents evidence of the YES program effects on community-level outcomes (eg, property improvements, violent crime incidents) and on individual level outcomes (eg, conflict avoidance, victimization). The literature review and the case study suggest the promise of engaging and empowering youth to plan and implement youth violence prevention programs. PMID- 22423466 TI - The importance of families to adolescents' physical activity and dietary intake. AB - The family environment plays a key role in the development and maintenance of adolescent physical activity and dietary behaviors. Specifically, family support and encouragement, behavior modeling by parents, and resources available in the home are important mechanisms through which families can promote, or discourage, physical activity and healthful eating. In this article, we have provided a comprehensive review of the current body of literature examining the role of the family environment in adolescent physical activity and nutrition. Additionally, we discuss strategies to intervene on the family environment through work with schools, with the family unit, and by clinical providers. PMID- 22423467 TI - Adolescent smoking cessation: promising strategies and evidence-based recommendations. AB - Most adult smokers began smoking as teenagers, and an estimated 6.4 million young people will eventually suffer premature mortality and/or diminished quality of life as a result of smoking-related diseases. Most teens who smoke want to stop but fail within a month of trying to quit independently. Reaching teens with effective treatments for smoking cessation is essential to their current and future health. This article highlights evidence-based interventions and provides practice recommendations to address adolescent smoking. These include behavioral approaches and initial research regarding pharmacotherapy as well as strategies for individual patient encounters, practice management, and public advocacy. PMID- 22423468 TI - Clinical approaches to improving alcohol education and counseling in adolescents and young adults. AB - Clinical prevention trials (approaches to educating and counseling) of adolescents (teens and young adults aged 12 to 25) about risks related to alcohol use indicate that reduction in adolescent alcohol use is possible with nonphysicians as interventionists and physicians as interventionists supported by patient counseling guides and resources. Opportunities for personalized, interactive adolescent education with goal setting appears key to intervention success. Physicians might also be more effective if they are aware of emerging alcohol problems among youth, systems-level resources for counseling adolescents about prevention, and appropriate guidance for parents. Recommendations and resources for clinicians working with adolescents regarding alcohol misuse are provided. PMID- 22423470 TI - Can I.T. keep the patients away? PMID- 22423469 TI - Emerging trends and innovations in the identification and management of drug use among adolescents and young adults. AB - One in four youths aged 12 to 17 years and more than half of young adults aged 18 to 25 years in the United States have used an illicit drug in their lifetime. A significant number progress to problematic use, and only 1 in 10 young people who meet criteria for dependence or abuse receive some form of treatment. Despite advances in the field, effectively intervening along the continuum of drug use involvement remains a challenge. In this article, we review the current epidemiology of illicit drug use by young people; describe recent advances in assessment, intervention and treatment; and highlight how technology can help overcome barriers to effective management of drug use among young people. PMID- 22423471 TI - Which way for data exchanges? PMID- 22423472 TI - Scenes from the 'Lollapalooza of HIT'. PMID- 22423473 TI - EHR game changer goal: rural hospital connectivity. AB - This is the second in a series of profiles of recipients of HDM's EHR Game Changer Awards, created to honor individuals who have been true game changers in the design, advocacy, deployment and development of electronic health records technology. PMID- 22423474 TI - Shining a light on usability. Interview by Elizabeth Gardner. PMID- 22423475 TI - [Nurse's role in the processes of hospital humanization and procedural pain relief in children]. AB - In childhood, hospital admission is frequently seen as something unexplanable and close to a "punishment". Involving parents/caretakers in the process of care is critical for the child to cope with the distress arising from hospital contacts and medical procedures. However, some grey zone remains for common procedures as venipuncture in hospital and ambulatory settings. We have conducted a literature review, searching for articles focused on procedural distress reduction/control in children. Several studies show that communication play a critical role and that children as young as 5 are able to "read" the way nurses and doctors interact with them and their approach is very important in reducing procedural distress. However, children attitude toward communication of health information may not be so linear, because they tend to continuously shift from a position of "passive bystander" to a "active participant" one, and viceversa. Nurse's role is crucial for the reduction of procedural distress because of her/his frequent contact with the young patients, but often she/he does not have the skills to help children to cope with procedural distress. Several approaches to this issue are discussed. PMID- 22423476 TI - [Skin antisepsis in premature infants]. AB - In some premature newborns, 7 months old and with less than 1 kg of body wheight, total parenteral nutrition is used for weeks, so that good antiseptics can cooperate to the prevention of nosocomial infections, associating the best biocide effects to the best topical tolerability. Details are reported on the biocide cutaneous properties of some chloro-derivates, as sodium hypochlorite and NaDCC, of ethyl and propyl alcohols, of chlorhexidine, of iodophors and also of triclosan and octenidine (even if these latter biocids are not normally available in Italy as cutaneous antiseptics). PMID- 22423477 TI - Formula milk feeding does not increase the release of the inflammatory marker calprotectin, compared to human milk. AB - Calprotectin is a protein released into stools, used as a marker of inflammation in inflammatory bowel diseases. We tested the hypothesis that cow's milk protein in formula milk may increase the intestinal release of calprotectin, as a consequence of a subclinical inflammatory reaction. At 12 weeks of age, we measured fecal calprotectin by an immunoenzyme assay (Calprest, Eurospital, Trieste, Italy), in 38 exclusively breastfed and in 32 exclusively formula-fed infants. Fecal calprotectin levels were not different in the two groups (p = 0.09), although a trend to higher values in infants with colic, or with family history of allergies was noted. This suggest that, in general, formula milk does not promote activation of an intestinal inflammatory reaction, compared to human milk, although a subclinical activation of the inflammatory response in infants at risk for allergic diseases may be present. PMID- 22423478 TI - Anorectal malformations (ARM): quality of life assessed in the functional, urologic and neurologic short and long term follow-up. AB - Imperforate anus represents a wide spectrum of anorectal malformations associated with urologic, neurologic and orthopedic malformations. The outcome from the various corrective measures has improved due to new surgical techniques as well as to a better understanding of the pathology. Other factors which influence the overall outcome include the degree of patient acceptance, family support as well as the ability of the health care structure to support the patient's needs on a clinical, functional and psychologic level. AIM OF THE STUDY: Assess (with the new techniques available) the quality of life in the adult patient with ARM and compare it to that experienced by a younger patient; also we wish to determine the correlation between the observed abnormalities with the functional, neurologic and urologic outcome. MATERIALS & METHODS: Sixty-six patients were subjected to PSARP (36 M; 30 F). Six presented with cloaca and 60 with ARM (23 high and 37 low). All patients underwent the same workup to include L/S MRI diagnostics, evaluation for incontinence (urinary and bowel), a urology screening, and if required, a subsequent urodynamic study with rehabilitation and/or bowel management. All answered questionnaires (AIMAR: Italian parent's association of ARM) in order to assess their satisfaction with the current health condition, with the information received and with the treatment and follow-up sessions. The patients were classified into one of two groups. Group A, totaled 33 patients (4 cloacae) with an age range between 2 and 12 years who were operated after 1995. The second, group B, was made up of 33 patients who had been surgically treated before 1995 (age range 15-41 years), had followed the study protocol and had also a neuropsychiatry consult. RESULTS: Overall fecal continence was 69% and of this number 37% were clean without constipation. Twe2nty-one patients (32%) suffered from some form of constipation. Constipation was the most common functional disorder observed in patients who have undergone PSARP. The highest incidence of constipation was found in the ARM (low type), a favorable prognostic group with 43% constipation. Patient with "high" defects and a cloaca had a lower incidence of constipation (18%). Of the 59 patients evaluated, 85% were urinary continent and 15% were incontinent. All of the incontinent patients were in the unfavorable prognostic group of malformations. Urodynamic studies showed 7 neurogenic bladders (NB) and 2 patients with a neurovescical dysfunction (NVD). Of the 50 "dry" patients. 20 had voiding disturbances due to a voiding dysfunction, in the absence of neurologic abnormalities, and presented occasional daytime or nighttime wetting. There was no correlation between the level of the anatomic defect and the urodynamic patterns in the group. Abnormal MRI findings were observed in thirty out of fifty two patients evaluated. The MRI findings were classified as follows. Severe abnormalities: 7 patients (13%) presented with a combination of skeletal (sacral/lumbar) and spinal cord anomalies. Only spinal cord abnormalities: 12 patients (21%). Only skeletal abnormalities: 11 (19%) patients. Patients were divided into high, low and cloacal malformations. A high degree of statistical correlation was noted between the patients belonging to the cloacae and high defect groups and the abnormal MRI findings. No significant correlation was found between the low defect group and dysrafism, abnormal MRI results and the severity of the malformation. The incidence of Tethered Cord (TC) in our limited number of patients was limited in our study (9% in the high and 7% in the low defect group) when compared to the current literature. Furthermore there was no statistically conclusive evidence that TC by itself affects the urinary or fecal control in our patients. Our recommendation is nevertheless to obtain an MRI study in all patients with ARM. CONCLUSION: All patients 17 and older reported a "good quality of life". Four are married, two with children. Aclose working relationship with the medical personnel is not only necessary but is also well received by the family particularly when younger patients are involved. The adult patient easily adapts even when information is initially scarce. He quickly reaches autonomy with personalized solutions but prefers a longer follow-up time during which, specialized medical facilities will play an important role in the treatment of ARM. Our findings illustrate the importance of both global disease-specific functioning and perceived psychosocial competencies for enhancing the QL of these patients. PMID- 22423479 TI - [The use of ondansetron in acute gastroenteritis. Its impact in a pediatric emergency department]. AB - BACKGROUND: Ondansentron is in consideration in literature for its use in vomiting secondary to acute gastroenteritis in children. OBJECTIVE: To evaluate its usefulness in children with acute gastroenteritis referred to a paediatric emergency department. METHODS: A retrospective study considered 967 children treated with ondansetron (0,06 mg/kg IM) plus oral rehydration, with a control group of 286 children who received only oral rehydration. RESULTS: The time spent into the short-stay observation unit and the total emergency department stay were significantly reduced in children receiving ondansentron. No adverse reactions to the drug were recorded. PMID- 22423480 TI - [Hand management in recessive dystrophic bullous epydermolysis]. AB - PURPOSE: Recessive distrofic epidermolysis bullosa creates severe hand deformities with disabling functional limitations. Hand surgeon should perform surgery when deformity inibits function, in order to restore the pinch. MATERIALS AND METHOD: We present our experience on 44 patients and 58 operated hands, with the following schema: hand degloving, grafting of the first web and intraoperative dynamic splinting. RESULTS: In 30 patient with an 8 years follow up, 25 had had good or excellent results, and the 5 remaining shows early recurrence. CONCLUSION: Association of a correct surgical approach and adequate intra and post-operative rehabilitation improve hand function and a slow down inevitable recurrence. PMID- 22423481 TI - A rare case of neonatal sepsis/meningitis caused by Pasteurella multocida complicated with status epilepticus and focal cerebritis. AB - Pasteurella multocida is normally present in respiratory and digestive tract of many domestic and wild animals, but is a rare pathogen in neonatal infection. Here we describe for the first time a case of meningitis complicated by status epilepticus and right parietal lobe cerebritis. The patient showed a dramatic clinical onset characterized by septic appearance and prolonged seizures. Multidrug anticonvulsivant therapy was used to control the status epilepticus, but despite the aggressive treatment electrical crises were still evident 24 hours after the admission. Furthermore, a brain MRI, performed to investigate a persistent intermittent fever even if CSF became sterile, showed a focus cerebritis in the right parietal lobe, early stage of the cerebral abscess. Prolonged antibiotic therapy with steroids was requested to solve the cerebritis area. Interestingly, direct contact between the patient and domestic animals was denied by the family, but the father reported a contact with a rooster, killed and cooked few days before, suggesting, as previously described, that Pasteurella may also be transmitted through asymptomatic human carrier. The patient had a favourable outcome with no medium-term sequelae one month after discharge, but the severity of the clinical course and the unpredictable way of transmission highlight the importance of hygiene measures approaching infants. PMID- 22423482 TI - Protective effect of aqueous suspension of dried latex of Calotropis procera against oxidative stress and renal damage in diabetic rats. AB - Calotropis species have been used in the traditional medicinal system for the treatment of diseases of the liver and abdomen. In view of the antioxidant and anti-hyperglycemic properties of an aqueous suspension obtained from the dried latex of Calotropis procera, the present study was carried out to evaluate its efficacy in affording protection against alloxan induced changes in rat kidney. A single intraperitoneal injection of alloxan (150 mg/kg) in rats produced hyperglycemia within 3 days and altered kidney functions over a period of 90 days. Daily oral administration of the aqueous suspension (100 and 400 mg/kg) in diabetic rats produced anti-hyperglycemic effect that was comparable to that of glibenclamide (10 mg/kg). Unlike glibenclamide, the aqueous suspension did not increase the serum insulin levels in diabetic rats. However, it produced a marked reduction in the levels of urinary glucose and protein and normalized the renal tissue levels of thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH) in diabetic rats and the effect was comparable to that of glibenclamide. The protection afforded by the aqueous suspension was also evident from the histological analysis of the renal tissue. Our study shows that by exhibiting antioxidant and anti-hyperglycemic property the aqueous suspension of dried latex of C. procera affords protection against the complications associated with diabetes. PMID- 22423483 TI - Apigenin inhibits cell migration through MAPK pathways in human bladder smooth muscle cells. AB - Apigenin, a nonmutagenic flavonoid, has been shown to possess free radical scavenging activities, anticarcinogenic properties, antioxidant and anti inflammatory effects. Recently, apigenin was reported to cause gastric relaxation in murine. To assess possible effects of apigenin on migration of bladder smooth muscle (SM) cell, we isolated SM cells from peri-cancer tissue of human bladder and established a cell model that was capable to overexpress transiently MEKK1 (MEK kinase 1). Results showed that overexpression of active human MEKK1 by adenoviruses infection induced migration of human bladder smooth muscle (hBSM) cells and phosphorylation of MAPKs, ERK, JNK and p38, which are the downstream molecules of MEKK1. Then, hBSM cell overexpressing MEKK1 were exposed to apigenin (50 microM). Our data indicated that apigenin inhibited significantly activation/phosphorylation of MAPKs and migration of hBSM cells induced by MEKK1 overexpression. Besides, apigenin inhibited actin polymerization, which underlines muscle contraction and cell migration. The results suggest that apigenin inhibits activation of MAPKs and thereby the cell migration. The mechanism might be that apigenin blocks signal transmission from MEKK1 to MAPKs. PMID- 22423484 TI - The actin filament network associated to Sertoli cell ectoplasmic specializations. AB - Junctional devices in Sertoli cells conform the blood-testis barrier and play a key role in maturation and differentiation of germ cells. The spacial distribution of ectoplasmic specializations of Sertoli cells was studied by beta actin immunolabelling, using laser confocal and transmission electron microscopy. For confocal microscopy, beta-actin immunolabelling of ectoplasmic specializations was studied over the background of either prosaposin or glutaredoxin immunolabelling of the Sertoli cytoplasm. Labelling was found near the basal lamina, surrounding early spermatocytes (presumably in leptotene zygotene) or at one of two levels in the seminiferous epithelium: (1) around deep infoldings of the Sertoli cell cytoplasm, in tubular stages before spermiation, and (2) in the superficial part of the seminiferous epithelium, in tubular stages after or during spermiation. For transmission electron microscopy, beta-actin immunolabelling of ectoplasmic specializations was also used. Ectoplasmic specializations were found at two different levels of the seminiferous epithelium. We also used freeze fracture to analyze the characteristics of tubulo bulbar complexes, a known component of apical ectoplasmic specializations. Also, these different approaches allowed us to study the complex arrangement of the actin cytoskeleton of Sertoli cells branches, which surround germ cells in different stages of the spermatogenic cycle. Our results show a consistent labelling for beta-actin before, during and after the release of spermatozoa in the tubular lumen (spermiation) suggesting a significant role of the actin network in spermatic cell differentiation. In conclusion, significant interrelations among the beta-actin network, the junctional complexes of the blood-testis barrier and the ectoplasmic specializations were detected at different stages of the seminiferous cycle. PMID- 22423485 TI - [Experiment with 5-day dry immersion: objectives, content and structure of the investigations, methods]. AB - The article features the goals and objectives, and methods of an all-round experiment with 5-d dry immersion performed in 2010. PMID- 22423486 TI - [Visual-manual tracking during 5-day dry immersion]. AB - Level dry immersion (DI), a model of the physiological effects of microgravity, support deprivation, minimization of muscle activity and proprioceptive afferentation specifically, was used to determine the effects of low proprioceptive, tactile and support afferentation on visual-manual tracking. Hand eye motor coordination was tested in 13 subjects in 5-d DI who tracked jerky and smooth (linear and pendulum-like horizontal and vertical, circular clockwise and counterclockwise) motions of point visual stimulus. Binocular electrooculography was used to register ocular movements and a joystick with a biological visual feedback to register manual motor acts (1 of 2 stimuli on the screen showed the actual joystick inclination). Computerized stimulation was provided with the help of virtual goggles. Evaluated parameters were latent and total reaction time, amplitude and velocity of eye and hand movements, coefficients of effectiveness (amplitudes ratio) and gain (velocity ratio). Testing was performed before DI, after 3 hours in DI, on DI days 3 and 5, during the first hours and in 3 days after DI (all subjects) and on post-DI days 5-7 (4 subjects). It was demonstrated that support deprivation and minimization of proprioceptive afferentation affect ocular tracking to a larger degree than accuracy of the manual motor act of following the visual stimulus. Manual tracking by all subjects was found more accurate than visual and did not alter significantly during tests sessions; on the contrary, visual tracking accuracy altered noticeably as in the course, so after DI. PMID- 22423487 TI - [Direct proteome profiling of human blood serum in the experiment with 5-day dry immersion]. AB - Purpose of the investigation was to determine changes in blood plasma proteome in healthy human subjects (n = 14, 19 to 26 y.o.) in an experiment with dry immersion (DI). Plasma samples were drawn 7 and 2 days before the exposure, on DI days 2, 3 and 5, and on days 1, 3, 7 and 15 after the experiment. Previous to direct MALDI-TOF mass-spectrometric profiling, serum samples were pre fractionated and enriched with magnetic particles MB WCX (WCX--a weak cation exchanger) on ClinProt (Bruker Daltonics). In each spectrum, 175 MS-peaks were detected on average within the mass range from 1000 to 17,000 Da with the signal/noise ratio = 5. Student's criterion (p < 0.05) was used to define reliable differences between DI and baseline samples from 48 peaks (27.4 % of all the proteome profile peaks). On DI days 2 and 3, growth of peak areas was observed in fragments of complement system proteins C3 and C4, high-molecular kininogen and fibrinogen that can be attributed to organism adaptation to conditions of the experiment. Significant increases of the peak area of apolipoprotein CI (reduced form with segregated threonine and proline) and C4 enzymes of the complement system, and fibrinogen on the first day after the experiment can be related to changes in motor activities of the subjects. PMID- 22423488 TI - [Dynamics of the protein content of human urine during 5-day immersion]. AB - Variations in the protein spectrum (12 groups) of native daily urine were studied during 5-day dry immersion (DI) of 14 subjects at the age of 19 to 26 years using gradient electrophoresis in polyacrylamide gel. Protein excretion with urine did not alter in the course of the experiment. However, the urine proteins spectrum trended to some shifts. Excretion of low-molecular proteins decreased and of albumin increased pointing to remodulation of tubular reabsorption initiated by the experimental conditions. Steady growth of the Tamm-Horsfall protein concentration seems to be a defense reaction. There was an incremental decrease in immunoglobulins that could be associated with a reduction of glomerular filter permeability for high-molecular proteins. PMID- 22423489 TI - [Renal functioning and human body liquids during 5-day dry immersion]. AB - Renal function and body composition, including liquids, were investigated in 14 essentially healthy male subjects during simulation of some spaceflight effects by 5-d dry immersion (DI). Noninvasive measurement of water spaces of organism was performed with the methods of bio-impedance analysis (BIA). Increase of renal excretion of liquids and appearance of negative water balance were observed. BIA revealed reductions of total body and extracellular liquids and a decrease of circulating plasma volume. This means, that DI induced hypohydration of organism. In the post-DI period, the hydration status regained its baseline level fairly soon. Lean body mass slightly decreased; adipose mass, on the contrary, exceeded baseline values. Moreover, the experiment evidenced technical impossibility to obtain valid impedansimetry data in DI. PMID- 22423490 TI - [Biomechanics and regulation of the external respiration in the conditions of 5 day dry immersion]. AB - The work was concerned with evaluation of the external respiration function and regulation in healthy human subjects participating in simulation of the microgravity effects by dry immersion (DI). In the baseline data collection period, in DI (days 2 and 4) and after DI completion pulmonary volumes were registered, the ratio of thoracic and abdominal components of quiet breathing and respiratory maneuvers calculated, and parameters of respiration regulation, i.e. length of breath-holding and ability to voluntary control breathing motions, were determined. It was shown that breathing pattern did not undergo gross changes in immersion as compared with pre-DI test data; however, inspiratory reserve volume grew (p < 0.05) and expiratory RV reduced (p < 0.01). DI did not alter the ventilation function of lungs; yet, most of the subjects trended to increase the abdominal component of quiet breathing and displayed a statistically significant increase of the parameter during the maneuver made to determine the vital capacity of lungs. Maximum breath-holding, equally in the course of inspiration and expiration in DI, did not differ from baseline values. Accuracy of voluntary breathing control was better in immersion. We believe that similar to microgravity, exposure in DI produces regular alterations of pulmonary RV (partly because of changed body position), thoracic-abdominal ratio in breathing motions, and shifts in voluntary respiration regulation. PMID- 22423491 TI - [Acoustic and spirometric indices of forced expiration noise in the conditions of 5-day dry immersion]. AB - Dynamic studies of forced expiration (FE) indices involved 7 normal males aged 21 to 25 participating in a 5-d experiment with dry immersion (DI). FE spirometry was conducted simultaneously with registration of tracheal noise with the help of a microphone. Indices included acoustic duration of tracheal noise (Ta), forced lung capacity (FLC), FE volume per a second (FEV1), peak expiratory rate (PER) and time to reach (T(PER)) before DI, on DI days 1 and 4, and next day after completion. PER showed a significant decrease by 8.4% on DI day-1 and rose by 8.9% on DI day-4, though remaining below pre-DI values. Throughout the experiment, FLC and FEV1 did not change on the average. There was a noticeable increase of Ta by 17 % after DI which may suggest strengthening of respiratory resistance and invites further investigation. A moderate negative correlation was stated between TA and the Gensler index (r = -0.63), whereas correlation with the other spirometric indices was weak or absent. PMID- 22423492 TI - [Characteristics of negative pressure inspiration effect on the cardiorespiratory system of humans in the conditions of 5-day dry immersion]. AB - Changes in external respiration and central hemodynamics induced by negative (relative to atmospheric) inspiration pressure were studied in supine subjects before and on day-4 of a dry immersion (DI) experiment. Changes in the cardiorespiratory system as a result of negative inspiration pressure included rise of the amplitude of breathing motions and reduction of their frequency, and distinct breathing-related HR fluctuations. Combination of immersion and altered pressure in the mask caused breathing-related variations of systolic pressure and plethysmogram signal, and improved arterial blood oxygenation. These results can be useful for developing pressure-gradient methods of counteracting the adverse effects of blood redistribution toward the cranial-end. PMID- 22423493 TI - [Volatile metabolites in expired air of humans during 5-day dry immersion]. AB - Both gas chromatography and mass-spectrometry were used to analyze make-up of air expired by 7 human subjects in a dry immersion (DI) experiment simulating some of the effects of microgravity. It was found that 5-d DI produces significant increases in expired amines, chiefly butylamine, 2-cyanacetimide, some aldehydes (isobutyl aldehyde, benzaldehyde), polyols (ethylene glycol, butyldiol), phenol, phenyl acetylene, ketones (methyl-ethyl-ketone), butylacetate and a significant decrease in fatty acids. PMID- 22423494 TI - [Indices of electrocardiogram dispersion mapping during 5-day exposure in dry immersion]. AB - The article presents the results of ECG dispersion mapping in the investigation of 13 young healthy people during 5-d dry immersion (DI). This was the first study of 24-hour variations in dispersion of ECG microoscillations. For this purpose, 20-30 min fragments were "cut out" of every hour of Holter monitoring records to analyze their means after averaging over every 4 hours. Heart rate (HR) and QRS-amplitude were analyzed simultaneously. Index of metabolic adaptation (HR(max/MiO(max)) was calculated. Based on the results, alterations in ECG signal became distinct on DI day-3. They started with a considerable rise of the main ECG amplitudes, especially at night (10.00 p.m. to 6.00 a.m.). The myocardium index makes a significant rise in the period from 10.00 p.m. till 2.00 a.m. However, this index reached its maximum values on DI day-5 in the time intervals from 3.00 till 6.00 p.m. and from 10 p.m. till 10.00 a.m. On DI day-5, of particular interest was a marked HR growth from 10.00 p.m. till 02.00 a.m., and in the post-sleep hours (07.00-10.00 a.m.). Consequently, all this looks like a series engagement of first electrical and then energy metabolism processes in the myocardium reaction to DI. Finally, the increased pulse rate suggests an integral nature of the cardiovascular reaction. This picture of alterations provides grounds for hypothesizing energy metabolism genesis of these reactions. PMID- 22423495 TI - [Examination of the morphofunctional properties of red blood cells of humans in 5 day dry immersioin]. AB - Blood of six normal male volunteers sampled before, immediately after and in 7 days since 5-d dry immersion was analyzed for morphological parameters, erythrocyte metabolism, lipids and phospholipids levels. The experimental exposure was shown to increase the erythrocyte count. Also, upward trends were displayed by hemoglobin and PCV on the first day after the experiment; a significant decrease in adenosine triphosphate and low level of reduced glutathione could be an outcome of enhanced oxidation in cell due to, maybe, LPO activation. There was a downward trend in the phospholipids fraction of erythrocyte membrane against steady levels of cholesterol and its ethers which might be linked with the reliable growth of the fraction of nonesterified fatty acids on day 1 and triglycerides on days 1 and 7 post the experiment. PMID- 22423496 TI - [Investigation of the evacuatory function of the gastrointestinal tract in 5-day dry immersion]. AB - Six male volunteers for dry immersion (DI) modeling the microgravity effects on human organism were subjects in the GI evacuatory function investigation. The investigation was aimed to evaluate liquid food evacuation from the stomach (13C acetate test) and time of chymus orocecal transit (H2-inulin test). The 13C acetate test did not reveal changes in stomach evacuatory activity after 4 days in DI. The H2-inulin test demonstrated shortening of chymus transit along the small intestine and extension of chymus passage from the ileum to cecum. Subsequent reduction of inulin metabolism in the large intestine suggested inhibited passage of these GI segments. The results showed that stability of liquid evacuation from the stomach and acceleration of chymus transit along the small intestine hinder evacuation of the large intestine content which is the primary cause for inhibition of GI evacuatory activity in DI. PMID- 22423497 TI - [Analysis of the relationships between the psychophysiological status and system of adaptive immunity in the conditions of 5-day dry immersion]. AB - Relationships of the T- and B-components of adaptive immunity and the psychophysiological status were studied in 14 volunteers for the experiment with 5-d dry immersion (DI) w/o countermeasures. Comparison of frequency of deviations in immunity parameters of psychologically different subjects demonstrated the highest frequency in non-anxious and extravert individuals on day-5 in DI. These differences in immune reactions as a function of psychological type and temperament point to existence of a neuroimmune typology and, therefore, the necessity of concurrent immunologic and psychological investigations in order to develop separate measures of rehabilitation from and prevention of stress in people with polar psychological status. PMID- 22423498 TI - [Health consequences of snoring and obstructive sleep apnea]. PMID- 22423499 TI - [Analysis of parent-child sleeping and living habits related to later bedtimes in children]. AB - PURPOSE: To find the relationship between parents' sleeping and living behaviors and their children's sleeping habits, and to investigate factors specifically related to children staying up late in recent Japan. METHODS: During regular health check-ups of children at three local health centers in the city A, we recruited the parents of one-and-half-year-old and three-year-old children to participate in the Child Sleep Cohort Project (ChiSCoP). Parents of 184 children who consented to participation were mailed three questionnaires by placement method. These are "sleeping diary for 10 days," "sleeping and lifetime rhythm survey," and "emotional behavior assessment scale (CBCL : Child Behavior Checklist 2rd/3rd edition)," of which valid data on 178 children were collected over two years and analyzed. ANALYSIS: Participants' demographic data, perceived and actual sleeping and living habits, and bedtime patterns were compared among the groups classified by bedtime of children. Bedtimes were classified as early (before 21 : 00), normal (21 : 00 to 21 : 59), and late (after 22 : 00). Using one-way analysis of variance with two (early vs. late) and three bedtime categories, significant differences were found among the three bedtime categories about childcare environmental factors (meal, daytime activity, TV, nap, and bath). So we performed logistic regression analysis with "late bedtime" as the dependent variable and scores of environmental factors (upper or lower than median values) as independent variables in a stepwise manner to eliminate collinear variables and to obtain adjusted odds ratios. RESULTS: 1) Among the 178 children, 96 and 82 were recruited during the physical check-up for one-and-half year-old and three-years-old, respectively. There were 49, 72, and 57 children in the early, normal, and late bedtime groups, respectively, and no significant difference in attribute factors was found. 2) In children of the early bedtime group, proportions of those with "efforts to establish good life rhythm" (P < 0.0001), "efforts to cultivate sleeping habits" (P < 0.0001), and "keeping a regular bedtime" (P < 0.05) were significantly higher, as well as for children who had more than 105 minutes of "daytime nap" compared to children who had less (P < 0.05). 3) Children's bedtimes were significantly correlated with "mother's wake-up time on weekdays" (r = 0.33) and "mother's bedtime on weekdays" (r = 0.33). Children's wake-up times were also correlated with "mother's wake-up time on weekdays and weekends" (r = 0.49) and "mother's bedtime on weekdays" (r = 0.34), which indicates that children's wake-up times had relationship with mother's sleeping and life habits. 4) Later "wake-up time on weekends" (odds ratio = 4.9) and "regular bedtime hour" (odds ratio = 3.53) were found to be the determinant of late bedtimes of children. CONCLUSIONS: To encourage earlier bedtimes in children, it is important to take he mother's sleeping and living habits into account and to maintain a regular wake-up and bedtime schedule across weekdays and weekends. PMID- 22423500 TI - A case of refractory adult-onset Still's disease with high serum interleukin-18 levels treated with monitoring of serum levels of cyclosporine. AB - We report the case of a 31-year-old woman who developed adult-onset Still's disease (AOSD) with a high level of serum interleukin (IL)-18. Although treated with high dose steroids, she suffered repeated remissions and her condition deteriorated. After we administered oral cyclosporine A (CsA), 200 mg/d, monitoring C2 and trough levels, her symptoms improved significantly. We decreased the dose of methylprednisolone slowly without noting a relapse. The use of CsA accompanied by C2 and trough level monitoring should be considered for refractory AOSD patients with high levels of serum IL-18. PMID- 22423501 TI - Will the real nurse leader please stand up? PMID- 22423502 TI - Blood pressure measurement: a commonly delegated task that requires quality attention. PMID- 22423503 TI - Who will take care of mother? PMID- 22423504 TI - The parish or faith community nurse. PMID- 22423505 TI - A 75-year history of nursing education in North Dakota 1903-1978. 1979. PMID- 22423506 TI - How epigenomics brings phenotype into being. AB - After sequencing the human genome, it has become clear that genetic information alone is not sufficient to understand phenotypic manifestations. The way the DNA code is translated into function depends not only on its sequence but also on the interaction with environmental factors. It is in this intersection where the science of epigenetics plays a crucial role. Epigenetic mechanisms like DNA methylation and histone modifications are essential for multiple physiological processes like development, establishment of tissue identity, imprinting, X chromosome inactivation, chromosomal stability and gene transcription regulation. Additionally, environmental factors like nutrition or maternal behavior in early childhood are able to induce epigenetic changes. This short review aims at summarizing the role of epigenetics in multiple aspects of biology and medicine, including development, cancer, non-tumoral diseases, environmentally induced phenotypic changes, and also in inheritance and evolution. PMID- 22423507 TI - How to analyse epigenetic marks? AB - By adding adaptable information about the activity of genes, epigenetics enables the activation of specific genes depending on the prevalent environmental conditions and individual requirements of a cell. Although epigenetic information is heritable, it is not stored in the sequence of the DNA but mainly in the modification pattern of the chromatin, i.e., the methylation of cytosine residues in the DNA or covalent modifications of the histones. By controlling gene activity and therefore the availability of the final gene product in the cell, epigenetic alterations can have similar effects as classical genetic mutations. Indeed, the recent past epigenetic modifications have become a focus for the clinic for diagnostics, prognostics, as well as therapeutic purposes. This review briefly summarizes the major aspects of epigenetics and presents a comprehensive overview about the fundamental principles of DNA methylation analysis. PMID- 22423508 TI - Molecular androgen memory in sex development. AB - Sex specific development in the human comprises irreversible sexual differentiation of the external genitalia during embryogenesis, sexual maturation of secondary sex characteristics during puberty (e.g., sex specific body proportions, pubertal voice change) and eventually sex specific development of extragenital tissues and organs, including the brain. The presence or absence of androgens acting via the androgen receptor plays a key role therein. At the single cell level, androgens cause reversible short term changes of gene transcription by activating the androgen receptor. From a developmental perspective, this often leads to irreversible long-term changes of anatomy (e.g., sex-specific differentiation of the external genitalia) and function (e.g., sex specific play behavior in children). These observations are discussed in the context of recent genome-wide gene expression studies and first published experimental data at the epigenome level. In essence, there is evidence for a molecular androgen memory at both the transcriptome and the epigenome level. PMID- 22423509 TI - Tumor risk and clinical follow-up in patients with disorders of sex development. AB - A subset of patients with disorders of sex development (DSD) is at risk for malignant germ cell tumors (GCTs). The degree of gonadal differentiation (or "testicularization" in the presence of a specific part of the Y chromosome), in combination with expression of embryonic germ cell markers, and (a) Y specific gene(s) related to cell-cycle control and proliferation, determines this risk. Incompletely matured Sertoli/granulosa cells are insufficiently capable of directing the normal mitotic block/meiotic induction germ cell program, and as a result, embryonic germ cells are delayed or blocked in their normal maturation process. Thereby, they remain pluripotent and gain increased mitotic and survival characteristics, being the first step in the pathogenesis of GCTs. The patient's underlying genetic defect and phenotype might be informative in assessing the degree of gonadal "testicularization" on a clinical basis. Current knowledge allows development of an informative cancer risk assessment of DSD patients. PMID- 22423510 TI - Clinical use of anti-Mullerian hormone (AMH) determinations in patients with disorders of sex development: importance of sex- and age-specific reference ranges. AB - Determination of postnatal AMH levels in circulation has been used for decades when evaluating a child with ambiguous genitalia. We describe the age- and gender specific changes of postnatal AMH serum levels to enable an appropriate clinical use of AMH assessment in pediatric endocrinology. In males, cord blood AMH is measurable at high levels (mean 148 (53-340) pmol/L), whereas AMH is undetectable (54%) or very low (95% CI: < 2-16 pmol/L) in female infants. AMH is constant through childhood in both sexes, boys having approximately 35 times higher levels than girls with no overlapping between the sexes until puberty. Ambiguous genitalia due to impaired androgen secretion or action may be a result of various conditions with low, normal or high AMH. Furthermore, low AMH is a marker of premature ovarian failure in Turner Syndrome girls. Measurement of AMH is an important tool in assessing gonadal function in children. In this context, detailed normative data are essential. PMID- 22423511 TI - From GHRH to IGF-1 and downstream: clinical phenotypes and biological mechanisms. AB - Genetic defects have been observed at almost all levels of the GHRH-IGF-1 axis. The first observations of GH-1 gene deletions date some 30 years ago. Whereas mutations in the GH-1 and GHRHR genes account for the majority of mutations detectable in patients with Isolated Growth Hormone Deficiency (IGHD) resulting in postnatal growth failure, the overall detection of genetic defects in these patients remains low with app. 10-15%. Similarly, at the lower end of the GHRH IGF-1 axis the frequency of defects within the IGF-1 and IGF-1 receptor (IGF1R) genes might hardly approach 10% of all cases with intrauterine and postnatal growth retardation. In this article we examine the pathomechanisms involved in the genetic defects at both ends of the GHRH-IGF-1 axis and describe the clinical and biochemical phenotypes involved. Although it seems tempting to increase the detection rate by limiting genetic investigations to patients with phenotypic characteristics described, at present it seems more appropriate to follow a permissive approach for such investigations as we are probably have not envisioned the full spectrum of phenotypic variability. PMID- 22423512 TI - Growth hormone deficiency: new approaches to the diagnosis. AB - International consensus statements based on expert experience recommended guide lines how to diagnose GHD. Most recommendations reached only a low level of evidence. Cut-offs for GH were central part of these recommendations, their definition however was arbitrary. Evidence based cut-offs are needed. Using newborn screening cards from healthy and affected newborns, the GH cut-off to detect severe congenital GHD was reassessed and redefined. A GH cut-off level of 7 microg/L confirmed the diagnosis of severe GHD with 100% sensitivity and 98% specificity on the basis of our assay method, if clinical evidence was present. The previous cut-off of 20 microg/L cited in the international consensus statements was based on old GH assays methods not used anymore. For the calculation of an non-arbitrary GH cut-off for biochemical testing in children, we defined an auxological gold standard for GH deficiency: non-familial short stature due to catch-down growth during the childhood phase of growth in combination with an effective catch-up growth in response to low-dose GH therapy, after exclusion of alternative growth disorders and other potential confounders of growth velocity (true positives). Reference cohorts were normally growing children with Turner syndrome or SGA short stature having the same age (true negatives). Using our in-house GH RIA, highest diagnostic accuracy was provided at a peak GH cutoff during spontaneous secretion at night of 7.3 microg/L (sensitivity, 96.8%; specificity, 82.4%; AUC = 0.93). For arginine, cut-off with the highest number of true test results was 6.6 microg/L (sensitivity, 84.3%; specificity, 75.5%; AUC = 0.83). Importantly, children diagnosed GHD in the past with GH test values above the new cut-offs showed a lower response to GH. In conclusion, by use of retrospective and prospective cohort studies evidence-based cut-offs for GH levels measured in newborns and children can be calculated. By use of these cut-offs, tests can be improved. Because of the well known intrinsic diagnostic inaccuracy of any GH test, the correct selection of the child to be tested remains of utmost importance. The diagnosis of growth hormone deficiency (GHD) in childhood is guided by recommendations of national and international consensus statements which are based on the experience of experts. Most of these recommendations reach only a low level of evidence. Research on two central topics of these guidelines has recently been published by us and will be reviewed here. PMID- 22423513 TI - Diagnosis and management of disorders of IGF-I synthesis and action. AB - After a proper medical history, growth analysis and physical examination of a short child, followed by radiological and laboratory screening, the clinician may decide to perform genetic testing. We recently proposed several clinical algorithms that can be used to establish the diagnosis. GH insensitivity (primary IGF-I deficiency) can be caused by genetic defects in GHR, STAT5B, IGF1, IGFALS, which all have their specific clinical and biochemical characteristics. IGF-I resistance is seen in heterozygous defects of IGF1R. If besides short stature additional abnormalities are present, these should be matched with known dysmorphic syndromes. If no obvious candidate gene can be determined, a whole genome approach can be taken to check for deletions, duplications and/or uniparental disomies (SNP-array) or whole exome sequencing. Children with GHR defects, and presumably STAT5B and homozygous IGF1 defects, can be treated with rhlGF-I. Children with IGF1R defects and mild or heterozygous IGF1 defects respond to GH treatment. PMID- 22423514 TI - Summary of the workshop "Management of CAH: the relevance of steroids in plasma, saliva and urine". PMID- 22423515 TI - Watching the behavioral patient--a patient centered team approach. AB - The continued increase in the number of behavioral patients in EDs, combined with reductions in staffing, are challenging the resources of hospital security departments. In this article, the author describes a team approach, involving public safety officers, RNs, and physicians, that has drastically reduced time spent by officers in the ED and increased their availability throughout the facility. PMID- 22423516 TI - Hospital security and patient elopement: protecting patients and your healthcare facility. AB - Regulatory and financial consequences of adverse events associated with patient elopements are bringing new challenges to healthcare security to develop policies and procedures to prevent and respond to such incidents. This article provides an overview of the problem of elopement in healthcare and what it means to the security function; gives a working knowledge of healthcare related standards and guidelines aimed at reducing patient elopement; and reviews the elements of an elopement prevention and response plan for your organization. PMID- 22423517 TI - Aspects of controlling fraud in healthcare facilities: taking the threat seriously. AB - Healthcare fraud siphons off an estimated $70 to $230 billion a year from the amount spent healthcare, according to the authors, who spell out the extent of the fraud and present the specifics of fraud reduction strategies involving in house security working in concert with auditors. PMID- 22423518 TI - Drugs, drugs--who has the drugs? AB - Drug diversion, although on the increase, is not the only problem involving drugs that hospital security officials should be concerned with. Growing drug shortages, offshore production, counterfeiting, and weaknesses in the drug supply chain in case of a world-wide pandemic, are even greater causes for concern, the author claims. PMID- 22423519 TI - An approach to security risk assessment. AB - Use of a brief survey instrument described in this article can be a useful means of obtaining actionable information in regards to risk assessment and crime prevention, the author points out. The survey yields data that assists in the prioritization of effort that can enhance the impact of a limited pool of qualified specialists. PMID- 22423520 TI - Active life threatening violence--are you prepared? AB - The need to develop and exercise a viable plan to cope with a critical incident has become mandatory, according to the author, who in this article presents a prescription for such a plan that includes beginning with a policy, preparing by training, exercising your plan to discover strengths and weaknesses, and then applying the lessons learned to improve and establish a strategy for recovery. PMID- 22423521 TI - Four hospitals in the path of killer tornadoes--what happened before ... during ... after. AB - In mid-and late-April, late May, and early June of 2011, tornadoes swept across states in the Midwest, South, Southeast, and even New England, killing hundreds, injuring thousands, destroying property in the billions in both rural and urban areas. Some hospitals in areas where the tornadoes struck did not escape damage and one was destroyed. This article describes what happened at four hospitals in cities hardest hit by the storms and the many roles played by security officers. PMID- 22423522 TI - Recruiting and selection of healthcare public safety officers. AB - The recruiting and selection of professional public safety officers is the first step in developing and maintaining a world class public safety service. Working closely with the human resources department, and utilizing techniques developed by the law enforcement community, the public safety director can build a strong foundation for future growth. This is the first of a series of articles on all aspects of public safety personnel administration. PMID- 22423523 TI - Women in healthcare security: overcoming the pitfalls to success. AB - This article, based on the author's personal experience as a security officer/supervisor in the healthcare industry for the past ten years, frankly describes the pitfalls facing a female security officer in a male-dominated profession and how they can be overcome. PMID- 22423524 TI - Rape aggression defense and workplace violence prevention. AB - An R.A.D. Basic Physical Defense program for women employees, launched by a health system's corporate security department, has proven to be a popular low cost method of workplace violence prevention, according to the author, one of the program's instructors. The initial investment in equipment and certification is negligible compared to the benefits and potential benefits it brings, she reports. PMID- 22423525 TI - Managing officer morale in 2012. AB - The stresses inherent in a hospital environment which impact on security may result in officers who do not see or feel positive results from the hard work they provide and, in experiencing low morale, can affect the performance of their peers, according to the author. In this article he describes what the healthcare security director can do to maintain high morale and, in doing so, retain the key members of his or her team. PMID- 22423526 TI - "Tag you're it!"--providing flawless customer service in the healthcare security environment. AB - An adaptation of a childhood game as a means of providing flawless service to customers will allow security departments to increase their scope and quality of service, the author points out. Teaching our officers the concept of playing "tag, " embracing being "it" and finishing the game will provide a significant return on investment by expanding the value of our departments, he says. PMID- 22423527 TI - The Joint Commission: an update on the environment of care and life safety challenges for 2011. AB - In this article, the author, one of country's leading healthcare regulatory compliance services executives, describes the powers to withdraw Medicare reimbursement given to The Joint Commission and how they are exercised, especially in the areas of Environment of Care and Life Safety. PMID- 22423528 TI - OSHA in healthcare--out of sight, out of mind? AB - Millions of employees across thousands of sites. The highest illness and injury rates in the nation. Millions of nosocomial infections and fatalities each year. Few OSHA inspections. Healthcare might feel exempt, but, according to the author, "it looks like we finally got their attention". PMID- 22423529 TI - The efficacy of best practices in recovery from cyberattacks. AB - Most healthcare facilities have comprehensive disaster plans, the author says, but he questions whether a cyberattack plan is included. In this article, he outlines the basics of such a plan. PMID- 22423530 TI - The electronic security partnership of safety/security and information systems departments. AB - The ever-changing world of security electronics is reviewed in this article. The author focuses on its usage in a hospital setting and the need for safety/security and information systems departments to work together to protect and get full value from IP systems. PMID- 22423531 TI - Security's role in morgue operations: needed--a foolproof plan. AB - If handling the remains of dead patients is a responsibility of your security department, or you are being pressured to take on the role because of budget cuts, the need to anticipate and plan for complications which may arise is critical, the author points out. PMID- 22423532 TI - Baby, it's cold outside.... AB - For officers and other employees stationed outdoors in parking areas or on perimeter patrol during cold weather the risks of hypothermia and frostbite may be very real. In this article, the author explains how these two serious medical conditions can be prevented and treated. PMID- 22423533 TI - Enforcing the new 'total' hospital smoking bans. AB - No more smoking shacks. No more designated smoking areas. No more smoking in automobiles. No more smokeless tobacco. No tobacco, period, anywhere on hospital property. That is the trend, nationwide, spurred by new Surgeon General warnings and mandated by local ordnances. This article describes the problems faced by some security managers called on to enforce the new "no alternative" smoking bans and how they are solving them. PMID- 22423534 TI - Simplification at last? AB - The HIPAA transaction standards-meant to streamline financial and administrative transactions--have instead devolved into a kind of free-for-all. Now the first operating rules are in hand to standardize use of the standards and gain the efficiencies originally intended. PMID- 22423535 TI - Metadata and meaningful use. AB - The healthcare industry will find out soon if ONC intends to include metadata requirements in stage 2 of the meaningful use program. Many feel it is too soon. But given metadata's potential to support health information exchange, the expanded and standardized use of metadata tagging in healthcare is ultimately a matter of when, not if. PMID- 22423536 TI - Ethics Update. Revisions strengthen AHIMA's code of ethics. AB - A new update to AHIMA's Code of Ethics addresses recent changes in technology, healthcare, and association management-and the accompanying complexity of competing interests and obligations they can bring. PMID- 22423537 TI - The 63rd REC. PMID- 22423538 TI - Communicating through the EHR. PMID- 22423539 TI - Seeing the big picture. Site provides access to healthcare data collected by the federal government. PMID- 22423540 TI - Calling HIM quality experts. PMID- 22423541 TI - Identifying issues in facility and provider mergers and acquisitions. PMID- 22423542 TI - CY 2012 OPPS update. PMID- 22423544 TI - Steady growth. PMID- 22423543 TI - CPT code updates for 2012. PMID- 22423545 TI - Graph theoretical analysis of organization of functional brain networks in ADHD. AB - This article presents a new methodology for investigation of the organization of the overall and hemispheric brain network of patients with attention-deficit hyperactivity disorder (ADHD) using theoretical analysis of a weighted graph with the goal of discovering how the brain topology is affected in such patients. The synchronization measure used is the nonlinear fuzzy synchronization likelihood (FSL) developed by the authors recently. Recent evidence indicates a normal neocortex has a small-world (SW) network with a balance between local structure and global structure characteristics. Such a network results in optimal balance between segregation and integration which is essential for high synchronizabilty and fast information transmission in a complex network. The SW network is characterized by the coexistence of dense clustering of connections (C) and short path lengths (L) among the network units. The results of investigation of C show the local structure of functional left-hemisphere brain networks of ADHD diverges from that of non-ADHD which is recognizable in the delta electroencephalograph (EEG) sub-band. Also, the results of investigation for L show the global structure of functional left-hemisphere brain networks of ADHD diverges from that of non-ADHD which is observable in the delta EEG sub-band. It is concluded that the changes in left-hemisphere brain's structure of ADHD from that of the non ADHD are so much that L and C can distinguish the ADHD brain from the non-ADHD brain in the delta EEG sub-band. PMID- 22423546 TI - Somatosensory-evoked spikes on electroencephalography (EEG): longitudinal clinical and EEG aspects in 313 children. AB - Somatosensory-evoked spikes (ESp) are high-voltage potentials registered on the EEG, which accompany each of the percussions on the feet or hands. The objective of this research was to study the longitudinal clinical and EEG aspects of children with ESp. A total of 313 children, 53.7% male, showing ESp on the EEG and with an average initial age of 6.82 (range from 2 to 14 years) were followed for a mean period of 35.7 months. In the initial evaluation, 118 (37.7%) had a history of nonfebrile epileptic seizures (ES). Epileptiform activity (EA) was observed on the EEG in 61% and showed a significantly greater occurrence in children with ES than in those without (P = .000). Of the 118 showing seizures from the start, 53 (44.9%) continued to have seizures; of the 195 without seizures at the start, only 13 (6.67%) developed them. Thus, only 66 (21.1%) children showed ES during the follow-up. ESp disappeared in 237 (75.7%) cases and EA in 221 (70.6%). In the children with ES, it was found that the presence of EA on the first EEG did not indicate continuation of the ES throughout the remaining period, while the 13 children who presented their first ES in a later period showed a greater occurrence of EA on the initial EEG than those who did not develop ES (P = .001). Evidence of brain injury was observed in 43 (13.7%) children and was associated with a greater continuity of the ES during the study (P = .018). ESp, EA, and ES tend to disappear, suggesting an age-dependent phenomenon. The finding of ESp, particularly in the absence of any evidence of brain injury, indicates a low association with ES and benign outcome. PMID- 22423547 TI - Evaluation of maturation and function of visual pathways in neonates: role of flash visual-evoked potentials revisited. AB - The purpose of our study was to establish the guidelines for interpreting neonatal flash visual-evoked potentials (FVEPs) by examining the correlation between maturation of the waveforms and conceptual age (CA). We retrospectively analyzed 220 consecutive neonatal FVEPs performed on premature and full-term infants. The CA of the participants ranged from 28 to 52 weeks. The FVEPs were categorized into 6 groups according to CA: 28 to 31+ weeks, 32 to 35+ weeks, 36 to 39+ weeks, 40 to 43+ weeks, 44 to 47+ weeks, and 48 to 52 weeks. The data were analyzed in each group and compared among these 6 groups. The waveforms changed from 28 weeks to 52 weeks of CA. In the CA age range 28 to 31+ weeks N3 was well visualized, followed by P3. The morphology of P2 including both latency and amplitude became prominent starting from CA age range 32 to 35+ weeks. The triphasic waveform with clear negative-positive-negative components (N2-P2-N3) presented after 32 weeks. Mean P2 latencies decreased steadily with increasing age. Mean amplitudes of all waveforms (P2-N3 and N3-P3) varied except that of N2 P2 which increased steadily with CA. We conclude that FVEPs can be useful in the evaluation of maturation and function of the visual pathway in neonates. The FVEP is abnormal when the waveforms N3 and P3 are nondetectable in neonates at 28 weeks of CA or older; and when the waveform P2 is non-detectable, or has low amplitude or prolonged latency, in neonates at 36 weeks of CA or older. PMID- 22423548 TI - Sensory gating-out and gating-in in normal and schizophrenic participants. AB - In contrast to sensory gating, the brain's ability to re-respond to relevant stimuli and the potential differences between healthy and schizophrenic participants have not been studied in great detail. Here, we explore what auditory paradigms are useful to measure this re-responding ability. Evoked potentials (EPs) were obtained from the Cz channel using 3 paired stimulus paradigms (pairs with equal stimuli {PE}, the second stimulus being lower {PL} or higher {PH} in frequency) and 2 short-train paradigms in which 5 identical stimuli were followed by a lower frequency stimulus (train lower {TL}) or higher frequency stimulus (train higher {TH}). Data were collected from 17 healthy control participants (NC) and 17 age and gender-matched patients with schizophrenia (SZ). Up to 4 data sets obtained on 4 different days were available for each participant. Ensemble averages were computed for each session, from which the P50, N100, and P200 latencies and amplitudes were obtained. No significant differences in amplitude or latency of the various EP components were found between the responses to the second stimulus obtained with the 5 paradigms. Neither did the responses to the fifth and sixth stimuli differ for the TL and TH paradigm, with the exception of the N100 latency of the fifth stimulus, which was longer for TH than TL for NC. Healthy participants had larger amplitudes and shorter latencies than the patients with schizophrenia for the responses to the first stimuli, with the latency differences continuing for the fifth and sixth response. Also, the amplitude and latency of the first response was larger than for the second response in both populations. In conclusion, none of the paradigms studied here, with the employed parameters, are useful to measure the re responding ability of the brain. Also, the shorter latencies for the repeated stimulus suggest that the neural mechanism underlying attenuation of repeated stimuli is of a facilitating nature. PMID- 22423549 TI - Application of multiscale amplitude modulation features and fuzzy C-means to brain-computer interface. AB - This study proposed a recognized system for electroencephalogram (EEG) data classification. In addition to the wavelet-based amplitude modulation (AM) features, the fuzzy c-means (FCM) clustering is used for the discriminant of left finger lifting and resting. The features are extracted from discrete wavelet transform (DWT) data with the AM method. The FCM is then applied to recognize extracted features. Compared with band power features, k-means clustering, and linear discriminant analysis (LDA) classifier, the results indicate that the proposed method is satisfactory in applications of brain-computer interface (BCI). PMID- 22423550 TI - Relationship between, sleep spindles and clinical recovery in patients with traumatic brain injury: a simultaneous EEG and MEG study. AB - Few methods can predict the prognosis and outcome of traumatic brain injury. Electroencephalographic (EEG) examinations have prognostic significance in the acute stage of posttraumatic coma, and some EEG variables have been correlated with outcome. Furthermore, spindle activity and reactivity in the acute stage have been associated with good recovery. Assessments of consciousness based on EEG and magnetoencephalographic (MEG) recordings provide valuable information for evaluating residual function, forming differential diagnoses and estimating prognosis. This study objectively investigated how fast spindles could relate to the recovery of consciousness and cognitive function during the post-acute to chronic stages of diffuse axonal injuries (DAIs). Sleep stage 2 was examined in 7 healthy participants and 8 patients with DAIs. Simultaneous EEG and MEG recordings were performed in the post-acute (mean 80 days) and chronic (mean 151 days) stages of recovery. Magnetoencephalography enabled equivalent current dipole estimates of fast spindle sources. Clinical recovery was evaluated by consciousness, neuropsychological examination, and outcome. Six severe and two moderate injuries were studied in patients with favorable 1-year outcomes. In the sub-acute stage, significant decreases were detected in the frequency, amplitude, and cortical activation source strengths of spindle activities, but these recovered during the chronic stage. In the chronic stage, the Wechsler adult intelligence factor scale and subset patterning revealed significant improvement in cognitive function. These results suggested that spindles may reflect recovery of consciousness and cognitive function following a DAI. PMID- 22423551 TI - The quantitative electroencephalogram and the low-resolution electrical tomographic analysis in posttraumatic stress disorder. AB - The electroencephalogram (EEG) is the recording of the brain electrical activity as measured on the scalp. Using mathematical algorithms, the 3-dimensional (3D) distribution of the electrical potential inside the brain can be calculated. One of the methods to calculate it is the low-resolution electrical tomographic analysis (LORETA). In this research, we seek to find the brain structures that differentiate patients with posttraumatic stress disorder (PTSD) from controls. Ten right-handed consenting adult male patients were recruited from a PTSD clinic. All patients fulfilled Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision [DSM-IV-TR]) criteria for chronic PTSD (duration >2 years.) and were on drug treatment regimens that had been stable for at least 2 months (involving only serotonin reuptake inhibitors [SSRIs] and benzodiazepines).The control group consisted of 10 healthy hospital staff members. All study participants underwent 19 channel EEG measurements according to current standards of practice. All artifact-free EEG strips were examined for spectral as well as LORETA analysis focusing on the theta (4-7 Hz) band which is suggested to reflect the activity of the limbic system. The theta band showed a statistically significant difference (P < .05) between the 2 groups in the right temporal lobe and in both the right and left frontal lobes. Our findings support existing research data obtained via other imaging technologies, which demonstrated structural alterations in the right temporal and frontal areas in PTSD. These results indicate that combining quantitative EEG (QEEG) and the LORETA method, among other methods, may improve the neuroanatomical resolution of EEG data analysis. PMID- 22423552 TI - A novel concealed information test method based on independent component analysis and support vector machine. AB - The concealed information test (CIT) has drawn much attention and has been widely investigated in recent years. In this study, a novel CIT method based on denoised P3 and machine learning was proposed to improve the accuracy of lie detection. Thirty participants were chosen as the guilty and innocent participants to perform the paradigms of 3 types of stimuli. The electroencephalogram (EEG) signals were recorded and separated into many single trials. In order to enhance the signal noise ratio (SNR) of P3 components, the independent component analysis (ICA) method was adopted to separate non-P3 components (i.e., artifacts) from every single trial. In order to automatically identify the P3 independent components (ICs), a new method based on topography template was proposed to automatically identify the P3 ICs. Then the P3 waveforms with high SNR were reconstructed on Pz electrodes. Second, the 3 groups of features based on time,frequency, and wavelets were extracted from the reconstructed P3 waveforms. Finally, 2 classes of feature samples were used to train a support vector machine (SVM) classifier because it has higher performance compared with several other classifiers. Meanwhile, the optimal number of P3 ICs and some other parameter values in the classifiers were determined by the cross-validation procedures. The presented method achieved a balance test accuracy of 84.29% on detecting P3 components for the guilty and innocent participants. The presented method improves the efficiency of CIT in comparison with previous reported methods. PMID- 22423553 TI - The electroencephalogram in neonatal maple syrup urine disease: a case report. AB - Untreated maple syrup urine disease (MSUD) leads to encephalopathy in neonates and causes abnormalities on the electroencephalogram (EEG). A case is presented of MSUD with unique features consisting of a comb-like rhythm before the therapy and its disappearance with therapy is presented. This case illustrates the potential use of the EEG in the identification of this specific cause of a neonatal encephalopathy. PMID- 22423554 TI - Each person is a treasure. PMID- 22423555 TI - Medical home model for improved patient care. PMID- 22423557 TI - Empowered patients are here to stay. PMID- 22423556 TI - Teamwork--the new way. PMID- 22423558 TI - Patient-family councils make the difference. PMID- 22423559 TI - Care across cultures: does every patient need to know? PMID- 22423560 TI - Spotlighting those moments: small acts become sacred encounters. PMID- 22423561 TI - Lessons from Pope John Paul II: 'theology of the body' underpins health care. PMID- 22423562 TI - Patient-centered care through a couple's eyes: HeartPrints eased the grief. PMID- 22423563 TI - We are body and spirit. Can we heal the divide? PMID- 22423564 TI - Physician employment in an era of health reform: using shared ideals to achieve social interests. PMID- 22423565 TI - Bishop urges dialogue for stronger church. PMID- 22423566 TI - The facebook frontier: compelling social media can transform health dialogue. PMID- 22423567 TI - Let's make donations more effective: don't waste these important efforts. PMID- 22423568 TI - System's mobile clinics help overcome neglect of dental health. PMID- 22423569 TI - Who is the person in person-centered care? To be ethical, is it enough to be 'person-centered"? PMID- 22423570 TI - Cellular damage markers in the temporal lobe of a patient with Dyke-Davidoff Masson Syndrome. AB - We studied the cellular damage in a patient with Dyke-Davidoff-Masson Syndrome and a history of chronic temporal lobe epilepsy resistant to treatment. The epileptogenic zone was localized to the right temporal lobe, and an extensive surgical removal of the temporal neocortex plus amygdala and hippocampus was performed. The specimens were immediately frozen in liquid nitrogen and stored at -75 degrees C for biochemical studies. Specimens were immersed and fixed in freshly prepared 4% paraformaldehyde for histopathological evaluation. Neurotransmitter levels were highest in the hippocampus compared to the temporal neocortex (T1, T2, and T3). In the amygdala, GABA was found whereas other amino acids were absent. We found marked dislamination in all areas of the cortex, neuronal loss, amylaceous bodies, and neuronal cytomegaly with cytoskeletal disorganization containing dense fibrillar cytoplasmic aggregates, nodular heterotopias, dysplastic and large neurons with high Nissl staining, intermixed with balloon cells with atypical nuclei, often with binucleation, and abundant glassy eosinophilic cytoplasm. Positive immunoreactive cells with nestin, vimentin, and enhanced expression of astrocytes were observed in all brain regions. This patient's syndrome should be considered as a postinfectious/post stroke event that caused hemiparesis and later recurrent seizures. Higher expression of nestin and vimentin has been observed in proliferative neuronal cells, the expression in astrocytes may mainly reflect an early response of these cells to injury. Nestin may play a role in protecting the brain from injury. It has been proposed that re-expression of embryonic genes by mature cells is associated with morphological plasticity. PMID- 22423571 TI - Effect of varying dose and administration of streptozotocin on blood sugar in male CD1 mice. AB - Streptozotocin (STZ) is used to induce experimental diabetes in rodents. There is however, controversy as to whether STZ induced diabetes models type 1 or 2 diabetes. We show that the grade of STZ-induced hyperglycemia in male CD1 mice is dependent on STZ dose. A single injection of high dose (130 or 150 mg/Kg body weight) or multiple injections (2, 3, 4 or 5) of low dose (40 mg/Kg body weight) STZ was administered intraperitonealy in non-fasted mice. Blood glucose and body weight were measured over 21 days for high dose and 21 and 28 days for low dose administration. On day three, high dose treatment produced hyperglycemia and body weight loss in comparison to mice without STZ, however unstable hyperglycemias and several deaths were observed during treatment. Hyperglycemia and body weight loss were seen with three or more injections of STZ at 21 days, whereas 4 and 5 injections produced severe hyperglycemia but not death. Mild hyperglycemia (250 450 mg/dL) was seen after 28 days following three injections of STZ. Therefore we concluded that a high dose STZ produces severe hyperglycemia in mice similar to a type 1 diabetic, and three successive administrations of STZ induces mild hyperglycemia in mice similar to type 2 diabetics. PMID- 22423572 TI - An overview of colorimetric assay methods used to assess survival or proliferation of mammalian cells. AB - The aim of this review is to briefly describe some colorimetric methods that are commonly used to evaluate a new chemical entity (NCE) on cell cultures in non clinical oncology discovery research. These methods have the distinct advantage over other techniques in that they can be applied and used in a cell monolayer or a suspension culture. Both protein assay determination and cell viability assays may be conducted using these culture systems. The viability of cell cultures is routinely assessed by utilizing the metabolic capacity of cells which biochemically convert chemicals (usually color dyes) which can then be conveniently measured at specific wavelengths using a multi-well plate reader. Resazurin (Alamar Blue) is an example of one of these metabolically active compounds. Resazurin is a nontoxic dye that can also be used to measure migration and cellular invasion without resorting to sacrifice of the cells during the test procedure. Another is 5-bromo-2-deoxyuridine (bromodeoxyuridine or BrdU) which is a thymidine analog that incorporates into the DNA of dividing cells during the S phase of the cell cycle. We will also discuss the colorimetric version of the traditional 3H-thymidine incorporation and immunoenzymatic assay used to measure DNA synthesis and its application to discovery research. PMID- 22423573 TI - Tio2-dopamine complex implanted unilaterally in the caudate nucleus improves motor activity and behavior function of rats with induced hemiparkinsonism. AB - Parkinson's disease (PD) is characterized by malfunction of dopaminergic systems, and the current symptomatic treatment is to replace lost dopamine. For investigating mechanisms of pathogenesis and alternative treatments to compensate lack of dopamine (DA) activity in PD, the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD has been useful, these animals display apomorphine-induced contralateral rotational behavior, when they are examined after lesion. The purpose of this study was to assess Titania-dopamine (TiO2-DA) complexes implanted on the caudate nucleus for diminishing motor behavior alterations of the 6-OHDA rat model. Rats with 6-OHDA unilateral lesions received TiO2 alone or TiO2-DA implants, and were tested for open field (OF) gross motor crossing and rearing behaviors, and apomorphine-induced rotation (G) behavior. TiO2 complex have no effects on rearing OF and G behaviors, and a significant reducing effect on crossing motor behavior of normal rats compared to control non-treated rats throughout 56 days of observation. Interestingly, TiO2-DA treatment significant recovered motor crossing and rearing behaviors in 6-OHDA-lesioned rats, and diminished the G behaviors during 56 days of examination. Additionally, in the 6 OHDA-lesioned rats TiO2 treatment had a moderate recovering effect only on crossing behavior compared to lesioned non treated rats. Our results suggest that continuous release of dopamine in the caudate nucleus from TiO2-DA complex is capable of reversing gross motor deficits observed in the 6-OHDA-lesioned rat model of PD. Thistype of delivery system of DA represents a promising therapy for PD in humans. PMID- 22423574 TI - Gait kinematic analysis evaluates hindlimb revascularization. AB - Peripheral arterial occlusive disease is described as vascular disorders associated with ischemia and may be the result of an obstructive vascular process or a lost revascularization response. We have shown that gait locomotion analysis by video filming represents an integrative model for the evaluation of mechanisms involved in the process of ischemia-induced revascularization. However, analysis by this method can be subjective and perception errors may be occurring. We present the optimization of a quantifiable, noninvasive, reproducible method that analyzes ankle kinematics in rats using a two-dimensional digital video system. Gait dynamics were filmed in hindlimb ischemic rats with a high speed digital video camera. Images were collected and analyzed at 125 frames per second. An algorithm using interactive data language (IDL) was devised to assess different parameters. In ischemic rats, stride time and knee joint angle remained altered 10 days post-surgery compared with sham animals. Gait kinematics were outlined in a highly reliable way by this computational analysis and corroborated the notion of hindlimb movement recovery associated with the revascularization process. PMID- 22423575 TI - Pharmacological modulation of the renin-angiotensin system by mathematical modeling. AB - The renin-angiotensin system (RAS) is one of the most important systems in blood pressure homeostasis and pathogenesis of cardiovascular-renal diseases. When blood volume goes down, juxtaglomerular cells in the kidneys secrete renin. Renin stimulates the production of angiotensin I (Ang I), which is then converted to angiotensin II (Ang II). Angiotensin II causes blood vessels to constrict, resulting in increased blood pressure. If the renin angiotensin system is over active, blood pressure will be too high. Most hypotensive drugs are designed to block this system at different points in the pathway. In this study, we developed a mathematical model of the renin-angiotensin system to emulate the response of the renin-angiotensin system in humans. This model consists of a set of differential equations. Special attention is paid to the estimation of all the model parameters from reported experimental data. These equations allow us to model hypertensive and normotensive patients and pharmacotherapeutic approaches to treatment. We show dose-response curves of blood pressure and biochemical components of the renin-angiotensin system. Our results reproduce clinical outcomes. We conclude that mathematical modeling of RAS is a useful approach for gaining insight into the complexities of homeostatic control of arterial pressure and pharmacotherapeutics. PMID- 22423576 TI - A role for cyclic nucleotide-gated channels in the capacitation of mammalian sperm. AB - In their transit through the female genital tract, mammalian sperm acquire the ability to fertilize the egg in a process called capacitation. During this event the intracellular levels of cAMP and cGMP increase, suggesting that cyclic nucleotide-gated (CNG) channels, which have been identified in mammalian sperm, play a functional role in their physiology. Here we report an electrophysiological characterization of the effect of cyclic nucleotides on mouse sperm. Using the patch-clamp technique in the whole-cell configuration, we show that macroscopic ionic currents are augmented by the addition of both, 8Br cAMP and 8Br-cGMP to non-capacitated mouse sperm. Although cyclic nucleotide regulates the activity of CNG channels, disparate effects of cyclic nucleotides may also occur. Addition of L-cis-diltiazem (50 microM), a specific inhibitor of CNG channels, partially blocked currents elicited by cGMP, suggesting that CNG channels play a role in the fertilization capability of mammalian sperm. PMID- 22423577 TI - Relationship among changes in hematocrit, albumin and corticosteroid dose on the disposition of tacrolimus during the first six months following renal transplantation. AB - Tacrolimus is a macrolide immunosuppressant that is safe and effective for the prevention of rejection after kidney transplantation. The oral bioavailability of tacrolimus averages 20% to 25%; however, the inter-individual variability in this parameter is large. Because of the poor correlation of dose to blood concentration between patients, the variability in pharmacokinetics and a relatively narrow therapeutic window, therapeutic drug monitoring of tacrolimus trough whole blood concentrations must be a standard practice. The objective of this evaluation was to determine the relationship among changes in hematocrit, albumin, and corticosteroid dosing on the disposition of tacrolimus during 6 months of treatment in renal transplant recipients. Blood samples for the determination of trough tacrolimus concentrations were taken immediately prior to the morning dose, samples were collected according to the request of the attending physician. Clinical and dosage data were reviewed 6 months after transplantation. The analysis was conducted including 11 patients who were analyzed for hematocrit and albumin at the same time they are measured tacrolimus blood levels. The mean age was 25.3 years (range 17 to 41 years) 4 of the patients were female. Levels of tacrolimus, hematocrit and albumin over the first 24 weeks post-transplant were documented and the estimated relative clearance of tacrolimus were calculated. Statistical evaluation of the data indicates poor correlation between relative clearance and both hematocrit and albumin levels and the mean oral steroid dose. This observation is of clinical significance because dose adjustment may be required to maintain blood concentrations within thetherapeutic range in patients in whom hematocrit or albumin concentrations are changing. PMID- 22423578 TI - Effects of bee products on pentylenetetrazole-induced seizures in the rat. AB - Bee products (BP) have been used for centuries as a diet complement with claimed curative properties. The aim of this study was to determine whether oral administration of BP prevented behavioral, histological, and biochemical alterations, caused by pentylenetetrazole (PTZ)-induced kindling in rats. Male Wistar rats were employed to evaluate seizure latency, number and duration, performance in the open field test, histological alterations and mortality following BP administration. Oral administration of BP at two doses, 30 and 60 mg/kg/day, significantly lengthened latency of both clonic and tonic PTZ-induced seizures, decreased the duration and frequency of seizures and reduced mortality. In the Open Field test, BP treated groups showed increases in the number of crossed squares and rearing counts, and on optimal dose, decreases in fecal boli. Histological analysis showed in PTZ (50 and 80 mg/kg) kindling rats, lungs with inflammatory peribronchiolar, and perialveolar infiltrates. In the liver, mild losses of trabeculae, multi-vesiculated hepatocytes (steatosis) and inflammatory infiltrates in hepatic parenchyma were observed. Interestingly, in the heart, fibers were markedly separated. In testis, stratified epithelium of seminal tubules lost its normal structure, tubules had epithelium loss, spermatids were absent, and spermatogonia and Leydig cells diminished. In PTZ kindling rats treated with BP, the lungs had no inflammatory infiltrates, although the heart showed some inflammatory infiltrates. Remaining structures had normal characteristics. These results, suggest that BP can protect rats from effects of PTZ-induced kindling. PMID- 22423579 TI - Anticonvulsant drugs, oxidative stress and nitric oxide. AB - Nitric Oxide (NO) is thought to play a fundamental role in the genesis and the spreading of epileptiform hyperactivity, although its function is unclear and controversial. As a free radical, NO may cause oxidative stress, which is emerging as an important mechanism in the etiology of seizure-induced neuronal death. Here we investigated the role of NO in seizure mechanisms through oxidative stress generation by studying the effect of anticonvulsant drugs such as amino oxyacetic acid (AAOA), valproate (VALP), diazepam (DIAZ) and gabapentin (GBPTNA) on oxidative stress in the brain, estimated as free carbonyls by the method of Dalle and Rossi, and by measuring NO by the indirect method based on the Griess reaction. Results show that, except for AAOA and VALP, anticonvulsants did not significantly affect or decreased free carbonyls, but reversed the oxidative stress produced by pentylenetetrazole (PTZ) induced convulsions. Anticonvulsants except AAOA diminished NO levels and with the exception of VALP, counteracted the increase in NO generated by PTZ. Anticonvulsants decreased oxidative stress and NO especially in hippocampus (HI) and cortex (CX), and reversed PTZ effects on both parameters. PTZ diminished NO in HI, which could be explained since PTZ caused an increase on endothelial NO synthase but a decrease in neuronal NOS expression in this brain area. Since the drugs studied are modulating GABA levels, our results suggest that seizures generated by alterations in GABAergic transmission produce oxidative stress caused by NO, which can be reversed by anticonvulsants. The effects described differ among the brain regions studied and the NO synthase isoform affected. PMID- 22423580 TI - Aminoglycosides: therapeutics, ototoxicity and hypersensitivity of mitochondrial genetic origin. AB - Aminoglycosides such as streptomycin or gentamycin are employed to treat stubborn infections. In Mexico, tuberculosis patients are successfully treated with 1 g/day for over 6 months. Ototoxicity is often seen as a consequence of prolonged treatment with aminoglycosides. In young people STP damages the vestibule of the ear; in elder patients it diminishes hearing and balance. These effects are due to streptidine, a metabolite of STP produced in elder patients and detected in blood by liquid chromatography. On occasion, sudden deafness is established after only a short treatment period as the result of the presence of a single nucleotide mutation in the mitochondrial 12S rRNA gene. In patients with this polymorphism, aminoglycosides produce a stereotypic conformation similar to the bacterial 16S rRNA thus inhibiting the synthesis of proteins. Many aminoglycoside sensitive mutations have been described in several ethnic groups, causing sudden deafness. We started similar studies in Mexican individuals, treated or not with an aminoglycoside, to determine whether similar alterations could be detected. To date in over 60 individuals analyzed we found only one case of polymorphism in a streptomycin treated patient. We developed a simple method to identify such mitochondrial gene in a larger population to make recommendations to use an alternative treatment which do not cause ototoxicity in the mutation bearing patient. PMID- 22423581 TI - Pharmacological evaluation of the immunomodulatory FL-6 in induced chronic hepatitis in Wistar rats. AB - The aim of this study was to evaluate the pharmacological effect of FL-6, a new immunomodulatory drug, in chronic hepatitis immunologically induced in rats via porcine-serum (PS) administration. Thirty-two male Wistar rats (150 g) were divided into 4 experimental groups: (1) Control (PBS 0.5 ml 3-times per week for 8-week); (2) FL-6 (50 ng/kg 3-times per week for 4-week); (3) Hepatitis (PS 373 mg/kg twice per week for 8-week); and (4) Hepatitis + FL-6 (doses as above). Rats were sacrificed at the end of treatment. ALT, AST, ALP and gamma-GT activities, as well as IL-6 and IL-10 levels, were evaluated in serum samples. Glutathione and malondialdehyde were also analyzed. A morphological analysis of liver tissue was carried out. The hepatitis group showed an increase in ALT (1.44-fold), AST (1.28-fold), ALP (1.83-fold), gamma-GT (3.91-fold), IL-6 (2.6-fold) and IL-10 (7.1-fold) levels when compared with controls (p < 0.05). Histopathological analysis revealed an inflammatory response characterized by inflammatory infiltrates and liver damage, which was accompanied by a reduction of 74.8% in glutathione levels (p < 0.05). However, animals with hepatitis treated with FL-6 had a reduction of ALT activity (17.74%), as well as a reduction in IL-6 (24.21%) and IL-10 (30.91%) levels (p < 0.05). These animals showed a reduction in inflammatory response characterized by a decrease in inflammatory infiltrate at the hepatic parenchyma and portal structures; livers showed less damage and a reduction of necrotic and apoptotic hepatocytes. In conclusion, the treatment with FL-6 improved liver function and reduced the inflammatory marker in rats with chronic hepatitis induced by PS-administration. PMID- 22423582 TI - 5-HT7 receptor-mediated meningeal dilatation induced by 5-carboxamidotryptamine in rats is not altered by 5-HT depletion and chronic corticosterone treatment. AB - Low brain serotonin levels and high circulating levels of corticosterone are features of migraine. The 5-HT7 receptor was shown to mediate dilator responses to the 5-HT1B/1D and 5-HT7 receptor agonist, 5-carboxamidotryptamine in the middle meningeal artery of rats. Here we analyzed the effect of serotonin depletion and chronic corticosterone treatment on 5-HT7 receptor-mediated dilatation induced by 5-carboxamidotryptamine in the middle meningeal artery of anesthetized rats. Two weeks before experiments, male Wistar rats received i.c.v. injections of vehicle or the neurotoxin, 5,7-dihydroxytryptamine; upon recovery, animals received a chronic s.c. treatment (2 weeks) with vehicle (1 ml/kg/day) or corticosterone (20 mg/kg/day). At the end of treatments, animals were anesthetized and prepared for recording of blood pressure and blood flow in the middle meningeal artery, and i.v. drug administration. All animals received the 5 HT1B/1D receptor antagonist GR-127935 (1 mg/kg, i.v.) alone or combined with the 5-HT7 receptor antagonist, SB-269970 (1 mg/kg, i.v.). Topical 5 carboxamidotryptamine (0.01-1000 microM) to the exposed dura mater encephala produced decreases in diastolic blood pressure, variable changes in meningeal blood flow and increases in conductance (i.e. dilatation) in the middle meningeal artery. Meningeal dilator responses to 5-carboxamidotryptamine did not differ among treatment groups. In all cases, the combined treatment with GR-127935 + SB 269970 inhibited hypotensive and meningeal dilator responses to 5- carboxamidotryptamine. Together, these data do not support the notion that 5-HT7 receptors mediating dilatation in the middle meningeal artery are regulated by low brain serotonin levels and/or chronically high circulating levels of corticosterone. Further studies are required to elucidate the potential impact of these conditions and the role of 5-HT7 receptors in migraine. PMID- 22423583 TI - Pharmacokinetics of lidocaine and its metabolite as a hepatic function marker in dogs. AB - Measuring hepatic metabolic function is critical for detection and treatment of liver failure. Several tests have been widely used to characterize the integrity of liver; however, they do not evaluate the metabolic function of the organ, most requiring multiple blood draws. The purpose of this study was to establish if the ratio of the lidocaine metabolite monoethylglycinexylidide (MEGX) divided by lidocaine concentration at 30 min post intravenous lidocaine administration is a good marker of metabolic activity of the liver. Nine healthy and two partially hepatectomized and auto-transplanted dogs were included in the study. A single 1.5 mg/kg intravenous dose of lidocaine and serum samples were obtained at selected times for 150 minutes. Serum concentrations of lidocaine and MEGX were determined by a validated high-performance liquid chromatographic method. Pharmacokinetic parameters were obtained by non-compartmental methods and ratio of AUC of MEGX divided by AUC of lidocaine was determined for each dog. This ratio was correlated with the ratio of the concentration of the compounds obtained 30 minutes after drug administration. A good concordance was obtained, suggesting that ratio obtained with a single sample may be useful to predict the hepatic metabolism function. To validate the test, dogs hepatectomized and auto transplanted were plotted and the results obtained were within the values obtained in healthy dogs. These results suggest that ratio of MEGX/lidocaine obtained 30 min after administration could be a good marker of hepatic metabolic function. PMID- 22423584 TI - Pre-transplant mycophenolate mofetil pharmacokinetics in Mexican children. AB - Mycophenolate mofetil is an immunosuppressive pro-drug frequently used to prevent renal graft rejection. It is hydrolyzed by esterases to obtain the active drug mycophenolic acid (MPA). There is high inter-patient variation in mycophenolic acid pharmacokinetics. Area under the concentration versus time curve (AUC) is used for therapeutic drug monitoring and recommended levels are 30-60 microg x hr/L. The aim of this study was to determine mycophenolic acid pharmacokinetics in children awaiting renal allograft in order to predict mycophenolate mofetil dose requirements. Children with end-stage renal disease on the waiting list for renal allograft transplantation were invited to participate in the study. A nine point pharmacokinetic profile was performed. All patients received a single dose (600 mg/m2, subcutaneously) of mycophenolate mofetil at time zero. Mycophenolic acid was measured by HPLC. The AUC0-12h was estimated by the trapezoidal rule. Ten children were included in the study. Mean age was 13.5 +/- 3.5 years. The median AUC0-12h was 20.3 microg x hr/L, median Cmax = 0.7 microg/mL. Two children (20%) had no detectable levels of mycophenolic acid after a single mycophenolate mofetil dose, other two patients had AUC > 60 microg x hr/L. One patient had abdominal pain 1 hr after the mycophenolate mofetil dose. Twenty percent of our patients had AUC0-12h higher than the recommended value after a single mycophenolate mofetil dose, those patients should receive lower mycophenolate mofetil dose since the beginning of the transplant to avoid adverse events, and another 20% of patients had no detectable mycophenolic acid levels after a single mycophenolate mofetil dose. UGT1A9 gene polymorphisms remain to be studied in our patients, since they could explain the differences in bioavailability. PMID- 22423585 TI - Ocular and systemic adverse effects of ophthalmic and non ophthalmic medications. AB - Information related to adverse drug effects caused by ocular medications and ocular adverse effects of systemically administered drugs has increased over the last several decades. Here we review the medical literature over the last four decades to both quantitatively and qualitatively determine the adverse effects of ocular drugs and ocular toxicity of non-ocular drugs. A systematic bibliographic review of the literature was performed with the following terms: "drug treatment", "drug therapy", "ocular adverse effects", "ocular side effects", "ocular toxicity", "systemic side effects", "systemic adverse effects", "systemic toxicity", "ocular drug" and "ophthalmic drug" using the Boolean operators or, and, not. Searches focused on: (1) Ocular side/adverse effects of ophthalmic drugs; (2) Ocular side/adverse effects of systemic drugs; (3) Systemic side/adverse effects of ophthalmic drugs. PubMed was used to perform searches. Limits included: species, human and field tag, abstract/title, dates from 01/01/1971 to 31/12/2010. A sub-selection of references was made by discarding articles that were irrelevant for the topics listed above. Adverse effects of alpha2-adrenergic agonists, beta-adrenergic antagonists, quinine derivatives and antituberculosis agents appear in the literature throughout the period of the review. Adverse effects of newer drugs such as amiodarone, phosphodiesterase 5 inhibitors, antiepileptics, tamoxifen, and its interactions have been published principally in the last two decades. It is imperative for patient safety that knowledge of the adverse effects of drugs on the eye whether topically or systemically administered, and the possible systemic effects of drugs given as ophthalmic medications be emphasized to clinicians. PMID- 22423586 TI - Effect of orlistat on lipid peroxidation, Na+, K+ ATPase, glutathione and serotonin in rat brain. AB - The aim of this study was to evaluate the effect of orlistat, a drug used in weight loss, on 5-HT and indicators of oxidative stress in rat brain. Orlistat, 12 mg/kg was administered to Wistar rats as single dose or successive doses on 3 consecutive days. Blood glucose and oxidative stress indicators were detected by measurement of lipid peroxidation, Na+, K+ ATPase, glutathione and serotonin levels using previous validated methods. The levels of glucose decreased in rats receiving successive doses. The activity of Na+, K+ ATPase and total ATPase was reduced in rats receiving successive doses, while the level of lipid peroxidation increased slightly in both groups. Glutathione underwent significant reduction in the successive doses group (p < 0.05). 5-HT increased significantly after single dose treatment (p < 0.05). Orlistat can induce pro-oxidant effects in the brain due to alteration of serotonergic metabolism and the reduction of glutathione. PMID- 22423587 TI - Ganoderma lucidum reduces kainic acid-induced hippocampal neuronal damage via inflammatory cytokines and glial fibrillary acid protein expression. AB - Ganoderma lucidum, a traditional Chinese medicine, has been shown to target the Central Nervous System. In this work we analyze whether G. lucidum, collected in Mexico, has a protective effect in the hippocampus of rats treated with kainic acid, a neurotoxin that causes seizures and neuronal loss. The aqueous extract of G. lucidum (10 mg/Kg, i.p.) was administered to rats 30 min before kainic acid injection (5 mg/Kg, i.p.). Animals that had received prior treatment with G. lucidum showed no tonic-clonic seizure activity. Histopathological analysis showed a significant decrease in neuronal loss and cellular alterations in the hippocampal CA3 region. Immunohistochemical analysis shows that when using G. lucidum in rats, there is less immunoreactivity for GFAP as well as TNF-alpha and IL-1beta in the CA3 region when compared with rats treated with kainic acid. Our results demonstrate that G. lucidum protects against kainic acid-induced alterations of hippocampal cells and expression of immunological markers in this model of excitotoxicity. PMID- 22423588 TI - Calmodulin antagonists inhibit sea urchin sperm hyperpolarization necessary for directed movement toward the egg. AB - Speract, a decapeptide from Strongylocentrotus purpuratus sea urchin eggs, transiently stimulates a membrane guanylyl cyclase and activates a K(+)-selective channel that hyperpolarizes the sperm. Membrane potential recordings with fluorescent dyes in sperm flagellar vesicles were used to determine if calmodulin participates in the signal transduction induced by speract. The vesicle hyperpolarization induced by speract was inhibited by the calmodulin antagonists: trifluoperazine, mastoparan; N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide, (W-7); and N-(6-Aminohexyl)-1-naphthalenesulfonamide, (W-5). Since that inhibition occurred at concentrations at which calmodulin action is inhibited by these compounds, the overall findings suggested that calmodulin could be involved in the speract response. The speract response was Ca(2+)-independent however. Ten millimolar EGTA does not inhibit the hyperpolarization and 2 mM BAPTA only partially inhibited the response. High concentrations of calmodulin-dependent kinase II and phosphatase inhibitors did not alter the response of the flagella vesicles to speract. Taken as a whole, these results indicate that the speract induced hyperpolarization involves the participation of calmodulin in a Ca2+ independent manner. PMID- 22423589 TI - Valproic acid modulates brain plasticity through epigenetic chromatin remodeling in the blind rat: implications for human sight recovery. AB - Blindness is a pervasive sensory condition that imposes diverse difficulties to carry on with activities of daily living. In blind individuals, the brain is subjected to a large scale reorganization characterized by expanded cortical territories associated with somatosensory and auditory functions and the recruitment of the former visual areas to perform bimodal somatosensory and auditory integration. This poses obstacles to efforts aimed at reassigning visual functions to the recruited visual cortex in the blind, especially after the end of the ontogentic sensitive period. Devising pharmacological measures to modulate the magnitude of brain plasticity could improve our chances of recovering visual functions in the blind. Here, by using the primary somatosensory cortex (S1) in the rat as a working model, we showed that valproic acid administered through the mother's milk prevents cortical reorganization in blinded rats by delaying neuronal histone de-acetylation. These results suggest that in the future, we might be able to devise epigenetic pharmacological measures that could improve our chances of reassigning visual functions to the once deprived former visual cortex in the blind, by modulating the magnitude of brain plasticity during critical times of development. PMID- 22423590 TI - Treatment with LA-419 prevents monocrotaline-induced pulmonary hypertension and lung injury in the rat. AB - We evaluated the therapeutic potential of LA-419, a hybrid organic nitrate that donates nitric oxide and thiol groups, to improve pulmonary arterial hypertension in an experimental model induced by monocrotaline in the rat. Treatment with LA 419 from the first day after monocrotaline administration prevented the increase in pulmonary pressure as well as the increases in ventricle/body weight and pulmonary artery wall thickness. Administration of LA-419 after establishment of hypertensive status also resulted in an improvement of these parameters. Both preventive and therapeutic treatments reduced mortality. The antioxidant effect of LA-419 was comparable to that achieved with a-tocopherol. Pulmonary remodeling accomplished by LA-419 could be attributed to a balanced antioxidant effect associated with its nitric oxide/SH donor capability. Thus, LA-419 might represent a new therapeutic approach in severe pulmonary hypertension in humans. PMID- 22423591 TI - Ageing, health and medication consumption in a sample of academic employees at a Mexican university. AB - Teachers and researchers are valuable resources of universities. A healthy life style includes appropriate utilization of medicines. In this work we explore health status and medicine consumption among a sample of academic employees over 40 years of age at a Mexican university. We analyzed answers to an on line survey in a random sample of academic employees, 40 years and older who work at the National University of Mexico. The 179 item survey was answered from November 2009 to October 2010, by 240 randomly selected academic employees. A section of the questionnaire was oriented toward health issues. We analyzed reported illness, self-perception of health status and medicine consumption. The bodies systems involved most often among those who report any kind of disease were: circulatory and endocrine and/or metabolic, followed by osteomuscular and digestive. Medicinal agents were consumed in the last two weeks by 52% of respondents. Among these, vitamins were consumed by 28%, drugs for pain by 17%, drugs for high blood pressure by 14%, drugs for high cholesterol by 13%, antibiotics by 8%, drugs for diabetes by 5%, cold medicines by 4%. It is suggested that medicinal drugs may not be consumed in situations in which they are indicated, such as in hypercholesterolemia and possibly in hypertension and diabetes. Others, such as vitamins are frequently utilized. Research and interventions should be directed toward better utilization of medicinal drugs. PMID- 22423593 TI - The illness/injury sensitivity index: validation of a German version of the ISI R. AB - Three fundamental fears-anxiety sensitivity, fear of negative evaluation, and illness/injury sensitivity-are considered integral components of anxiety-related psychopathology and also bear connections with chronic pain. Scales measuring the first two fears, the Anxiety Sensitivity Index and the Fear of Negative Evaluation Scale, have been translated into German; however, the nine-item Illness/Injury Sensitivity Index-Revised (ISI-R) that measures fears of injury and illness has not been available in German language yet. The aim of this study therefore was a translation of the ISI-R into German language and an initial validation of the translated scale in two different samples. The German ISI-R was translated by both professionals and laypersons, and a final version was decided on by consensus. In Study 1, participants included 96 undergraduate students (85% women) who completed the German version of the ISI as part of a larger study. An exploratory factor analysis with oblique rotation was conducted and suggested a two-factor-solution with one factor representing fears of illness and the other fears of injury. This factor structure was confirmed via a confirmatory factor analysis (CFA) in Study 2. Participants included 117 community members (79% women). Convergent validity was supported using a visual analogue scale for fear of illness in both samples and the German translation of the Whiteley Index in Study. Overall, the results supported the German translation of the ISI-R. Comprehensive results, limitations, and directions for future research are discussed. PMID- 22423592 TI - General practitioners' management of mental disorders: a rewarding practice with considerable obstacles. AB - BACKGROUND: Primary care improvement is the cornerstone of current reforms. Mental disorders (MDs) are a leading cause of morbidity worldwide and widespread in industrialised countries. MDs are treated mainly in primary care by general practitioners (GPs), even though the latter ability to detect, diagnose, and treat patients with MDs is often considered unsatisfactory. This article examines GPs' management of MDs in an effort to acquire more information regarding means by which GPs deal with MD cases, impact of such cases on their practices, factors that enable or hinder MD management, and patient-management strategies. METHODS: This study employs a mixed-method approach with emphasis on qualitative investigation. Based on a previous survey of 398 GPs in Quebec, Canada, 60 GPs representing a variety of practice settings were selected for further study. A 10 minute-long questionnaire comprising 27 items was administered, and 70-minute long interviews were conducted. Quantitative (SPSS) and qualitative (NVivo) analyses were performed. RESULTS: At least 20% of GP visits were MD-related. GPs were comfortable managing common MDs, but not serious MDs. GPs' based their treatment of MDs on pharmacotherapy, support therapy, and psycho-education. They used clinical intuition with few clinical tools, and closely followed their patients with MDs. Practice features (salary or hourly fees payment; psycho social teams on-site; strong informal networks), and GPs' individual characteristics (continuing medical education; exposure and interest in MDs; traits like empathy) favoured MD management. Collaboration with psychologists and psychiatrists was considered key to good MD management. Limited access to specialists, system fragmentation, and underdeveloped group practice and shared care models were impediments. MD management was seen as burdensome because it required more time, flexibility, and emotional investment. Strategies exist to reduce the burden (one-problem-per-visit rule; longer time slots). GPs found MD practice rewarding as patients were seen as grateful and more complying with medical recommendations compared to other patients, generally leading to positive outcomes. CONCLUSIONS: To improve MD management, this study highlights the importance of extending multidisciplinary GP practice settings with salary or hourly fee payment; access to psychotherapeutic and psychiatric expertise; and case-discussion training involving local networks of GPs and MD specialists that encourage both knowledge transfer and shared care. PMID- 22423594 TI - Speciation and release kinetics of zinc in contaminated paddy soils. AB - Zinc is an important nutrient for plants, but it can be toxic at high concentrations. The solubility and speciation of Zn is controlled by many factors, especially soil pH and Eh, which can vary in lowland rice culture. This study determined Zn speciation and release kinetics in Cd-Zn cocontaminated alkaline and acidified paddy soils, under various flooding periods and draining conditions, by employing synchrotron-based techniques and a stirred-flow kinetic method. Results showed almost no change in Zn speciation and release kinetics in the two soils, although the soils were subjected to different flooding periods and draining conditions. The mineral phases in which Zn is immobilized in the soil samples were constrained by linear least squares fitting (LLSF) analyses of bulk X-ray absorption fine structure (XAFS) spectra. Only two main phases were identified by LLSF, i.e., Zn-layered double hydroxides (Zn/Mg-hydrotalcite-like, and ZnAl-LDH) and Zn-phyllosilicates (Zn-kerolite). Under all soil pHs, flooding, and draining conditions, less than 22% of Zn was desorbed from the soil after a two-hour desorption experiment. The information on Zn chemistry obtained in this study will be useful in finding the best strategy to control Cd and Zn bioavailability in the Cd-Zn cocontaminated paddy soils. PMID- 22423595 TI - Assessing the zoonotic potential of Ascaris suum and Trichuris suis: looking to the future from an analysis of the past. AB - The two geohelminths, Ascaris lumbricoides and Trichuris trichiura, infect more than a billion people worldwide but are only reported sporadically in the developed part of the world. In contrast, the closely related species A. suum and T. suis in pigs have a truly global distribution, with infected pigs found in most production systems. In areas where pigs and humans live in close proximity or where pig manure is used as fertilizer on vegetables for human consumption, there is a potential risk of cross-infections. We therefore review this relationship between Ascaris and Trichuris in the human and pig host, with special focus on recent evidence concerning the zoonotic potential of these parasites, and identify some open questions for future research. PMID- 22423596 TI - New insights in the study of pyrene excimer fluorescence to characterize macromolecules and their supramolecular assemblies in solution. AB - This report highlights some of the recent developments that have been made in the quantitative analysis of fluorescence decays acquired with pyrene-labeled macromolecules. With these new analytical tools, macromolecules of different composition and architecture can now be labeled in a variety of ways with the pyrene chromophore, and the kinetics of pyrene excimer formation can be described to retrieve quantitative information about the internal dynamics of the macromolecules studied. In particular, this review presents the procedure that was followed to develop these new analytical tools and how the process of pyrene excimer formation with vinyl polymers, poly(L-glutamic acid), dendrimers, associative polymers, surfactants, and lipids labeled with pyrene has been successfully characterized thanks to these analysis programs. PMID- 22423597 TI - The experiences and needs of persons with spinal cord injury who can walk. AB - PURPOSE: The purpose was to explore the experiences and needs of persons with spinal cord injury (SCI) who can walk. METHOD: Thematic analysis was undertaken on the transcripts of semistructured interviews with 12 individuals who could walk following SCI. RESULTS: Experiences shared across the group were related to walking in hospital and community settings, fatigue, frustration and invisible impairments. A need was identified for psychological support whilst in hospital and beyond. Professional and peer support following discharge from hospital were needed to assist with adjusting to their injury. Differences were noted between the experiences and needs of persons who had sustained their injury through a traumatic cause and persons who had sustained their injury through nontraumatic cause and the rehabilitation environment in which participants were hospitalized. CONCLUSION: The lived experiences of the general cohort in this small-scale study suggest that innovative strategies/programs be developed to address the needs of walkers within inpatient settings and following their discharge into the community. Programs should include self-help mental health strategies. Programs are required to better inform health professionals of the needs of this subset of the spinal cord injured population. Attention should be drawn particularly towards the needs of persons who had sustained their injury through nontraumatic cause. PMID- 22423599 TI - o-Iodoxybenzoic acid mediated oxidative desulfurization initiated domino reactions for synthesis of azoles. AB - A systematic exploration of thiophilic ability of o-iodoxybenzoic acid (IBX) for oxidative desulfurization to trigger domino reactions leading to new methodologies for synthesis of different azoles is described. A variety of highly substituted oxadiazoles, thiadiazoles, triazoles, and tetrazoles have been successfully synthesized in good to excellent yields, starting from readily accessible thiosemicarbazides, bis-diarylthiourea, 1,3-disubtituted thiourea, and thioamides. PMID- 22423600 TI - Aptamer-mediated nanoparticle-based protein labeling platform for intracellular imaging and tracking endocytosis dynamics. AB - Although nanoparticles have been widely used as optical contrasts for cell imaging, the complicated prefunctionalized steps and low labeling efficiency of nanoprobes greatly inhibit their applications in cellular protein imaging. In this study, we developed a novel and general strategy that employs an aptamer not only as a recognizer for protein recognition but also as a linker for nanoreporter targeting to specifically label membrane proteins of interest and track their endocytic pathway. With this strategy, three kinds of nanoparticles, including gold nanoparticles, silver nanoparticles, and quantum dots (QDs), have been successfully targeted to the membrane proteins of interest, such as nucleolin or prion protein (PrP(C)). The following investigations on the subcellular distribution with fluorescent immunocolocalization assay indicated that PrP(C)-aptamer-QD complexes most likely internalized into cytoplasm through a classical clathrin-dependent/receptor-mediated pathway. Further single-particle tracking and trajectory analysis demonstrated that PrP(C)-aptamer-QD complexes exhibited a complex dynamic process, which involved three types of movements, including membrane diffusion, vesicle transportation, and confined diffusion, and all types of these movements were associated with distinct phases of PrP(C) endocytosis. Compared with traditional multilayer methods, our proposed aptamer mediated strategy is simple in procedure, avoiding any complicated probe premodification and purification. In particular, the new double-color labeling strategy is unique and significant due to its superior advantages of targeting two signal reporters simultaneously in a single protein using only one aptamer. What is more important, we have constructed a general and versatile aptamer mediated protein labeling nanoplatform that has shown great promise for future biomedical labeling and intracellular protein dynamic analysis. PMID- 22423601 TI - Chronic lymphocytic leukemia associated leukemia cutis presenting as acne rosacea. PMID- 22423602 TI - AATS Mitral Conclave 2011. Foreword. PMID- 22423603 TI - Management of systolic anterior motion after mitral valve repair: an algorithm. AB - OBJECTIVE: To evaluate the effectiveness and outcomes of an intraoperative and postoperative algorithm for managing systolic anterior motion (SAM) after mitral valve repair (MVRr). METHODS: All consecutive patients who underwent MVRr for degenerative disease from January 2002 to June 2011 were included, with the data collected retrospectively. Patients who underwent MVRr for primary SAM were excluded from the study. Patients who developed SAM after the repair were systematically treated according to the algorithm. The intraoperative algorithm first involved medical management techniques, followed by surgical correction for significant SAM (mild or greater mitral regurgitation, left ventricular outflow tract gradient > 50 mm Hg). The postoperative algorithm focused on medical management and symptoms to guide the treatment decisions. RESULTS: The overall in hospital incidence of SAM was 6.6% (52/785). In 41 patients, SAM was identified in the operating room, and in 11 patients, it was found postoperatively on the predischarge echocardiogram. Of the 41 patients with intraoperative SAM, 35 (85.4%) had resolution with medical management and 6 (14.6%) required surgical repeat repair while in the operating room. No patient required mitral valve replacement for persistent SAM. Postoperatively, 11 new cases were identified, and 7 cases of resolved intraoperative SAM recurred. These postoperative cases of SAM were managed according to the postoperative SAM algorithm. At last follow-up, 17 (94.4%) of 18 patients had resolution of SAM and 1 (5.6%) patient had mild SAM (less than mild mitral regurgitation, peak left ventricular outflow tract gradient < 50 mm Hg) and were asymptomatic. No patients with postoperative SAM required reoperation after their initial surgery. The median echocardiographic follow-up was 1.3 years. During follow-up, 1 early death (noncardiac) and 2 late deaths (1 noncardiac, 1 of unknown etiology) occurred. CONCLUSIONS: SAM is a relatively frequent complication after MVRr and can occur intraoperatively or postoperatively. A systematic approach addressing perioperative SAM after MVRr yields excellent mid-term results. PMID- 22423604 TI - EVEREST II randomized clinical trial: predictors of mitral valve replacement in de novo surgery or after the MitraClip procedure. AB - OBJECTIVE: The Endovascular Valve Edge-to-Edge Repair Study (EVEREST II) is a prospective, multicenter, randomized controlled trial comparing percutaneous repair with the MitraClip device to mitral valve (MV) surgery in the treatment of mitral regurgitation. The present study analyzed the patient characteristics and treatment effects on mitral repair versus replacement. METHODS: Of 279 patients enrolled, 80 surgical patients underwent 82 MV operations and 178 underwent an initial MitraClip procedure, of whom 37 underwent a subsequent MV operation within 1 year of their index the MitraClip procedure. A logistic regression model was used to predict MV replacement according to valve pathology, etiology of mitral regurgitation, age, previous cardiac surgery, and treatment group. RESULTS: The rate of percutaneous or surgical MV repair at 1 year was 89% (158/178) in patients initially receiving the MitraClip device versus 84% (67/80) in the surgical patients (P = .36). Surgical repair was performed after the MitraClip procedure in 20 (54%) of 37 patients (P < .001 vs surgery). In both the MitraClip device and surgery groups, MV replacement was significantly associated with anterior leaflet pathology (P = .035). Logistic regression analysis showed that anterior leaflet pathology predicted MV replacement. In 5 (13.5%) of 37 patients undergoing surgery after MitraClip therapy, replacement was performed in part because of MV injury associated with the MitraClip procedure. CONCLUSIONS: These data suggest that anterior leaflet pathology is strongly associated with MV replacement in patients undergoing either de novo MV surgery or surgery after MitraClip therapy. MitraClip therapy has a repair rate similar to surgery through 1 year but also imparts a risk of replacement of a potentially repairable valve. PMID- 22423605 TI - Comparative effectiveness of minimally invasive versus traditional sternotomy mitral valve surgery in elderly patients. AB - OBJECTIVES: This study assessed comparative effectiveness of minimally invasive versus traditional sternotomy mitral valve surgery in elderly patients. METHODS: From January 1, 2000, to December 31, 2008, 1005 patients underwent isolated mitral valve surgery at our institution. Patients >= 75-years-old were included in analysis (sternotomy, n = 105; minimally invasive, n = 70). Clinical outcomes included bypass and crossclamp time, length of hospitalization, morbidity, and mortality. To assess resource use, total hospital costs and discharge location were analyzed. Three standardized inpatient functional status outcomes were also assessed. RESULTS: The minimally invasive approach was associated with a 9.2 minute longer crossclamp time (P = .037) and a 25.2-minute longer bypass time (P < .001). Minimally invasive surgery was associated with a 3.1-day shorter hospitalization (P = .033). There were no significant differences in rate of major postoperative complications (P = .085) or long-term survival (P = .60). Minimally invasive approach was associated with a $6721 lower median cost of hospitalization (P = .007) and more common discharge to home, routinely or with a health aide, rather than to rehabilitation (P = .021). Minimally invasive patients achieved faster rates of independent ambulation (P = .039) and independent sit-to-stand activity (P = .003), although there were no differences in time to independent stair climbing (P = .31). CONCLUSIONS: Among elderly patients, minimally invasive mitral valve surgery is associated with slightly longer crossclamp and bypass times but with equivalent morbidity and mortality and shorter hospitalization, decreased resource use, and improved postoperative functional status. PMID- 22423606 TI - Retraction: Vitamin C and asthma in children: modification of the effect by age, exposure to dampness and the severity of asthma. PMID- 22423607 TI - Commentary to accompany 'Predictors of outcome after endovascular repair for chronic type B dissection'. PMID- 22423608 TI - "Young women with PAD are at high risk of cardiovascular complications". PMID- 22423609 TI - Innate immunity markers in culprit plaques of acute myocardial infarction or stable angina. AB - We analyzed the innate immunity markers, C-reactive protein (CRP), serum amyloid P component (SAP) and pentraxin-3 (PTX-3), and metalloproteinase-9 (MMP-9) in coronary atherectomy tissues obtained from patients with acute ST elevation myocardial infarction (STEMI) (n=27) or stable angina (n=15). The relative areas immunopositive for CRP and SAP were similar in the two groups. In contrast, the proportion of areas immunopositive for PTX-3 and MMP-9 was higher in the STEMI group, compared to the stable angina group. PTX-3 or MMP-9-stained areas largely overlapped with those positive for CD68. We concluded that PTX-3 plays a role in the pathogenesis of STEMI. PMID- 22423610 TI - Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework. AB - BACKGROUND: Priority setting for artemisinin-based antimalarial drugs has become an integral part of malaria treatment policy change in malaria-endemic countries. Although these drugs are more efficacious, they are also more costly than the failing drugs. When Tanzania changed its National Malaria Treatment Policy in 2006, priority setting was an inevitable challenge. Artemether-lumefantrine was prioritised as the first-line drug for the management of uncomplicated malaria to be available at a subsidized price at public and faith-based healthcare facilities. METHODS: This paper describes the priority-setting process, which involved the selection of a new first-line antimalarial drug in the implementation of artemisinin-based combination therapy policy. These descriptions were further evaluated against the four conditions of the accountability for reasonableness framework. According to this framework, fair decisions must satisfy a set of publicity, relevance, appeals, and revision and enforcement conditions.In-depth interviews were held with key informants using pretested interview guides, supplemented with a review of the treatment guideline. Purposeful sampling was used in order to explore the perceptions of people with different backgrounds and perspectives. The analysis followed an editing organising style. RESULTS: Publicity: The selection decision of artemether-lumefantrine but not the rationale behind it was publicised through radio, television, and newspaper channels in the national language, Swahili. RELEVANCE: The decision was grounded on evidences of clinical efficacy, safety, affordability, and formulation profile. Stakeholders were not adequately involved. There was neither an appeals mechanism to challenge the decision nor enforcement mechanisms to guarantee fairness of the decision outcomes. CONCLUSIONS: The priority-setting decision to use artemether-lumefantrine as the first-line antimalarial drug failed to satisfy the four conditions of the accountability for reasonableness framework. In our understanding, this is the first study to evaluate priority-setting decisions for new drugs in Tanzania against the accountability for reasonableness framework. In addition to the demand for enhanced stakeholder involvement, publicity, and transparency, the study also calls for the institution of formal appeals, revision, and regulatory mechanisms in the future change of malaria treatment policies. PMID- 22423611 TI - The implementation of malaria intermittent preventive trialtreatment with sulphadoxine-pyrimethamine in infants reduced all-cause mortality in the district of Kolokani, Mali: results from a cluster randomized control. AB - BACKGROUND: Malaria intermittent preventive treatment of malaria in infant with sulphadoxine-pyrimethamine (IPTi-SP) reduced the incidence of malaria and anaemia by 30% and 20% respectively. The strategy is now a recommended policy for malaria control. However, there was no published study on the impact of the strategy on mortality. The present study assessed the impact of the implementation of IPTi-SP in health services in Mali on all-cause mortality. METHODS: The 22 health sub districts of the district of Kolokani were randomized at a 1:1 ratio to either receive IPTi-SP or to serve as a control. The IPTi-SP was implemented for two years starting December 2006. Information on births and deaths through 31 March, 2009 was collected on all children who reached four months of age on 1 December, 2006, likely to be exposed to the intervention in 75 localities randomly selected in each zone. RESULTS: A total of 5,882 children (2,869 from the intervention zone and 3,013 from the nonintervention zone) who reached four months of age between 1 December, 2006 and 1 December, 2008 were surveyed between the age of four months to the age of 18 months from 1 December, 2006 to 31 March, 2009. In the cohort of four to 18 months of age, the mortality rate per 1,000 children was 2.53 in the intervention zone compared to 3.46 in the nonintervention zone, gender and season adjusted mortality rate ratio (MRR) = 0.73 (95% CI 0.55-0.97, p = 0.029). In the cohort of the four to 12 months of age, mortality rates per 1,000 children were 2.22 in the intervention zone and 3.13 in the non intervention zone, MRR = 0.71 (95% CI 0.49-1.02, p = 0.064) adjusted for gender and season. CONCLUSION: The implementation of the IPTi-SP resulted in a substantial reduction in all-cause mortality in children. The results of this study support the adoption and the implementation of IPTi-SP as malaria control strategy. TRIAL REGISTRATION: ClinicalTrials.govNCT00766662. PMID- 22423612 TI - The role of the NTPDase enzyme family in parasites: what do we know, and where to from here? AB - Nucleoside triphosphate diphosphohydrolases (NTPDases, GDA1_CD39 protein superfamily) play a diverse range of roles in a number of eukaryotic organisms. In humans NTPDases function in regulating the inflammatory and immune responses, control of vascular haemostasis and purine salvage. In yeast NTPDases are thought to function primarily in the Golgi, crucially involved in nucleotide sugar transport into the Golgi apparatus and subsequent protein glycosylation. Although rare in bacteria, in Legionella pneumophila secreted NTPDases function as virulence factors. In the last 2 decades it has become clear that a large number of parasites encode putative NTPDases, and the functions of a number of these have been investigated. In this review, the available evidence for NTPDases in parasites and the role of these NTPDases is summarized and discussed. Furthermore, the processes by which NTPDases could function in pathogenesis, purine salvage, thromboregulation, inflammation and glycoconjugate formation are considered, and the data supporting such putative roles reviewed. Potential future research directions to further clarify the role and importance of NTPDases in parasites are proposed. An attempt is also made to clarify the nomenclature used in the parasite field for the GDA1_CD39 protein superfamily, and a uniform system suggested. PMID- 22423613 TI - Parasite glycans and antibody-mediated immune responses in Schistosoma infection. AB - Schistosome infections in humans are characterized by the development of chronic disease and high re-infection rates after treatment due to the slow development of immunity. It appears that anti-schistosome antibodies are at least partially mediating protective mechanisms. Efforts to develop a vaccine based on immunization with surface-exposed or secreted larval or worm proteins are ongoing. Schistosomes also express a large number of glycans as part of their glycoprotein and glycolipid repertoire, and antibody responses to those glycans are mounted by the infected host. This observation raises the question if glycans might also form novel vaccine targets for immune intervention in schistosomiasis. This review summarizes current knowledge of antibody responses and immunity in experimental and natural infections with Schistosoma, the expression profiles of schistosome glycans (the glycome), and antibody responses to individual antigenic glycan motifs. Future directions to study anti-glycan responses in schistosomiasis in more detail in order to address more precisely the possible role of glycans in antibody-mediated immunity are discussed. PMID- 22423614 TI - The intrinsic apoptosis pathways as a target in anticancer therapy. AB - Tumor cells need to disrupt apoptosis pathways to escape the cytotoxic action of oncogene activation and microenvironmental stress during the carcinogenic process. However, the cytotoxic action of classical chemotherapy, and radiotherapy includes the induction of apoptotic cell death. Therefore, apoptosis resistance of tumor cells contributes to the failure of chemotherapy and radiotherapy. During the last two decades, extensive research aimed at an improved understanding of the complex signaling pathways that control apoptosis execution in normal cells and of the endogenous factors that mediate apoptosis resistance of cancer cells. Among these, the Bcl-2 protein family attracted major attention for the development of compounds that specifically target apoptosis resistance of cancer cells. Bcl-2 proteins are master regulators of the intrinsic apoptosis pathway that is crucial for apoptosis execution in response to DNA damage. The review will highlight current knowledge on the regulation of apoptosis pathways and discuss several approaches that target the Bcl-2 rheostat to counteract tumor cell intrinsic apoptosis resistance that may therefore be of value for a biological modulation of apoptosis resistance. PMID- 22423615 TI - Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer. AB - BACKGROUND: Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For inoperable patients, we evaluated in this study intensity-modulated and image-guided radiotherapy (IMRT-IGRT) by helical tomotherapy. METHODS: Twenty-four CRC patients with <= 5 metastases were enrolled, receiving a dose of 50 Gy in fractions of 5 Gy. No limitations concerning dimension or localization of the metastases were imposed. Whole body PET-CT was performed at baseline and 3 months after the initiation of RT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0. RESULTS: A total of 53 metastases were treated. Seventeen patients (71%) received previously >= 1 line of chemotherapy for metastatic disease, displaying residual (n = 7) or progressive (n = 10) metabolic active oligometastatic disease at time of inclusion. Most common sites were the lung, liver and lymphnodes. One patient (4%) experienced grade 3 dysphagia. Twenty-two patients were evaluated by post treatment PET-CT. Twelve patients achieved a complete (n = 6) or partial (n = 6) metabolic response, resulting in an overall metabolic response rate of 55%. At a median follow-up of 10 months, 7 patients (29%) are in remission, of which 5 received previous chemotherapy with residual oligometastatic disease at time of inclusion. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 14% and 78%. CONCLUSIONS: Helical tomotherapy delivering 10 fractions of 5 Gy resulted in a metabolic response rate of 55%, and appeared to be attractive as consolidation of inoperable oligometastatic disease after effective chemotherapy. TRIAL REGISTRATION: Eudract 2008-008300-40; NCT00807313. PMID- 22423616 TI - Pleiotrophin expression and role in physiological angiogenesis in vivo: potential involvement of nucleolin. AB - BACKGROUND: Pleiotrophin (PTN) is a heparin-binding growth factor with significant role(s) in tumour growth and angiogenesis. Although implication of endogenous PTN has been studied in several in vivo models of tumour angiogenesis, its role in physiological angiogenesis has not been addressed. In the present work, we studied expression and functional significance of endogenous PTN during angiogenesis in the chicken embryo chorioallantoic membrane (CAM). METHODS: Using molecular, cellular and biochemical assays, we studied the expression pattern of PTN in CAM and human endothelial cells and its possible interaction with nucleolin (NCL). CAM cells were transfected with a pCDNA3.1 vector, empty (PC) or containing full length cDNA for PTN in antisense orientation (AS-PTN). Angiogenesis was estimated by measuring total vessel length. In vitro, human endothelial cells migration was studied by using a transwell assay, and down regulation of NCL was performed by using a proper siRNA. RESULTS: Endogenous PTN mRNA and protein levels, as well as protein levels of its receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta) were maximal at early stages, when CAM angiogenesis is active. Application of AS-PTN onto CAM at days of active angiogenesis was not toxic to the tissue and led to dose-dependent decreased expression of endogenous PTN, ERK1/2 activity and angiogenesis. Interestingly, endogenous PTN was also immunolocalized at the endothelial cell nucleus, possibly through interaction with NCL, a protein that has a significant role in the nuclear translocation of many proteins. Down-regulation of NCL by siRNA in human endothelial cells significantly decreased nuclear PTN, verifying this hypothesis. Moreover, it led to abolishment of PTN-induced endothelial cell migration, suggesting, for the first time, that PTN-NCL interaction has a functional significance. CONCLUSIONS: Expression of endogenous PTN correlates with and seems to be involved in angiogenesis of the chicken embryo CAM. Our data suggest that NCL may have a role, increasing the number of growth factors whose angiogenic/tumorigenic activities are mediated by NCL. PMID- 22423617 TI - Mapping the coverage of attributes in validated instruments that evaluate primary healthcare from the patient perspective. AB - BACKGROUND: Primary healthcare in developed countries is undergoing important reforms, and these require evaluation strategies to assess how well the population's expectations are being met. Although numerous instruments are available to evaluate primary healthcare (PHC) from the patient perspective, they do not all measure the same range of constructs. To analyze the extent to which important PHC attributes are covered in validated instruments measuring quality of care from the patient perspective. METHOD: We systematically identified validated instruments from the literature and by consulting experts. Using a Delphi consensus-building process, Canadian PHC experts identified and operationally defined 24 important PHC attributes. One team member mapped instrument subscales to these operational definitions; this mapping was then independently validated by members of the research team and conflicts were resolved by the PHC experts. RESULTS: Of the 24 operational definitions, 13 were evaluated as being best measured by patients, 10 by providers, three by administrative databases and one by chart audits (some being best measured by more than one source). Our search retained 17 measurement tools containing 118 subscales. After eliminating redundancies, we mapped 13 unique measurement tools to the PHC attributes. Accessibility, relational continuity, interpersonal communication, management continuity, respectfulness and technical quality of clinical care were the attributes widely covered by available instruments. Advocacy, management of clinical information, comprehensiveness of services, cultural sensitivity, family-centred care, whole-person care and equity were poorly covered. CONCLUSIONS: Validated instruments to evaluate PHC quality from the patient perspective leave many important attributes of PHC uncovered. A complete assessment of PHC quality will require adjusting existing tools and/or developing new instruments. PMID- 22423618 TI - Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance. AB - BACKGROUND: Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparumhistidine rich protein 2 (PfHRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the PfHRP2 antigenaemia following curative treatment in endemic regions. METHODS: A model of PfHRP2 production and decay was developed to mimic the kinetics of PfHRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate PfHRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of PfHRP2. RESULTS: Fitting of the PfHRP2 dynamics model indicated that in malaria naive hosts, P. falciparum parasites of the 3D7 strain produce 1.4 * 10-13 g of PfHRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of PfHRP2, it is predicted that as few as 8 parasites/MUL may be required to maintain a positive RDT in a chronic infection. CONCLUSIONS: The results of the model indicate that good quality PfHRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti-PfHRP2 antibodies. PMID- 22423619 TI - Environmental influences predominate in remission from alcohol use disorder in young adult twins. AB - BACKGROUND: Familial influences on remission from alcohol use disorder (AUD) have been studied using family history of AUD rather than family history of remission. The current study used a remission phenotype in a twin sample to examine the relative contributions of genetic and environmental influences to remission. METHOD: The sample comprised 6183 twins with an average age of 30 years from the Australian Twin Registry. Lifetime history of alcohol abuse and dependence symptoms and symptom recency were assessed with a structured telephone interview. AUD was defined broadly and narrowly as history of two or more or three or more abuse or dependence symptoms. Remission was defined as absence of symptoms at time of interview among individuals with lifetime AUD. Standard bivariate genetic analyses were conducted to derive estimates of genetic and environmental influences on AUD and remission. RESULTS: Environmental influences alone accounted for remission in males and for 89% of influences on remission in females, with 11% due to genetic influences shared with AUD, which decreased the likelihood of remission. For women, more than 80% of influences on remission were distinct from influences on AUD, and environmental influences were from individual experiences only. For men, just over 50% of influences on remission were distinct from those on AUD, and the influence of environments shared with the co-twin were substantial. The results for the broad and narrow phenotypes were similar. CONCLUSIONS: The current study establishes young adult remission as a phenotype distinct from AUD and highlights the importance of environmental influences on remission. PMID- 22423620 TI - pH-responsive one-dimensional periodic relief grating of polymer brush-gold nanoassemblies on silicon surface. AB - In this work, we focus on the fabrication of the nanoassemblies consisting of the poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) brushes and gold nanoparticles (AuNPs). The employed process involves grafting of the PDMAEMA chains on an underlying substrate in a brush conformation followed by the immobilization of surface functionalized AuNPs by means of physical interaction (electrostatic attraction, entanglement, and hydrogen bonding). Atomic force microscopy (AFM), X ray photoelectron spectroscopy (XPS), and UV-vis spectroscopy have been employed to characterize the prepared PDMAEMA-AuNP nanoassemblies. Polymer brushes possessing various thicknesses have been found to suppress the nanoparticles' aggregation and, hence, facilitate the surface coverage. Furthermore, we patterned the PDMAEMA-AuNP nanoassemblies as an one-dimensional periodic relief grating (OPRG). The subwavelength structure of OPRG has the optical features including artificial refractive index, form birefringence and resonance and band gap effects. A mean refractive index of the PDMAEMA-AuNP nanoassemblies can be controlled by the filling factors of the OPRG structure, so that a desired distribution of refractive index of the polymer brushes-gold OPRG under various stimuli can be realized. The employed approach is simple and highly versatile for the modification of surfaces with a wide range of NPs. PMID- 22423621 TI - Evidence-based, non-surgical treatments for vitiligo: a review. AB - Vitiligo is an acquired pigmentary disorder characterized by depigmented macules and patches secondary to the loss of functional melanocytes. It is a chronic disease that affects between 0.1% and 2% of the general population, affecting both sexes and all races. The appearance and the unpredictable course are psychologically and socially devastating. The success of current therapeutic options is limited. The objective of this review was to assess non-surgical treatments of vitiligo and to determine if comparing these studies can lead to (1) practical applications in the clinical setting and (2) recommendations for future research including study design and topics to be investigated further. Combination therapies were found to be more effective than monotherapy, and most combinations included a form of phototherapy, of which narrow-band-UVB was found to be most effective with the least adverse effects. Topical treatment with corticosteroids, immunomodulators, vitamin D analogs, and psoralens had mixed outcomes. Oral therapies including antioxidants were helpful adjuvants to treatment. Studies lacked consistent design, mechanism of disease assessment, and long-term follow-up. Sample size was also frequently limited. This review found that while several non-surgical therapies exist for the treatment of vitiligo, their usefulness, especially in the long term, is not well understood. Those studies that were able to elicit repigmentation often lacked an assessment on quality of life and/or patient satisfaction. More standardized methods of study design and assessment are needed to compare outcomes and make definitive conclusions on treatment effectiveness. PMID- 22423622 TI - Thermodynamic description of liquid-state limits. AB - A state of random close packing (RCP) of spheres is found to have a thermodynamic status and a fundamental role in the description of liquid-state equilibria. The RCP limiting amorphous ground state, with reproducible density and well characterized structure, is obtained by well-defined irreversible and reversible processes. The limiting packing fraction y(RCP) = 0.6366 +/- 0.0005 (Buffon's constant within the uncertainty), and a residual entropy per sphere DeltaS((RCP FCC)) is approximately equal to k(B) (Boltzmann's constant). Since the Mayer virial expansion does not represent dense fluid equations-of-state for densities exceeding the available-volume percolation transition (rho(pa)), we infer that a RCP state belongs to the same thermodynamic phase as prepercolation equilibrium dense hard-sphere fluid and likewise for hard-core fluids with attractive forces. Monte Carlo (MC) calculation of the liquid-state coexistence properties of square well (SW) attractive spheres, together with existing MC results for liquid-vapor coexistence in the SW fluid, support this conclusion. Further findings for liquid vapor coexistence limits are reported. The extremely weak second-order available volume percolation transition of the hard-sphere fluid is strengthened by square well perturbation as temperature is reduced. At the critical temperature, this transition becomes first order, whereupon a liquid at the percolation density coexists in thermodynamic equilibrium with its vapor at a lower density. The critical coexisting vapor density relates to the extended-volume bonded cluster percolation transition rho(pe)(lambda) defined for given well width (lambda). Taking experimental liquid argon data as an example, it can be seen that the thermodynamic description of the coexistence limits, found here for square-well fluids, applies to real liquids. PMID- 22423623 TI - Black sesame pigment: DPPH assay-guided purification, antioxidant/antinitrosating properties, and identification of a degradative structural marker. AB - An improved purification procedure leading to black sesame ( Sesamum Indicum L.) pigment was developed involving fat removal by treatment of ground black sesame seeds with dichloromethane followed by an optimized hydrolytic protocol with 6 M HCl, at 100 degrees C, overnight. The black pigment thus obtained displayed good antioxidant efficiency by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical assay (82% reduction at 0.5 mg/mL), good ferric ion-reducing capacity (61 MUM Trolox equivalent concentration at 0.5 mg/mL), and potent antinitrosating properties (74% inhibition of 2,3-diaminonaphthalene (DAN) nitrosation at gastric pH at 2.5 mg/mL). A synthetic pigment obtained by oxidative polymerization of coniferyl alcohol (polyconiferyl alcohol, PCA), the putative biosynthetic precursor to the sesame pigment, was characterized as a reference standard. FT IR spectra of the purified sesame pigment and PCA supported the structural similarity. HPLC analysis of degradation products by alkaline hydrogen peroxide of purified black sesame pigment showed the formation of vanillic acid (VA) as the main isolable fragment. Similar yields of VA were obtained by degradation of PCA. A positive correlation between VA yields and DPPH activity was determined in samples of different purities. It is suggested that VA is a structural marker of black sesame pigment, confirming the biosynthetic origin from coniferyl alcohol and pointing to the o-methoxyphenol motif as the key factor accounting for the potent antioxidant properties of the pigment. PMID- 22423624 TI - Patterns of expression of CD56 and CD117 on neoplastic plasma cells and association with genetically distinct subtypes of plasma cell myeloma. AB - Plasma cell neoplasms are common hematopoietic malignancies that recently have been shown to be driven by specific genetic events. In the past decade, immunophenotyping by flow cytometry has become an important tool in the characterization of plasma cells. However, the clinical and prognostic significance of antigenic expression remains unclear. We analyzed 102 cases of plasma cell neoplasm by flow cytometric immunophenotyping for expression of CD56 and CD117 and correlated the results with immunohistochemical and cytogenetic findings. Expression of CD56 and CD117 was associated with hyperdiploidy and the absence of CD117 expression was associated with different immunoglobulin heavy chain gene (IGH) translocations. Assessment of CD117 expression on neoplastic plasma cells by flow cytometry is superior to immunohistochemistry. Simultaneous assessment of CD56 and CD117 expression by flow cytometry is a sensitive method for diagnostic evaluation of plasma cell neoplasms, and furthermore may function as a rapid adjunctive test providing independent prognostic information in the absence of cytogenetic data. PMID- 22423625 TI - Synthesis of antifungal glucan synthase inhibitors from enfumafungin. AB - An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively. PMID- 22423626 TI - A non-acidic sulfaphenazole analog demonstrating high intrinsic clearance and selectivity by canine CYP2C21. AB - In contrast to human CYP2C9, non-human CYP2C enzymes do not appear to preferentially bind and metabolize anionic drugs. Using analogs of sulfaphenazole, the effect of an acidic sulfonamide group on apparent affinity and turnover rates was characterized with canine CYP2C21. Blocking the sulfonamide with a methyl group increased the intrinsic clearance by CYP2C21 > 100-fold and decreased K(m). Furthermore, CYP2C21 demonstrated selectivity for formation of the benzylic hydroxylation product and a high estimated f(m,CYP) value. The findings suggest that canine CYP2C21, unlike human CYP2C9, does not derive ligand binding affinity from an anion binding interaction with sulfaphenazole analogs. PMID- 22423627 TI - A new eudesmane sesquiterpene glycosides from Liriope muscari. AB - A new eudesmane sesquiterpene glycoside, ophiopogonoside B (1), along with five known compounds, ophiopogonoside A (2), ruscogenin-1-O-[beta-D-glucopyranosyl (1 > 2)]-[beta-D-xylopyranosyl (1 -> 3)]-beta-D-fucopyranoside (3), palmitic acid (4), palmitic acid glyceride (5), and beta-sitosterol-D-glucopyranoside (6),was isolated from the tuberous roots of Liriope muscari (Decn.) Bailey (Liliaceae). Their structures were confirmed by 1D and 2D NMR spectroscopy. Among them, compounds 1, 2, 4, and 5 were the first reported from the genus Liriope. Ophiopogonoside B (1) showed moderate inhibitory activity to glycogen phosphorylase a. PMID- 22423628 TI - Effects of long-term home-based exercise on health-related quality of life in patients with chronic neck pain: a randomized study with a 1-year follow-up. AB - PURPOSE: To evaluate whether long-term neck and upper body exercises conducted in economical community-based outpatient clinic and home-based settings could improve health-related quality of life (HRQoL)for individuals affected by chronic neck pain. The effect of baseline HRQoL and neck pain values on training adherence was also studied. METHODS: Subjects (n = 101, 91 women/10 men, mean age 41.0 +/- 9.5 years) with chronic non-specific neck pain were randomized to a combined strength-training and stretching-exercise group (CSSG, n = 49) or to a stretching exercise group (SG, n = 52). HRQoL was assessed at baseline and after 12 months using the RAND-36 questionnaire. Comparisons between groups were performed using bootstrap-type analysis of covariance. The impact of HRQoL and neck pain values on training adherence, determined using participants' exercise logs, was studied using generalized estimating equations. RESULTS: CSSG showed significant improvements in five and SG in four of eight of the HRQoL dimensions. There were no significant differences between the groups. Adherence to long-term training was only slightly affected by baseline-assessed HRQoL and neck pain values. CONCLUSIONS: The two training protocols were feasible and equally effective in improving HRQoL. Baseline HRQoL and pain values had only a minor effect on training adherence. IMPLICATIONS FOR REHABILITATION: * Long-term strength training and stretching are effective in improving HRQoL in people with chronic neck pain. * Baseline HRQoL and neck pain values have little effect on training adherence. PMID- 22423629 TI - An audit of secondary peritonitis at a tertiary care university hospital of Sindh, Pakistan. AB - OBJECTIVE: Peritonitis is the most common life threatening surgical emergency, which requires urgent surgical intervention and is a significant cause of morbidity and mortality. The objective of this study was to highlight the frequency of secondary peritonitis and to analyze the site and causes of perforation, in our tertiary care setup. METHODS: A retrospective analysis of 311 patients of secondary peritonitis was done from July 2008 to June 2010 at Liaquat University Hospital Jamshoro, Hyderabad, Sindh, Pakistan. All cases found to have peritonitis as a result of perforation of any part of gastrointestinal tract at the time of surgery were included in the study. All cases with either primary peritonitis or that due to anastomotic dehiscence were excluded. RESULTS: A total of 311 patients were studied. Most of the patients were males (77%) and (89%) were in the third and fourth decades of life. Majority of the patients presented with pain (97%) associated with bowel symptoms. Most common site of perforation was small bowel (ileal 59%, jujenal 2%). In this series, most common risk factor of perforation was typhoid (43%). Ileostomy was the most commonly performed procedure. Overall morbidity was 48.5% and mortality was 17%. CONCLUSION: Considering the relatively higher rate of typhoid perforation quoted in this study, it is vital that typhoid fever ought to be eliminated by improved sanitation and immunizing programmes, otherwise surgeons will be confronted with its complications. PMID- 22423630 TI - Photo-induced macromolecular functionalization of cellulose via nitroxide spin trapping. PMID- 22423631 TI - Mobility of functionalized quantum dots and a model polystyrene nanoparticle in saturated quartz sand and loamy sand. AB - Quantum dots (QDs) are one example of engineered nanoparticles (ENPs) with demonstrated toxic effects. Yet, little is known about the behavior of QDs in the natural environment. This study assessed the transport of two commercial carboxylated QDs (CdTe and CdSe) and carboxylated polystyrene latex (nPL) as a model nanoparticle using saturated laboratory-scale columns. The influence of solution ionic strength (IS) and cation type (K(+) or Ca(2+)) on the transport potential of these ENPs was examined in two granular matrices - quartz sand and loamy sand. The retention of all three particles was generally low in the quartz sand columns within the range of studied IS (0.1-100 mM) for the monovalent salt (KCl). In contrast, the retention of the three ENPs in the quartz sand was significant in the presence of 10 mM Ca(2+). Moreover, ENP attachment efficiencies (alpha) were enhanced by at least 1 order of magnitude in columns packed with loamy sand (for IS between 0.1-10 mM KCl). Although all three ENPs used here are carboxylated, they differ in the type of surface coating (e.g., choice of polymers or polyelectrolytes). Regardless of the surface coatings, the three ENPs exhibit comparable mobility in the quartz sand. However, the ENPs demonstrate variable transport potential in loamy sand suggesting that differences in the binding affinities of surface-modified ENPs for specific soil constituents can play a key role in the fate of ENPs in soils. PMID- 22423632 TI - DNA microarray study of genes differentiating acute myocardial infarction patients from healthy persons. AB - OBJECTIVE: Using oligonucleotide microarrays HG-U133A, we here studied the expression levels of genes that could differentiate between patients with myocardial infarction (MI) from healthy subjects, as well as to select among such genes those that seem crucial for manifestation of cardiovascular diseases. MATERIALS AND METHODS: The microarray study was conducted using material derived from blood samples collected in 17 individuals. RESULTS: Analysis of gene expression data from 17 microarrays allowed identification of 28 genes strongly differentiating the examined groups. CONCLUSION: The differentiating genes that we tracked down indicate possible linkage with atherosclerotis and could be a prognostic marker for development of cardiovascular diseases. PMID- 22423633 TI - Biomechanical comparison of anterior cervical spine instrumentation techniques with and without supplemental posterior fusion after different corpectomy and discectomy combinations: Laboratory investigation. AB - OBJECT: The objective of this study was to compare the stiffness and range of motion (ROM) of 4 cervical spine constructs and the intact condition. The 4 constructs consisted of 3-level anterior cervical discectomy with anterior plating, 1-level discectomy and 1-level corpectomy with anterior plating, 2-level corpectomy with anterior plating, and 2-level corpectomy with anterior plating and posterior fixation. METHODS: Eight human cadaveric fresh-frozen cervical spines from C2-T2 were used. Three-dimensional motion analysis with an optical tracking device was used to determine motion following various reconstruction methods. The specimens were tested in the following conditions: 1) intact; 2) segmental construct with discectomies at C4-5, C5-6, and C6-7, with polyetheretherketone (PEEK) interbody cage and anterior plate; 3) segmental construct with discectomy at C6-7 and corpectomy of C-5, with PEEK interbody graft at the discectomy level and a titanium cage at the corpectomy level; 4) corpectomy at C-5 and C-6, with titanium cage and an anterior cervical plate; and 5) corpectomy at C-5 and C-6, with titanium cage and an anterior cervical plate, and posterior lateral mass screw-rod system from C-4 to C-7. All specimens underwent a pure moment application of 2 Nm with regards to flexion-extension, lateral bending, and axial rotation. RESULTS: In all tested motions the statistical comparison was significant between the intact condition and the 2 level corpectomy with anterior plating and posterior fixation construct. All other statistical comparisons between the instrumented constructs were not statistically significant except between the 3-level discectomy with anterior plating and the 2-level corpectomy with anterior plating in axial rotation. There were no statistically significant differences between the 1-level discectomy and 1-level corpectomy with anterior plating and the 2-level corpectomy with anterior plating in any tested motion. There was also no statistical significance between the 3-level discectomy with anterior plating and the 2-level corpectomy with anterior plating and posterior fixation. CONCLUSIONS: This study demonstrates that segmental plate fixation (3-level discectomy) affords the same stiffness and ROM as circumferential fusion in 2-level cervical spine corpectomy in the immediate postoperative setting. This obviates the need for staged circumferential procedures for multilevel cervical spondylotic myelopathy. Given that the posterior segmental instrumentation confers significant stability to a multilevel cervical corpectomy, the surgeon should strongly consider the placement of segmental posterior instrumentation to significantly improve the overall stability of the fusion construct after a 2-level cervical corpectomy. PMID- 22423634 TI - Resting-state fMRI as a biomarker for Alzheimer's disease? AB - Previous work indicates that resting-state functional magnetic resonance imaging (fMRI) is sensitive to functional brain changes related to Alzheimer's disease (AD) pathology across the clinical spectrum. Cross-sectional studies have found functional connectivity differences in the brain's default mode network in aging, mild cognitive impairment, and AD. In addition, two recent longitudinal studies have shown that functional connectivity changes track AD progression. This earlier work suggests that resting-state fMRI may be a promising biomarker for AD. However, some key issues still need to be addressed before resting-state fMRI can be successfully applied clinically. In a previous issue of Alzheimer's Research & Therapy, Vemuri and colleagues discuss the use of resting-state fMRI in the study of AD. In this commentary, I will highlight and expand upon some of their main conclusions. PMID- 22423635 TI - Discovering free energy basins for macromolecular systems via guided multiscale simulation. AB - An approach for the automated discovery of low free energy states of macromolecular systems is presented. The method does not involve delineating the entire free energy landscape but proceeds in a sequential free energy minimizing state discovery; i.e., it first discovers one low free energy state and then automatically seeks a distinct neighboring one. These states and the associated ensembles of atomistic configurations are characterized by coarse-grained variables capturing the large-scale structure of the system. A key facet of our approach is the identification of such coarse-grained variables. Evolution of these variables is governed by Langevin dynamics driven by thermal-average forces and mediated by diffusivities, both of which are constructed by an ensemble of short molecular dynamics runs. In the present approach, the thermal-average forces are modified to account for the entropy changes following from our knowledge of the free energy basins already discovered. Such forces guide the system away from the known free energy minima, over free energy barriers, and to a new one. The theory is demonstrated for lactoferrin, known to have multiple energy-minimizing structures. The approach is validated using experimental structures and traditional molecular dynamics. The method can be generalized to enable the interpretation of nanocharacterization data (e.g., ion mobility-mass spectrometry, atomic force microscopy, chemical labeling, and nanopore measurements). PMID- 22423636 TI - Biological activities of purified marennine, the blue pigment responsible for the greening of oysters. AB - Marennine, the blue pigment produced by the diatom Haslea ostrearia , exists in two different forms, the intra- and extracellular forms. We investigated the antibacterial, antiviral, and antiproliferative properties of both of these forms. Both forms of marennine inhibited the development of marine bacteria, in particular the pathogenic organism Vibrio aesturianus , at concentrations as low as 1 MUg/mL, but they did not display any effect on a wide range of pathogenic bacteria that are relevant for food safety. Both forms of the pigment produced by H. ostrearia also exhibited antiviral activity against the HSV1 herpes virus, with intra- and extracellular marennine having EC(50) values of 24.0 and 27.0 MUg/mL, respectively. These values are 2 orders of magnitude higher than the value for the reference drug, Zovirax. Moreover, both forms of marennine were effective in slowing or inhibiting the proliferation of cancer cells. This study confirms the potential of marennine as a biologically active organic molecule, which could have a protective effect on bivalves, which filter seawater and fix the pigment on their gills. Moreover, marennine could be used in food engineering and chemistry as a natural blue pigment. However, despite that it is eaten and possibly assimilated by green oyster consumers, it also deserves in depth evaluation before being considered for use as a nutraceutical. PMID- 22423637 TI - Design and testing of an MRI-compatible cycle ergometer for non-invasive cardiac assessments during exercise. AB - BACKGROUND: Magnetic resonance imaging (MRI) is an important tool for cardiac research, and it is frequently used for resting cardiac assessments. However, research into non-pharmacological stress cardiac evaluation is limited. METHODS: We aimed to design a portable and relatively inexpensive MRI cycle ergometer capable of continuously measuring pedalling workload while patients exercise to maintain target heart rates. RESULTS: We constructed and tested an MRI-compatible cycle ergometer for a 1.5 T MRI scanner. Resting and sub-maximal exercise images (at 110 beats per minute) were successfully obtained in 8 healthy adults. CONCLUSIONS: The MRI-compatible cycle ergometer constructed by our research group enabled cardiac assessments at fixed heart rates, while continuously recording power output by directly measuring pedal force and crank rotation. PMID- 22423638 TI - Integrated approach to prevent functional decline in hospitalized elderly: the Prevention and Reactivation Care Program (PReCaP). AB - BACKGROUND: Hospital related functional decline in older patients is an underestimated problem. Thirty-five procent of 70-year old patients experience functional decline during hospital admission in comparison with pre-illness baseline. This percentage increases considerably with age. METHODS/DESIGN: To address this issue, the Vlietland Ziekenhuis in The Netherlands has implemented an innovative program (PReCaP), aimed at reducing hospital related functional decline among elderly patients by offering interventions that are multidisciplinary, integrated and goal-oriented at the physical, social, and psychological domains of functional decline. DISCUSSION: This paper presents a detailed description of the intervention, which incorporates five distinctive elements: (1) Early identification of elderly patients with a high risk of functional decline, and if necessary followed by the start of the reactivation treatment within 48 h after hospital admission; (2) Intensive follow-up treatment for a selected patient group at the Prevention and Reactivation Centre (PRC); (3) Availability of multidisciplinary geriatric expertise; (4) Provision of support and consultation of relevant professionals to informal caregivers; (5) Intensive follow-up throughout the entire chain of care by a casemanager with geriatric expertise. Outcome and process evaluations are ongoing and results will be published in a series of future papers. TRIAL REGISTRATION: The Netherlands National Trial Register: NTR2317. PMID- 22423639 TI - Effect of iron concentration on the growth of carbon nanotubes on clay surface. AB - The successful growth of carbon nanotubes (CNTs) on montmorillonite (MMT) precursors treated with different concentrations of ferric nitrate at 50 degrees C (MMT(Fe)-50) and 100 degrees C (MMT(Fe)-100) was achieved via the in situ chemical vapor deposition (CVD) of acetylene. The as-obtained MMT-CNTs composites were characterized using X-ray diffraction, inductively coupled plasma emission spectrometry, scanning electron microscopy, and transmission electron microscopy. All Fe(3+) ions were intercalated into the MMT interlayers at either 50 or 100 degrees C in the case of [Fe(3+)]/[clay] = 1. However, the iron content in MMT(Fe)-100 increased rapidly with the amount of ferric nitrate added, whereas the iron content in MMT(Fe)-50 did not exhibit significant changes. On the other hand, the physical and chemical adsorption of Fe(3+) onto the MMT surface was believed to be responsible for the great diversity of iron contents in MMT(Fe)-50 and MMT(Fe)-100 at the same [Fe(3+)]/[clay] ratios. Moreover, the CNT yield showed variation similar to the iron content because the CNTs yield depends primarily on the amount of catalyst available. The CNTs embedded onto MMT(Fe)-100 exhibited narrower diameter distributions than those on the MMT(Fe)-50 precursors, with more CNTs with diameters less than 50 nm on the former. It is suggested that a porous structure with many pores formed by iron species and MMT laminas is related to the morphology and structure of CNTs embedded on the surface of MMT. PMID- 22423642 TI - In vitro dissolution profile of two commercially available iron preparations. AB - BACKGROUND: Current scientific evidence indicates that anemia in pregnancy, regardless of severity, is associated with an increased risk of maternal and fetal mortality. There is little published information about the bioavailability and bioequivalence of formulations containing both iron and folic acid. However, in vitro dissolution studies can provide important information on the likely relative bioavailability of various formulations. AIM: The objective of our study was to compare the in vitro dissolution of two similar commercially available formulations of iron- and folic acid-containing supplements, Folifer(r) (Bialport - Produtos Farmaceuticos, S.A., Portugal) and Ferroliver(r) (SM Pharma c.a., Venezuela), in order to determine the in vitro availability of their iron content. Folifer(r) and Ferroliver(r) were chosen because they contained similar amounts of elemental iron. METHODS: The amount of iron released from each tablet was evaluated over a 4-hour period in three dissolution media replicating gastric or intestinal juices with pH values ranging from 1.5 to 6.9. The samples were then titrated with a solution of cerium ammonium sulfate in order to calculate the amount of iron released in each specific pH condition. The percentage of dissolved iron was calculated as a cumulative frequency, using the percentage of dissolved iron at all timepoints. The dissolution similarity between the two commercially available formulations was evaluated using the &U0192;(2) statistic formula. RESULTS: During a 4-hour dissolution test, Folifer(r) released 59.4 mg of iron compared with 48.5 mg released by Ferroliver(r). The value obtained for the similarity factor, an indicator of likely bioequivalence, was 41. CONCLUSION: These data suggest that Folifer(r) releases more iron than Ferroliver(r), and that the two formulations are not equivalent in vitro. The superior dissolution of ferrous sulfate with Folifer(r) compared with ferrous fumarate in Ferroliver(r) might be responsible for the observed difference. PMID- 22423644 TI - A new phenolic compound from the stem of Hymenocardia wallichii. AB - Thirteen compounds were isolated from the stem of Hymenocardia wallichii Tul. A new phenolic compound, wallinol (1), was found in this plant. The other chemical components were squalene (2), stigmasterol (4), homopterocarpin (5), two triterpenes (3 and 13), two benzaldehyde derivatives (6 and 9), three cinnamyl derivatives (7, 11, and 12), a coumarin (8), and a monoglyceride (10). Their structures were elucidated on the basis of spectroscopic methods including IR, HR ESI-MS, and 1D and 2D NMR data. PMID- 22423645 TI - Selective C-acylation of 2-aminoimidazo[1,2-a]pyridine: application to the synthesis of imidazopyridine-fused [1,3]diazepinones. AB - A series of 20 optically pure 3,4-dihydro-5H-pyrido[1',2':1,2]imidazo[4,5 d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2 aminoimidazo[1,2-a]pyridine at C-3. PMID- 22423646 TI - Setting priorities for land management to mitigate climate change. AB - BACKGROUND: No consensus has been reached how to measure the effectiveness of climate change mitigation in the land-use sector and how to prioritize land use accordingly. We used the long-term cumulative and average sectorial C stocks in biomass, soil and products, C stock changes, the substitution of fossil energy and of energy-intensive products, and net present value (NPV) as evaluation criteria for the effectiveness of a hectare of productive land to mitigate climate change and produce economic returns. We evaluated land management options using real-life data of Thuringia, a region representative for central-western European conditions, and input from life cycle assessment, with a carbon-tracking model. We focused on solid biomass use for energy production. RESULTS: In forestry, the traditional timber production was most economically viable and most climate-friendly due to an assumed recycling rate of 80% of wood products for bioenergy. Intensification towards "pure bioenergy production" would reduce the average sectorial C stocks and the C substitution and would turn NPV negative. In the forest conservation (non-use) option, the sectorial C stocks increased by 52% against timber production, which was not compensated by foregone wood products and C substitution. Among the cropland options wheat for food with straw use for energy, whole cereals for energy, and short rotation coppice for bioenergy the latter was most climate-friendly. However, specific subsidies or incentives for perennials would be needed to favour this option. CONCLUSIONS: When using the harvested products as materials prior to energy use there is no climate argument to support intensification by switching from sawn-wood timber production towards energy-wood in forestry systems. A legal framework would be needed to ensure that harvested products are first used for raw materials prior to energy use. Only an effective recycling of biomaterials frees land for long-term sustained C sequestration by conservation. Reuse cascades avoid additional emissions from shifting production or intensification. PMID- 22423648 TI - Capillary forces between sediment particles and an air-water interface. AB - In the vadose zone, air-water interfaces play an important role in particle fate and transport, as particles can attach to the air-water interfaces by action of capillary forces. This attachment can either retard or enhance the movement of particles, depending on whether the air-water interfaces are stationary or mobile. Here we use three standard PTFE particles (sphere, circular cylinder, and tent) and seven natural mineral particles (basalt, granite, hematite, magnetite, mica, milky quartz, and clear quartz) to quantify the capillary forces between an air-water interface and the different particles. Capillary forces were determined experimentally using tensiometry, and theoretically assuming volume-equivalent spherical, ellipsoidal, and circular cylinder shapes. We experimentally distinguished between the maximum capillary force and the snap-off force when the air-water interface detaches from the particle. Theoretical and experimental values of capillary forces were of similar order of magnitude. The sphere gave the smallest theoretical capillary force, and the circular cylinder had the largest force due to pinning of the air-water interface. Pinning was less pronounced for natural particles when compared to the circular cylinder. Ellipsoids gave the best agreement with measured forces, suggesting that this shape can provide a reasonable estimation of capillary forces for many natural particles. PMID- 22423647 TI - Memory training interventions for older adults: a meta-analysis. AB - A systematic review and meta-analysis of memory training research was conducted to characterize the effect of memory strategies on memory performance among cognitively intact, community-dwelling older adults, and to identify characteristics of individuals and of programs associated with improved memory. The review identified 402 publications, of which 35 studies met criteria for inclusion. The overall effect size estimate, representing the mean standardized difference in pre-post change between memory-trained and control groups, was 0.31 standard deviations (SD; 95% confidence interval (CI): 0.22, 0.39). The pre-post training effect for memory-trained interventions was 0.43 SD (95% CI: 0.29, 0.57) and the practice effect for control groups was 0.06 SD (95% CI: 0.05, 0.16). Among 10 distinct memory strategies identified in studies, meta-analytic methods revealed that training multiple strategies was associated with larger training gains (p=0.04), although this association did not reach statistical significance after adjusting for multiple comparisons. Treatment gains among memory-trained individuals were not better after training in any particular strategy, or by the average age of participants, session length, or type of control condition. These findings can inform the design of future memory training programs for older adults. PMID- 22423649 TI - Inter-physician agreement on the readiness of sick-listed employees to return to work. AB - PURPOSE: To determine the agreement between occupational physician (OP) ratings of an employee's readiness to return to work (RRTW). METHOD: Anonymized written vignettes of 132 employees, sick-listed for at least 3 weeks, were reviewed by 5 OPs. The OPs intuitively rated RRTW as the ability (knowledge and skills) and willingness (motivation and confidence) of sick-listed employees to resume work. Inter-OP percentages of agreement were calculated and Cohen's kappas (kappa) were determined to correct for agreement by chance. RESULTS: The percentage of agreement between OPs was 57% (range 39-89%) on the ability and 63% (range 48 87%) on the willingness of sick-listed employees to resume work. The mean kappa was 0.14 (range from -0.21 to 0.79) for ability and 0.25 (range from -0.11 to 0.74) for willingness. The OP-rating of RRTW of employees sick-listed with mental disorders did not differ from the OP-rating of RRTW of employees with musculoskeletal disorders. CONCLUSION: The inter-OP agreement on intuitively rated RRTW showed a wide variability, which accentuates the need for instruments to establish an employee's RRTW and for training in giving well founded return to work recommendations. PMID- 22423650 TI - The role of natural killer cells in immunity against multiple myeloma. AB - Multiple myeloma (MM) is an essentially incurable malignancy associated with profound immune dysregulation. Despite the advent of novel therapies and improvements in survival over the last 10 years, death from progressive disease and infection remains a common outcome. Natural killer (NK) cells are CD56(+)CD3( ) large granular lymphocytes that constitute a key cellular subset of the innate immune system. For over 30 years, the relationship between NK cells and MM has been described in the clinical setting and characterized in the laboratory. Data suggest that NK cells may play a role in the immune response to MM; however, this effect is lost due to immunoevasive strategies utilized by MM. Nevertheless, progress in the understanding of the mechanisms perpetuating this effect have led to new opportunities to recover or augment NK cell function therapeutically in MM. In fact, the novel agents thalidomide, lenalidomide and bortezomib all confer anti-MM effects, in part, through enhancement of NK cell function. Currently, the development of therapies designed specifically to increase NK cell cytotoxicity against MM is under way. The present review summarizes the current understanding of the NK cell versus MM effect and characterizes therapeutic interventions that exert anti-MM efficacy via NK cell function against the disease. PMID- 22423651 TI - Demonstration of microchimerism in pregnant sows and effects of congenital PRRSV infection. AB - The presence of foreign cells within the tissue/circulation of an individual is described as microchimerism. The main purpose of the present investigation was to study if microchimerism occurs in healthy sows/fetuses and if porcine reproductive and respiratory syndrome virus (PRRSV) infection influences this phenomenon. Six dams were inoculated intranasally with PRRSV and three non inoculated dams served as controls. Male DNA was detected in female fetal sera of all dams via PCR. Male DNA was also detected in the maternal circulation. Sex typing FISH showed the presence of male cells in the female fetal organs and vice versa. PRRSV infection did not influence microchimerism, but might misuse maternal and sibling microchimeric cells to enter fetuses. PMID- 22423652 TI - Control of anti-thrombogenic properties: surface-induced self-assembly of fibrinogen fibers. AB - Wound healing is a complex process initiated by the formation of fibrin fibers and endothelialization. Normally, this process is triggered in a wound by thrombin cleavage of fibrinopeptides on fibrinogen molecules, which allows them to self spontaneously-assemble into large fibers that provide the support structure of the clot and promote healing. We have found that the fibrous structures can also form without thrombin on most polymer or metal surfaces, including those commonly used for stents. We show that the relatively hydrophobic E and D regions of the fibrinogen molecule are adsorbed on these surfaces, exposing the alphaC domains, which in turn results in the formation of large fiber structures that promote endothelial cell adhesion. We show that the entire process can be suppressed when stents or other substrates are coated with polymers that are functionalized to bind the alphaC domains, leading to the development of potentially nonthrombogenic implant materials. PMID- 22423653 TI - HMGB1: a smoking gun in lupus nephritis? PMID- 22423654 TI - [Vulnerability of retinal ganglion cells to mitochondrial defects]. PMID- 22423655 TI - [In vitro antibiotic susceptibility to fluoroquinolones]. AB - OBJECTIVE: To determine the antibiotic susceptibility of bacteria recovered from cultures of ocular infections in the Fundacion Oftalmologica de Santander - Clinica Carlos Ardila Lulle (FOSCAL). MATERIALS AND METHODS: Retrospective descriptive study of a series of registries of cultures of samples from ocular surfaces and intraocular fluids from the OCULAB-FOSCAL laboratory in Floridablanca (Colombia) made between January and December of 2007. Antibiotic sensitivity screening by the method of Kirby-Bauer with impregnated Sensi-DiscsTM of determined antibiotic concentrations was performed. RESULTS: A total of 352 samples were studied: 160 from conjunctiva, 150 from cornea and 42 from intraocular fluids. Of the total of the samples more than one microorganism was recovered 45.65% of the samples. Gram positive and Gram negative bacteria were identified in 78.7 and 18.4%, respectively. Resistance to gatifloxacin, moxifloxacin, ciprofloxacin and levofloxacin was observed in 6.3, 8.9, 33.2 and 35.6%, respectively, of Gram positive bacteria. Resistance to gatifloxacin, moxifloxacin, ciprofloxacin and levofloxacin was also observed in 7.4, 16.7, 16.7%and 25.9%, respectively, of Gram negative bacteria. The overall bacterial resistance (Gram positive and Gram negative) to moxifloxacin was 10.15%, and to gatifloxacin it was 6.46%, being which showed a statistically significant difference (P<.05). CONCLUSIONS: In our study the development of bacterial resistance to fourth generation fluoroquinolones was demonstrated in ocular samples. However, lower levels of resistance to fourth generation fluoroquinolones compared with that of third and second generation were found, particularly to Gram positive. Gatifloxacin showed lower resistance levels than moxifloxacin. Nevertheless, interpretation of this superiority must be made with caution in the clinical field, since other factors, like tissue penetration and in vivo activity, must be taken into account. PMID- 22423656 TI - [Conjunctival myeloid sarcoma in acute myeloblastic leukemia-M1]. AB - CLINICAL CASE: A 69-year-old man with a history of acute myeloblastic leukemia-M1 presented with bilateral conjunctival injection. Ophthalmological examination revealed lesions located at the upper tarsal conjunctiva of the right eye and lower tarsal conjunctiva of both eyes. Histological and immunohistochemical studies confirmed conjunctival myeloid sarcoma. The patient died due to multiorgan failure three months later. DISCUSSION: Extramedullary recurrence of leukemia can appear as an ocular manifestation that brings about a recurrence of the leukemia, leading to a poor prognosis. PMID- 22423657 TI - [Conjunctival keratoacanthoma: diagnosis, treatment and monitoring by conjunctival impression cytology]. AB - CASE REPORT: We present a case report of a 28-year-old patient with a lesion that is compatible both clinically and histopathologically with conjunctival keratoacanthoma. The treatment given was complete excision and 0.04% mitomycin C eye drops in the postoperative period. The outcome was a complete clinical remission during the follow-up period (6 months). DISCUSSION: It is important to make a correct differential diagnosis between keratoacanthoma and squamous cell carcinoma, as well as carrying out close monitoring after surgery due to the possibility of relapse and conversion to squamous cell carcinoma. For this reason, we propose the use of conjunctival impression cytology as a non-invasive method for monitoring such patients. PMID- 22423658 TI - [Serpiginous choroiditis in a patient with uterine cervix carcinoma]. AB - CASE REPORT: We report the case of a 70-year-old patient with serpiginous choroiditis and uterine cervix carcinoma. DISCUSSION: The etiology of serpiginous choroiditis is unknown, but similar lesions have been described in association with systemic lupus erythematosus, non-Hodgkin lymphoma, Crohn's disease, sarcoidosis, tuberculosis, herpes virus infection, autoimmune hepatitis and lung carcinoma. PMID- 22423659 TI - [Neurotaping: new therapeutic approach in essential blepharospasm]. PMID- 22423660 TI - [Macular toxoplasmosis and intravitreal clindamycin: an alternative to oral treatment]. PMID- 22423661 TI - [Phototoxicity (2): reflection of sunlight on large surfaces]. PMID- 22423662 TI - [Look up-look down optical illusions (XIX Century)]. PMID- 22423663 TI - A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line. AB - BACKGROUND: The Signal Transducer and Activator of Transcription 3 (STAT3) is activated in tumor cells, and STAT3-inhibitors are able to induce the death of those cells. Decoy oligodeoxynucleotides (dODNs), which bind to the DNA Binding Domain (DBD) of STAT3, are efficient inhibitors. However, they also inhibit STAT1, whose activity is essential not only to resistance to pathogens, but also to cell growth inhibition and programmed cell death processes. The aim of this study was to design STAT3-specific dODNs which do not affect STAT1-mediated processes. RESULTS: New dODNs with a hairpin (hpdODNs) were designed. Modifications were introduced, based on the comparison of STAT3- and STAT1-DBD interactions with DNA using 3D structural analyses. The designed hpdODNs were tested for their ability to inhibit STAT3 but not STAT1 by determining: i) cell death in the active STAT3-dependent SW480 colon carcinoma cell line, ii) absence of inhibition of interferon (IFN) gamma-dependent cell death, iii) expression of STAT1 targets, and iv) nuclear location of STAT3 and STAT1. One hpdODN was found to efficiently induce the death of SW480 cells without interfering with IFNgamma activated STAT1. This hpdODN was found in a complex with STAT3 but not with STAT1 using an original in-cell pull-down assay; this hpdODN also did not inhibit IFNgamma-induced STAT1 phosphorylation, nor did it inhibit the expression of the STAT1-target IRF1. Furthermore, it prevented the nuclear transfer of STAT3 but not that of IFNgamma-activated STAT1. CONCLUSIONS: Comparative analyses at the atomic level revealed slight differences in STAT3 and STAT1 DBDs' interaction with their DNA target. These were sufficient to design a new discriminating hpdODN that inhibits STAT3 and not STAT1, thereby inducing tumor cell death without interfering with STAT1-dependent processes. Preferential interaction with STAT3 depends on oligodeoxynucleotide sequence modifications but might also result from DNA shape changes, known to modulate protein/DNA interactions. The finding of a STAT3-specific hpdODN establishes the first rational basis for designing STAT3 DBD-specific inhibitors. PMID- 22423664 TI - Fanconi anaemia with bilateral diffuse pulmonary arterio venous fistulae: a case report. AB - BACKGROUND: We report a patient with cytogenetically confirmed Fanconi anaemia with associated diffuse bilateral pulmonary arterio-venous fistulae. This is only the second reported case of diffuse pulmonary arterio-venous fistulae with Fanconi anaemia. CASE PRESENTATION: A 16 year old Sri Lankan boy, with a cytogenetically confirmed Fanconi anaemia was admitted to University Medical Unit, National Hospital of Sri Lanka for further assessment and treatment. Both central and peripheral cyanosis plus clubbing were noted on examination. The peripheral saturation was persistently low on room air and did not improve with supplementary Oxygen. Contrast echocardiography failed to demonstrate an intra cardiac shunt but showed early crossover of contrast, suggesting the possibility of pulmonary arterio-venous fistulae. Computed tomography pulmonary angiogram was inconclusive. Subsequent right heart catheterisation revealed bilateral diffuse arterio-venous fistulae not amenable for device closure or surgical intervention. CONCLUSION: To our knowledge, this is the second reported patient with diffuse pulmonary arterio-venous fistulae associated with Fanconi anaemia. We report this case to create awareness among clinicians regarding this elusive association. We recommend screening patients with Fanconi anaemia using contrast echocardiography at the time of assessment with transthoracic echocardiogram. Though universal screening may be impossible given the cost constraints, such screening should at least be performed in patients with clinical evidence of desaturation or when a therapeutic option such as haematopoietic stem cell transplantation is considered. Treatment of pulmonary arteriovenous fistulae would improve patient outcome as desaturation by shunting worsens the anaemic symptoms by reducing the oxygen carrying capacity of blood. PMID- 22423665 TI - Pioglitazone and bladder cancer in human studies: is it diabetes itself, diabetes drugs, flawed analyses or different ethnicities? AB - This article reviews human observations on pioglitazone and bladder cancer risk. The PROspective pioglitAzone Clinical Trial In macroVascular Events trial showed an imbalance in bladder cancer between users of pioglitazone and placebo (14 versus six cases, p = 0.069). However, after excluding bladder cancer probably ascribed to other etiology, a blind assessment concluded that the imbalance might not be related to pioglitazone. Epidemiologic studies conducted in the United States and France using insurance databases independently suggested that pioglitazone use for >2 years might confer a 20%-40% higher risk. Another study evaluating bladder cancer risk in diabetic patients using the National Health Insurance in Taiwan did not find any incident bladder cancer case among 422 pioglitazone users for a follow-up of up to 3 years. Because observational studies may suffer from selection and information bias, and inadequate adjustment for confounders may inflate the estimated risk, causal inference from these studies should be interpreted with caution. While investigating cancer risk associated with a medication, indication bias should also be attended, especially when the medication is used at a late stage of the disease. Because pioglitazone is usually a second or third line antidiabetic agent, the users are always characterized by older age, longer diabetes duration, poorer glycemic control, and higher rates of complications and comorbidities. Biased estimates will also result if these differences are not appropriately addressed in the analyses. Current evidence neither concludes nor excludes a causal role of pioglitazone on bladder cancer. Clinical trials aiming at evaluating the risk of cancer associated with a medication is not ethical and may not be expected to provide an answer on the issue of pioglitazone-related bladder cancer. However, a meta analysis using all available clinical trials to compare the bladder cancer risk between pioglitazone and comparators will be helpful. Well-conducted epidemiologic observational studies are probably other options. Because bladder cancer incidence and their risk factors may differ significantly among different ethnicities, a clarification of such a link in different ethnicities is needed, better by using long-term databases with large and representative sample size and appropriate adjustment for confounders. Furthermore, the interactions with other comorbidities and concomitant medications should be addressed. PMID- 22423666 TI - Endoscopic submucosal dissection for early esophageal neoplasia: a single center experience in South Taiwan. AB - BACKGROUND/PURPOSE: Endoscopic submucosal dissection (ESD) is an advanced endoscopic procedure to resect early gastrointestinal neoplasm. It is technically more difficult and risky when used to treat early esophageal tumors. We report our experiences related to performing ESD for early esophageal neoplasia. The efficacy, complications, and outcome were also analyzed. METHODS: From December 2007 to April 2010, 22 patients with documented early esophageal neoplasm underwent ESD. All patients completed a meticulous endoscopic examination using conventional endoscopy followed by narrow-band imaging. Lugol's staining was performed to identify the margin of the suspicious lesion. Insulation-tipped diathermic knife 2 was used for ESD. RESULTS: A total of 26 neoplastic lesions (including 13 tumors with high-grade dysplasia, 12 tumors with squamous cell carcinoma, and one tumor with adenocarcinoma) in 22 patients were enrolled. All patients were men. The mean age was 47.6 +/- 8.6 years (range, 30-68 years). The mean size of tumors was 33.7 +/- 21.7 mm (range, 8-80 mm). ESD was performed for 24 lesions in 20 patients. The mean size of resected specimens was 43.1 +/- 19.2 mm (range, 15-90 mm). The mean operation time was 92.7 +/- 69 minutes (range, 30 310 minutes). There were three ESD-related complications, including one with delayed bleeding, one with subcutaneous emphysema, and one with perforation. Two patients received additional operations after ESD due to deep submucosal invasion by cancer. Three lesions in two patients (12.5%) developed post-ESD esophageal stricture that needed repeated endoscopic bougination. There was no procedure related mortality. No local recurrence was found during the follow-up period. CONCLUSION: ESD is a promising local curative treatment option for early esophageal neoplasia in Taiwan. However, this procedure may result in complications that are worth noting, especially post-ESD esophageal stricture. Education regarding this procedure and more hands-on training will facilitate endoscopists to improve the outcomes of patients undergoing this procedure. PMID- 22423667 TI - High false negative rate of Tc-99m MDP whole-body bone scintigraphy in detecting skeletal metastases for patients with hepatoma. AB - BACKGROUND/PURPOSE: Technetium-99m methylene diphosphonate (Tc-99m MDP) whole body bone scintigraphy (BS) has been widely used for detecting bone metastases. The aim of this study is to investigate the diagnostic accuracy of BS in detecting skeletal metastases for hepatocellular carcinoma (HCC) patients. In addition, the anatomic distribution of the metastatic bone lesions and the prognoses of the HCC patients are also analyzed. METHODS: We retrospectively reviewed BS results of 179 consecutive HCC patients from January 2005 to December 2006 in our institution. The false negative (FN) rate, sensitivity, and specificity of BS were evaluated by patient-based and region-based analyses. RESULTS: A total of 59 patients (33.0%) were confirmed of bone metastases. A total of 25 of these 59 patients (46.3%) had at least one lesion categorized as BS FN, and the bone metastatic status for 10 patients (17.0%) was underestimated by BS. The most observed metastatic site was spine while the most observed sites with FN of BS were the lower extremity. In total, there were 122 metastatic regions and 33 regions (27.0%) were FN of BS. Patients without any metastases survived significantly longer than any of other groups with metastases. CONCLUSION: High FN rate of Tc-99m MDP BS in detecting metastatic bone lesions for HCC patients was observed. In our opinion, careful history taking, meticulous examination, and a high index of suspicion are important for HCC patients with unexplained progressive pain in the musculoskeletal system. Even with negative results from Tc-99m MDP BS, the possibility of skeletal metastases cannot be indiscriminately excluded. PMID- 22423668 TI - Clinical experience of extracorporeal membrane oxygenation for acute respiratory distress syndrome associated with pneumonia in children. AB - BACKGROUND/PURPOSE: To describe a single center's experience with pediatric patients receiving extracorporeal membrane oxygenation (ECMO) for respiratory failure due to acute respiratory distress syndrome (ARDS) associated with pneumonia and to investigate the factors associated with mortality. METHODS: Retrospective chart review of all pediatric patients receiving ECMO for severe ARDS associated with pneumonia and sepsis from December 2001 to October 2009 in the pediatric intensive care unit (ICU) and cardiovascular surgery ICU at a tertiary medical center, to investigate the factors associated with mortality. RESULTS: Twelve patients had pneumonia and sepsis with progression to ARDS. The duration of intubation prior to ECMO was 19.92+/-10.40 hours. The duration of ECMO support was 241.08+/-194.93 hours. The range of PaO(2)/FiO(2) was 42-69.9, alveolar-arterial oxygen gradient (AaDO(2)) 602-645, and oxygenation index (OI) 27.4-68. The pre-ECMO intubation duration in the initial venoarterial ECMO group was significantly different from the venovenous ECMO group (9.4+/-10.93 vs. 151.25+/-152.16 hours). The overall survival to lung recovery rate was 66.7% (8/12) and survival to discharge rate 58.3%. The survival rate to lung recovery improved from 20% (between 2001 and 2003) to 100% (after 2004). Between the survival and nonsurvival groups, only ICU days and total intubated days were significantly longer in survivors. Although without statistical significance, the nonsurvivors tended to have lower white blood cell counts, higher C-reactive protein (CRP), and longer pre-ECMO intubation time. Seven of the 12 patients had bacterial pneumonia, higher CRP and creatinine values, and a lower hospital survival rate compared to the nonbacterial group (42.8% vs. 80%). CONCLUSION: Application of ECMO in pediatric patients with severe ARDS seems effective in improving survival, even under the conditions of pneumonia with septic shock. PMID- 22423669 TI - The influence of a behavior modification interventional program on body mass index in obese adolescents. AB - BACKGROUND/PURPOSE: The prevalence of obesity and overweight among children and adolescents is increasing rapidly. The present research was performed to determine the influence of a ''behavior modification'' program on body mass index (BMI) in obese public high school students in Iran. METHODS: In this study, 152 adolescence and their parents were selected from 12 high schools of Khorram Abad from 2004 to 2006, and they were randomly assigned to either the intervention or the control groups. The "behavior modification" interventional program consisted of nutritional education, modifying dietary habits, teaching exercise programs, teaching nutritional facts to the parents, and performing exercises 3 days a week. The height and weight as well as waist, hip, and wrist circumferences of the participants were measured before and after implementing the interventional program. BMI and waist to hip ratio (WHR) were calculated. The adolescents and parents completed a nutrition knowledge questionnaire. Adolescents also completed the Beck's Depression Questionnaire. RESULTS: Adolescent's mean weight, BMI, and waist and hip circumferences decreased significantly after implementing the interventional program, in the intervention group (p<=0.001). In addition, the students' and parents' nutrition knowledge increased in the intervention group after implementing the interventional program (p<0.046). The symptoms of depression decreased and the frequency of students without symptoms of depression increased in the case group, but it did not reveal a statistically significant difference between case and control groups. CONCLUSION: The ''behavior modification'' interventional program is effective in reducing BMI in obese students, and therefore, school principals and planners can play an important role in controlling obesity by implementing this program via the students, their parents, and the school staff. PMID- 22423670 TI - Is wider surgical margin justified for better clinical outcomes in patients with resectable hepatocellular carcinoma? AB - BACKGROUND/PURPOSE: Surgical resection for hepatocellular carcinoma (HCC) is regarded as a curable treatment; however, the postoperative recurrence still poses a challenge to surgeons. The effect of surgical margin on long-term outcome is still controversial, although it has been considered as the treatment-related risk factor for recurrence. A precise assessment of the effects of surgical margin on clinical outcome is required to clarify the issue. METHODS: A retrospective study was conducted on 407 patients with microscopically complete resection of HCC; they were divided into three groups with surgical margin negative by 1-5 mm (Group A, n = 156), 6-10 mm (Group B, n = 109), and wider than 10 mm (Group C, n = 142). The groups were compared for clinicopathologic characteristics, perioperative features, postoperative recurrence, and long-term outcome. RESULTS: The median follow-up time for all patients was 72.97 months. Recurrence rates were similar among these groups. There was no significant difference in the overall 1-, 3-, and 5-year actual survival rates for the groups on the log-rank test (p = 0.073). After controlling the independent risks for disease-free survival, there was also no significant difference in the 1-, 3-, and 5-year disease-free survival rates for the groups (p = 0.354). The patients with wider surgical margin had worse perioperative outcomes; more patients in this group needed blood transfusion (p < 0.001) and more patients suffered from postoperative complications (p = 0.020). They also had higher in-hospital mortality rate than that of other groups (1.41% vs. 0.64%). CONCLUSION: No superiority was seen in patients with wider surgical margin in either perioperative features or long-term outcome. PMID- 22423671 TI - Role of flexible transnasal esophagoscopy and patient education in the management of globus pharyngeus. AB - BACKGROUND/PURPOSE: Globus pharyngeus and dysphagia are common complaints of patients referred to ear, nose, and throat (ENT) clinics. We aimed to establish an efficient method to rule out the presence of malignancy in patients with globus pharyngeus and dysphagia. METHODS: The use of flexible transnasal esophagoscopy (TNE) was evaluated in 30 patients with globus pharyngeus and 6 patients with dysphagia. The patients were immediately informed of the findings on TNE examination, and then treatments were planned. All patients were treated with lansoprazole for 2 weeks and provided education on lifestyle changes at the initial examination and at the 3-month follow-up. RESULTS: The patients reported an improvement in symptoms of globus pharyngeus after treatment (p<0.001). Follow up TNE confirmed improvement with less dysphagia, erythema, and vocal cord edema evident (all p<0.001). CONCLUSION: The use of TNE and patient education are efficient management strategies for patients with symptoms of globus pharyngeus and dysphagia. PMID- 22423672 TI - Recurrence of primary aldosteronism after percutaneous ethanol injection. AB - Adrenalectomy is the definite treatment for aldosterone-producing adenoma (APA). Percutaneous ethanol or acetic acid injection with computed tomography (CT) guidance has been described as a safe, noninvasive, and effective alternative treatment modality in patients with high surgical risk. We report on a man who was 49 years of age and presented with treatment-resistant hypertension and was later diagnosed with APA. CT-guided percutaneous ethanol injection (PEI) was performed for this high surgical risk patient. He had aldosteronism recurrence 4 years after the ethanol injection, so a second PEI was performed. The tumor size was reduced and his blood pressure was normalized. Therefore, we suggest that clinicians should closely check aldosterone to renin ration and potassium level if percutaneous chemical ablation is considered in functioning adrenal adenomas. PMID- 22423673 TI - Cough-induced rib fracture in a young healthy man. PMID- 22423674 TI - New detection modality for label-free quantification of DNA in biological samples via superparamagnetic bead aggregation. AB - Combining DNA and superparamagnetic beads in a rotating magnetic field produces multiparticle aggregates that are visually striking, enabling label-free optical detection and quantification of DNA at levels in the picogram per microliter range. DNA in biological samples can be quantified directly by simple analysis of optical images of microfluidic wells placed on a magnetic stirrer without prior DNA purification. Aggregation results from DNA/bead interactions driven either by the presence of a chaotrope (a nonspecific trigger for aggregation) or by hybridization with oligonucleotides on functionalized beads (sequence-specific). This paper demonstrates quantification of DNA with sensitivity comparable to that of the best currently available fluorometric assays. The robustness and sensitivity of the method enable a wide range of applications, illustrated here by counting eukaryotic cells. Using widely available and inexpensive benchtop hardware, the approach provides a highly accessible low-tech microscale alternative to more expensive DNA detection and cell counting techniques. PMID- 22423675 TI - Occupation-differential construct validity of the Job Content Questionnaire (JCQ) psychological job demands scale with physical job demands items: a mixed methods research. AB - The construct validity of the Job Content Questionnaire (JCQ) psychological demands scale in relationship to physical demands has been inconsistent. This study aims to test quantitatively and qualitatively whether the scale validity differs by occupation. Hierarchical clustering analyses of 10 JCQ psychological and physical demands items were conducted in 61 occupations from two datasets: one of non-faculty workers at a university in the United States (6 occupations with 208 total workers) and the other of a Belgian working population (55 occupations with 13,039 total workers). The psychological and physical demands items overlapped in 13 of 61 occupation-stratified clustering analyses. Most of the overlaps occurred in physically-demanding occupations and involved the two psychological demands items, 'work fast' and 'work hard'. Generally, the scale reliability was low in such occupations. Additionally, interviews with eight university workers revealed that workers interpreted the two psychological demands items differently by the nature of their tasks. The scale validity was occupation-differential. PRACTITIONER SUMMARY: The JCQ psychological job demands scale as a job demand measure has been used worldwide in many studies. This study indicates that the wordings of the 'work fast' and 'work hard' items of the scale need to be reworded enough to differentiate mental and physical job demands as intended, 'psychological.' PMID- 22423676 TI - Increasing work-time influence: consequences for flexibility, variability, regularity and predictability. AB - This quasi-experimental study investigated how an intervention aiming at increasing eldercare workers' influence on their working hours affected the flexibility, variability, regularity and predictability of the working hours. We used baseline (n = 296) and follow-up (n = 274) questionnaire data and interviews with intervention-group participants (n = 32). The work units in the intervention group designed their own intervention comprising either implementation of computerised self-scheduling (subgroup A), collection of information about the employees' work-time preferences by questionnaires (subgroup B), or discussion of working hours (subgroup C). Only computerised self-scheduling changed the working hours and the way they were planned. These changes implied more flexible but less regular working hours and an experience of less predictability and less continuity in the care of clients and in the co-operation with colleagues. In subgroup B and C, the participants ended up discussing the potential consequences of more work-time influence without actually implementing any changes. PRACTITIONER SUMMARY: Employee work-time influence may buffer the adverse effects of shift work. However, our intervention study suggested that while increasing the individual flexibility, increasing work-time influence may also result in decreased regularity of the working hours and less continuity in the care of clients and co-operation with colleagues. PMID- 22423677 TI - Cognitive process modelling of controllers in en route air traffic control. AB - In recent years, various efforts have been made in air traffic control (ATC) to maintain traffic safety and efficiency in the face of increasing air traffic demands. ATC is a complex process that depends to a large degree on human capabilities, and so understanding how controllers carry out their tasks is an important issue in the design and development of ATC systems. In particular, the human factor is considered to be a serious problem in ATC safety and has been identified as a causal factor in both major and minor incidents. There is, therefore, a need to analyse the mechanisms by which errors occur due to complex factors and to develop systems that can deal with these errors. From the cognitive process perspective, it is essential that system developers have an understanding of the more complex working processes that involve the cooperative work of multiple controllers. Distributed cognition is a methodological framework for analysing cognitive processes that span multiple actors mediated by technology. In this research, we attempt to analyse and model interactions that take place in en route ATC systems based on distributed cognition. We examine the functional problems in an ATC system from a human factors perspective, and conclude by identifying certain measures by which to address these problems. This research focuses on the analysis of air traffic controllers' tasks for en route ATC and modelling controllers' cognitive processes. PRACTITIONER SUMMARY: This research focuses on an experimental study to gain a better understanding of controllers' cognitive processes in air traffic control. We conducted ethnographic observations and then analysed the data to develop a model of controllers' cognitive process. This analysis revealed that strategic routines are applicable to decision making. PMID- 22423678 TI - Influence of risk expectation on haptically cued corrective manoeuvres during near lane departure. AB - Some driving devices are designed to prevent road departures. One such device, motor priming (MP), provides small pulses to the steering wheel towards the lane centre, without correcting the trajectory itself. Compared with the other lane departure warning systems, its higher efficacy has been demonstrated; it is hypothesised that this relies on the action of haptic cues at the sensorimotor level (Navarro, J., Mars, F., and Hoc, J.M., 2007. Lateral control assistance for car drivers: a comparison of motor priming and warning systems. Human Factors, 49 (5), 950-960). The way in which corrective manoeuvres, primed by MP, can be influenced by processes that operate at higher levels of cognitive control, such as risk evaluation, is an issue. Results showed that MP improved all indicators of steering efficiency, starting with reaction times. Risk expectation and situation analysis did not influence reaction times but came into play soon after the corrective manoeuvre was initiated. Thus, although MP triggered the response at the sensorimotor level, higher levels of cognition (symbolic control) quickly modulated the execution of the corrective manoeuvre. PRACTITIONER SUMMARY: This paper showed that corrective manoeuvres following directional pulses on the steering wheel (motor priming) are modulated by risk expectation. The conclusion may be of interest for designers of haptics-based automation such as lane departure warning and lane keeping assistance systems. PMID- 22423679 TI - Power grip force is modulated in repeated elbow movement. AB - The objective of this study was to quantitatively investigate the modulation of power grip force under repeated elbow movement and its relation to muscle cocontraction and potential risk of developing cumulative trauma disorders (CTD). Thirteen right-handed participants without any neuromuscular disorders were recruited. Participants were instructed to hold a digital dynamometer in the hand with three levels of grip forces (20%, 40% and 60% of the maximum grip force) and perform repeated arm movement in the sagittal plane at three speeds (slow, self paced and fast) with the upper arm voluntarily held by side by the participant. With the increase of motion rate and target force level, the grip force fluctuation, finger flexor muscle activities, elbow muscles cocontraction and apparent stiffness were significantly increased (p < 0.01). This study suggests that the power grip coupled with fast arm movement be avoided as much as possible in the workplace. PRACTITIONER SUMMARY: Power grip is usually accompanied with arm movement in workplaces and the increased physical demand might result in higher muscle activities and potentially higher risk of repetitive musculoskeletal injuries. PMID- 22423680 TI - Phase change materials and the perception of wetness. AB - Phase change materials (PCMs) are increasingly incorporated in textiles in order to serve as a thermal buffer when humans change from a hot to a cold environment and the reverse. Due to the absence of wetness sensors in the skin, cooling of the skin may be perceived as a sensation of wetness instead of cold. In order to investigate if this phenomenon occurs when manipulating textiles, nine subjects were asked to touch or manipulate PCM-treated and untreated fabrics. In 75% of the cases, the subjects indicated that the treated material felt wetter than the untreated material independent of the way the textiles were manipulated. We conclude that incorporating PCMs in textiles may lead to a feeling of wetness which might be uncomfortable. Therefore, we recommend investigating a change in cooling properties to minimise this feeling. PRACTITIONER SUMMARY: This article describes a psychophysical experiment into the sensation of wetness of textiles treated with phase change materials. It was found that in 75% of the cases, subjects found the treated fabric to feel wetter than the untreated. This may affect the comfort of wearing clothes made of these textiles. PMID- 22423681 TI - Pulse propagation in an elastic medium with quadratic nonlinearity (L). AB - This letter examines the propagation of an acoustic pulse in an elastic medium with weak quadratic nonlinearity. Both a displacement pulse and a stress pulse of arbitrary shapes are used to generate the wave motion in the solid. By obtaining the explicit solutions for arbitrary pulse shapes, it is shown that for a sinusoidal tone-burst, in addition to a second order harmonic field, a radiation induced static strain field is also generated. These results help clarify some confusion in the recent literature regarding the shape of the propagating static displacement pulse. PMID- 22423682 TI - Green's functions for a volume source in an elastic half-space. AB - Green's functions are derived for elastic waves generated by a volume source in a homogeneous isotropic half-space. The context is sources at shallow burial depths, for which surface (Rayleigh) and bulk waves, both longitudinal and transverse, can be generated with comparable magnitudes. Two approaches are followed. First, the Green's function is expanded with respect to eigenmodes that correspond to Rayleigh waves. While bulk waves are thus ignored, this approximation is valid on the surface far from the source, where the Rayleigh wave modes dominate. The second approach employs an angular spectrum that accounts for the bulk waves and yields a solution that may be separated into two terms. One is associated with bulk waves, the other with Rayleigh waves. The latter is proved to be identical to the Green's function obtained following the first approach. The Green's function obtained via angular spectrum decomposition is analyzed numerically in the time domain for different burial depths and distances to the receiver, and for parameters relevant to seismo-acoustic detection of land mines and other buried objects. PMID- 22423683 TI - Velocity and attenuation of scalar and elastic waves in random media: a spectral function approach. AB - This paper investigates the scattering of scalar and elastic waves in two-phase materials and single-mineral-cubic, hexagonal, orthorhombic-polycrystalline aggregates with randomly oriented grains. Based on the Dyson equation for the mean field, explicit expressions for the imaginary part of Green's function in the frequency-wavenumber domain (omega, p), also known as the spectral function, are derived. This approach allows the identification of propagating modes with their relative contribution, and the computation of both attenuation and phase velocity for each mode. The results should be valid from the Rayleigh (low frequency) to the geometrical optics (high-frequency) regime. Comparisons with other approaches are presented for both scalar and elastic waves. PMID- 22423684 TI - Reflectance of acoustic horns and solution of the inverse problem. AB - A method is described for solving the inverse problem of determining the profile of an acoustic horn when time-domain reflectance (TDR) is known only at the entrance. The method involves recasting Webster's horn equation in terms of forward and backward propagating wave variables. An essential feature of this method is a requirement that the backward propagating wave be continuous at the wave-front at all locations beyond the entrance. Derivation of the inverse solution raises questions about the meaning of causality in the context of wave propagation in non-uniform tubes. Exact reflectance expressions are presented for infinite exponential, conical and parabolic horns based on exact solutions of the horn equation. Diameter functions obtained with the inverse solution are a good match to all three horn profiles. PMID- 22423685 TI - Propagation of guided waves through weak penetrable scatterers. AB - The scattering of a scalar wave propagating in a waveguide containing weak penetrable scatterers is inspected in the Born approximation. The scatterers are of arbitrary shape and present a contrast both in density and in wavespeed (or bulk modulus), a situation that can be translated in the context of SH waves, water waves, or transverse electric/transverse magnetic polarized electromagnetic waves. For small size inclusions compared to the waveguide height, analytical expressions of the transmission and reflection coefficients are derived, and compared to results of direct numerical simulations. The cases of periodically and randomly distributed inclusions are considered in more detail, and compared with unbounded propagation through inclusions. Comparisons with previous results valid in the low frequency regime are proposed. PMID- 22423686 TI - On acoustic propagation in three-dimensional rectangular ducts with flexible walls and porous linings. AB - The focus of this article is toward the development of hybrid analytic-numerical mode-matching methods for model problems involving three-dimensional ducts of rectangular cross-section and with flexible walls. Such methods require first closed form analytic expressions for the natural fluid-structure coupled waveforms that propagate in each duct section and second the corresponding orthogonality relations. It is demonstrated how recent theory [Lawrie, Proc. R. Soc. London, Ser. A 465, 2347-2367 (2009)] may be extended to a wide class of three-dimensional ducts, for example, those with a flexible wall and a porous lining (modeled as an equivalent fluid) or those with a flexible internal structure, such as a membrane (the "drum-like" silencer). Two equivalent expressions for the eigenmodes of a given duct can be formulated. For the ducts considered herein, the first ansatz is dependent on the eigenvalues/eigenfunctions appropriate for wave propagation in the corresponding two-dimensional flexible-walled duct, whereas the second takes the form of a Fourier series. The latter offers two advantages: no "root-finding" is involved and the method is appropriate for ducts in which the flexible wall is orthotropic. The first ansatz, however, provides important information about the orthogonality properties of the three-dimensional eigenmodes. PMID- 22423687 TI - The effect of dissipation on the resistive admittance of an elastic medium. AB - The effect of dissipation on the real part of the admittance of an elastic half space is typically thought to be unimportant if the loss factor zeta of the elastic medium is small. However, dissipation induces losses in the near field of the source and, provided the size of the source is small enough, this phenomenon can be more important than elastic wave radiation. Such losses give rise to a fundamental limit in the quality factor of an oscillator attached to a substrate. Near field losses associated with strains in the elastic substrate can actually be larger than intrinsic losses in the oscillator itself if the internal friction of the substrate is larger than the internal friction of the oscillator. For a uniform stress applied to a disk of radius a, a monopole source, such phenomena become significant for k(L)a pi* resonant excitation at both the carbon and oxygen 1s ionization edges opens pathways to potential surfaces in highly bent geometries in the dication. Evidence for a complete deformation of the molecule is found in the coincident detection of C(+) and O(2)(+) ions. The distinct alignment of this fragmentation channel indicates rapid deformation and subsequent fragmentation. Investigation of the complete atomization dynamics in the dication leading to asymmetric charge separation shows that the primary dissociation mechanisms, sequential, concerted, and asynchronous concerted, are correlated to specific fragment kinetic energies. The study shows that the bond angle in fragmentation can extend below 20 degrees . PMID- 22423835 TI - Accurate quantum wave packet calculations for the F + HCl -> Cl + HF reaction on the ground 1(2)A' potential energy surface. AB - We present converged exact quantum wave packet calculations of reaction probabilities, integral cross sections, and thermal rate coefficients for the title reaction. Calculations have been carried out on the ground 1(2)A' global adiabatic potential energy surface of Deskevich et al. [J. Chem. Phys. 124, 224303 (2006)]. Converged wave packet reaction probabilities at selected values of the total angular momentum up to a partial wave of J = 140 with the HCl reagent initially selected in the v = 0, j = 0-16 rovibrational states have been obtained for the collision energy range from threshold up to 0.8 eV. The present calculations confirm an important enhancement of reactivity with rotational excitation of the HCl molecule. First, accurate integral cross sections and rate constants have been calculated and compared with the available experimental data. PMID- 22423836 TI - Spectroscopic investigations of ThF and ThF+. AB - The electronic spectra of ThF and ThF(+) have been examined using laser induced fluorescence and resonant two-photon ionization techniques. The results from high level ab initio calculations have been used to guide the assignment of these data. Spectra for ThF show that the molecule has an X (2)Delta(3/2) ground state. The upper spin-orbit component, X (2)Delta(5/2) was found at an energy of 2575(15) cm(-1). The low-lying states of ThF(+) were probed using dispersed fluorescence and pulsed field ionization-zero kinetic energy (PFI-ZEKE) photoelectron spectroscopy. Vibronic progressions belonging to four electronic states were identified. The lowest energy states were clearly (1)Sigma(+) and (3)Delta(1). Although the energy ordering could not be rigorously determined, the evidence favors assignment of (1)Sigma(+) as the ground state. The (3)Delta(1) state, of interest for investigation of the electron electric dipole moment, is just 315.0(5) cm(-1) above the ground state. The PFI-ZEKE measurements for ThF yielded an ionization energy of 51 581(3) cm(-1). Molecular constants show that the vibrational constant increases and the bond length shortens on ionization. This is consistent with removal of a non-bonding Th-centered 6d or 7s electron. Laser excitation of ThF(+) was used to probe electronically excited states in the range of 19,000-21,500 cm(-1). PMID- 22423837 TI - Fragment momentum distributions obtained from coupled electron-nuclear dynamics. AB - We theoretically investigate fragmentation processes induced by femtosecond laser pulses within a model which incorporates electronic and nuclear motion. Single pulse excitation leads to diffraction patterns in the electron momentum distribution which depend on the nature of the electronic state and also on the nuclear charge distribution. Additional structures appear in the nuclear momentum distribution if two time-delayed pulses produce fragments in the same dissociation channel. It is shown that these functions are modified by the electronic degree-of-freedom. A simultaneous excitation of two different electronic states results in further interferences which are related to electronic wave-packet dynamics on the attosecond time-scale. PMID- 22423838 TI - Vibrationally resolved photoionization of N2 near threshold. AB - A recently developed velocity map imaging spectrometer has been used to study the photoionization of molecular nitrogen near threshold. The potentialities of the spectrometer have been exploited to measure simultaneously the energy and angular distribution of the photoelectrons corresponding to the residual N(2)(+) X(2)Sigma(g) v = 0-3 ion states. In a single experiment all the experimental observables, i.e., the total and partial cross sections, their branching ratios and the asymmetry parameter of the angular distributions have been determined. PMID- 22423839 TI - Photoelectron spectroscopy and density functional calculations of CuSi(n)- (n = 4 18) clusters. AB - We conducted a combined anion photoelectron spectroscopy and density functional theory study on the structural evolution of copper-doped silicon clusters, CuSi(n)(-) (n = 4-18). Based on the comparison between the experiments and theoretical calculations, CuSi(12)(-) is suggested to be the smallest fully endohedral cluster. The low-lying isomers of CuSi(n)(-) with n >= 12 are dominated by endohedral structures, those of CuSi(n)(-) with n < 12 are dominated by exohedral structures. The most stable structure of CuSi(12)(-) is a double chair endohedral structure with the copper atom sandwiched between two chair style Si(6) rings or, in another word, encapsulated in a distorted Si(12) hexagonal prism cage. CuSi(14)(-) has an interesting C(3h) symmetry structure, in which the Si(14) cage is composed by three four-membered rings and six five membered rings. PMID- 22423840 TI - Very accurate potential energy curve of the He2+ ion. AB - A very accurate ground-state potential energy curve (PEC) of the He(2)(+) molecule is calculated with 1200 explicitly correlated Gaussian functions with shifted centers in the range between 0.9 and 100 a(0). The calculations include the adiabatic corrections determined for the (3)He(4)He(+), (3)He(2)(+), and (4)He(2)(+) isotopologues. The absolute accuracy of the PEC is better than 0.05 cm(-1) and that of the adiabatic corrections is around 0.01 cm(-1). The depths of the PECs augmented with the adiabatic corrections for the three isotopologues are: 19 956.708 cm(-1) for (4)He(2)(+), 19 957.054 cm(-1) for (3)He(4)He(+), and 19 957.401 cm(-1) for (3)He(2)(+). The rovibrational energies are also determined. For (3)He(4)He(+) the computed rovibrational transitions corresponding to the nu = 1-0 band differ from the experiment by less than 0.005 cm(-1). For the rovibrational transitions corresponding to the nu = 23-22 band the difference is around 0.012 cm(-1). Presently, this represents the best agreement between theory and experiment for He(2)(+). PMID- 22423841 TI - A photoelectron spectroscopy and ab initio study of B21-: negatively charged boron clusters continue to be planar at 21. AB - The structures and chemical bonding of the B(21)(-) cluster have been investigated by a combined photoelectron spectroscopy and ab initio study. The photoelectron spectrum at 193 nm revealed a very high adiabatic electron binding energy of 4.38 eV for B(21)(-) and a congested spectral pattern. Extensive global minimum searches were conducted using two different methods, followed by high level calculations of the low-lying isomers. The global minimum of B(21)(-) was found to be a quasiplanar structure with the next low-lying planar isomer only 1.9 kcal/mol higher in energy at the CCSD(T)/6-311-G* level of theory. The calculated vertical detachment energies for the two isomers were found to be in good agreement with the experimental spectrum, suggesting that they were both present experimentally and contributed to the observed spectrum. Chemical bonding analyses showed that both isomers consist of a 14-atom periphery, which is bonded by classical two-center two-electron bonds, and seven interior atoms in the planar structures. A localized two-center two-electron bond is found in the interior of the two planar isomers, in addition to delocalized multi-center sigma and pi bonds. The structures and the delocalized bonding of the two lowest lying isomers of B(21)(-) were found to be similar to those in the two lowest energy isomers in B(19)(-). PMID- 22423842 TI - Icosahedral to double-icosahedral shape transition of copper clusters. AB - The lowest-energy isomers of Cu(N) clusters for N = 20-30 are identified using an unbiased search algorithm and density functional theory calculations. The low energy structures over this size range are dominated by those based on a 13-atom icosahedral (I(h)) core and a 19-atom double icosahedron (DI(h)) core. A transition in the ground-state isomers from I(h)-based to DI(h)-based structures is predicted overt N = 21-23. We discuss this transition in the broader context of the growth pattern for Cu(N) over N = 2-30 that features regions of gradual evolution in which atoms successively add to the cluster surface, separated by sudden changes to a different structural organization and more compact shape. These transitions result from a competition between interatomic bonding energy and surface energy. The implications of this growth pattern for the further evolution of copper from microstructure to bulk are discussed. PMID- 22423843 TI - Coherent dynamics of meta-toluidine investigated by quasielastic neutron scattering. AB - The coherent dynamics of a typical fragile glass former, meta-toluidine, was investigated at the molecular level using quasielastic neutron scattering, with time-of-flight and neutron spin echo spectrometers. It is well known that the static structure factor of meta-toluidine shows a prepeak originating from clustering of the molecules through hydrogen bonding between the amine groups. The dynamics of meta-toluidine was measured for several values of the wavevector transfer Q, which is equivalent to an inverse length scale, in a range encompassing the prepeak and the structure factor peak. Data were collected in the temperature range corresponding to the liquid and supercooled states, down to the glass transition. At least two dynamical processes were identified. This paper focuses on the slowest relaxation process in the system, the alpha relaxation, which was found to scale with the macroscopic shear viscosity at all the investigated Q values. No evidence of "de Gennes" narrowing associated with the prepeak was observed, in contrast with what happens at the Q value corresponding to the interparticle distance. Moreover, using partially deuterated samples, the dynamics of the clusters was found to be correlated to the single particle dynamics of the meta-toluidine molecules. PMID- 22423844 TI - Free energy partitioning analysis of the driving forces that determine ion density profiles near the water liquid-vapor interface. AB - Free energy partitioning analysis is employed to explore the driving forces for ions interacting with the water liquid-vapor interface using recently optimized point charge models for the ions and SPC/E water. The Na(+) and I(-) ions are examined as an example kosmotrope/chaotrope pair. The absolute hydration free energy is partitioned into cavity formation, attractive van der Waals, local electrostatic, and far-field electrostatic contributions. We first compute the bulk hydration free energy of the ions, followed by the free energy to insert the ions at the center of a water slab. Shifts of the ion free energies occur in the slab geometry consistent with the SPC/E surface potential of the water liquid vapor interface. Then the free energy profiles are examined for ion passage from the slab center to the dividing surface. The profiles show that, for the large chaotropic I(-) ion, the relatively flat total free energy profile results from the near cancellation of several large contributions. The far-field electrostatic part of the free energy, largely due to the water liquid-vapor interface potential, has an important effect on ion distributions near the surface in the classical model. We conclude, however, that the individual forms of the local and far-field electrostatic contributions are expected to be model dependent when comparing classical and quantum results. The substantial attractive cavity free energy contribution for the larger I(-) ion suggests that there is a hydrophobic component important for chaotropic ion interactions with the interface. PMID- 22423845 TI - Local structures in ionic liquids probed and characterized by microscopic thermal diffusion monitored with picosecond time-resolved Raman spectroscopy. AB - Vibrational cooling rate of the first excited singlet (S(1)) state of trans stilbene and bulk thermal diffusivity are measured for seven room temperature ionic liquids, C(2)mimTf(2)N, C(4)mimTf(2)N, C(4)mimPF(6), C(5)mimTf(2)N, C(6)mimTf(2)N, C(8)mimTf(2)N, and bmpyTf(2)N. Vibrational cooling rate measured with picosecond time-resolved Raman spectroscopy reflects solute-solvent and solvent-solvent energy transfer in a microscopic solvent environment. Thermal diffusivity measured with the transient grating method indicates macroscopic heat conduction capability. Vibrational cooling rate of S(1) trans-stilbene is known to have a good correlation with bulk thermal diffusivity in ordinary molecular liquids. In the seven ionic liquids studied, however, vibrational cooling rate shows no correlation with thermal diffusivity; the observed rates are similar (0.082 to 0.12 ps(-1) in the seven ionic liquids and 0.08 to 0.14 ps(-1) in molecular liquids) despite large differences in thermal diffusivity (5.4-7.5 * 10(-8) m(2) s(-1) in ionic liquids and 8.0-10 * 10(-8) m(2) s(-1) in molecular liquids). This finding is consistent with our working hypothesis that there are local structures characteristically formed in ionic liquids. Vibrational cooling rate is determined by energy transfer among solvent ions in a local structure, while macroscopic thermal diffusion is controlled by heat transfer over boundaries of local structures. By using "local" thermal diffusivity, we are able to simulate the vibrational cooling kinetics observed in ionic liquids with a model assuming thermal diffusion in continuous media. The lower limit of the size of local structure is estimated with vibrational cooling process observed with and without the excess energy. A quantitative discussion with a numerical simulation shows that the diameter of local structure is larger than 10 nm. If we combine this lower limit, 10 nm, with the upper limit, 100 nm, which is estimated from the transparency (no light scattering) of ionic liquids, an order of magnitude estimate of local structure is obtained as 10 nm < L < 100 nm, where L is the length or the diameter of the domain of local structure. PMID- 22423846 TI - Signatures of correlated excitonic dynamics in two-dimensional spectroscopy of the Fenna-Matthew-Olson photosynthetic complex. AB - Long-lived excitonic coherence in photosynthetic proteins has become an exciting area of research because it may provide design principles for enhancing the efficiency of energy transfer in a broad range of materials. In this publication, we provide new evidence that long-lived excitonic coherence in the Fenna-Mathew Olson pigment-protein (FMO) complex is consistent with the assumption of cross correlation in the site basis, indicating that each site shares bath fluctuations. We analyze the structure and character of the beating crosspeak between the two lowest energy excitons in two-dimensional (2D) electronic spectra of the FMO Complex. To isolate this dynamic signature, we use the two-dimensional linear prediction Z-transform as a platform for filtering coherent beating signatures within 2D spectra. By separating signals into components in frequency and decay rate representations, we are able to improve resolution and isolate specific coherences. This strategy permits analysis of the shape, position, character, and phase of these features. Simulations of the crosspeak between excitons 1 and 2 in FMO under different regimes of cross correlation verify that statistically independent site fluctuations do not account for the elongation and persistence of the dynamic crosspeak. To reproduce the experimental results, we invoke near complete correlation in the fluctuations experienced by the sites associated with excitons 1 and 2. This model contradicts ab initio quantum mechanic/molecular mechanics simulations that observe no correlation between the energies of individual sites. This contradiction suggests that a new physical model for long-lived coherence may be necessary. The data presented here details experimental results that must be reproduced for a physical model of quantum coherence in photosynthetic energy transfer. PMID- 22423847 TI - Melting of monatomic glass with free surfaces. AB - Melting of monatomic glass with free surfaces has been studied by molecular dynamics simulations in models with Lennard-Jones-Gauss interatomic potential. Models have been heated up from a glassy state toward a normal liquid state. Atomic mechanism of melting has been analyzed via monitoring spatio-temporal arrangements of liquid-like atoms occurred during heating process. Liquid-like atoms are detected via the Lindemann criterion of melting. It is clear that the transition from glass into supercooled liquid of our "ordinary" glass with free surfaces exhibits a non-heterogeneous behavior, i.e., although liquid-like atoms initiate/grow mainly in the surface shell, significant amount of liquid-like atoms also initiates/grows simultaneously in the interior during heating process. We found three characteristic temperatures of melting of glass with a free surface. Temperature dependence of structure and various thermodynamic quantities of the system upon heating is also presented and discussed. PMID- 22423848 TI - A molecular "phase ordering" phase transition leading to a modulated aperiodic composite in n-heptane/urea. AB - n-Heptane/urea is an aperiodic inclusion compound in which the ratio of host and guest repeats along the channel axis is very close to unity and is found to have a constant value (0.981) from 280 K to 90 K. Below 280 K, two phase transitions are observed. The first (T(c1) = 145 K) is a ferroelastic phase transition that generates superstructure reflections for the host while leaving the guest with 1D order. The second (T(c2) = 130 K) is a "phase ordering" transition to a four dimensional structure (P2(1)11(0betagamma)) with pronounced host-guest intermodulation and a temperature dependent phase shift between guests in adjacent channels. PMID- 22423849 TI - Calorimetric and relaxation properties of xylitol-water mixtures. AB - We present the first broadband dielectric spectroscopy (BDS) and differential scanning calorimetry study of supercooled xylitol-water mixtures in the whole concentration range and in wide frequency (10(-2)-10(6) Hz) and temperature (120 365 K) ranges. The calorimetric glass transition, T(g), decreases from 247 K for pure xylitol to about 181 K at a water concentration of approximately 37 wt. %. At water concentrations in the range 29-35 wt. % a plentiful calorimetric behaviour is observed. In addition to the glass transition, almost simultaneous crystallization and melting events occurring around 230-240 K. At higher water concentrations ice is formed during cooling and the glass transition temperature increases to a steady value of about 200 K for all higher water concentrations. This T(g) corresponds to an unfrozen xylitol-water solution containing 20 wt. % water. In addition to the true glass transition we also observed a glass transition-like feature at 220 K for all the ice containing samples. However, this feature is more likely due to ice dissolution [A. Inaba and O. Andersson, Thermochim. Acta, 461, 44 (2007)]. In the case of the BDS measurements the presence of water clearly has an effect on both the cooperative alpha-relaxation and the secondary beta-relaxation. The alpha-relaxation shows a non-Arrhenius temperature dependence and becomes faster with increasing concentration of water. The fragility of the solutions, determined by the temperature dependence of the alpha-relaxation close to the dynamic glass transition, decreases with increasing water content up to about 26 wt. % water, where ice starts to form. This decrease in fragility with increasing water content is most likely caused by the increasing density of hydrogen bonds, forming a network-like structure in the deeply supercooled regime. The intensity of the secondary beta-relaxation of xylitol decreases noticeably already at a water content of 2 wt. %, and at a water content above 5 wt. % it has been replaced by a considerably stronger water (w) relaxation at about the same frequency. However, the similarities in time scale and activation energy between the w-relaxation and the beta-relaxation of xylitol at water contents below 13 wt. % suggest that the w-relaxation is governed, in some way, by the beta-relaxation of xylitol, since clusters of water molecules are rare at these water concentrations. At higher water concentrations the intensity and relaxation rate of the w-relaxation increase rapidly with increasing water content (up to the concentration where ice starts to form), most likely due to a rapid increase of small water clusters where an increasing number of water molecules interacting with other water molecules. PMID- 22423850 TI - Signatures of fragile-to-strong transition in a binary metallic glass-forming liquid. AB - Classical molecular dynamics investigations of the evolution of the microscopic structure and atomic dynamics are found to provide signatures of fragile-to strong transition in a Cu-Zr bulk metallic glass forming alloy. Present study reveals that (i) the alloy exhibits a non-monotonic decoupling of the self diffusion coefficient D and the relaxation time tau as observed in case of supercooled water despite the difference in the intermolecular interactions compared to this system, (ii) the temperature dependence of D and tau suggests a crossover from non-Arrhenius to Arrhenius behavior near mode-coupling transition temperature T(C), and (iii) the alloy exhibits a crossover from Stokes-Einstein ((D ~ (tau/T)(-1)) to fractional Stokes-Einstein (D ? (tau/T)(-zeta)) with exponent zeta ~ 0.6. A weak first-order transition, associated with the fragile to-strong transition, has also been observed in the undercooled region. These findings are in accordance with the growing idea of fragile-to-strong crossover having larger generality than the traditional classification of the glass-forming liquids as fragile and strong. PMID- 22423851 TI - Exciton coherence lifetimes from electronic structure. AB - We model the coherent energy transfer of an electronic excitation within covalently linked aromatic homodimers from first-principles. Our results shed light on whether commonly used models of the bath calculated via detailed electronic structure calculations can reproduce the key dynamics. For the systems we model, the time scales of coherent transport are experimentally known from time-dependent polarization anisotropy measurements, and so we can directly assess whether current techniques are predictive for modeling coherent transport. The coupling of the electronic degrees of freedom to the nuclear degrees of freedom is calculated from first-principles rather than assumed, and the fluorescence anisotropy decay is directly reproduced. Surprisingly, we find that although time-dependent density functional theory absolute energies are routinely in error by orders of magnitude more than the coupling energy between monomers, the coherent transport properties of these dimers can be semi-quantitatively reproduced from these calculations. Future directions which must be pursued to yield predictive and reliable models of coherent transport are suggested. PMID- 22423852 TI - Efficient conducting channels formed by the pi-pi stacking in single [2,2]paracyclophane molecules. AB - The electronic transport properties of single [2,2]paracyclophane molecules directly connected to gold and platinum electrodes have been investigated both theoretically and experimentally by using first-principles quantum transport simulations and break-junction experiments. For comparison, investigations on [3,3]- and [4,4]-paracyclophanes have also been performed. Our calculations show that the strength of the pi-pi interaction in paracyclophanes is critically dependent on the inter-ring distance. In contrast to [4,4]paracyclophane in which the pi-pi interaction is very weak due to the large inter-ring distance, the pi pi interaction in [2,2]- and [3,3]-paracyclophanes is rather strong and dominates the electronic transport properties. In particular, for the asymmetric Au [2,2]paracyclophane-Au junction in which the [2,2]paracyclophane molecule is connected to each gold electrode through a Au adatom and the two Au adatoms are attached in eta(1)-fashion to two carbon atoms in the benzene backbones connecting with different ethylene groups, the transmission coefficient at the Fermi level is calculated to be 1.0 * 10(-2), in excellent agreement with experiments. When the gold electrodes are replaced by platinum, the calculated transmission coefficient at the Fermi level of the symmetric Pt [2,2]paracyclophane-Pt junction with one Pt adatom used as the linker group is increased to 0.83, demonstrating that the pi-pi stacking in [2,2]paracyclophane is efficient for electron transport when the molecule-electrode interfaces are electronically transparent. This is confirmed by our preliminary experimental studies on the Pt-[2,2]paracyclophane-Pt junctions, for which the low-bias junction conductance has reached 0.40 +/- 0.02 G(0) (G(0) is the conductance quantum). These findings are helpful for the design of molecular electronic devices incorporating pi-pi stacking molecular systems. PMID- 22423853 TI - Spin-spin and spin-orbit interactions in nanographene fragments: a quantum chemistry approach. AB - The relativistic behavior of graphene structures, starting from the fundamental building blocks--the poly-aromatic hydrocarbons (PAHs) along with other PAH nanographenes--is studied to quantify any associated intrinsic magnetism in the triplet (T) state and subsequently in the ground singlet (S) state with account of possible S-T mixture induced by spin-orbit coupling (SOC). We employ a first principle quantum chemical-based approach and density functional theory (DFT) for a systematic treatment of the spin-Hamiltonian by considering both the spin-orbit and spin-spin interactions as dependent on different numbers of benzene rings. We assess these relativistic spin-coupling phenomena in terms of splitting parameters which cause magnetic anisotropy in absence of external perturbations. Possible routes for changes in the couplings in terms of doping and defects are also simulated and discussed. Accounting for the artificial character of the broken-symmetry solutions for strong spin polarization of the so-called "singlet open-shell" ground state in zigzag graphene nanoribbons predicted by spin unrestricted DFT approaches, we interpolate results from more sophisticated methods for the S-T gaps and spin-orbit coupling (SOC) integrals and find that these spin interactions become weak as function of size and increasing decoupling of electrons at the edges. This leads to reduced electron spin-spin interaction and hence almost negligible intrinsic magnetism in the carbon-based PAHs and carbon nanographene fragments. Our results are in agreement with the fact that direct experimental evidence of edge magnetism in pristine graphene has been reported so far. We support the notion that magnetism in graphene only can be ascribed to structural defects or impurities. PMID- 22423854 TI - Semi-infinite boundary conditions for the simulation of interfaces: the Ar/CO2(s) model revisited. AB - We propose a method to account for the long tail corrections of dispersive forces in inhomogeneous systems. This method deals separately with the two interfaces that are usually present in a simulation setup, effectively establishing semi infinite boundary conditions that are appropriate for the study of the interface between two infinite bulk phases. Using the wandering interface method, we calculate surface free energies of vapor-liquid, wall-liquid, and wall-vapor interfaces for a model of Lennard-Jones argon adsorbed on solid carbon dioxide. The results are employed as input to Young's equation, and the wetting temperature located. This estimate is compared with predictions from the method of effective interface potentials and good agreement is found. Our results show that truncating Ar-Ar interactions at two and a half molecular diameters results in a dramatic decrease of the wetting temperature of about 40%. PMID- 22423855 TI - Anisotropic heat transport in nanoconfined polyamide-6,6 oligomers: atomistic reverse nonequilibrium molecular dynamics simulation. AB - While polymers are known as thermal insulators, recent studies show that stretched single chains of polymers have a very high thermal conductivity. In this work, our new simulation scheme for simulation of heat flow in nanoconfined fluids [H. Eslami, L. Mohammadzadeh, and N. Mehdipour, J. Chem. Phys. 135, 064703 (2011)] is employed to study the effect of chain ordering (stretching) on the rate of heat transfer in polyamide-6,6 nanoconfined between graphene surfaces. Our results for the heat flow in the parallel direction (the plane of surfaces) show that the coefficient of thermal conductivity depends on the intersurface distance and is much higher than that of the bulk polymer. A comparison of results in this work with our former findings on the heat flow in the perpendicular direction, with the coefficient of heat conductivity less than the bulk sample, reveal that well-organized polymer layers between the confining surfaces show an anisotropic heat conduction; the heat conduction in the direction parallel to the surfaces is much higher than that in the perpendicular direction. The origin of such anisotropy in nanometric heat flow is shown to be the dramatic anisotropy in chain conformations (chain stretching) beside the confining surfaces. The results indicate that the coefficients of heat conductivity in both directions, normal and parallel to the surfaces, depend on the degree of polymer layering between the surfaces and the pore width. PMID- 22423856 TI - Diffusion, sedimentation, and rheology of concentrated suspensions of core-shell particles. AB - Short-time dynamic properties of concentrated suspensions of colloidal core-shell particles are studied using a precise force multipole method which accounts for many-particle hydrodynamic interactions. A core-shell particle is composed of a rigid, spherical dry core of radius a surrounded by a uniformly permeable shell of outer radius b and hydrodynamic penetration depth kappa(-1). The solvent flow inside the permeable shell is described by the Brinkman-Debye-Bueche equation, and outside the particles by the Stokes equation. The particles are assumed to interact non-hydrodynamically by a hard-sphere no-overlap potential of radius b. Numerical results are presented for the high-frequency shear viscosity, eta(infinity), sedimentation coefficient, K, and the short-time translational and rotational self-diffusion coefficients, D(t) and D(r). The simulation results cover the full three-parametric fluid-phase space of the composite particle model, with the volume fraction extending up to 0.45, and the whole range of values for kappab, and a/b. Many-particle hydrodynamic interaction effects on the transport properties are explored, and the hydrodynamic influence of the core in concentrated systems is discussed. Our simulation results show that for thin or hardly permeable shells, the core-shell systems can be approximated neither by no shell nor by no-core models. However, one of our findings is that for kappa(b - a) ? 5, the core is practically not sensed any more by the weakly penetrating fluid. This result is explained using an asymptotic analysis of the scattering coefficients entering into the multipole method of solving the Stokes equations. We show that in most cases, the influence of the core grows only weakly with increasing concentration. PMID- 22423857 TI - Phase transitions between the rotator phases of paraffin investigated using silicon microcantilevers. AB - Nanogram amounts of paraffin were coated onto a silicon cantilever, and the resonance frequency and deflection of the cantilever were measured as a function of temperature. Changes in the cantilever resonance frequency were used to determine the temperatures at which phase transitions between the rotator phases of tricosane, tetracosane, and pentacosane occurred. The phase transition measured using the cantilever was found to be more apparent than that obtained using conventional methods. The thermal hysteresis in the resonance frequency of a tetracosane-coated cantilever differed from that of the tricosane- and pentacosane-coated cantilevers, which was attributed to the even-odd effect on the crystal structures of paraffin. The even-odd effect was also observed in the temperature dependent deflection measurements. Further, the overshoot at the transition R(V) -> crystal in the deflection measurement was observed and attributed to the steep increase in the modulus of paraffin during the transition. PMID- 22423858 TI - Nonlinearity and slip behavior of n-hexadecane in large amplitude oscillatory shear flow via nonequilibrium molecular dynamic simulation. AB - Molecular dynamic simulation is used to investigate the viscoelastic properties of n-hexadecane under oscillatory shear flow. Rheometric simulations of an ultra thin molecular film are studied and compared with the results of a bulk simulation. Strain amplitude sweep tests at a fixed frequency show that strain thinning (the dynamic modulus monotonically decreases with increasing strain amplitude) exists at extreme strain for both bulk and thin film systems. Fourier analysis is performed to characterize the nonlinear behavior of the viscoelasticity. No even harmonic was found in our study even though wall slip occurs. Furthermore, we show that a Fourier series with odd harmonics can be used to perfectly describe the simulation results by plotting Lissajous loops. Shear wave propagation appears when the frequency is larger than a certain value. Moreover, the molecular orientation and molecular potential energies, including those for bonding potential, intra- and intermolecular van der Waals interactions are plotted against the strain amplitude to examine the changes in the microscopic structures with respect to the macroscopic thermodynamic states. PMID- 22423859 TI - Effects of molecular architectures and solvophobic additives on the aggregative properties of polymeric surfactants. AB - The aggregative behavior of the polymeric surfactants with various molecular architectures in dilute solutions is studied by dissipative particle dynamics. The effects of the solvophobic/solvophilic length, polymeric architecture (linear, star, dendritic, and cyclic type), chain rigidity, and solvophobic additives on the critical micelle concentration (CMC) and the aggregative patterns are systematically investigated. It is found that molecular architectures have a noteworthy impact on the aggregative properties. For linear diblock copolymers, the CMC declines with increasing solvophobic length but rises with increasing solvophilic length. Nonetheless, the solvophobic group has comparatively greater influence on the CMC. Imposition of the star, dendritic, or cyclic structures onto the solvophobic or solvophilic parts of the polymeric surfactant leads to an increase in the CMC. On the contrary, polymers imposed with the greater degree of the rigidity on the solvophobic or solvophilic block have lower CMC. The addition of solvophobic additives results in a decrease of CMC as well. The effects of the concentration and length of the additives on the aggregative behaviors of polymer surfactants were investigated. Interesting supramolecular structures such as caterpillar and worm-like micelles were observed. PMID- 22423860 TI - Dynamic Monte Carlo simulations of double crystallization accelerated in microdomains of diblock copolymers. AB - We report dynamic Monte Carlo simulations of microphase separated diblock copolymers, to investigate how crystallization of one species could accelerate the subsequent crystallization of another species. Although the lattice copolymer model brings a boundary constraint to the long periods of microdomains, the single-molecular-level force balance between two blocks and its change can be revealed in this simple approach. We found two contrastable acceleration mechanisms: (1) the metastable lamellar crystals of one species become thicker at higher crystallization temperatures, sacrificing its microphase interfacial area to make a larger coil-stretching of another amorphous species and hence to accelerate subsequent crystallization of the latter with a more favorable conformation. (2) While in the case allowing chain-sliding in the crystal, the equilibrated lamellar crystals of one species become thinner at higher temperatures, sacrificing its thermal stability to gain a higher conformational entropy of another amorphous species and hence to accelerate subsequent crystallization of the latter with a stronger tension at the block junction. Parallel situations of experiments have been discussed. PMID- 22423861 TI - Polymer adsorption on a fractal substrate: numerical study. AB - We study the adsorption of flexible polymer macromolecules on a percolation cluster, formed by a regular two-dimensional disordered lattice at critical concentration p(c) of attractive sites. The percolation cluster is characterized by a fractal dimension d(s) (p(c))=91/49. The conformational properties of polymer chains grafted to such a fractal substrate are studied by means of the pruned-enriched Rosenbluth method. We find estimates for the surface crossover exponent governing the scaling of the adsorption energy in the vicinity of transition point, phi(s)(p(c))=0.425+/-0.009, and for adsorption transition temperature, T(A)(p(c))=2.64+/-0.02. As expected, the adsorption is diminished when the fractal dimension of the substrate is smaller than that of a plain Euclidean surface. The universal size and shape characteristics of a typical spatial conformation which attains a polymer chain in the adsorbed state are analyzed as well. PMID- 22423862 TI - Trapping of excess electrons at the microhydrated protonated amino groups in proteins. AB - We present a combined first-principles calculation and molecular dynamics simulation study of an excess electron (EE) in condensed phase of a microhydrated protonated amino group in proteins in this work. The protonated amino group, NH(3)(+), is modeled by a CH(3)NH(3)(+) and an amount of water molecules are included to form various microhydrated CH(3)NH(3)(+) clusters, and the states and the dynamics of the trapped EE are analyzed. In addition to the localized and delocalized states observed, the N-H/O-H bond cleavage phenomena followed by escape of a H atom are also observed for some hydrated clusters in which the NH(3)(+) group exposes on the surface of the cluster and directly participates in binding an EE. The state-to-state conversion is controlled by thermal motion of molecules in the clusters, and the cleavage of the N-H or the O-H bond and the H escape are determined by the binding modes of the EE. The H-escape nature could be attributed to the dissociation of the N-H or O-H bond induced by the trapped EE which transfers to their antibonding orbitals. This work provides a microscopical picture of the EE trapping at a microhydrated hydrophilic group in proteins, long-range electron migration, and the H-evolving mechanisms relevant for the lesions or damages of proteins or DNA. This is the first step in considering increasingly larger peptide fragments for further investigation of the detailed lesion/damage or charge migration mechanisms. Further work about this topic is underway. PMID- 22423863 TI - Comment on "Minimum free-energy pathway of nucleation" [J. Chem. Phys. 135, 134508 (2011)]. PMID- 22423864 TI - Synthesis of different-sized silver nanoparticles by simply varying reaction conditions with leaf extracts of Bauhinia variegata L. AB - Green synthesis of nanoparticles is one of the crucial requirements in today's climate change scenario all over the world. In view of this, leaf extract (LE) of Bauhinia variegata L. possessing strong antidiabetic and antibacterial properties has been used to synthesise silver nanoparticles (SNP) in a controlled manner. Various-sized SNP (20-120 nm) were synthesised by varying incubation temperature, silver nitrate and LE concentrations. The rate of SNP synthesis and their size increased with increase in AgNO(3) concentration up to 4 mM. With increase in LE concentration, size and aggregation of SNP was increased. The size and aggregation of SNP were also increased at temperatures above and below 40 degrees C. This has suggested that size and dispersion of SNP can be controlled by varying reaction components and conditions. Polarity-based fractionation of B. variegata LE has suggested that only water-soluble fraction is responsible for SNP synthesis. Fourier transform infrared spectroscopy analysis revealed the attachment of polyphenolic and carbohydrate moieties to SNP. The synthesised SNPs were found stable in double distilled water, BSA and phosphate buffer (pH 7.4). On the contrary, incubation of SNP with NaCl induced aggregation. This suggests the safe use of SNP for various in vivo applications. PMID- 22423865 TI - Hepatitis B surface antigen-antibody interactions studied by optical tweezers. AB - The protein-protein interactions between hepatitis B surface antigen (HBsAg) and its antibodies (anti-HBs) were studied by measuring the binding force between microspheres coated with such proteins using optical tweezers. The interaction force between the protein-coated microspheres was found to be strongly influenced by the acidity of the surrounding liquid medium, as well as the experimental temperature, and it reaches a maximum value at around pH 7.5 and temperature around 37 degrees C. By measuring the protein distribution on the surfaces of the microspheres and their contact areas using scanning electron microscopy, the specific binding force between an HBsAg and anti-HBs protein pair is estimated to be around 4.8 pN at the optimum pH value and temperature at an applied loading rate of around 1 pN/s. PMID- 22423866 TI - Fabrication of three-dimensional nano, micro and micro/nano scaffolds of porous poly(lactic acid) by electrospinning and comparison of cell infiltration by Z stacking/three-dimensional projection technique. AB - The use of electrospun extracellular matrix (ECM)-mimicking nanofibrous scaffolds for tissue engineering is limited by poor cellular infiltration. The authors hypothesised that cell penetration could be enhanced in scaffolds by using a hierarchical structure where nano fibres are combined with micron-scale fibres while preserving the overall scaffold architecture. To assess this, we fabricated electrospun porous poly(lactic acid) (PLA) scaffolds having nanoscale, microscale and combined micro/nano architecture and evaluated the structural characteristics and biological response in detail. Although the bioactivity was intermediate to that for nanofibre and microfibre scaffold, a unique result of this study was that the micro/nano combined fibrous scaffold showed improved cell infiltration and distribution than the nanofibrous scaffold. Although the cells were found to be lining the scaffold periphery in the case of nanofibrous scaffold, micro/nano scaffolds had cells dispersed throughout the scaffold. Further, as expected, the addition of nanoparticles of hydroxyapatite (nHAp) improved the bioactivity, although it did not play a significant role in cell penetration. Thus, this strategy of creating a three-dimensional (3D) micro/nano architecture that would increase the porosity of the fibrous scaffold and thereby improving the cell penetration, can be utilised for the generation of functional tissue engineered constructs in vitro. PMID- 22423867 TI - Probing the interaction of bovine haemoglobin with gold nanoparticles. AB - The interaction between gold nanoparticles (GNPs) and bovine haemoglobin (BHb) was studied by ultraviolet-visible (UV-Vis) absorption, circular dichroism (CD) and fluorescence spectroscopic techniques. The UV-Vis absorption spectrum demonstrated that there was interaction between GNPs and BHb, but no direct interaction between GNPs and haem groups of BHb. The fluorescence data revealed that GNPs effectively quenched the intrinsic fluorescence of BHb via static quenching. The binding of GNPs to BHb occurred at a single site. The binding process was a spontaneous molecular interaction procedure, in which hydrophobic force and hydrogen bonds played a major role. The alternations of protein secondary structure in the presence of GNPs were also determined by CD spectroscopy. This work is helpful to understand the interaction mechanism of GNPs with haemoglobin, which can guide the applications of GNPs in biomedicine. PMID- 22423868 TI - Light-switchable hemithioindigo-hemistilbene-containing peptides: ultrafast spectroscopy of the Z -> E isomerization of the chromophore and the structural dynamics of the peptide moiety. AB - Two hemithioindigo-hemistilbene (HTI) derivatives, designed to operate as structural switches in peptides, as well as two HTI peptides are characterized by ultrafast spectroscopy in the visible and the infrared. The two HTI switches follow the reaction scheme published for other HTI compounds with a picosecond excited state reaction (tau(1) ~ 6 ps) and isomerization from Z to E with tau(2) = 13 and 51 ps. As compared to the isolated chromophores, the isomerization reaction is slowed down in the chromopeptides to tau(2) = 24 and 69 ps. For the smaller peptide containing 6 amino acids, the structural changes of the peptide moiety observed via the IR spectrum in the amide I band follow the isomerization of the molecular switch closely. In the larger cyclic chromopeptide, containing 20 amino acids and mimicking a beta-hairpin structure in the Z-form of the chromophore, the peptide moiety also changes its structure during isomerization of the chromophore. However, the IR spectrum at the end of the observation period of 3 ns deviates significantly from the stationary difference spectrum. These signatures indicate that strong additional structural changes, e.g., breaking of interchain hydrogen bonds, also occur on longer time scales. PMID- 22423869 TI - The health of deaf people: communication breakdown. PMID- 22423870 TI - New guidance for colorectal cancer screening. PMID- 22423871 TI - Progress in sanitation needed for neglected tropical diseases. PMID- 22423872 TI - Deafness might damage your health. PMID- 22423874 TI - Gail Davey: raising the profile of "podo...what?". PMID- 22423875 TI - Medical students speak out on detrimental National Health Service reforms. PMID- 22423876 TI - Health and the financial crisis in Greece. PMID- 22423877 TI - Health and Social Care Bill: RCPCH responds. PMID- 22423878 TI - Health and the financial crisis in Greece. PMID- 22423880 TI - Avahan and impact assessment. PMID- 22423881 TI - Weight loss in a commercial setting. PMID- 22423883 TI - Launch of the international podoconiosis initiative. PMID- 22423884 TI - Mental health of deaf people. AB - Deafness is a heterogeneous condition with far-reaching effects on social, emotional, and cognitive development. Onset before language has been established happens in about seven per 10,000 people. Increased rates of mental health problems are reported in deaf people. Many regard themselves as members of a cultural minority who use sign language. In this Review, we describe discrepancies between a high burden of common mental health disorders and barriers to health care. About a quarter of deaf individuals have additional disabilities and a high probability of complex mental health needs. Research into factors affecting mental health of deaf children shows that early access to effective communication with family members and peers is desirable. Improved access to health and mental health care can be achieved by provision of specialist services with professionals trained to directly communicate with deaf people and with sign-language interpreters. PMID- 22423885 TI - Cardiac arrest and myocardial pseudoinfarction. PMID- 22423886 TI - Microwave drying for safe storage and improved nutritional quality of green gram seed (Vigna radiata). AB - The present study describes the effect of the microwave-heating method on disinfestations and physico characteristics, viz., grain size, grain hardness, and nutritional quality, of the stored green gram seed. It has been observed that the use of the microwave-heating method not only prolongs the storage duration of the green gram seed but also enhances its nutritional quality. The effect of independent parameters, viz., microwave power level and time of exposure, on the moisture content, insect mortality, color, and antinutrient factor (phyic acid) was optimized using response surface methodology (RSM), with the optimized value for power of 808 W and time at 80 s. The optimally treated green gram seed has 8.9% moisture, 99.5% insect mortality, 2.22 Deltaa* (green color of seed), and 591.79 mg/100 g of antinutrient factor (phytic acid). The grain size (geometric mean diameter, D(m)) of the control (untreated) sample was 3.75 mm, and that of the microwave-treated sample using optimum conditions was 3.99 mm. The grain hardness of the control sample was 3.31 kg, and that of the microwave-treated sample using optimum conditions was 1.305 kg. In vitro protein digestibility (IVPD) of the control (untreated) sample was 83 +/- 0.289%, and that of the microwave-treated sample using optimum conditions was 85 +/- 0.296%. These values are significantly difference (p < 0.05). The mineral elements studied were Zn, Fe, Mg, Mn, Cu, K, Ca, and Na. The microwave treatment resulted in a non significant (p < 0.05) effect for Mg, Mn, Cu, K, and Na but a significant (p < 0.05) effect for Zn, Ca, and Fe. The results indicate that the microwave heating not only increases the insect mortality but also reduces the moisture content and antinutritional factor (phytic acid), while the natural green color of the seed is not affected much. This study provides a novel and environmentally safe technique and increase in the nutritive quality. PMID- 22423887 TI - In vivo recovery effect of silibinin treatment on streptozotocin-induced diabetic mice is associated with the modulations of Sirt-1 expression and autophagy in pancreatic beta-cell. AB - Improper adjustments of autophagy and silent information regulator 1 (Sirt-1) expression were reported to be closely associated with metabolic disorders. In this study, we examined the roles of Sirt-1 and autophagy in streptozotocin induced diabetes mellitus, assessed the relationship between autophagy and Sirt 1, and investigated the protective mechanism of silibinin. Diabetes was induced in 6-week-old mice by intravenous injection of streptozotocin (150 mg/kg/day, for 2 weeks). In the treatment groups, silibinin (50 mg/kg/day, intramuscular injection, for 8 weeks) or inhibitors (50 mg/kg/day, subcutaneous injection, for 8 weeks) were given. Diabetic control animals received vehicle for the same time. Compared with diabetic controls, silibinin or autophagy inhibitor, 3 methyladenine, treated mice showed decreased levels of glycosylated hemoglobin A1C (P < 0.01), serum triglyceride (P < 0.01), cholesterol (P < 0.01), blood glucose (P < 0.05), autophagy (P < 0.05), and apoptosis ratio (P < 0.05) of pancreatic beta-cells. Systemic administration of silibinin reversed streptozotocin-induced downregulation of Sirt-1 expression. Sirt-1 may play a role in regulating the physiological level of autophagy and is associated with loss of pancreatic beta-cells and metabolic biochemical disorders. Through promoting Sirt-1 expression and recovering autophagy physiologically, silibinin may reverse hyperglycemia and repair damaged pancreatic beta-cells. PMID- 22423888 TI - Large-area ohmic top contact to vertically grown nanowires using a free-standing Au microplate electrode. AB - A method of electrically contacting vertically grown nanowires of uneven heights, a common scenario among as-grown nanowires, is reported here using a chemically synthesized single-crystalline Au microplate as top electrode. The contact is electrically activated and the contact formation is predominantly due to electromigration. With this approach, the electrode could ohmically contact several thousand nanowires at once. PMID- 22423889 TI - Ozonolysis of bicyclic 1,2-dioxines: initial scope and mechanistic insights. AB - The ozonolysis of bicyclic 1,2-dioxines was investigated using a variety of 1,4 disubstituted 1,2-dioxines along with a 1,3-dialkyl and steroidal example, with yields ranging from moderate to excellent. Two different pathways were observed upon reaction of the 1,4-disubstituted 1,2-dioxines with ozone; one pathway saw the "expected" results, that is, cleavage of the olefinic moiety with generation of 1,4-dicarbonyl 1,2-dioxines, while the other pathway revealed a previously unobserved rearrangement involving cleavage of the peroxide linkage along with loss of either CO or CO(2). Several unsymmetrical ozonolyses were also performed to further investigate the origins of this rearrangement, and initial mechanistic insights into the fragmentation pathways are discussed. PMID- 22423890 TI - Linking phosphorus sequestration to carbon humification in wetland soils by 31P and 13C NMR spectroscopy. AB - Phosphorus sequestration in wetland soils is a prerequisite for long-term maintenance of water quality in downstream aquatic systems, but can be compromised if phosphorus is released following changes in nutrient status or hydrological regimen. The association of phosphorus with relatively refractory natural organic matter (e.g., humic substances) might protect soil phosphorus from such changes. Here we used hydrofluoric acid (HF) pretreatment to remove phosphorus associated with metals or anionic sorption sites, allowing us to isolate a pool of phosphorus associated with the soil organic fraction. Solution (31)P and solid state (13)C NMR spectra for wetland soils were acquired before and after hydrofluoric acid pretreatment to assess quantitatively and qualitatively the changes in phosphorus and carbon functional groups. Organic phosphorus was largely unaffected by HF treatment in soils dominated by refractory alkyl and aromatic carbon groups, indicating association of organic phosphorus with stable, humified soil organic matter. Conversely, a considerable decrease in organic phosphorus following HF pretreatment was detected in soils where O-alkyl groups represented the major fraction of the soil carbon. These correlations suggest that HF treatment can be used as a method to distinguish phosphorus fractions that are bound to the inorganic soil components from those fractions that are stabilized by incorporation into soil organic matter. PMID- 22423891 TI - Too much impact for the impact factor: are a new generation of scientists in peril? PMID- 22423892 TI - In silico profiling of deleterious amino acid substitutions of potential pathological importance in haemophlia A and haemophlia B. AB - BACKGROUND: In this study, instead of current biochemical methods, the effects of deleterious amino acid substitutions in F8 and F9 gene upon protein structure and function were assayed by means of computational methods and information from the databases. Deleterious substitutions of F8 and F9 are responsible for Haemophilia A and Haemophilia B which is the most common genetic disease of coagulation disorders in blood. Yet, distinguishing deleterious variants of F8 and F9 from the massive amount of nonfunctional variants that occur within a single genome is a significant challenge. METHODS: We performed an in silico analysis of deleterious mutations and their protein structure changes in order to analyze the correlation between mutation and disease. Deleterious nsSNPs were categorized based on empirical based and support vector machine based methods to predict the impact on protein functions. Furthermore, we modeled mutant proteins and compared them with the native protein for analysis of protein structure stability. RESULTS: Out of 510 nsSNPs in F8, 378 nsSNPs (74%) were predicted to be 'intolerant' by SIFT, 371 nsSNPs (73%) were predicted to be 'damaging' by PolyPhen and 445 nsSNPs (87%) as 'less stable' by I-Mutant2.0. In F9, 129 nsSNPs (78%) were predicted to be intolerant by SIFT, 131 nsSNPs (79%) were predicted to be damaging by PolyPhen and 150 nsSNPs (90%) as less stable by I-Mutant2.0. Overall, we found that I-Mutant which emphasizes support vector machine based method outperformed SIFT and PolyPhen in prediction of deleterious nsSNPs in both F8 and F9. CONCLUSIONS: The models built in this work would be appropriate for predicting the deleterious amino acid substitutions and their functions in gene regulation which would be useful for further genotype-phenotype researches as well as the pharmacogenetics studies. These in silico tools, despite being helpful in providing information about the nature of mutations, may also function as a first-pass filter to determine the substitutions worth pursuing for further experimental research in other coagulation disorder causing genes. PMID- 22423893 TI - Intraneuronal Abeta detection in 5xFAD mice by a new Abeta-specific antibody. AB - BACKGROUND: The form(s) of amyloid-beta peptide (Abeta) associated with the pathology characteristic of Alzheimer's disease (AD) remains unclear. In particular, the neurotoxicity of intraneuronal Abeta accumulation is an issue of considerable controversy; even the existence of Abeta deposits within neurons has recently been challenged by Winton and co-workers. These authors purport that it is actually intraneuronal APP that is being detected by antibodies thought to be specific for Abeta. To further address this issue, an anti-Abeta antibody was developed (MOAB-2) that specifically detects Abeta, but not APP. This antibody allows for the further evaluation of the early accumulation of intraneuronal Abeta in transgenic mice with increased levels of human Abeta in 5xFAD and 3xTg mice. RESULTS: MOAB-2 (mouse IgG2b) is a pan-specific, high-titer antibody to Abeta residues 1-4 as demonstrated by biochemical and immunohistochemical analyses (IHC), particularly compared to 6E10 (a commonly used commercial antibody to Abeta residues 3-8). MOAB-2 did not detect APP or APP-CTFs in cell culture media/lysates (HEK-APPSwe or HEK-APPSwe/BACE1) or in brain homogenates from transgenic mice expressing 5 familial AD (FAD) mutation (5xFAD mice). Using IHC on 5xFAD brain tissue, MOAB-2 immunoreactivity co-localized with C-terminal antibodies specific for Abeta40 and Abeta42. MOAB-2 did not co-localize with either N- or C-terminal antibodies to APP. In addition, no MOAB-2 immunoreactivity was observed in the brains of 5xFAD/BACE-/- mice, although significant amounts of APP were detected by N- and C-terminal antibodies to APP, as well as by 6E10. In both 5xFAD and 3xTg mouse brain tissue, MOAB-2 co localized with cathepsin-D, a marker for acidic organelles, further evidence for intraneuronal Abeta, distinct from Abeta associated with the cell membrane. MOAB 2 demonstrated strong intraneuronal and extra-cellular immunoreactivity in 5xFAD and 3xTg mouse brain tissues. CONCLUSIONS: Both intraneuronal Abeta accumulation and extracellular Abeta deposition was demonstrated in 5xFAD mice and 3xTg mice with MOAB-2, an antibody that will help differentiate intracellular Abeta from APP. However, further investigation is required to determine whether a molecular mechanism links the presence of intraneuronal Abeta with neurotoxicity. As well, understanding the relevance of these observations to human AD patients is critical. PMID- 22423894 TI - Neural tension technique is no different from random passive movements in reducing spasticity in patients with traumatic brain injury. AB - PURPOSE: Neural tension technique (NTT) is a therapy believed to reduce spasticity and to increase range of motion (ROM). This study compared the ability of NTT and random passive movements (RPMs) to reduce spasticity in the knee flexors in 10 spastic patients with brain injury. METHODS: An RCT study with crossover design evaluated muscle tone measured by: 1) hand-held dynamometer; 2) Modified Ashworth Scale (MAS); 3) and ROM by; 4) angles of resistance onset "catch" (R1) compensatory movement (R2); and 5) 'subjectively perceived reduction in muscle tone'. Outcome measures were recorded by three raters before and after a single treatment session. RESULTS: Objective stiffness measured with the hand held device showed no significant changes for the NTT or RPM (p >= 0.09-0.79). The subjective measures showed significant changes after the NTT for the non blinded rater (MAS: p < 0.05: R1: p < 0.05; R2: p < 0.05), but for the blinded rater a significant reduction was found only for R1 (p < 0.05) and R2 (p < 0.05). For the non-blinded rater intervention effects were found for R1 (p < 0.01), R2 (p < 0.01) and subjectively perceived tone reduction (p < 0.01). For the blinded rater no intervention effect was found. CONCLUSIONS: An objective evaluation of NTT demonstrates that it does not reduce spasticity. However, it does increase ROM with the same effect as RPM. IMPLICATIONS FOR REHABILITATION: * Neural tension techniques does not reduce spasticity in patients with traumatic brain injury when evaluated with objective biomechanical evaluation methods. * Neural tension techniques may improve range of motion with the same effect as random passive movements. PMID- 22423895 TI - Advances in molecular imaging for breast cancer detection and characterization. AB - Advances in our ability to assay molecular processes, including gene expression, protein expression, and molecular and cellular biochemistry, have fueled advances in our understanding of breast cancer biology and have led to the identification of new treatments for patients with breast cancer. The ability to measure biologic processes without perturbing them in vivo allows the opportunity to better characterize tumor biology and to assess how biologic and cytotoxic therapies alter critical pathways of tumor response and resistance. By accurately characterizing tumor properties and biologic processes, molecular imaging plays an increasing role in breast cancer science, clinical care in diagnosis and staging, assessment of therapeutic targets, and evaluation of responses to therapies. This review describes the current role and potential of molecular imaging modalities for detection and characterization of breast cancer and focuses primarily on radionuclide-based methods. PMID- 22423896 TI - Effective Young's modulus of bacterial and microfibrillated cellulose fibrils in fibrous networks. AB - The deformation micromechanics of bacterial cellulose (BC) and microfibrillated cellulose (MFC) networks have been investigated using Raman spectroscopy. The Raman spectra of both BC and MFC networks exhibit a band initially located at ~ 1095 cm(-1). We have used the intensity of this band as a function of rotation angle of the specimens to study the cellulose fibril orientation in BC and MFC networks. We have also used the change in this peak's wavenumber position with applied tensile deformation to probe the stress-transfer behavior of these cellulosic materials. The intensity of this Raman band did not change significantly with rotation angle, indicating an in-plane 2D network of fibrils with uniform random orientation; conversely, a highly oriented flax fiber exhibited a marked change in intensity with rotation angle. Experimental data and theoretical analysis shows that the Raman band shift rate arising from deformation of networks under tension is dependent on the angles between the axis of fibrils, the strain axis, the incident laser polarization direction, and the back scattered polarization configurations. From this analysis, the effective moduli of single fibrils of BC and MFC in the networks were estimated to be in the ranges of 79-88 and 29-36 GPa, respectively. It is shown also that for the model to fit the data it is necessary to use a negative Poisson's ratio for MFC networks and BC networks. Discussion of this in-plane "auxetic" behavior is given. PMID- 22423897 TI - Molecular mechanisms of chromium in alleviating insulin resistance. AB - Type 2 diabetes is often associated with obesity, dyslipidemia and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown to reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID- 22423898 TI - Gender difference following high cholesterol diet induced renal injury and the protective role of rutin and ascorbic acid combination in Wistar albino rats. AB - BACKGROUND: An increased interest is given to the impact of high fat diet on health worldwide. Abnormalities in lipid metabolism induced by high cholesterol diet (HCD) were reported to exacerbate renal diseases via oxidative stress pathways. Rutin and ascorbic acid showed a protective role against oxidative stress-mediated diseases. Furthermore, both lipid metabolism and tissue response to oxidative stress damage was found to vary according to animal gender. Thus, the objective of this work was to examine possible gender-related differences and the possible protective effects of rutin and ascorbic acid supplementation on high cholesterol diet induced nephrotoxicity. METHODS: 96 young male and female Wistar albino rats were used. HCD supplemented animals were treated with rutin alone or in combination with ascorbic acid for 6 weeks. Creatinine plasma level was estimated. Furthermore, kidney levels of nucleic acids, total protein, malondialdehyde (MDA), reduced glutathione (GSH), total cholesterol, and triglycerides were determined. Finally, kidney tissues were used for histopathological examination. RESULTS: HCD supplementation decreased kidney level of nucleic acids, which was more prominent in female animals. Both vitamin combination significantly attenuated HCD induced decrease in nucleic acids. Moreover, kidney level of MDA was significantly altered by HCD in both genders, which was inhibited by rutin and ascorbic acid alone or in combination in male groups and by both vitamins in female groups. There was a reduction in kidney level of GSH by HCD, especially in male groups, which was attenuated by rutin and ascorbic acid combination. Kidney levels of total cholesterol and triglycerides were significantly increased by HCD supplementation in both genders. Coadministration with rutin and/or ascorbic acid protected from such increase, which was more obvious in both vitamins combination. Histopathological investigation supported vitamins protective effect, which was more prominent in male vitamins combination group. CONCLUSIONS: HCD-induced renal injury in female was higher than in male animals, suggesting a better anti-oxidative stress defense response in male's kidney. Moreover, the antioxidant and reno-protective effects of rutin and ascorbic acid were augmented following their combination. PMID- 22423899 TI - Necrotizing fasciitis involving the chest and abdominal wall caused by Raoultella planticola. AB - BACKGROUND: Raoultella planticola was originally considered to be a member of environmental Klebsiella. The clinical significance of R. planticola is still not well known. CASE PRESENTATION: We describe the first case of necrotizing fasciitis involving the chest and abdominal wall caused by R. planticola. The identity of the organism was confirmed using 16S rRNA sequencing. The patient was successfully treated with the appropriate antibiotics combined with operative drainage and debridement. CONCLUSIONS: R. planticola had been described as environmental species, but should be suspected in extensive necrotizing fasciitis after minor trauma in mild to moderate immunocompromised patients. PMID- 22423900 TI - Re: Evaluation of renal masses with contrast-enhanced ultrasound: initial experience. PMID- 22423902 TI - Re: Arterial spin labeling MR imaging for characterisation of renal masses in patients with impaired renal function: initial experience. PMID- 22423901 TI - Re: Utilizing pre-therapy clinical schema and initial CT changes to predict progression-free survival in patients with metastatic renal cell carcinoma on VEGF-targeted therapy: a preliminary analysis. PMID- 22423903 TI - Re: Metastatic renal cell carcinoma: relationship between initial metastasis hypoxia, change after 1 month's sunitinib, and therapeutic response: an 18F fluoromisonidazole PET/CT study. PMID- 22423904 TI - Re: Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or in haemodialysis. PMID- 22423905 TI - Re: Percutaneous ablation in the kidney. PMID- 22423906 TI - Re: Incidence of multiple sporadic renal cell carcinomas in patients referred for renal radiofrequency ablation: implications for imaging follow-up. PMID- 22423907 TI - Re: Zero ischemia laparoscopic partial nephrectomy after superselective transarterial tumor embolization for tumors with moderate nephrometry score: long term results of a single-center experience. PMID- 22423909 TI - Re: Germline mutations in HOXB13 and prostate cancer risk. PMID- 22423910 TI - Re: Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. PMID- 22423913 TI - Re: Long-term projections of the harm-benefit trade-off in prostate cancer screening are more favorable than previous short-term estimates. PMID- 22423912 TI - Re: Heparin prophylaxis and the risk of venous thromboembolism after robotic assisted laparoscopic prostatectomy. PMID- 22423914 TI - Re: The impact of hypertriglyceridemia on prostate cancer development in patients aged>=60 years. PMID- 22423915 TI - Re: Open radical prostatectomy in the elderly: a case for concern? PMID- 22423916 TI - Re: The clinical features and management of testicular germ cell tumours in patients aged 60 years and older. PMID- 22423917 TI - Re: Difference in willingness-to-pay for prostate cancer screening between ill informed and well-informed men: a contingent valuation survey. PMID- 22423918 TI - Re: Early experience with contrast-enhanced ultrasound in the diagnosis of testicular masses: a feasibility study. PMID- 22423919 TI - Re: Antimicrobial susceptibility of global inpatient urinary tract isolates of Escherichia coli: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program: 2009-2010. PMID- 22423920 TI - Re: Predictive value of antimicrobial susceptibility from previous urinary tract infection in the treatment of re-infection. PMID- 22423922 TI - Re: Hyperoxaluria: a gut-kidney axis? PMID- 22423923 TI - Re: Ethylene glycol induces calcium oxalate crystal deposition in malpighian tubules: a Drosophila model for nephrolithiasis/urolithiasis. PMID- 22423925 TI - Re: Validation of the Urinary Sensation Scale (USS). PMID- 22423926 TI - Re: Pelvic floor exercise for urinary incontinence: a systematic literature review. PMID- 22423927 TI - Re: Perceptions of "urgency" in women with interstitial cystitis/bladder pain syndrome or overactive bladder. PMID- 22423928 TI - Re: A qualitative study of women's preferences for treatment of pelvic floor disorders. PMID- 22423929 TI - Re: Bladder neck closure and suprapubic catheter placement as definitive management of neurogenic bladder. PMID- 22423930 TI - Re: The impact of anticholinergic burden in Alzheimer's dementia--the LASER-AD study. PMID- 22423931 TI - Re: Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. PMID- 22423932 TI - Re: The relation between cognitive function and UI in healthy, community dwelling, middle-aged and elderly people. PMID- 22423933 TI - Re: PSA levels in men with spinal cord injury and under intermittent catheterization. PMID- 22423934 TI - Re: Safety and feasibility of the prostatic urethral lift: a novel, minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). PMID- 22423937 TI - Re: Comparison of a new length measurement technique for inflatable penile prosthesis implantation to standard techniques: outcomes and patient satisfaction. PMID- 22423938 TI - Re: Early insertion of inflatable prosthesis for intractable ischemic priapism: our experience and review of the literature. PMID- 22423939 TI - Re: Analysis of GSTM1, GSTT1, and CYP1A1 in Idiopathic Male Infertility. PMID- 22423940 TI - Re: The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. PMID- 22423941 TI - Re: Anabolic steroids and male infertility: a comprehensive review. PMID- 22423943 TI - Re: What is the definition of a satisfactory erectile function after bilateral nerve sparing radical prostatectomy? PMID- 22423942 TI - Re: A feasibility study comparing pharmacist and physician recommendations for sildenafil treatment. PMID- 22423944 TI - Re: Diagnostic performance of ultrasound in nonpalpable cryptorchidism: a systematic review and meta-analysis. PMID- 22423945 TI - Re: Hypospadias repair with tubularized incised plate: does the obstructive flow pattern resolve spontaneously? PMID- 22423946 TI - Re: Ventral corporal body grafting for correcting severe penile curvature associated with single or two-stage hypospadias repair. PMID- 22423947 TI - Re: Are stone protocol computed tomography scans mandatory for children with suspected urinary calculi? PMID- 22423948 TI - Re: An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate. PMID- 22423949 TI - Re: Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. PMID- 22423950 TI - Re: Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. PMID- 22423951 TI - Re: Preventive but not curative efficacy of celecoxib on bladder carcinogenesis in a rat model. PMID- 22423953 TI - Re: Instillation of mitomycin C after transurethral resection of bladder cancer impairs wound healing: an animal model. PMID- 22423954 TI - Re: Oral administration of a retinoic acid receptor antagonist reversibly inhibits spermatogenesis in mice. PMID- 22423955 TI - Re: Evolutionary causes and consequences of sequential polyandry in anuran amphibians. PMID- 22423956 TI - Comparison of the stress response in patients undergoing gynecological laparoscopic surgery using carbon dioxide pneumoperitoneum or abdominal wall lifting methods. AB - BACKGROUND: Conventional laparoscopy is aided by CO(2) insufflation, but this may impair cardiorespiratory function, induce stress responses, and result in life threatening complications. CO(2) insufflation is usually conducted under general anesthesia, whereas gasless laparoscopy supposedly eliminates most of these disadvantages. In this study, we compared the changes of concentration of serum cortisol, tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-10, and heat shock protein 70 (Hsp70) in patients undergoing gynecological laparoscopic surgery in order to explore the severity of the stress response following CO(2) pneumoperitoneum or abdominal wall-lifting methods combined with the different anesthetic techniques performed. SUBJECTS AND METHODS: Fifty-seven patients scheduled for gynecological laparoscopy from July 2009 to February 2010 with American Society of Anesthesiologists I-II evaluation and scheduled operation times of less than 100 minutes were randomly divided into three groups (GC, GG, or EG) with 20 patients in each group. Group GC patients were operated on with the aid of CO(2) insufflation under general anesthesia. Group GG patients were operated on under general anesthesia using the gasless technique. Group EG patients underwent the same operative procedures under epidural anesthesia using the gasless technique. Serum cortisol, TNF-alpha, IL-6, IL-10, and Hsp70 were detected and analyzed at four time points: Before anesthesia (T(1)), 30 minutes after the beginning of the operation (T(2)), 10 minutes after the end of surgery (T(3)), and at 8:00 a.m. the following day (T(4)). RESULTS: There were no obvious differences in the levels of serum cortisol, TNF-alpha, IL-6, IL-10, or Hsp70 among the groups at T(1) (P>.05), but these values increased after the beginning of the operation and peaked in Group GC at T(3) and in Group GG and Group EG at T(4). The levels of serum cortisol and TNF-alpha were higher in Group GC than in Group GG at T(2) (P<.05). At T(3), levels of serum cortisol, TNF-alpha, IL-6, and Hsp70 were significantly higher in Group GC than in Group GG (P<.01) and were the same as the changes of IL-6 to IL-10 ratio (P<.05), while serum concentrations of cortisol, TNF-alpha, and IL-6 were also significantly higher in Group GG than in Group EG (P<.05). CONCLUSIONS: Gynecological laparoscopic surgery using abdominal wall-lifting methods could avoid the deleterious effects of CO(2) pneumoperitoneum, and reduce the stress response. The lowest stress response was found when abdominal wall-lifting methods were used with the patient under epidural anesthesia. PMID- 22423957 TI - The safety of direct trocar versus Veress needle for laparoscopic entry: a meta analysis of randomized clinical trials. AB - OBJECTIVE: This study assessed the safety of direct trocar insertion (DTI) versus Veress needle followed by primary trocar insertion (VN). METHODS: Ovid MEDLINE((r)), Cochrane Library, Google Scholar, Scopus, and the reference lists of published articles were searched up to September 2011 to identify randomized clinical trials comparing DTI with VN. This meta-analysis was restricted to randomized studies comparing the safety of these two laparoscopic entry techniques. RESULTS: Seven randomized studies consisting of 2940 women (VN, n=1525; DTI, n=1415) were identified. The data on the safety of two entry techniques were abstracted, integrated, and analyzed with the meta-analysis method and are presented as pooled relative risk (RR) with 95% confidence intervals (CI). There were 4 cases of a major complication in the VN group in contrast to none in the DTI group. Pooled results failed to show a statistically significant difference in the risk of major complications between the two groups. A significantly higher risk of minor complications was detected in the VN group (RR [95% CI]=10.78 [6.27-18.51]). Among minor complications, preperitoneal injuries (46.73 [11.55-189.10]) and omental injuries (4.51 [2.12-9.62]) were the two most common complications in the VN group. There were significantly increased risks of multiple insertions (more than two attempts) (2.99 [2.11-4.23]) and failed entry (2.21[1.07-4.56]) in the VN group. CONCLUSION: This meta-analysis suggests that the commonly used VN entry technique carries a significantly increased risk of minor complications. In addition, the likelihood of multiple insertions and failed entry are significantly higher in the VN group. PMID- 22423958 TI - Development and validation of an immunochromatographic assay for the rapid detection of quinoxaline-2-carboxylic acid, the major metabolite of carbadox in the edible tissues of pigs. AB - A new method was developed for the determination of quinoxaline-2-carboxylic acid, the marker residue of carbadox, in the edible tissues of food-producing animals using a colloidal gold probe-based immunochromatographic assay. The highly specific polyclonal antibody (PcAb), which was very sensitive to N butylquinoxaline-2-carboxylic acid (BQCA) with an IC(50) value of 2.38 ng ml(-1), was selected for the development of an immunochromatographic assay (ICA). Only 5 min were required to perform this assay; it had a visual detection limit of 25 ng g(-1) for quinoxaline-2-carboxylic acid. The results of the analysis of quinoxaline-2-carboxylic acid in animal tissues using the immunochromatographic assay showed good agreement with those obtained by HPLC. In conclusion, the method was rapid and accurate for screening residues of carbadox in the edible tissues of food-producing animals. PMID- 22423959 TI - Investigation of the differences in thermal stability of two recombinant human serum albumins with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine liposomes by UV circular dichroism spectropolarimetry. AB - Previous studies have demonstrated that liposome-protein interactions can result in changes to the thermal stability of the protein. We utilized far-UV circular dichroism spectropolarimetry and fluorescence spectroscopy to investigate the interaction of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes with two recombinant human serum albumins (rHSA). We demonstrate that rHSA expressed in Oryza sativa (OsrHSA) has improved secondary structure thermal stability compared to rHSA expressed in Pichia pastoris (PprHSA). A similar stability profile was observed when comparing bovine serum albumin (BSA) and defatted bovine serum albumin (dfBSA), suggesting the presence of fatty acids may be responsible for the improved stability of OsrHSA. Addition of DPPC liposomes reduced the thermal stability of both OsrHSA and BSA, but not of PprHSA or dfBSA. DPPC liposomes may disrupt stabilizing native fatty acids on OsrHSA and BSA. PMID- 22423960 TI - To die or not to die: Shigella has an answer. AB - Invasion of epithelial cells by Shigella is a critical step in the pathogenesis of bacillary dysentery. In this issue of Cell Host & Microbe, Bergounioux et al. (2012) uncover a complex interplay of proinvasion, prosurvival, and prodeath signals centered on the activation of calpain protease by the Shigella VirA protein. PMID- 22423961 TI - Crossing the Rubicon: new roads lead to host defense. AB - Rubicon is a protein known to engage the Beclin-1/Vps34-PI3K/UVRAG complex and inhibit endosome and autophagosomal fusion with lysosomes. Yang et al. (2012) uncover new roles for this adaptor protein within noncanonical p22(phox) or CARD9 complexes that regulate oxidative and cytokine responses in activated macrophages, respectively. Both complexes impact pathogen-specific host defense. PMID- 22423962 TI - A way to DAI. AB - RIP3-regulated necrosis has recently emerged as an important antiviral host defense mechanism. A new study by Upton et al. (2012) identifies DAI, a cytoplasmic DNA sensor, as a partner of RIP3 that is essential for the induction of regulated necrosis in cytomegalovirus-infected cells. PMID- 22423963 TI - Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. AB - Neutrophils are innate immune cells that counter pathogens by many mechanisms, including release of antimicrobial proteins such as calprotectin to inhibit bacterial growth. Calprotectin sequesters essential micronutrient metals such as zinc, thereby limiting their availability to microbes, a process termed nutritional immunity. We find that while calprotectin is induced by neutrophils during infection with the gut pathogen Salmonella Typhimurium, calprotectin mediated metal sequestration does not inhibit S. Typhimurium proliferation. Remarkably, S. Typhimurium overcomes calprotectin-mediated zinc chelation by expressing a high affinity zinc transporter (ZnuABC). A S. Typhimurium znuA mutant impaired for growth in the inflamed gut was rescued in the absence of calprotectin. ZnuABC was also required to promote the growth of S. Typhimurium over that of competing commensal bacteria. Thus, our findings indicate that Salmonella thrives in the inflamed gut by overcoming the zinc sequestration of calprotectin and highlight the importance of zinc acquisition in bacterial intestinal colonization. PMID- 22423964 TI - Calpain activation by the Shigella flexneri effector VirA regulates key steps in the formation and life of the bacterium's epithelial niche. AB - The enteropathogen Shigella flexneri invades epithelial cells, leading to inflammation and tissue destruction. We report that Shigella infection of epithelial cells induces an early genotoxic stress, but the resulting p53 response and cell death are impaired due to the bacterium's ability to promote p53 degradation, mainly through calpain protease activation. Calpain activation is promoted by the Shigella virulence effector VirA and dependent on calcium flux and the depletion of the endogenous calpain inhibitor calpastatin. Further, although VirA-induced calpain activity is critical for regulating cytoskeletal events driving bacterial uptake, calpain activation ultimately leads to necrotic cell death, thereby restricting Shigella intracellular growth. Therefore, calpains work at multiple steps in regulating Shigella pathogenesis by disrupting the p53-dependent DNA repair response early during infection and regulating both formation and ultimate death of the Shigella epithelial replicative niche. PMID- 22423965 TI - Disruption of PAMP-induced MAP kinase cascade by a Pseudomonas syringae effector activates plant immunity mediated by the NB-LRR protein SUMM2. AB - Pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) serves as a primary plant defense response against microbial pathogens, with MEKK1, MKK1/MKK2, and MPK4 functioning as a MAP kinase cascade downstream of PAMP receptors. Plant Resistance (R) proteins sense specific pathogen effectors to initiate a second defense mechanism, termed effector-triggered immunity (ETI). In a screen for suppressors of the mkk1 mkk2 autoimmune phenotype, we identify the nucleotide-binding leucine-rich repeat (NB-LRR) protein SUMM2 and find that the MEKK1-MKK1/MKK2-MPK4 cascade negatively regulates SUMM2-mediated immunity. Further, the MEKK1-MKK1/MKK2-MPK4 cascade positively regulates basal defense targeted by the Pseudomonas syringae pathogenic effector HopAI1, which inhibits MPK4 kinase activity. Inactivation of MPK4 by HopAI1 results in activation of SUMM2-mediated defense responses. Our data suggest that SUMM2 is an R protein that becomes active when the MEKK1-MKK1/MKK2-MPK4 cascade is disrupted by pathogens, supporting the hypothesis that R proteins evolved to protect plants when microbial effectors suppress basal resistance. PMID- 22423966 TI - Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. AB - Phagocytosis and autophagy are two important and related arms of the host's first line defense against microbial invasion. Rubicon is a RUN domain containing cysteine-rich protein that functions as part of a Beclin-1-Vps34-containing autophagy complex. We report that Rubicon is also an essential, positive regulator of the NADPH oxidase complex. Upon microbial infection or Toll-like receptor 2 (TLR2) activation, Rubicon interacts with the p22phox subunit of the NADPH oxidase complex, facilitating its phagosomal trafficking to induce a burst of reactive oxygen species (ROS) and inflammatory cytokines. Consequently, ectopic expression or depletion of Rubicon profoundly affected ROS, inflammatory cytokine production, and subsequent antimicrobial activity. Rubicon's actions in autophagy and in the NADPH oxidase complex are functionally and genetically separable, indicating that Rubicon functions in two ancient innate immune machineries, autophagy and phagocytosis, depending on the environmental stimulus. Rubicon may thus be pivotal to generating an optimal intracellular immune response against microbial infection. PMID- 22423967 TI - The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity. AB - Assembly of a scaffold consisting of CARD9, BCL10, and MALT1 (CBM complex) is critical for effective signaling by multiple pattern recognition receptors (PRRs) including Dectin and RIG-I. The RUN domain Beclin-1-interacting cysteine-rich containing Rubicon protein associates constitutively with the Beclin-UVRAG-Vps34 complex under normal conditions to regulate autophagy. Rubicon also interacts with the phagocytic NADPH-oxidase complex upon TLR stimulation to induce potent antimicrobial responses. Here, we show Rubicon is a physiological feedback inhibitor of CBM-mediated PRR signaling, preventing unbalanced proinflammatory responses. Upon Dectin-1- or RIG-I-mediated activation, Rubicon dynamically exchanges binding partners from 14-3-3beta to CARD9 in a stimulation-specific and phosphorylation-dependent manner, disassembling the CBM signaling complex and ultimately terminating PRR-induced cytokine production. Remarkably, Rubicon's actions in the autophagy complex, phagocytosis complex, and CBM complex are functionally and genetically separable. Rubicon thus differentially targets signaling complexes, depending on environmental stimuli, and may function to coordinate various immune responses against microbial infection. PMID- 22423968 TI - DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. AB - Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3(-/ ) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis. PMID- 22423969 TI - Pancreatic acinar cell-specific autophagy disruption reduces coxsackievirus replication and pathogenesis in vivo. AB - Autophagy protects against many infections by inducing the lysosomal-mediated degradation of invading pathogens. However, previous in vitro studies suggest that some enteroviruses not only evade these protective effects but also exploit autophagy to facilitate their replication. We generated Atg5(f/f)/Cre(+) mice, in which the essential autophagy gene Atg5 is specifically deleted in pancreatic acinar cells, and show that coxsackievirus B3 (CVB3) requires autophagy for optimal infection and pathogenesis. Compared to Cre(-) littermates, Atg5(f/f)/Cre(+) mice had an ~2,000-fold lower CVB3 titer in the pancreas, and pancreatic pathology was greatly diminished. Both in vivo and in vitro, Atg5(f/f)/Cre(+) acinar cells had reduced intracellular viral RNA and proteins. Furthermore, intracellular structural elements induced upon CVB3 infection, such as compound membrane vesicles and highly geometric paracrystalline arrays, which may represent viral replication platforms, were infrequently observed in infected Atg5(f/f)/Cre(+) cells. Thus, CVB3-induced subversion of autophagy not only benefits the virus but also exacerbates pancreatic pathology. PMID- 22423970 TI - Cofactors required for TLR7- and TLR9-dependent innate immune responses. AB - Pathogens commonly utilize endocytic pathways to gain cellular access. The endosomal pattern recognition receptors TLR7 and TLR9 detect pathogen-encoded nucleic acids to initiate MyD88-dependent proinflammatory responses to microbial infection. Using genome-wide RNAi screening and integrative systems-based analysis, we identify 190 cofactors required for TLR7- and TLR9-directed signaling responses. A set of cofactors were crossprofiled for their activities downstream of several immunoreceptors and then functionally mapped based on the known architecture of NF-kappaB signaling pathways. Protein complexes and pathways involved in ubiquitin-protein ligase activities, sphingolipid metabolism, chromatin modifications, and ancient stress responses were found to modulate innate recognition of endosomal nucleic acids. Additionally, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) was characterized as necessary for ubiquitin-dependent TLR9 targeting to the endolysosome. Proteins and pathways identified here should prove useful in delineating strategies to manipulate innate responses for treatment of autoimmune disorders and microbial infection. PMID- 22423971 TI - Chemometric characterization of fruit juices from Spanish cultivars according to their phenolic compound contents: I. Citrus fruits. AB - The data set composed by phenolic compound profiles of 83 Citrus juices (determined by HPLC-DAD-MS/MS) was evaluated by chemometrics to differentiate them according to Citrus species (sweet orange, tangerine, lemon, and grapefruit). Cluster analysis (CA) and principal component analysis (PCA) showed natural sample grouping among Citrus species and even the Citrus subclass. Most of the information contained in the full data set can be captured if only 15 phenolic compounds (concentration >=10 mg/L), which can be quantified with fast and accurate methods in real samples, are introduced in the models; a good classification which allows the confirmation of the authenticity of juices is achieved by linear discriminant analysis. Using this reduced data set, fast and routine methods have been developed for predicting the percentage of grapefruit in adulterated sweet orange juices using principal component regression (PCR) and partial least-squares regression (PLS). The PLS model has provided suitable estimation errors. PMID- 22423972 TI - Argutalactone, an unprecedented sesquiterpenoid lactone with a 6/5/7 tricyclic system from Incarvillea arguta. AB - Argutalactone (1), a novel sesquiterpenoid lactone featuring an unprecedented 6/5/7 rigid skeleton, was isolated from the roots of Incarvillea arguta. The structure and relative configuration of 1 were established by extensive analysis of spectroscopic data. The absolute configuration of 1 was determined as 2R,5S,10R,12S based on the analysis of biogenetical transformation, comparison of the optical rotation with literature data, and comparison of the experimental circular dichroism spectrum with the calculated electronic circular dichroism spectra. PMID- 22423973 TI - Defect-driven magnetism in luminescent n/p-type pristine and Gd-substituted SnO2 nanocrystalline thin films. AB - The effects of rare-earth-element Gd doping on the intrinsic magnetic ordering, photoluminescence, and electrical-conducting properties of the pristine SnO(2) nanocrystalline thin films fabricated by radio-frequency (RF) sputtering are investigated. The pristine SnO(2) thin film exhibits significant ferromagnetism while Gd doping results in an absence of intrinsic ferromagnetism. The presence of large amounts of singly ionized oxygen vacancies (V(O)(+)) is traced by photoluminescence spectroscopic analysis and they are found to be responsible for the observed ferromagnetism in pristine SnO(2) thin films. A significant reduction of oxygen vacancies is observed after Gd doping, and that might be insufficient to mediate long-range ferromagnetic ordering between V(O)(+) defects in a Gd-doped SnO(2) system. Although the associated magnetic moment is increased by 1 order of magnitude, because of the insertion of Gd(3+) ions, which have localized f-shell paramagnetic moment, there is no intrinsic FM ordering. Hall measurement reveals that the pure SnO(2) exhibits n-type behavior whereas Gd doped SnO(2) films show the p-type conductivity with higher resistivity. The studies demonstrate that only structural defects such as V(O)(+) defects, not magnetic ions such as Gd(3+), are responsible for inducing ferromagnetism in SnO(2) thin films. PMID- 22423974 TI - Beneficial influence of fungal metabolite nigerloxin on eye lens abnormalities in experimental diabetes. AB - Osmotic and oxidative stress have been implicated in the pathogenesis of diabetic cataract. Nigerloxin, a fungal metabolite, has been shown to possess aldose reductase inhibitory and free radical scavenging potential, in vitro. In the present study, the beneficial influence of nigerloxin was investigated on diabetes-induced alteration in the eye lens of rats treated with streptozotocin. Groups of diabetic rats were administered nigerloxin orally (100 mg.(kg body mass)(-1).day(-1)) for 30 days. The activity of lens polyol pathway enzymes (aldose reductase and sorbitol dehydrogenase), lipid peroxides, and advanced glycation end products (AGEs) were increased in the diabetic animals. Levels of glutathione as well as the activity of antioxidant enzymes (superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase) were decreased in the eye lens of the diabetic animals. The administration of nigerloxin significantly decreased levels of lipid peroxides and AGEs in the lens of the diabetic rats. Increase in the activity of aldose reductase and sorbitol dehydrogenase in the lens was countered by nigerloxin treatment. The activity of glutathione and antioxidant enzyme in the lens was significantly elevated in nigerloxin-treated diabetic rats. Examination of the treated rats' eyes indicated that nigerloxin delayed cataractogenesis in the diabetic rats. The results suggest the beneficial countering of polyol pathway enzymes and potentiation of the antioxidant defense system by nigerloxin in diabetic animals, implicating its potential in ameliorating cataracts in diabetics. PMID- 22423975 TI - Risk factors for morbidity and death in non-cystic fibrosis bronchiectasis: a retrospective cross-sectional analysis of CT diagnosed bronchiectatic patients. AB - INTRODUCTION: There is a relative lack of information about the death rate and morbidity of non-cystic fibrosis bronchiectasis and most studies are limited due to referral bias. We wanted to assess death rate and morbidity in those patients at our hospital. METHODS: Adult patients seen at our department between June 2006 and November 2009 were recruited if the key string "bronchiect-" was mentioned in electronic clinical records and if chest CT imaging was available. Clinical records of all patients with confirmed radiologic diagnosis of bronchiectasis were reviewed and clinical characteristics were analyzed. RESULTS: 539 patients with a radiographic diagnosis of non-cystic fibrosis bronchiectasis were identified in a retrospective cross-sectional analysis giving a prevalence of 2.6% in our hospital population. A wide range of etiologies was found with idiopathic bronchiectasis in 26%. In the 41 months interval, 57 patients (10.6%) died. We found a median exacerbation rate of 1.94 per year. Bacterial colonization status was associated with more deaths, exacerbation rate, symptoms and reduced pulmonary function. Pulmonary hypertension was found in 48% of our patients. CONCLUSIONS: We evaluated a large non-cystic fibrosis bronchiectasis population, and provided new epidemiological data on associations between clinical characteristics and deaths and morbidity in these patients. PMID- 22423976 TI - Relative and absolute reliability of the new "Step-Ex" step-execution test in elderly people with and without balance problems. AB - PURPOSE: To evaluate the relative and absolute test-re-test reliability of a new step-execution test, "Step-Ex", for clinical use in elderly with and without balance problems. METHOD: Test-re-test design to assess intrarater reliability. Thirty-four healthy community-dwelling elderly (65-87 years), 16 with balance problems, were tested twice two weeks apart. Step-Ex consists of two portable force platforms that register vertical ground reaction forces connected to a computer for easy detection of temporal events and phases (reaction-, preparation , stepping- and step execution phase). Standing with one foot on each platform, the subjects were given a tactile stimulus on the heel to initiate rapid steps forward. RESULTS: Test-re-test agreement was good to very good: ICC(2)(.6) 0.83 0.87 (without balance problems) and 0.71-0.83 (with balance problems) with no apparent systematic differences between the tests. The SEM, i.e. the smallest detectable change that may indicate a real clinical improvement for a group of individuals was small, 4.6-8.6%. The smallest real difference, representing the smallest change that reveals clinical improvement for a single individual, was 13 24%. CONCLUSION: Step-Ex is a highly reliable instrument and can be recommended as an outcome measure evaluating the effects of balance training in elderly people with and without balance deficits. IMPLICATIONS FOR REHABILITATION: * Balance deficits are common in the elderly population. * To evaluate the effects of treatment or changes over time it is of great importance to have reliable instruments. * Step-Ex is a highly reliable instrument and can be recommended as an outcome measure evaluating the effects of treatment or changes over time in elderly people with and without balance deficits. PMID- 22423978 TI - Bayesian approach to the analysis of fluorescence correlation spectroscopy data I: theory. AB - Fluorescence correlation spectroscopy (FCS) is a powerful tool to infer the physical process of macromolecules including local concentration, binding, and transport from fluorescence intensity measurements. Interpretation of FCS data relies critically on objective multiple hypothesis testing of competing models for complex physical processes that are typically unknown a priori. Here, we propose an objective Bayesian inference procedure for testing multiple competing models to describe FCS data based on temporal autocorrelation functions. We illustrate its performance on simulated temporal autocorrelation functions for which the physical process, noise, and sampling properties can be controlled completely. The procedure enables the systematic and objective evaluation of an arbitrary number of competing, non-nested physical models for FCS data, appropriately penalizing model complexity according to the Principle of Parsimony to prefer simpler models as the signal-to-noise ratio decreases. In addition to eliminating overfitting of FCS data, the procedure dictates when the interpretation of model parameters are not justified by the signal-to-noise ratio of the underlying sampled data. The proposed approach is completely general in its applicability to transport, binding, or other physical processes, as well as spatially resolved FCS from image correlation spectroscopy, providing an important theoretical foundation for the automated application of FCS to the analysis of biological and other complex samples. PMID- 22423977 TI - Network motif comparison rationalizes Sec1/Munc18-SNARE regulation mechanism in exocytosis. AB - BACKGROUND: Network motifs, recurring subnetwork patterns, provide significant insight into the biological networks which are believed to govern cellular processes. METHODS: We present a comparative network motif experimental approach, which helps to explain complex biological phenomena and increases the understanding of biological functions at the molecular level by exploring evolutionary design principles of network motifs. RESULTS: Using this framework to analyze the SM (Sec1/Munc18)-SNARE (N-ethylmaleimide-sensitive factor activating protein receptor) system in exocytic membrane fusion in yeast and neurons, we find that the SM-SNARE network motifs of yeast and neurons show distinct dynamical behaviors. We identify the closed binding mode of neuronal SM (Munc18-1) and SNARE (syntaxin-1) as the key factor leading to mechanistic divergence of membrane fusion systems in yeast and neurons. We also predict that it underlies the conflicting observations in SM overexpression experiments. Furthermore, hypothesis-driven lipid mixing assays validated the prediction. CONCLUSION: Therefore this study provides a new method to solve the discrepancies and to generalize the functional role of SM proteins. PMID- 22423979 TI - BRCA1 as a tumor suppressor linked to the regulation of epigenetic states: keeping oncomiRs under control. AB - BRCA1 is a tumor suppressor gene known to be implicated in the development of a subset of breast and ovarian cancers. The tumor suppressor properties of BRCA1 are generally thought to be linked to the gene's critical roles in the network of DNA damage response. In a recent report, BRCA1-mediated epigenetic repression at the promoter region of miRNA-155 was identified as a novel mechanism by which BRCA1 carries out its tumor suppressor functions. PMID- 22423980 TI - State of art: clinical ex vivo lung perfusion: rationale, current status, and future directions. AB - In recent years, ex vivo lung perfusion has emerged as an effective tool for increasing the number of available lungs accepted for transplant. As ex vivo lung perfusion use becomes more widespread, questions have arisen regarding the metabolic activity of the donor lung during ex vivo lung perfusion, optimal perfusion-ventilation strategy, and which parameters best define organ improvement or deterioration. Answers to many of these questions can be found in the published experience with the isolated perfused lung in the study of lung mechanics, pulmonary metabolism, and the effects of various interventions on lung quality. The purpose of this review is to summarize past and present evidence and to provide important background for clinicians and investigators using the ex vivo lung perfusion/isolated perfused lung system. PMID- 22423981 TI - Surface chemistry of ruthenium dioxide in heterogeneous catalysis and electrocatalysis: from fundamental to applied research. PMID- 22423982 TI - Induction of intestinal pro-inflammatory immune responses by lipoteichoic acid. AB - BACKGROUND: The cellular and molecular mechanisms of inflammatory bowel disease are not fully understood; however, data indicate that uncontrolled chronic inflammation induced by bacterial gene products, including lipoteichoic acid (LTA), may trigger colonic inflammation resulting in disease pathogenesis. LTA is a constituent glycolipid of Gram-positive bacteria that shares many inflammatory properties with lipopolysaccharide and plays a critical role in the pathogenesis of severe inflammatory responses via Toll-like receptor 2. Accordingly, we elucidate the role of LTA in immune stimulation and induced colitis in vivo. METHODS: To better understand the molecular mechanisms utilized by the intestinal microbiota and their gene products to induce or subvert inflammation, specifically the effect(s) of altered surface layer protein expression on the LTA mediated pro-inflammatory response, the Lactobacillus acidophilus surface layer protein (Slp) genes encoding SlpB and SlpX were deleted resulting in a SlpB- and SlpX- mutant that continued to express SlpA (assigned as NCK2031). RESULTS: Our data show profound activation of dendritic cells by NCK2031, wild-type L. acidophilus (NCK56), and purified Staphylococcus aureus-LTA. In contrary to the LTA-deficient strain NCK2025, the LTA-expressing strains NCK2031 and NCK56, as well as S. aureus-LTA, induce pro-inflammatory innate and T cell immune responses in vivo. Additionally, neither NCK2031 nor S. aureus-LTA supplemented in drinking water protected mice from DSS-colitis, but instead, induced significant intestinal inflammation resulting in severe colitis and tissue destruction. CONCLUSIONS: These findings suggest that directed alteration of two of the L. acidophilus NCFM-Slps did not ameliorate LTA-induced pro-inflammatory signals and subsequent colitis. PMID- 22423983 TI - Migrant tuberculosis: the extent of transmission in a low burden country. AB - BACKGROUND: Human migration caused by political unrest, wars and poverty is a major topic in international health. Infectious diseases like tuberculosis follow their host, with potential impact on both the migrants and the population in the recipient countries. In this study, we evaluate Mycobacterium tuberculosis transmission between the national population and migrants in Denmark. METHODS: Register study based on IS6110-RFLP results from nationwide genotyping of tuberculosis cases during 1992 through 2004. Cases with 100% identical genotypes were defined as clustered and part of a transmission chain. Origin of clusters involving both Danes and migrants was defined as Danish/migrant/uncertain. Subsequently, the proportion of cases likely infected by the "opposite" ethnic group was estimated. RESULTS: 4,631 cases were included, representing 99% of culture confirmed cases during 1992 through 2004. Migrants contributed 61.6% of cases. Up to 7.9% (95% CI 7.0-8.9) of migrants were infected by Danes. The corresponding figure was 5.8% (95% CI 4.8-7.0) for Danes. Thus, transmission from Danes to migrants occurred up to 2.5 (95% CI 1.8-3.5) times more frequent than vice versa (OR = 1). A dominant strain, Cluster-2, was almost exclusively found in Danes, particular younger-middle-aged males. CONCLUSIONS: Transmission between Danes and migrants is limited, and risk of being infected by the "opposite" ethnic group is highest for migrants. TB-control efforts should focus on continues micro-epidemics, e.g. with Cluster-2 in Danes, prevention of reactivation TB in high-risk migrants, and outbreaks in socially marginalized migrants, such as Somalis and Greenlanders. Fears that TB in migrants poses a threat for resident Danes seem exaggerated and unjustified. We believe this to be true for other low incidence countries as well. PMID- 22423984 TI - Fabrication and morphology of spongelike polymer material based on cross-linked sulfonated polystyrene particles. AB - A novel spongelike polymer material has been fabricated by gamma-ray induced polymerization of methylmethacrylate (MMA) in an emulsion containing cross-linked sulfonated polystyrene (CSP) particles. Scanning electron microscopy (SEM) images reveal that the spongelike structure is made up of interlinked nanosized PMMA particles with micrometer-sized CSP-PMMA particles embedded inside. The nitrogen adsorption isotherm discloses that the spongelike material has a high specific surface area of 29 m(2)/g and a narrow pore size distribution of 60-120 nm. The formation mechanism is discussed in this paper, which indicates that the key steps to form the spongelike material include a Pickering emulsion stabilized by the CSP particles, followed by the swelling process of MMA into these particles. This approach offers a more convenient alternative to prepare polymeric spongelike material without any etching procedure. PMID- 22423985 TI - Historical trends analysis of 2004 to 2009 toxicity and pesticide data for California's central valley. AB - The goals of this study were to conduct temporal trends analysis of 2004-2009 toxicity and pesticide data sets for four Central Valley Water Quality Coalitions in California. The general conclusions from analysis of 6 years of toxicity and pesticide data from these Central Valley Coalitions is that a significant decline has occurred with Ceriodaphnia toxicity, diazinon concentrations and chlorpyrifos concentrations. There was no data to support a significant increase in toxicity or pesticide concentrations from any of the data sets analyzed from 2004 to 2009. In addition, the percent of diazinon and chlorpyrifos samples exceeding water quality objectives of these organophosphate insecticides has also declined significantly from 2004 to 2009. Interpretation of all toxicity and pesticide data used in this analysis within a "weight of evidence context" suggests that water quality conditions have generally improved in the Central Valley Region of California from 2004 to 2009. PMID- 22423986 TI - Radioactivity of mining sites of lead, zinc and phosphate ores in Serbia. AB - Natural resources such as ores contain radioactive nuclides at various concentrations. Therefore it is important to investigate the radioactivity in these resources as well as in the soil at the locations of ore deposits. For that reason we conducted preliminary measurements in the soil samples taken from the locations of lead and zinc ore deposits in Bosilegrad and Raska and from the locations of phosphate ore deposits in Bosilegrad to estimate the environmental conditions prior to the ore excavation. The activity concentrations of radionuclides in soil, water and plant samples were determined by gamma spectrometry (HPGe detector, relative efficiency 23%). Results showed the presence of natural radionuclides (226)Ra, (232)Th, (40)K, (235)U, (238)U as well as the produced radionuclide (137)Cs (from the Chernobyl accident). Ambient gamma radiation dose rate in ground level air was also measured. In order to estimate the influence of subsequent mining on the working and living environment, radium equivalent (Ra(eq)), external hazard index (H(ex)), external gamma absorbed dose rate ([Formula: see text]) and annual effective dose (D(E)) were determined. PMID- 22423987 TI - Pollution level and health risk assessment of road dust from an expressway. AB - Thirteen road dust and four soil samples were analyzed using instrumental neutron activation analysis (INAA) to determine the elemental composition of road dust collected from Islamabad Expressway. The amounts of most of the elements determined were generally in the lower range of the global data with the exception of Ce, Nd, Sn and Zr, which were measured at higher concentrations in Islamabad. The magnitudes of Enrichment Factors (EFs) showed that the area around Islamabad Expressway is low to moderately polluted especially by elements such as Mg and Sb. Elemental health risk was assessed through dose calculations for carcinogenic and non-carcinogenic metals; and by the determination of LADD (lifetime average daily dose). The carcinogenic metals studied showed the following variation in their LADD values; Cr>Ni>Co>Cd>As. Dose calculations for non-cancerous and cancerous elements showed the data obtained to lie within the safe threshold of 10(-3)-10(-6) mg kg(-1) day(-1) for most elements. The Soil based elements Al, Fe, K, Mg, Na and Ti were the exception and originated from the exposed soil around the highway. Moreover highest Hazard Index (HI) was found to be associated with the presence of Al, Cr, Pb and V in road dust showing soil, transport and industry to be the major sources of road dust. PMID- 22423988 TI - Development of an analytical microbial consortia method for enhancing performance monitoring at aerobic wastewater treatment plants. AB - An analytical method to produce profiles of bacterial biomass fatty acid methyl esters (FAME) was developed employing rapid agitation followed by static incubation (RASI) using selective media of wastewater microbial communities. The results were compiled to produce a unique library for comparison and performance analysis at a Wastewater Treatment Plant (WWTP). A total of 146 samples from the aerated WWTP, comprising 73 samples of each secondary and tertiary effluent, were included analyzed. For comparison purposes, all samples were evaluated via a similarity index (SI) with secondary effluents producing an SI of 0.88 with 2.7% variation and tertiary samples producing an SI 0.86 with 5.0% variation. The results also highlighted significant differences between the fatty acid profiles of the tertiary and secondary effluents indicating considerable shifts in the bacterial community profile between these treatment phases. The WWTP performance results using this method were highly replicable and reproducible indicating that the protocol has potential as a performance-monitoring tool for aerated WWTPs. The results quickly and accurately reflect shifts in dominant bacterial communities that result when processes operations and performance change. PMID- 22423989 TI - A quantitative method evaluating the selective adsorption of molecularly imprinted polymer. AB - Adsorption isotherms of 4 estrogenic compounds, estrone, 17beta-estradiol, 17alpha-ethinylestradiol and Bisphenol A, using molecularly imprinted polymer were studied. The isotherms can be simulated by Langmuir model. According to the adsorption isotherms and the template's mass balance, an experimental concept, selective adsorption ratio, SAR, was proposed to assess how many template molecules extracted out of MIP could create selective binding sites. The SAR of the molecularly imprinted polymer was 74.3% for E2. This concept could be used to evaluate quantitatively the selective adsorption. PMID- 22423990 TI - Sugar phosphorylation activity in ruminal acetogens. AB - Acetogenic bacteria Acetitomaculum ruminis, Acetobacterium woodii, and Eubacterium limosum were compared for phosphoenolpyruvate (PEP) and ATP-dependent phosphorylation of glucose and 2-deoxy-glucose. Rate of phosphorylation activity was measured in toluene-treated acetogenic cells using PEP and ATP and radiolabled glucose or 2-deoxy glucose. Eubacterium limosum, most likely has a glucose phosphotransferase system (PTS). In contrast, A. ruminis, and A. woodii had PEP-dependent glucose phosphorylation rates very similar to control rates, suggesting the lack of PTS activity. These results were confirmed by PEP dependent 2-deoxyglucose phosphorylation data. The rates of ATP-dependent glucose phosphorylation were higher than PEP-dependent glucose dependent in all organisms surveyed. Only E. limosum appeared to have PTS. The presence of PTS in E. limosum could explain why it is not capable of utilizing sugars and H(2)/CO(2) simultaneously and why acetogenesis is not as prominant in the rumen because of the availability of carbohydrates as alternative energy substrates. PMID- 22423991 TI - Novel nanofiberous membrane fabricated via electrospinning of wastage fuzzes of mechanized carpet used for dye removal of the carpet dyeing wastewater. AB - Novel nanofibrous membrane was fabricated by using electrospinning of wastage fuzzes of mechanized carpet which was used to remove the dye of the textile wastewater. SEM images showed that nanofibers with average diameters of 200 nm were successfully fabricated by electrospinning technique. The physicochemical properties of electrospun nanofiberous membranes were studied by differential scanning calorimetry (DSC), energy-dispersive X-ray (EDX), and Fourier transform infrared (FTIR) spectroscopy. FTIR confirmed the presence of C=N, C=N, and C-N groups in the electrospun nanofibers which are the main functional groups of polyacrilonitrile (PAN). The resulting membrane showed dye retention of 96% of carpet dyeing wastewater, demonstrating the high separation potential of such membrane for wastewater treatment. We believe that simple approaches such as the present one would open up enormous possibilities in effective uses of wastage fuzzes of textile industry, considering the fact that electrospinning is a cost effective method for the mass scale production of nanofibers. PMID- 22423992 TI - Mercury speciation and effects on soil microbial activities. AB - To study Hg toxicity on soil microbes and their activities, it is necessary to understand its various forms in soils. The objectives of this study were to investigate Hg speciation in four soil types spiked with Hg (300 mg kg(-1) soil) and its effects on soil microbial respiration and enzymes (amidohydrolases and phosphatase) activities. An assessment of the chemical forms, amounts, reactions, and mobility of Hg in soils and sediments is of significant importance to improve and maintain soil and environmental health and sustainability. Mercury speciation analysis was investigated under acidic and alkaline conditions using a modified sequential procedure, which differentiates Hg into the four distinct fractions. Soil microbial respiration and enzymes activities were determined under laboratory settings, by incubating the soils at 25 degrees C for 30 days, and then determining the amount of CO(2) evolved. Speciation results revealed that the water soluble form was the least, with < 1% of the total Hg in the soil types investigated irrespective of the pH condition, while the residual fraction was the most abundant (> 80%) in Canisteo, Houston, and Ketona soils under acidic conditions and < 35% in Decatur soil. Under alkaline conditions, the residual fraction was <= 70% in Canisteo, Houston, and ketona and <= 29% in Decatur soil. The exchangeable fraction was the second most abundant fraction in the soils used ranging from 3.7-50.0% under acid conditions and 16.9-52.1% under alkaline conditions indicating that Hg desorption was found to be more favorable under alkaline than acidic conditions. Soil respiration was suppressed by Hg especially at the 100 mg kg(-1) concentration level. Amidohydrolases and phosphatases' response in the presence of Hg was variable. Amidohydrolases were more sensitive to Hg (18-90%) than phosphatase (0-35%) in all soils. This study demonstrated that the forms in which Hg exist in soils may determine its bioavailability and toxicity. Also microbial respiration and enzyme activities are potential bioindicators of heavy metal contamination of the environment. PMID- 22423993 TI - Evolution of filamentous bacteria during urban wastewater treatment by MBR. AB - Evolution of filamentous bacteria in two full-scale experimental MBR systems (microfiltration and ultrafiltration) was studied during two years. Sludge Retention Time (SRT) and Hydraulic Retention Time (HRT) were modified and acted as variables, together with temperature and variation in loading. With SRT values between 20 and 35 d and HRT between 31 and 40 h, both MBR systems presented a high density of filamentous bacteria, according to the Filamentous Index (FI) and Simplified Technique of Filamentous Count (STFC). Highest density was achieved when contaminant loads were high and temperature was low. However, the elevated presence of filamentous bacteria did not affect the quality of effluent or the permeability of the membranes. Nocardioform bacteria showed a high degree of adaptation to the characteristics of the system. Predominance of Nocardioforms gave rise to isolated episodes of massive growth at temperatures between 15 and 20 degrees C, which in turn caused episodes of intense foaming whose most significant consequence was a loss in biomass, leading to a slight increase in transmembrane pressure. In the light of these results, FI and STFC should not be considered as suitable tools for predicting operational problems deriving from filamentous bacteria in MBR systems, which could be prevented through identification. PMID- 22423994 TI - Effects of oxytetracycline on anammox activity. AB - Batch experiments were conducted to investigate the effects of oxytetracycline on anaerobic ammonium oxidation (anammox) process. The short-and long-term effects on anammox activity were studied by measuring ammonium (NH(4)(+)), nitrite (NO(2)(-)), and nitrate (NO(3)(-)) concentrations over time. Experiments were conducted at NH(4)(+)and NO(2)(-) concentrations of 60-90 mg N/L and 60-190 mg N/L, respectively (NH(4)(+):NO(2)(-) ratio from 1:1-1:2.25), oxytetracycline concentrations of 10-100 mg/L, and biomass concentrations of 300-800 mg/L. In the short-term study, anammox activity was inhibited by all oxytetracycline concentrations studied. However, daily addition of oxytetracycline to a concentration of 5 +/- 3.5 mg/L in the anammox sequencing batch reactor completely inhibited anammox activity in the fifth week. Fluorescent in situ hybridization was used to identify autotrophic ammonium oxidizing bacteria (Nitrosomonas spp., Nitrobacter spp., Nitrospira spp., Candidatus Brocadia anammoxidans, and Candidatus Kuenenia stuttgartiensis). The population of anammox culture was significantly decreased while Nitrosomonas spp. and Nitrospira spp. increased in the fifth week compared with the first week of experiment. A not competitive model fit the anammox inhibition data at oxytetracycline concentrations of 0-100 mg/L quite well with V(max) of 0.0435 mg N/mg VSS-hr and K(i) of 54.66 mg/L. PMID- 22423995 TI - Effect of salt concentration and mediators in salt bridge microbial fuel cell for electricity generation from synthetic wastewater. AB - The aim of this study was to investigate the feasibility of using agar salt bridges for proton transport in Microbial Fuel Cells (MFC). It also tries to elucidate and effect of mediators on electricity production from wastewaters through experimentation using a simulated wastewater. In order to offset the very high cost of proton exchange membrane, salt bridges have been used in dual chamber MFCs. When the concentration of salt was varied in agar salt bridges from 1% to 10%, the volumetric power density changed from 1.71 to 84.99 mW/m(3) with a concomitant variation in power density from 0.32 to 16.02 mW/m(2). The maximum power density was observed at 5% salt concentration with 10% agar, which was accompanied by 88.41% COD reduction. In the case of methylene blue (0.01 mM) as the electron mediator, the voltage and current generation were 0.551 V and 0.47 mA, respectively. A maximum open circuit voltage of 0.718 V was seen at 0.08 mM methylene blue concentration, whereas maximum power densities of 17.59 mW/m(2) and 89.22 mW/m(3) were obtained. Different concentrations of neutral red were also tried out as mediators. A maximum open circuit voltage of 0.730 V was seen at 0.01 mM neutral red, corresponding to a power density of 12.02 mW/m(2) (volumetric power density of 60.97 mW/m(3)). Biofilm formation on the electrode surface was not observed in the presence of mediators, but was present in the absence of mediators. The results clearly demonstrated the feasibility to use agar salt bridge for proton transport and role of mediators in MFCs to generate electricity. PMID- 22423996 TI - Analysis of anti-inflammatory, analgesic, stimulant and antidepressant drugs in purified water from wastewater treatment plants using SPE-LC tandem mass spectrometry. AB - This work presents an effective sample preparation method for the evaluation of seven pharmaceutical compounds belonging to different therapeutic classes in purified water from wastewater treatment plants (WWTPs). The target compounds include caffeine (stimulant), nicotine (stimulant), atenolol (beta blocker), metamizole (anti-inflammatory and analgesic), fluoxetine (antidepressant), paraxanthine (stimulant) and clofibric acid (lipid regulator). Solid-phase extraction (SPE) and liquid chromatography-mass spectrometry (LC-MS) were selected as extraction and detection techniques, respectively. A detailed study of the experimental conditions of extraction was performed. Under optimal conditions, recoveries obtained were in the range of 21% to 100%, and the relative standard deviations were below 12%. The detection and quantification limits of the method were in the range 2.2-97.4 and 21.1-324.7 ng L(-1), respectively. The developed method was successfully applied to evaluate the presence of these pharmaceutical compounds in wastewaters samples from wastewater treatment plants located on the Gran Canaria Island (Spain). Most of the compounds were detected at concentrations up to 12.31 MUg L(-1) in the WWTP influents that were studied. PMID- 22423997 TI - Evaluation of factors influencing Co2+ removal by calcinated bone sorbent using experimental design methodology. AB - Experimental design methodology was applied for evaluation of factors influencing Co(2+) sorption by thermally treated bovine bones. The major aim of this study was to determine factors which affect process the most, as well as their mutual interactions, in order to select conditions that provide maximum sorbent loading. Five process variables (sorbent mass, sorbate concentration, contact time, initial pH and agitation speed) were examined by full factorial design at two levels. The initial sorbate concentration and sorbent mass were found to be a principle factors influencing cation sorption. Furthermore, a considerable interaction effect between these two factors was detected. Optimal conditions for the maximum sorbent loading include the use of small sorbent doses and concentrated Co(2+) solution, without any previous pH adjustment, at least if the pH of actual waste water is within tested range (3 < pH < 6). The contact time and agitation speed, which within investigated ranges had no significant effect on sorption, may be set at their minimum levels (1 h; 10 rpm) to shorten the reaction time and reduce energy consumption. The influence of process factors on other system responses (amounts of Ca(2+) released from apatite phase of bones, and final pH values) were also determined and analyzed. Empirical mathematical models illustrated the dependences of responses on the process variables, whereas residual and statistical analysis confirmed model adequacy. PMID- 22423998 TI - Sorption of nonpolar neutral organic compounds to low-surface-area metal (hydr)oxide- and humic acid- coated model aquifer sands. AB - The roles of mineral-bound humic acid (HA) and mineral surfaces in the sorption of six nonpolar neutral organic compounds with relatively high aqueous solubility, S(w), (1,2,4-trichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, m xylene, toluene, and benzene) to low-surface-area (i.e., <= 1.2 m(2)/g) metal (hydr)oxide- and HA-coated sands with low organic carbon fractions (i.e., 0.006% <= f(oc) <= 0.044%) were investigated using well-characterized mineral surfaces [i.e., alpha-FeO(OH)- or Al(2)O(3)- coated sands], terrestrial HA, and solutions with relatively constant pH and ionic strength. Sorption isotherms of all six compounds to low-surface-area metal (hydr)oxide-and HA-coated sands were practically linear (i.e., 0.898 <= n <= 1.06), and resulted from a combination of sorption to both mineral-bound HA and mineral surfaces, with the dominance of either contribution depending on the properties of the sorbents (e.g., f(oc)) and organic compounds (e.g., S(w) and K(ow)). Compared to HA-associated high-surface area, pure metal (hydr)oxides or clay minerals illustrating that loading levels of HA significantly impacted sorption affinity (i.e., K(oc)) and linearity (i.e., n) for particularly hydrophobic compounds (i.e., phenanthrene, anthracene and pyrene) due to the changes in fractionation, and structural and chemical properties of mineral-bound HA, the subsequent changes of sorption affinity and linearity appeared to be insignificant for the sorption of organic compounds with relatively high S(w) to low-surface-area metal (hydr)oxide- and HA-coated sands with low f(oc) values. Thus, the predictive models for the sorption of organic compounds with relatively high S(w) to low-surface-area metal (hydr)oxide- and HA coated sands may not be remarkably improved by incorporating the complex changes of sorption affinity and linearity caused by the changes in fractionation, and structural and chemical properties of mineral-bound HA, although the mineral surfaces apparently caused physical and chemical changes of HA, and vice versa during adsorption onto mineral surfaces. PMID- 22423999 TI - An algorithmic approach to ST-elevation myocardial infarction triage: effective but not foolproof. PMID- 22424000 TI - Study design for the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial: A double-blind randomized controlled trial of intravenous glucose, insulin, and potassium for acute coronary syndromes in emergency medical services. AB - BACKGROUND: Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. OBJECTIVE: The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation. DESIGN: The IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a >=75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI. CONCLUSION: The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms. PMID- 22424001 TI - A multifaceted intervention to narrow the evidence-based gap in the treatment of acute coronary syndromes: rationale and design of the Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes (BRIDGE-ACS) cluster randomized trial. AB - Translating evidence into clinical practice in the management of acute coronary syndromes (ACS) is challenging. Few ACS quality improvement interventions have been rigorously evaluated to determine their impact on patient care and clinical outcomes. We designed a pragmatic, 2-arm, cluster-randomized trial involving 34 clusters (Brazilian public hospitals). Clusters were randomized to receive a multifaceted quality improvement intervention (experimental group) or routine practice (control group). The 6-month educational intervention included reminders, care algorithms, a case manager, and distribution of educational materials to health care providers. The primary end point was a composite of evidence-based post-ACS therapies within 24 hours of admission, with the secondary measure of major cardiovascular clinical events (death, nonfatal myocardial infarction, nonfatal cardiac arrest, and nonfatal stroke). Prescription of evidence-based therapies at hospital discharge were also evaluated as part of the secondary outcomes. All analyses were performed by the intention-to-treat principle and took the cluster design into account using individual-level regression modeling (generalized estimating equations). If proven effective, this multifaceted intervention would have wide use as a means of promoting optimal use of evidence-based interventions for the management of ACS. PMID- 22424002 TI - Design of the Rule Out Myocardial Ischemia/Infarction Using Computer Assisted Tomography: a multicenter randomized comparative effectiveness trial of cardiac computed tomography versus alternative triage strategies in patients with acute chest pain in the emergency department. AB - Although early cardiac computed tomographic angiography (CCTA) might improve the management of emergency department (ED) patients with acute chest pain, it could also result in increased testing, costs, and radiation exposure. ROMICAT II was a randomized comparative effectiveness trial enrolling patients 40 to 74 years old without known coronary artery disease who presented to the ED with chest pain but without ischemic electrocardiographic (ECG) changes or elevated initial troponin and who required further risk stratification. Overall, 1000 patients at 9 sites within the United States were randomized to either CCTA as the first diagnostic test following serial biomarkers or to standard of care, which included no testing or functional testing such as exercise ECG, stress radionuclide imaging, or stress echocardiography. Test results were provided to ED physicians, yet patient management was not driven by a study protocol in either arm. Data were collected on diagnostic testing, cardiac events, and cost of medical care for the index hospitalization and during the following 28 days. The primary end point was length of hospital stay. Secondary end points were cumulative radiation exposure, resource utilization, and costs of competing strategies. Tertiary end points were institutional, physician, and patient characteristics associated with primary and secondary outcomes. Rate of missed acute coronary syndrome within 28 days was the safety end point. The ROMICAT II will provide rigorous data on whether CCTA is more efficient than standard of care in the management of patients with acute chest pain at intermediate risk for acute coronary syndrome. PMID- 22424003 TI - A randomized controlled trial of oxygen therapy in acute myocardial infarction Air Verses Oxygen In myocarDial infarction study (AVOID Study). AB - BACKGROUND: The role of routine supplemental oxygen for patients with uncomplicated acute myocardial infarction (AMI) has recently been questioned. There is conflicting data on the possible effects of hyperoxia on ischemic myocardium. The few clinical trials examining the role of oxygen in AMI were performed prior to the modern approach of emergent reperfusion and advanced medical management. METHODS: Air Verses Oxygen In myocarDial infarction study (AVOID Study) is a prospective, multi-centre, randomized, controlled trial conducted by Ambulance Victoria and participating metropolitan Melbourne hospitals with primary percutaneous coronary intervention capabilities. The purpose of the study is to determine whether withholding routine supplemental oxygen therapy in patients with acute ST-elevation myocardial infarction but without hypoxia prior to reperfusion decreases myocardial infarct size. AVOID will enroll 490 patients, >18 years of age with acute ST-elevation myocardial infarction of less than 12 hours duration. CONCLUSIONS: There is an urgent need for clinical trials examining the role of oxygen in AMI. AVOID will seek to clarify this important issue. Results from this study may have widespread implications on the treatment of AMI and the use of oxygen in both the pre hospital and hospital settings. PMID- 22424004 TI - Rationale, design, and goals of the Advanced Cardiovascular Imaging Consortium (ACIC): A Blue Cross Blue Shield of Michigan collaborative quality improvement project. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) is an emerging noninvasive anatomical method for evaluation of patients with suspected coronary artery disease (CAD). Multicenter clinical registries are key to efforts to establish the role of CCTA in CAD diagnosis and management. The Advanced Cardiovascular Imaging Consortium (ACIC) is a statewide, multicenter collaborative quality initiative with the intent to establish quality and appropriate use of CCTA in Michigan. METHODS: The ACIC is sponsored by the Blue Cross Blue Shield of Michigan/Blue Care Network, and its 47 sites include imaging centers that offer CCTA and meet established structure and process standards for participation. Patients enrolled include those with suspected ischemia with or without known CAD, and individuals across the entire spectrum of CAD risk. Patient demographics, history, CCTA scan-related data and findings, and 90-day follow-up data are entered prospectively into a centralized database with strict validation tools and processes. Collaborative quality initiatives include radiation dose reduction and appropriate CCTA use by education and feedback to participating sites and referring physicians. CONCLUSIONS: Across a wide range of institutions, the ACIC permits evaluation of "real-world" utilization and effectiveness of CCTA and examines an alternative, nontraditional approach to utilization management wherein physicians and payers collaborate to address the growing problem of cardiac imaging overutilization. PMID- 22424005 TI - Ability of microvolt T-wave alternans to modify risk assessment of ventricular tachyarrhythmic events: a meta-analysis. AB - BACKGROUND: Prior studies have indicated that the magnitude of risk association of microvolt T-wave alternans (MTWA) testing appears to vary with the population studied. We performed a meta-analysis to determine the ability of MTWA to modify risk assessment of ventricular tachyarrhythmic events (VTEs) and sudden cardiac death (SCD) across a series of patient risk profiles using likelihood ratio (LR) testing, a measure of test performance independent of disease prevalence. METHODS: We identified original research articles published from January 1990 to January 2011 that investigate spectrally derived MTWA. Ventricular tachyarrhythmic event was defined as the total and arrhythmic mortality and nonfatal sustained or implantable cardioverter-defibrillator-treated ventricular tachyarrhythmias. Summary estimates were created for positive and nonnegative MTWA results using a random-effects model and were expressed as positive (LR+) and negative (LR-) LRs. RESULTS: Of 1,534 articles, 20 prospective cohort studies met our inclusion criteria, consisting of 5,945 subjects predominantly with prior myocardial infarction or left ventricular dysfunction. Although there was a modest association between positive MTWA and VTE (relative risk 2.45, 1.58-3.79) and nonnegative MTWA and VTE (3.68, 2.23-6.07), test performance was poor (positive MTWA: LR+ 1.78, LR- 0.43; nonnegative MTWA: LR+ 1.38, LR- 0.56). Subgroup analyses of subjects classified as prior VTE, post-myocardial infarction, SCD-HeFT type, and MADIT-II type had a similar poor test performance. A negative MTWA result would decrease the annualized risk of VTE from 8.85% to 6.37% in MADIT-II-type patients and from 5.91% to 2.60% in SCD-HeFT-type patients. CONCLUSIONS: Despite a modest association, results of spectrally derived MTWA testing do not sufficiently modify the risk of VTE to change clinical decisions. PMID- 22424006 TI - Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database. AB - BACKGROUND: The Cardiac Safety Research Consortium (CSRC) provides both "learning" and blinded "testing" digital electrocardiographic (ECG) data sets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This article reports the first results from a blinded testing data set that examines developer reanalysis of original sponsor-reported core laboratory data. METHODS: A total of 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel group TQT in 181 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer-measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. RESULTS: Developer and sponsor reported baseline-adjusted data were similar with average differences <1 ms for all intervals. Both developer- and sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject SD for triplicate QTcF measurements was significantly lower for developer- than sponsor-reported data (5.4 and 7.2 ms, respectively; P < .001). CONCLUSION: The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared with the sponsor-reported study, without the use of a manual core laboratory. These findings indicate that CSRC ECG data sets can be useful for evaluating novel methods and algorithms for determining drug-induced QT/QTc prolongation. Although the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to provide prospective, blinded comparisons of ECG technologies applied for QT/QTc measurement is illustrated. PMID- 22424007 TI - Development and validation of a prioritization rule for obtaining an immediate 12 lead electrocardiogram in the emergency department to identify ST-elevation myocardial infarction. AB - BACKGROUND: Current guidelines recommend an immediate (eg, <10 minutes) 12-lead electrocardiogram (ECG) to identify ST-elevation myocardial infarction (STEMI) among patients presenting to the emergency department (ED) with chest pain. Yet, one third of all patients with myocardial infarction do not have chest pain. Our objective was to develop a practical approach to identify patients, especially those without chest pain, who require an immediate ECG in the ED to identify STEMI. METHODS: An ECG prioritization rule was derived and validated using classification and regression tree analysis among >3 million ED visits to 107 EDs from 2007 to 2008. RESULTS: The final study population included 3,575,178 ED patient visits; of these, 6,464 (0.18%) were diagnosed with STEMI. Overall, 1,413 (21.9%) of patients with STEMI did not present to the ED with chest pain. Major predictors of those requiring an immediate ECG in the ED included age >=30 years with chest pain; age >=50 years with shortness of breath, altered mental status, upper extremity pain, syncope, or generalized weakness; and those with age >=80 years with abdominal pain or nausea/vomiting. When the ECG prioritization rule was applied to a validation sample, it had a sensitivity of 91.9% (95% CI 90.9% 92.8%) for STEMI and a negative predictive value 99.98% (95% CI 99.98%-99.98%). CONCLUSION: A simple ECG prioritization rule based on age and presenting symptoms in the ED can identify patients during triage who are at high risk for STEMI and therefore should receive an immediate 12-lead ECG, often before they are seen by a physician. PMID- 22424008 TI - Comparison of clinical and angiographic prognostic risk scores in patients with acute coronary syndromes: Analysis from the Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial. AB - BACKGROUND: Several prognostic risk scores have been developed for patients with coronary artery disease, but their comparative use in patients with non-ST segment elevation acute coronary syndromes (NSTEACS) undergoing percutaneous coronary intervention (PCI) has not been examined. We therefore investigated the accuracy of the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score, Clinical Synergy Between PCI With Taxus and Cardiac Surgery score (CSS), New Risk Stratification (NERS) score (NERS), Age, Creatinine, Ejection Fraction (ACEF) score, Global Registry for Acute Coronary Events (GRACE) score, and Thrombolysis in Myocardial Infarction (TIMI) score for risk assessment of 1-year mortality, cardiac mortality, myocardial infarction, target vessel revascularization, and stent thrombosis in patients with NSTEACS undergoing PCI. METHODS: The 6 scores were determined in 2,094 patients with NSTEACS treated with PCI enrolled in the angiographic substudy of the ACUITY trial. The prognostic accuracy of the 6 scores was assessed using the c statistic for discrimination and the Hosmer-Lemeshow test for calibration. The index of separation and net reclassification improvement (NRI) were also determined. RESULTS: Scores incorporating clinical and angiographic variables (CSS and NERS) showed the best tradeoff between discrimination and calibration for most end points, with the best discrimination for all end points and good calibration for most of them. The CSS had the best index of separation for most ischemic endpoints and displayed an NRI for cardiac death and myocardial infarction (MI) compared to the other scores, whereas NERS displayed an NRI for all-cause death and target vessel revascularization. The 3 scores-CSS, NERS, and SYNTAX-were the only scores to have both good discrimination and calibration for cardiac mortality. CONCLUSIONS: In patients with NSTEACS undergoing PCI, risk scores incorporating clinical and angiographic variables had the highest predictive accuracy for a broad spectrum of ischemic end points. PMID- 22424009 TI - Data quality in the American Heart Association Get With The Guidelines-Stroke (GWTG-Stroke): results from a national data validation audit. AB - BACKGROUND: Get With The Guidelines (GWTG)-Stroke is a national stroke registry and quality improvement program. We examined the accuracy and reliability of data entered in GWTG-Stroke. METHODS: Data entered by sites in the GWTG-Stroke database were compared with that abstracted from de-identified medical records by trained auditors. Accuracy for each individual data element and a composite accuracy measure were calculated. Reliability was assessed using kappa (kappa) statistics for categorical variables and intraclass correlation (ICC) for continuous variables. RESULTS: A random selection of 438 medical records from 147 GWTG-Stroke hospitals was obtained. Overall accuracy was above 90% for all variables abstracted except for weight (84.9%), serum creatinine (88.1%), deep venous thrombosis prophylaxis (79.0%), and date/time last known well (85.3%). Intermediate to good (kappa or ICC 0.40-0.75) or excellent agreement (kappa or ICC >=0.75) was observed for nearly all audited variables, including time-related performance measures such as arrival within 2 hours of symptom onset (kappa = 0.90) and door-to-needle time <=60 minutes (kappa = 0.72). The overall composite accuracy rate was 96.1%. The composite measure varied slightly by region and hospital academic status, but there were no significant differences in composite accuracy by bed size, ischemic stroke volume, primary stroke center certification, or Coverdell Registry participation. CONCLUSIONS: This audit establishes the reliability of GWTG-Stroke registry data. Individual data elements with suboptimal accuracy should be targeted for further data quality improvement. PMID- 22424010 TI - Renal failure and acute myocardial infarction: clinical characteristics in patients with advanced chronic kidney disease, on dialysis, and without chronic kidney disease. A collaborative project of the United States Renal Data System/National Institutes of Health and the National Registry of Myocardial Infarction. AB - BACKGROUND: Patients with chronic kidney disease (CKD) experience poor outcomes after acute myocardial infarction (AMI). We sought to compare clinical characteristics of advanced CKD, dialysis, and non-CKD patients hospitalized with AMI. METHODS: This observational study used record-linked data from the US Renal Data System and Third National Registry of Myocardial Infarction to identify 2,390 dialysis patients with AMI hospitalizations between April 1998 and June 2000. Advanced CKD patients (n = 29,319) were identified by baseline creatinine level >=2.5 mg/dL. Clinical characteristics of CKD, dialysis, and non-CKD patients (n = 274,777) were compared using the chi(2) test. RESULTS: Clinically significant differences among patients with advanced CKD (dialysis and non-CKD, respectively) on admission were chest pain, 40.4% (41.1% and 61.6%); diagnosis other than acute coronary syndrome, 44% (47.7% and 25.8%); and ST elevation, 15.9% (17.6% and 32.5%). In-hospital adverse outcomes were mortality, 23% (21.7% and 12.6%); unexpected cardiac arrest, 8.9% (12.3% and 6%); congestive heart failure, 41% (25.8% and 21.1%); and major bleeding, 4.9% (4.4% and 3%); P < .001 for all comparisons. In a logistic regression model, the adjusted odds ratio for in-hospital mortality for CKD (vs non-CKD) patients was 1.44 (95% CI 1.39-1.49). CONCLUSIONS: The clinical characteristics of non-dialysis-dependent, advanced CKD patients with AMI are similar to characteristics of dialysis patients and likely contribute to poor outcomes. Intensive efforts for timely, accurate recognition of AMI in advanced CKD patients are warranted. PMID- 22424011 TI - Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy. AB - BACKGROUND: Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are unknown. METHODS AND RESULTS: In 566 patients (age 77 +/- 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or >=0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. RESULTS: The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 [95% CI 1.27-3.07, P = .002] vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and beta-blocker use and allocation to N-terminal pro-B-type natriuretic peptide-guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. CONCLUSIONS: One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments. PMID- 22424012 TI - Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure. AB - BACKGROUND: The optimal type of stem cell for use in patients with ischemic heart disease has not been determined. A primitive population of bone marrow-derived hematopoietic cells has been isolated by the presence of the enzyme aldehyde dehydrogenase and comprises a multilineage mix of stem and progenitor cells. Aldehyde dehydrogenase-bright (ALDH(br)) cells have shown promise in promoting angiogenesis and providing perfusion benefits in preclinical ischemia studies. We hypothesize that ALDH(br) cells may be beneficial in treating ischemic heart disease and thus conducted the first randomized, controlled, double-blind study to assess the safety of the transendocardial injection of autologous ALDH(br) cells isolated from the bone marrow in patients with advanced ischemic heart failure. METHODS: Aldehyde dehydrogenase-bright cells were isolated from patients' bone marrow on the basis of the expression of a functional (aldehyde dehydrogenase) marker. We enrolled 20 patients (treatment, n = 10; control, n = 10). Safety (primary end point) and efficacy (secondary end point) were assessed at 6 months. RESULTS: No major adverse cardiovascular or cerebrovascular events occurred in ALDH(br)-treated patients in the periprocedural period (up to 1 month); electromechanical mapping-related ventricular tachycardia (n = 2) and fibrillation (n = 1) occurred in control patients. Aldehyde dehydrogenase-bright treated patients showed a significant decrease in left ventricular end-systolic volume at 6 months (P = .04) and a trend toward improved maximal oxygen consumption. The single photon emission computed tomography delta analysis showed a trend toward significant improvement in reversibility in cell-treated patients (P = .053). CONCLUSIONS: We provide preliminary evidence that treatment with the novel cell population, ALDH(br) cells, is safe and may provide perfusion and functional benefits in patients with chronic myocardial ischemia. PMID- 22424013 TI - Low-dose dobutamine test associated with interventricular dyssynchrony: a useful tool to identify cardiac resynchronization therapy responders: data from the LOw dose DObutamine stress-echo test in Cardiac Resynchronization Therapy (LODO-CRT) phase 2 study. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is effective in patients with heart failure, but 30% to 50% of subjects are classified as nonresponders. Identifying responders remains a challenging task. AIMS: The LODO-CRT trial investigated the association between left ventricular contractile reserve (LVCR) and clinical and echocardiographic long-term CRT response. METHODS: This is a multicenter, prospective, observational study. Left ventricular contractile reserve was detected using a dobutamine stress echocardiography test, defined as an ejection fraction increase of >5 points. Clinical CRT response was defined as the absence of major cardiovascular events (ie, cardiovascular death or heart failure hospitalization). Echocardiographic response was defined as a left ventricle end-systolic volume reduction of >10%. RESULTS: A total of 221 CRT indicated patients were studied (80% presented LVCR). During a mean follow-up of 15 +/- 5 months, 17 patients died and 16 were hospitalized due to heart failure. The proportion of clinical responders was 155 (88%) of 177 and 33 (75%) of 44 (P = .036) in the groups with and without LVCR, respectively. Kaplan-Meier analysis showed a significant difference in cardiac survival/hospitalization between patients with and without LVCR. The proportion of echocardiographic responders was 144 (87%) of 166 and 16 (42%) of 38 in the groups with and without LVCR (P < .001), respectively; LVCR showed 90% sensitivity and 87% positive predictive value to prefigure echocardiographic CRT responders. Multivariable analysis identified LVCR and interventricular dyssynchrony as independent predictors of CRT response. The concomitant presence of both factors showed 99% specificity and 83% sensitivity in detecting responders. CONCLUSION: The presence of LVCR helps in predicting a clinical and echocardiographic CRT response. Concomitant assessment of LVCR and interventricular dyssynchrony accurately stratifies responder and nonresponder patients. PMID- 22424014 TI - Sex differences in in-hospital mortality in acute decompensated heart failure with reduced and preserved ejection fraction. AB - BACKGROUND: There are no sex-specific survival comparisons between patients with heart failure (HF) with reduced and those with preserved ejection fraction. Large registries noting women have better survival than men combined HF patients with reduced and preserved EF. Other registries that compared patients with reduced and preserved EF did not analyze their data by sex. We sought to evaluate sex/EF differences in mortality and risk factors for survival in hospitalized patients with HF. METHODS: We included hospitals fully participating in Get With The Guidelines-Heart Failure that admitted HF patients with reduced (EF <40%) or preserved (EF >=50%) EF. The primary end point was in-hospital mortality. Multivariate generalized estimating equation logistic models were used to compute odds ratios accounting for hospital clustering. RESULTS: The study cohort consisted of 51,428 patients with EF <40% (36% women, 64% men) and 37,699 patients with EF >=50% (65% women, 35% men). Women compared with men with reduced and preserved EF were older and more likely to have hypertension, depression, or valvular heart disease and less likely to have coronary artery disease or peripheral vascular disease. There were no sex differences in in-hospital mortality (EF <40%, 2.69% women vs 2.89% men, P = .20; EF >=50%, 2.61% women vs 2.62% men, P = .96), and risk factors such as age, systolic blood pressure, heart rate, and history of renal failure/dialysis were highly predictive of death for each sex/EF subgroup. CONCLUSIONS: In a large, multicenter registry, we found that despite differences in baseline characteristics, women and men with reduced and preserved EF have similar in-hospital mortality and risk factors predicting death. PMID- 22424015 TI - Five-year follow-up of the Sirolimus-Eluting Stents vs Vascular Brachytherapy for Bare Metal In-Stent Restenosis (SISR) trial. AB - OBJECTIVES: The aim of this study was to evaluate the 5-year clinical safety and efficacy outcomes of patients treated for in-stent restenosis of bare-metal stents (BMSs). BACKGROUND: The SISR trial is a prospective, randomized trial that compared the safety and efficacy of sirolimus-eluting stent (SES) vs vascular brachytherapy (VBT) for the treatment of BMS in-stent restenosis. METHODS: A total of 384 patients with BMS in-stent restenosis were randomized to treatment with SES (n = 259) or VBT (n = 125) and were followed for 5 years. RESULTS: At 5 years, the rates of target lesion revascularization (TLR) had narrowed and were nonsignificant between the SES and VBT groups, with TLR rates of 24.7% and 31.2% (95% CI -16.3% to 2.8%, P = .179) respectively. Target vessel failure was 33.6% vs 36.8% (95% CI -13.5% to 6.7% P = .568) for SES compared with VBT. The rate of major adverse cardiac event at 5 years was 34.0% vs 36.8% (95% CI -13.1% to7.1%, P = .648) for the SES compared with VBT. There were no differences between SES and VBT in terms of survival free from TLR (72.9% vs 66.4%, log-rank P = .08) or from target vessel failure (64.4% vs 61.3%, log-rank P = .349). There were no significant differences in the rates of definite/probable stent thrombosis (5.9% vs 2.5%, 95% CI -7.9% to 1.3%, P = .182) between the 2 groups. CONCLUSIONS: At a 5-year follow-up, no differences in safety or efficacy outcomes were observed for treatment of BMS restenosis with SES vs VBT. There were no significant differences in survival free from TLR, target vessel revascularization, or major adverse cardiac events between the 2 groups at 5 years. Sirolimus-eluting stent is a viable treatment option compared with VBT for BMS restenosis. PMID- 22424016 TI - Five-year results of the Multicenter Randomized Controlled Open-Label Study of the CYPHER Sirolimus-Eluting Stent in the Treatment of Diabetic Patients with De Novo Native Coronary Artery Lesions (SCORPIUS) study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic patients. AB - BACKGROUND: Because a delayed arterial healing response after drug-eluting stent implantation has raised concerns about safety in diabetic patients, long-term effects of treatment with sirolimus-eluting stent (SES), as compared with bare metal stent (BMS), have to be established. The aim of the 5-year follow-up of the randomized, controlled, open-label multicenter SCORPIUS study was to assess long term safety and efficacy of the CYPHER (Cordis, Johnson & Johnson, Bridgewater, NJ) SES in percutaneous coronary intervention of diabetic patients. METHODS: A total of 190 patients with type 2 diabetes mellitus were randomized to receive either a SES (n = 95) or a BMS (n = 95). Dual-antiplatelet therapy (aspirin plus clopidogrel) was prescribed for at least 6 months. Clinical follow-up data were scheduled at 1, 8, and 12 months and 5 years. RESULTS: Treatment with SES resulted in a 16% decrease in the rate of major adverse cardiac events (36% vs 52%; hazard ratio 0.6, 95% CI 0.4-0.9; P = .02). This reduction in major adverse cardiac events with SES at 5 years was mostly attributable to a lower number of repeat target lesion revascularization (13% vs 29%; hazard ratio 0.4, 95% CI 0.2 0.7; P = .003). No differences between groups were observed for safety end points (all-cause mortality 21% vs 21%, cardiac death 15% vs 13%, repeat myocardial infarction 8% vs 9%, and stent thrombosis 5% vs 6%) at 5 years. CONCLUSIONS: The 5-year follow-up of the SCORPIUS trial demonstrates the long-term antirestenotic efficacy of SES in diabetic patients with significantly reduced target lesion revascularization and comparable rates of mortality, myocardial infarction, and stent thrombosis compared with BMS. PMID- 22424017 TI - Downstream procedures and outcomes after stress testing for chest pain without known coronary artery disease in the United States. AB - BACKGROUND: Millions of Americans with suspected coronary artery disease undergo noninvasive cardiac stress testing annually. Downstream procedures and subsequent outcomes among symptomatic patients without known coronary disease referred for stress testing are not well characterized in contemporary community practice. METHODS: We examined administrative insurance billing data from a national insurance provider from November 2004 through June 2007. After excluding patients with prior cardiac disease or chest pain evaluation, we identified 80,676 people age 40 to 64 years with outpatient cardiac stress testing within 30 days after an office visit for chest pain. We evaluated rates of invasive coronary angiography, coronary revascularization, and cardiovascular events after stress testing. RESULTS: Within 60 days, only 8.8% of stress test patients underwent cardiac catheterization and only 2.7% underwent revascularization; within 1 year, only 0.5% died and had myocardial infarction or stroke. There were marked geographic variations in 1-year rates of catheterization (3.8%-14.8%) and revascularization (1.2%-3.0%) across 20 hospital referral regions. CONCLUSIONS: In this large national cohort of middle-aged patients without previously coded cardiac diagnosis who were referred for stress testing after outpatient chest pain evaluation, few proceeded to invasive angiography or revascularization, and subsequent cardiovascular events were infrequent. PMID- 22424018 TI - Relationship of female sex to outcomes after myocardial infarction with persistent total occlusion of the infarct artery: analysis of the Occluded Artery Trial (OAT). AB - BACKGROUND: Long-term follow-up (up to 9 years) from the OAT allows for the examination of sex differences in outcomes and the effect of percutaneous coronary intervention (PCI) in a relatively homogeneous cohort of myocardial infarction (MI) survivors. METHODS: The OAT randomized 484 (22%) women and 1717 men to PCI of the occluded infarct-related artery vs medical therapy alone >24 hours post-MI. There was no benefit of PCI on the composite of death, MI, and class IV heart failure. We analyzed outcomes by sex and investigated for sex based trial selection bias using a concurrent registry. RESULTS: Women were older and more likely to have left anterior descending infarct-related artery, diabetes and hypertension, history of heart failure, and rales at randomization but were less likely to smoke. The proportion and characteristics of women enrolled in the trial and the registry were similar, including left ventricular ejection fraction and extent of disease. Women had higher rates of the primary composite (hazard ratio [HR] 1.48, P = .0002), death (HR 1.50, P = .001), and heart failure (HR 2.53, P < .0001) but not reinfarction (HR 1.12, P = .57). Female sex was not independently associated with the primary end point or death on multivariate analysis. There was a trend toward independent association of female sex with heart failure (HR 1.66, P = .02). CONCLUSION: Women in OAT had a higher primary end point event rate than did men, mainly driven by heart failure. Female sex was not independently associated with death or MI in this well-defined cohort with comparable extent of coronary artery disease, similar medical therapy, and equivalent left ventricular ejection fraction by sex. PMID- 22424019 TI - Association of number of live births with left ventricular structure and function. The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Pregnancy is associated with marked maternal cardiovascular/hemodynamic changes. A greater number of pregnancies may be associated with long-term subclinical changes in left ventricular (LV) remodeling. METHODS: Among 2,234 white, black, Hispanic, and Chinese women (mean age 62 years) in the MESA, we used linear regression to relate live births and cardiac magnetic resonance imaging LV measures. Covariates included age, ethnicity, height, income, education, birth country, smoking, menopause, and oral contraceptive duration. Models were additionally adjusted for potential mediators: systolic blood pressure, antihypertensive use, total/high-density lipoprotein cholesterol, triglycerides, diabetes, and body mass index. We performed sensitivity analyses excluding 763 women in the lowest socioeconomic group: annual income <$25,000 and lower high school level of education. RESULTS: With each live birth, LV mass increased 1.26 g; LV end-diastolic volume, 0.74 mL; and LV end-systolic volume, 0.45 mL; LV ejection fraction decreased 0.18% (P trend <0.05). Changes were most notable for the category of women with >=5 pregnancies. Upon adjustment for potential biologic mediators, live births remained positively associated with LV mass and end-systolic volume. Live births remained significantly associated with LV end-systolic, end-diastolic volumes, and LV mass (P trend <=0.02) after excluding women in the lowest socioeconomic group. CONCLUSIONS: Number of live births is associated with key LV structural and functional measures in middle to older ages, even after adjustment for sociodemographic factors and cardiovascular disease risk factors. Hemodynamic changes during pregnancy may be associated with cardiac structure/function beyond childbearing years. PMID- 22424020 TI - Immediate and late outcome of patients aged 80 years and older undergoing isolated aortic valve replacement: a systematic review and meta-analysis of 48 studies. AB - OBJECTIVE: This study was planned to evaluate the outcome of patients >=80 years old undergoing isolated conventional aortic valve replacement (AVR). METHODS: Systematic review of the literature and meta-analysis of data on octogenarians and nonagenarians who underwent isolated AVR were performed. RESULTS: The literature search yielded 48 observational studies reporting on 13 216 patients >=80 years old. Pooled proportion of immediate postoperative mortality was 6.7 % (95% CI 5.8-7.5, 47 studies, 13,092 patients), and it was 5.8% (95% CI 4.8-6.9) in 18 studies with a mid-date from 2000 to 2006 and 7.5% (95% CI 6.8-8.2) in 30 studies with a mid-date from 1982 to 1999 (P = .004). Pooled proportion of postoperative stroke was 2.4% (95% CI 2.1-2.7, 21 studies, 8,436 patients), that of postoperative dialysis was 2.6% (95% CI 1.6-3.8, 10 studies, 1,945 patients), and that of postoperative implantation of a pacemaker was 4.6% (95% CI 3.6-5.8, 6 studies, 1,470 patients). Pooled survival rates at 1, 3, 5, and 10 years after isolated AVR were 87.6%, 78.7%, 65.4%, and 29.7%, respectively. CONCLUSIONS: Immediate postoperative mortality and morbidity after isolated AVR in patients >=80 years old are rather low. Postoperatively mortality decreased even further in the most recent series. Importantly, isolated AVR in these high-risk patients was associated with good late survival. These findings suggest that advanced age alone cannot be considered as a contraindication to conventional isolated AVR and that any new valve prosthesis implanted in these patients should be durable enough to guarantee the results so far offered by conventional surgery. PMID- 22424021 TI - Natural history of exercise function in patients with Ebstein anomaly: A serial study. AB - BACKGROUND: The clinical manifestations of Ebstein anomaly (EA) vary greatly; criteria for surgical intervention remain undefined. Decisions regarding surgical intervention in asymptomatic/mildly symptomatic patients would be helpfully informed by a detailed, quantitative understanding of the natural history of exercise intolerance in these patients. However, past studies of exercise function in EA have been of a cross-sectional, rather than a serial, nature. We, therefore, analyzed serial cardiopulmonary exercise (CPX) tests from patients with unrepaired EA to better appreciate the natural history of their exercise function. METHODS: All patients with EA who had had at least 2 CPX tests, separated by at least 6 months, between November 2002 and October 2010 were identified. Patients with prior tricuspid valve surgery were excluded from the study. RESULTS: Cardiopulmonary exercise data from 23 patients (64 CPX tests; 2.8 +/- 1.0 tests/patient) were analyzed. The median time interval between the first and last CPX tests was 3.3 (range, 0.6-7.3) years. The percentage of predicted peak oxygen consumption declined slowly (1.87 +/- 8.04 percentage points/y) during the follow-up period. The decline was more pronounced (3.04 +/- 6.78 percentage points/y) in patients <18 years old. On multivariate modeling, only the change in oxygen pulse at peak exercise (a surrogate for forward stroke volume) and the change in peak heart rate over time emerged as statistically significant correlates of the change in percentage of predicted peak oxygen consumption. CONCLUSION: The exercise function of patients with EA tends to deteriorate over time. This deterioration appears to be related to a progressive decline in their ability to augment their forward stroke volume and heart rate during exercise. PMID- 22424022 TI - Safety of a conservative strategy of permanent pacemaker implantation after transcatheter aortic CoreValve implantation. AB - BACKGROUND: Conduction abnormalities are frequent after transcatheter aortic valve implantation with the CoreValve (Medtronic, Minneapolis, MN) and are often treated with liberal permanent pacemaker (PPM) implantation. Our aim was to assess the 1-year outcome of a conservative approach to pacing and to identify its predictors. METHODS: We analyzed 275 consecutive patients without a PPM before transcatheter aortic valve implantation who underwent successful CoreValve implantation at our 3 centers, sharing a conservative approach to pacing. RESULTS: Of the 47 patients (17.1%) who developed postprocedural complete atrioventricular block, 14 recovered spontaneous atrioventricular conduction <72 hours and did not receive a PPM. Sixty-six patients (24.0%) received a PPM before discharge, and 74 more patients (26.9%) developed a new left bundle-branch block (LBBB). Independent predictors of PPM implantation were as follows: lower CoreValve implantation below the aortic annulus (odds ratio [OR] 1.16/mm, 95% CI 1.03-1.30, P = .01), right bundle-branch block (OR 3.72, 95% CI 1.5-9.2, P = .004), left anterior hemiblock (OR 2.34, 95% CI 1.1-5.1, P = .03), and longer PR interval (OR 1.02/ms, 95% CI 1.00-1.04, P = .03). One-year survival was similar between patients who received a PPM and patients who did not receive a PPM (P = .90), with no case of sudden death in the latter group, and between patients with a new LBBB not receiving a PPM and patients without postprocedural LBBB (P = .37). CONCLUSION: A high CoreValve implantation level and avoidance of prophylactic pacing in patients with new LBBB without persistent bradyarrhythmias allowed for a relatively low rate of PPM implantation. This conservative approach spared unwarranted pacing and did not affect 1-year survival. PMID- 22424023 TI - A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: a magnetic resonance imaging study. AB - BACKGROUND: We sought to determine whether a 600-mg loading dose of clopidogrel reduces myocardial infarct size compared with a 300-mg dose using contrast enhanced magnetic resonance imaging in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). METHODS: In 198 patients undergoing primary PCI for STEMI, contrast enhanced magnetic resonance imaging was performed a median of 7 days after the index event. Infarct size was measured on delayed-enhancement imaging, and area at risk (AAR) was quantified on T2-weighted images. RESULTS: Baseline characteristics were not significantly different between the 600-mg clopidogrel loading group (n = 117) and the 300-mg group (n = 81). The median infarct size was significantly smaller in the 600-mg group than in the 300-mg group (17.3% [8.9%-26.2%] vs 21.7% [12.9%-30.0%], P = .03). Myocardial salvage index ([AAR - infarct size] * 100/AAR) was greater in the 600-mg group than in the 300-mg group (47.7 [33.7-60.9] vs 32.0 [23.6-51.5], P < .01). Patients in the 600-mg group also had a significantly lower extent of microvascular obstruction and smaller number of segments with >75% of infarct transmurality than did those in the 300 mg group. After propensity score matching, the 600-mg group had smaller infarct size and greater myocardial salvage index compared with the 300-mg group. In multivariate analysis, the use of a 600-mg clopidogrel loading dose significantly reduced the risk of a large infarct (odds ratio 0.53, 95% CI 0.29-0.98, P = .04). CONCLUSIONS: In patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage compared with a 300-mg loading dose. PMID- 22424024 TI - Effects of fenofibrate on cardiovascular events in patients with diabetes, with and without prior cardiovascular disease: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. AB - BACKGROUND: In the FIELD study, comparison of the effect of fenofibrate on cardiovascular disease (CVD) between those with prior CVD and without was a prespecified subgroup analysis. METHODS: The effects of fenofibrate on total CVD events and its components in patients who did (n = 2,131) and did not (n = 7,664) have a history of CVD were computed by Cox proportional hazards modeling and compared by testing for treatment-by-subgroup interaction. The analyses were adjusted for commencement of statins, use of other CVD medications, and baseline covariates. Effects on other CVD end points were explored. RESULTS: Patients with prior CVD were more likely than those without to be male, to be older (by 3.3 years), to have had a history of diabetes for 2 years longer at baseline, and to have diabetic complications, hypertension, and higher rates of use of insulin and CVD medications. Discontinuation of fenofibrate was similar between the subgroups, but more patients with prior CVD than without, and also more placebo than fenofibrate-assigned patients, commenced statin therapy. The borderline difference in the effects of fenofibrate between those who did (hazard ratio [HR] 1.02, 95% CI 0.86-1.20) and did not have prior CVD (HR 0.81, 95% CI 0.70-0.94; heterogeneity P = .045) became nonsignificant after adjustment for baseline covariates and other CVD medications (HR 0.96, 95% CI 0.81-1.14 vs HR 0.78, 95% CI 0.67-0.90) (heterogeneity P = .06). CONCLUSIONS: Our findings do not support treating patients with fenofibrate differently based on any history of CVD, in line with evidence from other trials. PMID- 22424025 TI - Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. METHODS: Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. RESULTS: Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5'-triphosphate-binding cassette A1- and scavenger receptor type BI-mediated cholesterol efflux increased. CONCLUSIONS: Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated. PMID- 22424026 TI - Impact of major bleeding and blood transfusions after cardiac surgery: analysis from the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial. AB - BACKGROUND: Prior retrospective studies have identified a relationship between bleeding after cardiac surgery and subsequent mortality. Whether this is attributable to bleeding, anemia, or transfusions is undetermined. METHODS: ACUITY was an international prospective trial of patients with acute coronary syndromes. Coronary artery bypass grafting (CABG) before hospital discharge was performed in 1,491 patients. Major bleeding was adjudicated as CABG- or non-CABG related. The relationship between CABG-related bleeding and 1-year mortality was determined using a time-updated covariate-adjusted Cox model. RESULTS: Coronary artery bypass grafting-related major bleeding after surgery occurred in 789 patients (52.9%); allogeneic blood product transfusions were administered in 612 patients (41.0%), including red blood cell (RBC) transfusions in 570 (38.2%, range 1-53 U), platelet transfusions in 180 (12.1%), and fresh-frozen plasma in 195 (13.1%). One-year mortality occurred in 95 patients (6.4%). Red blood cell transfusion (but not transfusion of platelets or fresh-frozen plasma, CABG related major bleeding per se, or nadir hemoglobin) was an independent predictor of 1-year mortality, but only after transfusion of >=4 U (adjusted hazard ratio for death after transfusion of 1-3, 4-6, and >=7 RBC units = 0.74, 2.01, and 5.22, respectively). Of the 95 deaths after CABG, 23 (24.2%) were attributable to CABG-related RBC transfusions. CONCLUSIONS: In patients with acute coronary syndromes, RBC transfusion of >=4 U after CABG is strongly associated with subsequent mortality. Future strategies should focus on reducing major hemorrhagic complications and RBC transfusions after CABG. PMID- 22424027 TI - "Funding source and author affiliation in TASER research are strongly associated with a conclusion of device safety". PMID- 22424028 TI - Biases in TASER research. PMID- 22424030 TI - Co-localization of Protein Z, Protein Z-Dependent protease inhibitor and coagulation factor X in human colon cancer tissue: implications for coagulation regulation on tumor cells. AB - INTRODUCTION: Several hemostatic system components, including factor X (FX), contribute to cancer progression. The Protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex directly inhibits factor Xa proteolytic activity. The aim of this study was to determine the antigenic distribution of ZPI and PZ, in relation to FX, as well as indicators of blood coagulation activation (F1+2 and fibrin) in human colon cancer tissue. MATERIALS & METHODS: Studies were performed on human colon cancer fragments. Immunohistochemical (IHC) ABC procedures and double staining method employed polyclonal antibodies against PZ, FX, F1+2 and monoclonal antibodies against ZPI and fibrin. In-situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either FX, PZ or ZPI mRNAs. RESULTS: Expression of FX, PZ and ZPI in association with colon cancer cells was observed by IHC. Moreover, the presence of both F1+2 and fibrin in association with colon cancer cells was found, which indicates that blood coagulation activation proceeds extravascularly at the tumor site. Furthermore, expression of FX and PZ was visualized in association with endothelial cells. In turn, colon cancer-associated macrophages were characterized by FX , PZ and ZPI presence. The double staining studies revealed strong FX/PZ, FX/ZPI, as well as PZ/ZPI co-localization on colon cancer cells. ISH studies revealed the presence of FX mRNA, PZ mRNA and ZPI mRNA in colon cancer cells indicating induced synthesis of these proteins. CONCLUSIONS: The localization of PZ/ZPI and FX in colon cancer cells indicates that PZ/ZPI may contribute to anticoagulant events at the tumor site. Strong co-localization of PZ/ZPI and FX in cancer cells, and the presence of the mRNAs encoding the proteins, suggests their role in the tumor's biology. However, the presence of F1+2 and fibrin at the colon cancer site also suggests that the regulation of FXa by the PZ/ZPI complex at this site is incomplete. PMID- 22424031 TI - Lipophilic toxin profiles detected in farmed and benthic mussels populations from the most relevant production zones in Southern Chile. AB - Lipophilic toxins associated with diarrhoeic toxins were found in Mytilus chilensis (Blue mussels) and Aulacomya ater (Ribbed mussels). These shellfish samples were collected from Chiloe Island, Southern Chile. The samples were tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After the analysis, four toxins were found: DTX-1, DTX-3, YTX and PTX. All toxins were identified by comparing their HPLC retention times with those of analytical standards and confirmed by LC-MS/MS. Dinophysistoxin-1 (DTX-1) and dinophysistoxin-3 (DTX-3) toxins were the major components within the mussel extracts. Nevertheless, the percentages of these toxins differed depending on the area they were collected from and/or the sampling date. The levels detected in Butacheuques Island for okadaic acid (OA) was 267 +/- 3.5 ug OA eq kg(-1) (p < 0.05) and for DTX-3 was 183.4 +/- 7.5 ug kg(-1) in ribbed mussels. Pectenotoxin (PTX) and yessotoxin (YTX) were the toxins detected in minor proportions in the toxic profile of the bivalves. The maximum concentration of YTX detected in ribbed mussels was 85.2 +/- 2.8 ug kg(-1) in Mechuque Island, whereas the PTX-2 level in ribbed mussels was 82.0 +/- 2.4 ug kg(-1) in Cailin Island. Analogues of YTX and PTX-2 were not detected in any of the analysed mussels, which did not support the supposed presence of isomers of toxins as a result of the enzymatic metabolism of bivalves. This study found evidence proving co-occurrence of lipophilic toxins - like PTX and YTX - with diarrhoeic toxin in samples collected in Southern Chile, which is, to date, the more complex mix of lipophilic toxins ever found in mussels samples from Southern Chile. PMID- 22424032 TI - Site-directed spin labeling of DNA reveals mismatch-induced nanometer distance changes between flanking nucleotides. AB - Multiple forms of DNA damages such as base modifications, double-strand breaks, and mispairings are related to inheritable diseases, cancer, and aging. Here, the structural changes of duplex DNA upon incorporation of mismatched base pairs are examined by EPR spectroscopy. Two ethynyl-7-deaza-2'-deoxyadenosine residues separated by two nucleotides were incorporated in DNA and functionalized with 4 azido-2,2,6,6-tetramethyl-piperidine-1-oxyl (4-azido TEMPO) by the click reaction. Mismatches such as dT.dT or dA.dA mispairs were positioned between these two spin labels in DNA duplexes. Pulse EPR experiments reveal that the mismatch-induced local conformational changes are transmitted to the flanking nucleotides and that the impact of this mismatch depends on the nearest neighbor environment. PMID- 22424033 TI - Esophageal cancer incidence trends in northeastern Iran: comparing rates over 36 years. PMID- 22424034 TI - Cancer incidence in Golestan Province: report of an ongoing population-based cancer registry in Iran between 2004 and 2008. AB - BACKGROUND: Golestan Province, at the western end of the Asian esophageal cancer (EC) belt in northeastern Iran, was reported to have one of the highest worldwide rates of EC in the 1970s. We have previously shown a declining incidence of EC in Golestan during the last decades. This study reports additional new results from the Golestan Population-based Cancer Registry (GPCR). METHODS: The GPCR collected data from newly diagnosed (incident) cancer cases from all 68 public and private diagnostic and therapeutic centers in Golestan Province. CanReg-4 software was used for data entry and analysis based on the guidelines of the International Agency for Research on Cancer (IARC). Age-standardized incidence rates (ASR) of cancers were calculated using the 2000 world standard population. RESULTS: From 2004 through 2008, 9007 new cancer cases were reported to the GPCR. The mean (SD) age was 55.5 (18.6) years, and 54% were diagnosed in men. The ASRs of all cancers were 175.3 and 141.1 per 100,000 person-years for males and females, respectively. Cancers of the stomach (ASR:30.7), esophagus (24.3), and lung (15.4) were the most common cancers in males. In females, breast cancer (ASR:26.9) was followed by malignancies of the esophagus (19.1) and stomach (12.4). The diagnosis of cancer was based on histopathological reports in 71% and on death certificate only in 9% of cases. CONCLUSIONS: The EC incidence rate continues to decline in Golestan, while the incidence rates of stomach, colorectal, and breast cancers continue to increase. PMID- 22424035 TI - Trends in change of mental health status in the population of Tehran between 1998 and 2007. AB - INTRODUCTION: According to a WHO report, the world will face great changes in the epidemiology of diseases in next three decades. Infectious and communicable diseases will be replaced by mental disorders at an alarming rate (9), making psychiatric disorders the most common cause of disability and premature death. This study compares trends and changes in the mental health of the residents of Tehran (>= 15 years old) in 1998 and 2007. METHODS: This study was an overview of two cross-sectional, descriptive researches that were performed in 1998 and 2007. The study populations in these two studies were residents of Tehran. Samples were recruited by regular randomized cluster sampling. In both studies, the General Health Questionnaire (GHQ-28) was used to assess mental health. Trained physicians and health experts completed questionnaires, and data were analyzed by SPSS software (Version 18). RESULTS: The results showed that 21.5% of participants in the 1998 survey suffered from mental disorders, of which 27.7% were women and 14.9% were men. In 2007, this figure increased to 34.2% (37.9% in woman and 28.6% in men). The prevalence of mental disorders increased from 1998 until 2007 by about 1.6 fold (1.4 fold for women and 1.9 fold for men). In both studies, the risk of mental disorders increased with increasing age. Anxiety symptoms were more prevalent in both studies compared to somatization, depression, and social dysfunction scales. DISCUSSION: The result shows a dramatic increase of mental disorder prevalence in Tehran from 1998 until 2007. We believe there is a lack of sufficient and qualified facilities for mental health provisions in Tehran. Based on these facts, policymakers and officials have to place greater importance in controlling stressful situations that predispose people to mental disorders, with the intent to improve the mental health of Tehran residents. PMID- 22424036 TI - Prevalence of psychiatric disorders in the general population of Kashan, Iran. AB - BACKGROUND: Mental health is one of the most important public health issues because of its major contribution in decreasing the global burden of disease and its important role in assurance, dynamism, and efficacy. The present study evaluates the prevalence of mental disorders in the over 18-year-old population in Kashan, Iran during 2008-2009. METHODS: This was a descriptive, cross sectional study. Subjects were selected via stratified random sampling. The study was conducted in two stages. In the first stage, subjects were evaluated using the General Health Questionnaire. In stage two, two psychiatrists used a DSM-IV checklist to conduct clinical interviews. The collected data were analyzed by SPSS version 16, OR, CI, Chi-square, and Mantel-Heanszel tests. RESULTS: The prevalence of mental disorders in Kashan was 29.2%. In women it was 35.5%, and in men, 21.2%. The most prevalent disorders were mood (9.3%) and anxiety disorders (4.7%). Among the 505 subjects with mental disorders based on clinical interviews, 162 (32.1%) suffered from mood disorders, 129 (25.6%) anxiety disorders, 21 (4.2%) psychotic disorders, 16 (3.4 %) neurologic disorders, 17 (3.4%) dissociative disorders, and 120 (23.7%) had other disorders. In this study, 7.8% of the subjects had at least one mental disorder. In the case of mood disorders, major depression (8.2%) was the most common; as for anxiety disorders, generalized anxiety disorder (7.2%) was the most prevalent. The prevalence was higher in people aged 56-65 (35.8%), widows (35.8%), the illiterate (42.8%), and the unemployed (38.8%). Mental disorder was significantly affected by gender, education, occupation, and marital status. CONCLUSIONS: The results show that psychiatric disorders in Kashan are higher than at the time of the previous research in this region (1999). Therefore, prevention programs and treatment of psychiatric disorders in this city are of great priority. PMID- 22424037 TI - Suicide epidemiology and characteristics among young Iranians at poison ward, Loghman-Hakim Hospital (1997-2007). AB - BACKGROUND: Suicide is a critical public health problem. In developing countries, the highest suicide rate is found in young adults with remarkable increasing rate. In this study, we have evaluated the epidemiology and characteristics of 8 16-year-old individuals who attempted suicideand were hospitalized in Loghman Hakim Hospital, Tehran, Iran from 1997 to 2007. METHODS: A total of 6414 hospitalized patients, ages 8-16, who attempted suicide and were residents of Loghman-Hakim Hospital were investigated. We performed a retrospective chart review to study the characteristics of cases in a 10-year period by review of psychiatric and medical records. RESULTS: Out of 6414 patients, 22.6% were males, 5978 patients were 12-16 years old and the rest were aged 8-12 years. During the 10-year period, suicides showed a rising trend among adults, while in children no significant increase was detected. Communicative disorders were the most common underlying risk factors, particularly in females. One patient out of five cases had psychiatric disorders, of which adjustment disorders were the most predominant. A remarkable peak in suicides was observed in May and July, while winter had the highest suicide rate among seasons. CONCLUSIONS: Suicide due to drug overdose is higher in females than males in young population. This increasing trend is a psychiatric concern and should be resolved by improving mental and public health. PMID- 22424038 TI - Xerostomia after radiotherapy and its effect on quality of life in head and neck cancer patients. AB - BACKGROUND: Xerostomia is one of the one complications following radiotherapy that can affect quality of life (QoL). This study aims to assess the severity of xerostomia in patients with head and neck cancers after radiotherapy and its effect on QoL. METHODS: In this longitudinal prospective study, the severity of xerostomia and related QoL were was assessed in 63 head and neck cancer patients who referred to the Radiotherapy Ward. Patients completed a xerostomia questionnaire (XQ) at the beginning, and 2, 4, and 6 weeks after treatment over a period of 6 months. Additionally, unstimulated saliva was collected using the spitting method at all 4 visits. RESULTS: QoL significantly worsened with increased time (P = 0.0001); meanwhile, the severity of xerostomia increased significantly (P = 0.0001). However, there was no significant change in the amount of saliva at these 4 time points (P = 0.23). Regression analysis showed that with each milliliter decrease in saliva secretion, the QoL score decreased 2.25%. With one score increase in xerostomia, from the QoL mean score there was a 1.65% decrease. CONCLUSION: The decrease in saliva and xerostomia that resulted from radiotherapy plays an important role in worsening QoL among patients who undergo radiotherapy for head and neck cancers. Although the amount of saliva has a significant association with QoL, the xerostomia score which shows subjects' general feeling also independently impacts QoL. In future studies, we recommend patient assessments for periods longer than 6 months. PMID- 22424039 TI - Impact of exploration of sensory branches of saphenous nerve in anterior cruciate ligament reconstructive surgery. AB - BACKGROUND: Post-operative sensory disturbances following anterior cruciate ligament (ACL) reconstruction using the quadruple hamstring tendon is a prevalent complication. This study evaluates the impact of exploration and salvage of superficial branches of the saphenous nerve on the incidence of post-operative sensory loss. METHODS: In a prospective descriptive study, 98 out of 120 patients with ACL reconstruction operated by the transfix method were followed 2 weeks and 6 months post-surgery. Hamstring tendon autograft was harvested through a 2-3 cm anteromedial oblique incision just over the pes anserinus. Meticulous dissection was done to find and save the superficial sensory branches of the saphenous nerve through the incision. Sensory changes were evaluated by physical examination for light touch; patients were requested to complete a specific diagram to evaluate sensory loss. RESULTS: In 44 patients at least one nerve was located and saved. The rate of hypoesthesia in this group of patients was 20.5%. In 54 patients we were unable to locate the nerve. The rate of hyposthesia in this group was 72%, which was statistically significant (P < 0.005). The overall rate of sensory disturbance in 98 patients was 48.9%. A total of 10 patients developed hyposthesia over the anteromedial part of the Mid-leg. CONCLUSION: Exploration and salvage of the sensory branches of the saphenous nerve has a tremendous effect on the rate of sensory deficit. PMID- 22424040 TI - Which information resources are used by general practitioners for updating knowledge regarding diabetes? AB - BACKGROUND: Little is known about the degree of utilization of information resources on diabetes by general practitioners (GPs) and its impact on their clinical behavior in developing countries. Such information is vital if GPs' diabetes knowledge is to be improved. METHODS: This cross-sectional study recruited 319 GPs in the summer of 2008. Questions were about the updates on diabetes knowledge in the previous two years, utilization of information resources (domestic and foreign journals, congresses, the Internet, reference books, mass media, and peers), attitude toward the importance of each resource, and impact of each resource on clinical behavior. RESULTS: A total of 62% of GPs had used information resources for improving their knowledge on diabetes in the previous two years. Domestic journals accounted for the highest utilization (30%) and the highest importance score (83 points from 100); with the importance score not being affected by sex, years elapsed after graduation, and numbers of diabetic visits. Clinical behavior was not influenced by the information resources listed; whereas knowledge upgrade, irrespective of the sources utilized, had a significantly positive correlation with clinical behavior. CONCLUSION: Domestic journals constituted the main information resource utilized by the GPs; this resource, however, in tandem with the other information resources on diabetes exerted no significant impact on the GPs' clinical behavior. In contrast to the developed countries, clinical guidelines do not have any place as a source of information and or practice. Indubitably, the improvement of diabetes knowledge transfer requires serious interventions to improve information resources as well as the structure of scientific gatherings and collaborations. PMID- 22424041 TI - Congenital anomalies in infants conceived by assisted reproductive techniques. AB - BACKGROUND: Many studies show that congenital defects in infants conceived by assisted reproductive techniques (ART) are more than infants of normal conception (NC). The aim of this study is to determine the frequency of congenital anomalies in ART infants from Royan Institute and to compare congenital anomalies between two ART techniques. METHODS: In a cross-sectional descriptive study, 400 ART infants from Royan Institute who resided in Tehran were selected by non-random, consecutive sampling. Infants were examined twice (until 9 months of age) by a pediatrician. Infants' congenital anomalies were described by each body system or organ and type of ART. Data were analyzed by SPSS version 16 and Fisher's exact test. RESULTS: The frequency of different organ involvement in the two examinations were: 40 (10%) skin, 25 (6.2%) urogenital system, 21 (5.2%) gastrointestinal tract, 13 (3.2%) visual, and 8 (2%) cardiovascular system. Major congenital defects in infants conceived by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) were hypospadiasis, inguinal hernia, patent ductus arteriosus plus ventricular septal defect (PDA + VSD), developmental dysplasia of the hip, lacrimal duct stenosis during the first year of life, hydronephrosis and urinary reflux over grade III, undescending testis, ureteropelvic junction stenosis, and torticoli. CONCLUSIONS: Two-thirds of ART infants had no defects. A total of 7% of IVF and ICSI infants had one of the major abovementioned congenital anomalies. This rate was higher than NC infants (2%-3%). There was no difference between the ICSI and IVF group. PMID- 22424042 TI - Chromosomal abnormality in patients with secondary amenorrhea. AB - BACKGROUND: Secondary amenorrhea is a condition in which there is cessation of menses after at least one menstruation. It is a symptom of different diseases, such as hormonal disturbances which range from pituitary to ovarian origin, as well as chromosomal abnormalities. Knowledge of the distinct cause of secondary amenorrhea is of tremendous benefit for the management and monitoring of patients. In this study, we determine the chromosomal abnormalities in patients with secondary amenorrhea in Southwest Iran. METHODS: We selected 94 patients with secondary amenorrhea who referred to our Cytogenetic Ward from 2004 until 2009. For karyotyping, peripheral blood lymphocyte cultures were set up by conventional technique. RESULTS: In this study, 5.3% (n=5) of patients with secondary amenorrhea presented with chromosomal abnormalities, of which all contained an X element. The chromosomal abnormalities were: i) 45, X (n=1); ii) 47, XXX (n=1); iii) 45, X [13]/ 45, Xi(X)q[17] (n=1); iv) 45, X[12]/46,X,+mar[12] (n=1); and v) 46,X,del(Xq)(q23q28) (n=1). CONCLUSION: Our study revealed that some causes of secondary amenorrhea could be due to chromosomal abnormalities. Therefore, cytogenetic studies should be important tests in the evaluation of patients with secondary amenorrhea. PMID- 22424043 TI - Augmentation rhinoplasty with combined use of Medpor graft and irradiated homograft rib cartilage in saddle nose deformity. AB - BACKGROUND: We used the irradiated homograft rib cartilage as an augmentation tip support and Medpore alloplast for reconstruction of the dorsum in patients with saddle nose deformities. Thereafter, the safety and efficiency of this method was evaluated to determine if this can be a safe and efficient technique for patients with saddle nose deformities. METHODS: A total of 32 patients who suffered from saddle nose deformities due to past trauma or aggressive rhinoplasty underwent reconstruction using the Medpor prosthesis for dorsum reconstruction and irradiated rib cartilage as acolumellar strut during the same technique. After at least one year follow up, patients' satisfaction and their aesthetic indexes were evaluated and compared with preoperative results. RESULTS: More than 84% of patients were satisfied from the results of the surgery and only one patient had a complication of the infection which resulted in removal of the prosthesis. There were statistically significant differences between most of the pre- and postoperative aesthetic indexes. CONCLUSION: Despite the superiority of autogenous material in nose reconstruction, lack of such materials in revision rhinoplasty cases present challenges to surgeons. This study proposes the safety and efficiency of the Medpor alloplast for reconstruction of the dorsum and irradiated rib cartilage for the tip, at least for a short period of time. PMID- 22424044 TI - Pathogenesis and glycemic management of type 2 diabetes mellitus: a physiological approach. AB - Type 2 diabetes (T2DM) is an incompletely understood chronic, progressive multifactorial disease with insulin resistance and decreased beta-cell function playing dominant roles in its genesis. The worldwide incidence of the disease is rapidly increasing to pandemic proportions. The increase in incidence of T2DM is attributable to changes in lifestyle, diet and obesity, but other causes remain to be defined. The disease is a major cause of early mortality due to atherosclerosis and cardiovascular disease (CVD), and is the leading cause of blindness, leg amputations, and chronic renal disease. Hyperglycemia inT2DM becomes manifest once insulin secretion is no longer adequate for the metabolic demands of the individual. The approach to glycemic management of the disease is increasingly based on understanding the underlying pathophysiology. Efforts to maintain and preserve beta-cell function during the earlier phases of the disease may have important implications in prevention of subsequent complications of T2DM. Finally, the approach to glycemic management of the disease should be individualized by considering the psycho-socio-economic condition of each patient, and glycemic targets should reflect presence of comorbid conditions, age of the patient, the stage of their disease in terms of duration, presence of macro- and micro-vascular complications, and propensity for severe hypoglycemia. PMID- 22424045 TI - Liver involvement in melamine-associated nephrolithiasis. AB - It is currently believed that melamine ingestion can lead to insoluble crystals in an animal's urinary system with subsequent physical obstruction or bladder carcinoma. However, whether melamine can cause injury of other tissues and organs in humans is yet unknown. In this study, we encountered 3 affected children with liver lesions, 2 males and 1 female, and detailed their clinical characterizations. Their ages were respectively 2, 6, and 10 months. Among the 3 patients with liver lesions, only 1 exhibited symptoms of gradual progressive jaundice, abdominal distention, hepatic intumesce, and bilirubin abnormality; the other 2 were asymptomatic. The mechanism associated with liver lesion may, at least in part, be due to physical deposition and blockage of the biliary tract system. Disturbance of the acid-base equilibrium may be another reason that accelerates stone formation in human tissues. PMID- 22424046 TI - Two novel familial balanced translocations t(8;11)(p23;q21) and t(6;16)(q26;p12) implicated in recurrent spontaneous abortion. AB - Reciprocal translocations represent one of the most common structural rearrangements observed in humans. Estimates of the population frequency range from 1/673 to 1/1000. We have described two novel balanced translocations in two unrelated families who experienced Recurrent spontaneous abortions (RSA) following their separate non-consanguineous marriages. Initial cytogenetic studies were performed on cultured blood cells. High resolution GTG-banding analysis using cytovision software performed on their chromosomes revealed a novel balanced translocation t(8;11)(p23;q21) in a brother (45 years) and his sister (27 years) in one family. The second novel balanced translocation t(6;16)(q26;p12) was observed in a consanguineous couple with 4 RSA. These two families have an increased risk of having children with unbalanced karyotypes or RSA, because of incorrect chromosomal segregation during meiosis. PMID- 22424047 TI - Bilateral psoas abscess: atypical presentation of spinal tuberculosis. AB - Three patients who came to the surgical outpatient department of 'Postgraduate Institute of Medical Education and Research', Chandigarh, India with features suggestive of acute abdomen are presented. On thorough evaluation, they had bilateral psoas abscess and on detailed investigations, tuberculosis was found to be the etiological factor. They were treated conservatively with good follow-up results. Psoas abscess may be clinically difficult to diagnose because of its rarity, insidious onset of the disease, and non-specific clinical presentation which can cause diagnostic delays resulting in high morbidity. Early diagnosis and appropriate management remains a challenge for clinicians. All three patients presented here have recovered following detailed investigation and appropriate management. The diagnosis of spinal tuberculosis should be considered in patients with vertebral osteomyelitis, psoas abscess, and appropriate risk factors such as a history of previous exposure in both developed and developing countries, as tuberculosis is re-emerging as an important etiological factor in spinal pathologies. PMID- 22424048 TI - Photoclinic. Generalized acanthosis nigricans. PMID- 22424049 TI - Impact of quality mentorship on achievements of Shiraz Medical School in the 1970s and the role of professor Faramarz Ismail-Beigi. AB - Almost four decades ago, an eminent physician, outstanding mentor and scholar, Professor Faramarz Ismail-Beigi (b. 1941) was appointed Chair of the Department of Internal Medicine at Shiraz Medical School. Soon, this proved to be the beginning of a golden era in medical education at that center. Professor Ismail Beigi invited outstanding teachers and physicians to collaborate with him. Their efforts during the next decade laid a strong and unique foundation for medical education based on quality mentorship and role-modeling. In this paper, we briefly highlight the importance of mentorship in medicine and medical education, followed by a glance at the academic life and career of Professor Ismail-Beigi and his role as a prominent mentor at the Shiraz School of Medicine. PMID- 22424051 TI - A new chromone from the leaves of Melaleuca cajuputi Powell. AB - A new chromone, 5,7-dihydroxy-2 -(hydroxymethyl)-6,8-dimethyl-chromen-4-one, named melachromone, together with 12 known compounds, including chromones, anthraquinone, flavonoids, flavonoid glycosides, benzene derivatives, ellagic acids and terpenes, were isolated from the leaves of Melaleuca cajuputi Powell. Their structures were characterised by spectroscopic methods. PMID- 22424052 TI - Relationships between cell parameters of dye-sensitized solar cells and dye adsorption parameters. AB - The performance of dye-sensitized solar cells (DSCs) is affected strongly by sensitizer-dye adsorption behavior on TiO(2) nanocrystal electrode. This study reports quantitative relationships between DSC cell performance parameters and dye-adsorption parameters for the first time. We discovered a logarithmic relationship between short-circuit photocurrent density (J(sc)) and dye adsorption equilibrium constant on TiO(2) surface, and a linear relationship between open-circuit potential (V(oc)) and dye-adsorption density on TiO(2) surface for DSCs. These relationships provide a convenient method for forecasting the performance of TiO(2) nanoparticles for DSCs from the dye-adsorption parameters, and also indicate future directions for the development of high performance TiO(2) nanoparticles for DSCs. PMID- 22424053 TI - A prospective cohort study of the long-term effects of CPAP on carotid artery intima-media thickness in obstructive sleep apnea syndrome. AB - OBJECTIVE: To examine the long-term effect of CPAP on carotid artery intima-media thickness (IMT) in patients with Obstructive sleep apnea syndrome(OSAS). METHODS: A prospective observational study over 12 months at a teaching hospital on 50 patients newly diagnosed with OSAS who received CPAP or conservative treatment (CT). Carotid IMT was assessed with B-mode Doppler ultrasound from both carotid arteries using images of the far wall of the distal 10 mm of the common carotid arteries at baseline, 6 months and 12 months. MEASUREMENTS AND RESULTS [MEAN (SE)]: Altogether 28 and 22 patients received CPAP and CT respectively without significant differences in age 48.8(1.8) vs 50.5(2.0)yrs, BMI 28.2(0.7) vs 28.0(1.2)kg/m2, ESS 13.1(0.7) vs 12.7(0.6), AHI 38(3) vs 39(3)/hr, arousal index 29(2) vs 29(2)/hr, minimum SaO2 75(2) vs 77(2)% and existing co-morbidities. CPAP usage was 4.6(0.3) and 4.7(0.4)hrs/night over 6 months and 1 year respectively. Carotid artery IMT at baseline, 6 months, and 12 months were 758(30), 721(20), and 705(20)micron for the CPAP group versus 760(30), 770(30), and 778(30)micron respectively for the CT group, p = 0.002. Among those free of cardiovascular disease(n = 24), the carotid artery IMT at baseline, 6 months and 12 months were 722(40), 691(40), and 659(30)micron for the CPAP group (n = 12) with usage 4.5(0.7) and 4.7(0.7) hrs/night over 6 months and 12 months whereas the IMT data for the CT group(n = 12) were 660(20), 685(10), and 690(20)micron respectively, p = 0.006. CONCLUSIONS: Reduction of carotid artery IMT occurred mostly in the first 6 months and was sustained at 12 months in patients with reasonable CPAP compliance. PMID- 22424054 TI - Are breast cancers driven by fusion genes? AB - For many years, it was assumed that gene fusions were a type of mutation confined largely to leukemias and sarcomas. However, fusion genes are now known to be important in several epithelial cancers and a number have been described in breast cancers. In the December 2011 issue of Nature Medicine, Robinson and colleagues reported many more gene fusions -including the first recurrent fusion, SEC16A-NOTCH1 - in breast cancers. Several genes, including members of the MAST (microtubule-associated serine threonine) kinase and Notch gene families, are fused more than once. This finding supports an emerging story that most breast cancers express a number of fusion genes. PMID- 22424055 TI - Amplified surface plasmon resonance and electrochemical detection of Pb2+ ions using the Pb2+-dependent DNAzyme and hemin/G-quadruplex as a label. AB - The hemin/G-quadruplex nanostructure and the Pb(2+)-dependent DNAzyme are implemented to develop sensitive surface plasmon resonance (SPR) and electrochemical sensing platforms for Pb(2+) ions. A complex consisting of the Pb(2+)-dependent DNAzyme sequence and a ribonuclease-containing nucleic acid sequence (corresponding to the substrate of the DNAzyme) linked to a G-rich domain, which is "caged" in the complex structure, is assembled on Au-coated glass surfaces or Au electrodes. In the presence of Pb(2+) ions, the Pb(2+) dependent DNAzyme cleaves the substrate, leading to the separation of the complex and to the self-assembly of the hemin/G-quadruplex on the Au support. In one sensing platform, the Pb(2+) ions are analyzed by following the dielectric changes at the surface as a result of the formation of the hemin/G-quadruplex label using SPR. This sensing platform is further amplified by the immobilization of the sensing complex on Au NPs (13 nm) and using the electronic coupling between the NPs and the surface plasmon wave as an amplification mechanism. This method enables the sensing of Pb(2+) ions with a detection limit that corresponds to 5 fM. The second sensing platform implements the resulting hemin/G-quadruplex as an electrocatalytic label that catalyzes the electrochemical reduction of H(2)O(2). This method enables the detection of Pb(2+) with a detection limit of 1 pM. Both sensing platforms reveal selectivity toward the detection of Pb(2+) ions. PMID- 22424056 TI - Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells. AB - BACKGROUND: Various by-products of the cellular metabolism, such as reactive carbonyl species (RCS) are potentially harmful to cells and tissues, and play a role in many physiological and pathological processes. Among various RCS is the highly reactive dicarbonyl glyoxal (GO), which is a natural physiological metabolite produced by the auto-oxidation of glucose, and can form covalent adducts known as advanced glycation endproducts (AGE). We have previously reported that GO accelerates ageing and causes premature senescence in normal human skin fibroblasts. RESULTS: Using a bone marrow-derived telomerase immortalised mesenchymal stem cell line hMSC-TERT we have observed that an exposure of cells to 0.75 mM and 1 mM GO induces irreversible cellular senescence within 3 days. Induction of senescence in hMSC-TERT was demonstrated by a variety of markers, including characteristic cell morphology and enlargement, vacuolisation, multinucleation, induction of senescence associated beta galactosidase, cell cycle arrest, and increased levels of a cell cycle inhibitor p16. These changes were accompanied by increased extent of DNA breaks as measured by the comet assay, and increased levels of the AGE product, carboxymethyl-lysine (CML). Furthermore, the in vitro differentiation potential of hMSC-TERT to become functional osteoblasts was highly reduced in GO-treated stem cells, as determined by alkaline phosphatase (ALP) activity and mineralized matrix (MM) formation. CONCLUSIONS: The results of our study imply that an imbalanced glucose metabolism can reduce the functioning ability of stem cells in vivo both during ageing and during stem cell-based therapeutic interventions. PMID- 22424057 TI - The application of the Drug User Quality of Life Scale (DUQOL) in Australia. AB - BACKGROUND: The concept of quality of life relates to the perceptions of individuals about their mental and physical health as well as non-health related areas. The evaluation of quality of life in the context of substance abuse has been conducted using generic instruments. The Drug Users Quality of Life Scale (DUQOL) is a specific assessment tool in which the most pertinent and salient areas to drug abusers are taken into consideration. In this study, the authors report the results of a validation study in which the DUQOL was used for the first time in Australia. METHODS: A sample of 120 participants from inpatient and outpatient treatment facilities completed a series of questionnaires, including the DUQOL and the World Health Organization Quality of Life Assessment-BREF (WHOQOL-BREF). Parameters investigated in this study included the demographic characteristics of the sample, internal structure, and convergent validity. Correlations between the DUQOL scale scores and the scores of the WHOQOL-Bref test were investigated via Pearson product-moment correlation analyses. RESULTS: The English version of the DUQOL attained a significant overall Cronbach's alpha of 0.868. The factorial analysis of the DUQOL identified one principal factor that accounted for 28.499% of the variance. Convergent validity analyses demonstrate significant correlations (p < 0.01) between the DUQOL scores and the scores of all four dimensions of the WHOQOL-BREF questionnaire. CONCLUSIONS: This study demonstrates that the DUQOL constitutes a reliable research instrument for evaluating quality of life of substance users in Australia. PMID- 22424058 TI - Candidiasis caused by Candida kefyr in a neonate: case report. AB - BACKGROUND: Systemic Candidia infections are of major concern in neonates, especially in those with risk factors such as longer use of broad spectrum antibiotics. Recent studies showed that also term babies with underlying gastrointestinal or urinary tract abnormalities are much more prone to systemic Candida infection. We report a very rare case of candidiasis caused by Candida kefyr in a term neonate. CASE PRESENTATION: Renal agenesis on the left side was diagnosed antenatally and anal atresia postnatally. Moreover, a vesico-ureteral reflux (VUR) grade V was detected by cystography. The first surgical procedure, creating a protective colostoma, was uneventful. Afterwards our patient developed urosepsis caused by Enterococcus faecalis and was treated with piperacillin. The child improved initially, but deteriorated again. A further urine analysis revealed Candida kefyr in a significant number. As antibiotic resistance data about this non-albicans Candida species are limited, we started liposomal amphotericin B (AMB), but later changed to fluconazole after receiving the antibiogram. Candiduria persisted and abdominal imaging showed a Candida pyelonephritis. Since high grade reflux was prevalent we instilled AMB into the child's bladder as a therapeutic approach. While undergoing surgery (creating a neo-rectum) a recto-vesical fistula could be shown and subsequently was resected. The child recovered completely under systemic fluconazole therapy over 3 months. CONCLUSIONS: Candidiasis is still of major concern in neonates with accompanying risk factors. As clinicians are confronted with an increasing number of non albicans Candida species, knowledge about these pathogens and their sensitivities is of major importance. PMID- 22424060 TI - Dissipation, half-lives, and mass spectrometric identification of endosulfan isomers and the sulfate metabolite on three field-grown vegetables. AB - Endosulfan 3 EC, a mixture of alpha- and beta-stereo isomers, was sprayed on field-grown pepper, melon, and sweet potato plants at the recommended rate of 0.44 kg A.I. acre(-1). Plant tissue samples (leaves, fruits, or edible roots) were collected 1 h to 30 days following spraying and analyzed for endosulfan isomers (alpha- and beta-isomers). Analysis of samples was accomplished using a gas chromatograph (GC) equipped with a mass detector in total ion mode. The results indicated the formation of endosulfan sulfate as the major metabolite of endosulfan sulfite and the relatively higher persistence of the beta-isomers as compared to the alpha-isomer. The initial total residues (alpha- and beta-isomers plus endosulfan sulfate) were higher on leaves than on fruits. On pepper and melon fruits, the alpha-isomer, which is the more toxic to mammals, dissipated faster (T(1/2) = 1.22 and 0.95 d, respectively) than the less toxic beta-isomer (T(1/2) = 3.0 and 2.5 d, respectively). These results confirm the greater loss of the alpha-isomer compared to the beta-isomer, which can ultimately impact endosulfan dissipation in the environment. Additionally, the higher initial residues of endosulfan on pepper and sweet potato leaves should be considered of great importance for timing field operations and the safe entry of harvesters due to the high mammalian toxicity of endosulfan. PMID- 22424061 TI - Residues behavior of some fungicides applied on two greenhouse tomato varieties different in shape and weight. AB - The degradation of 12 fungicides (azoxystrobin, cymoxanil, cyproconazole, cyprodinil, fenarimol, fludioxonil, iprovalicarb, mepanipyrim, penconazole, pyrimethanil, tolclofos-methyl, triadimenol), commonly used in pest management strategies on Sardinian greenhouse tomato crops was studied. A different residue behaviour was observed between the studied cultivar. On the smaller, a "cherry" type tomato, field data showed an initial residue mostly higher than the "beefsteak" tomato. In any case, except for penconazole, all pesticide residues were below their maximum residue levels (MRLs) reaching the pre-harvest interval (PHI). On both cultivar, triadimenol and cymoxanil residues completely disappeared reaching their PHI, while iprovalicarb, fenarimol, and fludioxonil disappeared in a time of 17 to 24 days. On the contrary, azoxystrobin, cyproconazole, cyprodinil, penconazole, tolclofos-methyl, mepanipyrim, and pyrimethanil showed a long persistence on both tested cultivar and may have residual problems due to an accumulation effect if repeated field treatments will be performed. The first group of molecules according to their rapid degradation could be used in low pesticide-input management in order to obtain tomatoes with low or no detectable residues. PMID- 22424062 TI - Residue determination and dissipation of ioxynil octanoate in maize and soil. AB - A simple and efficient residue analysis method for direct determination of ioxynil octanoate in maize and soil was developed and validated with High Performance Liquid Chromatography-Ultra Violet (HPLC-UV). The samples were extracted with mixtures of acetonitrile and deionized water followed by Solid Phase Extraction (SPE) to remove co-extractives prior to analysis by HPLC-UV. The recoveries of ioxynil octanoate extracted from maize and soil samples ranged from 86 %-104 % and 84 %-96 %, respectively, with relative standard deviation (RSD) less than 7.84% and sensitivity of 0.01 mg kg(-1). The method was applied to determine the residue of ioxynil octanoate in maize and soil samples from experimental field. Data had shown that the dissipation rate in soil was described as pseudo-first-order kinetics and the half-life (t(1/2)) was less than 1.78 days. No ioxynil octanoate residue (<0.01 mg kg(-1)) was detected in maize at harvest time withholding period of 60 days after treatments of the pesticide. Direct confirmation of the analytes in field trial samples was realized by Liquid Chromatography-Mass Spectrometry (LC-MS). PMID- 22424063 TI - Tank mixture additives approach to improve efficiency of bentazon against broadleaf weeds in peas. AB - Efficiency of different tank-mixed additives with bentazon at half rate was investigated on (Malva parviflora) and other broad leaf weeds compared with bentazon at the full recommended rate without additives in peas in open field. All the tested additives enhanced the efficiency of bentazon at the half rate. Nonyl phenol and toximol S proved to be the most effective additives in comparison with the full rate treatment. The tested treatments did not show any significant effect on chlorophyll content and soil microorganisms. Bentazon residues were determined in certain treatments to investigate the effect of the tested additives on bentazon deposition. Samples were extracted using QuEChERS method and residues were determined using LC-MS/MS. Residues after 24 hours in the half rate treatment reached 4 times lower than the Maximum Residues Limit (MRL) (0.11 mg kg(-1)), compared to the full rate treatment (0.51 mg kg(-1)), that was slightly above the MRL. PMID- 22424059 TI - DNA-multichromophore systems. PMID- 22424064 TI - Toxic effects of deltamethrin and lambda-cyhalothrin on Xenopus laevis tadpoles. AB - This study evaluates the toxic effects of deltamethrin and lambda-cyhalothrin on Xenopus laevis tadpoles after 168 h of exposure. The LC(50) of deltamethrin and lambda-cyhalothrin at 168 h was calculated as the MUg of active ingredient per liter (MUg AI/L). According to these values, the LC(50) was 6.26 and 3.94 MUg AI/L for deltamethrin and lambda-cyhalothrin, respectively. Several enzymes were studied for early signs of intoxication following exposure to the pesticides for 24 h. Glutathione-S-transferase,carboxylesterase, and lactate dehydrogenase were inhibited by lambda-cyhalothrin, and both pesticides inhibited acid phosphatase and aspartate aminotransferase. In contrast, acetylcholinesterase was activated by deltamethrin. The results suggest that X. laevis is sensitive to the pyrethroids that were tested, and the enzyme responses suggest that they are potential biomarkers for evaluating the toxic effect of pyrethroids on amphibians in environmental conditions. PMID- 22424065 TI - Toxicity of metalaxyl, azoxystrobin, dimethomorph, cymoxanil, zoxamide and mancozeb to Phytophthora infestans isolates from Serbia. AB - A study of the in vitro sensitivity of 12 isolates of Phytophthora infestans to metalaxyl, azoxystrobin, dimethomorph, cymoxanil, zoxamide and mancozeb, was conducted. The isolates derived from infected potato leaves collected at eight different localities in Serbia during 2005-2007. The widest range of EC(50) values for mycelial growth of the isolates was recorded for metalaxyl. They varied from 0.3 to 3.9 MUg mL(-1) and were higher than those expected in a susceptible population of P. infestans. The EC(50) values of the isolates were 0.16-0.30 MUg mL(-1) for dimethomorph, 0.27-0.57 MUg mL(-1) for cymoxanil, 0.0026 0.0049 MUg mL(-1) for zoxamide and 2.9-5.0 MUg mL(-1) for mancozeb. The results indicated that according to effective concentration (EC(50)) the 12 isolates of P. infestans were sensitive to azoxystrobin (0.019-0.074 MUg mL(-1)), and intermediate resistant to metalaxyl, dimethomorph and cymoxanil. According to resistance factor, all P. infestans isolates were sensitive to dimethomorph, cymoxanil, mancozeb and zoxamide, 58.3% of isolates were sensitive to azoxystrobin and 50% to metalaxyl. Gout's scale indicated that 41.7% isolates were moderately sensitive to azoxystrobin and 50% to metalaxyl. PMID- 22424066 TI - Comparative phytotoxicity of Rac-metolachlor and S-metolachlor on rice seedlings. AB - The toxicity of Rac-metolachlor and S-metolachlor on rice (IIYou92, Oryza sativa L.) seedlings was determined and compared in a hydroponics experiment. The elongation of shoot, main root, and the number of lateral roots were inhibited in both Rac- and S-metolachlor treatments. The 96 h- IC50 of Rac- and S-metolachlor were 12.32 and 9.44 MUM for shoot, and 4.69 and 1.75 MUM for root, respectively. The content of chlorophyll a, chlorophyll b and total chlorophyll of leaf treated by Rac-metolachlor was higher than that treated by S-metolachlor. The activities of superoxide dismutase, peroxidase, cytochrome P450 2E1, glutathione S transferase, and the content of glutathione increased after herbicide exposure, and the activities or the content was higher in the S-metolachlor treatment than in the exposure to Rac-metolachlor. Ultrastructural studies revealed that Rac- and S-metolachlor had adverse effects on leaf cells, and S-metolachlor treatment caused higher damage. PMID- 22424067 TI - Developmental exposure to diuron causes splenotoxicity in male Sprague-Dawley rat pups. AB - This study investigated whether perinatal exposure to diuron [3-(3,4 dichlorophenyl)-1-1-dimethylurea] might exert adverse effects on rat lymphoid organs. Pregnant Sprague-Dawley (SD) rats were exposed to diuron at 500, 750 or 1250 ppm in the diet from gestational days (GD) 12-21 and during lactation. At postnatal day (PND) 42, male pups were euthanized and thymus, spleen, mesenteric lymph node and femur were collected for histopathological analysis. Food consumption and body weight gain were significantly reduced in dams exposed to 1250 ppm during gestation period. Also, Diuron at 750 and 1250 ppm produced: (1) increased relative spleen weight associated histologically with severe congestion in red pulp, (2) enhanced extramedullary hematopoiesis and hemosiderosis as well as (3) depletion of lymphoid follicles in white pulp. Flow cytometric analysis revealed a significant reduction in B lymphocytes (CD45RA+) in male pups but T lymphocytes (CD4+, CD8+ and CD4+/CD8+) were not markedly affected. Thus, data suggest that Diuron-induced maternal toxicity in dams exposed to high dose and perinatal exposure to this herbicide produced spleen toxicity as evidenced by a reduction in B lymphocyte number in male SD pups. PMID- 22424068 TI - Interaction between BSM-contaminated soils and Italian ryegrass. AB - The interaction among the bensulfuron-methyl, growth of Italian ryegrass, and soil chemical/biochemical/microbiological parameters was investigated in a microcosm experiment. The bensulfuron-methyl added to the soil can be rapidly degraded by certain fungi and actinomycetes present in the original paddy rice soil. The growth of Italian ryegrass significantly accelerated the in-soil degradation of bensulfuron-methyl in its rhizosphere. The uptake of bensulfuron methyl by ryegrass increased with increasing dosage level of bensulfuron-methyl. However, the phytoextraction of bensulfuron-methyl by ryegrass contributed insignificantly to the total removal of the soil bensulfuron-methyl. Within the dosage range set in this study, the root development of ryegrass was not adversely affected by the presence of the soil bensulfuron-methyl although the fresh biomass of shoot was slightly reduced in the higher dosage treatments. This can be attributed to the adsorption of the added bensulfuron-methyl by soil colloids and consequently the reduction of bensulfuron-methyl level in the soil pore water to a concentration sufficiently lower than the toxic level. The growth of ryegrass significantly increased soil pH and the activities of phosphatase and peroxidase but reduced the EC and the activities of urease in the rhizospheric soil. PMID- 22424069 TI - Assessment of imidacloprid toxicity on reproductive organ system of adult male rats. AB - In the current study it was aimed to investigate the toxicity of low doses of imidacloprid (IMI) on the reproductive organ systems of adult male rats. The treatment groups received 0.5 (IMI-0.5), 2 (IMI-2) or 8 mg IMI/kg body weight by oral gavage (IMI-8) for three months. The deterioration in sperm motility in IMI 8 group and epidydimal sperm concentration in IMI-2 and IMI-8 groups and abnormality in sperm morphology in IMI-8 were significant. The levels of testosterone (T) and GSH decreased significantly in group IMI-8 compared to the control group. Upon treatment with IMI, apoptotic index increased significantly only in germ cells of the seminiferous tubules of IMI-8 group when compared to control. Fragmentation was striking in the seminal DNA from the IMI-8 group, but it was much less obvious in the IMI-2 one. IMI exposure resulted in elevation of all fatty acids analyzed, but the increases were significant only in stearic, oleic, linoleic and arachidonic acids. The ratios of 20:4/20:3 and 20:4/18:2 were decreased and 16:1n-9/16:0 ratio was increased. In conclusion, the present animal experiments revealed that the treatment with IMI at NOAEL dose-levels caused deterioration in sperm parameters, decreased T level, increased apoptosis of germ cells, seminal DNA fragmentation, the depletion of antioxidants and change in disturbance of fatty acid composition. All these changes indicate the suppression of testicular function. PMID- 22424070 TI - Cytotoxicity and DNA damage of five organophosphorus pesticides mediated by oxidative stress in PC12 cells and protection by vitamin E. AB - Previous studies have demonstrated that pesticides could induce cytotoxicity and genotoxicity in vivo and in vitro, and that oxidative stress may be an important factor involved. However, investigations comparing the capability of different organophosphorous (OP) compounds to induce cytotoxicity, genotoxicity and oxidative stress are limited. Hence, the aim of this paper was to access the cytotoxic and genotoxic effects of five OPs or metabolites, Acephate (ACE), Methamidophos (MET), Chloramidophos (CHL), Malathion (MAT) and Malaoxon (MAO), and to clarify the role of oxidative stress, using PC12 cells. The results demonstrated that MET, MAT and MAO caused significant inhibition of cell viability and increased DNA damage in PC12 cells at 40 mg L(-1). MAO was more toxic than the other OPs. ACE, MET, MAT and MAO increased the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), and decreased the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) at 20 mg L(-1) and 40 mg L(-1) to different degrees. Pre treatment with vitamin E(600 MUM)caused a significant attenuation in the cytotoxic and genotoxic effect; pre-treatment reversed subsequent OP-induced elevation of peroxidation products and the decline of anti-oxidant enzyme activities. These results indicate that oxidative damage is likely to be an initiating event that contributes to the OP-induced cytotoxicity. PMID- 22424071 TI - Modeling biodegradation and kinetics of glyphosate by artificial neural network. AB - An artificial neural network (ANN) model was developed to simulate the biodegradation of herbicide glyphosate [2-(Phosphonomethylamino) acetic acid] in a solution with varying parameters pH, inoculum size and initial glyphosate concentration. The predictive ability of ANN model was also compared with Monod model. The result showed that ANN model was able to accurately predict the experimental results. A low ratio of self-inhibition and half saturation constants of Haldane equations (< 8) exhibited the inhibitory effect of glyphosate on bacteria growth. The value of K(i)/K(s) increased when the mixed inoculum size was increased from 10(4) to 10(6) bacteria/mL. It was found that the percentage of glyphosate degradation reached a maximum value of 99% at an optimum pH 6-7 while for pH values higher than 9 or lower than 4, no degradation was observed. PMID- 22424072 TI - Mercury in European Blushers, Amanita rubescens, mushrooms and topsoils: bioconcentration potential and intake assessment. AB - Total mercury content has been determined in fruiting bodies of European Blushers and topsoils collected from 11 sites across Poland in 2006-2008. Mercury analysis was carried out using a validated analytical method and cold-vapour atomic absorption (CV-AAS). The European Blusher effectively accumulated mercury in fruiting bodies. The mean values of total mercury in caps of European Blushers from background (uncontaminated) areas were from 0.22 to 1.0 (0.067-3.2) and in stipes from 0.16 to 0.65 (0.071-2.7) MUg/g dry weight. In topsoil beneath to fruiting bodies, the median Hg concentration at 10 sites in Northern Poland varied between 0.030 and 0.072 (0.0096-0.19) MUg/g dw, and in one site in Southern Poland was 0.20 (0.079-0.34) MUg/g dw. Data on Hg in European Blushers from different countries were reviewed. The mean concentrations of total Hg in caps of European Blushers from two "pristine" sites in northern part of Poland were ~1.0 MUg/g dw. A meal made with 300-500 g of fresh caps of European Blushers collected at such sites (assuming 90% water content in caps) can result in Hg intake of 0.0003-0.0005 mg Hg/kg bm (assuming a 60 kg bm), which is a dose equipotent to a new provisional tolerable weekly intake (PTWI) value set for inorganic Hg. PMID- 22424073 TI - Comparison of homologous and heterologous formats in nanocolloidal gold-based immunoassays for parathion residue determination. AB - The effectiveness of homologous and heterologous formats in a nanocolloidal gold based immunoassay for pesticide residue determination was investigated. Parathion, one of the most toxic organophosphorus pesticides, was used as the target analyte. One-step homologous and heterologous test strips based on a nanocolloidal gold-labeled monoclonal antibody were developed for the rapid detection of parathion residues. The results showed that the heterologous format was more effective than the homologous format, being more sensitive, more specific to parathion and more tolerant of matrix interferences. The best competitive hapten was found to have a moderate heterology and the opposite electronic distribution to the immunizing hapten. The detection limits for parathion using the preferred heterologous strip were 1 MUg/L in water samples and 5 MUg/kg in soil and food samples. PMID- 22424074 TI - Cationic iron(III) porphyrin-catalyzed [4 + 2] cycloaddition of unactivated aldehydes with simple dienes. AB - Cationic iron(III) porphyrin was found to be an efficient catalyst for the highly chemoselective hetero-Diels-Alder-type reaction of aldehydes with 1,3-dienes. The catalyzed process did not require the use of electron-deficient aldehydes such as glyoxylic acid derivatives or activated electron-rich 1,3-dienes such as Danishefsky's diene and Rawal's diene. The high functional group tolerance and robustness of the catalyst were demonstrated. Further, the potential utility of the catalyst was demonstrated by performing the cycloaddition in the presence of water and by carrying out cycloaddition of an unactivated ketone such as cyclohexanone with a diene. PMID- 22424075 TI - Phase behavior of aqueous solutions of copolymers of N,N'-diisopropylfumaramide and N-isopropylacrylamide: effect of the density of side chains. AB - This letter describes the phase behavior of aqueous solutions of an N isopropylacrylamide (NIPAM) homopolymer and copolymers of N,N' diisopropylfumaramide (DIPFAM) and NIPAM as studied by transmittance measurements, infrared spectroscopy, and differential scanning calorimetry to reveal the effect of the density of N-isopropylamide side chain upon the phase behavior. The clouding-point and clearing-point temperatures decreased with increasing the mole fraction of DIPFAM (x(D)). It was noteworthy that only an extra side chain per ca. 7 NIPAM units had a remarkable effect on the phase behavior; the interactions between side chains were stronger, the intrapolymer contraction was less favorable, and the cooperativity of phase transition was lower at x(D) = 0.15 presumably because of the steric hindrance of dense side chains. PMID- 22424076 TI - Phase equilibria study of the binary systems (N-hexylisoquinolinium thiocyanate ionic liquid + organic solvent or water). AB - Liquid-liquid phase equilibria (LLE) of binary mixtures containing a room temperature ionic liquid N-hexylisoquinolinium thiocyanate, [HiQuin][SCN] with an aliphatic hydrocarbon (n-hexane, n-heptane), aromatic hydrocarbon (benzene, toluene, ethylbenzene, n-propylbenzene), cyclohexane, thiophene, water, and 1 alcohol (1-ethanol, 1-butanol, 1-hexanol, 1-octanol, 1-decanol) have been determined using a dynamic method from room temperature to the boiling-point of the solvent at ambient pressure. N-hexylisoquinolinium thiocyanate, [HiQuin][SCN] has been synthesized from N-hexyl-isoquinolinium bromide as a substrate. Specific basic characterization of the new compound including NMR spectra, elementary analysis, and water content have been done. The density and viscosity of pure ionic liquid were determined over a wide temperature range from 298.15 to 348.15 K. The mutual immiscibility with an upper critical solution temperature (UCST) for the binary systems {IL + aliphatic hydrocarbon, cyclohexane, or water} was detected. In the systems of {IL + aromatic hydrocarbon or thiophene} an immiscibility gap with a lower critical solution temperature (LCST) was observed. Complete miscibility in the liquid phase, over a whole range of ionic liquid mole fraction, was observed for the binary mixtures containing IL and an 1-alcohol. For the tested binary systems with immiscibility gap {IL + aliphatic hydrocarbon, aromatic hydrocarbon, cyclohexane, thiophene, or water}, the parameters of the LLE correlation have been derived using the NRTL equation. The basic thermal properties of the pure IL, that is, the glass-transition temperature as well as the heat capacity at the glass-transition temperature, have been measured using a differential scanning microcalorimetry technique (DSC). Decomposition of the IL was detected by simultaneous thermogravimetric/differential thermal analysis (TG/DTA) experiments. PMID- 22424077 TI - A standard telemental health evaluation model: the time is now. AB - The telehealth field has advanced historic promises to improve access, cost, and quality of care. However, the extent to which it is delivering on its promises is unclear as the scientific evidence needed to justify success is still emerging. Many have identified the need to advance the scientific knowledge base to better quantify success. One method for advancing that knowledge base is a standard telemental health evaluation model. Telemental health is defined here as the provision of mental health services using live, interactive video teleconferencing technology. Evaluation in the telemental health field largely consists of descriptive and small pilot studies, is often defined by the individual goals of the specific programs, and is typically focused on only one outcome. The field should adopt new evaluation methods that consider the co adaptive interaction between users (patients and providers), healthcare costs and savings, and the rapid evolution in communication technologies. Acceptance of a standard evaluation model will improve perceptions of telemental health as an established field, promote development of a sounder empirical base, promote interagency collaboration, and provide a framework for more multidisciplinary research that integrates measuring the impact of the technology and the overall healthcare aspect. We suggest that consideration of a standard model is timely given where telemental health is at in terms of its stage of scientific progress. We will broadly recommend some elements of what such a standard evaluation model might include for telemental health and suggest a way forward for adopting such a model. PMID- 22424078 TI - Feasibility and acceptability of clinic-based telepsychiatry for low-income Hispanic primary care patients. AB - BACKGROUND: The feasibility and acceptability of telepsychiatry for low-income Hispanic patients with major depression were assessed. SUBJECTS AND METHODS: In total, 167 adult Hispanic patients with major depression recruited from a community health center (CHC) were randomly assigned to receive psychiatry services through a video Webcam (WEB) (n=80) or to treatment as usual (TAU) (n=87). The WEB condition consisted of monthly telepsychiatry sessions at the CHC for 6 months provided by one of two Hispanic psychiatrists using an online virtual meeting program. TAU patients received their care from their providers. Acceptability was assessed by comparing appointment keeping for primary care versus telepsychiatry, patients' perceived working alliance with their provider, visit satisfaction, and antidepressant use. Feasibility was assessed using depression outcomes, functional days (unproductive or days lost), and whether WEB and TAU patients differed in their appointment keeping. RESULTS: WEB patients did not differ in the proportion of completed primary care versus telepsychiatry appointments and rated their working alliance with the psychiatrist and their visit satisfaction significantly higher than the TAU patients with their provider. Significantly more WEB than TAU patients used antidepressants. Although depression severity decreased faster among WEB than TAU patients, no differences were found in the overall depression score. WEB and TAU patients did not differ in the number of days that were lost or unproductive due to depression. Although WEB and TAU patients reported being willing to pay for mental health services provided by the CHC, almost proportionately twice as many WEB patients were willing to pay for telepsychiatry. CONCLUSIONS: Results show that for low-income depressed Hispanic patients, telepsychiatry service for depression is acceptable, although its feasibility is questionable. The benefits of telemedicine were discussed in terms of improving patient care in ways other than directly providing services to the patients. PMID- 22424079 TI - E-counseling in psychosocial cancer care: a survey of practice, attitudes, and training among providers. AB - OBJECTIVE: In the cancer setting, e-counseling interventions may be uniquely beneficial as they spare patients the cost and burden of traveling to a hospital or clinic for psychosocial care. However, the prevalence of e-counseling among psychosocial cancer care providers is unknown, as are the training needs with regard to e-counseling among this group of professionals. Thus, our group conducted an online professional training needs assessment with psychosocial cancer care providers. SUBJECTS AND METHODS: Participants (n=120) were recruited from the listservs of the Health Psychology Division of the American Psychological Association, the Society of Behavioral Medicine-Cancer Special Interest Group, the American Psychosocial Oncology Society, and the Association of Oncology Social Work. All completed a 14-item online survey. RESULTS: Although 84% of participants stated that e-counseling could be important to their clinical work with cancer patients and survivors, 88% reported that they did not have the skills to effectively conduct e-counseling, and 81% reported that there were no adequate e-counseling educational opportunities. When asked about future training opportunities, participants reported a preference for online training versus live training (p<0.001). CONCLUSIONS: Overall, the results highlight the need for online training programs in e-counseling for psychosocial cancer care providers. The training of psychosocial cancer care providers in e-counseling is a critical first step towards increasing implementation of e-counseling interventions and using the Internet to deliver effective interventions to cancer patients in need. PMID- 22424081 TI - Exploring therapeutic alliance with an internet-based self-management program with brief telephone support for youth with arthritis: a pilot study. AB - Findings from a pilot study are presented exploring therapeutic alliance between adolescent juvenile idiopathic arthritis patients and a trained nonprofessional health coach during the feasibility testing of a 12-week self-management program delivered online with brief telephone support. Therapeutic alliance was measured using the Working Alliance Inventory Client Scale (WAI-C), and qualitative information about the experience was gathered using the Distance Experience Questionnaire. WAI-C scores were found to be comparable to previously published pediatric face-to-face data and pediatric distance treatment data. Therapeutic alliance scores were also found to be correlated with improved treatment outcomes (decreased reported pain). PMID- 22424082 TI - Genomics, personalized medicine and cancer practice. PMID- 22424083 TI - The challenges of personalized medicine. PMID- 22424084 TI - Whether it is personalized, precision, or mechanistic medicine--- the clinical laboratory has a role. PMID- 22424085 TI - Application of support vector machine to three-dimensional shape-based virtual screening using comprehensive three-dimensional molecular shape overlay with known inhibitors. AB - In this study, machine learning using support vector machine was combined with three-dimensional (3D) molecular shape overlay, to improve the screening efficiency. Since the 3D molecular shape overlay does not use fingerprints or descriptors to compare two compounds, unlike 2D similarity methods, the application of machine learning to a 3D shape-based method has not been extensively investigated. The 3D similarity profile of a compound is defined as the array of 3D shape similarities with multiple known active compounds of the target protein and is used as the explanatory variable of support vector machine. As the measures of 3D shape similarity for our new prediction models, the prediction performances of the 3D shape similarity metrics implemented in ROCS, such as ShapeTanimoto and ScaledColor, were validated, using the known inhibitors of 15 target proteins derived from the ChEMBL database. The learning models based on the 3D similarity profiles stably outperformed the original ROCS when more than 10 known inhibitors were available as the queries. The results demonstrated the advantages of combining machine learning with the 3D similarity profile to process the 3D shape information of plural active compounds. PMID- 22424086 TI - Ligation of expressed protein alpha-hydrazides via genetic incorporation of an alpha-hydroxy acid. AB - Expressed protein ligation bridges the gap between synthetic peptides and recombinant proteins and thereby significantly increases the size and complexity of chemically synthesized proteins. Although the intein-based expressed protein ligation method has been extensively used in this regard, the development of new expressed protein ligation methods may improve the flexibility and power of protein semisynthesis. In this study a new alternative version of expressed protein ligation is developed by combining the recently developed technologies of hydrazide-based peptide ligation and genetic code expansion. Compared to the previous intein-based expressed protein ligation method, the new method does not require the use of protein splicing technology and generates recombinant protein alpha-hydrazides as ligation intermediates that are more chemically stable than protein alpha-thioesters. Furthermore, the use of an evolved mutant pyrrolysyl tRNA synthetase(PylRS), ACPK-RS, from M. barkeri shows an improved performance for the expression of recombinant protein backbone oxoesters. By using HdeA as a model protein we demonstrate that the hydrazide-based method can be used to synthesize proteins with correctly folded structures and full biological activity. Because the PylRS-tRNACUAPyl system is compatible with both prokaryotic and eukaryotic cells,the strategy presented here may be readily expanded to manipulate proteins produced in mammalian cells. The new hydrazide-based method may also supplement the intein-based expressed protein ligation method by allowing for a more flexible selection of ligation site. PMID- 22424087 TI - PupDB: a database of pupylated proteins. AB - BACKGROUND: Prokaryotic ubiquitin-like protein (Pup), the firstly identified post translational protein modifier in prokaryotes, is an important signal for the selective degradation of proteins. Recently, large-scale proteomics technology has been applied to identify a large number of pupylated proteins. The development of a database for managing pupylated proteins and pupylation sites is important for further analyses. DESCRIPTION: A database named PupDB is constructed by collecting experimentally identified pupylated proteins and pupylation sites from published studies and integrating the information of pupylated proteins with corresponding structures and functional annotations. PupDB is a web-based database with tools for browses and searches of pupylated proteins and interactive displays of protein structures and pupylation sites. CONCLUSIONS: The structured and searchable database PupDB is expected to provide a useful resource for further analyzing the substrate specificity, identifying pupylated proteins in other organisms and developing computational tools for predicting pupylation sites. PupDB is freely available at http://cwtung.kmu.edu.tw/pupdb. PMID- 22424088 TI - Comparative chemical composition and in vitro antioxidant activities of essential oil isolated from the leaves of Cinnamomum tamala and Pimenta dioica. AB - Cinnamomum tamala Nees and Eberm (tejpat) and Pimenta dioica (L.) Merr (pimento) leaves are commonly used for flavouring food and widely used in pharmaceutical preparations because of their hypoglycemic, carminative and stimulant properties. In this study, we compared the chemical composition and antioxidant activities of tejpat and pimento essential oils by employing various in vitro methods. GC and GC-MS analyses were done to find out the chemical composition, and the main constituent identified in tejpat and pimento leaf oils was eugenol. Both the oils showed significant radical scavenging activity against DPPH and superoxide radicals with a potent metal chelating activity and were compared with that of standard compound, eugenol. Among the two oils, tejpat oil showed better activity in terms of antioxidative potential. PMID- 22424089 TI - Competition between pentoses and glucose during uptake and catabolism in recombinant Saccharomyces cerevisiae. AB - BACKGROUND: In mixed sugar fermentations with recombinant Saccharomyces cerevisiae strains able to ferment D-xylose and L-arabinose the pentose sugars are normally only utilized after depletion of D-glucose. This has been attributed to competitive inhibition of pentose uptake by D-glucose as pentose sugars are taken up into yeast cells by individual members of the yeast hexose transporter family. We wanted to investigate whether D-glucose inhibits pentose utilization only by blocking its uptake or also by interfering with its further metabolism. RESULTS: To distinguish between inhibitory effects of D-glucose on pentose uptake and pentose catabolism, maltose was used as an alternative carbon source in maltose-pentose co-consumption experiments. Maltose is taken up by a specific maltose transport system and hydrolyzed only intracellularly into two D-glucose molecules. Pentose consumption decreased by about 20 - 30% during the simultaneous utilization of maltose indicating that hexose catabolism can impede pentose utilization. To test whether intracellular D-glucose might impair pentose utilization, hexo-/glucokinase deletion mutants were constructed. Those mutants are known to accumulate intracellular D-glucose when incubated with maltose. However, pentose utilization was not effected in the presence of maltose. Addition of increasing concentrations of D-glucose to the hexo-/glucokinase mutants finally completely blocked D-xylose as well as L-arabinose consumption, indicating a pronounced inhibitory effect of D-glucose on pentose uptake. Nevertheless, constitutive overexpression of pentose-transporting hexose transporters like Hxt7 and Gal2 could improve pentose consumption in the presence of D-glucose. CONCLUSION: Our results confirm that D-glucose impairs the simultaneous utilization of pentoses mainly due to inhibition of pentose uptake. Whereas intracellular D-glucose does not seem to have an inhibitory effect on pentose utilization, further catabolism of D-glucose can also impede pentose utilization. Nevertheless, the results suggest that co-fermentation of pentoses in the presence of D-glucose can significantly be improved by the overexpression of pentose transporters, especially if they are not inhibited by D-glucose. PMID- 22424090 TI - Cardiovascular health in the menopausal woman: impact of the timing of hormone replacement therapy. AB - The cardiovascular effects of hormone replacement therapy (HRT) have been the subject of much debate since the initial findings from the Women's Health Initiative (WHI) were reported. However, re-analyses of WHI results have suggested that the association between HRT use and cardiovascular risk is influenced by several factors and that, among these, age and time since menopause may play a key role. Preclinical and human studies have shown differential effects of estrogen on the vasculature of healthy subjects compared with those with existing atherosclerosis. Indeed, while HRT has shown no protective effects in the presence of established atherosclerotic disease, it may have beneficial or neutral effects on healthy vasculature or early atherosclerosis. However, the final cardiovascular effects of estrogens in non-hysterectomized women are influenced by the type, dosage, and route of administration of the progestin used in association. The results of ongoing studies on the timing of HRT initiation will help women make better informed decisions regarding their menopausal health. Current treatment guidelines recommend initiation of HRT in recently postmenopausal women for the relief of vasomotor symptoms. PMID- 22424091 TI - G-quadruplexes: targets and tools in anticancer drug design. AB - BACKGROUND: Guanosine (G)-rich DNA and RNA sequences can adopt a defined secondary structure, the G-quadruplex, which consists of multiple stacked G tetrads. Each G-tetrad has four Gs arranged in a planar configuration and held together by hydrogen bonding. G-quadruplexes are found in chromosomal DNA and RNA transcripts, particularly in telomeric sequences, and in regulatory regions of many genes including oncogenes. PURPOSE: This review summarizes how G quadruplexes can be employed for anticancer therapies and discusses possible mechanisms. METHODS: The Medline database was searched using the terms "G-rich oligonucleotide (GRO)", "G-tetrad", and "G-quadruplex". RESULTS: Drugs which bind to and stabilize G-quadruplexes can be employed to suppress the elongation of telomers and the gene transcription and translation of oncogenes. G-quadruplex stabilization results in senescence and apoptosis of cancer cells. Besides long chain nucleic acids, also GRO are able to acquire G-quadruplex conformation to build up a variety of stable structures. Selected aptamers show a highly specific binding capacity to their target molecules, similar to antibodies. Some GRO were shown to induce cell death, preferentially in cancer cells; they demonstrated remarkable anticancer activity in preclinical and first clinical studies. CONCLUSION: G-quadruplexes can be both, targets and tools in anticancer drug development. PMID- 22424095 TI - The mammary stem cell conundrum: is it unipotent or multipotent? AB - Exploring the normal biology and regulation of stem cells has the promise to yield insights into the etiological roots and survival of breast cancer cells. Many studies have supported the existence of a multipotent mammary stem cell that regenerates all aspects of glandular development. However, Van Keymeulen and colleagues (2011) illustrated the presence of lineage-restricted unipotent stem cells that self-renew and collaborate in postnatal mammary development, whereas multipotent stem cells were found only during embryonic mammogenesis. This prompts a re-evaluation of currently accepted mammary stem cell dynamics and conceivably its impact on the evolution of different breast cancer subtypes. PMID- 22424094 TI - Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study. AB - BACKGROUND: There are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated with risk of PSP, with both oxidative stress and mitochondrial dysfunction also implicated. We investigated whether specific single nucleotide polymorphisms (SNPs) in genes encoding enzymes of xenobiotic detoxification, mitochondrial functioning, or oxidative stress response, including debrisoquine 4 hydroxylase, paraoxonase 1 and 2, N-acetyltransferase 1 and 2 (NAT2), superoxide dismutase 1 and 2, and PTEN-induced putative kinase are associated with PSP. METHODS: DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 +/- 8 years; age at death 75 +/- 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 +/- 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay. RESULTS: The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001). CONCLUSIONS: Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP. PMID- 22424096 TI - Estimating global mortality from potentially foodborne diseases: an analysis using vital registration data. AB - BACKGROUND: Foodborne diseases (FBD) comprise a large part of the global mortality burden, yet the true extent of their impact remains unknown. The present study utilizes multiple regression with the first attempt to use nonhealth variables to predict potentially FBD mortality at the country level. METHODS: Vital registration (VR) data were used to build a multiple regression model incorporating nonhealth variables in addition to traditionally used health indicators. This model was subsequently used to predict FBD mortality rates for all countries of the World Health Organization classifications AmrA, AmrB, EurA, and EurB. RESULTS: Statistical modeling strongly supported the inclusion of nonhealth variables in a multiple regression model as predictors of potentially FBD mortality. Six variables were included in the final model: percent irrigated land, average calorie supply from animal products, meat production in metric tons, adult literacy rate, adult HIV/AIDS prevalence, and percent of deaths under age 5 caused by diarrheal disease. Interestingly, nonhealth variables were not only more robust predictors of mortality than health variables but also remained significant when adding additional health variables into the analysis. Mortality rate predictions from our model ranged from 0.26 deaths per 100,000 (Netherlands) to 15.65 deaths per 100,000 (Honduras). Reported mortality rates of potentially FBD from VR data lie within the 95% prediction interval for the majority of countries (37/39) where comparison was possible. CONCLUSIONS: Nonhealth variables appear to be strong predictors of potentially FBD mortality at the country level and may be a powerful tool in the effort to estimate the global mortality burden of FBD. DISCLAIMER: The views expressed in this document are solely those of the authors and do not represent the views of the World Health Organization. PMID- 22424097 TI - Inkjet printing of nanoporous gold electrode arrays on cellulose membranes for high-sensitive paper-like electrochemical oxygen sensors using ionic liquid electrolytes. AB - A simple approach to the mass production of nanoporous gold electrode arrays on cellulose membranes for electrochemical sensing of oxygen using ionic liquid (IL) electrolytes was established. The approach, combining the inkjet printing of gold nanoparticle (GNP) patterns with the self-catalytic growth of these patterns into conducting layers, can fabricate hundreds of self-designed gold arrays on cellulose membranes within several hours using an inexpensive inkjet printer. The resulting paper-based gold electrode arrays (PGEAs) had several unique properties as thin-film sensor platforms, including good conductivity, excellent flexibility, high integration, and low cost. The porous nature of PGEAs also allowed the addition of electrolytes from the back cellulose membrane side and controllably produced large three-phase electrolyte/electrode/gas interfaces at the front electrode side. A novel paper-based solid-state electrochemical oxygen (O(2)) sensor was therefore developed using an IL electrolyte, 1-butyl-3 methylimidazolium hexafluorophosphate (BMIMPF(6)). The sensor looked like a piece of paper but possessed high sensitivity for O(2) in a linear range from 0.054 to 0.177 v/v %, along with a low detection limit of 0.0075% and a short response time of less than 10 s, foreseeing its promising applications in developing cost effective and environment-friendly paper-based electrochemical gas sensors. PMID- 22424098 TI - PI3K/Akt contributes to increased expression of Toll-like receptor 4 in macrophages exposed to hypoxic stress. AB - Toll-like receptors (TLRs) play critical roles in triggering immune and inflammatory responses by detecting invading microbial pathogens and endogenous danger signals. Increased expression of TLR4 is implicated in aggravated inflammatory symptoms in ischemic tissue injury and chronic diseases. Results from our previous study showed that TLR4 expression was upregulated by hypoxic stress mediated by hypoxia-inducible factor-1 (HIF-1) at a transcriptional level in macrophages. In this study, we further investigated the upstream signaling pathway that contributed to the increase of TLR4 expression by hypoxic stress. Either treatment with pharmacological inhibitors of PI3K and Akt or knockdown of Akt expression by siRNA blocked the increase of TLR4 mRNA and protein levels in macrophages exposed to hypoxia and CoCl(2). Phosphorylation of Akt by hypoxic stress preceded nuclear accumulation of HIF-1alpha. A PI3K inhibitor (LY294002) attenuated CoCl(2)-induced nuclear accumulation and transcriptional activation of HIF-1alpha. In addition, HIF-1alpha-mediated upregulation of TLR4 expression was blocked by LY294002. Furthermore, sulforaphane suppressed hypoxia- and CoCl(2) induced upregulation of TLR4 mRNA and protein by inhibiting PI3K/Akt activation and the subsequent nuclear accumulation and transcriptional activation of HIF 1alpha. However, p38 was not involved in HIF-1alpha activation and TLR4 expression induced by hypoxic stress in macrophages. Collectively, our results demonstrate that PI3K/Akt contributes to hypoxic stress-induced TLR4 expression at least partly through the regulation of HIF-1 activation. These reveal a novel mechanism for regulation of TLR4 expression upon hypoxic stress and provide a therapeutic target for chronic diseases related to hypoxic stress. PMID- 22424099 TI - Highly selective asymmetric Rh-catalyzed hydroformylation of heterocyclic olefins. AB - A small family of new chiral hybrid, diphosphorus ligands, consisting of phosphine-phosphoramidites L1 and L2 and phosphine-phosphonites L3a-c, was synthesized for the application in Rh-catalyzed asymmetric hydroformylation of heterocyclic olefins. High-pressure (HP)-NMR and HP-IR spectroscopy under 5-10 bar of syngas has been employed to characterize the corresponding catalyst resting state with each ligand. Indole-based ligands L1 and L2 led to selective ea coordination, while the xanthene derived system L3c gave predominant ee coordination. Application of the small bite-angle ligands L1 and L2 in the highly selective asymmetric hydroformylation (AHF) of the challenging substrate 2,3 dihydrofuran (1) yielded the 2-carbaldehyde (3) as the major regioisomer in up to 68% yield (with ligand L2) along with good ee's of up to 62%. This is the first example in which the asymmetric hydroformylation of 1 is both regio- and enantioselective for isomer 3. Interestingly, use of ligand L3c in the same reaction completely changed the regioselectivity to 3-carbaldehyde (4) with a remarkably high enantioselectivity of 91%. Ligand L3c also performs very well in the Rh-catalyzed asymmetric hydroformylation of other heterocyclic olefins. Highly enantioselective conversion of the notoriously difficult substrate 2,5 dihydrofuran (2) is achieved using the same catalyst, with up to 91% ee, concomitant with complete regioselectivity to the 3-carbaldehyde product (4) under mild reaction conditions. Interestingly, the Rh-catalyst derived from L3c is thus able to produce both enantiomers of 3-carbaldehyde 4, simply by changing the substrate from 1 to 2. Furthermore, 85% ee was obtained in the hydroformylation of N-acetyl-3-pyrroline (5) with exceptionally high regioselectivities for 3-carbaldehyde 8Ac (>99%). Similarly, an ee of 86% for derivative 8Boc was accomplished using the same catalyst system in the AHF of N (tert-butoxycarbonyl)-3-pyrroline (6). These results represent the highest ee's reported to date in the AHF of dihydrofurans (1, 2) and 3-pyrrolines (5, 6). PMID- 22424100 TI - Growth kinetics of nanoclusters in solution. AB - We study the growth kinetics of nanoclusters in solution. There are two generic factors that drive growth: (a) reactions that produce the nanomaterial; and (b) diffusion of the nanomaterial due to chemical-potential gradients. We model the growth kinetics of ZnO nanoparticles via coupled dynamical equations for the relevant order parameters. We study this model both analytically and numerically. We find that there is a crossover in the nanocluster growth law: from L(t) ~ t(1/2) in the reaction-controlled regime to L(t) ~ t(1/3) in the diffusion controlled regime. PMID- 22424101 TI - What impedes working in rural areas? A study of aspiring doctors in the National Capital Region, India. AB - INTRODUCTION: The rural health system in India has long been disadvantaged by a shortage of health staff, including doctors. Providing medical students with a rural clinical placement has been suggested as one strategy to overcome this shortage. This study examined the attitudes of and inclination to rural healthcare careers among medical students. METHODS: A cross-sectional study was performed on 201 students (147 males and 54 females) from two medical colleges in the National Capital Region (NCR) of India. A pre-tested semi-open-ended questionnaire was used to obtain information about students' socio-demographic characteristics and their views about a rural health career. Students' open-ended responses were collated and coded into broad categories. RESULTS: Of the respondents, 160 (79.6%) had a rural background. The current status of rural health services in India was rated as unsatisfactory by 178 students (88.6%). In total 110 (54.7%) indicated an interest in working in a rural area after graduation with 68 (33.8%) willing to set up their practice in a rural area. Students with a rural background were more likely to be willing to practice in a rural area. Those whose parents were highly qualified (postgraduate education or higher) were significantly less likely to practice in a rural area (p=0.004). Potential benefits of working in a rural area included 'health services for the poor/ benefit for the nation', and 'gain of knowledge about rural people and their diseases'. Potential drawbacks included 'lack of infrastructural facilities', 'less salary' and 'low standard of living'. A majority of the students believe the undergraduate medical curriculum needed modification to improve student awareness of rural needs. CONCLUSION: The medical students surveyed had a positive view of the importance of rural health care. However, factors such as infrastructure and salary were perceived as potential barriers to a career in rural health. The findings are a starting point to understanding the attitude of medical students towards rural health care and designing specific strategies to overcome the shortage of rural doctors in India. PMID- 22424102 TI - Chemical constituents of Euphorbia tangutica. AB - Sixteen known compounds isolated from the whole plants of Euphorbia tangutica, including phorbol-13-actate (1) previously synthesised and obtained from a natural source for the first time, were evaluated in vitro against a panel of human cancer cell lines using the MTT method. Among them, ergosterol (6) exhibited significant cytotoxic activity against HL-60 cell line with an IC(50) value of 3.3 uM, and 3beta,5alpha-dihydroxy-15beta-cinnamoyloxy-14-oxolathyra-6 Z,12 E-diene (7) also displayed moderate activity. PMID- 22424103 TI - Predicting protein-protein interface residues using local surface structural similarity. AB - BACKGROUND: Identification of the residues in protein-protein interaction sites has a significant impact in problems such as drug discovery. Motivated by the observation that the set of interface residues of a protein tend to be conserved even among remote structural homologs, we introduce PrISE, a family of local structural similarity-based computational methods for predicting protein-protein interface residues. RESULTS: We present a novel representation of the surface residues of a protein in the form of structural elements. Each structural element consists of a central residue and its surface neighbors. The PrISE family of interface prediction methods uses a representation of structural elements that captures the atomic composition and accessible surface area of the residues that make up each structural element. Each of the members of the PrISE methods identifies for each structural element in the query protein, a collection of similar structural elements in its repository of structural elements and weights them according to their similarity with the structural element of the query protein. PrISEL relies on the similarity between structural elements (i.e. local structural similarity). PrISEG relies on the similarity between protein surfaces (i.e. general structural similarity). PrISEC, combines local structural similarity and general structural similarity to predict interface residues. These predictors label the central residue of a structural element in a query protein as an interface residue if a weighted majority of the structural elements that are similar to it are interface residues, and as a non-interface residue otherwise. The results of our experiments using three representative benchmark datasets show that the PrISEC outperforms PrISEL and PrISEG; and that PrISEC is highly competitive with state-of-the-art structure-based methods for predicting protein-protein interface residues. Our comparison of PrISEC with PredUs, a recently developed method for predicting interface residues of a query protein based on the known interface residues of its (global) structural homologs, shows that performance superior or comparable to that of PredUs can be obtained using only local surface structural similarity. PrISEC is available as a Web server at http://prise.cs.iastate.edu/ CONCLUSIONS: Local surface structural similarity based methods offer a simple, efficient, and effective approach to predict protein-protein interface residues. PMID- 22424104 TI - Glufosfamide: can we improve the process of anticancer agent development? AB - INTRODUCTION: Drug development is a complex and risky enterprise. Clinical development must be a thoroughly paced process sequenced by clinical and developmental questions logically ordered. Drug development parameters are changing due to better insights in system biology and mechanisms of actions. Therefore, there is a need to revisit how clinical trials are designed and sequenced. AREAS COVERED: In the context of this paper, the development of glufosfamide is placed in perspective of possible new trends for more optimal drug development. Glufosfamide is an alkylating agent with a favorable safety profile as its metabolic activation does not lead to the release of toxic metabolites such as acrolein. In addition, its cellular uptake mediated through the transmembrane receptors of glucose makes it an attractive agent for the treatment of highly proliferative tumors cells. These observations have served the rationale to bring this agent to the clinic from Phase I up to Phase III with a focus on pancreatic cancer. The pathways for its development have been challenging due in part to the fact that there is no proof of mechanism-based study for any alkylating agent, even those used in the clinic. EXPERT OPINION: Solid mechanism and translational research-based clinical trials providing evidence on the mechanism of action and how the agent interacts with the biology of the targeted disease are today an absolute requirement for the development of new agents. Optimal clinical trial design must complement system biology understanding so that 'trials designed to learn' may give robust grounds to 'clinical trials designed to conclude'. PMID- 22424105 TI - Burden of cancer in Malawi; common types, incidence and trends: national population-based cancer registry. AB - BACKGROUND: Cancer is a leading cause of morbidity and mortality worldwide with a majority of cases and deaths occurring in developing countries. While cancer of the lung, breast, colorectum, stomach and prostate are the most common types of cancer globally, in east and southern Africa these are less common and comprehensive data to inform policies are lacking. METHODS: Nationwide cancer registry was conducted between September and October 2010 in Malawi. New cancer cases registered from 2007 to 2010 were identified from hospital and clinic registers of 81 out of 84 health facilities providing cancer diagnosis, treatment or palliative care services. Demographic and cancer data were extracted from registers and case notes using a standard form. RESULTS: A total of 18,946 new cases of cancer were registered in Malawi from 2007-2010. Of these 55.9% were females, 7.2% were children aged less than 15 years, 76.5% were adults aged 15-59 years and 16.4% were elderly aged 60 years or more. Only 17.9% of the cases had histologically verified diagnosis, 33.2% were diagnosed clinically and 49.6% based on clinical and some investigations. Amongst females, cancer of the cervix was the commonest accounting for 45.4% of all cases followed by Kaposi sarcoma (21.1%), cancer of the oesophagus (8.2%), breast (4.6%) and non-Hodgkin lymphoma (4.1%). In males, Kaposi sarcoma was the most frequent (50.7%) then cancer of oesophagus (16.9%), non-Hodgkin lymphoma (7.8), prostate (4.0%) and urinary bladder (3.7%). Age-standardised incidence rate per 100,000 population for all types of cancer in males increased from 31 in 1999-2002 to 56 in 2007-2010. In females it increased from 29 to 69. Kaposi sarcoma and cancer of the oesophagus, cervical cancer and Kaposi sarcoma were the main causes for the increased incidence in males and females respectively. It was estimated that, annually at least 8,151 new cases of cancer (all types) occur in Malawi. CONCLUSIONS: This study provided data on common types and trends of cancer that could be used to focus prevention, treatment and control interventions in the context of limited resources. The problem of under-reporting and misdiagnosis of cancer cases has been highlighted. PMID- 22424106 TI - Age at menarche and current substance use among Canadian adolescent girls: results of a cross-sectional study. AB - BACKGROUND: Substance use is among the key public health threats that find its genesis during adolescence. Timing of puberty has been lately researched as a potential predictor of subsequent substance abuse. The present study, therefore, aims to assess the effect of age at menarche on current practices of smoking, alcohol drinking and drug use among 14-15 year old Canadian girls. METHODS: The analysis of the study was based on all female respondents aged 14 to 15 years during Cycle 4 (2000/2001) of the National Longitudinal Survey of Children & Youth (NLSCY). The main independent variable was age at menarche assessed as the month and year of the occurrence of the first menstrual cycle. The dependent variables were current smoking, heavy alcohol drinking in the past 12 months and drug use in the past 12 months. Three logistic regression models were performed to investigate the association between age at menarche and each of the substance use outcomes, adjusting for possible confounders. Bootstrapping was performed to account for the complex sampling design. RESULTS: The total weighted sample included in the analysis represented 295,042 Canadian girls. The prevalence of current smokers, heavy drinkers (drunk in the past 12 months) and drug users in the past 12 months was approximately 22%, 38% and 26%, respectively. After adjusting of all potential confounders, no association was found between age at menarche and any of the substance use outcomes. School performance and relationship with the father, however, stood out as the main variables to be associated with smoking, heavy drinking and drug use. CONCLUSIONS: Qualitative studies understanding the social and psychological changes experienced by early maturing Canadian adolescents are warranted to identify other correlates or pathways to substance use in this higher risk population. PMID- 22424107 TI - [Summary of the Information Sheet for Consumers. Help for dementia patients caregivers]. PMID- 22424109 TI - Organo-soluble porphyrin mixed monolayer-protected gold nanorods with intercalated fullerenes. AB - Organo-soluble porphyrin mixed monolayer-protected gold nanorods were synthesized and characterized. The resulting gold nanorods encapsulated by both porphyrin thiol and alkyl thiol on their entire surface with strong covalent Au-S linkages were very stable in organic solvents without aggregation or decomposition and exhibited unique optical properties different from their corresponding spherical ones. Alkyl thiol acts as a stabilizer not only to fill up the potential space on gold nanorod surface between bulky porphyrin molecules but also to provide space for further insertion of C(60) molecules forming a stable C(60)-porphyrin-gold nanorod hybrid nanostructure. PMID- 22424108 TI - Clinical review: Stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype? AB - A growing understanding of the complexity of the pathophysiology of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), coupled with advances in stem cell biology, has led to a renewed interest in the therapeutic potential of stem cells for this devastating disease. Mesenchymal stem cells appear closest to clinical translation, given the evidence that they may favourably modulate the immune response to reduce lung injury, while maintaining host immune-competence and also facilitating lung regeneration and repair. The demonstration that human mesenchymal stem cells exert benefit in the endotoxin-injured human lung is particularly persuasive. Endothelial progenitor cells also demonstrate promise in reducing endothelial damage, which is a key pathophysiological feature of ALI. Embryonic and induced pluripotent stem cells are at an earlier stage in the translational process, but offer the hope of directly replacing injured lung tissue. The lung itself also contains endogenous stem cells, which may ultimately offer the greatest hope for lung diseases, given their physiologic role in replacing and regenerating native lung tissues. However, significant deficits remain in our knowledge regarding the mechanisms of action of stem cells, their efficacy in relevant pre-clinical models, and their safety, particularly in critically ill patients. These gaps need to be addressed before the enormous therapeutic potential of stem cells for ALI/ARDS can be realised. PMID- 22424110 TI - beta3-integrin is required for differentiation in OC-2 cells derived from mammalian embryonic inner ear. AB - BACKGROUND: The mammalian inner ear contains the organ of Corti which is responsible for the conversion of sound into neuronal signals. This specialised epithelial tissue is the product of a complex developmental process where a common precursor cell type differentiates into the sound transducing hair cells and the non-innervated supporting cells. We hypothesised that integrin proteins, which are involved in cell attachment to extracellular matrix proteins and cellular signalling, play a role in the differentiation process of the precursor inner ear epithelial cells. To test our hypothesis we have utilised a cell line (OC-2) derived from E13 embryonic immortomouse inner ears. In vitro, by switching the incubation temperature from 33 degrees C to 39 degrees C, the OC-2 cells can be induced to differentiate and express hair cells markers, such as Myosin VIIa. The OC-2 cells are thus a useful model system for testing mechanism of hair cells differentiation. RESULTS: We have identified 4 integrin subunits which are expressed in OC-2 cells: alpha6, alphav, beta1 and beta3. Among these, the relative level of expression of the alphav, beta1 and beta3 subunits increased in a time dependent manner when the cells were exposed to the differentiating temperature of 39 degrees C, most notably so for beta3 which was not detectable at 33 degrees C. Treatment of fully differentiated OC-2 cells with siRNA against the four integrin subunits reduced the expression of not only the respective integrin proteins but also of the hair cell marker Myosin VIIa. Conversely over expression of beta3 was sufficient to induce the expression of Myosin VIIa at 33 degrees C. CONCLUSIONS: Our data demonstrate that modulation of integrin expression is associated with the differentiation process of the OC-2 cells. This suggests that the maturation of the organ of Corti, from where OC-2 cells are derived, may also depend on changes of gene expression associated with integrin expression. PMID- 22424111 TI - Euthymia, depression, and mania: what do we know about the switch? PMID- 22424112 TI - Transducing emotionality: the role of adenylyl cyclases. PMID- 22424113 TI - Label-free fluorescent detection of ions, proteins, and small molecules using structure-switching aptamers, SYBR Gold, and exonuclease I. AB - We have demonstrated a label-free sensing strategy employing structure-switching aptamers (SSAs), SYBR Gold, and exonuclease I to detect a broad range of targets including inorganic ions, proteins, and small molecules. This nearly universal biosensor approach is based on the observation that SSAs at binding state with their targets, which fold into secondary structures such as quadruplex structure or Y shape structure, show more resistance to nuclease digestion than SSAs at unfolded states. The amount of aptamer left after nuclease reaction is proportional to the concentrations of the targets and in turn is proportional to the fluorescence intensities from SYBR Gold that can only stain nucleic acids but not their digestion products, nucleoside monophosphates (dNMPs). Fluorescent assays employing this mechanism for the detection of potassium ion (K(+)) are sensitive, selective, and convenient. Twenty MUM K(+) is readily detected even at the presence of a 500-fold excess of Na(+). Likewise, we have generalized the approach to the specific and convenient detection of proteins (thrombin) and small molecules (cocaine). The assays were then validated by detecting K(+), cocaine, and thrombin in urine and serum or cutting and masking adulterants with good agreements with the true values. Compared to other reported approaches, most limited to G-quadruplex structures, the demonstrated method has less structure requirements of both the SSAs and their complexes with targets, therefore rending its wilder applications for various targets. The detection scheme could be easily modified and extended to detection platforms to further improve the detection sensitivity or for other applications as well as being useful in high-throughput and paralleled analysis of multiple targets. PMID- 22424114 TI - Letter to the editor. PMID- 22424115 TI - Predicting nicotine dependence profiles among adolescent smokers: the roles of personal and social-environmental factors in a longitudinal framework. AB - BACKGROUND: Although several studies have reported that symptoms of nicotine dependence can occur after limited exposure to smoking, the majority of research on nicotine dependence has focused on adult smokers. Insufficient knowledge exists regarding the epidemiology and aetiology of nicotine dependence among adolescent smokers. The objective of the present study is to identify the effects of theoretically driven social and individual predictors of nicotine dependence symptom profiles in a population-based sample of adolescent smokers. METHOD: A longitudinal study among 6,783 adolescents (12 to 14 years old at baseline) was conducted. In the first and second year of secondary education, personality traits and exposure to smoking in the social environment were assessed. Two and a half years later, adolescents' smoking status and nicotine dependence symptom profiles were assessed. A total of 796 adolescents were identified as smokers and included in the analyses. RESULTS: At follow-up, four distinct dependence symptom profiles were identified: low cravings only, high cravings and withdrawal, high cravings and behavioural dependence, and overall highly dependent. Personality traits of neuroticism and extraversion did not independently predict nicotine dependence profiles, whereas exposure to smoking in the social environment posed a risk for the initial development of nicotine dependence symptoms. However, in combination with environmental exposure to smoking, extraversion and neuroticism increased the risk of developing more severe dependence symptom profiles. CONCLUSIONS: Nicotine dependence profiles are predicted by interactions between personal and environmental factors. These insights offer important directions for tailoring interventions to prevent the onset and escalation of nicotine dependence. Opportunities for intervention programs that target individuals with a high risk of developing more severe dependence symptom profiles are discussed. PMID- 22424116 TI - Infant feeding bottle design, growth and behaviour: results from a randomised trial. AB - BACKGROUND: Whether the design of an anti-vacuum infant feeding bottle influences infant milk intake, growth or behavior is unknown, and was the subject of this randomized trial. METHODS: SUBJECTS: 63 (36 male) healthy, exclusively formula fed term infants. INTERVENTION: Randomisation to use Bottle A (n = 31), one-way air valve: Philips Avent) versus Bottle B (n = 32), internal venting system: Dr Browns). 74 breast-fed reference infants were recruited, with randomisation (n = 24) to bottle A (n = 11) or B (n = 13) if bottle-feeding was subsequently introduced. Randomisation: stratified by gender and parity; computer-based telephone randomisation by independent clinical trials unit. SETTING: Infant home. PRIMARY OUTCOME MEASURE: infant weight gain to 4 weeks. SECONDARY OUTCOMES: (i) milk intake (ii) infant behaviour measured at 2 weeks (validated 3-day diary); (iii) risk of infection; (iv) continuation of breastfeeding following introduction of mixed feeding. RESULTS: Number analysed for primary outcome: Bottle A n = 29, Bottle B n = 25. PRIMARY OUTCOME: There was no significant difference in weight gain between randomised groups (0-4 weeks Bottle A 0.74 (SD 1.2) SDS versus bottle B 0.51 (0.39), mean difference 0.23 (95% CI -0.31 to 0.77). SECONDARY OUTCOMES: Infants using bottle A had significantly less reported fussing (mean 46 versus 74 minutes/day, p < 0.05) than those using bottle B. There was no significant difference in any other outcome measure. Breast-fed reference group: There were no significant differences in primary or secondary outcomes between breast-fed and formula fed infants. The likelyhood of breastfeeding at 3 months was not significantly different in infants subsequently randomised to bottle A or B. CONCLUSION: Bottle design may have short-term effects on infant behaviour which merit further investigation. No significant effects were seen on milk intake or growth; confidence in these findings is limited by the small sample size and this needs confirmation in a larger study. TRIAL REGISTRATION: Clinical Trials.gov NCT00325208. PMID- 22424117 TI - Antioxidant and lipoxygenase inhibiting new iridoid glucosides from Caryopteris odorata. AB - The phytochemical investigation of the ethylacetate-soluble fraction of Caryopteris odorata (Ham. ex Roxb.) led to the isolation of four new iridoid glucosides (1-4): 8-O-trans-cinnamoyl caryoptoside (1), 8-O-trans-cinnamoyl shanzhiside methylester (2), 8-O-trans-cinnamoyl mussaenoside (3) and 8-O-cafeoyl massenoside (4). The structures of these compounds were determined by FAB-MS, IR, 1D and 2D-NMR spectroscopy and by comparing with the published data of the closely related compounds. The antioxidant potential of the isolated iridoids (1 4) was evaluated relative to conventionally used standards and these molecules exhibited good antioxidant potential. Moreover, their inhibitory potential was also screened against three enzymes, namely acetyl cholinesterase, butyrylcholinesterase and lipoxygenase. These iridoid glucosides were found to be inactive against acetyl and butyrylcholinesterases but active against lipoxygenase. PMID- 22424118 TI - Selective self assembly of glutamate molecules on polyelectrolyte multilayers. AB - The adsorption behavior of neurotransmitter biomolecule, glutamate, on terminal poly-(allylamine)hydrochloride (PAH) polyelectrolyte multilayer is compared with its adsorption on a terminal poly(styrenesulfonate) (PSS) polyelectrolyte multilayer. Using X-ray and neutron reflectivity experiments, the internal structure of such a supramolecular film has been revealed with high resolution and the volume fraction of the adsorbed glutamate is determined. It has been shown that the glutamate binds only to the terminal PAH multilayer. Multiple attenuated total reflection infrared spectroscopy indicates that glutamate is electrostatically physisorbed on PAH surface in the zwitterionic form. Index matching neutron experiments have been done where the scattering length density of the solvent is varied, by changing the ratio of heavy water and light water, until it completely matches with that of the polyelectrolyte layer. The resulting absorption of the glutamic acid leads to changes in scattering profile which are analyzed and it is seen that the adsorption is restricted only to the surface layers. On the other hand, terminal poly(styrenesulfonate) multilayers show resistance toward glutamate. Such repulsion and adsorption between the neurotransmitter and polyelectrolytes could be potentially used in a variety of medicinal applications. PMID- 22424119 TI - Targeting of polo-like kinases and their cross talk with Aurora kinases--possible therapeutic strategies in human acute myeloid leukemia? AB - INTRODUCTION: Five human polo-like kinases (PLKs) have been identified, and PLK1 4 seem to interact with Aurora kinases and act as cell cycle regulators in both normal and malignant human cells. AREAS COVERED: The present review describes i) experimental evidence for a role for PLKs and Aurora kinases in human leukemogenesis and ii) the results from clinical studies of PLK and Aurora kinase inhibitors in the treatment of human acute myeloid leukemia (AML). The review was based on searches in the PubMed and the ClinicalTrials.gov databases. These inhibitors have antiproliferative and proapoptotic effects in AML cells. Hematological and gastrointestinal toxicities are frequently dose limiting, and this may limit the use of these agents in combination with conventional AML therapy. Aurora kinase inhibitors seem to be most effective for patients with high expression of the target kinases, and the same may be true for PLK inhibitors. EXPERT OPINION: PLK inhibition is a promising strategy for the treatment of AML. Future clinical studies have to clarify i) whether this strategy is most effective for certain subsets of patients; ii) whether multikinase inhibitors targeting several cell cycle regulators should be preferred; and iii) how this therapeutic strategy eventually should be combined with conventional antileukemic chemotherapy. PMID- 22424120 TI - Determination of hexavalent chromium reduction using Cr stable isotopes: isotopic fractionation factors for permeable reactive barrier materials. AB - Cr stable isotope measurements can provide improved estimates of the extent of Cr(VI) reduction to less toxic Cr(III). The relationship between observed (53)Cr/(52)Cr ratio shifts and the extent of reduction can be calibrated by determining the isotopic fractionation factor for relevant reactions. Permeable reactive barriers (PRB) made of Fe(0) and in situ redox manipulation (ISRM) zones effectively remediate Cr-contaminated aquifers. Here, we determine the isotopic fractionations for dominant reductants in reactive barriers and reduced sediments obtained from an ISRM zone at the US DOE's Hanford site. In all cases, significant isotopic fractionation was observed; fractionation (expressed as epsilon) was -3.910/00 for Fe(II)-doped goethite, -2.110/00 for FeS, -2.650/00 for green rust, -2.670/00 for FeCO(3), and -3.180/00 for ISRM zone sediments. These results provide a better calibration of the relationship between Cr isotope ratios and the extent of Cr(VI) reduction and aid in interpretation of Cr isotope data from systems with reactive barriers. PMID- 22424121 TI - Atomic hydrogen production from semi-clathrate hydrates. AB - Atomic hydrogen has received recent attention because of its potential role in energy devices, silicon devices, artificial photosynthesis, hydrogen storage, and so forth. Here, we propose a highly efficient route for producing atomic hydrogen using semi-clathrate hydrates. Two major hydrogen radical sources, derived from guest/host materials, are closely examined. PMID- 22424122 TI - A novel TARDBP insertion/deletion mutation in the flail arm variant of amyotrophic lateral sclerosis. AB - Phenotypic variation in amyotrophic lateral sclerosis (ALS) is common, and one atypical form is the flail arm variant (FAV). Some classic ALS patients carry TARDBP mutations, and so we sought to establish whether TARDBP mutations are also present in the FAV of ALS. Mutation analysis of TARDBP, the gene encoding TDP-43, was performed in cohorts of classic and FAV ALS patients. An analysis of mutation effects was performed in patient fibroblasts. Results showed that a novel heterozygous in-frame insertion/deletion (indel), c.1158_1159delAT; c.1158_1159insCACCAACC, was identified in a highly conserved region encoding the glycine-rich area of TDP-43 in a patient with FAV. This indel was confirmed in the proband's mother, an obligate carrier, and was absent from 480 ethnically matched control individuals. Transcription of the mutant allele was confirmed. Under induced stress, indel-mutant fibroblasts showed a loss of normal nuclear TDP-43 immunoreactivity and formation of cytoplasmic inclusions of TDP-43, consistent with features seen in affected neurons. In conclusion, TARDBP missense mutations have previously been reported in classic ALS and frontotemporal lobar degeneration. The identification of a TARDBP indel mutation in a patient with FAV extends the spectrum of mutations and further supports the role of TDP-43 in a range of neurodegenerative phenotypes. PMID- 22424123 TI - Inappropriately chelated iron in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. AB - ALS is characterized by oxidative damage in the brain and cerebrospinal fluid, which is exerted by pro-oxidative activity of iron. Such activity of iron can be drastically increased in the presence of inappropriate iron ligands that catalyze redox cycling of iron, thereby promoting hydroxyl radical generation. The aim of our study was to determine the relative level of inappropriate iron ligands in the cerebrospinal fluid of ALS patients. To determine the levels of inappropriate iron ligands and redox activity of iron in cerebrospinal fluid (10 samples from ALS patients and 10 controls), we applied electron paramagnetic resonance spectroscopy. We have shown that cerebrospinal fluid of ALS patients comprises two-fold increased level of inappropriate iron ligands, proportionally increasing iron redox activity and hydroxyl radical production compared to controls. In conclusion, our results strongly support the pro-oxidative/detrimental role of inappropriately chelated iron in ALS pathophysiology. The identification of biomolecules that form such iron complexes and their therapeutic targeting may represent the future of ALS treatment. PMID- 22424124 TI - Reducing systemic hypermetabolism by inducing hypothyroidism does not prolong survival in the SOD1-G93A mouse. AB - ALS is commonly associated with a hypermetabolic state. In this study, we assess whether inhibition of this hypermetabolism via the induction of hypothyroidism can forestall disease onset and prolong life in the SOD1-G93A mouse. We treated a cohort of 16 SOD1-G93A mice with methimazole, a potent inhibitor of thyroid hormone synthesis and followed a second group of 23 untreated littermate control animals from approximately five weeks of age onward. Total thyroxine (T4) levels, weights, and rectal temperatures were obtained on a regular basis and animals were sacrificed when they were no longer able to feed themselves. Results revealed that T4 levels were effectively suppressed within two weeks of drug initiation. However, there was no significant difference between the two groups either in terms of clinical disease onset (120.1+/-9.3 days for treated animals and 116.7+/-6.3 days for untreated animals) or in terms of survival (131.4+/-11.7 days for treated animals and 134.0+/-10.0 days for untreated animals). A correlation analysis between mean T4 levels for each animal versus survival showed that, contrary to our hypothesis, higher T4 levels correlated with longer survival. In conclusion, these studies show that drug-induced hypothyroidism does not alter the disease course in the SOD1-G93A ALS mouse. PMID- 22424125 TI - Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis? AB - Amyotrophic lateral sclerosis (ALS) is typically regarded as a sporadic neurodegenerative disorder that results in a catastrophic failure of the motor system, with characteristically variable involvement of upper and lower motor neuronal populations. A wide range of evidence from clinical, histological, genetic, neurophysiological, neuroimaging and neuropsychological studies, suggests that a loss of central nervous system inhibitory neuronal influence is a contributing factor in ALS pathogenesis. This loss of inhibitory function points intuitively to an 'interneuronopathy', with natural differences in cortical and spinal inhibitory networks reflected in the hitherto unexplained variable compartmentalization of pathology within upper and lower motor neuron populations. An excitotoxic final common pathway might then result from unopposed glutamatergic activity. If correct, therapies aimed specifically at supporting interneuronal function may provide a novel therapeutic strategy. PMID- 22424126 TI - Effect of genetic background on onset and disease progression in the SOD1-G93A model of amyotrophic lateral sclerosis. AB - Knowledge of the potential effect of genetic background in disease models is important. The SOD1-G93A transgenic mouse is the most widely used model in amyotrophic lateral sclerosis (ALS). Since these animals show considerable variability both in the onset and the progression of the disease, this study aimed to characterize the potential differences between the two most widely used strains, C56BL/6 (B6) and B6SJL. A rotarod test was carried out to assess strength and motor coordination, while electrophysiology tests were performed to evaluate the function of upper and lower motor neurons. Survival of the animals and motor neuron loss were also studied. The results did not show any background effect regarding the rotarod test, despite the differences in the pattern of decline in central and peripheral motor conduction. The onset of motor neuron abnormalities was later in B6SJL mice, but progressed more rapidly. Lifespan was longer for B6 than for B6SJL animals. In conclusion, background differences in disease onset and progression are important. The characteristics of the strain should be taken into account in experimental design of therapeutic studies. PMID- 22424127 TI - A systematic review of behavioural changes in motor neuron disease. AB - Motor neuron disease (MND) and the behavioural variant of frontotemporal dementia (bvFTD) are thought to be part of a disease spectrum. There is uncertainty about the frequency and characteristics of behavioural changes in MND, and similarly, about a relation between bvFTD and the site of onset of MND. Our aim was to perform a systematic review of the publications on behavioural changes in MND. An extensive search for articles on behavioural changes in MND patients was performed. First, cohort studies of MND patients were reviewed to summarize the prevalence of bvFTD and mild behavioural changes. Secondly, data on bvFTD symptoms (mostly from case reports) of individual MND-bvFTD patients were used to analyse characteristics and pooled prevalences of bvFTD symptoms. In addition, site of onset, survival and demographic variables of MND-bvFTD patients were analysed. Results showed that in cohorts, 8.1% (95% CI 5.6 - 11.5%) of MND patients had bvFTD. In 170 individual patients with MND-bvFTD, perseveration (40%), apathy (29%) and disinhibition (26%) were the most frequently reported behavioural changes; 43% had memory disturbances and bulbar onset was found in 48%. In conclusion, 8% of MND patients have bvFTD, with perseveration being reported most frequently. MND-bvFTD is often accompanied by memory disturbances and is related to bulbar onset. PMID- 22424128 TI - Blood pressure measurements in a transgenic SOD1-G93A mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons, but non-motor manifestations including autonomic dysfunction have been reported. To better understand the autonomic involvement in ALS we measured blood pressure (BP) changes. We evaluated blood pressure (BP) in a transgenic (TG) SOD1-G93A mouse model of ALS. BP was recorded in awake mice from six to 19 weeks of age by the tail-cuff method. TG mice (n =15) had significantly elevated BP compared to their wild-type (WT) siblings (n =14) even prior to the clinical appearance of motor dysfunction (at age 10-11 weeks, p =0.026). BP gradually decreased in TG mice but not in WT mice from age 10-11 weeks until the advanced stages of the disease (p for trend <0.002). The results indicate impairment of cardiovascular control in this ALS model. PMID- 22424129 TI - Is head trauma a risk factor for amyotrophic lateral sclerosis? An evidence based review. AB - Our objective was to evaluate the epidemiological literature regarding the association between trauma to the head and ALS, in order to determine if trauma to the head is a risk factor for ALS. A Medline literature search was conducted for the period between 1980 and October 2010 using the search terms: ('head trauma' OR 'head injury') AND (ALS OR 'amyotrophic lateral sclerosis' OR MND OR 'motor neuron disease'). The references of primary articles and reviews were checked to assure completeness of the search. Articles with primary data and reference groups were reviewed. The American Academy of Neurology evidence based method for classification of evidence for inferring causality and assigning level of conclusion was used. Twelve of 14 articles published since 1980 met the inclusion criteria. One class II article and three class III articles showed an association between a single instance of head trauma and ALS that did not exceed what might be seen due to chance alone. Eight class IV evidence articles could not inform conclusions. We concluded that evidence based analysis of the epidemiologic literature does not permit concluding that a single instance of head trauma is a risk factor for, or causes, ALS (Level U conclusion). PMID- 22424130 TI - Protocols in the management of critical illness. AB - Care of the critically ill patient is becoming increasingly complex. Protocols, which standardize care of patients with similar diseases, represent a potential solution to managing multiple simultaneous problems in critically ill patients. In this article, we examine the advantages and disadvantages to care protocolization, and posit that careful and thoughtful implementation of protocols is likely to benefit patients. We also discuss the potential for unintended consequences, and even harm, with protocolization in critically ill patients using the Critical Illness Outcomes Study as a model to examine the effects of protocolization in large populations of intensive care patients. PMID- 22424131 TI - Responses of human adipose-derived mesenchymal stem cells to chemical microenvironment of the intervertebral disc. AB - BACKGROUND: Human adipose-derived mesenchymal stem cells (ADMSCs) may be ideal source of cells for intervertebral disc (IVD) regeneration, but the harsh chemical microenvironment of IVD may significantly influence the biological and metabolic vitality of ADMSCs and impair their repair potential. This study aimed to investigate the viability, proliferation and the expression of main matrix proteins of ADMSCs in the chemical microenvironment of IVD under normal and degeneration conditions. METHODS: ADMSCs were harvested from young (aged 8-12 years, n = 6) and mature (aged 33-42 years, n = 6) male donors and cultured under standard condition and IVD-like conditions (low glucose, acidity, high osmolarity, and combined conditions) for 2 weeks. Cell viability was measured by annexin V-FITC and PI staining and cell proliferation was measured by MTT assay. The expression of aggrecan and collagen-I was detected by real-time quantitative polymerase chain reaction and Western blot analysis. RESULTS: IVD-like glucose condition slightly inhibited cell viability, but increased the expression of aggrecan. In contrast, IVD-like osmolarity, acidity and the combined conditions inhibited cell viability and proliferation and the expression of aggrecan and collagen-I. ADMSCs from young and mature donors exhibited similar responses to the chemical microenvironments of IVD. CONCLUSION: IVD-like low glucose is a positive factor but IVD-like high osmolarity and low pH are deleterious factors that affect the survival and biological behaviors of ADMSCs. These findings may promote the translational research of ADMSCs in IVD regeneration for the treatment of low back pain. PMID- 22424132 TI - A synthetic rainbow trout linkage map provides new insights into the salmonid whole genome duplication and the conservation of synteny among teleosts. AB - BACKGROUND: Rainbow trout is an economically important fish and a suitable experimental organism in many fields of biology including genome evolution, owing to the occurrence of a salmonid specific whole-genome duplication (4th WGD). Rainbow trout is among some of the most studied teleosts and has benefited from substantial efforts to develop genomic resources (e.g., linkage maps. Here, we first generated a synthetic map by merging segregation data files derived from three independent linkage maps. Then, we used it to evaluate genome conservation between rainbow trout and three teleost models, medaka, stickleback and zebrafish and to further investigate the extent of the 4th WGD in trout genome. RESULTS: The INRA linkage map was updated by adding 211 new markers. After standardization of marker names, consistency of marker assignment to linkage groups and marker orders was checked across the three different data sets and only loci showing consistent location over all or almost all of the data sets were kept. This resulted in a synthetic map consisting of 2226 markers and 29 linkage groups spanning over 3600 cM. Blastn searches against medaka, stickleback, and zebrafish genomic databases resulted in 778, 824 and 730 significant hits respectively while blastx searches yielded 505, 513 and 510 significant hits. Homology search results revealed that, for most rainbow trout chromosomes, large syntenic regions encompassing nearly whole chromosome arms have been conserved between rainbow trout and its closest models, medaka and stickleback. Large conserved syntenies were also found between the genomes of rainbow trout and the reconstructed teleost ancestor. These syntenies consolidated the known homeologous affinities between rainbow trout chromosomes due to the 4th WGD and suggested new ones. CONCLUSIONS: The synthetic map constructed herein further highlights the stability of the teleost genome over long evolutionary time scales. This map can be easily extended by incorporating new data sets and should help future rainbow trout whole genome sequence assembly. Finally, the persistence of large conserved syntenies across teleosts should facilitate the identification of candidate genes through comparative mapping, even if the occurrence of intra-chromosomal micro rearrangement may hinder the accurate prediction their genomic location. PMID- 22424133 TI - HIF-prolyl hydroxylases and cardiovascular diseases. AB - Prolyl hydroxylases belong to the family of iron- and 2-oxoglutamate-dependent dioxygenase enzyme. Several distinct prolyl hydroxylases have been identified. The hypoxia-inducible factor (HIF) prolyl hydroxylase termed prolyl hydroxylase domain (PHD) enzymes play an important role in oxygen regulation in the physiological network. There are three isoforms that have been identified: PHD1, PHD2 and PHD3. Deletion of PHD enzymes result in stabilization of HIFs and offers potential treatment options for many ischemic disorders such as peripheral arterial occlusive disease, myocardial infarction, and stroke. All three isoforms are oxygen sensors that regulate the stability of HIFs. The degradation of HIF 1alpha is regulated by hydroxylation of the 402/504 proline residue by PHDs. Under hypoxic conditions, lack of oxygen causes hydroxylation to cease HIF-1alpha stabilization and subsequent translocation to the nucleus where it heterodimerizes with the constitutively expressed beta subunit. Binding of the HIF-heterodimer to specific DNA sequences, named hypoxia-responsive elements, triggers the transactivation of target genes. PHD regulation of HIF-1alpha mediated cardioprotection has resulted in considerable interest in these molecules as potential therapeutic targets in cardiovascular and ischemic diseases. In recent years, attention has been directed towards identifying small molecule inhibitors of PHD. It is postulated that such inhibition might lead to a clinically useful strategy for protecting the myocardium against ischemia and reperfusion injury. Recently, it has been reported that the orally absorbed PHD inhibitor GSK360A can modulate HIF-1alpha signaling and protect the failing heart following myocardial infarction. Furthermore, PHD1 deletion has been found to have beneficial effects through an increase in tolerance to hypoxia of skeletal muscle by reprogramming basal metabolism. In the mouse liver, such deletion has resulted in protection against ischemia and reperfusion. As a result of these preliminary findings, PHDs is attracting increasing interest as potential therapeutic targets in a wide range of diseases. PMID- 22424134 TI - Enhanced payload and photo-protection for pesticides using nanostructured lipid carriers with corn oil as liquid lipid. AB - With the aim to establish a novel nanocarrier system with higher payload and higher photo-protection for deltamethrin (active ingredient) compared to solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) were prepared by combining hot homogenization and sonication with different ratios of corn oil (liquid lipid) and beeswax (solid lipid). Compared to SLN, the incorporation of corn oil gave a higher payload, slower release rate and higher photo-protection for deltamethrin. Particularly, compared to beeswax solid lipid nanoparticles (BSLN), NLC gave a higher payload (approximately 1.79 times) with a high encapsulation efficiency (83.6%), higher photo-protection in direct photolysis (1.8 times) after 12 h exposure of ultraviolet light (UV) and in indirect photolysis (1.37 times) after 2 h exposure of UV in 2% (v/v) acetone solution used as a photosensitizer. This study demonstrated that novel nanocarrier possesses a wide range of applicability in protecting photo-labile compounds for the crop, food and pharmaceutical industries. PMID- 22424135 TI - No evidence for increased risk of cleft lip or cleft palate among infants exposed to antiretroviral drugs during pregnancy in the antiretroviral pregnancy registry. PMID- 22424137 TI - Disposable immunochips for the detection of Legionella pneumophila using electrochemical impedance spectroscopy. AB - The rapid diagnosis of Legionellosis is crucial for the effective treatment of this disease. Currently, most clinical laboratories utilize rapid immunoassays that are sufficient for the detection of Legionella serogroup 1, but not other clinically relevant serogroups. In this report, the development of a disposable immunochip system is described in connection with electrochemical impedance spectroscopy and fluorescence microscopy. The immunochips were prepared by covalently immobilizing fluorophore-conjugated L. pneumophilaantibodies on Au chips. The analytical performance of the immunochips was optimized as a prescreening tool for L. pneumophila. The versatile immunochips described here can be easily adapted for the monitoring of all Legionella serogroups in clinical and environmental samples. PMID- 22424138 TI - Soil-transmitted helminth infections and physical fitness in school-aged Bulang children in southwest China: results from a cross-sectional survey. AB - BACKGROUND: Chronic soil-transmitted helminth (STH) infections have been associated with reduced physical fitness, but available evidence is limited. The aim of this cross-sectional survey was to assess the feasibility of measuring children's physical fitness and to relate it to STH infections. Our study was carried out among school-aged children of the Bulang ethnic group in rural southwest People's Republic of China (P.R. China). Standardized, quality controlled methods were employed to determine STH infections (Kato-Katz technique), haemoglobin levels, anthropometry (body weight and height) and physical fitness (20-m shuttle run test). RESULTS: A compliance of 87% suggested good acceptance of the methods used. Among 69 children with complete data records, infection prevalence of Trichuris trichiura, Ascaris lumbricoides and hookworm were 81%, 44% and 6%, respectively. The maximum volume of oxygen that can be utilized within 1 min during exhaustive exercise (VO2 max estimate) of T. trichiura-infected children was 1.94 ml kg-1 min-1 lower than that of their non infected counterparts (P = 0.005). Until exhaustion, T. trichiura-infected children had completed 6.14 20-m laps less (P = 0.004). Additionally, the mean VO2 max estimate of stunted children was lowered by 1.63 ml kg-1 min-1 (P = 0.002) and they completed 5.32 20-m laps less (P = 0.001) compared to children of normal stature. No significant association between stunting and infection with any STH species could be established. CONCLUSIONS: Implementation of physical fitness tests in rural, resource-constraint settings is feasible. The physical fitness of children who are stunted or infected with STHs, particularly T. trichiura, is significantly impaired. We have launched a larger study and will determine the dynamics of school-aged children's physical fitness over a 7-month period after administration of anthelminthic drugs. PMID- 22424139 TI - Palladium-catalyzed dehydrogenative beta'-functionalization of beta-keto esters with indoles at room temperature. AB - The dehydrogenative beta'-functionalization of alpha-substituted beta-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and beta'-selective for the beta-keto ester) and good yields under mild palladium catalysis at room temperature with a variety of oxidants. Two possible mechanisms involving either late or early involvement of indole are presented. PMID- 22424140 TI - Pattern recognition of cancer cells using aptamer-conjugated magnetic nanoparticles. AB - Biocompatible magnetic nanosensors based on reversible self-assembly of dispersed magnetic nanoparticles into stable nanoassemblies have been used as effective magnetic relaxation switches (MRSw) for the detection of molecular interactions. We report, for the first time, the design of MRSw based on aptamer-conjugated magnetic nanoparticles (ACMNPs). The ACMNPs capitalize on the ability of aptamers to specifically bind target cancer cells, as well as the large surface area of MNPs to accommodate multiple aptamer binding events. The ACMNPs can detect as few as 10 cancer cells in 250 MUL of sample. The ACMNPs' specificity and sensitivity are also demonstrated by detection in cell mixtures and complex biological media, including fetal bovine serum, human plasma, and whole blood. Furthermore, by using an array of ACMNPs, various cell types can be differentiated through pattern recognition, thus creating a cellular molecular profile that will allow clinicians to accurately identify cancer cells at the molecular and single-cell level. PMID- 22424141 TI - Factors impacting knowledge and use of long acting and permanent contraceptive methods by postpartum HIV positive and negative women in Cape Town, South Africa: a cross-sectional study. AB - BACKGROUND: The prevention of unintended pregnancies among HIV positive women is a neglected strategy in the fight against HIV/AIDS. Women who want to avoid unintended pregnancies can do this by using a modern contraceptive method. Contraceptive choice, in particular the use of long acting and permanent methods (LAPMs), is poorly understood among HIV-positive women. This study aimed to compare factors that influence women's choice in contraception and women's knowledge and attitudes towards the IUD and female sterilization by HIV-status in a high HIV prevalence setting, Cape Town, South Africa. METHODS: A quantitative cross-sectional survey was conducted using an interviewer-administered questionnaire amongst 265 HIV positive and 273 HIV-negative postpartum women in Cape Town. Contraceptive use, reproductive history and the future fertility intentions of postpartum women were compared using chi-squared tests, Wilcoxon rank-sum and Fisher's exact tests where appropriate. Women's knowledge and attitudes towards long acting and permanent methods as well as factors that influence women's choice in contraception were examined. RESULTS: The majority of women reported that their most recent pregnancy was unplanned (61.6% HIV positive and 63.2% HIV negative). Current use of contraception was high with no difference by HIV status (89.8% HIV positive and 89% HIV negative). Most women were using short acting methods, primarily the 3-monthly injectable (Depo Provera). Method convenience and health care provider recommendations were found to most commonly influence method choice. A small percentage of women (6.44%) were using long acting and permanent methods, all of whom were using sterilization; however, it was found that poor knowledge regarding LAPMs is likely to be contributing to the poor uptake of these methods. CONCLUSIONS: Improving contraceptive counselling to include LAPM and strengthening services for these methods are warranted in this setting for all women regardless of HIV status. These study results confirm that strategies focusing on increasing users' knowledge about LAPM are needed to encourage uptake of these methods and to meet women's needs for an expanded range of contraceptives which will aid in preventing unintended pregnancies. Given that HIV positive women were found to be more favourable to future use of the IUD it is possible that there may be more uptake of the IUD amongst these women. PMID- 22424142 TI - Isotope effect in the carbonyl sulfide reaction with O(3P). AB - The sulfur kinetic isotope effect (KIE) in the reaction of carbonyl sulfide (OCS) with O((3)P) was studied in relative rate experiments at 298 +/- 2 K and 955 +/- 10 mbar. The reaction was carried out in a photochemical reactor using long path FTIR detection, and data were analyzed using a nonlinear least-squares spectral fitting procedure with line parameters from the HITRAN database. The ratio of the rate of the reaction of OC(34)S relative to OC(32)S was found to be 0.9783 +/- 0.0062 ((34)epsilon = (-21.7 +/- 6.2)0/00). The KIE was also calculated using quantum chemistry and classical transition state theory; at 300 K, the isotopic fractionation was found to be (34)epsilon = -14.80/00. The OCS sink reaction with O((3)P) cannot explain the large fractionation in (34)S, over +730/00, indicated by remote sensing data. In addition, (34)epsilon in OCS photolysis and OH oxidation are not larger than 100/00, indicating that, on the basis of isotopic analysis, OCS is an acceptable source of background stratospheric sulfate aerosol. PMID- 22424143 TI - Syntheses and characterization of nine quaternary uranium chalcogenides among the compounds A2M3UQ6 (A = K, Rb, Cs; M = Pd, Pt; Q = S, Se). AB - Nine compounds from the series A(2)M(3)UQ(6) (A = K or Rb or Cs; M = Pd or Pt; Q = S or Se) were synthesized by reacting U, M, and Q in ACl or A(2)Q(x) fluxes. These compounds crystallize with eight formula units in the NaBa(2)Cu(3)O(6) structure type, in space group Fmmm of the orthorhombic system. The structure contains hexagons formed from six edge-sharing square-planar coordinated M atoms, which in turn edge-share with trigonal-prismatically coordinated U atoms, forming layers along (010). These layers are separated by A atoms. Electrical resistivity measurements along the [100] direction of Rb(2)Pd(3)US(6) show typical semiconductor behavior. Magnetic susceptibility measurements on Rb(2)Pd(3)US(6) display marked magnetic anisotropy and unusually low magnetic moments owing to crystalline electric field effects. PMID- 22424145 TI - Cell-based in vitro models for predicting drug permeability. AB - INTRODUCTION: In vitro cell models have been used to predict drug permeation in early stages of drug development, since they represent an easy and reproducible method, allowing the tracking of drug absorption rate and mechanism, with an advantageous cost-benefit ratio. Such cell-based models are mainly composed of immortalized cells with an intrinsic ability to grow in a monolayer when seeded in permeable supports, maintaining their physiologic characteristics regarding epithelium cell physiology and functionality. AREAS COVERED: This review summarizes the most important intestinal, pulmonary, nasal, vaginal, rectal, ocular and skin cell-based in vitro models for predicting the permeability of drugs. Moreover, the similitude between in vitro cell models and in vivo conditions are discussed, providing evidence that each model may provisionally resemble different drug absorption route. EXPERT OPINION: Despite the widespread use of in vitro cell models for drug permeability and absorption evaluation purposes, a detailed study on the properties of these models and their in vitro in vivo correlation compared with human data are required to further use in order to consider a future drug discovery optimization and clinical development. PMID- 22424146 TI - Short-term clinical outcomes among treatment-experienced HIV-positive patients with early low level viremia. PMID- 22424147 TI - A phonetic investigation of single word versus connected speech production in children with persisting speech difficulties relating to cleft palate. AB - Objective : To investigate the phonetic and phonological parameters of speech production associated with cleft palate in single words and in sentence repetition in order to explore the impact of connected speech processes, prosody, and word juncture on word production across contexts. Participants : Two boys (aged 9 years 5 months and 11 years 0 months) with persisting speech impairments related to a history of unilateral cleft lip and palate formed the main focus of the study; three typical adult male speakers provided control data. Method : Audio, video, and electropalatographic recordings were made of the participants producing single words and repeating two sets of sentences. The data were transcribed and the electropalatographic recordings were analyzed to explore lingual-palatal contact patterns across the different speech conditions. Acoustic analysis was used to further inform the perceptual analysis and to make specific durational measurements. Results : The two boys' speech production differed across the speech conditions. Both boys showed typical and atypical phonetic features in their connected speech production. One boy, although often unintelligible, resembled the adult speakers more closely prosodically and in his specific connected speech behaviors at word boundaries. The second boy produced developmentally atypical phonetic adjustments at word boundaries that appeared to promote intelligibility at the expense of naturalness. Conclusion : For older children with persisting speech impairments, it is particularly important to examine specific features of connected speech production, including word juncture and prosody. Sentence repetition data provide useful information to this end, but further investigations encompassing detailed perceptual and instrumental analysis of real conversational data are warranted. PMID- 22424148 TI - Fragment-based design of symmetrical bis-benzimidazoles as selective inhibitors of the trimethoprim-resistant, type II R67 dihydrofolate reductase. AB - The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic molecules of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (K(i) = 2-4 MUM). The putative mode of inhibition is discussed according to molecular modeling supported by in vitro tests. PMID- 22424149 TI - Interaction of Au with thin ZrO2 films: influence of ZrO2 morphology on the adsorption and thermal stability of Au nanoparticles. AB - The model catalysts of ZrO(2)-supported Au nanoparticles have been prepared by deposition of Au atoms onto the surfaces of thin ZrO(2) films with different morphologies. The adsorption and thermal stability of Au nanoparticles on thin ZrO(2) films have been investigated using synchrotron radiation photoemission spectroscopy (SRPES) and X-ray photoelectron spectroscopy (XPS). The thin ZrO(2) films were prepared by two different methods, giving rise to different morphologies. The first method utilized wet chemical impregnation to synthesize the thin ZrO(2) film through the procedure of first spin-coating a zirconium ethoxide (Zr(OC(2)H(5))(4)) precursor onto a SiO(2)/Si(100) substrate at room temperature followed by calcination at 773 K for 12 h. Scanning electron microscopy (SEM) investigations indicate that highly porous "sponge-like nanostructures" were obtained in this case. The second method was epitaxial growth of a ZrO(2)(111) film through vacuum evaporation of Zr metal onto Pt(111) in 1 * 10(-6) Torr of oxygen at 550 K followed by annealing at 1000 K. The structural analysis with low energy electron diffraction (LEED) of this film exhibits good long-range ordering. It has been found that Au forms smaller particles on the porous ZrO(2) film as compared to those on the ordered ZrO(2)(111) film at a given coverage. Thermal annealing experiments demonstrate that Au particles are more thermally stable on the porous ZrO(2) surface than on the ZrO(2)(111) surface, although on both surfaces, Au particles experience significant sintering at elevated temperatures. In addition, by annealing the surfaces to 1100 K, Au particles desorb completely from ZrO(2)(111) but not from porous ZrO(2). The enhanced thermal stability for Au on porous ZrO(2) can be attributed to the stronger interaction of the adsorbed Au with the defects and the hindered migration or coalescence resulting from the porous structures. PMID- 22424150 TI - Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective. AB - Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF kappaB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcgamma receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome. PMID- 22424151 TI - A low protein diet during pregnancy provokes a lasting shift of hepatic expression of genes related to cell cycle throughout ontogenesis in a porcine model. AB - BACKGROUND: In rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. Adverse environmental conditions during fetal development provoke an intrauterine adaptive response termed 'fetal programming', which may lead to both persistently biased responsiveness to extrinsic factors and permanent consequences for the organismal phenotype. This leads to the hypothesis that the offspring's transcriptome exhibits short-term and long-term changes, depending on the maternal diet. In order to contribute to a comprehensive inventory of genes and functional networks that are targets of nutritional programming initiated during fetal life, we applied whole-genome microarrays for expression profiling in a longitudinal experimental design covering prenatal, perinatal, juvenile, and adult ontogenetic stages in a porcine model. Pregnant sows were fed either a gestational low protein diet (LP, 6% CP) or an adequate protein diet (AP, 12% CP). All offspring was nursed by foster sows receiving standard diets. After weaning, all offspring was fed standard diets ad libitum. RESULTS: Analyses of the hepatic gene expression of the offspring at prenatal (94 dies post conceptionem, dpc) and postnatal stages (1, 28, 188 dies post natum, dpn) included comparisons between dietary groups within stages as well as comparisons between ontogenetic stages within diets to separate diet-specific transcriptional changes and maturation processes. We observed differential expression of genes related to lipid metabolism (e.g. Fatty acid metabolism, Biosynthesis of steroids, Synthesis and degradation of ketone bodies, FA elongation in mitochondria, Bile acid synthesis) and cell cycle regulation (e.g. Mitotic roles of PLK, G1/S checkpoint regulation, G2/M DNA damage checkpoint regulation). Notably, at stage 1 dpn no regulation of a distinct pathway was found in LP offspring. CONCLUSIONS: The transcriptomic modulations point to persistent functional demand on the liver towards cell proliferation in the LP group but not in the AP group at identical nutritional conditions during postnatal life due to divergent 'programming' of the genome. Together with the observation that the offspring of both groups did not differ in body weight but in body composition and fat content, the data indicate that the activity of various genes led to diverse partitioning of nutrients among peripheral and visceral organs and tissues. PMID- 22424152 TI - Analytical challenges of microbial biofilms on medical devices. AB - Microbial colonization of medical devices is a widespread problem that tests the limits of conventional analytical methods. Successful analytical endeavors require collaboration between clinicians, microbiologists, biomedical engineers, and analytical chemists. PMID- 22424153 TI - Ophthalmic disorder may affect visuo-attentional performance in childhood. AB - The aim of this study was to explore the visuo-attentional skills of children with an ophthalmic disorder. Twenty-four patients and 60 healthy controls between the ages 4 and 7 years, all right-handed with normal or corrected-to-normal close visual acuity, were divided into four age groups. Patients' diagnoses included refractive disorders (e.g., myopia, hypermetropia), strabismus, amblyopia, cataract, and nystagmus. All participants performed nine paper-and-pencil visuospatial tasks aiming to assess selective attention (cancellation tasks), spatial working memory (symbol orientation task), fine visual analysis (embedded figures test), and simple perceptual analysis (shape-matching task). In healthy children, the results showed that performance on all visuo-attentional tasks improved with age. While perception, orientation of attention, and visual working memory develop by the time children begin school (age 5), more sophisticated abilities such as attention disengagement and motor control continue to develop during late childhood. Moreover, a spatial bias in attention orienting appeared with reading acquisition (6-7 years). In ophthalmic children, at 4 years of age defects were observed in all assessed functions, but at 7 years an attentional deficit was virtually the only one remaining. Overall, the results demonstrate that children with an ophthalmologic disorder may experience difficulties with visuospatial tasks despite corrected-to-normal visual acuity. PMID- 22424154 TI - Are hepatic steatosis and carotid intima media thickness associated in obese patients with normal or slightly elevated gamma-glutamyl-transferase? AB - BACKGROUND: Hepatic steatosis (HS) has been associated with obesity and metabolic syndrome (MS), conditions carrying a high risk of coronary artery disease. We aimed to determine whether HS was an independent factor of atherogenic risk beyond its association with MS and its components. METHODS: We assessed the circulating levels of the heat shock protein-70 (HSP-70), a chaperone involved in inflammation, endoplasmic reticulum stress and apoptosis at liver and endothelial level and the gamma-glutamyl transferase activity (gamma-GT) correlating them to carotid intima-media thickness (IMT), along with lipid profile, HOMA, C-reactive protein, fibrinogen, ferritin, adiposity type as well as spleen volume in 52 obese pts with grade 1, 128 with grade 2, and 20 with grade 3 of HS evaluated by sonography. RESULTS: Patients with different grade of HS demonstrated overlapping HSP-70 levels; similarly performed obese subjects regarding IMT. Using multiple regression analysis, IMT was predicted by age, visceral adiposity and by HOMA (beta = 0.50, p < 0.0001, beta = 0.30, p = 0.01 and beta = 0.18, p = 0.048 respectively, while the severity of HS was predicted by visceral and subcutaneous adiposity and HOMA (beta = 0.50, p < 0.0001 and beta = 0.27, p = 0.001 and beta = 0.18, p = 0.024, respectively). CONCLUSION: In our series of patients with normal or mild elevation of gamma-GT, the severity of HS does not entail higher IMT, which may be linked to MS stigmata. PMID- 22424155 TI - Fluorescently cationic conjugated polymer as an indicator of ligase chain reaction for sensitive and homogeneous detection of single nucleotide polymorphism. AB - Ligase chain reaction (LCR) offers a simple and robust alternative platform for nucleic acid amplification, but its application has been limited because the LCR products are mostly detected by gel electrophoresis separation or heterogeneous analysis. In this paper, we report a novel homogeneous LCR assay by using cationic conjugated polymers (CCPs) as an indicator for detection of single nucleotide polymorphism (SNP). For LCR, we design two pairs of unique target complement probes. Each pair of probes contains two adjacent probes, in which one probe is designed with phosphorothioate modification at its 3'-end, and the other probe is labeled with fluorescein at its 5'-end. After the LCR, the two adjacent probes are ligated to form one DNA strand with a fluorescein label at its 5'-end and phosphorothioate modification at its 3'-end, which is resistant to the exonuclease I and exonuclease III degradation. When the CCP is added, because of the strong electrostatic interactions between CCP and DNA, effective fluorescence resonance energy transfer (FRET) from the CCP to the fluorescein-labeled DNA can be observed. In contrast, the unligated fluorescein-labeled probes are degraded to the mononucleotides by exonuclease I and exonuclease III. Introduction of CCP leads to inefficient FRET results because much weaker electrostatic interactions between the fluorescein-labeled mononucleotides and CCP keep the fluorescein far away from CCP. Accordingly, homogeneous LCR for SNP detection is performed successfully. The method is sensitive and specific enough to detect 1 fM (600 zmol) DNA molecules. It is possible to quantify SNP and accurately determine the allele frequency as low as 1.0%. This proposed assay strategy extends the application of LCR and provides a new platform for homogeneous detection of SNP. PMID- 22424156 TI - Exploring protein flexibility: incorporating structural ensembles from crystal structures and simulation into virtual screening protocols. AB - The capacity of proteins to adapt their structure in response to various perturbations including covalent modifications, and interactions with ligands and other proteins plays a key role in biological processes. Here, we explore the ability of molecular dynamics (MD), replica exchange molecular dynamics (REMD), and a library of structures of crystal-ligand complexes, to sample the protein conformational landscape and especially the accessible ligand binding site geometry. The extent of conformational space sampled is measured by the diversity of the shapes of the ligand binding sites. Since our focus here is the effect of this plasticity on the ability to identify active compounds through virtual screening, we use the structures generated by these techniques to generate a small ensemble for further docking studies, using binding site shape hierarchical clustering to determine four structures for each ensemble. These are then assessed for their capacity to optimize enrichment and diversity in docking. We test these protocols on three different receptors: androgen receptor (AR), HIV protease, and CDK2. We show that REMD enhances structural sampling slightly as compared both to MD, and the distortions induced by ligand binding as reflected in the crystal structures. The improved sampling of the simulation methods does not translate directly into improved docking performance, however. The ensemble approach did improve enrichment and diversity, and the ensemble derived from the crystal structures performed somewhat better than those derived from the simulations. PMID- 22424157 TI - Increasing social support for depressed individuals: a cross-cultural assessment of an affect-expectancy approach. AB - Depression is a mental illness affecting 121 million people. The Substance Abuse and Mental Health Services Administration recently launched a national, bilingual (English and Spanish) campaign to motivate young adults to support friends with mental illness. This article highlights and assesses the usefulness of two theoretically derived variables for increasing the social support received by all depressed individuals: (a) affect and (b) social support outcome expectations. In accord with the Substance Abuse and Mental Health Services Administration's bilingual campaign, the authors conducted two studies using intercepts at 2 swap meets in the U.S. Southwest. One study sample consisted of Spanish-dominant Hispanics, the other non-Hispanics. For both samples, results indicate that affect, social support outcome expectations, and their interaction accounted for more than 50% of the variance of social support intentions (67% in the Hispanic sample when familism was considered). Affect is commonplace in the helping behavior literature; results indicate social support outcome expectations deserve equal consideration. Moreover, an unexpected finding emerged: Perceiving a lack of willpower, need for attention, and lack of moral character to be the cause of depression resulted in increased sympathy among the Hispanic sample but increased anger among non-Hispanics. PMID- 22424158 TI - The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. AB - BACKGROUND: Glucocorticoids are widely prescribed for a variety of diseases and are known to cause neuropsychiatric as well as somatic side effects. OBJECTIVE: This article will review the incidence, clinical characteristics, course, and treatment of neuropsychiatric effects of glucocorticoids. METHODS: We performed a literature review of the neuropsychiatric complications of glucocorticoids using the PubMed database. RESULTS: The neuropsychiatric effects of glucocorticoids involve affective, behavioral, and cognitive manifestations. Serious neuropsychiatric effects occur in about 6% of patients who receive steroids. Although the effects of glucocorticoids are unpredictable, the administered dose is the most significant risk factor for the development of neuropsychiatric symptoms. Dosage reduction typically results in clinical recovery. Although evidence from controlled trials is sparse, administration of antipsychotics or mood stabilizers may be beneficial in the prevention and treatment of neuropsychiatric effects of steroids. CONCLUSION: The neuropsychiatric effects of glucocorticoids are more diverse than the often-misleading term "steroid psychosis" suggests. This label should be limited to those patients who are truly psychotic, and specific designations applied to patients with other effects. The adverse neuropsychiatric effects of glucocorticoids remain poorly characterized in the literature (which consists largely of case reports and case series). Reliable risk factors (other than dose) that identify individuals at risk are lacking; guidelines for the prevention of neuropsychiatric effects are not evidence-based. Further controlled clinical studies are needed to elucidate the optimal management of glucocorticoid-induced neuropsychiatric symptoms. PMID- 22424159 TI - Pretransplant psychiatric and substance use comorbidity in patients with cholangiocarcinoma who received a liver transplant. AB - BACKGROUND: Psychopathology has been commonly observed in liver transplant candidates, and up to 40% have comorbid psychiatric disorders. This illness burden may negatively impact quality of life and transplant outcome. Liver transplantation for cholangiocarcinoma remains uncommon due to the complex treatment protocol. We assessed for pretransplant psychopathology and substance use disorders in liver transplant recipients with cholangiocarcinoma to better characterize this patient group. METHODS: We retrospectively reviewed the records of 143 liver transplant recipients who completed pretransplant psychological screening with the PAS, BDI-FS, BSI-18, and the SAAST between 2000 and 2004. The majority completed an evaluation by a transplant psychiatrist. Rates of pretransplant psychiatric and substance use symptoms and disorders were compared between 26 patients with cholangiocarcinoma and 117 other liver recipients using chi(2) or Fisher's exact tests. RESULTS: Of the total cohort, 35% had a pretransplant psychiatric diagnosis, 35% had a substance use disorder, and 43% were current or former smokers. The cholangiocarcinoma cohort had significantly lower scores on the PAS, BDI-FS, and the BSI-18. On interview, the cholangiocarcinoma group was less likely to have an alcohol use disorder (P = 0.03) or any substance use disorder (P = 0.04), but the two groups did not differ significantly in the likelihood of having a psychiatric disorder or smoking history. CONCLUSIONS: This study suggests that patients with cholangiocarcinoma have lower rates of alcohol and drug use disorders than other liver transplant recipients. They do not differ in rates of psychiatric disorders or smoking. Psychosocial assessment and support are recommended throughout the transplant process. PMID- 22424160 TI - The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT): a new tool for the psychosocial evaluation of pre-transplant candidates. AB - BACKGROUND: While medical criteria have been well established for each end-organ system, psychosocial listing criteria are less standardized. To address this limitation, we developed and tested a new assessment tool: the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT). METHODS: The SIPAT was developed from a comprehensive review of the literature on the psychosocial factors that impact transplant outcomes. Five examiners blindly applied the SIPAT to 102 randomly selected transplant cases, including liver, heart, and lung patients. After all subject's files had been rated by the examiners, the respective transplant teams provided the research team with the patient's outcome data. RESULTS: Univariate logistic regression models were fit in order to predict the transplant psychosocial outcome (positive or negative) using each rater's SIPAT scores. These results show that SIPAT scores are highly predictive of the transplant psychosocial outcome (P < 0.0001). The instrument has excellent inter-rater reliability (Pearson's correlation coefficient = 0.853), even among novice raters. CONCLUSIONS: The SIPAT is a comprehensive screening tool to assist in the psychosocial assessment of organ transplant candidates. Its strengths includes the standardization of the evaluation process and its ability to identify subjects who are at risk for negative outcomes after the transplant, in order to allow for the development of interventions directed at improving the patient's candidacy. Our goal is that the SIPAT, in addition to a set of agreed upon minimal psychosocial listing criteria, would be used in combination with organ-specific medical listing criteria in order to establish standardized criteria for the selection of transplant recipients. PMID- 22424161 TI - Cardiac transplantation in adult patients with mental retardation: do outcomes support consensus guidelines? AB - BACKGROUND: Selection criteria guidelines list mental retardation as a relative contraindication to heart transplantation, but not to kidney transplantation. OBJECTIVE: The authors present a case series of adults with mental retardation or comparable acquired intellectual disability who underwent heart transplantation. They discuss the literature on heart and kidney transplantation in people with mental retardation and the ethical reasoning that guides how recipients of solid organ grafts are chosen. METHOD: Literature review and retrospective review of long-term outcomes for five adult patients with mental retardation or comparable disability who received heart transplants. RESULTS: Among these cases, survival times to date ranged from 4 to 16 years, with a median survival of greater than 12 years. Medical non-adherence was a significant factor in only 1 of the 5 cases. In that case, the patient's medical non-adherence was due to a functional decline in the primary caretaker. CONCLUSION: People with mental retardation can receive long-term benefit from heart transplantation when they have the cognitive and social support necessary to ensure adherence to post-transplant regimens. There is no ethical or medical reason for guidelines to consider mental retardation, in and of itself, a contraindication to heart transplantation. The totality of the individual patient's circumstances should be considered in assessing transplant candidacy. PMID- 22424162 TI - Responsiveness of hypochondriacal patients with chronic low-back pain to cognitive-behavioral therapy. AB - BACKGROUND: Evidence has suggested that cognitive-behavioral therapy (CBT) is effective in reducing hypochondriacal symptoms, and another line of evidence has suggested that CBT is also effective in reducing pain and the psychological conditions associated with chronic low-back pain (CLBP). The purpose of this study was to examine the effectiveness of CBT among hypochondriacal patients with and without CLBP. METHODS: A total of 182 hypochondriacal patients were randomly assigned to a CBT or control group. The Somatic Symptom Inventory was used to define CLBP, and the Symptom Checklist 90R (SCL90R) was used to assess psychological symptoms. The outcome measures for hypochondriasis, the Whiteley Index (WI) and the Health Anxiety Inventory (HAI) were administered before the intervention and at 6 and 12 months after completion of the intervention. RESULTS: In the total sample, both WI and HAI scores were significantly decreased after treatment in the CBT group compared with the control group. Ninety-three (51%) patients had CLBP; the SCL90R scores for somatization, depression, phobic anxiety, paranoid ideation, and general severity were significantly higher in CLBP(+) group than in the CLBP(-) group at baseline. Although the WI and HAI scores were significantly decreased after treatment in the CLBP(-) group, such significant pre- to post-changes were not found in the CLBP(+) group. CONCLUSIONS: CBT was certainly effective among hypochondriacal patients without CLBP, but it appeared to be insufficient for hypochondriacal patients with CLBP. The core psychopathology of hypochondriacal CLBP should be clarified to contribute to the adequate management of hypochondriacal symptoms in CLBP patients. PMID- 22424163 TI - Dysfunctional beliefs about symptoms and illness in patients with hypochondriasis. AB - BACKGROUND: The cognitive model and empirical research underline the importance of dysfunctional beliefs about bodily symptoms and illness in health anxiety and hypochondriasis. However, specificity of such beliefs has not yet been adequately demonstrated for patients with hypochondriasis. OBJECTIVE: This study examined whether dysfunctional beliefs about bodily symptoms and illness are elevated in comparison to patients with anxiety disorders and, therefore, specific for patients with hypochondriasis. METHOD: Patients with hypochondriasis (n = 38), patients with anxiety disorders (n = 40), and healthy controls (n = 42) completed the Symptom and Outcomes Scale (SOS) measuring participants' estimation of the likelihood of various symptoms being indicative of a particular illness. Additionally, participants' general psychopathology (Brief Symptom Inventory), depressive (Beck Depression Inventory-II), and anxiety symptoms (Beck Anxiety Inventory) were evaluated. RESULTS: In comparison to patients with anxiety disorders and healthy controls, patients with hypochondriasis estimated bodily symptoms to be more likely an indicator for a catastrophic illness. Patients with anxiety disorders took a middle position between patients with hypochondriasis and healthy controls. Regarding the estimation of the likelihood of symptoms indicating a minor illness, no differences were found between the three groups. CONCLUSIONS: Dysfunctional beliefs about symptoms and illness are important and specific for patients with hypochondriasis, which is in line with the cognitive model. In order to reduce misinformation about serious illnesses in patients with hypochondriasis, more attention should be paid to psychoeducational strategies. PMID- 22424164 TI - A genetic predisposition to produce low levels of IL-10 is related to depressive symptoms: a pilot study of patients with end stage renal disease. AB - OBJECTIVE: Heightened levels of inflammation may be associated with an increased risk of depression, particularly among those with inflammatory medical conditions. Although elevated rates of both systemic inflammation and depression have been documented among patients with end stage renal disease (ESRD), the link between these factors has received little empirical evaluation. The goal of this pilot study was to investigate the association between cytokine gene polymorphisms (that are known to influence pro- and anti-inflammatory cytokine production) and depressive symptoms among patients with ESRD. METHODS: Ninety three patients with ESRD completed the Beck Depression Inventory-II and the disease-related symptom subscale of the Kidney Disease Quality of Life short form. Patients were genotyped for eight single nucleotide polymorphisms in genes coding for pro-inflammatory (TNF-alpha, IL-6, IFN-gamma) and anti-inflammatory (IL-10, TGF-beta1) cytokines. RESULTS: Regression analyses indicated that patients with the A/A genotype for the IL-10 -1082 polymorphism (lower IL-10 producers) reported significantly greater depressive symptoms than G allele carriers (higher IL-10 producers; b = 0.22, P = 0.011), even after controlling for relevant covariates. CONCLUSION: These findings provide some support for cytokine theories of depression in the medically ill, and specifically for the protective role of anti-inflammatory processes. Further research is needed to confirm these preliminary results and to explore the possibility of identifying subtypes of depressed patients based on inflammatory profiles, and those who may benefit from anti-inflammatory therapies. PMID- 22424165 TI - Wilson's disease--treatment of psychiatric manifestations in pregnancy. PMID- 22424166 TI - Steroid-induced mania treated with aripiprazole. PMID- 22424167 TI - Lower gastrointestinal bleeding and paroxetine use: two case reports. PMID- 22424168 TI - Intravenous lipid emulsion-associated catatonia, thrombocytopenia, and leukopenia: a case report and the role of NMDA receptor. PMID- 22424169 TI - Tsunami damage and its impact on mental health. PMID- 22424170 TI - Low voltage electrical injury induces psychosis. PMID- 22424171 TI - Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease. AB - We report the results of a long-term follow-up of subjects in a phase 1 study of AAV2-hAADC (adeno-associated virus type 2-human aromatic L-amino acid decarboxylase) gene therapy for the treatment of Parkinson's disease (PD). Ten patients with moderately advanced PD received bilateral putaminal infusions of either a low or a high dose of AAV2-hAADC vector. An annual positron emission tomography (PET) imaging with [(18)F]fluoro-L-m-tyrosine tracer was used for evaluation of AADC expression, and a standard clinical rating scale [Unified Parkinson's Disease Rating Scale (UPDRS)] was used to assess effect. Our previous analysis of the 6-month data suggested that this treatment was acutely safe and well tolerated. We found that the elevated PET signal observed in the first 12 months persisted over 4 years in both dose groups. A significantly increased PET value compared with the presurgery baseline was maintained over the 4-year monitoring period. The UPDRS in all patients off medication for 12 hr improved in the first 12 months, but displayed a slow deterioration in subsequent years. This analysis demonstrates that apparent efficacy continues through later years with an acceptable safety profile. These data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose. PMID- 22424172 TI - Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and sometimes the only curative therapy for patients with certain hematological diseases. Allo-HSCT has been practiced in China for approximately 30 years, and great improvements have been made within the past decade, particularly in fields such as the haploidentical HSCT system, strategies to overcome relapse and GVHD, and modified HSCT for elderly patients. This review will describe the current situation and provide a prospective of these unique aspects of Allo-HSCT in China. PMID- 22424173 TI - Direct observation of nanoparticle-cancer cell nucleus interactions. AB - We report the direct visualization of interactions between drug-loaded nanoparticles and the cancer cell nucleus. Nanoconstructs composed of nucleolin specific aptamers and gold nanostars were actively transported to the nucleus and induced major changes to the nuclear phenotype via nuclear envelope invaginations near the site of the construct. The number of local deformations could be increased by ultrafast, light-triggered release of the aptamers from the surface of the gold nanostars. Cancer cells with more nuclear envelope folding showed increased caspase 3 and 7 activity (apoptosis) as well as decreased cell viability. This newly revealed correlation between drug-induced changes in nuclear phenotype and increased therapeutic efficacy could provide new insight for nuclear-targeted cancer therapy. PMID- 22424174 TI - Electron vs energy transfer in arrays featuring two Bodipy chromophores axially bound to a Sn(IV) porphyrin via a phenolate or benzoate bridge. AB - In this report we describe the synthesis of multichromophore arrays consisting of two Bodipy units axially bound to a Sn(IV) porphyrin center either via a phenolate (3) or via a carboxylate (6) functionality. Absorption spectra and electrochemical studies show that the Bodipy and porphyrin chromophores interact weakly in the ground state. However, steady-state emission and excitation spectra at room temperature reveal that fluorescence from both the Bodipy and the porphyrin of 3 are strongly quenched suggesting that, in the excited state, energy and/or electron transfer might occur. Indeed, as transient absorption experiments show, selective excitation of Bodipy in 3 results in a rapid decay (tau ~ 2 ps) of the Bodipy-based singlet excited state and a concomitant rise of a charge-separated state evolving from the porphyrin-based singlet excited state. In contrast, room-temperature emission studies on 6 show strong quenching of the Bodipy-based fluorescence leading to sensitized emission from the porphyrin moiety due to a transduction of the singlet excited state energy from Bodipy to the porphyrin. Emission experiments at 77 K in frozen toluene reveal that the room-temperature electron transfer pathway observed in 3 is suppressed. Instead, Bodipy excitation in 3 and 6 results in population of the first singlet excited state of the porphyrin chromophore. Subsequently, intersystem crossing leads to the porphyrin-based triplet excited state. PMID- 22424175 TI - Selenium as a structural surrogate of sulfur: template-assisted assembly of five types of tungsten-iron-sulfur/selenium clusters and the structural fate of chalcogenide reactants. AB - Syntheses of five types of tungsten-iron-sulfur/selenium clusters, namely, incomplete cubanes, single cubanes, edge-bridged double cubanes (EBDCs), P(N) type clusters, and double-cuboidal clusters, have been devised using the concept of template-assisted assembly. The template reactant is six-coordinate [(Tp*)W(VI)S(3)](1-) [Tp* = tris(3,5-dimethylpyrazolyl)hydroborate(1-)], which in the assembly systems organizes Fe(2+/3+) and sulfide/selenide into cuboidal [(Tp*)WFe(2)S(3)] or cubane [(Tp*)WFe(3)S(3)Q] (Q = S, Se) units. With appropriate terminal iron ligation, these units are capable of independent existence or may be transformed into higher-nuclearity species. Selenide is used as a surrogate for sulfide in cluster assembly in order to determine by X-ray structures the position occupied by an external chalcogenide nucleophile or an internal chalcogenide atom in the product clusters. Specific incorporation of selenide is demonstrated by the formation of [WFe(3)S(3)Se](2+/3+) cubane cores. Reductive dimerization of the cubane leads to the EBDC core [W(2)Fe(6)S(6)Se(2)](2+) containing MU(4)-Se sites. Reaction of these species with HSe(-) affords the P(N)-type cores [W(2)Fe(6)S(6)Se(3)](1+), in which selenide occupies MU(6)-Se and MU(2)-Se sites. The reaction of [(Tp*)WS(3)](1-), FeCl(2), and Na(2)Se yields the double-cuboidal [W(2)Fe(4)S(6)Se(3)](2+/0) core with MU(2)-Se and MU(4)-Se bridges. It is highly probable that in analogous sulfide-only assembly systems, external and internal sulfide reactants occupy corresponding positions in the cluster products. The results further demonstrate the viability of template-assisted cluster synthesis inasmuch as the reduced (Tp*)WS(3) unit is present in all of the clusters. Structures, zero-field Mossbauer data, and redox potentials are presented for each cluster type. PMID- 22424176 TI - The article of the future - a new online article experience for increasing research efficiency, learning, and discovery. PMID- 22424177 TI - Complete 13C NMR chemical shifts assignment for cholesterol crystals by combined CP-MAS spectral editing and ab initio GIPAW calculations with dispersion forces. AB - We report here the first fully ab initio determination of (13)C NMR spectra for several crystal structures of cholesterol, observed in various biomaterials. We combine Gauge-Including Projector Augmented Waves (GIPAW) calculations at relaxed structures, fully including dispersion forces, with Magic Angle Spinning Solid State NMR experiments and spectral editing to achieve a detailed interpretation of the complex NMR spectra of cholesterol crystals. By introducing an environment dependent secondary referencing scheme in our calculations, not only do we reproduce the characteristic spectral features of the different crystalline polymorphs, thus clearly discriminating among them, but also closely represent the spectrum in the region of several highly overlapping peaks. This, in combination with spectral editing, allows us to provide a complete peak assignment for monohydrate (ChM) and low-temperature anhydrous (ChAl) crystal polymorphs. Our results show that the synergy between ab initio calculations and refined experimental techniques can be exploited for an accurate and efficient NMR crystallography of complex systems of great interest for biomaterial studies. The method is general in nature and can be applied for studies of various complex biomaterials. PMID- 22424178 TI - Detection of air trapping in chronic obstructive pulmonary disease by low frequency ultrasound. AB - BACKGROUND: Spirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication. METHODS: Seventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed DeltaF. Measurements were repeated after inhalation of salbutamol. RESULTS: We found significant differences in DeltaF between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably. CONCLUSIONS: We conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080924. PMID- 22424179 TI - Interpretation and misinterpretation of warning signage: perceptions of rockfalls in a naturalistic setting. AB - The aim of the present study was to investigate the factors relating to non adherence to warning signs about falling rocks from coastal cliff faces. Face-to face interviews (n = 62) in a naturalistic setting (in the vicinity of a high risk rockfall area) were conducted to investigate attention to and comprehension of warning signs, as well as beliefs relating to non-adherence of the signage. It was found that, while most participants could correctly identify the danger in the area and had noticed the warning signage, less than half of the participants could correctly interpret the signage. The perception of danger did not differ significantly between the participants who had, or had not, entered the high-risk zone. Differences in knowledge and beliefs between local residents and visitors to the area were identified. It was concluded that the warning signs did not provide enough detail for people to make informed decisions about safe behaviours. Comprehension of the signage may have been hampered by a lack of prior-knowledge of the particular risk, a failure to think carefully about the situation (i.e. low-effort processing), and the pictorial representation on the signs misleading the participants as to the true danger. PMID- 22424180 TI - Inhibitory effect of cisplatin and [Pt(dach)Cl2] on the activity of phospholipase A2. AB - This work has been focused on testing the influence of two selected Pt(II) complexes cisplatin, Pt(NH3)2Cl2, and [Pt(dach)Cl2] on the activity of porcine pancreatic phospholipase A2 (PLA2). It has been assumed that this enzyme plays a role in carcinogenesis and that it could be a target in the tumour therapy. The results of this study show that both Pt(II) complexes inhibit the activity of the enzyme, though they bind to it in a different manner. While cisplatin interacts with the enzyme in an acompetitive manner, the stable interaction of [Pt(dach)Cl2] with PLA2 could not be detected under our experimental conditions. PMID- 22424181 TI - Monoamine oxidase inhibition by monoterpene indole alkaloids and fractions obtained from Psychotria suterella and Psychotria laciniata. AB - Alkaloid fractions of Psychotria suterella (SAE) and Psychotria laciniata (LAE) as well as two monoterpene indole alkaloids (MIAs) isolated from these fractions were evaluated against monoamine oxidases (MAO-A and -B) obtained from rat brain mitochondria. SAE and LAE were analysed by HPLC-PDA and UHPLC/HR-TOF-MS leading to the identification of the compounds 1, 2, 3 and 4, whose identity was confirmed by NMR analyses. Furthermore, SAE and LAE were submitted to the enzymatic assays, showing a strong activity against MAO-A, characterized by IC(50) values of 1.37 +/- 1.05 and 2.02 +/- 1.08 MUg/mL, respectively. Both extracts were also able to inhibit MAO-B, but in higher concentrations. In a next step, SAE and LAE were fractionated by RP-MPLC affording three and four major fractions, respectively. The RP-MPLC fractions were subsequently tested against MAO-A and -B. The RP-MPLC fractions SAE-F3 and LAE-F4 displayed a strong inhibition against MAO-A with IC(50) values of 0.57 +/- 1.12 and 1.05 +/- 1.15 MUg/mL, respectively. The MIAs 1 and 2 also inhibited MAO-A (IC(50) of 50.04 +/- 1.09 and 132.5 +/- 1.33 MUg/mL, respectively) and -B (IC(50) of 306.6 +/- 1.40 and 162.8 +/- 1.26 MUg/mL, respectively), but in higher concentrations when compared with the fractions. This is the first work describing the effects of MIAs found in neotropical species of Psychotria on MAO activity. The results suggest that species belonging to this genus could consist of an interesting source in the search for new MAO inhibitors. PMID- 22424182 TI - beta-secretase inhibitory activity of phenolic acid conjugated chitooligosaccharides. AB - Eight kinds of phenolic acid conjugated chitooligosaccharides (COSs) were synthesized using hydroxyl benzoic acid and hydroxyl cinnamic acid. These phenolic acid conjugated-COSs with different substitution groups, including p hydroxyl, 3,4-dihydroxyl, 3-methoxyl-4-hydroxyl and 3,5-dimethoxyl-4-hydroxy groups, were evaluated for their inhibitory activities against beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE) and inhibited BACE with a ratio of 50.8%, 74.8%, 62.1%, 64.8% and 42.6%, respectively at the concentration of 1,000 MUg/mL. BACE is a critical component to reduce the levels of Abeta amyloid peptide in Alzheimer's disease (AD) which is based on the amyloid cascade theory in the brain, as this protease initiates the first step in Abeta production. Among them, Caffeic acid conjugated-COS (CFA-COS) was further analysed to determine mode of inhibition of BACE and it showed non-competitive inhibition. Hence in this study, we suggest that CFA-COS derivatives have potential to be used as novel BACE inhibitors to reduce the risk of AD. PMID- 22424184 TI - Headgroup effect on silane structures at buried polymer/silane and polymer/polymer interfaces and their relations to adhesion. AB - Sum frequency generation (SFG) vibrational spectroscopy was used to study the effect of silane headgroups on the molecular interactions that occur between poly(ethylene terephthalate) (PET) and various epoxy silanes at the PET/silane and PET/silicone interfaces. Three different silanes were investigated: (3 glycidoxypropyl) trimethoxysilane (gamma-GPS), (3-glycidoxypropyl) methyl dimethoxysilane (gamma-GPMS), and (3-glycidoxypropyl) dimethyl-methoxysilane (gamma-GPDMS). These silanes share the same backbone and epoxy end group but have different headgroups. SFG was used to examine the interfaces between PET and each of these silanes, as well as silanes mixed with methylvinylsiloxanol (MVS). We also examined the interfaces between PET and uncured or cured silicone with silanes or silane-MVS mixtures. Silanes with different headgroups were found to exhibit a variety of methoxy group interfacial segregation and ordering behaviors at various interfaces. The effect of MVS was also dependent upon silane headgroup choice, and the interfacial molecular structures of silane methoxy headgroups were found to differ at PET/silane and PET/silicone interfaces. Epoxy silanes have been widely used as adhesion promoters for polymer adhesives; therefore, the molecular structures probed using SFG were correlated to adhesion testing results to understand the molecular mechanisms of silicone-polymer adhesion. Our results demonstrated that silane methoxy headgroups play important roles in adhesion at the PET/silicone interfaces. The presence of MVS can change interfacial methoxy segregation and ordering, leading to different adhesion strengths. PMID- 22424185 TI - Synthesis, characterization, and in vitro studies of bis[1,3-diethyl-4,5 diarylimidazol-2-ylidene]gold(I/III) complexes. AB - Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4 OCH(3) or 4-F substituents in the aromatic rings and Br(-) (3a,b) or BF(4)(-) (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5 bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC(50) = 0.10 MUM (cisplatin, 1.6 MUM; 5-FU, 4.7 MUM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action. PMID- 22424186 TI - Genome wide expression profiling of two accession of G. herbaceum L. in response to drought. AB - BACKGROUND: Genome-wide gene expression profiling and detailed physiological investigation were used for understanding the molecular mechanism and physiological response of Gossypium herbaceum, which governs the adaptability of plants in drought conditions. Recently, microarray-based gene expression analysis is commonly used to decipher genes and genetic networks controlling the traits of interest. However, the results of such an analysis are often plagued due to a limited number of genes (probe sets) on microarrays. On the other hand, pyrosequencing of a transcriptome has the potential to detect rare as well as a large number of transcripts in the samples quantitatively. We used Affymetrix microarray as well as Roche's GS-FLX transcriptome sequencing for a comparative analysis of cotton transcriptome in leaf tissues under drought conditions. RESULTS: Fourteen accessions of Gossypium herbaceum were subjected to mannitol stress for preliminary screening; two accessions, namely Vagad and RAHS-14, were selected as being the most tolerant and most sensitive to osmotic stress, respectively. Affymetrix cotton arrays containing 24,045 probe sets and Roche's GS-FLX transcriptome sequencing of leaf tissue were used to analyze the gene expression profiling of Vagad and RAHS-14 under drought conditions. The analysis of physiological measurements and gene expression profiling showed that Vagad has the inherent ability to sense drought at a much earlier stage and to respond to it in a much more efficient manner than does RAHS-14. Gene Ontology (GO) studies showed that the phenyl propanoid pathway, pigment biosynthesis, polyketide biosynthesis, and other secondary metabolite pathways were enriched in Vagad under control and drought conditions as compared with RAHS-14. Similarly, GO analysis of transcriptome sequencing showed that the GO terms responses to various abiotic stresses were significantly higher in Vagad. Among the classes of transcription factors (TFs) uniquely expressed in both accessions, RAHS-14 showed the expression of ERF and WRKY families. The unique expression of ERFs in response to drought conditions reveals that RAHS-14 responds to drought by inducing senescence. This was further supported by transcriptome analysis which revealed that RAHS-14 responds to drought by inducing many transcripts related to senescence and cell death. CONCLUSION: The comparative genome-wide gene expression profiling study of two accessions of G.herbaceum under drought stress deciphers the differential patterns of gene expression, including TFs and physiologically relevant processes. Our results indicate that drought tolerance observed in Vagad is not because of a single molecular reason but is rather due to several unique mechanisms which Vagad has developed as an adaptation strategy. PMID- 22424187 TI - Pulmonary vascular permeability index should not be called extravascular lung water pulmonary blood volume ratio. PMID- 22424188 TI - The mirabilis period of autoimmunity. PMID- 22424189 TI - The role of environmental factors in the pathogenesis of non-organ-specific autoimmune diseases. AB - The immune system must be able to discriminate between self and non-self. However, mechanisms of doing so sometimes fail, causing the activation and clonal expansion of autoreactive lymphocytes and the development of autoimmune conditions. Although some autoimmune diseases have heritable components, these components are not sufficient to develop an autoimmune condition. A variety of environmental factors have been described as possible triggers of autoimmune diseases, including drugs, infectious agents, smoking, vaccination and adjuvants. The aim of this chapter is to review the most common environmental factors associated with autoimmune diseases. PMID- 22424190 TI - Scleroderma - new aspects in pathogenesis and treatment. AB - Systemic sclerosis (SSc) is a multisystem disease with a variable clinical course and a poor prognosis corresponding to extent of microangiopathy and skin and internal organ fibrosis. Microvascular damage provokes immune cells to produce autoantibodies, pro-inflammatory and pro-fibrotic cytokines and chemokines. The hallmark of SSc is excessive collagen production by activated fibroblasts and myofibroblasts, and its accumulation in skin and internal organs. Better understanding of SSc pathogenesis resulted in the development of drugs, such as prostanoids, endothelin-1 and phosphodiesterase inhibitors, for treatment of pulmonary arterial hypertension and digital ulcers. The use of biological therapies and anti-fibrotic agents is under investigation. Stem cell transplantation seems to be promising in restarting the immune system to diminish fibrosis and restore microvasculature. Future research will be directed at genetic factors, diagnostic and prognostic markers for fibrosis and microangiopathy, and development of drugs directed to pathogenic key cells and mediators. PMID- 22424191 TI - Idiopathic inflammatory myopathies. AB - Inflammatory myopathies are chronic, immune-mediated diseases characterised by progressive proximal muscle weakness. They encompass a variety of syndromes with protean manifestations. The diagnosis is based on Bohan and Peter's classification criteria, which nowadays seem to be obsolete. Our increasing knowledge about the risk factors, genetic susceptibility and immunological pathways in the disease mechanism leads to the establishment of a new, immunogenetically and serologically validated diagnostic criteria system. The treatment of idiopathic inflammatory myopathy is also a complex task requiring much experience. The aims of therapy are to increase muscle strength, prevent the development of contractures and manage the systemic manifestations of the disease. The most important one is the early detection of diseases and patients' immunological control in special centres. Using the basis therapeutic drugs temporary or permanent remission can be achieved, which improves patientsG' quality of life and functional ability. Rehabilitation and physiotherapy in the remission period may significantly improve the outcome of patients with functional disorders. The introduction of new biological therapies further allows us to control the myositis patients' state more effectively. The aim of this review is to summarise our knowledge about clinical symptoms, pathomechanism, as well as genetic, serologic and environmental risk factors. We would also like to present the way to diagnosis and the latest research about diagnostic criteria system, proposed outcome measures and therapeutic possibilities. PMID- 22424192 TI - Pregnancy and autoimmunity: a common problem. AB - Successful pregnancy is considered a Th1-Th2 cooperation phenomenon (Th, T helper), with a predominantly Th2-type lymphocytes response, together with the emerging role of interleukin (IL)-12, IL-15 and IL-18 and of other unidentified soluble factors dependent on natural killer (NK) cells. In the pathogenesis of recurrent spontaneous abortion (RSA), immunological factors have been involved such as decidual cells, complement system, cytokines and genes of the hystocompatibility complex that can determine the success or the failure of a pregnancy. A deeper insight into apparently unexplained RSA shows increasing evidences supporting both alloimmune and autoimmune mechanisms, with autoantibodies playing a major role. The best-characterised pathogenic autoantibodies are anti-phospholipid antibodies, and also other autoantibodies, such as anti-Ro/SSA and anti-La/SSB, have been found to be associated with an increased rate of abortion, poor pregnancy outcome and several other obstetric manifestations. This intriguing mixture has been unveiled only in the last few years with the discovery of novel pathogenic mechanisms that can be targeted in the prevention and treatment of obstetrical complications occurring in the course of an autoimmune disease. PMID- 22424193 TI - Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment. AB - The most common clinical manifestations of mixed connective disease are Raynaud's phenomenon, arthralgias, swollen joints, esophageal dysfunction, muscle weakness and fingers sausage-like appearance together with the presence of anti ribonucleoprotein (RNP) antibodies. However, organ involvement is more extensive than first descriptions reported. The disease can be serious with development of pulmonary, kidney, cardiovascular, gastrointestinal and central nervous system manifestations. The worst prognosis and high mortality are associated with the presence of pulmonary disease. Although a different set of clinical criteria have been proposed, there is no consensus about the most accurate. There is no full agreement about treatment and the initial impression of a satisfactory response to low doses of steroids is not always the rule. Herein, we review available evidence to a better approach to all previous topics. PMID- 22424194 TI - Undifferentiated CTD: a wide spectrum of autoimmune diseases. AB - The existence of systemic autoimmune diseases not fulfilling classification criteria for defined connective tissue diseases (CTDs) is a common clinical experience. These conditions have been variably defined as incomplete lupus erythematosus, early undifferentiated connective tissue diseases and undifferentiated connective tissue diseases (UCTDs). However, the definition of UCTD includes a wide spectrum of diseases ranging from 'organ-dominant' conditions (e.g., idhiopatic non-specific interstitial pneumonia) to simplified conditions (stable UCTD), to early CTDs or mild forms of CTDs. In the present article, the literature data on undifferentiated diseases and their clinical spectrum as well as the importance of the definition of new classificative criteria are discussed. PMID- 22424195 TI - Much more than thrombosis and pregnancy loss: the antiphospholipid syndrome as a 'systemic disease'. AB - Antiphospholipid syndrome is an auto-immune disorder characterised by recurrent thrombosis, pregnancy losses and the presence of antiphospholipid antibodies. Although it was initially considered an auto-immune coagulopathy, it is now clear that it is a complex and systemic disease. A large number of manifestations in different organs and tissues (cardiac, pulmonary, neurological, renal, cutaneous, haematologic, gastrointestinal, ocular, skeletal and endocrinologic) have been described in these patients. A small group of patients can have a microvascular involvement, which is the most common pathological finding in patients affected by the catastrophic variant of the syndrome. A strong relationship exists between the antiphospholipid syndrome and systemic lupus erythematosus, as demonstrated by common clinical, serological and genetic features and by the few but possible cases evolving from the first disease into the second one over years. Finally, the systemic nature of the antiphospholipid syndrome and the understanding of the mechanisms of antiphospholipid-mediated damage suggest a role of immunomodulation beyond anticoagulation in the therapeutic approach to the disease. PMID- 22424196 TI - Polymyalgia rheumatica in 2011. AB - Polymyalgia Rheumatica (PMR) is an inflammatory rheumatic disease that commonly affects individuals over 50 years of age, characterised by pain and morning stiffness of the shoulder and pelvic girdle. PMR can present as 'isolated' form or may be associated with giant cell arteritis. The progress of imaging techniques has helped in understanding different clinical patterns: subclinical vasculitis can occur in at least one-third of PMR patients, causing ischaemic complications. It is considered a polygenic disease and environmental factors may play a role in its pathogenesis, such as viral or bacterial triggers, both in the 'wide' form or assembled with adjuvants in vaccines. The response to steroid therapy is generally dramatic and side effects may occur, as well as the development of glucocorticoid resistance. The optimisation of therapy may require steroid-sparing agents as well as modified-release prednisone as 'nighttime' replacement therapy. PMID- 22424197 TI - Sjogren's syndrome, the old and the new. AB - Sjogren's syndrome is a chronic autoimmune disease characterised by progressive injury to exocrine glands accompanied by diverse extra-glandular manifestations. The spectrum of Sjogren's manifestations expanded in recent years to include new symptoms and signs such as small fibre neuropathy, and also well-defined activity and prognostic indexes. Similar to other non-organ-specific autoimmune diseases, a mosaic of factors have been linked with the development and appearances of Sjogren's syndrome. Progress has been made unravelling those factors, including susceptibility genes, immunological parameters and various environmental factors in the last decade, some of which may enable targeted therapies, biological and non-biological ones, for patients suffering from this disease. Thus, herein we review the postulated aetiologies, pathogenesis and new insights related to Sjogren's syndrome. PMID- 22424198 TI - Neurologic and other systemic manifestations in FMF: published and own experience. AB - OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, presenting with recurrent episodes of fever and polyserositis. Neurologic involvement in FMF is rare and usually considered fortuitous. The aim of this article is to review the spectrum of possible neurologic manifestations, which can be encountered in FMF patients, and to establish their relation to FMF. METHODS: We reviewed the literature based on Pubmed search to find neurologic manifestations, which were reported in FMF patients. To that we added our own experience on the subject, abstracted from our computerised FMF registry of 12000 FMF patients of the National FMF Center and the computerised database of Sheba Medical Center. RESULTS: A wide range of neurologic manifestations involving FMF patients was noted. A large part of these manifestations could be directly related to FMF, its complications, associated diseases and treatment adverse effects. The remaining were incidental, or of uncertain association to FMF. CONCLUSION: A physician, taking care of an FMF patient, can face various neurologic manifestations and should be aware of their origin. The current chapter provides an insight to this association of FMF. PMID- 22424199 TI - Spondyloarthropathies. AB - Spondyloarthropathies (SpA) are a group of common inflammatory rheumatic disorders characterised by axial and or peripheral arthritis, associated with enthesitis, dactylitis and potential extra-articular manifestations such as uveitis and skin rash. The diseases, which comprise the group, share a common genetic predisposition, the HLA-B27 gene; however, this association varies markedly among the various SpAs and among different ethnic groups. Environmental factors seem to be triggering the diseases in the genetically predisposed individuals. The radiographic hallmark of the group is sacroiliitis, which when present is of help in the diagnosis. Various sets of diagnostic and classification criteria were developed over the years including the European Spondyloarthropathy Study Group (ESSG) criteria which were until recently the most widely used. The new Assessment in SpondyloArthritis international Society (ASAS) international working group has recently proposed a new set of diagnostic criteria that would enable identification of SpA before structural changes develop in the spine. Magnetic resonance imaging (MRI) changes have now been included in the new classification criteria of early axial SpA and are now considered as a major tool in the diagnosis. Until recently, there were no real disease-modifying anti-rheumatic drugs which were able to halt the disease progression. Over the past decade, tumour necrosis factor (TNF)-alfa-blocking agents have been extensively investigated and became the mainstream of therapy providing the patients an effective treatment option. PMID- 22424200 TI - Psoriatic arthritis. AB - Psoriatic arthritis (PsA) is a chronic inflammatory spondyloarthritis that occurs in combination with psoriasis. The exact prevalence of PsA is unknown, and its pathogenesis has not yet been fully elucidated. Genetic, environmental, and immunologic factors have all been implicated. The appearance of arthritis might precede, succeed or occur concomitant with skin lesions. PsA is sometimes considered a benign form of arthritis, but it affects patient quality of life and also causes functional impairment. Up to 20% of affected patients exhibit extremely destructive and disfiguring forms of the disease, and PsA is associated with increased mortality. The treatment of PsA aims to provide relief from signs and symptoms of the disease, prevent structural damage to joints, improve patient quality of life and decrease mortality. The choice of treatment depends on the severity of clinical presentation. The use of immunobiological agents is restricted to cases that do not respond to conservative treatment. PMID- 22424201 TI - Tocilizumab - a novel therapy for non-organ-specific autoimmune diseases. AB - In the past decade, tocilizumab, an anti interleukin-6 agent, has been successfully developed as a therapeutic agent for the treatment of rheumatoid arthritis and systemic onset juvenile idiopathic arthritis. In addition to countering inflammation, tocilizumab is also known affect B cell as well as T cell function, thus modulating immune function, and impact osteoclasts, as well as vascular endothelial growth factor. As such, its efficacy is currently being explored in a large number of autoiommune conditions including a number of vasculitides, systemic lupus erythematosus, systemic sclerosis, polymyositis, graft versus host disease, relapsing polychondritis, as well as Behcet's syndrome, spondyloarthropathies, and tumor necrosis factor receptor associated periodic syndrome. PMID- 22424202 TI - Temperature dependency in motor skill learning. AB - The present study investigated the role of temperature as a contextual condition for motor skill learning. Precision grip task training occurred while forearm cutaneous temperature was either heated (40-45 degrees C) or cooled (10-15 degrees C). At test, temperature was either reinstated or changed. Performance was comparable between training conditions while at test, temperature changes decreased accuracy, especially after hot training conditions. After cold training, temperature change deficits were only evident when concurrent force feedback was presented. These findings are the first evidence of localized temperature dependency in motor skill learning in humans. Results are not entirely accounted for by a context-dependent memory explanation and appear to represent an interaction of neuromuscular and sensory processes with the temperature present during training and test. PMID- 22424203 TI - A two process memory-based account for mental and physical practice differences. AB - The authors investigated the underlying processing structures for mental and physical practice. Participants mentally or physically performed 4 tasks during practice. Halfway through practice, 2 tasks were switched from mental to physical practice, or vice versa. After completing practice trials, participants performed 2 retention tests. The first retention test required memory retrieval and the second retention test reinstated the practice context and did not require memory retrieval. Measures of response initiation and execution showed discrepant findings suggesting that different processing structures underlie response initiation and execution during mental and physical practice. Findings for the switch conditions supported this interpretation suggesting that different neural structures may facilitate processing related to mental and physical practice. PMID- 22424204 TI - Broad stance conditions change postural control and postural sway. AB - Intuitively, a broad stance (i.e., standing with the feet farther apart than usual) should significantly improve postural stability. However, this intuition was not confirmed in quiet stance. Hence, a motion analysis system (markers attached to the trunk and head) and a force platform were used to investigate 13 healthy, young adults who performed 8 trials in standard and broad stances. In broad stance, the medialateral center of pressure (COP) sway mean power frequency was expected to be greater, whereas the variability (standard deviation) of COP, head, and trunk sway and the mean velocity of head and trunk sway was expected to be significantly lower. Accordingly, adoption of a broad stance significantly increased the medialateral mean power frequency of COP sway; decreased the standard deviation of medialateral COP, trunk, and head sway; and decreased the medialateral mean velocity of head sway. A broad stance was also associated with lower variability for head and COP sways in the anteroposterior axis. Unexpectedly, an effect of trial repetition was found for the variability of medialateral trunk sway. This was probably due to the break halfway through the study. In practical terms, broad stance conditions can improve postural control in the medialateral and anteroposterior axes. PMID- 22424206 TI - A novel randomly textured phosphor structure for highly efficient white light emitting diodes. AB - We have successfully demonstrated the enhanced luminous flux and lumen efficiency in white light-emitting diodes by the randomly textured phosphor structure. The textured phosphor structure was fabricated by a simple imprinting technique, which does not need an expensive dry-etching machine or a complex patterned definition. The textured phosphor structure increases luminous flux by 5.4% and 2.5% at a driving current of 120 mA, compared with the flat phosphor and half-spherical lens structures, respectively. The increment was due to the scattering of textured surface and also the phosphor particles, leading to the enhancement of utilization efficiency of blue light. Furthermore, the textured phosphor structure has a larger view angle at the full width at half maximum (87 degrees ) than the reference LEDs. PMID- 22424207 TI - Serial and subjective clustering on a verbal learning test (VLT) in children aged 5-15: the nature of subjective clustering. AB - This study investigated which strategies children aged 5-15 years (N = 408) employ while performing a multitrial free recall test of semantically unrelated words. Serial clustering (i.e., a relatively passive strategy) is an index of the sequential consistency of recall order. Subjective clustering (i.e., a more active strategy) is based on similar word groupings in successive trials. Previously, Meijs et al. (2009) found that the level of (serial and subjective) clustering increases with age. At all ages, the level of serial clustering correlates positively with the ability to recall information on VLT trials. However, subjective clustering is more predictive of VLT performance than serial clustering after >= 3 trials, but only in children aged 8+. Knowledge on how children organize words (based on, for example, sound or meaning) and how this relates to developmental stage is still lacking. This study revealed that the level of subjective clustering is primarily determined by the position of words in a VLT list. More specifically, primacy (i.e., recall of words 1-3 of the VLT list - whether recalled in the same order or reversed) and recency (i.e., recall of words 14-15) effects primarily determine level subjective organization over successive trials. Thus, older children still organize words based on the serial position of the VLT list and are much less likely to organize them based on any other feature of the words, for example, sound or meaning. This indicates that the most important information to be learned needs to be presented first or last, even in older children and even with repeated presentations. PMID- 22424208 TI - Homodimerization of the PAS-B domains of hypoxia-inducible factors. AB - The Per-Arnt-Sim (PAS) domains of hypoxia-inducible transcription factors (HIF) mediate heterodimer formation between the HIF-alpha forms that are induced in the event of cellular hypoxia and the constitutive HIF-beta variants. Previous efforts toward structural characterization of the HIF-1alpha PAS domains were limited by protein stability. Using homology modeling based on the published crystal structure of the PAS-B domain of the homologous protein HIF-2alpha in complex with the partner HIF-beta (also known as ARNT), we have identified a variant of HIF-1alpha with improved solubility, monodispersity, and stability. Purified solutions of the PAS-B domains of HIF-1alpha and HIF-2alpha differ in their propensity for homodimer formation. In an attempt to understand the structural basis for this difference, and to document the structural changes that accompany homodimer formation, we have undertaken a comparative NMR study of the PAS-B domains of HIF-1alpha and HIF-2alpha and mutants of HIF-1alpha that mimic the behavior of HIF-2alpha. The NMR spectra of all of these domains are very similar, consistent with the similarity of their amino acid sequences. However, the greater propensity of the HIF-1alpha PAS-B domain to form dimers as the concentration was increased allowed us to determine the site of homodimerization and pointed toward possible sequence changes in HIF-1alpha that might discourage the formation of homodimers. PMID- 22424212 TI - C(sp)-C(sp3) bond formation through Cu-catalyzed cross-coupling of N tosylhydrazones and trialkylsilylethynes. AB - Copper-catalyzed cross-coupling of N-tosylhydrazones with trialkylsilylethynes leads to the formation of C(sp)-C(sp(3)) bonds. Cu carbene migratory insertion is proposed to play the key role in this transformation. PMID- 22424211 TI - Unexpected gynecologic findings during abdominal surgery. PMID- 22424213 TI - Catalytic Janus motors on microfluidic chip: deterministic motion for targeted cargo delivery. AB - We fabricated self-powered colloidal Janus motors combining catalytic and magnetic cap structures, and demonstrated their performance for manipulation (uploading, transportation, delivery) and sorting of microobjects on microfluidic chips. The specific magnetic properties of the Janus motors are provided by ultrathin multilayer films that are designed to align the magnetic moment along the main symmetry axis of the cap. This unique property allows a deterministic motion of the Janus particles at a large scale when guided in an external magnetic field. The observed directional control of the motion combined with extensive functionality of the colloidal Janus motors conceptually opens a straightforward route for targeted delivery of species, which are relevant in the field of chemistry, biology, and medicine. PMID- 22424214 TI - Systematic investigation of oxygen and growth factors in clinically valid ex vivo expansion of cord blood CD34(+) hematopoietic progenitor cells. AB - BACKGROUND AIMS: Cord blood is considered to be a superior source of hematopoietic stem and progenitor cells for transplantation, but clinical use is limited primarily because of the low numbers of cells harvested. Ex vivo expansion has the potential to provide a safe, effective means of increasing cell numbers. However, an absence of consensus regarding optimum expansion conditions prevents standard implementation. Many studies lack clinical applicability, or have failed to investigate the combinational effects of different parameters. METHODS: This is the first study to characterize systematically the effect of growth factor combinations across multiple oxygen levels on the ex vivo expansion of cord blood CD34(+) hematopoietic cells utilizing clinically approvable reagents and methodologies throughout. RESULTS: Optimal fold expansion, as assessed both phenotypically and functionally, was greatest with thrombopoietin, stem cell factor, Flt-3 ligand and interleukin-6 at an oxygen level of 10%. With these conditions, serial expansion showed continual target population expansion and consistently higher expression levels of self-renewal associated genes. CONCLUSIONS: This study has identified optimized fold expansion conditions, with the potential for direct clinical translation to increase transplantable cell dose and as a baseline methodology against which future factors can be tested. PMID- 22424215 TI - Signaling through Toll-like receptor 3 and Dectin-1 potentiates the capability of human monocyte-derived dendritic cells to promote T-helper 1 and T-helper 17 immune responses. AB - BACKGROUND AIMS: Recent studies have shown that the ligation of Toll-like receptor 3 (TLR3) or Dectin-1 on human monocyte-derived dendritic cells (MoDC) elicits their maturation, but with a different outcome on immunomodulation. Therefore the aim of this work was to study the response of MoDC to the combined effect of polyinosinic:polycytydilic acid [Poly (I:C)] and curdlan, selective TLR3 and Dectin-1 agonists, respectively. METHODS: Immature MoDC, generated from human monocytes, were treated with Poly (I:C), curdlan or their combination for 2 days. Phenotypic characteristics of MoDC were determined by flow cytometry, and cytokine production was measured by enzyme-linked immunosorbent assay (ELISA) and FlowCytomix, while the stimulatory capability of MoDC was tested using a mixed leukocyte reaction assay. RESULTS: The combination of Poly (I:C) and curdlan induced phenotypic maturation of MoDC with the capability to stimulate an alloreactive response. Such treated MoDC up-regulated the production of interleukin (IL)-12, IL-23 and IL-10, compared with the effect of Poly (I:C) alone. Curdlan-treated MoDC stimulated the production of IL-17 by alloreactive CD4 (+) T cells more strongly than Poly (I:C)-treated MoDC. The opposite effect was observed for interferon(IFN)-gamma production. When combined, these agonists primed MoDC to increase further the production of IFN-gamma by CD4 (+) T cells in co-culture, especially those of naive (CD45RA (+)) phenotype, and IL-17 by memory (CD45RO (+)) CD4 (+) T cells. CONCLUSIONS: Ligation of TLR3 and Dectin-1 receptor up-regulates T-helper (Th) 1 and Th17 immune responses compared with single agonists. These findings may have therapeutic implications for the use of MoDC in immunotherapy. PMID- 22424216 TI - Fetal liver-derived mesenchymal stromal cells augment engraftment of transplanted hepatocytes. AB - BACKGROUND AIMS: One important problem commonly encountered after hepatocyte transplantation is the low numbers of transplanted cells found in the graft. If hepatocyte transplantation is to be a viable therapeutic approach, significant liver parenchyma repopulation is required. Mesenchymal stromal cells (MSC) produce high levels of various growth factors, cytokines and metalloproteinases, and have immunomodulatory effects. We therefore hypothesized that co transplantation of MSC with human fetal hepatocytes (hFH) could augment in vivo expansion after transplantation. We investigated the ability of human fetal liver MSC (hFLMSC) to augment expansion of phenotypically and functionally well characterized hFH. METHODS: Two million hFH (passage 6) were either transplanted alone or together (1:1 ratio) with green fluorescence protein-expressing hFLMSC into the spleen of C57BL/6 nude mice with retrorsine-induced liver injury. RESULTS: After 4 weeks, engraftment of cells was detected by fluorescence in situ hybridization using a human-specific DNA probe. Significantly higher numbers of cells expressing human cytokeratin (CK)8, CK18, CK19, Cysteine-rich MNNG HOS Transforming gene (c-Met), alpha-fetoprotein (AFP), human nuclear antigen, mitochondrial antigen, hepatocyte-specific antigen and albumin (ALB) were present in the livers of recipient animals co-transplanted with hFLMSC compared with those without. Furthermore, expression of human hepatocyte nuclear factor (HNF) 4alpha and HNF-1beta, and cytochrome P450 (CYP) 3A7 mRNA was demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR) in these animals. In addition, significantly increased amounts of human ALB were detected. Importantly, hFLMSC did not transdifferentiate into hepatocytes. CONCLUSIONS: Our study reports the use of a novel strategy for enhanced liver repopulation and thereby advances this experimental procedure closer to clinical liver cell therapy. PMID- 22424217 TI - Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor alpha2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele. AB - BACKGROUND AIMS: Dendritic cell (DC)-based vaccination targeting tumor-associated antigens is an attractive approach to overcoming the limitations of current treatments for malignant gliomas (MG). Interleukin-13 receptor alpha2 chain (IL 13Ralpha2) is a promising target because of its abundant and specific expression in MG. We conducted a phase I trial of DC vaccination in patients with recurrent MG using two IL-13Ralpha2-derived peptides restricted to HLA-A*0201 and -A*2402. The objective was to evaluate the safety and clinical and immunologic responses. METHODS: Eight recurrent MG patients were enrolled. DC were generated from peripheral blood and pulsed with HLA-matched peptide; 1 * 10(7) DC were administered every 2 weeks for a maximum of six immunizations. The T-cell response in peripheral blood was evaluated by tetramer and ELISPOT assays in HLA A*2402 patients. RESULTS: All enrolled patients except one completed at least four DC vaccinations. No severe adverse events were observed. A positive T-cell response was detected in two out of three evaluable HLA-A*2402 patients. One patient achieved stable disease for 16 months and another patient showed a dramatic regression for one lesion for 4 months. CONCLUSIONS: The regimen was feasible and safe, and the HLA-A*24-restricted peptide exhibited a capacity to induce immune responses. These results warrant further studies to evaluate whether add-on regimens to post-operative chemoradiotherapy delays recurrence in newly diagnosed MG patients. PMID- 22424218 TI - Redefining clinical trials: the age of personalized medicine. AB - The triumph of personalized cancer therapeutics in recent years is prompting some oncologists to rethink clinical trial design; other researchers have different priorities for trial reform. PMID- 22424219 TI - Antibody-based immunotherapy of cancer. AB - By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. We discuss these innovative strategies and propose how they will impact the future of antibody based cancer therapy. PMID- 22424220 TI - Splice modulating therapies for human disease. AB - Dysregulation of splicing and alternative splicing underlies many genetic and acquired diseases. We present an overview of recent strategies and successes in modulating splicing therapeutically in clinical and preclinical contexts. Effective approaches include restoring open reading frames, influencing alternative splicing, and inducing exon inclusion to generate beneficial proteins and remove deleterious ones. PMID- 22424221 TI - Converting cancer therapies into cures: lessons from infectious diseases. AB - During the past decade, cancer drug development has shifted from a focus on cytotoxic chemotherapies to drugs that target specific molecular alterations in tumors. Although these drugs dramatically shrink tumors, the responses are temporary. Research is now focused on overcoming drug resistance, a frequent cause of treatment failure. Here we reflect on analogous challenges faced by researchers in infectious diseases. We compare and contrast the resistance mechanisms arising in cancer and infectious diseases and discuss how approaches for overcoming viral and bacterial infections, such as HIV and tuberculosis, are instructive for developing a more rational approach for cancer therapy. In particular, maximizing the effect of the initial treatment response, which often requires synergistic combination therapy, is foremost among these approaches. A remaining challenge in both fields is identifying drugs that eliminate drug tolerant "persister" cells (infectious disease) or tumor-initiating/stem cells (cancer) to prevent late relapse and shorten treatment duration. PMID- 22424222 TI - Life in the fast lane: mammalian disease models in the genomics era. AB - Analyses of the human genome have proven extremely successful in identifying changes that contribute to human disease. Genetically engineered mice provide a powerful tool to analyze these changes, although they are slow and costly and do not always recapitulate human biology. Recent advances in genomic technologies, rodent-modeling approaches, and the production of patient-derived reprogrammed cell lines now provide a plethora of complementary systems to study disease states and test new therapies. Continued evolution and integration of these model systems will be the key to realizing the benefits of the genomic revolution and refining our understanding and treatment of human diseases. PMID- 22424223 TI - Reprogramming cellular identity for regenerative medicine. AB - Although development leads unidirectionally toward more restricted cell fates, recent work in cellular reprogramming has proven that one cellular identity can strikingly convert into another, promising countless applications in biomedical research and paving the way for modeling diseases with patient-derived stem cells. To date, there has been little discussion of which disease models are likely to be most informative. Here, we review evidence demonstrating that, because environmental influences and epigenetic signatures are largely erased during reprogramming, patient-specific models of diseases with strong genetic bases and high penetrance are likely to prove most informative in the near term. We also discuss the implications of the new reprogramming paradigm in biomedicine and outline how reprogramming of cell identities is enhancing our understanding of cell differentiation and prospects for cellular therapies and in vivo regeneration. PMID- 22424224 TI - Regulated noise in the epigenetic landscape of development and disease. AB - In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After grounding our argument in a discussion of stochastic noise and nongenetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, thus contributing to tumor cell heterogeneity. PMID- 22424225 TI - Cellular metabolism and disease: what do metabolic outliers teach us? AB - An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states--often genetically programmed--that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of metabolism in cellular function and how modern concepts of metabolism can inform our understanding of common diseases like cancer and also considers the prospects of developing new metabolic approaches to disease treatment. PMID- 22424226 TI - Mitochondria: in sickness and in health. AB - Mitochondria perform diverse yet interconnected functions, producing ATP and many biosynthetic intermediates while also contributing to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. In addition, mitochondrial functions extend beyond the boundaries of the cell and influence an organism's physiology by regulating communication between cells and tissues. It is therefore not surprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative and metabolic disorders. We provide a current view of how mitochondrial functions impinge on health and disease. PMID- 22424227 TI - Diabetes mellitus and the beta cell: the last ten years. AB - Diabetes is a major global problem. During the past decade, the genetic basis of various monogenic forms of the disease, and their underlying molecular mechanisms, have been elucidated. Many genes that increase type 2 diabetes (T2DM) risk have also been identified, but how they do so remains enigmatic. Nevertheless, defective insulin secretion emerges as the main culprit in both monogenic and polygenic diabetes, with environmental and lifestyle factors, via obesity, accounting for the current dramatic increase in T2DM. There also have been significant advances in therapy, particularly for some monogenic disorders. We review here what ails the beta cell and how its function may be restored. PMID- 22424228 TI - MicroRNAs in stress signaling and human disease. AB - Disease is often the result of an aberrant or inadequate response to physiologic and pathophysiologic stress. Studies over the last 10 years have uncovered a recurring paradigm in which microRNAs (miRNAs) regulate cellular behavior under these conditions, suggesting an especially significant role for these small RNAs in pathologic settings. Here, we review emerging principles of miRNA regulation of stress signaling pathways and apply these concepts to our understanding of the roles of miRNAs in disease. These discussions further highlight the unique challenges and opportunities associated with the mechanistic dissection of miRNA functions and the development of miRNA-based therapeutics. PMID- 22424229 TI - The amyloid state of proteins in human diseases. AB - Amyloid fibers and oligomers are associated with a great variety of human diseases including Alzheimer's disease and the prion conditions. Here we attempt to connect recent discoveries on the molecular properties of proteins in the amyloid state with observations about pathological tissues and disease states. We summarize studies of structure and nucleation of amyloid and relate these to observations on amyloid polymorphism, prion strains, coaggregation of pathogenic proteins in tissues, and mechanisms of toxicity and transmissibility. Molecular studies have also led to numerous strategies for biological and chemical interventions against amyloid diseases. PMID- 22424230 TI - Alzheimer mechanisms and therapeutic strategies. AB - There are still no effective treatments to prevent, halt, or reverse Alzheimer's disease, but research advances over the past three decades could change this gloomy picture. Genetic studies demonstrate that the disease has multiple causes. Interdisciplinary approaches combining biochemistry, molecular and cell biology, and transgenic modeling have revealed some of its molecular mechanisms. Progress in chemistry, radiology, and systems biology is beginning to provide useful biomarkers, and the emergence of personalized medicine is poised to transform pharmaceutical development and clinical trials. However, investigative and drug development efforts should be diversified to fully address the multifactoriality of the disease. PMID- 22424231 TI - CNVs: harbingers of a rare variant revolution in psychiatric genetics. AB - The genetic bases of neuropsychiatric disorders are beginning to yield to scientific inquiry. Genome-wide studies of copy number variation (CNV) have given rise to a new understanding of disease etiology, bringing rare variants to the forefront. A proportion of risk for schizophrenia, bipolar disorder, and autism can be explained by rare mutations. Such alleles arise by de novo mutation in the individual or in recent ancestry. Alleles can have specific effects on behavioral and neuroanatomical traits; however, expressivity is variable, particularly for neuropsychiatric phenotypes. Knowledge from CNV studies reflects the nature of rare alleles in general and will serve as a guide as we move forward into a new era of whole-genome sequencing. PMID- 22424232 TI - Genetics of human cardiovascular disease. AB - Cardiovascular disease encompasses a range of conditions extending from myocardial infarction to congenital heart disease, most of which are heritable. Enormous effort has been invested in understanding the genes and specific DNA sequence variants that are responsible for this heritability. Here, we review the lessons learned for monogenic and common, complex forms of cardiovascular disease. We also discuss key challenges that remain for gene discovery and for moving from genomic localization to mechanistic insights, with an emphasis on the impact of next-generation sequencing and the use of pluripotent human cells to understand the mechanism by which genetic variation contributes to disease. PMID- 22424233 TI - The impact of the gut microbiota on human health: an integrative view. AB - The human gut harbors diverse microbes that play a fundamental role in the well being of their host. The constituents of the microbiota--bacteria, viruses, and eukaryotes--have been shown to interact with one another and with the host immune system in ways that influence the development of disease. We review these interactions and suggest that a holistic approach to studying the microbiota that goes beyond characterization of community composition and encompasses dynamic interactions between all components of the microbiota and host tissue over time will be crucial for building predictive models for diagnosis and treatment of diseases linked to imbalances in our microbiota. PMID- 22424234 TI - Outwitting evolution: fighting drug-resistant TB, malaria, and HIV. AB - Although caused by vastly different pathogens, the world's three most serious infectious diseases, tuberculosis, malaria, and HIV-1 infection, share the common problem of drug resistance. The pace of drug development has been very slow for tuberculosis and malaria and rapid for HIV-1. But for each disease, resistance to most drugs has appeared quickly after the introduction of the drug. Learning how to manage and prevent resistance is a major medical challenge that requires an understanding of the evolutionary dynamics of each pathogen. This Review summarizes the similarities and differences in the evolution of drug resistance for these three pathogens. PMID- 22424235 TI - Beyond empiricism: informing vaccine development through innate immunity research. AB - Although a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate immunity research have led to a better understanding of how existing vaccines work and have informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response, resulting in enhanced protection. PMID- 22424237 TI - SnapShot: Pain perception. PMID- 22424236 TI - Personal omics profiling reveals dynamic molecular and medical phenotypes. AB - Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity. PMID- 22424238 TI - Matrix metalloproteinases 2 and 9 increase permeability of sheep pleura in vitro. AB - BACKGROUND: Matrix metalloproteinases (MMPs) 2 and 9 are two gelatinase members which have been found elevated in exudative pleural effusions. In endothelial cells these MMPs increase paracellular permeability via the disruption of tight junction (TJ) proteins occludin and claudin. In the present study it was investigated if MMP2 and MMP9 alter permeability properties of the pleura tissue by degradation of TJ proteins in pleural mesothelium. RESULTS: In the present study the transmesothelial resistance (RTM) of sheep pleura tissue was recorded in Ussing chambers after the addition of MMP2 or MMP9. Both enzymes reduced RTM of the pleura, implying an increase in pleural permeability. The localization and expression of TJ proteins, occludin and claudin-1, were assessed after incubation with MMPs by indirect immunofluorescence and western blot analysis. Our results revealed that incubation with MMPs did not alter neither proteins localization at cell periphery nor their expression. CONCLUSIONS: MMP2 and MMP9 increase the permeability of sheep pleura and this finding suggests a role for MMPs in pleural fluid formation. Tight junction proteins remain intact after incubation with MMPs, contrary to previous studies which have shown TJ degradation by MMPs. Probably MMP2 and MMP9 augment pleural permeability via other mechanisms. PMID- 22424239 TI - Molecular cloning, characterization, and inhibition studies of a beta-carbonic anhydrase from Malassezia globosa, a potential antidandruff target. AB - A beta-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Malassezia globosa has been cloned, characterized, and studied for its inhibition with sulfonamides. This enzyme, designated MG-CA, has significant catalytic activity in the CO(2) hydration reaction and was inhibited by sulfonamides, sulfamates, and sulfamides with K(I) in the nanomolar to micromolar range. Several sulfonamides have also been investigated for the inhibition of growth of M. globosa, M. dermatis, M. pachydermatic, and M. furfur in cultures, whereas a mouse model of dandruff showed that treatment with sulfonamides led to fragmented fungal hyphae, as for the treatment with ketoconazole, a clinically used antifungal agent. These data prompt us to propose MG-CA as a new antidandruff drug target. PMID- 22424241 TI - Re-usable post-operative leg supports. AB - PURPOSE: To develop a low cost, safe, intuitive, and reusable post-operative lower leg support that can be delivered rapidly and usable for several months with minimal maintenance. METHODS: The lower leg support consists of a removable contoured pad secured to a support surface. This surface is attached to a double ball and socket arm which allows six degrees of freedom of movement. The double ball and socket joint is attached to the client's wheelchair using a "U-bolt" type clamp. RESULTS: The lower leg supports have been used clinically 14 times since September 2008. Financial records indicate the construction costs of each lower leg support are approximately $150 CDN ($90 parts, $60 Labour) which is below the $300 CDN limit for post-operative seating modifications in BC. Re-using these supports for other clients only increases their cost effectiveness. The intuitive operation of the lower leg supports enables quick and easy adjustment of the individual leg supports. Caregivers and community clinicians have used the leg supports during convalescence then returned them to be re-used. CONCLUSIONS: The functional longevity, easy installation, low cost and intuitive operation makes these leg supports suitable for post-operative lower leg positioning. PMID- 22424240 TI - Comparative mitochondrial proteomics: perspective in human diseases. AB - Mitochondria are the most complex and the most important organelles of eukaryotic cells, which are involved in many cellular processes, including energy metabolism, apoptosis, and aging. And mitochondria have been identified as the "hot spot" by researchers for exploring relevant associated dysfunctions in many fields. The emergence of comparative proteomics enables us to have a close look at the mitochondrial proteome in a comprehensive and effective manner under various conditions and cellular circumstances. Two-dimensional electrophoresis combined with mass spectrometry is still the most popular techniques to study comparative mitochondrial proteomics. Furthermore, many new techniques, such as ICAT, MudPIT, and SILAC, equip researchers with more flexibilities inselecting proper methods. This article also reviews the recent development of comparative mitochondrial proteomics on diverse human diseases. And the results of mitochondrial proteomics enhance a better understanding of the pathogenesis associated with mitochondria and provide promising therapeutic targets. PMID- 22424242 TI - Synthesis of three novel anionic gemini surfactants and comparative studies of their assemble behavior in the presence of bovine serum albumin. AB - Three novel anionic sulfonate gemini surfactants, sodium 4,4'-(10,19-dioxo 9,11,18,20-tetraazaoctacosane-9,20-diyl) dibenzenesulfonate (Surfactant I), sodium 4,4'-(12,21-dioxo-11,13,20,22-tetraazadotriacontane-11,22-diyl) dibenzenesulfonate (Surfactant II), and sodium 4,4'-(14,23-dioxo-13,15,22,24 tetraazahezatriacontane-13,24-diyl) dibenzenesulfonate (Surfactant III), with different lengths of hydrophobic tail have been synthesized, and their assembly behavior in the presence of bovine serum albumin (BSA) has been studied using spectral methods and molecular modeling methods at physiological pH and 298 K. Critical micelle concentrations (CMCs) of the three surfactants have been determined by surface tension measurements. Despite the obvious decrease of CMC with the increase of tail length, fluorescence spectra have shown much closer CAC in the presence of BSA. Surfactant II shows the highest CAC of 3.19 * 10(-5) mol L(-1) compared with the other two. The polarity of the microenvironment in BSA surfactant systems has been investigated using pyrene as the probe. In addition, far-UV CD spectra studied the change of the secondary structure content of BSA caused by the three surfactants. The features of the assembly behavior were discussed by three concentration regions. Surfactant II could unfold the protein much more efficiently than the other two surfactants at low concentration, but at high concentration, the change of the secondary structure and the formation of hydrophobic microenvironment show a direct relationship to the length of the hydrophobic tail with the increase of the surfactant concentration. PMID- 22424243 TI - Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment. AB - OBJECTIVES: The glutamatergic hypothesis of schizophrenia proposes alterations of excitatory amino acid transporters (solute carrier family, SLCs) expression and cerebellar dysfunctions. The influence of the neuregulin-1 (NRG1) risk genotype or effects of antipsychotics on expression of EAATs are unknown. METHODS: We compared post-mortem samples from the cerebellar hemispheres and vermis of 10 schizophrenia patients with nine normal subjects by investigating gene expression of SLC1A3, SLC1A1 and SLC1A6 by in-situ hybridization. We further assessed the allelic composition regarding the polymorphism rs35753505 (SNP8NRG221533) near the NRG1 gene. To control for effects due to antipsychotic treatment, we chronically treated rats with the antipsychotics haloperidol or clozapine and assessed gene expression of SLCs. RESULTS: Schizophrenia patients showed increased expression of SLC1A3 in the molecular layer of the vermis. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of SLC1A6 in the molecular layer of both hemispheres, compared to individuals homozygous for the T allele. The animal model revealed suppression of SLC1A6 by clozapine. CONCLUSIONS: Increased SLC1A3 expression indicates facilitated transport and may result in reduced glutamate neurotransmission. Decreased SLC1A6 expression in NRG1 risk variant may be an adaptive effect to restore glutamate signalling, but treatment effects cannot be excluded. PMID- 22424244 TI - Activity-based probes linked with laser-cleavable mass tags for signal amplification in imaging mass spectrometry: analysis of serine hydrolase enzymes in mammalian tissue. AB - A novel functional imaging mass spectrometry technology is described that utilizes activity-based probes for imaging enzyme active sites in tissue sections. We demonstrate this technology using an activity-based probe (fluorophosphate) that is specific for serine hydrolases. A dendrimer containing multiple mass tags that is attached to the activity-based probe is used to analyze the binding sites of the probe through release and measurement of the mass tags on laser irradiation. A generation 8 poly(amido amine) dendrimer with 1024 amino groups was labeled with an azide group, and then, more than 900 mass tags were attached in order to achieve signal amplification of nearly 3 orders of magnitude. The experimental protocol first involves binding of the activity-based probe containing an alkyne group to serine hydrolases in the tissue section followed by attachment of the dendrimer labeled with mass tags to the bound probe by Click chemistry. On irradiation of the labeled tissue by the laser beam in a raster pattern, the mass tags are liberated and recorded by the mass analyzer; consequently, the ion image of the mass tag reveals the distribution of serine hydrolases in the tissue. This process was shown using rat brain and mouse embryo sections. Targeted imaging has the advantage of providing high spatial resolution and high sensitivity through the use of signal amplification chemistry with high target specificity through the use of an enzyme activity probe. PMID- 22424245 TI - Chlamydia testing patterns for commercially insured women, 2008. AB - BACKGROUND: Annual chlamydia screening for sexually active women aged <=25 years is recommended, and chlamydia testing rates have continuously increased. However, several studies have shown that many providers screen all women of reproductive age in public settings. PURPOSE: To examine chlamydia testing patterns in private settings for women and young women aged 15-44 years (hereafter referred to as women). METHODS: A large commercial claims database was used to estimate the chlamydia testing rate for women aged 15-44 years who had reproductive health services in 2008. Such services and tests were identified using diagnostic and procedural codes in 2008. RESULTS: Of 3.2 million women aged 15-44 years who had reproductive health services in 2008, 19.2% had at least a claim for a sexually transmitted disease (STD), 29.3% for pregnancy, and 81.2% for a gynecologic exam. Of those 3.2 million, 22.3% had chlamydia testing: 34.2% aged 15-25 years vs 18.3% aged 26-44 years. Of the 0.7 million who were tested, 65% were aged 26-44 years, and the reason for the healthcare visit in which their first chlamydia test was performed was an STD for 22.7% and pregnancy for 33.5%. CONCLUSIONS: In this population of insured women, young women are undertested and older women are overtested for chlamydia. Efforts to improve screening practices should be evaluated. PMID- 22424246 TI - Using body mass index data in the electronic health record to calculate cardiovascular risk. AB - BACKGROUND: Multivariable cardiovascular disease (CVD) risk calculators, such as the Framingham risk equations, can be used to identify populations most likely to benefit from treatments to decrease risk. PURPOSE: To determine the proportion of adults within an electronic health record (EHR) for whom Framingham CVD risk scores could be calculated using cholesterol (lab-based) and/or BMI (BMI-based) formulae. METHODS: EHR data were used to identify patients aged 30-74 years with no CVD and at least 2 years continuous enrollment before April 1, 2010, and relevant data from the preceding 5-year time frame. Analyses were conducted between 2010 and 2011 to determine the proportion of patients with a lab- or BMI based risk score, the data missing, and the concordance between scores. RESULTS: Of 122,270 eligible patients, 59.7% (n=73,023) had sufficient data to calculate the lab-based risk score and 84.1% (102,795) the BMI-based risk score. Risk categories were concordant in 78.2% of patients. When risk categories differed, BMI-based risk was almost always in a higher category, with 20.3% having a higher and 1.4% a lower BMI- than lab-based risk score. Concordance between lab- and BMI based risk was greatest among those at lower estimated risk, including people who were younger, female, without diabetes, not obese, and those not on blood pressure- or lipid-lowering medications. CONCLUSIONS: EHR data can be used to classify CVD risk for most adults aged 30-74 years. In the population for the current study, CVD risk scores based on BMI could be used to identify those at low risk for CVD and potentially reduce unnecessary laboratory cholesterol testing. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT01077388. PMID- 22424248 TI - Physical activity and depressive symptoms in older adults: 11-year follow-up. AB - BACKGROUND: Few studies have explored the reciprocal relationships between naturally occurring changes in physical activity and depressive symptoms in later life. PURPOSE: This study examined the reciprocal associations between changes in physical activity and depressive symptoms in a population-based sample of Taiwanese older adults over an 11-year period. METHODS: Analyses were based on nationally representative data from the Taiwan's Health and Living Status of the Elderly Survey collected in 1996, 1999, 2003, and 2007. Data from the fixed cohort of 1160 participants aged >=67 years in 1996 with 11 years of follow-up were studied. Depressive symptoms were assessed using the ten-item Chinese version of the Center for Epidemiologic Studies-Depression Scale. Physical activity was self-reported as the number of sessions per week. Latent growth modeling was used to examine the bidirectional associations between changes in physical activity and depressive symptoms when controlling for sociodemographic variables, lifestyle behaviors, and health status. Data analyses were completed in 2011. RESULTS: With multivariate adjustment, initial levels of physical activity were negatively associated with changes in depressive symptoms (beta= 0.34, p<0.05). In contrast, early depressive symptoms were not related to change in physical activity (beta=-0.17, p>0.05). CONCLUSIONS: Physical activity engagement in later life is associated with a lower risk of subsequent depressive symptoms, but the reverse association is not supported. The finding has underlying implications for future physical activity and mental health promotion in aged populations. PMID- 22424247 TI - Adult body mass index trajectories and sexual orientation: the Nurses' Health Study II. AB - BACKGROUND: Cross-sectional research has documented elevated prevalence of obesity in lesbian and bisexual women relative to heterosexual women, but little is known about disparities in longitudinal patterns in BMI change during adulthood. PURPOSE: To examine sexual orientation-related disparities in individual BMI trajectories throughout adulthood. METHODS: Data on BMI, sexual orientation, and sociodemographics were gathered prospectively from 1989 through 2005 from 90,713 U.S. women in the Nurses' Health Study II and examined in 2011 using general growth mixture modeling to identify BMI trajectories from ages 25 to 59 years. Multinomial logistic regression was used to determine whether sexual orientation was associated with BMI trajectory group membership. RESULTS: Four BMI trajectory groups were identified and labeled based on mean BMI within each group at baseline and final follow-up: Group 1: slow-weight-gain trajectory; Group 2: moderate-weight-gain trajectory; Group 3: rapid-weight-gain trajectory; and Group 4: obese-to-overweight trajectory. Lesbian and bisexual women showed consistently higher odds of membership in Groups 2-4 (adverse-weight-gain trajectories) versus Group 1 (the slow-weight-gain trajectory) relative to heterosexual women. CONCLUSIONS: Both lesbian and bisexual women were more likely than heterosexual women to experience adverse-weight-gain trajectories in adulthood. New research efforts are needed to understand and eliminate these pronounced disparities. PMID- 22424249 TI - Mid-aged adults' sitting time in three contexts. AB - BACKGROUND: To develop evidence-based approaches for reducing sedentary behavior, there is a need to identify the specific settings where prolonged sitting occurs, associated factors, and variations. PURPOSE: To examine the sociodemographic and health factors associated with mid-aged adults' sitting time in three contexts and variations between weekdays and weekend days. METHODS: A mail survey was sent to 17,000 adults (aged 40-65 years) in 2007; 11,037 responses were received (68.5%); and 7719 were analyzed in 2010. Respondents indicated time spent sitting on a usual weekday and weekend day for watching TV, general leisure, and home computer use. Multivariate linear mixed models with area-level random intercepts were used to examine (1) associations between sociodemographic and health variables and sitting time, and (2) interaction effects of weekday/weekend day with each of gender, age, education, and employment status, on sitting time. RESULTS: For each context, longer sitting times were reported by those single and living alone, and those whose health restricted activity. For watching TV, longer sitting times were reported by men; smokers; and those with high school or lower education, not in paid employment, in poor health, and with BMI >=25. For general leisure, longer sitting times were reported by women, smokers, and those not employed full-time. For home computer use, longer sitting times were reported by men; and those aged 40-44 years, with university qualifications; in the mid income range; and with BMI >=30. Sitting times tended to be longer on weekend days than weekdays, although the extent of this differed among sociodemographic groups. CONCLUSIONS: Sociodemographic and health factors associated with sitting time differ by context and between weekdays and weekend days. PMID- 22424250 TI - Alternative HbA1c cutoffs to identify high-risk adults for diabetes prevention: a cost-effectiveness perspective. AB - BACKGROUND: New recommendations about the use of hemoglobin A1c (HbA1c) for diagnosing diabetes have stimulated a debate about the optimal HbA1c cutoff to identify prediabetes for preventive intervention. PURPOSE: To assess the cost effectiveness associated with the alternative HbA1c cutoffs for identifying prediabetes. METHODS: A Markov simulation model was used to examine the cost effectiveness associated with a progressive 0.1% decrease in the HbA1c cutoff from 6.4% to 5.5%. The target population was the U.S. nondiabetic population aged >=18 years. The simulation sample was created using the data of nondiabetic American adults from the National Health and Nutritional Examination Survey (NHANES 1999-2006). People identified as having prediabetes were assumed to receive a preventive intervention, with effectiveness the same as that in the Diabetes Prevention Program study under a high-cost intervention (HCI) scenario and in the Promoting a Lifestyle of Activity and Nutrition for Working to Alter the Risk of Diabetes study under a low-cost intervention (LCI) scenario. The analysis was conducted for a lifetime horizon from a healthcare system perspective. RESULTS: Lowering the HbA1c cutoff would increase the health benefits of the preventive interventions at higher costs. For the HCI, lowering the HbA1c cutoff from 6.0% to 5.9% and from 5.9% to 5.8% would result in $27,000 and $34,000 per QALY gained, respectively. Continuing to decrease the cutoff from 5.8% to 5.7%, from 5.7% to 5.6%, and from 5.6% to 5.5% would cost $45,000, $58,000, and $96,000 per QALY gained, respectively. For the LCI, lowering the HbA1c cutoff from 6.0% to 5.9% and from 5.9% to 5.8% would result in $24,000 and $27,000 per QALY gained, respectively. Continuing to lower the cutoff from 5.8% to 5.7%, 5.7% to 5.6%, and 5.6% to 5.5% would cost $34,000, $43,000 and $70,000 per QALY gained, respectively. CONCLUSIONS: Lowering the HbA1c cutoff for prediabetes leads to less cost-effective preventive interventions. Assuming a conventional $50,000/QALY cost-effectiveness benchmark, the HbA1c cutoffs of 5.7% and higher were found to be cost effective. Lowering the cutoff from 5.7% to 5.6% also may be cost effective, however, if the costs of preventive interventions were to be lowered. PMID- 22424251 TI - The impact of a 25-cent-per-drink alcohol tax increase. AB - BACKGROUND: Excessive alcohol consumption causes 79,000 deaths annually in the U.S., shortening the lives of those who die from it by approximately 30 years. Although alcohol taxation is an effective measure to reduce excessive consumption and related harm, some argue that increasing alcohol taxes places an unfair economic burden on "responsible" drinkers and socially disadvantaged people. PURPOSE: To examine the impact of a hypothetic tax increase based on alcohol consumption and sociodemographic characteristics of current drinkers, individually and in aggregate. METHODS: Data from the 2008 Behavioral Risk Factor Surveillance System survey were analyzed from 2010 to 2011 to determine the net financial impact of a hypothetic 25-cent-per-drink tax increase on current drinkers in the U.S. Higher-risk drinkers were defined as those whose past-30-day consumption included binge drinking, heavy drinking, drinking in excess of the U.S. Dietary Guidelines, and alcohol-impaired driving. RESULTS: Of U.S. adults who consumed alcohol in the past 30 days, 50.4% (or approximately 25% of the total U.S. population) were classified as higher-risk drinkers. The tax increase would result in a 9.2% reduction in alcohol consumption, including an 11.4% reduction in heavy drinking. Compared with lower-risk drinkers, higher-risk drinkers would pay 4.7 times more in net increased annual per capita taxes, and 82.7% of the net increased annual aggregate taxes. Lower-risk drinkers would pay less than $30 in net increased taxes annually. In aggregate, groups who paid the most in net tax increases included those who were white, male, aged 21-50 years, earning >=$50,000 per year, employed, and had a college degree. CONCLUSIONS: A 25 cent-per-drink alcohol tax increase would reduce excessive drinking, and higher risk drinkers would pay the substantial majority of the net tax increase. PMID- 22424252 TI - Nonparticipation in a population-based trial to increase colorectal cancer screening. AB - BACKGROUND: Many trials have tested different strategies to increase colorectal cancer (CRC) screening. Few describe whether participants are representative of the population from which they are recruited. PURPOSE: To determine risk factors related to nonparticipation among patients enrolled in an integrated health plan and not up to date for CRC testing, in a trial to increase screening rates. METHODS: Between July 2008 and October 2009, a total of 15,000 adults aged 50-74 years from 21 clinics in Washington State who were due for CRC screening were contacted. Nonparticipants were defined as English-speaking patients who did not engage in the call or refused participation while still potentially eligible. Log binomial regression models were used to estimate the relative risk of nonparticipation. Analyses were completed between October 2010 and June 2011. RESULTS: Patients who were nonwhite, had less education, used tobacco, had less continuity of care, and had lower rates of preventive care and cancer screening were more likely to be nonparticipants. Patients reporting never having received any type of CRC testing or screening were also more likely not to participate (62% of nonparticipants vs 46% of participants; adjusted RR=1.58, 95% CI=1.47, 1.70). Reasons for refusal included costs, risks of procedures, and not wanting their medical records reviewed. CONCLUSIONS: Patients eligible for but not participating in the trial were more likely to be from minority socioeconomic and racial groups and had behaviors that can negatively affect cancer outcomes. Additional efforts are needed to recruit patients who need CRC screening the most. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov NCT 00697047. PMID- 22424253 TI - Socioeconomic status, energy cost, and nutrient content of supermarket food purchases. AB - BACKGROUND: The relative affordability of energy-dense versus nutrient-rich foods may promote socioeconomic disparities in dietary quality and obesity. Although supermarkets are the largest food source in the American diet, the associations between SES and the cost and nutrient content of freely chosen food purchases have not been described. PURPOSE: To investigate relationships of SES with the energy cost ($/1000 kcal) and nutrient content of freely chosen supermarket purchases. METHODS: Supermarket shoppers (n=69) were recruited at a Phoenix AZ supermarket in 2009. The energy cost and nutrient content of participants' purchases were calculated from photographs of food packaging and nutrition labels using dietary analysis software. Data were analyzed in 2010-2011. RESULTS: Two SES indicators, education and household income as a percentage of the federal poverty guideline (FPG), were associated with the energy cost of purchased foods. Adjusting for covariates, the amount spent on 1000 kcal of food was $0.26 greater for every multiple of the FPG, and those with a baccalaureate or postbaccalaureate degree spent an additional $1.05 for every 1000 kcal of food compared to those with no college education. Lower energy cost was associated with higher total fat and less protein, dietary fiber, and vegetables per 1000 kcal purchased. CONCLUSIONS: Low-SES supermarket shoppers purchase calories in inexpensive forms that are higher in fat and less nutrient-rich. PMID- 22424254 TI - Public health interventions for asthma: an umbrella review, 1990-2010. AB - CONTEXT: Asthma is a chronic respiratory disease increasingly prevalent in the U.S., particularly among children and certain minority groups. This umbrella review sought to assess and summarize existing systematic reviews of asthma related interventions that might be carried out or supported by state or community asthma control programs, and to identify gaps in knowledge. EVIDENCE ACQUISITION: Eleven databases were searched through September 2010, using terms related to four concepts: asthma, review, intervention, and NOT medication. Reviews of the effectiveness of medications, medical procedures, complementary and alternative medicine, psychological interventions, family therapy, and nutrients or nutritional supplements were excluded. Two coders screened each record and extracted data from the included reviews. EVIDENCE SYNTHESIS: Data analysis was conducted from May to December 2010. Of 42 included reviews, 19 assessed the effectiveness of education and/or self-management, nine the reduction of indoor triggers, nine interventions to improve the provision of health care, and five examined other interventions. Several reviews found consistent evidence of effectiveness for self-management education, and one review determined that comprehensive home-based interventions including the reduction of multiple indoor asthma triggers are effective for children. Other reviews found limited or insufficient evidence because of study limitations. CONCLUSIONS: State or community asthma control programs should prioritize (1) implementing interventions for which the present review found evidence of effectiveness and (2) evaluating promising interventions that have not yet been adequately assessed. PMID- 22424255 TI - Home versus nonhome neighborhood: quantifying differences in exposure to the built environment. AB - BACKGROUND: Built environment and health research have focused on characteristics of home neighborhoods, whereas overall environmental exposures occur over larger spatial ranges. PURPOSE: Differences in built environment characteristics were analyzed for home and nonhome locations using GPS data. METHODS: GPS data collected in 2007-2008 were analyzed for 41 subjects in the Seattle area in 2010. Environmental characteristics for 3.8 million locations were measured using novel GIS data sets called SmartMaps, representing spatially continuous values of local built environment variables in the domains of neighborhood composition, utilitarian destinations, transportation infrastructure, and traffic conditions. Using bootstrap sampling, CIs were estimated for differences in built environment values for home (<833 m of home address) and nonhome (>1666 m) GPS locations. RESULTS: Home and nonhome built environment values were significantly different for more than 90% of variables across subjects (p<0.001). Only 51% of subjects had higher counts of supermarkets near than away from home. Different measures of neighborhood parks yielded varying results. CONCLUSIONS: SmartMaps helped measure local built environment characteristics for a large set of GPS locations. Most subjects had significantly different home and nonhome built environment exposures. Considering the full range of individuals' environmental exposures may improve understanding of effects of the built environment on behavior and health outcomes. PMID- 22424256 TI - Effects of alcohol retail privatization on excessive alcohol consumption and related harms: a community guide systematic review. AB - CONTEXT: Excessive alcohol consumption is the third-leading cause of preventable death in the U.S. This systematic review is one in a series exploring effectiveness of interventions to reduce alcohol-related harms. EVIDENCE ACQUISITION: The focus of this review was on studies evaluating the effects of the privatization of alcohol retail sales on excessive alcohol consumption and related harms. Using Community Guide methods for conducting systematic reviews, a systematic search was conducted in multiple databases up to December 2010. Reference lists of acquired articles and review papers were also scanned for additional studies. EVIDENCE SYNTHESIS: A total of 17 studies assessed the impact of privatizing retail alcohol sales on the per capita alcohol consumption, a well established proxy for excessive alcohol consumption; 9 of these studies also examined the effects of privatization on the per capita consumption of alcoholic beverages that were not privatized. One cohort study in Finland assessed the impact of privatizing the sales of medium-strength beer (MSB) on self-reported alcohol consumption. One study in Sweden assessed the impact of re-monopolizing the sale of MSB on alcohol-related harms. Across the 17 studies, there was a 44.4% median increase in the per capita sales of privatized beverages in locations that privatized retail alcohol sales (interquartile interval: 4.5% to 122.5%). During the same time period, sales of nonprivatized alcoholic beverages decreased by a median of 2.2% (interquartile interval: -6.6% to -0.1%). Privatizing the sale of MSB in Finland was associated with a mean increase in alcohol consumption of 1.7 liters of pure alcohol per person per year. Re monopolization of the sale of MSB in Sweden was associated with a general reduction in alcohol-related harms. CONCLUSIONS: According to Community Guide rules of evidence, there is strong evidence that privatization of retail alcohol sales leads to increases in excessive alcohol consumption. PMID- 22424257 TI - Recommendations on privatization of alcohol retail sales and prevention of excessive alcohol consumption and related harms. AB - The Community Preventive Services Task Force recommends against privatization of alcohol retail sales in settings with current government control of retail sales, based on strong evidence that privatization results in increased per capita consumption of alcoholic beverages, a well-established proxy for excessive consumption and related harms. PMID- 22424258 TI - Alcohol retail privatization: a commentary. PMID- 22424259 TI - The National Collaborative on Childhood Obesity Research catalogue of surveillance systems and measures registry: new tools to spur innovation and increase productivity in childhood obesity research. PMID- 22424260 TI - Redefining meaningful use: achieving interoperability with immunization registries. PMID- 22424261 TI - Secondary organic aerosol formation from low-NO(x) photooxidation of dodecane: evolution of multigeneration gas-phase chemistry and aerosol composition. AB - The extended photooxidation of and secondary organic aerosol (SOA) formation from dodecane (C(12)H(26)) under low-NO(x) conditions, such that RO(2) + HO(2) chemistry dominates the fate of the peroxy radicals, is studied in the Caltech Environmental Chamber based on simultaneous gas and particle-phase measurements. A mechanism simulation indicates that greater than 67% of the initial carbon ends up as fourth and higher generation products after 10 h of reaction, and simulated trends for seven species are supported by gas-phase measurements. A characteristic set of hydroperoxide gas-phase products are formed under these low NO(x) conditions. Production of semivolatile hydroperoxide species within three generations of chemistry is consistent with observed initial aerosol growth. Continued gas-phase oxidation of these semivolatile species produces multifunctional low volatility compounds. This study elucidates the complex evolution of the gas-phase photooxidation chemistry and subsequent SOA formation through a novel approach comparing molecular level information from a chemical ionization mass spectrometer (CIMS) and high m/z ion fragments from an Aerodyne high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). Combination of these techniques reveals that particle-phase chemistry leading to peroxyhemiacetal formation is the likely mechanism by which these species are incorporated in the particle phase. The current findings are relevant toward understanding atmospheric SOA formation and aging from the "unresolved complex mixture," comprising, in part, long-chain alkanes. PMID- 22424262 TI - The construction of a high-density linkage map for identifying SNP markers that are tightly linked to a nuclear-recessive major gene for male sterility in Cryptomeria japonica D. Don. AB - BACKGROUND: High-density linkage maps facilitate the mapping of target genes and the construction of partial linkage maps around target loci to develop markers for marker-assisted selection (MAS). MAS is quite challenging in conifers because of their large, complex, and poorly-characterized genomes. Our goal was to construct a high-density linkage map to facilitate the identification of markers that are tightly linked to a major recessive male-sterile gene (ms1) for MAS in C. japonica, a species that is important in Japanese afforestation but which causes serious social pollinosis problems. RESULTS: We constructed a high-density saturated genetic linkage map for C. japonica using expressed sequence-derived co dominant single nucleotide polymorphism (SNP) markers, most of which were genotyped using the GoldenGate genotyping assay. A total of 1261 markers were assigned to 11 linkage groups with an observed map length of 1405.2 cM and a mean distance between two adjacent markers of 1.1 cM; the number of linkage groups matched the basic chromosome number in C. japonica. Using this map, we located ms1 on the 9th linkage group and constructed a partial linkage map around the ms1 locus. This enabled us to identify a marker (hrmSNP970_sf) that is closely linked to the ms1 gene, being separated from it by only 0.5 cM. CONCLUSIONS: Using the high-density map, we located the ms1 gene on the 9th linkage group and constructed a partial linkage map around the ms1 locus. The map distance between the ms1 gene and the tightly linked marker was only 0.5 cM. The identification of markers that are tightly linked to the ms1 gene will facilitate the early selection of male-sterile trees, which should expedite C. japonica breeding programs aimed at alleviating pollinosis problems without harming productivity. PMID- 22424263 TI - Peripherally inserted central catheters: a walk down memory lane ... PMID- 22424264 TI - PALLAS: limiting indications for dronedarone treatment of atrial fibrillation? AB - Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated. PMID- 22424265 TI - Unusual heme binding properties of the dissimilative nitrate respiration regulator, a bacterial nitric oxide sensor. AB - AIMS: In the opportunistic pathogen Pseudomonas aeruginosa, nitric oxide (NO) triggers the respiration of nitrate (denitrification), thus allowing survival in chronic infection sites as a microaerobic-anaerobic biofilm. The NO-dependent induction of denitrification is mediated by the dissimilative nitrate respiration regulator (DNR), a transcription factor forming a stable complex with heme, which is required to sense the physiological messenger (i.e., NO). The molecular details of NO sensing in DNR and, more in general, in this class of sensors are largely unknown, and a study aimed at integrating microbiology and biochemistry is needed. RESULTS: Here we present a comprehensive study, including in vivo results and spectroscopy, kinetics, and protein engineering, that demonstrates the direct involvement of a histidine residue in heme iron coordination. Moreover, a peculiar phenomenon of ligand switching around heme iron, which hampers the identification of the second heme axial ligand, is also suggested. These results indicate that DNR is characterized by a remarkable flexibility in solution, as observed for other cAMP receptor protein/fumarate and nitrate reductase regulators (CRP-FNR) to which DNR belongs. INNOVATION: The present work represents one of the few studies focused on the biochemistry of NO sensing by bacterial transcriptional regulators. The data presented demonstrate that structural plasticity of DNR is crucial for the sensing activity and confers to the protein unusual heme binding properties. CONCLUSIONS: Protein flexibility and dynamics is a key structural feature essential to explain the evolutionary success and adaptability of CRP-FNR, and may represent a common strategy employed by heme-based redox sensors, which presents features deeply different from those of canonical hemeproteins. PMID- 22424266 TI - Miniature amperometric self-powered continuous glucose sensor with linear response. AB - Continuous glucose measurement has improved the treatment of type 1 diabetes and is typically provided by externally powered transcutaneous amperometric sensors. Self-powered glucose sensors (SPGSs) could provide an improvement over these conventionally powered devices, especially for fully implanted long-term applications where implanted power sources are problematic. Toward this end, we describe a robust SPGS that may be built from four simple components: (1) a low potential, wired glucose oxidase anode; (2) a Pt/C cathode; (3) an overlying glucose flux-limiting membrane; and (4) a resistor bridging the anode and cathode. In vitro evaluation showed that the sensor output is linear over physiologic glucose concentrations (2-30 mM), even at low O(2) concentrations. Output was independent of the connecting resistor values over the range from 0 to 10 MOmega. The output was also stable over 60 days of continuous in vitro operation at 37 degrees C in 30 mM glucose. A 5-day trial in a volunteer demonstrated that the performance of the device was virtually identical to that of a conventional amperometric sensor. Thus, this SPGS is an attractive alternative to conventionally powered devices, especially for fully implanted long-term applications. PMID- 22424267 TI - A- to B-form transition in DNA between gold surfaces. AB - Molecular dynamics simulations have been performed to characterize the conformation of DNA that is present when DNA links gold nanoparticles to form nanoparticle superlattice crystals. To model the DNA-linked gold nanoparticles, four strands of DNA are used to connect two gold surfaces, with a small interstrand separation and high added salt to match experiment. A-form DNA was assumed for the initial conformation, as this form of DNA has a length per base pair that matches lengths that have been inferred from X-ray measurements. The DNA structure was monitored for 40 ns, and the distributions of the slide and z(p) coordinates were obtained from the simulations. We find that all the double stranded DNA (ds-DNA) strands transform from A- to B-DNA during the simulations. In addition, single-stranded DNAa (ss-DNAs) that are used to connect the ds-DNA to each surface are found to become adsorbed on the gold surfaces during this process, and the ds-DNAs bend (~143 degrees ) at their junctions with the two gold surfaces to accommodate the observed distance between gold surfaces using B form DNA. We infer from this that the short length of DNA between the gold surfaces is not due to the presence of A-DNA. PMID- 22424268 TI - Structure of Co-2 * 2 nanoislands grown on Ag/Ge(111)-?3 * ?3 surface studied by scanning tunneling microscopy. AB - We have found that Co-2 * 2 islands grown on an Ag/Ge(111)-?3 * ?3 surface have hcp structure with the (11-20) orientation. The island evolution involves transformation of the unit cell shape from parallelogram into rectangular, which is accompanied by the island shape transformation from hexagonal into stripe like. Identified are two crystallographic directions for the island growth, the pseudo-[0001] and the pseudo-[1-100]. We have observed the occurrence of a lateral shift between the topmost and the underlying bilayers in the case of the island growth along the pseudo-[0001] direction. In contrast, the topmost and the underlying bilayers are unshifted for the growth along the pseudo-[1-100] direction. PMID- 22424269 TI - Ablative potential of four different pulses of Er:YAG lasers and low-speed hand piece. AB - OBJECTIVE: The aim of the study was to evaluate the ablation rate of caries in dentin with fluorescence-feedback controlled Er:YAG, Variable Square Pulse technology (VSPt) based Er:YAG working in different pulse durations, and steel bur. MATERIALS AND METHODS: Sixty human molar teeth with caries in dentin, extracted for periodontal reasons, were selected for this study. All selected teeth were randomly divided into five groups, each containing twelve specimens: (1) group FFC, fluorescence feedback-controlled Er:YAG laser; (2) group SSP (super short pulse: 50 MUs); (3) group MSP (medium short pulse; 100 MUs); (4) group SP (short pulse; 300 MUs); and (5) group SB, steel bur in a slow-speed hand piece. A profilometer was used to determine the volume of the ablated caries in dentin. The clinical and real ablation rates of caries in dentin were calculated. Two specimens from each experimental group were selected randomly and subjected to SEM examination. RESULTS: The volumes of the ablated caries in dentin in the SSP and SB groups were statistically significantly different in comparison with other experimental groups (p<0.05). The clinical and real ablation rate of caries in dentin was the highest for the SSP group (0.15+/-0.05 and 0.17+/-0.05 mm(3)/sec, respectively) and statistically significantly different in comparison with the MSP and SB groups (p<0.05). The SB and FFC groups revealed a dentin surface with a smear layer and closed dentinal tubules on SEM micrographs. In the SSP, MSP, and SP groups, an irregular surface without a smear layer was found. CONCLUSIONS: Taking into consideration the experimental conditions of the present study, SSP was the most efficient in ablation of caries in dentin, providing a smear layer-free surface with open dentinal tubules. PMID- 22424270 TI - Reactivity of monolayer chemical vapor deposited graphene imperfections studied using scanning electrochemical microscopy. AB - Imperfections that disrupt the sp(2) conjugation of graphene can alter its electrical, chemical, and mechanical properties. Here we report on the examination of monolayer chemical vapor deposited graphene imperfections using scanning electrochemical microscopy in the feedback mode. It was found that the sites with a large concentration of defects are approximately 1 order of magnitude more reactive, compared to more pristine graphene surfaces, toward electrochemical reactions. Furthermore, we successfully passivated the activity of graphene defects by carefully controlling the electropolymerization conditions of o-phenylenediamine. With further electropolymerization, a thin film of the polymer was formed, and it was found to be insulating in nature toward heterogeneous electron transfer processes. The use of spatially resolved scanning electrochemical microscopy for detecting the presence and the "healing" of defects on graphene provides a strategy for in situ characterization and control of this attractive surface, enabling optimization of its properties for application in electronics, sensing, and electrocatalysis. PMID- 22424271 TI - Ethical problems in pediatrics: what does the setting of care and education show us? AB - BACKGROUND: Pediatrics ethics education should enhance medical students' skills to deal with ethical problems that may arise in the different settings of care. This study aimed to analyze the ethical problems experienced by physicians who have medical education and pediatric care responsibilities, and if those problems are associated to their workplace, medical specialty and area of clinical practice. METHODS: A self-applied semi-structured questionnaire was answered by 88 physicians with teaching and pediatric care responsibilities. Content analysis was performed to analyze the qualitative data. Poisson regression was used to explore the association of the categories of ethical problems reported with workplace and professional specialty and activity. RESULTS: 210 ethical problems were reported, grouped into five areas: physician-patient relationship, end-of life care, health professional conducts, socioeconomic issues and health policies, and pediatric teaching. Doctors who worked in hospitals as well as general and subspecialist pediatricians reported fewer ethical problems related to socioeconomic issues and health policies than those who worked in Basic Health Units and who were family doctors. CONCLUSIONS: Some ethical problems are specific to certain settings: those related to end-of-life care are more frequent in the hospital settings and those associated with socioeconomic issues and public health policies are more frequent in Basic Health Units. Other problems are present in all the setting of pediatric care and learning and include ethical problems related to physician-patient relationship, health professional conducts and the pediatric education process. These findings should be taken into consideration when planning the teaching of ethics in pediatrics. TRIAL REGISTRATION: This research article didn't reports the results of a controlled health care intervention. The study project was approved by the Institutional Ethical Review Committee (Report CEP-HIJG 032/2008). PMID- 22424272 TI - Absolute configuration and 1H NMR characterization of rosmaridiphenol diacetate. AB - The correction of patented structure 1 of rosmaridiphenol, an antioxidant isolated from rosemary, Rosmarinus officinalis, was made recently. The correct structure is proposed as 11,12-dihydroxy-8,11,13-icetexatrien-1-one (2a) based on 2D NMR data. In order to further support the structure, this work reports the single-crystal X-ray analysis, the complete (1)H NMR assignment by full spin-spin simulation, and the absolute configuration of the diacetate 2b derived via vibrational circular dicroism measurements in comparison with density functional theory calculated data. PMID- 22424273 TI - From olefination to alkylation: in-situ halogenation of Julia-Kocienski intermediates leading to formal nucleophilic iodo- and bromodifluoromethylation of carbonyl compounds. AB - Iodo- and bromodifluoromethylated compounds are important synthetic intermediates and halogen-bond acceptors. However, direct introduction of -CF(2)I and -CF(2)Br groups through nucleophilic addition is particularly challenging because of the high tendency of decomposition of CF(2)Br(-) and CF(2)I(-) to difluorocarbene. In this work, we have developed a formal nucleophilic iodo- and bromodifluoromethylation for carbonyl compounds. The key strategy of the method is the halogenation of in situ-generated sulfinate intermediates from the Julia Kocienski reaction to change the reaction pathway from the traditional olefination to alkylation. Interesting halogen-pi interactions between the halocarbon and aromatic donors were observed in the crystal structures of the products. The method could also be extended to the introduction of other fluorinated groups, such as -CFClBr, -CFClI, -CFBr(2), and -CFMeI, which opens up new avenues for the synthesis of a wide range of useful fluorinated products. PMID- 22424274 TI - Ammunition identification by means of the organic analysis of gunshot residues using Raman spectroscopy. AB - The ability to unequivocally identify a gunshot residue (GSR) when a firearm is discharged is a very important and crucial part of crime scene investigation. To date, the great majority of the analyses have focused on the inorganic components of GSR, but the introduction of "lead-free" or "nontoxic" ammunitions makes it difficult to prevent false negatives. This study introduces a fast methodology for the organic analysis of GSR using Raman spectroscopy. Six different types of ammunition were fired at short distances into cloth targets, and the Raman spectra produced by the GSR were measured and compared with the spectra from the unfired gunpowder ammunition. The GSR spectrum shows high similarity to the spectrum of the unfired ammunition, allowing the GSR to be traced to the ammunition used. Additionally, other substances that might be found on the victim's, shooter's, or suspect's clothes and might be confused with GSR, such as sand, dried blood, or black ink from a common ballpoint pen, were analyzed to test the screening capability of the Raman technique. The results obtained evidenced that Raman spectroscopy is a useful screening tool when fast analysis is desired and that little sample preparation is required for the analysis of GSR evidence. PMID- 22424275 TI - Experimental fingerprints for redox-active terpyridine in [Cr(tpy)2](PF6)n (n = 3 0), and the remarkable electronic structure of [Cr(tpy)2]1-. AB - The molecular and electronic structures of the four members, [Cr(tpy)(2)](PF(6))(n) (n = 3-0; complexes 1-4; tpy = 2,2':6',2"-terpyridine), of the electron transfer series [Cr(tpy)(2)](n+) have been determined experimentally by single-crystal X-ray crystallography, by their electro- and magnetochemistry, and by the following spectroscopies: electronic absorption, X-ray absorption (XAS), and electron paramagnetic resonance (EPR). The monoanion of this series, [Cr(tpy)(2)](1-), has been prepared in situ by reduction with KC(8) and its EPR spectrum recorded. The structures of 2, 3, 4, 5, and 6, where the latter two compounds are the Mo and W analogues of neutral 4, have been determined at 100(2) K. The optimized geometries of 1-6 have been obtained from density functional theoretical (DFT) calculations using the B3LYP functional. The XAS and low-energy region of the electronic spectra have also been calculated using time-dependent (TD)-DFT. A consistent picture of the electronic structures of these octahedral complexes has been established. All one-electron transfer processes on going from 1 to 4 are ligand-based: 1 is [Cr(III)(tpy(0))(2)](PF(6))(3) (S = (3)/(2)), 2 is [Cr(III)(tpy(*))(tpy(0))](PF(6))(2) (S = 1), 3 is [Cr(III)(tpy(*))(2)](PF(6)) (S = (1)/(2)), and 4 is [Cr(III)(tpy(**))(tpy(*))](0) (S = 0), where (tpy(0)) is the neutral parent ligand, (tpy(*))(1-) represents its one-electron-reduced pi radical monoanion, (tpy(2-))(2-) or (tpy(**))(2-) is the corresponding singlet or triplet dianion, and (tpy(3-))(3-) (S = (1)/(2)) is the trianion. The electronic structure of 2 cannot be described as [Cr(II)(tpy(0))(2)](PF(6))(2) (a low-spin Cr(II) (d(4); S = 1) complex). The geometrical features (C-C and C-N bond lengths) of these coordinated ligands have been elucidated computationally in the following hypothetical species: [Zn(II)Cl(2)(tpy(0))](0) (S = 0) (A), [Zn(II)(tpy(*))Cl(NH(3))](0) (S = (1)/(2)) (B), [Zn(II)(tpy(2-))(NH(3))(2)](0) (S = 0 or 1) (C), and [Al(III)(tpy(3-))(NH(3))(3)](0) (S = (1)/(2) and (3)/(2)) (D). The remarkable electronic structure of the monoanion has been calculated and experimentally verified by EPR spectroscopy to be [Cr(III)(tpy(2-))(tpy(**))](1-) (S = (1)/(2)), a complex in which the two dianionic tpy ligands differ only in the spin state. It has been clearly established that coordinated tpy ligands are redox-active and can exist in at least four oxidation levels. PMID- 22424277 TI - Site-specific immobilization of enzymes on magnetic nanoparticles and their use in organic synthesis. AB - Magnetic nanoparticles (MNPs) are attractive materials that serve as a support for enzyme immobilization and facilitate separations by applying an external magnetic field; this could facilitate the recycling of enzymes and broaden their applications in organic synthesis. Herein, we report the methods for the immobilization of water-soluble and membrane-bound enzymes, and the activity difference between free and immobilized enzymes is discussed. Sialyltransferase (PmST1, from Pasteurella multocida ) and cytidine monophosphate (CMP)-sialic acid synthetase (CSS, from Neisseria meningitides ) were chosen as water-soluble enzymes and expressed using an intein expression system. The enzymes were site specifically and covalently immobilized on PEGylated-N-terminal cysteine MNPs through native chemical ligation (NCL). Increasing the length of the PEG linker between the enzyme and the MNP surface increased the activity of the immobilized enzymes relative to the free parent enzymes. In addition, the use of a fluorescent acceptor tag for PmST1 affected enzyme kinetics. In contrast, sialyltransferase from Neisseria gonorrheae (NgST, a membrane-bound enzyme) was modified with a biotin-labeled cysteine at the C-terminus using NCL, and the enzyme was then assembled on streptavidin-functionalized MNPs. Using a streptavidin-biotin interaction, it was possible to immobilize NgST on a solid support under mild ligation conditions, which prevented the enzyme from high temperature decomposition and provided an approximately 2-fold increase in activity compared to other immobilization methods on MNPs. Finally, the ganglioside GM3-derivative (sialyl-lactose derivative) was synthesized in a one pot system by combining the use of immobilized PmST1 and CSS. The enzymes retained 50% activity after being reused ten times. Furthermore, the results obtained using the one-pot two-immobilized-enzyme system demonstrated that it can be applied to large-scale reactions with acceptable yields and purity. These features make enzyme-immobilized MNPs applicable to organic synthesis. PMID- 22424278 TI - EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. PMID- 22424279 TI - In vitro percutaneous absorption enhancement of granisetron by chemical penetration enhancers. AB - Granisetron (GRN), a potent antiemetic agent, is frequently used to prevent nausea and vomiting induced by cancer cytotoxic chemotherapy and radiation therapy. OBJECTIVE: As part of our efforts to further modify the physicochemical properties of this market drug, with the ultimate goal to formulate a better dosage form for GRN, this work was carried out to improve its permeability in vitro. METHODS: The permeation behavior of GRN in isopropyl myristate (IPM) was investigated across excised rabbit abdominal skin and the enhancing activities of three novel O-acylmenthol derivatives synthesized in our laboratory as well as five well-known chemical enhancers were evaluated. RESULTS: It was found that the steady-state flux of granisetron free base (GRN-B) was about 26-fold higher than that of granisetron hydrochloride (GRN-H). The novel enhancer, 2-isopropyl-5 methylcyclohexyl heptanoate (M-HEP), was observed to provide the most significant enhancement for the absorption of GRN-B. When incorporated in the donor solution with the optimal enhancer M-HEP, the steady-state flux of GRN-B increased from (196.44 +/- 12.03) MUg.cm-2.h-1 to (1044.95 +/- 71.99) MUg.cm-2.h-1 (P < 0.01). CONCLUSION: These findings indicated that the application of chemical enhancers was an effective approach to increase the percutaneous absorption of GRN in vitro. PMID- 22424280 TI - Transcriptome analysis reveals the time of the fourth round of genome duplication in common carp (Cyprinus carpio). AB - BACKGROUND: Common carp (Cyprinus carpio) is thought to have undergone one extra round of genome duplication compared to zebrafish. Transcriptome analysis has been used to study the existence and timing of genome duplication in species for which genome sequences are incomplete. Large-scale transcriptome data for the common carp genome should help reveal the timing of the additional duplication event. RESULTS: We have sequenced the transcriptome of common carp using 454 pyrosequencing. After assembling the 454 contigs and the published common carp sequences together, we obtained 49,669 contigs and identified genes using homology searches and an ab initio method. We identified 4,651 orthologous pairs between common carp and zebrafish and found 129,984 paralogous pairs within the common carp. An estimation of the synonymous substitution rate in the orthologous pairs indicated that common carp and zebrafish diverged 120 million years ago (MYA). We identified one round of genome duplication in common carp and estimated that it had occurred 5.6 to 11.3 MYA. In zebrafish, no genome duplication event after speciation was observed, suggesting that, compared to zebrafish, common carp had undergone an additional genome duplication event. We annotated the common carp contigs with Gene Ontology terms and KEGG pathways. Compared with zebrafish gene annotations, we found that a set of biological processes and pathways were enriched in common carp. CONCLUSIONS: The assembled contigs helped us to estimate the time of the fourth-round of genome duplication in common carp. The resource that we have built as part of this study will help advance functional genomics and genome annotation studies in the future. PMID- 22424281 TI - Management of patients with refractory angina: Canadian Cardiovascular Society/Canadian Pain Society joint guidelines. AB - Refractory angina (RFA) is a debilitating disease characterized by cardiac pain resistant to conventional treatments for coronary artery disease including nitrates, calcium-channel and beta-adrenoceptor blockade, vasculoprotective agents, percutaneous coronary interventions, and coronary artery bypass grafting. The mortality rate of patients living with RFA is not known but is thought to be in the range of approximately 3%. These individuals suffer severely impaired health-related quality of life with recurrent and sustained pain, poor general health status, psychological distress, impaired role functioning, and activity restriction. Effective care for RFA sufferers in Canada is critically underdeveloped. These guidelines are predicated upon a 2009 Canadian Cardiovascular Society (CCS) Position Statement which identified that underlying the problem of RFA management is the lack of a formalized, coordinated, interprofessional strategy between the cardiovascular and pain science/clinical communities. The guidelines are therefore a joint initiative of the CCS and the Canadian Pain Society (CPS) and make practice recommendations about treatment options for RFA that are based on the best available evidence. Concluding summary recommendations are also made, giving direction to future clinical practice and research on RFA management in Canada. PMID- 22424282 TI - Cardiac syndrome X: mystery continues. PMID- 22424283 TI - Women, cardiac syndrome X, and microvascular heart disease. AB - New data suggest that persistent chest pain, despite normal coronary angiography, is less benign than previously thought. It has long been recognized that cardiac syndrome X (CSX) is associated with significant suffering, disability, and health care costs, but the biggest shift in thinking comes in terms of long-term risk. It is now recognized that the prognosis is not benign and that a significant proportion of patients are at increased cardiovascular disease risk. Of major debate is the question of whether the mechanisms that explain this chest pain are cardiac vs noncardiac. The most current definition of CSX is the triad of angina, ischemia, and normal coronary arteries, which is associated with an increased cardiovascular risk. This paper provides a review of CSX, epidemiology of the problem, proposed explanatory mechanisms, and important next steps in research. Central to this review is the proposition that new insights into CSX will be fostered by both clinical and scientific collaboration between cardiovascular and pain scientists. PMID- 22424284 TI - Patients with coronary artery disease unsuitable for revascularization: definition, general principles, and a classification. AB - In the present report, we review the phenotypes of coronary artery disease (CAD) patients unsuitable for revascularization procedures. We then analyze these phenotypes and propose a simple angiographic-based classification for patients with CAD unsuitable for revascularization. Under this classification, the following four distinct angiographic phenotypes are proposed: (1) suspected cardiac syndrome X; (2) limited territory at risk; (3) diffuse thread-like coronary atherosclerosis; and (4) end-stage CAD. It is hoped that such a classification system, as well as the general principles described in this report, will help to standardize the collection of epidemiological data on patients with refractory angina (RFA) and advanced CAD. It is also hoped that this system will be useful to extend the principles of clinical equipoise to the development of clinical trials of innovative therapies or devices for the treatment of RFA. Finally, we anticipate that the elaboration of this system, the first of its type in the literature, will stimulate discussion of what we feel to be a subject that has received insufficient attention in the literature, and ultimately to improved management of a challenging patient population. PMID- 22424285 TI - Nonischemic chest pain following successful percutaneous coronary intervention at a regional referral centre in southern Ontario. AB - BACKGROUND: The purpose of this study was to identify factors that predispose individuals to nonischemic chest pain following successful percutaneous coronary intervention (PCI). METHODS: We prospectively followed, for 6 months, a cohort of 110 patients who underwent PCI. We determined baseline factors associated with post PCI pain via nonlinear mixed model regression; a binomial distribution with logit link was used. RESULTS: The mean age of participants (n = 110) was 64 (SD +/- 11.19), 69% were male. The majority had 1 coronary vessel dilated (88%) and a single stent placement (67%). During follow-up, chest pain was prevalent in 54% (95% confidence interval [CI], 44.8-63.7) and 45% (95% CI, 36.0-54.8) of patients, at 3 and 6 months respectively. Less than half of those with chest pain were evaluated for ischemia. Of those evaluated, tests were negative for the majority; 74% and 61% at 3 and 6 months respectively. Higher baseline depression (odds ratio 1.50; 95% CI, 1.13-1.99) scores (Hospital Anxiety Depression Scale) were significantly associated with nonischemic chest pain during follow-up. CONCLUSION: Higher baseline depression scores were found to be significant risk factors for chest pain of nonischemic origin following successful PCI. A larger study is needed to confirm the predictive value of this and other factors that may contribute to this elusive pain problem. Further research is also required to develop pain management strategies for patients whose chest pain persists in the absence of discernible ischemic causes. PMID- 22424286 TI - From heart to brain: the genesis and processing of cardiac pain. AB - Angina pectoris is important because of its association with heart disease and risk of death. Historically after Heberden's account of angina in 1772, the association of pain with coronary artery disease quickly followed. Within a few years, Burns suggested an etiological role for ischemia. Subsequently, theories of differential myocardial stretch dominated thinking until Lewis' chemical hypothesis in 1932, in which the local release of chemical substances during ischemia was seen as the cause of pain. This review considers how ischemia at the tissue level triggers activation of afferent nociceptive pain fibres. The afferent projections of sympathetic and vagal afferent fibres are described, with a number of methodologies cited (eg, injection of pseudorabies virus into the heart with mapping of the retrograde viral transport pathways; and elevation of neuronal c-fos synthesis in brain regions activated by capsaicin application to the heart). Our own functional neuroimaging studies of angina are also reviewed. There are 2 intriguing features of angina. The first is the poor correlation between symptoms and extent of coronary disease. The spectrum ranges from entirely silent myocardial ischemia to that of a functional pain syndrome--the 'sensitive heart'--of cardiac syndrome X. An even more difficult aspect is the wide variability in symptoms experienced by an individual patient. A new paradigm is presented which, besides considering myocardial oxygen supply/demand imbalance, also draws insights from the broader field of pain research. Neuromodulation applies at multiple levels of the neuraxis--peripheral nerves, spinal cord, and brain--and it invites exploitation, whether pharmacological or electrical, for the benefit of the cardiac patient in pain. PMID- 22424287 TI - Stable angina pectoris: the medical management of symptomatic myocardial ischemia. AB - Coronary artery disease (CAD) remains an important cause of morbidity and mortality and is a serious public health problem. Over the last 4 decades there have been dramatic advances in the both the prevention and treatment of CAD. The management of CAD was revolutionized by the development of effective surgical and percutaneous revascularization techniques. In this review we discuss the importance of the medical management of symptomatic, stable angina. Medical management approaches to both the treatment and prevention of symptomatic myocardial ischemia are summarized. In Canada, organic nitrates, beta-adrenergic blocking agents, and calcium channel antagonists have been available for the therapy of angina for more than 25 years. All 3 classes are of proven benefit in the improvement of symptoms and exercise capacity in patients with stable angina. Although there is no clear first choice within these classes of anti-anginal agents, the presence of prior or concurrent conditions (for example, prior myocardial infarction and/or hypertension) plays an important role in the choice of anti-anginal class in individual patients. For some patients, combinations of different anti-anginal agents can be effective; however it is recommended that this approach be individualized. Although not currently available in Canada, other classes of anti-anginal agents have been developed; their mechanism of action and clinical efficacy is discussed. Patients with stable angina have an excellent prognosis. Patients in this category who obtain relief from symptomatic myocardial ischemia may do well without invasive intervention. PMID- 22424288 TI - Social reward and rejection sensitivity in eating disorders: an investigation of attentional bias and early experiences. AB - OBJECTIVES: People with eating disorders (EDs) have difficulties with social functioning. One explanatory mechanism is a problem with over-sensitivity to rejection and/or low sensitivity to social reward. The aim of this study is to investigate attentional bias to facial stimuli in people with a lifetime diagnosis of EDs and healthy controls (HCs) and to test whether these attentional biases are linked to adverse early experiences. METHODS: Forty-six participants with a current diagnosis of EDs (29 with anorexia nervosa (AN) and 17 with bulimia nervosa (BN)), 22 participants recovered from an eating disorder (13 with past AN and nine with past BN) and 50 HCs completed a dot-probe task with faces expressing rejection and acceptance. Participants reported on parental style and adverse early experiences. RESULTS: People with a lifetime diagnosis of EDs show an attentional bias to rejecting faces and a difficulty disengaging attention from these stimuli. Also, they had a sustained attentional avoidance of accepting faces. HCs demonstrated the opposite attentional pattern. The attentional bias to rejection was correlated with adverse childhood experiences. CONCLUSIONS: People with an EDs show vigilance to rejection and avoidance of social reward. This may contribute to the causation or maintenance of the illness. PMID- 22424289 TI - Efficient electroformation of supergiant unilamellar vesicles containing cationic lipids on ITO-coated electrodes. AB - Giant unilamellar vesicles (GUVs) represent a versatile in vitro system widely used to study properties of lipid membranes and their interaction with biomacromolecules and colloids. Electroformation with indium tin oxide (ITO) coated coverslips as electrodes is a standard approach to GUV production. In the case of cationic GUVs, however, application of this approach leads to notorious difficulties. We discover that this is related to aging of ITO-coated coverslips during their repeated use, which is reflected in their surface topography on the nanoscale. We find that mild annealing of the ITO-coated surface in air reverts the effects of aging and ensures efficient reproducible electroformation of supergiant (diameter > 100 MUm) unilamellar vesicles containing cationic lipids. PMID- 22424290 TI - Everyday life for users of electric wheelchairs - a qualitative interview study. AB - PURPOSE: The aim of this paper is to explore how users of electric wheelchairs experience their everyday life and how their electric wheelchairs influence their daily occupation. Occupation is defined as a personalized dynamic interaction between person, task and environment, and implies the value and meaning attached. METHOD: Nine semi-structured interviews were conducted with experienced electric wheelchair users. ValMo was used as the theoretical framework for both interviewing and the analysis. The transcribed interviews were analysed using thematic analysis. RESULTS: Findings revealed key elements in electric wheelchair users' experience of how the use of a wheelchair influences everyday life and occupation. Four central themes emerged from the participants' experiences 1) The functionality of the wheelchair, 2) The wheelchair as an extension of the body, 3) The wheelchair and social life, and 4) The wheelchair and identity issues. The themes were interrelated and show how all levels of occupation were influenced both in a positive and negative way, and how it affected identity. CONCLUSIONS: It is essential that professionals working with electric wheelchair users are aware of how all levels of occupation and identity are influenced by using a wheelchair. This will assist professionals in supporting the users living an autonomous and meaningful life. PMID- 22424291 TI - GCS overexpression is associated with multidrug resistance of human HCT-8 colon cancer cells. AB - PURPOSE: Multidrug resistance is one of the main impediments to the successful treatment of colon cancer. Glucosylceramide synthase (GCS) which is related to multidrug resistance (MDR) can reduce the level of ceramide and can help cells escape from the ceramide-induced cell apoptosis. However, the underlying mechanism is still unclear. METHODS: The cell proliferation and cell toxicity were measured with Cell Counting Kit-8 (CCK-8). The mRNA levels of GCS and MDR1 were detected by semiquantitative reverse transcription-PCR amplification, the protein levels of GCS, caspase-3 and P-gp proteins were indicated by Western blotting. The apoptosis rates of cells were measured with flow cytometry. RESULTS: The relative mRNA levels of GCS in HCT-8, HCT-8/VCR, HCT-8/VCR- sh-mock and HCT-8/VCR-sh-GCS were 71.4 +/- 1.1%, 95.1 +/- 1.2%, 98.2 +/- 1.5%, and 66.6 +/- 2.1% respectively. The mRNA levels of MDR1 were respectively 61.3 +/- 1.1%, 90.5 +/- 1.4%, 97.6 +/- 2.2% and 56.1 +/- 1.2%. The IC50 of Cisplatin complexes were respectively 69.070 +/- 0.253 MUg/ml, 312.050 +/- 1.46 MUg/ml, 328.741 +/- 5.648 MUg/ml, 150.792 +/- 0.967 MUg/ml in HCT-8, HCT-8/VCR, HCT-8/VCR-sh-mock and HCT-8/VCR-sh-GCS. The protein levels of caspase-3 were 34.2 +/- o.6%, 93.0 +/- 0.7%, 109.09 +/- 0.7%, 42.7 +/- 1.3% respectively. The apoptosis rates of cells were 8.77 +/- 0.14%, 12.75 +/- 0.54%, 15.39 +/- 0.41% and 8.49 +/- 0.23% respectively. CONCLUSION: In conclusion, our research indicated that suppression of GCS restores the sensitivity of multidrug resistance colon cancer cells to drug treatment. PMID- 22424292 TI - Coronary versus carotid blood flow and coronary perfusion pressure in a pig model of prolonged cardiac arrest treated by different modes of venoarterial ECMO and intraaortic balloon counterpulsation. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is increasingly used in cardiac arrest (CA). Adequacy of carotid and coronary blood flows (CaBF, CoBF) and coronary perfusion pressure (CoPP) in ECMO treated CA is not well established. This study compares femoro-femoral (FF) to femoro-subclavian (FS) ECMO and intraaortic balloon counterpulsation (IABP) contribution based on CaBF, CoBF, CoPP, myocardial and brain oxygenation in experimental CA managed by ECMO. METHODS: In 11 female pigs (50.3 +/- 3.4 kg), CA was randomly treated by FF versus FS ECMO +/- IABP. Animals under general anesthesia had undergone 15 minutes of ventricular fibrillation (VF) with ECMO flow of 5 to 10 mL/kg/min simulating low-flow CA followed by continued VF with ECMO flow of 100 mL/kg/min. CaBF and CoBF were measured by a Doppler flow wire, cerebral and peripheral oxygenation by near infrared spectroscopy. CoPP, myocardial oxygen metabolism and resuscitability were determined. RESULTS: CaBF reached values > 80% of baseline in all regimens. CoBF > 80% was reached only by the FF ECMO, 90.0% (66.1, 98.6). Addition of IABP to FF ECMO decreased CoBF to 60.7% (55.1, 86.2) of baseline, P = 0.004. FS ECMO produced 70.0% (49.1, 113.2) of baseline CoBF, significantly lower than FF, P = 0.039. Addition of IABP to FS did not change the CoBF; however, it provided significantly higher flow, 76.7% (71.9, 111.2) of baseline, compared to FF + IABP, P = 0.026. Both brain and peripheral regional oxygen saturations decreased after induction of CA to 23% (15.0, 32.3) and 34% (23.5, 34.0), respectively, and normalized after ECMO institution. For brain saturations, all regimens reached values exceeding 80% of baseline, none of the comparisons between respective treatment approaches differed significantly. After a decline to 15 mmHg (9.5, 20.8) during CA, CoPP gradually rose with time to 68 mmHg (43.3, 84.0), P = 0 .003, with best recovery on FF ECMO. Resuscitability of the animals was high, both 5 and 60 minutes return of spontaneous circulation occured in eight animals (73%). CONCLUSIONS: In a pig model of CA, both FF and FS ECMO assure adequate brain perfusion and oxygenation. FF ECMO offers better CoBF than FS ECMO. Addition of IABP to FF ECMO worsens CoBF. FF ECMO, more than FS ECMO, increases CoPP over time. PMID- 22424293 TI - Novel chelators for cancer treatment: where are we now? AB - SIGNIFICANCE: Under normal circumstances, cellular iron levels are tightly regulated due to the potential toxic effects of this metal ion. There is evidence that tumors possess altered iron homeostasis, which is mediated by the perturbed expression of iron-related proteins, for example, transferrin receptor 1, ferritin and ferroportin 1. The de-regulation of iron homeostasis in cancer cells reveals a particular vulnerability to iron-depletion using iron chelators. In this review, we examine the absorption of iron from the gut; its transport, metabolism, and homeostasis in mammals; and the molecular pathways involved. Additionally, evidence for alterations in iron processing in cancer are described along with the perturbations in other biologically important transition metal ions, for example, copper(II) and zinc(II). These changes can be therapeutically manipulated by the use of novel chelators that have recently been shown to be highly effective in terms of inhibiting tumor growth. RECENT ADVANCES: Such chelators include those of the thiosemicarbazone class that were originally thought to target only ribonucleotide reductase, but are now known to have multiple effects, including the generation of cytotoxic radicals. CRITICAL ISSUES: Several chelators have shown marked anti-tumor activity in vivo against a variety of solid tumors. An important aspect is the toxicology and the efficacy of these agents in clinical trials. FUTURE DIRECTIONS: As part of the process of the clinical assessment of the new chelators, an extensive toxicological assessment in multiple animal models is essential for designing appropriate dosing protocols in humans. PMID- 22424294 TI - Leukotrienes inhibit early stages of HIV-1 infection in monocyte-derived microglia-like cells. AB - BACKGROUND: Microglia are one of the main cell types to be productively infected by HIV-1 in the central nervous system (CNS). Leukotriene B4 (LTB4) and cysteinyl leukotrienes such as LTC4 are some of the proinflammatory molecules produced in infected individuals that contribute to neuroinflammation. We therefore sought to investigate the role of leukotrienes (LTs) in HIV-1 infection of microglial cells. METHODS: To evaluate the role of LTs on HIV-1 infection in the CNS, monocyte-derived microglial-like cells (MDMis) were utilized in this study. Leukotriene-treated MDMis were infected with either fully replicative brain derived HIV-1 isolates (YU2) or R5-tropic luciferase-encoding particles in order to assess viral production and expression. The efficacy of various steps of the replication cycle was evaluated by means of p24 quantification by ELISA, luciferase activity determination and quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: We report in this study that virus replication is reduced upon treatment of MDMis with LTB4 and LTC4. Additional experiments indicate that these proinflammatory molecules alter the pH-independent entry and early post-fusion events of the viral life cycle. Indeed, LT treatment induced a diminution in integrated proviral DNA while reverse-transcribed viral products remained unaffected. Furthermore, decreased C-C chemokine receptor type 5 (CCR5) surface expression was observed in LT-treated MDMis. Finally, the effect of LTs on HIV-1 infection in MDMis appears to be mediated partly via a signal transduction pathway involving protein kinase C. CONCLUSIONS: These data show for the first time that LTs influence microglial cell infection by HIV-1, and may be a factor in the control of viral load in the CNS. PMID- 22424295 TI - Carbonization in polyacrylonitrile (PAN) based carbon fibers studied by ReaxFF molecular dynamics simulations. AB - The carbonization mechanism in polyacrylonitrile (PAN) based carbon nanofibers is studied using ReaxFF molecular dynamics simulations. Simulations are performed at two carbonization temperatures, 2500 and 2800 K, and also at two densities, 1.6 and 2.1 g/cm(3), that are relevant to the experimental carbonization conditions. The results are analyzed by examining the evolution of species with time, including carbon-only ring structures and gaseous species. Formation mechanisms are proposed for species like N(2), H(2), NH(3), and HCN and five-, six-, and seven-membered carbon-only rings, along with polycyclic structures. Interestingly, the formation of five-membered rings follows N(2) formation and usually occurs as a precursor to six-membered rings. Elimination mechanisms for the gaseous molecules are found that are in agreement with previously proposed mechanisms; however, alternative mechanisms are also proposed. PMID- 22424296 TI - The impact of perceived self-efficacy on memory for aversive experiences. AB - Self-efficacy is a key construct underlying healthy functioning and emotional well-being. Perceptions of uncontrollability, unpredictability, and low self efficacy are consistently associated with negative mental health outcomes, such as post-traumatic stress disorder (PTSD). To test the causal relation between perceived coping self-efficacy and stress responses we employed a trauma film paradigm in which college students (N=33) viewed a graphic film of the aftermath of a motor vehicle accident following a high (HSE) or low self-efficacy (LSE) induction. Participants were tested for intrusions, distress, and memory recall for the film over the following 24 hours. LSE participants recalled more central details than HSE participants. Further, HSE participants reported fewer negative intrusions immediately following the film and at 24 hours. These findings suggest that strategies that increase perceived coping self-efficacy may reduce intrusive recollections of an aversive event, and also reduce the attentional bias associated with remembering aversive stimuli. PMID- 22424297 TI - Update on the epidemiology and management of cryptococcal meningitis. AB - Despite recent improvements in the diagnosis and treatment of cryptococcosis, cryptococcal meningitis is responsible for > 600,000 deaths/year worldwide. The aim of this work is to provide an update on the developments in its epidemiology and management. Understanding the pathogenesis of Cryptococcus has improved, and new insights for the virulence of the fungus and the host response have enabled scientists to design new ways to confront this infection. Additionally, invertebrate model hosts have greatly facilitated the research in this field. Importantly, the epidemiology of Cryptococcus gattii has continued to evolve, and the emergence of this highly virulent species in immunocompetent populations, especially in Northwestern America and British Columbia, warrants increased awareness because delayed diagnosis and inappropriate antifungal therapy is associated with high mortality. Diagnosis remains a challenge, but new techniques for early and inexpensive identification of the pathogen are under development. Management can vary, based on the patient population (HIV-seropositive, organ transplant recipients or non-transplant/non-HIV). In most patients, amphotericin B with flucytosine continues to be the most appropriate induction therapy. However, in organ transplant recipients the use of liposomal amphotericin B improves mortality compared with deoxycholate amphotericin B. Also, the combination of amphotericin B with fluconazole seems to be a reasonable alternative, while fluconazole with flucytosine is superior to fluconazole monotherapy. PMID- 22424298 TI - Microfluidic flow cytometer for quantifying photobleaching of fluorescent proteins in cells. AB - Traditional flow cytometers are capable of rapid cellular assays on the basis of fluorescence intensity and light scatter. Microfluidic flow cytometers have largely followed the same path of technological development as their traditional counterparts; however, the significantly smaller transport distance and resulting lower cell speeds in microchannels provides for the opportunity to detect novel spectroscopic signatures based on multiple, nontemporally coincident excitation beams. Here, we characterize the design and operation of a cytometer with a three beam, probe/bleach/probe geometry, employing HeLa suspension cells expressing fluorescent proteins. The data collection rate exceeds 20 cells/s under a range of beam intensities (5 kW to 179 kW/cm(2)). The measured percent photobleaching (ratio of fluorescence intensities excited by the first and third beams: S(beam3)/S(beam1)) partially resolves a mixture of four red fluorescent proteins in mixed samples. Photokinetic simulations are presented and demonstrate that the percent photobleaching reflects a combination of the reversible and irreversible photobleaching kinetics. By introducing a photobleaching optical signature, which complements traditional fluorescence intensity-based detection, this method adds another dimension to multichannel fluorescence cytometry and provides a means for flow-cytometry-based screening of directed libraries of fluorescent protein photobleaching. PMID- 22424299 TI - Generalized synthesis of hybrid metal-semiconductor nanostructures tunable from the visible to the infrared. AB - Hybrid superstructures allow a convenient route to the development of materials with multiple functionalities (e.g., sensor, marker, conductor) out of monofunctional (e.g., excitonic, plasmonic) building blocks. This work describes a general synthetic route to the preparation of metal|dielectric|quantum dot hybrid superstructures that have excitonic and plasmonic resonances independently tunable from the ultraviolet to the mid-infrared spectral region. We demonstrate that structural tuning can be used to control intercomponent coupling leading to the emergence of unique optical properties. We illustrate this capability by demonstrating single- and multicolor emission from coupled systems, and a significant enhancement of two-photon absorption cross sections of quantum dots. Such properties in a robust yet dispersible particle can be useful in a number of applications including bioimaging and microscopy, and in optoelectronic devices, as well as serve as a platform for fundamental studies of metal-semiconductor interactions. PMID- 22424300 TI - Polyhydroxylated macrolides from Seimatosporium discosioides and their effects on the activation of peroxisome proliferator-activated receptor gamma. AB - Two new polyhydroxylated macrolides, seimatopolides A (1) and B (2), were isolated from an EtOAc extract of Seimatosporium discosioides culture medium. The structures of the new compounds were established on the basis of spectroscopic analysis, including 1D and 2D NMR, and their absolute configurations were determined using the modified Mosher's method. Seimatopolides A (1) and B (2) activated peroxisome proliferator-activated receptor (PPAR)-gamma with EC(50) values of 1.15 and 11.05 MUM, respectively. The expression of PPAR-gamma target genes in HepG2 hepatocytes was significantly altered; in particular, expression of the gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was reduced upon stimulation with 1, supporting the proposal that compound 1 is both a PPAR-gamma agonist and a possible therapeutic candidate for treatment of diabetes. PMID- 22424301 TI - Analytic calculation of isotropic hyperfine structure constants using the normalized elimination of the small component formalism. AB - Based on the normalized elimination of the small component relativistic formalism, a new approach to the calculation of hyperfine structure parameters of paramagnetic molecules is developed and implemented. The new method is tested in the calculation of the isotropic hyperfine structure constant for a series of open-shell molecules containing mercury. The results of calculations carried out in connection with ab initio methods of increasing complexity demonstrate the high accuracy of the formalism developed. In view of its computational simplicity, the new approach provides the basis for an efficient and accurate calculation of the HFS parameters of large molecules. PMID- 22424302 TI - Structural insights into the ferroxidase site of ferritins from higher eukaryotes. AB - The first step of iron biomineralization mediated by ferritin is the oxidation at the ferroxidase active site of two ferrous ions to a diferric oxo/hydroxo species. Metal-loaded ferritin crystals obtained by soaking crystals of frog ferritin in FeSO(4) and CuSO(4) solutions followed by flash freezing provided X ray crystal structures of the tripositive iron and bipositive copper adducts at 2.7 and 2.8 A resolution, respectively. At variance with the already available structures, the crystal form used in this study contains 24 independent subunits in the asymmetric unit permitting comparison between them. For the first time, the diferric species at the ferroxidase site is identified in ferritins from higher eukaryotes. Anomalous difference Fourier maps for crystals (iron crystal 1) obtained after long soaking times in FeSO(4) solution invariantly showed diferric species with a Fe-Fe average distance of 3.1 +/- 0.1 A, strongly indicative of the presence of a MU-oxo/hydroxo bridge between the irons; protein ligands for each iron ion (Fe1 and Fe2) were also unequivocally identified and found to be the same in all subunits. For copper bound ferritin, dicopper(II) centers are also observed. While copper at site 1 is essentially in the same position and has the same coordination environment as Fe1, copper at site 2 is displaced toward His54, now acting as a ligand; this results in an increased intermetal distance (4.3 +/- 0.4 A). His54 coordination and longer metal-metal distances might represent peculiar features of divalent cations at the ferroxidase site. This oxidation-dependent structural information may provide key features for the mechanistic pathway in ferritins from higher eukaryotes that drive uptake of bivalent cation and release of ferric products at the catalytic site. This mechanism is supported by the X-ray picture obtained after only 1 min of soaking in FeSO(4) solutions (iron crystal 2) which reasonably contain the metal at different oxidation states. Here two different di-iron species are trapped in the active site, with intermetal distances corresponding to those of the ferric dimer in crystal 1 and of the dicopper centers and corresponding rearrangement of the His54 side chain. PMID- 22424303 TI - Sequence signatures involved in targeting the Male-Specific Lethal complex to X chromosomal genes in Drosophila melanogaster. AB - BACKGROUND: In Drosophila melanogaster, the dosage-compensation system that equalizes X-linked gene expression between males and females, thereby assuring that an appropriate balance is maintained between the expression of genes on the X chromosome(s) and the autosomes, is at least partially mediated by the Male Specific Lethal (MSL) complex. This complex binds to genes with a preference for exons on the male X chromosome with a 3' bias, and it targets most expressed genes on the X chromosome. However, a number of genes are expressed but not targeted by the complex. High affinity sites seem to be responsible for initial recruitment of the complex to the X chromosome, but the targeting to and within individual genes is poorly understood. RESULTS: We have extensively examined X chromosome sequence variation within five types of gene features (promoters, 5' UTRs, coding sequences, introns, 3' UTRs) and intergenic sequences, and assessed its potential involvement in dosage compensation. Presented results show that: the X chromosome has a distinct sequence composition within its gene features; some of the detected variation correlates with genes targeted by the MSL-complex; the insulator protein BEAF-32 preferentially binds upstream of MSL-bound genes; BEAF-32 and MOF co-localizes in promoters; and that bound genes have a distinct sequence composition that shows a 3' bias within coding sequence. CONCLUSIONS: Although, many strongly bound genes are close to a high affinity site neither our promoter motif nor our coding sequence signatures show any correlation to HAS. Based on the results presented here, we believe that there are sequences in the promoters and coding sequences of targeted genes that have the potential to direct the secondary spreading of the MSL-complex to nearby genes. PMID- 22424304 TI - Presenting evidence-based health information for people with multiple sclerosis: the IN-DEEP project protocol. AB - BACKGROUND: Increasingly, evidence-based health information, in particular evidence from systematic reviews, is being made available to lay audiences, in addition to health professionals. Research efforts have focused on different formats for the lay presentation of health information. However, there is a paucity of data on how patients integrate evidence-based health information with other factors such as their preferences for information and experiences with information-seeking. The aim of this project is to explore how people with multiple sclerosis (MS) integrate health information with their needs, experiences, preferences and values and how these factors can be incorporated into an online resource of evidence-based health information provision for people with MS and their families. METHODS: This project is an Australian-Italian collaboration between researchers, MS societies and people with MS. Using a four stage mixed methods design, a model will be developed for presenting evidence based health information on the Internet for people with MS and their families. This evidence-based health information will draw upon systematic reviews of MS interventions from The Cochrane Library. Each stage of the project will build on the last. After conducting focus groups with people with MS and their family members (Stage 1), we will develop a model for summarising and presenting Cochrane MS reviews that is integrated with supporting information to aid understanding and decision making. This will be reviewed and finalised with people with MS, family members, health professionals and MS Society staff (Stage 2), before being uploaded to the Internet and evaluated (Stages 3 and 4). DISCUSSION: This project aims to produce accessible and meaningful evidence-based health information about MS for use in the varied decision making and management situations people encounter in everyday life. It is expected that the findings will be relevant to broader efforts to provide evidence-based health information for patients and the general public. The international collaboration also permits exploration of cultural differences that could inform international practice. PMID- 22424305 TI - Racial/ethnic disparities in home health care: charting a course for future research. AB - Racial/ethnic disparities in health have been well-documented. However, we know little about the existence of or mechanisms that contribute to disparities in home health care. This article proposes a conceptual framework, based on a comprehensive review of the literature, to guide research to understand whether and how disparities emerge in home health care. The framework outlines the patient, agency, practice, and system factors that have been shown to or theoretically could contribute to disparities. Enhanced parity in home health care will impact society by reducing health costs due to morbidity, while directly benefiting minority patients. PMID- 22424306 TI - Unmet service needs: a comparison between dementia and non-dementia caregivers. AB - This study compared the unmet service needs between dementia and non-dementia caregivers using data extracted from the Caregiving in the U.S. survey. This study sample included 625 non-dementia caregivers and 208 dementia caregivers. Ordinary least squares (OLS) regression analysis was used in analysis. The study showed that a large percentage of dementia (78.8%) and non-dementia caregivers (69.9%) reported unmet needs in at least one service area. Dementia caregivers who reported higher levels of caregiving strain were likely to report greater unmet service needs (p = .05). To address caregivers' unmet service needs more effectively, a comprehensive assessment of caregivers and their care receivers and interventions addressing the needs of both caregivers and care receivers are needed. PMID- 22424307 TI - Racial/ethnic minority access to end-of-life care: a conceptual framework. AB - Minority underutilization of hospice care has been well-documented; however, explanations addressing disparities have failed to examine the scope of factors in operation. Drawing from previous health care access models, a framework is proposed in which access to end-of-life care results from an interaction between patient-level, system-level, and societal-level barriers with provider-level mediators. The proposed framework introduces an innovative mediating factor missing in previous models, provider personal characteristics, to better explain care access disparities. This article offers a synthesis of previous research and proposes a framework that is useful to researchers and clinicians working with minorities at end of life. PMID- 22424308 TI - Is home health care a substitute for hospital care? AB - A previous study used aggregate (region-level) data to investigate whether home health care serves as a substitute for inpatient hospital care and concluded that "there is no evidence that services provided at home replace hospital services." However, that study was based on a cross-section of regions observed at a single point of time and did not control for unobserved regional heterogeneity. In this article, state-level employment data are used to reexamine whether home health care serves as a substitute for inpatient hospital care. This analysis is based on longitudinal (panel) data--observations on states in two time periods--which enable the reduction or elimination of biases that arise from use of cross sectional data. This study finds that states that had higher home health care employment growth during the period 1998-2008 tended to have lower hospital employment growth, controlling for changes in population. Moreover, states that had higher home health care payroll growth tended to have lower hospital payroll growth. The estimates indicate that the reduction in hospital payroll associated with a $1,000 increase in home health payroll is not less than $1,542, and may be as high as $2,315. This study does not find a significant relationship between growth in utilization of home health care and growth in utilization of nursing and residential care facilities. An important reason why home health care may serve as a substitute for hospital care is that the availability of home health care may allow patients to be discharged from the hospital earlier. Hospital discharge data from the Healthcare Cost and Utilization Project are used to test the hypothesis that use of home health care reduces the length of hospital stays. Major Diagnostic Categories with larger increases in the fraction of patients discharged to home health care tended to have larger declines in mean length of stay (LOS). Between 1998 and 2008, mean LOS declined by 4.1%, from 4.78 to 4.59 days. The estimates are consistent with the hypothesis that this was entirely due to the increase in the fraction of hospital patients discharged to home health care, from 6.4% in 1998 to 9.9% in 2008. The estimated reduction in 2008 hospital costs resulting from the rise in the fraction of hospital patients discharged to home health care may have been 36% larger than the increase in the payroll of the home health care industry. PMID- 22424309 TI - Use of cementless, tapered femoral stems in patients who have a mean age of 20 years. AB - Young patients who undergo total hip arthroplasty are a unique group who has been challenging to successfully treat; however, newer prosthetic materials and designs have the potential to increase implant longevity. Fifty-three hips (40 patients who had a mean age of 20 years) underwent a total hip arthroplasty using a cementless, proximally hydroxyapatite-coated, tapered, femoral stem and a cementless acetabular cup. There was a 96% overall survivorship at approximately 5 years of mean follow-up (range, 2-7 years) with no femoral side failures. Younger patients undergoing total hip arthroplasty with newer component designs and materials may have similar excellent outcomes to older patients. PMID- 22424311 TI - Critical to assess soft tissue tension in an anatomically correct flexed position. PMID- 22424312 TI - Development of solid lipid nanoparticles and nanostructured lipid carriers for improving ocular delivery of acyclovir. AB - The objective of the present investigation was to improve the ocular bioavailability of acyclovir by incorporating it into solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). This required optimization of the process parameters, such as type of lipid, drug to lipid ratios, type and concentration of surfactants, and type and amount of liquid lipids used in the formulations. SLNs and NLCs were prepared by the modified hot oil in water microemuslion method. The prepared nanoparticles were evaluated for their particle size, zeta potential, entrapment efficiency, solid state characteristics, surface morphology, in vitro drug release, and permeation through excised cornea. The prepared nanoparticles were spherical and within the size range suitable for ocular drug delivery (400-777.56 nm). Incorporation of liquid oil in the structure of SLNs resulted in the formation of NLCs with high entrapment efficiency (25-91.64%) compared to SLNs (11.14%). The drug release from SLNs and NLCs was rather a surface-based phenomenon. In comparison to free drug solution, NLCs were capable of having faster permeation through the excised cornea indicating their potential enhanced corneal penetration properties. However, SLNs have reduced the permeation rate significantly. The results of the study suggest that SLNs can be successfully converted to physically superior NLCs, which have the potential to be developed further as ocular drug delivery systems for ACV. PMID- 22424313 TI - Comparative oncology: ErbB-1 and ErbB-2 homologues in canine cancer are susceptible to cetuximab and trastuzumab targeting. AB - To facilitate comparative oncology trials we compared the biological and molecular homologies of canine (dog; Canis lupus familiaris) and human tumor associated antigens ErbB-1 and -2. Further, we investigated whether they could serve as targets for anti-ErbB-1 (cetuximab) and anti-ErbB-2 antibodies (trastuzumab), which are highly relevant in human clinical oncology. Immunohistochemistry of canine mammary cancer showed ErbB-1 overexpression in 3/10 patients and ErbB-2 in 4/10. We report 91% amino acid homology for ErbB-1 and 92% for ErbB-2 between canine and human molecules. Modeling of canine on human ErbB-1 revealed that the cetuximab epitope only differs by 4 amino acids: Lys443 is replaced by Arg, Ser468 by Asn, Gly471 by Asp, and Asn473 by Lys in canines. The trastuzumab binding site is identical in human and canine ErbB-2 apart from a single amino acid change (Pro557 to Ser). Binding of cetuximab and trastuzumab to canine mammary carcinoma cells CF33, CF41, Sh1b and P114 was confirmed by flow cytometry. Both antibodies significantly inhibited canine tumor cell proliferation partly due to growth arrest in G(0)/G(1) phase. We explain the lower efficiency on the tested canine than on human SKBR3 and A431 cells, by a 2 log lower expression level of the canine ErbB-1 and -2 molecules. Our results indicate significant homology of human and canine Erb-1 and -2 tumor associated antigens. The fact that the canine homologues express the cetuximab and trastuzumab epitopes may facilitate antibody-based immunotherapy in dogs. Importantly, the striking similarities of ErbB-1 and -2 molecules open up avenues towards comparative strategies for targeted drug development. PMID- 22424314 TI - Sta c 3 epitopes and their application as biomarkers to detect specific IgE. AB - Sta c 3 was determined to be one of the major allergens from Stachybotrys chartarum sensu lato. This is among the most common fungi on wet building materials. Various cognizant authorities have found that mold and dampness are associated with exacerbation of asthma and increased upper respiratory disease. The primary amino-acid sequence of this allergen was reported, however the IgE binding epitopes were unknown. Using SPOT-synthesis techniques (SPOTs), one main linear epitope located between V91 and G105 was discovered by Western blot with atopic human sera. This was confirmed by inhibition ELISA assays with both synthesized epitopes and natural Sta c 3. Alanine scanning also revealed R100 and K101 are the critical amino acids for IgE binding. Using the binding-enhanced and alanine substituted epitopes as potential biomarkers, a reverse ELISA method was developed to detect the Sta c 3 sIgE in atopic human sera. This method employed streptavidin-biotinylated mutated epitopes as the capture matrix, probing the possibility of using small peptides for allergen/species specific IgE assays. PMID- 22424315 TI - Importance of RNA isolation methods for analysis of exosomal RNA: evaluation of different methods. AB - Exosomes are small RNA containing vesicles of endocytic origin, which can take part in cell-to-cell communication partly by the transfer of exosomal RNA between cells. Exosomes are released by many cells and can also be found in several biological fluids including blood plasma and breast milk. Exosomes differ compared to their donor cells not only in size but also in RNA, protein and lipid composition. The aim of the current study was to determine the optimal RNA extraction method for analysis of exosomal RNA, to support future studies determining the biological roles of the exosomal RNA. Different methods were used to extract exosomal and cellular RNA. All methods evaluated extracted high quality and purity RNA as determined by RNA integrity number (RIN) and OD values for cellular RNA using capillary electrophoresis and spectrophotometer. Interestingly, the exosomal RNA yield differed substantially between the different RNA isolation methods. There was also a difference in the exosomal RNA patterns in the electropherograms, indicating that the tested methods extract exosomal RNA with different size distribution. A pure column based approach resulted in the highest RNA yield and the broadest RNA size distribution, whereas phenol and combined phenol and column based approaches lost primarily large RNAs. Moreover, the use of phenol and combined techniques resulted in reduced yield of exosomal RNA, with a more narrow size distribution pattern resulting in an enrichment of small RNA including microRNA. In conclusion, the current study presents a unique comparison of seven different methods for extraction of exosomal RNA. As the different isolation methods give extensive variation in exosomal RNA yield and patterns, it is crucial to select an isolation approach depending on the research question at hand. PMID- 22424316 TI - Temperature variability analysis using wavelets and multiscale entropy in patients with systemic inflammatory response syndrome, sepsis, and septic shock. AB - BACKGROUND: Even though temperature is a continuous quantitative variable, its measurement has been considered a snapshot of a process, indicating whether a patient is febrile or afebrile. Recently, other diagnostic techniques have been proposed for the association between different properties of the temperature curve with severity of illness in the Intensive Care Unit (ICU), based on complexity analysis of continuously monitored body temperature. In this study, we tried to assess temperature complexity in patients with systemic inflammation during a suspected ICU-acquired infection, by using wavelets transformation and multiscale entropy of temperature signals, in a cohort of mixed critically ill patients. METHODS: Twenty-two patients were enrolled in the study. In five, systemic inflammatory response syndrome (SIRS, group 1) developed, 10 had sepsis (group 2), and seven had septic shock (group 3). All temperature curves were studied during the first 24 hours of an inflammatory state. A wavelet transformation was applied, decomposing the signal in different frequency components (scales) that have been found to reflect neurogenic and metabolic inputs on temperature oscillations. Wavelet energy and entropy per different scales associated with complexity in specific frequency bands and multiscale entropy of the whole signal were calculated. Moreover, a clustering technique and a linear discriminant analysis (LDA) were applied for permitting pattern recognition in data sets and assessing diagnostic accuracy of different wavelet features among the three classes of patients. RESULTS: Statistically significant differences were found in wavelet entropy between patients with SIRS and groups 2 and 3, and in specific ultradian bands between SIRS and group 3, with decreased entropy in sepsis. Cluster analysis using wavelet features in specific bands revealed concrete clusters closely related with the groups in focus. LDA after wrapper-based feature selection was able to classify with an accuracy of more than 80% SIRS from the two sepsis groups, based on multiparametric patterns of entropy values in the very low frequencies and indicating reduced metabolic inputs on local thermoregulation, probably associated with extensive vasodilatation. CONCLUSIONS: We suggest that complexity analysis of temperature signals can assess inherent thermoregulatory dynamics during systemic inflammation and has increased discriminating value in patients with infectious versus noninfectious conditions, probably associated with severity of illness. PMID- 22424317 TI - Serrumab: a human monoclonal antibody that counters the biochemical and immunological effects of Tityus serrulatus venom. AB - In Brazil, the species Tityus serrulatus is responsible for the most severe cases of scorpion envenomation. There is currently a need for new scorpion anti-venoms that are more effective and less harmful. This study attempted to produce human monoclonal antibodies capable of inhibiting the activity of T. serrulatus venom (TsV), using the Griffin.1 library of human single-chain fragment-variable (scFv) phage antibodies. Four rounds of phage antibody selection were performed, and the round with the highest phage antibody titer was chosen for the production of monoclonal phage antibodies and for further analysis. The scFv 2A, designated serrumab, was selected for the production and purification of soluble antibody fragments. In a murine peritoneal macrophage cell line (J774.1), in vitro assays of the cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-10 were performed. In male BALB/c mice, in vivo assays of plasma urea, creatinine, aspartate transaminase, and glucose were performed, as well as of neutrophil recruitment and leukocyte counts. It was found that serrumab inhibited the TsV induced increases in the production of IL-6, TNFalpha, and IL-10 in J774.1 cells. The in vivo inhibition assay showed that serrumab also prevented TsV-induced increases in the plasma levels of urea, creatinine, aspartate transaminase, and glucose, as well as preventing the TsV-induced increase in neutrophil recruitment. The results indicate that the human monoclonal antibody serrumab is a candidate for inclusion in a mixture of specific antibodies to the various toxins present in TsV. Therefore, serrumab shows promise for use in the production of new anti-venom. PMID- 22424318 TI - Polydioxythiophene nanodots, nonowires, nano-networks, and tubular structures: the effect of functional groups and temperature in template-free electropolymerization. AB - Various nanostructures, including nanofibers, nanodots, nanonetwork, and nano- to microsize tubes of functionalized poly(3,4-ethylenedioxythiophene) (EDOT) and poly(3,4-propylenedioxythiophene) (ProDOT) are created by using a template-free electropolymerization method on indium-tin-oxide substrates. By investigating conducting polymer nanostructures containing various functional groups prepared at different polymerization temperature, we conclude a synergistic effect of functional groups and temperature on the formation of polymer nanostructures when a template-free electropolymerization method is applied. For unfunctionalized EDOT and ProDOT, or EDOT containing alkyl functional groups, nanofibers and nanoporous structures are usually found. Interesting, when polar functional groups are attached, conducting polymers tend to form nanodots at room temperature while grow tubular structures at low temperature. The relationship between surface properties and their nanostructures is evaluated by contact angle measurements. The capacity and electrochemical impedance spectroscopy measurements were conducted to understand the electrical properties of using these materials as electrodes. The results provide the relationship between the functional groups, nanostructures, and electrical properties. We also discuss the potential restriction of using this method to create nanostructures. The copolymerization of different functionalized EDOTs may cause irregular and unexpected nanostructures, which indicates the complex interaction between different functionalized monomers during the electropolymerization. PMID- 22424319 TI - Comment. Flunitrazepam intake in male offenders. PMID- 22424320 TI - Pharmacotherapy of obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea syndrome is a common public health problem in the general population. The important health-related consequences of obstructive sleep apnea include cardiovascular disorders, such as myocardial infarction and hypertension, stroke, sudden death and difficult blood sugar control related to diabetes mellitus. The current main treatment options include body weight loss, continuous positive airway pressure, oral appliances and surgical treatment. The effects of pharmacotherapy on sleep apnea continue to be controversial and supplemental only. Current medications for sleep apnea mainly act through reducing risk factors, treating predisposing endocrine disorders, improving residual sleepiness post management and controlling associated hypertension and metabolic disorders. AREAS COVERED: This article discusses the pharmacotherapy of sleep apnea, including ventilatory stimulants, serotoninergic and REM sleep suppressant agents, acetylcholinesterase inhibitors, medications for predisposing endocrine disorders, stimulants, associated sleep apnea health problems and sleep apnea patient anesthetic precaution. Weight loss is not a direct pharmacological approach and is only briefly mentioned. EXPERT OPINION: At present, there is no appropriate pharmacological treatment for obstructive sleep apnea. There are adjunct treatments such as anti-allergy treatment, and, if residual sleepiness is present, nonamphetaminic stimulants can help. Usage of these stimulants will, however, produce negative effects in an anticipated rate of about 10% of subjects taking these medications. PMID- 22424321 TI - New interferometric technique to evaluate the electric charge of gas bubbles in liquids. AB - We report a new interferometric technique to measure the electric charge at the gas-liquid interface of a bubble in a liquid. The bubble rests by buoyancy against an electrode, and an alternating electric field excites its capillary oscillations. The oscillation amplitude of the quadrupolar mode frequency is measured by the interferometer, and it is used to evaluate the electric charge. The mode frequency scales with the square root of the interfacial tension and with a -(3)/(2) power law as a function of the bubble radius. For bubbles in the millimeter diameter range in pure water, the measured negative charge scales with the square of the radius, hence, giving a constant surface charge density on the order of 1.8 * 10(-5) C m(-2), which is rather consistent with the electrophoretic values reported in the literature. PMID- 22424322 TI - Heart disease in pregnant women: recent ESC guidelines. PMID- 22424323 TI - French Ministry of Health prospective multicentre study using bio-active stents coated with titanium nitride oxide: the EVIDENCE registry. AB - BACKGROUND: Coronary stents have evolved over time, from bare-metal stents to drug-eluting stents, and now to bioactive stents. AIMS: We sought to explore the immediate outcome of the titanium-nitride-oxide-coated bioactive stent, Titan2((r)), in real-world practice, and the incidence of major cardiac events at follow-up. METHODS: Consecutive patients admitted for percutaneous intervention for at least one significant (>=50%) lesion in a native coronary artery were treated with Titan2((r)) stent implantation. The primary endpoint was total major adverse cardiac events at 12-month follow-up. Secondary endpoints included target lesion revascularization at 12-month follow-up and the duration of dual antiplatelet therapy. RESULTS: Among 356 patients (mean age 67.4 +/- 12.1 years), 77.2% were male and 39.3% were treated for myocardial infarction (MI). A total of 546 Titan2((r)) stents were implanted in 420 lesions. Angiographic and clinical procedural success was achieved in all cases. No cases of in-hospital major adverse cardiac events or acute stent thrombosis were reported. Of 335 patients (94.1%) with 12-month clinical follow-up, four (1.2%) died, MI occurred in five (1.5%), target lesion revascularization was performed in 17 (5.1%) and major adverse cardiac events occurred in 24 (7.2%). One patient (0.3%) suffered late stent thrombosis during follow-up, but no cases of acute or subacute stent thrombosis occurred. Dual antiplatelet therapy continued beyond 6 months in 64.5% of patients. CONCLUSIONS: In real-world practice, Titan2((r)) stent implantation achieves an excellent immediate outcome, with a low incidence of major adverse cardiac events at 12-month follow-up. PMID- 22424324 TI - Testosterone improves cardiac function and alters angiotensin II receptors in isoproterenol-induced heart failure. AB - BACKGROUND: The renin-angiotensin-aldosterone system is known to play an important role in the pathophysiology and development of heart failure. Several studies have reported the benefits of testosterone in heart failure. However, the mechanisms of testosterone-induced effects on heart failure require further study. AIMS: To determine the effects of castration and testosterone administration on cardiac function and angiotensin II receptor function in rats with isoproterenol-induced heart failure. METHODS: Wistar rats were divided randomly into control and heart failure groups. The heart failure groups were further divided into the following groups: castration; castration+testosterone replacement; and sham castration. Echocardiography and haemodynamic measurements were used to evaluate cardiac function. Cardiocyte apoptosis and fibrosis were determined using terminal deoxyribonucleotide transferase-mediated dUTP nick-end labelling (TUNEL) staining and Masson's Trichrome staining, respectively. Angiotensin II receptor (AT1 and AT2) messenger ribonucleic acid (mRNA) expression levels were assayed using real-time reverse transcriptase-polymerase chain reactions, while Western immunoblotting was used to estimate Bcl-2 protein expression levels. RESULTS: Castration significantly increased cardiomyocyte apoptosis and fibrosis that was normally induced by isoproterenol (P<0.05). AT2 receptor mRNA expression in the castration group was increased and Bcl-2 protein expression was decreased compared with the castration+testosterone replacement group (P<0.05). CONCLUSION: These data suggest that androgen therapy could play an important role in pathophysiological changes in heart failure and have beneficial effects for its treatment. PMID- 22424325 TI - Prevalence of cardiovascular disease in Gabon: a population study. AB - BACKGROUND: Data supporting epidemiological transition from a predominant burden of infectious diseases to one of chronic diseases in Africa result mostly from hospital surveys. AIM: To estimate the cardiovascular disease (CVD) burden in Gabon. METHODS: The study was conducted in Ntoum (8765 inhabitants). All subjects aged greater or equal to 40 years were invited to participate. Participants were interviewed about CVD history and risk factors; they responded to questionnaires on claudication and angina and had a clinical examination, including lower limb pulse palpation and bilateral brachial pressure measurement. Subjects were considered to have CVD in case of history of CVD (coronary artery, cerebrovascular and peripheral arterial diseases), a positive questionnaire or an abnormal finding during clinical examination. RESULTS: The study included 736 subjects (313 men; 423 women). Systolic hypertension was highly prevalent (up to 47.7% and 53.7% in men and women aged 50 to 60 years, respectively). Of the 382 patients with hypertension, 74 (19.4%) were treated and only 22 (5.8%) were considered to have controlled hypertension. Overall, CVD was identified in 98 (13.3%) cases. Overall and newly diagnosed CVD prevalence rates were 14.7% and 11.5% for men and 14.9% and 8.9% for women, respectively. The presence of CVD was associated with hypertension (hazard ratio [HR] 3.69, 95% confidence interval [CI] 2.21-6.16; P<0.0001). Hypertension was predictive of stroke (HR 4.57, 95% CI 1.26-16.50; P<0.05), peripheral artery disease (HR 2.03, 95% CI 1.03-4.00; P<0.05) and subclavian artery stenosis (HR 5.79, 95% CI 2.21-15.2; P<0.05). CONCLUSIONS: Our findings provide strong evidence of ongoing epidemiological transition in Gabon, where CVD prevalence rates increase mainly with hypertension, affecting about one in six individuals aged over 40 years. PMID- 22424326 TI - Surgical management of patients with Marfan syndrome: evolution throughout the years. AB - AIM: To evaluate the evolution of surgical management in a large population of patients with Marfan syndrome. METHODS: This is a retrospective study of patients fulfilling the Ghent criteria for Marfan syndrome, who visited the Centre de reference national pour le syndrome de Marfan et apparentes and underwent a surgical event before or during follow-up in the centre. RESULTS: One thousand and ninety-seven patients with Marfan syndrome, according to international criteria, came to the clinic between 1996 and 2010. Aortic surgery was performed in 249 patients (22.7%; 20 children and 229 adults), including the Bentall procedure in 140 patients (56%) and valve-sparing surgery in 88 patients (35%); a supracoronary graft was performed in 19 patients (7.6%), usually for aortic dissection. During the past 20 years, the predominant reason for aortic surgery has switched from aortic dissection to aortic dilatation, while age at surgery has tended to increase (from 32.4 +/- 11.9 years to 35.2 +/- 12.4 years; P=0.075). Mitral valve surgery was performed in 61 patients (5.6%; six children and 55 adults), including 37 valvuloplasties (60.6%) and 18 mitral valve replacements (29.5%). No significant difference was observed when comparing mitral valve surgery before and after 2000. CONCLUSION: Surgery performed in patients with Marfan syndrome has switched from emergency surgery for aortic dissection to elective surgery for aortic dilatation; this is associated with surgery performed at an older age despite the indication for surgery having decreased from 60mm to 50mm. No significant evolution was observed for mitral valve surgery. PMID- 22424327 TI - Assessment of left ventricular ejection fraction using the wall motion score index in cardiac magnetic resonance imaging. AB - BACKGROUND: Left ventricular ejection fraction (LVEF) is an important indicator of left ventricular function and of the severity and prognosis of ischaemic heart disease. Assessment of regional function using the wall motion score index (WMSI) is an alternative means of evaluating left ventricular function. AIM: We attempted to evaluate LVEF by a method using the WMSI with cardiac magnetic resonance imaging (MRI). METHODS: One hundred and twenty-two patients referred for evaluation of heart disease had rest WMSI evaluation by cardiac MRI. The WMSI was evaluated using the 16-segment model and score proposed by the American Society of Echocardiography. In our first group of 80 patients, a correlation between WMSI and cardiac MRI LVEF was established and a regression equation was derived. This regression equation was then used in 42 consecutive patients to compare WMSI LVEF with the gold standard MRI LVEF. RESULTS: In the first 80 patients, MRI LVEF and WMSI correlated very well (r=0.93). Similarly, in the second group of 42 patients, WMSI LVEF derived from the regression equation correlated very well with MRI LVEF (r=0.94). CONCLUSION: An objective evaluation of LVEF can be easily made using the WMSI with cardiac MRI, which correlates very well with standard MRI planimetric methods. PMID- 22424328 TI - Birth weight and subsequent blood pressure: a meta-analysis. AB - Hypertension is becoming an important health problem in many countries. The 'small baby syndrome hypothesis' suggests that an inverse linear relationship exists between birth weight and later risk of hypertension; however, this relationship is under debate. We conducted a meta-analysis to examine the association between birth weight and subsequent blood pressure. Among 78 studies reporting on the association between birth weight and subsequent blood pressure, 20 articles (reporting 27 original studies) were eligible for inclusion. Low birth weight (< 2500 g) compared with birth weight greater than 2500 g was associated with an increased risk of hypertension (odds ratio [OR] 1.21; 95% confidence interval [CI] 1.13, 1.30); high birth weight (> 4000 g) compared with birth weight less than 4000 g was associated with a decreased risk of hypertension (OR 0.78; 95% CI 0.71, 0.86). When low birth weight (< 2500 g) was compared with birth weight greater than 2500 g, mean systolic blood pressure (SBP) increased by 2.28 mmHg (95% CI 1.24, 3.33); when high birth weight (> 4000 g) was compared with birth weight less than 4000 g, mean SBP decreased by 2.08 mmHg (95% CI -2.98, -1.17). These findings indicate that there is an inverse linear association between birth weight and later risk of hypertension, and that this association primarily exists between birth weight and SBP. PMID- 22424329 TI - Left ventricle assist device: when and which patients should we refer? AB - Progress in the medical treatment of patients with heart failure with systolic dysfunction, cardiac resynchronization therapy, internal cardiac defibrillators and multidisciplinary management programmes has resulted in dramatic improvements in survival and quality of life; however, this progress has led to an increase in the prevalence of advanced heart failure. In the context of organ shortage for cardiac transplantation, the technological developments in left ventricular assist devices, shown in recent positive clinical studies, provide real hope for patients with advanced heart failure. This article summarizes the most recent clinical studies concerning left ventricular assist devices and discusses for whom and when a left ventricular assist device should be proposed. PMID- 22424330 TI - A sword of Damocles in an asymptomatic man presenting with serendipitously detected ventricular pre-excitation. PMID- 22424331 TI - PET scan in suspected but unproven pacemaker endocarditis. PMID- 22424332 TI - Letter relating to the publication entitled "Evolution of acute coronary syndrome with normal coronary arteries and normal cardiac magnetic resonance imaging" by Chopard et al. (Arch Cardiovasc Dis 2011;104:509-17). PMID- 22424333 TI - The G protein-coupled estrogen receptor 1 (GPER/GPR30) does not predict survival in patients with ovarian cancer. AB - BACKGROUND: Even though ovarian tumors are not generally considered estrogen sensitive, estrogens may still have an impact on ovarian tumor progression. The recently identified trans-membrane estrogen receptor GPER is involved in rapid estrogen signaling. Furthermore, it binds selective estrogen receptor modulators with agonistic effect, which could explain tamoxifen controversies. METHODS: GPER mRNA was assayed with quantitative real-time PCR (qPCR) in 42 primary ovarian tumors and 7 ovarian cancer cell lines. ERalpha and ERbeta mRNA were analyzed for comparison. GPER protein was semi-quantified with densitometric scanning of Western blots and its tissue distribution analyzed with immunohistochemistry (IHC) in 40 ovarian tumors. In addition, IHC was evaluated in a tissue microarray (TMA) of 150 primary malignant ovarian tumors. RESULTS: All tumor samples contained GPER mRNA. The content of mRNA was not different between benign and malignant tumors, but one third of malignant samples over-expressed GPER mRNA. The content of ERalpha mRNA was higher in malignant than in benign tumors, whereas ERbeta mRNA was higher in benign than in malignant tumors. GPER mRNA was detected in all seven ovarian cancer cell lines with highest levels in TOV21G and TOV112D cells. Similar expression pattern was seen for ERbeta mRNA. Western blot demonstrated GPER protein in all tumor samples. Semi-quantification showed no difference between benign and malignant tumors, but about one third of malignant samples over-expressed GPER protein. GPER staining was localized mainly in epithelial cells. In the TMA study we found no correlation between GPER staining and clinical stage, histological grade or patient survival. CONCLUSIONS: GPER mRNA as well as GPER protein is present in both benign and malignant ovarian tumor tissue. About one third of malignant tumors over-expressed both GPER mRNA and protein. This, however, correlated neither with histological or clinical parameters nor with patient survival. PMID- 22424334 TI - Fate dynamics of environmentally exposed explosive traces. AB - The chemical and physical fates of trace amounts (<50 MUg) of explosives containing 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and pentaerythritol tetranitrate (PETN) were determined for the purpose of informing the capabilities of tactical trace explosive detection systems. From these measurements, it was found that the mass decreases and the chemical composition changes on a time scale of hours, with the loss mechanism due to a combination of sublimation and photodegradation. The rates for these processes were dependent on the explosive composition, as well as on both the ambient temperature and the size distribution of the explosive particulates. From these results, a persistence model was developed and applied to model the time dependence of both the mass and areal coverage of the fingerprints, resulting in a predictive capability for determining fingerprint fate. Chemical analysis confirmed that sublimation rates for TNT were depressed by UV (330-400 nm) exposure due to photochemically driven increases in the molecular weight, whereas the opposite was observed for RDX. No changes were observed for PETN upon exposure to UV radiation, and this was attributed to its low UV absorbance. PMID- 22424335 TI - Outcomes of prenatally diagnosed sacrococcygeal teratomas: the results of a Japanese nationwide survey. AB - BACKGROUND/PURPOSE: Few large multicenter surveys have been performed on sacrococcygeal teratomas (SCTs) describing both the prenatal and postnatal courses. The aim of this study was to review and report on the prenatal surveillance and postnatal outcome of a large cohort of fetuses with SCTs in Japan. METHODS: A nationwide retrospective cohort study was conducted on 97 fetuses prenatally diagnosed with SCTs between 2000 and 2009. The prenatal course, perinatal data, and postnatal outcome were reviewed. RESULTS: Eleven pregnancies were terminated before 22 weeks of gestation. Of the 86 remaining fetuses, 3 died in utero, and 83 were delivered. Three infants died before surgery, and 8 infants died after excisional surgery. The overall mortality was 26%, with a mortality excluding terminations of 16%. The gestational age at delivery was younger than 28 weeks in 5, 28 to 31 weeks in 13, 32 to 36 weeks in 27, and 37 weeks or more in 37 cases, with mortality rates of 60%, 38%, 11%, and 0%, respectively. The tumor component was predominantly cystic in 54 and predominantly solid in 32 cases, with mortality rates of 2% and 33%, respectively. CONCLUSIONS: The overall mortality of prenatally diagnosed SCTs excluding terminations was 16%. Early delivery and predominantly solid component tumors were associated with an increased risk of mortality. PMID- 22424336 TI - Hepatic mesenchymal hamartoma and infantile hemangioma: a rare association. AB - BACKGROUND/PURPOSE: The association between liver infantile hemangioma and mesenchymal hamartoma is rare. This communication reports the clinical, radiologic, and pathologic features of 3 infants with concurrent liver hemangioma and mesenchymal hamartoma. METHODS: We conducted a comprehensive search of the database of our Vascular Anomalies Center over the past 12 years (1999-2010) for the keywords mesenchymal hamartoma, liver, and hemangioma in a large cohort of patients with liver hemangioma. Medical records and imaging studies of multiple modalities were reviewed. The search included infants with histopathologically proven liver hemangioma and mesenchymal hamartoma confirmed by the clinical and imaging findings. RESULTS: There were 112 children with the diagnosis of liver hemangioma; 3 of them (0.027%) had concurrent mesenchymal hamartoma. Mesenchymal hamartoma predates the appearance of multifocal liver hemangiomas in 1 patient. CONCLUSIONS: The rare coexistence of liver infantile hemangioma and mesenchymal hamartoma could be a true association. PMID- 22424337 TI - Abnormal brain development and maturation on magnetic resonance imaging in survivors of severe congenital diaphragmatic hernia. AB - PURPOSE: The aim of the study was to evaluate the incidence of abnormal brain maturation in survivors of severe congenital diaphragmatic hernia (CDH). MATERIAL AND METHODS: Between July 2004 and December 2009, 50 CDH survivors underwent detailed brain magnetic resonance (MR) imaging before discharge. Magnetic resonance images were analyzed to evaluate the presence of structural brain abnormalities and to calculate overall brain maturation using the total maturation score (TMS). RESULTS: Thirty-two children (64%) underwent MR imaging between 39 and 43 weeks of gestation, allowing for evaluation of the TMS. Eighteen (36%) underwent MR imaging between 44 and 69 weeks of gestation, allowing for structural analysis of brain maturity only. The mean TMS was 14.1 +/ 1.2 and significantly lower than reported age-matched normative data in infants without CDH (15.3 +/- 1.0, P = .02). The TMS in 4 patients (12.5%) corresponded to a delay of 1 month in structural brain development. Eight infants (25%) demonstrated a 2-week delay. Periventricular leukomalacia was detected in 9 (18%), incomplete development of the opercula in 7 (14%), various degrees of intracranial hemorrhage in 24 (48%), and prominent extraaxial fluid spaces in 20 (40%) cases. CONCLUSIONS: Brain maturation in infants with severe CDH appears to be delayed. Long-term neurodevelopmental follow-up is needed to determine the significance of a lower-than-expected TMS and the presence of structural brain abnormalities on functional outcomes in this population. PMID- 22424338 TI - Modified Collis-Nissen procedure for long gap pure esophageal atresia. AB - BACKGROUND/PURPOSE: Esophageal reconstruction in long gap esophageal atresia (EA) is technically challenging, and several procedures have been described. The purpose of this study is to review our experience with the modified Collis-Nissen procedure in the repair of long gap pure EA. METHODS: Six patients with pure EA were treated at our institution from 1985 to 2008. Patients' demographics, surgical technique, timing of repair, early and late complications, and long-term functional outcomes were retrospectively reviewed. RESULTS: Five primary cases and 1 redo case were included. The mean gap length was 5.3 vertebral bodies (range, 4-6). Modified Collis-Nissen procedure was performed at a mean age of 11.6 months (range, 9-14 months) in primary cases. There was 1 anastomotic leak in the redo case, which healed spontaneously. Two patients had anastomotic strictures requiring balloon dilatations. Patients were weaned from tube feeding at a mean duration of 4 months (range, 1-6 months) postoperatively. All patients have normal oral intake at the last follow-up visit. Two adult patients had normal growth and development and no digestive symptoms. Endoscopic examination and pH monitoring showed no signs of significant gastroesophageal reflux. CONCLUSIONS: Modified Collis-Nissen procedure is a good option to consider in patients with long gap pure EA and is associated with an acceptable complication rate and promising short- and long-term results. PMID- 22424339 TI - Management of pediatric occult pneumothorax in blunt trauma: a subgroup analysis of the American Association for the Surgery of Trauma multicenter prospective observational study. AB - BACKGROUND: Occult pneumothorax (OPTX) represents air within the pleural space not visible on conventional chest radiographs. Increased use of computed tomography has led to a rise in the detection of OPTX. Optimal management remains undefined. METHODS: A pediatric subgroup analysis (age <18 years) from a multicenter, observational study evaluating OPTX management. Data analyzed were pneumothorax size, management outcome, and associated risk factors to characterize those that may be safely observed. RESULTS: Fifty-two OPTX (7.3 +/- 6.2 mm) in 51 patients were identified. None were greater than 27 mm; all those under 16.5 mm (n = 48) were successfully managed without intervention. Two patients underwent initial tube thoracostomy (one [21 mm] and the other with bilateral OPTX [24 mm, 27 mm]). Among patients under observation (n = 49), OPTX size progressed in 2; one (6.4mm) required no treatment, while one (16.5 mm) received elective intervention. Respiratory distress occurred in one patient (10.7 mm) who did not require tube thoracostomy. Nine received positive pressure ventilation; 8 did not have a tube thoracostomy. Twenty-four patients (51%) had one or more rib fractures; 3 required tube thoracostomy. CONCLUSION: No pediatric OPTX initially observed developed a tension pneumothorax or adverse event related to observation. Pediatric patients with OPTX less than 16 mm may be safely observed. Neither the presence of rib fractures nor need for PPV alone necessitates intervention. PMID- 22424340 TI - Management of pediatric splenic injuries in Canada. AB - PURPOSE: Nonoperative management (NOM) of blunt splenic injuries has become the standard of care in hemodynamically stable children. This study compares the management of these injuries between pediatric and nonpediatric hospitals in Canada. METHODS: Data were obtained from the Canadian Institute of Health Information trauma database on all patients aged 2 to 16 years, admitted to a Canadian hospital with a diagnosis of splenic injury between May 2002 and April 2004. Variables included age, sex, associated major injuries, splenic procedures, intensive care unit (ICU) admissions, blood transfusions, and length of stay. Hospitals were coded as pediatric or nonpediatric. Univariate analysis and logistic regression were used to determine associations between hospital type and outcomes. RESULTS: Of 1284 cases, 654 were managed at pediatric hospitals and 630 at nonpediatric centers. Patients at pediatric centers tended to be younger and more likely to have associated major injuries. Controlling for covariates, including associated major injuries, patients managed at pediatric centers were less likely to undergo splenectomy compared with those managed at nonpediatric centers (odds ratio [OR], 0.2; 95% confidence interval, 0.1-0.4). The risk of receiving blood products, admission to the ICU, and staying in hospital for more than 5 days was associated only with having associated major injuries. CONCLUSION: Even in the presence of other major injuries, successful NOM of blunt splenic injuries occurs more frequently in pediatric hospitals in Canada. This has policy relevance regarding education of adult surgeons about the appropriateness of NOM in children and developing guidelines on appropriate regional triaging of pediatric patients with splenic injury in Canada. PMID- 22424341 TI - High rate of postoperative mortality in patients with mucopolysaccharidosis I: findings from the MPS I Registry. AB - BACKGROUND/PURPOSE: Mucopolysaccharidosis I (MPS I) is a rare lysosomal storage disorder caused by deficiency of alpha-L-iduronidase, which results in progressive multisystemic disease. Patients with MPS I often require multiple common and uncommon surgeries and are at risk for surgical and anesthetic complications because of respiratory and cardiac disease. Surgery often precedes diagnosis; thus, surgeons and anesthesiologists may be unaware of potential risks. METHODS: We analyzed data from the MPS I Registry, a voluntary observational database, for deaths occurring within 1 month of a surgical procedure among the 932 patients enrolled as of July 2010. RESULTS: Among the 196 deceased patients, 186 reported 1 surgery or more, and 32 had 1 surgery or more within 1 month of death, including 20 who had 1 surgery or more within 10 days of death. Surgeries before death included hernia repair, central line placement, spinal surgery, tracheostomy, and ventriculo-peritoneal shunt. Most patients (28/32) had severe MPS I (Hurler), and 20 of 32 patients (all Hurler) died at 3 years or younger. In 6 of 32 patients, surgery was directly noted in the cause of death, including 4 patients with an attenuated form of MPS I. CONCLUSIONS: Patients with mucopolysaccharidosis have a high postoperative mortality because of underlying respiratory and cardiac diseases. PMID- 22424342 TI - Chest fast MRI: an imaging alternative on pre-operative evaluation of Pectus Excavatum. AB - BACKGROUND: Standard imaging methods in evaluating chest wall deformities, such as Pectus Excavatum (PE) in paediatric and adolescent patients, include baseline 2-view chest radiography and chest CT scan. Only few studies to date investigated the value of fast MRIin the pre operative assessment of patient affected by PE. OBJECTIVE: To evaluate the efficacy of chest fast MRI in pre-operative management of patient affected by PE. To obtain the Haller Index (HI) and Asymmetry Index (AI) from chest fast MRI protecting patients from radiation exposure. MATERIALS AND METHODS: We analyzed the data of 42 consecutive patients with severe PE who underwent minimally invasive repair between March 2007 and March 2010. All 42 patients received chest fast MRI, but only the first 5 in view of the results, were studied also with chest ultrafast CT scan. In both examinations, data at the deepest point of the depression were collected. RESULTS: Severity indices of the deformity using HI and AI, collected from CT scan and fast MRI in the first 5 patients, were comparable. In the remaining 37 fast chest MRI offered good images of the chest wall deformities with no radiation exposure, detailing anatomical information such as displacement and rotation of the heart or great vessels anomalies. CONCLUSION: This study suggests the use of chest MRI in pre operative workup for patients with PE to obtain severity indices (Haller Index and Asymmetry Index avoiding radiation exposure to paediatric patients. PMID- 22424343 TI - Experience with a simple technique for pectus bar removal. AB - BACKGROUND: There have been numerous reports of techniques used for pectus bar removal after correction of pectus excavatum. We use 2 operating tables positioned perpendicular to each other in a T-shaped configuration with the patients thorax circumferentially exposed so the bar is removed in 1 motion without bending the bar. In this study, we report the results of this procedure. METHODS: A retrospective chart review of patients undergoing bar removal after repair of pectus excavatum at our institution from August 2000 to March 2010 was performed. RESULTS: There were 230 patients with a mean age of 16.7 years (range, 7.8-25.3 years) at bar removal. Mean operative time for bar removal was 28.6 minutes, and average estimated blood loss (EBL) was 9.5 mL (range, 5-400 mL). One patient demonstrated significant hemorrhage from the bar tract after bar removal, which was controlled with circumferential compression wrap. Calcification was noted in 11 patients, and chondroma, in 8 patients. Wound infection after bar removal occurred in 3% of patients. No patient required the bar to be bent into a straight configuration for removal. CONCLUSIONS: Removal of pectus bars using this 2-table T-configuration technique is safe, is time efficient, and obviates the need for bending the bar. PMID- 22424344 TI - Delayed management of giant omphalocele using silver sulfadiazine cream: an 18 year experience. AB - BACKGROUND/PURPOSE: To assess the value of topical silver sulfadiazine (SSD) cream in the treatment of babies with a giant omphalocele. METHODS: From 1991 to 2008 inclusive, 20 infants with giant omphalocele (defined as >10 cm diameter) were treated with SSD, leaving a large ventral hernia to be repaired at a later date. RESULTS: There were 12 boys and 8 girls. Thirteen had prenatal ultrasound diagnosis at a mean gestational age of 23 weeks. The mean gestational age at delivery was 37 weeks, and mean birth weight was 2.5 kg. Nineteen had other anomalies and/or medical problems, 18 of them multiple. The most common was pulmonary hypoplasia (70%). Mechanical ventilation and/or oxygen treatment was required in 15 (75%) for a mean of 10 weeks. SSD was used as primary sac treatment in 5 and secondary treatment in 15 (after Silon pouch 11, Op-site 3, povidone-iodine 1). Six omphalocele sacs were ruptured within the first 5 days of life. SSD was used for a mean of 6 months at a cost of $1 per day. Complications included 2 instances of staphylococcal sepsis and 1 jejunal perforation inside a Silon pouch. Six (30%) died from pulmonary hypoplasia at a mean age of 18 weeks. There were 14 (70%) survivors who went home after a mean of 14 weeks. Of the 14 survivors, 12 had ventral hernias repaired (18 operations with 2 recurrences), and 2 remain with their original ventral hernia. CONCLUSIONS: Initial topical coverage with SSD is associated with excellent outcomes for infants with giant omphalocele who cannot undergo immediate closure. PMID- 22424345 TI - Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive familial intrahepatic cholestasis. AB - BACKGROUND/PURPOSE: The surgical treatment for patients with progressive familial intrahepatic cholestasis (PFIC) is either liver transplantation (LTX) or partial external biliary diversion (PEBD). Both procedures achieve a good short-term outcome. However, the treatment strategy for these children remains controversial because the long-term outcome after PEBD is unknown. The aim of our study was to assess the long-term outcome and complications after PEBD in our institution. METHODS: We retrospectively analyzed the characteristics of all patients with PFIC undergoing PEBD in our department from 1994 to 2008. The course of serum bile acids, pruritus, and liver enzymes was assessed in a regular follow-up. RESULTS: Twenty-four patients underwent PEBD. Thirteen patients (54%) improved significantly, with a normalization of serum bile acids (P < .001 vs postoperatively) and lessened pruritus (P < .05 vs preoperatively) at 12 months after PEBD. None of these patients showed progression of cholestasis during a median follow-up of 9.8 years (range, 1.6-14.3 years). Partial external biliary diversion failed to normalize bile acids in 11 patients, of whom 9 required secondary LTX at a 1-year follow-up, with a median interval of 1.9 years (range, 0.5-3.8 years). All 7 patients (100%) with liver cirrhosis at the time of PEBD and 2 of 17 patients without cirrhosis (12%) required secondary LTX (P < .001). CONCLUSIONS: Clinical improvement with normalization of serum bile acids within 1 year was associated with an excellent long-term outcome in patients with PEBD. The presence of liver cirrhosis at the time of PEBD indicated an unfavorable outcome. Thus, we recommend primary LTX only in PFIC patients with liver cirrhosis. PMID- 22424346 TI - Timing of surgery for prenatally diagnosed asymptomatic choledochal cysts: a prospective randomized study. AB - BACKGROUND/PURPOSE: Choledochal cysts (CDCs) are increasingly being diagnosed antenatally. The timing of surgery in this group of patients is unclear. We undertook a prospective randomized trial to establish the optimal timing of surgery for prenatally diagnosed asymptomatic CDCs. METHODS: Between 2003 and 2011, 68 fetuses with ultrasound-detected subhepatic cysts (ie, potential CDC) were randomized into 2 groups: (1) early (<=1 month) operation group (n = 34) and (2) late (>1 month) operation group (LO; n = 34). Operative time, postoperative hospital stay, drainage duration, postoperative complications, and perioperative ultrasonographic and laboratory results were analyzed. RESULTS: During the first month of life, 32 infants became symptomatic (eg, became jaundiced) and were excluded from the trial. This left 36 neonates who were asymptomatic (early operation, n = 16; LO, n = 20) and constituted the study group. It is noteworthy that a further 9 infants in the LO group then became symptomatic after 1 month of age. Grades III and IV hepatic fibroses were significantly more common in the LO group and in patients who were diagnosed during early pregnancy. Interestingly, liver functions in patients diagnosed at early fetal stage were only moderately deranged. Median follow-up period was 36 months. Neither mortality nor complications of bile leak or anastomotic stricture were encountered. However, complete liver function normalization was significantly delayed in the LO group and in patients with high-grade hepatic fibrosis. CONCLUSION: Prenatally diagnosed CDC is a distinct group with a tendency of developing liver fibrosis immediately after birth. Early surgical intervention is warranted in the neonatal period. PMID- 22424347 TI - Effects of selective bile duct ligation on liver parenchyma in young animals: histologic and molecular evaluations. AB - BACKGROUND/PURPOSE: The mechanisms of increased collagen production and liver parenchyma fibrosis are poorly understood. These phenomena are observed mainly in children with biliary obstruction (BO), and in a great number of patients, the evolution to biliary cirrhosis and hepatic failure leads to the need for liver transplantation before adolescence. However, pediatric liver transplantation presents with biliary complications in 20% to 30% of cases in the postoperative period. Intra- or extrahepatic stenosis of bile ducts is frequent and may lead to secondary biliary cirrhosis and the need for retransplantation. It is unknown whether biliary stenosis involving isolated segments or lobes may affect the adjacent nonobstructed lobes by paracrine or endocrine means, leading to fibrosis in this parenchyma. Therefore, the present study aimed to create an experimental model of selective biliary duct ligation in young animals with a subsequent evaluation of the histologic and molecular alterations in liver parenchyma of the obstructed and nonobstructed lobes. METHODS: After a pilot study to standardize the surgical procedures, weaning rats underwent ligation of the bile ducts of the median, left lateral, and caudate liver lobes. The bile duct of the right lateral lobe was kept intact. To avoid intrahepatic biliary duct collaterals neoformation, the parenchymal connection between the right lateral and median lobes was clamped. The animals were divided into groups according to the time of death: 1, 2, 3, 4, and 8 weeks after surgical procedure. After death, the median and left lateral lobes (with BO) and the right lateral lobe (without BO [NBO]) were harvested separately. A group of 8 healthy nonoperated on animals served as controls. Liver tissues were subjected to histologic evaluation and quantification of the ductular proliferation and of the portal fibrosis. The expressions of smooth muscle alpha-actin (alpha-SMA), desmin, and transforming growth factor beta1 genes were studied by molecular analyses (semiquantitative reverse transcriptase-polymerase chain reaction and real-time polymerase chain reaction, a quantitative method). RESULTS: Histologic analyses revealed the occurrence of ductular proliferation and collagen formation in the portal spaces of both BO and NBO lobes. These phenomena were observed later in NBO than BO. Bile duct density significantly increased 1 week after duct ligation; it decreased after 2 and 3 weeks and then increased again after 4 and 8 weeks in both BO and NBO lobes. The portal space collagen area increased after 2 weeks in both BO and NBO lobes. After 3 weeks, collagen deposition in BO was even higher, and in NBO, the collagen area started decreasing after 2 weeks. Molecular analyses revealed increased expression of the alpha-SMA gene in both BO and NBO lobes. The semiquantitative and quantitative methods showed concordant results. CONCLUSIONS: The ligation of a duct responsible for biliary drainage of the liver lobe promoted alterations in the parenchyma and in the adjacent nonobstructed parenchyma by paracrine and/or endocrine means. This was supported by histologic findings and increased expression of alpha-SMA, a protein related to hepatic fibrogenesis. PMID- 22424348 TI - Portal vein reconstruction in pediatric living donor liver transplantation for patients younger than 1 year with biliary atresia. AB - BACKGROUND/PURPOSE: Infants with biliary atresia undergoing living donor liver transplantation (LDLT) are at increased risk of portal vein (PV) complications because of their smaller vascular caliber and sclerosis because of previous Kasai portoenterostomy and recurrent cholangitis. METHOD: Of 154 children who underwent transplantation between November 2005 and January 2011, 34 with biliary atresia received a transplant while younger than 1 year. Six patients underwent PV reconstruction with an interposition vein graft, and the others underwent the branch patch technique. The clinical characteristics of those who underwent the interposition reconstruction or the branch patch technique were compared, and the PV complications were assessed. RESULTS: Portal vein complications occurred in 5 patients (14.7%) in the branch patch group. There were 4 patient deaths, and all of them had received branch patch reconstruction. The branch patch reconstruction cases with a sclerotic small caliber (<4 mm) determined by using preoperative ultrasonography showed a significantly high mortality rate (44.4%). All patients with interposition vein graft reconstruction are still alive with excellent graft function without anticoagulation therapy. CONCLUSION: The interposition vein graft appears to be a feasible option with better graft survival and less PV complications when performing LDLT for biliary atresia in infants younger than 1. PMID- 22424349 TI - Diagnosis and management of hydatid liver disease in children: a report of 156 patients with hydatid disease. AB - BACKGROUND/PURPOSE: There are many published reviews on adult hydatid disease and a guideline published by World Health Organization Informal Working Group (WHO IWGE) in 2010. However, there are very few reports on hydatid liver disease in children with limited numbers of patients, and no comments were offered on childhood hydatid liver disease in the WHO-IWGE 2010 guideline. The aim of this study is to present our 17-year experience with 156 pediatric patients with hydatid liver disease and provide a treatment algorithm for children. METHODS: The clinical records of 156 children with hydatid liver disease treated from January 1994 to January 2011 were retrospectively reviewed. Patient sex, age at diagnosis, symptoms, disease location, cyst numbers and sizes, treatment choices, medical treatment duration, surgical methods, and complications were recorded. Treatment of liver hydatidosis included 3 different schedules: (1) small (<5 cm) liver cysts treated with albendazole (ABZ) only, (2) cysts (>5 cm) located at the liver surface treated with surgery combined with ABZ, and (3) all (>5 cm) liver cysts embedded deep in the liver parenchyme treated with percutaneous drainage and ABZ. Albendazole was given (10 mg/kg twice a day) and continued for 6 months after initial therapy. RESULTS: There were 92 boys and 64 girls with an average age of 9.2 years (range, 1.1-15 years). A total of 376 cysts were detected in 156 patients. The follow-up period ranged from 1 to 10 years (median, 6.5 years). Complications were classified according to the Dindo classification. After the first 6 months of therapy, grade I complications occurred in 12.1% of patients, grade II complications in 7.4%, and grade IIIb complications in 7.3%. There were no grade IIIa, IVa, or IVb complications. At 1 year, grade II complications were recorded in 9.6% of 15 patients, and grade IIIb complications, in 1.2% of patients. During the 17 years reviewed, there were no mortalities (0% grade V complications). CONCLUSIONS: Based on this experience, we believe that suitable treatment should be chosen based on factors such as cyst number, cyst location (on the surface or deep in the organ), proximity to vascular structures, whether the cyst is complicated, and additional organ involvement or not. In addition, although the results of our study mostly agree with the results in the WHO-IWGE 2010 report, there are some noticeable differences between these 2 studies. Hence, we believe that the WHO-IWGE 2010 recommendations should be updated by incorporating the childhood observations. PMID- 22424350 TI - Streptococcus milleri in intraabdominal abscesses in children after appendectomy: incidence and course. AB - INTRODUCTION: Intraabdominal abscesses are a common complication after appendectomy, especially in children. In this study, we describe the incidence and course of this complication in relation to the cultured pathogens found in intraabdominal abscesses. METHODS: The charts of all patients between 1 and 18 years of age undergoing appendectomy in 3 hospitals between January 2006, and July 2009, were retrospectively reviewed. Presence of an intraabdominal abscess was confirmed with abdominal ultrasound examination. We collected all details concerning the appendectomy, pus cultures, and postoperative course in these patients. RESULTS: Two hundred fifty-nine patients underwent appendectomy during the study period. Subsequently, abdominal ultrasound studies showed an intraabdominal abscess in 18 (7%) patients. Intraabdominal abscesses developed more frequently after perforated appendicitis (23%) than after simple appendicitis (2%). The incidence of postoperative abscesses did not differ significantly between open (5.6%) or laparoscopic (6.3%) appendectomy. However, the rate was high (38%) in the patients in whom the appendectomy was converted from laparoscopic to open. In 15 out of the 18 patients with a postoperative abscess drainage was performed. In pus cultures of the drained abscesses Streptococcus milleri and Escherichia coli were the most commonly isolated pathogens. Presence of S milleri was associated with prolonged hospital stay (13.9 versus 9.0 days, P = .105) and prolonged antibiotic treatment (11.3 versus 4.8 days, P = .203). CONCLUSIONS: The incidence of intraabdominal abscesses is high after perforated appendicitis in children (23%). Our data suggest that the presence of S milleri correlates with a more complicated postoperative course after appendectomy in children. PMID- 22424351 TI - N-acetylcysteine may prevent severe intestinal damage in necrotizing enterocolitis. AB - OBJECTIVE: The aim of this study was to evaluate the preventive effect of N acetylcysteine (NAC) on the development of necrotizing enterocolitis (NEC) in an experimental rat model. MATERIAL AND METHODS: Thirty newborn Sprague-Dawley rats were randomly divided into 3 groups: NEC, NEC + NAC, and control. Necrotizing enterocolitis was induced by enteral formula feeding, exposure to hypoxia hyperoxia, and cold stress. Pups in the NEC + NAC group were administered NAC at a dose of 150 mg/kg daily by intraperitoneal route from the first day until the last day of the study. All pups were killed on the fifth day. Proximal colon and ileum were excised for histopathologic, immunohistochemical (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and caspase-3, caspase-8, caspase-9), and biochemical evaluation, including xanthine oxidase, total antioxidant status, total oxidant status, malondialdehyde, and myeloperoxidase activities. RESULTS: The pups in the NEC + NAC group had better clinical sickness scores compared with those in the NEC group (P < .05). In histopathologic and apoptosis evaluations (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and immunohistochemical evaluation for caspase-3 and caspase-9), the severity of bowel damage was significantly less in the NEC + NAC group compared with the NEC group (P < .01). Tissue malondialdehyde, myeloperoxidase, xanthine oxidase levels, and total oxidant status were significantly decreased in the NEC + NAC group, whereas total antioxidant status (TAS) was significantly increased in the NEC + NAC group (P < .01). CONCLUSION: N-acetylcysteine therapy significantly reduced the severity of intestinal damage in NEC. PMID- 22424352 TI - Is there a link between the calcium sensing receptor and Hirschsprung's disease? A mutational analysis. AB - INTRODUCTION: Hirschsprung's disease (HD) is a congenital malformation of the hindgut characterized by the absence of enteric ganglion cells in the submucosal and myenteric plexuses. Hirschsprung's disease is routinely treated by resection of the aganglionic bowel and pull-through procedure of the proximal ganglionated bowel to the anorectal region. Occasionally, after resection of the aganglionic bowel, HD patients still experience persistent disturbances in gut motility. The etiology of HD as well as the underlying pathomechanism for postoperative disturbances in gut motility is unclear. Molecular analysis of putative candidate genes may help to clarify the pathophysiology of these conditions. In the present study, we investigated the correlation between mutations and polymorphisms in the calcium sensing receptor (CaSR) and HD patients. METHODS: Mutational screening of the CaSR coding sequence was performed via polymerase chain reaction and direct sequencing of the amplified samples from 63 HD patients and 100 controls. RESULTS: We identified 3 common polymorphisms (p.A986S, p.G990R, and p.Q1011E) residing in exon 7 and 1 polymorphism in intron 5 (IVS 5-88 T>C) of the CaSR gene. Overall, 16 patients (25%) and 25 controls (25%) were carriers of the p.A986S polymorphism (P = 1). The incidence of p.R990G polymorphism of patients was twice as high as in the control group (P = .17). Furthermore, we verified a 4 times higher incidence of p.Q1011E polymorphism carriers in patients compared to the control group (P = .1). CONCLUSION: We found a higher incidence of R990G and Q1011E polymorphisms in HD patients compared to controls. However, there was no statistically significant association between HD and the 3 polymorphic variants in the intracellular signaling region of CaSR. It will be important to further investigate genetic variations in CaSR in more patient cohorts to better characterize the function of this gene and to establish a correlation between CaSR variants and HD. PMID- 22424353 TI - Up-regulated cystic fibrosis transmembrane conductance regulator after anal stenosis in rats. AB - BACKGROUND: The pathophysiology of fecal incontinence from fecal impaction and rectal distension is poorly understood. We hypothesize that fecal impaction elicits up-regulation of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated mucosal chloride channel. METHODS: The anus was ligated to produce 75% stenosis in rats. Controls received ligation without inducing stenosis. 24 to 48 hours after ligation the colon was removed. Mucosal short circuit current was measured by Ussing chamber. Western blot analysis was used to detect CFTR expression in the colonic mucosa. Ligated rats failed to defecate, whereas control rats stooled normally. RESULTS: Ligated colons were markedly stool filled and dilated. Water content of feces was significantly increased to 66.5% +/- 1.1% (P < .01, n = 12) 24 hours after ligation, vs controls (49.5 +/- 5.2%, n = 12). Baseline short-circuit current was significantly increased in the distal (78.8 +/- 7.4 MUA/cm(2), n = 8, P < .01) and mid colon (24.5 +/- 2.5 MUA/cm(2), n = 8, P < .05) 24 hours after ligation, compared to control rats (12.5 +/- 3.2 MUA/cm2, n = 8). CFTR expression was significantly increased 24 hours after ligation in the mid and distal colon. CONCLUSION: We observe that fecal impaction from anal ligation induces early compensatory up-regulation of CFTR, altering function from net absorption to net secretion in the mid and distal colon. PMID- 22424354 TI - Laparoscopic repair of anorectal malformations at the Red Cross War Memorial Children's Hospital: taking stock. AB - BACKGROUND: The current standard repair for anorectal malformations in children is a posterior sagittal anorectoplasty. Recently, laparoscopic-assisted anorectoplasty (LAARP) was performed at the Red Cross Children's Hospital. METHODS: A detailed case note review was conducted. Patient outcome was prospectively evaluated by colorectal nurse specialists using the Krickenbeck standardized questionnaire. Comparison among patients undergoing posterior sagittal anorectoplasty was performed. RESULTS: Between September 2005 and June 2009, 24 children underwent LAARP. Sixteen had associated anomalies, including 7 children with renal and 4 children with cardiac abnormalities. Median age at surgery was 7.5 months (range, 2.6-15.0 months). Subtypes of anorectal malformation were as follows: vestibular, 2; bulbar, 9; prostatic, 7; vesical, 3; and with no fistula, 3. There was a 16% early complication rate. Redo-anoplasty was required in 9 patients. Eleven children had difficulties with follow-up. Thirteen children had regular follow-up and were analyzed further. Toilet training had been completed in 7 children (median age, 4.3 years; range, 3.5-6 years). Six children developed voluntary bowel motions. Six children are awaiting toilet training or are unable to train because of incontinence. CONCLUSIONS: Anal stenosis was the most common complication post-LAARP. Etiology appeared to be multifactorial, but poor compliance with dilatations was a leading cause. PMID- 22424355 TI - Vaginal agenesis or distal vaginal atresia associated with anorectal malformations. AB - BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is defined as Mullerian aplasia with vaginal agenesis and uterine remnants. It is commonly associated with renal and sometimes vertebral anomalies. The MRKH syndrome or distal vaginal atresia is sometimes associated with anorectal malformations. The purpose of this study was to describe 7 girls with vaginal agenesis or distal vaginal atresia and an anorectal malformation and review the literature. METHODS: Seven patients with vaginal agenesis or distal vaginal atresia and anorectal malformation were operated on at 3 pediatric surgical centers in Madrid, Helsinki, and Stockholm. Case records were reviewed, and the previous literature was searched. RESULTS: Six patients had a reconstruction of the anorectum and vagina during the first year of life. In one case, the vagina was replaced at the time of a redo posterior sagittal anorectoplasty at the age of 11 years. The 4 patients with vaginal agenesis had a sigmoid colovaginoplasty. The 3 patients with a distal vaginal atresia had a vaginal pull-through. Four of the patients needed laxatives or enemas for mild constipation at last follow-up. Short-term gynecologic problems were minor in all patients. CONCLUSION: Vaginal reconstruction at the time of anorectoplasty results in good short-term outcome. For vaginal agenesis, a primary colovaginoplasty is suggested to be the preferred technique to replace the vagina. PMID- 22424356 TI - Morphological study of the residual ovarian tissue removed by laparoscopy or laparotomy in adolescents with benign ovarian cysts. AB - BACKGROUND/PURPOSE: The stripping of benign ovarian cysts has been reported to be preferable to cyst wall ablation. The procedure can be performed via either an open or laparoscopic approach. The aim of our study was to evaluate the efficacy of the technique of stripping performed by laparoscopy and laparotomy in the treatment of benign ovarian masses in the pediatric age group with respect to healthy ovarian tissue. METHODS: This retrospective study evaluated all the pediatric or adolescent patients admitted during a 5-year period (2006-2010) for a suspected benign ovarian cyst treated with a laparoscopic technique or traditional open surgery to remove the cyst. The morphological characteristics of the tissue were graded on a semiquantitative scale from 0 to 4. RESULTS: Thirty patients were treated and divided in 2 groups: group A laparoscopy (18 patients) and group B open (12 patients). The median age was 9.1 years. No ovarian tissue could be observed in 26 cases (86.7%). In the 4 remaining (2 laparoscopic and 2 open) cases (13.3%), ovarian tissue was found, but never more than 1 mm in thickness. This finding was always in endometriotic cysts. CONCLUSIONS: We demonstrated that, in the pediatric population, no ovarian tissue is removed together with the cyst if this is nonendometriotic. The type of surgical procedure does not influence the removal of ovarian tissue. Laparoscopic stripping of ovarian cysts is the preferable surgical procedure in patients with prospective potential fertility because of their young age. PMID- 22424357 TI - Total colonic aganglionosis with skip lesions: report of a rare case and management. AB - We present an unusual case of total colonic aganglionosis with well-documented skip lesions and discuss our staged approach for diagnosis and surgical management. To date, there have been few reported cases of total colonic aganglionosis with skip areas. This type of presentation challenges the accepted theory regarding the etiology of colonic aganglionosis. Although skip lesions in Hirschsprung disease are extremely rare, their existence must be appreciated especially when a patient's clinical and pathologic findings do not support classic Hirschsprung disease. If not considered, additional areas of aganglionosis can be missed at initial presentation, leading to a delay in definitive treatment. This case illustrates how careful mapping of bowel via multiple biopsies can identify and thereby preserve intervening segments of bowel with normal ganglions cells to yield the maximal amount of bowel possible. PMID- 22424358 TI - Life-threatening postoperative hemorrhage from hepatic artery pseudoaneurysm successfully treated by transcatheter embolization in a 5-year-old. AB - Upper gastrointestinal bleeding caused by a pseudoaneurysm after hepatobiliary operation is well described in adults. This can be successfully treated with transcatheter embolization under angiographic guidance. We report a case of massive upper gastrointestinal bleeding in a 5-year-old boy secondary to a pseudoaneurysm of the right hepatic artery after choledochal cyst excision. A coil embolization successfully treated this life-threatening event and spared the child, the morbidity of a challenging gastrointestinal and vascular reconstruction. Use of percutaneous interventional technique to treat this rare complication of choledochal cyst excision has not been previously described in the pediatric surgical literature. Transcatheter embolization of a pseudoaneurysm may be a safe and less morbid treatment alternative for this surgical complication even in the pediatric population. PMID- 22424359 TI - Small cell carcinoma of the ovary of hypercalcemic type: a case report. AB - The authors report a case of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), in a mother and daughter and discuss the possibility of a heritable risk. Both mother and daughter were treated at the same institution for SCCOHT. A 23-year-old woman presented with hypercalcemia 4 months after giving birth to her daughter. She was diagnosed as having SCCOHT. Despite surgery, chemotherapy, and radiation, she died of the disease 11 months after diagnosis. Eleven years later, her daughter presented with a histologically and immunophenotypically identical SCCOHT tumor. She received postoperative chemotherapy and radiation but, eventually, relapsed and died of the disease at 27 months after the initial diagnosis. Small cell carcinoma of the ovary, hypercalcemic type, is an uncommon and aggressive malignancy that occurs in young women, which is associated with a solid ovarian tumor and hypercalcemia. Despite aggressive multimodality treatment, most patients die within 2 years of diagnosis. Genetic counseling, sonographic ovarian surveillance and serum calcium monitoring at early age, and even prophylactic oophorectomy should be considered for surviving at-risk family members. PMID- 22424360 TI - Rare late complication of the Nuss procedure: a case report. AB - The Nuss procedure is a surgical repair technique for pectus excavatum with fewer delayed complications reported in the current literature. We report the case of a 23-year-old male who presented after a syncopal episode during activity. Further evaluation demonstrated a fibrous band causing severe right ventricle outflow obstruction from a prior Nuss procedure. PMID- 22424361 TI - Rectal bleeding, deep venous thrombosis, and coagulopathy in a patient with Klippel-Trenaunay syndrome. AB - Klippel-Trenaunay syndrome (KTS) is a rare noninheritable congenital disorder comprising vascular malformations that predispose patients to a paradoxical condition where bleeding occurs in a hypercoagulable state. A 16-year-old boy with a complicated lifetime course of KTS presented with massive rectal bleeding. He underwent a partial colectomy, endorectal resection, and splenectomy. Postoperatively, he developed a saddle pulmonary embolus, ultimately requiring placement of an inferior vena cava filter. He eventually did well and has since had his diverting ostomy reversed and resumed his usual activities. This report validates the use of endorectal resection for venous malformation of the rectum in patients with KTS and highlights the difficult balance of controlling bleeding by correction of a consumptive coagulopathy and the increased risk of thromboembolic complications. PMID- 22424362 TI - The risks of minimal access surgery in children: an aid to consent. AB - AIM: The aim of this study was to determine the risk of complications and conversions for minimally invasive procedures in children, thus allowing properly informed consent. METHODS: Data were retrieved for all minimally invasive surgical procedures performed between 1995 and 2009. RESULTS: There were 2352 cases performed in 2288 (1428 were male) patients. Of these, 2210 cases (94%) were laparoscopic, and 143 (6%), thoracoscopic. The median age at operation was 6 years and 4 months. The overall complication rate was 3.6%, with the risk of early reoperation at 1.7%. The risk was highest for fundoplication and pyloromyotomy at 3.2% and 4%, respectively. The risk of an infective complication was 0.5% and was highest for appendicectomy and nephrectomy. The risk of visceral injury overall in this series was 0.4%. Visceral injury, explicable only by port insertion, occurred in just under 1 in 1000 cases. The conversion rate was 2.3%. The lowest rates were observed with appendicectomy, fundoplication, and pyloromyotomy. Thoracoscopic cases, nephrectomies, and procedures for an underlying oncological diagnosis had a higher conversion rate. CONCLUSION: Informed consent requires knowledge of the risks of surgery. This series may serve as an aid for other units in obtaining consent for minimally invasive surgery in the pediatric population. PMID- 22424363 TI - Infected common iliac artery aneurysm repaired in an infant with cadaveric vein graft. AB - Aneurysms are rare in children. Causes include congenital, traumatic, inflammatory, and infectious etiologies. When and how to best surgically treat arterial aneurysms in a child remain unclear. We present the case of a 3-month old child with an aneurysm of the left common iliac artery, which was first detected on abdominal ultrasound and was successfully repaired with a cadaveric vein graft. PMID- 22424364 TI - Cecal bascule in a child: an unusual cause of postoperative bowel obstruction. AB - Cecal bascule is a rare type of intestinal obstruction that occurs when a mobile cecum folds upward and obstructs the ascending colon. Most often occurring in the elderly, we present the first reported case of cecal bascule in a child. The cecal bascule occurred in a 4-year-old with trisomy 13 syndrome 5 days after a laparoscopic Nissen fundoplication. After a delay in diagnosis and cecal reduction in the operating room, the bascule recurred after 1 year, and the child was treated with a cecostomy tube for both cecopexy and cecal decompression. Cecal bascule should be considered in the differential diagnosis of children with early postoperative bowel obstruction, especially in the developmentally delayed status-post laparoscopic surgery. For the pediatric patient with cecal bascule, we recommend operative management with either cecopexy or resection. PMID- 22424365 TI - Button cystostomy for bladder drainage: which children can benefit from this device? AB - AIM: The aim of this study is to define which children could benefit from a button cystostomy. We describe a safe way to perform the insertion of a button cystostomy for urinary diversion and provide more precise instructions concerning the best indications for this device. MATERIALS AND METHODS: We analyzed several criteria of the follow-up of all the patients who had a button cystostomy since 2007 including indications, age, urodynamic variables, and complications. RESULTS: Twenty-one patients underwent a button cystostomy. A group of young children was included in the study (mean age, 2 years), in which most of the failed procedures were observed, whereas we had better results with the second group of older children (mean age, 12 years). CONCLUSIONS: The analysis of indications and, more particularly, urodynamic variables regarding the quality of the results allows us to clearly define which children can benefit from this procedure with a good chance of success and low risk of complications. PMID- 22424366 TI - The slit-like adjusted Mathieu technique for distal hypospadias. AB - PURPOSE: The aims of this study were to describe the slit-like adjusted Mathieu technique (SLAM) for distal and midpenile hypospadias and report the midterm follow-up. MATERIALS AND METHODS: Between January 2005 and December 2009, the SLAM technique was performed in 923 patients. The key modification is the design of a converging incision and the technique of suturing. Patient age ranged between 4 months to 30 years (mean, 1.5 years). The records of 872 patients who maintained regular follow-up were reviewed. The technique was performed in all forms of distal hypospadias, regardless of the size of the glans or the degree of glans clefting. Cutaneous chordee was corrected by skin mobilization. Follow-up period ranged from 22 months to 6 years (mean, 38 months). A transurethral catheter was used for 1 to 3 days. RESULTS AND COMPLICATIONS: Satisfactory results were obtained in 848 patients (97%). Fourteen patients developed fistulae. Four patients developed meatal stenosis. Six patients had wound dehiscence. CONCLUSIONS: The SLAM technique is a reliable technique for correction of distal and midpenile hypospadias with persistent good results. It avoids the drawbacks of the classic Mathieu (a transverse rounded meatus that is not terminal). Multiple-layer closure and careful attention to technical details contributed to a 3% complication rate in primary distal hypospadias. PMID- 22424367 TI - Free health care in Sierra Leone: the effect on pediatric surgery. PMID- 22424368 TI - Multiple intestinal anastomoses to avoid short bowel syndrome and stimulate bowel maturity in type IV multiple intestinal atresia and necrotizing enterocolitis. PMID- 22424369 TI - Chest wall repair in Poland syndrome: complex single-stage surgery including Vertical Expandable Prosthetic Titanium Rib stabilization--a case report. AB - Various surgical techniques have been described for repair of chest wall defects in Poland syndrome. We describe the case of a 16-year-old boy who underwent autologous rib transposition after sternal osteotomy. Chest wall stabilization was achieved using a combination of K-wires and Vertical Expandable Prosthetic Titanium Rib (Synthes GmbH, Freiburg, Germany). Reconstruction of the soft tissue defect was accomplished by combined latissimus dorsi muscle flap and Permacol patch (Covidien Deutschland GmbH, Neustadt, Germany). This approach might be considered an effective 1-stage treatment option of this condition in postpubescent boys. PMID- 22424370 TI - A thoracoabdominal approach in revision of the hepatic hilum after left lobe living donor liver transplantation. AB - We present an approach to safely expose the hepatic hilum for revision procedures after left lobe living donor liver transplantation. A 14-year-old adolescent girl who had undergone left lobe living donor liver transplantation experienced repeated episodes of cholangitis. Because treatment with interventional techniques failed, surgical revision was indicated. The right thoracoabdominal approach was selected to minimize dissection. Intraoperative findings showed adhesive kinking of the Roux-Y limb just distal to the bilioenteric anastomosis, and a side-to-side jejunojejunostomy was performed. The thoracoabdominal approach leads to easy and excellent reoperative exposure of the hilar site of a left lobe liver graft. PMID- 22424371 TI - Trichobezoar causing pancreatitis: first reported case of Rapunzel syndrome in a boy in North America. AB - Trichobezoar is a mass of hair retained in the stomach, usually associated with trichotillomania. Large trichobezoars may extend into the small bowel and cause small bowel obstruction or pancreatic dysfunction, a condition known as Rapunzel syndrome. Here we report the first North American case of Rapunzel syndrome in a male patient. PMID- 22424372 TI - Thoracoscopic management of a communicating bronchopulmonary foregut malformation in a 23-month-old child. AB - A communicating bronchopulmonary foregut malformation is a rare anomaly characterized by a fistula between an isolated portion of respiratory tissue and the esophagus or stomach. We describe the thoracoscopic management of a communicating bronchopulmonary foregut malformation in a 23-month-old boy by division of an anomalous bronchus and right upper lobectomy. PMID- 22424373 TI - Surgical management of upper- and lower-lobe bronchiectasis without middle lobe involvement: is middle lobectomy necessary? AB - Postoperative quality of life is a crucial factor in decisions regarding surgical management of bronchiectasis. The goal of surgical treatment in such cases is to eradicate diseased portions of lung while preserving as much healthy lung parenchyma as possible. The volume of remaining lung must be sufficient to fill the pleural space. In patients with bronchiectasis, it is extremely unusual to have upper- and lower-lobe involvement without middle lobe involvement. A normal sized middle lobe alone is usually not adequate to fill the right hemithorax. When the disease involves both the upper and lower lung lobes, surgeons must assess whether pneumonectomy is required. Herein, we describe the case of a patient with bronchiectasis who was successfully treated with upper and lower lobectomy and preservation of the middle lobe. PMID- 22424374 TI - Primary pleural non-Hodgkin lymphoma in a child--an exceedingly rare disease. AB - Primary pleural lymphomas are very rare. Two types are described in the literature: primary effusion lymphoma, in the setting of human immunodeficiency virus infection, and pyothorax-associated lymphomas, with a strong Epstein-Barr virus association. We report a rare case of a primary pleural lymphoma in a 12 year-old immunocompetent girl who presented with a hemorrhagic pleural effusion and had plaque-like thickening of the pleura. The histologic and immunophenotypic findings conformed to that of a diffuse large B-cell lymphoma (CD20 positive). PMID- 22424375 TI - Congenital pancreatic cyst with Ivemark II syndrome: a rare case. AB - An infant with congenital pancreatic cyst with Ivemark II syndrome is reported because it is a rare association. The infant had associated situs inversus, asplenia, and complex congenital heart disease. The pancreatic cyst was successfully managed by cystoduodenostomy because of connection to the biliary tract. The infant succumbed as a result of heart failure at age 2 months. Prognosis depends on the presence of life-threatening malformations. PMID- 22424376 TI - Radiofrequency ablation in the treatment of liver tumors in children. AB - Hepatoblastoma and liver metastasis of Wilms' tumors are rare hepatic tumors in children. Treatment of both tumors consists of a combination of chemotherapy and liver surgery. Radiofrequency ablation (RFA) is frequently used for the treatment of adult liver tumors but is rarely mentioned as a treatment option in pediatric liver tumors. We present a patient with hepatoblastoma and 1 with liver metastasis from a Wilms' tumor. Both patients were treated according to the latest protocols except that surgery included use of RFA. Both are well and recurrence free 8 and 3 years after surgery. Radiofrequency ablation may be a good addition to the existing arsenal of treatment modalities for pediatric liver tumors. PMID- 22424377 TI - Electron paramagnetic resonance-based pH mapping using spectral-spatial imaging of sequentially scanned spectra. AB - The development of electron paramagnetic resonance (EPR)-based mapping of pH is an important advancement for the field of diagnostic imaging. The ability to accurately quantify pH change in vivo and monitor spatial distribution is desirable for the assessment of a number of pathological conditions in the human body as well as the monitoring of treatment response. In this work we introduce a method for EPR-based pH mapping utilizing a method of spectral-spatial imaging of sequentially scanned spectra to decrease the missing gradient rotation angle, without increasing the spatial field of view. Repeated in vitro measurements of pH phantom tubes demonstrated higher precision measurements of the hyperfine coupling constant (HFC) compared to previous EPR-based methods, resulting in mean pH values accurate to less than 0.1 pH across a range of physiologically observed values. PMID- 22424378 TI - High identification rates of endogenous neuropeptides from mouse brain. AB - Mass spectrometry-based neuropeptidomics is one of the most powerful approaches for identification of endogenous neuropeptides in the brain. Until now, however, the identification rate of neuropeptides in neuropeptidomics is relatively low and this severely restricts insights into their biological function. In the present study, we developed a high accuracy mass spectrometry-based approach to enhance the identification rates of neuropeptides from brain tissue. Our integrated approach used mixing on column for loading aqueous and organic extracts to reduce the loss of peptides during sample treatment and used charge state-directed tandem mass spectrometry to increase the number of peptides subjected to high mass accuracy fragmentation. This approach allowed 206 peptides on average to be identified from a single mouse brain sample that was prepared using 15 MUL of solutions per 1 mg of tissue. In total, we identified more than 500 endogenous peptides from mouse hypothalamus and whole brain samples. Our identification rate is about two to four times higher compared to previously reported studies conducted on mice or other species. The hydrophobic peptides, such as neuropeptide Y and galanin, could be presented and detected with hydrophilic peptides in the same LC-MS run, allowing a high coverage of peptide characterization over an organism. This will advance our understanding of the roles of diverse peptides and their links in the brain functions. PMID- 22424379 TI - Fatigue in multiple sclerosis: a diagnostic and therapeutic challenge. PMID- 22424381 TI - Problem solving interventions: an opportunity for hospice social workers to better meet caregiver needs. PMID- 22424382 TI - Exploring professional boundaries in end-of-life care: considerations for hospice social workers and other members of the team. AB - Hospice social workers and members of the interdisciplinary team develop close therapeutic relationships with patients and families as they journey toward death. During this process, situations can develop that challenge professional boundaries and blur the line between a professional and personal relationship. This article will examine professional boundaries within the context of hospice care through case studies identifying challenges that hospice social workers and members of the interdisciplinary team may encounter with recommendations for how to manage boundary concerns. PMID- 22424383 TI - Just give me hope: lived experiences of Medicaid patients with advanced cancer. AB - The purpose of this phenomenological exploration was to describe the lived experiences of persons diagnosed with advanced cancer who receive Medicaid. Themes emerged from the transcribed interviews of 10 participants in accordance with the cancer trajectory. Before diagnosis, participants were uninsured or underinsured and had more severe symptoms prior to late diagnosis. Upon diagnosis, they desired hopeful, respectful communication and experienced strong emotional reactions. There was also an abrupt change in the use of health care resources. During cancer treatment, they experienced social isolation from family and friends while receiving strong psychosocial support from the health care team. Throughout the cancer trajectory, they focused on living, reclaiming normalcy, and expressed resiliency and spirituality. Findings support the need to recognize the "fighting spirit" of patients regardless of prognosis or socioeconomic status; the impact of hopeful, respectful communication; and the value of oncology social work assistance when navigating the cancer experience. Lack of health care coverage prior to severe symptoms prevented earlier diagnosis and contributed to poor physical outcomes. Medicaid eligibility enabled these patients to receive quality health care and focus on living beyond cancer. PMID- 22424384 TI - Interdisciplinary hospice team processes and multidimensional pain: a qualitative study. AB - Hospice teams may address multidimensional pain through the synergistic interaction of team members from various professional disciplines during regularly scheduled team meetings. However, the occurrence of that critical exchange has not been adequately described or documented. The purpose of this qualitative study was to explore two processes in team pain palliation: communication and collaboration. Data were gathered through individual interviews and a 1-year observation of team members from two hospices (physicians, nurses, aides, chaplains, social workers). Utilizing constant comparison, 14 final thematic categories were discovered. Use of biopsychosocial/spiritual terms by all team members meant that the team had the common language needed to communicate about multidimensional pain. Interviews and observation revealed a gap in translating multidisciplinary communication in team meetings into collaborative acts for pain treatment. In addition, structural influences inhibited creativity in pain palliation. There was no mutual understanding of the purpose for team meetings, no recognition of the need to reflect on team process, or common definition of leadership. Social work roles in hospice should include leadership that moves teams toward interdisciplinary care for multidimensional pain. PMID- 22424385 TI - Using a LISTSERVTM to develop a community of practice in end-of-life, hospice, and palliative care social work. AB - An e-mail discussion group (SW-PALL-EOL) connects the growing number of social workers interested in palliative and end-of-life care. The article discusses the concept of a technology supported "Community of Practice." Using content analysis, the article shows empirically how this electronic discussion group has contributed to the growth and expansion of a Community of Practice dedicated to improving palliative and end-of-life care among social workers. Examples are provided of the topics posted by subscribers and the guidance provided by the group's facilitators. Comments indicate satisfaction with the electronic discussion group. PMID- 22424389 TI - Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model. AB - BACKGROUND: Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats. METHODS: Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus. RESULTS: We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function. CONCLUSIONS: We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia. PMID- 22424390 TI - Tyrosine modifications in aging. AB - SIGNIFICANCE: The understanding of physiological and pathological processes involving protein oxidation, particularly under conditions of aging and oxidative stress, can be aided by proteomic identification of proteins that accumulate oxidative post-translational modifications only if these detected modifications are connected to functional consequences. The modification of tyrosine (Tyr) residues can elicit significant changes in protein structure and function, which, in some cases, may contribute to biological aging and age-related pathologies, such as atherosclerosis, neurodegeneration, and cataracts. RECENT ADVANCES: Studies characterizing proteins in which Tyr has been modified to 3 nitrotyrosine, 3,4-dihydroxyphenylalanine, 3,3'-dityrosine and other cross-links, or 3-chlorotyrosine are reviewed, with an emphasis on structural and functional consequences. CRITICAL ISSUES: Distinguishing between inconsequential modifications and functionally significant ones requires careful biochemical and biophysical analysis of target proteins, as well as innovative methods for isolating the effects of the multiple modifications that often occur under oxidizing conditions. FUTURE DIRECTIONS: The labor-intensive task of isolating and characterizing individual modified proteins must continue, especially given the expanding list of known modifications. Emerging approaches, such as genetic and metabolic incorporation of unnatural amino acids, hold promise for additional focused studies of this kind. PMID- 22424391 TI - MTHFR 677T is a strong determinant of the degree of hearing loss among Polish males with postlingual sensorineural hearing impairment. AB - Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5-8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n = 302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p = 0.0013, p(cor.) = 0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio = 4.88, p = 0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation-an intervention which is simple, cheap, and devoid of side effects. PMID- 22424392 TI - Cytotoxicity, apoptosis, cellular uptake, cell cycle distribution, and DNA binding investigation of ruthenium complexes. AB - Three new ruthenium(II) polypyridyl complexes [Ru(bpy)(2)(BHIP)](2+) 1, [Ru(phen)(2)(BHIP)](2+) 2, and [Ru(dip)(2)(BHIP)](2+) 3 were synthesized and characterized. The cytotoxicity of the three complexes was evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptosis induced by the complexes was studied by cell morphology and flow cytometry. The results showed that the percentage of apoptotic cells is 7.19%, 75.58%, and 3.51% in the presence of complexes 1, 2, and 3, respectively. The cellular uptakes were also performed and the results indicated that complexes 1, 2, and 3 can enter into the cytoplasm and also into the nucleus. The studies on antiproliferative mechanism showed the induction of S-phase arrest by complexes 1, 2, and 3. DNA binding constants of these complexes with calf thymus DNA (CT-DNA) were determined to be 1.07 (+/- 0.47) * 10(5) M(-1) (s = 2.04), 1.21 (+/- 0.32) * 10(5) M(-1) (s = 1.88), and 2.75 (+/- 0.27) * 10(5) M(-1) (s = 2.17), respectively. Upon irradiation at 365 nm, complexes 1, 2, and 3 can induce cleavage of pBR322 DNA. PMID- 22424393 TI - Q & A: the Snyderome. AB - Michael Snyder answers Genome Biology's questions on the human and professional stories underlying his Snyderome integrative omics project. PMID- 22424394 TI - In situ study of the breakout crystallization in the poly(butadiene)-block poly(epsilon-caprolactone) thin film. AB - Despite its wide occurrence in soft confined block co-polymers, breakout crystallization remains poorly understood and is difficult to control. In this work, thin films of cylinder-forming poly(butadiene)-block-poly(epsilon caprolactone) (PB-b-PCL) diblock co-polymers, with PCL being the minority block, have been chosen as the study subject. We demonstrate a new route to study the breakout crystallization by obtaining the microphase separation structure within terraced lamellae first and then in situ tracking down the lamellar coalescence, resulting from the development of the crystal growth front. We find that the crystal growth front has sucked materials from the surrounding amorphous lamellae, which lead to the decrease of the lamellar zones and coalescence of the microphase separation structure. Dividing the breakout crystallization into parallel breakout and vertical breakout, we illustrate that it is the crystallization-driven molecular diffusion that make the molecules overcome the topography constraint and grow into large-scale spherulite. Moreover, the results show that the polymer microphase separation structure has a significant influence on the crystal nucleation and greatly retarded the crystal growth rate. With a well-designed microphase separation structure within terraces and an easily tunable atomic force microscopy in situ imaging technique, an intensive study of the breakout crystallization and concomitant microdomain coalescence has been offered. PMID- 22424395 TI - On being gay in medicine. PMID- 22424396 TI - Towards meaningful outcomes assessment: collaborative efforts in pediatric medical education. PMID- 22424397 TI - Learning from a distance: effectiveness of online spirometry training in improving asthma care. AB - OBJECTIVE: We evaluated the effectiveness of a virtually delivered quality improvement (QI) program designed to improve primary care management for children with asthma. METHODS: Thirty-six physicians, nurses, and medical assistants from 14 primary care pediatric practices (7 matched practice pairs) participated in a cluster randomized trial from October 2007 to September 2008. All practices received a spirometer and standard vendor training. A 7-month QI program delivered during the study period included: 1) Spirometry FundamentalsTM CD-ROM, a multimedia tutorial; 2) case-based, interactive webinars led by clinical experts; and 3) an internet-based spirometry quality feedback reporting system. Practice pairs were compared directly to each other, and between-group differences were analyzed with the use of mixed effects regression models. Our main outcome measures were the frequency of spirometry testing, percentage of acceptable quality spirometry tests, asthma severity documentation, and appropriate controller medication prescribing. RESULTS: Participating practices uploaded a total of 1028 spirometry testing sessions, of which 340 (33.1%) were of acceptable quality. During the 7-month intervention period, there was no difference between intervention and control practices in the frequency of spirometry tests performed. Intervention practices were estimated to have significantly greater odds of conducting tests with acceptable quality compared with matched control practices, adjusting for quality in the baseline period (odds ratio 2.85; 95% confidence interval 1.78-4.56, P < .001). Intervention providers also had significantly greater odds of documenting asthma severity during the intervention period (odds ratio 2.9, 95% confidence interval 1.8-4.5; P < .001). Although use of controller medications among patients with persistent asthma approached 100% for both groups, the proportion of asthma patients labeled as persistent increased from 43% to 62% among intervention practices, and decreased from 57% to 50% among controls (NS). CONCLUSIONS: A multifaceted distance QI program resulted in increased spirometry quality and improved assessment of asthma severity levels. Successful participation in QI programs can occur over distance. PMID- 22424398 TI - Probing DNA-lipid membrane interactions with a lipopeptide nanopore. AB - Association of DNA molecules with lipid bilayer membranes is of considerable interest for a large variety of applications in biotechnology. Here we introduce syringomycin E (SRE), a small pore-forming lipopeptide produced by the bacterium Pseudomonas syringae, as a facile sensor for the detection of DNA interactions with lipid membranes. SRE forms highly reproducible pores in cellular and artificial membranes. The pore structure involves bilayer lipids, which have a pronounced influence on open channel conductance and gating. SRE channels act as ionic diodes that serve as current rectifiers sensitive to the charge of the bilayer. We employ this intrinsic property to electronically monitor the association of DNA molecules with the membrane in a variety of different settings. We show that SRE can be used for quantitatively probing electrostatic interactions of DNA and DNA-cholesterol conjugates with a lipid membrane. Furthermore, we demonstrate that SRE channels allow monitoring of hybridization reactions between lipid-anchored probe strands and complementary strands in solution. In the presence of double-stranded DNA, SRE channels display a particularly high degree of rectification. Finally, the formation of multilayered structures assembled from poly-(L)-lysine and DNA oligonucleotides on the membrane was precisely monitored with SRE. PMID- 22424399 TI - Shigella flexneri utilize the spectrin cytoskeleton during invasion and comet tail generation. AB - BACKGROUND: The spectrin cytoskeleton is emerging as an important host cell target of enteric bacterial pathogens. Recent studies have identified a crucial role for spectrin and its associated proteins during key pathogenic processes of Listeria monocytogenes and Salmonella Typhimurium infections. Here we investigate the involvement of spectrin cytoskeletal components during the pathogenesis of the invasive pathogen Shigella flexneri. RESULTS: Immunofluorescent microscopy reveals that protein 4.1 (p4.1), but not adducin or spectrin, is robustly recruited to sites of S. flexneri membrane ruffling during epithelial cell invasion. Through siRNA-mediated knockdowns, we identify an important role for spectrin and the associated proteins adducin and p4.1 during S. flexneri invasion. Following internalization, all three proteins are recruited to the internalized bacteria, however upon generation of actin-rich comet tails, we observed spectrin recruitment to those structures in the absence of adducin or p4.1. CONCLUSION: These findings highlight the importance of the spectrin cytoskeletal network during S. flexneri pathogenesis and further demonstrate that pathogenic events that were once thought to exclusively recruit the actin cytoskeletal system require additional cytoskeletal networks. PMID- 22424400 TI - Cognitive-behaviour group therapy for men voluntary seeking help for intimate partner violence. AB - BACKGROUND: Domestic violence is a major problem in society. In spite of this, there are few studies on the treatment of men who voluntarily seek help to stop their violent behaviour towards intimate partners. Most studies are performed on court-ordered individuals. AIM: The objective of this study was to evaluate results of a manualized cognitive-behaviour group therapy for voluntarily treatment-seeking men, aware of and willing to change their abusive behaviour. METHODS: Thirty-six men recruited on a voluntary basis were offered a 15-week manualized group therapy. After initial assessment but before group therapy sessions they were randomly selected for immediate treatment or treatment after 4 months on a "waiting list". All 26 who started group therapy treatment fulfilled the programme. Changes in violent behaviour, before and after treatment, were assessed by self-reports using the Conflict Tactic Scales. Also, the men on the waiting list were compared after 4 months without treatment with the men receiving treatment immediately. RESULTS: All kinds of self-reported partner related violence were significantly reduced by treatment, but being on a waiting list for 4 months did not reduce violent behaviour compared with those immediately receiving treatment. The results indicate that that the group treatment had an effect in itself beyond the wish and intention from the men to reduce their partner violence. PMID- 22424401 TI - Molecular description of indigo oxidation mechanisms initiated by OH and OOH radicals. AB - In this work, we report a quantum chemistry mechanistic study of the hydroxyl (*OH) and hydroperoxyl (*OOH) radicals initiated oxidation of indigo, within the density functional theory framework. All possible hydrogen abstraction and radical addition reaction pathways have been considered. We find that the reaction between a free indigo molecule and an *OH radical occurs mainly through two competing mechanisms: H-abstraction from an NH site and *OH addition to the central C?C double bond. Although the latter is favored, both channels occur, the indigo chromophore group structure is modified, and thus the color is changed. This mechanism adequately accounts for the loss of chromophore in urban air, including indoor air such as in museums and in urban areas. Regarding the reactivity of indigo toward *OOH radicals, only *OOH-addition to the central double bond is thermodynamically feasible. The corresponding transition state free energy value is about 10 kcal/mol larger than the one for the *OH initiated oxidation. Therefore, even considering that the *OOH concentration is considerably larger than the one of *OH, this reaction is not expected to contribute significantly to indigo oxidation under atmospheric conditions. PMID- 22424402 TI - Controversies in HIV cure research. AB - BACKGROUND: Antiretroviral therapy significantly reduces HIV viral burden and prolongs life, but does not cure HIV infection. The major scientific barrier to a cure is thought to be the persistence of the virus in cellular and/or anatomical reservoirs. DISCUSSION: Most efforts to date, including pharmaco, immuno or gene therapy, have failed to cure patients, with the notable exception of a stem cell transplant recipient commonly known as the Berlin patient. This case has revived interest in the potential to cure HIV infection and has highlighted the need to resolve critical questions in the basic, pre-clinical and clinical research spheres as they pertain specifically to efforts to eradicate HIV from the body of an infected person (a sterilizing cure) or at least render the need for lifelong antiretroviral therapy obsolete (functional cure). This paper describes ongoing debates in each of these research spheres as they were presented and discussed at a satellite session that took place at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome in July 2011. SUMMARY: The resolution of these debates may have important implications for the search for a cure, the most efficient ways to identify and test promising interventions, and ultimately the availability of such a cure to diverse groups of HIV patients around the world. PMID- 22424403 TI - Nanocomposite pyrite-greigite reactivity toward Se(IV)/Se(VI). AB - A nanopyrite/greigite composite was synthesized by reacting FeCl(3) and NaHS in a ratio of 1:2 (Wei et al. 1996). Following this procedure, the obtained solid phases consisted of 30-50 nm sized particles containing 28% of greigite (Fe(2+)Fe(3+)(2)S(4)) and 72% pyrite (FeS(2)). Batch reactor experiments were performed with selenite or selenate by equilibrating suspensions containing the nanosized pyrite-greigite solid phase at different pH-values and with or without the addition of extra Fe(2+). XANES-EXAFS spectroscopic techniques revealed, for the first time, the formation of ferroselite (FeSe(2)) as the predominant reaction product, along with elemental Se. In the present experimental conditions, at pH 6 and in equilibrium with Se(0), the solution is oversaturated with respect to ferrosilite. Furthermore, thermodynamic computations show that reaction kinetics likely played a significant role in our experimental system. PMID- 22424404 TI - Health service use in families where children enter public care: a nested case control study using the General Practice Research Database. AB - BACKGROUND: At least 3% of children spend some of their childhood in public care and, as a group, have poor outcomes across a range of education, employment, health and social care outcomes. Research, using social care or government datasets, has identified a number of risk factors associated with children entering public care but the utility of risk factors in clinical practice is not established. This paper uses routine primary health care data to see if risk factors for children entering public care can be identified in clinical practice. METHODS: A nested case control methodology using routine primary care data from the United Kingdom. Health service use data were extracted for the 12 months before the case child entered public care and compared with 12 months of data for four control mother child pairs per case pair, matched on the age and sex of the child and the general practice. Exposures of interest were developed from a systematic review of the literature on risk factors associated with children entering public care. RESULTS: Conditional logistic regression was used to investigate the combined effect of more than one exposure of interest. Maternal mental illness (OR 2.51, 95% CI 1.55-4.05), maternal age at birth of the child, socio-economic status (5(th) quintile vs. 1(st) quintile OR 7.14, 95% CI 2.92 17.4), maternal drug use (OR 28.8, 95% CI 2.29-363), non attendance at appointments (OR 2.42, 95% CI 1.42-4.14), child mental illness (OR 2.65, 95% CI 1.42-4.96) and child admission to hospital (OR 3.31, 95% CI 1.21-9.02) were all significantly associated with children entering public care. Maternal use of primary care contraception services was negatively associated with children entering public care (OR 0.52, 95% CI 0.31-0.87). CONCLUSIONS: Differences in health service use can be identified from routine primary care data in mother child pairs where children enter public care after controlling for maternal age and socio-economic status. The interaction between different risk factors needs testing in a cumulative risk model using longitudinal datasets. PMID- 22424405 TI - From medical home to health neighborhood: transforming the medical home into a community-based health neighborhood. PMID- 22424418 TI - In vivo nanoelectrospray for the localization of bioactive molecules in plants by mass spectrometry. AB - The method for the localization of bioactive molecules in plants is highly needed since it provides a fundamental prerequisite for understanding their physiological and ecological functions. Here, we propose a simple method termed in vivo nanoelectrospray for the localization of bioactive molecules in plants without sample preparation. A capillary is partly inserted into the plant to sample liquid from a highly located region, and then, a high voltage is applied to the plant to generate an electrospray from the capillary tip for mass spectrometry analysis. Using this method, bioactive molecules such as saccharides, glycoalkaloids, flavonoids, organic acids, and glucosinolates (GLs) are detected in the target regions of living plants or fresh fruits. Original information for endogenous chemicals including liable molecules in plant can be obtained. A sketchy three-dimensional distribution of glycoalkaloids in a cherry tomato has been obtained. The present work provides a powerful tool for the study of bioactive molecules in a living plant by mass spectrometry. PMID- 22424419 TI - Proteomic analysis reveals an aflatoxin-triggered immune response in cotyledons of Arachis hypogaea infected with Aspergillus flavus. AB - An immune response is triggered in host cells when host receptors recognize conserved molecular motifs, pathogen-associated molecular patterns (PAMPs), such as beta-glucans, and chitin at the cell surface of a pathogen. Effector-triggered immunity occurs when pathogens deliver effectors into the host cell to suppress the first immune signaling. Using a differential proteomic approach, we identified an array of proteins responding to aflatoxins in cotyledons of peanut (Arachis hypogaea) infected with aflatoxin-producing (toxigenic) but not nonaflatoxin-producing (atoxigenic) strains of Aspergillus flavus. These proteins are involved in immune signaling and PAMP perception, DNA and RNA stabilization, induction of defense, innate immunity, hypersensitive response, biosynthesis of phytoalexins, cell wall responses, peptidoglycan assembly, penetration resistance, condensed tannin synthesis, detoxification, and metabolic regulation. Gene expression analysis confirmed the differential abundance of proteins in peanut cotyledons supplemented with aflatoxins, with or without infection with the atoxigenic strain. Similarly, peanut germination and A. flavus growth were altered in response to aflatoxin B1. These findings show an additional immunity initiated by aflatoxins. With the PAMP- and effector-triggered immune responses, this immunity constitutes the third immune response of the immune system in peanut cotyledon cells. The system is also a three-grade coevolution of plant pathogen interaction. PMID- 22424420 TI - Hydrochlorothiazide: is it a wise choice? AB - INTRODUCTION: Hydrochlorothiazide (HCTZ) has not been shown to reduce mortality or cardiovascular events when given as a single agent. In fact, HCTZ increased cardiovascular death and coronary artery disease (CAD) compared to placebo and usual care in 2 randomized trials, yet it is the most prescribed diuretic in the United States (U.S.). The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure does not recommend one thiazide diuretic over another. However, there are more clinical data for chlorthalidone and indapamide than HCTZ. AREAS COVERED: This review summarizes the differences between HCTZ, chlorthalidone and indapamide for pharmacological profile, surrogate marker data and clinical trial data. EXPERT OPINION: The use of the term 'thiazide diuretic' should be replaced with 'non-thiazide sulfonamide diuretic' for chlorthalidone and indapamide. Furthermore, chlorthalidone and indapamide, rather than HCTZ, should be recommended due to the lack of evidence and potential harm of the latter. PMID- 22424421 TI - Management of glenohumeral osteoarthritis in the young patient: ask the experts. PMID- 22424422 TI - Factors affecting the spontaneous motion of condensate drops on superhydrophobic copper surfaces. AB - The coalescence-induced condensate drop motion on some superhydrophobic surfaces (SHSs) has attracted increasing attention because of its potential applications in sustained dropwise condensation, water collection, anti-icing, and anticorrosion. However, an investigation of the mechanism of such self-propelled motion including the factors for designing such SHSs is still limited. In this article, we fabricated a series of superhydrophobic copper surfaces with nanoribbon structures using wet chemical oxidation followed by fluorization treatment. We then systematically studied the influence of surface roughness and the chemical properties of as-prepared surfaces on the spontaneous motion of condensate drops. We quantified the "frequency" of the condensate drop motion based on microscopic sequential images and showed that the trend of this frequency varied with the nanoribbon structure and extent of fluorination. More obvious spontaneous condensate drop motion was observed on surfaces with a higher extent of fluorization and nanostructures possessing sufficiently narrow spacing and higher perpendicularity. We attribute this enhanced drop mobility to the stable Cassie state of condensate drops in the dynamic dropwise condensation process that is determined by the nanoscale morphology and local surface energy. PMID- 22424423 TI - MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets. AB - ChIP-Seq is widely used to characterize genome-wide binding patterns of transcription factors and other chromatin-associated proteins. Although comparison of ChIP-Seq data sets is critical for understanding cell type dependent and cell state-specific binding, and thus the study of cell-specific gene regulation, few quantitative approaches have been developed. Here, we present a simple and effective method, MAnorm, for quantitative comparison of ChIP-Seq data sets describing transcription factor binding sites and epigenetic modifications. The quantitative binding differences inferred by MAnorm showed strong correlation with both the changes in expression of target genes and the binding of cell type-specific regulators. PMID- 22424424 TI - Biomarkers: hopes and challenges in the path from discovery to clinical practice. PMID- 22424427 TI - Biomarkers in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple phenotypes that cannot be identified through measurement of lung function alone. The importance of COPD risk assessment, phenotype identification, and diagnosis of exacerbation magnify the need for validated biomarkers in COPD. A large number of potential biomarkers have already been assessed and some appear promising, in particular fibrinogen, which is likely to be the first COPD biomarker presented to the Food and Drug Administration for qualification in the drug approval process. Blood fibrinogen and c-reactive protein (CRP) have been associated with the presence of COPD and, in some instances, future risk of developing COPD in targeted populations. Sputum neutrophil counts have been used preliminarily as biomarkers of favorable response to therapy in COPD, but use in clinical settings may be limited. Other potential blood biomarkers include pulmonary and activation regulated chemokine (PARC/CCL-18) and the clara cell secretory protein 16 (CC 16). Integrative indices, such as the BODE index, provide a framework to determine prognosis, predict outcome, and may be responsive to therapeutic interventions. Computed tomography provides a means to assess phenotypes and identify the relative extents of small airways disease and emphysema, which themselves may inform prognosis and therapeutic decision making. Fibrinogen and other markers of systemic inflammation are elevated in the context of acute COPD exacerbations and may also identify those at risk of accelerated lung function decline and hospitalization. So far, no single biomarker in COPD warrants wide acceptance emphasizing the need for future investigation of biomarkers in large scale longitudinal studies. PMID- 22424426 TI - Peripheral blood biomarkers in idiopathic pulmonary fibrosis. AB - In this article, we review the evidence for peripheral blood biomarkers in idiopathic pulmonary fibrosis (IPF), a life-threatening fibrotic lung disease of unknown etiology. We focus on selected biomarkers present in peripheral blood, as they are easy to obtain, can be measured longitudinally, and have the greatest likelihood of achieving clinical utility. This article concentrates on biomarkers with mechanistic plausibility that may be directly involved in the development of IPF, including KL-6, surfactant proteins A and D, matrix metalloproteases (MMP) 1 and 7, CCL18, VEGF, YKL-40, osteopontin, circulating fibrocytes, and T cells. After reviewing the evidence base for each, we designate the biomarkers that may have utility as: (1) diagnostic biomarkers to distinguish IPF from other interstitial lung diseases, (2) prognostic biomarkers that are correlated with disease progression or mortality, or (3) biomarkers that can be used as tools for serial monitoring of disease severity. Although there are no validated biomarkers that are currently available, the need for surrogates of diagnosis, prognosis, and monitoring of disease course with emerging therapies is great. PMID- 22424425 TI - Biomarkers in acute lung injury. AB - Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) result in high permeability pulmonary edema causing hypoxic respiratory failure with high morbidity and mortality. As the population ages, the incidence of ALI is expected to rise. Over the last decade, several studies have identified biomarkers in plasma and bronchoalveolar lavage fluid providing important insights into the mechanisms involved in the pathophysiology of ALI. Several biomarkers have been validated in subjects from the large, multicenter ARDS clinical trials network. Despite these studies, no single or group of biomarkers has made it into routine clinical practice. New high throughput "omics" techniques promise improved understanding of the biologic processes in the pathogenesis in ALI and possibly new biomarkers that predict disease and outcomes. In this article, we review the current knowledge on biomarkers in ALI. PMID- 22424428 TI - Biomarkers of heart transplant rejection: the good, the bad, and the ugly! AB - Acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV) are important limitations for the long-term survival of heart transplant recipients. Although much progress has been made in reducing ACR with modern immunosuppressive treatments and continuous biopsy surveillance, there is still a long way to go to better understand and treat AMR, to enable early detection of patients at risk of CAV, and to reduce the development and sustained progression of this irreversible disease that permanently compromises graft function. This review considers the advances made in ACR detection and treatment allowing a more prolonged survival and the risk factors leading to endothelial injury, dysfunction, inflammation, and subsequent CAV, as well as new treatment modalities for CAV. The review also evaluates the controversies around the definition, pathogenesis, and treatment of AMR. To date, much progress is still needed to significantly reduce post-transplant complications and increase graft and patient survival. PMID- 22424429 TI - Biomarkers in acute myocardial injury. AB - Acute coronary syndrome (ACS) is a significant cause of morbidity and mortality worldwide. The proper diagnosis of ACS requires reliable and accurate biomarker assays to detect evidence of myocardial necrosis. Currently, troponin is the gold standard biomarker for myocardial injury and is used commonly in conjunction with creatine kinase-MB (CK-MB) and myoglobin to enable a more rapid diagnosis of ACS. A new generation of highly sensitive troponin assays with improved accuracy in the early detection of ACS is now available, but the correct interpretation of assay results will require a careful consideration of assay characteristics and the clinical setting prior to incorporation into routine practice. B-type natriuretic peptides, copeptin, ischemia-modified albumin, heart-type fatty-acid binding protein, myeloperoxidase, C-reactive protein, choline, placental growth factor, and growth-differentiation factor-15 make up a promising group of other biomarkers that have shown the ability to improve prognosis and diagnosis of ACS compared with traditional markers. PMID- 22424430 TI - Developing and assessing cardiovascular biomarkers. AB - Atherosclerosis is a slow process that over time can lead to fatal events. Early identification and prediction of future risk can allow for preventive strategies to be instituted. There is an increasing interest in utilizing novel biomarkers in cardiovascular disease screening and management. These novel biomarkers may help in cardiovascular disease risk assessment and treatment monitoring, and some may be treatment targets. To be useful for risk prediction, novel biomarkers need to show a significant association with cardiovascular disease events and bring additional value in risk stratification when added to known risk prediction models. Biomarkers used for treatment monitoring need to show that they can serve as good surrogates of cardiovascular disease status. In this article, we present 3 biomarkers that are currently approved by the U.S. Food and Drug Administration for use in cardiovascular disease management and risk assessment: C-reactive protein, lipoprotein-associated phospholipase A2, and myeloperoxidase. Other new biomarkers have also been shown recently to help in cardiovascular disease risk prediction and management. In this article, we will review 2 of these new biomarkers: cardiac troponin T measured by a highly sensitive assay and brain natriuretic peptide. PMID- 22424431 TI - Marking renal injury: can we move beyond serum creatinine? AB - Acute kidney injury (AKI) is a prevalent and devastating condition associated with significant morbidity and mortality. Despite marked improvements in clinical care, the outcomes for subjects with AKI have shown limited improvement in the past 50 years. A major factor inhibiting clinical progress in this field has been the inability to accurately predict and diagnose early kidney dysfunction. The current gold standard clinical and biochemical criteria for diagnosis of AKI, Risk Injury Failure Loss End-stage renal disease, and its modification, Acute Kidney Injury Network criteria, rely on urine output and serum creatinine, which are insensitive, nonspecific, and late markers of disease. The recent development of a variety of analytic mass spectrometry-based platforms have enabled separation, characterization, detection, and quantification of proteins (proteomics) and metabolites (metabolomics). These high-throughput platforms have raised hopes of identifying novel protein and metabolite markers, and recent efforts have led to several promising novel markers of AKI. However, substantial challenges remain, including the need to systematically evaluate incremental performance of these markers over and beyond current clinical and biochemical criteria for AKI. We discuss the basic issues surrounding AKI biomarker development, highlight the most promising markers currently under development, and discuss the barriers toward widespread clinical implementation of these markers. PMID- 22424432 TI - Genomic biomarkers for chronic kidney disease. AB - Chronic kidney disease (CKD) remains a major challenge in nephrology and for public health care, affecting 14% to 15% of the adult US population and consuming significant health care resources. In the next 20 years, the number of patients with end stage renal disease is projected to increase by 50%. Ideal biomarkers that allow early identification of CKD patients at high risk of progression are urgently needed for early and targeted treatment to improve patient care. Recent success of integrating molecular approaches for personalized management of neoplastic diseases, including diagnosis, staging, prognosis, treatment selection, and monitoring, has strongly encouraged kidney researchers to pursue molecular definitions of patients with kidney disease. Challenges for molecular marker identification in CKD are a high degree of cellular heterogeneity of the kidney and the paucity of human tissue availability for molecular studies. Despite these limitations, potential molecular biomarker candidates have been uncovered at multiple levels along the genome--phenome continuum. Here we will review the identification and validation of potential genomic biomarker candidates of CKD and CKD progression in clinical studies. The challenges in predicting CKD progression, as well as the promises and opportunities resulting from a molecular definition of CKD will be discussed. PMID- 22424433 TI - Biomarkers in diabetes: hemoglobin A1c, vascular and tissue markers. AB - Biomarkers are conventionally defined as "biological molecules that represent health and disease states." They typically are measured in readily available body fluids (blood or urine), lie outside the causal pathway, are able to detect subclinical disease, and are used to monitor clinical and subclinical disease burden and response to treatments. Biomarkers can be "direct" endpoints of the disease itself, or "indirect" or surrogate endpoints. New technologies (such as metabolomics, proteomics, genomics) bring a wealth of opportunity to develop new biomarkers. Other new technologies enable the development of nonmolecular, functional, or biophysical tissue-based biomarkers. Diabetes mellitus is a complex disease affecting almost every tissue and organ system, with metabolic ramifications extending far beyond impaired glucose metabolism. Biomarkers may reflect the presence and severity of hyperglycemia (ie, diabetes itself) or the presence and severity of the vascular complications of diabetes. Illustrative examples are considered in this brief review. In blood, hemoglobin A1c (HbA1c) may be considered as a biomarker for the presence and severity of hyperglycemia, implying diabetes or prediabetes, or, over time, as a "biomarker for a risk factor," ie, hyperglycemia as a risk factor for diabetic retinopathy, nephropathy, and other vascular complications of diabetes. In tissues, glycation and oxidative stress resulting from hyperglycemia and dyslipidemia lead to widespread modification of biomolecules by advanced glycation end products (AGEs). Some of these altered species may serve as biomarkers, whereas others may lie in the causal pathway for vascular damage. New noninvasive technologies can detect tissue damage mediated by AGE formation: these include indirect measures such as pulse wave analysis (a marker of vascular dysfunction) and more direct markers such as skin autofluorescence (a marker of long-term accumulation of AGEs). In the future, we can be optimistic that new blood and tissue-based biomarkers will enable the detection, prevention, and treatment of diabetes and its complications long before overt disease develops. PMID- 22424435 TI - Biomarkers for systemic lupus erythematosus. AB - The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions. This lack of reliable, specific biomarkers for SLE hampers proper clinical management of patients with SLE and impedes development of new lupus therapeutics. As such, the intensity of investigation to identify lupus biomarkers is climbing a steep trajectory, lending cautious optimism that a validated panel of biomarkers for lupus diagnosis, monitoring, stratification, and prediction of flare may soon be in hand. PMID- 22424434 TI - Biomarkers in inflammatory bowel disease: current practices and recent advances. AB - Crohn's disease and ulcerative colitis represent the two main forms of the idiopathic chronic inflammatory bowel diseases (IBD). Currently available blood and stool based biomarkers provide reproducible, quantitative tools that can complement clinical assessment to aid clinicians in IBD diagnosis and management. C-reactive protein and fecal based leukocyte markers can help the clinician distinguish IBD from noninflammatory diarrhea and assess disease activity. The ability to differentiate between forms of IBD and predict risk for disease complications is specific to serologic tests including antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins. Advances in genomic, proteomic, and metabolomic array based technologies are facilitating the development of new biomarkers for IBD. The discovery of novel biomarkers, which can correlate with mucosal healing or predict long-term disease course has the potential to significantly improve patient care. This article reviews the uses and limitations of currently available biomarkers and highlights recent advances in IBD biomarker discovery. PMID- 22424436 TI - New paradigms in translational science research in cancer biomarkers. AB - Despite significant investments in basic science by the US National Institutes of Health, there is a concern that the return on this investment has been limited in terms of clinical utility. In the field of biomarkers, translational research is used to bridge the gap between the results of basic research that identify biomolecules involved in or the consequence of carcinogenesis and their incorporation into medical application. The cultural separation between different scientific disciplines often makes it difficult to establish the multidisciplinary and multi-skilled teams that are necessary for successful translational research. The field of biomarker research requires extensive interactions between academic researchers and industrial developers, and clinicians are needed to help shape the research direction that can be addressed only by a multidisciplinary, multi-institutional approach. In this article, we provide our perspective on the relatively slow pace of cancer biomarker translation, especially those for early detection and screening. PMID- 22424437 TI - Inhibition of HIV-1 replication with stable RNAi-mediated knockdown of autophagy factors. AB - Autophagy is a cellular process leading to the degradation of cytoplasmic components such as organelles and intracellular pathogens. It has been shown that HIV-1 relies on several components of the autophagy pathway for its replication, but the virus also blocks late steps of autophagy to prevent its degradation. We generated stable knockdown T cell lines for 12 autophagy factors and analyzed the impact on HIV-1 replication. RNAi-mediated knockdown of 5 autophagy factors resulted in inhibition of HIV-1 replication. Autophagy analysis confirmed a specific defect in the autophagy pathway for 4 of these 5 factors. We also scored the impact on cell viability, but no gross effects were observed. Upon simultaneous knockdown of 2 autophagy factors (Atg16 and Atg5), an additive inhibitory effect was scored on HIV-1 replication. Stable knockdown of several autophagy factors inhibit HIV-1 replication without any apparent cytotoxicity. We therefore propose that targeting of the autophagy pathway can be a novel therapeutic approach against HIV-1. PMID- 22424439 TI - Platelet function in patients with cirrhosis. PMID- 22424438 TI - EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. PMID- 22424441 TI - Cognition and HPA axis reactivity in mildly to moderately depressed outpatients: a case-control study. AB - BACKGROUND: Patients with depression display neurobiological changes of the hypothalamic-pituitary axis as well as cognitive disturbances. AIMS: To assess any association between hypothalamus-pituitary-adrenal (HPA) axis reactivity and memory-related cognitive functions. METHODS: Depressed outpatients (n = 83, ICD 10) were group-matched to healthy controls (n = 33), and tested on a number of cognitive domains. Salivary samples were collected at awakening, 30 min later and at 22:00 h. At 23:00 h, the participants ingested 1.0 mg of dexamethasone, and three saliva samples were collected the following day at the same times. RESULTS: Patients and controls did not differ on any memory-related cognitive skills. After dexamethasone the cortisol level was 1.7 nmol/l higher (95% CI 0.0-2.8, P = 0.05) in depressed patients compared with controls. In the control group, but not in the patients, a positive association between post-DST cortisol and Rey's Complex figure test (1.3; 95% CI 0.3-3.6; P = 0.02) was found. We found no significant associations between other memory functions and cortisol measures. CONCLUSIONS: Contrary to our hypothesis, we found a positive association between cortisol levels after dexamethasone and visuo-spatial memory primarily driven by the healthy controls. Otherwise, no association were found between HPA axis reactivity and memory-related cognitive function. PMID- 22424442 TI - Proteomic characterisation of endoplasmic reticulum-derived protein bodies in tobacco leaves. AB - BACKGROUND: The N-terminal proline-rich domain (Zera) of the maize storage protein gamma-zein, is able to induce the formation of endoplasmic reticulum (ER) derived protein bodies (PBs) when fused to proteins of interest. This encapsulation enables a recombinant fused protein to escape from degradation and facilitates its recovery from plant biomass by gradient purification. The aim of the present work was to evaluate if induced PBs encapsulate additional proteins jointly with the recombinant protein. The exhaustive analysis of protein composition of PBs is expected to facilitate a better understanding of PB formation and the optimization of recombinant protein purification approaches from these organelles. RESULTS: We analysed the proteome of PBs induced in Nicotiana benthamiana leaves by transient transformation with Zera fused to a fluorescent marker protein (DsRed). Intact PBs with their surrounding ER-membrane were isolated on iodixanol based density gradients and their integrity verified by confocal and electron microscopy. SDS-PAGE analysis of isolated PBs showed that Zera-DsRed accounted for around 85% of PB proteins in term of abundance. Differential extraction of PBs was performed for in-depth analysis of their proteome and structure. Besides Zera-DsRed, 195 additional proteins were identified including a broad range of proteins resident or trafficking through the ER and recruited within the Zera-DsRed polymer. CONCLUSIONS: This study indicates that Zera-protein fusion is still the major protein component of the new formed organelle in tobacco leaves. The analysis also reveals the presence of an unexpected diversity of proteins in PBs derived from both the insoluble Zera DsRed polymer formation, including ER-resident and secretory proteins, and a secretory stress response induced most likely by the recombinant protein overloading. Knowledge of PBs protein composition is likely to be useful to optimize downstream purification of recombinant proteins in molecular farming applications. PMID- 22424443 TI - Orthogonal amplification of nanoparticles for improved diagnostic sensing. AB - There remains an ongoing need for fast, highly sensitive, and quantitative technologies that can detect and profile rare cells in freshly harvested samples. Recent developments in nanomaterial-based detection platforms provide advantages over traditional approaches in terms of signal sensitivity, stability, and the possibility for performing multiplexed measurements. Here, we describe a bioorthogonal, nanoparticle amplification technique capable of rapid augmentation of detection sensitivities by up to 1-2 orders of magnitude over current methods. This improvement in sensitivity was achieved by (i) significantly reducing background noise arising from nonspecific nanoparticle binding, (ii) increasing nanomaterial binding through orthogonal rounds of amplification, and (iii) implementing a cleavage step to improve assay robustness. The developed method allowed sensitive detection and molecular profiling of scant tumor cells directly in unpurified human clinical samples such as ascites. With its high sensitivity and simplified assay steps, this technique will likely have broad utility in nanomaterial-based diagnostics. PMID- 22424444 TI - Grape antioxidant dietary fibre prevents mitochondrial apoptotic pathways by enhancing Bcl-2 and Bcl-xL expression and minimising oxidative stress in rat distal colonic mucosa. AB - Grape antioxidant dietary fibre (GADF) is a grape product rich in dietary fibre and natural antioxidants. We reported previously that GADF intake reduced apoptosis and induced a pro-reducing shift in the glutathione (GSH) redox status of the rat proximal colonic mucosa. The aim of the study was to elucidate the molecular mechanisms responsible for the anti-apoptotic effect of GADF and their association with the oxidative environment of the distal colonic mucosa. The ability of GADF to modify colonic crypt cell proliferation was also investigated. Male Wistar rats (n 20) were fed with diets containing either cellulose (control group) or GADF (GADF group) as fibre for 4 weeks. GADF did not modify cell proliferation but induced a significant reduction of colonic apoptosis. The anti apoptotic proteins Bcl-2 (B-cell lymphoma-2) and Bcl-xL (B-cell lymphoma extra large) were up-regulated in the mitochondria and down-regulated in the cytosol of the GADF mucosa, whereas the opposite was found for the pro-apoptotic protein Bax (Bcl-2-associated X protein), leading to an anti-apoptotic shift in the pattern of expression of the Bcl-2 family. Cytosolic cytochrome c and cleaved caspase-3 levels and caspase-3 activity were reduced by GADF. The modulation of the antioxidant enzyme system and the increase of the cytosolic GSH:glutathione disulfide (GSSG) ratio elicited by GADF helped to reduce oxidative damage. The cytosolic GSH:GSSG ratio was negatively related to apoptosis. These results indicate that GADF acts on the expression of the pro- and anti- apoptotic Bcl-2 proteins, attenuating the mitochondrial apoptotic pathway in the distal colonic mucosa. This effect appears to be associated with the antioxidant properties of GADF. PMID- 22424445 TI - Determinants for participation in a public health insurance program among residents of urban slums in Nairobi, Kenya: results from a cross-sectional survey. AB - BACKGROUND: The government of Kenya is making plans to implement a social health insurance program by transforming the National Hospital Insurance Fund (NHIF) into a universal health coverage program. This paper examines the determinants associated with participation in the NHIF among residents of urban slums in Nairobi city. METHODS: The study used data from the Nairobi Urban Health and Demographic Surveillance System in two slums in Nairobi city, where a total of about 60,000 individuals living in approximately 23,000 households are under surveillance. Descriptive statistics and multivariate logistic regression analysis were used to describe the characteristics of the sample and to identify factors associated with participation in the NHIF program. RESULTS: Only 10% of the respondents were participating in the NHIF program, while less than 1% (0.8%) had private insurance coverage. The majority of the respondents (89%) did not have any type of insurance coverage. Females were more likely to participate in the NHIF program (OR = 2.4; p < 0.001), while respondents who were formerly in a union (OR = 0.5; p < 0.05) and who were never in a union (OR = 0.6; p < 0.05) were less likely to have public insurance coverage. Respondents working in the formal employment sector (OR = 4.1; p < 0.001) were more likely to be enrolled in the NHIF program compared to those in the informal sector. Membership in microfinance institutions such as savings and credit cooperative organizations (SACCOs) and community-based savings and credit groups were important determinants of access to health insurance. CONCLUSIONS: The proportion of slum residents without any type of insurance is high, which underscores the need for a social health insurance program to ensure equitable access to health care among the poor and vulnerable segments of the population. As the Kenyan government moves toward transforming the NHIF into a universal health program, it is important to harness the unique opportunities offered by both the formal and informal microfinance institutions in improving health care capacity by considering them as viable financing options within a comprehensive national health financing policy framework. PMID- 22424446 TI - Size-dependent metamorphosis of electron binding motif in cluster anions of primary amide molecules. AB - Electron binding motifs in cluster anions of primary amides, (acetamide)(n)(-) and (propionamide)(n)(-), were studied with photoelectron spectroscopy. For both the amides, two band series due to distinct isomeric species in the multipole bound states were found in the low electron binding energy region (<~0.4 eV) of the photoelectron spectra at the excitation wavelength of 1064 nm. In the case of acetamide, the isomer of higher band peak energies is predominant for 6<= n <= 8, but it vanishes completely for n >= 9 to be replaced with the lower energy isomer. The same spectral behavior was seen for propionamide exhibiting an exception at n = 7. The isomers appearing in the lower and higher energy sides were attributed to the straight and folded forms of ladder-like hydrogen bond network structures, respectively, on the basis of density functional calculations. In the folded forms, the excess electron is held in the space between two terminal amide molecules of the ladder-like networks. Referring to calculations of potential energy curves with respect to the folding coordinate of the ladder-like networks, it is inferred that the major isomer alternation between n = 8 and 9 originates from an increase of stiffness of the molecular ladders depending on the cluster sizes. In photoelectron spectra at the 355 nm excitation, the valence anion state having a band peak around 2.5 eV was observed to emerge with threshold sizes of n = 13 and 9 for acetamide and propionamide, respectively. Static and dynamical effects of alkyl groups on the electron binding motifs are discussed in comparison with the previous study on formamide cluster anions. PMID- 22424447 TI - CheS-Mapper - Chemical Space Mapping and Visualization in 3D. AB - Analyzing chemical datasets is a challenging task for scientific researchers in the field of chemoinformatics. It is important, yet difficult to understand the relationship between the structure of chemical compounds, their physico-chemical properties, and biological or toxic effects. To that respect, visualization tools can help to better comprehend the underlying correlations. Our recently developed 3D molecular viewer CheS-Mapper (Chemical Space Mapper) divides large datasets into clusters of similar compounds and consequently arranges them in 3D space, such that their spatial proximity reflects their similarity. The user can indirectly determine similarity, by selecting which features to employ in the process. The tool can use and calculate different kind of features, like structural fragments as well as quantitative chemical descriptors. These features can be highlighted within CheS-Mapper, which aids the chemist to better understand patterns and regularities and relate the observations to established scientific knowledge. As a final function, the tool can also be used to select and export specific subsets of a given dataset for further analysis. PMID- 22424448 TI - Peroxiredoxins 3 and 4 are overexpressed in prostate cancer tissue and affect the proliferation of prostate cancer cells in vitro. AB - The present study aimed to investigate the proteome profiling of surgically treated prostate cancers. Hereto, 2D-DIGE and mass spectrometry were performed for protein identification, and data validation for peroxiredoxin 3 and 4 (PRDX3 and PRDX4) was accomplished by reverse phase protein arrays (RPPA). The Formal Concept Analysis (FCA) method was applied to assess whether the TMPRSS2-ERG gene fusion could influence the degree of overexpression of PRDX3 and PRDX4 in prostate cancer. Lastly, we performed an in vitro functional characterization of both PRDX3 and PRDX4 using the classical human prostate cancer cell lines DU145 and LNCaP. Reverse phase protein arrays verified that the overexpression of both PRDX3 and PRDX4 in tumor samples is negatively correlated with the presence of the TMPRSS2-ERG gene fusion. Functional characterization of PRDX3 and PRDX4 activity in PCa cell lines suggests a role of these members of the peroxiredoxin family in the pathophysiology of this tumor entity. PMID- 22424449 TI - Alkaline earth metal cation exchange: effect of mobile counterion and dissolved organic matter. AB - The goal of this research was to provide an improved understanding of the interactions between alkaline earth metals and DOM under conditions that are encountered during drinking water treatment with particular focus on cation exchange. Both magnetically enhanced and nonmagnetic cation exchange resins were converted to Na, Mg, Ca, Sr, and Ba mobile counterion forms as a novel approach to investigate the exchange behavior between the cations and the interactions between the cations and DOM. The results show that cation exchange is a robust process for removal of Ca(2+) and Mg(2+) considering competition with cations on the resin surface and presence of DOM. DOM was actively involved during the cation exchange process through complexation, adsorption, and coprecipitation reactions. In addition to advancing the understanding of ion exchange processes for water treatment, the results of this work are applicable to membrane pretreatment to minimize fouling, treatment of membrane concentrate, and precipitative softening. PMID- 22424450 TI - Klippel-Trenaunay syndrome: the quest for the proper diagnosis. PMID- 22424451 TI - Cystic adventitial disease and high spatial resolution magnetic resonance imaging. PMID- 22424452 TI - The expression of matrix metalloproteinases may be influenced by mechanical loading and intraluminal thrombus. PMID- 22424453 TI - Ultrasound assessment of morphological and functional vessel parameters should be a mandatory step before arteriovenous fistula placement. PMID- 22424454 TI - Comment on the effect of aspirin on adherence of slime-producing, coagulase negative Staphylococci to vascular grafts. PMID- 22424455 TI - Thrombolytic treatment of pulmonary embolism via catheter. PMID- 22424456 TI - Effect on tumor necrosis factor-alpha production and antioxidant ability of black alder, as factors related to its anti-inflammatory properties. AB - Alders exhibit several uses in different areas and also offer some nutritional and medicinal values. The bark and leaves from black alder [Alnus glutinosa (L.) Gaertn] are used in folk medicine for the treatment of inflammatory processes and other health disorders. This study assessed if an extract of A. glutinosa stem bark exhibits some biological properties linked to improving the inflammatory state, which could partly justify its ethnopharmacological use. Therefore, various aspects of antioxidant activity as well as the effect on tumor necrosis factor-alpha (TNF-alpha) production were evaluated. The phytochemical study revealed the presence of terpenes, saponins, tannins, flavonoids, and anthraquinones (by high-performance thin-layer chromatography). The betulinic acid content in the extract, determined by reversed-phase high-performance liquid chromatography (validated method), was 0.72+/-0.027%. In addition, high amounts for total phenols as well as flavonoids were determined. The extract exhibited a 2,2'-diphenylpicrylhydrazyl radical scavenging capacity similar to that of ascorbic acid and had a significant effect on superoxide anion scavenging, superior to that of ascorbic acid. It was also able to protect HeLa cells from induced oxidative stress. In the TNF-alpha assay, levels of this citokine were depressed by the extract in HL-60 cells. To test the effect of the extract on cell proliferation, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed. According to the results, the antioxidant properties displayed by the extract of A. glutinosa stem bark, together with the effect on TNF-alpha levels, suggest that these activities, linked to a successful reduction in inflammatory processes, may support, in part, its ethnopharmacological use. PMID- 22424457 TI - Antioxidant properties of Taraxacum officinale leaf extract are involved in the protective effect against hepatoxicity induced by acetaminophen in mice. AB - Acetaminophen (APAP) hepatotoxicity has been related to several cases of hepatitis, cirrhosis, and hepatic transplant. As APAP hepatotoxicity is related to reactive oxygen species (ROS) formation and excessive oxidative stress, natural antioxidant compounds have been tested as an alternative therapy to diminish the hepatic dysfunction induced by APAP. Taraxacum officinale Weber (Family Asteraceae), commonly known as dandelion, is used for medicinal purposes because of its choleretic, diuretic, antioxidant, anti-inflammatory, and hepatoprotective properties. This study evaluated the hepatoprotective activity of T. officinale leaf extract against APAP-induced hepatotoxicity. T. officinale was able to decrease thiobarbituric acid-reactive substance levels induced by 200 mg/kg APAP (p.o.), as well as prevent the decrease in sulfhydryl levels caused by APAP treatment. Furthermore, histopathological alterations, as well as the increased levels of serum aspartate and alanine aminotransferases caused by APAP, were prevented by T. officinale (0.1 and 0.5 mg/mL). In addition, T. officinale extract also demonstrated antioxidant activity in vitro, as well as scavenger activity against 2,2-diphenyl-1-picrylhydrazyl and nitric oxide radicals. Our results clearly demonstrate the hepatoprotective effect of T. officinale against the toxicity induced by APAP. The possible mechanisms involved include its scavenger activities against ROS and reactive nitrogen species, which are attributed to the content of phenolic compounds in the extract. PMID- 22424458 TI - Drinking deep seawater decreases serum total and low-density lipoprotein cholesterol in hypercholesterolemic subjects. AB - Drinking deep seawater (DSW) with high levels of magnesium (Mg) decreased serum lipids in animal studies. Therefore the effects of drinking DSW on blood lipids and its antioxidant capacity in hypercholesterolemic subjects were investigated. DSW was first prepared by a process of filtration and reverse osmosis, and then the concentrated DSW with high levels of Mg was diluted as drinking DSW. Forty two hypercholesterolemic volunteers were randomly divided into three groups: reverse osmotic (RO) water, DSW (Mg: 395 mg/L, hardness 1410 ppm), and magnesium chloride fortified (MCF) water (Mg: 386 mg/L, hardness 1430 ppm). The subjects drank 1050 mL of water daily for 6 weeks, and blood samples were collected and analyzed on weeks 0, 3, and 6. Drinking DSW caused a decrease in blood total cholesterol levels and this effect was progressively enhanced with time. Serum low-density lipoprotein-cholesterol (LDL-C) was also decreased by DSW. Further, total cholesterol levels of subjects in the DSW group were significantly lower than those in the MCF water or RO water groups. Compared with week 0, the DSW group had higher blood Mg level on weeks 3 and 6, but the Mg levels were within the normal range in all three groups. DSW consumption also lowered thiobarbituric acid-reactive substances (TBARS) values in serum. In conclusion, DSW was apparently effective in reducing blood total cholesterol and LDL-C, and also in decreasing lipid peroxidation in hypercholesterolemic subjects. PMID- 22424459 TI - Extract from Dioscorea batatas ameliorates insulin resistance in mice fed a high fat diet. AB - The aim of this study was to investigate whether Dioscorea batatas (DB) extract attenuates high-fat diet (HFD)-induced insulin resistance in the visceral adipose tissues of mice, and by what mechanism(s). Mice were fed a HFD for 4 weeks to induce the early development of insulin resistance. The DB extract was administered to mice fed a HFD by oral gavage at a dose of 100 mg/kg body weight daily for 7 weeks. Biochemical parameters in blood were measured using enzymatic kits, and the expression levels of glucose transporter 4 (GLUT4), phosphorylated (p-)S6K1, phosphorylated v-akt murine thymoma viral oncogene homolog (p-AKT), and phosphorylated extracellular regulated kinase (p-ERK) in epididymal fat tissue were determined by western blot analyses. The DB extract effectively reversed the HFD-induced elevations in plasma glucose and insulin levels, and the homeostasis model assessment for insulin resistance and oral glucose tolerance test values. The level of p-AKT protein was up-regulated, whereas the levels of p-ERK and p S6K1 proteins were down-regulated in the adipose tissues of DB mice compared with HFD mice. Furthermore, the DB extract significantly reversed the HFD-induced decrease in the plasma membrane GLUT4 level in the adipose tissue of mice. The DB extract improved glucose metabolism in HFD-fed mice through the up-regulation of plasma membrane GLUT4 content in the visceral adipose tissue. Activation of the insulin signaling cascade leading to GLUT4 translocation was the mechanism underlying the beneficial effects of the DB extract on early-stage obesity induced insulin resistance. PMID- 22424460 TI - Apple pomace, a by-product from the asturian cider industry, inhibits herpes simplex virus types 1 and 2 in vitro replication: study of its mechanisms of action. AB - The anti-herpes simplex virus type 1 and anti-herpes simplex virus type 2 effects of apple pomace, a by-product from the cider-processing industry, were investigated. The mechanisms of antiviral action were assessed using a battery of experiments targeting sequential steps in the viral replication cycle. The anti herpetic mechanisms of apple pomaces included the inhibition of virus attachment to the cell surface and the arrest of virus entry and uncoating. Quercitrin and procyanidin B2 were found to play a crucial role in the antiviral activity. PMID- 22424462 TI - Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PMID- 22424463 TI - Determinants of cardiorespiratory fitness at 3, 6 and 12 months poststroke. AB - PURPOSE: To better delineate intervention programs, knowledge of the factors that are associated with physical fitness in stroke survivors is crucial. This study aimed to predict cardiorespiratory fitness based on standardized measures along the several dimensions of the International Classification of Functioning, Disability and Health (ICF) model at several time intervals in the first year after stroke. METHODS: Forty patients were assessed at 3, 6 and 12 months poststroke. A symptom-limited graded cycle ergometer test was used to assess cardiorespiratory fitness. Outcome variables were VO(2) peak and the Oxygen Uptake Efficiency Slope (OUES). Impairments, activity limitations, participation restrictions, personal and environmental factors were assessed to determine predictive factors. RESULTS: Explained variance at 3, 6 and 12 months poststroke was 39%, 55% and 91% for VO(2) peak and 55%, 63% and 79% for OUES. A strong association between knee muscle strength and cardiorespiratory fitness was found at each measurement time, explaining up to 72 % of the variance in fitness. At 12 months poststroke, functional mobility, body mass index (BMI) and emotional status also contributed to explain variance. CONCLUSIONS: Knee muscle strength was found to be a very strong predictor of cardiorespiratory fitness during the first year after stroke and functional mobility became important at 12 months poststroke. PMID- 22424464 TI - Breastfeeding frequency, milk volume, and duration in mother-infant dyads with persistent nipple pain. AB - BACKGROUND: Nipple pain and insufficient milk supply are major causes of early weaning. We have found that persistent nipple pain was associated with strong infant sucking vacuums during breastfeeding. Several studies indicate that nipple pain and abnormal infant sucking have the potential to reduce milk transfer. We aimed to determine whether women with persistent nipple pain had low milk supply. SUBJECTS AND METHODS: The 24-hour milk production and feeding characteristics of mothers with persistent nipple pain (n=21) were compared with those mothers without nipple pain (n=21). Milk productions were measured by test-weighing the infant before and after every feed from each breast over a 24-26-hour period. Comparisons were made using Student's t tests and linear mixed models as appropriate. RESULTS: Lower milk productions were associated with longer meal durations for mothers with pain. There were no significant differences in the average 24-hour milk production or any feeding characteristics between the groups. However, four women with persistent nipple pain had milk production levels below 500 mL/day. CONCLUSIONS: The majority of breastfeeding women experiencing persistent nipple pain were able to achieve normal milk production levels. Feeding duration and frequency were similar to those of women not experiencing pain. However, longer meal durations in the pain group were associated with lower levels of milk production. Further investigation is necessary to identify mothers most affected by maternal nipple pain. PMID- 22424465 TI - An unusual traditional practice for damaged nipples during lactation. PMID- 22424466 TI - Does warming the breasts affect the amount of breastmilk production? AB - BACKGROUND AND OBJECTIVE: Increasing the amount of breastmilk is vital for both the nursing mother and child. Warming up breasts before using electrical pumps to pump out breastmilk may help to increase the amount of breastmilk, especially in the mothers of babies who are being nursed in the neonatal intensive care unit. SUBJECTS AND METHODS: Thirty-nine mothers whose babies had been admitted to the neonatal intensive care unit were analyzed. A breast compress that was warmed up in a microwave oven for 1 minute at 180 W was applied to one of the breasts for 20 minutes, and both breasts were sucked by an electrical breast pump for 15 minutes. The amount of breastmilk after each procedure was recorded. RESULTS: The amount of breastmilk that was obtained from warmed breasts was significantly higher than that obtained from nonwarmed breasts (maximum, 47.02 +/- 23.01 mL vs. 33.15 +/- 19.98 mL) (p=0.000). CONCLUSION: Warming up breasts by a breast compress is easy and affordable, and this procedure increases the amount of breastmilk, thus facilitating infant nutrition and recovery especially in the neonatal intensive care unit. PMID- 22424467 TI - Cultural practices and medical beliefs in pre-revolutionary Russia compared to modern textbook advice: did Russian women breastfeed the "wrong" way? AB - BACKGROUND AND AIMS: Historical accounts of infant feeding practices can inform our understanding of current-day practices and the ways in which cultural traditions are incorporated into infant care. Pre-revolutionary Russian feeding practices have not previously been summarized, to our knowledge. The purpose of this study is to collect information about pre-revolutionary feeding practices. We may then be able to better understand the motivation for suboptimal practices and tailor feeding messages to the specific population. METHODS: Materials were collected from libraries and from the Internet regarding medical, demographic, and ethnographic literature of the 19(th) century and early 21(st) century, primarily in Russian. RESULTS: Breastfeeding was pervasive in pre-revolutionary Russia, but suboptimal patterns such as withholding colostrum and early introduction of other foods and liquids were common. Breast problems were treated with folk remedies and comfort measures, some of which are similar to modern-day treatments. Around 1906, child rearing and infant feeding recommendations were subsumed by male physicians espousing the "scientific approach." CONCLUSIONS: Many of these medical recommendations were detrimental to the previously successful breastfeeding practices that, despite barriers, had allowed Russian women to continue breastfeeding for 2 years or longer. PMID- 22424468 TI - Survey of lactation instructors on folk traditions in breastfeeding. AB - OBJECTIVE: Women who choose to breastfeed are given advice from a variety of sources: some well researched and empirical, and some folkloric and rooted in oral tradition. This study aims to identify which folk practices are being discussed in the breastfeeding community and which have been adopted by lactation educators. MATERIALS AND METHODS: An Internet-based questionnaire was sent to certified lactation consultants affiliated with U.S. medical centers identified through an online database. Participants were asked to provide demographic information as well as open responses about the types of recommendations they had heard and that they provide to clients. RESULTS: One hundred twenty-four responses were received out of 293 surveys sent (42% response rate). Eighty-six lactation consultants (69%) reported hearing of folk remedies, and 80 (65%) recommended at least one of these methods. The most commonly recommended remedies fell into the categories of promoting lactation (58%), reducing pain (41%), and avoiding substances with adverse infant effects (19%). Specifically, the most common folk traditions recommended were fenugreek (57 responses) and blessed thistle (28 responses) for lactation and cabbage leaves (36 responses) for pain relief. Practitioners who made such recommendations were similar to those who did not in age, education, length of career, and location. CONCLUSIONS: Folk traditions are commonly communicated in breastfeeding education. The fact that experienced practitioners are promoting the use of traditional methods suggests that further research is necessary to prove the efficacy of methods whose success previously has been anecdotal. PMID- 22424469 TI - Awareness, intention, and needs regarding breastfeeding: findings from first-time mothers in Shanghai, China. AB - BACKGROUND AND OBJECTIVES: Despite efforts, a decline in breastfeeding rates has been documented in China recently. This study explored the awareness of the World Health Organization (WHO) guidelines for breastfeeding and intention to breastfeed among first-time mothers and identified the gap between mothers' needs and perinatal care provision regarding breastfeeding promotion. SUBJECTS AND METHODS: In total, 653 women at 5-22 gestational weeks were recruited from four community health centers in Shanghai, China. They completed a self-administered questionnaire at recruitment. Two focus group discussions were held among third trimester pregnant women who had received prenatal education. Twenty-four in depth interviews were conducted among postpartum mothers. RESULTS: During early pregnancy, a substantial proportion of mothers were not aware of the nutritional value of breastmilk (40%) or the value of exclusive breastfeeding for 6 months (80%) or any breastfeeding for 24 months (98%). The awareness of the WHO guidelines for breastfeeding was associated with intention to breastfeed (adjusted odds ratio [OR] 2.67, 95% confidence interval [CI] 1.88, 3.78) or intention to breastfeed exclusively (adjusted OR 3.31, 95% CI 1.81, 6.06). In late pregnancy and postpartum, most mothers were still not fully aware of the breastfeeding recommendations and nutritional value of breastmilk. Limited communications with healthcare providers and lack of support for dealing with breastfeeding difficulties were reported. CONCLUSIONS: Low awareness of the WHO breastfeeding guidelines was found among first-time mothers in Shanghai. Awareness of breastfeeding guidelines was independently associated with mothers' intention to breastfeed and intention to breastfeed exclusively. The health benefits of breastfeeding and the recommended duration of breastfeeding should be emphasized in prenatal education programs. PMID- 22424470 TI - Cultures of Holder-pasteurized donor human milk after use in a neonatal intensive care unit. AB - OBJECTIVE: Current guidelines state that human milk, once thawed, should be kept in a refrigerator for only 24 hours. We cultured Holder-pasteurized donor human milk (DHM) after thawing and refrigeration under clinical conditions. STUDY DESIGN: Bottles of pasteurized DHM were thawed and used in a regional level 3 neonatal intensive care unit (NICU) in standard clinical fashion and kept refrigerated when not in use. Once no longer needed clinically, aliquots were cultured for bacteria. RESULTS: In total, 30 bottles were returned for culture; six were excluded from analysis because human milk fortifier had been added, and two had been left out of the refrigerator. The remaining 22 bottles were culture negative after having been thawed for 7-122 hours. CONCLUSIONS: DHM without additives was culture-negative for 24 hours or longer after thawing and routine NICU handling. These data indicate that unfortified Holder-pasteurized DHM handled appropriately and refrigerated remains sterile for 24 hours after thawing and perhaps longer. Further study is needed to confirm this. PMID- 22424471 TI - Age-related changes in neuromuscular function and physiology: an introduction and perspective. PMID- 22424472 TI - Functional interconnections of HY1 with MYC2 and HY5 in Arabidopsis seedling development. AB - Arabidopsis seedling development is controlled by many regulatory genes involved in multiple signaling pathways. The functional relationships of these genes working in multiple signaling cascades have started to be unraveled. Arabidopsis HY1/HO1 is a rate-limiting enzyme involved in biosynthesis of phytochrome chromophore. HY5 (a bZIP protein) promotes photomorphogenesis, however ZBF1/MYC2 (a bHLH protein) works as a negative regulator of photomorphogenic growth and light regulated gene expression. Further, MYC2 and HY1 have been shown to play important roles in jasmonic acid (JA) signaling pathways. Here, we show the genetic interactions of HY1 with two key transcription factor genes of light signaling, HY5 and MYC2, in Arabidopsis seedling development. Our studies reveal that although HY1 acts in an additive manner with HY5, it is epistatic to MYC2 in light-mediated seedling growth and gene expression. This study further demonstrates that HY1 additively or synergistically functions with HY5, however it works upstream to MYC2 in JA signaling pathways. Taken together, this study demonstrates the functional interrelations of HY1, MYC2 and HY5 in light and JA signaling pathways. PMID- 22424473 TI - Impaired myogenic tone in mesenteric arteries from overweight rats. AB - BACKGROUND: Rats fed high fat (HFD) or high sucrose (HSD) diets develop increased adiposity as well as impaired vasodilatory responsiveness stemming from oxidative stress. Moreover, HFD rats become hypertensive compared to either control (Chow) or HSD fed rats, suggesting elevated vascular tone. We hypothesized that rats with increased adiposity and oxidative stress demonstrate augmented pressure induced vasoconstriction (i.e. myogenic tone) that could account for the hypertensive state. METHODS: Male Sprague-Dawley rats were fed Chow, HFD or HSD for 6 weeks. The effects of oxidative stress and endogenous nitric oxide on myogenic responses were examined in small mesenteric arteries by exposing the arteries to incremental intraluminal pressure steps in the presence of antioxidants or an inhibitor of nitric oxide synthase, LNNA (100 MUM). RESULTS: Contrary to the hypothesis, rats fed either HSD or HFD had significantly impaired myogenic responses despite similar vascular morphology and passive diameter responses to increasing pressures. Vascular smooth muscle (VSM) calcium levels were normal in HFD arteries suggesting that diminished calcium sensitivity was responsible for the impaired myogenic response. In contrast, VSM calcium levels were reduced in HSD arteries but were increased with pre-exposure of arteries to the antioxidants tiron (10 mM) and catalase (1200 U/mL), also resulting in enhanced myogenic tone. These findings show that oxidative stress impairs myogenic tone in arteries from HSD rats by decreasing VSM calcium. Similarly, VSM calcium responses were increased in arteries from HFD rats following treatment with tiron and catalase, but this did not result in improved myogenic tone. Nitric oxide is involved in the impaired myogenic response in HFD, but not HSD, rats since inhibition with LNNA resulted in maximal myogenic responses at lower intraluminal pressures and VSM calcium levels, further implicating reduced calcium sensitivity in the impaired response. CONCLUSION: The impaired myogenic responses observed in isolated arteries from HSD and HFD rats are attributed to changes in VSM calcium signaling. PMID- 22424475 TI - Single-nanoparticle detection using a low-aspect-ratio pore. AB - We explored single-particle translocation through a low thickness-to-diameter aspect ratio Si(3)N(4) pore mimicking graphene nanopore structure by a resistive pulse method. Ionic conductance of 0.05 aspect ratio pores scales linearly with the diameter, indicating predominant contribution of the access resistance to the ion transport. We find that the access resistance changes little during particle translocation. Furthermore, we observe enhanced particle capture rates via the strong electric field extended outside the low-aspect-ratio pore mouth. We also demonstrate electrical discrimination of two different sized particles using the low-aspect-ratio pore sensor with the constant access resistance assumption. The present findings indicate the potential utility of nucleotide-sized graphene nanopores as an electrical sensing platform for single-base identification via transmembrane ionic current blockade detections. PMID- 22424474 TI - The biology of sexual development of Plasmodium: the design and implementation of transmission-blocking strategies. AB - A meeting to discuss the latest developments in the biology of sexual development of Plasmodium and transmission-control was held April 5-6, 2011, in Bethesda, MD. The meeting was sponsored by the Bill & Melinda Gates Foundation and the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID) in response to the challenge issued at the Malaria Forum in October 2007 that the malaria community should re-engage with the objective of global eradication. The consequent rebalancing of research priorities has brought to the forefront of the research agenda the essential need to reduce parasite transmission. A key component of any transmission reduction strategy must be methods to attack the parasite as it passes from man to the mosquito (and vice versa). Such methods must be rationally based on a secure understanding of transmission from the molecular-, cellular-, population- to the evolutionary levels. The meeting represented a first attempt to draw together scientists with expertise in these multiple layers of understanding to discuss the scientific foundations and resources that will be required to provide secure progress toward the design and successful implementation of effective interventions. PMID- 22424476 TI - Increasing access and ownership of clinical services at an HIV prevention project for sex workers in Mysore, India. AB - Increasing sex workers' (SWs) access to and utilisation of health care services is a key part of HIV prevention. An HIV prevention project in Mysore, India, has been particularly successful in fostering a new norm of health care seeking among local SWs while facilitating community ownership of health care delivery. This paper describes how the use of occupational health ideologies, along with the creation of enabling environments, facilitated the uptake of project healthcare services and transformed power relationships between SWs and their healthcare providers. These changes led Mysore's SWs to initiate health-enhancing actions that moved beyond project imperatives to serve self-identified community needs. PMID- 22424477 TI - Effect of phytochemicals on phase II enzyme expression in infant human primary skin fibroblast cells. AB - Phase II metabolising enzymes enable the metabolism and excretion of potentially harmful substances in adults, but to date it is unclear whether dietary phytochemicals can induce phase II enzymes differently between adults and infants. We investigated the expression of phase II enzymes in an in vitro model of primary skin fibroblasts at three different developmental stages, 1 month, 2 years and adult, to examine potential differences in age-related phase II enzymes in response to different phytochemicals (5-20 MUm) including sulphoraphane, quercetin and catechin. Following phytochemical treatment, a significant increase in mRNA of glutathione S-transferase A1 (GSTA1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) was observed, with the most marked increases seen in response to sulphoraphane (3-10-fold for GSTA1, P = 0.001, and 6-35-fold for NQO1, P = 0.001-0.017). Catechin also induced 3-5-fold changes in NQO1 transcription, whereas quercetin had less effect on NQO1 mRNA induction in infant cells. Moreover, NQO1 protein levels were significantly increased in 2-year-old and adult cell models in response to sulphoraphane treatment. These results suggest that metabolic plasticity and response to xenobiotics may be different in infants and adults; and therefore the inclusion of phytochemicals in the infant diet may modulate their induction of phase II metabolism, thereby providing increased protection from potentially harmful xenobiotics in later life. PMID- 22424479 TI - Novel mutations and diverse clinical phenotypes in recombinase-activating gene 1 deficiency. AB - BACKGROUND: Severe combined immunodeficiency is within a heterogeneous group of inherited defects throughout the development of T- and/or B-lymphocytes. Mutations in recombinase-activating genes 1 or 2 (RAG1/2) represent approximately 10% of all SCID cases. RAG1/2 are essential for V(D)J rearrangement of the B- and T-cell receptors. OBJECTIVES: The aim of this study was to review clinical, immunological and molecular findings of Turkish SCID patients with RAG1 defects and to draw attention to novel mutations, genotype-phenotype correlations and the high rate of BCG infections within this group. METHODS: Eleven patients (F/M: 6/5) were included. Molecular, immunological and clinical data were evaluated. RESULTS: Five patients were classified as T-B-NK + SCID, four patients as T + B NK + SCID (two of these patients were diagnosed as classical Omenn syndrome) and two patients as T + B + NK + SCID with respect to clinical presentations and immunological data. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were: 33.0 +/- 42.8, 3.1 +/- 3.3 and 10.4 +/- 13.5 months, respectively. Consanguinity rate was 54%. Some novel mutations were found in RAG1 gene in addition to previously reported mutations. Genotype phenotype correlation was not significantly apparent in most of the cases. BCG infection was observed in 36.4% of patients (two BCG-osis and two BCG-itis). CONCLUSION: Epigenetic factors such as compound genetic defects, enviromental factors, and exposure to recurrent infections may modify phenotypical characteristics of RAG deficiencies. Inoculation of live vaccines such as BCG should be postponed until primary immunodeficiency disease is excluded with appropriate screening tests in suspected cases. PMID- 22424480 TI - Hypertensive nephropathy in children - do we diagnose early enough? AB - BACKGROUND/AIMS: The aim was to evaluate the level of neutrophil gelatinase associated lipocalin (NGAL), interleukin 18 (IL-18) and retinol binding protein (RBP) in children with primary hypertension and no features of hypertensive nephropathy. METHODS: The study group consisted of 19 children (15 males) aged 14.8 +/- 2.18 years with primary hypertension. Estimated glomerular filtration rate (eGFR) and albumin/creatinine ratio (ACR) were within the normal range. Mean blood pressure (BP) was 141/79 mmHg (mean systolic BP percentile was 98, mean diastolic BP percentile was 80). Ambulatory BP measurement (ABPM), blood and urine biochemical measurements and features of end organ damage were assessed. The control group consisted of 20 healthy children. RESULTS: Hypertensive children showed significantly increased serum and urine NGAL concentration vs controls. Urine RBP was significantly higher in the study group vs controls. A positive correlation was found between urine NGAL and the index of mean systolic BP measured in ABPM, between urine IL-18 and the index of office diastolic BP, between serum NGAL and ACR, and between urine NGAL concentration and serum HDL. CONCLUSION: In children with primary hypertension, increased serum and urine NGAL may reflect kidney injury earlier than typical markers of hypertensive nephropathy. PMID- 22424481 TI - High rate nitrogen removal in an alum sludge-based intermittent aeration constructed wetland. AB - A new development on treatment wetland technology for the purpose of achieving high rate nitrogen removal from high strength wastewater has been made in this study. The laboratory scale alum sludge-based intermittent aeration constructed wetland (AlS-IACW) was integrated with predenitrification, intermittent aeration, and step-feeding strategies. Results obtained from 280 days of operation have demonstrated extraordinary nitrogen removal performance with mean total nitrogen (TN) removal efficiency of 90% under high N loading rate (NLR) of 46.7 g N m(-2) d(-1). This performance was a substantial improvement compared to the reported TN removal performance in literature. Most significantly, partial nitrification and simultaneous nitrification denitrification (SND) via nitrite was found to be the main nitrogen conversion pathways in the AlS-IACW system under high dissolved oxygen concentrations (3-6 mg L(-1)) without specific control. SND under high dissolved oxygen (DO) brings high nitrogen conversion rates. Partial nitrification and SND via nitrite can significantly reduce the demand for organic carbon compared with full nitrification and denitrification via nitrate (up to 40%). Overall, these mechanisms allow the system to maintaining efficient and high rate TN removal even under carbon limiting conditions. PMID- 22424482 TI - Intrinsically disordered N-terminus of calponin homology-associated smooth muscle protein (CHASM) interacts with the calponin homology domain to enable tropomyosin binding. AB - The calponin homology-associated smooth muscle (CHASM) protein plays an important adaptive role in smooth and skeletal muscle contraction. CHASM is associated with increased muscle contractility and can be localized to the contractile thin filament via its binding interaction with tropomyosin. We sought to define the structural basis for the interaction of CHASM with smooth muscle tropomyosin as a first step to understanding the contribution of CHASM to the contractile capacity of smooth muscle. Herein, we provide a structure-based model for the tropomyosin binding domain of CHASM using a combination of hydrogen/deuterium exchange mass spectrometry (HDX-MS) and NMR analyses. Our studies provide evidence that a portion of the N-terminal intrinsically disordered region forms intramolecular contacts with the globular C-terminal calponin homology (CH) domain. Ultimately, cooperativeness between these structurally dissimilar regions is required for CHASM binding to smooth muscle tropomyosin. Furthermore, it appears that the type 2 CH domain of CHASM is required for tropomyosin binding and presents a novel function for this protein domain. PMID- 22424483 TI - Ankle fractures. AB - Ankle fractures are important injuries involving a weight-bearing joint critical to mobility. This article will discuss the necessity of and justification for surgical correction of virtually all ankle fractures. Various ankle fracture types will be explored, mechanisms illuminated and proper treatment outlined for these complex injuries. PMID- 22424484 TI - Fractures of the talus: a comprehensive review. AB - The talus, a highly specialized bone with a unique anatomic design, is crucial for normal ambulation. Although uncommon, talar fractures can be potentially devastating to the patient. Although all talar fractures require appropriate diagnosis and treatment, some require surgical skill for appropriate correction. This article reviews the literature on talar fractures and their treatments. PMID- 22424485 TI - Calcaneal fractures: update on current treatments. AB - Calcaneal fractures represent 2% of all fractures and account for approximately 60% of all tarsal injuries. Motor vehicle collisions and falls are the major causes of these large force compression injuries, causing widening of the heel, loss of heel height, and articular surface displacement. A correlation has been shown between restoration of normal anatomy and satisfactory functional outcome. Once the basic principles of calcaneal fractures are understood, including the anatomy, the radiographic findings, and the challenges that these complicated fractures present, the physician can then be ready with the armamentarium that allows for a patient-specific and injury-specific plan. PMID- 22424486 TI - Tarsometatarsal/Lisfranc joint. AB - Accurate early diagnosis with adequate reduction and maintenance of anatomic alignment of the dislocation or fracture within the Lisfranc joint complex have been found to be the key to successful outcomes regarding this injury. Because of the anatomic variations, the thin soft tissue envelop, and the abundance of ligamentous and capsular structures in the region, repair of these injuries can be a challenge. The classification systems used to describe these injuries aid in describing the mechanism of injury or displacement type present, which may aid in determining what treatment modality can provide the best outcome. PMID- 22424487 TI - Pilon fractures. AB - The nature of the pilon fracture has caused evolution of treatment methods and its historically high rate of complication and poor outcome continue to direct choice of treatment. Attention to the delicate soft tissue envelope surrounding the ankle and recognition of the severity of the initial injury is crucial to ensure a satisfactory outcome and to minimize complications. Understanding the importance of staging surgical interventions will help to improve outcomes, but even optimal treatment may result in less than satisfactory results. PMID- 22424488 TI - Overview of concepts and treatments in open fractures. AB - Open fractures are one of the few lower extremity surgical emergencies. These injuries require immediate treatment. If untreated, severe cases of open fracture can be limb threatening. This article is a review of the literature of open fractures and the current treatment guidelines. PMID- 22424489 TI - Treatment of the neglected Achilles tendon rupture. AB - Achilles tendon ruptures are best managed acutely. Neglected Achilles tendon ruptures are debilitating injuries and the increased complexity of the situation must be appreciated. Surgical management is recommended, and only in the poorest surgical candidate is conservative treatment entertained. Numerous treatment algorithms and surgical techniques have been described. A V-Y advancement flap and flexor halluces longus tendon transfer have been found to be reliable and achieve good clinical outcomes for defects ranging from 2 cm to 8 cm. This article focuses on the treatment options for the neglected Achilles tendon rupture. PMID- 22424490 TI - Compartment syndrome: a review of the literature. AB - Compartment syndrome is a rare but severe complication of lower extremity trauma. This article provides an extensive review of the literature, including incidence, physical examination findings, pathophysiology, compartment pressure evaluation, and surgical decompression techniques. Most of the recent compartment syndrome literature shows case reports of atypical causes of this limb-threatening disorder. Although the emphasis of this article is traumatic compartment syndrome, recent literature on chronic lower extremity compartment syndrome, secondary to exercise or activity, is also discussed. PMID- 22424491 TI - Puncture wounds of the foot. AB - Puncture wounds often appear benign but can cause significant pedal morbidity. Podiatric physicians who treat such wounds should educate local emergency room, urgent care center, and primary care physicians as to the potential complications associated with puncture wounds. Timely referral, recognition of the potential complications, and appropriate treatment ensure that the wound does not advance beyond a puncture wound. If complications have developed, aggressive treatment is required to eradicate the infection and prevent pedal amputation. PMID- 22424492 TI - Versatility of intrinsic muscle flaps for the diabetic Charcot foot. AB - Bone, joint, and/or tendon exposure following surgical debridement of diabetic foot infections requires careful consideration when choosing appropriate closure methods. The unique architecture of the foot, coupled with the functional demands of mobilization, makes soft tissue reconstruction for plantar defects especially challenging. Muscle flaps incorporate the muscle, associated nerve, and vascular pedicles during transposition. This article covers their unique properties for soft tissue coverage in the diabetic Charcot foot. PMID- 22424493 TI - Total extrusion of the cuboid: a case report. AB - The incidence of total extrusion of the cuboid is rare, without any known published data or surgical guidelines. This case report describes the management of an open extruded cuboid by staged surgical interventions. Arthrodesis of the lateral column with a structural bone graft is a viable option to address the shortening, instability, and severe bone loss caused by the total cuboid extrusion. PMID- 22424494 TI - Foot and ankle trauma. Foreword. PMID- 22424495 TI - Foot and ankle trauma. Preface. PMID- 22424496 TI - Comorbidities in amputation: a systematic review of hemiplegia and lower limb amputation. AB - PURPOSE: The purpose of this review of the scientific literature was to investigate the incidence and prevalence of hemiplegia with lower limb amputation, and to identify outcomes following the dual disability of hemiplegia and amputation. METHODS: Electronic searching of the literature identified major studies examining the effects of hemiplegia on rehabilitation following amputation. Data were extracted and levels of evidence assigned for each subtopic area. RESULTS: The summary conclusions are Level 4 evidence. The prevalence of amputation and hemiplegia is 8-18% and amputation and hemiplegia occur most often in the same leg. Once individuals with hemiplegia and lower limb amputation are selected for prosthetic rehabilitation, rate of successful functional ambulation is greater than 58%. In general there is a lower rate of prosthetic success and independence with hemiplegia than without. Predictive factors associated with success include less severe hemiplegia, laterality of hemiplegia (ipsilateral and right side), transtibial level of amputation and absence of impaired mental function. There is wide variation in length of hospital stay, but a specialty multidisciplinary team reduces length of stay. CONCLUSIONS: Patients with dual disability of hemiplegia and amputation generally benefit from a prosthetic rehabilitation program. Further study on predictive factors for outcome would be beneficial. IMPLICATIONS FOR REHABILITATION: * The prevalence of hemiplegia with lower limb amputation ranges from 8 to 18%, most frequently affecting the same leg. * The majority of patients attain successful functional levels of ambulation with prosthetic rehabilitation, although lower rates than nonhemiplegic patients. * Predictive factors associated with greater success include less severe hemiplegia, ipsilateral hemiplegia, transtibial level of amputation and absence of impaired mental function. PMID- 22424497 TI - Reduced 30-day mortality in men after elective coronary artery bypass surgery with minimized extracorporeal circulation-a propensity score analysis. AB - BACKGROUND: Impact of minimized extracorporeal circulation (MECC) for coronary surgery on mortality remains controversial and gender significantly influence outcome. METHODS: We analyzed 3,139 male patients undergoing elective coronary surgery between 01/2004 and 05/2009. Using propensity score matching after binary logistic regression, 1,005 patients (from 1,119 patients) undergoing surgery with MECC could be matched with 1,005 patients (from 2,020 patients) undergoing surgery with conventional extracorporeal circulation (CECC). Primary outcome was 30-day mortality. RESULTS: Unadjusted 30-day mortality was 2.7% in patients with CECC and 0.8% in those with MECC (mean difference -1.9%; p < 0.001). The adjusted mean difference (average treatment effect of the treated) after matching was 1.5% (95% confidence interval (CI) -2.6 to -0.4; p = 0.006). Postoperative hospital stay was shorter in patients operated with minimized systems (adjusted mean difference -0.8 days; 95% CI -1.46 to -0.09; p = 0.03) and incidence of postoperative neurocognitive dysfunction was also lower (adjusted mean difference -1.3%; 95% CI -2.2 to -0.4; p = 0.001). Chest tube drainage (adjusted mean difference +22 mL; 95% CI -47 to 91; p = 0.5) and risk for acute kidney injury, kidney injury and failure according to RIFLE criteria (adjusted mean difference 1.0%; 95% CI -2.5 to 0.6; p = 0.24) proved to be insignificant between both groups. Apart from reduced 30-day mortality, however, average treatment effects for intensive care unit stay, postoperative hospital stay, chest tube drainage and kidney injury did not significantly differ. CONCLUSION: Using propensity score analysis, we observed an association between MECC and reduced 30-day mortality in men, but our results call for further analysis. PMID- 22424498 TI - Analysis of saturated hydrocarbons by redox reaction with negative-ion electrospray Fourier transform ion cyclotron resonance mass spectrometry. AB - A novel technique was developed for characterization of saturated hydrocarbons. Linear alkanes were selectively oxidized to ketones by ruthenium ion catalyzed oxidation (RICO). Branched and cyclic alkanes were oxidized to alcohols and ketones. The ketones were then reduced to alcohols by lithium aluminum hydride (LiAlH(4)). The monohydric alcohols (O(1)) in the products obtained from the RICO and RICO-LiAlH(4) reduction reactions were characterized using negative-ion electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) for identification of iso-paraffins, acyclic paraffins and cyclic paraffins. Various model saturated compounds were used to determine the RICO reaction and ionization selectivity. The results from the FTICR MS analysis on the petroleum distillates derived saturated fraction were in agreement with those from field ionization gas chromatography time-of-flight mass spectrometry (FI GC-TOF MS) analysis. The technique was also used to characterize a petroleum vacuum residue (VR) derived saturates. The results showed that the saturated molecules in the VR contained up to 11 cyclic rings, and the maximum carbon number was up to 92. PMID- 22424501 TI - Aortic valve insufficiency: leaflet reconstruction techniques. AB - The introduction of effective and durable leaflet repair techniques have enabled repair of the regurgitant aortic valve. Aortic valve repair is favored to avoid the placement of a prosthesis that the patient will likely outgrow. Furthermore, repair has the potential to reduce the incidence of prosthesis-related complications, including endocarditis, thromboembolism, anticoagulant-related hemorrhage, and reoperation. The primary goal of all aortic valve repair is to restore a durable surface of coaptation to the regurgitant valve. The key to successful leaflet repair for aortic insufficiency is a thorough understanding of the mechanism of dysfunction. We have developed a systematic approach to the assessment and repair of aortic insufficiency because of leaflet disease. The combination of leaflet repair and functional aortic annulus annuloplasty can restore the proper geometry of the aortic valve complex and allow for successful repair of aortic insufficiency caused by both restriction and prolapse. PMID- 22424502 TI - Aortic valve reconstruction in the young infants and children. AB - Considering the structure and function of the aortic root, changes in the aortic valve leaflets and changes in the geometry of the aortic root are the two primary causes of aortic valve dysfunction. In adults, aortic valve sparing reconstruction has a long history beginning in the 1970s, where tensor fascia was used for leaflet repair in patients with isolated aortic regurgitation and ascending aortic replacement was used in patients with ascending aortic aneurysms or aortic ectasia. Subsequent progress in the 1980s and 1990s led to pericardial leaflet replacement and aortic root re-implantation and remodeling. However, it has not been until the last decade that these concepts and techniques have been applied in younger patients focusing on the conotruncus, valvar apparatus, sino tubular junction, and ascending aorta. PMID- 22424503 TI - Valve-sparing aortic root replacement. AB - Aortic aneurysms are rare in children and are often associated with connective tissue disorders. Because prosthetic valves are problematic in the young, operations that preserve the native aortic valve are attractive. This article describes an operative technique for valve sparing aortic root replacement that is simple and reproducible, and has probvided durable results at mid-term follow up. PMID- 22424504 TI - Valve-sparing options in tetralogy of Fallot surgery. AB - Given late outcomes of patients with tetralogy of Fallot repaired in the 1970s and 1980s, as well as a better understanding of the late deleterious effects of pulmonary regurgitation, there is a tendency toward preservation of the pulmonary valve function during primary repair of tetralogy of Fallot. The bar keeps moving downward, to include smaller and more dysmorphic pulmonary valves. This article reviews some useful indications and techniques for valve-sparing options, including intraoperative balloon dilation and cusp reconstruction using a patch. Just like other valve repair techniques, no one technique can be applied uniformly, and surgeons must master a wide armamentarium of techniques. PMID- 22424505 TI - Timing and technique of pulmonary valve replacement in the patient with tetralogy of Fallot. AB - Residual right ventricular (RV) outflow tract pathology is universal among patients with repaired tetralogy of Fallot, and pulmonary regurgitation (PR) is also commonly present. Although tolerated in early life, by the second decade of life PR is associated with an increased risk of death because of ventricular arrhythmias. Pulmonary valve replacement (PVR) is a safe procedure that will eliminate PR, but timing and indications are evolving. Patients with arrhythmias or prolonged QRS duration are candidates for PVR. Patients with symptomatic exercise intolerance are likely to have improvement in symptoms and quality of life and should be offered PVR. Cardiac magnetic resonance has become an essential component of the management of the patient with tetralogy of Fallot with PR, and has identified the potential for and limitations of RV remodeling following PVR. Among patients with severe RV enlargement, particularly those with diminished RV or left ventricular function, there is an increased risk of adverse events and even asymptomatic patients with severe PR should be considered for PVR. Valve replacement is accomplished with homografts or heterografts, either stented bioprosthetic valves or valved conduits. In a retrospective analysis of the Children's Hospital of Wisconsin experience with PVR, there was no difference in survival or freedom from reintervention between heterografts and homografts. PMID- 22424506 TI - Options for prosthetic pulmonary valve replacement. AB - This article reviews current data on various prostheses utilized for pulmonary valve replacement. Durability data is reviewed and risk factors for deterioration are examined. Finally, the choice of prosthesis should be tailored to the specific clinical scenario based on existing data regarding durability and risk factors. PMID- 22424507 TI - Ebstein's anomaly of the tricuspid valve: the cone repair. AB - Ebstein's anomaly is a cardiac malformation affecting the tricuspid valve and right ventricle with a wide range of anatomic and pathophysiologic presentations. The cone repair technique is described in detail, as applied to several types of this complex congenital heart disease. The importance of extensive mobilization of displaced and tethered tricuspid leaflets to permit a good leaflet-to-leaflet coaptation after the cone construction is highlighted. This technique was performed in 100 patients with a hospital mortality rate of 3.0%, good clinical outcome, and no need for tricuspid valve replacement. Echocardiograph results showed good anatomic and functional tricuspid valves at immediate and long-term postoperative follow-up. PMID- 22424508 TI - Surgical management of congenital (non-Ebstein) tricuspid valve regurgitation. AB - Congenital tricuspid valve regurgitation (TR) is a relatively uncommon condition that includes a heterogeneous group of lesions with a unique management strategy. There are wide anatomic variations that lead to congenital TR in patients without Ebstein malformation. Possible etiologies may include primary valve abnormalities (eg, congenital absence of chordae) or other forms of tricuspid valve dysplasia as in congenitally unguarded tricuspid valve, and patients with pulmonary atresia and intact ventricular septum, which can be similar to Ebstein's valves or secondary regurgitation in association with other anomalies as in atrioventricular septal defects, right ventricular outflow tract obstructive lesions (pulmonary stenosis or atresia with ventricular septal defect [VSD]), tricuspid valve annular dilatation in association with right ventricular volume overload lesions as in congenital coronary arterial fistula with secondary right ventricular enlargement, and Uhl's anomaly. Iatrogenic etiologies in the congenital population include TR secondary to previous VSD closure (chordal or leaflet injury), pacemaker or internal cardiac defibrillator lead-induced TR, and traumatic TR (ruptured chordae). Presentation depends on the severity of the disease and may be apparent in infancy, childhood, or adulthood. PMID- 22424509 TI - Tricuspid valve repair in single ventricle: timing and techniques. AB - Tricuspid valve performance in the systemic circulation is known to have important implications for survival and functional status after univentricular palliation of hypoplastic left heart syndrome (HLHS). Moderate to severe tricuspid valve regurgitation is not an uncommon finding in patients with HLHS undergoing staged surgical reconstruction. It can result from either abnormal valve morphology or incomplete leaflet coaptation, or both. But first and foremost, any aortic arch re-obstruction must be excluded. Development of significant tricuspid regurgitation (TR) remains an obstacle in improving survival after the Norwood procedure and likely compromised functional health after the Fontan procedure. Thus, surgical intervention for minimizing tricuspid valve deterioration and significant TR seems pivotal to improving long-term outcomes for patients with HLHS. This article provides an overview of the etiology and mechanisms of development of significant TR, natural history, indications for surgical intervention, and focuses on timing, techniques, and clinical outcomes of tricuspid valve repair in the setting of single ventricle. PMID- 22424510 TI - Congenital mitral valve stenosis: anatomic variants and surgical reconstruction. AB - Congenital mitral valve stenosis is a heterogeneous group of lesions that can occur as an isolated defect or, more commonly, in association with other left heart obstructive defects. Age at presentation, presence and severity of pulmonary hypertension, and location of the primary obstructing lesion have been shown to be important risk factors for survival and long-term outcomes. Anatomic features vary, and obstructing tissue or tethering structures can be present at all levels of the valve, including supra-annular, intra-leaflet, and sub-valvar. Surgical techniques aim to remove abnormal tissue that is causing the obstruction or impediment to adequate leaflet mobility, and improve the mobility of the sub valve structures. We describe a series of surgical options for mitral valve reconstruction that address the specific pathologies frequently found in congenital mitral stenosis. PMID- 22424511 TI - Mitral regurgitation in congenital heart defects: surgical techniques for reconstruction. AB - Mitral valve regurgitation (MR) is an important source of morbidity and mortality worldwide. While globally the primary etiology is rheumatic, the incidence of MR appears to be increasing in the United States as well. There are multiple etiologies for MR, and the specific pathologic anatomy varies widely. Similarly, there are a multitude of options for operative repair, and recent series report very good survival rates as well as freedom from re-intervention. PMID- 22424512 TI - The rheumatic mitral valve and repair techniques in children. AB - The mitral valve is the most commonly affected valve in acute and chronic rheumatic heart disease in the first and second decades of life. Pure or predominant mitral regurgitation with non-significant stenosis (mitral valve area > 1.5 cm(2) on echocardiography) is the most frequently encountered valvular dysfunction in children. In our experience, based on 428 children operated between 1993 and 2011 at our institution, functional classification based on leaflet motion assessed by echocardiography and reconfirmed peroperatively revealed pure annulus dilatation (type I) in 7% of patients, anterior leaflet prolapse (type IIa) in 33%, combination of anterior leaflet pseudoprolapse with restricted motion of the posterior leaflet (type pseudoIIa/IIIp) in 34%, and restricted anterior and posterior leaflet motion (type IIIa/p) in 26%. Patients with type III were older than those with type IIa and type pseudoIIa/IIIp. Different techniques can be used to repair rheumatic mitral valve lesions: prolapse of the anterior leaflet caused by chordal elongation or rupture can be treated by chordal shortening, chordal transfer, or artificial chordal replacement; restricted motion of the anterior and/or posterior leaflet can be treated by commissurotomy, splitting of the papillary muscles, resection of the secondary, or sometimes primary posterior chordae, posterior leaflet free edge suspension, leaflet thinning, and leaflet enlargement using autologous pericardium. Because mitral annulus dilatation is present in almost all patients with mitral regurgitation, concomitant ring annuloplasty offers more stability in valve repair, improving long-term outcome. The major causes for failure of rheumatic mitral valve repair are the presence of ongoing rheumatic inflammation at the time of surgery, use of inappropriate techniques, technical failures requiring early reoperation, lack of concomitant ring annuloplasty, and progression of leaflet and chordal disease further resulting in more leaflet retraction, thickening, and deformity. Freedom from reoperation depends on mitral regurgitation functional type, the type IIa and type pseudoIIa/IIIp having a better long-term outcome than type I and type III, in our series. In conclusion, mitral valve repair should be a preferred strategy in children with rheumatic heart disease whenever feasible, providing stable actuarial survival with fewer thromboembolic complications in a pediatric population noncompliant to anticoagulation. PMID- 22424513 TI - Atrioventricular valve repair for patient with heterotaxy syndrome and a functional single ventricle. AB - Heterotaxy syndrome is a mortality risk factor for patients with complex heart disease. These patients often have common atrioventricular valve (CAVV) morphology and significant atrioventricular valve regurgitation - yet another mortality risk factor in congenital heart disease. Thus, patients with both heterotaxy syndrome and atrioventricular valve regurgitation are at highest risk of mortality. A large number of patients with heterotaxy syndrome have CAVV and a functional single ventricle. These patients are more difficult to operate than patients with biventricular morphology because in the former, the CAVV is often less adapted to systemic afterload than the mitral valve. Herein, we present the results of atrioventricular valve repair surgeries performed at the Okayama University Hospital on patients with heterotaxy syndrome, atrial isomerism, and a functional single ventricle. In addition, we review the current literature in this typically challenging patient population. In-depth understanding of reasonable management strategies and resolution of technical issues will help guide surgeons during this procedure. PMID- 22424514 TI - 2011 Scientific Achievement Award recipient: Marc R. de Leval, MD. PMID- 22424515 TI - Should the use of transcatheter aortic valve implantation be rationed? PMID- 22424516 TI - Transcatheter aortic valve implantation should be controlled and monitored by the medical profession. PMID- 22424517 TI - Use of transcatheter valve should not be rationed. PMID- 22424519 TI - Transcatheter (TAVR) versus surgical (AVR) aortic valve replacement: occurrence, hazard, risk factors, and consequences of neurologic events in the PARTNER trial. AB - BACKGROUND: All neurologic events in the PARTNER randomized trial comparing transcatheter aortic valve replacement (TAVR) with surgical aortic valve replacement (AVR) were analyzed. METHODS: High-risk patients with aortic stenosis were stratified into transfemoral (TF, n = 461) or transapical (TA, n = 196) strata based on their arterial anatomy and randomized: 657 received treatment assigned ("as treated"), 313 underwent AVR, and 344 TAVR. Neurologic events were prospectively adjudicated by an independent Clinical Events Committee. Multivariable, multiphase hazard analysis elucidated factors associated with increased likelihood of neurologic events. RESULTS: Forty-nine neurologic events (15 transient ischemic attacks, 34 strokes) occurred in 47 patients (TAVR, n = 31; AVR, n = 16). An early peaking high hazard phase occurred within the first week, which declined to a constant late hazard phase out to 2 years. The risk in the early phase was higher after TAVR than AVR, and in the TAVR arm in patients with a smaller aortic valve area index. In the late risk phase, the likelihood of neurologic event was linked to patient-related factors in both arms ("non-TF candidate," history of recent stroke or transient ischemic attack, and advanced functional disability), but not by treatment (TAVR vs AVR) or any intraprocedural variables. The likelihood of sustaining a neurologic event was lowest in the AVR subgroup in the TF stratum during all available follow-up. CONCLUSIONS: After either treatment, there were 2 distinct hazard phases for neurologic events that were driven by different risk factors. Neurologic complications occurred more frequently after TAVR than AVR early, but thereafter the risk was influenced by patient- and disease-related factors. PMID- 22424518 TI - ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 appropriate use criteria for coronary revascularization focused update: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, American Society of Nuclear Cardiology, and the Society of Cardiovascular Computed Tomography. AB - The American College of Cardiology Foundation (ACCF), Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, and the American Association for Thoracic Surgery, along with key specialty and subspecialty societies, conducted an update of the appropriate use criteria (AUC) for coronary revascularization frequently considered. In the initial document, 180 clinical scenarios were developed to mimic patient presentations encountered in everyday practice and included information on symptom status, extent of medical therapy, risk level as assessed by noninvasive testing, and coronary anatomy. This update provides a reassessment of clinical scenarios the writing group felt to be affected by significant changes in the medical literature or gaps from prior criteria. The methodology used in this update is similar to the initial document, and the definition of appropriateness was unchanged. The technical panel scored the clinical scenarios on a scale of 1 to 9. Scores of 7 to 9 indicate that revascularization is considered appropriate and likely to improve patients' health outcomes or survival. Scores of 1 to 3 indicate revascularization is considered inappropriate and unlikely to improve health outcomes or survival. Scores in the mid-range (4 to 6) indicate a clinical scenario for which the likelihood that coronary revascularization will improve health outcomes or survival is uncertain. In general, as seen with the prior AUC, the use of coronary revascularization for patients with acute coronary syndromes and combinations of significant symptoms and/or ischemia is appropriate. In contrast, revascularization of asymptomatic patients or patients with low-risk findings on noninvasive testing and minimal medical therapy are viewed less favorably. The technical panel felt that based on recent studies, coronary artery bypass grafting remains an appropriate method of revascularization for patients with high burden of coronary artery disease (CAD). Additionally, percutaneous coronary intervention may have a role in revascularization of patients with high burden of CAD. The primary objective of the appropriate use criteria is to improve physician decision making and patient education regarding expected benefits from revascularization and to guide future research. PMID- 22424521 TI - Quantifying the incremental cost of complications associated with mitral valve surgery in the United States. AB - OBJECTIVE: The goal of this study was to quantify the net increase in resource use associated with complications after isolated mitral valve surgery. METHODS: Deidentified patient-level claims data on a random sample of mitral valve operations performed in the United States from January 1, 2006, to December 31, 2007, were obtained from the National Inpatient Sample (n = 16,788). Patients with major concomitant cardiac procedures were excluded from the analysis for a net sample size of 6297 patients. Risk-adjusted median total hospital costs and length of stay were analyzed by major complications, including pneumonia, sepsis, stroke, renal failure requiring hemodialysis, cardiac tamponade, myocardial infarction, gastrointestinal bleed, and venous thromboembolism. RESULTS: There were a total of 1323 complication events that occurred in 1089 patients. The most common complication was pneumonia (n = 346, 5.5%), which was associated with a $29,692 increase in hospital costs and a 10.2-day increase in median length of stay (P < .001). The most costly complication was cardiac tamponade, which resulted in an increase in hospital cost of $56,547 and an increase in length of stay of 19.3 days (P < .001). There was a stepwise association between the hospital costs and length of stay and the number of complications per patient (P < .001). There was also a significant association between the discharge location and the occurrence of a complication, with 25% more patients who underwent routine home discharge when there were no complications (P < .001). CONCLUSIONS: In patients undergoing isolated mitral valve surgery, postoperative complications were associated with significant increases in mortality, hospital costs, and length of stay, as well as with discharge location. With growing national attention to improving quality and containing costs, it is important to understand the nature and impact of complications on outcomes and costs. PMID- 22424523 TI - Pulmonary artery size at the time of bidirectional cavopulmonary shunt and Fontan surgery influences long-term outcomes. PMID- 22424525 TI - The selected segmental inflation technique for pulmonary segmentectomy: pros and cons. PMID- 22424527 TI - The use of radiofrequency ablation for patients with nondysplastic Barrett's esophagus. PMID- 22424528 TI - Venovenous extracorporeal membrane oxygenation in acute respiratory failure: do we need a new configuration? PMID- 22424531 TI - Removal of a large cement embolus from the right pulmonary artery 4 years after kyphoplasty: consideration of thrombogenicity. PMID- 22424532 TI - Pharmacotherapy of corneal transplantation. AB - INTRODUCTION: Corneal transplantation is a surgical procedure in which damaged or diseased cornea is replaced by cadaveric corneal tissue. It is the most common form of solid-tissue transplantation in humans but its pharmacotherapy (in relation to graft rejection) has changed little for several decades. The mainstay of treatment of corneal graft rejection remains corticosteroids but these are variably effective and are associated with potentially serious adverse effects. Newer immunosuppressive drugs are increasingly being employed to manage high-risk grafts. However, these drugs are also not without side-effects, some of which can be severe and life-threatening. AREAS COVERED: This review outlines the corneal transplant procedure and the treatment options available in the management of transplant rejection. EXPERT OPINION: The surgical technique of corneal lamellar grafting has allowed for transplantation of smaller quantities of donor tissue to the recipient, thereby reducing the antigen load as a means of preventing a rejection episode. With greater understanding of the underlying molecular mechanisms involved in corneal transplant rejection pathology, potentially newer medications that will target specific cytokines or cells involved in rejection, whilst minimizing the potential side effects to the graft recipient, will be made available. PMID- 22424533 TI - Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data. AB - BACKGROUND: Molecular studies of breast cancer revealed biological heterogeneity of the disease and opened new perspectives for personalized therapy. While multiple gene expression-based systems have been developed, current clinical practice is largely based upon conventional clinical and pathologic criteria. This gap may be filled by development of combined multi-IHC indices to characterize biological and clinical behaviour of the tumours. Digital image analysis (DA) with multivariate statistics of the data opens new opportunities in this field. METHODS: Tissue microarrays of 109 patients with breast ductal carcinoma were stained for a set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1alpha, SATB1, p53, and p16). Aperio imaging platform with the Genie, Nuclear and Membrane algorithms were used for the DA. Factor analysis of the DA data was performed in the whole group and hormone receptor (HR) positive subgroup of the patients (n = 85). RESULTS: Major factor potentially reflecting aggressive disease behaviour (i-Grade) was extracted, characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1alpha. The i-Grade factor scores revealed bimodal distribution and were strongly associated with higher Nottingham histological grade (G) and more aggressive intrinsic subtypes. In HR-positive tumours, the aggressiveness of the tumour was best defined by positive Ki67 and negative ER loadings. High Ki67/ER factor scores were strongly associated with the higher G and Luminal B types, but also were detected in a set of G1 and Luminal A cases, potentially indicating high risk patients in these categories. Inverse relation between HER2 and PR expression was found in the HR-positive tumours pointing at differential information conveyed by the ER and PR expression. SATB1 along with HIF-1alpha reflected the second major factor of variation in our patients; in the HR-positive group they were inversely associated with the HR and BCL2 expression and represented the major factor of variation. Finally, we confirmed high expression levels of p16 in Triple-negative tumours. CONCLUSION: Factor analysis of multiple IHC biomarkers measured by automated DA is an efficient exploratory tool clarifying complex interdependencies in the breast ductal carcinoma IHC profiles and informative value of single IHC markers. Integrated IHC indices may provide additional risk stratifications for the currently used grading systems and prove to be useful in clinical outcome studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1512077125668949. PMID- 22424534 TI - Negative inotropic effect of a CB2 agonist A-955840 in isolated rabbit ventricular myocytes is independent of CB1 and CB2 receptors. AB - A-955840, a selective CB2 agonist, has been shown to elicit concentration dependent decreases in cardiac contractility in the anesthetized dog (decreased maximal velocity of left ventricular pressure development [LV dP/dt max]). However, it is unknown whether this represents a direct effect or a response dependent on other factors (such as autonomic tone and neurohumoral factors) present in vivo. This study examined if A-955840 had a direct effect on contractility of isolated cardiac myocytes, and if so to determine the potential mechanisms. Contractility was assessed in vitro using percent changes in maximal shortening velocity of sarcomeres (dL/dt max) and fractional shortening of sarcomere length (FS) in rabbit left ventricular myocytes. L-type calcium current in myocytes was recorded using wholecell voltage-clamp techniques. A-955840 reduced dL/dt max and FS in a reversible and concentration-dependent manner with an IC50 of 11.4 MUg/mL (based on dL/dt max) which is similar to the estimated IC50 value of 9.8 MUg/mL based on the effects of A-955840 on LV dP/dt max in anesthetized dogs. A-955840 (4.1 MUg/mL) reduced myocyte contractility (%FS) to a similar extent in the absence and presence of a CB2 antagonist, SR-2 (24.0 +/- 3.4 vs 23.1 +/- 3.0 %, n=5) or a CB1 antagonist, Rimonabant (18.8 +/- 2.3 vs 19.8 +/- 2.7 %, n=5). A-955840 (4.1 MUg/mL) also reduced L-type calcium current of rabbit ventricular myocytes (1.05 +/- 0.11 vs 0.70 +/- 0.12 nA, n=5, P < 0.01). These results suggest that A-955840 exerts direct negative inotropic effects on isolated rabbit ventricular myocytes, which is mediated by neither CB2 nor CB1 receptors, and consistent with off-target negative inotropy mediated by inhibition of the cardiac L-type calcium current. PMID- 22424535 TI - Differences in medication adherence, satisfaction and clinical symptoms in schizophrenic outpatients taking different antipsychotic regimens. AB - OBJECTIVE: To investigate differences in medication adherence, treatment satisfaction and clinical symptoms in schizophrenic outpatients taking different antipsychotic treatment regimens. METHODOLOGY: Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS-8) while treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4). Psychiatric symptoms were measured using the 24-item expanded Brief Psychiatric Rating Scale (BPRS-E). Data were entered and analyzed using SPSS 16 for windows. RESULTS: A convenience sample of 131 schizophrenic patients was studied. Patients belonged to 7 groups based on their antipsychotic treatment regimens. There was no significant difference in the means of adherence (P=0.6) and BPRS domains: positive (P=0.6), negative (P=0.8), manic (P=0.2) and depression (P=0.9) scores among the studied groups. Satisfaction with side effect domain was significantly different among studied groups (P=0.006, F=3). However, no significant difference was found in other satisfaction domains: effectiveness (P=0.8), convenience (P=0.3), and global satisfaction (P=0.8). CONCLUSIONS: Medications adherence, most treatment satisfaction domains and clinical symptom scores were not significantly different among patients taking different antipsychotic regimens. PMID- 22424536 TI - Lithium and kidney, 60 years later. AB - Lithium, an old and invaluable psychiatric therapy, is still the best treatment option in several clinical circumstances, including acute mania, bipolar and unipolar recurrent mood disorders, suicidal ideation and behavior, recurrent or chronic unipolar depression that has not responded to other treatments, aggressive or impulsive behavior and alcoholism, especially when an affective component is manifest. However, lithium has a narrow therapeutic index and is associated with many serious acute and long-term side effects. Furthermore, monitoring requirements, i.e., frequent blood draws and frequent visits, discourage lithium use. Therefore, the drug is underused. Full awareness of lithium side effects and competence to minimize them is the only contrast to this ominous trend. Renal side effects are frequent in the course of lithium treatment. Although not serious in the large majority of cases, they may seldom become severe and result in chronic renal failure and end stage renal disease. The aim of the paper is reviewing the renal safety profile of lithium and the suggested strategies in the management of the lithium associated renal side effects. PMID- 22424537 TI - Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2 diabetes. AB - Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of drugs introduced in 2006 for treatment of type 2 diabetes. In clinical trials lasting up to 2 years, these agents are well tolerated. Incidence of hypoglycemia associated with the use of DPP-4 inhibitors is similar to placebo, but is markedly increased when used in conjunction with sulfonylureas (SUs). DPP-4 inhibitors have neutral effect on body weight but their combination with a thiazolidinedione (TZD) results in slight weight gain averaging 0.5 to 1.3 kg compared with placebo. Other adverse effects recorded more commonly with DPP-4 inhibitors versus placebo are mild, and include nasopharyngitis, headache, and possibly urinary tract infections (UTIs). In the postmarketing period, new adverse effects are reported such as angioedema, increased rates of infection, and skin toxicity. Pancreatitis is inconsistently reported in relationship to sitagliptin, and one analysis links this agent to elevated risk of pancreatic cancer. Pancreatitis is also a rare adverse effect observed in linagliptin clinical studies. There is no evidence that DPP-4 inhibitors increase cardiovascular events or death. Overall, although short-term safety of DPP-4 inhibitors is reassuring, their safety needs to be established by long-term clinical trials and close surveillance during the postmarketing period. PMID- 22424538 TI - Adverse drug reactions and safety considerations of NSAIDs: clinical analysis. AB - NSAIDs are the most frequently used drugs for treatment, in Europe and the United States, accounting for approximately 5% of all prescriptions. Moreover, the use of NSAIDs is increasing because these constitute the first-line drug therapy for a wide range of rheumatic conditions. This increase is in part the result of the increasing population of elderly patients, who constitute the group of patients with greatest demand for these agents. There are many types of NSAIDs that vary in potency, action and potential side effects. Thus various efforts have been made to determine the safety considerations including adverse drug effects, duration of drug therapy, drug interactions, precautions and other drugs applied to reduce side effects. Researchers have introduced some novel techniques to diagnose NSAIDs related adverse effects on the gastrointestinal mucosa. The researchers dealing with the development of drug delivery system for these drugs should aim at designing a therapeutically efficacious dosage form with reduced side/adverse effects. Thus an effort has been made in this review to deal with the safety parameters of various NSAIDs with a special emphasis on preclinical and clinical safety analysis and various attempts to minimize the side effects by structural modification or by drug delivery system. PMID- 22424539 TI - Considerations in the pharmacotherapy of bipolar disorder during and after pregnancy. AB - There are conflicting data on the course of bipolar disorder during pregnancy but childbirth is generally considered a time of high risk for the onset or exacerbation of mood and psychotic episodes in women with bipolar disorder. Despite the increasing use of psychotropic drugs in women with psychiatric disorders, there is a paucity of information in the pharmacological treatment of bipolar disorder during and after pregnancy. Optimal drug treatment requires an understanding of the illness course prior to, during, and after pregnancy; bipolar disorder type and dominant polarity, psychiatric comorbidity, physical health status, prior response to psychotropic drugs, effectiveness of medications in the acute and preventative treatment of mood episodes, side effect profile including teratogenicity, and finally family history of psychiatric illness. For women who discontinue psychotropic drugs abruptly upon finding out about the pregnancy, the withdrawal symptoms of medications should be distinguished from the symptoms of the disorder. Compatibility of drugs with breastfeeding is another important consideration. Antidepressants should be avoided as much as possible due to their association with manic switches, rapid cycling, and suicidality. An important aspect of pharmacotherapy in women with a personal or family history of bipolar I disorder or postpartum psychosis should be the management of insomnia that can either be an early symptom of, or a trigger for postpartum manic/mixed or psychotic episodes. Whereas polypharmacy may be unavoidable, every effort should be made to keep the overall number of medications and dosages to a minimum. PMID- 22424540 TI - Relaxin as a cardiovascular drug: a promise kept. AB - Relaxin (RLX), formerly known for its effects on reproduction and pregnancy, has been later shown to be a pleiotropic hormone, capable of also targeting numerous non-reproductive organs of the cardiovascular, nervous, respiratory, tegumental, excretory and digestive systems. Most of these effects have been studied in animal models, but there is compelling evidence that RLX also acts in humans. In more recent years, human luteal-type (H2) RLX synthesised by recombinant DNA technology has been investigated in clinical trials, mostly oriented to assess its therapeutic potential in cardiovascular disease. This indication was based on the accumulating pre-clinical evidence that RLX possesses prominent biological effects on systemic and coronary blood vessels, cardiomyocyte growth and differentiation, and cardiac/vascular connective tissue remodelling. This mini review was intended as an update of our previous article that appeared in this journal in 2009, as the last 2 years have been characterised by fundamental achievements on the clinical profile of RLX. Eventually, after many years of inconclusive studies, RLX appears to be about to reach a recognised dignity as a cardiovascular drug. PMID- 22424541 TI - Efficacy and toxicological studies of cremophor EL free alternative paclitaxel formulation. AB - PURPOSE: In the present study, Cremophor EL free paclitaxel elastic liposomal formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate was developed and optimized. The toxicological profile, antitumor efficacy and hemolytic toxicity of paclitaxel elastic liposomal formulation in comparison to Cremophor EL based marketed formulation were evaluated. METHODS: Paclitaxel elastic liposomal formulations were prepared and characterized in vitro, ex-vivo and in vivo. Single dose toxicity study of paclitaxel elastic liposomal and marketed formulation was carried out in dose range of 10, 20, 40, 80, 120, 160 and 200 mg/kg. Cytotoxicity of developed formulation was evaluated using small cell lung cancer cell line (A549). Antitumor activity of developed formulation was compared with the marketed formulation using CytoselectTM 96-well cell transformation assay. RESULTS: In vivo administration of paclitaxel elastic liposomal formulation into mice showed 6 fold increase in Maximum Tolerated Dose (MTD) in comparison to the marketed formulation. Similarly, LD50 (141.6 mg/kg) was also found to increase significantly than the marketed formulation (16.7 mg/kg). Result of antitumor assay revealed a high reduction of tumor density with paclitaxel elastic liposomal formulation. Reduction in hemolytic toxicity was also observed with paclitaxel elastic liposomal formulation in comparison to the marketed formulation. CONCLUSION: The carrier based approach for paclitaxel delivery demonstrated significant reduction in toxicity as compared to the Cremophor EL based marketed formulation following intra-peritoneal administration in mice model. The reduced toxicity and enhanced anti-cancer activity of elastic liposomal formulation strongly indicate its potential for safe and effective delivery of paclitaxel. PMID- 22424542 TI - Successful desensitization of three patients with hypersensitivity reactions to omalizumab. AB - BACKGROUND: Omalizumab is prescribed as a step-up therapy for patients with moderate to severe allergic asthma uncontrolled on high-dose inhaled corticosteroids and long acting beta agonists. However, hypersensitivity reactions may lead to its discontinuation and subsequent worsening or loss of asthma control. No successful desensitization protocols to omalizumab have been previously reported. OBJECTIVE: We aimed to determine the efficacy and safety of a novel one-day outpatient omalizumab desensitization protocol for patients with hypersensitivity reactions to omalizumab. METHODS: We retrospectively assessed the efficacy of omalizumab desensitization protocol performed in a university allergy-immunology clinic from July 2009 to July 2010. RESULTS: We successfully desensitized 3 patients with moderate-severe asthma to omalizumab. After desensitization all patients had improvement in asthma control and were able to discontinue or decrease chronic systemic steroid therapy. CONCLUSIONS: This novel outpatient omalizumab desensitization protocol was a safe and effective approach for the treatment of omalizumab hypersensitivity in patients with moderate to severe allergic asthma who required omalizumab therapy. PMID- 22424543 TI - Safety of intravenous thrombolysis in ischemic stroke caused by left atrial myxoma. AB - Intravenous thrombolytic treatment represents the gold standard for acute ischemic stroke treatment. However there is some concern to perform this treatment in patients with known cardiac myxomas for the risk of haemorragic complications. Here we described a 63-year-old patient with ischemic stroke due to embolization of atrial myxoma and treated with intravenous recombinant tissue plasminogen activator alteplase. The patient did not show improvement after treatment; 25 days later a brain CT showed an asymptomatic small hemorrhagic infarction, probably due to the large size of ischemic lesion. The lack of response might be explained by the embolization of a large tumor fragment. One year after cardiac surgery clinical follow-up did not reveal new neurological signs nor symptoms. This case report suggests that systemic thrombolysis is a safe procedure also in patient with atrial myxoma. The efficacy of therapy seems to be related to embolus composition. PMID- 22424544 TI - Lactic acidosis, hypotension, and sensorineural hearing loss following intentional metformin overdose. AB - Metformin and glyburide are antihyperglycemic agents that are widely used in the United States. There have been several cases of overdose of these medications reported in the world literature. Glyburide overdose is associated with hypoglycemia that can be severe, while metformin overdoses have been associated with lactic acidosis. In many cases of metformin overdose, lactic acidosis has led to profound hypotension and respiratory failure. In this article we will present the case of a 49-year-old man who ingested 52 grams of metformin and 350 mg of glyburide in a suicide attempt. The patient developed hypoglycemia, lactic acidosis, hypotension, respiratory failure and a profound sudden sensorineural hearing loss. We discuss prior cases of overdose with these agents, and the connection between overdose and the development of sudden sensorineural hearing loss. PMID- 22424545 TI - Oxygen bridges between NiO nanosheets and graphene for improvement of lithium storage. AB - Graphene has been widely used to dramatically improve the capacity, rate capability, and cycling performance of nearly any electrode material for batteries. However, the binding between graphene and these electrode materials has not been clearly elucidated. Here we report oxygen bridges between graphene with oxygen functional groups and NiO from analysis by X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and Raman spectroscopy and confirm the conformation of oxygen bridges by the first-principles calculations. We found that NiO nanosheets (NiO NSs) are bonded strongly to graphene through oxygen bridges. The oxygen bridges mainly originate from the pinning of hydroxyl/epoxy groups from graphene on the Ni atoms of NiO NSs. The calculated adsorption energies (1.37 and 1.84 eV for graphene with hydroxyl and epoxy) of a Ni adatom on oxygenated graphene by binding with oxygen are comparable with that on graphene (1.26 eV). However, the calculated diffusion barriers of the Ni adatom on the oxygenated graphene surface (2.23 and 1.69 eV for graphene with hydroxyl and epoxy) are much larger than that on the graphene (0.19 eV). Therefore, the NiO NS is anchored strongly on the graphene through a C-O-Ni bridge, which allows a high reversible capacity and excellent rate performance. The easy binding/difficult dissociating characteristic of Ni adatoms on the oxygenated graphene facilitates fast electron hopping from graphene to NiO and thus the reversible lithiation and delithiation of NiO. We believe that the understanding of this oxygen bridge between graphene and NiO will lead to the development of other high-performance electrode materials. PMID- 22424546 TI - Maternal morbidity: neglected dimension of safe motherhood in the developing world. AB - In safe motherhood programming in the developing world, insufficient attention has been given to maternal morbidity, which can extend well beyond childbirth. For every woman who dies of pregnancy-related causes, an estimated 20 women experience acute or chronic morbidity. Maternal morbidity adversely affects families, communities and societies. Maternal morbidity has multiple causes, with duration ranging from acute to chronic, severity ranging from transient to permanent and with a range of diagnosis and treatment options. This article addresses six selected relatively neglected aspects of maternal morbidity to illustrate the range of acute and chronic morbidities that can affect women related to pregnancy and childbearing that are prevalent in developing countries: anaemia, maternal depression, infertility, fistula, uterine rupture and scarring and genital and uterine prolapse. Based on this review, recommendations to reduce maternal morbidity include: expand the focus of safe motherhood to explicitly include morbidity; improve data on incidence and prevalence of maternal morbidity; link mortality and morbidity outcomes and programming; increase access to facility- and community-based maternal health care and reproductive health care; and address the antecedents to poor maternal health through a lifecycle approach. PMID- 22424547 TI - Effects of the time of antihypertensive drugs administration on the stage of primary open-angle glaucoma in patients with arterial hypertension. AB - Many patients with glaucoma suffer from arterial hypertension (AH). It has been proved that both AH and low blood pressure (BP) at night are important vascular risk factors for primary open-angle glaucoma (POAG). The aims of this study were to assess the severity of pathological changes within the optic nerve and characteristics of blood flow in selected arteries of the eyeball and orbit in patients with POAG and controlled hypertension, in relation to the time of hypotensive drugs administration. Eighty-eight patients with POAG and treated, controlled hypertension were examined. The patients were divided into two subgroups, consisting of group A (n = 43), in whom hypotensive drugs were dosed only in the morning and group B (n = 45), in whom hypotensive drugs were also taken in the evening. In patients who were taking hypotensive drugs also in the evening (group B), there was a statistically significant lower mean perfusion pressure at night, a greater visual field loss and reduced amplitude of evoked potentials. Our analysis showed significantly worse changes in the parameters relating to the optic nerve in patients taking hypertensive medicines in the evening and also significantly lower perfusion pressures at night. PMID- 22424548 TI - [Lemierre syndrome: thrombosis of the cavernous sinus and internal carotid artery occlusion secondary to acute sphenoid sinusitis]. AB - Lemierre syndrome (LS) typically consists of a septic thrombophlebitis of the internal jugular vein caused by Fusobacterium necrophorum. We present an unusual variant of LS with cavernous sinus thrombosis and occlusion of the ipsilateral internal carotid artery secondary to sphenoid sinusitis caused by Streptococcus viridans. PMID- 22424549 TI - Interaction of silica nanoparticles with a flat silica surface through neutron reflectometry. AB - Neutron reflectometry (NR) was employed to study the interaction of nanosized silica particles with a flat silica surface in aqueous solutions. Unlike other experimental tools that are used to study surface interactions, NR can provide information on the particle density profile in the solution near the interface. Two types of silica particles (25 and 100 nm) were suspended in aqueous solutions of varying ionic strength. Theoretical calculations of the surface interaction potential between a particle and a flat silica surface using the Derjaguin-Landau Verwey-Overbeek (DLVO) theory were compared to the experimental data. The theory predicts that the potential energy is highly dependent on the ionic strength. In high ionic strength solutions, NR reveals a high concentration of particles near the flat silica surface. Under the same conditions, theoretical calculations show an attractive force between a particle and a flat surface. For low ionic strength solutions, the particle concentration near the surface obtained from NR is the same as the bulk concentration, while depletion of particles near the surface is expected because of the repulsion predicted by the DLVO theory. PMID- 22424550 TI - Cooperative stabilization of microtubule dynamics by EB1 and CLIP-170 involves displacement of stably bound P(i) at microtubule ends. AB - End binding protein 1 (EB1) and cytoplasmic linker protein of 170 kDa (CLIP-170) are two well-studied microtubule plus-end-tracking proteins (+TIPs) that target growing microtubule plus ends in the form of comet tails and regulate microtubule dynamics. However, the mechanism by which they regulate microtubule dynamics is not well understood. Using full-length EB1 and a minimal functional fragment of CLIP-170 (ClipCG12), we found that EB1 and CLIP-170 cooperatively regulate microtubule dynamic instability at concentrations below which neither protein is effective. By use of small-angle X-ray scattering and analytical ultracentrifugation, we found that ClipCG12 adopts a largely extended conformation with two noninteracting CAP-Gly domains and that it formed a complex in solution with EB1. Using a reconstituted steady-state mammalian microtubule system, we found that at a low concentration of 250 nM, neither EB1 nor ClipCG12 individually modulated plus-end dynamic instability. Higher concentrations (up to 2 MUM) of the two proteins individually did modulate dynamic instability, perhaps by a combination of effects at the tips and along the microtubule lengths. However, when low concentrations (250 nM) of EB1 and ClipCG12 were present together, the mixture modulated dynamic instability considerably. Using a pulsing strategy with [gamma(32)P]GTP, we further found that unlike EB1 or ClipCG12 alone, the EB1-ClipCG12 mixture partially depleted the microtubule ends of stably bound (32)P(i). Together, our results suggest that EB1 and ClipCG12 act cooperatively to regulate microtubule dynamics. They further indicate that stabilization of microtubule plus ends by the EB1-ClipCG12 mixture may involve modification of an aspect of the stabilizing cap. PMID- 22424551 TI - Living experiences of middle-aged adults with early knee osteoarthritis in prediagnostic phase. AB - PURPOSE: The aim of this study was to understand the living experiences of middle aged Taiwanese adults with early knee osteoarthritis (OA). METHODS: A qualitative research design was used in this study. Participants (n = 17) were recruited by purposive sampling from orthopedic clinics at two medical centers in northern Taiwan. Data were collected through in-depth interviews from July to December 2010. The data were transcribed verbatim and summarized by content analysis. RESULTS: The results indicated that the lived experiences could be grouped into 4 main themes: awareness; surmise of causes; acquisition of strategies; and the search for confirmative diagnosis. CONCLUSIONS: This study found that patients' knowledge is insufficient for recognition of the presence of early OA. There is a need for clinicians to integrate knowledge of OA into the health education system and to develop interventions for early knee osteoarthritic patients. Patients' disease cognition must be promoted so that their ability to process early symptoms of this disease will improve. PMID- 22424552 TI - Surface modified microprojection arrays for the selective extraction of the dengue virus NS1 protein as a marker for disease. AB - While advances in assay chemistry and detection continue to improve molecular diagnostics technology, blood samples are still collected using the 150-year-old needle/syringe method. Surface modified microprojection arrays have been developed as a novel platform for in vivo, needle-free biomarker capture. These devices are gold coated silicon arrays with >20,000 projections per cm(2), which can be applied to the skin for tunable penetration into the epidermis or dermis. The microprojection array conceptually offers several advantages over the current methods including: minimally invasive sample collection, no need for sample processing and concentration of specific markers at the device surface for sensitive detection. In this study, Microprojection arrays were coated with antibodies to capture an early marker of dengue virus infection, NS1, from the skin of live mice. We also developed a complementary "total IgG" assay which could be used as a positive control for adequate penetration of the projections. Surface modifications designed for selective extraction were tested against standard microtiter plate ELISA. We also investigated the use of Protein G mediated antibody immobilization in order to orient capture antibodies. While we found that capture efficiency could be improved, the direct EDC-based antibody immobilization resulted in a significantly higher surface density leading to a higher degree of NS1 capture. Using mice intravenously injected with recombinant dengue virus type 2 NS1 as a pseudomodel for dengue infection, NS1 was successfully extracted using microprojection arrays sampling from skin fluid, with a detection limit of 8 MUg/mL. PMID- 22424553 TI - Molecular dynamics studies on the water mixtures of pharmaceutically important ionic liquid lidocaine HCl. AB - In this paper the molecular dynamics of a common local-anesthetic drug, lidocaine hydrochloride (LD-HCl), and its water mixtures were investigated. By means of broadband dielectric spectroscopy and calorimetric measurements it was shown that even a small addition of water causes a significant effect on the relaxation dynamics of analyzed protic ionic liquid. Apart from the two well-resolved relaxations (sigma- and gamma-processes) and the beta-mode, identified as the JG process, observed for anhydrous LD-HCl, a new relaxation peak (upsilon) is visible in the dielectric spectra of aqueous mixtures of this drug. Additionally, the significant effect of the water on the glass transition temperature of LD-HCl was found. The sample characterized with mole fraction of water X(w) = 0.44 reveals the glass transition temperature T(g), 42 K lower than that of anhydrous material (307 K). Finally, it was shown that by amorphization of the hydrochloride salt of lidocaine it is possible to obtain its room temperature ionic liquid form. PMID- 22424554 TI - Ex vivo gene therapy and vision. AB - Ex vivo gene therapy, a technique where genetic manipulation of cells is undertaken remotely and more safely since it is outside the body, is an emerging therapeutic strategy particularly well suited to targeting a specific organ rather than for treating a whole organism. The eye and visual pathways therefore make an attractive target for this approach. With blindness still so prevalent worldwide, new approaches to treatment would also be widely applicable and a significant advance in improving quality of life. Despite being a relatively new approach, ex vivo gene therapy has already achieved significant advances in the treatment of blindness in pre-clinical trials. In particular, advances are being achieved in corneal disease, glaucoma, retinal degeneration, stroke and multiple sclerosis through genetic re-programming of cells to replace degenerate cells and through more refined neuroprotection, modulation of inflammation and replacement of deficient protein. In this review we discuss the latest developments in ex vivo gene therapy relevant to the visual pathways and highlight the challenges that need to be overcome for progress into clinical trials. PMID- 22424555 TI - Viral and non-viral methods to genetically modify dendritic cells. AB - Dendritic cells (DCs) behave as antigenic or tolerogenic immune response inducers depending on the nature of their precursors, their differentiation pathway and their environment. As professional antigen presenting cells (APCs) it has been tempting to genetically modify them in order to improve their capacity to mount appropriate protective immune responses. Gene transfer may also be helpful to investigate fundamental issues about the DC biology. Of note, almost all strategies to deliver genes or interfering RNA into DCs have been used with different success rates. These methods are non-exhaustively presented and discussed here. We focused our attention on promising in vitro as well as in vivo lentiviral- mediated gene delivery solutions into murine or human DCs. PMID- 22424556 TI - Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes. AB - Obesity is characterised by a state of chronic low-grade inflammation and the elevated circulating and tissue levels of inflammatory markers, including inflammation-related adipokines, released from white adipose tissue. The expression and release of these adipokines generally rises as the adipose tissue expands and hypoxic conditions start to develop within the tissue. Here, the effect of betaine, a trimethylglycine having a biological role as an osmolyte and a methyl donor, on the expression of inflammation-related markers was tested in human adipocytes under hypoxia. Differentiated adipocytes were cultivated under low (1 %) oxygen tension for 8-20 h. The expression of different adipokines, including IL-6, leptin, PPARgamma, TNF-alpha and adiponectin, was measured by quantitative PCR by determining the relative mRNA level from the adipocytes. Hypoxia, in general, led to a decrease in the expression of PPARgamma mRNA in human adipocytes, whereas the expression levels of leptin and IL-6 mRNA were substantially increased by hypoxia. The cultivation of adipocytes under hypoxia also led to a reduction in the expression of TNF-alpha mRNA. The results showed that hypoxia increased the relative quantification of leptin gene transcription, and that betaine (250 MUmol/l) reduced this effect, caused by low oxygen conditions. Under hypoxia, betaine also reduced the mRNA level of the pro inflammatory markers IL-6 and TNF-alpha. These results demonstrate that the extensive changes in the expression of inflammation-related adipokines in human adipocytes caused by hypoxia can be diminished by the presence of physiologically relevant concentrations of betaine. PMID- 22424557 TI - Subgaleal coiling of the proximal and distal components of a ventriculoperitoneal shunt. AB - Migration is a rare complication of venticuloperitoneal shunts and is thought to be associated with the "memory" of the plastic tubing and the windlass effect of neck flexion and extension. The purpose of this case report is to detail a very rare case of complete distal to proximal shunt migration. PMID- 22424558 TI - Oral trasmucosal fentanyl citrate for breakthrough pain treatment in cancer patients. AB - INTRODUCTION: Breakthrough cancer pain has been defined as a transitory increase in pain intensity that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The availability of supplemental doses of oral opioids, in addition to the continuous analgesic medication, is the main treatment suggested to manage pain flares. AREAS COVERED: Oral transmucosal fentanyl citrate (OTFC) is the first product of a new generation of delivery systems, named rapid-onset opioids (ROOs), characterized by rapidity of effect and the short duration of analgesia. Controlled studies and long-term experience have shown that OTFC is an effective treatment for breakthrough pain management and its use should be considered in any patient experiencing breakthrough pain related to cancer. EXPERT OPINION: The onset of action of OTFC - demonstrated to start within 15 min - and the short time to maximum concentration make it a useful indication for breakthrough pain; dose titration is commonly recommended. However, it is likely that patients receiving high doses of opioids for background analgesia will not be candidates for titration with minimal initial doses of OTFC, as they are opioid tolerant and the process would be time consuming. PMID- 22424559 TI - A functional agility short-term fatigue protocol changes lower extremity mechanics. AB - The purpose of this study was to evaluate the effects of a functional agility fatigue protocol on lower extremity biomechanics between two unanticipated tasks (stop-jump and sidestep). The subjects consisted of fifteen female collegiate soccer athletes (19+/-0.7 years, 1.67+/-0.1 m, 61.7+/-8 kg) free of lower extremity injury. Participants performed five trials of stop-jump and sidestep tasks. A functional short-term agility protocol was performed, and immediately following participants repeated the unanticipated running tasks. Lower extremity kinematic and kinetic values were obtained pre and post fatigue. Repeated measures analyses of variance were conducted for each dependent variable with an alpha level set at 0.05. Knee position post-fatigue had increased knee internal rotation (11.4+/-7.5 degrees vs. 7.9+/-6.5 degrees p=0.011) than pre fatigue, and a decreased knee flexion angle (-36.6+/-6.2 degrees vs. -40.0+/-6.3 degrees , p = 0.003), as well as hip position post-fatigue had decreased hip flexion angle (35.5+/-8.7 degrees vs. 43.2+/-9.5 degrees , p = 0.002). A quick functional fatigue protocol altered lower extremity mechanics of Division I collegiate soccer athletes during landing tasks. Proper mechanics should be emphasized from the beginning of practice/game to aid in potentially minimizing the effects of fatigue in lower extremity mechanics. PMID- 22424560 TI - Renal cell carcinoma associated with peritumoral sarcoid-like reaction without intratumoral granuloma. AB - Non-necrotizing epithelioid granulomas have been described in association with many primary tumors. In such cases, they are designated as sarcoid-like reaction. Although it is more seen in carcinomas than in sarcomas, it is very rarely reported in renal carcinoma. Here, we describe a rare association of prominent peritumoral sarcoid-like reaction without intratumoral granulomas and conventional clear cell renal carcinoma in a 62-year-old-male, without clinical or laboratory finding of sarcoidosis. At 30 months follow-up, he had no recurrence. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4054525336657922. PMID- 22424561 TI - Resection and survival. PMID- 22424562 TI - Bilateral occlusion of the foramina of Monro after third ventriculostomy. AB - Occlusion of both foramina of Monro following third ventriculostomy is a very rare complication. The authors present the case of a 30-year-old female who underwent endoscopic third ventriculostomy (ETV) for occlusive hydrocephalus due to aqueductal stenosis. Thirty months after the ETV, she reported recurrent headaches. Magnetic resonance imaging demonstrated bilateral enlargement of the lateral ventricles with a collapsed third ventricle caused by bilateral stenosis of the foramina of Monro. Left-sided endoscopic foraminoplasty and stenting of the left foramen of Monro were performed with immediate neurological improvement. PMID- 22424563 TI - Cranial nerve dysfunction following Gamma Knife surgery for pituitary adenomas: long-term incidence and risk factors. AB - OBJECT: Gamma Knife surgery (GKS) has become a significant component of neurosurgical treatment for recurrent secretory and nonsecretory pituitary adenomas. Although the long-term risks of visual dysfunction following microsurgical resection of pituitary adenomas has been well studied, the comparable risk following radiosurgery is not well defined. This study evaluates the long-term risks of ophthalmological dysfunction following GKS for recurrent pituitary adenomas. METHODS: An analysis of 217 patients with recurrent secretory (n = 131) and nonsecretory (n = 86) pituitary adenomas was performed to determine the incidence of and risk factors for subsequent development of visual dysfunction. Patients underwent ophthalmological evaluation as part of post-GKS follow-up to assess for new or worsened cranial nerve II, III, IV, or VI palsies. The median follow-up duration was 32 months. The median maximal dose was 50 Gy, and the median peripheral dose was 23 Gy. A univariate analysis was performed to assess for risk factors of visual dysfunction post-GKS. RESULTS: Nine patients (4%) developed new visual dysfunctions, and these occurred within 6 hours to 34 months following radiosurgery. None of these 9 patients had tumor growth on post GKS neuroimaging studies. Three of these patients had permanent deficits whereas in 6 the deficits resolved. Five of the 9 patients had prior GKS or radiotherapy, which resulted in a significant increase in the incidence of cranial nerve dysfunction (p = 0.0008). An increased number of isocenters (7.1 vs 5.0, p = 0.048) was statistically related to the development of visual dysfunction. Maximal dose, margin dose, optic apparatus dose, tumor volume, cavernous sinus involvement, and suprasellar extension were not significantly related to visual dysfunction (p >0.05). CONCLUSIONS: Neurological and ophthalmological assessment in addition to routine neuroimaging and endocrinological follow-up are important to perform following GKS. Patients with a history of radiosurgery or radiation therapy are at higher risk of cranial nerve deficits. Also, a reduction in the number of isocenters delivered, along with volume treated, particularly in the patients with secretory tumors, appears to be the most reasonable strategy to minimize the risk to the visual system when treating recurrent pituitary adenomas with stereotactic radiosurgery. PMID- 22424564 TI - The effects of subthalamic and pallidal deep brain stimulation on postural responses in patients with Parkinson disease. AB - OBJECT: The effect of deep brain stimulation (DBS) for Parkinson disease (PD) on balance is unclear. The goal of this study was to investigate how automatic postural responses (APRs) were affected in patients randomized to either subthalamic nucleus (STN) or globus pallidus internus (GPi) surgery. METHODS: The authors tested 24 patients with PD who underwent bilateral DBS, 9 control patients with PD who did not undergo DBS, and 17 age-matched control volunteers. The electrode placement site was randomized and blinded to the patients and to the experimenters. Kinematic, kinetic, and electromyographic recordings of postural responses to backward disequilibrium via forward translations of the standing surface were recorded in the week prior to surgery while the patients were off (OFF) and on (ON) antiparkinsonian medication (levodopa), and then 6 months after surgery in 4 conditions: 1) off medication with DBS switched off (OFF/OFF); 2) off medication with DBS on (DBS); 3) on medication with DBS off (DOPA); and 4) with both medication and DBS on (DBS+DOPA). Stability of the automatic postural response (APR) was measured as the difference between the displacement of the center of pressure and the projected location of the center of body mass. RESULTS: Patients with PD had worse APR stability than controls. Turning the DBS on at either site improved APR stability compared with the postoperative OFF condition by lengthening the tibialis response, whereas medication did not show an appreciable effect. The STN group had worse APR stability in their best functional state (DBS+DOPA) 6 months after the DBS procedure compared with their best functional state (ON levodopa) before the DBS procedure. In contrast, the GPi group and the PD control group showed no change over 6 months. The APR stability impairment in the STN group was associated with smaller tibialis response amplitudes, but there was no change in response latency or coactivation with gastrocnemius. CONCLUSIONS: Turning the DBS current on improved APR stability for both STN and GPi sites. However, there was a detrimental DBS procedural effect for the STN group, and this effect was greater than the benefit of the stimulating current, making overall APR stability functionally worse after surgery for the STN group. PMID- 22424565 TI - Hand innervation. PMID- 22424566 TI - Magnetic resonance imaging volumetric assessment of the extent of contrast enhancement and resection in oligodendroglial tumors. AB - OBJECT: Oligodendrogliomas that enhance on MR images are associated with poor prognosis. However, the importance of the volume of enhancing tumor tissue, and the extent of its resection, is uncertain. The authors examined the prognostic significance of preoperative and residual postoperative enhancing tissue volumes in a large single-center series of patients with oligodendroglioma. They also examined the relationship between enhancement and characteristic genetic signatures in oligodendroglial tumors, specifically deletion of 1p and 19q (del 1p/19q). METHODS: The authors retrospectively analyzed 100 consecutive cases of oligodendroglioma involving patients who had undergone T1-weighted gadolinium enhanced MRI at diagnosis and immediately after initial surgical intervention. The presence of preoperative enhancement was determined by consensus. Preoperative and residual postoperative volumes were measured using a quantitative, semiautomated method by a single blinded observer. Intrarater reliability for preoperative volumes was confirmed by remeasurement in a subset of patients 3 months later. Intrarater and interrater reliability for residual postoperative volumes was confirmed by remeasurement of these volumes by both the original and a second blinded observer. Multivariate analysis was used to assess the influence of contrast enhancement at diagnosis and the volume of pre- and postoperative contrast-enhancing tumor tissue on time to relapse (TTR) and overall survival (OS), while controlling for confounding clinical, pathological, and genetic factors. RESULTS: Sixty-three of 100 patients had enhancing tumors at initial presentation. Presence of contrast enhancement at diagnosis was related to reduced TTR and OS on univariate analysis but was not significantly related on multivariate analysis. In enhancing tumors, however, greater initial volume of enhancing tissue correlated with shortened TTR (p = 0.00070). Reduced postoperative residual enhancing volume and a relatively greater resection of enhancing tissue correlated with longer OS (p = 0.0012 and 0.0041, respectively). Interestingly, patients in whom 100% of enhancing tumor was resected had significantly longer TTR (174 vs 64 weeks) and OS (392 vs 135 weeks) than those with any residual enhancing tumor postoperatively. This prognostic benefit was not consistently maintained with greater than 90% or even greater than 95% resection of enhancing tissue. There was no relationship between presence or volume of enhancement and del 1p/19q. CONCLUSIONS: In enhancing oligodendrogliomas, completely resecting enhancing tissue independently improves outcome, irrespective of histological grade or genetic status. This finding supports aggressive resection and may impact treatment planning for patients with these tumors. PMID- 22424567 TI - Cushing disease. PMID- 22424568 TI - Traumatic brain injury and hypothermia. PMID- 22424569 TI - Low levels of Human Cytomegalovirus Infection in Glioblastoma multiforme associates with patient survival; -a case-control study. AB - BACKGROUND: Glioblastoma multiforme (GBM) represent the most aggressive brain tumor with a median overall survival of about 12-15 months. Over 90% of GBM tumors have recently been shown to be infected with human cytomegalovirus (HCMV). In this case-control study, we evaluated whether there was an association between the grade of HCMV infection and long-term survival (> 18 months) in GBM patients. MATERIAL AND METHODS: Brain tumor tissue sections from consecutive GBMs patients who survived more than 18 months (n = 40), and an equal number of GBM patients, matched to date of diagnosis and surgery, operated at Karolinska University Hospital in 2000-2005 were selected. HCMV infection grade was determined by estimation of the number of HCMV positive cells (scored negative or grade 1-4) in tumor tissue specimens. Using Chi-Square test and logistic regression analysis, we analyzed whether there was an association between long-term survival and HCMV low-grade infection or other clinical parameters known to be associated with prolonged survival of GBM patients; age under 50 years, radical surgery or low recursive partition analysis (RPA) subclass. RESULTS: HCMV infection was detected in tumor samples from 79 of 80 patients (99%). Among patients surviving > 18 months, HCMV infection grade 1 in the GBM tumor was predominant. A low grade HCMV infection was found in 19 patients, of these 16 survived > 18 months. Thus, 16 of 40 (40%) GBM patients who lived > 18 months had low-grade HCMV infection while only 3 of 40 (8%) GBM patients who lived < 18 months did (p .0006, Chi-Square test). Multiple logistic regression analyses yielded an odds ratio estimate of 6.604 with 95% confidence interval (1.36-32.1) (p .019) for low grade HCMV after adjustment for RPA class III and IV, radical surgery, age and gamma knife treatment. CONCLUSION: In conclusion, we found that low-grade HCMV infection was strongly associated with long-term survival in GBM patients. PMID- 22424570 TI - IgG responses to the gSG6-P1 salivary peptide for evaluating human exposure to Anopheles bites in urban areas of Dakar region, Senegal. AB - BACKGROUND: Urban malaria can be a serious public health problem in Africa. Human landing catches of mosquitoes, a standard entomological method to assess human exposure to malaria vector bites, can lack sensitivity in areas where exposure is low. A simple and highly sensitive tool could be a complementary indicator for evaluating malaria exposure in such epidemiological contexts. The human antibody response to the specific Anopheles gSG6-P1 salivary peptide have been described as an adequate tool biomarker for a reliable assessment of human exposure level to Anopheles bites. The aim of this study was to use this biomarker to evaluate the human exposure to Anopheles mosquito bites in urban settings of Dakar (Senegal), one of the largest cities in West Africa, where Anopheles biting rates and malaria transmission are supposed to be low. METHODS: One cross-sectional study concerning 1,010 (505 households) children (n = 505) and adults (n = 505) living in 16 districts of downtown Dakar and its suburbs was performed from October to December 2008. The IgG responses to gSG6-P1 peptide have been assessed and compared to entomological data obtained in or near the same district. RESULTS: Considerable individual variations in anti-gSG6-P1 IgG levels were observed between and within districts. In spite of this individual heterogeneity, the median level of specific IgG and the percentage of immune responders differed significantly between districts. A positive and significant association was observed between the exposure levels to Anopheles gambiae bites, estimated by classical entomological methods, and the median IgG levels or the percentage of immune responders measuring the contact between human populations and Anopheles mosquitoes. Interestingly, immunological parameters seemed to better discriminate the exposure level to Anopheles bites between different exposure groups of districts. CONCLUSIONS: Specific human IgG responses to gSG6-P1 peptide biomarker represent, at the population and individual levels, a credible new alternative tool to assess accurately the heterogeneity of exposure level to Anopheles bites and malaria risk in low urban transmission areas. The development of such biomarker tool would be particularly relevant for mapping and monitoring malaria risk and for measuring the efficiency of vector control strategies in these specific settings. PMID- 22424571 TI - Combined elicitation of methyl-jasmonate and red light on stilbene and anthocyanin biosynthesis. AB - Vitis vinifera cell suspensions are a suitable system to study the metabolic regulation of a large range of polyphenols, including flavonoids and stilbenes that play important roles in plant development. Grape cv. Barbera petioles cell cultures were treated with red light and 10 MUM methyl-jasmonate (MeJA), alone or in combination, to investigate their influence and/or induction effect on the production of anthocyanins, catechins and free and mono-glucosylated stilbenes. The synthesis of total anthocyanins was slightly decreased by red light alone, while MeJA and MeJA plus red light increased the levels of these metabolites. When compared to the relative controls, the red light treatment decreased the amount of catechins and increased their release in the culture medium, while MeJA alone or in combination with red light increased their production. Red light treatment generally enhanced the amount of free and mono-glucosylated stilbenes during the entire observation period, as well as the percentage of their release in the media. Treatment with MeJA strongly promoted the production of total stilbenes, which was further elicited by the MeJA plus red light treatment. During the combined treatment, the presence of the light stimulus improved the effect of MeJA by anticipating the maximum increase of stilbenes which were also largely released (up to 90%). These results demonstrate that, in grapevine, as in other plant systems, the change of conditions in which the MeJA stimulus is perceived (e.g. going from total white to red light) drastically modifies the plant response to this hormone. The present paper confirms that the jasmonate transduction pathway is integrated into an elaborate signaling network that also comprehends the red light signaling pathway. PMID- 22424572 TI - ABA-deficiency results in reduced plant and fruit size in tomato. AB - Abscisic acid (ABA) deficient mutants, such as notabilis and flacca, have helped elucidating the role of ABA during plant development and stress responses in tomato (Solanum lycopersicum L.). However, these mutants have only moderately decreased ABA levels. Here we report on plant and fruit development in the more strongly ABA-deficient notabilis/flacca (not/flc) double mutant. We observed that plant growth, leaf-surface area, drought-induced wilting and ABA-related gene expression in the different genotypes were strongly correlated with the ABA levels and thus most strongly affected in the not/flc double mutants. These mutants also had reduced fruit size that was caused by an overall smaller cell size. Lower ABA levels in fruits did not correlate with changes in auxin levels, but were accompanied by higher ethylene evolution rates. This suggests that in a wild-type background ABA stimulates cell enlargement during tomato fruit growth via a negative effect on ethylene synthesis. PMID- 22424573 TI - Diet among people in the Terai region of Nepal, an area of micronutrient deficiency. AB - In the Terai region, despite its ecological richness, the people have long suffered from a deficiency of micronutrients such as vitamin A, iron and zinc. The aim of this study was to investigate dietary and nutritional intakes among people in the Terai region of Nepal. The results were compared by sex and ethnicity. Food consumption surveys (one-day weighed records) were conducted among 114 people (55 Mushar and 59 Tharu). Nutritional intakes were calculated using Nepali food composition and other tables. The diet in the Terai region was characterized by a large amount of rice consumed with a tiny amount of curry or dal as a side dish. Intakes of vitamin A, iron, riboflavin and selenium were less than 50% of the recommended daily allowance irrespective of ethnicity or sex (with the exception of iron intake among Tharu males). Intakes of thiamine, riboflavin, niacin, phosphorus and zinc were higher among the Tharu than the Mushar, while intakes of selenium and iodine were higher among the Mushar than the Tharu. The nutritional significance of these differences was slight. Protein intake (per kg body weight) was lower in females than in males, while the energy adjusted micronutrient intakes did not differ by sex. Intakes of vitamin A, iron, riboflavin and selenium were deficient among the participants. Intervention projects such as the introduction of kitchen gardens or fish farming may be effective, but will increase the degree of inequality between the two ethnic groups. PMID- 22424574 TI - Nasal epithelium integrity, environmental stressors, and allergic sensitization: a biomarker study in adolescents. AB - Changes in the airways epithelium caused by environmental insults might play a role in the development of allergic rhinitis. We measured albumin and Clara cell protein (CC16) in the nasal lavage fluid (NALF) from 474 adolescents (263 girls and 211 boys). The NALF CC16/albumin ratio, integrating the permeability and cellular integrity of the nasal epithelium, decreased mostly with time spent in chlorinated pools. In boys, a lower CC16/albumin ratio in NALF was associated with an increased risk of house dust mite sensitization. The results suggest that the CC16/albumin ratio in NALF can be used to detect nasal epithelium alterations linked to allergic sensitization. PMID- 22424575 TI - Pathologic assessment of complications with asymmetric or sulcus fixation of square-edged hydrophobic acrylic intraocular lenses. AB - OBJECTIVE: One-piece hydrophobic acrylic intraocular lenses (IOLs) are not indicated for sulcus fixation because of complications, such as uveitis-glaucoma hyphema syndrome. Similar complications may also be observed with 3-piece lenses that have a square optic edge on the anterior surface. The objective of this study was to provide pathologic evidence of complications related to out-of-the bag fixation of 1- or 3-piece hydrophobic acrylic IOLs with anterior and posterior square optic edges. DESIGN: Comparative case series with pathology. PARTICIPANTS: A total of 661 pseudophakic cadaver eyes obtained from eye banks within the United States, implanted with different IOLs. METHODS: Anterior segment scanning of whole eyes with a high-frequency ultrasound system or high resolution anterior segment magnetic resonance imaging, followed by gross examination. Selected eyes were processed for complete histopathologic analysis; some of them were explanted before histopathology to allow for direct light microscopic evaluation of the lenses. MAIN OUTCOME MEASURES: Findings from imaging, gross, and histopathologic evaluation that could be related to out-of the-bag fixation of the lenses. RESULTS: A total of 256 eyes were implanted with hydrophobic acrylic IOLs with anterior and posterior square optic edges; 18 of them exhibiting asymmetric or sulcus IOL fixation (six 1-piece and twelve 3-piece IOLs) underwent complete histopathologic evaluation and were compared with the contralateral eyes with symmetric in-the-bag IOL implantation. Pathologic findings were composed of IOL decentration and tilt, pigmentary dispersion within the anterior segment and on the IOL surface, iris transillumination defects, iris changes including vacuolization/disruption/loss of the pigmented layer, iris thinning, and iris atrophy, as well as synechiae and loop erosion in the case of 3-piece lenses. Findings were more significant in comparison with the control contralateral eyes and were particularly evident in relation to the sulcus fixated haptic in the case of 1-piece lenses. The majority of the eyes with 3 piece lenses showed signs of complicated surgery. CONCLUSIONS: This study provides pathologic correlation of complications that were clinically reported in the peer-reviewed literature in relation to sulcus fixation of 1-piece hydrophobic acrylic IOLs. The eyes with 3-piece lenses generally exhibited evidence of complicated surgery; therefore, all pathologic findings in those cases may not be strictly attributed to the out-of-the-bag fixation. PMID- 22424576 TI - Visual symptoms and retinal straylight after laser peripheral iridotomy: the Zhongshan Angle-Closure Prevention Trial. AB - OBJECTIVE: To assess the impact of laser peripheral iridotomy (LPI) on forward scatter of light and subjective visual symptoms and to identify LPI parameters influencing these phenomena. DESIGN: Cohort study derived from a randomized trial, using an external control group. PARTICIPANTS: Chinese subjects initially aged 50 or older and 70 years or younger with bilateral narrow angles undergoing LPI in 1 eye selected at random, and age- and gender-matched controls. METHODS: Eighteen months after laser, LPI-treated subjects underwent digital iris photography and photogrammetry to characterize the size and location of the LPI, Lens Opacity Classification System III cataract grading, and measurement of retinal straylight (C-Quant; OCULUS, Wetzlar, Germany) in the treated and untreated eyes and completed a visual symptoms questionnaire. Controls answered the questionnaire and underwent straylight measurement and (in a random one-sixth sample) cataract grading. MAIN OUTCOME MEASURES: Retinal straylight levels and subjective visual symptoms. RESULTS: Among 230 LPI-treated subjects (121 [58.8%] with LPI totally covered by the lid, 43 [19.8%] with LPI partly covered by the lid, 53 [24.4%] with LPI uncovered by the lid), 217 (94.3%) completed all testing, as did 250 (93.3%) of 268 controls. Age, gender, and prevalence of visual symptoms did not differ between treated subjects and controls, although nuclear (P<0.01) and cortical (P = 0.03) cataract were less common among controls. Neither presenting visual acuity nor straylight score differed between the treated and untreated eyes among all treated persons, nor among those (n = 96) with LPI partially or totally uncovered. Prevalence of subjective glare did not differ significantly between participants with totally covered LPI (6.61%; 95% confidence interval [CI], 3.39%-12.5%), partially covered LPI (11.6%; 95% CI, 5.07%-24.5%), or totally uncovered LPI (9.43%; 95% CI, 4.10%-10.3%). In regression models, only worse cortical cataract grade (P = 0.01) was associated significantly with straylight score, and no predictors were associated with subjective glare. None of the LPI size or location parameters were associated with straylight or subjective symptoms. CONCLUSIONS: These results suggests that LPI is safe regarding measures of straylight and visual symptoms. This randomized design provides strong evidence that treatment programs for narrow angles would be unlikely to result in important medium-term visual disability. PMID- 22424577 TI - Correlation between length of foveal cone outer segment tips line defect and visual acuity after macular hole closure. AB - PURPOSE: To determine whether the postoperative length of the photoreceptor cone outer segment tips (COST) line defect is significantly correlated with best corrected visual acuity (BCVA) after macular hole closure. DESIGN: Retrospective, consecutive, observational case series. PARTICIPANTS: Fifty-one eyes of 51 patients with a surgically closed macular hole were studied. METHODS: Spectral domain optical coherence tomography (SD-OCT) was used to obtain images of the foveal area, and the lengths of the COST line defect were measured in the images obtained 1, 3, 6, 9, and 12 months after macular hole surgery. The correlation between the length of COST line defect and the BCVA was determined. MAIN OUTCOME MEASURES: The lengths of the COST line defect, the inner segment/outer segment (IS/OS) junction defect, the external limiting membrane (ELM) line defect in the SD-OCT images, and the BCVA. RESULTS: The COST line defect was gradually restored centripetally 1 to 12 months postoperatively. The length of the COST line defect was significantly correlated with the BCVA at 1, 3, 6, 9, and 12 months postoperatively (P < 0.001). Forward stepwise regression analyses showed that the postoperative BCVA was significantly correlated with the length of the COST line defect (P < 0.001) but not with that of the IS/OS junction and ELM line defects after 6 months. The preoperative length of the COST line defect was significantly correlated with postoperative BCVA at 12 months (P = 0.020), but the length of the IS/OS junction and ELM line defects was not. The preoperative length of the COST line defect was significantly longer than the fluid cuff diameter of the macular hole (P = 0.020), indicating that the influence of the elevated neurosensory retina at the fluid cuff on the SD-OCT signals of the COST line was probably minimal. The postoperative BCVA at 12 months can be calculated by the following regression equation: BCVA = 0.00020 * (length of preoperative COST line defect [MUm]) - 0.23 (F value = 15.4; P < 0.001). CONCLUSIONS: The recovery of the foveal COST line defect is related to visual recovery after macular hole closure. The length of the preoperative COST line defect may predict the BCVA after macular hole surgery. PMID- 22424578 TI - Cattle fetal sex determination by polymerase chain reaction using DNA isolated from maternal plasma. AB - The objective of this study was to evaluate the use of polymerase chain reaction analysis (PCR) of fetal cells/DNA in the maternal plasma of pregnant cows to determine the sex of the fetus. Plasma was harvested from 35 cows of mixed genotype at different stages of pregnancy ranging from 5 to 35 weeks. A male calf and a heifer calf provided the control samples. Fetal sex was determined by amplification of Y-specific sequences. For the 35 cows, the fetal sex predicted by this technique was in accordance with the sex of the calf at birth in 88.6% of cases. The agreement between predicted and observed fetal sex was less for cows with a gestational length of 35-48 days (63.6%). Regression analysis showed that there was a strong relationship between the probability of correctly predicting fetal sex and the stage of gestation. It was estimated that the test performed at 43.8 days post fertilization would have 95% accuracy, increasing to 99% accuracy for testing at 48.4 days and 99.9% accuracy for tests at 55.0 days or later. It was concluded that PCR analysis of fetal cells in maternal plasma can be used to predict successfully the sex of the fetus in cattle. PMID- 22424579 TI - Network environ perspective for urban metabolism and carbon emissions: a case study of Vienna, Austria. AB - Cities are considered major contributors to global warming, where carbon emissions are highly embedded in the overall urban metabolism. To examine urban metabolic processes and emission trajectories we developed a carbon flux model based on Network Environ Analysis (NEA). The mutual interactions and control situation within the urban ecosystem of Vienna were examined, and the system level properties of the city's carbon metabolism were assessed. Regulatory strategies to minimize carbon emissions were identified through the tracking of the possible pathways that affect these emission trajectories. Our findings suggest that indirect flows have a strong bearing on the mutual and control relationships between urban sectors. The metabolism of a city is considered self mutualistic and sustainable only when the local and distal environments are embraced. Energy production and construction were found to be two factors with a major impact on carbon emissions, and whose regulation is only effective via ad hoc pathways. In comparison with the original life-cycle tracking, the application of NEA was better at revealing details from a mechanistic aspect, which is crucial for informed sustainable urban management. PMID- 22424580 TI - Comparison of two- and three-dimensional quantitative coronary angiography to intravascular ultrasound in the assessment of intermediate left main stenosis. AB - Angiographic evaluation of intermediate left main coronary artery stenosis (LMS) is often limited. Three-dimensional (3D) quantitative coronary angiography has recently developed to overcome 2-dimensional (2D) quantitative coronary angiographic (QCA) limitations. In patients with angiographically intermediate LMS, we investigated whether 3D quantitative coronary angiography was superior to 2D quantitative coronary angiography in predicting the presence of a significant LMS, defined as a minimum luminal area <6 mm(2) at intravascular ultrasound (IVUS). 2D and 3D quantitative coronary angiography were compared in their measurements of minimum luminal area, percent area stenosis, minimum luminal diameter, and percent diameter stenosis and in their prediction of an IVUS minimum luminal area <6 mm(2). In total 58 target lesions were interrogated, 25 (43%) of which had an IVUS minimum luminal area <6 mm(2). Correlation between 3D QCA minimum luminal area and IVUS minimum luminal area was stronger than the correlation between 2D-QCA minimum luminal area (or minimum luminal diameter) and IVUS minimum luminal area (R = 0.67, p = 0.0001, and R = 0.40, p = 0.001, respectively, p = 0.04 for comparison). To predict IVUS minimum luminal area <6 mm(2), the most accurate 2D-QCA measurement was minimum luminal diameter (area under curve 0.81, cutoff 2.2 mm, p = 0.0001), and the most accurate 3D-QCA measurement was minimum luminal area (area under curve 0.86, cutoff 5.6 mm(2), p = 0.0001). 2D-QCA percent diameter stenosis did not significantly predict IVUS minimum luminal area <6 mm(2) (area under curve 0.56, cutoff 38%, p = 0.45). In conclusion, the accuracy of quantitative coronary angiography in predicting LM IVUS minimum luminal area <6 mm(2) is limited. When IVUS is not available or contraindicated, 3D quantitative coronary angiography may assist in the evaluation of intermediate LMS. Among 2D-QCA parameters, minimum luminal diameter is more accurate than percent diameter stenosis in predicting significant LMS. PMID- 22424581 TI - Frequency and causes of stroke during or after transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is invariably associated with the risk of clinically manifest transient or irreversible neurologic impairment. We sought to investigate the incidence and causes of clinically manifest stroke during TAVI. A total of 214 consecutive patients underwent TAVI with the Medtronic-CoreValve System from November 2005 to September 2011 at our institution. Stroke was defined according to the Valve Academic Research Consortium recommendations. Its cause was established by analyzing the point of onset of symptoms, correlating the symptoms with the computed tomography-detected defects in the brain, and analyzing the presence of potential coexisting causes of stroke, in addition to a multivariate analysis to determine the independent predictors. Stroke occurred in 19 patients (9%) and was major in 10 (5%), minor in 3 (1%), and transient (transient ischemic attack) in 6 (3%). The onset of symptoms was early (<=24 hours) in 8 patients (42%) and delayed (>24 hours) in 11 (58%). Brain computed tomography showed a cortical infarct in 8 patients (42%), a lacunar infarct in 5 (26%), hemorrhage in 1 (5%), and no abnormalities in 5 (26%). Independent determinants of stroke were new-onset atrial fibrillation after TAVI (odds ratio 4.4, 95% confidence interval 1.2 to 15.6), and baseline aortic regurgitation grade III or greater (odds ratio 3.2, 95% confidence interval 1.1 to 9.3). In conclusion, the incidence of stroke was 9%, of which >1/2 occurred >24 hours after the procedure. New-onset atrial fibrillation was associated with a 4.4-fold increased risk of stroke. In conclusion, these findings indicate that improvements in postoperative care after TAVI are equally, if not more, important for the reduction of periprocedural stroke than preventive measures during the procedure. PMID- 22424582 TI - Gender and ethnic differences in red cell distribution width and its association with mortality among low risk healthy United state adults. AB - Limited information is available about gender and ethnic differences in red cell distribution width (RCDW) with regard to its relation to mortality in a population free of cardiovascular (CV) disease and diabetes. To assess gender and ethnic differences in RCDW and their effect on the association between RCDW and mortality, the Third National Health and Nutritional Examination Survey (n = 15,460, 1988 to 1994) data were examined. Multivariate adjusted Cox proportional hazard analysis was performed to assess effect of gender and ethnicity on the association between RCDW and mortality (total, CV disease, and coronary heart disease [CHD]). RCDW (mean +/- SE) was greater in black women (13.1 +/- 0.03) and men (13.4 +/- 0.02) compared to women of white (12.9 +/- 0.02) and other (13.0 +/ 0.07) ethnicities and men of white (13.3 +/- 0.02) and other (13.3 +/- 0.07) ethnicities, respectively (p <0.001). The interaction between RCDW and gender was statistically significant for all study outcomes (p <0.001) but nonsignificant for RCDW and ethnicity. After adjusting for key variables, RCDW in women was associated with adjusted hazard ratios of 1.22 (95% confidence interval [CI] 1.14 to 1.31) for all-cause mortality, 1.17 (95% CI 1.07 to 1.28) for CV deaths, and 1.18 (95% CI 1.03 to 1.35) for CHD deaths; in men, adjusted hazard ratios were 1.29 (95% CI 1.20 to 1.38) for all-cause mortality, 1.27 (95% CI 1.17 to 1.37) for CV deaths, and 1.25 (95% CI 1.13 to 1.39) for CHD deaths (p <0.05 for all). In conclusion, blacks and men have significantly greater RCDWs compared to whites and women. Greater RCDW is associated with a greater risk of mortality in men compared to women, whereas no effect modification is observed by ethnicity. PMID- 22424583 TI - Pain coping in injured workers with chronic pain: what's unique about workers? AB - PURPOSE: Pain caused by a work injury is a complex phenomenon comprising multiple factors, e.g. age, gender, prior health status, occupation, job demands, and severity of injury. Little research has focused on injured workers with chronic pain. This study investigates injured workers' pain coping. METHODS: A descriptive cross-sectional study design was used to measure coping strategies of injured workers in a work rehabilitation program. Differences in coping strategies by demographics, injury-related variables, pain, disability, and depression were measured. RESULTS: n = 479. The coping strategy with the highest mean score was "coping self statements" (Mean = 19.4, SD = 7.6), followed by "praying/hoping" (Mean = 18.2, SD = 9.7), and "catastrophizing" (Mean = 17.5, SD = 8.0). Statistical differences for coping strategies were noted between gender, marital status, depression levels, self-perceived disability levels, and pain (p < 0.01 for all). CONCLUSIONS: This study provided relevant information about how injured workers cope with pain. In conditions in which there may be a perceived lack of control (high pain intensity, high self-perceived disability, and high self rated depression), there were significantly higher amounts of both "catastrophizing" and "praying and hoping". Therefore, workers with high pain and high self-perceived disability are more likely catastrophize their pain, leading to poor recovery outcomes. PMID- 22424584 TI - Induction of labour at term for women over 35 years old: a survey of the views of women and obstetricians. AB - OBJECTIVES: To determine the views of UK women and obstetricians relating to induction of labour at term for women over 35 years of age. STUDY DESIGN: Cross sectional web-based survey sent to members of the British Maternal and Fetal Medicine Society (BMFMS) and pregnant or recently delivered members of a large social network site for parents (www.mumsnet.com). One hundred and twenty-eight consultant obstetrician members of BMFMS and 663 pregnant or recently delivered women responded. RESULTS: Two hundred and eighty-eight women (43%) would consider induction of labour for maternal age alone, and 192 women (29%) would consider participating in a randomised trial of induction of labour at term versus expectant management in a future pregnancy. Three percent (n=4) of consultant obstetricians offer induction of labour at term to women at 35-39 years of age, 37% (n=47) to women at 40-44 years of age and 55% (n=70) to those over 45 years. Sixty-one consultants (48%) would participate in a trial to test the effect of a policy of induction for nulliparous women over 35 years old. CONCLUSIONS: The policy of offering induction of labour at term for advanced maternal age is widespread and a significant percentage of women consider it to be a valid indication. PMID- 22424585 TI - Quality of life of early school-age French children born preterm: a cohort study. AB - OBJECTIVES: To describe the health-related quality of life (HRQL) of a cohort of children aged 6-10 years who were born preterm; and to determine whether sociodemographic factors, neonatal features and neurocognitive status were affecting their HRQL. STUDY DESIGN: All singleton infants born between 24 and 32 weeks of gestation between January 1997 and December 2001 at the study hospital, who were still alive in 2007 (age 6-10 years), and who had undergone complete clinical paediatric follow-up were included in the study. Maternal and perinatal data were obtained by chart review and regular clinical examination. The 'Battery for Rapid Evaluation of Cognitive Functions' (BREV) was used for cognitive evaluation when children were aged 4-8 years. HRQL data were collected in 2007 using the 'Vecu et Sante Percue de l'Adolescent et de l'Enfant' (VSP-A) questionnaire (parent version). The HRQL of the preterm children was compared with that of a French reference population. RESULTS: Of 202 children who fulfilled the inclusion criteria, 82 children participated in the study. Their mean age was 7.9 years [standard deviation (SD) 1.4], mean birth weight was 1130.0 g (SD 361.4), 23 children were born before 28 weeks of gestation, 46 were female and 11 had major neurocognitive disorders. These data were not significantly different for the non-respondents (n=120). Parents of preterm children reported a significantly lower perception of HRQL of their child compared with parents of children in the reference population, as reflected by VSP-A global index scores and scores for the 'body image', 'vitality', 'psychological well-being' and 'school performance' dimensions. In multivariate analyses, three factors were found to be significantly associated with at least one dimension in the VSP-A scale in the preterm children: presence of major neurocognitive disorders, negatively correlated with 'vitality', 'relationships with friends', 'physical well-being' and 'school performance' dimensions; maternal parity, positively correlated with the 'psychological well-being' dimension; and socio-economic status of family, positively correlated with the 'relationships with friends' dimension. The maximum R(2) was 15%. CONCLUSION: In addition to neurocognitive disorders, other variables such as socio-economic status of the family have a significant impact on the HRQL of preterm children at 6-10 years of age. Given the low proportion of variability in HRQL explained by the models, there is a need to explore other factors (e.g. environmental). PMID- 22424586 TI - Zolpidem for insomnia. AB - INTRODUCTION: The imidazopyridine derivative zolpidem , which acts as a benzodiazepine (BZ) receptor agonist, is the most widely prescribed hypnotic drug in the US. AREAS COVERED: This review addresses the neuroreceptor properties of zolpidem; clinical pharmacokinetics, pharmacodynamics and drug interactions; efficacy as a hypnotic; adverse effects; tolerance, dependence and withdrawal; relation to motor vehicle accidents and complex sleep behaviors; and new dosage forms. EXPERT OPINION: Approved doses of zolpidem (10 mg for adults, 5 mg for the elderly) are consistently effective in reducing sleep latency and consequently increasing sleep duration in patients with insomnia. However, favorable effects on sleep maintenance are observed less consistently. Residual daytime effects are unlikely with recommended doses, and provided that at least 8 h elapse prior to arising. Hypnotic efficacy is maintained with repeated nightly use, and the risk of rebound insomnia is low. Dependence and abuse of zolpidem are no more likely to occur than with typical benzodiazepines. Newly available novel dosage forms of zolpidem have increased therapeutic options for patients with insomnia variants such as sleep maintenance insomnia and middle-of-the-night awakening. PMID- 22424587 TI - Gender differences in the kinematics and ball velocity of overarm throwing in elite team handball players. AB - The aim of this study was to investigate the throwing velocity and kinematics of overarm throwing in team handball of elite female and male handball players. Kinematics and ball velocity of a 7 metre-throw in eleven elite male (age 23.6 +/ 5.2 yr, body mass 87.0 +/- 6.8 kg, height 1.85 +/- 0.05 m) and eleven elite female (age 20.3 +/- 1.8 yr, body mass 69.9 +/- 5.5 kg, height 1.75 +/- 0.05 m) team handball players were recorded. The analysis consisted of maximal joint angles, angles at ball release, maximal angular velocities of the joint movements, and maximal linear velocities of the distal endpoints of segments and their timing during the throw. The ball release velocity of the male handball players was significantly higher than the females (21.1 vs. 19.2 m . s(-1); p < 0.05). No major differences in kinematics were found, except for the maximal endpoint velocities of the hand and wrist segment, indicating that male and female handball players throw with the same technique. It was concluded that differences in throwing velocity in elite male and female handball players are generally not the result of changes in kinematics in the joint movements. PMID- 22424588 TI - In planta assays involving epigenetically silenced genes reveal inhibition of cytosine methylation by genistein. AB - BACKGROUND: Cytosine methylation is involved in epigenetic control of gene expression in a wide range of organisms. An increasing number of examples indicate that changing the frequency of cytosine methylation in the genome is a feasible tool to engineer novel traits in plants. Although demethylating effects of compounds have been analyzed in human cultured cells in terms of suppressing cancer, their effect in plant cells has not been analyzed extensively. Here, we developed in planta assay systems to detect inhibition of cytosine methylation using plants that contain a transgene transcriptionally silenced by an epigenetic mechanism. RESULTS: Seeds of two transgenic plants were used: a petunia line that has been identified as a revertant of the co-suppression of the chalcone synthase A (CHS-A) gene and contains CHS-A transgenes whose transcription is repressed; Nicotiana benthamiana plants that contain the green fluorescent protein (GFP) reporter gene whose transcription is repressed through virus-induced transcriptional gene silencing. Seeds of these plants were sown on a medium that contained a demethylating agent, either 5-azacytidine or trichostatin A, and the restoration of the transcriptionally active state of the transgene was detected in seedlings. Using these systems, we found that genistein, a major isoflavonoid compound, inhibits cytosine methylation, thus restoring transgene transcription. Genistein also restored the transcription of an epigenetically silenced endogenous gene in Arabidopsis plants. CONCLUSIONS: Our assay systems allowed us to assess the inhibition of cytosine methylation, in particular of maintenance of methylation, by compounds in plant cells. These results suggest a novel role of flavonoids in plant cells and that genistein is useful for modifying the epigenetic state of plant genomes. PMID- 22424589 TI - Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. AB - Bacteria encounter a myriad of potentially growth-compromising conditions in nature and in hosts of pathogenic bacteria. These 'stresses' typically elicit protective and/or adaptive responses that serve to enhance bacterial survivability. Because they impact upon many of the same cellular components and processes that are targeted by antimicrobials, adaptive stress responses can influence antimicrobial susceptibility. In targeting and interfering with key cellular processes, antimicrobials themselves are 'stressors' to which protective stress responses have also evolved. Cellular responses to nutrient limitation (nutrient stress), oxidative and nitrosative stress, cell envelope damage (envelope stress), antimicrobial exposure and other growth-compromising stresses, have all been linked to the development of antimicrobial resistance in Gram negative bacteria - resulting from the stimulation of protective changes to cell physiology, activation of resistance mechanisms, promotion of resistant lifestyles (biofilms), and induction of resistance mutations. PMID- 22424590 TI - Neoadjuvant chemotherapy modifies serum angiotensinase activities in women with breast cancer. AB - PURPOSE: The aim of this study was to investigate the putative changes in serum angiotensinase activities (aminopeptidase N, APN; aminopeptidase B, APB; aminopeptidase A, APA; aspartyl aminopeptidase, ASAP) involved in the renin angiotensin system (RAS) in women with breast cancer treated or not with a neoadjuvant therapy of paclitaxel and anthracycline and in healthy women volunteers. METHODS: We fluorometrically analysed serum APN, APB, APA and ASAP activities using their corresponding aminoacyl-beta-naphthylamides as substrates in women with breast cancer treated with a neoadjuvant therapy of paclitaxel and anthracycline. RESULTS: When compared with healthy controls, women with breast cancer not treated with neoadjuvant chemotherapy, showed a decrease in angiotensinase activity, which support the putative increase of angiotensin II (Ang II) levels, indicating that the tumour process would favour the development of the disease. Also, an increase in APN and APB activities was observed, which support a role for angiotensin IV (Ang IV). In women treated with a neoadjuvant therapy, we described an increase in ASAP and APA activities, supporting the idea that this treatment increases Ang II catabolism. The resulting decrease in Ang II level could lead to an inhibition of the tumour growth. CONCLUSION: Present results show changes in serum angiotensinase activities in women with breast cancer and in women with breast cancer treated with a neoadjuvant therapy of paclitaxel and anthracycline. Therefore, considerable attention should be focused on the development of RAS blockade therapy as a new strategy for breast cancer treatment. PMID- 22424591 TI - Environmental controls of cadmium desorption during CO2 leakage. AB - Geologic carbon sequestration represents a promising option for carbon mitigation. Injected CO(2), however, can potentially leak into water systems, increase water acidity, and mobilize metals. This study used column experiments to quantify the effects of environmental controls on cadmium desorption during CO(2) leakage in subsurface systems without ambient flow. Results show that fast leakage rates are responsible for earlier and larger amounts of Cd desorption. Long weathering time of Cd laden clay leads to low Cd desorption. Calcite content as low as 10% can mitigate the effect of pH reduction and result in zero Cd desorption. Increasing the salinity of the leaking fluid has a relatively minor effect, primarily due to the offsetting impacts of an increased extent of ion exchange and the decrease in CO(2) solubility (and therefore acidity). This work systematically quantifies, for the first time, the effects of environmental controls on Cd desorption and points to key parameters for risk assessment associated with metal mobilization during CO(2) leakage. PMID- 22424592 TI - Herpes simplex virus type 1 is the main cause of genital herpes in women of Natal, Brazil. AB - OBJECTIVES: The purpose of this study was to assess the prevalence of HSV-1 and HSV-2 in sexually active women who participated in the cervical cancer screening program in Natal, Brazil. STUDY DESIGN: The study included 261 sexually active women resident in the metropolitan area of Natal, Brazil and attending a public clinic for cervical screening. From each participant, a sample of exfoliated uterine cervical cells was collected, using a cytobrush which was conditioned in a tube containing a preserving solution (PBS+vancomycin+nystatin) and sent to a laboratory where it was processed for DNA extraction. The samples were analyzed for the presence of HSV-1 and HSV-2 DNA in separate reactions by PCRs using specific primers. RESULTS: HSV-1 in genital infection is four times more prevalent than HSV-2 in the population analyzed. The highest prevalence rates for both viruses were found in women aged 31-39years. We did not observe any association between the presence of both virus serotypes and socio-demographic characteristics in the population studied, nor with some classical risk factors for sexually transmitted diseases. CONCLUSIONS: HSV-1 was the major cause of genital infection by Herpes simplex virus in the women included in this study. No association was found between HSV infection and the socio-demographic characteristics or some classical risk factors for sexually transmitted diseases. PMID- 22424593 TI - [Outcomes after implantation of a trifocal diffractive IOL]. AB - PURPOSE: To assess the visual and refractive outcomes after implantation of the FineVision trifocal IOL (PhysIOL, Belgium). Site: Albi, France. METHODS: Twenty eyes of ten patients were implanted consecutively with the FineVision trifocal IOL between June and November 2010. This IOL is fully diffractive over the entire optic and presents a decrease of the diffractive step height from the center towards the periphery to improve distance vision in mesopic conditions. RESULTS: Uncorrected binocular visual acuity was 1.00 in all cases (1.00+/-0.00). Near vision was equal to or better than Parinaud 2 in all cases and intermediate vision was better than Parinaud 3. The photopic defocus curve showed no decrease in the intermediate range. The visual acuity decreased by only one line at 10% contrast, which is similar to published data with bifocal IOL's. CONCLUSION: Trifocality maintains distance and near vision performance while improving outcomes for intermediate vision. The third focal point is usable by the patient and does not create ghosting dysphotopsias. PMID- 22424594 TI - Diabetes insipidus as an atypical presentation of acute myeloid leukemia. PMID- 22424595 TI - [Body satisfaction and diet quality in female university students from the Basque Country]. AB - The aim of this study was to analyze the body weight satisfaction and the diet quality in a group of female university students and to assess the differences between degrees in different fields of knowledge. Participants were 47 women volunteers classified as normal weight, 29 from the degree in Human Nutrition and Dietetics and 18 from the degree in Social Work. Dietary intake was evaluated by a validated food frequency questionnaire. This information was used to estimate the Diet Quality Index. Recalled weight and desired weight were used to measure weight satisfaction. Furthermore, lifestyle variables were registered. Data were analyzed using SPSS vs 17.0. The proportion of students who were satisfied with their body weight was 27.7%, 57.4% were dissatisfied and 14.9% very dissatisfied. Differences between degree courses were not found in weight satisfaction classification. The mean Diet Quality Index was 38.5+/-6.7, and 83% of participants had a diet classified as "needs to improve". Human Nutrition and Dietetics students had higher Diet Quality Index scores (41.5+/-5.1) than Social Work students (33.7+/-6.5) (p<0.001). In conclusion, a large proportion of participants were dissatisfied with their body weight and they wished to weigh less than current weight values. It seems that the knowledge of Nutrition university student participants affects their food practice, but this is not enough to achieve a healthy diet and to reduce their body dissatisfaction. PMID- 22424596 TI - Pituitary apoplexy after myocardial perfusion scintigraphy. PMID- 22424597 TI - Clinical significance of preoperative neutrophil-lymphocyte versus platelet lymphocyte ratio in patients with operable colorectal cancer. AB - The objective of this study was to clarify whether the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are significant prognostic markers in patients with resectable colorectal cancer (CRC). A total of 200 patients who underwent curative resection for CRC were enrolled. The NLR and PLR were positively correlated (p < 0.001). Both the NLR and PLR were shown to be good prognostic biomarkers of overall survival (OS) (p=0.002 and p=0.001, respectively). The PLR was an independent prognostic factor of OS based on multivariate analysis (hazard ratio, 1.971; 95% confidence interval, 1.102-3.335; p=0.021). PMID- 22424598 TI - Staphylococcal enterotoxin A has potent superantigenic and emetic activities but not diarrheagenic activity. AB - Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus are pyrogenic superantigenic toxins that are involved in human diseases including food poisoning and toxic shock syndrome. Although the superantigenic activity of SEs has been well characterized, its role and mechanism in clinical symptoms of food poisoning remain poorly understood. In this study, house musk shrews (Suncus murinus), a small emetic animal model, were used to study the role of SEs in clinical manifestations of food poisoning. Administration of SEA induced a potent emetic response in vivo and showed significant superantigenic activity in vitro in house musk shrews. However, SEA revealed no diarrheagenic activity. SEA directly injected into the intestinal loops of house musk shrews failed to induce fluid exudation and consequent dilation of the intestinal segments. Rabbit intestinal loop experiments were further carried out to confirm the results and also showed that SEA induced no fluid exudation and consequent dilation. Furthermore, the SEA-producing S. aureus also failed to induce fluid exudation in the administered loops of these animal models. These results indicate that SEA has potent superantigenic and emetic activities, but does not have a diarrheagenic activity. PMID- 22424599 TI - Prenatal exposure to diagnostic ultrasound impacts blood-brain barrier permeability in rats. AB - The central nervous system vasculature consists of a tightly sealed endothelium that forms the blood-brain barrier (BBB); these blood vessels are impermeable to large-molecular-size agents. The aim of this study was to determine the influence of prenatal ultrasound exposure on blood-brain barrier (BBB) integrity as measured by the permeation of Evans blue (EB) through the BBB during the postnatal development of the rat. Diagnostic levels of ultrasound (2.89 MHz, mechanical index = 1.1, acoustic output power = 70.5 mW) for 1 h and 2 h per day, for 9 consecutive days were used on Sprague-Dawley rats. Offspring were assessed postnatally on days 10, 17, 24 and 38. Our analysis of over 139 animals reveals that, when exposed to diagnostic levels of ultrasound during embryonic development, a statistically significant amount of EB extravasation into the cerebrum and cerebellum could be detected on postnatal day 10 but not later. In addition, small changes in pup body weight, cerebrum weight and cerebellum weight were observed after relatively prolonged ultrasound exposure on all postnatal days. Taken together, these results emphasize the need for further investigation of the effects of ultrasound exposure during the potentially vulnerable period of intense BBB development in the human fetus. PMID- 22424600 TI - Mutations in ROGDI Cause Kohlschutter-Tonz Syndrome. AB - Kohlschutter-Tonz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping and exome sequencing, we identified a homozygous frameshift deletion, c.229_230del (p.Leu77Alafs(*)64), in ROGDI in two affected individuals from a consanguineous family. Molecular studies in two additional KTS-affected individuals from two unrelated Austrian and Swiss families revealed homozygosity for nonsense mutation c.286C>T (p.Gln96(*)) and compound heterozygosity for the splice-site mutations c.531+5G>C and c.532-2A>T in ROGDI, respectively. The latter mutation was also found to be heterozygous in the mother of the Swiss affected individual in whom KTS was reported for the first time in 1974. ROGDI is highly expressed throughout the brain and other organs, but its function is largely unknown. Possible interactions with DISC1, a protein involved in diverse cytoskeletal functions, have been suggested. Our finding that ROGDI mutations cause KTS indicates that the protein product of this gene plays an important role in neuronal development as well as amelogenesis. PMID- 22424601 TI - Transcript and metabolite profiling in cell cultures of 18 plant species that produce benzylisoquinoline alkaloids. AB - Benzylisoquinoline alkaloids (BIAs) are a large and diverse group of ~2500 specialized metabolites found predominantly in plants of the order Ranunculales. Research focused on BIA metabolism in a restricted number of plant species has identified many enzymes and cognate genes involved in the biosynthesis of compounds such as morphine, sanguinarine and berberine. However, the formation of most BIAs remains uncharacterized at the molecular biochemical level. Herein a compendium of sequence- and metabolite-profiling resources from 18 species of BIA accumulating cell cultures was established, representing four related plant families. Our integrated approach consisted of the construction of EST libraries each containing approximately 3500 unigenes per species for a total of 58,787 unigenes. The EST libraries were manually triaged using known BIA-biosynthetic genes as queries to identify putative homologs with similar or potentially different functions. Sequence resources were analyzed in the context of the targeted metabolite profiles obtained for each cell culture using electrospray ionization and collision-induced dissociation mass spectrometry. Fragmentation analysis was used for the identification or structural characterization coupled with the relative quantification of 72 BIAs, which establishes a key resource for future work on alkaloid biosynthesis. The metabolite profile obtained for each species provides a rational basis for the prediction of enzyme function in BIA metabolism. The metabolic frameworks assembled through the integration of transcript and metabolite profiles allow a comparison of BIA metabolism across several plant species and families. Taken together, these data represent an important tool for the discovery of BIA biosynthetic genes. PMID- 22424602 TI - Progressive multifocal leukoencephalopathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. PMID- 22424603 TI - Molecular basis of type I antithrombin deficiency in two women with recurrent venous thromboembolism in the first trimester of pregnancy. AB - Inherited antithrombin (AT) deficiency carries a 50% risk of venous thromboembolism (VTE) during pregnancy. Here, we investigated the molecular basis of type I AT deficiency in two women with recurrent VTE in the first trimester of pregnancy. Phenotype analysis showed both probands had almost 50% of normal AT levels. Two novel heterozygous AT mutations were identified: g.7920C>T resulting in a Trp225Cys mutation in case 1 and g.13863C>A causing an Ala404Asp mutation in case 2. Transient expression of either wild-type (WT) or mutant AT expression vectors in HEK293T and CHO cells showed impaired secretion of both AT mutant proteins. Immunofluorescence analysis revealed that the staining of AT-Trp225Cys in both endoplasmic reticulum (ER) and Golgi apparatus was similar to that of AT WT, and the staining of AT-Ala404Asp was mainly present in ER but was weaker than that of AT-WT. These results revealed that the type I AT deficiency in two patients was caused by impaired secretion of the AT-Trp225Cys and AT-Ala404Asp mutant proteins, respectively. The two mutations are associated with a high risk of thrombotic onset and women with these AT mutations are prone to VTE in early pregnancy. PMID- 22424604 TI - Red blood cell processing for cryopreservation: from fresh blood to deglycerolization. AB - BACKGROUND: Cryostorage of red blood cells (RBCs) represents a valid alternative to liquid storage, since units can be preserved safely for at least a decade while conserving RBC viability. While cryostorage has attracted a great deal of attention clinically, little is known about the biochemistry and physiology of cryostored erythrocyte concentrates. STUDY DESIGN AND METHOD: In the present study, we investigated cryostorage of RBCs through monitoring of cell processing steps (from fresh blood, to glycerolization, thawing and deglycerolization/washing) through repeated assays of standard parameters (MCV, RDW-SD) and scanning electron microscopy. RESULTS: Cell processing for cryostorage resulted in increased RBC volumes. Shape alterations caused an increase in osmotic fragility and permeability to ions. A significant pH drop was observed which could not to be attributed to a higher metabolic rate, since the levels of lactate did not show substantial fluctuation during the cell processing steps tested in this study. Membrane anomalies are likely related to the hemolysis observed which preferentially affected the densest and oldest cell sub populations, as confirmed by means of discontinuous density gradients. CONCLUSION: Our results indicate that cryostorage itself in presence of glycerol does not significantly affect RBCs. Most of the alterations observed were related to cell processing and, in particular, to the increase of cytosolic glycerol as a consequence of the glycerolyzation step. Further studies might profitably investigate replacing glycerol with non-penetrating cryoprotectants. PMID- 22424605 TI - A robust decentralized load frequency controller for interconnected power systems. AB - A novel design of a robust decentralized load frequency control (LFC) algorithm is proposed for an inter-connected three-area power system, for the purpose of regulating area control error (ACE) in the presence of system uncertainties and external disturbances. The design is based on the concept of active disturbance rejection control (ADRC). Estimating and mitigating the total effect of various uncertainties in real time, ADRC is particularly effective against a wide range of parameter variations, model uncertainties, and large disturbances. Furthermore, with only two tuning parameters, the controller provides a simple and easy-to-use solution to complex engineering problems in practice. Here, an ADRC-based LFC solution is developed for systems with turbines of various types, such as non-reheat, reheat, and hydraulic. The simulation results verified the effectiveness of the ADRC, in comparison with an existing PI-type controller tuned via genetic algorithm linear matrix inequalities (GALMIs). The comparison results show the superiority of the proposed solution. Moreover, the stability and robustness of the closed-loop system is studied using frequency-domain analysis. PMID- 22424606 TI - Single item on patients' satisfaction with condition provided additional insight into impact of surgery. AB - OBJECTIVE: To determine the value of a single item on patients' satisfaction with their condition for assessing outcome in four common surgical procedures. STUDY DESIGN AND SETTING: Four cohorts undergoing surgery for inguinal hernia (715), varicose veins (539), hip (8,383), or knee (10,187) disease. Patients completed questionnaires before and after surgery that included a single item on satisfaction with their health (based on the International Prostate Symptom Score [IPSS] Bother Question), disease-specific measures of symptoms/disability (Oxford Hip and Knee Scores, Aberdeen Varicose Vein Questionnaire), generic measures of symptoms/disability and of quality of life (QoL) (EQ [EuroQoL]-5D index), and single transitional items. Nonparametric Spearman's correlations explored relationships between measures. RESULTS: Before surgery, in all conditions, satisfaction was associated with other dimensions (P<0.05): generic QoL (r=0.5 0.7), disease-specific symptoms/disability (r=0.6-0.8), and generic symptoms/disability (r=0.2-0.4). Significant improvements in satisfaction after surgery correlated strongly with change in disease-specific symptoms/disability (r=0.6 for major operations and r=0.35 for minor surgery) and with single transitional items (r=0.4-0.6) but less so with change in generic QoL (0.3-0.4) and generic symptoms/disability (0.1-0.2). CONCLUSION: Inclusion of a single item on satisfaction provides additional insight into the impact of surgery. PMID- 22424607 TI - Discrete choice experiment produced estimates of acceptable risks of therapeutic options in cancer patients with febrile neutropenia. AB - OBJECTIVE: To use a discrete choice experiment (DCE) to describe patient/proxy tolerance for the number of clinic visits, and chances of readmission, intensive care unit admission, and mortality to accept oral outpatient management of low risk febrile neutropenia. STUDY DESIGN AND SETTING: Adults and children aged 12 18 years with cancer and parents of pediatric cancer patients were asked to choose between outpatient oral and inpatient intravenous management of low-risk febrile neutropenia. Using a DCE, we varied the attribute levels with the outpatient option and kept them constant for the inpatient option. RESULTS: Seventy-eight adults, 153 parents, and 43 children provided responses. All four attributes significantly affected choices. The mean tolerance (95% confidence interval) for the number of clinic visits per week was 3.6 (2.2-4.8), 2.1 (1.1 3.2), and 4.3 (2.5-6.0) to accept outpatient management among adults, parents, and children, respectively. With thrice weekly clinic visits and 7.5% chance of readmission, probabilities of accepting the outpatient strategy were 50% (44-54%) for adults, 43% (39-48%) for parents, and 53% (46-59%) for children. CONCLUSION: Using a DCE, we determined that a 7.5% chance of readmission and clinic visits more frequently than thrice weekly are unlikely to be acceptable. PMID- 22424608 TI - Including questionnaires with the invitation package appeared to increase the response fraction among women. AB - OBJECTIVE: The Breast Cancer Environment and Employment Study (BCEES) is a case- control study that began in 2009. The study experienced a lower than expected response fraction, a trend that appears to be occurring internationally. A 32 page questionnaire was included in the initial invitation to participate, and previous research suggests that long questionnaires decrease response fractions. The aim of this study was to test whether removal of the questionnaire from the invitation package increased participation. STUDY DESIGN AND SETTING: A randomized controlled trial was undertaken among the BCEES controls from June to August 2010. One group of 250 received the questionnaire in the initial invitation package, and the other group of 250 received only the invitation package and was sent the questionnaire after their consent was received. The proportion of responses for the two groups was compared using contingency tables and chi-square statistics. RESULTS: Those who received the questionnaire with the invitation package were more likely to consent to participate than those who did not (40.8% and 33.2%, respectively). However, this difference was not statistically significant (P=0.078). CONCLUSION: To improve response fractions and reduce time in following up nonresponses, questionnaires should be included in the invitation package. PMID- 22424609 TI - Postcricoid vascular abnormalities: hemangiomas, venous malformations, or anatomic variant. AB - OBJECTIVE: Ten children with pressure-dependent postcricoid masses (PDPCM) previously referred to in the literature as hemangiomas or vascular malformations are presented. We propose these lesions represent an anatomic variant. We review previously reported cases, and report the presentation, diagnosis, and management of the patients in our series, the largest series to date. METHODS: Ten patients, aged five weeks to nine months, were diagnosed, and treated or observed. Of the patients undergoing intervention, one was treated with a gastrostomy tube, fundoplication, and Propranolol therapy; and the other with CHARGE association underwent a tracheotomy. RESULTS: No PDPCMs demonstrated significant interval change in size or appearance, and eight of ten patients did well with observation. CONCLUSION: Based on current information, the majority of PDPCMs likely represent an anatomic variant rather than a hemangioma or vascular malformation. Diagnosis is most readily made with awake flexible fiberoptic laryngoscopy. Because the incidence of synchronous airway pathology is high, direct laryngoscopy and bronchoscopy without routine biopsy is recommended for symptomatic patients. Imaging should be individualized and may be helpful for ambiguous cases. Although numerous treatment modalities have been advocated based on the presumptive diagnosis of a hemangioma, treatment of PDPCMs is not necessary in the majority of cases, as most patients may be safely observed. PMID- 22424610 TI - The role of CTCF in regulating V(D)J recombination. AB - V(D)J recombination in B and T cells is required for the generation of receptors with a broad spectrum of specificity to foreign antigen. A total number of three immunoglobulin (Ig) and four T cell receptor (Tcr) loci can be targeted by the recombinase enzyme (RAG1/2) in a defined series of recombination events, which drive the progression of B and T cell development. This process is regulated at multiple levels to ensure lineage specific, ordered rearrangement and allelic exclusion. One key component of this is modulation of chromatin looping and locus contraction, which is important in bringing widely separated gene segments into close contact with each other to enable synapse formation for lineage and stage specific V gene rearrangement [2,3,4(*),5,6(*)]. Recent studies provide new insight into looping and its role in these processes. In this review we focus on the contribution of the 11 zinc finger nuclear protein, CTCF, in mediating loop formation and conformational changes that are important for the regulation of Ig and Tcr rearrangement. PMID- 22424611 TI - Synthesis and in vitro antiplasmodial activities of fluoroquinolone analogs. AB - Fluoroquinolone analogs were synthesized by simple alkylation followed by click chemistry and evaluated for their antimalarial in vitro against chloroquine sensitive strain of Plasmodium falciparum while ciprofloxacin was used as standard. Our results showed that the compound 12 was found most active with IC(50) value of 1.33 MUg/mL while ciprofloxacin showed IC(50) = 8.81 MUg/mL. Therefore, screening of either known or unknown quinolone/fluoroquinolone analogs are worthwhile to find more potent antimalarial drugs which might prove useful in the treatment of mild or severe malaria in human either alone or in combination with existing antimalarial drugs. PMID- 22424612 TI - Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists. AB - The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the beta-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pK(i) values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of beta arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research. PMID- 22424613 TI - A novel anti-tumor agent, Ln(III) 2-thioacetate benzothiazole induces anti angiogenic effect and cell death in cancer cell lines. AB - New complexes with a potent DNA-binding anti-tumor agent, europium(III)- and terbium(III)-2-thioacetate benzothiazole were synthesized and characterized. These complexes showed strong binding affinity to calf thymus DNA using fluorometric and electronic absorption spectroscopy. The synthesized complexes resulted in inhibition of proliferation of EAC cells and ascites formation. Their anti-tumor effect was found to be through anti-angiogenic activity as was evident by the reduction of microvessel density and down-regulation of VEGF receptor type 2 (Flk-1). It was found that EAC cells had distinct DNA fragmentation patterns analyzed by capillary electrophoresis in the treated animals. Moreover, the synthesized complexes exhibited significant cytotoxic activity against HepG2 and MCF7 cell lines. Furthermore, complexes showed a potent anti-bacterial activity against two pathogenic bacteria Escherichia coli and Salmonella. PMID- 22424614 TI - Design and synthesis of novel magnolol derivatives as potential antimicrobial and antiproliferative compounds. AB - A series of novel magnolol derivatives were synthesised and evaluated for in vitro antimicrobial and antiproliferative activities. We found that most of the compounds were effective inhibitors of Staphylococcus aureus, MRSA and VRE with MIC in the range of 1-64 MUg/mL and MBC in the range of 1-128 MUg/mL. Few derivatives also exhibited promising antifungal activity. Some magnolol analogues exhibited promising antiproliferative activity than parent magnolol when tested against three human cancer cell lines. PMID- 22424615 TI - Molecular and epigenetic analysis of the fragile histidine triad tumour suppressor gene in equine sarcoids. AB - BACKGROUND: Sarcoids are peculiar equine benign tumours. Their onset is associated with Bovine Papillomavirus type -1 or -2 (BPV-1/2) infection. Little is known about the molecular interplay between viral infection and neoplastic transformation. The data regarding papillomavirus infections in human species show the inactivation of a number of tumour suppressor genes as basic mechanism of transformation. In this study the putative role of the tumour suppressor gene Fragile Histidine Triad (FHIT) in sarcoid tumour was investigated in different experimental models. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissue. RESULTS: Nine paraffin embedded sarcoids and sarcoid derived cell lines were analysed for the expression of FHIT protein by immunohistochemistry, immunofluorescence techniques and western blotting. These analyses revealed the absence of signal in seven out of nine sarcoids. The two sarcoid derived cell lines too showed a reduced signal of the protein. To investigate the causes of the altered protein expression, the samples were analysed for the DNA methylation profile of the CpG island associated with the FHIT promoter. The analysis of the 32 CpGs encompassing the region of interest showed no significative differential methylation profile between pathological tissues and cell lines and their normal counterparts. CONCLUSION: This study represent a further evidence of the role of a tumour suppressor gene in equine sarcoids and approaches the epigenetic regulation in this well known equine neoplasm. The data obtained in sarcoid tissues and sarcoid derived cell lines suggest that also in horse, as in humans, there is a possible involvement of the tumour suppressor FHIT gene in BPV induced tumours. DNA methylation seems not to be involved in the gene expression alteration. Further studies are needed to understand the basic molecular mechanisms involved in reduced FHIT expression. PMID- 22424616 TI - Bioluminescence imaging as a tool to evaluate germ cells in vitro and transplantation in vivo as fertility preservation of prepubertal male mice. AB - OBJECTIVE: To determine the feasibility of bioluminescence imaging (BLI) to evaluate the efficiency of germ cell transplantation in vitro and in vivo in fertility preservation for infertile male mice. DESIGN: Transgenic mouse model. SETTING: University-based teaching hospital. ANIMAL(S): Transgenic mice. INTERVENTION(S): Busulfan was used to induce testicular failure in 3-week-old immature FVB/NJNarl wild-type recipient mice. At 8 weeks of age they received hemizygotic germinal cells from 3-week-old immature male FVB/N-Tg (PolII-luc) Ltc strain transgenic donor mice, transplanted into the seminiferous tubules. MAIN OUTCOME MEASURE(S): Isolated germinal cells were suspended in multiwell plates with the bioluminescent substrate d-luciferin in excess to quantify viable germ cells in vitro. Quantitatively in vivo BLI was applied to demonstrate the efficiency and success of transplantation and BLI of live pups born from wild type in vivo. RESULT(S): Live birth pup of FVB/N-Tg (PolII-luc) Ltc transgenic mouse were born and imaged by bioluminescence after mating FVB/NJNarl female wild type and male wild-type infertile recipient 4-6 months after transplantation of germinal cells of FVB/N-Tg (PolII-luc). CONCLUSION(S): The BLI could be applied successfully to this transgenic small animal model. It proved a useful tool for quantifying germ cells in vitro and for assessing the efficacy of germ cell transplantation in vivo. PMID- 22424617 TI - Glutathione transferase polymorphisms and risk of endometriosis associated with polychlorinated biphenyls exposure in Italian women: a gene-environment interaction. AB - OBJECTIVE: To investigate the occurrence of a gene-environment interaction between glutathione transferase (GST) gene polymorphisms (GSTM1, GSTT1, GSTP1, and GSTA1) and serum polychlorinated biphenyls (PCBs) levels. This is suggested as possible risk factors for endometriosis, a multifactorial gynecological disease. DESIGN: Case-control study conducted from 2002 to 2005. SETTING: Policlinico Umberto I, "Sapienza" University of Rome and Italian National Institute for Health, Rome. PATIENT(S): Italian women (N = 343), with laparoscopic diagnosis and histologic confirmation of the presence (cases, N = 181) or the absence (controls, N = 162) of endometriosis. INTERVENTION(S): Genomic DNA extraction, multiplex polymerase chain reaction (PCR), and restriction fragment length polymorphism analysis. Determination of serum concentrations of selected PCBs by ion-trap mass spectrometry (subgroup, 63 cases and 63 controls). MAIN OUTCOME MEASURE(S): Endometriosis diagnosis by laparoscopy, GST genotypes, serum PCB levels. RESULT(S): The genotype distributions of GSTM1, GSTA1, and GSTP1 did not show any statistically significant difference between cases and controls. The GSTT1 null genotype was negatively associated with the disease. The GSTP1 wild-type genotype in the presence of medium-high blood levels of PCB153, total PCBs, or of high levels of PCB180 significantly increased the risk of endometriosis, suggesting a multiplicative interaction. CONCLUSION(S): The GSTs polymorphisms per se do not increase the risk of developing endometriosis. However, a gene-environment interaction was observed for GSTP1(Ile/Ile) and GSTM1 null genotypes, modulating the effect of PCB153, PCB180, and of total PCBs on disease risk. PMID- 22424618 TI - Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. AB - OBJECTIVE: To investigate the presence of neurokinin B (NKB)/NK(3) receptor (NK(3)R) and kisspeptin/KISS1 receptor (KISS1R) messenger RNA (mRNA) and proteins throughout the human female genital tract. DESIGN: In vitro study. SETTING: Academic research laboratories and academic hospitals. PATIENT(S): Fifteen reproductive-age women and 16 postmenopausal women provided fresh samples of uterus, ovary, or oviduct, and 12 women provided archival samples of endometrium or oviduct. INTERVENTION(S): Fresh and archival samples of uterus, ovary, and oviduct obtained from reproductive-age and postmenopausal women. MAIN OUTCOME MEASURE(S): Results of reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry to investigate the pattern of expression of NKB/NK(3)R and kisspeptin/KISS1R in target tissues. RESULT(S): Expression of the genes encoding NKB (TAC3) and NK(3)R (TACR3), and kisspeptin (KISS1) and its receptor (KISS1R) was found in the uterus, ovary, and oviduct. Both NKB and NK(3)R immunoreactivity was detected in the endometrium, the oviduct, and the ovary, with marked expression in endometrial and oviductal epithelial cells, where intense coexpression of kisspeptin and KISS1R was also detected. Positive staining for NKB and NK(3)R was found in the myometrium where, in contrast, kisspeptin and KISS1R were absent. CONCLUSION(S): NKB/NK(3)R and kisspeptin/KISS1R are present in female peripheral reproductive tissues with colocalization of both systems in some non-neuronal cell populations of the human female genital tract. Our findings are compatible with a potential modulatory role of NKB and kisspeptin at peripheral reproductive tissues. PMID- 22424620 TI - The relationship between glucose excursion and cognitive function in aged type 2 diabetes patients. AB - OBJECTIVE: Evidence suggests that type 2 diabetes (T2DM) is associated with an increased risk of dementia and that glucose variability is an independent risk factor for diabetic complications. This study investigated the relationship between glucose excursion and cognitive function in aged T2DM patients. METHODS: A total of 248 aged T2DM patients wore a continuous glucose monitoring system (CGMS) for 3 days in order to evaluate glucose excursion, including mean amplitude of glycemic excursions (MAGE) and mean of daily difference (MODD). All subjects were evaluated with a number of accepted cognitive function tests, including the mini-mental status examination (MMSE). The relationship between MAGE and MODD and performance on these cognitive tests was assessed. RESULTS: The MAGE and MMSE score were negatively correlated, likewise with the correlation between MODD and MMSE. Liner multivariate regression analysis showed that MAGE and MODD were also negatively related to MMSE independent of age, sex, glycemic control, hypertension, smoking, or coronary heart disease history. CONCLUSION: Glucose excursion is related to cognitive function in aged T2DM patients. Elevated glucose excursion decreased the MMSE score, which reflects general cognitive function. Thus, therapy aimed at controlling glucose excursion may be beneficial for maintaining cognitive function in aged T2DM patients. PMID- 22424619 TI - p62: a versatile multitasker takes on cancer. AB - Since its initial discovery as an atypical protein kinase C (PKC)-interacting protein, p62 has emerged as a crucial molecule in a myriad of cellular functions. This multifunctional role of p62 is explained by its ability to interact with several key components of various signaling mechanisms. Not surprisingly, p62 is required for tumor transformation owing to its roles as a key molecule in nutrient sensing, as a regulator and substrate of autophagy, as an inducer of oxidative detoxifying proteins, and as a modulator of mitotic transit and genomic stability; all crucial events in the control of cell growth and cancer. PMID- 22424621 TI - Hyperinsulinemia, insulin resistance and cognitive decline in older cohort. AB - OBJECTIVE: Type 2 diabetes has been recently recognized as an important risk factor for cognitive decline of patients with Alzheimer's disease (AD). But the roles of hyperinsulinemia (HI) and insulin resistance (IR) in the development of AD are still controversial. This study was designed to evaluate whether HI or IR influenced the cognitive functions of older cohort. METHODS: The cognitive functions of 328 consecutive elderly patients were evaluated with a battery of cognitive rating scales. Their fasting blood glucose (FBG) and fasting insulin (FINS) were analyzed and IR was calculated with modified-Homa. The cognitive scores in different groups and the correlation of cognitive functions with HI or IR were analyzed. RESULTS: In our study, there were 180 participants with HI and 148 without HI, and 192 with IR and 136 without IR. The participants with HI showed worse cognitive functions than those without HI in MMSE, MOCA, CDR, orientation, delayed memory, and attention/calculation domains. Similarly, the elderly with IR had lower cognitive scores than those without IR in MMSE, MOCA, CDR, GDS, orientation, delayed memory, and attention/calculation domains. The insulin levels and Homa IR had negative correlation with the scores of MMSE and delayed memory, not only in the model 1 adjusted for FBG and diabetes history, but also in the model 2 adjusted for all nine demographic characteristics. CONCLUSION: HI and IR are important risk factors for cognitive decline of the elderly, especially for the dysfunctions in delayed memory domains. PMID- 22424622 TI - The impacts of maternal gestational diabetes mellitus (GDM) on fetal hearts. AB - OBJECTIVE: To evaluate the fetal cardiac function in gestational diabetes mellitus (GDM) pregnancies under different maternal glycemic controls. METHODS: Forty four GDM mothers received 78 fetal echocardiographic evaluations at three gestational periods (<28, 28-34 and >34 weeks) and were divided into poorly-(DM1) and well-(DM2) controlled groups according to their glycemic control at examination. Seventy uncomplicated mothers were selected as controls. Parameters of fetal cardiac anatomy and function were measured and analyzed. RESULTS: GDM fetuses' cardiac ventricular walls were thicker than controls', and the differences between DM1 and DM2 were not significant except for end-diastolic left ventricular walls. In both GDM groups, the aortic flow velocities increased earlier than pulmonary artery and DM1 fetuses changed earlier than DM2 ones. GDM fetuses' left atrial shortening fraction was smaller than the controls' in the period of ?34 weeks and negatively correlated with thicknesses of left ventricular walls and interventricular septum in DM1 fetuses (r=-0.438 and 0.506). The right ventricular diastolic function in DM1 and DM2 fetuses decreased after the period of 28-34 weeks and in the period of >34 weeks respectively. Tei index of both left and right ventricles increased in DM1 group after the period of <28 weeks and in DM2 group only in the period of ?34 weeks, with no significant differences between DM1 and DM2 groups in this period. CONCLUSION: Fetuses of GDM mothers showed cardiac function impairments. Good maternal glycemic control may delay the impairments, but cannot reduce the degree. Some cardiac changes in GDM fetuses were similar to those in pregestational diabetic pregnancies except for several parameters and their changing time. PMID- 22424623 TI - Association of a SLC30A8 genetic variant with monotherapy of repaglinide and rosiglitazone effect in newly diagnosed type 2 diabetes patients in China. AB - OBJECTIVE: To investigate a potential relationship between Solute carrier family 30 (zinc transporter) member 8 (SLC30A8) rs13266634 variant and efficacy of rosiglitazone or repaglinide in treating newly diagnosed Chinese type 2 diabetes patients. METHODS: A total of 209 diabetic patients without any antihyperglycemic history were recruited and treated with repaglinide or rosiglitazone randomly for 48 weeks (104 and 105 patients, respectively). Anthropometric measurements and clinical laboratory tests were carried out before and after the treatment. An non synonymous variant rs13266634 was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectroscopy. RESULTS: Ninety-one patients in repaglinide group and ninety-three patients in rosiglitazone group completed the study. Delta value of homeostasis model assessment of beta cell function (HOMA-B) and Delta value of fasting proinsulin levels were statistically significant between three genotype groups (P=0.0149 and 0.0246, respectively) after rosiglitazone treatment. However, no genotype association was observed in the repaglinide or rosiglitazone group with other parameters. CONCLUSION: The SLC30A8 variant was associated with the efficacy of insulin sensitizer monotherapy on insulin secretion in patients with newly diagnosed type 2 diabetes mellitus in Shanghai, China. PMID- 22424624 TI - Liver enzymes concentrations are closely related to prediabetes: findings of the Shanghai Diabetes Study II (SHDS II). AB - OBJECTIVE: To investigate the relationship of liver enzymes with hyperglycemia in a large population in Shanghai and identify the association between liver enzymes and insulin resistance. METHODS: A total of 3 756 participants were enrolled. Each participant underwent an oral glucose tolerance test and completed a questionnaire. Anthropometric indices were recorded and serum samples were collected for measurement. RESULTS: Liver enzymes concentrations were independently associated with i-IGT, IFG+IGT, and diabetes. With the increase of ALT and GGT concentrations, ORs for i-IGT, IFG+IGT, and diabetes increased gradually. By comparing patients in the highest quartile of GGT concentrations or ALT concentrations with those in the lowest quartile (Q1), ORs for i-IGT, IFG+IGT, or diabetes was significant after adjustment. Both ALT and GGT concentrations were linearly correlated with HOMA-IR and independently associated with HOMA-IR [ALT OR (95% CI): 2.56 (1.51-4.34) P=0.00; GGT OR (95% CI): 2.66 (1.53-4.65) P=0.00]. CONCLUSION: Serum ALT and GGT concentrations were closely related to pre-diabetes and diabetes in the Shanghai population and positively associated with insulin resistance. PMID- 22424625 TI - Metabolic disorders increase the risk to incident cardiovascular disease in middle-aged and elderly Chinese. AB - OBJECTIVE: The association of metabolic syndrome (MetS) with cardiovascular diseases (CVD) has not been adequately explored in middle-aged and elderly Chinese. This study aimed to investigate MetS' prevalence and its impact on the CVD incidence in this specific population group. METHODS: A data set of a community-based prospective cohort study was analyzed. A total of 2300 subjects aged 40-94 years were followed up for the CVD events. MetS defined according to the JCDCG criteria was assessed at baseline, and the middle-aged and elderly groups were classified by the WHO definition. RESULTS: As compared with the middle-aged group, the prevalence of MetS increased by 0.6 times (34.6% vs. 21.3%) and the incidence density of CVD increased by 4.9 times in the elderly group (52.3/1000 person-year vs. 8.9/1000 person-year). Furthermore, the multivariate Cox regression revealed that the risk to CVD incidence was independently related to increased waist circumference in the middle-aged group (HR=2.23, P<0.01) and to elevated blood glucose in the elderly group (HR=1.39, P<0.01). CONCLUSION: MetS was highly prevalent in middle-aged and elderly Chinese. MetS significantly increased the risk to CVD incidence in the elderly. All individuals with metabolic disorders should receive active clinical care to reduce the incidence of CVD. PMID- 22424626 TI - The intervention effect of Rosiglitozone in ovarian fibrosis of PCOS rats. AB - OBJECTIVE: To explore the Intervention effect of Rosiglitozone in ovarian fibrosis of PCOS rats. METHODS: 60 female SD rats were randomly divided into 3 groups: control group, model group and treatment group. The model and treatment groups were established by subcutaneous injection of DHEA, while the treatment group was given RGZ. The serum hormone values, pathohistology of ovarian structure of rats, ovarian ultrastructure and the expressions of TGF-beta(1) and CTGF were detected. RESULTS: The PCOS model was established successfully. The expression intensity of TGF-beta(1) and CTGF in Oocytes of the PCOS groups was 9.545+/-2.954 and 9.665+/-2.400, respectively and was significantly higher than that of the control group 6.636+/-2.264 and 7.036+/-2.133; after treatment with rosiglitazone, the expression was significantly decreased 6.980+/-2.421 and 6.642+/-2.721 as compared with that of the model group (P<0.05, P<0.001). The values in serum of the PCOS groups were 3.749+/-2.054 and 0.265+/-0.129, and 1.914+/-1.801 and 0.096+/-0.088 in the control group which had statistically significant difference (P<0.05, P<0.001). After treatment with rosiglitazone, the values were 2.3100+/-1.825 and 0.112+/-0.187 and were significantly different with those of the model group (P<0.05, P<0.001). CONCLUSION: TGF-beta(1) and CTGF play an important role in the development of ovary fibrosis in PCOS. However, RGZ may postpone the development of fibrosis by decreasing the levels of TGF-beta(1) and CTGF. PMID- 22424627 TI - Body mass index and hypertension hemodynamic subtypes in Yi farmers and migrants. AB - OBJECTIVE: To examine the relationship between overweight or obesity and the risk of the various hypertension hemodynamic subtypes in Yi farmers and migrants. METHODS: A cross-sectional study of 2 358 Yi farmers and 1 392 Yi migrants was carried out in the Liangshan Yi autonomous prefecture, Sichuan, China in 2007. RESULTS: The standardized prevalence of overweight in female Yi farmers (6.22%) was higher than in males (3.15%), whereas in Yi migrants 31.56% of males and 18.78% of females were overweight. The standardized prevalence of obesity was 0 and 0.61% in male and female Yi farmers, compared to 3.91% and 5.57% in male and female Yi migrants, respectively. For both genders the standardized prevalence of ISH, IDH, and SDH was higher in Yi migrants than Yi farmers. Overweight and obese Yi men and women had a higher risk for IDH and SDH (P<0.001) than non overweight/obese individuals. However, an association of overweight or obesity with ISH was observed only in men. CONCLUSION: Yi migrants have substantially higher proportion of overweight and obese individuals, as well as individuals affected by ISH, IDH, and SDH, than do Yi farmers. Overweight and obesity are significant risk factors for the development of hypertension in Yi people. PMID- 22424628 TI - Clinical predictors for diagnosing pandemic (H1N1) 2009 and seasonal influenza (H3N2) in fever clinics in Beijing, China. AB - OBJECTIVE: Symptomatic predictors of influenza could assess risks and improve decisions about isolation and outpatient treatment. To develop such predictors, we undertook a prospective analysis of pandemic (H1N1) 2009 and seasonal influenza (H3N2) in patients attending fever clinics. METHODS: From 1 May 2009 to 1 January 2010, all adult patients admitted to fever clinics for suspected influenza, confirmed by real time RT-PCR, were enrolled. Predictors of influenza virus infection were selected with logistic regression models. Measures of sensitivity, specificity, positive and negative likelihood ratios (LRs) were calculated to identify the best predictors. RESULTS: The clinical features and routine blood test results of influenza (H1N1) 2009 and seasonal influenza were similar. The positive and negative LRs of current US CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. Our modified clinic predictors improved the ability of the positive and negative LRs to recognize pandemic (H1N1) 2009 and seasonal influenza. The revised criteria are: fever >38 degrees C accompanied by at least one of the following-cough, arthralgia or relative lymphopenia. CONCLUSION: Patients with symptoms and signs that meet the new criteria are likely to have influenza and timely antiviral therapy may be appropriate. In addition, physicians should ascertain if influenza is circulating within the community or if there is a contact history of influenza and combine this information with the newly developed criteria to clinically diagnose influenza. PMID- 22424629 TI - A qualitative exploration of the role of antiretroviral therapy on Chinese rural life. AB - OBJECTIVE: To explore factors influencing the quality of life of people living with HIV/AIDS (PLHA) and receiving antiretroviral therapy (ART) in rural China. METHODS: In-depth interviews with 20 PLHA were conducted in March 1999. Participants were recruited from the USAID-funded Longitudinal Enhanced Evaluation of ART Project, which tracks a cohort of eligible PLHA receiving treatment at five collaborating treatment centers in Guangxi Autonomous Region, China. An interview guide (semi-structured with open-ended questions) was developed to provide a qualitative examination of the quality of life of PLHA. RESULTS: Participants identified that ART affects physical health, including the experience of pain, side effects, and opportunistic infections. ART imposes lifestyle constraints such as reduced mobility due to drug procurement, and social restrictions due to the daily drug regimen. Participants discussed the psychological burden of taking drugs, and the fear of accidental transmission to others, or having their disease status known by others, as well as optimistic feelings about their future due to ART. ART poses a significant drain on individual's economic resources due to related medical costs, and inability to seek seasonal migrant labor due to reduced mobility. CONCLUSION: While China's national free ART program improved the physical health of those surveyed, their social and economic needs were left unaddressed. To improve life outcomes for PLHA, and by extension, the wider Chinese population, quality of life measures should be included when evaluating the success of the ART program. PMID- 22424630 TI - Evaluation of a new real-time PCR assay for detection of Mycoplasma pneumoniae in clinical specimens. AB - OBJECTIVE: To establish and evaluate a real-time PCR assay to detect Mycoplasma pneumoniae (M.pneumoniae) in clinical specimens. METHODS: By analysing the whole p1 gene sequence of 60 M.pneumoniae clinical isolates in Beijing of China, an optimized real-time PCR assay (MpP1) using p1 gene conserved region was designed. The specificity and sensitivity of this assay were evaluated and compared with other two reported assays (RepMp1 and Mp181) using 40 positive and 100 negative clinical specimens. RESULTS: The detection limit of the new assay was 8.1 fg (about 1~3CFU) M.pneumoniae DNA. The sensitivity of MpP1, RepMp1, and Mp181 assays appeared to be 100%, 100%, and 85%, respectively. CONCLUSION: MpP1 assay is suitable for the detection of M.pneumoniae in Chinese clinical specimens. PMID- 22424631 TI - Evaluation of four candidate VNTR Loci for genotyping 225 Chinese clinical Mycobacterium tuberculosis complex strains. AB - OBJECTIVE: To evaluate four candidate variable number tandem repeat (VNTR) loci for genotyping Mycobacterium tuberculosis complex strains. METHODS: Genomic sequences for two M. tuberculosis strains (CCDC5079 and CCDC5180) were generated, and using published sequence data, four candidate VNTR loci were identified. The VNTRs were used to genotype 225 Chinese clinical M. tuberculosis complex strains. The discriminatory power of the VNTRs was evaluated using BioNumerics 5.0 software. RESULTS: The Hunter-Gaston Index (HGI) for BJ1, BJ2, BJ3, and BJ4 loci was 0.634, 0.917, 0.697, and 0.910, respectively. Combining all four loci gave an HGI value of 0.995, thus confirming that the genotyping had good discriminatory power. The HGI values for BJ1, BJ2, BJ3, and BJ4, obtained from Beijing family strain genotyping, were 0.447, 0.878, 0.315, and 0.850, respectively. Combining all four loci produced an HGI value of 0.988 for genotyping the Beijing family strains. We observed unique patterns for M. bovis and M. africanum strains from the four loci. CONCLUSION: We have shown that the four VNTR loci can be successfully used for genotyping M. tuberculosis complex strains. Notably, these new loci may provide additional information about Chinese M. tuberculosis isolates than that currently afforded by established VNTR loci typing. PMID- 22424632 TI - In vitro study of Nucleostemin gene as a potential therapeutic target for human lung carcinoma. AB - OBJECTIVE: Nucleostemin (NS) is a GTP-conjugated protein located in the nucleoli of stem cells and some cancer cells, and maintains cell self-renewal. We aimed to evaluate NS as a potential target for lung carcinoma gene therapy by investigating NS gene expression and its effect on A549 cell proliferation. METHODS: NS mRNA and protein expression in A549, HepG2, SMMC-7721, HeLa, and U251 cells was analyzed by RT-PCR and western blotting following transfection of NS siRNAs and negative control siRNA (NC). The effect on cell proliferation was also analyzed by MTT assays. RESULTS: NS mRNA and protein were both expressed in A549 cells and four other tumor cell lines; the relative expression levels were similar in all five cell lines. The three pairs of NS siRNA, either transfected alone or cotransfected into A549 cells, could effectively inhibit the expression of NS mRNA and protein. Moreover, the interference ratio showed an obvious concentration-dependent relationship. NS siRNA treatment resulted in significant inhibition of A549 cell proliferation by 35.7%. CONCLUSION: NS gene was not only highly expressed but also played an important role in A549 cell proliferation. Thus, targeting of NS may be a promising novel strategy for the treatment of lung carcinoma. PMID- 22424633 TI - Preparation and initial application of a monoclonal antibody specific for a newly discovered conserved linear epitope of rabies virus nucleoprotein. AB - OBJECTIVE: To prepare monoclonal antibodies against a newly discovered and conserved linear epitope of Rabies virus nucleoprotein and to use them in a rabies diagnostic test. METHODS: Synthetic peptide containing the epitope was used as immunogen to prepare hybridoma cell lines by classical hybridoma technology. Anti-peptide monoclonal antibodies produced in ascites of inoculated Balb/c mice were labeled with fluorescein isothiocyanate (FITC) after purification and used in fluorescent antibody test (FAT). RESULTS: Two positive hybridoma cell lines, RVNP-mAb1-CL and RVNP-mAb2-CL, were obtained. RVNP- mAb1-CL produced a higher concentration of monoclonal antibody RVNP-mAb1 in Balb/c ascites. FITC-labeled RVNP-mAb1 showed correct results on certain Rabies virus positive canine brain tissue samples and cells of a small subclone of baby hamster kidney 21 cell line (BSR). CONCLUSION: FITC-labeled RVNP-mAb1 has potential application for laboratory diagnosis of rabies. PMID- 22424634 TI - Identification of dual receptor-binding specific strains of human H5N1 viruses in China. AB - OBJECTIVE: Both the 2, 6 linkage and its topology on target cells are critical for the recognition by human influenza virus. The binding preference of avian flu virus H5N1 HA to the 2, 3-linked sialylated glycans is considered the major factor limiting its efficient infection and transmission in humans. To monitor potential adaptation of H5N1 virus in human population, the surveillance of receptor-binding specificity was undertaken in China. METHODS: The binding specificity of 32 human H5N1 virus strains isolated from 2003 to 2009 was tested by 2, 3-specific sialidase-treated chicken red blood cell (CRBC) agglutination assay and a solid-phase direct binding assay with synthetic sialylglycopolymers. RESULTS: Dual binding preference to 2, 3 and 2, 6-glycans were found in two strains: A/Guangdong/1/06 (A/GD/1/06) and A/Guangxi/1/08 (A/GX/1/08). Though minor effect of short-2, 6-binding was detected in A/GX/1/08 at a low virus titer, both showed high affinity to the oligosaccharide at a high load. Notably both are of the long-2, 6-recognition, with the same topology as that of human H1N1 and H3N2 viruses. CONCLUSION: The findings suggest that human H5N1 virus in China likely acquired the potential human-adaptation ability. Further research and surveillance on receptor-binding specificity of H5N1 viruses are required. PMID- 22424635 TI - An investigation of oxidative DNA damage in pharmacy technicians exposed to antineoplastic drugs in two Chinese hospitals using the urinary 8-OHdG assay. AB - OBJECTIVE: To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS (Pharmacy Intravenous Admixture Service) in two Chinese hospitals. METHODS: Urinary 8-OHdG served as a biomarker. 5-Fluorouracil (5-FU) concentrations in air, masks and gloves were determined. The spill exposure of each PIVAS technician to antineoplastic drugs was investigated. Eighty subjects were divided into exposed group I, II, and control group I, II. RESULTS: 5-FU concentration ratios for gloves and masks in exposed group I were significantly higher than those in exposed group II (P<0.05 or P<0.01). The average urinary 8-OHdG concentrations in exposed group I, control group I, exposed group II, and control group II were 14.69+/-0.93, 10.68+/-1.07, 10.57+/ 0.55, and 11.96+/-0.73 ng/mg Cr, respectively. Urinary 8-OHdG concentration in exposed group I was significantly higher than that in control group I or that in exposed group II (P<0.01). There was a significant correlation between urinary 8 OHdG concentrations and spill frequencies per technician (P<0.01). CONCLUSION: There was detectable oxidative DNA damage in PIVAS technicians exposed to antineoplastic drugs. This oxidative DNA damage may be associated with their spill exposure experience and contamination of their personal protective equipment. PMID- 22424636 TI - Comparative proteomic analysis in left ventricular remodeling following myocardial infarction in rats. AB - OBJECTIVE: Left ventricular remodeling (LVR) following myocardial infarction (MI) is a key pathophysiological process in which MI develops into heart failure. The exact mechanism of LVR remains unclear. We performed differential proteomic analysis on the myocardia of rats with LVR after MI, to explore the mechanism of ventricular remodeling after MI. METHODS: In the LVR group (n = 12), after the anterior descending coronary artery was ligated, the rats were fed for four weeks before the LVR models were established. Rats in the sham-operated group (n = 11) underwent thread-drawing without ligation. The hemodynamic parameters, pathological findings, and proteomics were compared between the two groups. RESULTS: In the LVR group, the left ventricular end-diastolic pressure increased, the maximal left ventricular pressure increase/decrease ratio decreased significantly, and the left ventricular systolic pressure decreased. H-E staining and Masson staining of cardiac muscle tissues of the LVR group showed myocytolysis, disarray, and collagen proliferation. Twenty-one differentially expressed proteins were detected by proteomic analysis. We validated two proteins using western blot analysis. The differentially expressed proteins could be divided into six categories: energy metabolism-related proteins, cytoskeletal proteins, protein synthesis-related proteins, channel proteins, anti-oxidation- related proteins, and immune-related proteins. CONCLUSION: These differentially expressed proteins might play key roles in LVR following MI. PMID- 22424637 TI - Oral bone loss induced by mineral deficiency in a rat model: effect of a synthetic bone mineral (SBM) preparation. AB - Osteoporosis affects the craniofacial and oral structures and has been associated with periodontal bone loss, tooth loss and reduced jaw bone mass. OBJECTIVE: This study aimed to test the therapeutic efficacy of synthetic bone mineral (SBM) in minimizing alveolar bone loss induced by mineral deficiency in a rat model. SBM consists of a calcium carbonate apatite (similar to bone apatite) matrix incorporating magnesium, zinc, and fluoride ions. DESIGN: Thirty female Sprague Dawley rats (2 months old) were randomly distributed into 3 groups (10 rats per group): GA (control), on basic diet; GB, on mineral deficient (MD) diet; and GC, on MD+SBM. The rats were sacrificed after 3 months, the jawbones were isolated and the soft tissues removed. Bone density was determined using X-ray radiography (Faxitron); mandibular cortical width, panoramic mandibular index, and alveolar resorption degree (M/M ratio) using BioquantOsteo; and bone micro-architecture micro-computed tomography and scanning electron microscopy. RESULTS: Compared to control (GA), the rats on MD diet (GB) experienced significant mandibular bone loss while the rats on MD+SBM diet (GC) experienced significantly less bone loss compared to the GB group. CONCLUSION: SBM, administered orally, may have the potential as an osteoporosis therapeutic agent in minimizing or preventing alveolar bone loss induced by mineral deficiency. PMID- 22424638 TI - A new approach for anthelmintic discovery for humans. AB - Natural product-based drug discovery has been deemphasized by the pharmaceutical industry. This situation is discordant with the fact that most people in developing countries rely on traditional medicines derived from local biodiversity for healthcare. Despite economic growth in the past 10 years, Africa remains plagued by parasitic infections, out of reach of eradication. Limited regional funding for drug discovery complicates the situation. Novel models are needed to bring sustainability to local drug discovery programs. This Opinion describes an innovative partnership that promotes local leadership to harness a recombinant yeast-based assay to screen for novel anthelmintic candidates in collections of African natural products. Implementation of this strategy in biodiversity-rich but resource-constrained settings can help build sustainable local capacity for drug discovery. PMID- 22424639 TI - Low plasma levels of L-arginine, impaired intraplatelet nitric oxide and platelet hyperaggregability: implications for cardiovascular disease in depressive patients. AB - BACKGROUND: Major depression (MD) is an independent cardiovascular risk factor, but the exact mechanisms are not clear. In this study we have investigated the intraplatelet L-arginine-nitric oxide (NO) pathway and platelet function in depressive patients. METHODS: Nineteen unmedicated patients with MD (34+/-4years) and 19 control subjects (CS, 34+/-3years) were included. L-[(3)H]-arginine influx, NO synthase (NOS) activity and intracellular cGMP levels were evaluated in platelets, as well as the expression of eNOS, iNOS, arginase and soluble guanylate cyclase (sGC), platelet aggregation and the systemic amino acid profile in MD patients and CS. RESULTS: L-arginine influx (pmol/10(9)cells/min) in platelets was reduced from 46.2+/-9.5 to 20.02+/-2.12 in depression. NOS activity (pmol/10(8) cells) was diminished in MD patients (0.09+/-0.01) compared to CS (0.17+/-0.01). Intracellular cGMP levels were also impaired in MD patients associated with hyperaggregability. Moreover, the concentration of plasma L arginine was reduced by 20% in MD patients. The expression of eNOS, iNOS, arginase II and sGC in platelet lysates was not affected by MD. LIMITATIONS: Small number of patients in the study. CONCLUSIONS: This study has demonstrated an impairment of L-arginine-NO signaling in platelets from MD patients, suggesting a role in platelet activation and cardiovascular events. PMID- 22424640 TI - Potential impact of sorafenib on the survival benefit of liver transplantation for hepatocellular carcinoma. PMID- 22424641 TI - Antiviral therapy and fibrosis progression in patients with mild-moderate hepatitis C recurrence after liver transplantation. A randomized controlled study. AB - BACKGROUNDS/AIMS: We evaluated the effect of antiviral therapy on fibrosis progression in patients with histological features of mild/moderate HCV disease recurrence defined by a Grading score>=4 and Staging score up to 3 (Ishak) at 1 year after liver transplantation. METHODS: Seventy-three consecutive patients with mild/moderate recurrence were randomized either to no treatment or to receive Pegilated-Interferon-alfa-2b and ribavirin for 52 weeks. Liver biopsies obtained at baseline (1 year after transplantation) and 2 years afterwards were evaluated for assessment of disease progression, defined as worsening of at least 2 staging points or progression to stage 4 or higher. RESULTS: As for these two major histological end points there were no statistically significant differences between the 2 groups (36.1% vs. 50%, p=0.34 and 36.1% vs. 38.9%, p=1). Fifteen treated patients (41%) achieved a sustained virological response which was associated with a reduced risk of fibrosis worsening for both endpoints when compared to viremic patients (p=0.04). CONCLUSIONS: Although antiviral-therapy was beneficial in preventing fibrosis progression in patients achieving a sustained virological response, the majority of the overall population of our patients with mild-moderate disease recurrence could not benefit from antiviral therapy either because they either could not be treated or did not respond to treatment (EudraCT number: 2005-005760). PMID- 22424643 TI - [Usefulness of magnetic resonance imaging in the prenatal study of malformations of the face and neck]. AB - Sonography has been the fundamental pillar of fetal diagnosis, and until relatively recently, no other valid and reliable noninvasive technique that could adequately determine fetal morphology was available. However, even after the technological advances in obstetric sonography, is still unable to detect some anomalies. One example of this shortcoming is the morphological study of the face and neck. Owing to the ossification of adjacent structures and interposition of the tongue, sonography is not accurate in the detection of some of the most common anomalies. Enormous advances have been made in fetal magnet resonance imaging since it was first described 25 years ago. The usefulness of this modality as a tool to complement sonography in fetal evaluation is now firmly established. MRI provides useful information about orofacial anatomy, enabling accurate evaluation of both the primary and secondary palates. PMID- 22424644 TI - Piloting an intervention to improve microbiological food safety in Peri-Urban Mali. AB - INTRODUCTION: Diarrhoeal diseases remain a major cause of preventable death among children under five years old in developing countries. Studies related to infant diarrhoea causation have demonstrated a higher level of faecal contamination in weaning foods than in drinking water. Many studies have examined the microbiological quality of such foods, but few of them have resulted in an intervention. The present study builds upon an experiment in which the HACCP approach was applied to preparation of two common weaning foods (moni and fish soup) and used to develop simple hygiene measures which mothers could take in preparing and serving foods to their children, to prevent contamination. METHODS: A randomly selected sample of 60 volunteer mothers was split into two groups of 30, the first receiving messages promoting implementation of the hygiene measures, and the second as a control. Samples of the food were taken in all 60 households at the point where they would have been served to a child. These were examined microbiologically, and physical parameters were measured. The process was repeated after the mothers had received three weeks' training in the preventive measures, and again three months later on an unannounced visit. RESULTS: Before the intervention, thermotolerant coliform (TTC) contamination levels exceeded 100 per gram in 55% of food samples cooled after cooking (prior to child service) and in 86% of samples of food stored prior to child service. After the intervention, the contamination was detected (i.e. >10TTC/g) in less than 17% of food samples cooled (prior to child service) after cooking and in only 4% of food samples reheated after storage and cooled prior to child service. The reduction in faecal contamination was highly significant (P<0.0001). The follow-up visit three months later produced still better results; only 0% to 17% of food samples failed to meet our standard of <10TTC/g. CONCLUSION: The HACCP approach can lead to effective measures for improving home food safety, and is applicable with modest resources for promotion of food hygiene and safety in a low-income community. PMID- 22424645 TI - Hand hygiene in medical students: performance, education and knowledge. AB - BACKGROUND: Despite several guidelines on hand hygiene (HH), compliance especially in physicians is reported to be low which has huge implications for healthcare-associated infections. To evaluate performance of HH, influence of teaching and influence of monitoring the results in medical students, we conducted an observational study. METHODS: Performance of hand disinfection was evaluated in first (N=28), third (N=193) and fifth (N=45) year medical students using fluorescent hand disinfectant. The influence of teaching and information about result control was assessed. The students perception of the impact of HH was also evaluated by a questionnaire. RESULTS: Presence of disinfectant gaps was observed significantly more often in first year medical students compared to third year ones (82% vs, 60%; p=0.02). In additional, > 3 gaps were seen significantly more often in first year medical students compared to fifth year students (36% vs. 9%; p=0.007). Both information about teaching and monitoring the results improved outcome significantly. For example, gaps were present in 92% without information and without teaching, in 70% (RR: 1.3 (1.0-1.6); p=0.003) with information about result control only, and in only 18% (5.1 (3.0-8.5); p=0.0001) after teaching. Notably, the medical students ascribed HH to be of a great importance regardless of their level of education. CONCLUSIONS: Performance of HH could be improved by practical training as evidenced by best HH performance being documented immediately after teaching and a training effect during the course of medical studies was also observed. Thus, we suggest implementing regular education and practical training on HH from early on in the medical studies curricula to improve overall quality of patient care. regular education and practical training on HH from early on in the medical studies curricula to improve overall quality of patient care. PMID- 22424646 TI - Effects of occupational environmental controls and work management on chromosomal damage in dental technicians in Japan. AB - Dental technicians use various materials, particularly metal alloys and monomers and polymers based on methylmethacrylate. Environmental hygiene issues surrounding the work of dental technicians have been recognized. Despite the need for observance of occupational environmental controls and work management, compliance among dental laboratories appears to be low. We evaluated the relationship between genotoxic effects in dental technicians and occupational environmental controls and work management. We used cytokinesis-blocked micronuclei (CB-MN) frequencies in peripheral lymphocytes and metal levels in scalp hair. We also assessed nutritional factors related to anti-genotoxic effects using a self-administered brief diet history questionnaire. Study subjects were 54 male dental technicians and 38 male clerical workers. The parameters on the micronuclei (MN) frequency in dental technicians and clerical workers were analyzed by forward stepwise multiple regression analyses. Age (P < 0.01, beta = 0.561), occupation as a dental technician (P < 0.01, beta = 0.636) and aluminum levels in scalp hair (P < 0.05, beta = 0.213) were risk factors that significantly increased MN frequency. The significant parameters on the MN frequency in dental technicians were observance of hand-washing as work management (P < 0.01, beta = -0.304), work period (P < 0.01, beta = 0.509), germanium levels in scalp hair (P < 0.01, beta = -0.314) and workplace (P < 0.05, beta = 0.235). To avoid genotoxic effects, observance of occupational environmental controls and work management is necessary for dental technicians. PMID- 22424647 TI - The effects of age on symbol comprehension in central rail hubs in Taiwan. AB - The purpose of this study was to investigate the effects of age and symbol design features on passengers' comprehension of symbols and the performance of these symbols with regard to route guidance. In the first experiment, 30 young participants and 30 elderly participants interpreted the meanings and rated the features of 39 symbols. Researchers collected data on each subject's comprehension time, comprehension score, and feature ratings for each symbol. In the second experiment, this study used a series of photos to simulate scenarios in which passengers follow symbols to arrive at their destinations. The length of time each participant required to follow his/her route and his/her errors were recorded. Older adults experienced greater difficulty in understanding particular symbols as compared to younger adults. Familiarity was the feature most highly correlated with comprehension of symbols and accuracy of semantic depiction was the best predictor of behavior in following routes. PMID- 22424648 TI - Update: antiemetics for vomiting associated with acute gastroenteritis in children. PMID- 22424649 TI - Lung carcinoma presenting with pathologic femur fracture and false-positive pregnancy test result. AB - beta-Human chorionic gonadotropin (betahCG) assays are routinely used to test for pregnancy. However, betahCG may be elevated in conditions other than pregnancy. We describe a case of metastatic lung adenocarcinoma presenting with a pathologic femur fracture and a false-positive urine pregnancy test. Lung cancer is the most common nongestational malignancy that produces betahCG among reproductive-age women. Emergency physicians should consider this rare cause of a positive pregnancy test result in women who deny recent sexual intercourse, especially if the patient is older than 40 years, has a history of tobacco use, or presents with respiratory complaints. PMID- 22424650 TI - An overview of the adaptive designs accelerating promising trials into treatments (ADAPT-IT) project. AB - Randomized clinical trials, which aim to determine the efficacy and safety of drugs and medical devices, are a complex enterprise with myriad challenges, stakeholders, and traditions. Although the primary goal is scientific discovery, clinical trials must also fulfill regulatory, clinical, and ethical requirements. Innovations in clinical trials methodology have the potential to improve the quality of knowledge gained from trials, the protection of human subjects, and the efficiency of clinical research. Adaptive clinical trial methods represent a broad category of innovations intended to address a variety of long-standing challenges faced by investigators, such as sensitivity to previous assumptions and delayed identification of ineffective treatments. The implementation of adaptive clinical trial methods, however, requires greater planning and simulation compared with a more traditional design, along with more advanced administrative infrastructure for trial execution. The value of adaptive clinical trial methods in exploratory phase (phase 2) clinical research is generally well accepted, but the potential value and challenges of applying adaptive clinical trial methods in large confirmatory phase clinical trials are relatively unexplored, particularly in the academic setting. In the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) project, a multidisciplinary team is studying how adaptive clinical trial methods could be implemented in planning actual confirmatory phase trials in an established, National Institutes of Health-funded clinical trials network. The overarching objectives of ADAPT-IT are to identify and quantitatively characterize the adaptive clinical trial methods of greatest potential value in confirmatory phase clinical trials and to elicit and understand the enthusiasms and concerns of key stakeholders that influence their willingness to try these innovative strategies. PMID- 22424651 TI - Identifying nontechnical skills associated with safety in the emergency department: a scoping review of the literature. AB - STUDY OBJECTIVE: Understanding the nontechnical skills specifically applicable to the emergency department (ED) is essential to facilitate training and more broadly consider interventions to reduce error. The aim of this scoping review is to first identify and then explore in depth the nontechnical skills linked to safety in the ED. METHODS: The review was conducted in 2 stages. In stage 1, online databases were searched for published empirical studies linking nontechnical skills to safety and performance in the ED. Articles were analyzed to identify key ED nontechnical skills. In stage 2, these key skills were used to generate additional key words, which enabled a second search of the literature to be undertaken and expand on the evidence available for review. RESULTS: In stage 1, 11 articles were retrieved for data analysis and 9 core emergency medicine nontechnical skills were identified. These were communicating, managing workload, anticipating, situational awareness, supervising and providing feedback, leadership, maintaining standards, using assertiveness, and decisionmaking. In stage 2, a secondary search, using these 9 skills and related terms, uncovered a further 21 relevant articles. Therefore, 32 articles were used to describe the main nontechnical skills linked to safety in the ED. CONCLUSION: This article highlights the challenges of reviewing a topic for which the terms are not clearly defined in the literature. A novel methodological approach is described that provides a structured and transparent process for reviewing the literature in emerging areas of interest. A series of literature reviews focusing on individual nontechnical skills will provide a clearer understanding of how the skills identified contribute to safety in the ED. PMID- 22424652 TI - Diagnosis of intussusception by physician novice sonographers in the emergency department. AB - STUDY OBJECTIVE: We investigate the performance characteristics of bedside emergency department (ED) ultrasonography by nonradiologist physician sonographers in the diagnosis of ileocolic intussusception in children. METHODS: This was a prospective, observational study conducted in a pediatric ED of an urban tertiary care children's hospital. Pediatric emergency physicians with no experience in bowel ultrasonography underwent a focused 1-hour training session conducted by a pediatric radiologist. The session included a didactic component on sonographic appearances of ileocolic intussusception, review of images with positive and negative results for intussusceptions, and a hands-on component with a live child model. On completion of the training, a prospective convenience sample study was performed. Children were enrolled if they were to undergo diagnostic radiology ultrasonography for suspected intussusception. Bedside ultrasonography by trained pediatric emergency physicians was performed and interpreted as either positive or negative for ileocolic intussusception. Ultrasonographic studies were then performed by diagnostic radiologists, and their results were used as the reference standard. Test characteristics (sensitivity, specificity, positive and negative predictive values) and likelihood ratios were calculated. RESULTS: Six pediatric emergency physicians completed the training and performed the bedside studies. Eighty-two patients were enrolled. The median age was 25 months (range 3 to 127 months). Thirteen patients (16%) received a diagnosis of ileocolic intussusception by diagnostic radiology. Bedside ultrasonography had a sensitivity of 85% (95% confidence interval [CI] 54% to 97%), specificity of 97% (95% CI 89% to 99%), positive predictive value of 85% (95% CI 54% to 97%), and negative predictive value of 97% (95% CI 89% to 99%). A positive bedside ultrasonographic result had a likelihood ratio of 29 (95% CI 7.3 to 117), and a negative bedside ultrasonographic result had a likelihood ratio of 0.16 (95% CI 0.04 to 0.57). CONCLUSION: With limited and focused training, pediatric emergency physicians can accurately diagnose ileocolic intussusception in children by using bedside ultrasonography. PMID- 22424654 TI - Development and validation of a tool to assess emergency physicians' nontechnical skills. AB - STUDY OBJECTIVE: Nontechnical skills are "the cognitive, social and personal resource skills that complement technical skills, and contribute to safe and efficient task performance." Our research team developed and evaluated the task of developing and validating a behavioral marker system for the observational assessment of emergency physicians' nontechnical skills. METHODS: The development of the tool was divided into 3 phases and used triangulation of data from a number of sources. During phase 1, a provisional assessment tool was developed according to published literature and curricula. Phase 2 used analysis of staff interviews and field observations to determine whether the skill list contained any significant omissions. These studies were also used to identify behavioral markers linked to nontechnical skills in the context of the emergency department (ED) and establish whether skills included in the tool were observable. Phase 3 involved evaluating the content validity index of exemplar behaviors, using a survey of experts. RESULTS: A behavioral marker system was developed that comprised 12 emergency medicine-specific nontechnical skills, grouped into 4 categories. Content validity was assessed with a survey of 148 emergency medicine staff, and 75% of items achieved the recommended content validity index greater than 0.75. Data from the survey enabled further refinement of the behavioral markers to produce a final version of the tool. CONCLUSION: Although further evaluative studies are needed, this behavioral marker system provides a structured approach to the assessment and training of nontechnical skills in the ED. PMID- 22424653 TI - Rapid sequence intubation for pediatric emergency patients: higher frequency of failed attempts and adverse effects found by video review. AB - STUDY OBJECTIVE: Using video review, we seek to determine the frequencies of first-attempt success and adverse effects during rapid sequence intubation (RSI) in a large, tertiary care, pediatric emergency department (ED). METHODS: We conducted a retrospective study of children undergoing RSI in the ED of a pediatric institution. Data were collected from preexisting video and written records of care provided. The primary outcome was successful tracheal intubation on the first attempt at laryngoscopy. The secondary outcome was the occurrence of any adverse effect during RSI, including episodes of physiologic deterioration. We collected time data from the RSI process by using video review. We explored the association between physician type and first-attempt success. RESULTS: We obtained complete records for 114 of 123 (93%) children who underwent RSI in the ED during 12 months. Median age was 2.4 years, and 89 (78%) were medical resuscitations. Of the 114 subjects, 59 (52%) were tracheally intubated on the first attempt. Seventy subjects (61%) had 1 or more adverse effects during RSI; 38 (33%) experienced oxyhemoglobin desaturation and 2 required cardiopulmonary resuscitation after physiologic deterioration. Fewer adverse effects were documented in the written records than were observed on video review. The median time from induction through final endotracheal tube placement was 3 minutes. After adjusting for patient characteristics and illness severity, attending-level providers were 10 times more likely to be successful on the first attempt than all trainees combined. CONCLUSION: Video review of RSI revealed that first attempt failure and adverse effects were much more common than previously reported for children in an ED. PMID- 22424655 TI - Errors of medical interpretation and their potential clinical consequences: a comparison of professional versus ad hoc versus no interpreters. AB - STUDY OBJECTIVE: To compare interpreter errors and their potential consequences in encounters with professional versus ad hoc versus no interpreters. METHODS: This was a cross-sectional error analysis of audiotaped emergency department (ED) visits during 30 months in the 2 largest pediatric EDs in Massachusetts. Participants were Spanish-speaking limited-English-proficient patients, caregivers, and their interpreters. Outcome measures included interpreter error numbers, types, and potential consequences. RESULTS: The 57 encounters included 20 with professional interpreters, 27 with ad hoc interpreters, and 10 with no interpreters; 1,884 interpreter errors were noted, and 18% had potential clinical consequences. The proportion of errors of potential consequence was significantly lower for professional (12%) versus ad hoc (22%) versus no interpreters (20%). Among professional interpreters, previous hours of interpreter training, but not years of experience, were significantly associated with error numbers, types, and potential consequences. The median errors by professional interpreters with greater than or equal to 100 hours of training was significantly lower, at 12, versus 33 for those with fewer than 100 hours of training. Those with greater than or equal to 100 hours of training committed significantly lower proportions of errors of potential consequence overall (2% versus 12%) and in every error category. CONCLUSION: Professional interpreters result in a significantly lower likelihood of errors of potential consequence than ad hoc and no interpreters. Among professional interpreters, hours of previous training, but not years of experience, are associated with error numbers, types, and consequences. These findings suggest that requiring at least 100 hours of training for interpreters might have a major impact on reducing interpreter errors and their consequences in health care while improving quality and patient safety. PMID- 22424656 TI - Hydroxocobalamin and epinephrine both improve survival in a swine model of cyanide-induced cardiac arrest. AB - STUDY OBJECTIVE: To determine whether hydroxocobalamin will improve survival compared with epinephrine and saline solution controls in a model of cyanide induced cardiac arrest. METHODS: Forty-five swine (38 to 42 kg) were tracheally intubated, anesthetized, and central venous and arterial continuous cardiovascular monitoring catheters were inserted. Potassium cyanide was infused until cardiac arrest developed, defined as mean arterial pressure less than 30 mm Hg. Animals were treated with standardized mechanical chest compressions and were randomly assigned to receive one of 3 intravenous bolus therapies: hydroxocobalamin, epinephrine, or saline solution (control). All animals were monitored for 60 minutes after cardiac arrest. Additional epinephrine infusions were used in all arms of the study after return of spontaneous circulation for systolic blood pressure less than 90 mm Hg. A sample size of 15 animals per group was determined according to a power of 80%, a survival difference of 0.5, and an alpha of 0.05. Repeated-measure ANOVA was used to determine statistically significant changes between groups over time. RESULTS: Baseline weight, time to arrest, and cyanide dose at cardiac arrest were similar in the 3 groups. Coronary perfusion pressures with chest compressions were greater than 15 mm Hg in both treatment groups indicating sufficient compression depth. Zero of 15 (95% confidence interval [CI] 0% to 25%) animals in the control group, 11 of 15 (73%; 95% CI 48% to 90%) in the hydroxocobalamin group, and 11 of 15 (73%; 95% CI 48% to 90%) in the epinephrine group survived to the conclusion of the study (P<.001). The proportion of animals with return of spontaneous circulation at 5 minutes was 4 of 15 (27%; 95% CI 10% to 52%), and that of return of spontaneous circulation at 10 minutes was 11 of 15 (73%; 95% CI 48% to 90%) in the 2 treatment groups. Additional epinephrine infusion after return of spontaneous circulation was administered for hypotension in 2 of 11 (18%; 95% CI 4% to 48%) hydroxocobalamin animals and in 11 of 11 (100%; 95% CI 70% to 100%) of the epinephrine animals (P<.001). At 60 minutes, serum lactate was significantly lower in the hydroxocobalamin group compared with the epinephrine group (4.9 [SD 2.2] versus 12.3 [SD 2.2] mmol/L), and the pH was significantly higher (7.34 [SD 0.03] versus 7.15 [SD 0.07]). Serial blood cyanide levels in the hydroxocobalamin group were also lower than that of the epinephrine group from cardiac arrest through the conclusion of the study. CONCLUSION: Intravenous hydroxocobalamin and epinephrine both independently improved survival compared with saline solution control in our swine model of cyanide-induced cardiac arrest. Hydroxocobalamin improved mean arterial pressure and pH, decreased blood lactate and cyanide levels, and decreased the use of rescue epinephrine therapy compared with that in the epinephrine group. PMID- 22424657 TI - Alcohol and drug use disorders among adults in emergency department settings in the United States. AB - STUDY OBJECTIVE: Improving identification and treatment for substance use disorders is a national priority, but data about various drug use disorders encountered in emergency departments (EDs) are lacking. We examine past-year substance use and substance use disorders (alcohol, 9 drug classes) among adult ED users. Prevalences of substance use and substance use disorders among ED nonusers are calculated for reference purposes. METHODS: Using data from the 2007 to 2009 National Surveys on Drug Use and Health, we assessed substance use disorders among noninstitutionalized adults aged 18 years or older who responded to standardized survey questions administered by audio computer-assisted self interviewing methods. RESULTS: Of all adults (N=113,672), 27.8% used the ED in the past year. ED users had higher prevalences than ED nonusers of coexisting alcohol and drug use (15.2% versus 12.1%), drug use (any drug, 16.9% versus 13.0%; marijuana, 12.1% versus 9.7%; opioids, 6.6% versus 4.1%), and alcohol or drug disorders (11.0% versus 8.5%). Among substance users, the ED group on average spent more days using drugs than the non-ED group; ED users manifested higher conditional rates of substance use disorders than ED nonusers (alcohol or drugs, 15.9% versus 11.7%; marijuana, 16.6% versus 13.2%; cocaine, 33.2% versus 22.3%; opioids, 20.6% versus 10.0%; stimulants, 18.6% versus 9.2%; sedatives, 35.0% versus 4.4%; tranquilizers, 12.4% versus 5.2%). Regardless of ED use status, substance-using young adults, men, and less-educated adults showed increased odds of having a substance use disorder. CONCLUSION: Drug use is prevalent and combined with high rates of drug use disorders among drug users treated in the ED. PMID- 22424659 TI - The effect of traditional birth attendant training on maternal and neonatal care. AB - OBJECTIVE: To determine whether traditional birth attendants (TBAs) trained via the "SMART Dai" method were superior to untrained TBAs in knowledge and practice regarding maternal and newborn care. METHODS: In a cluster-randomized trial in the Dera Ghazi Khan District of Punjab, Pakistan, 120 rural communities each with a population of approximately 5000 were randomly assigned to a community-based intervention (CBI) or a health systems intervention (HSI). In the CBI communities, 288 TBAs underwent an innovative 8-day training course on maternal and newborn care, initially evaluated by pre- and post-tests. After an average of 19 months post-training, 277 TBAs, together with 257 comparably chosen untrained TBAs from the HSI communities, were tested and interviewed. Patients from both referred and non-referred deliveries were also interviewed. RESULTS: Characteristics of TBAs in the two groups were similar. The TBAs were evaluated according to various measures of knowledge, skill, and practice (including referral), with patient reports on practice compared with TBA reports. By most measures, trained TBAs outperformed untrained ones, often to significant degrees. CONCLUSION: SMART Dai training seemed to be an important factor in the significant reduction in perinatal mortality in the CBI areas. Properly trained TBAs can substantially contribute to improved delivery outcomes. PMID- 22424658 TI - Nutrient sensing and the circadian clock. AB - The circadian system synchronizes behavioral and physiologic processes with daily changes in the external light-dark cycle, optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24h oscillations of energy storage and utilization. Recent studies indicate that clocks respond to nutrient signals and that a high-fat diet influences the period of locomotor activity under free running conditions, a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relation between metabolic and circadian pathways. Here the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems is highlighted. PMID- 22424660 TI - The use of TachoSil for the prevention of postoperative complications after groin dissection in cases of gynecologic malignancy. AB - OBJECTIVE: To evaluate the effect of TachoSil in preventing postoperative complications after groin dissection performed for primary or recurrent gynecologic malignancy. METHODS: In a case-control analysis, the incidence of postoperative complications-including lymphocyst formation, wound breakdown and/or infection, and chronic lymphedema-was examined among 8 patients who received TachoSil and 16 controls (standard technique) treated for vulvar cancer or recurrent ovarian/breast cancer at San Gerardo Hospital, Monza, Italy, from 2008 to 2011. RESULTS: Thirty-eight inguinal dissections were performed in the 24 patients. Bilateral groin dissection was performed in 14 patients (n=4 in the study group; n=10 in the control group). Patients in the study group had a lower mean daily drainage volume than those in the control group (133 mL [range, 50-356 mL] vs 320 mL [range, 67-472 mL]; P<0.001) and a lower incidence of lymphocyst requiring drainage (25.0% vs 62.5%), cellulitis (12.0% vs 25.0%), and wound infection (0.0% vs 25.0%). CONCLUSION: The use of TachoSil seems to be effective in reducing the rate of postoperative complications after inguinofemoral lymphadenectomy in cases of gynecologic malignancy. PMID- 22424661 TI - Differences in the perception of urgency of cesarean delivery between obstetricians and anesthetists. PMID- 22424662 TI - "Quilting" sutures to prevent hysterectomy in patients with postpartum hemorrhage. PMID- 22424663 TI - A prospective examination of disease management program use by complex cardiac outpatients. AB - BACKGROUND: The use of disease management programs (DMPs) by patients with cardiovascular disease (CVD) is associated with improved outcomes. Although rates of cardiac rehabilitation (CR) use are well established, less is known about other DMPs. The objectives of this study were to describe the degree of DMP utilization by CVD outpatients, and examine factors related to use. METHODS: This study represents a secondary analysis of a larger prospective cohort study. In hospital, 2635 CVD inpatients from 11 hospitals in Ontario Canada completed a survey that assessed factors affecting DMP utilization. One year later, 1803 participants completed a mailed survey that assessed DMP utilization. RESULTS: One thousand seventy-three (59.5%) participants reported using at least 1 DMP. Overall, 951 (52.7%) reported participating in cardiac rehabilitation, and among participants with a comorbid indication, 212 (41.2%) reported attending a diabetes education centre, 28 (25.9%) attended stroke rehabilitation, 35 (12.9%) used a heart failure clinic, and 13 (11.7%) attended a smoking cessation program. A multinomial logistic regression analysis showed that compared with no DMP use, participants that attended 1 or multiple programs were younger, married, diagnosed with a myocardial infarction, less likely to have had a percutaneous coronary intervention and had higher perceptions of personal control over their heart condition. There were few differences between participants that used 1 vs multiple DMPs, however, having diabetes or comorbid stroke significantly increased the likelihood of multiple DMP use. CONCLUSIONS: Approximately 40% of CVD outpatients do not access DMPs. An integrated approach to vascular disease management appears warranted. PMID- 22424664 TI - Whole-body magnetic resonance imaging and prostate cancer metastases: a new gold standard of detection, but does it help us and at what cost? PMID- 22424666 TI - International variation in prostate cancer incidence and mortality rates. AB - CONTEXT: Wide variation exists internationally for prostate cancer (PCa) rates due to differences in detection practices, treatment, and lifestyle and genetic factors. OBJECTIVE: We present contemporary variations in PCa incidence and mortality patterns across five continents using the most recent data from the International Agency for Research on Cancer. EVIDENCE ACQUISITION: PCa incidence and mortality estimates for 2008 from GLOBOCAN are presented. We also examine recent trends in PCa incidence rates for 40 countries and mortality rates for 53 countries from 1985 and onward via join-point analyses using an augmented version of Cancer Incidence in Five Continents and the World Health Organization mortality database. EVIDENCE SYNTHESIS: Estimated PCa incidence rates remain most elevated in the highest resource counties worldwide including North America, Oceania, and western and northern Europe. Mortality rates tend to be higher in less developed regions of the world including parts of South America, the Caribbean, and sub-Saharan Africa. Increasing PCa incidence rates during the most recent decade were observed in 32 of the 40 countries examined, whereas trends tended to stabilize in 8 countries. In contrast, PCa mortality rates decreased in 27 of the 53 countries under study, whereas rates increased in 16 and remained stable in 10 countries. CONCLUSIONS: PCa incidence rates increased in nearly all countries considered in this analysis except in a few high-income countries. In contrast, the increase in PCa mortality rates mainly occurred in lower resource settings, with declines largely confined to high-resource countries. PMID- 22424667 TI - FPGA based system for automatic cDNA microarray image processing. AB - Automation is an open subject in DNA microarray image processing, aiming reliable gene expression estimation. The paper presents a novel shock filter based approach for automatic microarray grid alignment. The proposed method brings up significantly reduced computational complexity compared to state of the art approaches, while similar results in terms of accuracy are achieved. Based on this approach, we also propose an FPGA based system for microarray image analysis that eliminates the shortcomings of existing software platforms: user intervention, increased computational time and cost. Our system includes application-specific architectures which involve algorithm parallelization, aiming fast and automated cDNA microarray image processing. The proposed automated image processing chain is implemented both on a general purpose processor and using the developed hardware architectures as co-processors in a FPGA based system. The comparative results included in the last section show that an important gain in terms of computational time is obtained using hardware based implementations. PMID- 22424668 TI - Interactive development of a CT-based tissue model for ultrasound simulation. AB - The objective of this study was to make an interactive method for development of a tissue model, based on anatomical information in computed tomography (CT) images, for use in an ultrasound simulator for training or surgical pre-planning. The method consisted of (1) comparison of true ultrasound B-mode images with corresponding ultrasound-like images, and (2) modification of tissue properties to decrease the difference between these images. Ultrasound-like images that reproduced many, but not all the properties of corresponding true ultrasound images were generated. The tissue model could be used for real-time simulation of ultrasound-like B-mode images on a moderately priced computer. PMID- 22424669 TI - [Heart failure with preserved ejection fraction: a systemic disorder?]. AB - When the syndrome of heart failure (HF) is due to left ventricular (LV) systolic dysfunction the clinical manifestations and natural history of the syndrome depend primarily on the severity of LV systolic dysfunction. In contrast, when the syndrome is attributed to LV diastolic dysfunction multiple comorbidities are responsible for the clinical manifestations and the natural history of the syndrome. The present review underscores the multifactorial pathogenesis of the syndrome of HF associated with LV diastolic dysfunction that nowadays is more properly referred to as HF with preserved LV ejection fraction (HFpEF) than to diastolic HF. The prognosis is similarly poor whether HF is due to systolic dysfunction or associated with diastolic dysfunction. The cause of death that is commonly non-cardiovascular in HFpEF supports the pathogenic importance of comorbidities in this condition. Hypertension, chronic kidney disease (CKD), diabetes, obesity and sleep disorder breathing are among the most frequent comorbidities in HFpEF. These comorbidities account for the multiple clinical presentations of the syndrome of HFpEF. Limited functional capacity is in HFpEF largely related to the downward spiral between CKD mediated fluid accumulation and LV stiffness as well as altered ventricular-vascular coupling. The diagnosis of HFpEF currently relies on 2D-Doppler echocardiography findings of impaired LV relaxation and increased LV stiffness and to a lesser extent on biomarkers. Owing to both lack of stringent inclusion and exclusion enrollment criteria and mistaken therapeutic target, placebo-controlled randomized therapeutic trials have been so far negative in HFpEF. PMID- 22424670 TI - Peptides for cell-selective drug delivery. AB - The ability to target specific cell types to achieve optimal distribution of therapeutic entities into diseased tissues, while limiting possible adverse off target effects, has long been a goal of many research groups and pharmaceutical organizations. This review focuses on peptidic tissue-specific biomarkers that allow peptides to act as homing devices for specific tissue types or organs, with a focus on homing peptides (HPs) and cell-penetrating homing peptides (CPHPs). These HPs, in addition to promoting cellular uptake, can deliver a variety of cargos (drugs, oligonucleotides and nanoparticles) into cells. Two such peptides that have entered clinical trials are the tumor-homing peptide asparagine-glycine arginine (NGR) (fused to human tumor necrosis factor), which selectively binds CD13, an aminopeptidase that is overexpressed on tumor blood vessels, and cyclo[Arg-Gly-Asp-D-Phe-(NMeVal)] (cRGD, cilengitide), an anti-angiogenic agent that targets the alpha(v)beta(3) and alpha(v)beta(5) integrins. PMID- 22424671 TI - Activation of the replicative DNA helicase: breaking up is hard to do. AB - The precise duplication of the eukaryotic genome is accomplished by carefully coordinating the loading and activation of the replicative DNA helicase so that each replication origin is unwound and assembles functional bi-directional replisomes just once in each cell cycle. The essential Minichromosome Maintenance 2-7 (Mcm2-7) proteins, comprising the core of the replicative DNA helicase, are first loaded at replication origins in an inactive form. The helicase is then activated by recruitment of the Cdc45 and GINS proteins into a holo-helicase known as CMG (Cdc45, Mcm2-7, GINS). These steps are regulated by multiple mechanisms to ensure that Mcm2-7 loading can only occur during G1 phase, whilst activation of Mcm2-7 cannot occur during G1 phase. Here we review recent progress in understanding these critical reactions focusing on the mechanism of helicase loading and activation. PMID- 22424672 TI - Characterization of the volatile organic compounds present in the headspace of decomposing animal remains, and compared with human remains. AB - Human Remains Detection (HRD) dogs can be a useful tool to locate buried human remains because they rely on olfactory rather than visual cues. Trained specifically to locate deceased humans, it is widely believed that HRD dogs can differentiate animal remains from human remains. This study analyzed the volatile organic compounds (VOCs) present in the headspace above partially decomposed animal tissue samples and directly compared them with results published from human tissues using established solid-phase microextraction (SPME) and gas chromatography/mass spectrometry (GC/MS) methods. Volatile organic compounds present in the headspace of four different animal tissue samples (bone, muscle, fat and skin) from each of cow, pig and chicken were identified and compared to published results from human samples. Although there were compounds common to both animal and human remains, the VOC signatures of each of the animal remains differed from those of humans. Of particular interest was the difference between pigs and humans, because in some countries HRD dogs are trained on pig remains rather than human remains. Pig VOC signatures were not found to be a subset of human; in addition to sharing only seven of thirty human-specific compounds, an additional nine unique VOCs were recorded from pig samples which were not present in human samples. The VOC signatures from chicken and human samples were most similar sharing the most compounds of the animals studied. Identifying VOCs that are unique to humans may be useful to develop human-specific training aids for HRD canines, and may eventually lead to an instrument that can detect clandestine human burial sites. PMID- 22424673 TI - Detection of diverse aquatic microbes in blood and organs of drowning victims: first metagenomic approach using high-throughput 454-pyrosequencing. AB - Current 454-pyrosequencing technology enables massive parallel sequencing. We used this technology to investigate the diversity of aquatic microbes in 14 specimens (blood and organs) of two drowning victims and in two water samples taken from the discovery sites. The 16S ribosomal RNA (rRNA) genes of microbes, which are often used to identify species (or genera), have nine highly variable regions (V1-V9), each of which is surrounded by conserved regions. Some parts within the conserved regions are common over domains of microbes, such as between bacteria and algae (16S rRNA genes on algal chloroplast genomes). We therefore simultaneously amplified the target regions (V7 and V8) of various microbes in the blood and organs of drowning victims using PCR with custom-designed primers that were based on the conserved regions. We then exhaustively analyzed the PCR products by pyrosequencing using the Genome Sequencer FLX Titanium system (Roche 454 Life Sciences). This approach identified a wide array of bacteria including cyanobacteria and algae including Bacillariophyceae (diatom), Cryptophyceae, Dictyochophyceae, Chrysophyceae and Trebouxiophyceae in the blood and organs of the victims and water at discovery sites. Our data further indicated that when conventional diatom testing of lungs yielded insufficient evidence of water aspiration, the detection of various exogenous microbes by 454-pyrosequencing is very useful to support a conclusion of death by drowning. To the best of our knowledge, this is the first attempt to use a new generation sequencer to investigate diverse aquatic microbes in the blood and closed organs of drowning victims. PMID- 22424674 TI - Classifying prostate cancer malignancy by quantitative histomorphometry. AB - PURPOSE: Prostate cancer is routinely graded according to the Gleason grading scheme. This scheme is predominantly based on the textural appearance of aberrant glandular structures. Gleason grade is difficult to standardize and often leads to discussion due to interrater and intrarater disagreement. Thus, we investigated whether digital image based automated quantitative histomorphometry could be used to achieve a more standardized, reproducible classification outcome. MATERIALS AND METHODS: In a proof of principle study we developed a method to evaluate digitized histological images of single prostate cancer regions in hematoxylin and eosin stained sections. Preprocessed color images were subjected to color deconvolution, followed by the binarization of obtained hematoxylin related image channels. Highlighted neoplastic epithelial gland related objects were morphometrically assessed by a classifier based on 2 calculated quantitative and objective geometric measures, that is inverse solidity and inverse compactness. The procedure was then applied to the prostate cancer probes of 125 patients. Each probe was independently classified for Gleason grade 3, 4 or 5 by an experienced pathologist blinded to image analysis outcome. RESULTS: Together inverse compactness and inverse solidity were adequate discriminatory features for a powerful classifier that distinguished Gleason grade 3 from grade 4/5 histology. The classifier was robust on sensitivity analysis. CONCLUSIONS: Results suggest that quantitative and interpretable measures can be obtained from image based analysis, permitting algorithmic differentiation of prostate Gleason grades. The method must be validated in a large independent series of specimens. PMID- 22424678 TI - Conservative management vs early surgery for high grade pediatric renal trauma- do nephrectomy rates differ? AB - PURPOSE: Guidelines for management of pediatric high grade renal injuries are currently based on limited pediatric data and algorithms from adults, for whom initial nonoperative management is associated with decreased nephrectomy risk. Using a national database, we compared nephrectomy rates between children with high grade renal injury managed conservatively and those undergoing early surgical intervention. MATERIALS AND METHODS: All children with high grade renal injuries were identified in the National Trauma Data Bank(r). High grade renal injuries were defined as American Association for the Surgery of Trauma grade IV or V renal injuries. After excluding fatalities within 24 hours of hospitalization, 419 pediatric patients comprised our study cohort. A total of 81 patients underwent early (within 24 hours of hospitalization) surgical intervention, while 338 were initially treated conservatively. Using stratified analysis with adjustment for relevant covariates, we compared nephrectomy rates between these groups. RESULTS: Nephrectomy was performed less often in patients treated conservatively (RR 0.24, 95% CI 0.16 to 0.36, adjusted for age, renal injury grade and injury mechanism). The decreased risk of nephrectomy was more marked among children with grade IV vs grade V renal injuries (adjusted RR 0.16, 95% CI 0.08 to 0.23). Multiple procedures were more common in patients initially observed. Of pediatric patients with grade IV and V renal injuries 11% still underwent nephrectomy. CONCLUSIONS: Conservative management of high grade renal injuries is common in children. Although mechanism of injury and renal injury grade impact initial clinical management decisions, the risk of nephrectomy was consistently decreased in children with high grade renal trauma managed conservatively regardless of injury characteristics. PMID- 22424679 TI - Editorial comment. PMID- 22424680 TI - Chyluria. PMID- 22424681 TI - Oncocytoma of the kidney. PMID- 22424683 TI - Re: extraperitoneal laparoscopic millin prostatectomy using finger enucleation: P. L. Chlosta, I. M. Varkarakis, T. Drewa, J. Dobruch, J. Jaskulski, A. A. Antoniewicz and A. Borowka, J Urol 2011; 186: 873-876. PMID- 22424684 TI - Editorial comment. PMID- 22424685 TI - Chronic kidney disease in children with unilateral renal tumor. AB - PURPOSE: In patients who have undergone nephrectomy lower stage chronic kidney disease may develop, which is an independent risk factor for cardiovascular disease and overall mortality. We investigated whether the prevalence of lower stage chronic kidney disease is related to the amount of renal parenchyma excised in children with unilateral renal tumor. MATERIALS AND METHODS: A total of 15 patients treated with nephrectomy and 10 treated with nephron sparing surgery were enrolled at a single academic center. The Kidney Disease Outcomes Quality Initiative guidelines were used to classify patients by chronic kidney disease stage based on estimated glomerular filtration rate values. The Modification of Diet in Renal Disease study equation and Schwartz equation were used in patients older and younger than 17 years, respectively. RESULTS: At a mean followup of more than 12 years 8 patients who had undergone nephrectomy and 1 treated with bilateral nephron sparing surgery presented with stage II chronic kidney disease (estimated glomerular filtration rate 60 to 89 ml/min/1.73 m(2)). Sequential measurements from diagnosis to 12 to 17 years postoperatively showed that stage II chronic kidney disease in patients who had undergone nephrectomy manifested as a negligible postoperative increase in mean +/- SD estimated glomerular filtration rate (75.7 +/- 25.5 vs 79.4 +/- 3.9 ml/min/1.73 m(2), p = 0.6). Five of the 8 patients presented with stage II chronic kidney disease even before nephrectomy. The other 7 patients who had undergone nephrectomy and those treated with nephron sparing surgery presented with a significant postoperative increase in mean +/- SD estimated glomerular filtration rate (81.1 +/- 24 vs 102.3 +/- 3 ml/min/1.73 m(2), p = 0.02, and 88.7 +/- 2 vs 107.4 +/- 14 ml/min/1.73 m(2), p = 0.005, respectively). CONCLUSIONS: A subset of children with unilateral renal tumor presents before and/or after nephrectomy, and not after nephron sparing surgery, with stage II chronic kidney disease, probably due to a reduced renal reserve capacity. Whether patients with preoperative renal dysfunction may benefit from nephron sparing surgery should be studied in a cooperative clinical trial setting. PMID- 22424686 TI - Re: the results of ureteral stenting after ureteroscopic lithotripsy for ureteral calculi: a systematic review and meta-analysis: S. Pengfei, L. Yutao, Y. Jie, W. Wuran, D. Yi, Z. Hao and W. Jia, J Urol 2011; 186: 1904-1909. PMID- 22424688 TI - Evaluation of outcomes in conservatively managed concomitant Type A and B posterolateral corner injuries in ACL deficient patients undergoing ACL reconstruction. AB - INTRODUCTION: There is paucity of literature regarding the outcomes of ACL reconstruction in ACL deficient knees with concomitant Type A and Type B PLC injuries. MATERIALS AND METHODS: A total of 102 patients undergoing isolated ACL reconstruction for an ACL injury were evaluated prospectively in this study. The patients with divided into three groups: group A with isolated ACL injury, group B1 with concomitant Type A PLC injury and group B2 with concomitant Type B PLC injury. The associated PLC injury in all these patients was managed conservatively. Outcome assessment was based on IKDC scores measured preoperatively and at last follow up visits. RESULTS: The mean age of the patients was 25.33 years (16-38 years) with 95 males and seven females. The average follow up was almost 2.5 years (13-46 months). Group A had 88 patients while groups B1 and B2 had six and eight patients respectively. The preoperative IKDC scores were comparable for all the groups. The follow up IKDC scores were similar (statistically insignificant, p value: 0.421) for group A and group B1. Group B2 had poorer follow up IKDC scores as compared to group A and this result was found to be statistically significant (p value: 0.0001). CONCLUSION: Conservative management of a concomitant Type B PLC injury adversely affects the outcomes of ACL reconstruction in these patients. Type A PLC injuries, on the other, do well without surgery and can be left as such even when associated with a concomitant ACL tear. LEVEL OF EVIDENCE: Level 2. PMID- 22424689 TI - Anatomic proximity of the peroneal nerve to the posterolateral corner of the knee determined by MR imaging. AB - BACKGROUND: The pie crusting technique has been extensively used to release the lateral soft tissue in total knee arthroplasty. However, it may place the peroneal nerve at direct injury risk when performed in a valgus knee. The aim of this study was to determine the anatomic proximity of the peroneal nerve to the posterolateral corner of the knee. METHODS: One hundred knees were measured on axial MR images for the proximity of peroneal nerve to the closest edge of the inner surface of joint capsule or the posterolateral corner of proximal tibia at the level of the joint line and the level of the tibial cut respectively. RESULTS: The distance between the peroneal nerve and the closest edge of the inner surface of joint capsule at the level of the joint line was 15.0 +/- 2.6mm (range, 8.5-22.3mm), and the distance between the peroneal nerve and the posterolateral corner of proximal tibia was 14.0 +/- 2.7 mm (range, 8.0-23.2mm). These distances were correlated with the anteroposterior diameter of the soft tissue of the knee, but not correlated with the size of the tibia. CONCLUSIONS: These results suggest that it is safe enough providing that the scalpel blade does not pierce more than 8mm deep. However, patients with smaller legs are at greater risk of direct peroneal nerve injury. PMID- 22424690 TI - Arthroscopic repair of medial patellofemoral ligament avulsion in acute patellar dislocation in skeletally immature patient--a case report. AB - Acute patellar dislocation is a severe injury to the knee and usually manifests with symptoms such as giving way, a sensation of lateral displacement of the patella accompanied by hemarthrosis and tenderness over the medial epicondylar region to palpation. Spontaneous reduction of the patella makes the diagnosis more difficult in initial evaluation. Radiographs often show a small bony avulsion at the medial border of the patella, which may represent an injury to the medial restraints. Magnetic resonance imaging may show a bone bruise on the medial patella, and/or on the lateral femoral condyle. The medial patellofemoral ligament (MPFL) may be avulsed distally, proximally or sustain in interstitial tear. Arthroscopic findings include hematoma and chondral or osteochondral lesions located on the central or medial facet of the patella or on the anterior lateral femoral condyle. We report a case of a patellar avulsion of medial patellofemoral ligament in a skeletally immature patient. PMID- 22424691 TI - Cognitive correlates of "neglect-like syndrome" in patients with complex regional pain syndrome. AB - Patients with complex regional pain syndrome (CRPS) often show distinct neurocognitive dysfunctions, which were initially termed "neglect-like symptoms." So far, particularly the patients' feelings about the affected extremity, motor, and sensory aspects of the "neglect-like symptoms" have been investigated, possibly pointing to a disturbed body schema. Because patients with classical neurological neglect show diminished awareness regarding the perception of their body, as well as of the space around them, our hypothesis was that CRPS patients exhibit some signs of personal neglect and extrapersonal visuospatial problems over and beyond those seen in patients simply suffering from limb pain. We used quantitative sensory testing and motor assessment aimed at detecting motor and sensory loss, a standardized questionnaire calculating a neglect score, and applied a detailed neuropsychological test battery assessing different parietal lobe functions, including visual neglect. We examined 20 CRPS patients and 2 matched control groups, one consisting of healthy subjects and the other one of patients with limb pain other than CRPS. Results show significant higher neglect scores for CRPS patients and the pain control group, but interestingly, CRPS patients and pain patients were indistinguishable. The results of the neuropsychological test battery did not demonstrate systematic variances, which would be indicative of a classical neurological neglect in CRPS patients, even though there were 3 CRPS patients who differed >= 2 SD from the mean of our healthy control group, with poorer results in >= 3 different tests. We assume that the "neglect-like syndrome" in most CRPS patients is different from typical neglect. PMID- 22424692 TI - An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat. AB - Antidepressants are often used for the treatment of neuropathic pain. Clinical studies suggest that the efficacy of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) for neuropathic pain is greater than that of selective 5-HT reuptake inhibitors (SSRIs). In the present study, we determined the efficacy and mechanisms involved in the antihyperalgesic effects of milnacipran, an SNRI, compared with paroxetine, an SSRI, and maprotiline, a selective NA reuptake inhibitor, using a rat model of neuropathic pain. Male Sprague-Dawley rats underwent spinal nerve ligation (SNL), and the withdrawal threshold to paw pressure was measured. Intraperitoneal injection of milnacipran (3-30mg/kg) produced a dose-dependent antihyperalgesic effect. The effect was reversed by intrathecal injection of the alpha(2)-adrenoceptor antagonist idazoxan (30MUg), but not by various 5-HT receptor antagonists. Paroxetine produced an antihyperalgesic effect only at the highest dose tested (10mg/kg). This effect was reversed by intrathecal injection of both idazoxan and ondansetron (30MUg), a 5-HT3 receptor antagonist. Maprotiline produced an antihyperalgesic effect (10 and 30mg/kg), and the effect was reversed by intrathecal idazoxan. In microdialysis studies, NA and 5-HT concentrations in the spinal dorsal horn were increased after injection of either milnacipran or paroxetine, and only NA was increased after maprotiline. Furthermore, the NA content in the spinal cord of SNL rats was greater than that in normal animals. These findings suggest that an increase in NA in the spinal cord plays an important role in the antihyperalgesic effects of not only NA reuptake inhibitors but also SSRIs. PMID- 22424693 TI - Nutrient restriction preserves calcium cycling and mitochondrial function in cardiac myocytes during ischemia and reperfusion. AB - Nutrient restriction (NR) prolongs longevity via enhanced mitochondrial function. We tested the hypothesis that NR enhances resistance to ischemia/reperfusion (IR) arrhythmias via preserved calcium (Ca) cycling and mitochondrial function. We examined the protective effects of NR on regional IR in cultured neonatal rat ventricular myocyte monolayers. Optical mapping of intracellular Ca and mitochondrial membrane potential Deltapsi(m) was performed using Rhod 2-AM and TMRE, respectively. Regional ischemia was mimicked by covering a portion of monolayer with a glass coverslip until loss of Ca propagation, and reperfusion was mimicked by removing the coverslip. NR was mimicked by culture in serum- and glucose-free medium for 24 h. Relative to controls, NR monolayers: (1) sustained Ca oscillations during longer periods of ischemia (19.2 +/- 1.8 min vs 10.4 +/- 1.4 min, p<0.001); (2) had attenuated increases in Ca transient duration (CaD) and time decay constant (Tau) during ischemia; (3) had preserved conduction velocity (CV) during early reperfusion, leading to protection against reperfusion arrhythmias; (4) had minimal "rebound" decreased CaD and Tau during reperfusion; and (5) had no depolarization of Deltapsi(m) during IR. NR attenuates IR arrhythmias via (1) stable calcium cycling and (2) prevention of Deltapsi(m) depolarization during IR. Enhanced mitochondrial resistance to IR arrhythmias may play a role in NR-induced longevity prolongation. PMID- 22424695 TI - Construct validity and test-retest reliability of the walking questionnaire in people with a lower limb amputation. AB - OBJECTIVE: To investigate the construct validity and test-retest reliability of the Walking Questionnaire, a patient-reported measure of activity limitations in walking in people with a lower limb amputation. DESIGN: Cross-sectional study. SETTING: Outpatient department of a rehabilitation center. PARTICIPANTS: People with a lower limb amputation (N=172; mean age +/- SD, 65+/-12y; 71% men; 82% vascular cause) participated in the study, 33 of whom also participated in the reliability study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Construct validity was investigated by testing 11 hypotheses: limitations in walking according to the Walking Questionnaire will be greater in people with a lower limb amputation who (1) are older, (2) have a bilateral amputation, (3) have a higher level of amputation, (4) underwent their rehabilitation treatment in a nursing home, (5) walk less (in terms of time), and (6) walk shorter distances. Furthermore, limitations in walking will be positively related to activity limitations according to the (7) Locomotor Capabilities Index, (8) "distance walked" question on the Prosthetic Profile of the Amputee Questionnaire, (9) Questionnaire Rising and Sitting Down, (10) Climbing Stairs Questionnaire, and (11) Special Interest Group on Amputation Medicine/Dutch Working Group on Amputations and Prosthetics mobility scale. Construct validity was quantified by using the Mann-Whitney U test and Spearman correlation coefficient. Test-retest reliability was assessed with a 3-week interval and quantified using the intraclass correlation coefficient. RESULTS: Construct validity (10 of 11 hypotheses not rejected) and test-retest reliability were good (intraclass correlation coefficient =.73; 95% confidence interval, .43-.88). CONCLUSIONS: The Walking Questionnaire has good construct validity and test retest reliability in people with a lower limb amputation. PMID- 22424696 TI - Adiponectin induces CCL20 expression synergistically with IL-6 and TNF-alpha in THP-1 macrophages. AB - Adiponectin (Ad) is an adipokine secreted from adipocytes. It is reported that Ad has many biological activities. However, its influence on inflammation is controversial. In the present study, we examined the influence of Ad on production of CCL20 from THP-1 macrophages. THP-1 macrophages were prepared from THP-1 monocytes by PMA treatment. THP-1 macrophages were cultured for 24h with Ad, IL-6, or TNF-alpha alone or with combinations of Ad and cytokines. CCL20 mRNA expression was then determined by real-time PCR. Full-length Ad (fAd) slightly but significantly induced CCL20 mRNA expression, and interestingly, co stimulation with fAd and IL-6 or with fAd and TNF-alpha synergistically increased the expression of CCL20 mRNA. We explored the mechanism behind the synergistic effect of fAd and these cytokines. fAd did not affect the expression of receptors for IL-6 and TNF, and IL-6 and TNF-alpha did not increase the expression of the receptor for Ad in THP-1 macrophages. The increased expression of CCL20 by fAd is much higher in THP-1 macrophages compared with THP-1 monocytes. Furthermore, MMP 12 production was increased by IL-6 and TNF-alpha in THP-1 macrophages but it was not detectable in THP-1 monocytes. Treatment of fAd with MMP-12 induced globular Ad (gAd), and the expression of CCL20 in THP-1 macrophages was increased more potently by gAd than by fAd. MMP inhibitor (UK370106) inhibited the expression of CCL20 induced by co-stimulation with fAd and IL-6 or TNF-alpha. In conclusion, gAd played an important role in CCL20 expression, and MMP-12 induced by IL-6 or TNF-alpha was involved in the synergistic effect of fAd and cytokines. PMID- 22424697 TI - Optimization of the algorithms for estimating the ultrasonic attenuation along the propagation path. AB - In this study, we perform statistical analysis on two methods used to estimate the total ultrasound attenuation along the propagation path from the surface of the transducer to a region of interest at a particular depth; namely, the spectral-fit method and the multiple-filter method. We derive mathematical equations for the bias and variance in the attenuation estimates as a function of region of interest (ROI) size, imaging system bandwidth, and number of independent Gaussian filters (for the multiple filter method). We use numerical simulations to validate the mathematical equations and compare the two algorithms. The results show that the variance in the total attenuation coefficient estimates obtained with the two methods are comparable, and that the estimates are unbiased. For the multiple filter method, the optimal number of Gaussian filters is two. PMID- 22424698 TI - Factors distinguishing youth who report self-injurious behavior: a population based sample. AB - OBJECTIVE: To identify factors distinguishing adolescents across 3 groups: no self-harm, nonsuicidal self-injury (NSSI) only, and NSSI and suicide attempt (NSSI + SA). METHODS: Data were from the 2007 Minnesota Student Survey. The sample included 61,330 students in grades 9 and 12. Logistic regression analysis determined factors that best distinguished adolescents who reported NSSI from those who reported no self-harm, and adolescents who reported NSSI + SA. Final models were developed over 3 stages of analysis that tested the importance of variables within risk factor, protective factor, and co-occurring health-risk behavior domains. RESULTS: For male and female subjects, factors that consistently distinguished youth who reported NSSI from those who reported no self-harm included depressive symptoms, hopelessness, physical abuse, less parent connectedness, running away from home, and maladaptive dieting behavior. Factors that distinguished the NSSI + SA group from the NSSI only group for both sexes were a mental health problem, depressive symptoms, hopelessness, physical abuse, and running away from home. Other factors, such as sexual abuse, were significant in models for males or females only. Hopelessness constituted the leading factor to increase the likelihood that youth who self-injured also attempted suicide. CONCLUSIONS: Youth engaging in NSSI experience diverse psychosocial stressors and significant distress. Clinicians and school personnel are well-positioned to offer support to these youth. Furthermore, they can help address NSSI among youth by identifying those who self-injure early, assessing for hopelessness and suicidality, facilitating connections to prosocial adults, addressing maladaptive dieting behavior, and supporting runaway youth. PMID- 22424699 TI - Deciduoid pleural mesothelioma--a rare entity in a young woman. AB - Deciduoid Mesothelioma is a rare variant of epithelioid mesothelioma; it was initially thought that it only occurred in the peritoneum of young women and had nothing to do with asbestos exposure. However, since these early findings it has also been observed in the pleura and the pericardium, with possible association to asbestos. In general the prognosis is poor compared to epithelioid mesothelioma. 45 cases have been reported in the literature up to now, 22 of these were located in the pleural cavity. The authors describe a case of deciduoid pleural mesothelioma in a 40-year-old-woman who presented with right pleuritic chest pain, with no history of asbestos exposure, treated with chemotherapy followed by surgery and who died postoperatively. PMID- 22424700 TI - How are acute care nurse practitioners enacting their roles in healthcare teams? A descriptive multiple-case study. AB - BACKGROUND: In many countries, acute care nurse practitioners contribute to patient care through an expanded scope of practice that includes nursing and medical activities. There have been calls across nations to establish better understanding of how nurse practitioners enact their roles in healthcare teams. The 2006 introduction of cardiology nurse practitioners in Quebec, Canada provides an opportunity to examine this process more closely. OBJECTIVES: The purpose of the study is to understand how nurse practitioners enact the medical and expanded nursing portions of their role in healthcare teams. DESIGN: A descriptive multiple-case study design was used. SETTINGS: The study was conducted in two university-affiliated teaching hospitals in Quebec. DATA SOURCES: Data were collected from March 2009 to May 2009. Data sources included interviews (N=59), field notes, documents, and a time and motion study (N=108 h 53 min) of nurse practitioner activities using a validated observation tool. METHODS: The interviews were conducted individually or in groups. Content analysis was used to analyse the qualitative data. Descriptive statistics were generated for the time and motion study. RESULTS: The clinical role component, including nursing and medical activities, occupied the largest portion of the nurse practitioners' work time. The pace of nurse practitioner work activities was faster in the first half of the workday in response to patient care demands. The enacted nurse practitioner scope of practice was sensitive to the local context, and the needs of team members, patients and families. Nursing and medical leadership, and the transfer of prescriptive authority and decision making autonomy affected how nurse practitioners enacted the medical and expanded nursing portions of their roles. Participants believed the pace of work influenced the nurse practitioners' ability to develop relationships with team members, and enact all the components of their role. CONCLUSIONS: The practitioners' scope of practice changed in response to pressures inside and outside healthcare teams or a lack of healthcare system structures. The study findings appear to be applicable to nurse practitioners working in other specialties, and in other countries. Future research needs to examine how the pace of work affects the nurse practitioners' ability to provide care. PMID- 22424701 TI - Management of displaced fractures of the waist of the scaphoid: meta-analyses of comparative studies. AB - INTRODUCTION: Scaphoid fractures with displacement have a higher incidence of nonunion that can cause pain and reduced movement, strength and function. The aim of this study was to review the evidence available and establish the risk of nonunion associated with management of displaced fractures of the waist of the scaphoid. METHODS: Electronic databases were searched using the Medical Subject Headings (MeSH) controlled vocabulary (scaphoid fractures, AND'd with displaced, or nonunion, or non-healing or cast immobilisation, or plaster or surgery). At present, there are no randomised, controlled trials or studies comparing fixation to plaster cast treatment of displaced fractures of the scaphoid. The search was therefore limited to observational studies of displaced fractures of the scaphoid treated in a plaster cast (non-operative group) or fixed surgically (operative group). The criterion for displacement was limited to gap or step of more than 1 mm. In the non-operative group, we compared the outcome of displaced and undisplaced fractures of the waist of the scaphoid treated in a plaster cast. In the operative group, contingency table analysis was used to calculate the odds ratio of nonunion with plaster treatment compared to surgery. RESULTS: In the non operative group, seven studies were included in a meta-analysis with a total of 1401 scaphoids. Ninety-three percent (1311 scaphoids) of these scaphoid fractures healed in a plaster cast. A total of 207 (15%) of all scaphoid fractures showed displacement of at least 1 mm (gap/step) between fracture fragments. Nonunion was identified in 18% (37/207) of displaced scaphoid fractures treated in a plaster cast. The pooled relative risk of fracture nonunion was 4.4 (95% confidence interval (CI): 2.3-8.7; p=0.00; I(2)=54.3%). In the surgical group, we identified six observational studies in which 157 'displaced' fractures of the scaphoid were surgically fixed. Only two of these fractures did not heal. The odds of nonunion were 17 times higher with plaster cast treatment than surgery. CONCLUSIONS: Displaced fractures of scaphoid have a four times higher risk of nonunion than undisplaced fractures when treated in a plaster cast, and the patients should be advised of this risk. Nonunion is more likely if a displaced fracture of the scaphoid is treated in a plaster cast. PMID- 22424702 TI - Patterns of triangular fibrocartilage complex (TFCC) injury associated with severely dorsally displaced extra-articular distal radius fractures. AB - PURPOSE: The aim of the study was to examine triangular fibrocartilage (TFCC) injury patterns associated with unstable, extra-articular dorsally displaced distal radius fractures. METHODS: Twenty adult patients with an Arbeitsgemeinschaft fur Osteosynthesefragen (AO), type A2 or A3, distal radius fracture with an initial dorsal angulation greater than 20 degrees were included. Nine had a tip fracture (distal to the base) of the ulnar styloid and 11 had no such fracture. They were all openly explored from an ulnopalmar approach and TFCC injuries were documented. Eleven patients also underwent arthroscopy and intra-articular pathology was recorded. RESULTS: All patients had TFCC lesions of varying severity, having an extensor carpi ulnaris subsheath avulsion in common. Eighteen out of 20 also displayed deep foveal radioulnar ligament lesions, with decreasingly dorsal fibres remaining. The extent of this foveal injury could not be appreciated by radiocarpal arthroscopy. CONCLUSIONS: Severe displacement of an extra-articular radius fracture suggests an ulnar-sided ligament injury to the TFCC. The observed lesions concur with findings in a previous cadaver study. The lesions follow a distinct pattern affecting both radioulnar as well as ulnocarpal stabilisers. PMID- 22424703 TI - The impact of wound age on the infection rate of simple lacerations repaired in the emergency department. AB - BACKGROUND: The influence of wound age on the risk of infection in simple lacerations repaired in the emergency department (ED) has not been well studied. It has traditionally been taught that there is a "golden period" beyond which lacerations are at higher risk of infection and therefore should not be closed primarily. The proposed cutoff for this golden period has been highly variable (3 24h in surgical textbooks). Our objective is to answer the following research question: are wounds closed via primary repair after the golden period at increased risk for infection? METHODS: We searched MEDLINE, EMBASE, and other databases as well as bibliographies of relevant articles. We included studies that enrolled ED patients with lacerations repaired by primary closure. Exclusion: (1) delayed primary repair or secondary closure, (2) wounds requiring intra-operative repair, skin graft, drains, or extensive debridement, and (3) grossly contaminated or infected at presentation. We compared the outcome of wound infection in two groups of early versus delayed presentations (based on the cut-offs selected by the original articles). We used "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) criteria to assess the quality of the included trials. RESULTS: 418 studies were identified. Four trials enrolling 3724 patients in aggregate met our inclusion/exclusion criteria. The overall quality of evidence was low. The infection rate in the wounds that presented with delay ranged from 1.4% to 32%. One study with the smallest sample size (only 19 delayed wounds), which only enrolled lacerations to hand and forearm, showed higher rate of infection in patients with delayed (older than 12h) wounds (relative risk of infection: 4.8, 95% confidence interval, 1.9-12.0). The infection rate in delayed wound groups in the remaining three studies was not significantly different. CONCLUSION: The existing evidence does not support the existence of a golden period nor does it support the role of wound age on infection rate in simple lacerations. PMID- 22424704 TI - Guidelines recommendations on care of adult patients receiving home parenteral nutrition: a systematic review of global practices. AB - BACKGROUND & AIMS: Because home parenteral nutrition (HPN) in adult patients can give rise to a variety of complications, good guidance is necessary. To achieve this, clarity and consistency in guidelines are essential. The aim of this review is to identify and compare evidence-based guidelines, and to compile a list of main recommendations, according to their evidence-based grade. METHODS: We searched Medline and the international guideline database for HPN guidelines, performed a content analysis of retrieved guidelines, and evaluated their quality. We then compiled a comparative table of guideline recommendations along with their assigned level of evidence. SUMMARY OF RESULTS: Six systematically developed evidence-based guidelines and one expert opinion-based standard for home care were retrieved. Of these guidelines, two were exclusively devoted to HPN. Although the guidelines generally covered the same topics, most did not provide information on intravenous medication, bone metabolic disease, and indications in patients with malignant disease. Moreover, we found grading discrepancies among various guidelines, as identical recommendations were often labeled with different grades. CONCLUSION: Our comparison of guidelines and standards for HPN revealed substantial differences among recommendations. Identification of these discrepancies and omissions should facilitate the development of more comprehensive and better justified guidelines in the future. PMID- 22424705 TI - Correlation of isokinetic and novel hand-held dynamometry measures of knee flexion and extension strength testing. AB - OBJECTIVES: Describe inter-rater reliability of, and correlations between a novel method of isometric knee extension and flexion and eccentric knee flexion strength using hand-held dynamometry and isokinetic testing for flexion/extension in the knees of athletic participants. Document strength data normalized to the individual's limb muscle mass. DESIGN: Observational and reliability study. METHODS: Inter-rater reliability for each of the hand-held dynamometry measures was established in both legs of 10 volunteers (6 male). During routine annual screening, 216 male professional football (soccer) players were examined using these same measures in addition to performing an isokinetic evaluation of knee flexion and extension strength. Intra-class correlation coefficients for inter rater reliability, Pearson r correlations between hand-held dynamometry and isokinetic dynamometry were calculated. Peak torque, peak torque normalized to: body weight; lean body mass; and lean limb mass were documented. RESULTS: Excellent inter-rater reliability was demonstrated with intra-class correlation2,1 values of 0.90, 0.91, and 0.96, for the eccentric hamstrings, isometric hamstrings, and isometric quadriceps measures respectively. Medium to high correlations (r=0.322-0.617) which were all significant (p<0.001) were found for the comparisons between the hand-held dynamometry and isokinetic measures. CONCLUSIONS: We present 3 novel and reliable methods of examining knee flexion and extension strength using hand-held dynamometry which require less skill and strength on the part of the examiner than previous measures. Correlations between these measures and isokinetic dynamometry are documented. The hand-held dynamometry examinations took less than 4 min per player to conduct and may be useful in clinical practice where isokinetic examination can be difficult to implement. PMID- 22424707 TI - Composition of plastics from waste electrical and electronic equipment (WEEE) by direct sampling. AB - This paper describes a direct analysis study carried out in a recycling unit for waste electrical and electronic equipment (WEEE) in Portugal to characterize the plastic constituents of WEEE. Approximately 3400 items, including cooling appliances, small WEEE, printers, copying equipment, central processing units, cathode ray tube (CRT) monitors and CRT televisions were characterized, with the analysis finding around 6000 kg of plastics with several polymer types. The most common polymers are polystyrene, acrylonitrile-butadiene-styrene, polycarbonate blends, high-impact polystyrene and polypropylene. Additives to darken color are common contaminants in these plastics when used in CRT televisions and small WEEE. These additives can make plastic identification difficult, along with missing polymer identification and flame retardant identification marks. These drawbacks contribute to the inefficiency of manual dismantling of WEEE, which is the typical recycling process in Portugal. The information found here can be used to set a baseline for the plastics recycling industry and provide information for ecodesign in electrical and electronic equipment production. PMID- 22424708 TI - Flap design and mandibular third molar surgery: a split mouth randomized clinical study. AB - The aim of this study was to investigate the effects of two commonly used flap designs (envelope and triangular) used for the removal of mandibular third molars (M3) on postoperative morbidity. 19 patients with bilateral symmetrically impacted mandibular M3 were studied using a split mouth design. Swelling, pain and trismus measures were recorded on days 2, 7 and 14; periodontal indices were recorded on days 7 and 14, one final measure of probing depth on the distal aspect of the mandibular second molar (M2) was taken at the last follow up appointment. Data were analysed using the chi(2) test, the Mann-Whitney U-test and Pearson's correlations. The mean age of the patients was 21.4 +/- 2.3 years (+/- SD). Facial swelling and the reduction in mouth opening were significantly greater in the early postoperative period (P<0.05) with pyramidal flap designs. There was no significant difference in pain scores, plaque accumulation and bleeding on probing indices between the two flap designs (P>0.05). Probing depth was significantly greater with envelope flaps in the early postoperative period (P<0.005). In conclusion, flap design in mandibular M3 surgery has an effect on postoperative recovery. PMID- 22424706 TI - Use of actigraphy for assessment in pediatric sleep research. AB - The use of actigraphs, or ambulatory devices that estimate sleep-wake patterns from activity levels, has become common in pediatric research. Actigraphy provides a more objective measure than parent-report, and has gained popularity due to its ability to measure sleep-wake patterns for extended periods of time in the child's natural environment. The purpose of this review is: 1) to provide comprehensive information on the historic and current uses of actigraphy in pediatric sleep research; 2) to review how actigraphy has been validated among pediatric populations; and 3) offer recommendations for methodological areas that should be included in all studies that utilize actigraphy, including the definition and scoring of variables commonly reported. The poor specificity to detect wake after sleep onset was consistently noted across devices and age groups, thus raising concerns about what is an "acceptable" level of specificity for actigraphy. Other notable findings from this review include the lack of standard scoring rules or variable definitions. Suggestions for the use and reporting of actigraphy in pediatric research are provided. PMID- 22424709 TI - Facial dimensions of Malay children with repaired unilateral cleft lip and palate: a three dimensional analysis. AB - This comparative cross-sectional study assessed the facial surface dimensions of a group of Malay children with unilateral cleft lip and palate (UCLP) and compared them with a control group. 30 Malay children with UCLP aged 8-10 years and 30 unaffected age-matched children were voluntarily recruited from the Orthodontic Specialist Clinic in Hospital Universiti Sains Malaysia (HUSM). For the cleft group, lip and palate were repaired and assessment was performed prior to alveolar bone grafting and orthodontic treatment. The investigation was carried out using 3D digital stereophotogrammetry. 23 variables and two ratios were compared three-dimensionally between both groups. Statistically significant dimensional differences (P<0.05) were found between the UCLP Malay group and the control group mainly in the nasolabial region. These include increased alar base and alar base root width, shorter upper lip length, and increased nose base/mouth width ratio in the UCLP group. There were significant differences between the facial surface morphology of UCLP Malay children and control subjects. Particular surgical procedures performed during primary surgeries may contribute to these differences and negatively affect the surgical outcome. PMID- 22424710 TI - Histone deacetylase inhibition restores cisplatin sensitivity of Hodgkin's lymphoma cells. AB - Increasing evidence suggest that epigenetic mechanisms (e.g. histone modification by histone deacetylases) play a major role in the pathogenesis of Hodgkin's lymphoma (HL). We treated HL cell lines with the histone deacetylase inhibitor vorinostat and investigated the gene expression profile of these cells by using DNA microarrays. Vorinostat inhibited cell proliferation and induced chances in the gene expression profile of HL cells, including down regulation of interleukin 26 and CD30. Vorinostat also increased sensitivity for cisplatin. Our data suggest that the combination of vorinostat and chemotherapy might be an interesting option for patients with chemoresistant HL. PMID- 22424711 TI - Genes encoding transcription factors have self-control: how important is this for cell differentiation? PMID- 22424712 TI - Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL. AB - To identify microRNAs regulated by oncogenic Notch signaling, we performed microarray-based miRNA profiling of T-cell acute lymphoblastic leukemia (T-ALL) cells before and after treatment with gamma-secretase inhibitor (GSI) to block Notch signaling. We show miR-223 levels increase after GSI treatment suggesting that active Notch signaling represses miR-223 expression. We also demonstrate that insulin-like growth factor-1 receptor (IGF1R) is regulated by miR-223 in this context, but observe no apparent effects on cell growth by overexpression or knock-down of miR-223 alone. We conclude that miR-223 contributes to IGF1R regulation, but may act in concert with other genes and/or microRNAs to alter T ALL biology. PMID- 22424713 TI - Combination of azacitidine and ESA in myelodysplastic patients: the need for prospective studies. PMID- 22424714 TI - Direct observation of biological molecules in liquid by environmental phase-plate transmission electron microscopy. AB - We have been developing a combination method for environmental TEM (E-TEM) and phase-plate TEM (P-TEM) that enables direct observations of the structure of biological molecules in aqueous solution. It is clearly demonstrated that the biological molecules in a water layer can be imaged by the combined method without any stain. The spatial resolution obtained in the present study was about 10nm. This should be improved by using energy filtering. The image contrast of the specimen in water was reduced in comparison with that in vacuum. A model calculation that includes the effects of beam broadening, intensity decrease, and background increase caused by scattering from the water layer around the specimen shows that an increase in the thickness of the water layer reduces the contrast, intensity, and resolution of the image. PMID- 22424715 TI - An atomic force microscopy investigation of cyanophage structure. AB - Marine viruses have only relatively recently come to the attention of molecular biologists, and the extraordinary diversity of potential host organisms suggests a new wealth of genetic and structural forms. A promising technology for characterizing and describing the viruses structurally is atomic force microscopy (AFM). We provide examples here of some of the different architectures and novel structural features that emerge from even a very limited investigation, one focused on cyanophages, viruses that infect cyanobacteria (blue-green algae). These were isolated by phage selection of viruses collected from California coastal waters. We present AFM images of tailed, spherical, filamentous, rod shaped viruses, and others of eccentric form. Among the tailed phages numerous myoviruses were observed, some having long tail fibers, some other none, and some having no visible baseplate. Syphoviruses and a podovirus were also seen. We also describe a unique structural features found on some tailed marine phages that appear to have no terrestrial homolog. These are long, 450 nm, complex helical tail fibers terminating in a unique pattern of 3+1 globular units made up of about 20 small proteins. PMID- 22424716 TI - A new linear transfer theory and characterization method for image detectors. Part II: experiment. AB - A novel generalized linear transfer theory describing the signal and noise transfer in image detectors has been developed in Part I (Niermann, this issue, [1]) of this paper. Similar to the existing notion of a point spread function (PSF) describing the transfer of the first statistical moment (the average), a noise spread function (NSF) was introduced to characterize the spatially resolved transfer of noise (central second moment, covariance). Following the theoretic results developed in Part I (Niermann, this issue, [1]), a new experimental method based on single spot illumination has been developed and applied to measure 2D point and 4D noise spread functions of CCD cameras used in TEM. A dedicated oversampling method has been used to suppress aliasing in the measured quantities. We analyze the 4D noise spread with respect to electronic and photonic noise contributions. PMID- 22424717 TI - Genetics of complex diseases: variations on a theme. AB - A complex disease with an inheritable component is polygenic, meaning that several different changes in DNA are the genetic basis for the disease. Such a disease may also be genetically heterogeneous, meaning that independent changes in DNA, i.e. various genotypes, can be the genetic basis for the disease. Each of these genotypes may be characterized by specific combinations of key genetic changes. It is suggested that even if all key changes are found in genes related to the biology of a certain disease, the number of combinations may be so large that the number of different genotypes may be close to the number of patients suffering from the disease. This hypothesis is based on a study of bipolar disorder. PMID- 22424718 TI - Inactivation of stable viruses in cell culture facilities by peracetic acid fogging. AB - Looking for a robust and simple method to replace formaldehyde fumigation for the disinfection of virus-handling laboratories and facilities, we tested peracetic acid fogging as a method to inactivate stable viruses under practical conditions. Peracetic acid/hydrogen peroxide (5.8%/27.5%, 2.0 mL/m3) was diluted in sufficient water to achieve >= 70% relative humidity and was vaporized as <10 MUm droplets in a fully equipped 95 m3 laboratory unit. High titers of reovirus 3, MVM parvovirus and an avian polyomavirus were coated on frosted glass carriers and were exposed to the peracetic acid fog in various positions in the laboratory. After vaporization, a 60 min exposure time, and venting of the laboratory, no residual virus was detected on any of the carriers (detection limit <1 infectious unit/sample volume tested). The log reduction values were 9.0 for reovirus, 6.4 for MVM parvovirus, and 7.65 for the polyomavirus. After more than 10 disinfection runs within 12 months, no damage or functional impairment of electrical and electronic equipment was noted. PMID- 22424719 TI - Diagnosis of congenital cervical cysts using carcinoembryonic antigen levels in cyst fluid. AB - OBJECTIVE: To investigate whether carcinoembryonic antigen (CEA) levels in the fluid of median or lateral cervical cysts can improve diagnosis. METHODS: Cyst fluid CEA levels in 10 cases of median cervical or lateral cervical cysts based on pathological diagnoses (congenital cervical cyst group) were measured. These results were compared with the CEA levels of the control group comprising 10 cases of other head and neck cyst disorders. RESULTS: The CEA levels in nine out of ten cases in the congenital cervical cyst group were >=10,000ng/mL. The CEA level in the remaining case was 8290ng/mL. In contrast, the CEA levels were low in the control group (>1000ng/mL). The optimal cut-off level between these groups was 8290ng/mL in the receiver operating characteristic curve (p<0.01). CONCLUSION: Cyst fluid CEA levels may assist in the diagnosis of median and lateral cervical cysts. PMID- 22424720 TI - Salivary gland carcinomas of the larynx: a national study in Denmark. AB - OBJECTIVE: Salivary gland carcinomas of the larynx are rare. The purpose of this study is to present a national series of laryngeal salivary gland carcinoma patients and to bring a review of recent literature. METHODS: By merging The Danish Cancer Registry, The National Pathology Registry and The National Patient Registry all registered patients with laryngeal salivary carcinomas diagnosed from 1990 to 2007 were identified. The histological slides were reviewed and data concerning age, sex, symptoms, topography, histology, treatment and outcome were registered. Based on a supplemented PubMed search a review of literature from 1991 to 2010 was performed. RESULTS: Six Danish patients with a malignant salivary gland tumor in the larynx were identified resulting in an incidence of 0.001/100,000 inhabitants/year. Four had adenoid cystic carcinoma and two a mucoepidermoid carcinoma. All patients were male. The patients were treated with surgery and/or radiotherapy. Three patients had recurrent disease. One died of the primary disease and one died of other causes. Four are alive with no evidence of disease. Merging of actual study group with patients from recent literature resulted in 83 cases. The male vs. female ratio was 2:1, the most common location was the supraglottic region (52%) and the most predominant histological subtypes were adenoid cystic carcinoma (46%), mucoepidermoid carcinoma (35%) and adenocarcinoma NOS (12%). CONCLUSION: Laryngeal salivary gland carcinoma is a rare disease with a male predominance and most often localized in the supraglottic region. Data concerning treatment and outcome are scarce, but primary surgery with utmost focus on free surgical margins is the treatment of choice. Recurrences are observed later than ten years after primary treatment and a long follow up time is advocated. PMID- 22424721 TI - Nevirapine-based therapy after suppression: can we switch? PMID- 22424722 TI - Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial. AB - BACKGROUND: Protease-inhibitor-based treatment is recommended as first-line for infants infected with HIV who have been previously exposed to nevirapine prophylaxis. However, long-term use poses adherence challenges, is associated with metabolic toxic effects, restricts second-line options, and is costly. We present the long-term outcomes of switching nevirapine-exposed children to nevirapine-based treatment after effective suppression of virus replication with a protease-inhibitor-based regimen. METHODS: We did a randomised trial to compare long-term viral suppression with nevirapine-based versus protease-inhibitor-based (ritonavir-boosted lopinavir) treatment in children who had achieved suppression with protease-inhibitor-based treatment. Randomisation (1:1) was by cohort blocks of variable size between eight and 12. Eligible children were younger than 24 months who were previously exposed to nevirapine for prevention of mother-to child transmission, and achieved virological suppression of less than 400 copies per mL when treated with the regimen based on ritonavir-boosted lopinavir in Johannesburg, South Africa. We gave all drugs as liquids and adjusted doses at each visit in accordance with growth. We continued follow-up for a minimum of 90 weeks and maximum of 232 weeks after randomisation. We quantified HIV RNA every 3 months. Our primary endpoint was any viraemia greater than 50 copies per mL. Our analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00117728. FINDINGS: We followed up the children for a median of 156 weeks and there were three deaths in each group. Children in the switch group (Kaplan-Meier probability 0.595) were less likely to experience non suppression greater than 50 copies per mL than in the control group (0.687; p=0.01) and had better CD4 and growth responses initially after switching (52 children in the switch group vs 66 control group met this endpoint). By 156 weeks after randomisation, more children had virological failure--which we defined as confirmed viraemia of more than 1000 copies per mL--in the switch group (22 children) than in the control group (ten children; p=0.009). We detected all 22 failures in the switch group by 52 weeks compared with five in the control group. Virological failure was related to non-adherence and pretreatment drug resistance. In children without pretreatment drug resistance, we did not identify a significant difference in virological failure between the switch (Kaplan-Meier probability 0.140) and control (0.095) groups (p=0.34; seven failures in the switch group vs five in the control group). Children in the switch group were significantly more likely to develop grade 1-3 alanine aminotransferase abnormalities over the duration of follow-up. INTERPRETATION: Viral-load testing through 52 weeks can identify all children likely to fail this protease-inhibitor switch strategy. Switching children once suppressed to a nevirapine-based regimen might be a valuable treatment option if adequate viral-load monitoring can be done. FUNDING: National Institutes of Child Health and Human Development and Secure the Future Foundation. PMID- 22424723 TI - Evaluation of the prenatally diagnosed mass. AB - With the advent of advanced imaging technologies, the field of prenatal diagnosis and counseling has grown rapidly. The use of fetal ultrasound and ultrafast magnetic resonance imaging has allowed for prenatal identification of structural anomalies as well as neoplasm. The differential diagnosis of a fetal mass is dependent upon its location and the tissue characteristics of the mass on imaging. The use of amniocentesis for chromosomal analysis and genetic testing for known tumor-related genetic abnormalities may aid in further refining the diagnosis. Herein we describe a general diagnostic algorithm for fetal masses based upon their location within the body and how the appropriate diagnostic modalities may be applied in the clinical setting. PMID- 22424724 TI - Cathepsin S dominates autoantigen processing in human thymic dendritic cells. AB - The interaction of developing thymocytes with peptide-MHC complexes on thymic antigen presenting cells (APC) is crucial for T cell development, both for positive selection of "useful" thymocytes as well as negative selection of autoreactive thymocytes to prevent autoimmunity. The peptides presented on MHC II molecules are generated by lysosomal proteases such as the cathepsins. At the same time, lysosomal proteases will also destroy other potential T cell epitopes from self-antigens. This will lead to a lack of presentation on negatively selecting thymic antigen presenting cells and consequently, escape of autoreactive T cells recognizing these epitopes. In order to understand the processes that govern generation or destruction of self-epitopes in thymic APC, we studied the antigen processing machinery and epitope processing in the human thymus. We find that each type of thymic APC expresses a different signature of lysosomal proteases, providing indirect evidence that positive and negative selection of CD4(+) T cells might occur on different sets of peptides, in analogy to what has been proposed for CD8(+) T cells. We also find that myeloid dendritic cells (DC) are more efficient in processing autoantigen than plasmacytoid DC. In addition, we observed that cathepsin S plays a central role in processing of the autoantigens myelin basic protein and proinsulin in thymic dendritic cells. Cathepsin S destroyed a number of known T cell epitopes, which would be expected to result in lack of presentation and consequently, escape of autoreactive T cells. Cathepsin S therefore appears to be an important factor that influences selection of autoreactive T cells. PMID- 22424725 TI - Primary leptomeningeal medulloblastoma: a rare case. PMID- 22424726 TI - Headaches related to psychoactive substance use. AB - AIM: To investigate a possible association between headache and psychoactive substance use. METHODS: 1055 psychoactive substance abusers were consecutively admitted. All patients filled out a detailed headache questionnaire and 1015 patients were included. RESULTS: Twenty seven percent of patients reported having headache. Eighteen percent of patients reported having headache attributed to a substance or its withdrawal and 1.4% had unclassified headache. The most commonly used substances were cannabis (80.5%), alcohol (74.6%), methylamphetamine (18.7%), benzodiazepine (10.4%), volatile solvent (5.8%), cocaine (4.4%), heroin (2.1%), opioids (0.5%), and other substances (1.7%). Fifteen patients reported that onset of headache occurred prior to onset of substance use, while 94.5% had headaches occurred after substance abuse. A higher incidence of headache was found in the benzodiazepine, methylamphetamine, cocaine, heroin, volatile solvent abusers. Seventy-eight percent of headache patients have never sought help from a physician despite the severity and frequency of headache. CONCLUSIONS: In our study, the prevalence of headache among all psychoactive substance abusers was 26.9%. Although this is one-group study without any comparison with non-addict population and associational data must be interpreted with caution, the results of this study indicate a possible relationship may exist between headache and substance use since 94.5% of substance users described headaches after the onset of substance use. The younger start and the longer duration of cannabis use caused the higher incidence of headache, but this correlation was not observed in other substance use. Migraine was far more prevalent in the abusers than in previously reported community populations. PMID- 22424727 TI - Fourth ventricle glioblastoma. PMID- 22424728 TI - Longitudinal myelitis caused by visceral larva migrans associated with Toxocara cati infection: case report. PMID- 22424729 TI - Development of an automated system to classify retinal vessels into arteries and veins. AB - There are some evidence of the association between the calibre of the retinal blood vessels and hypertension. Computer-assisted procedures have been proposed to measure the calibre of retinal blood vessels from high-resolution photopraphs. Most of them are in fact semi-automatic. Our objective in this paper is twofold, to develop a totally automated system to classify retinal vessels into arteries and veins and to compare the measurements of the arteriolar-to-venular diameter ratio (AVR) computed from the system with those computed from observers. Our classification method consists of four steps. First, we obtain the vascular tree structure using a segmentation algorithm. Then, we extract the profiles. After that, we select the best feature vectors to distinguish between veins and arteries. Finally, we use a clustering algorithm to classify each detected vessel as an artery or a vein. Our results show that compared with an observer-based method, our method achieves high sensitivity and specificity in the automated detection of retinal arteries and veins. In addition the system is robust enough independently of the radii finally chosen, which makes it more trustworthy in its clinical application. We conclude that the system represents an automatic method of detecting arteries and veins to measure the calibre of retinal microcirculation across digital pictures of the eye fundus. PMID- 22424730 TI - Adaptive blood glucose control for intensive care applications. AB - Control of blood glucose concentration for patients in intensive care units (ICUs) has been demonstrated to be beneficial in reducing mortality and the incidence of serious complications, for both diabetic and non-diabetic patients. However, the high degree of variability and uncertainty characterizing the physiological conditions of critically ill subjects makes automated glucose control quite difficult; consequently, traditional, nurse-implemented protocols are widely employed. These protocols are based on infrequent glucose measurements, look-up tables to determine the appropriate insulin infusion rates, and bedside insulin administration. In this paper, a novel automatic adaptive control strategy based on frequent glucose measurements and a self-tuning control technique is validated based on a simulation study for 200 virtual patients. The adaptive control strategy is shown to be highly effective in controlling blood glucose concentration despite the large degree of variability in the blood glucose response exhibited by the 200 simulated patients. PMID- 22424731 TI - Application of step-wise gradient high-performance counter-current chromatography for rapid preparative separation and purification of diterpene components from Pseudolarix kaempferi Gordon. AB - In general, simultaneously separation and purification of components with a broad polarity range from traditional Chinese medicine (TCM) is a challenge by an ordinary high-speed counter-current chromatography (HSCCC) method. In this paper, we describes a rapid and efficient separation method of combining three-step gradient elution and two-step flow-rate gradient elution using high-performance counter-current chromatography (HPCCC) to separate 8 diterpene compounds simultaneously within 80 min in a single run from the alcohol extract of Pseudolarix kaempferi Gordon. This separation process produced 166 mg pseudolaric acid B O-beta-d-glucopyranoside (PABGly), 152 mg pseudolaric acid C (PAC), 8 mg deacetylpseudolaric acid A (deacetylPAA), 5 mg pseudolaric acid A O-beta-d glucopyranoside (PAAGly), 484 mg pseudolaric acid B (PAB), 33 mg pseudolaric acid B methyl ester (PAB methyl ester), 10mg pseudolaric acid A (PAA) and 18 mg pseudolaric acid H (PAH) from 1.0 g crude sample with purities of 98.6%, 99.6%, 92.3%, 92.2%, 99.2%, 99.4%, 98.3%, 91.0%, respectively. Our study indicates that the suitable combination of step-wise gradient elution and flow-rate gradient elution using HPCCC is an effective strategy to separate complex components from natural products. PMID- 22424732 TI - Pareto-optimality study into the comparison of the separation potential of comprehensive two-dimensional liquid chromatography in the column and spatial modes. AB - The expected performance of spatial ("flat-bed") two-dimensional liquid chromatography ((x)LC*(x)LC) has been calculated using the Pareto-optimality strategy. This approach allowed different objectives (total peak capacity, total analysis time, and total dilution) to be considered simultaneously and to establish optimal parameters (pressure drop, particle size, bed length, and initial spot size). The performance of spatial two-dimensional chromatographic systems was compared with that of conventional on-line, real-time two-dimensional column-liquid-chromatography systems ((t)LC*(t)LC). The potential gain in peak capacity and/or analysis time of the spatial configuration was confirmed. By restricting the spatial parameters to realistic chromatographic conditions (limiting the stress, as counterbalance for the pressure drop through the sorbent bed, to 2500 kg) it was found that (x)LC*(x)LC is attractive for very fast analysis of complex samples, rather than for extremely efficient separations. For example, a peak capacity of 780 may be achieved in only 2.7 min using a 100*100 mm sorbent bed of a quality currently encountered thin-layer chromatography. Furthermore, if beds can be packed as efficiently as contemporary columns, the predicted peak capacity increases to around 1000, corresponding to a peak production rate of about 6.3 peaks/s. Possibilities to boost the performance of (x)LC*(x)LC further are briefly discussed. Unless we can overcome the severe stress requirements of high-performance (x)LC*(x)LC, conventional (t)LC*(t)LC may be more amenable to very complex separations, thanks to the very high peak capacities. However, (t)LC*(t)LC separations will require long analysis times (e.g. 10,000 peaks in 37 h, corresponding to 0.075 peaks/s at a pressure drop of 40 MPa). The best trade-off between total peak capacity, total analysis time, and total dilution under restricted (realistic) conditions was obtained using high pressures, small chromatographic beds, small particles, and relatively large sample spots. PMID- 22424733 TI - Therapeutic education and intermittent self-catheterization: recommendations for an educational program and a literature review. AB - PURPOSE: To review the literature and to clarify the recommendations for therapeutic education programs for intermittent self-catheterization. MATERIALS AND METHODS: The literature on Medline, Pubmed, and Cochrane Library, with specific keywords, as well as the recommendations based on expert consensus. RESULTS: Clean intermittent self-catheterization (CICS) is the gold standard for managing chronic urinary retention, which allows the patients to improve their quality of life and to reduce the complications of upper urinary tract infections. Patient education needs to have a structured procedure in order to evaluate the ability to understand, accept and perform CISC. CONCLUSION: Teaching self-catheterization is now well known; nevertheless, the effectiveness of CISC educational therapeutic programs remains to be demonstrated. PMID- 22424734 TI - Lysophosphatidic acid causes endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells. AB - AIM: The objective of this study was to determine the effects of lysophosphatidic acid (LPA) on endothelial functions and molecular alternations in both porcine coronary arteries and human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: The vessel rings and HCAECs were treated with clinically relevant concentrations of LPA for different times. Vasomotor reactivity was studied with a myograph tension system. LPA (10 and 50 MUM) treatment for the vessel rings significantly reduced endothelium-dependent vasorelaxation in response to bradykinin (*10(-5)M) by 32% and 49%, respectively, compared with the control (P<0.05). LPA decreased endothelial nitric oxide synthase (eNOS) mRNA and immunoreactivity levels in the vessel rings. In HCAECs, LPA reduced eNOS mRNA, phospho-eNOS and total eNOS protein levels. In addition, superoxide anion levels in LPA-treated vessel rings and HCAECs were significantly increased by lucegenin enhanced chemiluminescence assay and dihydroethidium staining, respectively. Mitochondrial membrane potential and ATP content in LPA-treated HCAECs were substantially decreased. The mRNA levels of reactive oxygen species generating enzymes NOX4 and p40(phox) were increased, while endogenous antioxidant enzyme superoxide dismutase 1 was decreased in response to LPA treatment in HCAECs. Furthermore, exogenous antioxidant molecule selenomethionine (SeMet) effectively reversed these LPA-induced effects in both porcine coronary arteries and HCAECs. CONCLUSIONS: LPA causes endothelial dysfunction by a mechanism associated with decreased eNOS expression and increased oxidative stress in porcine coronary arteries and HCAECs. PMID- 22424735 TI - Replication of murine coronavirus requires multiple cysteines in the endodomain of spike protein. AB - A conserved cysteine-rich motif located between the transmembrane domain and the endodomain is essential for membrane fusion and assembly of coronavirus spike (S) protein. Here, we proved that three cysteines within the motif, but not dependent on position, are minimally required for the survival of the recombinant mouse hepatitis virus. When the carboxy termini with these mutated motifs of S proteins were respectively introduced into a heterogeneous protein, both incorporation into lipid rafts and S-palmitoylation of these recombinant proteins showed a similar quantity requirement to cysteine residues. Meanwhile, the redistribution of these proteins on cellular surface indicated that the absence of the positively charged rather than cysteine residues in the motif might lead the dramatic reduction in syncytial formation of some mutants with the deleted motifs. These results suggest that multiple cysteine as well as charged residues concurrently improves the membrane-associated functions of S protein in viral replication and cytopathogenesis. PMID- 22424736 TI - Stress-activated protein kinases are involved in porcine reproductive and respiratory syndrome virus infection and modulate virus-induced cytokine production. AB - The present study examined the role of the p38 MAPK and JNK pathways during PRRSV infection in immortalized porcine alveolar macrophage (PAM) cells. Infection with PRRSV was found to progressively activate p38 and JNK1/2 up to 36 h postinfection and then their phosphorylation levels dramatically decreased to baseline at 48 h postinfection. In contrast, UV-inactivated PRRSV failed to trigger phosphorylation of these SAPKs, indicating that the post-entry process is responsible for their activation. Independent treatment of cells with a selective p38 or JNK inhibitor markedly impaired PRRSV infection, resulting in significant reduction in synthesis of viral genomic and subgenomic RNAs, viral protein expression, and progeny virus production. Notably, cytokine production in PAM cells infected with PRRSV was shown to be altered by inhibiting these SAPKs. Altogether, our data suggest that the p38 and JNK signaling pathways play pivotal roles in PRRSV replication and may regulate immune responses during virus infection. PMID- 22424737 TI - V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc. AB - HIV-1 develops resistance to CCR5 antagonists such as Maraviroc (MVC) and Vicriviroc (VVC) both in vitro and in vivo, with most changes arising in the gp120 V3 region. Both compounds bind to the same hydrophobic cavity in CCR5 in subtly different ways. Here, we investigated which V3 sequence changes are most associated with MVC and VVC resistance and how they affect the interaction between gp120 and the CCR5 NT. We found that VVC- and MVC-selected amino acid changes map to different V3 locations and involve residues that interact with the CCR5 NT in different ways. Changes in VVC-selected, but not MVC-selected, variants often involve charged residues. Although the overall V3 charge tends not to change, the introduction or removal of charged residues at specific positions affects the local electrostatic potential and could have structural and functional implications. In summary, VVC and MVC trigger the evolution of distinct HIV-1 resistance patterns in V3. PMID- 22424738 TI - Pearson syndrome: unique endocrine manifestations including neonatal diabetes and adrenal insufficiency. AB - PURPOSE: Pearson syndrome is a very rare metabolic disorder that is usually present in infancy with transfusion dependent macrocytic anemia and multiorgan involvement including exocrine pancreas, liver and renal tubular defects. The disease is secondary to a mitochondrial DNA deletion that is variable in size and location. Endocrine abnormalities can develop, but are usually not part of the initial presentation. We report two patients who presented with unusual endocrine manifestations, neonatal diabetes and adrenal insufficiency, who were both later diagnosed with Pearson syndrome. METHODS: Medical records were reviewed. Confirmatory testing included: mitochondrial DNA deletion testing and sequencing of the breakpoints, muscle biopsy, and bone marrow studies. RESULTS: Case 1 presented with hyperglycemia requiring insulin at birth. She had several episodes of ketoacidosis triggered by stress and labile blood glucose control. Workup for genetic causes of neonatal diabetes was negative. She had transfusion dependent anemia and died at 24 months due to multisystem organ failure. Case 2 presented with adrenal insufficiency and anemia during inturcurrent illness, requiring steroid replacement since 37 months of age. He is currently 4 years old and has mild anemia. Mitochondrial DNA studies confirmed a 4.9 kb deletion in patient 1 and a 5.1 kb deletion in patient 2. CONCLUSION: The patients reported highlight the importance of considering mitochondrial DNA disorders in patients with early onset endocrine dysfunction, and expand the knowledge about this rare mitochondrial disease. PMID- 22424739 TI - Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. AB - BACKGROUND: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation with highly variable biochemical, genetic, and clinical characteristics. SCADD has been associated with accumulation of butyryl-CoA byproducts, including butyrylcarnitine (C4), butyrylglycine, ethylmalonic acid (EMA), and methylsuccinic acid (MS) in body fluid and tissues. Differences in genotype frequencies have been shown between patients diagnosed clinically versus those diagnosed by newborn screening. Moreover, while patients diagnosed clinically have a variable clinical presentation including developmental delay, ketotic hypoglycemia, epilepsy and behavioral disorders, studies suggest patients diagnosed by newborn screening are largely asymptomatic. Scant information is published about the biochemical, genetic and clinical outcome of SCADD patients diagnosed by newborn screening. METHODS: We collected California newborn screening, follow-up biochemical levels, and ACADS mutation data from September, 2005 through April, 2010. We retrospectively reviewed available data on SCADD cases diagnosed by newborn screening for clinical outcomes. RESULTS: During the study period, 2,632,058 newborns were screened and 76 confirmed SCADD cases were identified. No correlations between initial C4 value and follow-up biochemical markers (C4, EMA or MS levels) were found in the 76 cases studied. We found significant correlation between urine EMA versus MS, and correlation between follow-up C4 versus urine EMA. Of 22 cases where ACADS gene sequencing was performed: 7 had two or more deleterious mutations; 8 were compound heterozygotes for a deleterious mutation and common variant; 7 were homozygous for the common variant c.625G>A; and 1 was heterozygous for c.625G>A. Significant increases in mean urine EMA and MS levels were noted in patients with two or more deleterious mutations versus mutation heterozygotes or common polymorphism homozygotes. Clinical outcome data was available in 31 patients with follow-up extending from 0.5 to 60 months. None developed epilepsy or behavioral disorders, and three patients had isolated speech delay. Hypoglycemia occurred in two patients, both in the neonatal period. The first patient had concomitant meconium aspiration; the other presented with central apnea, poor feeding, and hypotonia. The latter, a c.625G>A homozygote, has had persistent elevations in both short- and medium chain acylcarnitines; diagnostic workup in this case is extensive and ongoing. CONCLUSIONS: This study examines the largest series to date of SCADD patients identified by newborn screening. Our results suggest that confirmatory tests may be useful to differentiate patients with common variants from those with deleterious mutations. This study also provides evidence to suggest that, even when associated with deleterious mutations, SCADD diagnosed by newborn screening presents largely as a benign condition. PMID- 22424740 TI - Hellenic National Authority of Medically Assisted Reproduction. PMID- 22424741 TI - Thermoluminescence of zirconium oxide nanostructured to mammography X-ray beams. AB - In the present work thermoluminescent (TL) response of zirconium oxide (ZrO2) nanostructured induced by mammography X-ray radiation was investigated. Measurements were made of the response per unit air kerma of ZrO2 with mammography equipment parameters (semiautomatic exposure control, 24 kVp and 108 mAs). The calibration curves were obtained by simultaneously irradiating ZrO2 samples and ion chamber. Samples of ZrO2 showed a linear response as a function of entrance skin air kerma. The observed results in TL properties suggest that ZrO2 nanostructured could be considered as an effective material for X-ray beams dosimetry if appropriate calibration procedures are performed. PMID- 22424742 TI - Assembly of an alpha-gamma coincidence measuring device for checking alpha decay schemes. AB - Two new chambers for measuring alpha-particle emissions have been made: a low geometry chamber with a powerful magnet to eliminate conversion electrons, and an alpha-gamma coincidence chamber. Both devices incorporate a high-resolution Si detector, and the second chamber, a low-energy Ge detector as well. A dual parameter multichannel analyzer was used to register coincidences in the second device. Alpha-particle and gamma-ray detectors work simultaneously in both individual and dual modes, providing single and coincidence spectra. Some preliminary alpha-gamma coincidence spectra have been obtained. PMID- 22424743 TI - Half-life determination of 88Kr and 138Xe. AB - The half-lives of (88)Kr and (138)Xe have been determined with two high purity germanium (HPGe) detectors by the position relay method. Data have been recorded at regular time intervals during measurements covering more than nine times the respective half-lives. This article describes in detail the principle and process of the position relay method with two HPGe detectors. The determined half-lives of (88)Kr and (138)Xe are 2.804+/-0.015 h and 14.18+/-0.10 min, respectively. PMID- 22424744 TI - Precise practical measurements of 90Y used in radiopharmaceuticals using re entrant ionization chambers. AB - For diagnostic nuclear medicine, radiopharmaceuticals are labeled with gamma-ray emitting nuclides. Routine activity measurements for these drugs are mainly performed with re-entrant ionization chambers. For radiotherapeutic applications, beta-ray emitting nuclides are also used. Since very few gamma transitions are involved in these nuclides, an ionization chamber responds only to weak bremsstrahlung. In order to apply the re-entrant chamber method to routine activity assay for these beta-ray emitting nuclides, detailed studies were carried out. It was determined that the response was strongly affected by the choice of thickness of the inner wall of the well in the measurement of high energy beta particle emitting nuclides. The geometrical dependences were successfully reduced. Accordingly, routine assay of radioactivity of (90)Y therapeutic pharmaceuticals can be performed within an acceptable uncertainty with ordinary re-entrant dose calibrators that are commercially available and equipped in most hospitals. PMID- 22424745 TI - Effects of anisotropic fluences and angular depended spectra of beta-particles in the use of large area reference sources. AB - Calibrations of instrument efficiency of surface contamination meters are usually made with extended reference sources which are standardized in terms of 2pi surface beta-particle emission rates from the source surface including backscattered particles. Extended sources supplied from various metrology institutes or calibration laboratories, but the source-types such as structure, preparation method, backing and covering materials vary between manufacturers. In this work first we show how the calibration results are dependent on the source type. Second, in order to clarify the possible reason of such discrepancy, we examined the isotropy of beta-particle fluences by the use of a proportional counter and also observed the angular dependence of beta-particle spectra by the use of small plastic scintillation spectrometer, where the source mount can rotate relative to the detector window at various obliquities. The discrepancy in the instrument-calibration of surface contamination meters, which are mainly used under the conditions of large source-to-detector geometry, can be explained. PMID- 22424746 TI - Investigation of factors affecting the quality of americium electroplating. AB - Four different electrolyte solutions were used in the electrodeposition of americium and their influences on the quality of the thin layer of deposited americium isotopes in combination with three different cathode disc materials were investigated. The relations between alpha spectral resolution and disc surface properties were established. PMID- 22424747 TI - APMP comparison of measurement of surface emission rate of 36Cl large area source (APMP.RI(II)-K2.Cl-36). AB - An international comparison of measurement of beta particle surface emission rate from a (36)Cl large area source (APMP.RI(II)-S1.Cl-36) was carried out within the framework of the Asia-Pacific Metrology Program (APMP). Participants from APMP were NMIJ (Japan), KRISS (Korea) and INER (Chinese Taipei). Participants from the other RMOs were NIST (United States), PTB (Germany), NMISA (South Africa) and VNIIM (Russia). All the results of the participants agreed within +/-1%. This was the first international comparison of measurement of surface emission rate of beta particle from a large area source. PMID- 22424748 TI - The Missing Links Expeditions--or how the Peking Man was not found. PMID- 22424749 TI - [Pregnant women living in areas of endemic fluorosis in Senegal and low birthweight newborns: case-control study]. AB - BACKGROUND: In developing countries, maternal and neonatal mortality is high. Among the causes of death during the neonatal period, low birth weight is crucial. A dose of fluoride beyond 2mg/L causes enamel damage, possibly affecting the fetus. The aim of this study was to search for an association between dental fluorosis in the mother and low birthweight of the newborn. METHODOLOGY: This was a case-control study performed in an endemic area in Senegal (Diourbel). It included 108 mothers who gave birth to newborns weighing less than 2500 g (cases) and 216 mothers with newborns weighing greater or equal to 2500 g (controls). Data on socio-demographic, lifestyle, history and pregnancy variables were collected. Those related to water consumption during pregnancy and dental fluorosis (Dean's index) were measured. The data were analyzed by R software. Logistic regression was used to identify associations and the statistical significance level was set to 0.05. RESULTS: The proportions of mothers consuming well water were 62% among cases versus 43.5% among controls. The score 4 of Dean's Index was reported for 25.9% of cases versus 6.9% of controls. The water consumed and the modal score of Dean's Index were significantly associated with the occurrence of low birthweight adjusted for gender, consanguinity, anemia and hypertension. CONCLUSION: Low birthweight was associated with pregnant women living in endemic areas. Defluoridation programs and access for pregnant women and children to high quality water are necessary in areas of endemic fluorosis. PMID- 22424750 TI - A pivotal role for the general practitioner in a mixed mammographic screening model. AB - BACKGROUND: A mixed mammographic screening model presents a country or region with a complex problem. Promoting a significant shift within the target population from opportunistic breast cancer screening to participation in an organised screening programme offers many advantages. The objective was to explore the role of GPs as potential mediators by assessing their specific knowledge, attitudes, and experience on breast cancer and mammographic screening. METHODS: A detailed questionnaire was mailed in 2007 to 1500 GPs randomly sampled from the GP population in the province of Antwerp, Belgium. Levels of knowledge on epidemiology and screening, opinions and attitudes on systematic mammographic screening, and experience with breast cancer and mammography were evaluated. RESULTS: We received 317 completed questionnaires, 21.1% of the contacted GPs. General knowledge on basic concepts of mammographic screening was average, while the response to an open question on the differences between screening and opportunistic mammography was very limited. More than half of the participants had a positive or realistic attitude towards many aspects of systematic screening, and had satisfactory experience with breast cancer patients in their daily practice (about 82% saw one to four new cases a year). Many (72%) were favourably disposed towards systematic screening organised by the government. CONCLUSION: The answers of the GPs suggest a promising potential with regard to the official breast cancer screening programme. Many participants presented qualifications, which could contribute to a change from the mixed model in favour of the official screening system. A number of gaps, however, need to be filled and there is a continuing need to educate physicians on principles and risks and benefits of systematic screening of the target group. PMID- 22424751 TI - [Elements of completeness and results of the first year of registration of the "Registre general des cancers de Lille et de sa region"]. AB - BACKGROUND: In 2005, following the first cancer plan of the national health authorities, a general cancer registry was established in northern France, in a territory designated as a "zone in proximity to the city of Lille" (ZPL). The aim of the present work was to evaluate the completeness of the registry's first year of incident cancer registration (2005) and to compare the observed cancer incidence in the "ZPL" with the estimated incidence in France. METHODS: Completeness was assessed using the average number of sources per case, the percentage of histological verification and a method of independent case ascertainment (mortality/incidence ratio). A direct standardization on the world population was used to calculate the ZPL/France ratios of standardized incidence rates. Analyses were conducted for 21 cancer sites. RESULTS: In 2005, 3635 cases of invasive cancer were recorded by the registry. The average number of sources per case was 2.7 and histological proof was available for 91.4% of cases. Mortality/incidence ratios showed satisfactory completeness of the data for men for most cancer sites. For women however, for cancer sites for which the number of cases was low, data will have to be confirmed during the subsequent years of observation. A lack of completeness was found for cutaneous melanoma. In men, an overincidence was identified for cancers of lip-mouth-pharynx, larynx, esophagus, lung, liver, bladder, kidney and colon-rectum. In women, an overincidence has been identified for cancers of lip-mouth-pharynx, liver, bladder, colon-rectum, corpus uteri and ovaries. CONCLUSION: The first year of incidence validated at the "Registre general des cancers de Lille et de sa region" shows a completeness of records with regards to studied criteria. The comparison with national data shows an overincidence of cancers related to tobacco and alcohol consumption in the geographical area covered by the registry. The incidence of lip-mouth-pharynx cancer in men is the highest of all French registries. PMID- 22424752 TI - Effects of sulfide on microbial fuel cells with platinum and nitrogen-doped carbon powder cathodes. AB - Because of the advantages of low cost, good electrical conductivity and high oxidation resistance, nitrogen-doped carbon (NDC) materials have a potential to replace noble metals in microbial fuel cells (MFCs) for wastewater treatment. In spite of a large volume of studies on NDC materials as catalysts for oxygen reduction reaction, the influence of sulfide on NDC materials has not yet been explicitly reported so far. In this communication, nitrogen-doped carbon powders (NDCP) were prepared by treating carbon powders in nitric acid under reflux condition. Sodium sulfide (Na(2)S) was added to the cathodic electrolyte to compare its effects on platinum (Pt) and NDCP cathodes. Cell voltages, power density and cathodic potentials were monitored without and with Na(2)S and after Na(2)S was removed. The maximum cell voltage of the MFCs with Pt cathode decreased by 10% in the presence of Na(2)S that did not change the performance of the MFC with NDCP cathode, and the maximum power density of the MFC with NDCP cathode was even 11.3% higher than that with Pt cathode (222.5 +/- 8 mW m(-2) vs. 199.7 +/- 4 mW m(-2)). PMID- 22424753 TI - A novel approach to determining the affinity of protein-carbohydrate interactions employing adherent cancer cells grown on a biosensor surface. AB - The development of biological agents for the treatment of solid tumours is an area of considerable activity. We are pursuing carbohydrate-binding proteins (lectins) in a strategy aimed at targeting cancer-associated changes in glycosylation. To evaluate lectin-cancer cell interactions we developed a novel cell biosensor in which binding events take place at the cell surface, more closely mimicking an in vivo system. Metastatic, SW620, and non-metastatic, SW480, colorectal cancer cells were grown on the surface of a tissue-culture compatible polystyrene coated biosensor chip and housed in a quartz crystal microbalance (QCM) apparatus, the kinetics of binding of a diverse range of lectins was evaluated. The lectin Helix pomatia agglutinin (HPA) has been shown to bind aggressive metastatic cancer and was produced in recombinant form (His- and RFP-tagged). The affinity of HPA was in the nanomolar range to the metastatic SW620 cells but was only in the micromolar range to the non-metastatic SW480. Overall, the dissociation constant (K(D)) of the lectins tested in the new cell biosensor system was an order of magnitude lower (nanomolar range) than has generally been reported with systems such as QCM/SPR. This new cell-biosensor enables molecular interactions to be studied in a more relevant environment. An intrinsic problem with developing new biological therapies is the difficulty in determining the affinity with which proteins will interact with intact cell surfaces. This methodology will be of interest to researchers developing new biological approaches for targeting cell surfaces in a wide range of diseases, including cancer. PMID- 22424754 TI - Comparison of three genetically modified Escherichia coli biosensor strains for amperometric tetracycline measurement. AB - Three separate genetic strategies, based upon the induced expression of three different genes (lacZ, selA and nuoA) were tested to provide the SciTox assay with sensitive and specific detection of the antibiotic tetracycline (Tet). All three strategies relied on gene induction from the Tn10 tetA promoter. Both lacZ and nuoA biosensors responded specifically and sensitively to sub-inhibitory concentrations of Tet. However, the selA-based assay was not sensitive enough to detect Tet in the SciTox assay. The detection limits for Tet of the lacZ and nuoA biosensor strains were 0.11 MUg ml(-1) and 0.0026 MUg ml(-1), respectively, and their linear ranges were 0.1-1 MUg ml(-1) and 0-0.01 MUg ml(-1), respectively. While lacZ has previously been used as a reporter gene in an amperometric bioassay, nuoA is a novel and more sensitive reporter gene. This is the first report in which a respiratory gene was used as a reporter gene in an amperometric biosensor. The results indicate that this approach can produce a highly sensitive detection system. In order to test whether the new system could be used to detect other chemicals, the nuoA gene was re-engineered to be driven by the copper inducible copA promoter. Using this strain, the SciTox assay was found to be able to specifically detect copper and silver ions. PMID- 22424755 TI - Sweet and bitter tastants specific detection by the taste cell-based sensor. AB - Sweet and bitter tastants specific detection by cell-based sensor is investigated in this paper. Human enteroendocrine NCI-H716 cells, expressing G protein-coupled receptors and sweet receptors (type 1, member 2/type 1, member 3), and human enteroendocrine STC-1 cells, expressing G protein-coupled receptors and bitter receptors (type 2 members) are used as sensing devices. The HEK-293 cells, without taste receptor expression, are used as negative control. The electrochemical impedance spectrum data is recorded and processed by bistable stochastic resonance for signal-to-noise ratio calculation. NCI-H716 cell-based sensor selectively responds to sweeteners and sweet tastant mixtures. STC-1 cell based sensor selectively responds to bitter tastants and bitter tastant mixtures. The tastants species and concentrations can be decided by signal-to-noise ratio parameters. HEK-293 cell-based sensor lacks the tastants discriminating ability. The taste cell-based sensor is easy to prepare and operate. This work offers a useful way in gustatory mechanism research. PMID- 22424756 TI - Profile of fatty acids, muscle structure and shear force of musculus longissimus dorsi (MLD) in growing pigs as affected by energy and protein or protein restriction followed by realimentation. AB - Forty-eight gilts were submitted to a 30% restriction of feed (groups F and F1) or protein intake (group P) from 90 to 118 days of age, followed by realimentation from 119 to 168 days of age. Control pigs (C) were fed during the whole experiment according to a semi ad libitum scale. During realimentation all animals were fed according to semi ad libitum scale except pigs F1 which were fed ad libitum. Six pigs from each group were slaughtered at the end of restriction and realimentation. Restriction decreased the weight of musculus longissimus dorsi (MLD) and increased shear force. Restriction of feed intake depressed MUFA concentration and increased n-6/n-3 ratio while protein restriction decreased n 6/n-3 and PUFA:SFA ratios. Structure of fibers was not affected. After realimentation MLD mass was still lower in all previously restricted pigs, shear force was the lowest in F1 pigs. Only percentage of fast twich oxidative fibers was significantly greater in F1 pigs than in others. Significant correlations between parameters investigated during the study were found. PMID- 22424757 TI - Microvascular free flaps in head and neck surgery: complications and outcome of 1000 flaps. AB - This study analyzed the surgical outcome and complications of 1000 microvascular free flaps performed at the authors' institution in Germany, between 1987 and 2010. 972 patients underwent reconstruction with 1000 flaps: 28% latissimus dorsi flaps, 27% radial forearm flaps, 20% iliac crest flaps, 12% fibula flaps, 6% jejunal flaps, 2% anterolateral thigh flaps, and 5% other flaps. 130 failures (7.6%) were encountered, including 58 complete flap failures (44.6%) and 72 partial free-flap failures (55.4%). This study confirms that free flaps are extremely reliable in achieving successful reconstruction of the head and neck, but it is essential that complications be recognized and addressed early in their course to prevent or minimize devastating consequences. Owing to the large number of possible errors in flap transplantation, microsurgeons should always check everything for themselves. The on-duty doctors and nursing staff should not be trusted blindly. Venous thrombosis and cervical haematoma are the most common complications at the recipient site and are mainly responsible for flap failure, while complications occurring at the donor site may result from dehiscence and graft necrosis. When a compromised flap is identified, surgical re-exploration should not be deferred. PMID- 22424758 TI - Changes in muscle activation patterns when running step rate is increased. AB - Running with a step rate 5-10% greater than one's preferred can substantially reduce lower extremity joint moments and powers, and has been suggested as a possible strategy to aid in running injury management. The purpose of this study was to examine how neuromuscular activity changes with an increase in step rate during running. Forty-five injury-free, recreational runners participated in this study. Three-dimensional motion, ground reaction forces, and electromyography (EMG) of 8 muscles (rectus femoris, vastus lateralis, medial gastrocnemius, tibialis anterior, medial and lateral hamstrings, and gluteus medius and maximus) were recorded as each subject ran at their preferred speed for three different step rate conditions: preferred, +5% and +10% of preferred. Outcome measures included mean normalized EMG activity for each muscle at specific periods during the gait cycle. Muscle activities were found to predominantly increase during late swing, with no significant change in activities during the loading response. This increased muscle activity in anticipation of foot-ground contact likely alters the landing posture of the limb and the subsequent negative work performed by the joints during stance phase. Further, the increased activity observed in the gluteus maximus and medius suggests running with a greater step rate may have therapeutic benefits to those with anterior knee pain. PMID- 22424759 TI - Obstacle crossing during locomotion: visual exproprioceptive information is used in an online mode to update foot placement before the obstacle but not swing trajectory over it. AB - Although gaze during adaptive gait involving obstacle crossing is typically directed two or more steps ahead, visual information of the swinging lower-limb and its relative position in the environment (termed visual exproprioception) is available in the lower visual field (lvf). This study determined exactly when lvf exproprioceptive information is utilised to control/update lead-limb swing trajectory during obstacle negotiation. 12 young participants negotiated an obstacle wearing smart-glass goggles which unpredictably occluded the lvf for certain periods during obstacle approach and crossing. Trials were also completed with lvf occluded for the entirety of the trial. When lvf was occluded throughout, foot-placement distance and toe-clearance became significantly increased; which is consistent with previous work that likewise used continuous lvf occlusion. Both variables were similarly affected by lvf occlusion from instant of penultimate-step contact, but both were unaffected when lvf was occluded from instant of final-step contact. These findings suggest that lvf (exproprioceptive) input is typically used in an online manner to control/update final foot-placement, and that without such control, uncertainty regarding foot placement causes toe-clearance to be increased. Also that lvf input is not normally exploited in an online manner to update toe-clearance during crossing: which is contrary to what previous research has suggested. PMID- 22424760 TI - Effect of a rocker non-heeled shoe on EMG and ground reaction forces during gait without previous training. AB - Unstable shoes have been designed to promote "natural instability" and during walking they should simulate barefoot gait, enhancing muscle activity and, thus, attributing an advantage over regular tennis shoes. Recent studies showed that, after special training on the appropriate walking pattern, the use of the Masai Barefoot Technology (MBT) shoe increases muscle activation during walking. Our study presents a comparison of muscle activity as well as horizontal and vertical forces during gait with the MBT, a standard tennis shoe and barefoot walking of healthy individuals without previous training. These variables were compared in 25 female subjects and gait conditions were compared using ANOVA repeated measures (effect size:0.25). Walking with the MBT shoe in this non-instructed condition produced higher vertical forces (first vertical peak and weight acceptance rate) than walking with a standard shoe or walking barefoot, which suggests an increase in the loads received by the musculoskeletal system, especially at heel strike. Walking with the MBT shoe did not increase muscle activity when compared to walking with the standard shoe. The barefoot condition was more effective than the MBT shoe at enhancing muscle activation. Therefore, in healthy individuals, no advantage was found in using the MBT over a standard tennis shoe without a special training period. Further studies using the MBT without any instruction over a longer period are needed to evaluate if the higher loads observed in the present study would return to their baseline values after a period of adaptation, and if the muscle activity would increase over time. PMID- 22424761 TI - Quantifying gait abnormalities in persons with multiple sclerosis with minimal disability. AB - Abnormalities in gait kinematics in persons with multiple sclerosis (PwMS) who have mild disability have been noted using motion capture systems. However, it is not clear if these abnormalities can be detected with clinically feasible technology. This investigation examined if the spatiotemporal markers of gait including variability metrics can distinguish between PwMS with minimal disability and controls with clinically feasible technology. 43 PwMS with minimal disability and 43 healthy controls completed four walking trials along a 26 foot long pressure sensitive pathway (GAITRite). Spatiotemporal markers of gait including variability metrics were determined. Statistical analysis revealed that PwMS walked slower, with fewer, shorter, wider steps and spent a greater percentage of a gait cycle in double support than controls. Additionally, PwMS had greater variability in the time between steps, single support percent and step width than controls. Collectively, the results highlight that PwMS, in the absence of clinical gait impairment, have subtle but detectable differences in gait and that these alterations can be detected with clinically feasible technology. The current results raise the possibility of targeting walking deviations earlier in disability progression in PwMS. PMID- 22424762 TI - Is the ketogenic diet effective in specific epilepsy syndromes? AB - Is the ketogenic diet (KD) more effective in certain epilepsy syndromes? The KD has been shown to be effective in treating multiple seizure types and epilepsy syndromes. We review the effectiveness of the KD in Dravet syndrome, epilepsy with myoclonic-atonic seizures, mitochondrial disease, tuberous sclerosis, late infantile and juvenile neuronal ceroid lipofuscinosis, and febrile infection related epilepsy syndrome. In certain epilepsy syndromes, like epilepsy with myoclonic-atonic seizures, the diet should be considered early in the course of treatment. PMID- 22424763 TI - Cloning and characterization of a beta-ketoacyl-acyl carrier protein synthase II from Jatropha curcas. AB - A cDNA clone encoding a putative beta-ketoacyl-acyl carrier protein (ACP) synthase II (KASII), a key enzyme in fatty acid biosynthesis, was isolated from Jatropha curcas L., a woody oil plant. The isolated cDNA clone of JcKASII contained a 1722-bp open reading frame coding for 573 amino acids with a predicted molecular mass of about 60.98 kDa and the conserved Cys(324) residues that has been proposed as the active site of KASII proteins. The deduced amino acid sequence of the cDNA clone had about 70-84% identity with the KASII from other plants. The transcript of JcKASII was detected in all tissues examined and increased during seed maturation. Expression of JcKASII in the Arabidopsis KASII mutant (fab1) could complement the fatty acid composition of the mutant. Overexpression of JcKASII cDNA under the cauliflower mosaic virus 35S promoter in Arabidopsis resulted in decreasing 16-carbon fatty acids and increasing 18-carbon fatty acids in leaves and seeds. Taken together, these results show that JcKASII could function in 18-carbon fatty acids accumulation in plant and may be useful in the genetic engineering of J. curcas. PMID- 22424764 TI - Thermodynamic properties of micellization of Sulfobetaine-type Zwitterionic Gemini Surfactants in aqueous solutions--a free energy perturbation study. AB - In this article, the validity and accuracy of the free energy perturbation (FEP) model used in a previous article for ionic liquid-type Gemini imidazolium surfactants (ILGISs) is further evaluated by using it to model the Enthalpy entropy compensation of Sulfobetaine-type Zwitterionic Gemini Surfactants (SZGSs), with different carbon atoms of the hydrophobic group or the spacer chain length, in aqueous solutions. In the FEP model, the Gibbs free energy contributions to the driving force for micelle formation are computed using hydration data obtained from molecular dynamics simulations. According to the pseudo-phase separation model, the thermodynamic properties of micellization in aqueous solutions for SZGS were discussed. The results show that the micellization of SZGS in aqueous solutions is a spontaneous and entropy-driven process. It is linearly Enthalpy-entropy compensated and different from the micelle formation of ILGIS but similar to anionic surfactants. The compensation temperature was found to be (302+/-3)K which was lower than ILGIS. As the temperature rises, the micellization is easy initially but then becomes difficult with the unusual changes of enthalpy values from positive to negative. The contribution of entropy change to the micellization tends to decrease but the contribution of enthalpy change tends to increase. In particular, as the number carbon atoms in the alkyl chains and spacer chains are increased, the thermodynamic favorability and stability of the micelles both increase. PMID- 22424765 TI - High-capacity adsorption of hexavalent chromium from aqueous solution using magnetic microspheres by surface dendrimer graft modification. AB - The magnetic poly-(methyl acrylate-divinyl benzene) (MA-DVB) microspheres with micron size were synthesized by modified suspension polymerization method. Through stepwise reaction with methyl acrylate (MA) and ethylenediamine (EDA), the magnetic poly-(MA-DVB) microspheres with surface dendrimer containing amino groups were obtained. The above mentioned magnetic microspheres were applied for the adsorption of hexavalent chromium from aqueous solution. The effects of solution pH value, adsorption temperature, and adsorption and desorption of Cr(VI) were studied. The results showed that the optimum pH value for Cr(VI) adsorption was found at pH=3, and the adsorption capacity increased with the increase in adsorption temperature. The adsorption equilibrium of Cr(VI) was obtained in about 12 min and more than 98% of adsorbed Cr(VI) were desorbed from the magnetic microspheres in about 30 min using Na(2)SO(4) solution. By fitting the experimental data to Langmuir equation, the maximum capacity for Cr(VI) of magnetic poly-(MA-DVB) microspheres was estimated at 231.8 mg/g. PMID- 22424766 TI - One-step synthesis and assembly of one-dimensional parallel chains of CdS nanoparticles at the air-water interface templated by 10,12-pentacosadiynoic acid supermolecules. AB - Regular one-dimensional (1D) parallel chains composed of CdS nanoparticles with cubic zinc blende crystal structure were prepared at the air/water interface via one-step synthesis and assembly process. These nanostructures were produced through an interfacial reaction between Cd(2+) ions in the aqueous solution of cadmium acetate and H(2)S in the gaseous phase under Langmuir monolayers of 10,12 pentacosadiynoic acid (PDA). It was demonstrated that PDA molecules self assembled into parallelly aligned linear supermolecules at the air/water interface with the aid of pi-pi interactions and acted as templates for the formation of the superstructures. The experimental conditions including temperature and reaction time have great influences on the superstructure formation and the parameters of the parallel chains. PMID- 22424767 TI - Importance of early diagnosis of Stickler syndrome in newborns. AB - OBJECTIVE: The study aims to investigate a possible correlation between the main clinical and ophthalmological characteristics, age and Robin sequence in patients with the Stickler syndrome. INTRODUCTION: The Stickler syndrome is an autosomal dominant genetic disorder, characterised by ocular, orofacial and skeletal anomalies and/or auditory loss. Patients with Robin sequence features and respiratory complications are frequently diagnosed with the Stickler syndrome. The heterogeneous phenotypic manifestations may present a challenge for early clinical diagnosis. METHODS: We performed a retrospective study of the 98 patients with the Stickler syndrome, between November 1995 and June 2009. The data were compared to investigate their ocular alterations and association with the Robin sequence. To be included, patients had to present with the following triad: cleft palate, facial features (hypoplastic midface, micrognathia and prominent eyes) and ocular anomalies (myopia and/or abnormalities of the retina). RESULTS: Fifty-one percent of the patients presenting with Robin sequence features had been diagnosed with the Stickler syndrome. Ocular alterations were found in 50% of the patients. DISCUSSION: The Robin sequence may appear as an isolated condition or associated with other features, or else as part of other known syndromes. Currently, the diagnosis of the Stickler syndrome is based on clinical signs. Affected individuals eventually develop hearing loss, retinal detachment and blindness. The ophthalmological complications associated are usually progressive and can lead to blindness. CONCLUSION: Robin sequence may be an indicative sign of the Stickler syndrome. Early diagnosis is essential for specialised treatment, which is critical for preventing irreversible consequences of this pathology. PMID- 22424768 TI - Hyphenated chromatographic techniques for structural characterization and determination of masked mycotoxins. AB - Mycotoxins are secondary metabolites produced by fungi that can contaminate a wide range of food and feed commodities and that are harmful to humans for their poisonous and toxic effects. An increasing amount of data have been accumulated in the last years, showing that mycotoxins may also occur in modified forms originating by plant, fungi or animal metabolism or by food processing. In particular, this modified forms may be produced via conjugation with sugars or other biological components (masked mycotoxins) or may occur as non extractable forms on account of strong interaction, association or binding with macromolecules in the food matrix (bound or hidden mycotoxins). Analytical methods have been set up in order to check for the occurrence of these forms and to evaluate their amount, in order to obtain reliable data for toxicity and exposure studies. In this paper hyphenated chromatographic methods for the determination and structural characterization of masked mycotoxins are reviewed, with a particular emphasis on liquid chromatography-(tandem) mass spectrometry as the most effective approach for their determination. PMID- 22424769 TI - A comparison of overload behaviour for some sub 2 MUm totally porous and sub 3 MUm shell particle columns with ionised solutes. AB - The overloading performance of some 2.7 MUm shell and sub 2 MUm totally porous columns, including one pair manufactured from similar materials with similar bonding chemistries, was compared using strongly acidic and basic probe compounds. In general, the capacity of shell particles was not greatly reduced, despite containing a smaller porous volume. Nevertheless, at low pH, both types of column were overloaded by only small concentrations of ionised solute. Considerable improvement could be gained by increasing the buffer concentration, although sensitivity in mass spectrometric detection may be compromised. The capacity of columns of different internal diameter may not be directly compared merely by scaling the injection volumes, as it is possible that the sample is not homogeneously distributed across the column radius, especially in larger diameter columns, where the sample may travel preferentially through a central core of the packing. A totally porous charged surface hybrid phase gave much improved loading properties of the basic probe in low ionic strength mobile phases such as formic acid, often used in mass spectrometry. However, its relative advantage over conventional phases was reduced as the mobile phase ionic strength was increased. Furthermore, acidic compounds may give tailing on this phase. At pH 7, all columns tested showed evidence of interaction with ionised silanols; peak shapes improved as the buffer concentration was increased. Column efficiency first increased and then decreased as solute concentration was increased at constant buffer concentration, which can be attributed to the decreasing proportion of solute molecules retained by the ion exchange process. PMID- 22424770 TI - The flux of dissolved nitrogen from the UK--evaluating the role of soils and land use. AB - Fluvial dissolved nitrogen (dissolved organic nitrogen [DON], nitrate and ammonium) fluxes from the terrestrial biosphere of the UK to surrounding oceans are explained on the basis of combined predictions of soil to water transfer and in-stream loss. The flux of different nitrogen species from land to surface waters is estimated using an export coefficient model employing catchment soil, land use and hydroclimatic characteristics, fitted to flux estimates derived from the Harmonised Monitoring Scheme between 2001 and 2007 for 169 UK catchments. In stream losses of DON, nitrate and ammonium were estimated using a transit time filter in the fluvial network. Comparisons of modelled land to water N flux (2125 ktonnes N yr(-1)) with estimates of N fluxes to estuarine and ocean systems at the tidal limit (791 ktonnes N yr(-1)) suggest that significant in-channel N losses occur. These in transit losses are equivalent to up to 55 kg N ha(-1) yr( 1). PMID- 22424771 TI - A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2. AB - The association between hyperinflammatory states and numerous diseases is widely recognized, but our understanding of the molecular strategies that have evolved to prevent uncontrolled activation of inflammatory responses remains incomplete. Here, we report a critical, nontranscriptional role of GPS2 as a guardian against hyperstimulation of the TNF-alpha-induced gene program. GPS2 cytoplasmic actions are required to specifically modulate RIP1 ubiquitylation and JNK activation by inhibiting TRAF2/Ubc13 enzymatic activity. In vivo relevance of GPS2 anti inflammatory role is confirmed by inhibition of TNF-alpha target genes in macrophages and by improved insulin signaling in the adipose tissue of aP2-GPS2 transgenic mice. As the nontranscriptional role is complemented by GPS2 functioning as positive and negative cofactor for nuclear receptors, in vivo overexpression also results in elevated circulating level of Resistin and development of hepatic steatosis. Together, these studies define GPS2 as a molecular guardian required for precise control of inflammatory responses involved in immunity and homeostasis. PMID- 22424772 TI - The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis. AB - We report that mice ablated for the Sam68 RNA-binding protein exhibit a lean phenotype as a result of increased energy expenditure, decreased commitment to early adipocyte progenitors, and defects in adipogenic differentiation. The Sam68(-/-) mice were protected from obesity, insulin resistance, and glucose intolerance induced with a high-fat diet. To identify the alternative splice events regulated by Sam68, genome-wide exon usage profiling in white adipose tissue was performed. Adipocytes from Sam68(-/-) mice retained intron 5 within the mTOR transcript introducing a premature termination codon, leading to an unstable mRNA. Consequently, Sam68-depleted cells had reduced mTOR levels resulting in lower levels of insulin-stimulated S6 and Akt phosphorylation leading to defects in adipogenesis, and this defect was rescued by the exogenous expression of full-length mTOR. Sam68 bound intronic splice elements within mTOR intron 5 required for the usage of the 5' splice site. We propose that Sam68 regulates alternative splicing during adipogenesis. PMID- 22424773 TI - Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response. AB - The regulatory networks of the DNA damage response (DDR) encompass many proteins and posttranslational modifications. Here, we use mass spectrometry-based proteomics to analyze the systems-wide response to DNA damage by parallel quantification of the DDR-regulated phosphoproteome, acetylome, and proteome. We show that phosphorylation-dependent signaling networks are regulated more strongly compared to acetylation. Among the phosphorylated proteins identified are many putative substrates of DNA-PK, ATM, and ATR kinases, but a majority of phosphorylated proteins do not share the ATM/ATR/DNA-PK target consensus motif, suggesting an important role of downstream kinases in amplifying DDR signals. We show that the splicing-regulator phosphatase PPM1G is recruited to sites of DNA damage, while the splicing-associated protein THRAP3 is excluded from these regions. Moreover, THRAP3 depletion causes cellular hypersensitivity to DNA damaging agents. Collectively, these data broaden our knowledge of DNA damage signaling networks and highlight an important link between RNA metabolism and DNA repair. PMID- 22424774 TI - Leucyl-tRNA synthetase controls TORC1 via the EGO complex. AB - The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1 regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. This interaction is necessary and sufficient to mediate leucine signaling to TORC1 and is disrupted by the engagement of Cdc60 in editing mischarged tRNA(Leu). Thus, the EGOC-TORC1 signaling module samples, via the LeuRS-intrinsic editing domain, the fidelity of tRNA(Leu) aminoacylation as a proxy for leucine availability. PMID- 22424775 TI - Dynamic architecture of a minimal RNA polymerase II open promoter complex. AB - The open promoter complex (OC) is a central intermediate during transcription initiation that contains a DNA bubble. Here, we employ single-molecule Forster resonance energy transfer experiments and Nano-Positioning System analysis to determine the three-dimensional architecture of a minimal OC consisting of promoter DNA, including a TATA box and an 11-nucleotide mismatched region around the transcription start site, TATA box-binding protein (TBP), RNA polymerase (Pol) II, and general transcription factor (TF)IIB and TFIIF. In this minimal OC, TATA-DNA and TBP reside above the Pol II cleft between clamp and protrusion domains. Downstream DNA is dynamically loaded into and unloaded from the Pol II cleft at a timescale of seconds. The TFIIB core domain is displaced from the Pol II wall, where it is located in the closed promoter complex. These results reveal large overall structural changes during the initiation-elongation transition, which are apparently accommodated by the intrinsic flexibility of TFIIB. PMID- 22424776 TI - The politics and policies of HIV prevention in sex work. PMID- 22424777 TI - Burden of HIV among female sex workers in low-income and middle-income countries: a systematic review and meta-analysis. AB - BACKGROUND: Female sex workers are a population who are at heightened risk of HIV infection secondary to biological, behavioural, and structural risk factors. However, three decades into the HIV pandemic, understanding of the burden of HIV among these women remains limited. We aimed to assess the burden of HIV in this population compared with that of other women of reproductive age. METHODS: We searched PubMed, Embase, Global Health, SCOPUS, PsycINFO, Sociological Abstracts, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Science, and POPLine for studies of female sex workers in low-income and middle income countries published between Jan 1, 2007, and June 25, 2011. Studies of any design that measured the prevalence or incidence of HIV among female sex workers, even if sex workers were not the main focus of the study, were included. Meta analyses were done with the Mantel-Haenszel method with a random-effects model characterising an odds ratio for the prevalence of HIV among female sex workers compared with that for all women of reproductive age. FINDINGS: Of 434 selected articles and surveillance reports, 102 were included in the analyses, representing 99,878 female sex workers in 50 countries. The overall HIV prevalence was 11.8% (95% CI 11.6-12.0) with a pooled odds ratio for HIV infection of 13.5 (95% CI 10.0-18.1) with wide intraregional ranges in the pooled HIV prevalence and odds ratios for HIV infection. In 26 countries with medium and high background HIV prevalence, 30.7% (95% CI 30.2-31.3; 8627 of 28,075) of sex workers were HIV-positive and the odds ratio for infection was 11.6 (95% CI 9.1 14.8). INTERPRETATION: Although data characterising HIV risk among female sex workers is scarce, the burden of disease is disproportionately high. These data suggest an urgent need to scale up access to quality HIV prevention programmes. Considerations of the legal and policy environments in which sex workers operate and actions to address the important role of stigma, discrimination, and violence targeting female sex workers is needed. FUNDING: The World Bank, UN Population Fund. PMID- 22424778 TI - Relationship between oxidative stress and the success of artificial insemination in dairy cows in a pasture-based system. AB - This study was designed to evaluate whether the outcome of artificial insemination (AI) was affected by the metabolic and oxidative status of dairy cows. Seventy-nine inseminations in 40 cows, were classified, on the basis of blood progesterone (P4) and pregnancy-associated glycoprotein (PAG) concentrations and clinical confirmation of pregnancy into, three categories: (1) positive (AI+, resulted in pregnancy, n=26; 33%), (2) negative (AI-, did not result in pregnancy, n=49; 62%), and (3) embryonic mortality (EM, n=4; 5%). Reactive oxygen metabolites, biological antioxidant potential, oxidative stress index, body condition score, glucose, total proteins, albumin, urea, non esterified fatty acids (NEFAs), cholesterol, triglycerides, haptoglobin and advanced oxidative protein products (AOPPs) were measured on the day of AI (day 0), and 30 and 42 days later. Cows with EM had lower BCS scores (2.5) than AI+ (2.8) and AI- (2.9) cows (P<0.05). During the post-partum period, body condition score (BCS) increased and NEFAs decreased (P<0.05) suggesting a recovery from the negative energy balance (NEB). The only significant differences found were that the mean concentration of AOPPs was higher and that of albumin lower in EM cows than in AI+ and AI- (P<0.05) animals. Plasma concentration of reactive oxygen metabolites and biological antioxidant potential were not related to AI outcome. Further studies are required to confirm this finding and to clarify the role of oxidative status on cows' fertility. PMID- 22424779 TI - Physical fitness levels among independent non-institutionalized Spanish elderly: the elderly EXERNET multi-center study. AB - BACKGROUND: Physical fitness is gaining in importance in all population groups, including elderly, but data are still scarce. The aim of this study was to report gender and age specific physical fitness levels in non-institutionalized Spanish elderly. METHODS: A representative sample of 3136 elderly (>= 65 y), 724 men and 2412 women, from 6 Regions of Spain: Madrid, Aragon, Castilla y Leon, Castilla-La Mancha, Extremadura and Canarias were assessed in the elderly EXERNET multi center study between 2008 and 2009. The authors assessed static balance, muscular strength, flexibility, agility, walking speed and cardiorespiratory fitness using eight different fitness tests: one leg balance, chair stand, arm curl, chair sit and-reach, back scratch, 8-foot up-and-go, 30-m walk, and 6 min walk tests. RESULTS: The authors derived gender and age-specific normative values for physical fitness in the non-institutionalized Spanish elderly. The figures showed greater physical fitness in the elderly men than in women, except for the flexibility test, and a trend toward decreased physical fitness in both genders as their age increased. CONCLUSIONS: The normative values hereby provided will enable evaluation and correct interpretation of independent non-institutionalized Spanish elderly fitness status. PMID- 22424780 TI - Principal component based analysis of biomechanical inter-trial variability in individuals with chronic ankle instability. AB - BACKGROUND: Biomechanical variability during movement may influence joint stability in individuals with chronic ankle instability (CAI). The purpose of this study was to compare the kinematic and the kinetic inter-trial variability between healthy and CAI individuals. METHODS: Eleven individuals with CAI and 11 matched controls performed five repetitions of a single-leg landing task. Biomechanical data were collected from 100 ms before to 200 ms after touchdown, and were used to calculate touchdown angles, peak angles and moments at the ankle joint in the frontal and sagittal planes. In addition, principal component analyses were used to quantify kinematic and kinetic patterns in the same planes across the 300 ms time window. Five trial averages and inter-trial variability were calculated for all variables for each subject. Independent t-tests were used to compare variables between groups. FINDINGS: The CAI group displayed greater inter-trial variability for principal component scores in the sagittal and frontal planes. The sagittal plane principal component captured a phase shift in plantar-flexion motion before touchdown, while the frontal plane principal component captured the general magnitude of motion during the entire movement. The CAI group therefore exhibited greater inter-trial variability in the sagittal plane before touchdown and in the frontal plane during the entire movement. INTERPRETATION: While average motions did not differ between groups, the CAI group displayed greater kinematic inter-trial variability when analyzed with the principal component analysis. More variable joint motions may indicate less dynamic stability in the CAI group, which may originate from greater ligamentous laxity or diminished neuromotor control. PMID- 22424781 TI - Symmetry of foot alignment and ankle flexibility in paediatric Charcot-Marie Tooth disease. AB - BACKGROUND: Charcot-Marie-Tooth disease is the most common inherited nerve disorder and typically presents with pes cavus foot deformity and ankle equinus during childhood. Level in the variation of symmetry of musculoskeletal lower limb involvement across the clinical population is unknown, despite early reports describing gross asymmetry. METHODS: We measured foot alignment and ankle flexibility of the left and right limbs using accurate and reliable standardised paediatric outcome measures in 172 patients aged 3-20 years with a variety of disease subtypes recruited from the United States, United Kingdom, Italy and Australia. FINDINGS: While a large range of differences existed between left and right feet for a small proportion of children, there was no overall significant difference between limbs. INTERPRETATION: There are two important implications of these findings. Children with Charcot-Marie-Tooth disease generally exhibit symmetrical foot alignment and ankle flexibility between limbs. As such, analysing one limb only for biomechanical-related research is appropriate and satisfies the independence requirements for statistical analysis. However, because there are large differences between feet for a small proportion of children, an individualised limb-focused approach to clinical care is required. PMID- 22424782 TI - Secreted HLA recapitulates the immunopeptidome and allows in-depth coverage of HLA A*02:01 ligands. AB - HLA molecules are cell-surface glycoproteins that present peptides, derived from intracellular protein antigens, for surveillance by T lymphocytes. Secreted HLA (sHLA) technology is a powerful approach for studying these peptides, since it facilitates large-scale production of HLA-bound peptides. We compared secreted and membrane-bound forms of HLA A2 in terms of intracellular trafficking and their bound peptide repertoire (termed the immunopeptidome). We demonstrate that sHLA and membrane bound HLA (mHLA) negotiate intracellular compartments with similar maturation kinetics. Moreover, mass spectrometry revealed a substantial overlap in the immunopeptidome was observed when HLA A2-bound peptides were purified from various sources of sHLA and mHLA. By combining machine based algorithms with manual validation, we identified 1266 non-redundant peptides. Analysis of these peptides revealed a number bearing post-translational modifications, although some of these may arise spontaneously others represent modifications performed within the cell that survive antigen processing. Peptides bearing some of these modifications have not previously been described for HLA ligands, therefore, this compendium of 1266 non-redundant peptide sequences adds greatly to the existing database of HLA A2 ligands. Peptides from all sources displayed comparable HLA A2 consensus binding motifs, peptide lengths, predicted HLA A2 binding affinities and putative source antigens. We conclude that sHLA is a valid and useful technique for studying the immunopeptidome. PMID- 22424783 TI - An epigenetic mechanism for high, synergistic expression of indoleamine 2,3 dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-gamma: potential therapeutic use in autoimmune diseases. AB - IDO1 can be induced by interferon gamma (IFN-gamma) in multiple cell types. We have earlier described that the DNA methyltransferase inhibitor zebularine also induces IDO1 in several rat cell clones. We now describe a synergistic induction of IDO1 expression by IFN-gamma and zebularine. To elucidate the mechanism of the IDO1 induction we have studied the methylation status in the promoter region of the IDO1 gene from both human monocytic THP-1 cells and H1D2 rat colon cancer cells. Interestingly, the IDO1 promoter is hypermethylated and IFN-gamma is shown to induce a significant demethylation. The synergism in effect of zebularine and IFN-gamma on IDO1 expression is paralleled by a similar synergistic effect on expression of two other IFN-gamma-responsive genes, the transcription factors STAT1 and IRF1 with binding sites in the IDO1 promoter region. The demonstrated synergistic activation of IDO1 expression has implications in relation to therapeutic induction of immunosuppression in autoimmunity and chronic inflammation. PMID- 22424784 TI - Adenovirus type 35, but not type 5, stimulates NK cell activation via plasmacytoid dendritic cells and TLR9 signaling. AB - In hematopoietic stem cell transplant (HSCT) recipients, disseminated adenoviral infections during the first two months after HSCT can lead to severe complications and fatal outcome. Since NK cells are usually the first lymphocytes to reconstitute after HSCT and have been implicated in the clearance of adenovirus-infected cells, it was investigated whether NK cells are activated by adenovirus in vitro. Exposure of PBMC to human adenovirus type 5 (HAdV5) or HAdV35 resulted in the up-regulation of the activation marker CD69 on NK cells and enhanced the cytolytic activity of NK cells. HAdV5-induced NK cell activation relied on the contribution of T cells as the depletion of T cells from PBMC abolished NK cell activation. In contrast, NK cell activation in response to HAdV35 occurred in the absence of T cells. Plasmacytoid dendritic cells (pDC) were necessary and sufficient to mediate NK cell activation. HAdV35 induced significantly more interferon-alpha (IFN-alpha) production by pDC than HAdV5. The increased IFN-alpha production and NK cell activation correlated with a higher infection efficiency of viruses with the type 35 fiber. The IFN-alpha response of pDC was enhanced by the presence of NK cells, suggesting a reciprocal interaction between pDC and NK cells. Incubation with a TLR9 antagonist impaired the IFN alpha production by pDC as well as NK cell activation, implying that TLR9 signaling is critically involved in the IFN-alpha response of pDC and NK cell activation after HAdV35 exposure. In conclusion, two human adenovirus serotypes from two different species differ considerably in their capacity to stimulate pDC and NK cells. PMID- 22424785 TI - CD4+ Th2 cells function alike effector Tr1 and Th1 cells through the deletion of a single cytokine IL-6 and IL-10 gene. AB - Depending on polarizing cytokine signals during activation by antigen, naive CD4+ T cells can be stimulated and differentiated into distinct functional CD4+ T cell subsets such as Th1, Th2 and Tr1 cells. Among them, Th2 cells are pathogenic in allergic diseases such as asthma, which are characterized by transcription factor GATA3 expression and IL-4, IL-5, IL-6, and IL-10 cytokine secretion. The overlapping expression of some signature cytokines by Th2 and other subsets of CD4+ T cells may not only indicate the plasticity of CD4+ T cells, but could also suggest the possibility of the deletion of a single signature cytokine gene leading to the functional differentiation of naive CD4+ T cells into effector Th1 or Tr1 cells under Th2 differentiation conditions. In this work, we stimulated naive CD4+ T cells derived from OT II mice or OT II mice that were deficient in individual cytokines (IL-4, IL-5, IL-6 and IL-10) with OVA-pulsed dendritic cells (DC(OVA)) in the presence of IL-4 and anti-IFN-gamma, to generate OVA-specific wild-type (WT) Th2, and Th2(IL-4 KO), or Th2(IL-5 KO), or Th2(IL-6 KO), or Th2(IL 10 KO) cells, and to assess their capacity in modulating DC(OVA)-induced CD8+ cytotoxic T lymphocyte (CTL) responses, and antitumor immunity in WT C57BL/6 mice. We conclusively demonstrate that GATA-3-expressing Th2 cells enhance DC(OVA)-induced CTL responses via IL-6 secretion. We also show that IL-6 and IL 10 gene deficient Th2(IL-6 KO) and Th2(IL-10 KO) cells, but not IL-4 and IL-5 gene deficient Th2(IL-4 KO) and Th2(IL-5 KO) cells, behave like functional Tr1 and Th1 cells by inhibiting and enhancing DC(OVA)-induced OVA-specific CD8+ CTL responses and antitumor immunity, respectively. We further elucidate that inhibition and enhancement of DC(OVA)-induced OVA-specific CTL responses by Th2(IL-6 KO) and Th2(IL-10 KO) cells are mediated by their immune suppressive IL 10 and pro-inflammatory IL-6 secretion, respectively. Taken together, our study suggests that deletion of a single cytokine gene IL-6 and IL-10 makes CD4+ Th2 cells become effector CD4+ Tr1- and Th1-like cells, respectively. Our data thus not only provide new evidence for another type of CD4+ T cell plasticity, but also have a potential to impact the development of a new direction in immunotherapy of allergic diseases. PMID- 22424786 TI - Chaeoglobosin Fex inhibits poly(I:C)-induced activation of bone marrow-derived dendritic cells. AB - Dendritic cells (DCs) are implicated in the induction of autoimmune diseases and exist in lesions associated with several autoimmune inflammatory diseases. Chaeoglobosin Fex (Cha Fex), a cytochalasan-based alkaloid, was isolated from marine-derived endophytic fungus Chaetomium globosum QEN-14. In the present study, we evaluated the effect of Cha Fex on poly(I:C)-induced bone marrow derived DCs. The results showed that Cha Fex attenuated the production of IFN beta both at the mRNA and protein level in poly(I:C)-induced DCs. Cha Fex markedly inhibited the maturation and function of the DCs with a reduced capacity to uptake antigens and low level of expression of costimulatory molecules. Moreover, Cha Fex abrogated the ability of poly(I:C)-induced DCs to promotion of T cell proliferation, Furthermore, Cha Fex inhibited the phosphorylation of IkappaB-alpha and IRF-3 in poly(I:C)-induced DCs. Cha Fex also reduced the phosphorylation of p38 and JNK, without affecting ERK1/2. These data demonstrate that that Cha Fex can exhibit an immunosuppressive effect on mouse bone marrow derived DCs (BMDCs) via TLR3 signaling, which suggests potential application of Cha Fex in the treatment of autoimmune inflammatory diseases. PMID- 22424787 TI - Oxytocin can impair memory for social and non-social visual objects: a within subject investigation of oxytocin's effects on human memory. AB - Oxytocin is important to social behavior and emotion regulation in humans. Oxytocin's role derives in part from its effect on memory performance. More specifically, previous research suggests that oxytocin facilitates recognition of social (e.g., faces), but not of non-social stimuli (e.g., words, visual objects). We conducted the first within-subject study to this hypothesis in a double-blind, placebo-controlled design. We administered oxytocin (24IU) and placebo (saline) in two separate sessions and in randomized order to healthy men. To obtain a baseline measure for session-dependent memory effects, which are caused by proactive interference, an additional group of male subjects in each session received placebo unbeknownst to them and the experimenter. After administration, participants studied faces and houses. Exactly one day after each study session, participants were asked to make memory judgments of new and old items. In the first study-test session, participants administered with oxytocin showed reduced recollection of previously studied faces and houses. Oxytocin also interacted with proactive-interference effects. By impeding memory in the first session, it reduced proactive interference in the second. But oxytocin contributed additionally to the memory-reducing effect of proactive interference when administered in the second session. These results demonstrate that oxytocin can have a memory-impairing effect on both social and non-social visual objects. The present study also emphasizes the necessity of including a non-treated, baseline group in within-subject designs when investigating oxytocin's effects on human memory. PMID- 22424788 TI - Long-term changes in morphology, D2R expression and targets of regenerated dopaminergic terminals in the striatum after a partial lesion in the substantia nigra in the rat. AB - During Parkinson's disease (PD), compensatory regeneration or sprouting of fibers from surviving dopaminergic neurons in the striatum occurs in response to the lesion in the substantia nigra pars compacta (SNpc). The morphological characteristics of regenerated terminal have previously been shown to differ from normal terminals. Here, we provide insights into the morphological characteristics of regenerated dopaminergic terminals in the striatum over a 16 week period after a partial SNpc lesion. The dopaminergic fibers were almost completely lost in the dorsal part of the striatum 2weeks after the lesion, but returned to normal by 16weeks with an equal degree of dopaminergic neuron lesions in the SN at both time points. Morphologically, the regenerated dopaminergic terminals in the striatum were larger in size and had more small and large vesicles with a down-regulation of D(2) dopamine receptor (D(2)R). These terminals were more frequently in contact with D(2)R bearing neurons than D(1)R bearing neurons in the striatum. Therefore, the results indicate that dopaminergic fibers did regenerate in the dorsal part of the striatum after the SNpc lesion. Their morphological characteristics intuitively indicate that they were capable of delivering larger amounts of dopamine (DA) to compensate for the depletion, and to balance the secretion and re-uptake of DA after the lesion. The targeted change in regenerated dopaminergic terminals may disrupt the balance between the direct and indirect pathways in the basal ganglia, thereby resulting in the onset of PD symptoms. PMID- 22424789 TI - Spliceosomal small nuclear ribonucleoprotein biogenesis defects and motor neuron selectivity in spinal muscular atrophy. AB - The SMN protein is essential and participates in the assembly of macromolecular complexes of RNA and protein in all cells. The best-characterized function of SMN is as an assembler of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN performs this function as part of a complex with several other proteins called Gemins. snRNPs are assembled in the cytoplasm in a stepwise manner and then are imported to the nucleus where they participate globally in the splicing of pre mRNA. Mutations in the SMN1 gene result in the motor neuron disease, spinal muscular atrophy (SMA). Most of these mutations result in a reduction in the expression levels of the SMN protein, which, in turn, results in a reduction in snRNP assembly capacity. This review highlights current studies that have investigated the mechanism of SMN-dependent snRNP assembly, as well as the downstream effects on pre-mRNA splicing that result from a decrease in SMN. This article is part of a Special Issue entitled "RNA-Binding Proteins". PMID- 22424790 TI - Event-related potentials and oscillatory brain responses associated with semantic and Stroop-like interference effects in overt naming. AB - Picture-word interference is a widely employed paradigm to investigate lexical access in word production: Speakers name pictures while trying to ignore superimposed distractor words. The distractor can be congruent to the picture (pictured cat, word cat), categorically related (pictured cat, word dog), or unrelated (pictured cat, word pen). Categorically related distractors slow down picture naming relative to unrelated distractors, the so-called semantic interference. Categorically related distractors slow down picture naming relative to congruent distractors, analogous to findings in the colour-word Stroop task. The locus of semantic interference and Stroop-like effects in naming performance has recently become a topic of debate. Whereas some researchers argue for a pre lexical locus of semantic interference and a lexical locus of Stroop-like effects, others localise both effects at the lexical selection stage. We investigated the time course of semantic and Stroop-like interference effects in overt picture naming by means of event-related potentials (ERP) and time frequency analyses. Moreover, we employed cluster-based permutation for statistical analyses. Naming latencies showed semantic and Stroop-like interference effects. The ERP waveforms for congruent stimuli started diverging statistically from categorically related stimuli around 250 ms. Deflections for the categorically related condition were more negative-going than for the congruent condition (the Stroop-like effect). The time-frequency analysis revealed a power increase in the beta band (12-30 Hz) for categorically related relative to unrelated stimuli roughly between 250 and 370 ms (the semantic effect). The common time window of these effects suggests that both semantic interference and Stroop-like effects emerged during lexical selection. PMID- 22424791 TI - Gain of spinal motoneurons measured from square and ramp current pulses. AB - The gain of motoneurons (MNs) characterizes how variations in synaptic input are transformed in to variations in output firing and muscle contraction. Experimentally gain is often defined as the frequency-current relation observed in response to injected suprathreshold square current pulses or current ramps during intracellular recording. The gain of MNs is strongly affected by adaptation: transient gain in response to depolarization is usually higher than steady state gain measured during sustained depolarization. The transient and the stationary gain of neurons are separate entities that can be selectively modified. Here we investigated how the transient and the stationary gain of spinal MNs obtained from responses to square current pulses are related to gain estimated from the responses to the current ramps. We found, that the gain in response to current ramps is identical to the steady state gain during sustained depolarization. Therefore, gain modulation is more fully characterized with square current pulses than with current ramps. PMID- 22424792 TI - Characterisation of the effect of knockout of the amyloid precursor protein on outcome following mild traumatic brain injury. AB - The amyloid precursor protein (APP) increases following traumatic brain injury (TBI), although the functional significance of this remains unclear largely because the functions of the subsequent APP metabolites are so different: Abeta is neurotoxic whilst sAPPalpha is neuroprotective. To investigate this further, APP wildtype and knockout mice were subjected to mild diffuse TBI and their outcomes compared. APP knockout mice displayed significantly worse cognitive and motor deficits, as demonstrated by the Barnes Maze and rotarod respectively, than APP wildtype mice. This was associated with a significant increase in hippocampal and cortical cell loss, as well as axonal injury, in APP knockout mice and an impaired neuroreparative response as indicated by diminished GAP-43 immunoreactivity when compared to APP wildtype mice. This study is the first to demonstrate that endogenous APP is beneficial following mild TBI, suggesting that the upregulation of APP observed following injury is an acute protective response. PMID- 22424793 TI - Sodium Ferulate combined with bone marrow stromal cell treatment ameliorating rat brain ischemic injury after stroke. AB - Reports suggested that bone marrow stromal cells (BMSCs) could protect brain against ischemic injury. However, the limited number of BMSCs in the brain hampered their application. To explore a way that might improve the migration and differentiation of BMSCs in the brain after stroke, we investigated the additive therapeutic effect of combination Sodium Ferulate (SF) and BMSCs treatment of stroke. In general, BMSCs were primarily cultured from rat bone marrow and were identified by flow cytometry. Permanent middle cerebral artery occlusion (MCAo) was induced and the ischemic brain was observed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The neurological functional outcome was respectively evaluated at 0 hour, 24 hours, 48 hours, and 72 hours post-operation, and the stromal cell-derived factor-1 alpha (SDF-1alpha) /chemokine(CXC motif)receptor 4(CXCR4) mRNA and protein expressions at the marginal zone of the ischemic brain were respectively measured by real-time RT-PCR and Western Blot at 3days after stroke; furthermore, Nestin and BrdU double immunostaining was performed for identification of BMSC differentiation. Combination treatment of Stroke significantly improved the neurological functional recovery as early as 48 hours and up-regulated the SDF-1alpha /CXCR4 axis, enhanced BMSC migration into the ischemic brain and differentiation into Nestin-positive cells. We demonstrate that SF combined with BMSC administration can ameliorate rat brain ischemic injury and has beneficial effect on the rat neurological functional recovery after ischemic stroke. PMID- 22424794 TI - [Monitoring of vancomycin in pediatrics]. AB - OBJECTIVES: The authors wanted to determine if the current local practice (initial prescription and monitoring) in pediatrics allowed reaching vancomycin therapeutic concentrations. PATIENTS AND METHODS: Thirty patients that had received vancomycin for at least five days with at least one evaluation of serum concentration, at the Sainte-Justine university hospital center, were retrospectively studied. Vancomycin trough and peak levels were analyzed. RESULTS: The values of vancomycin serum concentration were within therapeutic ranges (local standards of 5 to 10mg/L for trough level and 20 to 40 mg/L for peak level) in 60% and 33% of cases at the fifth day of treatment for trough and peak levels, respectively. CONCLUSION: The current practice does not allow reaching vancomycin serum concentrations in the target range. Using a wider range for the trough values could be considered. PMID- 22424795 TI - Pneumococcus infections: is the burden still as heavy? AB - The death rate of invasive pneumococcal infections decreased by 100 fold in one century. This tremendous improvement was due mainly to antibiotic use and multiple attempts at antipneumococcal vaccinations; thus, this was true only for developed countries. However, in France, the incidence has increased, over the last 10 years, in all age classes except for children vaccinated by the heptavalent pneumococcal conjugate vaccine. The incidence of these infections remains high, when associated to some risk factors such as HIV infection, malignant blood diseases, solid cancers, bronchial diseases, or alcohol abuse. The pneumococcal vaccine should be prescribed first to patients with those risk factors. A change of serotypes distribution has been observed in children with a decrease of vaccine serotypes and predominance of related or non-vaccine serotypes. This reflects the effectiveness of vaccination and the need of to regularly update the vaccine. Thus, pneumococcal infections have been increasing and vaccination should be more widely proposed. PMID- 22424796 TI - How to improve the collection and analysis of hospital antibiotic consumption: preliminary results of the ConsoRes software experimental implementation. AB - OBJECTIVE: The online software ConsoRes is used to collect and analyze data on antibiotic consumption and evolution of bacterial resistance in healthcare institutions in every hospital ward (HW). We report the first results of ConsoRes implementation in the northeast hospitals of France. METHODOLOGY: ConsoRes was implemented in January 2011, in nine volunteer hospitals after performing an onsite assessment. Five of these hospitals were already monitoring antibiotic consumption with a network such as Raisin ATB or Antibiolor, providing feedback on the various evaluation tools. RESULTS: The ConsoRes data collection import function meets expectations of pharmacists, bacteriologists, or clinicians since it is user friendly, prevents redundant data input, and allows data transfer to the national databases. Importing the hospital organizational structure prevents mistakes on consumption allocation, which was noted in the previous databases, and makes comparison and benchmark analysis reliable. ConsoRes also provides a rapid consumption data feedback to all registered users within the hospital, whether in charge of a ward (clinician) or having a transversal function (pharmacist, bacteriologist). The availability of an automatic standard report or of an online customized report is another major feature of ConsoRes. CONCLUSION: Besides providing surveillance, the concomitant analysis of local antibiotic consumption and bacterial resistance should have an educational impact by allowing each user to implement actions within the framework of antibiotic stewardship. PMID- 22424797 TI - Strangulated lesser sac hernia. AB - Internal hernias account for less than 1% of acute mechanical bowel obstruction. Because of their rarety, they are often not considered in the clinical or radiologic diagnosis of bowel obstruction; diagnosis is often delayed, and is most often made at the time of surgery. We present images obtained during the management of a strangulated transomental internal hernia; computerized tomography permitted timely preoperative diagnosis and specifically adapted surgical therapy. PMID- 22424798 TI - Reducing dissolved inorganic nitrogen in surface runoff water from sugarcane production systems. AB - Nitrogen (N) lost from farms, especially as the highly bioavailable dissolved inorganic form, may be damaging Australia's Great Barrier Reef (GBR). As sugarcane is the dominant cropping system in GBR catchments, its N management practises are coming under increasing scrutiny. This study measured dissolved inorganic N lost in surface runoff water and sugarcane productivity over 3 years. The experiment compared the conventional fertiliser N application rate to sugarcane (average 180kg N/ha/year) and a rate based on replacing N exported in the previous crop (average 94kg N/ha/year). Dissolved inorganic N losses in surface water were 72%, 48% and 66% lower in the three monitored years in the reduced N fertiliser treatment. There was no significant difference in sugarcane yield between the two fertiliser N treatments, nor any treatment difference in soil mineral N - both of these results are indicators of the sustainability of the lower fertiliser N applications. PMID- 22424799 TI - Hyperalgesia in heroin dependent patients and the effects of opioid substitution therapy. AB - Evidence suggests that patients on opiate maintenance therapy for the treatment of addiction present with opioid-induced hyperalgesia. This study compared the experimental (cold-pressor, electrical stimulation) pain responses of 82 treatment-seeking heroin-dependent adults, randomized to methadone (METH, n = 11) or buprenorphine (BUP, n = 64) therapy, with matched drug free controls (n = 21). Heroin-dependent participants were evaluated at baseline (treatment entry), medication (METH or BUP) stabilization (4-8 weeks), and chronic administration (12-18 weeks), at trough (just prior to dosing) and peak (3 hours after dosing) plasma levels. Collection of the control group's pain responses occurred twice during a single session, 3 hours apart. Baseline comparisons indicate that heroin dependent individuals demonstrate significantly shorter latencies to threshold and tolerance for cold-pressor pain than the control group. Across pain stimuli and time points, little change in pain responses was found over time, the exception being cold pressor pain tolerance, for which hyperalgesia significantly increased at trough METH/BUP levels in both groups as they stabilized in treatment. We conclude that heroin-dependent individuals are hyperalgesic, and that once stabilized in treatment, are not different in pain responses regardless of treatment agent. The effects of nonpharmacologic therapy and previous heroin use may explain increased hyperalgesia found with treatment. PERSPECTIVE: To better understand the clinical phenomenon of opioid-induced hyperalgesia, this article describes experimental pain responses of heroin-dependent participants both prior to and over the course of maintenance therapy with methadone or buprenorphine. Hyperalgesia is present with illicit and treatment opioid use, and does not appear to appreciably improve over the course of treatment. PMID- 22424800 TI - "Moderate intensive insulin therapy" is associated with remission of high intracranial pressure in patients with vascular or infectious central nervous system diseases. AB - Intensive insulin therapy (IIT), targeting blood glucose between 80 mg/dL and 110 mg/dL ("strict IIT"), has been associated with rapid remission of high intracranial pressure (ICP), but its use is limited due to a high risk of hypoglycemia. The aim of this retrospective study was to assess whether "moderate IIT" (target range for blood glucose: 80-140 mg/dL) could have the same beneficial effect on ICP with a lower risk of hypoglycemia. We retrospectively analyzed the records of 64 patients with high ICP due to vascular or infectious central nervous system diseases. Patients treated with moderate IIT (n=32) after 2005 were compared with patients treated with a conventional approach (n=32, target <180 mg/dL) before 2005. We assessed daily ICP during the first 14 days. Secondary endpoints were the rate of hypoglycemic events and outcome. ICP was significantly lower during the second week in patients treated with moderate IIT (mean+/-standard deviation [SD] daily ICP on days 8-14: 16+/-5 mmHg compared to 12+/-4 mmHg, p<0.001). The risk of hypoglycemic events (<40 mg/dL) did not differ significantly between the groups (0 vs. 1 patient, p=0.5). Moderate IIT is associated with remission of high ICP. In contrast to strict IIT, its use seems not to be limited by an increased risk of severe hypoglycemia. PMID- 22424801 TI - Schizophrenia genetics: progress, at last. AB - The heritability of schizophrenia is well established, and has motivated the search for genetic variation that contributes to susceptibility. Recent progress from both genome-wide association and copy number variant studies have identified risk loci, however, these are at very different ends of the susceptibility spectrum with respect to allele frequency and effect size. It is likely that investigations of common variants have surrendered their full yield, but rare variant exploration is at the very beginning. PMID- 22424802 TI - New and Xisting regulatory mechanisms of X chromosome inactivation. AB - Equalization of X linked gene expression is necessary in mammalian cells due to the presence of two X chromosomes in females and one in males. To achieve this, all female cells inactivate one of the two X chromosomes during development. This process, termed X chromosome inactivation (XCI), is a quintessential epigenetic phenomenon and involves a complex interplay between noncoding RNAs and protein factors. Progress in this area of study has consequently resulted in new approaches to study epigenetics and regulatory RNA function. Here we will discuss recent developments in the field that have advanced our understanding of XCI and its regulatory mechanisms. PMID- 22424803 TI - Visual function through 4 contact lens-based pinhole systems for presbyopia. AB - PURPOSE: To evaluate the effects of different contact lens-based artificial pupil designs on visual performance. SETTING: University of Valencia, Burjassot, Spain, and University of Manchester, Manchester, United Kingdom. DESIGN: Comparative case series. METHODS: Presbyopic patients were evaluated using 4 artificial pupil designs in the nondominant eye. Binocular uncorrected distance visual acuity (UDVA), binocular corrected distance visual acuity (CDVA), binocular uncorrected near visual acuity (UNVA), binocular distance-corrected near visual acuity (DCNVA), defocus curve, binocular distance, and near contrast sensitivity under photopic and mesopic conditions, and stereoacuity were measured after contact lens fitting. RESULTS: The mean UDVA and CDVA ranged from 0.04 +/- 0.05 (SD) to 0.01 +/- 0.04 logMAR and from -0.02 +/- 0.05 to -0.05 +/- 0.03 logMAR, respectively. The UNVA and DCNVA ranged from 0.37 +/- 0.11 to 0.42 +/- 0.20 logMAR and from 0.35 +/- 0.17 to 0.38 +/- 0.12 logMAR, respectively. The difference in binocular distance contrast sensitivity was statistically significant between the pinhole systems and the control group (distance-corrected patients without pinhole lens) for 6 cycles per degree (cpd), 12 cpd, and 18 cpd; for near vision, differences were also significant for 3 cpd at the 2 luminance levels (P<.05). Stereoacuity values for near vision were not significantly different between the 4 pinhole systems (P>.05). CONCLUSIONS: Soft contact lens apertures provide good visual acuity at distance, functional intermediate vision, and poor near visual acuity and stereoacuity. An improvement in visual performance with decreasing pupil diameter was not found. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22424804 TI - Biaxial microincision cataract surgery versus conventional coaxial cataract surgery: metaanalysis of randomized controlled trials. AB - A comprehensive literature search of Cochrane Library, PubMed, and Embase was performed to identify relevant prospective randomized controlled trials (RCTs) comparing biaxial microincision cataract surgery (MICS) and conventional coaxial phacoemulsification. A metaanalysis was performed on the following outcome measures: effective phacoemulsification time (EPT), phacoemulsification power (%), corrected distance visual acuity (CDVA), surgically induced astigmatism (SIA), laser flare photometry value, percentage of endothelial cell loss, change in central corneal thickness (CCT), and complications. Eleven RCTs describing a total of 1064 eyes were identified. There were no significant differences between the techniques in CDVA, mean percentage of endothelial cell loss, laser flare photometry value, CCT change, and intraoperative and postoperative complications. However, EPT was statistically significantly shorter and the mean phaco power was statistically significantly lower in the biaxial group than in the coaxial group, and biaxial MICS induced less SIA. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22424805 TI - Peripheral refraction in pseudophakic eyes measured by infrared scanning photoretinoscopy. AB - PURPOSE: To obtain quantitative data of peripheral refractive errors in pseudophakic eyes including measurements up to +/-45 degrees on the retina. SETTING: University Eye Hospital, Tubingen, Germany. DESIGN: Population-based cross-sectional study. METHODS: Pseudophakic and phakic subjects were measured with a purpose-built scanning photorefractor. The instrument was improved over previous versions. It permits measurement of semicontinuous peripheral profiles over the central 90-degree field of the retina at a faster speed (4 s/scan). RESULTS: Twenty-four pseudophakic and 43 phakic subjects were enrolled. The intraocular lenses (IOLs) induced a mean myopic shift of 2.00 diopters (D) at +/ 45 degrees of eccentricity in the vertical pupil meridian. Ray-tracing simulations with phakic eye and pseudophakic eye models agreed well with the experimental data. They showed that changes induced by IOLs were a consequence of an increase in astigmatism with eccentricity and a myopic shift in the spherical equivalent. CONCLUSIONS: The peripheral refractions in pseudophakic eyes were more myopic than in phakic eyes as a consequence of the optical design of the IOLs. Whether a more myopic refraction of approximately 2.00 D at 45 degrees has significant effects on visual performance must be tested. Perhaps there is room for improvement in the peripheral optics of IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22424806 TI - Suture fixation of iris-claw intraocular lens. AB - We report a technique to surgically manage the damaged haptic of an iris-claw intraocular lens (IOL). An 89-year-old woman initially presented with a subluxated posterior chamber IOL that was exchanged for an Artisan iris-claw IOL. The IOL had been enclavated nasally and temporally, but it deenclavated nasally 4 weeks postoperatively. During surgery to reposition the IOL, 1 haptic of the nasal claw was seen to be damaged. It was sutured to the iris with 10-0 polypropylene using a CIF-4 needle. The postoperative outcome was good. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22424807 TI - Flap thickness in eyes with ectasia after laser in situ keratomileusis. AB - PURPOSE: To measure central flap thickness in eyes with ectasia after laser in situ keratomileusis (LASIK) and to compare these values with estimated anticipated flap thickness based on mean published values for each device used for flap creation. SETTING: Emory Vision at Emory University, Atlanta, Georgia, USA. DESIGN: Retrospective comparative case series, using published data for controls. METHODS: Confocal microscopic analysis was performed using the Confoscan 3 device to measure central flap thickness in eyes with ectasia after LASIK. Pre-LASIK records were evaluated for information, including basic patient demographics, preoperative corneal topographies, estimated anticipated flap thickness based on the mean average thickness values, and residual stromal bed (RSB) thickness calculations using measured and estimated flap thicknesses. RESULTS: Fifty eyes of 29 patients were evaluated. The mean measured flap thickness was 138 MUm +/- 26 (SD) (range 90 to 220 MUm). There were no significant differences between measured and estimated flap thicknesses (138 MUm versus 135 MUm; P=.5) or RSB thickness (329 MUm versus 332 MUm; P=.7), nor were there differences in flap thickness between eyes developing ectasia with normal corneal topographies and eyes with abnormal corneal topographies. One eye had a measured flap resulting in an unintended RSB thickness less than 250 MUm; this eye also had abnormal topography. CONCLUSIONS: Measured central flap thickness was not thicker than estimated in most eyes developing ectasia after LASIK. Thus, excessively thick flaps do not appear to be a major contributing factor to the pathogenesis of ectasia after LASIK. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22424808 TI - [Internal astigmatism with other ocular lesions]. AB - Astigmatism is a refractive defect whose origin is not always purely corneal, and is sometimes the result of corneal, crystalline lens or mixte contributions. The aim of our study is to report, through two cases, ocular lesions associated with a lenticular astigmatism and their evolution after treatment. In the first observation, it is a 25-year-old patient with a unilateral extra corneal astigmatism within the framework of the "tilted disc syndrome" associated with bilateral myopia. This patient has received treatment by Lasik. The postoperative course was good with a decline of 5 ans. The second observation is that of a patient aged 35 years without having a general history with a posterior lenticonus associated with keratoconus responsible for a major mixed astigmatism. She received combined surgery: penetrating keratoplasty with lens extraction and implantation of an artificial lens. The evolution was good with good visual recovery. The balance of internal astigmatism must include the systematic achievement of a subjective and objective refraction under cycloplegia and corneal topography. The search for etiology is critical to screen for eye or general disease and guide the therapeutic strategy. Knowledge of the refractive power of the cornea and crystalline lens of astigmatism separately would be important for surgery refractive and crystalline lens surgery. PMID- 22424809 TI - A retrospective study of tumours in black-tailed prairie dogs (Cynomys ludovicianus) submitted to a zoological pathology service. AB - Fifty-three tumours were diagnosed in samples originating from 167 different black-tailed prairie dogs (Cynomys ludovicianus) submitted to Northwest ZooPath (NZP) between 1996 and 2009. Three prairie dogs had more than one type of neoplasm. Thirty-two of the 50 prairie dogs were from zoological parks in the USA; 17 were owned privately and one was from a wildlife centre. Ages ranged from 2-9 years (median age 5.6 years) for 41 animals in which age was known. Thirty nine (73.6%) of the tumours were classified as malignant and 14 (26.4%) were benign. Common sites for tumours were the liver, the alimentary tract and the haemolymphoid and integumentary systems. Hepatocellular carcinoma, hepatocellular adenoma, lymphoid malignancies and elodontoma were diagnosed most commonly. PMID- 22424811 TI - [Physical restraint use in critical care units. Perceptions of patients and their families]. AB - INTRODUCTION: The use of physical restraints in Intensive Care Units (ICU) is common although little is known about patients' and relatives' perceptions of this use. OBJECTIVES: 1) To analyze the prevalence and use of physical restraints in a general adult ICU; 2) to know the perceptions of patients who experienced use of physical restraints and; 3) to know the perceptions of relatives of patients who used physical restraints. METHODS: This descriptive study, which used both quantitative and qualitative methods, was carried out in an adult ICU. For the first objective, all the patients (101) who had used any kind of physical restraint were analysed. For the second and third objectives, 30 patients and 30 relatives were interviewed using the guidelines of Strumpf & Evans as modified by Hardin (1993). All interviews were recorded, fully transcribed and then submitted to a language content analysis using the method of Hsieh & Shannon. RESULTS: The only physical restraint used was the wrist restraint with a prevalence of 43.47%. Seventy-two percent of patients wore the restraint <=12h and 28%>12h. Analysis of the patient interviews revealed 4 main themes: acceptance of the restraint conditioned by beliefs and information provided; feelings and sensations caused by the use of the restraint; alternatives proposed and future repercussions. Three themes emerged from the interviews with relatives: impressions caused by the use of the restrictions; reasons for accepting or rejecting them; alternatives to the use of restraints. CONCLUSIONS: Most patients used physical restraints for a short period of time and only the wrist restraint was used. Patients using physical restraints and their relatives expressed a wide range of feelings and sensations, with no negative future repercussions. In general, they agreed with the use of restraints although more precise information would lead to greater acceptance. PMID- 22424812 TI - Differences in the patient's and the physician's perspective of disease in psoriatic arthritis. AB - OBJECTIVE: To define the relative impact of disease components of psoriatic arthritis (PsA) on the global burden of disease and to compare physician's and patients' ratings of disease activity. METHODS: PsA patients fulfilling the Classification Criteria for Psoriatic Arthritis (N = 55) were asked for an evaluation of the absolute and relative impact of general and specific rheumatic symptoms (ie, arthritis, enthesitis, spinal disease, dactylitis), general and specific psoriatic symptoms (skin disease, nail disease), and other common symptoms (eg, fatigue). Results were related to the respective physician's evaluations of disease-related symptoms based on visual analog scale (VAS) ratings and comparative measures of disease activity (ie, swollen and tender joint counts, MASES, PASI, NAPSI). RESULTS: One-half of the global burden of disease in PsA patients was attributed to rheumatic symptoms with peripheral arthritis as the leading component, whereas the other one-half was equally distributed to psoriatic and additional common symptoms such as fatigue. In general, corresponding patient and physician ratings of global, rheumatic, and psoriatic disease activity showed good correlations when using VAS but at the same time revealed significantly lower ratings of the corresponding physician on VAS and transformed comparative measures (all P <= 0.02). CONCLUSIONS: Although we found good correlations of various disease activity measures, physicians usually evaluated the disease activity of PsA lower than patients. These results highlight the necessity of incorporating patient reported outcome measures into the assessment of disease activity in PsA, which can easily be visualized with the help of a spiderweb graph. PMID- 22424814 TI - A micellization study of medium chain length poly(3-hydroxyalkanoate)-based amphiphilic diblock copolymers. AB - In this article, we report the first micellization study of amphiphilic copolymers composed of bacterial medium chain length poly(3-hydroxyalkanoates) (mcl-PHAs). A series of diblock copolymers based on fixed poly(ethylene glycol) (PEG) block (5000 g mol(-1)) and a varying poly(3-hydroxyoctanoate-co-3 hydroxyhexanoate) (PHOHHx) segment (1500-7700 g mol(-1)) have been synthesized using "click" chemistry. These copolymers self-assembled to form micelles in aqueous media. The influence of PHOHHx block molar mass on the hydrodynamic size and on the critical micelle concentration (CMC) has been studied using dynamic light scattering and fluorescence spectroscopy, respectively. With increasing PHOHHx length, narrowly distributed micelles with diameters ranging from 44 to 90 nm were obtained, with extremely low CMC (up to 0.85 mg/L). Cryogenic transmission electron microscopy (Cryo-TEM) showed that micelles took on a spherical shape and exhibited narrow polydispersity. Finally, the colloidal stability of the micelles against physiological NaCl concentration has been demonstrated, suggesting they are promising candidates for drug delivery applications. PMID- 22424813 TI - Lipid testing in patients with rheumatoid arthritis and key cardiovascular related comorbidities: a medicare analysis. AB - OBJECTIVE: For patients with rheumatoid arthritis (RA) and comorbid cardiovascular disease (CVD), diabetes, or hyperlipidemia, annual lipid testing is recommended to reduce morbidity and mortality from comorbidities. Given trends encouraging complex patients to receive care in "medical homes," we examined associations between regularly seeing a primary care provider (PCP) and lipid testing in RA patients with cardiovascular-related comorbidities. METHODS: We performed a retrospective cohort study examining a 5% random USA Medicare sample (2004-06) of beneficiaries over 65 years old with RA and concomitant CVD, diabetes, or hyperlipidemia (n = 16,893). We examined the relationship between receiving lipid testing in 2006 and having at least 1 PCP visit per year in 2004, 2005, and 2006 using multivariate regression. RESULTS: Ninety percent of patients had prevalent CVD; 46% had diabetes, and 64% had hyperlipidemia. However, annual lipid testing was only performed in 63% of these RA patients. Thirty percent of patients saw a PCP less than once per year, despite frequent visits (mean >9) with other providers. Patients without at least 1 annual PCP visit were 16% less likely to have lipid testing. Increased age, complexity scores, hospitalization, and large town residence predicted decreased lipid testing. CONCLUSIONS: Despite comorbid CVD, diabetes, or hyperlipidemia, 30% of Medicare RA patients saw a PCP less than once per year, and 1 in 3 lacked annual lipid testing. Findings support advocating primary care visits at least once per year. Remaining gaps in lipid testing suggest the need for additional strategies to improve lipid testing in at risk RA patients. PMID- 22424815 TI - Adsorption of arsenic on multiwall carbon nanotube-zirconia nanohybrid for potential drinking water purification. AB - The adsorptive removal of arsenic from water using a multiwall carbon nanotube zirconia nanohybrid (MWCNT-ZrO(2)) is presented. The MWCNT-ZrO(2) with 4.85% zirconia was effective in meeting the drinking water standard levels of 10 MUg L( 1). The absorption capacity of the composite were 2000 MUg g(-1) and 5000 MUg g( 1) for As(III) and As(V) respectively, which were significantly higher than those reported previously for iron oxide coated MWCNTs. The adsorption of As(V) on MWCNT-ZrO(2) was faster than that of As(III), and a pseudo-second order rate equation effectively described the uptake kinetics. The adsorption isotherms for As(III) and As(V) fitted both the Langmuir and Freundlich models. A major advantage of the MWCNT-ZrO(2) was that the adsorption capacity was not a function of pH. PMID- 22424816 TI - Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study. AB - OBJECTIVE: To elucidate the mechanism of hypotension following intravenous administration of paracetamol (acetaminophen) to patients on the Intensive Care Unit. DESIGN: Prospective observational cross-over study. SETTING: Intensive Care Unit, University Hospital Kralovske Vinohrady, Prague, Czech Republic. METHODS: Ventilated critically ill patients monitored by PiCCO and administered intravenous paracetamol at the same time were eligible for the study. We recorded haemodynamic indices, as well as core and peripheral temperatures, continuously for 3 h after the dose of paracetamol. Ranitidine was then used as a control drug known not to influence haemodynamics. RESULTS: We included 6 subjects, and recorded 48 cycles of observations after administration of paracetamol, and 35 cycles after administration of the control drug. Haemodynamic parameters were not different at the baseline and administration of control drug did not result in any change in haemodynamics. After intravenous paracetamol, mean arterial pressure (MAP) dropped by 7% (p<0.001) with a nadir at the 19th minute. In 22 measurement cycles (45%) we noted >15% reduction in MAP with paracetamol. Analysis of these cycles suggests that hypotension with paracetamol can be caused by reduction of both cardiac index and systemic vascular resistance. In febrile cycles paracetamol caused narrowing of the gradient between central and peripheral temperatures suggesting skin vasodilation. These changes were not correlated to a change of systemic vascular resistance at any time point. CONCLUSION: Hypotension with intravenous paracetamol in critically ill patients is caused by a reduction of both cardiac output and systemic vascular resistance. We did not demonstrate any relation between haemodynamic changes and antipyretic action of paracetamol. A possibility that cardiac output is reduced with paracetamol might be clinically important. PMID- 22424817 TI - Accommodative lag and refractive error in infants and toddlers. AB - PURPOSE: To measure accommodative performance as a function of refractive error in very young children. METHODS: This was a prospective study of accommodation lag in multiethnic typically developing children ages 5 to 24 months. Accommodation lag was measured by means of a modified bell retinoscopy technique. Refraction was measured by cycloplegic retinoscopy, and right and left eye results were averaged. The study compared accommodative performance to cycloplegic spherical equivalent and astigmatic refractive error. RESULTS: Analysis of data from 189 of 203 subjects revealed that larger lags and lower gain of the accommodative response were more common in younger children, although most children of all ages accommodated well, with 95% having lags <1.25 D. Larger accommodation lags were associated with greater spherical equivalent refractive error, although only with hyperopia >=4.0 D were lags >=1.25 D observed in a majority of children. Larger lags in the more hyperopic meridian were seen with increasing hyperopic with-the-rule astigmatism, but lag in the more hyperopic meridian varied little with the amount of myopic or mixed astigmatism. CONCLUSIONS: Most 5- to 24-month-old children accommodate well over a range of moderate hyperopic refractive errors, but hyperopia >=4.0 D is rarely associated with normal accommodative performance. Hyperopic and mixed or myopic astigmatic children show different patterns of accommodation, which may explain the patterns of visual acuity deficits seen in these children. PMID- 22424818 TI - Release of offensive odorants from the combustion of barbecue charcoals. AB - A number of offensive odorants including volatile organic compounds (VOCs), reduced sulfur compounds (RSCs), carbonyls, and ammonia were measured along with several reference pollutants (like benzene (B), CS(2), SO(2), CO, and total hydrocarbon (THC)) from combusted fumes of barbecue charcoals produced from five different countries (Korea, China, Indonesia, Malaysia, and the US). Although the emission concentrations of most odorants were generally below the reference guideline set by the malodor prevention law in Korea, the mean concentration of some aldehydes (acetaldehyde, propionaldehyde, and isovaleraldehyde) and ammonia exceeded those guidelines. As such, aldehydes were the most dominant odorant released from charcoal combustion followed by VOC and ammonia. If odorant levels of charcoal products are compared, there are great distinctions between the products of different countries. If comparison is made using the concept of the sum of odor intensity (SOI), the magnitude of SOI for the charcoal products from the five different countries varied in the order of 4.30 (Korea), 3.10 (Indonesia), 2.97 (China), 2.76 (Malaysia), and 2.76 (the US). PMID- 22424819 TI - TiO2 nanotubes for bone regeneration. AB - Nanostructured materials are believed to play a fundamental role in orthopedic research because bone itself has a structural hierarchy at the first level in the nanometer regime. Here, we report on titanium oxide (TiO(2)) surface nanostructures utilized for orthopedic implant considerations. Specifically, the effects of TiO(2) nanotube surfaces for bone regeneration will be discussed. This unique 3D tube shaped nanostructure created by electrochemical anodization has profound effects on osteogenic cells and is stimulating new avenues for orthopedic material surface designs. There is a growing body of data elucidating the benefits of using TiO(2) nanotubes for enhanced orthopedic implant surfaces. The current trends discussed within foreshadow the great potential of TiO(2) nanotubes for clinical use. PMID- 22424820 TI - Lean mass and insulin resistance in women with polycystic ovary syndrome. AB - Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Muscle is the major tissue utilizing glucose while excess adipose tissue relates to insulin resistance. Thus, body composition is likely to be an important regulator of insulin sensitivity. Thirty-nine PCOS patients (age: 29.9+/-1.0 years; BMI: 33.8+/-1.2 kg/m(2)) participated in a cross sectional study. Body composition was measured by dual energy x-ray absorptiometry (DEXA). Insulin resistance and secretion were assessed using oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FS-IVGTT). In contrast with the conventional expectations, lean mass correlated directly (P<.05) with the insulin resistance measure HOMA (r=0.440); and inversely with the insulin sensitivity index QUICKI (r=-0.522) independent of fat mass. In 11 pairs of subjects matched for fat mass (35.6+/-2.2 and 35.6+/-2.4 kg) but with discordant lean mass (52.8+/-1.8 vs 44.4+/-1.6 kg), those with higher lean mass had a higher glucose response during OGTT (AUC(Glucose); P=.034). In contrast, 17 pairs matched for lean mass (48.7+/-1.7 and 48.9+/-1.6 kg) but discordant for fat mass (43.3+/-2.6 vs 30.3+/-8.9 kg) showed no differences in insulin resistance parameters. These novel findings indicate that lean mass relates directly to insulin resistance in PCOS. PMID- 22424821 TI - Elevated IgG levels against specific bacterial antigens in obese patients with diabetes and in mice with diet-induced obesity and glucose intolerance. AB - High fat diets increase the risk for insulin resistance by promoting inflammation. The cause of inflammation is unclear, but germfree mouse studies have implicated commensal gut bacteria. We tested whether diet-induced obesity, diabetes, and inflammation are associated with anti-bacterial IgG. Blood from lean and obese healthy volunteers or obese patients with diabetes were analyzed by ELISA for IgG against extracts of potentially pathogenic and pro-biotic strains of Escherichia coli (LF-82 and Nissle), Bacteroides thetaiotaomicron, and Lactobacillus acidophilus, and for circulating tumor necrosis factor alpha (TNFalpha). C57Bl/6 mice were fed low- or high-fat diets (10% or 60% kcal from fat) for 10 weeks and tested for anti-bacterial IgG, bodyweight, fasting glucose, and inflammation. Obese diabetic patients had significantly more IgG against extracts of E. coli LF-82 compared with lean controls, whereas IgG against extracts of the other bacteria was unchanged. Circulating TNFalpha was elevated and correlated with IgG against the LF-82 extract. Mice fed high-fat diets had increased fasting glucose levels, elevated TNFalpha and neutrophils, and significantly more IgG against the LF-82 extracts. Diabetes in obesity is characterized by increased IgG against specific bacterial antigens. Specific commensal bacteria may mediate inflammatory effects of high-fat diets. PMID- 22424822 TI - Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. AB - The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation (C-reactive protein, cytokines, body weight, HbA1c, among others) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were randomized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty two patients were included, 11.9+/-2.6 years old; 28 (12 males/16 females) received metformin and 24 placebo (11 males/13 females). Baseline characteristics were similar between groups (except for body mass index, which in the metformin group was slightly higher). Percentage weight loss was greater in the metformin group (-5.86% vs 2.75%, P<.05). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables (F=7.714; P<.006). Also, metformin was associated with a significant decrease in HOMA-IR index (P=.032) and HbA1c levels (P=.001), but no change was observed in the concentration of other markers of inflammation. Metformin resulted in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers. PMID- 22424823 TI - Hypothyroidism: age-related influence on cardiovascular nitric oxide system in rats. AB - This study investigates whether changes in nitric oxide (NO) production participate in the cardiovascular manifestations of hypothyroidism and whether these changes are age-related. Sprague-Dawley rats aged 2 and 18 months old were treated with 0.02% methimazole (wt/vol) during 28 days. Left ventricular function was evaluated by echocardiography. Measurements of arterial blood pressure, heart rate, nitric oxide synthase (NOS) activity and NOS/caveolin-1 and -3 protein levels were performed. Hypothyroidism enhanced the age-related changes in heart function. Hypothyroid state decreased atrial NOS activity in both young and adult rats, associated with a reduction in protein levels of the three NOS isoforms in young animals and increased caveolin (cav) 1 expression in adult rats. Ventricle and aorta NOS activity increased in young and adult hypothyroid animals. In ventricle, changes in NOS activity were accompanied by an increase in inducible NOS isoform in young rats and by an increase in caveolins expression in adult rats. Greater aorta NOS activity level in young and in adult Hypo rats would derive from the inducible and the endothelial NOS isoform, respectively. Thyroid hormones would be one of the factors involved in the modulation of cardiovascular NO production and caveolin-1 and -3 tissue-specific abundance, regardless of age. Hypothyroidism appears to contribute in a differential way to aging-induced changes in the myocardium and aorta tissues. Low thyroid hormones levels would enhance the aging effect on the heart. Age-related changes in NO production participate in the cardiovascular manifestations of hypothyroidism. PMID- 22424824 TI - Meta-analysis of the association between ecstasy use and risky sexual behavior. AB - A random-effects meta-analysis was conducted to examine the association between ecstasy use and risky sexual behavior. Analysis of 17 studies revealed a small to moderate sized effect (mean weighted r=0.211, 95% CI: 0.085-0.336). Random effects homogeneity testing was non-significant, thus formal moderator analyses were not performed. Moreover, numerical and visual diagnostics suggested that publication bias was not a concern. It is hoped that the present meta-analytic findings and recommendations will encourage investigators to broaden their research methodologies and will stimulate new insights into the association between ecstasy use and risky sexual behavior. PMID- 22424825 TI - Do normative perceptions of drinking relate to alcohol use in U.S. Military veterans presenting to primary care? AB - OBJECTIVE: The current cross sectional study sought to examine whether perceived social normative beliefs are associated with indicators of alcohol use in a sample of alcohol misusing veterans. METHOD: A sample of 107 U.S. Military Veterans presenting to primary care that screened positive for alcohol misuse on the alcohol use disorders identification test-consumption items (AUDIT-C) was recruited. Assessment measures were used to examine social normative beliefs and alcohol-related concerns as they relate to indicators of alcohol use at baseline. RESULTS: Our findings indicate mixed support for our two hypotheses in that perceived descriptive norms were associated with alcohol use indicators in the predicted direction; however, this was not the case for alcohol-related concerns. For perceived norms, we found that higher quantity beliefs were significantly related to greater alcohol consumption on a drinking day (p<.01), increased likelihood of dependence (p<.01), and frequency beliefs were significantly related to total number of drinking days (p<.01). Findings for alcohol-related concerns emerged contrary to our hypothesis, with results depicting increased alcohol-related concerns associated with higher alcohol consumption across indicators of use (ps<.01). SUMMARY: Findings of the current study suggest that social normative beliefs, specifically misperceptions about descriptive norms, are significantly associated with alcohol consumption in a sample of alcohol misusing veterans presenting to primary care. PMID- 22424826 TI - Cu2O-Au nanocomposites for enzyme-free glucose sensing with enhanced performances. AB - A facile method for the synthesis of Cu(2)O-Au nanocomposites has been reported by injecting Cu(2)O nanocubes into Au precursor directly with the assistance of ultrasound radiation at room temperature. The ultrasound radiation is not a necessary requirement but can make the distribution of Au nanoparticles more homogenous. The formation of Cu(2)O-Au nanocomposites is attributed to following two reasons. The first one is the difference in the reduction potential between Cu(2+)/Cu(2)O and AuCl(4)(-)/Au, which can also be considered as the driving force for the redox reaction. The other one is the low lattice mismatch between (200) planes of Cu(2)O and (200) facets of Au, which is favorable for the formation of heterostructure. The electrochemical investigation demonstrates that the performances of Cu(2)O nanocubes in enzyme-free glucose sensing have been improved significantly after the decoration of Au nanoparticles which may be derived from the polarization effect provided by Au nanoparticles. As-prepared Cu(2)O-Au nanocomposites have great potential in enzyme-free glucose sensing. PMID- 22424827 TI - Release mechanism studies on TFu nanoparticles-in-microparticles system. AB - This study was aimed at developing a nanoparticles-in-microparticles delivery system for N(3)-O-toluyl-5-fluorouracil (TFu), a new and potential antitumor prodrug of 5-fluorouracil (5-Fu), and intended to improve the release properties, bioavailability and therapeutic efficacy. TFu nanoparticles-in-microparticles system (TFu-NiMS), was prepared by ionotropic gelation technique, and the formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency. TFu-NiMS was characterized according to particle size, zeta potential, drug entrapment efficiency, drug loading and physical stability, respectively. The effects of various factors on drug release and in vitro release characteristics of TFu from NiMS were investigated and the release mechanisms were also explored. The optimum formulation was found to be relatively uniform in size (350.5 +/- 12.6 nm) with a positive zeta potential (13.4 +/- 0.9 mV). The drug entrapment efficiency and loading were (75.58 +/- 3.25%) and (10.19 +/- 0.24%), respectively. The in vitro release behavior of TFu from NiMS followed the Weibull or Ritger-Peppas kinetic equation and could be better expressed by the following equations: lnln[1/(1-Q/100)]=0.5577 lnt-0.3377, r=0.9768 and lnQ=0.5059 lnt+3.881, r=0.9759, respectively. TFu-NiMS presented controlled release properties in comparison with TFu solutions and the release properties of TFu from NiMS were fit a combination of diffusion controlled drug release and matrix dissolution mechanism. The TFu-NiMS were valued to develop as a practical preparation for oral or i.v. administration. PMID- 22424828 TI - Preparation and characterization of rifampicin-PLGA microspheres/sodium alginate in situ gel combination delivery system. AB - We prepared a complex drug delivery system consisted of rifampicin-poly(lactic-co glycolic acid) (PLGA) microspheres in combination with sodium alginate in situ gel. The microspheres were obtained by using a solvent evaporation method, the mean diameter was 1.748 MUm and the span of particle distribution was 0.78. The combination delivery system was obtained by adding microspheres to sodium alginate solution followed by physically mixing. In an in vitro study of drug release monitored for 11 days, the release of rifampicin from combination delivery system was slower than microspheres. The cumulative release percent of rifampicin from combination delivery system was 91.83 +/- 1.26%, which was lower than 97.36 +/- 3.41% of rifampicin released from microspheres. An in vivo fluorescence imaging study suggests that the gel adhered to lungs within 24h, and microspheres stayed in lungs at least for 504 h (21 days). In vivo drug release study indicates that the maximum local rifampicin concentration in lungs was 48.60 +/- 15.67 MUg mL(-1) 5h after administration. After 21 days, the local rifampicin concentration was 0.81+/-0.14MUgmL(-1), which was above the minimum inhibitory concentration of rifampicin. The combination delivery system significantly prolonged RFP release compared to microspheres, from which RFP released could only be detected for 10 days. This approach to control the release of rifampicin using PLGA microspheres/in situ gel combination delivery system in conjunction with interventional technology is useful for improving anti tuberculosis treatment effectiveness for patients. PMID- 22424829 TI - Poly(L-lysine)-based star-block copolymers as pH-responsive nanocarriers for anionic drugs. AB - Star-block copolymers PEI-g-(PLL-b-PEG) with a branched polyethylenimine (PEI) core, a poly(l-lysine) (PLL) inner shell, and a poly(ethylene glycol) (PEG) outer shell have been synthesised and evaluated as potential nanocarriers for anionic drugs. The star-block copolymers were synthesised by a ring-opening polymerisation of E-benzyloxycarbonyl-L-lysine N-carboxyanhydride initiated by the peripheral primary amino groups of PEI, surface modification with activated PEG 4-nitrophenyl carbonate, and subsequent deprotection of benzyl groups on the side chains of the PLL inner shell. The synthesised star-block copolymers were characterised by (1)H NMR, gel permeation chromatography (GPC), and dynamic light scattering (DLS). The encapsulation properties of these star-block copolymers were characterised by spectrophotometric titration and dialysis. These techniques demonstrated that anionic model dyes, such as methyl orange and rose Bengal, and the model drug diclofenac sodium can be encapsulated efficiently by PEI-g-(PLL-b PEG) at physiological pH. The entrapped model compounds demonstrated sustained release at physiological pH and accelerated release when the pH was either increased to 10.0-11.0 or decreased to 2.0-3.0. The efficient encapsulation as well as the pH-responsive releasing properties of these star-block copolymers could be potentially used in the controlled release of anionic drugs. PMID- 22424830 TI - Kinetics of de-N-acetylation of the chitin disaccharide in aqueous sodium hydroxide solution. AB - Chitosan is prepared from chitin, a process which is carried out at highly alkaline conditions, and that can be performed either on chitin in solution (homogeneous deacetylation) or heterogeneously with the chitin as a solid throughout the reaction. We report here a study of the de-N-acetylation reaction of the chitin dimer (GlcNAc-GlcNAc) in solution. The reaction was followed by (1)H NMR spectroscopy in deuterated aqueous sodium hydroxide solution as a function of time, sodium-hydroxide concentration and temperature. The (1)H NMR spectrum of GlcNAc-GlcNAc in 2.77 M deuterated aqueous sodium hydroxide solution was assigned. The interpretation of the (1)H NMR spectra allowed us to determine the rates of de-N-acetylation of the reducing and non-reducing ends, showing that the reaction rate at the reducing end is twice the rate at the non-reducing end. The total deacetylation reaction rate was determined as a function of the hydroxide ion concentration, showing for the first time that this de-N acetylation reaction is second order with respect to hydroxide ion concentration. No significant difference in the deacetylation rates in deuterated water compared to water was observed. The activation energy for the reaction (26-54 degrees C) was determined to 114.4 and 98.6 kJ/mol at 2.77 and 5.5 M in deuterated aqueous sodium hydroxide solution, respectively. PMID- 22424831 TI - Cholesterol granuloma of the middle ear invading the cochlea. AB - OBJECTIVES: To report a second case of cholesterol granuloma of the middle ear invading the cochlea. MATERIAL AND METHODS: A 54-year-old woman, who had undergone right-side tympanoplasty with stapedectomy, complained of intermittent right-side otorrhea associated with cophosis. Otomicroscopy found anterior eardrum perforation with mucopurulent effusion. Computed tomography (CT) showed a lesion filling the tympanic cavity, exposing the tympanic facial nerve, with destruction of the ossicles; the vestibule and cochlea were ossified except for the basal turn. The petrous apex was normal. Magnetic resonance imaging (MRI) showed invasion of the cavity and basal turn of the cochlea by a mass in heterogeneous hypersignal on T-1 weighted images, non-enhanced by gadolinium injection, and hyperintensity on T2-weighted images. Cholesterol granuloma of the middle ear was suspected, with surgery indicated due to the facial nerve exposure and cochlear invasion. RESULTS: A brownish-yellow compressive mass invading the basal turn of the cochlea, suggestive of cholesterol granuloma, was removed. Histologic examination confirmed diagnosis. CONCLUSION: Direct invasion of the otic capsule by cholesterol granuloma is extremely unusual. Surgery is indicated in such cases, to avoid onset of neurologic complications. PMID- 22424832 TI - Longitudinal effects of health-harming and health-protective behaviors within adolescent romantic dyads. AB - Most models exploring adolescent health behavior have focused on individual influences to understand behavior change. The goal of the current study was to assess the role of adolescent romantic partners on the expression of health behavior. Our sample utilized two waves of data from the U.S. National Longitudinal Study of Adolescent Health, which included 80 romantic dyads (160 individuals). A longitudinal multilevel analysis was conducted. We assessed individual and romantic partner health-harming behaviors (i.e., delinquency, alcohol use, smoking, and marijuana use), health-protective behaviors (i.e., physical activity, physical inactivity, sleep patterns, seatbelt use, and contraception motivations), as well as the role of gender and age. Participants average age was 16 years at baseline. We found evidence for partner similarity and partner influence with the majority of health-harming behaviors. Specifically, partner influence was evident for smoking and alcohol use with partner influence approaching significance for marijuana use. We found limited evidence for partner similarity and partner influence for health-protective behaviors. The importance of assessing romantic dyads was evident in these data. Interventions focusing on health-harming behavior for adolescent populations are important public health goals. It is recommended that future intervention efforts with adolescent health-harming behaviors should target not only peers, but also consider the role of romantic partners. PMID- 22424833 TI - Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study. AB - PURPOSE: To evaluate the efficacy of intraocular injections with bevacizumab in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO). DESIGN: Prospective, randomized, sham injection-controlled, double-masked clinical trial. PARTICIPANTS: Sixty patients with ME secondary to CRVO. METHODS: At baseline, patients were randomized 1:1 to receive intraocular injections of bevacizumab or sham injections every 6 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of patients gaining at least 15 letters at 6 months. Secondary outcome measures included mean change from baseline best-corrected visual acuity (BCVA), foveal thickness, and neovascular glaucoma. RESULTS: At the end of follow-up, 18 of 30 patients (60.0%) in the study group had gained >=15 letters compared with 6 of 30 patients (20.0%) in the control group (P=0.003). The BCVA improved by 14.1 letters at 24 weeks compared with a decrease of 2.0 letters in the control group (P < 0.003). The mean decrease in central retinal thickness (CRT) was significantly greater in the study group (426 MUm) than in the control group (102 MUm) at all time points up to week 24 (P < 0.001). No residual edema, defined as CRT <300 MUm at 24 weeks, was found in 26 of 30 patients (86.7%) in the treatment group compared with 6 of 30 patients (20%) in the control group (P < 0.001). In the sham group, 5 of 30 patients (16.7%) had developed iris rubeosis at week 24. No patients in the study group had rubeosis at week 24 (P=0.052). There were no events of endophthalmitis, retinal tear, or retinal detachment during the 24-week treatment period. No serious non-ocular adverse events were reported. CONCLUSIONS: Intraocular injections of bevacizumab given every 6 weeks for 6 months improve visual acuity (VA) and reduce ME significantly compared with sham. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 22424834 TI - Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results. AB - PURPOSE: To compare the efficacy and safety of same-day verteporfin photodynamic therapy (PDT) and intravitreal ranibizumab combination treatment versus ranibizumab monotherapy in neovascular age-related macular degeneration. DESIGN: Prospective, multicenter, double-masked, randomized, active-controlled trial. PARTICIPANTS: We included 255 patients with all types of active subfoveal choroidal neovascularization. METHODS: Patients were randomized 1:1 to as-needed (pro re nata; PRN) combination (standard-fluence verteporfin 6 mg/m(2) PDT and ranibizumab 0.5 mg) or PRN ranibizumab monotherapy (sham infusion [5% dextrose] PDT and ranibizumab 0.5 mg). Patients received 3 consecutive monthly injections followed by PRN retreatments based on protocol-specific retreatment criteria. MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) from baseline to month 12, and the proportion of patients with treatment-free interval >=3 months at any timepoint after month 2. RESULTS: The mean change in BCVA at month 12 was +2.5 and +4.4 letters in the combination and monotherapy groups, respectively (P = 0.0048; difference: -1.9 letters [95% confidence interval, 5.76 to 1.86], for having achieved noninferiority with a margin of 7 letters). The proportion of patients with a treatment-free interval of >=3 months at any timepoint after month 2 was high, but did not show a clinically relevant difference between the treatment groups. Secondary efficacy endpoints included the mean number of ranibizumab retreatments after month 2 (1.9 and 2.2 with combination and monotherapy, respectively [P = 0.1373]). The time to first ranibizumab retreatment after month 2 was delayed by 34 days (about 1 monthly visit) with combination (month 6) versus monotherapy (month 5). At month 12, mean +/- standard error central retinal thickness decreased by 115.3+/-9.04 MUm in the combination group and 107.7+/-11.02 MUm in the monotherapy group. The mean number of verteporfin/sham PDT treatments was comparable in the 2 groups (combination, 1.7; monotherapy, 1.9). The safety profiles of the 2 groups were comparable, with a low incidence of ocular serious adverse events. CONCLUSIONS: The combination PRN treatment regimen with verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy; however, the study did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months. The combination therapy was well tolerated. PMID- 22424835 TI - High-resolution alpha-particle spectrometry of the 230U decay series. AB - High-resolution alpha-particle spectrometry was performed on the (230)U decay series. A (230)U source was prepared on a stainless steel disc by electrodeposition in an ammonium nitrate solution. Spectrometry of the alpha particle energy spectrum was performed with ion-implanted planar silicon detectors in vacuum. A set of alpha emission probabilities is presented for (230)U and (226)Th. The measured peak intensities were corrected mathematically for coincidental detection of alpha-particles and conversion electrons emitted in the same decay. A good agreement with literature data was observed. The uncertainty budget and the correlation matrix are presented. The validity of the alpha-particle energies was tested and could be confirmed for most peaks within a few keV, but discrepancies were found for the 2nd peak of (226)Th and the main peak of (218)Rn. PMID- 22424836 TI - Accurate activity measurement of Lu-177 by the liquid scintillation 4pibeta-gamma coincidence counting technique. AB - This paper reports on absolute measurements made at the NMISA by the 4pi[LS]beta gamma coincidence extrapolation technique, which formed part of a key comparison of activity measurements of the radionuclide lutetium-177, a beta-gamma emitter. A detection efficiency analysis based on the decay scheme indicated that the coincidence extrapolation method is feasible for extracting the source disintegration rate of (177)Lu. A simulation was undertaken utilizing the efficiency equations to give an indication of the expected variation of the source count rate with efficiency for different gamma-ray windows. Both the simulation and experiment indicated that the window giving the highest counting efficiency was centered about the 208.4 keV photopeak, with the data showing linear variation in the upper efficiency range. The extracted activity concentration of the (177)Lu solution proved to be highly accurate, being higher than the proposed comparison reference value by 0.15%, well within one standard uncertainty (sigma=0.26%) as specified by the NMISA. PMID- 22424837 TI - Monte Carlo calculation of response functions to gamma-ray point sources for a spherical NaI(Tl) detector. AB - Response functions of a 7.62 cm-diameter spherical NaI(Tl) detector to gamma-ray point sources in the energy range up to 1.5 MeV were calculated by means of the Monte Carlo method using PENELOPE-2006 (Salvat et al., 2006). The detector materials and dimensions were modeled realistically. The calculated response functions agreed well with the experimental spectra. PMID- 22424838 TI - Absolute standardization of 241Pu by the TDCR technique and effect of the beta spectral shape. AB - The NMISA participated in the 2010 international key comparison of (241)Pu, standardizing the inter-comparison solution by the TDCR efficiency calculation technique. Special attention was paid to ensure accurate efficiency calculation for this low-energy, pure beta-emitter: in particular the effect of low-energy stopping powers on the calculation of ionization quenching was assessed and an optimal value for the quench parameter, kB, was determined. In addition, phototube efficiency mismatch was accounted for by a software minimization technique. The effect of the beta spectral shape on the activity extracted from data analysis was assessed and found to be significant. Based on the results of this work we propose a new value for the average beta-particle energy. PMID- 22424839 TI - Calibration of stack monitors for measurement of noble gases in nuclear facilities. AB - In nuclear facilities stack monitors are used for the measurement of the volumetric activity of noble gases. Spectrometric measurement is needed because the content of stack effluents is always a mixture of radionuclides. In some nuclear power plants new types of monitors were installed based on HPGe detectors. For efficiency calibration a standard with the radionuclide Xe-127 was developed and calibration curve constructed in the energy range 81 keV-1293 keV. Experiental efficiencies were checked using an MC model. PMID- 22424840 TI - Feasibility study of activity measurement of positron emitters based on gamma gamma coincident detection by two NaI(Tl) detectors. AB - Detection of two and more gamma-rays in coincidence by two NaI(Tl) detectors with almost 4pi geometry allows absolute characterization of radionuclides emitting coincidence gammas. The method is a generalization of the Eldridge-Crowther method developed originally for x-rays and low energy gamma-rays. This method is applied to the case of (94)Nb decay with two coincident gamma-rays emitted in one cascade. The application of this method for the case of coincident positron-gamma emission ((22)Na and (26)Al sources) meets some difficulties. In these decays, two 511 keV gamma quanta produced in positron annihilation are strongly correlated. Despite the fact that the third gamma emitted in (22)Na and (26)Al decays is not correlated with two annihilation quanta, the number of independent observables for (22)Na and (26)Al decays is less than the number of unknowns. The small parameter omega(00), the probability that both annihilation quanta escape detection in both NaI(Tl) detectors, cannot be determined. However, if this parameter is defined from experimental data for one source with known activity ((22)Na), the activity of the other source ((26)Al) can be calculated from experimental data for (26)Al decay. PMID- 22424841 TI - Determination of natural and anthropogenic radionuclides in soil--results of an European Union comparison. AB - A comparison was organised by the Institute for Reference Materials and Measurements (IRMM) among 73 environmental radioactivity monitoring laboratories for the determination of 15 radionuclides in soil. The reference material IAEA 375 soil was reprocessed to provide the comparison material and reference values traceable to SI units and SIR were established at IRMM. The analytical procedures used by participants laboratories are discussed and performances evaluted using relative deviations and E(n) numbers. This paper focuses on the results for (40)K, (90)Sr, (137)Cs, (226)Ra, (234)U, (235)U and (238)U. Worst performance was found for (90)Sr and (235)U, where 65% and 78% of the results, respectively, deviate more than 20% from the reference values. The use of the E(n) criterion revealed that the uncertainty estimation of many participants is poor. PMID- 22424842 TI - Ventricular allorhythmia during infarct-related ventricular tachycardia. AB - Ventricular allorhythmia is an electrocardiogram feature leading to a pattern of "regularly irregular" arrhythmia mainly reported during non-life-threatening organized atrial tachycardia. We report the infrequent case of a patient presenting with ventricular allorhythmia during infarct-related ventricular tachycardia. The potential mechanisms of this tachycardia are discussed. PMID- 22424843 TI - Adalimumab for the prevention and/or treatment of post-operative recurrence of Crohn's disease: a prospective, two-year, single center, pilot study. AB - BACKGROUND: Infliximab has shown efficacy at preventing post operative recurrence (POR) of Crohn's disease (CD). This study aimed at evaluating whether adalimumab can prevent and treat POR of CD. METHODS: This prospective, single-center, open label, two-year study included 23 patients who had undergone ileocecal resection for refractory or complicated CD and were at high-risk for POR. Patients received adalimumab from post operative day 14 (Group I, n=8) or at 6 months post operatively after confirmation of endoscopic recurrence (PO-ER) despite treatment with azathioprine, infliximab, or 5-ASA (patients intolerant to infliximab and azathioprine, Group II, n=15). Symptom assessment and laboratory tests were performed at monthly visits. Endoscopic findings were graded using the Rutgeerts score (RS) at 6 and 24 months after initiation of adalimumab. Primary end-points were maintenance (group I) or achievement of mucosal healing (Group II). Secondary end-points were prevention of post operative clinical recurrence (PO CR) (Group I) and endoscopic and clinical improvement (group II). RESULTS: In Group I, PO-ER (RS>=i2) was seen in one patient at 6 months PO, whereas a second patient developed PO-ER and PO-CR after 24 months of treatment. In Group II, all patients had PO-ER whereas 9 (60%) patients had PO-CR at study enrolment; after 24 months of treatment 9/15 (60%) patients achieved complete (RS-i0, n=3) or near complete (RS-i1, n=6) mucosal healing and 5/9 (56%) clinical remission. No serious adverse events were reported. CONCLUSIONS: This pilot study suggests that adalimumab may prevent PO-ER and treat PO-ER/CR in high risk patients for POR of CD. PMID- 22424844 TI - Olfactory ecology and the processing of complex mixtures. AB - Natural olfactory stimuli typically are mixtures of which the identities, concentrations, and ratios of chemical constituents are important for many odor mediated behaviors. Despite abundant behavioral examples, links between odor evoked behavior and the processing and discrimination of complex olfactory stimuli remains an area of active study. Coupling electrophysiological and behavioral experiments, recent studies in a variety of different insect models have provided new insights into the perceptual and neural mechanisms about how natural olfactory stimuli are processed, and how plasticity and internal state of the insect may influence the odor representation. These studies show that complex stimuli are represented in unique percepts that are different from their individual constituents, and that the representation may be modulated by experience and influenced by other sensory modalities. PMID- 22424845 TI - The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses. AB - Neurexins (NXs) and neuroligins (NLs) are transsynaptically interacting cell adhesion proteins that play a key role in the formation, maturation, activity dependent validation, and maintenance of synapses. As complex alternative splicing processes in nerve cells generate a large number of NX and NLs variants, it has been proposed that a combinatorial interaction code generated by these variants may determine synapse identity and network connectivity during brain development. The functional importance of NXs and NLs is exemplified by the fact that mutations in NX and NL genes are associated with several neuropsychiatric disorders, most notably with autism. Accordingly, major research efforts have focused on the molecular mechanisms by which NXs and NLs operate at synapses. In this review, we summarize recent progress in this field and discuss emerging topics, such as the role of alternative interaction partners of NXs and NLs in synapse formation and function, and their relevance for synaptic plasticity in the mature brain. The novel findings highlight the fundamental importance of NX NL interactions in a wide range of synaptic functions. PMID- 22424846 TI - Amygdala microcircuits mediating fear expression and extinction. AB - This review summarizes the latest developments in our understanding of amygdala networks that support classical fear conditioning, the experimental paradigm most commonly used to study learned fear in the laboratory. These recent advances have considerable translational significance as congruent findings from studies of fear learning in animals and humans indicate that anxiety disorders result from abnormalities in the mechanisms that normally regulate conditioned fear. Because of the introduction of new techniques and the continued use of traditional approaches, it is becoming clear that conditioned fear involves much more complex networks than initially believed, including coordinated interactions between multiple excitatory and inhibitory circuits within the amygdala. PMID- 22424847 TI - Association of deep venous thrombosis with calf vein diameter in acute hemorrhagic stroke. AB - We investigated the association between the development of deep venous thrombosis (DVT) and calf vein diameter in patients with acute hemorrhagic stroke. We measured the maximum diameter of paralytic side posttibial veins (PTVs) and peroneal veins (PVs) in 49 patients with intracerebral hemorrhage on admission and at 2 weeks after stroke onset by ultrasonography. We also examined for the presence or absence of DVT, and then analyzed the association of DVT with the maximum vein diameter. At 2 weeks after stroke, DVTs were detected in PTVs in 7 patients and in PVs in 6 patients. The maximum calf vein diameters at 2 weeks were significantly greater in patients with DVT compared with those without DVT (PTV, P = .033; PV, P = .015). Although calf vein diameter at admission did not influence the future incidence of DVT in patients with intracerebral hemorrhage, the presence of DVT was associated with calf vein dilatation. PMID- 22424848 TI - Deleterious effects of discography radiocontrast solution on human annulus cell in vitro: changes in cell viability, proliferation, and apoptosis in exposed cells. AB - BACKGROUND CONTEXT: Carragee et al. have recently shown that modern discography injections are associated with subsequent acceleration of disc degeneration, herniation, and loss of disc height. Although needle puncture and pressurization are known trauma events that can create disc degeneration in animal models, another likely culprit in clinical discography-associated degeneration is a direct effect of the contrast agent itself on disc cells. PURPOSE: To test the hypothesis that discography contrast solution would have a deleterious effect on human annulus cells in vitro. STUDY DESIGN: An in vitro study using cultured human annulus cells to assay cell death, cell proliferation, and apoptosis. PATIENT SAMPLE: Annulus cells from eight surgical disc specimens were evaluated (two Thompson Grade III discs and six Grade IV discs) for cell death and proliferation, and an additional five cultures were tested for apoptosis. OUTCOME MEASURES: The proportion of dead and live cells, cell proliferation, and the proportion of apoptotic cells in control and experimental groups. METHODS: After internal review board approval, experimental design used two sets of controls: untreated cells under our normal culture conditions (control) and a set with added glucose to adjust the osmolality to match respective Isovue radiocontrast solution treatments (glucose controls) using a freezing point osmometer. Treated cells received Isovue 200 (iopamidol, Isovue-M 200; Bracco Diagnostics, Inc., Princeton, NJ, USA) at 12.5, 25, 50, or 100 mg/mL. Twenty thousand cells/well were seeded in triplicate in 24 well plates, control or test media added, and incubated for 24 hours. At termination, dead cells were identified with trypan blue staining and percentage dead cells determined. Cells were also tested to determine the percentage of apoptotic cells after 50 or 100 mg/mL Isovue exposures. Proliferation assays used standard plate reader methods. Statistical analysis used repeated measures analysis of variance with SAS software (version 9.2; SAS Institute, Inc., Cary, NC, USA). RESULTS: Analysis of cell death showed a significant increase in the percentage of dead cells with increasing Isovue concentrations compared with control cells (p=.018-.0008). Cell proliferation analyses showed significantly reduced division in Isovue-treated cells (p=.004), and apoptosis assays revealed a significantly higher proportion of apoptotic cells in cells exposed to 50 and 100 mg/mL Isovue (p=.016 and .0003, respectively). CONCLUSIONS: Discography is used extensively in the evaluation of low back pain. Because the lifetime prevalence of disc degeneration and low back pain is high (80% in the general population), many patients may undergo this procedure. Data presented here show that cells exposed in vitro to a radiocontrast agent with adjustments for osmolality have significantly reduced proliferation, increased cell death, and increased programmed cell death (apoptosis). In light of the well-recognized age- and degeneration-related decrease in disc cell numbers, it is possible that radiocontrast exposure may be contributing significantly to disc cell loss with subsequent progression of disc degeneration. Findings presented here provide a plausible cell-based explanation for the previously reported disc degeneration in patients receiving discography contrast solutions. PMID- 22424849 TI - Arrhythmia-related workup in hereditary myopathies. AB - BACKGROUND: Arrhythmias determine life expectancy in patients with hereditary myopathies. AIMS: The aim of this study was to summarize recent advances in the diagnosis and management of arrhythmias in hereditary myopathies. METHODS: Literature search via PubMed and inclusion of own experiences were performed. RESULTS: All types of arrhythmias can be found in patients with hereditary myopathies, but some are more prevalent than others. Arrhythmias reported in myopathies include atrial fibrillation, atrial flutter, sick-sinus syndrome, preexcitation syndromes, atrioventricular conduction delay, intraventricular conduction delay, and ventricular tachycardia. Sudden cardiac death is a common finding in certain myopathies, and patients at risk for ventricular arrhythmias and sudden cardiac death should be identified early enough to implant a cardioverter-defibrillator to prevent a fatal outcome. Myopathies associated with a high risk for arrhythmias include laminopathies, Emery-Dreifuss muscular dystrophy, myotonic dystrophy I, mitochondrial myopathies, fatty-acid oxidation defects, and dystrophinopathies. To detect arrhythmias with high risk for sudden cardiac death, patients require close follow-up investigations or an implantable loop recorder. Documentation of severe arrhythmias requires immediate treatment according to established guidelines. CONCLUSIONS: Patients with certain hereditary myopathies carry an increased risk for developing severe supraventricular or ventricular arrhythmias and for dying of sudden cardiac death. Close follow-up and long-term surveillance of the electrocardiogram may prevent fatal complications of arrhythmias in these patients. PMID- 22424851 TI - [ISMP-Spain questionnaire and strategy for improving good medication practices in the Andalusian health system]. AB - OBJECTIVE: To describe the strategy employed by Andalusian public health service hospitals to foster safe medication use. The self-evaluation questionnaire on drug system safety in hospitals, adapted by the Spanish Institute for Safe Medication Practices was used as a fundamental tool to that end. MATERIAL AND METHOD: The strategy is developed in several phases. We analyse the report evaluating drug system safety in Andalusian public hospitals published by the Spanish Ministry of Health and Consumption in 2008 and establish a grading system to assess safe medication practices in Andalusian hospitals and prioritise areas needing improvement. We developed a catalogue of best practices available in the web environment belonging to the Andalusian health care quality agency's patient safety observatory. We publicised the strategy through training seminars and implemented a system allowing hospitals to evaluate the degree of compliance for each of the best practices, and based on that system, we were able to draw up a map of centres of reference. RESULTS: We found areas for improvement among several of the questionnaire's fundamental criteria. These areas for improvement were related to normal medication procedures in daily clinical practice. We therefore wrote 7 best practice guides that provide a cross-section of the assessment components of the questionnaire related to the clinical process needing improvement. CONCLUSIONS: The self-evaluation questionnaire adapted by ISMP-Spain is a good tool for designing a systematic, rational intervention to promote safe medication practices and intended for a group of hospitals that share the same values. PMID- 22424852 TI - Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population. AB - INTRODUCTION: PERC rule was created to rule out pulmonary embolism (PE) without further exams, with residual PE risk<2%. Its safety is currently not confirmed in high PE prevalence populations even when combined with low clinical probability assessed by revised Geneva score (RGS). As PERC rule and RGS are 2 similar explicit rules with many redundant criteria, we hypothesized that the combination of PERC rule with gestalt clinical probability could resolve this limitation. METHODS: We collected prospectively documented clinical gestalt assessments and retrospectively calculated PERC rules and RGS from a prospective study of PE suspected patients. We analyzed performance of combinations of negative PERC with low clinical probability assessed by both methods in high overall PE prevalence population. RESULTS: Among the final study population (n = 959), the overall PE prevalence was 29.8%. Seventy-four patients (7.7%) were classified as PERC negative and among them, 4 patients (5.4%) had final diagnosis of PE. When negative PERC was combined with low pretest probability assessed by RGS or gestalt assessment, PE prevalence was respectively 6.2% and 0%. This last combination reaches threshold target of 2% and unnecessary exams could easily have been avoided in this subgroup (6%). However, it confidence interval was still wide (0%; CI 0-5). CONCLUSIONS: PERC rule combined with low gestalt probability seems to identify a group of patients for whom PE could easily be ruled out without additional test. A larger study is needed to confirm this result and to ensure safety. PMID- 22424853 TI - Lower tissue factor inhibition in patients with ST segment elevation than in patients with non ST elevation acute myocardial infarction. AB - INTRODUCTION: Mechanisms to explain the different course of coronary thrombosis between ST elevation myocardial infarction (STEMI) and non-STEMI patients remain poorly defined. We hypothesize, however, that STEMI patients may present lower tissue factor plasma inhibition to partly account for their more persistent coronary thrombotic occlusion. MATERIALS AND METHODS: Total (t-TFPI ) and free tissue factor plasma inhibitor (f-TFPI), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), and fibrinogen were measured on admission and at 3 and 6 months in patients with a first STEMI (n:69) or non-STEMI (n:60). C reactive protein (CRP) was also measured on admission and at 3 months. RESULTS: STEMI patients showed lower admission levels of t-TFPI (p=0.001), f-TFPI (p=0.030) and fibrinogen (p=0.022), and higher vWF levels (p=0.005) than non-STEMI whereas TAT, PAI and CRP levels were comparable. At 3 and 6 months VWF, t-TFPI, f-TFPI, and TAT levels declined significantly in the 2 groups (p=0.002) reaching similar values. CRP levels also declined at 3 months (p=0.002). Moreover, the rate of cardiac mortality, non fatal MI or stroke during a 6 year follow-up were unrelated to admission coagulation parameters. CONCLUSIONS: The lower inhibition of tissue factor and greater endothelial dysfunction in STEMI than in non-STEMI patients may enhance thrombosis at the culprit lesion and adjacent coronary plaques, and hence, account at least in part for their different pathophysiology. This condition, however, is limited to the acute phase. PMID- 22424854 TI - Interpretation and management of INR results: a case history based survey in 13 countries. AB - INTRODUCTION: Standardisation of treatment with vitamin K antagonists (VKAs) is still an issue after 60 years of use. The study aimed to explore aspects of VKA monitoring in primary and secondary care. METHODS: Two case histories were distributed to physicians in 13 countries. Case history A focused on a patient with atrial fibrillation on stable anticoagulation (latest INR 2.3). Physicians were asked about frequency of INR measurement, when to change the VKA dose, and the patient's annual risk of ischemic stroke and bleeding. Case history B focused on a patient with an unexpected INR of 4.8, asking for the patient's 48-hour bleeding risk, the immediate dose reduction and time until a repeat INR. RESULTS: Altogether, 3016 physicians responded (response rate 8 - 38%), of which 82% were from primary care and 18% from secondary care. Answers varied substantially within and between countries regardless of level of care and VKA used. Median number of weeks between INR measurements was 4 - 6 weeks. Median threshold INR for increasing or decreasing the VKA dose was 1.9 and 3.1, respectively. Risk of ischemic stroke and bleeding were overestimated 2 - 3 times. In case history B, the median dose reduction the two first days was 75% for GPs and 55% for specialists, irrespective of estimates of bleeding risk; with one week to a repeat INR. CONCLUSION: Variation in VKA monitoring is substantial implying clinical consequences. Guidelines seem either unknown or may be considered impracticable. Further efforts towards standardisation of VKA management are needed. PMID- 22424855 TI - Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers. AB - INTRODUCTION: Flow cytometry allows the analysis of multiple antigens in a single tube at a single cell level. We present a rapid and sensitive two tube flow cytometric protocol for the detection of multiple platelet antigens and activation markers gated on a pure platelet population. MATERIALS AND METHODS: The presence of platelet specific antigens was analyzed in citrated whole blood of normal platelets and from patients diagnosed with platelet abnormalities. Quiescent platelets as well as stimulated platelets were analyzed using a gating strategy based on ubiquitously expressed platelet membrane markers. A ubiquitously expressed platelet marker was combined with antibodies against the activated alpha2b-beta3 (PAC-1), Lysosomal Activated Membrane Protein (CD63) and P-selectin (CD62P). RESULTS: We were able to detect the platelet antigens CD36, CD41, CD42a, CD42b and CD61 in one single tube. Our approach allowed the single tube determination of PAC-1, CD63 and CD62P after activation of platelets by thrombin, collagen, ADP and PAR-1, and determination of platelet abnormalities. CONCLUSIONS: Our two tube multi-parameter screening protocol is suited for the analysis of platelet antigens expressed on quiescent and activated platelets and allows the detection of aberrancies as found in blood of patients with thrombocytopathy such as Glanzmann Thrombasthenia, storage pool disease with diminished granule content and patients treated with clopidogrel and acetylsalicylic acid. PMID- 22424856 TI - Microparticles as a circulating source of procoagulant and fibrinolytic activities in the circulation. AB - Circulating microparticles (MP) are small membrane vesicles derived from a variety of cell types including platelets, erythrocytes, leukocytes, and endothelial cells. They harbor a large repertoire of cell surface receptors, mRNA and biological activities that are related to their involvement in many biological functions. MP subpopulations are well known for their procoagulant activity that relies mainly on the expression of phosphatidylserine and of tissue factor, the major cellular activator of the clotting system. In this review, we will discuss a new vision of MP as complex and ambivalent structures, expressing both activators and inhibitors of coagulation, but also conveying fibrinolytic properties, counteracting their procoagulant activities and identifying MP as integrative systems tuning the hemostatic balance. PMID- 22424857 TI - Clinical features of the pre-ictal state: mood changes and premonitory symptoms. AB - Identifying the pre-ictal state clinically would improve our understanding of seizure onset and suggest opportunities for new treatments. In our previous paper diary study, increased stress and less sleep predicted seizures. Utilizing electronic diaries, we expanded this investigation. Variables were identified by their association with subsequent seizure using logit-normal random effects models fit by maximum likelihood. Nineteen subjects with localization-related epilepsy kept e-diaries for 12-14 weeks and reported 244 eligible seizures. In univariate models, several mood items and ten premonitory features were associated with increased odds of seizure over 12h. In multivariate models, a 10 point improvement in total mood decreased seizure risk by 25% (OR 0.75, CI 0.61 0.91, p=004) while each additional significant premonitory feature increased seizure risk by nearly 25% (OR 1.24, CI 1.13-1.35, p<001) over 12h. Pre-ictal changes in mood and premonitory features may predict seizure occurrence and suggest a role for behavioral intervention and pre-emptive therapy in epilepsy. PMID- 22424858 TI - Pure ictal sensory seizures may represent a clinical manifestation of PLEDs. PMID- 22424859 TI - Pregabalin increases slow-wave sleep and may improve attention in patients with partial epilepsy and insomnia. AB - Insomnia is a common phenomenon particularly in patients with epilepsy. This study was performed to look at the effects of pregabalin, an anticonvulsant known to increase sleep depth and decrease arousals, in patients with insomnia and well controlled epilepsy. METHODS: This was a double-blind, placebo-controlled, crossover study of subjects with insomnia and epilepsy. Each subject was treated with pregabalin 150 mg BID or placebo for two weeks, followed by a two-week washout period, then the other treatment for two weeks. Polysomnography and neuropsychological testing were performed at baseline and at the end of each treatment arm. RESULTS: There was a significant increase in percentage of slow wave sleep and a decrease in stage 1 sleep when subjects were taking pregabalin. Sleep efficiency increased during pregabalin treatment, although this was not statistically significant (84.5+/-4.6% for placebo versus 90.4+/-2.6% for pregabalin). There were a significant improvement in attention in the pregabalin group based on trial one of the Rey-Auditory Verbal Learning Test and a trend toward improvement in the psychomotor vigilance task; other neuropsychological measures were not significantly changed. CONCLUSION: Concurrent treatment with pregabalin improves sleep depth in patients with insomnia and epilepsy and improves daytime attention. PMID- 22424860 TI - Ring chromosome 20 syndrome: electroclinical description of six patients and review of the literature. AB - BACKGROUND: Ring chromosome 20 syndrome is a rare chromosomal disorder. METHODS: In six patients, we focused on the presenting epileptic phenotype, the behavioral and mental problems and the relationship between the ratio of mosaicism and the age at onset of the epilepsy. RESULTS: All patients presented with pharmacoresistant frontal lobe complex partial seizures. The earliest onset of epilepsy was seen in patients without mosaicism. There were three patients out of six with behavioral disturbances before the onset of seizures. All patients had mild to moderate cognitive impairment. Electroencephalogram recordings showed rhythmic theta waves with frontal predominance and non-convulsive status epilepticus (NCSE). CONCLUSIONS: The ring chromosome 20 syndrome is characterized by childhood-onset refractory epilepsy continuing throughout adult life, mental disability, and behavioral disturbances which can originate before seizure onset. Ictal EEG reveals a unique pattern. Our findings indicate a possible link between the percentage of affected cells and the age of epilepsy onset. PMID- 22424861 TI - Analysis of cycloserine and related compounds using aqueous normal phase chromatography/mass spectrometry. AB - A new approach is evaluated for the analysis of cycloserine, a strongly hydrophilic drug. The method utilized is aqueous normal phase chromatography with a silica hydride-based stationary phase and mass spectrometry for detection. The samples are analyzed to determine the number of components and they are identified when possible. In addition, the composition change is monitored with respect to time and sample solvent. Analyses using both gradient and isocratic conditions are presented. The repeatability of inter- and intraday analyses is also determined. PMID- 22424862 TI - Therapeutic potential of PEGylated insulin-like growth factor I for skeletal muscle disease evaluated in two murine models of muscular dystrophy. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) is a fatal monogenetic disease with affected males displaying severe and progressive muscle wasting and weakness eventually leading to premature death. Possible therapeutic benefits of insulin like growth factor I (IGF-I) have been studied extensively in various models of muscle disease and DMD with IGF-I as a mediator of improved skeletal muscle regeneration by enhancing myoblast proliferation and differentiation. DESIGN: We tested the efficacy of a novel IGF-I analogue, a polyethylene glycol modified IGF I (PEG-IGF-I), to ameliorate the pathophysiology of muscular dystrophy in two mouse models of DMD. We used mdx mice which lack dystrophin (as in DMD) but exhibit only a relatively mild phenotype, and the dko mouse which is a transgenic model lacking utrophin in addition to dystrophin, and which exhibits a more severe, lethal phenotype like that in DMD. RESULTS: In young mdx mice, twice weekly PEG-IGF-I s.c. injections for 6 weeks protected the diaphragm muscle against fatigue and the tibialis anterior (TA) muscle against contraction-induced injury. However, this beneficial effect of PEG-IGF-I was less pronounced in mdx mice when treatment was initiated later in adulthood. In severely affected dko mice PEG-IGF-I treatment did not affect pathophysiological parameters including animal survival. CONCLUSIONS: These data suggest a therapeutic benefit with PEG IGF-I treatment only in mild muscle pathologies, since its potential to ameliorate the pathophysiology in models of severe muscular dystrophies was limited. Treatment should be initiated only for mild muscle pathologies if functional benefits are to be realised and therefore may be relevant as a short term therapy to hasten the functional repair of otherwise healthy muscles after injury. PMID- 22424863 TI - Targeting insulin-like growth factor in breast cancer therapeutics. AB - The insulin-like growth factor (IGF) pathway holds crucial role in cell growth, differentiation and proliferation. Aberrant regulation of the IGF system has been attributed to the pathogenesis of breast cancer and has been shown to contribute to various stages of breast carcinogenesis. Therefore, targeting the IGF-related axis represents a promising strategy, mainly aiming to bypass the resistance of currently employed treatment options in breast cancer patients. Nevertheless, major limitations have aroused despite the early stage of clinical development of various IGF-system modulators. The present review highlights the current status and considers the future perspectives of IGF-system targeting in breast cancer therapeutics. PMID- 22424864 TI - Risk factors for death from canine parvoviral-related disease in Australia. AB - Canine parvovirus (CPV) is a highly contagious cause of serious and often fatal disease in dogs worldwide despite the availability of safe and efficacious vaccines. Although a number of studies have focussed on identifying risk factors in disease development, risk factors associated with death from CPV are largely unknown. In this study we analysed a total of 1451 CPV cases reported from an Australian surveillance system - using univariate and multivariate techniques - to determine significant risk factors associated with death and euthanasia. A crude case fatality rate of 42.3% was estimated - higher than has been reported previously. We found that 3.3% of CPV cases had a history of vaccination in the previous 12 months, despite having completed the primary puppy vaccination course. The majority (89.5%) of these cases occurred in dogs <12 months of age, indicating failure of the primary vaccination course to provide protective immunity (most likely due to interference of the vaccine antigen with maternal antibodies but other reasons are discussed). Extending the age at which the final puppy vaccination is administered might be one of several strategies to consider. The final multivariate model showed that in non-litter CPV cases, risk of death was significantly associated with season of diagnosis (summer) and pedigree type (hounds and non-sporting dogs). Euthanasia in non-litter CPV cases was significantly associated with season of diagnosis (summer), state of residence (Northern Territory/South Australia/Tasmania combined), age (=65 years was significantly associated with lower GIP risk. In multivariate analyses, intact primary tumour and prior adjuvant radiotherapy were significantly associated with increased risk of GIP within 6 months after starting bevacizumab. A regression analysis that assessed the risk of GIP over time showed no cumulative risk associated with bevacizumab exposure. CONCLUSION: The observed rate of GIP in this large, community-based experience was consistent with rates reported in RCTs. Most events were successfully managed with surgical intervention. PMID- 22424881 TI - Cancer screening and health system resilience: keys to protecting and bolstering preventive services during a financial crisis. AB - The aim of this paper is to elucidate the rationale for sustaining and expanding cost-effective, population-based screening services for breast, cervical and colorectal cancers in the context of the current financial crisis. Our objective is not only to promote optimal delivery of high-quality secondary cancer prevention services, but also to underline the importance of strengthening comprehensive cancer control, and with it, health system response to the complex care challenges posed by all chronic diseases. We focus primarily on issues surrounding planning, organisation, implementation and resources, arguing that given the growing cancer burden, policymakers have ample justification for establishing and expanding population-based programmes that are well-organised, well-resourced and well-executed. In a broader economic context of rescue packages, deficits and cutbacks to government entitlements, health professionals must intensify their advocacy for the protection of vital preventive health services by fighting for quality services with clear benefits for population health outcomes. PMID- 22424882 TI - How should an incident case of atopic dermatitis be defined? A systematic review of primary prevention studies. AB - BACKGROUND: Eczema prevention is now an active area of dermatologic and allergy research. Defining an incident case is therefore a prerequisite for such a study. OBJECTIVE: We sought to examine how an incident case of atopic dermatitis was defined in previous atopic dermatitis prevention studies in order to make recommendations on a standard definition of new atopic dermatitis cases for use in future prevention trials. METHODS: We conducted a systematic review of controlled interventional atopic dermatitis prevention studies by using searches of MEDLINE and Cochrane databases for studies published from 1980 to the end of January 2011. Studies that included atopic dermatitis as a secondary outcome, such as asthma prevention trials, were included. RESULTS: One hundred two studies were included in the final analysis, of which 27 (26.5%) did not describe any criteria for defining an incident case of atopic dermatitis. Of the remaining 75 studies with reported disease criteria, the Hanifin-Rajka criteria were the most commonly used (28 studies). A disease definition unique to that particular study (21 studies) was the second most commonly used disease definition, although the sources for such novel definitions were not cited. CONCLUSIONS: The results from this systematic review highlight the need for improved reporting and standardization of the definition used for an incident case in atopic dermatitis prevention studies. Most prevention studies have used disease definitions such as the Hanifin-Rajka criteria that include disease chronicity. While acceptable for cumulative incidence outcomes, inclusion of disease chronicity precludes the precise measurement of disease onset. We propose a definition based on existing scientific studies that could be used in future prospective studies. PMID- 22424884 TI - Proliferation of equine bone marrow-derived mesenchymal stem cells in gelatin/beta-tricalcium phosphate sponges. AB - A three dimensional scaffold is essential in mesenchymal stem cells (MSCs) delivery in cell-based therapy for facilitating cell adherence, migration, proliferation, and differentiation. The objectives of this study were to evaluate the possibility of beta-tricalcium phosphate incorporated gelatin sponges (Gelatin/beta-TCP sponge) as scaffolds for equine MSCs and to examine the effects of seeding density and seeding method on the proliferation of equine MSCs in the Gelatin/beta-TCP sponges. Mononuclear cells and MSCs isolated from bone marrow were seeded into Gelatin/beta-TCP sponges at different densities by different seeding methods-static or agitated methods. Proliferation of the MSCs in Gelatin/beta-TCP was assessed using the Cell Counting Kit-8 assay and histological examination. Distribution and proliferation of MSCs in the Gelatin/beta-TCP sponge were observed, and the Gelatin/beta-TCP sponge supported limited growth when seeded at high density. We also found that the agitated seeding method enhanced the proliferation of MSCs. This study demonstrated the suitability of Gelatin/beta-TCP sponges for the proliferation and maintenance of equine MSCs. These results contribute to the application of MSC-seeded Gelatin/beta-TCP sponges in equine medicine. PMID- 22424883 TI - Genome-wide association study of lung function decline in adults with and without asthma. AB - BACKGROUND: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. OBJECTIVE: We conducted the first genome-wide association study on the age-related decrease in FEV(1) and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. METHODS: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV(1) and FEV(1)/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). RESULTS: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV(1) decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 * 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV(1)/FVC ratio decrease in asthmatic participants (P = 5.3 * 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. CONCLUSIONS: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. PMID- 22424885 TI - Identification of antigenic epitopes of the SapA protein of Campylobacter fetus using a phage display peptide library. AB - In this study, we immunized mice with prokaryotically expressed recombinant surface layer protein, SapA, of Campylobacter fetus, generated hybridomas secreting mouse monoclonal antibodies (mAb) targeting SapA, and purified the mAb A2D5 from mouse ascites using saturated ammonium sulfate solution. The mAb A2D5, coated onto ELISA plates, was used to screen the phage random 12-peptide library through three rounds of panning. Following panning, 15 phage clones were randomly chosen and tested for reactivity with mAb A2D5 by indirect ELISA. Single-stranded DNA from positive clones was sequenced and compared with the sequence of SapA to predict the key epitope. ELISA and/or Western blot analyses further validated that synthetic peptides and recombinant peptide mimotopes all interact with mAb A2D5. Nine of ten positive phage clones identified by screening were sequenced successfully. Seven clones shared the same sequence HYDRHNYHWWHT; one had the sequence LSKNLPLTALGN; and the final one had the sequence SGMKEPELRSYS. These three sequences shared high homology with SapA J05577 in the region GNEKDFVTKIYSIALGNTSDVDGINYW, in which the underlined amino acids may serve as key residues in the epitope. ELISA and/or Western blot analyses showed that mAb A2D5 not only interacted with the four synthetic peptide mimotopes, but also with 14 prokaryotically expressed recombinant peptide mimotopes. The mimotopes identified in this study will aid future studies into the pathological processes and immune mechanisms of the SapA protein of C. fetus. PMID- 22424886 TI - Ethanol consumption enhances periodontal inflammatory markers in rats. AB - OBJECTIVE: The aim of this study was to assess the short term effect of ethanol administration on periodontal disease in rats. DESIGN: Rats received either ethanol 2g/kg or water by gastric gavage twice a day. On the fifth day ligatures were tied around the molars of half of the rats to induce periodontitis. After 7days gingival tissue was removed and assayed for inflammatory markers. Finally, hemi-mandibles were extracted to evaluate bone loss by histomorphometrical techniques. RESULTS: The experimental periodontitis increased significantly the mRNA expression (p<0.001) and activity (p<0.001) of inducible nitric oxide synthase (iNOS) in the gingival tissue, whilst short time ethanol administration increased iNOS activity (p<0.05) and produced an additive effect on iNOS mRNA expression augmented by periodontitis (p<0.01). The short time ethanol administration also potentiated the periodontitis stimulatory effect on the mRNA expression of interleukin (IL)-1beta (p<0.01 and p<0.001, in semi-quantitative and real time PCR, respectively) and on the height of periodontal ligament (p<0.05). However, the ligature-induced periodontitis, but not ethanol administration, increased the prostaglandin E(2) content (p<0.05) and, diminished the alveolar bone volume (p<0.05), as compared to sham rats. CONCLUSION: The present results suggest that ethanol consumption could represent a risk indicator for periodontal disease since augments the expression of inflammatory markers, in healthy rats, and increases them, at short term, during the illness. However, scale longitudinal investigation and more case-control studies are needed to confirm this statement. PMID- 22424887 TI - Unilateral maxillary molar extraction influences AQP5 expression and distribution in the rat submandibular salivary gland. AB - OBJECTIVE: Mastication has been regarded as a crucial factor for maintaining the morphology and function of secretion in salivary glands. Although it is known that occlusion affects mastication, the detailed process for how occlusal changes affect the secretory function of salivary glands is still unknown. Aquaporin 5 (AQP5) is a membrane protein that forms water channels, and plays an important role in water transport. In this study, we investigated the structural changes and alterations in the expression and distribution of AQP5 in the rat submandibular salivary gland (SMG) under occlusal hypofunction after unilateral molar extraction. METHODS: Seven-week-old male Wistar rats (n = 36) were used in the study. In the experimental group, all of the right maxillary molars were extracted. Rats with no molar extraction were used as the control group. The rats were euthanized at 7, 14 or 28 days after the procedure, and the right SMGs were isolated and subjected to histological analyses. The expression and distribution of AQP5 were detected by immunohistochemistry. RESULTS: Morphological analyses revealed hypertrophic changes in the acinar cells in the experimental group. Immunohistochemical staining of AQP5 was detected in the apical membrane (APM) and intercellular secretory canaliculi of acinar cells in both groups. On the other hand, the AQP5 expression in the APM and intercellular secretory canaliculi of acinar cells was less prominent in the experimental group than in the control group. CONCLUSIONS: The present findings suggest that unilateral molar extraction has significant influences on the function of water transport in the rat SMG. PMID- 22424888 TI - [Quality control of dose delivered by in vivo dosimetry: can one tolerance be used for all localizations?]. AB - PURPOSE: In vivo dosimetry measurements are accepted when the difference between measured and calculated dose is under 5%. A statistical analysis has been conducted to determine whether this tolerance matched the clinical practice for the studied localizations: pelvis, thorax, head and neck, breast. MATERIALS AND METHODS: The technical characteristics of the detectors were checked before being used in clinical practice. Then an automatic statistical analysis was implemented using the 2450 in vivo dosimetry measurements obtained during 1 year. MAIN RESULTS: The global average is 1.10%, the standard deviation 2.46% and the percentage of out of level measurements 4.09%. By distinguishing the localizations, the 5% tolerance appeared to be too narrow for the breast localization. DISCUSSION/CONCLUSION: Several investigations were initiated to justify the modification of the tolerance for the breast localization. They highlighted an underestimation of the calculated dose when high beam angles are set: a new correction factor was defined to take account this error. A specific tolerance was also specified for the breast localization. PMID- 22424889 TI - [PET/CT and radiotherapy: indications and potential applications]. AB - The implementation of new techniques of imaging in the daily practice of the radiation oncologist is a major advance in these last 10 years. This allows optimizing the therapeutic intervals and locoregional control of the disease while limiting side effects. Among them, positron emission tomography (PET) offers an opportunity to the clinician to obtain data relative to the tumoral biological mechanisms, while benefiting from the morphological images of the computed tomography (CT) scan. Recently hybrid PET/CT has been developed and numerous studies aimed at optimizing its use in the planning, the evaluation of the treatment response and the prognostic value. The choice of the radiotracer (according to the type of cancer and to the studied biological mechanism) and the various methods of tumoral delineation, require a regular update to optimize the practices. We propose throughout this article, an exhaustive review of the published researches (and in process of publication) until December 2011, as user guide of PET/CT in all the aspects of the modern radiotherapy (from the diagnosis to the follow-up): biopsy guiding, optimization of treatment planning and dosimetry, evaluation of tumor response and prognostic value, follow-up and early detection of recurrence versus tumoral necrosis. In a didactic purpose, each of these aspects is approached by primary tumoral location, and illustrated with representative iconographic examples. The current contribution of PET/CT and its perspectives of development are described to offer to the radiation oncologist a clear and up to date reading in this expanding domain. PMID- 22424890 TI - Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression. AB - Treatment of bipolar disorder often results in patients taking several drugs in an attempt to alleviate residual depressive symptoms, which can lead to an accumulation of side effects. New treatments for bipolar depression that do not increase the side effect burden are needed. One nonpharmacological treatment with few side effects, bright light therapy, has been shown to be an effective therapy for seasonal affective disorder, yet has not been extensively studied for other forms of depression. Forty-four adults with bipolar disorder, depressed phase were randomized to treatment with bright light therapy, low-density or high density negative ion generator for 8 weeks. The primary measure of efficacy was the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS). Adverse events were assessed using the Young Mania Rating Scale (YMRS) and Systematic Assessment for Treatment Emergent effects (SAFTEE). All outcome variables were statistically analyzed using a mixed model repeated measure analysis of variance (ANOVA). The results showed no statistically significant differences between groups in any outcome measures at study end point; adverse events, including switches into hypomania, were rare. Further research is needed to determine the efficacy of bright light therapy in this population. PMID- 22424891 TI - Medical outcome of psychiatric inpatients with admission hyponatremia. AB - Hyponatremia at time of inpatient admission is associated with increased severity of illness and mortality in patients hospitalized for treatment of medical conditions. This study was conducted to determine the clinical outcome of psychiatric inpatients with admission hyponatremia. The cohort comprised 1000 adults consecutively admitted to a free-standing psychiatric hospital in 2010. Emergency transfer to a general hospital was used as a proxy marker for poor medical outcome. The point prevalence of hyponatremia (sodium level <136 mEq/l) at admission was 6.49%. Older age and a diagnosis of arterial hypertension were independent correlates of admission hyponatremia. Medical deteriorations occurred in 26.7% of hyponatremic patients and 13.1% of those with normal sodium levels. Admission hyponatremia is associated with an increased rate of significant medical deteriorations of psychiatric inpatients and should trigger enhanced clinical monitoring to identify and treat somatic disorders. PMID- 22424892 TI - Heterogeneity and symptom structure of schizophrenia. AB - Previous studies failed to identify a consistent factor structure of the BPRS-24 in schizophrenia. Our aims were to examine the fit of all previously published factor models and then to explore unobserved population heterogeneity and identify salient latent classes. Two hundred thirty-nine patients with ICD-10 schizophrenia admitted to a random sample of all Italian public and private acute inpatient units during an index period were administered the BPRS-24. Confirmatory factor analysis (CFA) was used to test all factor models derived in previous studies. Then, factor mixture analysis (FMA) with heteroscedastic components was carried out to explore unobserved population heterogeneity. No previously reported factor solution showed adequate fit in CFA. FMA indicated the presence of three heterogeneous groups and yielded a 5-factor solution (Depression, Positive Symptoms, Disorganization, Negative Symptoms, Activation). Group 1 was characterized by higher Disorganization, lower Activation, lower psychosocial functioning, greater lifetime number of admissions, more frequent history of compulsory admission. Group 2 displayed lower Disorganization. Group 3 showed higher Activation and more frequent history of recent self-harming behavior. Our finding that a reliable factor structure for the BPRS-24 could be obtained only after assuming population heterogeneity suggests that the difficulty in identifying a consistent factor structure may be ascribed to the clinical heterogeneity of schizophrenia. As compared with clinical subtypes, the psychopathological dimensions displayed much greater discriminatory power between groups identified by FMA. Though preliminary, our findings corroborate that a dimensional approach to psychopathology can facilitate the assessment of the clinical heterogeneity of schizophrenia. PMID- 22424893 TI - Posttraumatic stress disorder following asthma attack (post-asthma attack PTSD) and psychiatric co-morbidity: the impact of alexithymia and coping. AB - This study investigated the prevalence of post-asthma attack posttraumatic stress disorder (PTSD) and the severity of psychiatric co-morbidity among a group of college students and whether alexithymia and coping strategies would relate to health outcomes. This is a cross-sectional study in which 156 college students who had previously experienced asthma attack were recruited. They completed a demographic page, Asthma Symptom Checklist, PTSD Checklist, General Health Questionnaire-28, Toronto Alexithymia Scale and the COPE. They were also matched with 141 students without asthma. The results showed that 3% met the criteria for full-PTSD, 44% for partial and 53% for no-PTSD. There were no significant differences between the asthma and control groups in severity of psychiatric co morbid symptoms. Path analyses showed that asthma severity was significantly correlated with PTSD and psychiatric co-morbidity. It was also correlated with alexithymia which was in turn associated with psychiatric co-morbidity but not PTSD. Coping strategies were not correlated with health outcomes. To conclude, people can develop PTSD symptoms and degrees of psychiatric co-morbid symptoms after suffering asthma attack. The severity of these symptoms relates to people's perceptions of asthma severity and alexithymia. PMID- 22424894 TI - From mind-pops to hallucinations? A study of involuntary semantic memories in schizophrenia. AB - Involuntary semantic memories or mind-pops consist of isolated fragments of one's semantic knowledge (e.g., a word or a sentence, proper name, image or a melody) that come to mind unexpectedly, without any deliberate attempt to recall them. They can be experienced as alien and uncontrollable, and may share some phenomenological similarities with hallucinations. The aim of the present study was to investigate the nature and frequency of mind-pops in people with schizophrenia (N=37), as well as clinically depressed (N=31) and non-clinical controls (N=31). Results showed that schizophrenia patients reported experiencing mind-pops more frequently than both depressed and non-clinical controls. Schizophrenia patients also reported a wider range of different types of mind pops than non-clinical controls. The depressed group did not differ from non clinical controls in the frequency and range of mind-pops, indicating that mind pops are not characteristic of clinical populations in general, but may be particularly prevalent in patients with schizophrenia. The possible implications of this finding to current models of auditory verbal hallucinations are discussed and the need for future research in this area is emphasized. PMID- 22424895 TI - Psychiatric morbidities, sleep disturbances, suicidality, and quality-of-life in a community population with medically unexplained pain in Korea. AB - We examined the psychiatric morbidities, sleep disturbances, suicidality, quality of-life, and psychological distress of community-dwelling subjects in Korea who had medically unexplained pain. A total of 6510 subjects (age 18-65 years) participated in this study. A medically unexplained pain symptom (MUS-pain) was defined as pain lasting for 6 months or longer that was sufficiently severe to cause significant distress or to materially interfere with normal activities in the previous year, and that could not be explained by a medical condition or substance use/abuse. Diagnostic assessments were based on responses to the Composite International Diagnostic Interview, which was administered by lay colleagues. The presence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) disorders, sleep disturbances, suicidal tendency, quality-of-life issues, and psychological distress was determined in subjects with and without MUS-pain. There were significant positive associations between MUS-pain and nicotine dependence and withdrawal, alcohol dependence, major depressive disorder, dysthymic disorder, bipolar disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder, and psychotic disorder. In addition, subjects with MUS-pain reported more sleep disturbances, suicidality, psychological distress, and a poorer quality-of-life than did subjects without MUS-pain. The results of this study suggest that clinicians should carefully evaluate and treat comorbid psychiatric problems in individuals with MUS-pain. PMID- 22424896 TI - Response to 2009 pandemic influenza A H1N1 among public schools of Georgia, United States--fall 2009. AB - BACKGROUND: Little is known about the extent of implementation or the effectiveness of the Centers for Disease Control and Prevention's (CDC) recommended non-pharmaceutical interventions (NPIs) in schools to control the spread of 2009 pandemic influenza A H1N1 (pH1N1). METHODS: A web-based, cross sectional survey of all public K-12 schools in Georgia, USA was conducted about preparedness and response to pH1N1, and absenteeism and respiratory illness. Schools that reported >=10% absenteeism and at least two times the normal level of respiratory illness in the same week were designated as having experienced significant respiratory illness and absenteeism (SRIA) during that week. RESULTS: Of 2248 schools surveyed, 704 (31.3%) provided sufficient data to include in our analysis. Participating schools were spread throughout Georgia, USA and were similar to non-participating schools. Of 704 schools, 160 (22.7%) reported at least 1 week of SRIA. Most schools reported implementing the CDC recommendations for the control of pH1N1, and only two schools reported canceling or postponing activities. Schools that communicated with parents about influenza in the summer, had shorter school days, and were located in urban areas were less likely to experience SRIA. CONCLUSIONS: Most Georgia schools in the United States adopted the CDC recommendations for pH1N1 mitigation and few disruptions of school activities were reported. Early and timely communication with parents, as well as shorter school days, may have been effective in limiting the effect of pH1N1 on schools. PMID- 22424897 TI - Epigenetics and diabetes treatment: an unrealized promise? AB - Epigenetic mechanisms may contribute to the pathogenesis of complex diseases. Early or late environmental influences such as intrauterine malnutrition or sedentary lifestyle have been shown to lead to an increased risk of diabetes. Recently, epigenetic mechanisms were shown to be involved in endocrine cell differentiation and islet function. Genomic profiling of pancreatic islets in non diabetic and diabetic states is needed in order to dissect the contribution of epigenetic mechanisms to the declining proliferation potential of beta cells that we see with aging or the beta-cell failure observed in diabetes. In-depth understanding of epigenetic landscapes can help to improve protocols for in vitro differentiation towards the beta-cell fate, enhance beta-cell proliferation, and lead to the discovery of novel therapeutic targets. PMID- 22424898 TI - [Neonatal adrenal hemorrhage revealed by jaundice: a case report]. AB - The clinical presentation of adrenal hemorrhage varies, depending on the extent of hemorrhage as well as the amount of adrenal cortex involved by the hemorrhage. We report here a case of neonatal adrenal hemorrhage revealed by late onset of neonatal jaundice. This adrenal hemorrhage most probably resulted from shoulder dystocia. The aim of this work was to focus on the fact that jaundice can be caused by adrenal hemorrhage and to emphasize the crucial importance of abdominal ultrasound in cases of persistent jaundice. PMID- 22424899 TI - Letter in response to the Hynote article. PMID- 22424900 TI - Comparison of eight commercial enzyme immunoassays for the detection of Clostridium difficile from stool samples and effect of strain type. AB - We compared the performance of 8 Clostridium difficile enzyme immunoassays to cell cytotoxicity neutralization assay and toxigenic culture. The effect of strain type on assay performance was also examined. There were a total of 71 (14.4%) samples in which C. difficile was recovered; 58 (81.7%) of 71 were toxigenic. Compared to a composite reference standard of either C. difficile cytotoxin assay positive or toxigenic C. difficile culture positive, the sensitivities of these assays varied from 31.7% to 55.2%, while the specificities were excellent, ranging from 98.1% to 100%. Among the 57 C. difficile isolates, 30 (51.7%) were of the NAP1 genotype. Stool samples positive for the C. difficile NAP1 strain had a higher positivity rate for the toxin assays. PMID- 22424901 TI - Difference in Cryptococcus neoformans cellular and capsule size in sequential pulmonary and meningeal infection: a postmortem study. AB - Cryptococcus neoformans is an encapsulated yeast that primarily causes a life threatening meningoencephalitis in immunosuppressed individuals especially those with HIV/AIDS. Its main virulence factor is its polysaccharide capsule which interferes with complement-mediated phagocytosis. C. neoformans infections ensue following inhalation of small desiccated less encapsulated propagules leading to pulmonary pneumonia or colonization of the host's respiratory tract. Numerous murine experimental studies have shown major discrepancies in cryptococcal cell and capsule enlargement between the lung and brain. In this report, we describe a nonmurine experimental model of the striking variability between cryptococcal cell and capsule size diameters in histology sections of postmortem lung and brain in a fatal cryptococcal infection in a heart transplant recipient. PMID- 22424902 TI - Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. AB - Degeneration of medium spiny GABA neurons in the basal ganglia underlies motor dysfunction in Huntington's disease (HD), which presently lacks effective therapy. In this study, we have successfully directed human embryonic stem cells (hESCs) to enriched populations of DARPP32-expressing forebrain GABA neurons. Transplantation of these human forebrain GABA neurons and their progenitors, but not spinal GABA cells, into the striatum of quinolinic acid-lesioned mice results in generation of large populations of DARPP32(+) GABA neurons, which project to the substantia nigra as well as receiving glutamatergic and dopaminergic inputs, corresponding to correction of motor deficits. This finding raises hopes for cell therapy for HD. PMID- 22424903 TI - Abnormal recovery function of somatosensory evoked potentials in patients with primary insomnia. AB - Neurobiological correlates underlying insomnia are poorly understood. The hyperarousal of the central nervous system indicates that cortical excitability may be abnormal in patients with insomnia. The purpose of the present study was to investigate changes in cortical excitability by examining the recovery function of median nerve somatosensory evoked potentials (SEPs) in patients with primary insomia (PI). We studied the recovery function of median nerve SEPs in 12 medication-naive PI patients and in 12 age- and sex-matched healthy subjects. SEPs in response to single stimulus and paired stimuli at interstimulus intervals (ISIs) of 20, 60, 100 and 150 ms were recorded. The recovery function of the cortical components of frontal P20 and parietal N20 showed significantly reduced suppression in PI patients as compared to healthy controls. In conclusion, this is the first study investigating changes in cortical excitability in PI patients by examining the recovery function of median nerve SEPs. The present study suggests that cortical excitability is increased in PI patients. Dysfunction of inhibitory GABAergic interneurons of the cerebral cortex might contribute to the increased cortical excitability in PI patients. PMID- 22424904 TI - Differentiating PTSD symptomatology with the MMPI-2-RF (Restructured Form) in a forensic disability sample. AB - The current study was designed to explore models of assessing various forms of Post-Traumatic Stress Disorder (PTSD) symptomatology that incorporate both broad and more narrowly focused affective markers. We used broader markers of demoralization, negative activation, positive activation, and aberrant experiences to predict global PTSD scores, whereas more narrowly focused markers of positive and negative affect were used to differentiate between PTSD symptom clusters. A disability sample consisting of 347 individuals undergoing medico legal psychological evaluations was used for this study. All participants completed symptom measures of PTSD and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) (from which MMPI-2-RF scores were derived). The results indicated that demoralization was the best individual predictor of PTSD globally, and that more narrowly focused MMPI-2-RF Specific Problems scales provided a differential prediction of PTSD symptom clusters. Theoretical and practical implications of these findings are discussed within contemporary frameworks of internalizing personality and psychopathology. PMID- 22424905 TI - High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam. AB - The withdrawal syndrome from benzodiazepine (BZD) can be severe and in some cases may impede cessation of the use of the drug. We present here a case series of benzodiazepine detoxification by flumazenil infusion, stabilised with clonazepam. Patients were treated with flumazenil 1.35 mg/day for a median of 7 days. Self reported physical withdrawal symptoms were recorded daily. In addition to flumazenil, antidepressants were given before treatment commenced and clonazepam was administered nightly with both being continued after discharge. Twenty-nine patients were treated. No patients dropped out from the treatment programme. Nine patients (31%) required a temporary reduction/cessation of the infusion. The linear trend in the reduction of the daily withdrawal scores in the overall study population was significant. The linear trends were also significant in the group of patients for whom a temporary reduction/suspension of the flumazenil was required. Six months after treatment, 15 patients (53%) were abstinent from clonazepam and other BZDs. For five (21%) the BZD dependence were reinstated. More than two-thirds of the subjects tolerated the procedure well and about half had a good long term response. Slow flumazenil infusion appears to merit consideration as a possible future treatment. Suggestions for future research are examined. PMID- 22424907 TI - Aspects of cognitive functioning in schizotypy and schizophrenia: evidence for a continuum model. AB - This research consisted of two studies, the fundamental aim of which was to delineate the pattern of relationships between measures of cognitive task performance and both symptom subtypes in schizophrenia and their corresponding schizotypal personality traits in healthy individuals. Study 1 compared these relationships in healthy individuals using the Schizotypal Personality Questionnaire (SPQ) and Study 2 assessed the relationships between symptomatology assessed using the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms (SAPS/SANS) and cognitive task performance in a group of patients with schizophrenia. The contribution of fluid intelligence to task performance was also examined. In Study 1 high levels of negative schizotypy were associated with reduced verbal fluency, and high levels of disorganised schizotypy were associated with reduced negative priming in the healthy participants. In Study 2, closely corresponding relationships between symptom measures and these tasks were found in the patients with schizophrenia. The associations between the symptom and cognitive measures were independent of the effects of fluid IQ on performance. PMID- 22424906 TI - Advanced paternal age increases the risk of schizophrenia and obsessive compulsive disorder in a Chinese Han population. AB - Using the Structured Clinical Interview for DSM-IV, patient and non-patient version (SCID-P/NP), this study investigated 351 patients with schizophrenia, 122 with obsessive-compulsive disorder (OCD), and 238 unrelated healthy volunteers in a Chinese Han population. The relative risks posed by advanced paternal age for schizophrenia and OCD in offspring were computed under logistic regression analyses and adjusted for the participant's sex, age and co-parent age at birth. Compared to the offspring with paternal age of 25-29 years old, the relative risks rose from 2.660 to 10.183 in the paternal age range of 30-34 and >=35. The relative risks for OCD increased from 2.225 to 5.413 in 30-34 and >=35. For offspring with paternal age of <25, the odds ratios of developing schizophrenia and OCD were 0.628 and 0.289 respectively, whereas an association between increased maternal age and risk for schizophrenia/OCD was not seen. Interaction analysis showed an interaction effect between paternal age and maternal age at birth. Such a tendency of risk affected by parental age for schizophrenia and OCD existed after splitting out the data of early onset patients. Sex-specific analyses found that the relative risks for schizophrenia with paternal age of 30 34 and >=35 in male offspring were 2.407 and 10.893, and in female offspring were 3.080 and 9.659. The relative risks for OCD with paternal age of 30-34 and >=35 in male offspring were 3.493 and 7.373, and in female offspring 2.005 and 4.404. The mean paternal age of schizophrenia/OCD patients born before the early 1980s was much greater than that of patients who were born after then. The findings illustrated that advanced paternal age is associated with increased risk for both schizophrenia and OCD in a Chinese Han population, prominently when paternal age is over 35. Biological and non-biological mechanisms may both be involved in the effects of advanced paternal age on schizophrenia and OCD. PMID- 22424908 TI - Structure of the Health of the Nation Outcome Scales for Children and Adolescents: an ordinal factor analysis of clinician ratings of a sample of young people referred to community mental health services. AB - The Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) have been implemented as performance and research measures for youth mental health services in the UK and elsewhere. However, the factor structure of this instrument has not yet been reported. Clinician ratings from a representative sample of 1335 young people seen by community-based Child and Adolescent Mental Health Services were randomised into exploratory and confirmatory datasets. Parallel analysis followed by an exploratory factor analysis was performed on the former ratings. The potential structures elicited were tested using confirmatory factor analyses (CFA). The resulting structures were evaluated in the confirmatory dataset. On CFA a five-factor model with one cross-loading item provided the best fit to the data. However, the internal reliability consistency of some of the postulated subscales was poor. We conclude that the HoNOSCA is a multidimensional measure with a three-factor structure possibly providing the optimum compromise between fit and internal reliability. Thus, it may be most appropriate to summarise clinical outcomes using two symptom subscores, relating to behavioural and emotional problems, rather than using the total scores, as is current practice. Such subscales may be more sensitive to change than total summed scores. PMID- 22424909 TI - Social anxiety and social cognition: the influence of sex. AB - Current theoretical models predict a negative relationship between social anxiety and performance on measures of social cognition, yet there appears to be relatively little research that directly examines this relationship and the potential interaction of sex. Two samples of undergraduates self-reporting either a high (n=27; 59% female) or low (n=29; 62% female) level of social anxiety on the abbreviated Social Phobia and Anxiety Inventory completed two social cognition measures: the Reading the Mind in the Eyes Test (Eyes Test) and The Awareness of Social Inference Test-Parts 2 and 3). A multivariate analysis of variance revealed a significant group by sex interaction on overall social cognition performance. Follow-up analyses indicated that males with high and low levels of social anxiety did not differ on any of the social cognition measures. In contrast, females with high social anxiety performed significantly better on the Eyes Test and the TASIT-Part 3 than females with low social anxiety. Contrary to expectations, results of this study suggest that females with high social anxiety may exhibit better-developed social cognition abilities than those with low social anxiety. These preliminary results have clinical implications in the treatment of individuals with social phobia. PMID- 22424910 TI - Surgical decompression in endocrine orbitopathy. Visual evoked potential evaluation and effect on the optic nerve. AB - Endocrine orbitopathy (EO) represents the most frequent and important extrathyroidal stigma of Graves disease. This chronic autoimmune condition involves the orbital contents, including extraocular muscles, periorbital connective-fatty tissue and lacrimal gland. The increase of fat tissue and the enlargement of extraocular muscles within the bony confines of the orbit leads to proptosis, and in the most severe cases optic neuropathy, caused by compression and stretching of the optic nerve. The congestion and the pressure of the enlarged muscles, constrict the nerve and can lead to reduced sight or loss of vision with the so called "orbital apex syndrome". Generally surgical treatment of EO, based on fat and/or orbital wall expansion, is possible and effective in improving exophthalmos and diplopia. Since there are limited reports focussing on optic neuropathy recovery after fat and/or orbital walls decompression the Authors decided to perform a retrospective analysis on a series of patients affected by EO. The study population was composed of 10 patients affected by EO and presenting to the Unit of Cranio Maxillofacial Surgery, Center for Craniofacial Deformities & Orbital Surgery St. Anna Hospital and University, Ferrara, Italy, for evaluation and treatment. A complete Visual Evoked Potentials (VEP) evaluation was performed. There were seven women and three men with a median age of 55 years. Optic nerve VEP amplitude and latency were recorded as normal or pathological. Abnormal results were scored as moderate, mild and severe. Differences in VEP pre and post-operatively were recorded as present or absent (i.e. VEP Delta). Pearson chi square test was applied. There were 20 operated orbits. The first VEP evaluation was performed 3.2 months before surgery and post-operative VEP control was done after a mean of 18.7 months. Fat decompression was performed in all cases and eight patients had also bony decompression. VEP amplitude and latency were affected in 10 and 15 cases before operation and six and nine after surgery, respectively. VEP amplitude and latency significantly improved after orbital decompression. Fat and orbital wall decompression are of paramount importance not only to improve exophthalmos and diplopia in patients affected by EO but also as rescue surgery for severe cases where optic neuropathy caused by stretching of the optical nerve is detected by VEP. Imaging and functional nerve evaluation are mandatory in all cases of EO. PMID- 22424911 TI - Interaction of local and general anaesthetics with liposomal membrane models: a QCM-D and DSC study. AB - The behaviour of four local anaesthetics (lidocaine, levobupivacaine, ropivacaine and tetracaine) and one general anaesthetic (propofol) is compared when interacting with two types of model membranes: supported layers of liposomes and liposomes in solution. Several liposomal compositions were tested: dimyristoylphosphatidylcholine (DMPC), binary mixtures of DMPC with cholesterol (CHOL), and ternary mixtures of dipalmitoylphosphatidylcholine (DPPC), DMPC, and CHOL. A quartz crystal microbalance with dissipation, QCM-D, was used to assess changes in the properties of supported layers of liposomes. The effect of the anaesthetics on the phase behaviour of the liposomes in suspension was determined by differential scanning calorimetry. Both techniques show that all anaesthetics have a fluidizing effect on the model membranes but, apparently, the solid supported liposomes are less affected by the anaesthetics than the liposomes in solution. Although the different anaesthetics were compared at different concentrations, tetracaine and propofol seem to induce the strongest perturbation on the liposome membrane. The resistance of the liposomes to the anaesthetic action was found to increase with the presence of cholesterol, while adding DPPC to the binary mixture DMPC+CHOL does not change its behaviour. The novelty of the present work resides upon three points: (1) the use of supported layers of liposomes as model membranes to study interactions with anaesthetics; (2) application of QCM-D to assess changes of the adsorbed liposomes; (3) a comparison of the effect of local and general anaesthetics interacting with various model membranes in similar experimental conditions. PMID- 22424912 TI - Dose equivalence of immediate-release hydromorphone and once-daily osmotic controlled extended-release hydromorphone: a randomized, double-blind trial incorporating a measure of assay sensitivity. AB - Dose selection of a once-daily, osmotic-controlled extended-release (ER) hydromorphone assumes that this drug and immediate-release (IR) hydromorphone are dose equivalent. This trial evaluated dose equivalence using a measure of assay sensitivity. Patients were converted to open-label IR hydromorphone, underwent dose titration, and those on a satisfactory dose entered a randomized, double blind phase receiving 7 days of: 1) hydromorphone IR 5 times/day at approximately this dose; 2) once-daily hydromorphone ER at this dose; or 3) once-daily hydromorphone ER at one-half this dose. Efficacy was measured using breakthrough medication use, pain, sleep, and global assessments. Of 148 patients, 113 (76%) were randomized. IR and full-dose ER groups produced comparable effects on all measures. Although the prespecified primary analysis of the difference in total daily dose of breakthrough medication between the full-dose ER and half-dose ER groups was not significant, more patients in the half-dose ER group required an increase in breakthrough medication (P = .026) and the half-dose ER group both increased the number of breakthrough doses (P = .026) and had greater percent change in the total daily dose of breakthrough medication (P = .037) than the full-dose group, suggesting that switching from IR to ER hydromorphone at the same daily dose provides equivalent analgesia. PERSPECTIVE: In a randomized, double-blind trial, the same total daily dose of immediate-release hydromorphone and once-daily osmotic-controlled extended-release hydromorphone had comparable effects. Detection of different effects between blinded dose levels was used as a measure of assay sensitivity. The measure of assay sensitivity can enhance the interpretation of dose equivalence or noninferiority trials. PMID- 22424913 TI - Effects of the delta opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats. AB - The delta opioid receptor agonist SNC80 produces both antinociceptive and antidepressant effects in rodents. This profile suggests that SNC80 may also reverse prodepressant effects of pain. Accordingly, this study compared SNC80 effects in complementary assays of pain-stimulated and pain-depressed behavior in rats. Intraperitoneal injection of dilute acid served as an acute noxious visceral stimulus in rats to stimulate abdominal stretching (a pain-stimulated behavior) or depress intracranial self-stimulation of the medial forebrain bundle (ICSS; a pain-depressed behavior). When administered once per week to minimize acute tolerance, SNC80 (1-10 mg/kg IP) decreased acid-stimulated stretching but had little effect on acid-induced depression of ICSS. More frequent SNC80 administration produced tolerance to SNC80 effects on acid-stimulated stretching, but unmasked antinociception in the assay of acid-depressed ICSS. SNC80 did not facilitate ICSS in the absence of pain, and effects of SNC80 were not duplicated by ARM390, a reputed delta agonist congener of SNC80 that does not internalize delta receptors. These findings support continued consideration of delta agonists as candidate analgesics to treat prodepressant effects of pain and illustrate the potential for diametrically opposite effects of drug treatments on preclinical measures of pain-stimulated and pain-depressed behavior. PERSPECTIVE: The delta opioid agonist SNC80 blocked pain-related depression of intracranial self stimulation in rats, suggesting that delta agonists may be useful to treat prodepressant effects of pain. Repeated SNC80 produced tolerance to SNC80 antinociception in a conventional assay of pain-stimulated behavior but unmasked SNC80 antinociception in an assay of pain-depressed behavior. PMID- 22424915 TI - Validation of the numerical rating scale for pain intensity and unpleasantness in pediatric acute postoperative pain: sensitivity to change over time. AB - This study evaluates the construct validity (including sensitivity to change) of the numerical rating scale (NRS) for pain intensity (I) and unpleasantness (U) and participant pain scale preferences in children/adolescents with acute postoperative pain. Eighty-three children aged 8 to 18 years (mean = 13.8, SD = 2.4) completed 3 pain scales including NRS, Verbal Rating Scale (VRS), and faces scales (Faces Pain Scale-Revised [FPS-R] and Facial Affective Scale [FAS], respectively) for pain intensity (I) and unpleasantness (U) 48 to 72 hours after major surgery, and the NRS, VRS and Functional Disability Index (FDI) 2 weeks after surgery. As predicted, the NRSI correlated highly with the VRSI and FPS-R and the NRSU correlated highly with the VRSU and FAS 48 to 72 hours after surgery. The FDI correlated moderately with the NRS at both time points. Scores on the NRSI and NRSU at 48 to 72 hours were significantly higher than at 2 weeks after surgery. Children found the faces scales the easiest to use while the VRS was liked the least and was the hardest to use. The NRS has adequate evidence of construct validity including sensitivity for both pain intensity and unpleasantness. This study further supports the validity of the NRS as a tool to measure both intensity and unpleasantness of acute pain in children. PERSPECTIVE: This article evaluates the construct validity including sensitivity of the Numerical Rating Scale for pain intensity and pain unpleasantness over time in children after major surgery. The NRS could be used by clinicians to assess these 2 different dimensions of children's pain experience in acute pain settings. PMID- 22424914 TI - Pain-related fear and catastrophizing predict pain intensity and disability independently using an induced muscle injury model. AB - Timing of assessment of psychological construct is controversial and results differ based on the model of pain induction. Previous studies have not used an exercise-induced injury model to investigate timing of psychological assessment. Exercise-induced injury models may be appropriate for these investigations because they approximate clinical pain conditions better than other experimental stimuli. In this study we examined the changes of psychological constructs over time and determined whether timing of assessment affected the construct's association with reports of pain intensity and disability. One-hundred twenty-six healthy volunteers completed the Fear of Pain Questionnaire (FPQ-III), Pain Catastrophizing Scale (PCS), and Tampa Scale of Kinesiophobia (TSK) prior to inducing muscle injury to the shoulder. The PCS and TSK were measured again 48 and 96 hours postinjury induction. Pain intensity and disability were collected at 48 and 96 hours and served as dependent variables in separate regression models. Results indicated that the FPQ-III had the strongest prediction of pain intensity from baseline to 96 hours. After baseline the PCS and TSK were stronger predictors of pain intensity and disability, respectively. These data provide support for the use of psychological constructs in predicting outcomes from shoulder pain. However, they deviate from the current theoretical model indicating that fear of pain is a consequence of injury and instead suggests that fear of pain before injury may influence reports of pain intensity. PERSPECTIVE: The current study provides evidence that fear of pain can be assessed prior to injury. Furthermore, it supports that after injury pain catastrophizing and kinesiophobia are independently associated with pain and disability. Overall these data suggest that timing of psychological assessment may be an important consideration in clinical environments. PMID- 22424917 TI - It's not my fault: understanding nursing students' causal attributions in Pathophysiology. AB - Pathophysiology is a difficult subject matter for many nursing students. This course is also critical for safe clinical practice. However, little research has explored what variables may influence nursing students' success in this course. This study is the first in a forthcoming series that seeks to better understand how to facilitate student success in Pathophysiology. In this study, students' causal attributions for successes and failures were explored as these attributions greatly influence future academic motivation and behavior. Students were asked to respond to two open-ended questions in order to better understand what causal attributions students were making for their successes and failures in Pathophysiology. Seventy-five Bachelor of Science in Nursing students who were enrolled in Pathophysiology returned their responses (92.6% response rate). Content analysis was utilized to determine whether students were making internal or external causal attributions for their successes and failures. Additionally, responses were evaluated in order to identify common themes shared by respondents. The majority of respondents (84%) attributed their academic successes in Pathophysiology in part to internal causes, and the majority of respondents (68%) attributed their academic failures, in part, to external causes. In this study the majority of students attributed their successes to controllable, unstable causes-primarily effort. Research indicates that attributing success to effort may reflect that students' confidence in their abilities is suffering, and that attributing failures to external causes, such as task difficulty, are also detrimental to performance and learning (Siegle et al., 2009). The results of this study are further presented and discussed. PMID- 22424916 TI - NMDA or non-NMDA receptor antagonism within the amygdaloid central nucleus suppresses the affective dimension of pain in rats: evidence for hemispheric synergy. AB - The amygdala contributes to generation of affective behaviors to threats. The prototypical threat to an individual is exposure to a noxious stimulus and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study evaluated the contribution of glutamate receptors in CeA to generation of the affective response to acute pain in rats. Vocalizations that occur following a brief noxious tail shock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by bilateral injection into CeA of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5, 1 MUg, 2 MUg, or 4 MUg) or the non-NMDA receptor antagonist 6-Cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX, .25 MUg, .5 MUg, 1 MUg, or 2 MUg). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of AP5 or CNQX into CeA. Unilateral administration of AP5 or CNQX into CeA of either hemisphere also selectively elevated vocalization thresholds. Bilateral administration of AP5 or CNQX produced greater increases in vocalization thresholds than the same doses of antagonists administered unilaterality into either hemisphere indicating synergistic hemispheric interactions. PERSPECTIVE: The amygdala contributes to production of emotional responses to environmental threats. Blocking glutamate neurotransmission within the central nucleus of the amygdala suppressed rats' emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders. PMID- 22424918 TI - Tick prevention at a crossroad: new and renewed solutions. AB - Ticks have major economic impact through diseases they transmit, direct losses due to their detrimental effect and the efforts invested in prevention measures directed against them. Chemical acaricides represent the main line of anti-tick defense in both humans and domestic animals, but increasing concerns regarding development of acaricide resistance, especially in the cattle tick Rhipicephalus microplus, and environmental safety issues indicate the need for other, less aggressive but equally efficient methods. This paper aims to evaluate the potential, the scientific and economical limitations and future research directions regarding different alternative methods of tick control and their use in integrated pest management, with a separate reference to the pet industry. New research data in each field is presented and the economical aspects for each approach are individually emphasized. PMID- 22424919 TI - [The blues in post-survey]. PMID- 22424920 TI - Recent trends in biocatalysis engineering. AB - During the last 30 years the scope of biocatalysis has been expanding due to the advances in several technological fields. Diverse techniques as structural enzyme improvement (e.g. protein engineering, direct evolution), engineering approaches (e.g. ionic liquids, supercritical fluids) and physical stabilization (e.g. immobilization, CLEAS) have been developed, which in combination are powerful tools to improve biotransformation and to synthesize new products. In the present work, recent advances in biocatalysis are reviewed. PMID- 22424921 TI - Diplogelasinospora grovesii IMI 171018 immobilized in polyurethane foam. An efficient biocatalyst for stereoselective reduction of ketones. AB - Diplogelasinospora grovesii has been reported as a very active biocatalyst in the reduction of ketones. Along the text, the properties of this filamentous fungus as an immobilized catalyst are described. For this purpose, several immobilization supports as agar and polyurethane foam were tested. Experimental assays were also performed to test different co-substrates for the regeneration of the required enzyme cofactor. The fungus immobilized in polyurethane foam lead to the most stable and active catalyst. This derivative, using i-PrOH as co substrate, could be reused at least 18 times without appreciable activity loss (>90% activity remains). Kinetic runs experiments shown that the reduction of cyclohexanone, selected as model substrate, followed a pseudo-first kinetic order and that the rate controlling step was the mass transfer through the cell wall. The deactivation kinetic constants were also determined. The reduction of different chiral ketones showed that the ketone reductase activity followed the Prelog's rule. PMID- 22424922 TI - Combination of enzymatic hydrolysis and ethanol organosolv pretreatments: effect on lignin structures, delignification yields and cellulose-to-glucose conversion. AB - Enzymatic pre-hydrolysis using the industrial enzymatic cocktail Cellulyve(r) was assessed as a first step in a pretreatment process of Miscanthus biomass involving an aqueous-ethanol organosolv treatment. (13)C and (31)P Nuclear Magnetic Resonance and size exclusion chromatography were used to analyze the cellulose and lignin before and after treatment. It was demonstrated that despite a very low impact on the fibre structure (observed by Scanning Electron Microscopy) and composition (in terms of sugars and polyphenolics content), the enzymatic pre-treatment disrupted the lignocellulosic matrix to a considerable extend. This weakening permitted enhanced removal of lignin during organosolv pulping and increased hydrolysability of the residual cellulosic pulp for the production of monomeric glucose. Using this combined treatment, a delignification yield of 93% and an enzymatic cellulose-to-glucose conversion of 75% were obtained. PMID- 22424923 TI - Effect of imposed flux on fouling behavior in high rate membrane bioreactor. AB - The influence of imposed flux and aeration rates on membrane fouling in a submerged membrane bioreactor was studied. The experiments were conducted at four imposed fluxes and three aeration rates. The effect of flux on the reduction of membrane fouling was much higher than that caused by aeration rate. A lower flux of 20 L/m(2) h produced 75 times more water than a higher flux of 40 L/m(2) h with an aeration rate of 2 L/min. Low flux showed slightly higher removal of NH(4)-N and 93-96% removal of dissolved organic matter and chemical oxygen demand. Imposed flux also had a significant effect on the composition of organics present in the soluble microbial product (SMP) and extracellular polymeric substances (EPS). At a higher flux, both SMP and EPS had organics of high molecular weight (MW) of around 48 kDa as well as lower MW organics below 200 Da. PMID- 22424924 TI - A novel process for recovery and refining of L-lactic acid from fermentation broth. AB - This paper introduces a novel process for recovery and refining of L-lactic acid from a fermentation broth. The use of a solvent extraction step, in the novel approach, has significant impacts on the following centrifugal short-path distillation conditions (operating pressure, evaporator temperature and feed flow rate). As the conditions were varied, the l-lactic acid purity and yield in the distillate were monitored. For the purpose of comparison, a series of experiments were also carried out using the existing purification process. The results showed that both of the two processes can obtain l-lactic acid with a high purity around 91.3%, while the yield obtained using the novel process reached 61.73%, which was about 20.43% higher than that using the existing process. Additionally, multiple pass distillation observed special attention by improving the yield up to 74.63%. PMID- 22424925 TI - Kinetics of esterification of acidified oil with different alcohols by a cation ion-exchange resin/polyethersulfone hybrid catalytic membrane. AB - Hybrid catalytic membranes consisting of cation ion-exchange resin particles (CERP) and polyethersulfone (PES) were prepared by immersion phase inversion and used as heterogeneous catalysts for the esterification of acidified oil with methanol, ethanol, propanol and butanol. The membranes were characterized by ion exchange capacity and swelling degree tests. The membranes were annealed at different temperatures to improve catalytic activity and membranes annealed at 393 K had the highest catalytic activity. Butanol allowed the highest free fatty acids (FFAs) conversion of 95.28% since it has better miscibility than the other alcohols which strengthened mass and heat transfer. Furthermore, pseudo homogeneous kinetic models of the esterification of acidified oil with the four alcohols were established according to the experimental data. The kinetic models can well predict the FFA conversion. PMID- 22424926 TI - Temporal variation of decomposition gases from baled municipal solid wastes. AB - In this study, after nine cylindrical bales containing a mix of different waste materials were constructed, they were stored in the open air and temporal variations of CO(2), CH(4), O(2), and N(2) were monitored over 10 months. In each bale, different waste fractions were considered in order to represent different moisture contents. The results showed that CO(2) increased within very few days to approximately 80% and stabilized later in the range of between 10% and 35% in a month. The O(2) levels dropped from approximately 15% to significantly less than 1%. There was no significant anaerobic decomposition since CH(4) did not exceed 5% during the whole test period. N(2) exhibited an opposite pattern with CO(2). In addition, relationships between waste species in the bales and gas formations were determined by a bivariate correlation analysis. An empirical prediction model for the maximum CO(2) production was also developed. PMID- 22424927 TI - Biomass production of a Scenedesmus sp. under phosphorous-starvation cultivation condition. AB - Microalgae-based bioenergy has gained extensive attention, but the consumption of non-renewable resource such as phosphorous is inevitable in the production of its feedstock. In this work, the minimal phosphorous consumption for algal biomass production of Scenedesmus sp. LX1 was investigated by monitoring the growth and nutrient uptake under two different cultivation modes: phosphorous-starvation and luxury-nutrient. The results showed that continuous nitrogen and phosphorous feeding in luxury-nutrient mode had no stimulating effect on biomass productivity at the nutrient level in this study, TN: 245 mg L(-1), TP: 5.4 mg L(-1). However, the sustained growth of biomass after the exhaust of phosphate in phosphorous starvation mode led to significant increase in the biomass yield of phosphorous up to 160 g biomass/g -P, which was nearly six times more than that with nutrient feeding. To minimize phosphorous resource consumption in production of algal biomass, a phosphorous-starvation cultivation mode is proposed. PMID- 22424928 TI - Generation and characterization of monoclonal antibodies to equine CD16. AB - The low-affinity Fc receptor CD16 plays a central role in the inflammatory and innate immune responses of many species, but has not yet been investigated in the horse. Using the predicted extracellular region of equine CD16 expressed as a recombinant fusion protein with equine IL-4 (rIL-4/CD16), we generated a panel of mouse monoclonal antibodies (mAbs) that recognize equine CD16. Nine mAbs were chosen for characterization based upon recognition of CD16, but not IL-4, in ELISA. All nine mAbs recognized full-length, cell-surface CD16 expressed as a GFP fusion protein by CHO cells, but not the closely related Fc receptor CD32 expressed in the same system. In flow cytometric analysis with equine peripheral leukocytes, the mAbs labeled cells in the granulocyte, monocyte, and lymphocyte populations in a pattern consistent with other species. Monocytes that were strongly labeled with CD16 mAb 9G5 were also positive for the LPS receptor CD14. Cytospins made with peripheral leukocytes were immunohistochemically labeled and showed mAb recognition of primarily mononuclear cells. ELISA revealed that the nine mAbs can be grouped into three patterns of epitope recognition. These new antibodies will serve as useful tools in the investigation of equine immune responses and inflammatory processes. PMID- 22424929 TI - The temporal sequence of the mammalian neocortical neurogenetic program drives mediolateral pattern in the chick pallium. AB - The six-layered neocortex permits complex information processing in all mammalian species. Because its homologous region (the pallium) in nonmammalian amniotes has a different architecture, the ability of neocortical progenitors to generate an orderly sequence of distinct cell types was thought to have arisen in the mammalian lineage. This study, however, shows that layer-specific neuron subtypes do exist in the chick pallium. Deep- and upper-layer neurons are not layered but are segregated in distinct mediolateral domains in vivo. Surprisingly, cultured chick neural progenitors produce multiple layer-specific neuronal subtypes in the same chronological sequence as seen in mammals. These results suggest that the temporal sequence of the neocortical neurogenetic program was already inherent in the last common ancestor of mammals and birds and that mammals use this conserved program to generate a uniformly layered neocortex, whereas birds impose spatial constraints on the sequence to pattern the pallium. PMID- 22424930 TI - Cell-surface proteomics identifies lineage-specific markers of embryo-derived stem cells. AB - The advent of reprogramming and its impact on stem cell biology has renewed interest in lineage restriction in mammalian embryos, the source of embryonic (ES), epiblast (EpiSC), trophoblast (TS), and extraembryonic endoderm (XEN) stem cell lineages. Isolation of specific cell types during stem cell differentiation and reprogramming, and also directly from embryos, is a major technical challenge because few cell-surface proteins are known that can distinguish each cell type. We provide a large-scale proteomic resource of cell-surface proteins for the four embryo-derived stem cell lines. We validated 27 antibodies against lineage specific cell-surface markers, which enabled investigation of specific cell populations during ES-EpiSC reprogramming and ES-to-XEN differentiation. Identified markers also allowed prospective isolation and characterization of viable lineage progenitors from blastocysts by flow cytometry. These results provide a comprehensive stem cell proteomic resource and enable new approaches to interrogate the mechanisms that regulate cell fate specification. PMID- 22424931 TI - Radiological features of Gorham's disease. AB - AIM: To describe the key findings on plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) of Gorham's disease. MATERIALS AND METHODS: Eight children diagnosed with Gorham's disease between 1999 and 2009 were included. All imaging studies performed on each patient were reviewed with special attention to the extent of bone, soft tissue, and visceral involvement. RESULTS: All patients had bone lesions at diagnosis, most commonly in the vertebrae. CT showed generalized osteopenia, multiple lytic lesions, and heterogeneous bone density. MRI demonstrated altered signal intensity in bone marrow that was hyperintense on T1 imaging. Seven patients had soft-tissue lymphangiomatous lesions adjacent to identified osseous lesions. Four patients had chylous pleural effusions: three with bilateral and one with unilateral involvement. The spleen was involved in six patients. CONCLUSION: Splenic lesions and soft-tissue involvement are common in patients with Gorham's disease. The presence of extra-osseous lesions along with characteristic bone lesions on plain radiography may be pathognomonic of Gorham's disease. PMID- 22424932 TI - Inhibition of Listeria monocytogenes on bologna sausages by an antimicrobial film containing mustard extract or sinigrin. AB - The ability of Listeria (L.) monocytogenes to convert glucosinolates into antimicrobial isothiocyanates was investigated. Mustard glucosinolates in pure (sinigrin) or extract forms (sinigrin, oriental; sinalbin, yellow mustard) were used in broth media and in a polyvinyl polyethylene glycol graft copolymer (PPG) packaging film with bologna to examine their value as antimicrobial precursors for the control of L. monocytogenes viability and extension of bologna shelf-life at 4 degrees C. During broth tests with deodorized (myrosinase-inactivated) mustard extracts (10 d at 20 degrees C) or with purified sinigrin (21 d at 20 degrees C) L. monocytogenes was only inhibited when exogenous myrosinase was added. None the less, the organism was able to hydrolyze almost half the pure sinigrin by 21 d in tests without added enzyme. Reductions in sinigrin levels were measured by reversed-phase liquid chromatography, and in the absence of L. monocytogenes or added myrosinase the glucosinolate was stable. When pure sinigrin, oriental or yellow mustard extracts were incorporated in PPG films containing 3, 5 and 6% (w/w) of the corresponding glucosinolate and used to package bologna inoculated with 4 log CFU/g L. monocytogenes, the pathogen became undetectable in bologna packed with the oriental mustard extract at 52 d storage and remained undetectable at 70 d. The yellow mustard extract was less inhibitory and the pure sinigrin was not antimicrobial. L. monocytogenes numbers reached >7 log CFU/g in the film and untreated controls at 17 d storage. At 35 d storage, samples packed with control film contained sufficient numbers of lactic acid bacteria (LAB) (>7 log CFU/g) to be considered spoiled, whereas treatments containing mustard or sinigrin remained <7 log CFU/g LAB for <= 70 d. L. monocytogenes played a key role in exerting control over its own viability in bologna by hydrolysis of the glucosinolate in the oriental mustard film, but other antimicrobials in treatments may have contributed. PMID- 22424933 TI - Fundamental study on the influence of Fusarium infection on quality and ultrastructure of barley malt. AB - Barley infection with Fusarium species has been a long standing problem for the malting and brewing industries. In this study, we evaluate the impact of Fusarium culmorum infected raw barley on the final malt quality. Barley grains were infected for 5 days at optimum fungal growth conditions. Grains were fully characterized and compared to standard barley grains. Due to fungal infection, germinative energy of infected barley grains decreased by 45%; its water sensitivity increased dramatically, and grains accumulated 199 MUg/kg of deoxynivalenol (DON). Barley grains were subsequently malted for 8 days, fully characterized and compared to standard malt grains. Fungal growth behavior was evaluated during malting using a PCR-based assay and mycotoxins were measured using HPLC. Fungal biomass increased in grains, during all stages of malting. Infected malt accumulated 8-times its DON concentration during malting. Kernel ultrastructure was evaluated using scanning electron and confocal laser scanning microscopy. Infected malt grains were characterized by extreme structural proteolytic, (hemi)-cellulolytic and starch deterioration with increased friability and fragmentation. Infected grains had higher protease and beta glucanase activities, lower amylase activity, a greater proportion of free amino and soluble nitrogen, and a lower beta-glucan content. Malt loss was over 27% higher in infected malt in comparison to the control. The results of this study revealed that 20% F. culmorum infected barley kernels lead to a significant reduction in malt quality as well as mycotoxin formation. PMID- 22424934 TI - Optimization of microbial inactivation of shrimp by dense phase carbon dioxide. AB - Microbial inactivation of Litopenaeus vannamei by dense phase carbon dioxide (DPCD) treatment was investigated and neural network was used to optimize the process parameters of microbial inactivation. The results showed that DPCD treatment had a remarkable bactericidal effect on microorganism of shrimp. A 3*5*2 three-layer neural network model was established. According to the neural network model, the inactivation effect was enhanced with pressure, temperature and exposure time increasing and temperature was the most important factor affecting microbial inactivation of shrimp. Cooked appearance of shrimp by DPCD treatment was observed and seemed to be more positively acceptable by Chinese diet custom. Therefore, color change of shrimp by DPCD treatment could have a positive effect on quality attributes. Moderate temperature 55 degrees C with 15 MPa for 26 min treatment time achieved a 3.5-log reduction of total aerobic plate counts (TPC). The parameters combination might be appropriate for shrimp process by DPCD. PMID- 22424935 TI - Factors influencing selection for rehabilitation after stroke: a questionnaire using case scenarios to investigate physician perspectives and level of agreement. AB - OBJECTIVES: To explore the key factors involved in decision making when selecting patients for rehabilitation after stroke and to examine the level of agreement among physician assessors regarding admission to rehabilitation. DESIGN: Questionnaire. SETTING: Health services with rehabilitation units in Victoria, Australia. PARTICIPANTS: Rehabilitation unit physicians. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Questionnaire with 2 components: the clinical and nonclinical factors that influence decision making and clinical case scenarios. RESULTS: Responses were received from 17 physicians from 12 of the 18 health services in Victoria. The most influential clinical factors listed by the respondents were prognosis, social supports, anticipated discharge destination, age, and anticipated length of stay. Key nonclinical factors were prioritization of internal health service referrals, patient's residence, and workforce capacity. Analysis of the clinical scenarios of patients with severe stroke showed that there was variability in the responses, with high levels of agreement for some cases and low levels for others. Almost all respondents agreed that prognosis was a key factor, yet, within the case scenarios, the reasons given for accepting or not accepting the patient demonstrated different opinions on the prognosis of the case presented. CONCLUSIONS: The decision-making processes in selection for rehabilitation and the factors that influence that decision require further investigation to optimize the use and outcomes from rehabilitation resources. PMID- 22424936 TI - Musculoskeletal comorbidities in cardiac patients: prevalence, predictors, and health services utilization. AB - OBJECTIVES: To describe the prevalence of musculoskeletal conditions (MSKC) in patients with coronary artery disease (CAD); to examine the sociodemographic, clinical, and psychosocial predictors of these comorbidities; and to describe health care utilization by musculoskeletal comorbidity status. DESIGN: This was a cross-sectional, observational study in which patients were administered a questionnaire in the hospital and 1 year later. SETTING: Eleven hospitals in Ontario, Canada. PARTICIPANTS: CAD patients (N=1803). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sociodemographic, MSKC, clinical, and psychosocial factors were ascertained via questionnaire and in-hospital chart extraction. A health care utilization questionnaire was mailed 1 year later. RESULTS: Over half (56%) of the patients with CAD had MSKCs, with arthritis/joint pain accounting for 64.4% of these MSKCs. Patients who were older (odds ratio [OR]=1.03), women (OR=1.87), white (OR=1.80), with higher body mass index (OR=1.05), depressive symptoms (OR=1.92), and lower family income (OR=1.46) were more likely to present with MSKCs. One year posthospitalization, a greater proportion of those with MSKCs reported >=1 cardiac-related emergency department visit (33.2% vs 28.3%, P=.03), hospital admission (30.7% vs 22%, P=.006), more primary care physician visits (6.6+/-5.6 vs 5.7+/-4.6, P<.001), and fewer cardiac rehabilitation referrals (61.5% vs 70%, P<.001). After adjusting for depressive symptoms, body mass index, age, income, ethnicity, and sex, MSKCs predicted only hospital readmissions. CONCLUSIONS: Over half of the patients hospitalized for CAD have MSKCs. Those with MSKCs have a physical and psychosocial profile that places them at greater cardiovascular risk than those with CAD only, explaining, in part, their greater health care utilization. Despite a greater need for comprehensive risk factor management in patients with MSKCs, fewer were referred to cardiac rehabilitation. PMID- 22424937 TI - Kinetics of IL-6 and TNF-alpha changes in a canine model of sepsis induced by endotoxin. AB - Sepsis is a major cause of death in veterinary medicine, although a better prognosis can result from an early diagnosis. To speed the diagnosis, the biomarkers TNF-alpha and IL-6 can provide valuable information regarding systemic inflammatory response. The purpose of this study was to investigate the changes in cytokine levels in an experimental model of sepsis using ELISA and real-time PCR. Ten adult Beagles were studied; seven received an IV bolus of high dose lipopolysaccharide solution (1mg/kg) to induce sepsis. The remaining three beagles were the control group. Blood samples were collected before and 1, 3, 6, 12, 24 and 48 h after administering LPS. Serum IL-6 level peaked at 3h (1.89 +/- 0.10 ng/ml) and serum TNF-alpha peaked at 1h (1.11 +/- 0.01 ng/ml). The expression of IL-6 mRNA in peripheral blood mononuclear cells (PBMC) increased 62 fold compared to the control group at 1h; TNF-alpha mRNA increased by 4.5-fold at 1h. The expressions of IL-6 and TNF-alpha mRNA in PBMCs changed more rapidly than serum IL-6 and TNF-alpha concentrations. In addition, TNF-alpha mRNA levels in PBMCs remained elevated longer than serum TNF-alpha. Our study establishes the basis for future work aimed at a better understanding of the systemic inflammatory response to infection and sepsis in canine patients. PMID- 22424938 TI - Schmidingerothrix extraordinaria nov. gen., nov. spec., a secondarily oligomerized hypotrich (Ciliophora, Hypotricha, Schmidingerotrichidae nov. fam.) from hypersaline soils of Africa. AB - Schmidingerothrix extraordinaria nov. gen., nov. spec. was discovered in hypersaline soils from Namibia and Egypt. Its morphology and ontogenesis were studied with standard methods. Schmidingerothrix extraordinaria is a highly flexible, slender hypotrich with an average size of 90 * 15 MUm. Likely, it prefers a salinity around 1000/00 and feeds mainly on bacteria. Schmidingerothrix is extraordinary in having a frayed buccal lip, three-rowed adoral membranelles, only one frontal cirrus, a distinct gap between frontal and ventral adoral membranelles, and a miniaturized first frontal membranelle, while a paroral membrane, dorsal bristle rows, and buccal, transverse, and caudal cirri are absent. The ontogenesis is simple: the opisthe oral apparatus and frontoventral ciliature originate de novo, while parental structures are involved in the development of the ciliature of the proter. This special organization is used to define a new family, the Schmidingerotrichidae, which is likely related to the Cladotrichidae. Schmidingerothrix extraordinaria is very likely a secondarily oligomerized hypotrich, and the reduction occurred possibly very long ago because no traces of the ancestral ciliature remained in the ontogenetic processes. Possibly, the simple ciliature is an adaptation to highly saline habitats, where competition is low and bacterial food abundant. PMID- 22424939 TI - The Rubber Hand Illusion: two's a company, but three's a crowd. AB - On the one hand, it is often assumed that the Rubber Hand Illusion (RHI) is constrained by a structural body model so that one cannot implement supernumerary limbs. On the other hand, several recent studies reported illusory duplication of the right hand in subjects exposed to two adjacent rubber hands. The present study tested whether spatial constraints may affect the possibility of inducing the sense of ownership to two rubber hands located side by side to the left of the subject's hand. We found that only the closest rubber hand appeared both objectively (proprioceptive drift) and subjectively (ownership rating) embodied. Crucially, synchronous touch of a second, but farther, rubber hand disrupted the objective measure of the RHI, but not the subjective one. We concluded that, in order to elicit a genuine RHI for multiple rubber hands, the two rubber hands must be at the same distance from the subject's hand/body. PMID- 22424941 TI - Early clinical manifestations and eating patterns in patients with urea cycle disorders. AB - OBJECTIVES: To characterize dietary habits and eating patterns in patients with a urea cycle disorder (UCD), and to identify dietary habits that may serve as clues to lead to earlier diagnosis of these disorders. STUDY DESIGN: This was a retrospective study of clinical and dietary data from hospital records of all patients with UCD (n = 90) attending the Royal Children's Hospital in Melbourne between 1972 and 2010. RESULTS: Protein aversion, food refusal, frequent vomiting, poor appetite, and adverse reaction to high-protein-containing foods were documented in the majority of patients with available detailed dietary protein intake data. Fourteen of the 90 admissions for metabolic deterioration in which information regarding the precipitating factor(s) were available were directly related to protein intake (5 higher and 9 lower than prescribed). CONCLUSION: Protein aversion is a common feature of UCD and may serve as a diagnostic clue in patients presenting with food refusal, recurrent vomiting, behavioral problems, mental retardation, and "unexplained" episodes of altered consciousness. Dietary history should be included in the investigation of these symptoms, which might lead to earlier diagnosis. Metabolic decompensation is more frequently related to low energy/protein intake than to high protein intake in these patients. Special attention should be given to protein aversion, which often leads to eating patterns that make it difficult for a patient to achieve the prescribed daily protein requirement. PMID- 22424940 TI - Urine biomarkers predict acute kidney injury in newborns. AB - OBJECTIVE: To identify urine biomarkers predictive of acute kidney injury (AKI) in infants admitted to level 2 and 3 neonatal intensive care units with birth weight >2000 g and 5-minute Apgar score <= 7. STUDY DESIGN: A nested case-control study was performed comparing 8 candidate urine AKI biomarkers in infants with AKI (defined as a rise in serum creatinine of at least 0.3 mg/dL or a serum creatinine elevation >= 1.7 mg/dL persisting for 3 days) and 24 infants from the described cohort without AKI. Urine was analyzed for neutrophil gelatinase associated lipocalin, osteopontin, cystatin C, albumin, beta(2) microglobulin, epithelial growth factor, uromodulin (UMOD), and kidney injury molecule 1. RESULTS: Compared with the infants without AKI, those with AKI had higher levels of urine cystatin C (1123 pg/mL [95% CI, 272-4635 pg/mL] vs 90 pg/mL [95% CI, 39 205 pg/mL]; P < .004; area under the receiver operating characteristic curve [AUC] = 0.82), lower levels of UMOD (11.0 pg/mL [95% CI, 5.7-21.4 pg/mL] vs 26.2 pg/mL [95% CI, 17.4-39.4 pg/mL]; P < .03; AUC = 0.77), and lower levels of epithelial growth factor (6.7 pg/mL [95% CI, 4.0-11.3 pg/mL] vs 17.4 pg/mL [95% CI, 12.7-23.8 pg/mL; P = .003; AUC = 0.82). Although the differences were not statistically significant, levels of urine neutrophil-associated gelatinase lipocalin, kidney injury molecule 1, and osteopontin trended higher in infants with AKI. CONCLUSION: Urinary biomarkers can predict AKI in neonates admitted to level 2 and 3 neonatal intensive care units. PMID- 22424942 TI - Effects of endotracheal intubation and surfactant on a 3-channel neonatal electroencephalogram. AB - OBJECTIVE: To evaluate the effects of surfactant administration on the neonatal brain using 3-channel neonatal electroencephalography (EEG). STUDY DESIGN: A prospective cohort of 30 infants had scalp electrodes placed to record brain waves using 3-channel EEG (Fp1-O1, C3-C4, and Fp2-O2). Sixty-second EEG epochs were collected from a 10-minute medication-free baseline, during premedication for endotracheal intubation, at surfactant administration, and at 10, 20, and 30 minutes after surfactant administration for amplitude comparisons. Oxygen saturation and heart rate were monitored continuously. Blood pressure and transcutaneous carbon dioxide were recorded every 5 minutes. RESULTS: Eighteen of 29 infants (62%) exhibited brain wave suppression on EEG after surfactant administration (P <= .008). Four of those 18 infants did not receive premedication. Nine infants exhibited evidence of EEG suppression during endotracheal intubation, all of whom received premedication before intubation. Five infants had EEG suppression during endotracheal suctioning. Oxygen saturation, heart rate, and blood pressure were not independent predictors of brain wave suppression. CONCLUSION: Eighteen of 29 intubated infants (62%) had evidence of brain wave suppression on raw EEG after surfactant administration. Nine patients had evidence of brief EEG suppression with endotracheal intubation alone, a finding not previously reported in neonates. Intubation and surfactant administration have the potential to alter cerebral function in neonates. PMID- 22424943 TI - Does an elevated serum vitamin B(12) level mask actual vitamin B(12) deficiency in myeloproliferative disorders? AB - Elevation of the methylmalonic acid level is a sensitive marker of vitamin B(12) deficiency. Our cross-sectional observational study of 33 patients with myeloproliferative disorders found that 9 patients, 27.27% had occult deficiency despite having normal to elevated serum vitamin B(12) levels. Early detection of vitamin B(12) deficiency by using the methylmalonic acid measurement may prevent significant neurologic and hematologic complications in patients with myeloproliferative disorders. In patients with myeloproliferative disorders, normal to high serum vitamin B(12) concentrations have often been reported. The primary objective of this study was to determine whether normal or elevated serum vitamin B(12) levels in myeloproliferative disorders might actually mask the true underlying vitamin B(12) deficiency in some patients. Thirty-three patients (12 men, 21 women; mean age, 70.55 years [range, 37-90 years]) with polycythemia vera (n = 13), essential thrombocythemia (n = 12), chronic myelogenous leukemia (n = 5), and idiopathic myelofibrosis (IMF) (n = 3) were accrued over a period of 1 year, from March 2009 to February 2010. From all of the subjects, serum vitamin B(12) level, methylmalonic acid level, a basic complete blood cell count panel, and liver and renal function tests were obtained. Normal to elevated serum vitamin B(12) levels were recorded in all the patients. However, elevated serum methylmalonic acid levels were found in 9 (27.27%) patients, with a prevalence of 2 patients with polycythemia vera, 23% in polycythemia vera, 4 patients with essential thrombocythemia, 33.3% in essential thrombocythemia, 1 patient with chronic myelogenous leukemia, 20% in chronic myelogenous leukemia, and 2 patients with idiopathic myelofibrosis, 66.7% in IMF. Our data suggest that 27.27% of the total enrolled patients had occult vitamin B(12) deficiency despite normal to elevated vitamin B(12) levels on regular serum vitamin B(12) testing. PMID- 22424944 TI - Reversible posterior leukoencephalopathy syndrome induced by vinorelbine. AB - Reversible posterior leukoencephalopathy syndrome (RPLS) was first described in 1996; clinical symptoms include the presence of headache, visual disturbance,seizure, hypertension, and encephalopathy. The syndrome is most commonly encountered in association with chemotherapeutic agents or targeted therapy. Many chemotherapeutic agents, such as cisplatin,gemcitabine, methotrexate, were reported to be associated with RPLS. Vinorelbine is commonly used for the treatment of metastatic breast cancer, but vinorelbine-induced RPLS has not been reported. We reported a 34-year-old woman, diagnosed with invasive ductal carcinoma of the left breast, who experienced acute hypertension after vinorelbine intravenous infusion. Accompanied symptoms included headache,seizure, and conscious disturbance. Magnetic resonance imaging of the brain showed symmetric signal hyperintensity with the cortical and subcortical white matter of bilateral frontal, parietal, and occipital (predominant) lobes. Vinorelbine is a semisynthetic vinca alkaloid and prevents cell division by inhibiting tubulin polymerization.Brain metastasis or leptomeningeal carcinomatosis is an important issue for patients with breast cancer who present with headache, seizure, or altered consciousness.However, now RPLS may be a new consideration,especially with the presentation of acute hypertension. Unlike brain or meningeal metastasis, RPLS is usually benign, and most patients recover within 2 weeks. Our case highlights an association between vinorelbine and RPLS, and the drug has not been described as a predisposing factor of RPLS in past reports. In the era of cancer treatment with chemotherapy or targeted therapy,clinicians should be aware of this syndrome. PMID- 22424945 TI - Does hormonal therapy have a therapeutic role in metastatic primary small cell neuroendocrine breast carcinoma? Case report and literature review. AB - Primary neuroendocrine carcinoma of breast (NECB) is a very rare tumor; the World Health Organization(WHO) subcategorized these tumors into 3 major histologic subtypes: solid, small cell carcinoma (SMCC), and large cell NE carcinoma. The SMCC subtype is the least common and most aggressive and has been reported to be as aggressive as its pulmonary counterpart. SMCC is usually confirmed based on clinical, pathologic,and imaging studies. Local disease is usually managed in a fashion similar to that of the usual ductal breast cancer; in the metastatic SMCC setting, regimens that are implemented in small cell lung cancer are usually attempted, according to case reports and published small case series. Hormone receptors can be expressed in more than 90% of the solid tumor subtype; however its expression is manifested in about 50% of cases of SMCC. Although hormonal therapy can be used successfully to treat the usual metastatic ductal breast cancer,its utility in metastatic SMCC has not been reported. We report an impressive response to hormonal therapy in a patient with late relapse of breast carcinoma with a metastatic SMCC subtype that expressed hormone receptors. The response to hormonal therapy was sustained for about 12 months. The response to hormonal therapy is definitely an interesting finding that, to our knowledge, has not been described before in the setting of metastatic SMCC. We suggest considering adding hormonal therapy to the treatment pipeline for primary SMCC of the breast that express hormone receptors. PMID- 22424946 TI - Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1 signaling pathway. AB - Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1. PMID- 22424947 TI - Onychomadesis secondary to penicillin allergy in a child. PMID- 22424948 TI - Randomized controlled trial of early parenteral nutrition cycling to prevent cholestasis in very low birth weight infants. AB - OBJECTIVES: To compare the incidence of cholestasis in very low birth weight infants receiving cycled versus continuous parenteral nutrition, and to determine factors that predispose to parenteral nutrition-associated cholestasis (PNAC). STUDY DESIGN: Preterm infants weighing <= 1250 g (n = 70) at birth were randomly assigned within the first 5 postnatal days to either cycle (n = 34) or continuous (n = 36) parenteral nutrition. Liver function tests were obtained at baseline, and sequentially thereafter. Cholestasis was defined as direct bilirubin >2 mg/dL. Infants with major congenital anomalies, congenital hepatic disease, clinically apparent congenital viral infection, and those who required major abdominal surgery were excluded. RESULTS: The incidence of PNAC was similar in the 2 groups (cycle 32% vs continuous 31%; P = 1.0). Bilirubin and transaminases were similar in both groups by repeated measures of ANOVA. Gestational age, birth weight, and Apgar scores were significantly lower, and Clinical Risk Index for Babies II scores were significantly higher in infants who developed PNAC. Using backward selection logistic regression, bronchopulmonary dysplasia, duration of parenteral nutrition, and days to full enteral nutrition emerged as factors independently associated with PNAC. CONCLUSIONS: Early prophylactic parenteral nutrition cycling in very low birth weight infants in this study did not reduce cholestasis. Time to full feedings is a significant predictor for PNAC in very low birth weight infants. Preterm infants with bronchopulmonary dysplasia are more likely to have PNAC as a comorbidity. The Clinical Risk Index for Babies II score may help identify those preterm infants who might benefit from future prospective prevention trials. PMID- 22424949 TI - Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome. AB - OBJECTIVE: To investigate whether 24-hour urinary sodium excretion could be an indicator of the effectiveness of salt supplementation in children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN: The patient group comprised 30 children with POTS, and the control group comprised 10 healthy children. Serum sodium and 24-hour urinary sodium excretion were measured in all children, and the relationship between 24-hour urinary sodium and symptom severity was analyzed in the 30 patients. At 1 month after initiation of salt supplementation, the receiver operating characteristic curve was used to explore the probability of correctly discriminating responders to salt supplementation from nonresponders using 24-hour urinary sodium excretion as an indicator. RESULTS: Patients with POTS had lower 24-hour urinary sodium excretion than controls (P = .022). Symptom severity was negatively correlated with 24-hour urinary sodium excretion (OR, -0.754; P = .000). The receiver operating characteristic curve demonstrated a sensitivity of 76.9% and specificity of 93% for correct prediction of responders and nonresponders to salt supplementation when a 24-hour urinary sodium excretion of 124 mmol/24 hours was used as the cutoff value. CONCLUSION: Our results indicate that 24-hour sodium excretion of <124 mmol/24 hours is an indicator of the effectiveness of salt supplementation in children and adolescents with POTS. PMID- 22424950 TI - IQ may be normal, but are there future neurocognitive implications for infants with D-TGA? PMID- 22424951 TI - Headache in children with Tourette syndrome. AB - OBJECTIVE: The authors analyzed the frequency of occurrence of headaches in children and adolescents with Tourette syndrome (TS) to address their possible inclusion as a comorbidity. STUDY DESIGN: Using a prospective questionnaire, administered directly, we interviewed a total sample size of 109 patients with TS <= 21 years of age. The questionnaires were then analyzed according to the International Headache Society's diagnostic criteria. RESULTS: We found headaches to be present in 55% of the patients, with the 2 most common headache types being migraine headaches and tension-type headaches. The rate of migraine headache within the TS group was found to be 4 times greater than that of the general pediatric population, as reported in the literature. In addition, the rate of tension-type headache was found to be more than 5 times greater than that of the general pediatric population. CONCLUSIONS: Overall, the high rates of migraine and tension-type headache within this population support the proposition that headaches are a comorbidity of TS. PMID- 22424953 TI - Prenatal methamphetamine exposure and inhibitory control among young school-age children. AB - OBJECTIVE: To examine the association between prenatal methamphetamine exposure and inhibitory control in 66-month-old children followed since birth in the multicenter, longitudinal Infant Development, Environment, and Lifestyle study. STUDY DESIGN: The sample included 137 children with prenatal methamphetamine exposure and 130 comparison children matched for race, birth weight, maternal education, and type of insurance. Inhibitory control, an executive function related to emotional and cognitive control, was assessed using a computerized Stroop-like task developed for young children. Hierarchical linear modeling tested the relationship between the extent of prenatal methamphetamine exposure (heavy, some, or none) and accuracy and reaction time outcomes, adjusting for prenatal exposure to alcohol, tobacco, and marijuana; age; sex; socioeconomic status; caregiver IQ and psychological symptoms; Child Protective Services report of physical or sexual abuse; and site. RESULTS: In adjusted analyses, heavy prenatal methamphetamine exposure was related to reduced accuracy in both the incongruent and mixed conditions on the Stroop-like task. Caregiver psychological symptoms and Child Protective Services report of physical or sexual abuse were associated with reduced accuracy in the incongruent and mixed consitions and in the incongruent conditions, respectively. CONCLUSION: Heavy prenatal methamphetamine exposure, along with caregiver psychological distress and child maltreatment, are related to subtle deficits in inhibitory control during the early school-age years. PMID- 22424954 TI - The effect of dietary soyabean isoflavones on photodynamic therapy in K562 leukemia cells. AB - The soyabean isoflavones genistein (GEN) and daidzein (DA) are popular presented in diet. Isoflavones have a variety of biological activities including antioxidant and anticancer properties. On account of its antioxidant activity, isoflavones might protect cancer cells from free radical damage in photodynamic (PDT) during which reactive oxygen species (ROS) production was stimulated leading to irreversible tumor cell injury. In this study, the influence of GEN and DA on K562 cells in 5-aminolevulinic acid (ALA)-based PDT was demonstrated. The results showed that GEN inhibited cell proliferation and enhance cell apoptosis, lipid peroxidation, and DNA damage in ALA-PDT on K562 cells. However, DA did not enhance cell apoptosis, lipid peroxidation, and DNA damage in ALA-PDT. In conclusion, the results suggested that soy consumption during PDT did not decrease the effectiveness of cancer therapy on malignant cells. PMID- 22424952 TI - Empiric antifungal therapy and outcomes in extremely low birth weight infants with invasive candidiasis. AB - OBJECTIVE: To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants. STUDY DESIGN: This was a cohort study of infants with a birth weight <= 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). RESULTS: A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes. CONCLUSION: Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted. PMID- 22424955 TI - Ewing's sarcoma of the finger: report of two cases and literature review. AB - Ewing's sarcoma of the finger is extremely rare. Pain and swelling of the affected finger are the most frequent presenting features. We report two cases of Ewing's sarcoma located at ring finger and the thumb in two children aged 14 and 10 years. The first patient died of generalised metastases despite surgery, chemotherapy and radiation therapy. The second had no localised recurrence or metastases after surgery and chemotherapy at last follow-up of 4.5 years after tumour resection. The tumour's surgical accessibility, chemotherapy, and radiation therapy improve the prognosis of this tumour. PMID- 22424956 TI - Indications and results for the ExogenTM ultrasound system in the management of non-union: a 59-case pilot study. AB - INTRODUCTION: This pilot series sought to assess the use of external ultrasound stimulation (ExogenTM) in the treatment of femoral or tibial non-union. MATERIALS AND METHODS: A continuous retrospective study was conducted from 2004 to 2009. It included patients with a non-united fracture or osteotomy at 6 months or more post-surgery, with less than 10mm inter-fragment gap. Daily 20-min ultrasound sessions were continued until bone healing was achieved or for a maximum 6-month duration. Radio-clinical control was performed at months 3 and 6; treatment compliance and transmitter positioning were checked at each follow-up visit. RESULTS: Sixty non-unions were included in the series. One patient was excluded for early material breakage. Mean fracture-to-surgery interval was 271 days. The 6-month consolidation rate was 88%. There was no loss to follow-up. Mean ultrasound treatment duration was 151 days (range, 90-240 days). Bone healing correlated significantly with stability of the internal fixation assembly (P=0.01). The seven cases of failure included four fixations,considered unstable at inclusion, one femoral non-union associated with BMI 45 and one inadequate subchondral roughening (at the time of arthrodesis). There was a significant difference in delay to non-union treatment start between the groups with (251 days) and without (420 days) bone healing. DISCUSSION: The present results are in line with the literature. The main prognostic factors were fracture fixation stability, short time to treatment, and inter-fragment gap less than 10mm. Bone healing rates in the literature are around 80% for non-union treated at around 6 months, versus 60% for more than 12 months' delay. Factors such as gender, bone site, smoking, numbers of previous operations or type of osteosynthesis do not impact consolidation. External treatment offers an alternative to traditional surgery (graft, or bone-marrow concentrate or bone morphogenetic protein injection), provided that the fracture fixation is stable. Bone healing rates are better, and the procedure is non-invasive. External treatment results using ultrasound are similar to those using electromagnetic fields; the main difference lies in treatment session duration, which is 20 min for ultrasound, versus 3 hours for electromagnetic fields. Active patient commitment is vital, as the treatment is delivered at home, although the machine is equipped with a monitor to count treatment cycles. CONCLUSION: The 88% bone healing rate supports advocating first-line implementation in non-union of less than 10mm with stable osteosynthesis. This rate is higher than in traditional surgery, with a unit cost at least 60% lower: ?1772 for external therapy, versus ?4480 for decortication with or without fracture fixation exchange (itemized 08c50 under the French healthcare treatment coding system). LEVEL OF EVIDENCE: Level IV. Retrospective therapeutic study. PMID- 22424957 TI - Clinical clues for head injuries amongst Malaysian infants: accidental or non accidental? AB - Identifying the differences between infants with non-accidental head injuries (NAHI) and accidental head injuries (AHI) may help alert clinicians to recognize markers of abuse. A retrospective review of infants <1 year of age admitted to a tertiary referral centre in Malaysia over a two year period with a diagnosis of head injury or abnormal computed tomography head scans was conducted to identify the clinical features pointing towards a diagnosis of NAHI by comparing the socio demographics, presenting complaints, clinical features and the extent of hospital investigations carried out. NAHI infants were more likely to be symptomatic, under a non-related caregiver's supervision, and presented with inconsistent or no known mechanism of injury. Subdural haemorrhages were more common in NAHI infants. The history, mechanism of injury, presenting signs and symptoms as well as the nature of the injuries sustained are all valuable clues as to whether a head injury sustained during infancy is likely to be accidental or not. PMID- 22424958 TI - Awareness of disease state without explicit knowledge of memory failure in transient global amnesia. AB - INTRODUCTION: Transient global amnesia (TGA) is a syndrome characterised by the rapid onset of antero- and retrograde amnesia, accompanied by temporal disorientation and iterative questioning. It is now established that the acute phase is associated with a raised level of anxiety and a depressed mood. We conducted a thorough investigation of patients' perceptions of their disease state, focusing on the links between their lack of explicit knowledge of amnesia during the acute phase and their emotional experience. METHOD: Explicit knowledge of memory deficits was assessed during TGA by means of an original scale inspired by Bisiach et al. (1986) and self-reported scales measuring patients' perceptions of their current memory and their cognitive and behavioural functioning. At the same time, we probed the patients' emotional experience (sources of worry, and levels of worry, anxiety and depression) via questionnaires. Data were collected from 20 patients in the acute phase, 16 in the peri-acute phase, 16 who were assessed the day after the episode and 14 healthy controls. Each patient underwent a follow-up examination 2 months later. RESULTS: Patients in the acute phase displayed a lack of explicit knowledge of their amnesia and overestimated their memory performances. They also expressed higher levels of worry and anxiety than controls, and a more depressed mood. CONCLUSIONS: Although they were aware of their disease state, the TGA patients were unable to identify the nature of their memory deficits and overestimated their memory performances. These memory misperceptions and the inability to acknowledge memory failure occurred concomitantly with changes in the patients' emotional state. This particular pattern of awareness could be regarded as a reaction to the suddenness and massiveness of the amnesia. PMID- 22424960 TI - [ORION(r): a simple and effective method for systemic analysis of clinical events and precursors occurring in hospital practice]. AB - PURPOSE: Morbimortality review is now recommended by the French Health Authority (Haute Autorite de sante [HAS]) in all hospital settings. It could be completed by Comites de retour d'experience (CREX), making systemic analysis of event precursors which may potentially result in medical damage. As commonly captured by their current practice, medical teams may not favour systemic analysis of events occurring in their setting. They require an easy-to-use method, more or less intuitive and easy-to-learn. It is the reason why ORION((r)) has been set up. METHODS: ORION((r)) is based on experience acquired in aeronautics which is the main precursor in risk management since aircraft crashes are considered as unacceptable even though the mortality from aircraft crashes is extremely low compared to the mortality from medical errors in hospital settings. The systemic analysis is divided in six steps: (i) collecting data, (ii) rebuilding the chronology of facts, (iii) identifying the gaps, (iv) identifying contributing and influential factors, (v) proposing actions to put in place, (vi) writing the analysis report. When identifying contributing and influential factors, four kinds of factors favouring the event are considered: technical domain, working environment, organisation and procedures, human factors. Although they are essentials, human factors are not always considered correctly. The systemic analysis is done by a pilot, chosen among people trained to use the method, querying information from all categories of people acting in the setting. RESULTS: ORION((r)) is now used in more than 400 French hospital settings for systemic analysis of either morbimortality cases or event precursors. It is used, in particular, in 145 radiotherapy centres for supporting CREX. CONCLUSION: As very simple to use and quasi-intuitive, ORION((r)) is an asset to reach the objectives defined by HAS: to set up effective morbi-mortality reviews (RMM) and CREX for improving the quality of care in hospital settings. By helping the efforts of medical teams, ORION((r)) is an essential tool contributing to the patients' security. PMID- 22424959 TI - DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience. AB - Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine inter-individual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced DA release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R "Openness to Experience" and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders. PMID- 22424961 TI - The effect of automated telephone appointment reminders on HIV primary care no shows by veterans. AB - Appointment attendance for follow-up care and laboratory monitoring are central components of HIV treatment. In general, appointment reminders are an effective method of reducing outpatient no-shows; however, no single strategy has proven superior. This study tested the effectiveness of adding an automated telephone reminder for laboratory monitoring to the standard set of three appointment reminders to reduce subsequent HIV primary care no-shows. We conducted a quasi experimental design study in three geographically and administratively affiliated Veterans Administration HIV clinics with one clinic serving as the intervention facility and two others as control facilities. The intervention lasted 6 months. The data show that patients who were not homeless, who were not diagnosed with depression, and who had five or more appointments scheduled in 6 months had significantly fewer no-shows after intervention. The intervention was not effective in reducing no-shows among homeless patients, racial/ethnic minorities, and patients with mental health disorders. PMID- 22424962 TI - Changes in facial electromyographic activity in spider-phobic girls after psychotherapy. AB - Recent studies of spider phobia have indicated that disgust is a crucial disorder relevant emotion and that the facial electromyogram (EMG) of the levator labii region is a reliable disgust indicator. The present investigation focused on EMG effects of psychotherapy in thirty girls (aged between 8 and 14 years) suffering from spider phobia. They were presented with phobia-relevant, generally fear inducing, disgust-inducing and affectively neutral pictures in a first EMG session. Subsequently, patients were randomly assigned to either a therapy group or a waiting-list group. Therapy-group participants received a single session of exposure therapy in vivo. One week later a second EMG session was conducted. Patients of the waiting-list group received exposure therapy after the second EMG session. After therapy, the girls were able to hold a living spider in their hands and rated spiders more positive, and less arousing, fear- and disgust inducing. Moreover, they showed a reduction of average levator labii activity in response to pictures of spiders, reflecting the reduction of feelings of disgust. A positive side effect of the therapy was a significant drop in overall disgust proneness and a decreased average activity of the levator labii muscle in response to generally disgust-inducing pictures. Results emphasize the role of disgust feelings in spider-phobic children and suggest that overall disgust proneness should also be targeted in therapy. PMID- 22424963 TI - Circadian variability of pulse oximetry in healthy children under the age of 7. AB - BACKGROUND: Peripheral oxygen saturation (SpO(2)) measured by pulse oximetry is widely used in clinical practice, but its fluctuations over the course of the 24 h of a day have not been explored at length. Recently, we reported that children hospitalized due to non-cardiopulmonary causes had a circadian variation in SpO(2). This finding needed to be corroborated in healthy children, which is the objective of the present study. PATIENTS AND METHODS: Healthy children residing in a state foster home were studied with pulse oximetry every 2h for 24h. RESULTS: Eighty two children were included in the study, ranging in age from one month to 6.5 years (average +/- standard error of 3.06 +/- 0.16 years), with a weight-for-length/height percentile of 65.5 +/- 2.9. In 65 (79.3%) children, the SpO(2) levels followed a sinusoidal curve suggesting circadian rhythm. The total group of sinusoidal curves in this population had a mesor of 95.10 +/- 0.08% SpO(2), period of 21.05 +/- 0.54 h (in 53.8% of these children, the period was between 20 and 28 h). The maximum SpO(2) was reached at 3:14 pm +/- 16 min, and the minimum at 5:16 am +/- 48 min. When the 24 h were divided into four periods, it was demonstrated that the highest SpO(2) levels were reached between 2 pm and 8 pm. CONCLUSIONS: In this population of clinically healthy children, there was a circadian variation in pulse oximetry, with maximum values in the late afternoon and minimal values in the early morning. PMID- 22424964 TI - A voltammetric electronic tongue as tool for water quality monitoring in wastewater treatment plants. AB - The use of a voltammetric electronic tongue as tool for the prediction of concentration levels of certain water quality parameters from influent and effluent wastewater from a Submerged Anaerobic Membrane Bioreactor pilot plant applied to domestic wastewater treatment is proposed here. The electronic tongue consists of a set of noble (Au, Pt, Rh, Ir, and Ag) and non-noble (Ni, Co and Cu) electrodes that were housed inside a stainless steel cylinder which was used as the body of the electronic tongue system. As a previous step an electrochemical study of the response of the ions sulphate, orthophosphate, acetate, bicarbonate and ammonium was carried out in water using the electrodes contained in the electronic tongue. The second part of the work was devoted to the application of the electronic tongue to the characterization of the influent and effluent waters from the wastewater treatment plant. Partial Least Squares analysis was used to obtain a correlation between the data from the tongue and the pollution parameters measured in the laboratory such as soluble chemical oxygen demand (CODs), soluble biological oxygen demand (BODs), ammonia (NH(4)-N), orthophosphate (PO(4)-P), Sulphate (SO(4)-S), acetic acid (HAC) and alkalinity (Alk). A total of 28 and 11 samples were used in the training and the validation steps, respectively, for both influent and effluent water samples. The electronic tongue showed relatively good predictive power for the determination of BOD, COD, NH(4)-N, PO(4)-P, SO(4)-S, and Alk. PMID- 22424965 TI - The effect of nitrite inhibition on the anammox process. AB - The negative effect of nitrite on anammox activity has been reported widely during the past decade. Although the adverse effect is clear, conflicting reports exist on the level at which it occurs and its reversible/irreversible nature. An in depth study on nitrite inhibition therefore was performed in which the influence of environmental factors was evaluated. Anammox activity was measured in anammox granules by continuously monitored standardized manometric batch tests extending the interpretation by evaluation of lag times, maximum conversion rates during the tests and substrates/product conversion ratios. The granules where obtained from a one-stage anammox reactor, the dominant anammox organisms belonged to the Brocadia type. The observed 50% activity inhibition for nitrite (IC(50)) was 0.4 g N L(-1). The activity recovered fully after removal of the nitrite. Conversion in fresh medium after exposure to up to 6 g NO(2)(-)-N L(-1) for 24 h showed less then 60% loss of activity. Presence of ammonium during nitrite (2 g N L(-1)) exposure resulted in a stronger loss of activity after nitrite exposure (50% and 30% in presence and absence of ammonium respectively). Presence of oxygen during nitrite incubation led to a maximum activity reduction of 32%. The recovery after exposure indicates that the adverse effect of nitrite is reversible and thus inhibitory rather than toxic in nature. Similarities between exposure at three different pH-values indicate that nitrite rather than nitrous acid is the actual inhibiting compound. PMID- 22424966 TI - Nutrient and dissolved organic carbon removal from water using mining and metallurgical by-products. AB - Excess nutrient input to water bodies frequently results in algal blooms and development of oxygen deficient conditions. Mining or metallurgical by-products can potentially be utilised as filtration media within water treatment systems such as constructed wetlands, permeable reactive barriers, or drain liners. These materials may offer a cost-effective solution for the removal of nutrients and dissolved organic carbon (DOC) from natural waters. This study investigated steel making, alumina refining (red mud and red sand) and heavy mineral processing by products, as well as the low-cost mineral-based material calcined magnesia, in laboratory column trials. Influent water and column effluents were analysed for pH and flow rate, alkalinity, nutrient species and DOC, and a range of major cations and anions. In general, by-products with high Ca or Mg, and to a lesser extent those with high Fe content, were well-suited to nutrient and DOC removal from water. Of the individual materials examined, the heavy mineral processing residue neutralised used acid (NUA) exhibited the highest sorption capacity for P, and removed the greatest proportions of all N species and DOC from influent water. In general, NUA and mixtures containing NUA, particularly those with calcined magnesia or red mud/red sand were the most effective in removing nutrients and DOC from influent water. Post-treatment effluents from columns containing NUA and NUA/steel-making by-product, NUA/red sand and NUA/calcined magnesia mixtures exhibited large reductions in DOC, P and N concentrations and exhibited a shift in nutrient ratios away from potential N- and Si-limitation and towards potential P-limitation. If employed as part of a large-scale water treatment scheme, use of these mining and metallurgical by-products for nutrient removal could result in reduced algal biomass and improved water quality. Identification and effective implementation of mining by-products or blends thereof in constructed wetlands or other intervention structures to augment nutrient and DOC retention has considerable potential as an aquatic ecosystem management tool. PMID- 22424967 TI - Coronary death and myocardial infarction among Hispanics in the Northern Manhattan Study: exploring the Hispanic paradox. AB - PURPOSE: Prior studies have reported that Hispanics have lower cardiovascular disease (CVD) mortality despite a higher burden of risk factors. We examined whether Hispanic ethnicity was associated with a lower risk of nonfatal myocardial infarction (MI) coronary death (CD) and vascular death. METHODS: A total of 2671 participants in the Northern Manhattan Study without clinical CVD were prospectively evaluated. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association of race-ethnicity with nonfatal MI, CD, and vascular death after adjusting for demographic and CVD risk factors. RESULTS: Mean age was 68.8 (10.4) years; 52.8% were Hispanic (88% Caribbean-Hispanic). Hispanics were more likely to have hypertension (73.1% vs. 62.2%, p < .001) and diabetes (22.0% vs. 13.3%, p < .001), and less likely to perform any physical activity (50.1% vs. 69.2%, p < .001) compared to non Hispanic whites (NHW). During a mean 10 years of follow-up there were 154 nonfatal MIs, 186 CD, and 386 vascular deaths. In fully adjusted models, Hispanics had a lower risk of CD (adjusted HR = 0.36, 95% CI: 0.21-0.60), and vascular death (adjusted HR = 0.62, 95% CI: 0.43-0.89), but not nonfatal MI (adjusted HR = 0.95, 95% CI: 0.56-1.60) when compared to NHW. CONCLUSIONS: We found a "Hispanic paradox" for coronary and vascular deaths, but not nonfatal MI. PMID- 22424968 TI - [A participatory ergonomics program in a chemical company]. AB - We describe a participatory ergonomics program that started in April 2010 in a chemical company located in the autonomous region of Valencia, Spain. The program was introduced in the company, the intervention level was agreed (two working lines, 24 workers) and a working group was established (Ergo Group, including managers, technicians and safety representatives in the company) with the aim of leading the intervention. A questionnaire was applied to collect information on ergonomic injuries and exposures in workers at the selected working lines. This information was analyzed by the Ergo Group and was later discussed at prevention circles with the direct participation of affected workers. When the present article was being drafted, 16 improvements to working conditions had already been proposed. Some of these improvements had been implemented and, in the opinion of some of the participants, were effective. To develop this kind of program, which could benefit a substantial number of workers in Spain, a firm commitment to prevention by companies is required. PMID- 22424969 TI - [Access control management in electronic health records: a systematic literature review]. AB - OBJECTIVE: This study presents the results of a systematic literature review of aspects related to access control in electronic health records systems, wireless security and privacy and security training for users. METHODS: Information sources consisted of original articles found in Medline, ACM Digital Library, Wiley InterScience, IEEE Digital Library, Science@Direct, MetaPress, ERIC, CINAHL and Trip Database, published between January 2006 and January 2011. A total of 1,208 articles were extracted using a predefined search string and were reviewed by the authors. The final selection consisted of 24 articles. RESULTS: Of the selected articles, 21 dealt with access policies in electronic health records systems. Eleven articles discussed whether access to electronic health records should be granted by patients or by health organizations. Wireless environments were only considered in three articles. Finally, only four articles explicitly mentioned that technical training of staff and/or patients is required. CONCLUSION: Role-based access control is the preferred mechanism to deploy access policy by the designers of electronic health records. In most systems, access control is managed by users and health professionals, which promotes patients' right to control personal information. Finally, the security of wireless environments is not usually considered. However, one line of research is eHealth in mobile environments, called mHealth. PMID- 22424970 TI - [Current status of research in breast cancer screening in Spain: implications for prevention]. AB - OBJECTIVE: The consolidation of breast cancer screening programs, with full coverage of the target population in all Spanish regions, has encouraged the beginning of a joint research strategy. This strategy aims to improve the effectiveness of breast cancer screening by gathering information from distinct screening programs. METHODS: A retrospective cohort with information on over 1.5 million screened women was constructed to evaluate risk factors for a false positive result. The impact of the change from digital mammography to screen-film mammography was evaluated, while results for interval cancers and false negatives are currently being studied. RESULTS: The results are highly useful from the perspective of public health, as they can be used to identify and improve the information provided to women with a higher risk of experiencing an adverse effect. These results will also be helpful to identify screening program-related characteristics and women's personal characteristics, which will allow better prevention strategies to be developed. CONCLUSIONS: The results obtained will be included in mathematical models currently under development to evaluate the efficiency of breast cancer screening. These models could be highly useful to provide information and guide clinical and health policy decisions on cancer prevention and control. PMID- 22424971 TI - [Prevalence of overweight and obesity in schoolchildren in rural areas]. AB - OBJECTIVES: To estimate the prevalence of overweight and obesity in schoolchildren in rural areas. METHODS: A cross-sectional study was carried out in a sample of 1,513 schoolchildren aged 6, 11 and 14 years. Data were collected on height and weight with digital scales equipped with a measuring rod. We used three criteria to define overweight and obesity: Cole's points, the Centers for Disease Control and Prevention (CDC) criteria and Hernandez's tables. RESULTS: When Cole's points were used, 24.6% (95%CI: 22.5 - 26.8) were overweight and 11.6% (95%CI: 10-13.3) were obese; these percentages were higher in children aged 11 and 6 years, respectively. According CDC growth charts, 19.8% of children (95%CI: 17.9-21.9) were overweight and 16.5% (95%CI: 14.7-18.4) were obese, corresponding to higher percentages at 14 and 6 years. When Hernandez's tables were used, 11.5% (95%CI: 10-13.2) were overweight and 18.6% (95%CI: 16.7-20.6) were obese, and both disorders were higher in children aged 11 years. The risk of obesity and overweight was higher in small rural areas (<5,000 people), with OR = 1.49 (95%CI: 1.13-1.95) and OR = 1.33 (95%CI: 1.06-1.67), respectively. CONCLUSIONS: The prevalence of overweight and obesity in schoolchildren in rural areas is very high and is even higher in towns with less than 5,000 inhabitants. PMID- 22424972 TI - [The revision process of Francisco Xavier Balmis' translation of Moreau de la Sarthe's historical and practical treatise on vaccines]. AB - Moreau de la Sarthe's Traite historique et pratique de la vaccine, translated by Francisco Xavier de Balmis and published in 1803, was one of the protagonists of the Royal Philanthropic Expedition of the Vaccine, and became the first official vaccination manual recognized by a government. Balmis decided to translate Moreau's work in 1801, joining the first generation of disseminators of Edward Jenner's method in Spain. The translation process from return for review to final publication 16 months later is analyzed in this article. After Balmis submitted the still-incomplete work, the reviewer pointed out errors in style and in the translation itself, and omissions of passages from the original. After revision and correction, the translation was finally accepted. Balmis did not obtain the authorization to include a dedication to Queen Maria Luisa, however, which would have increased the book's impact, as it was not considered a singular work of its kind or one of outstanding merit. Finally, Balmis dedicated his work to the mothers of families. With an initial print run of 500 copies, which was followed immediately by 2,000 more, his work was widely distributed throughout Hispanic America. The study notes the influence of the reviewers in the quality of scientific production. PMID- 22424973 TI - Discovery of HIV fusion inhibitors targeting gp41 using a comprehensive alpha helix mimetic library. AB - The evaluation of a comprehensive alpha-helix mimetic library for binding the gp41 NHR hydrophobic pocket recognizing an intramolecular CHR alpha-helix provided a detailed depiction of structural features required for binding and led to the discovery of small molecule inhibitors (K(i) 0.6-1.3 MUM) that not only match or exceed the potency of those disclosed over the past decade, but that also exhibit effective activity in a cell-cell fusion assay (IC(50) 5-8 MUM). PMID- 22424974 TI - Discovery of new piperidine amide triazolobenzodiazepinones as intestinal selective CCK1 receptor agonists. AB - New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall. PMID- 22424975 TI - Sesquiterpene lactones from Tithonia diversifolia act as peroxisome proliferator activated receptor agonists. AB - Tithonia diversifolia is a well-known traditional Chinese medicine treating diabetes, hepatitis, and hepatocarcinoma but its molecular mechanism is not fully understood. Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are members of nuclear receptor superfamily. Their agonists are prescribed as antihyperlipidemic and antihyperglycemic drugs now. In this study, sesquiterpene lactones, tirotundin and tagitinin A, were isolated from T. diversifolia and evaluated for their activity against PPARs by the transient transfection reporter assay. Tirotundin and tagitinin A transactivated PPARgamma dependent promoters including PPRE (PPARgamma response element), SHP, and ABCA1 gene promoters in dose-dependent manner. Furthermore, the fluorescence polarization competitive binding assay showed that tirotundin (IC(50)=27 MUM) and tagitinin A (IC(50)=55 MUM) enhanced PPARgamma transactivation activity by directly binding to PPARgamma ligand binding domain. Additionally, they stimulated the transactivation of PPARalpha dependent SULT2A1 gene promoter by 2.3-fold of vehicle effect at 10 MUM. These results highly indicated that tirotundin and tagitinin A are the active components of T. diversifolia to exert anti-diabetic effect through PPARgamma pathway. Moreover, these sesquiterpene lactones behaved as PPARalpha/gamma dual agonists so they might be useful as the potential herbal treatment for diabetes. PMID- 22424976 TI - Deep-red fluorescent imaging probe for bacteria. AB - A versatile deep-red fluorescent imaging probe is described that is comprised of a bis(zinc(II)-dipicolylamine) targeting unit covalently attached to a pentamethine carbocyanine fluorophore with Cy5-like spectroscopic properties. A titration assay based on fluorescence resonance energy transfer is used to prove that the probe selectively associates with anionic vesicle membranes whose composition mimics bacterial cell membranes. Whole-body optical imaging experiments show that the probe associates with the surfaces of both Gram positive and Gram-negative bacteria cells, and it can target the site of bacterial infection in a living mouse. In vivo accumulation at the infection site and subsequent clearance occurs more quickly than a structurally related near infrared bis(zinc(II)-dipicolylamine) probe. The fact that the same deep-red probe molecule can be used for spectroscopic assays, cell microscopy, and in vivo imaging studies, is an important and attractive technical feature. PMID- 22424977 TI - Development of hypoxia-sensitive Gd3+-based MRI contrast agents. AB - Hypoxia occurs in various diseases, including cancer, ischemia, and acute and chronic vascular diseases. Here we describe the design and synthesis of the first hypoxia-sensitive MRI contrast agents, SAGds. SAGds showed a pH-dependent r(1) relaxivity change associated with intramolecular chelation of the nitrogen atom of the sulfonamide moiety to the Gd(3+) center. There was a correlation between the pK(a) of the r(1) relaxivity change and the sum of the Hammett sigma constants of substituents on the aromatic ring. Among the synthesized compounds, 4NO(2)2MeOSAGd was selectively reduced to the amine by rat liver microsomes under hypoxic conditions, resulting in a 1.8-fold increment of the r(1) relaxivity owing to the change in pK(a) of the arylsulfonamide moiety. This enhancement of the r(1) relaxivity could be clearly detected in T(1)-weighted MR images. Thus, 4NO(2)2MeOSAGd is a 'smart' MRI contrast agent for the detection of hypoxia under physiological conditions. PMID- 22424978 TI - Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors. AB - A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability. PMID- 22424979 TI - Synthesis and SAR studies of novel heteroaryl fused tetracyclic indole-diamide compounds: potent allosteric inhibitors of the hepatitis C virus NS5B polymerase. AB - Presented here are initial structure-activity relationship (SAR) studies on a series of novel heteroaryl fused tetracyclic indole-based inhibitors of the hepatitis C viral polymerase, NS5B. The introduction of alternative heterocyclic moieties into the indolo-fused inhibitor class significantly expands the reported SAR and resulted in the identification of pyridino analogs, typified by compounds 44 and 45 that displayed excellent potency against the NS5B polymerase of both HCV 1a and HCV 1b genotypes. PMID- 22424980 TI - Osteoblasts exhibit a more differentiated phenotype and increased bone morphogenetic protein production on titanium alloy substrates than on poly-ether ether-ketone. AB - BACKGROUND CONTEXT: Multiple biomaterials are clinically available to spine surgeons for performing interbody fusion. Poly-ether-ether-ketone (PEEK) is used frequently for lumbar spine interbody fusion, but alternative materials are also used, including titanium (Ti) alloys. Previously, we showed that osteoblasts exhibit a more differentiated phenotype when grown on machined or grit-blasted titanium aluminum vanadium (Ti6Al4V) alloys with micron-scale roughened surfaces than when grown on smoother Ti6Al4V surfaces or on tissue culture polystyrene (TCPS). We hypothesized that osteoblasts cultured on rough Ti alloy substrates would present a more mature osteoblast phenotype than cells cultured on PEEK, suggesting that textured Ti6Al4V implants may provide a more osteogenic surface for interbody fusion devices. PURPOSE: The aim of the present study was to compare osteoblast response to smooth Ti6Al4V (sTiAlV) and roughened Ti6Al4V (rTiAlV) with their response to PEEK with respect to differentiation and production of factors associated with osteogenesis. STUDY DESIGN: This in vitro study compared the phenotype of human MG63 osteoblast-like cells cultured on PEEK, sTiAlV, or rTiAlV surfaces and their production of bone morphogenetic proteins (BMPs). METHODS: Surface properties of PEEK, sTiAlV, and rTiAlV discs were determined. Human MG63 cells were grown on TCPS and the discs. Confluent cultures were harvested, and cell number, alkaline phosphatase-specific activity, and osteocalcin were measured as indicators of osteoblast maturation. Expression of messenger RNA (mRNA) for BMP2 and BMP4 was measured by real-time polymerase chain reaction. Levels of BMP2, BMP4, and BMP7 proteins were also measured in the conditioned media of the cell cultures. RESULTS: Although roughness measurements for sTiAlV (S(a)=0.09+/-0.01), PEEK (S(a)=0.43+/-0.07), and rTiAlV (S(a)=1.81+/ 0.51) varied, substrates had similar contact angles, indicating comparable wettability. Cell morphology differed depending on the surface. Cells cultured on Ti6Al4V had lower cell number and increased alkaline phosphatase specific activity, osteocalcin, BMP2, BMP4, and BMP7 levels in comparison to PEEK. In particular, roughness significantly increased the mRNA levels of BMP2 and BMP4 and secreted levels of BMP4. CONCLUSIONS: These data demonstrate that rTiAlV substrates increase osteoblast maturation and produce an osteogenic environment that contains BMP2, BMP4, and BMP7. The results show that modifying surface structure is sufficient to create an osteogenic environment without addition of exogenous factors, which may induce better and faster bone during interbody fusion. PMID- 22424981 TI - IFN-gamma up-regulates kappa opioid receptors (KOR) on murine macrophage cell line J774. AB - In this study we examined basal and IFN-gamma-regulated expression of kappa opioid receptors (KOR) on cells of a murine macrophage cell line, J774. Basal KOR expression was found both at transcriptional and protein levels. KOR protein was predominantly located intracellular (86.4+/-12.9% positive cells; n=4), and only in minority of J774 cells (9.1+/-6.4% positive cells; n=4) on plasma membranes, as revealed by Fluorescence-Activated Cell Sorter (FACS) analysis and immunocytochemistry. Proinflammatory cytokine IFN-gamma up-regulated KOR expression both at transcriptional (up to 24 times) and protein levels (up to 4.2 times). KOR expressed on J774 cells was functionally active as its ligation with Dynorphin-A(1-17) (100 nM and 1 MUM) triggered phosphorylation of ERK1/2. Involvement of KOR in the Dynorphin-A(1-17)-induced triggering of ERK1/2 phosphorylation is suggested since truncated Dynorphin-A(2-17), which does not bind to KOR, was ineffective. Collectively, we have shown for the first time that cells of J774 cell line constitutively express functionally active KOR, which triggers signalization via ERK1/2 phosphorylation and which could be up-regulated by proinflammatory IFN-gamma. The data may be relevant for better understanding of the role of KOR and their endogenous ligand Dynorphin-A in regulation of inflammatory and immune responses. PMID- 22424982 TI - Traditional extract of Pithecellobium dulce fruits protects mice against CCl(4) induced renal oxidative impairments and necrotic cell death. AB - The present study has been carried out to investigate the role of the aqueous extract of the fruits of Pithecellobium dulce (AEPD) against carbon tetrachloride (CCl(4)) induced renal oxidative injury in mice. HPLC analysis shows that AEPD contains phenolics, flavonoids and saponins as the major active components. Creatinine and blood urea nitrogen (BUN) levels were assayed to determine renal protective action of AEPD in CCl(4)-induced renal pathophysiology. Its antioxidant activity was determined by measuring radical scavenging activity, antioxidant enzymes activities, GSH content, protein carbonylation and lipid peroxidation. In addition, FACS analysis, DNA fragmentation and histological studies were carried out to determine its effect in CCl(4) induced renal oxidative injury and cell death. CCl(4) exposure increased the intracellular reactive oxygen species production, decreased intracellular antioxidant defence, reduced mitochondrial membrane potential, attenuated the intracellular ATP content and caused renal cell death mainly via the necrotic pathway as revealed by DNA fragmentation analysis. Treatment with AEPD both prior and post to the toxin exposure protected the organ from CCl(4) induced oxidative insult. Histological studies also support our results. Combining, results suggest that the protective role of AEPD against CCl(4) induced renal oxidative impairments is probably due to the antioxidative properties present in its active constituents. PMID- 22424983 TI - Primary testicular lymphoma. AB - Primary testicular non-Hodgkin lymphoma (PTL) comprises around 9% of testicular cancers and 1-2% of all non-Hodgkin lymphomas. Its incidence is increasing and it primarily affects older men, with a median age at presentation of around 67 years. By far the most common histological subtype is diffuse large B-cell lymphoma, accounting for 80-90% of PTLs. Most patients present with a unilateral testicular mass or swelling. Up to 90% of patients have stage I or II disease at diagnosis (60 and 30%, respectively) and bilateral testicular involvement is seen in around 35% of patients. PTL demonstrates a continuous pattern of relapse and propensity for extra-nodal sites such as the central nervous system and contralateral testis. Retrospective data have emphasised the importance of prophylactic radiotherapy in reducing recurrence rates within the contralateral testis. Recent outcome data from the prospective IELSG-10 trial have shown far better progression-free and overall survival than historical outcomes. This supports the use of orchidectomy followed by Rituximab- cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), central nervous system prophylaxis and prophylactic radiotherapy to the contralateral testis with or without nodal radiotherapy in patients with limited disease. Central nervous system relapse remains a significant issue and future research should focus on identifying the best strategy to reduce its occurrence. Here we discuss the evidence supporting combination chemotherapy and radiotherapy in PTL. PMID- 22424984 TI - How to weight chronic diseases in multimorbidity indices? Development of a new method on the basis of individual data from five population-based studies. AB - OBJECTIVE: In multimorbidity indices, chronic conditions are often weighted according to their severity or their impact on different outcomes. These weights are mostly developed on the basis of only one study population by using very specific study participants, such as hospital patients. To overcome the limited validity of the indices, mean weights across five population-based studies were calculated according to the impact of diseases on self-reported health status. STUDY DESIGN AND SETTING: Individual data was provided from the National Health Interview and Examination Survey (n=1,010), Dortmund Health Study (n=281), Memory and Morbidity in Augsburg Elderly Study (n=385), Survey of Health, Aging and Retirement in Europe Study (n=1,278), and Study of Health in Pomerania Study (n=962). By using logistic regression analysis, odds ratios (ORs) were calculated for reporting a fair or poor health status resulting from one of 10 different chronic conditions compared with a reference group without the specific disease, controlling for age and sex. If the results were homogenous across studies (I(2)<40%), significant pooled ORs were considered valid weights for a multimorbidity index. RESULTS: Myocardial infarction has the highest impact on self-reported health status across studies with a pooled OR of 3.9, followed by chronic obstructive pulmonary disease (pooled OR: 3.1). A medium impact was observed for arthrosis, asthma, diabetes mellitus, and osteoporosis. CONCLUSION: This method provided valid weights for seven chronic conditions. PMID- 22424985 TI - Published methodological quality of randomized controlled trials does not reflect the actual quality assessed in protocols. AB - OBJECTIVES: To assess whether the reported methodological quality of randomized controlled trials (RCTs) reflects the actual methodological quality and to evaluate the association of effect size (ES) and sample size with methodological quality. STUDY DESIGN AND SETTING: Systematic review. This is a retrospective analysis of all consecutive phase III RCTs published by eight National Cancer Institute Cooperative Groups up to 2006. Data were extracted from protocols (actual quality) and publications (reported quality) for each study. RESULTS: Four hundred twenty-nine RCTs met the inclusion criteria. Overall reporting of methodological quality was poor and did not reflect the actual high methodological quality of RCTs. The results showed no association between sample size and actual methodological quality of a trial. Poor reporting of allocation concealment and blinding exaggerated the ES by 6% (ratio of hazard ratio [RHR]: 0.94; 95% confidence interval [CI]: 0.88, 0.99) and 24% (RHR: 1.24; 95% CI: 1.05, 1.43), respectively. However, actual quality assessment showed no association between ES and methodological quality. CONCLUSION: The largest study to date shows that poor quality of reporting does not reflect the actual high methodological quality. Assessment of the impact of quality on the ES based on reported quality can produce misleading results. PMID- 22424986 TI - Search filters can find some but not all knowledge translation articles in MEDLINE: an analytic survey. AB - OBJECTIVE: Advances from health research are not well applied giving rise to over and underuse of resources and inferior care. Knowledge translation (KT), actions and processes of getting research findings used in practice, can improve research application. The KT literature is difficult to find because of nonstandardized terminology, rapid evolution of the field, and it is spread across several domains. We created multiple search filters to retrieve KT articles from MEDLINE. STUDY DESIGN AND SETTING: Analytic survey using articles from 12 journals tagged as having KT content and also as describing a KT application or containing a KT theory. RESULTS: Of 2,594 articles, 579 were KT articles of which 201 were about KT applications and 152 about KT theory. Search filter sensitivity (retrieval efficiency) maximized at 83%-94% with specificity (no retrieval of irrelevant material) approximately 50%. Filter performances were enhanced with multiple terms, but these filters often had reduced specificity. Performance was higher for KT applications and KT theory articles. These filters can select KT material although many irrelevant articles also will be retrieved. CONCLUSION: KT search filters were developed and tested, with good sensitivity but suboptimal specificity. Further research must improve their performance. PMID- 22424987 TI - Systematic reviews synthesized evidence without consistent quality assessment of primary studies examining epidemiology of chronic diseases. AB - OBJECTIVE: To evaluate how systematic reviews assess the quality of primary studies of incidence, prevalence, or risk factors for chronic diseases. STUDY DESIGN AND SETTING: We searched several databases, identified 145 systematic reviews, and evaluated methods of quality assessment and quantitative synthesis of evidence by external or internal validity or overall quality of primary studies. RESULTS: Of 145 reviews, 54 (37%) reported a planned quality assessment of primary studies with checklists or scales and 26 (18%) reported evaluation of some selected quality criteria. Thirty-nine percent of reviews judged appropriateness of sampling and proper controls for confounding factors in primary studies. Twelve percent synthesized evidence by overall quality, 17% by design, 42% by criteria of internal validity, and 24% by external validity of primary studies. Masking of quality assessment was conducted on 2.1% of reviews and 4% tested interobserver agreement for quality assessment. CONCLUSION: Evaluation of internal and external validity of primary studies is uncommon in systematic reviews of studies of incidence, prevalence, or risk factors for chronic diseases. Inconsistent quality assessment practices reflect the absence of uniformly accepted standards and tools to examine the quality of observational nontherapeutic studies. PMID- 22424988 TI - Intraabdominal focal fat infarction in a 75-year-old woman presenting as acute abdomen. AB - Epiploic appendagitis is a rare, self-limiting inflammation of the epiploic appendices or omental appendices. It presents as abdominal pain often misdiagnosed as appendicitis, cholecystitis, or diverticulitis. Epiploic appendagitis can be treated conservatively with anti-inflammatory and pain medications. It is important to diagnose this etiology of abdominal pain in order to avoid long-term hospital stay and other medical expenses including surgery. In this case report we present a rare case of epiploic appendagitis that presents in a 75 year old female patient. PMID- 22424989 TI - The influence of physician seniority on disparities of admit/discharge decision making for ED patients. AB - OBJECTIVES: Differences in disposition between emergency physicians (EPs) have been studied in select patient populations but not in general emergency department (ED) patients. After determining whether a difference existed in admit/discharge decision making of EPs for general ED patients, we focus our study in examining the influence of EP seniority on the decision to discharge ED patients. METHODS: In a 1-year retrospective study, we included a convenience sample of all 18 953 adult nontraumatic ED patients. We reviewed the admit/discharge dispositions at each shift made by 16 EPs. EPs were categorized by seniority to determine whether seniority influenced disposition. Three groups had 5, 4, and 7 EPs each, with >10 years, 5 to 9 years, and <5 years of working experience, respectively. RESULTS: Patient demographics, triage level, and number of patients per shift did not differ statistically between EPs and each group. The number of discharged patients per shift differed statistically between EPs (P < .001) and each group. The most senior EPs had the lowest discharge rates compared with EPs in intermediate and junior groups. They had lower discharge rates for patients at triage levels 1, 2, and 3 as well as for all patients. However, no difference in unscheduled ED revisit rates was found. CONCLUSIONS: EPs vary in their admit/discharge decision making for general ED patients. More importantly, the most senior EPs were found to have the lowest discharge rates compared with their junior colleagues. PMID- 22424990 TI - Factors associated with shock in anaphylaxis. AB - BACKGROUND: The aim of this study was to investigate the clinical characteristics of anaphylactic shock and the factors associated with anaphylactic shock in anaphylaxis. METHODS: Data were retrospectively collected from patients with anaphylaxis for 10 years. Study subjects were searched with broad disease codes including anaphyla-, adverse, angioedema, allergy, insect bite, bee, and hypersensitivity to prevent omission. All the 294 study subjects were divided into shock and nonshock groups. RESULTS: The mean age of the subjects was 43 years old, and males comprised 162 patients (55%). There were 119 patients (41%) in the shock group and 175 patients in the nonshock group. Age was older in the shock group than in the nonshock group; however, there was no difference in sex between 2 groups. Frequent causes of anaphylaxis were drugs in the shock group and food in the nonshock group. Nonsteroidal anti-inflammatory drugs and radiocontrast media were the most common cause of drug-induced anaphylaxis in the nonshock group and shock group, respectively. Cardiovascular symptoms were the most frequent symptoms in the shock group. Factors associated with the shock in cases with anaphylaxis were old age, emergency department (ED) arrival by emergency medical services use, radiocontrast material, symptoms with cyanosis, syncope, and dizziness. CONCLUSION: Elderly anaphylactic patients with symptoms of cyanosis, syncope, and dizziness were at increased risk for the development of shock. Physicians in the ED have to be alert to the possibility of progression to shock in patients with anaphylaxis, and early recognition of anaphylactic shock is critical for adequate treatment. PMID- 22424991 TI - Impact of metformin use on the prognostic value of lactate in sepsis. AB - OBJECTIVE: The objective of this study is to determine if metformin use affects the prevalence and prognostic value of hyperlactatemia to predict mortality in septic adult emergency department (ED) patients. METHODS: This is a single-center retrospective cohort study. Emergency department providers identified study subjects; data were collected from the medical record. PATIENTS: Adult ED patients with suspected infection and 2 or more systemic inflammatory response syndrome criteria were included. The outcome was 28-day mortality. The primary risk variable was serum lactate (<2.0, 2.0-3.9, >= 4.0 mmol/L) categorized by metformin use; covariates: demographics, Predisposition, Infection, Response, Organ Dysfunction score and metformin use contraindications. SETTING: The study was conducted at an urban teaching hospital; February 1, 2007 to October 31, 2008. RESULTS: A total of 1947 ED patients were enrolled; 192 (10%) were taking metformin; 305 (16%) died within 28 days. Metformin users had higher median lactate levels than nonusers (2.2 mmol/L [interquartile range, 1.6-3.2] vs 1.9 mmol/L [interquartile range, 1.3-2.8]) and a higher, although nonsignificant, prevalence of hyperlactatemia (lactate >= 4.0 mmol/L) (17% vs 13%) (P = .17). In multivariate analysis (reference group nonmetformin users, lactate <2.0 mmol/L), hyperlactatemia was associated with an increased adjusted 28-day mortality risk among nonmetformin users (odds ratio [OR], 3.18; P < .01) but not among metformin users (OR, 0.54; P = .33). In addition, nonmetformin users had a higher adjusted mortality risk than metformin users (OR, 2.49; P < .01). These differences remained significant when only diabetic patients were analyzed. CONCLUSIONS: In this study of adult ED patients with suspected sepsis, metformin users had slightly higher median lactate levels and prevalence of hyperlactatemia. However, hyperlactatemia did not predict an increased mortality risk in patients taking metformin. PMID- 22424992 TI - Twitter use during emergency medicine conferences. PMID- 22424993 TI - Optimal headrest height for the best laryngoscopic view: by anatomical measurements. AB - BACKGROUND: We hypothesized that the oro-pharyngolaryngeal axes, occipito-atlanto axial extension (OAA) angle and intubation distance would be influenced by the height of headrests. METHODS: Twenty patients were enrolled. The Macintosh 3 blade was used for direct laryngoscopy without a headrest or with the headrest of 6 or 12 cm high in randomized order, whereas a lateral radiograph of the neck was taken when the best laryngoscopic view was obtained. The following measurements were made: (1) the axis of the mouth (MA), the pharyngeal axis (PA), the laryngeal axis (LA), and the line of vision (LV). The various angles between these axes were defined: alpha angle between MA and PA, beta angle between PA and LA, and delta angle between LV and LA. (2) Intubation distance, (3) mentovertebral distance, and (4) OAA angle. RESULTS: Compared with 12-cm and no headrest, the delta angle decreased significantly with 6-cm headrest (19.4 degrees /29.2 degrees /29.2 degrees in 6-cm/12-cm/no headrest, respectively; P < .001), and the intubation distance increased significantly (46.2/37.3/38.7 mm in 6-cm/12-cm/no headrest, respectively; P < .001). Mentovertebral distance was smallest (107.0/106.7/98.5 mm; P < .05) at 12-cm headrest. Occipito-atlanto-axial extension angle was largest significantly (40.7 degrees /35.2 degrees /34.5 degrees ; P < .05) at 6-cm headrest. CONCLUSION: We conclude that compared with no or 12-cm headrest, 6-cm headrest could facilitate more alignment of these axes, increase the OAA angle, and enlarge the intubation distance. PMID- 22424994 TI - A hitch in hiccups. PMID- 22424995 TI - What do you think about the best time for surgical intervention in patients with massive pulmonary embolism? PMID- 22424996 TI - Comparison of ultrasonographic methods as a marker of blood loss. PMID- 22424997 TI - To-Go medications for decreasing ED return visits. AB - OBJECTIVES: The primary objective was to determine if providing patients with a complete course of antibiotics for select conditions would decrease the rate of return to the emergency department (ED) within 7 days of the initial visit. METHODS: In an urban, academic medical center, we compared patients who received medications at discharge (To-Go medications) with patients who received standard care (a prescription at discharge). Emergency department patients were included if they were older than 18 years; had a discharge diagnosis International Classification of Diseases, Ninth Revision, code for urinary tract infection, pyelonephritis, cellulitis, or dental infection; and presented initially between January and December 2010. Candidates had limited health insurance or were discharged when nearby pharmacies were closed. Return visits were included if the condition was related to the initial diagnosis. Wound checks and scheduled revisits were excluded. Medications dispensed were penicillin, clindamycin, sulfamethoxazole-trimethoprim, and nitrofurantoin. RESULTS: A total of 4257 individuals were seen in initial ED visits for the included conditions. Comparing the 243 individuals given medications with the 4014 who were not given medications, the To-Go medications group was less likely to return than the comparison group (2.5% vs 5.9%; P = .026). The cellulitis subgroup also showed a significant reduction in return visits (1.6% vs 6.9%; P = .024). Three hundred eighteen courses of medication were given to the 243 individuals for a total cost of $1123. CONCLUSIONS: For a 1-year expense of $1123, we demonstrated a 50% reduction in ED return visits for patients who were given a free, complete course of antibiotics at discharge for select conditions. PMID- 22424998 TI - Utilization of coronary computed tomography angiography for exclusion of coronary artery disease in ED patients with low- to intermediate-risk chest pain: a 1-year experience. AB - OBJECTIVE: We describe our preliminary experience with coronary computed tomography angiography (CCTA) in emergency department (ED) patients with low- to intermediate-risk chest pain. METHODS: A convenience cohort of patients with low- to intermediate-risk acute chest pain presenting to a suburban ED in 2009 were prospectively enrolled if the attending physician ordered a CCTA for possible coronary artery disease. Demographic and clinician data were entered into structured data collection sheets required before any imaging. The results of CCTA were classified as normal, nonobstructive (1%-50% stenosis), and obstructive (>50% stenosis). Outcomes included hospital admission and death within a 6-month follow-up period. RESULTS: In 2009, 507 patients with ED chest pain had a CCTA while in the ED. The median (interquartile range) age was 54 (47-62) years; 51.5% were female. Thrombolysis in myocardial infarction risk scores were 0 (42.6%), 1 (42.2%), 2 (11.8%), 3 (2.4%), and 4 (1.0%). The results of CCTA were normal (n = 363), nonobstructive (n = 123), and obstructive (n = 21). Admission rates by CCTA results were obstructive (90.5%), nonobstructive (4.9%), and normal (3.0%). None of the patients with normal or nonobstructive CCTA died within the 6-month follow up period (0%; 95% confidence interval, 0-0.9%). CONCLUSIONS: Many ED patients with low- to intermediate-risk chest pain have a normal or nonobstructive CCTA and may be safely discharged from the ED without any associated mortality within the following 6 months. PMID- 22424999 TI - Analysis of the appropriate age and weight for pediatric patient sedation for magnetic resonance imaging. AB - Sedatives with a long duration are required for pediatric magnetic resonance imaging (MRI) in the emergency department. The success rate of chloral hydrate for pediatric sedation is 80% to 100% according to some studies. However, the success rate varies by age, weight, and underlying disease. To identify factors affecting the success rate, we compared the chloral hydrate sedation success rate and adverse event rate by age, weight, and underlying disease. Compared with patients in the failure group, patients in the successful group were younger (23.8 vs 36.9 months, P < .01) and weighed less (11.4 vs 14.4 kg, P < .01). No differences in neurological problems, reasons for MRI, or adverse events were observed between the 2 groups. Patients 18 months old had a success rate greater than 95%, but the success rate decreased in children older than 18 months. The adverse event rate was about 10% in patients 18 months old and increased to 20% in patients older than 36 months. Patients 24 months of age who had a neurological problem (seizure disorder or developmental delay) had a success rate greater than 95%, but the adverse event rate increased after 24 months of age. Chloral hydrate sedation was appropriate for pediatric MRI in patients younger than 18 months. Although we observed no fatal adverse events, it is necessary to monitor patients until full recovery from sedation. PMID- 22425000 TI - Takotsubo cardiomyopathy associated with hypoglycemia: inverted takotsubo contractile pattern. AB - Classic takotsubo cardiomyopathy (TCM) is characterized by transient dysfunction of the apical portion of the left ventricle with hyperkinesis of the other parts of the heart wall. Recently, wall motion abnormalities in parts other than in the apical portion of the heart have been reported. Inverted TCM is one form of these anomalies. In this form, the basal segments rather than the apical part of the heart are akinetic/dyskinetic, and the apex is hyperdynamic. Emotional or physical stress is known to trigger TCM, leading some authors to call TCM stress induced cardiomyopathy (SC). Hypoglycemia is regarded as one of the physical stresses that cause TCM/SC. We present a case of inverted TCM/SC with hypoglycemia. In this case, a 60-year-old woman was brought to our hospital with loss of consciousness caused by hypoglycemia. Initially, the echocardiography revealed an inverted takotsubo contractile pattern. The patient was stabilized with continuous intravenous fluids and a glucose injection, whereas the echocardiography on day 4 showed an almost normal contractile pattern. Among the case reports regarding hypoglycemia as a preceding stressor of TCM/SC, a case of inverted TCM/SC with hypoglycemia is rare. Hypoglycemia is a relatively common case in emergency department; however wall motion abnormalities are not usually expected in hypoglycemic patients. Thus, undiagnosed self-limited TCM/SC cases are possible among hypoglycemic patients. TCM/SC is reported to be a cause of torsade de pointes, which can be fatal. This might warrant an echocardiogram for hypoglycemic patients so as not to overlook TCM/SC in the emergency department. PMID- 22425001 TI - Effect of intravenous fat emulsion therapy on glyphosate-surfactant-induced cardiovascular collapse. AB - Intravenous fat emulsion (IFE) therapy is an adjunct therapy administered to hemodynamically compromised patients with glyphosate-surfactant intoxication when they respond poorly to conventional therapies such as fluid resuscitation or vasopressors [1,2]. However, the use of IFE as an adjunct therapy in collapsed patients with glyphosate intoxication has not been reported previously. Here, we describe the case of a patient with glyphosate-surfactant-induced cardiovascular collapse who responded to IFE. PMID- 22425002 TI - Short- and long-term cardiac events in patients with chest pain with or without known existing coronary disease presenting normal electrocardiogram. AB - AIM: The aim of this study is to evaluate incidence of adverse cardiac events in patients with chest pain with or without known existing coronary disease presenting normal electrocardiogram (ECG) and initial troponin. METHODS: Prospective, nonrandomized study enrolled low-risk patients with normal ECG and troponin on admission who underwent observation and/or stress testing by unstandardized clinical judgment. Patients who experienced recurrent angina or positive ECGs or positive troponins during observation or patients with positive stress testing were admitted; otherwise, they were discharged. END POINT: The end points are cardiac events at short- and long-term follow-up including cardiovascular death, myocardial infarction, unstable angina, and revascularization. RESULTS: Of 5656 patients considered, 1732 with ischemic ECG were initially admitted and, therefore, excluded from the analysis; 2860 with pleuritic chest pain and normal ECG were discharged; 1064 with visceral chest pain and normal ECG were enrolled. Patients with known coronary disease (45%) were older and likely presented known vascular disease. Patients with known vascular disease, older age, female sex, diabetes mellitus, and lower chest pain score were likely managed with observation. In patients with known coronary disease as compared with patients without, overall cardiac events account for 35% vs 14%, respectively (P < .001), as follows: in-hospital, 23% vs 10%, (P < .001); 1 month, 4% vs 2% (P = .133); and 9.9 +/- 4.9 months, 8% vs 2%, respectively (P < .001). CONCLUSIONS: One-third of patients with chest pain with known coronary disease, negative ECG, and biomarkers were subsequently found to have adverse cardiac events. The value of this research for an emergency medicine audience could be extended to all clinicians and general practitioners beyond cardiologists. PMID- 22425003 TI - Potential synergy between advanced primary stroke centers and level I or II trauma centers in the United States. AB - OBJECTIVE: The objective of this study is to determine the number of primary stroke centers (PSCs) that exist concurrently (synergic relationship) with designated higher level trauma centers (level I or level II trauma centers) and associated characteristics. METHODS: We identified all PSCs certified by the Joint Commission or local state authorities in 2010. Concurrently, all the higher level trauma centers (designated level I or level II) were identified using data collected from the trauma information exchange program. Additional data was collected from the Accreditation Council for Graduate Medical Education and the American hospital directory. RESULTS: A total of 788 existing designated PSCs were identified in 2010; coexisting PSC-trauma centers were found in 252 centers (32%) with PSCs coexisting with level I trauma centers in 138 hospitals (17.5%). The remaining 536 PSCs (68%) are based in hospitals without trauma centers. There was a higher proportion of residency training programs including neurology, neurosurgery, and general surgery in coexisting PSC-trauma centers (P < .001). In a proof-of-concept analysis in 1 state, PSCs with level I trauma facilities were found to have the highest rates of thrombolytic administration as compared with PSCs with level II trauma centers and PSCs without trauma facilities (12.8% vs 3.8% vs 4.9%)(P < .0001). Primary stroke centers with level I trauma facilities were also more likely to follow the drip-and-ship paradigm (5.7% vs 1.8% vs 0.9%) (P < .0001). CONCLUSIONS: Despite evidence of higher capability among institutions with coexisting PSC-trauma centers, two thirds of PSCs are in hospitals without advanced trauma systems. These findings have implications for establishing stroke systems in the United States. PMID- 22425004 TI - Age variability in pediatric injuries from falls. AB - OBJECTIVE: The objective of this study is to examine the nature and circumstances surrounding pediatric fall-related injuries for specific age groups and their implications for age-appropriate injury prevention efforts. METHODS: This is a retrospective analysis of data (October 2006 to April 2009) from the trauma registry of a level 1 pediatric trauma center. Inclusion criteria are patients admitted because of fall-related injury younger than 15 years (n = 675). Injury mechanism specifics were obtained from medical records. RESULTS: Falls were the leading cause of admissions and accounted for 37% of all cases during this period. Most pediatric fall-related injuries (73%) occurred between 1 and 9 years of age. Although infants accounted for only 8% of fall injuries, a greater proportion of these children were more severely injured. The mean Injury Severity Score for infants was significantly greater than the overall average (P < .001). Causes of fall injuries vary by age and have been discussed. CONCLUSIONS: The high incidence of pediatric fall injuries warrants dedicated injury prevention education. Injury prevention efforts need to be age appropriate in terms of focus, target audience, and setting. Recommendations for injury prevention are discussed. PMID- 22425005 TI - External laryngeal manipulation does not improve the intubation success rate by novice intubators in a manikin study. AB - BACKGROUND: External laryngeal manipulation (ELM) is a technique used in cases of poor glottic view in direct laryngoscopy. Studies investigating ELM in the pediatric population are lacking. The objective of this study was to examine if use of ELM by inexperienced intubators improves the success rate of pediatric intubation. METHODS: We conducted a randomized, controlled, manikin study comparing intubation using ELM (study subjects) with standard intubation (controls). Study participants were paramedic students. Each participant performed 1 intubation attempt on 3 different pediatric airway manikins, independently. If an optimal Cormack-Lehane glottic view (CLGV) of more than 2 has been obtained, study subjects were previously instructed to perform the intubation using ELM; controls were instructed to continue with standard intubation. Outcome measures were single-attempt intubation success rate, preintubation CLGV, and duration of intubation. RESULTS: The study group included 13 subjects who performed 39 intubations. In 19 intubations, CLGV of more than 2 had been obtained; and ELM was used. The control group included 14 subjects who performed 42 intubations. In 20 intubations, CLGV of more than 2 was obtained. Median CLGV score improved from 3.5 before ELM to 2 when ELM was used. However, no difference was found between the groups in intubation success rate (10/19 vs 14/20, P = .43); and the duration of intubation was significantly shorter in controls (25.8 vs 37.8 seconds, P < .007). CONCLUSIONS: In this pediatric manikin study, ELM performed by novice intubators improved laryngeal view, but lengthened the duration of intubation and did not improve intubation success rate. PMID- 22425006 TI - Delayed presentation of hypovolemic shock after a simple pubic ramus fracture. AB - Although trauma-induced simple pubic ramus fracture is common in the emergency department (ED), it can result in life-threatening hemorrhagic shock. We describe a 58-year-old woman with closed minimally displaced simple pubic ramus fracture. Hemodynamic instability became apparent 2 hours later. She was successfully treated with transarterial embolization and discharged uneventfully 10 days later. Literature review showed involvement of the superior pubic ramus in all reported cases probably because of hemorrhage from "corona mortis" with delay in shock presentation mostly within 6 hours, suggesting at least an equivalent observation period for these patients, particularly those at high risk for hemorrhage. PMID- 22425007 TI - Role of folic acid depletion on homocysteine serum level in children and adolescents with epilepsy and different MTHFR C677T genotypes. AB - Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. An elevated total plasma Hcy concentration (tHcy) is a risk factor for vascular disease. The present study aimed to assess the role of antiepileptic drugs (AEDs) and C677T methylenetetrahydrofolate (MTHFR) polymorphisms on tHcy in pediatric patients with epilepsy treated for at least 6 months with various treatment regimens protocols including the newer AEDs. The study group was recruited from children and adolescents with epilepsy followed up in the Child Neuropsychiatry Clinic of the Second University of Naples, between January 2007 and March 2008. Inclusion criteria were: (1) patients with epilepsy, treated with one or more anticonvulsant drugs for at least 6 months; (2) age between 2 and 16 years. Plasma tHcy concentrations were considered elevated when they exceeded 10.4 MUmol/L, and folate concentrations <3 ng/mL were considered deficient. Serum vitamin B12 levels were considered normal between 230 and 1,200 pg/mL. The study group was composed of 78 patients (35 males, 43 females), aged between 3 and 15 years (mean 8.9 years). Thirty-five patients were taking AED monotherapy, 43 polytherapy. Sixty-three healthy sex- and age-matched children and adolescents served as controls. The mean tHcy value in the patient group was higher than the mean value in the control group (12.11 +/- 7.68 MUmol/L vs 7.4+/-4.01 MUmol/L; p<0.01). DNA analysis for the MTHFR C677T polymorphism showed the CT genotype in 46%, CC in 35% and TT in 17.8% of cases. Decreased folic acid serum levels significantly correlated with increased tHcy levels (p<0.003). Female sex was a less significant risk factor for increased tHcy levels (p=0.039). Our study confirms the association between hyperhomocysteinemia and epilepsy. The elevation of tHcy is essentially related to low folate levels. Correction of poor folate status, through supplementation, remains the most effective approach to normalize tHcy levels in patients on AED mono- or polytherapy. PMID- 22425008 TI - Clinical epidemiology of posttraumatic epilepsy in a group of Chinese patients. AB - OBJECTIVE: To explore the incidence, types of onset, and risk factors of posttraumatic epilepsy (PTE). METHODS: This is a retrospective follow-up study of patients discharged from the Affiliated Hospital of the Medical College of the Chinese People's Armed Police Forces between September 2004 and September 2008 with a diagnosis of traumatic brain injury (TBI). RESULTS: Complete clinical information was available on 2826 patients. Of the 2826 TBI patients, 141 developed PTE, providing an incidence rate of 5.0%. Twenty-four cases (0.8%) had posttraumatic seizures (PTS), of which 16 (66.7%) continued to experience after the acute phase of their TBI, accounting for 5.0% of the total PTE cases. A total of 125 cases (88.7%) were diagnosed as presenting with late-stage seizures, occurring from 10 days to three years after TBI (93/141 (66.0%) presented within six months after the TBI, 14/141 (9.9%) between six and twelve months, 22/141 (15.7%) between one and two years and only 12/141 (8.5%) between two and three years after the TBI. The severity of PTE was rated mild, medium, and severe in 3.6%, 6.9%, and 17% of the TBI patients. Multiple regression analysis was carried out to identify factors contributing to the risk of developing PTE. Five parameters contributed to the model: Older age, greater severity of brain injury, abnormal neuroimaging, surgical treatment, and early-stage seizures. CONCLUSION: Age, severity of brain injury, neuroimaging results, treatment methods, and early stage seizures are independent risk factors of PTE. PMID- 22425009 TI - Multiple causes of apnea in 1p36 deletion syndrome include seizures. AB - INTRODUCTION: Apneic episodes have not previously been described in children with 1p36 deletion syndrome with seizures. Having encountered one such patient, we reviewed our experience of breathing difficulties in this syndrome, with particular attention to evidence of ictal apnea. We describe four children with 1p36 deletion syndrome, seizures and apneic episodes. METHOD: Retrospective analysis of clinical features, seizure semiology and video-EEG data. RESULTS: All patients showed characteristic craniofacial features, mental retardation, and diffuse hypotonia and apnea. Seizure semiology included focal motor, +/- secondary generalized tonic clonic and tonic events. All had histories of status epilepticus; three showed clustering of their habitual seizures. Assessment of apnea was complicated by the presence of multiple other potential causes including obesity, reflux, respiratory, and cardiac problems Epileptic apneas were confirmed in one child by video-telemetry. In three other children, an epileptic basis for apneas was inferred from their clinical histories and treatment response supported by EEG findings. In three children, epileptiform discharges occurred over fronto-centro-temporal regions. CONCLUSION: Epileptic apnea is a feature of 1p36 deletion syndrome, though episodic apnea is multifactorial in these children, and may need repeated re-appraisal. PMID- 22425010 TI - Evaluation of the new cervical cancer screening program in Georgia. PMID- 22425011 TI - Distribution of HPV genotypes and HPV-16 and HPV-18 E2 gene disruption in South Brazilian women with cervical abnormalities. PMID- 22425012 TI - Pregnancy and delivery after liver transplantation. PMID- 22425013 TI - Tetanus in adults: clinical presentation, treatment and predictors of mortality in a tertiary hospital in Ethiopia. AB - BACKGROUND: Tetanus remains a major health problem in the developing world. The aim of this study was to evaluate the clinical presentation, risk factors, complications, treatment, outcome and predictors of death in patients with tetanus. METHODS: Patients aged >= 13 years admitted to Tikur Anbessa Hospital from June 2001 to May 2009 with the diagnosis of tetanus were included in this retrospective study. RESULTS: Data from 68 patients were analyzed; majority (77.9%) were males, the mean age was 33.8 years. None of them was vaccinated for tetanus. The types were: generalized (91.2%), cephalic (7.4%), localized (1.5%), severe (72.1%), moderate (19.1%) and mild (8.8%). One or more complication(s) occurred in 75%; dysautonomia (58.8%), pneumonia (44.1%) and hypoxemia (41.2%). Tracheostomy and mechanical ventilation was used in 45.6% and 11.8%, respectively. Case-fatality was 35.3%. Predictors of mortality were age >= 40 years, duration of symptoms prior to presentation < 4 days, severe tetanus, incubation period < 7 days, period of onset < 3 days and dysautonomia. The cause of death was early acute respiratory failure due to uncontrolled spasms in 87.5%. CONCLUSIONS: Most tetanus patients were young males and there was high case fatality due to acute respiratory failure. Age >= 40 years and dysautonomia were independent predictors of mortality. Preventing tetanus by vaccination and treating patients in a well equipped ICU is recommended. PMID- 22425014 TI - Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis. AB - Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. PMID- 22425015 TI - HPV-related (pre)malignancies of the female anogenital tract in renal transplant recipients. AB - Renal transplantations (RTs) are performed routinely in many countries. After RT, the administration of lifelong immunosuppressive therapy is required. As a consequence, renal transplant recipients (RTRs) have a high risk to develop virus associated (pre)malignancies, such as Human papillomavirus (HPV) related anogenital (pre)malignancies. It is known that the majority of the RTRs are infected with HPV and that these women have a 14-fold increased risk of cervical cancer, up to 50-fold of vulvar cancer and up to 100-fold of anal cancer. Often, treatment of these lesions requires concessions and may be suboptimal as radiation therapy and extensive surgery may damage the renal transplant. Therefore, prognosis may be compromised due to inadequately treated malignancies. Especially for these immunocompromised patients prevention is of utmost importance. Yearly cervical cancer screening for RTRs is advised, but appears to be executed poorly. For the future, optimizing screening and prevention of anogenital (pre)malignancies is an important issue for women after RT. This review gives a broad overview of all aspects regarding HPV-related (pre)malignancies of the female anogenital tract in RTRs. PMID- 22425016 TI - Update on the optimal management of patients with colorectal liver metastases. AB - Patients with colorectal liver metastases represent a distinct subset of metastatic colorectal cancer. Optimal management requires a multidisciplinary approach, local and systemic. Curative hepatic surgery is standard for resectable cases, but unfortunately, the majority of patients are not initially resectable due to the size, location, and/or extent of disease, inadequate remnant liver volume, or comorbidities. Other local approaches may be complementary (such as portal vein embolization) or alternative (such as ablation, hepatic arterial infusion, selective internal radiation therapy, and stereotactic body radiotherapy) to surgery. Systemic therapy can downsize disease, allowing surgical resection and, potentially, long-term survival, but it must be balanced against the potential for hepatotoxicity. Current standard approaches including cytotoxics and biologics, such as bevacizumab and particularly anti-epidermal growth factor receptor therapy, improve response rates and may enhance downsizing and resection rates. Optimization of local therapies and systemic conversion strategies via controlled, randomized trials is still a pending question. PMID- 22425017 TI - West of Ireland facial injury study. Part 2. AB - The pattern, presentation, and volume of facial injury in the west of Ireland are subjectively different from those in the United Kingdom. We know of no prospective regional study of facial injury in Ireland to date, and nationally there is no system in place to collect data on injury. The epidemiology of facial trauma has important implications for the development of health services, the education and training of clinicians, workforce planning, prevention of injury, and promotion of health. Over 1 week we did a multicentre prospective data collection study involving all emergency departments in the west of Ireland. All patients who attended with facial injuries were included (n=325), and those with injuries solely of the scalp and neck were excluded. The proforma recorded a patient's characteristics, details of injury and presentation, treatment and follow-up. It also included relation with sport, alcohol, assault, and animals. Eighty-two fractures were suspected, of which 46% were nasal. Accidents caused 75% of injuries and sport caused 27%. Fractures were sustained by 63% (n=5) of those wearing helmets while playing hurling, but by only 22% of those who were not. Helmets did, however, reduce the total number of injuries. Injuries were associated with alcohol (23%), assault (14%), falls (38%), and motor vehicle crashes (11%). Because of the differences in aetiology, different avenues and methods are required to prevent injury. Staff in emergency departments will need training in this area, given the large proportion of facial trauma in the region. PMID- 22425018 TI - Hemoglobin A1C is independently associated with severity and prognosis of brainstem infarctions. AB - OBJECTIVE: To assess the association of Hemoglobin A1C (HbA1c) with acute brainstem infarctions (BSIs) and to determine whether HbA1c is an independent risk factor in BSIs patients. METHODS: 96 only BSIs patients were categorized into four groups according to HbA1c as <6%, >= 6% but <7%, >= 7% but <8%, or >= 8%, respectively. The association of the four HbA1c groups with diffusion weighted imaging (DWI) infarct volumes (DIV), National Institutes of Health Stroke Scale (NIHSS), and follow-up modified Rankin Scale (FmRS) scores were analyzed. Patients also were categorized into two groups according to HbA1c<6% or >= 6%. Logistic regression analyses were performed to determine independent risk factors. RESULTS: There was a significant correlation between HbA1c and DIV (Spearman rho=0.339, P=0.001), NIHSS scores (rho=0.292, P=0.004) and FmRS scores (rho=0.315, P=0.002). The incidence of pons infarction was highest in BSIs and patients with HbA1c >= 6% showed significantly more frequent isolated pontine infarction. Logistic regression analyses showed that only HbA1c was independently associated with larger DIV (P=0.025) and FmRS scores (P=0.026). CONCLUSIONS: These results suggest that elevated HbA1c level may be a potential serologic marker in the evaluation of the severity and prognosis of acute BSIs. There is an urgent need to study control of diabetes mellitus (DM) before and after BSIs. PMID- 22425019 TI - Anxiety, depression and autonomic nervous system dysfunction in hypertension. AB - OBJECTIVES: This study examined the relationship between autonomic nervous system dysfunction, anxiety and depression in untreated hypertension. PATIENTS AND METHODS: 86 newly diagnosed hypertensive patients and 98 healthy volunteers were included in the study. The psychological parameters were assessed with Spielberger State-Trait Anxiety Inventory and Beck Depression Inventory by a skilled psychologist. Autonomic parameters were examined during tilt table examination (10min lying position, 10min passive tilt). Heart rate variability (HRV) was calculated by autoregressive methods. Baroreflex sensitivity (BRS) was calculated by non-invasive sequence method from the recorded beat to beat blood pressure values and RR intervals. RESULTS: Significantly higher state (42.6+/-9.3 vs. 39.6+/-10.7 p=0.05) and trait (40.1+/-8.9 vs. 35.1+/-8.6, p<0.0001) anxiety scores were found in the hypertension group. There was no statistically significant difference in the depression level. LF-RRI (Low Frequency-RR interval) of HRV in passive tilt (377.3+/-430.6 vs. 494.1+/-547, p=0.049) and mean BRS slope (11.4+/-5.5 vs. 13.2+/-6.4, p=0.07) in lying position were lower in hypertensives. Trait anxiety score correlates significantly with sympatho/vagal balance (LF/HF-RRI) in passive tilt position (Spearman R=-0.286, p=0.01). CONCLUSIONS: Anxiety could play a more important role than depression in the development of hypertension. Altered autonomic control of the heart could be one of the pathophysiological links between hypertension and psychological factors. PMID- 22425020 TI - Specialist versus generalist insect herbivores and plant defense. AB - There has been a long-standing hypothesis that specialist and generalist insects interact with plants in distinct ways. Although many tests exist, they typically compare only one species of each, they sometimes confound specialization and feeding guild, and often do not link chemical or transcriptional measures of the plant to actual resistance. In this review, we synthesize current data on whether specialists and generalists actually differ, with special attention to comparisons of their differential elicitation of plant responses. Although we find few consistencies in plant induction by specialists versus generalists, feeding guilds are predictive of differential plant responses. We outline a novel set of predictions based on current coevolutionary hypotheses and make methodological suggestions for improved comparisons of specialists and generalists. PMID- 22425021 TI - Prolonged elevation of cytokine levels after human acute ischaemic stroke with evidence of individual variability. AB - There is inflammation at the site of pathology in acute ischaemic stroke. In humans there is also elevation of levels of circulating cytokines in the days after stroke. We have previously found increased level of circulating T cells for up to three weeks after stroke. We have now measured cytokine levels for up to three weeks after stroke, looking for evidence of ongoing immune changes after the acute injury. Blood was collected from healthy controls and from subjects with acute ischaemic stroke on day 1, week 1 and week 3 after onset. Levels of interleukin 6 (IL6), interleukin 10 (IL10) and transforming growth factor beta (TGF-beta) were measured by ELISA. We compared the cytokine levels in males and females, and correlated levels with stroke type as classified by the Oxfordshire stroke classification and stroke severity assessed by the NIH Stroke Scale. In the total group, levels TGF-beta were significantly elevated at day 1. In the total group, levels of IL-6 were significantly elevated at all time-points. Levels of IL-10 were significantly elevated at week 1. The finding of elevated cytokine levels gives further evidence of ongoing immune activation for up to 3 weeks after acute ischaemic stroke. There was only a modest effect of stroke severity on levels of IL-6. There was also variability among individuals. PMID- 22425022 TI - CCL5, CCR1 and CCR5 in murine glioblastoma: immune cell infiltration and survival rates are not dependent on individual expression of either CCR1 or CCR5. AB - Glioblastoma multiforme (GBM) is the most malignant brain tumor. Microglia/macrophages are found within human GBM where they likely promote tumor progression. We report that CCL5, CCR1, and CCR5 are expressed in glioblastoma. Individual deletion of CCR1 or CCR5 had little to no effect on survival of tumor bearing mice, or numbers of glioblastoma-infiltrated microglia/macrophages or lymphocytes. CCL5 promoted in vitro migration of wild type, CCR1- or CCR5 deficient microglia/macrophages that was blocked by the dual CCR1/CCR5 antagonist, Met-CCL5. These data suggest that CCL5 functions within the glioblastoma microenvironment through CCR1 and CCR5 in a redundant manner. PMID- 22425024 TI - The fundamental role of subcellular topography in peripheral nerve repair therapies. AB - Clinical evidence suggests that nano- and microtopography incorporated into scaffolds does not merely improve peripheral nerve regeneration, but is in fact a prerequisite for meaningful restoration of nerve function. Although the biological mechanisms involved are not fully understood, grafts incorporating physical guides that mimic microscopic nerve tissue features (e.g., basal laminae) appear to provide a significant advantage over grafts that rely on purely chemical or macroscopic similarities to nerve tissue. Investigators consistently demonstrate the fundamental importance of nano- and micro-scale physical features for appropriate cell response in a wide range of biological scenarios. Additionally, recent in vivo research demonstrates that nerve regeneration scaffolds with cell-scale physical features are more effective than those that rely only on chemical or macro-scale features. Physical guidance at the cell-scale is especially important for long (>20 mm) nerve defects, for which the only reliable treatment is the autologous nerve graft. The lack of other available options exposes a clear need for the application of nano- and microfabrication techniques that will allow the next generation of engineered nerve guides to more closely mimic native tissue at those scales. This review examines current research to determine what elements of cell-scale topography in experimental scaffolds are most effective at stimulating functional recovery, and then presents an overview of fabrication techniques that could potentially improve future treatment paradigms. Relative advantages and disadvantages of these techniques are discussed, with respect to both clinical adaptation and likely effectiveness. Our intent is to more clearly delineate the remaining obstacles in the development of a next generation nerve guide, particularly for long defects, and offer new perspectives on steering current technologies towards clinically viable solutions. PMID- 22425023 TI - Long-term multimodal imaging of tumor draining sentinel lymph nodes using mesoporous silica-based nanoprobes. AB - The imaging of sentinel lymph nodes (SLNs), the first defense against primary tumor metastasis, has been considered as an important strategy for noninvasive tracking tumor metastasis in clinics. In this study, we report the development and application of mesoporous silica-based triple-modal nanoprobes that integrate multiple functional moieties to facilitate near-infrared optical, magnetic resonance (MR) and positron emission tomography (PET) imaging. After embedding near-infrared dye ZW800, the nanoprobe was labeled with T(1) contrast agent Gd(3+) and radionuclide (64)Cu through chelating reactions. High stability and long intracellular retention time of the nanoprobes was confirmed by in vitro characterization, which facilitate long-term in vivo imaging. Longitudinal multimodal imaging was subsequently achieved to visualize tumor draining SLNs up to 3 weeks in a 4T1 tumor metastatic model. Obvious differences in uptake rate, amount of particles, and contrast between metastatic and contra-lateral sentinel lymph nodes were observed. These findings provide very helpful guidance for the design of robust multifunctional nanomaterials in SLNs' mapping and tumor metastasis diagnosis. PMID- 22425025 TI - Co-delivery of SOX9 genes and anti-Cbfa-1 siRNA coated onto PLGA nanoparticles for chondrogenesis of human MSCs. AB - Some genes expressed in stem cells interrupt and/or enhance differentiation. Therefore, the aim of this study was to inhibit the expression of unnecessary genes and enhance the expression of specific genes involved in stem cell differentiation by using small interfering RNA (siRNA) and plasmid DNA (pDNA) incorporated into cationic polymers as co-delivery factors. To achieve co delivery of siRNA and pDNA to human mesenchymal stem cells (hMSCs), two different genes were complexed with poly(ethyleneimine) (PEI) and then coated onto poly(lactide-co-glycolic acid) (PLGA) nanoparticles (NP). To evaluate co-delivery of siRNA and pDNA into hMSCs, cells were transfected with green fluorescence protein (GFP) pDNA (GFP pDNA) and GFP siRNA (GFP siRNA). The percentage of GFP expressing hMSCs decreased from 25.35 to 3.7% after transfection with GFP DNA/PLGA NP (NPs) or GFP siRNA/PLGA NPs, whereas GFP-DNA/PLGA NPs and scramble siRNA (MOCK)/PLGA NPs had no effect on GFP expression. hMSCs cotransfected with coSOX9-pDNA/NPs and Cbfa-1-siRNA/NPs were tested both in vitro and in vivo using gel retardation, dynamic light scattering (DLS), and scanning electron microscope (SEM). The expression of genes and proteins associated with chondrogenesis was evaluated by FACS, RT-PCR, real time-qPCR, Western blotting, immunohistochemistry, and immunofluorescence imaging. PMID- 22425026 TI - Mesoporous carbon@silicon-silica nanotheranostics for synchronous delivery of insoluble drugs and luminescence imaging. AB - A hierarchical theranostic nanostructure with carbon and Si nanocrystals respectively encapsulated in the mesopores and within the framework of mesoporous silica nanoparticles (CS-MSNs) was constructed by a bottom-up self-assembly strategy combining an in situ one-step carbonization/crystallization approach. CS MSNs exhibited narrow size distribution, high payload of insoluble drugs and unique NIR-to-Vis luminescence imaging feature. The bio-conjugated CS-MSNs with a PEGylated phospholipid compound and hyaluronic acid showed excellent dispersivity and could specifically target cancer cells overexpressing CD44, deliver insoluble drugs into these cells and consequently kill them effectively, and also fluorescently image them simultaneously in a unique and attractive NIR-to-Vis luminescence imaging fashion, providing a promising opportunity for cancer theranostics. PMID- 22425027 TI - Impact of the UK colorectal cancer screening pilot studies on incidence, stage distribution and mortality trends. AB - OBJECTIVE: To assess the impact of the UK colorectal cancer guaiac faecal occult blood test screening pilot studies on incidence trends, stage distribution and mortality trends. DESIGN: Ecological study. SETTING: Scotland and the West Midlands. DATA: We extracted anonymised colorectal cancer (ICD-10 C18-C20) registration (1982-2006) and death records (1982-2007), along with corresponding mid-year population estimates. INTERVENTION: Residents of the screening pilot areas, in the age group 50-69 years, were offered biennial guaiac faecal occult blood test screening from 2000 onwards. Screening was not offered routinely in non-pilot areas until the start of the roll-out of the national screening programmes in England and in Scotland in 2006 and 2007, respectively. MAIN OUTCOME MEASURES: We analysed trends in age-specific incidence and mortality rates, and Dukes' stage distribution. Within each country/region, we compared the screening pilot areas to non-screening pilot ('control') areas using Chi square tests and Poisson regression modelling. RESULTS: Following the start of the screening pilots, as expected in the prevalent round of a new screening programme, in the pilot areas there was a short-lived increase in incidence of colorectal cancer among 50-69 year olds except for females in the West Midlands. A trend towards earlier stage and less advanced disease was also observed, with males showing significant increases in Dukes' A and corresponding decreases in Dukes' C in the screening pilot areas (all P < 0.03). With the exception of females in the West Midlands, mortality rates for colorectal cancer decreased significantly and at a faster rate in the populations invited for screening. CONCLUSION: The existence of a natural control population not yet invited for screening provided a unique opportunity to assess whether the benefits of colorectal cancer screening, beyond the setting of a randomised controlled trial, could be detected using routinely collected statistics. Our analysis suggests that screening will fulfil its aim of reducing mortality from colorectal cancer. PMID- 22425028 TI - Increasing supplemental nutrition assistance program/electronic benefits transfer sales at farmers' markets with vendor-operated wireless point-of-sale terminals. AB - BACKGROUND: Supplemental Nutrition Assistance Program (SNAP) (formerly Food Stamp Program) participants can use their benefits at many farmers' markets. However, most markets have only one market-operated wireless point-of-sale (POS) card swipe terminal for electronic benefits transfer (EBT) transactions. It is not known whether providing each farmer/vendor with individual wireless POS terminals and subsidizing EBT fees will increase SNAP/EBT purchases at farmers' markets. OBJECTIVE: To evaluate the effects of multiple vendor-operated wireless POS terminals (vs a single market-operated terminal) on use of SNAP benefits at an urban farmers' market. DESIGN: Time-series analyses of SNAP/EBT sales. SETTING: The Clark Park farmers' market in West Philadelphia, PA, which accounts for one quarter of all SNAP/EBT sales at farmers' markets in Pennsylvania. INTERVENTION: Vendors were provided with individual wireless POS terminals for 9 months (June 2008-February 2009.) The pilot program covered all equipment and wireless service costs and transaction fees associated with SNAP/EBT, credit, and debit sales. MAIN OUTCOME MEASURE: Monthly SNAP/EBT sales at the Clark Park farmers' market. STATISTICAL ANALYSES: SNAP/EBT sales data were collected for 48 months (January 2007-December 2010). Time-series regression analysis was used to estimate the effect of the intervention period (June 2008-February 2009) on SNAP/EBT sales, controlling for seasonal effects and total SNAP benefits issued in Philadelphia. RESULTS: The intervention was associated with a 38% increase in monthly SNAP/EBT sales. Effects were greatest during the busy fall market seasons. SNAP/EBT sales did not remain significantly higher after the intervention period. CONCLUSIONS: Providing individual wireless POS terminals to farmers' market vendors leads to increased sales. However, market vendors indicated that subsidies for equipment costs and fees would be needed to break even. Currently, SNAP provides some support for these services for supermarket and other SNAP retailers with landline access, but not for farmers' markets. PMID- 22425029 TI - Precursors and nitrogen origins of trichloronitromethane and dichloroacetonitrile during chlorination/chloramination. AB - The formation of trichloronitromethane (TCNM) and dichloroacetonitrile (DCAN) was investigated during chlorination and chloramination of 31 organic nitrogen (org N) compounds, including amino acids, amines, dipeptides, purines, pyrimidones and pyrroles. Tryptophan and alanine generated the greatest amount of TCNM during chlorination process and asparagine and tyrosine yielded the highest amount of TCNM during chloramination process. Tryptophan, tyrosine, asparagine, and alanine produced more DCAN than other org-N compounds regardless of chlorination or chloramination. TCNM and DCAN formation was higher by chlorination than by chloramination. NH(2)Cl:org-N molar ratios, reaction time, and pH affected N-DBPs formation in varying degrees. TCNM and DCAN yields were usually high during chloramination of tyrosine, asparagine, and methylpyrrole under the following reaction conditions: NH(2)Cl:org-N molar ratios greater than 10, reaction time for 1d, and at pH 7.2. NH(2)Cl as a major nitrogen origin in TCNM and DCAN was confirmed via labeled (15)N-monochloramine during chloramination of tyrosine, asparagine and methylpyrrole. In contrast, the majority of nitrogen in TCNM originated from glycine, and that in DCAN originated from pyrrole. Based on the intermediates identified by gas chromatography/mass spectrometry (GC/MS), a pathway scheme was proposed for TCNM and DCAN formation. PMID- 22425030 TI - Monitoring of atrazine in milk using a rapid tube-based ELISA and validation with HPLC. AB - Although atrazine has been banned in the European Union since 2007 it still persists in soil from where it can enter the food chain. Milk-producing animals accumulate atrazine from contaminated feed and water and since large quantities of milk and milk products are consumed its quality should be constantly monitored. The objective of this investigation was to develop a simple tube ELISA procedure suitable for use in non-specialised laboratories and in the field. A polyclonal antibody raised in sheep and the hapten-gelatine conjugate was immobilised onto polystyrene tubes. This enables the colour produced to be read on a basic spectrophotometer. Milk samples were collected from three farms in different regions of Poland and diluted before immunoassay was performed. Samples were extracted with hexane-acetone for HPLC analysis. The amount of fat in the milk samples interferes with the dose response so it essential that the standards are prepared in the same samples matrix. A good correlation between 1% and 2% was found between the two methods in the analysis of real samples. However the ELISA procedure was more sensitive that the HPLC method since atrazine was detected in some samples by the ELISA but was not confirmed by the HPLC method. The study demonstrated that the simple antigen-coated tube assay provides a cost effective and valuable screening test that can be easily modified for direct use as a screening tool in the field. PMID- 22425031 TI - Structure-activity relationship of selected polyphenol derivatives as inhibitors of Bax/Bcl-xL interaction. AB - This paper describes the synthesis of nine selected diaryl/heteroaryl-containing phenol and polyphenol derivatives which have been evaluated against Bax/Bcl-xL interaction in comparison with ABT-737. Using a BRET assay, six of these derivatives exhibit activity comparable to ABT-737 to disrupt Bax/Bcl-xL interaction. These preliminary results demonstrate that such polyphenol-derived molecules are attractive compounds regarding anticancer activity and that the phenol at position 3 is important regarding disruption of Bax/Bcl-xL interaction. PMID- 22425032 TI - Disparities in the geography of serious mental illness in Israel. AB - OBJECTIVE: The aim of this research is to test and apply a model of the disparities and variations in serious mental illness (SMI) to estimating prevalence in local areas throughout Israel. METHODS: This study employs a secondary analysis of data from the 2003/2004 Israel National Health Survey of 4859 adults aged 21 and over from the household population of legal residents and citizens. It uses small area estimation methods (SAE), specifically to: (i) estimate and test a multivariate logistic model of disparities in the risk of serious mental illness; (ii) use the foregoing model for computing estimates, using census data, for local areas; (iii) validate these estimates against the rate of psychiatric hospitalizations. RESULTS: The model uses standard demographic and socioeconomic variables to successfully predict 92.5% of respondents' statuses as SMI, with a sensitivity of 26.9%, specificity of 95.9%, and an AUC index of .797. The resulting estimates of the percentage of adults with an SMI in the 16 subdistricts ranged between 3.7% and 7.7%, with a national mean of 5.0%. The estimates have a partial correlation of .63 with rates of psychiatric hospitalization in Jewish localities, but elevated rates have not been validated in Arab localities. CONCLUSION: The use of small area estimation methods demonstrated the capacity for deriving local prevalence rates of serious mental illness, ones that can be validated against psychiatric hospitalization for the majority population group in Israel. PMID- 22425033 TI - Mouth breathing children and cephalometric pattern: does the stage of dental development matter? AB - OBJECTIVE: To test the hypothesis that there is no difference in the cephalometric pattern between mouth breathing children with primary dentition and mixed dentition. METHODS: Cephalometric measurements of 126 mouth breathing children (MB) were compared to 126 nasal breathing controls (NB). Both groups were divided into deciduous dentition (mean age 4 years, 8 months) and mixed dentition (mean age 7 years, 9 months) groups. RESULTS: A statistically significant difference was observed in the dentofacial patterns of MB children compared to NB children. The total length of the mandible was smaller in MB compared to NB children. However, this difference was found only in subjects with mixed dentition. The length of the mandibular corpus is similar in MB and NB children, although older MB children with mixed dentition had significantly smaller measurements. The lower anterior facial height was higher in MB compared to NB children, but this difference was evident only in younger children with primary dentition. Mandibular plane angle, Y-axis angle and lower anterior facial height to total anterior facial height ratio were greater, and posterior facial height to total anterior facial height ratio was smaller in MB than NB children, indicating that mouth breathers had a more vertical facial growth pattern. However, no differences were found in the vertical growth pattern associated with the stage of dental development. The ANB angle was not associated with the maturational status of occlusion. Linear measurements and the gonial angle were significantly different between children with primary and mixed dentition, but such differences were associated with normal vertical growth. CONCLUSIONS: The present investigation rejected the null hypothesis and showed significant cephalometric differences between primary and mixed dentition MB children. Mouth breathing children in the mixed dentition have a smaller mandible (in terms of total length and corpus length) than nasal breathers. In children with primary dentition, the lower anterior facial height is higher in MB than in NB children. There was no significant association between the stage of dental development of mouth breathing children (either in the primary or mixed dentition) and the other cephalometric patterns. PMID- 22425035 TI - Localized gray matter volume reductions in the pars triangularis of the inferior frontal gyrus in individuals at clinical high-risk for psychosis and first episode for schizophrenia. AB - Recent studies have suggested an important role for Broca's region and its right hemisphere counterpart in the pathophysiology of schizophrenia, owing to its roles in language and interpersonal information processing. Broca's region consists of the pars opercularis (PO) and the pars triangularis (PT). Neuroimaging studies have suggested that they have differential functional roles in healthy individuals and contribute differentially to the pathogenesis of schizophrenic symptoms. However, volume changes in these regions in subjects with ultra-high risk for psychosis (UHR) or first-episode schizophrenia (FES) have not been clarified. In the present 3 Tesla magnetic resonance imaging study, we separately measured the gray matter volumes of the PO and PT using a reliable manual-tracing volumetry in 80 participants (20 with UHR, 20 with FES, and 40 matched controls). The controls constituted two groups: the first group was matched for age, sex, parental socioeconomic background, and intelligence quotient to UHR (n=20); the second was matched for those to FES (n=20). Compared with matched controls, the volume of the bilateral PT, but not that of the PO, was significantly reduced in the subjects with UHR and FES. The reduced right PT volume, which showed the largest effect size among regions-of-interest in the both UHR and FES groups, correlated with the severity of the positive symptoms also in the both groups. These results suggest that localized gray matter volume reductions of the bilateral PT represent a vulnerability to schizophrenia in contrast to the PO volume, which was previously found to be reduced in patients with chronic schizophrenia. The right PT might preferentially contribute to the pathogenesis of psychotic symptoms. PMID- 22425034 TI - Adrenomedullin and pregnancy: perspectives from animal models to humans. AB - A healthy pregnancy requires strict coordination of genetic, physiologic and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin (AM) has recently been the focus of some exciting breakthroughs in the pregnancy field. Supported by mechanistic studies in genetic animal models, there continues to be a growing body of evidence demonstrating the importance of AM protein levels in a variety of human pregnancy complications. With more extensive mechanistic studies and improved consistency in clinical measurements of AM, there is great potential for the development of AM as a clinically relevant biomarker in pregnancy and pregnancy complications. PMID- 22425036 TI - Aluminium overload after 5 years in skin biopsy following post-vaccination with subcutaneous pseudolymphoma. AB - Aluminium hydroxide is used as an effective adjuvant in a wide range of vaccines for enhancing immune response to the antigen. The pathogenic role of aluminium hydroxide is now recognized by the presence of chronic fatigue syndrome, macrophagic myofasciitis and subcutaneous pseudolymphoma, linked to intramuscular injection of aluminium hydroxide-containing vaccines. The aim of this study is to verify if the subcutaneous pseudolymphoma observed in this patient in the site of vaccine injection is linked to an aluminium overload. Many years after vaccination, a subcutaneous nodule was discovered in a 45-year-old woman with subcutaneous pseudolymphoma. In skin biopsy at the injection site for vaccines, aluminium (Al) deposits are assessed by Morin stain and quantification of Al is performed by Zeeman Electrothermal Atomic Absorption Spectrophotometry. Morin stain shows Al deposits in the macrophages, and Al assays (in MUg/g, dry weight) were 768.10+/-18 for the patient compared with the two control patients, 5.61+/ 0.59 and 9.13+/-0.057. Given the pathology of this patient and the high Al concentration in skin biopsy, the authors wish to draw attention when using the Al salts known to be particularly effective as adjuvants in single or repeated vaccinations. The possible release of Al may induce other pathologies ascribed to the well-known toxicity of this metal. PMID- 22425037 TI - The health and well-being of Indigenous drug and alcohol workers: results from a national Australian survey. AB - The increasing demand for alcohol and other drug (AOD) treatment services among the Australian Indigenous population, complex organisational challenges and limitations, and high unemployment rates are likely to negatively impact Indigenous AOD workers' health and well-being. Building the capacity of Indigenous AOD workers is vital, as they play a crucial role in the delivery of treatment services and offer essential support to their communities. A national online survey was conducted to examine organisational, workplace and individual factors that might contribute to levels of stress and well-being among workers who provide services to Indigenous clients. A total of 294 eligible surveys were completed; 184 (63%) from Indigenous and 108 (37%) from non-Indigenous AOD workers. Multiple regression models were conducted to assess the significant predictors of mental health and well-being, job satisfaction, emotional exhaustion, and turnover intention. Indigenous AOD workers typically experienced above average levels of job satisfaction and relatively low levels of emotional exhaustion. However, 1 in 10 reported high levels of emotional exhaustion, a key predictor of turnover intention. Indigenous workers also experienced significantly lower levels of mental health and well-being and greater work/family imbalance, which was a significant contributor to emotional exhaustion. The findings highlight the importance of implementing workforce development strategies that focus on achieving culturally appropriate, equitable and supportive organisational conditions for Indigenous AOD workers. Preventing or managing levels of stress, ensuring adequate and equitable salaries and benefits, and providing more opportunities for career and personal growth may increase job satisfaction and reduce turnover intention among Indigenous workers in the drug and alcohol field. PMID- 22425038 TI - Rationale for and current status of prenatal cardiac intervention. AB - The idea of prenatal intervention in congenital heart defects was put forward over 20 years ago, arising from the observation that some forms of cardiac malformation progressed in severity as pregnancy advanced. The simultaneous development of minimally invasive catheter techniques in children, led to the concept of treating the foetal heart directly, in an attempt to prevent the changes which had been observed. Early efforts at prenatal valvuloplasty were largely set aside after poor results and the coincidental development of alternative, increasingly successful, postnatal surgical strategies. However, in the last 10 years or so, some centres have revived and extended the interventional techniques, with some success. The application of these techniques is limited to very few conditions, and suitable cases are relatively uncommon. Exploration of these procedures, therefore, should be limited to very few centres and the results should be closely scrutinised before this becomes an accepted management option. PMID- 22425039 TI - Cord blood 8-isoprostane in the preterm infant. AB - BACKGROUND: Cord blood 8-isoprostane (8-IP) is a marker of lipid peroxidation in the peripartum period. The independent association with degree of prematurity is not well-described. OBJECTIVE: To identify patterns of lipid peroxidation among early, moderate and late preterm infants, and to understand how cord blood 8-IP varies with gestational age (GA) and related covariates. STUDY DESIGN: Mother infant pairs from 237 preterm births were studied as part of a longitudinal birth cohort study. GA subgroups were defined as extremely (<=28w), moderately (29 33w), and late (34-36w) preterm. Cord blood 8-IP was measured using EIA. Elevated 8-IP (4th quartile) was the primary outcome for multivariate logistic regression models, which were adjusted for maternal age/race, multiple gestation and infant gender, as well as other relevant covariates. RESULTS: Elevated 8-IP was associated with extremely preterm birth (OR=4.31; 95% CI=1.90, 9.76), and was inversely associated with increasing GA (OR=0.88; 95% CI=0.80, 0.97). Elevated 8 IP was also associated with decreasing birth weight (BW), clinical chorioamnionitis, fetal inflammatory response of the placenta (FIR), and signs of perinatal depression. The GA on 8-IP association appeared to be modified by several maternal disease and fetal-infant factors. Lastly, the indirect associations between log-transformed 8-IP, GA and BW appeared to be most prominent for GA<30w and for BW<2000g. CONCLUSION: Lipid peroxidation in preterm birth, and the relative influence of accompanying peripartum factors, varies according to degree of prematurity. These findings have important implications for the developmental regulation of antioxidant defense and its impact on neonatal outcomes. PMID- 22425040 TI - Male rat genital tract infection with Chlamydia muridarum has no significant consequence on male fertility. AB - PURPOSE: Chlamydia trachomatis infection of the male genital tract was proposed to alter male fertility. We studied the putative consequences of chlamydial male genital tract infection on semen quality and male fertility in an experimental rat model of infection. MATERIALS AND METHODS: We used 36 male and 40 female Wistar rats. Male genital infection was created by inoculating Chlamydia muridarum in the meatal urethra. The presence of C. muridarum was evaluated by polymerase chain reaction in semen and male genital tract organs early (15 days) and late (80 days) after infection. Sperm quality parameters were assayed in seminal and epididymal sperm from sham infected and infected rats. Mating studies with sexually mature females were performed and fertility parameters were assayed, including potency, fecundity and fertility indexes, fetal size, and pre implantation and post-implantation embryo loss. RESULTS: Male rats showed ascending, disseminated infection 15 days after infection. Bacteria persisted in the prostate and seminal vesicles 80 days after infection. C. muridarum was detected in semen in most rats regardless of acute or chronic infection. Seminal or epididymal sperm quality did not differ in infected and sham infected rats 15 or 80 days after infection. Sperm apoptosis was also minimal in infected rats. No differences were observed in fertility parameters between infected and sham infected rats. CONCLUSIONS: C. muridarum infects the rat male genital tract and persists mainly in the prostate. Although C. muridarum was detected in semen during acute and chronic infection, no alterations in sperm quality were observed. C. muridarum infection does not impair male fertility. PMID- 22425041 TI - Transfer of laparoscopic radical prostatectomy skills from bench model to animal model: a prospective, single-blind, randomized, controlled study. AB - PURPOSE: Learning laparoscopic urethrovesical anastomosis is a crucial step in laparoscopic radical prostatectomy. Previously we noted that practice on a low fidelity urethrovesical model was more effective for trainees than basic suturing drills on a foam pad when learning laparoscopic urethrovesical anastomosis skills. We evaluated learner transfer of skills, specifically whether skills learned on the urethrovesical model would transfer to a high fidelity, live animal model. MATERIALS AND METHODS: A total of 28 senior residents, fellows and staff surgeons in urology, general surgery and gynecology were randomized to 2 hours of laparoscopic urethrovesical anastomosis training on a urethrovesical model (group 1) or to basic laparoscopic suturing and knot tying on foam pads (group 2). All participants then performed timed laparoscopic urethrovesical anastomosis on anesthetized female pigs. A blinded urologist scored subject videotaped performance using checklist, global rating scale and end product rating scores. RESULTS: Group 1 was significantly more adept than group 2 at the laparoscopic urethrovesical anastomosis pig task when measured by the checklist, global rating scale and end product rating (each p <0.05). Time to completion was similar in the 2 groups. No statistically significant difference was noted in global rating scale and checklist scores for laparoscopic urethrovesical anastomosis performed on the urethrovesical model vs the pig. CONCLUSIONS: Training on a urethrovesical model is superior to training with basic laparoscopic suturing on a foam pad for performing laparoscopic urethrovesical anastomosis skills on an anesthetized female pig. Skills learned on a urethrovesical model transfer to a high fidelity, live animal model. PMID- 22425042 TI - An ileal conduit--who takes care of the stoma? AB - PURPOSE: Urostomy care requires manual skills and emotional adaptation. We identified predictors of self-stomal care and their impact on quality of life after urostomy creation in patients with an ileal conduit. MATERIALS AND METHODS: A telephone questionnaire was administered to patients treated with urostomy creation in 2005 to 2010. Assessment included demographic data, stomal care patient education data and quality of life parameters. RESULTS: The study population included 65 patients, including 20% females and 80% males. Mean age was 72 years (range 40 to 88). Mean followup was 30 months (range 6 to 74). Of the patients 97% received stomal specific patient education preoperative but only 32 (49%) felt satisfactorily skilled in stomal care upon hospital discharge. Of the patients 34 (52%) self-managed the urostomy, including 85% of females but only 44% of males (p = 0.009). Predictors of long-term self-stomal care were patient perception that questions before surgery were answered (p = 0.04), better bag replacement training (p = 0.001) and early stomal care skill (p <0.001). Self stomal care was associated with a higher quality of life score and an improved psychological impact score. On multivariate analysis female gender (OR 15.9, p = 0.008) and higher postoperative education score (OR 5.8, p <0.001) predicted self stomal care. Preoperative education quality (beta = 0.44, p <0.001) and self stomal handling (beta = 0.25, p = 0.02) predicted higher quality of life and an improved psychological impact score. CONCLUSIONS: Only half of the patients with an ileal conduit care for the urostomy independently. Female gender, better patient education and early proficiency in stomal care predict long-term self stomal care. An association exists between self-stomal care and improved quality of life. PMID- 22425043 TI - Editorial comment. PMID- 22425044 TI - Development and initial validation of a disease specific quality of life survey for children with vesicoureteral reflux. AB - PURPOSE: Vesicoureteral reflux is believed to be a largely asymptomatic condition. However, previous studies have failed to assess the precise impact of vesicoureteral reflux on quality of life. We created and validated a survey for assessment of quality of life in children with vesicoureteral reflux. MATERIALS AND METHODS: Two surveys were created by a team of pediatric urologists and survey design specialists, 1 for general assessment and 1 for postoperative assessment in patients undergoing surgical treatment for vesicoureteral reflux. Cronbach alpha test was used to assess internal consistency reliability and the correlation coefficient for test-retest analysis. Surveys were distributed from November 2008 to January 2010 during routine office visits for vesicoureteral reflux. The postoperative survey was distributed 8 to 20 weeks following surgery. RESULTS: The general survey yielded a Cronbach alpha of 0.64 and a correlation coefficient of 0.78, while the postoperative survey results were 0.58 and 0.84, respectively, for the same parameters. Complete general surveys were obtained from 216 patients. All but 4 categories, related to repeat testing, office visits and medicine intake, reached greater than 80% positive quality of life responses. The postoperative survey was completed by 104 patients. Bladder spasm was the only category with less than 86% rate of positive quality of life response. CONCLUSIONS: Vesicoureteral reflux is shown to have little effect on quality of life in pediatric patients. These validated surveys should be applied to compare the effect of different management options on quality of life. PMID- 22425045 TI - Complications and associated factors of pediatric extracorporeal shock wave lithotripsy. AB - PURPOSE: We determined the safety, efficacy and complications of extracorporeal shock wave lithotripsy in managing pediatric urolithiasis and analyzed possible factors affecting the complication rate. MATERIALS AND METHODS: We retrospectively reviewed 128 patients younger than 16 years who had undergone extracorporeal shock wave lithotripsy with a Lithostar(r) lithotripter between January 2000 and December 2010. Stone clearance and complications were assessed at postoperative week 1, and months 1 and 3. Success was defined as no radiological evidence of stone, or fragments 4 mm or less. Treatment failure was analyzed to find any correlation with stone size. Complications were assessed with a specific focus on rehospitalizations during postoperative week 1. RESULTS: The overall success rate was 93.5% (115 of 123 patients). Repeat treatment rate was 56.1% (69 patients). Extracorporeal shock wave lithotripsy failed in 8 children, who subsequently required ancillary procedures. Mean stone size in the treatment failure group was 17.03 mm, compared to 13.04 mm in the successfully treated group. A total of 22 patients (17.8%) had complications in postoperative week 1 but only 19 (15.4%, 12 boys and 7 girls) were rehospitalized at that time. Presence of a metabolic risk factor was the only predictive factor for complications. By comparison, we found a lower success rate and higher ancillary procedure rate in the group with complications. CONCLUSIONS: Extracorporeal shock wave lithotripsy is effective for pediatric urolithiasis, with a small but substantial morbidity rate. Parents should be informed about possible rehospitalization following extracorporeal shock wave lithotripsy due to complications independent of stone size. PMID- 22425046 TI - Therapeutic potential of SOX2 inhibition for embryonal carcinoma. AB - PURPOSE: Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model. MATERIALS AND METHODS: SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model. RESULTS: In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo. CONCLUSIONS: This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor. PMID- 22425047 TI - High pressure balloon dilation of the ureterovesical junction--first line approach to treat primary obstructive megaureter? AB - PURPOSE: We describe the efficacy of dilation of the ureterovesical junction to treat primary obstructive megaureter. MATERIALS AND METHODS: A total of 13 patients with primary obstructive megaureter were treated from May 2008 to December 2010. Of these patients 8 were diagnosed prenatally and the others were diagnosed after a urinary tract infection. Preoperative studies included ultrasonography, voiding cystourethrography despite vesicoureteral reflux and diuretic isotopic renogram (mercaptoacetyltriglycine). With the patient under general anesthesia, high pressure balloon dilation of the ureterovesical junction was performed under direct and fluoroscopic vision until the disappearance of the narrowed ring. A Double-J((r)) catheter was positioned, and 2 months later it was withdrawn and the ureterovesical junction was reviewed. A secondary treatment was performed in those in whom the ureterovesical junction was still narrow. Followup was performed with ultrasonography, cystourethrography and isotopic diuretic renography. RESULTS: A total of 18 procedures were performed in 13 patients (median age 7 months, range 4 to 24). Median diameter of the distal ureter was 14 mm (range 10 to 26), and median diameter of the renal pelvis and calyx was 27 mm (range 10 to 47) and 12 mm (range 9 to 26), respectively. Significant postoperative improvement of hydroureteronephrosis was observed in 11 of 13 patients and vesicoureteral reflux was found in 2. Only 3 patients needed ureteral reimplantation after endoscopic treatment due to hydroureteronephrosis in 2 and high grade vesicoureteral reflux in 1. CONCLUSIONS: High pressure balloon dilation of the ureterovesical junction is effective in treating primary obstructive megaureter, but long-term followup is needed. PMID- 22425048 TI - Complications after use of gastric segments for lower urinary tract reconstruction. AB - PURPOSE: We retrospectively reviewed our experience with the use of gastric segments for lower urinary tract reconstruction with an emphasis on long-term complications. MATERIALS AND METHODS: A total of 29 patients underwent reconstruction of the lower urinary tract using gastric segments between 1993 and 2000. Diagnoses included neurogenic bladder (21), cloacal exstrophy (5), solitary kidney/ectopic ureter (1), posterior urethral valves (1) and rhabdomyosarcoma of prostate (1). Gastric segment was used as gastrocystoplasty (21), composite gastroenteric cystoplasty (6), demucosalized gastrocystoplasty (1) and continent gastric reservoir (1). RESULTS: Mean followup was 13.9 years (range 9 to 16.5). Complications were seen in 15 (51.7%) patients. Seven patients had the hematuria dysuria syndrome, which was intractable in 1 and necessitated excision of the gastric patch. Due to severe complications necessitating major reoperations 3 patients underwent re-augmentation with enteric segments without excision of the gastric tissue (composite). One patient who underwent demucosalized gastrocystoplasty had excision of the gastric tissue and re-augmentation with enteric segment due to contraction of the gastric patch. A stone developed in 1 patient with a composite gastroenteric reservoir. Malignancy developed in the reservoir in 3 patients 11, 12 and 14 years after gastrocystoplasty, and all 3 died of metastasis. CONCLUSIONS: We do not recommend the use of gastric segments for reconstruction of the lower urinary tract due to the high incidence of reoperations and complications. In patients in whom gastric segments were used in the past for lower urinary tract reconstruction, regular surveillance and close followup are strongly advocated. PMID- 22425049 TI - Comparison of intraprostatic ethanol diffusion using a microporous hollow fiber catheter versus a standard needle. AB - PURPOSE: Transurethral intraprostatic ethanol chemoablation of the prostate has shown promising preliminary clinical results for benign prostatic hyperplasia with some variability in clinical outcome. This is likely due to the uneven prostate diffusion caused by varying resistance of the tissue type in which the tip of the needle is embedded. We examined whether the distribution of the injectable in the canine prostate could be improved using a microporous hollow fiber catheter (Twin Star Medical, Minneapolis, Minnesota). MATERIALS AND METHODS: The prostate was exposed in 9 mongrel dogs. A single injection of 98% ethanol was delivered in each lobe using a microporous hollow fiber catheter and a standard needle. Prostates were harvested and fixed in 10% formalin. After injection 2.5 mm step sections were obtained and scanned. The ethanol induced tissue lesions were traced on hematoxylin and eosin sections. Three-dimensional reconstructions were created and the volume of each prostate lesion was calculated using stereology. RESULTS: Ethanol induced tissue changes were seen bilaterally in 8 of 9 ethanol injected prostates. In all cases the lesion created by microporous hollow fiber catheter injection was larger than that in the contralateral lobe injected with the control needle. When data were pooled, the hollow fiber catheter injection produced significantly greater tissue changes than the control needle injection (p = 0.03). CONCLUSIONS: Improved distribution and absent backflow were seen when using the microporous hollow fiber catheter, supporting its potential as a new method to treat prostate disease. PMID- 22425050 TI - Predictive value of decreased renal pelvis anteroposterior diameter in prone position for prenatally detected hydronephrosis. AB - PURPOSE: It is important to differentiate between those cases of prenatally detected hydronephrosis that are significant and those that are likely to resolve spontaneously. We evaluated the anteroposterior pelvic diameter of the renal pelvis postnatally in the supine and prone positions, and determined whether the difference between these 2 positions helps predict the outcome of prenatally detected hydronephrosis. MATERIALS AND METHODS: From May 2009 to June 2011, 38 infants with prenatally detected unilateral ureteropelvic junction type hydronephrosis were evaluated. The anteroposterior pelvic diameter was noted in the supine and prone positions. Functional evaluation was done by radionuclide renogram. Those with a split function of less than 40% underwent pyeloplasty. All other patients were followed by serial ultrasound examination. RESULTS: Six infants had an anteroposterior pelvic diameter larger than 40 mm with no change in diameter in the supine vs prone positions. Seven of 16 infants with an anteroposterior pelvic diameter between 30 and 40 mm, and 11 of 15 infants with an anteroposterior pelvic diameter between 15 and 30 mm had a smaller anteroposterior pelvic diameter in the prone position. These infants had normal renal function, improvement in hydronephrosis and did not need pyeloplasty. All the infants with no change in anteroposterior pelvic diameter in either position had poorer renal function, necessitating pyeloplasty. CONCLUSIONS: Those cases of prenatally detected ureteropelvic junction type of hydronephrosis in which the anteroposterior pelvic diameter is smaller in the prone position than in the supine position showed improvement in hydronephrosis, while those with no change in anteroposterior pelvic diameter had worsening of hydronephrosis and needed surgical intervention. PMID- 22425051 TI - Prospective tracking of pediatric urology consults: knowing is half the battle. AB - PURPOSE: The planned clinical activity of pediatric urologists has been well described. However, little is known about nonscheduled work (eg consultation requests). We describe the unplanned clinical activity of pediatric urologists at a high volume academic medical center. MATERIALS AND METHODS: Demographic data regarding inpatient, operating room and emergency department pediatric urology consults were prospectively entered into an internal database. Consults from July 2008 through June 2010 underwent retrospective chart abstraction to identify reasons for consultation. Bivariate and multivariate statistics were used to evaluate 1) temporal trends in unplanned clinical activity, and 2) patient and service specific factors associated with whether a consult was billable (ie seen by attending physician within 24 hours). RESULTS: During the study period 665 pediatric consults were obtained. Mean +/- SD patient age was 8.4 +/- 7.7 years. Nearly all consults were seen at the emergency department (51%) or the inpatient wards (47%). The most common primary diagnoses were infection, obstruction/hydronephrosis and neurogenic bladder. The number of consults per month decreased during the course of the academic year (r(2) = 0.1422). Nearly three fourths of consults were eligible for billing. The factors associated with consult eligibility for billing included specific attending physician (p = 0.03), location (p <0.0001) and house officer experience (p = 0.007). CONCLUSIONS: At our academic pediatric hospital we averaged nearly 1 unplanned pediatric urology consult per day. Several service specific factors (unrelated to patient diagnosis or acuity) were associated with whether the consult had the potential to generate revenue. Unplanned clinical activity is an important factor to consider when planning departmental funding, staffing and training. PMID- 22425052 TI - Expression and potential clinical significance of urothelial cytodifferentiation markers in the exstrophic bladder. AB - PURPOSE: We characterize the urothelium from patients with classic bladder exstrophy-epispadias complex for the expression of proteins associated with urothelial differentiation, and discuss a potential impact of urothelial phenotype on the structural and functional properties of the bladder template following bladder closure. MATERIALS AND METHODS: From 2005 to 2010 bladder biopsies from 32 infants with bladder exstrophy-epispadias complex obtained at primary bladder closure were collected. After histological assessment immunochemistry was used to investigate the expression of uroplakin IIIa, cytokeratin differentiation restricted antigens CK13 and CK20, and tight junction protein claudin 4. RESULTS: Overall tissue morphology showed gross alterations with inflammatory, proliferative and metaplastic changes in most specimens. Sections of intact epithelium were present in 78% of biopsies. With respect to urothelial phenotype, CK13 was expressed in all specimens, whereas UPIIIa and CK20 were absent in 76% of the tissues examined. Of the biopsies 52% revealed an irregular expression pattern of tight junction protein Cl-4. CONCLUSIONS: This is the first study to our knowledge to characterize the urothelium from infants with bladder exstrophy-epispadias complex for the expression of urothelial differentiation associated antigens. Our findings suggest urothelial differentiation changes in a majority of exstrophic bladders, at least at primary bladder closure. Although the underlying etiology remains to be established, abnormal urothelial differentiation may result in a dysfunctional urothelial barrier with implications for the structural and functional properties of the bladder template. Despite the study limitations, our preliminary findings provide a platform for further investigation of the significance of the urothelium for the exstrophic bladder. PMID- 22425053 TI - Re: improved prediction of long-term, other cause mortality in men with prostate cancer: T. J. Daskivich, K. Chamie, L. Kwan, J. Labo, A. Dash, S. Greenfield and M. S. Litwin, J Urol 2011; 186: 1868-1873. PMID- 22425054 TI - Confocal fluorescence microscopy in a murine model of microdissection testicular sperm extraction to improve sperm retrieval. AB - PURPOSE: Microdissection testicular sperm extraction markedly improves the sperm retrieval rates in men with nonobstructive azoospermia. However, localizing sperm foci can be time-consuming and it is not always successful. Fiberoptic confocal fluorescent microscopy offers the advantage of rapid in vivo detection of fluorescently labeled sperm in the seminiferous tubules. MATERIALS AND METHODS: After establishing the feasibility of fiberoptic confocal fluorescent microscopy to identify antibody labeled sperm in vivo C57/B6 mice underwent intraperitoneal injection of busulfan to induce azoospermia. During spermatogenesis reestablishment at approximately 16 weeks the mice were anesthetized and the testes were delivered through a low midline incision. Fluorescein isothiocyanate labeled antibody to intra-acrosomal protein Hs-14 was injected retrograde into a single murine rete testis. The testes were imaged in vivo with fiberoptic confocal fluorescent microscopy and sperm foci were detected. The respective seminiferous tubules were excised and squash prepared for immunofluorescence microscopy. RESULTS: Sperm foci were identified in the testis injected with fluorescently tagged antibody by in vivo fiberoptic confocal fluorescence microscopy. The contralateral control testis of each mouse showed no specific signal. Immunofluorescence microscopy of the excised tubules provided morphological confirmation of the presence of labeled sperm with an absence in controls. Findings were consistent in the feasibility portion of the study and in the busulfan model of nonobstructive azoospermia. CONCLUSIONS: Fiberoptic confocal fluorescent microscopy was feasible during microdissection testicular sperm extraction in an azoospermic mouse model to identify fluorescently labeled sperm in vivo. Translation to the clinical setting could decrease operative time and improve the sperm harvest rate. PMID- 22425055 TI - Molecular and functional characterization of ORAI and STIM in human corporeal smooth muscle cells and effects of the transfer of their dominant-negative mutant genes into diabetic rats. AB - PURPOSE: We investigated the molecular identity and functional activity of STIM1 and ORAI in human cavernous smooth muscle. We also determined whether transferring dominant negative mutants of the STIM1 or ORAI gene would correct diabetes related erectile dysfunction in a rat model. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction was done to identify ORAI and STIM in human cavernous smooth muscle. For the in vivo study intracavernous pressure, blood pressure and their ratio were assessed after cavernous nerve stimulation to diabetic rats transfected with pcDNA encoding the ORAI1(DN) or the STIM1(DN) gene. RESULTS: ORAI (1, 2 and 3) and STIM (1 and 2) were identified in human cavernous smooth muscle cells. After [Ca(2+)] depletion by thapsigargin and cyclopiazonic acid we recorded store operated Ca(2+) entry in human cavernous smooth muscle cells. Entry was decreased by the store operated Ca(2+) channel blockers La(3+) and SKF96365. Mean +/- SE intracavernous pressure/blood pressure in rats with ORAI1(DN) or STIM1(DN) gene transfer was 78.8% +/- 2.2% and 77.1% +/ 1.2% in 11 and 10, respectively. This result was significantly higher than that in 10 diabetic controls (51.0% +/- 3.7%) and similar to that in 9 normal controls (85.8% +/- 2.6%). Using reverse transcriptase-polymerase chain reaction we confirmed transgene expression in rat cavernous tissue. CONCLUSIONS: Transfer of ORAI(DN) or STIM1(DN) genes restored erectile function in diabetic rats. It might be applicable to develop new therapy for erectile dysfunction. PMID- 22425056 TI - Suppression of bladder overactivity by adenosine A2A receptor antagonist in a rat model of Parkinson disease. AB - PURPOSE: Overactive bladder is highly prevalent among patients with Parkinson disease. Adenosine is an important neurotransmitter in the central nervous system but it is not fully clarified how adenosine receptors regulate the micturition reflex. Thus, we examined the effect of an adenosine A2A receptor antagonist on the micturition reflex in a rat model of Parkinson disease. MATERIALS AND METHODS: In a rat model of Parkinson disease induced by 6-hydroxydopamine (Tocris Bioscience, Ellisville, Missouri) injection we examined the effects of the adenosine A2A receptor antagonist ZM241385, the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole on bladder activity. RESULTS: Intravenous administration of ZM241385 increased the intercontraction interval in a dose dependent manner in rats with Parkinson disease and sham operated rats but the inhibitory effect was greater in the Parkinson disease group. Intrathecal and intracerebroventricular administration of ZM241385 increased the intercontraction interval in each group. However, in rats with Parkinson disease the inhibitory effects induced by intracerebroventricular administration of ZM241385 were greater than in sham operated rats. Intravenous administration of SKF38393 increased the intercontraction interval in rats with Parkinson disease and subsequent administration of ZM further increased the intercontraction interval. However, SKF38393 did not increase the intercontraction interval after ZM241385 application. Also, ZM241385 increased the intercontraction interval without being affected by pre-administration or post-administration of quinpirole, which decreased the intercontraction interval. CONCLUSIONS: Results indicate that the adenosine A2A receptor mediated excitatory mechanism is enhanced at a supraspinal site to induce bladder overactivity and A2A receptor inhibition effectively suppresses bladder overactivity in rats with Parkinson disease. Thus, adenosine A2A receptor antagonists could be useful for bladder dysfunction in Parkinson disease cases. PMID- 22425057 TI - Superior weight loss and lower HbA1c 3 years after duodenal switch compared with Roux-en-Y gastric bypass--a randomized controlled trial. AB - BACKGROUND: Obesity is a rising threat to public health. The relative increase in the incidence of morbid obesity is most pronounced in the most severely obese. Roux-en-Y gastric bypass (RYGB) results in inferior weight loss in this group. Therefore, we have offered biliopancreatic diversion with duodenal switch (BPD/DS) as an alternative for this patient category. Our objective was to compare BPD/DS and RYGB in the surgical treatment of morbid obesity in patients with a body mass index (BMI) >48 kg/m(2). The setting was a university hospital in Sweden. METHODS: In a controlled trial (registration number ISRCTN10940791), 47 patients (25 men, BMI 54.5 +/- 6.1 kg/m(2)) were randomized to RYGB (n = 23) or BPD/DS (n = 24). Biochemical data were collected preoperatively and 1 and 3 years postoperatively. A questionnaire addressing weight, general satisfaction, and gastrointestinal symptoms was distributed a median of 4 years postoperatively. RESULTS: Both procedures were safe. The duration of surgery and postoperative morphine consumption were greater after BPD/DS than after RYGB (157 versus 117 min and 140 versus 93 mg, respectively). BPD/DS resulted in greater weight loss than RYGB (-23.2 +/- 4.9 versus -16.2 +/- 6.9 BMI units or 80% +/- 15% versus 51% +/- 23% excess BMI loss, P <.001). BPD/DS yielded lower glucose and glycated hemoglobin levels at 3 years. More patients listed troublesome diarrhea and malodorous flatus in the questionnaire after BPD/DS, but no significant difference was seen (P = .078 and P = .073, respectively). CONCLUSIONS: BPD/DS produced superior weight results and lower glycated hemoglobin levels compared with RYGB in patients with a BMI >48 kg/m(2). Both operations yield high satisfaction rates. However, diarrhea tended to be more common after BPD/DS. PMID- 22425058 TI - Alcohol and bariatric surgery: review and suggested recommendations for assessment and management. AB - BACKGROUND: Established clinical guidelines identify current alcohol abuse and dependence as contraindications for weight loss surgery. However, guidance on how to best assess alcohol use in bariatric patients has not been elucidated. Furthermore, concerns with postoperative alcohol use/abuse and increased sensitivity warrant the development of recommendations on appropriate interventions for patients pursuing weight loss surgery. Our objective was to review the current data on bariatric surgery and substance abuse/addiction, with an emphasis on alcohol use, offer guidance on how to assess the risk of such problems, and provide preliminary recommendations on treating high-risk patients. METHODS: The relevant published data on alcohol use, abuse, and dependence in pre and postoperative bariatric patients was reviewed. Also, the putative mechanisms of increased alcohol sensitivity after weight loss surgery were examined. RESULTS: Although current alcohol abuse/dependence is less than that in population-base rates, bariatric surgery candidates have a greater history of alcohol use disorders. Physiologic changes after surgery can also change vulnerability to problematic alcohol use, and many patients continue to consume alcohol after surgery. Assessment techniques and strategies to provide informed consent and education on alcohol were included from the Bariatric and Metabolic Institute at the Cleveland Clinic. CONCLUSION: Weight loss surgery candidates might have a greater lifetime risk of alcohol use disorders and greater sensitivity to the intoxicating effects of alcohol after surgery. Adequate screening, assessment, and preoperative preparation could help mitigate this risk. Future research should examine the efficacy of such risk management strategies. PMID- 22425060 TI - Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1--the patients' perspective. AB - Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinil's use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients. PMID- 22425061 TI - The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized. AB - PURPOSE: Patients with familial adenomatous polyposis (FAP) are at increased risk for colorectal cancer and extracolonic neoplasms. The prevalence of thyroid cancer (TC) and benign thyroid disease in this patient population is unclear, and guidelines for screening for TC in these patients are not well established. The purpose of this study was to report the prevalence of TC and benign thyroid disease in patients with FAP. METHODS: The prospectively maintained Hereditary Colorectal Cancer Family Registry at Memorial Sloan-Kettering Cancer Center was queried to identify patients with FAP and with TC and/or benign thyroid disease. RESULTS: Sixty-six patients with FAP were identified. There were 30 men and 36 women, with a median age of 38.6 years. Four (6.1%) patients had a history of TC. All were women, with a mean age at TC diagnosis of 36.5 years. Three of the 4 TCs were papillary thyroid cancer. Two patients with TC presented with palpable nodules. An additional 6 (9.1%) patients with FAP had a history of benign thyroid disease, including nodules (3), hypothyroidism (2), cysts (2), goiter (1), and thyroiditis (1). Three of 4 patients with TC and all 6 patients with benign thyroid disease had other extracolonic manifestations associated with FAP. CONCLUSIONS: The prevalences of TC (6.1%) and benign thyroid disease (9.1%) are increased in our patients with FAP and are higher than noted in some previous reports. Periodic thyroid ultrasound screening should be considered in patients with FAP to further elucidate the prevalence and for possible early detection of TC and benign thyroid disease in this population. PMID- 22425062 TI - Transmission dynamics of an insect-specific flavivirus in a naturally infected Culex pipiens laboratory colony and effects of co-infection on vector competence for West Nile virus. AB - We established a laboratory colony of Culex pipiens mosquitoes from eggs collected in Colorado and discovered that mosquitoes in the colony are naturally infected with Culex flavivirus (CxFV), an insect-specific flavivirus. In this study we examined transmission dynamics of CxFV and effects of persistent CxFV infection on vector competence for West Nile virus (WNV). We found that vertical transmission is the primary mechanism for persistence of CxFV in Cx. pipiens, with venereal transmission potentially playing a minor role. Vector competence experiments indicated possible early suppression of WNV replication by persistent CxFV infection in Cx. pipiens. This is the first description of insect-specific flavivirus transmission dynamics in a naturally infected mosquito colony and the observation of delayed dissemination of superinfecting WNV suggests that the presence of CxFV may impact the intensity of enzootic transmission of WNV and the risk of human exposure to this important pathogen. PMID- 22425063 TI - Objective reduction in adenoid tissue after mometasone furoate treatment. AB - OBJECTIVE: Chronic rhinitis and adenoid hypertrophy are the main causes of nasal obstruction in children and proper treatment of these factors seem essential for controlling nasal obstructive symptoms. This study aims to evaluate the effects of topical mometasone treatment on symptoms and size of adenoid tissue in children with complaints of nasal obstruction and to compare this approach to continuous nasal saline douching plus environmental control alone. METHODS: Fifty one children with nasal obstructive complaints were submitted to a semi structured clinical questionnaire on nasal symptoms, prick test and nasoendoscopy. Nasoendoscopic images were digitalized, and both adenoid and nasopharyngeal areas were measured in pixels. The relation adenoid/nasopharyngeal area was calculated. Patients were subsequently re-evaluated in two different periods: following 40 days of treatment with nasal douching and environmental prophylaxis alone; and after an subsequent 40 day-period, when topical mometasone furoate (total dose: 100MUg/day) was superposed. RESULTS: Nasal symptoms and snoring significantly improved after nasal douching, and an additional gain was observed when mometasone furoate was included to treatment. Saline douching did not influence the adenoid area, whereas a significant reduction on adenoid tonsil was observed after 40 days of mometasone treatment (P<0.0001). CONCLUSION: Nasal saline douching significantly improved nasal symptoms without interfering in adenoid dimension. In contrast, mometasone furoate significantly reduced adenoid tissue, and led to a supplementary improvement of nasal symptoms. PMID- 22425064 TI - Differential expression of Immunoglobulin A in the adenoids of children with and without exudative otitis media. AB - OBJECTIVE: To evaluate the variation of Immunoglobulin A (IgA) levels in the adenoids of children with otitis media with effusion (OME) and the correlation to age. METHODS: A total of 129 children were enrolled in this study, including 60 children with OME and 69 children without OME. The children were divided into two groups according to age: aged <= 4 years (33 children with OME and 39 children without OME) and aged > 4 years (27 children with OME and 30 children without OME). The samples were collected from hypertrophic adenoids, which could cause obstructive symptoms and/or OME. The IgA concentrations were analyzed by immunohistochemistry in the two groups. RESULTS: The expression of IgA in the adenoids of children <= 4 years was significantly lower than in those aged > 4 years. Among children > 4 years, lower levels of IgA in the adenoids were observed in patients with OME than in patients without OME. However, no statistically significant differences in the IgA levels were found between patients aged <= 4 years with and without OME. CONCLUSIONS: The differential expression of IgA in the adenoids between patients with and without OME was correlated to age. PMID- 22425065 TI - Quality of life of residents with dementia in traditional versus small-scale long term care settings: a quasi-experimental study. AB - BACKGROUND: The number of people living with dementia worldwide is increasing, resulting in a need for more residential care. In response to criticism of the traditional medical approach to residential dementia care, many large nursing homes are transforming their traditional care facilities into more home-like small-scale living facilities. OBJECTIVES: This study examined the assumed benefits of small-scale living for residents with dementia, compared to traditional long-term care in the Netherlands and Belgium. The primary outcome was quality of life, divided into nine different domains. DESIGN: The study had a longitudinal design within a one-year time interval. SETTINGS: Five long-term care settings in the Netherlands and Belgium containing four traditional and twelve small-scale living units participated in the study. PARTICIPANTS: Data were obtained from 179 residents with dementia (age>65 years) (Dutch small-scale N=51, traditional N=51, Belgian small-scale N=47, traditional N=30). METHODS: Nurses and nursing assistants were trained to fill in the questionnaires. RESULTS: In the Dutch sample, residents in small-scale settings had higher mean scores on 'social relations', 'positive affect', and 'having something to do' than residents in traditional settings. Moreover, mean scores on 'caregiver relation' and 'negative affect' remained stable over time among residents in small-scale settings, but decreased in traditional settings. These differences could not be explained by differences in behavioural characteristics, behavioural interventions, or social interaction. In the Belgian sample, fewer differences were found between traditional and small-scale settings. Nevertheless, residents in small-scale settings were reported to experience less 'negative affect' than those in traditional settings, which could be explained by differences in depression. Over time, however, residents 'felt more at home' in traditional settings, whereas no such increase was found for small-scale settings. Moreover, the mean quality of life scores on 'restless behaviour', 'having something to do' and 'social relations' decreased in small-scale settings, but remained stable in traditional settings. CONCLUSIONS: Both small-scale and traditional settings appear to have beneficial effects on different domains of quality of life of residents with dementia. Future research should focus more on the quality and content of the care provided, than on the effects of the scale and design of the environment in long-term care settings. PMID- 22425066 TI - Cortical magnetoencephalography of deep brain stimulation for the treatment of postural tremor. AB - The effects of deep brain stimulation (DBS) on motor cortex circuitry in Essential tremor (ET) and Parkinson's disease (PD) patients are not well understood, in part, because most imaging modalities have difficulty capturing and localizing motor cortex dynamics on the same temporal scale as motor symptom expression. Here, we report on the use of magnetoencephalography (MEG) to characterize sources of postural tremor activity within the brain of an ET/PD patient and the effects of bilateral subthalamic nucleus DBS on these sources. Recordings were performed during unilateral and bilateral DBS at stimulation amplitudes of 0 V, 1 V, and 3 V corresponding to no therapy, subtherapeutic, and therapeutic configurations, respectively. Dipole source localization in reference to the postural tremor frequency recorded with electromyography (EMG) showed prominent sources in both right and left motor cortices when no therapy was provided. These sources dissipated as the amplitude of stimulation increased to a therapeutic level (P = 0.0062). Coherence peaks between the EMG and MEG recordings were seen at both 4 Hz, postural tremor frequency, and at 8 Hz, twice the tremor frequency, with no therapy. Both peaks were reduced with therapeutic DBS. These results demonstrate the capabilities of MEG to record cortical dynamics of tremor during deep brain stimulation and suggest that MEG could be used to examine DBS in the context of motor symptoms of PD and of ET. PMID- 22425067 TI - Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis. AB - BACKGROUND: The Expanded Disability Status Scale (EDSS) is the most widely used measure of disability in MS, however because of its limitations surrogate markers of clinical disability progression are of high interest. Transcranial magnetic stimulation (TMS) measures of demyelination and cortical excitability correlate with disability levels in MS. OBJECTIVE: Aim of this study was testing whether paired pulse (pp) TMS represents a reliable surrogate marker to measure clinical disability in MS. METHODS: ppTMS measures of intracortical synaptic transmission such as short interval intracortical inhibition (SICI), long interval intracortical inhibition (LICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF) were collected from 74 patients affected by MS. Correlation of EDSS scores with ppTMS measures was analyzed. RESULTS: EDSS scores correlated with patient's age, disease duration, Motor Evoked Potentials latency and thresholds and SICF measures but not with age of onset, SICI, ICF and LICI. CONCLUSIONS: These findings support a possible use of SICF and MEP latency as surrogate markers of disability in MS. Further research is warranted to determine the role of SICF in the follow up of disease progression and to validate its use as an endpoint in multiple sclerosis clinical trials. PMID- 22425068 TI - The health implications of civic association in Russia. AB - Can civic and political participation influence health outcomes, and if so, does the general aversion to joining community activities have some connection to poor health outcomes in Russia? Using data from surveys of 18,000+ urban Russians conducted from 2003 to 2005 and controlling for a wide range of variables, we find that individuals who join collective civic and political activities report better health than non-joiners and that living in a participatory community may enhance one's health, regardless of one's own participation. PMID- 22425069 TI - Untangling the associations among distrust, race, and neighborhood social environment: a social disorganization perspective. AB - Over the past decade, interest in exploring how health care system distrust is associated with individual health outcomes and behaviors has grown substantially, and the racial difference in distrust has been well documented, with African Americans demonstrating higher distrust than whites. However, relatively little is known about whether the individual-level determinants of distrust differ by various dimensions of distrust, and even less is understood regarding whether the race-distrust association could be moderated by the neighborhood social environment. This study used a dual-dimensional distrust scale (values and competence distrust), and applied social disorganization theory to address these gaps. We combined the 2008 Philadelphia Health Management Corporation's household survey (N = 3746 adult respondents, 51% of which are of African American race) with neighborhood-level data (N = 45 neighborhoods) maintained by the 2000 U.S. Census and the Philadelphia Police Department. Using multilevel modeling, we found that first, after controlling for individual- and neighborhood-level covariates, African American residents have greater values distrust than whites, but no racial difference was found in competence distrust; second, competence distrust is more likely to be determined by personal health status and access to health care services than is values distrust; and third, ceteris paribus, the association between race and values distrust was weakened by the increasing level of neighborhood stability. These results not only indicate that different aspects of distrust may be determined via different mechanisms, but also suggest that establishing a stable neighborhood may ameliorate the level of distrust in the health care system among African Americans. As distrust has been identified as a barrier to medical research, the insight provided by this study can be applied to develop a health care system that is trusted, which will, in turn, improve population health. PMID- 22425070 TI - Functional implications of variation in lumbar vertebral count among hominins. AB - As early as the 1970s, Robinson defined lumbar vertebrae according to their zygapophyseal orientation. He identified six lumbar elements in fossil Sts 14 Australopithecus africanus, one more than is commonly present in modern humans. It is now generally inferred that the modal number of lumbar vertebrae for australopiths and early Homo was six, from which the mode of five in later Homo is derived. The two central questions this study investigates are (1) to what extent do differences in human lumbar vertebral count affect lordotic shape and lumbar function, and (2) what does lumbar number variation imply about lumbar spine function in early hominins? To address these questions, I first outline a biomechanical model of lumbar number effect on lordotic function. I then identify relevant morphological differences in the human modal and extra-modal variants, which I use to test the model. These tests permit evaluation of the human L6 variant as a model for reconstructing early hominin modal number and spine function. Application of the biomechanical model in reconstructing australopith/early Homo lumbar spines highlights shared principles of Euler column strength and sagittal spine flexibility among early and modern hominins. Within modern humans, the extra-modal L6 variant has an extended series of three cranially positioned kyphotic vertebrae and strongly oblique zygapophyseal facets at the last lumbar level. Although they share the same radius and length of lumbar curvature, the L6 variant differs functionally from the L5 mode in its expanded range of sagittal flexion/extension and enhanced resistance to shear. Given the modal number of six lumbar vertebrae in australopiths and early Homo, lumbar spine mobility and strength would have been key properties of vertebral function in early bipeds whose upper and lower body segments were coupled by close approximation of the thorax and iliac crests. PMID- 22425071 TI - A preliminary review of the use of deep peroneal neurectomy for the treatment of painful midtarsal and tarsometatarsal arthritis. AB - This report describes a retrospective analysis of chart and radiographic data pertaining to 10 consecutive cases performed over a 30-month period, undertaken in an effort to evaluate the preliminary efficacy of denervation for pain relief in high-risk surgical candidates with midfoot and tarsometatarsal joint arthritis. Ten patients (13 feet) were treated, and objective and subjective assessments were obtained using an index of subjective patient satisfaction. Results revealed 9 (69.2%) feet from 7 (70%) patients had greater than 75% relief. Two (15.4%) feet from 2 (20%) patients had at least 50% improvement and 2 (15.4%) feet from 1 (10%) patient claimed no relief. Our results indicate that this method of treatment can be an effective way to relieve pain associated with arthrosis involving the midfoot and tarsometatarsal joints. PMID- 22425072 TI - Gender and body mass index as risk factors for bladder perforation during primary transurethral resection of bladder tumors. AB - PURPOSE: Bladder cancer is the second most common tumor of the genitourinary system. Although transurethral resection is the standard diagnostic and therapeutic procedure, it is not morbidity free. Bladder perforation is the second most common complication and it can lead to severe further complications. We evaluated risk factors for bladder perforation in patients treated with transurethral resection of bladder tumors. MATERIALS AND METHODS: We retrospectively studied the records of 1,284 patients with bladder cancer who underwent transurethral resection of bladder tumors between 1986 and 2006. Data on risk factors for bladder perforation, including age, gender, body mass index, nicotine use, gross hematuria, transurethral catheterization, bladder stones, tumor stage and grade, number of tumors and resection weight, were analyzed with the chi-square or Fisher exact test. RESULTS: Of the 49 bladder perforations (3.8%) 89.8% were extraperitoneal and 10.2% were intraperitoneal. The risk of bladder perforation was associated with gender (female and male 7.2% and 2.6%, p <0.001), body mass index (less than 25, 25 to 30 and greater than 30 kg/m(2) 5.5%, 3.4% and 0.6%, p = 0.016), tumor stage (pTis, pTa, pT1 and pT2 or greater 3.7%, 2.6%, 4.5% and 6.7%, p = 0.049), infiltration depth (superficial and muscle invasive 3.2% and 6.6%, p = 0.023) and resection weight (less than 2.5 and 20 gm or greater 2.4% and 9.2%, respectively, p = 0.003). Patient age, nicotine use, gross hematuria at diagnosis, transurethral catheterization, bladder stones, number of tumors and tumor grade were not risk factors for bladder perforation. CONCLUSIONS: Aside from tumor characteristics female gender and low body mass index were risk factors for inadvertent bladder perforation during transurethral resection of bladder tumors. Each factor is readily apparent. PMID- 22425073 TI - Editorial comment. PMID- 22425074 TI - Half of visible and half of recurrent visible hematuria cases have underlying pathology: prospective large cohort study with long-term followup. AB - PURPOSE: Visible hematuria has a cancer yield of up to 24.2%. A large proportion of cases will have no etiology. In this study we determined the incidence of pathology (benign and malignant) in patients with visible hematuria and those with persistent and recurrent visible hematuria, and evaluated the policy for investigations. MATERIALS AND METHODS: Data were prospectively collected for 1,804 patients with visible hematuria at a United Kingdom teaching hospital from January 1999 to September 2007. In October 2010 the comprehensive hospital electronic database was checked for every individual patient to ensure no urological pathology was missed. All patients underwent standard hematuria investigations, including renal tract ultrasound and excretory urography or contrast enhanced computer tomography urogram, flexible cystoscopy and urine cytology. RESULTS: The male-to-female ratio was 4.8:1. Median age +/- SD was 67 +/- 17.0 years (range 21 to 109). Median followup was 6.6 +/- 2.5 years (range 1.5 to 11.6). No urological pathology was found in 965 (53.5%) patients. Malignant urological disease was found in 386 (21.4%) patients, of whom 329 had bladder tumors. There were 32 patients with persistent visible hematuria and no malignancy. Repeat investigation was performed in 69 patients reporting recurrence. Of these patients 35 received a significant urological diagnosis, including 12 (17.4%) urological malignancies, while 34 (49.3%) still had no diagnosis. Limitations include the possibility of missing pathology. CONCLUSIONS: Almost 50% of patients presenting with visible hematuria will have a diagnosis. Therefore, all cases of visible hematuria require full standard investigations. Patients with no diagnosis can be discharged from followup. Recurrent visible hematuria after full initial negative findings requires repeat full standard investigations because 11.6% will have malignant pathology. PMID- 22425075 TI - Editorial comment. PMID- 22425076 TI - Editorial comment. PMID- 22425077 TI - Is bilateral extended pelvic lymphadenectomy necessary for strictly unilateral invasive bladder cancer? AB - PURPOSE: We determined the necessary extent of pelvic lymph node dissection in patients with strictly unilateral bladder cancer. MATERIALS AND METHODS: A total of 40 patients with cystectomy and unilateral bladder cancer preoperatively underwent flexible cystoscopy guided injection of radioactive technetium into the contralateral bladder wall. Preoperatively single photon emission computerized tomography was done in all cases to detect and localize radioactive lymph nodes. Radioactive lymph nodes were confirmed intraoperatively by a gamma probe and removed separately. Backup extended pelvic lymph node dissection and ex vivo examination of the whole specimen with a gamma camera were done to preclude missed radioactive lymph nodes. Single photon emission computerized tomography and intraoperative findings were used to generate a 3-dimensional projection model of each lymph node site. RESULTS: A total of 228 radioactive lymph nodes (median 6, range 1 to 17) were detected, including 193 (85%) on the ipsilateral side of injection and 35 (15%) on the contralateral side. Of the contralateral lymph nodes 6%, 5% and 4% were in the external iliac, obturator fossa and common iliac region, respectively, but none were in the contralateral internal iliac region. At least 1 radioactive lymph node per patient was detected on the ipsilateral side. Additional lymphatic drainage to the contralateral side was found in 40% of patients. CONCLUSIONS: Crossover lymphatic drainage is a common phenomenon and unilateral pelvic lymph node dissection would have missed radioactive lymph nodes in 40% of patients. However, we noted no lymphatic drainage to the contralateral internal iliac region. Thus, when bladder tumors are strictly unilateral, contralateral pelvic lymph node dissection can be limited to the obturator fossa, and the external and common iliac regions. Consequently preserving the contralateral autonomic nerves situated close to the internal iliac vessels does not compromise surgical radicality. PMID- 22425078 TI - External validation of a nomogram using RENAL nephrometry score to predict high grade renal cell carcinoma. AB - PURPOSE: A novel nomogram using the RENAL ([R]adius maximal diameter in cm, [E]xophytic/endophytic properties, [N]earness of the tumor to the collecting system or sinus in mm, [A]nterior/Posterior, [L]ocation relative to the polar lines and [H]ilar) nephrometry score was developed to predict high grade renal cell carcinoma. It showed good performance in internal evaluation. We externally validated the prediction model. MATERIALS AND METHODS: We identified a cohort of 391 Chinese patients in whom renal cell carcinoma was surgically resected at our institution from 2008 to 2011. Fuhrman grade was reviewed by an experienced genitourinary pathologist and radiological images were independently assessed by 2 senior urologists. Using a 2-tiered system high grade disease was defined as Fuhrman grade III/IV. The statistical performance of the prediction model was evaluated by discrimination, calibration and clinical usefulness. RESULTS: Of the 391 patients 45.5% were considered to have high grade tumors. External validation of the nomogram revealed an AUC of 0.73. The calibration plot showed that the predicted probability of high grade disease had concordance comparable to the observed frequency. On decision curve analysis the prediction model provided a superior net benefit and reduction at a greater than 20% probability threshold. CONCLUSIONS: We confirm the predictive value of the nomogram using the RENAL nephrometry score to identify high grade renal cell carcinoma in an independent cohort. Further research is required to evaluate its performance using a head-to head comparison with renal biopsy results. PMID- 22425079 TI - Radical prostatectomy outcome in men 65 years old or older with low risk prostate cancer. AB - PURPOSE: A recent update of the Scandinavian Prostate Cancer Group Study-4 concluded that men older than 65 years treated with radical prostatectomy had no survival advantage compared to men treated with watchful waiting. We examined the proportion and outcomes of men 65 years old or older with low risk disease who underwent radical prostatectomy at our institution. MATERIALS AND METHODS: Our institutional radical prostatectomy database with more than 19,000 patients was queried for men 65 years old or older with low risk prostate cancer. Pathological and survival outcomes were assessed. Subanalysis was done on men 70 years old or older to determine whether outcomes among older men differed by age. RESULTS: A total of 1,560 men (8.1%) 65 years old or older with low risk prostate cancer underwent radical prostatectomy between 1983 and 2010. After radical prostatectomy 38.3% of the men had evidence of more aggressive cancer, including Gleason score 7 or greater, or extraprostatic extension. After radical prostatectomy actuarial 5, 10 and 15-year biochemical recurrence-free survival was 93.2%, 89.2% and 82.2%, prostate cancer specific survival was 99.7%, 98.4% and 97.2%, and overall survival was 96.1%, 83.5% and 60.2%, respectively. CONCLUSIONS: Fewer than 10% of men treated with radical prostatectomy at our institution were 65 years old or older with low risk prostate cancer. Despite a high prevalence of aggressive disease discovered at surgery these men experienced excellent long-term survival. Treatment recommendations in older men with low risk prostate cancer should be made after careful consideration of life expectancy based on comorbidities and potential adverse outcomes of treatment. PMID- 22425080 TI - The impact of collateral damage on urological care. PMID- 22425081 TI - Editorial comment. PMID- 22425082 TI - Editorial comment. PMID- 22425083 TI - Effect of central obesity on prostate specific antigen measured by computerized tomography: related markers and prostate volume. AB - PURPOSE: We assessed the effects of central adiposity represented by visceral adipose tissue on prostate volume, prostate specific antigen, and prostate specific antigen mass and mass ratio. MATERIALS AND METHODS: This cross-sectional study included 6,389 Asian men 30 to 79 years old. Prostate volume was estimated by transrectal ultrasound. Visceral and subcutaneous adipose tissue was measured by computerized tomography. Multivariate linear regression analysis was done between prostate specific antigen related variables and obesity indexes such as body mass index, waist circumference, and visceral and subcutaneous adipose tissue after adjusting for age. RESULTS: Body mass index, waist circumference and subcutaneous adipose tissue were inversely associated with prostate specific antigen (p for trend <0.001) but visceral adipose tissue showed no associations with prostate specific antigen (p for trend = 0.740). Waist circumference, and visceral and subcutaneous adipose tissue were positively associated with prostate specific antigen mass (p for trend = 0.014, <0.001 and 0.036, respectively). However, body mass index did not show this association (p for trend = 0.372). Body mass index, waist circumference and subcutaneous adipose tissue negatively affected the prostate specific antigen mass ratio (each p for trend <0.05) but there was no such significant correlation for visceral adipose tissue (p for trend = 0.187). When adjusted for visceral adipose tissue body mass index was not associated with prostate volume (p for trend = 0.152) but visceral adipose tissue remained positively associated with prostate volume even after adjusting for body mass index (p for trend = 0.005). CONCLUSIONS: Visceral adiposity is the main determining factor of the prostate volume increase and prostate specific antigen production. PMID- 22425084 TI - Tissue engineered oral mucosa for urethroplasty: past experience and future directions. PMID- 22425085 TI - Factors affecting kidney function and stone recurrence rate after percutaneous nephrolithotomy for staghorn calculi: outcomes of a long-term followup. AB - PURPOSE: There are few studies of the long-term outcome of percutaneous nephrolithotomy for staghorn calculi. We report the long-term outcome of percutaneous nephrolithotomy in patients with staghorn calculi. MATERIAL AND METHODS: A total of 265 study patients (272 renal units) were followed in the long term for greater than 12 months. The estimated glomerular filtration rate was calculated using the 4-variable modification of diet in renal disease equation. Cases were staged for chronic kidney disease by National Kidney Foundation guidelines. The impact of patient and procedure related factors on renal function as well as stone recurrence was analyzed retrospectively. RESULTS: At a mean +/- SD followup of 37.3 +/- 25.4 months the chronic kidney disease stage classification was maintained in 177 patients (66.8%) while the classification of 34 (12.8%) and 54 (20.4%) had improved and deteriorated, respectively. Multivariate analysis revealed that an immediate postoperative change in the estimated glomerular filtration rate was the only factor predicting a change in renal function in the long term. Stones recurred in 73 of the 234 kidneys (31.2%) that were stone free 3 months after percutaneous nephrolithotomy. Stone size increased in 24 of the 38 kidneys (63.2%) with residual stones after intervention. Recurrent urinary infections during followup and diabetes were associated with stone recurrence and residual stone enlargement. CONCLUSIONS: In almost 80% of patients with staghorn stones renal function was improved or maintained after percutaneous nephrolithotomy, as documented during long-term followup. Stones recurred in a third of the patients with staghorn calculi. PMID- 22425086 TI - Editorial comment. PMID- 22425087 TI - Editorial comment. PMID- 22425088 TI - Clinical and demographic characteristics associated with prostate cancer progression in patients on active surveillance. AB - PURPOSE: Active surveillance is an established management option for patients with low risk prostate cancer. However, little is known about the characteristics associated with the increased probability of progression in patients on active surveillance. We analyzed our active surveillance cohort in search of such features. MATERIALS AND METHODS: A total of 272 men with prostate cancer have enrolled in our active surveillance program since 1994, of whom 249 underwent at least 1 surveillance biopsy and were included in analysis. Our active surveillance inclusion criteria are biopsy Gleason grade less than 7, 2 or fewer positive biopsy cores, 20% or less tumor in any core and clinical stage T1-T2a. Changes in any of these parameters during followup that went beyond these limits were considered progression. Univariate and multivariate Cox regression analysis was done to determine patient characteristics associated with an increased risk of progression. RESULTS: A total of 64 patients (26%) showed progression at a median 2.9-year followup on a mean of 2.3 surveillance biopsies. The progression risk was significantly increased in black patients (adjusted HR 3.87-4.12), and in men with a smaller prostate and higher prostate specific antigen density. The latter 2 variables had no specific cutoff for an association with progression. CONCLUSIONS: Black men with low risk prostate cancer should be advised that the risk of progression on active surveillance may be higher than that in the available literature. Integral prognostic tools incorporating race and prostate specific antigen density may be useful to accurately assess the individual risk of progression in patients on active surveillance. PMID- 22425089 TI - The impact of varicocelectomy on sperm parameters: a meta-analysis. AB - PURPOSE: We determined the impact of 3 surgical techniques (high ligation, inguinal varicocelectomy and the subinguinal approach) for varicocelectomy on sperm parameters (count and motility) and pregnancy rates. MATERIALS AND METHODS: By searching the literature using MEDLINE and the Cochrane Library with the last search performed in February 2011, focusing on the last 20 years, a total of 94 articles published between 1975 and 2011 reporting on sperm parameters before and after varicocelectomy were identified. Inclusion criteria for this meta-analysis were at least 2 semen analyses (before and 3 or more months after the procedure), patient age older than 19 years, clinical subfertility and/or abnormal semen parameters, and a clinically palpable varicocele. To rule out skewing factors a bias analysis was performed, and statistical analysis was done with RevMan5((r)) and SPSS 15.0((r)). RESULTS: A total of 14 articles were included in the statistical analysis. All 3 surgical approaches led to significant or highly significant postoperative improvement of both parameters with only slight numeric differences among the techniques. This difference did not reach statistical significance for sperm count (p = 0.973) or sperm motility (p = 0.372). After high ligation surgery sperm count increased by 10.85 million per ml (p = 0.006) and motility by 6.80% (p <0.00001) on the average. Inguinal varicocelectomy led to an improvement in sperm count of 7.17 million per ml (p <0.0001) while motility changed by 9.44% (p = 0.001). Subinguinal varicocelectomy provided an increase in sperm count of 9.75 million per ml (p = 0.002) and sperm motility by 12.25% (p = 0.001). Inguinal varicocelectomy showed the highest pregnancy rate of 41.48% compared to 26.90% and 26.56% after high ligation and subinguinal varicocelectomy, respectively, and the difference was statistically significant (p = 0.035). CONCLUSIONS: This meta-analysis suggests that varicocelectomy leads to significant improvements in sperm count and motility regardless of surgical technique, with the inguinal approach offering the highest pregnancy rate. PMID- 22425090 TI - Radical prostatectomy in Austria from 1992 to 2009: an updated nationwide analysis of 33,580 cases. AB - PURPOSE: We analyzed the demographics and outcome of radical prostatectomy in Austria in a nationwide series. MATERIALS AND METHODS: We analyzed the records of all 33,580 patients who underwent radical prostatectomy at a public hospital, including 95% of all surgical procedures, in Austria between 1992 and 2009. Patient demographics, perioperative mortality, interventions for anastomotic strictures and urinary incontinence, and overall survival were determined. Data were provided by the Austrian Health Institute. RESULTS: The annual number of radical prostatectomies increased 688% from 396 in 1992 to 3,123 in 2007 and gradually decreased to 2,612 in 2009. Mean +/- SD patient age at surgery decreased slightly from 64.4 +/- 6.3 years in 1992 to 62.0 +/- 6.7 years in 2003. Age has remained at that level since then. Endourological intervention for anastomotic stricture and urinary incontinence was done in 7.5% and 2.8% of cases, respectively. The risk of each intervention increased with patient age and decreased in patients treated within the last 10 years compared to those treated before 2000. The 30-day mortality rate was 0.1%, which increased threefold from the youngest to the oldest age group. Ten-year overall survival decreased from 93% in patients 45 to 49 years old to 63% in those 70 years old or older at surgery. CONCLUSIONS: This nationwide analysis of a country that has had a public, equal access health care system for decades describes some current radical prostatectomy trends. Since 2007, the absolute number of radical prostatectomies has decreased. Data on morbidity, perioperative mortality and overall survival raise caution about performing radical prostatectomy in elderly men, eg those 70 years old or older. PMID- 22425091 TI - Transurethral holmium laser enucleation versus transurethral resection of the prostate and simple open prostatectomy--which procedure is faster? AB - PURPOSE: The longer operative time of holmium laser enucleation of the prostate compared to transurethral resection of the prostate or simple open prostatectomy reported in the literature might have been biased by the unavailability of a soft tissue morcellator, limited surgical experience with holmium laser prostate enucleation or the fact that significantly more tissue was removed by enucleation than by resection. We objectively compared the resection speed of contemporary holmium laser enucleation vs transurethral resection of the prostate and of holmium laser enucleation vs simple open prostatectomy. MATERIALS AND METHODS: The study cohort consisted of 100 cases of transurethral prostate resection and 60 of simple open prostatectomy from our previous randomized, controlled trials. These cases were subjected to matched pair analysis with greater than 1,000 from our prospective contemporary database on holmium laser prostate enucleation. Exact matches were made for the same amount of resected tissue. In all contemporary holmium laser enucleation cases a mechanical soft tissue morcellator was used. We calculated and compared the specific resection speed in gm per minute and operative time for the same amount of resected tissue. RESULTS: In groups 1 and 2 we matched 99 exact laser enucleation-transurethral resection pairs and 53 exact laser enucleation-simple open prostatectomy pairs, respectively. Resection speed and operative time for laser enucleation were statistically significantly faster than for resection (0.61 vs 0.51 gm per minute and 62 vs 73 minutes, p <0.01) and similar to those of simple open prostatectomy (0.92 vs 1.0 gm per minute and 101 vs 90 minutes, respectively, p >=0.21). CONCLUSIONS: Resection speed seems to be an objective criterion for comparing the efficacy of prostatic tissue removal. Based on resection speed holmium laser enucleation of the prostate is faster than transurethral resection of the prostate and similar to simple open prostatectomy. PMID- 22425093 TI - Editorial comment. PMID- 22425094 TI - Hospital volume, utilization, costs and outcomes of robot-assisted laparoscopic radical prostatectomy. AB - PURPOSE: Although robot-assisted laparoscopic radical prostatectomy has been aggressively marketed and rapidly adopted, there is a paucity of population based utilization, outcome and cost data. High vs low volume hospitals have better outcomes for open and minimally invasive radical prostatectomy (robotic or laparoscopic) but to our knowledge volume outcomes effects for robot-assisted laparoscopic radical prostatectomy alone have not been studied. MATERIALS AND METHODS: We characterized robot-assisted laparoscopic radical prostatectomy outcome by hospital volume using the Nationwide Inpatient Sample during the last quarter of 2008. Propensity scoring methods were used to assess outcomes and costs. RESULTS: At high volume hospitals robot-assisted laparoscopic radical prostatectomy was more likely to be done on men who were white with an income in the highest quartile and age less than 50 years than at low volume hospitals (each p <0.01). Hospitals at above the 50th volume percentile were less likely to show miscellaneous medical and overall complications (p = 0.01). Low vs high volume hospitals had longer mean length of stay (1.9 vs 1.6 days) and incurred higher median costs ($12,754 vs $8,623, each p <0.01). CONCLUSIONS: Demographic differences exist in robot-assisted laparoscopic radical prostatectomy patient populations between high and low volume hospitals. Higher volume hospitals showed fewer complications and lower costs than low volume hospitals on a national basis. These findings support referral to high volume centers for robot-assisted laparoscopic radical prostatectomy to decrease complications and costs. PMID- 22425095 TI - The effect of sunitinib on primary renal cell carcinoma and facilitation of subsequent surgery. AB - PURPOSE: We investigated the effect of sunitinib on locally advanced primary renal carcinoma tumors and the ability to facilitate subsequent surgery. MATERIALS AND METHODS: Patients with an unresectable primary renal tumor, with or without distant metastases, received 50 mg sunitinib with continuous daily dosing in a phase II trial. Computerized tomography was performed every 12 weeks to determine surgical resectability. The primary end point of the trial was the percentage of patients with renal cell carcinoma and initially unresectable primary tumors who could undergo nephrectomy after sunitinib therapy. RESULTS: Of 30 patients enrolled in the study (19 with distant metastases) 28 (35 total renal tumors) were evaluable for response. The median change in primary renal cell carcinoma tumors was a 22% decrease, corresponding to a median absolute reduction of 1.2 cm. The median reduction in primary renal cell carcinoma tumors of clear cell histology was -28% (absolute reduction 1.7 cm) compared to a 1.4% increase (0.1 cm absolute increase) in nonclear cell tumors. Of these patients 13 (45%) met the primary end point of being able to undergo nephrectomy after preoperative sunitinib. All patients had viable renal cell carcinoma in the surgical specimen and surgical morbidity was consistent with prior experience of nephrectomy in patients without preoperative therapy. CONCLUSIONS: Sunitinib as initial therapy in patients with locally advanced features of the primary tumor was feasible and resulted in an antitumor effect that enabled subsequent surgery in a subset of patients. Further prospective study is required to refine the most suitable application of this approach. PMID- 22425096 TI - Cost-effectiveness of fluorescent cystoscopy for noninvasive papillary tumors: pro. PMID- 22425097 TI - Vaginal mesh explantation: an emerging urological discipline. PMID- 22425098 TI - Whither the long march of LESS. PMID- 22425099 TI - The role of ultrasound in predicting surgical intervention for prenatal hydronephrosis. PMID- 22425101 TI - A critical assessment of post-prostatectomy prostate specific antigen doubling time acceleration--is it stable? AB - PURPOSE: We examined a retrospective cohort of patients with biochemical recurrence after prostatectomy to determine whether prostate specific antigen doubling time would remain stable with time. We also examined the relationship between other clinical parameters and the change in prostate specific antigen doubling time. MATERIALS AND METHODS: We retrospectively reviewed the prostate cancer database from 1989 to 2008 to identify patients treated with radical prostatectomy for prostate cancer who experienced prostate specific antigen recurrence. Of the 2,237 patients identified 329 had biochemical recurrence. Prostate specific antigen doubling time was calculated at each visit and linear regression of prostate specific antigen doubling time with time was fit. Rate of change in prostate specific antigen doubling time was defined as the slope of the least squares regression line. RESULTS: Median followup was 5 years (range 0.2 to 18). High Gleason score and local recurrence within 5 years were significantly associated with shorter 2-year prostate specific antigen doubling time and a decreased rate of change in doubling time (p = 0.0096, 0.0119, 0.0195 and 0.0258, respectively). Metastasis within 5 years was significantly associated with shorter 2 and 5-year doubling time (p = 0.0006 and 0.0014, respectively). Using all prostate specific antigen values within 5 years of initial biochemical recurrence yielded an overall median prostate specific antigen doubling time of 52.8 months (range 5.4 to 100.0). The median rate of change in doubling time was 1.05 (range -64.7 to 27.0). Median time to metastasis after biochemical recurrence was 12.9 years. CONCLUSIONS: Median prostate specific antigen doubling time decreases with time. This may influence the decision to offer secondary therapy to patients with biochemical recurrence sooner since initial prostate specific antigen doubling time is long and may not accurately reflect the biological nature of the disease. PMID- 22425102 TI - Decrease in and management of urolithiasis after kidney transplantation. AB - PURPOSE: Urolithiasis after kidney transplantation can involve several contributing factors and the treatment strategy is open to question. We determined the incidence and management of urolithiasis in kidney recipients. MATERIALS AND METHODS: We retrospectively reviewed a single center series of 3,000 kidney graft recipients during 32 years to identify those with urolithiasis. We analyzed data by the prevalence per decade, including perioperative procedures (preoperative assessment, anastomosis type and urinary drainage) and long-term followup (urinary stenosis, time to presentation, size, site, treatment type, renal function and survival). RESULTS: We identified 31 cases and noted a significant decrease in incidence from 2.1% to 0.6% during the 3 decades. Excluding 4 cases of donor in situ stones the mean time to diagnosis was 8.5 years. Surgical risk factors were ureteral obstruction in 41% of cases, infravesical obstruction in 14% and urinary-digestive anastomosis in 14%. A total of 12 cases (38%) were observed exclusively with 2 of spontaneous passage. With minor adaptations all mini-invasive procedures, including extracorporeal shock wave lithotripsy, endoscopy and percutaneous nephrolithotomy, were feasible in graft recipients. Antegrade procedures were facilitated by the ventral position of the graft. Eight patients (25%) were treated with open surgical ureteroureteral anastomosis. CONCLUSIONS: Prevention with a perioperative Double J(r) stent and early treatment of ureteral obstruction have decreased and stabilized the urolithiasis rate at around 0.6%. Careful surveillance or any currently available instrumental treatments of urinary stones can be valid options. PMID- 22425103 TI - Impact of nutritional factors on incident kidney stone formation: a report from the WHI OS. AB - PURPOSE: Increased fluid intake, and decreased dietary sodium and animal protein intake are thought to reduce the risk of kidney stones but the role of calcium intake is controversial. We evaluated the relationship between dietary factors and incident kidney stone formation. MATERIALS AND METHODS: Secondary analysis was done of 78,293 women from the prospective WHI OS (Women's Health Initiative Observational Study) with no history of nephrolithiasis who completed the validated food frequency questionnaire. Multivariate logistic regression was used to determine demographic and dietary factors, and supplement use independently associated with incident kidney stones. RESULTS: Overall 1,952 women (2.5%) reported an incident kidney stone in 573,575 person-years of followup. The risk of incident kidney stones was decreased by 5% to 28% (p = 0.01) with higher dietary calcium intake and by 13% to 31% (p = 0.002) with higher water intake after adjusting for nephrolithiasis risk factors. Conversely higher dietary sodium intake increased the risk of nephrolithiasis by 11% to 61% (p <0.001) after adjustment with the most pronounced effect in women with the highest intake. Higher body mass index independently increased the risk of incident nephrolithiasis (adjusted OR 1.19-2.01, p <0.001). Animal protein intake was not associated with nephrolithiasis on multivariate analysis. CONCLUSIONS: This study adds to the growing evidence underscoring the importance of maintaining adequate fluid and dietary calcium intake. Greater dietary calcium intake significantly decreased the risk of incident kidney stones. In contrast, excess sodium intake increased the risk of incident nephrolithiasis, especially in women with the highest intake. Animal protein intake was not independently associated with nephrolithiasis. PMID- 22425104 TI - Editorial comment. PMID- 22425105 TI - National practice patterns for immediate postoperative instillation of chemotherapy in nonmuscle invasive bladder cancer. AB - PURPOSE: We assessed the use of intravesical postoperative chemotherapy among United States urologists in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A national sample of United States based urologists (259) retrospectively assessed their practice patterns involving intravesical postoperative chemotherapy after transurethral resection in patients with nonmuscle invasive bladder cancer. These urologists reviewed the medical records of their last 4 patients with nonmuscle invasive bladder cancer, and completed a case report form for specific demographic, pathological and treatment information. Selection criteria included the pathological and patient factors of histologically confirmed diagnosis of nonmuscle invasive bladder cancer transitional cell carcinoma, completion of initial treatment plan with ongoing observation, candidate for or recipient of intravesical therapy, and no ongoing initial intravesical induction therapy. RESULTS: Overall the participation rate among those sampled was 61%. Of the 1,010 eligible patients with nonmuscle invasive bladder cancer 59.6% received instillation therapy during the initial treatment, of whom 28.4% (16.9% of patients overall) received intravesical postoperative chemotherapy. Primary, low risk patients most often received intravesical postoperative chemotherapy and 90.4% of the time patients received immediate instillation within 12 hours of surgery. However, of the urologists surveyed 66% never used intravesical postoperative chemotherapy, 17% used intravesical postoperative chemotherapy half (50%) of the time and only 2% used intravesical postoperative chemotherapy all (100%) of the time. CONCLUSIONS: Wide variation in the use of intravesical postoperative chemotherapy exists among urologists in the United States. The reason for the great diversity in the use of intravesical postoperative chemotherapy is speculative. However, physician awareness, physician bias, recurrence risk, and local pharmacy and hospital practice factors are all likely contributing factors. PMID- 22425106 TI - Editorial comment. PMID- 22425107 TI - Editorial comment. PMID- 22425108 TI - Editorial comment. PMID- 22425109 TI - Editorial comment. PMID- 22425111 TI - Editorial comment. PMID- 22425112 TI - Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry. AB - PURPOSE: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range. MATERIALS AND METHODS: Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined. RESULTS: All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group. CONCLUSIONS: Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined. PMID- 22425113 TI - The effect of elective sham dose escalation on the placebo response during an antimuscarinic trial for overactive bladder symptoms. AB - PURPOSE: We analyzed the effects of baseline symptom severity and placebo response magnitude on the decision to dose escalate in a 12-week, randomized, double-blind, flexible dose antimuscarinic trial of subjects with overactive bladder symptoms. MATERIALS AND METHODS: Data from the placebo arm of the trial were used for this post hoc analysis. Subjects could elect dose escalation at week 2. Those in the placebo arm received sham escalation. RESULTS: Most placebo treated subjects who continued to week 2 elected dose escalation (75% or 325 of 435). Overactive bladder symptoms at baseline were similar between placebo escalators and nonescalators. Nonescalators showed a significantly larger placebo response than escalators, as measured by improvements in bladder diary end points and patient reported outcomes, and by the incidence rate of adverse events before and after sham escalation. CONCLUSIONS: These findings suggest that the decision to dose escalate among placebo treated subjects is independent of baseline symptom severity but may be influenced by the placebo response magnitude for efficacy assessment and adverse events. Placebo nonescalators showed a rapid, large placebo response while placebo escalators showed a smaller placebo response even after sham escalation. These observations may have important implications for the design and interpretation of flexible dose trials using a placebo control. PMID- 22425114 TI - Purely transvaginal/perineal management of complications from commercial prolapse kits using a new prostheses/grafts complication classification system. AB - PURPOSE: Commercial prolapse mesh kits are increasingly used in the management of pelvic organ prolapse. We present our experience with the transvaginal/perineal management of synthetic mesh related complications from prolapse kits. In addition, we used the new ICS/IUGA (International Continence Society/International Urogynecological Association) prostheses/grafts complication classification system to report on our contemporary series. MATERIALS AND METHODS: A retrospective chart review of all patients who underwent surgical removal of transvaginal mesh for mesh related complications after prolapse kit use from November 2006 to April 2010 at 1 institution was performed. We report our contemporary series of mesh complications using the new ICS/IUGA prostheses/grafts complication classification system. Postoperative pain, degree of improvement and presence of continued symptoms were reported by patients at last followup. RESULTS: A total of 23 patients underwent transvaginal removal of mesh during the study period. Mean patient age was 61 years. Median period of latency to mesh related complication was 10 months (range 1 to 27). Indications for mesh removal included vaginal/pelvic pain (39%), dyspareunia (39%), vaginal mesh extrusion/exposure (26%), urinary incontinence (35%), recurrent pelvic organ prolapse (22%), bladder mesh perforation with recurrent urinary tract infection (22%), rectal mesh perforation (4%), ureteral perforation injury (4%), retained foreign body (surgical sponge) in the bladder (4%) and vesicovaginal fistula (9%), with most patients citing more than 1 reason. CONCLUSIONS: Although technically difficult in some cases, purely transvaginal mesh excision appears to be safe with resolution of almost all presenting symptoms. Although slightly cumbersome, the new ICS/IUGA prostheses/graft complication classification system can be used to report and more accurately characterize mesh complications. PMID- 22425115 TI - Repeat transurethral manipulation of bulbar urethral strictures is associated with increased stricture complexity and prolonged disease duration. AB - PURPOSE: We examined the association of previous transurethral manipulation with stricture complexity and disease duration among men referred for bulbar urethral reconstruction. MATERIALS AND METHODS: We retrospectively reviewed the records of 340 consecutive urethroplasties performed by a single surgeon between July 2007 and October 2010. Only men treated with initial open surgery for bulbar strictures were included in analysis, thus excluding those with hypospadias, lichen sclerosus, pelvic radiation, prior urethroplasty, incomplete data, or pure penile or posterior urethral stenosis. Cases were divided into 2 groups based on the history of transurethral treatment for urethral stricture before urethroplasty, including group 1-0 or 1 and group 2-2 or greater treatments. RESULTS: Of 101 patients with bulbar urethral stricture and all data available 50 and 51 underwent 0 to 1 and 2 or greater previous transurethral treatments, respectively. Repeat transurethral manipulation was strongly associated with longer strictures and the need for complex reconstruction. Repeat transurethral manipulation of bulbar urethral strictures was also associated with an eightfold increase in disease duration between stricture diagnosis and curative urethroplasty. CONCLUSIONS: Repeat transurethral manipulation of bulbar strictures is associated with increased stricture complexity and a marked delay to curative urethroplasty. PMID- 22425116 TI - Seasonality of testicular torsion: a 10-year nationwide population based study. AB - PURPOSE: Using a 10-year nationwide data set, we examined seasonal variability in the monthly incidence of testicular torsion in Taiwan. We also investigated the association between meteorological factors (ambient temperature, relative humidity, atmospheric pressure, rainfall and total hours of sunshine) and testicular torsion, stratified by age group. MATERIALS AND METHODS: This study retrieved data from the National Health Insurance Research Database. We identified 1,782 hospitalizations for testicular torsion between 2000 and 2009. Spearman's rank correlation was used to explore possible associations between climatic parameters and the monthly incidence of testicular torsion. In addition, we used the ARIMA method (Auto-Regressive Integrated Moving Average) to test for seasonality in the incidence of testicular torsion. RESULTS: The results demonstrated a fairly similar seasonal pattern in monthly incidence rates for testicular torsion across both age groups and the combined groups. January (midwinter) had the highest rates, which decreased in April to a trough in June (early summer). After adjusting for the time trend effect and climatic parameters, the ARIMA regression revealed that January had a significantly higher monthly incidence of testicular torsion compared to February. In addition, our results indicated that the monthly incidence of testicular torsion was negatively associated with ambient temperature. CONCLUSIONS: Our results suggest that the monthly incidence of testicular torsion was significantly associated with seasonality and ambient temperature. PMID- 22425117 TI - Laparoendoscopic single site reconstructive procedures in urology: medium term results. AB - PURPOSE: Despite numerous retrospective series of laparoendoscopic single site surgery, cohorts have generally been small and followup largely short-term. Therefore, we report intermediate term outcomes for patients undergoing reconstructive laparoendoscopic single site procedures at a single institution. MATERIALS AND METHODS: Upon review of our prospectively maintained laparoendoscopic single site urological database of 185 cases, 32 reconstructive procedures were identified including pyeloplasty (25), ileal interposition (3), ureteroneocystostomy (3) and retrocaval ureter repair (1). Perioperative data were reviewed, and clinical and radiographic success was noted. RESULTS: Median followup was 24.4 months for pyeloplasty, 35 months for ileal interposition, 29.4 months for ureteroneocystostomy and 20 months for retrocaval ureter repair. At last followup 24 of 25 patients treated with pyeloplasty, 2 of 3 with ileal ureter, 3 of 3 with ureteroneocystostomy and 1 of 1 with retrocaval ureter reported being asymptomatic or improved after the procedure. Delayed incisional hernia repair was required in 1 patient. One death occurred during the followup period, remote from the date of surgery. No other complications were noted. CONCLUSIONS: Intermediate term results after laparoendoscopic single site reconstructive procedures remain promising. Further followup of this patient population is required to ensure the durability of results. Prospective evaluation is also needed to assess if advantages exist for laparoendoscopic single site reconstructive procedures compared to standard minimally invasive approaches. PMID- 22425118 TI - ACE gene insertion/deletion polymorphism seminal associations in infertile men. AB - PURPOSE: We assessed seminal associations of the ACE gene insertion/deletion polymorphism in infertile men. MATERIALS AND METHODS: A total of 405 men were investigated, divided into healthy fertile men, and those with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia, respectively. They underwent semen analysis, and assessment of sperm acrosin activity, hypo-osmotic swelling, seminal 8-iso-prostaglandin-F(2alpha), total antioxidant capacity, alpha-glucosidase and ACE gene polymorphisms. RESULT: The ACE insertion/insertion genotype was noted in 182 men, including 76.5% of healthy fertile men, and 47.4%, 39.8% and 17.6% of those with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia, respectively. The ACE insertion/deletion genotype was noted in 133 men, including 13.7% of healthy fertile men, and 42.3%, 27.5% and 47.2% of those with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia, respectively. The ACE deletion/deletion genotype was identified in 90 men, including 9.8% of healthy fertile men, 10.3%, 32.70% and 35.2% of those with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia, respectively. Men with the ACE deletion/deletion and insertion/deletion genotypes showed a significant decrease in sperm count, motility, linear velocity and normal forms, acrosin activity index, hypo-osmotic swelling test and seminal alpha-glucosidase, and significantly increased seminal 8-iso-prostaglandin-F(2alpha) than those with the ACE insertion/insertion genotype. CONCLUSIONS: ACE gene deletion polymorphism is associated with abnormal seminal variables, such that carriers of the ACE deletion/deletion genotype have higher seminal oxidative stress. PMID- 22425119 TI - Mortality in older men with nocturia. A 15-year followup of the Krimpen study. AB - PURPOSE: Although nocturia seems to be related to increased mortality in older men, it is unclear whether this is an independent association. Therefore, we studied the association of nocturia and mortality in community dwelling older men. MATERIALS AND METHODS: A longitudinal, population based study was conducted among 1,688 men 50 to 78 years old. Recruitment started in 1995. At baseline all men completed a questionnaire and a 3-day frequency-volume chart. Nocturnal voiding frequency was derived from the frequency-volume chart and nocturia was defined as 2 or more voids per night. In 2010 all general practitioners' patient records were checked for possible date of death. Univariable and multivariable Cox regression analyses were performed. A subanalysis was performed to determine the effect of 3 longitudinal nocturia patterns (ie incident, persistent or transient/resolved) on the mortality rate. RESULTS: A total of 1,114 men were eligible for analysis. Median followup was 13.4 years (quartiles 1 to 3: 10.3 14.1) for a total of 12,790 person-years of followup. Univariably nocturia was associated with an increased mortality rate (HR 1.63, 95% CI 1.20-2.21, p = 0.002). After correction for possible confounding factors nocturia had no significant influence on mortality (p = 0.838) in contrast to age, chronic obstructive pulmonary disease, smoking and hypertension (all p <0.05). Men with persistent nocturia had the highest mortality rate compared to those without nocturia. However, this association was not significant (p = 0.083). CONCLUSIONS: In an analysis based on frequency-volume chart data, the association between nocturia and mortality was explained by confounding factors, predominantly age. Furthermore, the mortality risk was not associated with the 3 nocturia patterns. PMID- 22425120 TI - Robotic laparoendoscopic single site urological surgery: analysis of 50 consecutive cases. AB - PURPOSE: We present our cumulative experience with robotic laparoendoscopic single site urological surgery at a single institution. MATERIALS AND METHODS: Medical records of patients undergoing robotic laparoendoscopic single site procedures between May 2008 and December 2010 were analyzed. The da Vinci(r) S or Si systems and 3 different multichannel single port devices were used. Demographic, intraoperative and postoperative data were assessed. RESULTS: Overall, 50 patients were scheduled to undergo robotic laparoendoscopic single site urological surgery during the study period, representing 36% of the total patients undergoing laparoendoscopic single site surgery at our institution. Mean +/- SD patient age was 60.2 +/- 13.6 years. Mean body mass index was 27.0 +/- 4.5 kg/m(2). Specifically, 24 patients underwent robotic laparoendoscopic single site renal surgery and the same method was used in 26 patients undergoing pelvic surgery. Mean operative time was 207 +/- 74 minutes and mean estimated blood loss was 140 +/- 111 ml. Four cases were converted to laparoscopy (2 standard, 2 robotic assisted) and 6 cases required at least 1 additional trocar outside of the single site incision. A rectal injury occurred during radical cystectomy, which was recognized intraoperatively and closed primarily without sequelae. Postoperative complications occurred in 8 cases and 1 was Clavien grade IV. Mean length of hospital stay was 2.9 +/- 1.7 days. CONCLUSIONS: Our preliminary experience with robotic laparoendoscopic single site surgery has demonstrated feasibility and safety in the realm of urological surgery. Widespread adoption of this new approach will likely require redesign of the robotic system or development of a task specific robotic platform, and should be limited to centers with significant robotic, laparoscopic and laparoendoscopic single site surgery experience. PMID- 22425121 TI - Decreased amplitude of detrusor overactivity by repetitive swallowing. AB - PURPOSE: We determined whether swallowing has an effect on the degree of urinary urgency and on the amplitude of detrusor contraction during filling cystometry in patients with detrusor overactivity. MATERIALS AND METHODS: Included in study were 20 consecutive patients with detrusor overactivity. During urodynamics the mean peak pressure of each contraction was documented and compared. At the beginning of wave 2 patients were asked to perform 5 repetitive swallows. After each wave patients were asked to grade the severity of urgency on a visual analog scale. RESULTS: The mean +/- SD peak of the detrusor contraction was 39 +/- 15 vs 95 +/- 26 cm H(2)O with vs without swallowing (p <0.01). All patients reported that during swallowing the degree of urgency decreased. The mean visual analog scale score for urgency was significantly lower during repetitive swallowing than without swallowing (mean 3.4 +/- 1.5 vs 7.7 +/- 2.2, p <0.01). CONCLUSIONS: The repetitive swallowing maneuver inhibits urinary urgency and detrusor overactivity. The maneuver can be used during bladder training program or when micturition is not desirable. PMID- 22425122 TI - Complications of Foley catheters--is infection the greatest risk? AB - PURPOSE: Foley catheters cause a variety of harms, including infection, pain and trauma. Although symptomatic urinary tract infection and asymptomatic bacteriuria are frequently discussed, genitourinary trauma receives comparatively little attention. MATERIALS AND METHODS: A dedicated Foley catheter nurse prospectively reviewed the medical records of inpatients with a Foley catheter at the Minneapolis Veterans Affairs Medical Center from August 21, 2008 to December 31, 2009. Daily surveillance included Foley catheter related bacteriuria and trauma. Data were analyzed as the number of event days per 100 Foley catheter days. RESULTS: During 6,513 surveyed Foley catheter days, urinalysis/urine culture was done on 407 (6.3%) days. This testing identified 116 possible urinary tract infection episodes (1.8% of Foley catheter days), of which only 21 (18%) involved clinical manifestations. However, the remaining 95 asymptomatic bacteriuria episodes accounted for 39 (70%) of 56 antimicrobial treated possible urinary tract infection episodes (for proportion of treated episodes with vs without symptomatic urinary tract infection manifestations, p = 0.005). Concurrently 100 instances of catheter associated genitourinary trauma (1.5% of Foley catheter days) were recorded, of which 32 (32%) led to interventions such as prolonged catheterization or cystoscopy. Trauma prompting an intervention accounted for as great a proportion of Foley catheter days (0.5%) as did symptomatic urinary tract infection (0.3%) (p = 0.17). CONCLUSIONS: In this prospective surveillance project, intervention triggering Foley catheter related genitourinary trauma was as common as symptomatic urinary tract infection. Moreover, despite recent increased attention to the distinction between asymptomatic bacteriuria and symptomatic urinary tract infection in catheterized patients, asymptomatic bacteriuria accounted for significantly more antimicrobial treatment than did symptomatic urinary tract infection. Elimination of unnecessary Foley catheter use could prevent symptomatic urinary tract infection, unnecessary antimicrobial therapy for asymptomatic bacteriuria and Foley catheter related trauma. PMID- 22425123 TI - Obturator foramen dissection for excision of symptomatic transobturator mesh. AB - PURPOSE: Groin pain after transobturator synthetic mesh placement can be recalcitrant to conservative therapy and ultimately requires surgical excision. We describe our experiences with and technique of obturator foramen dissection for mesh excision. MATERIALS AND METHODS: The records of 8 patients treated from 2005 to 2010, were reviewed. Obturator dissection was performed via a lateral groin incision over the inferior pubic ramus at the level of the obturator foramen, typically in conjunction with orthopedic surgery. RESULTS: Five patients had transobturator mid urethral sling surgery for stress urinary incontinence, 2 had mid urethral sling and trocar based anterior vaginal wall mesh kits with transobturator passage of mesh arms for stress urinary incontinence and pelvic organ prolapse, and 1 had an anterior vaginal wall mesh kit for pelvic organ prolapse. Patients had 0 to 2 prior transvaginal mesh excisions before obturator surgery. All patients presented with intractable pain in the area of the obturator foramen and/or medial groin for which conservative treatment measures had failed. Six patients underwent concurrent vaginal and obturator dissection and 2 underwent obturator dissection alone. In all cases residual mesh (3 to 11 cm) was identified and excised from the obturator foramen. Mesh was closely associated to or traversing the adductor longus muscle and tendon with significant fibrous reaction in all cases. Postoperatively 5 patients were cured of pain and/or infection, and 3 reported no or some improvement at a mean followup of 6 months (range 1 to 12). CONCLUSIONS: Our experience suggests that surgical excision of residual mesh can alleviate many of the symptoms in many patients. In all cases mesh remnants were identified and removed, and typically involved neuromuscular structures adjacent to the obturator foramen. PMID- 22425124 TI - Functional recovery after partial nephrectomy: effects of volume loss and ischemic injury. AB - PURPOSE: We used what is to our knowledge a new method to estimate volume loss after partial nephrectomy to assess the relative contributions of ischemic injury and volume loss on functional outcomes. MATERIALS AND METHODS: We analyzed the records of 301 consecutive patients who underwent conventional partial nephrectomy between 2007 and 2010 with available data to meet inclusion criteria. Percent functional volume preservation was measured at a median of 1.4 years after surgery. Modification of diet in renal disease-2 estimated glomerular filtration rate was measured preoperatively and perioperatively, and a median of 1.2 years postoperatively. Statistical analysis was done to study associations. RESULTS: Hypothermia or warm ischemia 25 minutes or less was applied in 75% of cases. Median percent functional volume preservation was 91% (range 38%-107%). Percent glomerular filtration rate preservation at nadir and late time points was 77% and 90% of preoperative glomerular filtration rate, respectively. On multivariate analysis percent functional volume preservation and warm ischemia time were associated with nadir glomerular filtration rate while only percent functional volume preservation was associated with late glomerular filtration rate (each p <0.001). Late percent glomerular filtration rate preservation and percent functional volume preservation were directly associated (p <0.001). Recovery of function to 90% or greater of percent functional volume preservation predicted levels was observed in 86% of patients. In patients with de novo postoperative stage 3 or greater chronic kidney disease, percent functional volume preservation and Charlson score were associated with late percent glomerular filtration rate preservation. Warm ischemia time was not associated with late functional glomerular filtration rate decreases in patients considered high risk for ischemic injury. CONCLUSIONS: In this cohort volume loss and not ischemia time was the primary determinant of ultimate renal function after partial nephrectomy. Technical modifications aimed at minimizing volume loss during partial nephrectomy while still achieving negative margins may result in improved functional outcomes. PMID- 22425125 TI - The socioeconomic status of donors and recipients of living unrelated renal transplants in the United States. AB - PURPOSE: We evaluated unrelated living kidney donation in the United States and examined the characteristics of unrelated donor-recipient pairs. MATERIALS AND METHODS: We accessed United Network for Organ Sharing files to identify adult living donor renal transplant recipients who received a transplant between 1997 and 2007. We evaluated factors associated with unrelated donation and compared a composite index of the socioeconomic characteristics of donor and recipient ZIP Codes between living unrelated and living related renal transplantation pairs. Spousal pairs were categorized as living related. RESULTS: Of 39,168 adult renal transplant recipients 19% underwent living unrelated renal transplantation. These recipients were more likely white (vs black, Hispanic and other race OR 0.77 0.82, p <0.05) and more highly educated (college vs less than high school OR 0.66, 95% CI 0.54-0.77), and more commonly received care at high volume transplant centers (vs lowest volume centers OR 0.89, 95% CI 0.82-0.95). Living unrelated renal transplantation recipients and donors lived in higher socioeconomic status index ZIP Codes than living related recipients (mean +/- SD recipients and donors 0.62 +/- 3.74 and 0.44 +/- 3.63 vs 0.03 +/- 3.85 and 0.10 +/- 3.87, respectively, each p <0.001). CONCLUSIONS: Living unrelated renal transplantation donors and recipients are generally of higher socioeconomic status than their living related renal transplantation counterparts. There is restricted access to unrelated donors among underserved populations. PMID- 22425126 TI - Approach to management of iatrogenic foreign bodies of the lower urinary tract following reconstructive pelvic surgery. AB - PURPOSE: Evolving techniques and materials for pelvic reconstruction have resulted in corresponding increases in the risk of iatrogenic foreign bodies in the lower urinary tract and vagina. We review the presentation, management and outcomes of iatrogenic foreign bodies in the female lower urinary tract and vagina. MATERIALS AND METHODS: We performed a retrospective review of the records of all women undergoing removal of lower urinary tract foreign bodies during a 9 year period. All patients underwent a structured evaluation including history, physical examination, ancillary testing as indicated and subjective symptom appraisal. RESULTS: A total of 85 women were identified, of whom 48 had vaginal, 40 had lower urinary tract, and 3 had concomitant vaginal and lower urinary tract excision of foreign material. Of the lower urinary tract cases the foreign body was located in the urethra in 12, bladder neck in 10, bladder wall in 18 and trigone in 3, while the remainder of the cases was vaginal in location. Aggressive surgical management aimed at removal or debulking of the exposed foreign body necessitated cystorrhaphy/partial cystectomy (20), urethroplasty (18) and fistula repair (3). Of the patients with vaginal excision 36 (75%) reported cure (of presenting symptoms), 10 (20.8%) reported improvement and 2 were unavailable for followup. Of the patients with lower urinary tract excision 21 (52.5%) reported cure, 14 (35%) indicated improvement and 5 were unavailable for followup. CONCLUSIONS: In a complex group of women with vaginal or lower urinary tract foreign body extrusion, aggressive operative management resulted in high rates of subjective patient cure. Adequate assessment of newer reconstructive technologies is critical to assess the full impact of these complications. PMID- 22425127 TI - Quantifying the contribution of symptom improvement to satisfaction of men with moderate to severe benign prostatic hyperplasia: 4-year data from the CombAT trial. AB - PURPOSE: We quantified the magnitude of symptom improvement required to achieve different levels of patient reported satisfaction, as assessed by the Patient Perception of Study Medication questionnaire. MATERIALS AND METHODS: This multicenter, international, double-blind, randomized study included men 50 years old or older with International Prostate Symptom Score 12 or greater, prostate volume 30 cc or greater, total prostate specific antigen 1.5 to 10.0 ng/ml, maximum urinary flow greater than 5 and less than or equal to 15 ml per second and minimum voided volume 125 ml or greater. Patients were randomized to dutasteride (0.5 mg) and/or tamsulosin (0.4 mg) but results are reported without respect to treatment. International Prostate Symptom Score and Patient Perception of Study Medication responses were assessed at baseline and at 3-month intervals for 48 months. Using pooled data Patient Perception of Study Medication responses were correlated with changes in International Prostate Symptom Score from baseline for 2 Patient Perception of Study Medication measures, including 1) total score and 2) overall satisfaction on question 11, "Overall how satisfied are you with the study medication and its effect on your urinary problems?" RESULTS: Patient Perception of Study Medication total score and question 11 correlated significantly with the mean change in International Prostate Symptom Score from baseline (p <0.0001). A response of very satisfied to question 11 was associated with an International Prostate Symptom Score improvement of -9.4 points while a response of very dissatisfied was associated with 1.3-point worsening. There was only moderate correlation between Patient Perception of Study Medication question 11 and changes in symptoms (r = 0.38). Thus, factors other than lower urinary tract symptoms also contribute to satisfaction and they could not be formally analyzed in this report. CONCLUSIONS: We noted correlations between patient satisfaction and the magnitude of the International Prostate Symptom Score change from baseline, which allowed us to determine treatment outcomes in terms of true clinical instead of only statistical significance. PMID- 22425128 TI - Changes in initial expenditures for benign prostatic hyperplasia evaluation in the Medicare population: a comparison to overall Medicare inflation. AB - PURPOSE: Benign prostatic hyperplasia creates significant expenses for the Medicare program. We determined expenditure trends for benign prostatic hyperplasia evaluative testing after urologist consultation and placed these trends in the context of overall Medicare expenditures. MATERIALS AND METHODS: Using a 5% national sample of Medicare beneficiaries from 2000 to 2007 we developed a cohort of 40,253 with claims for new visits to urologists for diagnoses consistent with symptomatic benign prostatic hyperplasia. We assessed trends in initial inflation and geography adjusted expenditures within 12 months of diagnosis by evaluative test categories derived from the 2003 American Urological Association guideline on the management of benign prostatic hyperplasia. Using governmental reports on Medicare expenditure trends for benign prostatic hyperplasia we compared expenditures to overall and imaging specific Medicare expenditures. Comparisons were assessed by the Z-test and regression analysis for linear trends, as appropriate. RESULTS: Between 2000 and 2007 inflation adjusted total Medicare expenditures per patient for the initial evaluation of patients with benign prostatic hyperplasia seen by urologists increased from $255.44 to $343.98 (p <0.0001). Benign prostatic hyperplasia related imaging increases were significantly less than overall Medicare imaging expenditure increases (55% vs 104%, p <0.001). The increase in per patient expenditures for benign prostatic hyperplasia was significantly lower than the increase in overall Medicare expenditures per enrollee (35% vs 45%, p = 0.0015). CONCLUSIONS: From 2000 to 2007 inflation adjusted expenditures increased for benign prostatic hyperplasia related evaluations. This growth was slower than the overall growth in Medicare expenditures. The increase in BPH related imaging expenditures was restrained compared to that of the Medicare program as a whole. PMID- 22425129 TI - Does low intensity extracorporeal shock wave therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study. AB - PURPOSE: We investigated the clinical and physiological effect of low intensity extracorporeal shock wave therapy on men with organic erectile dysfunction who are phosphodiesterase type 5 inhibitor responders. MATERIALS AND METHODS: After a 1-month phosphodiesterase type 5 inhibitor washout period, 67 men were randomized in a 2:1 ratio to receive 12 sessions of low intensity extracorporeal shock wave therapy or sham therapy. Erectile function and penile hemodynamics were assessed before the first treatment (visit 1) and 1 month after the final treatment (followup 1) using validated sexual function questionnaires and venoocclusive strain gauge plethysmography. RESULTS: Clinically we found a significantly greater increase in the International Index of Erectile Function-Erectile Function domain score from visit 1 to followup 1 in the treated group than in the sham treated group (mean +/- SEM 6.7 +/- 0.9 vs 3.0 +/- 1.4, p = 0.0322). There were 19 men in the treated group who were initially unable to achieve erections hard enough for penetration (Erection Hardness Score 2 or less) who were able to achieve erections sufficiently firm for penetration (Erection Hardness Score 3 or greater) after low intensity extracorporeal shock wave therapy, compared to none in the sham group. Physiologically penile hemodynamics significantly improved in the treated group but not in the sham group (maximal post-ischemic penile blood flow 8.2 vs 0.1 ml per minute per dl, p <0.0001). None of the men experienced discomfort or reported any adverse effects from the treatment. CONCLUSIONS: This is the first randomized, double-blind, sham controlled study to our knowledge that shows that low intensity extracorporeal shock wave therapy has a positive short-term clinical and physiological effect on the erectile function of men who respond to oral phosphodiesterase type 5 inhibitor therapy. The feasibility and tolerability of this treatment, coupled with its potential rehabilitative characteristics, make it an attractive new therapeutic option for men with erectile dysfunction. PMID- 22425130 TI - Glucocorticoids are required for meal-induced changes in the expression of hypothalamic neuropeptides. AB - Glucocorticoid deficiency is associated with a decrease of food intake. Orexigenic peptides, neuropeptide Y (NPY) and agouti related protein (AgRP), and the anorexigenic peptide proopiomelanocortin (POMC), expressed in the arcuate nucleus of the hypothalamus (ARC), are regulated by meal-induced signals. Orexigenic neuropeptides, melanin-concentrating hormone (MCH) and orexin, expressed in the lateral hypothalamic area (LHA), also control food intake. Thus, the present study was designed to test the hypothesis that glucocorticoids are required for changes in the expression of hypothalamic neuropeptides induced by feeding. Male Wistar rats (230-280 g) were subjected to ADX or sham surgery. ADX animals received 0.9% NaCl in the drinking water, and half of them received corticosterone in the drinking water (B: 25 mg/L, ADX+B). Six days after surgery, animals were fasted for 16 h and they were decapitated before or 2 h after refeeding for brain tissue and blood collections. Adrenalectomy decreased NPY/AgRP and POMC expression in the ARC in fasted and refed animals, respectively. Refeeding decreased NPY/AgRP and increased POMC mRNA expression in the ARC of sham and ADX+B groups, with no effects in ADX animals. The expression of MCH and orexin mRNA expression in the LHA was increased in ADX and ADX+B groups in fasted condition, however there was no effect of refeeding on the expression of MCH and orexin in the LHA in the three experimental groups. Refeeding increased plasma leptin and insulin levels in sham and ADX+B animals, with no changes in leptin concentrations in ADX group, and insulin response to feeding was lower in this group. Taken together, these data demonstrated that circulating glucocorticoids are required for meal-induced changes in NPY, AgRP and POMC mRNA expression in the ARC. The lower leptin and insulin responses to feeding may contribute to the altered hypothalamic neuropeptide expression after adrenalectomy. PMID- 22425131 TI - Chronotype but not sleep length is related to salivary testosterone in young adult men. AB - Sex hormones, including testosterone, are hypothesized to have an influence on the human circadian system. We sampled male students in the period after adolescence. We used the Composite Scale of Morningness (CSM) to assess chronotype and saliva testosterone sampling in 106 University students (23.87+/ 3.56 years; range 19-37) between 26.4.2011 and 6.5.2011, always between 0800h and 0900h. There was a significant negative relationship between CSM scores and saliva testosterone (r(s)=-0.220, p=0.023, two-tailed test) but not between testosterone and average sleep length. Age and testosterone did not correlate with each other nor did age and CSM scores. Our data suggest that chronotype in men might be influenced by testosterone and that high testosterone levels lead to a stronger evening-orientation. Sleep duration was uncorrelated with testosterone, suggesting that timing of sleep - rather than sleep length itself - is influenced by testosterone. PMID- 22425132 TI - [Granulomatosis and primary immunodeficiency in adulthood]. AB - Primary immunodeficiency with granulomatosis in the adulthood mainly concern common variable immunodeficiency (CVID). Hypogammaglobulinemia in the adulthood is usually related to a secondary immunodeficiency. When a patient presents with the association of a hypogammaglobulinemia and a granulomatosis, an opportunistic infection must first be ruled out. For unknown reasons, about 10% of the patients affected by CVID also present with granulomatosis. Lesions usually affect the pulmonary tract or the mediastinum. Half of these patients are also affected by an autoimmune cytopenia. Treatment is not codified. Severe pulmonary complications can occur in about 50% of the patients. PMID- 22425133 TI - [Alcoholic hepatitis]. AB - Alcoholic hepatitis is one of the most severe presentations of alcoholic liver disease. It is usually revealed by the recent onset of jaundice in a patient with alcoholic cirrhosis. Maddrey's discriminant function can help to recognize patients with poor prognosis (the 6-month mortality is above 50% when it exceeds 32). Corticosteroids increase survival in those patients with high risk of death. Other treatments (pentoxifylline, N-acetyl-cysteine or enteral nutrition) need to be investigated further before to recommend their routine use instead of, or in association with, corticoids. Liver transplantation can be proposed to highly selected patients who do not respond to medical therapy. In any case, long-term prognosis will primarily depend on the maintenance of alcohol abstinence. PMID- 22425134 TI - What puts the adverse in 'adverse events'? Patients' perceptions of post treatment experiences in osteopathy--a qualitative study using focus groups. AB - Patients commonly report mild to moderate effects following all forms of manual therapy. These are often regarded as adverse events by practitioners but there is limited evidence on how patients view their post-treatment experiences, and what meaning they ascribe to them. This qualitative study used three focus group discussions (19 participants) to explore osteopathic patients' perspectives; a framework approach was used to analyse the data. There were four emergent themes (and 23 sub-themes). Interpretative (level two) analysis of the data led to a conceptual model of meaning with four inter-related components: Expectations; Personal investment; Osteopathic encounter; Clinical change, under an overarching construct, the 'global osteopathic experience'. These four components, designated EPOC, can have a profound impact on a patient's post-treatment experiences and their perception of what is adverse. This model suggests there is disparity between patient perceptions and clinical definitions of adverse events; awareness by practitioners of this disparity is essential for effective clinical management. PMID- 22425136 TI - Pulmonary hypertension in interstitial lung disease: prevalence, prognosis and 6 min walk test. AB - BACKGROUND: Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients. METHODS: 212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion <1.8 cm or right ventricular dilatation. If possible, PH was confirmed by right heart catheterisation. Pulmonary function tests and 6 min walk tests (6MWT) were performed. RESULTS: 29 patients (14%) had PH, 16 (8%) had mild and 13 (6%) had severe PH (mean pulmonary artery pressure >= 35 mmHg). Compared to patients without PH, lung function parameters were lower in PH patients, a larger proportion had idiopathic pulmonary fibrosis (IPF) (41 vs 21%, p = 0.006), and the hazard ratio for death was 8.5 (95% CI: 4-17). After correction for lung function parameters and the presence of IPF, 6MWT was significantly lower in patients with PH compared to non PH patients (difference +/- SEM: 58 +/- 22 m, p = 0.01). CONCLUSIONS: PH occurred in 14% of a cohort of patients with ILD and was associated to IPF and lower lung function parameters. Mortality was markedly higher in PH patients, and the presence of PH reduced 6MWT independently of lung function and the presence of IPF. The present results emphasize the need for intensified treatment of patients with ILD and PH. PMID- 22425137 TI - Prospective trial of adipose-derived regenerative cell (ADRC)-enriched fat grafting for partial mastectomy defects: the RESTORE-2 trial. AB - AIMS: Women undergoing breast conservation therapy (BCT) for breast cancer are often left with contour defects and few acceptable reconstructive options. RESTORE-2 is the first prospective clinical trial using autologous adipose derived regenerative cell (ADRC)-enriched fat grafting for reconstruction of such defects. This single-arm, prospective, multi-center clinical trial enrolled 71 patients post-BCT with defects <=150 mL. METHODS: Adipose tissue was collected via syringe lipoharvest and then processed during the same surgical procedure using a closed automated system that isolates ADRCs and prepares an ADRC-enriched fat graft for immediate re-implantation. ADRC-enriched fat graft injections were performed in a fan-shaped pattern to prevent pooling of the injected fat. Overall procedure times were less than 4 h. The RESTORE-2 protocol allowed for up to two treatment sessions and 24 patients elected to undergo a second procedure following the six month follow-up visit. RESULTS: Of the 67 patients treated, 50 reported satisfaction with treatment results through 12 months. Using the same metric, investigators reported satisfaction with 57 out of 67 patients. Independent radiographic core laboratory assessment reported improvement in the breast contour of 54 out of 65 patients based on blinded assessment of MRI sequence. There were no serious adverse events associated with the ADRC-enriched fat graft injection procedure. There were no reported local cancer recurrences. Injection site cysts were reported as adverse events in ten patients. CONCLUSION: This prospective trial demonstrates the safety and efficacy of the treatment of BCT defects utilizing ADRC-enriched fat grafts. PMID- 22425138 TI - Rehospitalization risks and outcomes in COPD patients receiving maintenance pharmacotherapy. AB - OBJECTIVE: To determine clinical and economic outcomes following COPD-related hospitalization/emergency department (ED) care in patients receiving COPD maintenance therapy. METHODS: In this retrospective, observational study using administrative claims data, we identified COPD patients age >=40 years who received maintenance therapy within 30 days of an initial COPD-related hospitalization or ED visit with: (1) fluticasone propionate/salmeterol combination (FSC 250 mcg/50 mcg) as new therapy, or (2) an anticholinergic (AC; tiotropium or ipratropium with or without albuterol). The FSC and AC patients were matched (1:3 ratio) on various baseline characteristics using propensity scores to mitigate selection bias at baseline. The proportion of patients with COPD-related healthcare events, the mean event rates, and the mean costs in the subsequent 12 months were calculated. RESULTS: The FSC cohort (N = 484) had a significantly lower proportion of rehospitalized patients during follow-up than did the AC cohort (N = 1452), 3.1% versus 4.6% (P = 0.047). The mean number of rehospitalizations was 0.03 in the FSC cohort and 0.07 in the AC cohort (P = 0.001). The proportion of patients with an exacerbation resulting in an ED or physician-outpatient visit and the mean number of such visits did not differ between cohorts. Total annual COPD-related medical costs were lower for FSC than for AC ($2080 versus $2636, P = 0.006), with lower medical and higher pharmacy costs. CONCLUSIONS: Patients receiving FSC as maintenance therapy following an initial COPD-related hospitalization or ED visit experienced better clinical and economic outcomes than patients receiving AC. PMID- 22425139 TI - Monocyte chemoattractant protein-1 in schizophrenia: -2518A/G genetic variant and protein levels in Armenian population. AB - Monocyte chemoattractant protein-1 (MCP-1) has been proposed as a contributory factor in pathophysiology of schizophrenia. The aim of the current study was to explore the possible association of the MCP-1-2518A/G genetic polymorphism and plasma levels of MCP-1 in patients with paranoid schizophrenia. The MCP-1-2518A/G (rs1024611) polymorphism and blood levels of MCP-1 in patients with paranoid schizophrenia and healthy subjects were evaluated and compared. One hundred and three chronic patients with paranoid schizophrenia treated with neuroleptics and 105 healthy subjects were genotyped using polymerase chain reaction with sequence specific primers (PCR-SSP) and their MCP-1 plasma levels were measured by a solid phase enzyme-linked immunosorbent assay (ELISA). When comparisons were made between patients and controls, the frequency of the MCP-1-2518*G minor allele (35% vs 23%, p=0.009, OR=1.77, 95% CI: 1.1-2.04) and also of the MCP-1-2518*G carriers (60% vs 40%, p=0.003, OR=2.27, 95% CI: 1.13-2.01) were higher in patients. The mean value of the MCP-1 plasma level in patients with schizophrenia was significantly higher than in controls. Interestingly, the patients with the GG genotype had the highest MCP-1 level (711.4 +/- 211.4 pg/ml), followed by those with the AG genotype (472.1 +/- 135.8 pg/ml) and AA (372.4 +/- 180.2 pg/ml) homozygotes. In conclusion, we report here the association of the -2518A/G genetic polymorphism and increased plasma levels of MCP-1 with schizophrenia and nominate -2518*G minor allele as a risk factor for schizophrenia in Armenian population. PMID- 22425140 TI - Single nucleotide polymorphisms (SNPs) of pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes in patients with acute ischemic stroke in relation to TOAST subtype. AB - BACKGROUND: The genetic basis of complex diseases like ischemic stroke probably consists of several predisposing risk factors, such as genes involved in inflammation and thrombotic pathways. On this basis the aim of our study was to evaluate the role of SNPs (single nucleotide polymorphisms) of some pro inflammatory/anti-inflammatory and coagulation/fibrinolytic genes in patients with acute ischemic stroke. METHODS: The study population consisted of 144 consecutive Caucasian adult patients who were hospitalized in the Internal Medicine Department at the University of Palermo between November 2006 and January 2008, and who met inclusion criteria. The cases were patients admitted with a diagnosis of acute ischemic stroke, and age-matched (+/- 3 years) control subjects: patients admitted to our Internal Medicine Department for any cause other than acute cardiovascular and cerebrovascular events and for routine checkup examinations. Molecular analysis of alleles at the -308 nucleotide ( 308G/A) of TNF-alpha gene, -1082/-819 haplotypes of IL-10 gene, IL-1RN exon 2 VNR polymorphism, alleles at the -174 nucleotide (-174G/C) of IL-6 gene, PAI-1675 5G/4G polymorphism, alleles at the -7351 nucleotide (-7351C/T) of tPA gene was undertaken in both patient groups. RESULTS: We analyzed 96 subjects with acute ischemic stroke and 48 control subjects. We observed a significantly higher frequency of IL-10 1082 AA genotype in stroke patients with a significant risk trend. We also reported a higher frequency in stroke subjects with a significant risk trend of the TPA 7351-CT genotype and of IL-1RN-VNTR 86 bp 2/2 genotype. Moreover, we observed a significant relationship with TOAST subtype only with regard to CC TPA genotype and 1/1 IL-1 VNTR 86 bp and lacunar strokes. CONCLUSIONS: Ischemic stroke is a common multifactor disease, which is affected by a number of genetic mutations and environmental factors. Our findings showing a relationship between pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes SNPs and ischemic stroke may contribute to delineate a possible stroke risk profile in subjects with cerebrovascular risk factors. PMID- 22425141 TI - Vertebroplasty and kyphoplasty--a systematic review of cement augmentation techniques for osteoporotic vertebral compression fractures compared to standard medical therapy. AB - After more than two decades the treatment effect of cement augmentation of osteoporotic vertebral compression fractures (VCF) has now been questioned by two blinded randomised placebo-controlled trials. Thus many practitioners are uncertain on the recommendation for cement augmentation techniques in elderly patients with osteoporotic VCF. This systematic review analyses randomised controlled trials on vertebroplasty and kyphoplasty to provide an overview on the current evidence. From an electronic database research 8 studies could be identified meeting our inclusion criteria of osteoporotic VCF in elderly (age>60 years), treatment with vertebroplasty or kyphoplasty, controlled with placebo or standard medical therapy, quality of life, function, or pain as primary parameter, and randomisation. Only two studies were properly blinded using a sham operation as control. The other studies were using a non-surgical treatment control group. Further possible bias may be caused by manufacturer involvement in financing of three published RCT. There is level Ib evidence that vertebroplasty is no better than placebo, which is conflicting with the available level IIb evidence that there is a positive short-term effect of cement augmentation compared to standard medical therapy with regard to QoL, function and pain. Kyphoplasty is not superior to vertebroplasty with regard to pain, but with regard to VCF reduction (evidence level IIb). Kyphoplasty is probably not cost effective (evidence level IIb), and vertebroplasty has not more than short-term cost-effectiveness (evidence level IV). Vertebroplasty and kyphoplasty cannot be recommended as standard treatment for osteoporotic VCF. Ongoing sham-controlled trials may provide further evidence in this regard. PMID- 22425142 TI - Transvaginal natural-orifice transluminal endoscopic surgery (NOTES) in adnexal procedures. AB - From August 2010 to June 2011, 10 consecutive patients underwent transvaginal NOTES of the adnexa, including tubal sterilization in 3, salpingectomy because of ectopic pregnancy in 3, and ovarian tumor enucleation in 4. The mean (SD; 95% CI) age of the patients was 34.8 (9.7; 27.9-41.8) years, and their body mass index was 21.6 (2.8; 19.4-23.8). In 9 of the 10 patients, the procedure was completed. The 3 tubal sterilization procedures were completed in 18 to 30 minutes, with negligible blood loss. Operative time for the 3 salpingectomies because of ectopic pregnancy was 62 to 116 minutes. One of these procedures included management of 2000 mL hemoperitoneum. Three of the 4 attempts at ovarian enucleation were successfully completed within 64 to 162 minutes, with estimated blood loss <= 50 mL. One NOTES procedure failed because of a misdiagnosed peritoneal mucinous tumor located anterior to the uterus and inaccessible, leading to subsequent conversion to transabdominal laparoscopy. Our preliminary results show that purely transvaginal NOTES is feasible and safe for use in performing uterine adnexal procedures in selected patients. However, the procedure cannot be used in patients with cul-de-sac disease, and could have limited use in treating lesions located anterior to the uterus. PMID- 22425143 TI - New hysteroscopy pump to monitor real-time rate of fluid intravasation. AB - This article describes the benefit of monitoring the intravasation rate in addition to the conventional measurement of fluid deficit in hysteroscopic surgical procedures. The intravasation rate is the rate, in milliliters per minute, at which fluid enters the systemic circulation, whereas fluid deficit is the amount of irrigation fluid, in milliliters, already absorbed by the patient. To determine the intravasation rate, a manually operated intravasation monitoring pump was constructed, with which one of us (Dr. Atul Kumar) performed 966 hysteroscopic procedures from May 1993 to February 2010. Because the intravasation rate had to be manually calculated by an assistant, it was decided to replace the assistant with a controller to monitor intravasation rate. The surgical experience gathered from the manually operated pump was used to develop algorithms for the controller. The controller-operated intravasation monitoring pump was constructed, with which 41 hysteroscopic procedures were performed from March 2010 to August 2011. In hysteroscopic procedures, this pump simultaneously displays the real-time intravasation rate and the fluid deficit on an LCD screen. PMID- 22425144 TI - [Long-term survival of ischemic stroke]. AB - OBJECTIVE: Ischemic stroke is a serious vascular disease whose long term prognosis in all of its dimensions is not known. We have studied the long-term survival and its predictors after a first episode of acute ischemic stroke (atherothrombotic and cardioembolic). PATIENTS AND METHODS: A retrospective cohort study was made of patients with a first episode of ischemic stroke. The ictus was classified into atherothrombotic, cardioembolic, lacunar and undetermined. Patients were followed up for 10 years. RESULTS: A total of 415 cases (60% men) with mean age of 68.4 years, were included. Mean follow-up was 66 months (95% CI: 24-108 months). Overall survival at 10 years was 55.4% (54.9 55.9) (atherothrombotic, 57.7% vs cardioembolic, 43.7%, P=.002). In the multivariate analysis, variables related to mortality in acute ischemic stroke were age, chronic renal failure, dyslipidemia, history of heart failure, atrial fibrillation (AF), presenting as hemiplegia, signs of acute ischemia and perilesional edema in the brain scan on hospital admission. Involvement of the territory of right middle cerebral artery and treatment with statins were associated to a better prognosis. CONCLUSIONS: Survival of patients after ischemic stroke at ten year is over 40%, and atherothrombotic stroke as a better prognosis than cardioembolic one. PMID- 22425145 TI - [Basic features in the current practice of clinical medicine in the tropics (I). Parasitic diseases]. AB - In recent years an increasing number of physicians want to spend part of their medical training in health facilities in developing countries. Working in these areas requires good clinical skills, particularly where diagnostic resources are limited. Trainees will attend patients with many different parasitic diseases such as malaria and soil transmitted helminthic infections. The aim of this work is to provide basic concepts of epidemiology, clinical characteristics, diagnosis and treatment of the principal parasitic diseases that could occur in a rural health post in the tropics. PMID- 22425146 TI - [Understanding current practice of clinical medicine in the tropics (II). Bacterial and viral diseases. Malnutrition]. AB - In recent years, a significant number of physicians want to spend part of their medical training in health facilities in developing countries. In this setting, clinical skills are extremely important due to the limited available diagnostic resources. Bacterial diseases are common, but bacterial cultures are rarely accessible. In Africa, tuberculosis affects over 200 cases per 100,000 persons, and more than 22 million people live with HIV infection; both diseases are a serious public health problem. Malnutrition is endemic in many countries in Africa and is compounded by the continuous humanitarian and food crisis. In this paper, basic concepts of epidemiology, clinical features, diagnosis and treatment of major diseases that can be found in a rural health post in the tropics are discussed. PMID- 22425147 TI - Kinesiological research: the use of surface electromyography for assessing the effects of spinal manipulation. AB - Decreasing an elevated muscle tone is an often cited benefit of spinal manipulation. Spinal manipulation is theorized to disrupt an assumed pain-spasm pain cycle that sufferers of low back pain may be experiencing. The current research has mostly investigated the short term influence of a single spinal manipulation on paraspinal muscle activity either at rest (e.g. standing or prone) or during simple movements (e.g. forward bend). The higher quality experiments to date have typically reported both reductions in muscle activity during lying prone or during the fully flexed position of forward bend. The only study measuring the long term influence of spinal manipulation has failed to document any change in muscle activity as measured with surface electromyography. Both manually delivered manipulations and manipulations delivered via a mechanical adjusting device have been associated with changes in muscle activation. Changes in muscle activity at muscles distant from the spinal joints manipulated (e.g. muscles in the upper limbs) have been documented following a single spinal manipulation however rather than the typical reduction in muscle activity an increase in resting activation has been reported. The state of muscle dysfunction (e.g. palpably tender or subjectively taut) may be a factor in achieving a myoelectric response to spinal manipulation. Currently, the clinical significance of short term changes in electromyographic amplitude following manipulation is unknown. PMID- 22425148 TI - Effects of UV 254 irradiation on residual chlorine and DBPs in chlorination of model organic-N precursors in swimming pools. AB - Ultraviolet (UV) irradiation is commonly applied as a secondary disinfection process in chlorinated pools. UV-based systems have been reported to yield improvements in swimming pool water and air chemistry, but to date these observations have been largely anecdotal. The objectives of this investigation were to evaluate the effects of UV irradiation on chlorination of important organic-N precursors in swimming pools. Creatinine, L-arginine, L-histidine, glycine, and urea, which comprise the majority of the organic-N in human sweat and urine, were selected as precursors for use in conducting batch experiments to examine the time-course behavior of several DBPs and residual chlorine, with and without UV(254) irradiation. In addition, water samples from two natatoria were subjected to monochromatic UV irradiation at wavelengths of 222 nm and 254 nm to evaluate changes of liquid-phase chemistry. UV(254) irradiation promoted formation and/or decay of several chlorinated N-DBPs and also increased the rate of free chlorine consumption. UV exposure resulted in loss of inorganic chloramines (e.g., NCl(3)) from solution. Dichloromethylamine (CH(3)NCl(2)) formation from creatinine was promoted by UV exposure, when free chlorine was present in solution; however, when free chlorine was depleted, CH(3)NCl(2) photodecay was observed. Dichloroacetonitrile (CNCHCl(2)) formation (from L histidine and L-arginine) was promoted by UV(254) irradiation, as long as free chlorine was present in solution. Likewise, UV exposure was observed to amplify cyanogen chloride (CNCl) formation from chlorination of L-histidine, L-arginine, and glycine, up to the point of free chlorine depletion. The results from experiments involving UV irradiation of chlorinated swimming pool water were qualitatively consistent with the results of model experiments involving UV/chlorination of precursors in terms of the behavior of residual chlorine and DBPs measured in this study. The results indicate that UV(254) irradiation promotes several reactions that are involved in the formation and/or destruction of chlorinated N-DBPs in pool settings. Enhancement of DBP formation was consistent with a mechanism whereby a rate-limiting step in DBP formation was promoted by UV exposure. Promotion of these reactions also resulted in increases of free chlorine consumption rates. PMID- 22425149 TI - [Detection of sickle cell trait by means of the urinary sediment]. PMID- 22425150 TI - [Human immunodeficiency virus infection as a model of premature aging: perspectives and implications]. PMID- 22425151 TI - [About liver abscesses following transplantation from non-heart-beating donors]. PMID- 22425152 TI - Cutaneous head and neck basal and squamous cell carcinomas with perineural invasion. AB - Perineural invasion (PNI) occurs in 2% to 6% of cutaneous head and neck basal and squamous cell carcinomas (SCCs) and is associated with mid-face location, recurrent tumors, high histologic grade, and increasing tumor size. Patients may be asymptomatic with PNI appreciated on pathologic examination of the surgical specimen (microscopic), or may present with cranial nerve (CN) deficits (clinical). The V and VII CNs are most commonly involved. Magnetic resonance imaging (MRI) may be obtained to detect and define the extent of PNI; computed tomography (CT) or ultrasound-guided fine needle aspiration cytology (UGFNAC) may assist with detecting or excluding regional lymph node metastases. Patients with apparently resectable cancers undergo surgery, usually followed by postoperative radiotherapy (RT). Patients with unresectable cancers are treated with definitive RT. Moreover, RT may be considered if significant functional or cosmetic impairment is expected after surgical treatment. The 5-year outcomes after treatment for clinically unsuspected microscopic compared with clinical PNI are: local control, 80% and 55%; cause-specific survival, 75% and 65%; and overall survival, 55% and 50%, respectively. The incidence of grade >= 3 complications is higher after treatment for clinical PNI versus microscopic PNI; approximately 35% compared with 15%, respectively. Proton beam RT may be used to reduce the risk of late complications by reducing RT dose to the visual apparatus and central nervous system (CNS). PMID- 22425153 TI - Gamma neurons mediate dopaminergic input during aversive olfactory memory formation in Drosophila. AB - Mushroom body (MB)-dependent olfactory learning in Drosophila provides a powerful model to investigate memory mechanisms. MBs integrate olfactory conditioned stimulus (CS) inputs with neuromodulatory reinforcement (unconditioned stimuli, US), which for aversive learning is thought to rely on dopaminergic (DA) signaling to DopR, a D1-like dopamine receptor expressed in MBs. A wealth of evidence suggests the conclusion that parallel and independent signaling occurs downstream of DopR within two MB neuron cell types, with each supporting half of memory performance. For instance, expression of the Rutabaga (Rut) adenylyl cyclase in gamma neurons is sufficient to restore normal learning to rut mutants, whereas expression of Neurofibromatosis 1 (NF1) in alpha/beta neurons is sufficient to rescue NF1 mutants. DopR mutations are the only case where memory performance is fully eliminated, consistent with the hypothesis that DopR receives the US inputs for both gamma and alpha/beta lobe traces. We demonstrate, however, that DopR expression in gamma neurons is sufficient to fully support short- and long-term memory. We argue that DA-mediated CS-US association is formed in gamma neurons followed by communication between gamma and alpha/beta neurons to drive consolidation. PMID- 22425154 TI - A unique advantage for giant eyes in giant squid. AB - Giant and colossal deep-sea squid (Architeuthis and Mesonychoteuthis) have the largest eyes in the animal kingdom [1, 2], but there is no explanation for why they would need eyes that are nearly three times the diameter of those of any other extant animal. Here we develop a theory for visual detection in pelagic habitats, which predicts that such giant eyes are unlikely to evolve for detecting mates or prey at long distance but are instead uniquely suited for detecting very large predators, such as sperm whales. We also provide photographic documentation of an eyeball of about 27 cm with a 9 cm pupil in a giant squid, and we predict that, below 600 m depth, it would allow detection of sperm whales at distances exceeding 120 m. With this long range of vision, giant squid get an early warning of approaching sperm whales. Because the sonar range of sperm whales exceeds 120 m [3-5], we hypothesize that a well-prepared and powerful evasive response to hunting sperm whales may have driven the evolution of huge dimensions in both eyes and bodies of giant and colossal squid. Our theory also provides insights into the vision of Mesozoic ichthyosaurs with unusually large eyes. PMID- 22425155 TI - Temporal predictive codes for spoken words in auditory cortex. AB - Humans can recognize spoken words with unmatched speed and accuracy. Hearing the initial portion of a word such as "formu..." is sufficient for the brain to identify "formula" from the thousands of other words that partially match. Two alternative computational accounts propose that partially matching words (1) inhibit each other until a single word is selected ("formula" inhibits "formal" by lexical competition) or (2) are used to predict upcoming speech sounds more accurately (segment prediction error is minimal after sequences like "formu..."). To distinguish these theories we taught participants novel words (e.g., "formubo") that sound like existing words ("formula") on two successive days. Computational simulations show that knowing "formubo" increases lexical competition when hearing "formu...", but reduces segment prediction error. Conversely, when the sounds in "formula" and "formubo" diverge, the reverse is observed. The time course of magnetoencephalographic brain responses in the superior temporal gyrus (STG) is uniquely consistent with a segment prediction account. We propose a predictive coding model of spoken word recognition in which STG neurons represent the difference between predicted and heard speech sounds. This prediction error signal explains the efficiency of human word recognition and simulates neural responses in auditory regions. PMID- 22425156 TI - A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity. AB - Axons damaged by acute injury, toxic insults, or during neurodegenerative diseases undergo Wallerian or Wallerian-like degeneration, which is an active and orderly cellular process, but the underlying mechanisms are poorly understood. Drosophila has been proven to be a successful system for modeling human neurodegenerative diseases. In this study, we established a novel in vivo model of axon injury using the adult fly wing. The wing nerve highlighted by fluorescent protein markers can be directly visualized in living animals and be precisely severed by a simple wing cut, making it highly suitable for large-scale screening. Using this model, we confirmed an axonal protective function of Wld(S) and nicotinamide mononucleotide adenylyltransferase (Nmnat). We further revealed that knockdown of endogenous Nmnat triggered spontaneous, dying-back axon degeneration in vivo. Intriguingly, axonal mitochondria were rapidly depleted upon axotomy or downregulation of Nmnat. The injury-induced mitochondrial loss was dramatically suppressed by upregulation of Nmnat, which also protected severed axons from degeneration. However, when mitochondria were genetically eliminated from axons, upregulation of Nmnat was no longer effective to suppress axon degeneration. Together, these findings demonstrate an essential role of endogenous Nmnat in maintaining axonal integrity that may rely on and function by stabilizing mitochondria. PMID- 22425157 TI - WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. AB - Wld(S) (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses, but how it exerts this effect remains unclear. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for Wld(S) neuroprotective function. Targeting the NAD(+) biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy Wld(S), and Wld(S) was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild-type axons induced a dramatic spike in axoplasmic Ca(2+) and termination of mitochondrial movement Wld(S) potently suppressed both of these events. Surprisingly, Wld(S) also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of Wld(S). Intriguingly, purified mitochondria from Wld(S) mice exhibited enhanced Ca(2+) buffering capacity. We propose that the enhanced Ca(2+) buffering capacity of Wld(S+) mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca(2+) elevation in axons, and thereby suppression of Wallerian degeneration. PMID- 22425158 TI - Centrosomes can initiate a polarity axis from any position within one-cell C. elegans embryos. AB - The stereotyped asymmetry of one-cell C. elegans embryos has proven to be an important model for identifying molecular determinants of cell polarity. How polarity is initiated is less well understood. Polarity establishment depends on centrosomes, which use two molecularly distinct pathways to break symmetry. In both, the centrosome's position adjacent to the cell cortex is thought to determine where polarization starts. Defects in centrosome-cortex juxtaposition correlate with defects in polarity establishment in several mutants, suggesting that these processes may be linked, but there is no direct test of this. Here we assess how centrosome position relative to the cortex affects polarity establishment. We find that centrosomes can initiate polarity from any position within the embryo volume, but centrosome-cortex proximity decreases the time required to initiate polarity. Polarization itself brings about close centrosome cortex proximity. Prior to polarization, cytoplasmic microtubules constrain centrosome movement near the cortex, expanding the controversial role of microtubules during polarity establishment. The ability of centrosomes to induce a single polarity axis from any position within the egg emphasizes the flexible, self-organizing properties of polarization in C. elegans embryos and contrasts the common view of C. elegans development as invariant. PMID- 22425159 TI - Transient structure associated with the spindle pole body directs meiotic microtubule reorganization in S. pombe. AB - BACKGROUND: Vigorous chromosome movements driven by cytoskeletal assemblies are a widely conserved feature of sexual differentiation to facilitate meiotic recombination. In fission yeast, this process involves the dramatic conversion of arrays of cytoplasmic microtubules (MTs), generated from multiple MT organizing centers (MTOCs), into a single radial MT (rMT) array associated with the spindle pole body (SPB), the major MTOC during meiotic prophase. The rMT is then dissolved upon the onset of meiosis I when a bipolar spindle emerges to conduct chromosome segregation. Structural features and molecular mechanisms that govern these dynamic MT rearrangements are poorly understood. RESULTS: Electron tomography of the SPBs showed that the rMT emanates from a newly recognized amorphous structure, which we term the rMTOC. The rMTOC, which resides at the cytoplasmic side of the SPB, is highly enriched in gamma-tubulin reminiscent of the pericentriolar material of higher eukaryotic centrosomes. Formation of the rMTOC depends on Hrs1/Mcp6, a meiosis-specific SPB component that is located at the rMTOC. At the onset of meiosis I, Hrs1/Mcp6 is subject to strict downregulation by both proteasome-dependent degradation and phosphorylation leading to complete inactivation of the rMTOC. This ensures rMT dissolution and bipolar spindle formation. CONCLUSIONS: Our study reveals the molecular basis for the transient generation of a novel MTOC, which triggers a program of MT rearrangement that is required for meiotic differentiation. PMID- 22425160 TI - A role for the centrosome and PAR-3 in the hand-off of MTOC function during epithelial polarization. AB - BACKGROUND: The centrosome is the major microtubule organizing center (MTOC) in dividing cells and in many postmitotic, differentiated cells. In other cell types, however, MTOC function is reassigned from the centrosome to noncentrosomal sites. Here, we analyze how MTOC function is reassigned to the apical membrane of C. elegans intestinal cells. RESULTS: After the terminal intestinal cell division, the centrosomes and nuclei move near the future apical membranes, and the postmitotic centrosomes lose all, or nearly all, of their associated microtubules. We show that microtubule-nucleating proteins such as gamma-tubulin and CeGrip-1 that are centrosome components in dividing cells become localized to the apical membrane, which becomes highly enriched in microtubules. Our results suggest that centrosomes are critical to specify the apical membrane as the new MTOC. First, gamma-tubulin appears to redistribute directly from the migrating centrosome onto the lateral then apical membrane. Second, gamma-tubulin fails to accumulate apically in wild-type cells following laser ablation of the centrosome. We show that centrosomes localize apically by first moving toward lateral foci of the conserved polarity proteins PAR-3 and PAR-6 and then move together with these foci toward the future apical surface. Embryos lacking PAR-3 fail to localize their centrosomes apically and have aberrant localization of gamma-tubulin and CeGrip-1. CONCLUSIONS: These data suggest that PAR proteins contribute to apical polarity in part by determining centrosome position and that the reassignment of MTOC function from centrosomes to the apical membrane is associated with a physical hand-off of nucleators of microtubule assembly. PMID- 22425161 TI - Clinical effects of using a reloading multiband ligator with an SD-c conductor for endoscopic variceal ligation over subsequent sessions. AB - OBJECTIVE: The aim of the study was to compare the cost-effectiveness, efficacy and safety of using a reloading multiband ligator with a neotype conductor (SD-c) with using a disposable one for endoscopic variceal ligation (EVL) over subsequent sessions. METHODS: Patients undergoing variceal ligation over subsequent sessions were randomly subjected to EVL using a reloading multiband ligator with an SD-c (reloading group) or a disposable ligator (control group). The cost, efficacy and safety were analyzed and compared between the two groups. RESULTS: A total of 460 patients underwent at least one session of EVL. Variceal obliteration was achieved in 124 patients (69%) in the reloading group and in 130 patients (70%) in the control group. The number of cases in which an extra band was released during deployment was three in the reloading group and two in the controls. Acute fever was seen in 38 cases after EVL in the reloading group and in 40 cases in the controls. In the reloading group, acute variceal bleeding events within the first 24h after EVL were seen in three out of 327 (0.92%) patients versus six out of 335 (1.79%) in the control group. However, there were no significant differences between the two groups (P>0.05). The cost savings were 2350 yuan/$369.89 for one session and 4277 yuan/$673.19 per patient on average. CONCLUSION: Although there were no statistically significant differences in efficacy or safety between the two patient groups, using a reloading multiband ligator for EVL is nevertheless a cost-savings procedure. PMID- 22425162 TI - Indirect laryngoscopy with rigid 70-degree laryngoscope as a predictor of difficult direct laryngoscopy. AB - INTRODUCTION AND OBJECTIVES: The commonly-used predictors for difficult airway management are not very accurate. We investigate the power of indirect laryngoscopy with the rigid 70-degree laryngoscope as a predictor of difficult visualisation of the larynx with direct laryngoscopy. METHODS: We performed preoperative indirect laryngoscopy with the rigid laryngoscope on 300 patients. The vision obtained was classified into four grades: 1 (vocal cords visible), 2 (posterior commissure visible), 3 (epiglottis visible) and 4 (no glottic structure visible). Grades 3 and 4 were considered predictors of difficult larynx visualisation. Next, direct laryngoscopy with the Macintosh laryngoscope was carried out on the patients under general anaesthesia. Positive value was defined as a Cormack and Lehane III and IV. Other common clinical predictors were also analysed. A logistic regression model using the relevant variables was elaborated. We also investigated predictors of difficult visualisation of the larynx with indirect laryngoscopy. RESULTS: The model found and the coefficients for preparing it were: f(x)= -10.097+5.145 indirect laryngoscopy (3-4)+3.489 retrognathia+2.548 mouth opening <3.5 cm+1.911 thyromental distance <6.5 cm+.352 snorer+(0.151 cm neck thickness). This model provided a correct result in 94.3% of cases. In the case of indirect laryngoscopy, the model found was: f(x)= 2.641+0.920 snorer+0.875 cervical mobility. CONCLUSIONS: Indirect laryngoscopy was the independent variable with the greatest predictive power. Snoring is a common predictor in both laryngoscopy models. PMID- 22425163 TI - Perceiving integration of a complementary medicine service within a general surgery department through documentation of consultations: a thematic analysis. AB - OBJECTIVE: This study aims to examine the meaning and practical implications of integration of a complementary medicine-based surgery service in a hospital setting (CISS--Complementary/Integrative Surgery Service) through analysis of consultation reports associated with this service. METHODS: Thematic analysis was used to evaluate CISS consultation reports in a hospital electronic consultant charting system during the first half year of the service's activity. RESULTS: 304 consultation reports were analyzed. Nurses initiated significantly more consultations than physicians (55% vs 7%). Consultation requests were gradually more focused on specific symptoms, possibly manifesting a better understanding of the scope of complementary medicine in the surgery setting. CISS practitioners responded in more biomedical language over time, albeit offering a more holistic perspective regarding patients' needs as well as clarifications regarding the nature of the treatment they provided. CONCLUSIONS: Diverse communication patterns in consultations evolved over time representing dynamics in multiple levels of integration of the CISS. PRACTICE IMPLICATIONS: Documented communication through consultations can provide a window to the process of integration of complementary medicine-based services in health systems. PMID- 22425164 TI - Child welfare policy and practice on children's exposure to domestic violence. AB - OBJECTIVES: This article reviews research, policy and programming in Australia, Canada and the US on the child welfare response to EDV. METHOD: The review draws on searches of standard research databases, interviews with researchers and practitioners, and the authors' own research. RESULTS: Although EDV is underreported, across studies 7% to 23% of youths in general population surveys experienced EDV, 36-39% of youth in DV cases have witnessed the violence, and 45 46% of primary caregivers in child maltreatment investigations have experienced DV. Mandatory reporting can increase the number of cases that come to the attention of child welfare, but without resources for training and programming can lead to inappropriate reports, lack of referral for further assessment, and strains on the child welfare system. Improving the child welfare response to EDV can include collaboration between child welfare workers and DV advocates; increased training on screening for DV; new protocols on DV; and dedicated DV staffing within child welfare agencies. In recent years, policy and program attention to EDV has also been embedded within broader national efforts to protect children from violence and maltreatment. Differential response models that eschew investigation in favor of assessment and service delivery hold promise for families with DV. CONCLUSIONS: Empirical data are limited, but current research and practice experience suggest that child welfare agencies seeking to improve the response to EDV should collaborate with other disciplines involved with preventing and responding to DV, seek resources to support training and programming, consider methods that avoid stigmatizing parents, and build in a program evaluation component to increase knowledge about effective practice. PMID- 22425165 TI - Parental child abuse potential and subsequent coping competence in disadvantaged preschool children: moderating effects of sex and ethnicity. AB - This study evaluated the effects of abuse potential in parents on subsequent coping competence domains in their children, using a model empirically supported in a high-risk community sample by Moreland and Dumas (2007). Data from an ethnically diverse sample of 579 parents enrolled in the PACE (Parenting Our Children to Excellence) program was used to evaluate whether parental child abuse potential assessed at pre-intervention negatively contributed to child affective, achievement, and social coping competence in preschoolers one year later, and whether these associations were moderated by sex or ethnicity. Cross-sectional results indicated that parental child abuse potential was negatively related to child affective and achievement coping competence, after accounting for variance associated with child behavior problems. However, child abuse potential was not predictive of subsequent coping competence in any domain after controlling for previous levels of child coping competence. No moderating effects were found for sex and ethnicity, but results showed main effects of sex and ethnicity in cross sectional analyses. Clinical implications and future directions are discussed. PMID- 22425166 TI - Hepatectomy for noncolorectal non-neuroendocrine metastatic cancer: a multi institutional analysis. AB - BACKGROUND: Although hepatic metastasectomy is well established for colorectal and neuroendocrine cancer, the approach to hepatic metastases from other sites is not well defined. We sought to examine the management of noncolorectal non neuroendocrine liver metastases. STUDY DESIGN: A retrospective review from 4 major liver centers identified patients who underwent liver resection for noncolorectal non-neuroendocrine metastases between 1990 and 2009. The Kaplan Meier method was used to analyze survival, and Cox regression models were used to examine prognostic variables. RESULTS: There were 420 patients available for analysis. Breast cancer (n = 115; 27%) was the most common primary malignancy, followed by sarcoma (n = 98; 23%), and genitourinary cancers (n = 92; 22%). Crude postoperative morbidity and mortality rates were 20% and 2%, respectively. Overall median survival was 49 months, and 1, 3, and 5-year Kaplan-Meier survival rates were 73%, 50%, and 31%. Survival was not significantly different between the various primary tumor types. Recurrent disease was found after hepatectomy in 66% of patients. In multivariable models, lymphovascular invasion (p = 0.05) and metastases >=5 cm (p = 0.04) were independent predictors of poorer survival. Median survival was shorter for resections performed between 1990 and 1999 (n = 101, 32 months) when compared with resections between 2000 and 2009 (n = 319, 66 months; p = 0.003). CONCLUSIONS: Hepatic metastasectomy for noncolorectal non neuroendocrine cancers is safe and feasible in selected patients. Lymphovascular invasion and metastases >=5 cm were found to be associated with poorer survival. Patients undergoing metastasectomy in more recent years appear to be surviving longer, however, the reasons for this are not conclusively determined. PMID- 22425167 TI - Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk. AB - BACKGROUND: Elevated levels of total plasma homocysteine are a risk factor for atherosclerotic disease. AIMS: The rationale behind this study is to explore the correlation between degree and site of coronary lesion and hyperhomocysteinemia in Lebanese CAD patients and assess environmental and genetic factors for elevated levels of total plasma homocysteine. METHODS: A total of 2644 patients were analyzed for traditional CAD risk factors. Logistic regression was performed to determine the association of hyperhomocysteinemia with degree and site of coronary lesions controlling for risk factors. Environmental and genetic factors for hyperhomocysteinemia were analyzed by logistic regression using a candidate gene approach. RESULTS: Traditional risk factors were correlated with stenosis. Hyperhomocysteinemia associated with increased risk of overall stenosis, and risk of mild and severe occlusion in major arteries. Hyperhomocysteinemia and hypertension were highly correlated suggesting that hyperhomocysteinemia acts as a hypertensive agent leading to CAD. Diuretics and genetic polymorphisms in MTHFR and SLCO1B1 were associated with hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is a medical indicator of specific vessel stenosis in the Lebanese population. Hypertension is a major link between hyperhomocysteinemia and CAD occurrence. Genetic polymorphisms and diuretics' intake explain partly elevated homocysteine levels. This study has important implications in CAD risk prediction. PMID- 22425168 TI - Inverse association between the existence of coronary artery disease and progression of abdominal aortic aneurysm. AB - OBJECTIVES: A strong degree of co-existence between coronary artery disease (CAD) and abdominal aortic aneurysm (AAA) is widely acknowledged, however, it remains to be elucidated whether the existence of CAD is associated with an accelerated expansion rate of AAA. Also, the relationship between preoperative CAD and postoperative major adverse cardiovascular events (MACE) has not been examined in Japanese patients. The aim of this study was to investigate the deleterious effects of CAD on the progression of AAA and the onset of postoperative MACE after elective AAA repair. METHODS AND RESULTS: A retrospective cohort study of 665 consecutive Japanese patients who underwent elective surgical repair for infrarenal AAA at 2 high-volume Tokyo hospitals from 2003 through 2010 was performed. Preoperative CAD was shown to be a significant determinant of postoperative MACE (HR 2.29; 95%CI, 1.12-4.66; p=0.02). In the analysis of 510 patients for whom there were at least 2 follow-up CT scans of the size of their AAA before repair, the existence of CAD was shown to be inversely associated with the accelerated expansion rate of AAA. CONCLUSION: This study on the patients undergone elective repair for infrarenal AAA identified an inverse association between the existence of CAD and progression of AAA as well as the significant impact of preoperative CAD on the occurrence of postoperative MACE after elective AAA repair. PMID- 22425170 TI - Using biomarkers in sewage to monitor community-wide human health: isoprostanes as conceptual prototype. AB - Timely assessment of the aggregate health of small-area human populations is essential for guiding the optimal investment of resources needed for preventing, avoiding, controlling, or mitigating exposure risks. Seeking those interventions yielding the greatest benefit with respect to allocation of resources is essential for making progress toward community sustainability, promoting social justice, and maintaining or improving health and well-being. More efficient approaches are needed for revealing cause-effect linkages between environmental stressors and human health and for measuring overall aggregate health of small area populations. A new concept is presented--community health assessment via Sewage Chemical Information Mining (SCIM)--for quickly gauging overall, aggregate health status or trends for entire small-area populations. The approach--BioSCIM- would monitor raw sewage for specific biomarkers broadly associated with human disease, stress, or health. A wealth of untapped chemical information resides in raw sewage, a portion comprising human biomarkers of exposure and effects. BioSCIM holds potential for capitalizing on the presence of biomarkers in sewage for accomplishing any number of objectives. One of the many potential applications of BioSCIM could use various biomarkers of stress resulting from the collective excretion from all individuals in a local population. A prototype example is presented using a class of biomarkers that measures collective, systemic oxidative stress--the isoprostanes (prostaglandin-like free-radical catalyzed oxidation products from certain polyunsaturated fatty acids). Sampling and analysis of raw sewage hold great potential for quickly determining aggregate biomarker levels for entire communities. Presented are the basic principles of BioSCIM, together with its anticipated limitations, challenges, and potential applications in assessing community-wide health. Community health assessment via BioSCIM could allow rapid assessments and intercomparisons of health status among distinct populations, revealing hidden or emerging trends or disparities and aiding in evaluating correlations (or hypotheses) between stressor exposures and disease. PMID- 22425169 TI - Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol. AB - OBJECTIVES: Vitamin D and serum lipid levels are risk factors for cardiovascular disease. We sought to determine if vitamin D (25OHD) interacts at established lipid loci potentially explaining additional variance in lipids. METHODS: 1060 individuals from Utah families were used to screen 14 loci for SNPs potentially interacting with dietary 25OHD on lipid levels. Identified putative interactions were evaluated for (1) greater effect size in subsamples with winter measures, (2) replication in an independent sample, and (3) lack of gene-environment interaction for other correlated dietary factors. Maximum likelihood models were used to evaluate interactions. The replicate sample consisted of 2890 individuals from the Family Heart Study. Putative 25OHD receptor binding site modifying SNPs were identified and allele-specific, 25OHD-dependent APOA5 promoter activity examined using luciferase expression assays. An additional sample with serum 25OHD measures was analyzed. RESULTS: An rs3135506-25OHD interaction influencing HDL-C was identified. The rs3135506 minor allele was more strongly associated with low HDL-C in individuals with low winter dietary 25OHD in initial and replicate samples (p=0.0003 Utah, p=0.002 Family Heart); correlated dietary factors did not explain the interaction. SNP rs10750097 was identified as a putative causative polymorphism, was associated with 25OHD-dependent changes in APOA5 promoter activity in HEP3B and HEK293 cells (p<0.01), and showed similar interactions to rs3135506 in family cohorts. Linear interactions were not significant in samples with serum 25OHD measures; however, genotype-specific differences were seen at deficient 25OHD levels. CONCLUSIONS: A 25OHD receptor binding site modifying APOA5 promoter polymorphism is associated with lower HDL-C in 25OHD deficient individuals. PMID- 22425171 TI - Airport environmental noise mapping and land use management as an environmental protection action policy tool. The case of the Larnaka International Airport (Cyprus). AB - The evidence from epidemiological studies on the association between exposure to traffic and aircraft noise and hypertension and ischemic heart disease has increased during the recent years. Both road traffic and aircraft noise increase the risk of high blood pressure. Environmental noise mapping, as per the 2002/49/EC Directive, is an obligation of all European Union (EU) member states. In the framework of the present article a complete Strategic Noise Mapping research and Action Noise Plans assessment and evaluation are presented and aim to access land use management as an effective tool for protection from aircraft noise. The case of the Larnaka International Airport in Cyprus, a typical Mediterranean airport, (considered as a "large airport" according to the above EU Directive and the recent Cyprus Legislation Law No. 224(Iota)/2004), is presented. In this paper a review of both assessment and action implementation procedures focusing on the dominant--in the area--aircraft traffic noise is presented, with emphasis to (a) a full calculation of Strategic Noise Map (SNM) scenarios of actual and future airport operation using the ECAC.CEAC Doc 29 methodology for both EU common indicators L(den) and L(night) in scales of 5 dB, (b) a full evaluation of results with emphasis to the Larnaka greater area land uses and the exposure of inhabitants in residences in various levels of environmental noise, and (c) a full evaluation of Noise Action Plans (NAP) introducing especially a new land use management scheme for the future Larnaka Town Land Use Plan. PMID- 22425172 TI - Haemocytic leukemia in Prince Edward Island (PEI) soft shell clam (Mya arenaria): spatial distribution in agriculturally impacted estuaries. AB - Intensive farming of potatoes in Prince Edward Island (PEI) relies on the repeated and widespread application of fertilizers and pesticides. In PEI the main potato farming areas are in close proximity and drain directly to estuaries. Runoff from high agricultural activity watersheds could impact benthic organism health in the depositional zone of downstream estuaries. The estuarine filter feeder Mya arenaria (soft-shell clam) could be particularly vulnerable to both particle-adsorbed and water soluble contaminants. M. arenaria is susceptible to haemocytic leukemia. In May 2009, we established that heavily proliferated leukemia (HPL) prevalence was generally higher in PEI estuaries located downstream of high intensity potato farming (Dunk and Wilmot estuaries) watersheds than in estuaries downstream of lower intensity areas. Using Mab-1E10 based immunocytochemistry we observed that leukemic haemocytes from the Dunk and Wilmot estuaries were 1E10 negative whereas those from the Ox/Sheep estuary (low potato farming intensity) were 1E10 positive. The expression of genes in the p53 tumour suppressor pathway enabled us to differentiate groups of leukemic and normal M. arenaria, validating our diagnoses. In October 2009, we confirmed that HPL prevalence was elevated in the Dunk and Wilmot estuaries compared to reference (Souris River). Moreover, leukemia prevalence declined with distance from the river mouths along transects through the Dunk and Wilmot estuaries. The pesticides beta-endosulfan and alpha-endosulfan were detected in surface sediments from the Dunk and Wilmot estuaries, but not in sediments from either the Souris River or several other lower intensity potato farming watersheds. Our study provides evidence of an association between intensity of potato farming and prevalence of clam leukemia at downstream estuaries in PEI. PMID- 22425173 TI - The seasonality of phosphorus transfers from land to water: implications for trophic impacts and policy evaluation. AB - The Nitrates Directive regulations are a Programme of Measures under the EU Water Framework Directive to protect waters from agricultural transfers of nitrogen and phosphorus. Soil phosphorus management to an agronomic optimum and closed winter periods for organic and inorganic fertiliser amendments are among a suite of policy measures to curtail diffuse pollution at catchment scale. In this investigation, two intensive grassland and two arable catchments (7-12 km(2)) in the Republic of Ireland were studied to link a high resolution spatial survey (<=2 ha) of soil P availability with P delivery in receiving rivers; monitored on a sub-hourly basis over one year. Data indicated that source risk, as defined by soil P availability and organic P loading, was less important than mobilisation and hydrological transfer potential which increased delivery due to runoff flashiness as described by a hydrological metric during the winter. Overall, however, annual TP loads were low to moderate (0.175 to 0.785 kg ha(-1) yr(-1)). The data also highlighted, without exception, the influences of summer background P loading and subsequent ecologically significant P concentrations from persistent point sources. This may have implications for expected ecological status and recovery in these catchments, which appeared more at risk in catchments with little buffering in terms of summer base flow dilution. Wetter winters and drier summers under climate change scenarios would likely increase stream P concentrations both during storms and during baseflows and would be particularly magnified in those catchments with flashy runoff and suppressed baseflow. These seasonal insights into source-to-delivery functions and risk (re)assessment were only possible with high resolution (spatial and temporal) data collection and will be important in influencing expectations of policies that are evaluated at larger scales but with coarser resolution sampling. PMID- 22425174 TI - Mercury accumulation in peatbogs at Czech sites with contrasting pollution histories. AB - Mercury (Hg) concentrations and accumulation patterns were studied in (210)Pb dated peat cores from three ombrotrophic sites in the Czech Republic with contrasting emission histories (Novodomske raseliniste, ND, and Bila Smeda, BS, in the polluted northern parts of the country, and Jezerni slat, JS, in a relatively pristine southern part of the Czech Republic). The Hg concentration varied significantly between sites. Whereas the sites in the northern part of the Czech Republic yielded a range of higher Hg concentrations (50-750 MUg kg(-1) for ND and 30-600 MUg kg(-1) for BS), a Hg concentration range of 40-220 MUg kg(-1) was reported at JS. At the northern localities, the highest Hg concentrations were detected at depths of 5-10 cm, corresponding to the period between the early 1960s until the late 1980s. In contrast, the highest Hg values at JS were observed at a depth of 10-15 cm, corresponding to the period between the early 1950s and the early 1970s. The maximum Hg accumulation rates were approximately 2* higher at the northern localities (ND: 106 MUg m(-2)yr(-1), BS: 90 MUg m( 2)yr(-1), JS: 43 MUg m(-2)yr(-1)). Although a decrease in the Hg concentration can be observed in the youngest segments of all the peat cores, a slight increase in Hg accumulation rates in the most recent peat segments (living Sphagnum moss) has been reported for all three sites (40-44 MUg m(-2)yr(-1)), which is approximately 2* higher than in peat bogs in western and northern Europe. This observation may either be related to a real recent increase in Hg emissions in Central Europe (active coal mining and burning and limited Hg pollution control in thermal power plants) or could indicate a preferential Hg binding mechanism in the living moss at the surface of the peat. PMID- 22425175 TI - Source strengths, transport pathways and delivery mechanisms of nutrients, suspended solids and coliforms within a small agricultural headwater catchment. AB - Analysis of water samples and accompanying flow data collected (on ~100 occasions) from well defined land drain outlets located in a small catchment in NE Scotland were made over a five year period. The complex relationship between individual sources that can exist even within a small (200 ha) agriculturally managed headwater catchment was clearly evident. On average ~60% of the measured flow from the catchment outlet was accounted for, with ~50% originating from field drains and 10% from the farmyard. Certain field drains stopped flowing during the summer. Flow from the farmyard was continuous, and because livestock were present all year round also represented a renewable source of potential contaminants. The majority of nitrate and suspended sediment originated directly from field drainage. The variability in nitrate concentration between individual field drains was large and probably reflected differences in soil drainage properties. Farmyard drainage contributed a large proportion of the ammonium, phosphate and Faecal Indicator Organisms (FIO) measured as a flux from the catchment. On numerous sampling occasions the combined flux from individual sources was greater than the corresponding loss measured at the catchment outlet. This was attributed to result from the temporary storage/retention mechanisms (sedimentation, transformation or biological uptake/exchange) that can operate within the stream channel. Despite many fields being grazed and/or receiving regular applications of slurry/manure, the majority ~60% of the total flux of FIO still originated from the 'farmyard', with significant contributions from the field drains only occurring during the autumn. The presence of field drinkers and secure well maintained fencing denying cattle access to the open drainage channel (often a recommended best management practice) may well have contributed to this observation. Benefits to water quality that might arise from riparian management, such as buffer strips in this particular situation may be limited due to the dominant contribution originating from land drains and farmyard. PMID- 22425176 TI - Contamination of benzotriazole ultraviolet stabilizers in house dust from the Philippines: implications on human exposure. AB - Seven compounds of benzotriazole ultraviolet stabilizers (BUVSs) were determined in house dust samples collected from a residential area (Malate: n = 17) and municipal dumping area (Payatas: n = 20) in the Philippines. Total concentrations of the 7 BUVSs in house dust ranged from ND (not detected) to 1020 ng/g in Malate and ND to 277 ng/g in Payatas. Among the target compounds, the most abundant BUVS was UV-234, with a median value of 84 ng/g (ND-813 ng/g) in Malate and 41 ng/g (ND-212 ng/g) in Payatas, respectively. Significantly higher concentrations of UV 326 (p<0.01) and UV-327 (p<0.05) were found in house dust samples from Malate than those from Payatas, suggesting that the household products are the major sources of contamination in the indoor microenvironment. The estimated daily intakes (EDIs) of BUVSs through house dust ingestion in the Philippines were two to four orders of magnitude lower than the guideline values. However, the EDI of 5 BUVSs for toddlers in this study was 5 times higher than those for adults, suggesting that toddlers are at higher risk. House dust may be an important exposure route of UV-234 (88%) and UV-326 (69%) in worst-case scenarios, which using high dust ingestion and worst-case exposure (P95). To our knowledge, this is the first comprehensive study on BUVSs in house dust samples from Asian developing countries and reporting the occurrence of UV-234 and UV-320 in dust samples. PMID- 22425177 TI - Neurodrinking: is alcohol a substrate in a novel, endogenous synthetic pathway for norepinephrine? AB - A number of preclinical and clinical studies indicate multiple types of interaction between ethanol intake and the mood-related neurotransmitter, norepinephrine (NE). For example, ethanol interacts with dopamine beta hydroxylase (DBH), an enzyme that plays an essential role in the only well established endogenous synthetic pathway for NE, whereby dopamine is hydroxylated to form NE. While the DBH pathway may indeed be the only endogenous mechanism for producing NE, another possibility is that multiple means have evolved for the biosynthesis of this very important neurotransmitter, where some pathways may be independent of DBH. If so, such redundancy would provide greater assurance that enough NE is available for the body to use in this neurotransmitter's various physiological roles. This paper puts forth the hypothesis ethanol is a substrate in a novel, endogenous synthetic pathway for NE, consistent with some studies showing that intake of ethanol increases the concentration of endogenous NE. Also consistent with this hypothesis, the molecular structure of ethanol is a physical subset of the structure of NE itself. If the hypothesis is correct, it may have important implications for understanding the physiological basis of alcohol use, abuse, and dependence in humans, as well as modeling these phenomena in animals. Importantly, the hypothesis is directly testable in rodents by presenting ethanol to DBH knockout mice, which are thought to lack NE, and then measuring if NE is synthesized in these animals. PMID- 22425178 TI - Michelangelo's eye disease. AB - Charged by the Pope Julius II for painting the Cappella Sistina in Rome (between 1508 and 1512), Michelangelo worked in an elevated scaffolding, in an anomalous position with dyes (including poisoning lead salts) and solvents (such as toxic turpentine) dripping on his face and continuously inhaling, in a dim environment illuminated only with oil lamps and candles, as he described himself and sketched in a sonet addressed to Giovanni da Pistoia. In 1510 he began suffering from eye disease: the main symptom was the necessity to elevate the document he was reading up to the level of his eyes. This defect disappeared few months after he finished painting his masterpiece. We hypothesize that the Michelangelo's eyes disease was a form of acquired and transitory nystagmus induced by the many hours he spent in up gaze, with a skew deviation, a form of ocular tilt reaction resulting from the impairment of spatial sensitivity (inversion illusion) due to the persistence of the artist's head in a horizontal position, looking upward. PMID- 22425179 TI - Factors associated with human papillomavirus vaccine-series initiation and healthcare provider recommendation in US adolescent females: 2007 National Survey of Children's Health. AB - OBJECTIVE: To identify factors associated with initiation of the human papillomavirus vaccine series and parental report of a healthcare provider recommendation of the human papillomavirus vaccine in adolescent females. DESIGN: Cross-sectional analysis of 2007 National Survey of Children's Health. PARTICIPANTS: Parents of 12-17 year-old US adolescent females. MAIN OUTCOME MEASURES: Associations of sociodemographic and healthcare factors with initiation of the human papillomavirus vaccine series and parental report of a healthcare provider recommendation of the human papillomavirus vaccine. RESULTS: Data were analyzed for 16,139 adolescent females. Almost 20% of adolescent females initiated the HPV vaccine series. Significantly higher proportions of adolescent females who initiated the human papillomavirus vaccine series vs. those who did not initiate the human papillomavirus vaccine series had a parental report of their healthcare provider recommending the human papillomavirus vaccine (84% vs. 20%). In multivariable analyses, adolescent females who were American Indian/Alaska Native, were multiracial, received the meningococcal vaccine, received the tetanus/tetanus-diphtheria/tetanus-diphtheria-acellular pertussis vaccine, or were poor had higher adjusted odds of initiating the human papillomavirus vaccine series; parental report of a healthcare provider recommendation of the human papillomavirus vaccine was associated with about 18 times the adjusted odds of initiating the human papillomavirus vaccine series. In separate multivariable analyses, adolescent females who were African-American and uninsured had lower adjusted odds of a parental report of a healthcare provider recommendation of the human papillomavirus vaccine. CONCLUSION: Parental report of a healthcare provider recommendation is significantly associated with human papillomavirus vaccine-series initiation. African-American race/ethnicity and uninsurance were associated with lower odds of a parental report of a healthcare provider recommendation of the human papillomavirus vaccine. Routine healthcare provider recommendation of human papillomavirus vaccination might improve adolescent females' human papillomavirus vaccination rates. PMID- 22425180 TI - Origin and evolution of X chromosome inactivation. AB - Evolution of the mammalian sex chromosomes heavily impacts on the expression of X encoded genes, both in marsupials and placental mammals. The loss of genes from the Y chromosome forced a two-fold upregulation of dose sensitive X-linked homologues. As a corollary, female cells would experience a lethal dose of X linked genes, if this upregulation was not counteracted by evolution of X chromosome inactivation (XCI) that allows for only one active X chromosome per diploid genome. Marsupials rely on imprinted XCI, which inactivates always the paternally inherited X chromosome. In placental mammals, random XCI (rXCI) is the predominant form, inactivating either the maternal or paternal X. In this review, we discuss recent new insights in the regulation of XCI. Based on these findings, we propose an X inactivation center (Xic), composed of a cis-Xic and trans-Xic that encompass all elements and factors acting to control rXCI either in cis or in trans. We also highlight that XCI may have evolved from a very small nucleation site on the X chromosome in the vicinity of the Sox3 gene. Finally, we discuss the possible evolutionary road maps that resulted in imprinted XCI and rXCI as observed in present day mammals. PMID- 22425181 TI - Lobaplatin induces apoptosis and arrests cell cycle progression in human cholangiocarcinoma cell line RBE. AB - The aim of this study was to determine the anticancer effects of lobaplatin in cholangiocarcinoma (CCA) RBE cells. We also explored the mechanism of action of lobaplatin by analyzing its influence on apoptosis and cell cycle. Our findings have shown that lobaplatin inhibits cell proliferations in human CCA cells with an IC50 value of approximately 5.26+/-0.63 MUg/mL. Flowcytometry assay confirmed that lobaplatin affected CCA cell survival by blocking cell cycle progression and inducing apoptosis. Lobaplatin treatment reduced Cyclin D1, CDK4, and CDK6 expression, which led to the blocking of G0/G1 transition. In addition, lobaplatin increased p53, Bax expression, caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage, and reduced Bcl-2 expression, which contributed to the apoptosis of CCA cells. Lobaplatin showed a good anti-tumour activity in in vitro models of human CCA cells. These results indicate that Lobaplatin, as the third-generation platinum antineoplastic agent, could be an effective chemotherapeutic agent in human CCA treatment through induction apoptosis and cell cycle arrest. PMID- 22425182 TI - The Rho-kinase inhibitor inhibits proliferation and metastasis of small cell lung cancer. AB - The purpose of this study was to investigate the effects of Rho-kinase inhibitor on the growth, proliferation, apoptosis, adhesion, invasion and migration of NCI H446 small cell lung cancer cells and to explore the underlying molecular mechanisms involved in this process. After treatment to NCI-H446 small cell lung cancer cells with Fasudil, a Rho-kinase inhibitor, cell biological behaviors were observed. Matrix metalloproteinase activity and Western blot assay were used to evaluate underlying molecular mechanisms. The IC50 of Fasudil to NCI-H446 small cell lung cancer cells was approximately 0.86 mg/ml (95% confidence limits: 0.65 1.17 mg/ml). After treatment with 0.75 mg/ml Fasudil, the ability of NCI-H446 small cell lung cancer cells, including growth, proliferation, adhesion, migration, and invasion were decreased, while their apoptosis was increased significantly. On the molecular level, the total amounts of active MMP2 and MMP9 were decreased about 20.5% (P<0.05) and 57.5% (P<0.01) respectively. Myosin phosphatase targeting subunit 1 phosphorylation (P-MYPT1) was reduced by 27.9% (P<0.05). The activation of caspase-3, and PARP cleavage in experimental group were significantly higher than those in normal control group (P<0.01). Meanwhile, treatment with Fasudil led to a remarkable reduction of the phosphorylated STAT3 (P-STAT3) (P<0.01). Taken together, our findings show that Fasudil prevents the growth, metastasis and induces apoptosis of NCI-H446 small cell lung cancer cells by inhibiting the Rho/Rho-kinase pathway. Changes in MMP2, MMP9, P-MYPT1, caspase 3, PARP cleavage and P-STAT3 may be one of its molecular mechanisms. PMID- 22425183 TI - Differential gene expression analysis related to extracellular matrix components in drug-resistant RPMI-8226 cell line. AB - Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for many types of cancers including multiple myeloma. It is becoming increasingly apparent that tumor microenvironment could provide a shelter to malignant plasma cells that allow their survival after initial drug exposure. This study demonstrates alterations in gene expression levels of several extracellular matrix (ECM) components in prednisone, vincristine and melphalan-resistant RPMI-8226 myeloma cells. Resistant RPMI-8226 cells were developed through stepwise selection of cells by increasing concentrations of drugs. Microarray analysis was carried out and genes up- or downregulated more than two-folds were considered as significant. Different types of ECM components were altered in different drug resistant RPMI-8226 sublines. ITGAL and ITGB2 were both overexpressed in vincristine resistant cell line whereas they were both downregulated in prednisone resistant subline. On the other hand, LAMC1 gene was drastically overexpressed in prednisone resistant subline whereas it was downregulated in its melphalan resistant variant. FN1 gene was only upregulated in vincristine resistant cells. However, COL21A1 which is an ECM component of the blood vessel walls, was drastically downregulated in all of the drug resistant RPMI-8226 sublines. ADAM17 gene was upregulated in melphalan resistant subline. This report provides a preliminary in vitro study to the relationship between drug resistance and ECM components in multiple myeloma. Since in vitro developed drug-resistant multiple myeloma sublines do not have similar microenvironment of tumor cells, correlation of ECM proteins with drug resistance requires further analysis. PMID- 22425184 TI - Long-lasting increase in [3H]CP55,940 binding to CB1 receptors following cocaine self-administration and its withdrawal in rats. AB - The present work has aimed on the neuroadaptive changes in CB1 receptor density that are evoked by self-administered cocaine use and subsequent withdrawal in rats. We employed a quantitative autoradiographic analysis using labeled [3H]CP55,940, a CB1 receptor agonist. To distinguish the passive pharmacological effects of cocaine from those related to motivation and the cognitive processes evoked by active cocaine self-administration, the "yoked" procedure was used. Our results demonstrate that repeated cocaine administration over 14 days induced up regulation of CB1 receptors in the cortical and subcortical brain areas of animals who received cocaine, whether the cocaine was actively self-administered or received passively (the "yoked" control group) and that the neuroadaptation of CB1 receptors persisted after the 10-day extinction phase. On the other hand, we found that only self-administering rats showed CB1 receptor up-regulation in numerous brain areas, which suggests that these structures may be directly linked to CB1 receptor control over motivational and cognitive processes. Moreover, the observed increase in [3H]CP55,940 binding in these brain areas likely indicates long-lasting neurobiological adaptations resulting from chronic cocaine self administration. In conclusion, we demonstrated that chronic cocaine self administration leads to increased CB1 receptor levels in numerous brain areas and that this neuroadaptation is maintained over a long-lasting extinction period. PMID- 22425185 TI - Suppression of electrical synapses between retinal amacrine cells of goldfish by intracellular cyclic-AMP. AB - Retinal amacrine cells of the same class in cyprinid fish are homotypically connected by gap junctions. The permeability of their gap junctions examined by the diffusion of Neurobiotin into neighboring amacrine cells under application of dopamine or cyclic nucleotides to elucidate whether electrical synapses between the cells are regulated by internal messengers. Neurobiotin injected intracellularly into amacrine cells in isolated retinas of goldfish, and passage currents through the electrical synapses investigated by dual whole-patch clamp recordings under similar application of their ligands. Control conditions led us to observe large passage currents between connected cells and adequate transjunctional conductance between the cells (2.02+/-0.82nS). Experimental results show that high level of intracellular cyclic AMP within examined cells block transfer of Neurobiotin and suppress electrical synapses between the neighboring cells. Transjunctional conductance between examined cells reduced to 0.23nS. However, dopamine, 8-bromo-cyclic AMP or high elevation of intracellular cyclic GMP leaves gap junction channels of the cells permeable to Neurobiotin as in the control level. Under application of dopamine (1.25+/-0.06nS), 8-bromo cyclic AMP (1.79+/-0.51nS) or intracellular cyclic GMP (0.98+/-0.23nS), the transjunctional conductance also remains as in the control level. These results demonstrate that channel opening of gap junctions between cyprinid retinal amacrine cells is regulated by high level of intracellular cyclic AMP. PMID- 22425186 TI - Hyperthyroidism differentially regulates neuropeptide S system in the rat brain. AB - Thyroid hormones play an important role in the regulation of energy balance, sleep and emotional behaviors. Neuropeptide S (NPS) is a recently discovered neuropeptide, regulating feeding, sleep and anxiety. Here, we examined the effect of hyperthyroidism on the gene and protein expression of neuropeptide S and its receptor (NPS-R) in the hypothalamus, brainstem and amygdala of rats. Our results showed that the expression of NPS and NPS-R was differentially modulated by hyperthyroidism in the rat brain. NPS and NPS-R mRNA and protein levels were decreased in the hypothalamus of hyperthyroid rats. Conversely NPS-R expression was highly increased in the brainstem and NPS and NPS-R expression were unchanged in the amygdala of these rats. These data suggest that changes in anxiety and food intake patterns observed in hyperthyroidism could be associated with changes in the expression of NPS and NPS-R. Thus, the NPS/NPS-R system may be involved in several hyperthyroidism-associated comorbidities. PMID- 22425187 TI - The thalidomide analgesic effect is associated with differential TNF-alpha receptor expression in the dorsal horn of the spinal cord as studied in a rat model of neuropathic pain. AB - The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is well recognized as a key player in nociceptive signaling. Yet, therapeutic capitalization of this knowledge requires a better understanding of how TNF receptors (TNFR) contribute to pain. To address this question, we studied TNFR expression in the chronic sciatic nerve constriction (CCI) model of neuropathic pain. CCI and sham operated rats received two subcutaneous injections (one immediately after surgery, the other on postoperative day 5) containing either saline, GABA-reuptake inhibitor (NO-711), insulin-like growth factor-1 (IGF-1), ZVAD or thalidomide. Mechanical (using von Frey filaments) and thermal hypersensitivity (Hargreaves test) were assessed preoperatively and weekly during the first four postoperative weeks. Spinal cord dorsal horn samples were collected from animals that were sacrificed at 2 weeks and 4 weeks after surgery, and analyzed for TNFR1 and TNFR2 mRNA levels by qPCR and protein levels by Western blot. Compared to saline, all applied drug treatments resulted in a faster recovery from mechanical and thermal hypersensitivity, yet in a potency order of thalidomide>ZVAD=IGF-1>NO-711. CCI resulted in increased TNFR1 and TNFR2 mRNA and protein levels in the ipsilateral dorsal horn. Thalidomide was the only treatment that attenuated these increases. Finally, animals that showed a poor behavioral recovery were characterized by a significantly higher TNFR1/TNFR2 mRNA ratio. These data show that differential expression of TNFR in the dorsal horn is associated with recovery from pain in this model and suggest that the analgesic effects of thalidomide may act via this mechanism. PMID- 22425188 TI - COMT Val158Met genotype and the common basis of error and conflict monitoring. AB - The present study investigated the possibility that different aspects of performance monitoring share a common dopaminergic foundation. For this purpose we analyzed the influence of the COMT Val(158)Met polymorphism on electrophysiological markers of conflict and error monitoring, respectively. An EEG was recorded while 65 healthy subjects completed a response-conflict evoking task. In the event-related potential (ERP), both the conflict-N400 as well as the error-related negativity (ERN) were diminished in homozygous carriers of the Met allele. Moreover, the shared variance of both deflections was substantially explained by the COMT Val(158)Met genotype. These findings suggest that the relation between error- and conflict-related processes in the medial frontal cortex is mediated by a common molecular mechanism, namely the individual magnitude of phasic dopaminergic transmission. PMID- 22425189 TI - An integrated analytical framework for quantifying the LCOE of waste-to-energy facilities for a range of greenhouse gas emissions policy and technical factors. AB - This study presents a novel integrated method for considering the economics of waste-to-energy (WTE) facilities with priced greenhouse gas (GHG) emissions based upon technical and economic characteristics of the WTE facility, MSW stream, landfill alternative, and GHG emissions policy. The study demonstrates use of the formulation for six different policy scenarios and explores sensitivity of the results to ranges of certain technical parameters as found in existing literature. The study shows that details of the GHG emissions regulations have large impact on the levelized cost of energy (LCOE) of WTE and that GHG regulations can either increase or decrease the LCOE of WTE depending on policy choices regarding biogenic fractions from combusted waste and emissions from landfills. Important policy considerations are the fraction of the carbon emissions that are priced (i.e. all emissions versus only non-biogenic emissions), whether emissions credits are allowed due to reducing fugitive landfill gas emissions, whether biogenic carbon sequestration in landfills is credited against landfill emissions, and the effectiveness of the landfill gas recovery system where waste would otherwise have been buried. The default landfill gas recovery system effectiveness assumed by much of the industry yields GHG offsets that are very close to the direct non-biogenic GHG emissions from a WTE facility, meaning that small changes in the recovery effectiveness cause relatively larger changes in the emissions factor of the WTE facility. Finally, the economics of WTE are dependent on the MSW stream composition, with paper and wood being advantageous, metal and glass being disadvantageous, and plastics, food, and yard waste being either advantageous or disadvantageous depending upon the avoided tipping fee and the GHG emissions price. PMID- 22425190 TI - Thyroid gland papillary carcinomas with "micropapillary pattern," a recently recognized poor prognostic finding: clinicopathologic and survival analysis of 7 cases. AB - Micropapillary carcinoma is a histologic pattern, rather than an independent entity, that has an aggressive clinical behavior regardless of location. Histologically, it is characterized by papillary cell groups in clear spaces. The micropapillary pattern in the thyroid gland has not been studied until recently but under other names such as hobnail features or oncocytic and, therefore, is poorly understood, and reported cases are few. We report the clinicopathologic features of 7 cases obtained from a cohort of 496 papillary thyroid carcinomas, which corresponds to a prevalence of 1.4%. The proportion of the micropapillary component accounted for between 5% and 20% of the tumors, was slightly more prevalent in men, correlated with the presence of lymphovascular permeation, and, in the survival analysis, showed lower survival (even at a short follow-up, 8.5 years) than conventional carcinoma without this component (P = .001); this is consistent with poor overall survival in the short term (2-5 years) reported for carcinomas with micropapillary pattern of other locations. We believe that owing to this difference in survival (>95% of patients with conventional papillary carcinoma are alive at 8.5 years versus 42% of those having at least 5% of micropapillary pattern), the micropapillary pattern should be correctly identified and stated in the pathology report when comprising at least 5% of the tumor. PMID- 22425191 TI - Evaluation of a visual feedback system in gait retraining: a pilot study. AB - Abnormal gait pattern of the frontal plane (i.e. Duchenne gait and Trendelenburg gait) may be caused by a variety of diseases. The aim of this pilot study was to evaluate the instantaneous effect of a visual feedback system on frontal plane pelvis and trunk movements in order to use it in patients with THR in subsequent studies. A total of 24 women (45-65 years) were included in the study. According to acute functional impairments the subjects were assigned to the control group (CG, no gait disorders, n=15, age=59+/-11 years, BMI=27+/-4) or to the intervention group (IG, n=9, age=61+/-4, BMI=29+/-5), respectively. First, in Measurement 1 (M1) kinematic reference values were captured in a standardized clinical gait analysis (MVN, XSens). Afterwards, the influence of a visual real time feedback on gait pattern was examined while using the feedback system (M2). While there was a significant difference of IG vs. CG in M1 in the mean inclination regarding pelvis and trunk movements, this was not detected in M2. Therefore it is concluded, especially in subjects with abnormal gait pattern, that the visualization leads to an improvement of the movement pattern of pelvis and trunk in the frontal plane while using the device. PMID- 22425192 TI - Dynamic equinus with hindfoot valgus in children with hemiplegia. AB - In children with hemiplegia, it is important to distinguish between equinus with hindfoot varus (equinovarus) or valgus (equinovalgus). Premature onset of medial gastrocnemius (GM) EMG in individuals with equinus is well documented. Premature onset of Peroneus longus (PL) EMG has been described in neurologically impaired adults with equinovalgus, but not in children. Our aim was to record the onset of PL and GM activity on the hemiplegic side of children with equinovalgus deformity. Fifteen children GMFCS 1 (3.8 yrs +/- 2) with hemiplegia had a goniometric assessment of passive ankle range of motion and assessment of ankle function from video and surface EMG recording during gait. The clinical and video observations were used to determine the equinovalgus, as defined by Wren, at initial contact (IC). The premature onset of muscle activity was normalised as a swing (SW) percentage prior to IC of the following stance (ST). A paired T-test compared the onset of muscle activity between PL and GM. The ankle passive dorsiflexion was 13 degrees +/- 12 degrees (hemiplegic side) versus 18 degrees +/- 10 degrees (non-involved side) (p<0.05). For the non-involved limb, the onset of GM activity was at 14% of the gait cycle (midstance), the onset of PL activity was at 19% (p<0.05). For the hemiplegic limb with equinovalgus, there was a premature onset activity of PL (-24%) and GM(-8%) (p<0.001). On the non involved side, the onset of PL activity occurred, as in adults, after the onset of GM activity, during ST. On the hemiplegic side, there was no triceps surae contracture and the onset of PL activity occurred prior to the onset of GM activity, during terminal SW. This study confirmed the overactivity of PL in hemiplegic children with equinovalgus. PMID- 22425193 TI - Residual gait deviations in adolescents treated during infancy for unilateral developmental dysplasia of the hip using Pemberton's osteotomy. AB - Early reduction using Pemberton's osteotomy has been suggested for treating DDH but no data on the long-term residual gait changes in such patients are available in the literature. This study aimed to bridge the gap by performing quantitative gait analysis on eleven females (age: 10.6 +/- 1.0 years) who were treated for unilateral DDH using open reduction with Pemberton's osteotomy at 1.6 +/- 0.5 years of age, and eleven age-matched healthy controls. Walking at a normal speed, the Pemberton group displayed significantly more anterior tilt, hiking at the affected side and rotation towards the unaffected side of the pelvis, and more knee flexion and ankle dorsiflexion in the affected limb. With this asymmetrical gait, they appeared to reduce the demands on the hip flexors and abductors, and knee extensors in the affected limb, which might have been involved during the osteotomy, but increased compensatory efforts from the hip extensors, ankle plantarflexors and knee flexors in the unaffected limb. PMID- 22425194 TI - Post-translational regulation of WRKY transcription factors in plant immunity. AB - Plants have evolved immune system to protect themselves against invading pathogens. Recent research has illustrated that signaling networks, after perception of diverse pathogen-derived signals, facilitate transcriptional reprogramming through mitogen-activated protein kinase (MAPK) cascades. WRKY proteins, which comprise a large family of plant transcription factors, are key players in plant immune responses. WRKY transcription factors participate in the control of defense-related genes either as positive or as negative regulators, and essentially are regulated at the transcriptional level. Emerging evidence emphasizes that group I WRKY transcription factors, which contain a conserved motif in the N-terminal region, are also activated by MAPK-dependent phosphorylation, underlining their importance in plant immunity. PMID- 22425195 TI - Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation. AB - OBJECTIVE: To investigate the role of activin-betaA subunit, activin type II receptors, inducible nitric oxide synthase (iNOS), and MUC1 in the pathogenesis of ectopic pregnancy (EP) and their involvement in the determination of the implantation site. DESIGN: Observational study. SETTING: Academic unit of reproductive and developmental medicine. PATIENT(S): Four women at the luteal phase, three pseudopregnant women at the time of hysterectomy for benign disease, and 10 archived cases of EP. We collected 14 Fallopian tubes were collected from four women at the luteal phase and three pseudopregnant women at the time of hysterectomy for benign disease; specimens from implantation site, trophoblast and remote sites from the implantation site were collected from 10 archived cases of EP. INTERVENTION(S): Immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE(S): Comparison of the expression of candidate molecules between the different groups. RESULT(S): The expression of activin-betaA subunit, activin type II receptors, and iNOS was statistically significantly increased and expression of MUC1 statistically significantly decreased in tubes bearing an EP. There was no statistically significant difference in the expression of the candidate molecules between the implantation and remote sites. Candidate molecules were also expressed in the trophoblast. CONCLUSION(S): The pathological expression of candidate molecules by tubes bearing an EP is not involved in the determination of implantation site. Additionally, candidate molecules may play a role in the regulation of trophoblast cells in vivo during early pregnancy. PMID- 22425196 TI - Development and validation of a three-dimensional in vitro model for uterine leiomyoma and patient-matched myometrium. AB - OBJECTIVE: To develop and validate a three-dimensional (3D) culture system of leiomyoma and myometrial cells. DESIGN: In vitro study of immortalized cultures of patient-matched leiomyoma and myometrium. SETTING: University hospital. PATIENT(S): Women undergoing hysterectomy for symptomatic leiomyomas. INTERVENTION(S): Immortalized cell cultures, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), cytoimmunofluorescence, and Western blot analysis. MAIN OUTCOME MEASURE(S): Morphologic features; expression of COL1A1, versican, fibronectin, dermatopontin, and transforming growth factor beta3 (TGF beta3); and integrin-mediated 3D structural formation. RESULT(S): Cells in 3D culture maintained spindle morphology. There was elevated expression of collagen 1A1 (6.66 +/- 1.5), total versican (4.78 +/- 0.5), fibronectin (3.94 +/- 0.3), and TGF-beta3 (2.21 +/- 0.1) as was seen in progenitor tissue. Dermatopontin gene was down-regulated (0.29 +/- 0.1), also similar to values in the surgical tissue sample. Myometrial cells in 3D culture responded to TGF-beta3 with increased gene expression of collagen 1A1, fibronectin, and versican, and decreased expression of dermatopontin gene recapitulating the leiomyoma phenotype. Integrin-beta1 inhibiting antibody disrupted the cell-extracellular matrix (ECM) communication and induced apoptosis. CONCLUSION(S): Three-dimensional 3D leiomyoma cell cultures maintain the molecular phenotype of progenitor tissue, produce ECM, and interact with the ECM directly. This model system allows for assessment of the mechanism of aberrant ECM formation as well as the effectiveness of various potential therapies. PMID- 22425197 TI - Administration of visfatin during superovulation improves developmental competency of oocytes and fertility potential in aged female mice. AB - OBJECTIVE: To examine whether visfatin administration during superovulation improves ovarian response, developmental competence of oocytes, and fertility in aged female mice. DESIGN: Controlled experimental study. SETTING: University hospital. ANIMAL(S): Two groups of differently aged C57BL female mice (6-11 and 26-31 weeks). INTERVENTION(S): Female mice were coinjected intraperitoneally with 5 IU pregnant mare's serum gonadotropin (PMSG) and visfatin of various doses (0 500 ng/mL), followed by 5 IU human chorionic gonadotropin (hCG) injection 48 hours later. Then the mice were immediately mated with an individual male. After 18 hours zygotes were cultured, and expression of ovarian visfatin and vascular endothelial growth factor (VEGF) was examined. Potential pregnancies of visfatin administered aged female mice were monitored for delivery of offspring. MAIN OUTCOME MEASURE(S): Number of zygotes retrieved, embryo developmental competency, fertility potential, ovarian visfatin and VEGF expression. RESULT(S): Ovarian visfatin expression was significantly decreased in the aged mice group compared with the young. Visfatin administration significantly increased embryo developmental rate and ovarian visfatin and VEGF expressions in the aged mice. Visfatin-administered aged mice delivered significantly higher numbers of offspring than controls. CONCLUSION(S): This study suggests that visfatin administration during superovulation plays an important role in regulating oocyte quality and can improve oocyte quality and fertility of aged female mice. PMID- 22425198 TI - A prospective cohort study of physical activity and time to pregnancy. AB - OBJECTIVE: To investigate the association between leisure-time physical activity (PA) and fecundability. DESIGN: Prospective cohort study. SETTING: Internet-based observational study of Danish women who were planning a pregnancy (2007-2009). PATIENT(S): A total of 3,628 women aged 18-40 years at baseline. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Time to pregnancy (TTP). Fecundability ratios (FRs) and 95% confidence intervals (CIs) were derived from discrete-time Cox models, with adjustment for potential confounders, such as body mass index (BMI). RESULT(S): We observed an inverse monotonic association between vigorous PA and fecundability (>= 5 h/wk vs. none: FR 0.68, 95% CI 0.54-0.85) and a weak positive association between moderate PA and fecundability (>= 5 vs. <1 h/wk: FR 1.18, 95% CI 0.98-1.43) after mutual adjustment for both PA types. Inverse associations between high vigorous PA and fecundability were observed within subgroups of age, parity status, and cycle regularity, but not among overweight or obese women (BMI >= 25 kg/m(2)). CONCLUSION(S): There was evidence for a dose-response relationship between increasing vigorous PA and delayed TTP in all subgroups of women with the exception of overweight and obese women. Moderate PA was associated with a small increase in fecundability regardless of BMI. These findings indicate that PA of any type might improve fertility among overweight and obese women, a subgroup at higher risk of infertility. Lean women who substitute vigorous PA with moderate PA may also improve their fertility. PMID- 22425199 TI - Evaluation of the ovarian reserve in women transplanted with frozen and thawed ovarian cortical tissue. AB - OBJECTIVE: To investigate ovarian reserve and ovarian function in women transplanted with frozen/thawed ovarian tissue. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): 18 women transplanted with their own frozen/thawed ovarian tissue. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Levels of antimullerian hormone (AMH), duration of function of the transplanted ovarian tissue, outcome of assisted reproduction. RESULT(S): Of the 18 women who received transplanted ovarian tissue, levels of AMH were measured in 12 women; AMH never exceed a concentration of 1 ng/mL, and in several cases they were below the detection limit of the assay in combination with regular menstrual cycles. Two women with AMH below the detection limit conceived spontaneously. The duration of function of the transplants was between 9 months and 7 years and still functioning. Twelve women received assisted reproduction therapy; in 72 cycles, 65 oocytes were retrieved. The pregnancy rate and live-birth rate per cycle were 6.9% (5 of 72) and 2.8% (2 of 72), respectively. CONCLUSION(S): The relatively poor outcome of assisted reproduction in women transplanted with frozen/thawed ovarian tissue may reflect reduced follicular selection rather than defective or aged oocytes. In normal women, reduced follicular selection with age may be part of explaining the decline in female fecundity with increasing age. PMID- 22425200 TI - Recurrent implantation failure: gamete and embryo factors. AB - Chromosomal abnormalities, sperm DNA damage, zona hardening, inadequate culture conditions, and suboptimal embryo development all play a significant role in the etiology of recurrent implantation failure. Evidence suggests that preimplantation genetic screening does not increase implantation or live birth rates. Comparative genomic hybridization array and analysis of single nucleotide polymorphisms could enable a more comprehensive screening of chromosomes. Assisted hatching may help to overcome zona hardening in selected cases. Optimal culture conditions and blastocyst transfer could contribute toward improving implantation and pregnancy rates. Novel embryo assessment and selection procedures, such as time-lapse imaging and metabolomics, may help in better evaluation of embryo quality and viability and help in selecting embryos with the highest implantation potential. The safety and efficacy of emerging treatment modalities should be evaluated in prospective randomized clinical trials before being applied in routine clinical practice. PMID- 22425201 TI - Intravenous recombinant tissue plasminogen activator thrombolysis in acute ischemic stroke due to middle cerebral artery dissection. AB - Beneficial effect of recombinant tissue plasminogen activator (rtPA) in cerebral arterial dissection is controversial. We experienced a 45-year-old man with acute ischemic stroke due to middle cerebral artery dissection, who was treated with rtPA. Characteristic vascular findings indicating dissection became evident only in subsequent angiographic examinations. Our case indicates that serial angiographic examinations should be essential after acute thrombolytic therapy, especially in young patients who are at a high risk of cerebral arterial dissection. PMID- 22425202 TI - The use of the Risky Sex Scale among adolescents receiving treatment services for substance use problems: factor structure and predictive validity. AB - This study evaluated the use of the Risky Sex Scale (RSS; T. O'Hare, 2001) among youth in outpatient treatment for substance use problems. An ethnically diverse sample of 394 adolescents (280 males; M(age) = 16.33 years, SD(age) = 1.15) was recruited from 2 treatment sites. The study was guided by two aims. First, a confirmatory factor analysis was conducted on RSS item responses. Findings replicated the factor structure identified in previous studies of undergraduate students cited for campus alcohol violations. Second, structural equation modeling was used to document associations between RSS subscales and self reported substance use and sexual risk behaviors. The risky sex expectancies subscale was significantly associated with co-occurring alcohol use and sex, alcohol use at last intercourse, and alcohol use during the prior 30 days. The risky sexual behaviors subscale was significantly associated with co-occurring drug use and sex, condom use at last intercourse, and unprotected intercourse during the prior 30 days. The factor structure of the RSS was consistent across age group (12-16 and 16-18 years) and across gender, and the links between the RSS subscales and health risk behaviors varied somewhat by gender but not by age group. These findings suggest that the RSS is an appropriate brief screening tool for predicting health risk behaviors among adolescents in substance abuse treatment. PMID- 22425203 TI - Comparison of complications by technique used in cochlear implants. AB - INTRODUCTION: Complications are a very sensitive indicator of the usefulness of a surgical technique. In cochlear implant surgery, there are 3 principal approaches: the classic approach uses the facial recess (FR), the suprameatal approach (SMA) does not require mastoidectomy and uses the creation of a tunnel over the facial nerve to enter the middle ear, and the endomeatal approach (EMA) is based on the completion of a groove in the posterior wall of external auditory canal. MATERIAL AND METHODS: A multicentre review of 208 patients with cochlear implants, comparing the different techniques. The complications were classified into major and minor. RESULTS: Among the 208 implanted patients, 10.5% (22 of 208) had complications. Of these, 2.88% (6 of 208) were major complications and 7.69% (16 of 208) were minor complications. Comparing the results obtained by the different approaches, the FR technique had the lowest rate of major complications (1.1%), followed by the EMA technique with 2.38% and SMA with 3.75%. As for minor complications, operations in the SMA group had the lowest rate (6.25%), followed by the EMA group (7.14%) and the group operated on using the FR technique presented the highest (10%). CONCLUSIONS: The 3 techniques described show very similar rates of complications. Consequently, we can conclude that they are safe and are alternatives. PMID- 22425204 TI - [Peritonsillar infections: prospective study of 100 consecutive cases]. AB - INTRODUCTION: Peritonsillar infection is the most frequent complication of acute tonsillitis. Peritonsillar infections are collections of purulent material, usually located between the tonsillar capsule and the superior constrictor of the pharynx. Peritonsillar infection can be divided into abscess and cellulitis. MATERIAL AND METHODS: We prospectively analysed the clinical data from 100 patients with peritonsillar infection from 2008 to 2010. The diagnosis of abscess or peritonsillar cellulitis was primarily based on obtaining pus through fine needle aspiration. RESULTS: Seventy-seven per cent of patients had no history of recurrent tonsillitis and 55% were receiving antibiotic treatment. Sixty-two cases were peritonsillar abscess and the rest were cellulitis. Trismus, uvular deviation and anterior pillar bulging were statistically associated with peritonsillar abscess (P<.005). All patients were admitted to hospital and treated with puncture-drainage, intravenous antibiotics (amoxicillin/clavulanate in 83% of cases) and a single dose of steroids. All patients were discharged on oral antibiotic therapy. The mean length of hospital stay was 3 days and the recurrence rate was 5%. CONCLUSIONS: Due to the absence of clinical practice guidelines, there are different therapeutic protocols. According to our experience, puncture-aspiration and administration of intravenous antibiotics is a safe, effective way to treat these patients. To determine the efficacy and safety of outpatient management, controlled studies would be needed. PMID- 22425205 TI - A new entity in the differential diagnosis of geniculate ganglion tumours: fibrous connective tissue lesion of the facial nerve. AB - Differential diagnosis of geniculate ganglion tumours includes chiefly schwannomas, haemangiomas and meningiomas. We report the case of a patient whose clinical and imaging findings mimicked the presentation of a facial nerve schwannoma.Pathological studies revealed a lesion with nerve bundles unstructured by intense collagenisation. Consequently, it was called fibrous connective tissue lesion of the facial nerve. PMID- 22425206 TI - Evolution of otosclerosis to cochlear implantation. AB - INTRODUCTION: Otosclerosis is an osteodystrophy of the labyrinthine capsule producing conductive hearing loss. If the process invades the cochlea, a sensorineural hearing loss usually takes place. The cochlear implant is a good alternative in these patients. OBJECTIVE: To ascertain the behaviour of cochlear implantation in otosclerosis. MATERIAL AND METHODS: We reviewed a database of 250 patients that underwent cochlear implantation, performing a retrospective study of 13 patients with clinical, audiological and/or imaging findings of bilateral otosclerosis. The 26 ears were studied as to their natural history, previous surgeries, evolution to profound hearing loss, computed tomography images, complications and functional results. RESULTS: Of the cases studied, 46% were female and 54% were men, with a mean age of 26 years at the onset of conductive hearing loss. Stapes surgery was performed in 19 ears (73%), with a mean patient age of 29 years, and 53% of them underwent cochlear implantation. Computed tomography results showed that there were signs of different degrees of radiological affectation in 54% of the ears. A total of 3 complications took place (23%): implant failure, overstimulation of the facial nerve and bilateral tinnitus were found. One year after implantation, the average percentages of correct 2-syllable words were 80% and 85% in open sentences. CONCLUSIONS: Patients having profound bilateral sensorineural hearing loss secondary to otosclerosis obtain great benefit from cochlear implantation. PMID- 22425207 TI - Optimization aspects of comprehensive two-dimensional gas chromatography. AB - Comprehensive two-dimensional gas chromatography (GC*GC) was first introduced nearly two decades ago. Currently, it is one of the most powerful and effective techniques for the characterization and analysis of a variety of complex mixtures. GC*GC is based upon separations utilizing two chromatographic columns of differing selectivity, connected in series through an interface known as the modulator. The main role of the modulator is to trap and/or sample the primary column effluent and periodically inject it into the secondary column. This increasingly popular technique results in an enhanced separation with greatly improved peak capacity. In addition, structured chromatograms are typically generated when compounds belonging to homologous series are present in the sample. However, method optimization in GC*GC can be difficult and time consuming. This review focuses on the optimization of main operational parameters in GC*GC. Consideration is given to aspects such as stationary phase chemistries, column dimensions, carrier gas flow, temperature programs, modulation and detector settings. PMID- 22425208 TI - Smart polymer mediated purification and recovery of active proteins from inclusion bodies. AB - Obtaining correctly folded proteins from inclusion bodies of recombinant proteins expressed in bacterial hosts requires solubilization with denaturants and a refolding step. Aggregation competes with the second step. Refolding of eight different proteins was carried out by precipitation with smart polymers. These proteins have different molecular weights, different number of disulfide bridges and some of these are known to be highly prone to aggregation. A high throughput refolding screen based upon fluorescence emission maximum around 340 nm (for correctly folded proteins) was developed to identify the suitable smart polymer. The proteins could be dissociated and recovered after the refolding step. The refolding could be scaled up and high refolding yields in the range of 8 mg L(-1) (for CD4D12, the first two domains of human CD4) to 58 mg L(-1) (for malETrx, thioredoxin fused with signal peptide of maltose binding protein) were obtained. Dynamic light scattering (DLS) showed that polymer if chosen correctly acted as a pseudochaperonin and bound to the proteins. It also showed that the time for maximum binding was about 50 min which coincided with the time required for incubation (with the polymer) before precipitation for maximum recovery of folded proteins. The refolded proteins were characterized by fluorescence emission spectra, circular dichroism (CD) spectroscopy, melting temperature (T(m)), and surface hydrophobicity measurement by ANS (8-anilino1-naphthalene sulfonic acid) fluorescence. Biological activity assay for thioredoxin and fluorescence based assay in case of maltose binding protein (MBP) were also carried out to confirm correct refolding. PMID- 22425209 TI - Determination of N-methyl-1,3-propanediamine in bovine muscle by liquid chromatography with triple quadrupole and ion trap tandem mass spectrometry detection. AB - Morantel, pyrantel and their drug-related metabolites in food of animal-origin are regulated as sum of residues which may be hydrolysed to N-methyl-1,3 propanediamine (NMPA). In this study, an isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method with pentafluoropropionic acid anhydride (PFPA) derivatization was developed for the determination of NMPA in bovine muscle. A stable isotope labeled internal standard N-methyl-d(3)-3,3'-d(2) propane-1,3-diamine (NMPA-d(5)) was synthesized as internal standard. NMPA was derivatized with PFPA to form an N,N'-bis (pentafluoroacyl) derivative (NMPA PFPA) and analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS/MS) and liquid chromatography ion trap mass spectrometry (LC-IT-MS/MS) using negative ion electrospray ionization (ESI). Chromatographic behavior of several perfluorocarboxylic acid anhydride derivatives of NMPA and other structurally related diamines on C-18 and perfluorophenyl (PFP) columns was studied. Conversion of the parent drugs to NMPA under various hydrolysis conditions was evaluated. In addition, comparison of the matrix effect and linearity with isotopically labeled internal standard (I.S.) and analogous I.S. were performed and investigated. The method was validated using fortified bovine muscle samples. The apparent recovery (obtained after correction with an isotopically labeled I.S.) was between 89% and 97% and repeatability was less than 10%. The lowest LOD and LOQ (0.42 and 1.39MUg/kg, respectively) were obtained with LC-QqQ-MS/MS. PMID- 22425210 TI - Monolithic column based on a poly(glycidyl methacrylate-co-4-vinylphenylboronic acid-co-ethylene dimethacrylate) copolymer for capillary liquid chromatography of small molecules and proteins. AB - A new polymer monolith with three modes of reverse-phase, hydrophilic and cation exchange interaction was synthesized in 100 MUm i.d. fused-silica capillary by in situ polymerization procedure. The pre-polymerization mixture consisted of glycidyl methacrylate (GMA) and 4-vinylphenylboronic acid (VPBA) as bifunctional monomers, ethylene dimethacrylate (EDMA) as crosslinker, 1,4-butanediol (BDO) and diethylene glycol (DEG) as binary porogenic solvents, and azobisisobutyronitrile (AIBN) as initiator. The resulting poly(GMA-co-VPBA-co-EDMA) monolith showed a relatively homogeneous monolithic structure, good permeability and mechanical stability. Different ratios of monomers and porogens were used for optimizing the properties of monolithic column. The column performance was assessed by the separation of a series of neutral solutes, charge solutes, phenols and anilines. Compared with poly(GMA-co-EDMA) monolith, the proposed monolith exhibited more flexible adjustment of selectivity in terms of hydrophobic, hydrophilic, as well as cation-exchange interaction in the same chromatographic conditions. High column efficiencies for benzene derivatives with 70,000-102,000 theoretical plates/m could be obtained at a linear velocity of 0.265 mm/s. The run-to-run, column-to-column, and batch-to-batch repeatabilities of the retention times were less than 8.23%. Additionally, the purposed monolith was also applied to efficient separation of alkaloids and proteins for demonstrating its potential in biomolecule separation. PMID- 22425211 TI - Thallium in fractions of sediments formed during the 2004 tsunami in Thailand. AB - Thallium is a highly toxic element. Its concentration in sediment fractions from the 2004 tsunami in Thailand was investigated. A modified BCR procedure was used for sequential extraction. Tl was determined by flow injection differential pulse anodic stripping voltammetry. It was found that the majority of thallium in the investigated tsunami sediments (86-97 percent) is entrapped in the alumosilicate parent matter i.e. it is entirely immovable. Only the total destruction of this residual fraction with hydrofluoric acid made this thallium available. The conclusion strongly supports the hypothesis that thallium is mainly entrapped in alumosilicate parent matter. Total thallium concentration in the investigated tsunami sediments was divergent in various samples from 0.37 to 1.13 MUg g(-1) and significantly different from the reference area (0.05 MUg g(-1)). Tsunami sediment fractions from different sampling points are divergent in terms of total thallium concentration and concentration of mobile thallium. Generally, mobile thallium concentration was growing in sequence: water soluble fraction>>quinalphos>methylparathion>parathion>methylparaoxon>paraoxon>fench orphos>profenofos>malathion. A detection limit as low as 1 * 10(-12)M for fenitrothion sensing is realized with a 2.4% relative standard deviation (RSD) of three consecutive runs. The per-6-amino-beta-cyclodextrin:Eu(III):pesticide complexes and their sensing mechanism are evidenced from emission, NMR, FT-IR, binding constant measurement, Job's plot, ICD spectra, ESI-MS, lifetime measurements and molecular modeling studies. The proposed sensing is a consequence of Absorption Energy Transfer Emission (AETE) process as a result of better encapsulation of fenitrothion inside the cavity of per-6-amino-beta cyclodextrin:Eu(III) complex. The remarkable sensitivity and selectivity of fenitrothion compared to other OPs, is attributed to a more deeper binding and tighter fit of fenitrothion inside the CD cavity, which is evident from binding constant values and molecular modeling studies. This tighter fit ensures the replacement of two coordinating water molecules on Eu(III) ion, which may have contributed to the more selective sensing of fenitrothion. PMID- 22425223 TI - Sensitive colorimetric visualization of dihydronicotinamide adenine dinucleotide based on anti-aggregation of gold nanoparticles via boronic acid-diol binding. AB - A facile, highly sensitive colorimetric strategy for dihydronicotinamide adenine dinucleotide (NADH) detection is proposed based on anti-aggregation of gold nanoparticles (AuNPs) via boronic acid-diol binding chemistry. The aggregation agent, 4-mercaptophenylboronic acid (MPBA), has specific affinity for AuNPs through Au-S interaction, leading to the aggregation of AuNPs by self-dehydration condensation at a certain concentration, which is responsible for a visible color change of AuNPs from wine red to blue. With the addition of NADH, MPBA would prefer reacting with NADH to form stable borate ester via boronic acid-diol binding dependent on the pH and solvent, revealing an obvious color change from blue to red with increasing the concentration of NADH. The anti-aggregation effect of NADH on AuNPs was seen by the naked eye and monitored by UV-vis extinction spectra. The linear range of the colorimetric sensor for NADH is from 8.0 * 10(-9)M to 8.0 * 10(-6)M, with a low detection limit of 2.0 nM. The as established colorimetric strategy opened a new avenue for NADH determination. PMID- 22425224 TI - Impact of immobilization support on colorimetric microarrays performances. AB - We report here a comparison of support materials for colorimetric hybridization assays on microarrays. Four surfaces with various chemistries and architectures (roughness and porosity) were evaluated: (i) bare and (ii) activated polystyrene surfaces classically used for ELISA; (iii) a double-sided adhesive support; and (iv) a porous nitrocellulose/cellulose acetate membrane. Each substrate was functionalized with a microarray of probes and subjected to an enzymatic colorimetric DNA hybridization test. Tests were carried out in a 96-well assembly suitable for automated high-throughput analysis. Colorimetry results, microscopy observations and a chemiluminescence study showed that the test efficiency not only depends on the surface probe density but that the capacity of the material to retain the colored enzymatic product is also a critical parameter. All parameters being considered, the adhesive coated surface proposes the best surface properties for efficient colorimetric microarrays. PMID- 22425225 TI - Frequently used sleep questionnaires in epidemiological and genetic research for obstructive sleep apnea: a review. AB - BACKGROUND & AIMS: Many sleep questionnaires are utilized by the epidemiological and genetic research communities. This paper reviewed sleep-related questions and answers commonly used in epidemiological studies (focused on sleep apnea and snoring), with an emphasis on the utility of the response options. METHODS: A literature search was conducted to identify relevant sleep questionnaires. Questionnaires were limited to the English language and had to include questions specific to snoring or stop breathing during sleep. Questionnaires had to demonstrate a citation count >10 through Web of Science. A comparison of questions and answers, and elements important in the design of good quality instruments was conducted. RESULTS: Fourteen questionnaires met the inclusion criteria for final review. Validation was conducted for many of these instruments, though the methods and validation populations were highly variable. Study sample sizes were also relatively small and differed in methods of data analysis. These questionnaires were very heterogeneous, with only some (n = 6) allowing a "don't know" alternative. Six specified the time period referred to as "past month", one referred to "last three months" and the remaining questionnaires had no specific timeframe. The response alternatives to specific questions were Yes/No (n = 5), wording only like "never", "seldom", "often" (n = 4), or a frequency scale indicating times per week (n = 8). CONCLUSIONS: There is a need for improved standardized instruments not only to capture relevant sleep information but also to allow greater comparability between studies. PMID- 22425226 TI - [Burnout syndrome: a "true" cardiovascular risk factor]. AB - The burnout syndrome is characterized by emotional exhaustion, depersonalization and reduced personal accomplishment in individuals professionally involved with others. The burnout syndrome is poorly recognized, particularly in France, as a distinct nosology from adaptation troubles, stress, depression, or anxiety. Several tools quantifying burnout and emotional exhaustion exist, the most spread is the questionnaire called Maslach Burnout Inventory. The burnout syndrome alters cardiovascular function and its neuroregulation by autonomic nervous system and is associated with: increased sympathetic tone to heart and vessels after mental stress, lowered physiological post-stress vagal rebound to heart, and lowered arterial baroreflex sensitivity. Job strain as burnout syndrome seems to be a real independent cardiovascular risk factor. Oppositely, training to manage emotions could increase vagal tone to heart and should be cardio protective. PMID- 22425227 TI - Nicotine modulates the immunological function of dendritic cells through peroxisome proliferator-activated receptor-gamma upregulation. AB - We examined the effects of nicotine on differentiation and function of monocyte derived human dendritic cells (DCs). NiDCs, which were the DCs differentiated in the presence of nicotine, showed lower levels of CD1a. Secretion of IL-12 and TNF alpha by lipopolysaccharide (LPS)-stimulated NiDCs was significantly suppressed compared to monocyte-derived DCs grown without nicotine. NiDCs displayed a diminished capacity to induce allogeneic T cell proliferation with a reduced production of IFN-gamma, and maintained/enhanced LPS-mediated expression of coinhibitory molecules. Interestingly, NiDCs enhanced the expression of nuclear receptor peroxisome proliferator-activated receptors gamma (PPAR gamma), which has immunomodulatory properties. Expression of PPAR gamma and PPAR gamma-target genes was significantly inhibited by pretreatment with d-tubocurarine, antagonist of non-selective nicotinic acetylcholine receptors (nAChR). In addition, reduction of Th1 responses was inhibited after blocking nAChR-mediated signal. These data suggest the effect of nicotine on altering DC immunogenicity by impeding Th1 immunity is partially mediated by upregulation of PPAR gamma. PMID- 22425228 TI - The human IL-7 receptor gene: deletions, polymorphisms and mutations. AB - Most T cell subsets depend on IL-7 for survival. IL-7 binds to IL-7Ralpha and gammac, initiating the signaling cascade. Deletion of IL-7Ra in humans has, for some time, been known to cause severe combined immunodeficiency. More recently, polymorphisms in IL-7R have been shown be a risk factor for a number of diseases that are autoimmune or involve excess immune and inflammatory responses including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease, atopic dermatitis, inhalation allergy, sarcoidosis and graft-versus host disease. The polymorphism that affects risk to most of these immunopathologies is T244I at the border of the extracellular domain and the transmembrane region. The same region has recently been shown to harbor gain-of-function mutations in acute lymphoblastic leukemia. These studies have suggested new therapies that target the IL-7 pathway. PMID- 22425229 TI - Solid state 13C NMR characterisation study on fourth generation Ziegler-Natta catalysts. AB - In this study, solid state (13)C NMR spectroscopy was utilised to characterize and identify the metal-ester coordination in active fourth generation (phthalate) Ziegler-Natta catalysts. It is known that different donors affect the active species in ZN catalysts. However, there is still limited data available of detailed molecular information how the donors and the active species are interplaying. One of the main goals of this work was to get better insight into the interactions of donor and active species. Based on the anisotropy tensor values (delta(11), delta(22), delta(33)) from low magic-angle spinning (MAS) (13)C NMR spectra in combination with chemical shift anisotropy (CSA) calculations (delta(aniso) and eta), both the coordinative metal (Mg/Ti) and the symmetry of this interaction between metal and the internal donor in the active catalyst (MgCl(2)/TiCl(4)/electron donor) system could be identified. PMID- 22425230 TI - Bacterial effector interplay: a new way to view effector function. AB - Bacterial pathogens are dependent on virulence factors to efficiently colonize and propagate within their hosts. Many Gram-negative bacterial pathogens rely on specialized proteinaceous secretion systems that inject virulence factors, termed effectors, directly into host cells. These bacterial effector proteins perform various functions within host cells; however, regulation of their function within the host cell is highly enigmatic. It is becoming increasingly apparent that many of these effectors directly influence and regulate each other and their mechanisms within the host cell. We discuss the emerging theme of bacterial effector interplay impacting infection and the importance of investigating this topic. PMID- 22425231 TI - Gastrointestinal bleeding with the HeartMate II left ventricular assist device. AB - BACKGROUND: Continuous flow left ventricular assist devices (CF-LVADs) have yielded improved outcomes compared with pulsatile flow devices for patients on long-term support. However, significant rates of gastrointestinal bleeding (GIB) have been observed during CF-LVAD support. METHODS: From March 2006 through March 2011, 86 patients with chronic heart failure underwent implantation of a CF-LVAD (HeartMate II; Thoratec Corp., Pleasanton, CA). Records were reviewed to determine the prevalence of post-implant GIB, location of the bleeding site and associated morbidity and mortality. Uni- and multivariate analyses were conducted to identify independent predictors of GIB. RESULTS: GIB occurred in 19 patients (22.1%) with a duration of support that ranged from 5 to 456 days. Sources of GIB included small bowel and rectum in 6 patients each, large bowel in 2 patients and stomach in 1 patient. No definite source was identified in 4 patients. There were no deaths referable to GIB. Recurrent GIB occurred in 4 patients. History of a GIB prior to LVAD implant was the only variable significantly different between patients with and without post-implant GIB (21.1% vs 10.4%, p = 0.016), and was the only independent predictor of GIB (OR = 2.24, 95% CI 2.121 to 2.435, p = 0.004). CONCLUSIONS: Gastrointestinal bleeding is a frequent source of morbidity for patients on HeartMate II LVAD support but does not significantly impact survival. As implantation of CF-LVADs with non-pulsatile flow gains popularity for both bridge-to-transplant and destination therapy, a better understanding of the pathophysiology of GIB in these patients will be needed for minimizing this complication. PMID- 22425232 TI - Impact of low-dose B-type natriuretic peptide infusion on urine output after total artificial heart implantation. PMID- 22425233 TI - Non-cardiac surgery in patients on long-term left ventricular assist device support. AB - BACKGROUND: An increasing number of patients on left ventricular assist device (LVAD) support are requiring non-cardiac surgical (NCS) procedures. We reviewed our experience with the management of patients on continuous flow (CF) LVAD support undergoing NCS. METHODS: From March 2006 through March 2011, 86 patients with chronic heart failure underwent implantation of a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD. Clinical records of these patients were reviewed to identify patients who underwent NCS while on LVAD support, with a focus on peri operative death, bleeding, thrombosis, and device malfunction, as well as management of pre-operative anti-coagulation. RESULTS: While on CF-LVAD support, 20 patients underwent 25 NCSs, comprising 13 major and 12 minor procedures. Operations were performed electively in 22 and as emergencies in 3. No peri operative deaths, thromboembolic complications, or device malfunctions occurred. The incidence of bleeding requiring transfusion of packed red blood cells was 36.0%, including 25% of patients undergoing minor NCSs and 46.2% undergoing major NCSs (p = 0.004). All bleeding complications occurred in patients on both warfarin and aspirin pre-operatively. The only significant differences between patients who did and did not require transfusion were pre-operative warfarin use and significantly higher pre-operative international normalized ratio in the transfused group (1.9 +/- 0.4 vs 1.4 +/- 0.3; p = 0.008). CONCLUSIONS: Non cardiac operations can be performed safely in patients with CF-LVADs. It may possible to reduce peri-operative bleeding by lowering pre-operative anti coagulation goals, especially before major surgery. However, additional analysis is required to determine if this can be performed safely. PMID- 22425234 TI - Left ventricular dilation and functional impairment assessed by gated SPECT are indicators of cardiac allograft vasculopathy in heart transplant recipients. AB - BACKGROUND: Coronary angiography (CA) is the standard method for diagnosis of cardiac allograft vasculopathy (CAV). Little is known about the value of measuring left ventricular function over time, which can be derived from gated myocardial perfusion single-photon emission computed tomography (SPECT). We evaluated the potential of measuring myocardial perfusion and left ventricular function with gated SPECT, as compared with CA, to detect CAV in the follow-up of heart transplantation. METHODS: One hundred sixty-one heart transplant recipients (137 men, 24 women, age 50.7 +/- 12.2 years) were followed-up for 4.2 +/- 2.0 years by annual routine gated perfusion SPECT and consecutive CA. Myocardial perfusion was quantified by summed stress, rest and difference scores (SSS, SRS and SDS, respectively). Left ventricular function (ESV, EDV and LVEF) was derived from gated SPECT. Both were compared with angiographically defined stages of CAV. RESULTS: ESV/EDV derived from gated SPECT increased from 61 +/- 25 ml/169 +/- 39 ml in patients with no CAV over 74 +/- 38 ml/188 +/- 55 ml in patients with moderate CAV to 153 +/- 75 ml/278 +/- 86 ml in patients with severe CAV (p < 0.01 and p < 0.001), whereas LVEF decreased from 64 +/- 10% over 62 +/- 11% to 47 +/- 13% in patients with severe CAV (p < 0.001). Perfusion quantified by SRS and SSS increased from 1.2 +/- 1.5/1.9 +/- 2.3 over 1.9 +/- 1.4/2.8 +/- 2.0 to 6.5 +/- 5.1/7.7 +/- 5.8 in patients with severe CAV (p < 0.01). Overall, for the prediction of severe CAV, accuracy was found to be higher for gated SPECT functional analysis as compared with perfusion analysis. CONCLUSIONS: Impaired left ventricular function, as assessed by gated SPECT, correlated significantly with CAV. Thus, for this purpose, gated SPECT offers higher sensitivity than analysis of perfusion while having a comparable specificity. PMID- 22425235 TI - Effects of exercise training on exercise capacity and quality of life in patients with a left ventricular assist device: a preliminary randomized controlled trial. AB - BACKGROUND: A paucity of studies has examined the effect of exercise training after left ventricular assist device (LVAD) implantation. Previous research has demonstrated that insertion of the LVAD alone improves exercise capacity and quality of life (QOL). This study investigated whether supervised exercise training results in a further improvement. METHODS: This prospective, randomized controlled trial with concealed allocation, assessor blinding, and intention-to treat analysis investigated the effect of exercise training on exercise capacity and QOL in 14 patients who underwent LVAD insertion as a bridge to heart transplantation. Exercise training consisted of 8 weeks of gym-based aerobic and strengthening exercises 3 times a week, with a progressive mobilization program, compared with the control group that completed mobilization alone. Exercise capacity was measured before and after the intervention using maximal cardiopulmonary exercise testing and 6-minute walk distance (6MWD). QOL was measured using the Short Form 36-item assessment. RESULTS: No adverse events were reported. There was a trend toward greater improvement in peak oxygen consumption (Vo(2)), 6MWD, and QOL in the exercise group (n = 7) compared with the control group (n = 7); however, no significant between-group difference was detected for improvements in peak Vo(2) [mean difference (exercise--control)] of 2.96 ml/kg/min (95% confidence interval, -1.04 to 6.97), 6MWD at 54 meters (-51 to 159 meters), and QOL scores over time (p > 0.05). CONCLUSION: Exercise training is feasible and safe in patients with a LVAD. Trends toward greater improvement in exercise capacity and QOL after exercise training warrant further investigation in a larger trial. PMID- 22425236 TI - Bronchial carcinoma after lung transplantation: a single-center experience. AB - BACKGROUND: Lung transplantation (LTx) remains the best option for selected patients with end-stage lung disease. Long-term survival is hampered by the development of chronic allograft dysfunction, which is the main reason for mortality at 3 to 5 years after LTx. Prevalence of and mortality due to solid organ tumors also increases and we specifically investigated the development of primary bronchial carcinoma (BC) and its outcome after LTx. METHODS: From January 2000 until June 2011, 494 lung and heart-lung transplantations were performed. Among this population, 13 patients developed bronchial carcinoma at 41 +/- 27 (mean +/- SD) months after LTx. Of these 13 patients, there were 9 men and 4 women. They were transplanted at a mean age of 59 +/- 2.8 years; 8 patients were transplanted for emphysema and 5 for pulmonary fibrosis. RESULTS: Nine of 92 single LTx patients (transplanted for emphysema or lung fibrosis) developed a bronchial carcinoma in their native lung, whereas only 4 of 224 bilateral LTx patients (also for emphysema or fibrosis) developed a bronchial carcinoma (p = 0.0026). At diagnosis, 4 patients had local disease (cT1N0M0 and cT2N0M0), whereas all others had locoregionally advanced or metastatic disease. Five patients were surgically treated; however, 1 had unforeseen N2 disease with additional pleural metastasis at surgery. All other patients (except 2 who died very soon after diagnosis) were treated with chemotherapy with or without radiotherapy. The median survival after diagnosis was only 10 +/- 7 months, with a significant survival difference between patients with limited and extensive disease (p = 0.037). The latter had a median survival of only 6 months compared with 21 months for patients with limited stages of bronchial carcinoma. CONCLUSIONS: Bronchial carcinoma, especially of the native lung after single LTx, is a significant problem and the survival after diagnosis is very poor, although patients with limited (operable) disease tend to have better results. PMID- 22425237 TI - Ultrasensitive and label-free detection of pathogenic avian influenza DNA by using CMOS impedimetric sensors. AB - This work presents miniaturized CMOS (complementary metal oxide semiconductor) sensors for non-faradic impedimetric detection of AIV (avian influenza virus) oligonucleotides. The signal-to-noise ratio is significantly improved by monolithic sensor integration to reduce the effect of parasitic capacitances. The use of sub-MUm interdigitated microelectrodes is also beneficial for promoting the signal coupling efficiency. Capacitance changes associated with surface modification, functionalization, and DNA hybridization were extracted from the measured frequency responses based on an equivalent-circuit model. Hybridization of the AIV H5 capture and target DNA probes produced a capacitance reduction of 13.2 +/- 2.1% for target DNA concentrations from 1 fM to 10 fM, while a capacitance increase was observed when H5 target DNA was replaced with non complementary H7 target DNA. With the demonstrated superior sensing capabilities, this miniaturized CMOS sensing platform shows great potential for label-free point-of-care biosensing applications. PMID- 22425238 TI - Target-size embracing dimension for sensitive detection of viruses with various sizes and influenza virus strains. AB - The focused ion beam (FIB) technique was employed to precisely fabricate hexagon like Au nano-rods (fibAu_h) arrays as a surface enhanced Raman scattering - active substrate. A "ring diameter" (D(R)) was created by the convergence of three fibAu_h with respect to the dimension of the target viruses (D(T)), such as adenovirus (Adeno), encephalomyocarditis virus (EMCV), influenza virus (H1N1) with different sizes. Three influenza A virus strains were also compared. The results indicate that as that with a D(R)/D(T) ratio of around 1, the discrimination ability for detecting the target viruses and SERS mechanism become obvious. The enhanced lightning rod effect surrounding the seized target virus is anticipated if its size and dimension is suitably embraced within three fibAu_h. Hence the as-designed fibAu_h sample with a target-size embracing dimension provides good discrimination ability for distinguishing virus of various sizes or virus strains. PMID- 22425239 TI - Cadmium ion-doped magnetic poly(styrene-acrylic acid) nanospheres for sensitive electrochemical immunoassay. AB - A novel class of molecular tags, cadmium ion-doped magnetic poly(styrene-acrylic acid) nanospheres (Cd-MPSA), was first synthesized and functionalized with polyclonal rabbit anti-human luteinizing hormone antibodies (PAb(2)) for highly efficient electrochemical immunoassay of luteinizing hormone (LH). Transmission electron microscope (TEM) and Fourier transform infrared spectroscope (FTIR) were employed to characterize the prepared Cd-MPSA. By using Cd-MPSA-labeled PAb(2) as molecular tags, a novel sandwich-type immunoassay protocol was built for determination of LH on monoclonal mouse anti-human luteinizing hormone antibody (MAb(1))-functionalized gold electrode. The assay was carried out in pH 5.3 HAc NaAc buffer solution by square wave voltammetry (SWV). The signal was obtained by the reduction of the doped cadmium ions in the Cd-MPSA. Under optimal conditions, the currents increased with the increasing LH level in the sample, and exhibited a linear range from 0.25 to 240 mIU mL(-1) with a detection limit of 0.08 mIU mL( 1) LH at 3s(B). The precision, reproducibility, and specificity were acceptable. No obvious difference was encountered in the analysis of spiking LH samples into newborn calf serum with the referenced values. PMID- 22425240 TI - New ages for Middle and Later Stone Age deposits at Mumba rockshelter, Tanzania: optically stimulated luminescence dating of quartz and feldspar grains. AB - The archaeological deposits at Mumba rockshelter, northern Tanzania, have been excavated for more than 70 years, starting with Margit and Ludwig Kohl-Larsen in the 1930s. The assemblages of Middle Stone Age (MSA) and Later Stone Age (LSA) artefacts collected from this site constitute the type sequences for these cultural phases in East Africa. Despite its archaeological importance, however, the chronology of the site is poorly constrained, despite the application since the 1980s of several dating methods (radiocarbon, uranium-series and amino acid racemisation) to a variety of materials recovered from the deposits. Here, we review these previous chronologies for Mumba and report new ages obtained from optically stimulated luminescence (OSL) and infrared stimulated luminescence (IRSL) measurements on single grains of quartz and multi-grain aliquots of potassium (K) feldspar from the MSA and LSA deposits. Measurements of single grains of quartz allowed the rejection of unrepresentative grains and the application of appropriate statistical models to obtain the most reliable age estimates, while measurements of K-feldspars allowed the chronology to be extended to older deposits. The seven quartz ages and four K-feldspar ages provide improved temporal constraints on the archaeological sequence at Mumba. The deposits associated with the latest Kisele Industry (Bed VI-A) and the earliest Mumba Industry (Bed V) are dated to 63.4 +/- 5.7 and 56.9 +/- 4.8 ka (thousands of years ago), respectively, thus constraining the time of transition between these two archaeological phases to ~60 ka. An age of 49.1 +/- 4.3 ka has been obtained for the latest deposits associated with the Mumba Industry, which show no evidence for post-depositional mixing and contain ostrich eggshell (OES) beads and abundant microlithics. The Nasera Industry deposits (Bed III) contain large quantities of OES beads and date to 36.8 +/- 3.4 ka. We compare the luminescence ages with the previous chronologies for Mumba, and briefly discuss how the revised chronology fits in the context of existing archaeological records and palaeoclimatic reconstructions for East Africa. PMID- 22425241 TI - Cost-effectiveness of carrier screening for cystic fibrosis in Australia. AB - BACKGROUND: Carrier screening for cystic fibrosis is not widely available in Australia, partly due to concerns regarding its cost-effectiveness. The benefit of information from pregnancy to pregnancy has not been widely considered in existing cost-effectiveness analyses. METHODS: A decision tree was constructed estimating costs and outcomes from screening, including both initial and subsequent pregnancies. Effectiveness was expressed in terms of CF births averted. Costs were collected using a health service perspective. All costs and outcomes were discounted at 5% per annum. RESULTS: Screening reduced the annual incidence of CF births from 34 to 14/100,000 births (an aggregate number of CF births of 100.9 and 41.9 respectively). In initial pregnancies, costs in the screening arm (A$16.6 million/100,000 births) exceed those in the non-screening arm (A$13.4 million/100,000 births). The incremental cost per CF birth in initial pregnancies is therefore approximately A$150,000. However, this was reversed for subsequent pregnancies, in that the pre-collected information reduces the incidence of CF in subsequent pregnancies at low additional costs. When aggregated, the results suggest screening is likely to be cost-saving. CONCLUSIONS: The introduction of national carrier screening for cystic fibrosis should be considered, as it is likely to reduce CF incidence at an acceptable (potentially negative) cost. PMID- 22425242 TI - Physical activity and physical functioning in Swedish and Iranian 75-year-olds - a comparison. AB - BACKGROUND AND PURPOSE: The pattern of population aging is highly complex and contextually based. Cross-national comparisons are helpful to explore related factors. Two cross-sectional studies designed to compare physical activity level, physical functioning and certain health related factors in 75-year-old women and men in Sweden and Iran. MATERIALS AND METHODS: Cohorts of 637 Swedish and 851 Iranian 75-year-olds were investigated with the same methods regarding physical activity level, physical functioning and health related factors. RESULTS: There were differences in physical activity level (p<0.001), self-reported physical functioning (p<0.001) objective physical functioning (p<0.001), health status (p<0.001) and most socio-demographic aspects between the two countries. Here the Swedish cohort had the advantage. There was no difference between the countries regarding prevalence of vertigo or falls. The only variables where the Iranian cohort had advantage over the Swedes were grip strength and smoking habits. There were larger gender differences in walking habits, self-selected walking speed, timed chair stand, and one-leg stance in Iran, and in grip strength in Sweden, all to the disadvantage of women. CONCLUSIONS: Iranian 75-years-olds had a lower physical activity level, a worse lower extremity physical function but a better grip strength, a worse physical health status, but smoked less than their Swedish counterparts. Despite this, there were no differences regarding vertigo or falls. In most aspects, the magnitude of gender differences was about the same and in disadvantage of women, although there were larger differences in Iran in some lower extremity functions. PMID- 22425243 TI - Stochastic resonance whole-body vibration training for chair rising performance on untrained elderly: a pilot study. AB - The present randomized controlled pilot study was conducted to determine the feasibility of the study protocol and the effects of four-week-long sessions involving stochastic resonance whole-body vibration (SR-WBV) training on chair rising in elderly individuals. Twenty elderly participants were divided into a SR WBV group or a sham group. Peak force, rate of force development, rising time, time to stabilization and total time during chair rising performance were investigated. Intraclass correlation coefficients, Mann-Whitney U-tests and Wilcoxon signed-ranked tests were used. Low volume SR-WBV over 12 training sessions might provide a safe treatment method. PMID- 22425244 TI - [Eruptive dysplastic nevi following melanotan use]. PMID- 22425245 TI - High prevalence of abdominal aortic aneurysms in brothers and sisters of patients despite a low prevalence in the population. AB - OBJECTIVE: Population-based screening for abdominal aortic aneurysms (AAAs) in elderly men is organized in many regions and countries in the Western world, and the prevalence of disease is reported to decline. Whether the prevalence among those with a family history also is declining is unknown. The primary purpose of this study was to assess the prevalence of AAAs among siblings of persons with AAAs and to investigate the proportion of siblings already diagnosed by opportunistic screening. METHODS: Patients treated for AAAs from January 2008 through December 2010 (n = 412) in Stockholm, Sweden, were screened for siblings. Seven hundred seventy-nine siblings were identified. All siblings <80 years residing in Stockholm County were considered eligible and were invited to participate in the study (n = 174). Deceased siblings were not included in the study, regardless of the cause of death. One hundred fifty siblings were enrolled in the study after informed consent was provided. One hundred thirty-four siblings were screened for AAAs with ultrasound scan and maximum aortic, infrarenal, anteroposterior, external (outer-to-outer) aortic diameter was measured. Characteristics of siblings with and without AAAs were compared. RESULTS: The mean age of the screened siblings was 66.4 years (standard deviation, 7.1). Of the siblings, 11% were found to have an AAA, 17% (n = 11) of the brothers, and 6% (n = 5) of the sisters. Only 11% of the siblings were screened for AAAs before the study. One of 16 siblings with AAAs was <65 years. Ever smoking was evident in 81% of the AAA siblings compared to 59% in the non AAA siblings. Factors associated with increased risk of AAAs in the multivariate regression analysis were: male sex (odds ratio, 3.4; 95% confidence interval, 1.1 10.8; P = .04) and age >65 (odds ratio, 10.8; 95% confidence interval, 1.3-86.4; P = .03). Ever smoking was not statistically significant as a risk. CONCLUSIONS: A strikingly high prevalence of AAAs in siblings was found as compared to the reported declining aneurysm prevalence in elderly men in the Western world. Systematic improvements regarding screening of first-degree relatives is mandated and selective screening of siblings is an underused tool to prevent death from aneurysm disease, both among men and women. PMID- 22425246 TI - Nasopharyngeal carcinoma: salvage of local recurrence. AB - Local control of nasopharyngeal carcinoma has substantially improved with advancing radiotherapy technology and appropriate combination with chemotherapy. However, when local recurrence occurs, this is one of the most difficult challenges. Aggressive treatment is indicated because long term salvage is achievable particularly for early recurrence, but high risk of complications is a serious concern. Treatment options include different methods of surgery and/or re irradiation with/without chemotherapy. Available information in the literature is grossly inadequate; most reports compose of small series of highly selected patients with heterogeneous characteristics and treatment. No randomized trials have been performed to evaluate the therapeutic ratio of different treatment methods. This article reviews available treatment options, their therapeutic benefits and risks of complications; the objective is to provide information for developing treatment recommendations and suggestions for future improvement. PMID- 22425247 TI - Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. AB - Overproduction of cytokines by T helper 2 (Th2) cells in the lung is thought to be a cause of asthma. Here we report that innate lymphocytes termed lung natural helper (LNH) cells are a T cell-independent source of Th2 cell-type cytokines in protease allergen-treated lungs. LNH (Lin(-)Sca-1(+)c-kit(+/lo)CD25(+)CD127(+)) cells, when stimulated by IL-33 plus IL-2, IL-7, or thymic stroma lymphopoietin (TSLP), produced large amounts of IL-5 and IL-13. Intranasal administration of protease allergen papain induced eosinophil infiltration and mucus hyperproduction in the lung of wild-type and Rag1(-/-) mice, but not in Rag2(-/ )Il2rg(-/-) mice that lack LNH cells. LNH cell depletion inhibited papain-induced airway inflammation in Rag1(-/-) mice whereas adoptive transfer of LNH cells enabled Rag2(-/-)Il2rg(-/-) mice to respond to papain. Treatment of lung explants with papain induced IL-33 and TSLP production by stroma cells and IL-5 and IL-13 production by LNH cells. Thus, LNH cells are critical for protease allergen induced airway inflammation. PMID- 22425248 TI - Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. AB - The evolutionary conserved Foxo transcription factors are important regulators of quiescence and longevity. Although, Foxo1 is known to be important in regulating CD8(+) T cell trafficking and homeostasis, its role in functional differentiation of antigen-stimulated CD8(+) T cells is unclear. Herein, we demonstrate that inactivation of Foxo1 was essential for instructing T-bet transcription factor mediated effector differentiation of CD8(+) T cells. The Foxo1 inactivation was dependent on mTORC1 kinase, given that blockade of mTORC1 abrogated mTORC2 mediated Akt (Ser473) kinase phosphorylation, resulting in Foxo1-dependent switch from T-bet to Eomesodermin transcription factor activation and increase in memory precursors. Silencing Foxo1 ablated interleukin-12- and rapamycin-enhanced CD8(+) T cell memory responses and restored T-bet-mediated effector functions. These results demonstrate an essential role of Foxo1 in actively repressing effector or terminal differentiation processes to promote memory CD8(+) T cell development and identify the functionally diverse mechanisms utilized by Foxo1 to promote quiescence and longevity. PMID- 22425249 TI - E protein transcription factors are required for the development of CD4(+) lineage T cells. AB - The double-positive (DP) to single-positive (SP) transition during T cell development is initiated by downregulation of the E protein transcription factors HEB and E2A. Here, we have demonstrated that in addition to regulating the onset of this transition, HEB and E2A also play a separate role in CD4(+) lineage choice. Deletion of HEB and E2A in DP thymocytes specifically blocked the development of CD4(+) lineage T cells. Furthermore, deletion of the E protein inhibitors Id2 and Id3 allowed CD4(+) T cell development but blocked CD8(+) lineage development. Analysis of the CD4(+) lineage transcriptional regulators ThPOK and Gata3 placed HEB and E2A upstream of CD4(+) lineage specification. These studies identify an important role for E proteins in the activation of CD4(+) lineage differentiation as thymocytes undergo the DP to SP transition. PMID- 22425251 TI - Highly catalytic spherical carbon nanocomposites allowing tunable activity via controllable Au-Pd doping. AB - We report the synthesis of highly catalytic spherical carbon composite particles with Au-Pd bimetallic nanoparticle doping using a microwave-assisted technique that allows control over the location of the nanoparticles (NPs), putting them into stable interior, but still near-surface locations (within a 100 nm thick shell). First, composite particles with Pd NPs inside of nanoporous carbon spheres (CSs) were synthesized. Subsequent immersion of the composite particles in HAuCl(4) solutions containing PVP led to an addition of Au near the Pd. Au Pd/CS composites with Au:Pd atomic ratios varying from 0.4 to 4.6 were prepared. The growth of Au and its location relative to the carbon's surface and the Pd are discussed. The catalytic activity towards the reduction of 4-nitrophenol is tunable via the Au:Pd atomic ratio. Optimizing the composition increases the activity a hundredfold over that of the corresponding monometallic Pd/CS. The catalytic activity arises from the synergy between different contributing mechanisms, here especially the interaction between the carbon matrix and metals, metal-metal interfaces, and the hydrogen absorption capabilities of Pd. PMID- 22425250 TI - Rank signaling links the development of invariant gammadelta T cell progenitors and Aire(+) medullary epithelium. AB - The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to alphabeta T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vgamma5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vgamma5(+) gammadelta T cells during thymus medulla formation for alphabeta T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation. PMID- 22425252 TI - Synthesis and visible light photocatalytic properties of polyoxometalate-thionine composite films immobilized on porous TiO2 microspheres. AB - Multilayer films (PW(12)-TH)(n) (PW(12)=PW(12)O(40)(3-), TH=thionine) were immobilized on porous anatase TiO(2) microspheres by layer-by-layer (LbL) self assembly method. The porous structure of TiO(2) was confirmed by transmission electron microscopy (TEM). Scanning electron microscopy (SEM) showed that TiO(2) template particles had a round shape with an average diameter of 250 nm. The composite films were characterized by FTIR spectroscopy, UV diffuse reflectance spectroscopy and XRD spectroscopy. The results confirmed the successful immobilization of (PW(12)-TH)(n) composite films onto TiO(2) microspheres, and the growth of PW(12)-TH layer pair was uniform. SEM and TEM were also used to characterize the morphology. When PW(12)-TH composite films were assembled on the template, the surface became rougher with the increasing number of layer pair. The lattice fringe of TiO(2) became weaker when immobilized (PW(12)-TH)(n). The photocatalytic properties of the microspheres toward a rhodamine B (RhB) solution were investigated under visible light irradiation. The combination of TiO(2) and PW(12) showed an excellent photocatalytic performance. Both TH sensitization and PW(12) adsorption played important roles during the process of photocatalysis. Moreover, the catalytic property and reusability of as-prepared catalyst were relevant to the number of PW(12)-TH bilayer. The kinetics of the photodecomposition to rhodamine B followed the first-order reaction. PMID- 22425253 TI - Effects of counter ions of clay platelets on the swelling behavior of nanocomposite gels. AB - The effects of replacing the native Na(+) counter ions associated with the clay platelets by various other cations on the swelling behavior of nanocomposite (NC) gels consisting of an organic (polymer)/inorganic (clay) network were investigated. The negative surface charge of the clay platelet conferred an ionic nature on the NC gels making them a type of polyelectrolyte gel; consequently, the swelling behavior of the NC gels was strongly influenced by the valence of the co-existing counter ions. NC gels containing monovalent cations such as Na(+), K(+) and Li(+) exhibited large swellings and subsequent deswelling in water after attaining maximum degrees of swelling. In contrast, introduction of multivalent cations such as Ca(2+), Mg(2+), and Al(3+) into NC gels depressed markedly both the swelling and subsequent deswelling. The decreased swelling and suppressed deswelling with multivalent ions were strongly influenced by the initial gel state and result from the formation of additional cross-links through ionic interactions between the clay platelets and the multivalent cations. Also, the similar swelling behaviors were observed for all NC gels with different clay concentration. Further, reversible absorption/desorption and selective absorption of multivalent cations were observed for the NC gels examined. PMID- 22425254 TI - Stepwise dansyl grafting on the kaolinite interlayer surface. AB - Here we describe the step-wise grafting of the fluorophore dansyl chloride on the interlayer aluminol groups of kaolinite. The modified clay was characterized by powder RD, TGA, FT-IR and (27)Al, (19)Si, (13)C MAS-NMR, which confirmed the achievement of the clay functionalization. The photophysical properties of the resulting nanohybrid material were evaluated by photoluminescence excitation and emission measurements. PMID- 22425255 TI - A genome-wide search for genetic influences and biological pathways related to the brain's white matter integrity. AB - A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ~73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 * 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 * 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 * 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA). PMID- 22425256 TI - ATAXIN2 CAG-repeat length in Italian patients with amyotrophic lateral sclerosis: risk factor or variant phenotype? Implication for genetic testing and counseling. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurons. Several studies indicated that intermediate CAG expansions in ataxin-2 gene (ATXN2) are associated with increased risk of ALS. We analyzed ATXN2 CAG repeats in 658 sporadic ALS patients (SALS), 143 familial ALS cases (FALS), 231 sporadic ataxic subjects, and 551 control subjects. The frequency of ATXN2 alleles with 27-30 repeats was similar in SALS and control subjects. Fifteen SALS subjects carried >= 31 CAG repeats. This difference was statistically significant (p = 0.0014). No alleles with >= 34 CAG were found. In FALS, the distribution of ATXN2 alleles was similar to control subjects. Our results further contributed in refining CAG-repeat range significantly associated with sporadic ALS. Literature data and our findings indicate that only alleles with >= 31 CAG may represent low-penetrance disease/susceptibility alleles associated with variable neurodegenerative phenotypes, including cerebellar ataxia, parkinsonism, and ALS. Overlapping phenotypes should be considered in genetic testing and counseling, both for patients and at-risk family members. PMID- 22425257 TI - Willingness to pay for compulsory deworming of pets entering Sweden to prevent introduction of Echinoccoccus multilocularis. AB - To investigate if the Swedish entry rules for pets to prevent the introduction of Echinococcus multilocularis (EM) are proportional (i.e. that their costs do not exceed the value of their benefits), a dichotomous-choice contingent valuation study was conducted. The study was performed before the first case of EM was detected in Sweden in February 2011. About 5000, randomly selected, Swedish citizens were invited to participate and 2192 of them (44%) accepted to do so. Missing information on whether or not one would accept to pay for keeping the rules for 143 respondents resulted in 2049 observations (41%) available for the estimation of willingness to pay (WTP), and missing information on personal characteristics for another 274 respondents reduced the number of observations available for sensitivity analysis to 1775 (36%). Annual expected WTP for keeping the rules ranged between ? 54.3 and ? 99.0 depending on assumptions about compensations demanded by respondents not willing to pay. The estimates are conservative since only answers from respondents that were absolutely certain they would pay the suggested bid were regarded as yes-responses. That WTP is positive implies that Swedish citizens perceived the benefits of the rules to be larger than their costs. PMID- 22425258 TI - Cement pulmonary embolism after percutaneous vertebroplasty and kyphoplasty: an overview. AB - BACKGROUND: Because of the aging of the American population, osteoporotic vertebral fractures are becoming a common problem in the elderly. Minimally invasive percutaneous vertebral augmentation techniques have gained a great deal of importance in relieving the pain associated with these fractures, and are becoming the standard of care. METHODS: These procedures involve the injection of polymethylmethacrylate (PMMA) into the vertebral body. However, these techniques have their complications, and among these, pulmonary embolism is one of the most feared. It is attributable to the passage of cement into the pulmonary vasculature. After encountering a case of PMMA embolism in our practice, we decided to highlight this topic and discuss the incidence, clinical presentation, diagnosis, and treatment of cement pulmonary embolisms. PMID- 22425259 TI - Practice patterns of heart failure nurses. AB - OBJECTIVE: Little is known about the practice patterns of nurses who work in the specialty of heart failure (HF). This specialty includes inpatient and outpatient sites for practice that incorporate intensive care to rehabilitation. The purpose of this study was to describe the current practice of nurses who are members of the American Association of Heart Failure Nurses (AAHFN). METHODS: A convenience sample of nurses attending the 2010 Annual Meeting of AAHFN was surveyed to determine current practice patterns. RESULTS: The mean age of the nurses completing the survey was 48 years (standard deviation [SD] +10), and the majority were white (85%) and female (98%). Approximately half (48%) completed a Master's degree. The mean time worked as a nurse was 23 years (SD +10), with a mean of 11 years (SD +8.2) caring for patients with HF. Both HF education and physical assessment were reported to be provided frequently. CONCLUSION: This survey provides insight into the practice patterns of HF nurses. Continued monitoring of this role is warranted and can serve to assist the AAHFN in advancing HF knowledge and skills. PMID- 22425260 TI - Association of estimated GFR with platelet inhibition in patients treated with clopidogrel. AB - BACKGROUND: The reasons that decreased glomerular filtration rate (GFR) might alter the clinical efficacy of clopidogrel are poorly understood. STUDY DESIGN: In this study, we sought to evaluate whether decreased GFR alters platelet response to clopidogrel in patients receiving a maintenance dose of clopidogrel (75 mg/d for at least 8 days). SETTINGS & PARTICIPANTS: 126 consecutive patients categorized by estimated GFR: stages 1-2 (>60 mL/min/1.73 m(2); n = 29), stage 3a (45-59 mL/min/1.73 m(2); n = 21); stage 3b (30-44 mL/min/1.73 m(2); n = 26), stage 4 (15-29 mL/min/1.73 m(2); n = 14), and stage 5 (<15 mL/min/1.73 m(2); n = 36) were prospectively enrolled. PREDICTOR: Residual platelet reactivity, defined in the VASP (Vasodilator Stimulated Phosphoprotein) flow cytometry test as platelet reactivity index (PRI) >=61% and in the VerifyNow turbidimetric-based assay as a value >235 PRU (adenosine diphosphate receptor reaction units) or percentage of platelet inhibition <15%. OUTCOMES: We examined factors associated with low response to clopidogrel using logistic regression. RESULTS: A significant relationship between estimated GFR, PRI, PRU, and percentage of inhibition was found. The prevalence of residual platelet reactivity was highest in patients with GFR stage 5. PRI >=61% occurred in 52.8% of patients with stage 5 versus 30.8% of stage 3b and 24.1% of stages 1-2 (P = 0.1). PRU >235 was found in 63.6% of patients with stage 5 versus 36.8% of stage 3b and 17.2% of stages 1 2 (P = 0.005). Inhibition <15% affected 66.7% of patients with stage 5 versus 21.1% of stage 3b and 17.2% of stages 1-2 (P < 0.001). In the multivariable model, GFR stage 5 (adjusted prevalence ratio [PR], 3.10; 95% CI, 1.23-9.43; P = 0.02), and obesity (adjusted PR, 1.92; 95% CI, 1.34-2.23; P = 0.004) were the sole predictors of residual platelet reactivity. LIMITATIONS: Interference of hemodialysis with the pharmacokinetics of clopidogrel could not be excluded. CONCLUSION: GFR stage 5 is associated with substantial impairment of platelet inhibition independently of diabetes mellitus. PMID- 22425262 TI - Burden of extragonadal germ cell tumours in Europe and the United States. PMID- 22425261 TI - The kidney disease quality of life cognitive function subscale and cognitive performance in maintenance hemodialysis patients. AB - BACKGROUND: Cognitive impairment is common but often undiagnosed in patients with end-stage renal disease, in part reflecting limited validated and easily administered tools to assess cognitive function in dialysis patients. Accordingly, we assessed the utility of the Kidney Disease Quality of Life Cognitive Function (KDQOL-CF) scale in comparison to an extensive neuropsychological battery, building on a prior assessment of this potential cognitive screen. STUDY DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: Maintenance hemodialysis patients at 6 Boston area dialysis units were administered an extensive neurocognitive battery and the KDQOL-CF at the beginning of a hemodialysis session. PREDICTORS: KDQOL-CF score, depression symptom burden, and demographic and clinical characteristics. OUTCOMES: Neurocognitive performance classified into executive function and memory domains, determined using principal components analysis. MEASUREMENTS: Univariate and multivariable linear regression models adjusting for age, sex, race, and end stage renal disease cause were used to evaluate the association between KDQOL-CF score and cognitive performance, and test metrics were determined for a KDQOL-CF cutoff score of 60 or less from a maximum score of 100. RESULTS: For 168 prevalent hemodialysis patients, KDQOL-CF score was 76 +/- 19 and 40 (24%) had scores of 60 or less, consistent with self-identified worse cognitive performance. There was no significant correlation between KDQOL-CF score and either memory (P = 0.2 and P = 0.3) or executive function (P = 0.1 and P = 0.4) in univariate and multivariable models, respectively. There was a strong correlation between higher KDQOL-CF score and fewer depression symptoms (P < 0.001). Sensitivity of the KDQOL-CF was poor (range, 0.28-0.36), with modest specificity (range, 0.77-0.81) for identifying worse executive function and memory. LIMITATIONS: Cross-sectional study, modest population size, and abbreviated gold-standard cognitive battery. CONCLUSIONS: The KDQOL-CF is a poor determinant of neurocognitive performance in hemodialysis patients, with limited sensitivity. To assess cognitive impairment in hemodialysis patients, better screening tests are essential. PMID- 22425263 TI - Anandamide inhibits the Wnt/beta-catenin signalling pathway in human breast cancer MDA MB 231 cells. AB - We previously showed that methyl-F-anandamide, a stable analogue of the anandamide, inhibited the growth and the progression of cultured human breast cancer cells. As accumulating evidences indicate that the constitutive activation of the canonical Wnt pathway in human breast cancer may highlight a key role for aberrant activation of the beta-catenin-TCF cascade and tumour progression, we studied the anandamide effect on the key elements of Wnt pathway in breast cancer cells. In this study we described that the treatment of human breast cancer cells, MDA MB 231 cells, with methyl-F-anandamide reduced protein levels of beta catenin in the cytoplasmic and nuclear fractions inhibiting the transcriptional activation of T Cell Factor (TCF) responsive element (marker for beta-catenin signalling). The anandamide treatment resulted in up-regulation of epithelial markers, like E-cadherin with a concomitant decrease in protein levels of mesenchymal markers, including vimentin and Snail1. We, furthermore, observed that the induction of experimental epithelial-mesenchymal transition by exposure to adriamycin in MCF7 human breast cancer cell line was inhibited by anandamide treatment. In the present study we reported a novel anticancer effect of anandamide involving the inhibition of epithelial-mesenchymal transition, a process triggered during progression of cancer to invasive state. PMID- 22425264 TI - Evaluation of treatment options for patients with advanced renal cell carcinoma: assessment of appropriateness, using the validated semi-quantitative RAND corporation/University of California, Los Angeles methodology. AB - A diverse range of treatment options and interventions are available for the management of renal cell carcinoma (RCC), allowing clinicians to tailor therapy to best meet their patient's needs and situation. However, choosing from the plethora of options can be problematic. RCC treatment guidelines advise on the most efficacious agents based upon specific clinical trial populations, but these do not always take into account all the patient factors that influence the suitability of treatment options for individual patients. This study used the validated RAND/UCLA (RAND corporation/University of California, Los Angeles) 'appropriateness methodology' to integrate clinical efficacy data with expert opinion concerning the use of specific RCC treatment options for particular patient scenarios, in an attempt to facilitate the widespread implementation of patient-focussed treatment choices. Use of the methodology has allowed us to develop treatment algorithms for patients with locally-advanced RCC and for those with metastatic disease post-nephrectomy or with primary tumour in situ. The algorithms take into account patient-specific characteristics such as tumour histology, prior treatment and known risk factors to advise whether a particular treatment intervention is appropriate, not appropriate or of uncertain appropriateness. Use of this methodology aims to develop a formalised process by which expert opinion can be integrated with clinical data and used as an additional source of information that can provide further guidance concerning difficult treatment decisions when data are absent or sparse. PMID- 22425265 TI - Genetic association study between Interleukin 10 gene and dental implant loss. AB - OBJECTIVE: Three single nucleotide polymorphisms (SNPs), -1082, -819 and -592, located on the promoter region of IL10 gene have been associated with high in vitro IL-10 production and autoimmune diseases. We aim to investigate whether polymorphisms in the IL10 gene would influence dental implant loss. METHODS: We evaluated a total of 277 unrelated patients, including 185 individuals presenting at least one osseointegrated implant in function for six months or more and with no implant failure, and 92 individuals presenting at least one implant loss. DNA was extracted from buccal mucosa cells and SNPs were genotyped using TaqMan((r)) probes-based assays. RESULTS: Multiple logistic regression showed association between dental implant failure with -819(C/T) genotype (OR=3.27; 95% CI=1.02 10.46; p=0.0334). However, considering the statistical significance level alpha=0.004 (adjusted by Bonferroni correction of multiple comparisons), these results lost their significance. No association of dental implant loss with genotypes and alleles of the -1082 and -592 SNPs, as well as IL10 haplotypes in genotype/allele forms were found (p=0.9400; p=0.8861). CONCLUSIONS: Neither the IL10 gene polymorphisms, nor haplotypes or other covariates were associated with susceptibility to dental implant failure in the studied population. PMID- 22425266 TI - Does it really matter how far from the fundus embryos are transferred? AB - OBJECTIVE: Embryo transfer (ET) is an important last step during the process of IVF. Over the years much has been learned about the importance of the details of this procedure including the potential impact of transfer depth on outcome. The objective of our study was to evaluate whether transfer depth assessed by air bubble location after ET is associated with clinical outcome. STUDY DESIGN: Retrospective analysis of the association between transfer distance from the fundus (assessed by air bubble location after ET) and IVF outcome based on cycles (N=409) of patients with good prognosis undergoing infertility treatment for various indications. Treatments followed standard stimulation, IVF-ICSI and ET procedures. The distance of the air bubble as a surrogate marker of embryo location after transfer was measured and was correlated with implantation (IR) and pregnancy rates (PR) after day 3 and day 5 ET. Univariate comparisons were performed by nonparametric methods and multiple logistic regression was used to further evaluate the association between pregnancy rate and those factors that might influence outcome. RESULTS: The distance of the bubble was similar in those cycles that led to a pregnancy and those that did not (6.7 vs 6.5mm; p=0.48) and PR were comparable when the transfer was in the upper or middle third of the cavity. The IR did not differ when embryos were transferred into the upper, middle or lower third of the uterine cavity. Outcome was analyzed separately based on the day of transfer (cleavage vs blastocyst stage) and the IR did not differ based on the location of the transfer. CONCLUSIONS: Transfer depth does not affect implantation and pregnancy rates when the ET is in the middle or upper third of the uterus. PMID- 22425267 TI - Age and mental health predict early device-specific quality of life in patients receiving prophylactic implantable defibrillators. AB - BACKGROUND: Ventricular arrhythmia is a significant cause of sudden death. Implantable cardioverter-defibrillators (ICDs) offer at-risk patients a prophylactic treatment option. This prophylaxis is largely responsible for growth in utilization of ICDs. Identification of factors that may impact device-specific quality of life (QOL) is warranted. The influence of preimplant patient variables on postimplant device-specific QOL is unknown. The study aimed to determine whether preimplant psychosocial, generic health-related quality of life (HRQOL), personality disposition, or demographic factors predicted early postimplant device-specific QOL. METHODS: A prospective cohort study design was employed in 70 adults receiving an ICD for primary prevention. Preimplant, we measured generic HRQOL, personality disposition, depressive symptoms, age, and sex. The primary outcome was 3-month ICD device-specific QOL as measured by the Florida Patient Acceptance Scale (FPAS). We applied hierarchical multivariate regression analysis. RESULTS: Mean age was 64.8 +/- 9.4 years; 12.9% were women. Most had ischemic heart disease (77%) and a heart failure history (54.3%). Preimplant prevalence of elevated depressive symptoms was 30%. Three months post implant, the mean adjusted FPAS score was 76.8 +/- 12.98. Of the variance in FPAS scores, 37% was explained by the independent variables. Younger age and poor preimplant mental HRQOL contributed most to lower FPAS scores. CONCLUSIONS: Patient support and psychosocial interventions should target younger ICD candidates and those reporting poor preimplant mental HRQOL; these patients may be at risk for poor postimplant device-specific QOL. PMID- 22425268 TI - Angiographically-derived SYNTAX score and its prognostic value in dialysis patients: comparison with the Khan index. AB - BACKGROUND: The aim of this study was to assess the value of the angiographically derived Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score in predicting mortality and major adverse cardiac events (MACEs) during a 3-year follow-up of dialysis patients undergoing a percutaneous coronary intervention or coronary artery bypass graft operation. We compared the aforementioned results with the clinical Khan index. METHODS: The SYNTAX score was calculated for 87 of 110 dialysis patients after coronary angiography. RESULTS: The mean SYNTAX score was 12.75 +/- 14.49. During the 3-year follow-up, 58% of the patients died, and 74% had at least 1 MACE. In a Kaplan-Meier survival analysis, the risk of death and MACEs increased in parallel with the SYNTAX score. A score greater than 12.75 was strongly associated with mortality and MACE (both Ps < 0.01). In receiver operating characteristic (ROC) curve analysis, the areas under the curves (AUCs) of the SYNTAX score and Khan index were significantly higher (both Ps < 0.001) than the area of diagnostic indifference. The predictive values for death as indicated by the SYNTAX score and the Khan index, respectively, were almost identical in the ROC analysis (AUC SYNTAX score, 0.6436; AUC Khan index, 0.6475; P = 0.9532). Areas under the ROC curves of both methods according to MACE were also significantly different from those for the random model (both Ps < 0.001). CONCLUSIONS: The SYNTAX score is a powerful predictor of mortality and MACEs in dialysis patients undergoing percutaneous coronary intervention or coronary artery bypass graft during a 3-year follow-up. The score provides prognostic information similar to that provided by the Khan index. PMID- 22425269 TI - RNA-protein interactions in vivo: global gets specific. AB - RNA-binding proteins (RBPs) impact every process in the cell; they act as splicing and polyadenylation factors, transport and localization factors, stabilizers and destabilizers, modifiers, and chaperones. RNA-binding capacity can be attributed to numerous protein domains that bind a limited repertoire of short RNA sequences. How is specificity achieved in cells? Here we focus on recent advances in determining the RNA-binding properties of proteins in vivo and compare these to in vitro determinations, highlighting insights into how endogenous RNA molecules are recognized and regulated. We also discuss the crucial contribution of structural determinations for understanding RNA-binding specificity and mechanisms. PMID- 22425270 TI - Diagnostic yield and safety of jumbo biopsy forceps in patients with subepithelial lesions of the upper and lower GI tract. AB - BACKGROUND: EUS-FNA often fails to make a definitive diagnosis in the evaluation of subepithelial lesions. The addition of jumbo biopsy forceps has the potential to improve diagnostic yield, but published series are limited. OBJECTIVE: To assess the likelihood of definitive diagnosis for subepithelial lesions by using jumbo biopsy forceps during EUS examination. DESIGN: Pooled retrospective analysis. SETTING: 6 tertiary referral centers. PATIENTS: All patients having undergone EUS examination for a subepithelial lesion in which jumbo biopsy forceps were used for tissue acquisition. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of jumbo biopsy forceps use, complication rates, and comparison of diagnostic yield with that of EUS-FNA. RESULTS: A total of 129 patients underwent EUS with jumbo biopsy forceps; 31 patients (24%) had simultaneous EUS-FNA. The lesion locations were stomach (n = 98), esophagus (n = 14), duodenum (n = 11), colon (n = 5), and jejunum (n = 1). The average lesion size was 14.9 mm +/- 9.3 mm. Overall, definitive diagnosis was obtained in 87 of 129 patients (67.4%) by using either method. A definitive diagnosis was provided by jumbo biopsy forceps use in 76 of 129 patients (58.9%) and by FNA in 14 of 31 patients (45.1%) (P = .175). The results in third-layer lesions were definitive with jumbo biopsy forceps in 56 of 86 lesions (65.1%) and with FNA in 6 of 16 lesions (37.5%) (P = .047). For fourth-layer lesions, the results with jumbo biopsy forceps were definitive in 10 of 25 (40.0%) and with FNA in 8 of 14 (57.1%) (P = .330). Forty five of 129 patients (34.9%) experienced significant bleeding after biopsy with jumbo forceps and required some form of endoscopic hemostasis. LIMITATIONS: Retrospective study. CONCLUSIONS: Jumbo forceps are a useful tool for the definitive diagnosis of subepithelial lesions. The greatest benefit appears to be with third-layer (submucosal) lesions. The risk of bleeding is significant. PMID- 22425271 TI - Failure to recognize serrated polyposis syndrome in a cohort with large sessile colorectal polyps. AB - BACKGROUND: Serrated polyposis syndrome (SPS) is a rare condition of multiple serrated colorectal polyps and cancers. Colorectal cancer risk is increased in SPS. OBJECTIVE: We determined the prevalence of SPS in a cohort of patients with large (>= 2 cm) sessile colorectal polyps and the rate at which the diagnosis was made by the clinicians. DESIGN: Review of patient care database. The 2010 World Health Organization (WHO) criteria were used to identify cases of SPS. SETTING: Tertiary academic center. PATIENTS: 529 consecutive patients referred for endoscopic resection of a sessile colorectal polyp >= 2 cm. MAIN OUTCOME MEASUREMENTS: Prevalence of SPS in the cohort and frequency with which the referring physician and the endoscopist recognized SPS. RESULTS: Of the 529 patients, 20 (4%) met the WHO criteria for SPS. Only 1 of these cases was suspected by a referring physician. Twelve cases (60%) were either diagnosed or suspected by the endoscopist at our center. Compared with all other patients without SPS, those with SPS were more likely to have an index lesion (the lesion that led to referral) that was serrated (60% vs 3.8%), to have a cecal or ascending colon index lesion (70% vs 45%), and to be current smokers (42% vs 15%). Including the first colonoscopy to remove the index lesion and 26 follow-up colonoscopies, the endoscopist at our center removed 183 serrated polyps from the 20 patients with SPS; of those polyps, 68 were >1 cm. Three patients were referred for surgical resection of involved colon. Eighteen of the 20 patients with SPS met the WHO criterion of 5 serrated polyps proximal to the sigmoid, of which 2 are >1 cm. Failure to recognize SPS by the referring physician was at least partly related to unrecognized serrated lesions. Failure to recognize SPS by the endoscopist at our institution was the result of not systematically applying WHO criteria to the polyp findings. LIMITATIONS: Retrospective study. CONCLUSIONS: SPS was common in a cohort of patients with large sessile colorectal polyps, and it was frequently unrecognized. These data suggest the need for better detection of serrated lesions, better awareness of SPS, and more consistent application of SPS criteria to the polyp findings of individual patients. PMID- 22425272 TI - Feasibility, safety, acceptability, and yield of office-based, screening transnasal esophagoscopy (with video). AB - BACKGROUND: Endoscopic screening for esophageal neoplasia can identify patients eligible for early intervention for precancerous lesions. Unsedated transnasal esophagoscopy may provide an efficient and accurate endoscopic assessment with fewer risks and less cost, compared with conventional upper endoscopy. OBJECTIVE: To assess the feasibility, safety, acceptability, and yield of unsedated transnasal esophagoscopy in a primary care population. DESIGN: Multicenter, prospective, cross-sectional study. SETTING: Two outpatient tertiary-care centers. PATIENTS: This study involved a general medical clinic population aged between 40 and 85 years. INTERVENTION: Unsedated, office-based transnasal esophagoscopy. MAIN OUTCOME MEASUREMENTS: Procedure yield; completeness of examination; procedure length; adverse events and complications; choking, gagging, pain, or anxiety during the examination; and overall tolerability. RESULTS: A total of 426 participants (mean [+/- standard deviation] age 55.8 +/- 9.5 years; 43% male) enrolled in the study, and 422 (99%) completed the examination. Mean (+/- standard deviation) examination time was 3.7 +/- 1.8 minutes. There were no serious adverse events, and 12 participants (2.8%) reported minor complications. Participants reported minimal choking, gagging, pain, or anxiety. The examination was well-tolerated by most participants. Overall, 38% of participants had an esophageal finding that changed management (34% erosive esophagitis, 4% Barrett's esophagus). LIMITATIONS: Nonrandomized study, tertiary-care centers only, self-selected population with a large proportion reporting esophageal symptoms. CONCLUSION: Unsedated transnasal esophagoscopy is a feasible, safe, and well-tolerated method to screen for esophageal disease in a primary care population. Endoscopic findings are common in this patient population. PMID- 22425273 TI - Development of a fast and simple liquid chromatography-tandem mass spectrometry method for the quantitation of argatroban in patient plasma samples. AB - An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the direct measurement of argatroban in human plasma was developed and compared with the activity-based Hemoclot Thrombin Inhibitors assay. UPLC-MS/MS was performed using diclofenac as an internal standard. In summary, argatroban and diclofenac were extracted from 100 MUL of plasma using a methanol precipitation protocol, and chromatographic separation was performed on an ACQUITY TQD mass spectrometer using a UPLC C18 BEH 1.7 MUm column with a water and methanol gradient containing 0.1% formic acid. The detection and quantitation were performed using positive ion electrospray ionization and multiple reaction monitoring (MRM) mode. The UPLC-MS/MS method was linear over the concentration range of 0.003-3.0 MUg/mL, with a lower limit of quantitation for argatroban of 0.003 MUg/mL. The intra- and inter-assay imprecision was less than 12% at the plasma argatroban concentrations tested. Good correlation was demonstrated between the UPLC-MS/MS method and the indirect activity-based assay for determination of argatroban. However, increased plasma fibrinogen levels caused underestimation of argatroban levels using the indirect activity-based assay, whereas the UPLC-MS/MS method was unaffected. UPLC-MS/MS provides a relatively simple, sensitive, and rapid means of argatroban monitoring. It has successfully been applied to assess plasma argatroban concentrations in hospitalized patients and may provide a more accurate determination of argatroban concentrations than an activity-based assay in certain clinical conditions. PMID- 22425274 TI - The effects of shoes with a rounded soft sole in the anterior-posterior direction on leg joint angle and muscle activity. AB - This study examines the effect of these shoes on the leg joint angle and muscle activity during walking. Ten healthy young male adults (mean age: 24.1+/-4.3 years) walked on a walkway while wearing one of three kinds of shoes with a rounded soft sole in the anterior-posterior direction (Stretch Walker: SW, mass: 440 g), MBT (Masai Barefoot Technology; similar to the SW in form and material, mass: 600 g), and flat-bottomed shoes (FS, mass: 420 g)). After familiarizing themselves with the shoes, subjects walked twenty laps on the walkway, which was about 40 m long (mean speed: 4.1 km/h). After a sufficient rest, they repeated this with the other shoes. During walking, the volume of muscle discharge was measured once every 2 laps. The mean value of the 10 measurements was used as the evaluation variable for integral values and joint angle, while the right foot touched the ground twice. In conclusion, the range of leg movement during walking was smaller when wearing shoes with a rounded soft sole in the anterior-posterior direction (SW and MBT) than when wearing normal shoes (FS). However, the effects of the SW and MBT on leg muscle activity during walking differ little from wearing the normal shoes during a leisurely 10-min walk. PMID- 22425275 TI - Sewage sludge fertiliser use: implications for soil and plant copper evolution in forest and agronomic soils. AB - Fertilisation with sewage sludge may lead to crop toxicity and environmental degradation. This study aims to evaluate the effects of two types of soils (forest and agronomic), two types of vegetation (unsown (coming from soil seed bank) and sown), and two types of fertilisation (sludge fertilisation and mineral fertilisation, with a no fertiliser control) in afforested and treeless swards and in sown and unsown forestlands on the total and available Cu concentration in soil, the leaching of this element and the Cu levels in plant. The experimental design was completely randomised with nine treatments and three replicates. Fertilisation with sewage sludge increased the concentration of Cu in soil and plant, but the soil values never exceeded the maximum set by Spanish regulations. Sewage sludge inputs increased both the total and Mehlich 3 Cu concentrations in agronomic soils and the Cu levels in plant developed in agronomic and forest soils, with this effect pronounced in the unsown swards of forest soils. Therefore, the use of high quality sewage sludge as fertiliser may improve the global productivity of forest, agronomic and silvopastoral systems without creating environmental hazards. PMID- 22425276 TI - Strengthening the link between climate, hydrological and species distribution modeling to assess the impacts of climate change on freshwater biodiversity. AB - To understand the resilience of aquatic ecosystems to environmental change, it is important to determine how multiple, related environmental factors, such as near surface air temperature and river flow, will change during the next century. This study develops a novel methodology that combines statistical downscaling and fish species distribution modeling, to enhance the understanding of how global climate changes (modeled by global climate models at coarse-resolution) may affect local riverine fish diversity. The novelty of this work is the downscaling framework developed to provide suitable future projections of fish habitat descriptors, focusing particularly on the hydrology which has been rarely considered in previous studies. The proposed modeling framework was developed and tested in a major European system, the Adour-Garonne river basin (SW France, 116,000 km(2)), which covers distinct hydrological and thermal regions from the Pyrenees to the Atlantic coast. The simulations suggest that, by 2100, the mean annual stream flow is projected to decrease by approximately 15% and temperature to increase by approximately 1.2 degrees C, on average. As consequence, the majority of cool- and warm-water fish species is projected to expand their geographical range within the basin while the few cold-water species will experience a reduction in their distribution. The limitations and potential benefits of the proposed modeling approach are discussed. PMID- 22425277 TI - Impact of organic and inorganic nanomaterials in the soil microbial community structure. AB - In this study the effect of organic and inorganic nanomaterials (NMs) on the structural diversity of the soil microbial community was investigated by Denaturing Gradient Gel Electrophoresis, after amplification with universal primers for the bacterial region V6-V8 of 16S rDNA. The polymers of carboxylmethyl-cellulose (CMC), of hydrophobically modified CMC (HM-CMC), and hydrophobically modified polyethylglycol (HM-PEG); the vesicles of sodium dodecyl sulphate/didodecyl dimethylammonium bromide (SDS/DDAB) and of monoolein/sodium oleate (Mo/NaO); titanium oxide (TiO(2)), titanium silicon oxide (TiSiO(4)), CdSe/ZnS quantum dots, gold nanorods, and Fe/Co magnetic fluid were the NMs tested. Soil samples were incubated, for a period of 30 days, after being spiked with NM suspensions previously characterized by Dynamic Light Scattering (DLS) or by an ultrahigh-resolution scanning electron microscope (SEM). The analysis of similarities (ANOSIM) of DGGE profiles showed that gold nanorods, TiO(2), CMC, HM CMC, HM-PEG, and SDS/DDAB have significantly affected the structural diversity of the soil bacterial community. PMID- 22425278 TI - Carbonaceous and ionic compositional patterns of fine particles over an urban Mediterranean area. AB - A carefully designed experimental study based on the monitoring of fine airborne particles, was carried out at three different locations (suburban background, traffic-industrial, coastal background) of an urban Mediterranean area, the Athens Basin. Understanding of the PM(2.5) and PM(1) nature has an important policy implication. In total, five hundred and nineteen samples were chemically analyzed with respect to carbonaceous (organic/elemental carbon) and ionic (NH(4)(+), K(+), Mg(2+), Ca(2+), NO(3)(-), Cl(-), SO(4)(2-)) species. The dataset consists one of the very few in the Mediterranean which simultaneously deals with the carbonaceous and ionic components of fine aerosol fractions, especially for PM(1). Daily PM(2.5) averages often exceeded the E.U. limit values, with their mass being mainly composed of PM(1). The most important constituents of secondary particles were SO(4)(2-) and organic carbon, with both accounting for 56.4%-64.3% and 60.5%-62.3% of the total PM(2.5) and PM(1) mass, respectively. Regional sources, marine/crustal elements, combustion sources and traffic were indicated by factor analysis as the greatest contributors to the mass of both PM(2.5) and PM(1) fractions, accounting for 85.3% and 83.6%, respectively of the total variance in the system. It is worthy to note, the key role of the prevailing atmospheric conditions to the configuration of the obtained picture of the particulate pollution. PMID- 22425279 TI - Association between urinary 3, 5, 6-trichloro-2-pyridinol, a metabolite of chlorpyrifos and chlorpyrifos-methyl, and serum T4 and TSH in NHANES 1999-2002. AB - Thyroid hormones are vital to a host of human physiological functions in both children and adults. Exposures to chemicals, including chlorpyrifos, have been found to modify thyroid signaling at environmentally relevant levels in animal studies. The aim of this study was to examine circulating T4 and TSH levels in relation to urinary concentrations of 3, 5, 6-trichloro-2-pyridinol (TCPY), a metabolite of the organophosphorus insecticides chlorpyrifos and chlorpyrifos methyl, using data from individuals 12 years and older from the U.S. National Health and Nutrition Examination Surveys (NHANES). NHANES datasets from 1999 to 2000 and 2001-2002 were combined, and individuals with thyroid disease, those taking thyroid medications, and pregnant women were excluded (N = 3249). Multivariable linear regression models for relationships between log-transformed urinary TCPY and serum total T(4) or log (TSH) were constructed adjusting for important covariates. Models were stratified by sex and a categorical age variable (12-18, 18-40, 40-60, and >60 years). In male participants, an interquartile range (IQR) increase in urinary TCPY was associated with statistically significant increases in serum T(4) of 3.8% (95th CI 0.75 to 7.0) among those 12-18 years of age and 3.5% (95th CI 0.13 to 7.0) in the 18-40 year age group, relative to median T4 levels using unweighted models. An IQR increase in TCPY was also associated with decreases in TSH of 10.7% (-18.7-2.05) among men 18-40 years old and 20.0% (95th CI -28.9 to -9.86) among men >60 years old. Conversely, urinary TCPY was positively associated with TSH in females >60 years of age. Further research to confirm these findings, elucidate mechanisms of action, and explore the clinical and public health significance of such alterations in thyroid hormones is needed. PMID- 22425280 TI - Fluorinated semiconductor photocatalysts: tunable synthesis and unique properties. AB - Semiconductor photocatalysts are of great significance in solar energy conversion and environmental remediation. To overcome serious drawbacks of these materials with respect to narrow light-response range and low quantum efficiency, a variety of strategies have been developed in the past decades to enhance the light harvesting and excitation as well as the charge transfer against recombination. In particular, fluorination of semiconductor photocatalysts can be employed to modify their surface and bulk properties, and consequently, to enhance their photocatalytic performance. This review presents a comprehensive description of the F-mediated synthesis and unique properties of fluorinated semiconductor photocatalysts, in particular titanium dioxide (TiO(2)). The available strategies for the synthesis of fluorinated photocatalysts include post-synthesis fluorination and in-situ fluorination. Depending on the synthesis route and conditions, it is possible to control the chemical nature of incorporated fluorine (such as adsorbed fluoride and lattice-doped fluorine) and the fluoride mediated crystal modification and organization, which often results in exceptional surface and bulk physicochemical properties, giving rise to unique photocatalytic properties. Significantly, the surface fluorination induces unusual adsorption behavior and interfacial charge transfer dynamics, directly affecting photocatalytic redox properties of the surface-fluorinated photocatalysts. The lattice fluorine-doping, sole or cooperative with other complementary co-dopants, introduces special localized electronic structures and surface defect states, accounting for the exceptional visible-light photoactivity of the fluorine-doped photocatalysts. Finally, recent advances in the synthesis and properties of fluorinated photocatalysts are summarized along with perspectives on further developments in this area of research. PMID- 22425281 TI - Internet use for information seeking in clinical practice: a cross-sectional survey among French general practitioners. AB - BACKGROUND: Medical information needs regarding patient care are particularly large for general practitioners (GPs). The Internet seems to be a relevant but underused tool to seek medical information. OBJECTIVE: We aimed to describe the characteristics of the French GPs using the Internet for information seeking, to identify the barriers to its use and the factors that could facilitate it. METHOD: We conducted a cross-sectional survey among GPs currently practicing in France, using an online questionnaire, in July 2009. We analysed the answers of 721 respondents. RESULTS: Most of the respondents used the Internet to seek information. They were significantly younger, worked in group practice, had Internet training and had Internet access at the practice. The main barriers were related to the physician (lack of knowledge or specific skills), to the practice conditions (lack of time, concerns about relationship with patient, financial non recognition) and to the information (information overload, quality concerns, low relevance, language barrier). Practitioners wanted more reliable and more relevant documents for daily practice. Websites with already selected resources could increase the GPs use of the Internet for medical information seeking. CONCLUSION: The reported obstacles were largely common with those previously described in other countries, except the language barrier and the financial non recognition. Even if the generalization of our results to all French GPs should be cautious, the study provided better insights into the obstacles to the Internet use to seek clinical information in family practice and the factors that could facilitate it. PMID- 22425282 TI - Clinical experience of using Oncotype DX as an additional treatment decision tool in early breast cancer - a retrospective analysis from 5 Greek institutions. AB - AIMS: The objective of this retrospective study was to describe the results from five institutions' experience of using Oncotype DX((r)) to identify patients who need chemotherapy despite the presence of primarily favorable characteristics. PATIENTS AND METHODS: Oncotype DX was performed in 106 pre- and postmenopausal patients with estrogen receptor-positive, HER2-negative, early breast cancer with a combination of favorable prognostic factors or favorable prognostic factors with at least one unfavorable characteristic (tumor size >2 cm, tumor grading of II-III, Ki-67 >= 10%, presence of lymph node micrometastases) in which it was unclear whether hormonal therapy only or chemotherapy plus hormonal therapy was the optimal adjuvant treatment. RESULTS: Sixty-four (60.4%) women had Recurrence Score (RS) values <18, 29 (27.4%) intermediate RS values of 18-30, and 13 (12.3%) high RS values of >=31. Tumor size, grading and presence of micrometastases were not associated with the RS. There was a significant association between Recurrence Score and the number of unfavorable characteristics as a categorical but not as a continuous variable. High Recurrence Scores were predictive of high Ki-67 but the converse was not true. Overall, 29 of 106 (27.4%) patients received chemotherapy because of an intermediate or a high Recurrence Score. CONCLUSION: The Recurrence Score helped in treatment decision-making for estrogen receptor positive, HER2-negative patients with favorable characteristics or an intermediate risk of recurrence due to the presence of at least one unfavorable factor. The results of the 21-gene assay increased the likelihood for patients with intermediate clinical and histopathological risk factors receiving chemotherapy. PMID- 22425283 TI - Robotic radical parametrectomy with pelvic lymphadenectomy: our experience and review of the literature. AB - AIMS: To evaluate the feasibility and safety of robotic radical parametrectomy (RRP) and pelvic lymphadenectomy for the management of occult invasive cervical cancer or local recurrence of endometrial cancer and to compare our outcomes with the evidence available in the literature. METHODS: Starting from 07/2008 consecutive patients submitted to RRP have been included in this study. A comprehensive literature review of published papers about this subject was carried out. RESULTS: During the study period 11 patients were managed; 7 and 4 patients had an occult cervical cancer and a vaginal recurrence of endometrial cancer, respectively. One intra-operative and one post-operative complications were recorded. Neither conversion to laparotomy, nor blood transfusions occurred. Three women required further adjuvant therapies. After a median follow-up of 19 months (range 8-36) one recurrence has been detected. The outcomes of other 200 women from 15 different papers have been collected and compared to our findings. CONCLUSIONS: Robotic surgery represents an effective alternative to accomplish radical parametrectomy with comparable results of those reported in the literature in terms of feasibility and safety. RRP is certainly a demanding procedure which however avoids radiotherapy in more than 80% of cases. PMID- 22425284 TI - Cloning and expression of three lipoxygenase genes from liverwort, Marchantia polymorpha L., in Escherichia coli. AB - Three genes homologous to plant lipoxygenase genes were identified from the EST libraries of Marchantia polymorpha, in order to clarify the function of LOXs in bryophytes. Full-length genes were isolated using 5'- and 3'-RACE methods and named MpLOX1, MpLOX2, and MpLOX3, respectively. To investigate the enzymatic activities of liverwort LOXs, recombinant MpLOX1, MpLOX2, and MpLOX3 proteins were prepared from Escherichia coli cells expressing the corresponding gene. LC MS/MS analyses and chiral column chromatography of their reaction products showed that MpLOX1 codes for 11S/15S-lipoxygenase against eicosapentaenoic acid and for 15S-lipoxygenase against arachidonic acid, and that MpLOX2 and MpLOX3 code for 15S-lipoxygenase against eicosapentaenoic and arachidonic acids. Phylogenetic analysis showed that the liverwort lipoxygenase genes separated from the ancestor of higher plants in the early stages of plant evolution. Quantification analyses suggested that arachidonic acid and eicosapentaenoic acid were preferred substrates. Furthermore, each liverwort lipoxygenase exhibited highest activity at pH 7.0 and dependency on Ca(2+) ion in the oxygenation reaction. PMID- 22425285 TI - Trans-alpha-xylosidase, a widespread enzyme activity in plants, introduces (1->4) alpha-d-xylobiose side-chains into xyloglucan structures. AB - Angiosperms possess a retaining trans-alpha-xylosidase activity that catalyses the inter-molecular transfer of xylose residues between xyloglucan structures. To identify the linkage of the newly transferred alpha-xylose residue, we used [Xyl (3)H]XXXG (xyloglucan heptasaccharide) as donor substrate and reductively aminated xyloglucan oligosaccharides (XGO-NH(2)) as acceptor. Asparagus officinalis enzyme extracts generated cationic radioactive products ([(3)H]Xyl.XGO-NH(2)) that were Driselase-digestible to a neutral trisaccharide containing an alpha-[(3)H]xylose residue. After borohydride reduction, the trimer exhibited high molybdate-affinity, indicating xylobiosyl-(1->6)-glucitol rather than a di-xylosylated glucitol. Thus the trans-alpha-xylosidase had grafted an additional alpha-[(3)H]xylose residue onto the xylose of an isoprimeverose unit. The trisaccharide was rapidly acetolysed to an alpha-[(3)H]xylobiose, confirming the presence of an acetolysis-labile (1->6)-bond. The alpha-[(3)H]xylobiitol formed by reduction of this alpha-[(3)H]xylobiose had low molybdate-affinity, indicating a (1->2) or (1->4) linkage. In NaOH, the alpha-[(3)H]xylobiose underwent alkaline peeling at the moderate rate characteristic of a (1->4) disaccharide. Finally, we synthesised eight non-radioactive xylobioses [alpha and beta; (1<->1), (1->2), (1->3) and (1->4)] and found that the [(3)H]xylobiose co chromatographed only with (1->4)-alpha-xylobiose. We conclude that Asparagus trans-alpha-xylosidase activity generates a novel xyloglucan building block, alpha-d-Xylp-(1->4)-alpha-d-Xylp-(1->6)-d-Glc (abbreviation: 'V'). Modifying xyloglucan structures in this way may alter oligosaccharin activities, or change their suitability as acceptor substrates for xyloglucan endotransglucosylase (XET) activity. PMID- 22425286 TI - Effects of chronic kidney disease on blood cells membrane properties. AB - Chronic kidney disease (CKD) is progressive loss of renal function associated among others with increased intracellular calcium concentration. The purpose of this study was to identify the effects of CKD on cell membrane properties such as human red blood cell Ca(2+) ATPase activity, lymphocyte plasma membrane P2X(7) receptor expression and function. This could help us in elucidating the origin of increased calcium concentration in blood cells. We found out Ca(2+) ATPase activity is decreased in early stage CKD patients resulting in altered calcium removal from cytoplasm. By means of flow cytometry we assessed that P2X(7) receptor expression on lymphocyte membrane is 1.5 fold increased for CKD patients. Moreover, we detected an increased uptake of ethidium bromide through this receptor in CKD at basal conditions. It means CKD lymphocyte membranes contain more receptors which are more permeable thus allowing increased calcium influx from extracellular milieu. Finally, we can state alterations in blood cell membranes are closely linked to CKD and may be responsible for intracellular calcium accumulation. PMID- 22425287 TI - Follow-up of gestational diabetes insipidus using magnetic resonance imaging. PMID- 22425288 TI - The relationship of premature progesterone rise with serum estradiol levels and number of follicles in GnRH antagonist/recombinant FSH-stimulated cycles. AB - OBJECTIVE(S): To investigate the relationship between premature progesterone (P) rise and serum estradiol (E(2)) levels and the number of follicles in GnRH antagonist/rec-FSH stimulated cycles. STUDY DESIGN: Two hundred and seven patients treated by IVF/ICSI at the Centre for Reproductive Medicine of the Dutch Speaking Brussels Free University were included in this observational study. They received 200 IU/day rec-FSH from day 2 of the cycle and daily GnRH antagonist starting on day 6 of stimulation. The criteria for hCG administration included the presence of >=3 follicles of >=17 mm diameter. Serum P, E(2) and LH were determined on the day of hCG administration. The outcome measure was to identify a threshold of E(2) and number of follicles on the day of hCG administration which would define a progesterone rise on the day of hCG administration (cut-off value of 1.5 ng/ml). RESULT(S): Patients with a P >1.5 ng/ml had significantly higher concentrations of E(2) and increased number of follicles on the day of hCG administration compared to those with P <=1.5 ng/ml. However, patients with a P >1.5 ng/ml the day of hCG showed lower pregnancy rates than those with P <1.5 ng/ml (17.8 vs. 32.7%, respectively; p<0.05). A ROC curve was employed in order to estimate a cut-off for E(2) on day of hCG >1790.5 pg/ml and more than 9.5 follicles of >=11 mm in diameter for progesterone rise over 1.5 ng/ml. CONCLUSION(S): A significant impact is shown on progesterone rise by E(2) and number of follicles on the day of hCG administration in GnRH antagonist/rec-FSH stimulated cycles. With this knowledge, an upcoming progesterone rise during follicular phase can be anticipated and prevented. PMID- 22425289 TI - Waiting times and socioeconomic status: evidence from England. AB - Waiting times for elective surgery, like hip replacement, are often referred to as an equitable rationing mechanism in publicly-funded healthcare systems because access to care is not based on socioeconomic status. Previous work has established that that this may not be the case and there is evidence of inequality in NHS waiting times favouring patients living in the least deprived neighbourhoods in England. We advance the literature by explaining variations of inequalities in waiting times in England in four different ways. First, we ask whether inequalities are driven by education rather than income. Our analysis shows that education and income deprivation have distinct effects on waiting time. Patients in the first quintile with least deprivation in education wait 9% less than patients in the second quintile and 14% less than patients in the third to-fifth quintile. Patients in the fourth and fifth most income-deprived quintile wait about 7% longer than patients in the least deprived quintile. Second, we investigate whether inequalities arise "across" hospitals or "within" the hospital. The analysis provides evidence that most inequalities occur within hospitals rather than across hospitals. Moreover, failure to control for hospital fixed effects results in underestimation of the income gradient. Third, we explore whether inequalities arise across the entire waiting time distribution. Inequalities between better educated patients and other patients occur over large part of the waiting time distribution. Moreover we find that the education gradient becomes smaller for very long waiting. Fourth, we investigate whether the gradient may reflect the fact that patients with higher socioeconomic status have a different severity as proxied through a range of types and the number of diagnoses (in addition to age and gender) compared to those with lower socioeconomic status. We find no evidence that differences in severity explain the social gradient in waiting times. PMID- 22425290 TI - Brugada syndrome phenotype cardiac arrest in a young patient unmasked during the acute phase of amiodarone infusion: disclosure and aggravation of Brugada electrocardiographic pattern. AB - We report a case of an outpatient cardiac arrest due to ventricular fibrillation and resuscitated with external automated defibrillator shocks in which acute amiodarone infusion unmasked a Brugada phenotype electrocardiographic pattern. Possible interferences by this drug and suitable therapeutic actions are discussed. PMID- 22425291 TI - The assessment of postural control with stochastic resonance electrical stimulation and a neoprene knee sleeve in the osteoarthritic knee. AB - OBJECTIVE: To determine whether the combination of stochastic resonance (SR) electrical stimulation and a neoprene knee sleeve could improve center of pressure (COP) measures of postural sway during single-leg stance in those with knee osteoarthritis (OA). DESIGN: Counterbalanced, repeated-measures intervention study of osteoarthritic adults during 6 different testing conditions: a control condition-control 1 (1); a counterbalance sequence of 4 treatment conditions-no stimulation with sleeve (2), 75% stimulation with sleeve (3), 100% stimulation with sleeve (4), and 150% stimulation with sleeve (5); and a second control condition-control 2 (6). SETTING: University sports medicine research laboratory. PARTICIPANTS: Subjects (N=52) with radiographically determined, minimal-to moderate medial knee OA. INTERVENTIONS: Neoprene knee sleeve and SR electrical stimulation. MAIN OUTCOME MEASURES: COP displacement in the medial-lateral and anterior-posterior directions was collected to resolve the mean velocity, SD, range, and total path length. RESULTS: No significant differences were found in the study measures between the testing conditions. Additionally, no significant differences were found between the 3 stimulation conditions or between the sleeve alone and stimulation conditions for any of the study measures. CONCLUSIONS: There were no significant improvements in balance with the use of a neoprene knee sleeve. Additionally, there was no added benefit of the SR stimulation as applied in the current configuration in this population. PMID- 22425292 TI - The prognostic value of the PCL-R in relation to the SUD treatment ending. AB - Scientific research about patients with substance use disorders (SUD) treated within the context of forensic compulsory addiction treatment is seldom available. Scientifically supported surveys regarding the treatability of SUD patients are rare. Some authors claim that the Psychopathy-Checklist-Revised (PCL R) has value for predicting therapeutic success. PCL-R scores rely on extensive interview data and a detailed review of criminal records and social history. The scores reflect 1) the affective and interpersonal psychological traits; and 2) socially deviant conduct. This study was conducted by the forensic professional clinic at the hospital for Psychiatry and Neurology Hildburghausen. We assessed 102 male patients using the PCL-R. This investigation evaluated the Total score of the PCL-R and the score of Factor 1 and Factor 2 in relation to the end of treatment by court order. The results showed significant differences between patients who completed treatment and those who did not. Patients that dropped out of treatment had a higher score in PCL-R. With the use of the PCL-R it is possible to make a quantitative statement about which patients will complete treatment. PMID- 22425293 TI - Relationships and sexuality of imprisoned men in the German penal system--a survey of inmates in a Berlin prison. AB - The lack of concrete scientific data on the sexual behavior of inmates in German prisons is surprising, especially given the extant international scholarship on prison culture and sexual violence. Historically, the most influential publications were Clemmer's "The Prison Community", and Sykes's "The Society of Captives", which both addressed the importance of sexual deprivation and analyzed the impact of sexual victimization on prisoners. Different forms of homosexual contact between inmates include prostitution and "protective pairing", both characterized as "dark" issues--nonconsensual sexual acts--which still have not been scientifically researched. The United States enacted the Prison Rape Elimination Act, 2003, revealing nationwide data on the prevalence of sexual assault within correctional facilities. Prison inmates suffer not only from separation from their spouses or partners, but also from sexual harassment, extortion, and the threat of rape, which has multiple implications for their mental and physical health. This article presents the first German study to record data about the relationships and sexuality of imprisoned men, and was conducted in an adult correctional facility for long-term prisoners in Berlin Tegel. The survey, which is based on results from a questionnaire taken by voluntary study participants, had a special focus on the occurrence of consensual homoerotic contacts between heterosexual inmates. The emphasis was on the potential impact of such contact on role behavior during confinement, as well as the impact on sexual identity after release. The survey revealed the first data on the incidence and prevalence of sexual violence and coercion within correctional facilities. This article presents the results of this survey for the first time. PMID- 22425294 TI - Common femoral vein thrombosis caused by a metal-on-metal hip arthroplasty related pseudotumor. AB - We present a case of a pseudotumor causing a deep femoral vein thrombosis 16 months after undergoing a metal-on-metal total hip arthroplasty. There is increasing concern over the effect of metal ions that are produced by wear in metal-on-metal hip arthroplasty systems. Recently, a number of articles have reported the development of an inflammatory pseudotumor causing a number of different problems early on in the lifespan of the implant necessitating revision surgery. This case reports the first presentation of a pseudotumor causing a serious venous thrombosis due to pressure effect and indicates further possible evidence for caution when considering metal-on-metal bearing hip arthroplasty. PMID- 22425295 TI - Long-term follow-up of anatomic graduated component total knee arthroplasty: a 15 to 20-year survival analysis. AB - The aims of this study were to determine survival rate, the clinical performance, and radiologic results of an Anatomic Graduated Component (AGC) total knee arthroplasty (TKA). Survival analysis was assessed by analyzing all hospital records of 211 AGC TKAs in 177 patients after 15 to 20 years. The survival rate was 87%, with failure defined as revision for any reason including infection. The main reasons for failure were infection and failure of the metal-backed patellar component. Clinical evaluation of 30 patients (33 TKAs) and questionnaires of 20 patients (23 TKAs) were taken, showing moderate to good results (mean Knee Society Score, 51; mean Western Ontario and McMaster Universities Osteoarthritis index, 82; mean University of California Los Angeles score, 4). Radiologic evaluation of 13 TKAs in 12 patients showed that none was suspect for loosening. Three knees showed significant medial wear but no clinical complaints. In conclusion, this is one of the first studies showing that AGC total knee prosthesis has good results 15 to 20 years after surgery. PMID- 22425296 TI - Popliteal pseudoaneurysm after total knee arthroplasty: a report of 3 cases. AB - Although the incidence of vascular injuries after total knee arthroplasty is quite low, clinical outcome could be significantly impaired. Quick response and accurate management are important to achieve the best possible outcome. We present 3 cases of popliteal pseudoaneurysm formation after total knee arthroplasty and their treatment by endovascular stenting together with a review of literature. PMID- 22425297 TI - Hip squeaking: a 10-year follow-up study. AB - The aim of the study was to analyze the incidence of squeaking with ceramic-on ceramic total hip arthroplasty (THA) after 10 years of follow-up and the potential complications that could occur related to this phenomenon. One hundred THAs implanted between November 1999 and December 2000 were evaluated. Incidence of squeaking was investigated clinically with a questionnaire. Implant positioning was analyzed on x-rays and computer tomography. Of the 100 THAs, 5 patients presented with squeaking. All of them were active, sporty, and heavy men. Functional scores were comparable with nonsqueaking patients. There was no malpositioning on the x-ray analysis, no wear, and no loosening. We could not demonstrate any relation between squeaking and ceramic fracture. Squeaking noise appeared at a mean of 66 months postsurgery. It appears to be an isolated phenomenon without any consequences at 10-year follow-up. PMID- 22425298 TI - Wear analysis of first-generation highly cross-linked polyethylene in primary total hip arthroplasty: an average 9-year follow-up. AB - This is a retrospective review of 46 primary total hip arthroplasties using a first-generation highly cross-linked ultrahigh-molecular-weight polyethylene liner (Crossfire; Stryker, Mahwah, NJ) with an average of 9-year follow-up. The purpose of this study was to measure linear penetration rate of first-generation polyethylene to determine if it maintains its wear resistance and fatigue strength over an extended period compared with conventional polyethylene. The mean (SD) total penetration was 0.339 (0.204) mm, and the mean (SD) penetration rate was 0.037 (0.022) mm/y. Our study demonstrated a 74% reduction in total penetration of highly cross-linked polyethylene when compared with historical controls using conventional polyethylene at an average of 9 years. Our results support the belief that highly cross-linked polyethylene does retain its wear resistance over an extended period. PMID- 22425299 TI - Analysis of total joint arthroplasty costs in Chinese patients. AB - All charges for patients undergoing unilateral and bilateral hip or knee arthroplasties at 1 hospital in Beijing, China, were identified and assigned to 1 of 11 charge categories: hospital room, nursing, radiology, laboratory, anesthesia, surgery, prosthesis, pharmacy, blood transfusion, materials, and miscellaneous. The prosthesis and pharmacy charges at this institution accounted for approximately 80% of the total charges; compared with published data from institutions in North America and Taiwan, these 2 charges accounted for a greater percentage of total charges. In distinction, labor costs in China accounted for a lower percentage of total charges. Importantly, because the percentage of costs covered by medical insurance was relatively low, a substantial financial burden was imposed on patients that may limit access to joint arthroplasty in China. PMID- 22425300 TI - Large-diameter modular metal-on-metal total hip arthroplasty: incidence of revision for adverse reaction to metallic debris. AB - Large-diameter modular metal-on-metal (MOM) total hip arthroplasty (THA) may offer reduction in wear debris and improved stability. Four studies are summarized here that used a large-diameter modular MOM system. A total of 1076 THAs were performed. This article presents data from 779 of these THAs with minimum 2-year follow-up (mean, 4.2 years) or revision since index THA (21 hips, with 1 more pending). Overall survivorship at 2 years was 98.6%; at 5 years, it was 97.0%. Seven revisions for an adverse reaction to metallic debris (ARMED), and 1 additional pending revision for ARMED, showed marked variability in presenting symptoms and intraoperative and postoperative findings. Data show good clinical performance of the modular MOM system, but suggest that surgeons must be diligent in monitoring MOM THA patients and aggressive in diagnosing and revising patients with a potential ARMED. PMID- 22425301 TI - Are hip resurfacing arthroplasties meeting the needs of our patients? A 2-year follow-up study. AB - Hip resurfacing arthroplasty (HRA) is a treatment of end-stage hip arthritis in young patients with excellent bone stock. One hundred four consecutive HRAs (Depuy ASR, Warsaw, Ind) were performed with 36-Item Short Form Health Survey (SF 36), Western Ontario and McMaster University Osteoarthritis Index, Harris Hip Scores, and University of California, Los Angeles activity ratings obtained preoperatively, at 6 months, and at 1 and 2 years postoperatively. Four patients required conversion to total hip arthroplasty. All patients showed significant improvements in their activity, pain, stiffness, and function postoperatively. Patients with lower SF-36 mental component scores (MCSs) improved their MCS compared with those of the general population, as well as improving their pain and physical functioning scores. These findings demonstrate reliable improvements in standard quality of life measures in patients undergoing HRA, including those with low preoperative SF-36 MCS. PMID- 22425302 TI - Interobserver and intraobserver reliability and validity of the Vancouver classification system of periprosthetic femoral fractures after hip arthroplasty. AB - The Vancouver classification system of periprosthetic fractures has been revalidated in this study, using the radiographs of 45 patients. Three consultants and 3 trainees reviewed the radiographs independently, on 2 separate occasions, at least 2 weeks apart. Interobserver and intraobserver agreement and validity were analyzed, using weighted kappa statistics. The mean kappa value for interobserver agreement was found to be 0.69 (0.63-0.72) for consultants and 0.61 (0.56-0.65) for the trainees, both representing substantial agreement. Intraobserver kappa values ranged from 0.74 to 0.90, showing substantial agreement. Validity analysis of 37 type B cases revealed 81% agreement within B1, B2, and B3 subgroups with a kappa value of 0.68 (substantial agreement). This study has reconfirmed the reliability and validity of the Vancouver classification while it also emphasizes the intraoperative assessment of implant stability. PMID- 22425303 TI - A prospective analysis of glove perforation in primary and revision total hip and total knee arthroplasty. AB - Literature in regard to glove perforation rates in revision total joint arthroplasty (TJA) is scarce. Our purpose was to determine the incidence of perforation in revision TJA. Gloves from all scrubbed personnel were tested based on the American Society for Testing and Materials. A total of 3863 gloves were collected from 58 primary and 36 revision arthroplasty cases. Surgeons had a 3.7% outer-glove perforation rate in primary TJA compared with 8.9% in revision TJA. When both gloves were perforated, the outer-glove perforation was recognized intraoperatively 100% of the time, and the inner-glove perforation was noted only 19% of the time. The surgeon has the highest rate of glove perforation. Outer glove perforations should prompt careful inspection of the inner glove. PMID- 22425304 TI - Preformed articulating knee spacers in 2-stage total knee revision arthroplasty: minimum 2-year follow-up. AB - Two-stage revision arthroplasty using articulating spacers for the treatment of infected total knee arthroplasty (TKA) is a successful management technique. Our purpose was to report our results using preformed, commercially available articulating spacers made of gentamicin-impregnated cement. Thirty-three patients with infected primary or revision TKAs were treated with these spacers using a 2 stage revision technique. In most cases, the spacers were modified intraoperatively by adding a stem of reinforced antibiotic-impregnated acrylic cement. Successful eradication was achieved in 30 of 33 cases at a minimum 2-year follow-up interval. Two patients required a second spacer before successful revision TKA. No spacer fractures or dislocations occurred in this series. No adverse soft tissue effects were noted from the use of this type of articulating spacer. PMID- 22425305 TI - Revision total hip arthroplasty in patients 80 years or older. AB - We evaluated all revisions performed from March 1996 to December 2008 and compared complications, mortality, and clinical outcomes between patients 80 years and older and patients younger than 80 years. Data were collected prospectively. There were 325 revisions, 84 (25.8%) in patients 80 years and older and 241 in patients younger than 80 years (62% revision for aseptic loosening in both groups). The mean follow-up was 4.3 years. The results, 80 years and older vs younger than 80 years, revealed the following: mortality, 5% vs 0% 3 months postoperatively; medical complications in 23.8% vs 6.2%; postoperative fractures, 9.5% vs 2.5%; and improved Merle d'Aubigne scores from 9.6 to 13.0 vs 10.4 to 14.3. Revision total hip arthroplasty in patients 80 years and older was associated with substantial clinical improvement and patient satisfaction. However, medical complications and 90-day mortality were higher, and postoperative fractures occurred more frequently. PMID- 22425306 TI - Removal of trabecular metal osteonecrosis intervention implant and conversion to primary total hip arthroplasty. AB - Core decompression and placement of the Trabecular Metal Osteonecrosis Intervention Implant have shown to be initially successful in treating early osteonecrosis. When treatment fails, however, patients often undergo primary total hip arthroplasty (THA) requiring removal of a previously inserted trabecular metal implant. We describe a technical tip for removal of a well ingrown trabecular metal screw. A metal-cutting trephine placed over the screw allows for removal in an efficient manner while minimizing additional dissection and bone loss during conversion to THA. PMID- 22425307 TI - Comparison of different distal designs of femoral components and their effects on bone remodeling in 1-stage bilateral total hip arthroplasty. AB - To evaluate the effects of distal design of a proximally coated femoral component on periprosthetic bone remodeling, we prospectively performed 21 one-stage bilateral total hip arthroplasties using a distally tapered and a distally cylindrical stem with the same proximal design, randomized to side. All hips showed good outcomes clinically and radiographically at the final follow-up, average of 7 years postoperatively. Cancellous condensation was always found in Gruen's zones 2 and 6 around the cylindrical stem and in regions between zones 2 and 3 and between zones 6 and 5 around the tapered stem. Bone mineral density of Gruen's zones 2 and 6 was significantly lower around the tapered stem. These results suggested more distal loading in hips with the tapered stem than in those with the cylindrical stem. PMID- 22425308 TI - A randomized controlled trial comparing bone mineral density changes of three different ACL reconstruction techniques. AB - INTRODUCTION: This study aimed to compare the changes in bone mineral density (BMD) of three different ACL reconstruction (ACLR) techniques and its association with early clinical and functional outcomes. METHODS: Sixty-two male adult patients undergoing primary ACLR were prospectively parallel randomized to bone patellar tendon-bone graft (BPTB), single-bundle (HT-SB) or double-bundle (HT-DB) hamstring graft. BMD (primary outcome) at the proximal tibia, distal femur, femoral neck and trochanteric region was measured blindly at day 1, 3 months, 5 months and 1 year after surgery. KT-1000, Lysholm, IKDC, one-leg hop test and Lachman test were performed blindly at baseline and 1 year post-reconstruction. RESULTS: There was a significant bone loss at the injured knee and hip at 3 and 5 months which was reversible at the knee, but not at the hip, at 1 year post operation. There was a significant improvement of early clinical and functional outcomes at 1 year. No significant differences in bone loss was detected among different surgical techniques, except BMD loss at the femoral neck, though a trend of greater BMD loss in the HT-SB group at 5 months after reconstruction was observed. There was a significant positive correlation between BMD at the distal femur and the single-leg hop distance at 1 year. CONCLUSION: In conclusion, the three surgical techniques were similar in transient bone loss at the knee region, irreversible bone loss at the hip, early clinical and functional outcomes up to 1 year post-reconstruction. BMD at the distal femur was positively associated with the single-leg hop distance at 1 year post-reconstruction. PMID- 22425309 TI - Expression of late viral proteins is restricted in nasal mucosal leucocytes but not in epithelial cells during early-stage equine herpes virus-1 infection. AB - Equine herpes virus (EHV)-1 replicates in the epithelial cells of the upper respiratory tract and reaches the lamina propria and bloodstream in infected mononuclear cells. This study evaluated expression of the late viral proteins gB, gC, gD and gM in respiratory epithelial and mononuclear cells using: (1) epithelial-like rabbit kidney cells and peripheral blood mononuclear cells infected with EHV-1 in vitro; (2) an equine ex vivo nasal explant system; and (3) nasal mucosa tissue of ponies infected in vivo. The viral proteins were expressed in all late-infected epithelial cells, whereas expression was not observed in infected leucocytes where proteins gB and gM were expressed in 60-90%, and proteins gC and gD in only 20% of infected cells, respectively. The results indicate that expression of these viral proteins during early-stage EHV-1 infection is highly dependent on the cell type infected. PMID- 22425310 TI - Comparison of ultrasonography, radiography and a single computed tomography slice for the identification of fluid within the tympanic bulla of rabbit cadavers. AB - Evaluation of the tympanic bulla (TB) in cases of otitis media in the rabbit can be a diagnostic challenge, although a feature often associated with the condition is the accumulation of fluid or material within the TB. Randomly selected TB from 40 rabbit cadavers were filled with a water-based, water-soluble jelly lubricant. A dorsoventral radiograph and single computed tomography (CT) slice were taken followed by an ultrasound (US) examination. Image interpretation was performed by blinded operators. The content of each TB was determined (fluid or gas) using each technique and the cadavers were frozen and sectioned for confirmation. CT was the most accurate diagnostic method, but US produced better results than radiography. Given the advantages of US over the other imaging techniques, the results suggest that further work is warranted to determine US applications in the evaluation of the rabbit TB and clinical cases of otitis media in this species. PMID- 22425311 TI - Acute pericarditis associated to onset of diabetes mellitus. PMID- 22425312 TI - Metabolic surgery: report of three cases. PMID- 22425313 TI - Dr. Jose Luis Rodriguez-Minon, a defender of Paulescu as the discoverer of insulin. PMID- 22425314 TI - Hyperthyroidism due to Graves-Basedow disease in a woman refractory to thyroid hormones. PMID- 22425315 TI - [Resolution of acromegalic cardiomyopathy after pituitary apoplexy]. PMID- 22425316 TI - [Neuroendocrinology in 2011]. PMID- 22425317 TI - Adenoviral delivery of constitutively active HIF1alpha into venous thrombus. PMID- 22425318 TI - Progestin-only contraception and venous thromboembolism. AB - Combined oral contraceptives (COC) are the most popular contraceptive method in developed countries. Since their introduction there have been numerous changes and modifications in its composition with the aim to improve safety and tolerability while maintaining contraceptive efficacy. Most of the changes have been conducted on the progestin component, since most of the combinations include ethinyl estradiol as oestrogen. One of the adverse effects of COC is the increased risk of venous thromboembolism (VTE) in two clinical forms of presentation: deep vein thrombosis or pulmonary embolism. This review details the changes in haemostasis induced by progestin-only contraceptives and the risk of VTE in women who utilize this type of contraception; the relationship with other risk factors such as thrombophilia; the interactions of these contraceptives with anticoagulant treatment and finally the eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers. PMID- 22425319 TI - Platelet tissue factor pathway inhibitor modulates intravascular coagulation. AB - Tissue factor pathway inhibitor (TFPI) is produced by megakaryocytes and is found internally within quiescent platelets but is not in alpha-granules. It is released in soluble form and expressed on the surface of platelets that are dual activated with thrombin plus collagen. Platelet TFPI is exclusively TFPIalpha, the most evolutionarily conserved TFPI isoform. It appears to be physiologically active as an inhibitor of tissue factor (TF) initiated FXa generation in vitro, and acts locally to dampen clot growth in a murine vascular injury model. These data suggest that platelet TFPI plays an important role in modulating TF activity within a growing clot thereby preventing formation of an occlusive clot. PMID- 22425320 TI - Splice variants of Tissue Factor and integrin-mediated signaling. AB - Full-length Tissue Factor (flTF) - the obligatory co-factor for the serine protease (factor) VII/VIIa - serves as the initiator of blood coagulation. The flTF/VIIa complex triggers a sequence of proteolytic events that lead to the formation of a hemostatic plug. Aside from hemostatic maintenance, flTF can contribute to thrombogenesis in some settings. The proteolytic properties of the flTF/VIIa complex (as well as the flTF/VIIa/Xa complex) account for non hemostatic functions of flTF, largely exerted through activation of intracellular signaling via Protease Activated Receptors (PARs). The flTF-PAR nexus impacts several kinases highly significant in the pathobiology of cancer and cardiovascular disease. Over the past decade, many advances have been made in the understanding of PAR-mediated functions of flTF, an important highlight of which was the finding that a sub-set of integrins - a diverse family of integral membrane proteins - cross-regulate flTF-elicited signaling. Concomitantly, an alternatively spliced TF form (asTF) was discovered in human and mouse. Initial studies characterizing asTF revealed that it is differentially expressed during development, continuously present in circulating blood and solid tissues, and possesses very low pro-coagulant activity. Hypomorphic nature of asTF's cofactor activity is the source of an ongoing controversy over whether asTF is pro coagulant, and how it may contribute to hemostatic maintenance and/or its aberrations. Very recently, a novel concept emerged in asTF biology: asTF can evidently trigger intracellular signaling that promotes the formation of new vessels from the existing ones (angiogenesis) and monocyte-endothelial interactions, via interaction with integrins. We provide a brief overview of the fl/asTF-integrin nexus with an emphasis on asTF's non-proteolytic, integrin mediated biological activity. PMID- 22425321 TI - A common polymorphism in the 5' region of the human protein c gene binds USF1. AB - INTRODUCTION: Genetic variation in the Protein C gene (PROC) is associated with altered risk of adverse outcome for a number of diseases. Common single nucleotide polymorphisms (SNPs) in the promoter region and the adjacent 5' region of PROC are associated with Protein C expression. We tested the hypothesis that common SNPs (minor allele frequency >10%) between the frequently studied promoter SNPs -1654 (rs1799808) and -1641 (rs1799809), and the end of PROC intron 2 alter nuclear transcription factor binding. MATERIALS AND METHODS: We used electrophoretic mobility shift assays with 25-mer oligonucleotides centered on each of the 10 SNPs assessed in this potential regulatory region of the Protein C gene to test for differential binding to nuclear factors isolated from Hep-G2 cells. RESULTS: We found that the G-allele oligo of the intron 2 SNP rs2069915[G/A] bound nuclear factors more avidly than the A-allele (p=1.9 * 10( 9), n=24). Similarly, we found that the C-allele oligo of the intron 2 SNP rs2069916[C/T] bound nuclear factors more avidly than the T-allele, (p=3.7 * 10( 6), n=19). Cold competition and supershift assays suggested that the protein differentially binding to the C-allele of rs2069916 was USF1. Notably, we observed minimal nuclear factor binding to oligos containing haplotypes of the previously reported -1654 and -1641 SNPs. Luciferase reporter assays that showed the A-T haplotype of rs2069915 and rs2069916 drives transcription significantly more than the C-G haplotype (t-test, P=0.015, n=12). CONCLUSION: Differential transcription factor binding occurs for common SNPs in the 5' intronic regions of PROC which may contribute to PROC regulation and reported PROC SNP - phenotype associations. PMID- 22425322 TI - [Sedation and analgesia in emergency structure. Which sedation and/or analgesia for the shocked patient?]. PMID- 22425323 TI - [Hypertension in Africa: a challenge?]. PMID- 22425324 TI - [Knowledge of the general population about hypertension and diabetes mellitus in South Kivu, Democratic Republic of Congo]. AB - BACKGROUND: In the Democratic Republic of Congo (DRC), a country in a post conflict period, high priority cannot be given to non-communicable diseases other than to emergencies. This certainly involves inadequacy in raising awareness for prevention of these diseases. OBJECTIVE: To evaluate the level of knowledge of the Congolese general population on hypertension and diabetes mellitus. METHODS: Responses to a questionnaire from 3% of the general population aged 15 and older in the city of Bukavu and two rural areas: Hombo and Walungu (South Kivu, eastern DRC), recruited after stratification by ward in the city of Bukavu and a group of prone villages were expected. The questions focused on identification, testing, causes, complications and treatment of hypertension and diabetes mellitus. RESULTS: Of the 7770 respondents, screening for hypertension and diabetes mellitus affected only 14.9% and 7.3% of subjects respectively. Knowledge of these two conditions was generally low in the general population, although better in the subgroups of patients and those with higher socioeconomic level (P<0.05). Use of the medias was also associated with better knowledge (P<0.05). CONCLUSIONS: This study shows that knowledge about hypertension and diabetes mellitus and their testing in South Kivu is low. It is imperative that the Congolese government includes non-communicable diseases in its priorities of the millennium. Similarly, the WHO should actively contribute to screening for them in low-income countries. PMID- 22425325 TI - Experimentally assessing molecular dynamics sampling of the protein native state conformational distribution. AB - The acute sensitivity to conformation exhibited by amide hydrogen exchange reactivity provides a valuable test for the physical accuracy of model ensembles developed to represent the Boltzmann distribution of the protein native state. A number of molecular dynamics studies of ubiquitin have predicted a well-populated transition in the tight turn immediately preceding the primary site of proteasome directed polyubiquitylation Lys 48. Amide exchange reactivity analysis demonstrates that this transition is 10(3)-fold rarer than these predictions. More strikingly, for the most populated novel conformational basin predicted from a recent 1 ms MD simulation of bovine pancreatic trypsin inhibitor (at 13% of total), experimental hydrogen exchange data indicates a population below 10(-6). The most sophisticated efforts to directly incorporate experimental constraints into the derivation of model protein ensembles have been applied to ubiquitin, as illustrated by three recently deposited studies (PDB codes 2NR2, 2K39 and 2KOX2K392KOX). Utilizing the extensive set of experimental NOE constraints, each of these three ensembles yields a modestly more accurate prediction of the exchange rates for the highly exposed amides than does a standard unconstrained molecular simulation. However, for the less frequently exposed amide hydrogens, the 2NR2 ensemble offers no improvement in rate predictions as compared to the unconstrained MD ensemble. The other two NMR-constrained ensembles performed markedly worse, either underestimating (2KOX) or overestimating (2K39) the extent of conformational diversity. PMID- 22425326 TI - Structural insights into the Type II secretion nanomachine. AB - The Type II secretion nanomachine transports folded proteins across the outer membrane of Gram-negative bacteria. Recent X-ray crystallography, electron microscopy, and molecular modeling studies provide structural insights into three functionally and spatially connected units of this nanomachine: the cytoplasmic and inner membrane energy-harvesting complex, the periplasmic helical pseudopilus, and the outer membrane secretin. Key advances include cryo-EM reconstruction of the secretin and demonstration that it interacts with both secreted substrates and a crucial transmembrane clamp protein, plus a biochemical and structural explanation of the role of low-abundance pseudopilins in initiating pseudopilus growth. Combining structures and protein interactions, we synthesize a 3D view of the complete complex consistent with a stepwise pathway in which secretin oligomerization defines sites of nanomachine biogenesis. PMID- 22425327 TI - Commentary to accompany 'Cost and effectiveness of laser with phlebectomies compared with foam sclerotherapy in superficial venous insufficiency. Early results of a randomised controlled trial'. PMID- 22425328 TI - Scaling from challenge experiments to the field: Quantifying the impact of vaccination on the transmission of bluetongue virus serotype 8. AB - Bluetongue (BT) is an economically important disease of ruminants caused by bluetongue virus (BTV) and transmitted by Culicoides biting midges. The most practical and effective way to protect susceptible animals against BTV is by vaccination. Data from challenge studies in calves and sheep conducted by Intervet International b.v., in particular, presence of viral RNA in the blood of challenged animals, were used to estimate vaccine efficacy. The results of the challenge studies for calves indicated that vaccination is likely to reduce the basic reproduction number (R(0)) for BTV in cattle to below one (i.e. prevent major outbreaks within a holding) and that this reduction is robust to uncertainty in the model parameters. Sensitivity analysis showed that the whether or not vaccination is predicted to reduce R(0) to below one depended on the following assumptions: (i) whether "doubtful" results from the challenge studies are treated as negative or positive; (ii) whether or not the probability of transmission from host to vector is reduced by vaccination; and (iii) whether the extrinsic incubation period follows a realistic gamma distribution or the more commonly used exponential distribution. For sheep, all but one of the vaccinated animals were protected and, consequently, vaccination will consistently reduce R(0) in sheep to below one. Using a stochastic spatial model for the spread of BTV in Great Britain (GB), vaccination was predicted to reduce both the incidence of disease and spatial spread in simulated BTV outbreaks in GB, in both reactive vaccination strategies and when an incursion occurred into a previously vaccinated population. PMID- 22425329 TI - Influence of diabetes mellitus on long-term (five-year) outcomes of drug-eluting stents and coronary artery bypass grafting for multivessel coronary revascularization. AB - Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and for diffuse and progressive atherosclerosis. We evaluated the outcomes of drug eluting stent (DES) placement and coronary artery bypass grafting (CABG) in 891 diabetic patients (489 for DES implantation and 402 for CABG) and 2,151 nondiabetic patients (1,058 for DES implantation and 1,093 for CABG) with multivessel CAD treated from January 2003 through December 2005 and followed up for a median 5.6 years. Outcomes of interest included death; the composite outcome of death, myocardial infarction (MI), or stroke; and repeat revascularization. In diabetic patients, after adjusting for baseline covariates, 5-year risk of death (hazard ratio 1.01, 95% confidence interval 0.77 to 1.33, p = 0.96) and the composite of death, MI, or stroke (hazard ratio 1.03, 95% confidence interval 0.80 to 1.31, p = 0.91) were similar in patients undergoing DES or CABG. However, rate of repeat revascularization was significantly higher in the DES group (hazard ratio 3.69, 95% confidence interval 2.64 to 5.17, p <0.001). These trends were consistent in nondiabetic patients (hazard ratio 0.80, 95% confidence interval 0.55 to 1.16, p = 0.23 for death; hazard ratio 0.77, 95% confidence interval 0.56 to 1.05, p = 0.10 for composite of death, MI, or stroke; hazard ratio 2.77, 95% CI 1.95 to 3.91, p <0.001 for repeat revascularization). There was no significant interaction between diabetic status and treatment strategy on clinical outcomes (p for interaction = 0.36 for death; 0.20 for the composite of death, MI, or stroke; and 0.40 for repeat revascularization). In conclusion, there was no significant prognostic influence of diabetes on long term treatment with DES or CABG in patients with multivessel CAD. PMID- 22425330 TI - Clinical implications of cardiovascular preventing pleiotropic effects of dipeptidyl peptidase-4 inhibitors. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel drugs for the treatment of type 2 diabetes mellitus. They exert their action through inhibition of the catabolism of locally secreted incretins such as glucagon-like peptide-4 (GLP-4) and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting enzyme DPP 4. GLP-1 and GIP are secreted from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the small intestine and colon, whereas GIP is secreted from K cells of the jejunum. These 2 incretins lower blood glucose levels and postprandial hyperglycemia by stimulating insulin release from b cells of the pancreas, thus increasing insulin sensitivity, delaying gastrointestinal emptying, decreasing food intake through early satiety, and causing weight loss in the long term. However, their action is short-lived (2 to 3 minutes) because of catabolism by the DPP-4 enzyme. The importance of DPP-4 inhibitors lies in their blockade of the DPP-4 enzyme leading to the prevention of their catabolism and thus increasing their blood levels, extending the duration of their action, and improving their blood glucose lowering effect. In addition to their antidiabetic action, recent experimental and clinical studies have demonstrated a pleiotropic cardiovascular protective effect of these agents independent of their antidiabetic action. They prevent atherosclerosis, improve endothelial dysfunction, lower blood pressure, and prevent myocardial injury. All these actions are discussed in this concise review. In conclusion, DPP-4 inhibitors are novel antidiabetic agents with pleiotropic cardiovascular protective effects in addition to their antidiabetic action. PMID- 22425331 TI - Relation of routine, periodic fasting to risk of diabetes mellitus, and coronary artery disease in patients undergoing coronary angiography. AB - Previously we discovered that routine periodic fasting was associated with a lower prevalence of coronary artery disease (CAD). Other studies have shown that fasting increases longevity in animals. A hypothesis-generating analysis suggested that fasting may also associate with diabetes. This study prospectively tested whether routine periodic fasting is associated with diabetes mellitus (DM). Patients (n = 200) undergoing coronary angiography were surveyed for routine fasting behavior before their procedure. DM diagnosis was based on physician reports of current and historical clinical and medication data. Secondary end points included CAD (physician reported for >= 1 lesion of >= 70% stenosis), glucose, and body mass index (BMI). Meta-analyses were performed by evaluation of these patients and 448 patients from a previous study. DM was present in 10.3% of patients who fasted routinely and 22.0% of those who do not fast (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.17 to 0.99, p = 0.042). CAD was found in 63.2% of fasting and 75.0% of nonfasting patients (OR 0.42, CI 0.21 to 0.84, p = 0.014), and in nondiabetics this CAD association was similar (OR 0.38, CI 0.16 to 0.89, p = 0.025). Meta-analysis showed modest differences for fasters versus nonfasters in glucose concentrations (108 +/- 36 vs 115 +/- 46 mg/dl, p = 0.047) and BMI (27.9 +/- 5.3 vs 29.0 +/- 5.8 kg/m(2), p = 0.044). In conclusion, prospective hypothesis testing showed that routine periodic fasting was associated with a lower prevalence of DM in patients undergoing coronary angiography. A reported fasting association with a lower CAD risk was also validated and fasting associations with lower glucose and BMI were found. PMID- 22425332 TI - Eugene Braunwald, MD and the early years of hypertrophic cardiomyopathy: a conversation with Dr. Barry J. Maron. PMID- 22425333 TI - Comparative value of coronary artery calcium and multiple blood biomarkers for prognostication of cardiovascular events. AB - The value of coronary artery calcium (CAC) scoring versus multiple biomarkers in increasing risk prediction for cardiovascular disease (CVD) remains unknown. The study group consisted of 1,286 asymptomatic participants (mean +/- SD 59 +/- 8 years old) with no known coronary heart disease. Mean follow-up time was 4.1 +/- 0.4 years with the primary outcome of combined CVD (cardiac death, myocardial infarction, stroke, and late target vessel revascularization). CAC was calculated by the method of Agatston. Biomarkers measured were C-reactive protein, interleukin-6, myeloperoxidase, B-type natriuretic peptide, and plasminogen activator-1. During follow-up 35 participants developed CVD events including cardiac deaths (6%), myocardial infarction (23%), strokes (17%), and late revascularizations (54%). In Cox proportional-hazards models adjusted for Framingham Risk Score (FRS), presence of log CAC beyond FRS was associated with increased hazards for CVD events (hazard ratio 1.7, 95% confidence interval [CI] 1.4 to 2.0, p <0.001). Multiple biomarkers score was also associated with increased risk beyond FRS (hazard ratio 2.1, p = 0.02) per 1-U increase in score; however, the c-statistic did not increase significantly (0.75, 95% CI 0.68 to 0.84, p = 0.32). The c-statistic increased when log CAC was incorporated into FRS without or with multiple biomarkers score (c-statistic 0.84, p = 0.003 and p = 0.008 respectively). Addition of CAC to risk factors showed significant reclassification (net reclassification improvement 0.35 (95% CI 0.11 to 0.58, p = 0.007; integrated discrimination index 0.076, p = 0.0001), whereas addition of multiple biomarkers score did not show significant reclassification. In conclusion, in this study of asymptomatic subjects without known CVD, addition of CAC but not biomarkers substantially improved risk reclassification for future CVD events beyond traditional risk factors. PMID- 22425334 TI - Inactivation of Alicyclobacillus acidoterrestris spores by high pressure CO2 in apple cream. AB - Alicyclobacillus acidoterrestris (A. acidoterrestris) is a bacillus-type spore former that causes significant alterations in fruit products. It is highly resistant to typical pasteurization regimes; thus, this work explored the use of high-pressure CO2 (HPCD) for its deactivation in apple cream. The assays were conducted in a high-pressure apparatus where the cream was placed in an agitated vessel and the CO2 passed over under different operating conditions for distinct periods of time. The HPCD was able to deactivate the A. acidoterrestris spores in the apple cream by four orders of magnitude at 30 degrees C and 10 MPa. On the other hand, the lethal effect of HPCD was independent of the thermal effect since the application of dry heat without CO2 at the same temperature did not cause any A. acidoterrestris deactivation. The important variables in terms of improving the method were the flow regime and the way to put in contact the HPCD and the cream. Finally, the HPCD treatment did not affect the most important sensorial and rheological properties of the cream; although there was a slight reduction in the vitamin C content due to thermal degradation. PMID- 22425335 TI - Discrimination between infectious and non-infectious human norovirus using porcine gastric mucin. AB - Human noroviruses (NoVs) are known to bind to human histo-blood group antigens, as well as to chemically-similar porcine gastric mucins. Here, the binding ability of NoV to porcine mucin is shown to be substantially deficient after UV, thermal, and high pressure treatments. Using qRT-PCR, >= 68% of GI.1 NoV (Norwalk strain) bound to porcine gastric mucin-conjugated magnetic beads (PGM-MBs). Application of 600-MPa high pressure treatments reduced binding of the virus to PGM-MBs by 4.7-log10, as determined by qRT-PCR, while a 300-MPa pressure treatment, reduced binding to PGM-MBs by only 0.45-log10. This is consistent with a previously reported clinical trial (Leon et al., 2011. Appl. Environ Microbiol. 77:5476-5482.) which demonstrated inactivation of 4-log10 of GI.1 NoV at 600-MPa. After thermal treatment, binding to PGM-MBs decreased when samples were heated from 0 to 80 degrees C. Ultraviolet treatments of 0.5 and 2 J/cm2 reduced observed PGM-MB binding of norovirus to 33% and negligible levels, respectively, from an initially observed 84% binding for untreated NoV. Although thermal and UV treatments are generally recognized to inactivate viruses, verification of NoV inactivation by these treatments may require volunteer studies. In total, these results suggest the loss of NoV binding to porcine mucin as a potential means to preferentially exclude non-infectious virus particles from subsequent RT-PCR detection. PMID- 22425336 TI - Automated sequence analysis and editing software for HIV drug resistance testing. AB - BACKGROUND: Access to antiretroviral treatment in resource-limited-settings is inevitably paralleled by the emergence of HIV drug resistance. Monitoring treatment efficacy and HIV drugs resistance testing are therefore of increasing importance in resource-limited settings. Yet low-cost technologies and procedures suited to the particular context and constraints of such settings are still lacking. The ART-A (Affordable Resistance Testing for Africa) consortium brought together public and private partners to address this issue. OBJECTIVES: To develop an automated sequence analysis and editing software to support high throughput automated sequencing. STUDY DESIGN: The ART-A Software was designed to automatically process and edit ABI chromatograms or FASTA files from HIV-1 isolates. RESULTS: The ART-A Software performs the basecalling, assigns quality values, aligns query sequences against a set reference, infers a consensus sequence, identifies the HIV type and subtype, translates the nucleotide sequence to amino acids and reports insertions/deletions, premature stop codons, ambiguities and mixed calls. The results can be automatically exported to Excel to identify mutations. Automated analysis was compared to manual analysis using a panel of 1624 PR-RT sequences generated in 3 different laboratories. Discrepancies between manual and automated sequence analysis were 0.69% at the nucleotide level and 0.57% at the amino acid level (668,047 AA analyzed), and discordances at major resistance mutations were recorded in 62 cases (4.83% of differences, 0.04% of all AA) for PR and 171 (6.18% of differences, 0.03% of all AA) cases for RT. CONCLUSIONS: The ART-A Software is a time-sparing tool for pre analyzing HIV and viral quasispecies sequences in high throughput laboratories and highlighting positions requiring attention. PMID- 22425337 TI - [Emergency transcranial doppler ultrasound: predictive value for the development of symptomatic vasospasm in spontaneous subarachnoid hemorrhage in patients in good neurological condition]. AB - PURPOSE: To examine the predictive value of an early transcranial Doppler ultrasound (TCD) study performed in the emergency department in patients with spontaneous subarachoniod hemorrhage (SAH) in good neurological condition, in order to know which patients are at high risk of developing delayed cerebral ischemia (DCI). DESIGN: A descriptive observational study was carried out involving a period of 3 years. SETTING: Critical Care and Emergency Department. PATIENTS: The study consecutively included patients with SAH of grade I-III on the Hunt and Hess scale. VARIABLES OF INTEREST: DCI (decrease of 2 points in GCS or focal deficit), Mean Velocity (MV) of middle cerebral arteries (MCA), Lindegaard Index (IL). Sonographic vasospasm pattern (SVP) was considered if MCA MV>120cm/sc and IL>3. RESULTS: The mean age of the 122 patients was 54.1+/-13.7 years; 57.3% were women. SVP was detected in 24 patients (19.7%), although high velocities patterns (HVP) were present in 38 patients (31.1%). DCI developed in 21 patients (MV183+/-49cm/sc), all with previous SVP. In this group MV increased 22+/-5cm/sc/day during the first 3 days. The group without HVP (84 patients/MV of 67+/-16.6cm/sc), compared with DCI group, showed differences in highest MV (p<0.001), and also DeltaMV/day (8.30+/-4,5cm/sc Vs 22+/-5cm/sc) during the first 3 days (p=0.009). In our series, ROC analysis selected the best cut-off value for DeltaMV/day as 21cm/sc (p<0.001). CONCLUSION: During the first 3 days, an increase of 21cm/s/24h in MCA-MV was associated with the development of symptomatic vasospasm. TCD is a useful tool for the early detection of patients at risk of DCI after SAH. PMID- 22425338 TI - [Hemodynamic and antipyretic effects of paracetamol, metamizol and dexketoprofen in critical patients]. AB - BACKGROUND: The objective was to study the antipyretic and hemodynamic effects of three different drugs used to treat fever in critically ill patients. METHODS: DESIGN AND SETTING: Prospective, observational study in a 16-bed, general ICU of a university hospital. PATIENT POPULATION: We studied 150 patients who had a febrile episode (temperature>38 degrees C): 50 received paracetamol, 50 metamizol and 50 dexketoprofen. INTERVENTIONS: None. Body temperature, systolic, diastolic and mean arterial pressure, heart rate, central venous pressure and oxygen saturation were determined at baseline and at 30, 60 and 120minutes after infusion of the drug. Additionally, we recorded temperature 180minutes after starting drug infusion. Diuresis and the need for or change of dose of vasodilator or vasoconstrictor drugs were also recorded. RESULTS: Patient characteristics, baseline temperature and hemodynamics were similar in all groups. We observed a significant decrease of at least 1 degrees C in temperature after 180minutes in 38 patients treated with dexketoprofen (76%), in 36 with metamizol (72%), and in 20 with paracetamol (40%) (p<0.001). After 120minutes, the mean decrease in mean arterial pressure was 8.5+/-13.6mmHg with paracetamol, 14.9+/-11.8mmHg with metamizol, and 16.8+/-13.7mmHg with dexketoprofen (p=0.005). CONCLUSIONS: Dexketoprofen was the most effective antipyretic agent at the doses tested. Although all three drugs reduced mean arterial pressure, the reduction with paracetamol was less pronounced. PMID- 22425339 TI - [Are we able to optimize the definition and diagnosis of severe acute respiratory distress syndrome?]. PMID- 22425340 TI - A comparison of predictive equations of energy expenditure and measured energy expenditure in critically ill patients. AB - PURPOSE: Multiple equations exist for predicting resting energy expenditure (REE). The accuracy of these for estimating energy requirements of critically ill patients is not clear, especially for obese patients. We sought to compare REE, calculated with published formulas, with measured REE in a cohort of mechanically ventilated subjects. MATERIALS AND METHODS: We retrospectively identified all mechanically ventilated patients with measured body mass index who underwent indirect calorimetry in the intensive care unit. Limits of agreement and Pitman's test of difference in variance were performed to compare REE by equations with REE measured by indirect calorimetry. RESULTS: A total of 927 patients were identified, including 401 obese patients. There were bias and poor agreement between measured REE and REE predicted by the Harris-Benedict, Owen, American College of Chest Physicians, and Mifflin equations (P > .05). There was poor agreement between measured and predicted REE by the Ireton-Jones equation, stratifying by sex. Ireton-Jones was the only equation that was unbiased for men and those in weight categories 1 and 2. In all cases except Ireton-Jones, predictive equations underestimated measured REE. CONCLUSION: None of these equations accurately estimated measured REE in this group of mechanically ventilated patients, most underestimating energy needs. Development of improved predictive equations for adequate assessment of energy needs is needed. PMID- 22425341 TI - Activity gains after reconstructions of elbow extension in patients with tetraplegia. AB - PURPOSE: Reconstruction of triceps function in persons with tetraplegia is an established surgical intervention. The purpose of this study was to investigate and evaluate patient perspective of gains in activity and satisfaction after surgical reconstruction of triceps function and subsequent rehabilitation. METHODS: We studied the effects of surgery and rehabilitation in 14 persons (19 arms) treated with deltoid-to-triceps transfer. We used Canadian Occupational Performance Measurement standards to capture the performance and satisfaction of patient-identified activity goals. Follow-up was performed at 6 and 12 months postoperatively. To make group analyses, we classified activity goals according to the International Classification of Function, Disability, and Health categories of activities and participation, as well as relative to the position of the arm in space. RESULTS: Patients reported improvement in performance after surgery, and satisfaction was rated even higher. Improvement was seen in all types of activities that patients had prioritized. No single goal was rated lower at 12 months' follow-up than before surgery. The most common activity gains were related to "driving a wheelchair" and the ability to "reach out," each of which represented 20% of expressed goals. Although "driving a wheelchair" and "moving the body" (transfers) were common goals, the smallest improvements for both performance and satisfaction after 12 months were seen in these areas. We observed the highest performance improvement in the category of "writing" and the ability to "stretch out the arm when lying down." CONCLUSIONS: Improvement in activity continues over the first year after triceps reconstruction. Complex activities continue to improve over a longer period than simpler activities. We saw the highest improvement in activities performed without the aid of gravity and activities highly dependent on coordination. Such actions are difficult to compensate for by technique or skills, and therefore elbow extension is essential for performance. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22425342 TI - An unusual case of pacemaker endocarditis in a patient with antiphospholipid syndrome. AB - We report the case of a 50-year-old woman with systemic lupus erythematosus who had previously undergone pacemaker implantation. She developed recurrent pulmonary thromboembolism and was diagnosed with antiphospholipid syndrome. During investigation, pacemaker endocarditis was discovered, and the system was surgically explanted. Surprisingly, all microbiological studies, including culture of the extracted material and extensive serological analysis, were negative and she remained well with anticoagulation plus her usual immunosuppressant regimen. The data indicate that her pacemaker endocarditis could be an equivalent of the nonbacterial thrombotic endocarditis often described in native valves. PMID- 22425343 TI - Caseous calcification of the mitral annulus: a multi-modality imaging perspective. AB - Mitral annulus calcification is a common echocardiographic finding, particularly in the elderly and in end-stage renal disease patients under chronic dialysis. Caseous calcification or liquefaction necrosis of mitral annulus calcification is a rare evolution of mitral annular calcification. Early recognition of this entity avoids an invasive diagnostic approach, since it is benign and, unlike intracardiac tumors and abscesses, has a favorable prognosis. The authors present the case of an 84-year-old woman with a suspicious large, echodense mass at the level of the posterior mitral leaflet with associated severe mitral regurgitation. Cardiac magnetic resonance imaging demonstrated a hypoperfused mass with strong peripheral enhancement 10 minutes after gadolinium administration. Multislice computed tomography showed the calcified nature of the mass. A multi-modality imaging approach confirmed the diagnosis of caseous calcification of the posterior mitral annulus. The patient refused surgical treatment. PMID- 22425344 TI - Isolated right ventricular infarction presenting with anterior ST-segment elevation: a case for careful assessment of right ventricular branch occlusion. AB - We describe the case of a 61-year-old man who presented with chest pain and ST segment elevation in the anterior precordial leads (V1-V5) due to proximal occlusion of the right ventricular branch of a codominant right coronary artery. Primary coronary angioplasty and stenting of this branch was performed resulting in resolution of the chest pain and ST-segment elevation. Our description illustrates a case of isolated right ventricular infarction as an uncommon but important differential diagnosis of anterior ST-segment elevation. In addition, it highlights the value of careful review of the angiographic images in this context, as the culprit lesion may be a right ventricular branch occlusion. To the best of our knowledge, this is the first reported case of primary percutaneous coronary intervention treatment of a right ventricular branch occlusion causing isolated acute right ventricular myocardial infarction and anterior ST-segment elevation. PMID- 22425345 TI - Sleep-disordered breathing in children with congenital muscular dystrophies. AB - OBJECTIVE: Most types of neuromuscular diseases are known to be associated with a high risk of sleep-disordered breathing. We performed a prospective study in a well individualized group of muscular disorders, congenital muscular dystrophies (CMD), to characterize the frequency of sleep-disordered breathing and thereby to determine the potential usefulness of sleep studies in such patients. METHODS: Twenty CMD children (12 F, 8 M, aged 4-17 years) were included. Using overnight polysomnography, we determined the following parameters: sleep stages, sleep latency, sleep efficiency index, wake time duration, total sleep time (TST), apnea/hypopnea index (AHI), arterial blood oxygen saturation, and nocturnal paroxysmal EEG activity. RESULTS: As compared to healthy controls, we detected in our study group frequent awakenings, a decreased TST (mean 448 +/- 44.4 min) and a decreased REM duration (mean 11.5 +/- 3.5% of TST). Significant increase in wake time duration (28-90 min) and decrease in REM duration were observed in 12 patients. An apnea/hypopnea syndrome was detected in 13 patients (65%) with central apneas in 8, obstructive apneas in 2 and 3 mixed apneas in 3 patients. AHI was >10 in 3 cases, <10> 5 in 4 cases and were concomitant with blood oxygen de-saturation in four cases. NPA were detected in 10 patients ranging from 10 to 40% of TST. INTERPRETATION: Our results confirm the high incidence of sleep disordered breathing in children with CMD, and thereby, the usefulness of overnight polysomnography recordings in such patients. PMID- 22425346 TI - Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors. AB - Compounds 1-4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1-4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1-4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [(125)I]1 and [(125)I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [(125)I]1 and [(125)I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [(18)F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [(18)F]3 and [(11)C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates. PMID- 22425347 TI - Fluorescence in situ hybridization (CARD-FISH) of microorganisms in hydrocarbon contaminated aquifer sediment samples. AB - Groundwater ecosystems are the most important sources of drinking water worldwide but they are threatened by contamination and overexploitation. Petroleum spills account for the most common source of contamination and the high carbon load results in anoxia and steep geochemical gradients. Microbes play a major role in the transformation of petroleum hydrocarbons into less toxic substances. To investigate microbial populations at the single cell level, fluorescence in situ hybridization (FISH) is now a well-established technique. Recently, however, catalyzed reporter deposition (CARD)-FISH has been introduced for the detection of microbes from oligotrophic environments. Nevertheless, petroleum contaminated aquifers present a worst case scenario for FISH techniques due to the combination of high background fluorescence of hydrocarbons and the presence of small microbial cells caused by the low turnover rates characteristic of groundwater ecosystems. It is therefore not surprising that studies of microorganisms from such sites are mostly based on cultivation techniques, fingerprinting, and amplicon sequencing. However, to reveal the population dynamics and interspecies relationships of the key participants of contaminant degradation, FISH is an indispensable tool. In this study, a protocol for FISH was developed in combination with cell quantification using an automated counting microscope. The protocol includes the separation and purification of microbial cells from sediment particles, cell permeabilization and, finally, CARD-FISH in a microwave oven. As a proof of principle, the distribution of Archaea and Bacteria was shown in 60 sediment samples taken across the contaminant plume of an aquifer (Leuna, Germany), which has been heavily contaminated with several ten-thousand tonnes of petroleum hydrocarbons since World War II. PMID- 22425348 TI - Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol. AB - The basal-like subtype of breast cancers, including those that contain germline mutations in BRCA1, tend to be triple-negative (i.e. lack expression of estrogen and progesterone receptors and lack overexpression/amplification of the HER2/neu oncogene), which renders them relatively insensitive to existing "targeted" therapy. BRCA1-mutated and basal-like breast cancers harbor compromised ability for repairing oxidative DNA damage by the DNA base-excision repair pathway. We found that this defective repair mechanism predicts sensitivity to elesclomol, an experimental therapeutic that produces elevated levels of oxidative DNA damage. In conclusion, BRCA1-mutated and/or basal-like breast cancers may benefit from treatment regimens that include elesclomol. PMID- 22425349 TI - Pentraxin 3 accelerates lung injury in high tidal volume ventilation in mice. AB - Mechanical ventilation is the major cause of iatrogenic lung damage in intensive care units. Although inflammation is known to be involved in ventilator-induced lung injury (VILI), several aspects of this process are still unknown. Pentraxin 3 (PTX3) is an acute phase protein with important regulatory functions in inflammation which has been found elevated in patients with acute respiratory distress syndrome. This study aimed at investigating the direct effect of PTX3 production in the pathogenesis of VILI. Genetically modified mice deficient and that over express murine Ptx3 gene were subjected to high tidal volume ventilation (V(T)=45 mL/kg, PEEP(zero)). Morphological changes and time required for 50% increase in respiratory system elastance were evaluated. Gene expression profile in the lungs was also investigated in earlier times in Ptx3 overexpressing mice. Ptx3 knockout and wild-type mice developed same lung injury degree in similar times (156+/-42 min and 148+/-41 min, respectively; p=0.8173). However, Ptx3 over-expression led to a faster development of VILI in Ptx3 overexpressing mice (77+/-29 min vs 118+/-41 min, p=0.0225) which also displayed a faster kinetics of Il1b expression and elevated Ptx3, Cxcl1 and Ccl2 transcripts levels in comparison with wild-type mice assessed by quantitative real-time polymerase chain reaction. Ptx3 deficiency did not impacted the time for VILI induced by high tidal volume ventilation but Ptx3-overexpression increased inflammatory response and reflected in a faster VILI development. PMID- 22425350 TI - Atomic resolution model of the antibody Fc interaction with the complement C1q component. AB - The globular C1q heterotrimer is a subunit of the C1 complement factor. Binding of the C1q subunit to the constant (Fc) part of antibody molecules is a first step and key event of complement activation. Although three-dimensional structures of C1q and antibody Fc subunits have been determined experimentally no atomic resolution structure of the C1q-Fc complex is known so far. Based on systematic protein-protein docking searches and Molecular Dynamics simulations a structural model of the C1q-IgG1-Fc-binding geometry has been obtained. The structural model is compatible with available experimental data on the interaction between the two partner proteins. It predicts a binding geometry that involves mainly the B-subunit of the C1q-trimer and both subunits of the IgG1-Fc dimer with small conformational adjustments with respect to the unbound partners to achieve high surface complementarity. In addition to several charge-charge and polar contacts in the rim region of the interface it also involves nonpolar contacts between the two proteins and is compatible with the carbohydrate moiety of the Fc subunit. The model for the complex structure provides a working model for rationalizing available biochemical data on this important interaction and can form the basis for the design of Fc variants with a greater capacity to activate the complement system for example on binding to cancer cells or other target structures. PMID- 22425351 TI - Identification, expression and bioactivity of a chitotriosidase-like homolog in amphioxus: dependence of enzymatic and antifungal activities on the chitin binding domain. AB - The mammalian chitinase family 18 consists of two members, chitotriosidase (ChT) and acidic chitinase (AMCase). Despite the enormous progress on mammalian ChT study, little information regarding ChT is available to date in lower animals. In this study, we identified a chitotriosidase-like gene from the amphioxus Branchiostoma japonicum, named BjChTl, which consisted of a signal peptide, a catalytic domain, a Ser/Thr-rich linker region and a chitin-binding domain (CB domain). Sequence comparison and phylogenetic analysis showed that BjChTl was the common ancestor of ChTs and AMCases, implicating that ChT and AMCase evolved from an ancient gene like BjBhTl via gene duplication. qRT-PCR analysis revealed that BjChTl was expressed in the hepatic caecum and hind gut in a tissue-specific fashion. Both chitin-binding and enzymatic activities as well as antifungal activity assays demonstrated that like human ChT, recombinant BjChTl was able to bind to chitin particles, to hydrolyze artificial chitin substrate 4 methylumbelliferyl-beta-D-N,N',N"-triacetylchitotrioside, and to inhibit the growth of the fungus Candida albicans. Surprisingly, recombinant BjChTl-CD lacking CB domain retained partial capacity to bind to chitin, but its enzymatic activity was almost completely lost. These findings suggest that the CB domain is necessary for the execution of both enzymatic and antifungal activities of recombinant BjChTl. It is also the first study showing the presence of a ChT-like homolog with both chitinolytic activity and fungistatic activity in non vertebrate species. PMID- 22425352 TI - Improved outcome of Pneumocystis pneumonia by early treatment. PMID- 22425353 TI - [Intestinal obstruction due to axial torsion and gangrene of a giant Meckel diverticulum]. PMID- 22425354 TI - [Municipal distribution and trends in the incidence of colorectal cancer in the health area of Leon (1994-2008)]. AB - BACKGROUND: There is an excess incidence of colorectal cancer (CRC) and mortality from this disease in the health area of Leon. The aim of the present study was to determine trends in CRC and its geographical distribution. METHODS: Cases included in the Hospital Registry of Tumors of the Centro Asistencial Universitario de Leon from 1994-2008 and occurring in patients residing in the health area of Leon were studied. Time trends were evaluated with a Poisson regression model. To analyze geographical distribution, the smoothed relative risks (RR) of the municipalities adjusted by the Besag, York and Mollie model were calculated, and their subsequent probability of an RR>1 (PP) was calculated using Bayesian methods. RESULTS: A total of 4,136 cases were included. Rates standardized to the European standard population ranged from 49.6 (1994-6) to 63.5 new cases per 100,000 inhabitants in men (2006-8) and from 29.6 to 33.8 in women. An annual 2% increase was found for all localizations, ranging from 1.8% in the rectum to 3.6% in the proximal colon. In all localizations, the increase was greater in men than in women. Several municipalities in the health area of Leon showed an excess risk. The geographical pattern observed was due especially to the distribution of colon cancer. CONCLUSIONS: The incidence rates observed were high and were increasing. Special attention should be paid to CRC in the health area of Leon, mainly in the municipalities with excess risk. PMID- 22425355 TI - [Peritoneal pseudomyxoma presenting as ascites in a patient with cirrhosis]. AB - We present the case of a cirrhotic patient with ascites and an albumin gradient of less than 1.1 g/dl. After endoscopic tests, including upper gastrointestinal endoscopic ultrasound-guided fine-needle aspiration, exploratory laparoscopy was performed to provide the diagnosis, revealing mucin throughout the peritoneal cavity and nodules on the parietal and visceral peritoneum. Histopathological analysis established the diagnosis as peritoneal pseudomyxoma. This uncommon entity, which has a poor prognosis without treatment, is most frequently associated with mucinous tumors of the appendix, and secondly, with tumors of the ovary. PMID- 22425356 TI - Update on totally implantable venous access devices. AB - The use of totally implantable venous devices (TIVAD) has changed the care and quality of life for cancer patients, these devices allow chemotherapy administration, and blood sampling without the need for repeated venipuncture. These ports are used mainly when IV access is needed only intermittently over a long period of time. We are presenting a brief overview on TIVADs, with focus on the mid and long-term complications associated with these devices with their management. PMID- 22425357 TI - Pravastatin reverses the membrane cholesterol reorganization induced by myocardial infarction within lipid rafts in CD14(+)/CD16(-) circulating monocytes. AB - Large numbers of monocytes are recruited in the infarcted myocardium. Their cell membranes contain cholesterol-rich microdomains called lipids rafts, which participate in numerous signaling cascades. In addition to its cholesterol lowering effect, pravastatin has several pleiotropic effects and is widely used as secondary prevention treatment after myocardial infarction (MI). The aim of this study was to investigate the effects of pravastatin on the organization of cholesterol within monocyte membrane rafts from patients who had suffered myocardial infarction. Monocytes from healthy donors and acute MI patients were cultured with or without 4MUM pravastatin. Lipid rafts were extracted by Lubrol WX, caveolae and flat rafts were separated using a modified sucrose gradient. Cholesterol level and caveolin-1 expression in lipid rafts were determined. In healthy donors, cholesterol was concentrated in flat rafts (63+/-3 vs 13+/-1%, p<0.001). While monocytes from MI patients presented similar cholesterol distribution in both caveolae and flat rafts. Cholesterol distribution was higher in flat rafts in healthy donors, compared to MI patients (63+/-3 vs 41+/-2%, p<0.001), with less distribution in caveolae (13+/-1 vs 34+/-2%, p<0.001). Pravastatin reversed the cholesterol distribution in MI patients cells between flat rafts (41+/-2 vs 66+/-3%, p<0.001) and caveolae (34+/-2 vs 18+/-1%, p<0.001). In conclusion, MI redistributes cholesterol from flat rafts to caveolae indicating monocyte membrane reorganization. In vitro pravastatin treatment restored basal conditions in MI monocytes, suggesting another effect of statins. PMID- 22425358 TI - Alcohol sclerotherapy to treat vascular malformations in the oral cavity. AB - OBJECTIVE: To present our experience in treating vascular malformations in the oral cavity solely by injecting ethanol into the lesions. MATERIAL AND METHODS: We treated 26 patients (12 men and 14 women) with oral malformations. The diagnosis was based on clinical findings (n=26), magnetic resonance imaging studies (n=19), angiography findings (n=5), and direct puncture venography (n=2). To achieve sclerosis, we administered absolute ethanol through direct puncture. All interventions were performed under deep sedation. RESULTS: The vascular malformations treated ranged from 7mm to 60mm (median: 24.5mm) in maximum diameter and had been present in the oral cavity for 0.2 to 54 years (mean: 13.6 years). The median age of the patients was 44.5 years (range: 12-87 years). The reason for treatment of the malformation was: an increase in size (n=8), local bleeding (n=11), risk of bleeding during dental extraction (n=5), pain (n=1), and esthetic purposes (n=3). Lesions were located in the mucosa of the cheek (n=12), in the facial gingiva (n=5), in the labial mucosa (n=6), in the tongue (n=3), in the pterygomandibular region (n=1), and in the palate (n=1). The median dose of ethanol was 3.2mL. Twenty lesions disappeared after a single injection session, five after two sessions, two after three sessions, and one after five sessions. In 20 cases all signs of the lesions disappeared, in 6 a bluish macule persisted, and in 2 a mass effect persisted. The symptoms improved in all patients. Only transient complications of sclerotherapy were observed: local inflammation, perioral paresthesia in two patients, and necrosis of the mucosa of the cheek in one. CONCLUSIONS: Alcohol sclerotherapy is an efficacious procedure for treating vascular malformations in the oral cavity. PMID- 22425359 TI - Scanning ion conductance microscopy for imaging biological samples in liquid: a comparative study with atomic force microscopy and scanning electron microscopy. AB - The present study was designed to show the applicability of scanning ion conductance microscopy (SICM) for imaging different types of biological samples. For this purpose, we first applied SICM to image collagen fibrils and showed the usefulness of the approach-retract scanning (ARS)/hopping mode for such samples with steep slopes. Comparison of SICM images with those obtained by AFM revealed that the ARS/hopping SICM mode can probe the surface topography of collagen fibrils and chromosomes at nanoscale resolution under liquid conditions. In addition, we successfully imaged cultured HeLa cells, with 15 MUm in height by ARS/hopping SICM mode. Because SICM can obtain non-contact (or force-free) images, delicate cellular projections were visualized on the surface of the fixed cell. SICM imaging of live HeLa cells further demonstrated its applicability to study the morphological dynamics associated with biological processes on the time scale of minutes under liquid conditions. We further applied SICM for imaging the luminal surface of the trachea and succeeded in visualizing the surface of both ciliated and non-ciliated cells. These SICM images were comparable with those obtained by scanning electron microscopy. Although the dynamic mode of AFM provides better resolution than the ARS/hopping mode of SICM in some samples, only the latter can obtain contact-free images of samples with steep slopes, rendering it an important tool for observing live cells as well as unfixed or fixed soft samples with complicated shapes. Taken together, we demonstrate that SICM imaging, especially using an ARS/hopping mode, is a useful technique with unique capabilities for imaging the three-dimensional topography of a range of biological samples under physiologically relevant aqueous conditions. PMID- 22425360 TI - Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. AB - Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS. PMID- 22425361 TI - [Minutes of the General Assembly of the EBCOG, Brussels, November 2011]. PMID- 22425362 TI - Riboflavin injection into the corneal channel for combined collagen crosslinking and intrastromal corneal ring segment implantation. AB - PURPOSE: To evaluate the effectiveness of intracorneal riboflavin injection for combined collagen crosslinking (CXL) and intrastromal corneal ring segment (ICRS) implantation. SETTING: Kudret Eye Hospital, Ankara, Turkey. DESIGN: Noncomparative case series. METHODS: Keratoconic eyes had combined ICRS (Intacs) implantation and transepithelial CXL with 20% alcohol application and riboflavin injection into the corneal channel. Outcome measures were uncorrected (UDVA) and corrected (CDVA) distance visual acuities, sphere, cylinder, and keratotomy (K) readings. RESULTS: The study enrolled 131 eyes (105 patients) with a mean follow up of 7.07 months +/- 4.66 (SD). The mean improvement was 0.26 +/- 0.16 logMAR in UDVA and 0.24 +/- 0.16 logMAR in CDVA (both P<.05). The mean manifest spherical refraction decreased from -3.87 +/- 4.55 diopters (D) to -1.25 +/- 2.31 D, the mean manifest cylinder improved from -3.89 +/- 1.97 D to -2.27 +/- 2.18 D, and the mean K reading improved from 50.50 +/- 5.26 D to 46.03 +/- 4.51 D (all P<.05). There were no intraoperative or postoperative complications. CONCLUSIONS: Combined ICRS and CXL treatment with intracorneal riboflavin injection was effective in keratoconic eyes. Intracorneal riboflavin injection into the tunnel was safe and may provide more penetration without epithelial removal. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22425363 TI - Resident experience with toric and multifocal intraocular lenses in a public county hospital system. AB - PURPOSE: To study the outcomes of toric and multifocal intraocular lens (IOL) implantation performed by resident surgeons. SETTING: Parkland Health and Hospital System, Dallas, Texas, USA. DESIGN: Case series. METHODS: Patients seen between July 2008 and May 2011 and meeting inclusion criteria (including >1.0 diopter [D] of astigmatism in toric group and <0.75 D astigmatism in multifocal group) were offered implantation of the study IOLs. Major outcomes were uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) and, for the multifocal IOL, near visual acuity. Residents were surveyed about their knowledge regarding these IOLs. RESULTS: Seventy-nine eyes of 60 patients received an Alcon Acrysof toric IOL. Eighteen eyes of 10 patients received an Alcon Acrysof Restor IOL. In the toric group, 57% of eyes achieved a postoperative UDVA of 20/25 or better and 90% achieved 20/40 or better. The CDVA was 20/25 or better in 92% of eyes. The mean refractive cylinder was 1.69 D preoperatively and 0.38 D postoperatively. In the multifocal group, 78% of patients achieved a UDVA of 20/25 or better and 94% achieved 20/40 or better. All patients had a CDVA of 20/25 or better. Near vision was Jaeger 3 or better in 94%. The survey showed that residents have a strong comfort level with preoperative and surgical techniques for premium IOLs after their experience in the residency setting. CONCLUSION: Residents in public county hospitals can be taught to use premium IOLs with good success rates, comparable to those in other published studies. FINANCIAL DISCLOSURE: Dr. McCulley is a consultant to Alcon Laboratories, Inc., and Dr. Aggarwal is on the speaker's bureau for Alcon Laboratories, Inc. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22425364 TI - Alterations in pulmonary structure by elastase administration in a model of emphysema in mice is associated with functional disturbances. AB - Several experimental studies of pulmonary emphysema using animal models have been described in the literature. However, only a few of these studies have focused on the assessment of ergometric function as a non-invasive technique to validate the methodology used for induction of experimental emphysema. Additionally, functional assessments of emphysema are rarely correlated with morphological pulmonary abnormalities caused by induced emphysema. The present study aimed to evaluate the effects of elastase administered by tracheal puncture on pulmonary parenchyma and their corresponding functional impairment. This was evaluated by measuring exercise capacity in C57Bl/6 mice in order to establish a reproducible and safe methodology of inducing experimental emphysema. Thirty six mice underwent ergometric tests before and 28 days after elastase administration. Pancreatic porcine elastase solution was administered by tracheal puncture, which resulted in a significantly decreased exercise capacity, shown by a shorter distance run (-30.5%) and a lower mean velocity (-15%), as well as in failure to increase the elimination of carbon dioxide. The mean linear intercept increased significantly by 50% in tracheal elastase administration. In conclusion, application of elastase by tracheal function in C57Bl/6 induces emphysema, as validated by morphometric analyses, and resulted in a significantly lower exercise capacity, while resulting in a low mortality rate. PMID- 22425365 TI - Giant intracranial capillary hemangioma in a 3-year-old child: case report and literature review. PMID- 22425366 TI - Postsurgical infection after myelomeningocele repair: a multivariate analysis of 60 consecutive cases. AB - OBJECTIVE: We investigate the demographic, clinical and surgical variables associated with wound and ventriculoperitoneal (VP) shunt infections in a well defined group of patients submitted to neurosurgical myelomeningocele repair. METHODS: We analyzed the data of sixty consecutive patients with a myelomeningocele diagnosis submitted to neurosurgical repair between January 2002 and December 2005. Multiple logistic regression analysis identified clinical, demographic and neurosurgical variables that were independently associated with the occurrence of wound and VP shunt infections. RESULTS: Seven patients (11.7%) developed wound infections after myelomeningocele repair and two (3.3%) presented with sepsis unrelated to the neurosurgical procedures. Forty-six patients (76.7%) received a VP shunt and nine of them (19.6%) had VP shunt infection. There was a non-significant trend (p=0.09) for a higher association between thoracic than lumbar or sacral topography and the occurrence of any type of infection. Among patients who underwent VP shunt placement, there was a non-significant trend for a higher association between VP shunt infection and thoracic topography compared to lumbar or sacral regions (adjusted OR 4.3; CI 95% 0.7-24.7; p=0.10). Evans' index scores higher than 70 were ten times more associated with VP shunt infection (adjusted OR 10.5; CI 95% 1.6-67.4; p=0.01) than lower scores. CONCLUSION: The thoracic topography of myelomeningocele has a trend for a higher association with infection in general and VP shunt infection. Evans' index scores higher than 70 were independently associated with VP shunt infection. PMID- 22425367 TI - Neurosurgical considerations on highly eloquent brainstem cavernomas during pregnancy. AB - OBJECTIVE: Cerebral cavernous malformations (CCMs) and especially cavernous malformations (CMs) in highly eloquent brain areas such as brainstem CMs are rare but possible events during pregnancy. Due to the few published cases in literature clear recommendations regarding the management are rare. In this study we evaluate the proceeding decision in pregnant patients with highly eloquent brainstem CMs. METHODS: In our series 43 patients with CMs in highly eloquent brain areas, including 39 patients with brainstem CMs, were surgically treated by the senior author between July 2007 and July 2010. Out of these, 29 patients were female and three of them presented with a symptomatic brainstem CMs during pregnancy and were included in this study. According to our experiences and to the available literature we analyzed demographic and clinical variables to provide recommendations for the management of pregnant patients with highly eloquent brainstem CMs. RESULTS: Only one patient was operated during pregnancy the other two patients were surgically treated after delivery, respectively. A thorough review of the literature revealed 12 patients with brainstem cavernomas during pregnancy there of only two patients were operated during pregnancy. CONCLUSION: Surgical treatment during pregnancy is rarely required, but needs to be performed right away in life-threatening and rapidly progressive clinical situations. Pregnant women with CMs in highly eloquent brain areas such as brainstem CMs need to be treated in specialized centers to assess the best point of time for surgery. Our study offers a useful tool to support the proceeding decision in this rare but important situation. PMID- 22425368 TI - Inspiratory- and finger-flexion-related cortical potentials in patients with amyotrophic lateral sclerosis--an exploratory study. AB - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons. Each voluntary movement, including inspiration, is preceded by movement-related cortical potential (MRCP) that can be recorded from the scalp. MRCPs of ALS patients with severe upper motor neuron involvement are smaller. Our aim was to explore whether the inspiratory-(sniffing)-related cortical potentials (SRCPs) and index-finger-flexion MRCPs (FFRCPs) can be used as markers of cortical involvement in ALS. METHODS: Thirteen ALS patients and 15 healthy volunteers were assessed for their hand dexterity and strength, respiratory function, speech capacity, spasticity, electromyographic parameters and functional rating scales. EEG was recorded during self-paced sniffing and the right index finger flexion. The MRCP amplitudes were assessed at the relevant electrode positions. RESULTS: No statistically significant difference was found between the MRCP amplitudes of the ALS patients and the control subjects. However, patients with more severely affected upper limb functions generated smaller FFRCPs and those with more affected respiratory functions generated smaller SRCPs. Excessively high FFRCPs were associated with better while excessively low FFRCPs with worse scores on some of the clinical measures of the upper limb function. CONCLUSION: Our preliminary results demonstrate that it is feasible to record SRCP in ALS patients, which combined with FFRCP, may be useful to determine the spectrum of motor control changes in this population. PMID- 22425369 TI - Severe neurobrucellosis in a young infant. PMID- 22425370 TI - The assessment of prognostic factors in surgical treatment of low-grade gliomas: a prospective study. AB - OBJECTIVE: A prospective volumetric analysis of extent of resection (EOR) was carried out to assess surgical outcomes in adults diagnosed with hemispheric low grade gliomas (LGGs). MATERIALS AND METHODS: 68 consecutive patients diagnosed with LGGs were enrolled in the study. Pre- and post-operative tumor volumes and EOR were measured based on FLAIR MRI. Dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC MRI) was used for the assessment of relative cerebral blood volume (rCBV). Three outcome measures were assessed: overall survival (OS), progression-free survival (PFS), and malignant degeneration-free survival (MFS). RESULTS: In 6 (9%) patients permanent neurologic deficits were observed. No statistically significant dependence between the EOR and the occurrence of permanent deficits was found. The eloquent or close to the eloquent location was statistically connected with lower EOR (p=0.023). The preoperative volume of tumors treated with gross total resection was significantly smaller than the volume of tumors in subtotal or partial resection groups (p=0.020, p<0.001, respectively). OS was predicted by age at diagnosis (p=0.032), and rCBV (p=0.002). Progression and malignant transformation occurred in 22 (32%) and 11 (16%) out of 68 patients. PFS was predicted by preoperative tumor volume (p=0.005), postoperative tumor volume (p=0.008), the EOR (p=0.001), and by the rCBV (p=0.033). MFS was predicted by preoperative tumor volume (p=0.034), the EOR (pp=0.020), and by rCBV (p=0.022). Postoperative tumor volume was associated with a trend of improved MFS (p=0.072). The univariate analysis shows the statistical trend for the relationship between histological subtype and PFS and MFS (p=0.079, p=0.078, respectively). Multivariate analysis selected preoperative tumor volume and rCBV as independently associated with PFS (p=0.009, p=0.019, respectively) and MFS (p=0.023, p=0.035, respectively). EOR was associated with a trend of improved PFS, and MFS (p=0.069, p=0.094, respectively). CONCLUSIONS: Tumor resection of LGG with the use of intraoperative monitoring and neuronavigation is associated with a low risk of new permanent deficits, but EOR significantly decreases with the size of the tumor and/or its location in/close to the eloquent areas. Smaller preoperative tumor volume and greater EOR are significantly associated with longer OS, PFS and MFS. Preoperative rCBV is one of the important prognostic factors significantly connected with survival. Prognosis in LGGs is still under discussion. Other factors such as age, histopathological subtype and KPS should not be underestimated. PMID- 22425371 TI - Isolated intracranial Rosai-Dorfman disease presenting as mental deterioration. PMID- 22425372 TI - Observation and relaxation properties of individual fast-relaxing proton transitions in [13CH3]-methyl-labeled, deuterated proteins. AB - A pair of NMR experiments is developed for separation of individual fast-relaxing transitions in (13)CH(3) methyl groups of methyl-protonated, highly deuterated proteins, and the measurement of their relaxation rates. Intra-methyl (1)H (1)H/(1)H-(13)C dipole-dipole cross-correlated spin relaxation that differentiates the rates of the fast-relaxing transitions depending on the state of (13)C spins, is measured in the selectively [(13)CH(3)]-methyl-labeled, deuterated ubiquitin at 10, 27, and 40 degrees C. In contrast with previous observations, the (1)H-(1)H/(1)H-(13)C cross-correlated relaxation rates measured from relaxation rates of single-quantum proton transitions serve as good measures of side-chain order even in proteins with global rotational correlation times significantly less than 10 ns. PMID- 22425373 TI - The impact of an empowering Internet-based Breast Cancer Patient Pathway programme on breast cancer patients' knowledge: a randomised control trial. AB - OBJECTIVE: The aim of this study was to analyse the effect of Breast Cancer Patient Pathway program. METHODS: In one Finnish university hospital during 2008 10 newly diagnosed breast cancer patients were randomised to the intervention (n = 50) and the control groups (n = 48). The breast cancer patient's knowledge expectations and perception of received knowledge, knowledge, the source of information and satisfaction in received patient education were measured. Baseline and one year follow up data collection was conducted. RESULTS: No differences were found in knowledge expectations between the groups at baseline. Patients in the control group evaluated their perception of received knowledge to be higher and they were more satisfied with the patient education they received from the hospital staff. However, the Intervention group's knowledge level was higher. The most important source of information was the healthcare professionals in both groups. CONCLUSION: The results of study indicate that when patient education increases, patients' knowledge expectations increase as well, while their perceptions of received knowledge decrease. Future research is needed to examine the relationship between patients' knowledge expectations and perception of received knowledge as patients' knowledge level increases. PRACTICE IMPLICATIONS: Patient education has to be individually adjusted, taking patients' expectations into account. PMID- 22425374 TI - Exploiting thermochromic materials for the rapid quality assurance of physiotherapy ultrasound treatment heads. AB - Significant nonuniformities in the acoustic intensity distribution generated by physiotherapy ultrasound treatment heads are not uncommon, potentially leading to significant localised temperature rises and tissue damage. An acoustic absorber tile containing a thermochromic pigment has been developed to provide rapid quality assurance of physiotherapy ultrasound treatment heads by virtue of a thermochromic colour change, indicating the time-averaged intensity distributions generated by these devices. As a bench-top device, the use of the tile is designed to mimic the nature of the physiotherapeutic application, requiring minimal training. Two designs where thermochromic pigments are added to the various polymeric layers of the tile are presented. Testing has been conducted with two physiotherapy treatment heads of differing performance, one of them notably exhibiting a strong "hot-spot" in localised acoustic time-averaged intensity. Findings show good qualitative agreement with classical hydrophone scans. Techniques are explored for the correction of nonlinearities in the thermochromic relationship, to enhance the accuracy of quantitative assessment. PMID- 22425375 TI - Radial extracorporeal pressure pulse therapy for the primary long bicipital tenosynovitis a prospective randomized controlled study. AB - Long bicipital tenosynovitis is regarded as one of the common causes of shoulder pain and dysfunction. The traditional therapeutic approach includes a variety of conservative treatments, but these treatments are not substantiated, owing to the lack of proven clinical efficacy. Radial extracorporeal shock wave therapy (rESWT) uses a pneumatically generated and radially propagating low-energy pressure pulse and has been clinically shown to be a new alternative form of treating refractory soft tissue inflammation. While treating patients suffering from long bicipital tenosynovitis, a randomized, controlled trial was conducted to analyze the effects of radial shock wave therapy on pain and function. Seventy nine adults with long bicipital tenosynovitis were randomized to receive either active (1500 pulses, 8 Hz, 3 bars) or sham treatment through four sessions that were held once a week. All of these adults were assessed before treatment and at time intervals of 1, 3 and 12 months since the completion of the treatment. The outcomes were measured through the visual analogue scale (VAS) and L'Insalata shoulder questionnaire. Mean VAS in the rESWT group showed significant and sustained reduction from 5.67 +/- 1.32 at baseline to 2.58 +/- 1.49 at one month, 1.83 +/- 1.25 at three months and 1.43 +/- 0.94 at 12 months from baseline, whereas the sham group's mean VAS was 6.04 +/- 0.97 before treatment and stabilized at 5.57 +/- 0.84 at 12 months. Similar trends were found for the function scores. Mean scores were increased after rESWT from 60.57 +/- 6.91 at baseline to 79.85 +/- 6.59 at 1 month and 83.44 +/- 5.21 at 12 months from baseline. Both pain and function scores showed significant differences between the two groups (p < 0.001). The rESWT group consisted of "invalid conservative treatment subgroup" and "none conservative treatment subgroup." Both groups showed good recovery and prognosis. Therefore, we recommend rESWT in treating primary long bicipital tenosynovitis. PMID- 22425376 TI - Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy. AB - Agents targeting vascular endothelial growth factor (VEGF) have been validated as cancer therapeutics, yet efficacy can differ widely between tumor types and individual patients. In addition, such agents are costly and can have significant toxicities. Rapid noninvasive determination of response could provide significant benefits. We tested if response to the anti-VEGF antibody bevacizumab (BV) could be detected using contrast-enhanced ultrasound imaging (CEUS). We used two xenograft model systems with previously well-characterized responses to VEGF inhibition, a responder (SK-NEP-1) and a non-responder (NGP), and examined perfusion-related parameters. CEUS demonstrated that BV treatment arrested the increase in blood volume in the SK-NEP-1 tumor group only. Molecular imaging of alpha(V)beta(3) with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in alpha(V)beta(3) vasculature following BV treatment in SK-NEP-1 tumors. Paralleling these findings, lectin perfusion assays detected a disproportionate pruning of smaller, branch vessels. Therefore, we conclude that the response to BV can be identified soon after initiation of treatment, often within 3 days, by use of CEUS molecular imaging techniques. The use of a noninvasive ultrasound approach may allow for earlier and more effective determination of efficacy of antiangiogenic therapy. PMID- 22425377 TI - Registration-based segmentation of three-dimensional ultrasound images for quantitative measurement of fetal craniofacial structure. AB - Segmentation of a fetal head from three-dimensional (3-D) ultrasound images is a critical step in the quantitative measurement of fetal craniofacial structure. However, two main issues complicate segmentation, including fuzzy boundaries and large variations in pose and shape among different ultrasound images. In this article, we propose a new registration-based method for automatically segmenting the fetal head from 3-D ultrasound images. The proposed method first detects the eyes based on Gabor features to identify the pose of the fetus image. Then, a reference model, which is constructed from a fetal phantom and contains prior knowledge of head shape, is aligned to the image via feature-based registration. Finally, 3-D snake deformation is utilized to improve the boundary fitness between the model and image. Four clinically useful parameters including inter orbital diameter (IOD), bilateral orbital diameter (BOD), occipital frontal diameter (OFD) and bilateral parietal diameter (BPD) are measured based on the results of the eye detection and head segmentation. Ultrasound volumes from 11 subjects were used for validation of the method accuracy. Experimental results showed that the proposed method was able to overcome the aforementioned difficulties and achieve good agreement between automatic and manual measurements. PMID- 22425378 TI - Early estimation of left ventricular systolic pressure and prediction of successful aortic constriction in a mouse model of pressure overload by ultrasound biomicroscopy. AB - Elevation of left ventricular end-systolic pressure (LVESP) and hypertrophic response in mice varies after transverse aorta constriction (TAC). Micromanometric catheterization, conventionally used to select mice with successful TAC, is invasive and nonreusable. We aimed to establish noninvasive imaging protocols for early estimation of successful TAC by ultrasound biomicroscopy (UBM). Out of 55 C57BL/6J mice, we randomly selected 45 as TAC group and 10 as controls. UMB was performed before TAC and, at day 3 and day 14, after TAC. In all mice, LVESP was measured with a Millar conductance catheter at day 14. With LVESP >= 150 mm Hg set as indicator of successful TAC (TAC+) and LVESP < 150 mm Hg as unsuccessful (TAC-), receiver operating characteristic curve analysis demonstrated that postoperative inner diameter at aortic banding site (IDb), peak flow velocity at aortic banding site (PVb) and peak flow velocity of right/left common carotid artery (PVr/l) at day 3 served as most effective predictors for LVESP at day 14 (area under curve = 0.9016, 0.9143, 0.8254, respectively. p < 0.01 for all). Among all UBM parameters at day 3, IDb, PVb, right common carotid artery peak flow velocity (PVr) and PVr/l correlated best with LVESP at day 14 (R(2) = 0.5740, 0.6549, 0.5208, 0.2274, respectively. p < 0.01 for all). Furthermore, IDb, PVb, and PVr/l at day 3 most effectively predict long-term cardiac hypertrophy, using the cut-off values of 0.45 mm, 2698.00 mm/s, 3.08, respectively. UBM can be a noninvasive and effective option for early prediction of successful TAC. PMID- 22425379 TI - A novel sonographic method of measuring patellar tendon length. AB - Obtaining accurate and readily repeatable measurements is a prerequisite for using measures of soft tissue structures both clinically and in the research setting. Few studies have evaluated the interrater reliability of ultrasound measurements of tendons. The objective of this study was to determine the accuracy and reliability of a new method of sonographic measurement of patellar tendon length using direct dissection as the gold standard. Four cadaveric knees were sonographically evaluated by two independent investigators. Two custom designed straps with nylon strapping and stainless steel wire were used to firmly mark position on the leg and create an acoustic shadow on the ultrasound image. Anatomic landmarks were the distal patellar pole and the bony ridge on the anterior proximal tibia. After sonographic evaluation, the knee was dissected to expose the patellar tendon, which was measured using digital calipers. Intraclass correlation coefficients (ICC) were used to determine reliability of measurements between observers, where ICC >0.75 was considered good and >0.9 was considered excellent. Validity was measured using a Bland-Altman plot, which measures bias between measurement methods as well as variability of scatter. Three sonographic measurements were made by each investigator on each tendon. The length of each of the four tendons based on the mean values of sonographic measurements was 53.8 mm, 53.4 mm, 49.4 mm and 46.8 mm. The length based on visual inspection of the dissected tissue was 54.6 mm, 52.8 mm, 49.8 mm and 46.9 mm. The calculated ICC between raters was 0.96. On the Bland-Altman plot, the bias, or mean difference between sonographic and visual measures, was 0.17 mm, with a standard deviation of 0.71. The 95% limit of agreement was -1.55 to 1.22 mm. Measurement of patellar tendon length with ultrasound using adjustable surface markers and calipers is highly accurate and has good interrater reliability. PMID- 22425380 TI - Effects of different therapeutic ultrasound intensities on fracture healing in rats. AB - Low-intensity pulsed ultrasound (LIPUS) with I(SATA)= 30 mW/cm(2) has been proven in facilitating fracture healing, which the spatial average intensity over the on period (I(SATP)) equals 150 mW/cm(2). As active ultrasound wave is only delivered during the on period, we postulate 150 mW/cm(2) is responsible for the beneficial effect of LIPUS. In this study, we compare the biologic effects of 30 mW/cm(2) and 150 mW/cm(2). We propose I(SATA) = 150 mW/cm(2) could further enhance fracture healing process. Closed femoral fractured Sprague-Dawley rats were randomized into control, LIPUS-30 (30 mW/cm(2)) and LIPUS-150 (150 mW/cm(2)) groups. Weekly radiographs and endpoint microCT, histomorphometry, and biomechanical tests were performed. The results show that LIPUS-30 had significantly higher low-density bone volume fraction and woven bone percentage than that of control and LIPUS-150 in microCT and histologic measurements, respectively. Mechanically, failure torque of LIPUS-30 was significantly higher than control and LIPUS-150 at week 6. In conclusion, LIPUS at I(SATA)= 150 mW/cm(2) did not further enhance fracture healing. PMID- 22425381 TI - Can ultrasound enable efficient intracellular uptake of molecules? A retrospective literature review and analysis. AB - Most applications of therapeutic ultrasound (US) for intracellular delivery of drugs, proteins, DNA/RNA and other compounds would benefit from efficient uptake of these molecules into large numbers of cells without killing cells in the process. In this study we tested the hypothesis that efficient intracellular uptake of molecules can be achieved with high cell viability after US exposure in vitro. A search of the literature for studies with quantitative data on uptake and viability yielded 26 published papers containing 898 experimental data points. Analysis of these studies showed that just 7.7% of the data points corresponded to relatively efficient uptake (>50% of cells exhibiting uptake). Closer examination of the data showed that use of Definity US contrast agent (as opposed to Optison) and elevated sonication temperature at 37 degrees C (as opposed to room temperature) were associated with high uptake, which we further validated through independent experiments carried out in this study. Although these factors contributed to high uptake, almost all data with efficient uptake were from studies that had not accounted for lysed cells when determining cell viability. Based on retrospective analysis of the data, we showed that not accounting for lysed cells can dramatically increase the calculated uptake efficiency. We further argue that if all the data considered in this study were re-analyzed to account for lysed cells, there would be essentially no data with efficient uptake. We therefore conclude that the literature does not support the hypothesis that efficient intracellular uptake of molecules can be achieved with high cell viability after US exposure in vitro, which poses a challenge to future applications of US that require efficient intracellular delivery. PMID- 22425382 TI - Study of factors affecting the magnitude and nature of ultrasound exposure with in vitro set-ups. AB - Therapeutic ultrasound is a clinically applied method to improve fracture healing and holds great potential as a manipulator of biologic material relevant to tissue engineering approaches. Unfortunately, the cell stimulating property of ultrasound is not known, which inhibits the optimal use of this technique. Additionally, many in vitro studies in this field use ultrasound configurations that are vulnerable to errors during calibration and use. These errors arise from the structural simplicity and incomplete characterization of these configurations. In this study, pulse-echo ultrasound, laser Doppler vibrometry and Schlieren imaging were applied to noninvasively characterize common in vitro experimental configurations. Fine wire thermocouple measurements were conducted to characterize any possible temperature rise during the ultrasound exposures. The results quantified the frequency dependent sound transmission through culture wells and the standing wave effect within the cell volume. These effects can cause uncertainty of up to 700% in the actual ultrasound exposure experienced by the cell. A temperature rise of 2.7 degrees C was measured from an ultrasound configuration commonly used in vitro ultrasound studies. Furthermore, wave mode conversion in culture wells was observed, emphasizing the complexity of these sonications. Similar type Lamb waves have been observed in bone in vivo. Thus, Lamb waves may be a mechanism for stimulating the cells. PMID- 22425383 TI - Increased accumulation and retention of micellar paclitaxel in drug-sensitive and P-glycoprotein-expressing cell lines following ultrasound exposure. AB - Ultrasound treatment has been shown to enhance the uptake of both hydrophilic and hydrophobic compounds into PC3 and Huvec cell lines using an insonation regimen of a single 10-s burst of high-frequency (4 MHz), moderate intensity (32 W/cm(2)) ultrasound. The purpose of this work was to evaluate the effect of this ultrasound regimen on the cellular accumulation of paclitaxel (PTX) loaded in copolymer micellar of methoxy poly(ethylene glycol)-block-poly(D,L-lactide) (MePEG-b-PDLLA) in both drug-sensitive (MDCKII and MCF-7) and P-glycoprotein (Pgp)-expressing (MDCKII-MDR and NCI-ADR) cell lines. There were no effects of ultrasound on hydrodynamic diameters of micelles and the release of FRET pairs, indicating the integrity of micelles was maintained. There was a two-fold increase in intracellular PTX for all ultrasound-treated drug-sensitive cell lines and their respective drug-resistant counterparts compared with no ultrasound. Significant decreases in drug efflux rates were observed at 20, 40 and 60 min for both drug-sensitive and -resistant cell lines receiving ultrasound. The enhanced accumulation and retention of PTX by ultrasound resulted in greater cytotoxicity in both MDCKII and MDCKII-MDR cell lines, as indicated by the MTS assay. These data suggest that ultrasound may facilitate the uptake of intact paclitaxel-loaded micelles into cells, allowing greater retention of drug in both Pgp and non-Pgp-expressing cells. PMID- 22425384 TI - Rapid and reliable quantitation of amino acids and myo-inositol in mouse brain by high performance liquid chromatography and tandem mass spectrometry. AB - Amino acids and myo-inositol have long been proposed as putative biomarkers for neurodegenerative diseases. Accurate measures and stability have precluded their selective use. To this end, a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method based on multiple reaction monitoring was developed to simultaneously quantify glutamine, glutamate, gamma-aminobutyric acid (GABA), aspartic acid, N-acetyl aspartic acid, taurine, choline, creatine, phosphocholine and myo-inositol in mouse brain by methanol extractions. Chromatography was performed using a hydrophilic interaction chromatography silica column within in a total run time of 15 min. The validated method is selective, sensitive, accurate, and precise. The method has a limit of quantification ranging from 2.5 to 20 ng/ml for a range of analytes and a dynamic range from 2.5-20 to 500-4000 ng/ml. This LC-MS/MS method was validated for biomarker discovery in models of human neurological disorders. PMID- 22425385 TI - HPLC-DAD protein kinase inhibitor analysis in human serum. AB - We here describe an HPLC-DAD method to analyse different protein kinase inhibitors. Potential applications of this method are pharmacokinetic studies and therapeutic drug monitoring. Optimised chromatography conditions resulted in a very good separation of seven inhibitors (vatalanib, bosutinib, canertinib, tandutinib, pazopanib, dasatinib - internal standard and erlotinib). The good sensitivity makes this method competitive with LC/MS/MS. The separation was performed with a Lichrospher 100-5 RP8, 250 mm * 4 mm column maintained at 30 +/- 1 degrees C, and with a mobile phase of 0.05 M H(3)PO(4)/KH(2)PO(4) (pH=2.3) acetonitrile (7:3, v/v) at a flow rate of 0.7 mL/min. A simple and fast sample preparation sequence with liquid-liquid extraction led to good recoveries (73 90%) of all analytes. The recovery hardly reached 50% only for pazopanib. This method can also be used for targeted protein kinase inhibitor quantification. A perfect linearity in the validated range (20-10,000 ng/mL) and an LOQ of 20 ng/mL were achieved. The relative standard deviations and accuracies of all examined drug concentrations gave values much lower than 15% both for between- and within batch calculations. All analysed PKIs were stable for 6 months in a 1mg/mL dimethyl sulfoxide stock solution. Vatalanib, bosutinib and erlotinib were also stable in human serum in the whole examined concentration range. PMID- 22425386 TI - Development and validation of a rapid high-performance liquid chromatography tandem mass spectrometry method for the determination of WJ-38, a novel aldose reductase inhibitor, in rat plasma and its application to a pharmacokinetic study. AB - WJ-38 is an aldose reductase inhibitor that is being developed for the treatment of diabetic complications. The present paper describes a sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of WJ 38 in rat plasma. Partial denaturation of plasma proteins with methanol followed by liquid-liquid extraction using ethyl acetate was used to extract strongly protein-bound WJ-38 from rat plasma. Chromatographic separation was performed on an Inertsil ODS-3 column with an isocratic mobile phase consisting of acetonitrile, water and formic acid (75:25:0.125, v/v/v). Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an ESI interface operating in positive ionization mode. Quantitation was performed using selected reaction monitoring of precursor-product ion transitions at m/z 392->246 for WJ-38 and m/z 446->321 for glipizide (internal standard). A linear calibration curve was obtained over the concentration range of 10.0-10,000 ng/mL for WJ-38 in rat plasma. The intra- and inter-day precisions were less than 13.6% and the accuracy was within +/- 5.3%. The extraction recovery of WJ-38 from rat plasma was over 66.0%. The validated method has been successfully applied to a pharmacokinetic study in rats after intragastrical administration of WJ-38. PMID- 22425387 TI - LC/LC-MS/MS of an innovative prostate human epithelial cancer (PHEC) in vitro model system. AB - This work describes the proteomic characterization of a novel in vitro prostate cancer model system, the clonal prostatic human epithelial cancer (PHEC) cell lines. The model is composed of three cell lines representing the three progressive cancer states found in vivo: non-tumorigenic, tumorigenic, and metastatic. The cell lines were evaluated for differential protein expression between states using two dimensional liquid:liquid chromatographic separation followed by mass spectral identification. The proteins from cellular extracts were first separated using liquid:liquid primary separation based on their isoelectric points and hydrophobicity. The resulting peptide fractions were applied to liquid chromatography-mass spectrometry (LC-MS) separation for mass determination and protein identification based on Mascot database inquiry. Over 200 proteins that change expression over the course of progression of this in vitro prostate cancer model were discovered during the comparative analysis of the three cell lines. The importance of these proteins on prostate cancer progression remains to be elucidated with further characterizations. The combination of the two dimensional liquid:liquid separation and mass spectral identifications was used to successfully analyze differential protein expression between multiple cell lines. PMID- 22425388 TI - Sensitive quantification of roflumilast and roflumilast N-oxide in human plasma by LC-MS/MS employing parallel chromatography and electrospray ionisation. AB - A high throughput bioanalytical method based on semi-automated liquid extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the sensitive quantification of roflumilast and its metabolite roflumilast N oxide, a phosphodiesterase (PDE) inhibitor in human plasma and serum. The sample work-up procedure comprised liquid extraction using penta-deuterated analogues of both analytes as internal standards. Chromatography was performed on C18 revered phase analytical columns at a flow rate of 0.5 mL/min in the dual column mode employing a column switching technique and a linear gradient from 18% to 54% acetonitrile in 0.005 M aqueous ammonium acetate containing 0.006% formic acid. Mass spectrometry was performed on an API 4000 instrument in the positive ion SRM mode (selected reaction monitoring) with the Turbo-V ionspray interface. The method showed linear detector responses over the entire calibration range between 0.1 ng/mL (lower limit of quantification (LLOQ)) and 50 ng/mL (upper limit of quantification (ULOQ)) for both analytes. Linear regression analysis with concentration-squared weighting (1/x(2) for roflumilast and 1/x for roflumilast N oxide) yielded inaccuracy and precision values <15% and coefficients of correlation (r) for the calibration curves >0.99 for both analytes. PMID- 22425389 TI - Do impairments in facial analysis underlie impaired social functioning in schizophrenia? PMID- 22425390 TI - Early abnormal amplitude-integrated electroencephalography (aEEG) is associated with adverse short-term outcome in premature infants. AB - BACKGROUND: In preterm infants with IVH the electrocortical background activity is affected and there is a correlation between the severity of cerebral injury to the degree of depression, however the usefulness of the early aEEG recordings has hardly been determined. AIM: To identify early aEEG features that could be used as prognostic markers for severe brain injury in prematures. METHODS: In 115 infants, 25-32 wk GA, aEEG recordings during the first 72 h of life were correlated with head ultrasound findings. Continuity (Co), sleep-wake cycling (Cy) and amplitude of the lower border (LB) of the aEEG were evaluated by semi quantitative analysis. RESULTS: The infants were divided into four groups based on head ultrasound findings: A (n=72, normal), B [n=16, grades 1-2 intraventricular hemorrhage (IVH)], C (n=21, grades 3-4 IVH) and D (n=6, periventricular leukomalacia). 18 infants (16 of group C and 2 of group D) died during hospitalization. Significantly lower values of all aEEG features were found in group C infants. The presence of pathological tracings (burst suppression, continuous low-voltage, flat trace) or discontinuous low-voltage (DLV), the absence of Cy and LB<3 MUV in the initial aEEG displayed a sensitivity of 88.9%, 63% and 51.9% respectively, for severe brain injury. Logistic regression of aEEG features and GA to the presence or absence of severe injury revealed that only Co was significantly correlated to outcome. Using this feature 83.19% of cases were correctly classified. CONCLUSION: Pathological tracings or DLV in the initial aEEG is predictive for poor short-term outcome in premature neonates. PMID- 22425391 TI - EPNS/SFNP guideline on the anticoagulant treatment of cerebral sinovenous thrombosis in children and neonates. AB - Anticoagulation of cerebral sinovenous thrombosis (CSVT) is recommended in adults and has been also approved in the paediatric setting. Some controversies remain however between the existing paediatric professional consensus, notably about its use in children with intra-cranial haemorrhage and in neonates. The publication of further original studies prompted the French Society for Paediatric Neurology (SFNP) in association with a panel of EPNS experts, to update the level of evidence and the knowledge in this domain. A bibliographic analysis revealed that anticoagulants are widely used in paediatrics. Anticoagulation is well tolerated by children (Class I, level of evidence B) and also probably by neonates (Class IIa, level of evidence B). During the acute phase, anticoagulation is probably effective in reducing the risk of death and sequelae in children (Class IIa, level of evidence B). It is not yet possible to draw any conclusions regarding neonates (Class IIb). Anticoagulation is also effective in reducing the risk of recurrence (Class I, level of evidence B). This risk is dependent on several individual factors such as the age of the child, the cause of the thrombosis, the persistence or the recurrence of thrombogenic factors, and the speed of sinus recanalisation. The duration of anticoagulation needs therefore to be individually tailored (Class I, level of evidence B). These observations have led to the following recommendations: -In the absence of any contraindication, it is reasonable to initiate anticoagulation during the acute phase of CSVT in children. Prolonged treatment over 3-6 months is justified according to individual factors. -In the absence of any contraindication, anticoagulation may be considered individually during the acute phase of CSVT in neonates for a duration of 6-12 weeks. PMID- 22425392 TI - [Marjolin's ulcer of the cheek developed on burn scar: a case report]. AB - Marjolin ulcers are scar carcinomas most often arising in old burn injuries. They arise mostly in the extremities. We report medical history of a 50-year-old female suffering from a scar carcinoma on her right cheek which was histopathologically identified as a mean differentiated squamous cell carcinoma. PMID- 22425393 TI - [Dermatologic adverse events of the new targeted anticancer therapies used in oncodermatology]. AB - The management of oncology patients has been deeply modified over recent years by the development of new targeted anticancer therapies. Though these new therapies generally have a good safety profile, the skin is probably the organ most affected by their toxicity, in terms of frequency and symptom diversity. This review describes the most frequent cutaneous side effects induced by the new targeted therapies used in oncodermatology, whether they are well-established drugs such as EGF receptor inhibitors (cetuximab, erlotinib) or imatinib, or new treatments for metastatic melanoma such as selective BRAF (vemurafenib) or MEK inhibitors (selumetinib) and CTLA-4 monoclonal antibodies (ipilimumab). PMID- 22425394 TI - Lessons learned after a three-year store and forward teledermatology experience using internet: Strengths and limitations. AB - PURPOSE: This paper presents a three-year teledermatology evaluation experience. The aim is to explain the methodology followed, present the evaluation results, discuss critically the issues that emerged during the experience and report the main lessons learned. METHODS: A complete design and evaluation methodology was conducted to fully address significant issues arising from other previous teledermatology experiences. First, system-design requirements and image quality issues were studied. Then, a detailed clinical concordance study was undertaken to determine the accuracy of diagnoses made using teledermatology in order to assess different dermatological clinics. Finally, an impact study on the health system was performed. Furthermore, clinical, technical, social and alignment outcomes were analyzed during the study and at the end of it, in order to understand how emerging factors affected the final setup of the teledermatology system. RESULTS: The most important results reported in this study can be summarized as follows. (1) A complete web-based environment for teledermatology support was developed as a result of a dynamic evaluation process with clinical personnel. (2) A total of 120 teleconsultations (82 pediatric and 28 adult) were made during the clinical concordance study. Concordance analysis was carried out for each dermatological disease group. High concordance rates were found in pediatrics for inflammatory dermatoses (76%) and also for adults (75%) with infections and infestations. (3) Physicians were satisfied with the teledermatology system but the time dedicated to consultation in primary care was a limiting factor (19min for each teleconsultation). (4) An extensive discussion about the successful and the limiting aspects of the teledermatology experience revealed the reasons behind the final decision not to proceed with its implementation. It was considered not to be aligned with Health Care Organization (HCO) strategy and consequently did not achieve high-level support for its long term implementation. CONCLUSIONS: A high degree of diagnostic accuracy both for pediatric and adult consultations was achieved using the teledermatology system with affordable technical requirements. Its usefulness for filtering dermatological referrals was also demonstrated in the study. Nevertheless, other factors such as the reorganization required for the physicians' time schedule, remuneration issues, absence of EHR (electronic health record) integration and lack of interaction with the HCO were important limiting factors. This led to the conclusion that under the evaluation conditions long-term set-up was not possible. It was also concluded that HCO participation would have been essential for both the evaluation study and the long-term set-up of the system. PMID- 22425395 TI - Reliability and validity of measuring scapular upward rotation using an electrical inclinometer. AB - The aim of this study was to assess the reliability and validity of a modified two-dimensional electrical inclinometer to measure scapular upward rotation during static humeral elevation. Numerous techniques have been proposed to qualitatively and quantitatively measure upward rotation of the scapula. These techniques are limited by expense or an inability to be synchronized with other measurements, such as muscle activity and force output. For validity testing, static scapular upward rotation was measured separately with a digital protractor and electrical inclinometer while participants were at rest and 60 degrees , 90 degrees and 120 degrees of humeral elevation in the scapular plane. For reliability testing, either 20 min before or 20 min after validity testing, participants performed the testing positions while measurements were taken with the electrical inclinometer only. Significant correlations existed between the modified electrical inclinometer and digital protractor at all four positions (r>0.996, p<0.001). The electrical inclinometer demonstrated good to excellent intra-rater reliability (ICC(3,1)>0.892, 95%CI: 0.785-0.988 and SEM<1.8 degrees ). These results support the use of the electrical inclinometer to measure scapular upward rotation. These findings provide clinicians and researchers with a practical instrument that can accurately measure scapular upward rotation in synchrony with other measurements, such as electromyography and isokinetic data. PMID- 22425396 TI - Migraine-like headache and ocular malformations may herald Moyamoya syndrome. PMID- 22425397 TI - A thermochemical pretreatment process to produce xylooligosaccharides (XOS), arabinooligosaccharides (AOS) and mannooligosaccharides (MOS) from lignocellulosic biomasses. AB - Efficient and high yield production of xylooligosaccharides, arabinooligosaccharide and mannooligosaccharides from biomasses is a significant boost to the nutraceutical and pharmaceutical industry. These organic compounds, also known as prebiotics, promote the growth of intestinal probiotic microorganisms thus improving the hosts' overall immune system. This work aimed at designing a thermochemical pretreatment of biomasses leading to production of high prebiotic yields and assessing the liquor quality based on resultant oligomer-monomer constituents. Four biomasses, namely Miscanthus sinensis, Panicum virgatum, Calamagrostis acutiflora and Bagasse, each having a dry weight xylan content of >= 20% were used. Identification and quantification using HPLC and ion chromatography systems showed xylooligomer yields of 65.0%, 84.2%, 87.9% and 92.3%, respectively. The xylooligomers also showed a degree of polymerization ranging from 2 to 25. These results demonstrate the potential of a low cost, pretreatment process of biomasses which may be suitable for a commercial scale production of prebiotics. PMID- 22425398 TI - Improved thermal performance of Thermomyces lanuginosus GH11 xylanase by engineering of an N-terminal disulfide bridge. AB - In order to increase the stability of thermophilic Thermomyces lanuginosus GH11 xylanase, TLX, a disulfide bridge Q1C-Q24C was introduced into the N-terminal region of the enzyme. The apparent temperature optimum shifted upwards at pH 6.5 by about 10 degrees C to 75 degrees C. The resistance to thermal inactivation also increased by about 10 degrees C. The melting temperature measured by CD spectroscopy increased from 66 to 74 degrees C. Therefore the N-terminal disulfide bridge increased both kinetic and thermodynamic stability almost equally. At pH 8 and 70 degrees C, the disulfide bridge increased the enzyme half life 20-fold in the presence of substrate. In contrast to the situation in acidic neutral pH, the substrate decreased the thermostability of xylanases in alkaline pH. The upper limit for the performance of the disulfide bridge mutant at pH 9 was 75 degrees C. This study showed that N-terminal disulfide bridges can stabilize even thermostable family GH11 xylanases. PMID- 22425399 TI - Comparison of the results of response surface methodology and artificial neural network for the biosorption of lead using black cumin. AB - In this study, Response Surface Methodology (RSM) and Artificial Neural Network (ANN) were employed to develop an approach for the evaluation of heavy metal biosorption process. A batch sorption process was performed using Nigella sativa seeds (black cumin), a novel and natural biosorbent, to remove lead ions from aqueous solutions. The effects of process variables which are pH, biosorbent mass, and temperature, on the sorbed amount of lead were investigated through two levels, three-factors central composite design (CCD). Same design was also utilized to obtain a training set for ANN. The results of two methodologies were compared for their predictive capabilities in terms of the coefficient of determination-R(2) and root mean square error-RMSE based on the validation data set. The results showed that the ANN model is much more accurate in prediction as compared to CCD. PMID- 22425400 TI - Direct ethanol production from cellulosic materials by the hypersaline-tolerant white-rot fungus Phlebia sp. MG-60. AB - White-rot fungus Phlebia sp. MG-60 was identified as a good producer of ethanol from several cellulosic materials containing lignin. When this fungus was cultured with 20 g/L unbleached hardwood kraft pulp (UHKP), 8.4 g/L ethanol was produced after 168 h of incubation giving yields of ethanol of 0.42 g/g UHKP, 71.8% of the theoretical maximum. When this fungus was cultured with waste newspaper, 4.2g/L ethanol was produced after 216 h of incubation giving yields of ethanol of 0.20 g/g newspaper, 51.1% of the theoretical maximum. Glucose, mannose, galactose, fructose and xylose were completely assimilated by Phlebia sp. MG-60 with ethanol yields of 0.44, 0.41, 0.40, 0.41 and 0.33 g/g of sugar respectively. These results indicated that Phlebia sp. MG-60 was a good candidate for bioethanol production from cellulosic materials. PMID- 22425401 TI - The effect of a mediolateral episiotomy during operative vaginal delivery on the risk of developing obstetrical anal sphincter injuries. AB - OBJECTIVE: The objective of the study was to evaluate the frequency of obstetrical anal sphincter injuries (OASIS) in women undergoing operative vaginal deliveries (OVD) and to assess whether a mediolateral episiotomy is protective for developing OASIS in these deliveries. STUDY DESIGN: We performed a retrospective cohort study. Maternal and obstetrical characteristics of the 2861 women who delivered liveborn infants by an OVD at term in the years 2001-2009 were extracted from a clinical obstetrics database and were analyzed in a logistic regression model. RESULTS: The frequency of OASIS was 5.7%. Women with a mediolateral episiotomy were at significantly lower risk for OASIS compared with the women without a mediolateral episiotomy in case of an OVD (adjusted odds ratio, 0.17; 95% confidence interval, 0.12-0.24). CONCLUSION: We found a 6-fold decreased odds for developing OASIS when a mediolateral episiotomy was performed in OVD. Therefore, we advocate the use of a mediolateral episiotomy in all operative vaginal deliveries to reduce the incidence of OASIS. PMID- 22425402 TI - Predictors of long-acting reversible contraception use among unmarried young adults. AB - OBJECTIVE: The objective of the study was to improve the understanding of long acting reversible contraception (LARC) use patterns among unmarried, young adults at risk of unintended pregnancy. STUDY DESIGN: We performed a secondary data analysis of a national survey conducted by Guttmacher Institute of unmarried women and men aged 18-29 years. LARC is defined as an intrauterine device (IUD) or implant. Predictors of LARC use and IUD knowledge among those at risk for unintended pregnancy (n = 1222) were assessed using chi(2) analysis and logistic regression models. RESULTS: LARC use was associated with older age, high IUD knowledge, and earlier onset of sexual activity. Respondents with high IUD knowledge were 6 times more likely to be current LARC users (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.4-28.8). Sociodemographic variables did not predict use. Respondents with lower education (OR, 1.76; 95% CI, 1.0-3.0), an external locus of control (OR, 1.6; 95% CI, 1.1-2.3), male sex (OR, 2.8; 95% CI, 1.9-4.1), and foreign language had less knowledge of IUD. CONCLUSION: Increasing knowledge of IUD among certain groups may improve LARC use among young, unmarried adults and in turn decrease unintended pregnancy. PMID- 22425403 TI - Like paper: a young woman delivered twins, but one was lost well before delivery. PMID- 22425404 TI - Antidepressant use during pregnancy: the benefit-risk ratio. AB - Antidepressants are used commonly in pregnancy. Physicians who provide health care for pregnant women with depression must balance maternal well-being with potential fetal risks of these medications. Over the last decade, scores of original and review articles have discussed whether selective serotonin reuptake inhibitors-selective serotonin norepinephrine reuptake inhibitors possess risks to the fetus; however, very little has been done to integrate these potential risks, if they exist, into an overall context of a benefit:risk ratio. This review aims at presenting an updated analysis of fetal and maternal exposure to selective serotonin or norepinephrine reuptake inhibitors to allow an evidence based benefit:risk ratio. When a psychiatric condition necessitates pharmacotherapy, the benefits of such therapy far outweigh the potential minimal risks of cardiac malformations, primary pulmonary hypertension of the newborn infant, or poor neonatal adaptation syndrome. PMID- 22425405 TI - Poor reliability of visual analysis of fetal heart rate tracings: what should be done about it? PMID- 22425406 TI - SOD1 suppresses maternal hyperglycemia-increased iNOS expression and consequent nitrosative stress in diabetic embryopathy. AB - OBJECTIVE: Hyperglycemia induces oxidative stress and increases inducible nitric oxide synthase (iNOS) expression. We hypothesized that oxidative stress is responsible for hyperglycemia-induced iNOS expression. STUDY DESIGN: iNOS luciferase activities, nitrosylated protein, and lipid peroxidation markers 4 hydroxynonenal and malondialdehyde were determined in parietal yolk sac-2 cells exposed to 5 mmol/L glucose or high glucose (25 mmol/L) with or without copper zinc superoxide dismutase 1 (SOD1) treatment. Levels of iNOS protein and messenger RNA, nitrosylated protein, and cleaved caspase-3 and -8 were assessed in wild-type embryos and SOD1-overexpressing embryos from nondiabetic and diabetic dams. RESULTS: SOD1 treatment diminished high glucose-induced oxidative stress, as evidenced by 4-hydroxynonenal and malondialdehyde reductions, and it blocked high glucose-increased iNOS expression, iNOS-luciferase activities, and nitrosylated protein. In vivo SOD1 overexpression suppressed hyperglycemia increased iNOS expression and nitrosylated protein, and it blocked caspase-3 and 8 cleavage. CONCLUSION: We conclude that oxidative stress induces iNOS expression, nitrosative stress, and apoptosis in diabetic embryopathy. PMID- 22425407 TI - A painful protuberance: a young woman had primary amenorrhea and an inguinal hernia. PMID- 22425408 TI - Mean, lowest, and highest pulsatility index of the uterine artery and adverse pregnancy outcome in twin pregnancies. PMID- 22425409 TI - Human birth observed in real-time open magnetic resonance imaging. AB - OBJECTIVE: Knowledge about the mechanism of labor is based on assumptions and radiographic studies performed decades ago. The goal of this study was to describe the relationship between the fetus and the pelvis as the fetus travels through the birth canal, using an open magnetic resonance imaging (MRI) scanner. STUDY DESIGN: The design of the study used a real-time MRI series during delivery of the fetal head. RESULTS: Delivery occurred by progressive head extension. However, extension was a very late movement that was observed when the occiput was in close contact with the inferior margin of the symphysis pubis, occurring simultaneously with gliding downward of the fetal head. CONCLUSION: This observational study shows, for the first time, that birth can be analyzed with real-time MRI. MRI technology allows assessment of maternal and fetal anatomy during labor and delivery. PMID- 22425410 TI - Impulsivity differences in recreational cannabis users and binge drinkers in a university population. AB - BACKGROUND: Recreational cannabis use and alcohol binge drinking are the most common drug consumption patterns in young adults. Impulsivity and several psychopathological signs are increased in chronic drug users, but the implications of recreational use are still poorly understood. METHODS: We evaluated impulsivity, sensation-seeking traits, impulsive decision-making, inhibitory control and possible symptoms of depression, anxiety and psychosis in three groups of young university adults: recreational cannabis users (N=20), alcohol binge drinkers (N=22) and non-drug users (N=26). RESULTS: The cannabis and binge drinking groups had increased scores for impulsivity and sensation seeking traits. Both groups also exhibited increased impulsive decision-making on the two-choice task and the Iowa gambling task; however, only the cannabis group was significantly different from the non-drug group regarding inhibitory control (go/no-go and stop tasks). The cannabis and binge drinking groups did not show differences in the psychopathological symptoms evaluated. CONCLUSIONS: Our observations of this population of non-dependent drug users are consistent with the increased impulsivity traits and behaviors that have been described previously in chronic drug abusers. In this study, compared to no drug use, the recreational use of cannabis was associated with a major dysfunction of the different facets of impulsive behaviors. However, alcohol binge drinking was related only to impulsive decision-making. These results suggest that impulsivity traits and behaviors are present not only in chronic drug abusers but also in recreational drug users. Future work should continue to investigate the long-term effects of these common consumption patterns on various impulsive behaviors and psychopathological symptoms. PMID- 22425411 TI - A stage I pilot study of acceptance and commitment therapy for methadone detoxification. AB - BACKGROUND: While agonist replacement therapies are effective for managing opioid dependence, community treatment programs are increasingly choosing detoxification. Unfortunately, success rates for opioid detoxification are very low, in part, due to physical and psychological symptoms associated with opioid withdrawal. Few behavior therapies specifically address the distressing experiences specific to opioid withdrawal. A novel behavioral treatment, acceptance and commitment therapy (ACT), works from the premise that the avoidance of unpleasant private experiences (thoughts, feelings, bodily sensations) is ubiquitous yet may be pathogenic, resulting in treatment drop-out and further drug use. METHODS: This Stage I pilot study developed and tested an ACT-based opioid detoxification behavioral therapy. Opioid dependent patients (N=56) who were attending a licensed methadone clinic were randomized to receive either 24 individual therapy sessions of ACT or drug counseling (DC) in the context of a 6-month methadone dose reduction program. RESULTS: While no difference was found on opioid use during treatment, 37% of participants in the ACT condition were successfully detoxified at the end of treatment compared to 19% of those who received DC. Fear of detoxification was also reduced across time in the ACT condition relative to DC. CONCLUSION: This first study of ACT to assist opioid detoxification indicates promise. Research is needed to refine specific treatment strategies for this population to further strengthen effects. PMID- 22425412 TI - Treatment of major depressive disorder by transcranial random noise stimulation: case report of a novel treatment. PMID- 22425413 TI - Vascular risk status as a predictor of later-life depressive symptoms: a cohort study. AB - BACKGROUND: Common etiology of vascular diseases and later-life depression may provide important synergies for prevention. We examined whether standard clinical risk profiles developed for vascular diseases also predict depressive symptoms in older adults. METHODS: Data were drawn from the Whitehall II study with baseline examination in 1991; follow-up screenings in 1997, 2003, and 2008; and additional disease ascertainment from hospital data and registry linkage on 5318 participants (mean age 54.8 years, 31% women) without depressive symptoms at baseline. Vascular risk was assessed with the Framingham Cardiovascular, Coronary Heart Disease, and Stroke Risk Scores. New depressive symptoms at each follow-up screening were identified by General Health Questionnaire caseness, a Center for Epidemiologic Studies Depression Scale score >=16, and use of antidepressant medication. RESULTS: Diagnosed vascular disease (that is, coronary heart disease or stroke) was associated with an increased risk for depressive symptoms, age- and sex-adjusted odds ratios from 1.5 (95% confidence interval 1.0-2.2) to 2.0 (1.4-3.0), depending on the indicator of depressive symptoms. Among participants without manifest vascular disease, the Stroke Risk Score was associated with Center for Epidemiologic Studies Depression Scale depressive symptoms before age 65 (age- and sex-adjusted odds ratio per 10% absolute change in the score = 3.1 [1.5-6.5]), but none of the risk scores predicted new-onset depressive symptoms in those aged >=65 (odds ratios from .8 to 1.2). CONCLUSIONS: These data suggest that public health measures to improve vascular risk status will influence the incidence of later-life depressive symptoms via reduced rates of manifest vascular disease. PMID- 22425414 TI - Standardization of 65Zn by sum-peak method. AB - A commercial solution of (65)Zn was standardized by the sum peak-method using a planar HPGe detector. The activity results were compared with measurements made with a well type 4pigamma ionization chamber, which is traceable to BIPM.RI (II) K2.Zn-65 key-comparison performed in 2002. The sum-peak value was 42.79 kBq/g and the ionization chamber value was 42.74 kBq/g both at the reference date. The uncertainty obtained in the sum peak standardization was 0.25% (k=1), and in the ionization chamber was 0.85% (k=1). The results showed that sum-peak method can be used in (65)Zn standardization and this method is easier, simpler and more practical than others methods. PMID- 22425415 TI - Standardization of (99m)Tc by means of a software coincidence system. AB - The procedure followed by the Nuclear Metrology Laboratory, at IPEN, for the primary standardization of (99m)Tc is described. The primary standardization has been accomplished by the coincidence method. The beta channel efficiency was varied by electronic discrimination using a software coincidence counting system. Two windows were selected for the gamma channel: one at 140 keV gamma-ray and the other at 20 keV X-ray total absorption peaks. The experimental extrapolation curves were compared with Monte Carlo simulations by means of code ESQUEMA. PMID- 22425416 TI - Standardization of a 85Sr solution by three methods. AB - A (85)Sr solution was measured in two liquid scintillation (LS) counters. Scintillation pulses from the delayed transitions in the (85)Sr decay were by and large lost as the dead time of the LS-counter was much longer than the lifetime of the (85)Rb excited level. The registration probability of these pulses has been defined and introduced into the counting efficiency calculation. The results of the (85)Sr solution standardization by the CIEMAT/NIST and the TDCR methods relative to the results from the 4pi(LS)-gamma coincidence and anticoincidence method were 0.997+/-0.012 and 0.971+/-0.019, respectively. PMID- 22425417 TI - STEFFY-software to calculate nuclide-specific total counting efficiency in well type gamma-ray detectors. AB - A software package is presented to calculate the total counting efficiency for the decay of radionuclides in a well-type gamma-ray detector. It is specifically applied to primary standardisation of activity by means of 4pigamma-counting with a NaI(Tl) well-type scintillation detector. As an alternative to Monte Carlo simulations, the software combines good accuracy with superior speed and ease-of use. It is also well suited to investigate uncertainties associated with the 4pigamma-counting method for a variety of radionuclides and detector dimensions. In this paper, the underlying analytical models for the radioactive decay and subsequent counting efficiency of the emitted radiation in the detector are summarised. PMID- 22425418 TI - Assessment of actinide decay data evaluations: findings of an IAEA Coordinated Research Project. AB - Organised under the auspices of the International Atomic Energy Agency, comprehensive decay scheme evaluations for over eighty actinides and their decay products have been completed on the basis of detailed assessments of the available experimental data. However, despite the application of sound evaluation procedures, such work cannot replace the need to perform and access good quality measurements for adoption. This evaluation programme provided a means of quantifying the quality of the underlying data to ensure that well-focused recommendations could be made for future experimental decay-data studies. PMID- 22425419 TI - Disintegration rate and gamma ray emission probability per decay measurement of 123I. AB - A series of (123)I measurements have been carried out in a 4pi(e(A),X)-gamma coincidence system. The experimental extrapolation curve was determined and compared to Monte Carlo simulation, performed by code ESQUEMA. From the slope of the experimental curve, the total conversion coefficient for the 159 keV total gamma transition, alpha(159), was determined. All radioactive sources were also measured in an HPGe spectrometry system, in order to determine the gamma-ray emission probability per decay for several gamma transitions. All uncertainties involved and their correlations were analyzed applying the covariance matrix methodology and the measured parameters were compared with those from the literature. PMID- 22425420 TI - Decay Data Evaluation Project (DDEP): evaluation of the main 243Cm and 245Cm decay characteristics. AB - The results of new decay data evaluations are presented for (243)Cm (alpha) decay to nuclear levels in (239)Pu and (245)Cm (alpha) decay to nuclear levels in (241)Pu. These evaluated data have been obtained within the Decay Data Evaluation Project using information published up to 2011. PMID- 22425421 TI - The use of solid angle for alpha detector efficiency in 226Ra analyses of soil samples. AB - In the frame of proficiency tests organized by IAEA and IRMM, the specific activity concentration of radium-226 in soil has been measured. The BaSO(4) co precipitation technique has been used. Normally, in this method, the detector efficiency of the alpha spectrometer is determined using a (226)Ra source with known activity. As an alternative to using a (226)Ra standard, we calculated the detector efficiency from the relative solid angle subtended by the detector on the soil samples. The accuracy of this method depends on the uncertainty of geometrical properties and the distribution of activity within the source. An uncertainty budget is provided. The method was applied successfully in the intercomparisons. PMID- 22425422 TI - A Campylobacter outbreak in a Barcelona school. AB - INTRODUCTION: Campylobacter outbreaks are less common and described than sporadic Campylobacteriosis. METHODS: We describe the epidemiological investigation including stool examination and bacteriological typing of a Campylobacter outbreak affecting 75 primary school children. RESULTS: The highest risk ratio was associated with the food served 4 days before the peak of cases, namely roast chicken and Russian salad. DISCUSSION: Poor food preparation practices and deficient kitchen facilities appear to be key issues for cross-contamination of Campylobacter from raw chicken to cooked food. PMID- 22425423 TI - Stressful life event appraisal and coping in patients with psychogenic seizures and those with epilepsy. AB - Understanding stress and coping among individuals with psychogenic nonepileptic seizures (PNES) may have important treatment implications. 40 patients with PNES, 20 with epilepsy (EPIL), and 40 healthy control (HC) participants reported the frequency of various stressful life events (both positive and negative) and appraised the distress these events induced. They also described their habitual coping behaviors. PNES patients reported no more frequent stressful life events than EPIL patients or HC. In addition, the stressors they experienced are not objectively more severe. However, they reported more severe distress due to negative life events, especially in the domains of work, social functioning, legal matters, and health. PNES patients also engaged in less planning and active coping than HC. Neither of these two coping behaviors was associated with distress ratings. The PNES group did not engage in more denial than either group. However, greater denial among PNES patients was associated with greater perceived distress. Coping in PNES is characterized by elevated levels of perceived distress and fewer action strategies than are normally employed to reduce the impact of a stressor. These findings may inform cognitive behavioral therapy of PNES patients. PMID- 22425424 TI - Self-efficacy for seizure management and youth depressive symptoms: caregiver and youth perspectives. AB - The aims of this study were to (1) compare caregiver and youth measures of self efficacy for seizure management (SESM), as well as report of depressive symptoms and suicidal ideation in youth with epilepsy (YWE) and (2) examine the potential relationship between caregiver SESM and caregiver report of depressive symptoms in YWE. Seventy-seven YWE ages 9-17 completed the Children's Depression Inventory (CDI) and the Seizure Self-Efficacy Scale for Children with Epilepsy (SSES-C). Sixty-five caregivers completed the Behavior Assessment System for Children (BASC II) and the Epilepsy Self-Efficacy Scale (ESES). Results showed no agreement between youth and caregiver self-efficacy scores. However, there was low to modest agreement in published classifications of depressive symptoms between youth and caregiver ratings of depressive symptoms in youth, with caregivers reporting higher levels of symptoms than the youth reported. Twenty-seven percent of YWE endorsed suicidal ideation. When caregiver report of their own self efficacy towards their child's seizures and their assessment of their child's depressive symptoms were compared, there was a significant inverse relationship. These findings suggest a multi-informant approach to assessment of depressive symptoms in YWE, the importance of including self-efficacy for seizure management in assessment and treatment of YWE, and provide support for transactional patterns of psychosocial adjustment. PMID- 22425425 TI - A comparison of propofol and amobarbital for use in the Wada test. AB - 129 Wada procedures were reviewed to examine the suitability of propofol (n=54) as a replacement to amobarbital (n=75) for use as an anaesthetic in the Wada test. Suitability was considered with respect to length of hemiplegia induced, the frequency of side effects and patient memory scores. Data was retrospectively collected from records of patients who had undergone the Wada procedure between 2004 and 2009 in Beaumont Hospital, Dublin. No significant differences were found between the two drugs on any of the measures. The results suggest that propofol represents a suitable alternative to amobarbital for use in the Wada procedure. PMID- 22425426 TI - Should we routinely use modified Atkins diet instead of regular ketogenic diet to treat children with epilepsy? AB - The modified Atkins diet (MAD) consists of a nearly balanced diet without any age dependent restriction of recommended daily calorie intake. Recently, there has been a marked increase in the use of the MAD in the treatment of epilepsy. Over the last 8 years, evidence suggesting that the MAD may exhibit similar anticonvulsant properties as the traditional ketogenic diet (KD) has been accumulating. KD is now an 'evidence-based' treatment for refractory epilepsy. Although there are currently no direct comparisons data from the literature suggest that the KD is more efficacious than the MAD. However, the MAD is easier to administer and has better tolerability. This review discusses when to consider each diet. The MAD may be the first diet of choice. In case of insufficient efficacy under the MAD, a switch from the MAD to the KD should be considered. PMID- 22425427 TI - Technical refinement and learning curve for attenuating neurapraxia during robotic-assisted radical prostatectomy to improve sexual function. AB - BACKGROUND: While radical prostatectomy surgeon learning curves have characterized less blood loss, shorter operative times, and fewer positive margins, there is a dearth of studies characterizing learning curves for improving sexual function. Additionally, while learning curve studies often define volume thresholds for improvement, few of these studies demonstrate specific technical modifications that allow reproducibility of improved outcomes. OBJECTIVE: Demonstrate and quantify the learning curve for improving sexual function outcomes based on technical refinements that reduce neurovascular bundle displacement during nerve-sparing robot-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective study of 400 consecutive RARPs, categorized into groups of 50, performed after elimination of continuous surgeon/assistant neurovascular bundle countertraction. SURGICAL PROCEDURE: Our approach to RARP has been described previously. A single-console robotic system was used for all cases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Expanded Prostate Cancer Index Composite sexual function was measured within 1 yr of RARP. Linear regression was performed to determine factors influencing the recovery of sexual function. RESULTS AND LIMITATIONS: Greater surgeon experience was associated with better 5-mo sexual function (p = 0.007) and a trend for better 12-mo sexual function (p = 0.061), with improvement plateauing after 250-300 cases. Additionally, younger patient age (both p<0.02) and better preoperative sexual function (<0.001) were associated with better 5- and 12-mo sexual function. Moreover, trainee robotic console time during nerve sparing was associated with worse 12-mo sexual function (p=0.021), while unilateral nerve sparing/non-nerve sparing was associated with worse 5-mo sexual function (p = 0.009). Limitations include the retrospective single-surgeon design. CONCLUSIONS: With greater surgeon experience, attenuating lateral displacement of the neurovascular bundle and resultant neurapraxia improve postoperative sexual function. However, to maximize outcomes, appropriate patient selection must be exercised when allowing trainee nerve-sparing involvement. PMID- 22425430 TI - A comparison of ECT dosing methods using a clinical sample. AB - BACKGROUND: Several methods have been used to determine ECT dose based on formulae, protocols or fixed-dosing. This study aims to explore the relative utility of these ECT dosing methods. METHODS: A sample of ECT patients from Aberdeen was analysed. Seizure thresholds derived empirically were used to calculate the proportions of patients who would have had a therapeutic stimulus had Half-Age or a fixed-dosing method (200 mC for those <65 years old and 250 mC for those >65 years old) been used. RESULTS: 62 patients were included. Initial seizure threshold varied 6 fold across the sample. Using the Half Age method 19.4% would have had a therapeutic seizure at first stimulation compared with 61.3% using an age based fixed protocol and 0% using the Royal College recommended dose titration method. Half Age and Fixed Dosing would have significantly (p<.0001) reduced the number of stimulations, the cumulative electrical dose delivered, the complexity of the procedure and the number of treatment sessions required. LIMITATIONS: This study applies only to patients receiving bilateral ECT for a major depressive episode. It uses a pragmatic design to explore a common clinical issue. This allows the feasibility of further work to be explored as this would be precluded by ethical concerns otherwise. It also uses ECT parameters which are common in UK practice which may limit its applicability internationally. CONCLUSIONS: Age based fixed-dosing would simplify the ECT process and result in more patients receiving effective treatment at first stimulation. PMID- 22425431 TI - Playing it safe: an examination of risk-avoidance in an anxious treatment-seeking sample. AB - It has been argued that individuals who are anxious are less likely and willing to take perceived risks across multiple behavioral domains (e.g., social, recreational, financial etc.), and that this bias is likely implicated in the etiology of pathological anxiety. While evidence is accumulating, there has been minimal research investigating the characteristics of risk-avoidance across anxiety disorders and across the specific risk-taking domains. The current study investigated risk-avoidance across domains in an anxious treatment-seeking sample. We hypothesized that: (i) individuals with anxiety would be more risk averse across domains relative to healthy controls; and, (ii) risk-avoidance would predict unique variance in anxiety symptoms, above and beyond other vulnerability factors (e.g., neuroticism). Individuals diagnosed with one or more anxiety disorders (n=67) completed measures of risk-taking, anxiety and depression symptoms, personality, and psychological distress. Healthy controls (n=58) completed measures of risk-taking and psychological distress. Results partially confirmed our hypotheses, demonstrating that anxious individuals were significantly more risk averse relative to controls across most domains, even after controlling for age and psychological distress. Furthermore, specific domains were found to account for unique variance in specific anxiety symptoms, as well as symptoms of depression. The results of this study provide novel evidence to suggest that risk-aversion is a possible transdiagnostic factor contributing to anxiety pathology. PMID- 22425433 TI - Long term follow up of suicide in a clinically depressed community sample. AB - BACKGROUND: The purpose of this study was to examine how sex differences in suicide rates unfolded in a long-term follow up of patients who had been diagnosed with major depression. METHOD: Patients who were diagnosed with major depression in the Chichester/Salisbury Catchment Area Study were followed for 49 years. Recorded deaths from suicide were compared with rates that were predicted from historical data on suicide mortality rates from 1960 onwards. FINDINGS: An overall suicide rate of 3.4% was found in the present sample. Sixteen women and three men died from suicide. Women's suicide rates were significantly higher than the level predicted based on general population trends. Men showed a barely non significant trend in the same direction. The diagnosis of clinical depression was associated more strongly with increased risk for suicide among women compared with men. Of the female suicides, 13 had been diagnosed with endogenous depression. CONCLUSIONS: While suicide rates are significantly higher for men in the general population, and for depressed patients of both sexes, the depression may be a particularly strong predictor of suicide risk among women. LIMITATIONS: The dataset does not provide information about processes that mediate the relationship between depression and suicide mortality. PMID- 22425432 TI - Functional connectivity in the cognitive control network and the default mode network in late-life depression. AB - BACKGROUND: Abnormalities have been identified in the Cognitive Control Network (CCN) and the Default Mode Network (DMN) during episodes of late-life depression. This study examined whether functional connectivity at rest (FC) within these networks characterizes late-life depression and predicts antidepressant response. METHODS: 26 non-demented, non-MCI older adults were studied. Of these, 16 had major depression and 10 had no psychopathology. Depressed patients were treated with escitalopram (target dose 20 mg) for 12 weeks after a 2-week placebo phase. Resting state time series was determined prior to treatment. FC within the CCN was determined by placing seeds in the dACC and the DLPFC bilaterally. FC within the DMN was assessed from a seed placed in the posterior cingulate. RESULTS: Low resting FC within the CCN and high resting FC within the DMN distinguished depressed from normal elderly subjects. Beyond this "double dissociation", low resting FC within the CCN predicted low remission rate and persistence of depressive symptoms and signs, apathy, and dysexecutive behavior after treatment with escitalopram. In contrast, resting FC within the DMN was correlated with pessimism but did not predict treatment response. CONCLUSIONS: If confirmed, these findings may serve as a signature of the brain's functional topography characterizing late-life depression and sustaining its symptoms. By identifying the network abnormalities underlying biologically meaningful characteristics (apathy, dysexecutive behavior, pessimism) and sustaining late-life depression, these findings can provide a novel target on which new somatic and psychosocial treatments can be tested. PMID- 22425434 TI - Influence of environmental temperature on the physiological, endocrine, and immune responses in livestock exposed to a provocative immune challenge. AB - Although livestock experience many stressors throughout their life, one of the most commonly experienced, and most difficult to control, is stress caused by fluctuations in environmental temperatures that extend beyond the thermoneutral (TN) zone for an animal. In swine, cold stress has long been recognized as a main cause of neonatal morbidity and mortality. A possible explanation for this increased morbidity and mortality may be related to their inability to generate a febrile response. Previously, we reported that the acute phase immune response, including the generation of fever, after exposure to lipopolysaccharide (LPS; Escherichia coli O111: B4; Sigma-Aldrich, St Louis, MO, USA) is substantially altered in neonatal pigs maintained in a cold environment (ie, 18 degrees C). Neonatal pigs that were maintained in a cold environment and administered LPS experienced a period of hypothermia coupled with altered endocrine and proinflammatory cytokine responses that could prove detrimental. In cattle, we previously reported differences in the acute phase immune response of two diverse breeds of Bos taurus cattle (Angus and Romosinuano) when maintained under TN conditions and exposed to LPS. More recently we have reported that differences in the stress and immune responses of Angus and Romosinuano heifers varies, depending on whether the cattle were housed at either TN or heat stress air temperatures. Our data clearly show that even intermittent periods of heat stress similar to that experienced in production environments can have significant effects on the stress and innate immune responses of cattle. Understanding the effect of thermal stress on livestock is critical to developing and implementing alternative management practices to improve their overall health and well-being. PMID- 22425435 TI - Porcine somatotropin alters insulin response in growing pigs by reducing insulin sensitivity rather than changing responsiveness. AB - Exogenous porcine somatotropin (pST) treatment consistently improves growth performance and reduces fat deposition in pigs, and it is hypothesized that one component of the mechanism is through altering the sensitivity and/or responsiveness to insulin. Therefore, a study was conducted to investigate the effect of pST treatment on whole-body glucose metabolism in response to varying doses of insulin. Eight barrows were surgically prepared with indwelling catheters and randomly assigned to one of two treatment groups (0 or 120 MUg pST/kg BW . d) for 13 d. Whole-body glucose kinetics were measured during infusion of [6-(3)H]-glucose under basal conditions and during hyperinsulinemic euglycemic clamps at various insulin infusion rates (7, 28, and 140, and 14, 70, and 280 ng insulin/kg BW . min) and alterations in the dose-response parameters were calculated with nonlinear regression. Treatment with pST increased basal plasma concentrations of glucose (36%; P = 0.005), insulin (276%; P = 0.001), and NEFAs (177%; P = 0.01) and decreased the rate of glucose disappearance (-59%; P = 0.001). The responsiveness (maximum response) for steady state glucose infusion rate to maintain glycemia was not altered by pST (112 vs 106 MUmol/min . kg; P = 0.78), whereas the sensitivity (effective dose at 50% of maximum response) was increased almost 7-fold (1.3 vs 8.7 ng/mL; P = 0.027). Similar responses were observed for rate of glucose disappearance and insulin-dependent glucose utilization. Therefore, pST-induced insulin resistance with regard to whole-body glucose uptake is due to a reduced sensitivity to insulin, rather than a change in responsiveness. PMID- 22425436 TI - Association of the intronic polymorphism rs891512 (G24943A) of the endothelial nitric oxide synthase gene with hypertension in Chilean type 2 diabetes patients. AB - We investigated two single nucleotide polymorphisms of the NOS3 gene in type 2 diabetic patients (n=93) and healthy non-diabetic controls (n=76) and their relationship with smoking habits, body mass index, hypertension and dyslipidemia. Results showed that eNOS polymorphism rs891512 (G24943A) is associated with hypertension in Chilean individuals (p<0.05). PMID- 22425437 TI - Improving quality of care of acute myocardial infarction: more focus needed on long-term optimal medical treatment and secondary prevention. PMID- 22425438 TI - Heparin-induced thrombocytopenia in essential thrombocytosis. AB - We report a 67-year-old woman with essential thrombocytosis who developed cerebral infarction and heparin-induced thrombocytopenia during treatment for the cerebral infarction. She developed additional cerebral infarcts, acute femoral artery occlusion, and thrombophlebitis of her lower extremities. She was successfully treated with argatroban. This is the first report of a patient with essential thrombocytosis who developed heparin-induced thrombocytopenia and serious conditions, which included multiple thromboembolisms and coagulation disorders mimicking disseminated intravascular coagulation. PMID- 22425439 TI - Immigrants' acculturation and changes in Body Mass Index. AB - We study Body Mass Index (BMI) changes among immigrants from Iran, Pakistan, Sri Lanka, Turkey, and Vietnam relative to native Norwegians in Oslo. We assess the effect of acculturation on BMI changes. We hypothesize that acculturation reduces the gap of BMIs between natives and immigrants. Acculturation is measured by immigrants' language skills. Our data come from two surveys in Oslo 2000-2002. Weights and heights were measured at the surveys; participants were asked to recall weights when they were 25 years old. Norwegian language skills and socio economic data were collected. Our findings support our hypothesis. Acculturation, as measured by proficiency in the Norwegian language, has the predicted effects on BMI changes. We do not find any effect of immigrants' time of residency on BMI changes. PMID- 22425440 TI - PET finding in Kleine-Levin syndrome. PMID- 22425441 TI - Comprehensive multiphase NMR spectroscopy: basic experimental approaches to differentiate phases in heterogeneous samples. AB - Heterogeneous samples, such as soils, sediments, plants, tissues, foods and organisms, often contain liquid-, gel- and solid-like phases and it is the synergism between these phases that determine their environmental and biological properties. Studying each phase separately can perturb the sample, removing important structural information such as chemical interactions at the gel-solid interface, kinetics across boundaries and conformation in the natural state. In order to overcome these limitations a Comprehensive Multiphase-Nuclear Magnetic Resonance (CMP-NMR) probe has been developed, and is introduced here, that permits all bonds in all phases to be studied and differentiated in whole unaltered natural samples. The CMP-NMR probe is built with high power circuitry, Magic Angle Spinning (MAS), is fitted with a lock channel, pulse field gradients, and is fully susceptibility matched. Consequently, this novel NMR probe has to cover all HR-MAS aspects without compromising power handling to permit the full range of solution-, gel- and solid-state experiments available today. Using this technology, both structures and interactions can be studied independently in each phase as well as transfer/interactions between phases within a heterogeneous sample. This paper outlines some basic experimental approaches using a model heterogeneous multiphase sample containing liquid-, gel- and solid-like components in water, yielding separate (1)H and (13)C spectra for the different phases. In addition, (19)F performance is also addressed. To illustrate the capability of (19)F NMR soil samples, containing two different contaminants, are used, demonstrating a preliminary, but real-world application of this technology. This novel NMR approach possesses a great potential for the in situ study of natural samples in their native state. PMID- 22425442 TI - Optimal control design of band-selective excitation pulses that accommodate relaxation and RF inhomogeneity. AB - Existing optimal control protocols for mitigating the effects of relaxation and/or RF inhomogeneity on broadband pulse performance are extended to the more difficult problem of designing robust, refocused, frequency selective excitation pulses. For the demanding case of T(1) and T(2) equal to the pulse length, anticipated signal losses can be significantly reduced while achieving nearly ideal frequency selectivity. Improvements in performance are the result of allowing residual unrefocused magnetization after applying relaxation-compensated selective excitation by optimized pulses (RC-SEBOPs). We demonstrate simple pulse sequence elements for eliminating this unwanted residual signal. PMID- 22425443 TI - Glycan analysis via derivatization with a fluorogenic pyrylium dye. AB - The expansion of glycomics analysis is reliant upon the development of robust, routine methods for carbohydrate characterization. Simple protocols to derivatize sugars with functionality that facilitate analysis-chromophores, fluorophores, charges, ionizable groups-are therefore necessary. Here we describe a method for the labeling of oligosaccharide mixtures with a fluorogenic pyrylium dye to enable analysis by capillary electrophoresis (CE) and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS). The unreacted free dye, Py-1, is effectively non-fluorescent but when conjugated to the analyte it displays strong fluorescence at 600-640 nm. Removal of excess dye following labeling is not required prior to analysis unlike for many traditional oligosaccharide labels. Labeling is achieved in two steps; the oligosaccharide mixtures are first functionalized with an ethylenediamine moiety via reductive amination at the reducing-end sugar, then the remaining free primary amine is reacted with the pyrylium dye (Py-1) under basic conditions to form a pyridinium ion. We have labeled mixtures of maltooligosaccharides and observed good peak separation in CE analysis using a SDS/borate pH 9.3 running buffer. Excellent sensitivity in MALDI-ToF-MS analysis enabled detection of oligosaccharides with up to 58 glucose units. PMID- 22425444 TI - A new arabinomannan from the cell wall of the chlorococcal algae Chlorella vulgaris. AB - A new arabinomannan has been isolated from the cell wall of the green algae Chlorella vulgaris by extraction with 0.1 M NaOH, dialysis and SEC fractionation. M(w) was about 8000 u. Terminal, 2- and 5-O-linked arabinofuranosyl residues, and 2,6-O-linked mannopyranosyl residues were detected as the main constituents beside some minor mannose components by methylation analysis. Electrospray ionisation mass spectrometry (ESI-MS) with collision induced dissociation (CID) up to MS(3) experiments of oligosaccharides obtained by partial methanolysis or partial acid hydrolysis indicated the presence of Man->Man- and Ara->Ara- as well as Ara->Man- and also Man->Ara-sequences. MS(2) experiments gave evidence of a (1 >6)-linked mannan, probably also including some (1->2)-linked mannosyl and 5 linked arabinofuranosyl residues. Mannooligosaccharides up to DP5 with mainly (1 >6)-, but at higher DP also (1->2)-linkages were obtained by acid hydrolysis, and arabino oligomers up to DP4 could be detected after mild methanolysis. In accordance with results from methylation analysis and ESI-MS/CID t-beta-Araf, 2 alpha-Araf, 5-alpha-Araf and 2,6-alpha-Manp were identified from homo- and heteronuclear 1D- and 2D NMR experiments in a molar ratio of ~2:2:1:2. A highly branched structure is suggested with a 6- and 2-O-linked mannan main chain, comprising 5-Araf residues. Araf-beta-[(1->2)-Araf-alpha-(1->](n) side chains with an average chain length of 2 are linked to the mannan main chain. The configuration of Ara is D. The new polysaccharide shows structural similarities with the (lipo)arabinomannans of Mycobacterium tuberculosis. PMID- 22425446 TI - Spinal SIRPalpha1-SHP2 interaction regulates spinal nerve ligation-induced neuropathic pain via PSD-95-dependent NR2B activation in rats. AB - The fact that neuropathic pain mechanisms are not well understood is a major impediment in the development of effective clinical treatments. We examined whether the interaction between signal regulatory protein alpha 1 (SIRPalpha1) and Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2), and the downstream spinal SHP2/postsynaptic density 95 (PSD-95)/N-methyl-d-aspartate receptor NR2B subunit signaling cascade play a role in neuropathic pain. Following spinal nerve ligation (L5), we assessed tactile allodynia using the von Frey filament test and analyzed dorsal horn samples (L4-5) by Western blotting, reverse transcription polymerase chain reaction, coimmunoprecipitation, and immunofluorescence. Nerve ligation induced allodynia, SIRPalpha1, SHP2, phosphorylated SHP2 (pSHP2), and phosphorylated NR2B (pNR2B) expression, and SHP2 PSD-95, pSHP2-PSD-95, PSD-95-NR2B, and PSD-95-pNR2B coimmunoprecipitation in the ipsilateral dorsal horn. In allodynic rats, injury-induced SHP2 immunoreactivity was localized in the ipsilateral dorsal horn neurons and coincident with PSD-95 and NR2B immunoreactivity. SIRPalpha1 silencing using small interfering RNA (siRNA; 1, 3, or 5MUg/rat for 7days) prevented injury-induced allodynia and the associated changes in protein expression, phosphorylation, and coimmunoprecipitation. Intrathecal administration of NSC-87877 (an SHP2 antagonist; 1, 10, or 100MUM/rat) and SIRPalpha1-neutralizing antibodies (1, 10, or 30MUg/rat) suppressed spinal nerve ligation-induced allodynia, spinal SHP2 and NR2B phosphorylation, and SHP2/phosphorylated SHP2-PSD-95 and PSD-95 NR2B/phosphorylated NR2B coprecipitation. SHP2 siRNA led to similar effects as the NSC-87877 and SIRPalpha1 antibody treatments, except it prevented the allodynia-associated spinal SHP2 expression. In conclusion, our results suggest that a spinal SIRPalpha1-SHP2 interaction exists that subsequently triggers SHP2/PSD-95/NR2B signaling, thereby playing a role in neuropathic pain development. PMID- 22425445 TI - Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels. AB - Spinal glial and proinflammatory cytokine actions are strongly implicated in pathological pain. Spinal administration of the anti-inflammatory cytokine interleukin (IL)-10 abolishes pathological pain and suppresses proinflammatory IL 1beta and tumor necrosis factor alpha (TNF-alpha). Drugs that bind the cannabinoid type-2 receptor (CB(2)R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB(2)R-related anti-inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB(2)R agonist, AM1710, in 2 animal models; unilateral sciatic nerve chronic constriction injury (CCI), and spinal application of human immunodeficiency virus-1 glycoprotein 120 (gp120), a model of peri-spinal immune activation. In CCI animals, lumbar dorsal spinal cord and corresponding dorsal root ganglia (DRG) were evaluated by immunohistochemistry for expression of IL 10, IL-1beta, phosphorylated p38-mitogen-activated-kinase (p-p38MAPK), a pathway associated with proinflammatory cytokine production, glial cell markers, and degradative endocannabinoid enzymes, including monoacylglycerol lipase (MAGL). AM1710 reversed bilateral mechanical hypersensitivity. CCI revealed decreased IL 10 expression in dorsal spinal cord and DRG, while AM1710 resulted in increased IL-10, comparable to controls. Adjacent DRG and spinal sections revealed increased IL-1beta, p-p38MAPK, glial markers, and/or MAGL expression, while AM1710 suppressed all but spinal p-p38MAPK and microglial activation. In spinal gp120 animals, AM1710 prevented bilateral mechanical hypersensitivity. For comparison to immunohistochemistry, IL-1beta and TNF-alpha protein quantification from lumbar spinal and DRG homogenates was determined, and revealed increased DRG IL-1beta protein levels from gp120, that was robustly prevented by AM1710 pretreatment. Cannabilactone CB(2)R agonists are emerging as anti-inflammatory agents with pain therapeutic implications. PMID- 22425447 TI - Results of routine shunting and patch closure during carotid endarterectomy. AB - BACKGROUND: The role of shunting and patching during carotid endarterectomy remains controversial. METHODS: This is a retrospective case series evaluating consecutive patients undergoing carotid endarterectomy with routine shunting and patching. The primary endpoints were perioperative stroke, arterial injury, and lesion recurrence by duplex. RESULTS: Of the 220 operations performed, 43% were for symptomatic disease. Successful shunt placement occurred in 98%, with no shunt-related injuries. There was 1 minor perioperative stroke and no major strokes. At a mean follow-up of 24 months (median = 12 months), there was 1 restenosis potentially related to shunt placement. The incidence of asymptomatic >50% stenosis in the patched segment was 8%. CONCLUSIONS: A combined policy of routine shunting and patching simplifies intraoperative decision making with results that rival or exceed those of trials in which their use was not standardized. Shunts need not be avoided because of concern of arterial injury. PMID- 22425448 TI - Thrombelastography-identified coagulopathy is associated with increased morbidity and mortality after traumatic brain injury. AB - BACKGROUND: The purpose of this study was to determine the relationship between coagulopathy and outcome after traumatic brain injury. METHODS: Patients admitted with a traumatic brain injury were enrolled prospectively and admission blood samples were obtained for kaolin-activated thrombelastogram and standard coagulation assays. Demographic and clinical data were obtained for analysis. RESULTS: Sixty-nine patients were included in the analysis. A total of 8.7% of subjects showed hypocoagulability based on a prolonged time to clot formation (R time, > 9 min). The mortality rate was significantly higher in subjects with a prolonged R time at admission (50.0% vs 11.7%). Patients with a prolonged R time also had significantly fewer intensive care unit-free days (8 vs 27 d), hospital free days (5 vs 24 d), and increased incidence of neurosurgical intervention (83.3% vs 34.9%). CONCLUSIONS: Hypocoagulability as shown by thrombelastography after traumatic brain injury is associated with worse outcomes and an increased incidence of neurosurgical intervention. PMID- 22425449 TI - Determinants of adverse events in vascular surgery. AB - BACKGROUND: Patient safety is a national priority. Patient Safety Indicators (PSIs) monitor potential adverse events during hospital stays. Surgical specialty PSI benchmarks do not exist, and are needed to account for differences in the range of procedures performed, reasons for the procedure, and differences in patient characteristics. A comprehensive profile of adverse events in vascular surgery was created. STUDY DESIGN: The Nationwide Inpatient Sample was queried for 8 vascular procedures using ICD-9-CM codes from 2005 to 2009. Factors associated with PSI development were evaluated in univariate and multivariate analyses. RESULTS: A total of 1,412,703 patients underwent a vascular procedure and a PSI developed in 5.2%. PSIs were more frequent in female, nonwhite patients with public payers (p < 0.01). Patients at mid and low-volume hospitals had greater odds of developing a PSI (odds ratio [OR] = 1.17; 95% CI, 1.10-1.23 and OR = 1.69; 95% CI, 1.53-1.87). Amputations had highest PSI risk-adjusted rate and carotid endarterectomy and endovascular abdominal aortic aneurysm repair had lower risk-adjusted rate (p < 0.0001). PSI risk-adjusted rate increased linearly by severity of patient indication: claudicants (OR = 0.40; 95% CI, 0.35-0.46), rest pain patients (OR = 0.78; 95% CI, 0.69-0.90), ulcer (OR = 1.20; 95% CI, 1.07 1.34), and gangrene patients (OR = 1.85; 95% CI, 1.66-2.06). CONCLUSIONS: Patient safety events in vascular surgery were high and varied by procedure, with amputations and open abdominal aortic aneurysm repair having considerably more potential adverse events. PSIs were associated with black race, public payer, and procedure indication. It is important to note the overall higher rates of PSIs occurring in vascular patients and to adjust benchmarks for this surgical specialty appropriately. PMID- 22425450 TI - Enzyme replacement therapy partially prevents invariant Natural Killer T cell deficiency in the Fabry disease mouse model. AB - Fabry disease is a lysosomal storage disease caused by deficient activity of the alpha-Galactosidase A (alpha-Gal A) enzyme, which leads to abnormal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in the lysosome. Glycosphingolipids are known to be invariant Natural Killer T (iNKT) cell antigens. Several animal models of lysosomal storage diseases, including Fabry disease, present a defect in iNKT cell selection by the thymus. We have studied the effect of age and the impact of enzyme replacement therapy on Gb3 accumulation and iNKT cells of Fabry knockout mice. At 4 weeks of age, Fabry knockout mice already showed Gb3 accumulation and a reduction in the percentage of iNKT cells. In older mice (12-week old), we observed an accentuated peripheral iNKT deficiency. 12-week old animals also showed a reduced splenic CD4+/CD4- iNKT cell ratio due to greater loss in the iNKT CD4+ subset. Treatment of Fabry knockout mice with alpha-Gal A replacement therapy efficiently reduced Gb3 deposition in the liver and spleen. Moreover, enzyme replacement therapy had a positive effect on the number of iNKT cells in an organ-dependent fashion. Indeed, treatment of Fabry knockout mice with alpha-Gal A did not alter iNKT cell percentage in the thymus and liver but increased splenic iNKT cell percentage when compared to untreated mice. Study of animals prior to treatment indicates that enzyme replacement therapy stabilized iNKT cell percentage in the spleen. This stabilization is due to a specific effect on the iNKT CD4+ subset, preventing the decrease on the number of these cells that occurs with age in Fabry knockout mice. This study reveals that enzyme replacement therapy has a positive organ and subset-dependent effect in iNKT cells of Fabry knockout mice. PMID- 22425451 TI - Immunoreactive Trypsinogen (IRT) as a Biomarker for Cystic Fibrosis: challenges in newborn dried blood spot screening. AB - On May 23-24, 2011, a workshop entitled "Immunoreactive Trypsinogen (IRT) as a Biomarker for Cystic Fibrosis: Technical Issues and Challenges" was held in Annapolis, Maryland. The two-day workshop was co-hosted by the National Newborn Screening and Genetics Resource Center, Austin, Texas, and the Association of Public Health Laboratories, Silver Spring, Maryland, in collaboration with the Health Resources and Services Administration and the Centers for Disease Control and Prevention. Participants included nearly 40 representatives from U.S. state public health and commercial laboratories performing newborn dried blood spot screening tests for cystic fibrosis (CF), the federal government, academic research institutions, and commercial vendors of products used in newborn screening. Representatives from selected European CF newborn screening programs were also present. The workshop focused on identifying key IRT testing issues and mechanisms for achieving their resolution and laboratory harmonization in order to reduce, or eliminate completely, the late identified CF cases following a negative newborn screen. Informative findings are reported, their impacts on improving IRT screening are described, and their implications are discussed. PMID- 22425452 TI - Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: alpha-Branched quaternary amines. AB - We report the synthesis and biological evaluation of a series of novel alpha branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12 g has an IC(50) of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 1 MUg kg(-1) at 1h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. PMID- 22425453 TI - Pyrazine-based Syk kinase inhibitors. AB - A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay. PMID- 22425454 TI - Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease. AB - A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization. PMID- 22425455 TI - Photo-degradation products of pramipexole. AB - Two pyrrolidine compounds (1 and 2) were isolated from photo-degradation of Bi Sifrol tablets. Compound 1 was esterified to p-bromophenacyl ester as single crystal, and then the structure was elucidated by single-crystal X-ray study. Compound 2 was determined by 2D NMR and mass spectra. Otherwise, we established that the photo-degradation of pramipexole was smoothly carried out in the methanol solution, and elucidate the degradation mechanism. PMID- 22425456 TI - [Quality management in a public health agency]. AB - This article describes the introduction of quality improvement actions in a public health organization. After ISO 17025 accreditation, which was legally mandated, was granted to the official control laboratory, the management decided to expand a quality policy in 2003, through a series of actions based on process analysis and proposals for improvement, further definition of standard operating procedures, exploration of users' opinions, the creation of improvement groups, and external audits or certification. The organizational response to these initiatives was diverse. External audit or certification of services seems to be the most powerful tool for change. Costing studies showed that up to 75% of the total expenditure of the agency in 2010 was spent on public health services subject to external audit or certification. PMID- 22425457 TI - [Predictors of the duration of non-work-related sick leave due to anxiety disorders]. AB - OBJECTIVES: To analyze the duration of non-work-related sick leave due to anxiety disorders and to identify demographic, occupational and clinical variables that may contribute to its prediction. METHODS: We performed a prospective cohort study of 1,161 workers with an episode of non-work-related sick leave due to an anxiety disorder, belonging to the insured population of a mutual insurance company. We assessed the duration of non-work-related sick leave episodes and the main potentially related demographic, occupational and clinical variables. All non-work-related sick leave processes were followed-up until discharge. Cox regression analyses were conducted to establish the predictors of non-work related sick leave duration. RESULTS: The median duration of non-work-related sick leave due to anxiety disorders was 83 days. In a multivariate analysis, the following factors were identified as being significantly associated with increases in the duration of sick leave (p <0.05): age of over 35 years, lower educational level (primary school studies, secondary school studies or high school diploma vs. university degree), and the existence of comorbidity and unemployment occurring during the sick leave. In contrast, being separated or divorced was associated with an earlier return to work (p <0.05). CONCLUSIONS: Anxiety disorders are associated with long periods of non-work-related sick leave compared with other disorders and standard time duration. Demographic, occupational and clinical variables collected at the initial assessment of the sick leave episode would help to identify groups with an increased risk of prolonged sick leave, requiring strategies to facilitate return to work. PMID- 22425458 TI - [Pathogenesis and treatment of idiopathic nephrotic syndrome in adults]. AB - Idiopathic nephrotic syndrome is the most frequent glomerular disease in children and in young adults. While genetic analyses have provided new insights into disease pathogenesis through the discovery of several podocyte genes mutated in distinct forms of inherited nephrotic syndrome, the molecular bases of minimal change nephrotic syndrome and focal and segmental glomerulosclerosis with relapses remain unclear. Although immune cell disorders, which may involve both innate and adaptive immunity, appear to play a role in the pathogenesis of steroid sensitive minimal change nephrotic syndrome, the mechanisms by which they induce podocyte dysfunction remain unresolved. It was postulated that podocyte injury results from a circulating factor secreted by abnormal T cells, but the possibility that bipolarity of the disease results from a functional disorder shared by both immune cells and the podocytes is not excluded. Minimal change nephrotic syndrome relapses are associated with an expansion of T and B cell compartments and production of growth factors as well as many cytokines. Dysfunction of T cells is supported by several findings including, inhibition of a type IV hypersensitivity reaction and unclassical T helper polarization, resulting from transcriptional interference between Th1 and Th2 transcriptional factors. A low serum level of some IgG fractions is frequently observed suggesting a defect in T-B cell cooperation, which remains to be explored. In this review, we discuss recent advances in the pathogenesis and the therapy of idiopathic nephrotic syndrome. PMID- 22425459 TI - [Renal biopsy practice: results of a French study and recommendations]. AB - BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, recommendations for RB procedures are still lacking. Our working group, appointed by the scientific commission of the Societe de nephrologie in France, aimed to depict the main aspects of the practice of RB in adults in France, before establishing some guidelines. METHODS: Members of the Societe de nephrologie in France were asked to participate to a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals, and 12 in private centers) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to less than ten per year. Transjugular RB was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of hemorrhagic risk factors, care of patients with antiplatelet agents and hemorrhagic risk factors, and radiological guidance. Early discharge (<12 hours) was the rule in three (4.1%) units for native kidney biopsies and in ten (28.6%) units for graft biopsies. CONCLUSIONS: Our study is the first to provide a representative picture of "everyday" RB practices in a country. Consensual recommendations on all points mentioned are provided here. PMID- 22425460 TI - Morbidity following sural nerve harvesting: a prospective study. AB - OBJECTIVE: To evaluate donor site morbidity following sural nerve harvesting, with special attention to the recovery of sensory loss. METHODS: We prospectively followed 38 subjects who underwent sural nerve harvest, including two with bilateral nerve excision. Symptoms related to sural nerve excision were evaluated and demarcation of the area with reduced touch sensation was quantified. Assessments were performed periodically up to 1 year after surgery and the results of different sensory evaluations were compared. RESULTS: A significant reduction of sensory deficit was identified between consecutive evaluations (p<0.05). Decreases of 26.85%, 20.69% and 24.29% were observed 3, 6 and 12 months after surgery, respectively. Shock-like pain (7.5%), stabbing pain (7.5%), and numbness (5%) were the most frequently reported symptoms. All symptoms were brief and resolved spontaneously 3-6 months after surgery. CONCLUSION: Sural nerve harvest can be performed with acceptable morbidity. When present, symptoms resolve between the third and sixth month after surgery and a significant reduction of sensory loss in the area innervated by the sural nerve was observed during the first year of follow-up. PMID- 22425461 TI - Isolated meningomyeloradiculitis following infection with tick borne encephalitis virus. PMID- 22425462 TI - Long-term adherence to interferon-beta treatment in a cohort of RRMS patients in Belgrade, Serbia. AB - OBJECTIVE: Long-term adherence to interferon-beta (IFNbeta) treatment in patients with multiple sclerosis (MS) varies considerably in daily clinical practice. The aim of the present study was to assess the frequency and reasons for stopping the INFbeta treatment in our relapsing-remitting (RR) MS patients' cohort. PATIENTS AND METHOD: All patients with RRMS initiating treatment with IFNbeta at the Clinic of neurology, CCS, in Belgrade, from January 2004 to June 2009, were included in the study. Treatment was initiated in RRMS patients with at least two relapses in the previous two years, and EDSS score at entry <=3.5. During the follow-up, patients underwent regular detailed clinical evaluation performed by MS specialists. RESULTS: The study comprised a total of 290 RRMS patients. During the 6-year follow up period (mean 3.5+/-2.1 years), 18% of patients stopped the treatment. The main reason for treatment discontinuation was lack of efficacy (54%); 21% of patients stopped therapy because of pregnancy and only 17% because of AE. CONCLUSION: The frequency of treatment discontinuation in our study pointed to the low permanent termination rate reflecting good adherence to IFNbeta in our RRMS patients. Our results support the notion that long-term adherence to IFNbeta treatment might be significantly influenced by optimizing the benefits to be achieved from therapy, adequate patient selection and easy accessibility of MS health professionals. PMID- 22425463 TI - A case of primary central nervous system histiocytic sarcoma. PMID- 22425464 TI - Stimulated peripheral production of interferon-gamma is related to fatigue and depression in multiple sclerosis. AB - OBJECTIVES: The aim of the study was to evaluate the stimulated production of interferon-gamma (IFNgamma) by peripheral CD3+CD4+ T lymphocytes in patients with multiple sclerosis (MS) with regard to the degree of fatigue, and to investigate relationships between immunological parameters, level of depression and clinical variables. METHODS: Forty MS patients (30 women, 10 men, aged 22-60 years): 20 fatigued and 20 non-fatigued were involved in the study. Fatigue was evaluated using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS), depression level - using Beck Depression Inventory (BDI). Production of IFNgamma by stimulated peripheral blood CD3+CD4+ T lymphocytes, assessed using flow cytometry, was compared between MS patients with different levels of fatigue and controls. Correlations were searched out between immunological findings and BDI, age, duration and course of MS, relapse rate, disability (assessed in Expanded Disability Status Scale - EDSS) and its progression. RESULTS: Stimulated production of IFNgamma by CD3+CD4+ T lymphocytes was higher in severely fatigued patients in comparison with non-fatigued ones and controls, tended to correlate with FSS and MFIS, and correlated with BDI. No relationships were found between immunological findings and disease-related variables. CONCLUSION: Stimulated production of IFNgamma by peripheral CD3+CD4+ T lymphocytes is related to fatigue and depression in MS patients. PMID- 22425465 TI - The response to stress in Brazilian children and adolescents with attention deficit hyperactivity disorder. AB - This study assessed the function of the hypothalamic-pituitary-adrenal (HPA) axis, during response to stress, through the measurement of salivary cortisol in 38 children with attention deficit hyperactivity disorder (ADHD) and its subtypes, who were matched to 38 healthy control subjects. These measures were made at four time intervals: 15 min before exposing the subjects to a stressor - the Continuous Performance Test (CPT) - and 20, 40, and 60 min after such exposure. The baseline cortisol levels were statistically similar in both groups. The mean values of cortisol at the four time intervals were not statistically different between the three subtypes of ADHD (inattentive, hyperactive-impulsive and combined); thus, the ADHD group was treated as a single group. Following the stressor test, the ADHD group had significantly higher levels of salivary cortisol than the control group at time intervals of 20 and 40 min, whereas in this latter group exposure to the CPT did not induce an increase of cortisol. These results suggest that the increased cortisol levels in the ADHD group could be due to the lack of comorbidities. In addition, these patients, when facing a computerized test, might have responded with a motivational pathway with an increase of cortisol. PMID- 22425466 TI - The state dependency of cognitive schemas in antisocial patients. AB - Patients with antisocial personality disorder (ASPD) typically report little psychopathology. Recent findings also showed this group to report high levels of healthy cognitions. Such a non-deviant cognitive profile might merely characterize ASPD under neutral assessment conditions. Indeed, hardly anything is known about how emotional states alter ASPD patients' cognitions. The current study therefore assessed the impact of autobiographical anger recollection on state cognitions. In a sample of N=147 participants, ASPD patients' (n=21) self reported schema modes were assessed before and after an anger interview, and compared with those of borderline (n=45) and cluster-C patients (n=46) and non patients controls (n=35). Results showed that ASP -patients' high baseline levels of healthy cognitions dropped drastically following the anger recollection. This finding suggests that reviving past anger-eliciting events breaks down the healthy veneer of ASPD patients and that their healthy cognitions are unstable. These findings underscore the importance of pathology assessment under emotional conditions in ASPD samples. PMID- 22425467 TI - Emotional face processing in neurotypicals with autistic traits: implications for the broad autism phenotype. AB - The present study investigated emotional face processing in neurotypicals selected for autistic traits (AT). Participants (N=81), who obtained scores one standard deviation above or below average on the Autism Spectrum Quotient, were tested using observational fear conditioning (FC), a face version of the attention probe task, and the "Reading the Mind in the Eyes" test. The results indicated that high AT participants displayed enhanced observational FC, no attentional bias to fearful faces, and increased latency (but normal accuracy) to recognizing the mental state of another. To a certain extent, this pattern resembles the social-emotional phenotype that was previously described in autism spectrum disorders. Therefore, these results may contribute to the broad autism phenotype perspective. PMID- 22425468 TI - The quantitative EEG theta/beta ratio in attention deficit/hyperactivity disorder and normal controls: sensitivity, specificity, and behavioral correlates. AB - The purpose of the present study was to determine if the theta/beta ratio, and theta and beta separately, correlate with behavioral parameters, and if these measures discriminate between children and adolescents with attention deficit/hyperactivity disorder (ADHD) and normal gender- and age-matched controls. Participants comprised 62 patients and 39 controls. A continuous performance test (CPT), a GO/NOGO test and two rating scales were used to measure behavior in the patient group. EEG spectra were analyzed in eyes-closed and eyes opened conditions, and in a GO/NOGO task in both groups. Neither the theta/beta ratio at CZ, nor theta and beta separately, discriminated significantly between patients and controls. When each person was compared with the database, significant elevations of theta were found in 25.8% of the patients and in only one control subject (2.6%). In the ADHD group, theta at CZ was positively correlated with inattention and executive problems and negatively correlated with hyperactivity/impulsivity. Beta correlated with good attention level in the control group, but with ADHD symptoms in the patients. Omission errors in the GO/NOGO test discriminated between patients and controls with an accuracy of 85%. For theta at CZ, the accuracy was 62%. Significantly elevated theta characterized a subgroup of ADHD patients, and correlated with inattention and executive problems. PMID- 22425469 TI - Validation of the Integrative Hope Scale in people with psychosis. AB - Hope is an important variable in mental health, particularly in the emergent field of research focused on recovery and well-being. This study validates the "Integrative Hope Scale" (IHS) for use in people with severe mental illness. Two hundred participants diagnosed with schizophrenia or schizoaffective disorder were assessed using the IHS, the Centre for Epidemiological Studies Depression Scale, and the Positive and Negative Syndrome Scale. Sixty participants were re assessed after 14 days to establish re-test reliability. Confirmatory factor analysis was carried out; correlations between the scales and kappa coefficients were used to establish validity and reliability. The factor analysis confirmed a four-factor solution with excellent model fit, after minor modifications to the initial model. Discriminant validity and internal consistency were excellent. Test-retest reliability was good except for one item. This study suggests the scale to be a valid, reliable and feasible tool for the assessment of hope in people with severe mental illness. It provides a sound basis for future research on hope in mental health. For use in people with psychosis, we suggest some minor modifications to the scale. PMID- 22425470 TI - Impaired executive control of emotional information in social anhedonia. AB - We examined the executive control of emotional information and its relationship to social functioning in individuals at risk for schizophrenia, defined by high social anhedonia (SA). Using the same structure as the Attentional Network Test (ANT), we developed a measure of executive control of emotional information (ANT Emotion) in which subjects identify the direction of an arrow flanked by irrelevant angry or neutral faces. Subjects completed the ANT, ANT-Emotion, and the Social Adjustment Scale, Self-Report (SAS-SR), a measure of social functioning. While there were no group differences in the alerting, orienting, and executive control networks assessed by the ANT, high SA individuals exhibited a specific impairment in the executive control of emotional information. High SA individuals also reported poorer social functioning. However, executive control of emotional information did not mediate the relationship between SA and social functioning. These findings indicate that, in high-risk populations, the impaired ability to inhibit emotional information allows negative affective stimuli to exert inappropriate influence on cognitive processes. These results are consistent with studies indicating similar findings in schizophrenia patients, suggesting that impaired inhibition of negative emotion may be part of the liability for the disorder. PMID- 22425471 TI - Nicotine and the hallucinating brain: effects on mismatch negativity (MMN) in schizophrenia. AB - Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs. PMID- 22425472 TI - Parental death during childhood and psychopathology in adulthood. AB - We examined the association between parental death during childhood and lifetime and 12-month psychopathology, age of onset, incidence of mental health problems, use of mental health services during adulthood and functional limitations during adulthood. We conducted a longitudinal, population-based epidemiological study in adults aged 18-64 years (N=7076). Mental disorders were assessed with a standardized diagnostic interview (Composite International Diagnostic Interview (CIDI)). Few indications were found that there was a significant increase in mental disorders in adulthood among people who had lost a parent before the age of 16 (N=541). Parental death was not associated with mental disorders (12 months; lifetime), age of onset, incidence of mental disorders, functional limitations or use of mental health services. The majority of children overcome the loss of a parent during childhood without experiencing increased mental health problems, reduced functional limitations or a greater need for mental health services during adulthood. PMID- 22425473 TI - Theory of mind and emotion processing training for patients with schizophrenia: preliminary findings. AB - Impairments in social cognition are critical predictors of social functioning in patients with schizophrenia. Emotion processing (EP) and theory of mind (ToM) are hypothesized to influence real-world behavior more directly than basic cognition and represent important targets of intervention. The use of video scenes depicting human interactions could constitute an appropriate tool to enhance understanding of the characters' behavior and stimulate inferences on mental states. The aim of our pilot study was to evaluate longitudinally, with a controlled trial, the feasibility and the efficacy of a single-paradigm emotion recognition and ToM training designed for outpatients affected by schizophrenia, with the goal to create an ecological treatment, overcoming artificial laboratory biases, by the use of specific videotaped material. Fifty-two outpatients were randomly assigned to an EP and ToM video-based training (n=27) or to a standard social cognitive rehabilitation treatment (n=24). They were assessed before and after 12 weeks of intervention and compared to a time-matched control group (n=24). Our results show a statistically significant improvement in ToM abilities, confirming the hypothesis of the enhancing potential of social cognitive interventions, but no changes with respect to EP; despite the need for a deeper examination, these data support further development of this treatment approach. PMID- 22425474 TI - Recovery of low plasma BDNF over the course of treatment among patients with bulimia nervosa. AB - Recent studies have suggested that brain-derived neurotrophic factor (BDNF) is associated with energy balance, eating behaviors, and psychological states such as depression. Although decreased BDNF levels in patients with bulimia nervosa (BN) have been reported, the mechanism is still unclear. Few studies have investigated longitudinal changes of BDNF in BN patients. We investigated changes in the levels of plasma BDNF before and after inpatient treatment. Subjects were 16 female patients with BN and 10 control females. The levels of plasma BDNF were measured. In seven patients who completed a 4-week inpatient treatment program based on cognitive behavior therapy, levels of plasma BDNF were measured twice, before and after inpatient treatment. Plasma BDNF levels were significantly lower in BN subjects than in controls. BDNF levels were significantly higher following inpatient treatment. Increased plasma BDNF after inpatient treatment suggests that lower plasma BDNF levels in BN patients are associated with abnormal eating behaviors, especially binge eating. PMID- 22425475 TI - Duration of untreated psychosis: relationship with baseline characteristics and three-year outcome in first-episode psychosis. AB - Duration of untreated psychosis (DUP) has been considered as one of the few potentially malleable prognostic factors in psychotic illness. The literature demonstrated that prolonged DUP predicted the level of positive symptoms, but its relationships with negative symptoms and functional outcome were less clear-cut. Thus far, most first-episode studies have been conducted in western countries. Yet, it is known that illness outcome might be modified by socio-cultural factors. In this study, we aimed to examine the impact of DUP on baseline characteristics, clinical and vocational outcomes over 3 years in 700 Chinese young people who presented with first-episode psychosis to a specialized early intervention service in Hong Kong. Our results showed that prolonged DUP was associated with male sex, younger age of onset, schizophrenia-spectrum diagnosis, insidious development of psychosis, fewer baseline positive symptoms and less likelihood of hospitalization at intake. Regression analyses revealed that prolonged DUP was significantly predictive of outcome on positive symptoms, recovery and sustained full-time employment in our first-episode psychosis cohort. Taken together, our study provided further supportive evidence regarding the prognostic value of DUP on illness outcome. Additionally, it suggested that an adverse impact of treatment delay for psychosis may likely be applied across regions of various ethno-cultural backgrounds. PMID- 22425476 TI - [Metastatic adrenal necrosis under sorafenib treatment for hepatocellular carcinoma]. PMID- 22425477 TI - [Telemedicine: application in the neurological emergencies]. AB - Telemedicine covers different fields going from teleconsultation to tele expertise. Thanks to different national and international studies, telemedicine applied to stroke (telestroke) should be considered as reliable, sure and efficient. Securized specific networks and standardised procedures are required. Telestroke can be used at each stage of stroke and every kind of stroke can benefit this technic. The main limitation is the lack of specific financial retribution. PMID- 22425478 TI - [Current trends in liver biopsy indications in chronic liver diseases]. AB - Liver biopsy (LB) remains a major tool in chronic liver disease evaluation. Main current indications of LB in chronic liver disease are reviewed in this manuscript. Major development of non-invasive tools for evaluation of liver fibrosis led to decrease of LB indications in patients with chronic hepatitis C. LB is the only tool for exploration of necroinflammatory and fibrosis lesions in chronic hepatitis B as well as in autoimmune hepatitis. LB is the sole exam that can differentiate between bland steatosis and steatohepatitis in the setting of metabolic syndrome and to confirm the diagnosis of alcoholic hepatitis when corticosteroids are indicated. PMID- 22425479 TI - Management of intentional overdose of insulin glargine. PMID- 22425480 TI - Letter to the editor: response to Dr. Friedl. PMID- 22425481 TI - Assessment of the quality of resin-dentin bonded interfaces: an AFM nano indentation, MUTBS and confocal ultramorphology study. AB - OBJECTIVE: The aim of this study was to assess by using confocal microscopy (CLSM), AFM nano-indentation and microtensile bond strength test (MUTBS) the quality of the resin-dentin interfaces created with selected bonding parameters. METHODS: Dentin conditioned with H(3)PO(4) or EDTA was bonded in ethanol- or water-wet condition using a HEMA-free or HEMA-containing adhesive. The resin bonded teeth were stored in distilled water (24h) and sectioned as match-sticks (0.9 mm(2)) for MUTBS. Further resin-bonded teeth were sectioned and analyzed using CLSM, and AFM nano-indentation. The AFM imaging and nano-indentation processes were undertaken using a Berkovich diamond indenter. The modulus of elasticity (Ei) and hardness (Hi) across the interface were evaluated with the specimens in a fully hydrated status. The AFM imaging was performed both in dry and wet conditions for evaluating the shrinkage of the hybrid layer on dehydration. RESULTS: The HEMA-containing adhesive applied onto H(3)PO(4)-etched ethanol or water-wet dentin created hybrid layers with the lowest biomechanical nano-properties (p<0.05); no significant differences in MUTBS were found between the two wet-bonding techniques (p>0.05). However, the ethanol-wet bonding reduced the dye penetration into the adhesive layer created with the HEMA-containing adhesive. Hybrid layers with high biomechanical properties, low micropermeability and no shrinkage were only possible when using HEMA-free adhesive applied in ethanol wet-dentin. In particular, a significant increase in Ei and Hi was achieved at the hybrid layer and underneath the resin-dentin interface of ethanol wet EDTA-treated dentin. SIGNIFICANCE: The use of HEMA-free adhesives applied onto ethanol-wet dentin may be considered as an alternative and suitable bonding strategy to achieve high quality resin-dentin interfaces. PMID- 22425482 TI - A large artery exiting the proximal aortic root: anatomic variation or physiologic compensatory response? PMID- 22425483 TI - Primary nasal mucosal melanoma in Brazil: clinicopathologic and immunohistochemical study of 12 patients. AB - Primary nasal melanoma is a rare tumor of unknown etiopathogenesis that occurs in adult and elderly patients usually diagnosed at advanced stages. The aim of this study was to analyze the clinicopathologic and immunohistochemical characteristics of 12 cases of primary nasal melanomas in Brazil. Twelve cases of primary nasal melanoma were analyzed histologically and by immunohistochemistry using the antibodies S-100 protein, HMB-45, Melan-A, CD63 (NKI/C3), CD68/KP1, fatty acid synthase (FASN), and Ki-67. The mean age of the patients was 60 years, and 7 of 12 patients were men. Microscopically, 10 cases presented level III of invasion; 4 were amelanotic; and in 7, cells were epithelioid. S-100 protein and FASN were positive in all cases, whereas 9, 8, 7, and 6 cases were positive for HMB-45, Melan-A, CD63 (NKI/C3), and CD68/KP1, respectively. Ki-67 labeling index ranged from 11.45% to 28.5% of positive cells. S-100 protein is more frequently expressed in nasal melanomas than in HMB-45, Melan-A, CD63 (NKI/C3), and CD68/KP1. FASN seems to be involved in the pathogenesis of nasal melanomas, and also, it can be helpful to confirm the diagnosis. PMID- 22425484 TI - Functional dissociation of brain rhythms in social coordination. AB - OBJECTIVES: The goal of this research was to investigate sub-band modulations in the mu domain in dyads performing different social coordination tasks. METHODS: Dyads of subjects performed rhythmic finger movement under three different task conditions: intrinsic - maintain self-produced movement while ignoring their partner's movement; in-phase - synchronize with partner; and anti-phase - maintain syncopation with partner. Movement profiles of the dyads were used to estimate a synchronization index (SI) to verify differences in coordination according to each task. EEG was recorded during task performance and at baseline (partner's actions hidden from view). Log power ratios of mu band activity (active against baseline) were used to assess the relative levels of synchronization/de-synchronization in both the upper and lower mu bands. RESULTS: Results confirm a functional dissociation of lower (8-10 Hz) and upper (10-12 Hz) mu bands in social coordination tasks. Lower mu band activity was independent of specific modulations across tasks and hemispheric preferences. Upper mu band activity was sensitive to coordination tasks and exhibited marked differences between the hemispheres. Accentuated de-synchronization of right relative to left hemisphere in the anti-phase task appeared related to the greater demand of perceptual-motor discrimination. Left hemisphere de-synchronization in both in phase and anti-phase coordination was interpreted in terms of successful production of imitation. Right hemisphere synchronization in the intrinsic task was interpreted as inhibition of an imitative response tendency. CONCLUSIONS: Functional dissociation of lower and upper mu band and hemispheric preferences exists in real-time social coordination. SIGNIFICANCE: This research attests to the merit of analyzing sub-band activity in the alpha-mu domain in order to identify neural correlates of social coordination. Such 'neuromarkers' may be relevant for brain disorders such as apraxia and autism. PMID- 22425485 TI - Scalp- and sLORETA-derived loudness dependence of auditory evoked potentials (LDAEPs) in unmedicated depressed males and females and healthy controls. AB - OBJECTIVE: As major depressive disorder (MDD) is associated with altered 5-HT activity, we probed intensity-dependent auditory evoked potentials (AEPs) and loudness dependence of the AEP (LDAEP) slopes, shown pre-clinically to be inversely related to 5-HT activity, in MDD. METHODS: AEPs and LDAEP slopes were measured in MDD (N=50; 27 females) and controls (N=43; 23 females). Correlations between scalp AEPs/LDAEPs and low-resolution electromagnetic tomography (sLORETA) derived indices were assessed. RESULTS: Smaller scalp intensity-dependent N1 and N1/P2 amplitudes in MDD versus control males and longer P2 latencies in MDD versus control females were found; no LDAEP group differences existed. Females had greater scalp AEPs, steeper N1 and N1/P2 scalp LDAEPs as well as greater intensity-dependent primary auditory cortex activation during the N1 than males. Scalp LDAEPs correlated weak-moderately with sLORETA counterparts. P2 LDAEP sLORETA correlated negatively with MADRS scores. Female P2 and N1/P2 LDAEP sLORETA correlated negatively with HAMD-17 and MADRS scores. CONCLUSIONS: MDD was not associated with altered LDAEPs. Impaired processing or potentiated inhibition of auditory stimuli was found in MDD males; longer processing existed in MDD females. Inverse relationships between LDAEPs and clinical scores may be related to treatment history, personality and/or MDD features. SIGNIFICANCE: MDD was not associated with an altered LDAEP, though subtle AEPs alterations were noted in MDD. PMID- 22425486 TI - Incidental sequence learning across the lifespan. AB - The purpose of the present study was to investigate incidental sequence learning across the lifespan. We tested 50 children (aged 7-16), 50 young adults (aged 20 30), and 50 older adults (aged >65) with a sequence learning paradigm that involved both a task and a response sequence. After several blocks of practice, all age groups slowed down when the training sequences were removed, providing indirect evidence for sequence learning. This performance slowing was comparable between groups, indicating no age-related differences. However, when explicit sequence knowledge was considered, age effects were found. For both children and older adults with no or only little explicit knowledge, incidental sequence learning was largely reduced and statistically not significant. In contrast, young adults showed sequence learning irrespective of the amount of explicit knowledge. These results indicate that different learning processes are involved in incidental sequence learning depending on age. PMID- 22425487 TI - Temporal analysis of heart rate variability as a predictor of post traumatic stress disorder in road traffic accidents survivors. AB - BACKGROUND: Road Traffic Accidents (RTA) are most probably the leading cause of post traumatic stress disorder (PTSD) in developed countries. The autonomic nervous system (ANS) disturbances, due to psychological trauma, are part of the pathophysiology of PTSD. The aim of the present study was to determine whether early heart rate variability (HRV) measurement, a biomarker of the ANS function, could act as a predictor of PTSD development after a RTA. METHODS: We prospectively investigated 35 survivors of RTA with both physical injury and psychological trauma. HRV data were obtained from 24-h Holter ECG monitoring, which was performed on the second day after the accident. Time domain analysis was applied to the inter-beat (RR) interval time series to calculate the various parameters of HRV. PTSD status was assessed 2 and 6 months after RTA. RESULTS: There was a global diminution of HRV measurements in the PTSD group at both 2 and 6 months. The variability index was the best predictor of PTSD with the area under the receiveroperating curve for discriminating PTSD at 6 months at 0.92 (95% CI: 0.785; 1.046). A cut-off at 2.19% yielded a sensitivity of 85.7% and a specificity of 81.8% for PTSD. Positive and negative predictive values were respectively 75% and 90%. However, initial heart rate (HR) data were relevant at 2 months but not at 6 months. CONCLUSION: RTA survivors exhibiting lower parasympathetic modulation of HR, indexed by temporal analysis of HRV, are more susceptible to developing PTSD as a short and long-term outcome. PMID- 22425488 TI - Two opposing roles of O-glycans in tumor metastasis. AB - Despite the high prevalence of metastatic cancers and the poor outcome for patients, the processes of tumor metastasis still remain poorly understood. It has been shown that cell-surface carbohydrates attached to proteins through the amino acids serine or threonine (O-glycans) are involved in tumor metastasis, with the roles of O-glycans varying depending on their structure. Core2 O-glycans allow tumor cells to evade natural killer (NK) cells of the immune system and survive longer in the circulatory system, thereby promoting tumor metastasis. Core3 O-glycans or O-mannosyl glycans suppress tumor formation and metastasis by modulating integrin-mediated signaling. Here, we highlight recent advances in our understanding of the detailed molecular mechanisms by which O-glycans promote or suppress tumor metastasis. PMID- 22425489 TI - Identification of type VI secretion systems in Moritella viscosa. AB - The study describes the identification of type VI secretion systems (T6SSs) in Moritella viscosa, the aetiological agent of winter ulcer disease. Despite the availability of commercial vaccines, M. viscosa causes significant financial losses in salmonid farming. The T6SS transports bacterial proteins from the cell into the environment or directly into host cells, and has been implicated with bacterial virulence. The aim of the study was to identify potential T6SSs in M. viscosa and to determine whether it possesses active T6S, providing further insight into the biology of the bacterium. The genome of M. viscosa 06/09/139 was screened for homology with known T6SS encoding genes. Two genetically distinct loci, termed Moritella Type Six Secretion 1 and 2 (mts1 and mts2), were identified as encoding putative T6SSs. Each locus contained known T6S core genes. The mts2 locus contained species specific genes, some of which have not previously been connected with T6S. The mts1 locus showed sequence homology and synteny to T6SSs of the fish pathogen Aliivibrio salmonicida and a non-pathogenic Moritella sp. PE36. The mts2 locus was more similar to a Vibrio parahaemolyticus T6SS. A functional T6SS was confirmed through identification of secreted Mts1-M, a hemolysin coregulated protein (Hcp) which is a part of the secretion system. Both virulent and avirulent M. viscosa isolates expressed two genes encoding Hcp, mts1-M and mts2-M. The results show that M. viscosa has a functional T6S, but the role of the secretion system and possible connections with virulence need further examination. PMID- 22425490 TI - Prevalence, mean intensity and site preference of Caligus rotundigenitalis Yu, 1933 (Copepoda: Caligidae) on cage cultured crimson snapper (Lutjanus erythropterus Bloch, 1790) from Bukit Tambun, Penang, Malaysia. AB - Snapper had been cultured in Malaysia since 1980 due to the fry availability and the high demand. However, details on the caligids infestation were not properly documented. This study was carried out to determine the prevalence, mean intensity and site preference of Caligus rotundigenitalis (Caligidae, Siphonostomatoida) a parasitic copepod on cage cultured crimson snapper, Lutjanus erythropterus from Bukit Tambun, Penang, Malaysia. A total of 70 specimens of cultured snapper were examined based on different infestation sites such as head, body as well as operculum. The specimens were separated into three groups according to the size of the fish. C. rotundigenitalis was found to be the only species infesting L. erythropterus with the prevalence and the mean intensity of 81.4% and 5.6+/-4.4, respectively. There was a significant difference between the prevalence of site infestation of the body and inner operculum sites. The prevalence of C. rotundigenitalis was highest on inner operculum of the fish followed by the body and head. However, there was no significant difference in the distribution of C. rotundigenitalis over the different infestation sites derived from the three groups. The information obtained from this study can be used for more effective control measures of ectoparasitic copepod infestation in floating cages. PMID- 22425491 TI - Transition to adulthood for young men with Duchenne muscular dystrophy: research from the UK. PMID- 22425492 TI - Robustness of two MALDI-TOF mass spectrometry systems for bacterial identification. AB - MALDI-TOF-MS systems (Microflex-Bruker Daltonics/BioTyperTM and Axima-Assurance Shimadzu/SARAMIS-AnagnosTec) were assessed for bacterial identification. Focusing on bacteria difficult to identify routinely, 296 strains were identified by molecular biology techniques as gold standard. MALDI-TOF-MS identification provided correct results at genus and species level for 94.9%, 83.4% and 83.8%, 65.9% with Biotyper and Saramis respectively. PMID- 22425493 TI - Emphysematous prostatic abscess: case series study and review. AB - OBJECTIVES: To report three cases of emphysematous prostatic abscess (EPA) and review the literature on this rare entity. METHODS: All relevant articles published in English over the last 50 years (1961-2011) were identified using a MEDLINE search for keywords 'emphysematous prostatitis' and 'emphysematous prostatic abscess'. A total of 12 patients were evaluated for their age, race, underlying disease, pathogens, diagnosis tool, treatment options, and clinical outcome. RESULTS: EPA is a high mortality disease (25%) and has an association with diabetes mellitus. The most common pathogen in the 12 cases was Klebsiella pneumoniae. CONCLUSIONS: The mortality of EPA is higher than that of emphysematous cystitis and emphysematous pyelonephritis. Timely recognition and prompt drainage are very important. PMID- 22425494 TI - Adjunctive surgery improves treatment outcomes among patients with multidrug resistant and extensively drug-resistant tuberculosis. AB - OBJECTIVES: To determine risk factors for poor outcomes among patients with pulmonary multidrug- or extensively drug-resistant (M/XDR) tuberculosis (TB) in Georgia. METHODS: This was a prospective, population-based observational cohort study. RESULTS: Among 380M/XDR-TB patients (mean age 38 years), 179 (47%) had a poor outcome: 59 (16%) died, 37 (10%) failed, and 83 (22%) defaulted. Newly diagnosed M/XDR-TB cases were significantly more likely to have a favorable outcome than retreatment cases (odds ratio (OR) 4.26, 95% confidence interval (CI) 1.99-9.10, p<0.001). In the multivariable analysis, independent risk factors for a poor treatment outcome included previous treatment history (OR 2.92, 95% CI 1.29-6.58), bilateral disease (OR 1.90, 95% CI 1.20-3.01), body mass index (BMI, kg/m(2)) <=18.5 (OR 1.91, 95% CI 1.11-3.29), and XDR-TB (OR 2.28, 95% CI 1.11 4.71). Patients who underwent surgical resection (OR 0.27, 95% CI 0.11-0.64) and had sputum culture conversion by 4 months (OR 0.33, 95% CI 0.21-0.52) were significantly less likely to have poor treatment outcomes. CONCLUSIONS: Adjunctive surgery appeared to be beneficial in treating patients with M/XDR-TB. Retreatment cases, XDR-TB, bilateral disease, and low BMI were associated with a poor outcome. Additional studies are needed to further define the apparent beneficial role of surgery in the treatment of M/XDR-TB. PMID- 22425495 TI - Prospective evaluation of hepatic steatosis in HIV-infected patients with or without hepatitis C virus co-infection. AB - BACKGROUND: Limited data are available on hepatic steatosis (HS) in HIV patients who are not infected with hepatitis C virus (HCV). The aims of this study were to assess the prevalence of HS and its risk factors in HIV patients with and without HCV infection, and to evaluate whether HS correlates with advanced liver fibrosis and/or cardiovascular disease risk. METHODS: Fifty-seven HIV mono-infected and 61 HIV/HCV co-infected patients were enrolled consecutively. All patients underwent liver ultrasound and transient elastography. The main parameters of liver function, HIV and HCV viral loads, CD4+ cell counts, and data on highly active antiretroviral therapy (HAART) were recorded. Cardiovascular disease risk was evaluated using the 10-year Framingham risk score. RESULTS: HS prevalence in the whole HIV population was 53% (54% in mono-infected patients and 51% in co infected patients). HS was associated with lipodystrophy and triglyceride values (p<0.0001), metabolic syndrome (p<0.0004), and total cholesterol levels (p<0.001) in both HIV groups. In HIV mono-infected patients, HS was linked with HAART exposure of >1 year (p<0.01). By multivariate analysis, only triglyceride levels (p<0.02) and Framingham risk score (p<0.05) were independently associated with HS in both HIV groups. No correlation was observed between HS and advanced liver fibrosis, measured by transient elastography. CONCLUSIONS: HS was common in HIV patients, occurring in about half of the population. HS was found to be linked with the Framingham risk score, but was not correlated with advanced liver fibrosis. We suggest that in our HIV population with HS, the burden of cardiovascular disease risk is greater than that of liver disease progression. PMID- 22425496 TI - Polymorphisms at MHC class II DRB1 exon 2 locus in Pyrenean chamois (Rupicapra pyrenaica pyrenaica). AB - Chamois (Rupicapra spp.) are mountain ungulates from Southern and Central Europe and the Near East. A newly reported border disease virus (BDV) has affected the easternmost populations of Pyrenean chamois, leading to a dramatic population decrease that may drive to genetic variability loss. The Major Histocompatibility Complex (MHC) is a sensitive marker for genetic variation of populations: polymorphism on the MHC genes is affected both by pathogens and population dynamics and it is ecologically relevant, as depending on host-pathogen relationships and life history features. In the present study MHC class II DRB1 exon 2 variation was investigated in 81 Pyrenean chamois (Rupicapra pyrenaica pyrenaica) belonging to four populations. Haplotype analysis, population genetics statistics and network analysis were carried out, in order to analyze variability, phylogeography and genealogy, and the effects of geography and demographic trend. Twenty-nine haplotypes were identified, 26 of them newly described, with high Gene diversity (Gd). The variability observed in the easternmost populations of Pyrenean chamois showed a higher genetic diversity than that previously reported for other populations of Pyrenean and Cantabrian chamois (Rupicapra pyrenaica parva). The most frequent allele was RupyDRB*15, previously undetected, which seems to play a significant role in genotyping the variability, suggesting a possible effect of positive selection. PMID- 22425497 TI - Congenital infiltrating lipomatosis of the face with associated involvement of the TMJ structures. Case report and review of the literature. AB - We report a case of congenital infiltrating lipomatosis of the face (CILF) with right TMJ ankylosis causing asymmetry and reduced mouth opening. The management involved soft tissue debulking combined with a right TMJ arthroplasty and is explained in detail. A review of the relevant literature revealed the rarity of this condition. The diagnosis of CILF remains challenging. The currently accepted treatment strategy is less aggressive as facial asymmetry tends to recur. Infiltration of the facial structures from adipose tissue requires several surgical procedures in most cases. Bony hypertrophy on the affected side has been a common finding in reported cases. There have been no previous reports of TMJ ankylosis associated with this condition. CILF is a benign condition with a good long term prognosis. After 2 years of follow up our patient, has maintained full function despite facial asymmetry. PMID- 22425498 TI - Analysis of the cytokine profiles of the synovial fluid in a normal temporomandibular joint: preliminary study. AB - The purpose of this study was to compare the cytokine profiles of the synovial fluid from the temporomandibular joint (TMJ) spaces of normal individuals and temporomandibular disorder (TMD) patients. Thirty-four patients with planned orthognathic surgery did not present abnormalities of the TMJ on magnetic resonance images and radiographs and did not show the symptoms identified by the Research Diagnostic Criteria for TMD (RDC-TMD); as a result, they were assigned to the control group. Twenty-two patients who sought treatment for TMD during the same period were assigned to the TMD group. Synovial fluid was collected from superior TMJ spaces, and cytokine expression was analysed by an enzyme-linked immunosorbent assay (ELISA). Significant differences were tested using Fisher's exact test (p<0.05). Granulocyte Macrophage Colony stimulating Factor (GM-CSF), interferon (INF), interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL-10 and tumour necrosis factor (TNF)-alpha were detected in the TMD group, whereas no cytokines were detected in the control group. The most prevalent cytokines in the TMD group were IL-1beta, IL-6 and GM-CSF. IL-4 and IL-5 were not detected in either the TMD group or in the control group. None of the cytokines that were detected in patients with TMD were found in the articular spaces of normal individuals. PMID- 22425499 TI - Assessing quality of life in patients with head and neck cancer in Spain by means of EORTC QLQ-C30 and QLQ-H&N35. AB - OBJECTIVES: The aim of this project was to evaluate the quality of life in patients undergoing treatment for head and neck cancer in the Murcia region (Spain). MATERIALS AND METHODS: The Quality of Life (QoL) of patients suffering head and neck cancer was assessed using Spanish translations of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Head and Neck Cancer Module (QLQ-H&N35). The questionnaires' scales and single items were compared according to age, sex, tumour location, stage of cancer and treatment type. RESULTS: Of the 109 patients who met the study's inclusion criteria, 94 completed the questionnaire. Quality of life was found to be associated with patient age (with patients <65 years obtaining higher scores) and also with tumour location. With regard to the stage of cancer, early stages obtained better scores than advanced ones. Patients who underwent surgical treatment combined with adjuvant radiotherapy and chemotherapy generally showed lower scores. CONCLUSIONS: The routine use of quality of life questionnaires among cancer patients enables health practitioners to discover in which areas and to what extent patients find their lives affected by the treatment they receive and its consequences. This allows health practitioners to provide information and treatments which are better adapted to patient needs. These results are similar to those obtained in populations from the north and centre of Europe. PMID- 22425500 TI - Mucormycosis of the head and neck. AB - INTRODUCTION: Mucormycosis of the head and neck is a rare disease increasingly occurring in immunocompromised patients. We report on two cases with different outcomes. CASE REPORTS: A 63-year-old female presented with a recently developed deformation of her right cheek and nose combined with a loosening of the teeth. Further examination revealed mucormycosis of the maxilla. Hemimaxillectomy and secondary bony reconstruction with oral rehabilitation were performed. The second patient was a 54-year-old male who suffered from multiple myeloma. After receiving an allogeneic haematopoietic stem cell transplant, he developed a necrotizing infection of the right midface. Histopathological investigation confirmed the diagnosis of mucormycosis. The patient died one day after radical surgical resection. DISCUSSION: These two cases demonstrate the variability of mucormycosis. Although slow progression of the disease is possible, a high level of attentiveness and expedient treatment are necessary due to the high risk of a devastating course. PMID- 22425501 TI - Osteo-odonto-keratoprosthesis - a maxillofacial perspective. AB - The OOKP (osteo-odonto-keratoprosthesis) is the treatment of choice for conditions like Stevens-Johnson syndrome, ocular cicatricial pemphigoid, trachoma, multiple failed grafts and chemical burns which are not amenable to penetrating keratoplasty. The OOKP is an autograft which replaces the cornea with a polymethacrylate cylinder mounted on a tooth-bone complex. The aim of this paper was to retrospectively analyze the records in 26 patients undergoing OOKP surgery between 2007 and 2011. The paper describes our experience with the procedure, with emphasis on its oral and maxillofacial aspects and management of associated complications. The aetiology of blindness in 23 patients was Stevens Johnson's syndrome and chemical burns in three. Twenty-two patients had their maxillary canines, two had mandibular canines and two had maxillary first premolars as the choice of donor tooth. An oroantral fistula developed in four patients. One patient needed to undergo a surgical procedure for closure of the same. Roots of adjacent teeth were exposed in 12 patients. Twenty-four patients underwent both stages of the procedure with 19 being visually rehabilitated successfully. There was no improvement in the vision of four patients. One patient was lost to follow-up. Two patients have yet to undergo Stage 2. PMID- 22425502 TI - [Surgical lung biopsy: Indications and therapeutic implications]. AB - Surgical biopsy of lung parenchyma can be used to establish a diagnosis in interstitial lung disease both of acute and chronic presentation. The present article summarizes the current indications, the therapeutic implications, the different surgical techniques and postoperative complications of the procedure. Common controversies and problems related to surgical lung biopsy are also presented. PMID- 22425503 TI - [Lung surgery for non-tumoral disease]. PMID- 22425504 TI - [Primitive thoracic lymphatic disease in adults]. AB - Primary thoracic lymphatic diseases are both infrequent and probably under diagnosed. Current classification distinguishes lymphangioma (solitary tumor), lymphangiectasies (dilatation), lymphangiomatosis (proliferation) and lymphatic dysplasia syndrome (dysplasia). Classifications' efforts and radiologic progress may lead to an improvement in the management of these patients. PMID- 22425505 TI - [Place of surgery in pulmonary aspergillosis and other pulmonary mycotic infections]. AB - Surgery is part of the therapeutic strategy of aspergillosis and mucormycosis. The aspergilloma is defined as a rounded mass, developing in a cavity by the proliferation of spores of Aspergillus. The most common complication was haemoptysis reported in 50-95% of cases. The pleuropulmonary lesions predisposing are: tuberculosis, residual pleural space, emphysema and lung destroyed by fibrosis or radiotherapy or bronchiectasis. The indications for surgery depend on symptoms, respiratory function, the parenchyma and the type of aspergilloma (simple or complex). In a patient with an intrapulmonary aspergilloma, lung resection preceded by embolization is recommended based on respiratory function. For intrapleural aspergilloma, thoracoplasty is recommended according to the patient's general condition. The invasive pulmonary aspergillosis (IPA) is characterized by an invasion of lung tissue and blood vessels by hyphae in immunocompromised patients. The death rate of patients who have an API after treatment for leukemia or lymphoma was 30 to 40%, after bone marrow transplantation 60%, after solid organ transplantation from 50 to 60% and after any other cause of immunocompromising from 70 to 85%. The main cause of these deaths is massive hemoptysis. Surgery (lobectomy) is indicated for the prevention of hemoptysis when the mass is in contact with the pulmonary artery or one of its branches, and if it increases in size with the disappearance of border security between the mass and the vessel wall. The patient will be operated in an emergency before the white blood cells do not exceed the threshold of 1000 cells/MUl. A persistent residual mass after antifungal treatment may justify a lung resection (lobectomy or wedge) before a new aggressive therapy. Mucormycosis affects patients following immunocompromising states--haematologic malignancy, diabetes mellitus, transplantation, burns and malnutrition. The treatment of pulmonary mucormycosis combines surgical and medical approach. PMID- 22425506 TI - Black Sea biogeochemistry: response to decadal atmospheric variability during 1960-2000 inferred from numerical modeling. AB - The long-term variability of the physical and biochemical structure of oxic and suboxic layers in the Black Sea was studied using a one-dimensional coupled hydrophysical and biogeochemical model. The focus was on the correlation between atmospheric forcing (2 m air temperature and dew point temperature, surface level pressure, surface wind) affected by the North Atlantic Oscillation in and the regional responses. The quality of model performance was demonstrated using observed vertical and temporal distribution of biogeochemical variables. It was shown that during 1960-2000, the long-term variability of simulated winter-mean SST in the Black Sea correlated reasonably well with the variability of 2 m air temperature. Furthermore, the thermal state of the upper ocean impacted largely on the variability of biogeochemical variables, such as oxygen, nitrate and phytoplankton concentration. The tele-connection between North Atlantic Oscillation and Black Sea biogeochemistry was manifested in a different way for the specific time-interval 1960-2000; the corresponding regime shifts were thus associated with the large scale forcing. One such extreme event occurred in 1976 leading to a pronounced shift in the oxygen and hydrogen sulfide state. PMID- 22425507 TI - Heel ultrasound can assess maintenance of bone mass in women with breast cancer. AB - Postmenopausal women with early stage breast cancer are at increased risk for bone loss and fractures. Bisphosphonates can prevent bone loss, but little data are available on changes in bone mass assessed by heel quantitative ultrasound (QUS). Our objectives were to determine if (1) heel QUS would provide a reliable and accessible method for evaluation of changes in bone mass in women with breast cancer when compared with the current standard of bone mass measurement, dual energy X-ray absorptiometry (DXA) and (2) oral risedronate could affect these changes. Eighty-six newly postmenopausal (up to 8 yr) women with nonmetastatic breast cancer were randomized to risedronate, 35 mg once weekly or placebo. Outcomes were changes in heel QUS bone mass measurements and conventional DXA derived bone mineral density (BMD). Over 2 yr, bone mass assessed by heel QUS remained stable in women on risedronate, whereas women on placebo had a 5.2% decrease (p <= 0.05) in heel QUS bone mass. Both total hip BMD and femoral neck BMD assessed by DXA decreased by 1.6% (p <= 0.05) in the placebo group and remained stable with risedronate. Spine BMD remained stable in both groups. Heel QUS was moderately associated with BMD measured by DXA at the total hip (r=0.50), femoral neck (r=0.40), and spine (r=0.46) at baseline (all p <= 0.001). In conclusion, risedronate helps to maintain skeletal integrity as assessed by heel QUS for women with early stage breast cancer. Heel QUS is associated with DXA derived BMD at other major axial sites and may be used to follow skeletal health and bone mass changes in these women. PMID- 22425508 TI - Dual-energy X-ray absorptiometry interpretation: a simple equation for height correction in preteenage children. AB - Dual-energy X-ray absorptiometry (DXA) results, even when corrected for age, gender, and ethnicity, can lead clinicians to erroneously diagnose osteoporosis in short healthy children and underdiagnose osteoporosis in tall children. We derived 2 simple equations for preteenagers =4) than either in the attention deficit/hyperactivity disorder group (1/20; P < .0001) or in the mental retardation group (5/20; P < .025). CONCLUSION: There seems to be a strong association between poor handshaking skills and autistic psychopathology, as compared with the 2 control groups. As was demonstrated by the brief and easy-to administer HAS assessment tool, it may be advisable to use handshaking more widely as a diagnostic procedure for ASD or include it in larger diagnostic batteries. Large-scale studies are needed to substantiate our observation. PMID- 22425525 TI - Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon. AB - Chlorpyrifos (CPF), one of the most widely-used organophosphorus (OP) insecticides in agriculture, is degraded in the field to its oxon form, chlorpyrifos-oxon (CPO), which can represent a significant contaminant in exposures to adults and children. CPO is also responsible for the acetylcholinesterase (AChE) inhibition associated with CPF exposures; CPF is converted by liver CYP450 enzymes to CPO, which binds to and inhibits AChE and other serine active-site esterases, lipases and proteases. Young children represent a particularly susceptible population for exposure to CPF and CPO, in part because levels of the plasma enzyme, paraoxonase (PON1), which hydrolyzes CPO, are very low during early development. While a number of studies have demonstrated developmental neurotoxicity associated with CPF exposure, including effects at or below the threshold levels for AChE inhibition, it is unclear whether these effects were due directly to CPF or to its active metabolite, CPO. PON1 knockout (PON1-/-) mice, which lack PON1, represent a highly sensitive mouse model for toxicity associated with exposure to CPF or CPO. To examine the neurobehavioral consequences of CPO exposure during postnatal development, PON1-/ mice were exposed daily from PND 4 to PND 21 to CPO at 0.15, 0.18, or 0.25 mg/kg/d. A neurobehavioral test battery did not reveal significant effects of CPO on early reflex development, motor coordination, pre-pulse inhibition of startle, startle amplitude, open field behavior, or learning and memory in the contextual fear conditioning, Morris water maze, or water radial-arm maze tests. However, body weight gain and startle latency were significantly affected by exposure to 0.25 mg/kg/d CPO. Additionally, from PNDs 15-20 the mice exposed repeatedly to CPO at all three doses exhibited a dose-related transient hyperkinesis in the 20 min period following CPO administration, suggesting possible effects on catecholaminergic neurotransmission. Our previous study demonstrated wide-ranging effects of neonatal CPO exposure on gene expression in the brain and on brain AChE inhibition, and modulation of both of these effects by the PON1(Q192R) polymorphism. The current study indicates that the neurobehavioral consequences of these effects are more elusive, and suggests that alternative neurobehavioral tests might be warranted, such as tests of social interactions, age-dependent effects on learning and memory, or tests designed specifically to assess dopaminergic or noradrenergic function. PMID- 22425527 TI - Association analysis of ZNF804A (zinc finger protein 804A) rs1344706 with therapeutic response to atypical antipsychotics in first-episode Chinese patients with schizophrenia. AB - 'The single-nucleotide polymorphism rs1344706 located in the ZNF804A zinc finger protein 804A gene is a well-established genome-wide significant variant for schizophrenia. The aim of this study was to investigate the potential association between this ZNF804A polymorphism and treatment response to atypical antipsychotic. Seventy-one first-episode inpatients with schizophrenia receiving olanzapine, aripiprazole, or quetiapine monotherapy were enrolled. Symptom response to treatment was assessed using the Positive and Negative Syndrome Scale (PANSS) on admission and reassessed after 4 weeks of treatment. Single-nucleotide polymorphism rs1344706 was genotyped by direct sequencing. There was substantial difference in treatment response among patients with 3 different genotypes regarding total PANSS score and positive subscore (for total PANSS score, F = 4.608, df = 2, P = .013; for positive subscore, F = 4.183, df = 2, P = .019). Compared with G homozygotes, T carriers showed significantly less improvement in total PANSS score as well as positive subscore (for total PANSS score, F = 8.724, df = 1, P = .004; for positive subscore, F = 9.392, df = 1, P = .005). Our results suggest that ZNF80A rs1344706 polymorphism may play a role in treatment response to atypical antipsychotic, although replication is required to confirm this finding. PMID- 22425528 TI - Investigating the development of temperament and character in school-aged children using a self-report measure. AB - BACKGROUND: Developmental studies of temperament and character dimensions are crucial for a better understanding of how genetic and environmental factors interact in shaping individual personality. However, although several studies have been conducted in adults, a few studies have addressed the evaluation of temperament and character in children. Here, we tested the suitability of self report evaluation and the developmental trend of temperament and character dimensions among school-aged children using an Italian version of the junior Temperament and Character Inventory (jTCI). METHODS: The jTCI was completed by 572 Italian children (292 girls and 280 boys) aged 8 to 12 years. We evaluated the internal consistency of the 7 jTCI scales at each age, the intercorrelations between the scales, and the factorial model of the questionnaires. Furthermore, we tested the differences between the development of the temperament and character dimensions in girls and boys. RESULTS: Although the data from 8-year children showed unacceptably low internal consistency, better reliability was observed for older children. Intercorrelations and factor analysis partially confirmed the hypothesized structure of the jTCI items, with problems observed for some items of the Novelty Seeking, Harm Avoidance, Reward Dependence (RD), and Self-Directedness scales. Furthermore, in keeping with previous studies, girls presented lower scores in Novelty Seeking and higher RD, Self-Directedness, and Cooperativeness scales than did boys, with the between-sex difference in RD becoming larger at older ages. CONCLUSIONS: Although the use of the self administered jTCI in clinical settings should be cautious, it may serve as a useful complementary instrument to describe the development of personality in childhood. PMID- 22425529 TI - Panic disorder and subthreshold panic in the light of comorbidity: a follow-up study. AB - Especially in the presence of agoraphobia and comorbid conditions, panic disorder causes significant impairment in life quality. Although there are several studies about epidemiology and clinical features, subthreshold symptoms and courses of comorbidity have not been studied sufficiently in panic disorder. The current study assessed the courses of panic disorder and subthreshold panic symptoms in consideration of the major and subthreshold comorbid conditions. Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed panic disorder were assessed using the panic disorder follow-up questionnaire, Panic and Agoraphobia Scale, Hamilton Depression Rating Scale, and State-Trait Anxiety Inventory. Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders was used to determine comorbidity, and all participants were received to 1-year follow-up. Comorbidity assessment showed that the threshold comorbidity decreased, while the subthreshold comorbidity increased at 1-year follow-up. Panic disorder symptom severity was decreased, but subthreshold panic symptoms continued to be present within the course of the illness. Presence of agoraphobia and duration of disease were significantly related with higher Panic and Agoraphobia Scale scores in the second assessment, and these relationships were independent from the treatment process. Even if the comorbidity and the severity of panic decrease with treatment, subthreshold panic and comorbid symptoms may still resist in panic disorder. PMID- 22425530 TI - The effect of dietary and physical activity pattern on metabolic profile in individuals with schizophrenia: a cross-sectional study. AB - OBJECTIVE: With the rate of obesity on the rise worldwide, individuals with schizophrenia represent a particularly vulnerable population. The aim of this study was to assess the metabolic profile of individuals with schizophrenia in relation to dietary and physical activity habits compared with healthy controls. METHODS: Dietary and physical activity habits of 130 individuals with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder were compared with 250 body mass index , age-, and sex-matched and racially matched controls from the 2005-2008 National Health and Nutrition Examination Surveys using a 24-hour diet recall and a self report physical activity questionnaire. RESULTS: Individuals with schizophrenia had significantly higher levels of glycosylated hemoglobin and insulin compared with matched controls. In addition, these individuals had an increased waist circumference and diastolic blood pressure than did the comparison group. Daily energy intake was not different between groups; however, individuals with schizophrenia consumed significantly greater amounts of sugar and fat. Individuals with schizophrenia reported engaging in moderate physical activity less frequently compared with the National Health and Nutrition Examination Surveys group, but there was no difference in reported vigorous physical activity. CONCLUSIONS: These findings suggest that the dietary and physical activity habits of individuals with schizophrenia contribute to an adverse metabolic profile. Increased opportunities for physical activity and access to healthy foods for individuals with schizophrenia may ease the burden of disease. PMID- 22425531 TI - Dissociative symptoms and dissociative disorder comorbidity in patients with obsessive-compulsive disorder. AB - The present study attempted to assess the dissociative symptoms and overall dissociative disorder comorbidity in patients with obsessive-compulsive disorder (OCD). In addition, we examined the relationship between the severity of obsessive-compulsive symptoms and dissociative symptoms. All patients admitted for the first time to the psychiatric outpatient unit were included in the study. Seventy-eight patients had been diagnosed as having OCD during the 2-year study period. Patients had to meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for OCD. Most (76.9%; n = 60) of the patients were female, and 23.1% (n = 18) of the patients were male. Dissociation Questionnaire was used to measure dissociative symptoms. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Dissociative Disorders interviews and Yale-Brown Obsessive Compulsive Checklist and Severity Scale were used. Eleven (14%) of the patients with OCD had comorbid dissociative disorder. The most prevalent disorder in our study was dissociative depersonalization disorder. Dissociative amnesia and dissociative identity disorder were common as well. The mean Yale-Brown score was 23.37 +/- 7.27 points. Dissociation Questionnaire scores were between 0.40 and 3.87 points, and the mean was 2.23 +/- 0.76 points. There was a statistically significant positive correlation between Yale-Brown points and Dissociation Questionnaire points. We conclude that dissociative symptoms among patients with OCD should alert clinicians for the presence of a chronic and complex dissociative disorder. Clinicians may overlook an underlying dissociative process in patients who have severe symptoms of OCD. However, a lack of adequate response to cognitive behavioral and drug therapy may be a consequence of dissociative process. PMID- 22425532 TI - Dmrt genes in the development and evolution of sexual dimorphism. AB - Most animals are sexually dimorphic, but different taxa have different sex specific traits. Despite major differences in the genetic control of sexual development among animal lineages, the doublesex/mab-3 related (Dmrt) family of transcription factors has been shown to be involved in sex-specific differentiation in all animals that have been studied. In recent years the functions of Dmrt genes have been characterized in many animal groups, opening the way to a broad comparative perspective. This review focuses on the similarities and differences in the functions of Dmrt genes across the animal kingdom. I highlight a number of common themes in the sexual development of different taxa, discuss how Dmrt genes have acquired new roles during animal evolution, and show how they have contributed to the origin of novel sex-specific traits. PMID- 22425533 TI - Characterization of dual effects induced by antimicrobial peptides: regulated cell death or membrane disruption. AB - BACKGROUND: Some reports describe lysis mechanisms by antimicrobial peptides (AMPs), while others describe the activation of regulated cell death. In this study, we compare the cell death-inducing activities of four beta-hairpin AMPs (gomesin, protegrin, tachyplesin and polyphemusin II) along with their linear analogs in the human erythroleukemia K562 cell line to investigate the relationship between their structure and activity. METHODS: K562 cells were exposed to AMPs. Morphological and biochemistry alterations were evaluated using light microscopy, confocal microscopy and flow cytometry. RESULTS: Gomesin and protegrin displayed cytotoxic properties that their linear counterparts did not. Tachyplesin and polyphemusin II and also their linear analogs induced cell death. We were able to distinguish two ways in which these AMPs induced cell death. Lower concentrations of AMPs induced controlled cell death mechanisms. Gomesin, tachyplesin and linear-tachyplesin promoted apoptosis that was characterized by annexin labeling, sensitivity to Z-VAD, and caspase-3 activation, but was also inhibited by necrostatin-1. Gomesin and protegrin induced cell death was dependent on intracellular Ca2+ mechanisms and the participation of free radicals was observed in protegrin induced cell death. Polyphemusin II and its linear analog mainly induced necrosis. Conversely, treatment with higher concentrations of AMPs primarily resulted in cell membrane disruption, but with clearly different patterns of action for each AMP tested. CONCLUSION: Different actions by beta-hairpin AMPs were observed at low concentrations and at higher concentrations despite the structure similarity. GENERAL SIGNIFICANCE: Controlled intracellular mechanism and direct membrane disruption were clearly distinguished helping to understand the real action of AMPs in mammalian cells. PMID- 22425534 TI - 1st International consensus guidelines for advanced breast cancer (ABC 1). AB - The 1st international Consensus Conference for Advanced Breast Cancer (ABC 1) took place on November 2011, in Lisbon. Consensus guidelines for the management of this disease were developed. This manuscript summarizes these international consensus guidelines. PMID- 22425535 TI - A comparison of surgical and radiotherapy breast cancer therapy utilization in Canada (British Columbia), Scotland (Dundee), and Australia (Western Australia) with models of "optimal" therapy. AB - BACKGROUND: Different jurisdictions report different breast cancer treatment rates. Evidence-based utilization models may be specific to derived populations. We compared predicted optimal with actual radiotherapy utilization in British Columbia, Canada; Dundee, Scotland; and Perth, Western Australia. DESIGN: Data were analyzed for differences in demography, tumor, and treatment. Epidemiological data were fitted to published Australian optimal radiotherapy utilization trees and region-specific optimal treatment rates were calculated. Optimal and actual surgery/radiotherapy rates from 2 population-based and 1 institution-based registries were compared for patients diagnosed with breast cancer between 2000 and 2004, and 2002 for British Columbia. RESULTS: Mastectomy rates differed between British Columbia (40%), Western Australia (44%), and Dundee (47%, p<0.01). Radiotherapy rates differed between British Columbia (60%), Western Australia (52%), and Dundee (49%, p<0.01). Actual radiotherapy utilization rates were lower than optimal estimates. Region-specific optimal utilization rates at diagnosis varied from 57% to 71% for radiotherapy and 62% to 64% when taking into account patient preference. Variation was attributed to local differences in demography and tumor stage. CONCLUSIONS: Actual treatment rates varied, and were associated with patterns of care and guideline differences. Actual radiotherapy rates were lower than optimal rates. Differences between optimal and actual utilization may be due to access shortfalls, and patient preference. PMID- 22425536 TI - Murine collagen antibody induced arthritis (CAIA) and primary mouse hepatocyte culture as models to study cytochrome P450 suppression. AB - Changes in cytochrome P450 expression incurred by inflammatory disease were studied in a murine collagen antibody induced arthritis (CAIA) model and compared to bacterial lipopolysaccharide-treated mice and to cytochrome P450 changes in primary mouse hepatocytes following combination treatments with cytokines IL 1beta, IL-6, or TNFalpha. CAIA in female mice increased serum IL-1beta, IL-6 and hepatic serum amyloid A (SAA) mRNA and significantly altered cytochrome P450 mRNA and activity levels. Most cytochrome P450 isoforms were down-regulated, although some, such as Cyp3a13, were up-regulated. Cytokine effects on cytochrome P450 levels in mouse hepatocytes were compared at in vitro cytokine concentrations similar to those measured in CAIA mouse serum in vivo. In vivo and in vitro cytochrome P450 suppression by cytokines was congruent for some cytochrome P450 isoforms (Cyp1a2, Cyp2c29, and Cyp3a11) but not for others (cytochrome P450 oxidoreductase (POR) and Cyp2e1). In mouse hepatocytes, IL-6 and IL-1beta in combination in vitro caused a synergistic increase in SAA mRNA expression, but not in cytochrome P450 suppression. IL-1beta and IL-6 were equipotent in the suppression of cytochrome P450 gene expression, while TNFalpha caused mild suppression only at the highest concentrations used. TNFalpha in combination with IL-1beta, IL-6, or both had a protective effect against IL-1beta and IL-6 mediated cytochrome P450 suppression. When IL-1beta or IL-6 was combined with low concentrations of TNFalpha, several P450 isoforms were induced rather than suppressed. These data highlight the complexities of performing in vitro-in vivo comparisons using disease models for cytochrome P450 regulation by cytokines. PMID- 22425537 TI - Integrating unseen events over time. AB - Events often share elements that guide us to integrate knowledge from these events. Integration allows us to make inferences that affect reactions to new events. Integrating events and making inferences are thought to depend on consciousness. We show that even unconsciously experienced events, that share elements, are integrated and influence reactions to new events. An unconscious event consisted of the subliminal presentation of two unrelated words. Half of subliminal word pairs shared one word ('winter red', 'red computer'). Overlapping word pairs were presented between 6s and 78 s apart. The test for integration required participants to judge the semantic distance between suprathreshold words ('winter computer'). Evidence of integration was provided by faster reactions to suprathreshold words that were indirectly related versus unrelated. This effect was independent of the time interval between overlapping word pairs. We conclude that consciousness is no requirement for the integration of discontiguous events. PMID- 22425538 TI - Low risk of hepatitis E virus reactivation after haematopoietic stem cell transplantation. AB - BACKGROUND: Hepatitis E virus (HEV) is an emerging cause of acute hepatitis in industrialized countries. HEV infection can evolve to chronic hepatitis in immunocompromised patients. Additionally, HEV reactivation after haematopoietic stem cell transplantation has been reported. OBJECTIVE: To assess the prevalence of anti-HEV antibodies in patients who underwent haematopoietic stem cell transplantation in south-western France and the risk of HEV reactivation after transplantation. STUDY DESIGN: We have investigated the prevalence of anti-HEV antibodies in 88 patients who underwent allogenic or autologous haematopoietic stem cell transplantation with two anti-HEV IgG assays and have evaluated the risk of HEV reactivation in pretransplant seropositive patients by testing for HEV RNA in blood samples collected after stem cell transplantation. RESULTS: While only 11 patients (12.5%) tested positive for anti-HEV IgG with the Adaltis assay, 32 patients (36.4%) tested positive for anti-HEV IgG with the Wantai assay before transplantation. Three anti-HEV IgG positive patients were also anti-HEV IgM positive. Plasma HEV RNA was negative in all the patients before transplantation. We looked for HEV reactivation in pretransplant seropositive patients by testing 89 blood samples for HEV RNA 1, 3 and 6 months after transplantation. We detected no reactivation. Similarly, we detected no HEV RNA in pretransplant seronegative patients after transplantation. CONCLUSION: Despite strong immunosuppression, the risk of HEV reactivation after stem cell transplantation appears to be very low. PMID- 22425539 TI - Residual disability 10 years after falling ill in Guillain-Barre syndrome: a prospective follow-up study. AB - OBJECTIVE: To describe residual disability 10years after onset of Guillain-Barre syndrome (GBS) and longitudinal changes from 2weeks after onset until 10years afterwards. The Erasmus GBS Outcome score (EGOS) was applied for predicting prognosis at 2 and 10years. METHODS: Twenty-nine patients, mean age at onset 49years, were followed prospectively from 2weeks to 10years after GBS onset. Measures included; GBS disability score, EGOS, Barthel Index, Frenchay Activity Index, Sickness Impact Profile (SIP), Overall Neuropathy Limitations Scale (ONLS), Walk-12, and Fatigue Severity Scale. RESULTS: At 10years, the facial paralysis found in 5 participants at 2years was still present, 11 participants (38%) experienced paresthesia, 6 (21%) had limitations in their arms, and 15 (52%) had limitations in walking. Decreased health-related quality of life on comparison to the general population was seen in the physical dimension of SIP at 10years. The median EGOS at 2weeks was 4.5, which correlated highly only with the Barthel Index at 2years and the ONLS arm scale at 10years. CONCLUSION: The residual disabilities at 1-2years comprised mainly of reduced walking ability, and are still persistent 10years after GBS onset. For some individuals, facial paralysis caused major disability. The EGOS only partly predicted residual disability at 2 and 10years after onset. PMID- 22425540 TI - LINGO1 and risk for essential tremor: results of a meta-analysis of rs9652490 and rs11856808. AB - BACKGROUND/OBJECTIVES: Recently, a genome-wide association study revealed a significant statistical association between LINGO1 rs9652490 and rs11856808 polymorphisms and the risk of developing essential tremor (ET) in Icelandic people. Because the results of further association studies were controversial, we conducted a meta-analysis including all the studies published on the risk of ET related with these polymorphisms. METHODS: The metaanalysis included 11 association studies between LINGO1 rs9652490 (3972 ET patients, 20,714 controls) and 7 association studies between LINGO1 rs11856808, and risk for ET (2076 ET patients, 18,792 controls), and was carried out by using the software Meta-Disc 1.1.1 (http://www.hrc.es/investigacion/metadisc.html; Unit of Clinical Statistics, Hospital Ramon y Cajal, Madrid, Spain). Heterogeneity between studies in terms of degree of association was tested using the Q-statistic. RESULTS: Global diagnostic odds-ratios (ORs) and 95% confidence intervals (CI) for rs9652490 and rs11856808 of the total series were, respectively, 1.17 (1.00-1.36) (p=0.069) and 1.20 (1.05-1.36) (p=0.016). After excluding data on Icelandic people of the discovery series (that was responsible of a high degree of heterogeneity for rs9652490 polymorphism), the ORs and CI were 1.10 (0.97-1.26) (p=0.063) and 1.12 (0.99-1.27) (p=0.034). Global ORs and 95% CI for rs9652490 and rs11856808 of familial ET patients were, respectively, 1.27 (1.03-1.57) (p=0.014) and 1.21 (1.10-1.44) (p=0.031). CONCLUSIONS: The results of the meta-analysis suggest a relationship between LINGO1 rs11856808 polymorphism and the risk for ET and for familial ET, while rs9652490 polymorphism was only related with the risk for familial ET. PMID- 22425541 TI - A cloning vector employing a versatile beta-glucosidase as an indicator for recombinant clones. AB - A mutant glucosidase, cpGluT, with activity toward chromogenic substrates (X-gal [5-bromo-4-chloro-3-idolyl-beta-d-galactoside] and indican) and a fluorogenic 4 methylumbeliferyl-beta-d-glucopyranoside (MUG) was constructed by replacing the monomeric beta-glucosidase region (E314-N326) with designed multiple cloning sites. When expressed in hosts (lacZ+ and lacZ-), a vector containing the cpGluT produced a colored or fluorescent phenotype according to the substrate supplemented on LB plates without any inducer. cpGluT is readily incorporable into customized vectors and does not require special hosts to detect recombinant plasmids, thereby making screening recombinants more effective and less expensive. PMID- 22425542 TI - Protocol for effective differentiation of 3T3-L1 cells to adipocytes. AB - In this note, we present a detailed procedure for highly effective and reproducible 3T3-L1 cell differentiation. Due to their potential to differentiate from fibroblasts to adipocytes, 3T3-L1 cells are widely used for studying adipogenesis and the biochemistry of adipocytes. However, using different kits and protocols published so far, we were not able to obtain full differentiation of the currently available American Type Culture Collection (ATCC) 3T3-L1 cell lots. Using rosiglitazone (2 MUM) as an additional prodifferentiative agent, we achieved apparently complete differentiation of 3T3-L1 cells within 10 to 12 days that persisted for at least up to cell culture passage 10. PMID- 22425544 TI - Non-motor symptoms of Parkinson's disease in China: a review of the literature. AB - Parkinson's disease (PD) is generally considered as a neurodegenerative disorder commonly characterized by bradykinesia, resting tremor, rigidity and postural instability. However, increasing evidence demonstrates that serial non-motor symptoms (NMSs), including sensory symptoms, dysautonomia, neurobehavioral disorders and sleep disturbances frequently occur prior to motor signs and invariably emerge with the disease progression. Compared with motor symptoms, the NMSs are frequently under-recognized and poorly managed in clinical practice. A growing number of clinical studies on NMSs of PD have been carried out in China over the past decade. They revealed that there were not only common features, but also some differences on NMSs between Chinese patients and those in the West. Meanwhile, pharmacological and non-pharmacological strategies are available for the treatment of some NMSs associated with PD in China contained in Chinese guidelines for the treatment of PD. Large cohort studies across the country are warranted in the future to explore the epidemiological and biological features of specific NMSs in Chinese PD patients. PMID- 22425545 TI - Abnormal striatal dopaminergic and cardiac sympathetic imaging in dementia with Lewy bodies: two sides of the same coin. PMID- 22425547 TI - Redescriptions of three tintinnid ciliates, Tintinnopsis tocantinensis, T. radix, and T. cylindrica (ciliophora, spirotrichea), from coastal waters off China. AB - In the present study the morphology and ciliary pattern of three marine tintinnid ciliates, namely Tintinnopsis tocantinensisKofoid and Campbell, 1929, Tintinnopsis radix (Imhof, 1886) Brandt, 1907, and Tintinnopsis cylindricaDaday, 1887, isolated from Chinese coastal waters off Shenzhen and Qingdao, respectively, were investigated using living observation and silver impregnation methods. Detailed ciliary patterns of T. tocantinensis and T. radix are reported here for the first time, comprising a ventral, dorsal, and posterior kinety as well as a right, left, and lateral ciliary field. Furthermore, based on previous and present investigations, redescriptions for all three species and improved diagnoses for T. tocantinensis and T. radix are supplied. PMID- 22425546 TI - SNCA polymorphisms, smoking, and sporadic Parkinson's disease in Japanese. AB - Several case-control studies and genome-wide association studies have examined the relationships between single nucleotide polymorphisms (SNPs) in the SNCA gene and Parkinson's disease (PD), and have provided inconsistent results. We investigated the relationships between SNPs rs356229, rs356219, rs356220, rs7684318, and rs2736990 and the risk of sporadic PD in Japan using data from a multicenter hospital-based case-control study. Included were 229 cases within 6 years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. Based on the recessive model, compared with subjects with the CC or CT genotype of SNP rs356220, those with the TT genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.42 (95% CI: 1.002-2.02). In the additive model, SNP rs2736990 was significantly related to the risk of sporadic PD: the adjusted OR was 1.30 (95% CI: 1.002-1.68). There were no significant relationships between SNP rs356229, rs356219, or rs7684318 and the risk of sporadic PD in any genetic model. The additive interactions between SNPs rs356219 and rs356220 and smoking with respect to sporadic PD were significant although the multiplicative interactions were not significant. This study suggests that SNCA SNPs rs356220 and rs2736990 are significantly associated with the risk of sporadic PD in Japanese. We also present new evidence for biological interactions between SNPs rs356219 and rs356220 and smoking that affect sporadic PD. PMID- 22425548 TI - Knowledge of morphology is still required when identifying new amoeba isolates by molecular techniques. AB - We have isolated several free-living amoeba strains from the environment in Ghana, which have internal transcribed spacers, including the 5.8S rDNA, sequences similar to sequences attributed to Vahlkampfiidae (Heterolobosea) in databases. However, morphological examination shows that the isolates belong to the Hartmannellidae (Amoebozoa). We provide evidence that the sequences in the databases are wrongly classified as belonging to a genus or species of the Vahlkampfiidae, but rather belong to strains of the genus Hartmannella. PMID- 22425549 TI - Frequency and biodiversity of symbionts in representatives of the main classes of Ciliophora. AB - Representatives of all classes of Ciliophora have been studied for the detection and investigation of both prokaryotic and eukaryotic (not algal) endo- (EnS) and ectosymbionts (EcS). Different methods including transmission electron microscopy (TEM) and fluorescence in situ hybridisation (FISH) have been used. Apparently, the capability of keeping symbionts varies among the different ciliate groups as it generally is the case in different protist taxa. Most of the prokaryotic EnSs detected belong to Alphaproteobacteria. Holospora or Holospora-like infectious bacteria of this group were found in representatives of Heterotrichea, Armophorea, Phyllopharyngea, Prostomatea and mainly of Oligohymenophorea. Bacteria associated with bacteriophages were found in species of Heterotrichea and Oligohymenophorea. This holds true also for bacteria with R-bodies. A quite rare type of EnS - motile bacteria - was found in ciliates of the same two classes as well, either in the cytoplasm (Heterotrichea) or in the macronucleus and its perinuclear space (Oligohymenophorea). EcSs are more common in Heterotrichea, Armophorea and Plagiopylea, but were never found in other groups. Among the eukaryotic EnSs of ciliates, very few representatives of Microsporidia and Trypanosomatidae were recorded. In conclusion, heterotrichs and oligohymenophoreans are the most promising groups of Ciliophora for the investigation of symbiosis. PMID- 22425550 TI - Exponential stability of delayed and impulsive cellular neural networks with partially Lipschitz continuous activation functions. AB - The paper discusses exponential stability of distributed delayed and impulsive cellular neural networks with partially Lipschitz continuous activation functions. By relative nonlinear measure method, some novel criteria are obtained for the uniqueness and exponential stability of the equilibrium point. Our method abandons usual assumptions on global Lipschitz continuity, boundedness and monotonicity of activation functions. Our results are generalization and improvement of some existing ones. Finally, two examples and their simulations are presented to illustrate the correctness of our analysis. PMID- 22425551 TI - Tumor vasculature targeting following co-delivery of heparin-taurocholate conjugate and suberoylanilide hydroxamic acid using cationic nanolipoplex. AB - The chemical conjugate of low molecular weight heparin with taurocholate (LHT7) was previously designed to offer anticancer activity while minimizing the anticoagulant activity. In the present study, we found that the systemic administration of LHT7 in nanolipoplex could substantially enhance tumor vasculature targeting and anticancer effects. Moreover, we found that co-delivery of LHT7 with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, in nanolipoplex could provide synergistic antitumor effect. LHT7/SAHA nanolipoplex was formulated by encapsulating SAHA inside cationic liposomes, followed by complexation of negatively charged LHT7 onto the cationic surfaces of SAHA-loaded liposomes (SAHA-L). LHT7/SAHA nanolipoplex was positively charged with a mean diameter of 117.6 nm, and stable in serum. The nanolipoplex form of LHT7 could alter its pharmacokinetics and biodistribution. Compared to the free form of LHT7, LHT7 in the nanolipoplex showed 1.9-fold higher mean residence time, and higher tumor vasculature accumulation after its intravenous administration. LHT7/SAHA nanolipoplex showed highest antitumor efficacy in SCC bearing mice, compared to LHT7, SAHA-L and sequential co-administration of LHT7 and SAHA-L. Consistent with the enhanced antitumor effect, the reduction of abnormal vessels in the tumor site was also the highest in the LHT7/SAHA nanolipoplex-treated group. These results suggested the potential of LHT7/SAHA nanolipoplex for enhanced tumor vasculature targeting, and the importance of nanolipoplex-mediated co-delivery with a histone deacetylase inhibitor for maximal anticancer effect. PMID- 22425552 TI - Long-term fate of silica nanoparticles interacting with human dermal fibroblasts. AB - The long-term fate of fluorescent non-porous FITC-SiO(2) nanoparticles of various sizes (10-200 nm) and charge is studied in the presence of human dermal fibroblasts. Particle aggregates are formed in the culture medium and uptaken, at least partially, by macropinocytosis. The smallest particles have a strong impact on cell viability and genotoxic effects can be observed for negatively-charged colloids 10 nm in size. Largest particles do not impact on cellular activity and can be monitored in cellulo via fluorescence and transmission electron microscopy studies over two weeks. These observations reveal a significant decrease in the size of silica particles located in endocytic vesicles. The dissolution process is confirmed by monitoring the cell culture medium that contains both colloidal and soluble silica species. Such dissolution can be explained on the sole basis of silica solubility and has great implication for the use of non-porous silica particles as intra-cellular drug release systems. PMID- 22425553 TI - Necrosis of cervical carcinoma by dichloroacetate released from electrospun polylactide mats. AB - It is still a great challenge to apply therapeutic concentration of anti-cancer drugs to the tumor site with low system toxicity. An in situ administration strategy was applied to reverse the aerobic glycolysis of tumor in vivo for the first time. Controlled release of therapeutic concentration of dichloroacetate (DCA) from polylactide (PLA) electrospun mats covering the solid tumor locally was designed to suppress the cervical carcinoma in vivo. A dramatic decrease in the volume and weight of tumors was observed for 19 days in tumor-bearing mice, and a totally 96% of the tumor suppression degree was obtained even the initial tumor volume was around 200 mm(3). Half of the mice recovered in less than 3 weeks. Necrosis was examined rather than apoptosis on the tumor cells as the main process of cell death induced by the DCA-loaded electrospun mats. A proposed necroptosis mechanism was presented to explain the signal pathways that were induced by the metabolic remodeling of DCA. It provided support for this strategy that target the bio-energy metabolism of the cervical carcinoma locally is a quick and effective pathway to cure the advanced-carcinoma of cervical. PMID- 22425554 TI - The protection of MSCs from apoptosis in nerve regeneration by TGFbeta1 through reducing inflammation and promoting VEGF-dependent angiogenesis. AB - Our previous report demonstrated that autologous adipose-derived mesenchymal stem cells (ADSCs) combined with xenogeneic acellular nerve matrix (XANM) can support the regeneration of defective nerves. Although ADSCs had the potential to replace Schwann cells in engineered-tissue nerves, apoptosis easily obstructed the ability to treat serious nerve injury in the host, such as a >50-mm-long nerve defect. In the present study, we found that, in combination with transforming growth factor beta1 (TGFbeta1), an ADSCs-XANM graft was sufficient to support the regeneration of a 50-mm sciatic nerve defect, which was not achieved using an ADSCs-XANM graft alone. Based on this finding, we further investigated how TGFbeta1 coordinated with ADSCs to enhance nerve regeneration. In vitro, cell culture experiments demonstrated that TGFbeta1 did not have a direct effect on ADSC proliferation, apoptosis, the cell cycle, or neural differentiation. The expression of VEGF, however, was significantly increased in ADSCs cultured with TGFbeta1. In vivo, fluorescence labeling experiments demonstrated that the survival of transplanted ADSCs inoculated with XANM-TGFbeta1 was higher than with XANM. Further study showed that TGFbeta1 was capable of impairing the host immune response that was trigged by transplanted XANM. Additionally, we discovered that XANM-ADSCs in immunodeficient mice had apoptosis rates similar to XANM-ADSCs TGFbeta1 over a short time course (7 days). Once we blocked VEGF with a neutralizing antibody, the protective effect of TGFbeta1 was impaired over a long time course (28 days). These results suggested that TGFbeta1 was capable of enhancing the regenerative capacity of an XANM-ADSCs graft, mainly by protecting transplanted ADSCs from apoptosis. This effect was achieved in part through decreasing inflammation and promoting VEGF-dependent angiogenesis. PMID- 22425555 TI - Venous perforators in DIEAP flaps: an observational anatomical study using duplex ultrasonography. AB - BACKGROUND: The DIEAP flap has gained popularity for breast reconstruction worldwide. Despite DIEAP flap arterial anatomy being well known, venous congestion is still an important complication and the literature on DIEAP flap venous anatomy is lacking. Venous drainage is less predictable and research on venous perforators is of increasing interest. The aim of this study was to investigate the anatomical distribution, diameters and relationships between arterial and venous perforators and their source vessels using Duplex ultrasonography, in order to evaluate the potential benefits of pre-operative evaluation of DIEAP flap venous perforators. METHODS: Prospectively, 140 patients undergoing DIEAP flap breast reconstruction, were pre-operatively assessed using Duplex ultrasonography for location and diameter of arterial and venous perforators, DIEA, DIEV, and SIEV. Perforators were plotted laterally and inferiorly from the umbilicus. Means were compared using t-tests. Pearson's correlation coefficients were calculated. RESULTS: We identified 702 arterial and 355 venous perforators in 280 lower hemi-abdomens. No venous perforators were identified in 9 (6.5%) patients; none on the right in 25 (17.9%) and none on the left in 36 (25.7%). Venous perforators were larger on the right (p=0.031) but DIEV and SIEV diameters were not statistically different on either sides. The diameters of DIEA, DIEV, perforating arteries and veins were correlated, but unrelated to the diameter of the SIEV. When a medium/large perforator vein is identified first, there is a 93.5% chance of finding an associated medium/large perforator artery; this reduces to 69.8% when a medium/large perforator artery is first identified. CONCLUSIONS: There is no correlation between the sizes of perforator veins and DIEV, and the size of the SIEV. Our data suggests that first identifying a medium/large venous perforator increases the chances of finding a better suitable perforator complex. Pre-operative evaluation of venous perforators may be of great interest for its potential clinical benefits. PMID- 22425556 TI - Anakinra as an interleukin 1 receptor antagonist, complicated genetics and molecular impacts--from the point of view of mouse genomics. AB - IL-1 receptor antagonist (IL-1rn) is a protein that binds to IL-1 receptors (IL 1r1) and inhibits the binding of IL-1alpha and IL-1beta. In recent years, IL-1rn has been implicated to be associated with many human health problems. The effects of treatment of several inflammatory disorders with anakinra, which is an interleukin-1 (IL-1) receptor antagonist, have also been reported. Both positive and negative effects have been described. In this review, we systematically analyzed the expression, correlation, and regulation of IL-1rn and its 13 partner genes using available gene expression profiles from a variety of tissues in a well known transcriptome database, Genenetwork. The 13 partner genes include IL 1r1, IL-1beta, IL-1alpha, Myd88, Irak1, Irak2, Irak4, Traf6, Tlr4, IL-1rap, Ikbkap, Nfkb1, and Nfkb2. Gene expression profiles are from 10 tissues including spleen, kidney, lung, whole brain, eye, prefrontal cortex, cerebellum, hippocampus, striatum, and nucleus accumbens. Our analysis indicated that the interactions among IL-1rn and its partner are complex and different from tissues to tissues, suggesting a broad spectrum of the effect of IL-1rn on biological and metabolic pathways. Transcripts and protein sequences resulted from different splicing, interaction with genomic background of individuals, and environmental factors affect function of IL-1rn. At present, our knowledge on the function of IL-1rn and its partner in various tissues or organs is very limited. The long term and extended effect of anakinra on human health needs further investigations. In the future, targeted sequences or oligos of Il-1rn might be ideal for therapeutic application with less toxic and more specific in the treatment of specific disease. Detailed study on the molecular function of IL-1rn and its interaction with other genes and environmental factors is essential for development therapeutic application using IL-1rn. PMID- 22425557 TI - A few nucleotide polymorphisms are sufficient to recruit nuclear factors differentially to the intron 1 of HPV-16 intratypic variants. AB - The HPV-16 E6/E7 genes, which contain intron 1, are processed by alternative splicing and its transcripts are detected with a heterogeneous profile in tumours cells. Frequently, the HPV-16 positive carcinoma cells bear viral variants that contain single nucleotide polymorphisms into its DNA sequence. We were interested in analysing the contribution of this polymorphism to the heterogeneity in the pattern of the E6/E7 spliced transcripts. Using the E6/E7 sequences from three closely related HPV-16 variants, we have shown that a few nucleotide changes are sufficient to produce heterogeneity in the splicing profile. Furthermore, using mutants that contained a single SNP, we also showed that one nucleotide change was sufficient to reproduce the heterogeneous splicing profile. Additionally, a difference of two or three SNPs among these viral sequences was sufficient to recruit differentially several splicing factors to the polymorphic E6/E7 transcripts. Moreover, only one SNP was sufficient to alter the binding site of at least one splicing factor, changing the ability of splicing factors to bind the transcript. Finally, the factors that were differentially bound to the short form of intron 1 of one of these E6/E7 variants were identified as TIA1 and/or TIAR and U1-70k, while U2AF65, U5-52k and PTB were preferentially bound to the transcript of the other variants. PMID- 22425558 TI - Diverse human rhinoviruses A and C from children with respiratory infections in Kuala Lumpur, Malaysia. PMID- 22425559 TI - Reprint of: resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning. AB - We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning. PMID- 22425560 TI - AAV8(gfp) preferentially targets large diameter dorsal root ganglion neurones after both intra-dorsal root ganglion and intrathecal injection. AB - Adeno-associated viral vectors (AAV) are increasingly used to deliver therapeutic genes to the central nervous system (CNS) where they promote transgene expression in post mitotic neurones for long periods with little or no toxicity. In adult rat dorsal root ganglia (DRG), we investigated the cellular tropism of AAV8 containing the green fluorescent protein gene (gfp) after either intra-lumbar DRG or intrathecal injection and showed that transduced DRG neurones (DRGN) expressed GFP irrespective of the delivery route, while non-neuronal cells were GFP(-). After intra-DRG delivery of AAV8(gfp), the mean DRGN transduction rate was 11%, while intrathecal delivery transduced a mean of 1.5% DRGN. After intra-DRG injection, 2% of small DRGN (<30 MUm in diameter) were GFP(+) compared with 32% of large DRGN (>60 MUm in diameter). Axons of transduced DRGN were also GFP(+); no intra-spinal neurones were transduced. A small number of contralateral DRGN were transduced after intra-DRG injection, suggesting that AAV8 may diffuse from injected DRG into the spinal canal. Microglia and astrocytes were highly ramified with increased GFAP(+) immunoreactivity (i.e. activated) in the neuropil around GFP(+) DRG axon projections within the cord after intra-DRG injection. This study showed that after both intra-DRG and intrathecal delivery, strong preferential AAV8 tropism exists for large DRGN unassociated with cell death, but GFP(+) axons projecting in the spinal cord induced local glial activation. These results open up opportunities for targeted delivery of therapeutics such as neurotrophic factors to the injured spinal cord. PMID- 22425561 TI - Homocysteine has anti-inflammatory properties in a hypercholesterolemic rat model in vivo. AB - Inflammation is a hallmark in many neurodegenerative diseases like Alzheimer's disease or vascular dementia. Cholesterol and homocysteine are both vascular risk factors which have been associated with dementia, inflammation and blood-brain barrier dysfunction. In previous studies we found that hypercholesterolemia but not hyperhomocysteinemia induced inflammation in rats in vivo. The aim of the present study was to investigate the effect of a combined treatment of Sprague Dawley rats with cholesterol and homocysteine for 5 months on spatial learning and memory, blood-brain barrier integrity and inflammation. Cholesterol treated rats showed severe learning deficits, while rats treated with cholesterol and homocysteine (Mix) counteracted the cholesterol-induced inflammation and partly the cortical blood-brain barrier disruptions, although cognition was still impaired. To study the potential protective effect of homocysteine, inflammation was induced in organotypic rat brain cortex slices and primary microglial cells by treatment with different inflammatory stimuli (e.g. lipopolysaccharide or tissue plasminogen activator). Tissue plasminogen activator-induced inflammation was counteracted by homocysteine. In conclusion, our data demonstrate that homocysteine significantly ameliorates cholesterol-induced inflammation and blood brain barrier disruption but not the memory impairment, possibly involving a tissue plasminogen activator-related mechanism. PMID- 22425562 TI - Histone deacetylase inhibitors block IFNgamma-induced STAT1 phosphorylation. AB - Signal transducer and activator of transcription 1 (STAT1) is important for innate and adaptive immunity. Histone deacetylase inhibitors (HDACi) antagonize unbalanced immune functions causing chronic inflammation and cancer. Phosphorylation and acetylation regulate STAT1 and different IFNs induce phosphorylated STAT1 homo-/heterodimers, e.g. IFNalpha activates several STATs whereas IFNgamma only induces phosphorylated STAT1 homodimers. In transformed cells HDACi trigger STAT1 acetylation linked to dephosphorylation by the phosphatase TCP45. It is unclear whether acetylation differentially affects STAT1 activated by IFNalpha or IFNgamma, and if cellular responses to both cytokines depend on a phosphatase-dependent inactivation of acetylated STAT1. Here, we report that HDACi counteract IFN-induced phosphorylation of a critical tyrosine residue in the STAT1 C-terminus in primary cells and hematopoietic cells. STAT1 mutants mimicking a functionally inactive DNA binding domain (DBD) reveal that the number of acetylation-mimicking sites in STAT1 determines whether STAT1 is recruited to response elements after stimulation with IFNgamma. Furthermore, we show that IFNalpha-induced STAT1 heterodimers carrying STAT1 molecules mimicking acetylation bind cognate DNA and provide innate anti-viral immunity. IFNgamma induced acetylated STAT1 homodimers are though inactive, suggesting that heterodimerization and complex formation can rescue STAT1 lacking a functional DBD. Apparently, the type of cytokine determines how acetylation affects the nuclear entry and DNA binding of STAT1. Our data contribute to a better understanding of STAT1 regulation by acetylation. PMID- 22425563 TI - Prospective acetylcholinesterase inhibitory activity of indole and its analogs. AB - Acetylcholinesterase (AChE) inhibitory activity is one of the proposed targets for indole analogs. Simple indoles with substitution of methoxy, carboxy or hydroxy at the benzene ring showed a low percent of inhibitory activity in eel AChE. Adding a side chain at the pyrrole ring, such as serotonin, beta-carbolines and quinolines (the bioisostere of indole), improved the inhibitory activity significantly. However, proper substitution and conformation of the ring were required for good binding. The result of inhibition in human-AChE of serotonin, beta-carbolines and quinolines showed similar profile as eel-AChE with lower magnitude. The data from molecular docking showed that they shared the same binding site as galantamine. PMID- 22425564 TI - Inhibition of hepatitis C virus NS5A by fluoro-olefin based gamma-turn mimetics. AB - The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these gamma-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A. PMID- 22425565 TI - Footprint-based identification of viral entry inhibitors targeting HIVgp41. AB - A targeted virtual screen to the N-helix hydrophobic pocket on HIVgp41 was performed using DOCK followed by re-ranking with a new footprint-based scoring function which employed native gp41 C-helix residues as a reference. Of ca. 500,000 small molecules screened, 115 were purchased, and 7 hits were identified with favorable binding (K(i)), cell-cell fusion (IC(50)), and cytotoxicity (CC(50)) profiles. Three of the seven active compounds would not have been discovered without the use of the footprints, demonstrating the utility of the method for structure-based design when a known reference compound or substrate is available. PMID- 22425566 TI - Consensus hologram QSAR modeling for the prediction of human intestinal absorption. AB - Consistent in silico models for ADME properties are useful tools in early drug discovery. Here, we report the hologram QSAR modeling of human intestinal absorption using a dataset of 638 compounds with experimental data associated. The final validated models are consistent and robust for the consensus prediction of this important pharmacokinetic property and are suitable for virtual screening applications. PMID- 22425567 TI - Unambiguous structure of atractyloside and carboxyatractyloside. AB - Atractyloside (ATR) was characterized in 1868 and until now structural studies on diterpenic moiety had been done through the characterization of ATR derivatives; while the glycosidic moiety seemed to be a beta-D-glucopyranose a recent crystal structure of the mitochondrial ATP/ADP carrier in complex with CATR showed an alpha-D-glucopyranose. We decided to re-examine the ATR and CATR structures by crystallographic study of ATR. PMID- 22425568 TI - Structure-activity studies of some berberine analogs as inhibitors of Toxoplasma gondii. AB - The shortfalls of the current treatment options against infections with the parasite Toxoplasma gondii (T. gondii) necessitates the development of non-toxic and well-tolerated alternatives. To address this problem a structurally diverse panel of berberine alkaloids was synthesized and evaluated for in vitro inhibition of T. gondii tachyzoites. Inhibitory doses (ID(50)) of less than 50 nM and therapeutic indices (TI) up to 4000 were observed. PMID- 22425569 TI - Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9 amino-alpha-noscapine from natural alpha-noscapine. AB - Facile synthesis of natural alpha-noscapine analogue, 9-amino-alpha-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo alpha-noscapine (obtained by bromination of natural alpha-noscapine) with NaN(3) in DMSO at 130 degrees C in the presence of L-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-alpha-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units. PMID- 22425570 TI - Efficient one-pot cyclization/folding of Rhesus theta-defensin-1 (RTD-1). AB - We report an efficient approach for the chemical synthesis of Rhesus theta defensin-1 (RTD-1) using Fmoc-based solid-phase peptide synthesis in combination with an intramolecular version of native chemical ligation. The corresponding linear thioester precursor was cyclized and folded in a one-pot reaction using reduced glutathione. The reaction was extremely efficiently yielding natively folded RTD-1 with minimal or no purification at all. This approach is fully compatible with the high throughput production of chemical libraries using this peptide scaffold. PMID- 22425571 TI - Aspects of silane coupling agents and surface conditioning in dentistry: an overview. AB - OBJECTIVES: To give an overview of aspects of silane coupling agents and surface conditioning in dentistry. METHODS: Currently, silane coupling agents are used as adhesion promoters. Silanes are effective in enhancing adhesion between resin composite and silica-based ceramics. They do not bond effectively to non-silica based dental restorative materials. Surface conditioning of non-silica based ceramics with silica coating improves the bonding. This current overview will focus on the silane coupling agents: their properties, limitations in adhesion promotion and the clinical problems with the use of silanes. It will also focus on the current surface conditioning methods as well as new surface conditioning techniques to enhance the bonding through conventional silanization approaches. RESULTS: Several surface conditioning methods are being used clinically to enhance the adhesion of resin composites to non-silica based restorative materials. Other approaches are under investigation. The clinical problem of using silanes in adhesion promotion is the bond degradation over time in oral environment. SIGNIFICANCE: The current silane coupling agents are not ideal. The current silane coupling agents can fulfill the minimum requirements in clinical practice to enhance the bonding of resin composite to dental restorative materials. Developments of novel surface conditioning methods and silane coupling agents are required to address the bond durability problem. PMID- 22425572 TI - Effect of specimen gripping device, geometry and fixation method on microtensile bond strength, failure mode and stress distribution: laboratory and finite element analyses. AB - OBJECTIVES: Innumerous modifications have been proposed for the microtensile test since its introduction; however, testing parameters are not often well described and wide variations in bond strength are commonly reported. The aim of this study was to evaluate the effect of the test specimen's gripping device, specimen geometry and fixation method on microtensile bond strength, failure mode, and stress distribution when using an etch-and-rinse 2-step adhesive system bonded to human dentin. METHODS: Resin-based composite bonded to occlusal dentin from 21 human molars was used to fabricate dumbbell- and stick-shaped test specimens which were divided into three groups: Di - dumbbell-specimens placed in a Dircks device; GeS - stick-specimens gripped in a Geraldeli's device with Superglue; GeZ - stick-specimens gripped in a Geraldeli's device with Zapit. Specimens were tested to failure in tensile mode and the failure mode was examined under stereomicroscopy and fracture initiation sites were verified by scanning electron microscopy and energy dispersive X-ray spectroscopy. Three-dimensional models of each device/specimen were created and finite element calculations were performed. RESULTS: The effect of the gripping devices on the bond strength was not significant, unless the bond test areas were normalized. The failure mode was influenced by the type of device. Dircks device was less sensitive to human error than Geraldeli's, and produced a more uniform stress distribution at the dumbbell specimen adhesive layer than did the Geraldeli's device at the stick layer. SIGNIFICANCE: Microtensile testing parameters can directly influence the results and consequently inter-study comparisons. PMID- 22425573 TI - Non-inverse-square force-distance law for long thin magnets-revisited. AB - OBJECTIVE: It had previously been shown that the inverse-square law does not apply to the force-distance relationship in the case of a long, thin magnet with one end in close proximity to its image in a permeable plane when simple point like poles are assumed. Treating the system instead as having a 'polar disc', arising from an assumed bundle of dipoles, led to a double integral that could only be evaluated numerically, and a relationship that still did not match observed behavior. Using an elaborate 'stretched' exponential polynomial to represent the position of an 'elastic' polar disc resulted in a fair representation of the physical response, but this was essentially merely the fitting of an arbitrary function. The present purpose was therefore to find an explicit formula for the force-distance relationship in the polar-disc problem and assess its fit to the previously obtained experimental data. METHODS: Starting from Coulomb's law a corrected integral formula for the force-distance relationship was derived. The integral in this formula was evaluated explicitly using rescaling, changes of order of integration, reduction by symmetry, and change of variables. The resulting formula was then fitted to data that had been obtained for the force exerted by eighty-five rod-shaped magnets (Alnico V, 3 mm diameter, 170 mm long) perpendicular to a large steel plate, as a function of distance, at small separations (<5 mm). Subsequently, the fit of alternative functions was explored. RESULTS: An explicit formula in terms of elliptic integrals was obtained for the polar-disc problem. Despite the greater fidelity, this too was found not to fit the observed physical behavior. Given that failure, nevertheless a simple formula that conforms closely and parsimoniously to the actual magnet data was found. A key feature remains the marked departure from inverse-square behavior. SIGNIFICANCE: The failure of the explicit formula to fit the data indicates an inadequate model of the physical system. Nonetheless it constitutes a useful tool for quantifying the force-distance relationship on the premise of polar discs. Given these insights, it may now be possible to address the original motivating problem of the behavior of real dental magnets. PMID- 22425574 TI - Peto's paradox and cancer: a response to Caulin and Maley. PMID- 22425575 TI - Immediate and overnight recumbence-dependent changes of neck circumference: relationship with OSA severity in obese and nonobese subjects. AB - BACKGROUND: Overnight increases in neck circumference - attributed to rostral fluid displacement - correlate with the severity of obstructive sleep apnea (OSA). No studies were found investigating the relationship between OSA severity and recumbence-related immediate changes in neck circumference. We evaluated the relationship of OSA severity with immediate recumbence-related and overnight changes in neck circumference in obese and nonobese subjects. METHODS: Male patients undergoing full-night in-laboratory polysomnography had their neck and ankle circumferences determined before and after sleep, both while standing and supine. Circumference changes were calculated by the difference between standing and recumbent positions (Immediate Change) and between before and after sleep (Overnight Change). RESULTS: Immediate Change in neck circumference showed a linear significant correlation with apnea-hypopnea index (AHI; r=0.37373; p=0.012) and with lowest O2 saturation (r=-0.35355; p=0.017). In a multivariate model to predict AHI, adjusting for age and obesity, Immediate Change in neck circumference is the only significant regressor (beta=0.34; p=0.03). The Overnight Change in neck circumference correlated neither with the AHI nor with the lowest SaO2. CONCLUSION: Correlation of AHI with the immediate increase in neck circumference on assuming recumbence indicates that fast components of tissue displacement, besides overnight fluid displacement, may have implications in the pathogenesis of OSA. PMID- 22425576 TI - Risk factors for incident chronic insomnia: a general population prospective study. AB - OBJECTIVE: The few population-based, prospective studies that have examined risk factors of incident insomnia were limited by small sample size, short follow-up, and lack of data on medical disorders or polysomnography. We prospectively examined the associations between demographics, behavioral factors, psychiatric and medical disorders, and polysomnography with incident chronic insomnia. METHODS: From a random, general population sample of 1741 individuals of the adult Penn State Sleep Cohort, 1395 were followed-up after 7.5 years. Only subjects without chronic insomnia at baseline (n = 1246) were included in this study. Structured medical and psychiatric history, personality testing, and 8-h polysomnography were obtained at baseline. Structured sleep history was obtained at baseline and follow-up. RESULTS: Incidence of chronic insomnia was 9.3%, with a higher incidence in women (12.9%) than in men (6.2%). Younger age (20-35 years), non-white ethnicity, and obesity increased the risk of chronic insomnia. Poor sleep and mental health were stronger predictors of incident chronic insomnia compared to physical health. Higher scores in MMPI-2, indicating maladaptive personality traits, and excessive use of coffee at baseline predicted incident chronic insomnia. Polysomnographic variables, such as short sleep duration or sleep apnea, did not predict incident chronic insomnia. CONCLUSION: Mental health, poor sleep, and obesity, but not sleep apnea, are significant risk factors for incident chronic insomnia. Focusing on these more vulnerable groups and addressing the modifiable risk factors may help reduce the incident of chronic insomnia, a common and chronic sleep disorder associated with significant medical and psychiatric morbidity and mortality. PMID- 22425577 TI - Descriptors of restless legs syndrome sensations. AB - BACKGROUND: Restless legs syndrome (RLS) is characterised by an urge to move in response to unusual sensations in the legs. Patients experience difficulty describing their RLS sensations, resulting in a diverse range of descriptors which have not been fully categorised. The purpose of this study was to describe RLS sensations and to evaluate the accuracy of current diagnostic descriptors. METHODS: Forty-one RLS participants completed an interview which involved: providing spontaneous descriptions of RLS sensations, completing the McGill Pain Questionnaire (MPQ), and selecting descriptors from a list of previously published RLS terms (prompted descriptors). RESULTS: The most frequent spontaneous descriptors were: "irritating" (17%), "painful" (17%), and "urge to move" (24%); prompted descriptors were: "restless" (88%), "uncomfortable" (78%), and "need to stretch" (76%); and MPQ words were: "tingling" (56%) and "jumping" (54%). DISCUSSION: The most frequently cited descriptors in this study differ from the terminology used in the RLS diagnostic criteria. Inclusion of these frequently used descriptors may improve the diagnostic accuracy of RLS. Our data emphasise the need for an international, large scale, multicultural study to determine the most accurate diagnostic descriptors to define RLS more clearly. PMID- 22425578 TI - Long-term outcomes and predictors of chronic insomnia: a prospective study in Hong Kong Chinese adults. AB - OBJECTIVES: We aimed to determine the longitudinal course and outcome of chronic insomnia in a five-year prospective study in Hong Kong Chinese adults. METHODS: Two thousand three hundred and sixteen middle-aged adults (53.3% females, 46.3 +/ 5.1 years old at follow-up) were recruited at baseline and follow-up. Participants were divided into three groups: non-insomnia, insomnia symptoms, and insomnia syndrome (insomnia symptoms plus daytime symptoms). Upper airway inflammatory diseases, mental problems, and medical problems were additionally assessed at follow up. RESULTS: The incidence of insomnia (symptoms and syndrome) was 5.9%. The persistence rate of insomnia syndrome was 42.7% for insomnia syndrome and 28.2% for insomnia symptoms. New incidence of insomnia was associated with younger age, unemployment, and daytime symptoms, while persistence of insomnia was associated with female sex, lower education level, and daytime symptoms at the baseline (p<0.05). Baseline insomnia syndrome was significantly associated with upper airway inflammatory diseases (including asthma and laryngopharyngitis; adjusted OR=1.97-17.9), mental problems, and medical conditions (including arthritis, psychiatric disorders, chronic pain, and gastroesophageal reflux disease; AOR=2.29-3.77), whereas baseline insomnia symptoms were associated with poor mental health (AOR=2.43), psychiatric disorders (AOR=2.39), and chronic pain (AOR=2.95). CONCLUSIONS: Chronic insomnia is a common problem with considerable persistence and incidence rates among middle-aged Chinese adults. Insomnia syndrome has a higher persistence rate with more mental and medical comorbidities when compared with insomnia symptoms without daytime consequences. PMID- 22425579 TI - A detailed identification study on high-temperature degradation products of oleic and linoleic acid methyl esters by GC-MS and GC-FTIR. AB - GC-MS and GC-FTIR were complementarily applied to identify oxidation compounds formed under frying conditions in methyl oleate and linoleate heated at 180 degrees C. The study was focused on the compounds that originated through hydroperoxide scission that remain attached to the glyceridic backbone in fats and oils and form part of non-volatile molecules. Twenty-one short-chain esterified compounds, consisting of 8 aldehydes, 3 methyl ketones, 4 primary alcohols, 5 alkanes and 1 furan, were identified. In addition, twenty non esterified volatile compounds, consisting of alcohols, aldehydes and acids, were also identified as major non-esterified components. Furanoid compounds of 18 carbon atoms formed by a different route were also identified in this study. Overall, the composition of the small fraction originated from hydroperoxide scission provides a clear idea of the complexity of the new compounds formed during thermoxidation and frying. PMID- 22425580 TI - [Management of WHO grade II and II meningiomas: retrospective study of surgical series of 36 cases at a single institution]. AB - INTRODUCTION: Atypical and malignant meningiomas are a rare disease whose histological definition is still recent. Their management is not consensual. The aim of this study was to review the outcome, prognostic factors and the role of complementary therapies. PATIENTS AND METHODS: Between 1999 and 2007, 36 patients with atypical or malignant meningiomas were managed in our hospital. All surgical specimens were reviewed according to the 2007 WHO classification system. The sex ratio was 1.25 male, the median age was 59 years. The median follow-up was 55 months. Thirty meningiomas were atypical and six were malignant. RESULTS: Five and 10 years overall survival rate are respectively 72 and 41%, whereas 5 and 10 years progression free survival rate are 61 and 23%. We only identify female sex, age over 70 years and Karnofsky status under 70% as negative prognostic factors. CONCLUSION: Atypical and malignant meningiomas are difficult to manage and have high recurrence and poor survival rates. The prognostic of OMS II meningiomas is heterogeneous. Adjuvant radiation therapy is recommended in case of malignant menigioma or in case of atypical meningioma if incomplete surgical excision is performed. PMID- 22425581 TI - [Brown-Sequard syndrom complicating a C6 teardrop fracture associate with an occult vertebral artery dissection: case report]. AB - CASE REPORT: We report the case of a 27-year-old man, presenting a C6 tear-drop fracture associated to medullar contusion with a Brown-Sequard syndrome. An asymptomatic right vertebral artery dissection in its V2 portion was also discovered by the radiologic investigations. A surgical treatment and antiplatelet therapy were performed. The patient outcome was quite satisfactory. PMID- 22425582 TI - [Eyelid approach and pediatric orbital tumors: indications and surgical technique. About three children]. AB - Interdisciplinary collaboration can offer unusual approaches for the treatment of orbital pathologies. The authors report their experience with the eyelid incision in treating three children with epidural orbitary hematoma, dermoid cyst of the upper outer quadrant and a dermoid cyst of the internal inferior quadrant. For all the children, removal was complete and cosmetic results satisfying. The authors discuss the indications and complications of this surgical approach. PMID- 22425583 TI - Cocksfoot mottle sobemovirus establishes infection through the phloem. AB - Cocksfoot mottle virus (CfMV) localization in oat plants was analyzed during three weeks post infection by immunohistochemical staining to follow its spread through different tissues. In early stages of infection, the virus was first detectable in phloem parenchyma and bundle sheath cells of inoculated leaves. Bundle sheath and phloem parenchyma were also the cell types where the virus was first detected in stems and systemic leaves of infected plants. In later stages of infection, CfMV spread also into the mesophyll surrounding vascular bundles and was seldom detected in xylem parenchyma of inoculated leaves. In systemic leaves, CfMV was not detected from xylem. Moreover, sometimes it was found from phloem only. In straw and roots, CfMV was detected both from phloem and xylem. According to our observations, CfMV predominantly moves through phloem, which makes the systemic movement of CfMV different from that of another monocot infecting sobemovirus, Rice yellow mottle virus (RYMV). PMID- 22425585 TI - Surface facial modelling and allometry in relation to sexual dimorphism. AB - Sexual dimorphism is responsible for a substantial part of human facial variability, the study of which is essential for many scientific fields ranging from evolution to special biomedical topics. Our aim was to analyse the relationship between size variability and shape facial variability of sexual traits in the young adult Central European population and to construct average surface models of adult males and females. The method of geometric morphometrics allowed not only the identification of dimorphic traits, but also the evaluation of static allometry and the visualisation of sexual facial differences. Facial variability in the studied sample was characterised by a strong relationship between facial size and shape of sexual dimorphic traits. Large size of face was associated with facial elongation and vice versa. Regarding shape sexual dimorphic traits, a wide, vaulted and high forehead in combination with a narrow and gracile lower face were typical for females. Variability in shape dimorphic traits was smaller in females compared to males. For female classification, shape sexual dimorphic traits are more important, while for males the stronger association is with face size. Males generally had a closer inter-orbital distance and a deeper position of the eyes in relation to the facial plane, a larger and wider straight nose and nostrils, and more massive lower face. Using pseudo-colour maps to provide a detailed schematic representation of the geometrical differences between the sexes, we attempted to clarify the reasons underlying the development of such differences. PMID- 22425584 TI - ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors. AB - The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors. PMID- 22425586 TI - Pathophysiology of unilateral asterixis due to thalamic lesion. AB - OBJECTIVE: Unilateral asterixis has been reported in patients with thalamic lesion. This study aims at elucidating the pathophysiology of the thalamic asterixis. METHODS: Two cases with unilateral asterixis caused by an infarction in the lateral thalamus were studied by analysing the asterixis-related cortical activities, transcranial magnetic stimulation (TMS) for motor cortex excitability and probabilistic diffusion tractography for the thalamo-cortical connectivity. RESULTS: Averaging of electroencephalogram (EEG) time-locked to the asterixis revealed rhythmic oscillations of a beta band at the central area contralateral to the affected hand. TMS revealed a decrease in the motor evoked potential (MEP) amplitude and a prolongation of the silent period (SP). The anatomical mapping of connections between the thalamus and cortical areas using a diffusion-weighted image (DWI) showed that the lateral thalamus involved by the infarction was connected to the premotor cortex, the primary motor cortex (M1) and the primary somatosensory cortex (S1) of the corresponding hemisphere. CONCLUSIONS: The thalamic asterixis is mediated by the sensorimotor cortex, which is subjected to excessive inhibition as a result of the thalamic lesion involving the ventral lateral nucleus. SIGNIFICANCE: This is the first demonstration of participation of the sensorimotor cortex in the generation of asterixis due to the lateral thalamic lesion. PMID- 22425587 TI - Minimum repetitions for stable measures of visual dependency using the dot version of the computer-based Rod-Frame test. AB - Visual dependency is a condition where spatial orientation is mainly dependent on visual information. It can be affected in conditions such as vestibular disorders, brain injuries and neck pain including whiplash. Visual dependency can be assessed with a computer-based, dot version, Rod-Frame test (C-RFT(dot)) by measuring the deviation of a rod (comprised of two dots) from the true vertical within tilted frames at 18 degrees in both clockwise and anticlockwise directions. However, the number of test repetitions differs between studies. The purpose of this study was to investigate the minimum number of repetitions to obtain stable C-RFTdot outcomes. Thirty-one asymptomatic subjects were recruited. With a frame tilt of 18 degrees (clockwise and anticlockwise), the rod was pre set at 20 degrees in both clockwise and anticlockwise directions. The rod could be rotated, using a mouse, to a minimum of 0.01 degrees . The clockwise and anticlockwise deviations from the true vertical were positive values and negative values, respectively. A session consisted of two measures of deviations of pre set rod conditions in each frame. Their signed values were averaged for analysis. Eight sessions were conducted. The differences between the mean values of N-1 and N repetitions (2 ? N ? 8) were measured. Differences were similar across repetitions and the standard deviations tended to decline over repetitions. Intraclass correlation coefficients (ICC) for five and more repetitions became >0.8 in each frame condition. Hence, five was considered the minimum number of testing so that the C-RFT(dot) can give consistent measures of deviation from the vertical in asymptomatic healthy individuals. PMID- 22425588 TI - Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. AB - Data from studies in animal models indicate that certain lipid metabolites, particularly diacylglycerol, ceramide, and acylcarnitine, disrupt insulin action. We evaluated the relationship between the presence of these metabolites in the liver (assessed by mass spectrometry) and hepatic insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp with stable isotope tracer infusion) in 16 obese adults (body mass index, 48 +/- 9 kg/m2). There was a negative correlation between insulin-mediated suppression of hepatic glucose production and intrahepatic diacylglycerol (r = -0.609; P = .012), but not with intrahepatic ceramide or acylcarnitine. These data indicate that intrahepatic diacylglycerol is an important mediator of hepatic insulin resistance in obese people with nonalcoholic fatty liver disease. PMID- 22425589 TI - Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis. AB - BACKGROUND & AIMS: It is important to identify patients with acute pancreatitis who are at risk for developing persistent organ failure early in the course of disease. Several scoring systems have been developed to predict which patients are most likely to develop persistent organ failure. We head-to-head compared the accuracy of these systems in predicting persistent organ failure, developed rules that combined these scores to optimize predictive accuracy, and validated our findings in an independent cohort. METHODS: Clinical data from 2 prospective cohorts were used for training (n = 256) and validation (n = 397). Persistent organ failure was defined as cardiovascular, pulmonary, and/or renal failure that lasted for 48 hours or more. Nine clinical scores were calculated when patients were admitted and 48 hours later. We developed 12 predictive rules that combined these scores, in order of increasing complexity. RESULTS: Existing scoring systems showed modest accuracy (areas under the curve at admission of 0.62-0.84 in the training cohort and 0.57-0.74 in the validation cohort). The Glasgow score was the best classifier at admission in both cohorts. Serum levels of creatinine and blood urea nitrogen provided similar levels of discrimination in each set of patients. Our 12 predictive rules increased accuracy to 0.92 in the training cohort and 0.84 in the validation cohort. CONCLUSIONS: The existing scoring systems seem to have reached their maximal efficacy in predicting persistent organ failure in acute pancreatitis. Sophisticated combinations of predictive rules are more accurate but cumbersome to use, and therefore of limited clinical use. Our ability to predict the severity of acute pancreatitis cannot be expected to improve unless we develop new approaches. PMID- 22425590 TI - Flow characteristics of the SAPIEN aortic valve: the importance of recognizing in stent flow acceleration for the echocardiographic assessment of valve function. AB - BACKGROUND: The percutaneously implanted Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) consists of cusps mounted within a stent. The individual impact of the stent and cusps on transvalvular flow and its implications for the echocardiographic assessment of valve function have not been previously reported. METHODS: The study group consisted of 40 patients who underwent successful implantation with the SAPIEN valve. Pulsed Doppler was recorded with sample volumes immediately proximal to the stent (prestent), within the stent but proximal to the cusps (in-stent precusp), and distal to the cusps (in-stent postcusp). The Doppler velocity index and effective orifice area were calculated using both prestent and in-stent precusp velocities to represent "subvalvular" flow and continuous-wave recordings of the left ventricular outflow tract and aortic valve to represent postvalvular flow. RESULTS: In all patients, there was flow acceleration at two levels: in-stent precusp and in-stent postcusp. The mean in-stent precusp peak velocities were significantly higher than the prestent values (1.5 +/- 0.2 vs 1.0 +/- 0.2 m/sec, P < .0001). Effective orifice area and Doppler velocity index calculated using the prestent versus in stent precusp velocities were also significantly different (1.79 +/- 0.34 vs 2.54 +/- 0.46 cm(2), P < .0001, and 0.48 +/- 0.12 vs 0.73 +/- 0.13, P < .0001, respectively). CONCLUSIONS: The SAPIEN valve demonstrates flow acceleration at two levels, representing contributions of both the stent and valve cusps to the total valve gradient. Failure to recognize this phenomenon may result in inappropriate selection of the in-stent precusp pulsed Doppler spectrum to represent "subvalvular" flow, thereby overestimating the effective orifice area and Doppler velocity index. PMID- 22425591 TI - Asymptomatic aortic stenosis: the influence of the systemic vasculature on exercise time. AB - BACKGROUND: Changes in the peripheral vasculature occur in patients with aortic stenosis (AS). The aims of the present study were to characterize peripheral arterial waveforms and aortic pulsewave velocity (PWV) in patients with AS and to determine their relationship to exercise time. METHODS: The study included 101 patients with a median age of 68 years (range, 27-84 years) with at least moderate AS. Patients underwent transthoracic echocardiography, an assessment of the radial artery waveform and PWV using a SphygmoCor device, and a treadmill exercise stress test. RESULTS: The mean brachial systolic blood pressure was 143 +/- 23 mm Hg in patients with severe AS and 135 +/- 15 mm Hg in patients with moderate AS (P = .04). The mean radial augmentation index was 102 +/- 20% in patients with severe AS and 89 +/- 16% in those with moderate AS (P < .001). The radial augmentation index was related to the effective valve orifice area (R = 0.45, P = .001), the peak transvalvular pressure difference (R = 0.33, P = .001), and the mean transvalvular pressure difference (R = 0.33, P = .001). On univariate analysis, exercise time was related to systemic arterial compliance (R = 0.312, P = .008) and PWV (R = -0.44, P < 0.001). On multivariate analysis, after adjusting for age, AS severity, and PWV, only age was a significant predictor of exercise time (beta = -0.46; P = .006; 95% confidence interval, -15 to -3). CONCLUSIONS: In patients with asymptomatic moderate to severe AS, exercise capacity is influenced only by age, not by resting measures of aortic valve stenosis or aortic stiffness. PMID- 22425592 TI - Expression of aquaporin water channels in canine fetal adnexa in respect to the regulation of amniotic fluid production and absorption. AB - Amniotic fluid (AF) is created by the flow of fluid from the fetal lung and bladder and reabsorbed in part by fetal swallowing and partly by the transfer across the amnion to the fetal circulation. Placental water flux is an important factor in determining AF volume and fetal hydration. In addition the fetal membranes might be involved in the regulation of fluid composition. To understand the mechanisms responsible for maintaining a correct balance of AF volume we evaluated the expression of aquaporins (AQPs) in canine fetal adnexa. AQPs are a family of integral membrane proteins permitting passive but physiologically rapid transcellular water movement. The presence of AQP1, 3, 5, 8 and -9 was immunohistochemically assessed in canine fetal adnexa, collected in early, middle and late-gestation during ovario-hysterectomies performed with fully informed owners' consent. Changes in AF volume and biochemical composition were also evaluated throughout pregnancy. Our results show distinct aquaporin expression patterns in maternal and extraembryonic tissues in relation to pregnancy period. AQP1 was localized in placental endothelia, allantochorion, amnion, allantois and yolk sac. AQP3 was present in the placental labyrinth, amnion, allantois and yolk sac. AQP8 was especially evident on the epithelia lining the glandular chambers, the amniotic and allantois sacs. AQP9, a channel highly permeable to water and urea, was observed in epithelia of amnion, allantois and yolk sac. In summary, AQP1, 3, 5, 8 and -9 have distinct expression patterns in canine fetal membranes and placenta in relation to pregnancy period, suggesting an involvement in mediating the AF changes during gestation. PMID- 22425593 TI - Presentation of an unusual patient with Lafora disease. AB - Lafora disease is a rare, fatal, autosomal recessive progressive myoclonic epilepsy. The condition is characterised by seizures, myoclonus and dementia. In this case report, a patient who presented with generalised tonic-clonic seizures at the age of 30 is discussed. Until the age of 48, the patient did not have myoclonic jerks or ataxia clinically, but had well controlled seizures. He developed dementia and late extrapyramidal signs. Axillary skin biopsy revealed typical Lafora inclusion bodies. Genetic analysis showed a mutation in the EMP2B gene. To our knowledge, this is the first description of a patient suffering from a Lafora disease without disabling myoclonus and ataxia but rather rare seizures, extrapyramidal signs, and dementia. PMID- 22425594 TI - A new Zn(II)(2)Cys(6)-type transcription factor BglR regulates beta-glucosidase expression in Trichoderma reesei. AB - BglR (PI: 52368, beta-glucosidaseregulator) was identified as a new transcription factor that up-regulates expression of specific genes encoding beta-glucosidases. Based on a comparative genomic analysis to verify SNPs between Trichoderma reesei mutant PC-3-7 and its parent KDG-12, 19 were confirmed. One of the SNPs was found to cause a missense mutation close to the end of the DNA-binding region of BglR that turned out to be a Zn(II)(2)Cys(6)-type fungal-specific transcription factor. BglR was found to share little homologous to amyR of Aspergillus oryzae that is commonly considered a key regulator of starch degradation. A mutant lacking the bglr gene as well as the PC-3-7 mutant exhibited elevated cellulase production during growth on cellobiose. Reversion of the SNP missence mutation within bglr to the wild-type allele resulted in reduced cellulase production. Expression of specific beta-glucosidase genes in a bglr gene disruptant was repressed with the mutant exhibiting little ability to hydrolyze cellobiose during early log phase even when induced. Thus, one of the functions of BglR is to up-regulate specific beta-glucosidase genes (with the exception of bgl1, which is seemingly under the direct control of Xyr1). The glucose produced then triggers carbon catabolite repression in cellobiose culture. PMID- 22425595 TI - Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin resistant mice. AB - Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by beta-amyloid peptide (Abeta) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg-1 d-1 metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db+mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Abeta levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Abeta as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice. PMID- 22425596 TI - Differential behavioral profiling of stimulant substances in the rat using the LABORASTM system. AB - Preclinical testing requires rapid and reliable evaluation of the main in vivo effects of novel test substances usually in rodents. Nevertheless, the techniques primarily used up to now involve either automated measurement of motor activity or direct observation of behavioral effects by extensively trained investigators. The advantages of these approaches are respectively high-throughput and comprehensive behavioral assessment. Nevertheless, motor activity is only one aspect of animal behavior and it cannot predict the full neurobehavioral profile of a substance, whereas direct observation is time-consuming. There is thus a need for novel approaches that combine the advantages of both automatic detection and comprehensive behavioral analysis. In the present study, we used the LABORASTM system to analyze motor and non-motor behavior in rats administered various stimulant substances with or without known psychotomimetic properties or abuse liability (amphetamine, cocaine dizocilpine (MK-801), ketamine, modafinil and nicotine). The data show that LABORASTM clearly detects the stimulating effects on motor behaviors of amphetamine, cocaine, dizocilpine and ketamine in a dose- and time-dependent manner. Differential effects of these test substances on non-motor behaviors, such as grooming, eating and drinking could also be detected. Nicotine displayed only slight stimulating effects on locomotion, whereas modafinil was virtually without effect on the behaviors evaluated by the system. These data with different stimulant substances suggest that LABORASTM presents an advantage over classical methods performing automated measurements restricted to locomotion. Furthermore, the procedure is considerably more rapid than behavioral observation procedures. Characterization of the behavioral profile of test substances using LABORASTM should therefore accelerate preclinical studies. In addition, the multi-faceted parameters measured by LABORASTM permit a more detailed comparison of the behavioral profiles of novel substances with standard reference substances, thereby providing important indicators for orienting further substance evaluation and supporting drug development. PMID- 22425597 TI - Rimonabant abolishes sensitivity to workload changes in a progressive ratio procedure. AB - Despite its propensity to increase motivation for food consumption, marijuana use in humans has been associated with "amotivational syndrome." This "amotivational syndrome" can be characterized by a reduction in response persistence in tasks requiring sustained, but not maximal, effort. To examine this hypothesis, dose effect functions for THC (0.03-10 mg/kg) and rimonabant (0.1-10 mg/kg) were first determined under a time-constrained PR 5 schedule. During the second phase of the study, doses of THC and rimonabant that did not affect the responses/total reinforced responses were chosen for further evaluation in a series of PR schedules with step sizes of PR 3, PR 5, PR 10, and PR exponential. THC and rimonabant produced decreases in responses per reinforcer, and response rate when behavior was maintained on a PR 5. Rimonabant also decreased session length. During the PR step size manipulation phase, rimonabant decreased responses/total reinforced responses, response rate, and session length, whereas THC only decreased response rate. These results are consistent with previous literature demonstrating that rimonabant decreases motivation for food both in cases where it is earned, as well as under free-feeding conditions, whereas the effects of cannabinoid agonists such as THC on responding for food exhibit greater dependence upon motivational and non-motivational factors, including workload and duration of the task. PMID- 22425598 TI - Neural evidence for direct meaning access from orthography in Chinese word reading. AB - A fundamental issue in the study of reading is to understand the processes involved in determining word meaning from print. We used functional magnetic resonance imaging (fMRI) and scanned participants performing lexical decision tasks to discriminate between real Chinese words and non-words, presented either visually or auditorily. For the visual task, two left inferior frontal cortical regions were significantly more activated for non-words than for words, one in BA (Brodmann's area) 44/45 implied in phonological processing, and one in BA47 implied in semantic processing. For the auditory task, stronger neural activity for non-words, relative to words, was only found in BA44/45 but not in BA47. The results were interpreted to suggest that printed words in Chinese can directly activate their semantic representations, independent of an indirect, mediated pathway through phonology. In reference to related imaging studies on English, our finding implies a greater reliance on orthography in Chinese reading. PMID- 22425599 TI - Comparative kinematics of cypriniform premaxillary protrusion. AB - Premaxillary protrusion has evolved multiple times within teleosts, and has been implicated as contributing to the evolutionary success of clades bearing this adaptation. Cypriniform fishes protrude the jaws via the kinethmoid, a median sesamoid bone that is a synapomorphy for the order. Using five cypriniform species, we provide the first comparative kinematic study of jaw protrusion in this speciose order. Our goals were to compare jaw protrusion in cypriniforms to that in other clades that independently evolved upper jaw protrusion, assess the variation in feeding kinematics among members of the order, and test if variation in the shape of the kinethmoid has an effect on either jaw kinematics or the degree of suction or ram used during a feeding event. We also examined the coordination in the relative timings of upper and lower jaw movements to gain insight on the cypriniform protrusile mechanism. Overall, speed of protrusion in cypriniforms is slower than in other teleosts. Protrusion speed differed significantly among cypriniforms but this is likely not due to kinethmoid shape alone; rather, it may be a result of both kinethmoid shape and branching patterns of the A1 division of the adductor mandibulae. In the benthic cypriniforms investigated here, upper jaw protrusion contributed up to 60% of overall ram of the strikes and interestingly, these species also produced the most suction. There is relatively little coordination of upper and lower jaw movements in cypriniforms, suggesting that previous hypotheses of premaxillary protrusion via lower jaw depression are not supported within Cypriniformes. Significant variation in kinematics suggests that cypriniforms may have the ability to modulate feeding, which could be an advantage if presented with the challenge of feeding on different types of prey. PMID- 22425600 TI - Posttranslational modification and trafficking of PIN auxin efflux carriers. AB - Cell-to-cell communication is absolutely essential for multicellular organisms. Both animals and plants use chemicals called hormones for intercellular signaling. However, multicellularity of plants and animals has evolved independently, which led to establishment of distinct strategies in order to cope with variations in an ever-changing environment. The phytohormone auxin is crucial to plant development and patterning. PIN auxin efflux carrier-driven polar auxin transport regulates plant development as it controls asymmetric auxin distribution (auxin gradients), which in turn modulates a wide range of developmental processes. Internal and external cues trigger a number of posttranslational PIN auxin carrier modifications that were demonstrated to decisively influence variations in adaptive growth responses. In this review, we highlight recent advances in the analysis of posttranslational modification of PIN auxin efflux carriers, such as phosphorylation and ubiquitylation, and discuss their eminent role in directional vesicle trafficking, PIN protein de /stabilization and auxin transport activity. We conclude with updated models, in which we attempt to integrate the mechanistic relevance of posttranslational modifications of PIN auxin carriers for the dynamic nature of plant development. PMID- 22425601 TI - Investigation of self-assembling proline- and glycine-rich recombinant proteins and peptides inspired by proteins from a symbiotic fungus using atomic force microscopy and circular dichroism spectroscopy. AB - Fiber-forming proteins and peptides are being scrutinized as a promising source of building blocks for new nanomaterials. Arabinogalactan-like (AGL) proteins expressed at the symbiotic interface between plant roots and arbuscular mycorrhizal fungi have novel sequences, hypothesized to form polyproline II (PPII) helix structures. The functional nature of these proteins is unknown but they may form structures for the establishment and maintenance of fungal hyphae. Here we show that recombinant AGL1 (rAGL1) and recombinant AGL3 (rAGL3) are extended proteins based upon secondary structural characteristics determined by electronic circular dichroism (CD) spectroscopy and can self-assemble into fibers and microtubes as observed by atomic force microscopy (AFM) and scanning electron microscopy (SEM). CD spectroscopy results of synthetic peptides based on repeat regions in AGL1, AGL2 and AGL3 suggest that the synthetic peptides contain significant amounts of extended PPII helices and that these structures are influenced by ionic strength and, at least in one case, by concentration. Point mutations of a single residue of the repeat region of AGL3 resulted in altered secondary structures. Self-assembly of these repeats was observed by means of AFM and optical microscopy. Peptide (APADGK)(6) forms structures with similar morphology to rAGL1 suggesting that these repeats are crucial for the morphology of rAGL1 fibers. These novel self-assembling sequences may find applications as precursors for bioinspired nanomaterials. PMID- 22425602 TI - In vitro activation of human leukocytes in response to contact with synthetic hernia meshes. AB - OBJECTIVES: Evaluation of an in vitro chemiluminescent screen to predict leukocyte ROS in response to surgical materials. DESIGN AND METHODS: 6 surgical meshes; manufacture and knitting variations of polypropylene (PP), polyester terephtalate (PET) and polyglycolic acid (PGA) trialled healthy human blood (n=5). Materials and blood were incubated with pholasin. Pholasin emits photons in the presence of reactive oxygen species; secreted by activated leukocytes. RESULTS: Multifilament-PGA mesh stimulated the greatest ROS response from blood derived human leukocytes. Multifilament-PET light weight and multifilament-PP meshes stimulated similar levels of ROS production which were greater than monofilament-PP light, monofilament-PP and monofilament-PET light meshes. Data demonstrated statistical variations in trans-donor response to the materials. CONCLUSIONS: An in vitro chemiluminescent assay can be used to assess leukocyte respiratory burst response to biomaterials. PGA mesh elicited the greatest ROS response. PP and PET monofilament meshes induce less ROS than multifilament equivalents. In vitro results correlate with previously published clinical responses to these materials. PMID- 22425603 TI - Effect of the interleukin-1B gene on serum oxidized low-density lipoprotein levels. AB - OBJECTIVES: To investigate the association of the +3953 IL-1B gene polymorphism in healthy subjects with serum oxidized LDL (oxLDL) levels. DESIGN AND METHODS: We selected 255 subjects who were non-smokers and who had no cardiovascular or other chronic degenerative diseases, and we measured the oxLDL and other glucose levels, lipid biomarkers and biological variables that are related to cardiovascular metabolism. The +3953 IL-1B gene polymorphism was determined using molecular genetics techniques (PCR-RFLP). RESULTS: A significant association among the +3953 IL-1B genotypes and the oxLDL level was observed. The TT genotype presented lower oxLDL levels than the other genotypes. A multivariate analysis showed that this result was independent of the sex, age, obesity and hypertension status of the subjects. CONCLUSIONS: Our results suggest that the IL-1B gene polymorphism affects the modulation of serum oxLDL levels. PMID- 22425604 TI - Plasma concentrations but not serum concentrations of brain-derived neurotrophic factor are related to pro-inflammatory cytokines in patients undergoing major abdominal surgery. AB - OBJECTIVES: To investigate peripheral brain-derived neurotrophic factor (BDNF) concentrations in the perioperative period, their relationship with transforming growth factor-beta1 (TGF-beta1 tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-6 genetics. DESIGN AND METHODS: Prospective, observational study. BDNF, TGF-beta1, IL-6 and TNF-alpha were analysed at baseline (T0), 5 h (T1), 24 h (T2) and 5 days (T3) after surgery, in 21 patients. The IL-6 -174 G/C polymorphism was genotyped. RESULTS: Serum BDNF concentrations decreased (P=0.048), correlated with TGF-beta1 (r=0.610 at T1, r=0.493 at T2, r=0.554 at T3). Plasma BDNF concentrations raised (P=0.049), correlated with IL-6 and TNF-alpha at T1 (r=0.495 and r=0.441, respectively). BDNF response was predictable from TNF-alpha and IL-6 concentrations and the IL-6 -174 G/C genotype. CONCLUSION: Serum and plasma BDNF concentrations could relate to platelet activation and inflammatory response, respectively. IL-6 genetics played a role in the BDNF acute response. PMID- 22425605 TI - The effects of freeze-thaw on beta-trace protein and beta2-microglobulin assays after long-term sample storage. AB - OBJECTIVES: To evaluate the effect of a freeze-thaw cycle on beta-trace protein (betaTP) and beta2-microglobulin (beta2M). DESIGN AND METHODS: We compared betaTP and beta2M concentrations before and after a single freeze-thaw cycle in long term stored samples from 172 participants of the Third National Health and Nutrition Examination Survey (NHANES III). RESULTS: Measurements of betaTP and beta2M before and after freeze-thaw were highly correlated with Spearman's coefficients of 0.90 and 0.99, respectively. Serum concentrations of betaTP were slightly lower after freeze-thaw (-0.05 mg/L, P=0.006). Measurements of beta2M did not differ before and after freeze-thaw (P=0.35). CONCLUSIONS: betaTP and beta2M measurements were robust to a single freeze-thaw cycle, although beta2M appeared more stable than betaTP. These results have implications for future studies of these biomarkers. PMID- 22425606 TI - Diet for the prevention of asthma and allergies in early childhood: much ado about something? AB - In the last decades there has been an increase in allergic disease throughout the world, particularly in children. Attempts have been made to identify the causes of this "allergy epidemic" in environmental changes and changes in population hygiene, lifestyle, socioeconomic level, and eating habits that would exert epigenetic effects. Dietetic hypotheses have been mainly focussed in long-chain polyunsaturated fatty acids, vitamin D, antioxidants, Mediterranean diet, and fruits, vegetables and fish consumption. Although the data suggest a certain association between diet and the development of asthma/allergy, there is no evidence that diet has an impact upon the prevalence of such diseases after early infancy. If indeed there is such an impact, it is likely to be confined to the prenatal period and the first months of life - when it is still possible to modulate the development of the respiratory, digestive and immune systems. Thus, once the most appropriate preventive measures have been defined, these should be implemented during pregnancy and lactation. The existing scientific evidence is unable to recommend any primary preventive measure in the general population or in different population subgroups. Special or restrictive diets in pregnant or nursing women are not indicated. Exclusive breastfeeding for six months is questioned, since solid foods should begin to be introduced at around four months of age. Once the atopic process has started, no nutritional strategies have been found to be effective as secondary or tertiary preventive measures. Longitudinal studies in cohorts of pregnant women or newborn infants could help clarify these issues. PMID- 22425607 TI - Dose-dense chemotherapy versus conventional chemotherapy for early breast cancer: a systematic review with meta-analysis. AB - BACKGROUND: Despite the widespread acceptance of dose-dense (DD) regimens as adjuvant chemotherapy for early breast cancer (EBC), studies of efficacy offer contradictory findings. This systematic review evaluates the real impact of DD chemotherapy. METHODS: Randomized controlled trials comparing conventional adjuvant chemotherapy versus a DD regimen for EBC patients were searched in electronic databases. Dose-dense regimens included the same drugs and total amount as conventional chemotherapy, but applied in shorter intervals. Meta analyses were performed using a fixed-effects model. Hazard ratios (HRs) or odds ratios (ORs) were expressed with 95% confidence intervals (95% CI). The outcomes were overall survival (OS), disease-free survival (DFS), and toxicities. Analyses were conducted according to tumor hormone receptor expression, plus tests for interaction. RESULTS: Four studies (3418 patients) were included. The meta analysis demonstrated that DD therapy can improve DFS (3356 patients; HR=0.83; 95% CI 0.73-0.95; p=0.005), independent of hormone receptor expression status. There was no OS benefit with DD therapy (3356 patients; HR=0.86; 95% CI 0.73 1.01; p=0.06) irrespective of tumor hormone receptor status (OS in hormone positive stratum HR=0.94; 95% CI 0.74-1.21; OS in hormone-negative stratum HR=0.78; 95% CI 0.62-0.99; interaction test p=0.28). DD regimens caused a small increase in anemia and mucositis, but had no impact on cardiac events, leukemia or myelodysplasia. CONCLUSIONS: DD adjuvant chemotherapy can improve DFS of EBC patients with little impact on safety. However there is no clear benefit in OS. Further research may indicate if there is any impact on OS not presently seen due to small sample size, and which patients may derive greater benefit. PMID- 22425608 TI - Simple thermodynamic model of unassisted proton shuttle uncoupling and prediction of activity from calculated speciation, lipophilicity, and molecular geometry. AB - A mechanistic model of uncoupling of oxidative phosphorylation by lipophilic weak acids (i.e. proton shuttles) was developed for the purposes of predicting the relative activity of xenobiotics of widely varying structure and of guiding the design of optimized derivatives. The model is based on thermodynamic premises not formulated elsewhere that allow for the calculation of steady-state conditions and of rate of energy dissipation on the basis of acid-dissociation and permeability behavior, the later estimated from partitioning behavior and geometric considerations. Moreover, permeability of either the neutral or of the ionized species is proposed to be effectively enhanced under conditions of asymmetrical molecular distribution. Finally, special considerations were developed to accommodate multi-protic compounds. The comparison of predicted to measured activity for a diverse testset of 48 compounds of natural origin spanning a wide range of activity yielded a Spearman's rho of 0.90. The model was used to tentatively identify several novel proton shuttles, as well as to elucidate core structures particularly conducive to proton shuttle activity from which optimized derivatives can be designed. Principles of design were formulated and examples of derivatives projected to be active at concentrations on the order of 10(-7)M are proposed. Among these are di-protic compounds predicted to shuttle two protons per cycle iteration and proposed to maximally exploit the proton shuttle mechanism. This work promotes the design of highly active, yet easily metabolized uncouplers for therapeutic applications, namely the indirect activation of AMP-kinase, as well as for various industrial applications where low persistence is desirable. PMID- 22425609 TI - Gene duplication and conversion events shaped three homologous, differentially expressed myosin regulatory light chain (MLC2) genes. AB - Myosin II is a hexameric protein complex consisting of two myosin heavy chains, two myosin essential light chains and two myosin regulatory light chains. Multiple subunit isoforms exist, allowing great diversity in myosin II composition which likely impacts on its contractile properties. Little is known about the evolutionary origin, expression pattern and function of myosin regulatory light chain (MLC2) isoforms. We analysed the evolutionary relationship between smooth muscle (sm), nonmuscle (nm) and nonmuscle-like (nml) MLC2 genes, which encode three homologous proteins expressed in nonmuscle cells. The three genes arose by successive gene duplication events. The high sequence similarity between the tandemly arranged nm- and nml-MLC2 genes is best explained by gene conversion. Urea/glycerol-polyacrylamide gel electrophoresis and RNA analysis were employed to monitor expression of sm-, nm- and nml-MLC2 in human and mouse cell lines. Conspicuous differences between transformed and non-transformed cells were observed, with sm-MLC2 being suppressed in Ras-transformed cells. Our findings shed light on the evolutionary history of three homologous MLC2 proteins and point to isoform-specific cell growth-related roles in nonmuscle cell myosin II contractility. PMID- 22425610 TI - Estimation of benchmark dose for micronucleus occurrence in Chinese vinyl chloride-exposed workers. AB - In this study, we estimated the possibility of using benchmark dose (BMD) to assess the dose-response relationship between vinyl chloride monomer (VCM) exposure and chromosome damage. A group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed control in Shandong Province northern China were examined for chromosomal damage in peripheral blood lymphocytes (PBL) using the cytokinesis-blocked micronucleus (CB-MN) assay of DNA damage. The exposed group (3.47 +/- 2.65)0/00 showed higher micronucleus frequency than the control (1.60 +/- 1.30)0/00 (P < 0.01). Occupational exposure level based on micronucleus occurrence in all individuals was analyzed with benchmark dose (BMD) methods. The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. Results showed a dose-response relationship between cumulative exposure and MN frequency, and a BMDL of 0.54 mg/m3 and 0.23 mg/m3 for males and females, respectively. Female workers were more susceptible to MN damage than male workers. PMID- 22425611 TI - Mechanics and resonance of the cyanobacterial circadian oscillator. AB - Recent experiments elucidated the structure and function of the cyanobacterial circadian oscillator, which is driven by sunlight intensity variation and therefore by Earth's rotation. It is known that cyanobacteria appeared about 3.5 billion years ago and that Earth's rotational speed is continuously decreasing because of tidal friction. What is the effect of the continuous slowdown of Earth's rotation on the operation of the cyanobacterial oscillator? To answer this question we derived the oscillator's equation of motion directly from experimental data, coupled it with Earth's rotation and computed its natural periods and its resonance curve. The results show that there are two resonance peaks of the "cyanobacterial oscillator-rotating Earth" system, indicating that cyanobacteria used more efficiently the solar energy during the geological period in which the day length varied from about 11 to 15h and make more efficient use of solar energy at the geological period which started with a day length of 21h and will end at a day length of 28h. PMID- 22425613 TI - Differentiating mass-forming intrahepatic cholangiocarcinoma from atypical hepatocellular carcinoma using gadoxetic acid-enhanced MRI. AB - AIM: To examine the differential features of mass-forming intrahepatic cholangiocarcinoma (ICC) from atypical hypovascular hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived informed patient consent. Seventy patients with pathologically proven ICCs (35) and hypovascular atypical HCCs (35) who had undergone preoperative gadoxetic acid-enhanced MRI were enrolled in this study. Images were analysed for the shape of the lesions and presence of hyperintensity on the T1-weighted image (T1WI) and hypo- or hyperintense areas on the T2-weighted image (T2WI). In addition, images were analysed for the presence of linear hyperintensity or multifocal, tiny, hyperintense foci on T2WI and the presence of rim enhancement during early dynamic phases and a central enhancement with a hypointense rim (target appearance) on the 10 and 20 min hepatobiliary phase images. The significance of these findings was determined by the X(2) test. RESULTS: Univariate analysis revealed that the following significant parameters favour ICC or hypovascular HCC; the presence of T2 hypo- and hyperintense areas and target appearance on the 10 min hepatobiliary phase images favour ICC, and the presence of T2 linear hyperintensity and T2 multifocal hyperintense foci favour hypovascular HCC (p < 0.05). Multivariate analysis revealed that only target appearance on the 10 min hepatobiliary phase was predictive of ICC (p = 0.002) as 30 ICCs (85.7%) showed this feature. However, the target appearance was also observed in all six scirrhous HCCs. CONCLUSION: A target appearance on the 10 min hepatobiliary phase images is the best predictor for identifying mass-forming ICC at gadoxetic acid enhanced MRI. PMID- 22425612 TI - Self-folding polymeric containers for encapsulation and delivery of drugs. AB - Self-folding broadly refers to self-assembly processes wherein thin films or interconnected planar templates curve, roll-up or fold into three dimensional (3D) structures such as cylindrical tubes, spirals, corrugated sheets or polyhedra. The process has been demonstrated with metallic, semiconducting and polymeric films and has been used to curve tubes with diameters as small as 2nm and fold polyhedra as small as 100nm, with a surface patterning resolution of 15nm. Self-folding methods are important for drug delivery applications since they provide a means to realize 3D, biocompatible, all-polymeric containers with well-tailored composition, size, shape, wall thickness, porosity, surface patterns and chemistry. Self-folding is also a highly parallel process, and it is possible to encapsulate or self-load therapeutic cargo during assembly. A variety of therapeutic cargos such as small molecules, peptides, proteins, bacteria, fungi and mammalian cells have been encapsulated in self-folded polymeric containers. In this review, we focus on self-folding of all-polymeric containers. We discuss the mechanistic aspects of self-folding of polymeric containers driven by differential stresses or surface tension forces, the applications of self folding polymers in drug delivery and we outline future challenges. PMID- 22425614 TI - Seizure-related adverse events during video-electroencephalography monitoring. AB - AIM: The aim of this study was to characterise seizure-related adverse events during video-electroencephalography (vEEG) monitoring. METHODS: Our study evaluated adverse events in 230 epilepsy patients during vEEG monitoring while patients were awake and asleep. RESULTS: A total of 588 seizures were recorded and 231 adverse events were identified including electrode displacement (14.5%), aspiration risk (8.5%), urinary incontinence (7.5%), postictal psychosis (5.8%), tongue biting (5.3%), and patient falls (0.5%). No severe types of adverse events were observed, such as choking or aspiration pneumonia. Of the seizures recorded, 39.1% occurred while patients were sleeping and 38.5% of adverse events occurred during this time, which included electrode displacement (48.2%), aspiration risk (28.0%), tongue biting (60.0%), postictal psychosis (16.7%), patient falls (66.7%), and urinary incontinence (38.6%). CONCLUSION: The occurrence of seizure related adverse events during vEEG monitoring is mild. vEEG is an acceptably safe procedure for epilepsy research and precautions should be put in place to prevent these events. PMID- 22425616 TI - Mere exposure and flavour-flavour learning increase 2-3 year-old children's acceptance of a novel vegetable. AB - Vegetable consumption is low among many children. This study compared the efficacy of the exposure learning strategies mere exposure, flavour-flavour and flavour-nutrient learning in changing children's intake of a novel vegetable. An unmodified artichoke puree was served at pre-testing. Hereafter children were exposed 10 times to unmodified puree (mere exposure, n=32), a sweetened puree (flavour-flavour learning, n=33) or an energy dense puree with added fat (flavour nutrient learning, n=39). Unmodified and sweet puree contained approximately 200 kJ/100g; the energy dense puree 580 kJ/100g. The unmodified puree was served again at post-testing, 3 and 6 months after last exposure to monitor long-term effects of learning. Intake of puree increased in the mere exposure and flavour flavour condition, and was unchanged in the flavour-nutrient condition. Mere exposure changed children's intake by the 5th exposure, flavour-flavour learning by the 10th. Mere exposure led to the largest increase in intake of unmodified puree at post-test and over 6 months. Children following flavour-flavour learning consumed more of the sweet puree than of unmodified puree. About 30-40% of the children were resistant to acceptance changes. The results of this study imply that mere exposure and flavour-flavour learning are powerful strategies for changing children's acceptance of a novel vegetable, even though a substantial number of children are resistant to these types of exposure learning. PMID- 22425615 TI - Neural dynamics of object-based multifocal visual spatial attention and priming: object cueing, useful-field-of-view, and crowding. AB - How are spatial and object attention coordinated to achieve rapid object learning and recognition during eye movement search? How do prefrontal priming and parietal spatial mechanisms interact to determine the reaction time costs of intra-object attention shifts, inter-object attention shifts, and shifts between visible objects and covertly cued locations? What factors underlie individual differences in the timing and frequency of such attentional shifts? How do transient and sustained spatial attentional mechanisms work and interact? How can volition, mediated via the basal ganglia, influence the span of spatial attention? A neural model is developed of how spatial attention in the where cortical stream coordinates view-invariant object category learning in the what cortical stream under free viewing conditions. The model simulates psychological data about the dynamics of covert attention priming and switching requiring multifocal attention without eye movements. The model predicts how "attentional shrouds" are formed when surface representations in cortical area V4 resonate with spatial attention in posterior parietal cortex (PPC) and prefrontal cortex (PFC), while shrouds compete among themselves for dominance. Winning shrouds support invariant object category learning, and active surface-shroud resonances support conscious surface perception and recognition. Attentive competition between multiple objects and cues simulates reaction-time data from the two object cueing paradigm. The relative strength of sustained surface-driven and fast-transient motion-driven spatial attention controls individual differences in reaction time for invalid cues. Competition between surface-driven attentional shrouds controls individual differences in detection rate of peripheral targets in useful-field-of-view tasks. The model proposes how the strength of competition can be mediated, though learning or momentary changes in volition, by the basal ganglia. A new explanation of crowding shows how the cortical magnification factor, among other variables, can cause multiple object surfaces to share a single surface-shroud resonance, thereby preventing recognition of the individual objects. PMID- 22425617 TI - Children and eating. Personality and gender are associated with obesogenic food consumption and overweight in 6- to 12-year-olds. AB - The role of children's personality traits in the consumption of potentially obesogenic foods was investigated in a sample of Norwegian children aged 6-12 years (N=327, 170 boys, 157 girls). Mothers rated their child's personality on the traits of the Five Factor Model (i.e., extraversion, benevolence, conscientiousness, neuroticism, and imagination). Mothers also completed a food frequency questionnaire assessing their child's consumption of sweet drinks, sweet foods, and fruit and vegetables, and reported their child's height and weight. Controlling for age and mothers' education, boys and girls who were less benevolent consumed more sweet drinks, and girls who were less conscientious and more neurotic consumed more sweet drinks. Boys and girls who were more benevolent and imaginative consumed more fruits and vegetables, and boys who were more extraverted, more conscientious, and less neurotic consumed more fruits and vegetables. Controlling for maternal education, boys and girls who were less extraverted, and girls who were less benevolent, less conscientious, and more neurotic were more likely to be overweight or obese. These findings suggest that children's personality traits play an important yet understudied role in their diet. Further investigation of mechanisms that relate child traits to obesogenic eating and overweight would be valuable. PMID- 22425618 TI - Dephosphorylation of eIF2alpha is essential for protein synthesis increase and cell cycle progression after sea urchin fertilization. AB - The eukaryotic Initiation Factor 2 (eIF2) is a key regulator of protein synthesis in eukaryotic cells, implicated in the initiation step of translation. Fertilization of the sea urchin eggs triggers a rapid increase in protein synthesis activity, which is necessary for the progress into embryonic cell cycles. Here we demonstrate that fertilization triggers eIF2alpha dephosphorylation, concomitant with an increase in protein synthesis and that induction of the eIF2alpha phosphorylation is intimately linked with an inhibition of protein synthesis and cell cycle arrest. Using a phospho-mimetic protein microinjected into sea urchin eggs, we showed that dephosphorylation of eIF2alpha is necessary for protein synthesis activity and cell division progression following fertilization. Our results demonstrate that regulation of eIF2alpha plays an important role in the protein synthesis rise that occurs during early development following fertilization. PMID- 22425619 TI - Neural crest progenitors and stem cells: from early development to adulthood. AB - In the vertebrate embryo, the neural crest forms transiently in the dorsal neural primordium to yield migratory cells that will invade nearly all tissues and later, will differentiate into bones and cartilages, neurons and glia, endocrine cells, vascular smooth muscle cells and melanocytes. Due to the amazingly diversified array of cell types it produces, the neural crest is an attractive model system in the stem cell field. We present here in vivo and in vitro studies of single cell fate, which led to the discovery and the characterization of stem cells in the neural crest of avian and mammalian embryos. Some of the key issues in neural crest cell diversification are discussed, such as the time of segregation of mesenchymal vs. neural/melanocytic lineages, and the origin and close relationships between the glial and melanocytic lineages. An overview is also provided of the diverse types of neural crest-like stem cells and progenitors, recently identified in a growing number of adult tissues in animals and humans. Current and future work, in which in vivo lineage studies and the use of injury models will complement the in vitro culture analysis, should help in unraveling the properties and function of neural crest-derived progenitors in development and disease. PMID- 22425620 TI - The sperm surface localization of the TRP-3/SPE-41 Ca2+ -permeable channel depends on SPE-38 function in Caenorhabditis elegans. AB - Despite undergoing normal development and acquiring normal morphology and motility, mutations in spe-38 or trp-3/spe-41 cause identical phenotypes in Caenorhabditis elegans-mutant sperm fail to fertilize oocytes despite direct contact. SPE-38 is a novel, four-pass transmembrane protein and TRP-3/SPE-41 is a Ca(2+)-permeable channel. Localization of both of these proteins is confined to the membranous organelles (MOs) in undifferentiated spermatids. In mature spermatozoa, SPE-38 is localized to the pseudopod and TRP-3/SPE-41 is localized to the whole plasma membrane. Here we show that the dynamic redistribution of TRP 3/SPE-41 from MOs to the plasma membrane is dependent on SPE-38. In spe-38 mutant spermatozoa, TRP-3/SPE-41 is trapped within the MOs and fails to reach the cell surface despite MO fusion with the plasma membrane. Split-ubiquitin yeast-two hybrid analyses revealed that the cell surface localization of TRP-3/SPE-41 is likely regulated by SPE-38 through a direct protein-protein interaction mechanism. We have identified sequences that influence the physical interaction between SPE-38 and TRP-3/SPE-41, and show that these sequences in SPE-38 are required for fertility in transgenic animals. Despite the mislocalization of TRP 3/SPE-41 in spe-38 mutant spermatozoa, ionomycin or thapsigargin induced influx of Ca(2+) remains unperturbed. This work reveals a new paradigm for the regulated surface localization of a Ca(2+)-permeable channel. PMID- 22425621 TI - Specific domains of FoxD4/5 activate and repress neural transcription factor genes to control the progression of immature neural ectoderm to differentiating neural plate. AB - FoxD4/5, a forkhead transcription factor, plays a critical role in establishing and maintaining the embryonic neural ectoderm. It both up-regulates genes that maintain a proliferative, immature neural ectoderm and down-regulates genes that promote the transition to a differentiating neural plate. We constructed deletion and mutant versions of FoxD4/5 to determine which domains are functionally responsible for these opposite activities, which regulate the critical developmental transition of neural precursors to neural progenitors to differentiating neural plate cells. Our results show that up-regulation of genes that maintain immature neural precursors (gem, zic2) requires the Acidic blob (AB) region in the N-terminal portion of the protein, indicating that the AB is the transactivating domain. Additionally, down-regulation of those genes that promote the transition to neural progenitors (sox) and those that lead to neural differentiation (zic, irx) involves: 1) an interaction with the Groucho co repressor at the Eh-1 motif in the C-terminus; and 2) sequence downstream of this motif. Finally, the ability of FoxD4/5 to induce the ectopic expression of neural precursor genes in the ventral ectoderm also involves both the AB region and the Eh-1 motif; FoxD4/5 accomplishes ectopic neural induction by both activating neural precursor genes and repressing BMP signaling and epidermal genes. This study identifies the specific, conserved domains of the FoxD4/5 protein that allow this single transcription factor to regulate a network of genes that controls the transition of a proliferative neural ectodermal population to a committed neural plate population poised to begin differentiation. PMID- 22425622 TI - Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway. AB - BACKGROUND & AIMS: Diacylglycerol kinases (DGKs) were recently recognized as key regulators in cell signaling pathways. We investigated whether DGKalpha is involved in human hepatocellular carcinoma (HCC) progression. METHODS: We silenced or overexpressed DGKalpha in HCC cells and assessed its effect on tumor progression. DGKalpha expression in 95 surgical samples was analyzed by immunohistochemistry, and the expression status of each sample was correlated with clinicopathological features. RESULTS: DGKalpha was detected in various HCC cell lines but at very low levels in the normal liver. Knockdown of DGKalpha significantly suppressed cell proliferation and invasion. Overexpression of wild type (WT) DGKalpha, but not its kinase-dead (KD) mutant, significantly enhanced cell proliferation. DGKalpha knockdown impaired MEK and ERK phosphorylation, but did not inhibit Ras activation in HCC cells. In a xenograft model, WT DGKalpha overexpression significantly enhanced tumor growth compared to the control, but KD DGKalpha mutant had no effect. Immunohistochemical studies showed that DGKalpha was expressed in cancerous tissue, but not in adjacent non-cancerous hepatocytes. High DGKalpha expression (>=20%) was associated with high Ki67 expression (p<0.05) and a high rate of HCC recurrence (p=0.033) following surgery. In multivariate analyses, high DGKalpha expression was an independent factor for determining HCC recurrence after surgery. CONCLUSIONS: DGKalpha is involved in HCC progression by activation of the MAPK pathway. DGKalpha could be a novel target for HCC therapeutics as well as a prognostic marker. PMID- 22425623 TI - Preventing and reversing the cellular consequences of Z alpha-1 antitrypsin accumulation by targeting s4A. AB - BACKGROUND & AIMS: The Z variant (Glu342Lys) of alpha(1)-antitrypsin (AT) polymerizes and accumulates in the hepatocyte endoplasmic reticulum (ER) predisposing to neonatal hepatitis and liver cirrhosis. The resultant secretory defect leaves the lungs vulnerable to elastolysis and early-onset emphysema. Our aim in this study was to evaluate the effect of targeting strand 4a (s4A) as a strategy to inhibit polymerization and restore plasma secretion. METHODS: HEK293 cells and HepG2 cells were transfected with Z-AT (Z-AT cells) or control M-AT (M AT cells). The effect of Ac-TTAI-NH(2) (4M), Ac-FLEAIG-NH(2) (6M), and Ac SEAAASTAVVIA-NH(2) (12M) on preventing and reversing intracellular Z-AT polymers and secretion of AT was evaluated by pulse-chase/immunoprecipitation, ELISA, and immunoblot with a polymer-specific antibody (ATZII). The ER overload response was assessed by RT-PCR for PERK, calnexin, and RGS16, and ELISA for NF-kappaB, IL-6, and IL-8. RESULTS: All peptides prevented the intracellular accumulation of Z-AT (4M>6M>12M) in comparison with control peptides, with detection of the AT Inhibitor complex in inclusion bodies. In so doing, 4M also significantly increased the concentration of secreted Z-AT and the elastase inhibitory activity. Furthermore, the 4M peptide was able to reverse the intracellular aggregation of Z-AT. The ER accumulation of Z-AT was shown to induce PERK dependent NF-kappaB, IL-6, IL-8, and RGS16 and calnexin; all of which could be abrogated effectively by 4M. 4M had no effect on apoptosis or cell viability. CONCLUSIONS: These findings are the first evidence that targeting s4A can prevent the cellular accumulation and deleterious effects of Z-AT and restore its plasma concentrations. As such, this is a major step towards treatment of patients with Z-AT-related disease. PMID- 22425624 TI - Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. AB - BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis associated with liver inflammation. Steatosis causes recruitment of lymphocytes into the liver and this is worsened by lipopolysaccharides (LPS). As macrophages may be involved in the lymphocyte homing, we studied the role of lipids in determining the phenotype of Kupffer cells (KCs) at the stage of steatosis. METHODS: Steatosis was induced in mice by a high fat diet. The turnover and the recruitment of KCs were analyzed in vivo by flow cytometry. KCs phenotype was assessed by optical and electron microscopy, cell culture and lymphocyte recruitment by in vitro chemotaxis. Lipidomic analysis was carried out by mass-spectrometry and gene expression analysis by TaqMan low density array. RESULTS: Although the number of KCs was not modified in steatotic livers compared to normal livers, their phenotypes were different. Electron microscopy demonstrated that the KCs from fatty livers were enlarged and loaded with lipid droplets. Lipid synthesis and trafficking were dysregulated in fat-laden KCs and toxic lipids accumulated. Fat-laden KCs recruited more CD4+ T and B lymphocytes in response to LPS stimulation than did control KCs and produced high levels of pro-inflammatory cytokines/chemokines, which could be reversed by inhibition of lipogenesis. CONCLUSIONS: Lipid accumulation in fat-laden KCs is due to a dysregulation of lipid metabolism and trafficking. Fat-laden KCs are "primed" to recruit lymphocytes and exhibit a pro-inflammatory phenotype, which is reversible with inhibition of lipogenesis. PMID- 22425625 TI - Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential. AB - BACKGROUND & AIMS: Perforin plays a central role in the immunopathogenesis of different viral infections. However, its role in hepatitis C virus (HCV) infection has not been fully understood. Here, we analyzed two closely related questions: first, is CD8+ T cell-mediated killing of HCV-replicating human hepatoma cells mediated by perforin? Second, if so, do HCV-specific CD8+ T cells obtained from chronically HCV infected patients express and upregulate perforin? METHODS: Susceptibility of HCV-replicating human hepatoma cells to the cytotoxic pathway was tested in vitro by addition of perforin substitute streptolysin O and granzyme B and by co-culture experiments with a perforin-expressing HCV-specific CD8+ T cell clone in the presence of perforin or caspase inhibitors. HCV-specific CD8+ T cells were obtained and analyzed for perforin expression and differentiation markers ex vivo from 12 chronically infected patients and 12 patients with resolved HCV infection. RESULTS: HCV-replicating human hepatoma cells were susceptible to cytotoxic killing in vitro and a dominant role of perforin in HCV-specific CD8+ T cell-mediated cytolysis was observed. However, HCV-specific CD8+ T cells obtained ex vivo from chronically HCV infected patients expressed only low levels of perforin and showed an impaired ability to upregulate perforin. This was tightly linked to the distinct differentiation stage of HCV-specific CD8+ T cell differentiation ex vivo since early and intermediate differentiated HCV-specific CD8+ T cells only showed weak perforin expression in contrast to late differentiated CD8+ T cells that displayed strong perforin expression. CONCLUSIONS: Our results suggest that perforin plays a dominant role in CD8+ T cell-mediated lysis of HCV-replicating human hepatoma cells but that lysis may be limited in human chronic viral infection by the low perforin expression of early/intermediate differentiated HCV-specific CD8+ T cells. PMID- 22425626 TI - Apolipoprotein A-I, apolipoprotein B, high-sensitivity C-reactive protein and severity of coronary artery disease in Tunisian population. AB - BACKGROUND: The relationship between Apolipoprotein A-I, Apolipoprotein B, C reactive protein and the severity coronary artery disease in Tunisian CAD patients has not been examined. We investigated the association between serum ApoA-I, ApoB, hs-CRP and the severity of coronary artery disease. METHODS: This study was carried out on 180 patients who underwent angiography and 129 healthy controls. ApoA-I and ApoB as well as the serum total cholesterol, HDL, triglyceride, LDL and hs-CRP levels were measured. The ApoB/ApoA-I ratio was calculated. RESULTS: We showed a decreased level of ApoA-I and an increased level of ApoB, ApoB/ApoA-I ratio and hs-CRP in CAD patients compared to the control group (P<.001). In addition, we showed a significant increase of ApoB, ApoB/ApoA I ratio and hs-CRP in CAD patients presenting 0 to 3 vessels stenosis (P<.001). Multivariate analysis showed that ApoB (P<.001), and hs-CRP (P<.001) were independent predictors of the severity of CAD. CONCLUSION: In this study, ApoB and hs-CRP levels were markedly associated with the severity of CAD in Tunisian patients. We suggested that synergistic effects between dyslipidemia and inflammation led to increase the risk of the severity of CAD. PMID- 22425627 TI - Phosphate: a stealthier killer than previously thought? AB - The kidneys excrete excess dietary phosphate, and patients with chronic kidney disease may suffer from phosphate overload and hyperphosphatemia. In chronic kidney disease, hyperphosphatemia has emerged as a risk factor for vascular calcification, cardiovascular mortality, left ventricular hypertrophy, and progression of chronic kidney disease. Serum phosphate at the upper limits of normal has also been associated with adverse outcomes in patients with relatively preserved kidney function. Of note, hyperphosphatemia is not a sensitive indicator of phosphate overload. In this regard, increased circulating fibroblast growth factor-23, a phosphatonin that is released in response to phosphate overload, is independently associated with adverse outcomes in patients with and without chronic kidney disease. Direct effects of extracellular phosphate on vascular calcification or cardiovascular cell biology; adverse consequences of adaptive mechanisms activated to limit phosphate overload, such as left ventricular hypertrophy induced by fibroblast growth factor-23; or epidemiological associations of additional cardiovascular risk factors with chronic kidney disease may underlie these observations. We now review the pathophysiology of phosphate, its relationship with cardiovascular outcomes, the potential consequences for patient care related to dietary phosphate and phosphate binders, and the clinical relevance for patients without overt chronic kidney disease. PMID- 22425628 TI - Pulmonary valve-in-valve implants: how long do they prolong reintervention and what causes them to fail? AB - BACKGROUND: The valve-in-valve (VinV) procedure is a minimally invasive, transcatheter, off-pump, alternative to conventional valve replacement, which uses a failing bioprosthesis to anchor a second transcatheter-delivered prosthesis. This technique appears effective for prolonging freedom from reintervention and treating early device failure. However, it is unknown as to how long reintervention can be avoided. METHODS: We present the pathological findings of a VinV explanted after 47 months, as well as the failure modes of these devices. RESULTS: The VinV approach in our case ultimately failed, likely due to the proximity of the host's tissues to the prosthetic device, resulting in a combination of pannus, calcification, and a cusp tear. CONCLUSIONS: Additional long-term follow-up of pulmonary VinV implantations is needed in order to determine the life span of VinVs and what causes them to fail. PMID- 22425629 TI - Parvovirus B19 is a bystander in adult myocarditis. AB - BACKGROUND: The genomic DNA of parvovirus B19, a small single-stranded DNA virus of the genus Erythrovirus, has been shown to persist in solid tissues of constitutionally healthy, immunocompetent individuals. Despite these data, many case reports and series have linked the presence of parvovirus B19 genomic DNA, detected through nucleic acid amplification testing, with myocarditis and cardiomyopathy. Herein, we use multiple tools to better assess the relationship between parvovirus B19 and myocarditis and cardiomyopathy. METHODS: Nucleic acid amplification testing, immunohistochemistry, in situ hybridization, and electron microscopy were used to assess the location and activity of parvovirus B19 in cases of myocarditis and in cases with no significant cardiac disease. RESULTS: Nucleic acid amplification testing for parvovirus B19 genomic DNA was positive in 73% of patients with myocarditis/cardiomyopathy and in 26% of patients with no significant disease. In situ hybridization and immunohistochemistry showed that, in cases with amplifiable parvovirus B19 DNA, parvovirus B19 genomic DNA and viral protein production were present in rare mononuclear cells. CONCLUSIONS: In a majority of cases of myocarditis and a significant number of otherwise normal hearts, nucleic acid amplification testing detected persistent parvovirus B19 genomic DNA that did not play a significant pathogenic role. The source of parvovirus B19 DNA appeared to be interstitial mononuclear inflammatory cells and not myocardial or endothelial cells. Therefore, nucleic acid amplification testing alone is not diagnostically helpful for determining the etiology of adult myocarditis. PMID- 22425630 TI - Structural and thermodynamic studies of binding saturated fatty acids to bovine beta-lactoglobulin. AB - Lactoglobulin is a globular milk protein for which physiological function has not been clarified. Due to its binding properties lactoglobulin might serve as a carrier for bioactive molecules. Binding of 12-, 14-, 16- and 18-carbon saturated fatty acids to bovine beta-lactoglobulin has been characterised by isothermal titration calorimetry and X-ray crystallography as a part of systematic studies of lactoglobulin complexes with ligands of biological importance. The thermodynamic parameters have been determined for lauric, myristic and palmitic acid complexes revealing systematic decrease of enthalpic and increase of entropic component of DeltaG with elongation of aliphatic chain. In all crystal structures determined with resolution 1.9-2.1A, single fatty acid molecule was found in the beta-barrel in extended conformation with individual pattern of interactions. Location of a fatty acid in the binding site depends on the length of aliphatic chain and influences polar interactions between protein and ligand. Systematic changes of entropic component indicate important role of water in binding process. PMID- 22425631 TI - Mitochondrial dynamics and their impact on T cell function. AB - Energy supply is the most prominent function of mitochondria, but in addition, mitochondria are indispensable for a multitude of other important cellular functions including calcium (Ca(2+)) signaling and buffering, the supply of metabolites and the sequestration of apoptotic factors. The efficiency of those functions highly depends on the proper positioning of mitochondria within the cytosol. In lymphocytes, mitochondria preferentially localize into the vicinity (~200nm) of the immune synapse (IS). This localization is regulated by motor based cytoskeleton-mediated transport, the fusion/fission dynamics of mitochondria, and probably also through tethering with the ER. IS formation also induces the accumulation of CRAC/ORAI1 Ca(2+) channels, the CRAC/ORAI channel activator STIM1, K(+) channels and plasma membrane Ca(2+) ATPase (PMCA) within the IS. Such a large agglomeration of Ca(2+) binding organelles and proteins highlights the IS as a critical cellular compartment for Ca(2+) dependent lymphocyte activation. At the IS, Ca(2+) microdomains generated beneath open CRAC/ORAI channels provide a rapid, robust and reliable mechanism for driving cellular responses in mast cells and T cells. Here, we discuss the relevance of motor-based mitochondrial transport, fusion, fission and tethering for mitochondrial localization in T cells and the importance of subplasmalemmal mitochondria to control local CRAC/ORAI1-dependent Ca(2+) microdomains at the IS for efficient T lymphocyte activation. PMID- 22425632 TI - Back pain during pregnancy and living conditions: a comparison between Beninese and Canadian women. AB - OBJECTIVE: The objective of this exploratory study was to investigate and underline the contrasts between African and Canadian pregnant women, and their living conditions. We also intended to evaluate how they compared on low back pain, a condition that seems common across all pregnant women everywhere in the world. SUBJECTS AND METHOD: Thirty Beninese and 50 Canadian women were surveyed with demographic disability questionnaires O.D.I at approximately 25 weeks of pregnancy. RESULTS: There were large differences between the two groups due to the differences between the life style. Beninese women were more likely to be self-employed or housewives, while Canadian women were more likely to be employed. Beninese women worked for 18hours more per week, and had on average one more child at home. A higher percentage of Beninese women reported back pain, 83% versus 58% for Canadian women, but the disability scores were in the "moderate disability" range for both groups. A higher percentage of Beninese women also reported at least severe disability, 33% versus 14% for Canadian women. CONCLUSION: The results suggest that the higher percentages of Beninese women affected by back pain and by severe back pain is related to the longer hours worked and more strenuous physical work performed. PMID- 22425633 TI - Analysis of locality of early-stage maturation in confluent state of human retinal pigment epithelial cells. AB - Retinal pigment epithelial (RPE) cells were cultured on the laminin-coated and plain surfaces. The measurement of local nucleus density in non-stratified region, which correlated with formation of tight junction, is the indicator of the maturation, and the parameters can be applied to the evaluation of the early stage maturation of RPE cells in culture. PMID- 22425634 TI - Prenatal diagnosis of a 12q22q23.2 interstitial deletion by array CGH in a malformed fetus. AB - We report the prenatal diagnosis of a 12q22q23.2 de novo interstitial deletion performed by array based comparative genomic hybridization (array CGH) in a fetus with cystic hygroma colli, intrauterine growth retardation, microcephaly and micrognathism. Haploinsufficiency for insuline-like growth factor 1 gene (IGF1), which is mapped in the deleted region, is suggested because of its implication in prenatal and postnatal growth and in neuronal maturation. This case demonstrates the contribution of array CGH in prenatal diagnosis for detecting small unbalanced chromosomal abnormalities in malformed fetuses and, subsequently, for genetic counselling. PMID- 22425635 TI - Effect of two selenium sources on hepatocarcinogenesis and several angiogenic cytokines in diethylnitrosamine-induced hepatocarcinoma rats. AB - This experiment was designed to compare the effect of two selenium sources at the dosage of therapeutic level on hepatocarcinogenesis and angiogenic cytokines in DEN-induced hepatocarcinoma rats to further approach their possible anticancer's mechanism. One hundred and seventy-eight Sprague-Dawley (SD) rats (average weight being 100-120g) were randomly divided into 5 groups (I-V). Animals in group I, group II and group III served as the negative control, sodium selenite control (SS) and positive controls respectively, and received 0.1, 3.0, and 0.1mg/kg selenium from sodium selenite supplemented diets during the whole experimental time. Rats in group IV and group V were fed with selenium from selenium-enriched malt (SEM) and sodium selenite (SS) supplemented diets (3mg/kg respectively). To balance the nutritional content among each group, normal malt which was not treated with selenium was added into the diets of the challenge groups. The nutrition contents, except the selenium of the diet in each group, were similar and in accordance with NRC standards. Rats in groups III-V were treated by aqueous diethylnitrosamine solution (100mg/L) at the dosage of 10mg/kg body weight every day for 16 weeks to induce hepatocarcinoma, and drank sterilized water for an additional two weeks. Rats in group I and group II drank sterilized water throughout the experiment. At 4th, 8th, 12th, 16th week, five rats in each group were then sacrificed by cervical decapitation. At the termination of the study, at 18th week, the surplus rats were sacrificed by cervical decapitation. Feed was withheld from the rats for 12h before sampling. The number of hepatoma nodules in liver and mortality of rats were calculated. The values of the following items, including alpha-fetoprotein (AFP), gamma-glutamyltranspeptidase (GGT), tumor necrosis factor-alpha (TNF-alpha), insulin-like growth factors-II (IGF-II), nitric oxide (NO) and total nitric oxide synthase (T-NOS) in plasma were determined. At the same time, the positive numbers of vascular endothelial growth factor (VEGF) and protein kinase C-alpha (PKCalpha) staining cells in tumor tissue were analyzed by immunohistochemistry using the Envision two step methods with a kit. The results indicated that SEM could significantly decrease the mortality of rats and the number of hepatoma nodules, values of GGT and AFP, and the levels of IGF-II, NO and NOS and lessen the positive numbers of VEGF and PKCalpha staining cells in tumor tissue. Moreover, SEM could increase the levels of TNF-alpha in the initiated time of hepatocarcinogenesis, whereas, decrease the levels of TNF-alpha in the progressive time of hepatocarcinogenesis. SS could only significantly inhibit the positive numbers of PKCalpha staining cells in tumor tissue, decrease the levels of GGT, AFP and TNF-alpha at minority sampling times, and increase the levels of NO. In conclusion, SEM could reduce the mortality. It might be related to deaden significantly the lesion of liver, delay the cause of hepatocarcinogenesis, and inhibit the progress of angiogenesis to increase the livability of DEN-induced hepatocarcinoma rats. SS at the same therapeutic dosage had less effect on the hepatocarcinogenesis by inhibiting angiogenesis and relative cytokines to some extent. PMID- 22425636 TI - Structure, function and targeting of human telomere RNA. AB - Human telomeres play an important role in critical processes underlying genome stability, cancer, and aging. For a long time, telomeres have been considered transcriptionally silent. A recent finding demonstrated that telomere DNA is transcribed into telomeric repeat-containing RNA (referred to as TERRA) in mammalian cells. The existence of TERRA RNA may reveal a new level of regulation and protection of chromosome ends that could promote valuable insight into fundamental biological processes such as cancer and aging. Revealing the structure and function of telomere RNA will be essential for understanding telomere biology and telomere-related diseases. NMR and X-ray crystallography have demonstrated that human telomere RNA forms G-quadruplex structures. More recently, human telomere RNA is suggested to form a G-quadruplex dimer in the living cells by employing a light-switching probe. The proposed structures may be a valuable target for anticancer agents directed against telomeres. This review highlights the structures and topologies for telomere RNA G-quadruplex and recent efforts in the design of telomere RNA G-quadruplex ligands. The future challenges in the field are outlined. PMID- 22425637 TI - Distal rectus femoris transfer as part of multilevel surgery in children with spastic diplegia--a randomized clinical trial. AB - The evidence in support of distal rectus femoris transfer (DRFT) as part of single-event multilevel surgery (SEMLS) is limited due to inconsistent outcome reports and a lack of randomized studies. The purpose of this prospective randomized trial was to establish whether the results of SEMLS without DRFT are similar to those of a conventional approach that includes DRFT in the SEMLS. In all, 32 children with spastic diplegia (GMFCS I-III) and an indication for DRFT were recruited and randomized into a DRFT (15 children) and a NON-DRFT group (17 children) using a minimization method. During SEMLS, bilateral DRFT was performed only in the DRFT group. Three-dimensional gait analysis and clinical examination were performed before and 1 year after surgery. In both groups a significant increase in range of motion during swing and knee flexion velocity were found, which was significantly higher in the DRFT group. While peak knee flexion in swing (pKFSw) was preserved in the DRFT group and significantly decreased in the NON-DRFT group, pKFSw timing was significantly earlier in both groups. The clinical relevance of the higher overall benefits in the DRFT group is limited, considering that 33% of patients in this group did not benefit from the procedure. Furthermore, 53% of the NON-DRFT patients did not undergo what proved to be an unnecessary DRFT. Subgroup analysis showed benefits for patients with decreased pKFSw, while those with severe flexed-knee gait (normal or increased pKFSw) did not profit from DRFT. This may explain the inconsistent overall results, and DRFT is therefore not recommended as a "prophylactic" procedure in patients with severe flexed-knee gait. PMID- 22425638 TI - Outcomes of correction of internal hip rotation in patients with spastic cerebral palsy using proximal femoral osteotomy. AB - Internal hip rotation (IHR) is the major cause of intoeing gait in patients with cerebral palsy (CP). Femoral derotation osteotomy (FDO) is the preferred treatment to correct excessive anteversion, however the condition may persist or recur postoperatively. Retrospective clinical and kinematic evaluation of 75 spastic diplegic CP patients was conducted for a mean duration of 22 months following proximal FDO. The patients were divided into two groups depending on the correction or persistence of IHR evident at kinematics after surgery. If corrected, mean patient follow-up was extended to 53 months. Outcomes were analyzed using Two Proportions Equality, Mann-Whitney and Wilcoxon tests. IHR persisted in 33.3% of cases at mean follow-up of 22 months and subtrochanteric femur osteotomy was more frequent in this group (p=0.033). Thirty-five of the fifty-four patients with first-round gait correction were monitored during the extended follow-up. Those for whom IHR recurred (9.5%) had undergone FDO at a comparatively younger age. Patient gender, operations prior to or at the time of femoral osteotomy, topographic classification, GMFCS level, or the extent of preoperative clinical and kinematic abnormalities had no apparent influence on persistence or recurrence of abnormal gait. PMID- 22425640 TI - Discrete RNA libraries from pseudo-torsional space. AB - The discovery that RNA molecules can fold into complex structures and carry out diverse cellular roles has led to interest in developing tools for modeling RNA tertiary structure. While significant progress has been made in establishing that the RNA backbone is rotameric, few libraries of discrete conformations specifically for use in RNA modeling have been validated. Here, we present six libraries of discrete RNA conformations based on a simplified pseudo-torsional notation of the RNA backbone, comparable to phi and psi in the protein backbone. We evaluate the ability of each library to represent single nucleotide backbone conformations, and we show how individual library fragments can be assembled into dinucleotides that are consistent with established RNA backbone descriptors spanning from sugar to sugar. We then use each library to build all-atom models of 20 test folds, and we show how the composition of a fragment library can limit model quality. Despite the limitations inherent in using discretized libraries, we find that several hundred discrete fragments can rebuild RNA folds up to 174 nucleotides in length with atomic-level accuracy (<1.5 A RMSD). We anticipate that the libraries presented here could easily be incorporated into RNA structural modeling, analysis, or refinement tools. PMID- 22425639 TI - Conformational heterogeneity of the SAM-I riboswitch transcriptional ON state: a chaperone-like role for S-adenosyl methionine. AB - Riboswitches are promising targets for the design of novel antibiotics and engineering of portable genetic regulatory elements. There is evidence that variability in riboswitch properties allows tuning of expression for genes involved in different stages of biosynthetic pathways by mechanisms that are not currently understood. Here, we explore the mechanism for tuning of S-adenosyl methionine (SAM)-I riboswitch folding. Most SAM-I riboswitches function at the transcriptional level by sensing the cognate ligand SAM. SAM-I riboswitches orchestrate the biosynthetic pathways of cysteine, methionine, SAM, and so forth. We use base-pair probability predictions to examine the secondary-structure folding landscape of several SAM-I riboswitch sequences. We predict different folding behaviors for different SAM-I riboswitch sequences. We identify several "decoy" base-pairing interactions involving 5' riboswitch residues that can compete with the formation of a P1 helix, a component of the ligand-bound "transcription OFF" state, in the absence of SAM. We hypothesize that blockage of these interactions through SAM contacts contributes to stabilization of the OFF state in the presence of ligand. We also probe folding patterns for a SAM-I riboswitch RNA using constructs with different 3' truncation points experimentally. Folding was monitored through fluorescence, susceptibility to base-catalyzed cleavage, nuclear magnetic resonance, and indirectly through SAM binding. We identify key decision windows at which SAM can affect the folding pathway towards the OFF state. The presence of decoy conformations and differential sensitivities to SAM at different transcript lengths is crucial for SAM-I riboswitches to modulate gene expression in the context of global cellular metabolism. PMID- 22425641 TI - Retronasal perception of odors. AB - We perceive odors orthonasally during sniffing; in contrast, we perceive odors retronasally during eating when they enter the nose through the pharynx. There are clear differences between orthonasal and retronasal olfaction in neuronal processing and perception, so that these two pathways convey two distinct sensory signals. The perception of foods is based on the interaction between ortho- and retronasal smell, taste, trigeminal activation and texture, so it is difficult to investigate one of these factors in isolation. Specific clinical aspects include effects of retronasal olfaction on satiation and swallowing. PMID- 22425642 TI - Environmental inversion effects in face perception. AB - Visual processing is highly sensitive to stimulus orientation; for example, face perception is drastically worse when faces are oriented inverted vs. upright. However, stimulus orientation must be established in relation to a particular reference frame, and in most studies, several reference frames are conflated. Which reference frame(s) matter in the perception of faces? Here we describe a simple, novel method for dissociating effects of egocentric and environmental orientation on face processing. Participants performed one of two face-processing tasks (expression classification and recognition memory) as they lay horizontally, which served to disassociate the egocentric and environmental frames. We found large effects of egocentric orientation on performance and smaller but reliable effects of environmental orientation. In a follow-up control experiment, we ruled out the possibility that the latter could be explained by compensatory ocular counterroll. We argue that environmental orientation influences face processing, which is revealed when egocentric orientation is fixed. PMID- 22425643 TI - Tumor-associated neutrophils: friend or foe? AB - Neutrophils play an established role in host defense and in killing invading microorganisms. Although neutrophils are traditionally considered in the context of their antibacterial functions, it is becoming increasingly clear that tumor associated neutrophils (TAN) play a major role in cancer biology. Neutrophils make up a significant portion of the inflammatory cell infiltrate in many models of cancer. Like all other leukocytes, they move into tissues under the influence of specific chemokines, cytokines and cell adhesion molecules. The tumor microenvironment has been shown to be responsible for their recruitment in cancer. We have found that TAN are a distinct population of neutrophils, differing markedly in their transcriptomic profile from both naive neutrophils and the granulocytic fraction of myeloid-derived suppressor cells. Studies have demonstrated specific examples of tumor-mediated signals (such as transforming growth factor-beta) that induce the formation of a pro-tumorigenic (N2) phenotype capable of supporting tumor growth and suppressing the antitumor immune response. However, there are also studies showing that TAN can also have an antitumorigenic (N1) phenotype. Herein, we explore the literature on the different mechanisms of TAN recruitment to tumors, the unique characteristics of TAN and what shapes their pro- and/or antitumor effects. PMID- 22425644 TI - Structure-based phylogeny of polyene macrolide antibiotic glycosyltransferases. AB - Antibiotic glycosyltransferases (AGts) attach unusual deoxy-sugars to aglycons so antibiotics can exert function. It has been reported that polyene macrolide (PEM) AGts have different evolutionary origin when compared with other polyketide AGts, and our previous analysis have suggested that they could be results of horizontal gene transfer (HGT) from eukaryotes. In this paper, we compared the structures of PEM AGts with structures of eukaryotes and other AGts, and then built models of the representative PEM AGts and GT-1 glycosyltransferases. We also constructed the Neighbor-Joining (NJ) trees based on the normalized Root Mean Square (RMS) distance, the Bayesian tree guided by structural alignments, and carried out analysis on several key conserved residues in PEM AGts. The NJ tree showed a close relationship between PEM AGts and eukaryotic glycosyltransferases, and Bayesian tree further supported their affinity with UDP-glucuronosyltransferases (UGTs). Analysis on key conserved residues showed that PEM AGts may have similar interaction mechanism such as in the formation of hydrogen bonds as eukaryotic glycosyltransferases. Using structure-based phylogenetic approaches, this study further supported that PEM AGts were the result of HGT between prokaryotes and eukaryotes. PMID- 22425645 TI - The impact of severe LDL receptor mutations on SREBP-pathway regulation in homozygous familial hypercholesterolemia (FH). AB - Familial hypercholesterolemia (FH), Niemann-Pick disease type C (NPC) and Tangier disease (TD) are genetic inherited disorders with impaired processing of cholesterol, caused by mutations in genes that regulate cellular uptake, intracellular movement and transport of cholesterol. Various studies have shown a crucial regulatory role of the SREBP-pathway for cellular cholesterol homeostasis in these diseases. Since cholesterol is an essential structural component of cells, we assessed the impact of a severe FH causing LDLR mutation (FH p.W556R) on the SREBP pathway in primary FH fibroblasts. Primary FH fibroblasts derived from patients with the LDL receptor mutation p.W556R were used for gene expression experiments. Gene expression studies revealed increased expressions of SREBP regulated genes HMGCR, LDLR, SREBP-2, SREBP-1, SR-BI, INSIG-1, but interestingly not SCAP. In contrast expression of ABCA1, was strongly decreased in homozygous, but not in heterozygous p.W556R fibroblasts. Gene expression experiments with LDL receptor lacking primary FH fibroblasts, revealed that SR-BI and ABCA1 are important regulators for cholesterol acquisition in FH cells, consistent with findings in cells from NPC and TD patients. PMID- 22425646 TI - Bioinformatic selection of putative epigenetically regulated loci associated with obesity using gene expression data. AB - There is considerable interest in defining the relationship between epigenetic variation and the risk of common complex diseases. Strategies which assist in the prioritisation of target loci that have the potential to be epigenetically regulated might provide a useful approach in identifying concrete examples of epigenotype-phenotype associations. Focusing on the postulated role of epigenetic factors in the aetiopathogenesis of obesity this report outlines an approach utilising gene expression data and a suite of bioinformatic tools to prioritise a list of target candidate genes for more detailed experimental scrutiny. Gene expression microarrays were performed using peripheral blood RNA from children aged 11-13years selected from the Newcastle Preterm Birth Growth Study which were grouped by body mass index (BMI). Genes showing >=2.0 fold differential expression between low and high BMI groups were selected for in silico analysis. Several bioinformatic tools were used for each following step; 1) a literature search was carried out to identify whether the differentially expressed genes were associated with adiposity phenotypes. Of those obesity-candidate genes, putative epigenetically regulated promoters were identified by 2) defining the promoter regions, 3) then by selecting promoters with a CpG island (CGI), 4) and then by identifying any transcription factor binding modules covering CpG sites within the CGI. This bioinformatic processing culminated in the identification of a short list of target obesity-candidate genes putatively regulated by DNA methylation which can be taken forward for experimental analysis. The proposed workflow provides a flexible, versatile and low cost methodology for target gene prioritisation that is applicable to multiple species and disease contexts. PMID- 22425647 TI - Predicted structural change in erythropoietin of plateau zokors--adaptation to high altitude. AB - Erythropoietin (EPO) is a glycoprotein hormone, expressed mainly in fetus liver and adult kidneys. EPO plays an important role in enhancing red blood cell formation in bone marrow under hypoxia. Plateau zokor (Myospalax baileyi), an subterranean burrowing endemic rodent inhabiting areas of 2 800-4 200 m above sea level on Qinghai-Tibet Plateau, is a typical high hypoxia tolerant mammal with high ratio of oxygen utilization in adaptation to the harsh plateau environment. To investigate the possible mechanisms of adaptation of plateau zokor EPO to high altitude, the complete cDNA and amino acid sequences of plateau zokor EPO have been described. Phylogenetic tree of Epo showed the convergence of the Spalax and Myospalax, indicating that, the convergent evolution was driven by similar hypoxic ecological niches. Our results showed that some common sites under positive selection in zokor (116M and 144A) and Spalax (102R, 116M, 144A and 152P) are the important sites for Epo biological activity. This study thus reports a gene level observation which may be involved in adaptation to underground life at high altitude. PMID- 22425648 TI - Suppressor of cytokine signaling 3 in the human hypothalamus. AB - In rodents, the mediobasal hypothalamus and the hypothalamic paraventricular nucleus (PVN) are implicated in leptin signaling. Surprisingly little data is available on the human hypothalamus. We set out to study the expression of suppressor-of-cytokine-signaling 3 (SOCS3), alpha-melanocyte stimulating hormone (alphaMSH) and agouti-related protein (AgRP) in the infundibular nucleus (IFN) and to investigate the relationship between these neuropeptide expressions and serum leptin concentrations in a blood sample taken within 24h before death. We studied post-mortem human brain material by means of quantitative immunocytochemistry. We found that SOCS3 immunoreactivity was widely distributed throughout the hypothalamus, and most prominent in the PVN, whereas expression levels in the IFN were low. Surprisingly, SOCS3 expression in the PVN was inversely related to serum leptin. A significant positive correlation was observed between AgRP and NPY expression in the IFN. The inverse correlation between SOCS3 expression in the PVN and serum leptin was unexpected and may be related to the hypothalamic adaptation to fatal illness rather than to nutritional status, or may represent an interspecies difference. PMID- 22425649 TI - Reduced food intake after exposure to subtle weight-related cues. AB - This research investigated the influence of weight-related cues on food intake. The first study used a screensaver showing three of the famous skinny human-like sculptures by Alberto Giacometti and found that participants in this condition consumed less chocolate than when they were exposed to a more neutral work of art. In the second study, participants had to indicate their body weight either before or after the tasting. Reporting their weight before the tasting resulted in reduced food intake. A gender effect was found for the second but not the first study. We suggest that the cues in the two studies might have been processed with different levels of awareness, which might explain the gender effect found in the second study. PMID- 22425650 TI - Pharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting. AB - Nausea and vomiting are among the most common and distressing consequences of cytotoxic chemotherapies. Nausea and vomiting can be acute (0-24h) or delayed (24 72 h) after chemotherapy administration. The introduction of 5-HT(3) receptor antagonists in the 90s was a major advance in the prevention of acute emesis. These receptor antagonists exhibited similar control on acute emesis but had no effect on delayed emesis. These findings led to the hypothesis that serotonin plays a central role in the mechanism of acute emesis but a lesser role in the pathogenesis of delayed emesis. In contrast, delayed emesis has been largely associated with the activation of neurokinin 1 (NK(1)) receptors by substance P. However, in 2003, a new 5-HT(3) receptor antagonist was introduced into the market; unlike first generation 5-HT(3) receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed chemotherapy induced nausea and vomiting. Recent mechanistic studies have shown that palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT(3) receptor, positive cooperativity, persistent inhibition of receptor function after the drug is removed and triggers 5-HT(3) receptor internalization. Further, in vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT(3) receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT(3) and NK(1) receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses. PMID- 22425651 TI - The cardioprotective effect of TG-6, a newly synthesized compound, on ischemia reperfusion injury in rats. AB - We tested 3-nitro-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl) benzoylguanidine tartrate (TG-6) which is combinated of two known cardioprotective agents cariporide and trimetazidine, whether additively to reduce ischemia-reperfusion injury in rats. Using models of in vitro perfusion (Langendorff system) and in vivo open chest left anterior descending coronary artery ligation causing ischemia-reperfusion injury. We also used Fura-2 to measure the cytosolic Ca2+ concentrations ([Ca2+]i) in cardiomyocytes, western blot analysis the protein expression of Kv1.4, Kv4.2, Kv4.3 in myocardial ischemia-reperfusion rats. TG-6 improved the cardiac function in both in vivo and in vitro models, lowered Lactate Dehydrogenase (LDH), Creatine Kinase (CK), Malodialdehyed (MDA) activity while enhanced Superoxide Dismutase (SOD) activity. High dose of TG-6 improved the hypoxia injury of cardiomyocytes induced by sodium dithionite (Na2S2O4), enhanced the viability and decreased the [Ca2+]i. It also down-regulated the expression of Kv1.4 and increased the expression of Kv4.2 and Kv4.3, so it might through regulating the expression of the transient outward potassium current (Ito) to improve the cardiac function. PMID- 22425652 TI - Possible induction of West syndrome by oxcarbazepine therapy in a patient with complex partial seizures. AB - Oxcarbazepine has been reported to precipitate myoclonic, generalised tonic clonic, absence, and complex partial seizures, and carbamazepine to precipitate absences, myoclonic seizures and spasms. Here, we report a one-year, six-month old girl with complex partial seizures who developed infantile spasms, developmental regression, and hypsarrhythmia during the two weeks directly following initiation of oxcarbazepine (14 mg/kg/day). All of these resolved within a few days after discontinuation of this medication. Although we cannot rule out that the above association may have been coincidental, or that the improvement may have been due to concurrent therapy, this case raises the possibility that oxcarbazepine, like carbamazepine, may precipitate infantile spasms and West syndrome. PMID- 22425653 TI - Assessment of swine worker exposures to dust and endotoxin during hog load-out and power washing. AB - Field measurements of personal and area dust and endotoxin concentrations were obtained while agricultural workers performed two work tasks that have been previously unreported: hog load-out and swine building power washing. Hog load out involves moving hogs from their pens in finishing buildings into a truck for transport to a meat processor. High pressure power washing is conducted for sanitation purposes after a building has been emptied of hogs to remove surface and floor debris. This debris consists of feed, feces, and hog dander as dust or an encrusted form. The hog load-out process necessarily increases pig activity which is known to increase airborne dust concentrations. An unintended consequence of power washing is that the material covering surfaces is forcibly ejected into the atmosphere, creating the potential for a highly concentrated aerosol exposure to workers. The load-out process resulted in a median personal inhalable mass concentration of 7.14 mg m(-) (3) and median endotoxin concentration of 12 150 endotoxin units (EU) m(-) (3). When converted to an 8-h time-weighted average for a 'total' sampler, one of the 19 samples exceeded a regulatory limit of 15 mg m(-) (3). An impinger was used to sample power washing endotoxin concentrations, which resulted in a median personal concentration of 40 350 EU m(-) (3). These concentrations were among the highest found in the literature for any occupation. With the lack of engineering controls present to reduce airborne contaminant concentrations in swine buildings, either respirator use or a reduction in exposure time is recommended while performing these tasks. PMID- 22425654 TI - A detailed urinary excretion time course study of captan and folpet biomarkers in workers for the estimation of dose, main route-of-entry and most appropriate sampling and analysis strategies. AB - Captan and folpet are two fungicides largely used in agriculture, but biomonitoring data are mostly limited to measurements of captan metabolite concentrations in spot urine samples of workers, which complicate interpretation of results in terms of internal dose estimation, daily variations according to tasks performed, and most plausible routes of exposure. This study aimed at performing repeated biological measurements of exposure to captan and folpet in field workers (i) to better assess internal dose along with main routes-of-entry according to tasks and (ii) to establish most appropriate sampling and analysis strategies. The detailed urinary excretion time courses of specific and non specific biomarkers of exposure to captan and folpet were established in tree farmers (n = 2) and grape growers (n = 3) over a typical workweek (seven consecutive days), including spraying and harvest activities. The impact of the expression of urinary measurements [excretion rate values adjusted or not for creatinine or cumulative amounts over given time periods (8, 12, and 24 h)] was evaluated. Absorbed doses and main routes-of-entry were then estimated from the 24-h cumulative urinary amounts through the use of a kinetic model. The time courses showed that exposure levels were higher during spraying than harvest activities. Model simulations also suggest a limited absorption in the studied workers and an exposure mostly through the dermal route. It further pointed out the advantage of expressing biomarker values in terms of body weight-adjusted amounts in repeated 24-h urine collections as compared to concentrations or excretion rates in spot samples, without the necessity for creatinine corrections. PMID- 22425655 TI - More on the dynamics of dust generation: the effects of mixing and sanding chrysotile, calcium carbonate, and other components on the characteristics of joint-compound dusts. AB - An ongoing research effort designed to reconstruct the character of historical exposures associated with use of chrysotile-containing joint compounds naturally raised questions concerning how the character (e.g. particle size distributions) of dusts generated from use of recreated materials compares to dusts from similar materials manufactured historically. This also provided an opportunity to further explore the relative degree that the characteristics of dusts generated from a bulk material are mediated by the properties of the bulk material versus the mechanical processes applied to the bulk material by which the dust is generated. In the current study, the characteristics of dusts generated from a recreated ready mix and recreated dry mix were compared to each other, to dusts from a historical dry mix, and to dusts from the commercial chrysotile fiber (JM 7RF3) used in the recreated materials. The effect of sanding on the character of dusts generated from these materials was also explored. Dusts from the dry materials studied were generated and captured for analysis in a dust generator-elutriator. The recreated and historical joint compounds were also prepared, applied to drywall, and sanded inside sealed bags so that the particles produced from sanding could be introduced into the elutriator and captured for analysis. Comparisons of fiber size distributions in dusts from these materials suggest that dust from commercial fiber is different from dusts generated from the joint compounds, which are mixtures, and the differences persist whether the materials are sanded or not. Differences were also observed between sanded recreated ready mix and either the recreated dry mix or a historical dry mix, again whether sanded or not. In all cases, however, such differences disappeared when variances obtained from surrogate data were used to better represent the 'irreducible variation' of these materials. Even using the smaller study-specific variances, no differences were observed between the recreated dry mix and the historical dry mix, indicating that chrysotile-containing joint compounds can be recreated using historical formulations such that the characteristics of the modern material reasonably mimic those of a corresponding historical material. Similarly, no significant differences were observed between dusts from sanded and unsanded versions of similar materials, suggesting (as in previous studies) that the characteristics of asbestos-containing dusts are mediated primarily by the properties of the bulk material from which they are derived. PMID- 22425656 TI - Three-dimensional interactive and stereotactic atlas of the cranial nerves and their nuclei correlated with surface neuroanatomy, vasculature and magnetic resonance imaging. AB - Knowledge of the cranial nerves and their nuclei is critical in clinical practice, medical research and education. However to our best knowledge, a comprehensive source capturing full three-dimensional (3D) relationships of the cranial nerves along with surrounding neuroanatomy is not yet available. This work addresses the construction and validation of an atlas of the cranial nerves with their nuclei, correlated with surface neuroanatomy, vasculature, and magnetic resonance imaging. The atlas is interactive, stereotactic, 3D, detailed, fully parcellated, completely labeled, consistent in 3D, electronically dissectible, and scalable. A 3D geometrical model of the 12 pairs of cranial nerves with nuclei was created from an in vivo magnetic resonance scan exploiting in-house developed tools and methods, including tubular and iso-surface modeling, interactive editing, and mesh compression. This virtual model contains 439 objects with 121 different names, labeled based on Terminologia Anatomica. The model was integrated with a 3D atlas of structure, vasculature and tracts developed earlier, and correlated with sectional magnetic resonance anatomy. The whole model or its components can be interactively rotated, zoomed, panned, and add or removed with a simple few clicks. The studied material can be adaptively selected in an in-depth manner by using controls available in the user interface. This atlas is potentially useful for anatomy browsing, user self-testing, automatic student assessment, preparing materials, and localization in clinical neurology. PMID- 22425657 TI - Response-adaptive designs for continuous treatment responses in phase III clinical trials: A review. AB - A variety of response-adaptive randomization procedures have been proposed in literature assuming binary outcomes. However, the list is not so long for continuous outcomes though many real clinical trials deal with continuous treatment responses. In this paper, we attempt to explore the available procedures together with a comparison of their performances. Some real-life adaptive trial is also reviewed. PMID- 22425658 TI - Galactose can be an inducer for production of therapeutic proteins by auto induction using E. coli BL21 strains. AB - Recently lactose mediated auto-induction in Escherichia coli has gained a lot of interest because higher protein titer could be achieved without the need to monitor growth and add inducer at the proper time. In this study a high level therapeutic protein production by auto-induction was observed in E. coli BL21 using either T7 or tac promoters in the modified Luria Bertani (mLB) medium containing soy peptone instead of tryptone in Luria Bertani (LB) medium. Based on medium analysis and spiking experiments it was found that 0.4 mM galactose from the soy peptone caused the auto-induction. E. coli cultures induced by galactose can saturate at considerably higher density than cultures induced by IPTG. Galactose is not consumed by E. coli BL21. Finally it has been demonstrated that auto-induction can be effectively used in fed-batch fermentation for the industrial production of a therapeutic protein. The principle of galactose mediated auto-induction should be able to apply to high throughput microplates, shake flasks and fed-batch fermentors for clone screening and therapeutic protein expression in E. coli gal(-) strains such as most commonly used BL21. PMID- 22425659 TI - Engineering genes for predictable protein expression. AB - The DNA sequence used to encode a polypeptide can have dramatic effects on its expression. Lack of readily available tools has until recently inhibited meaningful experimental investigation of this phenomenon. Advances in synthetic biology and the application of modern engineering approaches now provide the tools for systematic analysis of the sequence variables affecting heterologous expression of recombinant proteins. We here discuss how these new tools are being applied and how they circumvent the constraints of previous approaches, highlighting some of the surprising and promising results emerging from the developing field of gene engineering. PMID- 22425660 TI - A case of IgE-multiple myeloma presenting with a high serum Krebs von den Lungen 6 level. PMID- 22425661 TI - Integration of architectural and cytologic driven image algorithms for prostate adenocarcinoma identification. AB - INTRODUCTION: The advent of digital slides offers new opportunities within the practice of pathology such as the use of image analysis techniques to facilitate computer aided diagnosis (CAD) solutions. Use of CAD holds promise to enable new levels of decision support and allow for additional layers of quality assurance and consistency in rendered diagnoses. However, the development and testing of prostate cancer CAD solutions requires a ground truth map of the cancer to enable the generation of receiver operator characteristic (ROC) curves. This requires a pathologist to annotate, or paint, each of the malignant glands in prostate cancer with an image editor software - a time consuming and exhaustive process. Recently, two CAD algorithms have been described: probabilistic pairwise Markov models (PPMM) and spatially-invariant vector quantization (SIVQ). Briefly, SIVQ operates as a highly sensitive and specific pattern matching algorithm, making it optimal for the identification of any epithelial morphology, whereas PPMM operates as a highly sensitive detector of malignant perturbations in glandular lumenal architecture. METHODS: By recapitulating algorithmically how a pathologist reviews prostate tissue sections, we created an algorithmic cascade of PPMM and SIVQ algorithms as previously described by Doyle el al. [1] where PPMM identifies the glands with abnormal lumenal architecture, and this area is then screened by SIVQ to identify the epithelium. RESULTS: The performance of this algorithm cascade was assessed qualitatively (with the use of heatmaps) and quantitatively (with the use of ROC curves) and demonstrates greater performance in the identification of malignant prostatic epithelium. CONCLUSION: This ability to semi-autonomously paint nearly all the malignant epithelium of prostate cancer has immediate applications to future prostate cancer CAD development as a validated ground truth generator. In addition, such an approach has potential applications as a pre-screening/quality assurance tool. PMID- 22425662 TI - Overexpression of GRP78 in complete hydatidiform moles. AB - OBJECTIVE: Hydatidiform moles, subdivided into partial moles (PM) and complete moles (CM), are abnormal pregnancies with a disturbed invasive behavior. We had previously shown that MMP-2 and p53 proteins are overexpressed in CM versus PM, and that in primary cytotrophoblasts p53 protein is stabilized by complexing to the 78kDa glucose-regulated protein (GRP78) which is involved in cytotrophoblasts invasion process. The present study aims to compare the transcript expression profile of p53, MMP-2 and GRP78 in hydatidiform moles. METHODS: A retrospective study was performed by RT-qPCR and immunostaining on paraffin-embedded tissues of 19 PM, 16 CM and 16 control (CTRL) samples of gestational age 8-12 weeks. RESULTS: Expression of MMP-2 transcript was significantly overexpressed in CM compared to CTRL samples (p=0.031). In contrast, expression of p53 transcript was similar among the samples. This suggests a regulation of p53 in CM at the protein level. GRP78 cDNA was significantly overexpressed in CM compared to CTRL (p=0.021) and to PM (p=0.011). At the protein level, immunostaining of GRP78 was on average stronger in CM than PM samples. CONCLUSIONS: Collectively, present data suggest that in CM, p53 is normally expressed at the mRNA level but probably complexes at the protein level with the overexpressed GRP78, leading to accumulation of p53 protein. Moreover, since GRP78 and MMP-2 are increased in CM and known to play key roles in invasion, our results suggest that GRP78 and MMP-2 should be investigated as prognostic markers of hydatidiform moles. PMID- 22425663 TI - Concomitant boost plus large-field preoperative chemoradiation in locally advanced uterine cervix carcinoma: Phase II clinical trial final results (LARA-CC 1). AB - OBJECTIVE: To report the Phase II study final results in terms of pathological complete response (pCR) and complications in locally advanced cervical carcinoma (LACC) patients treated with chemoradiation (CT/RT) regimen based on accelerated fractionation, nodal extended fields and adjuvant radical surgery. METHODS: The sample size was quantified according to published data which shows that CT/RT followed by radical surgery in LACC patients provides a pCR rate above 45%. The 2 stage design by Simon was used to test the null hypothesis that the true pCR would improve by above 20%. The chemoradiation regimen was considered active if >24/43 pCRs were recorded. 40 Gy/2 Gy fraction in 4 weeks was delivered to nodal volume extending up to L3 vertebra, concurrently with chemotherapy. 45 Gy in 20 fractions with a concomitant boost strategy was delivered to the macroscopic disease only. RESULTS: 47 patients were enrolled. Median follow-up was 26 months (3-52 months). Pathological response was assessed in 44/47 patients: 17/44 (38.6%) showed a pCR to treatment, and 9/44 cases (20.5%) showed microscopic disease. Pelvic nodal metastases were documented in 9/44 cases (20.5%). 87.5% of recurrences were extra pelvic. Five patients (11%) developed acute severe gastrointestinal toxicity. The actuarial cumulative 2-year incidence of G >= 2 late cutaneous, gastrointestinal, and genitourinary toxicity was 10.3%, 8.3% and 24.9%, respectively. The 3-year DFS was 77.1%, while the 3-year OS was 80.5%. CONCLUSIONS: Our results confirm the high tolerability and efficacy of this accelerated regimen. However, based on the study design, 45 Gy as a concomitant boost CT/RT delivered by a 3D technique does not seem sufficient to increase pCR rate. PMID- 22425664 TI - Peritoneal washing cytology in patients with BRCA1 or BRCA2 mutations undergoing risk-reducing salpingo-oophorectomies: a 10-year experience and reappraisal of its clinical utility. AB - OBJECTIVE: To evaluate the utility of peritoneal washing cytology (PWC) for detecting occult primary peritoneal carcinoma in patients with BRCA1 or BRCA2 mutations, we reviewed PWCs obtained during risk-reducing salpingo-oophorectomy (RRSO) from 117 patients at our institution and correlated the results with surgical pathology findings. METHODS: Records of 128 PWCs from 125 patients with BRCA1 or BRCA2 mutations undergoing RRSO at MD Anderson Cancer Center between 2000 and 2010 were obtained. Slides were available for review for 119 PWCs from 117 patients (2 patients had 2 PWCs each). Cytopathologists, blinded to the RRSO histopathologic diagnoses, categorized the PWCs as benign, atypical, suspicious for malignancy, or malignant. These results were correlated with the RRSO histopathologic diagnoses. RESULTS: PWCs from 113 patients were benign. Of the remaining 4 patients, 2 had PWCs classified as atypical, 1 as suspicious for malignancy, and 1 as malignant. The corresponding RRSO histopathologic findings of the 2 atypical PWCs showed endosalpingiosis and cystadenofibroma in one case and showed no abnormalities in the other case. Both patients with suspicious or malignant PWCs, indicating the possibility of occult peritoneal carcinoma, had RRSO histopathologic diagnoses of endometriosis and endosalpingiosis. Nine patients had abnormal tubal or ovarian histologic findings, but all 9 of these patients had benign PWCs. CONCLUSION: PWC has the potential to detect occult peritoneal carcinoma in patients with BRCA1 or BRCA2 mutations. The clinical significance of a positive PWC without abnormal RRSO histology remains unclear and will require long-term follow-up for determination. PMID- 22425665 TI - BRCA1 and BRCA2 germline mutations in Moroccan breast/ovarian cancer families: novel mutations and unclassified variants. AB - OBJECTIVE: Breast cancer is the most common female cancer in Morocco. About 5 to 10% are due to hereditary predisposition and mutations in BRCA1 and BRCA2 genes are responsible for an important proportion of high-risk breast/ovarian cancer families. The relevance of BRCA1/2 mutations in the Moroccan population was not studied. The main objective of this study is to investigate the spectrum of BRCA1 and BRCA2 germline mutations in early onset and familial breast/ovarian cancer among Moroccan women. METHODS: We screened the entire coding sequences and intron/exon boundaries of BRCA1 and BRCA2 genes in 40 patients by direct sequencing. RESULTS: Nine pathogenic mutations were detected in ten unrelated families, five deleterious mutations in BRCA1 gene and four mutations in BRCA2 gene. Four novel mutations were found: one in BRCA1 (c.2805delA/2924delA) and three in BRCA2 (c.3381delT/3609delT; c.7110delA/7338delA and c.7235insG/7463insG). We also identified 51 distinct polymorphisms and unclassified variants (three described for the first time). CONCLUSIONS: Our data suggest that BRCA1 and BRCA2 mutations are responsible for a significant proportion of familial breast cancer in Moroccan patients. Therefore full BRCA1/2 screening should be offered to patients with a family history of breast/ovarian cancer. PMID- 22425666 TI - Does grasping in patient D.F. depend on vision? AB - A recently published study of grasping in patient D.F. challenges the well-known dissociation between vision-for-perception and vision-for-action, suggesting instead that D.F.'s preserved grip scaling depends entirely on haptic feedback. We argue that the results of the study are in fact fully consistent with the perception-action account. PMID- 22425668 TI - Parametric imaging with Bayesian priors: a validation study with (11)C-Altropane PET. AB - It has been suggested that Bayesian estimation methods may be used to improve the signal-to-noise ratio of parametric images. However, there is little experience with the method and some of the underlying assumptions and performance properties of Bayesian estimation remain to be investigated. We used a sample population of 54 subjects, studied previously with (11)C-Altropane, to empirically evaluate the assumptions, performance and some practical issues in forming parametric images. By using normality tests, we showed that the underpinning normality assumptions of data and parametric distribution apply to more than 80% of voxels. The standard deviation of the binding potential can be reduced 30-50% using Bayesian estimation, without introducing substantial bias. The sample size required to form the a priori information was found to be modest; as little as ten subjects may be sufficient and the choice of specific subjects has little effect on Bayesian estimation. A realistic simulation study showed that detection of localized differences in parametric images, e.g. by statistical parametric mapping (SPM), could be made more reliable and/or conducted with smaller sample size using Bayesian estimation. In conclusion, Bayesian estimation can improve the SNR of parametric images and better detect localized changes in cohorts of subjects. PMID- 22425667 TI - The social motivation theory of autism. AB - The idea that social motivation deficits play a central role in Autism Spectrum Disorders (ASD) has recently gained increased interest. This constitutes a shift in autism research, which has traditionally focused more intensely on cognitive impairments, such as theory-of-mind deficits or executive dysfunction, and has granted comparatively less attention to motivational factors. This review delineates the concept of social motivation and capitalizes on recent findings in several research areas to provide an integrated account of social motivation at the behavioral, biological and evolutionary levels. We conclude that ASD can be construed as an extreme case of diminished social motivation and, as such, provides a powerful model to understand humans' intrinsic drive to seek acceptance and avoid rejection. PMID- 22425669 TI - Very large fMRI study using the IMAGEN database: sensitivity-specificity and population effect modeling in relation to the underlying anatomy. AB - In this paper we investigate the use of classical fMRI Random Effect (RFX) group statistics when analyzing a very large cohort and the possible improvement brought from anatomical information. Using 1326 subjects from the IMAGEN study, we first give a global picture of the evolution of the group effect t-value from a simple face-watching contrast with increasing cohort size. We obtain a wide activated pattern, far from being limited to the reasonably expected brain areas, illustrating the difference between statistical significance and practical significance. This motivates us to inject tissue-probability information into the group estimation, we model the BOLD contrast using a matter-weighted mixture of Gaussians and compare it to the common, single-Gaussian model. In both cases, the model parameters are estimated per-voxel for one subgroup, and the likelihood of both models is computed on a second, separate subgroup to reflect model generalization capacity. Various group sizes are tested, and significance is asserted using a 10-fold cross-validation scheme. We conclude that adding matter information consistently improves the quantitative analysis of BOLD responses in some areas of the brain, particularly those where accurate inter-subject registration remains challenging. PMID- 22425670 TI - Multivariate pattern analysis of fMRI: the early beginnings. AB - In 2001, we published a paper on the representation of faces and objects in ventral temporal cortex that introduced a new method for fMRI analysis, which subsequently came to be called multivariate pattern analysis (MVPA). MVPA now refers to a diverse set of methods that analyze neural responses as patterns of activity that reflect the varying brain states that a cortical field or system can produce. This paper recounts the circumstances and events that led to the original study and later developments and innovations that have greatly expanded this approach to fMRI data analysis, leading to its widespread application. PMID- 22425671 TI - Detection of calcifications in vivo and ex vivo after brain injury in rat using SWIFT. AB - Calcifications represent one component of pathology in many brain diseases. With MRI, they are most often detected by exploiting negative contrast in magnitude images. Calcifications are more diamagnetic than tissue, leading to a magnetic field disturbance that can be seen in phase MR images. Most phase imaging studies use gradient recalled echo based pulse sequences. Here, the phase component of SWIFT, a virtually zero acquisition delay sequence, was used to detect calcifications ex vivo and in vivo in rat models of status epilepticus and traumatic brain injury. Calcifications were detected in phase and imaginary SWIFT images based on their dipole like magnetic field disturbances. In magnitude SWIFT images, calcifications were distinguished as hypointense and hyperintense. Hypointense calcifications showed large crystallized granules with few surrounding inflammatory cells, while hyperintense calcifications contained small granules with the presence of more inflammatory cells. The size of the calcifications in SWIFT magnitude images correlated with that in Alizarin stained histological sections. Our data indicate that SWIFT is likely to better preserve signal in the proximity of a calcification or other field perturber in comparison to gradient echo due to its short acquisition delay and broad excitation bandwidth. Furthermore, a quantitative description for the phase contrast near dipole magnetic field inhomogeneities for the SWIFT pulse sequence is given. In vivo detection of calcifications provides a tool to probe the progression of pathology in neurodegenerative diseases. In particular, it appears to provide a surrogate marker for inflammatory cells around the calcifications after brain injury. PMID- 22425672 TI - Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers. AB - The aim of this work was to develop a model simultaneously estimating (11)C AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain. AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed. The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200 nM. The density of the receptor binding sites was estimated to 800 nM and 200 nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify. PMID- 22425673 TI - Evolution goes GAGA: GAGA binding proteins across kingdoms. AB - Chromatin-associated proteins (CAP) play a crucial role in the regulation of gene expression and development in higher organisms. They are involved in the control of chromatin structure and dynamics. CAP have been extensively studied over the past years and are classified into two major groups: enzymes that modify histone stability and organization by post-translational modification of histone N Terminal tails; and proteins that use ATP hydrolysis to modify chromatin structure. All of these proteins show a relatively high degree of sequence conservation across the animal and plant kingdoms. The essential Drosophila melanogaster GAGA factor (dGAF) interacts with these two types of CAP to regulate homeobox genes and thus contributes to a wide range of developmental events. Surprisingly, however, it is not conserved in plants. In this review, following an overview of fly GAF functions, we discuss the role of plant BBR/BPC proteins. These appear to functionally converge with dGAF despite a completely divergent amino acid sequence. Some suggestions are given for further investigation into the function of BPC proteins in plants. PMID- 22425675 TI - Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2. AB - Prostanoids regulate angiogenesis in carcinoma and chronic inflammatory disease progression. Although prostanoid biosynthetic enzymes and signaling have been extensively analyzed in inflammation, little is known about how prostanoids mediate tumor-induced angiogenesis. Targeted cyclooxygenase (COX)-2 inhibition in tumor, stromal and endothelial cells is an attractive antiangiogenic strategy; however, the associated cardiovascular side effects have led to the development of a new generation of nonsteroidal anti-inflammatory drugs (NSAIDs) acting downstream of COX. These agents target terminal prostanoid synthases and prostanoid receptors, which may also include several peroxisome proliferator activated receptors (PPARs). Here, we discuss the role of prostanoids as modulators of tumor angiogenesis and how prostanoid metabolism reflects complex cell-cell crosstalk that determines tumor growth. Finally, we discuss the potential of new NSAIDs for the treatment of angiogenesis-dependent tumor development. PMID- 22425674 TI - Chromatin remodeling during glucocorticoid receptor regulated transactivation. AB - Steroid hormone receptor (SR) signaling leads to widespread changes in gene expression, and aberrant SR signaling can lead to malignancies including breast, prostate, and lung cancers. Chromatin remodeling is an essential component of SR signaling, and defining the process of chromatin and nucleosome remodeling during signaling is critical to the continued development of related therapies. The glucocorticoid receptor (GR) is a key SR that activates numerous promoters including the well defined MMTV promoter. The activation of MMTV by GR provides an excellent model for teasing apart the sequence of events between hormone treatment and changes in gene expression. Comparing hormone-induced transcription from stably integrated promoters with defined nucleosomal structure to that from transiently expressed, unstructured promoters permits key distinctions between interactions that require remodeling and those that do not. The importance of co activators and histone modifications prior to remodeling and the formation of the preinitiation complex that follows can also be clarified by defining key transition points in the propagation of hormonal signals. Combined with detailed mapping of proteins along the promoter, a temporal and spatial understanding of the signaling and remodeling processes begins to emerge. In this review, we examine SR signaling with a focus on GR activation of the MMTV promoter. We also discuss the ATP-dependent remodeling complex SWI/SNF, which provides the necessary remodeling activity during GR signaling and interacts with several SRs. BRG1, the central ATPase of SWI/SNF, also interacts with a set of BAF proteins that help determine the specialized function and fine-tuned regulation of BRG1 remodeling activity. BRG1 regulation comes from its own subdomains as well as its interactive partners. In particular, the HSA domain region of BRG1 and unique features of its ATPase homology appear to play key roles in regulating remodeling function. Details of the inter-workings of this chromatin remodeling protein continue to be revealed and promise to improve our understanding of the mechanism of chromatin remodeling during steroid hormone signaling. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22425676 TI - Small- and wide-angle X-ray scattering (SWAXS) for quantification of aspirin content in a binary powder mixture. AB - This article presents a novel application of small and wide angle X-ray scattering (SWAXS) in the assessment of aspirin and lactose content in a binary pharmaceutical powder formulation. It is shown that the content correlates with the intensity of the SAXS signal and the intensity of polymorph fingerprints in the WAXS spectra that are collected from the same samples. Because the polymorph WAXS fingerprints and the SAXS signal are two independent characteristics of the same sample, simultaneous SWAXS analysis provides the basis for a dual independent assessment of the same contents. PMID- 22425677 TI - A flow system for the on-line quantitative measurement of the retention of dosage forms on biological surfaces using spectroscopy and image analysis. AB - Measuring the retention, or residence time, of dosage forms to biological tissue is commonly a qualitative measurement, where no real values to describe the retention can be recorded. The result of this is an assessment that is dependent upon a user's interpretation of visual observation. This research paper outlines the development of a methodology to quantitatively measure, both by image analysis and by spectrophotometric techniques, the retention of material to biological tissues, using the retention of polymer solutions to ocular tissue as an example. Both methods have been shown to be repeatable, with the spectrophotometric measurement generating data reliably and quickly for further analysis. PMID- 22425678 TI - IgG anti-toxoplasma antibodies among asymptomatic HIV-infected patients in Marrakesh-Morocco. AB - Detection and monitoring of anti-Toxoplasma gondii antibodies are of a great interest among human immunodeficiency virus (HIV)-infected patients, since cerebral toxoplasmosis is a life-threatening opportunistic infection within this vulnerable population. The IgG anti-T. gondii seroprevalence was assessed in 95 asymptomatic HIV-infected adults living in Marrakesh city and its surrounding areas. Our results showed a seroprevalence of 62.1%, which is high compared to most other countries. The mean of CD(4+) T-cells count of involved patients was 381.9cells/MUl. Given these results, HIV-infected patients in Marrakesh region could be at high risk to develop toxoplasmosis disease, especially when CD(4+) T cells count falls below 100cells/MUl. Accordingly, there is a serious need of widening antiretroviral therapy and chemoprophylaxis against toxoplasmosis, when indicated, to ovoid toxoplasmosis reactivation among this population. PMID- 22425679 TI - Extinction and fixation times with dominance and inbreeding. AB - The effect of partial inbreeding on extinction and fixation times of a selected allele with partial dominance is studied using a diffusion model. Asymptotic approximations are obtained for large populations and the accuracy of the approximations was found to increase with inbreeding level. They show that inbreeding reduces extinction and fixation times compared to random mating at least by a factor 1+F, where F is Wright's fixation index. The reduction of extinction and fixation times due to inbreeding is stronger for strong selection and if alleles are either highly recessive or highly dominant. This bears implications for the effect of inbreeding on the signature of selective sweeps. These findings extend previous results obtained for random mating populations and help clarifying previous simulation and numerical results on the effect of inbreeding on the dynamics of selected alleles. PMID- 22425680 TI - Sleepiness and fatigue following traumatic brain injury. AB - OBJECTIVES: To compare individuals with traumatic brain injury (TBI) to healthy controls (CTLs) on measures of sleepiness, fatigue, and sleep, and explore correlates of sleepiness and fatigue separately for each group. METHODS: Participants were 22 adults with moderate/severe TBI (time since injury >= 1 year; mean=53.0 +/- 37.1 months) and 22 matched healthy CTLs. They underwent one night of polysomnographic (PSG) recording of their sleep followed the next day by the Maintenance of Wakefulness Test (MWT). They also completed a 14-day sleep diary, the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), and the Multidimensional Fatigue Inventory (MFI). RESULTS: There were no significant group differences on measures of objective (MWT) or subjective (ESS) sleepiness, both groups being quite alert. However, TBI participants reported greater consequences of sleepiness on their general productivity (FOSQ), spent more time in bed at night, and napped more frequently and for a longer time during the day. Subjective fatigue was significantly higher in TBI participants on the general, physical, and mental fatigue MFI subscales. There were no between-group differences on any sleep parameters derived either from PSG or sleep diary. CONCLUSIONS: Fatigue appeared to be a more prominent symptom than sleepiness when assessed between 1 and 11 years after TBI. Participants with TBI used compensatory strategies such as increasing time spent in bed and daytime napping in this sample. Future research should document the time course of sleepiness and fatigue after TBI and investigate treatment options. PMID- 22425681 TI - Attention in children with obstructive sleep apnoea: an event-related potentials study. AB - BACKGROUND: Obstructive sleep apnoea (OSA) in children has been causally implicated in neurobehavioural and cognitive dysfunction. Consequently, the American Academy of Paediatrics highlighted the need to study pertinent functional cognitive outcomes before and after treatment. However, neurocognitive function has thus far only been assessed by caregiver-completed questionnaires, which can be labour intensive and time consuming, such that the need for complementary and more objective measures has emerged. OBJECTIVE: The study aimed to identify electrophysiological correlates of neurocognitive alterations in children with OSA and investigate utility as a predictive tool. PATIENTS AND METHODS: Twenty-eight children (14 OSA and 14 matched controls) underwent overnight sleep studies and neurocognitive testing, as well as the oddball attention task while event-related potentials (ERPs) were recorded. ERPs were analysed using temporal principal components and source analyses that provided dependent variables for the subsequent repeated measures analysis of variance (ANOVA) and multiple regressions. Time-locked waveforms formed spatial models that localised electrical activity in the brain. ERP differences between groups were then correlated to neurocognitive outcomes. RESULTS: OSA children exhibited significantly altered ERP patterns of neural activation and impaired neurocognitive performance. Specific ERP variables exhibited accurate predictive ability regarding performance on neurobehavioural measures. CONCLUSION: Specific ERP events during a single attention task can reliably identify the presence of OSA-associated cognitive dysfunction. Electrophysiological approaches during specific cognitive tasks may serve as simple, complementary, and reliable reporters of cognitive dysfunction associated with OSA in children. PMID- 22425682 TI - Validity of RLS diagnosis in epidemiologic research: time to move on. PMID- 22425683 TI - The reticulons: guardians of the structure and function of the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by a specific class of curvature stabilizing proteins, the reticulons and DP1; however it is still unclear how the sheets are assembled. The ER is the cellular compartment responsible for secretory and membrane protein synthesis. The reducing conditions of ER lead to the intra/inter-chain formation of new disulphide bonds into polypeptides during protein folding assessed by enzymatic or spontaneous reactions. Moreover, ER represents the main intracellular calcium storage site and it plays an important role in calcium signaling that impacts many cellular processes. Accordingly, the maintenance of ER function represents an essential condition for the cell, and ER morphology constitutes an important prerogative of it. Furthermore, it is well known that ER undergoes prominent shape transitions during events such as cell division and differentiation. Thus, maintaining the correct ER structure is an essential feature for cellular physiology. Now, it is known that proper ER-associated proteins play a fundamental role in ER tubules formation. Among these ER-shaping proteins are the reticulons (RTN), which are acquiring a relevant position. In fact, beyond the structural role of reticulons, in very recent years new and deeper functional implications of these proteins are emerging in relation to their involvement in several cellular processes. PMID- 22425684 TI - Fatty acid compositions of preterm and term colostrum, transitional and mature milks in a sub-Saharan population with high fish intakes. AB - BACKGROUND: There are no data on the fatty acid (FA) compositions of preterm and term milks for sub-Saharan African populations with advancing lactation. However, it is generally acknowledged that our ancestors evolved in sub-Saharan East Africa, where they inhabited the land-water ecosystems. METHODS: We compared the FA-compositions of preterm (28-36 weeks) and term (37-42) colostrum (2-5 day), transitional (6-15) and mature (16-56) milks in rural African women with stable dietary habits and lifelong high freshwater fish intakes. RESULTS: From colostrum to mature milk: the median docosahexaenoic acid (DHA) content decreased from 1.11 to 0.75; and arachidonic acid (AA) from 0.93 to 0.69 g% in preterm milk. In term milk, DHA decreased from 0.81 to 0.53 and AA from 1.08 to 0.55 g%. Medium-chain saturated-FA (MCSAFA) increased from 16.9 to 33.7, and 7.92-29.0 g%, while mono unsaturated FA (MUFA) decreased from 32.5 to 22.6, and 40.0-26.5 g%, in preterm and term milk, respectively. Consistent with the literature, preterm colostrum contained higher DHA and MCSAFA, and lower MUFA compared to term colostrum. These differences vanished rapidly with advancing lactation. MUFA and MCSAFA were inversely related. CONCLUSIONS: The presently found DHA in preterm colostrum and mature milks and AA in premature mature milk proved the highest reported in the literature so far, as derived from analysis with capillary GC-columns. We confirmed the much higher MCSAFA and lower MUFA contents in milk of rural African, compared to Westernized women. The milk FA composition of this traditional population might show us the FA composition on which our species evolved and consequently to which our genome has become adapted to optimally support (infant) health. PMID- 22425685 TI - Gestational age dependent changes of the fetal brain, liver and adipose tissue fatty acid compositions in a population with high fish intakes. AB - INTRODUCTION: There are no data on the intrauterine fatty acid (FA) compositions of brain, liver and adipose tissue of infants born to women with high fish intakes. SUBJECTS AND METHODS: We analyzed the brain (n=18), liver (n=14) and adipose tissue (n=11) FA compositions of 20 stillborn infants with different gestational ages (range 8-38 weeks) born to Tanzanian women with low linoleic acid (LA) intakes and high intakes of docosahexaenoic (DHA) and arachidonic (AA) acids from local fish. RESULTS AND DISCUSSION: With advancing gestation, brain saturated-FA (SAFA; in g/100g FA), polyunsaturated-FA (PUFA), DHA, 20:3omega6, 22:4omega6 and 22:5omega6 increased, while monounsaturated-FA (MUFA), 20:3omega9, 22:3omega9 and AA decreased. Decreasing brain AA might be caused by increasing AA metabolism to 20:3omega6, 22:4omega6 and 22:5omega6. In the liver, SAFA, PUFA and LA increased, while MUFA decreased with gestation. The steep increase of (mostly de novo synthesized) SAFA in adipose tissue coincided with relative decreases of MUFA, PUFA, DHA, LA and AA with advancing gestation. Compared to Western infants, the currently studied African infants had higher DHA, lower AA, and a higher DHA/AA-ratio in brain and adipose tissue, while the LA content of adipose tissue was lower. CONCLUSION: The low LA and high DHA and AA intakes by the mothers of these infants might support optimal alpha-linolenic (ALA) vs. LA competition for Delta5D and Delta6D-activities and DHA vs. AA antagonism. Conversely, the Western diet, characterized by high LA and lower DHA and AA intakes, might disturb these evolutionary conserved mechanisms aiming at an optimal omega3/omega6-balance. PMID- 22425686 TI - Balint-like syndrome as an unusual representation of non-convulsive status epilepticus. AB - The clinical signs of posterior cortex dysfunction are, due to their paucity and subtlety, very often ignored as non-specific during clinical evaluation of non convulsive status epilepticus. Therefore, focal non-convulsive status epilepticus emerging from the posterior cortex, and especially the parietal lobes, can be fairly under-recognised. We report a 66-year-old patient with focal non convulsive status epilepticus presenting as isolated Balint-like syndrome, successfully treated to full clinical and electrophysiological recovery. The diagnostic and pathophysiological features are discussed. Focal non-convulsive status epilepticus can be associated with negative phenomena such as neuropsychological deficits mimicking those detected more often in degenerative and vascular brain diseases. [Published with video sequences]. PMID- 22425687 TI - Perfluorooctanoic acid induces gene promoter hypermethylation of glutathione-S transferase Pi in human liver L02 cells. AB - Perfluorooctanoic acid (PFOA) is one of the most commonly used perfluorinated compounds. Being a persistent environmental pollutant, it can accumulate in human tissues via various exposure routes. PFOA may interfere in a toxic fashion on the immune system, liver, development, and endocrine systems. In utero human exposure had been associated with cord serum global DNA hypomethylation. In light of this, we investigated possible PFOA-induced DNA methylation alterations in L02 cells in order to shed light into its epigenetic-mediated mechanisms of toxicity in human liver. L02 cells were exposed to 5, 10, 25, 50 or 100 mg/L PFOA for 72h. Global DNA methylation levels were determined by LC/ESI-MS, glutathione-S-transferase Pi (GSTP) gene promoter DNA methylation was investigated by methylation-specific polymerase chain reaction (PCR) with bisulfite sequencing, and consequent mRNA expression levels were measured with quantitative real-time reverse transcriptase PCR. A dose-related increase of GSTP promoter methylation at the transcription factor specificity protein 1 (SP1) binding site was observed. However, PFOA did not significantly influence global DNA methylation; nor did it markedly alter the promoter gene methylation of p16 (cyclin-dependent kinase inhibitor 2A), ERalpha (estrogen receptor alpha) or PRB (progesterone receptor B). In addition, PFOA significantly elevated mRNA transcript levels of DNMT3A (which mediates de novo DNA methylation), Acox (lipid metabolism) and p16 (cell apoptosis). Considering the role of GSTP in detoxification, aberrant methylation may be pivotal in PFOA mediated toxicity response via the inhibition of SP1 binding to GSTP promoter. PMID- 22425688 TI - Fragrance material review on 2,2,5-trimethyl-5-pentylcyclopentanone. AB - A toxicologic and dermatologic review of 2,2,5-trimethyl-5-pentylcyclopentanone when used as a fragrance ingredient is presented. 2,2,5-trimethyl-5 pentylcyclopentanone is a member of the fragrance structural group Ketones Cyclopentanones and Cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2,2,5-trimethyl-5-pentylcyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, and phototoxicity data. A safety assessment of the entire Ketones Cyclopentanones and Cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Ketones Cyclopentanones and Cyclopentenones in fragrances. PMID- 22425689 TI - Evaluation of safety and tolerance of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation: a randomized, placebo-controlled, double blind study. AB - Probiotic organisms have shown promise in treating diseases. Previously, we have reported on the efficacy of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation at lowering serum cholesterol levels in otherwise healthy hypercholesterolemic adults. This study investigates the safety and toxicology of oral ingestion of microencapsulated L. reuteri NCIMB 30242 in a yogurt formulation. A randomized group of 120 subjects received a dose of 5 * 10(10) CFU microencapsulated L. reuteri NCIMB 30242 in yogurt (n=59) or placebo yogurt (n=61) twice/day for 6 weeks. Clinical chemistry and hematological parameters of safety were analyzed. Fecal samples were collected at these time points for the analysis of deconjugated bile acids. The frequency, duration and intensity of adverse events (AEs) and clinical significance of safety parameters were recorded for both groups. No clinically significant differences between the probiotic yogurt and placebo yogurt treated groups were detected in either the blood clinical chemistry or hematology results and there was no significant increase in fecal deconjugated bile acids (P>0.05) between treated and control groups. The frequency and intensity of AEs was similar in the two groups. These results demonstrate the safe use of this formulation in food. PMID- 22425690 TI - Fragrance material review on 2-(p-Menth-1-ene-10-yl) cyclopentanone. AB - A toxicologic and dermatologic review of 2-(p-Menth-1-ene-10-yl) cyclopentanone when used as a fragrance ingredient is presented. 2-(p-Menth-1-ene-10-yl) cyclopentanone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-(p-Menth-1-ene-10-yl) cyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, repeated dose, and genotoxicity data. A safety assessment of the entire cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all cyclopentanones and cyclopentenones in fragrances. PMID- 22425691 TI - Particle filtering in the Hough space for instrument tracking. AB - In this paper we present a real-time tracking system of surgical instruments in laparoscopic operations. We combine Condensation tracking, with the Hough Transform in order to obtain an efficient and accurate tracking. The Condensation algorithm performs well in heavy clutter, and the Hough Transform is robust under illumination changes, occlusion and distractions. The Hough array is computed using the gradient direction image obtained by means of a Principal Component Analysis. This improves accuracy in the determination of edge orientation and speeds up computation of the Hough Transform. The experiments on image sequences of actual laparoscopic surgical operations show that the instrument tip is located even in the presence of smoke, occlusions or motion blurring. PMID- 22425692 TI - Kainate induces various domain closures in AMPA and kainate receptors. AB - Ionotropic glutamate receptors are key players in fast excitatory synaptic transmission within the central nervous system. These receptors have been divided into three subfamilies: the N-methyl-d-aspartic acid (NMDA), 2-amino-3-(3-hydroxy 5-methyl-4-isoxazolyl)propionic acid (AMPA) and kainate receptors. Kainate has previously been crystallized with the ligand binding domain (LBD) of AMPA receptors (GluA2 and GluA4) and kainate receptors (GluK1 and GluK2). Here, we report the structures of the kainate receptor GluK3 LBD in complex with kainate and GluK1 LBD in complex with kainate in the absence of glycerol. Kainate introduces a conformational change in GluK3 LBD comparable to that of GluK2, but different from the conformational changes induced in GluA2 and GluK1. Compared to their domain closures in a glutamate bound state, GluA2 and GluK1 become more open and kainate induces a domain closure of 60% and 62%, respectively, relative to glutamate (100%). In GluK2 and GluK3 with kainate, the domain closure is 88% and 83%, respectively. In previously determined structures of GluK1 LBD in complex with kainate, glycerol is present in the binding site where it bridges interlobe residues and thus, might contribute to the large domain opening. However, the structure of GluK1 LBD with kainate in the absence of glycerol confirms that the observed domain closure is not an artifact of crystallization conditions. Comparison of the LBD structures with glutamate and kainate reveals that contacts are lost upon binding of kainate in the three kainate receptors, which is in contrast to the AMPA receptors where similar contacts are seen. It was revealed by patch clamp electrophysiology studies that kainate is a partial agonist at GluK1 with 36% efficacy compared to glutamate, which is in between the published efficacies of kainate at GluK2 and AMPA receptors. The ranking of efficacies seems to correlate with LBD domain closures. PMID- 22425693 TI - 5-HIAA excretion is not associated with bone metabolism in carcinoid syndrome patients. AB - In patients with a carcinoid syndrome and neuroendocrine tumors of the digestive tract (carcinoids), elevated circulating serotonin (5-hydroxytryptamine, 5-HT) levels can be demonstrated. It can be hypothesized that bone metabolism will be affected in these patients, since serotonin receptors are expressed on bone cells and serotonin effects on bone have been demonstrated. However, to date, no data are available on bone metabolism parameters in patients with neuroendocrine tumors of the digestive tract (carcinoids). In the current retrospective study we have measured serum bone formation markers P1CP (pro-collagen type I C-terminal), and osteocalcin, and the bone resorption marker NTx (collagen breakdown product N terminal), in a group of 61 carcinoid patients with increased circulating serotonin levels as demonstrated by increased excretion of the serotonin breakdown product, 5-hydroxy indole acetic acid (5-HIAA), in the urine (>50 MUmol/24 h, so-called "hyper-secretors") and a control group of 23 carcinoid patients, without increased 5-HIAA excretion (so-called non-secretors). The 24-h urinary excretion of 5-HIAA reflects the 24-h production of serotonin. Measurements of markers of bone metabolism were performed in serum samples obtained before the start of medical treatment. The hypersecretor group had on average a 10-fold higher urinary 5-HIAA excretion than the control (non-secretor) group. No significant differences in bone metabolism parameters could be demonstrated between hyper-secretors and controls (non-secretors). Correlation and regression analyses could not demonstrate significant age- and sex-adjusted correlations between urinary 5-HIAA excretion and any of the markers for bone turnover. A limitation is that the exposure time to elevated levels of serotonin is unknown, which might have been too short to induce effects on bone metabolism. Treatment of human pre-osteoblasts SV-HFO with serotonin didn't change alkaline phosphatase activity throughout differentiation as well as mineralization. In conclusion, the current study in a unique group of untreated carcinoid patients could not demonstrate a major role for circulating serotonin in the control of bone metabolism. PMID- 22425694 TI - Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. AB - PURPOSE: Low 25-hydroxyvitamin D (25D), increased levels of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were reported to be risk factors for mortality in chronic kidney disease (CKD). However, the independent associations of these factors with cardiovascular disease (CVD), the leading cause of death among CKD patients, remain unclear. Our purpose was to identify which of these factors predict incident CVD in CKD. METHODS: In this prospective cohort study, we enrolled 738 predialysis outpatients in the two nephrology departments. We employed Cox proportional hazards analyses to elucidate predictors of the endpoint, defined as fatal or non fatal cardiovascular event requiring hospitalization. Multiple imputation was performed for missing values. RESULTS: Mean estimated glomerular filtration rate (eGFR) was 35 mL/min/1.73 m(2). During a median duration of 4.4 years, 86 patients developed the endpoint, of whom 62 patients achieved it before the initiation of dialysis. Multivariable analyses revealed that high serum intact FGF23 levels predicted the outcome preceding dialysis initiation (hazard ratio (HR) per lnFGF23 (SD), 1.64 (1.27-2.30)), while 25D, PTH, and bone-specific ALP did not. Adding FGF23 to the conventional model of age, sex, diabetes, prior CVD, pulse pressure, and eGFR, led to a net reclassification improvement of 6.87% (P=0.04). Not censoring the patients at the start of dialysis and continuing follow-up even after dialysis, FGF23 levels did not predict the outcome (HR, 1.16 (0.91-1.48)). Complete case analyses yielded similar results. CONCLUSIONS: Intact FGF23 levels in predialysis CKD predicted incident cardiovascular events requiring hospitalization before starting dialysis, but did not predict events during the entire follow-up period, including post dialysis initiation. PMID- 22425695 TI - Sexual health in women reporting a history of child sexual abuse. AB - OBJECTIVE: The present study examined the association between child sexual abuse (CSA) and sexual health outcomes in young adult women. Maladaptive coping strategies and optimism were investigated as possible mediators and moderators of this relationship. METHOD: Data regarding sexual abuse, coping, optimism and various sexual health outcomes were collected using self-report and computerized questionnaires with a sample of 889 young adult women from the province of Quebec aged 20-23 years old. RESULTS: A total of 31% of adult women reported a history of CSA. Women reporting a severe CSA were more likely to report more adverse sexual health outcomes including suffering from sexual problems and engaging in more high-risk sexual behaviors. CSA survivors involving touching only were at greater risk of reporting more negative sexual self-concept such as experiencing negative feelings during sex than were non-abused participants. Results indicated that emotion-oriented coping mediated outcomes related to negative sexual self concept while optimism mediated outcomes related to both, negative sexual self concept and high-risk sexual behaviors. No support was found for any of the proposed moderation models. CONCLUSIONS: Survivors of more severe CSA are more likely to engage in high-risk sexual behaviors that are potentially harmful to their health as well as to experience more sexual problems than women without a history of sexual victimization. Personal factors, namely emotion-oriented coping and optimism, mediated some sexual health outcomes in sexually abused women. The results suggest that maladaptive coping strategies and optimism regarding the future may be important targets for interventions optimizing sexual health and sexual well-being in CSA survivors. PMID- 22425696 TI - Incentive effect on inhibitory control in adolescents with early-life stress: an antisaccade study. AB - OBJECTIVE: Early-life stress (ES) such as adoption, change of caregiver, or experience of emotional neglect may influence the way in which affected individuals respond to emotional stimuli of positive or negative valence. These modified responses may stem from a direct alteration of how emotional stimuli are coded, and/or the cognitive function implicated in emotion modulation, such as self-regulation or inhibition. These ES effects have been probed on tasks either targeting reward and inhibitory function. Findings revealed deficits in both reward processing and inhibitory control in ES youths. However, no work has yet examined whether incentives can improve automatic response or inhibitory control in ES youths. METHOD: To determine whether incentives would only improve self regulated voluntary actions or generalize to automated motoric responses, participants were tested on a mixed eye movement task that included reflex-like prosaccades and voluntary controlled antisaccade eye movements. Seventeen adopted children (10 females, mean age 11.3 years) with a documented history of neglect and 29 typical healthy youths (16 females, mean age 11.9 years) performed the mixed prosaccade/antisaccade task during monetary incentive conditions or during no-incentive conditions. RESULTS: Across both saccade types, ES adolescents responded more slowly than controls. As expected, control participants committed fewer errors on antisaccades during the monetary incentive condition relative to the no-incentive condition. By contrast, ES youths failed to show this incentive related improvement on inhibitory control. No significant incentive effects were found with prepotent prosaccades trials in either group. Finally, co-morbid psychopathology did not modulate the findings. CONCLUSIONS: These data suggest that youths with experience of early stress exhibit deficient modulation of inhibitory control by reward processes, in tandem with a reward-independent deficit in preparation for both automatic and controlled responses. These data may be relevant to interventions in ES youths. PMID- 22425697 TI - Characteristics of childhood sexual abuse in lesbians and heterosexual women. PMID- 22425698 TI - Rapid, simple influenza RNA extraction from nasopharyngeal samples. AB - This report describes the development and pre-clinical testing of a new, random access RNA sample preparation system (TruTip) for nasopharyngeal samples. The system is based on a monolithic, porous nucleic acid binding matrix embedded within an aerosol-resistant pipette tip and can be operated with single or multi channel pipettors. Equivalent extraction efficiencies were obtained between automated QIAcube and manual TruTip methods at 10(6) gene copies influenza A per mL nasopharyngeal aspirate. Influenza A and B amended into nasopharyngeal swabs (in viral transport medium) were detected by real-time RT-PCR at approximately 745 and 370 gene copies per extraction, respectively. RNA extraction efficiency in nasopharyngeal swabs was also comparable to that obtained on an automated QIAcube instrument over a range of input concentrations; the correlation between threshold cycles (or nucleic acid recovery) for TruTip and QIAcube-purified RNA was R(2)>0.99. Preclinical testing of TruTip on blinded nasopharyngeal swab samples resulted in 98% detection accuracy relative to a clinically validated easyMAG extraction method. The physical properties of the TruTip binding matrix and ability to customize its shape and dimensions likewise make it amenable to automation and/or fluidic integration. PMID- 22425699 TI - Why men are at higher risk for hepatocellular carcinoma? PMID- 22425700 TI - FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. AB - BACKGROUND & AIMS: The pathogenesis of autoimmune hepatitis (AIH) is not understood, but it was suggested that AIH may be related to a numerical or functional impairment of CD4+CD25+FOXP3+ regulatory T cells (Treg), which are important mediators of immune tolerance to self-antigens. However, the role of Treg in AIH is not clear, since earlier studies reporting Treg impairment had used only CD25 as marker that cannot unambiguously distinguish Treg from activated effector T cells. METHODS: We assessed the frequency and suppressor function of Treg using current staining protocols that can distinguish Treg from activated effector T cells. RESULTS: The frequency of CD4+CD25(high)CD127(low)FOXP3+ Treg cells in blood of AIH patients was not reduced compared to healthy subjects, as shown by flow cytometry and confirmed by quantifying Treg-specific demethylation of the FOXP3 gene. Moreover, the suppressor function of Treg isolated from AIH patients was similar to that of Treg isolated from healthy subjects, indicating that Treg function was not impaired in AIH patients. However, we observed that the Treg frequency was significantly higher in those AIH patients with active disease than in those who were in a state of remission, suggesting that the Treg frequency may increase with the degree of inflammation. Indeed, analysis of FOXP3+ Treg in liver histology revealed that the intrahepatic Treg frequency was higher in AIH patients than in NASH patients and correlated with the inflammatory activity of the liver. CONCLUSIONS: The frequency and function of circulating Treg cells is not impaired in AIH. PMID- 22425701 TI - Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. AB - BACKGROUND & AIMS: The aim of this study was to characterize the relationship between the broad spectrum of hypothyroidism and NAFLD. METHODS: A cross sectional study with 4648 health check-up subjects (2324 cases with hypothyroidism vs. age- and sex-matched controls) was conducted. The subjects were categorized as having either subclinical [thyroid-stimulating hormone (TSH) >=4.1 mIU/L and normal free thyroixine (T(4)) level (0.7-1.8 ng/dl)] or overt hypothyroidism [free T(4)<0.7 ng/dl]. NAFLD was diagnosed on the basis of typical ultrasonographic findings, and alcohol consumption of less than 20 g/day in the absence of other causes of liver disease. RESULTS: The mean age of the subjects was 48.6+/-11.8 years and 62.4% were female. NAFLD was significantly associated with hypothyroidism (30.2% patients vs. 19.5% control, p<0.001). The prevalence of NAFLD and abnormal liver enzyme levels (ALT>33/25 IU/L) increased steadily with increasing grades of hypothyroidism (for NAFLD, subclinical: 29.9% and overt: 36.3%; for abnormal ALT, 20.1% and 25.9%, p<0.001, respectively). Multivariate regression analysis showed that NAFLD was statistically significantly associated with hypothyroidism (odds ratio (OR) 1.38, 95% confidence interval (CI), 1.17-1.62) and the grade of hypothyroidism in a dose dependent manner (OR 1.36, 95% CI, 1.16-1.61 in subclinical hypothyroidism and OR 1.71, 95% CI, 1.10-2.66 in overt hypothyroidism). CONCLUSIONS: Subclinical hypothyroidism, even in the range of upper normal TSH levels, was found to be related to NAFLD in a dose-dependent manner. Hypothyroidism is closely associated with NAFLD independently of known metabolic risk factors, confirming a relevant clinical relationship between these two diseases. PMID- 22425702 TI - The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection. AB - BACKGROUND & AIMS: SCY-635 is a non-immunosuppressive analog of cyclosporin A that inhibits cyclophilins A and B and hepatitis C virus (HCV) replication in vitro. In a phase 1b multi-dose escalation study, we evaluated the safety, plasma pharmacokinetics, and antiviral activity of 15 days of monotherapy with SCY-635 in adults with chronic genotype 1 HCV infection. METHODS: Twenty adults with chronic HCV genotype 1 were randomized to SCY-635 oral doses of 100, 200, or 300 mg three times daily for 15 days. RESULTS: No dose-limiting clinical or laboratory toxicities were identified. On day 15, the mean decline in plasma viremia was 2.24+/-1.74 log(10) IU/ml with SCY-635 900 mg/d. Individual antiviral responses correlated with host IL28B genotype. Post hoc analyses indicated treatment with SCY-635 increased plasma protein concentrations of interferon alpha (IFNalpha), IFNs lambda(1) and lambda(3), and 2'5' oligoadenylate synthetase 1 (2'5'OAS-1), with the greatest increases in IL28B CC and CT subjects. Changes in plasma concentrations for all markers were coincident with changes in the plasma concentration of SCY-635. Peaks of IFNs alpha, lambda(1), and lambda(3) and 2'5'OAS-1 were observed within 2 h after drug administration. In replicon cells, SCY-635 enhanced secretion of type I and type III IFNs and increased the expression of IFN-stimulated genes (ISG). CONCLUSIONS: These studies establish clinical proof of concept for SCY-635 as a novel antiviral agent and suggest that restoration of the host innate immune response to chronic hepatitis C infection may represent a major mechanism through which cyclophilin inhibitors exert clinical antiviral activity. PMID- 22425703 TI - Automatic office blood pressure measured without doctors or nurses present. AB - BACKGROUND: We evaluated the agreement between office blood pressure (OBP) measured by a mercury sphygmomanometer (Sphyg) and an automatic (Auto) device without any observers, and compared Auto and Sphyg OBP with ambulatory blood pressure (ABP) and home blood pressure (HBP). METHODS: OBP was measured in 75 hypertensive patients at two sites using an automatic monitor without a doctor or a nurse present and by Sphyg during three clinic visits. Between visits, monitoring of ABP and HBP was also performed. RESULTS: The mean Auto OBP was similar to that of Sphyg OBP and the values were closely correlated (intraclass correlation coefficient=0.84 for systolic OBP and 0.91 for diastolic OBP); however, the difference between Auto and Sphyg systolic OBP (1.6 +/- 8.2 mmHg) varied by the first office visit, sex, and the site. Auto systolic OBP was lower than both systolic awake ABP (137.1 +/- 14.7 mmHg) and HBP (139.2 +/- 15.6 mmHg). Auto systolic OBP and Sphyg OBP were similarly correlated with systolic awake ABP (both r=0.59, P<0.001). The mean Auto diastolic OBP was similar to that of Sphyg OBP (81.1 +/- 11.3 vs. 80.3 +/- 13.3 mmHg, P=0.20, intraclass correlation coefficient=0.91), and diastolic awake ABP and HBP. Auto diastolic OBP and Sphyg OBP were related to diastolic awake ABP (both r>0.68, P<0.001). In multivariable analyses, neither OBP measure was a significantly stronger predictor of out-of office blood pressure than the other. CONCLUSION: Auto systolic OBP measured without a doctor or a nurse present was lower than systolic awake ABP and HBP. Auto and rigorously assessed Sphyg OBP had similar means and were similarly related to awake ABP. Auto OBP might be an advantageous alternative to Sphyg measurements in the usual clinic setting. PMID- 22425704 TI - Evaluating home blood pressure in treated hypertensives in comparison with the referential value of casual screening of blood pressure: the Ohasama study. AB - OBJECTIVE: The target home blood pressure (BP) levels for antihypertensive treatment have not been fully investigated. We estimated home BP values that corresponded to the referential values of casual screening of BP using reduced major axis (RMA) regression for data from untreated and treated individuals in a general population. METHODS: The study included 2651 participants (778 treated) aged 20 years or above. The relationships between casual BP and home BP were examined using RMA regression to consider measurement errors. We calculated estimated home BP values that corresponded to casual BP using the regression equations. RESULTS: Although casual BPs and home BPs were significantly correlated (all: P<0.0001), the coefficients of determination in multiple regression were higher in untreated individuals than those in treated ones. When RMA regression was applied between casual BP (x) and morning home BP (y), the equations were expressed as y=0.78x+26.55 (systolic BP) and y=0.84x+14.34 (diastolic BP) in treated individuals and y=0.79x+19.29 (systolic BP) and y=0.85x+9.94 (diastolic BP) in untreated ones. The estimated home BPs corresponded to 140/90 mmHg of casual BP: 135.8/89.8 mmHg (morning), 132.2/86.6 mmHg (evening), and 133.9/87.8 mmHg (average) in treated individuals and 129.2/86.7 mmHg (morning), 127.8/84.8 mmHg (evening), and 128.2/85.2 mmHg (average) in untreated individuals. CONCLUSION: We estimated the referential values of home BP in treated hypertensives using a regression model; however, further intervention studies on home BP are needed to clarify the target treatment goals of home BP. PMID- 22425705 TI - Testing the phylogenetic affinities of Southeast Asia's rarest geckos: Flap legged geckos (Luperosaurus), Flying geckos (Ptychozoon) and their relationship to the pan-Asian genus Gekko. AB - Some of Southeast Asia's most poorly known vertebrates include forest lizards that are rarely seen by field biologists. Arguably the most enigmatic of forest lizards from the Indo Australian archipelago are the Flap-legged geckos and the Flying geckos of the genera Luperosaurus and Ptychozoon. As new species have accumulated, several have been noted for their bizarre combination of morphological characteristics, seemingly intermediate between these genera and the pan-Asian gecko genus Gekko. We used the first multilocus phylogeny for these taxa to estimate their relationships, with particular attention to the phylogenetic placement of the morphologically intermediate taxa Ptychozoon rhacophorus, Luperosaurus iskandari, and L. gulat. Surprisingly, our results demonstrate that Luperosaurus is more closely related to Lepidodactylus and Pseudogekko than it is to Gekko but that some species currently classified as Luperosaurus are nested within Gekko. The Flying Gecko genus Ptychozoon is also nested within Gekko, suggesting that higher-level taxonomic revision of the generic boundaries within Southeast Asian gekkonines will be a priority for the immediate future. PMID- 22425706 TI - Phylogenetic relationships and demographic histories of the Atherinidae in the Eastern Atlantic and Mediterranean Sea re-examined by Bayesian inference. AB - The aim of our study is to examine the phylogenetic relationship, divergence times and demographic history of the five close-related Mediterranean and North eastern Atlantic species/forms of Atherina using the full Bayesian framework for species tree estimation recently implemented in *BEAST. The inference is made possible by multilocus data using three mitochondrial genes (12S rRNA, 16S rRNA, control region) and one nuclear gene (rhodopsin) from multiple individuals per species available in GenBank. Bayesian phylogenetic analysis of the complete gene dataset produced a tree with strong support for the monophyly of each species, as well as high support for higher level nodes. An old origin of the Atherina group was suggested (19.2 MY), with deep split events within the Atherinidae predating the Messinian Salinity Crisis. Regional genetic substructuring was observed among populations of A. boyeri, with AMOVA and MultiDimensional Scaling suggesting the existence of five groupings (Atlantic/West Mediterranean, Adriatic, Greece, Black Sea and Tunis). The level of subdivision found might be consequence of the hydrographic isolation within the Mediterranean Sea. Bayesian inference of past demographic histories showed a clear signature of demographic expansion for the European coast populations of A. presbyter, possibly linked to post-glacial colonizations, but not for the Azores/Canary Islands, which is expected in isolated populations because of the impossibility of finding new habitats. Within the Mediterranean, signatures of recent demographic expansion were only found for the Adriatic population of A. boyeri, which could be associated with the relatively recent emergence of the Adriatic Sea. PMID- 22425707 TI - Phylogenetic history of paralogous gene quartets on human chromosomes 1, 2, 8 and 20 provides no evidence in favor of the vertebrate octoploidy hypothesis. AB - Fourfold paralogy regions in the human genome have been considered historical remnants of whole-genome duplication events predicted to have occurred early in vertebrate evolution. Taking advantage of the well-annotated and high-quality human genomic sequence map as well as the ever-increasing accessibility of large scale genomic sequence data from a diverse range of animal species, we investigated the prediction that the ancestral vertebrate genome was shaped by two rapid rounds of whole-genome duplication within a period of 10 million years. Both the map self-comparison approach and a phylogenetic analysis revealed that gene families identified as tetralogous on human chromosomes 1/2/8/20 arose by small-scale duplication events that occurred at widely different time points in animal evolution. Furthermore, the data discount the likelihood that tree topologies of the form ((A,B)(C,D)) are best explained by the octoploidy hypothesis. We instead propose that such symmetrical tree patterns are also consistent with local duplications and rearrangement events. PMID- 22425708 TI - Paradigm lost: how parasite control may alter pattern and process in human helminthiases. AB - Knowledge of pattern and process in helminth population biology is mostly based on the endemic equilibrium state that characterises infections before control. Current large-scale intervention programmes aim at controlling/eliminating helminth infection, transmission and morbidity. As a result, age-infection profiles will be modified; immune responses will be affected; underlying parasite distributions may become more aggregated; density-dependent regulatory processes will relax; and the contribution to transmission and morbidity of different host population groups will shift. There is an urgent need to understand how the paradigm that has guided parasite population biology research is changing under chemotherapy-based control programmes for this research to continue supporting parasite control efforts effectively. PMID- 22425709 TI - The endoplasmic reticulum is a target organelle for trivalent dimethylarsinic acid (DMAIII)-induced cytotoxicity. AB - The purpose of present study was to characterize the endoplasmic reticulum stress and generation of ROS in rat liver RLC-16 cells by exposing to trivalent dimethylarsinous acid (DMAIII) and compared with that of trivalent arsenite (iAsIII) and monomethylarsonous acid (MMAIII). Protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation was significantly induced in cells exposed to DMAIII, while there was no change in phosphorylated PERK (P-PERK) detected in cells after exposure to iAsIII or MMAIII. The generation of reactive oxygen species (ROS) after DMAIII exposure was found to take place specifically in the endoplasmic reticulum (ER), while previous reports showed that ROS was generated in mitochondria following exposure to MMAIII. Meanwhile, cycloheximide (CHX) which is an inhibitor of protein biosynthesis strongly inhibited the DMAIII induced intracellular ROS generation in the ER and the phosphorylation of PERK, suggesting the induction of ER stress probably occurs through the inhibition of the protein folding process. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mRNA were induced by all three arsenic species, however, evidence suggested that they might be induced by different pathways in the case of iAsIII and MMAIII. In addition, ER resident molecular chaperone glucose-regulated protein78 (GRP78) was not affected by trivalent arsenicals, while it was induced in positive control only at high concentration (Thapsigargin;Tg), suggesting the GRP78 is less sensitive to low levels of ER stress. In summary, our findings demonstrate that the endoplasmic reticulum is a target organelle for DMAIII-induced cytotoxicity. PMID- 22425710 TI - Case study: technology initiative led to advanced lead optimization screening processes at Bristol-Myers Squibb, 2004-2009. AB - In this paper, we review the key solutions that enabled evolution of the lead optimization screening support process at Bristol-Myers Squibb (BMS) between 2004 and 2009. During this time, technology infrastructure investment and scientific expertise integration laid the foundations to build and tailor lead optimization screening support models across all therapeutic groups at BMS. Together, harnessing advanced screening technology platforms and expanding panel screening strategy led to a paradigm shift at BMS in supporting lead optimization screening capability. Parallel SAR and structure liability relationship (SLR) screening approaches were first and broadly introduced to empower more-rapid and -informed decisions about chemical synthesis strategy and to broaden options for identifying high-quality drug candidates during lead optimization. PMID- 22425711 TI - Antimicrobial activity of stingless bee (Trigona sp.) propolis used in the folk medicine of Western Maharashtra, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Stingless bee (Trigona sp.) propolis is widely used in the folk medicine of Western Maharashtra, India to treat a variety of ailments. AIM OF THE STUDY: To determine the chemical composition and evaluate the antimicrobial activity of Indian stingless bee propolis. MATERIALS AND METHODS: Chemical composition of the ethanolic extract of propolis (EEP) was determined by GC-MS analysis. A range of bacteria including multidrug resistant (MDR) cultures as well as a yeast strain was tested for antimicrobial activity using EEP. MIC, MBC, MFC, Kill curves and post agent effect (PAE) of the EEP were assessed using standard microbiological methods. RESULTS: GC-MS analysis revealed that propolis contained 24 compounds (9 known and 15 newly reported). Many of these were known bioactive compounds, including antimicrobials. The MICs of EEP were in the range of 1.21-9.75MUg/mL while the MBCs/MFC were between 2.43 and 19.5MUg/mL. The time required to achieve 90% (1 log(10)) reduction in culture growth ranged between 1.06 and 3.53h at their respective MIC values. PAE for all the cultures was >24h. CONCLUSION: Indian stingless bee propolis has a complex nature with 24 chemical compounds. It has a potent broad-spectrum antimicrobial activity. The latter finding, in conjunction with other bioactive properties, could provide a scientific basis to its popular use in the Indian folk medicine. PMID- 22425712 TI - Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinoma. AB - OBJECTIVES: MicroRNA deregulation is a critical event in head and neck squamous cell carcinoma (HNSCC). Several microRNA profiling studies aimed at deciphering the microRNA signatures of HNSCC have been reported, but there tends to be poor agreement among studies. The objective of this study was to survey the published microRNA profiling studies on HNSCC, and to assess the commonly deregulated microRNAs in an independent sample set. MATERIALS AND METHODS: Meta-analysis of 13 published microRNA profiling studies was performed to define microRNA signatures in HNSCC. Selected microRNAs (including members of miR-99 family) were evaluated in an independent set of HNSCC cases. The potential contributions of miR-99 family to the tumorigenesis of HNSCC were assessed by in vitro assays. RESULTS: We identified 67 commonly deregulated microRNAs. The up-regulation of miR-21, miR-155, miR-130b, miR-223 and miR-31, and the down-regulation of miR 100, miR-99a and miR-375 were further validated in an independent set of HNSCC cases with quantitative RT-PCR. Among these validated microRNAs, miR-100 and miR 99a belong to the miR-99 family. Our in vitro study demonstrated that restoration of miR-100 to the HNSCC cell lines suppressed cell proliferation and migration, and enhanced apoptosis. Furthermore, ectopic transfection of miR-99 family members down-regulated the expression of insulin-like growth factor 1 receptor (IGF1R) and mechanistic target of rapamycin (mTOR) genes. CONCLUSION: In summary, we described a panel of frequently deregulated microRNAs in HNSCC, including members of miR-99 family. The deregulation of miR-99 family contributes to the tumorigenesis of HNSCC, in part by targeting IGF1R and mTOR signaling pathways. PMID- 22425713 TI - Malignant germ cell-like tumors, expressing Ki-1 antigen (CD30), are revealed during in vivo differentiation of partially reprogrammed human-induced pluripotent stem cells. AB - Because many of the genes used to produce induced pluripotent stem cells (iPSCs) from somatic cells are either outright established oncogenes, such as c-myc and Klf4, or potentially related to tumorigenesis in various cancers, both the safety and the risks of tumorigenesis linked to iPSC generation require evaluation. In this work, we generated, by lentivirus-mediated gene transfer of Oct4, Sox2, Nanog, and Lin28, two types of iPSCs from human mesenchymal stem cells and human amniotic fluid-derived cells: fully reprogrammed iPSCs with silencing of the four transgenes and partially reprogrammed iPSCs that still express one or several transgenes. We assessed the behavior of these cells during both their differentiation and proliferation using in vivo teratoma assays in nonobese diabetic mice with severe combined immunodeficiency. In contrast to fully reprogrammed iPSCs, 43% of partially reprogrammed iPSC cases (6 of 14 teratomas) generated major dysplasia and malignant tumors, with yolk sac tumors and embryonal carcinomas positive for alpha-fetoprotein, cytokeratin AE1/AE3, and CD30. This correlated with the expression of one or several transgenes used for the reprogramming, down-regulation of CDK 1A mRNA (p21/CDKN1A), and up-regulation of antiapoptotic Bcl-2 mRNA. Therefore, the oncogenicity of therapeutically valuable patient-specific iPSC-derived cells should be scrupulously evaluated before they are used for any clinical applications. PMID- 22425714 TI - Rapid expression profiling of brain microvascular endothelial cells by immuno laser capture microdissection coupled to TaqMan((r)) low density array. AB - Immuno-laser capture microdissection (immuno-LCM) enables highly selective retrieval of designated cell populations from their in situ locations in complex tissue like the brain. However, the amount of tissue acquired by immuno-LCM is extremely limited, and the RNA purification, amplification and labeling steps necessary for expression analysis by hybridization microarray are tedious and time consuming. This report therefore describes a protocol in which these RNA steps are eliminated altogether, yet allows for global gene profiling. Specifically, immuno-LCM tissue was solubilized and the extract directly subjected to reverse transcription to generate cDNA. Pre-amplification of cDNA was performed next, and then relative expression of 96 different immune-related genes simultaneously determined by quantitative real-time PCR using a microfluidic card TaqMan((r)) Low Density Array (TLDA). This protocol was highly reproducible and extremely sensitive, demonstrating high correlation of raw Ct values among both technical and biological replicate samples when using only 1/32 of total pre-amplified cDNA obtained from as little as 500 LCM 'shots.' As this abridged protocol takes only approximately 7h from LCM tissue acquisition to analysis by TLDA, it can prove a very effective tool for both screening and validation purposes when investigating gene regulation in health and disease of the nervous system and other tissues. PMID- 22425715 TI - Frontal lobe epilepsy with atypical seizure semiology resembling shuddering attacks or wet dog shake seizures. AB - We report a girl with a drug-resistant frontal lobe epilepsy caused by focal cortical dysplasia, who exhibited uncommon seizures. The seizures consisted of shoulder or whole body shuddering after a short psychic aura and face grimacing. Consciousness was fully preserved. The seizures resembled "wet dog shake" seizures described in rat models of epilepsy or shuddering attacks in infants. EEG findings were inconclusive, however, MRI showed a clear dysplastic lesion in the right frontal mesial and polar structures. The patient underwent an extended lesionectomy guided by neuronavigation and intraoperative electrocorticography. Focal cortical dysplasia type Ib was histologically confirmed and the patient has been seizure-free for the three years following resection. [Published with video sequences]. PMID- 22425716 TI - Characterization of thromboxane A2 receptor and TRPV1 mRNA expression in cultured sensory neurons. AB - Thromboxane A(2) (TxA(2)) is an arachidonic acid metabolite that stimulates platelet aggregation and vasoconstriction when released from platelets and other cell types during tissue trauma. More recent research has demonstrated that TxA(2) can also stimulate vagal and spinal sensory nerves. The purpose of this study was twofold. One, we compared the expression of the TxA(2) receptor (TxA2R) in neurons from two sensory ganglia: the nodose ganglion (NG) containing cell bodies of vagal afferent nerves and the thoracic dorsal root ganglion (DRG) containing cell bodies of spinal afferent nerves. Two, we determined if TxA2R co localizes with mRNA for the nociceptive marker, TRPV1, which is the receptor for the noxious substance capsaicin. We found a greater percentage of neurons in the NG that are positive for TxA2R expression than in the DRG. We also found that there was no correlation of expression of TxA2R with TRPV1. These data suggest that while TxA2R is expressed in both vagal and spinal neurons, TxA(2) may elicit stronger vagal or parasympathetic reflexes in the rabbit when released during tissue trauma depending on the location of release. Our data also indicate that TxA(2) is likely to stimulate both nociceptive and non-nociceptive neurons thereby broadening the types of neurons and reflexes that it may excite. PMID- 22425717 TI - Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease. AB - Huntington's Disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD. Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3T). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity. Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy. Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD. PMID- 22425718 TI - ADAMTS-13 is produced by glial cells and upregulated after spinal cord injury. AB - ADAMTS-13, a member of the family of disintegrins and metalloproteinases with thrombospondin motifs, is produced primarily in the liver, particularly by hepatic stellate cells. This metalloproteinase cleaves von Willebrand factor multimers and thereby regulates blood coagulation. Here, we investigated the expression of ADAMTS-13 in the central nervous system. ADAMTS-13 mRNA was expressed in cultured astrocytes and microglia but not in neurons. The protein production of ADAMTS-13 was also detected in these cultured glial cells. Furthermore, we found that the expression of ADAMTS-13 was significantly increased in the rat spinal cord after injury. Supporting the in vivo data, ADAMTS-13 protein was detected in GFAP- and CD11b-positive glial cells in injured spinal cord. Consistent with this, the proteolytic activity of ADAMTS-13 was increased after spinal cord injury. Our data suggest that ADAMTS-13 may have a critical role in the central nervous system, particularly after neuronal injuries. PMID- 22425719 TI - Shifting the focus of attention modulates amygdala and anterior cingulate cortex reactivity to emotional faces. AB - Functional neuroimaging studies have largely established the prominence of amygdala during emotion processing and prefrontal areas such as anterior cingulate cortex (ACC) during attentional modulation. In general, emotion processing paradigms known to probe amygdala have not been adapted to recruit prefrontal areas. In this study we used a well-known perceptual face matching paradigm, designed to elicit amygdala response, and asked volunteers to shift their focus in order to recruit regions responsible for attentional control. Stimuli comprised a trio of geometric shapes (circles, rectangles, triangles) presented alongside a trio of emotional faces (angry, fear, or happy) within the same field of view, and subjects were instructed to Match Faces or Match Shapes, as a means of attending to and away from the emotional content, respectively. We observed greater amygdala reactivity to Match Faces (>Match Shapes), and greater rostral ACC response to Match Shapes (>Match Faces). Results indicate that simply and volitionally directing attention toward or away from emotional content correspondingly modulates amygdala and ACC activity. PMID- 22425720 TI - Allocentrically implied target locations are updated in an eye-centred reference frame. AB - When reaching to remembered target locations following an intervening eye movement a systematic pattern of error is found indicating eye-centred updating of visuospatial memory. Here we investigated if implicit targets, defined only by allocentric visual cues, are also updated in an eye-centred reference frame as explicit targets are. Participants viewed vertical bars separated by varying distances, and horizontal lines of equivalently varying lengths, implying a "target" location at the midpoint of the stimulus. After determining the implied "target" location from only the allocentric stimuli provided, participants saccaded to an eccentric location, and reached to the remembered "target" location. Irrespective of the type of stimulus reaching errors to these implicit targets are gaze-dependent, and do not differ from those found when reaching to remembered explicit targets. Implicit target locations are coded and updated as a function of relative gaze direction with respect to those implied locations just as explicit targets are, even though no target is specifically represented. PMID- 22425721 TI - TREK1 activation mediates spinal cord ischemic tolerance induced by isoflurane preconditioning in rats. AB - The aim of this study is to examine the role of one of the two-pore (2P) domain K(+) channels, TREK (TWIK-related K(+) channels, TREK)-1, mediated neuroprotection on spinal cord afforded by isoflurane preconditioning. In Experiment 1, male Sprague-Dawley rats were randomly assigned to control (Con) group, an isoflurane preconditioning (Iso) group, and sham group. Twenty-four hours after the last pretreatment, spinal cord ischemia was induced in Con and Iso groups. Neurobehavioral testing and histopathologic examination were performed after reperfusion. In Experiment 2, the expression of the TREK1 in the spinal cord was assessed by immunohistochemistry, Western blot and real-time polymerase chain reaction. In Experiment 3, Amiloride, a blocker of stretch sensitive channels, was administered intraperitoneally immediately prior to each isoflurane preconditioning. Iso group showed a significant reductions in motor deficit index as well as increases in the number of normal neurons compared with the Con group. The expression of TREK1 protein and the level of mRNA after ischemia were higher in the rats of the Iso group than those in the Con group. Amiloride pretreatment abolished the protective effects of Iso preconditioning. These finding indicate that isoflurane preconditioning had a neuroprotective effect against spinal cord ischemia reperfusion injury. These effects may be mediated through the TREK1 pathway. PMID- 22425722 TI - Specificity in rehabilitation of word production: a meta-analysis and a case study. AB - Speech production impairment is a frequent deficit observed in aphasic patients and rehabilitation programs have been extensively developed. Nevertheless, there is still no agreement on the type of rehabilitation that yields the most successful outcomes. Here, we ran a detailed meta-analysis of 39 studies of word production rehabilitation involving 124 patients. We used a model-driven approach for analyzing each rehabilitation task by identifying which levels of our model each task tapped into. We found that (1) all rehabilitation tasks are not equally efficient and the most efficient ones involved the activation of the two levels of the word production system: the phonological output lexicon and the phonological output, and (2) the activation of the speech perception system as it occurs in many tasks used in rehabilitation is not successful in rehabilitating word production. In this meta-analysis, the effect of the activation of the phonological output lexicon and the phonological output cannot be assessed separately. We further conducted a rehabilitation study with DPI, a patient who suffers from a damage of the phonological output lexicon. Our results confirm that rehabilitation is more efficient, in terms of time and performance, when specifically addressing the impaired level of word production. PMID- 22425723 TI - Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. AB - We investigated the occurrence of goal-directed motivational change in the form of apathy in patients with frontotemporal dementia (FTD), particularly those with behavioral variant social and executive deficits (bvFTD). Standardized behavioral inventory was employed to survey and compare apathy ratings from patients and caregivers. In cases of bvFTD, apathy ratings were further related to measures of social cognition, executive function, and atrophy on brain MRI. Results indicated that caregivers rated bvFTD patients as having significantly elevated apathy scores though patient self-ratings were normal. Caregiver and self-ratings of FTD samples with progressive nonfluent aphasia and semantic dementia did not differ from healthy controls and their informants. In the bvFTD sample, caregiver apathy scores were not correlated with general cognitive screening or depression scores, but were significantly correlated with social cognition and executive function measures. Voxel-based morphometry revealed that apathy ratings in bvFTD were related to prominent atrophy in the right caudate (including the ventral striatum), the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum- anterior insula region. Findings suggest that bvFTD is associated with a significant breakdown in goal directed motivated behavior involving disruption of cortical-basal ganglia circuits that is also related to social and executive function deficits. PMID- 22425724 TI - The relationship of clinical, cognitive and social measures in schizophrenia: a preliminary finding combining measures in probands and relatives. AB - This study examines performance of schizophrenia patients, unaffected relatives and controls in social cognition, cognitive and psychiatric scales looking for possible markers of vulnerability in schizophrenia. Performance of schizophrenia patients from multiplex families, first-degree relatives, and matched controls was compared and, subsequently, discriminant analysis method was used for identifying the best predictors for group membership. By using Multigroup Discriminant Analyses on the three groups, the best predictors were PANSS, Premorbid Adjustment Scale, Faux Pas test, and a face/emotion categorizing task. This model obtained 82% correct global classification, suggesting that the combination of psychiatric scales and neuropsychological/social cognition tasks are the best approach for characterizing this disease. Although preliminary, our results suggest that social cognition tasks are robust markers of schizophrenia family impairments, and that combining clinical, social and neuropsychological measures is the best approach to asses patients and relatives vulnerability. PMID- 22425725 TI - Augmented input reveals word deafness in a man with frontotemporal dementia. AB - We describe a 57 year old, right handed, English speaking man initially diagnosed with progressive aphasia. Language assessment revealed inconsistent performance in key areas. Expressive language was reduced to a few short, perseverative phrases. Speech was severely apraxic. Primary modes of communication included gesture, pointing, gaze, physical touch and leading. Responses were 100% accurate when he was provided with written words, with random or inaccurate responses for strictly auditory/verbal input. When instructions to subsequent neuropsychological tests were written instead of spoken, performance improved markedly. A comprehensive audiology assessment revealed no hearing impairment. Neuroimaging was unremarkable. Neurobehavioral evaluation utilizing written input led to diagnoses of word deafness and frontotemporal dementia, resulting in very different management. We highlight the need for alternative modes of language input for assessment and treatment of patients with language comprehension symptoms. PMID- 22425726 TI - Successful escape of acute ischemic stroke patients from hospital to home: clinical note. AB - I describe four patients who successfully escaped from the hospital to their own home during the acute phase of ischemic stroke. This is a very rare phenomenon (seen in 0.35% of 1150 consecutive patients with first ischemic stroke within 24 h after onset), but the patients had rather uniform clinical characteristics. All were male, around 60 years old, had moderate to severe aphasia (Wernicke's in 2 patients, Broca's in 1, and transcortical motor in 1), and cerebral infarction of the left middle cerebral artery territory. None had significant motor weakness, hemispatial neglect, or hemianopia at the time of escape. Overall functional outcome was good for all but one patient, but aphasia persisted in three. Although none of the four patients sustained serious injury during the escape, patients with such clinical characteristics must be managed cautiously to prevent serious consequences. PMID- 22425727 TI - Characterization of multiple light damage paradigms reveals regional differences in photoreceptor loss. AB - Zebrafish provide an attractive model to study the retinal response to photoreceptor apoptosis due to its remarkable ability to spontaneously regenerate retinal neurons following damage. There are currently two widely-used light induced retinal degeneration models to damage photoreceptors in the adult zebrafish. One model uses constant bright light, whereas the other uses a short exposure to extremely intense ultraviolet light. Although both models are currently used, it is unclear whether they differ in regard to the extent of photoreceptor damage or the subsequent regeneration response. Here we report a thorough analysis of the photoreceptor damage and subsequent proliferation response elicited by each individual treatment, as well as by the concomitant use of both treatments. We show a differential loss of rod and cone photoreceptors with each treatment. Additionally, we show that the extent of proliferation observed in the retina directly correlates with the severity of photoreceptor loss. We also demonstrate that both the ventral and posterior regions of the retina are partially protected from light damage. Finally, we show that combining a short ultraviolet exposure followed by a constant bright light treatment largely eliminates the neuroprotected regions, resulting in widespread loss of rod and cone photoreceptors and a robust regenerative response throughout the retina. PMID- 22425728 TI - Hyperkalemic cardiac arrest in a 14-month-old following spica cast application. PMID- 22425729 TI - Brunfelsia (Solanaceae): a genus evenly divided between South America and radiations on Cuba and other Antillean islands. AB - Hallucinogenic or toxic species of Brunfelsia (Solanaceae: Petunieae) are important in native cultures throughout South America, and the genus also contains several horticulturally important species. An earlier morphological revision of the c. 50 species recognized three main groups, one consisting of the 23 Antillean species, another of southern South American and Andean species, and a third of species from the Amazon Basin and Guiana Shield. Based on plastid and nuclear DNA sequences from up to 65 accessions representing 80% of the species, we generated a phylogeny and a calibrated chronogram for Brunfelsia to infer clade expansion and shifts in pollinators and fruit types. Brunfelsia flowers offer nectar, and attract lepidoptera, hummingbirds, or bees; the fruits are dry or fleshy. Our results imply that Brunfelsia is 16-21 Myr old and entered the Antilles from South America early during its history, with subsequent expansion along the island arc. The ancestor of the Antillean clade was hawk-moth pollinated and had fleshy capsules, perhaps facilitating dispersal by birds. The only shift to hummingbird pollination occurred on Cuba, which also harbors the largest single radiation, with 11 species (10 included in our study) that apparently arose over the past 4 Myr. Jamaica, Hispaniola, and Puerto Rico each sustained smaller radiations. The data also reveal at least one new species. PMID- 22425730 TI - Arnica (Asteraceae) phylogeny revisited using RPB2: complex patterns and multiple d-paralogues. AB - The region coding for the second largest subunit of RNA polymerase II (RPB2) was explored for resolving interspecific relationships in Arnica and lower level taxa in general. The region between exons 17 and 23 was cloned and sequenced for 33 accessions of Arnica and four outgroup taxa. Three paralogues of the RPB2-d copy (RPB2-dA, B and C) were detected in Arnica and outgroup taxa, indicating that the duplications must have occurred before the divergence of Arnica. Parsimony and Bayesian analyses of separate alignments of the three copies reveal complex patterns in Arnica, likely reflecting a history of lineage sorting in combination with apomixis, polyploidization, and possibly hybridization. Cloned sequences of some taxa do not form monophyletic clades within paralogues, but form multiple strongly supported clades with sequences of other taxa. Some well supported groups are present in more than one paralogue and many groups are in line with earlier hypotheses regarding interspecific relationships within the genus. Low levels of homoplasy in combination with relatively high sequence variation indicates that the introns of the RPB2 region could be suitable for phylogenetic studies in low level taxonomy. PMID- 22425731 TI - Vasopressors in cardiac arrest: a systematic review. AB - OBJECTIVES: To review the literature addressing whether the use of vasopressors improves outcomes in patients who suffer cardiac arrest. METHODS: Databases were searched using the terms: "(adrenaline or noradrenaline or vasopressor) and (heart arrest or cardiac arrest) and therapy". Inclusion criteria were human studies, controlled trials, meta-analysis or case series. Exclusion criteria were articles with no abstract, abstract-only citations without accompanying article, non-English abstracts, vasopressor studies without human clinical trials, case reports, reviews, and articles addressing traumatic arrest. RESULTS: 1603 papers were identified of which 53 articles were included for review. The literature addressed 5 main therapeutic questions. (1) Outcomes comparing any vasopressor to placebo. (2) Outcomes comparing vasopressin (alone or in combination with epinephrine) to epinephrine. (3) Outcomes comparing high dose epinephrine to standard dose epinephrine. (4) Outcomes comparing any alternative vasopressor to epinephrine. (5) Outcomes examining vasopressor use in pediatric cardiac arrest. CONCLUSION: There are few studies that compare vasopressors to placebo in resuscitation from cardiac arrest. Epinephrine is associated with improvement in short term survival outcomes as compared to placebo, but no long-term survival benefit has been demonstrated. Vasopressin is equivalent for use as an initial vasopressor when compared to epinephrine during resuscitation from cardiac arrest. There is a short-term, but no long-term, survival benefit when using high dose vs. standard dose epinephrine during resuscitation from cardiac arrest. There are no alternative vasopressors that provide a long-term survival benefit when compared to epinephrine. There is limited data on the use of vasopressors in the pediatric population. PMID- 22425732 TI - The impact of a step stool on cardiopulmonary resuscitation: a cross-over mannequin study. AB - OBJECTIVE: Shallow chest compressions and incomplete recoil are common during cardiopulmonary resuscitation (CPR) and negatively affect outcomes. A step stool has the potential to alter these parameters when performing CPR in a bed but the impact has not been quantified. METHODS: We conducted a cross-over design, simulated study of in-hospital cardiac arrest. Rescuers performed a total of four 2-min segments of uninterrupted chest compressions, half of which were on a step stool. Compression characteristics were measured using a CPR-sensing defibrillator and subjective impressions were obtained from rescuer surveys. Paired analyses were performed to measure the impact of the step stool, taking into account rescuer characteristics, including height. RESULTS: Fifty subjects, of whom 36% were men, with a median height of 169.8 cm (range 148.6-190.5) volunteered to participate. Use of a step stool resulted in an average increase in compression depth of 4 mm (p<0.001) and 18% increase in incomplete recoil (p<0.001). However, unlike with incomplete recoil, the effect was more pronounced in rescuers in the lowest height tertile (9+/-9 mm vs 2+/-6 mm for those rescuers taller than 167 cm, p=0.006). CONCLUSIONS: Using a step stool when performing CPR in a bed results in a trade-off between increased compression depth and increased incomplete recoil. Given the nonlinear relationship between the increase in compression depth and rescuer height, the benefit of a step stool may outweigh the risks of incomplete release for rescuers <=167 cm in height. The benefit is less clear in taller rescuers. PMID- 22425733 TI - Oxidative stress responses in different organs of carp (Cyprinus carpio) with exposure to ZnO nanoparticles. AB - Changes in activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and non-enzymatic antioxidant reduced glutathione (GSH) content and levels of Lipid peroxidation (LPO) in gill, liver, brain and intestine of juvenile carp (Cyprinus carpio) were evaluated after exposure to different concentrations (0.5, 5.0 and 50.0mg/L) of waterborne nano-ZnO for 1, 3, 7, 10 and 14 day. The results showed that the variation trendency of antioxidant defense systems and LPO levels would be more significant with increasing concentration and exposure time. 50.0mg/L nano-ZnO caused significant decrease of several enzymes activities and GSH content and increase of LPO level. As a result, these biomarkers were all appropriate for monitoring oxidative stress status of fish after exposure to nano-ZnO. Gill, liver and brain might be more sensitive response organs, being intestine the least altered organ. Further ecotoxicological evaluation should be made concerning the risk of nano-ZnO on aquatic environment. PMID- 22425734 TI - Effect of water management, arsenic and phosphorus levels on rice in a high arsenic soil-water system: II. Arsenic uptake. AB - Rice consumption is one of the major pathways for As intake in populations that depend on a rice diet in several countries of South and South-east Asia. Pot experiments were undertaken to investigate the effects of water management (WM), arsenic (As) contaminated soil-water and Phosphorus (P) rates on As uptake in rice plants. There were 18 treatments comprising of three each of As rates (0, 20 and 40 mg kg(-1) soil) and P rates (0, 12.5 and 25 mg kg(-1) soil) and two WM (aerobic and anaerobic) strategies on winter (boro var. BRRI dhan 29) and monsoon (aman var. BRRI dhan 32) rice at the Wheat Research Center (WRC), Nashipur, Dinajpur, Bangladesh. Arsenic concentrations in rice grain and straw increased significantly (P <= 0.01) with the increasing As rates in the soil. Arsenic availability in soil pore-water solution was less (58%) under aerobic WM (redox potential-Eh=+135 to +138 mV; pH-6.50 at 24.3 degrees C) as compared to anaerobic WM (flooded: Eh=-41 to -76 mV; pH-6.43 at 23 degrees C). The highest total grain As content 2.23 +/- 0.12 mg kg(-1) and 0.623 +/- 0.006 mg kg(-1) was found in T(6) (P(12.5)As(40)-anaerobic) and T(9) (P(25)As(40)-anaerobic) in BRRI dhan 29 and BRRI dhan 32, respectively, which was significantly higher (41-45%) than in the same As and P treatments for pots under aerobic WM. The As content in rice straw (up to 24.7 +/- 0.49 ppm in BRRI dhan 29, 17.3 +/- 0.49 mg kg(-1) in BRRI dhan 32 with the highest As level) suggested that As can more easily be translocated to the shoots under anaerobic conditions than aerobic condition. BRRI dhan 29 was more sensitive to As than BRRI dhan 32. Under aerobic WM, P soil amendments reduced As uptake by rice plants. The study demonstrated that aerobic water management along with optimum P amendment and selection of arsenic inefficient rice varieties are appropriate options that can be applied to minimize As accumulation in rice which can reduce effects on human and cattle health risk as well as soil contamination. PMID- 22425735 TI - Flue gas compounds and microalgae: (bio-)chemical interactions leading to biotechnological opportunities. AB - Flue gases are a resource yet to be fully utilised in microalgal biotechnology, not only to moderate the anthropogenic effects on our climate, but also to steer microalgal resource management towards innovative applications of microalgal biomass compounds. These gases, both untreated and treated into current discharge standards, contain CO2, N2, H2O, O2, NOx, SOx, CxHy, CO, particulate matter, halogen acids and heavy metals. To better steer and engineer flue gas-fed microalgal cultures, all these compounds need to be considered. Therefore, here, we review (i) the chemical composition and treatment technologies of flue gas, (ii) the uptake pathways and removal of the different compounds in microalgae reactors, and (iii) the tolerance and effects on microalgae of all flue gas compounds. By emphasising the interactions between microalgae and flue gas compounds, we envisage new pathways for microalgal biomass valorisation such as enzyme production for environmental technology, novel biogas production and biosequestration of minerals. Furthermore, we highlight fundamental and applied research niches that merit further investigation. PMID- 22425736 TI - Predictive value of the Luminex single antigen panel for detecting flow cytometry cross-match positivity. AB - Anti-human leukocyte antigen (HLA) antibodies are a major cause of allograft loss. Solid-phase immunoassays, notably Luminex technology, have lately begun to replace traditional techniques for detecting these antibodies. This platform, however, carries some restrictions in the type of antibodies it detects. For this reason, results using these new technologies must be correlated with results using traditional techniques that have proven clinical significance. We have correlated flow cytometry cross-match (FCXM) outcomes with results from Luminex assays. Serum samples from patients awaiting transplantation who had known anti HLA antibodies as detected by Luminex were incubated with lymphocytes expressing (a) 1 of the HLA antigens detected by the sera or (b) several of them. Of the 169 T-cell FCXMs we performed, in 92 cases the target cell expressed only 1 of the HLA antigens detected by the serum. The results obtained correlated well with Luminex data (r = 0.84). A cutoff mean fluorescence intensity value of 6,500 for the Luminex single antigen assay yielded a sensitivity of 85% and specificity of 82% for detecting a positive FCXM. In the other 77 cases, the target cell expressed 2 or more of the HLA antigens detected by the serum. In this situation, the same cutoff proved a useful tool for differentiating negative from positive FCXMs. PMID- 22425737 TI - Tumor necrosis factor-like weak inducer of apoptosis increases CC chemokine ligand 20 production in interleukin 1beta-stimulated human gingival fibroblasts. AB - CC chemokine ligand 20 (CCL20) is related to T-helper (Th)-17 cell migration, and Th17 cells play important roles in exacerbation in periodontal disease. However, the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) on CCL20 production is unknown. In this study, we examined the mechanisms of TWEAK in combination with interleukin (IL)-1beta-induced CCL20 production in human gingival fibroblasts (HGFs). TWEAK alone did not induce CCL20 production in HGFs. However, TWEAK enhanced CCL20 expression from IL-1beta-stimulated HGFs in a dose dependent manner. Inhibitors of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and nuclear factor kappaB (NF-kappaB) significantly inhibited CCL20 production in TWEAK and IL-1beta-stimulated HGFs. Western blot analysis revealed that phosphorylations of ERK, Akt, and inhibitor of NF-kappaB were enhanced in TWEAK and IL-1beta-treated HGFs. These data suggest that TWEAK is positively related to Th17 cell migration in periodontally diseased tissues to enhance CCL20 production in IL-1beta stimulated HGFs. PMID- 22425738 TI - Low median fluorescence intensity could be a nonsafety concept of immunologic risk evaluation in patients with shared molecular eplets in kidney transplantation. AB - Human leukocyte antigen (HLA) antibodies are usually "epitope" and not "antigen" specific. This work presents an interesting case concerning Luminex median fluorescence intensity (MFI) levels in antibodies considered low risk (<1,000), but producing humoral rejection. These low-titer antibodies could play an important role in transplantation. A 42-year-old woman was retransplanted with a deceased donor with negative complement-dependent cytotoxicity cross-matching. Our patient was pretransplant (PrT) sensitized to HLA antigens (single antigens (SA) = 31%) for 1 previous transplant. Thus, the formerly detected sensitized antigens were A32, A30, A31, cross-reacting group 5C, and DQ3 with a MFI(max) ~ 4,127. In the posttransplantation period (PTP), the patient exhibited important instability in renal function and we detected an increased SA percentage (61%) with MFI(max) = 15,029 (A*32) with other antigens (detected with a low PrT MFI [<1,000]) as anti-A*03 (MFI(max) = 13,301) and anti-A*11 (MFI(max) = 13,714) specificities. Anti-A*03 was a donor-specific antibody (DSA). Renal biopsy was compatible with humoral rejection. The patient was pulsed with methylprednisolone, plasmapheresis, and intravenous immunoglobulin without improvement. Thus, we added anti-CD20 and the initial clinical response was highly favorable. Biopsies resulted in suggestive rejection reversion. MFI A*03 DSA decreased to 6,908 and later to MFI(max) = 5,505. After a 6-month PTP, the patient is well with MFI(max) = 3,124. It was possible to define exactly the potential immunizing epitope eplets whose recognition determined the specific antibody production. A*32:01, A*30:01, A*31:01 (detected PrT), A*11:01, and A*03:01 (detected PTP) alleles have several shared eplets (62QE, 70AQS, and 76VGT), with 62QE being the only eplet present on all alleles. In conclusion, low MFI levels in antibodies considered low risk could be important in posttransplant humoral rejection, although the patient's renal function can be restored. Thus, specific shared eplets should always be investigated with respect to previous transplant mismatches. PMID- 22425739 TI - The -346T polymorphism of the SH2D1A gene is a risk factor for development of autoimmunity/lymphoproliferation in males with defective Fas function. AB - Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome (ALPS) and its variant Dianzani autoimmune lymphoproliferative disease (DALD). Since a deleterious mutation of the SH2D1A gene protects MRLlpr/lpr mice from ALPS development, we investigated the role of SH2D1A, located in the X chromosome, in 51 patients with ALPS or DALD by mutational screening of coding and regulative sequences. Allelic frequency of the -346C>T polymorphism was different in male patients and controls (-346T: 61% vs 36%, p = 0.01), with similar frequencies in ALPS and DALD. By contrast, no differences were found among females or between the controls and patients with multiple sclerosis (229 males, 157 females). Further analyses showed that -346C was a methylation site in CD8(+) T and natural killer cells, and SH2D1A expression was higher in -346T than in -346C males. Finally, in vitro-activated T cells from -346T males produced lower amounts of interferon-gamma than those from -346C males. These data suggest that -346T is a predisposing factor for ALPS and DALD in males possibly because of its effect on SAP expression influencing the T cell response. PMID- 22425740 TI - MUC1 is a novel costimulatory molecule of human T cells and functions in an AP-1 dependent manner. AB - MUC1 mucin, primarily known as an epithelial antigen, has been demonstrated to be expressed on activated human T cells. In the present study, we first examined the expression of MUC1 on different subsets of T cells (naive, effector, effector/memory). MUC1 appears to be strongly upregulated on activated CD4(+) T cells in comparison with CD8(+) T cells. The cytoplasmic tail of MUC1 contains both immune tyrosine-based activation and inhibitory motifs; therefore, we investigated whether MUC1 can also act as a costimulatory molecule on human T cells. Nonpurified T-cell cultures from human peripheral blood exhibited enhanced proliferation and an increase in cytokine production when CD3 and MUC1 were cross linked and coligated. The intracellular mechanism of MUC1-mediated costimulation was determined to be mediated by the calcium-dependent NF-AT pathway. We further demonstrated that the cytoplasmic tail of MUC1 binds to the AP-1 transcription factors c-Fos and c-Jun, with c-Fos binding constitutively and c-Jun binding only after MUC1 stimulation. Their nuclear migration is then facilitated in a CD3 dependent manner. Our findings clearly demonstrate that MUC1 is a novel T-cell costimulatory molecule involved in immune regulation. These studies delineate important mechanisms of T-cell activation and regulation. PMID- 22425741 TI - Engineering humanized mice for improved hematopoietic reconstitution. AB - Humanized mice are immunodeficient animals engrafted with human hematopoietic stem cells that give rise to various lineages of human blood cells throughout the life of the mouse. This article reviews recent advances in the generation of humanized mice, focusing on practical considerations. We discuss features of different immunodeficient recipient mouse strains, sources of human hematopoietic stem cells, advances in expansion and genetic modification of hematopoietic stem cells, and techniques to modulate the cytokine environment of recipient mice, in order to enhance reconstitution of specific human blood lineage cells. We highlight the opportunities created by new technologies and discuss practical considerations on how to make best use of the widening array of basic models for specific research applications. PMID- 22425742 TI - Deep brain stimulation of the entopeduncular nucleus in rats prevents apomorphine induced deficient sensorimotor gating. AB - Pharmacologically induced stereotypies and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as endophenotypes for certain symptoms common to neuropsychiatric disorders, such as schizophrenia and Tourette's syndrome (TS) among others. We here investigated whether high frequency deep brain stimulation (DBS) of the rat's entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve PPI-deficits and stereotypies induced by the dopamine receptor agonist apomorphine. Electrodes were stereotactically implanted bilaterally in the EPN of 13 Sprague-Dawley rats. After one week of recovery the rats were stimulated with an amplitude 20% below their individual threshold for side effects (130 Hz, 80 MUs pulse width) or sham-stimulated for epochs of five days. At the end of each epoch the effect of ongoing stimulation or sham stimulation on apomorphine-induced stereotypies (vehicle and 0.5 mg/kg) and deficient PPI (vehicle and 1.0 mg/kg) were tested. In nine rats, in which the full protocol could be applied and in which the electrode position was histologically confirmed in the target, EPN DBS did not affect baseline PPI but counteracted the apomorphine-induced PPI-deficit, while apomorphine-induced stereotypies were not affected by DBS. This work indicates an important role of the EPN in the modulation of apomorphine-induced deficient prepulse inhibition. This model may be useful to further investigate the pathophysiological of deficient sensorimotor gating and mechanisms of action of DBS in certain neuropsychiatric disorders. PMID- 22425743 TI - Cooing- and babbling-related gamma-oscillations during infancy: intracranial recording. AB - We determined the spatio-temporal dynamics of intracranially-recorded gamma oscillations modulated by spontaneous cooing and babbling, which are considered to embody pre-linguistic language behaviors during infancy. Electrocorticographic (ECoG) signals were recorded from 110 cortical sites in the right hemisphere of a 10-month-old girl with focal epilepsy. Electrocorticographic signals were time locked to the onset of cooing or babbling. The amplitudes of gamma-oscillations during vocalizations were compared to those during preceding silent reference periods. Cooing and babbling elicited significant gamma-augmentation at 30-100 Hz at distinct sites of the inferior Rolandic region, whereas both forms of vocalizations elicited gamma-augmentation at an identical superior temporal site. The spatial, temporal and spectral characteristics of gamma-augmentation elicited by cooing and babbling were similar to those elicited by phoneme vocalization in older children and adults. Differential activation within the right inferior Rolandic region during cooing and babbling may reflect the mechanical or developmental difference between these two forms of vocalizations. The right superior temporal gyrus may participate in an auditory feedback system during vocalization. PMID- 22425744 TI - On the shoulders of giants: a historical perspective of unique experimental methods in mammary gland research. AB - While most organs undergo development in utero, the mouse mammary gland orchestrates five major developmental stages following birth: pre-puberty, puberty, pregnancy, lactation, and involution. Induced by both local and systemic factors, these five developmental stages transpire with dramatic alterations in glandular morphology and cellular function. As an experimental system, the mammary gland provides remarkable accessibility to processes regulating stem cell function, hormone response, and epithelial-stromal-extracellular matrix interactions. This review will provide a historical perspective of the unique in vitro and in vivo techniques used to study the mammary gland and how these methods have provided valuable insight into the biology of this organ. PMID- 22425745 TI - Non-coding RNAs in hepatitis B or C-associated hepatocellular carcinoma: potential diagnostic and prognostic markers and therapeutic targets. AB - Non-coding RNA (ncRNA), a class of RNAs that do not code protein but have regulatory functions, can regulate gene expression and replication of hepatitis B virus or hepatitis C virus and play an important role in the virus-host interaction and the development of hepatocellular carcinoma (HCC). Deregulated ncRNAs in surgically removed hepatic tissues and circulation can be prognostic and diagnostic markers, respectively. ncRNAs functioning as either tumor suppressors or oncogenes can be therapeutic options. Here, we summarize the deregulated ncRNAs associated with the infections and HCC and focus on their roles on early diagnosis, prognosis prediction and therapeutic option of HCC. PMID- 22425746 TI - Pilomotor seizures: a video case report. AB - Piloerection is a rare ictal manifestation usually associated with temporal lobe epilepsy. We present video and electrographic documentation of pilomotor seizures in a 75-year-old man with left temporal lobe epilepsy and remote herpes zoster encephalitis. In general, piloerection is most often localised to the temporal lobe. Unilateral piloerection is usually associated with an ipsilateral ictal onset. Bilateral piloerection has a less certain lateralising value, although earlier reports suggest left hemispheric predominance [Published with videosequences]. PMID- 22425747 TI - Ectopic expression of a T-box transcription factor, eomesodermin, renders CD4(+) Th cells cytotoxic by activating both perforin- and FasL-pathways. AB - During viral infection, CD8(+) cytotoxic T lymphocytes (CTL) play a central role to eliminate viruses by destructing virus-infected cells utilizing two cytolytic pathways, i.e., perforin/granzyme pathway and FasL-Fas pathway. It has been shown that effector functions of CTL are critically controlled by two T-box transcription factors, T-bet and eomesodermin (Eomes), although their precise activities in constructing CTL functions are not fully understood. To investigate the functional potency and activities of Eomes, the effects of ectopic expression of Eomes in two terminally differentiated murine CD4(+) Th lines, on their effector functions were analyzed. The results showed that in Eomes-transfected Th hybridoma, cell surface FasL expression upon Con A stimulation was markedly enhanced, although perforin expression was not induced. In normal, non transformed Th2 cells, introduction of Eomes elicited perforin expression, and also augmented FasL up-regulation. Interestingly, cyotlytic activity of Eomes transfectant was more efficient than that of perforin-transfected Th2 cells which expressed high levels of perforin and granzyme B mRNA, indicating that Eomes may play additional roles other than preparation of these cytolytic effector molecules. In contrast, stimulation-induced CD154 up-regulation, one of the typical helper T cell characteristics, was repressed in Eomes-transfectant. Collectively, these results suggest that Eomes may not only be involved in perforin/granzyme expression but also play various functions, including FasL up regulation, to develop the characteristics of CD8(+) CTL. These studies have also suggested that introduction of Eomes alone was sufficient to convert the functions of fully differentiated Th cells toward those of CTL. PMID- 22425748 TI - In vitro activity of N-benzenesulfonylbenzotriazole on Trypanosoma cruzi epimastigote and trypomastigote forms. AB - Chagas disease is still an important health problem in Central and South America. However, the only drugs currently available for specific treatment of this disease may induce toxic side effects in the host. The aim of this work was to determine the activity of N-benzenesulfonylbenzotriazole (BSBZT) against the protozoan parasite Trypanosoma cruzi. The effects of BSBZT and benzotriazole (BZT) were compared to those of benznidazole (BZL) on epimastigote and trypomastigote forms. BSBZT was found to have an in vitro growth inhibitory dose dependent activity against epimastigotes, with flow cytometry analysis confirming that the treated parasites presented size reduction. BSBZT showed an IC(50) of 21.56 MUg/mL (81.07 MUM) against epimastigotes at 72 h of incubation, whereas BZT did not affect the growth of this parasite form. Furthermore, the toxic effect of BSBZT, was stronger and appeared earlier (at 24h) in trypomastigotes than in epimastigotes, with the LC(50) of this compound being 28.40 MUg/mL (106.79 MUM) against trypomastigotes. The concentrations of BSBZT used in this study presented low hemolytic activity and cytotoxicity. Consequently, at concentrations near IC(50) and LC(50) (25MUg/mL), BSBZT caused only 2.4% hemolysis and 15% of RAW 264.7 cell cytotoxicity. These results reveal the potential of BSBZT as a prototype in drug design for developing new anti-T. cruzi compounds. PMID- 22425749 TI - Fasciola gigantica: the in vitro effects of artesunate as compared to triclabendazole on the 3-weeks-old juvenile. AB - The in vitro effect of artesunate (ATS) on the 3-week-old juveniles of Fasciola gigantica was compared with triclabendazole (TCZ) by incubating the parasites in M-199 medium containing the drugs at concentrations of 20, 40, and 80 MUg/ml for 1, 3, 6, 12, and 24h. The anthelmintic activities of these drugs were evaluated based on the relative motility value (RM) and the alterations of the tegument as observed by scanning (SEM) and transmission (TEM) electron microscopy. The RM values of TCZ-treated flukes decreased significantly from 6 to 24h for all dosages. For ATS-treated flukes, RM value decreased markedly from 12 to 24h, but the rates of decline were less than TCZ at the same doses. When observed by SEM, the tegument showed similar sequence of morphological changes after treatments with both drugs, comprising of swelling of tegumental ridges, followed by blebbing and later rupturing of the blebs, leading to erosion and lesion, and disruption of the tegument. When examined by TEM, ultrastructural changes in the tegument and associated structures after treatments with TCZ and ATS were similar which comprised of swelling, blebbing of the tegument, dilation of basal infoldings, and depolymerization of the microtrabecular network. After a longer incubation time, the tegument was completely sloughed off and the tegument cell bodies became necrotic. Additionally, in ATS-treated flukes, mitochondria showed severe swelling, rupturing of outer membrane, and their interior filled with flocculent materials. PMID- 22425750 TI - Effect of lead in water on the absorption of copper, iron, manganese and zinc by sheep (Ovis aries) infected with sheep tapeworm (Moniezia expansa). AB - The sheep tapeworm (Moniezia expansa) and its host Ovis aries were analyzed by inductively coupled plasma optical emission spectrometry (ICP-OES) for their copper, iron, manganese, zinc and lead levels. Element concentrations in cestode parasites were compared to those in various organs (liver, kidney, and muscle) of sheep. Tapeworms in the small intestine of sheep that were administered 2g of Pb(CH(3)COO)(2) per os daily (7 days) had significantly higher lead concentrations than sheep tissues. Cu levels significantly increased after Pb administration in sheep muscle and sheep tapeworms. Contrarily, Zn content significantly decreased in sheep muscle, but significantly increased in sheep tapeworms. However, Mn content significantly decreased after Pb administration in sheep tapeworms. Furthermore, Fe content significantly decreased after Pb administration in sheep liver and kidneys. PMID- 22425751 TI - Memantine facilitates memory consolidation and reconsolidation in the day-old chick. AB - Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been approved for the treatment of the cognitive deficits noted in Alzheimer's disease. While there is a body of research that supports memantine's facilitative action upon memory compromise, this series of studies aimed to investigate the effects of this drug in healthy animals with intact memory functioning. A 0.1 mM dose of memantine injected immediately after a weakly aversive training event (i.e. 20% v/v methyl anthranilate) was found to enhance passive avoidance learning for this event in day-old chicks up to 24 h following training. The same dose of memantine was also observed to enhance memory for the training event when it was administered in conjunction with a reminder trial. These results suggest that memantine is capable of facilitating both memory consolidation as well as memory reconsolidation. It was concluded that memantine's mechanism may involve the short-term or intermediate memory phases of the Gibbs and Ng model of memory, and that the current findings represent enhancement of intact memory, rather than amelioration of memory compromise. PMID- 22425752 TI - beta adrenergic receptor modulation of neurotransmission to cardiac vagal neurons in the nucleus ambiguus. AB - beta-adrenergic receptors are a class of G protein-coupled receptors that have essential roles in regulating heart rate, blood pressure, and other cardiorespiratory functions. Although the role of beta adrenergic receptors in the peripheral nervous system is well characterized, very little is known about their role in the central nervous system despite being localized in many brain regions involved in autonomic activity and regulation. Since parasympathetic activity to the heart is dominated by cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA), beta adrenergic receptors localized in the NA represent a potential target for modulating cardiac vagal activity and heart rate. This study tests the hypothesis that activation of beta adrenergic receptors alters the membrane properties and synaptic neurotransmission to CVNs. CVNs were identified in brainstem slices, and membrane properties and synaptic events were recorded using the whole-cell voltage-clamp technique. The nonselective beta agonist isoproterenol significantly decreased inhibitory GABAergic and glycinergic as well as excitatory glutamatergic neurotransmission to CVNs. In addition, the beta(1)-selective receptor agonist dobutamine, but not beta(2) or beta(3) receptor agonists, significantly decreased inhibitory GABAergic and glycinergic and excitatory glutamatergic neurotransmission to CVNs. These decreases in neurotransmission to CVNs persisted in the presence of tetrodotoxin (TTX). These results provide a mechanism by which activation of adrenergic receptors in the brainstem can alter parasympathetic activity to the heart. Likely physiological roles for this adrenergic receptor activation are coordination of parasympathetic-sympathetic activity and beta receptor-mediated increases in heart rate upon arousal. PMID- 22425753 TI - Liver X receptor activation attenuates inflammatory response and protects cholinergic neurons in APP/PS1 transgenic mice. AB - Alzheimer's disease (AD) is associated with beta-amyloid deposition, glial activation, and increased levels of the cytokines, as well as cholinergic dysfunction. Liver X receptor (LXR) has been found to inhibit the expression of pro-inflammatory genes. However, the effects of LXR activation on inflammatory response and on cholinergic system in AD are not yet clear. The present results revealed that LXR activation markedly attenuated several inflammatory markers and decreased microglial activation and reactive astrocytes in amyloid precursor protein (APP)/PS1 transgenic mice. Additionally, LXR activation significantly increased the number of cholinergic neurons in the medial septal regions and the basal nucleus of Meynert (NBM), and attenuated cognitive impairment. Furthermore, we observed that LXR activation inhibited the production of COX-2 and iNOS from Abeta(25-35)-induced microglia. LXR activation and nuclear factor kappa B (NF kappaB) inhibitor PDTC both attenuated Abeta(25-35) induction of NF-kappaB activation. These results suggest that LXR agonists suppress the production of pro-inflammatory molecules, at least in part, by modulating NF-kappaB-signaling pathway. Collectively, these studies suggest that LXR agonists may have therapeutic significance in AD. PMID- 22425754 TI - Detection of a few of biogenic volatile organic compounds by means of Raman scattering of isocyanide-adsorbed gold nanostructures. AB - We demonstrate that the NC stretching band of 2,6-dimethylphenylisocyanide (2,6 DMPI) adsorbed on poly(ethylenimine)-capped Au film is very susceptible to the kind of biogenic volatile organic compounds (VOCs) exposed, suggesting that the isocyanide-adsorbed noble metal nanostructures can be used as a platform for a biogenic VOC sensor operating via surface-enhanced Raman scattering (SERS). Specifically, first we demonstrate that highly SERS-active Au films can easily be fabricated onto the inner surfaces of glass capillaries, being able to measure the SERS spectra of 2,6-DMPI facilely and thus to monitor the shift of its NC stretching band rapidly in response to a variety of biogenic VOCs including isoprene, farnesol, and (+)-alpha-pinene. Secondly, we are able to deduce from the NC stretching peak shifts that farnesol must act as an electron acceptor so as to increase the surface potential of Au nanoparticles, while isoprene and (+) alpha-pinene are electron donors, resulting in the decrease in the surface potential of Au nanoparticles. To our knowledge, this is the first report, informing the applicability of SERS, though indirect, in the detection of biogenic VOCs. PMID- 22425755 TI - An alternative derivatization reaction to the determination of doramectin in bovine milk using spectrofluorimetry. AB - The doramectin (DOR), which belongs to the avermectins group (AVM), has a high antiparasitic activity and so it has been widely used in food-producing animals. The DOR shows low fluorescence quantum efficiency and as a consequence, chemical derivatization reactions are necessary to produce derivatives with improved luminescent properties before its determination by fluorimetry. As the presence of this compound in food represents a risk to human health, an easy, clean and low cost derivatization reaction, which is alternative to those usually employed and that enables its spectrofluorimetric determination in milk samples, was developed. Ethanolic solutions of DOR, containing sodium hydroxide at a final concentration of 0.25 mol L(-1), after 60 min of heating at 50 degrees C, produced fluorescent signals 1000 times higher than the original ethanolic solution. Using these optimized conditions, a linear response range that extended from 50.00 to 1000 MUg L(-1), with a value of (R(2)) equal to 0.9970, was obtained. Average recovery of DOR was 92.5+/-1.5% (n=3) in bovine milk fortified samples submitted to a liquid-liquid extraction at low temperature and pre concentration process, indicating the usefulness and effectiveness of the proposed method. The proposed spectrofluorimetric method is an alternative to high-performance liquid chromatography (HPLC) based methods, allowing rapid and simple detection of doramectin in milk samples. PMID- 22425756 TI - Effect of cocoa/chocolate ingestion on brachial artery flow-mediated dilation and its relevance to cardiovascular health and disease in humans. AB - Prospective studies indicate that high intake of dietary flavanols, such as those contained in cocoa/chocolate, are associated with reduced rates of cardiovascular related morbidity and mortality in humans. Numerous mechanisms may underlie these associations such as favorable effects of flavanols on blood pressure, platelet aggregation, thrombosis, inflammation, and the vascular endothelium. The brachial artery flow-mediated dilation (FMD) technique has emerged as a robust method to quantify endothelial function in humans. Collectively, the preponderance of evidence indicates that FMD is a powerful surrogate measure for firm cardiovascular endpoints, such as cardiovascular-related mortality, in humans. Thus, literally thousands of studies have utilized this technique to document group differences in FMD, as well as to assess the effects of various interventions on FMD. In regards to the latter, numerous studies indicate that both acute and chronic ingestion of cocoa/chocolate increases FMD in humans. Increases in FMD after cocoa/chocolate ingestion appear to be dose-dependent such that greater increases in FMD are observed after ingestion of larger quantities. The mechanisms underlying these responses are likely diverse, however most data suggest an effect of increased nitric oxide bioavailability. Thus, positive vascular effects of cocoa/chocolate on the endothelium may underlie (i.e., be linked mechanistically to) reductions in cardiovascular risk in humans. PMID- 22425757 TI - (-)-Epicatechin prevents TNFalpha-induced activation of signaling cascades involved in inflammation and insulin sensitivity in 3T3-L1 adipocytes. AB - Obesity is major public health concern worldwide and obese individuals exhibit a higher risk of chronic diseases such as type 2 diabetes. Inflammation plays a significant role in metabolic regulation and mounting evidence highlight the contribution of adipose tissue to systemic inflammatory state. Food extracts with a high content of (-)-epicatechin have been found to exert systemic anti inflammatory actions, however the anti-inflammatory actions of (-)-epicatechin on adipose tissue remain to be determined. The aim of this study was to investigate the capacity of (-)-epicatechin to prevent tumor necrosis alpha (TNFalpha) induced activation of cell signals involved in inflammation and insulin resistance (NF-kappaB, mitogen-activated protein kinases (MAPKs), AP-1, and peroxisome proliferator activated receptor gamma (PPARgamma)) in differentiated white adipocytes (3T3-L1). TNFalpha triggered the activation of transcription factors NF-kappaB and AP-1, and MAPKs ERK1/2, JNK, and p38. (-)-Epicatechin caused a dose (0.5-10 MUM)-dependent decrease in TNFalpha-mediated JNK, ERK1/2, and p-38 phosphorylation, and nuclear AP-1-DNA binding. (-)-Epicatechin also inhibited TNFalpha-triggered activation of the NF-kappaB signaling cascade, preventing TNFalpha-mediated p65 nuclear transport and nuclear NF-kappaB-DNA binding. (-)-Epicatechin also attenuated the TNFalpha-mediated downregulation of PPARgamma expression and decreased nuclear DNA binding. Accordingly, (-) epicatechin inhibited TNFalpha-mediated altered transcription of genes (MCP-1, interleukin-6, TNFalpha, resistin, and protein-tyrosine phosphatase 1B) involved in inflammation and insulin signaling. In conclusion, (-)-epicatechin can attenuate TNFalpha-mediated triggering of signaling cascades involved in inflammation and insulin resistance. These findings could be of relevance in the dietary management of obesity and metabolic syndrome. PMID- 22425758 TI - Tryparedoxin peroxidases and superoxide dismutases expression as well as ROS release are related to Trypanosoma cruzi epimastigotes growth phases. AB - Trypanosoma cruzi's antioxidant system is unique and relevant to the parasite. In this study, quantitative assays were performed to determine cytosolic and mitochondrial tryparedoxin peroxidases and superoxide dismutases expression (TcCPx, TcMPx, SODB and SODA) in correlation to H(2)O(2) release and O(2)(-) production. Differences were observed regarding H(2)O(2) release and O(2)(-) production between strains and along the growth curve. All of the enzymes studied exhibited varied expression as a function of time in culture. Although at lower levels, the Y strain exhibited the same pattern of Tulahuen 2 enzyme expression for all of the proteins studied, except SODA. In the stationary phase, the degree of expression of all of the enzymes in the Y strain returned to similar levels as those detected in the log phase with the exception of TcCPx and SODA. In Tulahuen 2, a higher expression of TcMPx, SODA and SODB was detected in the early stationary phase, and a slight decrease was observed in the late stationary phase for each enzyme, excluding TcMPx, which exhibited a marked decrease, and TcCPx, which increased its level. Because of the significance of ROS in redox signaling, these differences in enzyme expression underscore the importance of these parameters for epimastigote proliferation. PMID- 22425759 TI - Family meals. Associations with weight and eating behaviors among mothers and fathers. AB - Few studies have looked at the relationship between family meals and adult weight and health behaviors. The current study investigates the association between frequency of family meals and mothers' and fathers' body mass index (BMI), dietary intake, dieting behaviors and binge eating. Data from Project F-EAT (Families and Eating and Activity in Teens) were used for the current analysis. Socio-economically and racially/ethnically diverse mothers and fathers (n=3488) of adolescents participating in a multi-level population-based study (EAT 2010) completed surveys mailed to their homes. Predicted means or probabilities were calculated for each outcome variable at each level of family meal frequency. Interactions between race/ethnicity and marital status with family meals were evaluated in all models. Overall, results indicated that having more frequent family meals was associated with increased consumption of fruits and vegetables for mothers and fathers, after adjusting for age, educational attainment, marital status and race/ethnicity. Other findings including less fast food intake for fathers and fewer dieting and binge eating behaviors for mothers were significantly associated with family meal frequency, but not consistently across all family meal categories or with BMI. Interactions by race/ethnicity and marital status were non-significant, indicating that family meals may be important for more healthful dietary intake across race and marital status. Future research should confirm findings in longitudinal analyses to identify temporality and strength of associations. PMID- 22425760 TI - Impact of emotional awareness and parental bonding on emotional eating in obese women. AB - This study aimed to: (1) determine whether obese women have deficits in emotional awareness and more frequently use emotional eating to regulate their emotions, (2) assess the impact of emotional awareness on the use of emotional eating, and (3) explore the impact of parental bonding on patient level of emotional awareness. A sample of 94 obese women was compared with 56 control participants. All participants answered questionnaires concerning their eating habits (Dutch Emotional Behavior Questionnaire), emotional awareness (Level of Emotional Awareness Scale) and parental bonding (Parental Bonding Inventory). Obese women exhibited deficits in emotional awareness and used emotional eating as an emotion regulation strategy more often than controls. Regression analyses showed that paternal and maternal overprotection negatively influenced obese patients' levels of emotional awareness and that emotional awareness positively influenced their emotional eating. PMID- 22425761 TI - NOP14 promotes proliferation and metastasis of pancreatic cancer cells. AB - Pancreatic cancer (PC) is one of the most malignant cancers worldwide. We describe a novel gene, NOP14, which plays significant roles in PC cell proliferation and migration. Inhibition or overexpression of NOP14 expression in PC cells can reduce or promote motility, proliferation and metastatic capacity in vivo. In parallel, we observed changes in proteins related to migration, such as E-cadherin, vimentin, MMP9, RhoA and p53, along with proteins involved in proliferation, such as MAPK3 and CDK2. Taken together, our study provides new evidence for NOP14 in regulating PC cell proliferation and migration, and may provide new insights for clinical diagnosis and therapy. PMID- 22425762 TI - KRAS and BRAF mutation analysis in routine molecular diagnostics: comparison of three testing methods on formalin-fixed, paraffin-embedded tumor-derived DNA. AB - Accurate mutation detection assays are strongly needed for use in routine molecular pathology analyses to aid in the selection of patients with cancer for targeted therapy. The high-resolution melting (HRM) assay is an ideal prescreening tool, and SNaPshot analysis offers a straightforward genotyping system. Our present study was determined to compare these mutation testing methods on formalin-fixed, paraffin-embedded (FFPE) tumor-derived DNA. We compared the performance of HRM, followed by cycle sequencing (HRM-sequencing); multiplex PCR assay, followed by SNaPshot analysis (multiplex mutation assay); and a successor assay using HRM, followed by SNaPshot (HRM-SNaPshot) for mutation analysis of both KRAS (codon 12/13/61) and BRAF (codon 600/601). In a series of 195 FFPE-derived DNA specimens, a high genotypic concordance between HRM sequencing and multiplex mutation assay was found (kappa, 0.98; 95% CI, 0.94 to 1), underlining the potential of a combined HRM-SNaPshot approach. In reconstruction experiments, the analytical sensitivity of HRM-SNaPshot was twofold to fourfold higher than HRM-sequencing and multiplex mutation assay, respectively. In addition, HRM-SNaPshot had a good performance rate (99%) on FFPE tumor-derived DNA, and mutation detection was highly concordant with the predecessor assays (kappa for both, 0.98). The occurrence of BRAF and KRAS mutations is mutually exclusive. HRM-SNaPshot is an attractive method for mutation analysis in pathology, given its good performance rate on FFPE-derived DNA, high analytical sensitivity, and prescreening approach. PMID- 22425763 TI - The phenomenology and course of depressive syndromes in pre-trial detention. AB - This study focuses on the prevalence, the phenomenology and the course of depressive syndromes in pre-trial confinement. In the course of the first examination, socio-biographic data and information pertaining to subjects' psychiatric and forensic record and their current situation in imprisonment were collected from a random sample of 105 male prisoners in a Berlin pre-trial detention center, with the help of a semi-structured interview. The Beck Depression Inventory (BDI-II) and the Hamilton Depression Rating Scale (HAMD), each a self-rating questionnaire, taken together with a clinician rating were successively performed to assess the level of depression. A further examination was conducted approximately three weeks later. The subjects in the follow-up group (n=67) were questioned in a semi-structured follow-up interview regarding their confinement conditions and were requested again to fill in the BDI-II and HAMD questionnaires. The statistical analysis compares the results from administration of the two instruments at two points in time. Individual's symptoms of depression as well as potentially aggravating or protective factors relating to the development of depressive symptoms are taken note of separately. The results of the study reveal the prevalence of mild depressive syndromes in a pre-trial prison population and a tendency to improve within the period of pre trial confinement. PMID- 22425764 TI - The significance of offending behavior for predicting sexual recidivism among sex offenders of various age groups. AB - Based on a sample of 682 male sex offenders, this study investigated variables of the offending behavior for predicting sexual recidivism in different age groups. The sex offenders were allocated into four age groups. For each group, those characteristics of offending behavior showing a significant bivariate correlation with sexual recidivism were extracted. Using logistic regression, we then analyzed their incremental validity above and beyond a previously developed Crime Scene Behavior Risk (CBR)-Score, which measures the risk of sexual recidivism without taking into account the offenders' age (Dahle, Biedermann, Gallasch Nemitz, & Janka, 2010). Age-specific offending behavior variables with incremental validity were combined with the general CBR-Score into age-specific scores and examined for their predictive accuracy. We also analyzed the extent in which these age-specific scores showed incremental validity above and beyond the Static-99 (Hanson & Thornton, 1999). For three of the four age groups, age specific Crime Scene Behavior Risk-Scores could be determined which were incrementally valid above and beyond the Static-99. Predictive accuracy varied between AUC=.74 and AUC=.90 (r=.28 to r=.49) depending on age group. The results are discussed within context of recent findings on the latent dimensions of actuarial risk assessment variables. PMID- 22425765 TI - Aggressive behavior and measurement of psychopathy in female inmates of German prisons--a preliminary study. AB - Studies concerning inmate psychopathy (as measured by Psychopathy-Checklist Revised, PCL-R; Hare, 1991) have predominantly been concerned with male inmates. This study was the first to look into psychopathy using the PCL-R with the whole required procedure in German prisons with female inmates. The aims of the present study were to gain data about the prevalence of psychopathy in this sample and to examine potential relations between the types and motive of aggression, prosocial behavior and scores on the PCL-R. Sixty female inmates were examined. We obtained a prevalence rate of psychopathy of 17% (N=10, with a cut-off score of 25). Considering a wide range of subtypes of aggressive behaviors, we found that physical proactive, and relational reactive aggression as well as age predicted high scores of psychopathy. However, prosocial or helping behavior was not associated with psychopathy. Implications for diagnostic issues in forensics concerning female prisoners are discussed. PMID- 22425766 TI - Evergreening, patent challenges, and effective market life in pharmaceuticals. AB - Observers worry that generic patent challenges are on the rise and reduce the effective market life of drugs. A related concern is that challenges disproportionately target high-sales drugs, reducing market life for these "blockbusters." To study these questions, we examine new data on generic entry over the past decade. We show that challenges are more common for higher sales drugs. We also demonstrate a slight increase in challenges over this period, and a sharper increase for early challenges. Despite this, effective market life is stable across drug sales categories, and has hardly changed over the decade. To better understand these results, we examine which patents are challenged on each drug, and show that lower quality and later expiring patents disproportionately draw challenges. Overall, this evidence suggests that challenges serve to maintain, not reduce, the historical baseline of effective market life, thereby limiting the effectiveness of "evergreening" by branded firms. PMID- 22425767 TI - The effect of a hospital nurse staffing mandate on patient health outcomes: evidence from California's minimum staffing regulation. AB - We evaluate the impact of California Assembly Bill 394, which mandated maximum levels of patients per nurse in the hospital setting. When the law was passed, some hospitals already met the requirements, while others did not. Thus changes in staffing ratios from the pre- to post-mandate periods are driven in part by the legislation. We find persuasive evidence that AB394 had the intended effect of decreasing patient/nurse ratios in hospitals that previously did not meet mandated standards. However, these improvements in staffing ratios do not appear to be associated with relative improvements in measured patient safety in affected hospitals. PMID- 22425768 TI - Watchfully waiting: medical intervention as an optimal investment decision. AB - Watchfully waiting involves monitoring a patient's health state over time and deciding whether to undertake a medical intervention, or to postpone it and continue observing the patient. In this paper, we consider the timing of medical intervention as an optimal stopping problem. The development of the patient's health state in the absence of intervention follows a stochastic process (geometric Brownian motion). Spontaneous recovery occurs in case the absorbing state of "good health" is reached. We determine optimal threshold values for initiating the intervention, and derive comparative statics results with respect to the model parameters. In particular, an increase in the degree of uncertainty over the patient's development in most cases makes waiting more attractive. However, this may not hold if the patient's health state has a tendency to improve. The model can be extended to allow for risk aversion and for sudden, Poisson-type shocks to the patient's health state. PMID- 22425769 TI - Hospital ownership type and treatment choices. AB - In the face of increasing health care costs, taxing not-for-profit hospitals may be seen as the right choice to increase government revenues if not-for-profit hospitals are not different from their for-profit counterparts. This study investigates how hospital ownership type affects treatment choices to show whether ownership type and teaching status are correlated with choosing a procedure as the treatment and how these choices relate to patient insurance type. Not-for-profit hospitals significantly differ from for-profits in terms of treatment choices of less profitable patients and all hospitals are more likely to accord the procedure when the patient is privately insured than uninsured though teaching government hospitals are the most likely to accord the procedures for all insurance types. Considering treatment choices, not-for-profit hospitals have different objectives than for-profit and government hospitals and in terms of profit-seeking behavior, not-for-profit hospitals seem to lie between for profit and government hospitals. PMID- 22425770 TI - Do patients choose hospitals with high quality ratings? Empirical evidence from the market for angioplasty in the Netherlands. AB - A necessary condition for competition to promote quality in hospital markets is that patients are sensitive to differences in hospital quality. In this paper we examine the relationship between hospital quality, as measured by publicly available quality ratings, and patient hospital choice for angioplasty using individual claims data from a large health insurer. We find that Dutch patients have a high propensity to choose hospitals with a good reputation, both overall and for cardiology, and a low readmission rate after treatment for heart failure. Relative to a mean readmission rate of 8.5% we find that a 1%-point lower readmission rate is associated with a 12% increase in hospital demand. Since readmission rates are not adjusted for case-mix they may not provide a correct signal of hospital quality. Insofar patients base their hospital choice on such imperfect quality information, this may result in suboptimal choices and risk selection by hospitals. PMID- 22425771 TI - Expression of human carbonyl reductase 3 (CBR3; SDR21C2) is inducible by pro inflammatory stimuli. AB - Until today, the physiologic role of human carbonyl reductase 3 (CBR3; SDR21C2), a member of the short-chain dehydrogenase/reductase superfamily remains obscure. Since the transcriptional regulation is closely related to the function of a protein, elucidation of the regulation of CBR3 should help to understand its physiologic role. We recently identified CBR3 as a novel target gene of Nrf2, a cellular sensor of oxidative stress. In this study, we provide for the first time evidence that pro-inflammatory stimuli induce the expression of the CBR3 gene. Treatment of human cancer cells HT-29 (colon) and HepG2 (liver) with TNF-alpha, IL-1beta, and LPS induced CBR3 expression differentially. While TNF-alpha (50 ng/ml) or IL-1beta (1 and 10 ng/ml), induced CBR3 mRNA expression in HT-29 cells (up to 10-fold) and HepG2 cells (up to 20-fold), LPS activated the CBR3 gene only in HepG2 cells. Furthermore, overexpression of the NFkappaB subunits p65 and p50 alone or in combination elevated CBR3 mRNA levels (3.9-fold) in HT-29 cells. According to our results, CBR3 is a novel target gene of inflammatory stimuli, and elucidation of its detailed role in inflammation deserves further investigation. PMID- 22425772 TI - Transcellular distribution heterogeneity of Annexin A5 represents a protective response to lupus-related thrombophilia: a pilot Proteomics-based study. AB - Lupus-related vascular events are becoming a formidable obstacle to the improvement of long-term prognosis of systemic lupus erythematosus (SLE) and the existent findings lack for systematization. Proteomics is a strategic approach but its applications in this regard are rare and primarily involve proteome acquisition or biomarker screening, rather than functional identification. To provide further insight, we investigated the proteomic diversity of peripheral blood mononuclear cells (PBMCs) in SLE and the possible role of the identified Annexin A5 (AnxA5) in pathogenesis. The study involved 214 SLE and 183 healthy women. The two-dimensional electrophoresis gel images showed 649 +/- 25 and 676 +/- 19 protein spots from the PBMCs of the patients and controls, respectively. From these protein spots, 30 differentially expressed proteins were chosen, and 16 of these proteins were identified by mass spectrometer. Western blotting confirmed the over-expressed candidate, AnxA5, from the PBMCs of the patients (SLE:control=1.607:1, P=0.0004), but ELISAs indicated decreased levels of sera AnxA5 in the patients compared to healthy donors (SLE vs. control=26.8 +/- 3.0 vs. 49.0 +/- 3.3 ng/mL, P<0.0001). A positive correlation was demonstrated between the manifestation of thrombosis and AnxA5 (Mann-Whitney Z=-2.084, P=0.037), not anti-AnxA5, while searching for correlations between clinical parameters and the two molecular levels of patient sera. The coagulation assays using plasma from SLE patients revealed that elevated AnxA5 could shorten prothrombin time, activated partial thromboplastin time and prolonged thrombin time (P<0.001). Our data demonstrated the proteomic differences in the PBMCs between SLE patients and healthy persons. Moreover, the heterogeneous transcellular distribution, increased intracellular concentrations and decreased serum levels of AnxA5 represent a protective response to lupus-related thrombophilia; AnxA5 mostly participate in the common coagulation pathway in the thrombogenesis of SLE. PMID- 22425773 TI - Mechanisms involved in inhibition of chondrogenesis by activin-A. AB - OBJECTIVES: Activin-A, a member of the TGF-beta family, is known to be present in bone and cartilage. Although, involvement of the TGF-beta family in chondrogenesis has been reported, the mechanism by which activin-A regulates chondrogenesis has not been fully elucidated. The aim of this study was to investigate the effects of activin-A on chondrocyte differentiation in vitro. MATERIALS AND METHODS: Monolayer cultures of mouse chondrocyte ATDC cells were pretreated with a variety of inhibitors of major signaling pathways prior to addition of activin-A. The expressions of sox9, runx2, and osterix mRNA were detected using real-time PCR. To determine chondrocyte differentiation, sulfated glycosaminoglycans were stained with Alcian blue. To further elucidate the role of activin-A on chondrogenesis regulation, phosphorylation of Smad2/3, ERK, JNK, and Akt proteins was determined by western blotting. RESULTS: Activin-A suppressed the transcription of sox9, runx2, and osterix mRNA, as well as sulfated glycosaminoglycans accumulation. Activin-A also inhibited constitutive phosphorylation of JNK and Akt proteins. Furthermore, inhibition of the JNK and PI3K-Akt pathways by chemical inhibitors suppressed chondrogenesis in ATDC5 cells. CONCLUSIONS: These results indicate that activin-A may suppress chondrocyte differentiation in ATDC5 cells via down-regulation of JNK and Akt phosphorylation. PMID- 22425774 TI - Rev-erbalpha regulates circadian rhythms and StAR expression in rat granulosa cells as identified by the agonist GSK4112. AB - The Rev-erbalpha gene is regarded as a circadian clock gene and clock-regulated gene which regulates the circadian transcriptional/translational loop in a subtle way. Here, we first detected the circadian oscillation in mature granulosa cells from antral follicles using a real-time monitoring system of Per2 promoter activity with the addition of FSH. Then we used GSK4112, an agonist ligand of Rev erbalpha, to investigate the function of Rev-erbalpha. GSK4112 treatment significantly reduced the Per2-dLuc amplitude and induced the Per2 oscillation phase advance shift. GSK4112 significantly inhibited Bmal1 mRNA expression, whereas it did clearly stimulate expression of StAR mRNA in a dose-dependent manner. Our data are the first to show the Rev-erbalpha function in the steroid biosynthesis of rat granulosa cells, and to suggest that Rev-erbalpha may coordinate circadian rhythm and metabolism in rat ovaries. PMID- 22425775 TI - Heregulin-beta1-induced GPR30 upregulation promotes the migration and invasion potential of SkBr3 breast cancer cells via ErbB2/ErbB3-MAPK/ERK pathway. AB - Estrogen receptor (ER)-negative breast cancer cells are probably more aggressive with larger metastatic potential than ER-positive cells. Loss of ER in recurrent breast cancer is associated with poor response to endocrine therapy. G protein coupled receptor 30 (GPR30) is expressed in half of ER-negative breast cancers. Tumor cell-derived heregulin-beta1 (HRG-beta1) is also found mainly in ER negative cancer. In SkBr3 breast cancer cells that lack ER but express GPR30, HRG beta1 upregulates mRNA and protein levels of GPR30 by promoting ErbB2-ErbB3 heterodimerization and activating the downstream MAPK-ERK signaling pathway. Moreover, GPR30 boosts HRG-beta1-induced migration and invasion of SkBr3 cells after combinative treatment with E2, 4-hydroxy-tamoxifen or the specific GPR30 agonist G-1, which are blocked by the specific GPR30 antagonist G-15 or the transfection with the small interfering RNA for GPR30. The ErbB2 inhibitor AG825 and the MEK1/2 inhibitor U0126 also partly inhibit the enhanced migration and invasion. Therefore, HRG-beta1-induced migration and invasion partly depend on the upregulation of GPR30 expression through activation of the ErbB2-ERK pathway in SkBr3 cells. The results of this study indicate that the crosstalk between GPR30 and HRGs signaling is important for endocrine therapy resistance and may provide a new therapeutic way to treat breast cancer. PMID- 22425776 TI - Identification of methylation-dependent regulatory elements for intergenic miRNAs in human H4 cells. AB - MicroRNAs (miRNAs) are important post-transcriptional regulators of various biological processes. Although our knowledge of miRNA expression and regulation has been increased considerably in recent years, the regulatory elements for miRNA gene expression (especially for intergenic miRNAs) are not fully understood. In this study, we identified differentially methylated regions (DMRs) within 1000 bp upstream from the start site of intergenic miRNAs in human neuroglioma cells using microarrays. Then we identified a unique sequence pattern, C[N](6)CT, within the DMRs using motif analysis. Interestingly, treatment of cells with a methyl transferase inhibitor (5-aza-2-deoxycytidine, DAC) significantly increased expression of miRNA genes with a high frequency of the C[N](6)CT motif in DMRs. Statistical analysis showed that the frequency of the C[N](6)CT motif in DMRs is highly correlated with intergenic miRNA gene expression, suggesting that C[N](6)CT motifs associated with DNA methylation regions play a role as regulatory elements for intergenic miRNA gene expression. PMID- 22425777 TI - Identification of an intra-molecular disulfide bond in the sodium channel beta1 subunit. AB - The sodium channel beta1 subunit is non-covalently associated with the pore forming alpha-subunits, and has been proposed to act as a modulator of channel activity, regulator of channel cell surface expression and cell adhesion molecule. Its importance is evident since mutations of the beta1 subunit cause neurologic and cardiovascular disorders. The first described beta1 subunit mutation is the C121W, that is related to generalized epilepsy with febrile seizures plus (GEFS+), a childhood genetic epilepsy syndrome. This mutation changed a conserved cysteine residue in position 121 into a tryptophan, putatively disrupting a disulfide bridge that should normally maintain the beta1 extracellular immunoglobulin-like fold. Using the 2-D-diagonal-SDS-PAGE technique, we demonstrated the existence of this putative disulfide bridge in the Ig-like extracellular domain of the beta1 subunit and its disruption in the epileptogenic C121W mutant. PMID- 22425778 TI - The role of eye movements in decision making and the prospect of exposure effects. AB - The aim of the current study was to follow on from previous findings that eye movements can have a causal influence on preference formation. Shimojo et al. (2003) previously found that faces that were presented for a longer duration in a two alternative forced choice task were more likely to be judged as more attractive. This effect only occurred when an eye movement was made towards the faces (with no effect when faces were centrally presented). The current study replicated Shimojo et al.'s (2003) design, whilst controlling for potential inter stimuli interference in central presentations. As per previous findings, when eye movements were made towards the stimuli, faces that were presented for longer durations were preferred. However, faces that were centrally presented (thus not requiring an eye movement) were also preferred in the current study. The presence of an exposure duration effect for centrally presented faces casts doubt on the necessity of the eye movement in this decision making process and has implications for decision theories that place an emphasis on the role of eye movements in decision making. PMID- 22425779 TI - Assessment of the functional diversity of human myoglobin. AB - Myoglobin is presumably the most studied protein in biology. Its functional properties as a dioxygen storage and facilitator of dioxygen transport are widely acknowledged. Experimental evidence also implicates an essential role for myoglobin in the heart in regulating nitric oxide homeostasis. Under normoxia, oxygenated myoglobin can scavenge excessive nitric oxide, while under hypoxia, deoxygenated myoglobin can reduce nitrite, an oxidative product of nitric oxide, to bioactive nitric oxide. Myoglobin-driven nitrite reduction can protect the heart from ischemia and reperfusion injury. While horse and mouse myoglobin have been previously described to reduce nitrite under these conditions, a comparable activity has not been detected in human myoglobin. We here show that human myoglobin is a fully functional nitrite reductase. To study the role of human myoglobin for nitric oxide homeostasis we used repeated photometric wavelength scans and chemiluminescence based experiments. The results revealed that oxygenated human myoglobin reacts with nitrite-derived nitric oxide to form ferric myoglobin and that deoxygenated human myoglobin acts as a nitrite reductase in vitro and in situ. Rates of both nitric oxide scavenging and nitrite reduction were significantly higher in human compared to horse myoglobin. These data extend the existing knowledge about the functional properties of human myoglobin and are the basis for further translational studies towards the importance of myoglobin for nitric oxide metabolism in humans. PMID- 22425780 TI - Normoxic cyclic GMP-independent oxidative signaling by nitrite enhances airway epithelial cell proliferation and wound healing. AB - The airway epithelium provides important barrier and host defense functions. Recent studies reveal that nitrite is an endocrine reservoir of nitric oxide (NO) bioactivity that is converted to NO by enzymatic reductases along the physiological oxygen gradient. Nitrite signaling has been described as NO dependent activation mediated by reactions with deoxygenated redox active hemoproteins, such as hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase (XO) and NO synthase at low pH and oxygen tension. However, nitrite can also be readily oxidized to nitrogen dioxide (NO(2).) via heme peroxidase reactions, suggesting the existence of alternative oxidative signaling pathways for nitrite under normoxic conditions. In the present study, we examined normoxic signaling effects of sodium nitrite on airway epithelial cell wound healing. In an in vitro scratch injury model under normoxia, we exposed cultured monolayers of human airway epithelial cells to various concentrations of sodium nitrite and compared responses to NO donor. We found sodium nitrite potently enhanced airway epithelium wound healing at physiological concentrations (from 1 MUM). The effect of nitrite was blocked by the NO and NO(2). scavenger 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO). Interestingly, nitrite treatment did not increase cyclic guanosine monophosphate (cGMP) levels under these normoxic conditions, even in the presence of a phosphodiesterase 5 inhibitor, suggesting cGMP independent signaling. Consistent with an oxidative signaling pathway requiring hydrogen peroxide (H(2)O(2))/heme-peroxidase/NO(2). signaling, the effects of nitrite were potentiated by superoxide dismutase (SOD) and low concentration H(2)O(2), whereas inhibited completely by catalase, followed by downstream extracellular-signal-regulated kinase (ERK) 1/2 activation. Our data represent the first description of normoxic nitrite signaling on lung epithelial cell proliferation and wound healing and suggest novel oxidative signaling pathways involving nitrite-H(2)O(2) reactions, possibly via the intermediary, NO(2).. PMID- 22425781 TI - Resistance to extinction and behavioral momentum. AB - In the metaphor of behavioral momentum, reinforcement is assumed to strengthen discriminated operant behavior in the sense of increasing its resistance to disruption, and extinction is viewed as disruption by contingency termination and reinforcer omission. In multiple schedules of intermittent reinforcement, resistance to extinction is an increasing function of reinforcer rate, consistent with a model based on the momentum metaphor. The partial-reinforcement extinction effect, which opposes the effects of reinforcer rate, can be explained by the large disruptive effect of terminating continuous reinforcement despite its strengthening effect during training. Inclusion of a term for the context of reinforcement during training allows the model to account for a wide range of multiple-schedule extinction data and makes contact with other formulations. The relation between resistance to extinction and reinforcer rate on single schedules of intermittent reinforcement is exactly opposite to that for multiple schedules over the same range of reinforcer rates; however, the momentum model can give an account of resistance to extinction in single as well as multiple schedules. An alternative analysis based on the number of reinforcers omitted to an extinction criterion supports the conclusion that response strength is an increasing function of reinforcer rate during training. PMID- 22425782 TI - Extinction under a behavioral microscope: isolating the sources of decline in operant response rate. AB - Extinction performance is often used to assess underlying psychological processes without the interference of reinforcement. For example, in the extinction/reinstatement paradigm, motivation to seek drug is assessed by measuring responding elicited by drug-associated cues without drug reinforcement. However, extinction performance is governed by several psychological processes that involve motivation, memory, learning, and motoric functions. These processes are confounded when overall response rate is used to measure performance. Based on evidence that operant responding occurs in bouts, this paper proposes an analytic procedure that separates extinction performance into several behavioral components: (1-3) the baseline bout initiation rate, within-bout response rate, and bout length at the onset of extinction; (4-6) their rates of decay during extinction; (7) the time between extinction onset and the decline of responding; (8) the asymptotic response rate at the end of extinction; (9) the refractory period after each response. Data that illustrate the goodness of fit of this analytic model are presented. This paper also describes procedures to isolate behavioral components contributing to extinction performance and make inferences about experimental effects on these components. This microscopic behavioral analysis allows the mapping of different psychological processes to distinct behavioral components implicated in extinction performance, which may further our understanding of the psychological effects of neurobiological treatments. PMID- 22425783 TI - Extinction as discrimination: the molar view. AB - The traditional molecular view of behavior explains extinction as the dissipation or inhibition of strength, formerly built up by contiguous reinforcement. In obstinate opposition to this explanation was the partial-reinforcement extinction effect: a partially reinforced response extinguishes more slowly than a continuously reinforced response. It suggests instead that extinction is discrimination. Four pigeons were exposed to daily sessions in which a variable period of food delivery, produced by pecking on a variable-interval schedule, was followed by extinction. The rate of food delivery was varied over a wide range across conditions. Varying the amount of food per delivery inversely with rate of delivery kept response rate from varying excessively. The results confirmed and extended the partial-reinforcement effect; persistence of pecking and time to extinction were inversely related to rate of obtaining food. The results support the molar view of extinction, not as loss of strength of a particular discrete response, but as a transition from one allocation of time among activities to another. Although molecular theories dismiss discrimination due to repeated training and extinction as an impurity or complication, repeated cycles of availability and privation are probably typical of the environment in which most vertebrate species evolved. PMID- 22425784 TI - Factors affecting reoperations after anterior cervical discectomy and fusion within and outside of a Federal Drug Administration investigational device exemption cervical disc replacement trial. AB - BACKGROUND CONTEXT: The excellent clinical results of five US Federal Drug Administration (FDA) trials approved for cervical total disc replacement (TDR) (Prestige [Medtronic Sofamor Danek, Memphis, TN, USA], Bryan [Medtronic Sofamor Danek], ProDisc-C [Synthes, West Chester, PA, USA], Kineflex|C [SpinalMotion, Mountain View, CA, USA], and Mobi-C [LDR Spine, Austin, TX, USA]) have recently been published. In these prospective randomized studies, superiority or equivalency of TDR was claimed, citing an 8.7% (23/265), 9.5% (21/221), 8.5% (9/106), 12.2% (14/115), and 6.2% (5/81) (mean = 9.02%) rate of additional related cervical surgical procedures within 2 years in control anterior cervical discectomy and fusion (ACDF) patients, respectively, compared with 1.8% (5/276), 5.8% (14/242), 1.9% (2/103), 11% (15/136), and 1.2% (2/164) (mean = 4.34%) in patients receiving the cervical TDR. The rate of reoperation within 2 years after ACDF seems unusually high. PURPOSE: To assess the rate of and specific indications for early reoperation after ACDF in a cohort of patients receiving the ACDF as part of their customary care. These results are contrasted with similar patients receiving ACDF as the control arm of five FDA investigational device exemption (IDE) studies. STUDY DESIGN: Multisurgeon retrospective clinical series from a single institution. PATIENT SAMPLE: One hundred seventy-six patients with spondylotic radiculopathy or myelopathy underwent ACDF by three surgeons between 2001 and 2005 as part of their clinical practices. All patients had at least 2 years of follow-up with final follow-up within 6 months of completion of this study. OUTCOME MEASURES: Cervical reoperation rates at 2-year follow-up and at 3.5-year follow-up. METHODS: Review of medical records and telephone conversations were completed to determine the number of patients who had undergone a revision cervical procedure. RESULTS: At final follow-up, complete data were available for 159 ACDF patients. Of the 48 patients who underwent single-level ACDF and met criteria for inclusion in the IDE studies, one patient (2.1%) required additional surgery (adjacent-segment degeneration) within 2 years, the duration of follow-up of the five published IDE studies. Of the 159 patients who received single or multilevel ACDF at a mean follow-up of 3.5 years, 12 patients (7.6%) had undergone revision cervical surgery, with three patients (1.9%) undergoing same-level revisions (posterior fusion) and nine patients (5.7%) undergoing adjacent anterior level fusions. Patients who underwent revision same-level surgery typically had the intervention within the first year (mean, 11 months), whereas those requiring adjacent-level fusions typically had surgery later (mean, 29 months). CONCLUSIONS: The present study identifies a 2.1% rate of repeat surgery within 2 years of a single-level ACDF performed during routine clinical practice, which is lower than that reported in the control arm of the Prestige, ProDisc-C, Bryan, Kineflex|C, and Mobi-C FDA trials (mean=9%). Even with longer follow-up including multilevel cases, our reoperation rate (7.6%) compared favorably with the IDE rates. This discrepancy may reflect different thresholds for reoperation in the control arm of a device IDE study compared with routine clinical practice. Additionally, patients enrolled in the single-level-only IDE trial may have received multilevel procedures outside of the study. This factor could result in a higher rate of subsequent surgeries at adjacent levels not addressed at the index procedure. These data suggest that we need to better understand factors driving treatment and, in particular, decisions to reoperate both in and outside of a device trial. PMID- 22425785 TI - Regulatory mechanism of transforming growth factor beta receptor type II degradation by interleukin-1 in primary chondrocytes. AB - Interleukin-1beta (IL-1beta), a key-cytokine in osteoarthritis, impairs TGFbeta signaling through TbetaRII down-regulation by increasing its degradation. Here, we investigated the molecular mechanism that controls TbetaRII fate in IL-1beta treated cells. Chondrocytes were treated with IL-1beta in the presence of different inhibitors. TbetaRII and Cav-1 expression were assayed by Western blot and RT-PCR. We showed that IL-1beta-induced degradation of TbetaRII is dependent on proteasome and on its internalization in caveolae. In addition, IL-1beta enhances Cav-1 expression, a major constituent of lipid raft. In conclusion, we enlighten a new mechanism by which IL-1beta antagonizes TGFbeta pathway and propose a model of TbetaRII turnover regulation upon IL-1beta treatment. PMID- 22425786 TI - Organismal propagation in the absence of a functional telomerase pathway in Caenorhabditis elegans. AB - To counteract replication-dependent telomere shortening most eukaryotic cells rely on the telomerase pathway, which is crucial for the maintenance of proliferative potential of germ and stem cell populations of multicellular organisms. Likewise, cancer cells usually engage the telomerase pathway for telomere maintenance to gain immortality. However, in ~10% of human cancers telomeres are maintained through telomerase-independent alternative lengthening of telomeres (ALT) pathways. Here, we describe the generation and characterization of C. elegans survivors in a strain lacking the catalytic subunit of telomerase and the nematode telomere-binding protein CeOB2. These clonal strains, some of which have been propagated for >180 generations, represent the first example of a multicellular organism with canonical telomeres that can survive without a functional telomerase pathway. The animals display the heterogeneous telomere length characteristic for ALT cells, contain single stranded C-circles, a transcription profile pointing towards an adaptation to chronic stress and are therefore a unique and valuable tool to decipher the ALT mechanism. PMID- 22425787 TI - A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in adults 18-49 years of age. AB - BACKGROUND: The Ann Arbor strain-live attenuated influenza vaccine (LAIV) was licensed in 2003 for use in the United States for individuals aged 5-49 years of age. As part of a postmarketing commitment to safety, LAIV was studied in adults 18-49 years participating in the Kaiser Permanente Health Plan over 5 influenza seasons. METHODS: Individuals received LAIV as part of routine care from October 2003 through March 2008. Using Kaiser Permanente databases, rates of medically attended events (MAEs) and serious adverse events (SAEs) in LAIV recipients were compared with rates in multiple non-randomized control groups which included a self-control group, matched unvaccinated controls, and matched controls vaccinated with inactivated influenza vaccine (TIV). RESULTS: A total of 21,340, 18,316, and 21,340 subjects received LAIV, TIV and no vaccine, respectively. More than 5500 MAE incidence rate comparisons were performed, and of these, 257 (5%) yielded statistically significant differences with 72 and 185 occurring at a higher and lower rate after LAIV compared with control groups, respectively. The pattern of MAE rate differences did not suggest any safety signal associated with LAIV. There were 47 SAEs noted, and no individual SAE occurred at a significantly higher or lower rate in LAIV recipients relative to control groups in any comparison. Only 2 SAEs (migraine/sinusitis and Bell's palsy) were considered possibly or probably related to LAIV. CONCLUSION: The results of this post licensure evaluation of LAIV safety in individuals 18-49 years of age are consistent with pre- and post-approval clinical studies as well as reports to the U.S. Vaccine Adverse Events Reporting System, all of which demonstrated no significant adverse outcomes among eligible individuals following receipt of LAIV. PMID- 22425788 TI - Evaluation of immune responses to a Plasmodium vivax CSP-based recombinant protein vaccine candidate in combination with second-generation adjuvants in mice. AB - Plasmodium vivax is the major cause of malaria outside of sub-Saharan Africa and causes morbidity and results in significant economic impact in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study, groups of C57BL/6J mice were immunized subcutaneously three times with VMP001 emulsified with synthetic TLR4 (GLA) or TLR7/8 (R848) agonist in stable emulsion (SE), a combination of the TLR4 and TLR7/8 agonists, or SE alone. Sera and splenocytes were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of mice generated high titers of anti-P. vivax IgG antibodies as detected by ELISA and immunofluorescence assay. GLA-SE promoted a shift in the antibody response to a Th1 profile, as demonstrated by the change in IgG2c/IgG1 ratio. In addition, GLA-SE induced a strong cellular immune response characterized by multi functional, antigen-specific CD4(+) T cells secreting IL-2, TNF and IFN-gamma. In contrast, mice immunized with SE or R848-SE produced low numbers of antigen specific CD4(+) T cells, and these T cells secreted IL-2 and TNF, but not IFN gamma. Finally, R848-SE did not enhance the immune response compared to GLA-SE alone. Based on these results, we conclude that the combination of VMP001 and GLA SE is highly immunogenic in mice and may serve as a potential second-generation vaccine candidate against vivax malaria. PMID- 22425789 TI - Does HPV vaccination affect women's attitudes to cervical cancer screening and safe sexual behaviour? AB - The Human Papillomavirus (HPV) vaccine has the potential to greatly reduce the incidence of cervical cancer by protecting against HPV infections responsible for 70% of cervical cancer diagnoses. However, preliminary research has indicated that women vaccinated against HPV may be less likely to undergo cervical cancer screening and engage in safe sexual behaviour. The aim of the current study was to investigate whether vaccinated and unvaccinated women differ in their (i) knowledge of cervical screening guidelines, (ii) perceived vulnerability to cervical cancer, (iii) cervical screening intentions and uptake, and (iv) attitudes to and engagement in safe sexual behaviour. Participants were 193 female university students (119 vaccine recipients and 74 vaccine non-recipients) who completed online self-report questionnaires. Of all the assessed outcomes, attitudes to safe sexual behaviour were the only significant findings related to vaccination status (p<.001), such that vaccinated women held more positive attitudes to practicing safe sexual behaviour. Less than 5% of participants correctly identified screening guidelines. These findings do not support previous research concluding vaccination could have a detrimental impact on screening and sexual behaviour. Importantly, results highlight poor awareness of screening guidelines, poor levels of consistent condom use (50%) amongst those sexually active, and low uptake of screening (42%) amongst those eligible to be screened. Further research needs to specifically address young women's gaps in knowledge by developing initiatives promoting cervical screening. PMID- 22425790 TI - UV-inactivated vaccinia virus (VV) in a multi-envelope DNA-VV-protein (DVP) HIV-1 vaccine protects macaques from lethal challenge with heterologous SHIV. AB - The pandemic of HIV-1 has continued for decades, yet there remains no licensed vaccine. Previous research has demonstrated the effectiveness of a multi envelope, multi-vectored HIV-1 vaccine in a macaque-SHIV model, illustrating a potential means of combating HIV-1. Specifically, recombinant DNA, vaccinia virus (VV) and purified protein (DVP) delivery systems were used to vaccinate animals with dozens of antigenically distinct HIV-1 envelopes for induction of immune breadth. The vaccinated animals controlled disease following challenge with a heterologous SHIV. This demonstration suggested that the antigenic cocktail vaccine strategy, which has succeeded in several other vaccine fields (e.g. pneumococcus), might also succeed against HIV-1. The strategy remains untested in an advanced clinical study, in part due to safety concerns associated with the use of replication-competent VV. To address this concern, we designed a macaque study in which psoralen/ultraviolet light-inactivated VV (UV VV) was substituted for replication-competent VV in the multi-envelope DVP protocol. Control animals received a vaccine encompassing no VV, or no vaccine. All VV vaccinated animals generated an immune response toward VV, and all vaccinated animals generated an immune response toward HIV-1 envelope. After challenge with heterologous SHIV 89.6P, animals that received replication-competent VV or UV VV experienced similar outcomes. They exhibited reduced peak viral loads, maintenance of CD4+ T cell counts and improved survival compared to control animals that received no VV or no vaccine; there were 0/15 deaths among all animals that received VV and 5/9 deaths among controls. Results define a practical means of improving VV safety, and encourage advancement of a promising multi-envelope DVP HIV-1 vaccine candidate. PMID- 22425791 TI - Human monoclonal antibodies generated following vaccination with AVA provide neutralization by blocking furin cleavage but not by preventing oligomerization. AB - In order to identify the combination of antibody-mediated mechanisms of neutralization that result from vaccination with anthrax vaccine adsorbed (AVA), we isolated antibody secreting cells from a single donor seven days after booster vaccination with AVA and generated nine fully human monoclonal antibodies (hmAb) with high specificity for protective antigen (PA). Two of the antibodies were able to neutralize lethal toxin in vitro at low concentrations (IC(50): p6C01, 0.12 MUg/ml and p6F01, 0.45 MUg/ml). Passive transfer of either of these hmAbs to A/J mice prior to challenge with lethal toxin conferred 80-90% protection. We demonstrate that hmAb p6C01 is neutralizing by preventing furin cleavage of PA in a dose-dependent manner, but the mechanism of p6F01 is unclear. Three additional antibodies were found to bind to domain 3 of PA and prevent oligomerization, although they did not confer significant protection in vivo and showed a significant prozone-like effect in vitro. These fully human antibodies provide insight into the neutralizing response to AVA for future subunit vaccine and passive immunotherapeutic cocktail design. PMID- 22425792 TI - A small animal peripheral challenge model of yellow fever using interferon receptor deficient mice and the 17D-204 vaccine strain. AB - Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne pathogen that requires wild-type (wt), virulent strains to be handled at biosafety level (BSL) 3, with HEPA-filtration of room air exhaust (BSL3+). YFV is found in tropical regions of Africa and South America and causes severe hepatic disease and death in humans. Despite the availability of effective vaccines (17D 204 or 17DD), YFV is still responsible for an estimated 200,000 cases of illness and 30,000 deaths annually. Besides vaccination, there are no other prophylactic or therapeutic strategies approved for use in human YF. Current small animal models of YF require either intra-cranial inoculation of YF vaccine to establish infection, or use of wt strains (e.g., Asibi) in order to achieve pathology. We have developed and characterized a BSL2, adult mouse peripheral challenge model for YFV infection in mice lacking receptors for interferons alpha, beta, and gamma (strain AG129). Intraperitoneal challenge of AG129 mice with 17D-204 is a uniformly lethal in a dose-dependent manner, and 17D-204-infected AG129 mice exhibit high viral titers in both brain and liver suggesting this infection is both neurotropic and viscerotropic. Furthermore the use of a mouse model permitted the construction of a 59-biomarker multi-analyte profile (MAP) using samples of brain, liver, and serum taken at multiple time points over the course of infection. This MAP serves as a baseline for evaluating novel therapeutics and their effect on disease progression. Changes (4-fold or greater) in serum and tissue levels of pro- and anti-inflammatory mediators as well as other factors associated with tissue damage were noted in AG129 mice infected with 17D-204 as compared to mock-infected control animals. PMID- 22425793 TI - Microalbuminuria in adult outpatients not receiving nephrological care and with risk factors for chronic kidney disease in Peruvian nephrology departments. AB - Chronic kidney disease (CKD) is a public health issue and is considered a common and harmful, but treatable disease. Early diagnosis can prevent the possibility of severe vascular damage and its complications, facilitating prompt and aggressive therapeutic measures. OBJECTIVE: To determine the frequency of microalbuminuria (MAU) in outpatients with known risk factors and to analyse whether a patient model exists in which screening is more efficient. METHODS: Ours was an observational, cross-sectional study involving 2968 patients from 23 nephrology centres in Peru. Inclusion criteria were: male and female outpatients aged >=18 years with previous diagnosis of hypertension (AHT), diabetes mellitus (DM) and/or obesity. We obtained values for body mass index (BMI), waist hip ratio (WHR), blood pressure, and microalbuminuria by dipstick. We then tested for the association of these variables with MAU using odds ratios (OR). RESULTS: The mean age of our patients was 52.76 +/- 14.24 years, 68.41% were women, and 57.48% of the patients came from the capital. DM was diagnosed in 508 patients (19.29%), 1368 (51.93%) had hypertension, and 758 (28.78%) were obese. The frequency of MAU was 53.45%, and 8.96% of patients had MAU>100 mg/L. There was a highly significant correlation with DM (OR: 11.62; 95% CI: 8.55-15.78) and AHT (OR: 1.48; 95% CI: 1.24-1.76), while being from the capital (OR: 0.75; 95% CI: 0.64 0.89) and female sex (OR: 0.72; 95% CI: 10.60-0.86) acted as protective factors. conclusions: The frequency of microalbuminuria in the population studied was 53.45%. There was a highly significant correlation with diabetes and a hypertension found during evaluation, while being from the capital and female sex acted as protective factors. PMID- 22425794 TI - High doses of irbesartan offer long-term kidney protection in cases of established diabetic nephropathy. AB - BACKGROUND: Hypothetically, the greater the blockade of angiotensin AT1 receptors from ultra-high doses of angiotensin receptors blockers (ARB), the greater the expected renoprotection effects. The aim of our study was to evaluate the effects of ultra-high doses of irbesartan on proteinuria and renal function in diabetics with established or overt diabetic nephropathy (ODN). MATERIAL AND METHOD: Ours was a prospective, non-randomised 3-year follow-up study, using a multifactorial therapeutic approach based on irbesartan 600mg daily. Demographic variables, anthropometric data, and biochemical parameters were comparatively analysed at the beginning and end of the study. Forty patients (75% with type 2 diabetes) were included, average age 57.1 +/- 10, 29 male (72.5%). RESULTS: SBP (157.6 +/- 27mm Hg vs 130.1 +/- 14mm Hg) and DBP (88.8 +/- 10mm Hg vs 76.2 +/- 8mm Hg) decreased significantly at the end of follow-up (P<.001). Serum creatinine increased by only 0.17mg/dl, although this was a statistically significant difference (P<.05). Proteinuria markedly decreased from 2.64 +/- 1.99 to 0.98 +/- 1.18 (P<.0001), i.e. 59.2%. Twenty-five percent of patients had normal albuminuria at the end of the follow-up period. Lipid profiles significantly improved. No patients withdrew from the study due to side effects, and serum potassium did not change significantly over the course of the study. Except for BMI and HbA1c, all other therapeutic targets set out by ADA recommendations improved significantly. CONCLUSIONS: The treatment of ODN with ultra-high doses of irbesartan was highly effective and safe in reducing proteinuria and slowing the progressive course to ESRD. PMID- 22425795 TI - Intraperitoneal administration of daptomycin in recurrent peritonitis with suspected biofilm. AB - Forms of peritonitis are the most problematic infections in patients undergoing peritoneal dialysis since they can jeopardise the technique. Current treatment includes administering vancomycin, cephalosporins and aminoglycosides empirically until the cause of the infection is known. However, the current situation with regard to emerging bacterial resistances makes it necessary to include new drugs in the therapeutic array for complicated forms of peritonitis that may become recurrent and compromise dialyser efficacy. Daptomycin is a lipopeptide antibiotic used to treat gram-positive bacterial infections. It has not yet been approved for treatment of infections of this type, but it is starting to be used in this area due to being highly effective against methicillin-resistant bacteria with intermediate sensitivity to vancomycin, particularly when the bacteria are associated with biofilm formation. PMID- 22425796 TI - Spanish study of anticoagulation in haemodialysis. AB - OBJECTIVES: This study's objectives were to determine which anticoagulation methods are commonly used in patients who are undergoing haemodialysis (HD) in Spain, on what criteria do they depend, and the consequences arising from their use. MATERIAL AND METHOD: Ours was a cross-sectional study based on two types of surveys: a "HD Centre Survey" and a "Patient Survey". The first survey was answered by 87 adult HD units serving a total of 6093 patients, as well as 2 paediatric units. Among these units, 48.3% were part of the public health system and the remaining 51.7% units were part of the private health system. The patient survey analysed 758 patients who were chosen at random from among the aforementioned 78 HD units. RESULTS: A) HD Centre Survey: The majority of adult HD units (n=61, 70.2%) used both kinds of heparin, 19 of them (21.8%) only used LMWH and 7 of them (8%) only used UFH. The most frequently applied criteria for the use of LMWH were medical indications (83.3% of HD units) and ease of administration (29.5%). The most frequently used methods for adjusting the dosage were clotting of the circuit (88.2% of units), bleeding of the vascular access after disconnection (75.3%), and patient weight (57.6%). B) Patient Survey: The distribution of the types of heparin used was: UFH: 44.1%, LMWH: 51.5%, and dialysis without heparin in 4.4% of patients. LMWH was more frequently used in public medical centres (64.2% of patients) than in private medical centres (46.1%) (P<.001). LMWH was more frequently used in on-line haemodiafiltration (HF) than in high-flux HD (P<.001). Antiplatelet agents were given to 45.5% of patients, oral anticoagulants to 18.4% of patients, and both to 5% of patients. Additionally, 4.4% of patients had suffered bleeding complications during the previous week, and 1.9% of patients suffered thrombotic complications. Bleeding complications were more frequent in patients with oral anticoagulants (P=.001), although there was no association between the type of heparin and the occurrence of bleeding or thrombotic complications. CONCLUSIONS: We are able to conclude that there is a great amount of disparity in the criteria used for the medical prescription of anticoagulation in HD. It is advisable that each HD unit revise their own results as well as those from other centres, and possibly to create an Anticoagulation Guide in Haemodialysis. PMID- 22425797 TI - Study of arteriovenous fistula function by the temperature gradient method using the TwisterTM device. AB - INTRODUCTION: Periodic blood flow (QA) measurement is the preferred way for arteriovenous fistula (AVF) surveillance in chronic hemodialysis (HD) patients. Objectives. 1) Assess the efficacy of the temperature gradient method (TGM) on the QA determinations using the TwisterTM device and to compare the functional results with the Delta-H method. 2) Evaluate the effect of blood pressure on the AVF function. Patients and method. We measured the QA non invasively in 30 AVF (24 radial and 6 brachial; mean duration 53.4 +/- 78.5 months) during HD in 30 stable patients (mean age 59.9 +/- 14.1 years, males 60 %, females 40 %; mean time on HD 37.4 +/- 40.6 months, diabetic nephropathy 20 %) by the TGM, described and validated by Wijnen et al (Kidney Int 2007;72:736). The QA was calculated from the temperature values obtained by means of the blood temperature monitor (BTM), integrated into the Fresenius Medical Care 4008-S machine, at normal and reverse configurations of the HD blood lines, with no need for a thermal bolus. The TwisterTM device was used for reversing the blood lines without the need to disconnect them from the AVF lines nor to stop the blood pump. The QA was measured within the first hour of two consecutive HD sessions (the values were averaged). The mean arterial pressure MAP (diastolic pressure + 1/3 pulse pressure) was calculated simultaneous with the QA. In addition, the AVF blood flow was also determined during the same week in all patients by the Delta-H method using the Crit-Line III Monitor (ABF-mode, HemaMetrics, USA) during HD (manually switching lines). RESULTS: The mean QA was 1132.5 +/- 515.4 ml/min (range, 446-2233 ml/min). The mean coefficient of variation for duplicate QA measurements was 6.8 +/- 4.7 %; the MAP was not different when the reproducibility tests were performed (96.1 +/- 13.7 versus 96.6 +/- 12.8 mmHg, p = .72). No significant difference was found when comparing the mean QA between diabetic (n = 6, 966.4 +/- 340.7 ml/min) and nondiabetic (n = 24, 1174.4 +/- 548.3 ml/min) patients (p = .39). The mean QA was similar for patients with mean MAP < 100 mmHg (n = 18, 1101.0 +/- 552.7 ml/min) and for patients with mean MAP >_ 100 mmHg (n = 12, 1180.4 +/- 473.3 ml/min) (p = .69). No correlation was found between the mean QA and: age (r = 0.09, p = .62), time on HD (r = 0.06, p = .76), MAP (r = -0.21, p = .27), Kt/V index (r = 0.12, p = .51), distance between needles (r = - 0.17, p = .37) and AVF duration (r = -0.01, p = .96). The mean time required to measure QA with the TGM using the TwisterTM device (5.9+/- 1.9 min) was significantly shorter compared with the Delta-H technique (26.8 +/- 1.9 min) or with the TGM (n = 35, 8.9 +/- 3.5 min, manually reversing lines) reported by Wijnen et al (Kidney Int 2007;72:736).) (for both comparisons, p < .001). The mean QA obtained by the TGM was not different when compared to mean ABF determined by the Delta-H method (1138.4 +/- 502.3 ml/min) (p=.83).The calculated values of AVF blood flow obtained by TGM were highly correlated with those determined by the Delta-H technique (r = 0.963, p < .001). CONCLUSIONS: 1) The TGM is a valuable and reproducible indicator of QA during HD. 2) The TwisterTM device is useful to reduce the time for QA measurement by the TGM. 3) The AVF blood flow values obtained by the TGM and the Delta-H technique correlated highly with each other. 4) It has been shown the lack of relationship between the AVF function and the patient's blood pressure. PMID- 22425798 TI - Two prognostic scores for early mortality and their clinical applicability in elderly patients on haemodialysis: poor predictive success in individual patients. AB - INTRODUCTION: Few studies address the individual prognosis of an elderly patient beginning chronic haemodialysis (HD), despite the fact that doctors must frequently weigh the possible benefits and disadvantages of prescribing this treatment. OBJECTIVES: Evaluate the usefulness of the REIN Registry's prognosis score and the predictive index for early mortality proposed by the Catalan Registry of Renal Patients (RMRC, Registre de Malalts Renals de Catalunya) in elderly patients beginning HD by comparing indices with observed survival rates. METHODS: We studied patients aged 75 years and older who started and continued HD treatment in our Department between 2004 and 2009. Socio-demographic, clinical, co-morbidity and mortality data were recorded, in addition to whether or not initiating HD was planned. We calculated the REIN score and the RMRC probability of early mortality. RESULTS: We analysed 63 patients with a mean age of 80.4 +/- 3.9 years and a mean of 3.4 +/- 1.8 additional illnesses. Of these patients, 59% began HD with a catheter; 57.1% had cardiovascular disease, 15.9% neoplasia, 31.2% chronic obstructive pulmonary disease and 19% diabetic nephropathy. Survival rates observed at 6 and at 12 months were 79.4% and 73%, respectively. Patients who began HD on an emergency basis (47.7%) or who were unable to care for themselves (21%) had higher 6-month mortality rates. Analysis of ROC curves (Receiver Operating Characteristic) showed slight concordance between the observed mortality rates and both the REIN score (area 0.681, P=.046) and the RMRC index (area 0.594, P=.255). CONCLUSIONS: The RMRC 1-year mortality probability model is not well adapted for individual prognoses in clinical practice. The REIN score only shows slight concordance with the mortality rates observed in the first 6 months of HD. Poor functional independence was the main risk factor for early mortality in elderly patients beginning HD treatment. PMID- 22425799 TI - Chronic kidney disease progression in patients with autosomal dominant polycystic kidney disease. AB - OBJECTIVES: The aim of this study was to analyse the factors influencing chronic kidney disease (CKD) progression in patients with autosomal dominant polycystic kidney disease (ADPKD). MATERIAL AND METHOD: We studied 101 patients (mean age: 43 +/- 17.3 years, 43.56% male) followed during a median (interquartile range) follow-up time of 69 (35-128) months from 1997 to 2010. The primary end point was: time to a 50% decrease of estimated glomerular filtration rate (eGFR) (CKD EPI) since the first-time visit and/or time to initiation of renal replacement therapy, and the annual mean change of eGFR was also analysed. Clinical and demographic data, blood pressure, concomitant medications, and analytical parameters were collected at each visit. Baseline kidney size was also recorded by ultrasound. RESULTS: Thirty-one patients achieved the primary end point after a median (IQR) time of 102 (53-131) months. Those patients who achieved the primary end point had higher SBP and DBP (P=0.017 and P=0.001), higher LDL cholesterol (P=0.011), higher creatinine (P=0.006), higher uricemia (P=0.041), more severe proteinuria (P=0.033) and greater kidney size (P=0.05). The mean annual eGFR change was of -3.52 +/- 7.3ml/min/1.73m2. Forty-nine patients had a rapid decline in renal function: Group A (higher than -3.52ml/min/1.73m2) and 52 patients had a lower renal disease progression: Group B (<-3.2 ml/min/1.73 m2). Adjusted Cox regression analysis showed that higher SBP and younger age at the first visit were independent variables for poorer renal outcome (P=0.026). CONCLUSIONS: Initial kidney function, proteinuria, renal size, hypercholesterolemia, hyperuricemia, and SBP are the factors that influence CKD progression in ADPKD. SBP and younger age at diagnosis are the only factors that maintain their independent predictive value in a multivariant analysis. PMID- 22425800 TI - Recovery of renal function in patients receiving haemodialysis treatment. AB - The aim of this study was to review all cases of recovery of renal function in chronic haemodialysis patients, observed in the last ten years. During the study period, 218 chronic renal failure patients were managed on haemodialysis for a minimum of 90 days. In 17 cases (8%), it was possible to interrupt dialysis after 95 to 529 days. The probability of renal function recovery was higher in patients with chronic interstitial nephritis (P=.04) or autoimmune diseases (P=.07), as well as in those starting haemodialysis treatment at a frequency of two sessions per week (P=.02). No significant differences in age, gender, glomerular filtration rate at the beginning of haemodialysis treatment, or comorbidity rate were observed. Seven patients returned to haemodialysis treatment after a dialysis-free period of 11 +/- 7 months. Two patients died for reasons unrelated to renal failure treatment, and another patient was moved to another hospital following 35 months without dialysis. The other 14 patients are alive and 8 are dialysis-free, with a monitoring period of 13 to 106 months. The conclusion reached is that there is no reason why residual kidney function should inexorably worsen after the start of haemodialysis treatment, and that functional recovery is possible in some patients. PMID- 22425801 TI - Medical therapy with tranexamic acid in autosomal dominant polycystic kidney disease patients with severe haematuria. AB - BACKGROUND: Gross haematuria is a common manifestation of autosomal dominant polycystic kidney disease (ADPKD). It can be spontaneous or the result of trauma, renal calculi, tumour, or infection. Spontaneous cyst bleeding is important in this particular group of patients, since it can be prolonged by local activation of fibrinolysis by urokinase. The management of haematuria in ADPKD is usually conservative, including bed rest, blood transfusion, correction of blood disorders, and use of vasopressin and erythropoiesis-stimulating agents. In some patients, the management of gross or life-threatening haematuria may require embolisation and/or nephrectomy. Nonetheless, other methods have been tried to avoid prolonged hospitalisation and nephrectomy and preserve kidney function, such as the use of anti-fibrinolytics. Tranexamic acid was recently suggested as a tool to treat gross haematuria in ADPKD in isolated cases. OBJECTIVE: The aim of this study was to evaluate prospectively the response to tranexamic acid in a group of 8 patients with ADPKD and gross haematuria unresponsive to conventional treatment. RESULTS: The massive bleeding stopped within 2 to 5 days in all patients. The haemoglobin level and renal function subsequently stabilised. There were no side effects or thromboembolic events. In this case series, the largest prospective study so far published and the only one including different degrees of renal function, tranexamic acid is confirmed as a promising tool for treating haematuria due to intracystic bleeding in ADPKD. CONCLUSIONS: In summary, tranexamic acid can be used safely in ADPKD patients with chronic renal impairment or preserved renal function to treat severe haematuria poorly responsive to conventional therapy. Tranexamic acid can be administered orally or IV; and dose adjustment for renal impairment is important. Tranexamic acid therapy may preserve renal function in ADPKD directly, by stopping haematuria episodes, or indirectly, by preventing embolisation and/or nephrectomy. The major limitation of this study is the small sample size and the lack of an untreated control group. We suggest a prospective, randomised controlled study to confirm the efficacy of this treatment, its long-term safety, and the optimal dosage. Further larger and multicentre studies are needed to evaluate the cost-benefit ratio and the limits of this therapy in the clinical setting. PMID- 22425802 TI - Congestive heart failure in patients with advanced chronic kidney disease: association with pre-emptive vascular access placement. AB - INTRODUCTION: Congestive heart failure (CHF) is a common complication in patients with chronic kidney disease (CKD). In addition to classical risk factors (e.g. age and pre-existing cardiac diseases), other potential reversible abnormalities linked to CKD such as anaemia, volume overload, or vascular access placement may also influence the incidence and severity of acute exacerbations of CHF. OBJECTIVE: This study aims to determine the incidence and main determinants of CHF in a cohort of patients with stage 4-5 pre-dialysis CKD. PATIENTS AND METHOD: The study group consisted of 562 patients (mean age: 65 +/- 15 years, 260 females, 31% diabetics). Native arteriovenous fistulas (AVF) were created in 160 patients who chose haemodialysis as the initial technique for renal replacement therapy. The main outcome variables were: acute decompensated CHF (defined by standard criteria), dialysis initiation (planned and unplanned), and death before dialysis initiation. In addition to demographics, comorbidities, and clinical and biochemical data, AVF creation was also included as a potential determinant of CHF in multiple logistic regression models. RESULTS: Ninety-five patients (17%) developed at least one episode of acute decompensated CHF, and the incidence rate was 19 episodes per 1000 patient-years. In addition to classical risk factors (age, female sex, obesity, diabetes, and previous history of CHF or coronary artery disease), creation of a successful AVF significantly increased the risk of CHF (OR=9.54, 95% CI: 4.84-18.81, P<.0001). In 47 out of 95 patients who developed CHF, a functioning AVF had previously been created, 92% of which were upper arm native AVF, with a median of 51 days between the surgical procedure and CHF episode. The mortality of patients with CHF was similar to that of the rest of the study patients, although unplanned dialysis initiation was significantly more frequent in those who developed CHF. CONCLUSIONS: Acute decompensated CHF episodes are common in pre-dialysis CKD patients. In addition to classical risk factors, pre-emptive AVF placement was strongly associated with the development of CHF. PMID- 22425803 TI - Interactions between glycine transporter type 1 (GlyT-1) and some inhibitor molecules - glycine transporter type 1 and its inhibitors (review). AB - Glycine is a mandatory positive allosteric modulator of N-methyl-D-aspartate (NMDA)-type ionotropic glutamate receptors in the central nervous system. Elevation of glycine concentrations by inhibition of its reuptake in the vicinity of NMDA receptors may positively influence receptor functions as glycine B binding site on NR1 receptor subunit is not saturated in physiological conditions. Synaptic and extrasynaptic concentrations of glycine are regulated by its type-1 glycine transporter, which is primarily expressed in astroglial and glutamatergic cell membranes. Alteration of synaptic glycine levels may have importance in the treatment of various forms of endogenous psychosis characterized by hypofunctional NMDA receptors. Several lines of evidence indicate that impaired NMDA receptor-mediated glutamatergic neurotransmission is involved in development of the negative (and partly the positive) symptoms and the cognitive deficit in schizophrenia. Inhibitors of glycine transporter type-1 may represent a newly developed therapeutic intervention in treatment of this mental illness. We have synthesized a novel series of N-substituted sarcosines, analogues of the glycine transporter-1 inhibitor NFPS (N-[3-(4'-fluorophenyl)-3 (4'-phenylphenoxy)-propyl]sarcosine). Of the pyridazinone-containing compounds, SzV-1997 was found to be a potent glycine transporter-1 inhibitor in rat brain synaptosomes and it markedly increased extracellular glycine concentrations in conscious rat striatum. SzV-1997 did not exhibit toxic symptoms such as hyperlocomotion, restless movements, respiratory depression, and lethality, characteristic for NFPS. Besides pyridazinone-based, sarcosine-containing glycine transporter-1 inhibitors, a series of substrate-type amino acid inhibitors was investigated in order to obtain better insight into the ligand-binding characteristics of the substrate binding cavity of the transporter. PMID- 22425804 TI - Isointegral body surface maps and left ventricular hypertrophy in post-infarction heart failure patients. AB - AIM: Ventricular remodeling causes left ventricular hypertrophy (LVH) in myocardial infarction patients. We hypothesized that LVH can be evaluated using isointegral body surface maps. METHODS: Thirty-two patients with post-infarction stable chronic heart failure underwent a 64-electrode body surface mapping (isointegral QRS, QRST, ST and STT maps) and 2-D echocardiography. RESULTS: LVH was present in 16 of them (50%) according to 2D-echocardiography. Isointegral maxima increased and the minima were more negative in patients with LVH, and the differences were statistically significant for: isointegral QRS maxima (35+/-16 versus 60+/-21 mV.ms, p=0.0085) and minima (25+/-15 versus 69+/-14 mV.ms, p=0.0067), isointegral maxima and minima in the second third of the QRS complex, isointegral QRST minima and isointegral ST minima (5+/-2 versus 10+/-4 mV.ms, p=0.0026). Isointegral multipolar maps prevalence was increased in patients with LVH (75% versus 50%). Isointegral QRS and QRST maxima correlated best with the left ventricular mass (r=0.73 and 0.81). CONCLUSION: Body surface mapping is a useful method for the evaluation of patients with left ventricular hypertrophy in post-infarction heart failure. The most sensitive parameters are: isointegral QRS maxima and minima, especially in the second third of the QRS complex, isointegral QRST maps (minima, maxima and multipolarity) and isointegral ST minima. PMID- 22425805 TI - Modulation of radial blood flow during Braille character discrimination task. AB - PURPOSE: Human hands are excellent in performing sensory and motor function. We have hypothesized that blood flow of the hand is dynamically regulated by sympathetic outflow during concentrated finger perception. To identify this hypothesis, we measured radial blood flow (RBF), radial vascular conductance (RVC), heart rate (HR), and arterial blood pressure (AP) during Braille reading performed under the blind condition in nine healthy subjects. The subjects were instructed to read a flat plate with raised letters (Braille reading) for 30 s by the forefinger, and to touch a blank plate as control for the Braille discrimination procedure. RESULTS: HR and AP slightly increased during Braille reading but remained unchanged during the touching of the blank plate. RBF and RVC were reduced during the Braille character discrimination task (decreased by 46% and -49%, respectively). Furthermore, the changes in RBF and RVC were much greater during the Braille character discrimination task than during the touching of the blank plate (decreased by -20% and -20%, respectively). CONCLUSIONS: These results have suggested that the distribution of blood flow to the hand is modulated via sympathetic nerve activity during concentrated finger perception. PMID- 22425806 TI - The effect of the CYP 2C19*2 polymorphism on stroke care. AB - Clopidogrel is an inhibitor of platelet-aggregation used in the prevention of secondary stroke. The molecule is activated by the cytochrome P450 2C19 (CYP2C19) enzyme. The frequent CYP2C19*2 point mutation causes loss of enzyme function, a decreased (heterozygous form) or blocked (homozygous form) formation of the active molecule. Thus, for a patient harboring a mutated allele, clopidogrel does not provide effective protection against stroke. Multiple drugs inhibit the CYP2C19 enzyme and their simultaneous use with clopidogrel is especially hazardous for patients with genetically decreased enzyme activity. Frequency of the CYP2C19*2 is variable in different populations, highest rates were detected in some Asian groups. In our study the CYP2C19 genotype was determined in one Hungarian sample of 354 stroke patients and 221 healthy controls. Frequency of the minor allele was found to be 12.87% (12.85% in stroke patients, 12.89% in healthy controls). The proportion of the homozygous CYP2C19*2 variant causing total loss of gene function was 1.74%, rate of the heterozygous allele causing reduced enzyme activity was 22.26% in the total population. Our results for the allele frequencies of the CYP2C19*2 gene are similar to those found in other Caucasian populations. In conclusion, the homozygous mutation, causing ineffectiveness of clopidogrel is relatively rare. However, the heterozygous form in which interaction of CYP2C19 inhibitors causes further decrease in the genetically impaired enzyme activity is present in every fifth drug-taking patient. Based on our findings, we would like to emphasize that it is important to adjust individually antiplatelet treatment in ischemic stroke patients and to take into consideration genetic factors as well as drugs taken for comorbid conditions. PMID- 22425807 TI - Effects of treatment with coenzyme Q10 on exercised rat aorta. AB - In this study, the effect of long-term supplementation of coenzyme Q10 (CoQ10) on the responses of swim-trained rat aorta was investigated. Twenty-four adult male Wistar rats were divided into four groups: untrained, trained, untrained+CoQ10, and trained+CoQ10 group. In the trained groups rats swam for 60 min/day, five days/week for six weeks. The CoQ10 supplements were administered by intraperitoneal injection at a daily dose of 10 mg.kg-1 of body weight five days/week for six weeks. Swimming of the rats was performed in a container containing tap water. Rats were sacrificed and thoracic aortas were removed for ex vivo analysis after the last swimming session. The aortas were cut into rings 2.5 mm in length. Concentration-response curves for phenylephrine (PHE, 10-9-3*10 4 M) and potassium chloride (KCl, 5-100 mM) were isometrically recorded. The sensitivity and maximal responses to PHE and KCl of aortic rings obtained from trained rats were lower than those of untrained rats. CoQ10 supplementation decreased the responses to both vasoconstrictors in untrained and especially in trained groups. Although neither CoQ10 nor training did affect malondialdehyde (MDA) and protein carbonyl (PC) levels, creatine kinase (CK) activity decreased and superoxide dismutase (SOD) activity increased only with exercise training. Glutathione (GSH) levels increased in CoQ10 supplemented-untrained rats. In conclusion, our results suggest that CoQ10 supplementation may have beneficial effects during exercise. PMID- 22425808 TI - Resistin, visfatin and insulin sensitivity in selected phases of annual training cycle of triathletes. AB - The purpose of the study was to examine the effects of sport training on carbohydrate metabolic indices and adipokines concentrations in young male triathletes (n=10). Athletes performed the incremental running test in two periods of the training cycle: in the transitory and preparatory phases. In both analyzed terms, physical exercise was reflected by a significant increase in lactate (p<=0.01), insulin (p<=0.01), visfatin concentrations (p<=0.01, p<0.05, respectively) and only during transitory phase in glucose (p<=0.01) and resistin concentrations (p<0.05). Significant inter-period differences were noted in the pre-exercise insulin (p<=0.01) and also in pre- and post-exercise visfatin concentrations (p<0.05). Additionally, the differences (Delta) between post- and pre-exercise values of glucose (p<0.05) and visfatin (p<=0.01) significantly decreased in the preparatory phase comparing to the transitory phase. The inverse correlations between pre-exercise concentrations of visfatin and peak oxygen uptake (p<0.05) in the transitory phase and between post- and pre-exercise differences (Delta) of visfatin and lactate concentrations (p<0.05) in the preparatory phase were noted. During preparatory phase, pre-exercise visfatin concentrations inversely correlated with pre-exercise resistin, insulin and glucose levels (p<0.05). In conclusion, systematic training in elite triathletes modulates basal adipokine concentrations only to a small extent, however, influences on these molecules response on the acute exercise. PMID- 22425809 TI - The effects of chitosan and low dose dexamethasone on extrahepatic cholestasis after bile duct ligation in Wistar rats. AB - Inflammation and oxidative stress are important pathways in the development of liver fibrosis following biliary obstruction. AIM: To evaluate the effects of low dose dexamethasone and chitosan, a natural compound with no side-effects, on liver damage caused by bile duct ligation in rats. MATERIALS AND METHODS: Fifty female Wistar rats, randomly and equally divided in 5 groups: I (SHAM) underwent only laparotomy, II (BDL) with bile duct ligation, III (DEX) 0.125 mg/kg dexamethasone i.m. daily, IV (CS) 1 mg/kg chitosan by gavage and group V (DEX+CS), both substances. After six days, the following parameters were assessed from liver homogenates: malondialdehyde (MDA), protein carbonyls (PC), reduced glutathione (GSH), total SH groupings, nitric oxide (NO), and from plasma: MDA, gamma-glutamyltranspeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB). A histopathological examination was performed using some of the elements of the Knodell Histological Activity Index. RESULTS: BDL significantly increases the levels of MDA, liver enzymes, and the necro-inflammatory score compared to the sham group and it decreases the antioxidant capacity. DEX protects against lipid peroxidation and improves the antioxidant capacity, but it is not able to protect the hepatocytes. Chitosan significantly decreases (p<0.05) the levels of MDA (0.07+/-0.01 vs 0.10+/-0.01 nmoles/mg protein BDL group, p=0.027) and also ALT, TB, GGT and reduces liver necrosis and inflammation (2.75+/-0.95 vs 1+/-0, p<0.05). Both CS and DEX reduce the level of NO significantly. CONCLUSION: BDL induces severe oxidative stress damage after six days already. Chitosan proved very efficient in protecting the hepatocytes against oxidative stress, a fact supported by the histological findings. PMID- 22425810 TI - Effect of m-3m3FBS on Ca2+ handling and viability in OC2 human oral cancer cells. AB - The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl) benzenesulfonamide (m-3M3FBS), a presumed phospholipase C activator, on cytosolic free Ca2+ concentrations ([Ca2+]i) in OC2 human oral cancer cells is unclear. This study explored whether m-3M3FBS changed basal [Ca2+]i levels in suspended OC2 cells by using fura-2 as a Ca2+-sensitive fluorescent dye. M-3M3FBS at concentrations between 10-60 MUM increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced partly by removing extracellular Ca2+. M 3M3FBS-induced Ca2+ influx was inhibited by the store-operated Ca2+ channel blockers nifedipine, econazole and SK&F96365, and by the phospholipase A2 inhibitor aristolochic acid. In Ca2+-free medium, 30 MUM m-3M3FBS pretreatment inhibited the [Ca2+]i rise induced by the endoplasmic reticulum Ca2+ pump inhibitors thapsigargin and 2,5-di-tert-butylhydroquinone (BHQ). Conversely, pretreatment with thapsigargin, BHQ or cyclopiazonic acid partly reduced m-3M3FBS induced [Ca2+]i rise. Inhibition of inositol 1,4,5-trisphosphate formation with U73122 did not alter m-3M3FBS-induced [Ca2+]i rise. At concentrations between 5 and 100 MUM m-3M3FBS killed cells in a concentration-dependent manner. The cytotoxic effect of m-3M3FBS was not reversed by prechelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Propidium iodide staining data suggest that m-3M3FBS (20 or 50 MUM) induced apoptosis in a Ca2+-independent manner. Collectively, in OC2 cells, m-3M3FBS induced [Ca2+]i rise by causing inositol 1,4,5-trisphosphate-independent Ca2+ release from the endoplasmic reticulum and Ca2+ influx via phospholipase A2-sensitive store operated Ca2+ channels. M-3M3FBS also induced Ca2+-independent cell death and apoptosis. PMID- 22425811 TI - Effect of chronic L-Arginine supplementation on aortic fatty streak formation and serum nitric oxide concentration in normal and high-cholesterol fed rabbits. AB - Several reports indicated the beneficial effects of short-term L-Arginine (L-Arg) administration on atherosclerosis processes. The aim of this study was to evaluate the effect of chronic L-Arg supplementation on serum lipid profile, aortic Fatty Streak (FS) formation, and serum Nitric oxide (NO) concentration in Normal Diet (ND) and High-Cholesterol Diet (HCD) fed rabbits. 24 male rabbits were randomly divided into four groups (n=6 in each group) (i): ND for seven months; (ii): ND for 1 month plus ND + L-Arg for six months; (iii): HCD (1%) for 1 month plus HCD (0.5%) for six months; (iv): HCD (1%) for 1 month plus HCD (0.5%) + L-Arg for six months. At the end of the study, histological evaluation of aortic FS formation was performed. Blood samples were taken for serum lipid profile and NO concentrations. L-Arg did not change serum total cholesterol, triglyceride, LDL and LDL/HDL ratio in normal and hypercholesterolemic rabbits (p>0.05). Histological examination of thoracic aortae revealed that the HCD group had higher FS formation compared to the ND group (2.1 +/- 0.16 vs. 0 +/- 0; respectively; p<0.05) and L-Arg supplementation did not attenuate FS formation in the HCD group (1.93 +/- 0.17 compare to 2.1 +/- 0.16; p>0.05). Serum NO level in the HCD group was higher than ND groups (p<0.05). Chronic L-Arg supplementation did not alter serum NO concentration either in the hypercholesterolemic or in the ND group (p>0.05). It seems that chronic L-Arg supplementation does not have beneficial effects on aortic fatty streak formation, serum lipids and NO concentrations in this model of experimental hypercholesterolemia. PMID- 22425812 TI - Electrostatically embedded many-body method for dipole moments, partial atomic charges, and charge transfer. AB - Fragment methods have been widely studied for computing energies and forces, but less attention has been paid to nonenergetic properties. Here we extend the electrostatically embedded many-body (EE-MB) method to the calculation of cluster dipole moments, dipole moments of molecules in clusters, partial atomic charges, and charge transfer, and we test and validate the method by comparing to results calculated for the entire system without fragmentation. We also compare to calculations carried out by the conventional many-body (MB) method without electrostatic embedding. Systems considered are NH(3)(H(2)O)(11), (NH(3))(2)(H(2)O)(14), [Cl(H(2)O)(6)](-), (HF)(4), (HF)(5), (HF)(2)H(2)O, (HF)(3)H(2)O, and (HF)(3)(H(2)O)(2). With electrostatic embedding, we find that even at the pairwise additive level a quantitatively accurate description of a system's dipole moment and partial charge distribution and a qualitatively accurate description of the amount of intermolecular charge transfer can often be obtained. PMID- 22425813 TI - Learning CPR at school--everyone should do it. PMID- 22425814 TI - Structure and function of bacterial nitric oxide reductases: nitric oxide reductase, anaerobic enzymes. AB - The crystal structures of bacterial nitric oxide reductases (NOR) from Pseudomonas aeruginosa and Geobacillus stearothermophilus were reported. The structural characteristics of these enzymes, especially at the catalytic site and on the pathway that catalytic protons are delivered, are compared, and the corresponding regions of aerobic and micro-aerobic cytochrome oxidases, O(2) reducing enzymes, which are evolutionarily related to NOR are discussed. On the basis of these structural comparisons, a mechanism for the reduction of NO to produce N(2)O by NOR, and the possible molecular evolution of the proton pumping ability of the respiratory enzymes is discussed. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22425815 TI - In Polytomella sp. mitochondria, biogenesis of the heterodimeric COX2 subunit of cytochrome c oxidase requires two different import pathways. AB - In the vast majority of eukaryotic organisms, the mitochondrial cox2 gene encodes subunit II of cytochrome c oxidase (COX2). However, in some lineages including legumes and chlorophycean algae, the cox2 gene migrated to the nucleus. Furthermore, in chlorophycean algae, this gene was split in two different units. Thereby the COX2 subunit is encoded by two independent nuclear genes, cox2a and cox2b, and mitochondria have to import the cytosol-synthesized COX2A and COX2B subunits and assemble them into the cytochrome c oxidase complex. In the chlorophycean algae Chlamydomonas reinhardtii and Polytomella sp., the COX2A precursor exhibits a long (130-140 residues), cleavable mitochondrial targeting sequence (MTS). In contrast, COX2B lacks an MTS, suggesting that mitochondria use different mechanisms to import each subunit. Here, we explored the in vitro import processes of both, the Polytomella sp. COX2A precursor and the COX2B protein. We used isolated, import-competent mitochondria from this colorless alga. Our results suggest that COX2B is imported directly into the intermembrane space, while COX2A seems to follow an energy-dependent import pathway, through which it finally integrates into the inner mitochondrial membrane. In addition, the MTS of the COX2A precursor is eliminated. This is the first time that the in vitro import of split COX2 subunits into mitochondria has been achieved. PMID- 22425816 TI - A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine. AB - OBJECTIVE: To gain insights into individual variations in acute inflammation and physiology. DESIGN: Large-animal study combined with mathematical modeling. SETTING: Academic large-animal and computational laboratories. SUBJECTS: Outbred juvenile swine. INTERVENTIONS: Four swine were instrumented and subjected to endotoxemia (100 ug/kg), followed by serial plasma sampling. MEASUREMENTS AND MAIN RESULTS: Swine exhibited various degrees of inflammation and acute lung injury, including one death with severe acute lung injury (PaO(2)/FIO(2) ratio MU200 and static compliance MU10 L/cm H(2)O). Plasma interleukin-1beta, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, high mobility group box-1, and NO(2)/NO(3) were significantly (p MU .05) elevated over the course of the experiment. Principal component analysis was used to suggest principal drivers of inflammation. Based in part on principal component analysis, an ordinary differential equation model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces tumor necrosis factor-alpha in monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of high mobility group box-1, which in turn stimulates the release of interleukin 1beta from resident macrophages. The ordinary differential equation model also included blood pressure, PaO(2), and FIO(2), and a damage variable that summarizes the health of the animal. This ordinary differential equation model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the oxygen index in three of the four swine. CONCLUSIONS: The approach described herein may aid in predicting inflammation and physiologic dysfunction in small cohorts of subjects with diverse phenotypes and outcomes. PMID- 22425817 TI - Evaluation of stroke volume variations obtained with the pressure recording analytic method. AB - OBJECTIVE: To investigate whether stroke volume variations obtained with the pressure recording analytic method can predict fluid responsiveness in mechanically ventilated patients with circulatory failure. DESIGN: Prospective study. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: Thirty-five mechanically ventilated patients with circulatory failure for whom the decision to give fluid was taken by the physician were included. Exclusion criteria were: Arrhythmia, tidal volume <8 mL/kg, left ventricular ejection fraction<50%, right ventricular dysfunction, and heart rate/respiratory rate ratio <3.6. INTERVENTIONS: Fluid challenge with 500 mL of saline over 15 mins. MEASUREMENTS AND MAIN RESULTS: Stroke volume variations and cardiac output obtained with a pressure recording analytic method, pulse pressure variations, and cardiac output estimated by echocardiography were recorded before and after volume expansion. Patients were defined as responders if stroke volume obtained using echocardiography increased by >=15% after volume expansion. Nineteen patients responded to the fluid challenge. Median [interquartile range, 25% to 75%] stroke volume variation values at baseline were not different in responders and nonresponders (10% [8-16] vs. 14% [12-16]), whereas pulse pressure variations were significantly higher in responders (17% [13-19] vs. 7% [5-10]; p < .0001). A 12.6% stroke volume variations threshold discriminated between responders and nonresponders with a sensitivity of 63% (95% confidence interval 38% to 84%) and a specificity of 69% (95% confidence interval 41% to 89%). A 10% pulse pressure variation threshold discriminated between responders and nonresponders with a sensitivity of 89% (95% confidence interval 67% to 99%) and a specificity of 88% (95% confidence interval 62% to 98%). The area under the receiver operating characteristic curves was different between pulse pressure variations (0.95; 95% confidence interval 0.82-0.99) and stroke volume variations (0.60; 95% confidence interval 0.43-0.76); p < .0001). Volume expansion-induced changes in cardiac output measured using echocardiography or pressure recording analytic method were not correlated (r = 0.14; p > .05) and the concordance rate of the direction of change in cardiac output was 60%. CONCLUSION: Stroke volume variations obtained with a pressure recording analytic method cannot predict fluid responsiveness in intensive care unit patients under mechanical ventilation. Cardiac output measured by this device is not able to track changes in cardiac output induced by volume expansion. PMID- 22425818 TI - Noninvasive monitoring of blood pressure in the critically ill: reliability according to the cuff site (arm, thigh, or ankle). AB - OBJECTIVE: In the critically ill, blood pressure measurements mostly rely on automated oscillometric devices pending the intra-arterial catheter insertion or after its removal. If the arms are inaccessible, the cuff is placed at the ankle or the thigh, but this common practice has never been assessed. We evaluated the reliability of noninvasive blood pressure readings at these anatomic sites. DESIGN: Prospective observational study. SETTING: Medical-surgical intensive care unit. PATIENTS: Patients carrying an arterial line with no severe occlusive arterial disease. INTERVENTION: Each patient underwent a set of three pairs of noninvasive and intra-arterial measurements at each site (arm, ankle, thigh [if Ramsay sedation scale >4]) and, in case of circulatory failure, a second set of measurements after a cardiovascular intervention (volume expansion, change in catecholamine dosage). MEASUREMENTS AND MAIN RESULTS: In 150 patients, whatever the cuff site, the agreement between invasive and noninvasive readings was markedly higher for mean arterial pressure than for systolic or diastolic pressure. For mean arterial pressure measurement, arm noninvasive blood pressure was reliable (mean bias of 3.4 +/- 5.0 mm Hg, lower/upper limit of agreement of 6.3/13.1 mm Hg) contrary to ankle or thigh noninvasive blood pressure (mean bias of 3.1 +/- 7.7 mm Hg and 5.7 +/- 6.8 mm Hg and lower/upper limits of agreement of -12.1/18.3 mm Hg and -7.7/19.2 mm Hg, respectively). During acute circulatory failure (n = 83), arm noninvasive blood pressure but also ankle and thigh noninvasive blood pressure allowed a reliable detection of 1) invasive mean arterial pressure <65 mm Hg (area under the receiver operating characteristic curve of 0.98 [0.92-1], 0.93 [0.85-0.97], and 0.93 [0.85-0.98] for arm, ankle, and thigh noninvasive blood pressure, respectively); and 2) a significant (>10%) increase in invasive mean arterial pressure after a cardiovascular intervention (area under the receiver operating characteristic curve of 0.99 [0.92-1], 0.90 [0.80-0.97], and 0.96 [0.87-0.99], respectively). CONCLUSION: In our population, arm noninvasive mean arterial pressure readings were accurate. Either the ankle or the thigh may be reliable alternatives, only to detect hypotensive and therapy responding patients. PMID- 22425819 TI - Cyclosporine treatment improves cardiac function and systemic hemodynamics during resuscitation in a newborn piglet model of asphyxia: a dose-response study. AB - OBJECTIVES: Asphyxiated neonates often have myocardial depression, which is a significant cause of morbidity and mortality. Cardioprotective effects of cyclosporine have been observed in adult patients and animals with myocardial infarction. However, the cardioprotective effect of cyclosporine in neonates has not yet been studied. We hypothesize that cyclosporine will improve cardiac function and reduce myocardial injury in asphyxiated newborn piglets. DESIGN: Thirty-six piglets (1-4 days old, weighing 1.4-2.5 kg) were acutely instrumented for continuous monitoring of cardiac output and systemic arterial pressure. After stabilization, normocapnic alveolar hypoxia (10% to 15% oxygen) was instituted for 2 hrs followed by reoxygenation with 100% oxygen for 0.5 hrs and then 21% for 3.5 hrs. A nonasphyxiated, sham-operated group was included (n = 4) to control for effects of the surgical model. Plasma troponin and myocardial lactate concentrations were determined as well as morphologic examinations. SETTING: Neonatal asphyxia and reoxygenation. SUBJECTS: Newborn (1-4 days old) piglets. INTERVENTIONS: Piglets were block-randomized to receive intravenous boluses of cyclosporine A (2.5, 10, or 25 mg/kg) or normal saline (control) at 5 mins of reoxygenation (n = 8/group). MEASUREMENTS AND MAIN RESULTS: Cardiac index, heart rate, systemic oxygenation, plasma troponin, and left ventricular lactate were measured. Hypoxic piglets had cardiogenic shock (cardiac output 40% to 48% of baseline), hypotension (mean arterial pressure 27-31 mm Hg), and acidosis (pH 7.04). Cyclosporine treatment caused bell-shaped improvements in cardiac output, stroke volume, and systemic oxygen delivery (p < .05 vs. controls). Plasma troponin and left ventricle lactate were higher in controls than that of 2.5 and 10 mg/kg cyclosporine-treated groups (p < .05). Although histologic features of myocardial injury were not different among groups, severe damage was observed in mitochondria of control piglets but attenuated in that of cyclosporine (10 mg/kg) treatment. CONCLUSIONS: Postresuscitation administration of cyclosporine causes preservation of cardiac function and attenuates myocardial injury in newborn piglets after asphyxia-reoxygenation. PMID- 22425820 TI - Both high level pressure support ventilation and controlled mechanical ventilation induce diaphragm dysfunction and atrophy. AB - OBJECTIVES: Previous workers have demonstrated that controlled mechanical ventilation results in diaphragm inactivity and elicits a rapid development of diaphragm weakness as a result of both contractile dysfunction and fiber atrophy. Limited data exist regarding the impact of pressure support ventilation, a commonly used mode of mechanical ventilation-that permits partial mechanical activity of the diaphragm-on diaphragm structure and function. We carried out the present study to test the hypothesis that high-level pressure support ventilation decreases the diaphragm pathology associated with CMV. METHODS: Sprague-Dawley rats were randomly assigned to one of the following five groups:1) control (no mechanical ventilation); 2) 12 hrs of controlled mechanical ventilation (12CMV); 3) 18 hrs of controlled mechanical ventilation (18CMV); 4) 12 hrs of pressure support ventilation (12PSV); or 5) 18 hrs of pressure support ventilation (18PSV). MEASUREMENTS AND MAIN RESULTS: We carried out the following measurements on diaphragm specimens: 4-hydroxynonenal-a marker of oxidative stress, active caspase-3 (casp-3), active calpain-1 (calp-1), fiber type cross-sectional area, and specific force (sp F). Compared with the control, both 12PSV and 18PSV promoted a significant decrement in diaphragmatic specific force production, but to a lesser degree than 12CMV and 18CMV. Furthermore, 12CMV, 18PSV, and 18CMV resulted in significant atrophy in all diaphragm fiber types as well as significant increases in a biomarker of oxidative stress (4-hydroxynonenal) and increased proteolytic activity (20S proteasome, calpain-1, and caspase-3). Furthermore, although no inspiratory effort occurs during controlled mechanical ventilation, it was observed that pressure support ventilation resulted in large decrement, approximately 96%, in inspiratory effort compared with spontaneously breathing animals. CONCLUSIONS: High levels of prolonged pressure support ventilation promote diaphragmatic atrophy and contractile dysfunction. Furthermore, similar to controlled mechanical ventilation, pressure support ventilation-induced diaphragmatic atrophy and weakness are associated with both diaphragmatic oxidative stress and protease activation. PMID- 22425821 TI - Inhibition of vascular adenosine triphosphate-sensitive potassium channels by sympathetic tone during sepsis. AB - OBJECTIVE: Excessive opening of the adenosine triphosphate-sensitive potassium channel in vascular smooth muscle is implicated in the vasodilation and vascular hyporeactivity underlying septic shock. Therapeutic channel inhibition using sulfonylurea agents has proved disappointing, although agents acting on its pore appear more promising. We thus investigated the hemodynamic effects of adenosine triphosphate-sensitive potassium channel pore inhibition in awake, fluid resuscitated septic rats, and the extent to which these responses are modulated by the high sympathetic tone present in sepsis. Temporal changes in ex-vivo channel activity and subunit gene expression were also investigated. DESIGN: In vivo and ex vivo animal study. SETTING: University research laboratory. SUBJECTS: Male adult Wistar rats. INTERVENTIONS AND MEASUREMENTS: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Pressor responses to norepinephrine and PNU-37883A (a vascular adenosine triphosphate-sensitive potassium channel inhibitor acting on the Kir6.1 pore-forming subunit) were measured at 6 or 24 hrs, in the absence or presence of the autonomic ganglion blocker, pentolinium. The aorta and mesenteric artery were examined ex vivo for rubidium efflux as a marker of adenosine triphosphate-sensitive potassium channel activity, and for adenosine triphosphate-sensitive potassium channel subunit gene expression using quantitative reverse transcription-polymerase chain reaction. MAIN RESULTS: A total of 120 rats (50 sham-operated controls, 70 septic) were included. Septic rats became hypotensive after 12 hrs, with a 24-hr mortality of 51.7% (0% in controls). At 6 hrs, there was an attenuated pressor response to norepinephrine (p < .01) despite blood pressure being elevated (p < .01). PNU 37883A had no pressor effect, except in the presence of pentolinium (p < .01). Kir6.1 subunit mRNA increased significantly in the mesenteric artery while rubidium efflux was increased in both the aorta and mesenteric artery at 24 hrs. CONCLUSIONS: Despite evidence of increased adenosine triphosphate-sensitive potassium channel activity in sepsis, it appears to be inhibited in vivo by high sympathetic tone. This may explain, at least in part, the reduced efficacy of adenosine triphosphate-sensitive potassium channel blockers in human septic shock. PMID- 22425822 TI - Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs. AB - OBJECTIVE: Despite the introduction of mild therapeutic hypothermia into postcardiac arrest care, cerebral and myocardial injuries represent the limiting factors for survival after cardiac arrest. Administering xenon may confer an additional neuroprotective effect after successful cardiopulmonary resuscitation due to its ability to stabilize cellular calcium homeostasis via N-methyl-D aspartate-receptor antagonism. DESIGN: In a porcine model, we evaluated effects of xenon treatment in addition to therapeutic hypothermia on neuropathologic and functional outcomes after cardiopulmonary resuscitation. SETTING: Prospective, randomized, laboratory animal study. SUBJECTS: Fifteen male pigs. INTERVENTIONS: Following 10 mins of cardiac arrest and 6 mins of cardiopulmonary resuscitation, ten pigs were randomized to receive either mild therapeutic hypothermia (33 degrees C for 16 hrs) or mild therapeutic hypothermia 1 xenon (70% for 1 hr). Five animals served as normothermic controls. MEASUREMENTS AND MAIN RESULTS: Gross hemodynamic variables were measured using right-heart catheterization. Neurocognitive performance was evaluated for 5 days after cardiopulmonary resuscitation using a neurologic deficit score before the brains were harvested for histopathological analysis. All animals survived the observation period in the mild therapeutic hypothermia 1 xenon group while one animal in each of the other two groups died. Mild therapeutic hypothermia 1 xenon preserved cardiac output during the induction of mild therapeutic hypothermia significantly better than did mild therapeutic hypothermia alone (4.6 6 0.6 L/min vs. 3.2 6 1.6 L/min, p # .05). Both treatment groups showed significantly fewer necrotic lesions in the cerebral cortex, caudate nucleus, putamen, and in hippocampal sectors CA1 and CA3/4. However, only the combination of mild therapeutic hypothermia and xenon resulted in reduced astrogliosis in the CA1 sector and diminished microgliosis and perivascular inflammation in the putamen. Clinically, only the mild therapeutic hypothermia 1 xenon-treated animals showed significantly improved neurologic deficit scores over time (day 1 = 59.0 6 27.0 vs. day 5 = 4.0 6 5.5, p o .05) as well as in comparison to the untreated controls on days 3 through 5 after cardiopulmonary resuscitation. CONCLUSIONS: These results demonstrate that even a short exposure to xenon during induction of mild therapeutic hypothermia results in significant improvements in functional recovery and ameliorated myocardial dysfunction. PMID- 22425823 TI - Prospective evaluation of sedation-related adverse events in pediatric patients ventilated for acute respiratory failure. AB - OBJECTIVES: Sedation-related adverse events in critically ill pediatric patients lack reproducible operational definitions and reference standards. Understanding these adverse events is essential to improving the quality of patient care and for developing prevention strategies in critically ill children. The purpose of this study was to test operational definitions and estimate the rate and site-to site heterogeneity of sedation-related adverse events. DESIGN: Prospective cohort study. SETTING: Twenty-two pediatric intensive care units in the United States enrolling baseline patients into a prerandomization phase of a multicenter trial on sedation management. PATIENTS: Pediatric patients intubated and mechanically ventilated for acute respiratory failure. DATA EXTRACTION: Analysis of adverse event data using consistent operational definitions from a Web-based data management system. MEASUREMENTS AND MAIN RESULTS: There were 594 sedation-related adverse events reported in 308 subjects, for a rate of 1.9 adverse events per subject and 16.6 adverse events per 100 pediatric intensive care unit days. Fifty four percent of subjects had at least one adverse event. Seven (1%) adverse events were classified as severe, 347 (58%) as moderate, and 240 (40%) as mild. Agitation (30% of subjects, 41% of events) and pain (27% of subjects, 29% of events) were the most frequently reported events. Eight percent of subjects (n = 24) experienced 54 episodes of clinically significant iatrogenic withdrawal. Unplanned endotracheal tube extubation occurred at a rate of 0.82 per 100 ventilator days, and 32 subjects experienced postextubation stridor. Adverse events with moderate intraclass correlation coefficients included: Inadequate sedation management (intraclass correlation coefficient = 0.130), clinically significant iatrogenic withdrawal (intraclass correlation coefficient = 0.088), inadequate pain management (intraclass correlation coefficient = 0.080), and postextubation stridor (intraclass correlation coefficient = 0.078). CONCLUSIONS: Operational definitions for sedation-related adverse events were consistently applied across multiple pediatric intensive care units. Adverse event rates were different from what has been previously reported in single-center studies. Many adverse events have moderate intraclass correlation coefficients, signaling site to-site heterogeneity. PMID- 22425824 TI - Pseudomonas aeruginosa is not just in the intensive care unit any more: implications for empirical therapy. AB - OBJECTIVE: To improve empirical therapy for Pseudomonas aeruginosa using susceptibility surveillance by unit type (intensive care unit vs. nonintensive care unit) and to optimize antibacterial dosing using pharmacodynamic profiling. DESIGN: Prospective multicentered surveillance study. SETTING: Thirteen U.S. hospitals. SUBJECTS: Seven hundred thirty-six nonduplicate, nonurine P. aeruginosa isolates collected from first quarter, 2009, to second quarter, 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Isolate minimum inhibitory concentrations (MICs) to ten antimicrobials (three carbapenems-doripenem, imipenem and meropenem-plus three other beta-lactams, two fluoroquinolones, and two aminoglycosides) were determined by broth microdilution. Wilcoxon rank sums compared MIC distributions by unit type; chi-square tests compared agents and antibiotic classes. Cumulative fraction of response predicted likelihood of pharmacodynamic target attainment for antimicrobial dosing regimens vs. observed MIC distributions. Nonintensive care units contributed 65% of isolates with identifiable locations (n = 614). Carbapenem class nonsusceptibility nonsusceptible to 1 or more agent) differed by location (35% intensive care unit, 27% nonintensive care unit, p = .03); no other classes differed. Multidrug resistance (nonsusceptible to one or more drug in each of all four classes) was 12% intensive care unit and 5% in nonintensive care units (p < .01). Carbapenem MIC profile in intensive care units was (agent, MIC50, MIC90, percent susceptibility): Doripenem, 1, 8, 69%; imipenem, 2, 16, 67%; and meropenem, 1, 32, 70%; and by nonintensive care units: Doripenem, 0.5%, 8%, 78%; imipenem, 1, 16, 75%; and meropenem, 1, 16, 82%. MIC distributions differed by unit type only for imipenem (p < .01). The remaining nine agents were not different. Standard carbapenem regimens resulted in cumulative fraction of response (regimen, intensive care unit, nonintensive care unit): Doripenem at 500 mg every 8 hrs 1 hr infusion, 73%, 79%; imipenem at 500 mg every 6 hrs 0.5-hr infusion, 62%, 69%; meropenem at 500 mg every 6 hrs 0.5-hr infusion, 67%, 76%. More aggressive doses and prolonged infusion improved cumulative fraction of response: Doripenem at 1000 mg every 8 hrs 4-hr infusion, 92%, 97%; imipenem at 1000 mg every 8 h 3-h infusion, 77%, 83%; meropenem at 2000 mg every 8 hrs 3-hr infusion, 87%, 94%. CONCLUSIONS: Although multidrug-resistant and nonsusceptible carbapenem phenotypes were more common in intensive care units, the prevalence of P. aeruginosa among initial cultures of systemic isolates taken elsewhere was high (65%). Unit-specific antibiograms could benefit empirical therapy decisions; consideration of carbapenem, dose, and infusion time may enhance outcomes for P. aeruginosa infection. PMID- 22425825 TI - Intensive care unit environments and the fecal patina: a simple problem? PMID- 22425826 TI - Small to large, lots to some, many to few: in silico navigation of the Translational Dilemma. PMID- 22425827 TI - Statins for sepsis: has their time come? PMID- 22425828 TI - Does U.S. health care need a national institute of critical care? PMID- 22425829 TI - Within the black box: exploring how intensivists resolve conflict at the end-of life. PMID- 22425830 TI - Rehabilitation of mind and body after intensive care unit discharge: a step closer to recovery. PMID- 22425831 TI - Can the number of intensive care unit beds required be accurately predicted? PMID- 22425832 TI - Measuring intensive care unit palliative care: have we set the bar too low? PMID- 22425833 TI - Grading inhalation injury by admission bronchoscopy. PMID- 22425834 TI - Early mobilization of the critically ill patients: towards standardization. PMID- 22425835 TI - Hemorrhagic shock resuscitation: a critical issue on the development of posttraumatic multiple organ failure. PMID- 22425836 TI - The biochemical milieu after cardiac arrest: moving toward tailored postresuscitation care. PMID- 22425837 TI - Long-term mechanical ventilation: costs, consequences, and accountability for access disparities. PMID- 22425838 TI - Coma emergence and recovery: the new and the old. PMID- 22425839 TI - Pseudomonas aeruginosa bacteremia: targeting virulent phenotypes? PMID- 22425840 TI - Forced recognition of acute kidney injury. PMID- 22425841 TI - Predictions of death compete with earthquake and tsunami predictions. PMID- 22425842 TI - Hemodynamic support: focus on monitoring tools or treatments? PMID- 22425843 TI - Thinking outside the (cardiac output) box. PMID- 22425844 TI - Chest compression quality--push hard, push fast, but how deep and how fast? PMID- 22425845 TI - Integration and implementation of palliative care in the surgical intensive care unit. PMID- 22425846 TI - Blood pressure monitoring in the critically ill patient: a place for noninvasive assessment? PMID- 22425847 TI - The blood-brain barrier in sepsis: are intravenous immunoglobulins preventive? PMID- 22425848 TI - A little hypothermia goes a long way. PMID- 22425849 TI - Disseminated intravascular coagulation in heat stroke: a hot topic. PMID- 22425850 TI - Does cyclosporine A protect the heart in perinatal asphyxia? PMID- 22425851 TI - Mesenchymal stromal cells: cautious optimism for their potential role in the treatment of acute lung injury. PMID- 22425852 TI - Diaphragm activity during mechanical ventilation: a narrow therapeutic margin. PMID- 22425853 TI - One step back for adenosine triphosphate-sensitive potassium channel inhibition in sepsis but progress in the quest for the optimum vasopressor. PMID- 22425854 TI - Pharmacological effects of inhaled methane: plausible or not? PMID- 22425855 TI - Therapeutic strategies against ischemia-reperfusion injury: stem cell therapy and beyond. PMID- 22425856 TI - Hydrogen therapy: a future option in critical care? PMID- 22425857 TI - Moving beyond moderate therapeutic hypothermia for cardiac arrest. PMID- 22425858 TI - Atypical herpes simplex encephalitis after total cranial irradiation: casting a wider net? PMID- 22425859 TI - Noninvasive measurements of oxygenation defect in children: beyond research toward clinical prevention and therapeutics. PMID- 22425860 TI - The road to assessing the intensive care system and sedation-related adverse events: the journey continues. PMID- 22425861 TI - Dosing strategies to improve the treatment of Pseudomonas aeruginosa. PMID- 22425862 TI - Another beneficial effect of rituximab on refractory and relapsing thrombotic thrombocytopenic purpura: the role of interleukin-12 suppression? PMID- 22425863 TI - Can extravascular lung water predict progression to acute lung injury in patients at increased risk? Still an unanswered question. PMID- 22425864 TI - Importance of events per independent variable in logistic regression analysis. PMID- 22425866 TI - "Brain death" is a useful fiction. PMID- 22425868 TI - Modern medicine is a good goal to seek. PMID- 22425870 TI - Computer-assisted decision making in burns fluid resuscitation. PMID- 22425872 TI - Treatment of oropharyngeal squamous cell carcinoma with IMRT: patterns of failure after concurrent chemoradiotherapy and sequential therapy. AB - BACKGROUND: The optimal management of oropharyngeal squamous cell carcinoma (OPSCC) is controversial. Modern radiotherapy typically employs intensity modulated radiation therapy (IMRT), and herein, we report the Dana-Farber Cancer Institute (DFCI) experience with IMRT-based treatment of OPSCC. DESIGN: Retrospective study of all patients treated at DFCI for OPSCC with definitive or adjuvant IMRT between 8/04 and 8/09. The primary end point was overall survival (OS); secondary end points were locoregional control (LRC) and freedom from distant metastases (FFDM). Propensity score matching was used to create concurrent chemoradiotherapy (CCRT) and sequential therapy (ST) cohorts equally balanced for patient and disease characteristics. RESULTS: One hundred and sixty three patients were included with 75% presenting with stage IV disease. Fifty-six patients (34%) were treated with ST. The three-year actuarial OS, LRC, and FFDM rates for the entire cohort/ST subset were 86%/89%, 86%/87%, and 88%/93%, respectively. There were no differences in OS, LRC, or FFDM between CCRT and ST in the propensity-matched cohort. CONCLUSIONS: IMRT was associated with excellent OS, LRC, and FFDM. Although the results following ST were superb, there was no obvious benefit to ST after adjustment for selection bias. We recommend that ST be reserved for medically fit patients with a high risk of distant metastases. PMID- 22425873 TI - Reciprocal inhibiting interactive mechanism between the estrogen receptor and aryl hydrocarbon receptor signaling pathways in goldfish (Carassius auratus) exposed to 17beta-estradiol and benzo[a]pyrene. AB - In the aquatic environment, both the estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) responses are established biomarkers for assessing exposure to pollutants. These receptor responses can also be affected by the presence of other classes of pollutants and may result in misinterpretation of existing pollution. In this study, we investigated the interaction between ER-vitellogenin (VTG) and AhR-cytochrome P450 1A (CYP1A) signaling pathways in goldfish (Carassius auratus) after 10 days exposure to pollutants. 17beta-Estradiol (E(2)) and benzo[a]pyrene (BaP) were selected as the ER and AhR agonists, respectively. The messenger RNA (mRNA) expression of ER-VTG and AhR-CYP1A in liver was determined using quantitative real-time polymerase chain reaction (QRT-PCR). VTG, endogenous E(2) and 7-ethoxyresorufin-O-deethylase (EROD) were also studied. Exposure to E(2) and BaP alone significantly induced the gene expression of ERalpha-VTG and AhR2-CYP1A, respectively. Moreover, the obvious expression of related proteins was also observed. However, these inductions were significantly reduced after combined exposure to E(2) and lower concentrations of BaP (20 and 50 MUg/L), indicative of a reciprocal inhibiting ER-AhR interaction. However, high concentrations (100 MUg/L) of BaP did not affect the E(2)-induced gene expression. Changes in VTG protein were in accordance with the expression of VTG mRNA, and more VTG protein was observed in liver than in serum. The induced endogenous E(2) levels were suppressed by the presence of BaP. While the gene expression of CYP1A showed a concentration-dependent increase, EROD induction exhibited a bell-shaped concentration-response curve. Taken together, these results demonstrate a reciprocal inhibiting mode of ER-AhR interactions and may lead to a possible underestimation of actual exposure. PMID- 22425874 TI - Climate variability and change or multiple stressors? Farmer perceptions regarding threats to livelihoods in Zimbabwe and Zambia. AB - Climate variability is set to increase, characterised by extreme conditions in Africa. Southern Africa will likely get drier and experience more extreme weather conditions, particularly droughts and floods. However, while climate risks are acknowledged to be a serious threat to smallholder farmers' livelihoods, these risks do not exist in isolation, but rather, compound a multiplicity of stressors. It was important for this study to understand farmer perceptions regarding the role of climate risks within a complex and multifarious set of risks to farmers' livelihoods. This study used both qualitative and quantitative methods to investigate farmers' perceptions regarding threats to livelihoods in southern Zambia and south-western Zimbabwe. While farmers report changes in local climatic conditions consistent with climate variability, there is a problem in assigning contribution of climate variability and other factors to observed negative impacts on the agricultural and socio-economic system. Furthermore, while there is a multiplicity of stressors that confront farmers, climate variability remains the most critical and exacerbate livelihood insecurity for those farmers with higher levels of vulnerability to these stressors. PMID- 22425875 TI - Distribution and temporal evolution of pharmaceutically active compounds alongside sewage sludge treatment. Risk assessment of sludge application onto soils. AB - In this work, the distribution and the ecotoxicological risk of sixteen pharmaceutically active compounds belonging to seven different therapeutic groups (five anti-inflammatory drugs, two antibiotics, an anti-epileptic drug, a beta blocker, a nervous stimulant, four estrogens and two lipid regulators) have been studied in sewage sludge from wastewater treatment plants. Only three of the sixteen pharmaceutical compounds were never detected in sludge while eleven of the studied pharmaceuticals were still detected in compost. Mean concentration levels of the pharmaceutically active compounds ranged between 24.9 and 4105 MUg/kg dm, 14.5-944 MUg/kg dm, 3.29-636 MUg/kg dm and 9.19-974 MUg/kg dm in primary, secondary, digested sludge and compost, respectively. An increase in the concentration levels of most of the pharmaceuticals was observed from summer to winter (mean values in primary and secondary sludge were 304 and 85.1 MUg/kg dm in summer and 435 and 175 MUg/kg dm in winter, respectively) probably due to an increase of their consumption during the coldest season and a reduction of the microbial activity under colder temperatures. The highest ecotoxicological risk, in digested sludge and compost, was due to the estrogenic compound 17beta estradiol. The ecotoxicological risk significantly decreased after the application of digested sludge or compost to the soils (risk quotient values ranged between 0.04 and 252 in digested sludge and 0.002-37.8 in compost and decreased to 8.10(-4)-1.92 in digested sludge-amended soil and 1.10(-4)-0.23 in compost-amended soil). PMID- 22425876 TI - Restoration of eroded soil in the Sonoran Desert with native leguminous trees using plant growth-promoting microorganisms and limited amounts of compost and water. AB - Restoration of highly eroded desert land was attempted in the southern Sonoran Desert that had lost its natural capacity for self-revegetation. In six field experiments, the fields were planted with three native leguminous trees: mesquite amargo Prosopis articulata, and yellow and blue palo verde Parkinsonia microphylla and Parkinsonia florida. Restoration included inoculation with two of plant growth-promoting bacteria (PGPB; Azospirillum brasilense and Bacillus pumilus), native arbuscular mycorrhizal (AM) fungi, and small quantities of compost. Irrigation was applied, when necessary, to reach a rainy year (300 mm) of the area. The plots were maintained for 61 months. Survival of the trees was marginally affected by all supplements after 30 months, in the range of 60-90%. This variation depended on the plant species, where all young trees were established after 3 months. Plant density was a crucial variable and, in general, low plant density enhanced survival. High planting density was detrimental. Survival significantly declined in trees 61 months after planting. No general response of the trees to plant growth-promoting microorganisms and compost was found. Mesquite amargo and yellow palo verde responded well (height, number of branches, and diameter of the main stem) to inoculation with PGPB, AM fungi, and compost supplementation after three months of application. Fewer positive effects were recorded after 30 months. Blue palo verde did not respond to most treatments and had the lowest survival. Specific plant growth parameters were affected to varying degrees to inoculations or amendments, primarily depending on the tree species. Some combinations of tree/inoculant/amendment resulted in small negative effects or no response when measured after extended periods of time. Using native leguminous trees, this study demonstrated that restoration of severely eroded desert lands was possible. PMID- 22425877 TI - The role of sediment-transport evaluations for development of modeled instream flows: policy and approach in Texas. AB - Instream-flow scientists embrace streamflow as the master variable driving aquatic and riparian ecosystems, and that natural flow variability is imperative for river conservation and restoration efforts. Sediment transport, which is critical for maintenance of physical habitats in rivers and floodplains, has received less direct attention from instream-flow practitioners. This article serves to highlight the roles of sediment-transport evaluations in modifying or verifying instream-flow prescriptions based on hydrology alone. Two examples of sediment-transport evaluations are discussed in relation to the Texas Senate Bill 3 Environmental Flows allocation process, a mandate to "develop environmental flow analyses and a recommended flow regime" that "maintain(s) the viability of the state's streams, rivers, and bay and estuary systems" using "reasonably available science". The first example provides an evaluation of effective discharge of suspended-sediment load of the lower Brazos River. The magnitude and frequency of effective discharge occurs between typical high-flow pulses and overbank flows, indicating that hydrologic and physical processes are not optimally coupled in some flow-regime models. The second example utilizes the Hydrology-Based Environmental Flow Regime (HEFR) model to prescribe instream flows for the lower Sabine River, and compares modeled bed-material loads for observed and HEFR-prescribed flow regimes. Results indicate that annual water and sediment yields are greatly reduced for the modeled flow regime. It should be noted, however, that different input variables to the HEFR model would have resulted in different computations of water and sediment yields, reinforcing that instream-flow practitioners should exercise great caution when applying rule-of thumb procedures to generate flow prescriptions. PMID- 22425878 TI - Absorption and translocation of copper, zinc and chromium by Sesbania virgata. AB - Heavy metals (HM) incorporated to ecosystems as a mixture could interact and generate contamination, which might be mitigated through phytoremediation. The heavy metal tolerance of native species of Sesbania from the Argentinean Pampas is poorly documented. The objective of this work was to evaluate the effect of interactions between copper, zinc and chromium, in binary form, on Sesbania virgata biomass, absorption and translocation. The HM transfer from a contaminated soil to plants and into plant tissues are discussed in terms of the Bioconcentration Factor (BCF) and the Transfer Factor (TF). In a pot experiment, HM were added either individually or in binary mixture solutions of Cu, Zn and Cr, in low or high doses. In all treatments, the main accumulation of HM appeared in plant roots, and Zn is more removed from soils by S. virgata (BCF average in roots Zn > Cr > Cu). In the binary mixture of Cu and Zn, Sesbania plants absorbed the highest concentrations of these metals. In contrast, Cr was more absorbed in the individual treatments. While the co-presence of metals resulted in a greater reduction in S. virgata biomass than the presence of a single metal, S. virgata tolerated and stabilized high concentrations of Cu, Zn and Cr. In view of this tolerance, S. virgata is excellent specie to be used for heavy metals phytostabilization in contaminated soils. PMID- 22425879 TI - Emergy measures of carrying capacity and sustainability of a target region for an ecological restoration programme: a case study in Loess Hilly Region, China. AB - Evaluating the sustainability of a target region for an ecological restoration programme is challenging because it involves different aspects of human society and environment as well as multiple disciplines. Carrying capacity provides a useful measure of the sustainability of a given region where an ecological restoration programme is implemented. In this article, the Yangou catchment, a geomorphic unit, was used as a case study in the Loess Hilly Region of China, where emergy synthesis was used to measure the environmental resources base. The specific standard of living in terms of emergy was employed to calculate carrying capacity over the period 1998-2005 and to assess the sustainability of the Yangou catchment where an ecological restoration programme was carried out. The results of the evaluation indicated that after implementing the ecological restoration programme, there was some improvement in the environmental aspects of the Yangou catchment during the study period, suggesting that the ecological restoration programme alleviated ecological degradation. However, several emergy-based indices and the support areas also illustrated that the ecological restoration programme was not successful enough in terms of preservation and utilisation of environmental resources to enhance sustainability. This indicates that further actions are necessary on conserving environmental resources, improving the emergy input structure for agricultural production and in lifestyle changes for the local people in living in the Yangou catchment. PMID- 22425880 TI - Decision criteria for the selection of wet oxidation and conventional biological treatment. AB - The suitability of wet oxidation or biological treatments for the degradation of industrial wastewaters is here discussed. Advantages of these operations, either singly or in combination, are discussed on the basis of previous experimental results from laboratory and industry. Decision diagrams for the selection of conventional biological treatment, wet oxidation or a combination of both techniques are suggested according to the type of pollutant, its concentration and the wastewater flow rate. PMID- 22425881 TI - A model of the effect of analytical bias on clinical classification using the example of brain natriuretic peptide measurement. PMID- 22425882 TI - Use of RapidChek(r) SELECTTM Salmonella to detect shedding of live attenuated Salmonella enterica serovar Typhi vaccine strains. AB - Identification of individuals shedding Salmonella enterica serovar Typhi in stool is imperative during clinical trial safety evaluations. Recovery of live attenuated S. Typhi vaccine strains can be difficult because the mutations necessary for safety in humans often compromise survival in stringent selective enrichment media. RapidChek(r) SELECTTM Salmonella is a highly sensitive detection method for S. enterica species which utilizes a bacteriophage cocktail designed to reduce the growth of competitor microbes in mildly selective enrichment medium. Detection of Salmonella is enhanced by means of a Salmonella specific antibody strip targeted to lipopolysaccharide. The RapidChek(r) SELECTTM Salmonella method was compared to conventional enrichment and plating methods to determine the most sensitive method for detecting attenuated S. Typhi strains in human stool samples. Although traditional enrichment strategies were more sensitive to the presence of wild-type S. Typhi, RapidChek(r) SELECTTM Salmonella was superior at detecting attenuated strains of S. Typhi. Strains containing a wide variety of attenuating mutations were detected with equal sensitivity as the wild type by RapidChek(r) SELECTTM Salmonella. The presence of Vi capsule or mutations which affected O-antigen synthesis (Deltapmi, DeltagalE) did not decrease the sensitivity of the RapidChek(r) SELECTTM Salmonella assay. PMID- 22425883 TI - Responsiveness of the OARSI-OMERACT osteoarthritis pain and function measures. AB - OBJECTIVE: To assess the responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) measure, Hip Disability and Osteoarthritis Outcome Score Physical Function Short Form (HOOS-PS), and the Knee Disability and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS) in a pharmacological trial. METHODS: Data were obtained from a randomized double-blind trial comparing naproxcinod with naproxen and ibuprofen in individuals with hip or knee osteoarthritis (OA) (NCT00662896). Participants completed the ICOAP, HOOS PS/KOOS-PS, and Western Ontario and McMaster Universities OA Index (WOMAC) Likert version 3.0 before and 13 weeks after treatment. In hip and knee OA participants separately, the mean pre-post treatment change in scores, effect size (ES) and standardized response mean (SRM) were determined for each measure by treatment arm, and for all arms combined. RESULTS: Of 349 trial participants, 156 with knee OA and 48 with hip OA completed all measures at both time-points and were included (mean age 61 years; two-thirds female). Although there was both within treatment and between treatment variability in response, among knee OA participants, ICOAP intermittent, constant, and total scores and KOOS-PS scores showed, on average, moderate effects, with ESs ranging from 0.46 to 0.54 and SRMs from 0.49 to 0.56. Similar changes were seen for the WOMAC pain and function subscales (0.58 and 0.58, respectively). In those with hip OA, no significant improvement in symptoms was seen for any measure. CONCLUSION: Responsiveness to pharmaceutical intervention was demonstrated for ICOAP and KOOS-PS among participants with knee OA. Absence of treatment response precluded assessment of responsiveness in hip OA. PMID- 22425884 TI - MicroRNA-337 is associated with chondrogenesis through regulating TGFBR2 expression. AB - OBJECTIVE: MicroRNAs (miRNAs) have been implicated in regulating diverse cellular pathways and involved in development and inflammation. This study aimed to examine six miRNAs expression during the cartilage development and identify the key miRNA which is associated with chondrogenesis. METHODS: The expression of six miRNAs in cartilage tissue during development was screened by real-time quantitative polymerase chain reaction (RT-qPCR). Rat models of bone matrix gelatin induced endochondral ossification, collagen-induced arthritis and pristane-induced arthritis were established to examine whether miR-337 is involved in chondrogenesis. Furthermore, the regulation of transforming growth factor-b type II receptor (TGFBR2) expression by miR-337 was determined with the luciferase reporter gene assay and Western blot. The expression of some specific genes relevant to cartilage tissue was tested by RT-qPCR after miR-337 mimic or inhibitor transfection. RESULTS: MiR-337 expression was significantly down regulated and almost disappeared in the maturation phases of endochondral ossification. The results of histology and RT-qPCR from three rat models showed that miR-337 is directly bound up with chondrogenesis. Furthermore, the results from the luciferase reporter gene assay and Western blot indicated that miR-337 regulated TGFBR2 expression. Our study also found that the enhancement of miR-337 may modulate the expression of cartilage-specific genes such as AGC1 in C-28/I2 chondrocytes. CONCLUSION: We proved that miRNA-337 is associated with chondrogenesis through regulating TGFBR2 expression, and miRNA-337 can also influence cartilage-specific gene expression in chondrocytes. These findings may provide an important clue for further research in the arthritis pathogenesis and suggest a new remedy for arthritis treatment. PMID- 22425885 TI - Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles. AB - Gemcitabine hydrochloride (HCl) is approved for the treatment of a wide spectrum of solid tumors. However, the rapid development of resistance often makes gemcitabine less efficacious. In the present study, we synthesized several novel lipophilic monophosphorylated gemcitabine derivatives, incorporated them into solid lipid nanoparticles, and then evaluated their ability to overcome major known gemcitabine resistance mechanisms by evaluating their in vitro cytotoxicities in cancer cells that are deficient in deoxycytidine kinase (dCK), deficient in human equilibrative nucleoside transporter (hENT1), over-expressing ribonucleotide reductase M1 subunit (RRM1), or over-expressing RRM2. In dCK deficient cells, the monophosphorylated gemcitabine derivatives and their nanoparticles were up to 86-fold more cytotoxic than gemcitabine HCl. The majority of the gemcitabine derivatives and their nanoparticles were more cytotoxic than gemcitabine HCl in cells that over-expressing RRM1 or RRM2, and the gemcitabine derivatives in nanoparticles were also resistant to deamination by deoxycytidine deaminase. The gemcitabine derivatives (in nanoparticles) hold a great potential in overcoming gemcitabine resistance. PMID- 22425886 TI - Comparative analysis of perioperative differences between hybrid versus pedicle screw instrumentation in adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective review of patients with adolescent idiopathic scoliosis (AIS). OBJECTIVE: The objective of the study was to compare perioperative parameters and outcomes between pedicle screw and hybrid instrumentation for the treatment of AIS. SUMMARY OF BACKGROUND DATA: Pedicle screws have been shown to allow for better correction and fewer revisions than hybrid systems. However, no study has compared perioperative parameters and their effects on patient morbidity between these 2 types of instrumentation. METHODS: Fifty-six pediatric patients with AIS were included in the study. Twenty-seven patients were treated with hybrid instrumentation and 29 patients were treated with all pedicle screw (APS) instrumentation. Intraoperative and perioperative measures were compared. RESULTS: The mean preoperative major Cobb angle was 58.7 degrees in the hybrid group and 54.5 degrees in the APS group (P = 0.222). Patients in the hybrid group required more time in the intensive care unit (2.0 vs. 1.1 d, P = 0.041), more time to initial mobilization (5.1 vs. 2.1 d, P < 0.001), and more days using patient-controlled analgesia (5.7 vs. 4.4 d, P = 0.020). The hybrid group averaged less estimated blood loss than the APS group (619.6 vs. 947.4 mL, P = 0.011). There was no difference in surgical time (P = 0.183) or length of stay (P = 0.072) between the groups. Thoracolumbosacral orthoses were used in 81.5% of patients in the hybrid group, but in no patients in the APS group (P < 0.001). Postoperative complications occurred in 37.0% of patients in the hybrid group and 17.2% of patients in the APS group (P = 0.095). CONCLUSIONS: This study demonstrates several advantages of pedicle screw constructs over hybrid constructs in the surgical treatment of AIS. The benefits of pedicle screw systems extend directly to the patient and can lower the overall cost of treatment. PMID- 22425887 TI - Management of cerebrospinal fluid leakage after anterior decompression for ossification of posterior longitudinal ligament in the thoracic spine: the utilization of a volume-controlled pseudomeningocele. AB - STUDY DESIGN: Retrospective review OBJECTIVE: To determine the efficacy of management of cerebrospinal fluid (CSF) leakage after the anterior thoracic approach. SUMMARY OF BACKGROUND DATA: CSF leakage after incidental durotomy commonly occurs after anterior thoracic ossification of posterior longitudinal ligament (OPLL) surgery. Pseudomeningocele will invariably form under such circumstances. Among them, uncontrolled CSF leakage with a fistulous condition is problematic. As a solution, we have managed these durotomies with chest drains alone without any CSF drainage by the concept of a "volume-controlled pseudomeningocele." METHODS: Between 2001 and 2009, CSF leakage occurred in 26 patients (37.7%) of the total 69 patients who underwent anterior decompression for thoracic OPLL. In the initial 11 cases, subarachnoid drainage was utilized as an augmentive measure in combination with chest tube drainage in the postoperative period (group A). In the subsequent 15 cases, the durotomy was managed in a similar manner but in the absence of any subarachnoid drainage (group B). Various parameters such as the duration of postoperative hospital stay, clinical outcome score, drainage output, resolution of CSF leakage, complications, and additional surgery performed were analyzed and compared between the 2 groups. A resolution of the CSF leakage grading system was also proposed for the residual pseudomeningocele that formed in each group. RESULTS: There were statistically no significant differences in the outcome parameters between the 2 groups and also in patients with grade I or grade II residual pseudomeningocele of the new grading system. Two complications occurred in group A. No reexploration for persistent CSF leakage was required in both groups. CONCLUSIONS: CSF leakage managed with controlled chest tube drainage can produce a comparable result with those with additional subarachnoid drainage when watertight dural repair is impossible. The concept of controlled pseudomeningocele may be a useful and practical technique for the treatment of CSF leakage after anterior thoracic OPLL surgery. PMID- 22425888 TI - Comparative in vitro biomechanical analysis of a novel posterior cervical fixation technique versus conventional posterior-based constructs. AB - STUDY DESIGN: Comparative in vitro, cadaveric biomechanical study. OBJECTIVE: To compare the kinematic response of a new posterior cervical midline surgical technique versus that of conventional fixation techniques. SUMMARY OF BACKGROUND DATA: A new method was designed using alternating bilateral intralaminar screws connected with a single midline rod. This technique provides the theoretical benefits of less operative dissection and reduced implant cost, but the acute flexibility properties remain unknown. Using an in vitro cadaveric model, the study objective was to define the operative level(s) changes in multidirectional flexibility after posterior destabilization/reconstruction from C3 to C6. METHODS: A 6 degree of freedom spine stimulator was used to test flexibility in 7 human cadaveric specimens. Flexion-extension, lateral bending, and axial rotation were tested in the intact condition, followed by destabilization by a simulated posterior column injury from C3 to C6. Specimens were then reconstructed from C3 to C6 and tested in the following sequence: sublaminar hook rod (SH), lateral mass screw rod (LMR), midline laminectomy from C3 to C6 with LMR (MLR), and midline posterior fixation from C3 to C6 (SMF). Range of motion (ROM) and neutral zone were quantified and analyzed. RESULTS: Significant increases in ROM and neutral zone at C3 to C6 were found under all loading conditions for the destabilized condition and intact spine versus all other treatments (P<0.05). The conventional treatments: SH, LMR, and MLR resulted in significantly less ROM than the proposed SMF in flexion-extension and lateral bending (P<0.05). Axial rotation provided similar results; however, no differences were observed between the SH and SMF (P>0.05). Notably, LMR and MLR provided significantly more stability than SH in axial rotation (P<0.05). CONCLUSIONS: Data produced suggest that the new, midline rod fixation approach provides less biomechanical stability than conventional posterior cervical reconstruction techniques. In addition, the high incidence of laminar fracture during screw placement and close proximity of the screw trajectory and polyaxial heads to the dura suggest a practical limitation as well. PMID- 22425889 TI - Treatment of complete fracture-dislocation of thoracolumbar spine. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: We present our surgical experience with 11 patients who had complete fracture-dislocation of thoracolumbar spine. SUMMARY OF BACKGROUND DATA: Complete fracture-dislocation of thoracolumbar spine is one of the most severe spine traumas and usually results in neurological dysfunction with spine deformity. Treatment of such cases is rarely described in the literature. METHODS: We treated 11 patients with complete fracture-dislocation of the thoracolumbar spine surgically using a posterior approach. Reduction and stabilization was achieved by means of pedicle screws with rods at the help of intraoperative traction. Dura tear was repaired by autologous fat graft. Armpit-pelvic traction was applied to the patient who could not receive operation in time. RESULTS: Deformity correction was completely achieved in all the fracture-dislocations that were subjected to surgery within 3 weeks and was partly achieved in those subjected to surgery after 3 weeks. Cerebrospinal fluid leak were controlled well in 7 patients. Armpit-pelvic traction could partly ameliorate spine column shortening. Two patients with incomplete neurological deficit got their neurological function improved after surgery. CONCLUSIONS: Although difficult, satisfactory reduction of complete lumbar fracture-dislocation can be achieved through pedicle instrumentation. Intraoperative traction is necessary for the reduction procedure. Preoperative duration should be not >3 weeks. For the patient who cannot receive spine surgery in a few days after injury, preoperative traction should be applied. Covering dura sac by autologous fat graft is recommended for all the patients. PMID- 22425890 TI - Cervical laminectomy width and spinal cord drift are risk factors for postoperative C5 palsy. AB - BACKGROUND: Cervical laminectomy and fusion (CLF) is a treatment option for multilevel cervical spondylotic myelopathy. Postoperative C5 nerve palsy is a possible complication of CLF. It has been suggested that C5 nerve palsy may be due to posterior drift of the spinal cord related to a wide laminectomy trough. PURPOSE: To test the hypothesis that excessive spinal cord drift into a wide laminectomy trough is associated with C5 palsy. STUDY DESIGN: Retrospective case control study. PATIENT SAMPLE: Seventeen patients with C5 palsy, 8 patients as control group. OUTCOME MEASURES: Spinal cord positional measurements on magnetic resonance imaging (MRI). METHODS: All patients who underwent elective CLF for cervical spondylotic myelopathy or ossified posterior longitudinal ligament using posterior instrumentation between 2004 and 2008 were included. Patients who underwent CLF for trauma, infection, or tumors were excluded. Clinical and radiographic outcomes were assessed by chart review (minimum of 1 y follow-up). Patients who developed a new postoperative C5 nerve palsy underwent repeat MRI. The control group also underwent CLF, did not develop a neurological deficit, and received a postoperative MRI for evaluation of possible infection. MRI measurements included the width of the laminectomy trough, the distance from the posterior vertebral body or disk to the anterior spinal cord, the width of the spinal cord herniated into the laminectomy defect, and C2-7 sagittal alignment. Preoperative radiographic measurements included preoperative vertebral body diameter, spinal canal diameter, and sagittal vertical offset. RESULTS: There were seventeen patients with C5 nerve root palsy and 8 patients without C5 nerve root palsy. There were no baseline differences in fusion levels, instrumentation used, patient age, or sex. MRI measurements revealed an increase in mean postoperative cord drift in patients with C5 palsy at C3 (4.2 vs. 2.2 mm, P=0.002), C4 (4.6 vs. 2.8 mm, P=0.056), C5 (5.1 vs. 2.4 mm, P=0.011), and C6 (5.2 vs. 2.4 mm, P=0.003). There was a significant increase in C5 laminectomy trough width among patients with postoperative C5 palsy (17.9 vs. 15.2 mm, P=0.032), but there was no difference in sagittal alignment. CONCLUSIONS: A wider laminectomy at C5 was associated with an increased risk of postoperative C5 palsy. Increased preoperative spinal canal diameter is also associated with increased risk of C5 palsy. In addition, patients who experienced C5 nerve palsy had a significantly greater posterior spinal cord drift. Strategies to reduce postoperative laminectomy trough width and spinal cord drift may reduce the risk of postoperative C5 palsy. PMID- 22425891 TI - Optimal trajectory for the occipital condyle screw. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To understand what may constitute an optimal trajectory for an occipital condyle (OC) screw. SUMMARY OF BACKGROUND DATA: OC screws are an alternative to standard occipital plates as a cephalad fixation point in occipitocervical fusion. An optimal trajectory for placement of OC screws has not been described. METHODS: We conducted a computed tomography-based study of 340 human occipital condyls. All computed tomographies were negative for traumatic, degenerative, and neoplastic pathology. On the basis of the current literature, linear measurements of distances were made based on a constant entry point. Medial angulations of 10, 20, and 25 degrees relative to the sagittal midline were used. In addition, 10-, 5-degree cranial, 10- and 30 degree caudal angulations were studied to evaluate the incidence of hypoglossal canal and atlantooccipital joint compromise. RESULTS: Average distances were 17.1+/-2.8, 20.4+/-2.8, and 22.2+/-2.9 for 10, 20, and 25 degrees of medial angulation, respectively. Right-sided and left-sided measurements for each category were not significantly different. However, the difference in the measured distances between 10 versus 20 degrees, 10 versus 25 degrees, and 20 versus 25 degrees was all significantly different (P<0.01). Hypoglossal canal compromise incidence was 0% and 7.1% for 5- and 10-degree cranial angulation, respectively. Atlantooccipital joint compromise incidence was 21.8% and 99.1% for 10- and 30-degree caudal angulation, respectively. CONCLUSIONS: The condylar entry point should be medial to the condylar fossa, midcondylar, and >=2 mm caudal to the skull base. An optimal trajectory for the OC screw should have a medial angulation of >=20 degrees relative to the sagittal midline, trying to stay parallel to the skull base. Minor adjustments in angulation can be made, but any adjustment approaching 10 degrees cranial or caudal leads to an increased risk of hypoglossal canal cranially or atlantooccipital joint compromise caudally. PMID- 22425892 TI - Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma. AB - Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into severe combined immunodeficient (SCID) or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism-activation of p38 signaling in myeloma cells-by which myeloma cells induce osteolytic bone lesions, and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease. PMID- 22425893 TI - Retention of CD34+ CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. PMID- 22425894 TI - Curative one-shot systemic virotherapy in murine myeloma. AB - Current therapy for multiple myeloma is complex and prolonged. Antimyeloma drugs are combined in induction, consolidation and/or maintenance protocols to destroy bulky disease, then suppress or eradicate residual disease. Oncolytic viruses have the potential to mediate both tumor debulking and residual disease elimination, but this curative paradigm remains unproven. Here, we engineered an oncolytic vesicular stomatitis virus to minimize its neurotoxicity, enhance induction of antimyeloma immunity and facilitate noninvasive monitoring of its intratumoral spread. Using high-resolution imaging, autoradiography and immunohistochemistry, we demonstrate that the intravenously administered virus extravasates from tumor blood vessels in immunocompetent myeloma-bearing mice, nucleating multiple intratumoral infectious centers that expand rapidly and necrose at their centers, ultimately coalescing to cause extensive tumor destruction. This oncolytic tumor debulking phase lasts only for 72 h after virus administration, and is completed before antiviral antibodies become detectable in the bloodstream. Antimyeloma T cells, cross-primed as the virus-infected cells provoke an antiviral immune response, then eliminate residual uninfected myeloma cells. The study establishes a curative oncolytic paradigm for multiple myeloma where direct tumor debulking and immune eradication of minimal disease are mediated by a single intravenous dose of a single therapeutic agent. Clinical translation is underway. PMID- 22425895 TI - Newly described activating JAK3 mutations in T-cell acute lymphoblastic leukemia. PMID- 22425896 TI - Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. PMID- 22425897 TI - Mercury and docosahexaenoic acid levels in maternal and cord blood in relation to segmental maternal hair mercury concentrations at parturition. AB - Fish is a major source of harmful methylmercury (MeHg) and beneficial docosahexaenoic acid (DHA) in the developing brain. In this study, we investigated the correlations among maternal and umbilical cord (cord) MeHg and DHA levels at parturition, and mercury (Hg) concentration in 1-cm incremental segments hair samples which grew during gestation representing monthly MeHg exposure levels throughout the period. Whole blood Hg and plasma DHA levels were measured in blood sample pairs collected from 54 mothers at early gestation and parturition, and in cord blood. Maternal hair samples were collected at parturition, and Hg concentrations were measured in 1-cm incremental segments. Hg level in mothers at parturition was slightly lower than that at early gestation and the level in cord blood were approximately 1.9 times higher than that in mothers at parturition. On the other hand, DHA level in mothers at parturition was approximately 2.3 and 1.6 times higher than those in mothers at early gestation and in cord plasma, respectively. These results indicate that kinetics of these chemicals in mothers during gestation and placental transfer are completely different. However, Hg and DHA levels had significant positive correlation in fetal circulation. The cord blood Hg showed the strongest correlation with maternal hair Hg in the first 1-cm segment from the scalp at parturition (r=0.87), indicating that fetal MeHg level reflects maternal MeHg burden at late gestation. In contrast, maternal and cord plasma DHA concentrations at parturition showed the highest correlation coefficients with Hg in the fifth (r=0.43) and fourth (r=0.38) 1-cm hair segments, suggesting that maternal and fetal DHA levels reflects maternal fish intake during mid-gestation. PMID- 22425898 TI - Number of persistent organic pollutants detected at high concentrations in a general population. AB - BACKGROUND: Surveys of human exposure to environmental chemicals do not integrate the number of compounds detected per person and the concentration of each compound. This leaves untested relevant exposure scenarios, such as whether individuals with low concentrations of some compounds have high concentrations of the other compounds. OBJECTIVE: To analyze the number of persistent organic pollutants (POPs) detected at high concentrations. METHODS: Serum concentrations of 19 POPs were analyzed by gas chromatography with electron-capture detection in a representative sample of the general population of Catalonia, Spain (N=919). RESULTS: Over 58% of participants had concentrations in the top quartile of >=1 of the eight most prevalent POPs, and 34% of >=3 POPs. 83% of women 60 to 74 years old had concentrations of >=3 POPs in the top quartile; 56% of women 60 to 74 years had p,p'-DDE, HCB and beta-HCH all in their respective top quartiles, and 48% had concentrations of >=6 POPs in the top quartile. Over 30% of subjects had concentrations in the top decile of 1 to 5 of the eight most prevalent POPs. Half of the population had levels of 1 to 5 POPs >500 ng/g. Less than 4% had all eight POPs in the lowest quartile. CONCLUSIONS: More than half of the study population had concentrations in the top quartile of >=1 POPs. Significant subgroups of the population accumulate POP mixtures at high concentrations. POP concentrations appear low in most of the population only when each individual compound is looked at separately. PMID- 22425899 TI - Comparative toxicokinetics of low-viscosity mineral oil in Fischer 344 rats, Sprague-Dawley rats, and humans--implications for an Acceptable Daily Intake (ADI). AB - Oral repeated-dose studies with low-viscosity mineral oils showed distinct species and strain differences, which are hypothesized to be due to differences in bioavailability, with Fischer 344 rats being more susceptible than Sprague Dawley rats or dogs. Sensitive analytical methodology was developed for accurate measurement of low levels of mineral hydrocarbons and applied in single-dose toxicokinetics studies in rats and humans. Fischer 344 rats showed a 4-fold higher AUC(0-infinity) and consistently higher blood and liver concentrations were found than Sprague-Dawley rats. Hepatic mineral hydrocarbon concentration tracked the blood concentration in both strains, indicating that blood concentrations can serve as functional surrogate measure for hepatic concentrations. In human volunteers receiving 1mg/kg body weight of low-viscosity white oil, all blood concentrations of mineral hydrocarbons were below the detection limit. Comparison with threshold blood concentrations associated with NOAELs in both rat strains, indicate that the margin-of-exposure is at least 37 fold. Using an internal dose metric rather than applied dose reduces the uncertainty around the temporary ADI considerably since it intrinsically accounts for intra- and inter-species differences. The current data support replacement of the temporary ADI of 0.01 mg/kg/day by a (permanent) ADI of at least 1.0mg/kg/day for low- and medium-viscosity mineral oils. PMID- 22425900 TI - Identification of small non-coding RNAs in the planarian Dugesia japonica via deep sequencing. AB - Freshwater planarian flatworm possesses an extraordinary ability to regenerate lost body parts after amputation; it is perfect organism model in regeneration and stem cell biology. Recently, small RNAs have been an increasing concern and studied in many aspects, including regeneration and stem cell biology, among others. In the current study, the large-scale cloning and sequencing of sRNAs from the intact and regenerative planarian Dugesia japonica are reported. Sequence analysis shows that sRNAs between 18nt and 40nt are mainly microRNAs and piRNAs. In addition, 209 conserved miRNAs and 12 novel miRNAs are identified. Especially, a better screening target method, negative-correlation relationship of miRNAs and mRNA, is adopted to improve target prediction accuracy. Similar to miRNAs, a diverse population of piRNAs and changes in the two samples are also listed. The present study is the first to report on the important role of sRNAs during planarian Dugesia japonica regeneration. PMID- 22425901 TI - The role of calpains in myocardial remodelling and heart failure. AB - Calpains are cytosolic calcium-activated cysteine proteases. Recently, they have been proposed to influence signal transduction processes leading to myocardial remodelling and heart failure. In this review, we will first describe some of these molecular mechanisms. Calpains may contribute to myocardial hypertrophy and inflammation, mainly through the activation of transcription factors such as NF kappaB. They play an important role in the fibrosis process partly by activating transforming growth factor beta. They are also implicated in cell death as they cause the breakdown of sarcolemma and sarcomeres. Nevertheless, a key to understanding the molecular basis of calpain-mediated myocardial remodelling likely lies in the identification of mechanisms involved in calpain secretion, since cytosolic and extracellular proteases would have different functions. Finally, we will provide an overview of the available evidence that calpains are indeed actively involved in the common causes of heart failure, including hypertension, diabetes, atherosclerosis, ischaemia-reperfusion, atrial fibrillation, congestive failure, and mechanical unloading. PMID- 22425902 TI - Effects of peroxisome proliferator-activated receptor-gamma agonists on the generation of microparticles by monocytes/macrophages. AB - AIMS: Microparticles are membrane vesicles shed by cells upon activation and/or apoptosis. Microparticles are involved in several processes, including blood coagulation and thrombosis. In addition to their role in the regulation of lipid metabolism, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists exert other effects, both dependent on and independent of PPAR-gamma activation. Some PPAR-gamma agonists have been linked to an increased risk of thrombotic diseases. We aimed to investigate the potential role of PPAR-gamma agonists on the generation of procoagulant microparticles by human monocytes/macrophages. METHODS AND RESULTS: Monocytes/macrophages were isolated from the buffy coats of normal donors. Cells were incubated with three structurally unrelated PPAR-gamma agonists, namely, rosiglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2). Microparticle generation was assessed as phosphatidylserine concentration by a prothrombinase assay, after capturing the microparticles onto annexin V-coated wells. Intracellular calcium concentration was assessed by a fluorescent probe. Extracellular signal-regulated kinase (ERK) phosphorylation was assessed by western blot. Tissue factor expression on microparticles was measured with a one-stage clotting assay. Rosiglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), but not pioglitazone, caused a dose-dependent, significant increase in intracellular calcium mobilization and tissue factor-bearing microparticle generation. EGTA inhibited microparticle generation. The specific PPAR-gamma inhibitor, GW9662, also inhibited microparticle generation. Finally, rosiglitazone and 15-deoxy Delta(12,14)-prostaglandin J(2) caused phosphorylation of ERK; inhibition of ERK by PD98059 inhibited microparticle generation. CONCLUSION: The PPAR-gamma agonists rosiglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), but not pioglitazone, caused an increase in procoagulant, tissue factor-bearing microparticle generation by human monocytes/macrophages. The effect was dependent on ERK phosphorylation and partly mediated through intracellular calcium mobilization; however, direct activation of the PPAR-gamma ligand was also involved. PMID- 22425903 TI - NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter. AB - AIMS: Preservation of mitochondrial function is essential to limit myocardial damage in ischaemic heart disease. We examined the protective effects and mechanism of a new compound, NecroX-5, on rat heart mitochondria in a hypoxia/reoxygenation (HR) model. METHODS AND RESULTS: NecroX-5 reduced mitochondrial oxidative stress, prevented the collapse in mitochondrial membrane potential, improved mitochondrial oxygen consumption, and suppressed mitochondrial Ca(2+) overload during reoxygenation in an in vitro rat heart HR model. Furthermore, NecroX-5 reduced the ouabain- or histamine-induced increase in mitochondrial Ca(2+). CONCLUSION: These findings suggest that NecroX-5 may act as a mitochondrial Ca(2+) uniporter inhibitor to protect cardiac mitochondria against HR damage. PMID- 22425904 TI - Carbocyclic thymidine derivatives efficiently inhibit Plasmodium falciparum thymidylate kinase (PfTMK). AB - During the course of our research into new anti-malaria drugs, Plasmodium falciparum thymidylate kinase (PfTMK) has emerged as an important drug target because of its unique substrate specificity. Compared with human thymidylate kinase (HsTMK), PfTMK shows broader substrate specificity, which includes both purine and pyrimidine nucleotides. PfTMK accepts both 2'-deoxyguanosine monophosphate (dGMP) and thymidine monosphosphate (TMP) as substrates. We have evaluated the inhibitory activity of seven carbocyclic thymidine analogs and report the first structure-activity relationship for these inhibitors against PfTMK. The 2',3' dideoxycarbocyclic derivative of thymidine showed the most potent inhibition of the enzyme. The K(i)(dTMP) and K(i)(dGMP) values were 20 and 7 MUM respectively. Thus, further modifications of carbocyclic thymidine analogs represent a good strategy for developing more powerful thymidylate kinase inhibitors. PMID- 22425905 TI - Evaluation of antiulcer activity of chromanone fraction from Calophyllum brasiliesnse Camb. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Calophyllum brasiliense Camb. (Clusiaceae), popularly known as 'guanandi', is found in the tropical areas and swampy lands. The latex exuding from its bark is used in the treatment of gastric ulcer in folk medicine. Several active compounds have been isolated from its stem bark among them, are the chromanone acids. Therefore, this study aimed to evaluate antiulcer activity and probable mechanism(s) of action of a fraction containing a mixture of chromanone acids (BI), derived by column chromatography fractionation of the hexane extract of the stem bark of Calophyllum brasiliense (HECb), using experimental in vitro and in vivo models. MATERIALS AND METHODS: Ulcer was induced by oral administration of ethanol (75%, v/v) and indomethacin (50mg/kg). Malondialdehyde, reduced glutathione and catalase activity was measured in stomach tissue after ethanol induced ulcer. In order to evaluate the effect of BI on nitric oxide, ulcer was induced by ethanol in l-NAME pretreated animals. Anti Helicobacter pylori activity was verified in disk diffusion and broth microdilution in vitro assays, using cagA+ and vacA+ Helicobacter pylori strains. RESULTS: BI prevented the gastric ulceration caused by ethanol and indomethacin treatments. Its gastroprotective mechanism in ethanol-induced ulcer was partly due to reduction of MDA and CAT levels in the gastric tissue. BI did not affect the GSH levels and its gastroprotective effect was not reversed by pretreatment with l-NAME. BI showed anti-Helicobacter pylori in the both assays. CONCLUSION: The results indicate that BI is partly responsible for the HECb antiulcer and anti-Helicobacter pylori effects. PMID- 22425906 TI - An SSH library responsive to azadirachtin A constructed in Spodoptera litura Fabricius cell lines. AB - The present study revealed differentially expressed genes responsive to azadirachtin A (Aza) in Spodoptera litura cell line through suppression subtractive hybridization. In the Aza-responsive SSH library, approximately 270 sequences represent 53 different identified genes encoding proteins with various predicted functions, and the percentages of the gene clusters were 26.09% (genetic information processing), 11.41% (cell growth and death), 7.07% (metabolism), 6.52% (signal transduction/transport) and 2.72% (immunity), respectively. Eleven clones homologous to identified genes were selected to be confirmed through quantitative real time polymerase chain reaction. Among the eleven clones validated, all but one transcript of lipase showed an increase in SL cell line collected from ETA, whereas the transcripts of other genes were lower in the SL cell line collected from ETA compared with that of UETA. These genes were considered to be related to the response of SL cell line to Aza. These will provide a new clue to uncover the molecular mechanisms of Aza acting on SL cell line. PMID- 22425907 TI - Coupling between the voltage-sensing and pore domains in a voltage-gated potassium channel. AB - Voltage-dependent potassium (Kv), sodium (Nav), and calcium channels open and close in response to changes in transmembrane (TM) potential, thus regulating cell excitability by controlling ion flow across the membrane. An outstanding question concerning voltage gating is how voltage-induced conformational changes of the channel voltage-sensing domains (VSDs) are coupled through the S4-S5 interfacial linking helices to the opening and closing of the pore domain (PD). To investigate the coupling between the VSDs and the PD, we generated a closed Kv channel configuration from Aeropyrum pernix (KvAP) using atomistic simulations with experiment-based restraints on the VSDs. Full closure of the channel required, in addition to the experimentally determined TM displacement, that the VSDs be displaced both inwardly and laterally around the PD. This twisting motion generates a tight hydrophobic interface between the S4-S5 linkers and the C terminal ends of the pore domain S6 helices in agreement with available experimental evidence. PMID- 22425908 TI - Targeted next generation sequencing of clinically significant gene mutations and translocations in leukemia. AB - Leukemias are currently subclassified based on the presence of recurrent cytogenetic abnormalities and gene mutations. These molecular findings are the basis for risk-adapted therapy; however, such data are generally obtained by disparate methods in the clinical laboratory, and often rely on low-resolution techniques such as fluorescent in situ hybridization. Using targeted next generation sequencing, we demonstrate that the full spectrum of prognostically significant gene mutations including translocations, single nucleotide variants (SNVs), and insertions/deletions (indels) can be identified simultaneously in multiplexed sequence data. As proof of concept, we performed hybrid capture using a panel of 20 genes implicated in leukemia prognosis (covering a total of 1 Mbp) from five leukemia cell lines including K562, NB4, OCI-AML3, kasumi-1, and MV4 11. Captured DNA was then sequenced in multiplex on an Illumina HiSeq. Using an analysis pipeline based on freely available software we correctly identified DNA level translocations in three of the three cell lines where translocations were covered by our capture probes. Furthermore, we found all published gene mutations in commonly tested genes including NPM1, FLT3, and KIT. The same methodology was applied to DNA extracted from the bone marrow of a patient with acute myeloid leukemia, and identified a t(9;11) translocation with single base accuracy as well other gene mutations. These results indicate that targeted next generation sequencing can be successfully applied in the clinical laboratory to identify a full spectrum of DNA mutations ranging from SNVs and indels to translocations. Such methods have the potential to both greatly streamline and improve the accuracy of DNA-based diagnostics. PMID- 22425910 TI - Is it time to consider pleurectomy and decortication as the only surgical treatment for malignant pleural mesothelioma? PMID- 22425909 TI - Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node. AB - The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T cells (Foxp3(+)) and dendritic cells (conventional: CD11c(+), mature: CD86(+)) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunological primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared with those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathological variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with the negative non sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared with the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions. PMID- 22425911 TI - Inactivation of both FHIT and p53 cooperate in deregulating proliferation-related pathways in lung cancer. AB - INTRODUCTION: FHIT and p53 are the two most commonly altered tumor suppressor genes in lung cancer, and their molecular status regulates sensitivity to anticancer drugs. Although their functions are independent, there is evidence that their pathways might be interconnected, but little is known at the molecular level. METHODS: Microarray profiling of FHIT-transduced lung cancer cells and modulation of FHIT levels by RNA interference in human bronchial cells were used to generate a signature of FHIT-regulated transcripts. Expression of these genes was evaluated by real-time polymerase chain reaction in 55 primary lung cancer samples characterized for FHIT and p53 expression by immunehistochemistry. RESULTS: A signature of FHIT-transcripts, particularly enriched in genes involved in cell cycle control, was identified. This signature showed overlap with p53 regulated genes, indicating possible crosstalk between these proteins. Consistently, transcriptional deregulation after FHIT modulation was higher in p53-negative cells. In primary lung cancers, inactivation of either gene was detected in 48 of 55 cases (87%) and both genes in 23 of 55 (42%) cases, confirming the central role of these pathways. Primary tumors with inactivation of both FHIT and p53 displayed the strongest deregulation of growth-related pathways with high levels of expression of CCNB1, BUB1, CDC6, TOP2A, MCM6, and CENPF. CONCLUSIONS: FHIT and p53 seem to rely on common mediators, and inactivation of both genes results in prominent deregulation of growth-related pathways in lung cancer cell lines and primary tumors. This reveals crosstalk between these proteins and suggests a possible distinctive phenotype for tumors with inactivation of both genes. PMID- 22425912 TI - Solitary papillomas of the lower airways: epidemiological, clinical, and therapeutic data during a 22-year period and review of the literature. AB - INTRODUCTION: Solitary respiratory papillomas (SRPs) are considered uncommon yet benign neoplasms of the lower respiratory tract. Most of our understanding stems from single case reports or limited case series. OBJECTIVE: To determine the incidence of solitary SRPs and more accurately describe the localization, distribution of subtypes of solitary SRPs, clinical features, and the risk of malignant transformation. This retrospective report is based on data collected in a busy single-center bronchoscopy practice during a 22-year period. METHODS: Among 36,780 patients who underwent bronchoscopic procedures between 1986 and 2008, we identified 32 patients with SRPs. This patient group was compared with 69 patients with SRPs described in the English literature as case reports, case series, or diagnostic dilemmas. RESULTS: Twenty-three patients were men (male/female ratio of 3:1), and 21 patients were former smokers (65.6%). The mean age of initial presentation in men and women was 56.9 +/- 14.3 versus 53.3 +/- 14.4 years, respectively. The presenting symptoms included cough in 18 patients (40.6%), hemoptysis in 11 (25%), dyspnea in seven (21.8%), and fever in five patients (15.7%). Two patients with papillomas in the subglottic region had wheezing and were on aerosolized bronchodilator therapy. In one patient, the papilloma was incidentally discovered on a chest computed tomography scan. The histologic analysis of lesions revealed squamous papillomas in 65.6%, a glandular subtype in 18.75%, and a mixed subtype in 15.6%. Malignant transformation was observed in five patients (15.7%). The malignancies consisted of squamous cell carcinoma in two patients, and single cases of small cell lung carcinoma, glandular carcinoma, and low-grade carcinoma. CONCLUSION: In our experience, the estimated incidence of SRPs is 3.95 cases/100,000 patients/yr. SRPs occur more commonly in men (ratio 3:1). Squamous papillomas occur commonly during the fifth decade of life, glandular papillomas predominate in the sixth decade, and the distribution of mixed type papillomas is from the third to the sixth decade of life. Malignant transformation was observed in a minority of patients. PMID- 22425914 TI - Clinical utility of the pretreatment glasgow prognostic score in patients with advanced inoperable non-small cell lung cancer. AB - INTRODUCTION: Traditional tumor-based staging systems provide limited information on the best treatment option for individual patients with advanced inoperable non small cell lung cancer (NSCLC). The Glasgow prognostic score (GPS) reflects the host systemic inflammatory response and is a validated independent prognostic factor in these patients. The aim of this study was to examine the clinical application of the pretreatment GPS in a mature cohort of patients with inoperable NSCLC. METHODS: The data of 261 patients with inoperable NSCLC were collected prospectively and before treatment. Information on patient demographics, body mass index, performance status (PS), the modified Glasgow prognostic score (mGPS), the prognostic index, and treatment received were included. RESULTS: The majority of patients were aged 65 years or older (68%), were men (59%), had a body mass index more than 20 (89%), and an Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 or 1 (54%). Most patients had a pretreatment mGPS = 1 (62%) and pretreatment prognostic index = 1 (56%). During the follow-up period, 248 (95%) patients died, 246 from their disease. The median survival was 8 months. On multivariate analysis, age (p = 0.001), ECOG-PS (p < 0.05), mGPS (p < 0.0001), and tumor stage (p < 0.0001) were independently associated with cancer-specific survival. Using 5-year cancer specific mortality as an end point, the area under the receiver operator curve was 0.735 (95% confidence interval [CI], 0.566-0.903; p = 0.024) for the mGPS, 0.669 (95% CI, 0.489-0.848; p = 0.106) for ECOG-PS, and 0.622 (95% CI, 0.437 0.807; p = 0.240) for tumor, node, metastasis stage. Patients with an increased mGPS were more likely to have a poorer ECOG-PS (p < 0.05), an increased white cell count (p < 0.05), and received palliative treatment (p < 0.05). CONCLUSION: The pretreatment mGPS is a useful and important predictor of cancer-specific survival in patients with inoperable NSCLC. Basing clinical assessment on the mGPS has implications for the routine monitoring and treatment of the patients. PMID- 22425913 TI - CYFRA 21-1 as a prognostic and predictive marker in advanced non-small-cell lung cancer in a prospective trial: CALGB 150304. AB - BACKGROUND: Cytokeratin 19 and its soluble fragment CYFRA have been studied as markers that may be associated with response to therapy and survival in non-small cell lung cancer (NSCLC). As a prospective correlative study of Cancer and Leukemia Group B 30203, a randomized phase II trial of carboplatin/gemcitabine with eicosanoid modulators (celecoxib, zileuton, or both) in advanced NSCLC, serum CYFRA levels were obtained before and during treatment. METHODS: Serum CYFRA levels were measured at baseline and after the first cycle of treatment using an electrochemoluminescent assay. Paired specimens were available from 88 patients. The logarithms of the initial concentration and of the difference in concentrations were analyzed for association with overall survival (OS) and failure-free survival (FFS). RESULTS: Lower baseline CYFRA levels were associated with both longer OS and FFS (p < 0.0001 and p = 0.0003). In addition, larger reductions in CYFRA levels correlated with longer OS and FFS (p = 0.0255 and p = 0.0068). CONCLUSION: CYFRA and change in CYFRA were found to be reliable markers for response to chemotherapy for NSCLC; however, a precise threshold to mark response has yet to be determined. PMID- 22425915 TI - ERCC1 and BRAC1 mRNA expression levels in the primary tumor could predict the effectiveness of the second-line cisplatin-based chemotherapy in pretreated patients with metastatic non-small cell lung cancer. AB - INTRODUCTION: The potential predictive role of BRCA1 and ERCC1 expression levels in patients with metastatic non-small cell lung cancer (NSCLC) receiving second line platinum-based chemotherapy was investigated. METHODS: Real-time quantitative polymerase chain reaction after reverse transcription was used to assess the expression levels of BRCA1 and ERCC1 in 100 microdissected primary tumors from platinum-naive NSCLC patients treated with platinum-based chemotherapy in the second-line setting. RESULTS: Low ERCC1 mRNA levels were significantly associated with higher response rate (p = 0.011), longer median progression-free survival (PFS; p = 0.029), and median overall survival (mOS; p = 0.001) after the initiation of the second-line treatment. Similarly, low BRCA1 expression level was significantly correlated with higher response rate (p = 0.022), longer PFS (p = 0.041), and mOS (p = 0.005). In addition, patients with low ERCC1 and BRCA1 mRNA experienced increased median PFS (p = 0.021) and mOS (p < 0.001) in comparison with those who had both genes upregulated. A multivariate analysis revealed that low ERCC1 and low BRCA1 expression levels were significantly associated with increased PFS (hazard ratio [HR]: 0.6; 95% confidence interval [CI]: 0.4-0.8; p = 0.029 and HR: 0.7; 95% CI: 0.6-0.9; p = 0.043, respectively) and OS (HR: 0.5; 95% CI: 0.3-0.7; p = 0.003 and HR: 0.7; 95% CI: 0.6-0.9; p = 0.038, respectively). CONCLUSIONS: These results suggest that the ERCC1 and BRCA1 mRNA expression levels in the primary tumor at the time of diagnosis could be used for the prediction of platinum sensitivity in the treatment of NSCLC in the second-line setting. Cross-validation studies are warranted. PMID- 22425916 TI - EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy. AB - INTRODUCTION: The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI) sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate. METHODS: We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment. RESULTS: Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival. CONCLUSIONS: Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non-small-cell lung cancer patients. PMID- 22425917 TI - Transcutaneous computed bioconductance measurement in lung cancer: a treatment enabling technology useful for adjunctive risk stratification in the evaluation of suspicious pulmonary lesions. AB - Lung cancer is the number one cause of cancer deaths in North America and is rapidly increasing worldwide. Although there are advances being made in the multidisciplinary management and combined-modality therapies of lung cancers, most cases are still diagnosed in later noncurable stages. Early detection has hinged on clinical risk assessment and on the future possibility of screening by low-dose computed tomography of the chest; however, this will only vastly increase the number of indeterminate pulmonary lesions (IPLs) being detected. Given that the majority of radiographically detected lung lesions are benign, and tissue confirmation by various invasive biopsy tests has increased risks and costs, a noninvasive adjunctive test that can stratify likelihood of an indeterminate lung lesion as malignant or benign will be a useful treatment enabling technology to speed up diagnosis and treatment of lung cancers at a more curable stage and defer unnecessary invasive procedures that have potential for harm. Measurement of transcutaneous bioconductance using the differential conductivity properties of cancerous versus benign tissue has been previously demonstrated on nonlung lesions. Thus, it has the potential of being a noninvasive, simple-to-perform and repeatable test that may be valuable in assessing lung lesions. In this prospective study of subjects with known thoracic malignancies, computed bioconductance measurements discriminated between malignant lesions (29 primary lung cancers) from benign pathology (12) across a range of IPL sizes (0.8 cm and greater) with a sensitivity of 89.7% (positive predictive value 96.3%) and specificity of 91.7% (negative predictive value 78.5%). The technology seems to be effective across a range of tumor thoracic locations, cell types, and stages. Additional cohorts of subjects will be used to validate testing and for refinement of the current algorithm, which at present has a test performance with a receiver operating characteristic of 90.7%. Noninvasive transcutaneous computed bioconductance measurement can become a standard risk assessment and therapy-enabling tool in the evaluation of IPLs. PMID- 22425918 TI - A multiplexed serum biomarker immunoassay panel discriminates clinical lung cancer patients from high-risk individuals found to be cancer-free by CT screening. AB - INTRODUCTION: Clinical decision making in the setting of computed tomography (CT) screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk individuals with indeterminate pulmonary nodules. METHODS: To identify candidate serum biomarkers, we measured 70 cancer-related proteins by Luminex xMAP (Luminex Corporation) multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary non-small-cell lung cancer and 56 age-, sex-, and smoking-matched CT-screened controls. RESULTS: We identified a panel of 10 serum biomarkers-prolactin, transthyretin, thrombospondin-1, E-selectin, C-C motif chemokine 5, macrophage migration inhibitory factor, plasminogen activator inhibitor, receptor tyrosine-protein kinase, erbb-2, cytokeratin fragment 21.1, and serum amyloid A-that distinguished lung cancer patients from controls with an estimated balanced accuracy (average of sensitivity and specificity) of 76.0 +/- 3.8% from 20-fold internal cross validation. We then iteratively evaluated this model in an independent test and verification case/control studies confirming the initial classification performance of the panel. The classification performance of the 10-biomarker panel was also analytically validated using enzyme-linked immunosorbent assays in a second independent case/control population, further validating the robustness of the panel. CONCLUSIONS: The performance of this 10-biomarker panel-based model was 77.1% sensitivity/76.2% specificity in cross-validation in the expanded training set, 73.3% sensitivity/93.3% specificity (balanced accuracy 83.3%) in the blinded verification set with the best discriminative performance in stage I/II cases: 85% sensitivity (balanced accuracy 89.2%). Importantly, the rate of misclassification of CT-screened controls was not different in most control subgroups with or without airflow obstruction or emphysema or pulmonary nodules. These biomarkers have potential to aid in the early detection of lung cancer and more accurate interpretation of indeterminate pulmonary nodules detected by CT screening. PMID- 22425919 TI - A phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small cell lung cancer: a report of toxicities and clinical response. AB - BACKGROUND: The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC). METHODS: Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis. RESULTS: Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%). CONCLUSION: Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease. PMID- 22425920 TI - Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma. AB - INTRODUCTION: Local-regional control (LRC) rates for non-small cell lung cancer after chemoradiotherapy were studied (using two different definitions of LRC) for the association between LRC and survival. METHODS: Seven legacy Radiation Therapy Ooncology Group trials of chemoradiotherapy for locally advanced non-small cell lung cancer were analyzed. Two different definitions of LRC were studied: (1) freedom from local progression (FFLP-LRC), the traditional Radiation Therapy Oncology Group methodology, in which a failure is intrathoracic tumor progression by World Health Oorganization criteria; and (2) response-mandatory (strict-LRC), in which any patient not achieving at least partial response was considered to have failure at day 0. Testing for associations between LRC and survival was performed using a Cox multivariate model that included other potential predictive factors. RESULTS: A total of 1390 patients were analyzed. The LRC rate at 3 years was 38% based on the FFLP-LRC definition and 14% based on the strict-LRC definition. Performance status, concurrent chemotherapy, and radiotherapy dose intensity (biologically equivalent dose) were associated with better LRC (using either definition). With the strict-LRC definition (but not FFLP-LRC), age was also important. There was a powerful association between LRC and overall survival (p, 0.0001) on univariate and multivariate analyses. Age, performance status, chemotherapy sequencing, and biologically equivalent dose were also significantly associated with survival. Histology and gender were also significant if the strict-LRC model was used. CONCLUSIONS: LRC is associated with survival. The definition of LRC affects the results of these analyses. A consensus definition of LRC, incorporating functional imaging and/or central review, is needed, with the possibility of using LRC as a surrogate end point in future trials. PMID- 22425921 TI - Recurrence dynamics for non-small-cell lung cancer: effect of surgery on the development of metastases. AB - INTRODUCTION: We study event rates over time (event dynamics) in patients undergoing surgery for early-stage non-small-cell lung cancer (NSCLC). METHODS: Using a database of patients undergoing initial surgery for NSCLC, the event dynamics, based on the hazard rate, were evaluated. Events evaluated included time to any treatment failure, local recurrence, distant metastasis (DM), and development of a second primary lung cancer. RESULTS: Among 1506 patients, time to any treatment failure dynamics demonstrated an initial surge in the hazard rate 9 months after surgery, followed by two smaller peaks at the end of the second and fourth years, respectively. This pattern was dominated by DM events. Two distinguishable peaks were noted for local recurrence in the first and second years. In contrast, the hazard rate for second primary lung cancer exhibited a more uniform pattern over time. The DM dynamics was analyzed by sex and three peaks emerged for both sexes. The timing of the first peak was similar for both sexes, at 7 to 9 months after surgery. The second peak occurred earlier in men (18-20 months) than women (24-26 months). For both sexes the third peak appeared during the fourth year. CONCLUSIONS: Recurrence dynamics of resected early-stage NSCLC displays a multipeak pattern, which supports the hypothesis of a metastasis growth model previously described for early-stage breast cancer. The model assumes both cellular and micrometastatic tumor dormancy and a transient phase of acceleration of metastatic growth following surgical excision of the primary tumor. PMID- 22425922 TI - Efficacy and toxicity of belotecan for relapsed or refractory small cell lung cancer patients. AB - INTRODUCTION: Belotecan (Camtobell, CKD602) is a new camptothecin-derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this study was to evaluate the efficacy and safety of belotecan monotherapy as a second-line therapy in patients with relapsed or refractory small cell lung cancer (SCLC). METHODS: Between June 2008 and August 2011, a total of 50 patients with relapsed or refractory SCLC were treated with belotecan 0.5 mg/m for 5 consecutive days, every 3 weeks. We evaluated the overall response rate (ORR), the progression-free survival (PFS), and the overall survival (OS), and toxicity according to sensitivity to initial chemotherapy. RESULTS: The median age was 66 years (range, 43-84 years) and Eastern Cooperative Oncology Group performance was 0 or 1 in 34 patients (68%) and 2 in 16 patients (32%). Twenty patients (40%) had sensitive relapse and 30 patients (60%) had refractory disease. The ORR, PFS, and OS for sensitive patients were 20% (95% confidence interval [CI], 8-40), 2.8 months (95% CI, 0.53-5.06), and 6.5 months (95% CI, 1.58-11.42), respectively. In the refractory group, the ORR, PFS, and OS were 10% (95% CI, 1-21), 1.5 months (95% CI, 1.25-1.75), and 4.0 months (95% CI, 3.40-4.60), respectively. Most commonly reported grade-3 or -4 adverse events included neutropenia (54%), thrombocytopenia (38%), and anemia (32%). CONCLUSION: Belotecan showed modest activity with an acceptable safety profile as a second-line therapy in patients with relapsed or refractory SCLC. PMID- 22425923 TI - Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma. AB - INTRODUCTION: To compare the outcomes of two different multimodality regimens involving neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant radiotherapy versus pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy in patients with malignant pleural mesothelioma. METHODS: Nonrandomized prospective study of patients treated by multimodality therapy and operated on between January 2004 and June 2011. Second-line treatments were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan Meier method, log rank test, and Cox regression analysis. RESULTS: Twenty-five consecutive patients received neoadjuvant chemotherapy, 22 underwent EPP, and 17 received adjuvant radiotherapy. Over the same period, 54 consecutive patients underwent P/D and hyperthermic pleural lavage and received prophylactic radiotherapy and adjuvant chemotherapy. The 30-day mortality rate was 4.5%in the EPP group and nil in the P/D group. Fifteen patients (68%) in the EPP group and 15 (27.7%) in the P/D group experienced complications. There were no differences between the EPP and P/D groups for age, sex, histology, pathologic stage, and nodal status. Trimodality therapy was completed by 68%of the patients in the EPP group and 100%in the P/D group. Survival was significantly better in the P/D group: median survival was 23 months versus 12.8 months, 2-year survival was 49%versus 18.2 %, and 5-year survival was 30.1%versus 9%, respectively (p = 0.004). At multivariate analysis, epithelioid histology, P/D, and completeness of resection were independent prognostic factors. CONCLUSIONS: In our experience, P/D, hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy were superior to neoadjuvant chemotherapy, EPP, and adjuvant radiotherapy. PMID- 22425924 TI - NUT rearrangement is uncommon in human thymic epithelial tumors. AB - INTRODUCTION: Thymic carcinomas represent the most aggressive histotype of thymic epithelial tumors (TETs). The 2004 World Health Organization classification has assigned a subgroup of thymic carcinomas as t(15;19) carcinomas based on the presence of t(15;19), a translocation found in poorly differentiated and highly aggressive NUT midline carcinomas. These tumors are characterized byrearrangement of the NUT (nuclear protein in testis) gene on chromosome 15q14, which in most cases fuses to the bromodomain containing 4 (BRD4) gene on chromosome 19 p13.1 through reciprocal t(15;19) translocation, resulting in constitutive BRD4 NUTfusion protein expression. To our knowledge, NUT translocation has been reported only in four thymic carcinomas. Due to the rarity of TETs, the prevalence of NUT rearrangement in TETs has however never been systematically explored. METHODS: Formalin-fixed paraffin-embedded samples of histologically confirmed TETs were evaluated for NUT expression and rearrangement by immunohistochemistry and fluorescence in situ hybridization, respectively. RESULTS: A series of 148 TETs (37 carcinomas and 111 thymomas) were examined for NUT expression and rearrangement. Only one thymic carcinoma (2.7% of thymic carcinomas or 0.68% of TETs) was found positive for NUT expression and rearrangement. CONCLUSIONS: Rearrangement of NUT is infrequent in TETs. We propose that caution should be taken to distinguish t(15;19) thymic carcinoma from other mediastinal carcinomas, as NUT midline carcinomas are often associated with dreadful prognosis or overt lethality. PMID- 22425925 TI - Phase-II trial of rebeccamycin analog, a dual topoisomerase-I and -II inhibitor, in relapsed "sensitive" small cell lung cancer. AB - Relapsed small cell lung cancer (SCLC) carries a poor prognosis. Topoisomerase I and II inhibitors and DNA-damaging agents are considered among the most active agents against SCLC. Rebeccamycin analog (RA, Becatecarin) is an antitumor antibiotic with inhibitory activity against both topoisomerase I and II, and DNA intercalating properties. We performed a phase-II trial of RA in relapsed, sensitive SCLC with the primary end point of response rate. Patients with previously treated SCLC who relapsed more than 60 days after the completion of first-line chemotherapy were treated with RA-administered intravenously at a dose of 140 mg/m on days 1 to 5 of 21-day cycles for a maximum of six cycles. Eligibility included Eastern Cooperative Oncology Group performance status 0 to 2 and adequate organ function. A two-stage design was employed. Twenty evaluable patients were enrolled. Median age was 61 years. Two patients (10%) had a partial response and six had stable disease. The clinical benefit rate was 40% (95% confidence interval [CI], 23-64%). The median progression-free survival was 2 months (95% CI, 1.2-5.2 months). The median survival was 6.7 months (95% CI, 3.3 8.0 months). No treatment-related deaths occurred. Grade-4 neutropenia and thrombocytopenia occurred in 23% and 14% of the patients, respectively. In conclusion, RA has single-agent activity in relapsed, sensitive SCLC with manageable toxicities but is unlikely to provide any superiority compared to existing agents for this disease. PMID- 22425926 TI - Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report. AB - INTRODUCTION: We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment. METHODS: Patients with unresectable MM and no symptomatic effusions were given dasatinib 70 mg twice daily as part of a 28-day cycle. We also measured plasma vascular endothelial growth factor and platelet-derived growth factor b and colony stimulating factor 1 (CSF-1) and mesothelin-related protein at baseline and during therapy. RESULTS: Forty-six patients were enrolled in this study. Fifty percent of the first 12 patients enrolled experienced >=grade 3 treatment-related adverse events, and therefore, the starting dose was reduced to 50 mg twice daily. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). The overall disease control rate was 32.6%, and progression-free survival at 24 weeks was 23% (95% confidence interval: 13.5-40.0%). Survival was markedly longer in patients with lower pretreatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy. DISCUSSION: Single agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population. PMID- 22425927 TI - Sunitinib plus paclitaxel in patients with advanced esophageal cancer: a phase II study from the Hoosier Oncology Group. AB - The combination of sunitinb (37.5 mg orally daily) + paclitaxel (90 mg/m intravenously on days 1, 8, 15 every 4 weeks) was examined in patients with advanced esophageal or gastroesophageal junction cancer, and progression-free survival (PFS) was compared to that of historical controls. The end points included response rate, overall survival, and toxicities. Twenty-eight patients were enrolled at six centers. Median age was 59.5 years. The 24-week PFS rate was 25% (90% confidence interval [CI], 12-42%). Three (11%) of 23 evaluable patients had a response (1 complete response and 2 partial response) (90% CI, 3-25%). Median overall survival was 228 days (90% CI, 140-283 days). Grade 3/4 toxicities included leukopenia/neutropenia (25%), anemia (18%), fatigue (11%), and hemorrhage (11%). There were four grade 5 toxicities including upper gastrointestinal hemorrhage (n = 2), gastrointestinal/esophageal fistula (n = 1), and unexplained death (n = 1). In our study, we found that sunitinib + paclitaxel in patients with advanced esophageal or gastroesophageal junction cancer had a 24 week PFS no better than the PFS of historical controls. The combination also had a high rate of serious toxicities and will not be pursued. PMID- 22425928 TI - Ultra-late relapse with a single cerebellar metastasis 10 years after complete surgery for stage IIA non-small cell lung cancer (bronchioalveolar carcinoma). PMID- 22425929 TI - Detection of circulating lung cancer cells with strong thymidylate synthase reactivity in the peripheral blood of a patient with pulmonary adenocarcinoma treated with pemetrexed. PMID- 22425930 TI - ALK-rearranged lung cancer: adenosquamous lung cancer masquerading as pure squamous carcinoma. PMID- 22425931 TI - Erlotinib for whole-brain-radiotherapy-refractory leptomeningeal metastases after gefitinib failure in a lung adenocarcinoma patient. PMID- 22425932 TI - Epidermal growth factor receptor mutation and chemosensitivity. PMID- 22425934 TI - KRAS mutation spectrum notably diverges between non-small cell lung and colorectal carcinomas. PMID- 22425936 TI - Treated individuals who progress to action or maintenance for one behavior are more likely to make similar progress on another behavior: coaction results of a pooled data analysis of three trials. AB - OBJECTIVE: This study compared, in treatment and control groups, the phenomena of coaction, which is the probability that taking effective action on one behavior is related to taking effective action on a second behavior. METHODS: Pooled data from three randomized trials of Transtheoretical Model (TTM) tailored interventions (n=9461), completed in the U.S. in 1999, were analyzed to assess coaction in three behavior pairs (diet and sun protection, diet and smoking, and sun protection and smoking). Odds ratios (ORs) compared the likelihood of taking action on a second behavior compared to taking action on only one behavior. RESULTS: Across behavior pairs, at 12 and 24 months, the ORs for the treatment group were greater on an absolute basis than for the control group, with two being significant. The combined ORs at 12 and 24 months, respectively, were 1.63 and 1.85 for treatment and 1.20 and 1.10 for control. CONCLUSIONS: The results of this study with addictive, energy balance and appearance-related behaviors were consistent with results found in three studies applying TTM tailoring to energy balance behaviors. Across studies, there was more coaction within the treatment group. Future research should identify predictors of coaction in more multiple behavior change interventions. PMID- 22425937 TI - The importance of the shape of the protein-water interface of a kinesin motor domain for dynamics of the surface atoms of the protein. AB - A single kinesin motor domain immersed in water has been investigated using molecular dynamics. It has been found that local properties of water in the solvation shell change along with the nature of the neighboring protein surface. However, a detailed analysis leads to the conclusion that the geometrical features of hydrogen bonds and overall structure of kinesin hydration water are not very different from bulk water. The local values of diffusion coefficients (translational and rotational) of water adjacent to specific patches on the protein surface seem not to be correlated to the orientational ordering of hydration water, but instead they depend on spatial roughness and degree of exposure of the patch to the solvent. Finally, a relationship between the mobility of various surface atoms of the protein and the mean values of the diffusion coefficient of the adjacent water molecules has been observed. The latter finding suggests a close relationship between the dynamics of the inner kinesin movements and the behavior of solvation water which is in turn determined by the topography of the contact surface between the protein and the surrounding water molecules. PMID- 22425938 TI - Patulin: Mechanism of genotoxicity. AB - Patulin is a frequently found food contaminant mainly produced by the fungi Aspergillus and Penicillium. Patulin is suspected to be clastogenic, mutagenic, teratogenic and in higher concentrations cytotoxic. Here, we investigate the mechanism of the patulin-induced genotoxicity. Chromosomal damage was detected as micronucleus and nucleoplasmic bridge formation. Due to the activity of patulin on SH-groups, glutathione is a major compound in the cellular defense against patulin and the depletion of glutathione level with buthionine sulfoximine led to a strong increase in the genoxicity of patulin. A modified version of the alkaline comet assay was carried out to show the cross-linking properties of patulin. As a mechanistic hypothesis, we suspect patulin to cause structural DNA damage by cross-linking, yielding nucleoplasmic bridges and as a later consequence, micronucleus formation. The structural DNA damage may also lead to cell cycle delays, the consequence of which may be the observed centrosome amplification and formation of multipolar mitotic spindles. PMID- 22425939 TI - Estimated intake levels for Finnish children of methylmercury from fish. AB - Methylmercury (MeHg) is a well-known neurotoxic agent, and consumption of contaminated fish is the principal environmental source of MeHg exposure in humans. Children are more susceptible to adverse effects than adults. No previous specific data exist for intake by Finnish children of methylmercury from fish. We estimated fish consumption and MeHg intakes from species most commonly consumed by Finnish children aged 1-6 years. The total mercury concentrations were determined in fish species consumed, and age-specific methylmercury intakes were derived. We also examined safety margins and the proportion of children exceeding the tolerable daily intakes set by international expert bodies. The daily intake of MeHg ranged from 0 to 0.33 MUg/kg bw. The strictest reference value 0.1 MUg/kg bw/day for MeHg, proposed by USEPA, was exceeded by 1-15% of the study population, and FAO/WHO JECFA provisional tolerable weekly intake of 1.6 MUg/kg bw was exceeded by 1% of boys and 2.5% of girls aged 6 years. Intakes of 1-year old girls were higher than of boys, whereas for 3-year olds they were the opposite. The highest intakes were observed for 6-year-old boys and girls. There was great variation in the estimated MeHg intakes among Finnish children. PMID- 22425940 TI - Antimicrobial activity, phenolic profile and role in the inflammation of propolis. AB - Nowadays a great amount of information regarding chemical and biological aspects of bee products is available in the literature, but few data on its therapeutic uses are found. The aim of this study was to evaluate the phenolic profile, the in vitro antimicrobial activity and effect in the hyaluronidase enzyme (widely related with the inflammation process) of propolis harvested in Portugal. The efficacy of three extracts (hydro-alcoholic, methanolic and aqueous) was also compared. It was chosen the hydro-alcoholic extract, because this was the most effective for extracting phenolic compounds. The antimicrobial activity was accessed in Gram-positive and Gram-negative bacteria and yeasts, isolated from different biological fluids and the results were then compared with the obtained for reference microorganisms. The propolis from Braganca was the one that possessed the highest polyphenols' content. The sample from Beja showed the less significant inhibition of the hyaluronidase enzyme. Concerning the antimicrobial activity, Candida albicans was the most resistant and Staphylococcus aureus the most sensitive. The reference microorganisms were more sensitive than the ones isolated from biological fluids. PMID- 22425941 TI - Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. AB - OBJECTIVE: To determine the magnitude of the risk of incident cardiovascular disease (CVD; fatal and non-fatal), including acute myocardial infarction (MI), cerebrovascular accidents (CVA) and congestive heart failure (CHF), in patients with rheumatoid arthritis (RA) compared to the general population through a meta analysis of controlled observational studies. METHODS: The authors searched the Medline, Embase, LILACS and Cochrane databases from their inception to June 2011. Observational studies meeting the following criteria were included: (1) prespecified RA criteria; (2) predefined CVD criteria for incident CVD (MI, CVA or CHF); (3) a comparison group; and (4) RR estimates, 95% CI or data for calculating them. The authors calculated the pooled RR using the random-effects model and tested for heterogeneity using the bootstrap version of the Q statistic. RESULTS: Fourteen studies comprising 41 490 patients met the inclusion criteria. Overall, there was a 48% increased risk of incident CVD in patients with RA (pooled RR 1.48 (95% CI 1.36 to 1.62)). The risks of MI and CVA were increased by 68% (pooled RR 1.68 (95% CI 1.40 to 2.03)) and 41% (pooled RR 1.41 (95% CI 1.14 to 1.74)). The risk of CHF was assessed in only one study (RR 1.87 (95% CI 1.47 to 2.39)). Significant heterogeneity existed in all main analyses. Subgroup analyses showed that inception cohort studies were the only group that did not show a significantly increased risk of CVD (pooled RR 1.12 (95% CI 0.97 to 1.65)). CONCLUSIONS: Published data indicate that the risk of incident CVD is increased by 48% in patients with RA compared to the general population. Sample and cohort type influenced the estimates of RR. PMID- 22425942 TI - Fetuin-A serum levels are not correlated to kidney function in long-lived subjects. AB - OBJECTIVES: Serum Fetuin A has been identified as an inhibitor of ectopic calcification. It is reduced in subjects with chronic kidney disease (CKD) and it has been proposed as a potential link between CKD and the higher prevalence of arterial calcification observed in these patients. During aging both the stiffening of arterial wall due to calcification and a decline in kidney function are frequent. The aim of the study is to investigate if Fetuin A serum levels are associated with aging and with AHSG T256S polymorphism. Moreover, we aim at investigate whether serum Fetuin A is correlated to kidney function in this setting of senescence. DESIGN AND METHODS: 256 health long-lived subjects (age 92 [81-100]) were recruited for the study. Serum Fetuin A was evaluated by ELISA, Cystatin C by immune-nephelometry. AHSG T256S was determinated by PCR-RFLP. RESULTS: Serum Fetuin A shows a significant correlation with age (r=0.20; P=0.0048). AHSG TS and SS genotypes are associated to lower levels of serum protein (0.27 [0.19-0.29] g/L vs 0.42 [0.32-0.49] g/L; P<0.027 and 0.34 [0.25 0.41] g/L vs 0.42 [0.32-0.49] g/L; P<0.001, respectively). No significant correlation between Fetuin A and Cystatin C was observed. CONCLUSIONS: Serum Fetuin A increases with age in elder individuals and subjects with the TS or SS AHSG polymorphism have lower levels of the circulating protein. No correlation with kidney function decline was observed. Other mechanisms should be investigated to explain the increase of Fetuin A with age. PMID- 22425943 TI - [Epigenetics--a new perspective for the study of deafness]. AB - Hearing loss is the most common sensory disorder in humans. The newborn morbidity is 1/1000 approximately 3/1000. In most cases, the cause comes from abnormal development of inner-ear or degeneration of the cochlear hair cells. Genetic factors make a significant contribution to hearing impairment. Some genes and chromosome locus responsible for syndromic or non-syndromic hearing loss have been identified. However, etiology of deafness still remains obscure. In addition to some hot spot mutations (GJB2, SLC26A4, mitochondrial DNA C1494T, A1555G, etc.), epigenetics may also provide a significant contribution to this sensory disease. For example, miR-96 seed region mutations can result in progressive hearing loss in humans and mice, and aberrant CpG methylation has been linked to a few inherited syndromes that can induce hearing loss, etc.. This review aims to summarize the research progress of epigenetics in the fields of hearing and deafness. PMID- 22425944 TI - [The genetic safety of induced pluripotent stem (iPS) cells]. AB - Since Takahashi and Yamanaka first generated induced pluripotent stem (iPS) cells from mouse fibroblasts successfully in 2006, iPS cells have rapidly become a new hotspot in the field of stem cells research because of their broad potential application prospects. Meanwhile, more and more attentions are paid to the genetic safety of iPS cells. This article summarizes recent findings on genetic safety of iPS cells and reviews the possible causes leading to genetic instability of iPS cells. Hopefully, this review is helpful to improve the induction of iPS cells and obtain genetically safe iPS cells. PMID- 22425945 TI - [Hippo signaling pathway in mammals: a new therapeutic target for tumors]. AB - Hippo signaling pathway was first discovered in Drosophila as regulator of cell proliferation and apoptosis during development. It has been widely reported that Hippo signaling pathway plays an essential role in embryonic differentiation, pattern formation and adult cell homeostasis. Furthermore, Hippo signaling has close correlation with Wnt and Notch signaling pathways, and has an important effect on tumor initiation and progression. Recent studies have shown that the Drosophila Hippo signaling pathway is highly conserved over evolutionary time, the mammalian Hippo signaling pathway has been implicated in regulating cell contact inhibition, organsize and tumorigenesis. This review firstly focuses on the composition, regulatory mechanism and physiological functions of mammalian Hippo signaling pathway, and then lists the relationship with other signaling pathways and protein factors, and tumors in mammals. Finally, the therapeutic approaches to targeting Hippo signaling pathway components or regulators have also been summarized, which might be beneficial to tumor therapeutic intervention. PMID- 22425946 TI - [The neuroendocrine regulatory mechanisms of mammalian seasonal reproduction]. AB - The seasonal reproduction of mammal means the reproduction experiences an annual period from quiescence to renaissance. Studies have shown that kisspeptin and RFRP play an important role in the reproductive seasonality. The non-breeding season is characterized by an increase in the negative feedback effect of estrogen on GnRH, and this effect is transmitted by kisspeptin neurons, which may be an important factor affecting the reproduction activities. The expression of RFRP depends on melatonin secretion, and shows an apparent inhibition on reproduction in non-breeding season. In addition, thyroid hormones influence termination of the breeding season. Dopaminergic neuron A14/A15 also contributes to the seasonal changes in estrogen negative feedback. These neural systems may synergistically modulate the seasonal changes of reproductive function with the photoperiod. This review makes a systematic expatiation on the relationship between seasonal reproduction and these neural systems. PMID- 22425947 TI - [Function of the Lck and Fyn in T cell development]. AB - The development of T cell in the thymus and the activation of mature T cells in the secondary lymphoid tissues require T cell to make adaptive responses to signaling molecules of environment. The activation of T cell receptor (TCR) signaling pathway could be induced by the interaction of the TCR and its co receptor CD4 and CD8 with MHC/peptide complex. This process involves co stimulatory molecules and signals mediated by cytokine receptors, which eventually leads to the occurrence of T cell immune response. The Src-family kinases lymphocyte-specific protein tyrosine kinase (Lck) and proto-oncogene tyrosine-protein kinase (Fyn) are expressed in T cells and serve as the signaling molecules that are activated downstream of TCR. These signaling molecules play key roles in development, positive selection, and peripheral maintenance of naive T cells and lymphopenia-induced proliferation of peripheral T cells. Both Lck and Fyn are required for each of these TCR-based signaling pathways, and Lck seems to be the major contributor, while Fyn can only supplement some functions of Lck. In this review, we discussed the mechanisms by which these two proteins perform functions in T cell development based on our current understanding. PMID- 22425948 TI - [Molecular mechanism for dynamic regulation of endogenous ABA signal level]. AB - The process from stress signal perception and the trigger of ABA biosynthesis to dynamic regulation of ABA level is an important stress signaling pathway in cells. Compared to the downstream events in ABA signal transduction, the researches in this field are relatively lagged. Expression of synthase genes, such as ZEP in roots and rate-limiting enzyme genes NCED, AtRGS1 and ABA2, can be activated in response to stresses. However, the expression of genes encoding degradative enzymes, including 7'-, 8'-, 9'-hydroxylase and glucosyltransferase, negatively regulates ABA accumulation. Meanwhile, the expressions of the synthases, such as ZEP and NCED3, are induced by increasing endogenous ABA contents. Additionally, the analyses of gene expression and source-sink dynamics indicates that sustained supply from root-sourced ABA is required for the maintenance of leaf ABA dynamic pool. It is notable that miRNAs should be involved in ABA signal origin and ABA level dynamic adjustment. Further dynamic analysis of ABA metabolism revealed that endogenous ABA signal levels are synergistically controlled by the expressions of synthases and degradative enzymes. PMID- 22425949 TI - [A family-based association study of the EGR3 gene polymorphisms and schizophrenia]. AB - Previous studies showed that EGR3 gene located in chromosome 8p21.3 was involved in the etiology of schizophrenia. However, the finding failed to be replicated in several case-control studies. To investigate the genetic role of the EGR3 gene in Chinese psychiatric patients, we genotyped five single nucleotide polymorphisms (SNPs) in EGR3 gene locus using 93 nuclear families in Han Chinese, and performed transmission disequilibrium test (TDT). In this study, two SNPs (rs1996147 and rs3750192) showed significant association with schizophrenia (c2>4.40, P<0.05). In the linkage disequilibrium analysis, the significant association was also found in two- (rs3750192-rs35201266), three- (rs1877670- rs3750192-rs7009708) and four-SNP (rs1996147-rs1877670-rs3750192-rs7009708) tests of haplotype analyses (c2>7.10, global P<0.05). Overall, the results suggested that EGR3 gene may play an important role in schizophrenia susceptibility in the Han Chinese population, and further functional exploration of the EGR3 gene will contribute to the underlying molecular mechanism for schizophrenia pathogenesis. PMID- 22425950 TI - [Association between SUMO4 polymorphisms and type 2 diabetes mellitus]. AB - This study investigated the association between small ubiquitin-like modifier 4 (SUMO4) gene polymorphisms and type 2 diabetes mellitus (T2DM) in Chinese Han of Beijing area. Using the case-control method, we included 404 T2DM patients in T2DM group and 500 age- and gender- matched healthy subjects in control group. We detected the distribution of alleles and genotypes of the three single nucleotide polymorphisms (SNPs, rs237025, rs237024 and rs600739) with the polymerase chain reaction-high resolution melting curve (PCR-HRM) combined with gene sequencing, analysed the differences of glycosylated hemoglobin A1c (HbA1c) among different genotypes carriers in T2DM group, and conducted a haplotype analysis. In this study, the results showed that the frequency of the G allele of rs237025 was significantly higher in T2DM group than that of control group (0.334 vs. 0.282, P = 0.017). Compared with control group, the GA genotype carriers of T2DM patients had 1.563 times more susceptibility to T2DM [P =0.001; odds ratio (OR), 1.563; 95% confidence interval (CI), 1.189-2.053]. Meanwhile, the G allele carriers (GG+GA) of T2DM patients had 1.525 times more susceptibility to T2DM in the dominant model (GG+GA vs. AA, P = 0.002; OR,1.525; 95% CI,1.169-1.989). However, as for rs237024 and rs600739, no significant differences were found in the distribution of the genotypes and alleles between two groups (P >0.05).Although our study didn't observe any statistically significant results, we found that T2DM patients with GG and GA genotypes of rs237025, TT genotype of rs237024 and GG genotype of rs600739 had a higher level of HbA1c than counterparts in control group. In addition, the AAC, AGC and GGT haplotypes might contribute to susceptibility to T2DM (OR>1) , while the AAT and GAC haplotypes might be considered as protective factors against T2DM (OR<1). The results suggested that rs237025 polymorphisms was associated with susceptibility to T2DM, but rs237024 and rs600739 were not. PMID- 22425951 TI - [Cardiomycyte overexpression of miR-27b resulted in cardiac fibrosis and mitochondria injury in mice]. AB - Previous microRNA (miRNA) array results have shown that the expression of miR-27b is upregulated in heart tissues from human cardiomyopathy and pressure-overloaded hypertrophic mouse model, implying that miR-27b might play an important role in heart diseases. To study the in vivo function of miR-27b, we generated a transgenic mouse line overexpressing miR-27b under the control of the 5.5 kb promoter of a-myosin heavy chain (a-MHC). Real-time PCR results demonstrated that miR-27b precursor and mature miR-27b were significantly increased in the heart tissues of miR-27b transgenic mice. miR-27b transgenic mice not only displayed cardiac hypertrophy, but also exhibited significant cardiac fibrosis. Further study showed that matrix metalloproteinase 13 (MMP13), a key regulator involved in cardiac fibrosis, was the target of miR-27b. The expression of MMP13 was decreased and the expression of Col I and III was increased in miR-27b transgenic mice.. In addition, defects in ultrastructral architecture were also found in miR 27b trans-genic mice. The above results demonstrated that miR-27b might promote cardiac fibrosis through inhibiting MMP13. PMID- 22425952 TI - [mRNA expression of lipogenic genes in mouse mammary gland in different lactation stages]. AB - To investigate the expression pattern of lipogenic genes in mammary gland of mouse in different lactation stages, the relative mRNA abundance and expression of 20 genes involved in milk fat synthesis and secretion of lactating mammary tissues were assessed using real-time PCR. Results revealed the significant upregulation of mRNA expression for both high abundant genes (abundance > 5%), such as LPL, ACACA, SCD, XDH, BTN, and ADFP and moderate abundant genes (5% > abundance > 1%), such as CD36, FASN, AGPAT6, and DGAT in lactation stages compared to pregnancy (P < 0.05). The mRNA expression of lipogenic enzyme genes for ACACA, SCD, FASN, AGPAT6, and DGAT exhibited lower expression lever in early (6 d) and late (18 d) lactation stages but higher expression level at middle stage (12 d), demonstrating a low-high-low pattern. Besides, the mRNA levels of some gene regulators were also measured. The mRNA expression of SREBF gene increased gradually along with the lactation, which showed a 10-fold elevation at middle stage (12 d). The expression pattern of SREBF gene was the same as lipogenic enzyme genes, suggesting that SREBF may play an important role in the regulation of lipogenic enzyme genes in the lactating mammary gland. PMID- 22425953 TI - [Effect of TSA and VPA treatment on long-tailed macaque (Macaca fascicularis)-pig interspecies somatic cell nuclear transfer]. AB - Long-tailed macaque-pig interspecies somatic cell nuclear transfer (iSCNT) is beneficial to yield embryonic stem cells from iSCNT embryos with similar genetic background as human, which can be used as materials for medical and basic research. The primary objective of this study was to investigate the effects of concentrations and treatment duration of two histone deacetylase inhibitors Trichostatin A (TSA) and Valproic acid (VPA) and two different embryo culture media (PZM-3 and HECM-10) on the in vitro development of iSCNT embryos. The results suggested that when PZM-3 was used as the embryo culture medium, the blastocyst rate of 10 nmol/L TSA treatment for 48 h was significantly higher than the control group (22.78% vs 9.86%, P< 0.05). However, neither in PZM-3 nor in HECM-10, 2-10 mmol/L VPA treatment did not increase the in vitro developmental potential of iSCNT embryos. It was concluded that TSA treatment could enhance the in vitro developmental potential of long-tailed macaque-pig iSCNT embryos. PMID- 22425954 TI - [Specific gene silencing of At1g13770 and At2g23470 by artificial mi-croRNAs in Arabidopsis]. AB - DUF647 (domain of unknown function 647) protein family is found in diverse eukaryotic organisms and highly conserved in eukaryotes. It has 6 members in Arabidopsis genome. So far, the function of 4 members of Arabidopsis DUF647 family is unknown. In this report, using an endogenous Arabidopsis MIR319a precursor as the backbone, we constructed two artificial microRNAs (amiRNAs) to knock down the expression of two DUF647 family genes At1g13770 and At2g23470. Using the WMD (Web microRNA Designer) platform, we designed two amiRNAs targeting At1g13770 and At2g23470 genes, respectively. Both amiRNAs sequences were engineered into the MIR319a precursor using overlapping PCR and the amiRNAs backbones were transferred into the binary vector pCHF3. The resulting plasmids that harbor amiRNAs stem loop fragments were transformed into Arabidopsis by Agrobacterium-mediated floral diping. Upon constitutive expression of these two amiRNAs, the target genes were efficiently down-regulated in transgenic line. The decreased level of At2g23470 transcript in At2g23470-amiRNA transgenic plants resulted in severe sterility. This work will facilitate the functional analysis of At1g13770 and At2g23470 genes in Arabidopsis growth and development. PMID- 22425955 TI - [Isolation and characterization of an alkaline xylanasefrom a newly isolated Bacillus sp. QH14]. AB - Twenty-fivealkaline xylanase producing strains were isolated from Qinghai Lake side soil samples. Among these strains, QH14 produced 648.79 U/mLxylanase, and the enzymatic specific activity was 1148.56 U/mg after purification. This alkaline xylanase producing strain belongs to genus Bacillus based on16S rDNA sequencing analysis and then was designated as Bacillus sp. QH14. The alkalinexylanaseencoding gene, XynQH14, was cloned from Bacillus sp. QH14 and expressed in Escherichiacoli BL21 (DE3). The specific activity of the recombinant xylanase XynQH14 was 700.47 Umg-1 after purification by Ni-NTA affinity chromatography. The optimal temperature and pH of XynQH14 were 60C and pH9.2, respectively. Its activity was 50% of initial activity after incubation at 55 C for 1h, 80% at pH7-11 at 37 C for 24 h, and 31.02% at pH11 at 50C after 24 h, indicating that XynQH14 isthermostable and alkali-stable. These properties ofXynQH14 suggest its favorable potential applications in pulp and paper industries. PMID- 22425956 TI - [Molecular detection of tomato yellow leaf curl virus (TYLCV)]. AB - Tomato yellow leaf curl virus (TYLCV) is currently considered as one of the most devastating viruses in cultivated tomatoes (Solanum lycopersicum) worldwide. We reported here the development of a PCR-based method to quickly detect TYLCV using the primer pairs (TYLCV-F: 5'-ACG CAT GCC TCT AAT CCA GTG TA-3' and TYLCV-R: 5' CCA ATA AGG CGT AAG CGT GTA GAC-3'), which was designed based on the genome sequence of TYLCV. A TYLCV-specific band of 543 bp was amplified from infected tomato plants. This protocol provides a rapid, reliable, and sensitive tool for molecular detection and identification of TYLCV in the industrial seedling and virus resistance breeding to facilitate safe and sustainable production of tomato. PMID- 22425957 TI - [Purification of Taq DNA polymerase expressed in Escherichia coli]. AB - Taq DNA polymerase is one of the most commonly thermostable DNA polymerases in molecular biological researches, which shares its basic characters with others of the family, thereby its purifying strategy could be used not only in itself production but also in the extraction of the others as a reference. At present, the protocols reported for large scale preparation of Taq DNA are high cost, so a cheaper method was described here. In this protocol, by heat denaturation, ammonium sulfate precipitation and cation exchange chromatography of 724 resin, about 18 g powder of Na form resin could recover about 27.07 mg of Taq enzyme. The total activity and specific activity were approximately 2.2 * 105 U and 8131.98 U/mg. The total yield was about 48.92% with 59.35 of purification folds. Analysis of quality of purified enzyme indicated that only one protein 94 kDa was identified against SDS-PAGE and the remnant of DNA nuclease was not detected. For PCR reaction, The amplification ability of purified Taq polymerase was not different from that of the commercially avail-able ones. This method reported in the present study is effective and low cost, making it suitable for general purification in laboratories or business production. PMID- 22425958 TI - [Application of documentary in teaching genetics]. AB - This paper describes the advantages and the existing problems of the application of documentary in teaching genetics. Meanwhile, the corresponding improvement approaches were provided based on these problems. The advantages and function of documentary in teaching course will be fully developed and the teaching quality will be improved. PMID- 22425959 TI - Differential sensitivity of melanoma cell lines with differing B-Raf mutational status to the new oncogenic B-Raf kinase inhibitor UI-152. AB - Activating mutations in B-Raf kinase are common in malignant melanoma, an aggressive tumor of neuroectodermal origin. In the present study, the antiproliferative effect of the new oncogenic B-Raf targeting drug UI-152 on two types of melanoma cell lines with differing B-Raf mutational status was examined, and the underlying mechanisms were investigated. In cellular assays, UI-152 displayed high selectivity for tumor cells bearing B-Raf(V600E), showing more than 1000-fold higher inhibition of their proliferation than wild-type B-Raf bearing cells. As expected, UI-152 completely abolished MEK-ERK phosphorylation in A375P cells harboring B-Raf(V600E). In SK-MEL-2 cells expressing B-Raf(WT), UI 152 caused the paradoxical activation of the MAPK pathway but to a much lesser extent than that observed of other oncogenic B-Raf inhibitors. These data suggest that UI-152 may be a more ideal B-Raf inhibitor capable of preserving potency against oncogenic B-Raf while minimizing the paradoxical activation of MAPK signaling. In addition, we showed that UI-152 treatment of A375P cells simultaneously induced cellular autophagy and apoptosis. However, autophagy inhibition with 3-methyladenine and inhibition of apoptosis by overexpression of the X-linked inhibitor of apoptosis failed to rescue melanoma cells from UI-152 induced cell death, implying that apoptosis and autophagy may cooperate in the induction of cell death in UI-152-treated cells. Collectively, our data suggest that UI-152 may be an effective B-Raf inhibitor and a potential therapeutic strategy for B-Raf(WT) and Ras mutant melanoma. PMID- 22425960 TI - Anti-angiogenesis therapy in cancer: current challenges and future perspectives. AB - It has been nearly 9years since the FDA (Food and Drug Administration) approved the first anti-angiogenic drug (bevacizumab) for treatment of metastatic colorectal cancer. Other angiogenic inhibitors have since been approved or are in different stages of clinical trials. However, continued clinical and preclinical investigations have identified major drawbacks associated with the application of this class of agents, including inherent/acquired resistance and induction of tumor invasiveness. In addition, lack of thoroughly validated predictive biomarkers has been one of the major hurdles to stratify cancer patients and to monitor tumor progression and response to the therapy. Investigations in clinic and preclinical models have provided some molecular and cellular mechanisms for the above challenges. This review aims to provide a concise update from recent findings. PMID- 22425962 TI - Protein S-nitrosylation and cancer. AB - Protein S-nitrosylation is a covalent post-translational modification through coupling of a nitric oxide (NO) moiety with the reactive thiol group of a protein cysteine residue to form an S-nitrosothiol (SNO). S-nitrosylation is a key mechanism in the transmission of NO-based cellular signals in the vital cellular processes, including transcription regulation, DNA repair, and apoptosis. Contemporary research has implicated dysregulation of S-nitrosylation in severe pathological events, including cancer onset, progression, and treatment resistance. The S-nitrosylation status may be directly linked to many cancer therapy outcomes as well as therapeutic-resistance, emphasizing the need to develop S-nitrosylation-related anti-cancer therapeutics. The role of S nitrosylated proteins in the development and progression of cancer are varied, generating a critical need for a thorough review of the current dynamic research in this area. PMID- 22425963 TI - Introduction--Notch in development and disease. PMID- 22425961 TI - Overcoming nucleoside analog chemoresistance of pancreatic cancer: a therapeutic challenge. AB - Clinical refractoriness to nucleoside analogs (e.g., gemcitabine, capecitabine) is a major scientific problem and is one of the main reasons underlying the extremely poor prognostic state of pancreatic cancer. The drugs' effects are suboptimal partly due to cellular mechanisms limiting their transport, activation, and overall efficacy. Nonetheless, novel therapeutic approaches are presently under study to circumvent nucleoside analog resistance in pancreatic cancer. With these new approaches come additional challenges to be addressed. This review describes the determinants of chemoresistance in the gemcitabine cytotoxicity pathways, provides an overview of investigational approaches for overcoming chemoresistance, and discusses new challenges presented. Understanding the future directions of the field may assist in the successful development of novel treatment strategies for enhancing chemotherapeutic efficacy in pancreatic cancer. PMID- 22425964 TI - Looking back and thinking forward: 20 years of disability and rehabilitation research. AB - The National Center for Medical Rehabilitation Research recently celebrated its 20th Anniversary. The celebration included a symposium highlighting advances in rehabilitation science over the past 2 decades. The anniversary also reminds us of the challenges that remain in order to strengthen the foundation of disability and rehabilitation research. These challenges have been described in 3 reports published by the Institute of Medicine (IOM) in 1991, 1997, and 2007. Three areas of concern appear across the IOM reports. These include (1) the lack of a comprehensive disability monitoring program, (2) the need for better integration and coordination of federally supported disability research, and (3) funding levels that are inconsistent with the current and projected impacts of disability on individuals, families, and communities. In this commentary we examine the lack of progress in addressing the recommendations contained in the IOM reports. We conclude that renewed efforts by consumers, clinicians, educators, researchers, administrators, and policy makers are needed to achieve the promise of rehabilitation and disability science identified 20 years ago. PMID- 22425965 TI - Specific lipids influence the import capacity of the chloroplast outer envelope precursor protein translocon. AB - Recent studies demonstrated that lipids influence the assembly and efficiency of membrane-embedded macromolecular complexes. Similarly, lipids have been found to influence chloroplast precursor protein binding to the membrane surface and to be associated with the Translocon of the Outer membrane of Chloroplasts (TOC). We used a system based on chloroplast outer envelope vesicles from Pisum sativum to obtain an initial understanding of the influence of lipids on precursor protein translocation across the outer envelope. The ability of the model precursor proteins p(OE33)titin and pSSU to be recognized and translocated in this simplified system was investigated. We demonstrate that transport across the outer membrane can be observed in the absence of the inner envelope translocon. The translocation, however, was significantly slower than that observed for chloroplasts. Enrichment of outer envelope vesicles with different lipids natively found in chloroplast membranes altered the binding and transport behavior. Further, the results obtained using outer envelope vesicles were consistent with the results observed for the reconstituted isolated TOC complex. Based on both approaches we concluded that the lipids sulfoquinovosyldiacylglycerol (SQDG) and phosphatidylinositol (PI) increased TOC mediated binding and import for both precursor proteins. In contrast, enrichment in digalactosyldiacylglycerol (DGDG) improved TOC-mediated binding for pSSU, but decreased import for both precursor proteins. Optimal import occurred only in a narrow concentration range of DGDG. PMID- 22425966 TI - 7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome. AB - Smith-Lemli-Opitz syndrome (SLOS) is a recessive disease characterized by markedly elevated levels of 7-dehydrocholesterol (7-DHC) and reduced levels of cholesterol in tissues and fluids of affected individuals, due to defective 3beta hydroxysterol-Delta(7)-reductase (Dhcr7). Treatment of Sprague Dawley rats with AY9944 (an inhibitor of Dhcr7) leads to similar biochemical features as observed in SLOS. Eighteen oxysterols previously have been identified as oxidation products of 7-DHC (most of them distinct from cholesterol (Chol)-derived oxysterols) in solution, in cells, and in brains obtained from Dhcr7-KO mice and AY9944-treated rats, formed either via free radical oxidation (peroxidation) or P450-catalyzed enzymatic oxidation. We report here the identification of five 7 DHC-derived oxysterols, including 3beta,5alpha-dihydroxycholest-7-en-6-one (DHCEO), 4alpha- and 4beta-hydroxy-7-DHC, 24-hydroxy-7-DHC and 7-ketocholesterol (7-kChol, an oxysterol that is normally derived from Chol), in the retinas of AY9944-treated rats by comparing the retention times and mass spectrometric characteristics with corresponding synthetic standards in HPLC-MS analysis. Levels of 4alpha- and 4beta-hydroxy-7-DHC, DHCEO, and 7-kChol were quantified using d(7)-DHCEO as an internal standard. Among the five oxysterols identified, only 7-kChol was observed in retinas of control rats, but the levels of 7-kChol in retinas of AY9944-rats were 30-fold higher. Intravitreal injection of 7-kChol (0.25MUmol) into a normal rat eye induced panretinal degeneration within one week; by comparison, contralateral (control) eyes injected with vehicle alone exhibited normal histology. These findings are discussed in the context of the potential involvement of 7-DHC-derived oxysterols in the retinal degeneration associated with the SLOS rat model and in SLOS patients. PMID- 22425967 TI - Nucleotide sequencing and DNA polymorphism studies of BMP 15 gene in Corriedale and local Kashmir valley sheep (Ovis aries). AB - The families of TGF-beta proteins are the most important growth factors in the ovary for growth and differentiation of early ovarian follicles. Three related oocyte-derived members of the transforming growth factor-beta superfamily, namely GDF9, BMP15 and BMPR-IB have been shown to be essential for follicular growth and ovulation. The objective of the present study was to detect the incidence of mutation in intronic portion of BMP 15 gene in Corriedale and local Kashmir valley sheep breeds. Blood samples were collected from 85 ewes and genomic DNA was extracted using the modified phenol chloroform method. The quantity and quality of extracted DNA was examined using spectrophotometry and gel electrophoresis, respectively. A fragment with the size of 356 bp was amplified using polymerase chain reaction (PCR) with a pair of specific primers. The amplified PCR products were digested with Mph11031 restriction enzyme. In the presence of mutation at this locus, the Mph11031 enzyme cannot recognize the restriction site. However, here in the absence of mutations, the enzyme recognizes one restriction site and divides the amplified fragment into two fragments of 152 and 204 bp. The 356 bp fragment was also analyzed for polymorphism by SSCP technique. The results indicated two different banding patterns AA and AB for this fragment. Later on two different allelic forms A and B were confirmed by nucleotide sequencing. The 356 bp nucleotide sequence was subjected to alignment analysis and it was observed that sequence similarity of this fragment with that of other sheep and Jining grey goat was more than 97.8%. Phylogenetic analysis revealed that both designated A and B alleles as well as published sequence of sheep form a common cluster indicating their evolutionary closeness. The origin of Jining grey goat was located some distance away from the sheep. The overall frequencies of AA and AB genotypes were 0.79 and 0.21. The breed wise frequencies were 0.78 and 0.22 in Corriedale sheep and the frequencies in Kashmir valley sheep were 0.80 and 0.20 for AA and AB genotypes, respectively. The overall allelic frequencies of A and B alleles were 0.89 and 0.11 whereas allelic frequencies Corriedale sheep was 0.89 and 0.11 and that of Kashmir valley sheep were 0.90 and 0.10. PMID- 22425968 TI - Delivery of AP-2alpha siRNA into cultured bovine trophoblast cells by electroporation repressed key placenta-specific gene expression. AB - Binucleate trophoblast giant cells (BNC) characteristically appear early in gestation in the bovine placenta. They secret pivotal hormones and cytokines for feto-maternal communication, for example, expression of placental lactogens (CSH1), prolactin-related protein 1 (PRP1) and pregnancy-associated glycoprotein 1 (PAG1) are necessary for pregnancy establishment in bovine. These genes transcription are regulated in a temporal and spatial manner, however, molecular mechanisms by which these gene transcriptions are regulated in this manner have not been firmly elucidated. In this study, a cell culture model for bovine trophoblast cells was initially established, small interfering RNA duplexes against Activator Protein-2alpha (TFAP2A) was transfected into the cells by electroporation, and transcripts of CSH1, PRP1 and PAG1 were measured by qPCR. The results showed that trophoblast giant cells were confluent for 90% after cultured for 10 days, and BNC constituted of a population of more than 45% of the total cells. Using a fluorescein-labeled non-silencing siRNA duplex, an electroporation protocol yielding routinely >93% positive cells could be established, and siRNA duplex transfection demonstrated an efficient knockdown of cellular AP-2alpha mRNA level by 72.30 +/- 3.28% in electroporated cells. Finally, CSH1, PRP1 and PAG1 genes expression were effectively down-regulated by 65.45 +/- 6.38% (P<0.01), 40.73+/-11.72% (P<0.01) and 11.59 +/- 1.88% (P<0.05), respectively. It was therefore suggested that electroporating siRNA into bovine trophoblast cells could be an efficient method to manipulate BNC function and to study the regulation mechanism of specific gene transcription without the use of chemical transfection reagents. It was suggested that AP-2alpha could be at least involved in the regulation of expression CSH1 and PRP1 transcripts. PMID- 22425969 TI - Detection of truncated dystrophin lacking the C-terminal domain in a Chinese pedigree by next-generation sequencing. AB - Dystrophin (DMD) gene is the largest gene containing 79 exons involving various mutation types and regions, and targeted next-generation sequencing (NGS) was employed in detecting DMD gene mutation in the present study. A literature annotated disease nonsense mutation (c.10141C>T, NM_004006.1) in exon 70 that has been reported as Duchenne Muscular Dystrophy (DMD)-causing mutation was found in our two patients, the proband and his cousin. In the present study two main methods were used, the next-generation sequencing and the classic Sanger sequencing. The exon capture followed by HiSeq2000 sequencing was specifically used in this study. Combined applications of the next-generation sequencing platform and bioinformatics are proved to be effective methods for DMD diagnosis. PMID- 22425970 TI - Physical localization and probable transcriptional activity of 18S-5.8S-26S rRNA gene loci in some Asiatic Cymbidiums (Orchidaceae) from north-east India. AB - Fluorescence in situ hybridization based physical localization of 45S ribosomal DNA in eight horticulturally important species of Cymbidium (Orchidaceae) from north-east India (South-East Asia) has been carried for the first time. Observations revealed only one pair of chromosomes had NOR loci. Three, out of eight Cymbidiums showed decondensed, dispersed, extended form of hybridization signals of rDNA as dots of fluorescence (transcriptionally active), where as the rest of the Cymbidiums revealed condensed (non-active) forms, hence demonstrated the heteromorphism in size, intensities and their appurtenance which may be under epigenetic control. Except for the ribosomal genes, no other active genes have been reported to reside within the nucleoli. Such observations provide useful chromosome landmarks and provide valuable evidence about the genome evolution, speciation and ploidy both at molecular and chromosomal levels which is more or less highly ambiguous in family Orchidaceae. PMID- 22425971 TI - Genetic association of the gene encoding RPGRIP1L with susceptibility to vascular dementia. AB - A previous genome-wide association study (GWAS) failed to discover any nucleotide sequence variant associated with susceptibility to vascular dementia (VaD) and remained a problem of false negatives produced by a low statistical power. The current study was conducted to identify such potential false negatives and to provide comprehensive evidence for the most plausible predisposing genetic factor using large-scale Korean cohorts. We identified the gene encoding retinitis pigmentosa GTPase regulator-interacting protein 1-like (RPGRIP1L) with multiple nucleotide variants associated with susceptibility to VaD by a modest significant threshold (P<10(-4)). Genetic associations were intensively examined with its sequence variants using 207 VaD patients and 207 age- and gender-matched control subjects. Genetic association analysis with dense variants in the region associated with VaD revealed 3 variants (P<0.0017) in strong linkage. Further analysis with VaD-related phenotypes using Korean Association REsource (KARE) cohort data showed that the region of the gene was associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood pressure (BP) (P<7.6*10(-4)). The current study provided the first evidence of the association between RPGRIP1L gene and susceptibility of VaD. Functional studies are needed to understand underlying biological mechanism of the genetic association. PMID- 22425972 TI - Frequency distribution of single nucleotide polymorphisms in P-selectin gene in Chinese Tibetan and Han populations. AB - BACKGROUND: Chinese Tibetans have a series of distinctive physiological traits which enable them to tolerate the extreme environment of the Tibetan plateau. P selectin gene has been proved to be highly polymorphic in Europeans and Americans. Nevertheless, studies on either the frequency distributions of single nucleotide polymorphisms (SNPs) or haplotype diversity and linkage disequilibrium of P-selectin gene in Chinese Tibetan population are still unavailable. METHODS: The frequency distributions of 3 SNPs in P-selectin gene promoter (-2123C/G, 1969A/G, -1817T/C) and 3 SNPs in exon region (Ser290Asn, Val599Leu, Thr715Pro) were investigated by real-time PCR and high-resolution melting method among 314 Chinese Tibetans and 328 age- and sex-matched Han people. RESULTS: The frequencies of the -2123G and -1817T alleles among the Tibetan population had no significant differences from those of the Han population. Among the Tibetan population, the G allele frequency of -1969A/G and Ser290Asn were both higher than those of the Han population. Val599Leu and Thr715Pro did not show any polymorphism in the two populations. In the Tibetan population, -2123C/G, 1969A/G, -1817T/C and Ser290Asn were in tight linkage disequilibrium with each other. CONCLUSIONS: The frequency distributions of -1969A/G and Ser290Asn polymorphisms in the Tibetan population were different from those in the Han population. PMID- 22425973 TI - Isolation and characterization of Glu-1 genes from the St genome of Pseudoroegneria libanotica. AB - The St genome, which is present in nearly half of all Triticeae species, originates from the genus Pseudoroegneria. However, very little is known about the high molecular weight (HMW) subunits of glutenin which are encoded by the St genome. In this paper, we report the isolation from Pd. libanotica of four sequences encoding HMW subunits of glutenin. The four genes were all small compared to standard glutenin genes. All four sequences resemble y-type glutenins rather than x-types. However, their N-terminal domains contain a glutamine residue which is present in all x-type, but very few y-type subunits, and their central repetitive domains included some irregular motifs. The indication is therefore that the Glu-1St genes evolved earlier than other modern day homoeologues, so that they represent an intermediate state in the divergence between x- and y-type subunits. No x-type Glu-1St subunit genes were identified. PMID- 22425974 TI - Genomic organization, phylogenetic comparison and expression profiles of annexin gene family in tomato (Solanum lycopersicum). AB - Annexins have been suggested to play pivotal roles in stress resistance and plant development. However, related studies on fruit-bearing plants, especially on fruit development, are very limited. In the present study, we provide a comprehensive overview of the annexin family in tomato, describing the gene structure, promoter cis-regulatory elements, organ expression profile, and gene expression patterns under hormone and stress treatments. Bioinformatic analysis revealed that the nine tomato annexins were structurally different from their animal counterparts, but highly conserved annexin domains were still found in most of them. Cis-regulatory element prediction showed that there were important elements in the 2kb upstream promoter regions, including stress- and hormone responsive-related elements. The expression patterns of these genes were investigated, and the results revealed that they were regulated under developmental processes and environmental stimuli. Among them, AnnSl1.1 and AnnSl2 were highly expressed in most of the tested organs. Genes preferentially or specifically expressed in organs, such as stigma or ovary (AnnSl6), stamen (AnnSl8), and fruit pericarp (AnnSl1.2 and AnnSl9), were identified. Some annexin genes were induced by plant hormones including abscisic acid (AnnSl3, AnnSl6, AnnSl8, and AnnSl9) and gibberellic acid (AnnSl1.1, AnnSl1.2, AnnSl4, and AnnSl7). Most of these annexin genes were induced by salt, drought, wounding, and heat or cold stresses. The present study provides significant information for understanding the diverse roles of annexins in tomato growth and development. PMID- 22425975 TI - rs4215 SNP in zinc-alpha2-glycoprotein gene is associated with obesity in Chinese north Han population. AB - OBJECTIVE: Zinc-alpha2-glycoprotein (ZAG) has been identified recently as a novel adipokine due to its close link with lipid and glucose metabolism, as well as regulation of body weight. The aim of our present study is to investigate the ZAG genetic polymorphism association with obesity in Chinese north Han population. DESIGN AND METHODS: Five SNPs of ZAG gene including rs2247607 (A>T), rs4727442 (G>T), rs4215 (A>G), rs2527923 (C>T) and rs2527882 (C>T) were genotyped in 648 overweight/obese patients and 313 healthy controls by TaqMan-PCR methods. Crosstabs statistical analysis method with subjects stratifying by age (? 30 y, 31-45 y, ? 46 y) and gender was used. RESULTS: The results showed the constitution of three genotype frequencies in rs4215 (A>G) site significantly differs in male subgroup (aged 31-45 y) between overweight/obese and healthy control group (chi(2)=6.401, P=0.041). GG genotype frequency in overweight/obese group is 19.3% which is much higher than 6.1% in healthy control group. Further statistical analysis under a recessive inheritance model demonstrated odd ratio (OR) for GG vs. AA+AG in overweight/obese group was 3.674 (95% CI 1.049-12.866; P=0.035). Among three genotypes of rs4215, the subjects with GG genotype have much more higher body weight, BMI, waist circumference and SBP. CONCLUSION: Our data, for the first time, suggest the genotypes of rs4215 in ZAG gene are significantly associated with obesity in Chinese north Han population. GG genotype subjects in rs4215 site have an increased susceptibility to obesity when compared with the AA+AG genotype subjects. PMID- 22425976 TI - Identification and characterization of the microRNAs and their targets in Salmo salar. AB - MicroRNAs (miRNAs) are small, non-coding and regulatory RNAs about 18 to 26 nucleotides long. Their conserved nature among the various organisms makes them a good source of new miRNAs discovery by comparative genomics approach. The study resulted in novel 75 precursor miRNAs containing 102 mature sequences belonging to 46 families in an important aquatic environmental monitoring fish (Salmo salar). All the miRNA families (let-7, mir-1, 7, 9, 21, 22, 92, 96, 122, 126, 128, 129, 132, 133, 142, 144, 147, 148, 196, 202, 212, 223, 375, 429, 430, 449, 451, 457, 466, 682, 700, 1388, 1594, 1600, 1607, 1616, 1642, 1681, 1701, 1720, 1772, 1782, 1787, 1814, 2189 and 3540) are found for the first time in S. salar. All 75 miRNA precursors form stable minimum free energy stem loop and the mature miRNAs reside in the stem portion of the stem loop structure. Their target proteins are involved in transcription factors (28%), metabolism (23%), signaling (18%), transportation (9%), immunity (8%), stress related activity (5%), cancer and tumor related activity (5%), growth and development (3%), and cell division (1%). PMID- 22425977 TI - Promoter contribution to the testis-specific expression of Stellate gene family in Drosophila melanogaster. AB - Testis-specific tandemly repeated Stellate genes are part of the Ste-Su(Ste) genetic system required for male fertility in Drosophila melanogaster. Stellate genes encode a functional homolog of the beta-subunit of protein kinase CK2. Derepression of Stellate results in their over-expression, meiotic disturbances and male sterility. Stellate genes are represented by clustered copies in the X chromosome and carry promoters shared with another X-chromosome cluster, betaNACtes genes, encoding putative beta-subunits of the nascent polypeptide associated complex. Using Electrophoretic Mobility Shift Assay, we revealed in the Stellate promoter three cis-acting elements, E-boxes, the loss of which greatly diminished the reporter gene expression in Drosophila testes. We identified that these E-boxes were recognized by helix-loop-helix protein, dUSF (Drosophila ortholog of mammalian USF) in testis nuclear extract. All three E boxes were preserved in the promoters of both euchromatic and heterochromatic Stellate clusters. Two analogous E-boxes were detected in the promoters of 5' copies of the duplicated betaNACtes gene pairs, whereas the 3'-copies lacked these sites but possessed a new binding site for a testis protein distinct from dUSF. Here we characterized a new type of testis-specific core promoter and identified dUSF as its interacting transcription factor. PMID- 22425978 TI - Molecular cloning, bacterial expression and promoter analysis of squalene synthase from Withania somnifera (L.) Dunal. AB - Withania somnifera (ashwagandha) is a rich repository of large number of pharmacologically active secondary metabolites known as withanolides. Though the plant has been well characterized in terms of phytochemical profiles as well as pharmaceutical activities, but there is sparse information about the genes responsible for biosynthesis of these compounds. In this study, we have cloned and characterized a gene encoding squalene synthase (EC 2.5.1.21) from a withaferin A rich variety of W. somnifera, a key enzyme in the biosynthesis of isoprenoids. Squalene synthase catalyses dimerization of two farnesyl diphosphate (FPP) molecules into squalene, a key precursor for sterols and triterpenes. A full-length cDNA consisting of 1765 bp was isolated and contained a 1236 bp open reading frame (ORF) encoding a polypeptide of 411 amino acids. Recombinant C terminus truncated squalene synthase (WsSQS) was expressed in BL21 cells (Escherichia coli) with optimum expression induced with 1mM IPTG at 37 degrees C after 1h. Quantitative RT-PCR analysis showed that squalene synthase (WsSQS) expressed in all tested tissues including roots, stem and leaves with the highest level of expression in leaves. The promoter region of WsSQS isolated by genome walking presented several cis-acting elements in the promoter region. Biosynthesis of withanolides was up-regulated by different signalling components including methyl-jasmonate, salicylic acid and 2, 4-D, which was consistent with the predicted results of WsSQS promoter region. This work is the first report of cloning and expression of squalene synthase from W. somnifera and will be useful to understand the regulatory role of squalene synthase in the biosynthesis of withanolides. PMID- 22425979 TI - Methylglyoxal promotes oxidative stress and endothelial dysfunction. AB - Modern diets can cause modern diseases. Research has linked a metabolite of sugar, methylglyoxal (MG), to the development of diabetic complications, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether MG could directly influence endothelial function, oxidative stress and inflammation in Wistar and Goto-Kakizaki (GK) rats, an animal model of type 2 diabetes. Wistar and GK rats treated with MG in the drinking water for 3 months were compared with the respective control rats. The effects of MG were investigated on NO-dependent vasorelaxation in isolated rat aortic arteries from the different groups. Insulin resistance, NO bioavailability, glycation, a pro inflammatory biomarker monocyte chemoattractant protein-1 (MCP-1) and vascular oxidative stress were also evaluated. Methylglyoxal treated Wistar rats significantly reduced the efficacy of NO-dependent vasorelaxation (p<0.001). This impairment was accompanied by a three fold increase in the oxidative stress marker nitrotyrosine. Advanced glycation endproducts (AGEs) formation was significantly increased as well as MCP-1 and the expression of the receptor for AGEs (RAGE). NO bioavailability was significantly attenuated and accompanied by an increase in superoxide anion immunofluorescence. Methylglyoxal treated GK rats significantly aggravated endothelial dysfunction, oxidative stress, AGEs accumulation and diminished NO bioavailability when compared with control GK rats. These results indicate that methylglyoxal induced endothelial dysfunction in normal Wistar rats and aggravated the endothelial dysfunction present in GK rats. The mechanism is at least in part by increasing oxidative stress and/or AGEs formation with a concomitant increment of inflammation and a decrement in NO bioavailability. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of atherosclerosis and development of macrovascular diabetic complication. PMID- 22425980 TI - Serum profiling based on fucosylated glycoproteins for differentiating between chronic hepatitis B and hepatocellular carcinoma. AB - Chronic infection with hepatitis B virus (HBV) is associated with the majority of cases of hepatocellular carcinoma (HCC) in China. Despite this, there is no effective method for the early detection of HBV-induced liver cancer. Aberrant fucosylation is known to occur during the development of HCC. We, therefore, developed a method of applying matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS) to analyze the relationship between aberrant fucosylation, tumor genesis and progression of HBV-associated HCC, and to establish proteomic profiling of serum for early diagnosis of HCC. The MALDI TOF MS was based on Lens culinaris agglutinin (LCA) lectin magnetic beads and their affinity for separation. The method was applied initially to a 'training' cohort of 111 serum samples obtained from subjects in China with no liver disease (n=26), chronic hepatitis B without cirrhosis (n=21), HBV-infected cirrhosis (n=32), or HBV-infected HCC (n=32). In contrast to previous findings, the results of our profiling analysis demonstrated defucosylation on some of the glycoproteins involved in HCC. HCC was then diagnostically classified in a 'blind test' cohort (n=96). In this group we demonstrated that, HCC could be distinguished from all serum samples, HBV-associated chronic liver disease, and HBV-associated cirrhosis with a sensitivity/specificity of 70%/70%, 78%/74%, and 81%/82%, respectively. When combined with serum alpha-fetoprotein detection (AFP>20 ng/mL), the sensitivity/specificity improved to 78%/88%, 85%/88%, and 89%/91%, respectively. In conclusion, serum glycoprotein fucosylation abnormalities have diverse forms in patients with HCC. MALDI-TOF MS profiling of aberrant serum fucosylated glycoproteins distinguished HCC from controls with high accuracy. PMID- 22425981 TI - Monoubiquitination of pro-amphiregulin regulates its endocytosis and ectodomain shedding. AB - All members of epidermal growth factor (EGF) family are expressed as transmembrane precursors on cell surfaces and then proteolytically converted to soluble ligands for EGF receptor (EGFR) by a disintegrin and metalloproteases (ADAMs). As enzyme-substrate complex formation is essential for this "ectodomain shedding", alteration of cell surface retention could affect their physical interaction with ADAMs and eventually contribute to shedding efficiency. Here, we showed that monoubiquitination of pro-amphiregulin (pro-AREG, an EGFR ligand) accelerated its half-life on cell surface. Monoubiquitination occurred at lysine 240 of pro-AREG as the primary acceptor site. Using a chimeric protein of pro AREG and a monomeric ubiquitin mutant (pro-AREGmUb), immunocytochemical analysis and a cell surface biotinylation assay revealed that a significant portion of pro AREGmUb was expressed on the cell surface, immediately endocytosed, and predominantly localized to early endosomes. Importantly, ectodomain shedding of pro-AREGmUb induced by tetradecanoyl phorbol acetate was significantly reduced in comparison to wild-type pro-AREG. These results suggested that pro-AREG monoubiquitination and the subsequent trafficking to intracellular organelles is a novel shedding regulatory mechanism that contributes to the secretion of EGFR ligands in growth factor signaling. PMID- 22425982 TI - Evidence that truncated TrkB isoform, TrkB-Shc can regulate phosphorylated TrkB protein levels. AB - Tropomyosin receptor kinase B (TrkB) is best known as the receptor for brain derived neurotrophic factor (BDNF). In humans, three major isoforms of TrkB, the full-length receptor (TrkB-TK+) and two C-terminal truncated receptors (TrkB-TK- and TrkB-Shc) are expressed in various tissues. In comparison to TrkB-TK+ and TrkB-TK-, TrkB-Shc is less well characterized. In this study, we analyzed the biological function of the TrkB-Shc receptor in response to exogenous BDNF treatment. In experiments transiently overexpressing TrkB-Shc in CHOK1 cells, we found that TrkB-Shc protein levels were rapidly decreased when cells were exposed to exogenous BDNF. When we assessed the functional impact of TrkB-Shc on TrkB-TK+ activity, we found that phosphorylated TrkB-TK+ protein levels were significantly decreased in the presence of TrkB-Shc and moreso following BDNF exposure. Interestingly, while the reduction of phosphorylated TrkB-TK+ protein was more pronounced in the presence of TrkB-Shc following BDNF exposure, the stability of TrkB-Shc protein itself was increased. Our findings suggest that cells may increase TrkB-Shc protein levels in response to exogenous BDNF exposure to regulate TrkB-TK+ activity by increasing degradation of activated receptor complexes as a means to prevent overactivation or inappropriate temporal and spatial activation of BDNF/TrkB-TK+ signaling. PMID- 22425983 TI - VCC-1 over-expression inhibits cisplatin-induced apoptosis in HepG2 cells. AB - Vascular endothelial growth factor-correlated chemokine 1 (VCC-1), a recently described chemokine, is hypothesized to be associated with carcinogenesis. However, the molecular mechanisms by which aberrant VCC-1 expression determines poor outcomes of cancers are unknown. In this study, we found that VCC-1 was highly expressed in hepatocellular carcinoma (HCC) tissue. It was also associated with proliferation of HepG2 cells, and inhibition of cisplatin-induced apoptosis of HepG2 cells. Conversely, down-regulation of VCC-1 in HepG2 cells increased cisplatin-induced apoptosis of HepG2 cells. In summary, these results suggest that VCC-1 is involved in cisplatin-induced apoptosis of HepG2 cells, and also provides some evidence for VCC-1 as a potential cellular target for chemotherapy. PMID- 22425984 TI - Site-specific conjugation of a lanthanide chelator and its effects on the chemical synthesis and receptor binding affinity of human relaxin-2 hormone. AB - Diethylenetriamine pentaacetic acid (DTPA) is a popular chelator agent for enabling the labeling of peptides for their use in structure-activity relationship study and biodistribution analysis. Solid phase peptide synthesis was employed to couple this commercially available chelator at the N-terminus of either the A-chain or B-chain of H2 relaxin. The coupling of the DTPA chelator at the N-terminus of the B-chain and subsequent loading of a lanthanide (europium) ion into the chelator led to a labeled peptide (Eu-DTPA-(B)-H2) in low yield and having very poor water solubility. On the other hand, coupling of the DTPA and loading of Eu at the N-terminus of the A-chain led to a water-soluble peptide (Eu DTPA-(A)-H2) with a significantly improved final yield. The conjugation of the DTPA chelator at the N-terminus of the A-chain did not have any impact on the secondary structure of the peptide determined by circular dichroism spectroscopy (CD). On the other hand, it was not possible to determine the secondary structure of Eu-DTPA-(B)-H2 because of its insolubility in phosphate buffer. The B-chain labeled peptide Eu-DTPA-(B)-H2 required solubilization in DMSO prior to carrying out binding assays, and showed lower affinity for binding to H2 relaxin receptor, RXFP1, compared to the water-soluble A-chain labeled peptide Eu-DTPA-(A)-H2. The mono-Eu-DTPA labeled A-chain peptide, Eu-DTPA-(A)-H2, thus can be used as a valuable probe to study ligand-receptor interactions of therapeutically important H2 relaxin analogs. Our results show that it is critical to choose an approriate site for incorporating chelators such as DTPA. Otherwise, the bulky size of the chelator, depending on the site of incorporation, can affect yield, solubility, structure and pharmacological profile of the peptide. PMID- 22425985 TI - The N-terminal domain determines the affinity and specificity of H1 binding to chromatin. AB - Linker histone H1, one of the most abundant nuclear proteins in multicellular eukaryotes, is a key component of the chromatin structure mainly due to its role in the formation and maintenance of the 30nm chromatin fiber. It has a three domain structure; a central globular domain flanked by a short N-terminal domain and a long, highly basic C-terminal domain. Previous studies have shown that the binding abilities of H1 are at large determined by the properties of the C terminal domain; much less attention has been paid to role of the N-terminal domain. We have previously shown that H1 can be reconstituted via cytoplasmic mRNA injection in Xenopus oocytes, cells that lack somatic H1. The heterologously expressed H1 proteins are incorporated into in vivo assembled chromatin at specific sites and the binding event is monitored as an increase in nucleosomal repeat length (NRL). Using this setup we have here compared the binding properties of wt-H1.4 and hH1.4 devoid of its N-terminal domain (DeltaN-hH1.4). The DeltaN-hH1.4 displays a drastically lower affinity for chromatin binding as compared to the wild type hH1.4. Our data also indicates that DeltaN-hH1.4 is more prone to unspecific chromatin binding than the wild type. We conclude that the N-terminal domain of H1 is an important determinant of affinity and specificity of H1-chromatin interactions. PMID- 22425986 TI - Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells. AB - Deleted in liver cancer (DLC1), a tumor suppressor gene in multiple cancers, is recurrently down regulated or inactivated by epigenetic mechanisms in primary prostate carcinomas (PCAs). In this study the methylation and acetylation profile of the DLC1 promoter region was examined in three PCA cell lines with low or undetectable DLC1 expression: LNCaP, its derivative C4-2B-2, and 22Rv1. Two histone deacetylase inhibitors (HDAC), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) induced histone acetylation of the DLC1 promoter in all three lines. DLC1 promoter methylation and deacetylation were detected in LNCaP and C4-2B-2 cells while in 22Rv1 cells DLC1 is silenced by deacetylation. Treatment with SAHA or TSA efficiently increased DLC1 expression in all lines, particularly in 22Rv1 cells, and activated the DLC1 promoter through the same Sp1 sites. The 22Rv1 cell line was selected to evaluate the efficacy of combined DLC1 transduction and SAHA treatment on tumor growth in athymic mice. Individually, DLC1 transduction and SAHA exposure reduced the tumor size by 75-80% compared to controls and in combination almost completely inhibited tumor growth. The antitumor effect was associated with the induction of apoptosis and inhibition of RhoA activity. SAHA alone significantly reduced RhoA activity, showing that this RhoGTPase is a target for SAHA. These results, obtained with a reliable preclinical in vivo test, predict that combined therapeutic agents targeting the pathways governing DLC1 function and HDAC inhibitors may be beneficial in management of prostate cancer. PMID- 22425987 TI - Adhesive force behavior of single ATDC5 cells in chondrogenic culture. AB - Cellular mechanical properties are implicated in numerous cell behaviors, but their involvement in cell differentiation process has remained unclear. Since mechanical interactions between chondrogenic cells and their surrounding environment heavily affect the maintenance of their differentiation phenotype, here, using a chondrogenic cell strain ATDC5, we evaluated cell mechanical properties (e.g., adhesive force and spring constant) and gene expression levels in differentiation culture. The adhesive force appeared to be affected by both cellular cytoskeletal and adhesive constructions. Treatment with Y27632, which accordingly inhibits actin polymerization, decreased the adhesive force while increased chondrogenic gene expressions, suggesting the both of them are interrelated via the mediation of actin cytoskeleton. However, the mechanical property did not represent chondrogenic differentiative stages as obviously as the biochemical characteristics. Meanwhile, interestingly, changes in cell distribution maps of the force in the differentiation process indicated that the cells have different levels of mechanical properties in the undifferentiated state, whereas they tend to converge when the differentiative stage is in a lull. These results reaffirm the cellular diversity during differentiation from a mechanical perspective and provide important information to the fields of generation and scaffold-based tissue regeneration, where cell-substrate adhesion plays a role. PMID- 22425988 TI - Molecular characterization of the Trypanosoma cruzi specific RNA binding protein TcRBP40 and its associated mRNAs. AB - Trypanosoma cruzi is the causative agent of Chagas disease, a neglected disorder that affects millions of people in the Americas. T. cruzi relies mostly upon post transcriptional regulation to control stage specific gene expression. RNA binding proteins (RBPs) associate with functionally related mRNAs forming ribonucleoprotein complexes that define post-transcriptional operons. The RNA Recognition Motif (RRM) is the most common and ancient family of RBPs. This family of RBPs has been identified in trypanosomatid parasites and only a few of them have been functionally characterized. We describe here the functional characterization of TcRBP40, a T. cruzi specific RBP, and its associated mRNAs. We used a modified version of the recombinant RIP-Chip assay to identify the mRNAs with which it associates and in vivo TAP-tag assays to confirm these results. TcRBP40 binds to an AG-rich sequence in the 3'UTR of the associated mRNAs, which were found to encode mainly putative transmembrane proteins. TcRBP40 is differentially expressed in metacyclogenesis. Surprisingly, in epimastigotes, it is dispersed in the cytoplasm but is concentrated in the reservosomes, a T. cruzi specific organelle, which suggests a putative new function for this parasite organelle. PMID- 22425989 TI - The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells. AB - The selective ER modulator tamoxifen (TAM(1)) is the most widely used ER antagonist for treatment of women with hormone-dependent breast tumor. However, long-term treatment is associated with an increased risk of endometrial cancer. The aim of the present study was to demonstrate new insight into the role of G protein coupled receptor 30 (GPR30) in the activity of TAM, which promoted endometrial cancer. In endometrial cancer cell lines ISHIKAWA and KLE, the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, 17beta estradiol (E2) and G1, a non-steroidal GPR30-specific agonist to promote cell proliferation and invasion was evaluated. All agents above induced high proliferative and invasive effects, while the down-regulation of GPR30 or the interruption of MAPK signal pathway partly or completely prevented the action of the regent. Moreover, the RNA and protein expression of GPR30 was up-regulated by G1, E2 or OHT in both cell lines. The present study provided a new insight into the mechanism involved in the agonistic activity exerted by TAM in the uterus. PMID- 22425993 TI - Usability evaluation: results from "Evaluation of mobile information technology to improve nurses' access to and use of research evidence". AB - Usability evaluations are necessary to determine the feasibility of nurses' interactions with computerized clinical decision-support systems. Limitations and challenges of operations that inhibit or facilitate utilization in clinical practice can be identified. This study provided nurses with mobile information terminals, PDAs and tablet PCs, to improve point-of-care access to information. The purpose of this study was to determine usability issues associated with point of-care technology. Eleven nurses were self-selected. Nurses were videotaped and audiotaped completing four tasks, including setting up the device and three resource search exercises. A research team member completed a usability checklist. Completion times for each task, success rate, and challenges experienced were documented. Four participants completed all tasks, with an average time of 3 minutes 22 seconds. Three participants were unable to complete any of the three tasks. Navigating within resources caused the greatest occurrence of deviations with 39 issues among all participants. Results of the usability evaluation suggest that nurses require a device that (1) is manageable to navigate and (2) utilizes a user-friendly interface, such as a one-time log-in system. Usability testing can be helpful to organizations as they document issues to be cognizant of during the implementation process, increasing the potential for successful implementation and sustained usability. PMID- 22425994 TI - Teneurins instruct synaptic partner matching in an olfactory map. AB - Neurons are interconnected with extraordinary precision to assemble a functional nervous system. Compared to axon guidance, far less is understood about how individual pre- and postsynaptic partners are matched. To ensure the proper relay of olfactory information in the fruitfly Drosophila, axons of ~50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ~50 classes of projection neurons (PNs). Here, using genetic screens, we identified two evolutionarily conserved, epidermal growth factor (EGF)-repeat containing transmembrane Teneurin proteins, Ten-m and Ten-a, as synaptic-partner matching molecules between PN dendrites and ORN axons. Ten-m and Ten-a are highly expressed in select PN-ORN matching pairs. Teneurin loss- and gain-of-function cause specific mismatching of select ORNs and PNs. Finally, Teneurins promote homophilic interactions in vitro, and Ten-m co-expression in non-partner PNs and ORNs promotes their ectopic connections in vivo. We propose that Teneurins instruct matching specificity between synaptic partners through homophilic attraction. PMID- 22425995 TI - Wild-type microglia arrest pathology in a mouse model of Rett syndrome. AB - Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2 null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2 null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it. PMID- 22425996 TI - A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. AB - Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies. PMID- 22425997 TI - Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein. AB - The conversion of chemical energy into mechanical force by AAA+ (ATPases associated with diverse cellular activities) ATPases is integral to cellular processes, including DNA replication, protein unfolding, cargo transport and membrane fusion. The AAA+ ATPase motor cytoplasmic dynein regulates ciliary trafficking, mitotic spindle formation and organelle transport, and dissecting its precise functions has been challenging because of its rapid timescale of action and the lack of cell-permeable, chemical modulators. Here we describe the discovery of ciliobrevins, the first specific small-molecule antagonists of cytoplasmic dynein. Ciliobrevins perturb protein trafficking within the primary cilium, leading to their malformation and Hedgehog signalling blockade. Ciliobrevins also prevent spindle pole focusing, kinetochore-microtubule attachment, melanosome aggregation and peroxisome motility in cultured cells. We further demonstrate the ability of ciliobrevins to block dynein-dependent microtubule gliding and ATPase activity in vitro. Ciliobrevins therefore will be useful reagents for studying cellular processes that require this microtubule motor and may guide the development of additional AAA+ ATPase superfamily inhibitors. PMID- 22425998 TI - MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function. AB - The basic unit of skeletal muscle in all metazoans is the multinucleate myofibre, within which individual nuclei are regularly positioned. The molecular machinery responsible for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of numerous diseases of muscle, including centronuclear myopathies, but it is unclear whether correct nuclear positioning is necessary for muscle function. Here we identify the microtubule-associated protein ensconsin (Ens)/microtubule-associated protein 7 (MAP7) and kinesin heavy chain (Khc)/Kif5b as essential, evolutionarily conserved regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes. We find that these proteins interact physically and that expression of the Kif5b motor domain fused to the MAP7 microtubule-binding domain rescues nuclear positioning defects in MAP7-depleted cells. This suggests that MAP7 links Kif5b to the microtubule cytoskeleton to promote nuclear positioning. Finally, we show that myonuclear positioning is physiologically important. Drosophila ens mutant larvae have decreased locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by muscle-specific expression of Ens. We conclude that improper nuclear positioning contributes to muscle dysfunction in a cell-autonomous fashion. PMID- 22425999 TI - Endospore abundance, microbial growth and necromass turnover in deep sub-seafloor sediment. AB - Two decades of scientific ocean drilling have demonstrated widespread microbial life in deep sub-seafloor sediment, and surprisingly high microbial-cell numbers. Despite the ubiquity of life in the deep biosphere, the large community sizes and the low energy fluxes in this vast buried ecosystem are not yet understood. It is not known whether organisms of the deep biosphere are specifically adapted to extremely low energy fluxes or whether most of the observed cells are in a dormant, spore-like state. Here we apply a new approach--the D:L-amino-acid model -to quantify the distributions and turnover times of living microbial biomass, endospores and microbial necromass, as well as to determine their role in the sub seafloor carbon budget. The approach combines sensitive analyses of unique bacterial markers (muramic acid and D-amino acids) and the bacterial endospore marker, dipicolinic acid, with racemization dynamics of stereo-isomeric amino acids. Endospores are as abundant as vegetative cells and microbial activity is extremely low, leading to microbial biomass turnover times of hundreds to thousands of years. We infer from model calculations that biomass production is sustained by organic carbon deposited from the surface photosynthetic world millions of years ago and that microbial necromass is recycled over timescales of hundreds of thousands of years. PMID- 22426000 TI - Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice. AB - Synapse assembly requires trans-synaptic signals between the pre- and postsynapse, but our understanding of the essential organizational molecules involved in this process remains incomplete. Teneurin proteins are conserved, epidermal growth factor (EGF)-repeat-containing transmembrane proteins with large extracellular domains. Here we show that two Drosophila Teneurins, Ten-m and Ten a, are required for neuromuscular synapse organization and target selection. Ten a is presynaptic whereas Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization trans-synaptically and cell autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten m physically interacts with alpha-Spectrin. Genetic analyses of teneurin and neuroligin reveal that they have differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates target selection between specific motor neurons and muscles. Our study identifies the Teneurins as a key bi-directional trans-synaptic signal involved in general synapse organization, and demonstrates that proteins such as these can also regulate target selection. PMID- 22426001 TI - Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. AB - Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic vessels and, most prominently, in the tip of endothelial sprouts. DLL4 activates Notch in adjacent cells, which suppresses the expression of VEGF receptors and thereby restrains endothelial sprouting and proliferation. Here we show, by using inducible loss-of-function genetics in combination with inhibitors in vivo, that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 signalling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGF-A receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch. VEGFR3 kinase-activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signalling activity. Our results establish that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. We propose that successful anti-angiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signalling. PMID- 22426002 TI - Testosterone and imipramine have antidepressant effects in socially isolated male but not female rats. AB - RATIONALE: Affective disorders are twice as likely to occur in women as they are in men suggesting a critical role for gonadal hormones in their etiology. In particular, testosterone has been shown to have protective effects in men. OBJECTIVE: To investigate antidepressant effects and interactions between testosterone and imipramine in socially isolated male and female rats. METHODS: A chronic social isolation model was used to induce an anxiety and depressive-like state in adult gonadectomized (Gnx) male and ovariectomized (Ovx) female rats receiving chronic testosterone and imipramine treatments. Their anxiety and depression-like behaviors were examined using the light-dark box, elevated plus maze, open field, sucrose preference and novelty induced hypophagia tests. RESULTS: In socially isolated rats, the anxiolytic and antidepressant effects of testosterone and imipramine were limited to male rats. Additionally, testosterone enhanced the neurogenic effect of imipramine on hippocampal cell proliferation in male rats. Although female rats exhibited signs of anxiety and depressive-like behaviors following social isolation, testosterone and/or imipramine administration had no anxiolytic or antidepressant effects in Ovx females. CONCLUSIONS: Testosterone and imipramine had anxiolytic and antidepressant effects in socially isolated male, but not female rats. Testosterone enhanced the effect of imipramine on cell proliferation in the hippocampus of male rats. PMID- 22426003 TI - Glutathione synthetase promotes the reduction of arsenate via arsenolysis of glutathione. AB - The environmentally prevalent arsenate (As(V)) undergoes reduction in the body to the much more toxic arsenite (As(III)). Phosphorolytic enzymes and ATP synthase can promote the reduction As(V) by converting it into arsenylated products in which the pentavalent arsenic is more reducible by glutathione (GSH) to As(III) than in inorganic As(V). Glutathione synthetase (GS) can catalyze the arsenolysis of GSH (gamma-Glu-Cys-Gly) yielding two arsenylated products, i.e. gamma-Glu-Cys arsenate and ADP-arsenate. Thus, GS may also promote the reduction of As(V) by GSH. This hypothesis was tested with human recombinant GS, a Mg(2+) dependent enzyme. GS markedly increased As(III) formation when incubated with As(V), GSH, Mg(2+) and ADP, but not when GSH, Mg(2+) or ADP were separately omitted. Phosphate, a substrate competitive with As(V) in the arsenolysis of GSH, as well as the products of GSH arsenolysis or their analogs, e.g. glycine and gamma-Glu aminobutyrate, decreased As(V) reduction. Replacement of ADP with ATP or an analog that cannot be phosphorylated or arsenylated abolished As(V) reduction, indicating that GS-supported As(V) reduction requires formation of ADP-arsenate. In the presence of ADP, however, ATP (but not its metabolically inert analog) tripled As(V) reduction because ATP permits GS to remove the arsenolysis inhibitory glycine and gamma-Glu-Cys by converting them into GSH. GS failed to promote As(V) reduction when GSH was replaced with ophthalmic acid, a GSH analog substrate of GS containing no SH group (although ophthalmic acid did undergo GS catalyzed arsenolysis), indicating that the SH group of GSH is important for As(V) reduction. Our findings support the conclusion that GS promotes reduction of As(V) by catalyzing the arsenolysis of GSH, thus producing ADP-arsenate, which upon being released from the enzyme is readily reduced by GSH to As(III). PMID- 22426004 TI - Characterization and regulation of the hb9/mnx1 beta-cell progenitor specific enhancer in zebrafish. AB - Differentiation of insulin producing beta-cells is a genetically well defined process that involves functions of various conserved transcription factors. Still, the transcriptional mechanisms underlying specification and determination of beta-cell fate are poorly defined. Here we provide the description of a beta cell progenitor specific enhancer as a model to study initial steps of beta-cell differentiation. We show that evolutionary non-conserved upstream sequences of the zebrafish hb9 gene are required and sufficient for regulating expression in beta-cells prior to the onset of insulin expression. This enhancer contains binding sites for paired-box transcription factors and two E-boxes that in EMSA studies show interaction with Pax6b and NeuroD, respectively. We show that Pax6b is a potent activator of endodermal hb9 expression and that this activation depends on the beta-cell enhancer. Using genetic approaches we show that pax6b is crucial for maintenance but not induction of pancreatic hb9 transcription. As loss of Pax6b or Hb9 independently results in the loss of insulin expression, the data reveal a novel cross-talk between the two essential regulators of early beta cell differentiation. While we find that the known pancreatic E-box binding proteins NeuroD and Ngn3 are not required for hb9 expression we also show that removal of both E-boxes selectively eliminates pancreatic specific reporter expression. The data provide evidence for an Ngn3 independent pathway of beta cell specification that requires function of currently not specified E-box binding factors. PMID- 22426005 TI - Sm protein down-regulation leads to defects in nuclear pore complex disassembly and distribution in C. elegans embryos. AB - Nuclear pore complexes (NPCs) are large macromolecular structures embedded in the nuclear envelope (NE), where they facilitate exchange of molecules between the cytoplasm and the nucleoplasm. In most cell types, NPCs are evenly distributed around the NE. However, the mechanisms dictating NPC distribution are largely unknown. Here, we used the model organism Caenorhabditis elegans to identify genes that affect NPC distribution during early embryonic divisions. We found that down-regulation of the Sm proteins, which are core components of the spliceosome, but not down-regulation of other splicing factors, led to clustering of NPCs. Down-regulation of Sm proteins also led to incomplete disassembly of NPCs during mitosis, but had no effect on lamina disassembly, suggesting that the defect in NPC disassembly was not due to a general defect in nuclear envelope breakdown. We further found that these mitotic NPC remnants persisted on an ER membrane that juxtaposes the mitotic spindle. At the end of mitosis, the remnant NPCs moved toward the chromatin and the reforming NE, where they ultimately clustered by forming membrane stacks perforated by NPCs. Our results suggest a novel, splicing-independent, role for Sm proteins in NPC disassembly, and point to a possible link between NPC disassembly in mitosis and NPC distribution in the subsequent interphase. PMID- 22426006 TI - Plasma membrane cholesterol depletion disrupts prechordal plate and affects early forebrain patterning. AB - Cholesterol-rich membrane microdomains (CRMMs) are specialized structures that have recently gained much attention in cell biology because of their involvement in cell signaling and trafficking. However, few investigations, particularly those addressing embryonic development, have succeeded in manipulating and observing CRMMs in living cells. In this study, we performed a detailed characterization of the CRMMs lipid composition during early frog development. Our data showed that disruption of CRMMs through methyl-beta-cyclodextrin (MbetaCD) cholesterol depletion at the blastula stage did not affect Spemann's organizer gene expression and inductive properties, but impaired correct head development in frog and chick embryos by affecting the prechordal plate gene expression and cellular morphology. The MbetaCD anterior defect phenotype was recapitulated in head anlagen (HA) explant cultures. Culture of animal cap expressing Dkk1 combined with MbetaCD-HA generated a head containing eyes and cement gland. Together, these data show that during Xenopus blastula and gastrula stages, CRMMs have a very dynamic lipid composition and provide evidence that the secreted Wnt antagonist Dkk1 can partially rescue anterior structures in cholesterol-depleted head anlagen. PMID- 22426007 TI - Excitonic recombination in superstoichiometric nanocrystalline TiO2 grown by cluster precursors at room temperature. AB - Unprecedented room temperature excitonic emissions are achieved from TiO(2) nanocrystals synthesized at 300 K by supersonic cluster beams. Transmission electron microscopy studies show the crystalline nature of the nanoparticles (NPs) with a diameter ranging from 5 to 30 nm. All the samples show mixed rutile and anatase phases as confirmed by Raman spectroscopy. XPS core level analyses evidence an O/Ti ratio of the as-grown nanoparticles of 2.30 +/- 0.04. Two room temperature cathodoluminescence excitonic peaks observed at 3.16 and 3.25 eV are ascribed to the coexistence of rutile and anatase crystallographic phases respectively. Subsequent thermal treatments at 450 degrees C cause the complete quenching of the UV excitonic emissions and result in a more conventional broad visible band centered at 2.5 eV. HRTEM and XPS studies reveal that, after annealing, the NPs remain single crystals in nature with an O/Ti ratio of 2.20 +/ 0.04. These results suggest a correlation between the emission properties and the oxygen concentration of our NPs. The achieved ability to tune the optical properties of TiO(2) nanoparticles is very promising for sensing and energy applications. PMID- 22426008 TI - Flow-cytometry and cell sorting: an efficient approach to investigate productivity and cell physiology in mammalian cell factories. AB - The performance of cell lines used for the production of biotherapeutic proteins typically depends on the number of cells in culture, their specific growth rate, their viability and the cell specific productivity (qP). Therefore both cell line development and process development are trying to (a) improve cell proliferation to reduce lag-phase and achieve high number of cells; (b) delay cell death to prolong the production phase and improve culture longevity; (c) and finally, increase qP. All of these factors, when combined in an optimised process, concur to increase the final titre and yield of the recombinant protein. As cellular performance is at the centre of any improvement, analysis methods that enable the characterisation of individual cells in their entirety can help in identifying cell types and culture conditions that perform exceptionally well. This observation of cells and their complexity is reflected by the term "cytomics" and flow cytometry is one of the methods used for this purpose. With its ability to analyse the distribution of physiological properties within a population and to isolate rare outliers with exceptional properties, flow cytometry ideally complements other methods used for optimisation, including media design and cell engineering. In the present review we describe approaches that could be used, directly or indirectly, to analyse and sort cellular phenotypes characterised by improved growth behaviour, reduced cell death or high qP and outline their potential use for cell line and process optimisation. PMID- 22426009 TI - A fungal cell wall integrity-associated MAP kinase cascade in Coniothyrium minitans is required for conidiation and mycoparasitism. AB - Coniothyrium minitans is an important biocontrol agent against Sclerotinia diseases. Previously, a conidiation-deficient mutant ZS-1T1000 was screened out from a T-DNA insertional library of C. minitans. CmBCK1, encoding MAP kinase kinase kinase and homologous to BCK1 of Saccharomyces cerevisiae, was disrupted by T-DNA insertion in this mutant. Targeted disruption of CmBCK1 led to the mutants undergoing autolysis and displaying hypersensitivity to the cell wall degrading enzymes. The ?CmBCK1 mutants lost the ability to produce pycnidia and conidia compared to the wild-type strain ZS-1. ?CmBCK1 mutants could grow on the surface of sclerotia of Sclerotinia sclerotiorum but not form conidia, which resulted in much lower ability to reduce the viability of sclerotia of S. sclerotiorum. Furthermore, CmSlt2, a homolog of Slt2 encoding cell wall integrity related MAP kinase and up-regulated by BCK1 in S. cerevisiae, was identified and targeted disrupted. The ?CmSlt2 mutants had a similar phenotype to the ?CmBCK1 mutants. The ?CmSlt2 mutants also had autolytic aerial hyphae, hypersensitivity to cell wall-degrading enzymes, lack of conidiation and reduction of sclerotial mycoparasitism. Taken together, our results suggest that CmBCK1 and CmSlt2 are involved in conidiation and the hyperparasitic activities of C. minitans. PMID- 22426010 TI - Impact of terminal dimethylation on the resistance profile of alpha-N heterocyclic thiosemicarbazones. AB - Triapine is an alpha-N-heterocyclic thiosemicarbazone with promising anticancer activity against hematologic malignancies but widely ineffective against solid tumor types in clinical trials. The anticancer activity of thiosemicarbazones can be dramatically increased by terminal dimethylation. KP1089 is a gallium compound containing two terminal dimethylated thiosemicarbazone ligands. To gain insights on the vulnerability of this highly active terminal dimethylated thiosemicarbazone to drug resistance mechanisms, a new cell model with acquired resistance against the lead compound KP1089 was established. Subsequent genomic analyses (arrayCGH and FISH) revealed amplification of the ABCC1 gene on double minute chromosomal DNA in KP1089-resistant cells as well as overexpression of ABCC1 and ABCG2 on the protein level. KP1089 was further confirmed as a substrate of ABCC1 and ABCG2 but not of ABCB1 using a panel of ABC transporter overexpressing cell models as well as ABC transporter inhibitors. Moreover, glutathione depletion strongly enhanced KP1089 activity, although no glutathione conjugate formation by glutathione-S-transferase was observed. Thus, a co transport of KP1089 together with glutathione is suggested. Finally, a panel of thiosemicarbazone derivatives was tested on the new KP1089-resistant cell line. Notably, KP1089-resistant cells were not cross-resistant against thiosemicarbazones lacking terminal dimethylation (e.g. Triapine) which are less active than KP1089. This suggests that terminal dimethylation of thiosemicarbazones - linked with distinctly enhanced anticancer activity - leads to altered resistance profiles compared to classical thiosemicarbazones making this compound class of interest for further (pre)clinical evaluation. PMID- 22426011 TI - Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats. AB - The NOD-like receptor 3 (NLRP3) inflammasome-mediated inflammation is recently recognized in the development of renal injury. However, the mechanisms of the inflammasome-mediated inflammation and lipid accumulation in renal injury and the actions of lowing urate agents remain unclear. The present study used fructose to induce hyperuricemia and dyslipidemia, which caused renal NLRP3 inflammasome activation characterized by over-expression of the NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1, resulting in overproduction of interleukin (IL)-1beta and IL-18, as well as IL-6 and tumor necrosis factor alpha (TNF-alpha) in rats. The elevated levels of these pro-inflammatory cytokines impaired renal janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)/peroxisome proliferator-activated receptor alpha (PAPR alpha), and insulin receptor (IR)/insulin receptor substrate 1 (IRS1)/protein kinase B (Akt)/extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathways with over-expression of suppressor of cytokine signaling 3 (SOCS3), exacerbating renal lipid accumulation and injury in fructose-fed rats. The restoration of fructose-induced hyperuricemia and dyslipidemia by the treatment of allopurinol, quercetin and rutin blocked the NLRP3 inflammasome activation to improve the signaling impairments and reduce lipid accumulation in the kidney of rats. These results suggest that the activation of renal NLRP3 inflammasome may play an important role in the link among renal inflammation, JAK2/STAT3/PAPR alpha and IR/IRS1/Akt/ERK1/2 signaling impairment, and lipid accumulation driven by fructose. The NLRP3 inflammasome may be the target mediating the improvement of urate-lowering agents allopurinol, quercetin and rutin on fructose-induced renal lipid accumulation and injury. PMID- 22426012 TI - Assessment of target enrichment platforms using massively parallel sequencing for the mutation detection for congenital muscular dystrophy. AB - Sequencing individual genes by Sanger sequencing is a time-consuming and costly approach to resolve clinically heterogeneous genetic disorders. Panel testing offers the ability to efficiently and cost-effectively screen all of the genes for a particular genetic disorder. We assessed the analytical sensitivity and specificity of two different enrichment technologies, solution-based hybridization and microdroplet-based PCR target enrichment, in conjunction with next-generation sequencing (NGS), to identify mutations in 321 exons representing 12 different genes involved with congenital muscular dystrophies. Congenital muscular dystrophies present diagnostic challenges due to phenotypic variability, lack of standard access to and inherent difficulties with muscle immunohistochemical stains, and a general lack of clinician awareness. NGS results were analyzed across several parameters, including sequencing metrics and genotype concordance with Sanger sequencing. Genotyping data showed that both enrichment technologies produced suitable calls for use in clinical laboratories. However, microdroplet-based PCR target enrichment is more appropriate for a clinical laboratory, due to excellent sequence specificity and uniformity, reproducibility, high coverage of the target exons, and the ability to distinguish the active gene versus known pseudogenes. Regardless of the method, exons with highly repetitive and high GC regions are not well enriched and require Sanger sequencing for completeness. Our study demonstrates the successful application of targeted sequencing in conjunction with NGS to screen for mutations in hundreds of exons in a genetically heterogeneous human disorder. PMID- 22426013 TI - Detection of genomic variations in BRCA1 and BRCA2 genes by long-range PCR and next-generation sequencing. AB - Advances in sequencing technologies, such as next-generation sequencing (NGS), represent an opportunity to perform genetic testing in a clinical scenario. In this study, we developed and tested a method for the detection of mutations in the large BRCA1 and BRCA2 tumor suppressor genes, using long-range PCR (LR-PCR) and NGS, in samples from individuals with a personal and/or family history of breast and/or ovarian cancer. Eleven LR-PCR fragments, between 3000 and 15,300 bp, containing all coding exons and flanking splice junctions of BRCA1 and BRCA2, were obtained from DNA samples of five individuals carrying mutations in either BRCA1 or BRCA2. Libraries for NGS were prepared using an enzymatic (Nextera technology) method. We analyzed five individual samples in parallel by NGS and obtained complete coverage of all LR-PCR fragments, with an average coding sequence depth for each nucleotide of >30 reads, running from *7 (in exon 22 of BRCA1) to >*150. We detected and confirmed 100% of the mutations that predispose to the risk of cancer, together with other genomic variations in BRCA1 and BRCA2. Our approach demonstrates that genomic LR-PCR, together with NGS, using the GS Junior 454 System platform, is an effective method for patient sample analysis of BRCA1 and BRCA2 genes. In addition, this method could be performed in regular molecular genetics laboratories. PMID- 22426014 TI - Risk classification in mild cognitive impairment patients for developing Alzheimer's disease. AB - The objective of this study was to develop new risk classifications for conversion to Alzheimer's disease (AD) by comparing the relative reliability of classifiers in patients with mild cognitive impairment (MCI). The 397 MCI subjects and all baseline data, including characteristics, neuropsychological tests, cerebrospinal fluid biomarkers and MRI findings in Alzheimer's Disease Neuroimaging Initiative (ADNI), were used for analysis by Cox proportional hazard regression, bootstrap sampling, and c-index. Multivariate Cox regression analysis revealed the following factors to be associated with increased risk of conversion from MCI to AD during the 53-month follow-up period: AVLT 30-minute delayed recall, AVLT trial 1, Boston naming, logical delayed recall, trail-making B, CDR sob, ADAS13, the cortical thickness of the right inferior temporal lobe (st91ta), and the left hippocampus volume. The combinations of ADAS13 at a cutoff point of 15.67 with CDR-sob at 1.5 or with the cortical thickness of the right inferior temporal lobe at 2.56 mm3 produced high conversion rates of 92.7% (82.4%-100.0%) and 88.8% (77.3%-100.0%), respectively, at 48 months. The discriminative ability based on c-index for the proposed combination was 0.68. The sample size was estimated as 504 in the group with a combination of ADAS13 and CDR-sob whose conversion rate is highest. The combination of ADAS13 with CDR-sob at an optimal cutoff point has a high reliability in classifying the MCI patients into high- and low-risk conversion to AD and will be benefit for patients' assessment and potentially facilitate the clinical development of novel therapeutics. PMID- 22426015 TI - Anticholinergic drugs in late life: adverse effects on cognition but not on progress to dementia. AB - Impaired cognitive function associated with use of anticholinergic drugs may be partly attributed to underlying physical illness and exposure to factors that increase the risk of some physical disorders such as low socioeconomic status (SES) and less education. To estimate the extent of cognitive impairment and risk of progress to dementia associated with anticholinergic drug use and to estimate confounding by gender, APOE, family history of dementia, lower SES, less education, and lower childhood mental ability, we recruited 281 volunteers at age 77-78 without overt dementia who had taken part in the Scottish Mental Survey of 1932. Clinical histories, use of medications, self reported frequency of emotional symptoms and standardized tests of cognitive function were obtained. With and without adjustment for age and childhood IQ, there were significant between-group differences in tests of non-verbal reasoning and spatial ability. During 10 year follow-up, progress to overt dementia was not associated with anticholinergic drugs use on recruitment but female gender and a history of dementia in parent or sibling were associated with dementia. We concluded that anticholinergic drug use in this narrow age range sample was linked to cognitive impairment but not to subsequent dementia. PMID- 22426016 TI - Assessing candidate serum biomarkers for Alzheimer's disease: a longitudinal study. AB - Because of the growing impact of late onset cognitive loss, considerable effort has been directed toward the development of improved diagnostic techniques for Alzheimer's disease (AD) that may pave the way for earlier (and more effective) therapeutic efforts. Serum-based biomarkers are the least expensive and invasive modality for screening and routine monitoring. We systematically reviewed the literature to assemble a list of serum biomarkers relevant to AD. In parallel, we conducted a proteomic LC-MS/MS analysis of serum collected from neurologically normal subjects and subjects with mild cognitive impairment (MCI) and early AD (n = 6 in all). Complement C3 and alpha-2-macroglobulin were identified from both the literature review and our proteomic screen for further validation. For these two candidates, ELISA was performed on serum collected from a small independent cohort of subjects for longitudinal analysis. Serum was serially collected from neurologically normal subjects (n = 5) and subjects with MCI who were subsequently followed for a period of two years (n = 5) and regrouped into stable MCI and progressive MCI or AD (n = 6). The ability of each marker to predict which subjects with MCI would progress to dementia and which would remain cognitively stable was assessed. Patients with probable cerebral amyloid angiopathy were also identified (n = 3). This preliminary analysis tested the most-promising serum protein biomarkers for AD and we concluded that none are yet ready for use in the clinical diagnosis and management of dementia. However, a more thorough assessment in longitudinal studies with higher statistical power is warranted. PMID- 22426017 TI - PSEN1 mutation carriers present lower cerebrospinal fluid amyoid-beta42 levels than sporadic early-onset Alzheimer's disease patients but no differences in neuronal injury biomarkers. AB - Most cases of early-onset Alzheimer's disease (EOAD) are sporadic. A minority of EOAD are caused by specific genetic defects in PSEN1, PSEN2, or AbetaPP genes. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarker comparisons between sporadic and monogenic EOAD are practically inexistent. CSF and MRI data from 14 amnestic-onset sporadic EOAD (sEOAD) subjects were compared with data from 8 symptomatic PSEN1 mutation carriers (PSEN1) and 14 age-matched cognitively-preserved controls. CSF concentrations of amyloid-beta (Abeta)(42), total tau (t-tau), and phosphorylated tau (p-tau) were determined. Cortical thickness (CTh) and grey matter loss were compared between groups and correlated with CSF biomarkers. PSEN1 had significantly lower CSF Abeta(42) levels compared to sEOAD (mean 244.8 pg/ml versus 381.4 pg/ml; p = 0.006), but no differences in t-tau or p-tau. Both sEOAD and PSEN1 showed widespread CTh loss in AD target areas when compared with controls. No differences were found in the direct comparison between sEOAD and PSEN1 CTh after adjusting for age and Mini-Mental Status Examination scores. Neither was a correlation found between Abeta(42) levels and CTh. CTh in the left superior parietal and caudal middle frontal areas was negatively correlated with t-tau values. In conclusion, PSEN1 had lower Abeta(42) CSF levels compared with sEOAD, suggesting a greater cerebral deposition of Abeta(42). These differences in Abeta(42) deposition were not significantly reflected in the brain structure, and CTh was only correlated with total tau. The lack of significant differences in relation to t-tau and p-tau levels and to the severity of CTh or grey matter loss suggests a similar level of neuronal injury despite higher Abeta(42) load in PSEN1. PMID- 22426018 TI - Variability in blood-based amyloid-beta assays: the need for consensus on pre analytical processing. AB - Effective therapeutic interventions for Alzheimer's disease (AD) will require treatment regimes to move toward the earliest stages of the disease. For this to occur the field has to identify biomarkers that are able to accurately identify individuals at risk for progression toward AD in the presymptomatic stage. One very significant implication is that some form of population-based screening will need to be undertaken in order to identify those at risk. To date, efforts in neuroimaging brain amyloid-beta (Abeta) and changes in cerebrospinal fluid Abeta and tau levels shows promise, however, it is questionable as to whether these methods are applicable for screening the general population. The Abeta peptide is also found in blood which is the most economical and efficient biological fluid to analyze. Unfortunately, investigations into blood-based diagnostic markers have produced mixed results. This variability is likely to be the result of differences in the preanalytical processing of samples and as such is delaying progress in the field. Reported preanalytical processing techniques from 87 recent articles focusing on the measurement of Abeta in blood were compared, to investigate whether basic sample-handling techniques were comparable between studies. This comparison revealed that not only is it likely that some of the variability in blood-based results is attributable to discrepancies in preanalytical methodologies but also that the field is failing to adequately report sample processing techniques. This review highlights the current shortcomings in methodological reporting and recommends a standardized blood collection methodology based on the limited consensus of the reviewed articles. PMID- 22426019 TI - Neuronal uptake and neuroprotective effect of curcumin-loaded PLGA nanoparticles on the human SK-N-SH cell line. AB - Curcumin, a natural polyphenolic pigment present in the spice turmeric (Curcuma longa), is known to possess a pleiotropic activity such as antioxidant, anti inflammatory, and anti-amyloid-beta activities. However, these benefits of curcumin are limited by its poor aqueous solubility and oral bioavailability. In the present study, a polymer-based nanoparticle approach has been utilized to deliver drugs to neuronal cells. Curcumin was encapsulated in biodegradable poly (lactide-co-glycolide) (PLGA) based-nanoparticulate formulation (Nps-Cur). Dynamic laser light scattering and transmission electronic microscopy analysis indicated a particle diameter ranging from 80 to 120 nm. The entrapment efficiency was 31% with 15% drug-loading. In vitro release kinetics of curcumin from Nps-Cur revealed a biphasic pattern with an initial exponential phase followed by a slow release phase. Cellular internalization of Nps-Cur was confirmed by fluorescence and confocal microscopy with a wide distribution of the fluorescence in the cytoplasm and within the nucleus. The prepared nanoformulation was characterized for cellular toxicity and biological activity. Cytotoxicity assays showed that void PLGA-nanoparticles (Nps) and curcumin-loaded PLGA nanoparticles (Nps-Cur) were nontoxic to human neuroblastoma SK-N-SH cells. Moreover, Nps-Cur was able to protect SK-N-SH cells against H2O2 and prevent the elevation of reactive oxygen species and the consumption of glutathione induced by H2O2. Interestingly, Nps-Cur was also able to prevent the induction of the redox-sensitive transcription factor Nrf2 in the presence of H2O2. Taken together, these results suggest that Nps-Cur could be a promising drug delivery strategy to protect neurons against oxidative damage as observed in Alzheimer's disease. PMID- 22426020 TI - Changes in glycemic control are associated with changes in cognition in non diabetic elderly. AB - The aim of the present study was to examine the relationship of changes in long term glucose levels as measured by Hemoglobin A1c (HbA1c) with simultaneous changes in cognition. The sample included in the present analysis consisted of 101 community dwelling non-diabetic elderly subjects participating in ongoing longitudinal studies of cognition. Subjects were included in this study if they were cognitively normal at baseline, had at least one co-temporaneous follow-up assessment of HbA1c and the Mini Mental State Exam (MMSE), and complete data on age, gender, race, and years of education. MMSE decline over time was the main outcome measure. In TOBIT mixed regression models, MMSE was the dependent variable and HbA1c the time-varying covariate. Sociodemographic (age, gender, and education), cardiovascular (hypertension and APOE4 status), and lifestyle (smoking and physical activity) covariates were included in the statistical model. After adjusting for age at follow-up, there was a decrease of 1.37 points in the MMSE (p = 0.0002) per unit increase in HbA1c. This result remained essentially unchanged after adjusting also for gender and education (p = 0.0005), cardiovascular factors (p = 0.0003), and lifestyle (p = 0.0006). Additionally, results remained very similar after excluding subjects with potentially incipient diabetes with HbA1c between 6 and 7. These findings suggest that in non-diabetic non-demented elderly subjects, an increase in HbA1c over time is associated with cognitive decline. Such results may have broad clinical applicability since manipulation of glucose control, even in non-diabetics, may affect cognitive performance, perhaps enabling preventive measures against dementia. PMID- 22426021 TI - Mapping of hippocampal pH and neurochemicals from in vivo multi-voxel 31P study in healthy normal young male/female, mild cognitive impairment, and Alzheimer's disease. AB - Magnetic resonance spectroscopy (MRS) plays an important role in the understanding of membrane and energy metabolism. The outcome of MRS experiments helps to derive important cellular conditions (e.g., intracellular pH, energy, membrane metabolism, etc.), which are directly related to neuronal health. We present a novel multi-voxel 31P MRS imaging experimental scheme along with an advanced 31P signal processing technique to determine the pH and neurochemicals from both hippocampal areas in shorter time (13.2 min) for subjects (e.g. healthy young male/female, mild cognitive impairment (MCI) and Alzheimer's disease (AD)). Significant (p = 0.005) decrease of phosphomonoester (PME) and increase of phosphodiester (PDE) (p < 0.001), gamma-ATP (0.008), and PCr (p = 0.001) levels in the left hippocampus of AD patients (n = 6) compared to the control subjects (n = 12) were found based on post-hoc ANOVA. On the other hand, in the right hippocampus, decrease in PME (p = 0.008) and increase in PDE (p < 0.001) were significant between AD patients and controls. In case of AD subjects, pH in the left hippocampus is increased towards alkaline side compared to MCI but did not reach statistical significance level. The pH (left hippocampus) in AD is found to be negatively correlated (r = -0.829, p = 0.042) with PCr level (left hippocampus) in AD subjects. In the left hippocampus, the increase in pH to alkaline range (in normal aging, pH is decreased to acidic range) along with statistically significant increments of PCr, gamma-ATP, and PDE as well as decrease of PME in AD subjects provide extremely crucial clinical information, which can be used as biomarker for AD and potentially aid in the diagnosis. PMID- 22426022 TI - Human breast development. AB - This review is intended to give an overview of current knowledge on human breast development. It focuses on the limitations of our understanding on the origins of human breast cancer in the context of this mainly morphological and static assessment of what is known about human breast development. The world literature is very limited and caution is needed in drawing analogies with the mouse. There is an increasing emphasis on research to understand normal stem cells in the breast on the assumption that these are the targets for the initiation of breast cancer. It is thus a priority to understand normal human breast development, but there are major obstacles to such studies mainly due to ethical considerations and to tissue acquisition. PMID- 22426023 TI - Association among retinol-binding protein 4, small dense LDL cholesterol and oxidized LDL levels in dyslipidemia subjects. AB - OBJECTIVES: To investigate retinol-binding protein 4 (RBP4), small dense low density lipoprotein cholesterol (sdLDL-C) and oxidized low-density lipoprotein (ox-LDL) levels and their associations in dyslipidemia subjects. DESIGN AND METHODS: We determined RBP4, sdLDL-C, ox-LDL levels in 150 various dyslipidemia subjects and 50 controls. The correlation analysis and multiple linear regression analysis were performed. RESULTS: The RBP4, sdLDL-C and ox-LDL levels were found increased in various dyslipidemia subjects. The sdLDL-C levels were positively correlated with RBP4 (r=0.273, P=0.001) and ox-LDL (r=0.273, P=0.001). RBP4 levels were also correlated with ox-LDL (r=0.167, P=0.043). The multiple regression analysis showed that only sdLDL-C was a significant independent predictor for RBP4 (beta coefficient=0.219, P=0.009; adjusted R(2)=0.041) and ox LDL (beta coefficient=0.253, P=0.003; adjusted R(2)=0.057) levels, respectively. CONCLUSIONS: The independent associations of sdLDL-C with RBP4 and ox-LDL were observed in dyslipidemia subjects. RBP4 may play an important role in lipid metabolism of atherosclerosis, particularly in formation of sdLDL. PMID- 22426024 TI - Differential effects of inhalation exposure to PM2.5 on hypothalamic monoamines and corticotrophin releasing hormone in lean and obese rats. AB - Acute exposure to airborne pollutants, especially particulate matter (PM2.5) is known to increase hospital admissions for cardiovascular conditions, increase cardiovascular related mortality and predispose the elderly and obese individuals to cardiovascular conditions. The mechanisms by which PM2.5 exposure affects the cardiovascular system is not clear. Since the autonomic system plays an important role in cardiovascular regulation, we hypothesized that PM2.5 exposure most likely activates the paraventricular nucleus (PVN) of the hypothalamus to cause an increase in sympathetic nervous system and/or stress axis activity. We also hypothesized that these changes may be sustained in obese rats predisposing them to higher cardiovascular risk. To test this, adult male Brown Norway (BN) rats were subjected to one day or three days of inhalation exposures to filtered air (FA) or concentrated air particulate (CAP) derived from ambient PM2.5. Corpulent JCR-LA rats were exposed to FA or CAP for four days. Animals were sacrificed 24h after the last inhalation exposure. Their brains were removed, frozen and sectioned. The PVN and median eminence (ME) were microdissected. PVN was analyzed for norepinephrine (NE), dopamine (DA) and 5-hydroxy-indole acetic acid (5-HIAA) levels using HPLC-EC. ME was analyzed for corticotrophin releasing hormone (CRH) levels by ELISA. One day exposure to CAP increased NE levels in the PVN and CRH levels in the ME of BN rats. Repeated exposures to CAP did not affect NE levels in the PVN of BN rats, but increased NE levels in JCR/LA rats. A similar pattern was observed with 5-HIAA levels. DA levels on the other hand, were unaffected in both BN and JCR/LA strains. These data suggest that repeated exposures to PM2.5 continue to stimulate the PVN in obese animals but not lean rats. PMID- 22426025 TI - Sex-specific effects of prenatal stress on neuronal development in the medial prefrontal cortex and the hippocampus. AB - Evidence suggests that maternal stress during gestation in humans and animals can cause emotional and cognitive dysfunction in the offspring. In the present study, we examined neurons of the hippocampus and the medial prefrontal cortex of adult rats exposed to prenatal stress. Using a revised Golgi-Cox staining method, we found decreases in dendritic length and complexity in area CA3 and the dentate gyrus of male rats exposed to prenatal stress compared with the controls, as well as decreased dendritic complexity in the prelimbic cortex. In contrast, we did not detect any changes in dendrites of female rats exposed to prenatal stress. Our results suggest that prenatal stress can induce long-lasting morphological changes in the medial prefrontal cortex and the hippocampus that are sex specific. PMID- 22426026 TI - Transient changes in neuronal cell membrane permeability after blast exposure. AB - The biochemical mechanisms of explosive blast-induced traumatic brain injury and the subsequent long-term neurobehavioral abnormalities are still not completely understood. We studied the biochemical mechanism of blast traumatic brain injury using our recently reported in-vitro model system with a shock tube. Primary blast exposure of in-vitro models leads to neurobiological changes in an overpressure dose-dependent and time-dependent manner. Lactate dehydrogenase was released significantly into the extracellular medium without cell death after blast exposure, indicating compromised cell membrane integrity. We further explored the integrity of cell membrane after blast exposure by fluorescent dye uptake/release techniques in SH-SY5Y human neuroblastoma cells. Our data indicate that blast exposure leads to an overpressure-dependent transient increase in the release of preloaded calcein AM into the culture medium with proportional intracellular decrease. Uptake of an extracellular nucleic acid-binding dye TO PRO-3 iodide was also increased significantly after blast exposure, indicating that the increased molecular transport is bidirectional and nuclear membrane integrity is also affected by blast exposure. These results suggest that blast exposure perturbs the integrity of the neuronal cell membrane, leading to increased bidirectional transport of molecules--a potential mechanism that can lead to traumatic brain injury. PMID- 22426027 TI - Opioid antagonist naltrexone for the treatment of pathological gambling in Parkinson disease. AB - Pathological gambling (PG) is a potential complication related to the treatment of Parkinson disease (PD) with dopamine agonists (DA). The cause of this disorder is unknown, but altered dopamine neurotransmission may be involved. OBJECTIVE: We evaluated the efficacy and tolerability of the opioid antagonist naltrexone in the treatment of PG in PD. METHODS: Our cases included 3 patients with PD who developed PG after DA treatment. RESULTS: Pathological gambling did not improve after reduction or discontinuation of DA. These patients responded poorly to serotonin reuptake inhibitors, whereas treatment with opioid antagonist naltrexone resulted in the remission of PG. Naltrexone treatment was well tolerated. In one patient, higher dose of naltrexone resulted in hepatic abnormalities, which resolved after dosage reduction. CONCLUSIONS: The opioid antagonist naltrexone could be an effective option for the treatment of PG in PD. PMID- 22426028 TI - The most probable number of blocks for the partitions of the set of codons could have determined the number of standard amino acids. AB - Given a genetic code formed by 64 codons, we calculate the number of partitions of the set of encoding amino acid codons. When there are 0-3 stop codons, the results indicate that the most probable number of partitions is 19 and/or 20. Then, assuming that in the early evolution the genetic code could have had random variations, we suggest that the most probable number of partitions of the set of encoding amino acid codons determined the actual number 20 of standard amino acids. PMID- 22426029 TI - Association of Stat3 with HSF1 plays a critical role in G-CSF-induced cardio protection against ischemia/reperfusion injury. AB - Granulocyte colony-stimulating factor (G-CSF) has been shown to be cardio protective against ischemia through activating Jak2/Stat3 pathway, however, the mechanism is unclear. Heat shock transcription factor 1 (HSF1), a definite endogenous protective protein in cardiomyocytes, may interact with Stat family under stress conditions. We hypothesized that G-CSF could induce cardio protection against ischemia/reperfusion (I/R) through association of HSF1 with Stat3. To test the hypothesis, we built cardiac I/R injury model with HSF1 knockout (KO) mice and wild type (WT) mice by occlusion of the left anterior descending (LAD) coronary artery for 30min and subsequent release of the occlusion for 24h. These mice were administered with G-CSF (100MUg/kg/day) or vehicle subcutaneously for 3days before surgery. As expected, G-CSF induced significant cardio-protections against I/R injury, characterized by higher ejection fraction (EF%), lower left ventricular end diastolic pressure (LVEDP), increased dp/dt value and decreased infarct area as compared with the vehicle treatment in WT mice. In HSF1-KO mice, however, these cardio-protections induced by G-CSF were greatly attenuated. Inhibition of oxidative stress-induced cardiomyocyte apoptosis by G-CSF also disappeared due to the deficiency of HSF1 in vitro and in vivo. Furthermore, G-CSF increased the phosphorylation and the association of Stat3 with HSF1, which enhanced transcriptional activity of HSF1. Inhibition of either Stat3 or HSF1 by pharmacological agents suppressed G-CSF induced association of the two proteins and anti-apoptotic effect on cardiomyocytes. Our data suggest that G-CSF stimulates phosphorylation and association of Stat3 with HSF1 and therefore enhances transcriptional activity of HSF1, leading to the cardio-protection against I/R injury. PMID- 22426030 TI - Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. AB - Multiple intravenous injections of a cDNA library, derived from human melanoma cell lines and expressed using the highly immunogenic vector vesicular stomatitis virus (VSV), cured mice with established melanoma tumors. Successful tumor eradication was associated with the ability of mouse lymphoid cells to mount a tumor-specific CD4(+) interleukin (IL)-17 recall response in vitro. We used this characteristic IL-17 response to screen the VSV-cDNA library and identified three different VSV-cDNA virus clones that, when used in combination but not alone, achieved the same efficacy against tumors as the complete parental virus library. VSV-expressed cDNA libraries can therefore be used to identify tumor rejection antigens that can cooperate to induce anti-tumor responses. This technology should be applicable to antigen discovery for other cancers, as well as for other diseases in which immune reactivity against more than one target antigen contributes to disease pathology. PMID- 22426031 TI - Psychosocial correlates of pelvic floor disorders in women seeking bariatric surgery. AB - BACKGROUND: Women who struggle with obesity are at a significant risk for pelvic floor disorders (PFDs), defined as urinary incontinence, pelvic organ prolapse, and/or fecal incontinence. The association between PFDs and reduced quality of life has been demonstrated; however, the psychosocial correlates of PFDs in women undergoing bariatric surgery have yet to be examined. The present study explored the potential psychosocial correlates of PFD. The setting was an academic medical center. METHODS: Data were analyzed from 421 female patients evaluated for bariatric surgery. Based upon a screening questionnaire, participants were dichotomized as women with PFDs (n = 121) and women without PFDs (n = 300). Patients completed the "Minnesota Multiphasic Personality Inventory, 2nd ed., Restructured Form (MMPI-2-RF)," and medical records were reviewed for demographic data, body mass index, substance abuse/dependence history, history of physical and/or sexual abuse, psychiatric medication usage, and psychiatric diagnoses. MMPI-2-RF scales measuring depression, anxiety, somatic symptoms, and social support were examined. RESULTS: Women with PFDs were significantly older (F(1,420) = 3.87, P < .05) and more likely to evidence a history of substance abuse/dependence (chi-square = 4.53, P < .05) and depression (chi-square = 4.31, P < .05) than women without PFDs. There also was a trend for previous inpatient hospitalization (chi-square = 2.93, P < .09), outpatient behavioral health treatment (chi-square = 2.89, P < .09), and psychotropic medication usage (chi square = 3.32, P < .07). No differences were found in the objective psychological testing. CONCLUSION: Women with PFDs may be more psychiatrically vulnerable than other bariatric surgery candidates. Additional research on the association among PFDs, substance abuse, and depression is warranted. Future research should consider whether this potential relationship changes postoperative bariatric surgery. PMID- 22426032 TI - Neuropharmacological effect of Mangiferin on brain cholinesterase and brain biogenic amines in the management of Alzheimer's disease. AB - The present study was conducted to evaluate the neuropharmacological effect of Mangiferin on brain cholinesterase and brain biogenic amines along with its antioxidant status. Scopolamine and natural aging were employed as an experimental amnesia inducing agents. The tested dose of Mangiferin (40, 20 and 10 mg/kg) significantly improved the learning ability and retention of learned memory in Elevated plus Maze and Passive Shock Avoidance exteroceptive behavioural models. Pre-treatment with Mangiferin restored increased whole brain acetylcholinestrease, lipid peroxidation and reduced glutathione due to scopolamine and natural aging. Whole brain increased dopamine and nor-adrenaline content in brain in the inducing groups were reversed by tested doses of Mangiferin insignificantly. Moreover the cerebroprotective effect of Mangiferin was well supported by photomicrographs of Hippocampus of brain, where as severity of cell damage, number of pyknotic black neurons, formation of karyorrhexis, karyolysis and number of neuronal cell death were less comparative to scopolamine group. The observed effects of Mangiferin claim that it would be worthwhile to utilize in the treatment of Alzheimer's disease. PMID- 22426033 TI - Infections with Sarcocystis wenzeli are prevalent in the chickens of Yunnan Province, China, but not in the flocks of domesticated pigeons or ducks. AB - The distribution and prevalence of infections with species of Sarcocystis in domestic fowl in Asia are poorly known. Here, ducks, pigeons, and chickens from Yunnan Province, China were examined for evidence of parasitic infection with Sarcocystis spp. One hundred and ninety one chickens, 514 ducks, and nine pigeons were investigated. Whereas the ducks and pigeons lacked tissue cysts in their muscle, brain or peripheral nervous system, cysts of Sarcocystis wenzeli were identified in 17 of 191 chickens (8.9%). Morphologically, the cysts were thread like, ranging in size from 334-3169 * 41-117 MUm (mean 1093 * 65 MUm). Cysts were septate with dense, short finger-like protrusions which appeared radially striated. The cyst wall was 1.4-3.5 MUm (mean 2.4 MUm) thick. The bradyzoites were lancet shaped and measured 12.2-17.7 * 1.8-2.9 MUm (mean 14.6 * 2.5 MUm). Ultrastucturally, the primary sarcocyst wall had stubby villar protrusions, corresponding to the 'type 9' class previously designated. The protrusions measured 0.87-1.89 * 0.47-0.91 MUm (mean 1.27 * 0.59 MUm; n = 57). These findings confirm previous work from the vicinity of Kunming concerning the occurrence of S. wenzeli in chickens, and its use of both cats and dogs as definitive hosts, but indicate that corresponding infections may not occur in the regional domestic flocks of other types of fowl. PMID- 22426034 TI - Nitrite and nitric oxide metabolism in peripheral artery disease. AB - Peripheral artery disease (PAD) represents a burgeoning form of cardiovascular disease associated with significant clinical morbidity and increased 5 year cardiovascular disease mortality. It is characterized by impaired blood flow to the lower extremities, claudication pain and severe exercise intolerance. Pathophysiological factors contributing to PAD include atherosclerosis, endothelial cell dysfunction, and defective nitric oxide metabolite physiology and biochemistry that collectively lead to intermittent or chronic tissue ischemia. Recent work from our laboratories is revealing that nitrite/nitrate anion and nitric oxide metabolism plays an important role in modulating functional and pathophysiological responses during this disease. In this review, we discuss experimental and clinical findings demonstrating that nitrite anion acts to ameliorate numerous pathophysiological events associated with PAD and chronic tissue ischemia. We also highlight future directions for this promising line of therapy. PMID- 22426036 TI - Genetic polymorphisms of the CYP3A4, CYP3A5, CYP3A7 and CYP1A2 among the Jordanian population. AB - Cytochromes P450 (CYP450) plays an extremely vital role in oxidation, reduction, and peroxidation of numerous endogenous and exogenous compounds, like drugs and procarcinogens. Mainly, expression occurs in the liver, in varying polymorphic forms. Therefore, proposed as biomarkers of susceptibility to carcinogenicity and toxicity. The objective of this study was to find the allelic frequencies of CYP3A5*2,*3,*4,*5,*6,*7, CYP3A4*1B, CYP3A7*1C and CYP1A2*1C, *1D, *1E, *1F enzymes in Jordanians, and to compare them with other ethnic groups. We used polymerase chain reaction-restriction fragment length (PCR-RFLP) to genotype alleles, and we calculated frequencies using Hardy Weinberg's equation (HWE). Allelic frequencies results were: CYP3A5*2 (0.2%), CYP3A5*3 (86.6%), CYP3A5*6 (1.7%), CYP*3A5*4,*5*7 not detected, CYP3A4*1B (11.7%), CYP3A7*1C (1.7%). Finally 6.5%, 18.2%, 6.0%, 67.3% were the results of CYP1A2*1C, 1D, 1E and 1F, respectively. In conclusion, genotyping method and results of this study can be adopted or used in pharmacotherapy, toxicity and carcinogenic studies in Jordan. PMID- 22426035 TI - Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension. AB - Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent. PMID- 22426037 TI - Theoretical and experimental study of low band gap polymers for organic solar cells. AB - A combined theoretical and experimental investigation of the electronic structure and optical properties of poly(3-hexylthiophene) (P3HT), poly[3-(4 octylphenyl)thiophene] (POPT) and poly[3-(4-octylphenoxy)thiophene] (POPOT) is reported. In comparison with P3HT, POPT and POPOT exhibit better stabilities and the presence of an oxygen atom and/or a phenyl ring in the side chains enhances conjugation. Quantum chemical calculations have been performed on oligomers of increasing chain length to establish the changes in the electronic and optical properties when going from P3HT to the new derivative POPOT. The knowledge of the structure of these polymers is of utmost importance in understanding their optical properties in different phases (solution and condensed phase). The calculations indicate that, in opposition to P3HT and POPT polymers where the introduction of alkyl chains and the pendant phenyl disturbs the planarity of the backbone of the conjugated segment, POPOT has a better degree of organization in both states: the conjugated chain remains planar even in the presence of the phenoxy groups. Finally, the exciton binding energy is evaluated for these polymers and allows us to conclude that the POPOT is a promising polymer for photovoltaic applications when compared to P3HT and POPT. PMID- 22426038 TI - Downregulation of metallothionein 1F, a putative oncosuppressor, by loss of heterozygosity in colon cancer tissue. AB - PURPOSE: Downregulation of metallothionein (MT) genes has been reported in several tumors with discrepant results. This study is to investigate molecular mechanism of MT gene regulation in colon cancer which is characterized by tumor suppressor gene alterations. EXPERIMENTAL DESIGN: Integral analysis of microarray data with loss of heterozygosity (LOH) information was employed. Quantitative real-time PCR and immunohistochemistry were used to validate MT isoform expression in colon cancer tissues and cell lines. The effects of MT1F expression on RKO cell survival and tumorigenesis was analyzed. Bisulphite sequencing PCR (BSP) and methylation-specific PCR were employed to detect the methylation status of the MT1F gene in colon cancer tissues and cell lines. DNA sequencing was used to examine the LOH at the MT1F locus. RESULTS: MT1F, MT1G, MT1X, and MT2A gene expression was significantly downregulated in colon cancer tissue (p<0.05). Exogenous MT1F expression increased RKO cell apoptosis and inhibited RKO cell migration, invasion and adhesion as well as in vivo tumorigenicity. Downregulation of MT1F gene in majority of human colon tumor tissues is mainly through mechanism by loss of heterozygosity (p=0.001) while CpG island methylation of MT1F gene promoter region was only observed in poorly differentiated, MSI-positive RKO and LoVo colon cancer cell lines. CONCLUSIONS: MT1F is a putative tumor suppressor gene in colon carcinogenesis that is downregulated mainly by LOH in colon cancer tissue. Further studies are required to elucidate a possible role for MT1F downregulation in colon cancer initiation and/or progression. PMID- 22426039 TI - Impact of environmental DDT concentrations on gill adaptation to increased salinity in the tilapia Sarotherodon melanotheron. AB - Estuaries of tropical developing countries suffering from severe droughts induced by climate change are habitats to fish, which face drastic salinity variations and the contact with pollutants. The Western Africa tilapia Sarotherodon melanotheron is highly resistant to hypersalinity, but the effect of human released xenobiotics on its adaptation is barely known. Controlled experiments were conducted to observe S. melanotheron gill adaptation to abrupt salinity variations in the presence of waterborne DDT, at concentrations detected in their natural habitat. The gills appeared as an important site of DDT conversion to DDD and/or depuration. A 12-days DDT exposure resulted in decreased gill epithelium thickness at all salinities (from fresh- to hypersaline-water), and the structure of gills from freshwater fish was particularly altered, relative to controls. No unbalance in tilapia blood osmolality was observed following DDT exposure, which however caused a decrease in branchial Na(+)-K(+)-ATPase (NKA) activity. Gill cellular NKA expression was reduced in salt-water, together with the expression of the CFTR chloride channel in hypersaline water. Although S. melanotheron seems very resistant (especially in seawater) to short-term waterborne DDT contamination, the resulting alterations of the gill tissue, cells and enzymes might affect longer term respiration, toxicant depuration and/or osmoregulation in highly fluctuating salinities. PMID- 22426040 TI - Effect of aging on 5-hydroxymethylcytosine in the mouse hippocampus. AB - PURPOSE: Aging is believed to affect epigenetic marking of brain DNA with 5 methylcytosine (5mC) and possibly via the 5mC to 5-hydroxymethylcytosine (5hmC) conversion by TET (ten-eleven translocation) enzymes. We investigated the impact of aging on hippocampal DNA 5-hydroxymethylation including in the sequence of aging-susceptible 5-lipoxygenase (5-LOX) gene. METHODS: Hippocampal samples were obtained from C57BL6 mice. Cellular 5hmC localization was determined by immunofluorescence. The global 5mC and 5hmC contents were measured with the corresponding ELISA. The 5-LOX 5hmC content was measured using a glucosyltransferase/enzymatic restriction digest assay. TET mRNA was measured using qRT-PCR. RESULTS: Global hippocampal 5hmC content increased during aging as did the 5hmC content in the 5-LOX gene. This occurred without alterations of TET1 3 mRNAs and without changes in the content of 8-hydroxy-2-deoxy-guanosine, a marker of non-enzymatic DNA oxidation. CONCLUSIONS: The aging-associated increase of hippocampal 5hmC content (global and 5-LOX) appears to be unrelated to oxidative stress. It may be driven by an altered activity but not by the increased expression of the three TET enzymes. Global 5hmC content was increased during aging in the absence of 5mC decrease, suggesting that 5hmC could act as an epigenetic marker and not only as an intermediary in DNA demethylation. Further research is needed to elucidate the functional implications of the impact of aging on hippocampal cytosine hydroxymethylation. PMID- 22426041 TI - Encapsulated cell-based biodelivery of meteorin is neuroprotective in the quinolinic acid rat model of neurodegenerative disease. AB - PURPOSE: Encapsulated cell (EC) biodelivery is a promising, clinically relevant technology platform to safely target the delivery of therapeutic proteins to the central nervous system. The purpose of this study was to evaluate EC biodelivery of the novel neurotrophic factor, Meteorin, to the striatum of rats and to investigate its neuroprotective effects against quinolinic acid (QA)-induced excitotoxicity. METHODS: Meteorin-producing ARPE-19 cells were loaded into EC biodelivery devices and implanted into the striatum of rats. Two weeks after implantation, QA was injected into the ipsilateral striatum followed by assessment of neurological performance two and four weeks after QA administration. RESULTS: Implant-delivered Meteorin effectively protected against QA-induced toxicity, as manifested by both near-normal neurological performance and reduction of brain cell death. Morphological analysis of the Meteorin-treated brains showed a markedly reduced striatal lesion size. The EC biodelivery devices produced stable or even increasing levels of Meteorin throughout the study over 6 weeks. CONCLUSIONS: Stereotactically implanted EC biodelivery devices releasing Meteorin could offer a feasible strategy in the treatment of neurological diseases with an excitotoxic component such as Huntington's disease. In a broader sense, the EC biodelivery technology is a promising therapeutic protein delivery platform for the treatment of a wide range of diseases of the central nervous system. PMID- 22426042 TI - The adjuvanticity of Chiococca alba saponins increases with the length and hydrophilicity of their sugar chains. AB - The saponins of Chiococca alba are triterpene bidesmosides that contain glycidic moieties attached to the C-3 and C-28 carbon of their aglycone. We describe that their adjuvant potential increases in direct relationship to the length and hydrophilicity of the C-28 attached sugar chain which contains: arabinose rhamnose in the CA2, arabinose-rhamnose-xylose in the CA3X; arabinose-rhamnose apiose in the CA3 and arabinose-rhamnose-apiose-apiose in the CA4 saponin. The hydrophile/lipophile balance calculated for CA2 was 12.7, for CA3 and CA3X was 15.8 and for CA4 19.9. All saponins were formulated with the FML antigen for mice prophylaxis against visceral leishmaniasis. The immune response was studied using an ELISA-antibody assay and monitoring of the intradermal response (IDR) to Leishmania antigens, the cytokine expression in supernatants and the intracellular staining of in vitro cultured splenocytes. After challenge, significant increases of IgG and IgG2a antibodies were noted only in the CA4 vaccinated mice that showed extended IDR, higher IFN-gamma production by CD8+ and TNF-alpha production by CD4+ T cells, higher TNF-alpha secretion and the highest reduction of the parasite load (78%). The increases in IDR, CD4-TNF-alpha, CD8 IFN-gamma and CD8-TNF-alpha by the CA4 vaccine were strong correlates of protection and were significantly correlated to the decrease of parasite load (p= 0.007). Protection generated by the CA4 vaccine was mainly mediated by a CD4+ T cell and a TNF-alpha driven response with a lower contribution of CD8+ T cells, as confirmed by an in vivo depletion with monoclonal antibodies and by vaccination assays in TNF-alpha-receptor knock-out mice. Our results confirm that the superiority of the CA4 saponin is related to the higher hydrophilicity of its longer carbohydrate chain. C. alba saponins were non-toxic and only the xylose containing saponin CA3X was hemolytic (HD(50)=87 MUg/ml). The increase in sugar units of the saponins is positively correlated to the increase of IDR and to the decrease of parasite load. PMID- 22426043 TI - Long-term observation of respiratory function after unilateral phrenic nerve and multiple intercostal nerve transfer for avulsed brachial plexus injury. AB - BACKGROUND: Phrenic nerve transfer (PNT) or multiple intercostal nerve transfer (MIT) alone are reported to have no significant impact on pulmonary function in the short or medium term, but it has rarely been reported whether the combination of PNT-MIT could influence respiratory function in the long term. OBJECTIVE: Respiratory function was evaluated after PNT and PNT-MIT 7 to 19 years (mean, 10 years) postoperatively. METHODS: Twenty-three adult patients with brachial plexus avulsion injuries who underwent PNT-MIT were compared with 19 corresponding patients who underwent PNT. Pulmonary function testings, phrenic nerve conduction study, and chest fluoroscopy were performed. In the PNT-MIT group, further investigation was performed on the effect of the number of transferred intercostal nerves and the timing of MIT. RESULTS: In the PNT-MIT group, forced vital capacity, forced expiratory volume in one second, and total lung capacity were 73.69%, 72.04%, and 74.81% of predicted values without significant differences from the PNT group. Diaphragmatic paralysis permanently existed with 1 to 1.5 intercostal spaces (ICSs) elevation and near 1 ICS reduced excursion. There was no statistical difference between the PNT and PNT-MIT groups. Furthermore, 3 and 4 intercostal nerves transferred resulted in no further decrease in pulmonary function test results than 2 intercostal nerves. No significant difference was found when PNT and MIT were performed at the same stage or with an interval. CONCLUSION: PNT-MIT did not result in additional impairment in respiratory function in adult patients compared with PNT alone. It is safe to transfer 2 to 4 intercostal nerves at 1 to 2 months delay after PNT. PMID- 22426044 TI - Thalamic and subthalamic deep brain stimulation for essential tremor: where is the optimal target? AB - BACKGROUND: The ventrolateral thalamus (ventral intermediate nucleus [Vim]) is the traditional target for neurosurgical treatment of essential tremor. The target, however, has varied substantially among different neurosurgeons. OBJECTIVE: To evaluate the effect of deep brain stimulation in the thalamus and posterior subthalamic area (PSA) in relation to electrode location. METHODS: Thirty-six (17 Vim/19 PSA) patients with 44 deep brain stimulation electrodes were included in this retrospective study. The effect of stimulation was evaluated with standardized settings for each contact using items from the Essential Tremor Rating Scale. RESULTS: When each contact was evaluated in terms of the treated hand with standardized stimulation, the electrode contact providing the best effect in the individual patient was located in the zona incerta or radiation prelemniscalis in 54% and the Vim in 12%. Forty contacts provided a tremor reduction of > 90%. Of these, 43% were located in the PSA and 18% in the Vim according to the Schaltenbrand atlas. Of these 40 contacts, 37 were found in the PSA group. CONCLUSION: More contacts yielding an optimal effect were found in the PSA group than in the Vim. Many patients operated on in the Vim got the best effect from a contact located in the PSA. This might suggest that the PSA is a more efficient target than the Vim. PMID- 22426045 TI - Bone morphogenetic proteins and degenerative disk disease. AB - Bone morphogenetic proteins (BMPs) are involved not only in osteogenesis but also in chondrogenesis. They play an important role in the development and maintenance of the intervertebral disk (IVD). For this reason, an increasing amount of research has been performed to examine the relationship between BMPs and degenerative disk disease (DDD). Moreover, researchers are examining the safe use of BMPs as a potential treatment for diskogenic back pain. We performed a literature search using databases from the US National Library of Medicine and the National Institutes of Health to identify studies relating BMPs to DDD. According to in vitro and in vivo studies in different animal and human IVDs, BMP 2 and BMP-7 are upregulated with aging and with induced disk injury; this represents an anabolic response. Direct administration of BMP-2 to IVD cells results in increased production of components of the extracellular matrix. Upregulation of the BMP pathway via other agents, namely simvastatin and LIM mineralization protein-1, has resulted in similar outcomes. Adenoviruses loaded with BMPs, transfected either directly to IVD cells or via articular chondrocytic vectors, also resulted in reversal of the typical findings in DDD. We conclude that the use of BMPs to treat DDD has a promising future. Further studies are indicated to determine optimal delivery and efficacy in humans. PMID- 22426046 TI - Transfer of the distal terminal motor branch of the extensor carpi radialis brevis to the nerve of the flexor pollicis longus: an anatomic study and clinical application in a tetraplegic patient. AB - BACKGROUND: In tetraplegics, thumb and finger motion traditionally has been reconstructed via orthopedic procedures. Although rarely used, nerve transfers are a viable method for reconstruction in tetraplegia. OBJECTIVE: To investigate the anatomic feasibility of transferring the distal branch of the extensor carpi radialis brevis (ECRB) to the flexor pollicis longus (FPL) nerve and to report our first clinical case. METHODS: We studied the motor branch of the ECRB and FPL in 14 cadaveric upper limbs. Subsequently, a 24-year-old tetraplegic man with preserved motion in his shoulder, elbow, wrist, and finger extension, but paralysis of thumb and finger flexion underwent surgery. Seven months after trauma, we transferred the brachialis muscle with a tendon graft to the flexor digitorum profundus. The distal nerve of the ECRB was transferred to the FPL nerve. RESULTS: The branch to the ECRB entered the muscle in its anterior and proximal third. After sending out a first collateral, the nerve runs for 2.4 cm alongside the muscle and bifurcates intramuscularly. A main branch from the anterior interosseous nerve, which entered the muscle 3 cm from its origin on the radius, innervated the FPL. The ECRB and FPL nerves had similar diameters (~1 mm) and numbers of myelinated fibers (~180). In our patient, 14 months after surgery, pinching and grasping were restored and measured 2 and 8 kg strength, respectively. CONCLUSION: Transfer of the ECRB distal branch to the FPL is a viable option to reconstruct thumb flexion. PMID- 22426047 TI - Positron emission tomography imaging of meningioma in clinical practice: review of literature and future directions. AB - Meningiomas represent about 20% of intracranial tumors and are the most frequent nonglial primary brain tumors. Diagnosis is based on computed tomography (CT) and magnetic resonance imaging (MRI). Mainstays of therapy are surgery and radiotherapy. Adjuvant chemotherapy is tested in clinical trials of phase II. Patients are followed clinically by imaging. However, classical imaging modalities such as CT and MRI have limitations. Hence, we need supplementary imaging tools. Molecular imaging modalities, especially positron emission tomography (PET), represent promising new instruments that are able to characterize specific metabolic features. So far, these modalities have only been part of limited study protocols, and their impact on clinical routine management is still under investigation. It may be expected that their extended use will provide new aspects about meningioma imaging and biology. In the present article, we summarize PET imaging for meningiomas based on a thorough review of the literature. We discuss and illustrate the potential role of PET imaging in the clinical management of meningiomas. Finally, we indicate current limitations and outline directions for future research. PMID- 22426048 TI - Extravascular papillary endothelial hyperplasia mimicking neoplasm after radiosurgery: case report. AB - BACKGROUND AND IMPORTANCE: Papillary endothelial hyperplasia (PEH) is a rare form of exuberant reactive endothelial proliferation that can mimic neoplasm. We report the largest series of patients with histologically confirmed intracranial extravascular PEH developing in the field of previous treatment with stereotactic radiosurgery. CLINICAL PRESENTATION: We collected the clinical, radiological, surgical, and pathological findings from 4 patients in whom intracranial extravascular PEH developed after treatment with stereotactic radiosurgery. In all patients, the development of an enlarging hemorrhagic mass lesion at the site of previous radiotherapy on magnetic resonance imaging was radiographically suspicious for neoplasm and prompted biopsy or resection. All 4 patients elected to undergo biopsy or surgical resection. Histological examination of the biopsy and resection specimens in all patients demonstrated the classic features of PEH. CONCLUSION: The interval to the development of PEH ranged from 5 months to 6 years, 10 months. Clinical follow-up was available for 3 of the 4 patients. None of these 3 patients have demonstrated evidence of recurrence during a mean follow up period of 22 months (range, 15-30 months). These patients share common radiological features, potentially allowing preoperative diagnosis and improved guidance of clinical management. These cases suggest a link between radiosurgery and the development of PEH. These findings also suggest that PEH should be considered in the differential diagnosis for patients treated with radiosurgery in whom a hemorrhagic mass lesion subsequently develops at or near the site of previous treatment. We think that complete surgical excision is the best treatment for intracranial PEH. PMID- 22426052 TI - Bidirectional microevnironmental cues between neoplastic and stromal cells drive metastasis formation and efficiency. PMID- 22426053 TI - A novel target for ischemic stroke therapy: pannexins. PMID- 22426054 TI - The neurosurgeon's role in integrated health systems. PMID- 22426055 TI - State of the art in subdural grid design: a new flexible active electrode array. PMID- 22426056 TI - Dissecting the perivascular stem-cell niche: can we take tumor recurrence down a NOTCH? PMID- 22426057 TI - The future is now: smartphones to join scalpels and stethoscopes? PMID- 22426058 TI - Notch inhibition via micro-RNA blocks glioma development. PMID- 22426059 TI - Direct extracranial to intracranial bypass for stroke prevention. PMID- 22426060 TI - CD90 is identified as a marker for cancer stem cells in high-grade gliomas using tissue microarrays. PMID- 22426061 TI - Characterization of the ice-binding protein from Arctic yeast Leucosporidium sp. AY30. AB - Previously, we reported the ice-binding protein (LeIBP) from the Arctic yeast Leucosporidium sp. AY30. In this study we provide physicochemical characterization of this IBP, which belongs to a class of IBPs that exhibited no significant similarity in primary structure to other known antifreeze proteins (AFPs). We compared native, glycosylated and non-glycosylated recombinant LeIBPs. Interestingly, size-exclusion chromatography and analytical ultracentrifugation revealed that LeIBP self-associates with a reversible dimer with K(d) values in the range 3.45-7.24*10(-6) M. Circular dichroism (CD) spectra showed that LeIBP, glycosylated or non-glycosylated, is predominantly composed of beta-strand secondary structural elements (54.6%), similar to other beta-helical antifreeze proteins (AFPs). In thermal hysteresis (TH) activity measurements, native LeIBP was twice more active (0.87 degrees C at 15 mg/mL) than that of the recombinant IBPs (0.43-0.42 degrees C at 10.8 mg/mL). This discrepancy is probably due to uncharacterized enhancing factors carried over during ice affinity purification, because glycosylated and non-glycosylated recombinant proteins displayed similarly low activity. Ice recrystallization inhibition (RI) activities of the native and recombinant LeIBPs were comparable. Measurements of CD, TH activity, and RI showed that glycosylation does not cause structural changes and is not required for function. An ice-etching experiment using green fluorescent protein tagged IBP revealed that LeIBP binds, just as hyperactive AFPs, to both basal and pyramidal prism planes of the ice crystal. Taken together, our results indicate that LeIBP, structurally similar to hyperactive AFPs, is moderately active and that a reversible dimer has no effect on its activity. PMID- 22426062 TI - The ultrastructure of Drosophila heart cells. AB - The functionality of the Drosophila heart or dorsal vessel is achieved by contributions from several tissues. The heart tube itself is composed of different types of cardiomyocytes that form an anterior aorta and a posterior heart chamber, inflow tracts and intracardiac valves. Herein we present an in depth ultrastructural analysis of all cell types present in the Drosophila heart at different developmental stages. We demonstrate that the lumen-forming cardiomyocytes reveal a complex subcellular architecture that changes during development. We show that ostial cells, for which it was previously shown that they are specified during embryogenesis, start to differentiate at the end of embryogenesis displaying opening structures that allow inflow of hemolymph. Furthermore we found, that intracardiac valve cells differentiate during larval development and become enlarged during the 3. instar larval stages by the formation of cellular cytoplasmic free cavities. Moreover we were able to demonstrate, that the alary muscles are not directly connected to the heart tube but by extracellular matrix fibers at any stage of development. Our present work will provide a reference for future investigations on normal heart development and for analyses of mutant phenotypes that are caused by defects on the subcellular level. PMID- 22426063 TI - Expression of vasorin (Vasn) during embryonic development of the mouse. AB - The murine vasorin (Vasn) gene, initially known as Slit-like 2, encodes a transmembrane protein that shares structural similarities with the eponymous Slit proteins. However, whether it also shares functional similarities with these large secreted proteins remains to be elucidated. Here, we report expression of Vasn during embryonic and fetal development of the mouse using whole-mount in situ hybridization (WISH) and histochemical detection of beta-galactosidase expressed from a targeted Vasn(lacZ) knock-in allele. Comparison of whole-mount staining patterns of both approaches showed identical expression domains, confirming that Vasn promoter-driven beta-galactosidase expression faithfully reflects endogenous Vasn expression. Vasn is highly expressed in vascular smooth muscle cells (hence the name), a finding consistent with a previous report on its human homolog VASN, whose extracellular domain was shown to function as a TGF beta trap (Ikeda et al., 2004). Most striking, however, is Vasn's prominent expression in the developing skeletal system, starting as early as the first mesenchymal condensations appear. Moreover, distinct expression domains outside the bones, e.g., in the developing kidneys and lungs, suggest further roles for this gene in the mouse. Recently, it was shown that mitochondria-localized Vasn protects cells from TNFalpha- and hypoxia-induced apoptosis, and partial deletion of the Vasn coding sequence leads to increased sensitivity of hepatocytes to TNFalpha-induced apoptosis (Choksi et al., 2011). By providing a first comprehensive analysis of the Vasn expression pattern during mouse embryonic development, our study will help to further elucidate its biological functions. PMID- 22426065 TI - Comings and goings. PMID- 22426066 TI - The transformation of psychoanalysis in America: emigre analysts and the New York Psychoanalytic Society and institute, 1935-1961. AB - Part I reviews the role of the Emergency Committee on Relief and Immigration of the American Psychoanalytic Association, chaired by Lawrence Kubie and Bettina Warburg, members of the New York Psychoanalytic Society, in facilitating the immigration to the United States of scores of European analysts and candidates between 1938 and 1943. The challenges facing the committee are outlined in reports written by Kubie and Warburg. In particular, the intractable problem of how to integrate European lay analysts into the American Psychoanalytic Association was an ever present problem. Part II describes the impact emigre analysts had on the intellectual life of the New York Psychoanalytic Society and Institute, and considers how the psychoanalytic work of the emigres was influenced by their move to America. The reminiscences of two emigre analysts, Peter Neubauer and Kurt R. Eissler, on their experience of coming to the United States close the paper. PMID- 22426067 TI - Peter Heller's a Child Analysis with Anna Freud: the significance of the case for the history of child psychoanalysis. AB - A Child Analysis with Anna Freud, a collection of Anna Freud's detailed case notes of her treatment of the young Peter Heller between 1929 and 1932, was first published in English in 1990. Not only does this work give us direct access to Anna Freud's ways of thinking and working at a crucial period in the early history of child analysis; it is also one of the few records of an adult reflecting in depth on the experience of being in analysis as a child. Yet to date this work has received little attention in the psychoanalytic literature. In an attempt to redress this neglect, the Heller case study is placed in the context of Anna Freud's emerging ideas about child analysis. In particular, its significance in the development of her psychoanalytic thinking is investigated in the light of her 1927 book, The Technique of Child Analysis. PMID- 22426068 TI - A national survey of candidates: I. demographics, practice patterns, and satisfaction with training. AB - To better focus efforts in recruiting psychoanalytic candidates, current candidates' demographics, practice patterns, and satisfaction with psychoanalytic training were investigated. An anonymous web-based survey was distributed by e mail to all candidates subscribing to the affiliate member e-mail list in 2009 2010. Surveys were completed by 226 of 565 affiliate members, for a return rate of 40%. The majority of respondents were women 45 to 64 years of age, married, with a doctoral degree, in private practice, with an annual household income of over $100,000. Most candidates devoted 11 to 30 hours a week to training and had no analysts or candidates in their workplace. Almost half had considered training for more than four years before matriculation, with financial issues cited most frequently as delaying entry. Over 80% of respondents were satisfied with their training. The most frequently cited reasons for dissatisfaction were a negative institute atmosphere, concerns about teaching or the curriculum, and difficulty finding cases. Candidates in training for eight years or more accounted for almost 20% of the group and were more often dissatisfied with training. This study demonstrates that the majority of current candidates are satisfied with training but suggests that recruitment may become increasingly difficult unless factors related to time, cost, case finding, graduation requirements, and institute atmosphere can be addressed. PMID- 22426069 TI - Three problematic assumptions about psychoanalytic education: a brief communication. PMID- 22426070 TI - Research to the rescue? Introduction to a discussion. PMID- 22426071 TI - Response to Eagle and Wolitzky. PMID- 22426072 TI - Between a rock and hard science: how should psychoanalysis respond to pressures for quantitative evidence of effectiveness? PMID- 22426073 TI - Faustian science and the future of psychoanalysis. PMID- 22426074 TI - Is systematic quantitative research scientifically rigorous? methodological and statistical considerations. PMID- 22426075 TI - Response to commentaries. PMID- 22426077 TI - Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. AB - The DNA-damage response (DDR) arrests cell-cycle progression until damage is removed. DNA-damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously induced persistent DDR markers is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence. PMID- 22426078 TI - The actions of hyperthermia on the autonomic nervous system: central and peripheral mechanisms and clinical implications. AB - Hyperthermia is defined as an elevated body temperature due to failed thermoregulation. It can occur under physiological conditions such as intense exercise or due to pathology such as malignant hyperthermia and heat stroke. It has also been implicated as a cause for sudden infant death syndrome. High temperatures are also used in medical interventions - hyperthermic chemotherapy or radiofrequency ablation, for example, which have serious side effects. The effect of hyperthermia on the central nervous system has not been fully researched, but even less is known on the effects of hyperthermia on the peripheral autonomic nervous system. In this review we discuss how conditions such as malignant or therapeutic hyperthermia affect the central and peripheral components of the autonomic nervous system, smooth muscle, skeletal muscle and cardiac muscle. We conclude that there is sufficient evidence for the detrimental effect of hyperthermia on central nerves, and that these effects are long lasting, although the major mechanism for this remains unknown. Similarly, the direct damage of hyperthermia to the enteric nerves also seems to be long lasting. In contrast, the reduced contractility of cardiac muscle and gastrointestinal smooth muscle when exposed to hyperthermia is short-lived. The consensus is that inadequate calcium handling is the mechanism of heat damage to cardiac and skeletal muscle. There is no such consensus when dealing with smooth muscle. The mechanism of hyperthermic damage to autonomic end organs such as the gastrointestinal tract has yet to be elucidated and further research into both central and peripheral hyperthermia is necessary. PMID- 22426079 TI - Competitive allele specific TaqMan PCR for KRAS, BRAF and EGFR mutation detection in clinical formalin fixed paraffin embedded samples. AB - BACKGROUND: The development of targeted therapies has created a need for robust molecular characterization of cancer and it has become a challenge to validate methods to ensure accuracy in tumor mutation testing. METHODS: The current study was designed to evaluate KRAS, BRAF and EGFR genotyping by Competitive Allele Specific hydrolysis probes (TaqMan) PCR technology (CAST), on suboptimal formalin fixed paraffin embedded (FFPE) tumor samples. Assays were calibrated on FFPE samples and a minimal quantification cycle (Cq) cut-off was determined to standardize analyses and avoid over-interpretation of degraded material. Sensibility, specificity and blinded clinical sample screenings (n=63) were evaluated. RESULTS: CAST PCR allowed efficient amplification of FFPE samples, probes were highly specific and all assays had a sensibility inferior to 1% except for the EGFR p.T790M assay. 60/63 samples were correctly typed. The three missed mutations were EGFR exon 19 deletions that were not recognized by the DEL19 assays that were used. CONCLUSIONS: This technology is less laborious and prevent crossover of PCR products as compared to multistep methods. TaqMan(r) Mutation Detection assay is an important technology to consider in the field of mutation detection for KRAS, BRAF and EGFR point mutation screening. Assay calibration on FFPE samples may prevent erroneous interpretations that will ultimately harm clinical oncology practice. PMID- 22426081 TI - Utilizing RxNorm to support practical computing applications: capturing medication history in live electronic health records. AB - RxNorm was utilized as the basis for direct-capture of medication history data in a live EHR system deployed in a large, multi-state outpatient behavioral healthcare provider in the United States serving over 75,000 distinct patients each year across 130 clinical locations. This tool incorporated auto-complete search functionality for medications and proper dosage identification assistance. The overarching goal was to understand if and how standardized terminologies like RxNorm can be used to support practical computing applications in live EHR systems. We describe the stages of implementation, approaches used to adapt RxNorm's data structure for the intended EHR application, and the challenges faced. We evaluate the implementation using a four-factor framework addressing flexibility, speed, data integrity, and medication coverage. RxNorm proved to be functional for the intended application, given appropriate adaptations to address high-speed input/output (I/O) requirements of a live EHR and the flexibility required for data entry in multiple potential clinical scenarios. Future research around search optimization for medication entry, user profiling, and linking RxNorm to drug classification schemes holds great potential for improving the user experience and utility of medication data in EHRs. PMID- 22426082 TI - Influence of coupling bonds on the anti-tumor activity of polymer-pirarubicin conjugates. AB - Pirarubicin (THP) was conjugated onto the pendant carboxyl groups of poly(ethylene glycol)-block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate) [PEG-b-P(LA-co-MCC)] through hydrazone, ester, and amide bonds, respectively, and the conjugates were assembled into micelles with diameters between 30 and 60 nm. The in vitro THP release of the three conjugate micelles was conducted in pH 7.4 and 5.0 buffer solutions, and conjugate micelles with hydrazone linkage had the fastest THP release rate. Their in vitro cytotoxicity was tested using mouse mammary adenocarcinoma EMT6 cells and in vivo anti-tumor activity in Balb/c mice models bearing EMT6 tumors were compared with free THP and with each other. The results showed that the polymer-THP conjugates displayed higher cell-uptakes and better anti-tumor activities than free THP at 4h, and among the three micelles, those with hydrazone linkage had the highest anti-tumor activity in vivo, while those with amide linkage were the lowest. PMID- 22426080 TI - Ocular surface immunity: homeostatic mechanisms and their disruption in dry eye disease. AB - The tear film, lacrimal glands, corneal and conjunctival epithelia and Meibomian glands work together as a lacrimal functional unit (LFU) to preserve the integrity and function of the ocular surface. The integrity of this unit is necessary for the health and normal function of the eye and visual system. Nervous connections and systemic hormones are well known factors that maintain the homeostasis of the ocular surface. They control the response to internal and external stimuli. Our and others' studies show that immunological mechanisms also play a pivotal role in regulating the ocular surface environment. Our studies demonstrate how anti-inflammatory factors such as the expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in corneal cells, immature corneal resident antigen-presenting cells, and regulatory T cells play an active role in protecting the ocular surface. Dry eye disease (DED) affects millions of people worldwide and negatively influences the quality of life for patients. In its most severe forms, DED may lead to blindness. The etiology and pathogenesis of DED remain largely unclear. Nonetheless, in this review we summarize the role of the disruption of afferent and efferent immunoregulatory mechanisms that are responsible for the chronicity of the disease, its symptoms, and its clinical signs. We illustrate current anti-inflammatory treatments for DED and propose that prevention of the disruption of immunoregulatory mechanisms may represent a promising therapeutic strategy towards controlling ocular surface inflammation. PMID- 22426083 TI - Metabolism and cold tolerance of overwintering adult mountain pine beetles (Dendroctonus ponderosae): evidence of facultative diapause? AB - We sought evidence for a distinct diapause in adult overwintering mountain pine beetles (Dendroctonus ponderosae Hopkins) by measuring metabolic rate and supercooling ability of field collected beetles throughout the year. Metabolic rates measured at 0, 5, and 10 degrees C declined significantly from October through November, then rose slowly, reaching levels as high as those recorded in October by late May. From December to February metabolic rates were not correlated with minimum weekly phloem temperatures (R(2)=0.0%, P=0.592), but were correlated with phloem temperatures as winter advanced to spring (R(2)=44.8%, P=0.010), a pattern consistent with progression through the maintenance and termination phases of diapause. Supercooling points were also significantly lower in winter compared to fall and spring (F((8,143))=32.6, P<0.001) and were closely correlated with metabolic rates (R(2)>79% for all three temperatures). Dry mass declined linearly with winter progression (F((8,150))=8.34, P<0.001), explained by catabolism of metabolic reserves, with a concomitant accumulation of metabolic water (F((8,147))=35.24, P<0.001). The strong mid-winter metabolic suppression correlated with improved supercooling ability, coupled with their lack of response to variation in environmental temperature, are evidence of possible diapause in adult overwintering mountain pine beetles. PMID- 22426084 TI - Aedes aegypti pharate 1st instar quiescence affects larval fitness and metal tolerance. AB - The eggs of the mosquito Aedes aegypti possess the ability to undergo an extended quiescence hosting a fully developed 1st instar larvae within the chorion. As a result of this life history trait pharate larvae can withstand months of quiescence inside the egg where they depend on stored maternal reserves. A. aegypti mosquitoes are frequently associated with urban habitats that may contain significant metal pollution. Therefore, the duration of quiescence and extent of nutritional depletion may affect the physiology and survival of larvae that hatch in a suboptimal habitat. The aim of this study was to determine the effect of an extended quiescence on larval nutrient reserves and the subsequent effects of metal exposure on larval fitness, survival and development. We hypothesized that an extended quiescence would reduce nutritional reserves and alter the molecular response to metal exposure thereby reducing larval survival and altering larval development. As a molecular marker for metal stress responses, we evaluated transcriptional changes in the metallothionein gene (AaMtn) in response to quiescence and metal exposure. Extended 1st instar quiescence resulted in a significant decrease in lipid reserves and negatively affected larval fitness and development. AaMtn transcription and metal tolerance were compromised in first instars emerged from eggs that had undergone an extended quiescence. These findings suggest that newly emerged mosquito larvae that had survived a relatively long pharate 1st instar quiescence (as might occur during a dry season) are more vulnerable to environmental stress. Pharate 1st instar quiescence could have implications for vector control strategies. Newly emerged mosquito larvae at the end of the dry season or start of the wet season are physiologically compromised, and therefore potentially more susceptible to vector control strategies than mosquito larvae hatched subsequently throughout the wet season. PMID- 22426085 TI - High rate of advanced adenoma detection in 4 rounds of colorectal cancer screening with the fecal immunochemical test. AB - BACKGROUND & AIMS: Few data have been published on the performance of colorectal cancer (CRC) screens that use multiple rounds of the fecal immunochemical test (FIT). We evaluated outcomes of 4 screening rounds in over 7 years in an Italian population-based program. METHODS: We conducted a prospective cohort study of 2959 average-risk subjects, aged 50-74 years, who were invited for the first screening round in 2001. We assessed the participation rate, the yield of advanced adenomas and CRC detected in the screening examinations, and we collected information about interval CRCs, with a follow-up period of 8.5 years. RESULTS: Participation in each round varied from 56% to 63%; 48.1% of eligible subjects attended all 4 invitations. The positive predictive value of the FIT for advanced neoplasia (CRC or advanced adenoma) was 40% at the first round, and approximately 33% in the subsequent rounds. This decrease was attributable mainly to a decrease in the detection of CRC, although a high rate of advanced adenomas (range, 0.8%-1.7%) was observed over all rounds. To find one advanced neoplasia in the study period the number of people that needed to be screened was 28, and the number of tests needed was 74. CONCLUSIONS: About 60% of invited individuals participated in every single round of FIT screening for CRC, but less than 50% attended all 4 tests. A high detection rate of advanced adenomas in all rounds indicates that FIT screening could have a higher impact on incidence of CRC than the guaiac fecal occult blood test. PMID- 22426086 TI - Aspirin protects against Barrett's esophagus in a multivariate logistic regression analysis. AB - BACKGROUND & AIMS: Better criteria are needed to identify patients who should be screened for Barrett's esophagus (BE) to reduce overtesting and improve the cost effectiveness. There is evidence that chemopreventive agents such as nonsteroidal anti-inflammatory drugs, particularly aspirin, reduce the risk of esophageal adenocarcinoma (EAC), but little is known about their effects on BE. We analyzed characteristics of patients with BE for factors that might be used in screening and management. METHODS: In this case-controlled study, we identified 434 patients with BE diagnosed at the first endoscopy (incident cases) at a single institution (1997-2010). BE cases were matched with controls on the basis of indication for endoscopy, year of endoscopy, and endoscopist. Risk factors analyzed included age, sex, body mass index, medical and social history, and medications. We performed a multivariate logistic regression analysis to identify clinical risk factors for BE. RESULTS: In a multivariate regression model, men had a greater risk for developing BE (odds ratio, 3.2; 95% confidence interval, 2.3-4.4), whereas current aspirin users had a lower risk than nonusers (odds ratio, 0.56; 95% confidence interval, 0.39-0.80). A subset analysis, limited to patients who had endoscopies for symptoms of gastroesophageal reflux disease, yielded similar findings. No interactions were found between aspirin use and smoking or use of acid-suppressive medications. CONCLUSIONS: In a case-controlled study of 434 patients with BE, current aspirin use appeared to reduce the risk of BE; previous studies associated aspirin use with a reduced risk of EAC. Although efforts were made to minimize biases in our analysis, the possibility of residual confounding remains. PMID- 22426087 TI - Global prevalence of and risk factors for irritable bowel syndrome: a meta analysis. AB - BACKGROUND & AIMS: Many cross-sectional surveys have reported the prevalence of irritable bowel syndrome (IBS), but there have been no recent systematic review of data from all studies to determine its global prevalence and risk factors. METHODS: MEDLINE, EMBASE, and EMBASE Classic were searched (until October 2011) to identify population-based studies that reported the prevalence of IBS in adults (>=15 years old); IBS was defined by using specific symptom-based criteria or questionnaires. The prevalence of IBS was extracted for all studies and based on the criteria used to define it. Pooled prevalence, according to study location and certain other characteristics, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. RESULTS: Of the 390 citations evaluated, 81 reported the prevalence of IBS in 80 separate study populations containing 260,960 subjects. Pooled prevalence in all studies was 11.2% (95% CI, 9.8% 12.8%). The prevalence varied according to country (from 1.1% to 45.0%) and criteria used to define IBS. The greatest prevalence values were calculated when >=3 Manning criteria were used (14%; 95% CI, 10.0%-17.0%); by using the Rome I and Rome II criteria, prevalence values were 8.8% (95% CI, 6.8%-11.2%) and 9.4% (95% CI, 7.8%-11.1%), respectively. The prevalence was higher for women than men (OR, 1.67; 95% CI, 1.53-1.82) and lower for individuals older than 50 years, compared with those younger than 50 (OR, 0.75; 95% CI, 0.62-0.92). There was no effect of socioeconomic status, but only 4 studies reported these data. CONCLUSIONS: The prevalence of IBS varies among countries, as well as criteria used to define its presence. Women are at slightly higher risk for IBS than men. The effects of socioeconomic status have not been well described. PMID- 22426088 TI - Development of a hybrid percutaneous-endoscopic approach for the complete clearance of gallstones. AB - Cholecystitis is common and costly to the health care system. Cholecystectomy is curative and the treatment of choice. Alternatives to cholecystectomy, however, are needed for patients who cannot undergo this surgery. However, procedures such as percutaneous cholecystostomy, endoscopic transpapillary and transduodenal gallbladder drainage, and dissolution therapy have limitations such as continued gallstone burden. More effective and minimally invasive alternatives, therefore, are needed. We developed a hybrid percutaneous-endoscopic approach for complete gallstone clearance in an elderly patient who was not a candidate for surgery. If replicated and proven to be safe, this technique could be a minimally invasive alternative to cholecystectomy for patients with symptomatic gallstone disease who are not good candidates for surgery. PMID- 22426089 TI - An explicit expression for determining cometabolism kinetics using progress curve analysis. AB - We present an explicit expression for describing the kinetics of cometabolic biotransformation of environmental pollutants. This expression is based on the Lambert W function and explicitly relates the substrate concentration, S, to time, t, the two experimentally measured variables. This explicit relationship simplifies kinetic parameter estimation as differential equation solution and iterative estimation of the substrate concentration are eliminated. The applicability of this new expression for nonlinear kinetic parameter estimation was first demonstrated using noise containing synthetic data where final estimates of the kinetic parameters were very close to their actual values. Subsequently 1.1.1-trichloroethane degradation data at initial concentrations of 750 and 375 MUM were described using the explicit expression resulting in r and K(s) estimates of 0.26 MUM/mg d and 28.08 MUM and 0.30 MUM/mg d and 28.70 MUM, respectively, very similar to 0.276 MUM/mg d and 31.2 MUM, respectively, that were reported in the original study. The new explicit expression presented in this study simplifies estimation of cometabolic kinetic parameters and can be easily used across all computational platforms thereby providing an attractive alternative for progress curve analysis. PMID- 22426090 TI - Regulation of the pigment optical density of an algal cell: filling the gap between photosynthetic productivity in the laboratory and in mass culture. AB - An increasing number of investors is looking at algae as a viable source of biofuels, beside cultivation for human/animal feeding or to extract high-value chemicals and pharmaceuticals. However, present biomass productivities are far below theoretical estimations implying that a large part of the available photosynthetically active radiation is not used in photosynthesis. Light utilisation inefficiency and rapid light attenuation within a mass culture due to high pigment optical density of wild type strains have been proposed as major limiting factors reducing solar-to-biomass conversion efficiency. Analysis of growth yields of mutants with reduced light-harvesting antennae and/or reduced overall pigment concentration per cell, generated by either mutagenesis or genetic engineering, could help understanding limiting factors for biomass accumulation in photobioreactor. Meanwhile, studies on photo-acclimation can provide additional information on the average status of algal cells in a photobioreactor to be used in modelling-based predictions. Identifying limiting factors in solar-to-biomass conversion efficiency is the first step for planning strategies of genetic improvement and domestication of algae to finally fill the gap between theoretical and industrial photosynthetic productivity. PMID- 22426091 TI - Protein disulphide isomerase-induced refolding of sonochemically prepared Ribonuclease A microspheres. AB - The present communication describes for the first time the development of Ribonuclease A (RNase A) microspheres using the sonochemical method followed by an enzymatic treatment with protein disulphide isomerase (PDI). Ultrasound application induced changes on the protein physicochemical and biological properties: the enzymatic activity of RNase A was decreased in 35% and the free thiol groups content was significantly increased, probably due to the breakage of protein disulphide bonds and assembly of RNase A monomers. The deconvolution of amide I band, from Fourier Transform Infrared Spectroscopy, showed that the secondary structure of RNase A was slightly changed after microspherization. The PDI application on microspheres promoted the recovery of RNase A biological activity and induced the release of active protein into solution in its native state. These results were promoted by different states of PDI active site: oxidized and reduced, respectively. The PDI aptitude to catalyze the refolding of a protein substrate in the form of spheres is here reported. PMID- 22426092 TI - Improved thermostability of AEH by combining B-FIT analysis and structure-guided consensus method. AB - alpha-Amino ester hydrolases (AEH, E.C. 3.1.1.43) catalyze the synthesis and hydrolysis of alpha-amino beta-lactam antibiotics. The AEH enzymes have been shown to feature excellent synthetic capability but suffer from poor thermostability. AEH from Xanthomonas campestris exhibits an optimal activity temperature of 25 degrees C, an observed half-life of 5 min at 30 degrees C, and a "T-50" value, the temperature at which the half-life is 30 min, of 27 degrees C. To improve the thermostability of AEH, a modified structure-guided consensus model of seven homologous enzymes was generated along with analysis of the B-values from the available crystal structures of AEH from Xanthomonas citri. A family of stabilized variants was created including a consensus-driven triple variant, A275P/N186D/V622I. Independent NNK saturation of two high B-factor sites, K34 and E143, on the triple variant resulted in our best variant, the quadruple mutant E143H/A275P/N186D/V622I, with a "T-50" value of 34 degrees C (7 degrees C improvement) and 1.3-fold activity compared to wild-type. PMID- 22426093 TI - Autodisplay of functional CYP106A2 in Escherichia coli. AB - Cytochrome P450 enzymes catalyse a wide variety of reactions, including the hydroxylation and epoxidation of CC bonds, and dealkylation reactions. There is high interest in these reactions for biotechnology and pharmaceutical processes. Many P450s require membrane surroundings and have substrates that do not cross biological membranes. To circumvent these obstacles, CYP106A2 from Bacillus megaterium was expressed on the outer membrane of Escherichia coli cells by Autodisplay. Exposure on the surface was confirmed by a protease accessibility test and flow cytometry after immunolabelling. HPLC assays showed that 0.5 ml of cells displaying the enzyme (OD578 = 6) converted 9.13 MUmol of deoxycorticosterone to 15beta-OH-deoxycorticosterone within 1h. Imipramine and abietic acid were also accepted as substrates. The number of active enzyme molecules per cell was calculated to be 20,000. Surprisingly, surface-exposed CYP106A2 was active in E. coli BL21 without the external addition of the heme group. However, when CYP106A2 was expressed on the surface of an E. coli strain lacking the TolC channel protein (JW5503), enzymatic activity was almost completely abolished. The activity of CYP106A2 on the surface of E. coli JW5503 could be restored by the external addition of the heme group. This suggests, as has been reported before, that E. coli uses a TolC-dependent mechanism to export heme into the growth media, where it can be scavenged by a surface-displayed apoenzyme. Our results indicate that Autodisplay enables the functional surface display of P450 enzymes and provides a new platform to access their synthetic potential. PMID- 22426094 TI - Intestinal cell targeting of a stable recombinant Cu-Zn SOD from Cucumis melo fused to a gliadin peptide. AB - The mRNA encoding full length chloroplastic Cu-Zn SOD (superoxide dismutase) of Cucumis melo (Cantaloupe melon) was cloned. This sequence was then used to generate a mature recombinant SOD by deleting the first 64 codons expected to encode a chloroplastic peptide signal. A second hybrid SOD was created by inserting ten codons to encode a gliadin peptide at the N-terminal end of the mature SOD. Taking account of codon bias, both recombinant proteins were successfully expressed and produced in Escherichia coli. Both recombinant SODs display an enzymatic activity of ~5000U mg(-1) and were shown to be stable for at least 4h at 37 degrees C in biological fluids mimicking the conditions of intestinal transit. These recombinant proteins were capable in vitro, albeit at different levels, of reducing ROS-induced-apoptosis of human epithelial cells. They also stimulated production and release in a time-dependent manner of an autologous SOD activity from cells located into jejunum biopsies. Nevertheless, the fused gliadin peptide enable the recombinant Cu-Zn SOD to maintain a sufficiently sustained interaction with the intestinal cells membrane in vivo rather than being eliminated with the flow. According to these observations, the new hybrid Cu-Zn SOD should show promise in applications for managing inflammatory bowel diseases. PMID- 22426095 TI - From in silico to in vitro: modelling and production of Trichoderma reesei endoglucanase 1 and its mutant in Pichia pastoris. AB - In this study, a major cellulase, namely endoglucanase 1 (EGI) from Trichoderma reesei was mutated by the introduction of four different lysine and glycine rich loops to create a hotspot for directed crosslinking of EGI away from the active site. The impact of the inserted loops on the stability of the enzyme was analyzed using molecular dynamics (MD) and the effect on the active site was studied using molecular mechanics (MM) simulations. The best loop mutation predicted in silico (EGI_L5) was introduced to EGI via site directed mutagenesis. The loop mutant EGI_L5 and EGI were both expressed in Pichia pastoris. Enzymes were characterized and their activities against soluble substrates such as CMC and 4-MUC were determined. Both enzymes exhibited similar pH and temperature activity and thermal stability profiles. Moreover, specific activity of EGI_L5 against 4-MUC was found to be the same as the native enzyme. PMID- 22426096 TI - Can health systems be enhanced for optimal health services through disease specific programs? Results of field studies in Viet Nam and Cambodia. AB - Developing better health systems is the key to delivering optimal health services, although more evidence of effective strategies to do so is needed. Field surveys were conducted in Viet Nam and Cambodia to identify best practices in addressing health system bottlenecks to scale up disease control programs. The two countries were compared over time using a framework for analysis developed by the authors. In Viet Nam, a health system was in place for decades at the central to municipal levels, although it was fragile until the 1990s, when the government started taking measures. In Cambodia, the previous health system had been destroyed during previous internal conflict. In the post-conflict period, the health system was rebuilt with support for programs followed by centralization of health services. In different settings, different measures were taken to deal with similar bottlenecks. In Cambodia, vertical programs were dominant, so the government sought to centralize drug management to deal with shortages of essential drugs, while Viet Nam sought to mobilize resources to ensure drug distribution at all levels. This study shows there is no single successful approach to health systems, and a systemic approach needs to be taken because elimination of one bottleneck may reveal another. Efforts to enhance disease specific programs may not always contribute to overall enhancement of the health system, and the best possible approach may not be the same in different countries. Further study is needed to explore common issues and principles for effective strategies to enhance health systems in different contexts. PMID- 22426097 TI - A study on indoor environment contaminants related to dust mite in dwellings of allergic asthma patients and of healthy subjects. AB - This study investigated the pollution of dust mite allergens in the houses of 30 families and their infection to young allergic asthma patients in Shanghai. Medical records, family information, and dust samples were collected from the dwellings of 15 young allergic asthma patients and 15 healthy subjects. Der 1 allergen, which is a common allergen causing allergic asthma, was measured in collected dust samples using the Pharmacia Uni-CAP System. A significant correlation was found between the number of Der 1 allergens collected from floor surfaces and the number of Der 1 allergens collected from bed surfaces. Some factors influencing Der 1 allergen levels were found in this study. Relative humidity in dwellings was found to be most influential to the allergen levels. The findings suggested that traditional reduction methods for coarse particles, such as opening windows and periodic cleaning of beddings, may be effective in removing dust mite allergens. PMID- 22426098 TI - Characteristics of family caregivers with sleep dissatisfaction in Japan: identification using CHAID dendrograms. AB - The rapid increase in the population of the elderly has raised several social issues. The current study focused on sleep dissatisfaction in family caregivers to identify family caregivers with a heavy care burden. This study aimed to detect the characteristics of caregivers who are most likely to have sleep dissatisfaction. A chi-squared automatic interaction detection technique was used to analyze data collected from 92 research care managers who collected demographic and sleep dissatisfaction information from 280 caregivers and their care recipients. Caregivers whose care recipients were unstable and bedridden were most likely to have sleep dissatisfaction. When care recipients were not stable or non-bedridden, had severe dementia symptoms, and were physically independent, their caregivers were the second most likely to have sleep dissatisfaction. When care recipients were not stable or non-bedridden, had moderate dementia symptoms, and did not need help in transferring, their caregivers had the lowest risk of sleep dissatisfaction. Although many recent studies have found a high prevalence of insomnia among the elderly, describing the characteristics of caregivers who are most likely to have sleep dissatisfaction is a significant challenge. When care recipients are physically independent, the severity of the recipient's dementia symptoms relates to the caregiver's dissatisfaction with his/her sleep. In physically dependent care recipients, the severity of the recipient's dementia did not contribute to the caregiver's dissatisfaction with his/her sleep. PMID- 22426099 TI - Protective effect of naringenin-7-O-glucoside against oxidative stress induced by doxorubicin in H9c2 cardiomyocytes. AB - Doxorubicin (DOX) is one of the most effective chemotherapeutic agents, but cardiotoxicity limits its clinical use. Although the mechanisms are not entirely understood, reactive oxygen species (ROS) and cardiomyocyte apoptosis appear to be involved in DOX cardiotoxicity. Protection or alleviation of DOX cardiotoxicity can be achieved by administration of natural phenolic compounds via activating endogenous defense systems and antiapoptosis. Naringenin-7-O glucoside (NARG), isolated from Dracocephalum rupestre Hance, could protect from cardiomyocyte apoptosis and induce endogenous antioxidant enzymes against DOX toxicity, but the effects on intracellular ROS generation and cell membrane stability were not demonstrated. In the present study, we investigated the effects of NARG on H9c2 cell morphology, viability, lactate dehydrogenase (LDH) and creatine kinase (CK) leakage, glutathine peroxidase (GSH-Px) activity, intracellular Ca2+ concentration, and ROS generation. Compared with DOX alone treatment group, the morphological injury of the cells in groups treated by DOX plus NARG was alleviated, cell viability was increased, the amount of released LDH and CK was significantly decreased, the activity of GSH-Px was increased, the content of intracellular Ca2+ and ROS generation was lowered remarkably. These results suggest that NARG could prevent cardiomyocytes from DOX-induced toxicity by their property of stabilizing the cell membrane and reducing ROS generation. PMID- 22426100 TI - Experimental study on inhibition of rat ventricular Ik1 by RNA interference targeting the KCNJ2 gene. AB - The dominant-negative inhibition of KCNJ2-encoded inward rectifier potassium channels (Kir2) is currently considered the best approach to biological pacemakers. We hypothesized that inhibition of the inward rectifier potassium current (IK1) in ventricular myocytes by RNA interference (RNAi) would convert ventricular myocytes into pacemaker cells. Five pieces of short hairpin RNA (shRNA) were designed to target the KCNJ2 gene and then plasmids incorporating shRNA and green fluorescent protein (GFP) as a marker were constructed for transfection into rat ventricular myocytes. The levels of KCNJ2 mRNA were analyzed with real-time quantitative RT-PCR to screen for pieces of shRNA that were effective at inhibiting the expression of the KCNJ2 gene. The activity of potassium ionic channels was then studied in the transfected ventricular myocytes. In the recombinant plasmids, LYS2 transfection significantly inhibited the mRNA of the KCNJ2 gene in comparison to other groups (p < 0.05), and the beating frequency of ventricular myocytes increased after LYS2 transfection. The open probability of IK1 potassium ion channels of cardiac myocytes transfected with the LYS2 plasmid was significantly downregulated (p < 0.05) and the IK1 of ventricular myocytes was also significantly suppressed compared to the negative group (p < 0.05). Our study demonstrated that IK1 was clearly inhibited after the inhibition of KCNJ2 gene expression by RNAi, and this may represent a new approach to the study of biological pacemakers. PMID- 22426101 TI - Ageing in Werner syndrome. AB - Oxidative stress markers including pentosidine and homocysteine were examined comparing them with inflammation markers including highly sensitive C-reactive protein (hsCRP) and matrix metalloproteinase-9 (MMP-9) in serum from patients with Werner syndrome (WS) and healthy individuals. Elevation of serum pentosidine correlated significantly with normal aging in healthy individuals (p < 0.0004). Serum pentosidine in WS increased significantly compared with age-matched healthy individuals (p < 0.05). Serum homocysteine levels increased insignificantly with normal aging in healthy individuals and in WS compared with age-matched healthy individuals. As both pentosidine and homocysteine levels did not correlate with hsCRP or MMP-9, both oxidative stress markers may be differentially regulated by inflammation. PMID- 22426102 TI - Stroke volume variation and pleth variability index to predict fluid responsiveness during resection of primary retroperitoneal tumors in Hans Chinese. AB - Respiration variation in arterial pulse pressure (DeltaPP) and pulse oximetry plethysmographic waveform amplitude (DeltaPOP) are accurate predictors of fluid responsiveness in mechanically ventilated patients. We hypothesized that stroke volume variation (SVV) and pleth variability index (PVI) can predict fluid responsiveness in mechanically ventilated patients during major surgical procedures in Hans Chinese. This prospective study consisted of fifty-five Hans Chinese patients undergoing resection of primary retroperitoneal tumors (PRPT). During the surgical procedures, hemodynamic data [central venous pressure (CVP), cardiac index (CI), stroke volume index (SVI), SVV, and PVI] were recorded before and after volume expansion (VE) (8 ml*kg-1 of 6% hydroxyethyl starch 130/0.4). Fluid responsiveness was defined as an increase in SVI >= 10% after VE. Four patients were excluded from analysis for arrhythmia or obvious hemorrhage during VE. Baseline SVV correlated well with baseline PVI and the changes in SVV was correlated with the changes in PVI (p < 0.01) after VE. There were significant increases of CI, SVI and decreases of SVV, PVI in responder (Rs) after VE. ROC results showed that the areas for SVV, PVI were significantly higher than the areas for CI, MAP, CVP, PI (p < 0.05). The best threshold values to predict fluid responsiveness were more than 12.5% for SVV and more than 13.5% for PVI in the real surgical setting. The baseline value of SVV, and PVI correlated significantly with volume-induced changes in SVI (p < 0.01). Both SVV and PVI could be used to predict intraoperative fluid responsiveness during resection of PRPT in Hans Chinese. PMID- 22426103 TI - Resection of the second portion of the duodenum sacrificing the minor papilla but preserving the pancreas for a recurrent duodenal adenocarcinoma: report of a case. AB - Duodenal adenocarcinoma is a relatively rare malignancy and pancreaticoduodenectomy would be a standard procedure to achieve curative resection. We report a case of resection of the 2nd portion of the duodenum with nodal dissection preserving the pancreas. The patient was a 75-year-old man with right-sided paresis suffering from early cancer in the 2nd portion of the duodenum. Despite 3 times of endoscopic mucosal resections, mucosal local recurrence was found. The depth of the tumour involvement continued to be limited within the mucosal layer. We performed segmental duodenal resection with nodal dissection sacrificing the minor papilla, while preserving the pancreas and the major papilla. The pathological diagnosis was primary intramucosal adenocarcinoma; the surgical margin was negative for cancer and there was no nodal metastasis. This procedure can be an alternative to pancreaticoduodenectomy in patients with earlystage adenocarcinoma in the 2nd portion of the duodenum when the major papilla can be spared, especially in high-risk patients. PMID- 22426105 TI - Limited dedifferentiation provides replacement tissue during zebrafish fin regeneration. AB - Unlike humans, some vertebrate animals are able to completely regenerate damaged appendages and other organs. For example, adult zebrafish will regenerate the complex structure of an amputated caudal fin to a degree that the original and replacement fins are indistinguishable. The blastema, a mass of cells that uniquely forms following appendage amputation in regenerating animals, is the major source of regenerated tissue. However, the cell lineage(s) that contribute to the blastema and their ultimate contribution(s) to the regenerated fin have not been definitively characterized. It has been suggested that cells near the amputation site dedifferentiate forming multipotent progenitors that populate the blastema and then give rise to multiple cell types of the regenerated fin. Other studies propose that blastema cells are non-uniform populations that remain restricted in their potential to contribute to different cell lineages. We tested these models by using inducible Cre-lox technology to generate adult zebrafish with distinct, isolated groups of genetically labeled cells within the caudal fin. We then tracked populations of several cell types over the entire course of fin regeneration in individual animals. We found no evidence for the existence of multipotent progenitors. Instead, multiple cell types, including epidermal cells, intra-ray fibroblasts, and osteoblasts, contribute to the newly regenerated tissue while remaining highly restricted with respect to their developmental identity. Our studies further demonstrate that the regenerating fin consists of many repeating blastema "units" dedicated to each fin ray. These blastemas each have an organized structure of lineage restricted, dedifferentiated cells that cooperate to regenerate the caudal fin. PMID- 22426104 TI - Mapping mouse hemangioblast maturation from headfold stages. AB - The mouse posterior primitive streak at neural plate/headfold stages (NP/HF, ~7.5 dpc-8 dpc) represents an optimal window from which hemangioblasts can be isolated. We performed immunohistochemistry on this domain using established monoclonal antibodies for proteins that affect blood and endothelial fates. We demonstrate that HoxB4 and GATA1 are the first set of markers that segregate independently to endothelial or blood populations during NP/HF stages of mouse embryonic development. In a subset of cells, both proteins are co-expressed and immunoreactivities appear mutually excluded within nuclear spaces. We searched for this particular state at later sites of hematopoietic stem cell emergence, viz., the aorta-gonad-mesonephros (AGM) and the fetal liver at 10.5-11.5 dpc, and found that only a rare number of cells displayed this character. Based on this spatial-temporal argument, we propose that the earliest blood progenitors emerge either directly from the epiblast or through segregation within the allantoic core domain (ACD) through reduction of cell adhesion and pSmad1/5 nuclear signaling, followed by a stochastic decision toward a blood or endothelial fate that involves GATA1 and HoxB4, respectively. A third form in which binding distributions are balanced may represent a common condition shared by hemangioblasts and HSCs. We developed a heuristic model of hemangioblast maturation, in part, to be explicit about our assumptions. PMID- 22426106 TI - The involvement of the spinal release of glutamate and nitric oxide in peripheral noxious stimulation-induced pain-related behaviors--study in mouse spinal microdialysis. AB - The quantification of neurotransmitters in the dorsal horn of the spinal cord under pain conditions is important to investigate the mechanism of pain transmission. Microdialysis is widely used for the quantification of the release of endogenous substances in various tissues; however, most of the experiments have been conducted in rats. In the present study, we measured the spinal release of glutamate and NO(2)/NO(3) under pain conditions induced by formalin or capsaicin using mouse spinal microdialysis. We found an association between formalin- or capsaicin-induced nociceptive behaviors and the release of glutamate and NO(2)/NO(3) in the spinal cord. PMID- 22426107 TI - Acute footshock-stress increases spatial learning-memory and correlates to increased hippocampal BDNF and VEGF and cell numbers in adolescent male and female rats. AB - It is well known that the acute-stress enhances cognitive functions in adults, but is not known in adolescents. The purpose of this study is to investigate the effects of low and high intensities of acute-stress on hippocampus and spatial memory in the adolescent male and female rats. Thirty-eight days aged rats were subjected to 0.2 and 1.6 mA intensity of footshock-stress for 20 min. Spatial memory performance was assessed in the Morris water maze. Learning had been positively affected in stress groups. Neuron density in the CA1 hippocampal region and the gyrus dentatus as well as VEGF and BDNF levels of hippocampus increased in all stress groups. In females, learning process and BDNF levels increased in low-intensity-stress group than high-intensity-stress group. There was no difference in hippocampal apoptosis among groups. We conclude that adolescent hippocampus is affected positively from acute-stress; however, while there is no difference in male response with respect to intensity of stress, females are affected more positively from low-intensity of stress. PMID- 22426108 TI - Low survivorship of dauer larva in the nematode Caenorhabditis japonica, a potential comparative system for a model organism, C. elegans. AB - The nematode dauer larva (DL) is a non-aging diapause stage. The DL of the model nematode Caenorhabditis elegans has been studied as a model system for aging and longevity. However, information on DL in other nematode species is limited. In this study, the survivorship, storage, energy consumption, and oxidative stress tolerance of Caenorhabditis japonica DL were examined. C. japonica is a close relative of C. elegans, but has species-specific phoretic associations with the shield bug Parastrachia japonensis. Also, its DL has a much longer lifespan than C. elegans in a biological setting. However, when C. japonica DLs were detached from their phoretic host, they did not survive more than 10 days while more than 80% of C. elegans survived under the same conditions. Also, C. japonica DL showed more active movement (swimming) and lower tolerance to oxidative stress than C. elegans DL. Because the concentration of triacylglycerol (TAG), the energy source of nematodes, did not decrease significantly during the experiment, exhaustion of the energy reservoir did not cause the low survivorship of C. japonica. Instead, low tolerance to oxidizing stress and increased production of reactive oxygen species in C. japonica were the main causes of the reduced survivorship. The fact that C. japonica DL cannot survive away from its insect host indicates that its longevity is increased by unknown factors derived from the host. Despite these significant differences between C. japonica and C. elegans, these two species are phylogenetically closely related (they are derived from a common ancestor). Therefore, C. japonica could be a good comparative system for C. elegans, and further physiological and molecular analyses of C. japonica DL may provide important information about the internal and external factors affecting the longevity of nematodes in general. PMID- 22426109 TI - Use of mouse models to study the variability in virulence associated with specific genotypic lineages of Mycobacterium tuberculosis. AB - The host response against Mycobacterium tuberculosis show a wide spectrum of clinical manifestations in those patients who fail to control the infection. The course of the infection and its epidemiological consequences depend upon a complex interplay of host, environmental and bacterial factors. Experimental animal models have helped to define the influence of bacterial genetic diversity on virulence and on the immune response that is induced. For this purpose, experimental animals such as mice, guinea pigs and rabbits have been infected with selected clinical isolates obtained from outbreaks or from clinical epidemiology settings. Here we review the contribution of mouse models to defining the variability in virulence and immune response in relation to mycobacterial genetic diversity. Low dose aerosol infection in C57Bl mice or high dose intratracheal infection in BALB/c mice have demonstrated wide variability in virulence and immune responses induced by different bacterial genotypes, and each genotype has different phenotypes, with high and low virulence variants. In general, these studies have shown that high prevalent strains from big clusters are more virulent than low prevalent sporadic clinical isolates, and highly virulent strains induce non-protective immune responses with some correlation with clinical-epidemiological data. In the future selected strains from these types of studies should be analyzed with molecular technologies. These kinds of study will contribute to the identification of mycobacterial genes associated with virulence and immunogenicity. PMID- 22426110 TI - The SLC4A1 gene is under differential selective pressure in primates infected by Plasmodium falciparum and related parasites. AB - Malaria is a disease caused by Plasmodium parasites and is responsible for high mortality in humans. This disease is caused by four different species of Plasmodium though the main source of mortality is Plasmodium falciparum. Humans have a number of genetic adaptations that act to combat Plasmodium. One adaptation is a deletion in the SLC4A1 gene that leads to Southeast Asian ovalocytosis (SAO). There is evidence that SAO erythrocytes are resistant to multiple Plasmodium species. Here we analyze SLC4A1 in 23 primates and mammals to test for differential selective pressures among different primate lineages. Because primates are infected with both human Plasmodium parasites and their relatives, this analysis can be used to test which human Plasmodium parasite is the likely target of SAO. A significantly different pattern of molecular evolution was found in humans and African apes, species that are infected by P. falciparum and its relatives. This effect was restricted to the cytosolic domain of the SLC4A1 gene. The evidence is consistent with a different selective regime operating on this gene domain in humans and African apes, when compared to other primates and mammals. Alternatively, this pattern is consistent with a relaxation of selection or weak adaptive evolution operating on a small number of amino acids. The adaptive interpretation of the results is consistent with the SAO allele of the SLC4A1 gene interacting with P. falciparum in humans, rather than other Plasmodium parasites. However, additional investigation of the relationship between SLC4A1 variants and Plasmodium in humans and African apes is required to test whether the different selective regime in humans and African apes is due to natural selection or relaxed constraint. PMID- 22426112 TI - LYP inhibits T-cell activation when dissociated from CSK. AB - Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP-CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity. PMID- 22426113 TI - Programmable enantioselective one-pot synthesis of molecules with eight stereocenters. AB - We developed an enantioselectively catalyzed tandem synthesis of structurally and stereochemically complex molecules that forms four carbon-carbon bonds and sets eight stereocenters with high regio-, diastereo- and enantioselectivity. It can be programmed to yield different stereoisomers by varying only the order of combination of a common set of reagents and catalysts. We report what is to our knowledge the first synthesis of both enantiomers of a chiral compound using the same chiral catalyst. PMID- 22426114 TI - Signaling-mediated bacterial persister formation. AB - Here we show that bacterial communication through indole signaling induces persistence, a phenomenon in which a subset of an isogenic bacterial population tolerates antibiotic treatment. We monitor indole-induced persister formation using microfluidics and identify the role of oxidative-stress and phage-shock pathways in this phenomenon. We propose a model in which indole signaling 'inoculates' a bacterial subpopulation against antibiotics by activating stress responses, leading to persister formation. PMID- 22426115 TI - What is the "best" atomic charge model to describe through-space charge-transfer excitations? AB - We investigate the efficiency of several partial atomic charge models (Mulliken, Hirshfeld, Bader, Natural, Merz-Kollman and ChelpG) for investigating the through space charge-transfer in push-pull organic compounds with Time-Dependent Density Functional Theory approaches. The results of these models are compared to benchmark values obtained by determining the difference of total densities between the ground and excited states. Both model push-pull oligomers and two classes of "real-life" organic dyes (indoline and diketopyrrolopyrrole) used as sensitisers in solar cell applications have been considered. Though the difference of dipole moments between the ground and excited states is reproduced by most approaches, no atomic charge model is fully satisfactory for reproducing the distance and amount of charge transferred that are provided by the density picture. Overall, the partitioning schemes fitting the electrostatic potential (e.g. Merz-Kollman) stand as the most consistent compromises in the framework of simulating through-space charge-transfer, whereas the other models tend to yield qualitatively inconsistent values. PMID- 22426116 TI - IL-6 inhibits IFN-gamma induced autophagy in Mycobacterium tuberculosis H37Rv infected macrophages. AB - The significance of IL-6 production in tuberculosis is yet to be fully elucidated, although it is known for quite some time that IL-6 interferes with IFN-gamma induced signal. In order to know which cellular process induced by IFN gamma is actually counteracted by IL-6, we studied the role of IL-6 on IFN-gamma induced autophagy formation in virulent Mycobacterium tuberculosis infection in THP-1 cells, since it is well characterized that induction of autophagy by IFN gamma eliminates intracellular mycobacterium by overcoming the phagosome maturation block imposed by bacilli. We report here that IL-6 inhibits both IFN gamma and starvation induced autophagy in M. tuberculosis H37Rv infected cells. M. tuberculosis H37Rv infection results in time dependent production of IL-6 in THP-1 cells and neutralization of this endogenous IL-6 by anti-IL-6 antibody significantly enhances the IFN-gamma mediated killing of the intracellular bacteria. IL-6 time dependently lowers Atg12-Atg5 complex and therefore inhibits autophagosome biogenesis rather than autophagolysosome formation. IL-6 also affects IFN-gamma mediated stimulation of mTOR, p-38 and JNK pathways. These results clearly indicate that virulent mycobacteria strategically upregulate IL-6 production to combat innate immunity. PMID- 22426117 TI - The dynamic range of the human metabolome revealed by challenges. AB - Metabolic challenge protocols, such as the oral glucose tolerance test, can uncover early alterations in metabolism preceding chronic diseases. Nevertheless, most metabolomics data accessible today reflect the fasting state. To analyze the dynamics of the human metabolome in response to environmental stimuli, we submitted 15 young healthy male volunteers to a highly controlled 4 d challenge protocol, including 36 h fasting, oral glucose and lipid tests, liquid test meals, physical exercise, and cold stress. Blood, urine, exhaled air, and breath condensate samples were analyzed on up to 56 time points by MS- and NMR-based methods, yielding 275 metabolic traits with a focus on lipids and amino acids. Here, we show that physiological challenges increased interindividual variation even in phenotypically similar volunteers, revealing metabotypes not observable in baseline metabolite profiles; volunteer-specific metabolite concentrations were consistently reflected in various biofluids; and readouts from a systematic model of beta-oxidation (e.g., acetylcarnitine/palmitylcarnitine ratio) showed significant and stronger associations with physiological parameters (e.g., fat mass) than absolute metabolite concentrations, indicating that systematic models may aid in understanding individual challenge responses. Due to the multitude of analytical methods, challenges and sample types, our freely available metabolomics data set provides a unique reference for future metabolomics studies and for verification of systems biology models. PMID- 22426118 TI - ARTD1 deletion causes increased hepatic lipid accumulation in mice fed a high-fat diet and impairs adipocyte function and differentiation. AB - ADP-ribosyltransferase Diphtheria toxin-like 1 [ARTD1; formerly called poly-ADP ribose polymerase 1 (PARP1)] is a chromatin-associated enzyme involved in regulating metabolic homeostasis. The liver is at the core of glucose and lipid metabolism and is significantly affected by obesity and the metabolic syndrome. Here, we show that when fed a high-fat diet (HFD), mice lacking ARTD1 developed exacerbated hepatic steatosis. ARTD1(-/-) mice had a 19% higher liver weight than wild-type (WT) animals and exhibited a significantly increased serum concentration of cholesterol (38%) and impaired glucose tolerance. In addition, adipocyte function and size were significantly reduced in ARTD1(-/-) mice fed an HFD (7794 MUm(2) for WT and 5579 MUm(2) for ARTD1(-/-) mice). The significantly reduced adipogenic differentiation of adipose-derived stromal cells (ASCs) isolated from ARTD1(-/-) mice (28 vs. 11% Oil red O-positive cells in WT and ARTD1(-/-) ASCs, respectively) suggested that impaired adipogenesis as the underlying cause for this adipose tissue malfunction. This function of ARTD1 was specific for adipogenesis, since osteogenic differentiation was not affected by the ARTD1 deletion. In summary, we show that ARTD1(-/-) mice fed an HFD display impaired adipogenesis and show exacerbated hepatic steatosis, which can have important implications for nonalcoholic fatty liver disease. PMID- 22426119 TI - The potential of stem cell therapy for stroke: is PISCES the sign? AB - Substantial developments in the field of stem cell research point toward novel therapies for the treatment of diseases such as stroke. This review covers the establishment of tissue damage in stroke and the status of current therapies. We evaluate stem cell therapy with respect to other treatments, including clinical, preclinical, and failed, and provide a comprehensive account of stem cell clinical trials for stroke therapy currently underway. Finally, we describe mechanisms through which stem cells improve outcome in experimental stroke as well as potential pitfalls this basic research has identified. PMID- 22426120 TI - Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. AB - Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0*10(-6)) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R(2)=0.11, ANOVA P<0.001). Specifically, haloperidol was associated with higher ("control-like") methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future. PMID- 22426121 TI - HIF1alpha and pancreatic beta-cell development. AB - During early embryogenesis, the pancreas shows a paucity of blood flow, and oxygen tension, the partial pressure of oxygen (pO(2)), is low. Later, the blood flow increases as beta-cell differentiation occurs. We have previously reported that pO(2) controls beta-cell development in rats. Here, we checked that hypoxia inducible factor 1alpha (HIF1alpha) is essential for this control. First, we demonstrated that the effect of pO(2) on beta-cell differentiation in vitro was independent of epitheliomesenchymal interactions and that neither oxidative nor energetic stress occurred. Second, the effect of pO(2) on pancreas development was shown to be conserved among species, since increasing pO(2) to 21 vs. 3% also induced beta-cell differentiation in mouse (7-fold, P<0.001) and human fetal pancreas. Third, the effect of hypoxia was mediated by HIF1alpha, since the addition of an HIF1alpha inhibitor at 3% O(2) increased the number of NGN3 expressing progenitors as compared to nontreated controls (9.2-fold, P<0.001). In contrast, when we stabilized HIF1alpha by deleting ex vivo the gene encoding pVHL in E13.5 pancreas from Vhl floxed mice, Ngn3 expression and beta-cell development decreased in such Vhl-deleted pancreas compared to controls (2.5 fold, P<0.05, and 6.6-fold, P<0.001, respectively). Taken together, these data demonstrate that HIF1alpha exerts a negative control over beta-cell differentiation. PMID- 22426122 TI - Cdx1 is essential for the initiation of HoxC8 expression during early embryogenesis. AB - The Hox genes pattern the anterior-posterior axis in developing embryos through tightly regulated, partially overlapping, temporal and spatial expression domains. Initial regulation of Hox expression is important to establish these overlapping transcription domains. The Cdx homeodomain factors have been proposed as Hox regulators, but their precise role and mechanism during this regulatory interaction remain unclear. In Xenopus embryos, HoxC8 transcripts begin to accumulate during mid/late gastrula. Cdx1 overexpression and knockdown lead to precocious or slower HoxC8 expression, respectively. The mouse HoxC8 early enhancer when introduced into Xenopus embryos recapitulates the endogenous XHoxC8 temporal expression pattern and shows the same responsiveness to Cdx1 regulation. Three pairs of conserved Cdx binding sites were identified within the HoxC8 early enhancer. We demonstrate that Cdx1 binds directly these responsive elements during embryogenesis, as part of the mechanism for the timely activation of HoxC8 expression. We define the function and mechanism of Cdx1 regulation on HoxC8 expression and suggest the possibility that the temporal changes in Cdx activity levels during gastrulation, combined with differential DNA binding affinity, might play a role in the establishment of Hox sequential activation. PMID- 22426123 TI - Capillaroscopic pattern in inflammatory arthritis. AB - BACKGROUND: There are limited data about the role of nailfold capillaroscopy in inflammatory arthritis. OBJECTIVES: To study the role of capillaroscopy in inflammatory arthritis-rheumatoid arthritis (RA), psoriatic arthritis (PsA) and early arthritis. METHODS: Patients from the following groups were included in the study: 62 patients with RA; 34 patients with PsA with involvement of the joints of the hands; 9 women with early arthritis. Nailfold capillaroscopy was performed with videocapillaroscope. RESULTS: Raynaud's phenomenon (RP) was found in 30.6% (19/62) of RA patients, in 32.4% (11/34) of PsA patients and 44.4%, (4/9) of cases with early arthritis. The most frequent found capillaroscopic changes in RA patients were presence of elongated capillaries in 58% of cases (36/62) and prominent subpapillary plexus in 69% (43/62). Dilated capillaries were found in 78.9% (15/19) of patients with secondary RP and in 62.8% (27/43) of those without RP. "Scleroderma-like" capillaroscopic pattern was observed with low frequency in RA patients (14.5%/9/62). "Scleroderma-like" capillaroscopic pattern was also found in 11.1% (1/9) in the group of patients with early arthritis. The low frequency of the last type of capillaroscopic pattern in RA requires patients with such changes to be observed during regular follow-up for the development of systemic rheumatic disease different from inflammatory arthritis. In patients with PsA capillaries with specific morphology (tight terminal convolutions) were found in 58.8% (20/34) of cases. CONCLUSIONS: Results from the present study confirm the necessity for inclusion of the nailfold capillaroscopy in the diagnostic algorithm in patients with inflammatory arthritis. PMID- 22426124 TI - Activated protein C improves pial microcirculation in experimental endotoxemia in rats. AB - INTRODUCTION: The brain is one of the first organs affected clinically in sepsis. Microcirculatory alterations are suggested to be a critical component in the pathophysiology of sepsis. The aim of this study was to investigate the effects of recombinant human activated protein C (rhAPC) on the pial microcirculation in experimental endotoxemia using intravital microscopy. Our hypothesis is rhAPC protects pial microcirculation in endotoxemia. METHODS: Endotoxemia was generated in Lewis rats with intravenous injection of lipopolysaccharide (LPS, 5 mg/kg i.v.). Dura mater was removed through a cranial window to expose pial vessels on the brain surface. The microcirculation, including leukocyte-endothelial interaction, functional capillary density (FCD) and plasma extravasation of pial vessels was examined by fluorescent intravital microscopy (IVM) 2 h after administration of LPS, LPS and rhAPC or equivalent amount of saline (used as Control group). Plasma cytokine levels of interleukin 1 alpha (IL1-alpha), tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), Monocyte chemotactic protein-1 (MCP-1) and Granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated after IVM. RESULTS: LPS challenge significantly increased leukocyte adhesion (773+/-190 vs. 592+/-152 n/mm(2) Control), decreased FCD (218+/-54 vs. 418+/-74 cm/cm(2) Control) and increased proinflammatory cytokine levels (IL-1alpha: 5032+/-1502 vs. 8+/-21 pg/ml; TNF-alpha: 1823+/-1007 vs. 168+/-228 pg/ml; IFN-gamma: 785+/-434 vs. 0 pg/ml; GM-CSF: 54+/-52 vs. 1+/-3 pg/ml) compared to control animals. rhAPC treatment significantly reduced leukocyte adhesion (599+/-111 n/mm(2)), increased FCD (516+/-118 cm/cm(2)) and reduced IL-1alpha levels (2134+/-937 pg/ml) in the endotoxemic rats. CONCLUSION: APC treatment significantly improves pial microcirculation by reducing leukocyte adhesion and increasing FCD. PMID- 22426126 TI - A two-step activation mechanism of MALT1 paracaspase. PMID- 22426125 TI - An amino acid packing code for alpha-helical structure and protein design. AB - This work demonstrates that all packing in alpha-helices can be simplified to repetitive patterns of a single motif: the knob-socket. Using the precision of Voronoi Polyhedra/Delauney Tessellations to identify contacts, the knob-socket is a four-residue tetrahedral motif: a knob residue on one alpha-helix packs into the three-residue socket on another alpha-helix. The principle of the knob-socket model relates the packing between levels of protein structure: the intra-helical packing arrangements within secondary structure that permit inter-helix tertiary packing interactions. Within an alpha-helix, the three-residue sockets arrange residues into a uniform packing lattice. Inter-helix packing results from a definable pattern of interdigitated knob-socket motifs between two alpha-helices. Furthermore, the knob-socket model classifies three types of sockets: (1) free, favoring only intra-helical packing; (2) filled, favoring inter-helical interactions; and (3) non, disfavoring alpha-helical structure. The amino acid propensities in these three socket classes essentially represent an amino acid code for structure in alpha-helical packing. Using this code, we used a novel yet straightforward approach for the design of alpha-helical structure to validate the knob-socket model. Unique sequences for three peptides were created to produce a predicted amount of alpha-helical structure: mostly helical, some helical, and no helix. These three peptides were synthesized, and helical content was assessed using CD spectroscopy. The measured alpha-helicity of each peptide was consistent with the expected predictions. These results and analysis demonstrate that the knob-socket motif functions as the basic unit of packing and presents an intuitive tool to decipher the rules governing packing in protein structure. PMID- 22426127 TI - Concomitant lethal mutagenesis of human immunodeficiency virus type 1. AB - RNA virus population dynamics are complex, and sophisticated approaches are needed in many cases for therapeutic intervention. One such approach, termed lethal mutagenesis, is directed at targeting the virus population structure for extinction or error catastrophe. Previous studies have demonstrated the concept of this approach with human immunodeficiency virus type 1 (HIV-1) by use of chemical mutagens [i.e., 5-azacytidine (5-AZC)] as well as by host factors with mutagenic properties (i.e., APOBEC3G). In this study, these two unrelated mutagenic agents were used concomitantly to investigate the interplay of these distinct mutagenic mechanisms. Specifically, an HIV-1 was produced from APOBEC3G (A3G)-expressing cells and used to infect permissive target cells treated with 5 AZC. Reduced viral infectivity and increased viral mutagenesis were observed with both the viral mutagen (i.e., G-to-C mutations) and the host restriction factor (i.e., G-to-A mutations); however, when combined, they had complex interactions. Intriguingly, nucleotide sequence analysis revealed that concomitant HIV-1 exposure to both 5-AZC and A3G resulted in an increase in G-to-A viral mutagenesis at the expense of G-to-C mutagenesis. A3G catalytic activity was required for the diminution in G-to-C mutagenesis. Taken together, our findings provide the first demonstration for potentiation of the mutagenic effect of a cytosine analog by A3G expression, resulting in concomitant HIV-1 lethal mutagenesis. PMID- 22426128 TI - Improved modeling of side-chain--base interactions and plasticity in protein--DNA interface design. AB - Combinatorial sequence optimization for protein design requires libraries of discrete side-chain conformations. The discreteness of these libraries is problematic, particularly for long, polar side chains, since favorable interactions can be missed. Previously, an approach to loop remodeling where protein backbone movement is directed by side-chain rotamers predicted to form interactions previously observed in native complexes (termed "motifs") was described. Here, we show how such motif libraries can be incorporated into combinatorial sequence optimization protocols and improve native complex recapitulation. Guided by the motif rotamer searches, we made improvements to the underlying energy function, increasing recapitulation of native interactions. To further test the methods, we carried out a comprehensive experimental scan of amino acid preferences in the I-AniI protein-DNA interface and found that many positions tolerated multiple amino acids. This sequence plasticity is not observed in the computational results because of the fixed-backbone approximation of the model. We improved modeling of this diversity by introducing DNA flexibility and reducing the convergence of the simulated annealing algorithm that drives the design process. In addition to serving as a benchmark, this extensive experimental data set provides insight into the types of interactions essential to maintain the function of this potential gene therapy reagent. PMID- 22426129 TI - Hyperinsulinemia does not change atherosclerosis development in apolipoprotein E null mice. AB - OBJECTIVE: To determine the contribution of hyperinsulinemia to atherosclerosis development. METHODS AND RESULTS: Apolipoprotein E (Apoe) null mice that had knockout of a single allele of the insulin receptor (Insr) gene were compared with littermate Apoe null mice with intact insulin receptors. Plasma insulin levels in Insr haploinsufficient/Apoe null mice were 50% higher in the fasting state and up to 69% higher during a glucose tolerance test, but glucose tolerance was not different in the 2 groups. C-peptide levels, insulin sensitivity, and postreceptor insulin signaling in muscle, liver, fat, and aorta were not different between groups, whereas disappearance in plasma of an injected insulin analog was delayed in Insr haploinsufficient/Apoe null mice, indicating that impaired insulin clearance was the primary cause of hyperinsulinemia. No differences were observed in plasma lipids or blood pressure. Despite the hyperinsulinemia, atherosclerotic lesion size was not different between the 2 groups at time points up to 52 weeks of age when measured as en face lesion area in the aorta, cross-sectional plaque area in the aortic sinus, and cholesterol abundance in the brachiocephalic artery. CONCLUSIONS: Hyperinsulinemia, without substantial vascular or whole-body insulin resistance and without changes in plasma lipids or blood pressure, does not change susceptibility to atherosclerosis. PMID- 22426130 TI - PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRbeta heterodimers. AB - OBJECTIVE: In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration. METHODS AND RESULTS: Transduction of HO 1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRbeta/VEGFR2 complexes. This compromised PDGFRbeta phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration. CONCLUSIONS: These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRbeta complexes that attenuates effective PDGFRbeta signaling. PMID- 22426131 TI - BAFF receptor deficiency reduces the development of atherosclerosis in mice- brief report. AB - OBJECTIVE: The goal of this study was to assess the role of B-cell activating factor (BAFF) receptor in B-cell regulation of atherosclerosis. METHODS AND RESULTS: Male LDL receptor-deficient mice (Ldlr(-/-)) were lethally irradiated and reconstituted with either wild type or BAFF receptor (BAFF-R)-deficient bone marrow. After 4 weeks of recovery, mice were put on a high-fat diet for 6 or 8 weeks. BAFF-R deficiency in bone marrow cells led to a marked reduction of conventional mature B2 cells but did not affect the B1a cell subtype. This was associated with a significant reduction of dendritic cell activation and T-cell proliferation along with a reduction of IgG antibodies against malondialdehyde modified low-density lipoprotein. In contrast, serum IgM type antibodies were preserved. Interestingly, BAFF-R deficiency was associated with a significant reduction in atherosclerotic lesion development and reduced numbers of plaque T cells. Selective BAFF-R deficiency on B cells led to a similar reduction in lesion size and T-cell infiltration but in contrast did not affect dendritic cell activation. CONCLUSIONS: BAFF-R deficiency in mice selectively alters mature B2 cell-dependent cellular and humoral immune responses and limits the development of atherosclerosis. PMID- 22426132 TI - A detailed view of microparticle formation by in-process monitoring of the glass transition temperature. AB - Biodegradable poly(D,L-lactide-co-glycolide) microspheres were prepared by a well controlled emulsion solvent extraction/evaporation process. The objective of this study was to investigate how drug release can be modified by changing the morphology of the polymer matrix. The matrix structure was controlled by the preparation temperature which was varied between 10 and 35 degrees C, thus changing the 4 weeks release pattern from almost linear kinetics to a sigmoidal profile with a distinct lag phase and furthermore decreasing the encapsulation efficiency. By monitoring the glass transition temperature during the extraction process, it was shown that the preparation temperature determines the particle morphology by influencing the time span in which the polymer chains were mobile and flexible during the extraction process. Further factors determining drug release were found to be the molecular weight of the polymer and the rate of solvent removal. The latter, however, has also influence on the encapsulation efficiency with slow removal causing a higher drug loss. A secondary modification of the outer particle structure could be achieved by ethanolic post-treatment of the particles, which caused an extension of the lag phase and subsequently an accelerated drug release. PMID- 22426133 TI - A novel liquefied gas based oral controlled release drug delivery system for liquid drug formulations. AB - A novel liquefied gas based drug delivery system for the oral delivery of liquid and semi-solid drug formulations is presented. The capsule-shaped system is equipped with a capillary as an element controlling the release rate. The delivery mechanism is based on a constant vapor pressure produced by isopentane as a low-boiling liquefied gas. The liquid drug valproic acid (VA) was used as a model compound. The viscosity was increased by the addition of povidone (PVP). The VA-PVP gel exhibited pseudoplastic rheological properties, the shear rate was above 0.1s(-1), similar to a Newtonian liquid. The gels tested in the gas based delivery system provided near-zero-order release kinetics. The longest delivery time was up to ca. 8h. The system is characterized by high flexibility of the delivery rate, which can be achieved by adjusting system parameters such as the diameter and length of the capillary, the vapor pressure of the propellant and the viscosity of the drug formulation. PMID- 22426134 TI - Application of Quality by Design to the characterization of the cell culture process of an Fc-Fusion protein. AB - The production bioreactor step of an Fc-Fusion protein manufacturing cell culture process was characterized following Quality by Design principles. Using scientific knowledge derived from the literature and process knowledge gathered during development studies and manufacturing to support clinical trials, potential critical and key process parameters with a possible impact on product quality and process performance, respectively, were determined during a risk assessment exercise. The identified process parameters were evaluated using a design of experiment approach. The regression models generated from the data allowed characterizing the impact of the identified process parameters on quality attributes. The main parameters having an impact on product titer were pH and dissolved oxygen, while those having the highest impact on process- and product related impurities and variants were pH and culture duration. The models derived from characterization studies were used to define the cell culture process design space. The design space limits were set in such a way as to ensure that the drug substance material would consistently have the desired quality. PMID- 22426135 TI - Transport of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N methylpyridinium iodide (ASP+) in human respiratory epithelial cells. AB - Organic cation/carnitine transporters (OCT/N) mediate uptake of positively charged molecules. Their role in lung epithelium; however, is not well understood. OCT/N expression and activity was studied in cell lines of human alveolar (A549), bronchial (16HBE14o- and Calu-3) and intestinal (Caco-2) epithelium. Protein levels were largely comparable for all OCT/Ns in the respiratory epithelial cell lines studied; however, OCT2 was exclusively observed in A549 cells. OCT1 and -2 were present at significantly higher levels in Caco-2 cells, compared with the pulmonary epithelial cell types. OCTN1 and -2 were also more abundant in Caco-2. Only OCT3 was expressed evenly across all cell lines investigated. Uptake of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+)) was dependent on concentration, temperature, membrane potential and pH. In 16HBE14o-, Calu-3 and Caco-2 monolayers, substrate saturation of ASP(+) uptake was not reached. Alveolar A549 cells showed saturable ASP(+) uptake via two transporter sites with K(m) values of 12.5 +/- 4.0 MUM and 456.9 +/- 164.5 MUM, respectively. This uptake was sensitive to organic cations, but insensitive to carnitine and lysine. We conclude that uptake of organic cations is facilitated by distinct pathways in different regions of lung mucosa. Luminally localised OCT2 appears to be exclusively involved in the alveolar epithelium, whereas basolateral localised OCT3 might play a role in alveolar as well as in bronchial epithelial cells. PMID- 22426136 TI - Cell-matrix interactions regulate mesenchymal stem cell response to hydrostatic pressure. AB - Both hydrostatic pressure (HP) and cell-matrix interactions have independently been shown to regulate the chondrogenic differentiation of mesenchymal stem cells (MSCs). The objective of this study was to test the hypothesis that the response of MSCs to hydrostatic pressure will depend on the biomaterial within which the cells are encapsulated. Bone-marrow-derived MSCs were seeded into either agarose or fibrin hydrogels and exposed to 10 MPa of cyclic HP (1 Hz, 4 h per day, 5 days per week for 3 weeks) in the presence of either 1 or 10 ng ml(-1) of TGF-beta3. Agarose hydrogels were found to support a spherical cellular morphology, while MSCs seeded into fibrin hydrogels attached and spread, with clear stress fiber formation. Hydrogel contraction was also observed in MSC-fibrin constructs. While agarose hydrogels better supported chondrogenesis of MSCs, HP only enhanced sulfated glycosaminoglycan (sGAG) accumulation in fibrin hydrogels, which correlated with a reduction in fibrin contraction. HP also reduced alkaline phosphatase activity in the media for both agarose and fibrin constructs, suggesting that this stimulus plays a role in the maintenance of the chondrogenic phenotype. This study demonstrates that a complex relationship exists between cell-matrix interactions and hydrostatic pressure, which plays a key role in regulating the chondrogenic differentiation of MSCs. PMID- 22426137 TI - Sulfated hyaluronan and chondroitin sulfate derivatives interact differently with human transforming growth factor-beta1 (TGF-beta1). AB - This study demonstrates that the modification of hyaluronan (hyaluronic acid; Hya) and chondroitin sulfate (CS) with sulfate groups leads to different binding affinities for recombinant human transforming growth factor-beta1 (TGF-beta1) for comparable average degrees of sulfation (DS). In general, Hya derivates showed higher binding strength than CS derivatives. In either case, a higher degree of sulfation leads to a stronger interaction. The high-sulfated hyaluronan sHya3 (average DS~3) exhibited the tightest interaction with TGF-beta1, as determined by surface plasmon resonance and enzyme-linked immunosorbent assay. The binding strength was significantly weakened by carboxymethylation. Unmodified Hya and low sulfated, native CS showed weak or no binding affinity. The interaction characteristics of the different sulfated glycosaminoglycans are promising for incorporation into bioengineered coatings of biomaterials to modulate growth factor binding in medical applications. PMID- 22426138 TI - FGF-1 and proteolytically mediated cleavage site presentation influence three dimensional fibroblast invasion in biomimetic PEGDA hydrogels. AB - Controlled scaffold degradation is a critical design criterion for the clinical success of tissue-engineered constructs. Here, we exploited a biomimetic poly(ethylene glycol) diacrylate (PEGDA) hydrogel system immobilized with tethered YRGDS as the cell adhesion ligand and with either single (SSite) or multiple (MSite) collagenase-sensitive domains between crosslinks, to systematically study the effect of proteolytic cleavage site presentation on hydrogel degradation rate and three-dimensional (3-D) fibroblast invasion in vitro. Through the incorporation of multiple collagenase-sensitive domains between cross-links, hydrogel degradation rate was controlled and enhanced independent of alterations in compressive modulus. As compared to SSite hydrogels, MSite hydrogels resulted in increased 3-D fibroblast invasion in vitro, which occurred over a wider range of compressive moduli. Furthermore, encapsulated soluble acidic fibroblast growth factor (FGF-1), a potent mitogen during processes such as vascularization and wound healing, was incorporated into SSite and MSite PEGDA scaffolds to determine its in vitro potential on fibroblast cell invasion. Hydrogels containing soluble FGF-1 significantly enhanced 3-D fibroblast invasion in a dose-dependent manner within the different types of PEG matrices investigated over a period of 15 days. The methodology presented provides flexibility in designing PEG scaffolds with desired mechanical properties, but with increased susceptibility to proteolytically mediated degradation. These results indicate that effective tuning of initial matrix stiffness and hydrogel degradation kinetics plays a critical role in effectively designing PEG scaffolds that promote controlled 3-D cellular behavior and in situ tissue regeneration. PMID- 22426139 TI - Development of injectable, resorbable drug-releasing copolymer scaffolds for minimally invasive sustained ophthalmic therapeutics. AB - Copolymers based on N-isopropylacrylamide (NIPAAm), acrylic acid N hydroxysuccinimide (NAS) and varying concentrations of acrylic acid (AA) and acryloyloxy dimethyl-gamma-butyrolactone (DBA) were synthesized to create thermoresponsive, resorbable copolymers for minimally invasive drug and/or cell delivery to the posterior segment of the eye to combat retinal degenerative diseases. Increasing DBA content was found to decrease both copolymer water content and lower critical solution temperature. The incorporation of NAS provided an amine-reactive site, which can be exploited for facile conjugation of bioactive agents. Proton nuclear magnetic resonance analysis revealed the onset of hydrolysis-dependent opening of the DBA lactone ring, which successfully eradicated copolymer phase transition properties and should allow the gelled polymer to re-hydrate, enter systemic circulation and be cleared from the body without the production of degradation byproducts. Hydrolytic ring opening occurs slowly, with over 85% copolymer mass remaining after 130 days of incubation in 37 degrees C phosphate buffered saline. These slow-degrading copolymers are hypothesized to be ideal delivery vehicles to provide minimally invasive, sustained, localized release of pharmaceuticals within the posterior segment of the eye to combat retinal degenerative diseases. PMID- 22426140 TI - Nerve cell response to inhibitors recorded with an aluminum galliumnitride/galliumnitride field-effect transistor. AB - Experiments based on neuronal cell-transistor couplings were made from some groups during the last years. Pioneering work in this field was carried out by Fromherz and his group (Fromherz, 2003; Schmidtner and Fromherz, 2006). We were interested of the interaction of nerve cells to serine hydrolase inhibitor diisopropylfluorophosphate (DFP), monitored by using an aluminum galliumnitride/galliumnitride (AlGaN/GaN) electrolyte gate field effect transistor (EGFET). The biocompatibility study of our sensor materials with nerve cells shows a proliferation rate of at least 95%. The inhibitors were added to the medium and the source-drain current of the EGFET was recorded as a function of time. The inhibitor was added to the NG108-15 nerve cells growing directly on the sensor surface, resulting in a fast decrease in the drain current, I(DS). Control measurements show that this response is associated with cationic fluxes pumped through ionic channels present in the cellular membrane. The sensor enables analysis of the ion channel activity without cell destruction and simultaneously allows visual observation due to the optical transparency of the sensor material. PMID- 22426141 TI - Prostate stem cell antigen polymorphisms and susceptibility to gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: Many studies have reported that prostate stem cell antigen (PSCA) polymorphisms (rs2294008 and/or 2976392) are significantly associated with gastric cancer (GC) risk, although the published results are inconsistent. We conducted a systematic review and meta-analysis for relevant literatures to quantitatively evaluate the relationship between PSCA polymorphisms and GC susceptibility. METHODS: Extensive searches were conducted in three databases up to November 1, 2011. ORs and 95% CIs were used to assess the strength of the associations. The data were further stratified by ethnicity, histopathology, subsite, and study design. All of the associations were evaluated with dominant model and recessive model, respectively. Heterogeneity and publication bias were also assessed by Q test, I(2), and funnel plot accordingly. RESULTS: Nine articles including 11 case-control data sets were included, with 10,746 GC cases and 9,158 controls for rs2294008 and 6,060 cases and 4,824 controls for rs2976392. The results showed that risk allele carriers were significantly associated with GC risk compared with nonrisk allele homozygotes. In stratification analyses, these associations remained significant for majority of subgroups except for Caucasians and noncardia tumor in dominant model, and cardia tumor in both dominant and recessive model. Random model was used when heterogeneity among studies was detected. No publication bias was observed. CONCLUSIONS: The two loci of PSCA (rs2294008 and rs2976392) were both significantly associated with GC susceptibility and in linkage disequilibrium. IMPACT: More prospective studies on PSCA polymorphisms at multicenters with sufficient sample size and less heterogeneity will be needed for further validations. PMID- 22426142 TI - Circulating biomarkers of iron storage and clearance of incident human papillomavirus infection. AB - BACKGROUND: Iron is an essential mineral for both cellular and pathogen survival and is essential for viral replication. In turn, iron metabolism has been shown to be altered by several viral infections. However, little is known about the association between iron status and human papillomavirus (HPV) natural history. We hypothesize iron to be an HPV cofactor that is associated with longer duration of infection. METHODS: Ferritin and soluble transferrin receptor (sTfR) were measured in baseline serum samples from 327 women enrolled in the Ludwig-McGill cohort. Incident HPV clearance rates (any-type, oncogenic HPV, nononcogenic HPV, and HPV-16) over a 3 year time period were estimated from Cox proportional hazard models accounting for correlations between multiple infections. RESULTS: Women with ferritin levels above the median were less likely to clear incident oncogenic HPV [adjusted hazard ratio (AHR), 0.73; 95% confidence interval (CI), 0.55-0.96] and HPV-16 infections (AHR, 0.29; 95% CI, 0.11-0.73). Using physiologic cutoff points, women with enriched iron stores (>120 MUg/L) were less likely to clear incident oncogenic HPV infections than those with low levels of iron (<20 MUg/L; AHR, 0.34; 95% CI, 0.15-0.81). CONCLUSION: This study observed that women with the highest ferritin levels were less likely to clear incident oncogenic and HPV-16 infections than women with low ferritin. Rising iron stores may decrease probability of clearing new HPV infection, possibly by promoting viral activity and contributing to oxidative DNA damage. IMPACT: This novel study suggests that elevated iron stores may put women at risk for persistent HPV infection, an early event in cervical carcinogenesis. Further examination of the association between iron status and HPV natural history is warranted. PMID- 22426143 TI - Converting epidemiologic studies of cancer etiology to survivorship studies: approaches and challenges. AB - There are nearly 12 million cancer survivors living in the United States, and the number continues to rise with ongoing improvements in treatment and screening. Assuring the long-term health of these patients poses both clinical and public health concerns. Survivorship research covers multiple aspects of life after a cancer diagnosis, including quality of life, acute and late effects of cancer treatment and mortality. Answering these questions requires a wide array of data, including information on the outcomes of interest, treatment history, and lifestyle. One potentially efficient approach to studying late effects and survivorship is to convert or extend existing epidemiologic studies of cancer etiology. In this article, we evaluate the different potential approaches for doing this and the challenges this entails. Our evaluation highlights the combinations of research topic and design most likely to succeed. We show that any question that relates to the existing information including prediagnosis lifestyle factors or genetics (if samples are available) could be efficiently studied, with an appropriate design. On the other hand, most, though not all converted studies would be ill-suited to the evaluation of the effect of treatment and postdiagnosis lifestyle changes. In terms of endpoints, hard outcomes including mortality and second cancers are more likely to be available within the existing study framework than other morbidities or quality of life. In light of the costs and time required to build new cohorts, appropriately leveraging the existing studies offers an important opportunity to gain new insights into cancer survivorship for both clinicians and patients. PMID- 22426144 TI - Genome-wide association study identifies a possible susceptibility locus for endometrial cancer. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. METHODS: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). RESULTS: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03-1.16] for the A/G genotype and 1.17 (95% CI, 1.05-1.30) for the G/G genotype (P = 1.6 * 10(-4) in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04-1.18) and 1.21 (1.08-1.35), respectively (P = 2.4 * 10(-5)). CONCLUSIONS: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. IMPACT: This study identified a potential genetic locus for endometrial cancer risk. PMID- 22426145 TI - Cigarette smoking and renal cell carcinoma risk among black and white Americans: effect modification by hypertension and obesity. AB - BACKGROUND: Incidence of kidney cancer has been increasing over the past three decades, with more rapid increases and higher incidence rates among blacks than whites in the United States. An association between cigarette smoking and renal cell carcinoma (RCC), the most common form of kidney cancer, has been reported for whites, but the association in blacks is less clear. METHODS: The association between smoking and RCC was examined in 1,217 incident cases and 1,235 population controls frequency-matched on age, race, gender, and study site in the Kidney Cancer Study in Detroit, MI, and Chicago, IL. RESULTS: In white individuals, increasing duration and number of pack-years of both were associated with increased risk of RCCs after adjusting for age, gender, education, study site, body mass index (BMI) and history of hypertension (P(trend) = 0.0002 and P(trend) = 0.002, respectively). Among black individuals, RCC risk increased with duration of smoking (P(trend) = 0.02) but not other measures. Compared with current smokers, RCC risk decreased with increasing years of smoking cessation among both whites and blacks (P(trend) = 0.01 and 0.02, respectively). When examining risk according to hypertension history, associations between smoking and RCC risk were observed only among individuals who reported never having been diagnosed with hypertension. Similarly, cigarette smoking was associated with increased risk of RCCs among nonobese individuals but not among those with BMI >= 30 kg/m(2). CONCLUSION: Our observation that smoking is associated with RCC only in nonobese individuals and those with no history of hypertension are novel findings. IMPACT: The complex relationships between RCCs, smoking, hypertension, and obesity require additional confirmation. PMID- 22426146 TI - Addressing disparities in colorectal cancer burden: how far could equal health care access bring us? PMID- 22426147 TI - Hazard of recurrence among women after primary breast cancer treatment--a 10-year follow-up using data from SEER-Medicare. AB - BACKGROUND: Few studies have used SEER-Medicare data to describe recurrence of breast cancer after primary treatment for U.S. women. METHODS: We used SEER Medicare data to estimate the annual hazard rate (HR) of recurrence for women with breast cancer between 1991 and 1997 with 10 years of follow-up. The Kaplan Meier method was used to derive the HR. Multivariate Cox proportional hazards model was used to estimate the relative hazard of the recurrence-associated prognostic factors. RESULTS: Of 20,027 women, 36.8% had recurrence within 10 years, with most of these recurrences (81.9%) occurring within 5 years after diagnosis. Women with stage III cancer showed the highest HR peak and largest magnitude than women with stage I or II disease (both P < 0.01) within the first 5 years. Women with negative tumor hormone receptor status had a higher peak hazard of developing recurrence within the first 5 years (P < 0.01), but the hazards were remarkably lower beyond 5 years of follow-up than in women with positive or unknown hormone receptor status (P > 0.05). Women with poorly differentiated histologic grade tumors showed higher HR in the first 5 years than women with other grades after primary treatment (both P < 0.01). The increased risk of recurrence of breast cancer was associated with advanced stage, moderate and poorly differently grades, and negative hormone receptor status (all P < 0.01). CONCLUSION: The HRs of the recurrence are dynamic over 10 years and are markedly determined by prognostic factors at diagnosis. IMPACT: Our study suggests that the optimal follow-up may differ among women. PMID- 22426148 TI - The impact of race and comorbidity on survival in endometrial cancer. AB - BACKGROUND: Poorer survival from endometrial cancer in blacks than in whites is well documented. The aims of this study were to determine whether diabetes, hypertension, or other conditions influence survival and whether accounting for these conditions reduces this racial disparity. METHODS: Using the SEER-Medicare database, we investigated the influence of diabetes, hypertension, and other comorbid conditions on survival in black and white women age >=66 with endometrial cancer. We used Cox proportional hazards regression to evaluate the influence of comorbidities on survival for blacks and whites separately and to study survival differences between blacks and whites after adjustment for diabetes, hypertension, and other medical conditions, as well as for demographics, tumor characteristics, and treatment. RESULTS: In both racial subgroups, women with diabetes or other conditions had poorer overall survival, whereas hypertensive black women experienced better survival [HR, 0.74; 95% confidence interval (CI), 0.60-0.92]. For disease-specific survival, diabetes was associated with poorer survival in white women (HR, 1.19; 95% CI, 1.06-1.35) but not in blacks (HR, 0.97; 95% CI, 0.73-1.30); hypertension and other conditions were not significantly related to survival. After adjustment, black women had poorer survival than white women, with HRs of 1.16 (95% CI, 1.05-1.28) for overall and 1.27 (95% CI, 1.08-1.49) for disease-specific survival. CONCLUSIONS: Diabetes influences disease-specific survival in white women but not in blacks. The racial disparity in survival is not explained by the presence of other health conditions. IMPACT: Further research should focus on the unknown factors that lead to poorer survival in black women compared with whites. PMID- 22426149 TI - CTCF mediates effect of insulin on glucagon expression. AB - Pancreatic islet alpha-cell development and glucagon production are mainly regulated by Pax6 in the homeobox gene families. However, the molecular mechanism fine-tuning the regulation of these events in alpha-cell still remains unclear. In ocular cells, Pax6 transcription is regulated by CTCF through its binding to specific sites in Pax6 promoter. In this study, CTCF-mediated regulations of islet alpha-cell development and glucagon production were investigated in both CTCF transgenic mice and alpha-TC-1-6 cells. Over-expression of CTCF in transgenic mice affected development of pancreatic islets by significantly suppressing alpha-cell population in both embryonic and adult pancreases. The effect of CTCF on Pax6 gene expression and subsequently, on pro-glucagon production was however, examined in pancreatic islet alpha-cells. Over-expression and knock-down of CTCF directly affected Pax6 expression. More importantly, the CTCF binding sites upstream from Pax6 p0 promoter were required for regulating p0 promoter activity in islet alpha-cells. Stimulation of alpha-cells with insulin resulted in a significant increase in CTCF expression and a decrease in Pax6 expression, and consequently suppressed pro-glucagon expression. In contrast, these insulin-induced effects were blocked by knockdown of CTCF mRNA with specific siRNA in alpha-cells. Altogether, our results demonstrated for the first time that CTCF functions as a switch-like molecule between the insulin signaling and the regulations of Pax6 and glucagon expression in pancreatic islet alpha cells. PMID- 22426150 TI - Toxicity assay in repeated doses of Dermatophagoides siboney allergen extract in mice. AB - Allergen extracts are used for hyposensitivity and immunotherapy treatments, reducing significantly clinical symptoms of allergic diseases. Because of its wide use in immunoallergen therapy, we evaluated the Dermatophagoides siboney allergen extract to establish the potential toxicity following repeated subcutaneous dosing in Cenp:NMRI mice. Animals were randomly distributed into two groups, control (vehicle) and treated (166.6 UB/animal), and they were observed daily for clinical signs of toxicity following treatment. Body weight was weekly measured. At the end of the study, blood samples were collected for hematology and serum chemistry analysis and animals were euthanized for gross necropsy and histological examination of tissues. There were not significant differences in body weight or hematology parameters between control and treated animals. Differences were noted in uric acid, blood urea nitrogen and glucose; however, these alterations were not considered to be of biologic relevance. Pathology evaluations demonstrated hemorrhagic and inflammatory lesions at the administration site in both experimental groups. We conclude that repeated dosing of 166.6 UB did not cause significant toxic effects in the mouse model. PMID- 22426151 TI - Postrepolarization refractoriness in acute ischemia and after antiarrhythmic drug administration. PMID- 22426152 TI - Counterpoint: Mandatory ECG screening of young competitive athletes. PMID- 22426153 TI - Point/Mandatory ECG screening of young competitive athletes. PMID- 22426154 TI - Intracerebroventricular administration of urotensin II regulates food intake and sympathetic nerve activity in brown adipose tissue. AB - To clarify the functional roles of urotensin II in regulating energy balance, we investigated the effects of a central infusion of urotensin II on food intake, uncoupling protein (UCP) 1 mRNA expression, temperature, and sympathetic nervous system activity in brown adipose tissue (BAT), a site that regulates energy expenditure in rodents. A bolus central infusion of urotensin II at a dose of 1 nmol/rat into the third cerebral ventricle decreased food intake (p<0.05). Additionally, urotensin II induced c-Fos-like-immunoreactivity (c-FLI) in the paraventricular nucleus (PVN) as compared with that in the control (phosphate buffered saline [PBS]-treated) group. Furthermore, urotensin II increased BAT UCP 1 mRNA expression (p<0.05). Finally, central infusion of urotensin II significantly increased BAT sympathetic nerve activity, which was accompanied by a significant elevation in BAT temperature (p<0.05) in rats. Taken together, central infusion of urotensin II regulates food intake and BAT sympathetic nerve activity in rats. PMID- 22426155 TI - Developmental changes in renal function. AB - PURPOSE OF REVIEW: Although nephrogenesis in a term infant is complete, there are a number of functional changes that occur in the kidney as the infant matures. Understanding these changes will aid in the evaluation of neonates to delineate what is normal development versus a pathophysiologic problem. In addition, as many drugs are either cleared by the kidneys or can affect renal function, dosing regimens are dramatically different in the neonate as compared with the adult. These differences are greatly exaggerated in the preterm infant, making it more difficult to determine if there is a pathophysiologic problem. RECENT FINDINGS: While investigators in recent years have made great strides in understanding the early embryology of the kidney and the molecular signals involved in the formation of the kidney, there remains a paucity of functional studies. The most recent studies have re-examined the changes in the serum creatinine in the newborn and how this impacts the excretion of drugs. Developmental changes in the renal tubule transport systems and their regulation have also been more extensively studied. SUMMARY: The kidney undergoes many developmental physiologic changes as the neonate adapts to extra-uterine life. Understanding these changes will help in the medical management of these infants. PMID- 22426156 TI - Hypertension in the neonatal period. AB - PURPOSE OF REVIEW: Continued interest in neonatal hypertension has led to generation of new data on normal blood pressure (BP) values in neonates, identification of new causes of hypertension in the neonatal period, and improved insights into therapy. RECENT FINDINGS: Normal BP in neonates depends on a variety of factors, including gestational age, postnatal age, and birth weight, and may be influenced by other antenatal conditions. The incidence of neonatal hypertension is low, and it is most often seen in infants with concurrent conditions such as chronic lung disease (CLD) or renal disease, or in those that have undergone umbilical arterial catheterization. Although few data exist on efficacy and safety of antihypertensive medications in neonates, a wide variety of medications have been utilized in those who do require treatment. Hypertension resolves over time in most infants, although robust long-term outcome data are lacking. SUMMARY: Our understanding of neonatal hypertension continues to evolve. Although better data are available on normal BP and the incidence of hypertension, we still need studies focused on appropriate treatment and long term prognosis. PMID- 22426157 TI - Toxicity of energy drinks. AB - PURPOSE OF REVIEW: 'Energy drinks', 'energy shots' and other energy products have exploded in popularity in the past several years; however, their use is not without risk. Caffeine is the main active ingredient in energy drinks, and excessive consumption may acutely cause caffeine intoxication, resulting in tachycardia, vomiting, cardiac arrhythmias, seizures, and death. The effects of chronic high-dose caffeine intake in children and adolescents are unknown. Caffeine may raise blood pressure, disrupt adolescent sleep patterns, exacerbate psychiatric disease, cause physiologic dependence, and increase the risk of subsequent addiction. RECENT FINDINGS: Coingestion of caffeine and ethanol has been associated with increased risk-taking behaviors, harm to adolescent users, impaired driving, and increased use of other illicit substances. The toxicity of ingredients often present in energy drinks, such as taurine, niacin, and pyridoxine, is less well defined. Recent and significant literature describing adverse events associated with energy drink use are reviewed. SUMMARY: Although prior studies have examined the effects of caffeine in adolescents, energy drinks should be considered a novel exposure. The high doses of caffeine, often in combination with ingredients with unknown safety profiles, mandates urgent research on the safety of energy drink use in children and adolescents. Regulation of pediatric energy drink use may be a necessary step once the health effects are further characterized. PMID- 22426158 TI - Child abuse pediatrics: prevention, evaluation, and treatment. AB - PURPOSE OF REVIEW: This review is designed to update the general pediatrician with information about current child maltreatment literature. The authors have selected salient articles, which inform daily practice of any professional involved in the care of children who may be at risk of child abuse. RECENT FINDINGS: The field of child abuse pediatrics continues to engender controversy in both medical journals and courtrooms. As scrutiny about the basis for the diagnosis increases, clinicians and researchers work to build a solid base of scientific evidence with thorough and well-designed studies. This is most evident with regards to abusive head trauma, wherein both lay and scientific press challenge the possibility that infants can be severely injured or killed by shaking, blunt force trauma, or both. SUMMARY: Child abuse pediatrics is a well established and credible medical field. Although child physical and sexual abuse are age-old problems, public acknowledgement and intervention models are relatively new, and medical literature continues to reflect an increasing and deeper understanding of the impact of abuse throughout the world. PMID- 22426159 TI - Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. AB - Glucose regulated protein 78 (GRP78) has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found to be present in cell plasma membrane, cytoplasm, mitochondria, nucleus as well as cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor microenvironmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which feels and adapts to the alteration in the tumor microenvironment. This article reviews the potential contributions of GRP78 to the acquisition of cancer hallmarks based on intervening in stress responses caused by tumor niche alterations. The paper also introduces several potential GRP78 relevant targeted therapies. PMID- 22426160 TI - Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells. AB - Ginsenoside Rg3 (Rg3), one of the bioactive extracts found in ginseng root, was reported to have anti-cancer activity in various cancer models. The anti proliferation effect of Rg3 on prostate cancer cells has been well reported. To test whether Rg3 has an anti-metastatic effect on prostate cancer, we treated a highly metastatic PC-3M prostate cancer cell line with Rg3. We found that Rg3 (10MUM) led to remarkable inhibition of PC-3M cell migration. Simultaneously, exposure to Rg3 suppressed expression of the aquaporin 1 (AQP1) water channel protein, which has previously been reported to be involved in cell migration. Overexpression of AQP1 attenuated Rg3-induced inhibition of cell migration, and introduction of a shRNA targeting AQP1 abrogated the inhibitory effect of Rg3, although the basal level of cell migration was decreased by RNA interference. In mechanism study, estrogen receptor- and glucocorticoid receptor-dependent pathways are proved uninvolved in the AQP1 regulation by Rg3. However, Rg3 treatment triggered the activation of p38 MAPK; and SB202190, a specific inhibitor of p38 MAPK, antagonized the Rg3-induced regulation of AQP1 and cell migration, suggesting a crucial role for p38 in the regulation process. Deletion analysis of the promoter region of AQP1 was also conducted using dual-luciferase assay, which indicated that the -1000 bp to -200 bp promoter region was involved in the AQP1 regulation by Rg3. In all, we conclude that Rg3 effectively suppresses migration of PC-3M cells by down-regulating AQP1 expression through p38 MAPK pathway and some transcription factors acting on the AQP1 promoter. PMID- 22426161 TI - Protective effect of 17beta-estradiol on ischemic acute kidney injury through the renal sympathetic nervous system. AB - Enhanced renal sympathetic nerve activity during an ischemic period and renal venous norepinephrine overflow after reperfusion play important roles in the development of ischemic acute kidney injury. In this study, we examined the effect of 17beta-estradiol on the renal sympathetic nervous system and kidney function in ischemia/reperfusion-induced acute kidney injury in anesthetized rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after a contralateral nephrectomy. Intravenous injection of 17beta-estradiol (100 MUg/kg) 15 min before reperfusion suppressed enhanced renal sympathetic nerve activity during renal ischemia, also suppressed renal venous norepinephrine overflow after reperfusion, and attenuated ischemia/reperfusion-induced renal dysfunction with histological damage. The above renoprotective effects of 17beta-estradiol were reversed by pretreatment with tamoxifen (5 mg/kg), an estrogen receptor antagonist, or N(G) nitro-L-arginine methyl ester (0.3 mg/kg), a non-selective nitric oxide synthase inhibitor. These results indicate that 17beta-estradiol can suppress enhanced renal sympathetic nerve activity during renal ischemia, and its consequent effect on norepinephrine overflow from nerve endings, by nitric oxide production via estrogen receptors. These effects appear to contribute to renoprotection against ischemia/reperfusion-induced renal injury. PMID- 22426162 TI - The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats. AB - This study was carried out to assess the behavioral effects of the non psychostimulant drug atomoxetine, in rats prenatally-exposed to the organic compound trimethyltin chloride (TMT) and in spontaneously hypertensive rat (SHR), two rodent models of Attention Deficit/Hyperactivity Disorder (ADHD). At birth, neonatal reflexes (righting, cliff aversion, forelimb placing, forelimb grasping, bar holding and startle) had an earlier onset (i.e. percent of appearance) and completion (maximum appearance, i.e. 100% of the brood exhibiting each reflex) in prenatally TMT-exposed and SHR pups as compared to control groups. Two months after birth, TMT-exposed and SHR rats showed impaired cognitive performances in both the step-through passive avoidance test and the shuttle box active avoidance test. Atomoxetine (1, 3 and 6 mg/kg, i.p.), already at the lowest dose tested, improved learning and memory capacity of prenatally TMT-exposed rats and SHR; while methylphenidate (1, 3 and 6 mg/kg, i.p.), used here as positive control, elicited a significant cognitive enhancing effect only at the higher doses. In the open field test, both TMT-exposed rats and SHR displayed enhanced locomotor activity. Methylphenidate further increased locomotor activity in all groups, whereas atomoxetine reduced the enhanced locomotor activity of TMT-exposed rats and SHR down to the level of controls. These results suggest that prenatal TMT exposure could be considered as a putative experimental model of ADHD and further support the effectiveness of atomoxetine in the ADHD pharmacotherapy. Furthermore, despite the similar effect of the two drugs on cognitive tasks, they exhibit distinct profiles of activity on locomotion, in ADHD models. PMID- 22426163 TI - Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice. AB - This study investigates the gastroprotective effects of hecogenin, a steroid saponin isolated from Agave sisalana, on experimental models of gastric ulcer. Male Swiss mice were used in the models of ethanol- and indometacin-induced gastric ulcer. To clarify the hecogenin mechanism of action, the roles of nitric oxide (NO), sulfhydryls (GSH), K+(ATP) channels and prostaglandins were also investigated, and measurements of lipid peroxidation (TBARS assay) and nitrite levels in the stomach of hecogenin-treated and untreated animals were performed. Furthermore, the effects of hecogenin on myeloperoxidase (MPO) release from human neutrophils were assessed in vitro. Our results showed that hecogenin (3.1, 7.5, 15, 30, 60 and 90 mg/kg, p.o.) acutely administered, before ethanol or indomethacin, exhibited a potent gastroprotective effect. Although the pretreatments with L-NAME, an iNOS inhibitor, and capsazepine, a TRPV1 receptor agonist, were not able to reverse the hecogenin effect, this was reversed by glibenclamide, a K+(ATP) blocker, and indomethacin in the model of ethanol induced gastric lesions. The hecogenin pretreatment normalized GSH levels and significantly reduced lipid peroxidation and nitrite levels in the stomach, as evaluated by the ethanol-induced gastric lesion model. The drug alone increased COX-2 expression and this effect was further enhanced in the presence of ethanol. It also decreased MPO release and significantly protected the gastric mucosa. In conclusion, we showed that hecogenin presents a significant gastroprotective effect that seems to be mediated by K+(ATP) channels opening and the COX-2/PG pathway. In addition, its antioxidant and anti-inflammatory properties may play a role in the gastroprotective drug effect. PMID- 22426164 TI - Protein profiling of the secretome of FcepsilonRI activated RBL-2H3.1 cells. AB - BACKGROUND: Secretory proteins of IgE receptor activated mast cells and basophils play a pivotal role in the generation of immediate and long term immune responses in allergy and type I hypersensitivity. OBJECTIVE: The present study aims to generate a 2-D map and profile of proteins secreted from a high secretory variant of the rat basophilic leukemia cell line, RBL-2H3.1, which in view of the difficulty associated with gaining adequate numbers of pure primary mast cell and basophiles, represents an accepted model system for the study and standardization of the methodology to characterize the secretome of these cell types. METHODS: A 2-D map of secretory proteins was generated by 2-D PAGE and a shotgun mass spectrometric approach carried out for protein identification. RESULTS: Study resulted into identification of 299 proteins released from resting and IgE receptor activated RBL-2H3.1 cells after 90 s, 30 min and 3 h antigen challenge. Further sequence analysis identified ~53% of total proteins as secretory proteins which could be attributed to classical and non-classical secretory pathways. Additionally, functional classification of classic secretory proteins verified the presence of proteins belonged to cytokines, receptors, membrane proteins, lysosomal proteins and proteins associated with specific sub-cellular localizations such as endoplasmic reticulum, mitochondria, nucleus, cytoplasm and ribosome. According to this data the presence of some secretory proteins such as cytokines (e.g. MCP-2, PF-4, CSF-1 and TGF-beta1) are all subject to Ag challenge which may point to their importance toward pathogenesis in allergic diseases. CONCLUSION: In view of both a beneficial and adverse role of mast cell mediators in health and disease, an identification of temporal changes in the secretory pattern may form the basis for future tailor made intervention strategies that may enable us to harvest the therapeutic potential inherent in mast cell exocytosis while inhibiting/attenuating negative outcomes. PMID- 22426165 TI - Specific IgE to common food allergens in children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis is a major public health problem, often starting in early childhood and sometimes followed by other allergic diseases. Although hypersensitivity to foods is assumed to play an essential role in the development of atopic dermatitis in some patients, little is known about common food allergens in Iranian children with atopic dermatitis. OBJECTIVES: This study was designed to identify probable food allergens in Iranian children with atopic dermatitis and find the relationship between food sensitization and the severity of atopic dermatitis. METHODS: This study included 90 children aged 2-48 months with atopic dermatitis. Skin prick tests for cow's milk, hen's egg, almond, potato and soybean were done. Serum specific IgE to 20 food allergens was also screened. RESULTS: Among children with atopic dermatitis, the frequency of food sensitization was 40% by skin prick test and 51% by food-specific IgE. Children with atopic dermatitis were most commonly sensitized to cow's milk (31%), hen's egg (17.7%), tree nuts (17.7%), wheat (12.2%), potato (11.1%), tomato (8.8%) and peanut (8.8%). In 42 children with moderate to severe eczema, sensitivity to food allergens was 78.5% by skin prick test and 88% by serum specific IgE evaluation. CONCLUSION: Our results showed that cow's milk, hen's egg and tree nuts were the most common food allergens in Iranian children with atopic dermatitis. Sensitization to foods was much higher in patients with moderate to severe atopic dermatitis. Determining specific IgE in children with atopic dermatitis can be helpful in managing these patients. PMID- 22426166 TI - Association of KIR3DS1+HLA-B Bw4Ile80 combination with susceptibility to tuberculosis in Lur population of Iran. AB - BACKGROUND: Natural killer (NK) cells are the effector cells of innate immunity that respond to infection and tumor. Interactions between killer cell immunoglobulin like receptors (KIR) and human leukocyte antigen (HLA) class I molecules regulate NK cells responses to eliminate infected and transformed cells. OBJECTIVE: To investigate the impact of KIR genes, HLA ligand genes, and KIR-HLA combinations on susceptibility to tuberculosis (TB) in Lur population of Iran. METHODS: The genomic DNA of 50 patients with TB from Lorestan province of Iran was genotyped for sixteen KIR genes and their five major HLA class I ligands were determined by a polymerase chain reaction-sequence-specific primers (PCR SSP) assay. The results were compared with those of 200 healthy unrelated Iranian individuals. RESULTS: In Lur population of Iran, a significant decrease in frequency of KIR3DS1 was found in TB patients compared to control group (24% vs. 44.5%, OR=0.394, CI=0.194-0.798, p=0.013). Also, among the three activating genes that may use HLA class I molecules as their ligands, a significant decrease was shown in frequency of KIR3DS1 with HLA-B Bw4Ile80 ligand in TB patients compared to control group (4% vs. 23%, OR=0.14, CI=0.033-0.596, p=0.004). CONCLUSION: These findings imply a genetic imbalance between activating and inhibitory KIR genes and KIR-HLA combinations in Lur TB patients. Low level of activating KIR3DS1 and its combination with HLA-B Bw4Ile80 ligand might have an influence on the susceptibility to TB in Lur population of Iran. PMID- 22426167 TI - Infection by Cag A positive strains of Helicobacter pylori is associated with autoimmune thyroid disease in Iranian patients. AB - BACKGROUND: Infectious agents have been suspected as a triggering factor for development of autoimmune thyroid disease (ATD). Some reports from Western countries have suggested association between Helicobacter pylori (HP) infection and ATD. OBJECTIVE: To investigate the association of ATD with Cag A seropositivity in a population with high rate and early age of onset of HP infection. METHODS: IgG anti HP and anti Cag A antibodies were measured in 88 patients with ATD and compared with results of 112 healthy individuals. RESULTS: The rate of infection with HP was not significantly different in patient and control groups, but there was significant association between ATD and infection with Cag A strains (p<0.005). This association was significant for both hypothyroidism (p<0.005) and Graves' disease (p<0.02). Cag A antibody level correlated with titers of thyroid auto antibodies (p<0.001). CONCLUSION: In a population with high rate and early age of onset of HP infection, only infection with Cag A positive strains is associated with ATD, and this may be due to immune cross-reactivity. PMID- 22426168 TI - CD4+Foxp3+ Treg and its ICOS+ subsets in patients with myocardial infarction. AB - BACKGROUND: Atherosclerosis is a multifactorial disorder with chronic inflammatory conditions in which immune cells play a significant role in its pathogenic process. Regulatory T cells (Treg), as a part of immune system, are involved in controlling auto-immune and inflammatory diseases. Tregs have been shown to play an atheroprotective role and may also promote plaque stabilization. OBJECTIVE: To assess if inducible costimulatory molecule (ICOS) expression on one subtype of Treg cells with high suppressive potential correlates with the pathogenesis of atherosclerosis. METHODS: Patients with myocardial infarction (MI) and/or stable angina (SA), diagnosed as atherosclerosis by angiography, and a group of individuals with normal coronary angiography (NCA) were recruited for the present study. Peripheral blood mononuclear cells (PBMCs) were prepared and the expression of ICOS, Foxp3 and CD4 molecules was tested by flowcytometry. RESULTS: The percentage of CD4+Foxp3+ Treg cells was reduced in MI group compared to NCA and SA groups (p<0.005). Evaluation of the two Treg subsets according to ICOS expression showed a decreased ICOS+/ICOS- Treg ratio in MI and SA groups compared to NCA individuals (p=0.002 and p=0.048, respectively). CONCLUSION: The present data indicate that Tregs and its ICOS+ subsets are decreased in patients with MI or SA, suggesting a potential role for Treg in atherosclerosis progression or onset of acute coronary syndrome. PMID- 22426169 TI - Differential WNT gene expression in various subtypes of acute lymphoblastic leukemia. AB - BACKGROUND: Dysregulation of WNT signaling has been reported in many malignancies. OBJECTIVE: This study was conducted to investigate the expression pattern of 14 members of the WNT gene family in different immunophenotypic subtypes of ALL. METHODS: Semi-quantitative RT-PCR was performed on samples from 71 ALL patients and 36 age-matched healthy individuals. The ALL patients were categorized into B-ALL (76%), T-ALL (22.6%) and mixed lineage (1.4%) and the B ALL cases were further classified into pro-B, pre-BI, pre-BII and immature/mature B based on immuno-phenotypic results. RESULTS: Among the WNT genes, WNT-7B (p=0.026), WNT-9A (p=0.020) and WNT-16B (p=0.023) were significantly over expressed, whereas WNT-2B (p=0.033), WNT-5A (p=0.016), WNT-7A (p<0.0001) and WNT 10A (p<0.0001) were down-regulated in B-ALL. Among the T-ALL subtype, however, significant down-regulation of WNT-2B, WNT-5B, WNT-7A, WNT-10A and WNT-11 was evident. Comparison between B-ALL subtypes showed significant over-expression of WNT-7B, WNT-9A and WNT-5B in certain subtypes. CONCLUSION: Our results suggest contribution of the WNT genes in leukemogenesis of ALL. PMID- 22426170 TI - Identification and expression of nor efflux family genes in Staphylococcus epidermidis that act against gatifloxacin. AB - NorA, NorB, and NorC are efflux proteins in the Nor family that regulate the secretion of fluoroquinolones, and MgrA/NorR is a transcription factor of the Nor family. Overexpression of Nor family proteins provides fluoroquinolone resistance in Staphylococcus aureus. However, in coagulase-negative staphylococci (CNS), members of the Nor family had not been identified. In this work, the presence of Nor family proteins in Staphylococcus spp. and the expression of Nor family in gatifloxacin resistant S. epidermidis strains obtained from ocular infections (OI) were identified and analyzed. S. epidermidis strains from OIs (n = 44) and healthy skin (HS; n = 52) were isolated. The nor family genes were identified in CNS using PCR, sequencing and phylogenetic approaches. Nor family expression was determined by RT-PCR. NorA efflux activity was determined using the automated ethidium bromide method. In-silico analysis showed that norA, mgrA/norR, and "norB-like" and "norC-like" (norB/norC) genes are present in CNS. The nor family genes were distributed and constitutively expressed in all S. epidermidis strains studied. In one gatifloxacin resistant strain isolated from the endophthalmitis, treatment with gatifloxacin induced overexpression of the norA gene and resulted in high activity of NorA efflux. These results indicate that the Nor family of proteins is present in CNS, and the NorA efflux mechanism for gatifloxacin response occurs in at least one strain of S. epidermidis, contributing to gatifloxacin resistance. PMID- 22426172 TI - Foveal avascular zone and its relationship to foveal pit shape. AB - PURPOSE: To investigate the retinal microvasculature at the fovea and peripheral retina in humans using an adaptive optics scanning laser ophthalmoscope (AOSLO) and to examine the association of foveal avascular zone (FAZ) and foveal pit morphology. METHODS: Retinal imaging of the foveal capillary network was performed on 11 subjects (15 eyes; age range 20 to 54 years) with an AOSLO. Standard deviation maps of the AOSLO images were generated from ~10 to 30 frames, producing high-resolution maps delineating the complete capillary distribution of the retina. Foveal pit morphology was investigated in the same subjects by using a spectral domain optical coherence tomography. In an additional subject, only a relatively large retinal vasculature map was obtained using AOSLO. RESULTS: A well-demarcated FAZ was seen in 11 subjects tested with foveal capillary imaging. There was considerable individual variation in the size and shape of the FAZ. The mean FAZ area and mean FAZ effective diameter were 0.33 mm(2) and 622 MUm, respectively. Foveal thickness was found to be negatively correlated with the FAZ effective diameter. CONCLUSIONS: The structure of the capillary network could be evaluated in the fovea and parafovea using our approach. We find that a smaller FAZ is associated with a narrower foveal pit opening and a thicker fovea. PMID- 22426173 TI - Relative importance of factors affecting corneal hysteresis measurement. AB - PURPOSE: To evaluate the relative influences of several demographic, ocular, and systemic parameters on corneal hysteresis (CH). METHODS: This is a prospective, observational, cross-sectional study using subjects recruited from consecutive Albuquerque VAMC eye clinic patients. We classified eligible subjects as primary open-angle glaucoma (POAG), ocular hypertension, glaucoma suspect, or normal. We used the Ocular Response Analyzer, Pascal Dynamic Contour Tonometer, and Goldmann applanation tonometer to obtain intraocular pressure (IOP), CH, corneal resistance factor, and ocular pulse amplitude values. We also obtained corneal curvature, central corneal thickness (CCT), axial length, retinal nerve fiber layer thickness, clinical cup/disc ratio (CDR) estimates, and standard automated perimetry metrics (mean defect, pattern standard deviation). We gathered glycosylated hemoglobin (A1C) data through chart review. Multivariate regression analyses were used to determine independent relationships between CH and the other parameters. RESULTS: Three hundred seventeen eyes in 317 subjects were studied (116 POAG, 87 ocular hypertension, 47 glaucoma suspect, and 67 normal). In univariate regression analysis, CH varied directly with CCT (beta = 0.39, p < 0.001), corneal curvature (beta = 0.16, p = 0.01), corneal resistance factor (beta = 0.57, p < 0.001), A1C (beta = 0.15, p = 0.01), mean defect (beta = 0.29, p < 0.001), and retinal nerve fiber layer (beta = 0.31, p < 0.001). Factors inversely related to CH were age (beta = -0.22, p < 0.001), IOP (beta = -0.29, p < 0.001), ocular pulse amplitude (beta = -0.11, p = 0.04), CDR (beta = -0.34, p < 0.001), and pattern standard deviation (beta = -0.29, p < 0.001). CH was lower in POAG compared with the other diagnostic groups. In multivariate analysis, CH was independently associated with age, IOP, CCT, A1C, glaucoma diagnosis, and CDR. Of these factors, CCT and IOP demonstrated twice as much influence on CH compared with the other four factors. CONCLUSIONS: Although this study identified six separate variables that independently influence CH values, the overall r value indicates that these variables together only explain 40% of CH variability. These results suggest that other significant sources of variability exist and deserve investigation. PMID- 22426174 TI - Does ethnicity influence the short-term adaptation to first reading correction? AB - PURPOSE: Ethnic variations in accommodative amplitude (AA) are not uncommon. Accommodation can become reduced in response to short-term wear of first near spectacles. Whether ethnicity has an influence on the magnitude of this adaptation is not well understood. We investigated the impact of first near spectacles on changes in AA and on convergence cross-link interactions in incipient presbyopes of Chinese and Caucasian ethnicities. METHODS: Forty-one subjects (22 Caucasians and 19 Chinese) aged 36 to 44 years completed the study. Accommodative stimulus response function, AA, and AC/A and CA/C ratios were measured before and after single vision reading spectacles were used for near tasks over a 2-month period and then again 2 months after discontinuing near spectacle wear. RESULTS: After wearing reading spectacles for 2 months, the accommodative stimulus response slopes and AC/A and CA/C ratios remained invariant irrespective of ethnicity. The accommodative, but not vergence, bias decreased (p < 0.05). The nearpoint of accommodation shifted distally producing an average decrease in AA of 0.52 D from baseline (p < 0.05). Recovery to near baseline values occurred after discontinuing the reading glasses for 2 months. Differences based on ethnicity were not significant. The baseline AA vs. age plots showed steeper slopes for Chinese than the Caucasian subjects in the sample. CONCLUSIONS: The pattern of adaptation by accommodation and cross-link interactions to short-term first reading spectacles is not influenced by ethnicity. PMID- 22426175 TI - Efficacy of care solutions against contact lens-associated Fusarium biofilms. AB - PURPOSE: The aim of this study is to assess the effect of lens wear on the formation of soft contact lens-associated Fusarium biofilms and to determine the efficacy of marketed contact lens care products against such biofilms. METHODS: Using an established in vitro soft contact lens-Fusarium biofilm model, two clinical Fusarium isolates (F. solani B6914 and F. oxysporum B8996) were incubated with three different types (lotrafilcon A, etafilcon A, and balafilcon A) of worn contact lenses under conditions that facilitate biofilm formation. Unworn lenses were used as internal controls for biofilm formation. Biofilm was quantified using a tetrazolium XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H tetrazolium-5-carboxanilide) assay. In addition, susceptibilities of the fungal biofilm growth phases to the five most common multipurpose contact lens care solutions available at the time of study (three polymeric biguanide-preserved and two polyquaternium-preserved) and two hydrogen peroxide care solutions were assessed. RESULTS: Both Fusarium strains formed dense biofilms on each of the contact lens types tested. Worn lenses showed no differences in the ability of biofilm to form compared with unworn lenses except worn etafilcon A lenses which formed more biofilm with F. oxyspourm B8996 compared with unworn controls. Lens material did not influence biofilm formation. The biofilms of F. solani on all three lens types were consistently susceptible to both hydrogen peroxide care systems (growth reduction of 84 to 97%, p <= 0.001) and two of the five multipurpose solutions (MPSs) (growth reduction of 62 to 85% for a biguanide preserved MPS, p <= 0.05; growth reduction of 92 to 96% for a polyquaternium myristamidopropyl dimethylamine preserved MPS, p < 0.001). The biofilms of F. oxysporum on all three lens types were consistently susceptible to both hydrogen peroxide care systems (growth reduction of 79 to 99%, p <= 0.001) and one of the five MPSs (growth reduction of 93 to 96% for a polyquaternium-myristamidopropyl dimethylamine preserved MPS, p <= 0.001). CONCLUSIONS: F. solani and F. oxysporum form biofilms on lotrafilcon A, etafilcon A, and balafilcon A worn contact lenses, which are resistant to the antifungal activity of several soft contact lens care products. Only the hydrogen peroxide care systems and one polyquaternium-myristamidopropyl dimethylamine-preserved solution consistently demonstrated effective antifungal activity against both Fusarium strains on all three lens types. PMID- 22426176 TI - Axial length and proliferative diabetic retinopathy. AB - PURPOSE: To determine the correlation between axial length and diabetic retinopathy (DR) in patients with diabetes mellitus for 10 years or more. METHODS: This study was a prospective, observational, cross-sectional study. Patients with diabetes for 10 years or more were included. We excluded eyes with any other significant ocular disease or any prior intraocular surgery, except uncomplicated cataract surgery. Only one eye of each patient was included as the study eye. The severity of DR was graded as no DR, non-proliferative DR (NPDR), or proliferative DR (PDR). Axial length was measured by A-scan ultrasound (10 MHz Transducer, AL-2000 Biometer/Pachymeter; Tomey, Phoenix, AZ). Univariate logistic regression models were used to evaluate the relationship between the dependent variables (any DR, PDR) and all potential risk factors. Axial length and other factors with p value <0.1 were included in multivariate logistic regression models. Backward selection based on the likelihood ratio statistic was used to select the final models. RESULTS: We included 166 eyes from 166 patients (93 female and 73 male; mean age, 68.8 years). The mean diabetes duration was 15.4 years. Fifty-four (32.5%) eyes had no DR, 72 (43.4%) eyes had NPDR, and 40 (24.1%) eyes had PDR. In univariate analysis, hypertension (p = 0.009), renal impairment (p = 0.079), and insulin use (p = 0.009) were associated with developing any DR. Hypertension (p = 0.042), renal impairment (p = 0.014), insulin use (p = 0.040), pseudophakia (p = 0.019), and axial length (p = 0.076) were associated with developing PDR. In multivariate analysis, hypertension (p = 0.005) and insulin use (p = 0.010) were associated with developing any DR. Hypertension (p = 0.020), renal impairment (p = 0.025), pseudophakia (p = 0.006), and axial length (p = 0.024) were associated with developing PDR. CONCLUSIONS: This observational study suggests an inverse relationship between axial length and the development of PDR in patients with diabetes for 10 years or more. No relationship was found between axial length and the development of any DR. PMID- 22426177 TI - HuR post-transcriptionally regulates TNF-alpha-induced IL-6 expression in human pulmonary microvascular endothelial cells mainly via tristetraprolin. AB - HuR and tristetraprolin (TTP) are both RNA-binding proteins, which are characterized as binding to the AU-rich elements (AREs) in the 3'-untranslated regions (3'-UTRs) of target mRNAs. Studies have shown that some ARE-containing mRNAs are stabilized by HuR, whereas are destabilized by TTP. Our previous study showed that HuR upregulated tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-6 (IL-6) expression by stabilizing its mRNA in human pulmonary microvascular endothelial cells (HPMECs). Considering IL-6 mRNA has AREs, we decided to examine whether TTP was also involved in the regulation of TNF-alpha induced IL-6 expression in HPMECs and whether HuR and TTP influenced each other at protein and mRNA level. Here, we report that TTP silencing increased IL-6 levels. HuR silencing increased TTP expression. TTP had no effect on HuR expression and subcellular localization. Compared to TTP silencing alone, double knockdown of HuR and TTP did not significantly reduce IL-6 release. The RNA binding protein immunoprecipitation (RIP) results further showed that TTP but not HuR bound to intracellular IL-6 mRNA in HPMECs. We demonstrate for the first time that HuR post-transcriptionally regulates IL-6 expression mainly via TTP. PMID- 22426178 TI - Mitochondrial DNA deletion mutations in adult mouse cardiac side population cells. AB - We investigated the presence and potential role of mitochondrial DNA (mtDNA) deletion mutations in adult cardiac stem cells. Cardiac side population (SP) cells were isolated from 12-week-old mice. Standard polymerase chain reaction (PCR) was used to screen for the presence of mtDNA deletion mutations in (a) freshly isolated SP cells and (b) SP cells cultured to passage 10. When present, the abundance of mtDNA deletion mutation was analyzed in single cell colonies. The effect of different levels of deletion mutations on SP cell growth and differentiation was determined. MtDNA deletion mutations were found in both freshly isolated and cultured cells from 12-week-old mice. While there was no significant difference in the number of single cell colonies with mtDNA deletion mutations from any of the groups mentioned above, the abundance of mtDNA deletion mutations was significantly higher in the cultured cells, as determined by quantitative PCR. Within a single clonal cell population, the detectable mtDNA deletion mutations were the same in all cells and unique when compared to deletions of other colonies. We also found that cells harboring high levels of mtDNA deletion mutations (i.e. where deleted mtDNA comprised more than 60% of total mtDNA) had slower proliferation rates and decreased differentiation capacities. Screening cultured adult stem cells for mtDNA deletion mutations as a routine assessment will benefit the biomedical application of adult stem cells. PMID- 22426179 TI - A solid-state CdSe quantum dot sensitized solar cell based on a quaterthiophene as a hole transporting material. AB - A hybrid quantum dot sensitized solar cell (QDSC) composed of CdSe quantum dots (QDs) as light harvesters and TiO(2) and 3,3'''-didodecyl-quaterthiophene (QT12) as electron and hole conductors, respectively, has been fully processed in air. The sensitizer has been introduced into the TiO(2) nanoporous layer either by the successive ionic layer adsorption and reaction method or by attaching colloidal QDs either directly or through molecular cables (linkers). As previously observed for QDSCs based on liquid electrolytes, the efficiency depends on the way of QD attachment, the direct adsorption of QDs being the procedure yielding the best results. Thermal annealing was applied in order to enhance the device response under illumination. Remarkable open circuit potentials are attained (close to 1 V), leading to an efficiency of 0.34% (AM 1.5G) in initial tests. Although low, it ranks as one of the highest values reported for solid state QDSCs based on titanium dioxide and colloidal quantum dots. PMID- 22426180 TI - Towards a gold standard: regarding quality in public domain chemistry databases and approaches to improving the situation. AB - In recent years there has been a dramatic increase in the number of freely accessible online databases serving the chemistry community. The internet provides chemistry data that can be used for data-mining, for computer models, and integration into systems to aid drug discovery. There is however a responsibility to ensure that the data are high quality to ensure that time is not wasted in erroneous searches, that models are underpinned by accurate data and that improved discoverability of online resources is not marred by incorrect data. In this article we provide an overview of some of the experiences of the authors using online chemical compound databases, critique the approaches taken to assemble data and we suggest approaches to deliver definitive reference data sources. PMID- 22426189 TI - Biosynthesis: An HR-PKS stereo surprise. PMID- 22426190 TI - Ubiquitin ligases: Taming the APC. PMID- 22426191 TI - Neurodegeneration: Recall sugars, forget Alzheimer's. PMID- 22426192 TI - Infectious diseases: Transporter targeted in tuberculosis. PMID- 22426193 TI - General surgery: present and future. AB - General surgery is going through critical moments in recent years. Problems associated with the evolution and development of the specialty and training programs. Appearance of a sub-especialization in general surgery. All this in the context of an economic crisis of global impact. These changes have resulted in a state of emotional and mental fatigue known as burn out syndrome, in many cases. However not everything is negative and the development of the minimally invasive surgery techniques, NOTES, and single port surgery have been an incentive for surgeons in recent years. We must not fail to take into account the increase in cost of these procedures at the present time. I make some reflections about this topics, that although they reflect a very particular opinion I think they show the feeling of many surgeons. I think that in these times we are living in, we must fundamentally improve our efficiency and safety in daily practice. PMID- 22426194 TI - Targeted cargo delivery using a rotating nickel nanowire. AB - This paper reports an approach to perform basic noncontact and contact manipulation tasks using rotating nickel nanowires driven by a rotating magnetic field. A rotating nanowire is capable of propulsion and steering near a solid surface by a tumbling motion. The FEM simulation shows that fluid flow is induced around the rotating nanowire, which was applied to manipulate micro-objects in a noncontact fashion. Pushing, pulling, and rotation tests of individual polystyrene microbeads are conducted on a solid surface. In addition, targeted delivery tasks of biological samples, e.g., individual flagellated microorganisms and human blood cells, are demonstrated. The results imply that rotating magnetic nanowires are good tools for handling cellular and subcellular objects in an aqueous low-Reynolds-number environment and have potential for single-cell analysis. FROM THE CLINICAL EDITOR: In this study, the authors report the ability to push, pull, and rotate individual polystyrene microbeads on a solid surface. Furthermore, they demonstrate targeted delivery of biological samples, implying that rotating magnetic nanowires are good tools for handling cellular and subcellular objects. PMID- 22426195 TI - Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles. AB - Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug-drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these two drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface modified dual drug-loaded SLNPs. Brain permeation coefficient (K(in)) of folate grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain. FROM THE CLINICAL EDITOR: In this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clinical applications of lipophilic anticancer drugs to the brain. PMID- 22426196 TI - Functional characterization of transmembrane adenylyl cyclases from the honeybee brain. AB - The second messenger cAMP has a pivotal role in animals' physiology and behavior. Intracellular concentrations of cAMP are balanced by cAMP-synthesizing adenylyl cyclases (ACs) and cAMP-cleaving phosphodiesterases. Knowledge about ACs in the honeybee (Apis mellifera) is rather limited and only an ortholog of the vertebrate AC3 isoform has been functionally characterized, so far. Employing bioinformatics and functional expression we characterized two additional honeybee genes encoding membrane-bound (tm)ACs. The proteins were designated AmAC2t and AmAC8. Unlike the common structure of tmACs, AmAC2t lacks the first transmembrane domain. Despite this unusual topography, AmAC2t-activity could be stimulated by norepinephrine and NKH477 with EC(50s) of 0.07 MUM and 3 MUM. Both ligands stimulated AmAC8 with EC(50s) of 0.24 MUM and 3.1 MUM. In brain cryosections, intensive staining of mushroom bodies was observed with specific antibodies against AmAC8, an expression pattern highly reminiscent of the Drosophila rutabaga AC. In a current release of the honeybee genome database we identified three additional tmAC- and one soluble AC-encoding gene. These results suggest that (1) the AC-gene family in honeybees is comparably large as in other species, and (2) based on the restricted expression of AmAC8 in mushroom bodies, this enzyme might serve important functions in honeybee behavior. PMID- 22426197 TI - Direct reprogramming of human astrocytes into neural stem cells and neurons. AB - Generating neural stem cells and neurons from reprogrammed human astrocytes is a potential strategy for neurological repair. Here we show dedifferentiation of human cortical astrocytes into the neural stem/progenitor phenotype to obtain progenitor and mature cells with a neural fate. Ectopic expression of the reprogramming factors OCT4, SOX2, or NANOG into astrocytes in specific cytokine/culture conditions activated the neural stem gene program and induced generation of cells expressing neural stem/precursor markers. Pure CD44+ mature astrocytes also exhibited this lineage commitment change and did not require passing through a pluripotent state. These astrocyte-derived neural stem cells gave rise to neurons, astrocytes, and oligodendrocytes and showed in vivo engraftment properties. ASCL1 expression further promoted neuronal phenotype acquisition in vitro and in vivo. Methylation analysis showed that epigenetic modifications underlie this process. The restoration of multipotency from human astrocytes has potential in cellular reprogramming of endogenous central nervous system cells in neurological disorders. PMID- 22426198 TI - Intercellular transfer of apoptotic signals via electrofusion. AB - We determined whether cells that are induced to undergo anoikis by matrix detachment can initiate apoptosis in healthy cells following electroporation induced fusion. Separate populations of MDCK cells undergoing anoikis and stained with FITC-annexin or viable MDCK cells that were labeled with spectrally discrete fluorescent beads were electroporated. Cells were analyzed by flow cytometry for enumeration of viable cells with beads, apoptotic cells or fused cells. Electroporation promoted a 49-fold increase of the percentage of viable cells that had fused with apoptotic cells. Apoptotic cell-viable cell fusions were 8 fold more likely to not attach to cell culture plastic and 2.3-fold less likely to proliferate after 24hr incubation than viable cell fusion controls. These data demonstrate that apoptotic signals can be transferred between cells by electrofusion, possibly suggesting a novel investigative approach for optimizing targeted cell deletion in cancer treatment. PMID- 22426199 TI - Cellular characteristics of head and neck cancer stem cells in type IV collagen coated adherent cultures. AB - Although head and neck squamous carcinoma cancer stem cells (HNSC-CSCs) can be enriched in serum-free suspension cultures, it is difficult to stably expand HNSC CSC lines in suspension due to spontaneous apoptosis and differentiation. Here, we investigated whether HNSC-CSCs can be expanded without loss of stem cell properties by adherent culture methods. Cell culture plates were coated with type IV collagen, laminin, or fibronectin. We examined cancer stem cell traits of adherent HNSC-CSCs grown on these plates using immunocytochemistry for stem cell marker expression and analyses of chemo-resistance and xenograft tumorigenicity. We also assessed the growth rate, apoptosis rate, and gene transduction efficiency of adherent and suspended HNSC-CSCs. HNSC-CSCs grew much faster on type IV collagen-coated plates than in suspension. Adherent HNSC-CSCs expressed putative stem cell markers (OCT4 and CD44) and were chemo-resistant to various cytotoxic drugs (cisplatin, fluorouracil, paclitaxel, and docetaxel). Adherent HNSC-CSCs at the limiting dilution (1000 cells) produced tumors in nude mice. Adherent HNSC-CSCs also showed less spontaneous apoptotic cell death and were more competent to lentiviral transduction than suspended HNSC-CSCs. In conclusion, compared to suspension cultures, adherence on type IV collagen-coated culture plates provides better experimental conditions for HNSC-CSC expansion, which should facilitate various refined cellular studies. PMID- 22426200 TI - Molecular switches as photocontrollable "smart" receptors. AB - This critical review focuses on the development of photochromic compounds as sensors for cations, anions, and biologically important molecules. The review commences with a brief description of photochromism and the strategies to exploit photochromic molecular switches' properties for sensing application. This is followed by a summary of photoswitchable receptors emerged to date and classified according to the photochromic structure they are based on. These include azobenzenes, fulgides, dithienylethenes, dihydroindolizines, chromenes and spiropyrans. PMID- 22426201 TI - Alteration of serotonin system by polychlorinated biphenyls exposure. AB - Although commercial production of polychlorinated biphenyls (PCBs) was banned in 1979, PCBs continue to be an environmental and health concern due to their high bioaccumulation and slow degradation rates. In fact, PCBs are still present in our food supply (fish, meat, and dairy products). In laboratory animals, exposure to single PCB congener or to mixtures of different congeners induces a variety of physiological alterations. PCBs cross the placenta and even exposure at low level is harmful for the foetus by leading to neurodevelopment alterations. Serotonin system which regulates many physiological functions from platelet activation to high cerebral processes and neurodevelopment is one of the targets of PCBs toxicity. The effects of PCBs exposure on serotonin system have been investigated although to a lesser extent compared to its effect in other neurotransmitter systems. This review provides a summary of the results concerning the impact of PCBs exposure (in vitro and in vivo) on serotonin system. Further research is needed to correlate specific deficits with PCB-induced changes in the serotonin system. PMID- 22426202 TI - Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation. AB - The psychostimulant drug amphetamine is often prescribed to treat Attention Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ~175-350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ~135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0-3mg/kg) alone did not affect monoamine release, it dose dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine. PMID- 22426204 TI - Decoding ability makes waves in reading: deficient interactions between attention and phonological analysis in developmental dyslexia. AB - Whilst there is general consensus that phonological processing is deficient in developmental dyslexia, recent research also implicates visuo-attentional contributions. Capitalising on the P3a wave of event-related potentials as an index of attentional capture, we tested dyslexic and normal readers on a novel variant of a visual oddball task to examine the interplay of orthographic phonological integration and attentional engagement. Targets were animal words (10% occurrence). Amongst nontarget stimuli were two critical conditions: pseudohomophones of targets (10%) and control pseudohomophones (of fillers; 10%). Pseudohomophones of targets (but not control pseudohomophones) elicited a large P3 wave in normal readers only, revealing a lack of attentional engagement with these phonologically salient stimuli in dyslexic participants. Critically, both groups showed similar early phonological discrimination as indexed by posterior P2 modulations. Furthermore, phonological engagement, as indexed by P3a differences between pseudohomophone conditions, correlated with several measures of reading. Meanwhile, an analogous experiment using coloured shapes instead of orthographic stimuli failed to show group differences between experimental modulations in the P2 or P3 ranges. Overall, our results show that, whilst automatic aspects of phonological processing appear intact in developmental dyslexia, the breakdown in pseudoword reading occurs at a later stage, when attention is oriented to orthographic-phonological information. PMID- 22426205 TI - Differential prefrontal and frontotemporal oxygenation patterns during phonemic and semantic verbal fluency. AB - Movement artifacts are still considered a problematic issue for imaging research on overt language production. This motion-sensitivity can be overcome by functional near-infrared spectroscopy (fNIRS). In the present study, 50 healthy subjects performed a combined phonemic and semantic overt verbal fluency task while frontal and temporal cortex oxygenation was recorded using multi-channel fNIRS. Results showed a partial dissociation for phonemic and semantic word generation with equally increased oxygenation in frontotemporal cortices for both types of tasks whereas anterior and superior prefrontal areas were exclusively activated during phonemic fluency. Also, a general left-lateralization was found being more pronounced during semantic processing. These findings line up with earlier imaging and lesion studies emphasizing a crucial role of the temporal lobe for semantic word production, whereas phonemic processing seems to depend on intact frontal lobe function. PMID- 22426203 TI - Vitamin D and the kidney. AB - The kidney is essential for the maintenance of normal calcium and phosphorus homeostasis. Calcium and inorganic phosphorus are filtered at the glomerulus, and are reabsorbed from tubular segments by transporters and channels which are regulated by 1alpha,25-dihydroxyvitamin (1alpha,25(OH)(2)D) and parathyroid hormone (PTH). The kidney is the major site of the synthesis of 1alpha,25(OH)(2)D under physiologic conditions, and is one of the sites of 24,25-dihydroxyvitamin D (24,25(OH)(2)D) synthesis. The activity of the 25(OH)D-1alpha-hydroxylase, the mixed function oxidase responsible for the synthesis of 1alpha,25(OH)(2)D, is regulated by PTH, 1alpha,25(OH)(2)D, fibroblast growth factor 23 (FGF23), inorganic phosphorus and other growth factors. Additionally, the vitamin D receptor which binds to, and mediates the activity of 1alpha,25(OH)(2)D, is widely distributed in the kidney. Thus, the kidney, by regulating multiple transport and synthetic processes is indispensible in the maintenance of mineral homeostasis in physiological states. PMID- 22426206 TI - Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. AB - Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1alpha, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCdelta, reduced activity of HNF4alpha and HNF1alpha, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy. PMID- 22426207 TI - TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. AB - Herpes simplex viruses (HSVs) are highly prevalent neurotropic viruses. While they can replicate lytically in cells of the epithelial lineage, causing lesions on mucocutaneous surfaces, HSVs also establish latent infections in neurons, which act as reservoirs of virus for subsequent reactivation events. Immunological control of HSV involves activation of innate immune pattern recognition receptors such as TLR3, which detects double-stranded RNA and induces type I IFN expression. Humans with defects in the TLR3/IFN pathway have an elevated susceptibility to HSV infections of the CNS. However, it is not known what cell type mediates the role of TLR3 in the immunological control of HSV, and it is not known whether TLR3 sensing occurs prior to or after CNS entry. Here, we show that in mice TLR3 provides early control of HSV-2 infection immediately after entry into the CNS by mediating type I IFN responses in astrocytes. Tlr3-/- mice were hypersusceptible to HSV-2 infection in the CNS after vaginal inoculation. HSV-2 exhibited broader neurotropism in Tlr3-/- mice than it did in WT mice, with astrocytes being most abundantly infected. Tlr3-/- mice did not exhibit a global defect in innate immune responses to HSV, but astrocytes were defective in HSV-induced type I IFN production. Thus, TLR3 acts in astrocytes to sense HSV-2 infection immediately after entry into the CNS, possibly preventing HSV from spreading beyond the neurons mediating entry into the CNS. PMID- 22426208 TI - Endothelial HIF-2alpha regulates murine pathological angiogenesis and revascularization processes. AB - Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2alpha (HIF 2alpha) is highly expressed in vascular ECs and, along with HIF-1alpha, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2alpha regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2alpha expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2alpha-deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2alpha-dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2alpha-dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2alpha in ECs. These results indicate that HIF-1alpha and HIF 2alpha fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis. PMID- 22426209 TI - IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. AB - The cytokine IL-12 induces IFN-gamma production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL 12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-gamma independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12- and TIM-3-mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients. PMID- 22426210 TI - Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity. AB - The B cell-depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti-myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell-depleting therapies for autoimmune diseases. PMID- 22426211 TI - MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death. AB - Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abnormal increases in intracellular Ca2+ during myocardial reperfusion can cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Therapeutic modulation of Ca2+ handling provides some cardioprotection against the paradoxical effects of restoring blood flow to the heart, highlighting the significance of Ca2+ overload to IR injury. Cardiac IR is also accompanied by dynamic changes in the expression of microRNAs (miRNAs); for example, miR-214 is upregulated during ischemic injury and heart failure, but its potential role in these processes is unknown. Here, we show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The cardioprotective roles of miR-214 during IR injury were attributed to repression of the mRNA encoding sodium/calcium exchanger 1 (Ncx1), a key regulator of Ca2+ influx; and to repression of several downstream effectors of Ca2+ signaling that mediate cell death. These findings reveal a pivotal role for miR-214 as a regulator of cardiomyocyte Ca2+ homeostasis and survival during cardiac injury. PMID- 22426212 TI - PKCepsilon phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice. AB - Mechanical hyperalgesia is a common and potentially disabling complication of many inflammatory and neuropathic conditions. Activation of the enzyme PKCepsilon in primary afferent nociceptors is a major mechanism that underlies mechanical hyperalgesia, but the PKCepsilon substrates involved downstream are not known. Here, we report that in a proteomic screen we identified the NaV1.8 sodium channel, which is selectively expressed in nociceptors, as a PKCepsilon substrate. PKCepsilon-mediated phosphorylation increased NaV1.8 currents, lowered the threshold voltage for activation, and produced a depolarizing shift in inactivation in wild-type - but not in PKCepsilon-null - sensory neurons. PKCepsilon phosphorylated NaV1.8 at S1452, and alanine substitution at this site blocked PKCepsilon modulation of channel properties. Moreover, a specific PKCepsilon activator peptide, psiepsilonRACK, produced mechanical hyperalgesia in wild-type mice but not in Scn10a-/- mice, which lack NaV1.8 channels. These studies demonstrate that NaV1.8 is an important, direct substrate of PKCepsilon that mediates PKCepsilon-dependent mechanical hyperalgesia. PMID- 22426213 TI - Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease. AB - Actin-myosin interactions provide the driving force underlying each heartbeat. The current view is that actin-bound regulatory proteins play a dominant role in the activation of calcium-dependent cardiac muscle contraction. In contrast, the relevance and nature of regulation by myosin regulatory proteins (for example, myosin light chain-2 [MLC2]) in cardiac muscle remain poorly understood. By integrating gene-targeted mouse and computational models, we have identified an indispensable role for ventricular Mlc2 (Mlc2v) phosphorylation in regulating cardiac muscle contraction. Cardiac myosin cycling kinetics, which directly control actin-myosin interactions, were directly affected, but surprisingly, Mlc2v phosphorylation also fed back to cooperatively influence calcium-dependent activation of the thin filament. Loss of these mechanisms produced early defects in the rate of cardiac muscle twitch relaxation and ventricular torsion. Strikingly, these defects preceded the left ventricular dysfunction of heart disease and failure in a mouse model with nonphosphorylatable Mlc2v. Thus, there is a direct and early role for Mlc2 phosphorylation in regulating actin-myosin interactions in striated muscle contraction, and dephosphorylation of Mlc2 or loss of these mechanisms can play a critical role in heart failure. PMID- 22426215 TI - Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain. AB - BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG. METHODS: A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 ( 2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate. RESULTS: ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p=.068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G-rs10954173G-rs3828942G (p=.035) and AIWG. The rs7799039 G-allele (p=.042) and G-allele of rs3828942 (p=.032) were associated with higher weight gain. CONCLUSION: Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin-melanocortin pathway. PMID- 22426214 TI - Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. AB - Glaucoma is a common ocular disorder that is a leading cause of blindness worldwide. It is characterized by the dysfunction and loss of retinal ganglion cells (RGCs). Although many studies have implicated various molecules in glaucoma, no mechanism has been shown to be responsible for the earliest detectable damage to RGCs and their axons in the optic nerve. Here, we show that the leukocyte transendothelial migration pathway is activated in the optic nerve head at the earliest stages of disease in an inherited mouse model of glaucoma. This resulted in proinflammatory monocytes entering the optic nerve prior to detectable neuronal damage. A 1-time x-ray treatment prevented monocyte entry and subsequent glaucomatous damage. A single x-ray treatment of an individual eye in young mice provided that eye with long-term protection from glaucoma but had no effect on the contralateral eye. Localized radiation treatment prevented detectable neuronal damage and dysfunction in treated eyes, despite the continued presence of other glaucomatous stresses and signaling pathways. Injection of endothelin-2, a damaging mediator produced by the monocytes, into irradiated eyes, combined with the other glaucomatous stresses, restored neural damage with a topography characteristic of glaucoma. Together, these data support a model of glaucomatous damage involving monocyte entry into the optic nerve. PMID- 22426216 TI - Interpolar microtubules are dispensable in fission yeast meiosis II. AB - The mitotic spindle consists of two types of microtubules. Dynamic kinetochore microtubules capture kinetochores, whereas stable interpolar microtubules serve as the structural backbone that connects the two spindle poles. Both have been believed to be indispensable for cell division in eukaryotes. Here we demonstrate that interpolar microtubules are dispensable for the second division of meiosis in fission yeast. Even when interpolar microtubules are disrupted by a microtubule-depolymerizing drug, spindle poles separate and chromosomes segregate poleward in second division of meiosis in most zygotes, producing viable spores. The forespore membrane, which encapsulates the nucleus in second division of meiosis and is guided by septins and the leading-edge proteins, is responsible for carrying out meiotic events in the absence of interpolar microtubules. Furthermore, during physiological second division of meiosis without microtubule perturbation, the forespore membrane assembly contributes structurally to spindle pole separation and nuclear division, generating sufficient force for spindle pole separation and subsequent events independently of interpolar microtubules. PMID- 22426217 TI - The impact of asymmetrical light input on cerebral hemispheric specialization and interhemispheric cooperation. AB - Hemispheric specialization potentially provides evolutionary advantages by enhancing cognitive capacities. However, separation of function might be advantageous only with the presence of commissural systems allowing for efficient information exchange and cooperation between the hemispheres. Here we investigate hemispheric cooperation in pigeons as they possess an asymmetrically organized visual system that develops in response to biased ontogenetic light stimulation. This allows comparison of the integration capacities of lateralized (light incubated) and non-lateralized (dark-incubated) animals. We show that pigeons integrate information learnt separately with each hemisphere when confronted with a transitive reasoning task that they cannot solve with the knowledge of one hemisphere alone. Impairments in dark-incubated birds demonstrate that this ability depends on asymmetrical embryonic light stimulation. Our study provides for the first time direct evidence that lateralized environmental experience not only induces hemispheric specialization, but also affects the efficiency of interhemispheric crosstalk. Environmental factors can influence the tight interplay between the hemispheres, which in turn determines cognitive abilities. PMID- 22426218 TI - Male pygmy hippopotamus influence offspring sex ratio. AB - Pre-determining fetal sex is against the random and equal opportunity that both conceptus sexes have by nature. Yet, under a wide variety of circumstances, populations shift their birth sex ratio from the expected unity. Here we show, using fluorescence in situ hybridization, that in a population of pygmy hippopotamus (Choeropsis liberiensis) with 42.5% male offspring, males bias the ratio of X- and Y-chromosome-bearing spermatozoa in their ejaculates, resulting in a 0.4337+/-0.0094 (mean+/-s.d.) proportion of Y-chromosome-bearing spermatozoa. Three alternative hypotheses for the shifted population sex ratio were compared: female counteract male, female indifferent, or male and female in agreement. We conclude that there appears little or no antagonistic sexual conflict, unexpected by prevailing theories. Our results indicate that males possess a mechanism to adjust the ratio of X- and Y-chromosome-bearing spermatozoa in the ejaculate, thereby substantially expanding currently known male options in sexual conflict. PMID- 22426219 TI - New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole genome sequencing. AB - The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Otztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis. PMID- 22426220 TI - Repeated growth and bubbling transfer of graphene with millimetre-size single crystal grains using platinum. AB - Large single-crystal graphene is highly desired and important for the applications of graphene in electronics, as grain boundaries between graphene grains markedly degrade its quality and properties. Here we report the growth of millimetre-sized hexagonal single-crystal graphene and graphene films joined from such grains on Pt by ambient-pressure chemical vapour deposition. We report a bubbling method to transfer these single graphene grains and graphene films to arbitrary substrate, which is nondestructive not only to graphene, but also to the Pt substrates. The Pt substrates can be repeatedly used for graphene growth. The graphene shows high crystal quality with the reported lowest wrinkle height of 0.8 nm and a carrier mobility of greater than 7,100 cm(2) V(-1) s(-1) under ambient conditions. The repeatable growth of graphene with large single-crystal grains on Pt and its nondestructive transfer may enable various applications. PMID- 22426221 TI - Three-dimensional imaging of single nanotube molecule endocytosis on plasmonic substrates. AB - Investigating the cellular internalization pathways of single molecules or single nano objects is important to understanding cell-matter interactions, and to applications in drug delivery and discovery. Imaging and tracking the motion of single molecules on cell plasma membranes require high spatial resolution in three dimensions. Fluorescence imaging along the axial dimension with nanometre resolution has been highly challenging, but critical to revealing displacements in transmembrane events. Here, utilizing a plasmonic ruler based on the sensitive distance dependence of near-infrared fluorescence enhancement of carbon nanotubes on a gold plasmonic substrate, we probe ~10 nm scale transmembrane displacements through changes in nanotube fluorescence intensity, enabling observations of single nanotube endocytosis in three dimensions. Cellular uptake and transmembrane displacements show clear dependences to temperature and clathrin assembly on cell membrane, suggesting that the cellular entry mechanism for a nanotube molecule is via clathrin-dependent endocytosis through the formation of clathrin-coated pits on the cell membrane. PMID- 22426222 TI - Zigzag line defects and manipulation of colloids in a nematic liquid crystal in microwrinkle grooves. AB - Spatially confined liquid crystals exhibit non-uniform alignment, often accompanied by self-organised topological defects of non-trivial shape in response to imposed boundary conditions and geometry. Here we show that a nematic liquid crystal, when confined in a sinusoidal microwrinkle groove, exhibits a new periodic arrangement of twist deformations and a zigzag line defect. This periodic ordering results from the inherent liquid crystal elastic anisotropy and the antagonistic boundary conditions at the flat liquid crystal-air and the curved liquid crystal-groove interfaces. The periodic structure can be tuned by controlling the groove geometry and the molecular chirality, which demonstrates the importance of boundary conditions and introduced asymmetry for the engineering of topological defects. Moreover, the kinks in the zigzag defects can trap small particles, which may afford a new method for manipulation of colloids. Our system, which uses easily fabricated microwrinkle grooves, provides a new microfabrication method based on the arrangement of controllable defects. PMID- 22426223 TI - Network physiology reveals relations between network topology and physiological function. AB - The human organism is an integrated network where complex physiological systems, each with its own regulatory mechanisms, continuously interact, and where failure of one system can trigger a breakdown of the entire network. Identifying and quantifying dynamical networks of diverse systems with different types of interactions is a challenge. Here we develop a framework to probe interactions among diverse systems, and we identify a physiological network. We find that each physiological state is characterized by a specific network structure, demonstrating a robust interplay between network topology and function. Across physiological states, the network undergoes topological transitions associated with fast reorganization of physiological interactions on time scales of a few minutes, indicating high network flexibility in response to perturbations. The proposed system-wide integrative approach may facilitate the development of a new field, Network Physiology. PMID- 22426224 TI - Rats track odour trails accurately using a multi-layered strategy with near optimal sampling. AB - Tracking odour trails is a crucial behaviour for many animals, often leading to food, mates or away from danger. It is an excellent example of active sampling, where the animal itself controls how to sense the environment. Here we show that rats can track odour trails accurately with near-optimal sampling. We trained rats to follow odour trails drawn on paper spooled through a treadmill. By recording local field potentials (LFPs) from the olfactory bulb, and sniffing rates, we find that sniffing but not LFPs differ between tracking and non tracking conditions. Rats can track odours within ~1 cm, and this accuracy is degraded when one nostril is closed. Moreover, they show path prediction on encountering a fork, wide 'casting' sweeps on encountering a gap and detection of reappearance of the trail in 1-2 sniffs. We suggest that rats use a multi-layered strategy, and achieve efficient sampling and high accuracy in this complex task. PMID- 22426225 TI - Three decades of high-resolution coastal sea surface temperatures reveal more than warming. AB - Understanding and forecasting current and future consequences of coastal warming require a fine-scale assessment of the near-shore temperature changes. Here we show that despite the fact that 71% of the world's coastlines are significantly warming, rates of change have been highly heterogeneous both spatially and seasonally. We demonstrate that 46% of the coastlines have experienced a significant decrease in the frequency of extremely cold events, while extremely hot days are becoming more common in 38% of the area. Also, we show that the onset of the warm season is significantly advancing earlier in the year in 36% of the temperate coastal regions. More importantly, it is now possible to analyse local patterns within the global context, which is useful for a broad array of scientific fields, policy makers and general public. PMID- 22426226 TI - Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy. AB - Cellular functions are fundamentally regulated by intracellular temperature, which influences biochemical reactions inside a cell. Despite the important contributions to biological and medical applications that it would offer, intracellular temperature mapping has not been achieved. Here we demonstrate the first intracellular temperature mapping based on a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy. The spatial and temperature resolutions of our thermometry were at the diffraction limited level (200 nm) and 0.18-0.58 degrees C. The intracellular temperature distribution we observed indicated that the nucleus and centrosome of a COS7 cell, both showed a significantly higher temperature than the cytoplasm and that the temperature gap between the nucleus and the cytoplasm differed depending on the cell cycle. The heat production from mitochondria was also observed as a proximal local temperature increase. These results showed that our new intracellular thermometry could determine an intrinsic relationship between the temperature and organelle function. PMID- 22426227 TI - Perturbation of sodium channel structure by an inherited Long QT Syndrome mutation. AB - The cardiac voltage-gated sodium channel (Na(V)1.5) underlies impulse conduction in the heart, and its depolarization-induced inactivation is essential in control of the duration of the QT interval of the electrocardiogram. Perturbation of Na(V)1.5 inactivation by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. The carboxy terminus has an important role in channel inactivation, but complete structural information on its predicted structural domain is unknown. Here we measure interactions between the functionally critical distal carboxy terminus alpha-helix (H6) and the proximal structured EF-hand motif using transition-metal ion fluorescence resonance energy transfer. We measure distances at three loci along H6 relative to an intrinsic tryptophan, demonstrating the proximal-distal interaction in a contiguous carboxy terminus polypeptide. Using these data together with the existing Na(V)1.5 carboxy terminus nuclear magnetic resonance structure, we construct a model of the predicted structured region of the carboxy terminus. An arrhythmia-associated H6 mutant that impairs inactivation decreases fluorescence resonance energy transfer, indicating destabilization of the distal-proximal intramolecular interaction. These data provide a structural correlation to the pathological phenotype of the mutant channel. PMID- 22426228 TI - The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation. AB - Toll-like receptor 4 is an innate immune receptor responsible for the recognition of the Gram-negative cell wall component lipopolysaccharide. Here we show that transmembrane emp24 domain-containing protein 7 (TMED7) inhibits MyD88 independent toll-like receptor 4 signalling. TMED7 overexpression inhibits the ability of TRAM, an adaptor utilized by toll-like receptor 4, or lipopolysaccharide to activate the interferon regulatory factor 3-signalling pathway, whereas TMED7 knockdown enhances production of the cytokine, RANTES, following lipopolysaccharide stimulation. Upon lipopolysaccharide stimulation, TMED7 co-localizes with TRAM and toll-like receptor 4 in late endosomes where it encounters the negative regulator of TRAM, TAG. The TMED7 sequence is found in TAG because of a read-through from the tmed7 gene into the ticam2 gene. TMED7 is essential for TAG-mediated disruption of the TRAM/TRIF complex and the degradation of toll-like receptor 4. A TMED homologue, logjam, has a negative role in the Toll and IMD pathways in Drosophila melanogaster; therefore, TMEDs may have a conserved role in the regulation of innate immunity. PMID- 22426229 TI - Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. AB - Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress induced senescence are located at telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with telomeres. Finally, we report an age-dependent increase in frequencies of telomere-associated foci in gut and liver of mice, occurring irrespectively of telomere length. We conclude that telomeres are important targets for stress in vitro and in vivo and this has important consequences for the ageing process. PMID- 22426230 TI - Mapping of H3N2 influenza antigenic evolution in China reveals a strategy for vaccine strain recommendation. AB - One of the primary efforts in influenza vaccine strain recommendation is to monitor through gene sequencing the viral surface protein haemagglutinin (HA) variants that lead to viral antigenic changes. Here we have developed a computational method, denoted as PREDAC, to predict antigenic clusters of influenza A (H3N2) viruses with high accuracy from viral HA sequences. Application of PREDAC to large-scale HA sequence data of H3N2 viruses isolated from diverse regions of Mainland China identified 17 antigenic clusters that have dominated for at least one season between 1968 and 2010. By tracking the dynamics of the dominant antigenic clusters, we not only find that dominant antigenic clusters change more frequently in China than in the United States/Europe, but also characterize the antigenic patterns of seasonal H3N2 viruses within China. Furthermore, we demonstrate that the coupling of large-scale HA sequencing with PREDAC can significantly improve vaccine strain recommendation for China. PMID- 22426231 TI - Precise hierarchical self-assembly of multicompartment micelles. AB - Hierarchical self-assembly offers elegant and energy-efficient bottom-up strategies for the structuring of complex materials. For block copolymers, the last decade witnessed great progress in diversifying the structural complexity of solution-based assemblies into multicompartment micelles. However, a general understanding of what governs multicompartment micelle morphologies and polydispersity, and how to manipulate their hierarchical superstructures using straightforward concepts and readily accessible polymers remains unreached. Here we demonstrate how to create homogeneous multicompartment micelles with unprecedented structural control via the intermediate pre-assembly of subunits. This directed self-assembly leads to a step-wise reduction of the degree of conformational freedom and dynamics and avoids undesirable kinetic obstacles during the structure build-up. It yields a general concept for homogeneous populations of well-defined multicompartment micelles with precisely tunable patchiness, while using simple linear ABC triblock terpolymers. We further demonstrate control over the hierarchical step-growth polymerization of multicompartment micelles into micron-scale segmented supracolloidal polymers as an example of programmable mesoscale colloidal hierarchies via well-defined patchy nanoobjects. PMID- 22426232 TI - Ultra-rapid access to words in the brain. AB - Rapid information processing in the human brain is vital to survival in a highly dynamic environment. The key tool humans use to exchange information is spoken language, but the exact speed of the neuronal mechanisms underpinning speech comprehension is still unknown. Here we investigate the time course of neuro lexical processing by analyzing neuromagnetic brain activity elicited in response to psycholinguistically and acoustically matched groups of words and pseudowords. We show an ultra-early dissociation in cortical activation elicited by these stimulus types, emerging ~50 ms after acoustic information required for word identification first becomes available. This dissociation is the earliest brain signature of lexical processing of words so far reported, and may help explain the evolutionary advantage of human spoken language. PMID- 22426233 TI - Functional selectivity induced by mGlu4 receptor positive allosteric modulation and concomitant activation of Gq coupled receptors. AB - Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu(4) belongs to a subfamily of mGlus that is predominantly coupled to G(i/o) G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu(4)-expressing cells, an effect which is observed in the absence of co expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu(4) depends upon the presence of H(1) histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu(4)-mediated signaling events downstream of G(i/o) G proteins, such as cAMP inhibition, suggesting that the presence of G(q) coupled receptors such as H(1) may bias normal mGlu(4)-mediated G(i/o) signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu(4) is assessed, the potentiated signaling of mGlu(4) is further biased by histamine toward calcium-dependent pathways. These results suggest that G(i/o)-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of G(q) receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when G(q) receptors are co-activated. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22426234 TI - Application of baculovirus as a delivery vehicle for study of transcription and translation mechanism of parvovirus in non-permissive mammalian cells. AB - Human bocavirus (HBoV) is a parvovirus associated with respiratory and gastrointestinal diseases in humans. Recombinant baculoviruses have been used widely for many years to transduce transiently and stably a variety of mammalian cell types at high frequencies. In this study, to explore further the use of baculovirus as a gene delivery vehicle for study of transcription and translation mechanism of human bocavirus which lacks susceptible cell culture system, two recombinant baculoviruses were constructed: Bac-BoV-EGFP in which the EGFP gene was under the control of the HBoV1 promoter, and Bac-HBoV1 encompassing the nearly whole HBoV1 genome without both termini. The data demonstrated that efficient gene delivery and expression were observed in numerous mammalian cells transduced by Bac-BoV-EGFP and the transduction rate was much greater than that in plasmid-based transfected cells. The analysis of transcription and translation in Bac-HBoV1 transduced A549 cells showed that two transcripts from NP1 gene were detected by RT-PCR and the NP1 was localized in the nucleus, suggesting that the Bac-HBoV1 recombinant baculovirus delivered efficiently the HBoV1 genome into A549 cells. In summary, this system provides a useful tool for analysis of the transcription and translation of some viruses lacking a virus-cell replication system. PMID- 22426236 TI - Parent-of-origin testing for 15q11-q13 gains by quantitative DNA methylation analysis. AB - The Prader-Willi/Angelman syndrome critical region (PWS/ASCR), located at chromosome 15q11-q13, is associated with several diseases. Absence of paternally expressed genes in this region cause Prader-Willi syndrome (PWS), whereas absence of the maternally expressed UBE3A gene causes Angelman syndrome (AS). In addition, duplications and triplications of this region are also associated with distinct clinical features, indicating that the overexpression of genes within the PWS/ASCR can also lead to distinct phenotypes. Maternally inherited increases in copy number generally lead to a more severe phenotype do than paternally inherited increases. We describe a real-time methylation-sensitive PCR (Q-MSP) assay that quantifies methylation at the promoter of the differentially methylated SNRPN gene located within the PWS/ASCR. Q-MSP can detect both PWS and AS, as well as determine the parent of origin for the allele that carries the PWS/ASCR gains. In addition, Q-MSP requires only a small amount of DNA, is amenable to high-throughput analysis, and can be used in clinical testing as a reflex test to determine the parent of origin after identification of a gain of this region on chromosome 15. PMID- 22426235 TI - The germline MLH1 K618A variant and susceptibility to Lynch syndrome-associated tumors. AB - Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG->GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes. PMID- 22426237 TI - Characterization of the first coculture between human primary keratinocytes and the dorsal root ganglion-derived neuronal cell line F-11. AB - The epidermis can be considered as a sensory organ. Sensory neurons of the peripheral nervous system send many primary afferent fibers to the skin, creating a dynamic communication with epidermal cells. However, little is known about the functional interactions between the sensory fibers and the keratinocytes. It is therefore difficult to reproduce these interactions in vitro. We have developed an in vitro model based on the coculture of primary human keratinocytes and the dorsal root ganglion cell line F-11. F-11 cells have been classically used to mimic authentic peptidergic nociceptive neurons. We first investigated the morphological and functional characteristics of F-11 cells cultured in basal keratinocyte medium and then analyzed the influence of keratinocytes on these properties. We found that F-11 cells survived and differentiated well in this medium. Therefore, the addition of neurotrophins did not enhance their survival or differentiation. These neurons expressed sensory neuron markers and were able to release neuropeptides after capsaicin activation. We noted that neuropeptides release were obtained even at a low calcium concentration and that axonal outgrowth was not influenced by external calcium (Ca(2+)) levels. These properties were reproduced when F-11 cells were cocultured with keratinocytes, but they had no significant influence on axonal development or neuropeptide release. In this study, we describe for the first time the culture of F-11 neurons with another cell type. This coculture model in which keratinocytes and neurons are maintained in low Ca(2+) concentrations may be a useful in vitro alternative for studying and characterizing the close communication between keratinocytes and sensory neurons. PMID- 22426238 TI - Presynaptic enhancement by eugenol of spontaneous excitatory transmission in rat spinal substantia gelatinosa neurons is mediated by transient receptor potential A1 channels. AB - Eugenol, which is contained in several plants including clove, has been widely used as an analgesic and anti-inflammatory drug in the dental clinic. Eugenol also has anesthetic effects and produces sedation and the reduction of convulsion threshold. These benefits have been partly attributed to the effects of eugenol on neural tissues, such as inhibition of voltage-gated ion channels. As expected from the fact that eugenol is a vanilloid compound, this drug activates transient receptor potential (TRP) V1 channels in the peripheral nervous system (PNS). Although eugenol affects synaptic transmission in the central nervous system (CNS), this has not yet been fully examined. We investigated how eugenol affects spontaneous glutamatergic excitatory transmission in substantia gelatinosa (SG; lamina II of Rexed) neurons of adult rat spinal cord slices by use of the blind whole-cell patch-clamp technique. Bath-applied eugenol reversibly enhanced spontaneous excitatory transmission and produced an outward current at -70 mV in SG neurons. The former action was due to a large increase in the frequency of spontaneous excitatory postsynaptic current (sEPSC) with a small increase in the amplitude. These actions of eugenol were seen by its repeated application and resistant to a voltage-gated Na(+) channel blocker tetrodotoxin. The effect of eugenol on sEPSC frequency was concentration-dependent with an EC(50) value of 3.8 mM and unaffected by a TRPV1 antagonist capsazepine, whereas inhibited by a nonspecific TRP antagonist ruthenium red and a TRPA1 antagonist HC-030031. On the other hand, the eugenol-induced outward current was not affected by these TRP antagonists. It is concluded that eugenol activates TRPA1 channels in the SG, leading to an increase in the spontaneous release of L-glutamate to SG neurons, and that eugenol also produces a membrane hyperpolarization that is not mediated by TRP channels. Eugenol is suggested to activate different types of TRP channel between the PNS and CNS. PMID- 22426239 TI - Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer's disease. AB - Dysregulation in brain-derived neurotrophic factor (BDNF)/full-length TrkB (TrkB TK+) signaling is implicated in promoting neurodegeneration in Alzheimer's disease (AD). BDNF/TrkB-TK+ signaling can be modulated by the presence of truncated TrkB isoforms (TrkB-TK-, TrkB-Shc). All TrkB isoforms are encoded by different alternative transcripts. In this study, we assessed if expression of the three main TrkB alternative transcripts, TrkB-TK+, TrkB-TK-, and TrkB-Shc are altered in AD. Using a cohort of control and AD brains (n=29), we surveyed the hippocampus, temporal cortex, occipital cortex, and cerebellum and found specific increases in TrkB-Shc, a neuron-specific transcript, in the AD hippocampus. No significant changes were detected in TrkB-TK+ and TrkB-TK- transcript levels in AD in any brain region examined. Corresponding changes in truncated TrkB protein levels were found in the hippocampus, although a significant increase in the temporal cortex was also observed. Our findings suggested that neuron-specific changes in TrkB may be occurring in AD; thus, we determined whether TrkB-Shc expression could be modulated by amyloid beta 1-42 (Abeta(42)). We found increased TrkB-Shc mRNA levels in differentiated SHSY5Y neuronal cell-lines exposed to fibril-containing Abeta(42) preparations. When we assessed the cellular impact of increased TrkB-Shc, we found co-localization between TrkB-Shc and TrkB-TK+. Interestingly, TrkB-Shc overexpression selectively attenuated BDNF/TrkB-TK+-mediated signaling via the mitogen-activated protein kinase kinase (MEK) pathway, but not the protein kinase B pathway. In AD, MEK signaling is increased in vulnerable neurons and linked to abnormal phosphorylation of cytoskeletal proteins. Altogether, our findings suggest that elevated TrkB-Shc expression in AD may function as a compensatory response in neurons in AD to promote survival. PMID- 22426240 TI - Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment. AB - Schizophrenia is associated with increased oxidative stress, although the source of this redox disequilibrium requires further study. Altered tryptophan metabolism has been described in schizophrenia, possibly linked to inflammation and glutamate-directed excitotoxicity. Social isolation rearing (SIR) in rats induces various behavioural manifestations akin to schizophrenia, as well as altered frontal cortical glutamate N-methyl-d-aspartate (NMDA) receptor binding and increased oxidative stress, all reversed by antipsychotic treatment. Tryptophan is catabolized via the kynurenine pathway to kynurenine, 3 hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3-hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in post-natal SIR rats, and its response to clozapine treatment. Male Sprague-Dawley (SD) rats (10 rats/group) were exposed to SIR or social rearing for 8 weeks, whereupon they received either sub-chronic vehicle or clozapine (5 mg/kg i.p) treatment. Plasma tryptophan metabolites were analysed by liquid-chromatography electrospray ionization tandem mass spectrometry. Plasma tryptophan, kynurenine, anthranilic acid, 3-OHAA and QA were significantly elevated in SIR vs. socially housed rats. KYNA and the neuroprotective ratio were significantly decreased. The latter implies a decrease in KYNA (neuroprotective) but an increase in QA (neurodegenerative) directed components of the pathway. Clozapine significantly reversed all the above alterations in SIR animals. Concluding, SIR in rats significantly disrupts tryptophan metabolism via the kynurenine pathway with increased risk for neurodegenerative changes in the brain. These changes are reversed by clozapine, emphasising the importance of these findings for the neurobiology and treatment of schizophrenia. PMID- 22426241 TI - A model of prediction and cross-validation of fat-free mass in men with motor complete spinal cord injury. AB - OBJECTIVES: To establish and validate prediction equations by using body weight to predict legs, trunk, and whole-body fat-free mass (FFM) in men with chronic complete spinal cord injury (SCI). DESIGN: Cross-sectional design. SETTING: Research setting in a large medical center. PARTICIPANTS: Individuals with SCI (N=63) divided into prediction (n=42) and cross-validation (n=21) groups. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Whole-body FFM and regional FFM were determined by using dual-energy x-ray absorptiometry. Body weight was measured by using a wheelchair weighing scale after subtracting the weight of the chair. RESULTS: Body weight predicted legs FFM (legs FFM=.09*body weight+6.1; R(2)=.25, standard error of the estimate [SEE]=3.1kg, P<.01), trunk FFM (trunk FFM=.21*body weight+8.6; R(2)=.56, SEE=3.6kg, P<.0001), and whole-body FFM (whole body FFM=.288*body weight+26.3; R(2)=.53, SEE=5.3kg, P<.0001). The whole-body FFM(predicted) (FFM predicted from the derived equations) shared 86% of the variance in whole-body FFM(measured) (FFM measured using dual-energy x-ray absorptiometry scan) (R(2)=.86, SEE=1.8kg, P<.0001), 69% of trunk FFM(measured), and 66% of legs FFM(measured). The trunk FFM(predicted) shared 69% of the variance in trunk FFM(measured) (R(2)=.69, SEE=2.7kg, P<.0001), and legs FFM(predicted) shared 67% of the variance in legs FFM(measured) (R(2)=.67, SEE=2.8kg, P<.0001). Values of FFM did not differ between the prediction and validation groups. CONCLUSIONS: Body weight can be used to predict whole-body FFM and regional FFM. The predicted whole-body FFM improved the prediction of trunk FFM and legs FFM. PMID- 22426242 TI - Validity of the Veterans Health Administration's traumatic brain injury screen. AB - OBJECTIVE: To compare the results of Veterans Affairs' (VA's) initial traumatic brain injury (TBI) Clinical Reminder Screen with the more extensive second-level Comprehensive TBI Evaluation in a national sample. DESIGN: Criterion-standard. SETTING: Veterans Health Administration system of polytrauma care. PARTICIPANTS: The data were from VA's centralized database Patient Care Services on the TBI Clinical Reminder Screen and Comprehensive TBI Evaluation results of veterans (N=48,175). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value, and negative predictive value of the TBI Clinical Reminder Screen were calculated by using the Comprehensive TBI Evaluation findings as the comparative standard for TBI confirmation. RESULTS: The TBI Clinical Reminder Screen has generally good sensitivity (.87-.90) but poor specificity (.13-.18). In addition, the TBI Clinical Reminder Screen, when compared with the Comprehensive TBI Evaluation by a clinician, has generally poor negative predictive power (.31-.49) in this sample. However, negative predictive power is good with an estimated Veterans Health Administration system-wide TBI prevalence rate of 15% (.89). Positive predictive power was acceptable (.77) in this sample. The screen performs comparably across patient demographic and symptom severity characteristics, as well as across level of polytrauma care. Systematic evaluations by clinicians primarily reveal mental health-perceived causes of ongoing symptoms. CONCLUSIONS: In summary, VA's Clinical Reminder Screen, when evaluated against the follow-up Comprehensive TBI Evaluation, has good sensitivity but poor specificity. PMID- 22426243 TI - Methodologies for studying peripheral O2 chemosensing: past, present, and future. AB - The reduction of molecular oxygen in individual cells during the process of oxidative phosphorylation is central to oxidative metabolism and bioenergetic homeostasis. As such, any insufficiency in molecular oxygen availability represents a severe threat to sustained life. Thus, as with other similar multicellular organisms, the human body has evolved various peripheral chemosensory pathways that play a key role in sampling arterial PO2 values and initiating corrective reflex responses so as to maintain homeostasis. Research on these peripheral chemosensors can trace their origins to the cross circulation studies of Corneille Heymans in the early 20th century. Since then, it has become increasingly apparent that defects in these chemosensory pathways play a key role in various pathological conditions, e.g. Sudden Infant Death Syndrome (SIDS), and therefore an understanding of the underlying mechanisms is of critical importance. This review aims to discuss the advantages and disadvantages of the various experimental models employed in studying the mechanisms by which acute peripheral chemosensing occurs. PMID- 22426244 TI - Influence of royal jelly on the reproductive function of puberty male rats. AB - The adverse effects of royal jelly on the reproductive system of puberty male rats were investigated. Royal jelly was daily administered by gavage to Sprague Dawley rats at doses 200, 400, and 800 mg/kg for 4 weeks. The body weight and organ coefficients were determined. Sperm count, spermatozoa abnormality, and testicular histopathology were examined through light microscopy. Radioimmunoassay was used to detect serum hormones. The dietary exposure to royal jelly did not affect body weight, but the organ coefficients for the pituitary and testis in the high-dose group were decreased significantly compared with the control group, and significant changes in the microstructure of the testis were observed. No significant differences in sperm count were observed among all groups, however, the sperm deformity rate in the high-dose group increased significantly. Serum hormones in the high-dose group were significantly different from the control group. After royal jelly was stopped for 14 days, the adverse changes were partially reversed and returned to levels close to those in the control group. In conclusion, high-dose royal jelly oral administration for 4 weeks adversely affected the reproductive system of pubescent male rats, but the unfavorable effects are alleviated to some extent by cessation of administration. PMID- 22426245 TI - A simple route to full structural analysis of biophosphates and their application to materials discovery. AB - An integrated suite of synthesis and characterisation techniques that includes synchrotron-based single crystal, powder X-ray diffraction, nuclear magnetic resonance and electron diffraction have been employed to uncover two new distinct structures in the Ca(x)Ba(2-x)P(2)O(7) polymorphic phosphate system. These materials have particular relevance for their application as both biomaterials and phosphors. Calcium barium pyrophosphate, CaBaP(2)O(7), was shown by a combination of spectroscopic and diffraction techniques to have two polymorphs distinct in structure from all of the five previously reported polymorphs of Ca, Sr and Ba pyrophosphate. A high temperature polymorph HT-CaBaP(2)O(7) prepared at 1200 degrees C is orthorhombic, of space group P(212121) with a = 13.0494 A, b = 8.9677 A, c = 5.5444 A. A low temperature polymorph LT-CaBaP(2)O(7), prepared below 1000 degrees C, is monoclinic with space group P2(1)/c and dimensions a = 12.065 A, b = 10.582 A, c = 9.515 A, beta = 94.609 degrees . PMID- 22426246 TI - Anti-Trypanosoma cruzi and cytotoxic activities of Eugenia uniflora L. AB - Chagas disease is caused by Trypanosoma cruzi, being considered a public health problem. An alternative to combat this pathogen is the use of natural products isolated from fruits such as Eugenia uniflora, a plant used by traditional communities as food and medicine due to its antimicrobial and biological activities. Ethanolic extract from E. uniflora was used to evaluate in vitro anti epimastigote and cytotoxic activity. This is the first record of anti-Trypanosoma activity of E. uniflora, demonstrating that a concentration presenting 50% of activity (EC(50)) was 62.76 MUg/mL. Minimum inhibitory concentration (MIC) was <= 1024 MUg/mL. Our results indicate that E. uniflora could be a source of plant derived natural products with anti-epimastigote activity with low toxicity. PMID- 22426247 TI - A Bayesian adaptive design for multi-dose, randomized, placebo-controlled phase I/II trials. AB - We present a design for a randomized controlled trial (RCT) featuring two simultaneous iterative processes, dose escalation and cohort expansion. In this design, patient enrollment does not need to stop when transitioning from the evaluation of the dose safety and tolerability to the assessment of its efficacy. The cohort expansion used in dose-finding is adaptive, based on the interim comparisons between each dose and placebo. A set of Bayesian rules guides the decisions about dose cohort expansion. Operating characteristics of this design have been evaluated by simulations designed to mimic the trial conduct and outcome in a variety of dose toxicity and efficacy scenarios. Simulation studies demonstrated that our proposed adaptive design can reduce the total sample size as compared to the conventional approach. The sample size reduction was more profound in scenarios when the testing doses are not effective. Simulation studies also demonstrated that this proposed adaptive design controls the false positive error rate at the specified level and provides adequate statistical power to detect the treatment effect. Compared to the conventional approach, our proposed adaptive design removes ineffective doses, reduces the total sample size, and maintains adequate power for dose-finding. The proposed design has been implemented in an ongoing study and software for trial simulation is available at http://odin.mdacc.tmc.edu/~yuanj/soft.html. PMID- 22426248 TI - Characterization of atypical Listeria innocua isolated from swine slaughterhouses and meat markets. AB - Atypical Listeria innocua strains presenting phenotypic characteristics similar to those of Listeria monocytogenes were recently isolated from food and the environment. These isolates also tested positive for virulence genes specific to L. monocytogenes. Here we report the isolation of atypical hemolytic L. innocua strains from the environment of pork processing plants in Brazil. The strains were positive for L. monocytogenes virulence genes hly, inlA and inlB by PCR and presented genotypic similarities with human isolates of L. monocytogenes via the AFLP technique using HindIII single enzyme protocol. Phenotypic and genotypic similarities suggest that these atypical L. innocua may be pathogenic strains. PMID- 22426249 TI - New regulators of biofilm development in Candida glabrata. AB - Biofilm formation plays an important role in fungal pathogenesis. In this work, we used a genetic screen in order to identify and characterize genes involved in the formation of biofilms by the opportunistic fungal pathogen Candida glabrata. We identified the Cst6p transcription factor as a negative regulator of the EPA6 gene that encodes an adhesin central to C. glabrata biofilm formation. Analysis of single and double mutant strains showed that Cst6p acts in a pathway independent of the Yak1/Sir4 pathway also known to regulate expression of EPA6 and consequently biofilm formation. In contrast, we showed that the chromatin remodelling Swi/Snf complex positively regulates biofilm formation in C. glabrata. RT-qPCR experiments demonstrated that EPA6 expression, and thus biofilm formation, depends on the integrity of the Sir complex. Finally, we showed that Swi/Snf-dependent regulation of biofilm formation is adhesin-specific. PMID- 22426250 TI - The efficacy of complex decongestive physiotherapy (CDP) and predictive factors of response to CDP in lower limb lymphedema (LLL) after pelvic cancer treatment. AB - OBJECTIVE: The aim of this study was to estimate the efficacy of an intensive CDP program, as well as to identify the predictors associated with lymphedema severity and response to CDP in lower limb lymphedema (LLL) after pelvic cancer therapy. METHODS: We performed a retrospective review of post-pelvic cancer LLL patients that were treated with a CDP program between January 2004 and March 2011. RESULTS: Twenty-seven (61.4%) of the total 44 patients had cervical cancer, 9 (20.5%) had endometrial cancer, and 8 (18.2%) had ovarian cancer. The mean age was 62.2 years, 18 (40.9%) patients received radiotherapy and a mean of 12.6 sessions of daily CDP, and mean lymphedema duration was 34.8 months. The interval from pelvic cancer treatment to LLL development was 63.4 months. Lymphedema severity, baseline and post-CDP percentage of excess volume (PEV) were 32.9% +/- 18.4% and 18.8%+/- 16.7%. Baseline PEV was not correlated with duration of lymphedema, number of CDP sessions, age or radiotherapy, and was significantly different to post-CDP PEV (p<0.001). CDP efficacy, percentage reduction of excess volume (PREV), was -55.1%, and was correlated with baseline PEV, but not with the number of CDP sessions, duration of lymphedema, or age. PEV (p<0.001) was the only predictive factor for CDP efficacy. CONCLUSIONS: The key to predicting successful lymphedema treatment of LLL is the initial PEV. The intensive CDP program was effective and successful. We should encourage and refer patients to undergo treatment for LLL, even when the LLL is mild. PMID- 22426251 TI - Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer. AB - OBJECTIVE: To identify factors that increase the risk of neutropenic events in women with advanced ovarian carcinoma receiving initial chemotherapy. METHODS: Multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy from 1995 to 2008. Outcomes were severe (SN; absolute neutrophil count [ANC]<500/mm(3)) and febrile neutropenia (FN; ANC<1000/mm(3) and temperature>38.1 degrees C). Cumulative risk of neutropenic events was estimated by Kaplan Meier method. Multivariate analysis was by Cox proportional hazard regression. RESULTS: Three hundred twenty-six patients met inclusion criteria. There were 251 SN events among 140 (43%) patients and 24 FN events among 22 (7%) patients. Univariate predictors of SN were body surface area<2.0m(2) (p=0.03), body mass index (BMI)<30 kg/m(2) (p<0.01), Caucasian race (p<0.01), treatment on research protocols (p<0.01), non-carboplatin-containing regimens (p<0.01), and planned relative dose intensity (RDI)>85% of standard (p=0.02). Women over age 60 were more likely to develop FN (p=0.05). Multivariate predictors of SN were treatment on research protocols (hazard ratio [HR] 1.93; p<0.01), Caucasian race (HR 2.13; p=0.01), and planned RDI>85% (HR 1.69; p=0.05); predictors of FN were age>60 (HR 2.84; p=0.05) and non-carboplatin containing regimens (HR 4.06; p<0.01). CONCLUSION: While SN is fairly common, FN occurs infrequently in women with EOC undergoing taxane and platin-based chemotherapy and primary prophylactic growth factor support is not indicated. However, women older than 60 years of age receiving non-carboplatin containing regimens are at higher risk for FN and warrant closer surveillance. PMID- 22426252 TI - Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury. AB - Neuronal injury elicits potent cellular responses from glia, but molecular pathways modulating glial activation, phagocytic function and termination of reactive responses remain poorly defined. Here we show that positive or negative regulation of glial responses to axon injury is molecularly encoded by unique isoforms of the Drosophila melanogaster engulfment receptor Draper. Draper-I promotes engulfment of axonal debris through an immunoreceptor tyrosine-based activation motif (ITAM). In contrast, Draper-II, an alternative splice variant, potently inhibits glial engulfment function. Draper-II suppresses Draper-I signaling through a previously undescribed immunoreceptor tyrosine-based inhibitory motif (ITIM)-like domain and the tyrosine phosphatase Corkscrew (Csw). Intriguingly, loss of Draper-II-Csw signaling prolongs expression of glial engulfment genes after axotomy and reduces the ability of glia to respond to secondary axotomy. Our work highlights a novel role for Draper-II in inhibiting glial responses to neurodegeneration, and indicates that a balance of opposing Draper-I and Draper-II signaling events is essential to maintain glial sensitivity to brain injury. PMID- 22426253 TI - Netrin (UNC-6) mediates dendritic self-avoidance. AB - Dendrites from a single neuron may be highly branched but typically do not overlap. Self-avoidance behavior has been shown to depend on cell-specific membrane proteins that trigger mutual repulsion. Here we report the unexpected discovery that a diffusible cue, the axon guidance protein UNC-6 (Netrin), is required for self-avoidance of sister dendrites from the PVD nociceptive neuron in Caenorhabditis elegans. We used time-lapse imaging to show that dendrites fail to withdraw upon mutual contact in the absence of UNC-6 signaling. We propose a model in which the UNC-40 (Deleted in Colorectal Cancer; DCC) receptor captures UNC-6 at the tips of growing dendrites for interaction with UNC-5 on the apposing branch to induce mutual repulsion. UNC-40 also responds to dendritic contact through another pathway that is independent of UNC-6. Our findings offer a new model for how an evolutionarily conserved morphogenic cue and its cognate receptors can pattern a fundamental feature of dendritic architecture. PMID- 22426254 TI - Plasticity in gray and white: neuroimaging changes in brain structure during learning. AB - Human brain imaging has identified structural changes in gray and white matter that occur with learning. However, ascribing imaging measures to underlying cellular and molecular events is challenging. Here we review human neuroimaging findings of structural plasticity and then discuss cellular and molecular level changes that could underlie observed imaging effects. Greater dialog between researchers in these different fields would help to facilitate cross-talk between cellular and systems level explanations of how learning sculpts brain structure. PMID- 22426255 TI - Cortical oscillations and speech processing: emerging computational principles and operations. AB - Neuronal oscillations are ubiquitous in the brain and may contribute to cognition in several ways: for example, by segregating information and organizing spike timing. Recent data show that delta, theta and gamma oscillations are specifically engaged by the multi-timescale, quasi-rhythmic properties of speech and can track its dynamics. We argue that they are foundational in speech and language processing, 'packaging' incoming information into units of the appropriate temporal granularity. Such stimulus-brain alignment arguably results from auditory and motor tuning throughout the evolution of speech and language and constitutes a natural model system allowing auditory research to make a unique contribution to the issue of how neural oscillatory activity affects human cognition. PMID- 22426256 TI - Association between the human immune response and body mass index. AB - The aim of this study was to determine the strength of the association between the human immune response and body mass index (BMI) and whether differences exist in the effects of obesity on selected immune parameters between men and women. Two hundred ninety participants were divided into groups according to sex and BMI. Parameters CD3, CD4, CD8, CD16+56, CD19, HLADR, CD11b, CD11c, and CD54 were quantified. Leukocyte and differential counts were performed. We observed elevation with regard to the normal weight group in the parameters of white blood cells, neutrophils, monocytes, CD3, CD4, CD19, and CD11b for the whole study group. A decrease was observed in the expression of CD16+56. The effect of BMI on the immune system was much more apparent in women. BMI was correlated with the majority of the measured parameters, reflecting a strong association between BMI and the human immune system. PMID- 22426257 TI - The role of BCL11B in regulating the proliferation of human naive T cells. AB - The effect of the B-cell chronic lymphocytic leukemia/lymphoma 11B gene (BCL11B) on human T-cell regulation remains unclear. To characterize the functions of BCL11B, recombinant BCL11B and BCL11B siRNA were transfected into human naive T cells to overexpress or knock down BCL11B expression, respectively. After BCL11B overexpression, the proliferation ability and the T-helper (Th) subset were increased, whereas no significant alteration in the expression pattern and clonality of the T-cell receptor Vbeta subfamilies was observed. After BCL11B knockdown, a similar distribution of Vbeta subfamilies was detected in the naive T cells; however, the proliferation capacity substantially decreased. Global gene expression profiling revealed that the dysregulated genes were mainly involved in T-cell activation and proliferation. BCL11B could selectively promote Th-cell differentiation because of increased CXCL10 and CXCL11 expression. BCL11B suppression may inhibit proliferation and induce apoptosis, which may relate to changes in the expression of CFLAR-CASP8-CASP10 in the mitochondrial pathways. In conclusion, BCL11B is required for T-cell survival; its overexpression could effectively increase the T-cell activation and proliferation abilities and Th cell differentiation as well. PMID- 22426258 TI - Measures of outcome in rectal cancer surgery: a work in progress. PMID- 22426259 TI - Pretreatment high-resolution rectal MRI and treatment response to neoadjuvant chemoradiation. AB - BACKGROUND: Use of rectal MRI evaluation of patients with rectal cancer for primary tumor staging and for identification for poor prognostic features is increasing. MR imaging permits precise delineation of tumor anatomy and assessment of mesorectal tumor penetration and radial margin risk. OBJECTIVE: The aim of this study was to evaluate the ability of pretreatment rectal MRI to classify tumor response to neoadjuvant chemoradiation. DESIGN: This study is a retrospective, consecutive cohort study and central review. SETTING: This study was conducted at a tertiary academic hospital. PATIENTS: Sixty-two consecutive patients with locally advanced (stage cII to cIII) rectal cancer who underwent rectal cancer protocol high-resolution MRI before surgery (December 2009 to March 2011) were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the probability of good (ypT0-2N0) vs poor (>=ypT3N0) response as a function of mesorectal tumor depth, lymph node status, extramural vascular invasion, and grade assessed by uni- and multivariate logistic regression. RESULTS: Tumor response was good in 25 (40.3%) and poor in 37 (59.7%). Median interval from MRI to surgery was 7.9 weeks (interquartile range, 7.0-9.0). MRI tumor depth was <1 mm in 10 (16.9%), 1 to 5 mm in 30 (50.8%), and >5 mm in 21 (33.9%). Lymph node status was positive in 40 (61.5%), and vascular invasion was present in 16 (25.8%). Tumor response was associated with MRI tumor depth (p = 0.001), MRI lymph node status (p < 0.001) and vascular invasion (p = 0.009). Multivariate regression indicated >5 mm MRI tumor depth (OR = 0.08; 95% CI = 0.01-0.93; p = 0.04) and MRI lymph node positivity (OR = 0.12; 95% CI = 0.03-0.53; p = 0.005) were less likely to achieve a good response to neoadjuvant chemoradiotherapy. LIMITATIONS: Generalizability is uncertain in centers with limited experience with MRI staging for rectal cancer. CONCLUSION: MRI assessment of tumor depth and lymph node status in rectal cancer is associated to tumor response to neoadjuvant chemoradiotherapy. These factors should therefore be considered for stratification of patients for novel treatment strategies reliant on pathologic response to treatment or for the selection of poor-risk patients for intensified treatment regimens. PMID- 22426260 TI - FDG-PET assessment of rectal cancer response to neoadjuvant chemoradiotherapy is not associated with long-term prognosis: a prospective evaluation. AB - BACKGROUND: At present there is no defined role for routine FDG-PET in the preoperative evaluation of nonmetastatic rectal cancer. OBJECTIVE: The primary objective of this study was to evaluate the ability of FDG-PET to predict long term prognosis based on the response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. DESIGN: This was a prospective study. SETTINGS: This study was performed at an academic, tertiary care, comprehensive cancer center. PATIENTS: One hundred twenty-seven patients with locally advanced rectal cancer were enrolled between September 1999 and December 2005. INTERVENTIONS: All patients underwent FDG-PET scans before and after neoadjuvant chemoradiotherapy. MAIN OUTCOME MEASURES: FDG-PET parameters were evaluated by at least 2 study board-certified nuclear medicine physicians, and included mean standard uptake value, maximum standard uptake value, total lesion glycolysis, and visual response score. The main outcome measures were time to recurrence and disease-specific survival. RESULTS: Of 127 patients, 82 (65%) were men, the median age was 60 years (range, 27-82), 110 patients had stage II/III disease, and 17 patients had stage IV disease. Median follow-up among survivors was 77 months (range, 1-115 months). Nine patients had unresectable metastatic disease and were excluded from the time-to-recurrence analysis. At 5 years, 74% (95% CI = 66%-81%) of patients had not had recurrences (locally and/or distantly). The 5 year disease-specific survival was 89% (95% CI = 81%-93%). On univariate analysis, visual response score and time to recurrence came closest to having an association (HR = 0.83, 95% CI = 0.68-1.01, p = 0.06). On multivariate analysis, the visual response score was not significant (p = 0.85). No FDG-PET parameter was associated with disease-specific survival. CONCLUSIONS: Assessment of rectal cancer response to neoadjuvant chemoradiotherapy by FDG-PET provides no prognostic information. Therefore, serial FDG-PET before and after neoadjuvant chemoradiotherapy should not be performed for this purpose. PMID- 22426261 TI - Pelvic sepsis after IPAA adversely affects function of the pouch and quality of life. AB - BACKGROUND: Pelvic sepsis after IPAA predisposes to pouch failure. There are limited data on long-term pouch function for patients with pelvic sepsis. OBJECTIVE: The aim of this study was to investigate functional outcomes and quality of life for patients undergoing IPAA who develop pelvic sepsis and preserve their pouch long-term. DESIGN: This study is based on retrospective analysis of prospectively accrued data. SETTINGS: This study was conducted at a single-center institution. PATIENTS: All patients undergoing IPAA from 1983 to 2007 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were functional outcomes (urgency, incontinence, bowel movements) and quality-of-life (restrictions, energy, happiness) parameters. RESULTS: Two hundred (6.2%) of 3234 patients developed pelvic septic complications within 3 months of IPAA. In the comparison of complications at the time of IPAA for the 2 groups, patients with pelvic sepsis had higher rates of postoperative hemorrhage (13.5% vs 3.7%, p < 0.001), anastomotic leak (35% vs 3.7%, p < 0.001), wound infection (14% vs 7.4%, p < 0.001), and fistula formation (37% vs 7.1%, p < 0.001). The overall median follow-up was 7 years. Pelvic sepsis was associated with greater pouch failure (19.5% vs 4%, p < 0.001). For patients with follow-up (pelvic sepsis = 144, nonpelvic sepsis = 2677) with a retained pouch, for whom we compared functional outcomes and quality of life, incontinence was worse (never/rare: 69.5% vs 77.8%, p = 0.03). Urgency scores were lower in pelvic sepsis but not statistically significant. The overall Cleveland Global Quality of Life score (and components) in the sepsis group were significantly worse than in the nonsepsis group (0.74 vs 0.79, p < 0.001). Patients who developed sepsis were also less likely to recommend IPAA to others than patients who did not develop pelvic sepsis. LIMITATIONS: This study was limited by the retrospective analysis and the use of questionnaires. CONCLUSIONS: Pelvic sepsis after IPAA leads to worse functional outcomes and quality of life even when it does not lead to pouch failure. This finding argues for careful attention to preoperative and intraoperative planning and strategies aimed at reducing this complication after IPAA. PMID- 22426262 TI - Prognostic modeling of preoperative risk factors of pouch failure. AB - BACKGROUND: The prospect of pouch failure needs to be considered when evaluating the management strategy for patients who may be candidates for an ileo anal pouch. An ability to predict the likelihood and timing of failure preoperatively may influence surgical decision making. OBJECTIVE: The aim of this study was to define a preoperative prognostic model for ileoanal pouch failure. DESIGN: A novel random forest methodology was used to evaluate the prognostic significance of 21 preoperative potential risk factors for pouch failure. A forest of 3000 random survival trees was grown to estimate pouch failure for each patient and to identify important risk factors that maximize survival prediction. SETTINGS: This study took place at a tertiary referral department at a major academic medical center. PATIENTS: Patients undergoing an ileoanal pouch at this institution between 1983 and 2008 were included. MAIN OUTCOME MEASURES: The primary outcome measured was pouch survival. RESULTS: Between 1983 and 2008, 3754 patients underwent ileoanal pouch. Type of resection (total proctocolectomy vs completion proctectomy), type of anastomosis (stapled vs mucosectomy), patient diagnosis (mucosal ulcerative colitis and others vs Crohn's disease) and diagnosis of diabetes had the strongest effect on pouch survival. Predicted survival was worse for completion proctectomy (HR, 1.44; 95% CI, 1.08-1.93), Crohn's disease (HR, 2.37; 95% CI, 1.48-3.79), handsewn anastomosis (HR, 1.72; 95% CI, 1.23-2.42), and diabetes (HR, 2.31; 95% CI, 1.25-4.24). Pouch survival was worse for the oldest group of patients. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSION: Random forest techniques applied to a large number of patients undergoing the ileoanal pouch identify factors associated with pouch failure. Attention directed at these factors may improve outcomes for these patients. PMID- 22426263 TI - Comparative quality of life in patients following abdominoperineal excision and low anterior resection for low rectal cancer. AB - BACKGROUND: It is widely believed that quality of life is worse after abdominoperineal excision then after low anterior resection. However, this view is not supported unequivocally. OBJECTIVE: The aim of this study was to compare quality of life in patients 1 year following low anterior resection and abdominoperineal excision for low rectal cancer. DESIGN: Data were collected prospectively on 62 patients undergoing low anterior resection (32) and abdominoperineal excision (30) for low rectal adenocarcinoma within 6 cm of the anal verge. Patients with metastatic disease were excluded. Quality of life was assessed by the use of the European Organization for Research and Treatment of Cancer's QLQ-C30 and QLQ-CR38 modules and Coloplast stoma quality-of-life questionnaire. Bowel function was assessed by using the St Mark's bowel function questionnaire. Quality of life in patients who had low anterior resection was compared with those who had abdominoperineal excision both preoperatively and 1 year after surgery. SETTINGS: This study was conducted at 3 centers in the United Kingdom and 1 center in Europe. PATIENTS: Included were consecutive patients with rectal cancer within 6 cm of the anal verge, all of whom provided written consent for participation. MAIN OUTCOME MEASURES: Mann-Whitney U test comparisons of QLQ C30 and QLQ-CR38 module scores for patients undergoing low anterior resection and abdominoperineal excision were the main outcomes measured. RESULTS: Patients undergoing low anterior resection were younger (median age, 59.5 vs 67, p = 0.03) with higher tumors (4 vs 3, p < 0.001) and less likely to receive neoadjuvant therapy (p = 0.02). At 1 year postoperatively, global quality-of-life ratings were comparable, but patients undergoing abdominoperineal excision reported better cognitive (100 vs 83, p = 0.018) and social (100 vs 67, p = 0.012) function, and less symptomatology with respect to pain (0 vs 17, p = 0.027), sleep disturbance (0 vs 33, p = 0.013), diarrhea (0 vs 33, p = 0.017), and constipation (p = 0.021). Patients undergoing low anterior resection reported better sexual function (33 vs 0, p = 0.006), but 72% experienced a degree of fecal incontinence. LIMITATIONS: This study was limited by its relatively small sample size. CONCLUSION: Abdominoperineal excision should not be regarded as an operation that is inferior to low anterior resection in the management of low rectal cancer on the basis of quality of life alone. PMID- 22426264 TI - Early postoperative intraperitoneal chemotherapy following cytoreductive surgery for appendiceal mucinous neoplasms with isolated peritoneal metastasis. AB - BACKGROUND: Although cytoreductive surgery and intraperitoneal chemotherapy have been advocated as standard treatment for appendiceal neoplasms with isolated peritoneal metastasis, the optimal method of chemotherapy administration has not been established. At our institution, patients undergoing complete cytoreduction in this setting typically receive multiple cycles of early postoperative intraperitoneal chemotherapy. OBJECTIVES: The aim of this study was to describe patients with appendiceal neoplasms and peritoneal dissemination treated with complete cytoreductive surgery and early postoperative intraperitoneal chemotherapy and to document associated time to progression and morbidity. DESIGN: This is a retrospective study at a single specialty institution. Hospital and departmental databases were searched for patients presenting with primary appendiceal neoplasms undergoing cytoreductive surgery, placement of intraperitoneal port, and subsequent intraperitoneal chemotherapy from June 1995 to September 2009. SETTINGS: This study was conducted at Memorial Sloan-Kettering Cancer Center. PATIENTS: We identified 50 patients (30 female), median age 48 (range, 26-66) who met the criteria. INTERVENTIONS: Cytoreductive surgery, placement intraperitoneal port, and intraperitoneal chemotherapy were performed. RESULTS: All patients underwent intraperitoneal catheter placement after complete cytoreductive surgery, followed by a median of 4 cycles (range, 1-9) intraperitoneal 5-fluoro-2'-deoxyuridine (1000 mg/m daily for 3 days) plus leucovorin (240 mg/m). The median hospital length of stay was 9 days (maximum, 29). Thirty-four percent of the patients experienced complications; 12% experienced major complications (3 abdominal abscesses, 1 deep vein thrombosis, 1 abdominal hemorrhage, and 1 intraperitoneal port malfunction). There were no 30 day mortalities. Five-year recurrence-free interval was observed in 43%. Among 23 patients with recurrence, 18 had a recurrence only within the peritoneum. The median overall survival was 9.8 years. LIMITATIONS: This is a retrospective study. Many patients had surgery first at other institutions; therefore, pathologic examination of resected material was not possible in every case. Other factors possibly impacting time to recurrence (ie, preoperative chemotherapy, duration between onset of disease and presentation to our institution) varied among patients and were not controlled for. In the absence of a control arm undergoing complete cytoreduction without early postoperative intraperitoneal chemotherapy, we did not ascertain whether intraperitoneal chemotherapy confers additional benefit. CONCLUSIONS: Cytoreductive surgery plus multiple cycles of early postoperative intraperitoneal chemotherapy is safe, achieving survival results similar to published outcomes of other protocols (including hyperthermic intraperitoneal chemotherapy). Prospective trials are warranted to compare various methods of intraperitoneal chemotherapy in this setting. PMID- 22426265 TI - Criteria to determine readiness for hospital discharge following colorectal surgery: an international consensus using the Delphi technique. AB - BACKGROUND: Standardized discharge criteria are considered valuable to reduce the risk of premature discharge and avoid unnecessary hospital stays. The most appropriate criteria to indicate readiness for discharge after colorectal surgery are unknown. OBJECTIVE: The aim of this study is to achieve an international consensus on hospital discharge criteria for patients undergoing colorectal surgery. DESIGN: Fifteen experts from different countries participated in a 3 round Delphi process. In round 1, experts determined which criteria best indicate readiness for discharge and described specific end points for each criterion. In rounds 2 and 3, experts rated their agreement with the use of a 5-point Likert scale. MAIN OUTCOME MEASURES: Consensus was defined when criteria and end points were rated as agree or strongly agree by at least 75% of the experts in round 3. RESULTS: Experts reached consensus that patients should be considered ready for hospital discharge when there is tolerance of oral intake, recovery of lower gastrointestinal function, adequate pain control with oral analgesia, ability to mobilize and self-care, and no evidence of complications or untreated medical problems. Specific end points were defined for each of the criteria. Experts also agreed that after these criteria are achieved, discharge may take place as soon as the patient has adequate postdischarge support and is willing to leave the hospital. If a stoma was constructed, the patient or the patient's family should have received training on stoma care or had outpatient training arranged. LIMITATIONS: The panel comprised mostly experts from developed countries. This may restrict the applicability of these discharge criteria in countries where there are dissimilar health care resources. CONCLUSION: This Delphi study has provided substantial consensus on discharge criteria for patients undergoing colorectal surgery. We recommend that these criteria be used in clinical practice to guide decisions regarding patient discharge and applied in future research to increase the comparability of study results. PMID- 22426266 TI - Clostridium difficile of the ileum following total abdominal colectomy, with or without proctectomy: who is at risk? AB - BACKGROUND: Clostridium difficile enteritis is considered a rare entity, although recent data suggest a significant increase in prevalence and incidence. There is paucity of data evaluating risk factors of C difficile enteritis following total colectomy. OBJECTIVE: The aim of this study was to determine the incidence and risk factors of C difficile enteritis for patients who had undergone total abdominal colectomy with or without proctectomy. DESIGN: This study involves a retrospective chart review of 310 patients. Univariate analysis was performed on potential risk factors (p <= 0.05) with the use of a logistic regression model, and a Fisher exact test was used for variables that had no occurrences of C difficile. These groups of variables were then examined in a multiple variate setting with stepwise logistic regression analysis. SETTINGS: This study was conducted at a tertiary referral center. PATIENTS: A data analysis was performed on patients who had undergone total abdominal colectomy with or without proctectomy who were tested for C difficile of the ileum. RESULTS: Twenty-two of 137 patients that were tested (16%) were positive for C difficile of the ileum. Univariate analysis of known risk factors for C difficile demonstrated that black race was a protective factor against C difficile (p = 0.016). The multivariate analysis demonstrated that emergency surgery (p = 0.035), race (p = 0.003), and increasing age by decade (p = 0.033) were risk factors for C difficile. LIMITATIONS: This study was limited by the small patient sample, and it was not a randomized trial. CONCLUSIONS: Black race is protective, and whites are 4 times more likely to acquire C difficile of the ileum after undergoing a total abdominal colectomy with or without proctectomy. The data also demonstrated that an increased age by a decade and emergency surgery are risk factors for C difficile enteritis, whereas the described risk factors of C difficile of the colon and type of colon surgery do not appear to influence the risk of C difficile of the ileum. PMID- 22426267 TI - Obesity and laparoscopic colectomy: outcomes from the ACS-NSQIP database. AB - BACKGROUND: Previous reports comparing outcomes of laparoscopic colectomy in obese vs nonobese patients from small, single-institution series have included few obese patients and have shown variable results, some suggesting that obesity has no impact on outcomes. OBJECTIVE: We aimed to determine whether any intraoperative or short-term postoperative outcome of laparoscopic colectomy is affected by obesity, independent of other variables. DESIGN: We performed a retrospective study comparing outcomes of patients undergoing laparoscopic colectomy grouped by BMI. PATIENTS: We queried American College of Surgeons National Surgical Quality Improvement Program Participant Use Data Files for patients undergoing nonemergent, laparoscopic colectomy from 2005 through 2008. Cases with a secondary procedure (with the exception of laparoscopic lysis of adhesions, rigid proctosigmoidoscopy, or laparoscopic splenic flexure takedown) were excluded. MAIN OUTCOME MEASURES: We analyzed operative time, length of stay, transfusion requirement, reoperation within 30 days, wound complications, pulmonary complications, sepsis/septic shock, deep venous thrombosis, renal failure/insufficiency, and death. We tested for differences in outcomes using chi tests or analyses of variance, and when differences between BMI classes were found, we performed multivariable regression to adjust for preoperative and intraoperative variables. RESULTS: In an analysis of 9693 patients (30% with BMI >=30), significant differences were found among BMI classes for length of stay, operative time, and wound complication. Operative time correlated with BMI class independent of other variables; length of stay did not. After adjustment of all available variables, obesity remained an independent risk factor for wound complication, and the odds ratios increased with increasing obesity class. LIMITATIONS: Retrospective design and standardized outcome measures prevent examination of procedure-specific outcomes; therefore, this is not an intention to-treat analysis. CONCLUSIONS: These data confirm that, in patients undergoing laparoscopic colectomy, obesity is an independent risk factor for wound complications. Although obesity also increases operative time, the effect of obesity on wound complications remains after adjustment for this and other risk factors. PMID- 22426268 TI - Quality of life and functional outcome for individuals who underwent very early colectomy for familial adenomatous polyposis. AB - BACKGROUND: The major manifestation of familial adenomatous polyposis is colorectal adenomas, which, if untreated, lead to colorectal cancer. The impact of IPAA on quality of life in adolescents with familial adenomatous polyposis is favorable. There is a group of children who develop polyps at a younger age requiring earlier colectomy. Little is known about this very young subgroup in relation to bowel function or quality of life. OBJECTIVE: The aim of this study was to investigate the outcome in patients with familial adenomatous polyposis who had colectomy at <=14 years. DESIGN: A cross-sectional quantitative survey was designed to assess outcome. Standardized validated instruments included bowel/psychosocial functioning and quality of life. RESULTS: Among 1337 patients with familial adenomatous polyposis from 409 kindreds, 4% (n = 59) of patients underwent colectomy at <=14 years of age. Response rate was 84% (n = 32). The mean age at colectomy was 12 years (SD 2), with a current mean age of 24 years (SD 8.5). Fifty-seven percent of patients reported continence. Of the 43% reporting daytime or nighttime incontinence, the majority are <18 years (86%). Younger participants (currently less than 18 years of age) report more restrictions. Mental health is significantly lower among participants with incontinence. They report higher depression and anxiety symptoms, higher levels of intrusion and avoidance, and inferior mental health. The percentage of those worrying about risk of cancer is significantly higher in the younger group (71% vs 24%). Most patients (n = 24, 75%) have had surveillance endoscopy within the past 2 years. LIMITATIONS: This study is limited by study generalizability, selection bias, and small sample size. CONCLUSIONS: Twelve years after colectomy more than half of the patients have favorable bowel function. The rate of incontinence is high, especially among younger patients who have had a shorter time since surgery. Patients with incontinence reported lower psychosocial functioning, are very concerned about their cancer risk, and experience greater distress. This subgroup would benefit from added psychological interventions to enhance coping with familial adenomatous polyposis and surgery. PMID- 22426269 TI - Colonic volvulus: presentation and management in metropolitan Minnesota, United States. AB - BACKGROUND: Management approaches for colonic volvulus are infrequently described in the literature in the United States, and many studies only report operative cases. OBJECTIVE: The aim of this study was to define the demographics, diagnostic and treatment approaches, and outcomes for patients with this disorder in the United States. DESIGN: This study is a retrospective review. SETTINGS: The study was conducted at a 7-hospital health system. PATIENTS: All patients diagnosed with colonic volvulus by International Classification of Diseases, Ninth Revision code were included. MAIN OUTCOME MEASURES: The primary outcomes measured were recurrence, complications, and mortality. RESULTS: One hundred three cases of volvulus (50 sigmoid, 53 cecal) were identified in 92 patients. Compared with cecal volvulus, sigmoid volvulus was more common in men, patients with neurologic diagnoses, and residents of skilled nursing home. Eighty-five percent of the cases presented were acutely obstructed. The diagnosis was established by abdominal x-ray (17%), contrast enema study (27%), CT scan (35%), or laparotomy (17%). Abdominal x-rays were insufficient for definitive diagnosis in 85% of cecal and 49% of sigmoid cases (p = 0.002). All patients with cecal volvulus were treated surgically. Seventy-nine percent of patients with sigmoid volvulus underwent successful nonoperative reduction, of whom 38% had subsequent surgery. Fifty-eight percent of patients with sigmoid volvulus were treated operatively. Resection with primary anastomosis was chosen in most cases (78%). Resection with end ostomy (10%), reduction and pexy (7%), and reduction alone (4%) were other approaches. The mortality rate was 5% (cecal 0%, sigmoid 10%; p = 0.012). There were no readmissions for recurrent cecal volvulus. Nonoperative treatment for sigmoid volvulus often failed (48%). Complication rates were higher in sigmoid volvulus cases (cecal 17%, sigmoid 34%; p = 0.047). LIMITATIONS: This study was limited by its retrospective, nonexperimental design. CONCLUSIONS: Although incidences of cecal and sigmoid volvulus are similar in the present series, sigmoid volvuli are more common in men, individuals with neurologic disease, and residents of nursing homes. Plain radiograph is insufficient to confirm cecal volvulus. The diagnosis is most often made with CT scans. The nonoperative management of sigmoid volvulus is associated with a high recurrence rate. PMID- 22426270 TI - Complications after rectal prolapse surgery: does approach matter? AB - BACKGROUND: Data comparing surgical outcomes following abdominal and transperineal approaches for rectal prolapse are limited. OBJECTIVE: We sought to identify differences in postoperative complications following abdominal vs transperineal approaches to rectal prolapse. DESIGN: We studied a retrospective cohort in the American College of Surgeon's National Surgical Quality Improvement Program from January 2005 through December 2008. PATIENTS: We identified all patients who underwent surgical treatment for rectal prolapse. INTERVENTION: We compared surgical outcomes of standard abdominal approaches compared with standard transperineal approaches to rectal prolapse. MAIN OUTCOME MEASURES: The primary outcomes measured were the validated morbidity outcomes and 30-day mortality. RESULTS: During the study period, 1485 patients underwent rectal prolapse surgery (706 abdominal and 779 transperineal). Patients treated with abdominal approaches had significantly higher rates of infectious (9.8% vs 3.7%) and overall (12.9% vs 7.6%) complications in comparison with those treated with transperineal approaches. On multivariate analysis, risk factors for overall complications were ASA class 4 (OR 6.4) and abdominal surgery (OR 2.3), whereas an albumin level of >= 2.5 was protective (OR 0.05). Significant predictors of infectious complications were ASA class 4 (OR 7.5), BMI >25 (OR 1.8), and rectal prolapse surgery performed with an abdominal approach (OR 2.8). LIMITATIONS: The retrospective design introduces potential selection bias. CONCLUSIONS: Abdominal surgery for rectal prolapse is a predictor of both infectious and overall complications. Patients with significant comorbidities or a high BMI are at particularly high risk for complications and may be better suited for a transperineal rather than abdominal approach for the treatment of rectal prolapse. PMID- 22426271 TI - Factors influencing oncological outcomes in patients who develop pulmonary metastases after curative resection of colorectal cancer. AB - BACKGROUND: The prognostic factors after pulmonary resection in patients with colorectal pulmonary metastases remain controversial. OBJECTIVE: The study aimed to identify the predicting factors for oncological outcomes after curative resection in patients with colorectal cancer and pulmonary metastases. DESIGN: This study is a retrospective review of prospectively collected data. SETTING: This study was conducted at a tertiary care hospital/referral center in South Korea. PATIENTS: Between January 2000 and June 2010, 105 patients who developed pulmonary metastases after curative resection for colorectal cancer were enrolled. Forty-eight patients underwent pulmonary resection, and the remaining 58 were given chemotherapy and/or best supportive care. MAIN OUTCOME MEASURES: The primary outcomes measured were the predictive factors of survival and recurrence. RESULTS: During the 35.9-month median follow-up period, 3- and 5-year overall survival rates were 54.6% and 30.4%. On multivariate analysis, absence of adjuvant chemotherapy after pulmonary metastases (p = 0.003), presence of extrapulmonary metastases (p = 0.001), elevated prelaparotomy serum CEA level (p = 0.015), and absence of pulmonary resection (p = 0.048) were independent prognostic factors for poor overall survival. In patients who underwent pulmonary resection, the 3-year pulmonary recurrence-free survival rate was 78.3%. On multivariate analysis, elevated prelaparotomy serum CEA level (p = 0.018) and disease-free interval <= 12 months (p = 0.008) were independent risk factors associated with pulmonary re-recurrence after pulmonary resection. LIMITATIONS: This study took place at a single institution and had a small sample size. CONCLUSION: Although we admit, to some degree, the benefits of the selection mechanism, pulmonary metastasectomy from colorectal cancer may improve survival after curative resection of colorectal cancer. Adjuvant chemotherapy, extrapulmonary metastases, and prelaparotomy CEA value are independent prognostic factors for overall survival. Prelaparotomy serum CEA level may be an especially reliable predictor of both overall survival and recurrence-free survival after pulmonary metastasectomy in patients who undergo curative resection for colorectal cancer. PMID- 22426272 TI - Short-term effects of neoadjuvant chemoradiotherapy on internal anal sphincter function: a human in vitro study. AB - BACKGROUND: Neoadjuvant chemoradiotherapy is recommended in the treatment of locally advanced rectal cancer. Studies have suggested that chemoradiotherapy adversely affects anorectal function. However, the functional implication and the underlying neuromyogenic changes involved in radiation-induced damage are poorly understood. OBJECTIVE: This study evaluated the functional changes following chemoradiotherapy on the internal anal sphincter. DESIGN AND PATIENTS: This article describes an in vitro study on the internal anal sphincter collected from patients undergoing abdominoperineal resection or proctectomy. Five patients were treated by surgery alone (control group), and 6 received preoperative chemoradiotherapy (treatment group). Sphincter strips were mounted in organ bath, and the responses to electrical field stimulation and drugs were monitored. SETTINGS: The study was performed at the University of Oxford. MAIN OUTCOME MEASURES: The end points of this study were to investigate whether chemoradiotherapy has any significant effects on internal anal sphincter function and, subsequently, to establish the type of injury induced. RESULTS: Chemoradiotherapy strips developed similar tone, but significantly lower spontaneous activity (p = 0.001) than controls. Electrical field stimulation induced relaxation, followed by contraction. At 50 Hz, electrical field stimulation produced 25.6 +/- 4.9% (mean +/- SE) of maximum relaxation followed by a contraction of 5.5 +/- 0.9% of basal tone in chemoradiotherapy strips i9n comparison with 47.0 +/- 6.2% (p = 0.009) and 17.7 +/- 4.0% (p = 0.007) in controls. Relaxation was significantly attenuated by N-nitro-L-arginine. Significant differences were found in responses to carbachol (p = 0.018) and phenylephrine (p = 0.022), but not to sodium nitroprusside. LIMITATIONS: This work was limited by the relatively small number of patients enrolled, because of the difficulty of finding human tissue for laboratory studies, and the lack of long-term results. CONCLUSIONS: Chemoradiotherapy significantly impairs internal anal sphincter function and intrinsic nerves seem more susceptible than smooth muscle. The exclusion of anal canal from the radiation field is recommended, when oncologically safe. PMID- 22426273 TI - Internal anal sphincter parasympathetic-nitrergic and sympathetic-adrenergic innervation: a 3-dimensional morphological and functional analysis. AB - BACKGROUND: Little detailed information is available concerning morphological and functional autonomic nerve supply to the internal anal sphincter. However, denervation of the sphincter potentially affects anal function after rectal surgery for cancer. OBJECTIVE: The aim of this study was to identify the location and type (nitrergic, adrenergic, and cholinergic) of nerve fibers in the internal anal sphincter and to provide a 3-dimensional representation of their structural relationship in the human fetus. MATERIALS AND METHODS: serial transverse sections were obtained from 14 human fetuses (7 male, 7 female, 15-31 weeks of gestation) and were studied histologically and immunohistochemically; digitized serial sections were used to construct a 3-dimensional representation of the pelvis. MAIN OUTCOMES MEASURES: The location and type of internal anal sphincter nerves were assessed qualitatively. RESULTS: Posteroinferior fibers originating from the inferior hypogastric plexus posteroinferior angle projected to the posterolateral and posterior rectal wall and internal anal sphincter, forming the inferior rectal plexus. The inferior rectal plexus contained vesicular acetylcholine transporter-positive (cholinergic), tyrosine hydroxylase-positive (adrenergic/sympathetic), and neural nitric oxide synthase-positive (nitrergic) fibers. The intrasphincteric vesicular acetylcholine transporter-positive fibers included both neural nitric oxide synthase-negative fibers and neural nitric oxide synthase-positive fibers (nitrergic-parasympathetic). LIMITATIONS: The study focused on topographic and functional anatomy, so that quantitative data were not obtained. A small number of fetal specimens were available. CONCLUSIONS: We report the precise location and distribution of the autonomic neural supply to the internal anal sphincter. This description contributes to the understanding of neurogenic postoperative sphincteric dysfunction. Three-dimensional cartography of pelvic-perineal neurotransmitters provides an anatomical and physiological basis for the selection and development of pharmacological agents to be used in the treatment of primary or postoperative continence and evacuation disorders. PMID- 22426274 TI - Long-term outcomes of anal sphincter repair for fecal incontinence: a systematic review. AB - BACKGROUND: Thorough and objective analysis of long-term results following anal sphincter repair for fecal incontinence will permit the correct application of this operation in the context of newer treatment methods. OBJECTIVE: This investigation aimed to comprehensively review outcomes beyond 5 years in patients undergoing anal sphincter repair for fecal incontinence. DATA SOURCES: A systematic review of Embase and MEDLINE articles published between January 1991 and December 2010 was conducted; additional studies were identified by hand searching bibliographies. STUDY SELECTION: A 2-step process was used for screening articles examining sphincter repair or sphincteroplasty in adults with fecal incontinence, with a minimum follow-up of 60 months. MAIN OUTCOME MEASURES: Subjective or objective assessment of fecal incontinence in the postoperative period was completed. RESULTS: Data from 16 studies were examined, comprising nearly 900 repairs. There was significant heterogeneity in outcome measures, although most articles utilized at least one established incontinence instrument. In general, most series reported an initial subjectively "good" outcome in the majority of patients, with declines in this proportion over longer follow-up. There was poor correlation between quality of life and the severity of fecal incontinence, with all articles reporting high overall patient satisfaction even if continence declined with time or adaptive measures were needed. No consistent predictive factors for failure were identified. LIMITATIONS: This study was limited by the paucity of level I data with an adequate length of follow-up. CONCLUSION: Despite worsening results over time, most patients remain satisfied with their surgical outcome postsphincteroplasty. Efforts should be directed at identifying patients who may do poorly following sphincter repair, as well as establishing standardized long-term outcome benchmarks for comparing novel techniques for treating fecal incontinence. PMID- 22426275 TI - Pilonidal disease: time to reevaluate a common pain in the rear! PMID- 22426276 TI - Canadian Association of General Surgeons, the American College of Surgeons, the Canadian Society of Colorectal Surgeons, and the American Society of Colon and Rectal Surgeons: evidence based reviews in surgery - colorectal surgery. PMID- 22426277 TI - Randomized trial of the hemorrhoid laser procedure vs rubber band ligation: 6 month follow-up. PMID- 22426279 TI - Self-assessment quiz: answers, critiques, and references. Diverticulitis. PMID- 22426282 TI - Non-synonymous variants in pre-B cell leukemia homeobox (PBX) genes are associated with congenital heart defects. AB - Congenital cardiac malformations are one of the most common birth defects and most are believed to be multigenic/multifactorial in nature. Recently mice lacking Pre-B cell leukemia transcription homeobox (PBX) genes were created and found to have a range of ventricular outflow tract (OFT) malformations. Therefore, we screened 95 patients with congenital heart defects, including OFT malformations, for variants in genes encoding PBX proteins, as well as interacting proteins. The coding exons of PBX1-4, PKNOX1, PKNOX2, MEIS1-3, and PBXIP1 were amplified by polymerase chain reaction and the products analyzed on a lightscanner. Samples with abnormal melting profiles were analyzed by DNA sequencing. Seven non-synonymous variants (6 novel and 1 SNP) were identified in 5 proteins (Pbx3, Pbx4, Meis1, Meis3 and Pknox1). One Pbx3 variant, p.A136V, is located in a highly conserved polyalanine tract and predicted to be deleterious. This variant was present in 5.2% of heart defect patients compared with 1.3% of 380 race- and ethnicity-matched controls (P<0.05). None of the other variants were predicted to be damaging. In conclusion, our results support the Pbx3 Ala136Val variant as a modifier or risk allele for congenital heart defects and implicate PBX-related genes as candidates for CHD, especially those affecting the cardiac outflow tract. PMID- 22426283 TI - Hospital information systems: measuring end user computing satisfaction (EUCS). AB - Over the past decade, hospitals in Greece have made significant investments in adopting and implementing new hospital information systems (HISs). Whether these investments will prove beneficial for these organizations depends on the support that will be provided to ensure the effective use of the information systems implemented and also on the satisfaction of its users, which is one of the most important determinants of the success of these systems. Measuring end-user computing satisfaction has a long history within the IS discipline. A number of attempts have been made to evaluate the overall post hoc impact of HIS, focusing on the end-users and more specifically on their satisfaction and the parameters that determine it. The purpose of this paper is to build further upon the existing body of the relevant knowledge by testing past models and suggesting new conceptual perspectives on how end-user computing satisfaction (EUCS) is formed among hospital information system users. All models are empirically tested using data from hospital information system (HIS) users (283). Correlation, explanatory and confirmation factor analysis was performed to test the reliability and validity of the measurement models. The structural equation modeling technique was also used to evaluate the causal models. The empirical results of the study provide support for the EUCS model (incorporating new factors) and enhance the generalizability of the EUCS instrument and its robustness as a valid measure of computing satisfaction and a surrogate for system success in a variety of cultural and linguistic settings. Although the psychometric properties of EUCS appear to be robust across studies and user groups, it should not be considered as the final chapter in the validation and refinement of these scales. Continuing efforts should be made to validate and extend the instrument. PMID- 22426284 TI - Semi-automated solid-phase extraction method for studying the biodegradation of ochratoxin A by human intestinal microbiota. AB - A simple and rapid semi-automated solid-phase (SPE) extraction method has been developed for the analysis of ochratoxin A in aqueous matrices related to biodegradation experiments (namely digestive contents and faecal excreta), with a view of using this method to follow OTA biodegradation by human intestinal microbiota. Influence of extraction parameters that could affect semi-automated SPE efficiency was studied, using C18-silica as the sorbent and water as the simplest matrix, being further applied to the matrices of interest. Conditions finally retained were as follows: 5-mL aqueous samples (pH 3) containing an organic modifier (20% ACN) were applied on 100-mg cartridges. After drying (9 mL of air), the cartridge was rinsed with 5-mL H(2)O/ACN (80:20, v/v), before eluting the compounds with 3 * 1 mL of MeOH/THF (10:90, v/v). Acceptable recoveries and limits of quantification could be obtained considering the complexity of the investigated matrices and the low volumes sampled; this method was also suitable for the analysis of ochratoxin B in faecal extracts. Applicability of the method is illustrated by preliminary results of ochratoxin A biodegradation studies by human intestinal microbiota under simple in vitro conditions. Interestingly, partial degradation of ochratoxin A was observed, with efficiencies ranging from 14% to 47% after 72 h incubation. In addition, three phase I metabolites could be identified using high resolution mass spectrometry, namely ochratoxin alpha, open ochratoxin A and ochratoxin B. PMID- 22426285 TI - Internal standards in the quantitative determination of protein biopharmaceuticals using liquid chromatography coupled to mass spectrometry. AB - Following the increase in development of protein biopharmaceuticals, there is a growing demand for the sensitive and reliable quantification of these proteins in complex biological matrices such as plasma and serum to support (pre)-clinical research. In this field, ligand binding assays (LBAs) are currently the standard analytical technique, but in recent years, there is a trend towards the use of liquid chromatography hyphenated with (tandem) mass spectrometry (LC-MS/MS). One of the reasons for this trend is the possibility to use internal standards to correct for analytical variability and thus improve the precision and accuracy of the results. In the LC-MS/MS bioanalysis of small molecules, internal standardization is quite straightforward: either a stable-isotope labeled (SIL) form of the analyte or a structural analogue is used. For the quantification of biopharmaceutical proteins, the situation is more complex. Since the protein of interest is digested to a mixture of peptides, one of which is subsequently used for quantification, there are more options for internal standardization. A SIL form or a structural analogue of either the intact protein or the signature peptide can be used. In addition, a modified form of the SIL-peptide internal standard, containing one or more cleavable groups is a possibility, and an internal standard can be generated during the analysis by using differential derivatization techniques. In this paper we provide an overview of the different options for internal standardization in the field of absolute targeted quantification of protein biopharmaceuticals using LC-MS/MS, based on literature from 2003 to 2011. The advantages and disadvantages of the different approaches are evaluated both with regard to the correction they provide for the variability of the different steps of the analysis and with regard to their generic availability. As most of the approaches used lead to acceptable results in terms of accuracy and precision, we conclude that there currently is no clear preferable method for internal standardization in the field of protein quantification by LC-MS/MS. It is essential, however, that any step in the analysis that is not covered by the internal standard chosen, should be carefully optimized and controlled. PMID- 22426286 TI - Development and validation of LC-MS/MS assays for the quantification of bendamustine and its metabolites in human plasma and urine. AB - A sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) assay is described for the quantification of the anti-cancer agent bendamustine and its phase I metabolites gamma-hydroxy-bendamustine (M3) and N-des-methylbendamustine (M4) and for its product of two-fold hydrolysis, dihydroxy-bendamustine (HP2), in human plasma and urine. Like most alkylating nitrogen mustards, bendamustine is prone to chemical hydrolysis in aqueous solution. To minimize degradation of bendamustine, urine samples were stabilized by a 100-fold dilution with human plasma and then processed identically to plasma samples. Sample aliquots of 200 MUL were mixed with an internal standard solution and acidified before separation of the analytes from the biomatrix with solid phase extraction. Dried and reconstituted extracts were injected on a Synergi Hydro RP column for the analysis of bendamustine, M3 and M4 or a Synergi Polar RP column for the analysis of HP2. Gradient elution was applied using 5mM ammonium formate with 0.1% formic acid in water and methanol as mobile phases. Analytes were ionized using an electrospray ionisation source in positive mode and detected with a triple quadrupole mass spectrometer. The quantifiable range for bendamustine, M3 and M4 was 0.5-500 ng/mL in plasma and 0.5-50 MUg/mL in urine, and that for HP2 was 1 500 ng/mL in plasma and 0.1-50 MUg/mL in urine. The assays were accurate and precise, with inter-assay and intra-assay accuracies within +/- 20% of nominal and CV values below 20% at the lower limit of quantification and within +/- 15% of nominal and below 15% at the other concentration levels tested. These methods were successfully applied to evaluate the pharmacokinetic profile of bendamustine and its metabolites in cancer patients treated with bendamustine. PMID- 22426287 TI - Cell patterning via linker-free protein functionalization of an organic conducting polymer (polypyrrole) electrode. AB - The interaction of proteins and cells with polymers is critical to their use in scientific and medical applications. In this study, plasma immersion ion implantation (PIII) was used to modify the surface of the conducting polymer, polypyrrole, which possesses electrical properties. PIII treatment enabled persistent, covalent binding of the cell adhesive protein, tropoelastin, without employing chemical linking molecules. In contrast tropoelastin was readily eluted from the untreated surface. Through this differential persistence of binding, surface bound tropoelastin supported cell adhesion and spreading on the PIII treated but not the untreated polypyrrole surface. The application of a steel shadow mask during PIII treatment allowed for spatial definition of tropoelastin exclusively to PIII treated regions. The general applicability of this approach to other extracellular matrix proteins was illustrated using collagen I, which displayed similar results to tropoelastin but required extended washing conditions. This approach allowed fine patterning of cell adhesion and spreading to tropoelastin and collagen, specifically on PIII treated polypyrrole regions. We therefore present a methodology to alter the functionality of polypyrrole surfaces, generating surfaces that can spatially control cellular interactions through protein functionalization with the potential for electrical stimulation. PMID- 22426288 TI - The role of feature curvature in contact guidance. AB - This study examines the role of feature curvature in cellular topography sensing. To separate the effects of feature size and curvature we have developed a method to fabricate grooved substrates whose radius of curvature (r) varies from under 10nm to 400 nm, while all other dimensions are kept constant. With increasing r up to 200 nm mouse embryonic fibroblasts increased their spread area, but reduced their polarization (aspect ratio). Interestingly, on features with r ~ 200 and 400 nm, which had very little effect on spreading area and polarization, we find that internal structures such as stress fibers are nevertheless still strongly aligned with the topography. These findings are of importance to studies of both tissue engineering and curvature sensing proteins. PMID- 22426289 TI - Synthesis and characterization of poly(antioxidant beta-amino esters) for controlled release of polyphenolic antioxidants. AB - Attenuation of cellular oxidative stress, which plays a central role in biomaterial-induced inflammation, provides an exciting opportunity to control the host tissue response to biomaterials. In the case of biodegradable polymers, biomaterial-induced inflammation is often a result of local accumulation of polymer degradation products, hence there is a need for new biomaterials that can inhibit this response. Antioxidant polymers, which have antioxidants incorporated into the polymer backbone, are a class of biomaterials that, upon degradation, release active antioxidants, which can scavenge free radicals and attenuate oxidative stress, resulting in improved material biocompatibility. In this work, we have synthesized poly(antioxidant beta-amino ester) (PAbetaAE) biodegradable hydrogels of two polyphenolic antioxidants, quercetin and curcumin. The degradation characteristics of PAbetaAE hydrogels and the antioxidant activity of PAbetaAE degradation products were studied. Treatment of endothelial cells with PAbetaAE degradation products protected cells from hydrogen-peroxide-induced oxidative stress. PMID- 22426290 TI - Contribution of complement factor H Y402H polymorphism to sudden sensorineural hearing loss risk and possible interaction with diabetes. AB - Sudden sensorineural hearing loss (SSNHL) is one of the most common diseases encountered by otolaryngologists; however, the etiology is unclear. The aim of this study was to assess the association between SSNHL and polymorphism of complement factor H (CFH) Y402H, which is implicated in age-related macular degeneration. We conducted a case-control study, in which the cases were 72 SSNHL patients and the controls were 2161 residents selected randomly from the resident register. The odds ratio (OR) for SSNHL risk was determined using the additive genetic model of CFH Y402H polymorphism. The OR for SSNHL risk was 1.788 (95% confidence interval [CI]: 1.008-3.172) with no adjustments and 1.820 (CI: 1.025 3.232) after adjusting for age and sex. Of the three lifestyle-related diseases hypertension, dyslipidemia, and diabetes, only diabetes was significantly associated with SSNHL risk. We classified both the controls and SSNHL patients into those with or without diabetes, and the OR for SSNHL risk was 6.326 (CI: 1.885-21.225) in diabetic subjects and 1.214 (CI: 0.581-2.538) in nondiabetic subjects. We conclude that CFH Y402H polymorphism and SSNHL risk are significantly related, and that diabetic CFH Y402H minor allele carriers may be susceptible to SSNHL. PMID- 22426291 TI - Evolutionary rates of commonly used nuclear and organelle markers of Arabidopsis relatives (Brassicaceae). AB - Recovering the genetic divergence between species is one of the major interests in the evolutionary biology. It requires accurate estimation of the neutral substitution rates. Arabidopsis thaliana, the first whole-genome sequenced plant, and its out-crossing relatives provide an ideal model for examining the split between sister species. In the study, rates of molecular evolution at markers frequently used for systematics and population genetics, including 14 nuclear genes spanning most chromosomes, three noncoding regions of chloroplast genome, and one intron of mitochondrial genome, between A. thaliana and four relatives were estimated. No deviation from neutrality was detected in the genes examined. Based on the known divergence between A. thaliana and its sisters about 8.0-17.6 MYA, evolutionary rates of the eighteen genes were estimated. Accordingly, the ratio of rates of synonymous substitutions among mitochondrial, chloroplast and nuclear genes was calculated with an average and 95% confidence interval of 1 (0.25-1.75): 15.77 (7.48-114.09): 74.79 (36.27-534.61). Molecular evolutionary rates of nuclear genes varied, with a range of 0.383-0.856*10(-8) for synonymous substitutions per site per year and 0.036-0.081*10(-9) for nonsynonymous substitutions per site per year. Compared with orthologs in Populus, a long life span tree, genes in Arabidopsis evolved faster in an order of magnitude at the gene level, agreeing with a generation time hypothesis. The estimated substitution rates of these genes can be used as a reference for molecular dating. PMID- 22426292 TI - A submicroscopic deletion involving part of the CREBBP gene detected by array-CGH in a patient with Rubinstein-Taybi syndrome. AB - We report a girl with Rubinstein-Taybi syndrome (RSTS) who was found to have copy number loss on 16p13.3 by array-CGH. She has developmental delay and other features of RSTS including downslanting palpebral fissures, a prominent nose with the nasal septum extending below the alae nasi, broad thumbs and big toes, postaxial polydactyly of the right foot and constipation from birth. We report the junction sequence across the breakpoint region for a microdeletion in RSTS. The sequencing results also showed that the deletion was 81.4kb involving three genes DNASE 1, TRAP 1, and CREBBP. PMID- 22426293 TI - Identification of new altered genes in rat cochleae with noise-induced hearing loss. AB - Because genes that are highly expressed in the cochlea after noise stress may have crucial regulatory roles in hearing, the identification of these genes may be useful for restoring normal auditory function. This study assessed altered gene expression at 1h following the cessation of noise exposure by using microarrays and real-time polymerase chain reaction (qPCR) in rats. In addition, the auditory threshold shifts and morphological changes of hair cells were observed. This study indicated that applied noise induced outer hair cell loss and a 40-50 dB hearing loss. Totally 239 altered genes were involved in the immune system process, response to stress, or response to stimulus. The expression of five up-regulated genes (Reg3b, Lcn2, Serpina3n, Nob1 and Hamp) was confirmed by qPCR. Future experiments will focus on several of these new candidate genes and may provide insight into the underlying auditory pathophysiology. PMID- 22426294 TI - Transfer of HBV genomes using low doses of adenovirus vectors leads to persistent infection in immune competent mice. AB - Studies of mechanisms responsible for the persistence of hepatitis B virus (HBV) infection have been hindered by a lack of appropriate animal models. HBV genomes can be delivered to livers of mice using hydrodynamic injection or high doses of an adenoviral vector; these lead to clearance of HBV. We found that infection of immunocompetent mice with low doses of an adenoviral vector resulted in persistent HBV infection; the mice neither underwent seroconversion to production of antibodies against HBV nor developed a strong HBV-specific effector T-cell response. As in patients with chronic HBV infection, DNA vaccination failed to generate T cells that cleared infection. This model of persistent HBV infection could be used to study the pathogenesis of chronic HBV infection and develop new therapeutic strategies. PMID- 22426295 TI - Fluoride in low concentration modifies expression and activity of 15 lipoxygenase in human PBMC differentiated monocyte/macrophage. AB - Epidemiological and experimental evidences demonstrate positive correlation between environmental and occupational fluoride exposure and risk to various cardio-respiratory disorders. That fore we decided to examine the effect of fluorides on activity and expression of 15LOX enzyme which is implicated in biosynthesis of inflammatory mediators. Expression of 15LOX-1 and -2 enzymes mRNA and protein was analyzed using RT PCT and immunoblotting methods respectively whereas HPLC method was used to measure the levels of 15 lipoxygenases end products. Additionally AA and LA concentration in cells was measured using GC method. We observed that fluoride in small concentration may significantly decrease activity of 15LOX-1 and -2 in human PBMC macrophages and then concentration of its end products: 15-HETE, 12-HETE and 9+13-HODE, what may cause development of inflammation through the cholesterol arrest into the macrophages and its differentiation to foam cell. Noted by our team overexpression of the 15LOX-1 enzyme in macrophages after addition of lowest fluoride concentrations (1 and 3 MUM) may be aimed at fighting inflammation development and excessive intracellular lipid accumulation. But highest fluoride concentrations (6 and 10 MUM) added to cell culture slowly declined expression of this enzyme probably because of developing inflammation. Additional 15LOX-2 expression in macrophages after fluoride addition was low in 1 and 3 MUM concentrations, but increased significantly after 10 MUM fluoride addition what may suggest developing acute inflammation, because 15LOX-2 is associated to increased local hypoxia. This study indicated that even in small concentrations fluorides changes the amounts and activity of 15 LOX-1 and -2 enzymes taking part in the development of inflammatory process. PMID- 22426296 TI - Identification of a novel set of biomarkers for evaluating phospholipidosis inducing potential of compounds using rat liver microarray data measured 24-h after single dose administration. AB - Phospholipid accumulation manifests as an adverse effect of cationic amphiphilic drugs in particular. Detection, however, by histopathology examination is time consuming and may require repeated administration of compounds for several weeks. To eliminate compounds with potential for inducing phospholipidosis from the discovery pipeline, we have identified and validated a set of biomarkers for predicting the phospholipidosis-inducing potential utilizing a comprehensive rat transcriptome microarray database created by the Japanese Toxicogenomics and Toxicogenomics Informatics Projects (TGP/TGP2) together with in-house data. The set of biomarkers comprising 25 Affymetrix GeneChip probe sets was identified using genetic algorithm optimization on 24-h time-point microarray data from rats treated with single doses of hepatotoxic compounds including amiodarone, clomipramine, haloperidol, hydroxyzine, imipramine, and perhexiline. The set of novel biomarkers represents an early time-point gene-expression pattern characteristic for a condition eventually leading to phospholipidosis. This implies significant advantages in terms of time and resources over currently published biomarkers derived using repeated-dosing late time-point data. The biomarker set was validated by 11 independent compounds. Accuracy, sensitivity, and specificity values were 82%, 67%, and 100%, respectively and the area under the receiver operating characteristic curve was 0.97. These results show that the biomarker set possesses a high classification accuracy for novel compounds. Pathway analysis was carried out for the biomarkers and the detection of pathways related to lipid-metabolism was statistically significant. These pathways most probably reflect lipid metabolism changes associated with phospholipidosis supporting the validity of our novel biomarkers. PMID- 22426297 TI - Maternal bisphenol A oral dosing relates to the acceleration of neurogenesis in the developing neocortex of mouse fetuses. AB - Bisphenol A (BPA), an endocrine-disruptor, is widely used in the production of plastics and resins. Human perinatal exposure to this chemical has been proposed to be a potential risk to public health. Animal studies indicate that postnatal exposure to BPA may affect neocortex development in embryos by accelerated neurogenesis and causing neuronal migration defects. The detailed phenotypes and pathogenetic mechanisms, especially with regard to the proliferation and differentiation of neural stem/progenitor cells, however, have not been clarified. C57BL/6J pregnant mice were orally administered BPA at 200MUg/kg from embryonic day (E) 8.5 to 13.5, and the fetuses were observed histologically at E14.5. To clarify the histological changes, especially in terms of neurogenesis, proliferation and cell cycle, we performed histological analysis using specific markers of neurons/neural stem cells and cell cycle-specific labeling experiments using thymidine-analog substances. Cortical plate was hyperplastic and the number of neural stem/progenitor cells was decreased after the exposure to BPA. In particular, the maternal BPA oral dosing related to the effects on intermediate progenitor cells (IPCs, neural progenitor cells) in the subventricular zone (SVZ) of dorsal telencephalon. Exposure to BPA associated the promotion of the cell cycle exit in radial glial cells (RGCs, neural stem cells) and IPCs, and decreased the proliferation resulting from the prolong cell cycle length of IPCs in the SVZ. Our data show that maternal oral exposure to BPA related to the disruption of the cell cycle in IPCs and the effects of neurogenesis in the developing neocortex. PMID- 22426298 TI - Fever and skin lesions in a healthy 6-month-old boy. Diagnosis: Ecthyma gangrenosum. PMID- 22426299 TI - Two closely related strains associated with pertussis resurgence in Israel. AB - Eighty-two isolates of Bordetella pertussis analyzed by pulsed-field gel electrophoresis from the epidemic years, 2007 to 2008, revealed 4 strains with 2 closely related isolates accounting for 95% of the circulating strains. The most common Israeli strain has the same pulsed-field gel electrophoresis cluster as the dominant European BpSR11 strain (pulsed-field gel electrophoresis cluster IVbeta) identified in the 1999 to 2004 EU Pertstrain II project. PMID- 22426300 TI - Bacteremic pneumococcal community-acquired pneumonia in children less than 5 years of age in Italy. AB - BACKGROUND: This study was designed to determine the proportion of bacteremic pneumococcal cases in a group of pediatric subjects with community-acquired pneumonia (CAP), the importance of the different serotypes and the impact of the currently available pneumococcal conjugate vaccines (PCVs). METHODS: The study involved children who were <=5 years with radiographically confirmed CAP admitted to hospital in Italy between September 2008 and March 2011. A diagnosis of laboratory-confirmed bacteremic pneumococcal CAP was made in the presence of a culture and/or real-time polymerase chain reaction (PCR) positive for Streptococcus pneumoniae. RESULTS: A total of 510 children were included in the study. Pneumococcal CAP was diagnosed in 73 cases (14.3%): S. pneumoniae was identified by means of positive real-time PCR in 67 cases (91.8%), a positive blood culture in 1 (1.4%) and both in 5 (6.8%). Complicated pneumonia was observed significantly more often in the pneumococcal-positive cases (P=0.02) and empyema was the main complication (P=0.007). Serotype 19A was most frequently encountered (17 cases; 25.8%), followed by serotypes 14 (10 cases, 15.1%), 4 (5 cases, 7.6%) and 3 (4 cases, 6.1%). The theoretical coverage offered by the available PCVs was calculated to be 31% for PCV7, 37% for PCV10 and 71% for PCV13. CONCLUSIONS: In Italy, bacteremic pneumococcal CAP accounts for a significant number of CAP cases in children who were <=5 years, with serotypes 19A and 14 being the most frequent. This suggests that PCV13 is the best means of preventing pneumococcal CAP. PMID- 22426301 TI - Cholestasis as the initial feature of Kawasaki disease. AB - Hepatobiliary involvement is uncommon in Kawasaki disease, and it is usually described as obstructive jaundice. From January 01, 2000 to August 31, 2010, 31 Kawasaki disease cases were diagnosed in our center. Three of them (9.7%) developed jaundice, but there were no gallbladder or bile duct abnormalities by ultrasonography, a feature rarely reported. Resolution of cholestasis paralleled improvement of the illness. PMID- 22426302 TI - Activation of a cryptic splice site in a potentially lethal coagulation defect accounts for a functional protein variant. AB - Changes at the invariable donor splice site +1 guanine, relatively frequent in human genetic disease, are predicted to abrogate correct splicing, and thus are classified as null mutations. However, their ability to direct residual expression, which might have pathophysiological implications in several diseases, has been poorly investigated. As a model to address this issue, we studied the IVS6+1G>T mutation found in patients with severe deficiency of the protease triggering coagulation, factor VII (FVII), whose absence is considered lethal. In expression studies, the IVS6+1G>T induced exon 6 skipping and frame-shift, and prevented synthesis of correct FVII transcripts detectable by radioactive/fluorescent labelling or real-time RT-PCR. Intriguingly, the mutation induced the activation of a cryptic donor splice site in exon 6 and production of an in-frame 30bp deleted transcript (8 +/- 2%). Expression of this cDNA variant, lacking 10 residues in the activation domain, resulted in secretion of trace amounts (0.2 +/- 0.04%) of protein with appreciable specific activity (48 +/- 16% of wt-FVII). Altogether these data indicate that the IVS6+1G>T mutation is compatible with the synthesis of functional FVII molecules (~0.01% of normal, 1pM), which could trigger coagulation. The low but detectable thrombin generation (352 +/- 55nM) measured in plasma from an IVS6+1G>T homozygote was consistent with a minimal initiation of the enzymatic cascade. In conclusion, we provide experimental clues for traces of FVII expression, which might have reverted an otherwise perinatally lethal genetic condition. PMID- 22426303 TI - Aminoanthraquinone-based chemosensors: colorimetric molecular logic mimicking molecular trafficking and a set-reset memorized device. AB - The synthesis, photophysical properties, protonation and metal-ion coordination features of a family of four (3-6) anthraquinone-based schiff base derivatives are reported. The outstanding UV-vis absorption properties of the 1 aminoanthraquinone chromophore allowed the efficient visual detection and quantification of Cu(2+) and/or Ni(2+) in buffered aqueous solution. Analysis of spectrophotometric data with SPECFIT yielded the macroscopic and microscopic stability constants of the complexes. Furthermore, the different optical output signals (i.e. absorbance) observed with addition of various metal ions to a solution of 6 can be used for mimicking the operation of a traffic signal and "Set-Reset" molecular level information processing device. PMID- 22426304 TI - Association of frailty with survival: a systematic literature review. AB - Frailty is a known risk factor for those aged 65 and over, and its prevalence increases with age. Definitions of frailty vary widely, and prevalence estimates are affected by the way frailty is defined. Systematic reviews have yet to examine the literature on the association between definitions of frailty and mortality. We examined the definitions and prevalence of frailty and its association with survival in older community-dwelling adults. We conducted a systematic review of observational population-based studies published in English. We calculated pooled prevalence of frailty with a random effects model. We identified 24 population-based studies that examined frailty in community dwelling older adults. The pooled prevalence was 14% when frailty was defined as a phenotype exhibiting three or more of the following: weight loss, fatigue/exhaustion, weakness, low physical activity/slowness, and mobility impairment. The pooled prevalence was 24% when frailty was defined by accumulation of deficits indices that included up to 75 diseases and impairments. The prevalence of frailty increased with age and was greater in women and in African Americans. Frailty in older adults was associated with poor survival with a dose-responsive reduction in survival per increasing number of frailty criteria. Taking into account population prevalence and multivariate adjusted relative risks, we estimated that 3-5% of deaths among older adults could be delayed if frailty was prevented. Frailty is a prevalent and important geriatric syndrome associated with decreased survival. Geriatric assessment of frailty provides clinically important information about functional status and survival of older adults. PMID- 22426306 TI - Mechanical failure begins preferentially near resorption cavities in human vertebral cancellous bone under compression. AB - The amount of bone turnover in the body has been implicated as a factor that can influence fracture risk and bone strength. Here we test the idea that remodeling cavities promote local tissue failure by determining if microscopic tissue damage (microdamage) caused by controlled loading in vitro is more likely to form near resorption cavities. Specimens of human vertebral cancellous bone (L4, 7 male and 2 female, age 70+/-10, mean+/-SD) were loaded in compression to the yield point, stained for microscopic tissue damage and submitted to three-dimensional fluorescent imaging using serial milling (image voxel size 0.7*0.7*5.0 MUm). We found the resulting damage volume per bone volume (DV/BV) was correlated with percent eroded surface (p<0.01, r(2)=0.65), demonstrating that whole specimen measures of resorption cavities and microdamage are related. Locations of microdamage were more than two times as likely to have a neighboring resorption cavity than randomly selected sites without microdamage (relative risk 2.39, 95% confidence interval of relative risk: 2.09-2.73), indicating a spatial association between resorption cavities and microdamage at the local level. Individual microdamage sites were 48,700 (40,100; 62,700) MUm(3) in size (median, 25th and 75th percentiles). That microdamage was associated with resorption cavities when measured at the whole specimen level as well as at the local level provides strong evidence that resorption cavities play a role in mechanical failure processes of cancellous bone and therefore have the potential to influence resistance to clinical fracture. PMID- 22426307 TI - Changes in vitamin D metabolites during teriparatide treatment. AB - Parathyroid hormone (PTH) increases the conversion of 25-hydroxyvitamin D [25(OH)D] to 1,25 dihydroxyvitamin D [1,25(OH)(2)D]. The purpose of this study was to assess the changes in serum concentration of vitamin D metabolites 1,25 dihydroxyvitamin D [1,25(OH)(2)D] and 25-hydroxyvitamin D [25(OH)D] during teriparatide 20 MUg/day (teriparatide) therapy in the double-blind Fracture Prevention Trial of postmenopausal women with osteoporosis and in the male study of men with osteoporosis. Patients were randomized to teriparatide or placebo and received daily supplements of calcium 1000 mg and vitamin D 400-1200 IU. Serum concentrations of 1,25(OH)(2)D and 25(OH)D were measured. In women (N=336), median 1,25(OH)(2)D concentrations at 1 month increased from baseline by 27% (P<0.0001) in the teriparatide group versus -3% (P=0.87) in the placebo group (between group P<0.0001). At 12 months, the increase was 19% (P<0.0001) in the teriparatide group versus -2% (P=0.23) in the placebo group (P<0.0001). Median 25(OH)D concentrations at 12 months decreased by 19% (P<0.0001) in the teriparatide group versus 0% (P=0.13) in the placebo group (P<0.0001). In men (N=287), median 1,25(OH)(2)D concentrations at 1 month increased by 22% (P<0.0001) in the teriparatide group versus 0% (P=0.99) in the placebo group (P<0.0001). At 12 months, the increase was 14% (P<0.0001) in the teriparatide group versus 5% (P=0.004) in the placebo group (P=0.17). Median 25(OH)D concentrations at 12 months decreased by 11% (P=0.001) in the teriparatide group versus an increase of 1% (P=0.20) in the placebo group (P=0.003). Therefore, treatment with teriparatide increases 1,25(OH)(2)D concentrations and decreases 25(OH)D concentrations. PMID- 22426308 TI - Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. AB - By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B. PMID- 22426309 TI - Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. AB - We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment. PMID- 22426310 TI - Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. AB - We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium. PMID- 22426311 TI - Factors influencing in-hospital delay in treatment with intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: Shortening door-to-needle time (DNT) for the thrombolytic treatment of stroke can improve treatment efficacy by reducing onset-to-treatment time. The goal of our study was to explore the association between DNT and outcome and to identify factors influencing DNT to better understand why some patients are treated late. METHODS: Prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST: 9 central and eastern European countries) on all patients treated with thrombolysis between February 2003 and February 2010 were analyzed. Multiple logistic regression analysis was used to identify predictors of DNT <= 60 minutes. RESULTS: Altogether, 5563 patients were treated with thrombolysis within 4.5 hours of symptom onset. Of these, 2097 (38%) had DNT <= 60 minutes. In different centers, the proportion of patients treated with DNT <= 60 minutes ranged from 18% to 84% (P<0.0001). Patients with longer DNT (in 60-minute increments) had less chance of achieving a modified Rankin Scale score of 0 to 1 at 3 months (adjusted OR, 0.86; 95% CI, 0.77-0.97). DNT <= 60 minutes was independently predicted by younger age (in 10-year increments; OR, 0.92; 95% CI, 0.87-0.97), National Institutes of Health Stroke Scale score 7 to 24 (OR, 1.44; 95% CI, 1.2-1.7), onset-to-door time (in 10-minute increments; OR, 1.19; 95% CI, 1.17-1.22), treatment center (P<0.001), and country (P<0.001). CONCLUSIONS: Thrombolysis of patients with older age and mild or severe neurological deficit is delayed. The perception that there is sufficient time before the end of the thrombolytic window also delays treatment. It is necessary to improve adherence to guidelines and to treat patients sooner after arrival to hospital. PMID- 22426312 TI - Apolipoprotein-E controls adenosine triphosphate-binding cassette transporters ABCB1 and ABCC1 on cerebral microvessels after methamphetamine intoxication. AB - BACKGROUND AND PURPOSE: Methamphetamine is a powerful addictive, which has been associated with ischemic stroke and brain hemorrhage in humans. Whether and how methamphetamine influences the expression of tight junctions and adenosine triphosphate-binding cassette transporters, which have previously been shown to be regulated by apolipoprotein-E (ApoE) under conditions of brain ischemia, was unknown. METHODS: C57BL/6J mice received intraperitoneal injections of methamphetamine (3 times 4 mg/kg separated by 3 hours) either alone or in combination with the ApoE receptor-2 inhibitor receptor-associated protein (40 MUg/kg) or the inducible nitric oxide synthase inhibitor 1400W (5 mg/kg). Animals were euthanized 3 or 24 hours after methamphetamine exposure. Tissue responses were evaluated with Western blots, immunoprecipitation, and immunohistochemistry using total brain and cerebral microvessel extracts. RESULTS: Methamphetamine induced a transient activation of stress kinases c-Jun N-terminal kinase 1/2 and p38 in the brain parenchyma and increased intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on cerebral microvessels without inducing loss of tight junction proteins and without inducing IgG extravasation. Methamphetamine transiently increased the expression of the luminal adenosine triphosphate-binding cassette transporter ABCB1 on cerebral microvessels and reduced the expression of the abluminal transporter ABCC1. Elevated expression of ApoE was noted in the brain parenchyma by methamphetamine, activating ApoE receptor-2 on brain capillaries, deactivating c-Jun N-terminal kinase 1/2 and c Jun, and regulating ABCB1 and ABCC1 expression. Indeed, ApoE receptor-2 and inducible nitric oxide synthase inhibition prevented the ABCB1 and ABCC1 expression changes. CONCLUSIONS: Acute exposure to methamphetamine at doses comparable to those consumed in drug addiction does not induce tight junction breakdown but differentially regulates adenosine triphosphate-binding cassette transporters through the ApoE/ApoE receptor-2/c-Jun N-terminal kinase 1/2 pathway. PMID- 22426313 TI - Contemporary outcome measures in acute stroke research: choice of primary outcome measure. AB - BACKGROUND AND PURPOSE: The diversity of available outcome measures for acute stroke trials is challenging and implies that the scales may be imperfect. To assist researchers planning trials and to aid interpretation, this article reviews and makes recommendations on the available choices of scales. The aim is to identify an approach that will be universally accepted and that should be included in most acute trials, without seeking to restrict options for special circumstances. METHODS: The article considers outcome measures that have been widely used or are currently advised. It examines desirable properties for outcome measures such as validity, relevance, responsiveness, statistical properties, availability of training, cultural and language issues, resistance to comorbidity, as well as potential weaknesses. Tracking and agreement among outcomes are covered. RESULTS: Typical ranges of scores for the common scales are described, along with their statistical properties, which in turn influence optimal analytic techniques. The timing of recovery on scores and usual practice in trial design are considered. CONCLUSIONS: The preferred outcome measure for acute trials is the modified Rankin Scale, assessed at 3 months after stroke onset or later. The interview should be conducted by a certified rater and should involve both the patient and any relevant caregiver. Incremental benefits at any level of the modified Rankin Scale may be acceptable. The modified Rankin Scale is imperfect but should be retained in its present form for comparability with existing treatment comparisons. No second measure should be required, but correlations with supporting scales may be used to confirm consistency in direction of effects on other measures. PMID- 22426314 TI - Statistical analysis of the primary outcome in acute stroke trials. AB - Common outcome scales in acute stroke trials are ordered categorical or pseudocontinuous in structure but most have been analyzed as binary measures. The use of fixed dichotomous analysis of ordered categorical outcomes after stroke (such as the modified Rankin Scale) is rarely the most statistically efficient approach and usually requires a larger sample size to demonstrate efficacy than other approaches. Preferred statistical approaches include sliding dichotomous, ordinal, or continuous analyses. Because there is no best approach that will work for all acute stroke trials, it is vital that studies are designed with a full understanding of the type of patients to be enrolled (in particular their case mix, which will be critically dependent on their age and severity), the potential mechanism by which the intervention works (ie, will it tend to move all patients somewhat, or some patients a lot, and is a common hazard present), a realistic assessment of the likely effect size, and therefore the necessary sample size, and an understanding of what the intervention will cost if implemented in clinical practice. If these approaches are followed, then the risk of missing useful treatment effects for acute stroke will diminish. PMID- 22426315 TI - Very urgent carotid endarterectomy confers increased procedural risk. AB - BACKGROUND AND PURPOSE: Current Swedish guidelines recommend that carotid endarterectomy should be performed within 14 days of a qualifying neurological event, but it is not clear if very urgent surgery after an event is associated with increased perioperative risk. The aim of this study was to determine how the time between the event and carotid endarterectomy affects the procedural risk of mortality and stroke. METHODS: We prospectively analyzed data on all patients who underwent carotid endarterectomies for symptomatic carotid stenosis between May 12, 2008, and May 31, 2011, with records in the Swedish Vascular Registry (Swedvasc). Patients were divided according to time between the qualifying event and surgery (0-2 days, 3-7 days, 8-14 days, 15-180 days). Stroke rate and mortality at 30 days postsurgery were determined. RESULTS: We analyzed data for 2596 patients and found that the combined mortality and stroke rate for patients treated 0 to 2 days after qualifying event was 11.5% (17 of 148) versus 3.6% (29 of 804), 4.0% (27 of 677), and 5.4% (52 of 967) for the groups treated at 3 to 7 days, 8 to 14 days, and 15 to 180 days, respectively. In a multivariate analysis, time was an independent risk factor for perioperative complications: patients treated at 0 to 2 days had a relative OR of 4.24 (CI, 2.07-8.70; P<0.001) compared with the reference 3- to 7-day group. CONCLUSIONS: In this study of patients treated for symptomatic carotid disease, it was safe to perform surgery as early as Day 3 after a qualifying neurological event in contrast to patients treated within 0 to 2 days, which has a significantly increased perioperative risk. PMID- 22426316 TI - Does body mass index impact on the relationship between systolic blood pressure and cardiovascular disease?: meta-analysis of 419 488 individuals from the Asia pacific cohort studies collaboration. AB - BACKGROUND AND PURPOSE: Elevated blood pressure and excess body mass index (BMI) are established risk factors for cardiovascular disease (CVD) but controversy exists as to whether, and how, they interact. METHODS: The interactions between systolic blood pressure and BMI on coronary heart disease, ischemic and hemorrhagic stroke and CVD were examined using data from 419 448 participants (>= 30 years) in the Asia-Pacific region. BMI was categorized into 5 groups, using standard criteria, and systolic blood pressure was analyzed both as a categorical and continuous variable. Cox proportional hazard models, stratified by sex and study, were used to estimate hazard ratios, adjusting for age and smoking and the interaction was assessed by likelihood ratio tests. RESULTS: During 2.6 million person-years of follow-up, there were 10 877 CVD events. Risks of CVD and subtypes increased monotonically with increasing systolic blood pressure in all BMI subgroups. There was some evidence of a decreasing hazard ratio, per additional 10 mm Hg systolic blood pressure, with increasing BMI, but the differences, although significant, are unlikely to be of clinical relevance. The hazard ratio for CVD was 1.34 (95% CI, 1.32-1.36) overall with individual hazard ratios ranging between 1.28 and 1.36 across all BMI groups. For coronary heart disease, ischemic stroke, and hemorrhagic stroke, the overall hazard ratios per 10 mm Hg systolic blood pressure were 1.24, 1.46, and 1.65, respectively. CONCLUSIONS: Increased blood pressure is an important determinant of CVD risk irrespective of BMI. Although its effect tends to be weaker in people with relatively high BMI, the difference is not sufficiently great to warrant alterations to existing guidelines. PMID- 22426317 TI - Infarct volume is a pivotal biomarker after intra-arterial stroke therapy. AB - BACKGROUND AND PURPOSE: Pretreatment infarct volume appears to predict clinical outcome after intra-arterial therapy. To confirm the importance of infarct size in patients undergoing intra-arterial therapy, we sought to characterize the relationship between final infarct volume (FIV) and long-term functional outcome in a prospective cohort of endovascularly treated patients. METHODS: From our prospective intra-arterial therapy database, we identified 107 patients with acute ischemic stroke with anterior circulation proximal artery occlusions who underwent final infarct imaging and had 3-month modified Rankin Scale scores. Clinical, imaging, treatment, and outcome data were analyzed. RESULTS: Mean age was 66.6 years. Median admission National Institutes of Health Stroke Scale score was 17. Reperfusion (Thrombolysis In Cerebral Infarction 2A-3) was achieved in 78 (72.9%) patients. Twenty-seven (25.2%) patients achieved a 3-month good outcome (modified Rankin Scale 0-2), and 30 (28.0%) died. Median FIV was 71.4 cm(3). FIV independently correlated with functional outcome across the entire modified Rankin Scale. In receiver operating characteristic analysis, it was the best discriminator of both good outcome (area under the curve=0.857) and mortality (area under the curve=0.772). A FIV of approximately 50 cm(3) demonstrated the greatest accuracy for distinguishing good versus poor outcome, and a FIV of approximately 90 cm(3) was highly specific for a poor outcome. The interaction term between FIV and age was the only independent predictor of good outcome (P<0.0001). The impact of FIV was accentuated in patients <80 years. CONCLUSIONS: Among patients with anterior circulation acute ischemic stroke who undergo intra arterial therapy, final infarct volume is a critical determinant of 3-month functional outcome and appears suitable as a surrogate biomarker in proof-of concept intra-arterial therapy trials. PMID- 22426318 TI - Contemporary outcome measures in acute stroke research: choice of primary outcome measure and statistical analysis of the primary outcome in acute stroke trials. PMID- 22426319 TI - Whole-brain arterial spin labeling perfusion MRI in patients with acute stroke. AB - BACKGROUND AND PURPOSE: Perfusion MRI can be used to identify patients with acute ischemic stroke who may benefit from reperfusion therapies. The risk of nephrogenic systemic fibrosis, however, limits the use of contrast agents. Our objective was to evaluate the ability of arterial spin labeling (ASL), an alternative noninvasive perfusion technique, to detect perfusion deficits compared with dynamic susceptibility contrast (DSC) perfusion imaging. METHODS: Consecutive patients referred for emergency assessment of suspected acute stroke within a 7-month period were imaged with both ASL and DSC perfusion MRI. Images were interpreted in a random order by 2 experts blinded to clinical information for image quality, presence of perfusion deficits, and diffusion-perfusion mismatches. RESULTS: One hundred fifty-six patients were scanned with a median time of 5.6 hours (range, 3.0-17.7 hours) from last seen normal. Stroke diagnosis was clinically confirmed in 78 patients. ASL and DSC imaging were available in 64 of these patients. A perfusion deficit was detected with DSC in 39 of these patients; ASL detected 32 of these index perfusion deficits, missing 7 lesions. The median volume of the perfusion deficits as determined with DSC was smaller in patients who were evaluated as normal with ASL than in those with a deficit (median [interquartile range], 56 [10-116] versus 114 [41-225] mL; P=0.01). CONCLUSIONS: ASL can depict large perfusion deficits and perfusion-diffusion mismatches in correspondence with DSC. Our findings show that a fast 2½ minute ASL perfusion scan may be adequate for screening patients with acute stroke with contraindications to gadolinium-based contrast agents. PMID- 22426320 TI - Helicopter Emergency Medical Services save lives: outcome in a cohort of 1073 polytraumatized patients. AB - BACKGROUND: In many Western countries, Helicopter Emergency Medical Services (HEMS) have become standard in the prehospital care of severely injured patients. Several studies have shown that HEMS have a positive effect on patient's outcome, although it remains unclear which specific patients benefit most from its care. The aim of this study was to assess the effect of HEMS on the outcome of a large polytraumatized (Injury Severity Score>=16) population. METHODS: All polytraumatized patients treated at the scene of the accident by EMS and/or HEMS and presented in the VU University Medical Center during a period of 6 years were included and retrospectively analyzed. The total population was divided into two groups according to the presence of HEMS on-scene. Prehospital, in-hospital, and outcome parameters were compared. The Trauma Injury Severity Score method was used to calculate the probability of survival. RESULTS: Almost 60% of all included patients (n=1073) were treated only by an EMS crew on-scene. The remaining 446 patients received additional HEMS care. Significant differences between these two groups were observed in the demographic characteristics, showing that the HEMS group was more severely injured. The predicted survival was calculated using the Trauma Injury Severity Score method, as well as the observed survival, both showing a significantly higher outcome for the EMS group (0.88 vs. 0.66% and 87.7 vs. 71.3%). However, the Z-statistic showed a significant positive difference between the predicted and the observed survival for the HEMS group (P<0.005) and no significant differences for the EMS group (P>0.1), indicating that the chance of surviving in the HEMS group was higher. Per 100 HEMS dispatches, 5.4 additional lives were saved. A correlation of the observed survival with the first measured Revised Trauma Score on-scene showed a positive effect for the HEMS group when the Revised Trauma Score reached a value of 9 or lower. CONCLUSION: On-scene HEMS care has a positive effect on the survival of polytraumatized patients, saving 5.4 additional lives per 100 HEMS deployments. This positive effect is especially observed in patients with abnormal vital signs (respiratory and hemodynamically). Research and revision of dispatch criteria are important to reach patients that benefit most from HEMS care. PMID- 22426321 TI - Is transdermal iontophoretic delivery of naloxone sufficient for the management of intoxication in opioid-overdosed patients? PMID- 22426322 TI - In situ controlled crystallization as a tool to improve the dissolution of Glibenclamide. AB - For pharmaceutical purpose, micro-sized drugs are needed for many delivery systems, such as pulmonary and oral drug delivery systems. Many strategies have been employed to reduce the particle size of poorly water soluble drugs. Microcrystals could be produced by controlled association of drug in order to obtain naturally grown particles. The aim of this work was to increase the aqueous solubility and dissolution of Glibenclamide. The in situ controlled crystallization process was conducted in the presence of the non-ionic surfactants, Cremophor RH40 and Solutol HS-15 (0.75 and 1.5%, w/v), as protective stabilizing agents against agglomeration. In addition, these surfactants inhibit P-glycoprotein that reduces intestinal absorption of Glibenclamide by efflux transportation. Crystal shape was changed and particle size was reduced by about 15-folds, compared to control untreated drug. Differential Scanning Calorimetry (DSC) results indicated no interaction between the drug and the stabilizer. Microcrystals showed marked increase in the drug dissolution, Solutol HS-15 at 1.5% (w/v) concentration showing the highest dissolution efficiency. It could be concluded that in situ controlled crystallization using surfactants are promising method to improve dissolution of Glibeclamide as a model poorly water soluble drug. PMID- 22426323 TI - Regulation of human monocarboxylate transporter 4 in skeletal muscle cells: the role of protein kinase C (PKC). AB - In the present study, to clarify the role of protein kinase C (PKC) in the regulation of monocarboxylate transporter 4 (MCT4) expression, we examined the regulation mechanism of MCT4 expression in human rhabdomyosarcoma (RD) cells, an in vitro skeletal muscle model. Exposure of RD cells to PMA, a PKC activator, for 24 h resulted in a two-fold increase in the amount of lactic acid in the growth medium. In parallel to an increase in lactic acid release from RD cells, the level of MCT4 mRNA and protein were also significantly increased in RD cells. A PKC inhibitory study indicated that PMA-induced stimulation of MCT4 expression can be mediated through a novel PKC isoform, especially PKCdelta. Moreover, rottlerin, a selective PKCdelta inhibitor, decreased PMA-induced MCT4 promoter activity. Deletion and mutational analysis suggested that the potential hypoxia response elements (HREs) played a major role in the observed modulation of MCT4 expression by PMA. Furthermore, we found that small interfering RNA (siRNA) mediated knockdown of hypoxia-inducible factor 1alpha (HIF-1alpha) significantly inhibited PMA-induced MCT4 promoter activity. Our results show that the effects of PMA on MCT4 expression are mediated through an indirect pathway partially involving PKCdelta and HIF-1alpha transcription factor. PMID- 22426324 TI - Characterization of steroid sulfatase in the MC3T3-E1 mouse pre-osteoblastic cell line. AB - Regulation of bone density is partly dependent upon steroid hormones, with estrogens playing an important role. Inactive conjugated estrogens may serve as precursors to active estrogens, especially in post-menopausal women, via steroid sulfatase, which converts conjugated estrogens into unconjugated estrogens. The purpose of this study was to characterize steroid sulfatase in the MC3T3-E1 mouse pre-osteoblastic cell line. Enzyme conversion assays were performed on whole MC3T3-E1 cells in culture and on microsomes prepared by differential centrifugation. (3)H-E(1)S and (3)H-DHEAS were used as tracers, and radioinert E(1)S and DHEAS were used as substrate. Whole cells and microsomes exhibited steroid sulfatase activity, which was blocked by the specific inhibitor estrone-3 O-sulfamate (EMATE). The K(m) of steroid sulfatase in microsomes averaged 83 MUM when using E(1)S as substrate and 64 MUM when using DHEAS. Western blotting of MC3T3-E1 microsomes for steroid sulfatase was performed, after SDS-PAGE, using an antibody generated against a peptide based on a conserved region of steroid sulfatase. Western blotting revealed three bands of cross-reactivity, ranging from 50 to 79 kDa. Reverse transcriptase polymerase chain reaction (RT-PCR), using specific primers, resulted in a single cDNA band of the expected size (100 bp) and sequence, indicating the presence of steroid sulfatase mRNA. Growth assays revealed that the MC3T3-E1 cells were stimulated by estradiol-17beta, and also by estrone sulfate and DHEAS, revealing that the cells can use steroid sulfatase to produce active estrogens. Furthermore, growth of these cells in the presence of estradiol, estrone and estrone sulfate was inhibited by the estrogen receptor blocker ICI 182,780, indicating that stimulation of cell growth is mediated by the estrogen receptor. In our studies, four lines of evidence (enzyme activity, immunoassay, RT-PCR and growth assays) demonstrated the presence of steroid sulfatase in mouse MC3T3-E1 bone cells. The existence of steroid sulfatase in these pre-osteoblastic cells, along with the ability of sulfated steroids to promote their growth, suggest the possibility that this enzyme is involved in regulation of bone density in mice. PMID- 22426325 TI - Global transcriptional response to ISCOM-Matrix adjuvant at the site of administration and in the draining lymph node early after intramuscular injection in pigs. AB - ISCOM vaccines induce a balanced Th1/Th2 response, long-lasting antibody responses and cytotoxic T lymphocytes. The mode of action for the adjuvant component, the ISCOM-Matrix, is known to some extent but questions remain regarding its mechanism of action. The Affymetrix GeneChip(r) Porcine Genome Array was applied to study the global transcriptional response to ISCOM-Matrix in pigs at the injection site and in the draining lymph node 24h after i.m. injection. Gene enrichment analysis revealed inflammation, innate immunity and antigen processing to be central in the ISCOM-Matrix response. At the injection site, 594 genes were differentially expressed, including up-regulation of the cytokines osteopontin (SPP1), IL-10 and IL-18 and the chemokines CCL2, CCL19 and CXCL16. Of the 362 genes differentially expressed in the lymph node, IL-1beta and CXCL11 were up-regulated whereas IL18, CCL15 and CXCL12 were down-regulated. ISCOM-Matrix also modulated genes for pattern recognition receptors at the injection site (TLR2, TLR4, MRC1, PTX3, LGALS3) and in the lymph node (TLR4, RIG I, MDA5, OAS1, EIF2AK2, LGALS3). A high proportion of up-regulated interferon regulated genes indicated an interferon response. Thus, several genes, genetic pathways and biological processes were identified that are likely to shape the early immune response elicited by ISCOM-based vaccines. PMID- 22426326 TI - A possible relationship of natural killer T cells with humoral immune response to 23-valent pneumococcal polysaccharide vaccine in clinical settings. AB - Pneumococcal polysaccharide vaccine (PPV), a type-2 thymus-independent antigen, induces the activation of B cells by directly triggering their antigen receptors. Although this type of antigen generally does not undergo class switching from IgM to IgG, PPV has been known to induce IgG2 in vaccinated subjects, which suggests the possible involvement of certain innate immune lymphocytes supporting the activation of B cells and their class switching. In the present study, we addressed the possibility that natural killer (NK) T cells are involved in Ab production caused by PPV. We measured serum levels of IgG against pneumococcal capsular polysaccharides and the numbers of CD4(+), CD8(+) and CD4(-)CD8(-) double negative (DN) invariant NKT (iNKT) cells and CD3(+)CD56(+) NKT cells in the peripheral blood before and after PPV injection. IgG was increased after PPV injection, peaking at 4 weeks after injection in serotypes 6B, 19F and 23F and at 3 months in serotype 14. Low responders, whose serum concentrations of IgG peaked at less than double their original levels, constituted 16%, 13%, 13% and 16% of vaccinated subjects with regard to serotypes 6B, 14, 19F and 23F, respectively. A significant positive correlation was detected between an increase in DN iNKT cells and the elevation of anti-serotype 14 IgG; in serotype 19F, DN iNKT cells were more markedly increased in responders than in low responders. These results suggest that DN iNKT cells may be involved in IgG production caused by vaccination against pneumococcal capsular polysaccharides. PMID- 22426327 TI - Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, Phase I clinical trial. AB - There is an urgent need for a novel vaccine that is effective against human Enterovirus 71 (EV71) outbreaks. A double-blind, randomized controlled study was to evaluate the safety and immunogenicity of a human EV71 vaccine in healthy adults, children and infants. The vaccine dosages were 200 U and 400 U for children and adults, and 100 U, 200 U and 400 U for infants. Subjects were randomized to receive different dosages of the vaccine or placebo. Adults received intramuscular injection on Days 0, 14 and 28. Children and Infants received on Days 0, 28 and 56. The novel human EV71 inactivated vaccine was well tolerated and highly immunogenic in healthy volunteers, especially in infant populations. For immune response, the seropositive rates (with titers >=>=1:8) of neutralizing antibody [NTAb] increased to 100% for all dosage groups after the second vaccination. For NTAb seronegative infants before vaccination, after one dose, the NTAb GMTs were 29.7 (95% CI, 13.1-67.2), 10.1 (95% CI, 6.6-15.3), and 27.4 (95% CI, 14.3-52.2) in the 100 U, 200 U, and 400 U vaccine groups, respectively; after two doses, the GMTs were 114.1 (95% CI, 44.5-292.4), 159.5 (95% CI, 49.3-515.3), and 509.0 (95% CI, 181.3-1429.1), respectively. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01273246 and NCT01273233. PMID- 22426328 TI - The expression of ferritin, lactoferrin, transferrin receptor and solute carrier family 11A1 in the host response to BCG-vaccination and Mycobacterium tuberculosis challenge. AB - Iron is an essential cofactor for both mycobacterial growth during infection and for a successful protective immune response by the host. The immune response partly depends on the regulation of iron by the host, including the tight control of expression of the iron-storage protein, ferritin. BCG vaccination can protect against disease following Mycobacterium tuberculosis infection, but the mechanisms of protection remain unclear. To further explore these mechanisms, splenocytes from BCG-vaccinated guinea pigs were stimulated ex vivo with purified protein derivative from M. tuberculosis and a significant down-regulation of ferritin light- and heavy-chain was measured by reverse-transcription quantitative-PCR (P<=0.05 and <=0.01, respectively). The mechanisms of this down regulation were shown to involve TNFalpha and nitric oxide. A more in depth analysis of the mRNA expression profiles, including genes involved in iron metabolism, was performed using a guinea pig specific immunological microarray following ex vivo infection with M. tuberculosis of splenocytes from BCG vaccinated and naive guinea pigs. M. tuberculosis infection induced a pro inflammatory response in splenocytes from both groups, resulting in down regulation of ferritin (P<=0.05). In addition, lactoferrin (P<=0.002), transferrin receptor (P<=0.05) and solute carrier family 11A1 (P<=0.05), were only significantly down-regulated after infection of the splenocytes from BCG vaccinated animals. The results show that expression of iron-metabolism genes is tightly regulated as part of the host response to M. tuberculosis infection and that BCG-vaccination enhances the ability of the host to mount an iron restriction response which may in turn help to combat invasion by mycobacteria. PMID- 22426329 TI - Oral administration of HPV-16 L2 displayed on Lactobacillus casei induces systematic and mucosal cross-neutralizing effects in Balb/c mice. AB - The human papillomavirus (HPV) minor capsid protein, L2, is a good candidate for prophylactic vaccine development because L2-specific antibodies have cross neutralizing activity against diverse HPV types. Here, we developed a HPV mucosal vaccine candidate using the poly-gamma-glutamic acid synthetase A (pgsA) protein to display a partial HPV-16 L2 protein (N-terminal 1-224 amino acid) on the surface of Lactobacillus casei (L. casei). The oral immunization with L. casei-L2 induced productions of L2-specific serum IgG and vaginal IgG and IgA in Balb/c mice. To examine cross-neutralizing activity, we used a sensitive high-throughput neutralization assay based on HPV-16, -18, -45, -58, and bovine papillomavirus 1 (BPV1) pseudovirions. Our results revealed that mice vaccinated with L. casei-L2 not only generated neutralizing antibodies against HPV-16, but they also produced antibodies capable of cross-neutralizing the HPV-18, -45, and -58 pseudovirions. Consistent with previous reports, vaccination with HPV-16 L1 virus-like particles (VLPs) failed to show cross-neutralizing activity. Finally, we found that oral administration of L. casei-L2 induced significant neutralizing activities against genital infection by HPV-16, -18, -45, and -58 pseudovirions encoding a fluorescence reporter gene. These results collectively indicate that oral administration of L2 displayed on L. casei induces systemic and mucosal cross neutralizing effects in mice. PMID- 22426330 TI - Oral vaccination with Lactococcus lactis expressing the Vibrio cholerae Wzm protein to enhance mucosal and systemic immunity. AB - A gene associated with lipopolysaccharide (LPS) transport was cloned from a local clinical Vibrio cholerae O1 strain of the Ogawa serotype by using the Lactococcus lactis nisin-controlled expression (NICE) system. The V. cholerae wzm gene, which codes for an integral membrane transporter protein, was expressed and targeted to the cytoplasmic membrane, and was crudely isolated through simple centrifugation and SDS solubilization. To examine seroreactivity of this construct, rabbits were orally fed with 10(9) cfu/ml of live, recombinant L. lactis carrying the wzm gene, induced with nisin prior to administration. Recombinant plasmids were retrieved from L. lactis cultured directly from stool samples of inoculated rabbits. Reverse-transcriptase PCR of wzm using the retrieved plasmids confirmed transcription of this gene, indicating viability and stability of the recombinants in vivo. The L. lactis-Wzm construct elicited substantial levels of IgG and sIgA, and challenge with virulent V. cholerae O1 evoked severe diarrhoea in the naive, non-immunised control group, but not in those fed with either recombinant or non-recombinant L. lactis. Oral administration with recombinant L. lactis expressing the V. cholerae wzm gene increases both systemic and mucosal immunity, whereas L. lactis itself appears capable of protecting against the diarrhoeal symptoms caused by V. cholerae. Wzm is a conserved membrane protein associated with the LPS endotoxin, and together with the food-grade L. lactis, represent an attractive target for the development of a safer, live anti infective therapy against V. cholerae. PMID- 22426331 TI - Sliding inguinal hernias. AB - PURPOSE: To evaluate the frequency and anatomic presentation of sliding inguinal hernias as well as to analyze the technical difficulties during surgery and recurrence rate. METHODS: During 18 months we have recorded in a prospective manner data on all patients operated in one hospital for non-complicated inguinal hernia. All patients suspected of sliding variant have had their hernia sac opened and the sliding organ identified. All repairs were done using tension free technique. One year after discharge a telephone interview was performed with all patients to verify if they are free of recurrence. RESULTS: 464 patients were electively operated on for inguinal hernia during the study period. Sliding variant was diagnosed in 16 patients (3.4%). The sliding organs were: sigmoid colon in 10 patients (62.5%), urinary bladder in 2 patients (12.5%), appendix in 2 cases (12.5%) and caecum in 2 cases (12.5%). The tension free repair according to Lichtenstein or Rutkow-Robbins technique was performed in all cases. No major surgical complication was recorded. During 18 months follow-up we have seen one recurrence 3 months postoperatively. CONCLUSIONS: The sliding inguinal hernia is a rare finding. The risk of injury of sliding organ is minimal. If tension free technique is used, the risk of recurrence is similar to that of patients with non sliding inguinal hernia. PMID- 22426332 TI - Benign fibrous histiocytoma: particular aspects on confocal laser scanning microscopy. PMID- 22426333 TI - Principal component and cluster analysis of layer V pyramidal cells in visual and non-visual cortical areas projecting to the primary visual cortex of the mouse. AB - The long-distance corticocortical connections between visual and nonvisual sensory areas that arise from pyramidal neurons located within layer V can be considered as a subpopulation of feedback connections. The purpose of the present study is to determine if layer V pyramidal neurons from visual and nonvisual sensory cortical areas that project onto the visual cortex (V1) constitute a homogeneous population of cells. Additionally, we ask whether dendritic arborization relates to the target, the sensory modality, the hierarchical level, or laterality of the source cortical area. Complete 3D reconstructions of dendritic arbors of retrogradely labeled layer V pyramidal neurons were performed for neurons of the primary auditory (A1) and somatosensory (S1) cortices and from the lateral (V2L) and medial (V2M) parts of the secondary visual cortices of both hemispheres. The morphological parameters extracted from these reconstructions were subjected to principal component analysis (PCA) and cluster analysis. The PCA showed that neurons are distributed within a continuous range of morphologies and do not form discrete groups. Nevertheless, the cluster analysis defines neuronal groups that share similar features. Each cortical area includes neurons belonging to several clusters. We suggest that layer V feedback connections within a single cortical area comprise several cell types. PMID- 22426334 TI - Different timescales for the neural coding of consonant and vowel sounds. AB - Psychophysical, clinical, and imaging evidence suggests that consonant and vowel sounds have distinct neural representations. This study tests the hypothesis that consonant and vowel sounds are represented on different timescales within the same population of neurons by comparing behavioral discrimination with neural discrimination based on activity recorded in rat inferior colliculus and primary auditory cortex. Performance on 9 vowel discrimination tasks was highly correlated with neural discrimination based on spike count and was not correlated when spike timing was preserved. In contrast, performance on 11 consonant discrimination tasks was highly correlated with neural discrimination when spike timing was preserved and not when spike timing was eliminated. These results suggest that in the early stages of auditory processing, spike count encodes vowel sounds and spike timing encodes consonant sounds. These distinct coding strategies likely contribute to the robust nature of speech sound representations and may help explain some aspects of developmental and acquired speech processing disorders. PMID- 22426335 TI - Compensatory plasticity in the action observation network: virtual lesions of STS enhance anticipatory simulation of seen actions. AB - Observation of snapshots depicting ongoing motor acts increases corticospinal motor excitability. Such motor facilitation indexes the anticipatory simulation of observed (implied) actions and likely reflects computations occurring in the parietofrontal nodes of a cortical network subserving action perception (action observation network, AON). However, direct evidence for the active role of AON in simulating the future of seen actions is lacking. Using a perturb-and-measure transcranial magnetic stimulation (TMS) approach, we show that off-line TMS disruption of regions within (inferior frontal cortex, IFC) and upstream (superior temporal sulcus, STS) the parietofrontal AON transiently abolishes and enhances the motor facilitation to observed implied actions, respectively. Our findings highlight the critical role of IFC in anticipatory motor simulation. More importantly, they show that disruption of STS calls into play compensatory motor simulation activity, fundamental for counteracting the noisy visual processing induced by TMS. Thus, short-term plastic changes in the AON allow motor simulation to deal with any gap or ambiguity of ever-changing perceptual worlds. These findings support the active, compensatory, and predictive role of frontoparietal nodes of the AON in the perception and anticipatory simulation of implied actions. PMID- 22426336 TI - Distinct frontal networks are involved in adapting to internally and externally signaled errors. AB - Errors trigger changes in behavior that help individuals adapt to new situations. The dorsal anterior cingulate cortex (dACC) is thought to be central to this response, but more lateral frontal regions are also activated by errors and may make distinct contributions. We investigated error processing by studying 2 distinct error types: commission and timing. Thirty-five subjects performed a version of the Simon Task designed to produce large number of errors. Commission errors were internally recognized and were not accompanied by explicit feedback. In contrast, timing errors were difficult to monitor internally and were explicitly signaled. Both types of error triggered changes in behavior consistent with increased cognitive control. As expected, robust activation within the dACC and bilateral anterior insulae (the Salience Network) was seen for commission errors. In contrast, timing errors were not associated with activation of this network but did activate a bilateral network that included the right ventral attentional system. Common activation for both error types occurred within the pars operculari and angular gyri. These results show that the dACC does not respond to all behaviorally salient errors. Instead, the error-processing system is multifaceted, and control can be triggered independently of the dACC when feedback is unexpected. PMID- 22426337 TI - miR-143, miR-222, and miR-452 are useful as tumor stratification and noninvasive diagnostic biomarkers for bladder cancer. AB - Altered microRNA (miRNA) expression may occur early in bladder cancer and may play a role in carcinogenesis and tumor behavior. We evaluated whether alterations in miRNA expression could improve disease stratification and outcome prognosis in bladder tumors and noninvasive diagnosis in urinary samples. miR 143, miR-222, and miR-452 expression levels were analyzed by quantitative RT-PCR (RT-qPCR) in paired urinary and matching tumors and in two independent prospective series of tumors and urinary specimens. Differential expression of miR-143, miR-222, and miR-452 in urine were verified by in situ hybridization in matching tumors. Tumor miRNA expression by RT-qPCR correlated with tumor grade, size, and presence of carcinoma in situ for miR-222, recurrence (miR-222 and miR 143), progression (miR-222 and miR-143), disease-specific survival (miR-222), and overall survival (miR-222). Protein expression patterns of potential miRNA targets, including vascular endothelial growth factor, BCL2, v-erb-b2 erythroblastic leukemia viral oncogene (ERBB) homolog 3, and ERBB4, were evaluated by IHC in tissue arrays containing tumors for which miRNAs were assessed by RT-qPCR. Target expression correlated with expression of their predicted regulatory miRNAs, recurrence (ERBB3), progression (ERBB4), disease specific survival (ERBB3 and ERBB4), and overall survival (ERBB3 and ERBB4). Furthermore, RT-qPCR of miR-452 (area under the curve, 0.848) and miR-222 (area under the curve, 0.718) in urine provided high accuracies for bladder cancer diagnosis. Thus, bladder tumors were characterized by changes in miRNA expression that could aid in tumor stratification and clinical outcome prognosis, and miRNAs were detected in urinary specimens for noninvasive diagnosis. PMID- 22426338 TI - Focal immune-mediated white matter demyelination reveals an age-associated increase in axonal vulnerability and decreased remyelination efficiency. AB - In addition to being an established risk factor for neurodegenerative diseases, age is increasingly recognized as adversely influencing regeneration. Accumulating evidence also suggests that age plays important, although poorly understood, roles with respect to course and prognosis in the degenerative and untreatable later phase of multiple sclerosis. Two experimental models of multiple sclerosis have been particularly influential in modeling the different aspects of neuronal injury and regeneration: global experimental autoimmune encephalomyelitis and focal toxin-mediated injury. Against this background, we report a focal model of immune-mediated demyelinating injury that reliably generates targeted primary demyelination and axonal injury. A detailed pathologic characterization of this model, modified extensively from an earlier study, showed that aged adult animals exhibited increased vulnerability to axonal injury and reduced efficiency of remyelination compared with younger animals. More important, remyelination in aged animals was predominantly Schwann cell mediated, in contrast to the central oligodendrocyte-mediated remyelination that predominated in younger rodents. Together, these findings establish an experimental platform to further study the influence of age on injury and repair in a biologically relevant model of human demyelinating injury. PMID- 22426339 TI - IFN-gamma-driven IDO production from macrophages protects IL-4Ralpha-deficient mice against lethality during Schistosoma mansoni infection. AB - The balance between alternatively activated macrophages (AAMs)/M2 cells and classically activated macrophages (M1 cells) is largely dependent on the effects of IL-4 and interferon (IFN)-gamma, respectively. Although AAM/M2 cells can suppress inflammation and repair damaged tissue, M1 cells produce an array of pro inflammatory molecules. Macrophage effector functions are critical for host protection against many infectious diseases, but it remains unknown whether lethal immunopathological characteristics, caused by Schistosoma mansoni infection in IL-4 receptor alpha-deficient mice (IL-4Ralpha(-/-)), results from the absence of M2 cells or increased numbers of M1 cells. In this study, we generated mice that completely lack IL-4Ralpha signaling in the context of a macrophage-specific loss of IFN-gamma responsiveness (MIIG * IL-4Ralpha(-/-)). Contrary to what we expected, acute schistosomiasis resulted in greater liver injury and mortality in MIIG * IL-4Ralpha(-/-) mice compared with IL-4Ralpha(-/-) mice. Greater tissue injury in MIIG * IL-4Ralpha(-/-) mice was likely because of a lack of indoleamine 2,3 dioxygenase (IDO), a critical regulator of immunosuppression. Indeed, MIIG * IL-4Ralpha(-/-) failed to up-regulate IDO expression, and IL-4Ralpha(-/-) mice treated with an IDO antagonist underwent greater liver damage and mortality compared with mock-treated IL-4Ralpha(-/-) mice. Thus, we propose that, in the absence of AAM/M2 cells, IFN-gamma-induced M1 cells suppress tissue-damaging inflammation during acute schistosomiasis through an IDO-dependent mechanism. PMID- 22426341 TI - Tafa-3 encoding for a secretory peptide is expressed in the mouse pars tuberalis and is affected by melatonin 1 receptor deficiency. AB - The hypophysial pars tuberalis (PT) is an important interface between neuroendocrine brain centers (hypothalamus, pineal organ) and the anterior lobe of the hypophysis (PD). The best investigated role of the PT is the control of seasonally changing functions. In mammals, melatonin secreted from the pineal organ represents a major input signal to the PT. By acting upon melatonin type 1 receptors (MT1) melatonin controls the functional activity of the PT. Most interestingly, the PT sends its output signals in two directions: via a "retrograde" pathway to the hypothalamus and via an "anterograde" pathway to the PD. TSH has been identified as "retrograde" messenger, while endocannabinoids function as messengers of the "anterograde" pathway. Here we show in mice that the PT expresses Tafa-3 encoding for a secretory peptide. In the PT of wild type mice Tafa-3 mRNA levels varied between day and night: they were low at mid-day and high at mid-night. This day/night difference was not observed in the PT of mice with a targeted deletion of the MT1 receptor indicating that Tafa-3 mRNA expression in the PT is controlled by melatonin acting through the MT1 receptor. Notably, Tafa-3 expression was not restricted to the PT, but was also found in other brain regions, such as the hippocampus, the habenular and thalamic nuclei. In these regions, Tafa-3 expression did not display a day/night difference and was not affected by MT1-deficiency. Thus, Tafa-3 expression appears to be controlled by region-specific mechanisms. Our data suggest that TAFA-3 is a signaling molecule from the PT and provides further evidence for the emerging concept that the PT rather than relying upon highly organ-specific messengers employs a cocktail of signaling molecules that also operate in other brain systems. PMID- 22426342 TI - BioQ: tracing experimental origins in public genomic databases using a novel data provenance model. AB - Public genomic databases, which are often used to guide genetic studies of human disease, are now being applied to genomic medicine through in silico integrative genomics. These databases, however, often lack tools for systematically determining the experimental origins of the data. RESULTS: We introduce a new data provenance model that we have implemented in a public web application, BioQ, for assessing the reliability of the data by systematically tracing its experimental origins to the original subjects and biologics. BioQ allows investigators to both visualize data provenance as well as explore individual elements of experimental process flow using precise tools for detailed data exploration and documentation. It includes a number of human genetic variation databases such as the HapMap and 1000 Genomes projects. AVAILABILITY AND IMPLEMENTATION: BioQ is freely available to the public at http://bioq.saclab.net. PMID- 22426343 TI - GRiP: a computational tool to simulate transcription factor binding in prokaryotes. AB - MOTIVATION: Transcription factors (TFs) are proteins that regulate gene activity by binding to specific sites on the DNA. Understanding the way these molecules locate their target site is of great importance in understanding gene regulation. We developed a comprehensive computational model of this process and estimated the model parameters in (N.R.Zabet and B.Adryan, submitted for publication). RESULTS: GRiP (gene regulation in prokaryotes) is a highly versatile implementation of this model and simulates the search process in a computationally efficient way. This program aims to provide researchers in the field with a flexible and highly customizable simulation framework. Its features include representation of DNA sequence, TFs and the interaction between TFs and the DNA (facilitated diffusion mechanism), or between various TFs (cooperative behaviour). The software will record both information on the dynamics associated with the search process (locations of molecules) and also steady-state results (affinity landscape, occupancy-bias and collision hotspots). AVAILABILITY: http://logic.sysbiol.cam.ac.uk/grip, program and source code PMID- 22426344 TI - Proteus: a web-based, context-specific modelling tool for molecular networks. AB - SUMMARY: Molecular networks are often studied in diverse cellular or experimental contexts, with highly context-specific details. Modelling introduces further choices as to levels of mathematical description. The resulting possibilities are difficult to explore rapidly, hampering the integration of modelling and experiment. We have developed Proteus, a web-based, context-specific tool for building compartmentalized, ordinary differential equation (ODE) models. It is inspired by the idea of a molecular 'toolkit' for Ca(2+) signalling. Toolkits in Proteus are context-independent representations of biological systems as sets of components, which may correspond to mechanisms of differing levels of complexity. Users pick and choose components from a toolkit and, for each component, pick and choose from different mechanisms, each of which describes a different instantiation of the component's mechanism. Proteus combines these choices into a system of ODEs, which may then be downloaded in SBML (Systems Biology Markup Language), Matlab or Fortran format and independently analyzed. Toolkits, components and mechanisms are user-constructible, either de novo or by cannibalizing existing models, including all those in the Biomodels database. A wide variety of context-specific models may thereby be rapidly built, modified and explored. AVAILABILITY AND IMPLEMENTATION: Proteus, implemented in C#, and a prototype toolkit for modelling calcium signalling are freely and universally available at www.modularmodeling.com CONTACT: gnad.florian@gene.com; jeremy@hms.harvard.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22426345 TI - GOHTAM: a website for 'Genomic Origin of Horizontal Transfers, Alignment and Metagenomics'. AB - MOTIVATION: This website allows the detection of horizontal transfers based on a combination of parametric methods and proposes an origin by researching neighbors in a bank of genomic signatures. This bank is also used to research an origin to DNA fragments from metagenomics studies. RESULTS: Different services are provided like the possibility of inferring a phylogenetic tree with sequence signatures or comparing two genomes and displaying the rearrangements that happened since their separation. AVAILABILITY AND IMPLEMENTATION: http://gohtam.rpbs.univ-paris diderot.fr/ PMID- 22426346 TI - EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. AB - PURPOSE: To assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. METHODS: In this multicenter, double-masked, primarily indocyanine green angiography-guided trial, 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly ranibizumab/sham injections starting Day 1, and re-treated (Months 3-5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine green angiography-assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected visual acuity at Month 6 and safety. RESULTS: At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change +/- standard deviation in best corrected visual acuity (letters) was 10.9 +/- 10.9 (verteporfin PDT + ranibizumab), 7.5 +/- 10.6 (verteporfin PDT), and 9.2 +/- 12.4 (ranibizumab). There were no new safety findings with either drug used alone or in combination. CONCLUSION: Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy. All treatments were well tolerated over 6 months. PMID- 22426347 TI - The physiological origin of task-evoked systemic artefacts in functional near infrared spectroscopy. AB - A major methodological challenge of functional near-infrared spectroscopy (fNIRS) is its high sensitivity to haemodynamic fluctuations in the scalp. Superficial fluctuations contribute on the one hand to the physiological noise of fNIRS, impairing the signal-to-noise ratio, and may on the other hand be erroneously attributed to cerebral changes, leading to false positives in fNIRS experiments. Here we explore the localisation, time course and physiological origin of task evoked superficial signals in fNIRS and present a method to separate them from cortical signals. We used complementary fNIRS, fMRI, MR-angiography and peripheral physiological measurements (blood pressure, heart rate, skin conductance and skin blood flow) to study activation in the frontal lobe during a continuous performance task. The General Linear Model (GLM) was applied to analyse the fNIRS data, which included an additional predictor to account for systemic changes in the skin. We found that skin blood volume strongly depends on the cognitive state and that sources of task-evoked systemic signals in fNIRS are co-localized with veins draining the scalp. Task-evoked superficial artefacts were mainly observed in concentration changes of oxygenated haemoglobin and could be effectively separated from cerebral signals by GLM analysis. Based on temporal correlation of fNIRS and fMRI signals with peripheral physiological measurements we conclude that the physiological origin of the systemic artefact is a task evoked sympathetic arterial vasoconstriction followed by a decrease in venous volume. Since changes in sympathetic outflow accompany almost any cognitive and emotional process, we expect scalp vessel artefacts to be present in a wide range of fNIRS settings used in neurocognitive research. Therefore a careful separation of fNIRS signals originating from activated brain and from scalp is a necessary precondition for unbiased fNIRS brain activation maps. PMID- 22426348 TI - The story of the initial dip in fMRI. AB - Over the past 20 years much attention has been given to characterizing the spatial accuracy of fMRI based signals and to techniques that improve on its co localization with neuronal activity. While the vast majority of fMRI studies have always used the conventional positive BOLD signal, alternative contrast options have demonstrated superior spatial specificity. One of these options surfaced shortly after the initial BOLD fMRI demonstrations and was motivated by optical imaging studies which revealed an early signal change that was much smaller but spatially more specific than the delayed positive response. This early signal change was attributed to oxygenation changes prior to any subsequent blood flow increases. After observation of this biphasic hemodynamic response in fMRI, because this early response resulted in a small MR signal decrease prior to the onset of the large signal increase, it became known as the "initial dip". While the initial dip in fMRI was subsequently reported by many studies, including those in humans, monkeys, and cats, there were conflicting views about the associated mechanisms and whether it could be generalized across brain regions or species, in addition to whether or not it would prove fruitful for neuroscience. These discrepancies, along with the implications that the initial dip might increase the spatial specificity of BOLD fMRI from 2 to 3mm to something more closely associated with neural activity, resulted in lot of buzz and controversy in the community for many years. In this review, the authors provide an account of the story of the initial dip in MR based functional imaging from the Minnesota perspective, where the first demonstrations, characterizations, and applications of the initial dip commenced. PMID- 22426349 TI - Functional imaging correlates of impaired distractor suppression following sleep deprivation. AB - Sleep deprivation (SD) has been shown to affect selective attention but it is not known how two of its component processes: target enhancement and distractor suppression, are affected. To investigate, young volunteers either attended to houses or were obliged to ignore them (when attending to faces) while viewing superimposed face-house pictures. MR signal enhancement and suppression in the parahippocampal place area (PPA) were determined relative to a passive viewing control condition. Sleep deprivation was associated with lower PPA activation across conditions. Critically SD specifically impaired distractor suppression in selective attention, leaving target enhancement relatively preserved. These findings parallel some observations in cognitive aging. Additionally, following SD, attended houses were not significantly better recognized than ignored houses in a post-experiment test of recognition memory contrasting with the finding of superior recognition of attended houses in the well-rested state. These results provide evidence for co-encoding of distracting information with targets into memory when one is sleep deprived. PMID- 22426350 TI - Effects of lactate on the early visual cortex of non-human primates, investigated by pharmaco-MRI and neurochemical analysis. AB - In contrast to the limited use of functional magnetic resonance imaging (fMRI) in clinical diagnostics, it is currently a mainstay of neuroimaging in clinical and basic brain research. However, its non-invasive use in combination with its high temporal and spatial resolution would make fMRI a perfect diagnostic tool. We are interested in whether a pharmacological challenge imposed on the brain can be reliably traced by the blood oxygen level-dependent (BOLD) signal and possibly further exploited for diagnostics. We have chosen a systemic challenge with lactate and pyruvate to test whether the physiological formation of these monocarboxylic acids contributes to the BOLD signal and can be detected using fMRI. This information is also of interest because lactate levels in the cerebrospinal fluid rise concomitantly with reduced vascular responsiveness of the brain during the progression of Alzheimer disease (AD). We studied the BOLD response after a low-dose lactate challenge and monitored the induced plasma lactate levels in anesthetized non-human primates. We observed reliable lactate induced BOLD responses, which could be confirmed at population and individual level by their strong correlation with systemic lactate concentrations. Comparable BOLD effects where observed after a slow infusion of pyruvate. We show here that physiological changes in lactate and pyruvate levels are indeed reflected in the BOLD signal, and describe the technical prerequisites to reliably trace a lactate challenge using BOLD-fMRI. PMID- 22426351 TI - A BOLD signature of eyeblinks in the visual cortex. AB - We are usually unaware of the brief but large illumination changes caused by blinks, presumably because of blink suppression mechanisms. In fMRI however, increase of the BOLD signal was reported in the visual cortex, e.g. during blocks of voluntary blinks (Bristow, Frith and Rees, 2005) or after spontaneous blinks recorded during the prolonged fixation of a static stimulus (Tse, Baumgartner and Greenlee, 2010). We tested whether such activation, possibly related to illumination changes, was also present during standard fMRI retinotopic and visual experiments and was large enough to contaminate the BOLD signal we are interested in. We monitored in a 3T scanner the eyeblinks of 14 subjects who observed three different types of visual stimuli, including periodic rotating wedges and contracting/expanding rings, event-related Mondrians and graphemes, while fixating. We performed event-related analyses on the set of detected spontaneous blinks. We observed large and widespread BOLD responses related to blinks in the visual cortex of every subject and whatever the visual stimulus. The magnitude of the modulation was comparable to visual stimulation. However, blink-related activations lay mostly in the anterior parts of retinotopic visual areas, coding the periphery of the visual field well beyond the extent of our stimuli. Blinks therefore represent an important source of BOLD variations in the visual cortex and a troublesome source of noise since any correlation, even weak, between the distribution of blinks and a tested protocol could trigger artifactual activities. However, the typical signature of blinks along the anterior calcarine and the parieto-occipital sulcus allows identifying, even in the absence of eyetracking, fMRI protocols possibly contaminated by a heterogeneous distribution of blinks. PMID- 22426353 TI - Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update. AB - Electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) is an age-related, self-limiting disorder characterised by epilepsy with different seizure types, global or selective neuropsychological regression, motor impairment, and a typical EEG pattern of continuous epileptiform activity for more than 85% of non-rapid eye movement (NREM) sleep. Although the first description of ESES/CSWS dates back to 1971, an agreement about the optimal treatment for this condition is still lacking. ESES/CSWS is rare (incidence is 0.2-0.5% of all childhood epilepsies) and no controlled clinical trials have been conducted to establish the efficacy of different antiepileptic drugs; only uncontrolled studies and case reports are reported in the literature. Treatment options for ESES/CSWS include some antiepileptic drugs (valproic acid, ethosuximide, levetiracetam, and benzodiazepines), steroids, immunoglobulins, the ketogenic diet, and surgery (multiple subpial transections). In this study, the comparative value of each of these treatments is reviewed and a personal therapeutic approach is proposed. PMID- 22426352 TI - Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus. AB - The development and maturation of semi-invariant natural killer T cells (iNKT cells) rely on the recognition of self antigens presented by CD1d restriction molecules in thymus. The nature of the stimulatory thymic self lipids remains elusive. We isolated lipids from thymocytes and found that ether-bonded mono alkyl glycerophosphates and the precursors and degradation products of plasmalogens stimulated iNKT cells. Synthetic analogs showed high potency in activating thymic and peripheral iNKT cells. Mice deficient in the peroxisomal enzyme glyceronephosphate O-acyltransferase (GNPAT), essential for the synthesis of ether lipids, had significant alteration of the thymic maturation of iNKT cells and fewer iNKT cells in both thymus and peripheral organs, which confirmed the role of ether-bonded lipids as iNKT cell antigens. Thus, peroxisome-derived lipids are nonredundant self antigens required for the generation of a full iNKT cell repertoire. PMID- 22426354 TI - Training-dependent cognitive advantage is suppressed at high altitude. AB - Ascent to high altitude is associated with decreases in cognitive function and work performance as a result of hypoxia. Some workers with special jobs typically undergo intensive mental training because they are expected to be agile, stable and error-free in their job performance. The purpose of this study was to determine the risk to cognitive function acquired from training following hypoxic exposure. The results of WHO neurobehavioral core tests battery (WHO-NCTB) and Raven's standard progressive matrices (RSPM) tests of a group of 54 highly trained military operators were compared with those of 51 non-trained ordinary people and were investigated at sea level and on the fifth day after arrival at high altitudes (3900m). Meanwhile, the plasma levels of brain-derived neurotrophic factor (BDNF), interleukin 1beta (IL-1beta) and vascular endothelial growth factor (VEGF) were examined. The result showed that at sea level, the trained group exhibited significantly better performance on neurobehavioral and RSPM tests. At high altitude, both groups had decreased accuracy in most cognitive tests and took longer to finish them. More importantly, the highly trained subjects showed more substantial declines than the non-trained subjects in visual reaction accuracy, auditory reaction speed, digit symbol scores, ability to report correct dots in a pursuit aiming test and total RSPM scores. This means that the training-dependent cognitive advantages in these areas were suppressed at high altitudes. The above phenomenon maybe associated with decreased BDNF and elevated inflammatory factor during hypoxia, and other mechanisms could not be excluded. PMID- 22426355 TI - Reaction of the mussel Mytilus galloprovincialis (Bivalvia) to Eugymnanthea inquilina (Cnidaria) and Urastoma cyprinae (Turbellaria) concurrent infestation. AB - In total 480 individuals of Mytilus galloprovincialis were sampled monthly from October 2009 to September 2010, at the shellfish farm in the Mali Ston Bay, south Adriatic Sea (Croatia) in order to assess the extent of pathology imposed by two parasites, Eugymnanthea inquilina (Cnidaria) and Urastoma cyprinae (Turbellaria). Although a deteriorating impact on host reproduction or condition index was lacking, we evidenced ultrastructural and functional alteration in host cells at the attachment site. Ultrastructural changes included hemocytic encapsulation of the turbellarian and cell desquamation in medusoid infestation. Caspase positive reaction inferred by immunohistochemistry (IHC) was triggered in cases of turbellarian infestation, in contrast with hydroids, suggesting that the former exhibits more complex host-parasite interaction, reflected in the persistent attempts of the parasite to survive bivalve reaction. We have evidenced that both organisms trigger specific host reaction that although not costly in terms of host reproductive cycle or growth, results in mild tissue destruction and hemocyte activation. A lower degree of tissue reaction was observed in cases of hydroid infestation, compared to turbellarian. PMID- 22426356 TI - Uncaria tomentosa extracts protect human erythrocyte catalase against damage induced by 2,4-D-Na and its metabolites. AB - The effect of ethanolic and aqueous extracts from leaves and bark of Uncaria tomentosa was studied, with particular attention to catalase activity (CAT - EC. 1.11.1.6). We observed that all tested extracts, at a concentration of 250 MUg/mL were not toxic to erythrocyte catalase because they did not decreased its activity. Additionally, we investigated the protective effect of extracts on changes in CAT activity in the erythrocytes incubated with sodium salt of 2,4 dichlorophenoxyacetic acid (2,4-D-Na) and its metabolites i.e., 2,4 dichlorophenol (2,4-DCP) and catechol. Previous investigations showed that these chemicals decreased activity of erythrocyte catalase (Bukowska et al., 2000; Bukowska and Kowalska, 2004). The erythrocytes were divided into two portions. The first portion was incubated for 1 and 5h at 37 degrees C with 2,4-D-Na, 2,4 DCP and catechol, and second portion was preincubated with extracts for 10 min and then incubated with xenobiotics for 1 and 5h. CAT activity was measured in the first and second portion of the erythrocytes. We found a protective effect of the extracts from U. tomentosa on the activity of catalase incubated with xenobiotics studied. Probably, phenolic compounds contained in U. tomentosa scavenged free radicals, and therefore protected active center (containing -SH groups) of catalase. PMID- 22426357 TI - Hypercalcemia, hypervitaminosis A and 3-epi-25-OH-D3 levels after consumption of an "over the counter" vitamin D remedy. a case report. AB - Intoxication from vitamin D supplements has been rarely reported but, nowadays, it occurs more frequently. 3-epi-25-OH-D(3) is highly prevalent in adults and it is considered of biological relevance. We report a case of vitamin D toxicity with hypercalcemia, acute renal failure and hypervitaminosis A after consuming an over-the-counter vitamin D supplement. Our data suggest that the contribution of 3-epi-25-OH-D(3) is not altered during vitamin D toxicity, although the serum levels of 25-OH-D(3) and 3-epi-25-OH-D(3) may display a different rate of clearance. The patient also displayed hypervitaminosis A unrelated to diet, possibly caused by renal failure related to the hypercalcemia induced by vitamin D toxicity. Because of the increasing use of over-the-counter vitamin D supplements and the potential iatrogenic hypercalcemia related to hypervitaminosis A, the present case highlights the importance of evaluating both the use of (non-) prescribed medication and vitamin A status during vitamin D toxicity. PMID- 22426359 TI - Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities. AB - Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure-activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. PMID- 22426358 TI - Sodium arsenite represses the expression of myogenin in C2C12 mouse myoblast cells through histone modifications and altered expression of Ezh2, Glp, and Igf 1. AB - Arsenic is a toxicant commonly found in water systems and chronic exposure can result in adverse developmental effects including increased neonatal death, stillbirths, and miscarriages, low birth weight, and altered locomotor activity. Previous studies indicate that 20 nM sodium arsenite exposure to C2C12 mouse myocyte cells delayed myoblast differentiation due to reduced myogenin expression, the transcription factor that differentiates myoblasts into myotubes. In this study, several mechanisms by which arsenic could alter myogenin expression were examined. Exposing differentiating C2C12 cells to 20 nM arsenic increased H3K9 dimethylation (H3K9me2) and H3K9 trimethylation (H3K9me3) by 3 fold near the transcription start site of myogenin, which is indicative of increased repressive marks, and reduced H3K9 acetylation (H3K9Ac) by 0.5-fold, indicative of reduced permissive marks. Protein expression of Glp or Ehmt1, a H3 K9 methyltransferase, was also increased by 1.6-fold in arsenic-exposed cells. In addition to the altered histone remodeling status on the myogenin promoter, protein and mRNA levels of Igf-1, a myogenic growth factor, were significantly repressed by arsenic exposure. Moreover, a 2-fold induction of Ezh2 expression, and an increased recruitment of Ezh2 (3.3-fold) and Dnmt3a (~2-fold) to the myogenin promoter at the transcription start site (-40 to +42), were detected in the arsenic-treated cells. Together, we conclude that the repressed myogenin expression in arsenic-exposed C2C12 cells was likely due to a combination of reduced expression of Igf-1, enhanced nuclear expression and promoter recruitment of Ezh2, and altered histone remodeling status on myogenin promoter (-40 to +42). PMID- 22426360 TI - Taurine protects methamphetamine-induced developmental angiogenesis defect through antioxidant mechanism. AB - Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using 1H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed a more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-kappaB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use. PMID- 22426361 TI - Building bridges between the public and private sectors. PMID- 22426363 TI - Positive Phase II interim data on AE37 cancer vaccine released. PMID- 22426365 TI - Letter from the editor. PMID- 22426366 TI - Use of intranasal live attenuated influenza vaccine in individuals with asthma or a history of wheezing. PMID- 22426367 TI - The cost efficiency of HPV vaccines is significantly underestimated due to omission of conisation-associated prematurity with neonatal mortality and morbidity. AB - INTRODUCTION: Cervical intraepithelial neoplasia (CIN) represents the precursor of invasive cervical cancer and is associated with human papillomavirus infection (HPV) against which two vaccines have been approved in the last years. Standard treatments of high-grade CIN are conisation procedures, which are associated with an increased risk of subsequent pregnancy complications like premature delivery and possible subsequent life-long disability. HPV vaccination has therefore the potential to decrease neonatal morbidity and mortality. This has not been taken into account in published cost-effectiveness models. MATERIAL AND METHODS: We calculated the possible reduction rate of conisations for different vaccination strategies for Germany. Using this rate, we computed the reduction of conisation associated preterm deliveries, life-long disability and neonatal death due to prematurity. The number of life-years saved (LYS) and gain in quality-adjusted life-years (QALYs) was estimated. The incremental costs per LYS / additional QALY were calculated. RESULTS: The reduction of conisation procedures was highest in scenario I (vaccination coverage 90% prior to HPV exposition) with about 50%. The costs per LYS or additional QALY were lowest in scenario I, II and III with 45,101 ? or 43,505-47,855 ? and rose up to 60,544 ? or 58,401-64,240 ? in scenario V (50% vaccinated prior to sexual activity + additional 20% catch-up at a mean age of 20 y). CONCLUSION: Regarding the HPV 16 / 18 vaccines as "vaccines against conisation-related neonatal morbidity and mortality" alone, they already have the potential to be cost-effective. This effect adds up to reduction of cervical cancer cases and decreased costs of screening for CIN. Further studies on cost-effectiveness of HPV vaccination should take the significant amount of neonatal morbidity and mortality into account. PMID- 22426368 TI - Bexsero: a multicomponent vaccine for prevention of meningococcal disease. AB - Serogroup B meningococcal (MenB) disease remains a serious public health problem for which a cross-protective vaccine effective against a wide range of MenB isolates has not been available. Novartis Vaccines has developed a vaccine for the prevention of MenB disease that contains four antigenic components: factor H binding protein (fHbp), neisserial adhesin A (NadA), Neisseria heparin binding antigen (NHBA) and outer membrane vesicles from a New Zealand epidemic strain (which provides PorA). This vaccine has been submitted for regulatory review in Europe so it is timely to review the design of the vaccine, results to date in clinical studies and the potential strain coverage provided by the vaccine. It is also critical to discuss the key issues for the long-term success of the vaccine which include strain coverage, potential persistence of protection, potential effects on carriage of MenB strains, potential for escape mutants and cost effectiveness. PMID- 22426369 TI - Characterization and long-term persistence of immune response following two doses of an AS03A-adjuvanted H1N1 influenza vaccine in healthy Japanese adults. AB - Background Long-term persistence of immune response and safety of two doses of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an alpha-tocopherol oil-in-water emulsion-based Adjuvant System) administered 21 d apart was evaluated in Japanese adults [NCT00989612]. Methods One-hundred healthy subjects aged 20-64 y (stratified [1:1] into two age strata 20-40 y and 41-64 y) received 21 d apart, two doses of AS03-adjuvanted 3.75ug haemagglutinin (HA) H1N1 2009 vaccine. Immunogenicity data by haemagglutination inhibition (HI) assay six months after the first vaccine dose (Day 182) and microneutralization assay following each of the two vaccine doses (Days 21 and 42) and at Day 182 are reported here. Results Persistence of strong HI immune response was observed at Day 182 that met the US and European regulatory thresholds for pandemic influenza vaccines (seroprotection rate: 95%; seroconversion rate: 93%; geometric mean fold rise: 20). The neutralizing antibody response against the A/Netherlands/602/2009 strain (antigenically similar to vaccine-strain) persisted for at least up to Day 182 (vaccine response rate: 76%; geometric mean titer: 114.4) and paralleled the HI immune response at all time points. No marked difference was observed in HI antibody persistence and neutralising antibody response between the two age strata. The vaccine had a clinically-acceptable safety profile. Conclusion Two priming doses of H1N1 2009 pandemic influenza vaccine induced an immune response persisting for at least six months after the first vaccine dose. This could be beneficial in evaluating the importance and effect of vaccination with this AS03 adjuvanted pandemic influenza vaccine. PMID- 22426370 TI - Improvement of influenza vaccine strain A/Vietnam/1194/2004 (H5N1) growth with the neuraminidase packaging sequence from A/Puerto Rico/8/34. AB - H5N1 influenza candidate vaccine viruses were developed using the "6+2" approach. The hemagglutinin (HA) and neuraminidase (NA) genes were derived from the popular H5N1 virus and the remaining six internal segments were derived from the A/Puerto Rico/8/34 strain (H1N1, PR8). However, some of these candidate strains have been reported to produce relatively low yields in vaccine manufacture. In this study, we found that the NA vRNA of the A/Vietnam/1194/2004 strain (H5N1, VN1194) was poorly packaged into recombinant viruses with a backbone of PR8 genes, which resulted in the formation of defective virions that did not include the NA vRNA in the genome. Using recombinant DNA techniques, we constructed a chimeric NA gene with the coding region of VN1194 NA flanked by the packaging signal sequence of the PR8 NA gene (41 bp form the 3' end of the vRNA and 67 bp from the 5' end). The packaging of the NA vRNA was restored to normal levels in the recombinant viruses containing the chimeric NA gene. Recombinant viruses containing the chimeric NA replicated much better in chicken embryonated eggs than viruses with the wild-type NA from VN1194. These findings suggest a novel strategy to improve in ovo growth of vaccine strains and to increase the number of vaccine doses available to save people if a pandemic were to occur. PMID- 22426371 TI - Superior immunogenicity of seasonal influenza vaccines containing full dose of MF59 ((r)) adjuvant: results from a dose-finding clinical trial in older adults. AB - BACKGROUND: MF59-adjuvanted influenza vaccines have superior immunogenicity in older adults compared with non-adjuvanted vaccines. We assessed whether changing formulation (i.e., increasing H3N2 antigen or decreasing the quantity of adjuvant) of the licensed, MF59-adjuvanted trivalent influenza subunit vaccine Fluad ((r)) (Novartis Vaccines and Diagnostics) improves the risk-benefit profile in vaccinees aged >= 65 years. RESULTS: A significant dose-response relationship was observed between antibody levels and MF59 dose; full dose formulations elicited the strongest immune responses, meeting immunogenicity licensure criteria by Day 8. Doubling H3N2 antigen content did not increase the response to this antigen. Increased frequency of circulating CD4+ T-cells specific for vaccine antigens were detected by Day 8; magnitude and functional profile of the CD4+ T-cell response was comparable across the different vaccination groups. Mild to moderate solicited local reactions were more common with vaccines formulated with higher doses of MF59 ((r)) , but there were no MF59- or antigen dose-related increase in the frequency of solicited systemic reactions or unsolicited adverse events and serious adverse events. METHODS: We report on 357 subjects who received one of eight intramuscular vaccine formulations. Hemagglutination inhibiting antibodies were assayed on Days 1, 8 and 22; magnitude and functional profile of CD4+ T-cell responses to vaccine antigens were assessed in subsets. Solicited adverse reactions were reported via diary cards for seven days after vaccination and spontaneous adverse events were monitored throughout the study. CONCLUSION: This study confirms that the current formulation is the optimal one for MF59-adjuvanted influenza vaccine for use in older adults. PMID- 22426372 TI - Evaluation of the establishment of herd immunity in the population by means of serological surveys and vaccination coverage. AB - The necessary herd immunity blocking the transmission of an infectious agent in the population is established when the prevalence of protected individuals is higher than a critical value, called the herd immunity threshold. The establishment of herd immunity in the population can be determined using the vaccination coverage and seroepidemiological surveys. The vaccination coverage associated with herd immunity (V(c)) can be determined from the herd immunity threshold and vaccine effectiveness. This method requires a vaccine-specific effectiveness evaluation, and it can be used only for the herd immunity assessment of vaccinated communities in which the infectious agent is not circulating. The prevalence of positive serological results associated with herd immunity can be determined from the herd immunity threshold, in terms of prevalence of antibodies (p(c)) and serological test performance. The herd immunity is established when the prevalence of antibodies is higher than pc. This method can be used to assess the establishment of herd immunity in different population groups, both when the infectious agent is circulating and when it is not possible to assess vaccine effectiveness. The herd immunity assessment in Catalonia, Spain, showed that the additional vaccination coverage required to establish herd immunity was 3-6% for measles, mump and varicella and 11% poliovirus type III in school children, 17-59% for diphtheria in youth and adults and 25-46% for persussis in school children, youth and adults. PMID- 22426373 TI - Are age-based strategies effective in increasing influenza vaccination coverage?: the Spanish experience. AB - We investigated the effectiveness of applying age-based strategies to improve influenza vaccination coverage in Spain. We described and compared influenza vaccination coverage from 2003 to 2010 between those Spanish autonomous regions (AR) that lowered the age limit to 60 y and those regions that maintained the limit at 65 y. We used data collected from two surveys covering a representative sample of the Spanish population aged >= 16 y [Spanish National Health Survey (SNHS) 2003/2004 and the European Health Survey for Spain (EHSS) 2009/2010]. The study population (persons aged >= 60 y) comprised 7,496 persons in the SNHS and 7,686 in the EHSS. In 2010, those AR which had reduced the age limit had higher coverage for all age groups analyzed-regardless of the presence of associated chronic conditions-than AR which continued vaccination for those >= 65 y. The greatest differences appeared in individuals aged 60 to 64 y (36.9% vs. 24.4% for individuals without chronic conditions, 59.1% vs. 52.9% for those with chronic conditions, and 43.3% vs. 32.3% for the entire age group). Multivariate analysis showed that those AR which lowered the age limit increased total coverage for all age groups, specifically among individuals with chronic conditions aged 60 to 64 y (IRR 1.18; 95% CI, 1.01-1.54) and >= 65 y (IRR 1.07; 95% CI, 1.00-1.14). No significant changes were observed over time for the AR that continued vaccinating people aged >= 65 y. Our results suggest that age-based strategies are effective for improving influenza vaccination coverage in Spain. PMID- 22426374 TI - Safety, immunogenicity and efficacy of pneumococcal conjugate vaccine in HIV infected individuals. AB - Streptococcus pneumoniae is the leading bacterial opportunistic infection in HIV infected individuals. Anti-retroviral treatment (ART) of HIV-infected individuals reduces their risk of invasive pneumococcal disease (IPD), however, it remains 20 to 40-fold greater compared with age-matched general population. This review summarizes the available published data on the immunogenicity, safety and efficacy of pneumococcal polysaccharide-protein conjugate vaccines (PCV) in HIV infected children and adults. Several studies have demonstrated that PCV are safe in the HIV-infected persons. Although PCV are immunogenic in HIV-infected infants, the antibodies produced are functionally impaired, there is possibly a lack or loss of anamnestic responses and immunity declines in later life However, quantitative and qualitative antibody responses to PCV in HIV-infected infants are enhanced when vaccination occurs whilst on ART, as well as if vaccination occurs when the CD4+ cell percentage is >= 25% and if the nadir CD4+ is > 15%. Although the efficacy of PCV was lower, the vaccine preventable burden of hospitalization for IPD and clinical pneumonia were 18-fold and 9-fold greater, respectively, in HIV-infected children compared with -uninfected children. In HIV-infected adults, PCV vaccination induces more durable and functional antibody responses in individuals on ART at the time of vaccination than in ART-naive adults, independently of baseline CD4+ cell count, although there does not appear to be much benefit from a second-dose of PCV. PCV has also been shown to reduce the risk of recurrent IPD by 74% in HIV-infected adults not on ART, albeit, also with subsequent decline in immunity and protection. PMID- 22426375 TI - Rotavirus vaccine can save millions of children's lives in developing countries. PMID- 22426376 TI - Immunogenicity of a multi-epitope DNA vaccine against hantavirus. AB - Hemorrhagic fever with renal syndrome (HFRS) is a severe epidemic disease caused by hantaviruses including Hantaan virus (HTNV), Seoul virus (SEOV), Dobrava virus (DOBV) and Puumala virus. Three of the four HFRS hantaviruses, HTNV, SEOV, and PUUV are found in China. Currently, there is no effective strategy available to reduce infection risk. In this study, we constructed a multi-epitope chimeric DNA vaccine that encodes expressing 25 glycoprotein epitopes from SEOV, HTNV and PUUV (designated as SHP chimeric gene). Vaccination of BALb/c mice with SHP multi epitope chimeric DNA vaccine led to a dramatic augmentation of humoral and cellular responses. The SHP vaccine DNA was detected in many organs but not for more than 60 d. There was no risk of mutation due to integration. Thus, the SHP multi-epitope chimeric DNA vaccine is a potential effective and safe DNA vaccine against infection by SEOV, HTNV, and PUUV. PMID- 22426377 TI - The burden of hospitalizations for anus and penis neoplasm in Spain (1997-2008). AB - An epidemiological retrospective study has been performed to assess the burden of hospitalization by anus and penis neoplasm in the general population in Spain. All hospital discharges and deaths related to anal malign neoplasm and penile malign neoplasm from 1997 to 2008 in Spain were obtained. A total of 19,608 hospital admissions were recorded during the study period: 11,965 were related to anal malign neoplasm (4,992 in women and 6,973 in men) and 7,643 to penis malignant neoplasm. This corresponds to a hospitalization rate of 1.97 (CI 95%: 1.91-2.02) hospitalizations per 100,000 women/ year, 2.84 (CI 95%: 2.77-2.91) hospitalizations per 100,000 men/ year and 3.11 (CI 95%: 3.04- 3.18) hospitalizations per 100,000 men/ year, respectively during the study period. The hospitalization rate increased significantly during the study period in all locations. It also increased significantly with age for all locations. Hospitalization and mortality rates in men were 50% higher than in women A total of 530 deaths related to penis malignant neoplasm and 738 deaths related to anus malignant neoplasm in men and 488 in women were reported during the 12-y study period. Although a decrease in smoking prevalence has led to a decrease in the incidence of cancers in the last decade, the hospitalizations due to anal and penile malign neoplasm have not declined in our study. This might be attributed to a high prevalence of HPV infection in these particular genital malign neoplasms. PMID- 22426379 TI - Comparison of antigen expression from plasmid DNA in tumor-free and antigen expressing tumor-bearing mice. AB - Reduced antigen expression after DNA vaccination could be a factor that limits its therapeutic effects in antigen-expressing tumor-bearing hosts. To examine whether the presence of an antigen-positive tumor results in the destroy of antigen-expressing cells, pCMV-OVA plasmid expressing ovalbumin (OVA), a model antigen, was intradermaly injected to tumor-free mice and those bearing an EG7 OVA tumor, which stably expresses OVA. For a quantitative evaluation of the elimination of antigen-expressing cells, a plasmid independently expressing firefly luciferase and OVA (pCMV-Luc/OVA) was injected to mice that had been untreated or administered with pCMV-OVA, and luciferase activity was measured one week after the administration. In both tumor-free and tumor-bearing mice, a pre injection of pCMV-OVA reduced the luciferase expression from pCMV-OVA/Luc compared with a pre-injection of an empty plasmid, suggesting that an immune response to antigen-expressing cells is induced. In tumor-bearing mice, OVA specific humoral and cellular immune responses were detected even before the vaccination, but such responses had no significant effects on the luciferase expression from pCMV-OVA/Luc. These results indicate that DNA vaccination can induce antigen-specific immune response even in tumor-bearing mice, although it is not strong enough to reject the tumor burden. PMID- 22426380 TI - Preparation and evaluation of immunogenic conjugates of Salmonella enterica serovar Typhi O-specific polysaccharides with diphtheria toxoid. AB - Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is a major health problem particularly in developing countries. The available vaccines have certain limitations regarding their efficacy, and inability to induce an immune response especially in individuals under 2 years of age. Conjugate vaccines which consist of a bacteria-specific polysaccharide chemically bound to a carrier protein overcome these problems by inducing a T-cell dependent immune response characterized by enhanced immunogenicity in all ages. In this study, O-specific polysaccharides (OSP) of S. Typhi were conjugated to diphtheria toxoid (DT) using adipic acid dihydrazide (ADH) as a linker. These conjugates (OSP-AH-DT) were then evaluated for their immunogenicity using mice as a model and showed significantly higher levels of IgG ELISA titers (P = 0.0241 and 0.0245) than lipopolysaccharides alone. Different immunization schedules were compared and it was found that schedule-B (three injections with 4-weeks interval) induced higher immune responses than schedule-A (three injections with 2-weeks interval). We showed that diphtheria toxoid can be successfully employed as a carrier protein for conjugation with Salmonella OSP and play an important role in facilitating adequate immune response. PMID- 22426381 TI - Current cell-based influenza vaccine production technology as pandemic contingency. PMID- 22426382 TI - Luminescent lanthanoid complexes of a tetrazole-functionalised calix[4]arene. AB - p-t-Butylcalix[4]arene functionalised at the lower rim with two tetrazole moieties is found to be a useful receptor for lanthanoid cations. The luminescence of the resulting complexes can be controlled by addition of base, with emission achieved in the visible and infrared regions. PMID- 22426383 TI - Routine assessment of quality of life: the next step in helping children with chronic medical conditions thrive. PMID- 22426384 TI - Molecular cloning and characterization of antimicrobial peptides from skin of the broad-folded frog, Hylarana latouchii. AB - Seven cDNA sequences encoding antimicrobial peptide (AMP) precursors were cloned by screening the skin-derived cDNA library of the broad-folded frog, Hylarana latouchii. Seven of the deduced peptides are highly similar to AMPs in five families of brevinin-2 (brevinin-2LTa, brevinin-2LTb, and brevinin-2LTc), esculentin-1 (esculentin-1LTa), esculentin-2 (esculentin-2LTa), palustrin-2 (palustrin-2LTa), and temporin (temporin-LTe). The actual sequences and characteristics of mature AMPs were analyzed by RP-HPLC and LC-MS/MS-based proteomics approaches in combination of four different protein digestion processes and by LTQ XL in combination of gas-phase fractionation (GPF) analysis. Moreover, most of the peptides found in this study hardly display hemolytic activity in vitro, suggesting they are promising antimicrobial drug candidates. PMID- 22426385 TI - Functional and biochemical characterisation of the Escherichia coli major facilitator superfamily multidrug transporter MdtM. AB - Multidrug resistance (MDR) occurs when bacteria simultaneously acquire resistance to a broad spectrum of structurally dissimilar compounds to which they have not previously been exposed. MDR is principally a consequence of the active transport of drugs out of the cell by proteins that are integral membrane transporters. We characterised and purified the putative Escherichia coli MDR transporter, MdtM, a 410 amino acid residue protein that belongs to the large and ubiquitous major facilitator superfamily. Functional characterisation of MdtM using growth inhibition and whole cell transport assays revealed its role in intrinsic resistance of E. coli cells to the antimicrobials ethidium bromide and chloramphenicol. Site-directed mutagenesis studies implied that the MdtM aspartate 22 residue and the highly conserved arginine at position 108 play a role in proton recognition. MdtM was homologously overexpressed and purified to homogeneity in dodecyl-beta-D-maltopyranoside detergent solution and the oligomeric state and stability of the protein in a variety of detergent solutions was investigated using size-exclusion HPLC. Purified MdtM is monomeric and stable in dodecyl-beta-D-maltopyranoside solution and binds chloramphenicol with nanomolar affinity in the same detergent. This work provides a firm foundation for structural studies on this class of multidrug transporter protein. PMID- 22426386 TI - Erythrocytes express chondroitin sulphate/dermatan sulphate, which undergoes quantitative changes during diabetes and mediate erythrocyte adhesion to extracellular matrix components. AB - Glycosaminoglycans (GAGs) such as chondroitin sulphate/dermatan sulphate (CS/DS) are complex molecules that are widely expressed on the cell membrane and extracellular matrix (ECM). They play an important role in wide range of biological activities especially during pathological conditions. Diabetes, a metabolic disorder characterized by sustained hyperglycemia, is known to affect GAGs in different tissues and affect erythrocyte adhesion. The present investigation was aimed at exploring the nature of GAGs present in erythrocytes and its role on adhesion of erythrocytes from control and diabetic rats to major extracellular matrix components. GAGs isolated from erythrocytes were demonstrated to be CS/DS and a 2-fold increase was observed in erythrocytes from diabetic rats. Disaccharide composition analysis by HPLC after depolymerization by the enzyme, chondroitinase ABC showed the presence of 4-O sulphated disaccharide units with small amounts of non-sulphated disaccharides, in both control and diabetic erythrocytes. Erythrocytes from diabetic rats, however, showed significantly increased binding to poly-l-ornithine (P-orn), type IV collagen, laminin and fibronectin, which was abrogated on treatment with chondroitinase ABC to various degrees. This study sheds new light on CS/DS in erythrocytes and its likely biological implications in vivo. PMID- 22426387 TI - Frontal white matter integrity is related to psychomotor retardation in major depression. AB - Altered frontal white matter integrity has been reported in major depression. Still, the behavioral correlates of these alterations are not established. In healthy subjects, motor activity correlated with white matter integrity in the motor system. To explore the relation of white matter integrity and motor activity in major depressive disorder, we investigated 21 medicated patients with major depressive disorder and 21 matched controls using diffusion tensor imaging and wrist actigraphy at the same day. Patients had lower activity levels (AL) compared with controls. Fractional anisotropy (FA) differed between groups in frontal white matter regions and the posterior cingulum. AL was linearly associated with white matter integrity in two clusters within the motor system. Controls had an exclusive positive association of FA and AL in white matter underneath the right dorsal premotor cortex. Only patients had a positive association within the posterior cingulum. Furthermore, patients had negative associations of FA and AL underneath the left primary motor cortex and within the left parahippocampal gyrus white matter. These differences in the associations between structure and behavior may contribute to well-known impaired motor planning or gait disturbances in major depressive disorder. Therefore, signs of psychomotor slowing in major depressive disorder may be linked to changes of the white matter integrity of the motor system. PMID- 22426388 TI - A multifunctional peptide rescues memory deficits in Alzheimer's disease transgenic mice by inhibiting Abeta42-induced cytotoxicity and increasing microglial phagocytosis. AB - Alzheimer's disease (AD) is characterized by progressive memory loss due to extracellular senile plaques and intracellular neurofibrillary tangles. The toxic beta-amyloid (Abeta) aggregates that form in AD can induce the overproduction of reactive oxygen species (ROS), nitric oxide (NO), and proinflammatory cytokines. These Abeta aggregates likely play a pivotal role in the onset and progression of AD. Reducing Abeta generation, inhibiting Abeta toxicity, and improving Abeta clearance are promising therapeutic strategies for AD. The present paper is the first to reveal a heptapeptide (XD4) isolated from a Ph.D.-C7C library through phage display that significantly inhibited Abeta cytotoxicity, increased the microglial phagocytosis of Abeta, decreased the Abeta-induced generation of ROS and NO, and attenuated the disequilibrium of calcium homeostasis in vitro. Remarkably, XD4 also attenuated memory deficits in beta-amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) transgenic mice, and reduced amyloid plaque burden and Abeta40/42 levels. The results of the present study indicate that this peptide, which specifically targets Abeta, may be a promising new therapy for patients exhibiting cognitive impairment and increased Abeta burden. PMID- 22426389 TI - Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury. AB - Limiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site. Lastly, D-JNKI1 treated animals show a lower increase of erythrocyte extravasation and blood brain barrier permeability, thus indicating protection of the vascular system. In total, these results clearly point out JNK inhibition as a promising neuroprotective strategy for preventing the evolution of secondary damage after spinal cord injury. PMID- 22426391 TI - Regulated protein expression for in vivo gene therapy for neurological disorders: progress, strategies, and issues. AB - The field of in vivo gene therapy has matured to the point where there are numerous clinical trials underway including late-stage clinical trials. Several viral vectors are especially efficient and support lifetime protein expression in the brain and a number of clinical trials are underway for various progressive or chronic neurological disorders including Parkinson's disease, Alzheimer's disease, and Batten's disease. To date, however, none of the vectors in clinical use have any direct way to reverse or control their transgene product in the event continued protein expression should become problematic. Several schemes that use elements within the vector design have been developed that allow an external drug or pro-drug to alter ongoing protein expression after in vivo gene transfer. The most promising and most studied regulated protein expression methods for in vivo gene transfer are reviewed. In addition, potential scientific and clinical advantages of transgene regulation for gene therapy are discussed. PMID- 22426390 TI - Brain, blood, and iron: perspectives on the roles of erythrocytes and iron in neurodegeneration. AB - The terms "neuroacanthocytosis" (NA) and "neurodegeneration with brain iron accumulation" (NBIA) both refer to groups of genetically heterogeneous disorders, classified together due to similarities of their phenotypic or pathological findings. Even collectively, the disorders that comprise these sets are exceedingly rare and challenging to study. The NBIA disorders are defined by their appearance on brain magnetic resonance imaging, with iron deposition in the basal ganglia. Clinical features vary, but most include a movement disorder. New causative genes are being rapidly identified; however, the mechanisms by which mutations cause iron accumulation and neurodegeneration are not well understood. NA syndromes are also characterized by a progressive movement disorder, accompanied by cognitive and psychiatric features, resulting from mutations in a number of genes whose roles are also basically unknown. An overlapping feature of the two groups, NBIA and NA, is the occurrence of acanthocytes, spiky red cells with a poorly-understood membrane dysfunction. In this review we summarise recent developments in this field, specifically insights into cellular mechanisms and from animal models. Cell membrane research may shed light upon the significance of the erythrocyte abnormality, and upon possible connections between the two sets of disorders. Shared pathophysiologic mechanisms may lead to progress in the understanding of other types of neurodegeneration. PMID- 22426392 TI - Cathepsin proteases mediate photoreceptor cell degeneration in Drosophila. AB - Endocytosis-mediated cell death is a form of degeneration displayed in several Drosophila mutants. This form of degeneration is displayed in several Drosophila mutant lines including flies lacking the eye-specific PLC (norpA). The cell death pathway is initiated by the stabilization of complexes between rhodopsin and arrestin which undergo massive endocytosis into the cell body. The internalized rhodopsin becomes insoluble and builds up in the late endosomal system, wherein it triggers cell death. Cathepsins are resident late endosome/lysosome proteases that have been shown to mediate apoptosis in many disease models. Therefore we sought to test the involvement of cathepsins in endocytosis-mediated retinal degeneration. Here we show that cathepsins mediate cell death in light-exposed norpA eyes. Moreover, we show that the cathepsin L-like cysteine protease, CP1, specifically mediates retinal degeneration, while the aspartyl protease, cathepsin D, does not. Furthermore, eye-specific expression of pan-cathepsin inhibitors also blocks cell death. Western blot analysis demonstrates that cathepsin L levels remain unchanged during retinal degeneration. However, whole mount immunohistochemistry performed on light-exposed retinas revealed a decrease in cathepsin L levels and a loss of rhodopsin/ CP1 colocalization, suggesting that cathepsin L translocates during the degeneration process. Lastly, we show that the retinal degeneration can be enhanced by the overexpression of cathepsin L in the sensitized norpA background. Together these data show that cathepsins play a crucial role in endocytosis-mediated retinal degeneration and are consistent with a model where rhodopsin internalization and accumulation in the endosomal/lysosomal system triggers cathepsin translocation to the cytosol. PMID- 22426394 TI - The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases. AB - The development of neurologic disease is a complex and multi-faceted process. Several factors, such as physiology, environment and genetics may play key roles in the manifestation of the associated illnesses. During the past decades, it has become clear that, at the cellular level, mitochondria function as more than "just" an energy source for our cells and plays a significant role in such aspects as neuronal development, maintenance and degeneration. Malfunctions in mitochondrial respiration and ATP production may prove disastrous for our cells and neurons, ultimately resulting in apoptosis, neurodegeneration and consequently, neurodegenerative diseases. PMID- 22426393 TI - NMDA receptor mediated phosphorylation of GluR1 subunits contributes to the appearance of calcium-permeable AMPA receptors after mechanical stretch injury. AB - Alterations in neuronal cytosolic calcium is a key mediator of the traumatic brain injury (TBI) pathobiology, but less is known of the role and source of calcium in shaping early changes in synaptic receptors and neural circuits after TBI. In this study, we examined the calcium source and potential phosphorylation events leading to insertion of calcium-permeable AMPARs (CP-AMPARs) after in vitro traumatic brain injury, a receptor subtype that influences neural circuit dynamics for hours to days following injury. We found that both synaptic and NR2B containing NMDARs contribute significantly to the calcium influx following stretch injury. Moreover, an early and sustained phosphorylation of the S-831 site of the GluR1 subunit appeared after mechanical injury, and this phosphorylation was blocked with the inhibition of either synaptic NMDARs or NR2B containing NMDARs. In comparison, mechanical injury led to no significant change in the S-845 phosphorylation of the GluR1 subunit. Although no change in S-845 phosphorylation appeared in injured cultures, we observed that inhibition of NR2B containing NMDARs significantly increased S-845 phosphorylation 1h after injury while blockade of synaptic NMDARs did not change S-845 phosphorylation at any time point following injury. These findings show that a broad class of NMDARs are activated in parallel and that targeting either subpopulation will reverse some of the consequences of mechanical injury, providing distinct paths to treat the effects of mechanical injury on neural circuits after TBI. PMID- 22426395 TI - Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Abeta accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer's disease. AB - Several studies have implicated the enzyme acetylcholinesterase (AChE) as well as several biometals in the pathogenesis of Alzheimer's disease (AD). A multifunctional molecule, the hybrid tacrine-8-hydroxyquinoline (named IQM-622), displays cholinergic, antioxidant, copper-complexing and neuroprotective properties. Using in vitro and in vivo models, we investigated the modulating effects of IQM-622 on amyloid beta-protein (Abeta)-induced pathology as well as on chemically induced neurodegeneration by domoic acid. In the first experimental model, we observed a significant decrease in brain Abeta deposits in IQM-622 treated APP/Ps1 mice for four weeks. Moreover, IQM-622 promoted the degradation of intracellular Abeta in astrocytes, and protected against Abeta toxicity in cultured astrocytes and neurons. These findings suggest that the neuroprotective effect of IQM-622 is not only related to AChE inhibition, but also involves other mechanisms, including the modulation of Abeta-degradation pathways in AD brain. In this study we also compare the neuronal loss in CA1 hippocampal field of AD patients and of mice treated with domoic acid, giving similar patterns. Thus, we used a second experimental model by killing hippocampal neurons by domoic acid damage, in which IQM-622 increased survival in the CA1 and dentate gyrus regions of the hippocampus. Our observations suggest that administration of IQM-622 may have significant beneficial effects in neurodegenerative diseases, including AD, which course with acute or progressive neuronal death. PMID- 22426396 TI - Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury. AB - Neuronal programmed cell death (PCD) contributes to delayed tissue damage after traumatic brain injury (TBI). Both caspase-dependent and caspase-independent mechanisms have been implicated, with the latter including apoptosis inducing factor (AIF). The peptidyl-proplyl isomerase Cyclophilin A (CypA) transports AIF from the cytosol to the nucleus, a key step for AIF-dependent cell death. We compared the effects of single versus combined inhibition of caspase and AIF pathways in a mouse controlled cortical impact (CCI) model, by examining the effects of CypA gene knockout (CypA(-/-)), caspase inhibition with a pan-caspase inhibitor (boc-aspartyl(OMe)-fluoromethylketone, BAF), or combined modulation. TBI caused caspase activation as well as translocation of AIF to the nucleus. Markers of caspase activation including caspase-specific fodrin cleavage fragments and number of FLIVO-positive cells were reduced in BAF-treated CypA(+/+) mice, whereas markers of AIF activation including AIF/H2AX interaction and AIF translocation to the nucleus were attenuated in CypA(-/-) mice. Each single intervention, (CypA(-/-) or BAF-treated CypA(+/+)) reduced the number of apoptotic cells (TUNEL-positive) in the cortex and improved long-term sensorimotor function; CypA(-/-) also attenuated microglial activation after injury. Importantly, BAF-treated CypA(-/-) mice, showed greater effects than either intervention alone on multiple outcomes including: reduction in TUNEL positive cells, decrease in neuroinflammation, improved motor and cognitive recovery, and attenuation of lesion volume and neuronal loss in the hippocampus. Using two in vitro neuronal cell death models known to induce AIF-mediated PCD, we also showed that neurons from CypA(-/-) animals were protected and that effects were unrelated to caspase activation. These data indicate that AIF mediated and caspase-dependent pathways contribute independently and in parallel to secondary injury after TBI, and suggest that combined therapeutic strategies directed at multiple PCD pathways may provide superior neuroprotection than those directed at single mechanisms. PMID- 22426397 TI - Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain accumulation of amyloid-beta peptide and neurofibrillary tangles, which are believed to initiate a pathological cascade that results in progressive impairment of cognitive functions and eventual neuronal death. To obtain a mouse model displaying the typical AD histopathology of amyloidosis and tauopathy, we generated a triple-transgenic mouse line (TauPS2APP) by overexpressing human mutations of the amyloid precursor protein, presenilin2 and tau genes. Stereological analysis of TauPS2APP mice revealed significant neurodegeneration of GABAergic septo-hippocampal projection neurons as well as their target cells, the GABAergic hippocampal interneurons. In contrast, the cholinergic medial septum neurons remained unaffected. Moreover, the degeneration of hippocampal GABAergic interneurons was dependent on the hippocampal subfield and interneuronal subtype investigated, whereby the dentate gyrus and the NPY positive interneurons, respectively, were most strongly affected. Neurodegeneration was also accompanied by a change in the mRNA expression of markers for inhibitory interneurons. In line with the loss of inhibitory neurons, we observed functional changes in TauPS2APP mice relative to WT mice, with strongly enhanced long-term potentiation in the medial-perforant pathway input to the dentate gyrus, and stereotypic hyperactivity. Our data indicate that inhibitory neurons are the targets of neurodegeneration in a mouse model of amyloidosis and tauopathy, thus pointing to a possible role of the inhibitory network in the pathophysiological and functional cascade of Alzheimer's disease. PMID- 22426398 TI - How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans. AB - There is evidence that excessive stress exposure of the brain, mediated through the neurotoxic effects of cortisol and possibly neuroinflammation, causes damage to brain structure and function: the glucocorticoid cascade hypothesis. Functional changes of hypothalamic-pituitary-adrenal (HPA) axis as well as alterations in brain structures like the hippocampus have been consistently reported in major depression. However, there has not been a lot of emphasis on bringing findings from studies on early childhood stress, HPA axis functioning and hippocampal imaging together. This is the subject for this systematic review of the literature on how developmental stress, specifically childhood maltreatment, may impact on HPA axis function and hippocampal structure. We will also review the literature on the relationship between HPA axis function and hippocampal volume in healthy, depressed and other disease states. There is evidence that prenatal stress and childhood maltreatment is associated with an abnormally developing HPA system, as well as hippocampal volume reduction. Smaller hippocampal volumes are associated with increased cortisol secretion during the day. We conclude that a model integrating childhood maltreatment, cortisol abnormalities and hippocampal volume may need to take other factors into account, such as temperament, genetics or the presence of depression; to provide a cohesive explanation of all the findings. Finally, we have to conclude that the cascade hypothesis, mainly based on preclinical studies, has not been translated enough into humans. While there is evidence that early life maltreatment results in structural hippocampal changes and these are in turn more prominent in subjects with higher continuous cortisol secretion it is less clear which role early life maltreatment plays in HPA axis alteration. PMID- 22426399 TI - Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice. AB - Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6 weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3 weeks. At 11 weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippocampus of male BDNF heterozygous mice treated with corticosterone. In the ventral hippocampus, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippocampal sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive effects of reduced levels of BDNF expression and corticosterone treatment on spatial memory and startle in male and female mice, accompanied by significant, but region-specific changes in NMDA receptor subunit levels in the dorsal and ventral hippocampus. These results could be important for our understanding of the interaction of neurodevelopmental stress and BDNF deficiency in cognitive and anxiety-related symptoms of psychiatric illnesses, such as schizophrenia. PMID- 22426400 TI - Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway. AB - Expansion of polyglutamine repeats is the cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease (HD). It is widely accepted that deregulation of the transcriptional coactivator CBP by expanded huntingtin (htt) plays an important role in HD molecular pathogenesis. In this study, we report on a novel target of expanded polyglutamine stretches, the transcriptional coactivator Jun activation domain-binding protein 1 (Jab1), which shares DNA-sequence-specific transcription factor targets with CBP. Jab1 also plays a major role in the degradation of the cyclin-dependent-kinase inhibitor and putative transcription cofactor p27(Kip1). We found that Jab1 accumulates in aggregates when co-expressed with either expanded polyglutamine stretches or N terminal fragments of mutant htt. In addition, the coactivator function of Jab1 was suppressed both by aggregated expanded polyglutamine solely and by mutant htt. Inhibition by mutant htt even preceded the appearance of microscopic aggregation. In an exon 1 HD cell model, we found that endogenous Jab1 could be recruited into aggregates and that this was accompanied by the accumulation of p27(Kip1). Accumulation of p27(Kip1) was also found in brains derived from HD patients. The repression of Jab1 by various mechanisms coupled with an increase of p27(Kip1) at late stages may have important transcriptional effects. In addition, the interference with the Jab1-p27(Kip1) pathway may contribute to the observed lower incidence of cancer in HD patients and may also be relevant for the understanding of the molecular pathogenesis of polyglutamine disorders in general. PMID- 22426401 TI - A pro-convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain. AB - Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood-brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood-brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify (14)C metabolites deriving from the parent (14)C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from (14)C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. (14)C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. PMID- 22426402 TI - Regional deficiencies in chaperone-mediated autophagy underlie alpha-synuclein aggregation and neurodegeneration. AB - In neurodegenerative diseases, it remains unclear why certain brain regions are selectively vulnerable to protein aggregation. In transgenic mice expressing human A53T alpha-synuclein, the brainstem and spinal cord develop the most prominent alpha-synuclein inclusions which correlate with age-dependent motor dysfunction. Herein we present the novel finding that this selective aggregation is in part dependent on the inability of chaperone-mediated autophagy (CMA) to effectively degrade alpha-synuclein in these brain regions. Lysosomal assays revealed that CMA activity was significantly decreased in aggregation-prone regions compared to the remainder of the brain. Previously, CMA activity has been shown to be proportional to levels of the CMA receptor Lamp-2a. Using antibodies, brain tissue from Lamp-2a null mice, enzymatic deglycosylation, and mass spectrometry, we identified Lamp2a as a novel 72kDa glycoprotein in the mouse brain. Examination of Lamp-2a levels revealed differences in expression across brain regions. The brainstem and the spinal cord had a more than three-fold greater levels of Lamp-2a as compared to regions less vulnerable to aggregation and exhibited a selective upregulation of Lamp-2a during development of alpha synuclein inclusions. Despite this dynamic response of Lamp-2a, the levels of substrates bound to the brain lysosomes as well as the rates of substrate uptake and degradation were not proportional to the levels of Lamp-2a. These regional differences in CMA activity and Lamp-2a expression were found in both non transgenic mice as well as A53T alpha-syn mice. Therefore, these are inherent variations and not a transgene-specific effect. However, differences in CMA activity may render select brain regions vulnerable to homeostatic dysfunction in the presence of stressors such as overexpression of human A53T alpha-syn. Collectively, the data provide a potential mechanism to explain the dichotomy of vulnerability or resistance that underlies brain regions during aggregate formation in neurodegenerative disease. PMID- 22426403 TI - Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. AB - Hypoxic preconditioning of stem cells and neural progenitor cells has been tested for promoting cell survival after transplantation. The present investigation examined the hypothesis that hypoxic preconditioning of bone marrow mesenchymal stem cells (BMSCs) could not only enhance their survival but also reinforce regenerative properties of these cells. BMSCs from eGFP engineered rats or pre labeled with BrdU were pre-treated with normoxia (20% O(2), N-BMSCs) or sub lethal hypoxia (0.5% O(2). H-BMSCs). The hypoxia exposure up-regulated HIF-1alpha and trophic/growth factors in BMSCs, including brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) and its receptor FIK-1, erythropoietin (EPO) and its receptor EPOR, stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). Meanwhile, many pro-inflammatory cytokines/chemokines were down regulated in H-BMSCs. N-BMSCs or H-BMSCs were intravenously injected into adult rats 24h after 90-min middle cerebral artery occlusion. Comparing to N-BMSCs, transplantation of H-BMSCs showed greater effect of suppressing microglia activity in the brain. Significantly more NeuN-positive and Glut1-positive cells were seen in the ischemic core and peri-infarct regions of the animals received H BMSC transplantation than that received N-BMSCs. Some NeuN-positive and Glut-1 positive cells showed eGFP or BrdU immunoflourescent reactivity, suggesting differentiation from exogenous BMSCs into neuronal and vascular endothelial cells. In Rotarod test performed 15days after stroke, animals received H-BMSCs showed better locomotion recovery compared with stroke control and N-BMSC groups. We suggest that hypoxic preconditioning of transplanted cells is an effective means of promoting their regenerative capability and therapeutic potential for the treatment of ischemic stroke. PMID- 22426404 TI - Primary chemotherapy for inoperable ovarian, fallopian tube, or primary peritoneal cancer with or without delayed debulking surgery. AB - OBJECTIVE: To describe the outcome of primary chemotherapy for women with advanced-stage epithelial ovarian or primary peritoneal cancer and delayed surgery when optimal debulking surgery cannot be achieved at diagnosis. METHODS: Between 1998 and 2006, we retrospectively reviewed the overall survival and examined prognostic markers in consecutive patients who were not suitable for initial radical surgery because of the extent of disease and/or poor performance status. They were treated with a policy of primary platinum-based chemotherapy, followed whenever possible in responding patients by debulking surgery. RESULTS: A total of 171 patients received least one cycle of chemotherapy. Eighty-six patients proceeded to surgery and 53 (31% of 171 and 62% of 86) had optimal (<1 cm) residual disease. Eighty-five patients did not undergo surgery because they remained unfit or had not responded sufficiently to chemotherapy. The median overall survival was 18.7 months (95% confidence interval [CI], 16.5-24.2). The median OS in the surgical group for optimal and suboptimal surgery was 40.8 (95% CI, 32.5-50.0) and 22.5 (95% CI, 17.7-37.1) months (P = 0.005). On multivariate analysis, interval surgery and optimal surgery were the only independent prognostic factors (hazard ratios, 0.45 and 0.43, respectively; P = 0.009). In the nonsurgical group, CA125 response was an independent prognostic factor (hazard ratio, 0.34; P = 0.001) with an OS of 21.7 months (95% CI, 14.0-35.4) in women with a normal CA125 after treatment compared with 6.7 (95% CI, 4.5-7.8) months. CONCLUSIONS: In one third of the women, the tumor was optimally debulked after primary chemotherapy and their median survival was 40.8 months. Suboptimal debulking surgery after primary chemotherapy did not result in a better survival than that achieved after a chemotherapy response alone, suggesting that surgery may be avoided when imaging after chemotherapy demonstrates residual disease that cannot be optimally debulked. PMID- 22426405 TI - Trends in of late-stage squamous cell vulvar carcinomas: analysis of the surveillance, epidemiology, and end results (SEER) database. AB - OBJECTIVE: To describe the trends in the rate, treatment, and survival of late stage vulvar carcinomas (LSVCs) over a 20-year period in the United States. METHODS: Demographic, pathologic, treatment, and survival data were collected from the Surveillance, Epidemiology, and End Results registry between 1988 and 2007. Trends concerning the rate of LSVC (International Federation of Gynecology and Obstetrics [FIGO] stages III and IV), its management, and outcome were studied. Five-year overall and disease-specific survival rates were calculated. RESULTS: The rate of LSVC (32.4%) as compared with early-stage disease (67.6%) did not change significantly from 1988 to 2007 (P = 0.59). Of the 2630 patients with LSVC, the median age at diagnosis was 72 years, with 88.5% of them being white. Surgery and radiation therapy were performed in 73.8% and 60.6% of cases, respectively, with 37% of the patients having no lymph node dissection. A significant trend toward removing fewer lymph nodes (P = 0.02) and offering more radiation therapy (P = 0.02) has been observed across the study period. Five-year overall and disease-specific survival rates did not change (P = 0.44 and P =0.26, respectively) from 1988 to 2007. On multivariate analysis, node positivity (hazard ratio, 3.12 [95% confidence interval, 2.30-4.24]) and surgery (hazard ratio, 0.41 [95% confidence interval, 0.24-0.69]) were found to be the 2 most predictive variables for cancer mortality, followed by age and tumor size. CONCLUSION: Less extensive surgery and more radiation therapy did not compromise survival of LSVC over the 20-year period. PMID- 22426406 TI - Serum HE4 as a useful biomarker in discriminating ovarian cancer from benign pelvic disease. AB - OBJECTIVE: To evaluate the role of the novel tumor marker human epididymal secretory protein E4 (HE4) in discriminating ovarian cancer from benign pelvic disease in patients with a pelvic mass. METHODS: Serum samples from 131 patients with epithelial ovarian cancer (EOC) and 126 patients with various benign pelvic diseases were collected preoperatively and tested for cancer antigen (CA)125 and HE4 levels. Receiver operator characteristic curves were constructed, and the area under the curve (AUC) was compared between the markers. RESULTS: The median CA125 and HE4 levels were significantly higher in the patients with EOC than in those with benign disease (P < 0.001). Using benign controls as the comparison group for all cases, the AUC for combined HE4 and CA125 (0.955) was significantly higher than that for HE4 (0.941) or CA125 alone (0.924; P < 0.05). A comparison of premenopausal benign controls to EOC cases showed that the AUC for combined HE4 and CA125 (0.97) was significantly higher than that for CA125 (0.93; P < 0.004). The AUC for HE4 was significantly higher compared to that of CA125 in discriminating EOC from ovarian endometriosis (0.969 vs 0.904; P = 0.014) and pelvic inflammatory disease (0.909 vs 0.819; P = 0.034). CONCLUSION: Serum HE4 testing is a more powerful tool than CA125 assay to discriminate EOC from ovarian endometriosis and pelvic inflammatory disease. For patients with a pelvic mass, especially premenopausal patients, the serum concentration of HE4 adds valuable information to CA125 in identifying patients with EOC from those with benign pelvic disease. PMID- 22426407 TI - Better anatomical and cosmetic results using tunneled lotus petal flap for plastic reconstruction after demolitive surgery for vulvar malignancy. AB - OBJECTIVE: To evaluate the efficacy of tunneled lotus petal flap in terms of anatomical and cosmetic results in patients who underwent vulvoperineal reconstruction for vulvar malignancy. METHODS: Between March 2010 and July 2011, 22 women underwent vulvoperineal reconstruction using tunneled lotus petal flap for primary or recurrent disease at San Gerardo Hospital, Monza. In 16 cases, lotus flaps were bilateral, whereas in 6 cases, they were monolateral. RESULTS: The median age was 72 years (range, 53-87 years). The mean operating time was 85 minutes. The mean length of follow-up was 10 months (range, 2-16 months). Postoperative complications occurred in 2 patients, including one case of partial flap necrosis and one case of donor site breakdown. CONCLUSIONS: Tunneled lotus petal flap is safe, easy and fast to perform, has a low rate of complications, and good functional and cosmetic results. This technique represents an optimal solution for plastic reconstruction in case of primary or recurrent vulvar disease, or in case of introital stenosis after primary inadequate closure. PMID- 22426408 TI - Weekly paclitaxel-carboplatin regimen in patients with primary advanced or recurrent endometrial carcinoma. AB - OBJECTIVE: The objective of the study was to evaluate the response of weekly paclitaxel/carboplatin in patients with primary advanced or recurrent endometrial cancer. METHODS: Eighteen cycles of paclitaxel (60 mg/m2) and carboplatinum (area under the plasma concentration-time curve, 2.7) were administered weekly. Response rates were evaluated according to Response Criteria in Solid Tumors criteria. RESULTS: Paclitaxel/carboplatin weekly was administered to 29 patients. Median age was 62 years (range, 44-80 years). Main histopathologic types were serous/clear cell (n = 16) and endometrioid (n = 9). Patients were divided into a chemonaive group (n = 16) (group 1) and a group with previous chemotherapy (n = 13) (group 2). Response rate for group 1 was as follows: partial remission, n = 8 (50%); stable disease, n = 1 (6%); and progressive disease, n = 7 (44%). Response for group 2: partial remission, n = 5 (39%), and progressive disease, n = 8 (62%). Median progression-free survival and overall survival were 9 months (range, 5-27 months) and 12 months (range, 2-27 months), respectively, for group 1 and 8 months (range, 6-10 months) and 9 months (range, 2-18 months), respectively, for group 2.Overall 411 weekly treatments were administered. Because of grade 4 bone marrow toxicity, treatments needed to be adjusted as follows: dose reduction of 50% to 75%, n = 81 (20%); dose delay, n = 66 (16%); not administered, n = 6 (1%); and changed to paclitaxel/cisplatin, n = 4 (1%). Twenty-three patients (85%) needed treatment adjustment because of toxicity. Neutropenic fever occurred in 1 patient (4%). The most common nonhematologic toxicities were grade 1 to 2 fatigue (89%) and grade 2 nausea (37%). Seven percent had grade 2 neuropathy. No grade 2 alopecia occurred. CONCLUSIONS: Paclitaxel/carboplatin weekly seems effective, however, with a considerable hematologic toxicity. Larger trials are needed to confirm these data. PMID- 22426409 TI - Does significant medical comorbidity negate the benefit of up-front cytoreduction in advanced ovarian cancer? AB - BACKGROUND: The objective of the study was to determine if initial surgery (IS) or initial chemotherapy (IC) affects rates of optimal surgery and survival in a population with significant medical comorbidities. METHODS: Data of all patients with stage III-IV ovarian, peritoneal, and fallopian tube cancers diagnosed from 1995 to 2008 were reviewed. Clinical and pathologic data were abstracted. RESULTS: There were 551 cases for review: 255 (46.3%) received IS, and 296 (53.7%) received IC. Patients who received IC had higher stage (P < 0.001), higher-grade cancers (P < 0.001), higher mean CA-125 (P = 0.015), higher rates of diabetes (P = 0.006), hypertension (P = 0.008), and presurgical embolism (P < 0.022) and were older (P = 0.043). There was no difference with respect to body mass index, albumin, extent of surgery, or intensive care use. Rates of optimal cytoreduction were higher with IC compared with IS (72.7% vs 56.1%, P < 0.001). IS was associated with more blood loss (P = 0.005) and higher rates of postsurgical venous thrombosis (P < 0.001). Optimal cytoreduction predicted survival in both groups. Among optimal patients, IS improved median survival: progression-free survival of 14 months (IS) versus 12 months (IC), P = 0.004; overall survival of 58 months (IS) versus 34 months (IC), P = 0.002. Factors influencing this difference were receipt of IC and history of diabetes; both predictors of mortality: hazard ratios, 1.9 (95% confidence interval, 1.3-2.8; P < 0.001) and 1.8 (95% confidence interval, 1.02-3.1; P = 0.042), respectively. CONCLUSIONS: The achievement of optimal cytoreduction continues to be a significant predictor of survival, regardless of treatment approach. Patients selected for IS and in whom optimal cytoreduction was achieved had improvements in both progression-free survival and overall survival. However, the differences could not be explained by surgical effort alone as diabetes was independently associated with mortality. PMID- 22426410 TI - Prognosis in patients with serous and mucinous stage I borderline ovarian tumors. AB - INTRODUCTION: The purpose to this study was to compare the clinicopathologic characteristics and prognosis of patients with serous stage I borderline ovarian tumors (BOTs) to patients with mucinous stage I BOTs. METHODS: This was a retrospective cohort series of patients with stage I BOTs diagnosed and treated between 1995 and 2009 at a single institution. The records were analyzed for patients' clinicopathologic information. The recurrence rates were compared using the Kaplan-Meier method. RESULTS: During the study period, 198 patients (73.6%) with mucinous BOTs and 71 patients (26.4%) with serous BOTs were identified. Patients with serous tumors tended to be asymptomatic (53.5%) and frequently had elevated CA-125 levels and positive results from peritoneal cytology. Conversely, mucinous tumors were more related to the presence of symptoms (70.7%), elevated CA-19-9 levels, and pseudomyxoma and were larger tumors with a mean size of 15.6 cm. After a median follow-up of 56.5 months, 15 patients had developed 16 recurrences. Among these, 14 borderline recurrences developed in 6 patients with mucinous tumors and in 7 patients with serous tumors, and 2 invasive recurrences developed in only patients with mucinous tumors. No difference in recurrence rate between mucinous and serous tumors was observed. In addition, no disease-related death occurred. CONCLUSIONS: Our study found that, although distinct differences in clinical and pathologic characteristics between stage I mucinous and serous BOTs are seen, result from tumor histology was not associated with disease prognosis. PMID- 22426411 TI - Practical perspectives of personalized healthcare in oncology. AB - There is an increasing prevalence of drug-diagnostic combinations in oncology. This has placed diagnostic stakeholders directly into the complex benefit-risk, cost, value and uncertainty-driven development paradigm traditionally the preserve of the drug development community. In this review we focus on the delivery of the clinical data required to advance such drug-diagnostic combination development programmes and ultimately satisfy regulators and payors of the value of contemporaneous changes in diagnostic and treatment practice. Ideally all stakeholders would like to initially estimate, and ultimately specify, the comparative benefit-risk for a new treatment option with and without changing diagnostic practice. Hence, in an ideal world clinical trial design is focused on acquiring biomarker treatment interaction data. In this review we describe the key scientific and feasibility inputs required to design and deliver such trials and the drivers, advantages and disadvantages associated with departing from this model. We do not discuss the discovery of new biomarkers nor the analytical validation and marketing of diagnostic products. Following on from trial design we describe how subsequent success then depends upon the concepts that guide trial design being driven into the complex world of large, multinational clinical trial delivery. For every aspect of a traditional clinical drug trial such as supply, recruitment and adherence, there is a corresponding concept for the diagnostic element. In practice, this means that each patient's contribution to the decision making data-set is subject to double jeopardy (attrition on clinical outcome and biomarker status). Historically, this has led to significantly reduced power for detecting biomarker-treatment interactions, reduced decision making confidence and a waste of valuable human and financial resources. We describe recent practice changes and experience that have led to the successful delivery of such trials focusing on both pre- and on trial aspects. The former includes the pivotal role of tissue banks in accurate estimation of evaluability and prevalence for biomarker assays and the latter several practices designed to engage and incentivize key stakeholders particularly CRAs and pathologists. The result is that in the new world of developing personalized treatments for cancer patients the real-time acquisition and monitoring of biomarker data receives similar support to that traditionally reserved for clinical outcome data and far more patients contribute to the testing of personalized medicine hypotheses. PMID- 22426412 TI - Parietal lobe epilepsy: the great imitator among focal epilepsies. AB - AIM: Comprising large areas of association cortex, the parietal lobe is part of an extensive synaptic network elaborately intertwined with other brain regions. We hypothesize that such widespread projections are responsible for producing inaccurate localisation readings on scalp EEG and clinical semiology in patients with parietal lobe epilepsies, as opposed to frontal or temporal lobe epilepsies. METHODS: Our study included 50 patients with pharmacoresistant focal epilepsy, who were subsequently rendered seizure-free for >=12 months (median: 23 months) following resections limited to the frontal (n=17), temporal (n=17), or parietal (n=16) lobes. Interictal and ictal EEG data with accompanying seizure video recordings were extracted from archived files of scalp video-EEG monitoring. Two blinded raters independently reviewed the EEG according to predetermined criteria. Videos of seizures were then observed, as raters formulated their final electroclinical impression (ECI), identifying patients' abnormal neuronal activities with parietal, temporal, and frontal lobe epilepsy, or unspecified localisation. RESULTS: Groups did not differ significantly in demographics, age at epilepsy onset, or presence of MRI abnormalities. Interictal discharges in parietal lobe epilepsy showed the greatest magnitude of scatter outside the lobe of origin; the majority of patients with parietal lobe epilepsy had more than one spike population (p<0.045). Localised ictal EEG recognition was most frequent in temporal, followed by frontal and parietal lobe epilepsy cases (p=0.024). Whenever raters confidently limited their ECI to one lobar subtype, overall accuracy was excellent. Lobar classifications by ECI were highly accurate for temporal lobe epilepsy, vacillating in frontal lobe epilepsy, and least accurate in parietal lobe epilepsy subjects. CONCLUSION: Scalp EEG readings of parietal lobe epilepsy patients showed a more variable scatter of interictal discharges and a lower localisation value of ictal recordings compared to temporal and frontal lobe epilepsy subjects, suggesting an increased likelihood of misidentification and mislocalisation of parietal lobe epilepsy. Combining seizure semiology with scalp interictal and ictal EEG readings facilitates a more accurate lobar classification in patients with temporal and frontal, but not parietal, lobe epilepsy. PMID- 22426413 TI - Stress-induced sex differences: adaptations mediated by the glucocorticoid receptor. AB - Clinical evidence has indicated that women are more susceptible to stress-related and autoimmune disorders than men. Although females may be more susceptible to some disease states, males do not escape unscathed and are more susceptible to metabolic dysfunction. The hypothalamic-pituitary-axis plays a pivotal role in the sexually dimorphic effects of chronic stress through alterations in negative feedback. Recent evidence has implicated the glucocorticoid receptor and its co chaperones in the etiology of psychiatric and somatic diseases. Gonadal hormones heavily interact with both glucocorticoid receptor expression and glucocorticoid receptor action either through direct or indirect effects on proteins in the chaperone and co-chaperone complex. Diverse systems including the hypothalamic pituitary-axis, the immune system, and metabolism are affected differently in males and females, possibly through the glucocorticoid receptor system. New considerations of glucocorticoid regulation through the co-chaperone complex in the brain will be vital to the development of treatment strategies for men and women afflicted by neuropsychiatric and somatic disorders. PMID- 22426414 TI - ERalpha17p, a peptide reproducing the hinge region of the estrogen receptor alpha associates to biological membranes: A biophysical approach. AB - Recently, we identified a peptide (ERalpha17p, P(295)LMIKRSKKNSLALSLT(311)) that corresponds to the 295-311 sequence of the estrogen receptor alpha (ERalpha, hinge region) and which exerts a panel of pharmacological effects in breast cancer cells. Remarkably, these effects can result from the interaction of ERalpha17p with the plasma membrane. Herein, we show that ERalpha17p adopts a beta-sheet secondary structure when in contact with anionic phospholipids and that it is engulfed within the lipid bilayer. While ERalpha17p increases the fluidity of membrane mimics, it weakly internalizes in living cells. In light of the above, one may evoke one important role of the 295-311 region of the ERalpha: the corresponding peptide could be secreted/delivered to the extracellular medium to interact with neighboring cells, both intracellularly and at the membrane level. Finally, the 295-311 region of ERalpha being in proximity to the cystein 447, the palmitoylation site of the ERalpha raises the question of its involvement in the interaction/stabilization of the protein with the membrane. PMID- 22426415 TI - Connectivity measures applied to human brain electrophysiological data. AB - Connectivity measures are (typically bivariate) statistical measures that may be used to estimate interactions between brain regions from electrophysiological data. We review both formal and informal descriptions of a range of such measures, suitable for the analysis of human brain electrophysiological data, principally electro- and magnetoencephalography. Methods are described in the space-time, space-frequency, and space-time-frequency domains. Signal processing and information theoretic measures are considered, and linear and nonlinear methods are distinguished. A novel set of cross-time-frequency measures is introduced, including a cross-time-frequency phase synchronization measure. PMID- 22426416 TI - Regulation of p53: size matters. PMID- 22426417 TI - Old and fat, oncogenes make you. PMID- 22426418 TI - On the (C)USP(2a) of new targets for bladder cancer therapy? PMID- 22426419 TI - Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. AB - Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility. PMID- 22426420 TI - CITED2 links hormonal signaling to PGC-1alpha acetylation in the regulation of gluconeogenesis. AB - During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor gamma coactivator 1alpha (PGC-1alpha) in concert with various other transcriptional regulators. Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid- and aspartic acid-rich COOH-terminal domain 2) interacts with many of these molecules, the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1alpha. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP-protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1alpha by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5-like 2 (GCN5). The consequent downregulation of PGC-1alpha acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)-thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1alpha activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC 1alpha acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis in diabetic mice, suggesting it as a therapeutic target for hyperglycemia. PMID- 22426421 TI - A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. AB - Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance. PMID- 22426422 TI - Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. AB - Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process. PMID- 22426423 TI - A mitosis-specific AMPK trimer? PMID- 22426424 TI - Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice. AB - Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral beta-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing. PMID- 22426425 TI - Sex differences in components of imagined perspective transformation. AB - Little research to date has examined whether sex differences in spatial ability extend to the mental self rotation involved in taking on a third party perspective. This question was addressed in the present study by assessing components of imagined perspective transformations in twenty men and twenty women. Participants made speeded left-right judgements about the hand in which an object was held by front- and back- facing schematic human figures in an "own body transformation task." Response times were longer when the figure did not share the same spatial orientation as the participant, and were substantially longer than those made for a control task requiring left-right judgements about the same stimuli from the participant's own point of view. A sex difference in imagined perspective transformation favouring males was found to be restricted to the speed of imagined self rotation, and was not observed for components indexing readiness to take a third party point of view, nor in left-right confusion. These findings indicate that the range of spatial abilities for which a sex difference has been established should be extended to include imagined perspective transformations. They also suggest that imagined perspective transformations may not draw upon those empathic social-emotional perspective taking processes for which females show an advantage. PMID- 22426426 TI - The effect of landmarks in human path integration. AB - The effect of landmarks in human path integration was investigated using virtual hallway-mazes. Participants traveled along random 5-segment paths either with or without distinctive landmarks at some segment intersections. They were required to directly return to the origin or to one of the landmark locations from the end of the path. Results showed that knowledge of the return targets prior to the outbound trip significantly reduced RTs to both the origin and the landmarks. Moreover, RTs in the return-to-origin trials were longer with landmarks present than without landmarks. This effect was eliminated when the return target was given prior to the trip. These results suggest that processing of the origin and the landmarks interfere with each other. However this interference is not obligatory and can be eliminated or reduced by prior knowledge about the target. The influences of landmarks on path integration and spatial updating were discussed. PMID- 22426427 TI - Video game practice optimizes executive control skills in dual-task and task switching situations. AB - We examined the relation of action video game practice and the optimization of executive control skills that are needed to coordinate two different tasks. As action video games are similar to real life situations and complex in nature, and include numerous concurrent actions, they may generate an ideal environment for practicing these skills (Green & Bavelier, 2008). For two types of experimental paradigms, dual-task and task switching respectively; we obtained performance advantages for experienced video gamers compared to non-gamers in situations in which two different tasks were processed simultaneously or sequentially. This advantage was absent in single-task situations. These findings indicate optimized executive control skills in video gamers. Similar findings in non-gamers after 15 h of action video game practice when compared to non-gamers with practice on a puzzle game clarified the causal relation between video game practice and the optimization of executive control skills. PMID- 22426428 TI - The premotor theory of attention as an account for the Simon effect. AB - The Simon effect refers to the phenomenon that responses are faster when the irrelevant location of a stimulus corresponds with the response location than when these locations do not correspond. In the current paper we examined the viability of an updated version of the premotor theory of attention (PMTA) as an account for the Simon effect. Two predictions were evaluated. First, in the case of focused attention at the relevant target position a strong reduction of the Simon effect should be observed as the Simon effect according to PMTA crucially depends on attentional orienting. Secondly, if attention is directed towards a location then this orienting by itself should already be sufficient for producing a Simon effect, as stimulus presence is not required. Our data confirmed these predictions thereby supporting the relevance of the PMTA for the Simon effect. PMID- 22426429 TI - What can the same-different task tell us about the development of magnitude representations? AB - We examined the development of magnitude representations in children (Exp 1: kindergartners, first-, second- and sixth graders, Exp 2: kindergartners, first-, second- and third graders) using a numerical same-different task with symbolic (i.e. digits) and non-symbolic (i.e. arrays of dots) stimuli. We investigated whether judgments in a same-different task with digits are based upon the numerical value or upon the physical similarity of the digits. In addition, we investigated whether the numerical distance effect decreases with increasing age. Finally, we examined whether the performance in this task is related to general mathematics achievement. Our results reveal that a same-different task with digits is not an appropriate task to study magnitude representations, because already late kindergarteners base their responses on the physical similarity instead of the numerical value of the digits. When decisions cannot be made on the basis of physical similarity, a similar numerical distance effect is present over all age groups. This suggests that the magnitude representation is stable from late kindergarten onwards. The size of the numerical distance effect was not related to mathematical achievement. However, children with a poorer mathematics achievement score seemed to have more difficulties to link a symbol with its corresponding magnitude. PMID- 22426430 TI - CD4+ T cell-mediated neuroprotection is independent of T cell-derived BDNF in a mouse facial nerve axotomy model. AB - BACKGROUND: The production of neurotrophic factors, such as BDNF, has generally been considered an important mechanism of immune-mediated neuroprotection. However, the ability of T cells to produce BDNF remains controversial. METHODS: In the present study, we examined mRNA and protein of BDNF using RT-PCR and western blot, respectively, in purified and reactivated CD4(+) T cells. In addition, to determine the role of BDNF derived from CD4(+) T cells, the BDNF gene was specifically deleted in T cells using the Cre-lox mouse model system. RESULTS: Our results indicate that while both mRNA expression and protein secretion of BDNF in reactivated T cells were detected at 24 h, only protein could be detected at 72 h after reactivation. The results suggest a transient up regulation of BDNF mRNA in reactivated T cells. Furthermore, in contrast to our hypothesis that the BDNF expression is necessary for CD4(+) T cells to mediate neuroprotection, mice with CD4(+) T cells lacking BDNF expression demonstrated a similar level of facial motoneuron survival compared to their littermates that expressed BDNF, and both levels were comparable to wild-type. The results suggest that the deletion of BDNF did not impair CD4(+) T cell-mediated neuroprotection. CONCLUSION: Collectively, while CD4(+) T cells are a potential source of BDNF after nerve injury, production of BDNF is not necessary for CD4(+) T cells to mediate their neuroprotective effects. PMID- 22426431 TI - The occurrence of preterm delivery is linked to pregnancy-specific distress and elevated inflammatory markers across gestation. AB - There is mounting evidence that stress during pregnancy can have detrimental effects on gestation and birth. Existing studies indicate that prenatal stress may increase levels of circulating inflammatory markers that are associated with prematurity and pregnancy complications, suggesting that stress-related changes in the cytokine milieu may increase the risk of poor pregnancy outcome. Previous studies, however, have not clearly connected stress during pregnancy to changes in inflammatory mediators and, in turn, to clinically-relevant outcomes such as premature delivery. The present study sought to directly connect prenatal stress and changes in inflammatory markers to preterm delivery and gestational age at birth (GAB). A sample of 173 women was recruited during the first trimester of pregnancy and followed through delivery. Overall stress, pregnancy-specific distress, and inflammatory markers were assessed early and later in pregnancy, and the predictive value of these measures for preterm birth and GAB was determined. There were significant differences in pregnancy-specific distress, IL 6, and TNF-alpha between women who delivered prematurely versus those who delivered at term, and elevated levels of pregnancy-specific distress, IL-6, and TNF-alpha were predictive of shortened GAB overall. Importantly, in many cases, the effects of overall stress and pregnancy-specific distress on GAB were mediated by levels of circulating inflammatory markers. Collectively, these data provide strong evidence that prenatal stress experiences can affect the timing of parturition via alterations in circulating inflammatory mediators, and underscore the need for ongoing research aimed at further understanding the mechanisms and effects of prenatal stress on maternal and infant health. PMID- 22426432 TI - Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene * environment interaction. AB - There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene * environment interactions in the etiology of schizophrenia. PMID- 22426433 TI - The consequences of chromosomal aneuploidy on the transcriptome of cancer cells. AB - Chromosomal aneuploidies are a defining feature of carcinomas, i.e., tumors of epithelial origin. Such aneuploidies result in tumor specific genomic copy number alterations. The patterns of genomic imbalances are tumor specific, and to a certain extent specific for defined stages of tumor development. Genomic imbalances occur already in premalignant precursor lesions, i.e., before the transition to invasive disease, and their distribution is maintained in metastases, and in cell lines derived from primary tumors. These observations are consistent with the interpretation that tumor specific genomic imbalances are drivers of malignant transformation. Naturally, this precipitates the question of how such imbalances influence the expression of resident genes. A number of laboratories have systematically integrated copy number alterations with gene expression changes in primary tumors and metastases, cell lines, and experimental models of aneuploidy to address the question as to whether genomic imbalances deregulate the expression of one or few key genes, or rather affect the cancer transcriptome more globally. The majority of these studies showed that gene expression levels follow genomic copy number. Therefore, gross genomic copy number changes, including aneuploidies of entire chromosome arms and chromosomes, result in a massive deregulation of the transcriptome of cancer cells. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22426434 TI - Speciation in chestnut-shouldered fairy-wrens (Malurus spp.) and rapid phenotypic divergence in variegated fairy-wrens (Malurus lamberti): a multilocus approach. AB - The chestnut-shouldered fairy-wrens comprise a subgroup of four species in the genus Malurus (Passeriformes: Maluridae). Collectively, they are widespread across the Australian continent but phenotypic variation is strongly structured geographically in just one species, M. lamberti. Earlier phylogenetic analyses of this group have been limited to one or two individuals for each species and have not represented all currently recognised subspecies of M. lamberti. Historically, the taxonomy and nomenclature of the M. lamberti complex has been debated, in part because of morphological similarities among its subspecies and another member of the group, M. amabilis. We reconstructed the phylogeny of all four species of chestnut-shouldered fairy-wrens including all four subspecies of M. lamberti using a mitochondrial gene (ND2), five anonymous nuclear loci and three nuclear introns. Phylogenetic analysis of the mitochondrial ND2 gene nests M. amabilis within M. lamberti rendering the latter paraphyletic. Individual nuclear gene trees failed to reliably resolve each of the species boundaries or the phylogenetic relationships found in the mtDNA tree. When combined, however, a strongly supported overall topology was resolved supporting the monophyly of M. lamberti and its sister species relationship to M. amabilis. Current subspecific taxonomy of M. lamberti was not concordant with all evolutionary lineages of M. lamberti, nominotypical M. l. lamberti being the only subspecies recovered as a monophyletic group from mtDNA. Some genetic structuring is evident and potential barriers to gene flow are discussed. PMID- 22426435 TI - Constructing phylogenetic supernetworks based on simulated annealing. AB - Different partial phylogenetic trees can be derived from different sources of evidence and different methods. One important problem is to summarize these partial phylogenetic trees using a supernetwork. We propose a novel simulated annealing based method called SNSA which uses an optimization function to produce a simple network that still retains a great deal of phylogenetic information. We report the performance of this new method on real and simulated datasets. PMID- 22426436 TI - Evolutionary history of synthesis pathway genes for phloroglucinol and cyanide antimicrobials in plant-associated fluorescent pseudomonads. AB - Plant-beneficial fluorescent Pseudomonas spp. play important ecological roles. Here, their evolutionary history was investigated by a multilocus approach targeting genes involved in synthesis of secondary antimicrobial metabolites implicated in biocontrol of phytopathogens. Some of these genes were proposed to be ancestral, and this was investigated using a worldwide collection of 30 plant colonizing fluorescent pseudomonads, based on phylogenetic analysis of 14 loci involved in production of 2,4-diacetylphloroglucinol (phlACBDE, phlF, intergenic locus phlA/phlF), hydrogen cyanide (hcnABC, anr) or global regulation of secondary metabolism (gacA, gacS, rsmZ). The 10 housekeeping loci rrs, dsbA, gyrB, rpoD, fdxA, recA, rpoB, rpsL, rpsG, and fusA served as controls. Each strain was readily distinguished from the others when considering allelic combinations for these 14 biocontrol-relevant loci. Topology comparisons based on Shimodaira-Hasegawa tests showed extensive incongruence when comparing single locus phylogenetic trees with one another, but less when comparing (after sequence concatenation) trees inferred for genes involved in 2,4 diacetylphloroglucinol synthesis, hydrogen cyanide synthesis, or secondary metabolism global regulation with trees for housekeeping genes. The 14 loci displayed linkage disequilibrium, as housekeeping loci did, and all 12 protein coding loci were subjected to purifying selection except for one positively selected site in HcnA. Overall, the evolutionary history of Pseudomonas genes involved in synthesis of secondary antimicrobial metabolites important for biocontrol functions is in fact similar to that of housekeeping genes, and results suggest that they are ancestral in pseudomonads producing hydrogen cyanide and 2,4-diacetylphloroglucinol. PMID- 22426437 TI - Metastasis: understanding is the beginning of order in chaos. PMID- 22426438 TI - Alcohol habits in patients with long-term musculoskeletal pain: comparison with a matched control group from the general population. AB - This prospective study aimed to describe alcohol habits in patients with chronic pain compared with those in a matched control group from the general Swedish population. In total, 100 consecutive patients enrolled were matched against 100 individuals in a control group on the basis of age and sex. Alcohol habits were measured using the Alcohol Use Disorders Identification Test in both groups. The patients were recruited if they underwent a biopsychosocial pain analysis for possible participation in pain rehabilitation. The patients with chronic pain drank alcohol significantly less, less often, in smaller quantities, and became intoxicated less than the control group did. The study was rather small and at a single site, but its strengths were the comprehensive and simple design and the possibility to describe the sample's representativeness compared with other clinics on the basis of data from a national quality register. PMID- 22426439 TI - Synthesis, structure and magnetic study of a novel mixed-valent Co(II)10Co(III)4 shield constructed by mixed pyridine-alcoholate ligands. AB - A novel tetradecanuclear mixed-valent cobalt cluster, formulated as [Co(II)(10)Co(III)(4)(OH)(2)O(6)(hmp)(10)(pdm)(4)(CH(3)OH)(2)].5H(2)O (1), was obtained using mixed ligands of 2-(hydroxymethyl)pyridine (hmpH) and 2,6 pyridinedimethanol (pdmH(2)). The cobalt ions in 1 are connected by ten chelating hmp(-) ligands, four tris-chelating pdm(2-) ligands and six MU(3)-oxide/hydroxide anions, forming a unique shield-like planar structure that is rarely observed for Co-based clusters. Compound 1 displays slight frequency dependence at static zero field below 4.5 K, suggesting that it might be a single molecule magnet (SMM). PMID- 22426440 TI - Analgesic effects of lidocaine, morphine and diclofenac on movement-induced nociception, as assessed by the Knee-Bend and CatWalk tests in a rat model of osteoarthritis. AB - Pain is the major symptom of osteoarthritis (OA) and the main reason for patients seeking medical care, but its treatment is not optimal. Animal studies are necessary to elucidate mechanisms underlying OA-induced pain and assess analgesics' efficacy. Previously, we showed that the Knee-Bend test and dynamic weight bearing by the CatWalk test are clinically relevant methods for assessing movement-induced nociception in the mono-iodoacetate (MIA) OA model. Using the same tests, in the present study we investigate the effects of lidocaine (5 mg, 10% solution, intra-articular), morphine (6 mg/kg, subcutaneous) and diclofenac (30 mg/kg per os) on nociceptive behavior in OA animals, on days 3 and 20 of OA evolution. Morphine reduced nociceptive behavior in both tests at both time points. Lidocaine also decreased nociceptive behavior in both tests on day 3, but on day 20 only reduced the Knee-Bend score. Diclofenac was highly effective in both tests on day 3, while on day 20 it induced a less pronounced decrease in the Knee-Bend score and was ineffective in the CatWalk test. The results showed that the Knee-Bend and CatWalk tests are reliable alternative methods for evaluating movement-induced nociception in OA animals, and measure nociception in a clinically relevant way, since an analgesic profile similar to the one described in humans was observed. Therefore, these tests might be important as good predictors of drug efficacy. PMID- 22426441 TI - PET follow-up in a case of anti-NMDAR encephalitis: arguments for cingulate limbic encephalitis. AB - BACKGROUND: The lack of specific MRI abnormalities in anti-NMDA receptor encephalitis makes the identification of the most affected areas difficult. Functional neuroimaging could be useful to identify brain dysfunction associated with psychiatric symptoms, but few precise data are available up to now. CASE STUDY: A 27-year-old woman was referred for recent behavioural changes and jerks of the right foot. Serial left fronto-temporal seizures were recorded. Identification of anti-NMDA receptor antibodies in CSF indicated a diagnosis of anti-NMDA receptor encephalitis. Two foci of hypermetabolism, in the left prefrontal cortex and the anterior cingulate cortex, were identified using 18 fluorodeoxyglucose PET and both disappeared after treatment. Brain MRI was normal, except for a mild left prefrontal hypersignal. CONCLUSIONS: The increase in marker uptake in motor and premotor regions in our case probably corresponds to epileptic activity. Our data suggest that the anterior cingulate cortex could play an important role in psychiatric symptoms. Other studies are needed to better understand the pathophysiology of anti-NMDA receptor encephalitis. PMID- 22426442 TI - Real-time in vivo cellular imaging of graft-versus-host disease and its reaction to immunomodulatory reagents. AB - Visualizing the in vivo dynamics of individual donor cells after allogeneic hematopoietic stem cell transplantation (HSCT) will enable deeper understanding of the process of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). In this study, using non-invasive in vivo fluorescence imaging of the ear pinna, we successfully visualized green fluorescent protein (GFP) donor cells at the single cell level in the skin. This imaging model enabled visualization of the movement of GFP cells into blood vessels in real time after allogeneic HSCT. At day 1, a few donor cells were detected, and the movement of donor cells in blood vessels was readily observed at day 4. Early donor cell infiltration into non-lymphoid tissue was increased by treatment with croton oil, as an inflammatory reagent. Treatment with dexamethasone, as an anti-inflammatory reagent, suppressed donor cell infiltration. The in vivo cellular fluorescence imaging model described here is a very useful tool for monitoring individual donor cells in real-time and for exploring immunomodulatory reagents for allogeneic HSCT, as well as for understanding the mechanism of GVHD. PMID- 22426443 TI - Synthesis and characterization of novel dual-responsive nanogels and their application as drug delivery systems. AB - In this study, a temperature/pH dual-response nanogel based on NIPAm, MAA, and PEGMA was synthesized via emulsion polymerization and characterized by (1)H-NMR, FT-IR, TEM and DLS. By introducing a novel initiator, through which PEG-AIBN-PEG was synthesized, it was revealed that the PEG segments from PEG-AIBN-PEG with a dosage of initiator had a significant influence over the macro-state and stability of the nanogels. In order to optimize the feeding prescription for better application as a drug delivery system, the effect of the co-monomer contents on the response to stimuli (temperature and pH value) and cytotoxicity of the nanogels has been studied in detail. The results demonstrated that the responsiveness, reversibility and volume phase transition critical value of the nanogels could be controlled by adjusting the feeding ratio of the co-monomers in the synthesis process. MTT assay results revealed that nanogels with appropriate compositions showed good biocompatibility and relatively low toxicity. Most importantly, by studying the drug loading behavior, it was found that the dimensions of the drug molecules had a considerable influence on the drug loading efficiency and loading capacity of the nanogels, and that the mechanism by which drug molecule sizes influence the drug loading behavior of nanogels needs further investigation. The results indicated that such PNMP nanogels might have potential applications in drug delivery and other medical applications, but that the drug loading mechanism must be further developed. PMID- 22426444 TI - The application of an age-structured model to the north Aegean anchovy fishery: an evaluation of different management measures. AB - The objective of this paper is the integration of existing biological and fishery knowledge of anchovy into a unified modelling framework in order to advance our understanding of species' population dynamics under different fishing strategies. The model simulates the anchovy biomass by combining an age-specific growth equation and a continuous age-structured population model based on the McKendrick Von Foerster equation. Model predictions were compared to the biomass estimates and annual catches during the period 2003-2008. The present work provided direct evidence for the significance of the prespawning period as a critical life period for the management of anchovy stock in the Aegean Sea. It was found that the introduction of additional management measures could increase the profits in the long run for the fishery. However, for these to become apparent they will require a minimum of four years. Results also indicated that the reduction of fishing mortality directed at the spawning stock (recruitment overfishing) and the selective harvesting of younger individuals may be a plausible means of increasing stock's total anchovy biomass. Finally, as a criterion of long-term population survival, we have considered the mathematical notation of persistence. The numerical criteria of persistence in the present model indicated that the anchovy population could be considered viable. PMID- 22426445 TI - Postoperative changes in spinal rod contour in adolescent idiopathic scoliosis: an in vivo deformation study. AB - STUDY DESIGN: Prospective case series. OBJECTIVE: To evaluate the change in spinal rod contour from before implantation to after surgical correction of thoracic curves in patients with adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: With segmental pedicle screw spinal instrumentation and vertebral derotation, many authors have reported a loss of thoracic kyphosis postoperatively. Although surgeons anticipate some flattening of the preimplantation rod contour in the sagittal plane, the magnitude of this change in shape has not been documented. METHODS: The concave and convex rod shapes of 5.5-mm ultrahigh-strength steel spinal rods (200 KSI) from patients with thoracic adolescent idiopathic scoliosis (n = 27), which were contoured with benders by the surgeon, were traced prior to insertion. Postoperative (average, 5 weeks) sagittal rod shape was determined from lateral 2-dimensional radiographs. Maximal rod deflection and angle of the tangents to rod end points (Cobb) were measured. Repeated measures analysis of variance assessed differences between pre- and postoperation. RESULTS: The scoliosis of 55 degrees +/-14 degrees was corrected 72% to 15 degrees +/- 5 degrees . The preinsertion rod shapes were more kyphotic for the concave (45.6 degrees ) than for the convex (31.4 degrees ) rods. Following correction, the concave rods flattened, with decrease in deflection of 13 mm and reduction in angle of 21 degrees (both P < 0.001). The convex rods increased 1.5 mm in deflection and 2 degrees in angle (P < 0.01, P = 0.18). The sagittal profile was maintained postoperatively as measured from T5-T12: 19 degrees +/-14 degrees versus 22 degrees +/- 6 degrees (pre vs. post, P > 0.1). CONCLUSION: We found a significant difference between pre- and postoperative rod contour, particularly for concave rods. Rod overcontouring (by ~20 degrees for concave rod) resulted in high degrees of correction without loss of sagittal alignment. The resulting deformations are likely associated with substantial in vivo deforming forces. PMID- 22426446 TI - Anatomic and morphometric analysis of manubrium sterni as a source of autograft for anterior cervical fusion surgery using quantitative 3-dimensional computed tomographic scans. AB - STUDY DESIGN: A morphologic study of manubrium sterni using 3-dimensional computed tomography (3D-CT). OBJECTIVE: To investigate the anatomic features of adult manubrium as a source of bone graft and to measure the sizes and available cancellous bone volume of manubrium. SUMMARY OF BACKGROUND DATA: Manubrium bone graft has been reported as a potential ideal material in anterior cervical fusion surgery, whereas the related applied anatomy is lacking in the literature. METHODS: One hundred twenty adult manubria from 68 male and 52 female patients were scanned and reformatted with 3D-CT. Configurations of manubrium was observed on 3D volume-rendered images. The breadths, height, medullar thickness, and thickness distribution of manubrium were evaluated. A safe area for procurement of graft was proposed and the available cancellous bone volume of manubrium was measured. RESULTS: Frontal manubrium bears a prominent pentagonal area, which was a bare area without muscle attachments. The breadths, height, and thickness of male manubrium were significantly larger than those of female manubrium. Maximal medullar thickness for male patient was 10.4 +/- 1.1 (range, 8.8-12.8) mm, and for female patient it was 9.4 +/- 1.4 (range, 6.6-11.9) mm. Minimal medullar thickness for male was 6.8 +/- 1.1 (range, 4.9-9.4) mm, and for female it was 5.8 +/- 0.9 (range, 4.2-7.4) mm. The thickest region of manubrium located at the level of lower clavicular notches, whereas the thinnest region located at the junction between upper two-thirds and lower third of manubrium. Available volume of cancellous bone was 10.1 +/- 2.2 (range, 6.6-15.6) cm(3) in male and 7.7 +/- 2.5 (range, 3.6-12) cm(3) in female. CONCLUSION: The size of male manubrium is significantly larger than that of female manubrium. Manubrium bone is far more sufficient for most adult anterior cervical fusion surgeries. Safe area for procurement of graft is defined as the upper two-thirds of manubrium, and the optimal site to access medullar cavity is suggested at bare area. However, because considerable variability of manubrium size exists, preoperative evaluation of manubrium is suggested to avoid pitfalls, especially when manubrium graft is intended in a female patient. PMID- 22426447 TI - Learning curve and clinical outcomes of minimally invasive transforaminal lumbar interbody fusion: our experience in 86 consecutive cases. AB - STUDY DESIGN: Consecutive case series with prospective data collection. OBJECTIVE: To define and analyze the learning curve for minimally invasive transforaminal lumbar interbody fusion (TLIF). SUMMARY OF BACKGROUND DATA: Minimally invasive TLIF using a unilateral approach has recently been gaining popularity because of its potential for minimizing soft-tissue damage and reducing recovery time. However, a steep learning curve has been described for surgeons first performing this technique. METHODS: Eighty-six consecutive patients with degenerative lumbar diseases who were treated by TLIF were included in the study. Surgeries were performed using a tubular retractor, and a cage was inserted using a unilateral transforaminal approach by a single surgeon. The corresponding segments were fixed with percutaneous pedicle screws. Eighty-three patients were followed up for more than 1 year, and the average follow-up period was 25 months. Single-level TLIF was performed in 60 cases, single-level TLIF plus adjacent-level decompression was performed in 13 cases, and double-level TLIF was performed in 13 cases. Corrected operative time per level, operative blood loss, postoperative blood drainage, total blood loss, and ambulation recovery time were measured. Transfusion rates and complication incidence were also identified. Clinical results were assessed using the Oswestry Disability Index (ODI) and a visual analogue scale (VAS). The learning curve was assessed using a logarithmic curve-fit regression analysis. In the single-level TLIF group (n = 60), 22 patients were defined as the "early" group (among the first 30 cases of the series), and the subsequent 38 cases were defined as the "late" group for comparison. RESULTS: Corrected operative time gradually decreased as the series progressed, and an asymptote was reached after about 30 cases. ODI significantly decreased from an average of 24 at the preoperative stage to 10 at the final follow-up. Average VAS scores for lower back pain and radiating pain also significantly decreased from an average of 5.2 to 1.9 and 6.8 to 0.9, respectively. In the single-level TLIF series, operative time was significantly shorter in the late group (183 +/- 23 min) than the early group (254 +/- 44 min), and blood loss during the operation was significantly reduced in the late group (292 +/- 280 mL) compared with the early group (508 +/- 278 mL). Ambulation recovery time significantly decreased from 2.4 +/- 0.6 days in the early group to 2.0 +/- 0.5 in the late group. ODI and VAS scores for lower back pain and radiating pain did not differ between the 2 groups. CONCLUSION: Although it is not easy to master the minimally invasive TLIF technique, the surgeon's experience with this operation correlated with reduced operation time and blood loss during surgery. After the initial learning curve, this technique could be an effective and reliable option for the surgical treatment of lumbar degenerative disease. PMID- 22426448 TI - Validation of the simplified chinese version of the functional rating index for patients with low back pain. AB - STUDY DESIGN: Cross-cultural translation and psychometric testing of the functional rating index (FRI). OBJECTIVE: To evaluate the reliability and validity of the adapted simplified Chinese FRI (SC-FRI) for patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: The FRI is a reliable and valid instrument to assess the perception of function and pain for patients with LBP. However, there is no culturally adapted, reliable, and validated FRI for use in mainland China. METHODS: The translation and cross-cultural adaptation were performed following international guidelines. The SC-FRI was administered to 115 patients with LBP along with the simplified Chinese version of the Oswestry disability index, 36-item short form health survey, and the visual analogue scale. Psychometric testing included internal consistency, test-test reliability, concurrent criterion validity, and construct validity. RESULTS: A high completion rate of 96% and no floor or ceiling effects were noted for the SC-FRI. The internal consistency was good (i.e., Cronbach alpha = 0.897 for the overall SC FRI; range, 0.851-0.890, if an item was deleted). Test-retest reliability was excellent, with an intraclass correlation coefficient of 0.948 (95% confidence interval, 0.917-0.968). Concurrent criterion validity assessment demonstrated that the SC-FRI significantly correlated with the visual analogue scale (r = 0.852, P < 0.0001) and the simplified Chinese version of the Oswestry disability index (r = 0.958, P < 0.0001). Construct validity was confirmed by the significant Pearson correlation between the SC-FRI and physical functioning (r = 0.802, P < 0.0001), Bodily Pain (r = -0.698, P < 0.0001), social functioning (r = -0.573, P < 0.0001), role-physical (r = -0.503, P < 0.0001), and general health (r = -0.502, P < 0.0001) domains of the 36-Item Short Form Health Survey. CONCLUSION: The SC-FRI showed excellent reliability and validity in the evaluation of pain and the functional health status of Chinese-speaking patients with LBP. It is simple and easy to use and can be recommended in clinical and research practice in mainland China. PMID- 22426449 TI - Psychometric evaluation of a decision quality instrument for treatment of lumbar herniated disc. AB - STUDY DESIGN: Retrospective and prospective patient surveys and a physician survey using a sample from American Medical Association master file. OBJECTIVE: To evaluate the performance of a new instrument designed to measure the quality of decisions about treatment of herniated disc. SUMMARY OF BACKGROUND DATA: There is growing consensus on the importance of engaging and informing patients to improve the quality of significant medical decisions, yet there are no instruments currently available to measure decision quality. METHODS: The herniated disc-decision quality instrument (HD-DQI) was developed with input from clinical experts, survey research experts, and patients. The HD-DQI produces 2 scores each scaled to 0% to 100%, with higher scores indicating better quality: (1) a total knowledge score and (2) a concordance score (indicating the percentage of patients who received treatments that matched their goals). We examined hypotheses relating to the acceptability, feasibility, validity, and reliability of the instrument, using data from 3 samples. RESULTS: The HD-DQI survey was feasible to implement and acceptable to patients, with good response rates and low missing data. The knowledge score discriminated between patients who had seen a decision aid or no decision aid (55% vs. 38%, P < 0.001) and between providers and patients (73% vs. 46%, P < 0.001). The knowledge score also had good retest reliability (intraclass correlation coefficient = 0.85). Most patients (78%) received treatments that matched their goals. Patients who received treatments that matched their goals were less likely to regret the decision than those who did not (13% vs. 39%, P = 0.004). CONCLUSION: The HD-DQI met several criteria for high-quality patient-reported survey instruments. It can be used to determine the quality of decisions for treatment of herniated disc. More work is needed to examine acceptability for use as part of routine patient care. PMID- 22426450 TI - S1 tuberculosis treated with segmental lumbopelvic fixation: a case report. AB - STUDY DESIGN: A case report. OBJECTIVE: To describe an effective surgical option for sacral tuberculosis (TB). SUMMARY OF BACKGROUND DATA: Sacral TB is a rare cause of low back pain. A differential diagnosis of TB should always be made, especially in India where TB cases are on a rampant rise with increasing drug resistance and immunosuppressed population. METHODS: A retrospective review. RESULTS.: We report on a 24-year-old woman with low back pain and radiculopathy. Magnetic Resonance Imaging (MRI) showed a destructive lesion in S1 body. Empirical antitubercular treatment was started elsewhere with no relief but worsening of the lesion. She underwent a Computed Tomography (CT)-guided biopsy and drug sensitivity test, which did not reveal anything. The patient was bedridden for almost a year. A lumbopelvic instrumented fixation and S1 body reconstruction with structural allograft was performed. Culture sensitivity revealed multidrug resistance. After surgery, the patient responded rapidly, and at 2-year follow-up, she is symptom-free. CONCLUSION: TB should always be considered as a differential diagnosis of sacral lesions, and identifying multidrug resistance is equally important in its treatment. Lumbopelvic fixation is a safe and reliable option as it unloads the S1 segment by achieving fixation in the lumbosacral spine and iliac wings. PMID- 22426451 TI - Lumbar bone mass predicts low back pain in males. AB - STUDY DESIGN: Longitudinal study of lumbar bone mass as predictor of low back pain (LBP). OBJECTIVE: To investigate whether low bone mineral content (BMC) and bone mineral density (BMD) values at the age of 36 years are associated with the prevalence of LBP at the age of 42 years among the study population of the Amsterdam Growth and Health Longitudinal Study. SUMMARY OF BACKGROUND DATA: Results of epidemiological, clinical, and in vitro studies indicate that spinal injuries, caused by mechanical loading, might be a cause of LBP. BMC and BMD are determinants of spinal strength. We therefore hypothesized that BMC and BMD are associated with LBP. METHODS: At the age of 36 years, the lumbar BMC and BMD were determined by dual-energy x-ray absorptiometry in 140 men and 152 women. At the age of 42 years, the participants were asked whether they had experienced LBP in the previous 12 months. Logistic regression analyses were performed to determine odds ratios (ORs)-adjusted for stature, body weight, physical activity, and smoking-for the relationship of BMC and BMD with LBP. RESULTS: BMC and BMD at the age of 36 years were significantly associated with the reported 12-month prevalence of LBP at the age of 42 years. This association, however, was observed only for men and not for women. Men within the quartile with the lowest BMC or BMD values had higher odds for LBP with ORs of 4.78 (95% confidence interval, 1.52-15.00) and 3.48 (95% confidence interval, 1.23-9.85), respectively. CONCLUSION: For a male population that is not characterized by osteoporosis or old age, lower lumbar BMC and BMD values at the age of 36 years are associated with an increased risk of reporting to have had LBP in the previous 12 months at the age of 42 years. PMID- 22426452 TI - Does patient diagnosis predict blood loss during posterior spinal fusion in children? AB - STUDY DESIGN: A retrospective review. OBJECTIVE: To assess the relationship between diagnosis and blood loss in children undergoing posterior spinal fusion surgery for deformity correction. SUMMARY OF BACKGROUND DATA: To our knowledge, this relationship is not well established. It has important implications for understanding the mechanisms for blood loss and planning for surgery. METHODS: Clinical records were reviewed for all patients 10 to 18 years of age who underwent spinal fusion surgery (at least 5 levels) by the senior author from 2001 through 2011. Patients were excluded for antifibrinolytic use, vertebral column resections, history of spinal surgery, nonpedicle screw instrumentation, cervical spine fusion, or anterior approaches. The 617 patients (with 37 diagnoses) were categorized into 5 groups: idiopathic scoliosis (IS), Scheuermann kyphosis (SK), cerebral palsy, other neuromuscular disorders, and genetic and syndromic disorders. Analysis of covariance was used to assess differences in blood loss across the diagnostic groups. Normalized blood loss (NBL) was calculated by dividing blood loss by number of levels fused and by patient's weight; NBL differences between groups were analyzed using Bonferroni correction method. Significance was set at P < 0.05. RESULTS: Blood loss differed significantly by diagnostic group, adjusting for extent of fusion and patient weight (P < 0.001). Patients with cerebral palsy had a significantly higher NBL than patients with IS (P < 0.001), SK (P < 0.001), other neuromuscular disorders (P = 0.049), or genetic and syndromic disorders (P = 0.006). Patients with other neuromuscular disorders had a significantly higher NBL than patients with IS (P < 0.001) or SK (P < 0.001). Patients with genetic and syndromic disorders also had a significantly higher NBL than patients with IS (P < 0.001) or SK (P < 0.001). CONCLUSION: There is a significant relationship between patient diagnosis and blood loss during posterior spinal fusion surgery in children. PMID- 22426453 TI - Predictors of treatment choice in lumbar spinal stenosis: a spine patient outcomes research trial study. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: In this article, we examined the Spine Patient Outcomes Research Trial lumbar stenosis observational cohort to determine baseline patient characteristics that are predictive of the treatment patients chose. We also evaluated cutoff points on validated patient questionnaires that differentiate patients who chose surgery from those who chose nonsurgical management. SUMMARY OF BACKGROUND DATA: Although the evidence from current studies suggests that surgical intervention is effective for lumbar spinal stenosis, the same studies show that nonoperative patients also improve. Thus, the reasons for patients choosing surgery versus nonoperative care are of continuing interest. METHODS: Baseline patient and clinical characteristics between those who received operative intervention and those who received nonoperative care were compared to determine baseline predictors of lumbar spinal stenosis management. Also, an evaluation of responses to the 36-Item Short Form Health Survey Bodily Pain (BP), 36-Item Short Form Health Survey Physical Function (PF), and the modified Oswestry Disability Index (ODI) questionnaires was performed to determine the percentage of patients choosing surgical versus nonoperative care relative to their initial questionnaire values. RESULTS: This analysis looked at the 356 patients in the observational spinal stenosis cohort of Spine Patient Outcomes Research Trial who completed at least 1 follow-up visit. Patients choosing surgery were younger (P = 0.022), had worse BP (P < 0.001), worse PF (P < 0.001), worse ODI (P < 0.001), worse Stenosis Bothersomeness Index (P < 0.001), were dissatisfied with their symptoms (P = 0.001), and had a worse self-assessed health trend (P < 0.001). Patients tended to choose surgery if they had lateral recess stenosis (P = 0.022). Kaplan-Meier curves demonstrate that patients with a BP score of 32 or less, PF score of 30 or less, and ODI greater than 29 chose surgery 75% of the time. CONCLUSION: A greater understanding of baseline characteristics that influence patient choices in the treatment of lumbar spinal stenosis can aid the patient and the surgeon during the shared decision-making process. PMID- 22426454 TI - Spinal deformity correction in Marfan syndrome versus adolescent idiopathic scoliosis: learning from the differences. AB - STUDY DESIGN: Retrospective case control study. OBJECTIVE: To compare patients with Marfan syndrome and matched patients with adolescent idiopathic scoliosis (AIS) to illustrate the differences and identify areas for potential surgical improvement. SUMMARY OF BACKGROUND DATA: Patients with Marfan syndrome commonly require spinal deformity surgery, but practice guidelines and results are not as established as those for patients with AIS. METHODS: We matched 34 adolescents with Marfan syndrome with patients with AIS (ratio, 1:2) for age, sex, and degree of major deformity. Overall mean age was 14 +/- 2 years and mean curves were 51 degrees thoracic and 46 degrees lumbar. Mean follow-up was 5.3 and 3.6 years, respectively. RESULTS: The Marfan syndrome group had significantly more thoracolumbar kyphosis correction (9.5 degrees vs. 0.1 degrees , P = 0.05), significantly more levels fused (12 +/- 2 vs. 9 +/- 3, P <= 0.01), significantly more fusions to the pelvis (7 vs. 0, P = 0.01), and significantly more correction of sagittal imbalance (2.4 vs. -0.6 cm, P = 0.035). The Marfan syndrome group also had more intraoperative cerebrospinal fluid leaks (3 vs. 0, P = 0.01), significantly more instrumentation complications (3 vs. 1, P = 0.007), more reoperations for indications [such as fixation failure, distal degeneration, and spine fracture (9 vs. 0, P = 0.01)], and lower SRS-22 total (3.9 vs. 4.5, P = 0.01) and partial (P < 0.015) subscores. There were no significant differences between the groups in progression of unfused proximal thoracic curves, blood loss, neurological deficit, hospital stay, percent correction, or infection rate. CONCLUSION: Patients with Marfan syndrome differ in several ways from those with AIS: they require more levels of surgical correction, more distal fusion, greater correction of sagittal balance, and more reoperations, and they have more intraoperative cerebrospinal fluid leaks and instrumentation-related complications. Knowledge of these differences is important for planning surgery. PMID- 22426455 TI - Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule. AB - Certain combinations of non-competitive anti-EGFR antibodies have been reported to produce new effects on cells compared to either antibody used separately. New and enhanced combination-activity includes increased inhibition of signaling, increased receptor internalization and degradation, reduced proliferation of tumor cell lines and induction of complement-dependent cytotoxicity (CDC) effector function. To test requirements and mechanisms to elicit enhanced combination-activity with different EGFR binding domains, we created an anti-EGFR biparatopic antibody. A biparatopic antibody interacts through two different antigen-binding sites to a single antigen. A heterodimeric antibody with one binding domain derived from the C225 antibody and one binding domain derived from the humanized 425 (hu425) antibody was built on the strand-exchange engineered domain (SEED) scaffold. This anti-EGFR biparatopic-SEED antibody was compared to parental antibodies used alone and in combination, and to the corresponding monovalent anti-EGFR-SEED antibodies used alone or in combination. We found that the anti-EGFR biparatopic-SEED had enhanced activity, similar to the combination of the two parental antibodies. Combinations of monovalent anti-EGFR-SEED antibodies did not produce enhanced effectiveness in cellular assays. Our results show that the anti-EGFR biparatopic antibody created using the SEED scaffold has enhanced combination-activity in a single molecule. Furthermore, these data suggest that the potential to cross-link the two different epitopes is an important requirement in the mechanism of enhanced combination-activity. PMID- 22426456 TI - Governing bodies and spaces: a critical analysis of mandatory human immunodeficiency virus testing in correctional facilities. AB - As it currently stands, mandatory human immunodeficiency virus (HIV) testing of prisoners is performed by nurses in more than 24 states and throughout the federal correctional system. The aim of this article was to bring to the attention of the nursing community the inner workings of mandatory HIV testing and its implications for HIV-positive prisoners. Building on a recent report published by Human Rights Watch, we critically examine the deployment of mandatory HIV testing in state correctional facilities located in Alabama and South Carolina. We, therefore, intend to situate this practice within a bio political logic and explore its human rights consequence. PMID- 22426457 TI - A silica sol-gel design strategy for nanostructured metallic materials. AB - Batteries, fuel cells and solar cells, among many other high-current-density devices, could benefit from the precise meso- to macroscopic structure control afforded by the silica sol-gel process. The porous materials made by silica sol gel chemistry are typically insulators, however, which has restricted their application. Here we present a simple, yet highly versatile silica sol-gel process built around a multifunctional sol-gel precursor that is derived from the following: amino acids, hydroxy acids or peptides; a silicon alkoxide; and a metal acetate. This approach allows a wide range of biological functionalities and metals--including noble metals--to be combined into a library of sol-gel materials with a high degree of control over composition and structure. We demonstrate that the sol-gel process based on these precursors is compatible with block-copolymer self-assembly, colloidal crystal templating and the Stober process. As a result of the exceptionally high metal content, these materials can be thermally processed to make porous nanocomposites with metallic percolation networks that have an electrical conductivity of over 1,000 S cm(-1). This improves the electrical conductivity of porous silica sol-gel nanocomposites by three orders of magnitude over existing approaches, opening applications to high current-density devices. PMID- 22426458 TI - Infrared metamaterial phase holograms. AB - As a result of advances in nanotechnology and the burgeoning capabilities for fabricating materials with controlled nanoscale geometries, the traditional notion of what constitutes an optical device continues to evolve. The fusion of maturing low-cost lithographic techniques with newer optical design strategies has enabled the introduction of artificially structured metamaterials in place of conventional materials for improving optical components as well as realizing new optical functionality. Here we demonstrate multilayer, lithographically patterned, subwavelength, metal elements, whose distribution forms a computer generated phase hologram in the infrared region (10.6 MUm). Metal inclusions exhibit extremely large scattering and can be implemented in metamaterials that exhibit a wide range of effective medium response, including anomalously large or negative refractive index; optical magnetism; and controlled anisotropy. This large palette of metamaterial responses can be leveraged to achieve greater control over the propagation of light, leading to more compact, efficient and versatile optical components. PMID- 22426459 TI - Liquid-liquid transition without macroscopic phase separation in a water-glycerol mixture. AB - The existence of more than two liquid states in a single-component substance and the ensuing liquid-liquid transitions (LLTs) has attracted considerable attention because of its counterintuitive nature and its importance in the fundamental understanding of the liquid state. Here we report direct experimental evidence for a genuine (isocompositional) LLT without macroscopic phase separation in an aqueous solution of glycerol. We show that liquid I transforms into liquid II by way of two types of kinetics: nucleation and growth, and spinodal decomposition. Although liquid II is metastable against crystallization, we could access both its static and dynamical properties experimentally. We find that liquids I and II differ in density, refractive index, structure, hydrogen bonding state, glass transition temperature and fragility, and that the transition between the two liquids is mainly driven by the local structuring of water rather than of glycerol, suggesting a link to a plausible LLT in pure water. PMID- 22426460 TI - Polyvalent choline phosphate as a universal biomembrane adhesive. AB - Phospholipids in the cell membranes of all eukaryotic cells contain phosphatidyl choline (PC) as the headgroup. Here we show that hyperbranched polyglycerols (HPGs) decorated with the 'PC-inverse' choline phosphate (CP) in a polyvalent fashion can electrostatically bind to a variety of cell membranes and to PC containing liposomes, the binding strength depending on the number density of CP groups per macromolecule. We also show that HPG-CPs can cause cells to adhere with varying affinity to other cells, and that binding can be reversed by subsequent exposure to low molecular weight HPGs carrying small numbers of PCs. Moreover, PC-rich membranes adsorb and rapidly internalize fluorescent HPG-CP but not HPG-PC molecules, which suggests that HPG-CPs could be used as drug-delivery agents. CP-decorated polymers should find broad use, for instance as tissue sealants and in the self-assembly of lipid nanostructures. PMID- 22426461 TI - Characterization of supercooled liquid Ge2Sb2Te5 and its crystallization by ultrafast-heating calorimetry. AB - Differential scanning calorimetry (DSC) is widely used to study the stability of amorphous solids, characterizing the kinetics of crystallization close to the glass-transition temperature T(g). We apply ultrafast DSC to the phase-change material Ge(2)Sb(2)Te(5) (GST) and show that if the range of heating rates is extended to more than 10(4) K s(-1), the analysis can cover a wider temperature range, up to the point where the crystal growth rate approaches its maximum. The growth rates that can be characterized are some four orders of magnitude higher than in conventional DSC, reaching values relevant for the application of GST as a data-storage medium. The kinetic coefficient for crystal growth has a strongly non-Arrhenius temperature dependence, revealing that supercooled liquid GST has a high fragility. Near T(g) there is evidence for decoupling of the crystal-growth kinetics from viscous flow, matching the behaviour for a fragile liquid suggested by studies on oxide and organic systems. PMID- 22426462 TI - Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types. AB - Inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene results in the development of schwannomas and meningiomas. Using NF2-deficient meningioma cells and tumors, together with the normal cellular counterparts that meningiomas derive, arachnoid cells, we identified merlin as a novel negative regulator of mTOR complex 1 (mTORC1). We now show that merlin positively regulates the kinase activity of mTORC2, a second functionally distinct mTOR complex, and that downstream phosphorylation of mTORC2 substrates, including Akt, is reduced upon acute merlin deficiency in cells. In response to general growth factor stimulation, Akt signaling is attenuated in merlin RNA interference suppressed human arachnoid and Schwann cells by mechanisms mediated by hyperactive mTORC1 and impaired mTORC2. Moreover, Akt signaling is impaired differentially in a cell type-dependent manner in response to distinct growth factor stimuli. However, contrary to activation of mTORC1, the attenuated mTORC2 signaling profiles exhibited by normal arachnoid and Schwann cells in response to acute merlin loss were not consistently reflected in NF2-deficient meningiomas and schwannomas, suggesting additional genetic events may have been acquired in tumors after initial merlin loss. This finding contrasts with another benign tumor disorder, tuberous sclerosis complex, which exhibits attenuated mTORC2 signaling profiles in both cells and tumors. Finally, we examined rapamycin, as well as the mTOR kinase inhibitor, Torin1, targeting both mTOR complexes to identify the most efficacious class of compounds for blocking mTOR-mediated signaling and proliferation in merlin-deficient meningioma cells. These studies may ultimately aid in the development of suitable therapeutics for NF2-associated tumors. PMID- 22426463 TI - Degradation of human RAP80 is cell cycle regulated by Cdc20 and Cdh1 ubiquitin ligases. AB - Receptor-associated protein 80 (RAP80) is a component of the BRCA1-A complex that recruits BRCA1 to DNA damage sites in the DNA damage-induced ubiquitin signaling pathway. RAP80-depleted cells showed defective G(2)-M phase checkpoint control. In this study, we show that RAP80 protein levels fluctuate during the cell cycle. Its expression level peaked in the G(2) phase and declined during mitosis and progression into the G(1) phase. Also, RAP80 is polyubiquitinated and degraded by the anaphase-promoting complex (APC/C)(Cdc20) or (APC/C)(Cdh1). Consistent with this, knockdown of Cdc20 or Cdh1 expression by transfecting with small interfering RNAs blocked RAP80 degradation during mitosis or the G(1) phase, respectively. A conserved destruction box (D box) in RAP80 affected its stability and ubiquitination, which was dependent on APC/cyclosome(Cdc20) (C(Cdc20)) or APC/cyclosome(Cdh1) (C(Cdh1)). In addition, overexpression of RAP80 destruction box1 deletion mutant attenuated mitotic progression. Thus, APC/C(Cdc20) or APC/C(Cdh1) complexes regulate RAP80 stability during mitosis to the G(1) phase, and these events are critical for a novel function of RAP80 in mitotic progression. PMID- 22426464 TI - Adenovirally delivered IFN-beta exerts antitumor effects through transient T lymphocyte depletion and Ag-specific T-cell proliferation. AB - Type I interferons (IFNs), including IFN-beta, are known to enhance antigen (Ag) presentation and to promote the expansion, survival and effector function of CD8+ cytotoxic lymphocytes (CTL) during viral infections. Furthermore, IFN-beta is a potent candidate for antitumor drugs; however, recombinant IFN-beta is too unstable for use in tumor therapy in vivo. In this study, we therefore examined the efficacy and mechanism of exogenous IFN-beta as a biomolecule for tumor therapy, using adenovirus encoding IFN-beta (Ad-IFNbeta) as a therapeutic agent in a mouse model. Ag104Ld and 4T1 tumor cells exposed to Ad-IFNbeta showed growth retardation and cell death in vitro, and tumor growth as well as tumor metastasis was inhibited in vivo. The Ad-IFNbeta-mediated antitumor effect was dependent on CD8+ T cells in vivo, rather than on a direct cytotoxic effect of Ad-IFNbeta. Transient T lymphocyte depletion was observed in tumor tissue after intratumoral injection with Ad-IFNbeta. Despite the T lymphocyte depletion, the proliferation of Ag-specific CD8+ T cells was increased in Ad-IFNbeta-treated mice compared to control virus-treated mice. These results suggest that IFN-beta might contribute to the inhibition of tumor growth by depleting Ag-nonspecific T lymphocytes and enhancing proliferation of Ag-specific CD8+ T cells. PMID- 22426465 TI - Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: indications for central and peripheral mechanisms. AB - A promising target for memory improvement is phosphodiesterase type 5 (PDE5), which selectively hydrolyzes cyclic guanosine monophosphate (cGMP). In rodents, PDE5 inhibitors (PDE5-Is) have been shown to improve memory performance in many behavioral paradigms. However, it is questioned whether the positive effects in animal studies result from PDE5 inhibition in the central nervous system or the periphery. Therefore, we studied the effects of PDE5 inhibition on memory and determined whether compound penetration of the blood-brain barrier (BBB) is required for this activity. Two selective PDE5-Is, vardenafil and UK-343,664, were tested in the object recognition task (ORT) in both a MK-801- and scopolamine-induced memory deficit model, and a time-delay model without pharmacological intervention. Compounds were dosed 30 min before the learning trial of the task. To determine if the PDE5-Is crossed the BBB, their concentrations were determined in plasma and brain tissue collected 30 min after oral administration. Vardenafil improved object recognition memory in all three variants of the ORT. UK-343,664 was ineffective at either preventing MK-801 induced memory disruption or time-dependent memory decay. However, UK-343,664 attenuated the memory impairment of scopolamine. Vardenafil crossed the BBB whereas UK-343,664 did not. Further, co-administration of UK-343,664 and scopolamine did not alter the brain partitioning of either molecule. This suggests that the positive effect of UK-343,664 on scopolamine-induced memory decay might arise from peripheral PDE5 inhibition. The results herein suggest that there may be multiple mechanisms that mediate the efficacy of PDE5 inhibition to improve memory performance in tasks such as the ORT and that these involve PDE5 located both within and outside of the brain. To further elucidate the underlying mechanisms, the cellular and subcellular localization of PDE5 needs to be determined. PMID- 22426466 TI - Multimodal monitoring in subarachnoid hemorrhage. PMID- 22426467 TI - Proportion of patients treated with thrombolysis in a centralized versus a decentralized acute stroke care setting. AB - BACKGROUND AND PURPOSE: Today, treatment of acute stroke consists of tissue-type plasminogen activator (tPA), admission to a stroke unit, and aspirin. Although tPA treatment is the most effective, there is substantial undertreatment. Centralized care may affect rate, timing, and outcome of thrombolysis compared to decentralized treatment in community hospitals. The present study aimed to assess the impact of organizational models on the proportion of patients undergoing tPA treatment. METHODS: A prospective, multicenter, observational study among 13 hospitals in the North of the Netherlands was conducted. In the centralized model, tPA treatment for 4 hospitals was administered in 1 stroke center. The decentralized model comprised 9 community hospitals. Primary outcome was the proportion of patients treated with tPA. Secondary outcome measures were proportion of patients arriving within 4.5 hours, safety, 90-day functional outcome, and onset-to-door, door-to-needle, and onset-to-needle times. Potential confounders were adjusted using logistic regression analysis. RESULTS: Two hundred eighty-three and 801 ischemic stroke patients were enrolled in the centralized and decentralized settings. Numbers of patients treated with tPA were 62 (21.9%) and 113 (14.1%) (OR, 1.72; 95% CI, 1.22-2.43). Adjusting for potential confounders did not alter results (OR, 2.03; 95% CI, 1.39-2.96). In the centralized setting, significantly more patients arrived at the hospital within the 4.5-hour time window (P<0.01), and shorter door-to-needle times were reached (35 versus 47 minutes). Other secondary outcome measures did not differ across setting. CONCLUSIONS: In a centralized setting, the results demonstrate a 50% increased likelihood of treatment. Prehospital factors seem to contribute to this result. PMID- 22426468 TI - A new bioinformatics insight into human cancer-associated proteins. AB - Cancer is a complex disease caused by multiple factors including genetic mutations, and environmental factors. Cancer-associated proteins are potential biomarkers or targets for diagnostic and therapeutic interventions in cancer. The Universal Protein Resourse (UniPort) is a well-annotated comprehensive resourse for protein sequence records. In the present study, we performed data mining of Uniprot proteins as a proteomic resource. we generated a catalog of 1653 cancer associated proteins including 344 secretory proteins and 300 cell surface proteins. Integrated bioinformatic analysis including ontological classification, functional enrichment and pathway construction were performed. These proteins could serve as a reference for further studies to discover cancer targets, and the enriched bioinformatic analysis provides new insights into cancer proteomics research. PMID- 22426469 TI - Amino acid derivatives of the (-) enantiomer of gossypol are effective fusion inhibitors of human immunodeficiency virus type 1. AB - T20 and maraviroc are the only two currently available entry inhibitors that have shown efficacy in treating HIV-1-infected individuals who have failed to respond to first-line antiretroviral drugs. Gossypol is a polyphenolic aldehyde extracted from cotton plants. By modifying the (-) enantiomer of gossypol with a series of small molecules, we have found that neutral amino acids with aliphatic group derivatives of (-) gossypol show the strongest inhibitory activity and the lowest cytotoxicity in vitro among all the derivatives tested. Additionally, the selectivity index of the (-) gossypol-neutral amino acid conjugates is increased 100-fold when compared with (-) gossypol alone. It is widely accepted that gossypol and gossypol derivatives inhibit HIV-1 replication by targeting reverse transcriptase. However, from the results of our time-of-addition assay, HIV-1 mediated cell fusion assay and VSV-G pseudotyped virus assay, we demonstrate that the alanine-(-) gossypol derivative ((-)G-Ala) is an effective HIV-1 entry inhibitor. Further mechanistic analysis revealed that (-)G-Ala neither blocks gp120-CD4 binding nor interacts with the HIV-1 co-receptor CXCR4. Results from sandwich ELISA, native-PAGE and circular dichroism (CD) show that (-)G-Ala inhibits the cell fusion-activated gp41 core domain. Moreover, (-)G-Ala binds to the HIV-5-Helix protein and blocking D-peptide (PIE7) binding to the hydrophobic pocket on the surface of the gp41 internal trimeric coiled-coil domain. The contraceptive properties of (-) gossypol and amino acid derivatives of (-) gossypol are also discussed. Collectively, our results indicate that (-)G-Ala may bind to the gp41 hydrophobic pocket and block the formation of the cell fusion activated gp41 core to inhibit HIV-1-mediated membrane fusion and subsequent viral entry. PMID- 22426470 TI - An engineered inhibitor RNA that efficiently interferes with hepatitis C virus translation and replication. AB - Hepatitis C virus (HCV) translation is mediated by a highly conserved internal ribosome entry site (IRES), mainly located at the 5'untranslatable region (5'UTR) of the viral genome. Viral protein synthesis clearly differs from that used by most cellular mRNAs, rendering the IRES an attractive target for novel antiviral compounds. The engineering of RNA compounds is an effective strategy for targeting conserved functional regions in viral RNA genomes. The present work analyses the anti-HCV potential of HH363-24, an in vitro selected molecule composed of a catalytic RNA cleaving domain with an extension at the 3' end that acts as aptamer for the viral 5'UTR. The engineered HH363-24 efficiently cleaved the HCV genome and bound to the essential IIId domain of the IRES region. This action interfered with the proper assembly of the translationally active ribosomal particles 48S and 80S, likely leading to effective inhibition of the IRES function in a hepatic cell line. HH363-24 also efficiently reduced HCV RNA levels up to 70% in a subgenomic replicon system. These findings provide new insights into the development of potential therapeutic strategies based on RNA molecules targeting genomic RNA structural domains and highlight the feasibility of generating novel engineered RNAs as potent antiviral agents. PMID- 22426471 TI - Efficacy and safety of ziprasidone in the treatment of first-episode psychosis: an 8-week, open-label, multicenter trial. AB - The aim of this study was to investigate the efficacy and safety of ziprasidone in first-episode psychosis. This was an 8-week, open-label, multicenter trial. In total, 27 patients (14 male patients, 13 female patients) with a Diagnostic and Statistical Manual of Mental Disorders--Fourth Edition diagnosis of schizophreniform disorder, schizoaffective disorder, schizophrenia, or psychotic disorder not otherwise specified comprised the study population. The initial recommended dose of ziprasidone was 40 mg/day. Within the first 2 weeks, the dose could be increased to 120-160 mg/day depending on the patient's condition. The primary outcome variables were scores on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity scale; secondary measures included the Calgary Depression Scale for Schizophrenia and others. To assess safety, we measured drug-related adverse events, weight, lipid variables, prolactin, and corrected QT (QTc) interval. Among the 27 enrolled participants, 16 dropped out [lack of efficacy (n = 7), loss to follow-up (n = 7), withdrawn consent (n = 1), and serious adverse event (n = 1)]. The mean total daily and endpoint doses of ziprasidone were 120.30 +/- 40.34 and 131.85 +/- 51.22 mg/day, respectively. The administration of ziprasidone resulted in significant improvement in the PANSS (P < 0.0001) and CGI scores (P < 0.0001) over time. Significant improvement in the Calgary Depression Scale for Schizophrenia score (P < 0.0001) was also observed at week 8. The response rate (defined as a 30% or greater decrease in the PANSS total score from baseline to last observation) was 51.85%. No significant differences in extrapyramidal symptoms rating scale scores, and lipid and prolactin levels from baseline to last observation were found. However, modest side effects regarding the incidence of extrapyramidal symptoms and hyperprolactinemia, and weight change from baseline in male patients were observed. These results indicate that ziprasidone is effective in the treatment of the positive, negative, and depressive symptoms of first-episode psychosis and has a modest side-effect burden. PMID- 22426472 TI - Skull base osteomyelitis and potential cerebrovascular complications in children. AB - Skull base osteomyelitis is an aggressive, life-threatening infection that can be challenging to diagnose and treat. It occurs predominantly in elderly immunocompromised patients, but it has also been reported in children with normal immunological status. Typical skul base osteomyelitis arises as a complication to ear infection mainly involving the temporal bone and is usually caused by Pseudomonas aeruginosa. Atypical or central skul base osteomyelitis originates from paranasal infections, is primarily centred on the clivus and is usually caused by Aspergillus, Pseudomonas, Salmonella or Staphylococcus species. Potential complications include retropharyngeal abscesses, cranial neuropathies, meningitis, intracranial abscesses, sinovenous thrombosis, and carotid artery involvement with or without ischemic infarcts. The purpose of this pictorial essay is to illustrate the spectrum of imaging findings and potential complications of skul base osteomyelitis. PMID- 22426473 TI - Lack of association of polymorphism in miRNA-196a2 with Parkinson's disease risk in a Chinese population. AB - MicroRNAs (miRNAs) are a new class of non-protein coding RNA molecules, which participate in diverse biological pathways. We hypothesized that miRNA-196a2 polymorphism is associated with the risk of Parkinson's disease (PD) in a Chinese population. In a case-control study of 549 PD patients and 736 control subjects frequency matched by age and gender, we genotyped the single-nucleotide polymorphism (SNP) rs11614913 (T>C) in miRNA-196a2, whose target mRNA was alpha synuclein, and assessed its association with risk of PD by TaqMan Genotyping method. No association was found for the miR-196a2 rs11614913 CT/CC genotype (odds ratio (OR), 0.879, 95% confidence interval (CI), 0.681-1.135 for CT genotype; OR, 1.085, 95% CI, 0.793-1.484 for CC genotype) with risk of PD, compared with the TT genotype. These results suggest that SNP rs11614913 in miRNA 196a2 may not contribute to the susceptibility to PD. PMID- 22426474 TI - Expectation decreases brain susceptibility to fearful stimuli: ERP evidence from a modified emotion evaluation task. AB - Expectation decreased the susceptibility to fearful stimuli in prior studies using distracting tasks. The present study tests whether expectation remains effective in decreasing this susceptibility, when subjects focus attention on emotional properties. Event-related potentials were recorded for fearful and neutral faces, while subjects performed a modified emotion evaluation task during unpredictable and predictable conditions. Behavioral data showed faster response latencies during predictable versus unpredictable conditions. ERP data showed prolonged peak latencies in N1 (80-130ms) and larger amplitudes in P2 (130-180ms) and N200-300 components, for unpredictable fearful versus neutral faces. Conversely, all these components showed similar responses to predictable fearful and neutral faces. Source analysis suggested that medial temporal lobe mediated ERPs elicited by unpredictable fearful faces, while ventromedial prefrontal cortex mediated those elicited by predictable fearful faces, in the 130-180ms interval. Thus, we propose emotional expectation as a cognitive regulation strategy that reliably dampens human susceptibility to fearful stimuli. PMID- 22426475 TI - A redox series of gallium(III) complexes: ligand-based two-electron oxidation affords a gallium-thiolate complex. AB - We have prepared a series of gallium(III) complexes of the redox active iminopyridine ligand (IP). Reaction of GaCl(3) with iminopyridine ligand (IP) in the presence of either two or four equivalents of sodium metal resulted in the formation of deep green (IP(-))(2)GaCl (1), or deep purple [(DME)(3)Na][(IP(2 ))(2)Ga] (2a), respectively. Complex 1 is paramagnetic with a room temperature magnetic moment of 2.3 MU(B) which falls to 0.5 MU(B) at 5 K. These observations indicate that two ligand radicals comprise a triplet at room temperature which becomes a singlet due to antiferromagnetic coupling at low temperature. Complex 2 is diamagnetic. Cyclic voltammograms recorded on 0.3 M Bu(4)NPF(6) THF solutions of [Na(THF)(6)][(IP(2-))(2)Ga](-) (2b) indicate that oxidation of 2b occurs in two two-electron steps at -1.31 V and -0.54 V vs. SCE. The observation of two electron redox events indicates that electronic coupling through the gallium(III) center is minimal and that the two IP ligand on 2b are oxidized concurrently. Oxidation of 2 with one equivalent of MeS-SMe afforded the two-electron oxidized product (IP(-))(2)Ga(SMe) (3). This complex has an electronic structure analogous to 1. Accordingly, both 1 and 3 are deep green in color and magnetic susceptibility measurements performed on 3 confirm the triplet character of the complex at room temperature. Electron paramagnetic resonance experiments on 1 and 3 display a quartet signal at g = 2.0 which confirmed the triplet nature of the compounds, and a half field signal consistent with the integer spin state. PMID- 22426476 TI - Activation of the Wnt/beta-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however, the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, beta-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/beta-catenin signaling pathway. We determined the expression of Wnt3a, beta-catenin, and Cyclin D1 in the adult spinal cord of SOD1(G93A) ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, beta-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, beta-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, beta-catenin or Cyclin D1 in mature GFAP(+) astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest that neurodegeneration activates the Wnt/beta-catenin signaling pathway, which is associated with glial proliferation in the adult spinal cord of ALS transgenic mice. This mechanism may be significant in clinical gene therapy. PMID- 22426477 TI - Toxicoproteomic analysis of a mouse model of nonsteroidal anti-inflammatory drug induced gastric ulcers. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are valuable agents; however, their use has been limited by their association with mucosal damage in the upper gastrointestinal tract. NSAIDs inhibit cyclooxygenase and consequently block the synthesis of prostaglandins, which have cytoprotective effects in gastric mucosa; these effects on prostaglandins have been thought to be major cause of NSAID induced ulceration. However, studies indicate that additional NSAID-related mechanisms are involved in formation of gastric lesions. Here, we used a toxicoproteomic approach to understand cellular processes that are affected by NSAIDs in mouse stomach tissue during ulcer formation. We used fluorogenic derivatization-liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS)-which consists of fluorogenic derivatization, separation and fluorescence detection by LC, and identification by LC-tandem mass spectrometry-in this proteomic analysis of pyrolic stomach from control and diclofenac (Dic)-treated mice. FD-LC-MS/MS results were highly sensitive; 10 differentially expressed proteins were identified, and all 10 were more highly expressed in Dic-treated mice than in control mice. Specifically, expression levels of 78 kDa glucose-regulated protein (GRP78), heat shock protein beta-1 (HSP27), and gastrin were more than 3-fold higher in Dic-treated mice than in control mice. This study represents a first step to ascertain the precise actors of early NSAID-induced ulceration. PMID- 22426478 TI - The small GTPase Cdc42 modulates the number of exocytosis-competent dense-core vesicles in PC12 cells. AB - Although the small GTPase Rho family Cdc42 has been shown to facilitate exocytosis through increasing the amount of hormones released, the precise mechanisms regulating the quantity of hormones released on exocytosis are not well understood. Here we show by live cell imaging analysis under TIRF microscope and immunocytochemical analysis under confocal microscope that Cdc42 modulated the number of fusion events and the number of dense-core vesicles produced in the cells. Overexpression of a wild-type or constitutively-active form of Cdc42 strongly facilitated high-KCl-induced exocytosis from the newly recruited plasma membrane vesicles in PC12 cells. By contrast, a dominant-negative form of Cdc42 inhibited exocytosis from both the newly recruited and previously docked plasma membrane vesicles. The number of intracellular dense-core vesicles was increased by the overexpression of both a wild-type and constitutively-active form of Cdc42. Consistently, activation of Cdc42 by overexpression of Tuba, a Golgi associated guanine nucleotide exchange factor for Cdc42 increased the number of intracellular dense-core vesicles, whereas inhibition of Cdc42 by overexpression of the Cdc42/Rac interactive binding domain of neuronal Wiskott-Aldrich syndrome protein decreased the number of them. These findings suggest that Cdc42 facilitates exocytosis by modulating both the number of exocytosis-competent dense-core vesicles and the production of dense-core vesicles in PC12 cells. PMID- 22426479 TI - Isolation of miRNAs that target EGFR mRNA in human lung cancer. AB - Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains the leading cause of cancer-related deaths worldwide. Although epidermal growth factor receptor (EGFR) signaling is important and well studied with respect to NSCLC progression, little is known about how miRNAs mediate EGFR signaling to modulate tumorigenesis. To identify miRNAs that target EGFR, we performed a bioinformatics analysis and found that miR-542-5p down-regulates EGFR mRNA and protein expression in human lung cancer cells (H3255, A549, Hcc827). We observed increases in EGFR association with Ago2 in miR-542-5p-transfected cells. Interestingly, we observed an inverse correlation of miR-542-5p expression and EGFR protein levels in human lung cancer tissue samples, suggesting that miR-542 5p directly targets EGFR mRNA. Furthermore, we found that miR-542-5p inhibited the growth of human lung cancer cells. Our findings suggest that miR-542-5p may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel therapeutic target in lung cancer. PMID- 22426480 TI - Androgen receptor is up-regulated by a BLT2-linked pathway to contribute to prostate cancer progression. AB - The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. AR expression is maintained throughout the progression of prostate cancer and is also associated with an aggressive, castration-resistant (CR) phenotype. Despite the critical roles of AR expression in prostate cancer progression, the exact signaling mechanism regulating AR expression remains unclear. In this study, we demonstrated that AR expression was increased by a low-affinity leukotriene B(4) receptor (BLT2)-linked pathway. We found that BLT2 was overexpressed in AR-positive prostate cancer cells, such as LNCaP cells, and BLT2 inhibition, using an inhibitor or siRNA knockdown, clearly attenuated AR expression and triggered apoptosis in these cells. These results suggest a role for BLT2 in AR expression and the survival of AR-positive prostate cancer cells. Moreover, we found that the NADPH oxidase family protein, Nox4, lay downstream of BLT2 and mediated the production of reactive oxygen species (ROS) and subsequent NF-kappaB stimulation, thereby inducing AR expression. Taken together, our results demonstrate that BLT2 plays a critical role in AR expression via a Nox4-ROS-NF-kappaB-linked pathway, thereby mediating the survival of AR-positive prostate cancer cells. Our findings point to BLT2 as a key regulator of AR expression and will contribute to the development of novel therapies for AR-positive prostate cancers, including androgen-responsive and CR prostate cancers. PMID- 22426481 TI - Epigallocatechin-3-gallate inhibits apoptosis and protects testicular seminiferous tubules from ischemia/reperfusion-induced inflammation. AB - Testicular torsion (TT) is a urologic emergency that may result in future infertility problems. The pathologic process of TT is similar to an ischemia reperfusion injury (IRI). The purpose of this study was to evaluate the effect of epigallocatechin-3-gallate (EGCG) on reversing the damaging consequences of TT induced IRI by examining its inhibitory effects on the expression of inflammatory and apoptosis mediators in a unilateral TT rat model. Eighteen male Sprague Dawley rats were divided into 3 groups. Group 1 underwent a sham operation of the left testis under general anesthesia. Group 2 underwent ischemia for 1h followed by 4h reperfusion in the presence of saline. The third group was similar to group 2, however, EGCG (50 mg/kg) was injected i.p. 30 min after ischemia induction. The in vivo protective effect of EGCG was tested by measuring testicular levels of TNF-alpha, IL-6 and IL-1beta by ELISA and mRNA expression of iNOS, MCP-1, p53, Bax, Bcl-2 and survivin by real-time PCR. Also, testicular morphological changes and damage to spermatogenesis were evaluated using H&E staining and Johnsen's scoring system, respectively. EGCG treatment improved testicular structures in the ipsilateral testis, markedly inhibited germ cell apoptosis (GCA) and significantly decreased testicular cytokine levels. In addition, EGCG was able to down regulate the mRNA expression of iNOS, MCP-1 and pro-apoptosis genes in favor of cell survival. For the first time we show that in vivo EGCG treatment rescued the torsed testes from IRI-induced inflammation, GCA and damage to spermatogenesis thus suggesting a new preventive approach to inhibiting the inflammatory and apoptotic consequences of TT-induced IRI. PMID- 22426482 TI - Inhibitory RNA aptamer against SP6 RNA polymerase. AB - Aptamers are attractive tools for modulating function of a desired target. In this study, we isolated an RNA aptamer that specifically inhibits transcription of SP6 RNA polymerase. The dissociation constant and 50% inhibitory concentration of the aptamer were estimated 9.5 nM and 24.8 nM, respectively. Doped-SELEX and mutational analysis revealed that the aptamer adopts the structure including two stems, two loops, and 5' single-stranded region. Based on the results, the aptamer could be engineered to circular permutant and binary construct forms without decreasing the activity. The aptamer would be applicable for the construction of expression regulation systems. PMID- 22426483 TI - Flt1 and Flk1 mediate regulation of intraocular pressure and their double heterozygosity causes the buphthalmia in mice. AB - Flt1 and Flk1 are receptor tyrosine kinases for vascular endothelial growth factor-A which play a crucial role in physiological and pathological angiogenesis. To study genetic interaction between the Flt1 and Flk1 genes, we crossed between Flt1 and Flk1 heterozygous (Flt1(+/-) and Flk1(+/-)) mice. We found that Flt1; Flk1 double heterozygous (Flt1(+/-); Flk1(+/-)) mice showed enlarged eyes similar to the buphthalmia detected in human congenital glaucoma with elevation of intraocular pressure (IOP). Actually, IOP was elevated in Flt1(+/-); Flk1(+/-) mice and also in Flt1 or Flk1 single heterozygous mice. However, none of these mutants showed hallmarks of glaucoma such as ganglion cell death and excavation of optic disc. To clarify the pathological causes for enlarged eyes and elevated IOP, we investigate the mice from matings between Flt1(+/-) and Flk1(+/-) mice. Flt1(+/-) mice showed enlarged Schlemm's canal and disordered collagen fibers in the sclera, whereas Flk1(+/-) mice showed atrophied choriocapillaris in the choroid. These tissues are a part of the main outflow and alternative uveoscleral outflow pathway of the aqueous humor, suggesting that these pathological changes found in Flt1(+/-) and Flk1(+/-) mice are associated with the buphthalmia in Flt1(+/-); Flk1(+/-) mice. PMID- 22426484 TI - The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7. AB - Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-alpha reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability. PMID- 22426485 TI - Transient periodic lateralised epileptiform discharges (PLEDs) following internal carotid artery stenting. AB - Background. Periodic lateralised epileptiform discharges (PLEDs) are EEG patterns consisting of periodic or pseudoperiodic unilateral, focal or hemispheric epileptiform discharges at a rate of 1-2 Hz. PLEDs may be triggered by acute brain injuries or systemic metabolic changes such as fever, hyperglycaemia or electrolyte imbalance and may result in disturbance of consciousness and/or neurological deficits. Case report. A 58-year-old female with a history of focal epilepsy and deep brain haematoma presented with acute change in awareness, associated with EEG evidence of PLEDs, three days after a left internal carotid artery stenting procedure. Clinical examination, laboratory testing and MRI were unchanged with respect to pre-stenting investigations. Conclusion. In this patient, PLEDs may have been triggered by local haemodynamic changes due to reperfusion after stenting in a previously damaged brain area. PMID- 22426486 TI - Current advances in the management of malignant germ cell and sex cord-stromal tumors of the ovary. PMID- 22426487 TI - Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women. AB - OBJECTIVE: Human epididymal secretory protein E4 (HE4) is a new promising tumor marker developed for the diagnostics and follow up of ovarian cancer. It has yet to become widely accepted in clinical practice, and its biological properties have not been inclusively studied. The aim of this study was to investigate whether serum HE4 concentration varies within the normal menstrual cycle and whether common gynecological hormonal treatments have an effect on HE4 values. METHODS: Our study population consisted of 180 women, including 126 endometriosis patients and 54 healthy women. We measured their serum HE4 and CA125 concentrations and evaluated the effect of the menstrual cycle and the possible hormonal medication on these marker concentrations. RESULTS: We found no significant variation in serum HE4 concentrations in samples taken at different phases of the menstrual cycle. The median HE4 concentrations in proliferative, secretory and menstrual phase were 41.5, 45.1 and 35.3 pM in healthy women, and 43.4, 44.3 and 43.0 pM in endometriosis patients, respectively. The use of combined estrogen and progestin contraceptives did not affect serum HE4 levels significantly. CONCLUSIONS: The present study shows that the HE4 measurement in healthy premenopausal women as well as in women with endometriosis can be carried out at any phase of the menstrual cycle, and irrespective of hormonal medication, extending the benefits of HE4 use in clinical practice. PMID- 22426488 TI - Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent. AB - OBJECTIVE: To determine serum insulin levels, expression and phosphorylation of InsR, IRS-1 and Akt in endometrial cancer (EC) tissues, and to explore the correlation between them. To investigate if insulin-induced mitogenic and anti apoptotic effects are PI3K-dependent in EC cells. METHODS: Serum insulin levels were measured by radioimmunoassay. We performed RT-PCR and western blotting to evaluate the expression and activation of key proteins of PI3K/Akt pathway in 63 EC tissues. The proliferation and apoptosis rates were determined with MTT, BrdU and annexin V/PI assays. RESULTS: Serum insulin levels and InsR, IRS-1 and Akt expression and phosphorylation were significantly elevated in patients with EC compared to those without EC. Additionally, levels of p-InsR, p-IRS-1, and p-Akt were significantly higher in patients with high-grade, advanced stage, deep myometrial invasion, and lymph-node metastasis. The expression and activation of InsR, IRS-1, and p-Akt were positively related with the levels of serum insulin. The insulin-induced mitogenic and anti-apoptotic effects in EC cells were blocked when cells were pre-incubated with LY294002. Ishikawa 3-H-12 cells showed increased p-Akt levels after treatment with insulin at 10(-8)M for 15min. The insulin-induced Akt activation was inhibited by LY294002 in a dose-dependent manner. CONCLUSION: Insulin played an essential role in EC tumorigenesis. Activation of InsR, IRS-1, and Akt was associated with features of aggressive EC. Insulin was a mitogenic and anti-apoptotic agent for EC cells, and these effects were dependent on PI3K/Akt pathway. Decreasing insulin level and blocking the InsR-IRS-PI3K-Akt pathway could be viable preventive and therapeutic strategies for EC. PMID- 22426489 TI - Integrated nanopore sensing platform with sub-microsecond temporal resolution. AB - Nanopore sensors have attracted considerable interest for high-throughput sensing of individual nucleic acids and proteins without the need for chemical labels or complex optics. A prevailing problem in nanopore applications is that the transport kinetics of single biomolecules are often faster than the measurement time resolution. Methods to slow down biomolecular transport can be troublesome and are at odds with the natural goal of high-throughput sensing. Here we introduce a low-noise measurement platform that integrates a complementary metal oxide semiconductor (CMOS) preamplifier with solid-state nanopores in thin silicon nitride membranes. With this platform we achieved a signal-to-noise ratio exceeding five at a bandwidth of 1 MHz, which to our knowledge is the highest bandwidth nanopore recording to date. We demonstrate transient signals as brief as 1 MUs from short DNA molecules as well as current signatures during molecular passage events that shed light on submolecular DNA configurations in small nanopores. PMID- 22426490 TI - Tracking protein aggregation and mislocalization in cells with flow cytometry. AB - We applied pulse-shape analysis (PulSA) to monitor protein localization changes in mammalian cells by flow cytometry. PulSA enabled high-throughput tracking of protein aggregation, translocation from the cytoplasm to the nucleus and trafficking from the plasma membrane to the Golgi as well as stress-granule formation. Combining PulSA with tetracysteine-based oligomer sensors in a cell model of Huntington's disease enabled further separation of cells enriched with monomers, oligomers and inclusion bodies. PMID- 22426491 TI - Detecting overlapping protein complexes in protein-protein interaction networks. AB - We introduce clustering with overlapping neighborhood expansion (ClusterONE), a method for detecting potentially overlapping protein complexes from protein protein interaction data. ClusterONE-derived complexes for several yeast data sets showed better correspondence with reference complexes in the Munich Information Center for Protein Sequence (MIPS) catalog and complexes derived from the Saccharomyces Genome Database (SGD) than the results of seven popular methods. The results also showed a high extent of functional homogeneity. PMID- 22426492 TI - Unsupervised pattern discovery in human chromatin structure through genomic segmentation. AB - We trained Segway, a dynamic Bayesian network method, simultaneously on chromatin data from multiple experiments, including positions of histone modifications, transcription-factor binding and open chromatin, all derived from a human chronic myeloid leukemia cell line. In an unsupervised fashion, we identified patterns associated with transcription start sites, gene ends, enhancers, transcriptional regulator CTCF-binding regions and repressed regions. Software and genome browser tracks are at http://noble.gs.washington.edu/proj/segway/. PMID- 22426493 TI - Immune cell populations and cytokine production in spleen and mesenteric lymph nodes after laparoscopic surgery versus conventional laparotomy in mice. AB - PURPOSE: There is evidence that open as well as minimally invasive abdominal surgery impair post-operative innate and acquired immune function. To compare the impact of these approaches as well as the one of different peritoneal gas exposures on immune function, we investigated cellular as well as cytokine-based immune parameters in mesenteric lymph nodes and the spleen postoperatively. METHODS: Mice (n = 26) were randomly assigned to the 4 study groups: (1) sham controls undergoing anesthesia alone, (2) laparotomy, and (3) air, or (4) carbon dioxide pneumoperitoneum. Mice were sacrificed 48 h after the intervention, and their spleens and mesenteric lymph nodes were harvested. Cytokine production (TNF alpha, IL-6, IL-10, and IFN-gamma), splenic T cell subpopulations (cytotoxic T cells, T helper cells, and regulatory T cells) were analyzed. RESULTS: TNF-alpha production of splenocytes 16 h after ex vivo lipopolysaccharides (LPS) stimulation was significantly increased in the laparotomy group compared to all other groups. In contrast, TNF-alpha production of lymph node cells and IL-6 production of splenocytes after ex vivo LPS stimulation did not differ significantly between the groups. The numbers of regulatory T cells (Treg) in the spleen differed between groups. A significant reduction in Treg cell frequency was detected in the CO(2) insufflation group compared to the laparotomy and the air insufflation group. CONCLUSION: Our findings demonstrate a distinct difference in immune effector functions and cellular composition of the spleen with regard to splenic TNF-alpha production and increased numbers of Treg cells in the spleen. These findings are in line with a higher peritoneal inflammatory status consequent to peritoneal air rather than CO(2) exposure. Treg turned out to be key modulators of postoperative dysfunction of acquired immunity. PMID- 22426494 TI - Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7. AB - Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder associated with cerebellar neurodegeneration caused by expansion of a CAG repeat in the ataxin-7 gene. Hepatocyte growth factor (HGF), a pleiotrophic growth factor, displays highly potent neurotrophic activities on cerebellar neurons. A mutant c met/HGF receptor knockin mouse model has revealed a role for HGF in the postnatal development of the cerebellum. The present study was designed to elucidate the effect of HGF on cerebellar neurodegeneration in a knockin mouse model of SCA7 (SCA7-KI mouse). SCA7-KI mice were crossed with transgenic mice overexpressing HGF (HGF-Tg mice) to produce SCA7-KI/HGF-Tg mice that were used to examine the phenotypic differences following HGF overexpression. The Purkinje cellular degeneration is thought to occur via cell-autonomous and non-cell autonomous mechanisms mediated by a reduction of glutamate transporter levels in Bergmann glia. The Purkinje cellular degeneration and reduced expression of glutamate transporters in the cerebellum of SCA7-KI mice were largely attenuated in the SCA7-KI/HGF-Tg mice. Moreover, phenotypic impairments exhibited by SCA7-KI mice during rotarod tests were alleviated in SCA7-KI/HGF-Tg mice. The bifunctional nature of HGF on both Purkinje cells and Bergmann glia highlight the potential therapeutic utility of this molecule for the treatment of SCA7 and related disorders. PMID- 22426495 TI - Identification and quantification of differentially expressed proteins in plasma of spinocerebellar ataxia type 12. AB - Spinocerebellar ataxia 12 (SCA12) is a unique dominant type of ataxia characterized by early and prominent action tremors, memory deficit, neuropathy, dysarthria, etc. The expansion of DNA triplet (CAG) repeats in 5'UTR of PPP2R2B gene appears to be the cause for the pathogenesis of the neurodegenerative disorder, SCA12. The objective of the current study was to identify the aberrantly expressed plasma proteins for their potential application in therapy or diagnosis/prognosis of SCA12. Sixty-two clinically suspected patients were assessed using International Co-operative Ataxia Rating Scale (ICARS) and genetic confirmation was done using PCR followed by DNA sequencing. Twenty patients who were genetically confirmed were included in the study. 2D-DIGE analyses of plasma proteins of SCA12 patients revealed 14 differentially expressed protein spots, which were confirmed as nine proteins by LC-MS/MS. The 6 downregulated and 3 upregulated proteins are known to have physiological role in transport (thyroxin and retinol to brain), lipid metabolism, memory, scavenging of free haemoglobin, etc. Altered expression of some of the proteins of interest, transthyretin, haptaglobin, apolipoprotein C-II, apolipoprotein C-III are indicative of clinical manifestations such as neuropathy, cognitive impairment and altered lipid metabolism in SCA12. PMID- 22426496 TI - Conditioned fear stress combined with single-prolonged stress: a new PTSD mouse model. AB - There are still some defects in current single-prolonged stress (SPS) model and conditioned fear (CF) stress model of post-traumatic stress disorder (PTSD). The purpose of this study is to evaluate a novel mouse model of PTSD. Male KM mice suffered the double stresses-SPS and CF. After incubation time, the novel model exhibited the PTSD-like behaviors: sensitive fear and conditioned fear, low activities and defects in novel object recognition abilities. The apoptosis in the hippocampus was significantly increased, which was induced by the double stresses and further caused the synaptic structure damages in the hippocampus. The electron microscopy analysis further proved the synaptic losses and neuronal impairments in the hippocampus. Our results indicated this combined stresses mouse model was better than the SPS model and CF model. In addition, in order to further verify this model, paroxetine was administered after the double stresses. The results showed that paroxetine administration reduced PTSD-like behaviors, hippocampal apoptosis and structure damages. We conclude that this mouse model is novel and more predictably mimicked the clinical characteristics of PTSD, and this model can be further used for investigating the mechanisms of PTSD and screening effective therapeutics agents. PMID- 22426497 TI - Diversity and roles of (t)RNA ligases. AB - The discovery of discontiguous tRNA genes triggered studies dissecting the process of tRNA splicing. As a result, we have gained detailed mechanistic knowledge on enzymatic removal of tRNA introns catalyzed by endonuclease and ligase proteins. In addition to the elucidation of tRNA processing, these studies facilitated the discovery of additional functions of RNA ligases such as RNA repair and non-conventional mRNA splicing events. Recently, the identification of a new type of RNA ligases in bacteria, archaea, and humans closed a long-standing gap in the field of tRNA processing. This review summarizes past and recent findings in the field of tRNA splicing with a focus on RNA ligation as it preferentially occurs in archaea and humans. In addition to providing an integrated view of the types and phyletic distribution of RNA ligase proteins known to date, this survey also aims at highlighting known and potential accessory biological functions of RNA ligases. PMID- 22426498 TI - Effect of co-morbidities on fracture risk: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). AB - INTRODUCTION: Greater awareness of the relationship between co-morbidities and fracture risk may improve fracture-prediction algorithms such as FRAX. MATERIALS AND METHODS: We used a large, multinational cohort study (GLOW) to investigate the effect of co-morbidities on fracture risk. Women completed a baseline questionnaire detailing past medical history, including co-morbidity history and fracture. They were re-contacted annually to determine incident clinical fractures. A co-morbidity index, defined as number of baseline co-morbidities, was derived. The effect of adding the co-morbidity index to FRAX risk factors on fracture prevention was examined using chi-squared tests, the May-Hosmer test, c index and comparison of predicted versus observed fracture rates. RESULTS: Of 52,960 women with follow-up data, enrolled between October 2006 and February 2008, 3224 (6.1%) sustained an incident fracture over 2 years. All recorded co morbidities were significantly associated with fracture, except for high cholesterol, hypertension, celiac disease, and cancer. The strongest association was seen with Parkinson's disease (age-adjusted hazard ratio [HR]: 2.2; 95% CI: 1.6-3.1; P<0.001). Co-morbidities that contributed most to fracture prediction in a Cox regression model with FRAX risk factors as additional predictors were: Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, osteoarthritis, and heart disease. CONCLUSION: Co-morbidities, as captured in a co-morbidity index, contributed significantly to fracture risk in this study population. Parkinson's disease carried a particularly high risk of fracture; and increasing co-morbidity index was associated with increasing fracture risk. Addition of co-morbidity index to FRAX risk factors improved fracture prediction. PMID- 22426499 TI - Risk factors for osteoporosis in Caucasian patients with moderate chronic obstructive pulmonary disease: a case control study. AB - The prevalence of osteoporosis is high in chronic obstructive pulmonary disease (COPD) patients. The gold standard for the diagnosis of osteoporosis is bone mineral density (BMD) measurements as assessed by dual energy absorptiometry (DXA) scanning as well as vertebral fractures as assessed by instant vertebral assessment (IVA). The aim of this study was to compare COPD GOLD II patients (that is, patients with moderate COPD, stage II, according to the GOLD classification) with osteoporosis (cases) to COPD GOLD II patients without osteoporosis (controls) to identify risk factors for osteoporosis. The diagnosis of osteoporosis was based on BMD and vertebral fractures. Cases (n=49) were matched for gender, age and forced expiratory volume in the first second to controls (n=49). We assessed pulmonary function, body composition, vitamin D, emphysema score (by high-resolution computer tomography), medical history and medication use in all patients. Variables that were significantly different between the cases and controls were included in a logistic regression analysis. COPD patients with osteoporosis had a significantly lower body mass index (BMI) and higher residual volume as the percentage of total lung capacity (RV%TLC) compared to COPD patients without osteoporosis. Decreasing BMI and increasing RV%TLC increased the odds ratio for osteoporosis. Overweight and obese BMI values were protective for osteoporosis. Screening for osteoporosis should be performed even in moderate COPD patients, especially in those with a low BMI and/or a high RV%TLC. PMID- 22426500 TI - Organizational factors associated with work-related sleep problems in a nationally representative sample of Korean workers. AB - PURPOSE: The purpose of this study was to assess the association of organizational factors with work-related sleep problems (WRSP) among Korean workers. METHODS: The data were derived from the First Korean Working Conditions Survey conducted in 2006 with a representative sample of the Korean working population (n = 10,039). RESULTS: The overall prevalence of WRSP was 5.1% (95% confidence interval (CI) 4.7-5.5). Those who experienced sexual harassment at work (adjusted odds ratio (aOR) 3.47: 95% CI 1.77-6.81), discrimination due to sex (aOR 2.44: 95% CI 1.36-4.36) or age (aOR 2.22: 95% CI 1.52-3.23), violence at work (aOR 1.98: 95% CI 1.06-3.68), threat of violence (aOR 1.96: 95% CI 1.05 3.66), poor work-life balance (aOR 1.78: 95% CI 1.44-2.20), low job satisfaction (aOR 1.69: 95% CI 1.37-2.09), high cognitive (OR 1.64: 95% CI 1.32-2.03) and emotional (aOR 1.53: 95% CI 1.22-1.91) demands, job insecurity (aOR 1.32: 95% CI 1.07-1.63), and high work intensity (aOR 1.55: 95% CI: 95% CI 1.25-1.92) had an increased risk of WRSP compared to their respective counterparts (p < 0.01). Low social support was not significantly associated with WRSP (aOR 0.88: 95% CI 0.67 1.15). CONCLUSION: The results revealed that poor psychosocial working conditions may be related to a high prevalence of WRSP among representative Korean workers. PMID- 22426501 TI - Spatiotemporal behavior of nuclear cyclophilin B indicates a role in RNA transcription. AB - Cyclophilin B (CypB) is an ubiquitously expressed protein, which performs several intra- and extracellular functions. Despite its abundant use as a household protein, little is known about its exact cellular localization and dynamics. In the present study we show that endogenous CypB localizes in one of two distinct compartments, either within the endoplasmic reticulum (ER) or inside the nucleus, accumulating in the fibrillar centers of the nucleoli. By means of a genetic deletion screen, we identified a minimal nucleolar localization signal for efficient relocation to the nucleoli. Within the fibrillar centers, CypB colocalized with RNA polymerase, upstream binding factor-1 (UBF), fibrillarin and dyskerin (DCK1). Even after chemical disruption of the nucleoli, a strong interaction with these proteins remained. Using live cell imaging, we showed a persistent colocalization of CypB with proteins involved in the ribosome biogenesis during the transcriptionally more active phases of the cell cycle. Supported by in silico data, our observations suggest that CypB interacts with these proteins and is involved in ribosome biogenesis and RNA transcription. PMID- 22426502 TI - Gastrointestinal stromal tumor: psychosocial characteristics and considerations. AB - OBJECTIVE: Gastrointestinal stromal tumors (GIST) are very rare, especially within the pediatric population. The National Institutes of Health initiated a multidisciplinary clinic to bring together a worldwide group of healthcare providers with experience in the study and treatment of GIST in order to better understand the disease and to examine whether this is a population at psychosocial risk. METHODS: Seven GIST clinics have been held to date. Participants completed a GIST Psychosocial Assessment containing items covering demographic factors, family stressors, general health, psychosocial concerns, psychiatric history, and self-identified needs. Our sample consists of 60 adult patients (ages 18-66) and 18 pediatric patients (ages 9-17). RESULTS: Living with pain at least a few days a week was endorsed by those whose self-reported health status was good to excellent (49% of the adult cohort and 25% of the pediatric cohort). Pain was significantly associated with anxiety, difficulties with family relationships, behavior problems, and psychotropic medication use. Body image and appearance concerns were endorsed by over half of the cohort. Post-trauma symptoms were prevalent for those newly diagnosed and those living with GIST for over 15 years. CONCLUSIONS: This is the first study to explore the psychosocial impact of GIST. Individuals living with GIST experience chronic pain, post-trauma symptoms and significant anxiety along with an expressed need for interventions to help them manage their anxiety. Due to the chronic nature of this disease, the GIST population is at risk for long-term psychological distress. Psychosocial interventions in pediatric and adult care settings are offered. PMID- 22426503 TI - Impact of oxaliplatin-induced neuropathy: a patient perspective. AB - INTRODUCTION: Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment, producing initial acute neurotoxicity and chronic neuropathy with increasing exposure. The improvement in survival for patients with early-stage colorectal cancer treated with oxaliplatin has highlighted the need for valid and reliable assessment of peripheral neuropathy. OBJECTIVES: The objective of this paper was to explore neuropathic symptoms in oxaliplatin-treated patients as assessed using different methods. METHODS: Consecutive symptomatic patients reporting peripheral neuropathy after oxaliplatin chemotherapy for colorectal cancer were interviewed using a semi-structured clinical interview. Neurotoxicity was also assessed using the National Cancer Institute Common Toxicity Criteria scale (clinician-rated), patient 'self-report' questionnaires (PNQ), nerve conduction and clinical assessment. RESULTS: Twenty patients were assessed, 12.6 +/- 2.8 months after treatment cessation (mean cumulative oxaliplatin dose, 789 mg/m(2)). In 40% of patients, neurotoxicity necessitated early cessation of treatment. Only 10% of patients were designated by clinicians with severe neurotoxicity, whilst, in contrast, patient interviews and self-report questionnaires described significant physical limitations due to neuropathic symptoms in 60% of patients. The majority (85%) of patients had objective evidence of sensory neuropathy with nerve conduction studies. Reports from clinical interviews were strongly correlated with patient self-assessment (Pearson coefficient = 0.790, p < 0.0005). CONCLUSION: Given the discrepancies in symptom prevalence highlighted by these findings, the monitoring of oxaliplatin induced neurotoxicity would benefit from more informative clinical assessment, with inclusion of patient-reported outcome measures. Such an approach would be beneficial in a clinical trial setting to monitor the efficacy of interventions and in prospective studies of survivorship to determine the true burden of peripheral neuropathy in oxaliplatin-treated patients. PMID- 22426504 TI - Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-kappaB-dependent pathway. AB - Glioblastoma multiforme (GBM) is the most common intracranial tumor, with a dismal prognosis. Although temozolomide (TMZ)-based chemotherapy following neurosurgery has been proven to be effective, not all patients benefit clinically because of TMZ resistance. Given that protein expression of O(6)-methylguanine DNA-methyltransferase (MGMT) is the most important determinant of TMZ resistance, great efforts have been made to suppress it by regulating MGMT-related transcription factors. The study presented here demonstrates that resveratrol, a natural polyphenol, is able to reverse TMZ resistance of glioblastoma T98G cells which have relatively high MGMT activity. The data showed that combination treatment with TMZ and resveratrol resulted in an enhanced antitumor potential of TMZ, decreased the 50% inhibiting concentration (IC50) of TMZ and increased the induction of apoptosis in TMZ-resistant T98G cells. Hoechst 33258 staining revealed increased apoptotic morphology, such as chromatin aggregation and nuclear and cytoplasmic condensation, in cells receiving combination treatment. Western blot analysis manifested a significant decreased intracellular content and nuclear translocation of NF-kappaB and increased cleavage of caspase-3 in cells exposed to combination treatment, compared to those in cells treated with TMZ alone. In addition, recombinant expression of NF-kappaB subunit p65 remarkably promoted nuclear translocation of NF-kappaB and abolished the TMZ resistance reversal induced by combination treatment, suggesting an underlying NF kappaB-dependent mechanism. Our study improved the knowledge on the mechanism of TMZ resistance and suggested a novel strategy for TMZ-based chemotherapy in glioblastoma patients. PMID- 22426505 TI - A comparison of psychosocial risk factors between 3 groups of cardiovascular disease patients referred for outpatient cardiac rehabilitation. AB - PURPOSE: Few studies have examined psychosocial risk factors for cardiovascular disease (CVD) between diagnostic groups of CVD patients. We compared levels of depression, anxiety, hostility, exhaustion, positive affect, and social support, and the prevalence of type D personality between patient groups with a primary diagnosis of coronary heart disease (CHD), chronic heart failure (CHF), or peripheral arterial disease (PAD). METHODS: We examined 548 CHD patients, 105 CHF patients, and 79 PAD patients who completed the Hospital Anxiety and Depression Scale, the cynical hostility subscale of the Minnesota Multiphasic Personality Inventory-2, the short form of the Maastricht Vital Exhaustion Questionnaire, the type D personality questionnaire, the positive mood scale of the Global Mood Scale, and the Enhancing Recovery in CHD Social Support Inventory, all in the first week of cardiac rehabilitation. Group differences in psychosocial factors were adjusted for sociodemographic factors, previous myocardial infarction, traditional cardiovascular risk factors, and medications. RESULTS: Relative to patients with PAD, those with CHD and those with CHF both showed greater exhaustion (P <= .001) and lower positive affect (P <= .03). The effect sizes of these differences were clinically relevant (Cohen's d between 0.32 and 0.49). There were no significant differences in psychosocial risk factors between CHD and CHF patients. CONCLUSIONS: The profile of psychosocial risk factors for CVD revealed clinically relevant variability between different diagnostic groups of CVD patients. The findings imply that patients with distinct cardiac diagnosis might additionally benefit from comprehensive cardiac rehabilitation if the program includes psychosocial risk factor-specific interventions. PMID- 22426506 TI - Isolation and characterization of unusual multinuclear Schiff base complexes: rearrangements reactions and octanuclear cluster formation. AB - The isolation and full characterization of multinuclear Schiff base complexes is reported, and their relevance as precursors for octanuclear Zn(8) salen cluster complex formation is discussed. Starting from simple precursors, three tetranuclear Zn(4) complexes were accessed that incorporate typical half-salen units and comprise of bridging acetates. The use of alternative reaction conditions or a step-wise approach smoothly leads to Zn(8) cluster formation. In addition, the tetranuclear Zn(4) complexes themselves may also serve as precursors toward Zn(8) cluster formation when treated under appropriate reaction conditions. The influence of the solvent medium in the latter Zn(4) -> Zn(8) conversion was separately studied and revealed the formation of unusual pyridine ligated multinuclear structures with fully condensed salen coordination pockets, providing a possible prelude to octanuclear cluster formation. PMID- 22426507 TI - Role of D1/D2 dopamine receptors in the CA1 region of the rat hippocampus in the rewarding effects of morphine administered into the ventral tegmental area. AB - Considerable evidences show that the VTA, as a major source of dopamine neurons projecting to cortical and limbic regions, has a major role in cognitive and motivating aspects of addiction. The current study assessed the ability of the selective D1 receptor antagonist SCH 23390 and D2 receptor antagonist sulpiride administrated into the CA1 region of hippocampus (dorsal hippocampus) to alter the rewarding effects of intra-VTA administration of morphine using the conditioned place preference (CPP). After bilaterally implantation of cannulae into the CA1 and/or VTA in adult male Wistar rats weighing 210-310 g, dose response effects of different doses of intra-VTA morphine (0.03, 0.1, 0.3, 1 and 3 MUg/side) on CPP paradigm were evaluated and animal displacement, conditioning score and locomotor activity were recorded by Ethovision software. In the next experiments, SCH 23390 (0.02, 0.05, 0.2 and 0.5 MUg/side) or sulpiride (0.25, 0.75, 1.5 and 3 MUg/side) were injected into the CA1, 5 min after intra-VTA injection of morphine during 3 days conditioning phase. Our results showed that intra-VTA morphine dose-dependently induces CPP in rats. Moreover, the blocking D1 and D2 receptors in the dorsal hippocampus decreased intra-VTA morphine induced CPP significantly (P<0.01). Intra-CA1 administration of these antagonists alone, in all doses, could not induce CPP. We suggest that D1 and D2 receptors in the CA1 region of hippocampus have a key role in the development of CPP induced by morphine at the level of the VTA. It seems that there is an interaction between dopaminergic and opioidergic systems in these areas in reward circuit. PMID- 22426508 TI - Architectures, electronic structures, and stabilities of Cu-doped Ge n clusters: density functional modeling. AB - The present study reports the geometries, electronic structures, growth behavior, and stabilities of neutral and ionized copper-doped germanium clusters containing 1-20 Ge atoms within the framework of linear combination of atomic orbitals density functional theory (DFT) under the spin-polarized generalized gradient approximation. It was found that Cu-capped Ge(n) (or Cu-substituted Ge( n+1)) and Cu-encapsulated Ge(n) clusters mostly occur in the ground state at a particular cluster size (n). In order to explain the relative stabilities of the ground state clusters, parameters such as the average binding energy per atom (BE), the embedding energy (EE), and the fragmentation energy (FE) of the clusters were calculated, and the resulting values are discussed. To explain the chemical stabilities of the clusters, parameters such as the energy gap between the highest occupied and the lowest unoccupied molecular orbitals (the HOMO-LUMO gap), the ionization energy (IP), the electron affinity (EA), the chemical potential (MU), the chemical hardness (eta), and the polarizability were calculated, and the resulting values are also discussed. Natural atomic orbital (NAO) and natural bond orbital (NBO) analyses were also used to determine the electron-counting rule that should be applied to the most stable Ge(10)Cu cluster. Finally, the relevance of the calculated results to the design of Ge based superatoms is discussed. PMID- 22426509 TI - Molecular modeling and computational simulation of the photosystem-II reaction center to address isoproturon resistance in Phalaris minor. AB - Isoproturon is the only herbicide that can control Phalaris minor, a competitive weed of wheat that developed resistance in 1992. Resistance against isoproturon was reported to be due to a mutation in the psbA gene that encodes the isoproturon-binding D1 protein. Previously in our laboratory, a triazole derivative of isoproturon (TDI) was synthesized and found to be active against both susceptible and resistant biotypes at 0.5 kg/ha but has shown poor specificity. In the present study, both susceptible D1((S)), resistant D1((R)) and D2 proteins of the PS-II reaction center of P. minor have been modeled and simulated, selecting the crystal structure of PS-II from Thermosynechococcus elongatus (2AXT.pdb) as template. Loop regions were refined, and the complete reaction center D1/D2 was simulated with GROMACS in lipid (1-palmitoyl-2 oleoylglycero-3-phosphoglycerol, POPG) environment along with ligands and cofactor. Both S and R models were energy minimized using steepest decent equilibrated with isotropic pressure coupling and temperature coupling using a Berendsen protocol, and subjected to 1,000 ps of MD simulation. As a result of MD simulation, the best model obtained in lipid environment had five chlorophylls, two plastoquinones, two phenophytins and a bicarbonate ion along with cofactor Fe and oxygen evolving center (OEC). The triazole derivative of isoproturon was used as lead molecule for docking. The best worked out conformation of TDI was chosen for receptor-based de novo ligand design. In silico designed molecules were screened and, as a result, only those molecules that show higher docking and binding energies in comparison to isoproturon and its triazole derivative were proposed for synthesis in order to get more potent, non-resistant and more selective TDI analogs. PMID- 22426510 TI - Targeting imidazoline site on monoamine oxidase B through molecular docking simulations. AB - Monoamine oxidase (MAO) is an enzyme of major importance in neurochemistry, because it catalyzes the inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine. In the last decade it was demonstrated that imidazoline derivatives were able to inhibit MAO activity. Furthermore, crystallographic studies identified the imidazoline-binding domain on monoamine oxidase B (MAO-B), which opens the possibility of molecular docking studies focused on this binding site. The goal of the present study is to identify new potential inhibitors for MAO-B. In addition, we are also interested in establishing a fast and reliable computation methodology to pave the way for future molecular docking simulations focused on the imidazoline-binding site of this enzyme. We used the program 'molegro virtual docker' (MVD) in all simulations described here. All results indicate that simplex evolution algorithm is able to succesfully simulate the protein-ligand interactions for MAO-B. In addition, a scoring function implemented in the program MVD presents high correlation coefficient with experimental activity of MAO-B inhibitors. Taken together, our results identified a new family of potential MAO-B inhibitors and mapped important residues for intermolecular interactions between this enzyme and ligands. PMID- 22426511 TI - A novel halogen bond and a better-known hydrogen bond cooperation of neonicotinoid and insect nicotinic acetylcholine receptor recognition. AB - Neonicotinoid insecticides target the insect nicotinic acetylcholine receptor (nAChR) and are highly effective against the piercing-sucking pests. To explore the molecular interaction mechanism between the neonicotinoids and the insect nAChR, some key neonicotinoid compounds were docked into Aplysia californica acetylcholine binding protein (Ac-AChBP), which serves as a suitable structural surrogate of the insect nAChR. The binding mode study showed that the hydrogen bond force between the electronegative pharmacophore of the neonicotinoids and Cys190NH of the target binding pocket is crucial to the high efficiency of the neonicotinoids. Increasing the coplanarity between the guanidine or amidine and the electronegative pharmacophore of the neonicotinoids could increase the Pi-Pi stacking effect with Tyr188 of the Ac-AChBP and thus enhance the insecticidal potency. The introduction of an azide group to the chloropyridine ring of the neonicotinoids would reduce its binding ability due to the disappearance of a novel halogen bonding interaction. A series of novel neonicotinoid molecules were designed based on the halogen bonding interaction and two compounds with 6 bromopyridine-3-yl and 6-(trifluoromethyl)-3-pyridinyl were found to be with potential insecticidal activities. PMID- 22426512 TI - A vaccine targeting angiomotin induces an antibody response which alters tumor vessel permeability and hampers the growth of established tumors. AB - Angiomotin (Amot) is one of several identified angiostatin receptors expressed by the endothelia of angiogenic tissues. We have shown that a DNA vaccine targeting Amot overcome immune tolerance and induce an antibody response that hampers the progression of incipient tumors. Following our observation of increased Amot expression on tumor endothelia concomitant with the progression from pre neoplastic lesions to full-fledged carcinoma, we evaluated the effect of anti Amot vaccination on clinically evident tumors. Electroporation of plasmid coding for the human Amot (pAmot) significantly delayed the progression both of autochthonous tumors in cancer prone BALB-neuT and PyMT genetically engineered mice and transplantable TUBO tumor in wild-type BALB/c mice. The intensity of the inhibition directly correlated with the titer of anti-Amot antibodies induced by the vaccine. Tumor inhibition was associated with an increase of vessels diameter with the formation of lacunar spaces, increase in vessel permeability, massive tumor perivascular necrosis and an effective epitope spreading that induces an immune response against other tumor associated antigens. Greater tumor vessel permeability also markedly enhances the antitumor effect of doxorubicin. These data provide a rationale for the development of novel anticancer treatments based on anti-Amot vaccination in conjunction with chemotherapy regimens. PMID- 22426513 TI - The clinical need for a method of identification of embryos destined to become a blastocyst in assisted reproductive technology cycles. AB - PURPOSE: To provide a rationale for continuation of efforts to improve the outcome of Assisted Reproductive Technology outcomes, thereby increasing the likelihood of the live birth of healthy neonates. METHODS: Description of rationale and a framework leading to improvement in Assisted Reproductive Technology outcomes. RESULTS: The opportunity for improvement in the success rate for Assisted Reproductive Technology outcome is predicated on selection of the highest quality embryo(s) for transfer. However, such approaches must be balanced by a limit to the number of embryos transferred so as to reduce the risk for multiple births and particularly higher order multiple gestations. Blastocyst transfer offers one such successful approach, but is confounded by suggestions of an increased risk of both pregnancy complications and epigenetic disorders. CONCLUSION: There is a need for development of approaches which, individually or in combination, may assist in the early detection of embryos destined to develop into blastocysts. PMID- 22426514 TI - Seeing the charge within. PMID- 22426515 TI - Electrical control of a solid-state flying qubit. AB - Solid-state approaches to quantum information technology are attractive because they are scalable. The coherent transport of quantum information over large distances is a requirement for any practical quantum computer and has been demonstrated by coupling super-conducting qubits to photons. Single electrons have also been transferred between distant quantum dots in times shorter than their spin coherence time. However, until now, there have been no demonstrations of scalable 'flying qubit' architectures-systems in which it is possible to perform quantum operations on qubits while they are being coherently transferred in solid-state systems. These architectures allow for control over qubit separation and for non-local entanglement, which makes them more amenable to integration and scaling than static qubit approaches. Here, we report the transport and manipulation of qubits over distances of 6 um within 40 ps, in an Aharonov-Bohm ring connected to two-channel wires that have a tunable tunnel coupling between channels. The flying qubit state is defined by the presence of a travelling electron in either channel of the wire, and can be controlled without a magnetic field. Our device has shorter quantum gates (<1 um), longer coherence lengths (~86 um at 70 mK) and higher operating frequencies (~100 GHz) than other solid-state implementations of flying qubits. PMID- 22426516 TI - Snakes antibodies. AB - Immunoglobulins are basic molecules of the immune system of vertebrates. In previous studies we described the immunoglobulins found in two squamata reptiles, Anolis carolinensis and Eublepharis macularius. Snakes are squamata reptiles too but they have undergone an extreme evolutionary process. We therefore wanted to know how these changes affected their immunoglobulin coding genes. To perform this analysis we studied five snake transcriptomes and two genome draft sequences. Sequences coding for immunoglobulin M (IgM), immunoglobulin D (IgD) and two classes of immunoglobulin Y (IgY - named IgYa and IgYb-) were found in all of them. Moreover, the Thamnophis elegans transcriptome and Python molurus genome draft sequences showed a third class of IgY, the IgYc, whose constant region only presents three domains and lacks the CH2. All data suggest that the IgYb is the evolutionary origin of this IgYc. An exhaustive search of the light chains were carried out, being lambda the only light chain found in snakes. The results provide a clear picture of the immunoglobulins present in the suborder Serpentes. PMID- 22426517 TI - Is the motor or the garage more important to the car? The difference between semantic associations in single word and sentence production. AB - The aim of the present study was to investigate the impact of part-whole (e.g., car-motor) and functional associations (e.g., car-garage) on single word (Experiment 1) and sentence production (Experiment 2). In Experiment 1, a classical picture-word task was used. In Experiment 2, the same stimuli and distractors were embedded into a sentence. The relation between target and distractor was either part-whole, functional or unrelated. At single word level, part-whole and functional relations facilitate naming. Additionally, the facilitation effect was stronger for part-whole in comparison to functional associations. During sentence production, facilitation shifted to interference. The difference between both relations disappeared. The findings of the different effects between functional and part-whole associations depend on the length of utterances and highlight the divergent impact of associations. The differences between part-whole and functional associations in single word production might reflect a differential organization of associative links at the conceptual level. In contrast, during sentence production the syntactic processing at the lexical level seem to be more important than types of semantic associations at the conceptual level. PMID- 22426518 TI - Evidence that aberrant protein metabolism contributes to chemoresistance in multiple myeloma cells. AB - Multiple myeloma (MM) is an incurable B lymphocyte cancer. To date, a comparative analysis of global protein metabolism for the MM cell line CCL-155 (RPMI-8226) and the non-cancerous B lymphocyte cell line CCL-156 (RPMI-1788) has not been published. Here, we report that both global protein synthesis and degradation occur at a higher rate in MM cells and demonstrate that alkylating agents can reduce global protein degradation in both cell lines, but the effect is greater in CCL-156 cells. Treatment with melphalan plus the proteasome inhibitor MG132 reduced global protein degradation for MM cells to roughly 60% of that seen without drugs, but the reduction was approximately three times greater for CCL 156 cells. This drug combination was growth inhibitory for both cell lines, but CCL-156 inhibition was 2-fold greater than that of the MM cell line. Additionally, treatment with melphalan plus the lysosomal inhibitor chloroquine did not affect growth of MM cells more than melphalan alone, whereas this combination drastically inhibited growth of CCL-156 cells despite protein degradation being maintained at 60% level for both cell lines. This suggests that a lysosomal function other than protein degradation is required for recovery from alkylation damage in CCL-156 cells. In general, CCL-156 cells were affected to a greater extent for both protein degradation and growth inhibition with most drug combinations tested. Statistical analysis of our data (p=0.066) provides evidence that aberrant proteasome-mediated protein degradation correlates with chemoresistance in MM cells, but that lysosome-mediated protein degradation does not. PMID- 22426519 TI - Screening of PC and PMMA-binding peptides for site-specific immobilization of proteins. AB - In the present study, we used proteomic research technology to develop a method for the screening and evaluation of material-binding peptides for protein immobilization. Using this screening method, soluble Escherichia coli proteins that preferentially adsorbed onto polycarbonate (PC) and poly(methylmethacrylate) (PMMA) as model plastic materials were first isolated and identified by 2 dimensional electrophoresis (2DE) combined with peptide mass fingerprinting (PMF). The genes of identified protein candidates (ELN, MLT, OMP, and BIF) that exhibited a hexahistidine tag (6*His-tag) were over-expressed by E. coli BL21 (DE3), and the proteins were purified by IMAC affinity chromatography. The candidates for PC and PMMA-binding peptides were isolated from peptide fragments from affinity protein candidates, which were digested with trypsin and chymotrypsin. Consequently, 5 candidates for the PC-binding peptide and 2 candidates for the PMMA-binding peptide were successfully identified by MALDI-TOF MS. All of the peptides identified were introduced to the C-terminus of glutathione S-transferase (GST) as a model protein for immobilization. Adsorption of peptide-fused and wild-type GSTs onto the plastic surfaces was directly monitored using a quartz crystal microbalance (QCM) device. Consequently, genetic fusion of PC-MLT8 and PC-OMP6 as PC-binders and PM-OMP25 as a PMMA-binder significantly enhanced the adsorption rates of GST, achieving an adsorption density that was more than 10 times higher than that of wild-type GST. Furthermore, the residual activity levels of GST-PC-OMP6 and GST-PM-OMP25 in the adsorption state were 2 times higher than that of wild-type GST. Thus, the PC and PMMA-binding peptides identified in this study, namely PC-OMP6 and PM-OMP25, were considerably useful for site-specific immobilization of proteins, while maintaining a higher adsorption density and residual activity levels. The method demonstrated in this study will be applicable to the isolation of a variety of material-binding peptides against the surfaces of unique materials. PMID- 22426520 TI - Zanthoxylum avicennae extracts inhibit cell proliferation through protein phosphatase 2A activation in HA22T human hepatocellular carcinoma cells in vitro and in vivo. AB - Hepatocellular carcinoma is a common type of cancer that is usually associated with poor prognosis. In this study, we examined the in vitro and in vivo mechanisms of the traditional Vietnamese herb Zanthoxylum avicennae on the inhibition of HA22T human hepatocellular carcinoma cell proliferation. HA22T cells were treated with different concentrations of Zanthoxylum avicennae extracts (YBBEs) and analyzed with the MTT assay, western blot analysis, flow cytometry, siRNA transfection assays and co-immunoprecipitation assay. Additionally, the HA22T-implanted xenograft nude mouse model was applied to confirm the cellular effects. YBBEs showed a strong inhibition of HA22T cell viability in a dose-dependent manner and significantly reduced cell proliferation related proteins as well as induced cell cycle arrest in the G2/M phase. Protein phosphatase 2A (PP2A) siRNA or okadaic acid totally blocked YBBE-mediated cell proliferation inhibition. In addition, an HA22T-implanted nude mouse model further confirmed that YBBEs inhibit HA22T tumor cell growth and downregulate the survival and cell cycle regulating proteins, as well as activate the PP2A protein. Our findings indicate that the inhibition of HA22T cell proliferation by YBBEs is mediated through PP2A activation. PMID- 22426527 TI - Simultaneous analysis of irbesartan and hydrochlorothiazide: an improved HPLC method with the aid of a chemometric protocol. AB - Experimental design method was used for HPLC determination of irbesartan and hydrochlorothiazide in combined dosage forms. The traditional approach for optimization of experiments is time-consuming, involves a large number of runs and does not allow establishing the multiple interacting parameters. The main advantages of the experimental design method include the simultaneous screening of a larger number of factors affecting response and the estimation of possible interactions. On the basis of preliminary experiments, three factors-independent variables were selected as inputs (methanol content, pH of the mobile phase and temperature) and as dependent variables, five responses (resolution, symmetry of irbesartan peak, symmetry of hydrochlorothiazide peak, retention factor of irbesartan and retention factor of hydrochlorothiazide) were chosen. A full 23 factorial design, where factors were examined at two different levels ("low" and "high") was used to determine which factors had an effect on the studied response. Afterwards, experimental design was used to optimize these influent parameters in the previously selected experimental domain. The novelty of our method lies in the optimization step accomplished by Derringer's desirability function. After optimizing the experimental conditions a separation was conducted on a Supelcosil C(18) (150 mm * 4.6 mm, 5 mm particle size) column with a mobile phase consisting of methanol-tetrahydrofuran-acetate buffer 47:10:43 v/v/v, pH 6.5 and a column temperature of 25 degrees C. The developed method was successfully applied to the simultaneous separation of these drug-active compounds in their commercial pharmaceutical dosage forms. PMID- 22426526 TI - Folliculitis induced by EGFR inhibitors, preventive and curative efficacy of tetracyclines in the management and incidence rates according to the type of EGFR inhibitor administered: a systematic literature review. AB - INTRODUCTION: Folliculitis is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs). It is often apparent, altering patients' quality of life and possibly impacting compliance. Variations in terms of the treatment-related incidence and intensity have not been fully elucidated. Tetracyclines have been recommended for the prophylaxis and treatment of folliculitis but their efficacy is yet to be established. MATERIALS AND METHODS: We carried out two systematic literature reviews. The first assessed the preventive and curative efficacy of tetracyclines. The second assessed the incidence of grade 3-4 folliculitis in the main clinical studies published. RESULTS: In four randomized studies, preventive tetracycline treatment was associated with a significantly lower incidence of grade 2-3 folliculitis and a better quality of life in three of the four studies. In curative terms, tetracycline efficacy was not evaluated in any randomized study, but an improvement in grade >=2 folliculitis was reported in case series. The frequency and severity of folliculitis seem to be greater with the antibodies than with the tyrosine kinase inhibitors. Analysis restricted to lung cancer studies showed a statistically greater incidence in terms of grade 3-4 folliculitis with cetuximab (9%) and erlotinib (8%) than with gefitinib (2%) (p < .0001). CONCLUSION: Unless contraindicated, a tetracycline should be routinely prescribed prophylactically for patients treated with an EGFRI (level of evidence, B2). In curative therapy, the level of evidence for tetracycline efficacy is low (level of evidence, D). The incidence of grade 3-4 folliculitis induced by EGFRIs appears to be lower with gefitinib. PMID- 22426528 TI - Synthesis and antimicrobial activity of N'-heteroarylidene-1 adamantylcarbohydrazides and (+/-)-2-(1-adamantyl)-4-acetyl-5-[5-(4-substituted phenyl-3-isoxazolyl)]-1,3,4-oxadiazolines. AB - The reaction of adamantane-1-carbohydrazide (1) with heterocyclic aldehydes, namely 5-(4-chlorophenyl)isoxazole-3-carboxaldehyde (2a), 5-(4 methylphenyl)isoxazole-3-carboxaldehyde (2b), 5-(4-methoxyphenyl)isoxazole-3 carboxaldehyde (2c), 1H-imidazole-2-carboxaldehyde and 2-butyl-4-chloro-1H imidazole-5-carboxaldehyde, in ethanol, yielded the corresponding N' heteroarylidene-1-adamantylcarbohydrazides 3a, 3b, 3c, 4 and 5, respectively, in good yields. The 4-acetyl-1,3,4-oxadiazoline analogues 6a-c were prepared in 48 55% yields by heating their corresponding N'-heteroarylidene-1 adamantylcarbohydrazides 3a-c with acetic anhydride for two hours. Compounds 3a c, 4, 5 and 6a-c were tested for in vitro activities against a panel of Gram positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 4 and 5 displayed potent broad-spectrum antimicrobial activity, while compounds 3a-c showed good activity against the Gram-positive bacteria. PMID- 22426529 TI - Synthesis and preliminary investigations of the siRNA delivery potential of novel, single-chain rigid cationic carotenoid lipids. AB - The success of nucleic acid delivery requires the development of safe and efficient delivery vectors that overcome cellular barriers for effective transport. Herein we describe the synthesis of a series of novel, single-chain rigid cationic carotenoid lipids and a study of their preliminary in vitro siRNA delivery effectiveness and cellular toxicity. The efficiency of siRNA delivery by the single-chain lipid series was compared with that of known cationic lipid vectors, 3beta-[N-(N',N'-dimethylaminoethane)carbamoyl]-cholesterol (DC-Chol) and 1,2-dimyristoyl-sn-glyceryl-3-phosphoethanolamine (EPC) as positive controls. All cationic lipids (controls and single-chain lipids) were co-formulated into liposomes with the neutral co-lipid, 1,2-dioleolyl-sn-glycerol-3 phosphoethanolamine (DOPE). Cationic lipid-siRNA complexes of varying (+/-) molar charge ratios were formulated for delivery into HR5-CL11 cells. Of the five single-chain carotenoid lipids investigated, lipids 1, 2, 3 and 5 displayed significant knockdown efficiency with HR5-CL11 cells. In addition, lipid 1 exhibited the lowest levels of cytotoxicity with cell viability greater than 80% at all (+/-) molar charge ratios studied. This novel, single-chain rigid carotenoid-based cationic lipid represents a new class of transfection vector with excellent cell tolerance, accompanied with encouraging siRNA delivery efficiency. PMID- 22426530 TI - ATAC-king the complexity of SAGA during evolution. AB - The yeast SAGA (Spt-Ada-Gcn5-acetyltransferase) coactivator complex exerts functions in gene expression, including activator interaction, histone acetylation, histone deubiquitination, mRNA export, chromatin recognition, and regulation of the basal transcription machinery. These diverse functions involve distinct modules within this multiprotein complex. It has now become clear that yeast SAGA has diverged during metazoan evolution into two related complexes, SAGA and ATAC, which exist in two flavors in vertebrates. The compositions of metazoan ATAC and SAGA complexes have been characterized, and functional analyses indicate that these complexes have important but distinct roles in transcription, histone modification, signaling pathways, and cell cycle regulation. PMID- 22426531 TI - A conserved role for COMA/CENP-H/I/N kinetochore proteins in the spindle checkpoint. AB - The COMA/CENP-H/I kinetochore complex regulates microtubule dynamics at kinetochores. The complex is also required to generate spindle checkpoint signals in both yeast and human cells under conditions where Aurora B activity is compromised. Our data explain why mammalian cells treated with Aurora inhibitors still have a functional spindle assembly checkpoint (SAC), since the checkpoint signals through CENP-H/I/N. The SAC effect from depleting the CENP-H/I/N complex cannot be explained by a weakened SAC signal, and the complex has no role in the SAC response to paclitaxel. We propose a model to explain the differential response of human cells to nocodazole and paclitaxel. PMID- 22426532 TI - RpoS proteolysis is controlled directly by ATP levels in Escherichia coli. AB - The master regulator of stationary phase in Escherichia coli, RpoS, responds to carbon availability through changes in stability, but the individual steps in the pathway are unknown. Here we systematically block key steps of glycolysis and the citric acid cycle and monitor the effect on RpoS degradation in vivo. Nutrient upshifts trigger RpoS degradation independently of protein synthesis by activating metabolic pathways that generate small energy molecules. Using metabolic mutants and inhibitors, we show that ATP, but not GTP or NADH, is necessary for RpoS degradation. In vitro reconstitution assays directly demonstrate that ClpXP fails to degrade RpoS, but not other proteins, at low ATP hydrolysis rates. These data suggest that cellular ATP levels directly control RpoS stability. PMID- 22426533 TI - Regulation of maternal phospholipid composition and IP(3)-dependent embryonic membrane dynamics by a specific fatty acid metabolic event in C. elegans. AB - Natural fatty acids (FAs) exhibit vast structural diversity, but the functional importance of FA variations and the mechanism by which they contribute to a healthy lipid composition in animals remain largely unexplored. A large family of acyl-CoA synthetases (ACSs) regulates FA metabolism by esterifying FA to coenyzme A. However, little is known about how particular FA-ACS combinations affect lipid composition and specific cellular functions. We analyzed how the activity of ACS 1 on branched chain FA C17ISO impacts maternal lipid content, signal transduction, and development in Caenorhabditis elegans embryos. We show that expression of ACS-1 in the somatic gonad guides the incorporation of C17ISO into certain phospholipids and thus regulates the phospholipid composition in the zygote. Disrupting this ACS-1 function causes striking defects in complex membrane dynamics, including exocytosis and cytokinesis, leading to early embryonic lethality. These defects are suppressed by hyperactive IP(3) signaling, suggesting that C17ISO and ACS-1 functions are necessary for optimal IP(3) signaling essential for early embryogenesis. This study shows a novel role of branched chain FAs whose functions in humans and animals are unknown and uncovers a novel intercellular regulatory pathway linking a specific FA-ACS interaction to specific developmental events. PMID- 22426534 TI - DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase. AB - Replication forks encounter impediments as they move through the genome, including natural barriers due to stable protein complexes and highly transcribed genes. Unlike lesions generated by exogenous damage, natural barriers are encountered in every S phase. Like humans, Schizosaccharomyces pombe encodes a single Pif1 family DNA helicase, Pfh1. Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II. In addition, converged replication forks accumulated at all of these sites in the absence of Pfh1. The effects of Pfh1 on DNA replication are likely direct, as it had high binding to sites whose replication was impaired in its absence. Replication in the absence of Pfh1 resulted in DNA damage specifically at those sites that bound high levels of Pfh1 in wild-type cells and whose replication was slowed in its absence. Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks. Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites. PMID- 22426535 TI - The DNA helicase Pfh1 promotes fork merging at replication termination sites to ensure genome stability. AB - Bidirectionally moving DNA replication forks merge at termination sites composed of accidental or programmed DNA-protein barriers. If merging fails, then regions of unreplicated DNA can result in the breakage of DNA during mitosis, which in turn can give rise to genome instability. Despite its importance, little is known about the mechanisms that promote the final stages of fork merging in eukaryotes. Here we show that the Pif1 family DNA helicase Pfh1 plays a dual role in promoting replication fork termination. First, it facilitates replication past DNA-protein barriers, and second, it promotes the merging of replication forks. A failure of these processes in Pfh1-deficient cells results in aberrant chromosome segregation and heightened genome instability. PMID- 22426536 TI - Identification and characterization of ToRC, a novel ISWI-containing ATP dependent chromatin assembly complex. AB - SNF2-like motor proteins, such as ISWI, cooperate with histone chaperones in the assembly and remodeling of chromatin. Here we describe a novel, evolutionarily conserved, ISWI-containing complex termed ToRC (Toutatis-containing chromatin remodeling complex). ToRC comprises ISWI, Toutatis/TIP5 (TTF-I-interacting protein 5), and the transcriptional corepressor CtBP (C-terminal-binding protein). ToRC facilitates ATP-dependent nucleosome assembly in vitro. All three subunits are required for its maximal biochemical activity. The toutatis gene exhibits strong synthetic lethal interactions with CtBP. Thus, ToRC mediates, at least in part, biological activities of CtBP and Toutatis. ToRC subunits colocalize in euchromatic arms of polytene chromosomes. Furthermore, nuclear localization and precise distribution of ToRC in chromosomes are dependent on CtBP. ToRC is involved in CtBP-mediated regulation of transcription by RNA polymerase II in vivo. For instance, both Toutatis and CtBP are required for repression of genes of a proneural gene cluster, achaete-scute complex (AS-C), in Drosophila larvae. Intriguingly, native C-terminally truncated Toutatis isoforms do not associate with CtBP and localize predominantly to the nucleolus. Thus, Toutatis forms two alternative complexes that have differential distribution and can participate in distinct aspects of nuclear DNA metabolism. PMID- 22426537 TI - The nonhistone, N-terminal tail of an essential, chimeric H2A variant regulates mitotic H3-S10 dephosphorylation. AB - H2A.Y is an essential, divergent Tetrahymena thermophila histone variant. It has a long nonhistone N terminus that contains leucine-rich repeats (LRR) and an LRR cap domain with similarity to Sds22p, a regulator of yeast protein phosphatase 1 (PP1) activity in the nucleus. In growing cells, H2A.Y is incorporated into micronuclei only during S phase, which occurs immediately after micronuclear mitosis. Depletion of H2A.Y causes prolonged retention of mitosis-associated histone H3-S10 phosphorylation and mitotic abnormalities that mimic S10E mutation. In cells where H2A.Y is depleted, an inducible chimeric gene, in which the H2A.Y N terminus is attached to H2A.X, is shown to regulate micronuclear H3 S10 phosphorylation. H2A.Y can also be specifically coimmunoprecipitated with a Tetrahymena PP1 ortholog (Ppo1p). Taken together, these results argue that the N terminus of H2A.Y functions to regulate H3-S10 dephosphorylation. This striking in vivo case of "cross-talk" between a H2A variant and a specific post translational modification of another histone demonstrates a novel function for a histone variant. PMID- 22426538 TI - Acute skin toxicity-related, out-of-pocket expenses in patients with breast cancer treated with external beam radiotherapy: a descriptive, exploratory study. AB - PURPOSE: Acute skin toxicity is one of the most common side effects of breast cancer radiotherapy. To date, no one has estimated the nonmedical out-of-pocket expenses associated with this side effect. The primary aim of the present descriptive, exploratory study was to assess the feasibility of a newly developed skin toxicity costs questionnaire. The secondary aims were to: (1) estimate nonmedical out-of-pocket costs, (2) examine the nature of the costs, (3) explore potential background predictors of costs, and (4) explore the relationship between patient-reported dermatologic quality of life and expenditures. METHODS: A total of 50 patients (mean age = 54.88, Stage 0-III) undergoing external beam radiotherapy completed a demographics/medical history questionnaire as well as a seven-item Skin Toxicity Costs (STC) questionnaire and the Skindex-16 in week 5 of treatment. RESULTS: Mean skin toxicity costs were $131.64 (standard error [SE] = $23.68). Most frequently incurred expenditures were new undergarments and products to manage toxicity. Education was a significant unique predictor of spending, with more educated women spending more money. Greater functioning impairment was associated with greater costs. The STC proved to be a practical, brief measure which successfully indicated specific areas of patient expenditures and need. CONCLUSIONS: Results reveal the nonmedical, out-of-pocket costs associated with acute skin toxicity in the context of breast cancer radiotherapy. To our knowledge, this study is the first to quantify individual costs associated with this treatment side effect, as well as the first to present a scale specifically designed to assess such costs. RELEVANCE: In future research, the STC could be used as an outcome variable in skin toxicity prevention and control research, as a behavioral indicator of symptom burden, or as part of a needs assessment. PMID- 22426539 TI - Real value prediction of protein folding rate change upon point mutation. AB - Prediction of protein folding rate change upon amino acid substitution is an important and challenging problem in protein folding kinetics and design. In this work, we have analyzed the relationship between amino acid properties and folding rate change upon mutation. Our analysis showed that the correlation is not significant with any of the studied properties in a dataset of 476 mutants. Further, we have classified the mutants based on their locations in different secondary structures and solvent accessibility. For each category, we have selected a specific combination of amino acid properties using genetic algorithm and developed a prediction scheme based on quadratic regression models for predicting the folding rate change upon mutation. Our results showed a 10-fold cross validation correlation of 0.72 between experimental and predicted change in protein folding rates. The correlation is 0.73, 0.65 and 0.79, respectively in strand, helix and coil segments. The method has been further tested with an extended dataset of 621 mutants and a blind dataset of 62 mutants, and we observed a good agreement with experiments. We have developed a web server for predicting the folding rate change upon mutation and it is available at http://bioinformatics.myweb.hinet.net/fora.htm. PMID- 22426540 TI - Modest associations between self-reported physical workload and neck trouble: a population-based twin control study. AB - OBJECTIVES: To investigate the relationship between self-reported physical workload and neck trouble (NT) in twins. Additionally, to explore whether the relationship between physical workload and NT is influenced by genetic factors. METHODS: A twin control study was performed within a population-based, cross sectional questionnaire study using 3,208 monozygotic (MZ) and same-sexed dizygotic (DZ) twins aged 19-70. Twin pairs discordant for self-reported NT during the past year ("Any NT") were included. Self-reported physical workload in four categories was used as exposure ("sitting," "sitting and walking," "light physical," and "heavy physical" work). Paired analyses including conditional logistic regression were made for all participants and for each sex, and MZ and DZ pairs separately. RESULTS: No marked associations between physical workload and NT were seen. A moderate risk elevation in "heavy physical" work was seen in DZ men (odds ratio 2.3, 95% confidence intervals 1.3-4.0), but not in MZ men or the MZ or DZ women. CONCLUSIONS: The findings in some degree supported that "heavy physical" work is a determinant of NT, perhaps only in men, but hardly of any greater importance. The different results between DZ and MZ men suggest that genetic factors influence the relationship between physical workload and NT. PMID- 22426541 TI - Validity of self-reports of knee-straining activities at work: a field study with 6-month follow-up. AB - OBJECTIVES: To measure short-term and long-term validity of self-reported duration of kneeling and squatting at work and to examine the possibility of differential misclassification due to knee complaints. METHODS: Work-related kneeling and squatting were analysed for 190 male subjects (mean age, 35.0 and SD, 11.5) in field by both measurements and questionnaires. Posture capturing was performed with an ambulatory measuring system (CUELA). Immediately after the measurement (t(0)), each participant was asked to estimate frequency and duration of five specific knee postures taken during the measurement period. After 6 months (t(1)), the survey was repeated (n = 125). Health status of all subjects was recorded by Nordic questionnaire. Statistical analysis was performed by using nonparametric tests, correlations, and Bland-Altman plots. RESULTS: At both time points, subjects were able to recall the occurrence of knee postures rather well (100.0-57.6% agreement) but many of them failed in quantifying their knee load. We found poor-to-moderate correlations between measurements and self-reports for all examined postures in both surveys (0.23 < rho < 0.63). The durations of knee postures were both over- and underestimated but overestimations predominated (t(0), 74.7% and t(1), 87.2% overestimations). High-exposed subjects seemed to misjudge their exposure to a greater extent than low-exposed ones, while knee complaints seemed to have no impact on the assessment behaviour. CONCLUSIONS: As our study showed, self-reported knee loading may deviate widely from measured exposure. These limitations of self-reporting emphasise the arguments in favour of using objective data whenever possible, for example by complementing self reported occurrence of knee postures with quantitative measurement data. PMID- 22426542 TI - Harnessing chemoselective imine ligation for tethering bioactive molecules to platinum(IV) prodrugs. AB - Platinum(II) anticancer drugs are among the most effective and often used chemotherapeutic drugs. In recent years, there has been increasing interest in exploiting inert platinum(IV) scaffolds as a prodrug strategy to mitigate the limitations of platinum(II) anticancer complexes. In this prodrug strategy, the axial ligands are released concomitantly upon intracellular reduction to the active platinum(II) congener, offering the possibility of conjugating bioactive co-drugs which may synergistically enhance cytotoxicity on cancer cells. Existing techniques of tethering bioactive molecules to the axial positions of platinum(IV) prodrugs suffer from limited scope, poor yields and low reliability. This report explores the applications of current chemoselective ligation chemistries to platinum(IV) anticancer complexes with the aim of addressing the aforementioned limitations. Here, we describe the synthesis of a platinum(IV) complex bearing an aromatic aldehyde functionality and explored the scope of imine ligation with various hydrazide and aminooxy functionalized substrates. As a proof of concept, we tethered a six sequence long peptide mimetic (AMVSEF) of the anti-inflammatory protein, ANXA1. PMID- 22426543 TI - Immunohistochemical expression of thrombomodulin in vestibular schwannoma. AB - Many vestibular schwannomas (VS) manifest intratumoral microhemorrhages whose underlying mechanisms are not fully understood. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes the thrombin-mediated formation of activated protein C that inhibits thrombus formation. We investigated the existence of TM in VS and its potential role in the development of microhemorrhages. We used immunohistochemical staining to study the expression of TM in tissues derived from 25 patients with VS. Hemosiderin deposition was examined by Berlin blue staining and compared with the expression of TM. Vascular endothelial cells in all 25 VS tissues expressed TM. The TM-positive vessel ratio, calculated by dividing the number of TM-positive by the number of CD34 positive lumens, was significantly higher in hemosiderin-laden than hemosiderin negative tissues (0.71 +/- 0.17 vs. 0.53 +/- 0.31, p = 0.049, Mann-Whitney U test). Our findings suggest a close relationship between the expression of TM and microhemorrhage in VS. PMID- 22426544 TI - Podcasting: a technology, not a toy. PMID- 22426545 TI - Insights into dynein motor domain function from a 3.3-A crystal structure. AB - Dyneins power the beating of cilia and flagella, transport various intracellular cargos and are necessary for mitosis. All dyneins have a ~300-kDa motor domain consisting of a ring of six AAA+ domains. ATP hydrolysis in the AAA+ ring drives the cyclic relocation of a motile element, the linker domain, to generate the force necessary for movement. How the linker interacts with the ring during the ATP hydrolysis cycle is not known. Here we present a 3.3-A crystal structure of the motor domain of Saccharomyces cerevisiae cytoplasmic dynein, crystallized in the absence of nucleotides. The linker is docked to a conserved site on AAA5, which is confirmed by mutagenesis as functionally necessary. Nucleotide soaking experiments show that the main ATP hydrolysis site in dynein (AAA1) is in a low nucleotide affinity conformation and reveal the nucleotide interactions of the other three sites (AAA2, AAA3 and AAA4). PMID- 22426546 TI - Control of RNP motility and localization by a splicing-dependent structure in oskar mRNA. AB - oskar RNA localization to the posterior pole of the Drosophila melanogaster oocyte requires splicing of the first intron and the exon junction complex (EJC) core proteins. The functional link between splicing, EJC deposition and oskar localization has been unclear. Here we demonstrate that the EJC associates with oskar mRNA upon splicing in vitro and that Drosophila EJC deposition is constitutive and conserved. Our in vivo analysis reveals that splicing creates the spliced oskar localization element (SOLE), whose structural integrity is crucial for ribonucleoprotein motility and localization in the oocyte. Splicing thus has a dual role in oskar mRNA localization: assembling the SOLE and depositing the EJC required for mRNA transport. The SOLE complements the EJC in formation of a functional unit that, together with the oskar 3' UTR, maintains proper kinesin-based motility of oskar mRNPs and posterior mRNA targeting. PMID- 22426547 TI - Structure of the activating IL-1 receptor signaling complex. AB - Interleukin-1 (IL-1)-family cytokines are mediators of innate and adaptive immunity. They exert proinflammatory effects by binding a primary receptor that recruits a receptor accessory protein to form a signaling-competent heterotrimeric complex. Here we present the crystal structure of IL-1beta bound to its primary receptor IL-1RI and its receptor accessory protein IL-1RAcP, providing insight into how IL-1-type cytokines initiate signaling and revealing an evolutionary relationship with the fibroblast growth factor receptor family. PMID- 22426548 TI - The molecular architecture of human Dicer. AB - Dicer is a multidomain enzyme that generates small RNAs for gene silencing in eukaryotes. Current understanding of Dicer structure is restricted to simple forms of the enzyme, whereas that of the large and complex Dicer in metazoans is unknown. Here we describe a new domain localization strategy developed to determine the structure of human Dicer by EM. A rearrangement of the nuclease core, compared to the archetypal Giardia lamblia Dicer, explains how metazoan Dicers generate products that are 21-23 nucleotides in length. The helicase domains form a clamp-like structure adjacent to the RNase III active site, facilitating recognition of pre-miRNA loops or translocation on long dsRNAs. Drosophila melanogaster Dicer-2 shows similar features, revealing that the three dimensional architecture is conserved. These results illuminate the structural basis for small RNA production in eukaryotes and provide a versatile new tool for determining structures of large molecular machines. PMID- 22426549 TI - Clinical spectrum of antenatally detected urinary tract abnormalities with respect to hydronephrosis at postnatal ultrasound scan. AB - AIM: The purpose of this study was to compare the outcome of infants having antenatally detected urinary tract abnormalities (AUTAs) with respect to the presence of hydronephrosis in postnatal ultrasonography (US) examination. PATIENTS AND METHODS: Between January 1999 and October 2009, 256 infants diagnosed with AUTAs were prospectively followed. Infants were divided into two groups according to the presence of hydronephrosis in postnatal US examination: Group 1, infants with hydronephrosis; Group 2, infants without hydronephrosis (including renal cyst, agenesis, ectopic kidney). The events of interest were the presence and diagnoses of uropathy, AUTA resolution, urinary tract infection (UTI), development of renal parenchymal defects (RPDs)--focal or global scarring, dysplasia--, acute kidney injury (AKI) and chronic kidney disease (CKD), and the need for surgery and dialysis treatment. RESULTS: The most commonly detected underlying abnormalities were ureteropelvic junction obstruction (44.8 %), vesicoureteral reflux (VUR) (30.0 %) and megaureter (9.5 %) in patients with postnatal hydronephrosis. On the other hand, multicystic dysplastic kidney (43.5 %), renal agenesis (19.4 %) and VUR (19.4 %) were mostly encountered abnormalities in patients without postnatal hydronephrosis. RPDs were significantly more common among patients with postnatal hydronephrosis compared to those without hydronephrosis (37 vs. 21 %, P = 0.02). The incidence of UTI and VUR was higher in infants with postnatal hydronephrosis than in infants without hydronephrosis. There was no statistically significant difference in terms of the development of AKI and CKD and the need for surgery and dialysis treatment between patients with hydronephrosis and those without hydronephrosis. CONCLUSION: Infants with AUTAs should be investigated postnatally. The findings from this study will help to identify the natural history and outcome of infants with AUTAs according to the postnatal US parameters. PMID- 22426551 TI - Automated segmentation of basal ganglia and deep brain structures in MRI of Parkinson's disease. AB - PURPOSE: Template-based segmentation techniques have been developed to facilitate the accurate targeting of deep brain structures in patients with movement disorders. Three template-based brain MRI segmentation techniques were compared to determine the best strategy for segmenting the deep brain structures of patients with Parkinson's disease. METHODS: T1-weighted and T2-weighted magnetic resonance (MR) image templates were created by averaging MR images of 57 patients with Parkinson's disease. Twenty-four deep brain structures were manually segmented on the templates. To validate the template-based segmentation, 14 of the 24 deep brain structures from the templates were manually segmented on 10 MR scans of Parkinson's patients as a gold standard. We compared the manual segmentations with three methods of automated segmentation: two registration based approaches, automatic nonlinear image matching and anatomical labeling (ANIMAL) and symmetric image normalization (SyN), and one patch-label fusion technique. The automated labels were then compared with the manual labels using a Dice-kappa metric and center of gravity. A Friedman test was used to compare the Dice-kappa values and paired t tests for the center of gravity. RESULTS: The Friedman test showed a significant difference between the three methods for both thalami (p < 0.05) and not for the subthalamic nuclei. Registration with ANIMAL was better than with SyN for the left thalamus and was better than the patch based method for the right thalamus. CONCLUSION: Although template-based approaches are the most used techniques to segment basal ganglia by warping onto MR images, we found that the patch-based method provided similar results and was less time-consuming. Patch-based method may be preferable for the subthalamic nucleus segmentation in patients with Parkinson's disease. PMID- 22426552 TI - Developmental regulation of MURF E3 ubiquitin ligases in skeletal muscle. AB - The striated muscle-specific tripartite motif (TRIM) proteins TRIM63/MURF1, TRIM55/MURF2 and TRIM54/MURF3 can function as E3 ubiquitin ligases in ubiquitin mediated muscle protein turnover. Despite the well-characterised role of MURF1 in skeletal muscle atrophy, the dynamics of MURF isogene expression in the development and early postnatal adaptation of skeletal muscle is unknown. Here, we show that MURF2 is the isogene most highly expressed in embryonic skeletal muscle at E15.5, with the 50 kDa A isoform predominantly expressed. MURF1 and MURF3 are upregulated only postnatally. Knockdown of MURF2 p50A by isoform specific siRNA results in delayed myogenic differentiation and myotube formation in vitro, with perturbation of the stable, glutamylated microtubule population. This underscores that MURF2 plays an important role in the earliest stages of skeletal muscle differentiation and myofibrillogenesis. During further development, there is a shift towards the 60 kDa A isoform, which dominates postnatally. Analysis of the fibre-type expression shows that MURF2 A isoforms are predominantly slow-fibre associated, whilst MURF1 is largely excluded from these fibres, and MURF3 is ubiquitously distributed in both type I and II fibres. PMID- 22426554 TI - Jolkinolide B induces apoptosis in MDA-MB-231 cells through inhibition of the PI3K/Akt signaling pathway. AB - The phosphoinositol-3-kinase (PI3K)/Akt signal transduction pathway is critically important for tumor cell growth, proliferation and apoptosis. Apoptosis activation has been reported to be a good target in cancer therapies. In this study, we have found that jolkinolide B (JB), a diterpenoid from the traditional Chinese medicinal herb Euphorbia fischeriana Steud, strongly inhibited the expression of the PI3K p85 subunit and the phosphorylation of Akt. Furthermore, we evaluated the effects of JB on the proliferation and apoptosis of MDA-MB-231 human breast cancer cells. Our results show significant induction of apoptosis in MDA-MB-231 cells incubated with JB. This effect was enhanced by combination with LY294002. In addition, treatment with JB could induce downregulation of the Bcl 2/Bax ratio, and subsequent promotion of mitochondrial release of cytochrome c and activation of caspase-3. Taken together, JB-induced apoptosis of MDA-MB-231 cells occurs through the mitochondrial pathway. Further, the PI3K/Akt signaling cascade plays a role in the induction of apoptosis in JB-treated cells. These observations suggest that JB may have therapeutic applications in the treatment of cancer. PMID- 22426555 TI - Association of modifiable lifestyle behaviors with hypertension by various body mass index categories in Tianjin province of China: a cross-sectional study. AB - The present study was conducted to identify the difference of the relationship between lifestyle behaviors with hypertension (HTN) by various body mass index (BMI) categories. A cross-sectional study was conducted among Tianjin urban communities. A total of 26 438 subjects were randomly selected. The authors evaluated associations of lifestyle behaviors with HTN among normal, overweight, and obese adults using a hierarchical logistic model considering the gross domestic product of residence as socioeconomic proxy. A positive association was found between BMI and the risk of HTN among male and female subjects. Current smoking was associated with a higher risk of HTN in overweight (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36) and obese groups (OR = 1.20, 95% CI = 1.03-1.53). There were statistically significant associations of current drinking with risk of HTN in normal weight (OR = 1.18, 95% CI = 1.01-1.31) and overweight groups (OR = 1.22, 95% CI = 1.07-1.40). The prevention of overweight and obesity is important in preventing HTN. Additionally, adherence to healthy lifestyle is associated with less risk of HTN in various BMI categories. PMID- 22426556 TI - Toothbrushing habits and risk indicators of severe early childhood caries among aboriginal Taiwanese. AB - The purpose of this study was to investigate the toothbrushing habits and risk indicators among aboriginal children with severe early childhood caries (S-ECC). This was a cross-sectional purposive sampling study that included 281 aboriginal children aged 2 to 5 years living in remote regions in southern Taiwan. Participant received dental examinations and questionnaires that were completed by caretakers. From among the 281 participants, 238 children (84%) presented with S-ECC. A low-frequency toothbrushing habit among the children with S-ECC was associated with caretakers with low-frequency toothbrushing (P = .001). The odds ratio of a child using improper toothbrushing methods having a caretaker with a low brushing frequency was 3.45 (P = .0157). Low-frequency toothbrushing and improper toothbrushing methods were associated with S-ECC. The caretakers' brushing frequency was a risk indicator associated with the children's poor oral hygiene. PMID- 22426557 TI - Prospective associations between household-, work-, and leisure-based physical activity and all-cause mortality among older Taiwanese adults. AB - Most studies on the health effects of leisure time physical activity have focused on mortality. There has been limited research regarding physical activity undertaken at work or around the home and mortality. This study assessed the associations between leisure, work, and household physical activity and subsequent all-cause mortality among older adults aged 65 years and older (n = 2133) in Taiwan, over 8 years. Physical activity was evaluated with the Physical Activity Scale for the Elderly. Cox proportional hazard models were used to estimate the association of physical activity with the risk of mortality. This study demonstrated that a low level of total physical activity is predictive of increased all-cause mortality in both men and women in an East Asian population. It also indicates that leisure- and household-related but not work-related activity are significant contributors to this relationship. PMID- 22426558 TI - Tobacco smoking among school children in Colombo district, Sri Lanka. AB - Tobacco smoking is an important problem among schoolchildren. The authors studied the patterns of tobacco smoking among schoolchildren in Colombo, Sri Lanka, using a self-administered questionnaire. Multistaged stratified random sampling was used to select 6000 students. Response rate was 90.7% (5446), out of which 53.4% were males. Prevalence rates for males and females, respectively, were as follows: having smoked at least 1 complete cigarette: 27.0% and 13.3%, smoked more than 100 cigarettes: 2.3% and 0.3%, daily smoking: 1.8% and 0.2%. Mean age of starting to smoke was 14.16 years. The tobacco products most used were cigarettes (91.5%) and bidis (3.8%). In univariate analysis, male gender, parental smoking, studying non-science subjects, peer smoking, and participating in sports were significantly associated with smoking of at least 1 complete cigarette (P < .05). In multivariate analysis, the most significant correlates were having close friends (odds ratio = 3.29, confidence interval = 2.47-4.37) or parents who smoked (odds ratio = 1.86, confidence interval = 1.28-2.71). Female smoking has increased from previously reported values. These high-risk groups can be targets for preventive programs. PMID- 22426559 TI - Health behaviors of native Hawaiian and Pacific Islander adults in California. AB - Smoking, diet and physical activity are associated with chronic diseases, but representative prevalence data on these behaviors for Native Hawaiian and Pacific Islander (NHPI) adults are scarce. Data from the 2005 California Health Interview Survey were analyzed for self-identified NHPI and non-Hispanic white (NHW) adults. Ethnic and NHPI gender differences were examined for socio-demographic variables, obesity and health behaviors. Compared to NHW, NHPI displayed higher prevalence of obesity (p<0.001), smoking (p<0.05) and consumption of unhealthy foods and beverages (p<0.05). NHPI males were more likely than females to smoke (p<0.001). NHPI adults appear to be at higher risk for chronic disease than NHW due to obesity, smoking and intake of unhealthy foods and beverages. Culturally specific health promotion interventions are needed to reduce risks among the underrepresented NHPI population. PMID- 22426560 TI - Safe delivery practices: experience from cross-sectional data of Bangladeshi women. AB - This study examines the safe delivery practices of Bangladeshi women using data on 4905 ever-married women aged 15 to 49 years from the 2007 Bangladesh Demographic and Health Survey. Variables that included age, region of origin, education level of respondent and spouse, residence, working status, religion, involvement in NGOs, mass media exposure, and wealth index were analyzed to find correlates of safe delivery practices. More than 80% of the deliveries took place at home, and only 18% were under safe and hygienic conditions. The likelihood of safe deliveries was significantly lower among younger and older mothers than middle-aged mothers and higher among educated mothers and those living in urban areas. Economically better-off mothers and those with greater exposure to mass media had a significantly higher incidence of safe delivery practices. A significant association with religion and safe delivery practices was revealed. Demographic, socioeconomic, cultural, and programmatic factors that are strongly associated with safe delivery practices should be considered in the formulation of reproductive health policy. PMID- 22426561 TI - Gender disparity in delayed treatment-seeking behavior for cataract: 6 years of experience from Impact Jibon Tari Floating Hospital, Bangladesh. AB - OBJECTIVE: This study was conducted to explore the role of gender in delayed treatment seeking for cataract at the Impact Jibon Tari Floating Hospital in rural Bangladesh. METHOD: Existing clinical records were analyzed for patient characteristics based on sex and the role of gender in delayed cataract surgery. RESULTS: A total of 11 174 patients (41.7% female) received surgical treatment for cataract, among which 69.9% (male = 67.7%; female = 73.2%) had visual acuity (VA) of less than 6/60. After adjustment for hypertension, diabetes, side of eye with cataract, and age above 65, women were more likely to come to surgery after VA became less than 6/60 (adjusted odds ratio = 1.19; 95% confidence interval = 1.1-1.29). DISCUSSION AND CONCLUSION: Gender appeared to play a role in seeking treatment at later stages of cataract. Further qualitative studies are needed to determine the mechanism of delayed treatment among women. PMID- 22426562 TI - Men's role in women's antenatal health status: evidence from rural Rajshahi, Bangladesh. AB - This study aimed to extend notions of men's role in women's antenatal care (ANC) status in rural Rajshahi, Bangladesh. The analyses were based on response of 480 men aged 15 to 54 years, living with at least 1 child younger than 3 years. Only 27% men accompanied their wives for ANC. Men's perception of actual roles for ANC services was low: 63% approved of women undergoing checkups; 33% discussed their wives' pregnancy with health professionals. Only 18% scored highly on the overall index of knowledge. From multivariate analysis, it was found that the number of men accompanying their wives for ANC was higher among those respondents who were married for the first time in the age-group 25 to 34 years and aged 35 years or more, had their last child at age-group 20 to 24 years or 25 to 34 years, had completed primary or secondary and higher education, and had mass media facilities. PMID- 22426563 TI - Disparities in early childhood caries and its impact on oral health-related quality of life of preschool children. AB - This study aimed to investigate the caries experience and its impact on preschool children's quality of life and the associations between these outcomes and underlying determinants. A survey was conducted on 5- to 6-year-old children (503 in all) in Bangkok who were orally examined and interviewed on their oral health related quality of life (OHRQoL). In addition, behavioral questionnaires were sent to parents. Associations between determinants and oral health outcomes were tested through logistic regression. It was found that 28% of children experienced high-level impacts on quality of life, mostly dental pain (58.3%) and eating difficulties (45.9%). Children of low socioeconomic status were more likely to have a high level of dental caries and subsequent OHRQoL impact. Oral status was related to oral behaviors and OHRQoL. Social disparities in preschool children's OHRQoL were identified. PMID- 22426564 TI - Risk factors for metabolic syndrome in a cohort study in a north China urban middle-aged population. AB - As China undergoes urbanization, lifestyles and disease profiles are changing. In this study, metabolic syndrome (MetS) was discovered in 53.5% and 42.7% of men and women, respectively. In 3 age cohorts (44, 48, and 52 years), prevalence of MetS among women was 33.3%, 41.4%, and 50.8%, respectively (chi(2) = 10.27, P = .006), whereas among men it was 51.5%, 56.3%, and 52.3%, respectively (chi(2) = 0.46, P = .796). The component contributing to the presence of MetS was increased waist circumference, especially among women. MetS among men results from higher rates of elevated triglycerides, blood pressure, and blood glucose when compared with women. Risk factors for MetS included less than 60 minutes of exercise a week (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.4) and rarely consuming milk (OR = 1.7, 95% CI = 1.2-2.3). Abstaining from or occasionally consuming alcohol (OR = 0.7, 95% CI = 0.4-1.1) and having parents with no chronic disease (OR = 0.4, 95% CI = 0.2-0.6) suggest increased protection against MetS. PMID- 22426565 TI - Lifestyle of young Australian adults with asthma. AB - Asthma is a highly prevalent disease that may affect the lifestyle adopted by young adults. This study investigated whether asthma status influences fruit and vegetable consumption, physical activity level, tobacco smoking, and alcohol drinking behavior of young adults in Australia. Information of 2619 participants aged 18 to 29 years was extracted from the 2007-2008 Australian National Health Survey database. The level of physical activity and fruit consumption were found to be similar between young adults with and without asthma. Participants with asthma symptoms in the past 12 months were more likely to achieve the dietary recommendation for vegetable intake, but they tended to smoke tobacco and consume alcohol above safe levels. It may be necessary to develop prevention strategies targeting young adults with asthma that include screening for harmful use of substances. PMID- 22426566 TI - MRI assessment of bone marrow in children with juvenile idiopathic arthritis: intra- and inter-observer variability. AB - BACKGROUND: Bone marrow oedema (BMO) is included in MRI-based scoring systems of disease activity in adults with rheumatoid arthritis. Similar systems in juvenile idiopathic arthritis (JIA) are lacking. OBJECTIVE: To assess the reproducibility in a multi-centre setting of an MRI BMO scoring system in children with JIA. MATERIALS AND METHODS: Seventy-six wrist MRIs were read twice, independently, by two experienced paediatric radiologists. BMO was defined as ill-defined lesions within the trabecular bone, returning high and low signal on T2- and T1-weighted images respectively, with or without contrast enhancement. BMO extension was scored for each of 14 bones at the wrist from 0 (none) to 3 (extensive). RESULTS: The intra-observer agreement was moderate to excellent, with weighted kappa ranging from 0.85 to 1.0 and 0.49 to 1.0 (readers 1 and 2 respectively), while the inter-observer agreement ranged from 0.41 to 0.79. The intra- and inter observer intraclass correlation coefficients were excellent and satisfactory, respectively. CONCLUSION: The scoring system was reliable and may be used for grading bone marrow abnormality in JIA. The relatively large variability in aggregate scores, particularly between readers, underscores the need for thorough standardisation. PMID- 22426567 TI - Pseudoachondroplasia and the seven Ovitz siblings who survived Auschwitz. AB - This historical report focuses on the first clinical description of pseudoachondroplasia and its radiographic findings. Only half a century ago, pseudoachondroplasia was recognized as a genetic disorder with a distinct but variable phenotype of short stature, normal facial features, and progressive joint problems starting in adolescence. Radiologically, the disease is particularly intriguing because the patients appear normal at birth. The patients develop the typical gait disturbances when they begin to walk. Radiographs show the characteristic anterior tongue-shaped lumbar vertebral body changes that develop after the first year of life. This account presents the most well-known group of individuals affected by pseudoachondroplasia, the Ovitz family, who narrowly escaped death in the concentration camp of Auschwitz in 1944 because of SS physician Dr. Josef Mengele's fascination with dwarfs. It was not until 1995 that the underlying genetic defect in the COMP gene was identified on chromosome 19. PMID- 22426568 TI - Tracheobronchomalacia in children: review of diagnosis and definition. AB - Tracheobronchomalacia is characterised by excessive airway collapsibility due to weakness of airway walls and supporting cartilage. The standard definition requires reduction in cross-sectional area of at least 50% on expiration. However, there is a paucity of information regarding the normal range of central airway collapse among children of varying ages, ethnicities and genders, with and without coexisting pulmonary disease. Consequently, the threshold for pathological collapse is considered somewhat arbitrary. Available methods for assessing the airway dynamically--bronchoscopy, radiography, cine fluoroscopy, bronchography, CT and MR--have issues with reliability, the need for intubation, radiation dose and contrast administration. In addition, there are varying means of eliciting the diagnosis. Forced expiratory manoeuvres have been employed but can exaggerate normal physiological changes. Furthermore, radiographic evidence of tracheal compression does not necessarily translate into physiological or functional significance. Given that the criteria used to make the diagnosis of tracheobronchomalacia are poorly validated, further studies with larger patient samples are required to define the threshold for pathological airway collapse. PMID- 22426569 TI - Demonstration of fourth ventricular choroid plexus on neonatal cranial ultrasonography. AB - The choroid plexus of the fourth ventricle can be identified on neonatal cranial US via the mastoid fontanelle, particularly when transducers of high frequency are used. Its presence as a normal, echogenic structure might not be appreciated by all sonographers. It should not be mistaken for vermian hemorrhage or clotted blood within the fourth ventricle or cisterna magna. PMID- 22426570 TI - Stable transfection and continuous expression of heterologous genes in Entamoeba invadens. AB - Amoebiasis is spread by the ingestion of dormant Entamoeba histolytica cysts. Intervention of encystation could break the transmission cycle, thereby reducing disease burden. The model system used to study trophozoite to cyst differentiation is Entamoeba invadens. Here we describe an electroporation-based method for stable transfection of E. invadens with a plasmid pEiNEO-LUC containing the neomycin phosphotransferase gene under the control of E. invadens ribosomal protein gene S10 promoter. The plasmid also contains luciferase reporter gene expressed from the promoter of ribosomal protein gene L3. After electroporation, cells receiving the plasmid were selected by growth in 10MUgml( 1) G418 and stable lines were obtained in four to five weeks. The plasmid was replicated episomally to ~10 copies per haploid genome. In the absence of drug selection 50% of the plasmid copies were lost in 9-10 days. In cells growing under drug selection the reporter gene was continuously expressed throughout the differentiation process from trophozoite to cyst and back, making this system suitable for analysis of genes involved in differentiation. PMID- 22426571 TI - Autophagy protein 16-mediated autophagy is required for the encystation of Acanthamoeba castellanii. AB - Autophagy, an evolutionarily conserved protein degradation pathway in eukaryotes, plays essential roles during starvation and cellular differentiation by eliminating unwanted and/or unnecessary cell material including organelles. Autophagy protein 16 (Atg16) is an essential component of the autophagic machinery. The present study identified and characterized an Atg16 homologue (AcAtg16) in Acanthamoeba, an opportunistic pathogen responsible for several distinct diseases in humans. AcAtg16 was highly expressed during encystation and was found to be associated with small or large vesicular structures that partially colocalized with autophagolysosomes. Small interfering RNA against AcAtg16 inhibited autophagosome formation and reduced the encystation efficiency of Acanthamoeba. Moreover, most mitochondria remained undigested in these knockdown cells. Taken together, these results indicate that AcAtg16 is involved in autophagosome formation and plays an essential role in the encystation of Acanthamoeba. PMID- 22426572 TI - IL-6 induction of hepatocyte proliferation through the Tmub1-regulated gene pathway. AB - The expression of transmembrane and ubiquitin-like domain containing 1 (Tmub1) is upregulated during liver regeneration, however, the function and underlying molecular mechanisms responsible for Tmub1 action remain to be determined. This study utilized BRL-3A rat liver cells for Tmub1 shRNA lentivirus infection and IL 6 stimulation. Semi-quantitative RT-PCR and western blot analysis were used to detect mRNA and protein expression levels, respectively. A [3H]thymidine incorporation assay was performed to assess changes in cell proliferation rates. Laser scanning confocal microscopy and immunoprecipitation-western blotting were used to assess the interaction between Tmub1 and calcium-modulating cyclophilin ligand (CAML) protein. The effect of Tmub1 on calcium ion influx into BRL-3A cells was measured by inverted fluorescence microscopy. The data showed that IL-6 treatment induced proliferation of rat hepatocytes and expression of Tmub1 mRNA and protein, while Tmub1 shRNA knocked down Tmub1 expression at both the mRNA and protein levels. Furthermore, compared to the negative control, Tmub1 shRNA infected BRL-3A cells were highly proliferative with or without IL-6 stimulation. Tmub1 is colocalized with CAML in the hepatocellular cytoplasm, whereas knockdown of Tmub1 expression upregulated expression of CAML protein. Influx of Ca2+ into rat liver cells was also affected after Tmub1 knockdown. The data from the current study demonstrate that Tmub1 plays a negative role in IL-6-induced hepatocyte proliferation, and indicate that the interaction between Tmub1 and CAML may mediate the function of Tmub1 in hepatocytes. PMID- 22426573 TI - Emerging disease-modifying therapies in multiple sclerosis. AB - OPINION STATEMENT: The past two decades have seen tremendous expansion in therapeutic options for multiple sclerosis (MS). While the growing armamentarium of therapies provides physicians and patients an array of available options, it also brings in its wake the challenging responsibility of choosing the optimal therapy for an individual patient. In a newly diagnosed patient with relapsing disease, the current practice is to start one of the interferons (interferon beta) or glatiramer acetate. With increasing experience and if there are no new safety concerns, use of fingolimod as a first-line agent in relapsing-remitting MS could expand. BG-12 appears to have a safety and efficacy profile that would make it a first-line agent, while tolerability would need to be considered. Teriflunomide is another oral agent that is under review by the US Food and Drug Administration and, apart from the pregnancy concerns, seems a potential first line choice as well. For patients with high disease activity at onset or those refractory to current first-line agents, natalizumab and fingolimod are the two options considered most often at present. With the potential availability of alemtuzumab in the near future, that will provide an additional option considered highly efficacious. Its efficacy would have to be weighed carefully against its safety profile. Advances in genetics and biomarkers may allow the development of personalized medicine, and thus, the determination of the "best therapy" for an individual patient. Risk stratification strategies such as serum JC virus antibody status and pre-determination an individual's risk of autoimmune disease on alemtuzumab may facilitate early initiation of optimal therapies. Treatments for MS have come a long way and the future looks even more promising and will provide us with better and greater options in treating patients, meaning we can hope to see even less of an impact of the disease in the lives of patients with MS. PMID- 22426574 TI - Posterior ankle and subtalar arthroscopy: indications, technique, and results. AB - Over the decades, arthroscopy has grown in popularity for the treatment of many foot and ankle pathologies. While anterior ankle arthroscopy is a widely accepted technique, posterior ankle/subtalar arthroscopy is still a relatively new procedure. The goal of this review is to outline the indications, surgical techniques, and results of posterior ankle/subtalar arthroscopy. The main indications include: 1) osteochondral lesions (of subtalar and posterior ankle joint); 2) posterior soft tissue or bony impingement; 3) os trigonum syndrome; 4) posterior loose bodies; 5) flexor hallucis longus (FHL) tenosynovitis; 6) posterior synovitis; 7) subtalar (or ankle) joint arthritis; 8) posterior tibial, talar, or calcaneal fractures (for arthroscopic reduction and internal fixation). Although posterior ankle/subtalar arthroscopy has shown to be safe and effective in the treatment of many of the above mentioned conditions, thorough knowledge of the anatomy, correct indications, and a precise surgical technique are essential to produce good outcomes. PMID- 22426575 TI - Effect of different stimulus configurations on the visual evoked potential (VEP). AB - The purpose of this study was to assess changes in the response profile of the pattern visual evoked potential (VEP) using three stimulus configurations simulating visual-field scotomas: central circular and central blank fields increasing incrementally in diameter from 1 degrees to 15 degrees , hemi-field, and quadrant patterns. Five visually normal adult subjects (ages 22-68 years) were tested binocularly at 1 m for each stimulus configuration on 5 separate days. A checkerboard test pattern (64 * 64 black-and-white checks, 85% contrast, 64 cd/m(2) luminance, 20 s of stimulus duration, 2-Hz temporal frequency) was used. The group mean VEP amplitude increased in a linear manner with increase in the central circular diameter (y = 0.805x + 2.00; r = 0.986) and decrease in central blank field diameter (y = -0.769x + 16.22; r = 0.987). There was no significant change in latency in nearly all cases. The group mean coefficient of variability results indicated that the VEP amplitude was repeatable for the different stimulus configurations. The finding of VEP response linearity for the circular stimulus fields, and repeatability for all stimulus configurations, suggests that the clinician may be able to use the VEP technique with the suggested test patterns as a rapid and simple tool for objective assessment for several types of visual-field defects for a range of abnormal visual conditions and special populations. PMID- 22426576 TI - Electroretinographic (ERG) responses in pediatric patients using vigabatrin. AB - The antiepileptic drug vigabatrin is known to cause retinal and visual dysfunction, particularly visual field defects, in some patients. Electroretinography (ERG) is used in an attempt to identify adverse effects of vigabatrin (VGB) in patients who are not candidates for conventional perimetry. We report data from 114 pediatric patients taking VGB referred for clinical evaluation; median age at test was 22.9 (2.4 to 266.1) months, and median duration of VGB use was 9.7 (0.3 to 140.7) months. Twenty-seven of them were tested longitudinally (3 to 12 ERG tests). ERG responses to full-field stimuli were recorded in scotopic and photopic conditions, and results were compared to responses from healthy control subjects. We found that abnormalities of photoreceptor and post-receptor ERG responses are frequent in these young patients. The most frequently abnormal scotopic parameter was post-receptor sensitivity, log sigma, derived from the b-wave stimulus-response function; the most frequently abnormal photopic parameter was the implicit time of the OFF response (d-wave) to a long (150 ms) flash. Abnormal 30-Hz flicker response amplitude, previously reported to be a predictor of visual field loss, occurred infrequently. For the group as a whole, none of the ERG parameters changed significantly with increasing duration of VGB use. Four of the 27 patients tested longitudinally showed systematic worsening of log sigma with duration of VGB use. In a subset of patients who underwent perimetry (N = 39), there was no significant association of any ERG parameter with visual field defects. We cannot determine whether the ERG abnormalities we found were due solely to the effects of VGB. We caution against over-reliance on the ERG to monitor pediatric patients for VGB toxicity and recommend further development of a reliable test of peripheral vision to supplant ERG testing. PMID- 22426577 TI - Effect of ambient temperature on endurance performance while wearing cross country skiing clothing. AB - This study assessed the effects of exposure to cold (-14 and -9 degrees C), cool (-4 and 1 degrees C) and moderate warm (10 and 20 degrees C) environments on aerobic endurance performance-related variables: maximal oxygen consumption (VO(2max)), running time to exhaustion (TTE), running economy and running speed at lactate threshold (LT). Nine male endurance athletes wearing cross-country ski racing suit performed a standard running test at six ambient temperatures in a climatic chamber with a wind speed of 5 m s(-1). The exercise protocol consisted of a 10-min warm-up period followed by four submaximal periods of 5 min at increasing intensities between 67 and 91 % of VO(2max) and finally a maximal test to exhaustion. During the time course mean skin temperature decreased significantly with reduced ambient temperatures whereas T (re) increased during all conditions. T (re) was lower at -14 degrees C than at -9 and 20 degrees C. Running economy was significantly reduced in warm compared to cool environments and was also reduced at 20 degrees C compared to -9 degrees C. Running speed at LT was significantly higher at -4 degrees C than at -9, 10 and 20 degrees C. TTE was significantly longer at -4 and 1 degrees C than at -14, 10 and 20 degrees C. No significant differences in VO(2max) were found between the various ambient conditions. The optimal aerobic endurance performance wearing a cross country ski racing suit was found to be -4 and 1 degrees C, while performance was reduced under moderate warm (10 and 20 degrees C) and cold (-14 and -9 degrees C) ambient conditions. PMID- 22426578 TI - The determinants of performance in master swimmers: a cross-sectional study on the age-related changes in propelling efficiency, hydrodynamic position and energy cost of front crawl. AB - The decrease in swimming performance (v (max)) that occurs with age is a not only consequence of the physiological decrease in maximal metabolic power ([Formula: see text]) but can also be expected to depend on an increase in the energy cost of swimming (C) [Formula: see text] In turn, for a given speed and stroke C = W (d) / (eta(P)eta(o)) where W (d) is hydrodynamic resistance, eta(P) is propelling efficiency and eta(o) is overall efficiency. The aim of this study was to measure C in 47 male masters (31-85 years old) swimming the front crawl at sub-maximal, aerobic, speeds. During the experiments propelling efficiency and projected frontal area (A (eff), an index of W (d)) were also determined by kinematic analysis. "Elder" masters (60-80 years) swam at a significantly slower pace (0.65 vs. 0.91 m s(-1)), with a lower eta(P) (0.23 vs. 0.31) and a larger A (eff) (0.39 vs. 0.23 m(2)) than "younger" masters (30-60 years). No significant differences in C (1.45 kJ m(-1), on the average) were observed as a function of age or speed, but C values were significantly higher than those assessed in young elite swimmers at the very same speeds; the difference increasing with age with a rate of 0.75 % per year. With the due considerations (in this study the observed changes in eta(P), A (eff) and C can be either attributed to changes in speed or age) these data confirm the hypothesis that an increase in C contributes to the decrease in swimming performance that occurs with age. PMID- 22426579 TI - Limited end-user knowledge of methotrexate despite patient education: an assessment of rheumatologic preventive practice and effectiveness. AB - BACKGROUND: Methotrexate (MTX) is a first-line disease-modifying agent and anchor drug for biologic therapy used in rheumatoid arthritis and other inflammatory rheumatic disorders. Adverse effects are a common cause of drug discontinuation and include preventable serious incidents that may result in patient harm or death. OBJECTIVES: The objective of this study was to audit adherence by health professionals to national and international guidelines for patient education and risk reduction in patients prescribed MTX for inflammatory rheumatic diseases. METHODS: A combination of interviews, case record reviews, and self-administered patient knowledge questionnaires with individual patient feedback was used. The setting was the rheumatology outpatient department of a district general hospital. RESULTS: Fifty-one patients participated in the audit. The mean age was 58.6 (SD, 13.1) years and median duration of disease was 3.7 years (interquartile range, 1.7-7.6 years). Nurse-led patient education was documented at baseline for 94.1% of participants. Despite this, only 11.8% of participants recognized the potentially lethal drug-drug interaction with trimethoprim/Septrin (co trimoxazole), and less than 60.8% recognized possible major adverse effects related to MTX. Although lifestyle implications relating to alcohol consumption and pregnancy/breast-feeding were recognized by the majority, only 52.9% of males were aware of recommendations in relation to conception. Univariable and multivariable analyses identified male sex, not speaking English as a first language, and a longer duration of therapy as predictors of lower levels of patient knowledge. CONCLUSIONS: Despite consistent baseline patient education, end-user knowledge and awareness pertinent to MTX safety are limited. Good quality written information in the most appropriate language, patient feedback on educational programs, follow-up testing of patient knowledge, and targeted reeducation are recommended to address individual deficiencies in core knowledge. PMID- 22426580 TI - Living with gout in New Zealand: an exploratory study into people's knowledge about the disease and its treatment. AB - BACKGROUND: In New Zealand, gout disproportionately affects Maori and Pacific people who also experience symptoms at an earlier age. Gout occurs predominantly in men and is associated with cardiovascular disease, diabetes, and renal disease. The impact on daily social activities, family, and work is enormous, and many people remain inadequately treated. OBJECTIVES: The objectives of this study were to explore the knowledge and perceptions of people with gout toward the disease and to determine the impact gout has on lifestyle including possible barriers to treatment. METHODS: Sixty people with gout from the Auckland and Waikato regions of New Zealand were invited to participate in 30-minute semistructured interviews. The data were analyzed using a general inductive thematic approach. RESULTS: Although 85% of participants were aware of dietary triggers of gout, these were not always avoided. Less than 50% knew something about how their medicines worked, and only 33% knew which medicines to use both acutely and chronically. The negative impact of gout episodes was noted through the number participants unable to work or participate in family activities. Healthcare professionals were not always the main source of information, which is an area that could be developed to improve knowledge about gout. CONCLUSIONS: There were substantial gaps in the knowledge about gout and its causes and management. All healthcare providers could help identify patients with suboptimal knowledge and improve the management of gout. PMID- 22426581 TI - Treatment of hemophagocytic lymphohistiocytosis with alemtuzumab in systemic lupus erythematosus. AB - Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by cytokine dysregulation and uncontrolled activation of T lymphocytes and macrophages. It is categorized as primary when associated with specific genetic mutations or secondary when associated with infections, malignancies, or autoimmune disorders. Clinical features of HLH include unexplained fever, hepatosplenomegaly, pancytopenia, and severe hyperferritinemia. Treatment of primary HLH has become standardized based on the HLH-2004 protocol using cyclosporine, etoposide, and dexamethasone with or without intrathecal methotrexate followed by hematopoietic stem cell transplantation. Treatment of secondary HLH is directed at control of the underlying condition. If unsuccessful, cytotoxic agents such as those in HLH-2004, steroids, intravenous gamma-globulin, or targeted immune therapy have been used. Immunotherapy targeting CD52 expressed on immune effector cells of HLH is a rational therapeutic approach in patients too ill for traditional cytotoxic chemotherapy. We describe the successful use of alemtuzumab to treat HLH due to systemic lupus erythematosus. PMID- 22426582 TI - Long-term follow-up of an HIV-infected patient with reactive arthritis treated with infliximab. PMID- 22426583 TI - Innovative virtual interactive teaching tool "Arthur" for clinical diagnosis of musculoskeletal diseases. PMID- 22426584 TI - Are hospitalized patients with fragile fractures managed properly in relation to underlying osteoporosis? AB - BACKGROUND: Osteoporotic fractures are an important reason of morbidity and mortality in the elderly population and impose huge economic burden on health services. There have been major advances in the treatment of osteoporosis, and many steps can be taken to prevent or even reduce the risk of fractures. Orthopedic surgeons manage most of these fractures and are often the only clinician seen by the patient. METHODS: We performed a survey of 515 patients with osteoporotic fractures who were admitted to 3 level I trauma hospitals in Tehran, Iran. Patients were evaluated with a questionnaire to determine whether orthopedic surgeons informed their patients about aspects of osteoporosis other than their fracture, and if appropriate, evaluation and treatment for osteoporosis were initiated. The questionnaires were completed in 2 years (mean) from their admissions. RESULTS: Only 10.5% patients reported that they had been told by an orthopedic surgeon that they had osteoporosis. Only 3.3% had bone mineral density appointments. Few had received treatment for osteoporosis-only 8.2% of patients had been treated with calcium and vitamin D, and 3.5% with a bisphosphonate. DISCUSSION: We believe that the majority of the orthopedic surgeons lacked sufficient training in osteoporosis; therefore, engaging other providers in their healthcare system can create a pathway for the assessment and treatment of osteoporosis, to guarantee the patient the best care. PMID- 22426585 TI - Rheumatologic manifestations in myelodysplastic syndrome. PMID- 22426586 TI - Gouty arthritis and panniculitis: extensive involvement of the dermis and severe joint damage. PMID- 22426587 TI - Identification of oral bacterial DNA in synovial fluid of patients with arthritis with native and failed prosthetic joints. AB - OBJECTIVE: We examined the presence of bacterial DNA in synovial fluids of native or clinically aseptically failed prosthetic joints from patients having periodontal disease and arthritis to determine whether there is bacterial spread from the oral cavity to the joints. METHODS: A total of 36 subjects were enrolled in the study. Among these, 11 were diagnosed with rheumatoid arthritis (RA) and 25 were diagnosed with osteoarthritis (OA). Eight patients with OA and 1 patient with RA had failed prostheses. Synovial fluid was aspirated from the affected hip or knee joint. Pooled subgingival plaque samples were collected, followed by clinical periodontal examination. Bacterial DNA was extracted from the collected synovial fluid and dental plaque samples were followed by polymerase chain reactions and DNA sequence analysis of the 16S-23S rRNA genes. RESULTS: Of the 36 patients, bacterial DNA was detected in the synovial fluid samples from 5 patients (13.9%): 2 with RA (1 native and 1 failed prosthetic joints) and 3 with OA (1 native and 2 failed prosthetic joints). Of these 5 patients, 2 were diagnosed with periodontitis and had identical bacterial clones (Fusobacterium nucleatum and Serratia proteamaculans, respectively) detected in both the synovial fluid and the dental plaque samples. Fusobacterium nucleatum was the most prevalent, detected in 4 of the 5 positive samples. No cultures were done and no patients were treated with antibiotics or developed clinical infection. CONCLUSIONS: The present findings of bacterial DNA in the synovial fluid suggest the possibility of organisms translocating from the periodontal tissue to the synovium. We suggest that patients with arthritis or failed prosthetic joints be examined for the presence of periodontal diseases and be treated accordingly. PMID- 22426588 TI - Idiopathic mediastinal fibrosis presenting with antiphospholipid antibody syndrome and manifestations suggestive of connective tissue disease. PMID- 22426589 TI - A highly contagious psoriasiform eruption on the scalp of a patient with systemic lupus erythematosus. PMID- 22426590 TI - False-negative dual-energy computed tomography in a patient with acute gout. AB - Gout is a painful inflammatory arthropathy caused by crystallization of monosodium urate within the joints. We present the case of a patient with primary gout who had positive results of joint aspiration and synovial biopsy for monosodium urate crystals in the third metacarpophalangeal joint but false negative results of dual-energy computed tomography. PMID- 22426591 TI - Perioperative chemotherapy and liver resection for hepatic metastases of colorectal cancer. AB - Surgical resection has played a major role in the treatment for colorectal liver metastases. The safety and efficacy of surgery for liver metastasis are obvious, although there are some differences between the western countries and Japan concerning the surgical indication, procedures, timing of chemotherapies in a perioperative period, and treatment of a primary disease. In future, long-term outcomes after surgical resection for colorectal liver metastases would be expected to be prolonged by combination of surgery and chemotherapies. PMID- 22426592 TI - Proposal for a morphological classification of intraductal papillary neoplasm of the bile duct (IPN-B). AB - PURPOSE: We propose a morphological classification of intraductal papillary neoplasm of the bile duct (IPN-B). METHODS: A retrospective analysis of 16 patients with IPN-B who had undergone surgical resection was conducted. These 16 cases were classified into three types based on the primary lesion's anatomical location: branch duct type (6 cases), main duct type (5 cases) and mixed type (5 cases). In this paper we have analyzed the characteristics of IPN-B according to our new classification. RESULTS: All branch duct type IPN-B was located in the left lobe and 5 of them were resected by left hepatectomy without extrahepatic bile duct resection (EBDR). On the other hand, all patients with main duct and mixed type IPN-B underwent EBDR in addition to hepatectomy or pancreatoduodenectomy. Microscopically, 2 of 6 patients with branch duct type IPN B had no malignant component and, in the remaining 4 patients, cancer invasion was restricted to within the ductal wall. There were no cases of branch duct type IPN-B with lymph node metastasis and superficial intraductal tumor spread. In contrast, all patients with main duct and mixed duct type IPN-B had the malignant component. In all cases, lymph node metastasis was not observed, but superficial intraductal tumor spread was frequently found in extrahepatic bile duct lesions: 3 of main duct type and 3 of mixed type. Four patients with superficial intraductal spread had non-curative resection due to a cancer-positive ductal margin. Most patients with IPN-B obtained a good prognosis, but two patients with a cancer-positive ductal margin developed local recurrence. CONCLUSIONS: Our classification vividly reflects clinical and pathological characteristics of IPN B and is useful to determine appropriate surgical strategy. PMID- 22426593 TI - Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine. AB - BACKGROUND: Gemcitabine is a key drug for the treatment of pancreatic cancer. Human equilibrative nucleoside transporter 1 (hENT1) is a major transporter responsible for gemcitabine uptake into cells. This study was conducted to elucidate the association between expression level of hENT1 and outcome for pancreatic cancer patients treated with neoadjuvant therapy including gemcitabine. METHODS: Sixty-three patients who underwent neoadjuvant chemoradiation followed by curative surgery for pancreatic ductal adenocarcinomas were included. Immunohistochemistry was performed using resected specimens and the staining intensity of hENT1 was scored as having no staining, low staining, or high staining; the former two were defined as negative expression of hENT1. The association between expression level of hENT1 and overall survival was evaluated by Cox proportional regression model. RESULTS: Expression level of hENT1 was evaluated as positive in 22 (35%) patients, and as negative in 41 (65%) patients. Univariate analysis showed that regional lymph node metastasis, vascular permeation, and perineural invasion are prognostic factors; however, expression level of hENT1 did not reach statistical significance. Multivariate analysis showed only vascular permeation as a prognostic factor. CONCLUSIONS: Expression level of hENT1 was not associated with prognosis for pancreatic cancer patients who were treated with neoadjuvant chemoradiation including gemcitabine. PMID- 22426594 TI - Molecular cloning and identification of mouse epididymis-specific gene mHong1, the homologue of rat HongrES1. AB - Previous studies have shown that rat epididymis-specific gene HongrES1 plays important roles in sperm capacitation and fertility. In this study, we cloned the mouse homologue gene by sequence alignment and RT-PCR methods and designated it as mHong1. The mHong1 gene is located on chromosome 12p14, spanning five exons. The cDNA sequence consists of 1257 nucleotides and encodes a 419 amino-acid protein with a predicted N-terminal signal peptide of 20 amino acids. The mHong1 mRNA shows similarity with HongrES1 in the expression patterns: (i) specific expression in epididymal tissue, especially in the cauda region; and (ii) androgen-dependence but testicular fluid factor independence. Its protein product shows 71% similarity with HongrES1 and contains a classical serpin domain as does HongrES1. A polyclonal antibody against mHong1 with high specificity and sensitivity was raised. Like HongrES1, the mHong1 protein shows a checker-board expression pattern in the epididymal epithelium and is secreted into the epididymal lumen. The mHong1 protein shows higher glycosylation than HongrES1. Although both of them are deposited onto the sperm head surface, mHong1 is localized to the equatorial segment, which is different from that of HongrES1. The mHong1 protein can be removed from the sperm membrane by high ionic strength and therefore can be classed as an extrinsic membrane protein. Collectively, we conclude that mHong1 is the homologue of HongrES1 and the present work paves the way for establishing animal models to elucidate the precise functions of HongrES1 and mHong1. PMID- 22426595 TI - Penile reconstruction. AB - During the most recent years, a variety of new techniques of penile reconstruction have been described in the literature. This paper focuses on the most recent advances in male genital reconstruction after trauma, excision of benign and malignant disease, in gender reassignment surgery and aphallia with emphasis on surgical technique, cosmetic and functional outcome. PMID- 22426596 TI - Primary central nervous system anaplastic large-cell lymphoma mimicking lymphomatosis cerebri. AB - Primary central nervous system lymphoma (PCNSL) is usually diffuse large B-cell lymphoma. Anaplastic large-cell lymphoma (ALCL) rarely occurs in the central nervous system. PCNSL always presents as single or multiple nodular contrast enhancing mass lesions within T2-hyperintense areas on magnetic resonance imaging (MRI). Infrequently, diffuse infiltrating change with little contrast enhancement called lymphomatosis cerebri can be seen in PCNSL. In this report, we describe a 75-year-old immunocompetent man who had progressive dementia. On MRI, diffuse white matter lesions with little contrast enhancement were observed to gradually progress, which was clinically consistent with his worsening condition. A biopsy specimen revealed non-destructive, diffusely infiltrating, anaplastic large CD30 positive lymphoma, indicating a diagnosis of ALCL. After the biopsy, he was treated by whole brain irradiation (total 46 Gy) and focal boost irradiation (total 14 Gy). However, his performance status worsened and there was no symptom improvement. The patient died 8 months after symptom onset. The clinical course, diagnostic workup, pathologic correlates, and treatment outcomes are described herein. PMID- 22426597 TI - Recent trauma is associated with antiretroviral failure and HIV transmission risk behavior among HIV-positive women and female-identified transgenders. AB - Trauma and posttraumatic stress disorder disproportionally affect HIV-positive women. Studies increasingly demonstrate that both conditions may predict poor HIV related health outcomes and transmission-risk behaviors. This study analyzed data from a prevention-with-positives program to understand if socio-economic, behavioral, and health-related factors are associated with antiretroviral failure and HIV transmission-risk behaviors among 113 HIV-positive biological and transgender women. An affirmative answer to a simple screening question for recent trauma was significantly associated with both outcomes. Compared to participants without recent trauma, participants reporting recent trauma had over four-times the odds of antiretroviral failure (AOR 4.3; 95% CI 1.1-16.6; p = 0.04), and over three-times the odds of reporting sex with an HIV-negative or unknown serostatus partner (AOR 3.9; 95% CI 1.3-11.9; p = 0.02) and <100% condom use with these partners (AOR 4.5; 95% CI 1.5-13.3; p = 0.007). Screening for recent trauma in HIV-positive biological and transgender women identifies patients at high risk for poor health outcomes and HIV transmission-risk behavior. PMID- 22426598 TI - Transanal endorectal pull-through for Hirschsprung's disease using long cuff dissection and short V-shaped partially resected cuff anastomosis: early and late outcomes. AB - BACKGROUND: Transanal endorectal pull-through was described by De la Torre Mondragon's technique. In the original transanal pull-through procedure, a long rectal muscular cuff was dissected and left for anocolic anastomosis, which would sometimes lead to postoperative obstructive symptoms and enterocolitis. While a modified short mucosal dissection may increase the risk of injury to pelvic and perirectal nerves and other structures when dissected on the outside of the rectum deep in the pelvis. We report early and late results of the modified transanal procedure for Hirschsprung's disease (HD) over 8 years. METHODS: The clinical course of all children with aganglionic rectum or sigmoid colon receiving the modified transanal pull-through between May 2003 and April 2011 were reviewed. The main modifications were rectal mucosa dissection with a long cuff, coloanal anastomosis with a short cuff and a V-shaped partial resection in the posterior wall of the muscular cuff. Children with preliminary stoma or total colonic disease were excluded. RESULTS: Short- and long-term follow-up was obtained in 137 patients with HD operated upon by the same surgeon. The aganglionic segment was located in the rectum or sigmoid colon in all patients. The mean age at surgery was 165 +/- 74 days. The mean operating time was 108 +/- 38 min. Mean intra-operative blood loss was estimated to be 15 +/- 10 ml. No patient required a blood transfusion. Mean postoperative hospital stay was 7 +/- 2 days. Early postoperative complications included perianal excoriation in 38 patients (27.7 %), enterocolitis in two patients (1.4 %), and anastomotic leak in two patients (1.4 %). Late postoperative complications included perianal excoriation in 16 patients (11.7 %), anal stricture in two patients (1.4 %), constipation in four patients (2.8 %), enterocolitis in 10 patients (7.3 %), and soiling problems in six patients (4.4 %). Mean follow-up was 56 months (6 months 9 years). In patients older than 4 years, 85.4 % of them had excellent/good bowel function, 9.4 % had fair bowel function, and 5.2 % of patients had bad bowel function. CONCLUSION: Transanal endorectal pull-through with a long cuff dissection and a short V-shaped resected cuff anastomosis is a safe and effective procedure for HD. It reduced incidence of anastomotic stricture and constipation without an increased soiling incidence. PMID- 22426599 TI - Perianal rhabdomyosarcoma presenting 21 months after hamartoma excision. AB - Perianal rhabdomyosarcoma is a rare type of tumor with a relatively poor prognosis. We present the case of a patient who presented with a cutaneous perianal hamartoma at the age of 6 weeks. 21 months latter a recurrent mass at the excision site proved to be an embryonal rhabdomyosarcoma involving the anal sphincter. A pathologic review of the two specimens confirmed their relatedness. This report highlights the need to maintain a high level of suspicion in cases of recurrence following excision of a benign lesion. PMID- 22426601 TI - Subcutaneous chronic implantable defibrillation systems in humans. AB - The recent introduction of subcutaneous implantable cardioverter defibrillator (S ICD) has raised attention about the potential of this technology for clinical use in daily clinical practice. We review the methods and results of the four studies conducted in humans for approval of this innovative technology for daily practice. Two studies using a temporary S-ICD system (acute human studies) were conducted to search for an appropriate lead configuration and energy requirements. For this purpose, 4 S-ICD configurations were tested in 78 patients at the time of transvenous (TV)-ICD implantation. The optimal configuration was tested in 49 more patients to comparatively assess the subcutaneous defibrillation threshold (S-DFT) versus the standard TV-ICD. Long-term implants were evaluated in 55 patients using an implanted system (chronic human study). The acute humans studies led to an optimal S-ICD configuration comprising a parasternal electrode and left anterolateral thoracic pulse generator. Both configurations successfully terminated 98% of induced ventricular fibrillation (VF), but significantly higher energy levels were required with S-ICD than with TV-ICD systems (36.6 +/- 19.8 J vs. 11.1 +/- 8.5 J). In the chronic study, all 137 VF episodes induced at time of implant were detected with a 98% conversion rate. Two pocket infections and four lead revisions were required during 10 +/- 1 months of follow-up. During this period, survival was 98%, and 12 spontaneous ventricular tachyarrhythmias were detected and treated by the device. These data show that the S-ICD systems here consistently detected and converted VF induced at time of implant as well as sustained ventricular tachyarrhythmias occurring during follow-up (248). PMID- 22426602 TI - The accumulation of DNA demethylation in Sat alpha in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals. AB - Helicobacter pylori (HP) infection is widely recognized as a risk factor for gastric cancer, but only a minority of infected individuals develop gastric cancer. The aim of this study was to determine whether DNA demethylation in non cancerous gastric mucosa (NGM) significantly enhances susceptibility to gastric cancer. A total of 165 healthy volunteers, including 83 HP-positive and 82 negative individuals, as well as 83 patients with single and 18 with synchronous double gastric cancer (GC) were enrolled in this study. The relative demethylation levels (RDLs) of repetitive sequences, including Alu, LINE-1 and Sat alpha, were quantified by real-time methylation-specific polymerase chain reaction. The Alu RDL did not exhibit any differences within each respective group, whereas LINE-1 RDL was significantly elevated in cancer tissues compared with the NGM in the other groups (P<0.001). Our results indicated that a gradual increase in Sat alpha RDL correlated with HP infection and cancer development. Sat alpha RDL was significantly elevated in the NGM in HP-positive compared with HP-negative (P<0.001), and significantly elevated in cancer tissues (P<0.001). Although the Sat alpha RDL of the NGM in the total population increased in an age dependent manner, it was significantly increased in a fraction of younger GC patients (<45 years) compared with all of the others (45 years or older, P=0.0391). In addition, double GC exhibited a significantly higher Sat alpha RDL in the NGM compared with single GC (P=0.0014). In these two fractions, Sat alpha RDL in the NGM exhibited an inverse correlation with age. In conclusion, the present study demonstrated that the accumulation of DNA demethylation in Sat alpha RDL in the NGM with HP infection potentially renders susceptibility to gastric cancer in a fraction of GC patients younger than 45 years or in patients with multiple cancers. PMID- 22426603 TI - Emodin inhibits tumor necrosis factor-alpha-induced migration and inflammatory responses in rat aortic smooth muscle cells. AB - Emodin, a naturally occurring anthraquinone derivative in oriental herbal medicine, has been shown to exert a variety of pharmacological activities. The goal of this study was to determine the effects of emodin on the modulation of cell proliferation, migration, inflammatory responses, and matrix metalloproteinase (MMP)-2 and MMP-9 expression in tumor necrosis factor (TNF) alpha-induced rat aortic smooth muscle cells (RASMCs). Cell proliferation and migration were measured using the MTT assay and the transwell chamber assay, respectively. Quantitative real-time PCR and western blot analysis were used to detect MMP expression. Gel shift was used for analysis of nuclear factor (NF) kappaB activation. In addition, the expression of several inflammatory genes was also analyzed. Treatment of RASMCs with emodin significantly and dose-dependently attenuated TNF-alpha-induced proliferation, migration, mRNA and protein expression of MMP-2 and MMP-9, and NF-kappaB activation. Furthermore, emodin significantly inhibited TNF-alpha-evoked inflammatory responses, as demonstrated by the reduction in the expression of inflammatory genes. These results suggest that emodin inhibits TNF-alpha-induced proliferation, migration, MMP-2 and MMP-9 expression as well as inflammatory responses in cultured RASMCs, supporting the notion that emodin may have potential application in clinical atherosclerosis disease. PMID- 22426604 TI - Public health initiatives: science versus politics. What will the outcome be? PMID- 22426606 TI - Evaluation of thermography as a screening and diagnostic tool for breast cancer. PMID- 22426605 TI - Interhospital and emergency transfers in New Zealand. PMID- 22426607 TI - Paediatric spina bifida inpatient treatment at Wellington Regional Hospital: a cost analysis of sequential patients. AB - AIMS: To sample and analyse the number, type, length of stay and costs of admissions for children with spina bifida, and to review operations requiring general anaesthesia and radiological investigations of patients undergoing surgical management for spina bifida. METHODS: Six sequential adolescents with spina bifida managed through the paediatric surgical services at Wellington Regional Hospital (Wellington, New Zealand) from November 2008 to November 2009 were sampled for retrospective analysis. One neonatal case was also chosen. All hard copy notes, radiology packets, electronic notes and radiological studies were requested and reviewed for these seven patients covering all lifetime admissions. Inpatient length of stay and operation costs were also analysed. RESULTS: Six adolescent patients(10-21 years) had undergone a total of 124 operations requiring general anaesthesia--average 20.67 (19-28). There were 125 admissions in total for this group--average 20.83 (14-34) with an average length of stay of 8.53 days per admission and an average cumulative length of stay of 177.67 days. As a group, the adolescents had spent 1066 days as inpatients. Adolescents received an average of 75.33 (36-164) radiological procedures, including an average of 7.5 CT scans (4-13). The neonate had 10 operations, four admissions, 67 radiological investigations and a total length of stay of 194 days. The average cumulative cost per adolescent was NZ$944,000 ($472,000 $1,202,000) with a total cost of NZ$5,664,000. The cost for the neonate was NZ$678,340. CONCLUSIONS: This study found inpatient costs for paediatric spina bifida patients were significantly higher than the only previous estimate carried out in New Zealand. This study also shows the burden on patients and their families/whanau in the high numbers of admissions, major operations, long periods spent as inpatients and the high number of radiological investigations. PMID- 22426608 TI - Air transport by the Wellington Flight Service: a descriptive analysis of interhospital transfers over a 5-year period in the Wellington region of New Zealand. AB - AIM: To describe and characterise the interhospital transport workload of a New Zealand based flight service over a 5-year period. METHOD: Wellington Flight Service database records from 1 November 2005 to 31 October 2010 were reviewed. Details of mission purpose, timings, transport type, severity of illness, clinical service requesting the transfer, and medical crew in attendance, were examined. RESULTS: The Flight Service completed 4046 transport missions over 5 years. The median mission duration was 4.5 hours, but 9% of missions took 8 hours or more. Fixed wing aircraft were used for most transports (70%) with the trend for helicopter use decreasing steadily (from 23% down to 13%). High proportions of transfers were requested by cardiac services (25%), neurosurgery (14%) and ICU (9%), and 72% of those transported were critically (Category A) or seriously ill (Category B). A doctor accompanied a specialist flight nurse for Category A transports but for only 14% of Category B transports. 26% of missions began after 4pm and a further 6% began after midnight. Missions undertaken during the night were usually transfers of the critically or seriously ill (90%), with most (70%) being retrieved to Wellington Hospital for tertiary care. CONCLUSION: The Wellington Flight Service undertakes 2.2 interhospital transfers per day. Further examination of clinical outcomes in this cohort of patients transported to tertiary care is required to fully evaluate these services. PMID- 22426609 TI - Difficulties with defining lymphoedema after axillary dissection for breast cancer. AB - AIM: Axillary lymph node dissection(AND) is a common treatment for breast cancer. An important side effect of the surgery is lymphoedema (LO). The primary aims of this study were to assess the local prevalence of LO in patients who had undergone AND and how the subjective symptoms described by patients compare with objective measurements. Secondary aims were to investigate the relationship between risk factors and the prevalence of LO and to establish an easy and convenient way to detect LO patients in surgical clinics. METHOD: Eligible women after AND for breast cancer underwent three circumference measurements on the operated and non operated (control) arm. LO was defined as one or more measurements with an increase >=7.5% than control after dominant arm correction. Questionnaires were used to assess severity of symptoms related to lymphoedema. 73 patients also had serial measurements in arms and change in arm volume in operated arm was calculated using Casley-Smith method and LO was defined as >=20% increase in volume. RESULTS: 193 women with AND were analysed. Mean age was 61 years and mean time since surgery was 56 months. The overall prevalence of LO was 23.3%. LO prevalence by arm volume was 8.2%. Using volume as the standard, an arm circumference increase of >=7.5% and >=10% showed a sensitivity and specificity of 83% and 81%, and 66% and 89% respectively. Significant risk factors for LO were age, radiotherapy and infection to the operated arm CONCLUSION: Circumference measures are a simple office method of screening for LO. A patient history and >=10% increase in any circumference is optimal for determining LO after AND. PMID- 22426610 TI - The epidemiology of serious skin infections in New Zealand children: comparing the Tairawhiti region with national trends. AB - AIM: Serious skin infections are an increasing problem for New Zealand children with the highest national incidence in the Gisborne (Tairawhiti) region on the East Coast of New Zealand's North Island. This study aimed to describe the epidemiology of serious skin infections in children in this region, and make comparisons with equivalent national data to identify factors that might be contributing to elevated infection rates. METHODS: Hospitalisation data were reviewed for 0-14 year old children in the Tairawhiti region discharged from hospital with a serious skin infection between 1990 and 2007. A range of demographic variables were compared to equivalent data for New Zealand cases over the same period. The ratio of observed to expected discharges was calculated after indirectly standardising the Tairawhiti population age, ethnicity and deprivation composition to that of the total New Zealand population. RESULTS: In Tairawhiti the age-adjusted incidence of serious skin infections increased from 641.1/100,000 in 1990-1999 to 988.4/100,000 in 2000-2007, while the New Zealand incidence increased from 354.3/100,000 to 531.7/100,000. Preschool-aged children, Maori children, and those living in deprived neighbourhoods had the highest infection rates in all regions. The disparity between Maori and non-Maori children was significantly greater in Tairawhiti than nationally. The standardised ratio of observed to expected discharges in Tairawhiti compared with New Zealand was 1.42 (95%CI 1.32-1.52) in 1990-1999 and 1.28 (95%CI 1.19-1.36) in 2000-2007. CONCLUSIONS: Serious skin infections are an increasing problem for all New Zealand children, but incidence rates in the Tairawhiti region are consistently greater than average national trends, with significantly larger ethnic disparities. The population composition of this region only partly accounts for the difference, suggesting the involvement of other unknown aetiological factors; these warrant further research. PMID- 22426611 TI - Serious skin infections in children: a review of admissions to Gisborne Hospital (2006-2007). AB - AIM: Serious skin infections are an important and increasing problem in New Zealand children. The highest national rates are in the Tairawhiti (Gisborne) region on the East Coast of New Zealand's North Island, where evidence of significant ethnic disparities exists. This study aimed to describe the characteristics of serious skin infections in children hospitalised in the Tairawhiti region. METHODS: The hospital charts of all children aged 0-14 years admitted to Gisborne Hospital between 1 January 2006 and 31 December 2007 for a serious skin infection were retrospectively reviewed and data on a range of variables analysed. RESULTS: There were 163 cases of serious skin infections during the study period with 83% occurring in Maori children. The most common types of infection were cellulitis (38%) and subcutaneous abscesses (36%), and the most frequent sites of infection were the head, face and neck (32%) and lower limbs (32%). A previous episode of skin infection was recorded in 34% of children, with previous hospitalisation in 12%. A skin injury preceded infection in 37% of cases, more than reported in the Auckland and Wellington regions. Of the 77% of children who saw a GP 60% required immediate hospital admission. Compared with figures from the Auckland region, there were longer delays to medical care with a mean duration of symptoms of 2.5 days prior to visiting a GP. The most frequently isolated organisms were Staphylococcus aureus (48%) and Streptococcus pyogenes (20%) with similar proportions and resistance patterns to other New Zealand settings. CONCLUSIONS: The characteristics of serious skin infections in the Tairawhiti region are largely similar to those reported in other New Zealand regions. However, some differences in preceding skin injuries and delays in seeking medical care exist which may contribute to the high incidence of hospitalised infections in the region. These differences require further investigation. PMID- 22426612 TI - Skin infections in children in a New Zealand primary care setting: exploring beneath the tip of the iceberg. AB - AIM: Over the past two decades there has been a documented steady rise in the incidence of hospitalised serious skin infections in New Zealand children. However there are few surveillance data from the primary care setting, where the majority of children with skin infections initially present. We aimed to describe the epidemiology of childhood skin infections presenting to primary care in a region of New Zealand with a particularly high burden of infection and compare this to hospitalised cases during the same period. METHODS: A sample of general practitioners in the Tairawhiti (Gisborne) region recorded all cases of skin infections in 0-14 year old children diagnosed over a 10-week period in 2008. Observed case rates were directly standardised by age and ethnicity to the Tairawhiti population to give estimated rates for the whole region. Demographic data from primary care cases were compared to similar data from hospitalised cases during the same period. RESULTS: There were 110 incident cases of skin infections seen by the nine participating general practitioners during the study period, equivalent to an annual incidence rate of 106.7 (95%CI: 85.2-127.2) cases per 1000 children in the region. For every one hospitalisation there were an estimated 14 primary care cases. Three quarters of skin infections in both primary care and hospital settings occurred in Maori children. There was no gender predominance in either setting, however hospitalised cases of serious skin infections were more likely to occur in the preschool age group whereas children aged 5-9 years predominated at the primary care level. CONCLUSION: Skin infections are a common childhood complaint in primary care in the Tairawhiti region, with hospital-based surveillance using coded discharge data only capturing a small proportion of the overall community disease burden. Previously observed ethnic disparities in hospitalisation rates for serious skin infections reflect similar disparities in skin infection rates in primary care. The establishment of a sentinel surveillance system in the New Zealand primary care setting would facilitate further research and monitoring of this and other important conditions. PMID- 22426613 TI - Thermography as a screening and diagnostic tool: a systematic review. AB - AIMS: To determine the effectiveness of digital infrared thermography for the detection of breast cancer in a screening population, and as a diagnostic tool in women with suspected breast cancer. METHODS: A comprehensive search of electronic databases together with a search of international websites was conducted. Diagnostic studies comparing thermography with mammography for screening in asymptomatic populations; or comparing thermography with histology in women with suspected breast cancer; were eligible for inclusion. Quality of included studies was appraised using the QUADAS criteria. RESULTS: One study reported results for thermography in screening population and five studies reported diagnostic accuracy of thermography in women with suspected breast cancer. Overall, studies were of average quality. Sensitivity for thermography as a screening tool was 25% (specificity 74%) compared to mammography. Sensitivity for thermography as a diagnostic tool ranged from 25% (specificity 85%) to 97% (specificity 12%) compared to histology. CONCLUSIONS: Currently there is not sufficient evidence to support the use of thermography in breast cancer screening, nor is there sufficient evidence to show that thermography provides benefit to patients as an adjunctive tool to mammography or to suspicious clinical findings in diagnosing breast cancer. PMID- 22426614 TI - Latrodectism: case report of a katipo spider (Latrodectus katipo) bite and review of the literature. AB - We describe the case of a 29-year-old man who was bitten on the leg by a katipo spider, a relative of the Australian redback and American black widow spiders, while camping in sand dunes at Mahanga Beach, Mahia (North Island of New Zealand). Symptoms of latrodectism developed within hours, and were not diminished until two doses of the antivenom had been administered. This is only the second case report of a katipo spider bite in the recent literature. The katipo spider bite produces significant symptoms, however an antivenom is available in some hospital pharmacies. PMID- 22426615 TI - Medical image. Discoid eczema. PMID- 22426616 TI - National prescribing data for dabigatran. PMID- 22426617 TI - A review of effects of retailer education on cigarette sales to minors in the greater Wellington region. PMID- 22426618 TI - Fifty years since the Royal College Report: more action needed to achieve the "Smokefree New Zealand by 2025" goal. PMID- 22426619 TI - The effects of intimate partner violence before, during, and after pregnancy in nurse visited first time mothers. AB - To determine the prevalence of intimate partner violence (IPV) before, during and after pregnancy in a national sample of women enrolled in the Nurse Family Partnership (NFP); and, to determine correlates of IPV exposure. Clients enrolled in the NFP between 2002 and 2005 were selected. Data were extracted from NFP client encounter forms including demographic, health habits, family and relationships, and maternal and infant health information. IPV was measured by self-report and assessed during three time periods: 12 months prior to enrollment into the NFP program; during pregnancy up to 36 weeks; and, 12 months since the infant's birth. Multiple imputation methods were used to account for missing data; univariate, and multivariate analyses were conducted to determine characteristics of IPV exposure over time. IPV in the 12 months prior to pregnancy and at NFP enrollment was 8.1% (95% CI: 5.8-11.2%); 4.7% (4.3.0-5.1%) of women reported IPV during the first 36 weeks of their pregnancy; and, 12.4% (8.5-17.6%) of women reported IPV in the 12 months following delivery. Several IPV correlates were noted, including relationship status (having a partner before and after pregnancy, p < 0.001, p = 0.023, respectively), and maternal health and habits such as smoking (before, during and after pregnancy, p < 0.001, p < 0.001, p = 0.001, respectively). In longitudinal follow-up, reduced use of contraception following the birth of her infant, and rapid repeat pregnancy were significantly associated with IPV exposure. For NFP visited mothers, IPV prevalence is lowest during pregnancy, compared to periods before and after pregnancy. IPV had no demonstrable effect on perinatal outcomes such as gestational age, and birth weight; however, IPV was associated with lower rates of contraceptive use and higher rates of rapid repeat pregnancy in longitudinal follow-up. PMID- 22426620 TI - Complement modulates the function of the ubiquitin-proteasome system and endoplasmic reticulum-associated degradation in glomerular epithelial cells. AB - In experimental membranous nephropathy, complement C5b-9 induces sublethal glomerular epithelial cell (GEC) injury and proteinuria. C5b-9 also activates mechanisms that restrict injury or facilitate recovery. The ubiquitin-proteasome system (UPS) selectively degrades damaged or abnormal proteins, while misfolded proteins in the endoplasmic reticulum (ER) undergo ER-associated degradation (ERAD). In this study, we investigated the effect of complement on the UPS and ERAD. We monitored UPS function by transfection of rat GECs with a UPS reporter, GFP(u) (CL1 degron fused with green fluorescent protein). By analogy, CD3delta yellow fluorescent protein (YFP) was employed as a reporter of ERAD. We demonstrated decreased GFP(u) levels in GECs after incubation with antibody and complement, compared with control. Using C8-deficient serum with or without purified C8, cycloheximide (an inhibitor of protein synthesis), and the proteasome inhibitor, MG132, we confirmed that the decrease of GFP(u) was mediated by C5b-9, and subsequent proteasomal degradation of the reporter. Inhibition of the c-Jun N-terminal kinase attenuated the effect of complement on GFP(u) degradation. Complement, however, increased the level of CD3delta-YFP in GECs, implying an impairment of ERAD, likely due to an overabundance of misfolded proteins in the ER. The overall ubiquitination of proteins was enhanced in complement-treated GECs and in glomeruli of rats with experimental membranous nephropathy, although ubiquitin mRNA was unchanged in GECs. Proteasome inhibition with MG132 increased the cytotoxic effect of complement in GECs. Complement stimulated UPS function, by accelerating removal of damaged proteins, may be a novel mechanism to limit complement-induced injury. PMID- 22426621 TI - Prolactin and epidermal growth factor stimulate adipophilin synthesis in HC11 mouse mammary epithelial cells via the PI3-kinase/Akt/mTOR pathway. AB - The aim of the present study is to estimate the role played by cortisol, prolactin (PRL) and epidermal growth factor (EGF) in the synthesis of adipocyte differentiation-related protein (ADRP) as compared to the well-studied regulation of? beta-casein synthesis by these hormones in the mammary epithelial cell line HC11. This comparison between a cytoplasmic lipid droplet-associated protein, which is strictly specific to both lipid accumulation and secretion by lactating mammary epithelial cells, and an archetypal milk protein is useful for evaluating the extent to which a mechanistic relationship exists between biosynthesis, transport and secretion of these two major milk components. We found that cortisol inhibits PRL-stimulated ADRP synthesis, as opposed to its known stimulating effect on beta-casein synthesis. The involvement of PRL and EGF in ADRP synthesis was explored by means of a battery of inhibitors. The Jak2 inhibitor AG490 provoked a stimulation of ADRP synthesis whereas it totally suppressed that of beta-casein. The use of AG1478, a specific inhibitor of EGF receptor phosphorylation, or of PD98059, a specific MEK inhibitor, revealed that the Ras/Raf/MEK/ERK1/2 pathway has no significant influence on ADRP levels. Inhibition of JNK was also ineffective. In contrast, incubation of the cells with SB 203580, a specific inhibitor of p38, slightly stimulated ADRP synthesis and induced a proportional dose-response inhibition of PRL-induced beta-casein synthesis. Finally, cell treatment with wortmannin or LY294002 revealed that both PRL and EGF positively regulate ADRP and beta-casein synthesis through PI3-kinase signaling. Because both the Akt inhibitor MK-2206 and the mTOR inhibitor rapamycin provoked a strong diminution of PRL-induced synthesis of the two proteins, and because oleate induced phosphorylation of Akt, we concluded that, in the mammary epithelial cell line HC11, the PI3-kinase/Akt/mTOR signaling pathway strongly participates in beta-casein synthesis and is a main regulator of ADRP expression. PMID- 22426622 TI - Monitoring bacterial community structure and variability in time scale in full scale anaerobic digesters. AB - Using a high-throughput pyrosequencing technology, this study assessed bacterial community structure and time-scale variability in great detail in seven full scale anaerobic digesters operated variously in terms of influent substrate, digestion temperature, and reactor configuration. Pyrosequencing generated a total of 83,774 sequence reads from 40 digester sludge samples collected monthly for six months. The highest number of sequence reads were detected within Proteobacteria (20.5%), followed by those within Bacteroidetes (19.7%), Firmicutes (17.8%), and Chloroflexi (4.8%). The relative composition of bacterial populations was varied within the digesters as well as between the digesters, and the bacterial community structures were mainly influenced by digestion temperature. Detailed bacterial community structures were assessed by analyzing the operational taxonomic units (OTUs) based on 97% sequence similarity, which resulted in a total of 9051 OTUs. Among these, a total of 31 core OTUs were analyzed and inferred phylogenetically, which enabled us to classify the sequences within an unclassified phylum. Unclassified sequences were mostly affiliated with the sequences within Spirochaetes and Firmicutes. Interestingly, numerically dominant novel phylotypes (18% of the total sequence reads) presumably involved in anaerobic digestion within Spirochaetes were identified. Temporal variability was further explored using a non-metric multidimensional scaling ordination which demonstrated that the variability of the bacterial community within the digesters was smaller than between digesters. Correlation analysis demonstrated that digester performance and operational conditions affected the pattern of bacterial community in the ordination. Additionally, a multi-response permutation procedure revealed that the bacterial communities within the digesters were more similar than those belonging to other digesters statistically, demonstrating a patchiness of the digesters in the distribution of bacterial populations. Overall, this study revealed the correlation of bacterial community structure and time-scale variability with digester performance and operating conditions. PMID- 22426623 TI - The limits of the Buddhist embrace of science. Commentary on "Compassion, ethics, and neuroscience: neuroethics through Buddhist eyes". AB - The readiness of Buddhists to dialogue with and embrace modern science has caused some to worry that this encounter will deform Buddhist traditions for the sake of acceptance by the West. But their strong tradition of epistemological skepticism and intellectual pluralism makes it unlikely that Buddhists will embrace scientific positivism. Given the tensions between religion and science in contemporary western society, it is perhaps this feature of Buddhism that can make the most fruitful contribution in its dialogue with science. PMID- 22426624 TI - Monosomy 13 in metaphase spreads is a predictor of poor long-term outcome after bortezomib plus dexamethasone treatment for relapsed/refractory multiple myeloma. AB - We retrospectively investigated the prognostic impact of high-risk cytogenetic abnormalities (CAs) on the outcome of treatment with bortezomib plus dexamethasone (BD) in 43 relapsed/refractory (Rel/Ref) multiple myeloma patients. Fluorescence in situ hybridization (FISH) analysis identified del(13q) in 25 patients, t(4;14) in 14, t(14;16) in 4, 1q21 abnormality in 12 and del(17p) in 2, while G-banding also detected chromosome 13 monosomy (-13) in metaphase spreads from 7 patients. Eighteen of 25 patients with FISH-detected chromosome 13 abnormalities also exhibited other abnormalities. Median observation period was 510 days, and median overall survival (OS) and progression-free survival (PFS) were 912 days and 162 days, respectively. Detection of del(13q), t(4;14), t(14;16) or 1q21 abnormalities by FISH and co-occurrence of chromosome 13 abnormality with other abnormalities were not associated with poorer outcomes. In contrast, detection of -13 by G-banding in metaphase spreads showed significant association with shorter OS, although the overall response rate and PFS were not inferior to those for patients without -13 detected by G-banding. BD therapy may be a potent weapon for overcoming most classical high-risk CAs, while the detection of -13 in metaphase spreads may serve as a predictor of highly progressive disease, even when treated with BD. PMID- 22426625 TI - Co-existing chronic myeloid leukaemia and multiple myeloma: rapid response to lenalidomide during imatinib treatment. PMID- 22426626 TI - Predation by the phyllosoma larva of Ibacus novemdentatus on various kinds of venomous jellyfish. AB - The phyllosoma, a larva of spiny and slipper lobsters, has an exceptionally flat body and long appendages. It is known to associate with several species of cnidarian jellyfish, a behavior that is not rare in crustaceans. Indeed, phyllosomas clinging onto jellyfish have been observed both in the laboratory and in the natural environment. Wild phyllosomas have been found to contain jellyfish tissues in their hepatopancreas and feces, suggesting that the larvae utilize jellyfish as a food source; however, how they capture jellyfish and what species of jellyfish they prefer have rarely been investigated. The few previous studies conducted have suggested that phyllosomas have a high specificity for jellyfish (preying on only a few species); in contrast, the results of our study indicate that specificity is low. We show that phyllosomas prey on a variety of jellyfish species including deadly stinging types, on a variety of jellyfish developmental stages, and on various parts of the jellyfish body. When making contact with a jellyfish, phyllosomas first cling onto its exumbrella, feed on its tentacles or oral arms, and then consume the exumbrella. Phyllosomas may be capable of defending themselves against any types of nematocyst sting, and it is likely that they have evolved to utilize venomous jellyfish as a food in the open sea, where food may be scarce. PMID- 22426627 TI - Reproductive traits of the cold-seep symbiotic mussel Idas modiolaeformis: gametogenesis and larval biology. AB - We describe the first reproductive features of a chemosynthetic mussel collected at cold seeps from the eastern Mediterranean Sea. Idas modiolaeformis (Bivalvia, Mytilidae) is a hermaphroditic species in which production of male and female gametes likely alternates, a feature regarded as an adaptation to patchy and ephemeral habitats. By using fluorescent in situ hybridization, we demonstrate that bacterial symbionts, while present within the gills, are absent within acini that enclose female gametes and male gametes. This supports the hypothesis of environmental acquisition of symbionts in chemosynthetic mytilids. Prodissoconch I (PI) is relatively small compared to prodissoconch II (PII), suggesting a planktotrophic larval stage. Diameters of the two larval shells are in the range of sizes reported for mytilids, with a PII size between that of the shallow Mytilus edulis and that of the cold-seep mussel "Bathymodiolus" childressi. PMID- 22426628 TI - Helicospiral growth in the whip black coral Cirrhipathes sp. (Antipatharia, Antipathidae). AB - The coiling pattern of the whip black coral Cirrhipathes sp. (Antipatharia, Antipathidae) was studied in four sites of the Bunaken Marine Park (North Sulawesi, Indonesia) characterized by different hydrodynamic conditions. The colonies show a helicospiral growth, with the polyps irregularly arranged on the external convex side of the turns of the stem. Only the colonies living in a very slow current environment reach the greatest lengths (up to 5 m) and show the highest number of rotations (up to 10, 3600 degrees ). The turns shape changes along the stem of the colonies, from the base to the apex, as evidenced by the ratio between the pitch and the diameter of each coil. In particular, the turns close to the basal plate have a smaller diameter and a larger pitch, while in the most distal turns, the diameter increases and the pitch decreases concurrently. We hypothesize that the shape variation of the whorls is triggered by the relationship between the growing stem and the intensity of the prevailing current. In this way, the colony can initially grow fast, moving away from the bottom, and then extend into the current, maximizing the plankton capture. PMID- 22426629 TI - Structure and topographic distribution of oral denticles in elasmobranch fishes. AB - The placoid scales, or denticles, of the external epidermis of elasmobranchs are well known as a hard protective coat over the skin to reduce abrasion or as elements to reduce hydrodynamic drag. However, the structure and function of denticles within the oral cavity is uncertain. Using stereological and scanning electron microscopy, this study examines the structure and distribution of oral denticles in a range of elasmobranchs. Of the batoids analyzed, only members of the Rhinobatidae possessed oral denticles, with no denticles found in the members sampled in the Gymnuridae or Dasyatidae. In contrast, oral denticles were located in all the selachians examined, except for members of the Orectolobidae. Within the selachians, the denticles of the Carcharhinidae have a grooved surface and a central spine, which is angled toward the posterior of the mouth. These denticular adaptations are beneficial to reduce hydrodynamic drag, an advantage for these free-swimming species with ram ventilation. Alternatively, members of the Hemiscyllidae have broad bulbous denticles that often overlap, providing a hard surface to protect the epithelium from abrasion during the consumption of hard-bodied prey. The distribution and high number of oral denticles appears to spatially compromise the capacity for oral (taste) papillae to populate the oropharyngeal cavity but provides increased friction and grip on prey items as they are manipulated within the mouth. PMID- 22426630 TI - Opposite patterns of diurnal activity in the box jellyfish Tripedalia cystophora and Copula sivickisi. AB - Cubozoan medusae have a stereotypic set of 24 eyes, some of which are structurally similar to vertebrate and cephalopod eyes. Across the approximately 25 described species, this set of eyes varies surprisingly little, suggesting that they are involved in an equally stereotypic set of visual tasks. During the day Tripedalia cystophora is found at the edge of mangrove lagoons where it accumulates close to the surface in sun-lit patches between the prop roots. Copula sivickisi (formerly named Carybdea sivickisi) is associated with coral reefs and has been observed to be active at night. At least superficially, the eyes of the two species are close to identical. We studied the diurnal activity pattern of these two species both in the wild and under controlled conditions in laboratory experiments. Despite the very similar visual systems, we found that they display opposite patterns of diurnal activity. T. cystophora is active exclusively during the day, whereas C. sivickisi is actively swimming at night, when it forages and mates. At night T. cystophora is found on the muddy bottom of the mangrove lagoon. C. sivickisi spends the day attached to structures such as the underside of stones and coral skeletons. This species difference seems to have evolved to optimize foraging, since the patterns of activity follow those of the available prey items in their respective habitats. PMID- 22426631 TI - Visual wavelength discrimination by the loggerhead turtle, Caretta caretta. AB - Marine turtles are visual animals, yet we know remarkably little about how they use this sensory capacity. In this study, our purpose was to determine whether loggerhead turtles could discriminate between objects on the basis of color. We used light-adapted hatchlings to determine the minimum intensity of blue (450 nm), green (500 nm), and yellow (580 nm) visual stimuli that evoked a positive phototaxis (the phototaxis "threshold" [pt]). Juvenile turtles were later trained to associate each color (presented at 1 log unit above that color's pt) with food, then to discriminate between two colors (the original rewarded stimulus plus one of the other colors, not rewarded) when both were presented at 1 log unit above their pt. In the crucial test, turtles were trained to choose between the rewarded and unrewarded color when the colors varied in intensity. All turtles learned that task, demonstrating color discrimination. An association between blue and food was acquired in fewer trials than between yellow and food, perhaps because some prey of juvenile loggerheads in oceanic surface waters (jellyfishes, polyps, and pelagic gastropods) are blue or violet in color. PMID- 22426632 TI - Influence of hypoxia on bacteremia in the Dungeness crab, Cancer magister. AB - We examined the possibility that decreased environmental oxygen can elevate the levels of indigenous bacteria in the hemolymph of Cancer magister. Crabs were exposed to air-saturated and hypoxic (50% air-saturation) water for 3 days and levels of culturable bacteria in hemolymph were measured every 24 h as the total number of colony-forming units (CFU) per milliliter of hemolymph. Bacteremia increased after 24 h of exposure to hypoxia and persisted for 72 h, whereas crabs exposed to normoxia had no measurable change in number of culturable bacteria. The predominant persistent bacteria in the hemolymph was isolated and identified by DNA sequence-based methods as Psychrobacter cibarus. Crabs were injected with P. cibarus or with buffered saline as a control after 3 h of hypoxia. Levels of culturable bacteria were significantly higher in hypoxic crabs than in normoxic ones (about 2500 versus 1000 CFU ml(-1) 80 min post-injection, respectively), and circulating levels of oxygen were significantly reduced in infected animals compared to uninfected ones after 48 h in hypoxia and after 72 h in air-saturated water post-injection. These data demonstrate that P. cibarius is present in Dungeness crabs, that environmental hypoxia can dramatically elevate levels of persistent bacteria, and that hypoxia in the presence of hemolymph bacteria may ultimately reduce immune and respiratory ability. PMID- 22426633 TI - Transmission of cyanobacterial symbionts during embryogenesis in the coral reef ascidians Trididemnum nubilum and T. clinides (Didemnidae, Ascidiacea, Chordata). AB - Vertical transmission of cyanobacterial symbionts occurs in didemnid ascidians harboring Prochloron as an obligate symbiont; the photosymbionts are transferred from the parental ascidian colony to the offspring in various ways depending on host species. Although several didemnids harbor non-Prochloron cyanobacteria in their tunics, few studies have reported the processes of vertical transmission in these didemnids. Here we describe the histological processes of the transmission of cyanobacteria in two didemnids, Trididemnum nubilum harboring Synechocystis and T. clinides harboring three cyanobacterial species. In both species, the photosymbionts in the tunic of the parent colony were apparently captured by the tunic cells of the host and transferred to the embryos brooded in the tunic. The symbiont cells were then incorporated into the inner tunic of the embryo. This mode of transmission is essentially the same as that of T. miniatum harboring Prochloron in the tunic, although there are some differences among species in the timing of the release of the symbionts from the tunic cells. We suggest that the similar modes of vertical transmission are an example of convergent evolution caused by constraints in the distribution patterns of symbiont cells in the host colony. PMID- 22426634 TI - Comparative photobehavior of marine cercariae with differing secondary host preferences. AB - Light may serve as an important exogenous cue for parasitic larvae that have multi-host lifecycles and need to locate specific microhabitats, thereby increasing the probability of encountering their next host. We studied light as an initiating and orienting cue for swimming in two species of marine cercariae (Trematoda), Euhaplorchis sp. and Probolocoryphe lanceolata, which initially parasitize the same species of benthic snail, but then utilize different second intermediate hosts located in pelagic and benthic habitats, respectively. When tested in a laboratory simulation of underwater angular light distribution, dark adapted Euhaplorchis cercariae swam slowly in darkness but ascended quickly toward downwelling light at quantal intensities over 4.0 * 10(15) photons m(-2) s(-1). They oriented toward a directional light source in a horizontal trough, confirming that light plays both an initiating and an orienting role in phototactic behavior that results in ascent in the water column to locate a fish host. In contrast, Probolocoryphe lanceolata cercariae exhibited haphazard vertical swimming in darkness, with downward swimming upon exposure to angular light at lower quantal intensities (>4.0 * 10(14) photons m(-2) s(-1)) than initiated swimming in Euhaplorchis. However, P. lanceolata cercariae did not swim in response to a directional light source, suggesting that while light initiated descent behavior, its orientation was controlled by another factor. These differences in photobehavior support the idea that trematode cercariae use light in selecting for microhabitats frequented by potential hosts: an adaptive benefit that optimizes their contact and transmission to the next host. PMID- 22426635 TI - Excess weight among colorectal cancer survivors: target for intervention. AB - BACKGROUND: Healthy lifestyle might improve outcome among colorectal cancer (CRC) survivors. In this study we investigated the proportion of survivors who meet recommended lifestyle and weight guidelines and compared this to the general population. Factors that predict current behaviour were also assessed. METHOD: A random sample of CRC survivors diagnosed between 1998 and 2007 were surveyed. Percentages of current smokers, alcohol consumers, excess weight and clustering of these variables were calculated. Using logistic regression we assessed demographical and clinical factors that predict current lifestyle and excess weight. RESULTS: We included 1349 (74% response rate) survivors in this study of whom only 8 and 16% of male and female survivors met the recommended lifestyle and body weight. Among male survivors up to 10% had at least two unhealthy lifestyle factors and among women, up to 19%. The proportion of smokers and those who had ever consumed alcohol was lower compared to the general population (13 vs. 31%, 82 vs. 86% respectively), but excess weight (BMI at least 25 kg/m(2)) was more prevalent among survivors (69 vs. 53% respectively). Having received chemotherapy was significantly associated with being overweight (adjusted odd ratio 1.5, 95% confidence interval 1.05-2.3). Younger patients, male gender and survivors of lower socioeconomic status were more likely to show non-compliance to healthy lifestyle recommendations. CONCLUSION: The observed clustering of unhealthy lifestyle warrants interventions targeting multiple behaviours simultaneously. Reducing excess weight should be one of the most important targets of interventions, particularly for males, those who had chemotherapy and survivors of lower socioeconomic status. PMID- 22426636 TI - Patients with chronic hepatitis C express a high percentage of CD4(+)CXCR5(+) T follicular helper cells. AB - BACKGROUND: T follicular helper (T(FH)) cells are a subpopulation of T-helper cells which regulate humoral immune responses. The role of T(FH) cells in viral infection is unclear. This study examined the possible involvement of CD4(+)CXCR5(+) T(FH) cells in chronic hepatitis C (HCV) infection. METHODS: The percentages of peripheral blood CD4(+)CXCR5(+) T(FH) cells, inducible T-cell costimulator cells, and/or programmed death 1-positive CD4(+)CXCR5(+) T(FH) cells in 39 HCV-infected patients, 12 patients with spontaneously resolved HCV infection (SR-HCV), and 12 healthy controls were characterized by flow cytometry analysis. The subjects' serum HCV RNA loads and alanine aminotransferase and aspartate aminotransferase levels were measured. The potential association of the percentage of peripheral CD4(+)CXCR5(+) T(FH) cells with clinical data was analyzed. RESULTS: Higher percentages of peripheral blood CD4(+)CXCR5(+) T(FH) cells were found in SR-HCV and HCV-infected patients as compared with healthy controls. Interestingly, a statistically significant negative correlation was found between the percentage of CD4(+)CXCR5(+) T(FH) cells and the HCV RNA load. CONCLUSIONS: These data suggest that CD4(+)CXCR5(+) T(FH) cells may participate in HCV-related immune responses. Increased T(FH) cells in peripheral blood may help to control HCV infection. PMID- 22426637 TI - Mortality and morbidity of hepatectomy, radiofrequency ablation, and embolization for hepatocellular carcinoma: a national survey of 54,145 patients. AB - BACKGROUND: Reported mortalities and morbidities of therapeutic procedures for liver tumors vary between studies, because of different designs and small sample sizes. We investigated the mortalities and complication rates for hepatectomy, radiofrequency ablation (RFA), and trans-catheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) in a large sample, using a nationwide Japanese database (the Diagnosis Procedure Combination database). METHODS: Data from the Diagnosis Procedure Combination database were analyzed for July 1 to December 31, 2007 and the same period in 2008. We identified 54,145 patients with HCC who underwent hepatectomy (n = 5,270), RFA (n = 11,688), or TAE (n = 37,187). In hospital mortality and morbidity were analyzed for each procedure. The relationships between mortality and factors including patient characteristics and procedural backgrounds were assessed. RESULTS: In-hospital mortalities associated with hepatectomy, RFA, and TAE were 2.6 % [95 % confidence interval (CI) 2.2 3.1], 0.3 % (0.2-0.4), and 1.0 % (0.9-1.1), and post-procedural complication rates were 14.5 % (13.5-15.5), 4.5 % (4.2-4.9), and 4.5 % (4.3-4.7), respectively. Increased mortality following hepatectomy was significantly associated with older age, extended lobectomy (vs. partial hepatectomy; odds ratio [OR] 3.80, p < 0.001), lower hospital volume (OR 2.74, p < 0.001), and renal comorbidity (OR 3.01, p = 0.02). Older age and cardiac comorbidity (OR 5.14, p = 0.001) were significantly associated with RFA-related mortality, and lower hospital volume was significantly associated with TAE-related mortality (OR 1.60, p < 0.001). CONCLUSIONS: Mortalities and morbidities associated with therapeutic procedures for liver tumors were acceptably low in Japan, but were affected by patient and institutional characteristics. PMID- 22426638 TI - Estimate or calculate? How surgeons rate volumes and surfaces. AB - PURPOSE: Surgeons frequently describe the shape of intraoperative findings using visual judgement and their own sense of proportion or describing these findings in comparison to commonly used or metaphoric subjects. The aim of the study was to analyse the reliability of surgeon's estimations of dimensions. METHODS: The study was performed in two phases. First, physicians had to estimate the metric proportions of four well-known objects. Second, surgeons were asked intraoperatively to estimate the liver resection surface after partial hepatectomy. The exact surface of the resection plane was measured using computed tomography-guided planimetry of the resection specimen. Physician's estimations and the exact measurements of the well-known objects and the liver resection surface were compared. Systematic error was defined by the natural logarithm of estimated/real size. RESULTS: We found a large individual discrepancy in estimating the metric proportions of commonly used objects and a tendency to underestimate both commonly used objects and liver resection surface. Experienced liver surgeons were more accurate in estimating liver resection surface compared with younger staff members. CONCLUSIONS: We found a large bias in estimating the dimension of both commonly used objects and the surface area of liver parenchyma transection. Obviously, estimating errors are more influenced by the individual subject who estimates than by the object itself. In clinical routine, surgeons should rely more on simple measuring devices than on their own sense of proportion. Education in how to estimate more correctly human liver resection surfaces can be achieved by ex vivo studies using porcine livers. PMID- 22426639 TI - Detection of "oncometabolite" 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma. AB - Somatic mutations in isocitrate dehydrogenase (IDH)1 and 2 have been identified in a subset of gliomas, rendering these tumors with elevated levels of "oncometabolite," D-2-hydroxyglutarate (2HG). Herein, we report that 2HG can be precisely detected by magnetic resonance (MR) in human glioma specimens and used as a reliable biomarker to identify this subset of tumors. Specifically, we developed a two-dimensional correlation spectroscopy resonance method to reveal the distinctive cross-peak pattern of 2HG in the complex metabolite nuclear MR spectra of brain tumor tissues. This study demonstrates the feasibility, specificity, and selectivity of using MR detection and quantification of 2HG for the diagnosis and classification of IDH1/2 mutation-positive brain tumors. It further opens up the possibility of developing analogous non-invasive MR-based imaging and spectroscopy studies directly in humans in the neuro-oncology clinic. PMID- 22426640 TI - A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg rhArg1) in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. METHODS: Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. RESULTS: Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients. CONCLUSION: Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients. PMID- 22426641 TI - Independent evolution of functional MHC class II DRB genes in New World bat species. AB - Genes of the major histocompatibility complex (MHC) play a pivotal role in the vertebrate immune system and are attractive markers for functional, fitness related, genetic variation. Although bats (Chiroptera) represent the second largest mammalian order and are prone to various emerging infectious diseases, little is known about MHC evolution in bats. In the present study, we examined expressed MHC class II DRB sequences (exons 1 to 4) of New World bat species, Saccopteryx bilineata, Carollia perspicillata, Noctilio albiventris and Noctilio leporinus (only exon 2). We found a wide range of copy number variation of DRB loci with one locus detected in the genus Noctilio and up to ten functional loci observed in S. bilineata. Sequence variation between alleles of the same taxa was high with evidence for positive selection. We found statistical support for recombination or gene conversion events among sequences within the same but not between bat species. Phylogenetic relationships among DRB alleles provided strong evidence for independent evolution of the functional MHC class II DRB genes in the three investigated species, either by recent gene duplication, or homogenization of duplicated loci by frequent gene conversion events. Phylogenetic analysis of all available chiropteran DRB exon 2 sequences confirmed their monophyletic origin within families, but revealed a possible trans-species mode of evolution pattern in congeneric bat species, e.g. within the genera Noctilio and Myotis. This is the first study investigating phylogenetic relationships of MHC genes within bats and therefore contributes to a better understanding of MHC evolution in one of the most dominant mammalian order. PMID- 22426643 TI - Role of relative aldosterone excess in salt-sensitive hypertension among African ancestry. PMID- 22426647 TI - microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis. AB - microRNA-155 (miR-155), an important multifunctional microRNA, has been implicated in the development of multiple solid tumors, yet, its role in gastric cancer cells has not been fully elucidated. In this study, we find that miR-155 was significantly downregulated in gastric cancer cell lines compared with an immortalized gastric epithelial cell line (GES-1). Overexpression of miR-155 in SGC-7901 and MKN-45 gastric cancer cells dramatically suppressed cell migration, invasion and adhesion in vitro. Overexpression of miR-155 significantly reduced the protein levels of SMAD2 and repressed the activity of a luciferase reporter containing one of the two predicted miR-155 binding sites in SMAD2 3'-UTR, indicating that SMAD2 may be a miR-155 target gene. miR-155 expression was also remarkably restored by a DNA demethylating agent (5-Aza-2-deoxycytidine) in SGC 7901 and MKN-45 gastric cancer cells. Taken together, these data suggest that miR 155 may function as a tumor suppressor to regulate gastric cancer cell metastasis by targeting SMAD2, and its downregulation in gastric cancer cells may be partly ascribed to DNA methylation. PMID- 22426648 TI - Clinical Trial Educator program - a novel approach to accelerate enrollment in a phase III International Acute Coronary Syndrome Trial. AB - BACKGROUND: The conduct of current cardiovascular outcome trials requires investigation of thousands of patients at hundreds of investigator sites. Such large trials are clinically and logistically highly demanding and often tend to finish with significant delays, consequently delaying patient access to new medicines. PURPOSE: To address this issue, we designed and implemented a novel approach - a Clinical Trial Educator (CTE) program - to accelerate enrollment in the Thrombin-Receptor Antagonist for Clinical Event Reduction (TRA*CER) trial. This article analyzes the effect of this approach on the study milestones: patient recruitment, site start-up time, and recruitment rate. METHODS: Scientifically qualified and specifically trained CTEs regularly visited TRA*CER investigator sites in 18 European countries where they trained and educated investigators and site personnel to support them address recruitment challenges. Patient recruitment was assessed in absolute numbers and as recruitment rates, both in relation to CTE site visits. RESULTS: CTEs performed 2184 visits at 373 European TRA*CER sites (out of 921 global sites). Of sites visited by a CTE, significantly less remained without enrolling any patient than of sites not visited by a CTE (5.9% vs. 15.3%; p < 0.001). Sites visited within 30 days after initiation showed a significantly shortened median time to recruitment of the first patient (28 vs. 59 days with visits <=30 or >30 days after initiation; p < 0.001). Mean patient recruitment rates were significantly higher at visited than at not-visited sites (1.13 vs. 0.89 patients per site per month, p < 0.001) and significantly increased after the first CTE site visit (from 0.70 to 1.17 patients per site per month; p < 0.001). Finally, there were fewer low-recruiting sites and more high-recruiting sites among the CTE-visited sites compared to the not-visited sites, and the mean recruitment rate at high-recruiting sites visited by CTEs was significantly higher than at high-recruiting sites without CTE visits (2.07 vs. 1.64 patients per site per month; p < 0.01). LIMITATIONS: The possibility for selection bias is inherent to this post hoc analysis of a nonrandomized data set. The European focus of the CTE program described here might add some geographical bias. Also, other activities such as investigator meetings conducted in parallel with CTE activities might have partly masked the results of our analysis. Finally, the analysis is limited to recruitment-related parameters, and the aspect of cost-effectiveness has not been quantitatively assessed. CONCLUSION: We found a significant positive association between CTE site visits and the assessed recruitment-related study milestones in the TRA*CER trial, and enrollment finished ahead of plan. We propose that a CTE program could efficiently accelerate enrollment in other clinical trials and therapeutic areas and could contribute to shortening patient access time to novel and potential lifesaving treatments in cardiovascular medicine and beyond. PMID- 22426649 TI - Implementation past, present, ... and future? PMID- 22426650 TI - Development of a self-assessed consumer recovery outcome measure: my voice, my life. AB - We report the development of a self-assessed consumer recovery outcome measure by way of a consumer led and focused iterative process, informed by exploratory and confirmatory factor analysis. The process began with a deliberately over inclusive preliminary measure of 127 items, based on 12 presumptive domains derived from the recovery literature and consumer consultation, being piloted with over 500 mental health consumers. The full 504 participant data set was randomly split into two discrete sets of 300 and 204 to provide one for the initial exploratory factor analysis and another (of independence) for the subsequent confirmatory factor analysis and reliability estimation. Analyses identified and confirmed (using the separate data sets) a robust factor structure, with 11 distinct and relatively independent factors (relationships; day-to-day life; culture; physical health; quality of life; mental health; recovery; hope and empowerment; spirituality; resources; and satisfaction with services) underlying one substantial principal construct (that we refer to as consumer recovery). The measure was refined to 65 items, between three and ten items for each of the 11 domains, the reliabilities for which are uniformly high. PMID- 22426652 TI - In vivo evaluation of titanium oxide and hydroxyapatite as an artificial cornea skirt. AB - Keratoprosthetic devices are subject to chronic inflammatory, pathological processes and the external environment that affect their stability and biocompatibility with the ocular surface and adjacent ocular tissues. We compared the corrosion resistance property and tissue-implant reaction of titanium oxide (TiO(2)) with hydroxyapatite (HA) in artificial tear fluid and a rabbit skin implantation model. The dissolution properties of the implant surfaces were evaluated with scanning electronic microscope (SEM) and atomic force microscope (AFM). Tissue inflammatory reactions were evaluated by Hematoxylin & Eosin staining, avidin biotin peroxidase complex (ABC) immunoassay and immunofluorescence. SEM and AFM images showed that there was less pitting corrosion on the surface of TiO(2) implants compared with HA. TiO(2) and HA exhibited a similar pattern of foreign body capsule formation and inflammatory cellular responses. The Collagen I/Collagen III ratio of the TiO(2) capsule was higher than that of the HA capsule. TiO(2) implants possess a high corrosion resistance property both in vitro and in vivo and the inflammatory cellular response to TiO(2) is similar to HA. With regards to corrosion resistance and inflammatory tissue responses, TiO(2) appears to be a promising material for keratoprosthetic skirt devices. PMID- 22426651 TI - Preventive interventions for preterm children: effectiveness and developmental mechanisms. AB - This article provides an integrative review of the effectiveness of and possible developmental mechanisms associated with preventive interventions for preterm children. An analysis of randomized clinical trials carried out within the last 15 years was framed within a contemporary developmental model emphasizing the role of parental adjustments to preterm children's characteristics. Evidence suggested positive outcomes could be understood in terms of improvements in developmental pathways associated with parental sensitive-responsiveness and child participation in intensive intervention-oriented child care. Implications for the critical role of the Medical Home model for preventive interventions for preterm children were discussed. PMID- 22426653 TI - Silver coated bioactive glass particles for wound healing applications. AB - Bioactive glass particles (0.42SiO(2)-0.15CaO-0.23Na(2)O-0.20ZnO) of varying size (<90 MUm and 425-850 MUm) were synthesized and coated with silver (Ag) to produce Ag coated particles (PAg). These were compared against the uncoated analogous particles (Pcon.). Surface area analysis determined that Ag coating of the glass particles resulted in increased the surface area from 2.90 to 9.12 m(2)/g (90 MUm) and 1.09-7.71 m(2)/g (425-850 MUm). Scanning electron microscopy determined that the Ag coating remained at the surface and there was little diffusion through the bulk. Antibacterial (Escherichia coli--13 mm and Staphylococcus epidermidis--12 mm) and antifungal testing (Candida albicans--7.7 mm) determined that small Ag-coated glass particles exhibited the largest inhibition zones compared to uncoated particles. pH analysis determined an overall higher pH consider in the smaller particles, where after 24 h the large uncoated and Ag coated particles were 8.27 and 8.74 respectively, while the smaller uncoated and Ag coated particles attained pH values of 9.63 and 9.35 respectively. PMID- 22426654 TI - A challenging hernia: primary venous aneurysm of the proximal saphenous vein. AB - INTRODUCTION: Primary venous aneurysm is a rare, but essential consideration in the differential diagnosis of an inguinal and femoral hernia. METHODS: We report a case of a 43-year-old man who was referred for evaluation and treatment of a femoral hernia. RESULTS: The patient presented with a 3-month history of an asymptomatic tumor on his right upper inner thigh. Physical examination noted a non-tender, non-indurated tumor. CONCLUSION: Surgical exploration demonstrated a primary venous aneurysm of the proximal saphenous vein. PMID- 22426655 TI - Astragaloside II induces osteogenic activities of osteoblasts through the bone morphogenetic protein-2/MAPK and Smad1/5/8 pathways. AB - Radix Astragalus has been identified to exert beneficial effects in preventing postmenopausal bone loss. However, the active ingredients and mechanism of action remain unknown. In this study, we examined the effect of Astragaloside II (AST II), which is a monomer of Astragalus saponin, on the viability, proliferation, differentiation and maturation of rat primary osteoblasts, as well as its relevant molecular mechanism. We found that AST II exhibits a significant induction of proliferation, differentiation and mineralization in primary osteoblasts. AST II stimulates osteoblast differentiation at various stages, from early to late stage of differentiated osteoblasts. Furthermore, induction of differentiation by AST II is associated with increased expression of bone morphogenetic protein-2 (BMP-2), activation of Smad1/5/8, ERK1/2 and p38, and increased expression of core-binding factor 1 (Cbfa1)/Runx2. BMP antagonist (Noggin) blocks the effect of AST II on cell differentiation, and Smad1/5/8, p38, Cbfa1 expression, but only partly decreases ERK1/2 activation. This indicates that BMP-2 is essential in AST II-mediated osteoblast differentiation and Smad1/5/8, p38, Cbfa1 activation, and is partly involved in ERK1/2 activation. In conclusion, although in vivo studies are required in the future, as a phyto saponin of Radix Astragalus, AST II may become a novel candidate that is beneficial for stimulating the osteoblastic activity resulting in bone formation, which has not been recognized and reported previously. PMID- 22426656 TI - Recurrent diplopia over a 30-year period: natural history of a Lewis and Sumner syndrome. AB - We described the case of a patient with recurrent episodes of isolated diplopia over the last 30 years. On her last event, neurological examination revealed not only a right third and sixth cranial nerves involvement, but also a right peripheral facial palsy and a motor weakness on the left ulnar territory. Electrophysiological nerves motor conduction study revealed a conduction block on the left ulnar nerve and a less severe on the right ulnar nerve. Asymmetrical upper limb sensorimotor weakness combined with conduction block and cranial nerves palsy led to a diagnosis of Lewis and Sumner syndrome (LSS). This case is unusual by the presentation of the disease and is, to our knowledge the longer natural disease course of LSS reported. Moreover, it suggests that the recurrent diplopia variant may represent a separate entity with a good prognosis even in absence of invasive treatment. PMID- 22426657 TI - Cryptogenic embolic stroke in a girl with a trisomy 21 mosaic. AB - Stroke in trisomy 21 may be due to cardioembolism, atherosclerosis, vasculitis, moyamoya disease, sinus venous thrombosis, internal carotid hypoplasia or infections like endocarditis with septic emboli, meningitis or brain abscess. In rare cases, however, stroke etiology remains unexplained. We present a 19 year old Caucasian girl with trisomy 21 with a 47XX+21 karyotype who suffered at age 11 years from a transient ischemic attack with left hemiparesis, and at age 17 years from an ischemic stroke in the territory of the right cerebral medial artery. She suffered from arterial hypertension, obesity and hypercholesterolemia. Since blood coagulation studies, immunologic parameters, blood cultures, 24-h Holter monitoring, transthoracic and transesophageal echocardiography, magnetic resonance angiography of the extra- and intracranial vessels, thoracic and abdominal aorta and renal arteries did not provide any explanation for the stroke, implantation of a loop recorder is considered in order to detect episodes of clinically silent atrial fibrillation. PMID- 22426658 TI - Diffusion MRI and tensor tractography in ischemic optic neuropathy. AB - Ischemic optic neuropathies (IONs) are among the most prevalent diseases causing visual impairment in middle-aged and elderly people. While arteritic ION is an ocular emergency and requires early diagnosis and immediate treatment with systemic high-dose corticosteroids to prevent further visual loss, treatment options for non-arteritic ION remain limited. We describe the case of a woman with unilateral right-sided non-arteritic posterior ischemic optic neuropathy. The diagnosis was made on clinical and radiographic grounds. Diffusion-weighted sequences and apparent diffusion coefficient maps revealed markedly restricted diffusion in the right optic nerve. It was very helpful to precise the posterior topography of the optic nerve lesion. Furthermore, we reported the diffusion tensor tractography study which appears to be an objective tool to assess the incomplete visual recovery. These MRI techniques including tensor tractography remain to be evaluated in large cohort of ION patients' particularly in future therapeutic trials. PMID- 22426659 TI - Plasma oxidative and inflammatory markers in patients with idiopathic Parkinson's disease. AB - Parkinson's disease (PD) is the most common neurodegenerative disorder after alzheimer's disease. Neuroinflammation and oxidative damage are implicated to be responsible for the pathogenesis of neurodegenerative diseases. However, there are a few studies showing the changes in the biomarkers for neuroinflammation and oxidative damage in neurodegenerative diseases. In our study we aimed to examine the role of the molecules that are involved in oxidative stress and inflammation in PD patients taking L: -dopa treatment. Oxidized-LDL (ox-LDL), high-sensitivity C-reactive protein (hs-CRP) and the soluble intracellular adhesion molecule (ICAM) were chosen as biomarkers for systemic inflammation and oxidative damage. The patients were classified according to the Hoehn-Yahr staging system. Forty five idiopathic L: -dopa-given PD patients and 25 age-matched healthy controls were examined. Plasma ox-LDL and ICAM levels were significantly higher in PD patients when compared with controls (p < 0.001 and p < 0.05, respectively). PD patients at all stages had significantly higher plasma ox-LDL levels than controls (p < 0.001). Plasma ICAM levels at stage 1 and 2 and CRP levels at stage 2 patients were significantly higher than controls (p < 0.05, p < 0.05, and p < 0.01, respectively). We insist that further studies have to be conducted to establish neuroinflammation and oxidative damage in PD. Establishing the roles of these pathological processes in PD might be the key to effective therapy at an early stage by antioxidants and/or anti-inflammatory drugs. PMID- 22426660 TI - As a rare cause of drug-induced cough: topiramate. AB - The most common causes of chronic cough in nonsmokers are postnasal drip syndrome, asthma, and gastroesophageal reflux disease. Drugs are also important in the etiology of resistant cough. Most common drugs inducing cough are the ACE inhibitors. Many drugs other than ACE inhibitors can also cause dry cough and one among them is topiramate. It is a new generation, efficacy-proved antiepileptic drug that is used widely for migraine prophylaxis in many countries. Most common adverse events of topiramate are paresthesia, cognitive symptoms, fatigue, insomnia, nausea, loss of apetite, anxiety, and dizziness. There is only one case report about topiramate associated cough in the literature. The present report refers to a patient, presenting with cough who is on topiramate treatment for migraine prophylaxis. PMID- 22426661 TI - Midbrain tremor: a tremor resistant to treatment. AB - Midbrain tremor is a resting, postural, action and intentional tremor of the upper extremity. Partial response to pharmacological agents makes the treatment of this tremor difficult. We report, herein, three cases of patients with midbrain tremors involving their midbrain and thalamic area in ischemic and hemorrhagic strokes. In the first case, the patient presented with a midbrain tremor of the right upper extremity involving left midbrain and thalamic area. After MRI examination, he was placed on benztropine, amantadine, pramipexole and eventually levodopa for treatment, all of which were unsuccessful in improving his tremor. In the second case, the patient presented with a midbrain tremor of the right upper extremity after an hemorrhagic stroke. After viewing CT and MRI scans, the patient was placed on amantadine, pramipexole and eventually levodopa, all of which made no contributions to his tremor. The patient in the third case presented with a blunt trauma to the head which led to the development of a midbrain tremor of his left arm. CT and MRI scans showed abnormalities in the right side of the midbrain and pons. He was initially started on amantadine, with no improvement of his tremor. However, he was eventually placed on trihexyphenidyl which contributed to a 70% improvement in his tremor. In the event of midbrain tremor, treatment should be assessed on a case by case basis, and all options should be considered after a risk-benefit assessment. PMID- 22426662 TI - Granulomatous meningitis due to rheumatoid arthritis. AB - Meningoencephalitis is a rare but aggressive complication of rheumatoid arthritis (RA). The most common complications of RA occur in the severe and chronic stages of the disease. Only a few cases have been reported in the literature. The symptoms are usually nonspecific, and arthralgia may be missing. Brain MRI and CSF analysis are useful to guide the diagnosis. However, a biopsy is required to demonstrate the existence of granulomatous lesions and the lack of mycobacterium infection. Early detection is essential to prevent neurological complications. Treatment consists of intravenous high doses of corticoid followed by oral tapered doses associated with immunosuppressive therapy. The present case is remarkable by the presence of granulomatous lesions in the lung and meninges and the dramatic improvement after immunosuppressive therapy. PMID- 22426663 TI - Characteristics of 478 very old neurologic outpatients evaluated over 20 years in Guayaquil, Ecuador. AB - There is scarce information on the diseases affecting very old neurologic outpatients in the developing world. We evaluated 478 neurologic outpatients aged 80 years or more over a 20-year period, to analyze data concerning reason for consultation, diagnosis and follow-up. The mean age was 83.9 +/- 3.8 years, and 59% were women. Most common reasons for consultation were cognitive decline (24.7%), focal deficits (22.8%) and movement disorders (19.7%). Common categories of neurologic diseases included cerebrovascular (27.4%), degenerative (27.2%) and diseases of uncertain/unknown etiology (20.5%). We found significant variations in the reasons for consultation and in the prevalence of some neurologic diseases according to the year in which patients were evaluated. During the past few years, cognitive decline outnumbered patients with focal neurologic deficits and movement disorders. From 1990 to 1994, degenerative diseases accounted for only 14.5% of our patients, but from 2005 on, these conditions were responsible for 33.9% of the cases. When analyzing pre-existing conditions and diseases occurring at follow-up, we identified a subset of older patients who developed stroke and Alzheimer's disease/mild cognitive impairment. There was a dynamic pattern of neurologic diseases over the years, with significant variations in the reason for consultation and the category of disease. Nowadays, distribution of neurologic symptoms and diseases in our population of very old neurologic patients is more similar to that reported from the developed world than it was 20 years ago. PMID- 22426664 TI - Are irreversible morphological [corrected] signs of portal hypertension in neurological form of Wilson's disease associated with treatment delay? A pilot study. AB - Aim of this study was to evaluate the rate of morphological liver and spleen abnormalities in patients with neurological clinical presentation of Wilson's disease (WD). Fourteen patients with neurological presentation of WD divided into group A (5 patients who initiated chelating therapy <24 months from the first symptoms) and group B (9 patients whose therapy started >=24 months after the initial symptoms) underwent abdominal MRI examination. Abnormal findings on abdominal MRI were present in 28% of patients with neurological form of WD. Significant hepatosplenomegaly was present in none of the patients from group A and in 4 (44%) patients from group B. In addition, macronodular liver cirrhosis and peritoneal effusion were evident in two and one patient from group B, respectively, and in none of the patients from group A. Our results suggest that severe portal hypertension and liver damage in patients with neurological presentation of WD might be reversible or do not even develop if chelating treatment is initiated <2 years after the onset of symptoms. PMID- 22426665 TI - Consciousness disturbance and poikilothermia revealing brain involvement in neuromyelitis optica. AB - A 21-year-old woman was admitted due to altered mental status and hypothermia. The patient had a diagnosis of neuromyelitis optica (NMO) for 12 years and she was positive for serum anti-aquaporin 4 antibody. On admission, physical examination revealed coma with decerebration rigidity and poikilothermia. Magnetic resonance images of the brain revealed widespread, gadolinium enhancing lesions in the periventricular areas and the diencephalic structures. Laboratory investigations revealed hyponatremia and hypothyroidism. The patient was treated with high dose steroids. Both symptomatic and asymptomatic brain lesions may develop in patients with NMO. However, poikilothermia has not been reported in patients with NMO before. PMID- 22426666 TI - Sick sinus syndrome and orthostatic hypotension in Parkinson's disease. AB - We present a case of Parkinson's disease patient whose initial symptoms were sick sinus syndrome and orthostatic hypotension. Our case illustrates difficulties in distinguishing syncope of primary cardiac or neurological origin and highlights the importance of a diagnostic workup including neurological examination. PMID- 22426667 TI - Sjogren-Larsson syndrome: phenotypic variability in two brothers with a neurocutaneous disorder. AB - Sjogren-Larsson syndrome (SLS) is a rare autosomal recessively inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. It is characterized by an unusual combination of cutaneous and neurologic signs and symptoms. The authors describe two brothers of consanguineous parents with SLS, one of whom was born from a dizygotic twin pregnancy (with an apparently normal sister), and they focus on the variability of the clinical findings of the syndrome even among siblings and twins. PMID- 22426668 TI - Knee MRI showing thickened peripheral nerves in Charcot-Marie-Tooth disease. PMID- 22426669 TI - MRI findings in acute hyperammonemic encephalopathy resulting from decompensated chronic liver disease. AB - Hyperammonemic encephalopathy is a type of metabolic encephalopathy with diversified etiology. Hyperammonemia is the end result of several metabolic disorders such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathy, Reye's syndrome and other toxic encephalopathies. Non-specific clinical presentation poses a great challenge in early diagnosis of this entity. Irrespective of the underlying etiology, hyperammonemia causes a distinctive pattern of brain parenchymal injury. The cingulate gyrus and insular cortex are more vulnerable to this type of toxic insult. Characteristic magnetic resonance imaging findings in combination with laboratory parameters can help to differentiate this entity from other metabolic encephalopathy and thus aiding in early diagnosis and treatment. PMID- 22426670 TI - Decompressive hemicraniectomy: dissociation between clinical and radiological findings. PMID- 22426671 TI - Intraneural ganglion cysts of obturator nerve causing obturator neuropathy. PMID- 22426672 TI - Large doughnut-shaped internal carotid artery aneurysm. PMID- 22426673 TI - Human short-term exposure to electromagnetic fields emitted by mobile phones decreases computer-assisted visual reaction time. AB - The worldwide dramatic increase in mobile phone use has generated great concerns about the detrimental effects of microwave radiations emitted by these communication devices. Reaction time plays a critical role in performing tasks necessary to avoid hazards. As far as we know, this study is the first survey that reports decreased reaction time after exposure to electromagnetic fields generated by a high specific absorption rate mobile phone. It is also the first study in which previous history of mobile phone use is taken into account. The aim of this study was to assess both the acute and chronic effects of electromagnetic fields emitted by mobile phones on reaction time in university students. Visual reaction time (VRT) of young university students was recorded with a simple blind computer-assisted-VRT test, before and after a 10 min real/sham exposure to electromagnetic fields of mobile phones. Participants were 160 right-handed university students aged 18-31. To assess the effect of chronic exposures, the reaction time in sham-exposed phases were compared among low level, moderate and frequent users of mobile phones. The mean +/- SD reaction time after real exposure and sham exposure were 286.78 +/- 31.35 ms and 295.86 +/ 32.17 ms (P < 0.001), respectively. The age of students did not significantly alter the reaction time either in talk or in standby mode. The reaction time either in talk or in standby mode was shorter in male students. The students' VRT was significantly affected by exposure to electromagnetic fields emitted by a mobile phone. It can be concluded that these exposures cause decreased reaction time, which may lead to a better response to different hazards. In this light, this phenomenon might decrease the chances of human errors and fatal accidents. PMID- 22426674 TI - Severe dolichoectasia of the intracranial arteries. PMID- 22426675 TI - Hormonal therapy for fertility and huge meningioma: a purely random association? AB - Sexual hormones have been related to the growth of meningiomas, also due to the almost constant expression of hormonal receptors by tumoral cells. A case of a woman with previous history of multiple treatment for infertility, harboring a huge meningioma is here described. The tumor was surgically resected and the immunohistochemical examination revealed a high expression of progesterone receptors on tumoral cells surface. A putative role of past progesterone administration in the growth of meningioma has been hypothesized. Particular caution should be paid whenever adopting sexual hormonal therapy, especially for fertility. A radiological examination (ideally MRI) could be advised before starting therapy, in order to rule out any intracranial meningioma. PMID- 22426676 TI - Acute ataxia due to anti-Yo antibody paraneoplastic cerebellar degeneration 4 months prior to diagnosis of uterine carcinoma. PMID- 22426677 TI - Natural history of intradural-extramedullary spinal cord tumors. AB - The objective of the present study was to investigate the natural history of intradural-extramedullary spinal cord tumors. Nine cases of intradural extramedullary tumors were observed over the 2 years. The physical and magnetic resonance imaging (MRI) examination were performed in the first examination and every other year. Tumors were classified as the schwannoma type and the meningioma type based on the MRI findings. The tumor volume was calculated by the craniocaudal length on a sagittal image and maximum transverse diameter on an axial image of MRI, every year. The annual growth rate, which was defined as the change in the volume each year compared to the volume of the previous year, was examined. There were six cases in the schwannoma type and three cases in the meningioma type. The schwannoma type tumors presented several growth patterns: unchanging, continuous slight growth, and initial slight growth followed by rapid growth during the observation period (6.7 +/- 2.7 years), while the meningioma type tumors presented the continuous growth pattern during the observation period (4.3 +/- 2.5 years). The average annual growth rate was 2.3 +/- 5.5% in the schwannoma type and 7.0 +/- 8.5% in the meningioma type. Schwannoma type tumors showed relatively less change in their size and would be observed for a longer time. PMID- 22426679 TI - Postpartum RCVS and PRES with normal initial imaging findings. AB - Postpartum angiopathy as clinical presentation of reversible cerebral vasoconstriction syndrome remains an intriguing phenomenon. The diagnosis needs to be considered in women presenting with thunderclap headache with or without associated neurological deficits. Here, we present a patient with thunderclap headache with initial normal laboratory and cerebral imaging findings, including intracranial angiography. Her condition worsened over several days and magnetic resonance imaging revealed changes initially compatible with posterior reversible encephalopathy syndrome, sequentially ischemic stroke and narrowing of the intracranial arteries. Although the patient was in coma for several days, she completely recovered and the focal vasoconstriction fully resolved. This case underscores the complex and variable presentation of postpartum angiopathy and illustrates the diagnosis to be (re)considered even if cerebral vasoconstriction is not documented at the onset of symptoms. PMID- 22426680 TI - Primary breast lymphoma sequentially relapsed in the peripheral and central nervous system. AB - Primary breast lymphoma (PBL) is an uncommon extranodal type of lymphoma, exhibiting more aggressive behavior and poorer prognosis. Patients with PBL have a higher incidence to relapse in central nervous system (CNS), which is always leading to a dismal outcome even treating with high intensity chemotherapy plus radiotherapy. Lymphoma involving the peripheral nervous system (PNS), either primarily or secondarily, is also rare. But no PBL with PNS relapse has been reported before. Herein, we reported a case of PBL who presented with subsequent relapse in two discrete sites of the PNS followed by the CNS. PMID- 22426681 TI - Demographic, clinical, and polysomnographic features in patients with narcolepsy: an experience of 181 patients with narcolepsy from a Turkish sleep center. AB - The present study was designed to describe the socio-demographic, clinical, and polysomnographic features of patients diagnosed with narcolepsy in our sleep center. This retrospective cross-sectional study was conducted on 181 patients diagnosed with narcolepsy based on the results of clinical evaluation, polysomnography (PSG), and multiple sleep latency test (MSLT) between 1993 and 2009. Approximately 70% of the patients had cataplexy, whereas 42% had hallucinations and 55.8% had sleep paralysis. Although sleep efficiency was higher (91.28 +/- 5.89%) in patients with narcolepsy, they woke frequently during the night, and their percentages of deep sleep were low (stage 3, 5.12 +/- 3.08%, stage 4, 9.60 +/- 7.10%). Our study group was divided into two based on age: individuals aged <30 years (n = 152) and >30 years (n = 29). REM latency on PSG was shorter (t = 2.96, p = 0.004) and sleep onset REM (SOREM) on MSLT was higher (t = 2.56, p = 0.011) in the older group than in the younger group. Cataplexy is seen in most patients with narcolepsy. In older patients, REM latency on PSG is shorter and the number of SOREM on MSLT is higher. PMID- 22426682 TI - Subdural hematoma in a young woman with an "old" brain. PMID- 22426683 TI - Headache in migraine patients receiving topiramate: a mere migraine attack or a harbinger of ciliochoroidal effusion syndrome? PMID- 22426684 TI - Progressive monomelic proximal upper limb amyotrophy. PMID- 22426685 TI - A rare case of lumbar lateral meningocele. PMID- 22426686 TI - Clinical characteristics and use of antiepileptic drugs among adolescents with uncomplicated epilepsy at a referral center in Novi Sad, Serbia. AB - The study aimed to investigate the type and etiology of epileptic seizures and the use of antiepileptic drugs for the treatment of various forms of epileptic seizures among adolescents with active but uncomplicated epilepsy at a tertiary referral center in Novi Sad, Serbia. The study design was cross sectional. Data were obtained from patients and medical records. A total of 103 adolescents (39 males and 64 females) with active but uncomplicated epilepsy were included. Patients with primary generalized seizures had significantly better control of epilepsy than those with partial seizures with or without secondary generalization. A total of 80 (77.7%) adolescents had no known underlying etiology based on initial diagnosis and evaluation. All adolescents were classified into known idiopathic syndromes (54.4%), non-classifiable cryptogenic etiology (23.3%), and secondary epilepsy attributed to MRI-identified lesions (22.3%). Eighty-eight percent of adolescents were taking monotherapy and 64.8% of these were taking valproate. New antiepileptic drugs (AEDs), topiramate and lamotrigine, the only drugs available free of charge at the Serbian market, were used in 19.4% of patients. A total of 57.3% adolescents were seizure-free, 24.2% had occasional seizures, and 18.5% had seizures despite AED treatment. PMID- 22426687 TI - Surgical outcome of right liver donors in living donor liver transplantation: single-center experience with 500 cases. AB - BACKGROUND: With the increasing number of living donor liver transplantation (LDLT), concerns regarding morbidity and mortality of donors have become inevitable. Thus, the aim of the present study was to find ways to reduce the rate of morbidity and mortality of donors by analyzing our experience. METHODS: A retrospective clinicopathologic analysis was performed for 500 consecutive living donors who underwent donor right hepatectomy between May 1999 and February 2011. We chronologically divided those procedures into three periods: period A (n = 100), period B (n = 200), and period C (n = 200). Surgical outcomes according to each period were then compared. RESULTS: Over time, the following factors have decreased: the operative time, the amount of transfusions during surgery, hospital stay, and the incidence of biliary complications. No mortality developed. Even though the total complication rate was high (21.6 %, n = 108) including 10.6 % (n = 53) of biliary complications, the grade 3 complication rate was only 9.4 % (n = 47). In most patients with grade 3 complication, interventional therapies via radiologic or endoscopic approaches corrected these complications, and reoperation was required for ten patients (2 %). Whereas biliary complications were related with operation period (period B or C compared to period A; relative risk [RR] 2.10, P = 0.049, 95 % CI 1.01-4.39) and operative time (RR 1.01, P = 0.027, 95 % CI 1.00-1.02), postoperative hyperbilirubinemia (serum total bilirubin >= 5 mg/dL) was related with male gender (RR 2.68, P = 0.039, 95 % CI 1.05-6.85) and >= 25 % liver steatosis (RR 3.35, P = 0.053, 95 % CI 0.99-11.38). CONCLUSIONS: Optimization of donor selection as well as institutional experience is imperative to improve the surgical outcome. Even though donor hepatectomy was associated with relatively higher complication rate, most complications showed low-grade severity which could be corrected by interventional therapies. PMID- 22426688 TI - Prognostic significance of serum cystatin C in multiple myeloma. AB - Multiple myeloma (MM) is frequently complicated by renal insufficiency, which is associated with an unfavorable prognosis. Serum cystatin C is a new and accurate marker of glomerular filtration rate. Global gene expression analysis has revealed serum cystatin C as one of the most highly upregulated genes in MM. Recent data have shown serum cystatin C as an independent prognostic marker in MM. To further elucidate the prognostic significance of serum cystatin C, we investigated pretreatment serum cystatin C levels in 68 newly diagnosed patients homogeneously treated with high-dose melphalan followed by autologous stem cell transplantation. Median serum cystatin C level in MM patients was significantly higher than in the 66 healthy controls (1.07 vs. 0.74 mg/L [p = 0.002]). Median serum cystatin C levels significantly increased with higher International Staging System (ISS) stages (stage I 0.72 mg/L; stage II 0.89 mg/L; stage III 1.28 mg/L; p < 0.0001). Higher serum cystatin C was positively correlated with higher serum levels of creatinine (r = 0.84; p < 0.0001), beta2-microglobulin (r = 0.72; p < 0.0001), LDH (r = 0.43; p = 0.0003), white blood cell counts (r = 0.61; p < 0.0001) and calcium (r = 0.29; p = 0.016), and negatively correlated with lower serum albumin levels (r = 0.44; p < 0.0001) and hemoglobin levels (r = 0.31; p = 0.01). Using ROC analysis, patients with serum cystatin C levels >=0.95 mg/L (n = 24) had a significantly shorter event-free survival (EFS) and overall survival (OS) than patients with serum cystatin C levels <0.95 mg/L (median EFS: 26 vs. 44 months, p < 0.0001; median OS: 54 vs. 68 months, p = 0.05). Moreover, the combination of serum cystatin C level and genomic aberrations further refined the prognostic information (EFS and OS) provided by either one of the factors. The level of serum cystatin C is not only a sensitive marker of renal function, but also reflects tumor burden and delivers prognostic information in MM. PMID- 22426689 TI - Protective effect of extract of chicken meat on restraint stress-induced liver damage in mice. AB - In this study, we investigated the protective effects of the extract of chicken meat (EC) on liver damage in mice caused by restraint stress. Our results showed that 18 h of restraint stress-induced liver damage was marked by an increase of plasma alanine aminotransferase (ALT) and aspartate aminotransferase(AST) levels. However, oral administration of EC (0.12 and 0.24 mL/10 g per day, 7 d) was found to reduce the increased plasma ALT and AST levels in stressed mice. Meanwhile, EC significantly decreased the contents of malondialdehyde and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) in plasma or liver of stressed mice. The gene expressions of antioxidative enzymes (Cu/Zn-SOD, Mn-SOD and GPX) were also up-regulated in the EC-treated group when compared with the stressed group. In addition, EC administration was found to resist a stress-induced increase of plasma corticosterone levels and down regulation of liver glucocorticoid receptor gene expression. These results suggested that EC could protect against restraint stress-induced liver damage by smoothing stress and promoting antioxidative processes. PMID- 22426690 TI - Angiotensin II receptor type 1 blockers suppress the cell proliferation effects of angiotensin II in breast cancer cells by inhibiting AT1R signaling. AB - Chronic stress and a high-fat diet are well-documented risk factors associated with the renin-angiotensin system in the development of breast cancer. The angiotensin II type 1 receptor (AT1R) is a novel component of the renin angiotensin system. Several recent studies have focused on the function of AT1R in cell proliferation during cancer development. Thus, we hypothesized that angiotensin II (Ang II) can promote proliferation of breast cancer via activated AT1R; the activation of AT1R may play an important role in promoting breast cancer growth, and AT1R blocker (ARB) may suppress the promotional effect on proliferation by antagonizing AT1R. The expression level of AT1R was found to be significantly upregulated in breast cancer cells by immunohistochemistry, but no correlation between AT1R expression and ER/PR/Her-2 expression was observed. The AT1R(+)-MCF-7 cell line exhibited high expression of AT1R protein, and we generated the AT1R(-)-MCF-7 cell line using RNA interference. ARBs, and in particular irbesartan, effectively inhibited the effects of Ang II on cell proliferation, cell cycle development and downstream AT1R signaling events, including the activation of the Ras-Raf-MAPK pathway and the transcription factors NF-kappaB and CREB. Irbesartan also significantly altered p53, PCNA and cyclin D1 expression, which was also influenced by activated AT1R in AT1R(+)-MCF 7 cells. These results suggest that ARBs may be useful as a novel preventive and therapeutic strategy for treating breast cancer. PMID- 22426691 TI - Carbohydrate antigen 19-9 is a valuable prognostic factor in colorectal cancer patients with normal levels of carcinoembryonic antigen and may help predict lung metastasis. AB - PURPOSE: We retrospectively analyzed preoperative levels of carbohydrate antigen (CA) 19-9 in colorectal cancer (CRC) patients to determine the prognostic value of CA19-9 in CRC patients with normal carcinoembryonic antigen (CEA) levels. METHODS: A total of 639 patients who underwent curative surgery at Taipei Veterans General Hospital between 2002 and 2006 were enrolled. We excluded 254 patients (39.7 %) with high preoperative CEA levels and analyzed 385 patients with normal CEA levels. The measured endpoint was the postoperative disease-free survival (DFS). The prognostic value of CA19-9 was determined using log-rank test and Cox regression analysis. RESULTS: High CA19-9 levels were significantly associated with advanced disease and were detected in 5.8 % of patients with stage I disease, 11.7 % of those with stage II disease, and 22.5 % of those with stage III disease (P < 0.001). The 5-year DFS in patients with normal CA19-9 levels was 82.0 %, which was significantly higher than that in patients with high CA19-9 levels (68 %; P < 0.001). In a multivariate analysis, the most important independent factor affecting the 5-year DFS was tumor-node-metastasis stage (95 % CI, 1.26-2.36; HR = 1.72). After stratification by other factors, high CA19-9 level remained an independent prognostic factor for patients with normal CEA levels. Patients with high CA19-9 levels also showed a higher incidence of lung metastasis (23.1 %) than those with normal CA19-9 levels (7.2 %). CONCLUSIONS: CA19-9 may be a prognostic factor for CRC patients with normal CEA levels. An aggressive follow-up protocol for lung metastasis should be used for these patients. PMID- 22426692 TI - Confirmation of three inflammatory bowel disease susceptibility loci in a Chinese cohort. AB - PURPOSE: Recent genome-wide association studies have identified a number of inflammatory bowel diseases (IBD) susceptibility loci in White populations. The aim of our study was to evaluate whether these susceptibility loci also existed in a Chinese Han IBD population. METHODS: Peripheral blood DNA samples from groups of patients with Crohn's disease (CD) (n = 48), ulcerative colitis (UC) (n = 49), and healthy controls (n = 50) were genotyped for eight genes. Then, an extended analysis of the relationship between genotype and phenotype was performed. RESULTS: NOD2-P268S (P = 0.025) was found to contribute susceptibility to CD in the Chinese population. IL23R-rs11805303 was detected to confer a strong protective effect against UC (P = 0.010), whereas PTPN2-rs2542151 was significantly associated with an increased risk of UC (P = 0.001). Further phenotype-genotype analysis revealed that P268S was associated with early age of onset (P = 0.028), ileal disease (P = 0.003), and enteric cavity narrowing (P = 0.007). CONCLUSIONS: The study indicates that IL23R-rs11805303 and PTPN2 rs2542151 might contribute to the development of UC and NOD2-P268S might be involved in the etiology of CD in the Chinese Han population. PMID- 22426693 TI - In brief: the Mason classification of radial head fractures. PMID- 22426694 TI - Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice. AB - AIM: To develop a rational immunotherapy against tumor metastasis by combining a Toll-like-receptor 2 (TLR2)-neutralizing antibody with a TLR9 agonist CpG ODN, and then investigate the mechanism of action for this combinational regimen. METHODS: After mouse melanoma B16-F10 cell inoculation, female C57BL/6 mice were treated with either CpG ODN (0.5 mg/kg) or the anti-TLR2 antibody (200 MUg/kg), or with a combination of the two agents. Pulmonary metastases were evaluated by counting metastatic nodes on the lung surface using anatomical microscopy. Flow cytometry was used to evaluate the cytotoxicity of the immune cells in tumor draining lymph nodes, the cell population in the spleen, and the infiltration of immune cells within the lungs. Cytokine and enzyme expression in the lung tissue was evaluated using ELISA or immunostaining. RESULTS: Anti-metastatic effects were detected in mice treated with either CpG ODN or the anti-TLR2 antibody alone. However, treatment with CpG ODN plus the anti-TLR2 antibody synergistically suppressed the metastasis as compared with treatment with either single agent. The combinational treatment resulted in enhanced infiltration of natural killer cells and cytotoxic T cells, reduced recruitment of type 2 macrophages and Tregs, and decreased expression of immunosuppressive factors including TGF-beta1, cyclooxygenase-2 and indoleamine 2,3-dioxygenase, thus stimulated tumor cytotoxicity and suppressed metastasis. The anti-metastatic effect of the combinational regimen was further confirmed in spontaneous metastatic mouse model of Lewis lung carcinoma. CONCLUSION: Our studies suggest that combining a TLR9 agonist with an anti-TLR2 antibody, which eliminates immunosuppressive factors from the tumor environment, is critical for an effective anti-metastatic immunotherapy. PMID- 22426695 TI - Strontium fructose 1,6-diphosphate prevents bone loss in a rat model of postmenopausal osteoporosis via the OPG/RANKL/RANK pathway. AB - AIM: To evaluate the protective effects of strontium fructose 1,6-diphosphate (FDP-Sr), a novel strontium salt that combined fructose 1,6-diphosphate (FDP) with strontium, on bone in an ovariectomy-induced model of bone loss. METHODS: Eighty female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated. Three months later, the rats were assigned to six groups (10 for each): sham operated, OVX control, OVX+FDP-Sr (110, 220, or 440 mg/kg), or OVX+strontium ranelate (SR, 180 mg/kg). Drugs were administered orally for 3 months. When the treatment was terminated, the following parameters were assessed: bone mineral density (BMD), the biomechanical properties of the femur and lumbar vertebrae, trabecular histomorphology, serum phosphorus, calcium, bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRACP5b), N telopeptide of type I collagen (NTx) and a series of markers for oxidative stress. Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) levels in serum were measured using ELISA and their gene expression levels in the bone were measured using R-T PCR. RESULTS: Treatment with FDP-Sr (220 or 440 mg/kg) or SR (180 mg/kg) significantly increased the BMD and improved the bone microarchitecture and bone strength in OVX rats. The treatments also decreased in the levels of H(2)O(2) and MDA, restored the CAT level in serum and bone marrow, increased the serum B-ALP and decreased NTx and TRACP 5b in OVX rats. Treatment with FDP-Sr decreased the RANKL level, and increased the OPG level in serum in a dose-dependent manner. It also significantly down-regulated the RANKL expression and up-regulated OPG expression in bone marrow. CONCLUSION: FDP-Sr may be an effectve treatment for postmenopausal osteoporosis that acts, in part, via a decrease in osteoclastogenesis through the OPG?RANKL?RANK pathway. PMID- 22426696 TI - Gambogic acid inhibits TNF-alpha-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-kappaB signaling pathways. AB - AIM: To investigate the mechanisms underlying the inhibitory effect of gambogic acid (GA) on TNF-alpha-induced metastasis of human prostate cancer PC3 cells in vitro. METHODS: TNF-alpha-mediated migration and invasion of PC3 cells was examined using migration and invasion assays, respectively. NF-kappaB transcriptional activity and nuclear translocation were analyzed with luciferase reporter gene assays, immunofluorescence assays and Western blots. The ability of p65 to bind the promoter of Snail, an important mesenchymal molecular marker, was detected using a chromatin immunoprecipitation (ChIP) assay. After treatment with Snail-specific siRNA, the expression of invasiveness-associated genes was measured using quantitative real-time PCR and Western blot. RESULTS: GA significantly inhibited the viability of PC3 cells at 1-5 MUmol/L, but did not produce cytotoxic effect at the concentrations below 0.5 MUmol/L. GA (0.125-0.5 MUmol/L) dose-dependently inhibited the migration and invasion of PC3 cells induced by TNF-alpha (10 ng/mL). Moreover, the TNF-alpha-mediated activation of phosphatidylinositol-3-OH kinase/protein kinase B (PI3K/Akt) and NF-kappaB pathways was suppressed by GA (0.5 MUmol/L). Furthermore, this anti-invasion effect of GA was associated with regulation of Snail. Snail expression was significantly down-regulated by treatment with GA (0.5 MUmol/L) in the TNF-alpha stimulated PC3 cells. CONCLUSION: GA inhibits TNF-alpha-induced invasion of PC3 cells via inactivation of the PI3K/Akt and NF-kappaB signaling pathways, which may offer a novel approach for the treatment of human prostate cancer. PMID- 22426697 TI - Contribution of myostatin gene polymorphisms to normal variation in lean mass, fat mass and peak BMD in Chinese male offspring. AB - AIM: Myostatin gene is a member of the transforming growth factor-beta (TGF-beta) family that negatively regulates skeletal muscle growth. Genetic polymorphisms in Myostatin were found to be associated with the peak bone mineral density (BMD) in Chinese women. The purpose of this study was to investigate whether myostatin played a role in the normal variation in peak BMD, lean mass (LM), and fat mass (FM) of Chinese men. METHODS: Four hundred male-offspring nuclear families of Chinese Han ethnic group were recruited. Anthropometric measurements, including the peak BMD, body LM and FM were measured using dual-energy X-ray absorptiometry (DXA). The single nucleotide polymorphisms (SNPs) studied were tag-SNPs selected by sequencing. Both rs2293284 and +2278GA were genotyped using TaqMan assay, and rs3791783 was genotyped with PCR-restriction fragment length polymorphism (RFLP) analysis. The associations of the SNPs with anthropometric variations were analyzed using the quantitative transmission disequilibrium test (QTDT). RESULTS: Using QTDT to detect within-family associations, neither single SNP nor haplotype was found to be associated with peak BMD at any bone site. However, rs3791783 was found to be significantly associated with fat mass of the trunk (P<0.001). Moreover, for within-family associations, haplotypes AGG, AAA, and TGG were found to be significantly associated with the trunk fat mass (all P<0.001). CONCLUSION: Our results suggest that genetic variation within myostatin may play a role in regulating the variation in fat mass in Chinese males. Additionally, the myostatin gene may be a candidate that determines body fat mass in Chinese men. PMID- 22426698 TI - CPU86017-RS attenuate hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and pro-inflammatory cytokines. AB - AIM: Downregulation of androgen biosynthesis genes StAR (steroidogenic acute regulatory) and 3beta-HSD (3beta-hydroxysteroid dehydrogenase) contributes to low testosterone levels in hypoxic mice and is possibly related to increased expression of pro-inflammatory cytokines in the testis. The aim of this study is to investigate the effects of CPU86017-RS that block Ca(2+) influx on hypoxia induced testis insult in mice. METHODS: Male ICR mice were divided into 5 groups: control group, hypoxia group, hypoxia group treated with nifedipine (10 mg/kg), hypoxia groups treated with CPU86017-RS (60 or 80 mg/kg). Hypoxia was induced by placing the mice in a chamber under 10%+/-0.5% O2 for 28 d (8 h per day). The mice were orally administered with drug in the last 14 d. At the end of experiment the testes of the mice were harvested. The mRNA and protein levels of StAR, 3beta-HSD, connexin 43 (Cx43), matrix metalloprotease 9 (MMP9), endothelin receptor A (ET(A)R) and leptin receptor (OBRb) were analyzed using RT-PCR and Western blotting, respectively. The malondialdehyde (MDA), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) levels were measured using biochemical kits. Serum testosterone concentration was measured with radioimmunoassay. RESULTS: Hypoxia significantly increased the MDA level, and decreased the LDH, ACP and SDH activities in testes. Meanwhile, hypoxia induced significant downregulation of StAR and 3beta-HSD in testes responsible for reduced testosterone biosynthesis. It decreased the expression of Cx43, and increased the expression of MMP9, ETAR and OBRb, leading to abnormal testis function and structure. These changes were effectively diminished by CPU86017-RS (80 mg/kg) or nifedipine (10 mg/kg). CONCLUSION: Low plasma testosterone level caused by hypoxia was due to downregulation of StAR and 3beta-HSD genes, in association with an increased expression of pro-inflammatory cytokines. These changes can be alleviated by CPU86017-RS or nifedipine. PMID- 22426699 TI - Traditional Chinese medicine formula Qing Huo Yi Hao as superoxide anion scavenger in high glucose-treated endothelial cells. AB - AIM: To investigate the effects of a traditional Chinese medicine formula Qing Huo Yi Hao (QHYH) and its components on hydroxyl radical (HO(*)) production in vitro and the activity of QHYH against free radicals in cultured endothelial cells induced by high glucose. METHODS: Hydroxyl radicals (HO(*)) were generated through Fenton reactions in vitro, and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was used as a spin trap to form DMPO/HO(*) adducts detected using electron paramagnetic resonance (EPR). Immortalized mouse cerebral microvascular endothelial (bEnd.3) cells were treated with high glucose (35 mmol/L). The free radical scavenging ability of QHYH in the cells was evaluated using EPR. Superoxide dismutase (SOD) was used to identify the free radicals scavenged by QHYH in the cells. RESULTS: QHYH and its 8 components concentration-dependently reduced DMPO/HO(*) signaling. The DMPO/HO(*) adduct scavenging ability of QHYH was 82.2%, which was higher than each individual component. The free radical scavenging ability of 1% QHYH in high glucose-treated bEnd.3 cells was approximately 70%. In these cells, the free radicals were also specifically reduced by SOD (400 U/mL), implying that the free radicals were primarily superoxide anions. CONCLUSION: The results demonstrate that the QHYH formula is potent antioxidant acting as scavenge of superoxide anions in high glucose treated endothelial cells. PMID- 22426701 TI - Influence of temperature on the effectiveness of a biogenic carbonate surface treatment for limestone conservation. AB - So far, most studies on microbiologically induced carbonate precipitation for limestone conservation have been performed at temperatures optimal for the activity of the calcinogenic bacteria (i.e., 20-28 degrees C). Successful application in practice, however, requires adequate performance in a wide range of environmental conditions. Therefore, the aim of this study was to select microorganisms that are most suited for biodeposition at temperatures relevant for practice. In a first step, ureolytic microorganisms were screened for their growth and ureolytic activity at different temperatures (10, 20, 28, and 37 degrees C). Large differences in calcinogenic activity could be observed between experiments performed on agar plates and those performed in solution and in limestone. In a second step, the influence of temperature on the performance of the biodeposition treatment with different ureolytic microorganisms was evaluated, both on the consolidative and protective effect of the treatment. In contrast with the experiments on agar plates, the Sporosarcina psychrophila strains failed to produce significant amounts of calcium carbonate on limestone in conditions relevant for practice, even at 10 degrees C. This resulted in a poor performance of the treatment. From experiments performed on limestone prisms, it appeared that the mesophilic Bacillus sphaericus produced the highest amount of carbonate in the shortest amount of time at all temperatures tested. As a result, compared to the untreated specimens, the highest consolidative (64 % lower weight loss upon sonication) and protective effect (46 % decreased sorptivity) were observed for the treatments with this species. From this study, it appears that among all ureolytic strains tested, B. sphaericus is most suited for biodeposition applications in practice. PMID- 22426700 TI - Retinol induces morphological alterations and proliferative focus formation through free radical-mediated activation of multiple signaling pathways. AB - AIM: Toxicity of retinol (vitamin A) has been previously associated with apoptosis and/or cell malignant transformation. Thus, we investigated the pathways involved in the induction of proliferation, deformation and proliferative focus formation by retinol in cultured Sertoli cells of rats. METHODS: Sertoli cells were isolated from immature rats and cultured. The cells were subjected to a 24-h treatment with different concentrations of retinol. Parameters of oxidative stress and cytotoxicity were analyzed. The effects of the p38 inhibitor SB203580 (10 MUmol/L), the JNK inhibitor SP600125 (10 MUmol/L), the Akt inhibitor LY294002 (10 MUmol/L), the ERK inhibitor U0126 (10 MUmol/L) the pan PKC inhibitor Go6983 (10 MUmol/L) and the PKA inhibitor H89 (1 MUmol/L) on morphological and proliferative/transformation-associated modifications were studied. RESULTS: Retinol (7 and 14 MUmol/L) significantly increases the reactive species production in Sertoli cells. Inhibition of p38, JNK, ERK1/2, Akt, and PKA suppressed retinol-induced [(3)H]dT incorporation into the cells, while PKC inhibition had no effect. ERK1/2 and p38 inhibition also blocked retinol-induced proliferative focus formation in the cells, while Akt and JNK inhibition partially decreased focus formation. ERK1/2 and p38 inhibition hindered transformation-associated deformation in retinol-treated cells, while other treatments had no effect. CONCLUSION: Our results suggest that activation of multiple kinases is responsible for morphological and proliferative changes associated to malignancy development in Sertoli cells by retinol at the concentrations higher than physiological level. PMID- 22426704 TI - A cohort-controlled trial of the addition of customized foot orthotics to standard care in fibromyalgia. AB - Customized foot orthotics are widely prescribed for patients with chronic, non specific low back pain and lower limb pain, but there are few trials demonstrating effectiveness, and none for fibromyalgia. A total of 67 consecutive patients presenting with chronic, widespread pain, who met the 1990 American College of Rheumatology criteria for fibromyalgia, were included in the study. A total of 32 subjects were prescribed a spinal exercise therapy program along with analgesics. These subjects formed the Control group. A second group, comprised of 35 subjects, received the same therapy, along with customized foot orthotics (Orthotics group). All subjects completed the Revised Fibromyalgia Impact Questionnaire (FIQR) at the initiation of the study and at 8 weeks follow-up. The number of subjects using any type of prescription analgesic or other medication for chronic pain at baseline and at 8 weeks was also recorded. A total of 30 subjects in the Control group and 33 in the Orthotics group completed the study. All subjects completed the baseline and 8-week FIQR. The two groups were well matched in terms of age (45.3 +/- 11.5 years in the Orthotics group vs. 47.2 +/- 8.7 years in the cohort Control), medication use, duration of pain (6.5 +/- 4.3 years in the Orthotics group vs. 6.2 +/- 3.4 years in the cohort Control group), as well as baseline FIQR scores (55.2 +/- 11.0 in the Orthotics group vs. 56.3 +/ 12.2 in the cohort Control group). At 8 weeks, the Orthotics group had a greater reduction in the FIQR score than the cohort Control group (reduction of 9.9 +/- 5.9 vs. 4.3 +/- 4.4, respectively), and this was mainly due to changes in the 'function' domain of the FIQR (reduction of 19.6 +/- 9.4 in the Orthotics group vs. 8.1 +/- 4.3 in the cohort Control group). As part of a complex intervention, in a cohort-controlled trial of primary care patients with fibromyalgia, the addition of custom-made foot orthotics to usual care appears to improve functioning in the short term. PMID- 22426702 TI - Interactions between the C-terminus of Kv1.5 and Kvbeta regulate pyridine nucleotide-dependent changes in channel gating. AB - Voltage-gated potassium (Kv) channels are tetrameric assemblies of transmembrane Kv proteins with cytosolic N- and C-termini. The N-terminal domain of Kv1 proteins binds to beta-subunits, but the role of the C-terminus is less clear. Therefore, we studied the role of the C-terminus in regulating Kv1.5 channel and its interactions with Kvbeta-subunits. When expressed in COS-7 cells, deletion of the C-terminal domain of Kv1.5 did not affect channel gating or kinetics. Coexpression of Kv1.5 with Kvbeta3 increased current inactivation, whereas Kvbeta2 caused a hyperpolarizing shift in the voltage dependence of current activation. Inclusion of NADPH in the patch pipette solution accelerated the inactivation of Kv1.5-Kvbeta3 currents. In contrast, NADP(+) decreased the rate and the extent of Kvbeta3-induced inactivation and reversed the hyperpolarizing shift in the voltage dependence of activation induced by Kvbeta2. Currents generated by Kv1.5DeltaC+Kvbeta3 or Kv1.5DeltaC+Kvbeta2 complexes did not respond to changes in intracellular pyridine nucleotide concentration, indicating that the C-terminus is required for pyridine nucleotide-dependent interactions between Kvbeta and Kv1.5. A glutathione-S-transferase (GST) fusion protein containing the C-terminal peptide of Kv1.5 did not bind to apoKvbeta2, but displayed higher affinity for Kvbeta2:NADPH than Kvbeta2:NADP(+). The GST fusion protein also precipitated Kvbeta proteins from mouse brain lysates. Pull-down experiments, structural analysis and electrophysiological data indicated that a specific region of the C-terminus (Arg543-Val583) is required for Kvbeta binding. These results suggest that the C-terminal domain of Kv1.5 interacts with beta-subunits and that this interaction is essential for the differential regulation of Kv currents by oxidized and reduced nucleotides. PMID- 22426705 TI - Geological sources of fluoride and acceptable intake of fluoride in an endemic fluorosis area, southern Iran. AB - The present study is the first attempt to put forward possible source(s) of fluoride in the Dashtestan area, Bushehr Province, southern Iran. In response to reports on the high incidence of dental fluorosis, 35 surface and groundwater samples were collected and analysed for fluoride. The results indicate that dissolved fluoride in the study area is above the maximum permissible limit recommended by the World Health Organization (WHO). An additional 35 soil and rock samples were also collected and analysed for fluoride, and rock samples were subjected to petrographic investigations and X-ray diffraction. The results of these analyses show that the most likely source for fluoride in the groundwater is from clay minerals (chlorite) and micas (muscovite, sericite, and biotite) in the soils and rocks in the area. We also note that due to the high average temperatures all year round and excessive water consumption in the area, the optimum fluoride dose level should be lower than that recommended by the WHO. PMID- 22426706 TI - Use of an electronic problem list by primary care providers and specialists. AB - BACKGROUND: Accurate patient problem lists are valuable tools for improving the quality of care, enabling clinical decision support, and facilitating research and quality measurement. However, problem lists are frequently inaccurate and out of-date and use varies widely across providers. OBJECTIVE: Our goal was to assess provider use of an electronic problem list and identify differences in usage between medical specialties. DESIGN: Chart review of a random sample of 100,000 patients who had received care in the past two years at a Boston-based academic medical center. PARTICIPANTS: Counts were collected of all notes and problems added for each patient from 1/1/2002 to 4/30/2010. For each entry, the recording provider and the clinic in which the entry was recorded was collected. We used the Healthcare Provider Taxonomy Code Set to categorize each clinic by specialty. MAIN MEASURES: We analyzed the problem list use across specialties, controlling for note volume as a proxy for visits. KEY RESULTS: A total of 2,264,051 notes and 158,105 problems were recorded in the electronic medical record for this population during the study period. Primary care providers added 82.3% of all problems, despite writing only 40.4% of all notes. Of all patients, 49.1% had an assigned primary care provider (PCP) affiliated with the hospital; patients with a PCP had an average of 4.7 documented problems compared to 1.5 problems for patients without a PCP. CONCLUSIONS: Primary care providers were responsible for the majority of problem documentation; surgical and medical specialists and subspecialists recorded a disproportionately small number of problems on the problem list. PMID- 22426707 TI - Self-rated health as a comprehensive indicator of lifestyle-related health status. AB - OBJECTIVES: To evaluate the usefulness of self-rated health (SRH) as a comprehensive indicator of lifestyle-related health status by examining the relationships between SRH and: (1) history of cancer and cardiovascular disease; (2) treatment of hypertension, diabetes, and dyslipidemia; (3) abnormalities in clinical parameters including blood pressure, fasting glucose, and lipids; and (4) lifestyle habits. METHODS: 3744 health-check examinees at Tokai University Hachioji Hospital seen between April 2009 and March 2010 were enrolled. SRH was graded as "good," "relatively good," "relatively poor," or "poor." For statistical comparison, the differences among "healthy" (=good), "relatively healthy" (=relatively good), and "unhealthy" (=relatively poor plus poor) groups were examined. Mantel-Haenszel odds ratios were calculated to remove the confounding effect of age, using the healthy group as the reference. The Mantel extension method was used as a trend test. RESULTS: 1049 subjects rated their health as good, 2194 as relatively good, 428 as relatively poor, and 73 as poor. The prevalence of all diseases showed significant odds ratios and trends as SRH deteriorated. Obesity, blood pressure, glucose metabolism, and lipids deteriorated significantly as SRH became poorer, and a trend was observed in all parameters. Weight change, exercise, smoking, and rest showed significant odds ratios and trends as SRH deteriorated. CONCLUSION: SRH appears useful as a comprehensive indicator of lifestyle-related health status. PMID- 22426708 TI - Which factors prognosticate spinal instability following lumbar laminectomy? AB - PURPOSE: Reduced strength and shear stiffness (SS) of lumbar motion segments following laminectomy may lead to instability. The purpose of the present study was to assess a broad range of parameters as potential predictors of shear biomechanical properties of the lumbar spine. METHODS: Radiographs and MRI of all lumbar spines were obtained to classify geometry and degeneration of the motion segments. Additionally, dual X-ray absorptiometry (DXA) scans were performed to measure bone mineral content and density (BMC and BMD). Facet sparing lumbar laminectomy was performed either on L2 or L4, in 10 human cadaveric lumbar spines (mean age 72.1 years, range 53-89 years). Spinal motion segments were dissected (L2-L3 and L4-L5) and tested in shear, under simultaneously loading with 1600 N axial compression. Shear stiffness, shear yield force (SYF) and shear force to failure (SFF) were determined and statistical correlations with all parameters were established. RESULTS: Following laminectomy, SS, SYF, and SFF declined (by respectively 24, 41, and 44%). For segments with laminectomy, SS was significantly correlated with intervertebral disc degeneration and facet joint degeneration (Pfirrmann: r = 0.64; Griffith: r = 0.70; Lane: r = 0.73 and Pathria: r = 0.64), SYF was correlated with intervertebral disc geometry (r = 0.66 for length; r = 0.66 for surface and r = 0.68 for volume), BMC (r = 0.65) and frontal area (r = 0.75), and SFF was correlated with disc length (r = 0.73) and BMC (r = 0.81). For untreated segments, SS was significantly correlated with facet joint tropism (r = 0.71), SYF was correlated with pedicle geometry (r = 0.83), and SFF was correlated with BMC (r = 0.85), BMD (r = 0.75) and frontal area (r = 0.75). SS, SYF and SFF could be predicted for segments with laminectomy (r (2) values respectively: 0.53, 0.81 and 0.77) and without laminectomy (r (2) value respectively: 0.50, 0.83 and 0.83). CONCLUSIONS: Significant loss of strength and SS are predicted by BMC, BMD, intervertebral disc geometry and degenerative parameters, suggesting that low BMC or BMD, small intervertebral discs and absence of osteophytes could predict the possible development of post operative instability following lumbar laminectomy. PMID- 22426709 TI - Lipases: an overview. AB - Lipases are ubiquitous enzymes, widespread in nature. They were first isolated from bacteria in the early nineteenth century and the associated research continuously increased due to the particular characteristics of these enzymes. This chapter reviews the main sources, structural properties, and industrial applications of these highly studied enzymes. PMID- 22426710 TI - Lipases or esterases: does it really matter? Toward a new bio-physico-chemical classification. AB - Carboxylester hydrolases, commonly named esterases, consist of a large spectrum of enzymes defined by their ability to catalyze the hydrolysis of carboxylic ester bonds and are widely distributed among animals, plants, and microorganisms. Lipases are lipolytic enzymes which constitute a special class of carboxylic esterases capable of releasing long-chain fatty acids from natural water insoluble carboxylic esters. However, up to now, several unsuccessful attempts aimed at differentiating "lipases" from "esterases" by using various criteria. These criteria were based on the first substrate used chronologically, primary sequence comparisons, some kinetic parameters, or some structural features.Lipids are biological compounds which, by definition, are insoluble in water. Taking into account this basic physico-chemical criterion, we primarily distinguish lipolytic esterases (L, acting on lipids) from nonlipolytic esterases (NL, not acting on lipids). In view of the biochemical data accumulated up to now, we proposed a new classification of esterases based on various criteria of physico chemical, chemical, anatomical, or cellular nature. We believe that the present attempt matters scientifically for several reasons: (1) to help newcomers in the field, performing a few key experiments to figure out if a newly isolated esterase is lipolytic or not; (2) to clarify a debate between scientists in the field; and (3) to formulate questions which are relevant to the still unsolved problem of the structure-function relationships of esterases. PMID- 22426711 TI - Study of new feruloyl esterases to understand lipase evolution: the case of Bacillus flexus. AB - Recently, the crystal structure of the feruloyl esterase A from Aspergillus niger (AnFaeA) was elucidated. This enzyme displays an alpha/beta hydrolase fold and a catalytic triad similar to that found in fungal lipases (30-37% identity). Surprisingly, AnFaeA showed an overall fold similarity with the Rhizomucor miehei and other related fungal lipases. All these data strongly suggest that the ancestral function (lipase) had shifted, with molecular adaptation leading to a novel enzyme (type-A feruloyl esterase). The discovery of new feruloyl esterases could lead to get insight into the evolutionary pathways of these enzymes and into new possibilities of directed evolution of lipases. In this chapter, the production of Bacillus flexus NJY2 feruloyl esterases is described. Unlike the previously described feruloyl esterases, which mostly belong to eukaryotes (mainly fungus), this unique feruloyl esterases from a prokaryotic alkaliphile microorganism could be the starting point for new discoveries on lipase and feruloyl esterase evolutionary relationships. PMID- 22426712 TI - Phospholipases: an overview. AB - Phospholipids are present in all living organisms. They are a major component of all biological membranes, along with glycolipids and cholesterol. Enzymes aimed at cleaving the various bonds in phospholipids, namely phospholipases, are consequently widespread in nature, playing very diverse roles from aggression in snake venom to signal transduction, lipid mediators production, and digestion in humans. Although all phospholipases target phospholipids as substrates, they vary in the site of action on the phospholipids molecules, physiological function, mode of action, and their regulation. Significant studies on phospholipases characterization, physiological role, and industrial potential have been conducted worldwide. Some of them have been directed for biotechnological advances, such as gene discovery and functional enhancement by protein engineering. Others reported phospholipases as virulence factors and major causes of pathophysiological effects. In this introductory chapter, we provide brief details of different phospholipases. PMID- 22426713 TI - High-throughput screening method for lipases/esterases. AB - High-throughput screening (HTS) methods for lipases and esterases are generally performed by using synthetic chromogenic substrates (e.g., p-nitrophenyl, resorufin, and umbelliferyl esters) which may be misleading since they are not their natural substrates (e.g., partially or insoluble triglycerides). In previous works, we have shown that soluble nonchromogenic substrates and p nitrophenol (as a pH indicator) can be used to quantify the hydrolysis and estimate the substrate selectivity of lipases and esterases from several sources. However, in order to implement a spectrophotometric HTS method using partially or insoluble triglycerides, it is necessary to find particular conditions which allow a quantitative detection of the enzymatic activity. In this work, we used Triton X-100, CHAPS, and N-lauroyl sarcosine as emulsifiers, beta-cyclodextrin as a fatty acid captor, and two substrate concentrations, 1 mM of tributyrin (TC4) and 5 mM of trioctanoin (TC8), to improve the test conditions. To demonstrate the utility of this method, we screened 12 enzymes (commercial preparations and culture broth extracts) for the hydrolysis of TC4 and TC8, which are both classical substrates for lipases and esterases (for esterases, only TC4 may be hydrolyzed). Subsequent pH-stat experiments were performed to confirm the preference of substrate hydrolysis with the hydrolases tested. We have shown that this method is very useful for screening a high number of lipases (hydrolysis of TC4 and TC8) or esterases (only hydrolysis of TC4) from wild isolates or variants generated by directed evolution using nonchromogenic triglycerides directly in the test. PMID- 22426714 TI - Functional-based screening methods for lipases, esterases, and phospholipases in metagenomic libraries. AB - The use of metagenomic techniques for enzyme discovery constitutes a powerful approach. Functional screens, in contrast to sequence homology search, enable us to select enzymes based on their activity. It is noteworthy that they additionally guarantee the identification of genes coding for enzymes that exhibited no sequence similarity to known counterparts from public databases and that even do not match any putative catalytic residues, involved in the selected catalytic function. Therefore, this strategy not only provides new enzymes for new biotechnological applications, but also allows functional assignment of many proteins, found in abundance in the databases, currently designated as "hypothetical" or "conserved hypothetical" proteins. In the past decade, there has been an exponential increase in the design of functional screening programmes, the majority of them established for hydrolases and oxidoreductases. Here, functional screening methods that guarantee the greatest enzyme diversity, for mining esterases and lipases, are described. PMID- 22426715 TI - Plant lipases: partial purification of Carica papaya lipase. AB - Lipases from plants have very interesting features for application in different fields. This chapter provides an overview on some of the most important aspects of plant lipases, such as sources, applications, physiological functions, and specificities. Lipases from laticifers and particularly Carica papaya lipase (CPL) have emerged as a versatile autoimmobilized biocatalyst. However, to get a better understanding of CPL biocatalytic properties, the isolation and purification of individual C. papaya lipolytic enzymes become necessary. In this chapter, a practical protocol for partial purification of the latex-associated lipolytic activity from C. papaya is given. PMID- 22426716 TI - Plant phospholipases: an overview. AB - Plant phospholipases can be grouped into four major types, phospholipase D, phospholipase C, phospholipase A1 (PLA(1)), and phospholipase A2 (PLA(2)), that hydrolyze glycerophospholipids at different ester bonds. Within each type, there are different families or subfamilies of enzymes that can differ in substrate specificity, cofactor requirement, and/or reaction conditions. These differences provide insights into determining the cellular function of specific phospholipases in plants, and they can be explored for different industrial applications. PMID- 22426717 TI - Lipase and phospholipase inhibitors: design and applications. AB - Lipases are important drug discovery targets since they play central roles in signal transduction and metabolism. Many inhibitors have been isolated from natural sources and others derived through synthesis of substrate analogs or biomimetics. Because lipids are hydrophobic, there are special procedures needed for their study. This chapter covers two commonly used procedures for assay of lipases and phospholipases and how they can be adapted for the discovery and analysis of inhibitors. PMID- 22426718 TI - High-throughput assay of secreted phospholipases A2 inhibitors. AB - Attempts to characterize, quantify, and/or modulate the activity of the secreted phospholipase A(2) family of enzymes result from the diversity of physiological roles for which these enzymes have been implicated. The 1-palmitoyl-2-(10 pyrenedecanoyl)-phosphatidylglycerol (pyrenePG)-based fluorometric assay is a sensitive and readily adaptable method for further elucidating phospholipase function under various experimental conditions, as well as a tool for screening chemical libraries for potent inhibitors of this enzymatic activity. This assay is based on the observed difference in fluorescent emission of pyrene aggregated in vesicles compared to sequestered in monomeric form by binding to bovine serum albumin after lipolytic activity, thus allowing direct quantification of hydrolyzed fatty acids by the measurement of the corresponding monomeric emission intensity. The assay can be carried out in multiwell plates for high-throughput screening of compound libraries. PMID- 22426719 TI - Heterologous expression systems for lipases: a review. AB - The production of heterologous lipases is one of the most promising strategies to increase the productivity of the bioprocesses and to reduce costs, with the final objective that more industrial lipase applications could be implemented. In this chapter, an overview of the most common microbial expression systems for the overproduction of microbial lipases is presented. Prokaryotic system as Escherichia coli and eukaryotic systems as Saccharomyces cerevisiae and Pichia pastoris are analyzed and compared in terms of productivity, operational, and downstream processing facilities. Finally, an overview of heterologous Candida rugosa and Rhizopus oryzae lipases, two of the most common lipases used in biocatalysis, is presented. In both cases, P. pastoris has been shown as the most promising host system. PMID- 22426720 TI - Streptomyces phospholipase D cloning and production. AB - The transphosphatidylation catalytic ability of phospholipase D (PLD, EC 3.1.4.4) is a powerful biochemical tool for the acquisition of rare phospholipids (PLs), e.g., phosphatidylglycerol (PG) and phosphatidylserine (PS), and artificial phospholipids, which do not occur in nature. Specifically, actinomycete PLD recognizes not only the alcohols (i.e., glycerol or serine) corresponding to the polar head groups of natural PLs, but also secondary alcohols, aromatic alcohols, saccharides, N-heterocyclic alcohols, and vitamins as acceptors. Therefore, actinomycete PLD is a valuable enzyme in food, cosmetics, fine chemical and pharmaceutical industries. Here, we describe a protocol for the screening for PLD producing microorganisms, several PLD assays and methods of PLD production purification and the strategy of cloning of the Streptomyces PLD gene. PMID- 22426721 TI - Cloning of PLD2 from baculovirus for studies in inflammatory responses. AB - The enzyme PLD hydrolyzes phosphodiester bonds of lipids in cell membranes. Phosphatidic acid, a chief product of PLD enzymatic activity, is a pleiotropic second messenger with key roles in membrane trafficking, cell invasion, cell growth, and anti-apoptosis. We describe in the present study molecular, cellular, and physiological methods to understand the mechanism of how the PLD2 isozyme regulates the process of inflammation. We describe here (1) a method that details phospholipase D2 (PLD2) cloning in the pBac expression vector, (2) the large scale infection of Sf21 insect cells for protein production, (3) protein purification by TALON cobalt metal affinity matrix and subsequent assessment of PLD2 protein and lipase activity, (4) application of purified PLD2 protein for the study of Rac2 GTPase biology involving GTP binding by a pull-down assay and GTP/GDP exchange activity, (5) a method of PLD2 expression that involves mammalian cells, (6) a physiological application as relates to adhesion, chemotaxis, and phagocytosis, and (7) a model that integrates the results of a PLD-GTPase interaction from the molecular to the physiological contexts. PMID- 22426722 TI - Lipases production by solid-state fermentation: the case of Rhizopus homothallicus in perlite. AB - Lipases are widely used in the industry for different purposes. Although these enzymes are mainly produced by submerged fermentation, lipase production by solid state fermentation (SSF) has been gaining interest due to the advantages of this type of culture. Major advantages are higher production titers and productivity, less catabolite repression, and use of the dried fermented material as biocatalyst. This chapter describes a traditional methodology to produce fungal (Rhizopus homothallicus) lipases by SSF using perlite as inert support. The use of different devices (glass columns or Erlenmeyer flasks) and type of inoculum (spores or growing mycelium) is considered so that lipase production by SSF could be easily performed in any laboratory. PMID- 22426723 TI - Lipases and esterases from extremophiles: overview and case example of the production and purification of an esterase from Thermus thermophilus HB27. AB - Extremophiles are organisms that have evolved to exist in a variety of extreme environments. They fall into a number of different classes that include thermophiles, halophiles, acidophiles, alkalophiles, psychrophiles, and barophiles (piezophiles). Extremophiles have the potential to produce uniquely valuable biocatalysts that function under conditions in which usually the enzymes of their nonextremophilic counterparts could not. Among novel enzymes isolated from extremophilic microorganisms, hydrolases, and particularly lipases and esterases are experiencing a growing demand. Lipases (EC 3.1.1.3) and esterases (EC 3.1.1.1) catalyze the cleavage of ester bounds in aqueous media and the reverse reaction in organic solvents. Both lipolytic enzymes have relevant applications in food, dairy, detergent, biofuel, and pharmaceutical industries. Here, we summarize the properties of lipases and esterases from the main extremophile groups: thermophiles and hyperthermophiles, psychrophiles, halophiles, alkalophiles/acidophiles, and solvent-resistant microorganisms.We report the biomass and lipolytic activity production by Thermus thermophilus HB27 in 5-L stirred-tank bioreactor at 70 degrees C. Suitability of thermal spring water for culture media formulation is shown. In addition, a protocol to isolate and purify a cell-bound esterase from this microorganism is described. PMID- 22426724 TI - Purification, biochemical and kinetic properties of recombinant Staphylococcus aureus lipase. AB - We have compared the purification procedures as well as the biochemical and kinetic properties of wild type (wt-SAL3), untagged recombinant (rec(-His)SAL3), and tagged recombinant (rec(+His)SAL3) purified forms of Staphylococcus aureus lipase (SAL3). We used the pH-stat method (with emulsified tributyrin and olive oil as substrates) and the monomolecular film technique (with the three dicaprin isomers spread in the form of monomolecular films at the air-water interface). The data obtained showed that the recombinant expression process as well as the presence of a his-tag at the N-terminus of recombinant SAL3 affects significantly many biochemical and catalytic properties. The effects of the heterologous expression process on the catalytic properties of the staphylococcal lipases are three times more deleterious than the presence of an N-terminal tag extension. PMID- 22426725 TI - Phospholipase A2 purification and characterization: a case study. AB - We compared here the purification procedures, the pH, the calcium, the bile salts, and the temperature dependencies as well as the catalytic activities on phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of two purified secreted PLA2 from chicken pancreatic (ChPLA2-IB) and chicken intestinal (ChPLA2 IIA) origins. Interestingly, ChPLA2-IB hydrolyzes efficiently both purified PC and PE, whereas ChPLA2-IIA hydrolyzes only PE and not PC, even after a long incubation period. These analytical results clearly indicate that the catalytic activity of ChPLA2-IIA, measured with the pH-stat and using egg yolk as substrate, is mainly due to the hydrolysis of the PE fraction present in egg yolk. PMID- 22426726 TI - The yeast Yarrowia lipolytica as a generic tool for molecular evolution of enzymes. AB - It has been 20 years since strains of the yeast Yarrowia lipolytica were developed for the expression of recombinant proteins as alternative host to the commonly used yeasts, Pichia pastoris and Saccharomyces cerevisiae. Recently, a new strain, JMY1212, was engineered for protein evolution. With this new strain, a very high reproducibility in protein expression level was demonstrated, thus enabling its use for both rational and directed evolution strategies. Indeed, the coefficient of variation was shown to be of 10.7% for the whole process when all the steps are optimized, i.e. transformation of this strain with the gene of interest, cell growth, and protein production under oleic acid induction, and until activity screening assay. The object of this article is to summarize the fruit of these works and show the interest of Y. lipolytica strain JMY1212 for molecular evolution of enzymes, for both rational and directed evolution strategy. Lipase Lip2 from Y. lipolytica is taken here as an example to describe both strategies of molecular evolution. In these two methods, a first step of PCR creates either one targeted (rational design) or various random mutations (directed evolution), and is followed by the incorporation of the expression cassette in the genome of Y. lipolytica. An easy and direct comparison of variant properties is then allowed thanks to the extracellular and reproducible production of variants. PMID- 22426727 TI - Molecular modeling of lipase binding to a substrate-water interface. AB - Interactions of lipases with hydrophobic substrate-water interfaces are of great interest to design improved lipase variants and engineer reaction conditions. This chapter describes the necessary steps to carry out molecular dynamics simulations of Candida antarctica lipase B at tributyrin-water interface using the GROMACS simulation software. Special attention is drawn to the preparation of the protein and the substrate-water interface and to the analysis of the obtained trajectory. PMID- 22426728 TI - Different strategies for hyperactivation of lipase biocatalysts. AB - One important parameter for the application of lipase catalysts in chemical industries is the specific activity displayed towards natural or unnatural substrates. Different strategies to enhance the lipase activity have been described. The immobilization of lipases on hydrophobic supports by interfacial adsorption at low ionic strength permitted the hyperactivation of these enzymes by fixing the open conformation of the lipase on the hydrophobic support. Improvements of activity from 1.2- up to 20-fold with respect to the initial one have been observed for lipases from different sources.A second strategy was based on the presence of additives, in particular surfactants, with hydrophobic character to enhance the activity of lipases immobilized on macroporous supports up to 8 fold and even more than 100-fold in some cases for soluble lipases.Finally, a third strategy to improve the activity in lipases was based on a site-directed chemical modification of the protein on a unique reactive cysteine of the enzyme by disulfide exchange using different tailor-made activated polymers. PMID- 22426729 TI - Rational design of immobilized lipases and phospholipases. AB - Immobilization of lipases and phospholipases on, mainly, water insoluble carriers, helps in their economic reuse and in the development of continuous bioprocesses. Design of efficient lipases and phospholipases-immobilized system is rather a difficult task. A lot of research work has been done in order to optimize immobilization techniques and procedures and to develop an efficient immobilized system. A new rational design of immobilized derivatives strategy (RDID) has been conceived in favor of the successful synthesis of optimal lipases and phospholipases-immobilized derivatives, aiming prediction of the immobilized derivative's functionality and the optimization of load studies. RDID begins with the knowledge of structural and functional features of synthesis components (protein and carrier), and the practical goal of immobilized product. RDID was implemented in software named RDID ( 1.0 ). The employment of RDID allows selecting the most appropriate way to prepare immobilized derivatives more efficient in enzymatic bioconversion processes and racemic mixture resolution. PMID- 22426730 TI - Thermodynamical methods for the optimization of lipase-catalyzed reactions. AB - A basic insight on different thermodynamical strategies reported for the optimization of lipase-catalyzed reactions is presented. The significance of selecting the appropriate reaction media in order to enhance selectivity and operational stability of enzymes is discussed. From this analysis, the importance of developing thermodynamic strategies for controlling both the reaction kinetics and equilibrium is emphasized. A theoretical model (Conductor-like Screening Model for Realistic Solvation) for calculating thermodynamic properties in fluid phases is proposed as a powerful tool for predicting equilibrium and kinetic behavior in biocatalytic processes. PMID- 22426731 TI - Lipases as biocatalysts for the synthesis of structured lipids. AB - Structured lipids (SL) are broadly referred to as modified or synthetic oils and fats or lipids with functional or pharmaceutical applications. Some structured lipids, such as triglycerides that contain both long-chain (mainly essential) fatty acids and medium- or short-chain fatty acids and also artificial products that mimic the structure of natural materials, namely human milk fat substitutes and cocoa butter equivalents, have been discussed. Further, other modified or synthetic lipids, such as structured phospholipids and synthetic phenolic lipids are also included in this chapter. For all the products described in this chapter, enzymatic production in industry has been already conducted in one way or another. Cocoa butter equivalents, healthy oil containing medium-chain fatty acids, phosphatidyl serine, and phenol lipids from enzyme technology have been reported for commercial operation. As the demand for better quality functional lipids is increasing, the production of structured lipids becomes an interesting area. Thus, in this chapter we have discussed latest developments as well as present industrial situation of all commercially important structured lipids. PMID- 22426732 TI - Lipase-catalyzed modification of phenolic antioxidants. AB - The chemical acylation of natural antioxidants may improve their oxidative and thermal stability, as well as modify their hydrophile-lipophile balance (HLB). These processes are generally carried out under harsh conditions using strongly corrosive acids. In contrast, lipase-catalyzed acylation is characterized by mild reaction conditions, low energy requirements, and a minimization of side reactions. We report the one-step enzymatic acylation of a phenolic antioxidant (alpha-tocopherol) and a polyphenol (resveratrol) by lipase-catalyzed transesterification. In particular, the regioselectivity of resveratrol acylation can be controlled by an adequate selection of the biocatalyst. PMID- 22426733 TI - Lipases as catalysts in synthesis of fine chemicals. AB - The application of lipases as catalysts in the synthesis of an intermediate of alfuzosin and lapyrium chloride is described. In the first case, the one-pot procedure to obtain the intermediate involves the treatment of tetrahydrofuroic acid with ethanol in the presence of Candida antarctica lipase followed by the addition of N-methyl-1,3-diaminopropane. In the second part of the chapter, an efficient route for large-scale preparation of lapyrium chloride is developed from chloroacetic acid in four steps, three of them enzymatic. Due to the chemoselective behavior of the lipases, both products described in the present chapter were obtained in a high degree of purity and yield, applying mild reaction conditions, and following a low environmental impact methodology. PMID- 22426734 TI - Lipases in green chemistry: acylation and alcoholysis on steroids and nucleosides. AB - In this article, we describe the application of lipases in acylation and alcoholysis reactions on steroids and nucleosides. In the field of steroids, a variety of acetyl and fatty acid derivatives of androstanes, pregnanes, and cholestanes have been prepared through lipase-catalyzed acylation and alcoholysis reactions taking advantage of the high regio- and stereoselectivity of these enzymes. The substrates as well as the products show a high degree of biological activity as neurosteroids, hormones, and glucocorticoids. The regioselective preparation of diacylated nucleosides by means of an enzymatic alcoholysis allowed the synthesis of nucleosides prodrugs or modified nucleosides. The quantitative full deacylation and dealkoxycarbonylation of nucleosides and steroids is a mild synthetic method for the deprotection of these labile compounds. Some of the reported steroid and nucleoside products are novel, and it is not possible to obtain them satisfactorily by following traditional synthetic procedures. The advantages presented by this methodology, such as selectivity, mild reaction conditions, and low environmental impact, make the lipases an important tool in the application of the principles of Green Chemistry, offering a convenient way to prepare derivatives of natural compounds with a great potential in the pharmaceutical industry. PMID- 22426735 TI - Lipases as biocatalyst for biodiesel production. AB - The global shortages of fossil fuels, significant increase in the price of crude oil, and increased environmental concerns have stimulated the rapid growth in biodiesel production. Biodiesel is generally produced through transesterification reaction catalyzed either chemically or enzymatically. Enzymatic transesterification draws high attention because that process shows certain advantages over the chemical catalysis of transesterification and it is "greener." This paper reviews the current status of biodiesel production with lipase-biocatalysis approach, including sources of lipases, kinetics, and reaction mechanism of biodiesel production using lipases, and lipase immobilization techniques. Factors affecting biodiesel production and economic feasibility of biodiesel production using lipases are also covered. PMID- 22426736 TI - Synthesis of biodegradable polymers using biocatalysis with Yarrowia lipolytica lipase. AB - Yarrowia lipolytica lipase (YLL) was used as catalyst in the enzymatic ring opening polymerization (ROP) of epsilon-caprolactone. This low-cost solid-state lipase produces low-molecular-weight polyesters with unique multiphase morphology as determined by carbon-13 NMR. YLL attaches sugar head groups to polycaprolactone in a one-pot biocatalytic pathway. Synthesis of alpha-omega telechelic (polymer with two reactive hydroxyl end groups) PCL diols is achieved by enzymatic ROP with YLL immobilized on the macroporous resin Lewatit VPOC 1026, and in the presence of diethylene glycol or poly(ethylene glycol). Biodegradable linear polyester urethanes are prepared by polycondensation between synthesized PCL diols and hexamethylene-diisocyanate. PMID- 22426737 TI - Phospholipases in food industry: a review. AB - Mammal, plant, and mainly microbial phospholipases are continuously being studied, experimented, and some of them are even commercially available at industrial scale for food industry. This is because the use of phospholipases in the production of specific foods leads to attractive advantages, such as yield improvement, energy saving, higher efficiency, improved properties, or better quality of the final product. Furthermore, biocatalysis approaches in the food industry are of current interest as non-pollutant and cleaner technologies. The present chapter reviews the most representative examples of the use of phospholipases in food industry, namely edible oils, dairy, and baking products, emulsifying agents, as well as the current trend to the development of novel molecular species of phospholipids with added-value characteristics. PMID- 22426738 TI - Lipase and phospholipase biosensors: a review. AB - Recent advances in the field of biology, electronics, and nanotechnology have improved the development of biosensors. A biosensor is a device composed of a biological recognition element and a sensor element. Biosensor applications are becoming increasingly important in areas such as biotechnology, pharmaceutics, food, and environment. Lipases and phospholipases are enzymes which have been used widely in food industry, oleochemical industry, biodegradable polymers, detergents, and other applications. In the medical industry, lipases and phospholipases are used as diagnostic tools to detect triglycerides, cholesterol, and phospholipids levels in blood samples. Therefore, the development of lipase and phospholipase biosensors is of paramount importance in the clinical area. This chapter introduces the reader into the preliminaries of biosensor and reviews recent developments of lipase and phospholipase biosensors. PMID- 22426739 TI - Clinicians' perspectives on cognitive therapy in community mental health settings: implications for training and implementation. AB - Policymakers are investing significant resources in large-scale training and implementation programs for evidence-based psychological treatments (EBPTs) in public mental health systems. However, relatively little research has been conducted to understand factors that may influence the success of efforts to implement EBPTs for adult consumers of mental health services. In a formative investigation during the development of a program to implement cognitive therapy (CT) in a community mental health system, we surveyed and interviewed clinicians and clinical administrators to identify potential influences on CT implementation within their agencies. Four primary themes were identified. Two related to attitudes towards CT: (1) ability to address client needs and issues that are perceived as most central to their presenting problems, and (2) reluctance to fully implement CT. Two themes were relevant to context: (1) agency-level barriers, specifically workload and productivity concerns and reactions to change, and (2) agency-level facilitators, specifically, treatment planning requirements and openness to training. These findings provide information that can be used to develop strategies to facilitate the implementation of CT interventions for clients being treated in public-sector settings. PMID- 22426740 TI - Sensory reception of the primer pheromone ethyl oleate. AB - Social work force distribution in honeybee colonies critically depends on subtle adjustments of an age-related polyethism. Pheromones play a crucial role in adjusting physiological and behavioral maturation of nurse bees to foragers. In addition to primer effects of brood pheromone and queen mandibular pheromone- both were shown to influence onset of foraging--direct worker-worker interactions influence adult behavioral maturation. These interactions were narrowed down to the primer pheromone ethyl oleate, which is present at high concentrations in foragers, almost absent in young bees and was shown to delay the onset of foraging. Based on chemical analyses, physiological recordings from the antenna (electroantennograms) and the antennal lobe (calcium imaging), and behavioral assays (associative conditioning of the proboscis extension response), we present evidence that ethyl oleate is most abundant on the cuticle, received by olfactory receptors on the antenna, processed in glomeruli of the antennal lobe, and learned in olfactory centers of the brain. The results are highly suggestive that the primer pheromone ethyl oleate is transmitted and perceived between individuals via olfaction at close range. PMID- 22426741 TI - Functional MRI using robotic MRI compatible devices for monitoring rehabilitation from chronic stroke in the molecular medicine era (Review). AB - The number of individuals suffering from stroke is increasing daily, and its consequences are a major contributor to invalidity in today's society. Stroke rehabilitation is relatively new, having been hampered from the longstanding view that lost functions were not recoverable. Nowadays, robotic devices, which aid by stimulating brain plasticity, can assist in restoring movement compromised by stroke-induced pathological changes in the brain which can be monitored by MRI. Multiparametric magnetic resonance imaging (MRI) of stroke patients participating in a training program with a novel Magnetic Resonance Compatible Hand-Induced Robotic Device (MR_CHIROD) could yield a promising biomarker that, ultimately, will enhance our ability to advance hand motor recovery following chronic stroke. Using state-of-the art MRI in conjunction with MR_CHIROD-assisted therapy can provide novel biomarkers for stroke patient rehabilitation extracted by a meta analysis of data. Successful completion of such studies may provide a ground breaking method for the future evaluation of stroke rehabilitation therapies. Their results will attest to the effectiveness of using MR-compatible hand devices with MRI to provide accurate monitoring during rehabilitative therapy. Furthermore, such results may identify biomarkers of brain plasticity that can be monitored during stroke patient rehabilitation. The potential benefit for chronic stroke patients is that rehabilitation may become possible for a longer period of time after stroke than previously thought, unveiling motor skill improvements possible even after six months due to retained brain plasticity. PMID- 22426742 TI - Regulation of colon cancer cell migration and invasion by CLIC1-mediated RVD. AB - The metastasis of colorectal cancer is one of the most common causes of death in the world. In this investigation, we used the human colon cancer cell lines LOVO and HT29 as model systems to determine the role of the chloride intracellular channel 1 (CLIC1) in the metastasis of colonic cancer. In the present study, we found that regulatory volume decrease (RVD) capacity was markedly up-regulated in LOVO cells, which are characterized by a high metastatic potential. Functionally suppressing CLIC1 using the specific chloride intracellular channel 1 blocker Indanyloxyacetic acid 94 inhibited RVD and decreased the migration and invasion of colon cancer cells. Moreover, these effects occurred in a dose-dependent manner. The migration and invasion abilities in two cell lines also were inhibited by the knockdown of CLIC1 using small interfering RNA transfection. The mRNA and protein expression of CLIC1 is up-regulated in LOVO cells. In human colon cancer cells, CLIC1 is primarily located in the plasma membrane, where it functions as a chloride channel. Taken together, the results suggest that CLIC1 modulates the metastasis of colon cancer through its RVD-mediating chloride channel function. This study demonstrates, for the first time, that CLIC1 regulates the migration and invasion of colon cancer. PMID- 22426743 TI - Single line particle focusing induced by viscoelasticity of the suspending liquid: theory, experiments and simulations to design a micropipe flow-focuser. AB - We perform 3D numerical simulations, heuristic modeling and microfluidic experiments to demonstrate, for the first time, the presence of a bistability scenario for transversal migration of particles suspended in a viscoelastic liquid flowing in a pipe. Our results show that particle migration, either at the centerline or at the wall, can be controlled by the rheological properties of the suspending liquid and by the relative dimensions of the particle and tube. Proper selection of these parameters can promote strict aligning of particles on a line, i.e., 3-D focusing. Simple design rules are given to rationally control particle focusing under flow in micropipes. PMID- 22426744 TI - Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties. AB - Although mortality related with primary tumors is approximately 10%, metastasis leads to 90% of cancer-associated death. The majority of brain metastases result from lung cancer, but the metastatic mechanism remains unclear. In general, chemotherapy for treating brain diseases is disrupted by the brain blood barrier (BBB). As an approach to improve treatment of lung cancer metastasis to the brain, we employed genetically engineered stem cells (GESTECs), consisting of neural stem cells (NSCs) expressing a suicide gene. Cytosine deaminase (CD), one of the suicide genes, originating from bacterial (bCD) or yeast (yCD), which can convert the non-toxic prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5 FU), can inhibit cancer cell growth. We examined the therapeutic efficacy and migratory properties of GESTECs expressing yCD, designated as HB1.F3.yCD, in a xenograft mouse model of lung cancer metastasis to the brain. In this model, A549 lung cancer cells were implanted in the right hemisphere of the mouse brain, while CM-DiI pre-stained HB1.F3.yCD cells were implanted in the contralateral brain. Two days after the injection of stem cells, 5-FC was administered via intraperitoneal injection. The tumor-tropic effect of HB1.F3.yCD was evident by fluorescent analysis, in which red-colored stem cells migrated to the lung tumor mass of the contralateral brain. By histological analysis of extracted brain, the therapeutic efficacy of HB1.F3.yCD in the presence of 5-FC was confirmed by the reduction in density and aggressive tendency of lung cancer cells following treatment with 5-FC, compared to a negative control or HB1.F3.yCD injection without 5-FC. Taken together, these results indicate that HB1.F3.yCD expressing a suicide gene may be a new therapeutic strategy for lung cancer metastases to the brain in the presence of a prodrug. PMID- 22426745 TI - A novel bioactive vitroceramic presents similar biological responses as autogenous bone grafts. AB - Bioactive glasses represent an interesting class of bone substitute's biomaterials. The present study investigated the repair of bone defects filled with a novel bioactive vitroceramic (Biosilicate((r))), alone or in association with particulate autogenous bone grafts in calvaria defects of rabbits. After 7, 14, and 30 days the specimens were retrieved for histological, histomorphometric and immunohistochemistry analysis. Satisfactory bone formation was observed in all groups, and direct bone-biomaterial surface was noted. Histomorphometric assessment did not show statistically significant differences in bone formation among the groups and periods, except for BG group at day 14. Immunoexpression of Runx-2 was similar among the groups containing the graft and the biomaterial, being more intense than in control group. Similar result was observed for VEGF expression, especially in the last experimental period. These results revealed that Biosilicate((r)) presented a favorable behavior, comparable to autogenous bone graft. PMID- 22426746 TI - Preparation of low-crystalline apatite nanoparticles and their coating onto quartz substrates. AB - We prepared low-crystalline apatite nanoparticles and coated them onto a surface of a Au/Cr-plated quartz substrate by the electrophoretic deposition (EPD) method or by using a self-assembled monolayer of 11-mercaptoundecanoic acid (SAM method). Low-crystalline apatite nanoparticles around 10 nm in size with extremely low contents of undesirable residual products were obtained by adding (NH(4))(2)HPO(4) aqueous droplets into a modified synthetic body fluid solution that contained Ca(CH(3)COO)(2). The apatite nanoparticles were successfully coated by either the EPD method or the SAM method; the nanoparticle coating achieved by the SAM method was more uniform than that achieved by the EPD method. The present SAM method is expected to be a promising technique for obtaining a quartz substrate coated with apatite nanoparticles, which can be used as a quartz crystal microbalance device. PMID- 22426747 TI - Wild redfronted lemurs (Eulemur rufifrons) use social information to learn new foraging techniques. AB - Recent research has claimed that traditions are not a unique feature of human culture, but that they can be found in animal societies as well. However, the origins of traditions in animals studied in the wild are still poorly understood. To contribute comparative data to begin filling this gap, we conducted a social diffusion experiment with four groups of wild redfronted lemurs (Eulemur rufifrons). We used a 'two-option' feeding box, where these Malagasy primates could either pull or push a door to get access to a fruit reward to study whether and how these two behavioural traits spread through the groups. During a pre training phase, two groups were presented with boxes in which one technique was blocked, whereas two groups were presented with unblocked boxes. During a subsequent unconstrained phase, all four groups were confronted with unblocked boxes. Nearly half of the study animals were able to learn the new feeding skill and individuals who observed others needed fewer unsuccessful task manipulations until their first successful action. Animals in the two groups with pre-training also discovered the corresponding alternative technique but preferred the seeded technique. Interestingly, animals in the two groups without pre-training discovered both techniques, and one group developed a group preference for one technique whereas the other did not. In all groups, some animals also scrounged food rewards. In conclusion, redfronted lemurs appear to use social information in acquiring a novel task, and animals in at least in one group without training developed a group preference for one technique, indicating that they have the potential to develop behavioural traditions and conformity. PMID- 22426748 TI - Effects of dietary selenium, vitamin E, and their combination on growth, serum metabolites, and antioxidant defense system in skeletal muscle of broilers under heat stress. AB - This experiment was conducted to evaluate the effects of dietary vitamin E, selenium (Se), and a combination of the two, on the performance, serum metabolites and oxidative stability of skeletal muscle of broilers during heat stress. The broilers raised in either a thermoneutral (23.9 degrees C constant) or heat stress (23.9 degrees C to 37 degrees C cycling) environment were assigned to 6 dietary treatments (0, 0.5, or 1 mg/kg Se; 125 and 250 mg/kg vitamin E; or 0.5 mg/kg Se plus 125 mg/kg vitamin E) from 1 to 49 days of age. At the end of the experiment, blood samples were collected from chicks, the chicks sacrificed, and pectoralis superficialis muscle was used for measurement of malondialdehyde (MDA) concentration and enzyme activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD). The heat-stressed chicks consumed less feed, gained less weight, and had higher feed conversion ratio when compared to thermoneutral chicks (P<0.05). Serum concentrations of iron (Fe) and zinc (Zn) were decreased by heat stress (P<0.05), whereas the serum concentrations of copper (Cu), glucose, and uric acid were significantly increased under heat stress (P<0.05). The chicks that received supplemental of vitamin E exhibited significantly higher serum concentrations of Zn (P<0.05) and significantly lower concentrations of Cu, glucose, and uric acid (P<0.05) when exposed to heat stress. Dietary Se also caused a significant decrease in serum glucose, uric acid, and Cu concentrations of heat-stressed broilers (P<0.05), but had no significant effect on Zn concentration (P>0.05). The GPx activity remained relatively constant (P>0.05), though SOD activity and MDA levels in skeletal muscle were enhanced on exposure to heat stress (P<0.05). The heat-stressed chicks that received the combined supplementary level of vitamin E and Se had the lowest concentration of MDA and the highest activity of SOD in the skeletal muscle (P<0.05). Dietary Se also caused a significant increase in enzyme activity of GPx in the skeletal muscle (P<0.05). These results indicate that the derangement of blood parameters and oxidative stability in broilers under heat stress are improved by supplemental vitamin E and Se. PMID- 22426749 TI - Evaluation of allogeneic hematopoietic SCT in younger adults with adverse karyotype AML. AB - To illustrate methodological issues, we compared donor vs no-donor to transplant vs no-transplant comparisons in a cohort of 107 patients aged ?50 years with adverse karyotype AML in first CR. Adverse karyotypes were defined as -7, del(7q), -5, del(5q), t(9;22), 11q23, 3q26 or complex abnormalities. Mantel-Byar estimations and hematopoietic SCT (HSCT) as a time-dependent variable were used to compare transplant vs no-transplant cumulative incidence of relapse (CIR), relapse-free survival (RFS) and OS. In all, 52 patients had a sibling donor, but only 35 of them were transplanted in first CR, whereas 9 patients received HSCT from alternative stem cell sources. Donor-based analysis showed lower CIR in the donor group, not translating in prolonged RFS or OS. Conversely, transplant-based analysis showed that HSCT in the first CR improved the three CIR (multivariate hazard ratio (HR), 0.31; P<0.001), RFS (multivariate HR, 0.57; P=0.047) and OS (multivariate HR, 0.54; P=0.03) endpoints. At 5 years, OS was estimated at 33% in transplanted vs 18% in non-transplanted patients. The positive effect of HSCT was more pronounced in patients aged ?35 years and/or in those transplanted in the more recent years. These results confirm that HSCT is likely the best curative option in younger patients with adverse karyotype AML. PMID- 22426750 TI - Outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome. AB - HLA-identical sibling donor transplantation remains the treatment of choice for Wiskott-Aldrich Syndrome (WAS). Since 1990, utilization of alternative donor sources has increased significantly. We report the hematopoietic cell transplantation (HCT) outcomes of 47 patients with WAS treated at a single center since 1990. Improved outcomes were observed after 2000 despite the increased number of alternative donors. Five-year OS improved from 62.5% (95% CI: 34.9% to 81.1%) to 90.8% (95% CI: 67.7% to 97.6%) for patients transplanted during 1990 2000 and 2001-2009, respectively. In multivariate analysis, transplant era significantly impacted OS (P=0.04), whereas age was only marginally significant (P=0.06, Cox proportional hazard analysis). No TRM occurred within the first 100 days among patients transplanted during 2001-2009 compared with 3/16 during 1990 2000, (P=0.03, Fisher's exact test). The extent of HLA mismatch did not significantly affect the incidence of acute GVHD, chronic GVHD or survival. Post HCT autoimmune cytopenias were frequently diagnosed after 2001: 17/31 (55%) patients. Their occurrence was not associated with transplant donor type (P=0.53), acute GVHD (P=0.74), chronic GVHD (P=0.12), or post-transplant mixed chimerism (P=0.50). PMID- 22426751 TI - Evidence for clinical activity of artesunate in multidrug-resistant herpes simplex infection following HSCT. PMID- 22426752 TI - A phase I/II study of CY and topotecan in patients with high-risk malignancies undergoing autologous hematopoietic cell transplantation: the St Jude long-term follow-up. AB - Fifty-eight consecutive children with high-risk malignancies were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study. Twelve participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m(2) per day, with subsequent doses targeted to total systemic exposure of 100+/-20 ng h/mL and CY 750 mg/m(2) per day. Seven participants received dose level 2. CY dose escalation to 1 g/m(2) per day was considered excessively toxic; one died from irreversible veno-occlusive disease and two experienced reversible hepatotoxicity. These adverse events halted further dose escalation. A total of 46 participants were enrolled in phase II; results are on the 51 participants who received therapy at dose level 1, the maximum tolerated dose. Diagnoses included neuroblastoma (26), sarcoma (9), lymphoma (8), brain tumors (5), Wilms (2) and retinoblastoma (1). Twenty participants (39.3%) were in ?CR1 at enrollment; median age was 5.1 years. Most common non-hematological grade III-IV toxicity was gastrointestinal (n=37). Neutrophil and platelet engraftment occurred at a median of 15 and 24 days, respectively. Twenty-six (51%) participants remain alive at a median of 6.4 years after AHCT. CY 3.75 g/m(2), and targeted topotecan followed by AHCT are feasible and produce acceptable toxicity in children with high-risk malignancies. PMID- 22426753 TI - Putting caution in TEAM: high-dose chemotherapy with autologous HSCT for primary central nervous system lymphoma. PMID- 22426754 TI - Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion. AB - We investigated the efficacy of lacrimal punctal occlusion surgery with a cautery device in patients with chronic GVHD (cGVHD)-related dry eye, with recanalization of puncta and recurrent punctal plug extrusion. A total of 23 puncta from 14 eyes of 10 patients with chronic GVHD (cGVHD)-related dry eye underwent punctual thermal cauterization with a high-temperature disposable cautery device. All patients were refractory to conventional treatment, including artificial tear eye drops, autologous serum eye drops and vitamin A eye drops, and had a history of recanalization and recurrent punctal plug extrusion. The effect of lacrimal punctal cauterization by thermal cautery device was evaluated by changes in subjective symptom scores, corrected distance visual acuity, Schirmer's test values, fluorescein staining scores, rose bengal staining scores, and tear-film break-up time before and 3 months after the surgery. Subjective symptom scores, Schirmer's test values, fluorescein and rose bengal scores, and tear-film break up time improved significantly 3 months after the surgery. Recanalization of puncta was not observed in all the cases (0 of 14 eyes, 0%). Lacrimal punctal cauterization was effective with no recanalization and significant improvements in subjective symptoms and the ocular surface environment in cGVHD-related dry eye patients who had been refractory to conventional treatments. PMID- 22426755 TI - Consumption of red meat and whole-grain bread in relation to biomarkers of obesity, inflammation, glucose metabolism and oxidative stress. AB - PURPOSE: To examine the association of red meat and whole-grain bread consumption with plasma levels of biomarkers related to glucose metabolism, oxidative stress, inflammation and obesity. METHODS: Our cross-sectional study was based on 2,198 men and women who were selected as a sub-cohort for an investigation of biological predictors of diabetes and cardiovascular diseases from the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Circulating levels of glycated hemoglobin, adiponectin, hs-CRP, gamma-glutamyltransferase, alanine-aminotransferase, fetuin-A, HDL-cholesterol and triglycerides were measured from random blood samples. Diet and lifestyle data were assessed by questionnaires, and anthropometric data were measured. RESULTS: After multivariable adjustment, higher consumption of whole-grain bread was significantly (P trend <0.05) associated with lower levels of GGT, ALT and hs CRP, whereas higher consumption of red meat was significantly associated with higher levels of GGT and hs-CRP when adjusted for potential confounding factors related to lifestyle and diet. Further adjustment for body mass index and waist circumference attenuated the association between red meat and hs-CRP (P = 0.19). CONCLUSIONS: The results of this study suggest that high consumption of whole grain bread is related to lower levels of GGT, ALT and hs-CRP, whereas high consumption of red meat is associated with higher circulating levels of GGT and hs-CRP. PMID- 22426756 TI - Alterations in peripheral purinergic and muscarinic signaling of rat bladder after long-term fructose-induced metabolic syndrome. AB - PURPOSE: We explored the pathophysiologic mechanisms of long-term fructose induced lower urinary tract symptoms (LUTS) in rats. METHODS: Male Wistar rats were fed with fructose for 3 or 6 months. Biochemical and transcystometric parameters were compared between fructose-fed and age-matched normal-diet rats. Pelvic nerve and external urethral sphincter-electromyogram activity recordings were performed to investigate fructose effects on neural control of bladders. Mitochondrial structure, ATP and acetylcholine content and purinergic and muscarinic cholinergic receptors were examined. Cytosolic cytochrome C staining by Western blot and immunocytochemistry for mitochondrial injury and PGP 9.5 stain for nerve density were also determined. RESULTS: The fructose-fed rats with higher plasma triglyceride, LDL and fasting glucose levels displayed LUTS with increased frequency and suppressed voiding contractile amplitude in phase 1 and phase 2 duration versus normal-diet control. Fructose feeding altered the firing types in pelvic afferent and efferent nerves and external urethral sphincter electromyogram activity. Increased mast cell number, disrupted and swollen mitochondria, increased cytosolic cytochrome C stain and expression and decreased nerve density in bladder smooth muscle layers appeared in the fructose-fed rats. Fructose feeding also significantly reduced ATP and acetylcholine content and enhanced protein expression of postsynaptic P(2)X(1), P(2)X(2) and P(2)X(3) purinergic receptors and M(2) and M(3) muscarinic cholinergic receptors expression in the smooth muscles of urinary bladder. CONCLUSION: Long-term fructose feeding induced neuropathy and myopathy in the urinary bladders. Impaired mitochondrial integrity, reduced nerve density, ATP and acetylcholine content and upregulation of purinergic and muscarinic cholinergic receptors expression may contribute to the bladder dysfunction of fructose-fed animals. PMID- 22426757 TI - Intravenous thrombolysis for acute ischaemic stroke in patients not fully adhering to the European licence in Poland. AB - BACKGROUND AND PURPOSE: The European licence for alteplase excludes from thrombolysis large groups of acute stroke patients. The Polish licence was revised in 2010, but until then many patients could receive the treatment only off-label. Our aim was to evaluate the safety and effectiveness of intravenous alteplase in Polish patients not fully adhering to the original European drug licence compared to patients treated strictly on-label. MATERIAL AND METHODS: We analysed all patient data contributed to the Safe Implementation of Thrombolysis in Stroke registry from Polish centres between October 2003 and July 2009. RESULTS: Off-label thrombolysis was administered in 224/946 (23.7%) patients. The most frequent deviations were: use of intravenous antihypertensives (8.2%), age > 80 years (5.4%), time-to-treatment > 3 hours (4.5%), oral anticoagulation (4.2%), previous stroke with concomitant diabetes (2.1%), and previous stroke <= 3 months (1.5%). We found no differences in the ratio of symptomatic intracranial haemorrhage (sICH) according to SITS, ECASS and NINDS definitions. Adjusted odds for 3-month mortality were similar (OR 0.86, 95% CI: 0.51-2.41), excluding patients with previous stroke <= 3 months (OR 3.48, 95% CI: 0.96-12.7). Adjusted odds for death or dependency were slightly increased (OR 1.40, 95% CI: 0.92 2.13), especially in patients aged > 80 years (OR 2.80, 95% CI: 1.11-7.05), and with previous stroke <= 3 months (OR 4.07, 95% CI: 0.97-17.1). CONCLUSIONS: Polish stroke patients receiving off-label thrombolysis tended to achieve a less favourable outcome, but they were not at increased risk of sICH or death. Considering the current Polish license for alteplase, it may be reasonable to additionally stratify the risk in patients aged > 80 years or with previous stroke <= 3 months. PMID- 22426758 TI - Weekend versus weekday admissions in Polish stroke centres -- could admission day affect prognosis in Polish ischaemic stroke patients? AB - BACKGROUND AND PURPOSE: Disparities in resources, access to the expertise and healthcare providers both at hospital and before admission, or patients' awareness of stroke symptoms can cause differences in weekend and weekday stroke severity and prognosis. The aim of the study was to explore differences in baseline characteristics and outcomes of ischaemic stroke patients admitted on weekdays and weekends. MATERIAL AND METHODS: A questionnaire based on the WHO Step Stroke and Swedish Stroke Registry was used to collect data on patients admitted to centres participating in the POLKARD Hospital Stroke Registry between June 1st, 2004 and May 31st, 2005. To ensure the quality, only centres reporting at least 100 patients were analysed. Clinical characteristics and early outcomes (death rate and poor outcome defined as modified Rankin scale score of 3 or above) were compared between patients admitted on weekdays and weekends. RESULTS: A total of 19667 ischaemic stroke patients, including 5924 admitted during weekends, were reported by 72 stroke centres. Weekend patients were older, more often disabled prior to stroke and more commonly presented with atrial fibrillation and coronary heart disease. Weekend patients were more likely to present consciousness disturbances at admission. More patients admitted on weekends died during hospitalization or had poor outcome at discharge than weekday patients (15.9% and 59.8% vs. 14.1% and 55.3%, respectively). After adjusting for baseline severity of stroke and case-mix, the regression model showed that weekend ischaemic stroke patients had worse prognosis (odds of 1.137 and 1.147 for death and poor outcome, respectively). CONCLUSIONS: Admissions on weekends are associated with higher mortality and poor outcome, and that can be only partially explained by differences in baseline characteristics of admitted patients. PMID- 22426759 TI - Evaluation of the relationship between leptin, resistin, adiponectin and natural regulatory T cells in relapsing-remitting multiple sclerosis. AB - BACKGROUND AND PURPOSE: Data suggest that adipocytokines and natural regulatory T (nTreg) cells play a pivotal role in the immunopathogenesis of multiple sclerosis and the associated inflammation. The purpose of this study was to evaluate selected adipocytokines and nTreg cells and to assess their relationship with relapsing-remitting multiple sclerosis (RRMS). MATERIAL AND METHODS: The study was conducted among 25 patients with RRMS and 25 healthy individuals. Blood samples were collected within two weeks after the beginning of acute relapse of RRMS. The body mass index (BMI) of each patient was calculated. Serum adipocytokine concentrations were determined by ELISA and nTreg cells were evaluated using multicolour flow cytometry. RESULTS: Patients and controls had similar BMI, regardless of gender. Significantly higher leptin and resistin levels and significantly lower adiponectin levels were found in patients with RRMS in comparison to the control group (p < 0.0001). The percentage of nTreg cells (p < 0.01) and the mean fluorescence channel (MFC) of FoxP3 were significantly reduced in patients with RRMS (p < 0.001). There was an inverse correlation be-tween leptin concentration and MFC of the transcription factor Foxp3 nTreg in patients with RRMS (r = -0.7, p < 0.05). CONCLUSIONS: Proinflammatory adipocytokine profile and decreased percentage of nTreg cells suggest their implication in the inflammatory response in RRMS regardless of corticosteroid therapy. The correlation between leptin and the MFC of the transcription factor Foxp3 in nTreg cells in patients with RRMS suggests its inhibitory effect on FoxP3 expression. PMID- 22426760 TI - The influence of botulinum toxin on auditory disturbances in hemifacial spasm. AB - BACKGROUND AND PURPOSE: Hemifacial spasm (HFS) is frequently accompanied by other symptoms, such as visual and auditory disturbances or pain. The aim of the study was to assess the occurrence of auditory symptoms accompanying HFS using subjective and objective methods, their relation with other HFS symptoms, and their resolution after botulinum toxin (BTX-A) treatment. MATERIAL AND METHODS: The occurrence of hypoacusis, ear clicks and tinnitus was assessed by questionnaire in 126 HFS patients from an electronic database which included medical data such as severity of HFS rated by clinical scale and magnetic resonance imaging focused on the presence of vascular nerve VII and VIII conflict. Forty consecutive patients treated with BTX-A and 24 controls matched by sex and age underwent laryngological examination including audiometry, tympanometry and acoustic middle ear reflex before injection and two weeks later. RESULTS: About 45.2% of patients complained of auditory disturbances (31.7% hypoacusis, 30.2% ear clicks and 7.1% tinnitus) on the side of HFS. Auditory disturbances correlated with severity of HFS symptoms but not with age, disease duration, or neurovascular conflict with nerves VII and VIII. We did not find abnormalities in audiometric and tympanometric assessment in patients in comparison with controls. No abnormalities were detected in brainstem evoked potentials comparing the sides with and without HFS symptoms. Tinnitus and absence of ipsilateral acoustic middle ear reflex occurred more often in patients with auditory symptoms than those without them. BTX-A treatment caused resolution of subjective acoustic symptoms without any improvement in audiometric assessment. CONCLUSIONS: Auditory disturbances accompanying HFS are probably caused by dysfunction of the Eustachian tube, which improves after BTX-A treatment. PMID- 22426761 TI - The relationship between efficacy of surgical treatment of Cushing disease and pathological -- immunohistochemical and ultrastructural -- confirmation of corticotroph tumour presence. AB - BACKGROUND AND PURPOSE: The most common cause of Cushing disease (CD) is ACTH secreting pituitary adenoma. Transsphenoidal selective adenomectomy is the treatment of choice. Frequency of remission varies from 60% to 90%, depending on the site and the surgeon's experience. This study aims to answer the question whether confirmation of corticotroph adenoma in pathological examinations increases the probability of surgical cure for CD. MATERIAL AND METHODS: The prospective study involved 36 patients with CD operated on with the transsphenoidal approach and followed up for at least 18 months. Following the surgical procedure, the specimen was examined by a pathologist. The study evaluated the significance of positive histological (immunohistochemical and ultrastructural) examination results for achieving surgical cure for CD. RESULTS: Twenty-three of 36 patients (63.9%) were regarded as being surgically cured of CD. Persistent CD was confirmed in 13 patients (36.1%). Pituitary insufficiency was found in 5 patients (13.9%), whereas 3 patients (8.3%) were diagnosed with diabetes insipidus. A significant difference was demonstrated between the cured and the non-cured group with reference to the results of pathological examination of surgical specimens. Pathomorphological confirmation of corticotroph adenoma was significantly more frequently observed in the cured group in comparison with the non-cured group (p = 0.028). CONCLUSIONS: Pathological confirmation of corticotroph pituitary adenoma may be regarded as an important predictor of the surgical cure of CD. PMID- 22426762 TI - Fluorescence-guided resection of primary and recurrent malignant gliomas with 5 aminolevulinic acid. Preliminary results. AB - BACKGROUND AND PURPOSE: Extent of resection plays a key role in the treatment of malignant gliomas (MGs). Patients with complete glioma removal, followed by chemoradiation, obtain the longest overall and progression-free survival. Fluorescence-guided resection of MGs enables intraoperative visualization of glioma tissue and increases control of the resection. The authors present preliminary results of 5-aminolevulinic acid (5-ALA) application during the resection of primary and recurrent MGs. MATERIAL AND METHODS: Six patients with either a suspected malignant glioma based on magnetic resonance imaging (MRI) or with recurrent glioblastoma multiforme were enrolled in the study. The extent of resection was calculated according to the postoperative MRI performed within 72 hours. Preoperative and early postoperative neurological status and Karnofsky Performance Scale (KPS) were compared. RESULTS: Fluorescence of tumour tissue was observed in 5/6 patients (five with the histopathological diagnosis of glioblastoma multiforme and one with neurotoxoplasmosis and AIDS). Complete tumour resection was achieved in 5 patients. Postoperative KPS and neurological status deteriorated in 2 cases. Radiotherapy and chemotherapy did not interfere with the sensitivity of the fluorescence guided tumour visualization. CONCLUSIONS: Fluorescence-guided resection of primary and recurrent MGs with 5 ALA improves control of the tumour resection. It enables the cytoreduction to be maximized but experience in neuro-oncological surgery is required to avoid serious, postoperative neurological deficits. PMID- 22426763 TI - [Stereotactic radiosurgery for movement disorders]. AB - Nowadays, functional neurosurgery is an established treatment for movement disorders such as Parkinson's disease, essential tremor, and dystonia. The effectiveness and safety of neuromodulation procedures (deep brain stimulation) replaced in the last years ablative irreversible stereotactic lesions for movement disorders. Stereotactic radiosurgery with gamma knife is a non-invasive form of treatment for movement disorders. The main limitation of stereotactic radiosurgery is the impossibility of electrophysiological confirmation of the target structure. Nevertheless, patients with advanced age and significant medical conditions that preclude classic open stereotactic procedures or patients who must receive anticoagulation therapy may gain great functional benefit using gamma knife stereotactic radiosurgery. PMID- 22426764 TI - [Levodopa in the treatment of Parkinson disease -- yesterday and today]. AB - Levodopa has an established position in the treatment of Parkinson's disease for the last 40 years. It is still called a gold standard therapy. The treatment is relatively easy in the first uncomplicated stage of Parkinson's disease, but the results of many studies performed in recent years showed that the time of treatment initiation and the mode of initial treatment may influence the course of disease in following years. At the late stages the levodopa treatment is a challenge due to the changes in reactivity to single doses as a result of changes in its pharmacokinetics, reactivity of dopamine receptors and progressive loss of dopaminergic neurons. This review paper aims to show the recent views on treatment of Parkinson's disease with levodopa still being a core of this therapy. PMID- 22426765 TI - Primary intracranial extraskeletal myxoid chondrosarcoma. AB - Extraskeletal myxoid chondrosarcomas (EMC) are extremely rare and are usually located in the deep soft tissues of the lower extremities. Less than 10 cases of intracranial EMC have been reported in the literature, making their management and early diagnosis difficult. We present a new case of intracranial EMC occurring in a 70-year-old woman presenting with a right frontal mass initially assumed to be a brain metastasis from breast adenocarcinoma. The optimal management of these tumours is also discussed. Analysis from the literature suggests that complete resection should be recommended, whenever feasible. Although the high risk for relapse after surgery encourages postoperative treatments, relative resistance to both radio-therapy and chemotherapy characterizes EMC. Future perspectives might include multimodal treatments with highly conformal radiotherapy modalities for dose escalation strategies or use of new molecules. Knowledge of these unusual malignant tumours will be the first step for improving patients' outcome. PMID- 22426766 TI - Symptomatic ganglion cyst of ligamentum flavum as a late complication of lumbar fixation. AB - We report the case of a 72-year-old man who underwent surgery for a mobile spondylolisthesis L4-L5. Six months later, magnetic resonance imaging revealed an extradural cyst of the ligamentum flavum at L5-S1, which was then removed. Histological examination revealed a ganglion cyst of the ligamentum flavum. Cyst formation could be explained primarily according to the natural history of chronic degenerative disease of spine elements. Nevertheless, we could also consider the cyst formation as demonstrative of an adjacent segment syndrome: hypermobility of the L5-S1 segment just below three fixed vertebral segments would have triggered the mechanical stress necessary for L5-S1 ligamentum flavum degeneration. PMID- 22426767 TI - Percutaneous closure of the left atrial appendage to prevent ischaemic stroke in patients with atrial fibrillation who require but have contraindications to oral anticoagulation. AB - Atrial fibrillation (AF) is associated with a five-fold increased risk for stroke due to cardioembolic events. Most strokes in patients with AF arise from thrombus formation in the left atrial appendage (LAA). Oral anticoagulation is a standard treatment of AF patients with high risk of stroke. However, the main drawbacks of oral anticoagulation are high risk of major bleeding and imperfect effectiveness dependent on a very narrow therapeutic range. In this article, based on two case reports, we describe a method of percutaneous closure of the LAA. We discuss indications, describe the procedure and mention possible complications. LAA closure seems to be a promising tool to prevent AF-related strokes in a selected group of patients. PMID- 22426768 TI - A rare case of Trichosporon brain abscess, successfully treated with surgical excision and antifungal agents. AB - Trichosporonosis is an acute, sometimes fatal infection with the potential capability of disseminating to multiple deep organs. More than 100 cases of trichosporonosis have been described, particularly in patients with neutropenia or haematological malignancies. In 1970, Watson et al. described the first case of brain trichosporonosis; the patient died 4 weeks after admission. Herein, we describe a 34-year-old man with a history of autoimmune hepatitis, hypothyroidism, and alopecia totalis, treated with corticosteroids, who was admitted with left lower limb weakness. Brain MRI revealed a diffuse brain lesion in the right frontoparietal area mimicking a brain abscess. After resection of the lesion, Trichosporon asahii was isolated from the abscess. Further treatment with antifungal agents resulted in improvement in clinical status. To the best of our knowledge, this is the second case of Trichosporon brain abscess since the first description in 1970 and the first case of successful treatment of Trichosporon brain abscess. PMID- 22426769 TI - [Egas Moniz: a genius, unlucky looser or a Nobel committee error?]. AB - Portuguese neurologist Antonio Egas Moniz is one of the most intriguing figures in the history of medicine. While an invention of angiography in 1927 is his acknowledged merit, lobotomy, invented in 1935 became a black legend of psychiatry, although sporadically it is performed also today. There are even postulates to withdraw the Nobel Prize, which Moniz received in 1949 for inventing the lobotomy. Moniz in fact re-invented lobotomy, primarily introduced in 1888 by a Swiss psychiatrist Gottlieb Burckhardt and later forgotten. Its popularisation, including its abuses was chiefly done by American neurologists Walter Freeman and James Watts. Aside the science, Moniz was an exceptionally colourful person, a merited politician, Portuguese minister of foreign affairs, the head of its delegation at Versailles in 1918, in 1951 he was even proposed a position of a President of Portugal. He was a versatile humanist and a writer, even a gambling expert. His person is hard for black and white evaluation, definitely deserving a re-evaluation from today's historical perspective. PMID- 22426770 TI - Trends in stroke incidence rates and stroke risk factors in Rotterdam, the Netherlands from 1990 to 2008. AB - Stroke incidence rates have decreased in developed countries over the past 40 years, but trends vary across populations. We investigated whether age-and-sex specific stroke incidence rates and associated risk factors as well as preventive medication use have changed in Rotterdam in the Netherlands during the last two decades. The study was part of the Rotterdam Study, a large population-based cohort study among elderly people. Participants were 10,994 men and women aged 55 94 years who were stroke-free at baseline. Trends were calculated by comparing the 1990 subcohort (n=7516; baseline 1990-1993) with the 2000 subcohort (n=2883; baseline 2000-2001). Poisson regression was used to calculate incidence rates and incidence rate ratios in age-and-sex-specific strata. We further compared the prevalence of stroke risk factors and preventive medication use in the two subcohorts. In the 1990 subcohort 467 strokes occurred during 45,428 person years; in the 2000 subcohort 115 strokes occurred in 18,356 person years. Comparing the subcohorts, incidence rates decreased by 34% in men, but remained unchanged in women. Blood pressure levels increased between 1990 and 2000, whereas the proportion of current cigarette smokers decreased in men, but not in women. There was a strong increase in medication use for treatment of stroke risk factors across all age categories in both sexes. Our findings suggest that in Rotterdam between 1990 and 2008 stroke incidence rates have decreased in men but not in women. PMID- 22426772 TI - Laparoscopic appendectomy as a teaching procedure: experiences with 1,197 patients in a community hospital. AB - PURPOSE: Since laparoscopic procedures have become more common, resident surgeons have to learn complex laparoscopic skills at an early stage of their career. The aim of this study was to compare the short-term clinical outcome parameters of laparoscopic appendectomy (LA) performed by resident surgeons (RS) or attending surgeons (AS). METHODS: A total of 1197 LA and 57 open appendectomies were performed in a Swiss community hospital between 1999 and 2009. RS performed 684 operations. Parameters including the duration of the operation and hospital stay, intraoperative complications, surgical reinterventions, and a 30-day morbidity and mortality were observed. RESULTS: The mean age of the patients was 35.6 +/- 18.17 years. The duration of the operation was longer (61.34 +/- 25.73 min [RS] vs. 53.65 +/- 29.89 [AS] min; p = 0.0001), but the hospital stay was shorter, in patients treated by RS (3.92 +/- 2.61 days [RS] vs. 4.87 +/- 3.23 [AS] days; p = 0.0001). The rate of intraoperative complications was not significantly different between the two groups (1.02 % [RS] vs. 0.8 % [AS]; p = 0.6). The need for surgical reintervention (0.6 % [RS] vs. 2.5 % [AS]; p = 0.005) and the 30-day morbidity were higher in patients treated by AS (3.7 % [AS] vs. 1.8 % [RS]; p = 0.04). There was no postoperative mortality. CONCLUSIONS: Under appropriate supervision, surgical residents are able to perform LA with results comparable to those of experienced surgeons. PMID- 22426773 TI - An intrapericardial foregut cyst: report of a thoracoscopically resected case. AB - Intrapericardial foregut cysts are rare, and are usually found serendipitously. An abnormal shadow was incidentally found on a chest X-ray film of a 45-year-old asymptomatic female undergoing a regular check-up. Computed tomography revealed a smooth-walled, left mediastinal cyst (70 * 46 mm) immediately adjacent to the pericardium and left ventricle. We performed video-assisted thoracic surgery, which suggested that the lesion had macroscopically originated from the epicardium. However, the resected cyst was histologically determined to be an intrapericardial foregut cyst. This experience taught us that, while intrapericardial cysts possess the latent possibility of causing sudden death, cardiac failure, or eventual malignant changes, carefully planned and meticulously executed resection, avoiding damage to adjacent organs or vessels, is recommended. PMID- 22426774 TI - The epidemiology of cervical spondylotic myelopathy. AB - OBJECTIVES: This is an observational study looking at the epidemiology of cervical spondylotic myelopathy of patients presenting to our hospital. MATERIALS AND METHODS: The notes and MRI scans of 41 patients presenting to the Leicester General Hospital with a clinical diagnosis of cervical myelopathy between January 2004 and December 2008 were reviewed retrospectively. RESULTS: Cervical myelopathy was found to be more common in male patients to the ratio of approximately 2.7:1, with an average age at diagnosis of 63.8 years. Multi-level disease was seen in the majority of patients, with C5/6 being the most commonly affected level. CONCLUSIONS: Cervical myelopathy predominantly affects men in their 7th decade of life. It is often a multi-level disease with C5/6 being the most commonly affected. It has little in common with cervical radiculopathy and is more analogous to lumber spinal stenosis. PMID- 22426775 TI - Quantifying the contribution of pincer deformity to femoro-acetabular impingement using 3D computerised tomography. AB - OBJECTIVE: To provide a simple, reliable method for the three-dimensional quantification of pincer-type hip deformity. MATERIALS AND METHODS: Computerised tomography scans of 16 normal female hips and 15 female hips with clinical femoro acetabular impingement (FAI) and radiographic signs of pincer secondary to acetabular protrusio were analysed. After orientating the pelvis in the anterior pelvic plane, the acetabular centre was determined, and the ratios of its coordinates to the corresponding pelvic dimensions were calculated. Acetabular coverage of the femoral head and centre-edge angles were also measured for the two groups. RESULTS: In hips with a pincer, the hip was medialised by 37 % (p = 0.03), more proximal by 5 % (p = 0.05) and more posterior by 9 % (p = 0.03) compared with the normal hips. Coverage of the femoral head in protrusio hips was significantly greater than normal (average 71 % vs 82 %, p = 0.0001). Both the lateral centre-edge angle and the combined anterior-posterior centre-edge angle were greater in protrusio hips than in the normal ones (48 degrees vs 37 degrees , p < 0.001; and 216 degrees vs 176 degrees , p < 0.0001 respectively). CONCLUSION: Displacement in acetabular protrusio occurs in all planes. This CT based method allows for the accurate and standardised quantification of the extent of displacement, as well as 3D measurement of femoral head coverage. In the adult female population, a combined centre-edge angle of over 190 degrees suggests an acetabulum that is too deep and a potential cause of symptoms of femoro-acetabular impingement. Conversely, an acetabulum that has a combined centre-edge angle of less than 190 degrees may be considered to be of normal depth, and therefore not contributing a pincer to FAI should it occur. PMID- 22426776 TI - The role of ultrasound in the assessment of post-operative complications following hip arthroplasty. AB - Hip arthroplasty is one of the most commonly performed orthopedic procedures. Clinicians can be faced with the diagnostic dilemma of the patient presenting with a painful hip following arthroplasty and satisfactory post-operative radiographs. Identifying the cause of symptoms can be challenging and ultrasound is increasingly being utilized in the evaluation of potential soft tissue complications following hip surgery. In this article, we describe the common surgical approaches used during hip arthroplasty as this can influence the nature and location of subsequent complications. A review of the literature is presented along with the imaging appearances frequently encountered when imaging this patient population. PMID- 22426777 TI - Utility of in vitro culture to the study of plant mitochondrial genome configuration and its dynamic features. AB - Recombination activity plays an important role in the heteroplasmic and stoichiometric variation of plant mitochondrial genomes. Recent studies show that the nuclear gene MSH1 functions to suppress asymmetric recombination at 47 repeat pairs within the Arabidopsis mitochondrial genome. Two additional nuclear genes, RECA3 and OSB1, have also been shown to participate in the control of mitochondrial DNA exchange in Arabidopsis. Here, we demonstrate that repeat mediated de novo recombination is enhanced in Arabidopsis and tobacco mitochondrial genomes following passage through tissue culture, which conditions the MSH1 and RECA3 suppressions. The mitochondrial DNA changes arising through in vitro culture in tobacco were reversible by plant regeneration, with correspondingly restored MSH1 transcript levels. For a growing number of plant species, mitochondrial genome sequence assembly has been complicated by insufficient information about recombinationally active repeat content. Our data suggest that passage through cell culture provides a rapid and effective means to decipher the dynamic features of a mitochondrial genome by comparative analysis of passaged and non-passaged mitochondrial DNA samples following next-generation sequencing and assembly. PMID- 22426778 TI - Veratric acid ameliorates hyperlipidemia and oxidative stress in Wistar rats fed an atherogenic diet. AB - An investigation was made to reveal the protective effects of veratric acid (VA), a phenolic acid against atherogenic diet-induced hyperlipidemic rats. Male albino Wistar rats were fed with atherogenic diet (4% cholesterol, 1% cholic acid, and 0.5% 2-thiouracil) daily for 30 days and treated with VA (40 mg/kg body weight) daily for a period of 30 days. Rats fed with atherogenic diet showed significant (P < 0.05) elevation in the level of plasma lipids, systolic and diastolic blood pressure, oxidative stress markers (thiobarbituric acid reactive substances, lipid peroxides) and significant (P < 0.05) reduction in the activities of enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non enzymatic (vitamin C, vitamin E, and reduced glutathione) antioxidants in erythrocytes, plasma, and tissues (liver, kidney, and aorta). Oral administration of VA (40 mg/kg body weight) for 30 days to atherogenic diet fed rats markedly attenuates systolic, diastolic blood pressure and lipid peroxidation products. Further, VA treatment significantly improved enzymatic and non-enzymatic antioxidants levels and showed beneficial effects on lipid profile in atherogenic diet rats. All the above alterations were supported by histopathological observations. These results indicate that oral administration of VA ameliorates atherogenic diet-induced hyperlipidemia in rats by its free radical scavenging; improving the antioxidants and lipid lowering properties. PMID- 22426779 TI - Characterization of the high-affinity uptake of fructose-1,6-bisphosphate by cardiac myocytes. AB - Previously, we reported that fructose-1,6-bisphosphate (FBP) was taken up by rat cardiac myocytes by two processes: a component that was saturable at micromolar levels and a nonsaturable component that dominated at millimolar levels. Here, we continued to characterize the saturable high-affinity component, with the aim of identifying the physiological substrate and role for this activity. ATP, ADP, and AMP inhibited the uptake of FBP with apparent affinities of 0.2-0.5 mM. Fumarate and succinate were very weak inhibitors. Several phosphorylated sugars (ribulose 1,5-phosphate, fructose-1-phosphate, ribose-5-phosphate, and inositol-2 phosphate) inhibited FBP uptake with apparent affinities of 40-500 MUM. As in our previous study, no tested compound appeared to bind as well as FBP. The data suggest that the best ligands have two phosphoryl groups separated by at least 8 A. The rates of FBP uptake were measured from 3 degrees to 37 degrees . The calculated activation energy was 15-50 kJ/mol, similar to other membrane transport processes. Uptake of FBP was tested in several types of cells other than cardiac myocytes, and compared to the uptake of 2-deoxyglucose and L: glucose. While FBP uptake in excess of that of L: -glucose was observed in some cells, in no case was the uptake as high as in cardiac myocytes. The physiological substrate and role for the high-affinity FBP uptake activity remain unknown. PMID- 22426780 TI - Perturbation of glycerol metabolism in hepatocytes from n3-PUFA-depleted rats. AB - Second generation n3-PUFA-depleted rats represent a good animal model of metabolic syndrome as they display several features of the disease such as liver steatosis, visceral obesity and insulin resistance. The goal of our study was to investigate the influence of n3-PUFA deficiency on hepatic glycerol metabolism. Aquaglyceroporin 9 (AQP9) allows hepatic glycerol transport and consequently contributes to neoglucogenesis. AQP9 knockout mice display hypertriacyl glycerolemia, one of the hallmarks of the metabolic syndrome. Our data show reduced AQP9 expression at the protein level in n3-PUFA-depleted rats, without any changes at the mRNA levels. [U-14C]glycerol uptake was increased in hepatocytes from n3-PUFA-depleted animal cells. The apparent discrepancy between decreased AQP9 protein expression, and increased [U-14C]glycerol uptake could be explained by an observed increase in glycerol kinase activity. PMID- 22426782 TI - Genetics of physical activity and physical inactivity in humans. AB - Emerging evidence suggests that physical activity and sedentary behavior [reflected in physical inactivity (PI)], might be two different phenotypes that may have distinct underlying physiological mechanisms. The purpose of this review is to summarize the existing literature on the genetic determinants of PA and PI phenotypes in humans, considering them as distinct behaviors. Completed in January 2011, this review includes family studies, twin studies, association studies, genome-wide linkage studies and genome-wide association scan (GWAs) reporting different physical activity/inactivity-related phenotypes. In regards to PA, familial aggregation studies resulted in heritability estimates ranging from 0 to 60 %, and twin studies yielded heritability estimates (a(2)) and shared environment (c(2)) scores for PA phenotypes ranging from 0.00 to 0.85 and 0.00 to 0.84, respectively. Unique environmental (e(2)) results are well dispersed from 0.12 to 0.72. Suggestive linkages were found with markers nearby different activity-related genes: EDNRB, MC4R, UCP1, FABP2, CASR, SLC9A9. Significant associations with PA phenotypes were found for Ace, Gln223ARrg, MC4R and DRD2 genes. We found one GWAs that reported novel SNPs in the PAPSS2 gene on chromosome 10q23.2 and in two intergenic regions on chromosomes 2q33.1 and 18p11.32. Heritability estimates for PI ranged from 25 to 60 % and linkage studies recorded higher LOD scores for PI versus PA. The ACE genotype was strongly associated with PI. There are potentially different genetic influences on PA versus PI phenotypes. Future studies should focus on the different genetic influences on PA and PI to improve our understanding of underlying determinants of these behaviors. PMID- 22426781 TI - The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language. AB - Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language. PMID- 22426783 TI - Involvement of ER-alpha36, Src, EGFR and STAT5 in the biphasic estrogen signaling of ER-negative breast cancer cells. AB - It is well established that estrogen is a potent mitogen in cells expressing estrogen receptors (ER). However, a large body of evidence has demonstrated that the effects of mitogenic estrogen signaling exhibit a non-monotonic or biphasic, dose-response curve; estrogen at low concentrations, elicits a mitogenic signaling pathway to stimulate cell proliferation, while at high concentrations, estrogen inhibits cell growth. The molecular mechanism underlying this paradoxical effect of estrogen on cell proliferation remains largely unknown. Recently, we reported that ER-alpha36, a variant of ER-alpha, mediates mitogenic estrogen signaling in ER-negative breast cancer cells. Here, we investigated the molecular mechanisms underlying the biphasic estrogen signaling in MDA-MB-231 and MDA-MB-436 ER-negative breast cancer cells. We found that 17beta-estradiol (E2beta) at l nM induced the phosphorylation of Src-Y416, an event that activates Src, while at 5 uM failed to induce Src-Y416 phosphorylation but induced Src-Y527 phosphorylation an event that inactivates Src. E2beta at 1 nM, but not at 5 uM, also induced phosphorylation of MAPK/ERK and activated Cyclin D1 promoter activity through the Src/EGFR/STAT5 pathway. Knockdown of ER-alpha36 abrogated the biphasic estrogen signaling in these cells. Our results thus indicate that in ER-negative breast cancer cells Src functions as a switch in ER-alpha36-mediated biphasic estrogen signaling through the EGFR/STAT5 pathway. PMID- 22426784 TI - A miniaturized and integrated gel post platform for multiparameter PCR detection of herpes simplex viruses from raw genital swabs. AB - Herpes simplex virus (HSV) is one of the most prevalent viruses, with acute and recurrent infections in humans. The current gold standard for the diagnosis of HSV is viral culture which takes 2-14 days and has low sensitivity. In contrast, DNA amplification by polymerase chain reaction (PCR) can be performed within 1-2 h. We here describe a multiparameter PCR assay to simultaneously detect HSV-1 and HSV-2 DNA templates, together with integrated positive and negative controls, with product detection by melting curve analysis (MCA), in an array of semi-solid polyacrylamide gel posts. Each gel post is 0.67 MUL in volume, and polymerized with all the components required for PCR. Both PCR and MCA can currently be performed in one hour and 20 min. Unprocessed genital swabs collected in universal transport medium were directly added to the reagents before or after polymerization, diffusing from atop the gel posts. The gel post platform detects HSV templates in as little as 2.5 nL of raw sample. In this study, 45 genital swab specimens were tested blindly as a preliminary validation of this platform. The concordance of PCR on gel posts with conventional PCR was 91%. The primer sequestration method introduced here (wherein different primers are placed in different sets of posts) enables the simultaneous detection of multiple pathogens for the same sample, together with positive and negative controls, on a single chip. This platform accepts unprocessed samples and is readily adaptable to detection of multiple different pathogens or biomarkers for point-of-care diagnostics. PMID- 22426785 TI - Conformational distributions of denatured and unstructured proteins are similar to those of 20 * 20 blocked dipeptides. AB - Understanding intrinsic conformational preferences of amino-acids in unfolded proteins is important for elucidating the underlying principles of their stability and re-folding on biological timescales. Here, to investigate the neighbor interaction effects on the conformational propensities of amino-acids, we carried out (1)H NMR experiments for a comprehensive set of blocked dipeptides and measured the scalar coupling constants between alpha protons and amide protons as well as their chemical shifts. Detailed inspection of these NMR properties shows that, irrespective of amino-acid side-chain properties, the distributions of the measured coupling constants and chemical shifts of the dipeptides are comparatively narrow, indicating small variances of their conformation distributions. They are further compared with those of blocked amino acids (Ac-X-NHMe), oligopeptides (Ac-GGXGG-NH(2)), and native (lysozyme), denatured (lysozyme and outer membrane protein X from Escherichia coli), unstructured (Domain 2 of the protein 5A of Hepatitis C virus), and intrinsically disordered (hNlg3cyt: intracellular domain of human NL3) proteins. These comparative investigations suggest that the conformational preferences and local solvation environments of the blocked dipeptides are quite similar to not only those of other short oligopeptides but also those of denatured and natively unfolded proteins. PMID- 22426786 TI - From migralepsy to ictal epileptic headache: the story so far. AB - In the last few years several cases of headache as sole manifestation of an epileptic seizure have been reported and the term "ictal epileptic headache" has been recently proposed to identify an EEG-recorded epileptic seizure with migraine/headache-like features. Among the potential practical implications arising from these clinical observations, there is the urgent need for a revision of both International Classifications of Epilepsy and Headache disorders. We discuss these topics and provide additional comments about the physiopathological links between epilepsy and migraine. PMID- 22426787 TI - A case of Leber hereditary optic neuropathy plus dystonia caused by G14459A mitochondrial mutation. PMID- 22426788 TI - Role of 5alpha-reductase inhibitors in modulation of the analgesic effects of morphine: an emerging concept in pain management. PMID- 22426791 TI - Knowledge of lung cancer symptoms and risk factors in the U.K.: development of a measure and results from a population-based survey. AB - OBJECTIVES: To develop and validate a lung cancer awareness measure (Lung CAM) and explore the demographical and social predictors of lung cancer awareness in the general population. METHODS STUDY 1: Symptoms and risk factors for lung cancer were identified from the medical literature and health professional expertise in an iterative process. Test-retest reliability, internal reliability, item analyses, construct validity and sensitivity to changes in awareness of the Lung CAM were assessed in three samples (total N=191). RESULTS STUDY 1: The Lung CAM demonstrated good internal (Cronbach's alpha=0.88) and test-retest reliability (r=0.81, p<0.001). Validity was supported by lung cancer experts scoring higher than equally educated controls (t(106)=8.7, p<0.001), and volunteers randomised to read lung cancer information scoring higher than those reading a control leaflet (t(81)=3.66, p<0.001). METHODS STUDY 2: A population based sample of 1484 adults completed the Lung CAM in a face-to-face, computer assisted interview. RESULTS STUDY 2: Symptom awareness was low (average recall of one symptom) and there was little awareness of risk factors other than smoking. Familiarity with cancer, and being from a higher socioeconomic group, were associated with greater awareness. CONCLUSIONS: Using a valid and reliable tool for assessing awareness showed the UK population to have low awareness of lung cancer symptoms and risk factors. Interventions to increase lung cancer awareness are needed to improve early detection behaviour. PMID- 22426792 TI - Serum levels and genotype distribution of alpha1-antitrypsin in the general population. AB - RATIONALE: alpha1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management of replacement therapy require the availability of precise and updated ranges for protein serum levels. OBJECTIVE: This paper aims to provide ranges of serum AAT according to the main genotype classes in the general population. METHODS: The authors correlated mean AAT serum levels with the main SERPINA1 variants (M1Ala/M1Val (rs6647), M3 (rs1303), M2/M4 (rs709932), S (rs17580) and Z (rs28929474)) in 6057 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) cohort. RESULTS: The following ranges (5th-95th percentile) of AAT were found in the serum (g/litre): 1.050-1.640 for PI*MM, 0.880-1.369 for PI*MS, 0.730-1.060 for PI*SS, 0.660-0.997 for PI*MZ and 0.490-0.660 for PI*SZ. There was very little overlap in AAT serum levels between genotype classes generally not believed to confer an enhanced health risk (MM and MS) and those associated with an intermediate AAT deficiency and a potentially mildly enhanced health risk (SS, MZ). CONCLUSION: This work resulted in three important findings: technically updated and narrower serum ranges for AAT according to PI genotype; a suggestion for a population-based 'protective threshold' of AAT serum level, used in decision-making for replacement therapy; and more precise ranges framing the intermediate AAT deficiency area, a potential target for future primary prevention. PMID- 22426793 TI - Solvent penetration rate in tablet measurement using video image processing. AB - We describe a simple technique for the measurement of solvent penetration rates into spray-dried lactose (DCL) tablets and tablets made of blended materials using digital video image processing. The results of the experimental study show that the penetration rate in some cases appears to be close to linear with time, which corresponds to non-Fickian or Case II-type diffusion. We discuss relevant capillary invasion models in order to explain the observed penetration rate. The proposed technique allows fast diffusion rate acquisition/processing and can be useful when designing immediate release tablets that require a large number of measurements corresponding to different formulations and processing parameters. PMID- 22426794 TI - "Conditional Conditioning" in cardiac bypass surgery. PMID- 22426795 TI - Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor. AB - Exercise protects against myocardial ischemia-reperfusion (I-R) injury but the mechanism remains unclear. Protection can be transferred from a remotely preconditioned human donor to an isolated perfused rabbit heart using a dialysate of plasma. We hypothesized that physical exercise preconditioning also confers cardioprotection through a humorally mediated effector dependent on opioid receptor activation. Thirteen male volunteers performed vigorous exercise (four 2 minute bouts of high-intensity exercise) and 1 week later they underwent remote ischemic preconditioning (four cycles of 5 min upper limb ischemia and reperfusion). Dialysates were prepared from blood collected before (control) and after the two interventions. Isolated rabbit hearts were perfused with the dialysates without and with co-administration of naloxone (opioid receptor antagonist) prior to 40 min regional ischemia and 2 h reperfusion. Exercise and remote ischemic preconditioning (rIPC) reduced infarct size from 60 +/- 5 to 35 +/- 5 % and from 57 +/- 7 to 27 +/- 3 % of the area at risk, respectively (p < 0.05 and < 0.01). Furthermore, post-ischemic left ventricular developed pressure was improved compared with controls (p = 0.08 for exercise and p = 0.04 for rIPC). Co-perfusion with naloxone abrogated the protective effects of exercise and remote ischemic preconditioned dialysates. In conclusion, high-intensity exercise preconditioning elicits cardioprotection through a humorally mediated dependent on opioid receptor activation, similar to rIPC. PMID- 22426796 TI - The nucleus pararaphales in the human, chimpanzee, and macaque monkey. AB - The human cerebral cortex and cerebellum are greatly expanded compared to those of other mammals, including the great apes. This expansion is reflected in differences in the size and organization of precerebellar brainstem structures, such as the inferior olive. In addition, there are cell groups unique to the human brainstem. One such group may be the nucleus pararaphales (PRa); however, there is disagreement among authors about the size and location of this nucleus in the human brainstem. The name "pararaphales" has also been used for neurons in the medulla shown to project to the flocculus in the macaque monkey. We have re examined the existence and status of the PRa in eight humans, three chimpanzees, and four macaque monkeys using Nissl-stained sections as well as immunohistochemistry. In the human we found a cell group along the midline of the medulla in all cases; it had the form of interrupted cell columns and was variable among cases in rostrocaudal and dorsoventral extent. Cells and processes were highly immunoreactive for non-phosphorylated neurofilament protein (NPNFP); somata were immunoreactive to the synthetic enzyme for nitric oxide, nitric oxide synthase, and for calretinin. In macaque monkey, there was a much smaller oval cell group with NPNFP immunoreactivity. In the chimpanzee, we found a region of NPNFP-immunoreactive cells and fibers similar to what was observed in macaques. These results suggest that the "PRa" in the human may not be the same structure as the flocculus-projecting cell group described in the macaque. The PRa, like the arcuate nucleus, therefore may be unique to humans. PMID- 22426797 TI - The relation between human exposure to mercury and thyroid hormone status. AB - The aim of this study was to investigate total mercury (THg) and methylmercury (MeHg) exposure of 75 mother-child pairs in relation to their thyroid hormone status (thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (fT3), thyroxine (T4), and free thyroxine (fT4)). THg and MeHg in blood samples were measured by atomic absorption spectrometry and gas chromatography-inductively coupled plasma-mass spectrometry, respectively. The median THg and MeHg levels in maternal blood, cord blood, and blood of 6-month old children were 0.50, 0.53, and 0.32 and 0.22, 0.32, and 0.08 MUg/L, respectively. There were significant correlations between paired maternal-cord blood levels for THg and MeHg, with a greater transplacental transport of MeHg compared with THg (mean cord/maternal blood ratio, 1.80 vs. 1.24). The maternal blood THg was found to be a better predictor of TSH levels in children than their current THg exposure. There was a positive correlation between maternal THg and children's TSH. T3 and fT3 levels in children were negatively related to cord blood THg in the majority (Caucasian) subgroup, whereas these associations were positive in the Roma subgroup. Mothers with dental amalgam fillings had significantly lower T4 and fT4 levels. Moreover, fT4 in the mothers of boys negatively correlated with maternal THg levels. MeHg exposure lowered T3 levels in the mothers of girls. Our results suggest that low-level exposure to Hg can affect thyroid hormone status during prenatal and early postnatal exposure depending on the form of Hg, gender, ethnicity, lifestyle, or socioeconomic status (dental amalgam fillings). PMID- 22426798 TI - Ferritin levels and hepcidin mRNA expression in peripheral mononuclear cells from anemic type 2 diabetic patients. AB - This study aims to measure iron nutrition parameters and to determine the presence of anemia in obese type 2 diabetic patients and to analyze the mRNA relative abundance of genes related to inflammation, immune system, iron metabolism, and mitochondrial activity. Obese type 2 diabetic (OBDM, n=30) and healthy subjects (Cn, n=30) were studied. Biochemical, anthropometric, and iron nutrition parameters were determined. Peripheral mononuclear cells from type 2 diabetic and control group were challenged with high concentrations of iron (Fe) and glucose and total mRNA was isolated. The frequency of anemia among diabetic patients was 4/30. OBDM patients with or without anemia had higher levels of ferritin and high-sensitivity C-reactive protein than the Cn group. mRNA relative abundance of nuclear factor kappa-light-chain-enhancer of activated B cells was elevated in OBDM with anemia, and mRNA expression of interleukin-6 and toll-like receptor (TLR) 2 was increased in OBDM group in basal high Fe and high glucose concentrations. The expression of tumor necrosis factor alpha and TLR-4 was increased in OBDM with anemia in all experimental conditions. Hepcidin mRNA expression was increased in OBDM with anemia even in basal Fe concentration, and mitofusin 2 was decreased in all experimental conditions. This study shows that obese type 2 diabetic patients have iron distribution disorders associated to their proinflammatory state, and anemic subjects have a marked elevation of hepcidin mRNA expression. PMID- 22426799 TI - Clinical study on tongyan spray for post-stroke dysphagia patients: a randomized controlled trial. AB - OBJECTIVE: To observe the effectiveness and safety of Tongyan spray composed of Chinese medicine for post-stroke dysphagia patients. METHOD: One hundred and twenty-two post-stroke dysphagia patients were randomly assigned to the treatment group (61 cases) and the control group (61 cases). Basic treatment was given to both groups, with Tongyan spray additionally used in oropharynx for the treatment group, and the placebo used for the control group. After 28-day treatment, the clinical effect and safety were evaluated according to the standard swallowing assessment (SSA) scale. RESULTS: One patient dropped out in each group, and 120 patients reached the final analysis of the study. The total effective rate for the treatment group was 71.7% (43/60), higher than 46.7% (28/60) in the control group (P<0.05), and the improvement on SSA scores of the two groups were significantly different after treatment (P<0.05). For grade 1 dysphagia patients (completely depending on nasogastric tube), the effective rate of the treatment group was 40.9% (9/22), and 12.5% (2/16) of the control group, without significant difference (P>0.05), while the improvement of SSA score was significantly different between the two groups after treatment (P<0.05). For grade 2-3 dysphagia patients (oral and nasogastric tube feeding), the total effective rate of the treatment group was 89.5% (34/38), higher than 59.1% (26/44) in the control group (P<0.05), and also the improvement on SSA scores was significantly different between the two groups after treatment (P<0.05). CONCLUSION: Tongyan spray was an effective and safe method for post-stroke dysphagia patients. PMID- 22426800 TI - Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance. AB - AIMS/HYPOTHESIS: Vitamin D deficiency may increase the risk of type 2 diabetes. We therefore investigated whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] would predict the development of prediabetes (impaired fasting glucose, impaired glucose tolerance or the two combined) and type 2 diabetes, either on their own or when combined with serum concentrations of IGF-1 or IGF-binding protein-1 (IGFBP-1), which may interact with 25(OH)D. METHODS: At baseline, participants aged 35-56 years without known type 2 diabetes were examined using OGTTs, 25(OH)D and IGF peptide measurements, and anthropometric and lifestyle data. Participants who had prediabetes or type 2 diabetes at follow-up 8-10 years later were selected as cases; these were then age- and sex-matched to controls with normal glucose tolerance (NGT) at both baseline and follow-up, giving a total of 980 women and 1,398 men. RESULTS: Men but not women in the highest quartile of 25(OH)D level had a decreased OR for developing type 2 diabetes after adjustment for confounders (OR 0.52, 95% CI 0.30, 0.90), an effect accounted for by individuals with prediabetes, but not with NGT, at baseline. In both sexes, progression from prediabetes to type 2 diabetes was reduced by about 25% per 10 nmol/l increase in 25(OH)D. A high IGFBP-1 value was a better predictor of a reduced risk of type 2 diabetes than high 25(OH)D for both sexes, whereas high IGF-1 concentrations predicted a decreased risk only in men. CONCLUSIONS/INTERPRETATION: High serum 25(OH)D concentrations predict a reduced risk of type 2 diabetes in individuals with prediabetes, but not NGT. There were no significant interactions between 25(OH)D and IGFBP-1 or IGF-1 in terms of risk of diabetes. Our data suggest that vitamin D supplementation should be evaluated for the prevention of type 2 diabetes in prediabetic individuals. PMID- 22426801 TI - Normative optical coherence tomography measurements in children. PMID- 22426802 TI - Making expensive dirhodium(II) catalysts cheaper: Rh(II) recycling methods. AB - Dirhodium(II) catalysts have been widely used as a remarkable tool in organic synthesis, ultimately resulting in a myriad of transformations and formation of a wide variety of compounds, every so often intermediaries in drug synthesis. Aiming at a more sustainable chemistry, several methods suitable for the reutilisation of expensive dirhodium complexes have been developed. Herein, we provide a combined overview of the available methods for recovering and reusing dirhodium(II) metal complexes in catalysis, covering homogeneous catalysis as well as heterogenisation methods. PMID- 22426803 TI - 1H-MRS in autism spectrum disorders: a systematic meta-analysis. AB - We conducted a systematic review and meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies comparing autism spectrum disorder (ASD) patients with healthy controls, with the aim of profiling ASD-associated changes in the metabolites N-acetyl-aspartate (NAA) and Creatine (Cr). Meta-regression models of NAA and Cr levels were employed, using data from 20 eligible studies (N = 852), to investigate age-dependent differences in both global brain and region-specific metabolite levels, while controlling for measurement method (Cr-ratio versus absolute concentrations). Decreased NAA concentrations that were specific to children were found for whole-brain grey and white matter. In addition, a significant decrease in NAA was evident across age categories in the parietal cortex, the cerebellum, and the anterior cingulate cortex. Higher levels of Cr were observed for ASD adults than children in global grey matter, with specific increases for adults in the temporal lobe and decreased Cr in the occipital lobe in children. No differences were found for either NAA or Cr in the frontal lobes. These data provide some evidence that ASD is characterized by age-dependent fluctuations in metabolite levels across the whole brain and at the level of specific regions thought to underlie ASD-associated behavioural and affective deficits. Differences in Cr as a function of age and brain region suggests caution in the interpretation of Cr-based ratio measures of metabolites. Despite efforts to control for sources of heterogeneity, considerable variability in metabolite levels was observed in frontal and temporal regions, warranting further investigation. PMID- 22426804 TI - Magnetic resonance neurography of median neuropathies proximal to the carpal tunnel. AB - This review provides magnetic resonance neurography (MRN) imaging appearances of median neuropathy proximal to the carpal tunnel. Carpal tunnel syndrome (CTS) and its imaging have been extensively described in the literature; however, there is a relative paucity of information on the MR imaging appearances of different pathologies of the median nerve proximal to the carpal tunnel. PMID- 22426805 TI - Heritability of body mass index in pre-adolescence, young adulthood and late adulthood. AB - Increased body mass index (BMI) is a worldwide health issue. Individual differences in the susceptibility to increased BMI could be related to genes or environment. We performed a systematic review of genetic studies on BMI in pre adolescence, young adulthood and late adulthood. We searched PubMed and EMBASE with heritability, body mass index, BMI, weight, height, anthropometry and twins as search terms. Studies reporting intra-pair correlations of healthy twin pairs that were raised together were included. This resulted in the inclusion of 8,179 monozygotic (MZ) and 9,977 dizygotic (DZ) twin pairs from twelve published studies in addition to individual participant data for 629 MZ and 594 DZ pairs from four twin registries. Structural equation modelling with intra-pair twin correlations showed that the heritability of BMI remained high over all age categories ranging from 61% (95% CI 54-64%) to 80% (95% CI 76-81%) for male and female subjects combined, while unique environmental influences increased from 14% (95% CI 13-15%) to 40% (95% CI 37-43%) with increasing age. Heritability of BMI remains consistently high over different age categories. Environmental changes over time do not seem to have as big a relative impact on an individual's weight as previously reported, suggesting a mainly genetic influence on variation in BMI over the years. PMID- 22426806 TI - Structural and functional changes of carotid wall properties in patients with acromegaly are not restored after 1 year of GH/IGF1 normalization. AB - Vascular changes are common in acromegaly (ACM). Current therapies can normalise the levels of both growth hormone (GH) and insulin-like growth factor (IGF1). OBJECTIVE: To establish whether the ACM vascular changes in patients with effectively managed disease are different from those in patients with an active condition. METHODS: 64 ACM patients were tested for serum GH (random and during an oral glucose tolerance test) and IGF1. Ultrasonography of the right common carotid (RCC) explored structural (the carotid diameter and intima-media thickness index (IMT)) and functional (the augmentation index (AIx), elastic modulus (Ep), and local pulse wave velocity (PWV)) arterial parameters in the ACM patients (groups A and B) and an age- and sex-matched control group of 21 patients without acromegaly (group C). RESULTS: The ACM patients were divided into 2 subgroups that had similar cardiovascular risk factor profiles: A (n=10, with controlled ACM), and B (n=54, with active ACM). The AIx was higher in groups A (27.7% [2.2-54.3]) and B (20.0% [ - 38.2-97.1]) than in group C (3.5% [ - 11.3 31.1]), p=0.01 and 0.002, respectively. The group B patients presented with poorer functional carotid wall parameters than the control subjects: Ep-95.5 [33 280] KPa vs. 77.5 [39-146] KPa, p=0.01; and PWV-6 [3.6-10.4] m/s vs. 5.4 [3.9 7.2] m/s, p=0.03.The ACM patients had greater RCC diameters (6.4 +/- 0.6 mm vs. 5.7 +/- 0.6 mm, p<0.001) and IMT values (0.72 +/- 0.13 mm vs. 0.58 +/- 0.08 mm, p<0.001) than the subjects in group C. CONCLUSIONS: Both the controlled and active ACM patients showed structural arterial changes. After 1 year of disease control, the patients with controlled ACM showed improvements in the functional, but not the structural, arterial parameters compared with the patients with an active condition. PMID- 22426807 TI - Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth of tumors by activating tumor-specific Th1-type immune responses. AB - Because IL-4 and CpG oligodeoxynucleotides (CpG-ODNs) are immune stimulants, we evaluated the antitumor effects of IL-4 gene therapy and CpG-ODN treatment in a poorly immunogenic murine cancer model. We used a murine colorectal cancer MC38 cell line overexpressing the IL-4 gene (MC38-IL4). Incubation with MC38-IL4 and CpG-ODN enhanced bone marrow-derived dendritic cell (DC) maturation in vitro. In addition, interferon (IFN)-gamma production was significantly increased in naive splenocytes after they were coincubated with MC38-IL4 and CpG-ODN. When mice bearing MC38 wild-type tumors were inoculated subcutaneously with MC38-IL4 cells and CpG-ODN, the outgrowth of established parental tumors was significantly suppressed compared to those in the MC38-IL4-treated group (IL-4 vs. IL-4 + CpG ODN, p=0.015). A marked infiltration of CD8+ cells in the established parental tumors of mice treated with MC38-IL4 and CpG-ODN was confirmed by immunohistochemical analyses (MC38-IL4, 2.8 +/- 1.9 cells/field vs. MC38-IL4 + CpG-ODN, 20.7 +/- 15.3 cells/field, p=0.027). Significant tumor-specific cytolysis was detected when splenocytes of MC38-IL4 + CpG-ODN-treated mice were stimulated by gamma-irradiated MC38-IL4 cells and CpG-ODN twice weekly in vitro and used as effector cells in a chromium-release assay (32.2 +/- 3.5% for MC38 cells vs. 3.2 +/- 1.1% for YAC-1 cells; at an effector to target ratio of 40). These results suggest that IL-4 and CpG-ODN treatment promotes potent Th1-type antitumor immune responses. Therefore, the combination of IL-4 gene therapy and CpG-ODN treatment for cancer should be evaluated in clinical trials. PMID- 22426808 TI - Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer. AB - Ginsenoside compound K (C-K) is an intestinal microbiota metabolite of ginsenoside Rb1, a major constituent in American ginseng. However, previous ginseng anti-cancer observations were largely focused on ginseng parent compounds but not metabolites, and anti-colorectal cancer studies on C-K were limited. This study investigated the anti-proliferative effects of C-K when compared to those of Rb1, and the related mechanisms of action, in HCT-116 and SW-480 colorectal cancer cells. The effects of Rb1 and C-K on the proliferation of HCT-116 and SW 480 human colorectal cancer cells were compared using an MTS assay. Cell cycle and cell apoptosis were assayed using flow cytometry. Enzymatic activities of caspases were determined by colorimetric assay, and interactions of C-K and caspases were explored by docking analysis. C-K showed significant anti proliferative effects in HCT-116 and SW-480 cells at concentrations of 30-50 uM. At the same concentrations, Rb1 did not show any effects, while C-K arrested the cells in the G1 phase, and significantly induced cell apoptosis. Compared to HCT 116 (p53 wild-type), the p53 mutant cell line SW-480 was more sensitive to C-K as assessed by cell cycle regulation and apoptosis induction. C-K activated expression of caspases 8 and 9, consistent with docking analysis. The docking data suggested that C-K forms hydrogen bonds with Lys253, Thr904 and Gly362 in caspase 8, and with Thr62, Ser63 and Arg207 in caspase 9. C-K, but not its parent ginsenoside Rb1, showed significant anti-proliferative and pro-apoptotic effects in human colorectal cancer cells. These results suggest that C-K could be a potentially effective anti-colorectal cancer agent. PMID- 22426809 TI - Expression of peroxisome proliferator activated receptor-gamma (PPAR-gamma) in human non-small cell lung carcinoma: correlation with clinicopathological parameters, proliferation and apoptosis related molecules and patients' survival. AB - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has currently been considered as molecular target for the treatment of human metabolic disorders. PPAR-gamma has also been implicated in the pathogenesis and progression of several types of cancer, being associated with cell differentiation, growth and apoptosis. The present study aimed to evaluate the clinical significance of PPAR gamma expression in non-small cell lung carcinoma (NSCLC). PPAR-gamma protein expression was assessed immunohistochemically in tumoral samples of 67 NSCLC patients and was statistically analyzed in relation to clinicopathological parameters, proliferation and apoptosis related molecules and patients' survival. Positive PPAR-gamma expression was prominent in 30 (45 %) out of 67 NSCLC cases. PPAR-gamma positivity was more frequently observed in squamous cell lung carcinoma cases compared to lung adenocarcinoma ones (p = 0.048). PPAR-gamma positivity was significantly associated with bcl-2 positivity (p = 0.016) and borderline with c-myc positivity (p = 0.052), whereas non associations with grade of differentiation, TNM stage, Ki-67, p53, bax proteins' expression and patients' survival were noted. In the subgroup of squamous cell lung carcinoma cases, PPAR gamma positivity was significantly associated with tumor size (p = 0.038), while in lung adenocarcinoma ones with histopathological grade of differentiation (p = 0.026). The present study supported evidence for possible participation of PPAR gamma in the biological mechanisms underlying the carcinogenic evolution of the lung. Although the survival prediction using PPAR-gamma expression as a marker seems uncertain, the observed correlation with apoptosis related proteins reinforces the potential utility of PPAR-gamma ligands as cell cycle modulators in future therapeutic approaches in lung cancer. PMID- 22426811 TI - Respiratory mechanics during repeated lung lavages in pulmonary alveolar proteinosis. PMID- 22426810 TI - Prognostic value of TOP2A gene amplification and chromosome 17 polysomy in early breast cancer. AB - The aim of this study was to analyze the occurrence of TOP2A gene amplification and chromosome 17 polysomy in patients with early breast cancer and to correlate the status of these alterations with the prognostic significance expressed as patients' clinical features and survival. Such concurrent analyses of TOP2A gene status and chromosome 17 polysomy have not been performed before. Study group included 149 consecutive stage I-III patients administered standard multimodality treatment. TOP2A abnormalities were examined by standard fluorescence in situ hybridization (FISH) and developed by our group quantitative real-time PCR (qPCR). TOP2A amplification and deletion assessed by FISH were found in 23% and 7% of the tumours, respectively, and by qPCR in 31% and 11% of the tumours, respectively. Chromosome 17 polysomy was detected in 40% of the cases. TOP2A amplification (by qPCR) correlated with shorter disease-free survival (p = 0.03) and overall survival (p = 0.047), and the prognostic value of TOP2A was confirmed in the multivariate analysis (HR = 3.22, 95% CI 1.09-9.56, p = 0.03). TOP2A gene amplification, but not chromosome 17 polysomy, carries negative prognostic information in early breast cancer. Given the aforementioned results, qPCR might serve as a prognostic tool in determining the patient's prognosis. PMID- 22426812 TI - An unusual syncope. PMID- 22426813 TI - Optimized search strategy for detecting scientifically strong studies on treatment through PubMed. AB - Our study was designed to optimize the search strategies based on the work of Haynes et al. for detecting randomized controlled trials (RCTs) through PubMed. In particular, we aimed to improve precision for broad and narrow searches on interventional studies. We used in addition to the string suggested by the Hedge Team the following: {NOT ((animals [mh] NOT humans [mh]) OR (review [pt] OR meta analysis [pt]))} and tested its effectiveness. The search was carried out on a year's worth of articles from the PubMed database. We analyzed 35,590 bibliographic citations about four relevant major topics in internal medicine (hypertension, diabetes, heart failure, and hepatitis). Precision, percentage gain between the Hedge Team search strategies and the new one were computed and reported in the text. Moreover, a pooled analysis was carried out in terms of absolute precision difference. We observed better precision for both broad and narrow searches. However, effective gain resulted only for broad searches. In this case, bibliographic citation recall effectively reduced (-24 to -35 % retrieved citation with a gain of 32-54 %) without loss of information. The search strategy improved broad searches regarding each of the four considered topics. We think this new search strategy, based on a previous work of the Hedge team, could be a step forward and can save some time by researchers. PMID- 22426815 TI - Micronucleus assay as a biomarker of genotoxicity in the occupational exposure to agrochemicals in rural workers. AB - This paper aims to evaluate the genotoxic effect of agrochemicals in rural workers occupationally exposed by the micronucleus assay in peripheral blood lymphocytes and to promote the development of health and environmental preventive and protective practices. A total of 30 blood samples from 20 individuals occupationally exposed to different agrochemicals and 10 unexposed persons, who formed the reference group, were analyzed. We found statistically significant differences (p < 0.0005, Student's t Test) in the frequency of micronuclei between the two groups (7.20 +/- 1.55 and 15.15 +/- 5.10 CBMN for reference and exposed groups respectively). The analysis of age showed a positive correlation (Pearson Correlation Test) with the frequency of micronuclei in exposed population (p < 0.05; r(2) = 0.47), in contrast with smoking habits and years of exposure. Micronucleus assay allows an early detection of populations at higher risk of having genetic damage, allowing us to implement strategies of intervention for the purpose of contributing to reduce that risk. PMID- 22426814 TI - Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential. AB - Acute endotoxemia (LPS, 10 mg/kg ip, Sprague Dawley rats, 45 days old, 180 g) decreased the O2 consumption of rat heart (1 mm3 tissue cubes) by 33% (from 4.69 to 3.11 MUmol O2/min. g tissue). Mitochondrial O2 consumption and complex I activity were also decreased by 27% and 29%, respectively. Impaired respiration was associated to decreased ATP synthesis (from 417 to 168 nmol/min. mg protein) and ATP content (from 5.40 to 4.18 nmol ATP/mg protein), without affecting mitochondrial membrane potential. This scenario is accompanied by an increased production of O2.- and H2O2 due to complex I inhibition. The increased NO production, as shown by 38% increased mtNOS biochemical activity and 31% increased mtNOS functional activity, is expected to fuel an increased ONOO- generation that is considered relevant in terms of the biochemical mechanism. Heart mitochondrial bioenergetic dysfunction with decreased O2 uptake, ATP production and contents may indicate that preservation of mitochondrial function will prevent heart failure in endotoxemia. PMID- 22426816 TI - Effect of Acanthocephalus lucii infection on total mercury concentrations in muscle and gonads of fish host (Perca fluviatilis). AB - The samples from 13 perches (Perca fluviatilis) - muscle with skin and bones; fish gonads; and acanthocephalan parasites were analysed for mercury (Hg). Hg concentrations were present in all analysed samples. There were found no statistically significant difference in Hg concentration in fish tissues between perches either with or without infection by the acanthocephalan parasite, Acanthocephalus lucii). In this study there was no evidence that acanthocephalan worms accumulate mercury from hosts. For this reason, A. lucii is not a suitable bioindicator for mercury pollution. PMID- 22426817 TI - Effects of different calcium, magnesium, and zinc concentrations supplemented on hepatopancreatic cell proliferation of kuruma prawn, Penaeus japonicus. AB - The effects of different calcium (Ca(2+)), magnesium (Mg(2+)), and zinc (Zn(2+)) concentrations supplemented on hepatopancreatic cell proliferation of kuruma prawn, Penaeus japonicus was studied. The culture system consists of medium 199 (M 199) supplemented with 0.060 mol/L NaCl, 1.011 g/L glucose, 1,000 UI/ml penicillin, 1,000 MUg/ml treptomycin, heat inactivated fetal calf serum (FCS) 20% for primary cell culture and 10% for subculture. The RNA/DNA ratio of the cell cultures was measured. The results show that the cell division of hepatopancreatic cells of P. japonicus was enhanced by the optimal concentration of inorganic salt (Ca(2+), 1.0 g/L; Mg(2+), 5.0 g/L; Zn(2+), 80 MUg/L). The hepatopancreatic cell culture system and improved culture conditions described here will be very useful for in vitro experiments to study viruses responsible for infections in shrimp leading to tremendous economic losses. PMID- 22426818 TI - Antifungal activity and cytotoxicity of zinc, calcium, or copper alginate fibers. AB - The antifungal properties and cytotoxicity of alginate fibers were investigated to widen their application in tissue engineering. Calcium, zinc, and copper alginate fibers were separately prepared by replacing Na(+) with Ca(2+), Zn(2+), or Cu(2+). The antifungal properties of the three alginate fibers were studied after coming into contact with Candida albicans. Then, the fungal inhibitory rates were measured using the plate-count method following shake-flask test. Moreover, an inhibition-zone test and observation by scanning electron microscopy were carried out. The inhibitory rate of the calcium, copper, and zinc alginate fibers were, respectively, 49.1, 68.6, and 92.2 %. The results from inhibition zone test and shake-flask test show that zinc alginate fibers have the most significant antifungal action and that copper alginate fibers have obvious inhibitory action, but the calcium alginate fibers have weak inhibitory effects. The scanning electron micrographs similarly illustrate that the fungal surfaces show most scraggly after the interaction between C. albicans and zinc alginate fibers. Moreover, the relative growth rates of zinc or calcium alginate fibers in human embryonic kidney cells and human fibroblast cells were more than 100 %. No significant results were obtained (P>0.05). The calcium alginate fibers in human fibroblast cells were not much different from the negative control group (P>0.05). However, zinc alginate fibers had a significant change (P<0.05). Therefore, the excellent antifungal property of zinc alginate fibers demonstrates potential application in skin tissue engineering comparing with calcium or copper alginate fibers. PMID- 22426819 TI - The PI3K/Akt inhibitor LY294002 reverses BCRP-mediated drug resistance without affecting BCRP translocation. AB - Cellular responses toward cytotoxic drugs are influenced by crosstalk between oncogenic signals and resistance mechanisms. Inhibition of the PI3K/Akt pathway is effective in sensitizing cancer cells of various organs, although the mechanisms largely remain to be elucidated. Breast cancer resistance protein (BCRP)/ABCG2, a drug efflux pump, confers resistance to multiple anticancer agents such as SN-38 and topotecan. Previous studies reported that inhibition of the PI3K/Akt pathway, by gene knockout or PI3K inhibitors, modulated BCRP mediated drug transport via BCRP translocation in hematopoietic stem cells, renal polarized cells and glioma stem-like cells of mammals. In this study, we assessed the effects of PI3K inhibitors, LY294002 and wortmannin, on BCRP-mediated anticancer drug resistance of human cancer MCF-7 and A431 cells. LY294002, but not wortmannin, reversed the BCRP-mediated SN-38 and topotecan resistance. LY294002 treatment did not affect total or cell surface BCRP levels as determined by western blotting and flow cytometry but blocked BCRP-mediated topotecan efflux in a dose-dependent manner. Immunohistochemical analyses also demonstrated unchanged cellular BCRP distribution. BCRP overexpression in MCF-7 and A431 cells did not confer LY294002 resistance, suggesting that LY294002 is not a transported substrate of BCRP. LY294002 is a derivative of quercetin, a member of flavonoids. Taken together, these results suggest that LY294002 inhibits BCRP-mediated drug transport not by BCRP translocation through the PI3K/Akt signal but putatively as a competitive inhibitor in a major subset of cancer cells. Due to its dual effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment. PMID- 22426820 TI - Rolandic area meningioma resection controlled and guided by intraoperative cortical mapping. AB - BACKGROUND: The resection of convexity meningiomas should harbour a low rate of morbidity. Functional preservation should be the main goal of surgery and have higher priority over radicality. Involvement of the primary motor cortex (PMC) increases surgical risk. The goal of this study was to evaluate the effect of cortical mapping on surgical morbidity after rolandic area meningioma treatment. METHODS: From January 2005 to March 2011, 42 patients were operated on for rolandic meningioma involving or compressing the PMC. The cohort consisted of 25 (59.5%) convexity, 10 (23.8%) parasagittal and 7 (16.7%) falcine meningiomas. Four patients were treated for recurrent disease and 25 (59.5%). Intraoperative cortical mapping was used to identify location of PMC. The threshold stimulation current was set at every site of cortical monopolar anodal stimulation around the tumour and at the tumour-cortex junction repeatedly during the meningioma dissection. RESULTS: Radical resection (Simpson 1 and 2) was achieved in 30 patients (71.4%) and partial resection (Simpson 4) in 12 (28.6%). New permanent deficit occurred in three patients (7.1%). All patients had moderate preoperative deficit (muscle strength <= 3). WHO-I was in 28 cases (66.7%), WHO-II in 14 cases (33.3%). Average follow-up was 33.2 months. Five patients (11.9%) suffered from recurrence after an average of 23.8 months. CONCLUSIONS: Rolandic area meningiomas should be classified as a higher risk group. Intraoperative cortical mapping is in our experience useful in a situation when the cleavage plane at the PMC is lost. In such a scenario, resection outside the PMC is radical and only at the PMC is a thin remnant left without cortical damage, which helps to be safer with a better long-term prognosis. PMID- 22426821 TI - Mycobacterium bovis infection in a young Dutch adult: transmission from an elderly human source? AB - A young female health professional was diagnosed with pulmonary tuberculosis caused by Mycobacterium bovis. Source finding and contact tracing was initiated by the regional municipal health service using both tuberculin skin test and QuantiFERON((r))-TB Gold (QFT-GIT (IGRA). The strain appeared near-identical to that of an elderly Dutch patient. PMID- 22426822 TI - Copper-mediated domino synthesis of pyrimido[4,5-b]carbazolones via Ullmann N arylation and aerobic oxidative C-H amidation. AB - New pyrimido[4,5-b]carbazolone derivatives have been synthesized through cascade Ullmann N-arylation and aerobic oxidative C-H amidation reactions catalyzed by CuBr under air and ligand-free conditions. PMID- 22426823 TI - ACR Appropriateness Criteria((r)) blunt chest trauma--suspected aortic injury. AB - The purpose of these guidelines is to recommend appropriate imaging for patients with blunt chest trauma. These patients are most often imaged in the emergency room, and thus emergency radiologists play a substantial role in prompt, accurate diagnoses that, in turn, can lead to life-saving interventions. The ACR Appropriateness Criteria(r) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Imaging largely focuses on the detection and exclusion of traumatic aortic injury; a large proportion of patients are victims of motor vehicle accidents. For those patients who survive the injury and come to emergency radiology, rapid, appropriate assessment of patients who require surgery is paramount. PMID- 22426824 TI - PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma. AB - Osteosarcoma (OS) is a primary malignancy of the bone, with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, more than 30% of patients develop distant metastases, and the prognosis of patients with metastases is essentially poor. Members of the protein kinase D (PKD) family are serine/threonine kinases, and have been studied in various cancers. Among the three different isoforms of this family, PKD1 is one of the best understood for its role in human malignancies; however, its role in musculoskeletal tumors has not been studied. In the present study, we investigated the role of PKD1 in human OS. We first analyzed PKD1 mRNA expression in human musculoskeletal tumor tissue samples by quantitative real-time PCR. PKD1 expression in OS samples was significantly lower than that in benign schwannoma samples, and this was correlated with metastatic potential. In in vitro studies, overexpression of PKD1 by plasmid transfection decreased OS cell invasion, migration and proliferation, and significantly decreased matrix metalloproteinase (MMP)2 mRNA expression. Conversely, siRNA knockdown of PKD1 increased invasion, migration and proliferation of OS cells, and MMP2 expression was markedly increased. Furthermore, overexpression of PKD1 significantly reduced in vivo tumor growth of OS cells. These results demonstrated that low expression of PKD1 may contribute to increased cell invasion, migration and proliferation ability of human OS. Taken together, our findings strongly suggest that PKD1 may negatively regulate the malignant potential of human OS, and may be a therapeutic target for human OS in the clinical setting. PMID- 22426825 TI - Statement of the AGNP in the Context of the Planned Formation of a Fixed Reference Price Group "GABA-Analogues", November 21, 2011. PMID- 22426826 TI - Biochemical changes in rat brain exposed to low intensity 9.9 GHz microwave radiation. AB - Present study concerns with various biochemical changes in the developing rat brain exposed to 9.9 GHz (square wave modulated, 1 kHz) at power density 0.125 mW/cm(2) (specific absorption rate 1.0 W/kg) for 2 h/day for 35 days. Thirty days old male wistar rats were used for this present study. Each group consists of eight animals. After the exposure, biochemical assays such as calcium ion efflux, calcium-dependent protein kinase (PKC), and ornithine decarboxylase (ODC) were performed on the brain tissue. Results of this study reveal that chronic exposure of rat to microwave radiation alter the activity of certain enzymes. There was a significant increase in calcium ion efflux and the activity of ODC. On the other hand, there is a significant decrease in PKC activity. Since these enzymes are related to growth, any alteration may lead to affect functioning of the brain and its development. PMID- 22426827 TI - Impact of a new ultrafast CZT SPECT camera for myocardial perfusion imaging: fewer equivocal results and lower radiation dose. AB - PURPOSE: The new ultrafast cardiac single photon emission computed tomography (SPECT) cameras with cadmium-zinc-telluride (CZT)-based detectors are faster and produce higher quality images as compared to conventional SPECT cameras. We assessed the need for additional imaging, total imaging time, tracer dose and 1 year outcome between patients scanned with the CZT camera and a conventional SPECT camera. METHODS: A total of 456 consecutive stable patients without known coronary artery disease underwent myocardial perfusion imaging on a hybrid SPECT/CT (64-slice) scanner using either conventional (n = 225) or CZT SPECT (n = 231). All patients started with low-dose stress imaging, combined with coronary calcium scoring. Rest imaging was only done when initial stress SPECT testing was equivocal or abnormal. Coronary CT angiography was subsequently performed in cases of ischaemic or equivocal SPECT findings. Furthermore, 1-year clinical follow-up was obtained with regard to coronary revascularization, nonfatal myocardial infarction or death. RESULTS: Baseline characteristics were comparable between the two groups. With the CZT camera, the need for rest imaging (35 vs 56%, p < 0.001) and additional coronary CT angiography (20 vs 28%, p = 0.025) was significantly lower as compared with the conventional camera. This resulted in a lower mean total administered isotope dose per patient (658 +/- 390 vs 840 +/- 421 MBq, p < 0.001) and shorter imaging time (6.39 +/- 1.91 vs 20.40 +/- 7.46 min, p < 0.001) with the CZT camera. After 1 year, clinical outcome was comparable between the two groups. CONCLUSION: As compared to images on a conventional SPECT camera, stress myocardial perfusion images acquired on a CZT camera are more frequently interpreted as normal with identical clinical outcome after 1-year follow-up. This lowers the need for additional testing, results in lower mean radiation dose and shortens imaging time. PMID- 22426828 TI - FDG PET/CT metabolic tumour volume in small-cell lung cancer: better staging and prognostic stratification for an improved therapeutic strategy. PMID- 22426829 TI - Skin lesions, elevated serum lipase level and abnormal bone scintigraphy. PMID- 22426830 TI - Technical problems with dynamic compliance evaluation in neonates and infants. PMID- 22426831 TI - Anesthesia recordkeeping: accuracy of recall with computerized and manual entry recordkeeping. AB - Anesthesia information management systems (AIMS) are rapidly gaining widespread acceptance. Aggressively promoted as an improvement to manual-entry recordkeeping systems (MERS) in the areas of accuracy, quality improvement, billing and vigilance, these systems record all patient vital signs and parameters, providing a legible hard copy and permanent electronic record. Concern exists that the practitioner may be less vigilant unless this data is recorded manually. This study's purpose was to determine if vigilance, as measured by the ability to recall important data, is influenced by the method of recordkeeping. This study analyzed differences in the accuracy of Certified Registered Nurse Anesthetists' (CRNAs) recall of specific patient variables during the course of an actual anesthetic case. CRNAs using AIMS were compared to CRNAs using MERS. Accuracy of recalled values of 10 patient variables was measured: highest and lowest values for heart rate, systolic blood pressure, inspiratory pressure, and end-tidal carbon dioxide levels, lowest oxygen saturation and total fluid volume. Four tertiary care facilities participated in this research; two of which used MERS, two utilized AIMS. A total of 214 subjects participated in this study; 106 in the computerized recordkeeping group, and 108 in the manual entry recordkeeping group. Demographic covariates were analyzed to ensure homogeneity between groups and facilities. No significant statistical differences were identified between the accuracy of recall among the groups. There was no difference in the accuracy of practitioners' recall of patient variables when using computerized or manual entry recordkeeping systems, suggesting little impact on vigilance. PMID- 22426832 TI - Dietary supplementation with 22-S-hydroxycholesterol to rats reduces body weight gain and the accumulation of liver triacylglycerol. AB - This study explores the pharmacokinetics of 22-S-hydroxycholesterol (22SHC) in vivo in rats. We also carried out a metabolic study to explore whether the beneficial effects observed of 22SHC on glucose and lipid metabolism in vitro could be seen in vivo in rats. In the pharmacokinetic study, rats were given 50 mg/kg of [3H]22-S-hydroxycholesterol before absorption, distribution and excretion were monitored. In the metabolic study, the effect of 22SHC (30 mg/kg/day for 3 weeks) in rats on body weight gain [chow and high-fat diet (HFD)], serum lipids triacylglycerol (TAG) content and gene expression in liver and skeletal muscle were examined. Results showed that 22SHC was well absorbed after oral administration and distributed to most organs and mainly excreted in feces. Rats receiving 22SHC gained less body weight than their controls regardless whether the animals received chow diet or HFD. Moreover, we observed that animals receiving HFD had elevated levels of serum TAG while this was not observed for animals on HFD supplemented with 22SHC. The amount of TAG in liver was reduced after 22SHC treatment in animals receiving either chow diet or HFD. Gene expression analysis revealed that two genes (carnitine palmitoyltransferase 2 and uncoupling protein 3) involved in fatty acid oxidation and energy dissipation were increased in liver. Ucp3 expression (both protein and mRNA level) was increased in skeletal muscle, but insulin-stimulated glucose uptake and TAG content were unchanged. In conclusion, 22SHC seems to be an interesting model substance in the search of treatments for disorders involving aberrations in lipid metabolism. PMID- 22426833 TI - alpha-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system. AB - The source of Parkinson disease-linked alpha-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, beta-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and beta-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF. PMID- 22426835 TI - The first phase of a migraine attack resides in the cortex. AB - Migraine headache is generated by the complex interaction of various players such as genetic predisposition, environmental triggers and intrinsic factors. The initial mechanism of a migraine attack has long been a controversial topic and exploring its origin is a challenging task. The scientific evidences so far indicate neuronal dysfunction in the cerebral cortex and particularly cortical spreading depression waves, as upstream to cascade of events leading to a migraine attack. Neocortex, evolutionary valuable part of the brain, is surrounded by pain sensing system that is finely tuned for detecting noxious signals. Abnormal functioning of more than one cortical area in migraineurs may suggest that hyperexcitable neocortex could be more easily challenged, overreacts and depolarize to repetitive sensorial stimuli and could switch to extreme excitability state where spreading depression waves occur. In this paper, I will review the data supporting the notion that migraine is a neuronal disorder where cortex has prime importance. Despite clear demonstration of cortical participation in migraine, the contribution of brain structures other than cortex to the development of migraine remains unclear. PMID- 22426834 TI - Where does a migraine attack originate? In the brainstem. AB - Migraine is a common, paroxysmal, highly disabling primary headache disorder. The origin of migraine attacks is enigmatic. Numerous clinical and experimental results suggest that the activation of distinct brainstem nuclei is crucial in its pathogenesis, but the primary cause of this activation is not fully understood. We conclude that the initialization of a migraine attack can be explained as an altered function of the neuronal elements of the brainstem nuclei. In light of our findings and the literature data, we can assume that migraine is a subcortical disorder of a specific brainstem area. PMID- 22426836 TI - Why all migraine patients should be treated with magnesium. AB - Magnesium, the second most abundant intracellular cation, is essential in many intracellular processes and appears to play an important role in migraine pathogenesis. Routine blood tests do not reflect true body magnesium stores since <2% is in the measurable, extracellular space, 67% is in the bone and 31% is located intracellularly. Lack of magnesium may promote cortical spreading depression, hyperaggregation of platelets, affect serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters. Migraine sufferers may develop magnesium deficiency due to genetic inability to absorb magnesium, inherited renal magnesium wasting, excretion of excessive amounts of magnesium due to stress, low nutritional intake, and several other reasons. There is strong evidence that magnesium deficiency is much more prevalent in migraine sufferers than in healthy controls. Double-blind, placebo-controlled trials have produced mixed results, most likely because both magnesium deficient and non deficient patients were included in these trials. This is akin to giving cyanocobalamine in a blinded fashion to a group of people with peripheral neuropathy without regard to their cyanocobalamine levels. Both oral and intravenous magnesium are widely available, extremely safe, very inexpensive and for patients who are magnesium deficient can be highly effective. Considering these features of magnesium, the fact that magnesium deficiency may be present in up to half of migraine patients, and that routine blood tests are not indicative of magnesium status, empiric treatment with at least oral magnesium is warranted in all migraine sufferers. PMID- 22426837 TI - Should magnesium be given to every migraineur? No. AB - Migraine is one of the most common neurological disorders that affects young people, causing a considerable degree of disability in the active population, with an enormous consequent socio-economic impact. Despite intensive research, the pathomechanism of migraine is not completely understood and its fully effective therapy remains to be achieved. A number of experimental studies have implicated the importance of magnesium ion in the pathophysiology of this condition. Magnesium has been also administered for both prophylactic and acute therapy in migraine, but the question of its efficacy has not been studied adequately. The data available suggest that magnesium has a potential role in the prophylaxis, but the results in acute therapy are far less convincing. With a good side effect profile, magnesium is a relatively safe drug with a possible beneficial effect in the prophylaxis of migraine headache, and it may have its niche in the treatment of migraine patients. However, the current medical evidence that has accumulated and the fact that there are far more effective treatment possibilities clearly indicate that this drug is definitely not to be used by every migraineur. PMID- 22426838 TI - Structure, stereochemistry and synthesis of enantiopure cyclohexenone cis-diol bacterial metabolites derived from phenols. AB - Biotransformation of 3-substituted and 2,5-disubstituted phenols, using whole cells of P. putida UV4, yielded cyclohexenone cis-diols as single enantiomers; their structures and absolute configurations have been determined by NMR and ECD spectroscopy, X-ray crystallography, and stereochemical correlation involving a four step chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites. An active site model has been proposed, to account for the formation of enantiopure cyclohexenone cis-diols with opposite absolute configurations. PMID- 22426839 TI - Lmx1b can promote the differentiation of embryonic stem cells to dopaminergic neurons associated with Parkinson's disease. AB - The introduction of genes associated with the fate of dopaminergic (DA) neurons may help to facilitate the differentiation of embryonic stem cells (ESC) to DA neurons. Here we used lentiviral vectors to drive lmx1b, a key transcription factor of dopaminergic neurons development, expression in ESC. Tyrosine hydroxylase-positive neurons were increased from 18% to nearly 50% when exogenous lmx1b was transduced. The enhanced Pitx3, Girk2, Nurr1 and DAT suggested that the increased differentiated neurons were mature A9 DA neurons. The results of [(3)H]dopamine reuptake assay indicated these differentiated neurons were all functional. Our study demonstrated that lmx1b was capable of promoting the differentiation of ESC to DA neurons. PMID- 22426840 TI - Improving the thermal stability of avian myeloblastosis virus reverse transcriptase alpha-subunit by site-directed mutagenesis. AB - Avian myeloblastosis virus reverse transcriptase (AMV RT) is a heterodimer consisting of a 63 kDa alpha-subunit and a 95 kDa beta subunit. Moloney murine leukaemia virus reverse transcriptase (MMLV RT) is a 75 kDa monomer. These two RTs are the most extensively used for conversion of RNA to DNA. We previously developed several mutations that increase the thermostability of MMLV RT and generated a highly stable MMLV RT variant E286R/E302K/L435R/D524A by combining three of them (Glu286->Arg, Glu302->Lys, and Leu435->Arg) and the mutation to abolish RNase H activity (Asp524->Ala) [Yasukawa et al. (2010) J Biotechnol 150:299-306]. To generate a highly stable AMV RT variant, we have introduced the triple mutation of Val238->Arg, Leu388->Arg, and Asp450->Ala into AMV RT alpha subunit and the resulted variant V238R/L388R/D450A, was expressed in insect cells and purified. The temperature decreasing the initial activity by 50 %, measured over 10 min, of the variant with or without template primer (T/P), poly(rA) p(dT)(15), was 50 degrees C; for the wild-type AMV RT alpha-subunit (WT) this was 44 degrees C. The highest temperature at which the variant exhibited cDNA synthesis activity was 64 degrees C; the WT was 60 degrees C. A highly stable AMV RT alpha-subunit is therefore generated by the same mutation strategy as applied to MMLV RT and that positive charges are introduced into RT at positions that have been implicated to interact with T/P by site-directed mutagenesis. PMID- 22426841 TI - Expression and purification of human TAT-p53 fusion protein in Pichia pastoris and its influence on HepG2 cell apoptosis. AB - P53 is an attractive target in molecular cancer therapeutics because of its critical role in regulating cell cycle arrest and apoptosis. The limitations in the development of p53-based cancer therapeutic strategy include its inefficient transmission through cell membrane of tumor cells and low protein yields in the expression system. In the present study, p53 was fused with HIV TAT protein, which can cross cell membranes, and expressed by Pichia pastoris. Stable production of Tat-p53 was achieved. After being transduced with Tat-p53 protein, the growth of cancer cell line, HepG2, was inhibited by increased apoptosis in culture. This expression system could thus be utilized to produce human Tat-p53 fusion protein. PMID- 22426842 TI - Quantitatively analyzing the protective effect of mesenchymal stem cells on cardiomyocytes in single-cell biochips. AB - To understand how stem cells benefit native cardiomyocytes is crucial for cell based therapies to rescue cardiomyocytes (CMCs) damaged during heart infarction and other cardiac diseases. However, the current conclusions on the protective effect of mesenchymal stem cells (MSCs) were obtained by analyzing the overall amount of protein and factor secretion in a conventional co-culture system. These results neglected the heterogeneity of MSC population and failed to determine the importance of cellular contact to the protective effects. To address these issues, we have constructed two biochips by microfabrication methods and laser guided cell micropatterning technique. Using the biochips, the protective effect of MSCs on CMCs can be quantitatively analyzed at single-cell level with defined cellular contact. The role of cellular contact on protective effect can be clarified according to our statistical results. PMID- 22426843 TI - Monitoring of toxic elements present in sludge of industrial waste using CF-LIBS. AB - Industrial waste is one of the main causes of environmental pollution. Laser induced breakdown spectroscopy (LIBS) was applied to detect the toxic metals in the sludge of industrial waste water. Sludge on filter paper was obtained after filtering the collected waste water samples from different sections of a water treatment plant situated in an industrial area of Kanpur City. The LIBS spectra of the sludge samples were recorded in the spectral range of 200 to 500 nm by focusing the laser light on sludge. Calibration-free laser-induced breakdown spectroscopy (CF-LIBS) technique was used for the quantitative measurement of toxic elements such as Cr and Pb present in the sample. We also used the traditional calibration curve approach to quantify these elements. The results obtained from CF-LIBS are in good agreement with the results from the calibration curve approach. Thus, our results demonstrate that CF-LIBS is an appropriate technique for quantitative analysis where reference/standard samples are not available to make the calibration curve. The results of the present experiment are alarming to the people living nearby areas of industrial activities, as the concentrations of toxic elements are quite high compared to the admissible limits of these substances. PMID- 22426844 TI - Biosorption of Pb(II) and Cr(III) from aqueous solutions: breakthrough curves and modeling studies. AB - The sorption capacity parameters obtained for batch studies provide useful information about biosorption system. However, such data fail to explain the process under continuous-flow conditions. The present study is an attempt to explore the biosorption of Pb(II) and Cr(III) by straw from local wheat (Triticum aestivum). The biosorbent has been characterized by using Fourier transform infrared spectroscopy and surface area and elemental analyses and found to be porous and polyfunctional. S-shaped breakthrough curves were obtained at different column heights for the both metal ions. Various breakthrough parameters and saturation times have been determined. The column data have been successfully used to study the Bohart-Adams' bed depth service time (BDST) model and Yoon and Nelson's model. It was found that BDST model quite efficiently explained the whole column data whereas Yoon and Nelson model could explain it below 90% breakthrough concentration. The predicted and calculated BDST parameters were in agreement with each other. Yoon and Nelson's constant decreased with an increase in the column height for both metal ions. Effect of change in flow rate on the Pb(II) biosorption has also been discussed with respect to BDST approach. PMID- 22426845 TI - Insulin secretion and sensitivity after single-dose amisulpride, olanzapine or placebo in young male subjects: double blind, cross-over glucose clamp study. AB - INTRODUCTION: Increased risks of weight gain and diabetes mellitus have been reported for schizophrenic patients under long-term treatment with several atypical antipsychotic drugs including olanzapine. Among other antipsychotic drugs, treatment with the selective dopamine D2 and D3 receptor antagonist amisulpride has been implicated with a lower risk for metabolic complications. PATIENTS AND METHODS: In this study we compared the acute, non-adiposity related effects of a single dose of olanzapine, amisulpride and placebo on insulin sensitivity and secretion in 10 healthy subjects in a randomised, double blind cross-over design. Subjects underwent euglycemic-hyperinsulinemic and hyperglycemic clamp tests using an automated clamp device. C-peptide and pro insulin levels were determined using highly specific immuno-assays. RESULTS: Insulin sensitivity was not significantly different between both verum medications and placebo. However, C-peptide secretion during hyperglycemic clamp was significantly higher after administration of amisulpride than after olanzapine or placebo. This was true both for the early phase and for the second phase of insulin secretion (C-peptide at 0, 5,10 and 30 min: amisulpride 1.49+/ 0.49; 4.22+/-1.45; 3.19+/-1.22; 5.33+/-1.85; olanzapine 1.35+/-0.47; 3.84+/-1.37; 2.72+/-0.91; 4.28+/-1.96; placebo 1.72+/-0.82; 3.59+/-1.19; 2.71+/-1.02; 4.54+/ 1.42 ng/mL, mean+/-SD; ANOVA p=0.043). Pro-insulin levels did not differ significantly between groups. DISCUSSION: A low dose of the D2/D3 antagonist amisulpride, but not olanzapine appears to acutely increase pancreatic insulin secretion in healthy controls. Stimulation of beta-cells could be a protective factor against the development of diabetes mellitus. PMID- 22426846 TI - Lack of interaction between sertraline and lamotrigine in psychiatric patients: a retrospective study. AB - INTRODUCTION: This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. METHODS: We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. RESULTS: The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 MUmol/L * 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 MUmol/L * 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). DISCUSSION: The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant. PMID- 22426847 TI - The effect of age, sex, smoking and co-medication on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions. AB - INTRODUCTION: Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of age, sex, smoking, and co-medication on serum levels of VEN and its metabolite O-desmethylvenlafaxine (ODVEN) in patients treated with VEN under naturalistic conditions. METHODS: We retrospectively evaluated 478 TDM analyses of VEN requested in the Pychiatric University Hospitals of Mainz, Regensburg, and Wurzburg. The determination of serum levels was performed by virtually identical chromatographic methods in the TDM laboratories of the participating hospitals. RESULTS: Serum levels varied widely on each dose level. Women had about 30% higher dose-corrected serum levels of VEN and ODVEN than men (p<0.01), and patients older than 60 years showed about 46% higher levels of both compounds than younger ones (p<0.01). In smokers, mean serum levels of ODVEN were 21% lower than in non-smokers. Combining these variables a considerable increase of the differences between the subgroups was found indicating an additive effect. ANOVA over the 8 different groups was significant for ODVEN (p<0.01) and sum (p<0.01), but not for VEN (n.s.). Co-medication with other psychotropic drugs was associated with a decreasing ODVEN/VEN ratio indicating a reduced metabolism in patients receiving polypharmacy. DISCUSSION: These findings show that TDM is useful to identify factors affecting the pharmacokinetic properties of VEN. It is concluded that sex, age and smoking should be considered for optimal dosing of patients with VEN. PMID- 22426848 TI - Altered neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. AB - INTRODUCTION: Modifications in neurotrophins, neuropeptides, cytokines and nitric oxide (NO) levels in autism may represent different biological aspects of the disease. In the present study we investigate simultaneously all these variables as an attempt to clarify their interrelationships in autism. METHODS: Plasma levels of vasoactive intestinal peptide (VIP), neurotrophin-3 (NT-3), cytokines and nitric oxide (NO) were determined in children with DSM-IV autistic disorder (n = 24) and in age- and gender-matched healthy controls (n = 24). VIP, NT-3, IFN gamma and IL-1beta levels were measured by ELISA, TNF-alpha, IL-10, IL-6, IL-4, IL-2 were evaluated by fl ow cytometry, and NO by Griess reaction. RESULTS: Plasma levels of VIP, IFN-gamma and NO were significantly higher and NT-3 plasma levels were significantly lower in children with autism, compared to the healthy subjects. In children with autism there was a positive correlation between plasma levels of NO and IFN-gamma. DISCUSSION: Our results indicate the presence of altered levels of neurotrophin and neuropeptide in infantile autism and provide additional evidence that higher levels of IFN-gamma may be associated with increased oxidative stress in autism. PMID- 22426849 TI - Impact of aggregate of risk factors for isolated locoregional failure in breast cancer patients treated with mastectomy without radiotherapy. AB - BACKGROUND: The impact of aggregate of risk factors on isolated locoregional failure after mastectomy without radiotherapy was assessed. METHODS: We reviewed 1091 patients who had stage I-III unilateral breast cancer and received mastectomy between 1990 and 2002. RESULTS: Median follow-up time was 67 (1-175) months. On multivariate analysis, four or more positive axillary lymph nodes (AXLN >=4), pT4, primary tumor larger than 5 cm (T >5 cm), severe lymphatic invasion (ly2-3), and negative hormone receptor status (HR negative) were the statistically significant risk factors (hazard ratios 5.78, 2.31, 2.47, 2.99, and 3.40, respectively). The 8-year isolated locoregional failure-free rates of patients with single risk factor were 88% for AXLN >=4, 93% for pT4, 93% for T >5 cm, 98% for ly2-3, and 97% for HR negative. Considering impact on isolated locoregional failure, AXLN >=4 was termed the major risk factor and other factors were termed minor risk factors. The 8-year isolated locoregional failure-free rates were 98% for patients with only 0-1 minor risk factors (low-risk group), 86% for patients with the major risk factor alone or with only 2-4 minor risk factors (intermediate-risk group), 72% for patients with the major risk factor plus 1-2 minor risk factors (high-risk group), and 28% for patients with the major risk factor plus 3-4 minor risk factors (very high-risk group). CONCLUSIONS: Aggregate of risk factors increased the risk of isolated locoregional failure significantly. Patients with the major risk factor plus one or more minor risk factors seemed to be candidates for postmastectomy radiotherapy. PMID- 22426850 TI - Cerulenin-induced apoptosis is mediated by disrupting the interaction between AIF and hexokinase II. AB - Fatty acid synthase (FASN) is a key enzyme that plays a critical role in numerous metabolic functions by catalyzing the synthesis for long-chain fatty acids. FASN is highly expressed in various human cancers. This preferential expression makes FASN an attractive target for anticancer therapy. Hexokinase II (HKII) is overexpressed in most cancer cells, and it generally localizes to the outer mitochondrial membrane. Recent studies have demonstrated the protective role of mitochondrial HKII in preservation of mitochondrial integrity. The association of hexokinase with mitochondria has emerged as a powerful mechanism in protecting numerous cell types against cell death. We performed this study to examine the mechanism underlying apoptosis induced by cerulenin and with specific focus on its effect on HKII in ZR-75-1 human breast cancer cells. Additionally, we sought to elucidate whether inhibition of the PI3K/Akt pathway can potentiate the anticancer effect of cerulenin. Here, we showed that cerulenin disrupts the physical association between HKII and AIF, leading to eventual cell death. In addition, LY294002, a PI3K/Akt inhibitor, sensitized ZR-75-1 breast cancer cells to cerulenin-induced apoptosis. Collectively, cerulenin induces apoptosis via disrupting the interaction between AIF and HKII and inhibition of PI3K sensitizes cells to cerulenin-induced apoptosis in ZR-75-1 cells. PMID- 22426851 TI - Causes of obesity. AB - The prevalence of obesity has been rising steadily over the last several decades and is currently at unprecedented levels: more than 68% of US adults are considered overweight, and 35% are obese (Flegal et al., JAMA 303:235-241, 2010). This increase has occurred across every age, sex, race, and smoking status, and data indicate that segments of individuals in the highest weight categories (i.e., BMI > 40 kg/m(2)) have increased proportionately more than those in lower BMI categories (BMI < 35 kg/m(2)). The dramatic rise in obesity has also occurred in many other countries, and the causes of this increase are not fully understood (Hill and Melanson, Med Sci Sports Exerc 31:S515-S521, 1999). PMID- 22426852 TI - Kinematics of a highly congruent mobile-bearing total knee prosthesis. AB - PURPOSE: Limited or absent axial rotation of the mobile insert of total knee prostheses could lead to high contact stresses and stresses at the bone-implant interface, which in turn might lead to implant loosening. The aim of this study was to assess knee kinematics and muscle activation and their possible change over time in patients with a highly congruent, mobile-bearing total knee prosthesis. METHODS: A prospective series of 11 rheumatoid arthritis patients was included to participate in this fluoroscopic and EMG study; only 7 patients completed the study. Kinematic evaluations took place 7 months, 1 and 2 years post-operatively. Repeated measurements ANOVA and linear mixed-effects model for longitudinal data were used to compare the differences between the follow-ups. RESULTS: There are no significant changes in axial rotations between follow-up moments for the femoral component as well as the mobile insert. The insert remained mobile and followed the femoral component from 0 degrees until approximately 60 degrees of knee flexion. Diverging and reversed axial rotations and translations were seen during the dynamic motions. CONCLUSIONS: Knee kinematics and muscle activation do not appear to change in the first 2 post operative years. Reversed and divergent axial rotations with increasing knee flexion indicate that as soon as the congruency decreases, the femoral component is no longer forced in a certain position by the insert and moves to a self imposed position. At lower knee flexion angles, the femoral component might be obstructed by the highly congruent insert and therefore might not be able to move freely. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 22426853 TI - Lateral release and medial plication for recurrent patella dislocation. AB - PURPOSE: This study aims to report the long-term results of lateral release and medial plication in patients with recurrent patellar dislocation. METHODS: In this study, 31 patients who underwent surgery for recurrent patellar dislocation were retrospectively reviewed between 1994 and 2004. Among the 31 patients were 12 male and 19 female patients. The average age was 23.9 +/- 4.8 years, and the mean follow-up period was 11.6 +/- 2.4 years. RESULTS: Three patients had postoperative dislocations. The mean Kujala score significantly improved from 57.5 +/- 13.2 points preoperatively to 89.2 +/- 8.7 points at the final follow-up (P < 0.0001). The median Tegner activity score significantly improved from 3 (range, 1-5) at preoperative examination to 7 (range, 3-9) at the final follow-up (P < 0.0001). Ten patients were rated as excellent, 18 as good, 2 as fair, and 1 as poor. The congruence angle improved from 16.5 degrees +/- 3.0 degrees to 2.8 degrees +/- 2.7 degrees , and the lateral patellofemoral angle improved from -4.2 degrees +/- 1.9 degrees to 8.2 degrees +/- 2.5 degrees . There was no case of osteoarthritis at the final follow-up. CONCLUSIONS: Percutaneous lateral release and medial plication showed satisfactory results with limited morbidity in the long-term follow-up. This traditional method remains a simple and effective surgical procedure for recurrent patellar dislocation. LEVEL OF EVIDENCE: Therapeutic, Level IV. PMID- 22426854 TI - Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. AB - C9ORF72-hexanucleotide repeat expansions and ubiquilin-2 (UBQLN2) mutations are recently identified genetic markers in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We investigate the relationship between C9ORF72 expansions and the clinical phenotype and neuropathology of ALS and FTLD. Genetic analysis and immunohistochemistry (IHC) were performed on autopsy confirmed ALS (N = 75), FTLD-TDP (N = 30), AD (N = 14), and controls (N = 11). IHC for neurodegenerative disease pathology consisted of C9ORF72, UBQLN, p62, and TDP-43. A C9ORF72 expansion was identified in 19.4 % of ALS and 31 % of FTLD-TDP cases. ALS cases with C9ORF72 expansions frequently showed a bulbar onset of disease (57 %) and more rapid disease progression to death compared to non expansion cases. Staining with C9ORF72 antibodies did not yield specific pathology. UBQLN pathology showed a highly distinct pattern in ALS and FTLD-TDP cases with the C9ORF72 expansion, with UBQLN-positive cytoplasmic inclusions in the cerebellar granular layer and extensive UBQLN-positive aggregates and dystrophic neurites in the hippocampal molecular layer and CA regions. These UBQLN pathologies were sufficiently unique to allow correct prediction of cases that were later confirmed to have C9ORF72 expansions by genetic analysis. UBQLN pathology partially co-localized with p62, and to a minor extent with TDP-43 positive dystrophic neurites and spinal cord skein-like inclusions. Our data indicate a pathophysiological link between C9ORF72 expansions and UBQLN proteins in ALS and FTLD-TDP that is associated with a highly characteristic pattern of UBQLN pathology. Our study indicates that this pathology is associated with alterations in clinical phenotype, and suggests that the presence of C9ORF72 repeat expansions may indicate a worse prognosis in ALS. PMID- 22426855 TI - BRCA1--conductor of the breast stem cell orchestra: the role of BRCA1 in mammary gland development and identification of cell of origin of BRCA1 mutant breast cancer. AB - Breast cancer treatment has been increasingly successful over the last 20 years due in large part to targeted therapies directed against different subtypes. However, basal-like breast cancers still represent a considerable challenge to clinicians and scientists alike since the pathogenesis underlying the disease and the target cell for transformation of this subtype is still undetermined. The considerable similarities between basal-like and BRCA1 mutant breast cancers led to the hypothesis that these cancers arise from transformation of a basal cell within the normal breast epithelium through BRCA1 dysfunction. Recently, however, a number of studies have called this hypothesis into question. This review summarises the initial findings which implicated the basal cell as the cell of origin of BRCA1 related basal-like breast cancers, as well as the more recent data which identifies the luminal progenitor cells as the likely target of transformation. We compare a number of key studies in this area and identify the differences that could explain some of the contradictory findings. In addition, we highlight the role of BRCA1 in breast cell differentiation and lineage determination by reviewing recent findings in the field and our own observations suggesting a role for BRCA1 in stem cell regulation through activation of the p63 and Notch pathways. We hope that through an increased understanding of the BRCA1 role in breast differentiation and the identification of the cell(s) of origin we can improve treatment options for both BRCA1 mutant and basal-like breast cancer subgroups. PMID- 22426856 TI - Identification of mitochondrial thiamin diphosphate carriers from Arabidopsis and maize. AB - It is currently held that thiamin is made in chloroplasts and converted in the cytosol to the active cofactor thiamin diphosphate (ThDP), and that mitochondria and plastids import ThDP. The organellar transporters that mediate ThDP import in plants have not been identified. Comparative genomic analysis indicated that two members of the mitochondrial carrier family (MCF) in Arabidopsis (At5g48970 and At3g21390) and two in maize (GRMZM2G118515 and GRMZM2G124911) are related to the ThDP carriers of animals and Saccharomyces cerevisiae. Expression of each of these plant proteins in a S. cerevisiae ThDP carrier (TPC1) null mutant complemented the growth defect on fermentable carbon sources and restored the level of mitochondrial ThDP and the activity of the mitochondrial ThDP-dependent enzyme acetolactate synthase. The plant proteins were targeted to mitochondria as judged by dual import assays with purified pea mitochondria and chloroplasts, and by microscopic analysis of the subcellular localization of green fluorescent protein fusions in transiently transformed tobacco suspension cells. Both maize genes were shown to be expressed throughout the plant, which is consistent with the known ubiquity of mitochondrial ThDP-dependent enzymes. Collectively, these data establish that plants have mitochondrially located MCF carriers for ThDP, and indicate that these carriers are highly evolutionarily conserved. Our data provide a firm basis to propagate the functional annotation of mitochondrial ThDP carriers to other angiosperm genomes. PMID- 22426857 TI - Cognitive-behavioral and pharmacological interventions for premenstrual syndrome or premenstrual dysphoric disorder: a meta-analysis. AB - The current meta-analysis investigates the efficacy of psychotherapeutic interventions and psychopharmacotherapy for premenstrual syndrome (PMS) and premenstrual dysphoric disorder. Based on a multiple-phase literature search, controlled trials were selected according to a priori defined inclusion criteria. Data were extracted on the basis of a standardized coding scheme. The standardized weighted mean difference (random effects model) was used as effect size index. Dependent on outcome, 22 included studies obtained small to medium effect sizes for cognitive-behavioral interventions (range: d(+) = 0.24-0.70) and for serotonergic antidepressants (range: d(+) = 0.29-0.58), at post-assessment. Follow-ups were performed only in studies of cognitive-behavioral interventions (range: d(+) = 0.46-0.74). There was no evidence of a publication bias. For both cognitive-behavioral interventions and serotonergic antidepressants, efficacy in treatment of PMS was found to not be satisfactory. Future research should possibly focus more on a combination of both approaches. PMID- 22426859 TI - Chemoselective cyclization of unprotected linear peptides by alpha-ketoacid hydroxylamine amide-ligation. AB - Cyclic peptides are important synthetic targets due to their constrained conformation, enhanced metabolic stability and improved bioavailability, which combine to make them promising lead compounds for drug candidates. They are typically synthesized by a multi-step sequence of carefully orchestrated protecting group manipulations and cyclization of side-chain protected linear precursors. In the present manuscript we disclose an alternative approach to the synthesis of peptide macrocycles by the alpha-ketoacid-hydroxylamine (KAHA) ligation. This reaction allows readily prepared linear peptides to be cyclized without reagents or side-chain protecting groups and delivers a native backbone amide bond at the ligation site. The precursors are prepared with Fmoc-based solid phase peptide synthesis using reagents that we have previously disclosed. No post-cyclization manipulations or deprotections other than purification are required. This protocol was applied to five different cyclic peptide natural products of varying ring sizes and side chain functionalities. PMID- 22426858 TI - Pain in cognitively impaired children: a focus for general pediatricians. AB - Pain in children with cognitive impairment and cerebral palsy is a particularly relevant issue due to its high prevalence and impact on quality of life. We review available evidence about prevalence of pain, causes and specific treatment, recognition and use of specific pain scales, physiology, and consequences of pain in this subset of patients. CONCLUSIONS: Pain is very common and is a critical determinant of quality of life in children with cognitive impairment and cerebral palsy. The diseases and associated complications that frequently expose these patients to pain can be treated and pain prevented. For patients with communication difficulties, appropriate, effective, validated tools are available and should be used to diagnose pain in itself, to >choose analgesic treatment and to determine effectiveness of these therapies. The level of awareness of pediatricians towards this issue seems to be quite low. PMID- 22426860 TI - Differential expression of coxsackievirus and adenovirus receptor on alveolar epithelial cells between fetal and adult mice determines their different susceptibility to coxsackievirus B infection. AB - Coxsackievirus B (CVB) can cause aseptic meningitis, myocarditis and respiratory disease, especially in newborn infants. To compare the susceptibility to CVB infection of fetal and adult mice, we prepared primary alveolar epithelial cells (AECs) from lungs of BALB/c mice. In contrast to fetal mouse AECs, those of adults were less susceptible to CVB3 infection, as indicated by decreased cytopathic effects, and reduced levels of viral particles bound at the cell surface. In adult mouse AECs, amplification of the viral genome and virus capsid protein VP1 synthesis were concomitantly reduced. In addition, the cell-surface expression of coxsackievirus and adenovirus receptor (CAR), which plays a key role in the initiation of CVB and pulmonary infection, was downregulated in adult mouse AECs. These findings demonstrate that adult mouse AECs are less susceptible to CVB3 due to decreased CAR levels. Thus, these findings strongly indicate that the level of virus receptors on AECs is one of the crucial determinants for the age-dependence of CVB virulence in the mouse lung. PMID- 22426861 TI - Isolation of H9N2 avian influenza virus from bobwhite quail (Colinus virginianus) in Egypt. AB - This study describes the first isolation of H9N2 avian influenza virus (AIV) from commercial bobwhite quail (Colinus virginianus) in Egypt. Infected birds showed neither clinical signs nor mortality. Virus isolation and real-time reverse transcription polymerase chain reaction confirmed the presence of the H9N2 virus in cloacal swab samples collected at 35 days of age and the absence of other AIV subtypes, including H5 and H7. The hemagglutinin and neuraminidase genes of the isolated virus showed 99.1% and 98.2% nucleotide identity and 97.3% and 100% amino acid identity, respectively, to those of H9N2 viruses currently circulating in poultry in the Middle East. Phylogenetically, the Egyptian H9N2 virus was closely related to viruses of the G1-like lineage isolated from neighbouring countries, indicating possible epidemiological links. PMID- 22426862 TI - Beta-glucosylceramide administration (i.p.) activates natural killer T cells in vivo and prevents tumor metastasis in mice. AB - Natural killer (NK) T cells are well known to play important roles in both tumor rejection and the defense against infectious. Therefore, the antitumor potential of NKT cell-activating antigens have been the focus for the development of NKT cell-based immunotherapies. Up to now, several studies have revealed that the administrations of glycolipids (e.g. alpha-galactosylceramide) can successfully treat certain metastatic tumors. However, liver injuries appeared upon the application of these antigens. We previously examined the potential of using beta glucosylceramide (beta-GlcCer) to inhibit tumor metastasis to the liver. The aim of this study was to determine the antimetastatic effects of beta-GlcCer and its impact on the activation of NKT cells. Intraperitoneal administration of beta GlcCer enhanced the production of interferon-gamma from hepatic lymphocytes containing NKT cells, and increased the cytotoxicity of hepatic lymphocytes against tumor cells. Moreover, beta-GlcCer administration suppressed the hepatic metastasis of tumors in wild type (WT) mice, but not in CD1d (-/-) or Jalpha18 ( /-) mice. The drawback associated with the other glycolipids in liver injury was not noted in WT mice treated with the continuous daily administration of beta GlcCer for 2 weeks. The present study demonstrated that beta-GlcCer treatment activates invariant NKT cells, thus resulting in the inhibition of tumor metastasis. PMID- 22426863 TI - Nephron sparing surgery in von Hippel-Lindau associated renal cell carcinoma; clinicopathological long-term follow-up. AB - We evaluated the clinicopathological outcome of von Hippel-Lindau (VHL)-patients who had mainly undergone nephron sparing surgery (NSS) for renal cell carcinoma (RCC) when the tumour diameter has reached 4.0 cm. Multiple, bilateral RCC with high recurrence rates and subsequent repeated interventions, followed by increasing risk for end-stage renal failure and metastases is characteristic for VHL. NSS is widely used for VHL-associated RCC at 3.0 cm cut-off. 54 VHL patients underwent NSS, nephrectomy or thermal ablation for RCC. We analysed time to second treatment, overall and cancer specific survival, intra- and post-operative data as well as tumour characteristics. We also examined the effects of delaying removal of RCC to 4.0 cm cut-off. Median follow-up was 67 months. 54 patients underwent 97 kidney treatments. 96 % of first and 67 % of second interventions comprised of NSS. 0 % metastases were observed in the group with largest tumour size <=4 cm. The probability for second surgery was 21 %, at 5 years and 42 % at 10 years. Median time to second NSS was 149.6 months. The overall and cancer specific survival rate was 96.5 and 100 % at 5-year follow-up, and 82.5 and 90.5 % respectively at 10-year follow-up. Median delay to second NSS at 4.0 cm cut-off versus 3.0 cm was 27.8 months. NSS was both successfully used in first and second surgery and to some extent even in third surgery. By following a strict surveillance protocol it is possible to support a 4.0 cm-threshold strategy for NSS, based on the assumption that delaying time to second NSS prevents patients from premature renal failure. PMID- 22426864 TI - Improvement of myocardial glycolipid metabolic disorder in diabetic hamster with Astragalus polysaccharides treatment. AB - The objective of the present study is to observe the effect of Astragalus polysaccharide (APS) on myocardial glucose and lipid metabolism in diabetes (DM) hamster and to explore its mechanism in intervention of DM cardiomyopathy. Low dose- streptozotocin-induced hamsters (STZ, 40 mg/kg * 3 days, i.p.) with blood glucose >13.9 mmo/L were considered as type 2 diabetic models. We measure blood glucose, serum lipid, insulin, C-peptide, myocardial enzyme levels, myocardial glycogen staining, myocardial ultrastructure, fluorescence quantitative RT-PCR detection of myocardial PPAR-alpha and the target genes (FATP, ACS) and GLUT4 mRNA expression in normal control group, DM group and APS treatment group hamsters. There was significant glycolipid metabolic disorders in DM group compared with normal group. Glucose, glycosylated serum protein, myocardial enzymes and lipid levels in APS treatment group decreased significantly than DM group, but insulin and C-peptide levels was no difference. Myocardial glycogen staining and abnormal myocardial ultrastructure in APS treatment group were significantly improved than in DM group. Gene expression of myocardial PPAR-alpha and its target genes (FATP, ACS) in APS group were significantly lower than in DM group, while gene expression of GLUT4 in APS group was higher than DM group. APS can partially improve myocardial glucose and lipid metabolism disorders in diabetic hamsters and protect myocardium in some extent. PMID- 22426865 TI - The cloning of growth associated protein 43 of Gekko japonicus and its effect on cell morphology. AB - The growth-associated protein 43 (GAP-43) gene of Gekko japonicus was obtained from a brain and spinal cord cDNA library. The results of northern blot analysis showed the gecko GAP-43 gene transcript is 1.7 kb in length, and it was abundantly expressed in tissues of brain, spinal cord and ovary. Gecko GAP-43 promoted the outgrowth of Gsn3 cells and PC12 cell in vitro, and phosphorylation at serine 42 modulated the effect of GAP-43 on cell spreading and morphology. The change in GAP-43 expression in the spinal cord after tail amputation was examined by reverse transcription polymerase chain reaction (RT-PCR). The level of GAP-43 in the spinal cord was increased during the time course we examined, indicating a possible correlation between GAP-43 expression and the spinal cord injury and regeneration. PMID- 22426866 TI - [Shaping the future together]. PMID- 22426867 TI - [Consensus recommendations of the German Radiology Society (DRG), the German Cardiac Society (DGK) and the German Society for Pediatric Cardiology (DGPK) on the use of cardiac imaging with computed tomography and magnetic resonance imaging]. AB - Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) have been developed rapidly in the last decade. Technical improvements and broad availability of modern CT and MRI scanners have led to an increasing and regular use of both diagnostic methods in clinical routine. Therefore, this German consensus document has been developed in collaboration by the German Cardiac Society, German Radiology Society, and the German Society for Pediatric Cardiology. It is not oriented on modalities and methods, but rather on disease entities. This consensus document deals with coronary artery disease, cardiomyopathies, arrhythmias, valvular diseases, pericardial diseases and structural changes, as well as with congenital heart defects. For different clinical scenarios both imaging modalities CT and MRI are compared and evaluated in the specific context. PMID- 22426868 TI - [MDCT of a coronary sinus defect as a rare from of atrial septal defect]. PMID- 22426869 TI - [Aneurysm development of the superficial femoral artery after multiple stent fractures]. PMID- 22426870 TI - [Boerhaave syndrome in norovirus infection]. PMID- 22426871 TI - [Letter to the Editor on the article by Andresen R et al. Interventional pain relief using balloon-kyphoplasty in patients with osteoporotic-based fatigue fractures of the Os sacrum. Fortschr Rontgenstrahlen 2012; 184: 32-36]. PMID- 22426872 TI - A systematic review of clinical studies of electrical stimulation for treatment of lower urinary tract dysfunction. AB - INTRODUCTION AND HYPOTHESIS: The aim of this manuscript was to provide a systematic literature review of clinical trial evidence for a range of electrical stimulation therapies in the treatment of lower urinary tract symptoms (LUTS). METHODS: The databases MEDLINE, BIOSIS Previews, Inside Conferences, and EMBASE were searched. Original clinical studies with greater than 15 subjects were included. RESULTS: Seventy-three studies were included, representing implanted sacral nerve stimulation (SNS), percutaneous posterior tibial nerve stimulation (PTNS), and transcutaneous electrical stimulation (TENS) therapy modalities. CONCLUSIONS: Median mean reductions in incontinence episodes and voiding frequency were similar for implanted SNS and PTNS. However, long-term follow-up data to validate the sustained benefit of PTNS are lacking. Despite a substantial body of research devoted to SNS validation, it is not possible to definitively define the appropriate role of this therapy owing largely to study design flaws that inhibited rigorous intention to treat analyses for the majority of these studies. PMID- 22426873 TI - Anatomic and functional outcomes of sacrocolpopexy with or without posterior colporrhaphy. AB - INTRODUCTION AND HYPOTHESIS: The optimal surgery for combined apical and posterior vaginal prolapse is not well defined. Our objective was to examine the anatomic and functional outcomes following sacrocolpopexy (SCP) with or without posterior colporrhaphy (PC). METHODS: We retrospectively evaluated 258 women who underwent abdominal (n = 62) or laparoscopic (n = 196) SCP with or without PC. Preoperative anatomic support and standardized bowel symptoms were compared to 6 week and 1-year postoperative values, using Student's t test and Wilcoxon rank sum test, respectively. RESULTS: Six-week follow-up data were available for 235 of 258 (91.1 %) women, while 125 of 258 (48.4 %) women had 1-year anatomic and functional outcomes recorded. While the SCP + PC group had worse posterior descent and bowel function preoperatively, there were no significant differences in postoperative anatomic support or symptoms. Long-term pelvic floor function was similar, as measured by three validated instruments. Reduction in the proportion of women with splinting was greater in the SCP + PC group. CONCLUSIONS: SCP with or without PC is associated with improved posterior support and decreased obstructive and irritative bowel symptoms at 1 year in women with apical and posterior prolapse. PMID- 22426874 TI - Risk factors that affect the treatment of interstitial cystitis using intravesical therapy with a dimethyl sulfoxide cocktail. AB - INTRODUCTION AND HYPOTHESIS: Dimethyl sulfoxide (DMSO) bladder instillation is a standard therapy for interstitial cystitis (IC); however, there are varying degrees of success. We hypothesize that first-line intravesical therapy with a DMSO cocktail will optimize treatment outcome. METHODS: Ninety women with newly diagnosed IC were enrolled consecutively for the treatment. The IC symptom and problem index was used as an outcome measure. RESULTS: Six (6.7%) patients dropped out of the treatment due to intolerable bladder irritation. Fifty-five (65.5%) of the remaining 84 patients, who completed the treatment, experienced ?50% symptomatic improvement. After a regression analysis, three clinical variables were found to affect treatment adversely, i.e., the presence of advanced cystoscopic glomerulations, microscopic hematuria, and urodynamic detrusor underactivity, respectively. CONCLUSIONS: Our results suggest bladder instillation with a DMSO cocktail may well be considered as first-line therapy for IC patients. However, there exists a subgroup of nonresponders who may have severe disease. PMID- 22426875 TI - Female sexual dysfunction: what Arab gynecologists think and know. AB - INTRODUCTION AND HYPOTHESIS: We aimed to assess the knowledge and practice of gynecologists (Gyns) from different Arab countries with regard to female sexual dysfunction (FSD) in comparison with members of the American Urogynecologic Society (AUGS) and the British Society of Urogynecology (BSUG). METHODS: An anonymous questionnaire was used to survey attendees of the annual meeting of the Saudi Obstetrics and Gynecology Society. RESULTS: Six hundred and forty questionnaires were distributed, and the response rate was 66%. The majority of Arab Gyns (73%) were unsatisfied with their training, and 87% never or rarely screened for FSD compared with 47% and 23% of BSUG and AUGS members, respectively (p < 0.001). CONCLUSION: Our results reveal an apparent global lack of adequate education in female sexuality and expose the breadth of the problem among Arab Gyns. Therefore, there is a need to improve training at the undergraduate and postgraduate levels to enable Gyns in Arab countries to provide better sexual healthcare. PMID- 22426876 TI - Biofeedback for the treatment of female pelvic floor muscle dysfunction: a systematic review and meta-analysis. AB - Biofeedback (BF) has been widely used in the treatment of pelvic floor dysfunctions, mainly by promoting patient learning about muscle contraction with no side effects. However, its effectiveness remains poorly understood with some studies suggesting that BF offers no advantage over the isolated pelvic floor muscle training (PFMT). The main objective of this study was to systematically review available randomized controlled trials assessing the effectiveness of BF in female pelvic floor dysfunction treatment. Trials were electronically searched and rated for quality by use of the PEDro scale (values of 0-10). Randomized controlled trials assessing the training of pelvic floor muscle (PFM) using BF in women with PFM dysfunction were selected. Outcomes were converted to a scale ranging from 0 to 100. Trials were pooled with software used to prepare and update Cochrane reviews. Results are presented as weighted mean differences with 95 % confidence intervals (CI). Twenty-two trials with 1,469 patients that analyzed BF in the treatment of urinary, anorectal, and/or sexual dysfunctions were included. PFMT alone led to a superior but not significant difference in the function of PFM when compared to PFMT with BF, by using vaginal measurement in the short and intermediate term: 9.89 (95 % CI -5.05 to 24.83) and 15.03 (95 % CI -9.71 to 39.78), respectively. We found a few and nonhomogeneous studies addressing anorectal and sexual function, which do not provide the cure rate calculations. Limitations of this review are the low quality and heterogeneity of the studies, involving the usage of distinct protocols of interventions, and various and different outcome measures. The results of this systematic review suggest that PFMT with BF is not more effective than other conservative treatments for female PFM dysfunction. PMID- 22426877 TI - Continence and pelvic floor status in nulliparous women at midterm pregnancy. AB - INTRODUCTION AND HYPOTHESIS: A Cochrane review recommends antenatal pelvic floor muscle training (PFMT) in urinary incontinence (UI) prevention. The aim of the study was to investigate nulliparous pregnant women's knowledge about and practising of PFMT, their pelvic floor muscle (PFM) function, and ability to contract correctly. It was hypothesized that continent women had higher PFM strength and endurance than women with UI. METHODS: Three hundred nulliparous women at gestational week 18-22 were included in a cross-sectional study. Vaginal resting pressure, maximum voluntary contraction, and PFM endurance were measured by manometer. UI was assessed by International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form (ICIQ-UI-SF). Comparisons of PFM function in continent women and women with UI were analyzed using independent samples t test. Mean differences with 95 % confidence interval (CI) are presented. RESULTS: Of 300 women, 89 % had heard of PFMT at mid pregnancy, and 35 % performed PFMT once or more a week. After thorough instruction 4 % were unable to contract correctly. Thirty-five percent reported UI, of whom 48 % performed PFMT once or more a week. Continent women had significantly higher PFM strength and endurance when compared with women having UI, with mean differences of 6.6 cmH(2)O (CI 2.3-10.8, p = 0.003), and 41.5 cmH(2)Osec (CI 9.8-73.1, p = 0.010), respectively. No difference was found for vaginal resting pressure (p = 0.054). CONCLUSIONS: Most nulliparous pregnant women knew about PFMT. Thirty-five percent performed PFMT once or more a week. Incontinent nulliparous pregnant women had weaker PFM than their continent counterparts. More emphasis on information regarding PFM function and PFMT is warranted during pregnancy. PMID- 22426878 TI - Population growth enhances the mean fixation time of neutral mutations and the persistence of neutral variation. AB - A fundamental result of population genetics states that a new mutation, at an unlinked neutral locus in a randomly mating diploid population, has a mean time of fixation of ~4N(e) generations, where N(e) is the effective population size. This result is based on an assumption of fixed population size, which does not universally hold in natural populations. Here, we analyze such neutral fixations in populations of changing size within the framework of the diffusion approximation. General expressions are derived for the mean and variance of the fixation time in changing populations. Some explicit results are given for two cases: (i) the effective population size undergoes a sudden change, representing a sudden population expansion or a sudden bottleneck; (ii) the effective population changes linearly for a limited period of time and then remains constant. Additionally, a lower bound for the mean time of fixation is obtained for an effective population size that increases with time, and this is applied to exponentially growing populations. The results obtained in this work show, among other things, that for populations that increase in size, the mean time of fixation can be enhanced, sometimes substantially so, over 4N(e,0) generations, where N(e,0) is the effective population size at the time the mutation arises. Such an enhancement is associated with (i) an increased probability of neutral polymorphism in a population and (ii) an enhanced persistence of high-frequency neutral variation, which is the variation most likely to be observed. PMID- 22426879 TI - The nearly neutral and selection theories of molecular evolution under the fisher geometrical framework: substitution rate, population size, and complexity. AB - The general theories of molecular evolution depend on relatively arbitrary assumptions about the relative distribution and rate of advantageous, deleterious, neutral, and nearly neutral mutations. The Fisher geometrical model (FGM) has been used to make distributions of mutations biologically interpretable. We explored an FGM-based molecular model to represent molecular evolutionary processes typically studied by nearly neutral and selection models, but in which distributions and relative rates of mutations with different selection coefficients are a consequence of biologically interpretable parameters, such as the average size of the phenotypic effect of mutations and the number of traits (complexity) of organisms. A variant of the FGM-based model that we called the static regime (SR) represents evolution as a nearly neutral process in which substitution rates are determined by a dynamic substitution process in which the population's phenotype remains around a suboptimum equilibrium fitness produced by a balance between slightly deleterious and slightly advantageous compensatory substitutions. As in previous nearly neutral models, the SR predicts a negative relationship between molecular evolutionary rate and population size; however, SR does not have the unrealistic properties of previous nearly neutral models such as the narrow window of selection strengths in which they work. In addition, the SR suggests that compensatory mutations cannot explain the high rate of fixations driven by positive selection currently found in DNA sequences, contrary to what has been previously suggested. We also developed a generalization of SR in which the optimum phenotype can change stochastically due to environmental or physiological shifts, which we called the variable regime (VR). VR models evolution as an interplay between adaptive processes and nearly neutral steady-state processes. When strong environmental fluctuations are incorporated, the process becomes a selection model in which evolutionary rate does not depend on population size, but is critically dependent on the complexity of organisms and mutation size. For SR as well as VR we found that key parameters of molecular evolution are linked by biological factors, and we showed that they cannot be fixed independently by arbitrary criteria, as has usually been assumed in previous molecular evolutionary models. PMID- 22426880 TI - A non-Mendelian MAPK-generated hereditary unit controlled by a second MAPK pathway in Podospora anserina. AB - The Podospora anserina PaMpk1 MAP kinase (MAPK) signaling pathway can generate a cytoplasmic and infectious element resembling prions. When present in the cells, this C element causes the crippled growth (CG) cell degeneration. CG results from the inappropriate autocatalytic activation of the PaMpk1 MAPK pathway during growth, whereas this cascade normally signals stationary phase. Little is known about the control of such prion-like hereditary units involved in regulatory inheritance. Here, we show that another MAPK pathway, PaMpk2, is crucial at every stage of the fungus life cycle, in particular those controlled by PaMpk1 during stationary phase, which includes the generation of C. Inactivation of the third P. anserina MAPK pathway, PaMpk3, has no effect on the development of the fungus. Mutants of MAPK, MAPK kinase, and MAPK kinase kinase of the PaMpk2 pathway are unable to present CG. This inability likely relies upon an incorrect activation of PaMpk1, although this MAPK is normally phosphorylated in the mutants. In PaMpk2 null mutants, hyphae are abnormal and PaMpk1 is mislocalized. Correspondingly, stationary phase differentiations controlled by PaMpk1 are defective in the mutants of the PaMpk2 cascade. Constitutive activation of the PaMpk2 pathway mimics in many ways its inactivation, including an effect on PaMpk1 localization. Analysis of double and triple mutants inactivated for two or all three MAPK genes undercover new growth and differentiation phenotypes, suggesting overlapping roles. Our data underscore the complex regulation of a prion-like element in a model organism. PMID- 22426881 TI - Allopolyploidization lays the foundation for evolution of distinct populations: evidence from analysis of synthetic Arabidopsis allohexaploids. AB - Polyploidization is an important mechanism for introducing diversity into a population and promoting evolutionary change. It is believed that most, if not all, angiosperms have undergone whole genome duplication events in their evolutionary history, which has led to changes in genome structure, gene regulation, and chromosome maintenance. Previous studies have shown that polyploidy can coincide with meiotic abnormalities and somatic cytogenetic mosaics in Arabidopsis allotetraploids, but it is unclear whether this phenomenon can contribute to novel diversity or act as a mechanism for speciation. In this study we tested the hypothesis that mosaic aneuploidy contributes to the formation of incipient diversity in neoallopolyploids. We generated a population of synthesized Arabidopsis allohexaploids and monitored karyotypic and phenotypic variation in this population over the first seven generations. We found evidence of sibling line-specific chromosome number variations and rapidly diverging phenotypes between lines, including flowering time, leaf shape, and pollen viability. Karyotypes varied between sibling lines and between cells within the same tissues. Cytotypic variation correlates with phenotypic novelty, and, unlike in allotetraploids, remains a major genomic destabilizing factor for at least the first seven generations. While it is still unclear whether new stable aneuploid lines will arise from these populations, our data are consistent with the notion that somatic aneuploidy, especially in higher level allopolyploids, can act as an evolutionary relevant mechanism to induce rapid variation not only during the initial allopolyploidization process but also for several subsequent generations. This process may lay the genetic foundation for multiple, rather than just a single, new species. PMID- 22426882 TI - Modular TRAPP complexes regulate intracellular protein trafficking through multiple Ypt/Rab GTPases in Saccharomyces cerevisiae. AB - Ypt/Rab are key regulators of intracellular trafficking in all eukaryotic cells. In yeast, Ypt1 is essential for endoplasmic reticulum (ER)-to-Golgi transport, whereas Ypt31/32 regulate Golgi-to-plasma membrane and endosome-to-Golgi transport. TRAPP is a multisubunit complex that acts as an activator of Ypt/Rab GTPases. Trs85 and Trs130 are two subunits specific for TRAPP III and TRAPP II, respectively. Whereas TRAPP III was shown to acts as a Ypt1 activator, it is still controversial whether TRAPP II acts as a Ypt1 or Ypt31/32 activator. Here, we use GFP-Snc1 as a tool to study transport in Ypt and TRAPP mutant cells. First, we show that expression of GFP-Snc1 in trs85Delta mutant cells results in temperature sensitivity. Second, we suggest that in ypt1ts and trs85Delta, but not in ypt31Delta/32ts and trs130ts mutant cells, GFP-Snc1 accumulates in the ER. Third, we show that overexpression of Ypt1, but not Ypt31/32, can suppress both the growth and GFP-Snc1 accumulation phenotypes of trs85Delta mutant cells. In contrast, overexpression of Ypt31, but not Ypt1, suppresses the growth and GFP Snc1 transport phenotypes of trs130ts mutant cells. These results provide genetic support for functional grouping of Ypt1 with Trs85-containing TRAPP III and Ypt31/32 with Trs130-containing TRAPP II. PMID- 22426883 TI - V-ATPase V1 sector is required for corpse clearance and neurotransmission in Caenorhabditis elegans. AB - The vacuolar-type ATPase (V-ATPase) is a proton pump composed of two sectors, the cytoplasmic V(1) sector that catalyzes ATP hydrolysis and the transmembrane V(o) sector responsible for proton translocation. The transmembrane V(o) complex directs the complex to different membranes, but also has been proposed to have roles independent of the V(1) sector. However, the roles of the V(1) sector have not been well characterized. In the nematode Caenorhabditis elegans there are two V(1) B-subunit genes; one of them, vha-12, is on the X chromosome, whereas spe-5 is on an autosome. vha-12 is broadly expressed in adults, and homozygotes for a weak allele in vha-12 are viable but are uncoordinated due to decreased neurotransmission. Analysis of a null mutation demonstrates that vha-12 is not required for oogenesis or spermatogenesis in the adult germ line, but it is required maternally for early embryonic development. Zygotic expression begins during embryonic morphogenesis, and homozygous null mutants arrest at the twofold stage. These mutant embryos exhibit a defect in the clearance of apoptotic cell corpses in vha-12 null mutants. These observations indicate that the V(1) sector, in addition to the V(o) sector, is required in exocytic and endocytic pathways. PMID- 22426884 TI - APJ1 and GRE3 homologs work in concert to allow growth in xylose in a natural Saccharomyces sensu stricto hybrid yeast. AB - Creating Saccharomyces yeasts capable of efficient fermentation of pentoses such as xylose remains a key challenge in the production of ethanol from lignocellulosic biomass. Metabolic engineering of industrial Saccharomyces cerevisiae strains has yielded xylose-fermenting strains, but these strains have not yet achieved industrial viability due largely to xylose fermentation being prohibitively slower than that of glucose. Recently, it has been shown that naturally occurring xylose-utilizing Saccharomyces species exist. Uncovering the genetic architecture of such strains will shed further light on xylose metabolism, suggesting additional engineering approaches or possibly even enabling the development of xylose-fermenting yeasts that are not genetically modified. We previously identified a hybrid yeast strain, the genome of which is largely Saccharomyces uvarum, which has the ability to grow on xylose as the sole carbon source. To circumvent the sterility of this hybrid strain, we developed a novel method to genetically characterize its xylose-utilization phenotype, using a tetraploid intermediate, followed by bulk segregant analysis in conjunction with high-throughput sequencing. We found that this strain's growth in xylose is governed by at least two genetic loci, within which we identified the responsible genes: one locus contains a known xylose-pathway gene, a novel homolog of the aldo-keto reductase gene GRE3, while a second locus contains a homolog of APJ1, which encodes a putative chaperone not previously connected to xylose metabolism. Our work demonstrates that the power of sequencing combined with bulk segregant analysis can also be applied to a nongenetically tractable hybrid strain that contains a complex, polygenic trait, and identifies new avenues for metabolic engineering as well as for construction of nongenetically modified xylose fermenting strains. PMID- 22426885 TI - Novel live alkaline phosphatase substrate for identification of pluripotent stem cells. PMID- 22426886 TI - Who is being referred to cancer genetic counseling? Characteristics of counselees and their referral. AB - Both physician and patient play a role in the referral process for cancer genetic counseling. Access to such counseling is not optimal because some eligible patients are not being reached by current referral practice. We aimed to identify factors associated with the initiator of referral. During a 7-month period, we recorded demographic characteristics like gender, personal and family history of cancer, ethnicity and eligibility for genetic testing for 406 consecutive counselees using a specially designed questionnaire. Counselees were seen in a university hospital or a community hospital (n = 7) in the Netherlands. We also recorded educational level of each counselee, clinical setting and who initiated referral. Descriptive statistics were used to describe the counselees' general characteristics. We analysed the association between counselee characteristics and the initiator of referral by logistic regression. The majority of counselees seemed to have initiated referral themselves but were indeed eligible for genetic testing. In comparison to the general population in the Netherlands, the counselees had a higher level of education, and there were fewer immigrants, although a higher level of education was not found to be a facilitating factor for referral. The clinical setting where a counselee was seen was associated with initiator of referral, although this relationship was not straightforward. There is a complex interaction between clinical setting and initiator of referral, which warrants further research to elucidate the factors involved in this relationship. Patients seen in cancer genetic counseling do not reflect the general population in terms of educational level or ethnicity. PMID- 22426887 TI - Biomimetic hydrogels gate transport of calcium ions across cell culture inserts. AB - Control of the in vitro spatiotemporal availability of calcium ions is one means by which the microenvironments of hematopoietic stem cells grown in culture may be reproduced. The effects of cross-linking density on the diffusivity of calcium ions through cell culture compatible poly(2-hydroxyethyl methacrylate) [poly(HEMA)]-based bioactive hydrogels possessing 1.0 mol% 2-methacryloyloxyethyl phosphorylcholine (MPC), 5 mol% N,N-(dimethylamino)ethylmethacrylate (DMAEMA) and ca. 17 mol% n-butyl acrylate (n-BA) have been investigated to determine if varying cross-link density is a viable approach to controlling transport of calcium across hydrogel membranes. Cross-linking density was varied by changing the composition of cross-linker, tetraethyleneglycol diacrylate (TEGDA). The hydrogel membranes were formed by sandwich casting onto the external surface of track-etched polycarbonate membranes (T = 10 MUm, phi = 0.4 MUm pores) of cell culture inserts, polymerized in place by UV light irradiation and immersed in buffered (0.025 HEPES, pH 7.4) 0.10 M calcium chloride solution. The transport of calcium ions across the hydrogel membrane was monitored using a calcium ion selective electrode set within the insert. Degree of hydration (21.6 +/- 1.0%) and void fraction were found to be constant across all cross-linking densities. Diffusion coefficients, determined using time-lag analysis, were shown to be strongly dependent on and to exponentially decrease with increasing cross-linking density. Compared to that found in buffer (2.0-2.5 * 10-6 cm2/s), diffusion coefficients ranged from 1.40 * 10-6 cm2/s to 1.80 * 10-7 cm2/s and tortuosity values ranged from 1.7 to 10.0 for the 1 and 12 mol% TEGDA cross-linked hydrogels respectively. Changes in tortuosity arising from variations in cross-link density were found to be the primary modality for controlling diffusivity through novel n BA containing poly(HEMA)-based bioactive hydrogels. PMID- 22426888 TI - Clinical evidence of particle beam therapy (carbon). AB - Carbon ion radiotherapy (CIRT) is unique as it possesses well-localized and superior-depth dose distribution in addition to less repairable radiobiological effects. The use of CIRT for various diseases has been explored as clinical trials at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Since 1994, when the first clinical study of cancer therapy with carbon ion beams was started, about 50 clinical studies have been completed safely and effectively. These studies revealed that intractable cancers such as inoperable bone and soft tissue sarcomas can be cured safely in a shorter overall treatment time, as can cancers in the head, neck, lung, liver, prostate, and postoperative pelvic recurrence of rectal cancer. The number of patients receiving CIRT has reached 6,000, and the therapy was approved as a highly advanced medical technology in 2003. Based on these experiences, we embarked on the research and development of new-generation beam delivery facilities such as a 3D scanning method with a pencil beam and a compact rotating gantry. Clinical research using pencil-beam scanning has been in operation since May 2011. PMID- 22426889 TI - Clinical evidence of particle beam therapy (proton). AB - Proton beam therapy (PBT) makes it possible to deliver a high concentration of radiation to a tumor using its Bragg peak, and it is simple to utilize as its radiobiological characteristics are identical to those of photon beams. PBT has now been used for half a century, and more than 60,000 patients worldwide are reported to have been treated with proton beams. The most significant change to PBT occurred in the 1990s, when the Loma Linda University Medical Center became the first hospital in the world to operate a medically dedicated proton therapy facility. Following its success, similar medically dedicated facilities have been constructed. Internationally, results have demonstrated the therapeutic superiority of PBT over alternative treatment options for several disease sites. Further advances in PBT are expected from both clinical and technological perspectives. PMID- 22426890 TI - Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin 2 and metronomic cyclophosphamide: results from a phase II trial. AB - Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7 13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-gamma ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed. PMID- 22426891 TI - Comment on "Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy" by Gustav J. Ullenhag et al. PMID- 22426892 TI - The social integration of a myrmecophilous spider does not depend exclusively on chemical mimicry. AB - Numerous animals have evolved effective mechanisms to integrate into and exploit ant societies. Chemical integration strategies are particularly widespread among ant symbionts (myrmecophiles), probably because social insect nestmate recognition is predominantly mediated by cuticular hydrocarbons (CHCs). The importance of an accurate chemical mimicry of host CHCs for social acceptance recently has been demonstrated in a myrmecophilous silverfish. In the present study, we investigated the role of chemical mimicry in the myrmecophilous spider Gamasomorpha maschwitzi that co-occurs in the same host, Leptogenys distinguenda, as the silverfish. To test whether spiders acquire mimetic CHCs from their host or not, we transferred a stable isotope-labeled hydrocarbon to the cuticle of workers and analyzed the adoption of this label by the spiders. We also isolated spiders from hosts in order to study whether this affects: 1) their chemical host resemblance, and 2) their social integration. If spiders acquired host CHCs, rather than biosynthesizing them, they would be expected to lose these compounds during isolation. Spiders acquired the labeled CHC from their host, suggesting that they also acquire mimetic CHCs, most likely through physical contact. Furthermore, isolated spiders lost considerable quantities of their CHCs, indicating that they do not biosynthesize them. However, spiders remained socially well integrated despite significantly reduced chemical host similarity. We conclude that G. maschwitzi depends less on chemical mimicry to avoid recognition and aggressive rejection than the silverfish previously studied, suggesting that the two myrmecophiles possess different adaptations to achieve social integration. PMID- 22426893 TI - A novel synthetic odorant blend for trapping of malaria and other African mosquito species. AB - Estimating the biting fraction of mosquitoes is of critical importance for risk assessment of malaria transmission. Here, we present a novel odor-based tool that has been rigorously assessed in semi-field assays and traditional African villages for estimating the number of mosquitoes that enter houses in search of a blood meal. A standard synthetic blend (SB) consisting of ammonia, (S)-lactic acid, tetradecanoic acid, and carbon dioxide was complemented with isovaleric acid, 4,5 dimethylthiazole, 2-methyl-1-butanol, and 3-methyl-1-butanol in various combinations and concentrations, and tested for attractiveness to the malaria mosquito Anopheles gambiae. Compounds were released through low density polyethylene (LDPE) material or from nylon strips (nylon). Studies were done in a semi-field facility and two traditional villages in western Kenya. The alcohol 3 methyl-1-butanol significantly increased the attraction of SB. The other compounds proved less effective or inhibitory. Tested in a village, 3-methyl-1 butanol, released from LDPE, increased the attraction of SB. Further studies showed a significantly enhanced attraction of adding 3-methyl-1-butanol to SB compared to previously-published attractive blends both under semi-field and village conditions. Other mosquito species with relevance for public health were collected with this blend in significantly higher numbers as well. These results demonstrate the advent of a novel, reliable odor-based sampling tool for the collection of malaria and other mosquitoes. The advantage of this odor-based tool over existing mosquito sampling tools is its reproducibility, objectiveness, and relatively low cost compared to current standards of CDC light traps or the human landing catch. PMID- 22426894 TI - Tunicamycin sensitizes human prostate cells to TRAIL-induced apoptosis by upregulation of TRAIL receptors and downregulation of cIAP2. AB - The addition of tunicamycin to prostate cancer cells enhances cell death mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we investigated whether tunicamycin, an endoplasmic reticulum stress inducer, can potentiate TRAIL-induced apoptosis in human prostate cancer cells. We evaluated the combination of tunicamycin and TRAIL and found synergistic promotion of apoptosis in prostate cancer cells. The combined treatment with tunicamycin and TRAIL significantly induced apoptosis, and stimulated caspase-3, 8 and -9 activity, as well as the cleavage of poly (ADP-ribose) polymerase. We found that tunicamycin promoted TRAIL-induced apoptosis by the upregulation of death receptor (DR)4 and DR5 and the downregulation of cellular inhibitor of apoptosis 2 (cIAP2). In addition, downregulation of cIAP2 expression using small interfering RNA significantly attenuated the apoptosis induced by TRAIL. Taken together, our results demonstrate that the combination of tunicamycin and TRAIL may provide a novel strategy for treating prostate cancer by overcoming critical mechanisms of apoptosis resistance. PMID- 22426895 TI - Involvement of CtBP2 in LPS-induced microglial activation. AB - CtBP2 (C-terminal binding protein 2), which is widely expressed during developmental processes and differentiation, acts as a transcriptional repressor following recruitment to target promoters through repressors or other co repressor proteins. In this study, we elucidated the dynamic expression changes and localization of CtBP2 in lipopolysaccharide (LPS)-induced neuroinflammatory processes in adult rats. CtBP2 expression was strongly induced in active glia cells (microglia and astrocytes) in inflamed spinal cord. In vitro studies indicated that the up-regulation of CtBP2 may be involved in the subsequent microglia activation following LPS exposure. And the knock-down of CtBP2 in microglia cell line HAPI by siRNA showed that CtBP2 increased the activation of microglia induced by LPS. Collectively, these results suggested CtBP2 may be important in host defense in microglia-mediated immune response. Understanding the cell signal pathway may provide a novel strategy against inflammatory and immune reaction in neuroinflammation in central nervous system. PMID- 22426896 TI - Hepatitis C virus amino acid sequence diversity correlates with the outcome of combined interferon/ribavirin therapy in Chinese patients with chronic hepatitis C. AB - Evidence has shown that the p7, NS2 and NS3 genes affect the outcome of pegylated IFN-alpha/ribavirin (PEG-IFN/RBV) combination therapy in different populations with HCV infections. Here, we test the hypothesis that diversity in the p7, NS2 and NS3 genes influences the probability of obtaining either a sustained (SVR) or non-sustained (non-SVR) viral response in Chinese patients with genotype 1b chronic hepatitis C. There were significantly more unique variations in the p7, NS2 and NS3 genes in the sequences from SVR than non-SVR patients. Inter-patient variations related to treatment outcome in NS3 were concentrated in the protease domain. There were no significant differences in the frequency of variations in the core, E1 and E2 proteins between the groups. In conclusion, increased amino acid sequence diversity in the p7, NS2 and NS3 genes is associated with an SVR to PEG-IFN/RBV therapy in Chinese patients with genotype 1b chronic hepatitis C. PMID- 22426897 TI - Novel circovirus in European catfish (Silurus glanis). AB - Circular single-stranded DNA viral genomes had been identified worldwide in different species and in environmental samples. Among them, viruses belonging to the genus Circovirus of the family Circoviridae are present in birds and pigs, and recently, they were detected in barbels. The present study reports the identification of a new circovirus in fish. PCR amplification and sequencing were used to identify the novel circular DNA virus in European catfish (Silurus glanis). Full genome characterization and phylogenetic analysis showed that the virus belonged to the family Circoviridae and that it was distantly related to the previously described barbel circovirus. PMID- 22426899 TI - Relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis. AB - BACKGROUND: Decline in forced vital capacity (FVC) over time reliably predicts mortality in patients with idiopathic pulmonary fibrosis. The use of this measure in clinical practice is recommended by current evidence-based guidelines. It is unknown if the method of calculating decline in FVC (relative vs. absolute change) impacts its frequency or its ability to predict mortality. METHODS: Patients with idiopathic pulmonary fibrosis from two prospective cohorts were included if they had a baseline and 12-month follow-up FVC. A >=10% decline in FVC from baseline was calculated in two ways: a relative decline of 10% (e.g., from 60% predicted to 54% predicted) and an absolute decline of 10% (e.g., from 60% predicted to 50% predicted). The frequency of a >=10% decline in FVC and its ability to predict 2-year transplant-free survival were compared between these two methods. Declines in FVC of >=5% and >=15% were similarly compared. Analyses were performed unadjusted and adjusted for age, gender, use of oxygen, baseline FVC and baseline diffusion capacity for carbon monoxide. RESULTS: The frequency of any given FVC decline was significantly greater using the relative change in FVC method. For >=10% decline, both methods predicted 2-year transplant-free survival with similar accuracy, and remained significant predictors after adjusting for baseline characteristics. The absolute change method appeared more predictive for >=5% decline. CONCLUSIONS: Using the relative change in FVC maximises the chance of identifying a >=10% decline in FVC without sacrificing prognostic accuracy. This may not hold true for >=5% decline in FVC. These findings have important implications for clinical practice and the design of clinical trials. PMID- 22426900 TI - Should we be pursuing the earlier diagnosis of lung cancer in symptomatic patients? PMID- 22426902 TI - Effective teaching in medical schools. Guiding principles. AB - Clinical teachers have high qualifications in their specialty, but some of them do not have training, or proficiency in teaching, and education. Therefore, they may face the challenge of effective teaching in their daily practice. The objective of this study is to present some basic guiding principles for novices and expert academic health professionals. An overview from the perspective of the authors on critical fields in education was conducted. Seventeen principles (supported by one or more relevant examples) are discussed. To improve the quality of their teaching practice, academic health professionals need to study the pedagogy of education, and to seek feedback from colleagues who have already studied and practiced the principles of learning and teaching. PMID- 22426901 TI - Diagnostic performance of MDCT, PET/CT and gadoxetic acid (Primovist((r))) enhanced MRI in patients with colorectal liver metastases being considered for hepatic resection: initial experience in a single centre. AB - PURPOSE: To compare the relative diagnostic performance of MDCT, PET/CT and Primovist-enhanced MRI (P-MRI) in the pre-resection work-up of colorectal cancer (CRC) liver metastases. METHOD AND MATERIALS: This was a retrospective study of consecutive referrals for CRC liver metastases. All patients had MDCT, PET/CT and P-MRI examinations within 3 months of each other. They were divided into 2 groups: resected and unresected. Patients in the resected group underwent liver resection within 3 months of the imaging studies. In the unresected group, patients were unresectable by imaging criteria or are awaiting surgery. Standard of reference (SOR) was intra-operative ultrasound findings and pathology for the resected group. Intermodality comparison was the SOR for the unresected group. Number of lesions identified by each imaging modality for each patient was recorded. Sensitivity (95% CI) and PPV were calculated for each imaging modality in the resected group. RESULTS: There were 19 patients in the resected group and 11 patients in the unresected group. The sensitivity (96%) and PPV (0.91) of P MRI were both superior to that of MDCT (P = 0.0009) and PET/CT (P = 0.0003). Intermodality comparison showed that P-MRI detected more lesions than MDCT and PET/CT. CONCLUSION: The sensitivity and PPV of P-MRI was superior to that of MDCT and PET/CT. P-MRI probably has the most added value if used after MDCT and PET/CT in patients still considered eligible for liver resection. PMID- 22426903 TI - The effects of sevoflurane and propofol anesthesia on renal sodium-potassium adenosine triphosphatase activity during pneumoperitoneum in rats. AB - OBJECTIVE: To evaluate the renal sodium-potassium adenosine triphosphatase (Na+/K+ATPase) activity, kidney morphology, and the probable protective effects of 2 different anesthetic agents used during pneumoperitoneum (PP). METHODS: The study was performed at Gazi University Experimental Research Center, Ankara, Turkey between January and July 2009. Twenty-four Wistar albino male rats weighing 320-380 g were randomly allocated to 4 groups after receiving ethics committee approval. All rats were cannulated, intubated, and ventilated under ketamine anesthesia. No further surgical intervention was performed for group I. An intraabdominal pressure (IAP) of 10 mm Hg was created by CO2 insufflation in 18 animals for one hour. The animals in group II received no further anesthetic agents, while the animals in groups III and IV received propofol and sevoflurane. At the end of the protocol, all animals underwent left nephrectomy without sacrificing. Urine was collected from each animal for the following 24 hour for the evaluation of urine creatinine and protein. RESULTS: The activity of renal Na+/K+ATPase was significantly lower in groups II (p=0.014), III (p=0.019), and IV (p=0.032) compared to group I. The pathological score was significantly higher in groups II (p=0.017), III (p=0.028), and IV (p=0.039) compared to group I. No statistically significant difference was found among groups II, III, and IV in terms of Na+/K+ATPase activity and pathological scores. CONCLUSION: Elevated IAP is related with impaired kidney functions and morphology, and the so-called renoprotective agents neither improved, nor worsened PP-related renal impairment. PMID- 22426904 TI - The effects of acetazolamide on ischemia reperfused isolated hearts of 2- and 8 week-old rabbits. AB - OBJECTIVE: To investigate the effects of acetazolamide on the ischemia-reperfused isolated hearts of 2- and 8-week-old rabbits. METHODS: This study was conducted at the Kermanshah Medical Biology Research Center, Kermanshah, Iran from March to September 2011. Two- (n=17) and 8-week old (n=17) rabbits were separately divided into 2 control (n=9), and test (n=8) groups. Isolated hearts were subjected to 35 minutes ischemia and 30 minutes reperfusion. Acetazolamide (100 microgr/l) was added to the perfusion solution for 10 minutes before ischemia in the test group. Cardiac parameters including ventricular pressure, heart rate (HR), and rate pressure product (RPP) were measured. Data sets were analyzed by t-test. RESULTS: Following acetazolamide administration the change percentage of HR was significantly different in the 2-week (91 +/- 1.1%) compared with the 8-week (96 +/- 0.8%) test groups (p=0.0016). Recovery percentage of RPP in reperfusion was lower (p=0.005) in the 8- (28.9 +/- 3.4%) than the 2-week test groups (45.2 +/- 3.5%). CONCLUSION: The 2-week hearts elicited more rapid response to carbonic anhydrase (CA) inhibition than the 8-week group. However, acetazolamide does not exacerbate ischemia-reperfusion (I/R) injury in the 2-week hearts. Therefore, it was revealed that after inhibition of CA, the age dependent pattern of I/R injury was similar to that of the normal hearts. Inspite of the CA important role in the normal heart function, it is not a determining factor in I/R injury in different ages. PMID- 22426905 TI - Evaluation of left ventricular mechanical dyssynchrony in patients with heart failure after myocardial infarction by real-time three-dimensional echocardiography. AB - OBJECTIVE: To evaluate the incidence and prevalence of left ventricular (LV) dyssynchrony in patients with heart failure after myocardial infarction (MI) by real- time three-dimensional echocardiography (RT-3DE), and to investigate the clinical application value of using RT-3DE as a method of providing more detailed information for clinical strategy. METHODS: This cross-sectional study was carried out in Renmin Hospital of WuHan University, Hubei Province, China from July 2009 to December 2010. The RT-3DE was performed on 43 patients with chronic heart failure after MI and 30 normal subjects, to analyze LV volume and left ventricular ejection fraction (LVEF), also the LV systolic dyssynchrony index (SDI). RESULTS: The dyssynchrony rate of the total MI patients was 83.7%, and was 100% in the severe dysfunction group. The SDI of MI patients was significantly higher than the control subjects (p less than 0.01), and the SDI of those whose LVEF = 10%, were genotyped in 69 MBC patients who were treated with docetaxel plus capecitabine. Pearson's chi(2) test or Fisher's exact test was used to investigate the influence of SNPs on objective response as appropriate. Log-rank test was used to assess the association between SNPs and survival outcomes. RESULTS: There is no significant association between polymorphisms and both objective response and OS. Only one SNP, CYP1A1 rs1048943 A>G (Ile462Val), was significantly associated with PFS (P = 0.0003). Multivariate analysis confirmed its prognostic significance for PFS (P = 0.004). CONCLUSION: CYP1A1 rs1048943 A>G (Ile462Val) polymorphism is a potential prognostic marker for survival outcome after docetaxel plus capecitabine chemotherapy in MBC patients. However, confirmatory study is needed to validate this finding. PMID- 22426924 TI - Extraction of plasma from whole blood using a deposited microbead plug (DMBP) in a capillary-driven microfluidic device. AB - We presented a deposited microbead plug (DMBP)-based microfluidic device capable of extracting plasma from whole blood by capillary forces. This device was fabricated by reversibly bonding a PDMS slab with a straight channel to a hydrophilic glass substrate. The DMBP was easily constructed at the inlet of the channel within 2 min by a method of natural deposition of microbeads without the need of weirs or photopolymerization. Capillary forces generated mainly on the hydrophilic glass substrate provided a driving force during the fabrication of the DMBP and plasma extraction, resulting in simplicity of operations. The DMBP only allows blood plasma to pass through but blocks blood cells, which was demonstrated experimentally using sheep blood. The DMBP enabled to remain in its initial configuration during plasma extraction. The high quality plasma was obtained without contamination of microbeads and blood cells. This easy-to-use, easy-to-integrate, disposable the DMBP-based microfluidic device has the potential to be integrated with on-chip bioanalytical units for the applications of point-of-care diagnostics. PMID- 22426925 TI - Intracranial relapse rates and patterns, and survival trends following post resection cavity radiosurgery for patients with single intracranial metastases. AB - The objective of this study is to evaluate the patterns of relapse and survival trends in patients with single brain metastases treated with post-operative adjuvant Gamma knife stereotactic radiosurgery (GKS) without whole brain radiotherapy (WBRT). Retrospective analysis of all consecutive patients who underwent GKS to the tumor cavity following resection of solitary brain metastasis was performed at a single institution. Between March 2001 and June 2010, 56 patients underwent GKS to the resection cavity following resection of intracranial metastases; no patient received pre- or post-operative WBRT as an adjuvant (salvage WBRT was permissible). The mean marginal dose was 17.1 Gy (range 14-20 Gy). The mean follow-up period was 24 months (range 3-99 months). Five patients (8.9%) had local recurrence in the immediate vicinity of the resection cavity, qualifying as "local failures", and 21 (37.5%) recurred at distant intracranial sites. Median intracranial recurrence free survival was 13 months. Median overall survival was 20.5 months. Salvage interventions were required in 26 patients, and included repeat radiosurgery in 17 patients, further surgery in two patients, and salvage WBRT in eight (14.3%; two of whom had also been locally salvaged with repeat radiosurgery) patients. As expected, avoidance of WBRT results in a high rate of intracranial failure (26/56 patients, 46%), even in well-selected patients with only single brain metastases. As anticipated, the majority of failures (21, 37.5%) are "distant intracranial", and in this well selected cohort the local failure rate is low (5/56 patients, <9%). All patients failing intracranially (46%) are potential candidates for salvage therapies, but WBRT as salvage was utilized in only 14.3% of patients. The median intracranial relapse-free was 13 months and overall survival was 20.5 months. PMID- 22426926 TI - Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi center study. AB - We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 * 10(-6)mm(2)/s +/- 224 (SD), and mean LCP was 0.71 +/- 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study. PMID- 22426927 TI - Cytokine-based therapy in psoriasis. AB - Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2-3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL 17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment. PMID- 22426928 TI - Injection of methylene blue solution into the inferior mesenteric artery of resected rectal specimens for rectal cancer as a method for increasing the lymph node harvest. AB - BACKGROUND: The aim of the present study was to determine whether the injection of methylene blue solution into the inferior mesenteric artery could improve the lymph node harvest in rectal specimens of rectal cancer patients treated with rectal resection with total mesorectal excision. METHODS: The study group consisted of 20 randomly selected fresh rectal specimens from patients with stages I-III rectal cancer treated at the Surgery Clinic at the Institute of Oncology of Vilnius University during the period from February 2008 to December 2010, and 20 specimens were selected under the same conditions to serve as the control group. The patients underwent conventional rectal resection with total mesorectal excision and coloanal anastomosis for low rectal cancer performed by the same surgeon, did not receive preoperative radiotherapy and had no distant metastases. After the removal of the specimen, 30 ml of 0.5% methylene blue solution was injected into the inferior mesenteric artery of the specimens in the study group (methylene blue group). The specimens from both the methylene blue and control groups were examined using the standards established by the Lithuanian National Centre of Pathology. The pathologist was not required to make any special macroscopic preparations. A retrospective analysis of clinical and histopathological records was performed. RESULTS: Comparison of the mean lymph node harvest showed a significant difference between methylene blue and control groups with average lymph node numbers per specimen of 18 +/- 5 and 14 +/- 6, respectively (p = 0.025). The specimens from 12 of the 20 patients in the methylene blue group and the specimens from 7 of the 20 patients from the control group had positive nodes. CONCLUSIONS: Injecting methylene blue solution into the inferior mesenteric artery is an efficient and simple method for improving the lymph node harvest in the histopathological examination of rectal specimens of rectal cancer patients treated with rectal resection with total mesorectal excision. PMID- 22426929 TI - Laparoscopic intracorporeal distal rectal transection with the CONTOUR((r)) device. AB - Laparoscopic rectal resection is considered technically more demanding than laparoscopic colectomy. Rectal transection is a challenging part of laparoscopic low anterior rectal resection and restorative proctocolectomy. We describe our technique for laparoscopic rectal transection with a curved cutter, a device initially designed for open surgery, combined with the use of a ring-mounted sterile drape that allows maintenance of sufficient intra-abdominal gas pressure in a series of 34 patients. PMID- 22426930 TI - Critical analysis of tibial fracture healing following unreamed nailing. AB - PURPOSE: Unreamed nails have revolutionised the treatment of tibial shaft fractures. Many authors, however, have reported increasing bone healing complications with these implants. Unfortunately, few studies have addressed the factors affecting bone healing after unreamed tibial nailing. METHODS: One hundred and sixty tibial fractures in 158 patients (mean age 39.5 years) fixed using unreamed nails were reviewed. There were 78 AO type-A, 65 type-B and 17 type-C fractures (115 closed and 45 open fractures). Twelve patient, injury and surgery variables were analysed for their influence on fracture healing. RESULTS: Union occurred in all fractures after a mean time of 24.3 weeks. Additional surgery to achieve union, apart from dynamisation, was done in nine (6%) cases. The most important variables affecting healing were the mechanism of trauma (p=0.005), fracture site gap (p=0.01), degree of comminution (p=0.0003), associated soft tissue injuries (p=0.02) and the time to dynamisation (p=0.0001). CONCLUSIONS: High-energy trauma and fracture comminution have a negative impact on bone union and require close follow-up. It is essential to avoid distraction over three millimetres with unreamed nailing. Dynamisation is advised within ten weeks in axially stable fractures to encourage bone healing and avoid failure of the locking screws. PMID- 22426931 TI - Medial Achilles tendon island flap--a novel technique to treat reruptures and neglected ruptures of the Achilles tendon. AB - PURPOSE: There is a strong consensus for surgical treatment of reruptures and neglected ruptures of the Achilles tendon. A number of different surgical techniques have been described and several of these methods include extensive surgical exposure to the calf and technically demanding tendon transfers. The overall risk of complications is high and in particular the risk for wound healing problems, which are triggered by an increased tension in the skin when inserting a bulky graft to cover the rupture. In order to reduce the risk for wound healing problems a new, less complicated surgical technique was developed, as described in this study. METHODS: Nine consecutive patients (including six chronic ruptures and three reruptures) with complicating co-morbidities and with a tendon defect between three and eight centimetres were operated upon using the described novel technique. Patient-reported functional outcome was reported after two to eight years. RESULTS: All tendon defects were successfully repaired. Neither early nor late surgical complications occurred. High patient satisfaction was reported for all patients. CONCLUSIONS: The new surgical technique with a medial Achilles tendon island flap seems to be safe and results in a good patient reported outcome. PMID- 22426932 TI - Are MRI-based, patient matched cutting jigs as accurate as the tibial guides? AB - PURPOSE: The aim of this study is to evaluate the accuracy of VISIONAIRE (Smith & Nephew Inc., Memphis, TN, USA) Patient Matched cutting tibial jigs in comparison with extramedullary (EM) tibial instrumentation by analysing data as detected by intra-operative use of VectorVision knee navigation software from BrainLAB (Redwood City, CA, USA). METHODS: Twelve patients were selected for unilateral total knee replacement (TKR). They underwent a full-length weight-bearing anteroposterior (AP) radiograph and magnetic resonance imaging (MRI). During surgery, once the EM guides were placed and fixed on the tibia, the orientation in the coronal and sagittal planes was checked by the navigator and then compared with the data obtained by measuring the orientation of VISIONAIRE Patient Matched cutting tibial jigs. An unsatisfactory result was considered an error >=2 degrees in both coronal and sagittal planes for the tibial component as a possible error of 4 degrees could result. RESULTS: In the coronal plane the mean deviation of the EM tibial guides from the ideal alignment (0 degrees ) was 0.7 +/- 0.39 degrees and of the VISIONAIRE was 129 +/- 1.55 degrees (P = 0.22). In the sagittal plane the mean deviation of the EM tibial guides from 3 degrees of posterior slope was -1.62 +/- 1.78 degrees and of the VISIONAIRE was +1.16 +/- 4.29 degrees (P < 0.05). Negative values indicate a more posterior slope from the ideal and positive values an anterior slope. CONCLUSIONS: This preliminary study documented only a fair accuracy of the method with a consistent risk of error of more of 3 degrees especially in the sagittal plane. We could speculate that the problem in the sagittal plane was due to the fact that the pre-operative protocol does not include a lateral X-ray projection of the knee and only includes an AP standing X-ray of the straight leg and MRI. PMID- 22426933 TI - Higher stability with locking plates in hand surgery? Biomechanical investigation of the TriLock system in a fracture model. AB - PURPOSE: The aim of this study was to determine the biomechanical characteristics of locking plates with the TriLock system with different design and screw settings compared to a non-locking plate in a diaphyseal metacarpal fracture. METHODS: Oblique diaphyseal shaft fractures in porcine metacarpal bones were created in a biomechanical fracture model. After reduction they were fixed with three different locking plates with the TriLock interlocking mechanism or a non locking linear plate in mono- or bicortical screw fixations. In load to failure tests the maximum load and stiffness were measured. RESULTS: For linear plates, the maximum load was higher for the non-locking plate compared with the locking plate. The maximum load could be increased for the locking plates using a double row design and a higher screw number. No differences were found for the stiffness between all groups. In contrast to the non-locking plate, the mode of failure of the locking plates in many cases (86 %) was a loss of the interlocking mechanism. CONCLUSIONS: The results suggest that the locking plates with the TriLock system achieve no higher stability compared to a non-locking plate in load to failure tests. Adaptions to increase the stability of the interlocking mechanism are desirable. PMID- 22426934 TI - The use of an injectable calcium sulphate/calcium phosphate bioceramic in the treatment of osteonecrosis of the femoral head. AB - PURPOSE: The purpose of our study is to describe the rationale, the surgical technique and the early clinical and radiographic results of the treatment of patients with early stage osteonecrosis of the femoral head (ONFH) by performing: core decompression, injection of autologous bone marrow concentrate and the use of a new composite injectable bone substitute (PRO-DENSE((r))), as a mechanical supplementation associated with decompression. METHODS: The study included 37 hips (31 patients, 14 females, 17 males; mean age 43.9 years, range 24-56 years) with stages IC-IIIA ONFH. The outcome was determined by the changes in the Harris hip score (HHS), by progression in radiographic stages and by the need for hip replacement. The mean follow-up was 20.6 months (range 12-32 months). RESULTS: At final follow-up the mean HHS increased from 68 points pre-operatively to 86 points post-operatively. The radiological results showed that 29 hips (78.4 %) improved or had no further collapse. The overall clinical success rate of the procedure was 86.5 %, with three conversions to THA, and a failure rate of only 3.3 % in the pre-collapse group. CONCLUSIONS: We are encouraged by these early results using core decompression, injection of the autologous bone marrow concentrate and backfilling the defect with an injectable bioceramic for the treatment of early stages of ONFH; as far as a conclusion can be drawn from the current data, this treatment seems to relieve hip pain and prevent the progression of ONFH in the majority of the cases. PMID- 22426935 TI - Smartphones in orthopaedics. AB - With the introduction of the European Working Time Directive, surgical trainees are facing limited training opportunities and doctors are required to maximise their training opportunities. Smartphone sales have been rapidly increasing over the last five years and can be used as a training tool for the orthopaedic trainee and surgeon. Common uses include applications (AO, eLogbook and PubMed), Ebooks, online Logbooks, Guidelines and surgical techniques. In addition, smartphones can be used to immediately complete work-based assessments, in the absence of computers, hopefully increasing completion rates and reliability. Some journals now provide podcasts and video tutorials which may be accessed on smartphones, which is useful for higher examinations. Smartphones can also be used in the clinical setting to take photographs of wounds. Smartphones are enjoying increased uptake and application in the workplace and we review their use for orthopaedic surgeons and trainees to allow them to make the most out of their training opportunities. PMID- 22426936 TI - Endoscopic bursectomy for the treatment of septic pre-patellar bursitis: a case series. AB - INTRODUCTION: Operative treatment for septic pre-patellar bursitis generally involves open debridement in addition to an extended course of intravenous antibiotics. Skin necrosis and wound breakdown are potential complications of this procedure in addition to scar sensitivity and a prolonged recovery. METHOD: We report endoscopic bursectomy for the treatment of septic pre-patellar bursitis in eight patients over a 3-year period. All patients had microbiological confirmation of an infective process. The average age was 36 years (23-68 years). The average hospital stay was 6 days (4-9 days). RESULTS: No patient had a recurrence or complained of tenderness or hypoaesthesia around their wound. No patient experienced wound complications or skin necrosis. The average return to work time was 18 days (7-22 days). CONCLUSION: We conclude that endoscopic bursectomy is a safe and effective treatment for septic pre-patellar bursitis with a shortened hospital stay and a quicker return to work than conventional open debridement. PMID- 22426937 TI - Stage distribution of breast cancer diagnosed before and after implementation of population-based mammographic screening. AB - PURPOSE: The German mammographic screening program is very similar to the Norwegian Breast Cancer Screening Program (NBCSP), which started about 10 years earlier. This study analyzes the stage distribution of invasive breast cancers diagnosed in the pre-screening and screening period, and evaluates the overall mortality in women aged 55-74 in the pilot and non-pilot counties of the NBCSP. MATERIALS AND METHODS: The NBCSP invites women aged 50-69 to participate in two view mammography biennially. Chi-square statistics were used to compare percentages of the stage and treatment of invasive breast cancers diagnosed in women residing in the four pilot counties in the pre-screening (1984-1995) and screening (1996-2007) period. An ecological approach was used to analyze the age specific mortality in the pilot and non-pilot counties for the period 1970-2007. RESULTS: 50% of the breast cancers diagnosed in the pre-screening period, 70% of the cases detected with screening, 43% of the interval cancers, and 52% of the cancers diagnosed outside the NBCSP were stage I. Stage III+was present in 11% of the cancers in the pre-screening period, and in 1% of the cancers detected with screening. In the screening period, the breast cancer mortality rate decreased substantially more in the pilot counties than in the non-pilot counties. CONCLUSION: The stage distribution of breast cancer diagnosed in the NBCSP is prognostically favorable compared to cancers diagnosed outside the screening program. The reduction in the breast cancer mortality rate was more pronounced in the four pilot counties compared to the non-pilot counties. It is necessary to evaluate the program based on individual data. PMID- 22426938 TI - [Advanced interventional techniques and therapies in the treatment of peripheral artery disease below the knee]. AB - In patients with peripheral artery disease, the options for interventional therapy of critical limb ischemia have increased within the last few years. Different antegrade and retrograde techniques for vascular recanalization are used to pass even complex and long stenoses or occlusions below the knee (BTK). A variety of diverse wires, catheters and stent types allows arterial recanalization of the lower leg and increases the impact of therapeutic efforts. This review article describes indications, advanced techniques as well as materials in BTK interventions and summarizes current evidence-based study results. PMID- 22426939 TI - MR imaging findings in flexed abducted supinated (FABS) position and clinical presentation following refixation of distal biceps tendon rupture using bioabsorbable suture anchors. AB - PURPOSE: To correlate MRI findings after suture anchor repair of distal biceps tendons with symptoms. MATERIALS AND METHODS: 24 men with 25 distal biceps tendon ruptures (one bilateral) treated with suture anchor repair were retrospectively included. Follow-up after a mean of 31 months (range, 12-74) included clinical examination and MRI. The pain level and flexion strength compared to the uninvolved arm were recorded. MRI was performed at 1.5 T obtaining FABS position images (both elbows in 7 patients) and evaluated for artifacts, signal abnormalities, and rerupture by two experienced readers in consensus and blinded to symptoms. Pain and loss of flexion strength>20% were tested against MRI findings as dichotomous data using Fisher's exact chi-square tests (p<0.05). Crosssectional areas of operated and uninvolved tendons were measured and evaluated with the Wilcoxon signed rank test (p<0.05). RESULTS: FABS views enabled good evaluation in 96% of tendons. Rerupture was present in 3 of 25 elbows. Tendinous signal increase was seen in 59% of intact tendons. We found activity-related pain or pain at rest in 32% and a loss of flexion strength in 27 % of these cases. Testing revealed no significant correlation for any of the MRI features with any of the clinical parameters (p>0.05). There was a 2.7-fold mean increase of the tendon cross-sectional area on the repaired side compared to the uninvolved contralateral tendon (p=0.02). CONCLUSION: We found good MRI visualization of postoperative tendons, but no correlation between symptoms and MRI signal abnormalities or rerupture. The increase in caliber of the repaired tendon might promote an impingement in pronation. PMID- 22426940 TI - Tumor microRNA-29a expression and the risk of recurrence in stage II colon cancer. AB - There is emerging evidence for the prognostic role of various microRNA (miRNA) molecules in colon cancer. The aim of this study was therefore to compare the miRNA profiles in the primary tumor of patients with recurrent and non-recurrent colon cancer. The study population included 110 patients, 51 (46%) with stage I and 59 (54%) with stage II disease, who underwent curative colectomies between 1995 and 2005 without adjuvant therapy and for whom reliable miRNA expression data were available. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor samples. Initial profiling, using microarrays, was done in order to identify potential biomarkers of recurrence. The miRNA expression was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 months of surgery (bad prognosis group, n=23, 21%) and those who did not (good prognosis group, n=87, 79%) in the entire group and within each stage. The results showed that in stage I, none of the 903 miRNAs tested showed differential expression between patients with good prognosis compared with those with poor prognosis. In contrast, in stage II, one miRNA, miR-29a, showed a clear differential expression between the groups (p=0.028). High expression of miR-29a was associated with a longer disease-free survival (DFS), on both univariate and multivariate analyses. Using miR-29a, the positive predictive value for non-recurrence was 94% (2 recurrences among 31 patients). The differential expression of miR-29a was verified by qRT-PCR, showing a similar impact of this miR on DFS. In conclusion, this study demonstrated a significant impact of miR-29a on the risk of recurrence in patients with stage II but not in patients with stage I colon cancer. Based on these results, a validation study is planned. PMID- 22426941 TI - Effect of COX-2 inhibitor lumiracoxib and the TNF-alpha antagonist etanercept on TNBS-induced colitis in Wistar rats. AB - Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. On the other hand, the anti-tumour necrosis factor alpha (TNF-alpha) treatment has brought benefits to these patients. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, and Etanercept (ETC), a TNF-alpha antagonist on the 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced experimental colitis. A total of 47 Wistar rats were randomized into seven groups, as follows: (1) Sham: sham induced-colitis; (2) TNBS: nontreated induced-colitis; (3) Lumiracoxib control; (4) Lumiracoxib-treated induced colitis; (5) ETC control; (6) ETC-treated induced-colitis; (7) Lumiracoxib-ETC treated induced-colitis. Rats from groups 6 and 7 presented significant improvement of macroscopic and histopathological damages in the distal colon. The gene expression of COX-2 mRNA, as well of TNF-alpha mRNA, decreased significantly in groups 6 and 7 compared to the TNBS nontreated and lumiracoxib-treated groups. The treatment only with lumiracoxib did not reduce the inflammation on TNBS induced experimental colitis. ETC attenuated the damage seen in the colon and reduced the inflammation caused by TNBS. Our results suggest that down-regulation of TNF-alpha and COX-2 resulted in a decrease in inflammation caused by TNBS and thus provided some protection from the colonic damage caused by TNBS. PMID- 22426942 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a review of molecular and clinical literature. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is heritable cardiomyopathy that may result in arrhythmia, heart failure, and sudden cardiac death (SCD). Approximately 50-60% of ARVD/C patient will have an identifiable pathogenic mutation in one of seven genes associated with the cardiac desmosome and other cardiac pathways. Genetic counseling remains complicated, however, because of great variable expressivity and reduced penetrance, even within members of the same family. Diagnosis of ARVD/C is made by meeting a set of major and minor diagnostic criteria, revised in 2010. Despite this, misdiagnosis is a chronic problem. Management of ARVD/C is aimed at reducing risk of sudden death/arrhythmias and preventing progression of disease. Strenuous physical activity is increasingly recognized as a significant risk factor in disease presentation and progression and is an important factor in preventative management. Anticipation of the psychosocial implications of this disease is also an important aspect of patient management. This review presents an overview of the clinical diagnosis, management, as well as disease mechanism and genetics of this rare cardiomyopathy. PMID- 22426943 TI - A high-coverage artificial chromosome library for the genome-wide screening of drug-resistance genes in malaria parasites. AB - The global spread of drug-resistant parasites is a serious problem for the treatment of malaria. Although identifying drug-resistance genes is crucial for the efforts against resistant parasites, an effective approach has not yet been developed. Here, we report a robust method for identifying resistance genes from parasites by using a Plasmodium artificial chromosome (PAC). Large genomic DNA fragments (10-50 kb) from the drug-resistant rodent malaria parasite Plasmodium berghei were ligated into the PAC and directly introduced into the drug-sensitive (i.e., wild-type) parasite by electroporation, resulting in a PAC library that encompassed the whole genomic sequence of the parasite. Subsequently, the transformed parasites that acquired resistance were selected by screening with the drug, and the resistance gene in the PAC was successfully identified. Furthermore, the drug-resistance gene was identified from a PAC library that was made from the pyrimethamine-resistant parasite Plasmodium chabaudi, further demonstrating the utility of our method. This method will promote the identification of resistance genes and contribute to the global fight against drug-resistant parasites. PMID- 22426944 TI - Potential predictors in neonaticide: the impact of the circumstances of pregnancy. AB - This study aims to evaluate the psychosocial factors of neonaticide, especially the circumstances before delivery, the relationships of the pregnant women, and their social environment awareness of women's pregnancy. This nationwide study was register-based, comprising all known neonaticides in Austria and Finland between 1995 and 2005. Cases (n = 28) were obtained by screening the death certificates from coroner's departments and by analyzing them along with all further available reports. Few women (17.9 %, 5/28) admitted their pregnancy to others. Although most (16/28) offenders were in a relationship, the partner had knowledge of the pregnancy in only three cases. The main motive for negation of the pregnancy (named in 60.8 % of cases) was fear of abandonment/negative response from others. The fertility rate among the women was high, but half of those with children had lost the custody of them. In neonaticide, the lack of awareness surrounding offenders' pregnancy, as well as the awareness of social environment, is more relevant than any other social variable. PMID- 22426945 TI - Patients with positive axillary lymph nodes: how to use genomic assays. AB - OPINION STATEMENT: The treatment of breast cancer is continually evolving. Standard treatment for early stage, node positive breast cancer has included adjuvant chemotherapy. As we learn more about differences in a tumor's genetic makeup that result in different patterns of recurrence and survival, we are starting to include gene expression in addition to the routine clinical and pathological factors when we make treatment recommendations. For lymph node negative, early stage breast cancer, there are two genomic assays in routine use to predict prognosis and benefit from adjuvant chemotherapy. There is emerging data to support that the same tests may also predict prognosis and chemotherapy benefit, or lack thereof, in lymph node positive tumors. Currently there are no standard of care and this is an area in which more research is being done. Given that the biology of breast tumors is independent of nodal status, there are certainly cases of node positive early stage breast cancer where clinicians can feel comfortable making treatment decisions based on genomic assays. These include women with micrometastases in the lymph nodes or those with one to three positive lymph nodes. Currently, the genomic assays are limited to use in tumors that are estrogen receptor positive. It is still clearly the standard of care to administer chemotherapy to estrogen receptor negative, lymph node positive tumors. PMID- 22426946 TI - Behavioural and magnetoencephalographic evidence for the interaction between semantic and episodic memory in healthy elderly subjects. AB - The relationship between episodic and semantic memory systems has long been debated. Some authors argue that episodic memory is contingent on semantic memory (Tulving 1984), while others postulate that both systems are independent since they can be selectively damaged (Squire 1987). The interaction between these memory systems is particularly important in the elderly, since the dissociation of episodic and semantic memory defects characterize different aging-related pathologies. Here, we investigated the interaction between semantic knowledge and episodic memory processes associated with faces in elderly subjects using an experimental paradigm where the semantic encoding of famous and unknown faces was compared to their episodic recognition. Results showed that the level of semantic awareness of items affected the recognition of those items in the episodic memory task. Event-related magnetic fields confirmed this interaction between episodic and semantic memory: ERFs related to the old/new effect during the episodic task were markedly different for famous and unknown faces. The old/new effect for famous faces involved sustained activities maximal over right temporal sensors, showing a spatio-temporal pattern partly similar to that found for famous versus unknown faces during the semantic task. By contrast, an old/new effect for unknown faces was observed on left parieto-occipital sensors. These findings suggest that the episodic memory for famous faces activated the retrieval of stored semantic information, whereas it was based on items' perceptual features for unknown faces. Overall, our results show that semantic information interfered markedly with episodic memory processes and suggested that the neural substrates of these two memory systems overlap. PMID- 22426947 TI - Aged peripheral retinal lesions originating from the ciliary body sweep away the retinal pigmented epithelium. AB - AIMS: To investigate age-related lesions in the far-anterior retina that migrate from the ciliary body (CB) and how they affect the neural retina and retinal pigmented epithelium (RPE). METHODS: One eye from three healthy subjects aged 87, 92 and 93 years were used. Retinae were photographed, embedded in resin and then sectioned at 2 MUm. RESULTS: Multiple elliptically shaped lesions were present in the CB. Larger lesions extended into the peripheral retina. Lesions resulted from deposits that had lenticular qualities. These develop centrally along Bruch's membrane sweeping away the RPE, such that piles of RPE cells were present around the deposits that resulted in retinal atrophy. The internal composition of the deposits revealed large numbers of spherical bodies, unlike those seen in drusen. RPE cells adjacent to these deposits and their underlying lesions became highly irregular, with melanin granules spacing themselves out within the cell and adopting similar orientations. This is a highly distinctive feature. CONCLUSIONS: These far-anterior deposits were different in nature from drusen in terms of morphology, composition and origin. They swept away the RPE, exposing the Bruch's membrane and isolating the retina, leading to atrophy. They appeared to originate from the CB and progressed centrally. The deposits may have developed from the ciliary muscle, which would account for their elongated orientation. Their impact on melanin distribution in RPE cells was unexpected and unusual, implying that they release a signal that influences melanin organisation. PMID- 22426948 TI - Mooren's ulcer in children. AB - PURPOSE: To describe the epidemiology, clinical features, management and outcomes of paediatric Mooren's peripheral ulcerative keratitis. METHODS: All patients with Mooren's ulcer aged < 18 years presenting at a single centre from 1987 to 2010 were enrolled. Epidemiological features, symptomatology, clinical signs, disease severity, investigations, treatment, outcomes and complications were studied. Main outcome measures were anatomical and functional outcomes, disease activity and complications. RESULTS: 14 eyes of 11 children (seven males and four females with an average age of 12.45 +/- 2.25 years at presentation) with Mooren's ulcer were included. Eight cases were unilateral and three bilateral. Symptoms at presentation were more severe than in adults. Trauma was the commonest predisposing factor. Eight eyes had severe corneal involvement. Medical management included intensive topical steroid therapy, oral steroid therapy and immunosuppressant agents. Surgical therapy included tissue adhesive and bandage contact lens application, amniotic membrane transplantation, optical penetrating keratoplasty and limbal stem cell transplantation and was performed in most eyes as part of primary management or later during the disease course. Patients were followed up for a mean of 69.1 weeks. Ten eyes healed successfully and one developed descemetocele. Three eyes developed secondary infections, one of which ultimately became phthisical. In most eyes, final vision either remained stable or was better than at presentation. CONCLUSIONS: Our data suggest demographic and clinical features of Mooren's ulcer in children differ from those in adults. Good anatomical results and stable visual results can be achieved with appropriate medical and surgical therapies. Systemic steroids and immunosuppression should be used judiciously with close monitoring. PMID- 22426949 TI - Deep anterior lamellar keratoplasty using an original manual technique. AB - AIMS: To evaluate the clinical findings and visual outcomes of deep anterior lamellar keratoplasty (DALK) using an original manual dissection technique. METHODS: 288 eyes (268 patients) with corneal pathologies without endothelial involvement were treated by DALK using an original manual dissection technique guided by a calibrated knife incision based on ultrasonic pachimetry values. Clinical records were examined retrospectively at 2 months, 6 months, 1 year and 2 years. The following outcomes were measured: visual acuity, topographic parameters, endothelial cell density and recipient stromal residue thickness. RESULTS: At the 2-year postoperative follow-up, the mean logarithm of the minimum angle of resolution best spectacle corrected visual acuity (BSCVA) was 0.131+/ 0.087 and topographic astigmatism was 2.87+/-1.57 diopters. In 12 cases (4.2%) a perforation of Descemet's membrane required conversion of the procedure to penetrating keratoplasty. Mean optical coherence tomography (OCT) residue thickness (measured in 82 eyes with OCT Visante) was 31.63+/-24.57 MUm; lower values of recipient residue thickness were significantly associated with higher BSCVA (Spearman coefficient 0.635, p< 0.001). CONCLUSION: DALK using a dry manual dissection technique provides visual, refractive and clinical results comparable to other deep lamellar techniques. Eyes with lower values of recipient residue thickness are associated with better visual acuity. PMID- 22426950 TI - ERG monitoring of retinal function during systemic chemotherapy for retinoblastoma. AB - BACKGROUND/AIMS: We have previously introduced electroretinography (ERG) as a proxy for visual function to monitor for retinal toxicity due to intra-arterial chemotherapy for retinoblastoma in young children. In this paper, we report ERG results for patients with retinoblastoma receiving initial treatment with systemic chemotherapy. METHODS: Inclusion criteria were patients presenting with retinoblastoma at <3 months of age or <6.0 kg in weight, with large tumours not amenable to local laser treatment, cryotherapy or plaque brachytherapy. Patients received intravenous carboplatin 18.7 mg/kg every 3-5 weeks, contingent on recovery of blood counts, until they had grown sufficiently to receive intra arterial chemotherapy. ERG was performed during examination under anaesthesia at monthly intervals, using contact lens electrodes and a hand-held ganzfeld stimulator. 30-Hertz flicker responses are reported. RESULTS: Four patients were treated for bilateral retinoblastoma. All eyes responded well to systemic chemotherapy. 30-Hertz flicker ERGs improved during treatment in all eyes, significantly in six of eight eyes, and at least in one eye of each patient. CONCLUSION: Effective systemic chemotherapy for retinoblastoma in children who are too small for intra-arterial chemotherapy is compatible with significant increases in ERG amplitudes, even in eyes presenting with extinguished ERGs. ERG signals may increase independent of resolution of retinal detachment. PMID- 22426951 TI - Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients. AB - In female nursing home patients, homoarginine was associated with lower bone turnover, higher bone density, lower mortality and, by trend, with muscle strength. INTRODUCTION: Homoarginine, a cationic amino acid, may be relevant for muscusloskeletal health because it inhibits alkaline phosphatases (AP) and is involved in nitric oxide and energy metabolism. We aimed to evaluate whether homoarginine serum concentrations are associated with bone density and metabolism, muscle strength, fractures and mortality. METHODS: We examined a cohort of female nursing home patients that underwent quantitative bone ultrasound (QUS) measurements and assessments of knee extensor strength. Measurements of serum homoarginine, C-terminal telopeptide cross-links (beta CTxs) and osteocalcin were also performed at baseline. Thereafter, patients were followed-up with respect to fractures and mortality. RESULTS: Serum homoarginine concentrations were determined in 506 female study participants (mean age: 83.9 +/- 6.0 years). Homoarginine was inversely correlated with beta-CTxs (r = -0.26; p < 0.001) and osteocalcin (r = -0.21; p < 0.001), and these associations remained significant in multiple regression analyses. Multivariate regression analyses showed that homoarginine is significantly associated with calcaneus stiffness (beta coefficient = 0.11; p = 0.020) and by trend with knee extensor strength (beta coefficient = 0.09; p = 0.065). During a mean follow-up time of 27 +/- 8 months, we recorded 119 deaths (23.5%) and 63 fractures (12.5%). In multivariate analyses, homoarginine was associated with significantly reduced risk of mortality and the combined endpoint of fractures and mortality. CONCLUSIONS: Whether homoarginine metabolism is critically involved into the pathogenesis of musculoskeletal diseases and fatal events warrants further studies. PMID- 22426952 TI - Effects of morning vs. evening teriparatide injection on bone mineral density and bone turnover markers in postmenopausal osteoporosis. AB - A 12-month morning teriparatide (TPTD) administration resulted in a larger increase in the lumbar spine bone mineral density (BMD) than the evening application. The results indicate that the response of bone cells to teriparatide treatment depends on dosing time. INTRODUCTION: The aim of this study was to assess the long-term effects of the morning vs. the evening teriparatide administration on BMD and bone turnover markers (BTMs) in postmenopausal osteoporosis. METHODS: Fifty women with established postmenopausal osteoporosis were randomized to 12-month treatment with 20 MUg of TPTD, administered daily in the morning or in the evening. The BMD and serum concentrations of C-terminal telopeptide of type I collagen, N-terminal propeptide of type I procollagen (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) were measured at baseline, after 6 and 12 months. General linear model-repeated measurements were used to analyze the data. RESULTS: After 12 months, the lumbar spine BMD grew markedly (p < 0.001) with a significantly greater increase in the morning arm compared to the evening arm (9.1% vs. 4.8%, respectively, p < 0.05). The BMD at the distal radius significantly decreased (p < 0.001), with no differences between the arms. The BMD at proximal femur did not change significantly. After 6 months, the BTMs were significantly increased compared with baseline (p < 0.001). The increases in the evening arm vs. the morning arm, however, were more pronounced in PINP (+358% vs. +215%, respectively) and in TRAP 5b (+70% vs. +37%, respectively) (both p < 0.05). CONCLUSION: 12-month morning administration of TPTD resulted in a larger increase in the lumbar spine BMD than the evening application. The timing of TPTD administration may be important for its efficacy. PMID- 22426953 TI - Can one or two high doses of oral vitamin D3 correct insufficiency in a non supplemented rheumatologic population? AB - SUMMARY: We evaluated the effectiveness of supplementation with high dose of oral vitamin D3 to correct vitamin D insufficiency. We have shown that one or two oral bolus of 300,000 IU of vitamin D3 can correct vitamin D insufficiency in 50% of patients and that the patients who benefited more from supplementation were those with the lowest baseline levels. INTRODUCTION: Adherence with daily oral supplements of vitamin D3 is suboptimal. We evaluated the effectiveness of a single high dose of oral vitamin D3 (300,000 IU) to correct vitamin D insufficiency in a rheumatologic population. METHODS: Over 1 month, 292 patients had levels of 25-OH vitamin D determined. Results were classified as: deficiency <10 ng/ml, insufficiency >=10 to 30 ng/ml, and normal >=30 ng/ml. We added a category using the IOM recommended cut-off of 20 ng/ml. Patients with deficient or normal levels were excluded, as well as patients already supplemented with vitamin D3. Selected patients (141) with vitamin D insufficiency (18.5 ng/ml (10.2-29.1) received a prescription for 300,000 IU of oral vitamin D3 and were asked to return after 3 (M3) and 6 months (M6). Patients still insufficient at M3 received a second prescription for 300,000 IU of oral vitamin D3. Relation between changes in 25-OH vitamin D between M3 and M0 and baseline values were assessed. RESULTS: Patients (124) had a blood test at M3. Two (2%) had deficiency (8.1 ng/ml (7.5-8.7)) and 50 (40%) normal results (36.7 ng/ml (30.5-5.5)). Seventy-two (58%) were insufficient (23.6 ng/ml (13.8-29.8)) and received a second prescription for 300,000 IU of oral vitamin D3. Of the 50/124 patients who had normal results at M3 and did not receive a second prescription, 36 (72%) had a test at M6. Seventeen (47%) had normal results (34.8 ng/ml (30.3-42.8)) and 19 (53%) were insufficient (25.6 ng/ml (15.2-29.9)). Of the 72/124 patients who receive a second prescription, 54 (75%) had a test at M6. Twenty-eight (52%) had insufficiency (23.2 ng/ml (12.8-28.7)) and 26 (48%) had normal results (33.8 ng/ml (30.0-43.7)). At M3, 84% patients achieved a 25-OH vitamin D level >20 ng/ml. The lowest the baseline value, the highest the change after 3 months (negative relation with a correlation coefficient r = -0.3, p = 0.0007). CONCLUSIONS: We have shown that one or two oral bolus of 300,000 IU of vitamin D3 can correct vitamin D insufficiency in 50% of patients. PMID- 22426954 TI - Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3+ regulatory T-cell responses in mice. AB - Crohn's disease (CD) is characterized by the activation of Th1 and Th17 cells and deficiency of regulatory T cells (Tregs), leading to intestine tissue injury and destruction. As a novel cytokine of the interleukin (IL)-1 family, the role and underlying mechanisms of IL-33 in CD remain poorly understood. Here, we assess the effects and mechanisms of IL-33 on the trinitrobenzene sulfonic acid (TNBS) induced experimental colitis that mimics human CD. We found that IL-33 levels were increased in the TNBS-treated mice, whereas recombinant IL-33 (rIL-33) administration substantially ameliorated TNBS-mediated colonic tissue injury and clinical symptoms of colitis. The protective effect of rIL-33 was partly associated with the markedly increased induction of Th2-type cytokines. Importantly, rIL-33 treatment resulted in prominently upregulated Foxp3 expression in the TNBS-treated mice, and depletion of Tregs significantly abrogated the impact of IL-33 on reducing the development of colitis. Notably, the level of CD103+ dendritic cells (DCs), which promotes development of Tregs, is also increased in mesenteric lymph node and lamina propria of rIL-33-treated mice. The impact of rIL-33 on CD103+ DC induction was the result of indirectly upregulating intestine epithelial cells that produce thymic stromal lymphopoietin and retinoic acid but do not directly act on DCs. In conclusion, our data provide clear evidence that IL-33 plays a protective role in TNBS-induced colitis, which is closely related to a Th1-to-Th2/Treg switch. Thus, IL-33 is a promising candidate for the development of new treatments for CD. PMID- 22426955 TI - Synthesis of CuO nanowalnuts and nanoribbons from aqueous solution and their catalytic and electrochemical properties. AB - One dimensional copper hydroxide nanostrands, two dimensional Cu(2)(OH)(3)NO(3) nanoribbons and three dimensional CuO nanowalnuts were synthesized from the same diluted copper nitrate solution with ethanolamine at room temperature and 10 degrees C, respectively. The Cu(2)(OH)(3)NO(3) nanoribbons were formed by slowly hydrolyzing ethanolamine at low temperature. The CuO nanowalnuts were formed through dehydration of copper hydroxide nanostrands in aqueous solution at room temperature. Although their average size is about 500 nm, the specific surface area of the CuO nanowalnuts can be as large as 61.24 m(2) g(-1), due to their particular morphology with assembling of 8 nm grains. The Cu(2)(OH)(3)NO(3) nanoribbons were converted to CuO porous nanoribbons, keeping the shape. The catalytic performance of the CuO nanowalnuts for CO oxidation is 160 mL h(-1) g(cat)(-1) which is 23 times higher than those of the CuO porous nanoribbons and 40 nm commercial CuO nanoparticles, respectively. The electrochemical properties of the CuO nanowalnuts were also examined in a lithium-ion battery. After 30 cycles, the capacity of the as-prepared CuO nanowalnuts could sustain 67.1% (407 mA h g(-1)) of the second cycle (607 mA h g(-1)) at a rate of 0.1 C. PMID- 22426956 TI - BRAF(V600E) mutation in Turkish patients with papillary thyroid cancer: strong correlation with indicators of tumor aggressiveness. AB - Papillary thyroid cancer (PTC) constitutes more than 90% of the thyroid cancers. MAP kinase/ERK pathway plays an important role in the development of several cancers. BRAF which is a member of Raf-kinase family activates this way. BRAF gene activating mutations lead to neoplastic transformation in thyroid follicle cells. In PTC, this mutation itself is a poor prognostic sign independent of other clinicopathological characteristics. We evaluated BRAF(V600E) mutation and clinical-pathological characteristics in Turkish population with PTC. We assessed 109 patients with PTC (88 female, 21 male). The average age was 38.7 +/- 9.9 (17 71). BRAF(V600E) mutation was detected using polymerase chain reaction and fluorescent melting curve analysis. The results show that BRAF(V600E) mutation rate was found in 39.45% of our patients. We observed that BRAF(V600E) mutation was significantly higher in men, in tumors larger than 1 cm in size, and in patients with classical PTC. Moreover, statistically significant correlations of BRAF(V600E) with indicators of tumor aggressiveness such as thyroid capsular invasion, multifocality, lymph node metastasis, and extrathyroidal spread were found. Patient groups below and over the age of 45 did not differ in mutation frequency. Patients with micro-PTC were evaluated separately, it was found that BRAF(V600E) mutation was more frequent in the classic type and that lymph node metastasis rate significantly increased when the mutation was present. We concluded that BRAF(V600E) was correlated with indicators of tumor aggressiveness in our study population. This fact is taken into consideration in treatment and follow-up of our patients with PTC and positive BRAF(V600E) mutation. PMID- 22426957 TI - Synchronous thyroid and gastric diffuse large B-cell lymphoma. PMID- 22426958 TI - Pituitary autoimmune disease: nuances in clinical presentation. AB - Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH. PMID- 22426959 TI - The bodies fight against cancer: is human leucocyte antigen (HLA) class 1 the key? AB - INTRODUCTION: Loss of human leucocyte antigen (HLA) class I expression has been implicated in tumour progression and metastasis; however, studies reporting its relationship with long-term survival are few in number with conflicting reports. The aim of this review was to assess the prognostic value of HLA class I expression in gastrointestinal cancer. METHODS: Major electronic databases, including Medline, Embase, Cochrane Library and Pubmed were searched for original studies. Two independent reviewers assessed each study against inclusion and exclusion criteria. All data were specific to gastrointestinal cancer surgery. RESULTS: Fourteen original studies were included in this present review. In oesophageal cancer, reduced expression of HLA-A, HLA-B, HLA-C and HLA-G were associated with poorer survival. However, in gastric and colorectal cancer, the prognostic value of HLA-A, HLA-B, HLA-C and HLA-G remains conflicting. Antibody use and reporting methodology was different between all 14 studies examined. CONCLUSION: Variability in antibody use makes it difficult to validate HLA class I expression as an independent prognostic marker in GI cancer. Consensus guidelines, incorporating heavy and light chain antibodies, are required with further studies on HLA class I expression being performed to validate its prognostic value. PMID- 22426960 TI - Survivin inhibition by an interacting recombinant peptide, derived from the human ferritin heavy chain, impedes tumor cell growth. AB - BACKGROUND: Proteins involved in the aberrant regulation of signaling pathways and their downstream effectors are promising targets for cancer therapy. Survivin is an anti-apoptotic and cell cycle-promoting protein, which is consistently overexpressed in cancer cells. In normal cells, its expression is tightly controlled by signaling pathways and their associated transcriptional activators and repressors. In cancer cells, its expression is enhanced as a consequence of oncogenic signaling. We investigated the potential of a novel, peptide-based survivin inhibitor in breast cancer (SK-BR-3, MDA-MB-468) and glioblastoma (Tu9648) cells. These cells express high levels of survivin. MATERIALS AND METHODS: We downregulated survivin expression in tumor cells with a lentiviral gene transfer vector encoding a specific shRNA and a recombinant fusion protein, rSip, comprising the FTH1-derived survivin interaction domain, the human thioredoxin and a protein transduction domain. RESULTS: Downregulation of survivin expression decreased the growth and viability of tumor cells in culture and reduced growth of the cancer cells upon transplantation into immunodeficient mice. rSip selectively targets the anti-apoptotic function of survivin and causes tumor cell death. Non-transformed NIH/3T3 and MCF10A cells remain unaffected. CONCLUSIONS: rSip provides a lead structure for the development of drugs targeting the tumor cell "addiction protein" survivin. PMID- 22426962 TI - Free surface flow between two horizontal concentric cylinders. AB - Results are reported on a combined experimental and numerical investigation of a free surface flow at small Reynolds numbers. The flow is driven by the rotation of the inner of two horizontal concentric cylinders, with an inner to outer radius ratio of 0.43. The outer cylinder is stationary. The annular gap is partially filled, from 0.5 to 0.95 full, with a viscous liquid leaving a free surface. When the fraction of the annular volume filled by liquid is 0.5, a thin liquid film covers the rotating inner cylinder and reenters the liquid pool. For relatively low rotation speeds, the evolution of the film thickness is consistent with the theory for a plate being withdrawn from an infinite liquid pool. The overall liquid flow pattern at this condition consists of two counter-rotating cells: one is around the inner cylinder and the other with weaker circulation rate is in the bottom part of the annulus and nearly symmetric about the vertical axis. With increasing rotation rate, the free surface becomes more deformed, and the dynamics of the stagnation line and the cusp line dividing the cells are tracked as quantitative measures of the interface shape. In addition, the recirculating flow cells lose symmetry and the cusp deforms the free surface severely. A comparison of numerically computed flow which describes the interface by a phase-field method confirms the dynamics of the two cells and the interface deformation. For filling fraction 0.75, the liquid level is slightly above the inner cylinder and a significant decrease in size of the bottom cell with increasing rotation rate is found. For filling fractions approaching unity, the liquid flow consists of one single cell and the surface deformation remains small. PMID- 22426961 TI - Effect of shRNA targeting survivin on ovarian cancer. AB - PURPOSE: This study investigated the effect of shRNA targeting survivin on cultured ovarian cancer cells and on a murine ovarian cancer xenograft. METHODS: An RNAi plasmid for survivin was transfected into SKOV3 cells, and the effect of shRNA targeting survivin on the expression of survivin was determined. Transmission electron microscopy (TEM), flow cytometry, and TUNEL staining were used to assess apoptosis. The MTT assay was used to measure cell growth and changes in cisplatin sensitivity. SKOV3 cells were injected into nude mice, and the effect of shRNA targeting the survivin gene on tumor growth was assessed. RESULTS: SKOV3 cells transfected with an RNAi plasmid against survivin had increased apoptosis and slower growth. At the molecular level, these cells also had lower expression of survivin. Nude mice inoculated with SKOV3 cells developed cancers, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers with no obvious side effects. CONCLUSIONS: Our studies of SKOV3 cells and ovarian cancer xenografts in nude mice indicate that shRNA targeting survivin has potential for the treatment of ovarian cancer. PMID- 22426963 TI - Stress propagation in a concentrated colloidal suspension under shear. AB - The stress propagation in a concentrated attractive colloidal suspension under shear is studied using numerical simulations. The spatial correlations of the intercolloidal stress field are studied and an inertia-like tensor is defined in order to characterize the anisotropic nature of the stress field. It is shown that the colloids remain in a liquid order, the intercolloidal stress is strongly anisotropic. A transition under flow is observed: during a transient regime at low deformation, the stress propagates along the compression direction of the shear, whereas at larger deformations, the stress is organized into layers parallel to the (flow, vorticity) plane. PMID- 22426964 TI - Stability influences the biodistribution, toxicity, and anti-tumor activity of doxorubicin encapsulated in PEG-PE micelles in mice. AB - PURPOSE: To investigate the influences of stability of doxorubicin (DOX) retained in PEG-PE/HSPC micelles on its biodistribution, toxicity and anti-tumor activity in mice. METHODS: We incorporated HSPC into PEG-PE micelles at various molar ratios by a self-assembly procedure. Micelles were characterized by dynamic light scattering, transmission electron microscope, atomic force microscopy. Agarose gel electrophoresis assay was used to detect stable retention of DOX in micellar preparations. Biodistribution, toxicity and anti-tumor activity of doxorubicin encapsulated in PEG-PE/HSPC micelles in mice were investigated. RESULTS: HSPC incorporation not only changed the size and shape of PEG-PE micelles, but also decreased the ability of DOX stable retained in PEG-PE micelles, resulting in a great discrepancy in biodistribution, toxicity and anti-tumor activity among micellar DOX preparations. DOX encapsulated in PEG-PE micelles (M1-DOX), with narrower size distribution and greater stability, demonstrated better cytotoxicity in vitro and low systemic toxicity with superior anti-tumor metastasis activity in vivo. CONCLUSIONS: Encapsulation of DOX into PEG-PE micelles showed the best therapeutic activity and lowest systemic toxicity compared to other HSPC-incorporated PEG-PE micellar preparations. Stable retention of drugs within micelles is important and is determined by compatibility between drugs and polymer blocks. PMID- 22426965 TI - [Establishing an Ambulatory Health-Care Centre (AHCC) at a University Hospital]. AB - BACKGROUND: Since January 2004 hospitals have the opportunity to establish an ambulatory health-care centre (Medizinisches Versorgungszentrum - MVZ) as a result of the introduction of the Health-care Modernisation Act (Gesetz zur Modernisierung der gesetzlichen Krankenversicherung - GMG). After about a half year preparatory phase, the UKE, in September 2004, began operation of the "Ambulanzzentrum des UKE GmbH" (a limited liability company) as the first MVZ at a university hospital in Germany. We report here on the establishment of the MVZ and the experience made. MATERIALS AND METHODS: In the initial phase, only the medical fields of radiation therapy and nuclear medicine were represented. Both disciplines, especially radiation therapy, were existentially threatened by the extensive loss of ambulatory patients. The central motive for the establishment of the ambulatory health-care centre was to secure the survival of both disciplines and to preserve existing jobs. After it was put into operation, the referrals from practice-based colleagues to both radiation therapy and nuclear medicine increased quickly. The positive developments caused other departments of the UKE to express their interest in supplementing their outpatient activities with facilities in the MVZ. RESULTS: Over the following years, the ambulance centre grew steadily. Now 24 departments are represented in the MVZ, and the centre has a total of 49 positions for physicians contracted by and registered within the German public health insurance system. The number of salaried doctors has risen to 85, although many of these only work part time in the MVZ. Also more than 83 non-medical staff members were hired over the years. These were mostly physiotherapists, radiographers, and medical assistants. With the growing number of departments in the MVZ, the number of treated cases grew steadily. Currently approximately 20 000 cases are treated in each quarter of a year. CONCLUSIONS: The experience made while establishing an ambulatory health-care centre is very positive. Better cross-sectoral medicine, support of referring practice-based colleagues, content of centre-physicians and a strengthening of research and teaching summarise the experience of the last 7 years accurately. The outpatient centre of UKE GmbH will strive to continue to expand its range of medical services into other medical fields whenever it makes sense. PMID- 22426966 TI - [Disease-adapted closure of the appendicular stump in laparoscopic appendectomy]. AB - The frequency of laparoscopic appendectomy has dramatically increased with it now being the standard procedure for acute appendicitis in many hospitals in Germany. Hence, these hospitals require the personnel, the technique as well as the expertise to guarantee a top standard and quality of appendectomies at all times. Only this will meet the requirements of the high case load and the socio economical importance of appendectomies. The closure of the appendicular stump is a critical step of this procedure. The three most commonly used techniques consist of the endo-loop, the clip and the endo-stapler. The endo-stapler has the advantage of offering closure and transection of the appendix in one step; it can be employed in all cases of appendicular inflammation; and it allows a partial caecal resection. However, it is quite expensive. The clip and the endo-loop offer the same cost-effectiveness, yet the clip appears to be simpler in use compared to the loop. Also, sharing this feature with the stapler, it offers the possibility of closing and transecting the appendix before dissecting the mesoappendix. A disadvantage of the clip not being shared with the loop is the limitation of clips to appendicular diameters of only up to 16 mm. In summary, we propose a cost-effective disease-adapted closure of the appendicular stump employing the clip in standard appendectomies, with the endo-loop being a good alternative. If clip or loop cannot be applied the stapler is the technique of choice. In particular, it should be used if the base of the appendix is inflamed. Adopting this pathway helps to control the still somewhat higher costs of laparoscopic appendectomies compared to classical open appendectomies. PMID- 22426967 TI - [Second primary malignancy among cancer survivors - epidemiology, prognosis and clinical relevance]. AB - BACKGROUND: Rising population age and advances in treatment with improved survival from cancer have led to more frequent survivors of cancer treatment and subsequently to more patients with a second primary tumour. The consequences are presented in this overview. METHOD: For the literature review, the Medline database (PubMed) was searched under the key words "multiple primary malignant tumors" and "(Neoplasms, second primary) AND "Neoplasms, Second Primary"[Mesh]". Primarily, publications in the last 7 years (2005 - 2011) were sought. RESULTS: The prevalence of patients with second primary cancer is reported in various cancer registries with 6.6 % to 9 %. Here, the risk of developing new primary cancer in cancer survivors, depending on age, compared to the general population is increased at least by 20 %. Among childhood cancer survivors, the risk was even 3 - to 6-times higher than would have been expected in the general population. The incidence of second malignant neoplasms is crucially dependent on the prognosis of the first tumour. Fifteen years after initial diagnosis, in patients with prognostically unfavourable tumours such as pancreatic or gastric carcinoma, second primary malignancies are detected in less than 5 %. However, the cumulative incidence of all second cancers combined is approximately 15 % at 25 years in patients with colorectal or thyroid cancer. CONCLUSION: Implications from these data arise for primary diagnostics which must look at cancers with frequent synchronous second malignancies for respective tumours before treatment. Examples are synchronous colorectal lesions in patients with colorectal carcinoma or synchronous cancers of the oral cavity and pharynx in patients with oesophageal carcinoma. Another consequence is a targeted follow-up of corresponding risk populations. This includes the screening for metachronous colorectal cancer, the exclusion of gastrointestinal second malignancies in patients with GIST, or the breast cancer screening in young female thyroid cancer survivors. Since radiotherapy increases the rate of second primary neoplasms, adjuvant radiotherapy should be well justified. Nevertheless, this is true only for young patients, mainly in childhood. The risk of a second cancer after irradiation in adults is small. PMID- 22426968 TI - [Acute appendicitis - clinical health-service research on the current surgical therapy]. AB - INTRODUCTION: With about 135,000 operations every year appendectomy is one of the most frequent surgical operations in Germany. Acute appendicitis has shown changes in diagnosis and therapy with time. The status of the laparoscopic appendectomy has had to be redefined recently. The aim of this study was to make an analysis of the current surgical therapy for appendicitis and the individual procedures. PATIENTS AND METHODS: Three prospective multi-centre quality assurance studies (1988 / 89, 1996 / 97; 2008 / 09) of the "An-Institut" acquired 17,732 treatments from all supply levels of Germany. RESULTS: The average age of patients increased within of the three studies from 25.7 to 34.6 years. Within the studies in 1996 / 97 and in 2008 / 09 the share of laparoscopic appendectomy advanced from 33.1 to 85.8 percent. In the study from 2008 / 09 the laparoscopic appendectomy showed a significant advantage over the conventional technique in terms of wound-healing disturbances (p < 0.001) and a clinical duration of stay (p < 0.001). At no stage of the appendix inflammation did the laparoscopic appendectomy lead to a significant increase of intraabdominal abscesses. Compared with the conventional technique the operating time was shorter (46.6 min vs. 53.5 min). Currently the use of a stapler is the mostly frequently applied method of appendiceal stump closure (83.6 percent). CONCLUSION: The laparoscopic appendectomy is the most common method of current operative therapy. In comparison to former publications, there is no proof of any disadvantages of laparoscopic appendectomy. PMID- 22426969 TI - [Beyond the horizon of health-care delivery - medical marketing]. AB - BACKGROUND: The progress in medical health care and demographic changes cause increasing financial expenses. The rising competitive environment on health-care delivery level calls for economisation and implementation of a professional marketing set-up in order to ensure long-term commercial success. METHODS: The survey is based on a questionnaire-analysis of 100 patients admitted to a trauma department at a university hospital in Germany. Patients were admitted either for emergency treatment or planned surgical procedures. RESULTS: Competence and localisation represent basic criteria determing hospital choice with a varying focus in each collective. Both collectives realise a trend toward economisation, possibly influencing medical care decision-making. Patients admitted for planned surgical treatment are well informed about their disease, treatment options and specialised centres. The main source of information is the internet. Both collectives claim amenities during their in-hospital stay. CONCLUSION: Increasing economisation trends call for a sound and distinct marketing strategy. The marketing has to be focused on the stakeholders needs. Concomitant factors are patient satisfaction, the establishment of cooperation networks and maintenance/improvement of medical health-care quality. PMID- 22426970 TI - [Single-port access cholecystectomy is a safe alternative to conventional laparoscopic cholecystectomy: a retrospective comparison of single-port access versus standard laparoscopic cholecystectomy]. AB - PURPOSE: As laparoscopic surgery develops, one current goal is the reduction of scarring and operative trauma to a minimum. Single-port access surgery (SPA) uses a single small incision hidden in the umbilicus. This report describes our experiences with 69 SPA cholecystectomies compared to the conventional laparoscopic approach. METHODS: Within two years 69 SPA cholecystectomies were performed. Data including demographic distribution, incision to closure time, duration of the postoperative hospital stay, rates of intraoperative and postoperative complications, and conversion rates were collected retrospectively. Data for a matched control group treated by standard laparoscopic cholecystectomy were gathered within the same time frame and then compared. RESULTS: There were no significant differences in the rates of intraoperative or postoperative complications in the SPA group when compared to the standard laparoscopy group. The incision-to-closure time strongly depended on the surgeon but did not depend on the method. The duration of postoperative hospital stay was slightly decreased in the SPA group. However, this effect was statistically not significant. CONCLUSIONS: For selected patient groups, SPA cholecystectomy is on par with the conventional laparoscopic method. The cosmetic advantage that it offers does not come at the cost of any loss of safety. PMID- 22426971 TI - Validity of the Problem Gambling Severity Index interpretive categories. AB - The Problem Gambling Severity Index (PGSI) is a widely used nine item scale for measuring the severity of gambling problems in the general population. Of the four gambler types defined by the PGSI, non-problem, low-risk, moderate-risk and problem gamblers, only the latter category underwent any validity testing during the scale's development, despite the fact that over 95% of gamblers fall into one of the remaining three categories. Using Canadian population data on over 25,000 gamblers, we conducted a comprehensive validity and reliability analysis of the four PGSI gambler types. The temporal stability of PGSI subtype over a 14-month interval was modest but adequate (intraclass correlation coefficient = 0.63). There was strong evidence for the validity of the non-problem and problem gambler categories however the low-risk and moderate-risk categories showed poor discriminant validity using the existing scoring rules. The validity of these categories was improved with a simple modification to the scoring system. PMID- 22426972 TI - Anti-HuC and -HuD autoantibodies are differential sero-diagnostic markers for small cell carcinoma from large cell neuroendocrine carcinoma of the lung. AB - Aiming to identify novel sero-diagnostic markers for neuroendocrine carcinomas of the lung, the two-dimensional gel electrophoresis-immunoblot method was used to analyze tumor-associated autoantibodies in patients with small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Several autoantigens were revealed and anti-HuC autoantibody was detected only in sera of SCLC patients. Since Hu family proteins including HuC are well-known causes of paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/SN), the expression of HuC as well as HuD mRNAs and their proteins was studied in 11 lung cancer cell lines. The expression of HuC and HuD mRNAs and proteins was only detected in SCLC and LCNEC-derived cells. To validate the existence of anti-HuC and -HuD auto antibodies, we studied a large number of sera including those from lung cancer patients employing dot blot analysis. Anti-HuC and -HuD autoantibodies were detected only in SCLC cases with or without PEM/SN, and not in the sera of LCNEC patients. The mechanism leading to different anti-HuC and -HuD autoantibody production between SCLC and LCNEC is unclear; however, the results from the present and previous studies suggest that anti-HuC and -HuD auto-antibodies are novel differential sero-diagnostic markers for SCLC from LCNEC. PMID- 22426973 TI - Renal dysfunction in acute and chronic heart failure: prevalence, incidence and prognosis. AB - Most patients with heart failure have mild or moderate renal dysfunction. This reflects the combined impact of chronic renal parenchymal disease, renal artery disease, renal congestion and hypoperfusion, neuroendocrine and cytokine activation and the effects of treatments for heart failure. Remarkably, with good treatment, the average annual rate of decline in renal function is similar in patients with chronic heart failure and healthy people of a similar age. Urea appears to be a stronger marker of an adverse prognosis than creatinine-based measures of renal function. Recent evidence suggests that minor, transient increases in creatinine in the setting of acute heart failure are not prognostically important but persistent deterioration does indicate a higher mortality. The poor prognosis of patients with worsening renal function ensures that few require renal dialysis but this may change as methods to prevent sudden death improve and new ways are found to control fluid congestion. Reversing renal dysfunction and stopping its progression remain important targets for treatment of heart failure. PMID- 22426974 TI - Effects of ionizing radiation and preservation on biomechanical properties of human costal cartilage. AB - Tissue banks around the world store human cartilage obtained from cadaveric donors for use in diverse reconstructive surgical procedures. To ensure this tissue is sterile at the time of distribution, tissues may be sterilized by ionizing radiation. In this work, we evaluate the physical changes in deep frozen costal cartilage (-70 degrees C) or costal cartilage preserved in high concentrations of glycerol (>98 %) followed by a terminal sterilization process using ionizing radiation, at 3 different doses (15, 25 and 50 kGy). Tension and compression tests were carried out to determine the mechanical changes related both to the different preservation methods and irradiation doses. For both methods of preservation, tension strength was increased by about 24 %, when cartilage tissue was irradiated with 15 kGy. Deep frozen samples, when irradiated with 25 or 50 kGy, had a decrease in their mechanical performance, albeit to a lesser extent than when tissues were preserved in high concentration of glycerol and equally irradiated. In conclusion, processing in high concentration of glycerol did not increase tissue protection against radiation damage; while cartilage preserved in high concentrations of glycerol withstands radiation up to 25 kGy, deep frozen human costal cartilage may be sterilized with a doses up to 50 kGy without significant mechanical impact. PMID- 22426975 TI - The timing of implantable cardioverter-defibrillator implantation in patients with heart failure. AB - Patients who survive a myocardial infarction (MI) are at increased risk of sudden death due to fatal ventricular arrhythmias. Implantable cardioverter defibrillators (ICDs) reduce mortality in appropriately selected patients with heart failure and left ventricular dysfunction, regardless of etiology. Post hoc analyses from landmark trials have evaluated the effect of time (both since MI and duration of nonischemic cardiomyopathy) before ICD implantation on the efficacy of ICD therapy. Time remains a clinically important variable in the decision of if and when to implant an ICD. Future trials should focus on invasive and/or noninvasive risk stratification of patients with ischemic and nonischemic cardiomyopathy for better identification of those who would benefit from early ICD implantation, and those in whom a watch and wait approach is appropriate. PMID- 22426976 TI - Emerging technology of in situ cell free expression protein microarrays. AB - Recently, in situ protein microarrays have been developed for large scale analysis and high throughput studies of proteins. In situ protein microarrays produce proteins directly on the solid surface from pre-arrayed DNA or RNA. The advances in in situ protein microarrays are exemplified by the ease of cDNA cloning and cell free protein expression. These technologies can evaluate, validate and monitor protein in a cost effective manner and address the issue of a high quality protein supply to use in the array. Here we review the importance of recently employed methods: PISA (protein in situ array), DAPA (DNA array to protein array), NAPPA (nucleic acid programmable protein array) and TUSTER microarrays and the role of these methods in proteomics. PMID- 22426977 TI - China connection of the Arnold Arboretum of Harvard University. PMID- 22426978 TI - Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. AB - The inflammasome is an emerging new pathway in innate immune defense against microbial infection or endogenous danger signals. The inflammasome stimulates activation of inflammatory caspases, mainly caspase-1. Caspase-1 activation is responsible for processing and secretion of IL-1beta and IL-18 as well as for inducing macrophage pyroptotic death. Assembly of the large cytoplasmic inflammasome complex is thought to be mediated by members of NOD-like receptor (NLR) family. While functions of most of the NLR proteins remain to be defined, several NLR proteins including NLRC4 have been shown to assemble distinct inflammasome complexes. These inflammasome pathways, particularly the NLRC4 inflammasome, play a critical role in sensing and restricting diverse types of bacterial infections. Here we review recent advances in defining the exact bacterial ligands and the ligand-binding receptors involved in NLRC4 inflammasome activation. Implications of the discovery of the NAIP family of inflammasome receptors for bacterial flagellin and type III secretion apparatus on future inflammasome and bacterial infection studies are also discussed. PMID- 22426980 TI - Multifaceted functions of Siva-1: more than an Indian God of Destruction. AB - Siva-1, as a p53-inducible gene, has been shown to induce extensive apoptosis in a number of different cell lines. Recent evidence suggests that Siva-1 functions as a part of the auto-regulatory feedback loop that restrains p53 through facilitating Mdm2-mediated p53 degradation. Also, Siva-1 plays an important role in suppressing tumor metastasis. Here we review the current understanding of Siva 1-mediated apoptotic signaling pathway. We also add comments on the p53-Siva-1 feedback loop, the novel function of Siva-1 in suppressing tumor metastasis, and their potential implications. PMID- 22426979 TI - Genomic basis for light control of plant development. AB - Light is one of the key environmental signals regulating plant growth and development. Therefore, understanding the mechanisms by which light controls plant development has long been of great interest to plant biologists. Traditional genetic and molecular approaches have successfully identified key regulatory factors in light signaling, but recent genomic studies have revealed massive reprogramming of plant transcriptomes by light, identified binding sites across the entire genome of several pivotal transcription factors in light signaling, and discovered the involvement of epigenetic regulation in light regulated gene expression. This review summarizes the key genomic work conducted in the last decade which provides new insights into light control of plant development. PMID- 22426981 TI - Crystal structures of D-psicose 3-epimerase from Clostridium cellulolyticum H10 and its complex with ketohexose sugars. AB - D-psicose 3-epimerase (DPEase) is demonstrated to be useful in the bioproduction of D-psicose, a rare hexose sugar, from D-fructose, found plenty in nature. Clostridium cellulolyticum H10 has recently been identified as a DPEase that can epimerize D-fructose to yield D-psicose with a much higher conversion rate when compared with the conventionally used DTEase. In this study, the crystal structure of the C. cellulolyticum DPEase was determined. The enzyme assembles into a tetramer and each subunit shows a (beta/alpha)(8) TIM barrel fold with a Mn(2+) metal ion in the active site. Additional crystal structures of the enzyme in complex with substrates/products (D-psicose, D-fructose, D-tagatose and D sorbose) were also determined. From the complex structures of C. cellulolyticum DPEase with D-psicose and D-fructose, the enzyme has much more interactions with D-psicose than D-fructose by forming more hydrogen bonds between the substrate and the active site residues. Accordingly, based on these ketohexose-bound complex structures, a C3-O3 proton-exchange mechanism for the conversion between D-psicose and D-fructose is proposed here. These results provide a clear idea for the deprotonation/protonation roles of E150 and E244 in catalysis. PMID- 22426982 TI - Study of drug function based on similarity of pathway fingerprint. AB - Drugs sharing similar therapeutic function may not bind to the same group of targets. However, their targets may be involved in similar pathway profiles which are associated with certain pathological process. In this study, pathway fingerprint was introduced to indicate the profile of significant pathways being influenced by the targets of drugs. Then drug-drug network was further constructed based on significant similarity of pathway fingerprints. In this way, the functions of a drug may be hinted by the enriched therapeutic functions of its neighboring drugs. In the test of 911 FDA approved drugs with more than one known target, 471 drugs could be connected into networks. 760 significant associations of drug-therapeutic function were generated, among which around 60% of them were supported by scientific literatures or ATC codes of drug functional classification. Therefore, pathway fingerprints may be useful to further study on the potential function of known drugs, or the unknown function of new drugs. PMID- 22426983 TI - CloudLCA: finding the lowest common ancestor in metagenome analysis using cloud computing. AB - Estimating taxonomic content constitutes a key problem in metagenomic sequencing data analysis. However, extracting such content from high-throughput data of next generation sequencing is very time-consuming with the currently available software. Here, we present CloudLCA, a parallel LCA algorithm that significantly improves the efficiency of determining taxonomic composition in metagenomic data analysis. Results show that CloudLCA (1) has a running time nearly linear with the increase of dataset magnitude, (2) displays linear speedup as the number of processors grows, especially for large datasets, and (3) reaches a speed of nearly 215 million reads each minute on a cluster with ten thin nodes. In comparison with MEGAN, a well-known metagenome analyzer, the speed of CloudLCA is up to 5 more times faster, and its peak memory usage is approximately 18.5% that of MEGAN, running on a fat node. CloudLCA can be run on one multiprocessor node or a cluster. It is expected to be part of MEGAN to accelerate analyzing reads, with the same output generated as MEGAN, which can be import into MEGAN in a direct way to finish the following analysis. Moreover, CloudLCA is a universal solution for finding the lowest common ancestor, and it can be applied in other fields requiring an LCA algorithm. PMID- 22426985 TI - Histochemical distribution of sialic acids and antimicrobial substances in porcine carpal glands. AB - The localization of sialic acids and antimicrobial products (lysozyme, IgA, lactoferrin, beta-defensin 2) as well as Rab3D in the carpal glands of pig was studied by sialoglycoconjugate histochemistry and immunohistochemistry. The secretory epithelium of the carpal glands consisted of dark and clear cells. The dark cells of these glands exhibited high levels of sialoglycoconjugates, including O-acetylated sialic acids, whereas the localization of sialic acids linked to alpha2-3Gal1-4GlcNAc was confined to a subpopulation of the dark cells. Furthermore, all antimicrobial substances and Rab3D were mainly detectable in a subpopulation of the dark cells. The results obtained are discussed with regard to the functional significance of these glands. Our findings suggested that Rab3D is involved in the secretory regulation of sialoglycoconjugates and antimicrobial substances. These secretory products may create a defensive barrier against microbial invasion and play an essential role in the preservation of skin integrity. PMID- 22426986 TI - Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis. AB - Serum IL-17 levels and IL-17 mRNA expression have been reported to be higher in psoriatic skin than normal skin. There are very limited data in the literature about difference in the levels of this cytokine in various clinical disease subtypes. We aimed to evaluate whether there is a difference in the level of this cytokine according to clinical subtypes of psoriasis. 70 psoriasis patients (30 plaque psoriasis, 20 guttate psoriasis, and 20 pustular psoriasis) and 50 age- and sex-matched healthy volunteers were included in the study. Serum IL-17 levels were determined by ELISA. Skin biopsies obtained from lesions and non-lesional skin area of 12 patients and healthy individuals (n = 5) were analyzed by quantitative PCR (qPCR) to measure the mRNA levels of IL-17. Statistically, the serum IL-17 levels did not exhibit any difference between the patients and control groups. However, analysis of each subgroup revealed that the IL-17 levels were significantly higher in pustular psoriasis group (10.09 +/- 12.6 pg/ml) than controls (4.4 +/- 4.1 pg/ml) (p = 0.02). In addition, the IL-17 levels of plaque psoriasis patients with PASI score >=10 (11.30 +/- 6.0 pg/ml) were significantly higher than that of patients with PASI score <10 (3.39 +/- 2.6 pg/ml) and controls (p < 0.001). The Pearson correlation analysis showed a positive correlation between the serum IL-17 levels and PASI. Lesional skin samples of psoriasis patients showed significantly higher levels of IL-17 mRNA compared with perilesional skin samples (p = 0.017). Also, in the pustular psoriasis, IL-17 mRNA levels were found to be distinctively high in comparison with other clinical subtypes and healthy controls. Our results indicate that IL-17 and Th17 cells have an important role in pustular psoriasis and severe psoriasis. PMID- 22426987 TI - Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors. AB - The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. The presence of certain somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene is associated with clinical response to TK inhibitors (TKI) in patients with lung adenocarcinoma. In this study we evaluated the status of somatic mutations in the entire TK domain of the EGFR gene by direct sequencing using early passage peritoneal mesothelioma cells, established cell lines as well as 33 peritoneal mesothelioma tumor samples. No novel mutations were found in the cell lines. Sequence analysis of the EGFR TK domain revealed the presence of a silent polymorphism (c.2607G -> A, Q787Q) at exon 20 of both peritoneal mesothelioma cell lines as well as tumor specimens. The frequency of genotypes AA and GA was 42.8 and 57.2% in the cell lines and 33.3 and 57.6% in tumor specimens, respectively. The TKI erlotinib showed an IC50 in the range of 10-50 uM in five out of the seven cell lines with a GA genotype while all five cell lines with the AA genotype had an IC50 >50 uM. Of the 33 peritoneal mesothelioma tumor samples analyzed none had an EGFR TKI sensitizing mutation and only one specimen showed an earlier reported somatic mutation at codon 850 in exon 21 of the EGFR gene. Our data show that patients with peritoneal mesothelioma do not harbor somatic mutations in the EGFR TK domain that would make them sensitive to EGFR TKI. PMID- 22426988 TI - Structural and functional insights into the heme-binding domain of the human soluble guanylate cyclase alpha2 subunit and heterodimeric alpha2beta1. AB - Soluble guanylate cyclase (sGC) mediates NO signaling for a wide range of physiological effects in the cardiovascular system and the central nervous system. The alpha1beta1 isoform is ubiquitously distributed in cytosolic fractions of tissues, whereas alpha2beta1 is mainly found in the brain. The major occurrence and the unique characteristic of human sGC alpha2beta1 indicate a special role in the mediation of neuronal communication. We have efficiently purified and characterized the recombinant heme-binding domain of the human sGC alpha2 subunit (hsGC alpha2(H)) and heterodimeric alpha2beta1 (hsGC beta1(H) alpha2(H)) by UV-vis spectroscopy, circular dichrosim spectroscopy, EPR spectroscopy, and homology modeling. The heme dissociation and related NO/CO binding/dissociation of both hsGC alpha2(H) and hsGC beta1(H)-alpha2(H) were investigated. The two truncated proteins interact with heme noncovalently. The CO binding affinity of hsGC alpha2(H) is threefold greater than that of human sGC alpha1(H), whereas the dissociation constant k (1) for dissociation of NO from hsGC alpha2(H) is sevenfold larger than that for dissociation of NO from hsGC alpha1(H), although k (2) is almost identical. The results indicate that in comparison with the alpha1beta1 isoform, the brain alpha2beta1 isoform exhibits a distinctly different CO/NO affinity and binding rate in favor of NO signaling, and this is consistent with its physiological role in the activation and desensitization. Molecular modeling and sequence alignments are consistent with the hypothesis that His105 contributes to the different CO/NO binding properties of different isoforms. This valuable information is helpful to understand the molecular mechanism by which human sGC alpha2beta1 mediates NO/CO signaling. PMID- 22426989 TI - Prevalence of arterial hypertension among Seventh-Day Adventists of the Sao Paulo state capital and inner area. AB - BACKGROUND: Inadequate life habits are known to favor hypertension, and Adventists recommend healthy life habits. OBJECTIVE: To assess the prevalence of hypertension among Seventh-Day Adventists from the inner Sao Paulo state and Sao Paulo state capital. METHODS: This study assessed 264 Adventists (mean age, 41.17 +/- 15.27 years; women, 59.8%) with a high religiosity level assessed by use of the Duke University Religion Index. Blood pressure was measured with a validated automatic device. The significance level adopted was p < 0.05. RESULTS: The total prevalence of hypertension was 22.7% (27.4% in the inner state and 15% in the capital). The Adventists from the capital differed from those of inner state as follows (p < 0.05), respectively: higher education (62% vs 36.6%); employed by a third party (44%) vs self-employed (40.9%); family income (8.39 +/- 6.20 vs 4.59 +/- 4.75 minimum wages); individual income (4.54 +/- 5.34 vs 6.35 +/- 48; couple responsible for family income (35% vs 39.6%); vegetarianism (11% vs 3%); blood pressure (115.38 +/- 16.52/68.74 +/- 8.94 vs 123.66 +/- 19.62/74.88 +/- 11.85 mmHg); white ethnicity (65% vs 81.1%); married (53% vs 68.9%); lower tangible support in the social aspect (15.7 +/- 5.41 vs 16.9 +/- 4.32); and recalling the last time one's blood pressure was measured (65% vs 48.8%). On multivariate analysis, hypertension associated with the following: 1) vegetarianism (OR 0.051; 95% CI: 0.004-0.681); 2) educational level (OR 5.317; 95% CI: 1.674-16.893); 3) recalling the last time one's blood pressure was measured (OR 2.725; 95% CI: 1.275-5.821); 4) being retired (OR 8.846; 95% CI: 1.406-55.668); and 5) being responsible for family income (OR 0.422; 95% CI: 0.189-0.942). CONCLUSION: The prevalence of hypertension among Adventists was lower as compared with that reported in Brazilian studies, and it was lower in the Sao Paulo state capital as compared with that in the inner Sao Paulo state, possibly because of the better socioeconomic conditions and life habits of the former. PMID- 22426990 TI - Development and validation of the Brazilian Portuguese version of the Cardiac Rehabilitation Barriers Scale. AB - BACKGROUND: Cardiovascular diseases show high incidence and prevalence in Brazil; however, participation in Cardiac Rehabilitation (CR) is limited and has been poorly investigated in the country. The Cardiac Rehabilitation Barriers Scale (CRBS) was developed to assess the barriers to participation and adherence to CR. OBJECTIVE: To translate, cross-culturally adapt and psychometrically validate CRBS to Brazilian Portuguese. METHODS: Two independent initial translations were performed. After the reverse translation, both versions were reviewed by a committee. The new version was tested in 173 patients with coronary artery disease (48 women, mean age = 63 years). Of these, 139 (80.3%) participated in CR. Internal consistency was assessed by Cronbach's alpha, test-retest reliability by intraclass correlation coefficient (ICC) and construct validity by factor analysis. T-tests were used to assess criterion validity between participants and non-participants in CR. The applied test results were evaluated regarding patient characteristics (gender, age, health status and educational level). RESULTS: The Brazilian Portuguese version of the CRBS had Cronbach's alpha of 0.88, ICC of 0.68 and disclosed five factors, most of which showed to be internally consistent and all were defined by the items. The mean score for patients in CR was 1.29 (SD = 0.27) and 2.36 for ambulatory patients (SD = 0.50) (p <0.001). Criterion validity was also supported by significant differences in total scores by gender, age and educational level. CONCLUSION: The Brazilian Portuguese version of CRBS has shown adequate validity and reliability, which supports its use in future studies. PMID- 22426991 TI - Dietary variety is a protective factor for elevated systolic blood pressure. AB - BACKGROUND: Diet directly influences systemic arterial hypertension (SAH), which is one of the main risk factors for cardiovascular disease. OBJECTIVE: To associate hypertension with dietary factors in adults clinically selected for a change-of-lifestyle program. METHODS: Cross-sectional study comprising 335 individuals, aged between 44 and 65 years, clinically selected for a change-of lifestyle program. We evaluated anthropometric data (BMI, %body fat and waist circumference), biochemical components (plasma glucose, triglycerides, total cholesterol, HDL-C and LDL-c) and diet, through the 24-hour recall method. The quality of the diet was assessed by the Healthy Eating Index. Blood pressure was measured according to the V Brazilian Guidelines on Hypertension and classified according to NCEP-ATPIII. Logistic regression was performed to determine the likelihood of changes in SBP and DBP according to dietary intake. The level of significance was set at p <0.05. RESULTS: There was a positive correlation between diastolic blood pressure and sugar and cholesterol intake, and a negative one with intake of fiber, portions of oil and fats and diet quality. Dietary variety with >= 8 food items showed a protective effect for alterations in systolic blood pressure, OR = 0.361 (0.148 to 0.878). CONCLUSION: A greater dietary variety had a protective effect on the systolic blood pressure. PMID- 22426992 TI - [Semilunar bone necrosis (Kienbock's disease) - first clinical results after free microvascularised bone graft from the distal femur]. AB - BACKGROUND: Idiopathic aseptic osseous necrosis of the semilunar bone is also called Kienbock's disease after Robert Kienbock who firstly described this disease. The clinical picture is characterised by a stage-like course. Internationally the classification according to Lichtman and Ross has achieved the most acceptance. The actual therapy is dependent on the present disease stage. Basically, various pressure-relieving operative procedures are possible, on the other hand operative interventions via revascularisation represent a therapeutic option. In the case of advanced disease only, "salvage procedures" like partial or total arthrodesis of the wrist are available. However, such operations are associated with marked restrictions in the range of motion and unsatisfactory clinical results. The present study reports on our clinical experiences after operative therapy for aseptic lunar bone necrosis via free microvascularised bone grafting from the distal femur. PATIENTS AND METHODS: Between 01/2005 and 12/2010 nineteen patients with idiopathic semilunar bone necrosis underwent operative care via a free microvascularised bone graft from the distal femur at our institution. 16 patients could be re-evaluated retrospectively on follow-up examination at 26.5 months (range 16-42) on average after primary care. Mean age was 43.8 years (range 24-66). Clinical assessment was performed according to the Mayo wrist score (MWS) and the disabilities of the arm, shoulder and hand (DASH) score. Radiological assessment was performed according to the classification of Lichtman and Ross. RESULTS: On operative treatment 14 patients were graded II at least according to the Lichtman classification. An additional 2 patients showed a stage III B disease. The median operative time amounted to 254 min (range 233-362). The postoperative course did not reveal any complications, in particular concerning wound healing. Only one patient (6 %) showed no trabecular integration between the inserted graft and the lunar bone. Clinical evaluation according to the MWS with a median of 82.5 points (65-100), and the DASH score with a median of 29.5 points (24.2-102.2) documented good to excellent clinical results. CONCLUSION: Operative treatment for idiopathic semilunar bone necrosis via a free microvascularised bone graft from distal femur achieves good clinical results without an increase of postoperative complications even with advanced stages of the disease. However, long-term results and larger patient samples are required to prove the final success of this operative technique. PMID- 22426993 TI - A WEKA interface for fMRI data. PMID- 22426994 TI - A novel group ICA approach based on multi-scale individual component clustering. Application to a large sample of fMRI data. AB - Functional connectivity-based analysis of functional magnetic resonance imaging data (fMRI) is an emerging technique for human brain mapping. One powerful method for the investigation of functional connectivity is independent component analysis (ICA) of concatenated data. However, this research field is evolving toward processing increasingly larger database taking into account inter individual variability. Concatenated data analysis only handles these features using some additional procedures such as bootstrap or including a model of between-subject variability during the preprocessing step of the ICA. In order to alleviate these limitations, we propose a method based on group analysis of individual ICA components, using a multi-scale clustering (MICCA). MICCA start with two steps repeated several times: 1) single subject data ICA followed by 2) clustering of all subject independent components according to a spatial similarity criterion. A final third step consists in selecting reproducible clusters across the repetitions of the two previous steps. The core of the innovation lies in the multi-scale and unsupervised clustering algorithm built as a chain of three processes: robust proto-cluster creation, aggregation of the proto-clusters, and cluster consolidation. We applied MICCA to the analysis of 310 fMRI resting state dataset. MICCA identified 28 resting state brain networks. Overall, the cluster neuroanatomical substrate included 98% of the cerebrum gray matter. MICCA results proved to be reproducible in a random splitting of the data sample and more robust than the classical concatenation method. PMID- 22426995 TI - Awareness, acceptability and uptake of human papilloma virus vaccine among Cameroonian school-attending female adolescents. AB - The purpose of this study is to assess awareness, knowledge and beliefs about HPV, cervical cancer HPV vaccine and willingness to vaccinate among adolescent females aged 12-26 years at clinics and schools in the North West Region of Cameroon where the Cameroon Baptist Convention Health Services (CBCHS) conducted a sensitization and education campaign. A questionnaire survey was administered among female adolescents in schools and clinics. Descriptive statistics including frequencies, percentages and proportions were generated for independent variables and bivariate analyses (Chi square test) were used to assess the relationship between independent and outcome variables. Data were analyzed using SAS Version 9.2. Out of a sample of 650 adolescent girls 553 willingly participated in this anonymous survey. Awareness of HPV (86.8%), cervical cancer (82.3%), and prevention of HPV infections through vaccination (75.9%) was significantly higher than in previous studies conducted in Cameroon and other developing countries. Higher perceptions of risk were associated with being sexually active (p = 0.0013), age (p = 0.0031) and level of education (p = 0.0274). Age and educational level were associated with HPV knowledge (p = 0.007 and p = 0.0008), respectively. The mean level of interest in HPV vaccination was 4.0 (SD = 1.27), which is above the mean. Our data indicate high awareness about HPV, cervical cancer and HPV vaccine among adolescents, and interest in receiving the vaccine and learning about the disease. CBCHS' community education strategy effectively raised acceptability and generated demand for HPV vaccine, making it a potential model for HPV immunization in Cameroon and other developing countries. PMID- 22426996 TI - Study of the regulation of the inotropic response to 5-HT4 receptor activation via phosphodiesterases and its cross-talk with C-type natriuretic peptide in porcine left atrium. AB - We studied how 5-HT(4) receptor-mediated inotropic responses are regulated at the level of cAMP in porcine left atrium. We used selective phosphodiesterase (PDE) inhibitors to assess which PDE subtypes are responsible for the fade with time of inotropic responses to 5-HT(4) receptor activation with 5-HT and the 5-HT(4) receptor agonist prucalopride. A possible cross-talk via PDEs between cGMP and 5 HT(4) receptor-induced cAMP signalling was evaluated. Electrically paced left atrial pectinate muscles from young male pigs (15-25 kg) were studied in vitro. Simultaneous inhibition of PDE3 plus PDE4 subtypes was necessary to increase the amplitude and completely prevent the fade of the inotropic response to 5-HT and prucalopride. When responses to 5-HT or prucalopride had faded 1 h after addition, the nonspecific PDE-inhibitor IBMX still fully recovered inotropic responses. Stimulation of particulate guanylyl cyclase, together with PDE2 and PDE4 inhibition, delayed the fade of the response to 5-HT, while stimulation of soluble guanylyl cyclase independently of PDEs accelerated the fade of the response to 5-HT. In conclusion, both PDE3 and PDE4 subtypes are responsible for the suppression and the fade of the inotropic response to 5-HT and prucalopride. Signalling through the 5-HT(4) receptor remains fully active for at least 90 min with PDEs continuously regulating the response. cGMP levels, elevated by activation of particulate guanylyl cyclase under PDE2 inhibition, can indirectly enhance 5-HT(4) receptor-mediated signalling, at least when also PDE4 is inhibited, presumably through inhibition of PDE3. Elevation of cGMP generated by soluble guanylyl cyclase attenuates responses to 5-HT independently of PDEs. PMID- 22426997 TI - TRPA1 is functionally expressed in melanoma cells but is not critical for impaired proliferation caused by allyl isothiocyanate or cinnamaldehyde. AB - Melanoma is the most dangerous form of skin cancer occurring in Caucasians with rising incidence. They are remarkably resistant to conventional anti-tumour therapies like chemotherapy and radiotherapy. Therefore, new treatment strategies are urgently needed. Anti-tumour effects of phytochemicals such as allyl isothiocyanate or cinnamaldehyde have been demonstrated in various melanoma models in vitro and in vivo. Considering their high potency as transient receptor potential A1 (TRPA1)-activating compounds, we examined the functional expression of TRPA1 channels in different melanoma cell lines as well as in non-malignantly transformed primary melanocytes. The presence of TRPA1 transcripts could be detected in most of the melanoma cell lines. Furthermore, single-cell calcium imaging and patch clamp electrophysiology confirmed the presence of functional TRPA1 channels in those cell lines. Proliferation assays revealed that allyl isothiocyanate and cinnamaldehyde clearly reduce the proliferation of melanoma cells, but this effect is independent of an activation of TRPA1 channels, making it unlikely that ionic currents through TRPA1 are responsible for the anti-tumour effects of mustard oil and cinnamaldehyde. PMID- 22426998 TI - Changes in plasma and IgG N-glycome during childhood and adolescence. AB - Despite the importance of protein glycosylation in all physiological and pathological processes and their potential as diagnostic markers and drug targets, the glycome of children is still unexplored. We analyzed N-linked plasma and IgG glycomes in 170 children and adolescents between 6 and 18 years of age. The results showed large biological variability at the population level as well as a large number of associations between different glycans and age. The plasma N glycome of younger children was found to contain a larger proportion of large complex glycan structures (r = -0.71 for tetrasialylated glycans; r = -0.41 for trisialylated glycans) as well as an increase in disialylated biantennary structures (r = 0.55) with age. Core fucosylation and the level of agalactosylated plasma and IgG glycans decreased while digalactosylated glycans increased with age. This pattern of age-dependent changes in children differs from changes reported in adult population in both, direction and the intensity of changes. Also, sex differences are much smaller in children than in adults and are present mainly during puberty. These important observations should be accounted for when glycan-based diagnostic tests or therapeutics are being developed or evaluated. PMID- 22426999 TI - USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells. AB - BACKGROUND: Hyperactivation of phosphatidylinositol 3-kinase/Akt signaling is commonly associated with human tumors including lung cancers. PH domain leucine rich repeat protein phosphatase 1 (PHLPP1), which terminates Akt signaling by directly dephosphorylating and inactivating Akt, has been identified as a tumor suppressor. The protein level of PHLPP1 is regulated by E3 ligase beta-TRCP, however, the deubiquitinase for PHLPP1 is still not known. METHODS: The mRNA levels of USP1 and PHLPP1 in lung cancer cells and tissues were determined by real-time PCR. The half-life of PHLPP1 was detected by CHX assay. The interaction between USP1 and PHLPP1 was examined by immunoprecipitation and GST pull-down assay. RESULTS: Both USP1 and PHLPP1 are low expressed in lung cancer cells and tissues and silencing of USP1 by RNA interference significantly decreased the half-life of PHLPP1, which in turn amplified Akt1 phosphorylation. Our data identified a novel USP1-PHLPP1-Akt signaling axis, and decreased USP1 level in lung cancer cells may play an important role in lung cancer progress. PMID- 22427000 TI - Sociodemographic differences in medication use, health-care contacts and sickness absence among individuals with medication-overuse headache. AB - The objective of this study was to analyse sociodemographic differences in medication use, health-care contacts and sickness absence among individuals with medication-overuse headache (MOH). A cross-sectional, population survey was conducted, in which 44,300 Swedes (>=15 years old) were interviewed over telephone. In total, 799 individuals had MOH. Of these, 47 % (n = 370) only used over-the-counter medications. During the last year, 46 % (n = 343) had made a headache-related visit to their physician and 14 % (n = 102) had visited a neurologist. Among individuals aged <30 years, the number of days/month with headache was greater than the number of days with medication use, whereas the opposite was true for those >=30 years. Both the proportion using prophylactic medication and the proportion having consulted a neurologist were smaller among those who only had elementary school education than among those with higher education (p = 0.021 and p = 0.046). Those with a lower level of education also had a higher number of days/month with headache and with medication use than those with a higher educational level (p = 0.011 and p = 0.018). The MOH sufferers have limited contacts with health-care and preventive measures thus need to include other actors as well. Particular efforts should be directed towards those with low educational levels, and more research on medication use in relation to age is required. PMID- 22427001 TI - Cutaneous side effects associated with sunitinib: an analysis of 8 cases. AB - OBJECTIVE: Sunitinib is an antineoplastic agent, specifically a tyrosine kinase inhibitor. Thanks to its targeted action, this drug is relatively well tolerated. The main side effects are asthenia, gastrointestinal disturbances, and dermatological effects. The aim of our study was to collect information about dermatological side effects and assess them in patients treated with sunitinib. METHOD: A retrospective study was performed on 8 patients treated with sunitinib between January 2006 and July 2009. RESULTS: Twelve different types of side effects were observed: genital lesion (9), cutaneous eruption (7), hand-foot syndrome (6), yellow discoloration of skin (4), hair depigmentation (4), xerosis (4), pigmented lesion (4), vascular lesion (3), erythema (3), splinter haemorrhage of fingernails (1), facial oedema (1), and pruritus (1). To date vascular and pigmented lesions associated with sunitinib have not been recorded in literature, genital lesions have only been described in the scrotal region. These genital lesions led to discontinuation of treatment by 4 patients in our study. CONCLUSION: Although the risk/benefit ratio is favourable for sunitinib, all health care professionals must be aware of the risk of such adverse events. When genital lesions are observed, dose adjustment is recommended. Thorough clinical examination and patient interviews are necessary to detect these effects. PMID- 22427002 TI - Loss of imprinting of IGF2 correlates with hypomethylation of the H19 differentially methylated region in the tumor tissue of colorectal cancer patients. AB - Expression of the imprinted genes insulin-like growth factor 2 (IGF2) and H19 depends on the methylation pattern of their differentially methylated region (DMR) located on chromosome 11p15. In the present study, we examined the imprinting status of the IGF2 gene in 120 human colorectal cancer (CRC) patients and 150 normal controls. In addition, we analyzed the DNA methylation of the sixth CTCF-binding site in the DMR of IGF2/H19 in 81 CRC patients using bisulfate sequencing. Of a total of 81 informative (heterozygous) samples, 51 samples showed bialleic IGF2 expression in tumor samples; however, only 15 of 69 informative samples showed loss of imprinting (LOI) of IGF2 in normal controls. Statistically significant differences in the methylation status between the retention of imprinting (ROI) and LOI groups (66.1+/-14.9 vs. 16.7+/-9.2, p=0.008) were observed. The results of the present study suggest that LOI of IGF2 is important in the carcinogenesis of CRC. Hypomethylation of the sixth CTCF binding site in the DMR of IGF2/H19 is linked to LOI and the common IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to human CRC. PMID- 22427003 TI - Identification of swamp deer (Cervus duvauceli duvauceli Cuvier) potential habitat in Jhilmil Jheel Conservation Reserve, Uttarakhand, India using multi criteria analysis. AB - The present study aims to identify the potential habitat for swamp deer (Cervus duvauceli duvauceli Cuvier) in Jhilmil Jheel Conservation Reserve in the Uttarakhand province of India using multi-criteria analysis. The study area represents one of the last remnant habitats of the flagship species, the swamp deer in Uttarakhand, which is considered as vulnerable. The study showed that only 6.08% of the study area (225 km(2)) was highly suitable to suitable for the swamp deer. An area of 135.52 km(2) (60.23%) turned out to be moderately suitable. Within the officially designated Conservation Reserve (area 37.84 km(2)), 10.91% (4.13 km(2)) area was found highly suitable to suitable, while 74.19% (28.07 km(2)) happens to be moderately suitable. Only 14 km(2) area, which was found as suitable habitat for swamp deer falls short of the space required by a population of 134 animals. The problem could be mitigated if the agricultural land (2.47 km(2)) adjacent to the Jhilmil Jheel is brought under the Reserve management. This would provide additional area to meet the fodder requirement. The study brings out a particularly grim situation with limited options for conservation and management of the swamp deer in the Indo-Gangetic plains. It also emphasizes the role of geospatial techniques in quick appraisal of habitat attributes and identification of potential sites for protected areas. PMID- 22427004 TI - A review of parenting programs in developing countries: opportunities and challenges for preventing emotional and behavioral difficulties in children. AB - Many children in developing countries are at risk of emotional and behavioral difficulties, which are likely to be elevated due to the effects of poverty. Parenting programs have shown to be effective preventative strategies in high income countries, but to date the research on their effectiveness in lower-income countries is limited. International organizations such as the World Health Organization have called for the implementation of programs to prevent behavioral difficulties through the development of stable relationships between children and their parents. The aim of the present paper was to review the literature on parenting programs in developing countries in order to identify challenges, opportunities and directions for further research. First, reports of international organizations were reviewed in order to gain a preliminary overview of the field. In a second stage, a non-systematic review was carried out. Databases were searched in order to identify empirical evaluations of parenting programs in low-income countries. Finally, a systematic review was carried out to specifically identify evaluations of programs targeting emotional or behavioral outcomes. Only one study had a strong methodology among those designed to prevent emotional and behavioral outcomes. Opportunities for further program development and research are identified. PMID- 22427005 TI - Is it time to screen for the haptoglobin genotype to assess the cardiovascular risk profile and vitamin E therapy responsiveness in patients with diabetes? AB - Diabetes mellitus (DM) carries an increased risk for cardiovascular complications. Haptoglobin (Hp) is an abundant plasma protein with an antioxidant function by virtue of its ability to block the oxidative activity of extracorpuscular hemoglobin. There exist two common functional alleles at the Hp genetic locus, denoted 1 and 2, with three Hp genotypes (Hp 1-1, 2-1, and 2-2). The Hp protein expressed in Hp 2-2 individuals is markedly inferior in protecting against hemoglobin-induced oxidative stress. Hp 2-2 DM individuals have been shown to be at increased risk for the development of diabetes complications, particularly diabetic cardiovascular disease (CVD). We review the biological mechanisms underlying the interaction between the Hp genotype and DM on CVD and the accumulating evidence in favor of Hp genotyping all individuals with DM and providing antioxidant vitamin E supplementation specifically to Hp 2-2 DM individuals to reduce their CVD morbidity and mortality. PMID- 22427006 TI - Tuberculous pericarditis with and without HIV. AB - The human immunodeficiency virus (HIV) has altered the epidemiology, clinical manifestations, treatment considerations and natural history of tuberculous (TB) pericarditis with significant implications for clinicians. The caseload of TB pericarditis has risen sharply in TB endemic areas of the world where co infection with HIV is common. Furthermore, TB is the cause in greater than 85 % of cases of pericardial effusion in HIV-infected cohorts. In the absence of HIV, the morbidity of TB pericarditis is primarily related to the ferocity of the immune response to TB antigens within the pericardium. In patients with HIV, because TB pericarditis more often occurs as part of a disseminated process, the infection itself has a greater impact on the morbidity and mortality. HIV associated TB pericarditis is a more aggressive disease with a greater degree of myocardial involvement. Patients have larger pericardial effusions with more frequent hemodynamic compromise and more significant ST segment changes in the electrocardiogram. HIV alters the natural history and outcomes of TB pericarditis. Immunocompromised participants appear less likely to develop constrictive pericarditis and have a significantly higher mortality compared with their immunocompetent counterparts. Finally co-infection with HIV has resulted in a number of areas of uncertainty. The mechanisms of myocardial dysfunction are unclear, new methods of improving the yield of TB culture and establishing a rapid bacterial diagnosis remain a major challenge, the optimal duration of anti TB therapy has yet to be established, and the role of corticosteroids has yet to be resolved. PMID- 22427007 TI - Comparison of magnesium sulfate and mannitol in treatment of eclamptic women with posterior reversible encephalopathy syndrome. AB - OBJECTIVE: To evaluate and compare the effectiveness of magnesium sulfate (MgSO(4)) and mannitol in the treatment of posterior reversible encephalopathy syndrome (PRES) in eclamptic women. STUDY DESIGN: This retrospective analysis includes 62 eclamptic women between 22 and 40 weeks of gestation who were diagnosed with PRES in a tertiary care center. To treat neurological symptoms, 34 women received magnesium sulfate (Group 1) and the remaining 28 received 20% mannitol (Group 2) at the discretion of treating physician. RESULTS: Ten patients from both Group 1 (29%) and Group 2 (35.7%) were normotensive at admission. 59 of 62 patients presented with seizure. All patients underwent fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Parietooccipital region and cerebellum were the most commonly affected areas. The duration of treatment was significantly shorter in Group 1 than Group 2 (p < 0.001). Neurological examinations and the recovery after treatment were significantly better in favor of MgSO(4) group (p = 0.039). CONCLUSION: Mannitol is not superior to magnesium sulfate in achieving neurological recovery. Magnesium sulfate seems to be the agent of choice for treatment of PRES. PMID- 22427008 TI - Does obesity complicate perioperative course in patients undergoing abdominal hysterectomy? AB - AIM: Obesity is traditionally believed to increase the incidence of perioperative complications in abdominal surgery. Recently this paradigm has been challenged mainly by observations from surgical specialties other than gynecology. Our aim was to assess the impact of obesity on perioperative course in women undergoing total abdominal hysterectomy. METHODS: We analyzed medical charts of 126 patients who underwent total abdominal hysterectomy for benign gynecological conditions through a low transverse incision in the Department of Obstetrics and Gynecology of the Provincial Specialist Hospital in Czestochowa, Poland. Perioperative course was compared between obese [n = 55; body mass index (BMI) >= 30 kg/m(2): mean 32.6 +/- 3.2 kg/m(2)] and non-obese patients (n = 71; mean BMI 24.3 +/- 3 kg/m(2)). RESULTS: The mean operative time in obese women was significantly prolonged (112 +/- 32 vs. 100 +/- 31 min, P = 0.036). However, complication rates and other perioperative outcomes were comparable between the groups. CONCLUSION: In our study, mild obesity does not significantly affect the perioperative course in women undergoing total abdominal hysterectomy. PMID- 22427009 TI - Posterior tibial nerve stimulation for the treatment of voiding dysfunction 8 years after radical hysterectomy. PMID- 22427010 TI - Isolated contralateral groin relapse in vulvar cancer. PMID- 22427011 TI - Effect of placenta previa on fetal growth restriction and stillbirth. AB - AIM: To examine the association between placenta previa and adverse perinatal outcomes such as low birth weight, preterm delivery, stillbirth and fetal growth restriction (FGR). METHODS: This retrospective cohort study includes 12,034 delivered pregnant women who were recruited for the study between 2004 and 2010 in Ege University Hospital. Data were collected by browsing the clinic's archives. The association between placenta previa and adverse perinatal outcomes was determined via Chi-square tests and Student's t test. Logistic regression analysis was used to adjust for confounding factors in evaluating the association between placenta previa and the adverse perinatal outcomes. RESULTS: There was no significant relationship between placenta previa and FGR or stillbirth. Low birth weight and preterm delivery were significantly higher in the placenta previa group. According to logistic regression analysis, low birth weight was associated with an OR of 3.01 (95 % CI 2.05-4.52) and preterm delivery was associated with an OR of 8.14 (95 % CI 5.60-11.83); while, placenta previa did not affect FGR and stillbirth significantly. CONCLUSION: Although there is no consensus on the association between placenta previa and FGR in previous studies, we suggest that placenta previa is not a reason for placental insufficiency. Management of placenta previa especially depends on maternal hemodynamic parameters such as heavy hemorrhage and hypotensive shock rather than fetal well-being protocols based on serial growth ultrasound and fetal Doppler investigation. PMID- 22427012 TI - Type II cGMP-dependent protein kinase inhibits EGF-induced MAPK/JNK signal transduction in breast cancer cells. AB - Our previous research data showed that type II cGMP-dependent protein kinase (PKGII) inhibited EGF-induced MAPK/ERK-mediated signal transduction through blocking the phosphorylation of EGFR caused by EGF. Since EGFR also mediates other MAPK-mediated signal transduction pathways, this study was designed to investigate whether PKGII inhibits EGF-induced MAPK/c-Jun N-terminal kinase (JNK) signal transduction. MCF-7 human breast cancer cells were infected with adenoviral constructs encoding the cDNA of PKGII (pAd-PKGII) to increase the expression of PKGII and treated with 8-pCPT-cGMP to activate the enzyme. Western blotting was applied to detect the phosphorylation/activation of EGFR, JNK, MKK7 and c-Jun. The Pull-down method was used to detect the activation of Ras protein. Co-IP was used to analyze the binding between Grb2 and Sos1. TUNEL staining was used to detect the apoptosis of MCF-7 cells. The results showed that EGF treatment increased the phosphorylation of EGFR, the binding between Grb2 and Sos1, the activation of Ras, and the phosphorylation/activation of MKK7, JNK and c-Jun, but decreased the apoptosis of the cells. Increase of PKGII activity through infection with pAd-PKGII and stimulation with 8-pCPT-cGMP efficiently reversed the above changes caused by EGF. The results suggest that PKGII also inhibits EGF-induced MAPK/JNK-mediated signal transduction and further confirmed that PKGII can block the activation of EGFR. PMID- 22427013 TI - The rhapsody of NLRPs: master players of inflammation...and a lot more. AB - The Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing (NLRP) family and corresponding inflammasomes are important intracellular sensors of microbial pathogens and stress signals that promote caspase-1-mediated release of IL-1beta and IL-18. Studies using targeted disruption of NLRP1 and NLRP3 have revealed key roles for these inflammasomes in innate immunity and inflammation, as well as in autoimmune diseases, metabolic disorders, and cancers. The newly identified family members NLRP6, NLRP10, and NLRP12 are emerging as important molecules regulating gut homeostasis in mouse models, as well as being correlated to human diseases. Here, we review our current knowledge of NLRP1 and NLRP3 biology, from molecular structure, function, and proposed models of activation to associations with several human disorders. New insights into novel NLRPs that act as regulators of intestinal immunity are also discussed. PMID- 22427014 TI - T cells specific for lipid antigens. AB - Lipid-specific T cells are important participants in human immune responses. Recognition of lipid antigens contributes to host defense against pathogens that can cause debilitating diseases, including mycobacterial, viral, and parasitic infections. Lipid-specific T cells also play important roles in various autoimmune diseases, atherosclerosis, and in tumor surveillance. A better understanding of the mechanisms that regulate lipid-reactive T-cell functions will enable the development of novel therapies across a wide range of diseases. In recent years, our laboratory has investigated lipid antigen specificities, mechanisms of lipid antigen presentation, molecular interaction of lipid antigens with CD1 antigen-presenting molecules, and the pathogenic and regulatory functions of lipid-specific T cells in a variety of disease settings. In this review, we present recent data that illustrate the critical role played by lipid specific immune responses in host protection, with a particular focus on human studies. PMID- 22427015 TI - Taking inflammatory bowel disease up a Notch. AB - The epithelium of the gastrointestinal tract, which represents the largest surface area of the body, is constantly exposed to the contents of its surrounding environment. The intestinal epithelium forms barriers that are essential in maintaining equilibrium within the human body. This barrier supports nutrient and water transport while preventing microbial invasion. Intestinal epithelial cells (IECs) sit at the interface between an antigen-rich lumen and a lymphocyte-rich lamina propria (LP). IECs have the capability to discriminate between "peaceful" and "harmful" antigens. The epithelium is constantly sampling luminal contents and making molecular adjustments accordingly. These molecular changes influence the actions of innate and adaptive immune cells. The crosstalk that occurs between the epithelium and the immune compartments serves to maintain intestinal homeostasis. A better understanding of the nature of the interactions between normal LP lymphocytes (LPLs) and IECs will ultimately provide insights into the defects occurring in inflammatory bowel disease patients. PMID- 22427016 TI - Surgical removal of a partial ossified sacrotuberous ligament for refractory pudendal nerve entrapment syndrome. PMID- 22427017 TI - Pain distribution and response to total hip arthroplasty: a prospective observational study in 113 patients with end-stage hip disease. AB - PURPOSE: The aim of this study was to investigate the pain patterns in patients with end-stage hip disease and to assess the response after total hip arthroplasty (THA). METHODS: The pain patterns of patients undergoing THA for end stage hip diseases were prospectively evaluated by requesting them to mark a map of body areas before and after surgery. Patients were excluded if they had coexisting pathology of the knee or spine. The pain measurements were quantified using visual analog scales, and factors that may contribute to different pain patterns were also evaluated. RESULTS: Among 113 patients (113 hips) enrolled in the study, the groin, anterior thigh, buttock, anterior knee, and greater trochanter were the most common pain locations before THA. Pain over the lower back, shin, and calf areas, which were not generally considered referral pain areas from hip diseases, was present in 21.2, 7.1, and 2.7% patients, respectively. The presence of lower back pain (LBP) was statistically more common in patients with longer duration of hip symptoms. Regardless of the different pain patterns, 97.3% (110 of 113) of patients reported complete pain relief within 12 weeks after THA. CONCLUSIONS: The distribution of pain from end-stage hip diseases is versatile, and presence of pain in areas other than around the hip is not uncommon. LBP was more common in patients with longer duration of symptoms. THA satisfactorily resolves the pain in all areas soon after surgery. PMID- 22427018 TI - A feasibility study for evaluation of mechanical properties of articular cartilage with a two-electrode electrical impedance method. AB - BACKGROUND: Since articular cartilage has important mechanical properties such as load-bearing, shock absorption and lubrication for activities in daily life, it is important to evaluate the mechanical properties of repaired cartilage in terms of whether those properties are the same as those of natural cartilage. The purpose of this study was to investigate the effectiveness of an electrical impedance method for quantitatively measuring the mechanical properties of cartilage. METHODS: Cartilage specimens were harvested from porcine knee joint, and two kinds of enzyme-treated cartilages were prepared to investigate the correlation between mechanical and electrical properties resulting from changes in the structure of the extracellular matrix. Collagenase solution and hyaluronidase solution were used to digest the collagen fibril and proteoglycan, respectively. Electrical impedance measurement, indentation test and biochemical analysis were carried out for the enzyme-treated cartilages. RESULTS: The water content increased with enzyme treatment time, and the permeability of the treated cartilages increased with decreasing glycosaminoglycan content for both types of enzyme-treated cartilages. The aggregate modulus and the electrical resistivity for both types of enzyme-treated cartilages decreased with increasing permeability after 12-h treatment. The aggregate modulus and the electrical resistivity for both types of treated cartilages decreased with increasing water content and permeability after 24-h treatment. The electrical resistivity and the aggregate modulus of articular cartilage depended not only on the water content, but also on the permeability, and the electrical resistivity for both types of enzyme-treated cartilages was found to be significantly linearly correlated with the aggregate modulus. CONCLUSIONS: These results showed that the aggregate modulus of articular cartilage can be estimated by measuring its electrical impedance. PMID- 22427019 TI - Ultrasonographic anatomy of the lower extremity superficial veins. AB - A simple, precise, and consistent anatomical terminology is necessary for evaluating and treating patients with varicose veins. A clear understanding of the anatomy is also very important to correctly diagnose and perform the best treatment for varicose veins. Because the anatomy depicted by ultrasonography has many variations, anatomic definition for at least some of the veins still require clarification. Studies focusing on different segments of the veins are needed to obtain detailed anatomical knowledge given this great variability. PMID- 22427020 TI - Influence of caffeine on the liking of novel-flavored soda in adolescents. AB - BACKGROUND: Soda manufacturers claim that caffeine is added to soda as a flavor enhancer, but many researchers have speculated that caffeine is added to increase the hedonic and reinforcing properties of the soda. Studies in adults have demonstrated that caffeine can condition flavor preferences when added to novel flavored beverages. OBJECTIVES: The purpose of this study was to test the hypothesis that caffeine added to novel-flavored drinks would increase liking and preference in adolescents. METHODS: Adolescents (n = 99) between the ages of 12 and 17 rated and ranked seven novel soda drinks. They were then randomly assigned to consume one of these beverages paired with either caffeine (1 or 2 mg/kg) or placebo over four consecutive days and rate liking. On the final visit, participants retasted the seven beverages and provided hedonic ratings and rankings. RESULTS: Participants in the 2-mg/kg caffeine group increased the liking of the beverage over the exposure period after an initial decrease, but there was no change in liking for those in the placebo group or in the 1-mg/kg group. The increase in liking in the 2-mg/kg group was accompanied by a decrease in perceived bitterness, but no change in beverage ranking or consumption during the post-test. CONCLUSIONS: Caffeine added to novel beverages results in a decrease in liking followed by an increase in liking with repeated exposures that may result from habituation to the bitterness of caffeine. Change in bitter perception may be the mechanism by which adolescents establish regular caffeine use. PMID- 22427021 TI - Transient compensatory smoking in response to placebo cigarettes. AB - RATIONALE: To address the public health problems caused by smoking, researchers have suggested a gradual reduction in the nicotine content of cigarettes. There remain concerns, however, about the potential for smokers to compensate for reductions in nicotine content by altering their smoking behavior. Such compensatory behaviors may negate any potential cessation and/or harm reduction benefits. OBJECTIVE: The purpose of this study was to quantify smoking behavior (e.g., puff number, volume, duration, interpuff interval, and peak flow) in response to cigarettes, varying only in nicotine content, administered repeatedly. METHODS: Sixty-seven dependent smokers participated in this two session, within-subject study. Moderate nicotine content and placebo cigarettes (Quest(c) brand) were administered in a double-blind and counterbalanced manner. Each session required 12 h of tobacco abstinence and included four ad lib smoking bouts of the condition-assigned cigarette with 40 minutes separating each bout. RESULTS: Placebo cigarettes produced increases in total puff volume and duration and decreases in total interpuff interval relative to cigarettes with moderate nicotine content. Differences in total puff volume and duration generally dissipated across smoking bouts, with differences in total puff volume nonexistent by the third and fourth bouts. CONCLUSIONS: Placebo cigarettes produce compensatory smoking during initial exposures; however, these effects appear to be short lived. These findings are consistent with the previous work where smoking compensation has been observed in response to a single cigarette, but not over several days of smoking. PMID- 22427023 TI - Avian malaria infections in western European mosquitoes. AB - In the complex life cycle of avian malaria parasites (Plasmodium sp.), we still have a poor understanding on the vector-parasite relationships. This study described the community of potential avian malaria vectors in four Portuguese reedbeds. We tested if their geographical distribution differed, and investigated on their Plasmodium infections. The mosquitoes' feeding preferences were evaluated using CO(2), mice, and birds as baits. The most abundant species were Culex pipiens, Culex theileri, and Ochlerotatus caspius (and, in one site, Coquillettidia richiardii). Plasmodium lineages SGS1 and SYAT05 were found in unengorged Cx. pipiens and Cx. theileri, respectively, suggesting that these mosquitoes were competent vectors of those lineages. The species' abundance was significantly different among sites, which may help to explain the observed differences in the prevalence of SGS1. At the study sites, SGS1 was detected in the most abundant mosquito species and reached a high prevalence in the most abundant passerine species. Probably, this parasite needs abundant hosts in all phases of its cycle to keep a good reservoir of infection in all its stages. Cq. richiardii showed an opportunistic feeding behavior, while Cx. pipiens appeared to be more mammophilic than previously described, perhaps because the used avian bait was not its preferential target. In one of the study sites, mosquitoes seem to be attracted to the Spotless Starling Sturnus unicolor, an abundant bird species that may be an important local reservoir of avian malaria infections. To our knowledge, this is the first report of detection of avian Plasmodium DNA from European mosquitoes. PMID- 22427024 TI - Zinc PVA versus potassium dichromate for preservation of microsporidian spores of human origin. AB - Microsporidia are emerging opportunistic parasites. Preservation of the biological properties of microsporidian spores is often required in research work. The present study compared two preservatives; zinc polyvinyl alcohol (zinc PVA) and potassium dichromate solutions for preservation of microsporidian spores separated from human faecal samples. After 0, 1, 2 and 4 months of storage, morphological features and staining characters of the spores were assessed by light microscopy in modified trichrome-stained smears and their viability percentages were calculated using acridine orange/ethidium bromide mixture. Also, spore infectivity was evaluated by faecal spore shedding and intestinal spore load in mice orally inoculated with the preserved spores. Results revealed that morphological features, staining characters and viability of the spores were maintained in both solutions throughout the study period. Spore infectivity was completely preserved in zinc PVA solution but showed significant reduction in potassium dichromate solution at the fourth month of the preservation duration. PMID- 22427025 TI - Serum biomarker screening for the diagnosis of early gastric cancer using SELDI TOF-MS. AB - In this study, we performed a proteomic analysis of sera from stage I gastric cancer patients using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and established a diagnostic model for the early diagnosis of stage I gastric cancer. Serum samples from 169 gastric cancer patients and 83 age- and gender-matched healthy individuals were analyzed by SELDI-TOF-MS ProteinChip array technology. The SELDI-TOF-MS spectral data were analyzed using the Biomarker WizardTM and Biomarker PatternsTM software to find differential proteins and develop a classification tree for gastric cancer. A total of 34 mass peaks were identified. Six peaks at a mass-to-charge ratio (m/z) of 2873, 3163, 4526, 5762, 6121 and 7778 were used to construct the diagnostic model. The model effectively distinguished gastric cancer samples from control samples, achieving a sensitivity and specificity of 93.49 and 91.57%, respectively. In addition, we identified 3 of the 6 protein peaks at 2873, 6121 and 7778 m/z, which distinguished between stage I and stage II/III/IV gastric cancer. The model had an accuracy of 88.89% for the identification of stage I gastric cancer. In conclusion, the diagnostic model for the detection of serum proteins by SELDI-TOF-MS ProteinChip array technology correctly distinguishes gastric cancer from healthy samples, and has the ability to screen and distinguish between early gastric cancer from advanced gastric cancer. PMID- 22427026 TI - Light-dependent changes in plastid differentiation influence carotenoid gene expression and accumulation in carrot roots. AB - Carrot is an important nutritional crop due to the high levels of pro-vitamin A carotenoids (beta-carotene and, to a lower extent, alpha-carotene) that accumulate in its storage root during secondary growth. In this work we show that in carrots, contrary to that reported for aerial organs of other plant species, light has a profound effect on root development by inhibiting root thickening, preventing the differentiation of chromoplasts and eventually repressing the expression of most genes required for the biosynthesis of beta-carotene and alpha carotene and to a lesser extent genes for xanthophylls and apocarotenoids biosynthesis. We observed a correlation in the carotenoid profile and the patterns of gene expression during the development of root segments grown either in the light or in the dark, which suggests a transcriptional regulation for carotenoid synthesis during carrot root development. Furthermore, our work supports the conclusion that the differentiation of chromoplasts coincides with carotenoid accumulation during the later stages of development of underground storage roots. PMID- 22427027 TI - Luminal breast cancer metastasis is dependent on estrogen signaling. AB - Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-beta signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer. PMID- 22427028 TI - Morphological analysis of the vertebral and basilar arteries in the Chinese population provides greater diagnostic accuracy of vertebrobasilar dolichoectasia and reveals gender differences. AB - PURPOSE: Previous studies suggest that cerebral artery diameter and position differ with both gender and ethnicity, making diagnosis of vertebrobasilar dolichoectasia (VBD) difficult. Thus, the current study investigated the morphology and potential gender differences of the vertebral (VA) and basilar arteries (BA) in the Chinese population. The data collected also enabled some criteria to be suggested for the diagnosis of VBD by MRI. METHODS: A total of 200 healthy participants who underwent magnetic resonance imaging (MRI) were enrolled. The diameters of the BA and VA were measured using high resolution MRI and the height of the basilar artery bifurcation and the position of the basilar artery were also analyzed. The 95 % confident intervals (CI) of vessel diameter were calculated. RESULTS: The diameters of each artery measured, significantly differed with gender (p < 0.01). The 95 % CI of the BA were 2.2-4.2 mm and 2.0 4.0 mm for males and females, respectively. The 95 % CI of the VA were 1.7-3.7 mm and 1.5-3.5 mm for males, and 1.4-3.4 mm and 1.1-3.1 mm for females for the left and right side, respectively. No significant gender difference was found in height of the BA bifurcation or the position of the BA. CONCLUSIONS: There are significant gender differences in the diameter of both the VA and BA, indicating that gender needs to be considered in the diagnosis of VBD. These results also provide much needed quantitative data for the diagnosis of VBD in Chinese people. PMID- 22427029 TI - Preparation of nose for nasal endoscopy: cotton pledget packing versus topical spray. A prospective randomized blinded study. AB - During nasal endoscopy it is essential to have proper visualization of structures with minimal discomfort to patient and surgeon. For this it is essential that the nose is well prepared before the procedure. The main objective of the study is to compare and evaluate the efficacy of cotton pledget packing versus topical sprays in preparation of nose for nasal endoscopy. The method includes prospective randomized blinded study on 100 patients. Patients were randomly divided in two groups. In first group the nose was packed with 4% lignocaine with xylometazoline nasal drops and in the other group it was prepared with 10% lignocaine topical spray and xylometazoline nose drops. Following the procedure, patient and the surgeon were asked a pre-formed questionnaire to know their experience during endoscopy. It was observed the packing group required more preparatory time as compared to the spray group. The group which was packed had less discomfort, less pain while endoscopy. The visualization of structures was significantly better in the packed group. Eight patients in the packed group did have some mucosal bleed during the process of packing which was not seen in the spray group. Both methods of preparation have merits and demerits but in terms of discomfort, pain during procedure and visualization of structure, packing of nasal cavity with 4% lignocaine and xylometazoline drops is better than spraying of nose with 10% lignocaine and xylometazoline drops. PMID- 22427030 TI - Polymorphisms of DNA repair genes and risk of squamous cell carcinoma of the head and neck in young adults. AB - Squamous cell carcinoma of the head and neck (HNSCC) most frequently arise in the epithelial tissues of the upper aerodigestive tract. Patients with HNSCC, aged <45 years are categorized as young adults (YA). They are characterized by more severe form of this disease and often lack of classical, causative risk factors (tobacco smoking, alcohol abusing) in comparison to older (typical) patients (OP). The study purpose was to establish an anticipated protective role of DNA repair genes polymorphisms against cancer-causing agents. It was assumed that the polymorphisms in these genes may have a significant role in the etiology of HNSCC in YA. Studies were carried out on three groups: YA group with HNSCC (n = 90), young healthy group without cancer (YH, n = 160) and OP with HNSCC (n = 205). Three polymorphisms in DNA repair genes were analyzed: XPD ex23: A35931C, XRCC1 ex10: G28152A, and XRCC3 ex7: C18067T. The choice of these genes was connected with their involvement in three different DNA repair pathways. Genotyping was carried out by polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) technique. Statistical analysis included: calculation of odds ratio (ORs), 95 % confidence intervals (CIs) and p value. There was no significant difference in the distribution of XPD genotypes in YA compared to OP or YH. The XRCC1 AA genotype variant was observed less frequently in HNSCC YA (4.7 %) than in YH and in OP group (17.1 and 10.8 %, respectively). XRCC3 CT genotype variant was observed more frequently in HNSCC YA (61.8 %) than in YH (36.3 %) and this result is statistically significant. This variant was associated with the borderline increased risk of HNSCC development in an early age, however, a similar tendency was not observed in case of double mutated TT variant. The established differences of genotypes distribution do not seem to differentiate substantially YA and OP in head and neck cancer risk. PMID- 22427031 TI - Genomic instability in chronic myeloid leukemia: targets for therapy? AB - Philadelphia positive (Ph+) chronic myeloid leukemia (CML) is characterized by the occurrence of nonrandom genetic and cytogenetic abnormalities during disease progression. Many of these abnormalities are markers for genes which, when altered, can drive the blastic transformation process. Thus, such genetic alterations may be manifestations of an underlying genomic instability resulting from a compromised DNA damage and repair response, leading to advanced stages of CML and resistance to therapy. This article examines the molecular pathways that may lead to genomic instability in CML and the potential of these pathway constituents to be therapeutic targets. PMID- 22427032 TI - The expression of ARHI in pT2a and pT2b stage gastric cancer and its clinical significance. AB - ARHI is a novel tumor suppressor gene located on chromosome 1p31. Downregulation of ARHI expression has been detected in many types of cancer. However, the effects of ARHI in gastric cancer remain unclear. The aim of this study was to identify the relationship between ARHI expression and gastric cancer clinicopathological features. In this study, 81 pT2 stage gastric cancer specimens were subclassified by pT2a and pT2b stage. ARHI mRNA and protein levels were evaluated by real-time PCR and western blot analysis, respectively. Methylation plays an important role in suppressor gene silencing. We utilized methylation-specific PCR to identify the status of CpG islands in the ARHI gene. We used immunohistochemistry to determine the expression of the protein and analyzed clinicopathological features. The levels of ARHI mRNA in gastric cancer were lower compared to normal tissues (P<0.01). Similarly, the levels of ARHI protein in the cancer specimens were lower (P<0.05). DNA hypermethylation was identified in 79.1% of gastric cancer specimens without ARHI expression. Immunohistochemistry results were significantly correlated with the pT2 category (P<0.05). The cumulative survival rate of patients with ARHI expression was significantly higher compared to those without ARHI expression (P<0.05). ARHI as a suppressor is not only an important factor in the pathogenesis of gastric cancer, but also a potential factor for tumor aggravation. ARHI expression in gastric cancer can be employed to indicate favorable prognosis for the disease. PMID- 22427033 TI - Factors influencing smokeless tobacco use in rural Ohio Appalachia. AB - The burden of smokeless tobacco (ST) use disproportionally impacts males in rural Ohio Appalachia. The purpose of this study was to describe the cultural factors contributing to this disparity and to articulate the way in which culture, through interpersonal factors (i.e. social norms and social networks) and community factors (i.e. marketing and availability), impacts ST initiation and use of ST among boys and men in Ohio Appalachia. Fifteen focus groups and 23 individual qualitative interviews were conducted with adult (n = 63) and adolescent (n = 53) residents in Ohio Appalachian counties to ascertain factors associated with ST use and the impact of ST marketing. Transcriptions were independently coded according to questions and themes. ST use appears to be a rite of passage in the development of masculine identity in Ohio Appalachian culture. Interpersonal factors had the greatest influence on initiation and continued use of ST. Ohio Appalachian boys either emulated current ST users or were actively encouraged to use ST through male family and peer networks. Users perceived their acceptance into the male social network as predicated on ST use. Community factors, including ST advertisement and access to ST, reinforced and normalized underlying cultural values. In addition to policy aimed at reducing tobacco marketing and access, interventions designed to reduce ST use in Ohio Appalachia should incorporate efforts to (1) shift the perception of cultural norms regarding ST use and (2) address male social networks as vehicles in ST initiation. PMID- 22427034 TI - Genetic variation and comparison of orchardgrass (Dactylis glomerata L.) cultivars and wild accessions as revealed by SSR markers. AB - Orchardgrass is a highly variable, perennial forage grass that is cultivated throughout temperate and subtropical regions of the world. Despite its economic importance, the genetic relationship and distance among and within cultivars are largely unknown but would be of great interest for breeding programs. We investigated the molecular variation and structure of cultivar populations, compared the level of genetic diversity among cultivars (Baoxing, Anba, Bote, and Kaimo), subspecies (Dactylis glomerata ssp Woronowii) and advanced breeding line (YA02-116) to determine whether there is still sufficient genetic diversity within presently used cultivars for future breeding progress in China. Twenty individuals were analyzed from each of six accessions using SSR markers; 114 easily scored bands were generated from 15 SSR primer pairs, with an average of 7.6 alleles per locus. The polymorphic rate was 100% among the 120 individuals, reflecting a high degree of genetic diversity. Among the six accessions, the highest genetic diversity was observed in Kaimo (H = 0.2518; I = 0.3916; P = 87.3%) and 02-116 had a lower level of genetic diversity (H = 0.1806; I = 0.2788; P = 58.73%) compared with other cultivars tested. An of molecular variance revealed a much larger genetic variation within accessions (65%) than between them (35%). This observation suggests that these cultivars have potential for providing rich genetic resource for further breeding program. Furthermore, the study also indicated that Chinese orchardgrass breeding has involved strong selection for adaptation to forage production, which may result in restricted genetic base of orchardgrass cultivar. PMID- 22427035 TI - Development and characterization of 70 novel microsatellite markers for the sea cucumber (Apostichopus japonicus). AB - The sea cucumber (Apostichopus japonicus) is an important item in Asian cuisine. It is currently produced through aquaculture, especially in China, after being overexploited in the wild in the 1990s. We isolated 70 novel polymorphic microsatellite loci using an enrichment-colony hybridization protocol. All loci were characterized in 48 individuals from a natural population in Rongcheng (Shandong, China) using genomic DNA isolated from muscle tissue. The number of alleles ranged from 2 to 17 (mean 7.0), and the observed and expected heterozygosities varied from 0.0010 to 1.0000 and from 0.2125 to 0.9477, respectively. Thirty-one of the 70 loci exhibited departure from Hardy-Weinberg equilibrium. These microsatellite markers should be useful resources for population genetic studies and for molecular marker-assisted breeding of A. japonicus. PMID- 22427036 TI - Development of a species-specific sequence-characterized amplified region marker for roses. AB - DNA fingerprints of four rose species, Rosa centifolia, R. Gruss-an-Teplitz, R. bourboniana, and R. damascena, were developed using RAPD-PCR. We identified a unique polymorphic band in R. centifolia. This 762-bp fragment was produced by the random primer GLI-2. The fragment was eluted and directly cloned in a TA cloning vector, pTZ57R/T. Digestion of the plasmid with EcoRI confirmed the cloning of GLI-2(762) in pTZ57R/T. A second enzyme, PstI, used in combination with EcoRI, gave complete digestion of the plasmid, and the 762-bp fragment was confirmed on the gel. Subsequently, the polymorphic amplicon was sequenced with an AB1 373 DNA sequencer system using the PRISM(TM) Ready Reaction DyeDeoxy(TM) Terminator Cycle Sequencing kit. After sequencing, specific primers (23 bp long) were designed based on the sequence of the flanking regions of the original RAPD fragment. These primers will effectively allow fingerprinting for the identification of R. centifolia species. In essence, we developed an SCAR marker to authenticate the identity of R. centifolia species and to distinguish it from its substitutes. Such techniques are required not only to complement conventional parameters in creating the passport data of commercial and medicinal products of rose, but also for routine quality control in commercial and government rosaries and rose nurseries. PMID- 22427037 TI - Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings. AB - Osteochondroma is a cartilage capped benign tumor developing mainly at the juxta epiphyseal region of long bones. The rate of malignant transformation, mainly into chondrosarcoma, is estimated to be less than 1-3%. Transformation into osteosarcoma is very rare and has been reported only thirteen times. There is little information on treatment and outcome. We report the case of a secondary osteosarcoma arising in the left tibia of a 23-year-old male, 10 years after the initial diagnosis of osteochondroma and after two partial resections. Malignant transformation occurred at the stalk and not at the cartilage cap, as would normally be expected. Chromosome banding analysis revealed the karyotype: 46,XY, t(3;13)(q21;q34) [2]/46,XY [18]. Records from additional cases will help determine the parameters that define these rare secondary bone lesions. PMID- 22427038 TI - Lack of association between Gly82Ser, 1704G/T and 2184A/G of RAGE gene polymorphisms and retinopathy susceptibility in Malaysian diabetic patients. AB - Diabetic retinopathy is the most common diabetic eye disease, occurring in about 60% of type 2 diabetic patients. Other than known clinical risk factors, the influence of genes has been suggested as part of the development of diabetic retinopathy. We investigated the association of Gly82Ser, 1704G/T and 2184A/G polymorphisms in the RAGE gene with retinopathy in type 2 diabetic patients in Malaysia. Ninety-eight unrelated retinopathy patients and 185 unrelated healthy controls from all over Malaysia were recruited in this study. The allele and genotype frequencies of the three gene polymorphisms were investigated using PCR RFLP. The allele frequency of the three polymorphisms did not differ significantly between the control and the retinopathy group (P > 0.05). Analysis of the frequency of GA+AA, GT+TT and AG+GG in the retinopathy group did not reveal significant differences (P > 0.05) compared to the control group. We conclude that RAGE gene Gly82Ser, 1704G/T and 2184A/G polymorphisms are not associated with retinopathy development in the Malaysian population. PMID- 22427039 TI - Frequency of human papillomavirus types 16, 18, 31, and 33 and sites of cervical lesions in gynecological patients from Recife, Brazil. AB - Human papilloma virus (HPV) is a well-established cause of cervical cancer. While many studies have been performed so far on HPV viral biology, mode of infection and prevention measures, scanty information is available on lesion sites of infected women and the incidence of viral types at specific locations. We looked for a possible relationship between the most common viral types (HPVs 16, 18, 31, 33) found in Recife, PE, Brazil, and lesion sites. We examined 396 HPV-positive women at the Gynecological Unit of the IMIP at Recife; 288 women were positive for HPV 16, 18, 31, or 33, present as a single-virus type or as co infection. HPV 16 was the most frequent virus type found in the vulva, vagina, uterine cervix-vagina, and uterine cervix. HPV 31 was the second prevalent virus type in vulva, vagina, uterine cervix-vagina, uterine cervix, and mole. HPVs 18 and 33 were present with similar frequencies in the mole-vulva region. Among the co-infections, HPV 16/18 and HPV16/31 were the most frequent in our study group, followed by HPV 16/33. PMID- 22427040 TI - Gene expression profiles in the cerebellum of transgenic mice over expressing the human FMR1 gene with CGG repeats in the normal range. AB - Modifications in the GABA pathway are considered to be responsible for motor alterations in animal models for fragile X-associated tremor ataxia syndrome. We analyzed the expression profile in the cerebellum in a transgenic mouse model that over expresses the human FMR1 gene with CGG repeats in the normal range. We used the "GeneChip Mouse Gene 1.0 ST Array" from Affymetrix analyzing 28,853 well-described and -characterized genes. Based on data from the comparative analysis of the expression profile, we detected a significant gradient with a P value <0.1 and changes in expression equal to or greater than 1.5 times compared to the control mouse genes. There were significant changes in the expression of 104 genes, among which 72% had decreased and 28% had increased expression. With the exception of GabarapL2, no changes in expression of genes from the GABA pathway were observed, which may explain the absence of an altered motor phenotype in these mice. These results further support the view that toxic effects in fragile X-associated tremor ataxia syndrome are due to expansion of CGG repeats rather than increased mRNA levels, since in the transgenic mice the FMR1 mRNA levels were increased 20-100 times compared with those of control littermates. PMID- 22427041 TI - Medial orbital wall reconstruction with flexible Ethisorb patches. AB - OBJECTIVES: The aim of this study was to analyse the long-term result after reconstruction of the medial orbital wall with a flexible, biodegradable material (Ethisorb). MATERIALS AND METHODS: During a period of almost 8 years, 31 patients with a medial orbital wall fracture were analysed retrospectively. Inclusion criteria were patients with a maximum size fracture of the orbital medial wall measuring 1.5-2 cm(2). Exophthalmos, enophthalmos, bulbus motility, diplopia and skin sensation were investigated over a period of 6 months. In all patients, the medial orbital wall was reconstructed with Ethisorb patches. RESULTS: No significant intraoperative complications were detected. No postoperative infection, abscess or seroma was found in any of the patients receiving an Ethisorb patch. CONCLUSIONS: The advantage of the semiflexibility of the Ethisorb patch is that it supplies an anatomically correct fit to the orbital medial wall but does not require fixation by screws or the use of sutures. CLINICAL RELEVANCE: The low rate of reported bulbus motility disturbance, diplopia, exophthalmos and enophthalmos demonstrates acceptable results after medial orbital wall reconstruction using the Ethisorb patch. PMID- 22427042 TI - Patient socioeconomic determinants of the choice of generic versus brand name drugs in the context of a reference price system: evidence from Belgian prescription data. AB - The generic reference price system (RPS) can impose a financial penalty for patients using a brand name drug instead of its generic alternative. Previous studies on the impact of the RPS have not considered the potentially differential effect of using generic alternatives for individuals with a different socioeconomic background. However, patients' characteristics might determine their overall knowledge of the existence of the system and thus of the financial burden to which they may be confronted. The association between patients' characteristics and the use of generic drugs versus brand name drugs was analyzed for ten highly prescribed pharmaceutical molecules included in the Belgian generic reference price system. Prescriptions were obtained from a 10% sample of all general practitioners in 2008 (corresponding to 120,670 adult patients and 368,101 prescriptions). For each pharmaceutical molecule, logistic regression models were performed, with independent variables for patient socioeconomic background at the individual level (work status, having a guaranteed income and being entitled to increased reimbursement of co-payments) and at the level of the neighborhood (education). The percentage of generic prescriptions ranged from 24.7 to 76.4%, and the mean reference supplement in 2008 ranged from ?4.3 to ?37.8. For seven molecules, higher use of a generic alternative was associated with either having a guaranteed income, with receiving increased reimbursement of co-payments or with living in areas with the lowest levels of education. Globally, results provided evidence that the generic RPS in Belgium does not lead to a higher financial burden on individuals from a low socioeconomic background. PMID- 22427043 TI - Damage control and point of injury care: extending the care continuum to military prehospital providers. AB - Damage control principles are well founded, well proven, and have been incorporated into many specialties of clinical care in both military and civilian practice. Theories regarding hemostatic and hypovolemic resuscitation and preventing the Lethal Triad have had profound effects on the survival of wounded during the present conflicts. As we continue to refine these practices, implementation of this theory should be extended to military prehospital providers. The impacts of damage control practices from those providing initial treatment could complete the continuity of care, prime patients for additional success, and affect overall morbidity and mortality. The basic tenets of damage control theory are easily transferred to the Role I provider in the field and may even address their unique requirements more appropriately. Understanding the working concept of damage control would improve decision-making skills in both therapeutics and evacuation while managing casualties in the uncontrolled environment of combat. Military prehospital damage control differs greatly from in-hospital use, in that the principles must incorporate both medical and tactical considerations for care of the wounded. Introducing damage control principles to established casualty care guidelines will recognize and unite an often underappreciated level of care into a successful practice. PMID- 22427044 TI - Management of scalp hemorrhage and lacerations. AB - Scalp lacerations can vary in severity from a minor injury up to a complete degloving of the scalp. Severe scalp injuries can occur in a combat zone as a result of blunt trauma, penetrating trauma or blast-related mechanisms. More severe scalp wounds tend to cause a greater than expected blood loss and can contribute to patient destabilization relatively quickly. This article will discuss the source of blood supply to the scalp and concentrate on the management of scalp wounds with before and after pictures to demonstrate these techniques. The cases presented will exclude cranial fractures and concentrate more on the management of lacerations specifically. PMID- 22427045 TI - An analysis of battlefield cricothyrotomy in Iraq and Afghanistan. AB - OBJECTIVE: Historical review of modern military conflicts suggests that airway compromise accounts for 1?2% of total combat fatalities. This study examines the specific intervention of pre-hospital cricothyrotomy (PC) in the military setting using the largest studies of civilian medics performing PC as historical controls. The goal of this paper is to help define optimal airway management strategies, tools and techniques for use in the military pre-hospital setting. METHODS: This retrospective chart review examined all patients presenting to combat support hospitals following prehospital cricothyrotomy during combat operations in Iraq and Afghanistan during a 22-month period. A PC was determined ?successful? if it was documented as functional on arrival to the hospital. All PC complications that were documented in the patients? record were also noted in the review. RESULTS: Two thirds of the patients died. The most common injuries were caused by explosions, followed by gunshot wounds (GSW) and blunt trauma. Eighty-two percent of the casualties had injures to face, neck or head. Those injured by gunshot wounds to the head or thorax all died. The largest group of survivors had gunshot wounds to the face and/or neck (38%) followed by explosion related injury to the face, neck and head (33%). Pre-hospital cricothyrotomy was documented as successful in 68% of the cases while 26% of the PC?s failed to cannulate the trachea. In 6% of cases the patient was pronounced dead on arrival without documentation of PC function. The majority of PC?s (62%) were performed by combat medics at the point of injury. Physicians and physician assistants (PA) were more successful performing PC than medics with a 15% versus a 33% failure rate. Complications were not significantly different than those found in civilian PC studies, including incorrect anatomic placement, excessive bleeding, air leak and right main stem placement. CONCLUSIONS: The majority of patients who underwent PC died (66%). The largest group of survivors had gunshot wounds to the face and/or neck (38%) followed by explosion related injury to the face, neck and head (33%). Military medics have a 33% failure rate when performing this procedure compared to 15% for physicians and physician assistants. Minor complications occurred in 21% of cases. The survival rate and complication rates are similar to previous civilian studies of medics performing PC. However the failure rate for military medics is three to five times higher than comparable civilian studies. Further study is required to define the optimal equipment, technique, and training required for combat medics to master this infrequently performed but lifesaving procedure. PMID- 22427046 TI - Advanced Medical Technology Capacity Building and the Medical Mentoring Event: A Unique Application of SOF Counterinsurgency Medical Engagement Strategies. AB - Background The Medical Civic Assistance Program (MEDCAP) is a military commander?s tool developed during the Vietnam War to gain access to and positively influence an indigenous population through the provision of direct medical care provided by military medical personnel, particularly in Counter Insurgency Operations (COIN). An alternative to MEDCAPs is the medical seminar (MEDSEM). The MEDSEM uses a Commander?s military medical assets to share culturally appropriate medical information with a defined indigenous population in order to create a sustainable training resource for the local population?s health system. At the heart of the MEDSEM is the ?train the trainer? concept whereby medical information is passed to indigenous trainers who then pass that information to an indigenous population. The MEDSEM achieves the Commander?s objectives of increasing access and influence with the population through a medical training venue rather than direct patient care. Previous MEDSEMS conducted in Afghanistan by military forces focused on improvement of rural healthcare through creation of Village Health Care Workers. This model can also be used to engage host nation (HN) medical personnel and improve medical treatment capabilities in population centers. The authors describe a modification of the MEDSEM, a Medical Mentorship (MM), conducted in November 2010 in Kabul, Afghanistan, at the Afghan National Army (ANA) National Medical Hospital. This training was designed to improve intubation skills in Afghan National Army Hospitals by ANA medical providers, leave residual training capability, and build relationships within the institution that not only assist the institution, but can also be leveraged to foster Commanders? objectives, such as health and reconstruction initiatives and medical partnering for indigenous corps and medical forces described below. Methods We, the authors, developed a culturally appropriate endotracheal intubation training package including a Dari and Pashto instruction manual, Dari video training program, video laryngoscope and difficult airway training mannequin to be used by indigenous medical personnel to train other indigenous medical personnel in the skill of endotracheal intubation. Utilizing Special Operations medical personnel, University of Nebraska medical personnel and local Afghan medical instructors, we coordinated with local authorities and ISAF medical authorities. We trained approximately 100 ANA physician assistant (PA) students and ten ANA intensive care unit (ICU) and Anesthesia medical staff in endotracheal intubation. The video laryngoscope was used as a training aid to guide each student?s direct intubation technique. Results We validated the Medical Mentorship (MM) concept as a means to engage an indigenous population?s medical personnel. The indigenous medical training facilities capability was augmented by use of the video laryngoscope as a training aid. This improvement was sustained over the observable period. Relationships were developed and enhanced for medical support of coalition partner forces supporting SOF operations. Introducing the video laryngoscope to the ICU increased direct care capabilities within the medical institution. Conclusions The MEDSEM is a viable option for military commanders to leverage medical assets to positively engage an indigenous population during COIN operations. MEDSEMs leave residual sustainable medical capabilities, in contrast to MEDCAP models. This report describes a modification of the MEDSEM concept?Medical Mentoring Event (MME)?a short term focused intervention designed to insert medical technology or techniques into an indigenous medical facility that creates sustainable, tangible benefits to patient care while fostering a SOF Commanders objectives. Follow up with embedded NATO trainers at National Military Hospital (NMH) shows that the video laryngoscope continues to be used successfully in airway management training and in difficult intubations, enhanced the teaching impact of imbedded NATO medical mentors, left a residual training capability for Afghan medical instructors and created relationships between SOF medical providers and the host institution that can facilitate healthcare for SOF partner forces. PMID- 22427047 TI - The expanded scope of emergency medical practice necessary for initial disaster response: lessons from Haiti. AB - A team of emergency physicians and nurses from Stanford University responded to the devastating January 2010 earthquake in Haiti. Because of the extreme nature of the situation, combined with limited resources, the team provided not only acute medical and surgical care to critically injured and ill victims, but was required to uniquely expand its scope of practice. Using a narrative format and discussion, it is the purpose of this paper to highlight our experience in Haiti and use these to estimate some of the skills and capabilities that will be useful for physicians who respond to similar future disasters. PMID- 22427048 TI - Immunoglobulin M and immunoglobulin G seronegative Q fever: a hypothesis for veterans? Medically unexplained chronic multi-symptom illnesses. AB - We present Q fever as a credible hypothesis for Gulf War Veterans? Illnesses (GWVIs) and as a possible etiology for prevalent symptomologies affecting currently serving servicemembers. Q fever is caused by the bacteria Coxiella burnetii, which is endemic throughout the Middle East. Q fever may manifest in many forms of widely varying and often inconstant symptoms. Due to false-negative interpretations in current and past diagnostic testing, Q fever has not received appropriate consideration as a possible causative agent for medically unexplained veterans? illnesses. Review of current literature invites us to consider that a form of Q fever involving an incomplete immune response is a potential cause of these debilitating illnesses. We hypothesize C. burnetii infection coincidental to exposures suppressing antibody-specific immune response results in infection mediated by immunoglobulin D (IgD). Literature indicates that successful treatment for this form of Q fever requires the concurrent administration of doxycycline and hydroxychloroquine. PMID- 22427049 TI - A salmon thrombin-fibrinogen dressing controls hemorrhage in a swine model compared to standard kaolin-coated gauze. AB - BACKGROUND: Battlefield hemorrhage remains the primary cause of death in potentially survivable combat injuries with noncompressible hemorrhage. Fibrin dressings have great potential for reducing mortality, however are limited by cost, availability, and disease transmission. METHODS: Dressings comprising a soluble dextran dressing with lyophilized salmon thrombin and fibrinogen (STF) were tested against Combat Gauze (CG) as a control in a standard swine femoral artery hemorrhage model. Ten female swine were used in each arm of the study. RESULTS: Survival, blood loss, and time to hemostasis were similar between the two dressings. Two of the CGtreated animals that survived exsanguinated during the simulated walking maneuver. Three CG-treated animals formed a clot within the wound, but the clot did not adhere to the femoral artery injury. All ten of the STF-treated animals formed a clot in the wound that adhered and sealed the arterial injury site, even in three animals that did not survive. None of the STF treated animals bled following the simulated walking maneuver. Three of five STF treated animals reestablished blood flow distal to the injury as demonstrated by angiography. CONCLUSIONS: The STF dressing is as efficacious as CG in treating hemorrhage in this model of a lethal injury. Further, the STF dressing formed a fibrin sealant over the injury, whereas CG achieved hemostasis by occlusive compression of the artery. The sealant property of the STF dressing allowed reestablishment of antegrade blood flow into the distal limb, demonstrating that this dressing has the potential of limb salvage in addition to control of life threatening hemorrhage. PMID- 22427050 TI - A medical training event for special forces medical sergeants. AB - Special Forces Medical Sergeants (SFMS) are independent multidisciplinary medical personnel who possess unique medical skill sets that require regular practice in order to maintain proficiency. Due to high operational tempo, the windows of opportunity to practice these abilities are usually limited to short periods of required training to maintain credentials. A Special Forces (SF) Battalion allowed their medical section to orchestrate a weeklong medical training event that included emergency procedure lectures, human cadaver training, ultrasound familiarization, medical administration instruction, and behavioral health discussions. This training enabled the SFMS to hone their competencies and increase their clinical confidence while working and learning from each other and other medical providers. The training event was a great success. PMID- 22427051 TI - F-cell world drive 2011: are tactical medicine principles applicable to a civilian scenario? AB - In 2011, a Mercedes Benz (MB) conducted the F-Cell World Drive tour around the globe in 125 days. While crossing Asia from Shanghai (China) to Helsinki (Finland) by car, en route medical care was provided by embedded emergency physicians. The designated route crossed four different countries, multiple climate zones, and challenging road conditions. There was only limited information provided about hospitals and emergency medical services within different host nations in the planning phase, so we adopted tactical medical principles for mission planning and execution, as we were facing remote conditions and limitations to equipment, staffing, and patient transport. PMID- 22427052 TI - Since when is a calorie a calorie? PMID- 22427053 TI - High expression and nuclear localization of beta-catenin in diffuse large B-cell lymphoma. AB - The Wnt/beta-catenin signaling pathway plays diverse roles in embryonic development and maintenance of organs and tissues in adults as well as in the pathogenesis of a range of diseases, including many types of carcinomas. beta catenin, the principal downstream effector of the Wnt/beta-catenin pathway, migrates to the nucleus and mediates the activation of the Wnt/beta-catenin pathway. The aim of the present study was to investigate the expression and localization of beta-catenin in diffuse large B-cell lymphoma (DLBCL) tissues and to illuminate the role of beta-catenin in the pathogenesis of DLBCL. The mRNA expression levels of beta-catenin were determined by quantitative polymerase chain reaction (PCR), while beta-catenin protein levels were detected by western blot analysis and immunohistochemical staining. DLBCL showed a higher expression of beta-catenin in contrast to reactive hyperplasia of lymph node tissues at both the mRNA and protein levels (P<0.001). Immunohistochemical analysis indicated nuclear localization of beta-catenin in 14 (46.67%) DLBCL cases, whereas no inflammatory lymph node tissue showed nuclear accentuation of beta-catenin. The overexpression and nuclear accentuation of beta-catenin were strongly correlated to the clinical staging of patients with DLBCL (P<0.05). These results suggest that the Wnt/beta-catenin pathway is partly activated in DLBCL and may contribute to its pathogenesis. PMID- 22427054 TI - Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells. AB - This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM) induced apoptosis and drug resistance in human breast cancer cells. Drug sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF 7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCdelta but decreased expression of PKCalpha in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCdelta and increased levels of PKCalpha. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCdelta, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCalpha, which promoted ERK phosphorylation. These results suggest that PKCdelta enhances apoptosis in TAM treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCalpha pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCalpha and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells. PMID- 22427055 TI - Highlights from the IV International Symposium of Thrombosis and Anticoagulation (ISTA), October 20-21, 2011, Salvador, Bahia, Brazil. AB - To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fourth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, from October 20-21, 2011. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coracao Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings. PMID- 22427057 TI - Our experience with the surgical management of paranasal sinus osteomas. AB - The aim of this work is to describe our experience with the management of osteomas of the fronto-ethmoidal region, and to evaluate the limits and possibilities of different approaches: endonasal endoscopic versus external surgical resection of symptomatic osteomas. A review of 26 patients with detected osteomas in tertiary health care center was accomplished. We analysed the 26 adult patients, which detected paranasal sinus (PNS) osteomas--patients who underwent paranasal sinus CT examinations almost exclusively for other reasons. We analysed the patient's symptoms, localization and size of osteomas, clinical and imaging signs, in relation to adjacent structures. Of the 26 cases, 16 located in the etmoid sinus, eight in the frontal sinus, of which two with orbital one with an ethmoid extension, and one isolated maxillary and sphenoid sinus were involved. We treated 11 patients with endoscopic (eight cases) and external surgical approaches (three cases). Besides this surgical excision; 15 cases were kept in follow up, because of asymptomatic nature of the PNS osteomas or patients lack of consent. While the extranasal approach is still a part of the treatment concept for removing osteomas; over the last years, in suitable cases, the endoscopically controlled endonasal approach has greatly gained importance due to the improved surgical equipment and experience. PMID- 22427058 TI - Electron spray ionization mass spectrometry and 2D 31P NMR for monitoring 18O/16O isotope exchange and turnover rates of metabolic oligophosphates. AB - A new method was here developed for the determination of (18)O-labeling ratios in metabolic oligophosphates, such as ATP, at different phosphoryl moieties (alpha-, beta-, and gamma-ATP) using sensitive and rapid electrospray ionization mass spectrometry (ESI-MS). The ESI-MS-based method for monitoring of (18)O/(16)O exchange was validated with gas chromatography-mass spectrometry and 2D (31)P NMR correlation spectroscopy, the current standard methods in labeling studies. Significant correlation was found between isotopomer selective 2D (31)P NMR spectroscopy and isotopomer less selective ESI-MS method. Results demonstrate that ESI-MS provides a robust analytical platform for simultaneous determination of levels, (18)O-labeling kinetics and turnover rates of alpha-, beta-, and gamma phosphoryls in ATP molecule. Such method is advantageous for large scale dynamic phosphometabolomic profiling of metabolic networks and acquiring information on the status of probed cellular energetic system. PMID- 22427059 TI - Six years on: a prospective cohort study of male juvenile offenders in secure care. AB - Longitudinal studies are helpful in understanding developmental trajectories and recognising opportunities for early intervention. This paper describes the long term needs and mental health of an initial sample of male juvenile offenders, now adults 6 years after their index admission to secure care. In this prospective cohort study of 97 male juvenile offenders admitted to secure, offenders were assessed initially on admission, 2 and 6 years later. Interviews were conducted with 54 offenders at the 6-year follow-up and included an assessment of psychosocial need, mental health and psychopathy. Outcome data on offending behaviour were collected on a total of 71 offenders. Persistent offenders have needs in multiple domains as they transition into adulthood. The majority of offenders were single and about a half were in neither employment nor training. Almost nine out of ten offenders had a substance misuse disorder and a similar number met the criteria for a diagnosis of antisocial personality disorder. Substance misuse in adolescence was strongly correlated with later substance misuse in adulthood, emphasising the importance of early intervention. A diagnosis of antisocial personality disorder and living with friends and family were both significantly associated with persistent offending behaviour. Many offenders continued to reoffend despite receiving offence-related interventions and custodial care. Interventions currently aimed at reducing recidivism in more severe offenders appear to be ineffective. Persistent offenders would benefit from a multi-modal approach based on individual needs, rather than receiving generic interventions. PMID- 22427060 TI - Fibronectin promotes migration, alignment and fusion in an in vitro myoblast cell model. AB - Myogenesis is a complex process in which committed myogenic cells differentiate and fuse into myotubes that mature into the muscle fibres of adult organisms. This process is initiated by a cascade of myogenic regulatory factors expressed upon entry of the cells into the myogenic differentiation programme. However, external signals such as those provided by the extracellular matrix (ECM) are also important in regulating muscle differentiation and morphogenesis. In the present work, we have addressed the role of various ECM substrata on C2C12 myoblast behaviour in vitro. Cells grown on fibronectin align and fuse earlier than cells on laminin or gelatine. Live imaging of C2C12 myoblasts on fibronectin versus gelatine has revealed that fibronectin promotes a directional collective migratory behaviour favouring cell-cell alignment and fusion. We further demonstrate that this effect of fibronectin is mediated by RGD-binding integrins expressed on myoblasts, that N-cadherin contributes to this behaviour, and that it does not involve enhanced myogenic differentiation. Therefore, we suggest that the collective migration and alignment of cells seen on fibronectin leads to a more predictable movement and a positioning that facilitates subsequent fusion of myoblasts. This study highlights the importance of addressing the role of fibronectin, an abundant component of the interstitial ECM during embryogenesis and tissue repair, in the context of myogenesis and muscle regeneration. PMID- 22427061 TI - Intestinal proteases of free-living and parasitic astigmatid mites. AB - Among arthropod pests, mites are responsible for considerable damage to crops, humans and other animals. However, detailed physiological data on these organisms remain sparse, mainly because of their small size but possibly also because of their extreme diversity. Focusing on intestinal proteases, we draw together information from three distinct mite species that all feed on skin but have separately adapted to a free-living, a strictly ecto-parasitic and a parasitic lifestyle. A wide range of studies involving immunohistology, molecular biology, X-ray crystallography and enzyme biochemistry of mite gut proteases suggests that these creatures have diverged considerably as house dust mites, sheep scab mites and scabies mites. Each species has evolved a particular variation of a presumably ancestral repertoire of digestive enzymes that have become specifically adapted to their individual environmental requirements. PMID- 22427063 TI - Trps1 is necessary for normal temporomandibular joint development. AB - Mutation of the human TRPS1 gene leads to trichorhinophalangeal syndrome (TRPS), which is characterized by an abnormal development of various organs including the craniofacial skeleton. Trps1 has recently been shown to be expressed in the jaw joints of zebrafish; however, whether Trps1 is expressed in the mammalian temporomandibular joint (TMJ), or whether it is necessary for TMJ development is unknown. We have analyzed (1) the expression pattern of Trps1 during TMJ development in mice and (2) TMJ development in Trps1 knockout animals. Trps1 is expressed in the maxillo-mandibular junction at embryonic day (E) 11.5. At E15.5, expression is restricted to the developing condylar cartilage and to the surrounding joint disc progenitor cells. In Trps1 knockout mice, the glenoid fossa of the temporal bone forms relatively normally but the condylar process is extremely small and the joint disc and cavities do not develop. The initiation of condyle formation is slightly delayed in the mutants at E14.5; however, at E18.5, the flattened chondrocyte layer is narrowed and most of the condylar chondrocytes exhibit precocious chondrocyte maturation. Expression of Runx2 and its target genes is expanded toward the condylar apex in the mutants. These observations underscore the indispensable role played by Trps1 in normal TMJ development in supporting the differentiation of disc and synoviocyte progenitor cells and in coordinating condylar chondrocyte differentiation. PMID- 22427062 TI - Model systems for studying trophoblast differentiation from human pluripotent stem cells. AB - This review focuses on a now well-established model for generating cells of the trophoblast (TB) lineage by treating human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) with the growth factor BMP4. We first discuss the opposing roles of FGF2 and BMP4 in directing TB formation and the need to exclude the former from the growth medium to minimize the co-induction of mesoderm and endoderm. Under these conditions, there is up-regulation of several transcription factors implicated in TB lineage emergence within 3 h of BMP4 exposure and, over a period of days and especially under a high O(2) gas atmosphere, gradual appearance of cell types carrying markers for more differentiated TB cell types, including extravillous TB and syncytioTB. We describe the potential value of including low molecular weight pharmaceutical agents that block activin A (INHBA) and FGF2 signaling to support BMP4-directed differentiation. We contend that the weight of available evidence supports the contention that BMP4 converts human ESC and iPSC of the so-called epiblast type unidirectionally to TB. We also consider the argument that BMP4 treatment of human ESC in the absence of exogenous FGF2 leads only to the emergence of mesoderm derivatives to be seriously flawed. Instead, we propose that, when signaling networks supporting pluripotency ESC or iPSC become unsustainable and when specification towards extra-embryonic mesoderm and endoderm are rendered inoperative, TB emerges as a major default state to pluripotency. PMID- 22427064 TI - Neuroimmune connections in ovine pharyngeal tonsil: potential site for prion neuroinvasion. AB - Recent studies have established the involvement of nasal-associated lymphoid tissues, mainly the pharyngeal tonsil, in prion pathogenesis. However, the mechanisms of the associated neuroinvasion are still debated. To determine potential sites for prion neuroinvasion inside the ovine pharyngeal tonsil, the topography of heavy (200 kDa) and light (70 kDa) neurofilaments and of glial fibrillar acidic protein has been semi-quantitatively analysed inside the various compartments of the tonsil. The results show that the most innervated areas are the interfollicular area and the connective tissue located beneath the respiratory epithelium. The existence of rare synapses between follicular dendritic cells and nerve fibres inside the germinal centre indicates that this mechanism of neuroinvasion is possible but, since germinal centres of lymphoid follicles are poorly innervated, other routes of neuroinvasion are likely. The host PRNP genotype does not influence the pattern of innervation in these various tonsil compartments, unlike ageing during which an increase of nerve endings occurs in a zone of high trafficking cells beneath the respiratory epithelium. A minimal age-related increase of innervation inside the lymphoid follicles has also been observed. An increase in nerve fibre density around the lymphoid follicles, in an area rich in mobile cells such as macrophages and dendritic cells capable of capturing and conveying pathogen prion protein (PrPd), might ensure more efficient infectivity, not in the early phase but in the advanced phase of lymphoinvasion after the amplification of PrPd; alternatively, this area might even act as a direct site of entry during neuroinvasion. PMID- 22427065 TI - In-vitro regulation of odontogenic gene expression in human embryonic tooth cells and SHED cells. AB - The bud-to-cap stage transition during early tooth development is a time when the tooth-inducing potential becomes restricted to the mesenchyme. Several key genes, expressed in the mesenchyme at this stage, are an absolute requirement for the progression of tooth development. These include the transcription factors Msx1 and Pax9. The inductive potential of tooth mesenchyme cells is a key requisite for whole-tooth bioengineering and thus identification of cells that can retain this property following expansion in culture is an important as yet unresolved, goal. We show here that in-vitro culture of embryonic human tooth mesenchyme cells and SHED cells express low levels of PAX9 and MSX1 and that these levels can be significantly upregulated by activation of different signalling pathways. Such in-vitro manipulation may thus offer a simple way of maintaining/restoring/inducing the odontogenic-inducing capacity in mesenchymal cells. PMID- 22427066 TI - Expression of the male reproduction-related gene (Mar-Mrr) in the spermatic duct of the giant freshwater prawn, Macrobrachium rosenbergii. AB - Phosphorylated sperm proteins are crucial for sperm maturation and capacitation as a priori to their fertilization with eggs. In the freshwater prawn, Macrobrachium rosenbergii, a male reproduction-related protein (Mar-Mrr) was known to be expressed only in the spermatic ducts as a protein with putative phosphorylation and may be involved in sperm capacitation in this species. We investigated further the temporal and spatial expression of the Mar-Mrr gene using RT-PCR and in situ hybridization and the characteristics and fate of the protein using immunblotting and immunocytochemistry. The Mar-Mrr gene was first expressed in 4-week-old post larvae and the protein was produced in epithelial cells lining the spermatic ducts, at the highest level in the proximal region and decreased in the middle and distal parts. The native protein had a MW of 17 kDa and a high degree of serine/threonine phosphorylation. It was transferred from the epithelial cells to become a major protein at the anterior region of the sperm. We suggest that it is involved in sperm capacitation and fertilization in this open thelycal species and this is being investigated. PMID- 22427067 TI - Region-specific gene expression in the epididymis. AB - The epididymis is responsible for post-testicular sperm maturation, which consists in the acquisition of forward motility and fertilizing ability. This organ is composed of three main anatomical regions - the caput, corpus and cauda epididymidis - which possess distinct gene expression profiles, ensuring different epididymal functions essential to the different steps of sperm maturation. Since many genes display spatially restricted expression in the epididymis, this organ constitutes a model of choice to study the mechanisms that govern region-specific gene expression. Factors such as steroid hormones, lumicrine factors and temperature affect the pattern of gene expression in the epididymis. Recently, the contribution of small RNAs in epididymal gene regulation has been investigated and constitutes a promising avenue for clinical application with regard to male fertility. PMID- 22427068 TI - Follicular determinants of pregnancy establishment and maintenance. AB - Synchronization of dominant follicle development and control of ovulation/oocyte retrieval are commonly used assisted reproductive technologies in both cattle and humans. The final maturation of the dominant follicle is intimately tied to the final maturation of the oocyte, preovulatory secretion of estradiol, preparation of follicular cells for luteinization, postovulatory secretion of progesterone and endocrine control of the oviductal and uterine environment for gamete and embryo development. The physiological maturity of a dominant/ovulatory follicle can affect the establishment and maintenance of pregnancy. Premature induction of the ovulatory process can reduce pregnancy rates and increase late embryonic/fetal mortality in cattle, which is likely mediated through inadequate oocyte competence and a compromised maternal environment. Oocyte competence increases with follicular maturity and is dependent upon acquisition of a complete complement of mRNA transcripts and establishment of the appropriate epigenetic marking of the oocyte genome before the preovulatory gonadotropin surge. Preovulatory secretion of estradiol is a reflection of follicular maturity and affects the oocyte, follicular cells, oviduct and uterus. The corpus luteum is a continuation of follicular maturation and rate of progesterone secretion following ovulation is linked to fertility. Advancements in our understanding of how the follicular microenvironment affects pregnancy establishment and maintenance will improve the efficiency of assisted reproductive technologies in all species. The purpose of this review is to discuss how follicular microenvironment, oocyte competence, preovulatory secretion of estradiol and postovulatory secretion of progesterone can affect pregnancy establishment and embryo/fetal survival, with an emphasis on cattle. PMID- 22427069 TI - Disentangling the effects of migration, selection and acculturation on weight and body fat distribution: results from a natural experiment involving Vietnamese Americans, returnees, and never-leavers. AB - We distinguish between selection and true migration effects on weight and body fat for Vietnamese immigrants; and examine the role of acculturation on these outcomes. Data (n = 703) were collected among three population-based samples of working-age Vietnamese immigrants, repatriated emigrants and never-migrated Vietnamese nationals. This allows for a decomposition exercise to separate the effects of migration effects from selection effects on body mass index (BMI) and waist-hip ratio (WHR). Immigrants are more likely to be overweight and to have high WHR, relative to both never-leavers and returnees, a pattern reflecting the importance of migration over selection. Among immigrants, coming to the US at a younger age is associated with higher BMI and WHR levels. And longer length of residence in the US is related to higher BMI. While higher Vietnamese language proficiency is related to a lower BMI level, being bilingual (proficient in both English and Vietnamese) is associated with lower risks for being overweight. The distinct pattern of results suggests that more problematic weight status and fat distribution among Vietnamese immigrants relative to Vietnamese nationals are not artifacts of the types of persons choosing to emigrate, but rather are due to acculturation to American diet and lifestyles. While efforts to promote and maintain traditional patterns of diet and lifestyle are likely to help Vietnamese and other immigrants avoid the perils of American patterns, facilitating a bi cultural orientation is perhaps the most realistic approach for preserving protective features of the culture of origin with regard to body weight and fat distribution. PMID- 22427071 TI - Molecular analysis of the glutamate decarboxylase locus in Streptococcus thermophilus ST110. AB - gamma-aminobutyric acid (GABA) is generated from glutamate by the action of glutamic acid decarboxylase (GAD) and characterized by hypotensive, diuretic, and tranquilizing effects in humans and animals. The production of GABA by lactic acid starter bacteria would enhance the functionality of fermented dairy foods including cheeses and yogurt. The survey of 42 strains of the yogurt starter culture Streptococcus thermophilus by PCR techniques indicated the presence of a glutamate decarboxylase gene (gadB) in 16 strains. DNA sequencing data indicated that the GAD/GABA antiporter locus (gadB/gadC) in GAD(+) S. thermophilus strains is flanked by transposase elements (5' and 3') and positioned between the luxS (5') and the HD-superfamily hydrolase genes (3'). The PCR amplification product of a ca. 2-kb genomic fragment that included the gadB and its putative promoter region was inserted into a shuttle vector, which was used to transform Escherichia coli DH5alpha. Subsequently, the recombinant plasmid pMEU5a-1/gadB (7.24 kb) was electrotransformed into the GAD-negative strain S. thermophilus ST128. The ST128 transformants carrying the plasmid-encoded gadB produced functional GAD enzyme as evidenced by the conversion of glutamate to GABA at a rate similar to strains with the gadB/gadC operon located on the chromosome. The results demonstrated the potential to impart to non-GABA-producing strains of S. thermophilus and other lactic acid bacteria the GAD(+) phenotype that improves their appeal in possible applications in the development of health-promoting functional foods. PMID- 22427070 TI - Hypertension in postmenopausal women. AB - Blood pressure is typically lower in premenopausal women than in men. However, after menopause, the prevalence of hypertension in women is higher than it is in men. Hypertension is a major risk factor for cardiovascular disease in women and men, but cardiovascular disease is the leading cause of death in women. Furthermore, there is evidence that blood pressure may not be as well-controlled in women as in men, despite the fact that most women adhere better to their therapeutic regimens and medications than do men, and have their blood pressures measured more frequently than do men. This review describes possible mechanisms by which blood pressure may be increased in postmenopausal women. PMID- 22427072 TI - Prognostic significance of ST segment changes in lead aVR in patients with acute inferior myocardial infarction with ST segment elevation. AB - BACKGROUND: Patients with inferior wall ST segment elevation myocardial infarction (STEMI) are considered to be at lower risk than patients with anterior wall STEMI. Nonetheless, 30-40% of all acute inferior wall MI cases have a poor prognosis. AIM: To assess the frequency of ST segment changes (elevation or depression) in lead aVR in inferior STEMI patients, and to determine the clinical course and short-term prognosis of such patients. METHODS: The study retrospectively analysed the records of 320 consecutive patients with inferior wall STEMI (206 males, 114 females, mean age 65.6 +/- 11.1 years). Patients were divided into three groups based on treatment: group A, primary percutaneous coronary intervention (134 patients); group B, fibrinolytic therapy (96 patients); and group C, conservative treatment (no reperfusion therapy) (90 patients). The mean time from onset of pain to the first ECG for all patients was 6.1 h. The total number of in-hospital deaths was 29 (9.0%), comprising 11 (8.2%) in group A, seven (7.3%) in group B, and 11 (12.2%) in group C (NS). The mean maximum creatine phosphokinase was 2,021 +/- 1,837 U/L in group A, 1,734 +/- 1,581 U/L in group B, and 1,217 +/- 981 U/L in group C (p = 0.01). The mean left ventricular ejection fraction was 50.2% +/- 9.0%, 54.9 +/- 8.6%, and 51.3% +/- 9.7% for groups A, B and C, respectively (NS). RESULTS: ST segment changes in lead aVR were observed in 135 (42.2%) patients, comprising elevation in 47 (14.7%) patients and depression in 88 (27.5%) patients. The in-hospital mortality rates for patients with ST segment elevation, ST segment depression, and no ST segment changes were 27.7%, 16.5%, and 1.0%, respectively (p < 0.001). For group A, the in-hospital mortality rate was higher in patients with ST segment elevation than in patients with no ST segment changes (15.4% vs 1.2%, p < 0.001). For group B, the in-hospital mortality rates were 33.3%, 12.9%, and 0%, in patients with ST segment elevation, ST segment depression, and no ST changes, respectively (p = 0.006). For group C, the in-hospital mortality rate was higher in patients with ST segment elevation (32%) than in patients with ST segment depression (12.5%) and patients with no ST segment changes (2%, p = 0.006). Logistic regression analysis found that female gender, diabetes, hypertension, lower ejection fraction, and cardiogenic shock on admission were independent predictors of ST segment elevation. CONCLUSIONS: ST segment changes in lead aVR occurred in approximately half of inferior wall STEMI patients. The presence of such ST segment changes was associated with a poorer prognosis during the hospital stay, and the changes were not associated with the type of reperfusion treatment. PMID- 22427073 TI - [11?12]. PMID- 22427074 TI - [Conduction disturbances and permanent cardiac pacing after transcatheter implantation of the CoreValve aortic bioprosthesis: initial single centre experience]. AB - BACKGROUND: The rate of significant conduction disturbances requiring permanent pacemaker implantation (PPI) following surgical aortic valve replacement (AVR) is 2-8%. Transcatheter aortic valve implantation (TAVI) is an alternative management approach in patients with severe aortic stenosis who are not considered candidates for AVR. The TAVI using the CoreValve (CV) bioprosthesis is associated with a nearly 30% rate of conduction disturbances requiring postprocedural PPI. AIM: To provide an initial evaluation of the rate of conduction disturbances and the need for PPI, and to analyse factors that increase the risk of this complication in patients undergoing TAVI using CV bioprosthesis. In addition, we evaluated the rate of permanent conduction disturbances in patients who underwent PPI at one year after TAVI. METHODS: We studies 22 initial patients in a single centre who underwent CV bioprosthesis implantation in 2009-2010. After exclusion of 6 patients with preprocedural PPI, we ultimately evaluated 16 patients. Uni- and multivariate analyses were performed using chi(2), Fisher, and Wilcoxon tests, and logistic regression analysis was performed using the SAS software. RESULTS: Overall, 8 (50%) patients in our study group required PPI after TAVI (TAVI + PPI), and the remaining 8 patients did not require PPI (TAVI). The most common indication for PPI was complete heart block. The decision to implant a pacemaker was made on average at 9 +/- 7 days following TAVI (range 3 to 22 days). When we analysed risk factors for PPI that were unrelated to the TAVI procedure, we found that the TAVI + PPI group was characterised (vs the TAVI group) by a significantly larger diameter of the native aortic valve (p = 0.03) and a larger left ventricular outflow tract (LVOT) dimension in the frontal (p = 0.02) and the corresponding frontal dimension in the transverse view (p = 0.01) by computed tomography angiography. Logistic regression analysis showed that the risk of PPI increased more than 2.5 times for each increase in the aortic annulus diameter by 1 mm (OR 2.64; 95% CI 0.90-7.74). None of the risk factors related to TAVI resulted in a significant increase in the rate of PPI. Among the patients who underwent PPI, we only noted a trend for a larger valvulotomy balloon diameter (p = 0.08), shorter procedure duration (p = 0.06), and deeper CV insertion within LVOT (p = 0.09). In addition, the bioprosthesis was inserted deeper in those patients who developed new LBBB after TAVI (p = 0.06). The ECG analysis at one day after the procedure showed a significant prolongation of PR, QRS, QT, and QTc intervals, and increased left axis deviation in the TAVI + + PPI group. In addition, the TAVI + PPI group showed increased QRS duration (p = 0.03) and increased left axis deviation (p = 0.049) compared to the TAVI group. Each increase in QRS duration by 10 ms was associated with 2.5-fold increase in the risk of PPI (OR 1.10; 95% CI 0.97-1.22), and each increase in PR interval duration by 10 ms with a 23% increase in risk (OR 1.02; 95% CI 0.99-1.05). New LBBB following CV implantation was noted significantly more frequently in the TAVI + PPI group vs the TAVI group (p < 0.0003). Pacemaker interrogation at one year after TAVI showed that the mean percentage of ventricular pacing in all patients with a pacemaker (DDD and VVI) pacing was 41%, and it was less than 10% in 2 patients. CONCLUSIONS: 1. Transcatheter implantation of a CV bioprosthesis is associated with an increased risk of persistent conduction disturbances and subsequent PPI. 2. New LBBB after TAVI may predict the need for PPI. 3. Careful ECG monitoring is necessary for one week after CV bioprosthesis implantation due to a risk of atrioventricular conduction disturbances and the need for PPI. 4. Patients at an increased risk of postprocedural PPI may be those with deep bioprosthesis insertion in LVOT, larger LVOT diameter, and larger aortic annulus diameter in the frontal view. These observations require confirmation in a larger group of patients. PMID- 22427075 TI - [Conduction disturbances and TAVI]. PMID- 22427076 TI - Superior early diagnostic performance of a sensitive cardiac troponin assay as compared to a standard troponin test in the diagnosis of acute myocardial infarction. AB - BACKGROUND: New generation cardiac troponin assays have sufficient precision to detect and quantify plasma troponin concentrations below the lower threshold of detection of the currently employed troponin tests. However, diagnostic performance of the newer generation assays in daily clinical practice is not well established. AIM: To evaluate the diagnostic performance of a sensitive assay as compared to a standard assay in a single reading at admission in the diagnosis of acute myocardial infarction (AMI) in patients presenting to the Emergency Department with chest pain. METHODS: The study comprised 187 consecutive patients admitted to the Institute of Cardiology in Warsaw in June and July 2010 with chest pain in whom the attending physician ordered troponin assay to rule AMI in or out. In all of these patients, in addition to the standard Dimension Flex Troponin I (Siemens Healthcare Diagnostics, Inc.) the sensitive Architect Stat Troponin I (Abbott Diagnostics) test was assayed. The triage of patients as well as all diagnostic and treatment decisions were left to the discretion of the attending physician who was blinded to the sensitive troponin test readings. The final diagnosis was adjudicated by a team of two cardiologists on the basis of all the available medical records except for sensitive troponin test results. RESULTS: Mean age of the study cohort (n = 187) was 64.3 +/- 13.9 years and 119 (63.6%) were males. The final diagnosis of AMI was adjudicated in 84 (44.9%) patients (mean age 67.5 +/- 12.9 years; 119 [63.6%] males). Receiver operating characteristic (ROC) analysis showed greater area under the curve (AUC) for the sensitive cardiac troponin assay compared to the standard assay (AUC = 0.916, 95% CI = 0.866-0.951 vs AUC = 0.863, 95% CI = 0.806-0.909, respectively; p = 0.02) in a single reading at admission. Sensitive assay was characterised by higher sensitivity (87%), specificity (88%), positive (86%) and negative (89%) predictive values in the detection of AMI compared to the standard troponin test (82%, 81%, 78%, and 85% respectively). CONCLUSIONS: The newer generation sensitive cardiac troponin assay presented superior diagnostic accuracy in the diagnosis of AMI compared to the standard troponin test in a single reading at admission with improved sensitivity and specificity. The sensitive troponin assay has the potential to improve early detection and/or exclusion of AMI. PMID- 22427077 TI - [A highly sensitive troponin standard - not only benefits]. PMID- 22427078 TI - Knowledge about arterial hypertension in the Polish population: the WOBASZ study. AB - BACKGROUND: Insufficient knowledge on cardiovascular disease (CVD) risk factors and unawareness of CVD and their complications limit effectiveness of CVD prevention. Thus, monitoring knowledge regarding health issues is necessary in order to prepare prevention projects. AIM: To evaluate knowledge on hypertension (HT) in relation to gender, age, education level, personal HT status, and a family history of death due to CVD. METHODS: A representative sample of the Polish population including 6977 men and 7792 women aged 20-74 years was studied in the WOBASZ study in 2003-2005. Data were collected using a questionnaire. We analysed how many respondents knew their blood pressure (BP) and classified it correctly, knew the upper limit of normal BP values (BPlim), and complications of untreated HT. Statistical analysis was performed using the chi(2) test. RESULTS: Overall, 51% of men and 56% of women reported they knew BPlim (p < 0.0001), but about 50% of them identified it within the normotensive range, 40% reported it at the level corresponding to stage I HT, and 8% of men and 6% of women even reported it as > 160/100 mm Hg. Fifty-nine percent of men and 69% women (p < 0.0001) reported being aware of their own BP, but only 72% of these men and 80% of these women classified it correctly. The most often mentioned HT complications were stroke (58% men and 69% women, p < 0.01) and myocardial infarction (60% and 65%, respectively, p < 0.01), and 32% of men and 23% of women did not know any complications of HT (p < 0.01). Older, more educated persons and those with HT or family history of death to CVD had greater knowledge on HT. CONCLUSIONS: Knowledge concerning HT is still insufficient in the Polish population, with women being more knowledgeable than men. Age, education level, HT status, and a family history of death due to CVD were significant independent predictors of knowledge level. PMID- 22427079 TI - [Awareness of the risks of hypertension in Poland: current status and ways to improve]. PMID- 22427080 TI - [The relevance of junctional rhythm during neurocardiogenic reaction provoked by tilt testing]. AB - BACKGROUND: During neurocardiogenic reaction provoked by tilt testing (TT), different arrhythmias such as sinus bradycardia, sinus arrest, atrioventricular block or junctional rhythm or beats (JR) may occur. The characteristics of the JR during neurocardiogenic reaction have not yet been systematically assessed. It is not known whether the presence of JR during neurocardiogenic reaction is related to clinical characteristics of syncopal patients or the outcome of TT. AIM: To assess whether clinical outcome of TT and clinical data are related to the presence of JR during TT. METHODS: The study group consisted of 532 patients aged 43.3 +/- 18.2 years with positive TT, divided into four groups on the basis of the presence of JR and/or a ventricular pause (VP) during neurocardiogenic reaction: group VP(-)/JR(+) - JR present and VP absent, group VP(+)/JR(+) - both JR and VP present, group VP(+)/JR(-) - JR absent and VP present, and group VP( )/JR(-) - both JR and VP absent. The control group consisted of 53 patients with no history of syncope or presyncope, including 46 patients with negative TT and seven patients with false positive TT. RESULTS: Total loss of consciousness during TT occurred in group VP(-)/JR(+) less frequently than in groups VP(+)/JR(+) and VP(+)/JR(-), and more frequently than in group VP(-)/JR(-) (80% vs 96% vs 94% vs 62%; p < 0.05 for both comparisons). Group VP(-)/JR(+) was significantly younger than group VP(-)/JR(-) (37.3 +/- 16.3 years vs 45.8 +/- 18.9 years; p < 0.05) and had a lower number of syncopal events than group VP(+)/JR(+) and VP(+)/JR(-) (median [IQ]: 2.5 (1-6) vs 4 (2-12) and 4 (2-10), respectively; p < 0.05) and lower rate of traumatic injuries than group VP(+)/JR(+) and VP(+)/JR(-) (22% vs 45% and 39%, respectively; p < 0.05). Logistic regression analysis revealed that the presence of JR was associated with younger age, male gender, history of blood-instrumentation-injection phobia and higher number of syncopal spells in medical history. The ROC curve analysis revealed that a junctional rate of no more than 49 bpm was related to the total loss of consciousness during TT (p < 0.05). CONCLUSIONS: 1. JR frequently occurs during positive TT and in no subjects with negative TT. 2. Among patients with JR, two groups may be chosen on the basis of a VP occurrence, and these groups differ in respect to clinical characteristics and TT outcome. 3. Relatively rapid JR without VP is related to consciousness preservation during neurocardiogenic reaction at TT and fewer syncopal spells as well as syncope associated with injury in the past. 4. In patients with JR and VP, the JR is slower, of shorter duration, and more frequently single or pairs of junctional beats occur, which indicates high parasympathetic activity, whereas relatively rapid and stable JR may be the symptom of simultaneously increased sympathetic and parasympathetic activity. PMID- 22427081 TI - [ECG monitoring is a central issue in syncope]. PMID- 22427082 TI - Sense of coherence as a personality predictor of the quality of life in men and women after myocardial infarction. AB - BACKGROUND: The vast majority of research on the quality of life (QoL) after myocardial infarction (MI) concentrates on such factors as: the type and course of MI, methods and stage of treatment or the patient's occupational and family status. Drawing from general psychological knowledge we may assume that some individual factor, especially personality, is also a significant contributor. The present study focused on a specific personality dimension: sense of coherence (SOC). It is defined as a global life orientation to perceive life as comprehensible (rational, predictable and structured), manageable (adequate and sufficient resources to overcome adversities are perceived as available) and meaningful (the demands created by adversities are seen as challenges and worthy of engagement). AIM: To compare the QoL one year after MI in men and women and to examine the role of SOC as a predictor of the QoL one year after MI, in groups of men and women. METHODS: The study group consisted of 83 participants (including 34 women), aged 35-59 (50.2 +/- 6.2) years. They had a history of uncomplicated MI and were referred for post-hospitalisation cardiac rehabilitation in the sanatorium setting. SOC was measured with the Polish version of SOC-13 by A. Antonovsky. The QoL was evaluated with the MacNew questionnaire by N.B. Oldridge and L. Lim. The SOC was assessed during the stay at the heart centre. One year after their MI the participants completed the QoL questionnaires (sent to them by post). RESULTS: Men in comparison to women demonstrated stronger SOC (p < 0.004) and a better QoL in all dimensions: physical (p < 0.001), emotional (p < 0.001), social (p < 0.001) and as a global score (p < 0.001). The SOC turned out to be a significant predictor of the QoL one year after MI even after controlling for demographic and medical factors. Its predictive value was higher for women. CONCLUSIONS: Research on the QoL in patients after MI should take into account personality factors. The SOC is a significant predictor, especially in women. Persons after MI scoring low on SOC at the early stage of rehabilitation should receive psychological intervention. PMID- 22427083 TI - [Individual personality differences]. PMID- 22427084 TI - [Early bioprosthetic mitral valve thrombosis]. AB - We present a case of a 70 year-old woman operated due to severe mitral regurgitation. Early after surgery transthoracic echocardiography revealed the decreased effective orifice area of the implanted bioprosthetic valve and the stenotic features of transvalvular flow. Transesophageal echocardiography (TEE) disclosed a thrombotic cause of heterograft dysfunction. Due to the clinical deterioration and the unclear cause of prosthesis stenosis, the patient was reoperated. Intra-operatively bioprosthetic mitral valve thrombosis was confirmed. Precipitating factors of this rare complication including cardiac device related infective endocarditis (CDRIE) and the diagnostic applicability of TEE in this clinical scenario are discussed. PMID- 22427085 TI - [Co-existence of severe aortic valve stenosis and recoarctation of the aorta treated surgically in childhood]. AB - Coarctation of the aorta is treated surgically in most of patients during childhood. However, some of them experience recoarctation in future. A 57 year old woman suffering from chest pain and decreased activity tolerance was admitted to the cardiac department. Physical examinations, lab tests and cardiovascular imaging revealed severe aortic valve stenosis and insignificant narrowing of the aorta. The patient underwent a surgical replacement of the aortic valve without recoarctation repair. PMID- 22427086 TI - [Primary percutaneous coronary intervention facilitated with supersaturated oxygen therapy in a patient with anterior myocardial infarction: a case report and literature review]. AB - Infarct size is regarded as the main factor determining short- and long-term prognosis after acute myocardial infarction. Effective reperfusion therapy reduces infarct size by half. Despite broad implementation of primary percutaneous coronary interventions, the prognosis in many patients with large infarcts remains serious. We present a case report on a patient with an anterior wall ST-segment elevation myocardial infarction successfully treated interventionally with the use of supersaturated oxygen delivery. PMID- 22427087 TI - [Origin of right pulmonary artery branch from descending aorta. Case report of the successful treatment]. AB - This report describes an extremely rare case involving anomalous origin of part of the right pulmonary branch from the thoracic aorta in a 3 month-old boy and its successful repair. PMID- 22427088 TI - [Is it worth estimating C-reactive protein in venous thromboembolism disease?]. PMID- 22427089 TI - [Right heart thrombi - still a clinical challenge. Review of present state of knowledge]. PMID- 22427090 TI - [Advanced programming of cardiac resynchronisation therapy under echocardiographic examination: is it feasible and efficient?]. AB - In patients with heart failure treated with cardiac resynchronisation therapy (CRT), proper programming of the device can enhance the benefits of stimulation. Nowadays, adjustment of atrio-ventricular delay (AVD) is usually guided by echocardiography and performed only in resting conditions. The issue of optimal CRT programming during exercise, and the decision regarding the use of rate adaptive pacing and rate-adaptive AVD algorithm during CRT, are largely empirical. We present a case report, and we indicate that programming of rate adaptive pacing and rate-adaptive AVD algorithm on the basis of extended echocardiographic evaluation can further benefit the individual patient. PMID- 22427091 TI - [Acute coronary syndrome during dissection of left main as a complication of radiofrequency ablation]. AB - We present a case of 44 year-old female who was admitted to the hospital due to performed radio frequency ablation because of VF during WPW syndrome, which was complicated by dissection of left main. The dissection was treated with success by primary percutaneous coronary intervention with two metal stents. PMID- 22427094 TI - [Not Available]. PMID- 22427093 TI - [Use of non-contact mapping to localise distant from endocardium origin of atrial tachycardia]. AB - A 65 year-old woman developed tachycardia and hypotension during haemodialysis. The non-contact mapping system was used to localise the origin of focal atrial tachycardia, and showed a remote from the endocardium focus. We discuss techniques that are helpful in identifying the origin, the area of preferential conduction, and the endocardial breakthrough of tachycardia. PMID- 22427095 TI - [Not Available]. PMID- 22427096 TI - Treatment of elevated pulmonary artery pressure in a child after Glenn procedure: transcatheter closure of pulmonary artery banding with subsequent sildenafil therapy. AB - An additional source of pulmonary blood flow in a patient with bidirectional Glenn procedure (BGD) may cause elevation of mean pulmonary artery pressure (MPAP), precluding safe completion of the Fontan operation. We present a case of single ventricle physiology after pulmonary artery banding (PAB) and Glenn procedure. At the age of six years, cardiac catheterisation revealed in the patient elevated MPAP (22 mm Hg). The PAB was closed through the right internal jugular vein with an Amplatzer Atrial Septal Occluder. After the procedure, MPAP remained at a similar level. Sildenafil oral therapy was applied for six months. Subsequent heart catheterisation confirmed complete closure of PAB and decrease of MPAP to 10 mm Hg. The abovementioned complex treatment of elevated MPAP pressure in a child after Glenn therapy allowed safe completion of the Fontan operation. PMID- 22427097 TI - [Oskar Widmann, a significant Polish contributor to the investigation of the symptoms and pathology of tetralogy prior to Etienne-Louis Arthur Fallot]. PMID- 22427098 TI - [Optimal antiplatelet and antithrombotic therapy in patients with ST elevation myocardial infarction]. PMID- 22427099 TI - [Letter to Kardiologia Polska concerning optimal treatment of myocardial infarction]. PMID- 22427100 TI - Radio-sensitization of SHG44 glioma cells by Aidi injection in vitro. AB - In this study, we aimed to explore the radio-sensitization of the SHG44 glioma cell line by Aidi injection and the possible mechanisms involved. The growth curve, cloning efficiency and divisional index of the SHG44 cell line were observed. The inhibition ratio was determined by MTT assay, the change in the cell cycle was analyzed by flow cytometry and the expression of cyclin B1 and Wee1 was detected by western blot analysis. The reproductive activity of the group treated with irradiation (IR) and Aidi injection was suppressed significantly, and the cloning efficiency and divisional index also declined. Aidi injection (15 ug/ml) induced G2/M phase arrest efficiently in the cell line after 48 h. The expression of cyclin B1 decreased in the group treated with IR and Aidi injection compared with either of those with IR or Aidi injection alone. The expression of Wee1 increased in the group treated with IR and Aidi injection compared with that in the groups treated with either IR or Aidi injection alone. In conclusion, Aidi injection is effective in radio-sensitization. The possible mechanisms involved may be associated with G2/M phase cell arrest, the downregulation of cyclin B1 and upregulation of Wee1 expression. PMID- 22427101 TI - CD147 silencing via RNA interference reduces tumor cell invasion, metastasis and increases chemosensitivity in pancreatic cancer cells. AB - CD147, which belongs to the immunoglobulin superfamily, is a multifunctional glycoprotein that has been shown to increase tumor invasion, metastasis and multidrug resistance. To define the role of CD147 in invasion and metastasis more precisely, we utilized gene silencing to inhibit the expression of CD147 in pancreatic cancer cells. We observed that CD147 expression was significantly impeded at both the mRNA and protein levels and resulted in a decrease of MMP-2 and MMP-9 activities. There was also a decrease of MCT1 expression in the invasion and metastasis potential of pancreatic cancer cells, as well as increased chemosensitivity to gemcitabine in Panc-1 cells. Overall, these results suggest that CD147 plays an important role in the invasion, metastasis and chemosensitivity of the human pancreatic cancer cell line Panc-1, indicating that CD147 may be a promising therapeutic target for pancreatic cancer. PMID- 22427102 TI - Clinical implications of molecular neuropathology and biomarkers for malignant glioma. AB - Malignant gliomas are currently diagnosed based on morphological criteria and graded according to the World Health Organization classification of primary brain tumors. This algorithm of diagnosis and classification provides clinicians with an estimated prognosis of the natural course of the disease. It does not reflect the expected response to specific treatments beyond surgery (eg, radiotherapy or alkylating chemotherapy). Clinical experience has revealed that gliomas sharing similar histomorphological criteria might indeed have different clinical courses and exhibit highly heterogenous responses to treatments. This was very impressively demonstrated first for oligodendrogliomas. The presence or lack of combined deletions of the chromosomal segments 1p/19q was associated with different benefit from radiotherapy and chemotherapy. We review current molecular markers for malignant gliomas and discuss their current and future impact on clinical neuro-oncology. PMID- 22427104 TI - Exploration of the relationship between sleep position and isolated tongue base or multilevel surgery in obstructive sleep apnea. AB - This study aimed to elucidate the role of sleep position as a confounding factor on apnea hypopnea index (AHI) and surgical success in isolated tongue base or multilevel surgery. This study was conducted using retrospective analysis of patients who underwent hyoid suspension because of obstructive sleep apnea (OSA), in the St. Lucas Andreas Hospital, Amsterdam, The Netherlands, from 2004 to 2011. Concurrent surgical treatment was documented. Sleep positions and corresponding AHIs before and after surgery were compared. A total of 130 patients were included. 94 patients underwent surgery of base of tongue and palate (either uvulopalatopharyngoplasty or Z-palatoplasty), of whom 72 underwent concurrent radiofrequent thermotherapy of the base of tongue. 36 patients underwent base of tongue surgery alone, of whom 22 underwent concurrent radiofrequent thermotherapy of the base of tongue. 65 patients either had a successful reduction in AHI or in AI. Isolated tongue base or multilevel surgery was as successful on the supine AHI as it was on the AHI in other sleeping positions. Surgery was not more successful in the group with position-dependent patients as compared with the non position-dependent patients (P = 0.615). Successful and non-successful surgical results could not be explained by variations in percentages of supine sleep position. Sleep position is not a confounding factor on surgical outcomes in tongue base surgery. The results of isolated base of tongue or multilevel surgery in position-dependent OSA patients leave room for improvement, possibly through positional therapy. PMID- 22427105 TI - Carbon nanotube enhanced mediator-type biosensor for real-time monitoring of glucose concentrations in fish. AB - We have developed a mediator-type biosensor to rapidly monitor blood glucose concentrations in fish, which are an indicator of stress. Glucose oxidase was used to detect glucose concentrations and ferrocene was used to limit the effect of oxygen. We also improved the sensitivity and durability of the sensor for better performance. Single-walled carbon nanotubes were used to enhance sensor sensitivity. Affixing the carbon nanotubes (30 mg ml(-1)) to the working electrode increased the sensor sensitivity to 61.9 mM nA(-1) mm(-2), twice the value for the sensor without single-walled carbon nanotubes. A fabricated mediator-type biosensor sensor was used to perform real-time in vivo measurements. The sensor was implanted into the interstitial fluid of a fish eyeball, and detection was transmitted to a personal computer by a wireless potentiostat. Continuous measurement of the glucose concentration was possible for 78 hours. Stress was artificially applied to the fish during the measurement, and the change of blood glucose concentrations were observed. Our proposed sensor is applicable for effectively monitoring stress in free-swimming fish. PMID- 22427106 TI - Pressurized liquid extraction as a sample preparation method for the analysis of isoflavones in pulses. AB - In this work, we describe a rapid and simple analytical method that exploits pressurized liquid extraction (PLE) and liquid chromatography with diode array detection for the determination of isoflavones in samples of Spanish pulses. Confirmation of the analytes present was performed using ion-trap mass spectrometry. To optimize the PLE extraction, variables such as the dispersing agent, type of solvent and sample amount, and the experimental parameters, such as temperature and the number of extraction cycles, were studied. Separation was carried out using a reverse-phase C18 with polar endcapping as the stationary phase and acetonitrile/water with 0.2 % of formic acid, under a gradient regime, as the mobile phase. Optimal extraction of formononetin and biochanin-A from chickpeas with PLE was achieved using Hydromatrix as a dispersant agent, methanol/water (50:50), a temperature of 90 degrees C, and three cycles. The same optimal conditions-except methanol/water (75:25)-for solvent extraction were obtained for the extraction of daidzin, genistin, and formononetin from lentils. Recoveries ranged from 97 to 110 %, and standard deviations lower than 20 % were obtained. The contents obtained for daidzin in lentils using the proposed method were not significantly different from those obtained using another official method of analysis. PMID- 22427107 TI - Corticospinal tractography with morphological, functional and diffusion tensor MRI: a comparative study of four deterministic algorithms used in clinical routine. AB - PURPOSE: Diffusion tensor imaging permits study of white matter fibre bundles; however, its main limitation is lack of validation on anatomical data, especially in crossing fibre regions. Our study aimed to compare four deterministic tractography algorithms used in clinical routine. We studied the corticospinal tract, the bundle mediating voluntary movement. Our study seeks to evaluate tractography provided by algorithms through comparative analysis by expert neuroradiologists. METHODS: MRI data from 15 right-handed volunteers (30.8 years) were studied. Regions of interest (ROIs) were segmented on morphological and functional MRI. Diffusion weighted images (15 directions) were performed, then for each voxel the tensor was estimated. Tractography of the corticospinal tract was performed using four fibre-tracking algorithms. Three numerical integration methods Euler, Runge-Kutta second (RK2) and fourth order (RK4), and a tensor deflection method (TEND). Quantitative measurement was performed. Qualitative evaluation was carried out by two expert neuroradiologists using Kappa test concordance. RESULTS: For the quantitative aspect, only RK2 and TEND presented no significant difference concerning the number of fibres (p = 0.58). There was no difference between right and left side for each algorithm. Regarding the qualitative aspects, there was a lack of fibres from the ventrolateral part of the functional ROIs. Comparison by expert neuroradiologists revealed low rather than high concordance. The algorithm ranked first was RK2 according to expert preferences. CONCLUSIONS: Different algorithms used in clinical routine failed to show realistic anatomical bundles. The most mathematically robust algorithm was not selected, nor was the algorithm defining more fibres. Validation of anatomical data provided by tractography remains a challenge. PMID- 22427108 TI - Factors that influence diabetes self-management in Hispanics living in low socioeconomic neighborhoods in San Bernardino, California. AB - The growing incidence of diabetes among Hispanics is a serious public health concern. To identify factors that influence diabetes self-management in Hispanics, qualitative data gathered through five focus group interviews was examined using grounded theory methods. Four major themes emerged which were perceived by participants as enhancing or limiting factors: (1) access to resources, (2) struggle with diet, (3) self-efficacy, and (4) social support. The family's role as a determinant of diabetes self-management emerged as the underlying sub-theme to all four themes and underscores its importance among Hispanics living with diabetes. Results suggest that for the family to be an enhancing factor, health care providers need to educate, empower, and include the family in diabetes management and prevention. Programs which aim to improve the practice of self-management should incorporate the sociocultural and socioeconomic context in which Hispanics with diabetes live. PMID- 22427109 TI - Nativity differences in chronic health conditions between nationally representative samples of Asian American, Latino American, and Afro-Caribbean American respondents. AB - Immigrants on average have better health than native-born residents. However, no clear understanding of prevalence of chronic conditions across foreign-born groups exists, and few studies include Afro-Caribbean populations. This study utilizes the National Latino and Asian American Study and the National Survey of American Life to investigate nativity differences in reports of chronic cardiovascular, respiratory, and pain conditions between foreign-born (n = 3,579) and native-born (n = 1,409) respondents. Native-born respondents were significantly more likely than foreign-born counterparts to report chronic respiratory [c2(1, n = 4,958) 30.78, P <= .05] and pain [c2(1, n = 4,958) 3.77, P <= .05] conditions. Logistic regression models reveal significant associations between chronic conditions and other demographic factors known to influence immigrant health. Afro-Caribbean populations were less likely than other foreign born respondents to report respiratory and pain conditions. Findings illustrate the importance of comparing health profiles across native-born and foreign-born counterparts with the inclusion of Afro-Caribbean Americans. PMID- 22427110 TI - Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma. AB - Although external beam radiation is an essential component to the current standard treatment of primary brain tumors, its application is limited by toxicity at doses more than 80 Gy. Recent studies have suggested that brachytherapy with liposomally encapsulated radionuclides may be of benefit, and we have reported methods to markedly increase the specific activity of rhenium 186 ((186)Re)-liposomes. To better characterize the potential delivery, toxicity, and efficacy of the highly specific activity of (186)Re-liposomes, we evaluated their intracranial application by convection-enhanced delivery in an orthotopic U87 glioma rat model. After establishing an optimal volume of 25 uL, we observed focal activity confined to the site of injection over a 96-hour period. Doses of up to 1850 Gy were administered without overt clinical or microscopic evidence of toxicity. Animals treated with (186)Re-liposomes had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), compared with 49 days (95% CI, 44-53 days) for controls. Log-rank analysis between these 2 groups was highly significant (P = .0013) and was even higher when 100 Gy was used as a cutoff (P < .0001). Noninvasive luciferase imaging as a surrogate for tumor volume showed a statistically significant separation in bioluminescence by 11 days after 100 Gy or less treatment between the experimental group and the control animals (chi(2)[1, N= 19] = 4.8; P = .029). MRI also supported this difference in tumor size. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model, with clear separation in bioluminescence at 6 days after treatment (chi(2)[1, N= 9] = 4.7; P = .029); median survival in treated animals was not reached at 120 days because lack of mortality, and log-rank analysis of survival was highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis. These results support the potential efficacy of the highly specific activity of brachytherapy by (186)Re-liposomes convection-enhanced delivery in glioma. PMID- 22427111 TI - Henipavirus membrane fusion and viral entry. AB - Nipah (NiV) and Hendra (HeV) viruses cause cell-cell fusion (syncytia) in brain, lung, heart, and kidney tissues, leading to encephalitis, pneumonia, and often death. Membrane fusion is essential to both viral entry and virus-induced cell cell fusion, a hallmark of henipavirus infections. Elucidiation of the mechanism(s) of membrane fusion is critical to understanding henipavirus pathobiology and has the potential to identify novel strategies for the development of antiviral therapeutic agents. Henipavirus membrane fusion requires the coordinated actions of the viral attachment (G) and fusion (F) glycoproteins. Current henipavirus fusion models posit that attachment of NiV or HeV G to its cell surface receptors releases F from its metastable pre-fusion conformation to mediate membrane fusion. The identification of ephrinB2 and ephrinB3 as henipavirus receptors has paved the way for recent advances in our understanding of henipavirus membrane fusion. These advances highlight mechanistic similarities and differences between membrane fusion for the henipavirus and other genera within the Paramyxoviridae family. Here, we review these mechanisms and the current gaps in our knowledge in the field. PMID- 22427112 TI - betaA3/A1-crystallin is required for proper astrocyte template formation and vascular remodeling in the retina. AB - Nuc1 is a spontaneous rat mutant resulting from a mutation in the Cryba1 gene, coding for betaA3/A1-crystallin. Our earlier studies with Nuc1 provided novel evidence that astrocytes, which express betaA3/A1-crystallin, have a pivotal role in retinal remodeling. The role of astrocytes in the retina is only beginning to be explored. One of the limitations in the field is the lack of appropriate animal models to better investigate the function of astrocytes in retinal health and disease. We have now established transgenic mice that overexpress the Nuc1 mutant form of Cryba1, specifically in astrocytes. Astrocytes in wild type mice show normal compact stellate structure, producing a honeycomb-like network. In contrast, in transgenics over-expressing the mutant (Nuc1) Cryba1 in astrocytes, bundle-like structures with abnormal patterns and morphology were observed. In the nerve fiber layer of the transgenic mice, an additional layer of astrocytes adjacent to the vitreous is evident. This abnormal organization of astrocytes affects both the superficial and deep retinal vascular density and remodeling. Fluorescein angiography showed increased venous dilation and tortuosity of branches in the transgenic retina, as compared to wild type. Moreover, there appear to be fewer interactions between astrocytes and endothelial cells in the transgenic retina than in normal mouse retina. Further, astrocytes overexpressing the mutant betaA3/A1-crystallin migrate into the vitreous, and ensheath the hyaloid artery, in a manner similar to that seen in the Nuc1 rat. Together, these data demonstrate that developmental abnormalities of astrocytes can affect the normal remodeling process of both fetal and retinal vessels of the eye and that betaA3/A1-crystallin is essential for normal astrocyte function in the retina. PMID- 22427113 TI - Transient expression of artificial microRNAs targeting Grapevine fanleaf virus and evidence for RNA silencing in grapevine somatic embryos. AB - Grapevines are affected worldwide by viruses that compromise fruit yield and quality. Grapevine fanleaf virus (GFLV) causes fanleaf degeneration disease, a major threat to grapevine production. Transgenic approaches exploiting the RNA silencing machinery have proven suitable for engineering viral resistance in several crop species. However, the artificial microRNA (amiRNA)-based strategy has not yet been reported in grapevine. We developed two amiRNA precursors (pre amiRNAs) targeting the coat protein (CP) gene of GFLV and characterised their functionality in grapevine somatic embryos. To create these pre-amiRNAs, natural pre-miR319a of Arabidopsis thaliana was modified by overlapping PCR in order to replace miR319a with two amiRNAs targeting different regions of the CP gene: amiR(CP)-1 or amiR(CP)-2. Transient expression of these two pre-amiRNA constructs was tested in grapevine somatic embryos after co-cultivation with Agrobacterium tumefaciens. Expression of amiR(CP)-1 and amiR(CP)-2 was detected in plant tissues by an endpoint stem-loop RT-PCR as early as 1 day after a 48-h co cultivation, indicating active processing of pre-amiRNAs by the plant machinery. In parallel, GUS-sensor constructs (G(CP)-1 and G(CP)-2) were obtained by fusing the target sequence of amiR(CP)-1 or amiR(CP)-2 to the 3' terminus of the GUS gene. Co-transformation assays with GUS-sensors and the pre-amiRNA constructs provided evidence for in vivo recognition and cleavage of the 21-nt target sequence of GUS-sensors by the corresponding amiRNA. This is the first report of amiRNA ectopic expression in grapevine. The constructs we developed could be useful for engineering GFLV-resistant grapes in the future. PMID- 22427114 TI - Cyanate attenuates insulin secretion in cultured pancreatic beta cells. AB - The vast majority of long-term complications in transplanted patients are associated with cardiovascular disease. Previously, an alternative and dominant mechanism for cyanate formation in atherosclerotic lesions has been discovered. This study was designed to determine the effect of cyanate on insulin secretion in cultured pancreatic beta cells (INS-1 cells). The cytotoxicity of cyanate was determined by 3-(4,5-Desethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Insulin secretion was measured by ELISA in cyanate-treated INS-1 cells. Reactive oxygen species (ROS) generation was also determined by measuring the fluorescent oxidized product of 2,7-dichlorefluorescein in cyanate-treated INS-1 cells. FACS analysis was carried out to determine the effect of cyanate on the apoptosis of INS-1 cells. Firstly, we found that cyanate, within concentration ranges in which no cytotoxic effect was observed (0.01, 0.1 and 1.0 mM), decreased insulin secretion dose-dependently in both non-glucose-stimulated and glucose-stimulated INS-1 cells. Cyanate at a 1.0 mM concentration inhibited insulin secretion by more than 50% in non-glucose-stimulated cells and glucose (5 and 10 mM) stimulated cells. Cyanate, however, did not affect ROS generation. Furthermore, no pro- or anti-apoptotic effect was observed in cyanate-treated INS-1 cells. The results in this study suggest the possible inhibitory effect of cyanate on insulin secretion in INS-1 pancreatic beta cells. The inhibitory effect was not mediated either by ROS generation or by apoptosis. Further studies to determine the underlying mechanisms will be of benefit. PMID- 22427115 TI - Kinases, phosphatases and proteases during sperm capacitation. AB - Fertilization is the process by which male and female haploid gametes (sperm and egg) unite to produce a genetically distinct individual. In mammals, fertilization involves a number of sequential steps, including sperm migration through the female genital tract, sperm penetration through the cumulus mass, sperm adhesion and binding to the zona pellucida, acrosome exocytosis, sperm penetration through the zona and fusion of the sperm and egg plasma membranes. However, freshly ejaculated sperm are not capable of fertilizing an oocyte. They must first undergo a series of biochemical and physiological changes, collectively known as capacitation, before acquiring fertilizing capabilities. Several molecules are required for successful capacitation and in vitro fertilization; these include bicarbonate, serum albumin (normally bovine serum albumin, BSA) and Ca(2+). Bicarbonate activates the sperm protein soluble adenylyl cyclase (SACY), which results in increased levels of cAMP and cAMP dependent protein kinase (PKA) activation. The response to bicarbonate is fast and cAMP levels increase within 60 s followed by an increase in PKA activity. Several studies with an anti-phospho-PKA substrate antibody have demonstrated a rapid increase in protein phosphorylation in human, mouse and boar sperm. The target proteins of PKA are not known and the precise role of BSA during capacitation is unclear. Most of the studies provide support for the idea that BSA acts by removing cholesterol from the sperm. The loss of cholesterol has been suggested to affect the bilayer of the sperm plasma membrane making it more fusogenic. The relationship between cholesterol loss and the activation of the cAMP/PKA pathway is also unclear. During early stages of capacitation, Ca(2+) might be involved in the stimulation of SACY, although definitive proof is lacking. Protein tyrosine phosphorylation is another landmark of capacitation but occurs during the late stages of capacitation on a different time-scale from cAMP/PKA activation. Additionally, the tyrosine kinases present in sperm are not well characterized. Although protein phosphorylation depends upon the balanced action of protein kinases and protein phosphatase, we have even less information regarding the role of protein phosphatases during sperm capacitation. Over the last few years, several reports have pointed out that the ubiquitin-proteasome system might play a role during sperm capacitation, acrosome reaction and/or sperm-egg fusion. In the present review, we summarize the information regarding the role of protein kinases, phosphatases and the proteasome during sperm capacitation. Where appropriate, we give examples of the way that these molecules interact and regulate each other's activities. PMID- 22427116 TI - Refined sensory measures of neural repair in human spinal cord injury: bridging preclinical findings to clinical value. AB - Sensory input from the periphery to the brain can be severely compromised or completely abolished after an injury to the spinal cord. Evidence from animal models suggests that endogenous repair processes in the spinal cord mediate extensive sprouting and that this might be further attenuated by targeted therapeutic interventions. However, the extent to which sprouting can contribute to spontaneous recovery after human spinal cord injury (SCI) remains largely unknown, in part because few measurement tools are available in order to non invasively detect subtle changes in neurophysiology. The proposed application of segmental sensory evoked potentials (e.g., dermatomal contact heat evoked potentials and somatosensory evoked potentials) to assess conduction in ascending pathways (i.e., spinothalamic and dorsal column, respectively) differs from conventional approaches in that individual spinal segments adjacent to the level of lesion are examined. The adoption of these approaches into clinical research might provide improved resolution for measuring changes in sensory impairments and might determine the extent by which spontaneous recovery after SCI is mediated by similar endogenous repair mechanisms in humans as in animal models. PMID- 22427117 TI - The VD1/RPD2 alpha1-neuropeptide is highly expressed in the brain of cephalopod mollusks. AB - In certain gastropod mollusks, the central neurons VD(1) and RPD(2) express a distinct peptide, the so-called VD(1)/RPD(2) alpha1-neuropeptide. In order to test whether this peptide is also present in the complex cephalopod central nervous system (CNS), we investigated several octopod and squid species. In the adult decapod squid Idiosepius notoides the alpha1-neuropeptide is expressed throughout the CNS, with the exception of the vertical lobe and the superior and inferior frontal lobes, by very few immunoreactive elements. Immunoreactive cell somata are particularly abundant in brain lobes and associated organs unique to cephalopods such as the subvertical, optic, peduncle, and olfactory lobes. The posterior basal lobes house another large group of immunoreactive cell somata. In the decapod Idiosepius notoides, the alpha1-neuropeptide is first expressed in the olfactory organ, while in the octopod Octopus vulgaris it is first detected in the olfactory lobe. In prehatchlings of the sepiolid Euprymna scolopes as well as the squids Sepioteuthis australis and Loligo vulgaris, the alpha1-neuropeptide is expressed in the periesophageal and posterior subesophageal mass. Prehatchlings of L. vulgaris express the alpha1-neuropeptide in wide parts of the CNS, including the vertical lobe. alpha1-neuropeptide expression in the developing CNS does not appear to be evolutionarily conserved across various cephalopod taxa investigated. Strong expression in different brain lobes of the adult squid I. notoides and prehatching L. vulgaris suggests a putative role as a neurotransmitter or neuromodulator in these species; however, electrophysiological evidence is still missing. PMID- 22427118 TI - Gene expression profile of Campylobacter jejuni-induced GBS in Bama miniature pigs. AB - Our aim was to investigate the in vivo gene expression pattern of the Guillain Barre syndrome (GBS) with DNA microarrays and bioinformatics tools. Oral-infusion model animals mimicking human infection of GBS were analyzed. Tissue samples and body fluids were collected to perform antibody tests and biopsy assays. Gene expression microarray was conducted with nerve tissues and GBS-related genes were elucidated via bioinformatics tools. Model animals showed typical symptoms of GBS in that mild demyelination was shown by cerebellar white matter and by lumbar enlargement of model animals. Then, 81.25% of the model animals were positive with GM1-IgG antibodies by ELISA. In the microarray analysis, 1,261 genes were identified with statistically different expression (P < 0.05), 21 of which were associated with gene function analysis, gene pathway identification, signal transduction and co-expression network construction. Furthermore, quantitative PCR was used to characterize the gene expression level. We found that genes of HPRT1, PKC and PPARGC-1 were in the core of the network, while the expression of PPARGC-1, SUS2DD and AMPKA2 were significantly inhibited. A total of 21 genes were found to be actively involved in the process of protein transportation, transcriptional regulation, antigen identification and cell cycle regulation during the GBS infection period. The co-expression network indicated an important association between GBS and the 21 genes, especially the down-regulated ones. In conclusion, we demonstrated that GBS-affected hosts had a specific gene expression profile, which may guide the direction of GBS research and therapy. PMID- 22427119 TI - Bladder expression of CD cell surface antigens and cell-type-specific transcriptomes. AB - Many cell types have no known functional attributes. In the bladder and prostate, basal epithelial and stromal cells appear similar in cytomorphology and share several cell surface markers. Their total gene expression (transcriptome) should provide a clear measure of the extent to which they are alike functionally. Since urologic stromal cells are known to mediate organ-specific tissue formation, these cells in cancers might exhibit aberrant gene expression affecting their function. For transcriptomes, cluster designation (CD) antigens have been identified for cell sorting. The sorted cell populations can be analyzed by DNA microarrays. Various bladder cell types have unique complements of CD molecules. CD9(+) urothelial, CD104(+) basal and CD13(+) stromal cells of the lamina propria were therefore analyzed, as were CD9(+) cancer and CD13(+) cancer-associated stromal cells. The transcriptome datasets were compared by principal components analysis for relatedness between cell types; those with similarity in gene expression indicated similar function. Although bladder and prostate basal cells shared CD markers such as CD104, CD44 and CD49f, they differed in overall gene expression. Basal cells also lacked stem cell gene expression. The bladder luminal and stromal transcriptomes were distinct from their prostate counterparts. In bladder cancer, not only the urothelial but also the stromal cells showed gene expression alteration. The cancer process in both might thus involve defective stromal signaling. These cell-type transcriptomes provide a means to monitor in vitro models in which various CD-isolated cell types can be combined to study bladder differentiation and bladder tumor development based on cell-cell interaction. PMID- 22427120 TI - Proteases and the gut barrier. AB - Serine proteases, cysteine proteases, aspartic proteases and matrix metalloproteinases play an essential role in extracellular matrix remodeling and turnover through their proteolytic action on collagens, proteoglycans, fibronectin, elastin and laminin. Proteases can also act on chemokines, receptors and anti-microbial peptides, often potentiating their activity. The intestinal mucosa is the largest interface between the external environment and the tissues of the human body and is constantly exposed to proteolytic enzymes from many sources, including bacteria in the intestinal lumen, fibroblasts and immune cells in the lamina propria and enterocytes. Controlled proteolytic activity is crucial for the maintenance of gut immune homeostasis, for normal tissue turnover and for the integrity of the gut barrier. However, in intestinal immune-mediated disorders, pro-inflammatory cytokines induce the up-regulation of proteases, which become the end-stage effectors of mucosal damage by destroying the epithelium and basement membrane integrity and degrading the extracellular matrix of the lamina propria to produce ulcers. Protease-mediated barrier disruption in turn results in increased amounts of antigen crossing into the lamina propria, driving further immune responses and sustaining the inflammatory process. PMID- 22427121 TI - [Identifying depression in the general population - a comparison of PHQ-9, PHQ-8 and PHQ-2]. AB - OBJECTIVE: To examine the comparability of depression as defined by PHQ-9, PHQ-8 and PHQ-2 in the German general population. METHODS: The PHQ-9 was assessed in a representative sample (N = 2524). Depression diagnosis and depression severity as measured either by PHQ-9, PHQ-8 or PHQ-2 were compared. RESULTS: PHQ-8 and PHQ-9 performed comparably in identifying depressive persons, though there are slight differences in rating depression severity. In comparison, the PHQ-2 showed the best performance in the detection of any depressive disorder. CONCLUSIONS: The PHQ-9 should be used in clinical settings, whereas in research and when persons are being approached via telephone/mail/internet the PHQ-8 is preferable. The PHQ 2 is recommended as a very economic and brief screener for depressive disorders. PMID- 22427122 TI - [The protective impact of optimistic expectations in male cancer patients]. AB - OBJECTIVES: This study investigates the course of psychological distress, need for psychosocial support and quality of life in prostate cancer patients with respect to their dispositional optimism. METHODS: A sample of 253 patients with prostate carcinoma completed questionnaires measuring optimism (LOT), psychological distress (PHQ-4), quality of life (EORTC QLQ-C30) and need for psychosocial support (HSI) during hospitalization (T1), two weeks (T2) and three months (T3) after discharge. RESULTS: Optimism at T1 is negatively correlated with psychological distress and the need for support at T3. Even after controlling for the baseline levels of these variables, we found that optimism explained incremental variance three months later. The proportion of patients with an expressed need for support ranged from 45 % at T1 to 30 % at T3. Depression is - compared to the German general population - elevated only at T1, while anxiety remains heightened over the entire course. CONCLUSIONS: Patients with a high level of pessimism are at risk for higher levels of mental distress in the course of the disease. Their need for counselling should be considered by the psychosocial care system. PMID- 22427123 TI - ["There she was - lying like Jesus on the cross ..." - Fathers' experiences of childbirth]. AB - OBJECTIVES: While 50 years ago fathers/partners were not allowed in the delivery room, nowadays their presence seems to be necessary. Research about this topic is summarized, and the results of a longitudinal study are presented. METHOD: Expecting fathers (N = 30) were interviewed about one month predelivery (t1) and six months postpartum (t4) by a same-sex interviewer about their plans for delivery and their experiences during labor and childbirth. The interviews were then content-analyzed. RESULTS: Quotations from the prebirth interviews show that all men explicitly stated that they wanted to be present at the childbirth, although 13 % gave the impression that for them it was impossible to say "no" to this matter. And in fact all were present (100 %). Their experience of labor and delivery was characterized by intensive positive (joy, relief) and negative (e.g., fears, anxiety, worries, shock, helplessness, disgust, flight impulses) feelings. The newborn baby evoked deep feelings of joy and emotion - but also great helplessness and alienation were described. CONCLUSIONS: The implications for childbirth preparation, obstetrics, risks of mental disorders, the parents' relationship, sexuality and the respective research are discussed. PMID- 22427124 TI - [Evaluation of outpatient treatment units according to the Crime Victims' Regulation Act]. AB - OBJECTIVE: Over the past years, 35 trauma outpatient units have been established in accordance with the Crime Victims' Compensation Act in the federal state of North Rhine-Westphalia (Germany) for both children and adolescents as well as for adults. They are operated by the social welfare authorities and, since 2008, by the regional authorities of Westphalia-Lippe and Rhineland. They enable victims to receive qualified psychotraumatological help within the first few days after suffering violence. Since trauma units have now been set up across most parts of this federal state, the time has come to assess the effectiveness of their acute care provision to victims of violence. METHODS: In 2007, on the order of the Ministry of Labour, Health and Social Affairs of the federal state of North Rhine Westphalia, trauma outpatient units were subjected to scientific evaluation. In 17 trauma outpatient units, a data assessment protocol was officially implemented that included repeat measurements (immediately before the initial contact, after completion of intervention, at follow-up six months after intervention) of traumatized subjects aged 14 and older. Socio-demographic data were gathered, and the scores of the Impact of Event Scale - Revised (IES-R), the Symptom Checkliste 27 (SCL-27), the simplified Beck Depressions Inventory (BDI-V), the Global Assessment of Functioning Scale (GAF) as well as the Cologne Risk Index (CRI) (expert rating) were collected. RESULTS: Nearly three-fourths (65.9 %) of the traumatic experiences of the 211 patients investigated can be characterized as type-1 traumatisation. 31.8 % of patients were victims of crimes involving violations of the right to sexual self-determination (94.0 % of sexual offences being committed against girls and women). Crimes against physical integrity, which according to crime statistics are the most frequent of crimes against individuals (88.8 %, 34.8 % females), were suffered by 36.0 % of all patients of the trauma outpatient units (63.2 % being females). In 57.1 % of the victims, the interval between the traumatic event and initial intervention was less than a month. In 51.7 % (n = 109), suspicion of PTBS (F43.1) was raised at the initial presentation. The average of all instruments yielded an effect size of d = 1.04 (SD = 0.28) in a pre-post comparison. Pair-wise comparison showed highly significant differences in averages between pre and post (that is, between initial and follow-up measurements) in the sense of marked symptom reduction for all scales. CONCLUSIONS: The services of the trauma outpatient units are utilized in a timely and targeted fashion. The calculated effects show that the trauma outpatient units offer highly effective services to crime victims seeking help there. PMID- 22427125 TI - [Structural change as an outcome paradigm in psychodynamic psychotherapy - results of the PAL-Study (long-term psychoanalytic psychotherapy study]. AB - OBJECTIVE: Psychodynamic psychotherapies have proved to lead to relevant symptomatic improvement. An unresolved question, however, is what amount of psychodynamic change can be expected beyond symptom relief. For theoretical and methodological reasons rooted in the psychodynamic approach, this question has been difficult to answer until now. METHOD: In the German study PAL (long-term psychoanalytic psychotherapy), 32 patients in psychoanalytic therapy and 27 patients in psychodynamic psychotherapy were studied from the perspective of therapists, patients and researchers through three years post-treatment. In this paper we study the aspect of psychodynamic change of dysfunctional relations, unconscious conflicts and structural aspects as diagnosed by the Operationalized Psychodynamic Diagnostic method. Structural change is rated by the Heidelberg Structural Change Scale. RESULTS: A comparison of the two forms of therapy shows more structural change in long-term psychoanalytic psychotherapy compared to the shorter psychodynamic psychotherapy. A comparison of patients with a high level and a low level of structural change revealed that the highly changed patients showed greater symptom relief and greater satisfaction with therapy, and that their therapists perceived a better overall result of treatment. DISCUSSION: For psychodynamic psychotherapies structural change seems to be a relevant paradigm of outcome in addition to symptom relief. In longer and more frequent psychoanalytic therapies more structural change occurs compared to shorter psychodynamic psychotherapies. Beside the amount and length of treatment, the different therapy targets - working through vs. supportive - seem to be important. PMID- 22427126 TI - [Changes in self-referent emotions during inpatient psychotherapy: the role of mindfulness and acceptance]. AB - OBJECTIVES: Current theoretical and clinical approaches conceive the avoidance and acceptance of emotions as critical factors in the maintenance and alleviation of psychological problems. This study investigates the role of mindfulness, experiential avoidance (EA), and positive and negative meta-emotions (emotional reactions towards the emotional self) on the symptoms and psychological well being of inpatients. METHOD: Changes of mindfulness measured during a 6-week stay at a psychosomatic clinic were explored in a sample of 293 inpatients with diverse psychological problems. Multivariate analyses were performed to determine the predictive power of mindfulness and acceptance on symptoms and psychological well-being. RESULTS: Staying on an inpatient ward was associated with reductions in EA and negative meta-emotions as well as improvements in mindful awareness and positive meta-emotions, i.e., participants reported greater acceptance of their own emotional reactions. These aspects were associated with a reduction in symptom severity and greater psychological well-being. A differentiation of meta emotions allowed the meaningful identification of possible processes of change. CONCLUSIONS: Anger and contempt seem to have distinctive functions in self regulation. Reducing the amount of contempt/shame for one's own emotions and generating greater interest were associated with symptom reduction and greater psychological well-being. Self-compassion was negatively associated with symptoms, though it had no association with psychological well-being. The theoretical implications are discussed. PMID- 22427127 TI - [The influence of relationship dynamics on the psychosocial outcome of genetically related and unrelated living kidney donor-recipient pairs]. AB - OBJECTIVES: Renal diseases and their treatment can cause distress and psychosocial problems for both patients and relatives. METHODS: Relationship dynamics and parameters of quality of life were assessed in 10 genetically related (brothers) and 14 genetically unrelated donor-recipient pairs (spouses) involved in living kidney donation (LKD). RESULTS: LKDs were described by related donors and recipients as fundamentally positive and in many cases led to an intensification of the relationship between donor and recipient. LKDs between unrelated donors and recipients appeared to achieve the same results as donations between related donors and recipients. Particularly the general desire to help determined the decision-making process of donors. CONCLUSION: In addition to general clinical parameters, especially motivational and relationship dynamics should be evaluated in the pre- and postoperative clinical psychological assessment of potential donors and recipients of LKD. PMID- 22427128 TI - The effects of 5-HT4 receptor agonist, mosapride citrate, on visceral hypersensitivity in a rat model. AB - BACKGROUND AND AIMS: Mosapride citrate is known to affect gastric motility. However, whether mosapride citrate has any effect on visceral pain in the colon or rectum is not certain. The aim of this study was to assess the effects of mosapride citrate on visceral pain in a rat visceral hypersensitivity model. METHODS: The perception of visceral pain was evaluated by the visceromotor response to colorectal distension observed on electromyographs of the abdominal musculature in urethane-anesthetized rats. Visceral hypersensitivity was induced by the intrarectal instillation of 4% acetic acid or 1.5% zymosan. Mosapride citrate was administered intraperitoneally 3 h later. VMRs to CRD were recorded prior to the instillation of acetic acid or zymosan and before and after mosapride citrate treatment. RESULTS: The intracolonic instillation of acetic acid resulted in a significant increase in VMRs of the abdominal muscles to CRD, compared with the pretreatment state (174 +/- 24%, P < 0.05). The intracolonic instillation of zymosan resulted in a significant increase in VMRs of the abdominal muscles to CRD, compared with the pretreatment state (144 +/- 9%, P < 0.05). Intraperitoneal injection of mosapride citrate resulted in a significant reduction in the VMRs to CRD in an acetic acid-induced visceral hypersensitivity rat model (61 +/- 9%, P < 0.05). The intraperitoneal injection of mosapride citrate also resulted in a significant reduction in the VMRs to CRD in a zymosan induced visceral hypersensitivity rat model (67 +/- 9%, P < 0.05). CONCLUSIONS: Mosapride citrate diminished visceral pain in rats. PMID- 22427129 TI - Variables associated with stress ulcer prophylaxis misuse: a retrospective analysis. AB - BACKGROUND: Stress ulcer prophylaxis (SUP) is commonly used in hospitals. Although its indications are better delineated for intensive care unit (ICU) patients, its use in non-ICU settings is somewhat arbitrary and based on judgment. OBJECTIVE: We attempted to assess the extent of SUP overuse in our hospital. We also carefully collected and analyzed several variables to detect associations governing this flawed behavior and its financial burden on the hospital's budget. MATERIALS AND METHODS: We retrospectively analyzed charts of patients admitted to the medical floor of a tertiary referral university hospital over a 1 year period. All adult patients admitted to the medical ward who received at least one dose of SUP were included and reviewed for a multitude of variables in addition to the appropriateness of acid suppression therapy (AST). RESULTS: We included 320 charts and found that 92% of patients admitted during that period were not eligible for SUP. The total inappropriateness of SUP was noted to be 58% (p = 0.015). Increasing age and male gender were found to be significant variables in AST misuse (p = 0.045 and p = 0.010), much like duration of hospital stay (p = 0.008). Comorbidities was also found to be a defining variable for AST overuse (odds ratio [OR] = 3.27). Patients with two or more minor risk factors were also subjected more to SUP inappropriately (OR = 3.53), in addition to patients of certain specialties (Neurology, Infectious Diseases, etc.). Our calculated financial burden was more than $23,000 per year for the medical floor. CONCLUSION: This retrospective study confirmed the growing suspicion that SUP misuse is evident on the medical floors. We also delineated several factors and variables associated with and affecting SUP overuse. PMID- 22427130 TI - Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). AB - BACKGROUND: A role of an altered dietary pattern (e.g., a diet rich in sugar) but also alterations at the level of the intestinal barrier have repeatedly been discussed to be involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). AIMS: To determine if the nutritional intake, intestinal flora, and permeability and the development of NAFLD are related in humans. METHODS: Ten controls and 20 patients with NAFLD ranging from simple steatosis to steatohepatitis were included in the study. Bacterial overgrowth, orocecal transit time, and intestinal permeability were assessed. Alcohol, endotoxin, and plasminogen activator inhibitor (PAI-) 1 concentration were determined in plasma. Nutritional intake was assessed using a dietary history. RESULTS: Despite no differences in the prevalence of bacterial overgrowth and in the orocecal transit time, intestinal permeability, alcohol, and endotoxin levels in plasma were significantly higher in patients with NAFLD than in controls. Similar results were also found for PAI-1 plasma concentrations. Patients with NAFLD had a significantly higher intake of protein, total carbohydrates, and mono- as well as disaccharides than controls. PAI-1, endotoxin, and ALT plasma levels were positively related to total protein and carbohydrate intake. CONCLUSIONS: Taken together, our results indicate that intestinal permeability, endogenous alcohol synthesis, and nutritional intake are markedly altered in patients with NAFLD. PMID- 22427131 TI - Hydrogen sulfide: a rescue molecule for mucosal defence and repair. PMID- 22427133 TI - Audio-visual facilitation of the mu rhythm. AB - Previous studies demonstrate that perception of action presented audio-visually facilitates greater mirror neuron system (MNS) activity in humans (Kaplan and Iacoboni in Cogn Process 8(2):103-113, 2007) and non-human primates (Keysers et al. in Exp Brain Res 153(4):628-636, 2003) than perception of action presented unimodally. In the current study, we examined whether audio-visual facilitation of the MNS can be indexed using electroencephalography (EEG) measurement of the mu rhythm. The mu rhythm is an EEG oscillation with peaks at 10 and 20 Hz that is suppressed during the execution and perception of action and is speculated to reflect activity in the premotor and inferior parietal cortices as a result of MNS activation (Pineda in Behav Brain Funct 4(1):47, 2008). Participants observed experimental stimuli unimodally (visual-alone or audio-alone) or bimodally during randomized presentations of two hands ripping a sheet of paper, and a control video depicting a box moving up and down. Audio-visual perception of action stimuli led to greater event-related desynchrony (ERD) of the 8-13 Hz mu rhythm compared to unimodal perception of the same stimuli over the C3 electrode, as well as in a left central cluster when data were examined in source space. These results are consistent with Kaplan and Iacoboni's (in Cogn Process 8(2):103-113, 2007), findings that indicate audio-visual facilitation of the MNS; our left central cluster was localized approximately 13.89 mm away from the ventral premotor cluster identified in their fMRI study, suggesting that these clusters originate from similar sources. Consistency of results in electrode space and component space support the use of ICA as a valid source localization tool. PMID- 22427134 TI - Treatment-related changes in brain activation in patients with fibromyalgia syndrome. AB - Little is known about the effects of successful treatment on brain function in chronic pain. This study examined changes in pain-evoked brain activation following behavioral extinction training in fibromyalgia patients. Using functional magnetic resonance imaging, brain activation to painful mechanical stimuli applied to the 2nd phalanx of the left 2nd digit (m. flexor digitorum) was assessed in 10 patients with fibromyalgia syndrome (FM) before and after behavioral extinction training. The behavioral treatment significantly reduced interference from pain in the FM patients. Mechanical pain threshold and pain tolerance increased significantly after treatment. Activation in the insula shifted bilaterally from a more anterior site before treatment to a more posterior location after treatment. The pre- to post-treatment reduction in both interference related to pain and pain severity were significantly associated with bilateral activation in pain-evoked activity in the posterior insula, the ipsilateral caudate nucleus/striatum, the contralateral lenticular nucleus, the left thalamus and the primary somatosensory cortex contralateral to the stimulated side. These data show a relation between successful behavioral treatment and higher activation bilaterally in the posterior insula and in the contralateral primary somatosensory cortex. Future studies should compare responders and non-responders for differential treatment effects and examine in more detail the mechanisms underlying these changes. PMID- 22427135 TI - Processing false solutions in additions: differences between high- and lower skilled arithmetic problem-solvers. AB - This paper focuses on the capacity to solve numerical incongruities in high- and lower-skilled arithmetic problem-solvers by investigating event-related brain potentials elicited by incorrect solutions to additions. Fifteen high-skill and fifteen low-skill individuals were presented with simple addition problems in a verification task. The proposed solution was manipulated by presenting correct solutions and incorrect solutions very close to the correct ones. Incorrect solutions elicited a negative component followed by a late positive component (LPC/P3b), whose amplitude was smaller for the low-skill group than for the high skill group. Because the LPC/P3b amplitude has been taken as an indicator of the plausibility of the stimulus, this result suggests that incorrect solutions close to the correct ones appear more plausible to low-skilled individuals than to their high-skilled counterparts. This result is interpreted in terms of differences in the strength of association between problems and potential solutions depending on arithmetical skill. PMID- 22427136 TI - What is the role of infant banging in the development of tool use? AB - Throughout the first year, infants are known to engage in repetitive motor behaviors. The current study examines the changes in the hand trajectory of one such behavior, banging, during the second half-year and the implications of these changes for tool use development. Fourteen (7- to 14-month-old) infants were seated at a table and presented with a small wooden cube. Kinematic measurements of their banging movements were recorded at 240 Hz. Analyses revealed stable temporal characteristics of the hand trajectories within and across infants. Results further indicated that as infants became older, their hands moved more efficiently in straighter up-and-down trajectories, with developmental changes especially pronounced for upward excursions of the hand: Younger infants' arm movements were less straight on the way up than down, but there was no difference in the straightness of the two movement phases for older infants. These changes with age may reflect improvements in overcoming constraints associated with gravity and/or in motor planning. Additionally, the angle at which infants hit the table became more perpendicular with age. Collectively, the reported changes lead to more efficient movements, better aim and improved force delivery, enabling spontaneous banging movements to become well suited for instrumental hammering and tool use, more generally, later in childhood. PMID- 22427137 TI - Brief mental breaks and content-free cues may not keep you focused. AB - The dominant theory amongst vigilance researchers is resource theory. From this theoretical perspective the increase in lapses with time on task, the vigilance decrement, is due to the depletion of the cognitive resources necessary for the maintenance of performance. Alternative under-load theories have recently been suggested: mindlessness and goal habituation. Advocates of mindlessness theory suggest the vigilance decrement results from conscious disengagement due to task monotony. From this theoretical perspective, the inclusion of content unrelated cues should draw the participants out of their mindless state. An alternative proposal is that vigilance decrements are a result of goal habituation. From this perspective a momentary deactivation and reactivation of task goal by inserting a brief task switch in a vigilance task should eliminate the vigilance decrement. In order to examine these alternative theories, we had 498 participants perform a visual vigilance task with either the inclusion of brief task switches, content free cues, or in comparative control conditions during the vigilance task. All experimental groups had an equivalent robust vigilance decrement measured by both a decline in perceptual sensitivity over time and an increase in response latency over time. There was, moreover, no difference in self-reported mental workload or task-unrelated thoughts across the experimental groups. Bayesian analyses resulted in substantial evidence in favour of the null hypothesis, in agreement with the expectations based on resource theory and contrary to the expectations based on either the mindlessness or goal-habituation theories. PMID- 22427138 TI - Arterial spin labeling: its time is now. PMID- 22427139 TI - I could never quite get it together: lessons for end-of -life care in Harold Pinter's The Caretaker. AB - Pinter's play The Caretaker explores interpersonal tensions relating to terminal illness. This paper interrogates notions of care, suffering, ownership, dignity and the consequences of active intervention and inaction in two key sections of the play: Aston's monologue concerning his own brutal treatment (active intervention) and Davies's final rejection by the brothers who fail to provide accommodation and care (inaction). This interprofessional analysis combines theatrical and clinical perspectives to create insights which can enhance empathy improve decision-making in end of life care and can inform the education of healthcare professionals. PMID- 22427140 TI - Intercellular cross-talk among bone cells: new factors and pathways. AB - Intercellular communication within the bone microenvironment is critical for the maintenance of normal bone structure. Osteoblast-lineage cells at all stages of differentiation, from pluripotent precursors to matrix-embedded osteocytes, produce regulatory factors that modulate the differentiation and activity of both bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoclasts can also release factors that feed back to regulate osteoblast activity. Intercellular cross-talk within the bone microenvironment is not restricted only to these bone cells. Other cells within the bone marrow microenvironment, including adipocytes, T cells, and macrophages, play key roles that influence the processes of bone formation and resorption. This review discusses recent work that provides new insights into some of these communication networks and the factors involved, including osteocytic production of receptor activator of nuclear factor-kappaB ligand (RANKL) and sclerostin, osteoblastic production of interleukin-33, osteoclast-derived Semaphorin 4D, ephrin signaling, and signals from T helper cells and resident osteal macrophages (osteomacs). PMID- 22427141 TI - Livin mediates tumor cell invasion in the DU-145 cell line via NF-kappaB. AB - Livin is a member of the family of inhibitors of apoptosis proteins (IAPs) and tumor cell invasion is a general property of multiple IAPs. Livin is highly expressed in prostate cancer (PCa) tissues. Livin overexpressing cells are more resistant to apoptotic stimuli than normal cells. Thus, aberrantly increased cell survival is an invariable requirement of metastasis. In this study, we investigated whether livin signaling affects metastasis by transfecting siRNA targeting livin into the DU-145 prostate cancer cell line to confirm the anti invasion effect and blockade of the livin gene. We found that livin knockdown inhibited DU-145 prostate carcinoma cell invasion. We investigated how livin promotes tumor cell invasion, and found that livin induction of fibronectin contributed to tumor cell invasion. In addition, we found that livin induction of fibronectin regulates tumor cell invasion via nuclear factor kappaB (NF-kappaB) signaling. These data showed that livin, as a gene directly promoting metastasis, can be useful for therapeutic intervention against advanced and disseminated PCa. PMID- 22427142 TI - Circulating microRNA-122 as a potential biomarker for liver injury. AB - Liver-specific microRNA-122 (miR-122) is involved in the replication of hepatitis C virus (HCV) and its potential as a target for antiviral intervention was recently assessed. However, the use of circulating miR-122 in the evaluation of liver function has never been reported. In the present study, changes of serum miRNA levels were first evaluated in acute human hepatotoxicity due to paraquat exposure. Serum samples were collected and analyzed using real-time reverse transcription PCR. The results showed a positive correlation between serum miR 122 and alanine aminotransferase, a clinical biomarker for liver function. Furthermore, serum miR-122 was assessed in patients with hepatitis B and hepatocarcinoma, resulting in distinct miR-122 profiles in these two closely related diseases. In addition to miR-122, another small RNA, U6 small nuclear RNA, was downregulated in hepatocarcinoma patients, suggesting its prognostic significance in this disease. Taken together, these lines of evidence indicate that serum miR-122 may provide a biomarker for diverse liver diseases and, more importantly, suggest that a combination of nucleic acid biomarkers may be used as a sensitive and specific index for discriminating closely related diseases. PMID- 22427143 TI - Stochastic population growth in spatially heterogeneous environments. AB - Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. For sedentary populations in a spatially homogeneous yet temporally variable environment, a simple model of population growth is a stochastic differential equation dZ(t) = MUZ(t)dt + sigmaZ(t)dW(t), t >= 0, where the conditional law of Z(t+Deltat)-Z(t) given Z(t) = z has mean and variance approximately z MUDeltat and z2sigma2Deltat when the time increment Deltat is small. The long-term stochastic growth rate lim(t->infinity) t-1 log Z(t) for such a population equals MU - sigma2/2 . Most populations, however, experience spatial as well as temporal variability. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study an analogous model X(t) = (X1(t) , . . . , X(n)(t)), t >= 0, for the population abundances in n patches: the conditional law of X(t+Deltat) given X(t) = x is such that the conditional mean of X(i)(t+Deltat) - X(i)(t) is approximately [x(i)MU(i) + Sigma(j) (x(j) D(ji) - x(i) D(i j) )]Deltat where MU(i) is the per capita growth rate in the ith patch and D(ij) is the dispersal rate from the ith patch to the jth patch, and the conditional covariance of X(i)(t+Deltat)- X(i)(t) and X(j)(t+Deltat) - X(j)(t) is approximately x(i)x(j)sigma(ij)Deltat for some covariance matrix Sigma = (sigma(ij)). We show for such a spatially extended population that if S(t) = X1(t)+. . .+ X(n)(t) denotes the total population abundance, then Y(t) = X(t)/S(t), the vector of patch proportions, converges in law to a random vector Y(infinity) as t -> infinity, and the stochastic growth rate lim(t->infinity) t-1 log S(t) equals the space-time average per-capita growth rate Sigma(i)MU(i)E[Y(i)(infinity)] experienced by the population minus half of the space-time average temporal variation E[Sigma(i,j) sigma(i j)Y(i)(infinity) Y(j)(infinity)] experienced by the population. Using this characterization of the stochastic growth rate, we derive an explicit expression for the stochastic growth rate for populations living in two patches, determine which choices of the dispersal matrix D produce the maximal stochastic growth rate for a freely dispersing population, derive an analytic approximation of the stochastic growth rate for dispersal limited populations, and use group theoretic techniques to approximate the stochastic growth rate for populations living in multi-scale landscapes (e.g. insects on plants in meadows on islands). Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology. For example, our analysis implies that even in the absence of density-dependent feedbacks, ideal-free dispersers occupy multiple patches in spatially heterogeneous environments provided environmental fluctuations are sufficiently strong and sufficiently weakly correlated across space. In contrast, for diffusively dispersing populations living in similar environments, intermediate dispersal rates maximize their stochastic growth rate. PMID- 22427144 TI - Clinical and pathological manifestations of human henipavirus infection. AB - The clinicopathological features of human Nipah virus and Hendra virus infections appear to be similar. The clinical manifestations may be mild, but if severe, includes acute encephalitic and pulmonary syndromes with a high mortality. The pathological features in human acute henipavirus infections comprise vasculopathy (vasculitis, endothelial multinucleated syncytia, thrombosis), microinfarcts and parenchymal cell infection in the central nervous system, lung, kidney and other major organs. Viral inclusions, antigens, nucleocapsids and RNA are readily demonstrated in blood vessel wall and numerous types of parenchymal cells. Relapsing henipavirus encephalitis is a rare complication reported in less than 10% of survivors of the acute infection and appears to be distinct from the acute encephalitic syndrome. Pathological evidence suggests viral recrudescence confined to the central nervous system as the cause. PMID- 22427145 TI - Charles Bonnet plus syndrome: apropos of a case. AB - PURPOSE: Charles Bonnet syndrome plus is an exceedingly rare variant of this disorder. The variant has been described in patients with sight impairment and severe hypoacusis, and is usually characterized by complex visual and auditory- musical--hallucinations that the patients recognize as unreal. METHOD: Case report. RESULTS: A 75-year-old woman diagnosed with Usher syndrome presented with visual acuity of light perception in both eyes, which did not improve with the use of a pinhole occluder. She also had coptosis in right ear and severe hypoacusis in left ear, confirmed through audiometry. Audiometric tests were normal once the implant and the hearing aid were connected. The patient was referred to the Neuro-Ophthalmology Unit after recounting experiencing complex visual hallucinations, as well as auditory (musical) ones at night after disconnecting the hearing aid. She described the latter as a nightly occurrence of hearing "cabaret music." Nevertheless, she was aware of reality and of her sensory impairments. The patient was diagnosed at the interdisciplinary Neuro Ophthalmology Unit, and began pharmacologic treatment with clear improvement. CONCLUSIONS: Knowledge of Charles Bonnet syndrome and in particular of Charles Bonnet syndrome plus--due to its infrequency--on the part of ophthalmologists is fundamental to adequately diagnose and treat this rare disorder. PMID- 22427146 TI - Ozil IP torsional mode versus combined torsional/longitudinal microcoaxial phacoemulsification. AB - PURPOSE: To compare the safety and efficacy of microcoaxial phacoemulsification surgeries performed with the Ozil Intelligent Phaco (IP) torsional mode and combined torsional/longitudinal ultrasound (US) mode using the Infiniti Vision System (Alcon Laboratories). METHODS: In this prospective randomized comparative study, 60 eyes were assigned to 2.2-mm microcoaxial phacoemulsification using the Ozil IP torsional mode (group 1) or combined torsional/longitudinal US mode (group 2). The primary outcome measures were US time (UST), cumulative dissipated energy (CDE), longitudinal and torsional ultrasound amplitudes, mean operation time, mean volume of balanced salt solution (BSS) used, and surgical complications. RESULTS: Both groups included 30 eyes. Mean UST, CDE, and longitudinal and torsional ultrasound amplitudes in group 1 were 1 minute 15+/ 34.33 seconds, 8.74+/-5.64, 0.43+/-0.74, and 25.56+/-8.56, respectively, and these parameters in group 2 were 1 minute 40+/-51.44 seconds, 9.28+/-5.99, 3.64+/ 1.55, and 3.71+/-1.34, respectively. UST and longitudinal amplitudes were found to be significantly low in group 1 (p<0.001, p<0.001), whereas torsional amplitude was found to be significantly high in this group (p=0.001). Mean volumes of BSS used in groups 1 and 2 were 63.30+/-18.00 cc and 84.50+/-28.65 cc, respectively (p=0.001). CONCLUSIONS: The Ozil IP torsional mode may provide more effective lens removal than the combined torsional/longitudinal US mode with a lower UST and volume of BSS used. PMID- 22427147 TI - Gomez-Lopez-Hernandez syndrome: another consideration in corneal neurotrophic ulcers. AB - PURPOSE: To report a case of a Gomez-Lopez-Hernandez syndrome (GLHS) variant with corneal neurotrophic ulcer. METHODS: Case report and review of the literature. RESULTS: A 6-year-old child presented with watering in the right eye for 3 days without ocular inflammation or pain. He had a peculiar facial phenotype and scalp alopecia in the right side. Slit-lamp examination showed an epithelial defect in the right eye and a corneal scar around the defect. Belmonte noncontact esthesiometry showed reduced corneal mechanosensory and thermal sensitivity. In vivo confocal microscopy revealed the absence of innervation in the right cornea. There was also an evident insensitivity in the alopecic region. Despite normal magnetic resonance imaging, the phenotypic manifestations along with ocular features suggested the diagnosis of a GLHS variant. CONCLUSIONS: Patients with GLHS remain asymptomatic even when they develop a corneal ulcer. Parents should be advised regarding the susceptibility of an affected child to the development of corneal lesions and the importance of regular follow-up and prompt treatment to prevent vision-threatening abnormalities. PMID- 22427148 TI - Various confocal scan features of cysts and trophozoites in cases with Acanthamoeba keratitis. AB - PURPOSE: To describe the various confocal scan features of cysts and trophozoites in patients with Acanthamoeba keratitis and to specify the associated findings. METHODS: In a retrospective study of cases between June 2005 and June 2010, we reviewed all the recorded confocal scan images of patients given a high index in regards to clinical suspicion of Acanthamoeba keratitis, in order to specify the various morphometric and morphologic features of Acanthamoeba cysts and trophozoites and to characterize the associated findings in such cases. RESULTS: Confocal scan images of 170 eyes from 170 patients were reviewed. Bilayered, target-shaped, coffee-bean and rod-shaped appearances of the cysts were observed in 100%, 82.9%, 36.4%, and 17.5% of cases, respectively. Single file arrangement of the cysts was noticed in 22 cases. The mean size of the cysts was 18.9 um (range 10-39.6). In all cases, trophozoites were observed as pear-shaped or irregularly wedge-shaped structures, some surrounded by a brilliant halo and some exhibiting fine pseudopodia-like extensions, with mean size of 30.2 um (range 19.2-55.6). Keratoneuritis and the anterior stromal honeycomb pattern were seen in 28.2% and 5.9% of cases, respectively. CONCLUSIONS: To our knowledge, this is the largest case-series study on confocal scan features of Acanthamoeba cysts and trophozoites in cases with clinical diagnosis of Acanthamoeba keratitis specifying the morphologic and morphometric criteria of this infectious organism and the associated findings. PMID- 22427149 TI - Optic disc morphology in porencephaly. AB - PURPOSE: To report a porencephalic cyst in a child with large optic disc cup but normal-sized discs. METHODS: Case report with figures. RESULTS: Clinical findings of a patient with porencephaly presenting with large cups in normal-sized optic discs are discussed. CONCLUSIONS: Optic disc morphology is not a reliable indicator of the timing of ischemic brain injury. Intracranial pathology should be suspected in children with disc cupping but no other features of glaucoma. PMID- 22427150 TI - Pediatric retinal detachment in cutis aplasia and cutis marmorata telangiectasia. AB - PURPOSE: This is a report of 2 cases of cutis aplasia and cutis marmorata telangiectasia with associated retinal detachment. METHODS: Retrospective case report. RESULTS: Illustration of ophthalmic associations of the rare congenital dermatologic presentations and description of successful treatment with laser photocoagulation. CONCLUSIONS: Awareness of the association between retinal detachment and cutis aplasia and cutis marmorata should be acted upon as laser photocoagulation has been shown in this case report to successfully treat the associated retinal detachment. PMID- 22427151 TI - Relevance of orbitofrontal neurochemistry for the outcome of cognitive behavioural therapy in patients with obsessive-compulsive disorder. AB - Since the advent of non-invasive methods such as proton magnetic resonance spectroscopy ((1)H-MRS), obsessive-compulsive disorder (OCD) has been increasingly associated with an altered composition of neurometabolites and neurotransmitters in several brain areas. Particularly, Inositol has not only been implicated in OCD pathophysiology, but also shown effective in pilot studies in therapy-refractory OCD patients. However, the relevance of regional brain neurochemistry for therapy outcome has not yet been investigated. Whereas numerous neuroimaging findings support a dysfunction of the orbitofrontal cortex (OFC) in OCD, MR-spectroscopic investigations of this region are missing. (1)H MRS and psychometric measurements were obtained from twenty unmedicated patients with OCD, subsequently enrolled in a 3-month structured inpatient cognitive behavioural therapy programme, and from eleven matched control subjects. Multiple regression of symptom score changes (Y-BOCS) on (myo-)inositol concentrations in three areas (right orbitofrontal cortex (OFC), right striatum and anterior cingulate cortex) was performed. The concentration of (myo-)inositol in the OFC only predicted the outcome of subsequent CBT regarding Y-BOCS score reduction (Spearman's r(s) = .81, P < 0.003, corrected). The (myo-)inositol concentration did not differ between OCD patients and healthy controls and did not change during therapy. We provide preliminary evidence for a neurochemical marker that may prove informative about a patient's future benefit from behaviour therapy. Inositol, a metabolite involved in cellular signal transduction and a spectroscopic marker of glial activity, predicted the response to CBT selectively in the OFC, adding to the evidence for OFC involvement in OCD and highlighting neurobiological underpinnings of psychotherapy. PMID- 22427152 TI - The lifetime and past-year prevalence of dual diagnosis in people with schizophrenia across Europe: findings from the European Schizophrenia Cohort (EuroSC). AB - Relatively little is known about rates of comorbid drug and alcohol problems in people with schizophrenia outside the USA. Most studies have recruited from single countries. Newly available data provided an unmatched opportunity to investigate the prevalence of comorbid dependence on alcohol and other psychoactive substances in people with schizophrenia in France, Germany and the UK at the same time. The European Schizophrenia Cohort study data set used semi structured clinical interviews to establish DSM-IV diagnoses. 1,208 patients were interviewed in nine centres. The lifetime rate for comorbid dependence on any substance was highest in the UK (35 %), but considerably lower in Germany (21 %) and in France (19 %), and generally more than double the past-year rates. Dependence on alcohol and on other psychoactive substances showed similar variations (comorbid alcohol dependence: UK 26 %; Germany 18 %; France 14 %; comorbid drug dependence: UK 18 %; Germany 8 %; France 7 %). Differences within countries persisted after controlling for individual characteristics. The relative odds of dependence were higher than in the general population, but varied between countries and centres. Dependence disorders are a common problem in people with schizophrenia in Western Europe, although effective service configurations have yet to be developed. Overall, these European rates are less than those reported from the USA. Research comparing people with current comorbidity with those who are no longer dependent is needed. PMID- 22427153 TI - Connexin43 modulation inhibits scarring in a rabbit eye glaucoma trabeculectomy model. AB - We investigated whether one subconjunctival injection of connexin43 antisense oligodeoxynucleotides (Cx43 AsODN) modulates postoperative scarring in a rabbit model of glaucoma trabeculectomy surgery. In a randomised, controlled, masked observer study, 39 rabbits underwent trabeculectomy surgery with insertion of a 22-gauge cannula in the right eyes and were randomly divided into three treatment groups. Each rabbit received an injection of Cx43 AsODN in Pluronic gel, balanced salt solution or Pluronic gel alone into the formed bled. The animals were euthanized at 8 and 24 h and at 5 and 21 days. Histology and immunohistochemistry results demonstrated that Cx43 AsODN decreased Cx43 upregulation at 8 and 24 h which led to less myofibroblast upregulation at days 5 and 21 and reduced scarring at day 21 compared to controls. We conclude that postoperative use of Cx43 AsODN inhibited subconjunctival scarring and fibrosis. Cx43 AsODN injection may be a safe and effective anti-scarring agent in glaucoma trabeculectomy surgery. PMID- 22427154 TI - Inhibition of titanium particle-induced inflammation by the proteasome inhibitor bortezomib in murine macrophage-like RAW 264.7 cells. AB - Wear particle-induced inflammatory osteolysis is the major cause of aseptic loosening after total joint replacement. The predominant cell type within periprosthetic tissues is macrophages. We investigate the anti-inflammatory effects of the proteasome inhibitor bortezomib (Bzb) on murine macrophage-like RAW 264.7 cells stimulated with titanium (Ti) particles. RAW 264.7 cells were cultured with 1 nM Bzb and 0.1 mg/ml Ti particles for 48 h; cells without Ti and Bzb or without Bzb were used as negative and loading controls. Results showed that the expression of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL 10), chemokines [monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1alpha)], and inflammatory enzymes [inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)] increased in RAW 264.7 cells cultured with Ti. Bzb treatment significantly reduced the expression of TNF alpha, IL-1beta, IL-6, MCP-1, MIP-1alpha, iNOS, and COX-2 and induced the expression of IL-10 in a time-dependent manner. These results suggest that Bzb inhibits Ti-induced inflammation in macrophages, and provide a promising therapeutic target for treating or preventing aseptic loosening. PMID- 22427155 TI - Evidence for changes in RREB-1, ZIP3, and Zinc in the early development of pancreatic adenocarcinoma. AB - PURPOSE: Pancreatic adenocarcinoma is an untreatable cancer with a 5-year survival rate of about 6 % or less for the past 35 years. This lack of significant progress is largely due to the lack of elucidation and understanding of the factors involved in the development of this cancer. Recent studies identified and implicated zinc in the development and progression of pancreatic cancer. This study was conducted to establish the changes in zinc, ZIP3 zinc transporter, and Ras-responsive element-binding protein 1 (RREB-1) transcription factor as early events in the development of malignancy. METHODS: In situ relative zinc determination and immunohistochemical analysis of ZIP3 and RREB-1 were performed on archived human pancreatic tissue sections and tissue microarrays. Normal/benign versus adenocarcinoma pancreas was compared. Panc1 cells were employed to determine the influence of RREB-1 on ZIP3 expression. RESULTS: Zinc levels of normal ductal and acinar epithelium were markedly and consistently decreased in adenocarcinoma. Pancreatic intraepithelial neoplasia (PanIN) lesions also exhibited a loss of zinc. ZIP3 and RREB-1 were also markedly downregulated. Initial results indicate that RREB-1 regulates ZIP3 expression. CONCLUSIONS: These results corroborate the earlier report that zinc, ZIP3, and RREB-1 are markedly decreased in early stage adenocarcinoma. Additionally and most importantly, these changes occur in PanIN, which are thought to be precancerous lesions leading to ductal adenocarcinoma. These results support a concept that downregulation of RREB-1 causes downregulation of ZIP3, which results in decreased zinc in premalignant and carcinoma cells. The decrease in zinc is essential to remove its cytotoxic effects on malignant cells. This relationship constitutes a new concept of early genetic/metabolic events in the progressive transformation of normal cells to premalignant cells to malignant cells in the development of pancreatic cancer. PMID- 22427156 TI - Interleukin-1beta causes fluoxetine resistance in an animal model of epilepsy associated depression. AB - Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1beta (IL1-beta) signaling, and consequently that the blockade of IL1-beta may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1beta signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1beta blockers in conjunction with SSRI may represent an effective therapeutic approach. PMID- 22427158 TI - [Health risk for the vulnerable population exposed to arsenic in the province of Buenos Aires, Argentina]. AB - OBJECTIVE: To analyze the concentration of arsenic in water collected in localities of the province of Buenos Aires, Argentina, and the epidemiological relationship of that concentration to factors of susceptibility and associated pathologies. METHODS: In 152 samples from 52 localities of Buenos Aires from 2003 2008, the concentration of arsenic was quantified through the generation of hydride spectrophotometry of atomic absorption. A composite index of health (CIH) was constructed using the content of arsenic and the percentages of households with unmet basic needs and dwellings without access to the potable water. Through the CIH, risk areas associated with mortality from malignant neoplasms related to arsenic were defined. RESULTS: Concentrations of arsenic spanned a broad range from 0.3 to 187 mg/L, with a median of 40 mg/L. Of the samples, 82% presented levels of arsenic higher than the acceptable limit of 10 mg/L, and more than half of those came from households with potable water connections. In the departments studied, the average mortality (deaths/100 000 inhabitants) from tumors was greater in men than in women: respiratory tract (310 versus 76), urinary tract (44 versus 11), and skin (21 versus 11), respectively. The regions with greater concentrations of arsenic and of poverty, together with the lack of potable water connections, had a two-to-four times greater risk. CONCLUSIONS: The findings from the composite index of health summarized the health risk from exposure to arsenic for lower socioeconomic levels of the population for a broad area of the province of Buenos Aires. PMID- 22427157 TI - Animal models of neurologic disorders: a nonhuman primate model of spinal cord injury. AB - Primates are an important and unique animal resource. We have developed a nonhuman primate model of spinal cord injury (SCI) to expand our knowledge of normal primate motor function, to assess the impact of disease and injury on sensory and motor function, and to test candidate therapies before they are applied to human patients. The lesion model consists of a lateral spinal cord hemisection at the C7 spinal level with subsequent examination of behavioral, electrophysiological, and anatomical outcomes. Results to date have revealed significant neuroanatomical and functional differences between rodents and primates that impact the development of candidate therapies. Moreover, these findings suggest the importance of testing some therapeutic approaches in nonhuman primates prior to the use of invasive approaches in human clinical trials. Our primate model is intended to: 1) lend greater positive predictive value to human translatable therapies, 2) develop appropriate methods for human translation, 3) lead to basic discoveries that might not be identified in rodent models and are relevant to human translation, and 4) identify new avenues of basic research to "reverse-translate" important questions back to rodent models. PMID- 22427159 TI - Migration, remittances, and health care utilization in Ecuador. AB - OBJECTIVE: To examine the relationship between migration and migrant remittances and health care utilization in Ecuador, and to identify any potential equalizing effects. METHODS: Using data from the 2004 National Demographic and Maternal & Child Health Survey (ENDEMAIN), a multilevel multivariate analysis was conducted to assess the relationship of two migrant predictors (households with an international migrant; use of migrant remittances) with use of preventive care, number of curative visits, hospitalization, and use of antiparasitic medicines. Relevant predisposing, enabling, and need factors were included following Andersen's Model of Health Care Utilization Behavior. Interaction terms were included to assess the potential equalizing effects of migration and remittances by ethnicity, area of residence, and economic status. RESULTS: Migrant predictors were strongly associated with use of antiparasitic medicines, and to a lesser extent, with curative visits, even after adjusting for various predisposing, enabling, and need factors. Interaction models showed that having an international migrant increased use of these services among low-income Ecuadorians (quintiles 1 and 2). No significant relationship was found between migrant predictors and use of preventive services. CONCLUSIONS: Migration and remittances seem to have an equalizing effect on access to antiparasitic medicines, and to a lesser extent, curative health care services. Health care reform efforts should take into account the scope of this effect when developing public policy. PMID- 22427160 TI - [Index of Nutritional Purchasing Power Parity: comparison of caloric costs of a healthy versus an unhealthy diet]. AB - OBJECTIVE: Develop the Index of Nutritional Purchasing Power Parity (Nut3-CiO) as an instrument to compare the caloric costs of a healthy versus an unhealthy diet between regions or cities in a country over time. METHODS: Indices of caloric prices were constructed and the "law of one price" was used to derive the Nut3 CiO index. Caloric inflation rates were obtained using basic descriptive statistics. The Nut3-CiO was applied in the major cities of Mexico during the period from January 1996 to December 2010. RESULTS: The statistical behavior of the Nut3-CiO revealed that, in Mexican cities, products for a typical diet are less expensive than products for a healthy diet. The findings showed a cyclical behavior to the index, a high correlation between inflation for the typical diet and inflation for the market basket, and a high persistence of prices. CONCLUSIONS: The Nut3-CiO index makes it possible to periodically compare the price differential of two types of diets-typical and healthy-between cities in a single country. This instrument could help health authorities identify the cities where it is easier or more difficult for consumers to access a typical or healthy diet in terms of cost. Furthermore, it makes it possible to estimate the percentage adjustment necessary in each city to attain levels of nutritional purchasing power parity. PMID- 22427161 TI - [Religion and fertility among adolescents in Brazil]. AB - OBJECTIVE: The objective of this study was to examine the association between the age of having one's first child in adolescence and before marriage and religious involvement in Brazil, measured by religious affiliation and frequency of attendance at religious services or masses. The objective of this study was to examine the association between the age of having one's first child in adolescence and before marriage and religious involvement in Brazil, measured by religious affiliation and frequency of attendance at religious services or masses. METHODS: Transverse data obtained from the National Survey of Demographics and Health of 1996 and the National Survey of Demographics and Health of Women and Children of 2006 were utilized. Cox proportional risks models were employed to estimate the association between religion and age of having one's first child premaritally and during adolescence. RESULTS: The results indicate a strong association between premarital fertility in adolescence and religious involvement in both 1996 and 2006. In 1996, frequency of attendance at religious service s or masses was more important than religious affiliation in explaining the age at which one had her first child. In 2006, belonging to a Pentecostal church comes to predominate. CONCLUSIONS: The results presented in this study are encouraging insofar as they show that Protestant adolescents, particularly Pentecostals, have a reduced risk of adolescent premarital motherhood. This result was not expected, given that Pentecostalism predominates in the less advantaged population groups, with lower incomes and levels of education and residence in urban areas, where adolescent fertility is also concentrated in Brazil. Future studies must be undertaken with the purpose of understanding how the various mechanisms of religious influence operate in the life and behavior of adolescents in Brazil. PMID- 22427162 TI - [Validation of the Spanish version of the Primary Care Assessment Survey questionnaire]. AB - OBJECTIVE: Adapt the Primary Care Assessment Survey (PCAS) questionnaire to the Spanish language and determine its validity and reliability in identifying strengths and weaknesses in primary health care (PHC). METHODS: Study of the adaptation and validation of a questionnaire-survey. The suitable sample selected was 244 users of PHC services. The users were over 18 years of age and had had at least two institutional visits prior to being included in the study. The variables used were access, continuity, comprehensiveness, integration, clinical interaction, interpersonal treatment, and trust. Participation was confirmed through analysis of the distribution of responses; participation and patterns of nonresponse; the construct, through exploratory factorial analysis, using principal component analysis and the varimax rotation; the criterion, through the Pearson product-moment correlation coefficient; and reliability using Cronbach's alfa and the intraclass correlation coefficient. RESULTS: The exploratory factorial analysis obtained 11 factors that explain 68.38% of the original variability. The criterion validity showed a sufficient correlation between the summary measure of the scale and the ad hoc variables Q33b (value of r x1x2 = 0.569; P = 0.01) and Q32 (value of r x1x2 = 0.600; P = 0.01). The scale obtained a coefficient of Cronbach's alfa of 0.94. The test-retest reliability (F [1 140] = 0.155 [P = 0.694]) demonstrated that the scale is stable over time. CONCLUSIONS: The psychometric properties of the adapted version of the PCAS questionnaire make it possible to state that it is a valid and reliable scale to evaluate primary care from a standpoint of ongoing care based on the physician patient relationship. PMID- 22427163 TI - Strategic alliances: an analysis of Catalan hospitals. AB - OBJECTIVE: To analyze the strategic alliances that Catalan hospitals form with other health care entities and other types of institutions to foster technological and organizational innovation. METHODS: Qualitative case studies were conducted at a sample of 16 public hospitals in Catalonia, Spain. The sample was limited to three (Level 1-3) of Catalonia's four levels of hospitals (classified according to the complexity of the diagnoses and treatments they provide), but Level 4 hospitals were considered as part of the network in the analysis of the alliances. At each hospital, interviews were conducted with the manager, the medical director, and the service director, using a questionnaire that gathered information on strategic alliances with a focus on telemedicine. Qualitative data processing was applied to identify patterns of alliances between hospitals and other institutions. RESULTS: Catalan hospitals interact with other health care agents through three main types of associations: alliances with other hospitals (the most frequent type); alliances with primary care centers (reported mostly by Level 2 hospitals); and alliances with other institutions (e.g., local government, medical companies, and universities). Human resource-sharing (staff mobility) and training were reported most frequently as reasons for creating the alliances. CONCLUSIONS: Strategic alliances are formed between hospitals and other health care agents to help improve performance, competitiveness, and services provided to users. These results may help health care system managers promote strategic alliances as a means of optimizing system efficiency without reducing user satisfaction-a key challenge within the context of the current economic situation. PMID- 22427164 TI - [Oral Candida in Mexican children with malnutrition, social marginalization, or HIV/AIDS]. AB - OBJECTIVE: Determine the frequency of candida in the oral cavity of children with a risk of developing opportunistic infections, and establish if there is an association between the frequency of this oral colonization and three categories of at-risk populations. METHODS: Four infant population groups in Mexico were studied: an HIV/AIDS group undergoing highly active antiretroviral therapy (35 girls and 25 boys); a malnourished group (26 girls and 29 boys); a group from the Tarahumara indigenous people, one of the poorest ethnic populations in the country (37 girls and 20 boys); and a control group (8 girls and 21 boys in apparently good health). The children with HIV/AIDS were immunologically and virologically classified according to the EC Clearinghouse criteria, while malnutrition was determined through the World Health Organization's weight/height index. A sample of oral mucosa was taken with a sterile swab, which was incubated in Sabouraud dextrose agar and in Candida CHROMagar(r). The species of candida were confirmed through the API ID32C test. RESULTS: The HIV/AIDS and malnutrition groups showed the higher frequency of Candida spps (51.7% and 38.2%, respectively), while the frequency level in the Tarahumara group was similar to that of the control group (17.5% versus 10.3%). With regard to the species of candida, the malnutrition group had the greatest diversity: C. albicans, C. tropical, C. krusei, and C. glabrata. CONCLUSIONS: The children with HIV/AIDS and malnutrition require strategies designed to reduce oral candidal colonization and reduce the risk of opportunistic infections. PMID- 22427165 TI - [Family, friends, and other sources of information associated with the initiation of sexual relations by adolescents in El Salvador]. AB - OBJECTIVE: The objective of this study is to verify the influence of messages Salvadorian youth receive about sexuality, affection, and leisure from family, friends, and the media on the initiation of sexual activity. METHODS: Cross sectional study based on a representative sample of 2 615 students (from 13 to 19 years of age) in El Salvador. A random systematic sampling was used to select 30 schools. Sociodemographic aspects, lifestyles, and sources of information on sexuality and love used by the young people were collected. RESULTS: The average age of the young people studied was 15 (SD = 1.8). In all, 638 (24.4%) of the young people stated that they had had sexual relations. The following factors are associated with a greater probability of having had sexual relations: a perception that siblings (OR = 1.8, CI 95%: 1.2-2.7) or friends (OR = 1.7, CI 95%: 1.3-2.2) encourage them to have sex. Protective factors were found to be the supervision of parents (OR = 0.5, CI 95%: 0.4-0.7); messages received from friends that encourage abstinence (OR = 0.7, CI 95%: 0.6-1.0) or from siblings (OR = 0.7, CI 95%: 0.5-0.8); and favorable messages related to marriage received from parents (OR = 0.4, CI 95%: 0.3-0.6). CONCLUSIONS: Messages from family and friends are factors that seem to influence the initiation of sexual activity by young people. Sexual health promotion programs in El Salvador should take these factors into account. PMID- 22427166 TI - [Cost of drugs used to treat cardiovascular disease in Brazil]. AB - OBJECTIVE: Diseases of the circulatory system are a principal cause of mortality in Brazil. Using as a basis drugs dispensed through Brazil's Popular Pharmacy Program (FPB, for its name in Portuguese), prices for drugs used to treat circulatory diseases were analyzed to identify the advantages of using generic drugs and the FPB. METHODS: Drug prices were obtained using Brazil's Pharmacy Price Guide and FPB price tables. The costs of 15 drugs available through the FPB were compared with those of three generic pharmaceutical products, three similar products, and the reference drug. RESULTS: The generic drugs were lower in price for 10 of the drugs and for four of the similar products. The FPB drugs were of the lowest price. CONCLUSIONS: Generic and FPB drugs are easily accessed by the population and thus facilitate the continuity of pharmacotherapy when these drugs are not available through the Unified Health System and/or are not affordable through other means. Access to drugs should be taken into consideration at the time prescriptions are filled, especially as regards those used to treat chronic diseases. PMID- 22427167 TI - [Association between hematopoietic nutrient intake and the origin of nutritional anemia in women of childbearing age in Colombia]. AB - OBJECTIVES: Compare the nutritional origin of anemia by sociodemographic variables and analyze its association with deficient hematopoietic nutrient intake. METHODS: The database of Colombia's 2005 National Survey of Nutritional Status was used. The data were obtained through complex representative sampling of the population and processed using SPSS v.15. Anemic women of childbearing age were selected and divided into two groups according to serum ferritin levels. Their customary hematopoietic nutrient intake and risk of deficiency were determined. The proportions of anemia types were compared by sociodemographic variables using the F-distribution, the Rao-Scott second order correction (P < 0.05). The association between the origin of the anemia and classification of the nutrient was analyzed using the odds ratio (OR). RESULTS: SAMPLE: 595 women. Non hypoferric anemia (67.2%) predominated, with no statistical difference by sociodemographic variable, except in the Pacific region (hypoferric anemia, 52.1%). The prevalence of deficiency in the customary intake of hematopoietic nutrients was high. There was no significant association between the deficit in consumption and the origin of the anemia. CONCLUSIONS: Non-hypoferric anemia was most common, with no difference by sociodemographic indicators except in the Pacific region. All the women were at high risk of deficiency in their customary hematopoietic nutrient intake, but a statistically significant association between the deficiency and the origin of the nutritional anemia was not observed. Programs to improve nutrient intake and a continued search for causes of nutritional anemia other than iron deficiency are justified. PMID- 22427168 TI - United States-Mexico cross-border health insurance initiatives: Salud Migrante and Medicare in Mexico. AB - While U.S. health care reform will most likely reduce the overall number of uninsured Mexican-Americans, it does not address challenges related to health care coverage for undocumented Mexican immigrants, who will remain uninsured under the measures of the reform; documented low-income Mexican immigrants who have not met the five-year waiting period required for Medicaid benefits; or the growing number of retired U.S. citizens living in Mexico, who lack easy access to Medicare-supported services. This article reviews two promising binational initiatives that could help address these challenges-Salud Migrante and Medicare in Mexico; discusses their prospective applications within the context of U.S. health care reform; and identifies potential challenges to their implementation (legal, political, and regulatory), as well as the possible benefits, including coverage of uninsured Mexican immigrants, and their integration into the U.S. health care system (through Salud Migrante), and access to lower-cost Medicare supported health care for U.S. retirees in Mexico (Medicare in Mexico). PMID- 22427169 TI - Critical analysis of cystic echinococcosis control programs and praziquantel use in South America, 1974-2010. AB - Cystic echinococcosis (CE) is one of the most prevalent zoonoses in Argentina, Brazil, Chile, Peru, and Uruguay. Control programs in South America were originally modeled after programs developed in insular territories, such as Tasmania and New Zealand. The advent and proven effectiveness of praziquantel, plus the experience of insular models, produced high expectations for rapid advances; however, after 30 years of praziquantel use, no endemic area in South America has obtained eradication. In fact, only modest gains in CE control have been made and impact on prevalence among humans has been slight. A major impediment has been the infrastructure needed to administer praziquantel to dogs in rural areas 8 times per year over numerous years, a requirement for rapid attack stage 1. Such an infrastructure has not been financially or politically sustainable in endemic areas, which tend to be the poorest. On the other hand, certain areas in Argentina have had success with simple and economically viable alternatives. Based primarily on continuous field work supported by the local community, these strategies have significantly decreased transmission to humans, the health sector's main objective. In addition, new possibilities and tools, such as the EG95 vaccine, are being evaluated; as are early detection and treatment of asymptomatic carriers. PMID- 22427170 TI - [Genetic epidemiology research designs]. AB - This article describes the features of the epidemiologic research designs most commonly used in genetic association studies. Case-control studies are efficient in evaluating associations between candidate genes and disease. Cohort studies, in contrast, yield a greater degree of causality but are not efficient for the initial exploration to identify gene-disease associations. Cross-sectional studies are less expensive, require less time, and are useful for estimating the prevalence of diseases, risk factors, and genetic variants. Family-based studies have been successful in finding alleles that confer greater risk for developing Mendelian inheritance disorders. PMID- 22427171 TI - Choice of initial antihypertensive drugs and persistence of drug use--a 4-year follow-up of 78,453 incident users. AB - PURPOSE: To investigate patterns of initial drug therapy for the treatment of hypertension and to evaluate treatment persistence and change of treatment during a 4-year period in patients receiving thiazides (TZs) and/or angiotensin II receptor blockers (ARBs) as first-line treatment. METHODS: All initial users of antihypertensive drugs in 2005 and 2009 registered in the Norwegian Prescription Database were included. Treatment on five index dates at 1-year intervals was recorded. A patient was considered to be under treatment on an index date if a drug had been dispensed within the previous 180 days and to have maintained treatment persistence if he/she was on any antihypertensive treatment on the index date and all previous index dates. RESULTS: Among 78,453 new users of antihypertensives in 2005, women started more often with TZs than men (30 vs. 25 %) and less often with ARBs (22 vs. 25 %). In men, the hazard of non-persistence with antihypertensive treatment was significantly lower among initial ARB users than among TZ users (hazard ratio 0.87, 95 % confidence interval 0.81-0.94); in women no significant difference was found. After 4 years, 49 % of the men and 51 % of the women who had started with plain TZs were still using TZs, whereas 65 % of the male ARB users and 60 % of the female ARB users were still using ARBs. CONCLUSION: TZs and ARBs were the most widely used first-line antihypertensives. Among the men enrolled in the study, ARB users had a somewhat better persistence with antihypertensive treatment than TZ users. Among both genders, continuation on ARBs was more common than continuation on TZs. PMID- 22427172 TI - Morphological abnormalities of the recto-anal inhibitory reflex reflects symptom pattern in neurogenic bowel. AB - BACKGROUND: Bowel dysfunction amongst multiple sclerosis (MS) and spinal cord injury (SCI) patients often manifests as fecal incontinence (FI) or constipation, but the pathophysiology is poorly understood. Anorectal physiology provides an objective assessment of lower bowel functions and is increasingly being used in clinical practice. AIM: The purpose of this study was to correlate symptoms of bowel dysfunction in patients with spinal cord disease with findings in anorectal physiology. We hypothesized that specific abnormalities will correlate with symptoms: prolonged recto-anal inhibitory reflex in patients with incontinence and decreased rectal mucosal blood flow in patients with constipation. METHODS: Forty-nine patients with MS (35 with predominant FI and 14 constipation), 46 supraconal SCI (mixed symptom load), and 21 healthy volunteers matched for age and sex were studied. Subjects completed validated constipation and FI symptom questionnaires. Patients underwent standard anorectal physiology, including assessment of rectal mucosal blood flow and recto-anal inhibitory reflex (RAIR). RESULTS: Severity of constipation correlates significantly with distension sensitivity (urge volume [r = 0.68, p = 0.002] and maximal volume [r = 0.39, p = 0.03]). Severity of constipation also correlated with diminished rectal mucosal blood flow in both patient groups (r = -0.51, p = 0.006). In both groups, constipation correlated with diminished relaxation of the sphincters in the RAIR whilst fecal incontinence correlated with a prolonged duration of RAIR (r = 0.33, p = 0.009) and recovery phase (r = 0.37, p = 0.05). CONCLUSION: Bowel symptoms in patients with MS and SCI correlate with specific alterations of anorectal physiology. This provides objective assessment of bowel symptoms and may allow tailored treatment to individual patients. PMID- 22427173 TI - Hereditary breast and ovarian cancer and other hereditary syndromes: using technology to identify carriers. AB - PURPOSE AND METHODS: Most patients who harbor a genetic mutation for hereditary breast cancer have not been identified, despite the availability of genetic testing. Developing an effective approach to the identification of high-risk individuals is the key to preventing and/or providing early diagnosis of cancer in this patient population. This educational review addresses these issues. RESULTS AND DISCUSSION: Using data available on the internet, and making assumptions regarding the types and results of genetic testing, we have estimated the number of mutation carriers in the country and the number who have been tested and identified as such. Overall, our ability to fund and more effectively manage carriers is weak. A technological solution is discussed. PMID- 22427174 TI - Identification of health-related quality of life (HRQOL) issues relevant to individuals with Huntington disease. AB - This qualitative study explored health-related quality of life (HRQOL) in individuals with Huntington disease (HD). Sixteen focus groups were conducted (n = 6 groups with symptomatic HD individuals; n = 5 with individuals who are at risk or prodromal for HD; n = 3 non-clinical HD caregivers; n = 2 groups with HD clinicians). Qualitative analysis indicated that 28% of focus group comments were related to emotional health, 27% to social participation, 26% to physical health, 10% to cognitive health, and 9% to end of life issues. Findings highlight the importance of developing HD-targeted items to ensure sensitive assessment of HRQOL in HD research and clinical practice. PMID- 22427175 TI - How to measure the QoS of a web-based EHRs system: development of an instrument. AB - The quality of service (QoS) can be treated as a set of concepts whose satisfaction/dissatisfaction generates a global positive/negative vision about the service provided by any application. The different nature of the services and its features require an analysis of the factors that have the greatest influence on the users' opinion and, therefore, measuring the quality of service in each application requires a specific instrument. This paper will introduce an instrument to measure the QoS offered to users by a general Web application for Electronic Health Records (EHRs). The collection of opinions from a pilot sample and the performance of an explanatory factor analysis will bring together the factors that best sum up the quality of an EHRs application. Subsequently, a confirmatory factor analysis will be performed to make the study reliable and, as its name suggests, to confirm that indeed the structure of the instrument developed measures the QoS in accordance with the requirements of the users. PMID- 22427176 TI - Apple snails and their endosymbionts bioconcentrate heavy metals and uranium from contaminated drinking water. AB - PURPOSE: The differential ability of apple snail tissues, endosymbionts, and eggs to bioaccumulate several metals (Sb, As, Ba, Br, Zn, Cr, Fe, Hg, Se, and U) was investigated. METHODS: Metal concentrations were determined by neutron activation analysis in several tissues, endosymbionts, and eggs from mature apple snails cultured in either drinking water or reconstituted water (prepared with American Society for Testing and Materials type I water). RESULTS: The highest bioconcentration factors (BCFs) in the midgut gland were found for Ba, Zn, Se, As, U, Br, and Hg (in decreasing order), while the highest in the kidney were for Ba, Br, and Hg. The foot showed the highest BCFs for Ba, Hg, Br, and Se (in decreasing order). Calcified tissues (uterus, shell) and eggs showed low BCFs, except for Ba. Both C corpuscles and gland tissue showed statistically higher BCFs than K corpuscles for Ba, Fe, U, Br, and Sb. The concentration of most of the studied elements was significantly lower in tissues and endosymbionts obtained from snails cultured in reconstituted water instead of drinking water. Snails cultured in reconstituted water and then exposed or not to Hg, As, and U (at the maximum contaminant level allowed by the US Environmental Protection Agency) also resulted in high levels accumulated in midgut gland, endosymbionts and kidney. CONCLUSIONS: Our findings suggest that the midgut gland (and the symbionts contained therein), the kidney, and the foot of Pomacea canaliculata may be useful bioindicators of Hg, As and U pollution in freshwater bodies and that the unrestricted use of ampullariid snails as human and animal food must be considered with caution. PMID- 22427177 TI - Equilibrium, kinetic, and thermodynamic biosorption of Pb(II), Cr(III), and Cd(II) ions by dead anaerobic biomass from synthetic wastewater. AB - PURPOSE: Heavy metals are toxic pollutants released into the environment as a result of different industrial activities. Biosorption of heavy metals from aqueous solutions is a new technology for the treatment of industrial wastewater. The aim of the present research is to highlight the basic biosorption theory to heavy metal removal. MATERIALS AND METHODS: Heterogeneous cultures mostly dried anaerobic bacteria, yeast (fungi), and protozoa were used as low-cost material to remove metallic cations Pb(II), Cr(III), and Cd(II) from synthetic wastewater. Competitive biosorption of these metals was studied. RESULTS: The main biosorption mechanisms were complexation and physical adsorption onto natural active functional groups. It is observed that biosorption of these metals was a surface process. The main functional groups involved in these processes were hydroxyl (-OH) and carboxylic groups (C=O) with 37, 52, and 31 and 21, 14, and 34 % removal of Pb(II), Cr(III), and Cd(II), respectively. Langmuir was the best model for a single system. While extended Langmuir was the best model for binary and ternary metal systems. The maximum uptake capacities were 54.92, 34.78, and 29.99 mg/g and pore diffusion coefficients were 7.23, 3.15, and 2.76 * 10(-11) m(2)/s for Pb(II), Cr(III), and Cd(II), respectively. Optimum pH was found to be 4. Pseudo-second-order was the best model to predict the kinetic process. Biosorption process was exothermic and physical in nature. CONCLUSIONS: Pb(II) offers the strongest component that is able to displace Cr(III) and Cd(II) from their sites, while Cd(II) ions are the weakest adsorbed component. PMID- 22427178 TI - Removal of copper from water by electrocoagulation process--effect of alternating current (AC) and direct current (DC). AB - PURPOSE AND AIM: In general, direct current (DC) is used in an electrocoagulation processes. In this case, an impermeable oxide layer may form on the cathode as well as corrosion formation on the anode due to oxidation. This prevents the effective current transfer between the anode and cathode, so the efficiency of electrocoagulation processes declines. These disadvantages of DC have been diminished by adopting alternating current (AC) in electrocoagulation processes. The main objective of this study is to investigate the effects of AC and DC on the removal of copper from water using magnesium alloy as anode and cathode. MATERIALS AND METHODS: Magnesium alloy of size 2.0 dm(2) was used as anode and as cathode. To optimize the maximum removal efficiency, different parameters like effect of initial concentration, effect of temperature, pH, and effect of current density were studied. Copper adsorbed magnesium hydroxide coagulant was characterized by SEM, EDAX, XRD, and FTIR. RESULTS: The results showed that the optimum removal efficiency of copper is 97.8 and 97.2 % with an energy consumption of 0.634 and 0.996 kWh/m(3) at a current density of 0.025 A/dm(2), pH of 7.0 for AC and DC, respectively. The adsorption of copper is preferably fitting the Langmuir adsorption isotherm for both AC and DC respectively. The adsorption process follows the second-order kinetics model with good correlation. Temperature studies showed that adsorption was endothermic and spontaneous in nature. CONCLUSIONS: The magnesium hydroxide generated in the cell removes the copper present in the water, reducing the copper concentration to less than 1 mg/L, making it safe for drinking. The results of the scale-up study show that the process was technologically feasible. PMID- 22427179 TI - Focused review of interdisciplinary pain rehabilitation programs for chronic pain management. AB - Interdisciplinary pain rehabilitation programs (IPRPs) are based on a functional restoration approach to treating complex chronic pain conditions. With a greater appreciation for a biopsychosocial approach to more effectively manage patients with chronic pain has come the development of more comprehensive treatment programs with less of a biomedical emphasis (i.e., interventional therapy, unimodal physical therapy, and passive modalities) and more of a biopsychosocial one. Interdisciplinary programs involve the use of multiple disciplines such as physical and occupational therapy, pain psychology, medical pain management, vocational rehabilitation, relaxation training, and nursing educations. Multiple psychometric tools are used in the assessment process and along treatment to better assess outcomes. This article will examine components of IPRPs, discuss desirable features of successful programs and teams, and more closely review four established outpatient pain programs in the United States. A greater understanding of the unique features and shared values of successful programs will help one better understand how these programs can be more widely used and available. The review will also highlight common psychometric outcomes tools used in assessing patients and monitoring outcomes. Most importantly, the review will help to answer a common question, even among pain physicians: "What goes on in those chronic pain programs?" PMID- 22427180 TI - Rab15 alternative splicing is altered in spheres of neuroblastoma cells. AB - Neuroblastoma is an aggressive pediatric tumor that accounts for 15% of cancer related deaths in children. More than half of high-risk neuroblastoma patients develop tumor relapse that is lethal in most cases. A small population of tumor initiating cells (TICs), recently identified from high-risk neuroblastoma patients as spheres, is believed to be responsible for tumor relapse. Rab family small G proteins are essential in controlling membrane traffic and their misregulation results in several cancers. Rab15 was originally isolated as a brain-specific Rab protein regulating the endocytic recycling pathway and was recently identified as a downstream target of the neural transcription factor Atoh1. Previously, we identified two alternatively spliced Rab15 isoforms in neuroblastoma cells and showed a significant correlation between Rab15 expression and neuronal differentiation. As aberrant alternative splicing is intimately associated with an increasing number of cancers, its use as a new diagnostic and/or prognostic biomarker has attracted considerable attention. In the present study, we explored cancer-associated changes of Rab15 alternative splicing in neuroblastoma TICs. We found that Rab15 alternative splicing generated two novel isoforms designated as Rab15(AN2) and Rab15(AN3) in addition to two known isoforms designated as Rab15(CN) and Rab15(AN1). Although both Rab15(AN2) and Rab15(AN3) contained premature termination codons, they were detected in not only neuroblastoma cells but also in normal human tissues. One isoform was predominantly expressed in the brain and testis, while the other isoform was more specifically expressed in the brain. In neuroblastoma, Rab15 isoform balance measured by the Rab15(CN)/Rab15(AN1+AN2+AN3) ratio was significantly decreased in spheres compared to parental cells. These results suggest that Rab15 alternative splicing may serve as a biomarker to discriminate TICs from non-TICs in neuroblastoma. PMID- 22427181 TI - Pasteurella multocida and immune cells. AB - Pasteurella multocida was first discovered by Perroncito in 1878 and named after Louis Pasteur who first isolated and described this Gram-negative bacterium as the cause of fowl disease in 1880. Subsequently, P. multocida was also found to cause atrophic rhinitis in pigs, haemorrhagic septicaemia in cattle and respiratory diseases in many other animals. Among other factors such as lipopolysaccharide, outer membrane proteins and its capsule, the protein toxin (PMT) of P. multocida is an important virulence factor that determines the immunological response of the host's immune system. However, the exact molecular mechanisms taking place in cells of the innate and adaptive immune system are largely unknown for any of these virulence factors. Due to the obvious function of PMT on cells of the porcine skeletal system where it causes bone destruction, PMT was regarded as an osteolytic protein toxin. However, it remained unclear what the actual benefit for the bacteria would be. Recently, more attention was drawn to the osteoimmunological effects of PMT and the interplay between bone and immune cells. This review summarises the knowledge of effects of P. multocida virulence factors on the host's immune system. PMID- 22427182 TI - Optimization of the unhairing leather processing with enzymes and the evaluation of inter-fibrillary proteins removal: an environment-friendly alternative. AB - In this work is described the isolation of a new proteases-producing strain of Bacillus subtilis, screened from aerobic tannery sludge, to be applied in leather production. The optimization of culture conditions to enhance the proteolytic activity was carried out using central composite design. The enzymatic extract was characterized and the hide unhairing and the inter-fibrillary removal capabilities of the enzymatic extract were evaluated by scanning electron microscopy and by the determination of proteoglycans and glycosaminoglycans. The leather quality obtained with this enzymatic preparation was assessed for possible damages to hide collagen by measuring the amount of hydroxyproline released into the reaction medium. Temperature was the most significant factor for culture conditions optimization. The crude enzymatic extract showed the best values for proteolytic activities at pH 9 and 10, temperature between 37 and 55 degrees C, and showed good thermal stability up to 45 degrees C. The treated hides presented few remaining hairs; for the enzymatic process, the removal of inter-fibrillary proteins was approximately fourfold for glycosaminoglycans and sixfold for proteoglycans, when compared with the conventional unhairing process. The enzyme application was successful for hide treatment, suggesting that this enzymatic preparation can be used in an environment-friendly leather production to replace the conventional chemical process. PMID- 22427183 TI - Making better use of our brain MRI research data. PMID- 22427184 TI - Perfusion MRI for the prediction of treatment response after preoperative chemoradiotherapy in locally advanced rectal cancer. AB - OBJECTIVES: To evaluate the utility of perfusion MRI as a potential biomarker for predicting response to chemoradiotherapy (CRT) in locally advanced rectal cancer. METHODS: Thirty-nine patients with primary rectal carcinoma who were scheduled for preoperative CRT were prospectively recruited. Perfusion MRI was performed with a 3.0-T MRI system in all patients before therapy, at the end of the 2nd week of therapy, and before surgery. The K (trans) (volume transfer constant) and V (e) (extracellular extravascular space fraction) were calculated. RESULTS: Before CRT, the mean tumour K (trans) in the downstaged group was significantly higher than that in the non-downstaged group (P = 0.0178), but there was no significant difference between tumour regression grade (TRG) responders and TRG non-responders (P = 0.1392). Repeated-measures analysis of variance (ANOVA) showed significant differences for evolution of K (trans) values both between downstaged and non-downstaged groups (P = 0.0215) and between TRG responders and TRG non-responders (P = 0.0001). Regarding V (e), no significant differences were observed both between downstaged and non-downstaged groups (P = 0.689) or between TRG responders and TRG non-responders (P = 0.887). CONCLUSION: Perfusion MRI of rectal cancer can be useful for assessing tumoural K (trans) changes by CRT. Tumours with high pre-CRT K (trans) values tended to respond favourably to CRT, particularly in terms of downstaging criteria. KEY POINTS: * Perfusion MRI can now assess therapeutic response of tumours to therapy. * Tumours with high initial K ( trans ) values responded favourably to chemoradiotherapy. * Perfusion MRI of rectal cancer may help with decisions about management. PMID- 22427185 TI - Establishment of epigenetic patterns in development. AB - The distinct cell types of the body are established from the fertilized egg in development and assembled into functional tissues. Functional characteristics and gene expression patterns are then faithfully maintained in somatic cell lineages over a lifetime. On the molecular level, transcription factors initiate lineage specific gene expression programmmes and epigenetic regulation contributes to stabilization of expression patterns. Epigenetic mechanisms are essential for maintaining stable cell identities and their disruption can lead to disease or cellular transformation. Here, we discuss the role of epigenetic regulation in the early mouse embryo, which presents a relatively well-understood system. A number of studies have contributed to the understanding of the function of Polycomb group complexes and the DNA methylation system. The role of many other chromatin regulators in development remains largely unexplored. Albeit the current picture remains incomplete, the view emerges that multiple epigenetic mechanisms cooperate for repressing critical developmental regulators. Some chromatin modifications appear to act in parallel and others might repress the same gene at a different stage of cell differentiation. Studies in pluripotent mouse embryonic stem cells show that epigenetic mechanisms function to repress lineage specific gene expression and prevent extraembryonic differentiation. Insights into this epigenetic "memory" of the first lineage decisions help to provide a better understanding of the function of epigenetic regulation in adult stem cell differentiation. PMID- 22427186 TI - Intra-arterial therapies for acute ischemic stroke: unsafe and without proven value. PMID- 22427187 TI - There is sufficient evidence to support intra-arterial therapy of ischemic stroke. PMID- 22427189 TI - Use of RNA isolated from feces as a promising tool for the early detection of colorectal cancer. AB - Colorectal cancer is one of the most common forms of cancer worldwide. Early detection would allow patients to be treated surgically and halt the progression of the disease; however, the current methods of early detection are invasive (colonoscopy and sigmoidoscopy) or have low sensitivity (fecal occult blood test). The altered expression of genes in stool samples of patients with colorectal cancer can be determined by RT-PCR. This is a noninvasive and highly sensitive technique for colorectal cancer screening. According to information gathered in this review and our own experience, the use of fecal RNA to determine early alterations in gene expression due to malignancy appears to be a promising alternative to the current detection methods and owing to its low cost could be implemented in public health services. PMID- 22427188 TI - SNARE requirements en route to exocytosis: from many to few. AB - Although it has been known for almost two decades that the ternary complex of N ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) constitutes the functional unit driving membrane fusion, our knowledge about the dynamical arrangement and organization of SNARE proteins and their complexes before and during vesicle exocytosis is still limited. Here, we review recent progress in this expanding field with emphasis on the question of fusion complex stoichiometry, i.e., how many SNARE proteins and complexes are needed for the fusion of a vesicle with the plasma membrane. PMID- 22427190 TI - Combined mutational analysis of KRAS, NRAS and BRAF genes in Indian patients with colorectal carcinoma. AB - The epidermal growth factor receptor (EGFR) is an excellent candidate for targeted therapy in colorectal cancer. Recent studies have demonstrated that apart from wild-type KRAS, a wild-type BRAF and NRAS genotype is required for response to anti-EGFR therapy. This suggests that NRAS and BRAF genotype criteria should be used together with KRAS genotype to select patients who will likely benefit from anti-EGFR therapy. We investigated the prevalence of mutations in the KRAS, BRAF and NRAS genes and its correlation with demographic characteristics, tumor location and stage in 100 colorectal carcinoma patients from India. The frequency of KRAS, BRAF and NRAS mutations was found to be 23%, 17% and 2.0%, respectively. There was no significant difference in KRAS, NRAS and BRAF mutation with respect to gender, age, tumor location (colon vs rectum) and clinicopathological stage. In addition, we found a novel point variant (T20I) of unknown significance in NRAS exon 1 in addition to a KRAS codon 12 mutation in one of the rectal carcinoma patients. In the present study, combined evaluation of genetic biomarkers (KRAS, NRAS and BRAF) was able to classify 42% of colorectal cancer patients as likely non-responders to anti-EGFR therapy. PMID- 22427191 TI - Reactions of microsolvated organic compounds at ambient surfaces: droplet velocity, charge state, and solvent effects. AB - The exposure of charged microdroplets containing organic ions to solid-phase reagents at ambient surfaces results in heterogeneous ion/surface reactions. The electrosprayed droplets were driven pneumatically in ambient air and then electrically directed onto a surface coated with reagent. Using this reactive soft landing approach, acid-catalyzed Girard condensation was achieved at an ambient surface by directing droplets containing Girard T ions onto a dry keto steroid. The charged droplet/surface reaction was much more efficient than the corresponding bulk solution-phase reaction performed on the same scale. The increase in product yield is ascribed to solvent evaporation, which causes moderate pH values in the starting droplet to reach extreme values and increases reagent concentrations. Comparisons are made with an experiment in which the droplets were pneumatically accelerated onto the ambient surface (reactive desorption electrospray ionization, DESI). The same reaction products were observed but differences in spatial distribution were seen associated with the "splash" of the high velocity DESI droplets. In a third type of experiment, the reactions of charged droplets with vapor phase reagents were examined by allowing electrosprayed droplets containing a reagent to intercept the headspace vapor of an analyte. Deposition onto a collector surface and mass analysis showed that samples in the vapor phase were captured by the electrospray droplets, and that instantaneous derivatization of the captured sample is possible in the open air. The systems examined under this condition included the derivatization of cortisone vapor with Girard T and that of 4-phenylpyridine N-oxide and 2 phenylacetophenone vapors with ethanolamine. PMID- 22427192 TI - Systemic alcohol-protective effects of quercetin besides its ameliorating effect on alcohol-induced neuropathic pain. PMID- 22427193 TI - Left ventricular noncompaction cardiomyopathy in Barth syndrome: an example of an undulating cardiac phenotype necessitating mechanical circulatory support as a bridge to transplantation. AB - Barth syndrome (BTHS) is associated with myocardial disease, frequently left ventricular noncompaction cardiomyopathy, which may necessitate cardiac transplantation or lead to death in some patients. We report a child with BTHS who had an "undulating cardiac phenotype" and ultimately developed decompensated heart failure requiring mechanical circulatory support with a ventricular assist device as a bridge to transplantation. His course was complicated by acute lung injury requiring placement of an in-line oxygenator to maintain end-organ function. Not only was his course complicated by cardiac and respiratory failure but his BTHS associated comorbidities complicated the management of his therapy using mechanical assist device support. He was successfully supported and subsequently was transplanted. Here we discuss the management of a child with BTHS using mechanical circulatory support and describe the use of an in-line oxygenator, Quadrox, with the Berlin Excor device. PMID- 22427194 TI - Noninvasive measurement of cardiac output during exercise in children with tetralogy of Fallot. AB - In patients with surgically repaired tetralogy of Fallot (TOF), reported peak oxygen consumption (VO(2)) is decreased compared with control subjects. The measurement of exercise cardiac output (CO) could be a useful adjunct for assessing cardiovascular fitness. There are few data assessing noninvasive CO, cardiac index (CI), and stroke volume (SV) during exercise for these patients. This study sought to measure noninvasive CI and SV during rest and exercise in children with repaired TOF. The authors compared 21 asymptomatic children with repaired TOF ages 11-17 years during rest and exercise and 42 gender- and age matched healthy control children without structural heart disease. Using a Bruce exercise protocol, exercise data were measured noninvasively by a novel inert gas rebreathing technique including peak duration and heart rate, as well as VO(2), CO, CI, and SV measured at 90 % of peak predicted theoretical heart rate (90 % ppHR). Statistical correlation between peak VO(2) and CI was performed. At baseline, there was no statistically significant difference in any of the measures between the groups. At 90 % ppHR, there was an increase in CI during exercise of 140 % in the TOF children and 180 % in the control children. During exercise, SV changed minimally in the patient group, whereas it increased more than 30 % in the control children. At 90 % ppHR, the patient group showed an increase in VO(2) during exercise similar to that of their healthy peers. The patients had a significantly shorter peak exercise duration than normal control subjects. The patients had a lower CI during exercise because they were less able to increase SV. Therefore, at similar heart rates, patients who have had TOF repair must rely on increased peripheral muscle extraction, with a higher arteriovenous oxygen difference (SaO(2)-MvO(2)) during exercise, which may limit peak exercise capacity. In this cohort of TOF patients, noninvasive CI measurement was feasible, and correlation with VO(2) was good. PMID- 22427195 TI - Genetic testing of inherited arrhythmias. AB - Syncope and risk of sudden death due to ventricular tachyarrhythmia are the common manifestations of several inherited disorders. Abnormalities of the genetic makeup may directly affect proteins controlling cardiac excitability in a structurally normal heart. Other diseases manifest primarily with ventricular arrhythmias even though the genetic mutations cause structural abnormalities of the myocardium. This is the case of arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy. Groundbreaking discoveries, starting from the 1990s until the beginning of the current decade, have provided fundamental knowledge on the major genes that confer an increased risk of arrhythmias and sudden death. Stems of such knowledge are the availability of genetic diagnosis, genotype-phenotype correlation, and genotype-based risk stratification schemes currently used in the clinical practice. This review provides a concise description of the known genes and key mechanisms involved in the pathogenesis of inherited arrhythmias. In addition, we outline possibilities, limitations, advantages, and potential threats of genetically screening for these genes. PMID- 22427196 TI - Automated estimation of collagen fibre dispersion in the dermis and its contribution to the anisotropic behaviour of skin. AB - Collagen fibres play an important role in the mechanical behaviour of many soft tissues. Modelling of such tissues now often incorporates a collagen fibre distribution. However, the availability of accurate structural data has so far lagged behind the progress of anisotropic constitutive modelling. Here, an automated process is developed to identify the orientation of collagen fibres using inexpensive and relatively simple techniques. The method uses established histological techniques and an algorithm implemented in the MATLAB image processing toolbox. It takes an average of 15 s to evaluate one image, compared to several hours if assessed visually. The technique was applied to histological sections of human skin with different Langer line orientations and a definite correlation between the orientation of Langer lines and the preferred orientation of collagen fibres in the dermis (p < 0.001, R(2) = 0.95) was observed. The structural parameters of the Gasser-Ogden-Holzapfel (GOH) model were all successfully evaluated. The mean dispersion factor for the dermis was kappa = 0.1404+/-0.0028. The constitutive parameters MU, k(1) and k(2) were evaluated through physically-based, least squares curve-fitting of experimental test data. The values found for MU, k(1) and k(2) were 0.2014 MPa, 243.6 and 0.1327, respectively. Finally, the above model was implemented in ABAQUS/Standard and a finite element (FE) computation was performed of uniaxial extension tests on human skin. It is expected that the results of this study will assist those wishing to model skin, and that the algorithm described will be of benefit to those who wish to evaluate the collagen dispersion of other soft tissues. PMID- 22427197 TI - Aromatic constituents of Cymbidium Great Flower Marie Laurencin and their antioxidative activity. AB - Two novel aromatic glucosides, named marylaurecinosides B (1) and C (2), were isolated from Cymbidium Great Flower Marie Laurencin, together with six known aromatic compounds (3-8). These structures were determined on the basis of NMR experiments as well as chemical evidence. All of the isolated compounds (1-8) were tested for antioxidative activity using a superoxide dismutase-like assay. PMID- 22427198 TI - Transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification results in cetuximab resistance that is reversed by trastuzumab treatment. AB - The recent identification of HER2 gene amplification as a novel predictor of resistance to the EGFR (HER2)-targeted antibody cetuximab and of response to combination therapies against EGFR and HER2 in wild-type KRAS tumor settings may represent a further step toward personalized medicine for patients with colorectal cancer. Herein, we show that transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification is a molecular phenomenon that takes place in EGFR-dependent, wild-type KRAS squamous cell carcinoma (SCC) cells that acquire resistance to cetuximab. Since cetuximab activity against cetuximab-refractory SCC cells can be fully restored in the presence of the anti HER2 monoclonal antibody trastuzumab, our findings suggest that, beyond HER2 gene amplification, we might need to redefine the threshold values for HER2 positivity to improve the accuracy of the selection of cetuximab-refractory patients with wild-type KRAS that may benefit from receiving a cetuximab/trastuzumab combination. PMID- 22427199 TI - Aqueous extracts of Lippia turbinata and Aloysia citriodora (Verbenaceae): assessment of antioxidant capacity and DNA damage. AB - The aim of the present work was to make a contribution to the knowledge of aqueous extracts of Lippia turbinata and Aloysia citriodora (Verbenaceae; infusion and decoction) in relation with the establishment of its antioxidant activity and lack of DNA damage, for its potential use in therapeutics. The cytogenotoxic profile was evaluated through genotoxic biomarkers such as mitotic index, cellular proliferation kinetics, sister chromatid exchanges, single-cell gel electrophoresis assay, and micronucleus test in human peripheral blood lymphocyte cultures. No statistical differences were found (P > .05) between control and exposed cultures, even between both aqueous extracts. The total antioxidant capacity was shown to be higher in the decoction than in the infusion and both aqueous extracts protected against protein carbonylation and lipid peroxidation, the decoction being more efficient than the infusion (P < .005). These results suggest the safe use of these medicinal plants as chemoecologic agents in therapeutics. PMID- 22427200 TI - An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model. AB - Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes. PMID- 22427201 TI - Integrated protein quality-control pathways regulate free alpha-globin in murine beta-thalassemia. AB - Cells remove unstable polypeptides through protein quality-control (PQC) pathways such as ubiquitin-mediated proteolysis and autophagy. In the present study, we investigated how these pathways are used in beta-thalassemia, a common hemoglobinopathy in which beta-globin gene mutations cause the accumulation and precipitation of cytotoxic alpha-globin subunits. In beta-thalassemic erythrocyte precursors, free alpha-globin was polyubiquitinated and degraded by the proteasome. These cells exhibited enhanced proteasome activity, and transcriptional profiling revealed coordinated induction of most proteasome subunits that was mediated by the stress-response transcription factor Nrf1. In isolated thalassemic cells, short-term proteasome inhibition blocked the degradation of free alpha-globin. In contrast, prolonged in vivo treatment of beta-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free alpha-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free alpha-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess alpha-globin. Therefore, beta-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cell-protective mechanisms. PMID- 22427202 TI - CD47 functions as a molecular switch for erythrocyte phagocytosis. AB - CD47 on erythrocytes inhibits phagocytosis through interaction with the inhibitory immunoreceptor SIRPalpha expressed by macrophages. Thus, the CD47 SIRPalpha interaction constitutes a negative signal for erythrocyte phagocytosis. However, we report here that CD47 does not only function as a "do not eat me" signal for uptake but can also act as an "eat me" signal. In particular, a subset of old erythrocytes present in whole blood was shown to bind and to be phagocytosed via CD47-SIRPalpha interactions. Furthermore, we provide evidence that experimental aging of erythrocytes induces a conformational change in CD47 that switches the molecule from an inhibitory signal into an activating one. Preincubation of experimentally aged erythrocytes with human serum before the binding assay was required for this activation. We also demonstrate that aged erythrocytes have the capacity to bind the CD47-binding partner thrombospondin-1 (TSP-1) and that treatment of aged erythrocytes with a TSP-1-derived peptide enabled their phagocytosis by human red pulp macrophages. Finally, CD47 on erythrocytes that had been stored for prolonged time was shown to undergo a conformational change and bind TSP-1. These findings reveal a more complex role for CD47-SIRPalpha interactions in erythrocyte phagocytosis, with CD47 acting as a molecular switch for controlling erythrocyte phagocytosis. PMID- 22427203 TI - Salidroside stimulates DNA repair enzyme Parp-1 activity in mouse HSC maintenance. AB - Salidroside is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea, which has potent antioxidant properties. Here we show that salidroside prevented the loss of hematopoietic stem cells (HSCs) in mice under oxidative stress. Quiescent HSCs were recruited into cell cycling on in vivo challenge with oxidative stress, which was blocked by salidroside. Surprisingly, salidroside does not prevent the production of reactive oxygen species but reduces hydrogen peroxide-induced DNA-strand breaks in bone marrow cells enriched for HSCs. We tested whether salidroside enhances oxidative DNA damage repair in mice deficient for 5 DNA repair pathways known to be involved in oxidative DNA damage repair; we found that salidroside activated poly(ADP-ribose)polymerase-1 (PARP-1), a component of the base excision repair pathway, in mouse bone marrow HSCs as well as primary fibroblasts and human lymphoblasts. PARP-1 activation by salidroside protects quiescent HSCs from oxidative stress-induced cycling in native animals and self-renewal defect in transplanted recipients, which was abrogated by genetic ablation or pharmacologic inhibition of PARP-1. Together, these findings suggest that activation of PARP-1 by salidroside could affect the homeostasis and function of HSCs and contribute to the antioxidant effects of salidroside. PMID- 22427204 TI - Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency. AB - EBV-associated smooth muscle tumors are found in immunocompromised patients, most commonly HIV/AIDS. We present a 12-year-old girl with the first documented case of EBV-related smooth muscle tumors in the presence of a rare classic NK cell deficiency. This sheds light on the role of NK cells in controlling EBV-related smooth muscle tumors. PMID- 22427205 TI - Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. AB - BM stromal cells (BMSCs) are key players in the microenvironmental support of multiple myeloma (MM) cell growth and bone destruction. A spliced form of the X box-binding protein-1 (XBP1s), a major proximal effector of unfolded protein response signaling, is highly expressed in MM cells and plays an indispensable role in MM pathogenesis. In the present study, we found that XBP1s is induced in the BMSCs of the MM microenvironment. XBP1s overexpression in healthy human BMSCs enhanced gene and/or protein expression of VCAM-1, IL-6, and receptor activator of NF-kappaB ligand (RANKL), enhancing BMSC support of MM cell growth and osteoclast formation in vitro and in vivo. Conversely, deficiency of XBP1 in healthy donor BMSCs displayed a range of effects on BMSCs that were opposite to those cells with overexpression of XBP1s. Knock-down of XBP1 in MM patient BMSCs greatly compromised their increased VCAM-1 protein expression and IL-6 and RANKL secretion in response to TNFalpha and reversed their enhanced support of MM-cell growth and osteoclast formation. Our results demonstrate that XBP1s is a pathogenic factor underlying BMSC support of MM cell growth and osteoclast formation and therefore represents a therapeutic target for MM bone disease. PMID- 22427206 TI - Mitochondrial myopathy caused by arsenic trioxide therapy. AB - Arsenic trioxide (ATO) has been successfully used as a treatment for acute promyelocytic leukemia (APL) for more than a decade. Here we report a patient with APL who developed a mitochondrial myopathy after treatment with ATO. Three months after ATO therapy withdrawal, the patient was unable to walk without assistance and skeletal muscle studies showed a myopathy with abundant cytoplasmic lipid droplets, decreased activities of the mitochondrial respiratory chain complexes, multiple mitochondrial DNA (mtDNA) deletions, and increased muscle arsenic content. Six months after ATO treatment was interrupted, the patient recovered normal strength, lipid droplets had decreased in size and number, respiratory chain complex activities were partially restored, but multiple mtDNA deletions and increased muscle arsenic content persisted. ATO therapy may provoke a delayed, severe, and partially reversible mitochondrial myopathy, and a long-term careful surveillance for muscle disease should be instituted when ATO is used in patients with APL. PMID- 22427207 TI - Long-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase associated Parkinson's disease. PMID- 22427208 TI - Estrogen upregulates the IGF-1 signaling pathway in lung cancer through estrogen receptor-beta. AB - The estrogen receptor (ER) signaling and the insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Here, we sought to investigate whether estrogen regulated the IGF-1R signaling in non small cell lung cancer (NSCLC) and the underlying mechanisms. We examined and analyzed the correlation of the expression of aromatase (Arom), ERbeta, ERalpha, insulin-like growth factor-1 (IGF-1), and IGF-1R in NSCLC. Tissue-microarray and immunohistochemistry analysis of tissue specimens from 162 NSCLC patients and 38 patients with benign pulmonary lesions showed that Arom, ERbeta, IGF-1, and IGF 1R were overexpressed while ERalpha was not expressed in NSCLC. Furthermore, ERbeta expression was positively correlated with that of Arom, IGF-1, and IGF-1R (r=0.554, 0.649, 0.496, respectively, P values are equal to 0.000), while Arom expression was positively associated with that of IGF-1 and IGF-1R (r=0.657, 0.714, respectively, P values are equal to 0.000). Additionally, ERbeta, IGF-1, and phospho-IGF-1R, but not ERalpha, were expressed in A549 cells. Immunoblotting assays showed that A549 cells treated with E2 showed significantly higher IGF-1 and p-IGF-1R levels than those receiving the combination treatment of 17beta estradiol (E2) and fulvestrant (Ful, ER antagonist) (P=0.042, 0.002, respectively) or controls (P values are equal to 0.000). The MTT assays further revealed that E2 and IGF-1 synergistically promoted A549 cell proliferation. Together, our study provides the first direct evidence for an interaction between ER and IGF-1R in lung cancer. We showed that estrogen upregulated the IGF-1R signaling through ERbeta in lung cancer tissues and A549 cells. These findings shed further light on the mechanisms whereby estrogen promotes lung cancer and highlight the ER and IGF-1R signaling pathways as promising targets for combinational therapy for lung cancer. PMID- 22427209 TI - Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated with sorafenib. AB - Some patients with advanced hepatocellular carcinoma (HCC) progressing under sorafenib remain eligible for further systemic therapy. Little is known on the feasibility of systemic treatment beyond sorafenib in this setting. Consecutive HCC patients pre-treated with sorafenib received gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2 every 14 days. Exclusion criteria included Child C cirrhosis, PS>=3, creatinine clearance<20 ml/min, albumin<25 g/L and bilirubin>54 MUmol/L. Pre-treatment body composition was evaluated by CT scan to detect muscle wasting (sarcopenia). The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, and progression-free (PFS) and overall survival (OS). Eighteen patients (median age: 64 years, range 25-77) received a total of 90 cycles (median per patient: 4, range 1-16). Eight patients (44.4 %) had a PS of 2, 5 (27.8%) had Child-Pugh B cirrhosis and 13 (72.2%) had a CLIP score>3. The most frequent toxicities were thrombocytopenia (grade 2-4: n=7, 38.9%) and peripheral neuropathy (grade 2-3: n=7, 38.9%). The overall response rate was 18.8% (95% CI: 0-37.9), and another 18.8 % of patients had stable disease. The median PFS and OS were 3.2 (95% CI: 2.3-3.9) and 4.7 (95% CI: 3.8 8.1) months, respectively. Overall survival was significantly longer in patients without sarcopenia [10.0 months (95% CI: 7.0-13.8) vs. 3.0 months (95 % CI: 2.5 3.9), p<0.001] and in patients with an ECOG PS<2 [8.1 months (95% CI: 7.0-13.8) vs. 3.8 months (95% CI: 2.5-3.9), p=0.017]. In our experience, gemcitabine oxaliplatin was feasible and had detectable clinical activity in HCC patients pre treated with sorafenib. Further studies are needed to confirm these findings. PMID- 22427211 TI - The cardiorespiratory function and electrical activity of the brain of the ringed seal during the transition from wakefulness to sleep. PMID- 22427210 TI - A review of the pharmacobiotic regulation of gastrointestinal inflammation by probiotics, commensal bacteria and prebiotics. AB - The idea that microbes induce disease has steered medical research toward the discovery of antibacterial products for the prevention and treatment of microbial infections. The twentieth century saw increasing dependency on antimicrobials as mainline therapy accentuating the notion that bacterial interactions with humans were to be avoided or desirably controlled. The last two decades, though, have seen a refocusing of thinking and research effort directed towards elucidating the critical inter-relationships between the gut microbiome and its host that control health/wellness or disease. This research has redefined the interactions between gut microbes and vertebrates, now recognizing that the microbial active cohort and its mammalian host have shared co-evolutionary metabolic interactions that span millennia. Microbial interactions in the gastrointestinal tract provide the necessary cues for the development of regulated pro- and anti-inflammatory signals that promotes immunological tolerance, metabolic regulation and other factors which may then control local and extra-intestinal inflammation. Pharmacobiotics, using nutritional and functional food additives to regulate the gut microbiome, will be an exciting growth area of therapeutics, developing alongside an increased scientific understanding of gut-microbiome symbiosis in health and disease. PMID- 22427212 TI - Role of inversion of interhemispheric asymmetry of phospholipid content in rat brain synaptosomes under stress conditions. PMID- 22427213 TI - Influence of anomalous high water temperatures on the development of the plankton community in the Middle Volga reservoirs in summer 2010. PMID- 22427214 TI - Comparative analysis of skull development in African barbs (Labeobarbus (=Barbus); Cyprinidae; Teleostei) from Lake Tana (Ethiopia). PMID- 22427215 TI - Severe industrial pollution increases the beta-diversity of plant communities. PMID- 22427216 TI - Dwarf char, a new form of chars (the genus Salvelinus) in Lake Kronotskoe. PMID- 22427217 TI - Intraspecific variation of some morphological characters of Calanus finmarchicus (Copepoda) in Western Arctic Seas. PMID- 22427218 TI - Distribution and variation of the amphipod fauna (Crustacea, Amphipoda) in the Kola Section (Barents Sea). PMID- 22427219 TI - The structure of the muscular system in the planktonic larva of colonial Kamptozoa. PMID- 22427220 TI - Morphological estimation of retinal resolution of a killer whale (Orcinus orca). PMID- 22427221 TI - Effect of docosahexaenoyl dopamine on the in vitro development of early mouse embryos. PMID- 22427222 TI - Structure of the organic component of soil gels. PMID- 22427223 TI - Phytohormone interplay controls proliferation of in vitro cultivated cells of Arabidopsis thaliana ethylene-insensitive mutants. PMID- 22427224 TI - Formation of the external skeleton in early jawless vertebrates (Agnatha, Vertebrata). PMID- 22427225 TI - Paternal care, social rank, and testosterone secretion in males of mongolian and midday gerbils (Meriones unguiculatus and M. meridianus). PMID- 22427226 TI - Adaptation of the light-harvesting complex of the Barents Sea brown seaweed Fucus vesiculosus L. to light conditions. PMID- 22427227 TI - The mechanisms of inactivation of the Tag7-Hsp70 cytotoxic complex. PMID- 22427228 TI - Outcomes of initial hemodialysis access surgery in an Asian population. AB - PURPOSE: Access-related morbidity contributes substantially to the costs of hemodialysis. The aim of this study was to examine the outcomes of initial hemodialysis access surgery at a single center in Singapore and to analyze factors which might influence survival of the surgically-created access. METHODS: Patients undergoing their first hemodialysis access operations between January 2003 and December 2007 were retrospectively identified. Primary and assisted primary patency rates were determined by the Kaplan-Meier method. Data on age, sex, diabetic status, and prior tunneled central venous catheter (CVC) use were analyzed against the outcome of arteriovenous fistulas (AVF). RESULTS: During the study period, 410 primary upper limb access operations were performed: 297 forearm AVF (72.4%), 91 upper arm AVF (22.2%), and 22 arteriovenous grafts (AVG; 5.4%). Men comprised 55.4%, 271 (66.1%) had diabetes, and 316 patients (77.1%) came to surgery with pre-existing CVC. Sixty-two percent of forearm AVF and 67% of arm AVF were used successfully. Age, sex, diabetes, and prior use of a CVC did not significantly affect the ability to use an AVF. Only in the female diabetic subgroup was an earlier loss of primary assisted patency of AVF recorded. CONCLUSIONS: In our Asian population, we have demonstrated AVF patency rates equivalent to those of international centers. We now face the challenge of achieving a higher rate of pre-emptive AVF placement with a subsequent reduction in CVC use. PMID- 22427229 TI - What is happening in the world of vascular access? Research and innovations are flowing through. AB - Vascular access perfectly reproduces myointimal hyperplasia that can be found in coronary or peripheral arteries and has a major advantage that these other sites cannot match: it is quite superficial and not close to a major vital organ and also affects a population that will attend the hospital for dialysis on a very regular basis. It therefore appears obvious to try and develop a tool that will mitigate myointimal hyperplasia and that could later be tested on coronary or peripheral arteries. Over the past few years several trials have been organized and we are now at a stage where some results have become available. PMID- 22427230 TI - Associations between interleukin-10 polymorphisms and susceptibility to psoriasis: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether three specific interleukin-10 (IL-10) polymorphisms confer susceptibility to psoriasis. METHODS: A meta-analysis was conducted on the associations between the IL-10-1082 G/A, 592 C/A polymorphisms and haplotypes of the IL-10-1082 G/A, -592 C/A, -819 C/T polymorphisms and psoriasis. RESULTS: A total of eight studies involving 1,018 psoriasis patients and 1,186 controls were considered in the meta-analysis. No association was found between psoriasis and the IL-10-1082 G allele in all study subjects [odds ratio (OR) = 1.098, 95 % confidence interval (CI) = 0.923-1.306, p = 0.291] or between this allele and psoriasis in Europeans (OR = 0.990, 95 % CI = 0.809-1.214, p = 0.925), but a significant association was found in Asians (OR = 1.785, 95 % CI = 1.144-2.76, p = 0.011). Three polymorphisms at the promoter region of IL-10 (-1082 G/A, -819 C/T, -592 C/A) are known to be in complete linkage disequilibrium, but no association was found between the haplotype and psoriasis. CONCLUSIONS: This meta-analysis shows that the IL-10-1082 G/A polymorphism confers susceptibility to psoriasis in Asians, and suggests that the IL-10 promoter -1082 polymorphism has an ethnicity-specific effect. PMID- 22427231 TI - The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter -174 G/C and -572 G/C polymorphisms confer susceptibility to rheumatoid arthritis (RA) in ethnically different populations. METHODS: Meta-analysis was conducted on the associations between these IL-6 polymorphisms and RA. RESULTS: A total of nine studies involving 3,851 subjects (RA 2,053 and controls 1,798) were considered in this study and ethnicity specific meta-analysis was performed on European subjects. In all study subjects, meta-analysis revealed a trend toward to an association between RA and the IL-6 174 G allele (odds ratio [OR] = 0.699, 95 % confidence interval [CI] = 0.463 1.054, p = 0.088). Stratification by ethnicity indicated a significant association between RA and the IL-6 -174 G/C polymorphism in Europeans using the dominant (OR = 0.329, 95 % CI = 0.155-0.699, p = 0.004) and recessive (OR = 0.823, 95 % CI = 0.679-0.997, p = 0.047) models. Meta-analysis of the IL-6 -572 G/C polymorphism showed no association between RA and the IL-6 -572 G allele in all study subjects (OR = 1.641, 95 % CI = 0.613-4.397, p = 0.324). CONCLUSIONS: This meta-analysis shows that the IL-6 -174 G/C polymorphism may confer susceptibility to RA in Europeans. PMID- 22427232 TI - Syringe acquisition experiences and attitudes among injection drug users undergoing short-term opioid detoxification in Massachusetts and Rhode Island. AB - Access to sterile syringes for injection drug users (IDUs) is a critical part of a comprehensive strategy to combat the transmission of HIV, hepatitis C virus, and other bloodborne pathogens. Understanding IDUs' experiences and attitudes about syringe acquisition is crucial to ensuring adequate syringe supply and access for this population. This study sought to assess and compare IDUs' syringe acquisition experiences and attitudes and HIV risk behavior in two neighboring states, Massachusetts (MA) and Rhode Island (RI). From March 2008 to May 2009, we surveyed 150 opioid IDUs at detoxification facilities in MA and RI, stratified the sample based on where respondents spent most of their time, and generated descriptive statistics to compare responses among the two groups. A large proportion of our participants (83%) reported pharmacies as a source of syringe in the last 6 months, while only 13% reported syringe exchange programs (SEPs) as a syringe source. Although 91% of our sample reported being able to obtain all of the syringes they needed in the past 6 months, 49% had used syringes or injection equipment previously used by someone else in that same time period. In comparison to syringe acquisition behaviors reported by patients of the same detoxification centers in 2001-2003 (data reported in previous publication), we found notable changes among MA participants. Our results reveal that some IDUs in our sample are still practicing high-risk injection behaviors, indicating a need for expanded and renewed efforts to promote safer injection behavior among IDUs. Our findings also indicate that pharmacies have become an important syringe source for IDUs and may represent a new and important setting in which IDUs can be engaged in a wide array of health services. Efforts should be made to involve pharmacists in providing harm reduction and HIV prevention services to IDUs. Finally, despite limited SEP access (especially in MA), SEPs are still used by approximately one of the three IDUs in our overall sample. PMID- 22427234 TI - Acoustic signal perception in a noisy habitat: lessons from synchronising insects. AB - Acoustically communicating animals often have to cope with ambient noise that has the potential to interfere with the perception of conspecific signals. Here we use the synchronous display of mating signals in males of the tropical katydid Mecopoda elongata in order to assess the influence of nocturnal rainforest noise on signal perception. Loud background noise may disturb chorus synchrony either by masking the signals of males or by interaction of noisy events with the song oscillator. Phase-locked synchrony of males was studied under various signal-to noise ratios (SNRs) using either native noise or the audio component of noise (<9 kHz). Synchronous entrainment was lost at a SNR of -3 dB when native noise was used, whereas with the audio component still 50% of chirp periods matched the pacer period at a SNR of -7 dB. Since the chirp period of solo singing males remained almost unaffected by noise, our results suggest that masking interference limits chorus synchrony by rendering conspecific signals ambiguous. Further, entrainment with periodic artificial signals indicates that synchrony is achieved by ignoring heterospecific signals and attending to a conspecific signal period. Additionally, the encoding of conspecific chirps was studied in an auditory neuron under the same background noise regimes. PMID- 22427236 TI - CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? AB - OBJECTIVE: In chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes. DESIGN: 660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis. RESULTS: Frequencies of CFTR variants p.R75Q, p.I148T, 5T allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9 fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001). CONCLUSIONS: Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development. PMID- 22427237 TI - NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. AB - OBJECTIVE: Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. DESIGN: The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. RESULTS: When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH fibrosis. Ja18-/- and CD1d-/- mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. CONCLUSION: Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis. PMID- 22427238 TI - Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. AB - OBJECTIVE: Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure. DESIGN: Utilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis. RESULTS: The frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36-40%), followed by falls in the caecum (12-22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27-35% in other sites; p<0.0001). CONCLUSIONS: The frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours. PMID- 22427239 TI - In vivo targeting of colonic dysplasia on fluorescence endoscopy with near infrared octapeptide. AB - OBJECTIVE: To demonstrate a near-infrared (NIR) peptide that is highly specific for colonic adenomas on fluorescence endoscopy in vivo. DESIGN: A 3 mm diameter endoscope was adapted to deliver 671 nm illumination and collect NIR fluorescence (696-736 nm). Target (QPIHPNNM) and control (YTTNKH) peptides were labelled with Cy5.5, a NIR dye, and characterised by mass spectra. The peptides were topically administered separately (100 MUM) through the endoscope's instrument channel into the distal colon of CPC;Apc mice, genetically engineered to spontaneously develop adenomas. After 5 min for incubation, the unbound peptides were rinsed off, and images were collected at a rate of 10 frames/s. Regions of interest were identified around the adenoma and adjacent normal-appearing mucosa on white light. Intensity measurements were made from these same regions on fluorescence, and the target-to-background ratio (TBR) was calculated. RESULTS: An image resolution of 9.8 MUm and field of view of 3.6 mm was achieved at a distance of 2.5 mm between the distal end of the instrument and the tissue surface. On mass spectra, the experimental mass-to-charge ratio for the Cy5.5-labelled target and control peptides agreed with expected values. The NIR fluorescence images of adenomas revealed individual dysplastic crypts with distorted morphology. By comparison, only amorphous surface features could be visualised from reflected NIR light. The average TBR for adenomas was found to be 3.42 +/- 1.30 and 1.88 +/ 0.38 for the target and control peptides, respectively, p=0.007. CONCLUSION: A NIR peptide was shown to be highly specific for colonic adenomas on fluorescence endoscopy in vivo and to achieve sub-cellular resolution images. PMID- 22427240 TI - Fluorescein angiography, optical coherence tomography, and histopathologic findings in a VEGF(165) animal model of retinal angiogenesis. AB - BACKGROUND: To establish an animal model of retinal neovascularization using vascular endothelial growth factor (VEGF165) and analyze the model using optical coherence tomography (OCT), fluorescein angiography (FA), and histopathologic evaluation. METHODS: Twelve rabbits were divided into groups as follows: group 1 (n = 3), sham intravitreous injections of 0.1 ml of balanced saline; group 2 (n = 6), one 10-MUg intravitreal injection of VEGF165 on day 0; and group 3 (n = 3), two 10-MUg intravitreal injections of VEGF165, one on day 0 and one on day 7. Follow-up evaluations (days 0, 3, 7, 14, 21, 28) included obtaining fundus color photographs and FA, OCT, and histopathologic examinations. Eyes were enucleated and stained with hematoxylin and eosin (H&E). RESULTS: One injection of VEGF (group 2) was associated with dilatation and tortuosity of the retinal blood vessels that developed within 72 h. Retinal neovascularization was present by day 7 and regressed by day 14. However, even on day 28, the capillaries were still tortuous. Two VEGF injections (group 3) caused increased leakage and neovascularization up to day 14; severe capillary nonperfusion was seen during week 4. At the end of the follow-up period, OCT and histopathologic examination of group 3 showed peripapillary tractional retinal detachments. By day 7, the differences between the retinal thickness seen on OCT in groups 2 and 3 and the group 1 control group were significant (p < 0.001). The histologic findings showed increased vessel size in groups 2 and 3 by days 14 and 28 compared with the controls. CONCLUSIONS: FA, OCT, and histopathologic findings showed that this retinal neovascularization model is efficient, sustainable, and reliable. One injection of VEGF165 created neovascularization that peaked after 1 week; two injections created more intense neovascularization that evolved to retinal detachments after 4 weeks. PMID- 22427241 TI - Reproducibility of nearwork-induced transient myopia measurements using the WAM 5500 autorefractor in its dynamic mode. AB - PURPOSE: To evaluate the reproducibility of nearwork-induced transient myopia (NITM) measurements obtained objectively using an open-field autorefractor (WAM 5500) in its dynamic mode. METHODS: NITM was assessed in 22, visually-normal, teen-aged and young-adult subjects using an infrared autorefractor (WAM-5500) in the dynamic mode. Measurements were obtained from the right eye in two test sessions separated by either 30 minutes or 2 days. Initial NITM and its decay were assessed monocularly by the same experimenter immediately after binocularly viewing and performing a detailed near task (5D) for 5 minutes incorporating a cognitive demand, with habitual distance refractive correction in place. Data were averaged over 10-second bins for 3 minutes (180 seconds; 18 bins) for the decay analysis. The NITM post- minus pre-task difference and its limits of agreement (LOA), as well as intraclass correlation coefficient (ICC), were calculated to evaluate reproducibility over the two test sessions for the initial NITM magnitude and its decay. RESULTS: The group mean (+/-SE) initial NITM and its decay duration were 0.33 +/- 0.09 D and 0.28 +/- 0.08 D, and 118.6 +/- 14.3 seconds and 132.3 +/- 12.2 seconds respectively, for each test session, which were not significantly different (p > 0.05). The difference (range), LOA, and ICC (95% confidence interval [CI]) were 0.06D (-0.15, 0.64), -0.29 to 0.40D, and 0.90D (0.77, 0.96) for the initial NITM; they were -13.6 (-150.0, 140.0) seconds, -174.5 to 147.3 seconds, and 0.14 (0.00, 0.52) for decay duration, respectively, for each test session. The ICC range for the first 50 secs of the NITM response/decay was 0.90 to 0.96. CONCLUSIONS: The initial NITM was highly repeatable. The initial decay phase was moderately repeatable, with the later decay phase being more variable, yet still yielding acceptable reproducibility in many cases. Both of these key parameters, namely initial NITM and its early decay, can be assessed reliably and with good reproducibility. This is important in future longitudinal studies of NITM, and its possible relation to refractive development. PMID- 22427242 TI - Do task-irrelevant direction-associated motion verbs affect action planning? Evidence from a Stroop paradigm. AB - Does simply seeing a word such as rise activate upward responses? The present study is concerned with bottom-up activation of motion-related experiential traces. Verbs referring to an upward or downward motion (e.g., rise/fall) were presented in one of four colors. Participants had to perform an upward or downward hand movement (experiments 1 and 2a/2b) or a stationary up or down located keypress response (experiment 3) according to font color. In all experiments, responding was faster if the word's immanent motion direction matched the response (e.g., upward/up response in case of rise); however, this effect was strongest in the experiments requiring an actual upward or downward response movement (experiments 1 and 2a/2b). These findings suggest bottom-up activation of motion-related experiential traces, even if the task does not demand lexical access or focusing on a word's meaning. PMID- 22427243 TI - [Current role of prostatic transrectal ultrasound in the diagnosis of CaP]. AB - INTRODUCTION: Cancer of the prostate (PCa) is now recognized as one of the most important medical problems facing the male population. In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer (1). According to the EAU guidelines, the main diagnostic tools to obtain evidence of PCa include DRE, serum concentration of PSA and transrectal ultrasonography (TRUS). But, does TRUS affect the diagnostic process? MATERIAL AND METHODS: Between March 2007 and March 2011 we performed 441 prostate biopsies to compare the results with clinical, laboratory and ultrasonographic features of every patient. We investigated sensitivity, specificity, accuracy, positive and negative predictive value and likelihood ratio about every diagnostic tool (PSA, DRE and TRUS). RESULTS: The transrectal ultrasonography has a low diagnostic accuracy for prostate cancer because it shows: Low sensitivity and specificity (higher incidence of false positives than true positives); Variability of ultrasound situations within which the tumor occurs. CONCLUSIONS: In our opinion TRUS may be considered only a complement to PSA and DRE. PMID- 22427244 TI - [Origin of motion in the human ureter: mechanics, energetics and kinetics of the myosin molecular motors]. AB - BACKGROUND: Ureteral peristalsis is the result of coordinated mechanical motor performance of longitudinal and circular smooth muscle layer of the ureter wall. The main aim of this study was to characterize in smooth muscle of proximal segments of human ureter, the mechanical properties at level of muscle tissue and at level of myosin molecular motors. METHODS: Ureteral samples were collected from 15 patients, who underwent nephrectomy for renal cancer. Smooth muscle strips longitudinally and circularly oriented from proximal segments of human ureter were used for the in vitro experiments. Mechanical indices including the maximum unloaded shortening velocity (Vmax), and the maximum isometric tension (P0) normalized per cross-sectional area, were determined in vitro determined in electrically evoked contractions of longitudinal and circular smooth muscle strips. Myosin cross-bridge (CB) number per mm2 (Psi) the elementary force per single CB (Psi) and kinetic parameters were calculated in muscle strips, using Huxley's equations adapted to nonsarcomeric muscles. RESULTS: Longitudinal smooth muscle strips exhibited a significantly (p<0.05) faster Vmax (63%) and a higher P0 (40%), if compared to circular strips. Moreover, longitudinal muscle strips showed a significantly higher unitary force (Psi) per CB. However, no significant differences were observed in CB number, the attachment (f1) and the detachment (g2) rate constants between longitudinal and circular muscle strips. CONCLUSIONS: The main result obtained in the present work documents that the mechanical, energetic and unitary forces per CB of longitudinal layer of proximal ureter are better compared to the circular one; these preliminary findings suggested, unlike intestinal smooth muscle, a major role of longitudinal smooth muscle layer in the ureter peristalsis. PMID- 22427245 TI - Cognitive development masks support for attributional style models of depression in children and adolescents. AB - Attributional style models of depression in adults (Abramson et al. 1989, 1978) have been adapted for use with children; however, most applications do not consider that children's understanding of causal relations may be qualitatively different from that of adults. If children's causal attributions depend on children's level of cognitive development, then support for attributional models of depression in young people will vary with cognitive development. In this paper, a new measure of cognitive development, the Peabody Causal Reasoning Test (PCRT), is introduced to assess children's understanding of ability versus effort, task difficulty, and luck as causal factors. Analyses revealed that in 8- to 16-year-old children, failure to control for level of cognitive development suppressed empirical support for cognitive diathesis-stress models of depression. Statistically controlling for measures of cognitive development strengthened support for this model. PMID- 22427246 TI - Understanding phonological memory deficits in boys with attention deficit/hyperactivity disorder (ADHD): dissociation of short-term storage and articulatory rehearsal processes. AB - The current study dissociated and examined the two primary components of the phonological working memory subsystem--the short-term store and articulatory rehearsal mechanism--in boys with ADHD (n = 18) relative to typically developing boys (n = 15). Word lists of increasing length (2, 4, and 6 words per trial) were presented to and recalled by children following a brief (3 s) interval to assess their phonological short-term storage capacity. Children's ability to utilize the articulatory rehearsal mechanism to actively maintain information in the phonological short-term store was assessed using word lists at their established memory span but with extended rehearsal times (12 s and 21 s delays). Results indicate that both phonological shortterm storage capacity and articulatory rehearsal are impaired or underdeveloped to a significant extent in boys with ADHD relative to typically developing boys, even after controlling for age, SES, IQ, and reading speed. Larger magnitude deficits, however, were apparent in short term storage capacity (ES = 1.15 to 1.98) relative to articulatory rehearsal (ES = 0.47 to 1.02). These findings are consistent with previous reports of deficient phonological short-term memory in boys with ADHD, and suggest that future attempts to develop remedial cognitive interventions for children with ADHD will need to include active components that require children to hold increasingly more information over longer time intervals. PMID- 22427247 TI - Directions of effects between adolescent psychopathic traits and parental behavior. AB - The present study examined the directions of effects between adolescent psychopathic traits and parental behaviors. The data are from a community-based cohort-sequential study. Data were collected annually over 4 years. Participants were 875 adolescents, aged 13-15 at Time 1, and we analyzed their reports of negative and positive parental behavior, delinquency, and psychopathic traits. In results from cross-lagged models, adolescent psychopathic traits predicted changes over time in all of the parental behaviors at nearly all of the time intervals, whereas the prediction from parental behaviors to psychopathic traits was inconsistent across parenting measures and time intervals. These findings suggest that parental behavior is more a reaction than a predictor of psychopathic traits in adolescence. PMID- 22427248 TI - Predicting transitions in low and high levels of risk behavior from early to middle adolescence: the TRAILS study. AB - The present study examined the joint development of substance use and externalizing problems in early and middle adolescence. First, it was tested whether the relevant groups found in previous studies i.e., those with an early onset, a late onset, and no onset or low levels of risk behavior could be identified, while using a developmental model of a single, underlying construct of risk behavior. Second, departing from Moffitt's taxonomy of antisocial behavior, it was tested if early, but not late, onset risk behavior is predicted by a problematic risk profile in childhood. Data were used from TRAILS, a population based cohort study, starting at age 11 with two follow-ups at mean ages of 13.6 and 16.3 years. Latent transition analyses demonstrated that, both in early and middle adolescence, a single underlying construct of risk behavior, consisting of two classes (labeled as low and high risk behavior), adequately represented the data. Respondents could be clearly classified into four possible transition patterns from early to middle adolescence, with a transition from high to low being almost non-existent (2.5 %), low to low (39.4 %) and low to high (41.8 %) being the most prevalent, and high to high (16.2 %) substantial. As hypothesized, only the high-high group was characterized by a clear adverse predictor profile in late childhood, while the low-high group was not. This study demonstrates that the development of substance use is correlated with externalizing problems and underscores the theory that etiologies of early and later onset risk behavior are different. PMID- 22427249 TI - 7,8-Dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-kappaB and MAPK signaling pathways in lipopolysaccharide-treated RAW264.7 cells. AB - 7,8-Dihydroxyflavone (7,8-DHF), a member of the flavonoid family, has received considerable attention as a selective tyrosine kinase receptor B agonist. Several studies have indicated that 7,8-DHF has neurotrophic and antioxidant activities. However, little is known about the cellular and molecular mechanisms underlying the anti-inflammatory activity of 7,8-DHF. Therefore, we investigated whether 7,8 DHF affects the expression of inflammatory mediators in lipopolysaccharide (LPS) stimulated RAW264.7 cells. Our results indicated that 7,8-DHF significantly attenuated secretion of LPS-induced inflammatory mediators nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-1beta (IL-1beta) in RAW264.7 cells. Additionally, LPS-induced expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2 and IL-1beta was decreased by pre-treatment with 7,8-DHF. Our results also showed that 7,8-DHF reduces LPS-induced nuclear factor-kappaB (NF-kappaB) activity via the suppression of the nuclear translocation of NF kappaB p65 and the degradation of inhibitor kappaB (lkappaB). In addition, 7,8 DHF inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) such as extracellular-signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). These results suggest that the anti-inflammatory property of 7,8 DHF is related to the downregulation of iNOS, COX-2 and IL-1beta, due to NF kappaB inhibition as well as to the negative regulation of MAPK activation in RAW264.7 cells. Thus, 7,8-DHF may be a novel therapeutic agent for the prevention of various inflammatory diseases. PMID- 22427250 TI - Generation and comparative characterization of glycosylated and aglycosylated human IgG1 antibodies. AB - Monoclonal antibodies (mAbs) are the fastest growing class of biopharmaceuticals reflecting their diverse applications in research and the clinic. The correct glycosylation of mAbs is required to elicit effector functions such as complement dependent and antibody-dependent cell-mediated cytotoxicity, although these may be undesirable for the treatment of certain chronic diseases. To gain insight into the properties of glycan-deficient mAbs, we generated and characterized six different aglycosylated human IgG1 mAbs (carrying the N297A mutation) and compared them to their glycosylated counterparts. We found no differences in solubility or heterogeneity, and all mAbs the remained stable in stress tests at 4 and 37 degrees C. Surface plasmon resonance spectroscopy showed no differences in binding affinity, and the in vivo terminal serum half-life and plasma clearance were similar in rats. However, differential scanning calorimetry revealed that the aglycosylated mAbs contained a less stable C(H)2 domain and they were also significantly more susceptible to pH-induced aggregation. We conclude that aglycosylated mAbs are functionally equivalent to their glycosylated counterparts and could be particularly suitable for certain therapeutic applications, such as the treatment of chronic diseases. PMID- 22427251 TI - Prediction of carotid plaques in hypertensive patients by risk factors, left ventricular hypertrophy, and epicardial adipose tissue thickness. AB - Hypertension and other risk factors (RFs) predispose to carotid plaques (CPs). An association between left ventricular hypertrophy (LVH) or epicardial adipose tissue (EAT) and CPs has also been reported. The aim of the study was to evaluate whether the assessment of LVH and EAT thickness, beyond RFs, would be of additive value in predicting CPs in hypertensive subjects. We studied 548 hypertensive patients aged >= 50 years without carotid bruit. LVH and CPs were evaluated and defined according to standard criteria. EAT was measured by echocardiography above the free wall of the right ventricle at end diastole. The presence of LVH and EAT thickness above the median value (3.9 mm) together significantly increased prevalence of CPs in subjects with 0-1 risk factor, but not in those with >= 2 RFs who showed high prevalence of CPs independently of LVH and/or EAT. Receiver operating characteristic curve analysis showed that the addition of LVH and higher EAT thickness together significantly improved prediction of CPs in patients with 0-1 risk factor. Indeed, the area under the curve improved from 0.63 (0.56-0.69) to 0.73 (0.67-0.79), which was significantly higher (p < 0.05). In patients with >= 2 RFs, the addition of LVH and EAT did not significantly improve prediction of CPs. This study shows that the presence of LVH and higher EAT thickness together improves prediction of CPs in hypertensive patients with 0 1 risk factor and that those with >= 2 RFs show high prevalence of CPs independently of LVH and/or EAT. PMID- 22427252 TI - Lipid-lowering and anti-inflammatory effect of ezetimibe in hyperlipidemic patients with coronary artery disease. AB - We evaluated the effects of adding ezetimibe to statin therapy in hypercholesterolemic patients with coronary artery disease (CAD) who could not achieve the target cholesterol levels recommended in the 2007 Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases on statin monotherapy. Ezetimibe (10 mg) was added to basal statin therapy for 12 weeks in 35 patients with hypercholesterolemia and a history of CAD who had not achieved their target cholesterol level with statin monotherapy. Changes in serum lipids, obesity markers, an oxidative stress marker, inflammatory markers, and laboratory values were investigated. Total cholesterol (from 200.6 +/- 30.4 mg/dL in week 0 to 173.4 +/- 33.3 mg/dL in week 12, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (121.3 +/- 29.4 vs. 94.6 +/- 30.4 mg/dL, P < 0.001), and remnant lipoprotein cholesterol (6.4 +/- 3.5 vs. 5.3 +/- 3.0 mg/dL, P < 0.05) all decreased significantly after addition of ezetimibe. The LDL-C/high-density lipoprotein cholesterol ratio also decreased significantly (2.5 +/- 0.8 in week 0 vs. 1.9 +/- 0.7 in week 12, P < 0.001). The percentage of patients achieving the target LDL-C level (<100 mg/dL) increased significantly (70.8 % in week 4 and 65.4 % in week 12, P < 0.001). There were no significant changes in the obesity or oxidative stress markers and high sensitivity C-reactive protein (an inflammatory marker). However, another inflammatory marker (tumor necrosis factor-alpha) was decreased significantly by ezetimibe (1.36 +/- 1.06 in week 0 vs. 0.96 +/- 0.24 in week 12, P = 0.042). In conclusion, when ezetimibe was added to basal statin therapy, serum lipids improved significantly and the rate of achieving the target cholesterol level increased. Thus, ezetimibe efficiently decreases LDL-C and might prevent arteriosclerosis in hypercholesterolemic patients with CAD when added to basal statin therapy. PMID- 22427253 TI - The multidimensional anxiety scale for children: a further validation with Australian adolescents with and without ADHD. AB - OBJECTIVE: To examine the factor structure of the Multidimensional Anxiety Scale for Children (MASC) with Australian adolescents with and without ADHD. METHOD: The MASC was administered to 210 high school-aged adolescents (109 males, 101 females), 115 of whom were clinically diagnosed as ADHD (86 males, 29 females). The remaining 95 were non-ADHD community comparisons. RESULTS: Analyses supported a three-factor model, with a reduced item pool, which combined the Harm Avoidance and Separation Anxiety scales together. This model was invariant across younger and older participants, and across boys and girls. The model was largely invariant across ADHD and non-ADHD groups. The ADHD group had significantly higher Physical Symptom factor scores than the non-ADHD group. CONCLUSION: The MASC is useful for assessing anxiety in adolescents with and without ADHD, but items reflecting the Harm Avoidance and Separation Anxiety scales may need revising. PMID- 22427256 TI - Burkitt's lymphoma: a rare cause of isolated trigeminal neuralgia in a child. PMID- 22427255 TI - CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis. AB - The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing's sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone. PMID- 22427257 TI - Do equity funds protect the poor? Case studies from north-western Madagascar. AB - BACKGROUND: User fees, if applied indiscriminately, have the potential to impose catastrophic costs on poor households at a time when a family member is sick and the household vulnerable. This can drive households into, or further into, poverty. In October 2003, Madagascar instituted a user fee policy that created 'equity funds' at public health centres to subsidize free medicine for the poor. OBJECTIVE: This study aims to assess the outcomes of the equity funds in Madagascar from three perspectives: accuracy of targeting; improvement in health care access for the poor; and reduction in financial burden on the poor. METHODS: Data collection took place in the Boeny region, Madagascar, between March and October 2006. Structured questionnaires asking about health-seeking behaviour and health expenditures were administered to all equity fund member households and two of their neighbouring, non-member households in each study site. RESULTS: The mean socio-economic status of equity fund members was lower than that of non members. However, both leakage and under-coverage occurred under the equity fund scheme, the degree of which varied between sites. Equity fund members were more likely to seek care at public health centres than non-members, although variation existed among study sites, with particularly negative results at one site. Equity fund members who were aware of their member status were more likely to seek care at public health centres. Although out-of-pocket payments for outpatient consultation were significantly lower for members than for non-members, no significant difference was found for medicine payments at public health centres. CONCLUSION: The effectiveness outcomes varied across case studies and the ability of the Madagascan equity funds to protect households against financial risk was ambiguous. To some extent, contextual factors explain these outcome variations. Consequently, nationwide policy should be designed with consideration of the broader health system context and incorporate measures to manage contextual factors to achieve benefit for the entire population. PMID- 22427258 TI - Protecting health care workers from tuberculosis in China: a review of policy and practice in China and the United States. AB - Tuberculosis causes >1.7 million deaths worldwide each year and is frequently transmitted in hospitals. Outbreaks of multidrug-resistant tuberculosis have led to illness and death among health care workers (HCWs) in many countries. Some countries, such as the United States, implemented occupational health policies that substantially reduced tuberculosis rates among HCWs. Inadequate tuberculosis infection control in China may contribute to its high burden of tuberculosis and multidrug-resistant tuberculosis, which are both the second highest worldwide. Occupational health policies in China for tuberculosis control can be strengthened. We reviewed the development and content of tuberculosis infection control policies in the United States and China. Sources included published academic literature, Chinese Ministry of Health policies, US government agency reports, legal databases, personal observations of hospitals, review of internet discussion sites, and discussions with HCWs and health care and law experts. In the United States, slow acceptance of the tuberculosis problem in HCWs resulted in decades of inaction. Tuberculosis infection control policies, based mostly on expert opinion, were implemented only after tuberculosis resurged in the 1980s. Effective evidence-based policies were developed only after multiple cycles of policy implementation, evaluation and revision. These policies have now substantially reduced occupational tuberculosis. In China, tuberculosis has not been formally recognized as an occupational disease, and data regarding the burden in HCWs are sparse. Vagueness of current labour laws and suboptimal alignment of infection control authority and expertise result in varied and sometimes absent protection of HCWs against tuberculosis. Formal evaluations of occupational tuberculosis policies have not been reported. By collecting data on its current HCW tuberculosis burden and infection control practices, refining policies, continually evaluating its policies based on accumulated evidence and rapidly identifying unsuspected tuberculosis cases, China can develop a more comprehensive strategy to ensure the health of HCWs and reduce transmission of tuberculosis and multidrug-resistant tuberculosis. PMID- 22427259 TI - Evaluation of the cytopathicity (fusion/hemifusion) of patient-derived HIV-1 envelope glycoproteins comparing two effector cell lines. AB - HIV-1 envelope glycoprotein (Env) is a major determinant of viral pathogenicity. The evaluation of the biological properties of patient-derived envelopes by comparing two effector cell lines (293T and HeLa) is reported. A standard cell-to cell fusion assay was used to evaluate fusogenicity, whereas a coculture with CD4(+) cells was used to evaluate absolute cell loss, single cell death, and hemifusion events. Fusion and absolute cell loss assays showed that Env expressing 293T and HeLa cells had different fusion efficiencies; fusion was magnified in 293T cells despite a significantly lower cell-surface Env expression. Conversely, gp41-mediated single cell death and hemifusion induced in CD4(+) cells by 293T-Env-positive cells were significantly lower than that induced by HeLa-Env-positive cells. These data showed that the effector cell line used in the in vitro assays is crucial, and a combination of assays is recommended to evaluate the biological properties of patient-derived envelope glycoproteins: preferentially, 293T-Env-positive cells for the evaluation of fusogenicity and HeLa-Env-positive cells for the evaluation of cell death parameters. The combination of assays described in our work could be a valuable tool for dual screenings of large collections of primary Envs or Env mutants and drugs acting on these Envs. PMID- 22427260 TI - Brief report: the medical care of adults with autism spectrum disorders: identifying the needs. AB - There is a lack of information concerning adults with autism spectrum disorder (ASD), especially with regards to their access to health care. A paper and electronic survey was sent to 1,580 primary care physicians in Connecticut. 346 respondents returned a survey and provided care to adults with an ASD. This physician survey provides data on adults with ASD such as: reasons for physician visits, living arrangements, employment status, and any services they are receiving. Responses revealed inadequate training in the care of adults with an ASD and physicians interest in obtaining additional training. The ability to provide a medical home for adults with autism will need to address effective strategies to train current and future physicians. PMID- 22427261 TI - Battery life following pallidal deep brain stimulation (DBS) in children and young people with severe primary and secondary dystonia. AB - BACKGROUND: The finite life of non-rechargeable batteries powering implantable pulse generators (IPG) necessitates their periodic replacement. Children receiving deep brain stimulation (DBS) may require frequent battery changes over their treatment lifetime. OBJECTIVES: We aimed to determine the battery life of IPGs used in pallidal DBS for the treatment of dystonia in children and young people. METHODS: We make use of a review of case notes of all children and young people undergoing DBS surgery at our institution from June 2005 to May 2010. RESULTS: A total of 54 children and young people underwent surgery on at least one occasion, with a total of 76 IPGs implanted. Replacement IPGs due to battery failure were required in 15 out of 54 (27.8%). The average time to battery failure was 24.5 +/- 2.9 months (95% confidence interval), with a range of 13-39 months. Battery life was significantly longer in primary compared to subsequent IPGs. No difference in longevity was seen between different IPG devices. CONCLUSIONS: IPG battery life may be short in children and young people receiving treatment for dystonia. These findings highlight the potential benefits of the recently introduced rechargeable neurostimulators. PMID- 22427262 TI - A double-clear variant of epithelial-myoepithelial carcinoma of the parotid gland. AB - The hallmark of the histology of epithelial-myoepithelial carcinoma (EMC) is the presence of a regular repetitive mixture of bilayered duct-like structures with an outer layer of myoepithelial cells and inner ductal epithelial cells. Clear cell change in the myoepithelial component is common, but clearing of both cell types, giving an impression of a monocellular neoplasm, is rare. A parotid biopsy was received from an 83-year-old male and subject to routine histologic processing for conventional staining and immunohistochemistry. The encapsulated tumour was composed of sheets of PAS/diastase negative clear cells, separated by fibrous septae. The clear myoepithelial cells were positive for S-100 protein, SMA, and p63 and negative for CK19 and surrounded CK19-positive luminal cells. It is important to utilise immunohistochemistry to differentiate this tumour from others with a similar histologic pattern. Information about the behaviour of the double-clear EMC is limited since there are few cases reported. PMID- 22427263 TI - Comparison of ovarian FMR1 genotypes and sub-genotypes in oocyte donors and infertile women. AB - PURPOSE: We recently described ovarian genotypes and sub-genotypes of the FMR1 gene with distinctly associated ovarian aging patterns, which in infertile women follow a typical X-linked distribution pattern. Whether normally fertile women, however, also demonstrate the same distribution, is unknown. METHODS: We, therefore, investigated ovarian FMR1 genotype and sub-genotype distribution in 182 oocyte donor candidates in comparison to 339 infertile controls. As previously reported, genotype designation was made, based on a normal range of CGG ( n = 26-34) (median 30), defining women as normal (norm), heterozygous (het) or homozygous (hom). Het and hom genotypes were further subdivided into sub genotypes, based on whether abnormal alleles were above (high) or below normal range (low). RESULTS: Oocyte donors presented with 47.8% norm, 45.1% het and 7.1% hom genotypes, confirming a typical X-linked distribution pattern. They, however, still subtly differed from infertility patients, especially in het sub-genotypes. CONCLUSION: These findings validate recently newly described ovarian genotypes and sub-genotypes, reaffirming their relevance to female fertility/infertility. PMID- 22427264 TI - Learning from your mistakes: is aneuploidy so bad, after all? PMID- 22427265 TI - Loving-kindness brings loving-kindness: the impact of Buddhism on cognitive self other integration. AB - Common wisdom has it that Buddhism enhances compassion and self-other integration. We put this assumption to empirical test by comparing practicing Taiwanese Buddhists with well-matched atheists. Buddhists showed more evidence of self-other integration in the social Simon task, which assesses the degree to which people co-represent the actions of a coactor. This suggests that self-other integration and task co-representation vary as a function of religious practice. PMID- 22427266 TI - Reasoning with base rates is routine, relatively effortless, and context dependent. AB - We tested models of base rate "neglect" using a novel paradigm. Participants (N = 62) judged the probability that a hypothetical person belonged to one of two categories (e.g., nurse/doctor) on the basis of either a personality description alone (NoBR) or the personality description and a base rate probability (BR). When base rates and descriptions were congruent, judgments in the BR condition were higher and more uniform than those in the NoBR condition. In contrast, base rates had a polarizing effect on judgments when they were incongruent with the descriptions, such that estimates were either consistent with the base rates or discrepant with them. These data suggest that the form of base rate use (i.e., whether base rates will be integrated with diagnostic information) is context dependent. In addition, judgments made under instructions to respond intuitively were influenced by the base rates and took the same length of time in the two conditions. These data suggest that the use of base rates is routine and effortless and that base rate "neglect" is really a mixture of two strategies, one that is informed primarily by the base rate and the other by the personality description. PMID- 22427267 TI - SISCOM technique with a variable Z score improves detectability of focal cortical dysplasia: a comparative study with MRI. AB - OBJECTIVE: Focal cortical dysplasia (FCD) is one of the causes of epilepsy, but its diagnosis by MRI remains difficult. The purpose of this study was to evaluate the use of subtraction ictal SPECT coregistered to MRI (SISCOM) and MRI to detect the epileptogenic focus in patients with FCD. METHODS: MRI and SISCOM findings of 20 patients with pathologically proven FCD were retrospectively reviewed. MRI was visually assessed for detecting FCD. SISCOM was evaluated by a new method selecting a higher standard deviation (Z score) area as the epileptogenic focus. We scored the detectability in both SISCOM and MRI while referring to the pathology. RESULTS: Sixteen patients agreed with pathology on SISCOM and 14 patients on MRI. Although MRI could not point out foci in two cases of FCD type I, SISCOM could do so in both of them. A combined diagnosis of SISCOM and MRI agreed with the pathology in 18 patients. CONCLUSIONS: Narrowing the target by elevating the Z score on SISCOM seems to be an appropriate method to detect the foci without the need for expertise of radiologists. We recommend this combined method of SISCOM and MRI for presurgical evaluation in patients with FCD. PMID- 22427268 TI - Reevaluation of FDG-PET/CT in patients with hoarseness caused by vocal cord palsy. AB - OBJECTIVE: Vocal cord palsy (VCP) is a potential cause of hoarseness that results in decreasing mobility of the vocal cord. VCP can arise from a variety of causes; so, systematic screening is warranted for the management of patients with VCP. Asymmetrical fluorodeoxyglucose (FDG) uptake in vocal cords is a well-known feature in patients with VCP, but no detailed analysis has been performed. This study aimed at reevaluating the (18)F-FDG positron emission tomography/computed tomography (PET/CT) for patients with VCP. METHODS: We retrospectively surveyed the results of FDG-PET/CT for 59 patients with VCP, compared to laryngoscopic findings. Quantitative analysis was performed using maximum standardized uptake value (SUVmax), and regions of interest were drawn over bilateral vocal cords as confirmed from the CT portion of PET/CT. Patients were divided into 3 groups: Group 1 (n = 14), in which VCP was caused by the lesion of the laryngeal area; Group 2 (n = 40), in which VCP was caused by the lesion on the root of the recurrent laryngeal nerve; and Group 3 (n = 5), in which VCP was caused by the lesion from the vagal center to the proximal vagus nerve. RESULTS: For Group 1, higher FDG uptake in the paralyzed vocal cord was seen in 86 % of patients (mean SUVmax 8.1 +/- 5.3 vs. 2.3 +/- 0.4, paralyzed vs. non-paralyzed, respectively; P < 0.002). The sensitivity of FDG-PET/CT for indicating the lesion causing VCP was 79 % for Group 1. Group 2 showed dominant FDG uptake in the non-paralyzed vocal cord (mean SUVmax 2.1 +/- 0.9 vs. 1.5 +/- 0.4, non-paralyzed vs. paralyzed, respectively; P < 0.001). The sensitivity of FDG-PET/CT for indicating the lesion causing VCP was 93 % for Group 2. Group 3 showed no statistically significant difference in FDG accumulation between non-paralyzed and paralyzed vocal cords (mean SUVmax 1.8 +/- 0.3 vs. 1.7 +/- 0.3, non- paralyzed vs. paralyzed, respectively; P = 0.30). The sensitivity of FDG-PET/CT for indicating the lesion causing VCP was 60 % for Group 3. CONCLUSIONS: FDG accumulation in the vocal cords is dependent on the lesion site causing VCP. In addition, FDG-PET/CT can contribute to identification of the lesion responsible for inducing VCP. PMID- 22427270 TI - Sustained inflammation induces degeneration of the temporomandibular joint. AB - The temporomandibular joint (TMJ) undergoes degenerative changes among patients who suffer from arthritis, and yet the pathogenesis of TMJ osteoarthritis and rheumatoid arthritis is poorly understood. We hypothesized that sustained inflammation in the TMJ induces structural abnormalities, and accordingly characterized the disc and synovium in a novel model with double injections of complete Freund's adjuvant (CFA), using behavioral, morphological, cellular, and molecular assessments. Thirty-five days following double CFA injections in seven week-old female Sprague-Dawley rats, the disc in the CFA-induced inflammation group demonstrated multiple degenerative changes, including marked thickening, opacity, and deformation. The discs in the CFA group further showed significantly greater wet and net weights, and elevated collagen, aggrecan, and total glycosaminoglycan contents. The synovium in the CFA-induced inflammation group showed marked infiltration of mononucleated cells and accumulated sub-synovial adipose tissue. Both the disc and synovium had significantly higher iNOS and IL 1beta mRNA expression than controls (saline injections). These findings are consistent with our hypothesis that sustained TMJ inflammation, even within the presently observed 35 days, may be a predisposing factor for structural abnormalities. Insight into TMJ inflammation and degeneration is anticipated to improve our understanding of the pathogenesis of TMJ arthritis and help design clinically relevant strategies for tissue engineering. PMID- 22427271 TI - Improving the experience of care for people using NHS services: summary of NICE guidance. PMID- 22427272 TI - Doctors' duty to report poor practice. PMID- 22427273 TI - Putting patients first. PMID- 22427274 TI - NICE backs new oral anticoagulant for stroke prevention. PMID- 22427275 TI - Move to local control has led to poorer care for neurological patients. PMID- 22427276 TI - Food companies ignore calorie count guidelines as attempts to tackle obesity crisis fail. PMID- 22427277 TI - Estimating mortality differences in developed countries from survey information on maternal and paternal orphanhood. AB - In general, the use of indirect methods is limited to developing countries. Developed countries are usually assumed to have no need to apply such methods because detailed demographic data exist. However, the potentialities of demographic analysis with direct methods are limited to the characteristics of available macro data on births, deaths, and migration. For instance, in many Western countries, official population statistics do not permit the estimation of mortality by socioeconomic status (SES) or migration background, or for estimating the relationship between parity and mortality. In order to overcome these shortcomings, I modify and extend the so-called orphanhood method for indirect estimation of adult mortality from survey information on maternal and paternal survival to allow its application to populations of developed countries. The method is demonstrated and tested with data from two independent Italian cross-sectional surveys by estimating overall and SES-specific life expectancy. The empirical applications reveal that the proposed method can be used successfully for estimating levels and trends of mortality differences in developed countries and thus offers new prospects for the analysis of mortality. PMID- 22427279 TI - The income and health effects of tribal casino gaming on American Indians. AB - The legalization of American Indian casino gaming in the late 1980s allows examination of the relationship between income and health in a quasi-experimental way. Revenue from gaming accrues to individual tribes and has been used both to supplement tribe members' income and to finance tribal infrastructure. We assembled annual data from 1988-2003 on tribal gaming, health care access (from the Area Resource File), and individual health and socioeconomic characteristics data (from the Behavioral Risk Factors Surveillance System). We use this information within a structural, difference-in-differences framework to study the effect of casino gaming on tribal members' income, health status, access to health care, and health-related behaviors. Our difference-in-differences framework relies on before-after comparisons among American Indians whose tribe has at some time operated a casino and with-without comparisons between American Indians whose tribe has and those whose tribe has not initiated gaming. Our results provide identified estimates of the positive effect of gaming on American Indian income and on several indicators of American Indian health, health-related behaviors, and access to health care. PMID- 22427278 TI - Widowhood and mortality: a meta-analysis and meta-regression. AB - The study of spousal bereavement and mortality has long been a major topic of interest for social scientists, but much remains unknown with respect to important moderating factors, such as age, follow-up duration, and geographic region. The present study examines these factors using meta-analysis. Keyword searches were conducted in multiple electronic databases, supplemented by extensive iterative hand searches. We extracted 1,377 mortality risk estimates from 123 publications, providing data on more than 500 million persons. Compared with married people, widowers had a mean hazard ratio (HR) of 1.23 (95% confidence interval (CI), 1.19-1.28) among HRs adjusted for age and additional covariates and a high subjective quality score. The mean HR was higher for men (HR, 1.27; 95% CI, 1.19-1.35) than for women (HR, 1.15; 95% CI, 1.08-1.22). A significant interaction effect was found between gender and mean age, with HRs decreasing more rapidly for men than for women as age increased. Other significant predictors of HR magnitude included sample size, geographic region, level of statistical adjustment, and study quality. PMID- 22427280 TI - Bilateral Kienbock's disease in association with type 1 diabetes. PMID- 22427281 TI - A new era for ANB has begun. PMID- 22427282 TI - To control or not? A motivational perspective on coping with pain. AB - Pain relief is often the primordial treatment objective in pain patients. However, an exclusive focus upon pain relief may have costs. Evidence is accumulating that persistent attempts to gain control over pain may, paradoxically, hinder successful adaptation to pain and increase frustration and limitations due to pain. To better understand these apparently paradoxical findings, we propose to adopt a motivational perspective on coping with pain. Within this perspective, pain control is recast as an attempt to protect and restore valued life goals threatened by pain. This framework explains why some patients engage excessively in pain control strategies despite the costs associated with this, such as overuse of medication. A clinical implication is that cautiousness is warranted in promoting strategies exclusively aimed at pain relief. Beyond standard medical care, interventions should also be aimed at the improvement of functioning despite pain. Certainly those patients for whom there is no definite or sound cure to pain and who increasingly experience emotional and physical problems due to pain might benefit from paramedical help by psychologists and/or physiotherapists. PMID- 22427283 TI - Therapeutic challenges in a patient with POEMS syndrome and recurrent stroke: presentation of a case and review of the literature. AB - POEMS syndrome includes the clinical features of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. A severe complication of patients with this syndrome is ischemic stroke, which has been described only occasionally despite the hematologic abnormalities that may be associated with the disease. In the literature, only eight patients have been reported as suffering from multiple or recurrent strokes until now. We present a 54-year-old woman from Sri Lanka with POEMS syndrome who experienced recurrent ischemic strokes followed by an acute abdomen and global heart failure. On the basis of a literature review, we discuss current therapeutic approaches and their possible side effects. PMID- 22427284 TI - Dilative arteriopathy in metabolic myopathies, particularly Pompe's disease. AB - There is increasing evidence that some metabolic myopathies are associated with dilative arteriopathy. This review aimed at summarizing recent findings concerning the pathogenesis, presentation, diagnosis and treatment of dilative arteriopathies in patients with metabolic myopathies. Dilative arteriopathy manifests as ectasia or aneurysms. Dilative arteriopathy most frequently occurs in patients with Pompe's disease. More rarely, dilative arteriopathy occurs in other glycogenoses or mitochondrial disorders. Complications of dilative arteriopathy may be intracerebral or subarachnoid bleeding, dissection of the arterial wall or ischemic stroke. Because of the often fatal complications, patients at risk for developing dilative arteriopathy should be screened for it as soon as the diagnosis of a metabolic myopathy has been established. Dilative arteriopathy is a phenotypic feature, particularly of Pompe's disease. Early recognition of ectasias and aneurysms and appropriate interventions by enzyme replacement therapy, stenting, coiling or surgery may prevent mild or severe cerebrovascular complications or even death in some of these patients. PMID- 22427285 TI - Prediction of hospitalization duration for acute stroke in Belgium. AB - We aim to predict the duration of hospitalization for acute stroke in Belgium by evaluating the external validity of the prolonged length of stay (PLOS) score and by formulating a new prediction score that may be better suited for the Belgian healthcare system. This single-center retrospective study is based on data collected prospectively from the departmental stroke registry. To validate the PLOS score, receiver operating characteristic curves were constructed and Hosmer Lemeshow tests were implemented. Odds ratios were calculated by models of logistic regression, based on predictors of length of stay (LOS) with significance in univariate analyses, and were translated into a new risk score. C statistics for prediction of LOS >=7 days, LOS >=14 days, and LOS >=30 days using the PLOS score were in the range of 0.6-0.7. Thrombolytic therapy, mortality, and need for institutionalization had a notable negative influence on the discrimination of the PLOS score. Overall, the PLOS score performed better for prediction of LOS >=14 days than for LOS >=7 days and >=30 days. The Belgian length of stay for stroke (BLOSS) score is proposed as a simplified prediction model based only on the NIHSS score and age. The PLOS score showed moderate value for prediction of hospitalization duration for acute stroke in this Belgian cohort. A prediction model based only on age and stroke severity may be a worthy alternative. PMID- 22427286 TI - Periodic leg movements in sleep in patients with supratentorial cerebral infarction. AB - The pathophysiology of periodic leg movements in sleep (PLMS) is complex, and still lacks a consensus. Consecutive 35 patients with the diagnosis of acute supratentorial ischemic stroke and 35 age- and sex-matched control subjects were prospectively investigated. Clinical and sociodemographic evaluation and a whole night polysomnographic recording were performed. In patients with supratentorial ischemic stroke, 27 patients (77.2%) had PLMS-index more than 5/h, and 19 out of 35 patients (54.3%) had PLMS-index more than 15/h; while only 10 participants (28.5%) in control group had PLMS-index more than 5/h, and 6 participants (17.1%) had PLMS-index more than 15/h (p < 0.05). None of the demographic variables showed statistically significant relationship with PLMS, such as gender (p = 0.952) and age (p = 0.435). Territorial localization of ischemic lesions showed no relation with the presence of PLMS (p = 0.867), PLMS-index (p = 0.432), or restless legs syndrome (p = 0.833). All patients demonstrated PLMS contralateral to ischemic lesion except eight patients with bilateral PLMS; these were also more prominent contralaterally. Our study supports the hypothesis that destructive lesions causing the loss of cortical or subcortical inhibition exerting on the reticular formation on spinal pathways could lead to the development of PLMS. PMID- 22427287 TI - Hallucinations in Parkinson's disease: cross-sectional study. AB - The aim of this study was to estimate the prevalence and risk factors for the development of hallucinations in patients with Parkinson's disease (PD). This cross-sectional study included 180 consecutive, non-demented patients with PD. Out of them, 24 patients (13%) experienced some kind of hallucinations. Visual hallucinations were present in 22/24 (90%) subjects. Univariate logistic regression analysis has shown relationship between presence of hallucinations and the following variables: age of patients (p = 0.025), PD duration (p = 0.001), duration of levodopa treatment (p = 0.001), total daily dose of levodopa (p = 0.033), presence of levodopa-induced dyskinesia (p = 0.002) and their duration (p = 0.021), and experience of nightmares (p = 0.042). Hallucinations were also associated with higher scores of the UPDRS (p = 0.001), HDRS (p = 0.001) and the NPI total score (p = 0.001), and higher H-Y stages of the disease (p = 0.001). Multivariate regression analysis has demonstrated that the duration of PD (p = 0.024) as well as NPI total score (p = 0.002) was significant independent risk factors for hallucinations in PD. PMID- 22427288 TI - Diagnostic approach of patients with longitudinally extensive transverse myelitis. AB - The aim of this study is to present a diagnostic and therapeutic approach in patients with LETM. In a period between June 2008 and June 2010, all patients who fulfilled criteria for LETM were included in the study. All patients underwent a standardized protocol of investigations presented in this paper. Ten patients were included (5 male, 5 female, with the age distribution from 24 to 70 years). Four patients were diagnosed with NMO/spatially limited NMO spectrum disorder, three patients were diagnosed with spinal cord ADEM, two multiple sclerosis (MS) and one patient with copper deficiency myelopathy. Laboratory support for the diagnosis of NMO was positive NMO-IgG antibody; for the diagnosis of ADEM signs of peripheral nervous system involvement on electromyoneurography; and for the diagnosis of MS brain MRI lesions typical for MS, as well as positive oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). All cases with inflammatory myelopathy were treated either with steroids or plasma exchange and copper replacement was started in the case of copper deficiency. The mean time from the first symptom until the final diagnosis was 16.3 months (range 1 month to 7 years). As each of idiopathic inflammatory demyelinating diseases that can present with LETM have specific therapy, the postponement in making the correct diagnosis can lead to a poor recovery. In patients with LETM, a standardized diagnostic approach can result in a correct diagnosis and appropriate treatment. PMID- 22427289 TI - Association of inflammatory biomarkers with sleep disorders in hemodialysis patients. AB - The aim of this study was to investigate the relationship between sleep disorders and C-reactive protein (CRP), hallmark of inflammation, and other biomarkers which may alter in hemodialysis patients. Our study included 108 patients who were dialyzed at least for 3 months. Before hemodialysis, blood samples were collected and serum levels of CRP, ferritin, albumin, phosphorus, parathyroid hormone, and hemoglobin were measured. Sleep disorders were confirmed by the presence of at least one of following criteria: insomnia, restless leg syndrome (RLS), obstructive sleep apnea syndrome (OSAS), narcolepsy, nightmare, sleepwalking, and poor sleep. 82.4% of patients demonstrated sleep disorders; insomnia (50%), RLS (32.4%), OSAS (7.4%), narcolepsy (15.7%), nightmare (15.7%), sleepwalking (0.9%), and poor sleep (71.3%). Our results revealed that CRP >=3.8 MUg/ml and advanced age were significantly associated with sleep disorders in these patients (p = 0.004 and p = 0.006, respectively). We concluded that inflammation has a close relation with sleep disorders in hemodialysis patients. PMID- 22427290 TI - Efficacy and safety of cinnarizine in the prophylaxis of migraine headaches in children: an open, randomized comparative trial with propranolol. AB - Migraine headaches are common in children. Early diagnosis and appropriate interventions are mandatory to prevent decades of suffering and diminished quality of life. There is need for data regarding the efficacy and safety of prophylactic agents in children with migraine; therefore, we designed a randomized clinical trial to compare the efficacy and safety of cinnarizine with that of a well-known prophylactic agent (propranolol) in the prophylaxis of pediatric migraine headache. A total of 120 patients aged between 6 and 17 years were recruited and 113 patients succeeded in completing all phases of the trial. Of them, 57 patients were given cinnarizine, and propranolol was administered in 56 patients. Reduction in headache frequency was the main response to treatment. Cinnarizine reduced the baseline headache frequency by more than 50% in 74.6% of patients and the mean headache frequency per month was reduced from 11.851 +/- 0.739 (mean +/- SEM) to 3.358 +/- 0.739 (mean +/- SEM) attacks per month (P < 0.001). In the propranolol group, more than 50% reduction of the baseline headache frequency was seen in 72.5% of patients and the mean headache frequency per month was reduced from 10.264 +/- 0.830 (mean +/- SEM) to 2.774 +/- 0.830 (mean +/- SEM) attacks per month (P < 0.001). No significant difference was seen in 50% reduction of the baseline headache frequency between treatment groups (P = 0.358). No significant adverse effects were reported. In this open study, cinnarizine appeared thus as effective as propranolol and safe for the prophylaxis of migraine in children, but this remains to be confirmed in a double blind placebo-controlled trial. PMID- 22427291 TI - Phenotypic heterogeneity in hereditary motor neuropathy type V: a new case report series. AB - Previous studies have revealed a wide phenotypic heterogeneity in hereditary motor neuropathy type V in which upper and lower motor neurons and peripheral motor axons are variously affected, even within the same family. In this case series, we describe the genetic, clinical and electrophysiological features of patients belonging to a four-generation Italian family. Because of a possible anticipation phenomenon, the disorder became apparent at an earlier age as it passed to the next generation, with a median age of onset of 65 years for the first 2 generations, 32 for the third, and 13.5 for the fourth. The symptoms at onset varied considerably among the sufferers, with a predominant impairment of the hands in seven cases, the impairment of the four limbs in one patient and only of the lower limbs in another. Also muscle atrophy was variable, from very mild to severe (wasting of the distal muscles of the limbs). Moreover, electrophysiological results were heterogeneous, including cases with isolated and with diffuse axonal motor neuropathy, and one case of motor sensory polyneuropathy. A novel polymorphism G->T was also found in the Berardinelli-Seip congenital lipodystrophy 2 gene on intron 4. This broad phenotypic and genotypic spectrum calls the clinician attention to this rare and still insufficiently known disease. PMID- 22427292 TI - Exacerbation of myasthenia gravis after postoperative radiotherapy for a thymoma. PMID- 22427293 TI - Diffusion restriction in the splenium of the corpus callosum in a patient with the syndrome of transient headache with neurological deficits and CSF lymphocytosis (HaNDL): a challenge to the diagnostic criteria? AB - The diagnosis of transient headache with neurological deficits and CSF lymphocytosis (HaNDL) is essentially based on the clinical and CSF findings, and the absence of MRI abnormalities. We present a young man with the clinical characteristics of HaNDL, but also an area of diffusion restriction in the splenium of the corpus callosum (SCC). When considering the limited experience with this MRI technique in this disorder, we wonder if a normal MRI can be maintained as an indispensable criterion for diagnosis. Similar MRI abnormalities limited to the SCC have been found in mild forms of meningoencephalitis, but their origin remains obscure. In at least some cases not only a clinical, but also a radiological overlap could exist between both disorders. PMID- 22427294 TI - Giant cell ependymoma of the thoracic spinal cord. AB - We report a new case of giant cell ependymoma (GCE) of the thoracic spinal cord. Ependymomas predominate in children and young adults and are frequently intracranial and infra-tentorial. However, a second age peak at 30-40 years is reported for spinal tumours. Microscopically, ependymomas show a large variety of histological features, among which a rare variant with giant cells. This 59-year old woman presented with a 6-month history of numbness and burning sensation affecting the left lower limb and hemi-trunk. A cervico-thoracic MRI revealed a solid intra-medullary tumour at the level of T1-T3, slightly T1-hypointense, T2 hyperintense and contrast enhancing. A complete surgical resection was carried out through a C7 to T4 laminectomy. Recovery was complete with no sign of recurrence at 18-month follow-up. The initial histological diagnosis of glioblastoma was challenged on the basis of the imaging and operative findings of a well-circumscribed tumour. The case was sent to us for second opinion and we diagnosed a GCE, WHO grade II, with a biphasic pattern including a predominant giant cell component (>90%), with genetic evidence of polyploidy, and a very limited classic component, showing a characteristic loss of chromosome 22. Our report adds to the clinical, imaging, pathological and genetic characterisation of GCE and brings the first genetic evidence that these rare tumours are at least bi-clonal. It also suggests that GCE have a good prognosis after complete surgical resection. PMID- 22427295 TI - Spinal tanycytic ependymoma with diffusion restriction on MRI. AB - Tanycytic ependymoma is a rare spindle-cell variant of ependymoma derived from tanycytes. Primitive neuroectodermal tumors usually have diffusion restriction, whereas ependymomas do not. Here, we present a case of tanycytic ependymoma with diffusion restriction. As far we are aware, this is the first case of tanycytic ependymoma in the English literature with diffusion restriction. PMID- 22427296 TI - Topiramate-induced acute myopia with MRI contrast enhancement. AB - Topiramate is a sulfamate-substituted monosaccharide mainly used to treat epilepsy in children and adults and prophylaxis of migraine. This article describes a case of topiramate-induced acute transient myopia. The underlying mechanism and management is discussed. A 13-year-old female complained of sudden onset of blurred vision; 7 days prior to this she had commenced topiramate therapy for migraine prophylaxis. Visual acuity was reduced in both eyes. Examination revealed myopic refractive changes which resolved quickly following discontinuation of the drug. An MRI showed uveoscleral and subcutaneous cellular tissue abnormalities in the T1 contrasted images. PMID- 22427297 TI - Giant frontal mucocele complicated by subdural empyema: treatment of a rare association. AB - Giant frontal mucocele (GFM) is an extremely rare cause of frontal lobe syndrome. Subdural empyema (SDE) is an uncommon complication of paranasal sinisutis, for which craniotomy and decompressive craniotomy are the most effective surgical procedures. A 54-year-old man was brought unconscious to the emergency room where recurrent generalized seizures occurred. Heroine abuse, HCV-related hepatitis, prolonged antibiotic therapy for treatment of purulent rhinorrhea, along with recent personality changes were reported. High white blood cell count, pansinusitis, GFM, SDE and cerebritis were documented. The patient underwent bifrontal craniotomy in emergency, extensive drilling of the inner aspect of the frontal bone, surgical toilet of the enlarged frontal sinus and its "cranialization". Prevotella intermedia and Fusobacterium nucleatum were isolated and antibiotic therapy was started intravenously and then continued orally for 3 months. 2 years later the patient has recovered, though minor signs of frontal lobe syndrome persist. To the authors knowledge, this is the first case of GFM with SDE reported in the literature. Although decompressive craniectomy is advocated in extreme conditions, as in this case, "internal decompressive craniectomy", obtained with craniotomy and cranialization of the frontal sinuses, is strongly advocated in cases of SDE associated with megasinuses. PMID- 22427298 TI - Disproportionately large communicating fourth ventricle resulting from adjustable valve shunt in an infant. AB - Disproportionately large communicating fourth ventricle (DLCFV) is usually experienced in adults with no previous experience of shunting. We present a case of an infant with an enlarged fourth ventricle similar to isolated fourth ventricle (IFV) which appeared after shunting. The patient's brain stem symptoms and the abnormal appearance of the fourth ventricle were dramatically ameliorated simply by reducing the opening pressure of the adjustable valve of the ventriculo peritoneal shunt. The present case suggests that in the present era, with adjustable or programmable valve shunt a common procedure, DLCFV may occur, at least temporarily, even in infants and even after shunting. PMID- 22427299 TI - Combination of blepharospasm and apraxia of eyelid opening: a condition resistant to treatment. AB - Blepharospasm is seen in many cases of Parkinsonism including progressive supranuclear palsy. These patients usually respond well to botulinum toxin, however some patients subsequently fail to respond to even higher doses of botulinum toxin after an initial good response. They should not be considered failure of treatment with botulinum toxin, as a significant number of these patients have underlying apraxia of eyelid opening in addition to blepharospasm, which may be the cause of failure to respond to botulinum toxin. Combination of eyelid crutches or myomectomy with botulinum toxin is more effective in these patients as compared to an individual treatment modality. In this report, we present two patients with progressive supranuclear palsy who failed to respond to botulinum toxin because they had underlying apraxia of lid opening. Partial myomectomy in one patient and eyelid crutches in the other in combination with botulinum toxin lead to a much better response to botulinum toxin. PMID- 22427300 TI - Fourth ventricular meningioma: a case report and literature review. AB - A 60-year-old man was admitted with slowly progressive dizziness. Cranial nerve evaluation found no abnormalities. Magnetic resonance imaging revealed a well circumscribed mass with homogeneous enhancement located in the fourth ventricle. The patient underwent surgery for the removal of the tumor via the bilateral suboccipital approach. Subtotal removal of the tumor was achieved in a piecemeal fashion. Histological diagnosis was meningothelial meningioma. Fourth ventricular meningiomas are extremely rare. We reviewed the literature and discussed the features of fourth ventricular meningiomas. PMID- 22427301 TI - Late-onset post-irradiation vasculopathy of the posterior cerebral vasculature. AB - Radiotherapy is extensively used in the treatment of malignant tumors of the central nervous system, but may also cause considerable morbidity and mortality, probably through damage to the remarkably vulnerable vascular system. We present two cases of infarction in the posterior cerebral vasculature related to earlier irradiation for a pineal gland tumor. Two patients were irradiated for a pineal gland tumor in young adulthood. Respectively 20 and 35 years later, they presented with a progressive neurological decline, related to early progressive atherosclerosis in the posterior cerebral vasculature. In conclusion, irradiation of the posterior cerebral territory may produce precocious atherosclerosis of posterior circulation vasculature, even decades later. When a progressive clinical decline with accumulating ischemic events is observed, together with signs of atherosclerosis, radiotherapy-related vasculopathy may be considered. PMID- 22427302 TI - Brain MRI in global hypoxia-ischemia: a map of selective vulnerability. AB - Hypoxic-ischemic injury to the brain is a devastating occurrence that frequently results in death or profound long-term neurologic disability. In this report, we describe the neuroradiological findings of a patient suffering from a global brain hypoxic-ischemic injury. Our findings clearly display that the areas of the brain with the highest metabolic activity, such as basal ganglia, thalami, and occipital and perirolandic cortex, are most susceptible to hypoxic injury. The MRI images delineate a map of the brain areas with selective vulnerability to hypoxia. PMID- 22427303 TI - Hyperglycemia-induced hemichorea-hemiballism (HCHB). PMID- 22427304 TI - Bilateral medial medullary infarction. PMID- 22427305 TI - Subperiostal orbital hematomas as an unusual complication of liver cirrhosis. PMID- 22427306 TI - Descending corticospinal tract Wallerian degeneration after stroke: an old sign, a new prognostic marker? PMID- 22427307 TI - Trends in socioeconomic inequalities in risk of sudden infant death syndrome, other causes of infant mortality, and stillbirth in Scotland: population based study. AB - OBJECTIVES: To compare changes in inequalities in sudden infant death syndrome with other causes of infant mortality and stillbirth in Scotland, 1985-2008. DESIGN: Retrospective cohort study. SETTING: Scotland 1985-2008, analysed by four epochs of six years. PARTICIPANTS: Singleton births of infants with birth weight >500 g born at 28-43 weeks' gestation. MAIN OUTCOME MEASURES: Sudden infant death syndrome, other causes of postneonatal infant death, neonatal death, and stillbirth. Odds ratios expressed as the association across the range of seven categories of Carstairs deprivation score. RESULTS: The association between deprivation and the risk of all cause stillbirth and infant death varied between the four epochs (P=0.04). This was wholly explained by variation in the risk of sudden infant death syndrome (P<0.001 for interaction). Among women living in areas of low deprivation, there was a sharp decline in the rate of sudden infant death syndrome from 1990 to 1993. Among women living in areas of high deprivation, there was a slower decline in sudden infant death syndrome rates between 1992 and 2004. Consequently, the odds ratio for the association between socioeconomic deprivation and sudden infant death syndrome increased from 2.04 (95% confidence interval 1.53 to 2.72) in 1985-90, to 7.52 (4.62 to 12.25) in 1991-6, and 9.50 (5.46 to 16.53) in 1997-2002 but fell to 1.78 (0.87 to 3.65) in 2002-8. The interaction remained significant after adjustment for maternal characteristics. CONCLUSION: The rate of sudden infant death syndrome declined throughout Scotland in the early 1990s. The decline had a later onset and was slower among women living in areas of high deprivation, probably because of slower uptake of recommended changes in infant sleeping position. The effect was to create a strong independent association between deprivation and sudden infant death syndrome where one did not exist before. PMID- 22427308 TI - Efficacy and safety of a single-pill fixed-dose combination of high-dose telmisartan/hydrochlorothiazide in patients with uncontrolled hypertension. AB - OBJECTIVE: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent(r) (medium dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi(r)BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. METHODS: In total, 44 hypertensive patients (22 males, age 71+/-14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent(r) were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent(r) to Micombi(r)BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. RESULTS: Systolic BP and diastolic BP significantly decreased (125+/-15/69+/-11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent(r) showed similar BP lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. CONCLUSION: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP. PMID- 22427309 TI - Patients from across Europe have similar views on patient-centred care: an international multilingual qualitative study in infertility care. AB - BACKGROUND: International patient centredness concepts were suggested but never conceptualized from the patients' perspective. Previously, a literature review and a monolingual qualitative study defined 'patient-centred infertility care' (PCIC). The present study aimed to test whether patients from across Europe value the same aspects of infertility care. METHODS: An international multilingual focus group (FG) study with 48 European patients from fertility clinics in Austria, Spain, the UK and Belgium, with deductive content analysis. RESULTS: All specific care aspects important to participants from all countries could be allocated to the 10 dimensions of PCIC, each discussed in every FG, including: 'information provision', 'attitude of and relationship with staff', 'competence of clinic and staff', 'communication', 'patient involvement and privacy', 'emotional support', 'coordination and integration', 'continuity and transition', 'physical comfort' and 'accessibility'. Most specific care aspects (65%) were discussed in two or more countries and only a few new codes (11%) needed to be added to the previously published coding tree. Rankings from across Europe clearly showed that 'information provision' is a top priority. CONCLUSIONS: The PCIC-model is the first patient-centred care (PCC) model based on the patients' perspective to be validated in an international setting. Although health-care organization and performance differ, the similarities between countries in the infertile patients' perspective were striking, as were the similarities with PCC models from other clinical conditions. A non-condition specific international PCC model and a European instrument for the patient centredness of infertility care could be developed. European professionals can learn from each other on how to provide PCC. PMID- 22427310 TI - The effect of different catheter balloon dilatation modes on cricopharyngeal dysfunction in patients with dysphagia. AB - The primary aim of this study was to investigate the outcomes of two different modes (active and passive) of balloon dilatation therapy on cricopharyngeal dysfunction (CPD). Thirty-eight CPD patients with neurological disorders were recruited between 2006 and 2010. Twenty-one of them received active balloon dilatation therapy, and the remaining 17 received passive dilatation therapy for an average of 4 weeks. The patients' swallowing function before and after the intervention was evaluated using the Functional Oral Intake Scale (FOIS) and the upper esophageal sphincter (UES) opening was studied with the videofluoroscopic swallow study. Both modes of balloon dilatation therapy yielded improvements in the FOIS (active group: z = -3.767, p < 0.001; passive group: z = -3.472, p < 0.001) and the UES opening (both groups: p < 0.01). Active dilatation showed a significantly better FOIS result (p = 0.028) than passive dilatation for CPD. Both active and passive balloon dilatation benefits patients with neurological disorders but active balloon dilatation is better. PMID- 22427311 TI - Perfectionism in doctors. PMID- 22427312 TI - Indian health groups welcome country's first compulsory licence. PMID- 22427313 TI - Extensive coronary aneurysms with thrombosis in resistant Kawasaki disease. AB - Giant coronary artery aneurysms that occur in 0.5 to 1% of patients with Kawasaki disease can be fatal if associated with thrombosis. Some patients may show persistent inflammation and fever despite treatment with repeated doses of intravenous immunoglobulin (IVIG), steroids, and aspirin. This report describes an infant boy with resistant Kawasaki disease who presented with extensive coronary artery involvement and coronary thrombosis. His inflammation was not controlled with multiple doses of IVIG, parenteral and oral steroids, or high dose aspirin, and he finally needed infliximab, a monoclonal antibody against tumor necrosis factor alpha. The progression of coronary thrombosis was arrested by the platelet glycoprotein 2b/3a receptor blocker, abciximab, during the acute phase of the disease. PMID- 22427314 TI - Left hemitruncus with tetralogy of fallot and right aortic arch: rare survival beyond the first decade. AB - Hemitruncus is an uncommon congenital anomaly that has been described in isolation or in association with other congenital cardiac malformations. This report describes a rare case of left hemitruncus with tetralogy of Fallot and a right-sided aortic arch. The patient presented to us in the early second decade. The diagnosis was suspected with echocardiography and confirmed with cardiac catheterization. The patient underwent successful surgical correction of the anomaly. PMID- 22427316 TI - Elementary school-located influenza vaccine programs: key stakeholder experiences from initiation to continuation. AB - This study examined the initiation and logistics, funding, perceived barriers and benefits, and disruption of school activities by school-located influenza vaccination (SLIV) programs conducted during the 2008-2009 influenza season. Seventy-two interviews using a structured protocol were conducted with 26 teachers, 16 school administrators, and 30 health care professionals from 34 schools in 8 school districts. SLIV programs used a variety of locations, scheduling and staffing options, and methods for receiving parental consent and screening children. Health care professionals were primarily responsible for implementing SLIV programs, and most administrators and health care professionals considered programs easy to initiate. Health care professionals identified successful programs as requiring adequate planning/coordination, a dedicated program coordinator, and a consistent funding source. Most respondents (96%) reported minimal school-day disruptions. The perception of most stakeholders is that SLIV programs can be relatively easy to initiate, minimally disruptive and can become more efficient with experience, especially with feedback from all stakeholders. PMID- 22427315 TI - Congenital nephrogenic diabetes insipidus: the current state of affairs. AB - The anti-diuretic hormone arginine vasopressin (AVP) is released from the pituitary upon hypovolemia or hypernatremia, and regulates water reabsorption in the renal collecting duct principal cells. Binding of AVP to the arginine vasopressin receptor type 2 (AVPR2) in the basolateral membrane leads to translocation of aquaporin 2 (AQP2) water channels to the apical membrane of the collecting duct principal cells, inducing water permeability of the membrane. This results in water reabsorption from the pro-urine into the medullary interstitium following an osmotic gradient. Congenital nephrogenic diabetes insipidus (NDI) is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their pro-urine, which leads to a high risk of dehydration. This review focuses on the current knowledge regarding the cell biological aspects of congenital X-linked, autosomal recessive and autosomal-dominant NDI while specifically addressing the latest developments in the field. Based on deepened mechanistic understanding, new therapeutic strategies are currently being explored, which we also discuss here. PMID- 22427317 TI - Exercise deficit disorder in youth: an emergent health concern for school nurses. AB - Although the benefits of regular physical activity are widely acknowledged, recent findings indicate that a growing number of youth are not as active as they should be. The impact of a sedentary lifestyle during childhood on lifelong pathological processes and associated health care costs have created a need for immediate action to manage, if not prevent, unhealthy behaviors during this vulnerable period of life. The concept of identifying children with exercise deficit disorder early in life and prescribing effective interventions to prevent the cascade of adverse health outcomes later in life is needed to raise public awareness, focus on primary prevention, and impact the collective behaviors of health care providers and public health agencies. School nurses are in a unique position to take advantage of well-child visits as an ideal opportunity to assess physical activity habits and encourage daily participation in play, recess, sports, planned exercise, and physical education. PMID- 22427318 TI - The perceptions of obese school children in Hong Kong toward their weight-loss experience. AB - Most studies related to addressing weight management of obese children have focused on understanding the perceptions of parents and health professionals. This study identifies the factors that obese children who have tried to lose weight perceive as affecting their efforts. This descriptive qualitative study has sought to identify factors affecting obese children's weight-loss decision making and process and to explore the development of an effective weight-loss program. This study screened 603 primary school children equivalent to U.S. Grades 5 and 6 of age 10-12. Seventy-nine out of 93 obese children who had been trying on their own to lose weight for at least 1 month formed 6 focus groups. Four themes were identified: Making the decision, self-efficacy, social influences, and environmental constraints. The results suggest that the design of a weight-loss program for obese children should include the contribution of family members, school, and health professionals. PMID- 22427319 TI - Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus. AB - We compared outcomes of alveolar hemorrhage (AH) in juvenile (JSLE) and adult onset SLE (ASLE). From 263 JSLE and 1522 ASLE, the AH occurred in 13 (4.9%) and 15 (1.0%) patients, respectively (p < .001). Both groups had comparable disease duration (2.6 +/- 3.0 vs. 5.6 +/- 7.0 years, p = .151) and median SLEDAI scores [17.5 (2 to 32) vs. 17.5 (3 to 28), p = 1.000]. At AH onset, a higher frequency of JSLE were already on a high prednisone dose ( > 0.5 mg/kg/day) compared to ASLE (54% vs. 15%, p = .042). The mean drop of hemoglobin was significantly lower in JSLE (2.9 +/- 0.9 vs. 5.5 +/- 2.9 g/dL, p = .006). Although treatments with methylprednisolone, plasmapheresis, intravenous immunoglobulin and cyclophosphamide were similar in both groups (p > .050), regarding outcomes, there was a trend in high frequency of mechanical ventilation use (85% vs. 47%, p = .055) and also significant mortality (69% vs. 13%, p = .006) in JSLE compared to ASLE. The sepsis frequency was comparable in both groups (50% vs. 27%, p = .433). We have identified that AH in JSLE has a worse outcome most likely related to respiratory failure. The AH onset in JSLE already treated with high-dose steroids raises the concern of inadequate response to this treatment and reinforces the recommendation of early aggressive alternative therapies in this group of patients. PMID- 22427320 TI - Ryanodine receptor S2808 phosphorylation in heart failure: smoking gun or red herring. PMID- 22427321 TI - Targeting T cell costimulation to prevent atherothrombosis. PMID- 22427322 TI - Golgi export signal ties proper folding to AP1 binding. PMID- 22427323 TI - Margaret Buckingham: studying the choreography of cardiogenesis. Interviewed by Ruth Williams. PMID- 22427324 TI - Zebrafish in the study of early cardiac development. AB - Heart development is a complex process that involves cell specification and differentiation, as well as elaborate tissue morphogenesis and remodeling, to generate a functional organ. The zebrafish has emerged as a powerful model system to unravel the basic genetic, molecular, and cellular mechanisms of cardiac development and function. We summarize and discuss recent discoveries on early cardiac specification and the identification of the second heart field in zebrafish. In addition to the inductive signals regulating cardiac specification, these studies have shown that heart development also requires a repressive mechanism imposed by retinoic acid signaling to select cardiac progenitors from a multipotent population. Another recent advance in the study of early zebrafish cardiac development is the identification of the second heart field. These studies suggest that the molecular mechanisms that regulate the second heart field development are conserved between zebrafish and other vertebrates including mammals and provide insight into the evolution of the second heart field and its derivatives. PMID- 22427325 TI - Multiple roles for neutrophils in atherosclerosis. AB - Because of their rare detection in atherosclerotic lesions, the involvement of neutrophils in the pathophysiology of atherosclerosis has been largely denied. However, over the past couple of years, studies have provided convincing evidence for the presence of neutrophils in atherosclerotic plaques and further revealed the causal contribution of neutrophils during various stages of atherosclerosis. This review describes mechanisms underlying hyperlipidemia-mediated neutrophilia and how neutrophils may enter atherosclerotic lesions. It also highlights possible mechanisms of neutrophil-driven atherogenesis and plaque destabilization. Knowledge of the contribution of neutrophils to atherosclerosis will allow for exploration of new avenues in the treatment of atherogenesis and atherothrombosis. PMID- 22427327 TI - Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson's disease. AB - Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted. PMID- 22427326 TI - Lymphocytes and the adventitial immune response in atherosclerosis. AB - Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature. PMID- 22427328 TI - Language networks in anophthalmia: maintained hierarchy of processing in 'visual' cortex. AB - Imaging studies in blind subjects have consistently shown that sensory and cognitive tasks evoke activity in the occipital cortex, which is normally visual. The precise areas involved and degree of activation are dependent upon the cause and age of onset of blindness. Here, we investigated the cortical language network at rest and during an auditory covert naming task in five bilaterally anophthalmic subjects, who have never received visual input. When listening to auditory definitions and covertly retrieving words, these subjects activated lateral occipital cortex bilaterally in addition to the language areas activated in sighted controls. This activity was significantly greater than that present in a control condition of listening to reversed speech. The lateral occipital cortex was also recruited into a left-lateralized resting-state network that usually comprises anterior and posterior language areas. Levels of activation to the auditory naming and reversed speech conditions did not differ in the calcarine (striate) cortex. This primary 'visual' cortex was not recruited to the left lateralized resting-state network and showed high interhemispheric correlation of activity at rest, as is typically seen in unimodal cortical areas. In contrast, the interhemispheric correlation of resting activity in extrastriate areas was reduced in anophthalmia to the level of cortical areas that are heteromodal, such as the inferior frontal gyrus. Previous imaging studies in the congenitally blind show that primary visual cortex is activated in higher-order tasks, such as language and memory to a greater extent than during more basic sensory processing, resulting in a reversal of the normal hierarchy of functional organization across 'visual' areas. Our data do not support such a pattern of organization in anophthalmia. Instead, the patterns of activity during task and the functional connectivity at rest are consistent with the known hierarchy of processing in these areas normally seen for vision. The differences in cortical organization between bilateral anophthalmia and other forms of congenital blindness are considered to be due to the total absence of stimulation in 'visual' cortex by light or retinal activity in the former condition, and suggests development of subcortical auditory input to the geniculo-striate pathway. PMID- 22427330 TI - Huntington's disease: fighting on many fronts. PMID- 22427331 TI - KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas. AB - In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name 'focadhesin'. Since KIAA1797 genetic variation has been implicated in Alzheimer's disease, our data are also relevant for neurodegeneration. PMID- 22427329 TI - A developmental and genetic classification for malformations of cortical development: update 2012. AB - Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development. PMID- 22427332 TI - Graph analysis of functional brain networks for cognitive control of action in traumatic brain injury. AB - Patients with traumatic brain injury show clear impairments in behavioural flexibility and inhibition that often persist beyond the time of injury, affecting independent living and psychosocial functioning. Functional magnetic resonance imaging studies have shown that patients with traumatic brain injury typically show increased and more broadly dispersed frontal and parietal activity during performance of cognitive control tasks. We constructed binary and weighted functional networks and calculated their topological properties using a graph theoretical approach. Twenty-three adults with traumatic brain injury and 26 age matched controls were instructed to switch between coordination modes while making spatially and temporally coupled circular motions with joysticks during event-related functional magnetic resonance imaging. Results demonstrated that switching performance was significantly lower in patients with traumatic brain injury compared with control subjects. Furthermore, although brain networks of both groups exhibited economical small-world topology, altered functional connectivity was demonstrated in patients with traumatic brain injury. In particular, compared with controls, patients with traumatic brain injury showed increased connectivity degree and strength, and higher values of local efficiency, suggesting adaptive mechanisms in this group. Finally, the degree of increased connectivity was significantly correlated with poorer switching task performance and more severe brain injury. We conclude that analysing the functional brain network connectivity provides new insights into understanding cognitive control changes following brain injury. PMID- 22427333 TI - Regulation of Arabidopsis embryo and endosperm development by the polypeptide signaling molecule CLE8. AB - The plant seed is a major nutritional source for humans as well as an essential embryo development and dispersal unit. To ensure proper seed formation, fine spatial and temporal coordination between the embryo, endosperm, and maternal seed components must be achieved. However, the intercellular signaling pathways that direct the synchronous development of these tissues are poorly understood. Here we show that the Arabidopsis thaliana peptide ligand CLAVATA3/embryo surrounding region-related8 (CLE8) is exclusively expressed in young embryos and endosperm, and that it acts cell and noncell autonomously to regulate basal embryo cell division patterns, endosperm proliferation, and the timing of endosperm differentiation. CLE8 positively regulates expression of the transcription factor gene Wuschel-like homeobox8 (WOX8), and together CLE8 and WOX8 form a signaling module that promotes seed growth and overall seed size. These results demonstrate that seed development is coordinated by a secreted peptide ligand that plays a key early role in orchestrating cell patterning and proliferation in the embryo and endosperm. PMID- 22427334 TI - Analysis of the developmental roles of the Arabidopsis gibberellin 20-oxidases demonstrates that GA20ox1, -2, and -3 are the dominant paralogs. AB - Gibberellin (GA) biosynthesis is necessary for normal plant development, with later GA biosynthetic stages being governed by multigene families. Arabidopsis thaliana contains five GA 20-oxidase (GA20ox) genes, and past work has demonstrated the importance of GA20ox1 and -2 for growth and fertility. Here, we show through systematic mutant analysis that GA20ox1, -2, and -3 are the dominant paralogs; their absence results in severe dwarfism and almost complete loss of fertility. In vitro analysis revealed that GA20ox4 has full GA20ox activity, but GA20ox5 catalyzes only the first two reactions of the sequence by which GA(12) is converted to GA(9). GA20ox3 functions almost entirely redundantly with GA20ox1 and -2 at most developmental stages, including the floral transition, while GA20ox4 and -5 have very minor roles. These results are supported by analysis of the gene expression patterns in promoter:beta-glucuronidase reporter lines. We demonstrate that fertility is highly sensitive to GA concentration, that GA20ox1, -2, and -3 have significant effects on floral organ growth and anther development, and that both GA deficiency and overdose impact on fertility. Loss of GA20ox activity causes anther developmental arrest, with the tapetum failing to degrade. Some phenotypic recovery of late flowers in GA-deficient mutants, including ga1-3, indicated the involvement of non-GA pathways in floral development. PMID- 22427335 TI - The GCP3-interacting proteins GIP1 and GIP2 are required for gamma-tubulin complex protein localization, spindle integrity, and chromosomal stability. AB - Microtubules (MTs) are crucial for both the establishment of cellular polarity and the progression of all mitotic phases leading to karyokinesis and cytokinesis. MT organization and spindle formation rely on the activity of gamma tubulin and associated proteins throughout the cell cycle. To date, the molecular mechanisms modulating gamma-tubulin complex location remain largely unknown. In this work, two Arabidopsis thaliana proteins interacting with gamma-tubulin complex protein3 (GCP3), GCP3-interacting protein1 (GIP1) and GIP2, have been characterized. Both GIP genes are ubiquitously expressed in all tissues analyzed. Immunolocalization studies combined with the expression of GIP-green fluorescent protein fusions have shown that GIPs colocalize with gamma-tubulin, GCP3, and/or GCP4 and reorganize from the nucleus to the prospindle and the preprophase band in late G2. After nuclear envelope breakdown, they localize on spindle and phragmoplast MTs and on the reforming nuclear envelope of daughter cells. The gip1 gip2 double mutants exhibit severe growth defects and sterility. At the cellular level, they are characterized by MT misorganization and abnormal spindle polarity, resulting in ploidy defects. Altogether, our data show that during mitosis GIPs play a role in gamma-tubulin complex localization, spindle stability and chromosomal segregation. PMID- 22427336 TI - The lectin receptor kinase-VI.2 is required for priming and positively regulates Arabidopsis pattern-triggered immunity. AB - Plant cells can be sensitized toward a subsequent pathogen attack by avirulent pathogens or by chemicals such as beta-aminobutyric acid (BABA). This process is called priming. Using a reverse genetic approach in Arabidopsis thaliana, we demonstrate that the BABA-responsive L-type lectin receptor kinase-VI.2 (LecRK VI.2) contributes to disease resistance against the hemibiotrophic Pseudomonas syringae and the necrotrophic Pectobacterium carotovorum bacteria. Accordingly, LecRK-VI.2 mRNA levels increased after bacterial inoculation or treatments with microbe-associated molecular patterns (MAMPs). We also show that LecRK-VI.2 is required for full activation of pattern-triggered immunity (PTI); notably, lecrk VI.2-1 mutants show reduced upregulation of PTI marker genes, impaired callose deposition, and defective stomatal closure. Overexpression studies combined with genome-wide microarray analyses indicate that LecRK-VI.2 positively regulates the PTI response. LecRK-VI.2 is demonstrated to act upstream of mitogen-activated protein kinase signaling, but independently of reactive oxygen production and Botrytis-induced kinase1 phosphorylation. In addition, complex formation between the MAMP receptor flagellin sensing2 and its signaling partner brassinosteroid insensitive1-associated kinase1 is observed in flg22-treated lecrk-VI.2-1 mutants. LecRK-VI.2 is also required for full BABA-induced resistance and priming of PTI. Our work identifies LecRK-VI.2 as a novel mediator of the Arabidopsis PTI response and provides insight into molecular mechanisms governing priming. PMID- 22427337 TI - Retrotransposons control fruit-specific, cold-dependent accumulation of anthocyanins in blood oranges. AB - Traditionally, Sicilian blood oranges (Citrus sinensis) have been associated with cardiovascular health, and consumption has been shown to prevent obesity in mice fed a high-fat diet. Despite increasing consumer interest in these health promoting attributes, production of blood oranges remains unreliable due largely to a dependency on cold for full color formation. We show that Sicilian blood orange arose by insertion of a Copia-like retrotransposon adjacent to a gene encoding Ruby, a MYB transcriptional activator of anthocyanin production. The retrotransposon controls Ruby expression, and cold dependency reflects the induction of the retroelement by stress. A blood orange of Chinese origin results from an independent insertion of a similar retrotransposon, and color formation in its fruit is also cold dependent. Our results suggest that transposition and recombination of retroelements are likely important sources of variation in Citrus. PMID- 22427338 TI - A microRNA cascade in plant defense. PMID- 22427339 TI - The Arabidopsis ARCP protein, CSI1, which is required for microtubule stability, is necessary for root and anther development. AB - Armadillo repeat-containing proteins (ARCPs) are conserved across eukaryotic kingdoms and function in various processes. Regulation of microtubule stability by ARCPs exists widely in mammals and algae, but little is known in plants. Here, we present the functional characterization of an Arabidopsis thaliana ARCP, which was previously identified as Cellulose synthase-interactive protein1 (CSI1), and prove its crucial role in anther and root development. CSI1 is highly expressed in floral tissues, and knockout mutants of CSI1 (three allelic lines) accordingly exhibit defective anther dehiscence, which can be partially rescued by mammalian microtubule-stabilizer MAP4, suggesting that CSI1 functions by stabilizing the microtubular cytoskeleton. CSI1 binds microtubules in vitro, and immunofluorescence and coimmunoprecipitation studies confirmed the physical interactions between CSI1 and microtubules in vivo. Analysis using oryzalin, a microtubule-disrupting drug, further revealed the destabilized microtubules under CSI1 deficiency and confirmed the crucial role of CSI1 in microtubule stability. The dynamic change of CSI1 in response to dehydration strongly suggests the important function of CSI1 in dehydration-induced microtubule depolymerization and reorganization, which is crucial for anther development. These results indicate the pivotal role of CSI1 in anther development by regulating microtubule stability and hence cell morphogenesis. PMID- 22427340 TI - The interferon stimulated gene 12 inactivates vasculoprotective functions of NR4A nuclear receptors. AB - RATIONALE: Innate and adaptive immune responses alter numerous homeostatic processes that are controlled by nuclear hormone receptors. NR4A1 is a nuclear receptor that is induced in vascular pathologies, where it mediates protection. OBJECTIVE: The underlying mechanisms that regulate the activity of NR4A1 during vascular injury are not clear. We therefore searched for modulators of NR4A1 function that are present during vascular inflammation. METHODS AND RESULTS: We report that the protein encoded by interferon stimulated gene 12 (ISG12), is a novel interaction partner of NR4A1 that inhibits the transcriptional activities of NR4A1 by mediating its Crm1-dependent nuclear export. Using 2 models of vascular injury, we show that ISG12-deficient mice are protected from neointima formation. This effect is dependent on the presence of NR4A1, as mice deficient for both ISG12 and NR4A1 exhibit neointima formation similar to wild-type mice. CONCLUSIONS: These findings identify a previously unrecognized feedback loop activated by interferons that inhibits the vasculoprotective functions of NR4A nuclear receptors, providing a potential new therapeutic target for interferon driven pathologies. PMID- 22427341 TI - Localization of Islet-1-positive cells in the healthy and infarcted adult murine heart. AB - RATIONALE: The transcription factor Islet-1 is a marker of cardiovascular progenitors during embryogenesis. The isolation of Islet-1-positive (Islet-1(+)) cells from early postnatal hearts suggested that Islet-1 also marks cardiac progenitors in adult life. OBJECTIVE: We investigated the distribution and identity of Islet-1(+) cells in adult murine heart and evaluated whether their number or distribution change with age or after myocardial infarction. METHODS AND RESULTS: Distribution of Islet-1(+) cells in adult heart was investigated using gene targeted mice with nuclear beta-galactosidase inserted into the Islet 1 locus. nLacZ-positive cells were only present in 3 regions of the adult heart: clusters in the interatrial septum and around the pulmonary veins, scattered within the wall of the great vessels, and a strictly delimited cluster between the right atrium and superior vena cava. Islet-1(+) cells in the first type of clusters coexpressed markers for parasympathetic neurons. Positive cells in the great arteries coexpressed smooth muscle actin and myosin heavy chain, indicating a smooth muscle cell identity. Very few Islet-1(+) cells within the outflow tract expressed the cardiomyocyte marker alpha-actinin. Islet-1(+) cells in the right atrium coexpressed the sinoatrial node pacemaker cell marker HCN4. Cell number and localization remained unchanged between 1 to 18 months of age. Consistently Islet-1 mRNA was detected in human sinoatrial node. Islet-1(+) cells could not be detected in the infarct zone 2 to 28 days after myocardial infarction, aside from 10 questionable cells in 1/13 hearts. CONCLUSIONS: Our results identify Islet-1 as a novel marker of the adult sinoatrial node and do not provide evidence for Islet-1(+) cells to serve as cardiac progenitors. PMID- 22427342 TI - High concordance between expert anaesthetists' actions and advice of decision support system in achieving oxygen delivery targets in high-risk surgery patients. AB - BACKGROUND: Goal-directed therapy has a secure place in perioperative care. Algorithms are based on Starling's law of the heart, notwithstanding that this does not numerically define volume or heart performance variables. These have been developed based on a Guytonian view of the circulation and are implemented in a computerized decision support system (NavigatorTM). We studied the feasibility and performance of the graphical display of the system in an intervention and a control group of patients undergoing major abdominal surgery. METHODS: Patients were randomized to either graphically (intervention) or numerically (control) guided administration of therapy. Goals were set and treatments and concordance with guidance noted, where applicable. Anaesthesia was provided by one of three experienced anaesthetists well acquainted with NavigatorTM. The primary objective was to determine whether the use of graphical display decision support more efficiently enables the achievement of oxygen delivery targets. This was quantitated as percentage time in the target zone and averaged standardized distance from the target centre. RESULTS: The mean percentage time in the target zone was 36.7% for control and 36.5% for intervention. The averaged standardized difference was 1.5 in control and 1.6 in intervention. There was no significant difference in fluid balances. There was a high level of concordance between decision support recommendation and anaesthetist action (84.3%). CONCLUSIONS: In experienced hands, the addition of a graphical display for haemodynamic guidance resulted in a similar time in target and averaged standardized difference. The haemodynamic guidance system should be explored in a comparative study to anaesthesia management without guidance. PMID- 22427343 TI - Heat shock factor HsfB1 primes gene transcription and systemic acquired resistance in Arabidopsis. PMID- 22427344 TI - The microRNA156-SQUAMOSA PROMOTER BINDING PROTEIN-LIKE3 module regulates ambient temperature-responsive flowering via FLOWERING LOCUS T in Arabidopsis. AB - The flowering time of plants is affected by modest changes in ambient temperature. However, little is known about the regulation of ambient temperature responsive flowering by small RNAs. In this study, we show that the microRNA156 (miR156)-SQUAMOSA PROMOTER BINDING PROTEIN-LIKE3 (SPL3) module directly regulates FLOWERING LOCUS T (FT) expression in the leaf to control ambient temperature responsive flowering. Overexpression of miR156 led to more delayed flowering at a lower ambient temperature (16 degrees C), which was associated with down regulation of FT and FRUITFULL expression. Among miR156 target genes, SPL3 mRNA levels were mainly reduced, probably because miR156-mediated cleavage of SPL3 mRNA was higher at 16 degrees C. Overexpression of miR156-resistant SPL3 [SPL3( )] caused early flowering, regardless of the ambient temperature, which was associated with up-regulation of FT and FRUITFULL expression. Reduction of miR156 activity by target mimicry led to a phenotype similar to that of SUC2::rSPL3 plants. FT up-regulation was observed after dexamethasone treatment in GVG-rSPL3 plants. Misexpression and artificial microRNA-mediated suppression of FT in the leaf dramatically altered the ambient temperature-responsive flowering of plants overexpressing miR156 and SPL3(-). Chromatin immunoprecipitation assay showed that the SPL3 protein directly binds to GTAC motifs within the FT promoter. Lesions in TERMINAL FLOWER1, SHORT VEGETATIVE PHASE, and EARLY FLOWERING3 did not alter the expression of miR156 and SPL3. Taken together, our data suggest that the interaction between the miR156-SPL3 module and FT is part of the regulatory mechanism controlling flowering time in response to ambient temperature. PMID- 22427345 TI - Prevalence of cervical human papillomavirus (HPV) infection in Vanuatu. AB - To provide information on human papillomavirus (HPV) prevalence and the distribution of individual HPV types in Pacific Islands, we conducted a population-based survey in Vanuatu, South Pacific. Nine hundred and eighty-seven women between 18 and 64 years of age were included. GP5(+)/6(+)-mediated PCR assay was used for HPV testing. The prevalence of 44 HPV types was 28.4% corresponding to an age (world)-standardized prevalence of 25.0% [95% confidence interval (CI), 21.9%-28.0%]. The prevalence of high-risk (HR) HPV types was 21.7% (age-standardized prevalence of 19.2%; 95% CI, 16.4%-22.0%). Among 840 women with adequate cytologic results, 13.6% showed cervical abnormalities, including 3.6% with high-grade squamous intraepithelial lesions (HSIL) and 0.8% with invasive cervical carcinoma. HPV prevalence declined from 46.1% in women aged <=21 to 15.3% in those >=45 years. Being single was significantly associated with HPV positivity. HR HPV findings by PCR assay and hybrid capture 2 (HC2; conducted in Vanuatu) were moderately correlated (kappa test = 0.59). The positive predictive values of HR HPV positivity for HSIL or worse were 27.6% for PCR and 35.2% for HC2 among women aged >=30. Nearly half of screening-positive women could not be reevaluated mainly on account of the difficulty to trace back women. The availability of a rapid HPV testing method that allows see-and-treat approaches at the same visit would be, therefore, essential. On account of their high cumulative burden of cervical lesions, also women older than 40 years should be included in at least the first screening round in unscreened populations. PMID- 22427346 TI - The chemopreventive effect of mifepristone on mammary tumorigenesis is associated with an anti-invasive and anti-inflammatory gene signature. AB - Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR- and non-PR mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12 dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-alpha-positive (ER(+)) transgenic mice expressing the dominant-negative Pax8PPARgamma (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways. PMID- 22427347 TI - Competing risk analyses: how are they different and why should you care? AB - Competing risks are events in which at least one precludes the observation of the other, such as toxicity and death. This commentary discusses and distinguishes between the two common types of competing risk analyses, the Kaplan-Meier and cumulative incidence curves. PMID- 22427348 TI - New strategies in refractory and recurrent neuroblastoma: translational opportunities to impact patient outcome. AB - Neuroblastoma remains responsible for a disproportionate amount of childhood cancer morbidity and mortality despite recent significant advances in understanding the genetic basis of tumor initiation and progression. About half of newly diagnosed patients can be reliably identified as having tumors of low malignant potential, and these children have cure rates of greater than 95% with little or no cytotoxic therapy. On the other hand, the other half of neuroblastomas typically present in an explosive fashion with widely metastatic disease, and reliable tumor-specific biomarkers have been defined for this phenotype as well. Empiric approaches to high-risk neuroblastoma therapy have relied on dramatic escalation of chemotherapy dose intensity and, recently, the incorporation of targeted immunotherapy, but nearly 50% of children with high risk disease will be refractory to therapy or suffer a relapse, both of which are invariably fatal. Future improvements in high-risk neuroblastoma outcomes will require the identification of disease and patient-specific oncogenic vulnerabilities that can be leveraged therapeutically. Rational development of novel approaches to neuroblastoma therapy requires forward-thinking strategies to unequivocally prove activity in the relapse setting and, ultimately, efficacy in curing patients when integrated into frontline treatment plans. PMID- 22427349 TI - Pharmacogenomics in early-phase oncology clinical trials: is there a sweet spot in phase II? AB - Many clinical trials of oncology drugs now include at least a consideration of pharmacogenomics, the study of germline or acquired genetic factors governing a drug's response and toxicity. Besides the potential benefit to patients from the consideration of personalized pharmacogenomic information when making treatment decisions, the incentive is clear for oncology drug developers to incorporate pharmacogenomic factors in the drug development process, because pharmacogenomic biomarkers may allow predictive characterization of subpopulations within a disease that may particularly respond or may allow preidentification of patients at highest risk for adverse events. There is, however, a lack of agreement in actual practice about at what point in the oncology clinical drug development process pharmacogenomic studies should be incorporated. In this article, we examine the recent growth of pharmacogenomics in oncology clinical trials, especially in early-phase studies, and examine several critical questions facing the incorporation of pharmacogenomics in early oncologic drug development. We show that phase II clinical trials, in particular, have a favorable track record for showing positive pharmacogenomic signals, worthy of additional follow-up and validation, and that the phase II setting holds significant promise for potentially accelerating and informing future phase III trials. We conclude that phase II trials offer an ideal "sweet spot" for routine incorporation of pharmacogenomic questions in oncology drug development. PMID- 22427350 TI - Upregulated JAG1 enhances cell proliferation in adrenocortical carcinoma. AB - PURPOSE: The purpose of this study was to examine the expression and molecular significance of JAG1, a ligand for the Notch developmental signaling pathway, in adrenocortical carcinoma (ACC). EXPERIMENTAL DESIGN: Human microarray data were analyzed for genes expressing ligands for the Notch pathway and validated with quantitative real-time PCR (QPCR) and immunoblots of RNA and protein, respectively. ACC cells lines were assessed for Notch pathway member expression by immunoblot, QPCR, and immunofluorescence. Notch pathway activity was also determined using a reporter gene (luciferase) activation. Proliferation experiments using a Jag1 knockdown strategy (Jag1KD) and an inhibitor of Notch dependent transcription (DNMaml) used a coculture system with fluorescence activated cell-sorting (FACS) analysis. Tumor stage and mitotic rate of human ACC samples were correlated to JAG1 expression. RESULTS: The Notch ligand JAG1 mRNA and protein are upregulated in ACCs. JAG1 upregulation can be modeled in the Y1 mouse ACC cell line that expresses Jag1, Notch receptors, downstream signaling molecules, and exhibits density-dependent Notch activation. Jag1 enhances cell proliferation through activation of canonical Notch signaling as shown through Jag1KD and coculture experiments. Inhibition of Notch signaling at the level of postreceptor signaling (DNMaml), results in similar inhibition of cell proliferation. Analysis of clinical data indicates that Jag1 expression correlates with both grade and stage of ACCs, supporting a role of JAG1-dependent Notch activation in late-stage ACCs. CONCLUSIONS: JAG1 is the primary upregulated Notch ligand in ACCs and enhances ACC cell proliferation and tumor aggressiveness in a non-cell-autonomous manner through activation of Notch signaling in adjacent cells. PMID- 22427351 TI - Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells. AB - During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1 dependent tumor progression in NK cell-controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit(-) (CD11b(-)) into Kit(+) natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit(+) NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit(+) NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1-dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18 binding protein dramatically reduced the accumulation of Kit(+)CD11b(-) NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit(+)CD11b(-) NK cells endowed with B7-H1-dependent immunoablative functions in mice. PMID- 22427352 TI - MDR, XDR, TDR tuberculosis: ominous progression. PMID- 22427353 TI - Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. AB - BACKGROUND: Abdominal adiposity and obesity influence the association of polycystic ovary syndrome (PCOS) with insulin resistance and diabetes. We aimed to characterize the intermediate metabolism phenotypes associated with PCOS and obesity. METHODS: We applied a nontargeted GC-MS metabolomic approach to plasma samples from 36 patients with PCOS and 39 control women without androgen excess, matched for age, body mass index, and frequency of obesity. RESULTS: Patients with PCOS were hyperinsulinemic and insulin resistant compared with the controls. The increase in plasma long-chain fatty acids, such as linoleic and oleic acid, and glycerol in the obese patients with PCOS suggests increased lipolysis, possibly secondary to impaired insulin action at adipose tissue. Conversely, nonobese patients with PCOS showed a metabolic profile consisting of suppression of lipolysis and increased glucose utilization (increased lactic acid concentrations) in peripheral tissues, and PCOS patients as a whole showed decreased 2-ketoisocaproic and alanine concentrations, suggesting utilization of branched-chain amino acids for protein synthesis and not for gluconeogenesis. These metabolic processes required effective insulin signaling; therefore, insulin resistance was not universal in all tissues of these women, and different mechanisms possibly contributed to their hyperinsulinemia. PCOS was also associated with decreased alpha-tocopherol and cholesterol concentrations irrespective of obesity. CONCLUSIONS: Substantial metabolic heterogeneity, strongly influenced by obesity, underlies PCOS. The possibility that hyperinsulinemia may occur in the absence of universal insulin resistance in nonobese women with PCOS should be considered when designing diagnostic and therapeutic strategies for the management of this prevalent disorder. PMID- 22427354 TI - Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention. AB - Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC MS/MS analyses of post-treatment samples revealed a delivery gradient with highest fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in fenretinide-treated oral mucosa (mean: 5.65 MUM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1-TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1 UGT1A1) exhibited fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels <5 MUM, reduced Ki-67 indices >5 MUM) relative to blank treated epithelium. All fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4-CYP3A4) responsible for conversion of fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed fenretinide and 4-oxo-4-HPR's preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials. PMID- 22427355 TI - Statistical mechanics for natural flocks of birds. AB - Flocking is a typical example of emergent collective behavior, where interactions between individuals produce collective patterns on the large scale. Here we show how a quantitative microscopic theory for directional ordering in a flock can be derived directly from field data. We construct the minimally structured (maximum entropy) model consistent with experimental correlations in large flocks of starlings. The maximum entropy model shows that local, pairwise interactions between birds are sufficient to correctly predict the propagation of order throughout entire flocks of starlings, with no free parameters. We also find that the number of interacting neighbors is independent of flock density, confirming that interactions are ruled by topological rather than metric distance. Finally, by comparing flocks of different sizes, the model correctly accounts for the observed scale invariance of long-range correlations among the fluctuations in flight direction. PMID- 22427356 TI - Long-range mechanical force enables self-assembly of epithelial tubular patterns. AB - Enabling long-range transport of molecules, tubules are critical for human body homeostasis. One fundamental question in tubule formation is how individual cells coordinate their positioning over long spatial scales, which can be as long as the sizes of tubular organs. Recent studies indicate that type I collagen (COL) is important in the development of epithelial tubules. Nevertheless, how cell-COL interactions contribute to the initiation or the maintenance of long-scale tubular patterns is unclear. Using a two-step process to quantitatively control cell-COL interaction, we show that epithelial cells developed various patterns in response to fine-tuned percentages of COL in ECM. In contrast with conventional thoughts, these patterns were initiated and maintained by traction forces created by cells but not diffusive factors secreted by cells. In particular, COL dependent transmission of force in the ECM led to long-scale (up to 600 MUm) interactions between cells. A mechanical feedback effect was encountered when cells used forces to modify cell positioning and COL distribution and orientations. Such feedback led to a bistability in the formation of linear, tubule-like patterns. Using micro-patterning technique, we further show that the stability of tubule-like patterns depended on the lengths of tubules. Our results suggest a mechanical mechanism that cells can use to initiate and maintain long scale tubular patterns. PMID- 22427357 TI - Using sketch-map coordinates to analyze and bias molecular dynamics simulations. AB - When examining complex problems, such as the folding of proteins, coarse grained descriptions of the system drive our investigation and help us to rationalize the results. Oftentimes collective variables (CVs), derived through some chemical intuition about the process of interest, serve this purpose. Because finding these CVs is the most difficult part of any investigation, we recently developed a dimensionality reduction algorithm, sketch-map, that can be used to build a low dimensional map of a phase space of high-dimensionality. In this paper we discuss how these machine-generated CVs can be used to accelerate the exploration of phase space and to reconstruct free-energy landscapes. To do so, we develop a formalism in which high-dimensional configurations are no longer represented by low-dimensional position vectors. Instead, for each configuration we calculate a probability distribution, which has a domain that encompasses the entirety of the low-dimensional space. To construct a biasing potential, we exploit an analogy with metadynamics and use the trajectory to adaptively construct a repulsive, history-dependent bias from the distributions that correspond to the previously visited configurations. This potential forces the system to explore more of phase space by making it desirable to adopt configurations whose distributions do not overlap with the bias. We apply this algorithm to a small model protein and succeed in reproducing the free-energy surface that we obtain from a parallel tempering calculation. PMID- 22427358 TI - Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance. AB - Mammalian acyl-CoA thioesterases (Acots) catalyze the hydrolysis of fatty acyl CoAs to form free fatty acids plus CoA, but their metabolic functions remain undefined. Thioesterase superfamily member 1 (Them1; synonyms Acot11, StarD14, and brown fat inducible thioesterase) is a long-chain fatty acyl-CoA thioesterase that is highly expressed in brown adipose tissue and is regulated by both ambient temperature and food consumption. Here we show that Them1(-/-) mice were resistant to diet-induced obesity despite greater food consumption. Them1(-/-) mice exhibited increased O(2) consumption and heat production, which were accompanied by increased rates of fatty acid oxidation in brown adipose tissue and up-regulation of genes that promote energy expenditure. Them1(-/-) mice were also protected against diet-induced inflammation in white adipose tissue, as well as hepatic steatosis, and demonstrated improved glucose homeostasis. The absence of Them1 expression in vivo and in cell culture led to markedly attenuated diet- or chemically induced endoplasmic reticulum stress responses, providing a mechanism by which Them1 deficiency protects against insulin resistance and lipid deposition. Taken together, these data suggest that Them1 functions to decrease energy consumption and conserve calories. In the setting of nutritional excess, the overproduction of free fatty acids by Them1 provokes insulin resistance that is associated with inflammation and endoplasmic reticulum stress. PMID- 22427359 TI - Albumin from rice: why and wherefore? PMID- 22427360 TI - Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. AB - Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo. PMID- 22427361 TI - Better to die than to leave a friend behind: industry strategy to reach the young. PMID- 22427362 TI - Pictorial warnings on tobacco products at the point of sale in India. PMID- 22427363 TI - European ancestry decreases the risk of early onset, severe lupus nephritis in a single center, multiethnic pediatric lupus inception cohort. AB - PURPOSE: To determine whether pediatric SLE patients without European ancestry are at higher risk for development of severe lupus nephritis (ISN/RPS class III, IV or V). METHODS: Ninety-eight of 101 patients with pediatric SLE (age <18 years at diagnosis) were enrolled. Race/ethnicity of four grandparents, socioeconomic status (SES) and language proficiency were collected. The primary outcome was time to development of severe lupus nephritis. RESULTS: Based on patient report of four grandparent ancestry, 29% had at least one grandparent of European ancestry (14% had all four grandparents of European ancestry). Patients without European ancestry were 46% Hispanic, 47% Asian, and 3% African American. In the entire 98 patient cohort, 12% had >=3 different ancestries. Patients without European ancestry had significantly lower SES levels and English proficiency. There was no significant difference between patients with or without European ancestry in duration of SLE, age of onset, and lag time between symptoms and diagnosis. Patients with at least one grandparent of European ancestry had a decreased risk of developing severe lupus nephritis, which remained significant after controlling for age, gender, SES and English proficiency (hazard ratio 0.4, 95% confidence interval 0.2-0.9). CONCLUSION: This study demonstrates that presence of at least one grandparent of European ancestry decreases the risk of severe lupus nephritis, a finding that is not explained by measurable socioeconomic differences and language barriers. PMID- 22427364 TI - Associations between the p53 codon 72 polymorphisms and susceptibility to systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether the p53 codon 72 polymorphism confers susceptibility to systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). METHODS: A meta-analysis was conducted on the associations between the p53 codon 72 polymorphism and SLE or RA using: 1) allele contrast; 2) the recessive model; 3) the dominant model; and 4) the additive model. RESULTS: A total of 10 studies, that is, 6 SLE and 4 RA studies, involving 1578 patients and 3138 controls were considered in the meta-analysis. Meta analysis of the p53 codon 72 polymorphism showed no association between patients and the C allele (odds ratio (OR) = 0.834, 95% confidence interval (CI) = 0.599 1.161, p = 0.282), or between SLE and the p53 C allele (OR = 0.998, 95% CI = 0.765-1.302, p = 0.989). However, stratification by ethnicity showed an association between the p53 C allele and SLE in Asians (OR = 1.410, 95% CI = 1.044-1.906, p = 0.025), but not in Europeans (OR = 0.871, 95% CI = 0.625-1.214, p = 0.415). Furthermore, an association was found between the polymorphism and SLE in Asians using recessive and additive models. However, no association was found between RA and the p53 codon 72 polymorphism in all study subjects or in Europeans. CONCLUSIONS: This meta-analysis demonstrates that the p53 codon 72 polymorphism may confer susceptibility to SLE in Asians, but not in Europeans. PMID- 22427365 TI - Anti-beta2-glycoprotein I antibody and cerebellar ataxia in breast cancer. PMID- 22427366 TI - Care of the patient with an autism spectrum disorder by the general physician. AB - Autism spectrum disorders (ASD), comprising classic autism, Asperger syndrome, Rett syndrome, childhood disintegrative disorder and pervasive development disorder-not otherwise specified, represent complex neurodevelopmental conditions characterised by impaired social interactions, difficulties with communication and repetitive, stereotyped behaviours. It is estimated that up to 1% of the general population may be affected by an ASD. Whether due to improved diagnostic techniques or a true rise in incidence, the prevalence of patients with ASD is rising, and these individuals are increasingly encountered in a variety of healthcare settings. Care givers of patients with an ASD report frequently that lack of awareness of the complications of these disorders and the method of appropriately assessing these individuals impair the effective delivery of healthcare to this patient population. It is now clear that patients with an ASD, in addition to the defining characteristics of these disorders, can present to the outpatient, emergency department and inpatient settings with a variety of psychiatric, neurological, gastrointestinal, nutritional/metabolic, dental, ophthalmological, cardiovascular, gynaecological, traumatic and musculoskeletal conditions that can require acute intervention. In addition, the common treatments given to patients with an ASD may result in side effects and complications that may require acute intervention. For physicians who encounter patients with an ASD, the combination of impaired social interactions, difficulties with communication and stereotyped behaviours creates an additional barrier to diagnosis and treatment of these individuals. Careful preparation of the examination environment, direct engagement of care givers and the patient and the use of communication techniques and pharmacological adjuncts can aid physicians in treating the patient with an ASD in the outpatient, emergency department and inpatient settings. PMID- 22427367 TI - Ventricular septal rupture and intraseptal pseudo-aneurysm complicating acute myocardial infarction: management in the multimodality imaging era. PMID- 22427368 TI - Bayesian processing of context-dependent text: reasons for appointments can improve detection of influenza. AB - OBJECTIVE: This article aims to examine whether words listed in reasons for appointments could effectively predict laboratory-verified influenza cases in syndromic surveillance systems. METHODS: Data were collected from the Armed Forces Health Longitudinal Technological Application medical record system. We used 2 algorithms to combine the impact of words within reasons for appointments: Dependent (DBSt) and Independent (IBSt) Bayesian System. We used receiver operating characteristic curves to compare the accuracy of these 2 methods of processing reasons for appointments against current and previous lists of diagnoses used in the Department of Defense's syndromic surveillance system. RESULTS: We examined 13,096 cases, where the results of influenza tests were available. Each reason for an appointment had an average of 3.5 words (standard deviation = 2.2 words). There was no difference in performance of the 2 algorithms. The area under the curve for IBSt was 0.58 and for DBSt was 0.56. The difference was not statistically significant (McNemar statistic = 0.0054; P = 0.07). CONCLUSIONS: These data suggest that reasons for appointments can improve the accuracy of lists of diagnoses in predicting laboratory-verified influenza cases. This study recommends further exploration of the DBSt algorithm and reasons for appointments in predicting likely influenza cases. PMID- 22427369 TI - Adaptation of clinical prediction models for application in local settings. AB - BACKGROUND: When planning to use a validated prediction model in new patients, adequate performance is not guaranteed. For example, changes in clinical practice over time or a different case mix than the original validation population may result in inaccurate risk predictions. OBJECTIVE: To demonstrate how clinical information can direct updating a prediction model and development of a strategy for handling missing predictor values in clinical practice. METHODS: A previously derived and validated prediction model for postoperative nausea and vomiting was updated using a data set of 1847 patients. The update consisted of 1) changing the definition of an existing predictor, 2) reestimating the regression coefficient of a predictor, and 3) adding a new predictor to the model. The updated model was then validated in a new series of 3822 patients. Furthermore, several imputation models were considered to handle real-time missing values, so that possible missing predictor values could be anticipated during actual model use. RESULTS: Differences in clinical practice between our local population and the original derivation population guided the update strategy of the prediction model. The predictive accuracy of the updated model was better (c statistic, 0.68; calibration slope, 1.0) than the original model (c statistic, 0.62; calibration slope, 0.57). Inclusion of logistical variables in the imputation models, besides observed patient characteristics, contributed to a strategy to deal with missing predictor values at the time of risk calculation. CONCLUSIONS: Extensive knowledge of local, clinical processes provides crucial information to guide the process of adapting a prediction model to new clinical practices. PMID- 22427370 TI - The role of Mycobacterium tuberculosis Rv3166c protein-derived high-activity binding peptides in inhibiting invasion of human cell lines. AB - Given the urgent need for designing a new antituberculosis vaccine conferring total protection on patients of all ages, following the line of research adopted by our institute, this work has identified Mycobacterium tuberculosis (Mtb) Rv3166c protein high-activity binding peptides (HABPs) which are able to inhibit bacterial invasion of U937 (monocyte-derived macrophages) and A549 (type II alveolar epithelial cells) cell lines. The presence and transcription of the rv3166c gene in the Mtb species complex was confirmed by polymerase chain reaction (PCR) and reverse transcriptase-PCR; Rv3166c expression was evaluated by western blot and cellular localisation confirmed by immunoelectron microscopy. Its presence was mainly determined on cell surface. Sixteen peptides covering its entire length were chemically synthesised and tested for their ability to bind to U937 and A549 cells. Two U937 HABPs were identified and three for A549, one of them being shared by both cell lines. The four HABPs found inhibited Mtb entry by 15.07-94.06%. These results led us to including Rv3166c HABPs as candidates for further studies contributing towards the search for a multiepitope, chemically synthesised, subunit-based antituberculosis vaccine. PMID- 22427371 TI - Enhanced growth of Juniperus thurifera under a warmer climate is explained by a positive carbon gain under cold and drought. AB - Juniperus thurifera L. is an endemic conifer of the western Mediterranean Basin where it is subjected to a severe climatic stress characterized by low winter temperatures and summer drought. Given the trend of increased warming-induced drought stress in this area and the climatic sensitivity of this species, we expect a negative impact of climate change on growth and ecophysiological performance of J. thurifera in the harsh environments where it dominates. To evaluate this, we measured long- and short-term radial growth using dendrochronology, photosynthesis and water-use efficiency in males, females and juveniles in three sites in Central Spain. Climate was monitored and completed with historical records. Mean annual temperature has increased +0.2 degrees C per decade in the study area, and the main warming trends corresponded to spring (+0.2 degrees C per decade) and summer (+0.3 degrees C per decade). Radial growth and maximum photosynthesis peaked in spring and autumn. Positive photosynthetic rates were maintained all year long, albeit at reduced rates in winter and summer. Radial growth was enhanced by wet conditions in the previous autumn and by warm springs and high precipitation in summer of the year of tree ring formation. Cloud cover during the summer increased growth, while cloudy winters led to impaired carbon gain and reduced growth in the long term. We argue that maintenance of carbon gain under harsh conditions (low winter temperatures and dry summer months) and plastic xylogenesis underlie J. thurifera's ability to profit from changing climatic conditions such as earlier spring onset and erratic summer rainfall. Our results highlight that not only the magnitude but also the sign of the impact of climate change on growth and persistence of Mediterranean trees is species specific. PMID- 22427372 TI - Use of thermal imaging to determine leaf conductance along a canopy gradient in European beech (Fagus sylvatica). AB - Using an infrared camera, we measured the leaf temperature across different canopy positions of a 23-m-tall deciduous forest tree (Fagus sylvatica L.) including typical sun and shade leaves as well as intermediate leaf forms, which differed significantly in specific leaf area (SLA). We calculated a temperature index (I(G)) and a crop water stress index (CWSI) using the surface temperatures of wet and dry reference leaves. Additional indices were computed using air temperature plus 5 degrees C (I(G) + 5, CWSI + 5) as dry references. The minimum temperature of the wet leaf and the maximum temperature of the dry leaf proved to be most suitable as reference values. We correlated the temperature indices with leaf area-related conductance to water vapor (g(L)) using porometry at the leaf level and using xylem sap flow at the branch level. At the leaf and at the branch level, I(G) and CWSI were equally well suited as proxies of g(L), whereas the relationships of I(G) + 5 and CWSI + 5 with g(L) were only weak or even insignificant. At the leaf level, the correlations of I(G) and CWSI with g(L) were significant in all parts of the crown. The slopes of g(L) vs. I(G) and CWSI did not differ significantly among the crown parts; this indicates that they were not influenced by SLA or irradiance. At the branch level, close correlations (r > 0.8) were found between temperature indices and g(L) across the crown. These results demonstrate that satisfactory relationships between temperature indices and g(L) can be established in tall trees even in those canopy parts that are exposed to relatively low levels of irradiance and exhibit relatively low values of g(L). PMID- 22427373 TI - Does homeostasis or disturbance of homeostasis in minimum leaf water potential explain the isohydric versus anisohydric behavior of Vitis vinifera L. cultivars? PMID- 22427374 TI - Degradation of chloroplast DNA during natural senescence of maple leaves. AB - The fate of chloroplast DNA (cpDNA) during plastid development and conversion between various plastid types is still not very well understood. This is especially true for the cpDNA found in plastids of naturally senescing leaves. Here, we describe changes in plastid nucleoid structure accompanied with cpDNA degradation occurring during natural senescence of the free-growing deciduous woody species Acer pseudoplatanus L. Natural senescence was investigated using three types of senescing leaves: green (G), yellow-green (YG) and yellow (Y). The extent of senescence was evaluated at the level of photosynthetic pigment degradation, accumulation of starch and plastid ultrastructure. Determination of cpDNA amount was carried out by in planta visualization with 4,6-diamidino-2 phenylindole, by Southern hybridization, and by dot-blot using an rbcL gene probe. During natural senescence, plastid nucleoids undergo structural rearrangements accompanied by an almost complete loss of cpDNA. Furthermore, senescence-associated protein components exhibiting strong binding to an ~10kbp rbcL-containg cpDNA fragment were identified. This interaction might be important for rbcL expression and Rubisco degradation during the course of natural senescence in trees. PMID- 22427375 TI - Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal beta-cell adaptation and gestational diabetes mellitus. AB - Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the beta cell. However, whether HGF/c-Met has a role in maternal beta-cell adaptation during pregnancy is unknown. To address this issue, we characterized glucose and beta-cell homeostasis in pregnant mice lacking c-Met in the pancreas (PancMet KO mice). Circulating HGF and islet c-Met and HGF expression were increased in pregnant mice. Importantly, PancMet KO mice displayed decreased beta-cell replication and increased beta-cell apoptosis at gestational day (GD)15. The decreased beta-cell replication was associated with reductions in islet prolactin receptor levels, STAT5 nuclear localization and forkhead box M1 mRNA, and upregulation of p27. Furthermore, PancMet KO mouse beta-cells were more sensitive to dexamethasone-induced cytotoxicity, whereas HGF protected human beta-cells against dexamethasone in vitro. These detrimental alterations in beta-cell proliferation and death led to incomplete maternal beta-cell mass expansion in PancMet KO mice at GD19 and early postpartum periods. The decreased beta-cell mass was accompanied by increased blood glucose, decreased plasma insulin, and impaired glucose tolerance. PancMet KO mouse islets failed to upregulate GLUT2 and pancreatic duodenal homeobox-1 mRNA, insulin content, and glucose-stimulated insulin secretion during gestation. These studies indicate that HGF/c-Met signaling is essential for maternal beta-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus. PMID- 22427376 TI - Metabolic alterations induced by sucrose intake and Alzheimer's disease promote similar brain mitochondrial abnormalities. AB - Evidence shows that diabetes increases the risk of developing Alzheimer's disease (AD). Many efforts have been done to elucidate the mechanisms linking diabetes and AD. To demonstrate that mitochondria may represent a functional link between both pathologies, we compared the effects of AD and sucrose-induced metabolic alterations on mouse brain mitochondrial bioenergetics and oxidative status. For this purpose, brain mitochondria were isolated from wild-type (WT), triple transgenic AD (3xTg-AD), and WT mice fed 20% sucrose-sweetened water for 7 months. Polarography, spectrophotometry, fluorimetry, high-performance liquid chromatography, and electron microscopy were used to evaluate mitochondrial function, oxidative status, and ultrastructure. Western blotting was performed to determine the AD pathogenic protein levels. Sucrose intake caused metabolic alterations like those found in type 2 diabetes. Mitochondria from 3xTg-AD and sucrose-treated WT mice presented a similar impairment of the respiratory chain and phosphorylation system, decreased capacity to accumulate calcium, ultrastructural abnormalities, and oxidative imbalance. Interestingly, sucrose treated WT mice presented a significant increase in amyloid beta protein levels, a hallmark of AD. These results show that in mice, the metabolic alterations associated to diabetes contribute to the development of AD-like pathologic features. PMID- 22427377 TI - Prevention of autoimmune diabetes by ectopic pancreatic beta-cell expression of interleukin-35. AB - Interleukin (IL)-35 is a newly identified inhibitory cytokine used by T regulatory cells to control T cell-driven immune responses. However, the therapeutic potential of native, biologically active IL-35 has not been fully examined. Expression of the heterodimeric IL-35 cytokine was targeted to beta cells via the rat insulin promoter (RIP) II. Autoimmune diabetes, insulitis, and the infiltrating cellular populations were analyzed. Ectopic expression of IL-35 by pancreatic beta-cells led to substantial, long-term protection against autoimmune diabetes, despite limited intraislet IL-35 secretion. Nonobese diabetic RIP-IL35 transgenic mice exhibited decreased islet infiltration with substantial reductions in the number of CD4(+) and CD8(+) T cells, and frequency of glucose-6-phosphatase catalytic subunit-related protein-specific CD8(+) T cells. Although there were limited alterations in cytokine expression, the reduced T-cell numbers observed coincided with diminished T-cell proliferation and G1 arrest, hallmarks of IL-35 biological activity. These data present a proof of principle that IL-35 could be used as a potent inhibitor of autoimmune diabetes and implicate its potential therapeutic utility in the treatment of type 1 diabetes. PMID- 22427378 TI - Platelet isoprostane overproduction in diabetic patients treated with aspirin. AB - Aspirin modestly influences cardiovascular events in patients with type 2 diabetes mellitus (T2DM), but the reason is unclear. The aim of the study was to determine whether in T2DM patients aspirin enhances platelet isoprostanes, which are eicosanoids with proaggregating properties derived from arachidonic acid oxidation by platelet NOX2, the catalytic subunit of reduced NAD phosphate oxidase. A cross-sectional study was performed comparing T2DM patients, treated (n = 50) or not treated (n = 50) with 100 mg/day aspirin, with 100 nondiabetic patients, matched for age, sex, atherosclerosis risk factors, and aspirin treatment. A short-term (7 days) treatment with 100 mg/day aspirin also was performed in 36 aspirin-free diabetic and nondiabetic patients. Higher platelet recruitment, platelet isoprostane, and NOX2 activation was found in diabetic versus nondiabetic patients and in aspirin-treated diabetic patients versus nontreated patients (P < 0.001). Platelet thromboxane (Tx) A(2) (P < 0.001) was inhibited in all aspirin-treated patients. In the interventional study, aspirin similarly inhibited platelet TxA(2) in diabetic and nondiabetic patients (P < 0.001). Platelet recruitment, isoprostane levels, and NOX2 activation showed a parallel increase in diabetic patients (P < 0.001) and no changes in nondiabetic patients. These findings suggest that in aspirin-treated diabetic patients, oxidative stress-mediated platelet isoprostane overproduction is associated with enhanced platelet recruitment, an effect that mitigates aspirin-mediated TxA(2) inhibition. PMID- 22427379 TI - MicroRNA dysregulation in diabetic ischemic heart failure patients. AB - Increased morbidity and mortality associated with ischemic heart failure (HF) in type 2 diabetic patients requires a deeper understanding of the underpinning pathogenetic mechanisms. Given the implication of microRNAs (miRNAs) in HF, we investigated their regulation and potential role. miRNA expression profiles were measured in left ventricle biopsies from 10 diabetic HF (D-HF) and 19 nondiabetic HF (ND-HF) patients affected by non-end stage dilated ischemic cardiomyopathy. The HF groups were compared with each other and with 16 matched nondiabetic, non HF control subjects. A total of 17 miRNAs were modulated in D-HF and/or ND-HF patients when compared with control subjects. miR-216a, strongly increased in both D-HF and ND-HF patients, negatively correlated with left ventricular ejection fraction. Six miRNAs were differently expressed when comparing D-HF and ND-HF patients: miR-34b, miR-34c, miR-199b, miR-210, miR-650, and miR-223. Bioinformatic analysis of their modulated targets showed the enrichment of cardiac dysfunctions and HF categories. Moreover, the hypoxia-inducible factor pathway was activated in the noninfarcted, vital myocardium of D-HF compared with ND-HF patients, indicating a dysregulation of the hypoxia response mechanisms. Accordingly, miR-199a, miR-199b, and miR-210 were modulated by hypoxia and high glucose in cardiomyocytes and endothelial cells cultured in vitro. In conclusion, these findings show a dysregulation of miRNAs in HF, shedding light on the specific disease mechanisms differentiating diabetic patients. PMID- 22427380 TI - Human apolipoprotein(a) kringle V inhibits ischemia-induced retinal neovascularization via suppression of fibronectin-mediated angiogenesis. AB - Retinal neovascularization is observed in progression of diabetic retinopathy. New vessels grow into the vitreous cavity in proliferative diabetic retinopathy, resulting in traction retinal detachment and vitreous hemorrhage. To overcome the catastrophic visual loss due to these complications, efforts have been focused on the treatment of retinal neovascularization. In this study, we demonstrated the inhibitory effect of recombinant human apolipoprotein(a) kringle V (rhLK8) in an animal model of ischemia-induced retinal neovascularization. rhLK8 induced no definite toxicity on endothelial cells and retinal tissues at the therapeutic dosage. Interestingly, rhLK8 showed antiangiogenic effect, particularly on fibronectin-mediated migration of endothelial cells. Further experiments demonstrated high binding affinity of rhLK8 to alpha3beta1 integrin, and suppression of it might be the mechanism of antiangiogenic effect of rhLK8. Furthermore, rhLK8 inhibited phosphorylation of focal adhesion kinase, resulting in suppression of activation of consequent p130CAS-Jun NH(2)-terminal kinase. Taken together, our data suggested the possible application of rhLK8 in the treatment of retinal neovascularization by suppression of fibronectin-mediated angiogenesis. PMID- 22427381 TI - A missing piece of pancreas. PMID- 22427382 TI - Importance and management of chronic sleep apnoea in cardiology. AB - Sleep apnoea is a common, yet underestimated, chronic disorder with a major impact on morbidity and mortality in the general population. It is quickly becoming recognized as an independent risk factor for cardiovascular impairment. Hypertension, coronary artery disease, diabetes, cardiovascular rhythm and conduction abnormalities, cerebrovascular disease, and heart failure have all been linked to this syndrome. This review will explore the critical connection between sleep apnoea and chronic cardiovascular diseases while highlighting established and emerging diagnostic and treatment strategies. PMID- 22427383 TI - Fertile green: green facilitates creative performance. AB - The present research sought to extend the nascent literature on color and psychological functioning by examining whether perception of the color green facilitates creativity. In four experiments, we demonstrated that a brief glimpse of green prior to a creativity task enhances creative performance. This green effect was observed using both achromatic (white, gray) and chromatic (red, blue) contrast colors that were carefully matched on nonhue properties, and using both picture-based and word-based assessments of creativity. Participants were not aware of the purpose of the experiment, and null effects were obtained on participants' self-reported mood and positive activation. These findings indicate that green has implications beyond aesthetics and suggest the need for sustained empirical work on the functional meaning of green. PMID- 22427384 TI - Low-effort thought promotes political conservatism. AB - The authors test the hypothesis that low-effort thought promotes political conservatism. In Study 1, alcohol intoxication was measured among bar patrons; as blood alcohol level increased, so did political conservatism (controlling for sex, education, and political identification). In Study 2, participants under cognitive load reported more conservative attitudes than their no-load counterparts. In Study 3, time pressure increased participants' endorsement of conservative terms. In Study 4, participants considering political terms in a cursory manner endorsed conservative terms more than those asked to cogitate; an indicator of effortful thought (recognition memory) partially mediated the relationship between processing effort and conservatism. Together these data suggest that political conservatism may be a process consequence of low-effort thought; when effortful, deliberate thought is disengaged, endorsement of conservative ideology increases. PMID- 22427385 TI - Observer perceptions of moral obligations in groups with a history of victimization. AB - The authors investigated when observers assign contemporary group members moral obligations based on their group's victimization history. In Experiment 1, Americans perceived Israelis as obligated to help Sudanese genocide victims and as guiltworthy for not helping if reminded of the Holocaust and its descendants were linked to this history. In Experiment 2, participants perceived Israelis as more obligated to help and guiltworthy for not helping when the Holocaust was presented as a unique victimization event compared with when genocide was presented as pervasive. Experiments 3 and 4 replicated the effects of Experiment 1 with Cambodians as the victimized group. Experiment 5 demonstrated that participants perceived Cambodians as having more obligations under high just world threat compared with low just world threat. Perceiving victimized groups as incurring obligations is one just world restoration method of providing meaning to collective injustice. PMID- 22427386 TI - Clinical features of psoroptic mange in cattle in England and Wales. AB - The clinical signs, treatments used and spread of psoroptic mange in cattle from October 2007 until March 2011 are described. The disease was first diagnosed in South West Wales, having not been reported in Great Britain since the 1980s. The likely source was identified as a farm that had imported two animals from mainland Europe in the summer of 2006. Since that time, disease has been diagnosed on a further 22 premises, the majority in South West Wales but also in South East and Mid Wales and on one farm in England. Bought in animals harbouring the Psoroptes species mite but not showing clinical signs were considered the greatest risk of introducing the infestation into a herd. This, together with the difficulties of treatment to eliminate the parasite, means that it is unlikely that this outbreak has been controlled. There is also a continuing threat of importing the disease from abroad. The disease is not notifiable in the UK. PMID- 22427387 TI - Serology and PCR for bovine leptospirosis: herd and individual approaches. PMID- 22427388 TI - Cuing consumerism: situational materialism undermines personal and social well being. AB - Correlational evidence indicates that materialistic individuals experience relatively low levels of well-being. Across four experiments, we found that situational cuing can also trigger materialistic mind-sets, with similarly negative personal and social consequences. Merely viewing desirable consumer goods resulted in increases in materialistic concerns and led to heightened negative affect and reduced social involvement (Experiment 1). Framing a computer task as a "Consumer Reaction Study" led to a stronger automatic bias toward values reflecting self-enhancement, compared with framing the same task as a "Citizen Reaction Study" (Experiment 2). Consumer cues also increased competitiveness (Experiment 3) and selfishness in a water-conservation dilemma (Experiment 4). Thus, the costs of materialism are not localized only in particularly materialistic people, but can also be found in individuals who happen to be exposed to environmental cues that activate consumerism-cues that are commonplace in contemporary society. PMID- 22427389 TI - What makes the difference between the natural course of a remaining type B dissection after type A repair and a primary type B aortic dissection? AB - OBJECTIVES: To analyse the outcome and need for intervention [surgery or thoracic endovascular aortic repair (TEVAR)] in patients after surgery for remaining type B dissection after type A repair and primary type B aortic dissection. METHODS: Within a 10-year period, 247 patients with remaining type B after type A, and 112 patients with primary type B aortic dissection were analysed. We assessed the clinical outcome as well as the need for intervention (surgery or TEVAR) within the aortic arch and the thoracoabdominal aorta as well as risk factors. RESULTS: The median follow-up was 23 months (interquartile range 5-52). There was a significant difference with regard to the status of the primary entry tear between patients after surgical repair of an acute type A aortic dissection and primary acute type B aortic dissection (patent vs. non-patent entry 35 vs. 83%, P < 0.001). The overall need for any kind of intervention (surgery or TEVAR) was 19%. Multivariate Cox regression analysis revealed a patent primary entry tear in patients after surgery for acute type A aortic dissection as an independent predictor for intervention (surgery or TEVAR) during follow-up [odds ratio (OR) 6.4; confidence interval (CI) 1.39-29.81, P = 0.017]. Multivariate Cox regression analysis did not reveal a patent primary entry tear in patients after acute type B aortic dissection as an independent predictor for intervention (surgery or TEVAR) during follow-up (OR 0.67; CI 0.27-1.69, P = 0.671). Finally, the thrombosis status of the false lumen was not an independent predictor for intervention (surgery or TEVAR) either in patients after surgery for acute type A aortic dissection (OR 3.46; CI 0.79-15.16, P = 0.100) or in patients after acute type B aortic dissection (OR 0.77; CI 0.31-1.93, P = 0.580). CONCLUSIONS: A remaining type B dissection after type A repair and a primary type B aortic dissection represent two distinct pathophysiological entities with regard to late outcome. The need for any kind of intervention in the thoracoabdominal aorta is significantly higher in primary type B aortic dissections. A remaining patent primary entry tear independently predicts the need for intervention (surgery or TEVAR) in patients after surgery for acute type A aortic dissection and, thereby, remains the main target of initial therapy. The thrombosis status of the false lumen seems to be of secondary importance. PMID- 22427390 TI - Right-sided infective endocarditis: surgical management. AB - Right-sided infective endocarditis (RSIE) accounts for 5-10% of all cases of infective endocarditis and is predominantly encountered among injecting drug users (IDUs). RSIE diagnosis requires a high index of suspicion as respiratory symptoms predominate. Prognosis of isolated RSIE is favourable, and most cases (70-80%) resolve following antibiotic administration. Surgical intervention is indicated in patients with persistent infection that does not respond to antibiotic therapy, recurrent pulmonary emboli, intractable heart failure and if the size of a vegetation increases or persists at >1 cm. Techniques can be divided into 'prosthetic' (valve replacement or prosthetic annular implantation) or 'non-prosthetic' ones (Kay's or De Vega's annuloplasty, bicuspidalization or valvectomy). In IDUs who run a high risk of complications, vegetectomy and valve repair, avoiding artificial material should be considered as the first line of surgical management as is associated with better late survival. PMID- 22427391 TI - Enhancing departmental quality control in minimally invasive mitral valve surgery: a single-institution experience. AB - OBJECTIVES: In recent years, there has been an increasing interest in monitoring the quality of cardiac surgical performance. The aim of the present study was to apply control charts (CUSUM curves) to monitor the performance of minimally invasive mitral valve procedures to enhance quality control for that operation. METHODS: A total of 936 minimally invasive mitral valve procedures were performed from September 2003 to March 2011 by seven surgeons (range 26-401 procedures) at a single institution. Institutional and individual surgeons' performances were monitored using descriptive statistics and control charts, with a predetermined acceptable failure rate of 10% and calculated 80% alert and 95% alarm lines. Perioperative death or one or more of seven adverse events constituted failure. RESULTS: The incidence of in-hospital mortality was 1.8% (17/936) and compared favourably with the predicted mortality (logistic EuroSCORE 7.3%). Institutional CUSUM analysis revealed an initial learning curve and then the surgical process remained in control for all the study period. There were differences between surgeons with regard to the learning curves and perioperative complications (7.3 11.3%, P = 0.9). Five surgeons crossed the 95% reassurance boundary between operations 23 and 48. One surgeon crossed the 95% reassurance boundary after 116 operations. No surgeon crossed the 95% alarm line, which indicates unacceptably high failure rates. CONCLUSIONS: Minimally invasive mitral surgery can be safely performed with low morbidity and mortality. CUSUM curve analysis is a simple statistical method to implement continuous individual and departmental performance monitoring. PMID- 22427392 TI - Editorial comment: Re: Negative microbiological results are not mandatory in deep sternal wound infections before wound closure. PMID- 22427393 TI - An effective method of pleurodesis involving absorbable mesh for repetitive catamenial pneumothorax. AB - Catamenial pneumothorax (CPX) is an aetiologically very complex disease for which the treatments for pneumothorax and endometriosis are generally adapted. However, emphasizing secondary prevention, we developed a new method. This powerful new technique for prevention of pneumothorax during menstruation by surgical pleurodesis using absorbable mesh is presented. CPX is a relatively rare disease characterized by recurrent pneumothorax during menstruation. Although pathological diagnosis is desirable, CPX is clinically defined as recurrent pneumothorax synchronized with the menstrual cycle. Unfortunately, conventional therapy, including hormonal treatment and surgical procedures, seems to be associated with a high rate of recurrence; there is no well-established treatment for CPX. Recently, we developed a useful and effective operative method for spontaneous pneumothorax, with which one can remove the lesion site and sew a polyglactin mesh on the lung concurrently by endoscopic linear cutter under video assisted thoracoscopic surgery, dressing the lung with polyglactin mesh to reinforce the stump and facilitating pleural adhesion for secondary prevention. We have used this method to resect pathological lung lesions and promote pleurodesis to prevent recurrence. In addition, polyglycolate felt was placed to cover the lesion site in the diaphragm in four cases of repetitive and treatment resistant CPX as surgical pleurodesis, and successful results were obtained. PMID- 22427395 TI - Non-ST elevation myocardial infarction? Intervene! PMID- 22427396 TI - Paravertebral blockade in thoracoscopic surgery. PMID- 22427397 TI - Aortic pseudoaneurysm due to piercing ring injury. PMID- 22427398 TI - Rudimentary ventricle in univentricular physiology. PMID- 22427399 TI - Editorial comment: Re-operation: a thing of the past? Transcatheter aortic valve in-valve implantation for failed surgical bioprosthesis. PMID- 22427400 TI - Impact of residual regurgitation after aortic valve replacement. AB - OBJECTIVES: Mild-to-moderate aortic regurgitation (AR) is not infrequently encountered after standard aortic valve replacement, and reportedly more often following transcatheter aortic valve implantation. Patients are usually managed by observational follow-up, but the clinical significance and natural history of residual AR are unknown. The goal of this study was to determine its impact on the outcome of these patients. METHODS: Between 1992 and 2011, 3201 consecutive patients underwent isolated standard aortic valve replacement in our institution. Of these, 135 patients (4.2%) were found to have paravalvular leak >1/4. Clinical, intraoperative as well as early and late postoperative outcome variables were studied. Factors associated with residual AR and their impact on survival were assessed by multivariate analysis. RESULTS: Mean follow-up was 4.5 +/- 3.4 years. The use of a bioprosthesis, longer cardiopulmonary bypass duration and preoperative atrial fibrillation were associated with a higher risk of presenting residual AR. Survival was negatively affected by commonly identified comorbidities (diabetes, stroke, pulmonary disease, renal failure, peripheral vascular disease) but also by the presence of >1/4 residual AR. Survival in the latter group was lower than for patients with <=1/4 AR at all time points: 91.4 vs 96.7%, 77.5 vs 82.4% and 44.1 vs 54.5% at 1, 5 and 10 years, respectively (P < 0.01). CONCLUSIONS: Postoperative residual AR >1/4 is an independent predictor of postoperative mortality and should be considered in the selection of surgical approach and management strategy for patients in need of standard and transcatheter aortic valve replacement. PMID- 22427401 TI - Safety of echocardiographic contrast in hospitalized patients with pulmonary hypertension: a multi-center study. AB - AIMS: Echocardiographic contrast (EC) improves the diagnostic accuracy of suboptimal echocardiograms. In October 2007, the Food and Drug Administration (FDA) placed a black box warning on the label of the perflutren-based agents Definity and Optison, contraindicating their use in patients with pulmonary hypertension (PHT) and unstable cardiopulmonary status, after serious cardiopulmonary reactions occurred in temporal relation to EC administration. In 2008 and 2011, the FDA revised the black box warning allowing their use in this same population. However, limited data exist regarding the safety profile of these agents in patients with PHT. METHODS AND RESULTS: Consecutive hospitalized patients with PHT who were referred for echocardiographic evaluation, but required the use of EC, were included. All our patients received the EC agent Definity. We evaluated these patients for serious adverse events (respiratory decompensation, hypotension, syncope, convulsions, arrhythmias, anaphylactic reactions, or death) occurring within 24 h of EC administration. The study group included 1513 patients (age 69 +/- 14 years, 55% males, BMI 33 +/- 9 kg/m(2)), of which 911 (60%) had mild PHT, 515 (34%) had moderate PHT, and 87 (6%) had severe PHT. The mean pulmonary artery systolic pressures (PASP) in the groups with mild, moderate, and severe PHT were 41 +/- 4 (range 35-49) mmHg, 55 +/- 5 (range 50-69) mmHg, and 78 +/- 9 (range 70-122) mmHg, respectively. The incidence of adverse events in all subgroups was rare (0.002%) and they were not attributed to EC because of temporal and clinical considerations. CONCLUSION: The use of the EC agent Definity is safe in hospitalized patients with PHT. PMID- 22427402 TI - Two-dimensional speckle tracking of the left ventricle in patients with systemic sclerosis for an early detection of myocardial involvement. AB - AIMS: Myocardial involvement is associated with poor prognosis in patients with systemic sclerosis (SSc). Two-dimensional speckle-tracking echocardiography (STE) is a powerful novel modality for the assessment of subclinical cardiac left ventricular (LV) dysfunction that, so far, has not been investigated in SSc patients. The aim of this study was to evaluate deformation analyses derived from STE for early detection of LV systolic dysfunction in patients with SSc having preserved left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Twenty two patients with SSc (57.1 +/- 13.3 years, LVEF 64 +/- 3.1%, mean time of 5.4 +/ 4.6 years from diagnosis) and 22 gender- and age-matched healthy subjects (57.4 +/- 14.0 years, LVEF 65 +/- 2.7%) underwent echocardiography with STE to assess global and regional LV function. The global longitudinal 2D peak systolic strain (PSS) of the left ventricle was significantly lower in the SSc group compared with controls: -19.0 +/- 2.4 vs. -21.1 +/- 2.5% (P = 0.008). This was mainly driven by a reduced strain in the basal segments. Strain in the medial segments and in the apex did not differ significantly. In addition, there was a significant difference between both groups regarding the global longitudinal PSS rate of the left ventricle (-1.19 +/- 0.18 vs. -1.43 +/- 0.26 s(-1), P = 0.001). CONCLUSION: LV deformation analysis by STE is a sensitive method to detect early LV systolic impairment primarily in the basal segments in patients with SSc having preserved LVEF. PMID- 22427403 TI - Usefulness of nefopam in treating pain of severe uncomplicated renal colics in adults admitted to emergency units: a randomised double-blind controlled trial. The 'INCoNU' study. AB - BACKGROUND: Renal colic pain is a frequent cause of emergency department admissions (1-2% of admissions). It is extremely painful, often requiring intravenous morphine titration. The aim of this study was to estimate the effect of adding nefopam to ketoprofen upon subsequent morphine consumption and the time needed to achieve adequate analgesia in renal colic. METHODS: The authors undertook a prospective, monocentric, randomised, double-blind, placebo controlled, parallel-group study, using an intent-to-treat analysis. Patients admitted to the emergency department for suspected hyperalgesic (evaluated with a visual analogue scale (VAS)) renal colic were enrolled in the study. They were administered an initial treatment of ketoprofen before being randomly assigned to either the placebo or nefopam group. RESULTS: Thirty patients admitted to the emergency department were enrolled in the study. Morphine analgesia was necessary for 10 patients (66.6%) (95% CI 40% to 90%) in the nefopam group and 8 (53.3%) (95% CI 30% to 80%) in the placebo group, with no statistically significant difference found (difference 13.3%, 95% CI -51% to 24%). The time needed to achieve adequate analgesia in the case of morphine titration was 8.3 min (95% CI 4.2 to 12.5) in the nefopam group and 9 min (95% CI 2.7 to 15.3) in the placebo group, with no statistically significant difference (difference 0.7, 95% CI 7.25 to 8.58). CONCLUSION: This study did not reveal any significant difference between nefopam and placebo. This may be due to lack of statistical power or lack of effectiveness. CLINICAL TRIAL REGISTRATION NUMBER: http://ClinicalTrials.gov ID number NCT00639574. PMID- 22427404 TI - Modified early warning score with rapid lactate level in critically ill medical patients: the ViEWS-L score. AB - OBJECTIVES: To examine whether the predictive value of the early warning score (EWS) could be improved by including rapid lactate levels, and to compare the modified EWS with the pre-existing risk scoring systems. DESIGN: Retrospective observational study in South Korea. SETTING: An urban, academic, tertiary hospital. PARTICIPANTS: Consecutive adult patients who were admitted to the medical intensive care unit via the emergency department (ED). OUTCOME MEASURES: A newly developed EWS--the VitalPAC EWS (ViEWS), was used in the present study. Lactate level, ViEWS and HOTEL score were obtained from patients at presentation to the ED, and APACHE II, SAPS II and SAPS III scores were obtained after admission. The area under curve of each risk scoring system for in-hospital, 1 week, 2-week and 4-week mortality was compared. RESULTS: 151 patients were enrolled and the mortality was 42.4%. The ViEWS-L score was calculated as follows: ViEWS-L score=ViEWS+lactate (mmol/l) according to the regression coefficient. The mean ViEWS-L score was 11.6+/-7.3. The ViEWS-L score had a better predictive value than the ViEWS score for hospital mortality (0.802 vs 0.742, p=0.009), 1-week mortality (0.842 vs 0.707, p<0.001), 2-week mortality (0.827 vs 0.729, p<0.001) and 4-week mortality (0.803 vs 0.732, p=0.003). The ViEWS-L score also had a better predictive value than the HOTEL and APACHE II scores. The predictive value of ViEWS-L was comparable with SAPS II and SAPS III. CONCLUSIONS: The ViEWS-L score performed as well as or better than the pre existing risk scoring systems in predicting mortality in critically ill medical patients who were admitted to the medical intensive care unit via the ED. PMID- 22427405 TI - Hanging-associated out-of-hospital cardiac arrests in Melbourne, Australia. AB - INTRODUCTION: Hanging is an infrequent but devastating cause of out-of-hospital cardiac arrest (OHCA). We determine the characteristics and outcomes of hanging associated OHCA in Melbourne Australia. METHODS: A 10-year retrospective case review of all adult hangings (aged >=16 years) associated with OHCA, was conducted using data from the Victorian Ambulance Cardiac Arrest Registry. RESULTS: Between 2000 and 2009, the emergency medical service (EMS) attended 33 178 adult OHCAs of which 1321 (4%) had hanging as the aetiology. The median age (IQR) of hanging-associated OHCA cases was 39 (29-51) years and 1162 were men (88%). The first recorded rhythm by EMS was asystole seen in 1276 (75.5%) patients, pulseless electrical activity (PEA) in 38 (13.4%) cases and ventricular fibrillation in 7 cases (0.5%). EMS attempted resuscitation in 208 (15.7%) patients of whom 61 (29.3%) achieved return of spontaneous circulation (ROSC) and were transported, and 7 (3.3%) survived to hospital discharge. Hanging-associated OHCAs were younger (median (IQR) 38 (29-51) years versus 74 (61-82) years, p<0.001), less likely to have a shockable rhythm (0.5% vs 17.2%, p<0.001), receive bystander cardiopulmonary resuscitation (14.1% vs 25.5%, p<0.001) or an attempted resuscitation by EMS (15.7% vs 36.1%, p<0.001) compared with OHCA cases with an aetiology of 'presumed cardiac' arrest. Multivariable logistic regression identified factors associated with EMS decision to attempt resuscitation; the adjusted OR (95% CI) for 'presence of bystander cardiopulmonary resuscitation' was 15.8 (10.70-23.30) and for 'witnessed arrest' was 5.26 (1.17-23.30). CONCLUSION: Attempted resuscitation was not always futile with a survival of 3.3%. A preventive focus is needed. PMID- 22427406 TI - Dentofacial and upper airway characteristics of mild and severe class II division 1 subjects. AB - The aim of this retrospective, cross-sectional study was to assess whether mild and severe Class II division 1 subjects have craniofacial and upper airway characteristics, which relate to the severity of Class II as judged by overjet or ANB angle. The sample consisted of pre-treatment lateral cephalograms and dental casts of 131 males and 115 females (mean age 10.4 +/- 1.6). Inclusion criteria were: healthy Caucasian subjects, at least ¾ Class II first molar relationship on both sides and overjet >= 4 mm. The cephalograms were traced and digitized. Distances and angular values were computed. Mild and severe Class II was defined by overjet (<10 mm/>= 10 mm) or by ANB angle (<7 degrees/>=7 degrees). Statistics were performed with two-sample t-test and Pearson's correlation analysis. In the two overjet groups, significant differences were mainly found for incisor inclination while the two ANB groups differed significantly in SNA, WITS, Go-Pg, SpaSpp/MGo, SN/MGo, and Ar-Gn. The shortest airway distance between the soft palate and the posterior pharyngeal wall was significantly correlated to the NS/Ar angle. Statistical analysis revealed several significant correlations. Patients with a large overjet or ANB angle differed significantly from patients with a small overjet or ANB angle mainly in their incisor inclination. In the present sample, the overjet and to some extent also the ANB angle is determined by soft tissue or individual tooth position rather than by skeletal background. In retrognathic patients, a tendency towards smaller airway dimensions was found. However, statistical analysis did not reveal a strong connection between upper airway and dentoskeletal parameters, but a large interindividual variation. PMID- 22427407 TI - Impaired quality of life after chikungunya virus infection: a 2-year follow-up study. AB - OBJECTIVES: To measure the frequency of and risk factors for rheumatic manifestations after chikungunya virus (CHIKV) infection and to assess their impact on quality of life (QoL). METHODS: In a cohort study among 509 cases diagnosed in France, demographic and clinical characteristics were collected at baseline, and QoL status by 36-item short-form health survey (SF-36), a short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF) and General Health Questionnaire (GHQ-12) at follow-up. SF-36 scores were compared with population norms. Factors associated with QoL were identified in multivariate linear regression models. RESULTS: A total of 391 (77%) patients participated (53.5% female, mean age 50.2 years). Median time from onset at follow-up was 23.4 months. Among 176 recovered patients, a shorter duration of symptoms was observed in younger age groups and male patients. The probability of full recovery at 1 year was 0.39. Those not recovered were older, had more comorbidities and a longer acute stage with joint swelling. Scores of physical and mental components of the SF-36 and GHQ-12 were low. The AIMS2-SF was affected mainly in symptoms, psychological and social dimensions. Recovered patients did not differ significantly from age- and gender-matched population SF-36 norms. Older age (P = 0.01-0.002) was associated with lower SF-36 scores. Other factors associated with lower SF-36, lower GHQ12 scores and higher AIMS2-SF dimensions were lack of recovery (P = 0.017 to <0.0001), presence of comorbidity (P = 0.005 to <0.0001) and a longer duration of acute stage (P = 0.047 to <0.0001). CONCLUSION: Medical follow-up with special attention to comorbidity providing information on possible chronic symptoms and giving support for potential depression and anxiety are recommended. PMID- 22427408 TI - Mapping pathogenesis of arthritis through small animal models. AB - Animal models have been used for a number of decades to study arthritis and have contributed greatly to unravelling mechanisms of pathogenesis and validating new targets for treatment. All animal models have sets of limitations and over the years there has been natural refinement of existing models as well as creation of new ones. The success of genetic modification in mice has fuelled an exponential increase in the use of murine models for arthritis research and has significantly increased our understanding of disease processes. This review focuses on those rodent models of RA and OA that have current utility and are widely used by the research community. We highlight the subtle but important differences in existing models by positioning them on a pathogenesis map whereby model selection is determined by the specific aspect of disease to be studied. We discuss the evolving challenges in in vivo arthritis studies and our perceived gaps for future new model development. The document includes technical and cost implications of performing the described models, and the ethical considerations of such approaches. PMID- 22427409 TI - Development of an ELISA for detection of autoantibodies to nuclear matrix protein 2. AB - OBJECTIVES: Autoantibodies characterizing certain forms of inflammatory myopathy, which are myositis-specific autoantibodies, are useful in the diagnosis and prediction of prognosis in DM/PM. This study aimed to identify a subset of DM patients who have anti-nuclear matrix protein 2 (anti-NXP-2) antibodies by using biotinylated recombinant proteins, and to clarify the clinical features of DM patients with these antibodies. METHODS: Sera from 170 Japanese patients with CTDs including 106 with DM, 8 with PM, 21 with SLE, 20 with SSc, 15 with myositis overlap syndrome and 20 healthy controls were screened for anti-NXP-2 antibodies by our novel ELISAs. Positive sera were further examined by immunoprecipitation. RESULTS: Sera from 6 of the 170 patients with CTDs were confirmed to be positive for anti-NXP-2 antibodies. These six positives were from female patients, with five of the six sera being from adult DM patients and only one of the six being from 1 of the 12 JDM patients. All these patients had myositis. None of the anti NXP-2-positive patients had interstitial lung disease, but one patient was complicated with ovarian cancer. CONCLUSION: Our newly developed ELISA is applicable for the measurement of anti-NXP-2 antibodies. The results show that anti-NXP-2 antibodies, which have been characterized in JDM, exist in adult DM patients. Further studies using large populations are necessary to elucidate the characteristic clinical features and the prognosis of patients with anti-NXP-2 antibodies, especially for adult patients. PMID- 22427410 TI - Update of the literature review on treatment with biologics as a basis for the first update of the ASAS/EULAR management recommendations of ankylosing spondylitis. AB - OBJECTIVE: To perform a literature review as basis for the update of the Assessment in SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) treatment recommendations with biologics in AS. METHODS: A literature search of all publications found in MedLine, Embase and Cochrane database between 2005 and 2009 and in the EULAR/ACR meetings between 2007 and 2009 was performed. The research evidence and strength of recommendation (SOR) for biologics were provided. RESULTS: Out of 247 reports on AS treatment with biologics, 98 contained efficacy data and 25 had complete data for analysis. The treatment effect sizes (95% CI) for anti-TNF vs placebo varied between 0.34 (0.08, 0.6) and 1.5 (0.45, 2.5) for BASDAI and 0.33 (0.07, 0.59) and 2.5 (1.3, 3.7) for BASFI. The calculation of the numbers needed to treat all the different outcomes varied between 2.3 and 3.0 patients for all ASAS outcomes and between 2.7 and 6.5 patients for ASAS partial remission. Data on biologics other than anti-TNF and for TNF blockers on juvenile SpA were limited. The incidence rates of uveitis during anti-TNF treatment varied between 4.4/100 patient-years (pys) and 15.6/100 pys during placebo (P < 0.05). The incidence rates of IBD flares were significantly less during infliximab treatment (0.2/100 pys). The rate of infections was higher in patients treated with anti-TNF as compared with placebo, but there was no difference in the incidence of serious infections for treatment with anti-TNF vs placebo. CONCLUSIONS: The overall evidence was very high for anti-TNF treatment (1b, SOR: A) with respect to efficacy and safety, while it was low for biologic treatment other than anti-TNF (3, SOR: C). PMID- 22427411 TI - Mucocutaneous leishmaniasis in a patient treated with anti-TNF-alpha therapy. PMID- 22427412 TI - Work status and its determinants among patients with systemic sclerosis: a systematic review. AB - OBJECTIVE: To describe work status and factors associated with work disability (WD) in patients with SSc. METHODS: A systematic search strategy in various electronic databases from 1990 to 2011 was performed. All clinical studies concerning SSc patients containing quantitative information on work status and/or factors associated with WD were selected. Extracted were study characteristics, data on work status and/or factors associated with WD. The methodological quality was evaluated in three quality aspects (selection bias, information bias and statistical analysis bias). A best evidence synthesis was employed to analyse the association between potential determinants and WD. RESULTS: Twelve studies, described in 13 papers, including 2758 SSc patients were selected. The methodological quality of one study was high. Employment rates varied between 11 and 82% after an average disease duration ranging from 2.5 to 14 years. There was moderate evidence for an association between more functional disability, more disease-specific symptoms and poorer quality of life on one side and presence of WD on the other. There was moderate evidence for the absence of an association between WD and age, sex and disease subset. Inconsistent evidence was seen for an association between WD and education and disease duration. CONCLUSION: WD is a major consequence of the disease in patients with SSc and is associated with more functional disability, more disease-specific symptoms and poorer quality of life. This emphasizes the need for research into interventions to prevent or reduce WD in patients with SSc, especially in those with a poorer health status. PMID- 22427413 TI - Minister hears of BVA's concerns about pace of change at AHVLA. PMID- 22427414 TI - Veterinary checks take effect at Crufts. PMID- 22427415 TI - SBV cases increase in cattle. PMID- 22427417 TI - New board to oversee changes to veterinary surveillance in Scotland. PMID- 22427418 TI - Royal praise for food safety and sustainability research at Moredun. PMID- 22427419 TI - Encouraging the farm vets of the future. PMID- 22427420 TI - Controlling pony numbers on Dartmoor. PMID- 22427421 TI - Vets make best companies list. PMID- 22427422 TI - Pets' role in saving lives. PMID- 22427423 TI - Working together to eradicate BVD in Scotland. PMID- 22427424 TI - Bog spavin: recognising the problem is the first step towards recovery. PMID- 22427425 TI - Recognising veterinary specialists. PMID- 22427426 TI - Prescribing of antimicrobials by veterinary practitioners. PMID- 22427427 TI - Echinococcus risk from imported beavers. PMID- 22427429 TI - The beta-arrestin-like protein Rim8 is hyperphosphorylated and complexes with Rim21 and Rim101 to promote adaptation to neutral-alkaline pH. AB - beta-Arrestin proteins are critical for G-protein-coupled receptor desensitization and turnover. However, beta-arrestins have recently been shown to play direct roles in nonheterotrimeric G-protein signal transduction. The Candida albicans beta-arrestin-like protein Rim8 is required for activation of the Rim101 pH-sensing pathway and for pathogenesis. We have found that C. albicans Rim8 is posttranslationally modified by phosphorylation and specific phosphorylation states are associated with activation of the pH-sensing pathway. Rim8 associated with both the receptor Rim21 and the transcription factor Rim101, suggesting that Rim8 bridges the signaling and activation steps of the pathway. Finally, upon activation of the Rim101 transcription factor, C. albicans Rim8 was transcriptionally repressed and Rim8 protein levels were rapidly reduced. Our studies suggest that Rim8 is taken up into multivesicular bodies and degraded within the vacuole. In total, our results reveal a novel mechanism for tightly regulating the activity of a signal transduction pathway. Although the role of beta-arrestin proteins in mammalian signal transduction pathways has been demonstrated, relatively little is known about how beta-arrestins contribute to signal transduction. Our analyses provide some insights into potential roles. PMID- 22427430 TI - Tetrahymena thermophila JMJD3 homolog regulates H3K27 methylation and nuclear differentiation. AB - Histone H3K27me3 modification is an important regulator for development and gene expression. In Tetrahymena thermophila, the complex chromatin dynamics of H3K27me3 marks during nuclear development suggested that an H3K27me3 demethylase might exist. Here, we report an H3K27me3 demethylase homolog, JMJ1, in Tetrahymena. During conjugation, JMJ1 expression is upregulated and the protein is localized first in the parental macronucleus and then in the new macronucleus. In conjugating cells, knockdown of JMJ1 expression resulted in a severe reduction in the production of progeny, suggesting that JMJ1 is essential for Tetrahymena conjugation. Furthermore, knockdown of JMJ1 resulted in increased H3K27 trimethylation in the new macronucleus and reduced transcription of genes related to DNA elimination, while the DNA elimination process was also partially blocked. Knockdown of the H3K27 methyltransferase EZL2 but not that of EZL1 partially restored progeny production in JMJ1-knockdown cells and reduced abnormal H3K27me3 accumulation in the new macronucleus. Taken together, these results demonstrate a critical role for JMJ1 in regulating H3K27me3 during conjugation and the importance of JMJ1 in regulating gene expression in the new macronucleus but not in regulating the formation of heterochromatin associated with programmed DNA deletion. PMID- 22427431 TI - Outer dynein arm light chain 1 is essential for controlling the ciliary response to cyclic AMP in Paramecium tetraurelia. AB - The individual role of the outer dynein arm light chains in the molecular mechanisms of ciliary movements in response to second messengers, such as Ca(2+) and cyclic nucleotides, is unclear. We examined the role of the gene termed the outer dynein arm light chain 1 (LC1) gene of Paramecium tetraurelia (ODAL1), a homologue of the outer dynein arm LC1 gene of Chlamydomonas reinhardtii, in ciliary movements by RNA interference (RNAi) using a feeding method. The ODAL1 silenced (ODAL1-RNAi) cells swam slowly, and their swimming velocity did not increase in response to membrane-hyperpolarizing stimuli. Ciliary movements on the cortical sheets of ODAL1-RNAi cells revealed that the ciliary beat frequency was significantly lower than that of control cells in the presence of >= 1 mM Mg(2+)-ATP. In addition, the ciliary orientation of ODAL1-RNAi cells did not change in response to cyclic AMP (cAMP). A 29-kDa protein phosphorylated in a cAMP-dependent manner in the control cells disappeared in the axoneme of ODAL1 RNAi cells. These results indicate that ODAL1 is essential for controlling the ciliary response by cAMP-dependent phosphorylation. PMID- 22427432 TI - Exploring the world of phospholipids and their interactions with proteins: the work of William Dowhan. PMID- 22427433 TI - Inconvenient truths for PRMT6 kinetic studies. PMID- 22427434 TI - A new structural insight into differential interaction of cyanobacterial and plant ferredoxins with nitrite reductase as revealed by NMR and X-ray crystallographic studies. AB - Ferredoxin (Fd), which plays a pivotal role in photosynthesis as an electron carrier, forms a transient complex with various Fd-dependent enzymes, such as nitrite reductase (NiR), to achieve efficient intermolecular electron transfer. We studied the protein-protein interaction of Fd and NiR by NMR spectroscopy and determined three acidic regions of Fd to be major sites for the interaction with NiR, indicating that the complex is stabilized through electrostatic interaction. During this study, we found Fds from higher plant and cyanobacterium, in spite of their high structural similarities including the above acidic regions, differ remarkably in the interaction with cyanobacterial NiR. In activity assay of NiR, K(m) value for maize Fd (74.6 uM) was 9.6 times larger than that for Leptolyngbya boryana Fd (7.8 uM). The two Fds also showed a similar difference in binding assay to NiR-immobilized resin. Comparative site-specific mutagenesis of two Fds revealed that their discriminative ability for the interaction with NiR is attributed mainly to non-charged residues in the peripheral region of [2Fe-2S] cluster. These non-charged residues are conserved separately between Fds of plant and cyanobacterial origins. Our data highlight that intermolecular force(s) other than electrostatic attraction is(are) also crucial for the molecular interaction between Fd and partner enzyme. PMID- 22427435 TI - Atrial fibrillation and cardiac resynchronization therapy: how should rate be controlled? PMID- 22427436 TI - What a nice 'scoobie'!! PMID- 22427437 TI - Heat shock factor 1 regulates the expression of the TRPV1 gene in the rat preoptic-anterior hypothalamus area during lipopolysaccharide-induced fever. AB - The TRPV1 cation channel is a member of the thermo-TRP family of ionic channels activated by noxious heat and various endogenous mediators. Expression of TRPV1 is widespread and includes hypothalamic neurons. The preoptic-anterior hypothalamus area (PO/AH) are required for regulation of body temperature, suggesting that resident thermosensitive TRPV1 channels may be involved in thermoregulation. Heat shock factor 1 (HSF1) is a ubiquitous heat-sensitive transcription factor that co-ordinates the genomic response to noxious heat, but it is not known whether TRPV1 expression is part of this adaptive mechanism. We therefore investigated whether HSF1 regulates TRPV1 transcription in response to lipopolysaccharide (LPS)-induced fever in rats. Expression of TRPV1 and nuclear translocation of HSF1 were transiently upregulated during LPS-induced fever, with temporal profiles that mirrored the rise and fall in body temperature. We used a series of luciferase reporter vectors encoding different spans of the TRPV1 gene 5'-flanking region to identify possible HSF1-binding sites. Reporter assays in transfected PC12 cells demonstrated that only TRPV1 promoters with the -1160 to 821 region drove reporter expression in response to heat shock. This region contains one putative heat shock-responsive element (HSE) for HSF1 binding at 919 to -910. Site-directed mutagenesis of this HSE abrogated reporter activity in response to heat shock, indicating that -919 to -910 contains the specific HSF1 binding sequence. In the PO/AH, electrophoretic mobility shift assay and chromatin immunoprecipitation assay analyses demonstrated that HSF1 is recruited to the HSE of the TRPV1 gene in PO/AH cells during LPS-induced fever, resulting in enhanced TRPV1 expression. Based on these findings, we conclude that HSF1 regulates TRPV1 gene expression in PO/AH of rats with LPS-induced fever. PMID- 22427439 TI - Patients' perceptions of nutrition care provided by general practitioners: focus on Type 2 diabetes. AB - BACKGROUND: In Australia, GPs are central to managing individuals with chronic disease. Due to the influence of lifestyle behaviour on chronic disease health outcomes, GPs may counsel an individual about nutrition to assist the individual to improve their nutrition behaviour. Patients with a positive regard for their health care are more likely to adhere to lifestyle changes which have been recommended by a health professional. It is unclear whether this relationship extends to the context of nutrition and general practice. The management of Type 2 diabetes presents as a relevant scenario to investigate patients' perceptions of nutrition care provided by Australian GPs. OBJECTIVES: This study examines the perceptions of individuals with Type 2 diabetes regarding the nutrition care they have received from GPs. METHODS: Nine hundred and thirty-nine individuals with Type 2 diabetes completed a 54-item online survey. Individual survey items related to demographic information, health-related attributes, perspectives on ideal care and reflections on previous care. RESULTS: Eighty-four per cent of respondents perceived that ideal management of Type 2 diabetes by GPs includes nutrition care, however, only 43% of respondents report to have received this care from a GP. Over 91% of respondents are satisfied with their GP regarding nutrition care, but only 34% of respondents believe this care has been effective in improving their personal nutrition behaviour. CONCLUSION: Patients do not receive nutrition care from GPs as often as they would like, and despite being satisfied with the overall care received, are concerned about the effectiveness of the nutrition care component. PMID- 22427438 TI - Remote ischaemic pre- and delayed postconditioning - similar degree of cardioprotection but distinct mechanisms. AB - Myocardial ischaemia-reperfusion injury can be significantly reduced by an episode(s) of ischaemia-reperfusion applied prior to or during myocardial ischaemia (MI) to peripheral tissue located at a distance from the heart; this phenomenon is called remote ischaemic conditioning (RIc). Here, we compared the efficacy of RIc in protecting the heart when the RIc stimulus is applied prior to, during and at different time points after MI. A rat model of myocardial ischaemia-reperfusion injury involved 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Remote ischaemic conditioning was induced by 15 min occlusion of femoral arteries and conferred a similar degree of cardioprotection when applied 25 min prior to MI, 10 or 25 min after the onset of MI, or starting 10 min after the onset of reperfusion. These RIc stimuli reduced infarct size by 54, 56, 56 and 48% (all P < 0.001), respectively. Remote ischaemic conditioning applied 30 min into the reperfusion period was ineffective. Activation of sensory nerves by application of capsaicin was effective in establishing cardioprotection only when elicited prior to MI. Vagotomy or denervation of the peripheral ischaemic tissue both completely abolished cardioprotection induced by RIc applied prior to MI. Cardioprotection conferred by delayed remote postconditioning was not affected by either vagotomy or peripheral denervation. These results indicate that RIc confers potent cardioprotection even if applied with a significant delay after the onset of myocardial reperfusion. Cardioprotection by remote preconditioning is critically dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning appears to rely on a different signalling pathway(s). PMID- 22427440 TI - The use of classification and regression trees to predict the likelihood of seasonal influenza. AB - BACKGROUND: Individual signs and symptoms are of limited value for the diagnosis of influenza. OBJECTIVE: To develop a decision tree for the diagnosis of influenza based on a classification and regression tree (CART) analysis. METHODS: Data from two previous similar cohort studies were assembled into a single dataset. The data were randomly divided into a development set (70%) and a validation set (30%). We used CART analysis to develop three models that maximize the number of patients who do not require diagnostic testing prior to treatment decisions. The validation set was used to evaluate overfitting of the model to the training set. RESULTS: Model 1 has seven terminal nodes based on temperature, the onset of symptoms and the presence of chills, cough and myalgia. Model 2 was a simpler tree with only two splits based on temperature and the presence of chills. Model 3 was developed with temperature as a dichotomous variable (>=38 degrees C) and had only two splits based on the presence of fever and myalgia. The area under the receiver operating characteristic curves (AUROCC) for the development and validation sets, respectively, were 0.82 and 0.80 for Model 1, 0.75 and 0.76 for Model 2 and 0.76 and 0.77 for Model 3. Model 2 classified 67% of patients in the validation group into a high- or low-risk group compared with only 38% for Model 1 and 54% for Model 3. CONCLUSIONS: A simple decision tree (Model 2) classified two-thirds of patients as low or high risk and had an AUROCC of 0.76. After further validation in an independent population, this CART model could support clinical decision making regarding influenza, with low-risk patients requiring no further evaluation for influenza and high-risk patients being candidates for empiric symptomatic or drug therapy. PMID- 22427442 TI - Mycobacterium yongonense sp. nov., a slow-growing non-chromogenic species closely related to Mycobacterium intracellulare. AB - A slow-growing non-chromogenic mycobacterium was isolated from a patient with pulmonary disease. Phenotypically, strain 05-1390(T) was similar to Mycobacterium intracellulare ATCC 13950(T). The 16S rRNA gene sequence (1385 bp) of strain 05 1390(T) showed a high degree of similarity to those of the M. intracellulare complex, namely Mycobacterium marseillense 5351974(T) (100 %), M. intracellulare ATCC 13950(T) (99.8 %) and Mycobacterium chimaera DSM 44623(T) (99.9 %). Phylogenetic analysis based on internal transcribed spacer 1 (ITS1) and the hsp65 gene indicated that strain 05-1390(T) was closely related to M. intracellulare ATCC 13950(T), but that it was a distinct phylogenetic entity. Of particular interest, an analysis based on the rpoB gene (701 bp) showed that it is closely related to Mycobacterium parascrofulaceum ATCC BAA-614(T) (99.4 %), a scotochromogenic strain, rather than to the M. intracellulare-related strains. Unique MALDI-TOF MS profiles also supported the taxonomic status of this strain as a distinct species. These data support the conclusion that strain 05-1390(T) represents a novel mycobacterial species, for which the name Mycobacterium yongonense sp. nov. is proposed; the type strain is 05-1390(T) ( = DSM 45126(T) = KCTC 19555(T)). PMID- 22427443 TI - Silanimonas mangrovi sp. nov., a member of the family Xanthomonadaceae isolated from mangrove sediment, and emended description of the genus Silanimonas. AB - A novel Gram-negative, rod-shaped, motile bacterium, designated strain AK13(T), was isolated from a sediment sample collected from mangrove of Namkhana, Sunderbans, West Bengal, India. Strain AK13(T) was positive for oxidase, DNase and lipase activities and negative for catalase, gelatinase, ornithine decarboxylase, lysine decarboxylase, nitrate reductase, aesculinase and urease activities. The fatty acids were dominated by iso-C(11 : 0), iso-C(11 : 0) 3-OH, iso-C(15 : 0), iso-C(16 : 0), iso-C(17 : 1)omega9c and summed feature 3 (C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH). Strain AK13(T) contained Q-8 as the major respiratory quinone and diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, two unidentified aminolipids, one unidentified glycolipid and one unidentified lipid as the polar lipids. The DNA G+C content of strain AK13(T) was 55.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the type strain of Silanimonas lenta, of the family Xanthomonadaceae (phylum Proteobacteria), was the closest neighbour of strain AK13(T), with 95.2 % sequence similarity. Other members of the family showed sequence similarities <94.4 %. Based on the phenotypic characteristics and phylogenetic inference, strain AK13(T) is proposed as a member of a novel species of the genus Silanimonas, Silanimonas mangrovi sp. nov.; the type strain is AK13(T) (= MTCC 11082(T) = DSM 24914(T)). An emended description of the genus Silanimonas is also provided. PMID- 22427444 TI - Algimonas porphyrae gen. nov., sp. nov., a member of the family Hyphomonadaceae, isolated from the red alga Porphyra yezoensis. AB - Three Gram-negative, stalked, motile bacteria, designated 0C-2-2(T), 0C-17 and LNM-3, were isolated from the red alga Porphyra yezoensis. 16S rRNA gene sequence analysis revealed that the three novel strains belonged to the family Hyphomonadaceae, and were closely related to Litorimonas taeanensis G5(T) (96.5 % 16S rRNA gene sequence similarity) and Hellea balneolensis 26III/A02/215(T) (94.3 %). The DNA G+C contents of the novel isolates (58.5-60.2 mol%) were clearly distinguished from those of L. taeanensis G5(T) (47.1 mol%) and H. balneolensis DSM 19091(T) (47.9 mol%). The G+C content of L. taeanensis G5(T) obtained in this study was quite different from a previous report (63.6 mol%). DNA-DNA hybridization experiments showed that the novel strains constituted a single species. Eleven phenotypic features of the three isolates differed from those of both related genera. The predominant respiratory quinone was ubiquinone-10 and the major fatty acid was C(18 : 1)omega7c. On the basis of this polyphasic taxonomic analysis, the novel strains represent a novel genus and species, for which the name Algimonas porphyrae gen. nov., sp. nov. is proposed. The type strain of Algimonas porphyrae is 0C-2-2(T) (= LMG 26424(T) = NBRC 108216(T)). PMID- 22427445 TI - Winogradskyella damuponensis sp. nov., isolated from seawater. AB - A novel bacterium, designated F081-2(T), isolated from seawater from Damupo beach in Pohang, Korea, was investigated using a polyphasic taxonomic approach. Cells were yellow-pigmented, strictly aerobic, motile by gliding, Gram-negative staining and rod-shaped. The temperature, pH and NaCl ranges for growth were 4-35 degrees C, pH 5.5-9.5 and 1.0-5.0 %, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain F081-2(T) belonged to a distinct lineage in the genus Winogradskyella of the family Flavobacteriaceae, sharing 93.7-98.1 % similarity with recognized members of the genus. Low levels of DNA DNA relatedness values were found between strain F081-2(T) and Winogradskyella eximia KCTC 12219(T) (61.1 %), Winogradskyella thalassocola KCTC 12221(T) (47.0 %), Winogradskyella echinorum KCTC 22026(T) (39.3 %), Winogradskyella rapida CCUG 56098(T) (34.3 %) and Winogradskyella arenosi JCM 17633(T) (33.4 %). The major cellular fatty acids were iso-C(15 : 0) (25.3 %), iso-C(15 : 1) G (14.6 %), iso C(17 : 0) 3-OH (9.3 %), anteiso-C(15 : 0) (7.8 %) and iso-C(15 : 0) 3-OH (7.6 %). The polar lipid profile was composed of phosphatidylethanolamine, one unidentified aminolipid, one unidentified phospholipid, one unidentified aminophospholipid and six unidentified lipids. The major respiratory quinone was menaquinone-6 and the DNA G+C content of the strain was 32.3 mol%. On the basis of phenotypic, phylogenetic and genotypic data, strain F081-2(T) represents a novel species within the genus Winogradskyella, for which the name Winogradskyella damuponensis sp. nov. is proposed. The type strain is F081-2(T) (=KCTC 23552(T) = JCM 17633(T)). PMID- 22427446 TI - Pontibacter lucknowensis sp. nov., isolated from a hexachlorocyclohexane dump site. AB - A Gram-negative, orange-pigmented, rod-shaped, motile and aerobic bacterial strain designated DM9(T) was isolated from hexachlorocyclohexane (HCH) contaminated soil (Lucknow, India) and its taxonomic position was determined using a polyphasic approach. 16S rRNA gene sequence analysis showed that the isolate belonged to the phylum Bacteroidetes and confirmed its placement in the genus Pontibacter, with sequence similarity ranging from 93.92 to 96.21 % with other members of the genus Pontibacter. The major cellular fatty acids of the novel strain were iso-C(17 : 0) 3-OH (6.00 %), iso-C(15 : 0) (21.54 %) and summed feature 4 (comprising C(17 : 1) iso I/anteiso B; 32.3 %). The polar lipid profile of strain DM9(T) showed the presence of phosphatidylethanolamine, an unidentified aminophospholipid, two unknown aminolipids and four unknown polar lipids. Strain DM9(T) contained MK-7 as the predominant menaquinone and its DNA G+C content was 49.2 mol%. sym-Homospermidine was the major polyamine observed in the cell. The results obtained on the basis of phenotypic characteristics, phylogenetic analysis, biochemical and physiological tests clearly distinguished DM9(T) from closely related members of the genus Pontibacter. It is proposed that DM9(T) represents a novel species, Pontibacter lucknowensis sp. nov.; the type strain is DM9(T) (= CCM 7955(T) = MTCC 11079(T)). PMID- 22427447 TI - Pedobacter ruber sp. nov., a psychrophilic bacterium isolated from soil. AB - A Gram-staining-negative, red-pigmented, psychrophilic, non-motile and rod-shaped bacterial strain, designated W1(T), was isolated from soil and subjected to a polyphasic taxonomic investigation. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain W1(T) grouped with members of the genus Pedobacter and formed a distinct cluster with the type strain of Pedobacter composti (97.8 % 16S rRNA gene sequence similarity). Levels of 16S rRNA gene sequence similarity between strain W1(T) and the type strains of all other recognized species of the genus Pedobacter available at the time of writing were <97.0 %. The predominant cellular fatty acids (>= 10 %) of strain W1(T) were summed feature 3 (iso-C(15 : 0) 2-OH and/or C(16 : 1)omega7c) and anteiso-C(15 : 0). The only menaquinone was MK-7. The genomic DNA G+C content was 39.0 mol% (HPLC). Combined data from phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain W1(T) is a representative of a novel species of the genus Pedobacter, for which we propose the name Pedobacter ruber sp. nov. The type strain is W1(T) ( = DSM 24536(T) = LMG 26240(T)). PMID- 22427448 TI - Description of Riemerella columbipharyngis sp. nov., isolated from the pharynx of healthy domestic pigeons (Columba livia f. domestica), and emended descriptions of the genus Riemerella, Riemerella anatipestifer and Riemerella columbina. AB - A group of 11 bacterial strains was isolated during microbiological investigations of pharyngeal swabs collected from domestic pigeons (Columba livia f. domestica). Phenotypic properties of the isolates closely resembled those of members of the genus Riemerella within the family Flavobacteriaceae. The genus presently contains two species, Riemerella anatipestifer and Riemerella columbina. The pigeon isolates differed from R. columbina by their lack of pigment production and negative CAMP co-haemolysis reaction. They grew more slowly at 37 degrees C under microaerobic conditions and showed reduced viability during storage under aerobic conditions at different temperatures, compared with both Riemerella species. Comparisons of protein profiles with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) MS analysis allowed differentiation between the new pigeon isolates and both R. anatipestifer and R. columbina. Phylogenetic analysis based on 16S rRNA gene and rpoB gene (encoding RNA polymerase beta subunit) sequences supported the affiliation of the 11 strains to a novel species within the genus Riemerella, for which we propose the name Riemerella columbipharyngis sp. nov. The type strain is 8151(T) (=DSM 24015(T) = LMG 26094(T)). Emended descriptions of the genus Riemerella and of its species Riemerella anatipestifer and Riemerella columbina are also presented. PMID- 22427449 TI - Pedobacter tournemirensis sp. nov., isolated from a fault water sample of a deep Toarcian argillite layer. AB - A Gram-negative bacterium, designated TF5-37.2-LB10(T), was isolated from subsurface water of the Toarcian geological layer of Tournemire, France. Cells were non-motile straight rods that formed cream to light pink colonies on 10-fold diluted LB agar. Strain TF5-37.2-LB10(T) contained menaquinone 7 and its major fatty acids were iso-C(15 : 0), summed feature 3 (iso-C(15 : 0) 2-OH and/or C(16 : 1)omega7c), iso-C(17 : 0) 3-OH and iso-C(17 : 1)omega9c. The G+C content of the genomic DNA was 46 mol%. Phylogenetic analysis of the 16S rRNA gene sequence placed strain TF5-37.2-LB10(T) within the genus Pedobacter, family Sphingobacteriaceae. Pedobacter composti TR6-06(T) and Pedobacter oryzae DSM 19973(T) were the closest phylogenetic relatives (93.5 and 93.3 % 16S rRNA gene sequence similarity, respectively). On the basis of 16S rRNA gene sequence comparison and physiological and biochemical characteristics, strain TF5-37.2 LB10(T) represents a novel species of the genus Pedobacter, for which the name Pedobacter tournemirensis sp. nov. is proposed. The type strain is TF5-37.2 LB10(T) (= DSM 23085(T) = CIP 110085(T) = MOLA 820(T)). PMID- 22427450 TI - Description of Cobetia amphilecti sp. nov., Cobetia litoralis sp. nov. and Cobetia pacifica sp. nov., classification of Halomonas halodurans as a later heterotypic synonym of Cobetia marina and emended descriptions of the genus Cobetia and Cobetia marina. AB - A group of five Gram-negative, aerobic, halotolerant, non-pigmented bacteria isolated from shallow sediment samples and invertebrate specimens collected from the Gulf of Alaska and the Sea of Japan was subjected to taxonomic study. On the basis of 16S rRNA gene sequence analysis, the novel isolates were affiliated to the genus Cobetia, sharing the highest sequence similarity of 99.3-99.9 % with Cobetia marina DSM 4741(T). DNA-DNA hybridization experiments between and among the novel strains and C. marina DSM 4741(T) and Cobetia crustatorum JCM 15644(T) revealed that the five strains represent three separate genospecies, which could be differentiated in their morphological, physiological and biochemical characteristics. Halomonas halodurans NBRC 15607(T) was included in this study as it has recently been reported to exhibit high 16S rRNA gene sequence similarity to C. marina DSM 4741(T), and it showed a high DNA relatedness value of 96 % with C. marina DSM 4741(T), indicating that they belong to the same species. On the basis of phylogenetic analysis, DNA-DNA hybridization and phenotypic characterization, three novel species are proposed, named Cobetia amphilecti sp. nov. (type strain KMM 1561(T) = NRIC 0815(T) = CCUG 49560(T)), Cobetia litoralis sp. nov. (type strain KMM 3880(T) =NRIC 0814(T) =CCUG 49563(T)) and Cobetia pacifica sp. nov. (type strain KMM 3879(T) = NRIC 0813(T) = CCUG 49562(T)). It is also proposed that Halomonas halodurans is a later heterotypic synonym of Cobetia marina, and emended descriptions of the genus Cobetia and the species Cobetia marina are provided. PMID- 22427451 TI - Description of Kordiimonas aquimaris sp. nov., isolated from seawater, and emended descriptions of the genus Kordiimonas Kwon et al. 2005 emend. Xu et al. 2011 and of its existing species. AB - A Gram-negative, aerobic, rod-shaped (0.6-0.9 * 0.7-1.2 um), motile marine bacterium, designated MEBiC06554(T), was isolated from seawater collected from the East Sea, Korea (also known as the Sea of Japan). 16S rRNA gene sequence analysis revealed that strain MEBiC06554(T) was affiliated to the order Kordiimonadales and showed high similarity to Kordiimonas gwangyangensis GW14 5(T) (95.4 %), but formed a distinct phyletic line. Growth was observed at 10.5 35.0 degrees C (optimum 20 degrees C), at pH 5.0-8.0 (optimum pH 7.0) and with 0-13 % (w/v) NaCl (optimum 3.0-3.5 %). The predominant cellular fatty acids were iso-C(15 : 0) (14.9 %), iso-C(17 : 1)omega9c (44.6 %), iso-C(17 : 0) (6.3 %) and summed feature 3 (comprising iso-C(15 : 0) 2-OH and/or C(16 : 1)omega7c; 13.9 %). The DNA G+C content was 50.3 mol%. The major respiratory quinone was Q-10. Phosphatidylethanolamine, two unidentified glycolipids, six unidentified aminolipids, three unidentified lipids and one unidentified aminophospholipid were detected as major polar lipids. On the basis of the data from our polyphasic taxonomic study, strain MEBiC06554(T) should be classified within a novel species of the genus Kordiimonas, as Kordiimonas aquimaris sp. nov. The type strain is MEBiC06554(T) (= KCCM 42940(T) = JCM 16665(T)). Emended descriptions of the genus Kordiimonas and of its species Kordiimonas gwangyangensis and Kordiimonas lacus are also proposed. PMID- 22427452 TI - Gordonia alkaliphila sp. nov., an actinomycete isolated from tidal flat sediment. AB - A Gram-stain-positive, non-motile, aerobic actinobacterium, designated strain CJ10(T), was isolated from tidal flat sediment from the Yellow Sea in South Korea. Strain CJ10(T) grew on tryptic soy agar in the presence of 0-4 % (w/v) NaCl (optimum growth in the absence of NaCl) and at pH 6-11 (optimum pH 9). On the basis of 16S rRNA gene sequence analysis, strain CJ10(T) belonged to the genus Gordonia and showed the highest sequence similarity to Gordonia hirsuta DSM 44140(T) (97.9 %) and Gordonia hydrophobica DSM 44015(T) (97.6 %). DNA-DNA relatedness levels of strain CJ10(T) were 47.4 % (CJ10(T) as probe) and 42.2 % (G. hirsuta DSM 44140(T) as probe) to G. hirsuta DSM 44140(T) and 8.6 % (CJ10(T) as probe) and 9.3 % (G. hydrophobica DSM 44015(T) as probe) to G. hydrophobica DSM 44015(T). The major isoprenoid quinone was MK-9(H(2)). The polar lipid profile of strain CJ10(T) consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The predominant cellular fatty acids were C(18 : 1)omega9c (38.0 %), C(16 : 0) (30.1 %) and summed feature 3 (C(16 : 1)omega6c and/or C(16 : 1)omega7c; 17.4 %). The DNA G+C content was 67.7 mol%. Therefore, the results from our polyphasic taxonomic study suggest that strain CJ10(T) represents a novel species in the genus Gordonia, for which the name Gordonia alkaliphila sp. nov. is proposed; the type strain is CJ10(T) (= KACC 16561(T) = JCM 18077(T)). PMID- 22427453 TI - Aestuariibaculum suncheonense gen. nov., sp. nov., a marine bacterium of the family Flavobacteriaceae isolated from a tidal flat and emended descriptions of the genera Gaetbulibacter and Tamlana. AB - A Gram-staining-negative, yellow-pigmented, strictly aerobic bacterium, designated strain SC17(T), was isolated from sediment of a tidal flat of Suncheon bay in South Korea. Cells were halotolerant, catalase- and oxidase-positive and non-motile rods. Growth of strain SC17(T) was observed at 5-40 degrees C (optimum, 25-30 degrees C), at pH 6.0-8.5 (optimum, pH 7.0) and in the presence of 1-8 % (w/v) NaCl (optimum, 1-2 %). The major cellular fatty acids were iso C(15 : 0), summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c and/or iso-C(15 : 0) 2-OH), iso-C(17 : 0) 3-OH, iso-C(15 : 1) G and anteiso-C(15 : 0.) The polar lipid content consisted of phosphatidylethanolamine and unidentified amino lipids and lipids. The G+C content of the genomic DNA was 46.4 mol% and the only respiratory quinone detected was menaquinone-6 (MK-6). Phylogenetic inference based on 16S rRNA gene sequences showed that strain SC17(T) formed a distinct phyletic lineage within the family Flavobacteriaceae and was most closely related to members of the genera Gaetbulibacter and Tamlana with 95.0-95.8 % sequence similarity. On the basis of phenotypic and molecular features, strain SC17(T) represents a novel genus of the family Flavobacteriaceae, for which the name Aestuariibaculum suncheonense gen. nov., sp. nov. is proposed. The type strain is SC17(T) (= KACC 16186(T) = JCM 17789(T)). Emended descriptions of the genera Gaetbulibacter and Tamlana are also proposed. PMID- 22427454 TI - Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice. AB - Our previous investigation demonstrated that ginsenoside Rg3 was active in promotion of the immune response. In this study, two epimers, 20(R)-Rg3 and 20(S) Rg3, were compared for their adjuvant effects on the immune response against ovalbumin (OVA). BALB/c mice were immunized subcutaneously with 10 MUg of OVA alone or with 10 MUg of OVA mixed in 20(R)-Rg3 (50 MUg) or 20(S)-Rg3 (50 MUg) on days 1 and 15. Two weeks after the last immunization, blood was sampled to test IgG and the IgG subclasses as well as IFN-gamma and IL-5; splenocytes were prepared to measure proliferative responses to stimulations with Con A, LPS and OVA and mRNA expressions of cytokines and transcription factors by reverse transcription-PCR. Results indicated that both 20(R)-Rg3 and 20(S)-Rg3 exhibited the adjuvant effect on OVA-induced immune responses. 20(R)-Rg3 promoted significantly higher serum-specific IgG and the IgG isotype responses in association with highly up-regulated serum IFN-gamma and IL-5 than 20(S)-Rg3. In addition, 20(R)-Rg3 significantly enhanced splenocyte proliferative responses to Con A, LPS and OVA as well as mRNA expression of IFN-gamma, IL-12, IL-4 and IL-10 and transcription factors T-bet and GATA-3 by splenocytes when compared with the 20(S)-Rg3. Therefore, ginsenoside Rg3 is stereospecific in stimulation of the immune response, and 20(R)-Rg3 has more potent adjuvant activity than 20(S)-Rg3. PMID- 22427455 TI - The impact of state behavioral health reform on Native American individuals, families, and communities. AB - In 2005, the State of New Mexico undertook a sweeping transformation of all publicly funded behavioral health services. The reform was intended to enhance the cultural responsiveness and appropriateness of these services. To examine achievement of this objective, we conducted a qualitative study of the involvement of Native Americans in reform efforts and the subsequent impacts of reform on services for Native Americans. We found that the reform was relatively unsuccessful at creating mechanisms for genuine community input or improving behavioral health care for this population. These shortcomings were related to limited understandings of administrators concerning how tribal governments and health care systems operate, and the structural limitations of a managed care system that does not allow flexibility for culturally appropriate utilization review, screening, or treatment. However, interaction between the State and tribes increased, and we conclude that aspects of the reform could be strengthened to achieve more meaningful involvement and service improvements. PMID- 22427456 TI - A metasynthesis of midwife-led care. AB - The purpose of this metasynthesis is to describe and interpret qualitative research relating to midwife-led care to see if it sheds light on why low-risk women experience fewer birth interventions within this model of care. Eleven articles were included in the review. Three themes emerged: (a) relationally mediated benefits for women that resulted in increased agency and empathic care; (b) the problematic interface of midwife-led units with host maternity units, stemming from a clash of models and culture; and (c) greater agency for midwives within midwife-led models of care though bounded by the relationship with the host maternity unit. This metasynthesis suggests that lower rates of interventions could be linked to the greater agency experienced by women and midwives within midwife-led models, and that these effects are mediated, in part, by the smallness of scale in these settings. PMID- 22427457 TI - Exploring the mutual constitution of racializing and medicalizing discourses of immigrant tuberculosis in the Canadian press. AB - Drawing on critical discourse analysis of Canadian press coverage of the immigrant tuberculosis problem, we expose the complex relationship between press constructed discourses of immigrant health and current tuberculosis control policies in Canada. The focus of these policies is on screening and surveillance of immigrants rather than addressing social inequalities underlying the problem of immigrant tuberculosis. The biomedical focus and racializing character of current policies were reinforced in the Canadian press by depicting tuberculosis as a biomedical (rather than a social) disease imported to Canada by immigrants. The status of the immigrant body as health threat was produced by and through preexisting and mutually constitutive racializing and medicalizing discourses materialized in press coverage and tuberculosis control policies. Deracialization and demedicalization of health information disseminated in the press are potentially important factors to be considered when revising health policies that would address the socioeconomic and political factors that determine the health status of Canadian immigrants. PMID- 22427458 TI - Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission is not that simple. PMID- 22427460 TI - Curculigoside isolated from Curculigo orchioides prevents hydrogen peroxide induced dysfunction and oxidative damage in calvarial osteoblasts. AB - Reactive oxygen species (ROS), including H(2)O(2), play a critical role in the pathophysiology of osteoporosis. Therefore, agents or antioxidants that can inhibit ROS production have a high clinical value in the treatment of osteoporosis. Curculigoside (CUR), one of the main bioactive phenolic compounds isolated from the rhizome of Curculigo orchioides Gaertn., is reported to have potent antioxidant and anti-osteoporotic properties. However, there is no direct evidence to link the antioxidant capacity of CUR with the observed anti osteoporotic effect, and relevant molecular mechanisms remain unclear. Therefore, we investigated the protective effects of CUR against oxidative stress in calvarial osteoblasts and discussed the related mechanisms. It was found that osteoblast viability decreased significantly after 48-h exposure to 400 MUM of H(2)O(2), compared with vehicle-treated cells, and the cytotoxic effect of H(2)O(2) was reversed significantly when pretreated with 0.1-10 MUM of CUR (P< 0.05). Pretreatment with 0.1-10 MUM of CUR decreased ROS production and lipid peroxidation, and increased the activities of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase in osteoblasts induced by H(2)O(2). In addition, H(2)O(2)-induced reduction of differentiation markers such as alkaline phosphatase, calcium deposition, and Runx2 level was significantly recovered in the presence of CUR. CUR also reversed H(2)O(2)-induced stimulation of extracellular signal-regulated kinase 1/2, and nuclear factor-kappaB signaling and the inhibition of p38 mitogen-activated protein kinase activation. These results provide new insights into the osteoblast-protective mechanisms of CUR through reducing the production of ROS, suggesting that CUR may be developed as a bio-safe agent for the prevention and treatment of osteoporosis and other bone related human diseases. PMID- 22427461 TI - Induction of apoptosis by casticin in cervical cancer cells: reactive oxygen species-dependent sustained activation of Jun N-terminal kinase. AB - Casticin, a polymethoxyflavone from Fructus viticis used as an anti-inflammatory agent in Chinese traditional medicine, has been reported to have anti-cancer activity. The purpose of this study was to examine the apoptotic activity of casticin on human cervical cancer cells and its molecular mechanism. We revealed a novel mechanism by which casticin-induced apoptosis occurs and showed for the first time that the apoptosis induced by casticin is mediated through generation of reactive oxygen species (ROS) and sustained activation of c-Jun N-terminal kinase (JNK) in HeLa cells. Casticin markedly increased the levels of intracellular ROS and induced the expression of phosphorylated JNK and c-Jun protein. Pre-treatment with N-acetylcysteine and SP600125 effectively attenuated induction of apoptosis by casticin in HeLa cells. Moreover, casticin induced ROS production and apoptotic cell death in other cervical cancer cell lines, such as CasKi and SiHa. Importantly, casticin did not cause generation of ROS or induction of apoptosis in normal human peripheral blood mononuclear cells and embryonic kidney epithelium 293 cells. These results suggest that ROS generation and sustained JNK activation by casticin play a role in casticin-induced apoptosis and raise the possibility that treatment with casticin might be promising as a new therapy against human cervical cancer. PMID- 22427462 TI - Cep70 promotes microtubule assembly in vitro by increasing microtubule elongation. AB - Microtubules are dynamic cytoskeletal polymers present in all eukaryotic cells. In animal cells, they are organized by the centrosome, the major microtubule organizing center. Many centrosomal proteins act coordinately to modulate microtubule assembly and organization. Our previous work has shown that Cep70, a novel centrosomal protein regulates microtubule assembly and organization in mammalian cells. However, the molecular details remain to be investigated. In this study, we investigated the molecular mechanism of how Cep70 regulates microtubule assembly using purified proteins. Our data showed that Cep70 increased the microtubule length without affecting the microtubule number in the purified system. These results demonstrate that Cep70 could directly regulate microtubule assembly by promoting microtubule elongation instead of microtubule nucleation. PMID- 22427463 TI - NRSF/REST is required for gastrulation and neurogenesis during zebrafish development. AB - Repressor element 1-silencing transcription factor (REST) was recognized as a transcription suppressor regulating nervous system differentiation. However, the role of REST during early development has not been clarified. We cloned the zebrafish homolog of human REST. Real-time polymerase chain reaction results showed that zebrafish REST mRNA was both maternal and zygotic with the higher expression level from blastula to the late segmentation period. Whole-mount in situ hybridization showed that REST was strongly expressed in the blastoderm since dome stage and dynamically expressed mainly in developing brain, especially in the border of the brain subdivisions in early segmentation period. Knockdown of REST using translation blocking morpholino (MO-tra) technique resulted in gastrulation delay or even blockage, and subsequently led to embryo lethality by early segmentation period with deficient neurogenesis. However, splicing blocking morpholino for REST did not show obviously abnormal phenotype until 48 hpf (hours post-fertilization), indicating that maternal REST was an important regulator for gastrulation. Further study revealed that the abnormal development in MO-tra morphants was at least partly due to the dysfunction of protein transportation from the yolk to the blastoderm. Our results showed that REST (especially maternal supplied REST) was required for gastrulation and neurogenesis during zebrafish early embryogenesis. PMID- 22427464 TI - A new method for quantifying the needling component of acupuncture treatments. AB - OBJECTIVES: The highly variable nature of acupuncture needling creates challenges to systematic research. The goal of this study was to test the feasibility of quantifying acupuncture needle manipulation using motion and force measurements. It was hypothesised that distinct needling styles and techniques would produce different needle motion and force patterns that could be quantified and differentiated from each other. METHODS: A new needling sensor tool (Acusensor) was used to record needling in real time as performed by six New England School of Acupuncture staff from the 'Chinese acupuncture' (style 1) and 'Japanese acupuncture' (style 2) programmes (three from each). Each faculty expert needled 12 points (6 bilateral locations) in 12 healthy human subjects using tonification (technique 1) and dispersal (technique 2). Parameters calculated from the raw needling data were displacement amplitude, displacement frequency, rotation amplitude, rotation frequency, force amplitude and torque amplitude. RESULTS: Data analysis revealed significant differences in the amplitude of displacement and rotation between needling performed by staff from two different acupuncture styles. Significant overall differences in the frequency of displacement between techniques 1 and 2 that were not dependent of the style of acupuncture being performed were also found. The relationships between displacement and rotation frequencies, as well as between displacement and force amplitudes showed considerable variability across individual acupuncturists and subjects. CONCLUSIONS: Needling motion and force parameters can be quantified in a treatment-like setting. Needling data can subsequently be analysed, providing an objective method for characterising needling in basic and clinical acupuncture research. PMID- 22427465 TI - [Personalized medicine in psychiatry -- an old concept from a new aspect]. PMID- 22427466 TI - [Changes in psychosocial symptoms of opiate users over six months with buprenorphine/naloxone substitution therapy]. AB - AIMS: The main target of our research was to measure the changes in psychological symptoms (anxiety, depression, craving) of patients receiving buprenorphine naloxone substitution treatment for six months, and the evaluation of the changes using the clients' dependency parameters (ASI). METHODS: The level of dependency was investigated using the Addicton Severity Index (ASI). The psychiatric symptoms related to Axis I and II disorders were examined using the Structured Clinical Interview for DSM-IV, SCID I and SCID II. The degree of craving was measured using the Heroin Craving Questionnaire, the assessment of the symptoms of depression using BDI and HAM-D, recorded by the medical attendant of the patient. To survey the extent of anxiety, we used STAI-S, and HAM-A. All patients receiving Suboxone therapy in Hungary between November 2007 and April 2008 were included in the study (n=80). During this time, Suboxone therapy was available in 6 locations. RESULTS: We found significant improvement in almost all observed fields of behavioural and symptomatic dimensions during the first month. The only exception was the dimension of subsistence/livelihood of ASI, the changes were only at the tendency level. During the next five months of therapy, there was no further sign of improvement or decline in the observed fields, the only exception was again the subsistence/livelihood dimension of the ASI. CONCLUSIONS: Our results indicate that buprenorphine/naloxone treatment is a promising possibility for patients in need of opiate-substitution treatment. PMID- 22427467 TI - [Achetylcholinesterase (AChE) inhibition and serum lipokines in Alzheimer's disease: friend or foe?]. AB - Throughout the natural progression of Alzheimer's disease (AD), the body mass index (BMI) decreases. This is believed to be brought on by the disturbance in the central lipid metabolism, but the exact mechanism is yet unknown. Adipokines (adiponectin, leptin), hormones produced by the adipose tissue, change glucose and lipid metabolism, and have an anorectic effect through increasing energy consumption in the hypothalamus. The goal of our study was to examine donepezil - an acetylcholinesterase inhibitor (AChEI) currently used in AD therapy -, and to what degree it influences the serum adipokine levels and metabolic parameters of AD patients. During the self-evaluation of 26 clinically diagnosed mild to moderate AD patients, therapy with 10 mg/day donepezil was started according to current protocols. We measured serum adiponectin, leptin, LDL, HDL, trigliceride levels, and BMI and ApoE polymorphism at the beginning of our study, and at 3 and 6-months intervals respectively. All data were analyzed with SPSS 17. In comparison with pre-donepezil therapy values, at the third month interval serum adiponectin levels showed an increasing and leptin levels a decreasing tendency. At the six month interval, adiponectin levels significantly increased (p=0.007), leptin levels decreased (p=0.013), BMI (p=0.001) and abdominal circumference (p=0.017) was significantly lower at 6 months as compared to control values. We did not observe any changes in the lipid profile, and ApoE4 allele carrying showed no association with the parameters. To our knowledge, we are the first to publish that AChEI therapy with donepezil alters lipokine levels, which positively influences the currently known pathomechanism and numerous risk factors of AD. The AChEI treatment-induced weight loss should be considered in the long-term therapy of AD patients. PMID- 22427468 TI - The "blue" side of glutamatergic neurotransmission: NMDA receptor antagonists as possible novel therapeutics for major depression. AB - In spite of the wide-ranging, continuously expanding arsenal of antidepressants and intensive research on depression, the treatment of severe, recurrent mood disorders as well as antidepressant-resistant refractory mood disturbances has not yet entirely been solved. In this article we attempt to review some data from the growing body of evidence that underlie the presumed implication of the glutamatergic neurotransmission in severe mood disorders and thereby some strategies allowing reinstatement of the normal functioning of the glutamatergic system, particularly through N-methyl-d-aspartate (NMDA) receptors. Thus, here we focus on one of the most promising ones, the NMDA receptor-modulating agents including competitive NMDA antagonists, glycine site partial antagonists and channel site antagonists: high- and low-affinity non-competitive NMDA receptor blockers. The glutamate-modulating therapies that specifically affect this system, above all low-affinity non-competitive NMDA receptor antagonists such as amantadine and its derivative memantine which are clinically well tolerated and currently used in other indications hold considerable promise for the development of new, improved antidepressants to treat severe, recurrent and refractory mood disorders. PMID- 22427469 TI - [Economic recession, unemployment and suicide]. AB - Considering the ongoing global economic crisis which began in 2007 it is reasonable to discuss its possible and expectable effects on mental health. In our narrative review we have summarized the scientific literature on the relationship between economic downturns, unemployment and suicide rate. In addition, we have summarized the theories about the background of this relationship as well. Suicide is an extremely complex phenomenon since it is influenced by several environmental and genetic factors. Furthermore, some of these factors are mutually interrelated, so the independent effect of these frequently remains elusive and hard to investigate from a methodological point of view. Although results are somewhat contradictory, it seems that unemployment is an independent risk factor for both suicide and depression. The first papers about the effect of the current economic crisis on suicide rates have been published and their results confirmed the association between the rise of unemployment rate and the increase of suicide rate in both old and new members of the European Union. Although psychiatric, and primarily depressive illness is a major risk factor for suicide, understanding the contributing role of other etiologic factors in their complex relationship may be an important task in predicting and preventing suicide both at the level of at risk individuals and the whole population. PMID- 22427470 TI - [Adulthood -- childhood -- adulthood: long-term therapy in child and adolescent psychiatry]. AB - The aggregation of psychiatric disorders within families is well-known. The relative role of biological, psychogenic and socialization-related factors varies with the individual case. Another well-known fact is that parents play a very important role in influencing whether their child gets the right treatment when it is necessary. In this paper we highlight the complex links between childhood and adulthood through the presentation of three psychiatric cases. The first story starts with a lactation psychosis of a mother and ends when the daughter who became psychotic at the age of 15 enters adulthood. During these 18 years several psychiatrically relevant episodes happened in the family. During our care, step by step, in relation to emerging psychological problems, the family revealed more and more secrets, explaining past events, and offering a possibility for psychoeducation and psychotherapy. Knowledge concerning the life and psychiatric history of parents, in spite of the fears of the family, largely contributed to evaluating the symptoms of the daughter, reaching a diagnosis, initiating and maintaining therapy and achieving the present balanced state. The next two cases present the stories of two boys with Attention Deficit/Hyperactivity Disorder (ADHD). One of the children was 6 years old when the family sought professional help, and now he is 11, the other child was 8 years old when the parents sought help and he is 15 now. The two families reacted differently to the offered treatment, but in both cases the family stayed continuously in touch with their child psychiatrists. With these two different stories on ADHD we would like to present several issues and successes which may surface during the long-term treatment of ADHD. PMID- 22427471 TI - CD40 and tolerance induction. AB - CD40 is recognized as a member of tumor necrosis factor receptor super family. It is expressed by the immune and non-immune cells. Its interaction with CD40 ligand (CD154) brings about a regulatory effect on the cellular and humoral immunity. The pathway of CD40-CD154 is influential in various diseases. Investigations on such diseases have revealed dimensional mechanisms whereby this route intensifies host protection. Moreover, through these mechanisms, pathogens subvert the signaling of the CD40, conditions in which the CD40-CD154 pathway promotes disease and also through the relevant modulation for immunotherapy. This review focuses on the role of CD40-CD40L (CD154) interactions in dendritic cells (DCs) regulation, tolerogenic dendritic cells, role of CD40 in autoimmune disease, allograft rejection and induction of tolerance by down regulation of CD40. According to these roles, it is assumed that CD40 is a functional molecule in the pathologies of conditions like autoimmune diseases and allograft rejection caused by activated T and B cells. PMID- 22427472 TI - The impact of HLA-E polymorphisms in graft-versus-host disease following HLA-E matched allogeneic hematopoietic stem cell transplantation. AB - The non-classical MHC class-I mainly involves in the regulation of innate immune responses where HLA-E plays a significant role in the cell identification by natural killer cells. HLA-E is a main regulatory ligand for natural killer cells and given the importance of these effector cells in hematopoietic stem cell transplantation, we investigated the effect of HLA-E polymorphisms on post hematopoietic stem cell transplantation outcomes. The study group included 56 donor-patient pairs with underlying malignant hematological disorders undergoing HLA-E matched allogeneic hematopoietic stem cell transplantation. They were genotyped for HLA-E locus using a sequence specific primer-polymerase chain reaction. The median follow-up was 20.6 months (range 0.2-114.8) and the parameters assessed were acute and chronic graft-versus-host disease and overall survival. We showed a lower frequency of acute graft-versus-host disease (grade II or more; p=0.02) and chronic graft-versus-host disease (extensive; p=0.04) in the patients with HLA-E*0103/0103 genotype compared to other genotypes of HLA-E. There was also an association between HLA-E*0103/0103 and improved overall survival (p=0.001). Conclusively, our results suggest a protective role for HLA E*0103/0103 genotype against acute graft-versus-host disease (grade II or more) and chronic graft-versus-host disease (extensive) as well as an association between this genotype and a better overall survival after HLA-E matched allogeneic hematopoietic stem cell transplantation. PMID- 22427473 TI - Evaluation of factors contributed in nonadherence to medication therapy in children asthma. AB - Asthma is one of the most common chronic inflammatory disorders in children. Nonadherence to medical therapy is a major cause of poor clinical outcome the objective of this study was evaluating factors, which are resulted in nonadherence to medical therapy in children with asthma.In this descriptive study, 150 children with asthma and nonadherent to medication therapy were enrolled. General information and probable causes of nonadherence were recorded in self-report questionnaire and data were analyzed. In our study, 57.3% of children were male. Approximately 43%of children belonged to age group 6-9 years old. Prevalence of probable causes of nonadherence to treatment were concern about treatment expenses(34.7%) ,fear of cardiac complications(34.7%), concern about drug dependency(38.7%), belief to growth inhibition(30.7%) and fear of osteopenia (32%). There was statistically significant reverse association between treatment with multi-drug regimens and concern about bone mineral abnormalities, cardiac complications and drug dependency (p=0.0001, 0.014 and 0.012 respectively). In addition, there was a significant association between mild asthma and fear about drug dependency (p=0.001).According to our results, factors such as prolonged duration of treatment, various therapeutic regimens, and receiving multiple drugs before diagnosis of asthma pose the highest frequencies for nonadherence. PMID- 22427474 TI - Cow's milk anaphylaxis in children first report of Iranian Food Allergy Registry. AB - Cow's milk anaphylaxis is the most common food-induced anaphylaxis in Iranian children. The clinical and laboratory findings of cow's milk anaphylaxis are evaluated in this study. All children who had experienced cow's milk anaphylaxis and had been referred to Immunology, asthma and allergy research center during a 5-year period were considered. After fulfilling a questionnaire, patients underwent measurement of total IgE and cow's milk-specific IgE by Immunocap test and Skin prick test (SPT) with cow's milk extract. Patients with a convincing history and one positive cow's milk-specific IgE test (SPT or Immunocap test) and patients with both positive tests were enrolled, in this study.Out of 49 patients, 59.2% were male. Patients' mean age was 5 years old and their mean age at the time of first attack was 5.7 months (SD = 4.3). Most of the patients have experienced more than one episode of anaphylaxis (79.5%) and in 85.7% of all cases, first attack occurred during the first year of life. Severity grading 1-5 were 2%, 6.1%, 18.4%, 69.4%, 4.1% respectively. Most common manifestations were cutaneous 98%, Respiratory 91.8%, Gastrointestinal 55.1%, Cardiovascular 46.9% and neurologic 46.9% signs and symptoms respectively. Twenty four patients showed positive SPT. Mean total IgE was 239.6+/-3.3 (IU/mL) and mean cow's milk-specific IgE was 19.28+/-27.2 (IU/mL). Most patients showed reactions only after ingestion of cow's milk or after dairy foods (81.6%).It is concluded that cow's milk anaphylaxis may happen early in life. Regarding the severity of attacks and remarkable number of patients with several attacks, poor knowledge about this disorder is evident. PMID- 22427475 TI - Gene polymorphisms of 22 cytokines in Macedonian children with atopic dermatitis. AB - Atopic dermatitis (AD) is a common chronically relapsing skin disease associated with abnormal cytokine production, and activation of T-helper 2 cells. The aim if this study was to determine whether cytokine gene polymorphisms might influence the development of AD. Single nucleotide polymorphisms in the genes for I L1alpha, IL-1beta, IL-1R, IL-2, IL-4, IL-6, IL-10, IL-12, TGF beta, TNF and IFNgamma were investigated by PCR and sequence specific primers in Macedonian patients with AD (67 children, age of 6 months to 5 years) and 301 normal unrelated individuals. Susceptible cytokine polymorphisms for AD for eleven genotypes (IL-4 -33/T:T IL-4 -1098/G:G, TGFbeta cdn25C:G, IL-4 -1098/T:T, IL 1alpha -889/C:T, IL-2 +166/T:T, IL-1beta -511/C:T, IL-12 -1188/C:T, IL-10 1082/A:G, IL-1beta +3962/C:T, IFNgamma +874/A:T), five diplotypes, six haplotypes, and for alleles were found. Protective cytokine polymorphisms for AD for seven cytokine genotypes (IL-4 -1098/G:T, TGFbeta cdn25/G:G, IL-4 -33/C:C, IL 1alpha -889/C:C, IFNgamma +874/A:A, IL-10 -1082/A:A, IL-1beta -511/C:C), one cytokine diplotypes, two cytokine haplotypes, and four cytokine alleles were also found. We concluded that several cytokine polymorphisms are protective, or susceptible associated with AD in population of Macedonians. PMID- 22427476 TI - Prevention and control of infections in patients with severe congenital neutropenia; a follow up study. AB - Severe congenital neutropenia is one of primary immunodeficiency disorders that characterized by severe neutropenia and is associated with severe systemic bacterial infections from early infancy. Granulocyte colony stimulating factor (GCSF) is clinically used as a treatment for congenital and acquired neutropenia. The aim of this study was evaluation of GCSF (PD- Grastim) in treatment of these patients. Patients with severe congenital neutropenia referred to Immunology, Asthma and Allergy Research Institute between Jan 2007 and Dec 2010 enrolled the study. Other causes of neutropenia were excluded by serial CBC and bone marrow studies, medical and drug histories and immunological tests. Patients were visited and examined monthly to evaluate their CBC and ANC (absolute neutrophil count), GCSF side effects and dosage adjustment. Cytogenetic studies were being done for all the patients for early detection of progression to AML/MDS. From twenty two patients who enrolled this study, 16 patients regularly evaluated. They were ten males and six females, range in age from 2 to 18 years old. Two patients failed to continue our follow up unfortunately and four patients died due to disease complications. Patients were followed for 24 to 48 months. In a period of 12-24 months before treatment, the mean of hospitalization frequency was 3.1 times and duration was 10 days; while during receiving treatment, they decreased to 0.2 times and 3 days, respectively (p<0.01). Also significant increase in mean ANC was observed during follow up (315/ul before treatment versus 1749/ul after 12 month regular treatment). Bone pain was the most common side effect. There have been no evidences of developing AML/MDS up to present time. Treatment with GCSF significantly reduced the duration and the frequency of hospitalization. Because of plausible progression to AML/MDS, regular follow-up of patients should be continued. PMID- 22427477 TI - Physicians awareness on primary immunodeficiency disorders in Iran. AB - Primary immunodeficiency diseases (PIDs) consist of a group of genetic disorders that predispose the patients to immune-mediated complications. The aim of this study was to assess the knowledge of Iranian general practitioners and pediatricians about PIDs.A questionnaire consisting 52 closed questions on clinical symptoms, laboratory data, associated syndromes and management of PIDs patients was made valid and reliable by a pair pilot study. Then the questionnaire was filled by pediatricians, general practitioners and pediatric residents from different regions of Iran. Totally, 333 physicians (50 general practitioners, 52 pediatric residents, 182 pediatric specialists, and 49 pediatric sub specialists) participated in this study. The mean total score was 55.9+/-14.3 (i.e. about 29 correct answers out of 52 questions). One hundred and five participants (31.9%) answered correctly more than two third of all questions. In order to qualitatively compare the groups a ranking system was used. Total scores was significantly different between physicians groups (p<0.01). Pediatric subspecialties gained the highest rank, which was significantly over the other participants (p<0.05). This study showed that there is a considerable lack of awareness on PIDs in physicians. This may be one of the major reasons in late diagnosis and the delay in adequate treatment deteriorating patients' morbidity and mortality. Retraining classes and reconsidered educating schedules are needed as an efficient strategies and improving physicians' knowledge about PIDs. PMID- 22427478 TI - Evaluation of psychological status in patients with asthma and COPD. AB - Chronic obstructive pulmonary disease (COPD) and asthma are major public health problems, which seems to have close association with psychiatric disorders. The present study was conducted to compare the psychological status between asthmatic and COPD patients and clarify the relationship with severity of pulmonary obstruction. This cross-sectional study was planned to compare the psychological status in 67 stable obstructive lung patients (17 asthma, 24 asthmatic bronchitis and 26 COPD) referred to respiratory clinic of Ghaem hospital and 33 healthy controls, in Mashhad city, north east of Iran. Severity of pulmonary obstruction was determined based on GOLD criteria. "Beck Depression Inventory", "Hamilton Anxiety Rating Scale" and "SCL-90-R" questionnaires were used to determine the psychological status. Prevalence of general psychopathology in asthma, COPD, asthmatic bronchitis and control groups were 64.7%, 42.3%, 33.3% and 36.4% respectively. Psychological status was directly related to severity of pulmonary obstruction (p=0.048), Prevalence of depression in asthmatic, COPD and asthmatic bronchitis groups were 66.7%, 54.2% and 44.4% respectively. Depression score was related to severity of pulmonary obstruction (p=0.000).Prevalence of anxiety in asthma, COPD and asthmatic bronchitis were 46.7%, 45.8% and 40.7% respectively. Anxiety score was related to marital status and satisfaction with income Asthmatic and COPD patients are at equal risk of developing psychiatric disorders and both require psychological evaluations in respiratory clinics. Therapists must pay more attention to patients with severe pulmonary disease. PMID- 22427479 TI - The atopic march: from skin to the airways. AB - Many patients with atopic eczema (AE) would "march" to develop allergic rhinitis (AR) and asthma. Physicians, patients and their families often do not appreciate the significance of these diseases as co-morbidities of atopy.The aim of this study was to evaluate the prevalence and severity of airway atopies in patients with AE. AR and asthma severity were assessed in consecutive AE patients seen at a pediatric dermatology clinic by ARS (allergic rhinitis score) and ACT (asthma control test). Eczema severity (SCORAD and Nottingham Eczema Severity Score: NESS) were recorded.110 patients with AE and 42 patients without AE were recruited. Allergic rhinitis and asthma were significantly more prevalent in patients with AE [odds ratio for AR was 2.9 (CI: 1.3 - 6.5) and for asthma 4.3 (CI: 1.3 - 16.10)]. 23 (45%) of the AE patients with AR reported that they were currently on oral antihistamine whereas none of the non-AE group reported such usage. Both groups reported relatively higher sneezing and nasal congestion scores and low "eye watering" score. Comparing mild with moderate-to-severe AE, there was essentially no difference between the prevalence of allergic rhinitis and asthma, or severity of symptoms by ARS and ACT, but females reported more severe symptoms of sneezing and itching nose.We conclude that allergic disorders of airway are very common among AE patients independent of the eczema severity. Most of the patients have mild-to-moderate AR and asthma. There is a lot of room for parent/patient education, and childhood eczema may prompt early awareness of these airway co-morbidities of atopy. PMID- 22427480 TI - Pneumomediastinum is a possible acute complication of severe occupational asthma. AB - Occupational asthma has been reported to be the most common chronic respiratory occupational disease in many developed countries, and as with other occupational lung diseases, occupational asthma is potentially preventable. We report the case of a 24-year-old baker who experienced pneumomediastinum as a consequence of workplace exposure. This is the first report of pneumomediastinum as an acute complication of occupational asthma, and it exemplarily shows that the lack of medical surveillance at the workplace may lead to an acute, although unusual, complication. PMID- 22427481 TI - Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor. AB - BACKGROUND: The addition of direct-acting antivirals to pegylated interferon alpha plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease. METHODS: This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8). RESULTS: In total, 48 HV and 40 HCV infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group. CONCLUSIONS: Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1 infected patients. PMID- 22427482 TI - Crosslinked electrospun PVA nanofibrous membranes: elucidation of their physicochemical, physicomechanical and molecular disposition. AB - The effects of modifying electrospun poly(vinyl alcohol) (PVA) nanofibers through crosslinking using glutaraldehyde (GA) are explored in this paper. Various concentrations of PVA solutions containing model drugs rifampicin (RIF) and isoniazid (INH) were electrospun and thereafter crosslinked using GA vapors. PVA nanofibers demonstrated high drug entrapment efficiency of 98.77% +/- 1.384% and 95.07% +/- 1.988% for the INH- and RIF-loaded PVA nanofibers, respectively. The surface morphology, molecular vibrational transitions, tensile attributes and in vitro drug release were characterized and supported by in silico molecular mechanics simulations. Results indicated that crosslinking caused a significant reduction in the rate of drug release where 81.11% +/- 2.35% of INH and 59.31% +/ 2.57% of RIF were released after 12 h. Tensile properties such as the ultimate strength and Young's modulus increased after crosslinking, caused by crosslinks forming between PVA nanofibers as was revealed through scanning electron microscopy analysis. Fourier Transform infrared analysis was conducted to further support the mode of crosslinking. Additionally, image processing analysis was carried out to quantify the effect of formulation variables on the morphology of nanofibers. Furthermore, the effect of GA-induced crosslinking and addition of drugs on the performance of electrospun fibers was further elucidated and conceptualized using a molecular mechanics assisted model building and energy refinement approach via molecular mechanics energy relationships by exploring the spatial disposition of energy-minimized molecular structures of the polymer, crosslinker and the drugs. PMID- 22427483 TI - An analysis of fingerprint ridge density in the Indo-Mauritian population and its application to gender determination. AB - Gender determination is an important aspect of personal identification, which is often required in medicolegal practice. Many experts believe that there are finer and more epidermal ridges on the fingers of women as compared with men. However, it is important to establish numerical cut-off values in terms of ridge counts to facilitate the gender determination within a particular population. The present study was conducted in the Department of Forensic Medicine, SSR Medical College, Mauritius with the objective to describe the ridge density in the Indo-Mauritian population and to devise a numerical model which is capable of identifying the sex of an individual from this population on the basis of the ridge counts obtained from the corresponding finger prints. The study was focused on 200 healthy medical students (100 men and 100 women) within the age range of 20-30 years. Multivariate analysis of variance results shows a significant gender difference in the sense that women tend to have higher ridge density then men in the distal region of all 10 digits (F = 41.83, P <= 0.005). The maximum mean ridge density over all fingers in men (12.26~12) is less than the minimum mean ridge density over all fingers in women (12.71~13). A linear discriminant function is derived from numerical modelling, which is used to predict (with a high reliability index, 0.92) the sex of the person whose fingerprints are obtained. PMID- 22427484 TI - Determination of sex from an autopsy sample of adult hyoid bones. AB - Determination of sex is the first and crucial step in the process of identifying human remains in forensic casework. Sex determination from skeletal remains is well studied and an extensively documented subject. The hyoid bone, however, has drawn less attention in studies of this nature. The present study was designed to derive a model for the determination of sex from the adult hyoid in a sample of the Indian Bengali population using discriminant function analysis on 50 adult bones (38 men and 12 women). The following discriminant function was obtained: DF = 0.103W + 0.118AP + 0.130CR + 0.483AW + 0.117DR - 20.64. Overall, 90% of the cases could be correctly classified into the two sexes by means of five predictors (overall width, length of the greater cornu, anteroposterior length, width of the body of hyoid and the distance between the lesser cornua) in the model. Cross-validated results showed correct classification in 90% of the cases. The results of this preliminary study show that these variables contribute to discrimination between the two sexes in the study population. Sexing of the adult human hyoid bone is thus possible with reasonable accuracy using the discriminant function on a sample obtained from the same population. PMID- 22427485 TI - Rapid-prototyped PLGA/beta-TCP/hydroxyapatite nanocomposite scaffolds in a rabbit femoral defect model. AB - Bone tissue engineering scaffolds composed of poly(d,l-lactide:glycolide) (DL PLGA) and beta-tricalcium phosphate (beta-TCP) nanocomposites were prepared and characterized. Scaffolds with two specific architectures were produced via fused deposition modeling (FDM), a type of extrusion freeform fabrication. Microfilaments deposited at angles of 0 degrees and 90 degrees were designated as the 'simple' scaffold architecture, while those deposited at angles alternating between 0 degrees , 90 degrees , 45 degrees and -45 degrees were designated as the 'complex' scaffold architecture. In addition, the simple and complex scaffolds were coated with hydroxyapatite (HA). The surface morphology of the scaffolds was assessed before and after HA coating and uniform distribution of HA coating on the surface was observed by scanning electron microscopy. The scaffolds were implanted into rabbit femoral unicortical bone defects according to four treatment groups based on pore structure and HA coating. After 6 and 12 weeks, scaffolds and host bone were recovered and processed for histology. Data suggest that all configurations of the scaffolds integrated with the host bone and were biocompatible and thus may offer an exciting new scaffold platform for delivery of biologicals for bone regeneration. PMID- 22427486 TI - Spectrophotometric assessment of salivary beta-galactosidases in halitosis. AB - The aim of this work was to develop a spectrophotometric method for the measurement of salivary beta-galactosidase for the evaluation of oral malodor. A comparison between different methods for estimating oral malodor has been conducted on 94 healthy adult volunteers. For organoleptic measurements, the subjects were instructed to exhale briefly through the mouth at a distance of approximately 10 cm from the noses of two trained judges. The evaluation of beta galactosidase activity was accomplished in unstimulated whole saliva of all participants through the colorimetric method and spectrophotometry. A significant association among spectrophotometric evaluation of beta-galactosidase and organoleptic measurements was assessed by Spearman correlations. Although colorimetric and spectrophotometric assessments of beta-galactosidases were estimated to have the same sensitivity, the last method is characterized by a higher specificity. The results suggest that the use of the UV-vis spectrophotometer increases the specificity of the evaluation of salivary beta galactosidases. PMID- 22427487 TI - Decline of exhaled isoprene in lung cancer patients correlates with immune activation. AB - Isoprene (2-methylbuta-1,3-diene) represents a precursor molecule of isoprenoids (steroids, terpens), and available data suggest that isoprene is related to cholesterol biosynthesis. Breath concentrations of isoprene have been reported to be altered in a number of clinical conditions. However, the physiological meaning of isoprene changes has not yet been established. Utilizing proton-transfer-mass spectroscopy, we analyzed isoprene concentrations (m/z 69, tentatively identified as isoprene) in breath samples in Tedlar bags collected from 79 lung cancer patients (23 females, 56 males). Results were compared to the concentrations of immune activation marker neopterin (ELISA, BRAHMS, Hennigsdorf, Germany), lipid parameters (routine enzymology) and C-reactive protein (CRP). Isoprene concentrations were median 92.5 ppb (25th-75th percentile: 79-131 ppb). There was no relationship with staging, grading or age, but isoprene concentrations correlated significantly with total cholesterol (rs = 0.281, p < 0.01) and LDL cholesterol (rs = 0.236, p < 0.05). There was no significant relationship between exhaled isoprene concentrations and HDL cholesterol (rs = 0.048), triglycerides (rs = 0.164) and CRP (rs = -0.115; all not significant). A significant inverse correlation existed between isoprene and neopterin concentrations (rs = -0.215, p < 0.05); the latter also correlated with total cholesterol (rs = -0.343, p = 0.001), HDL cholesterol (rs = -0.273, p = 0.01), LDL cholesterol (rs = -0.236, p < 0.05) and CRP (rs = 0.230, p < 0.05) but not with triglycerides (rs = 0.035, not significant). Results suggest that immune activation might play a role in the decline of isoprene which is probably related to lipid metabolic changes. Interestingly, similar relationships between elevated neopterin and decreased lipid concentrations have been reported earlier in other clinical conditions, e.g. in patients with HIV-1 infection. PMID- 22427488 TI - A recurrent neural network for closed-loop intracortical brain-machine interface decoders. AB - Recurrent neural networks (RNNs) are useful tools for learning nonlinear relationships in time series data with complex temporal dependences. In this paper, we explore the ability of a simplified type of RNN, one with limited modifications to the internal weights called an echostate network (ESN), to effectively and continuously decode monkey reaches during a standard center-out reach task using a cortical brain-machine interface (BMI) in a closed loop. We demonstrate that the RNN, an ESN implementation termed a FORCE decoder (from first order reduced and controlled error learning), learns the task quickly and significantly outperforms the current state-of-the-art method, the velocity Kalman filter (VKF), using the measure of target acquire time. We also demonstrate that the FORCE decoder generalizes to a more difficult task by successfully operating the BMI in a randomized point-to-point task. The FORCE decoder is also robust as measured by the success rate over extended sessions. Finally, we show that decoded cursor dynamics are more like naturalistic hand movements than those of the VKF. Taken together, these results suggest that RNNs in general, and the FORCE decoder in particular, are powerful tools for BMI decoder applications. PMID- 22427489 TI - Partner notification uptake for sexually transmitted infections in China: a systematic literature review. AB - OBJECTIVE: China's sexually transmitted infection (STI) epidemic requires comprehensive control programmes. Partner services are traditional pillars of STI control but have not been widely implemented in China. This study was a systematic literature review to examine STI partner notification (PN) uptake in China. METHODS: Four English and four Chinese language databases were searched up to March 2011 to identify articles on PN of STIs including HIV in China. PN uptake was defined as the number of partners named, notified, evaluated or diagnosed per index patient. RESULTS: A total of 11 studies met inclusion criteria. For STI (excluding HIV) PN, a median 31.6% (IQR 27.4%-65.8%) of named partners were notified, 88.8% (IQR 88.4%-90.8%) of notified partners were evaluated and 37.9% (IQR 33.1%-43.6%) of evaluated partners were diagnosed. For HIV PN, a median 15.7% (IQR 13.2%-36.5%) of named partners were notified, 86.7% (IQR 72.9%-90.4%) of notified partners were evaluated and 27.6% (IQR 24.1%-27.7%) of evaluated partners were diagnosed. A mean of 80.6% (SD=12.6%) of patients attempted PN, and 72.4% (IQR 63.8%-81.1%) chose self-referral when offered more than one method of PN. Perceived patient barriers included social stigma, fear of relationship breakdown, uncertainty of how to notify and lack of partner contact information. Perceived infrastructure barriers included limited time and trained staff, mistrust of health workers and lack of PN guidelines. CONCLUSION: PN programmes are feasible in China. Further research on STI PN, particularly among men who have sex with men and other high-risk groups, is an important public health priority. PN policies and guidelines are urgently needed in China. PMID- 22427490 TI - Peripheral arterial disease is prevalent but underdiagnosed and undertreated in the primary care setting in central Greece. AB - We investigated the prevalence of peripheral arterial disease (PAD). Primary Care Health Centers (n = 14) in Thessaly (central Greece) recruited 436 participants, mean age 71 (50-79) years. Peripheral arterial disease was considered present if the ankle-brachial index (ABI) was <0.9 or >1.4 in at least 1 leg. Asymptomatic PAD was defined as an abnormal ABI and no symptoms or history of limb revascularization. The prevalence of PAD was 13% (mostly asymptomatic, 11.7%). Only 5 (8.77%) of 57 patients with PAD were aware of their disease and only in these patients were the physicians aware of the presence of PAD. The risk factors associated with PAD were age, smoking, and the combination of diabetes mellitus and coronary artery disease. All symptomatic patients were on antiplatelet therapy but 33% did not take statins. For asymptomatic patients, 74.5% were not on antiplatelet therapy and 57% did not receive statins. In the primary health care setting, PAD is underdiagnosed and undertreated. PMID- 22427491 TI - Development of an engineered bioluminescent reporter phage for detection of bacterial blight of crucifers. AB - Bacterial blight, caused by the phytopathogen Pseudomonas cannabina pv. alisalensis, is an emerging disease afflicting important members of the Brassicaceae family. The disease is often misdiagnosed as pepper spot, a much less severe disease caused by the related pathogen Pseudomonas syringae pv. maculicola. We have developed a phage-based diagnostic that can both identify and detect the causative agent of bacterial blight and differentiate the two pathogens. A recombinant "light"-tagged reporter phage was generated by integrating bacterial luxAB genes encoding luciferase into the genome of P. cannabina pv. alisalensis phage PBSPCA1. The PBSPCA1::luxAB reporter phage is viable and stable and retains properties similar to those of the wild-type phage. PBSPCA1::luxAB rapidly and sensitively detects P. cannabina pv. alisalensis by conferring a bioluminescent signal response to cultured cells. Detection is dependent on cell viability. Other bacterial pathogens of Brassica species such as P. syringae pv. maculicola, Pseudomonas marginalis, Pectobacterium carotovorum, Xanthomonas campestris pv. campestris, and X. campestris pv. raphani either do not produce a response or produce significantly attenuated signals with the reporter phage. Importantly, the reporter phage detects P. cannabina pv. alisalensis on diseased plant specimens, indicating its potential for disease diagnosis. PMID- 22427492 TI - Natural product biosynthetic gene diversity in geographically distinct soil microbiomes. AB - The number of bacterial species estimated to exist on Earth has increased dramatically in recent years. This newly recognized species diversity has raised the possibility that bacterial natural product biosynthetic diversity has also been significantly underestimated by previous culture-based studies. Here, we compare 454-pyrosequenced nonribosomal peptide adenylation domain, type I polyketide ketosynthase domain, and type II polyketide ketosynthase alpha gene fragments amplified from cosmid libraries constructed using DNA isolated from three different arid soils. While 16S rRNA gene sequence analysis indicates these cloned metagenomes contain DNA from similar distributions of major bacterial phyla, we found that they contain almost completely distinct collections of secondary metabolite biosynthetic gene sequences. When grouped at 85% identity, only 1.5% of the adenylation domain, 1.2% of the ketosynthase, and 9.3% of the ketosynthase alpha sequence clusters contained sequences from all three metagenomes. Although there is unlikely to be a simple correlation between biosynthetic gene sequence diversity and the diversity of metabolites encoded by the gene clusters in which these genes reside, our analysis further suggests that sequences in one soil metagenome are so distantly related to sequences in another metagenome that they are, in many cases, likely to arise from functionally distinct gene clusters. The marked differences observed among collections of biosynthetic genes found in even ecologically similar environments suggest that prokaryotic natural product biosynthesis diversity is, like bacterial species diversity, potentially much larger than appreciated from culture-based studies. PMID- 22427493 TI - Impact of nutritional factors on the proteome of intestinal Escherichia coli: induction of OxyR-dependent proteins AhpF and Dps by a lactose-rich diet. AB - To study the impact of nutritional factors on protein expression of intestinal bacteria, gnotobiotic mice monoassociated with Escherichia coli K-12 were fed three different diets: a diet rich in starch, a diet rich in nondigestible lactose, and a diet rich in casein. Two-dimensional gel electrophoresis and electrospray-tandem mass spectrometry were used to identify differentially expressed proteins of bacteria recovered from small intestine and cecum. Oxidative stress response proteins such as AhpF, Dps, and Fur, all of which belong to the oxyR regulon, were upregulated in E. coli isolates from mice fed the lactose-rich diet. Luciferase reporter gene assays demonstrated that osmotic stress caused by carbohydrates led to the expression of ahpCF and dps, which was not observed in an E. coli DeltaoxyR mutant. Growth of ahpCF and oxyR deletion mutants was strongly impaired when nondigestible sucrose was present in the medium. The wild-type phenotype could be restored by complementation of the deletions with plasmids containing the corresponding genes and promoters. The results indicate that some OxyR-dependent proteins play a major role in the adaptation of E. coli to osmotic stress. We conclude that there is an overlap of osmotic and oxidative stress responses. Mice fed the lactose-rich diet possibly had a higher intestinal osmolality, leading to the upregulation of OxyR-dependent proteins, which enable intestinal E. coli to better cope with diet-induced osmotic stress. PMID- 22427494 TI - Genomic sequence of bacteriophage ATCC 8074-B1 and activity of its endolysin and engineered variants against Clostridium sporogenes. AB - Lytic bacteriophage ATCC 8074-B1 produces large plaques on its host Clostridium sporogenes. Sequencing of the 47,595-bp genome allowed the identification of 82 putative open reading frames, including those encoding proteins for head and tail morphogenesis and lysis. However, sequences commonly associated with lysogeny were absent. ORF 22 encodes an endolysin, CS74L, that shows homology to N acetylmuramoyl-L-alanine amidases, and when expressed in Escherichia coli, the protein causes effective lysis of C. sporogenes cells when added externally. CS74L was also active on Clostridium tyrobutyricum and Clostridium acetobutylicum. The catalytic domain expressed alone (CS74L(1-177)) exhibited a similar activity and the same host range as the full-length endolysin. A chimeric endolysin consisting of the CS74L catalytic domain fused to the C-terminal domain of endolysin CD27L, derived from Clostridium difficile bacteriophage PhiCD27, was produced. This chimera (CSCD) lysed C. sporogenes cells with an activity equivalent to that of the catalytic domain alone. In contrast, the CD27L C terminal domain reduced the efficacy of the CS74L catalytic domain when tested against C. tyrobutyricum. The addition of the CD27L C-terminal domain did not enable the lysin to target C. difficile or other CD27L-sensitive bacteria. PMID- 22427495 TI - Key enzymes enabling the growth of Arthrobacter sp. strain JBH1 with nitroglycerin as the sole source of carbon and nitrogen. AB - Flavoprotein reductases that catalyze the transformation of nitroglycerin (NG) to dinitro- or mononitroglycerols enable bacteria containing such enzymes to use NG as the nitrogen source. The inability to use the resulting mononitroglycerols limits most strains to incomplete denitration of NG. Recently, Arthrobacter strain JBH1 was isolated for the ability to grow on NG as the sole source of carbon and nitrogen, but the enzymes and mechanisms involved were not established. Here, the enzymes that enable the Arthrobacter strain to incorporate NG into a productive pathway were identified. Enzyme assays indicated that the transformation of nitroglycerin to mononitroglycerol is NADPH dependent and that the subsequent transformation of mononitroglycerol is ATP dependent. Cloning and heterologous expression revealed that a flavoprotein catalyzes selective denitration of NG to 1-mononitroglycerol (1-MNG) and that 1-MNG is transformed to 1-nitro-3-phosphoglycerol by a glycerol kinase homolog. Phosphorylation of the nitroester intermediate enables the subsequent denitration of 1-MNG in a productive pathway that supports the growth of the isolate and mineralization of NG. PMID- 22427496 TI - Markerless gene deletion system for sphingomonads. AB - Here, we suggest that natural streptomycin resistance of many sphingomonads resides within rpsL. We constructed a dominant, streptomycin-sensitive rpsL allele and demonstrated its use as a counterselection marker in several sphingomonads. An rpsL-based markerless gene deletion system was developed and validated by deleting four genes in Sphingomonas sp. strain Fr1. PMID- 22427497 TI - Metagenomic analysis of Streptomyces lividans reveals host-dependent functional expression. AB - Most functional metagenomic studies have been limited by the poor expression of many genes derived from metagenomic DNA in Escherichia coli, which has been the predominant surrogate host to date. To expand the range of expressed genes, we developed tools for construction and functional screening of metagenomic libraries in Streptomyces lividans. We expanded on previously published protocols by constructing a system that enables retrieval and characterization of the metagenomic DNA from biologically active clones. To test the functionality of these methods, we constructed and screened two metagenomic libraries in S. lividans. One was constructed with pooled DNA from 14 bacterial isolates cultured from Alaskan soil and the second with DNA directly extracted from the same soil. Functional screening of these libraries identified numerous clones with hemolytic activity, one clone that produces melanin by a previously unknown mechanism, and one that induces the overproduction of a secondary metabolite native to S. lividans. All bioactive clones were functional in S. lividans but not in E. coli, demonstrating the advantages of screening metagenomic libraries in more than one host. PMID- 22427498 TI - Remarkable ability of Pandoraea pnomenusa B356 biphenyl dioxygenase to metabolize simple flavonoids. AB - Many investigations have provided evidence that plant secondary metabolites, especially flavonoids, may serve as signal molecules to trigger the abilities of bacteria to degrade chlorobiphenyls in soil. However, the bases for this interaction are largely unknown. In this work, we found that BphAE(B356), the biphenyl/chlorobiphenyl dioxygenase from Pandoraea pnomenusa B356, is significantly better fitted to metabolize flavone, isoflavone, and flavanone than BphAE(LB400) from Burkholderia xenovorans LB400. Unlike those of BphAE(LB400), the kinetic parameters of BphAE(B356) toward these flavonoids were in the same range as for biphenyl. In addition, remarkably, the biphenyl catabolic pathway of strain B356 was strongly induced by isoflavone, whereas none of the three flavonoids induced the catabolic pathway of strain LB400. Docking experiments that replaced biphenyl in the biphenyl-bound form of the enzymes with flavone, isoflavone, or flavanone showed that the superior ability of BphAE(B356) over BphAE(LB400) is principally attributable to the replacement of Phe336 of BphAE(LB400) by Ile334 and of Thr335 of BphAE(LB400) by Gly333 of BphAE(B356). However, biochemical and structural comparison of BphAE(B356) with BphAE(p4), a mutant of BphAE(LB400) which was obtained in a previous work by the double substitution Phe336Met Thr335Ala of BphAE(LB400), provided evidence that other residues or structural features of BphAE(B356) whose precise identification the docking experiment did not allow are also responsible for the superior catalytic abilities of BphAE(B356). Together, these data provide supporting evidence that the biphenyl catabolic pathways have evolved divergently among proteobacteria, where some of them may serve ecological functions related to the metabolism of plant secondary metabolites in soil. PMID- 22427499 TI - Detection of human food-borne and zoonotic viruses on irrigated, field-grown strawberries. AB - This study evaluated the presence of pathogenic human and zoonotic viruses on irrigated, field-grown strawberries. Norovirus genogroup I, rotavirus, and swine hepatitis E virus genogroup 3 were detected on strawberries, and irrigation water is suspected as the contamination origin. PMID- 22427501 TI - Quantitative fluorescence in situ hybridization analysis of microbial consortia from a biogenic gas field in Alaska's Cook Inlet basin. AB - Filter-collected production water samples from a methane-rich gas field in the Cook Inlet basin of Alaska were investigated using whole-cell rRNA-targeted fluorescence in situ hybridization (FISH) and 16S rRNA tag pyrosequencing. Both techniques were consistent in determining the microbial community composition, including the archaeal or bacterial dominance of samples. The archaeal community is dominated by the obligate methylotrophic methanogen genus Methanolobus as well as the nutritional generalist methanogen genus Methanosarcina, which is capable of utilizing acetate, CO(2), and methyl-bearing compounds. The most-abundant bacterial groups are Firmicutes, notably of the Acetobacterium genus, and Cytophaga-Flexibacter-Bacteroides species (CFBs) affiliated with the order Bacteroidales. We observed spatial variation among samples in both the percentage of members of Archaea compared to that of members of Bacteria and the dominant members of the bacterial community, differences which could not be explained with the available geochemical data. Based upon the microbial community composition and the isotopic signature of methane associated with the Cook Inlet basin site, we propose a simplified reaction network beginning with the breakdown of coal macromolecules, followed by fermentation and methylotrophic and acetoclastic methane production. PMID- 22427500 TI - Heterologous expression of polycyclic aromatic hydrocarbon ring-hydroxylating dioxygenase genes from a novel pyrene-degrading betaproteobacterium. AB - A betaproteobacterium within the family Rhodocyclaceae previously identified as a pyrene degrader via stable-isotope probing (SIP) of contaminated soil (designated pyrene group 1 or PG1) was cultivated as the dominant member of a mixed bacterial culture. A metagenomic library was constructed, and the largest contigs were analyzed for genes associated with polycyclic aromatic hydrocarbon (PAH) metabolism. Eight pairs of genes with similarity to the alpha- and beta-subunits of ring-hydroxylating dioxygenases (RHDs) associated with aerobic bacterial PAH degradation were identified and linked to PG1 through PCR analyses of a simplified enrichment culture. In tandem with a ferredoxin and reductase found in close proximity to one pair of RHD genes, six of the RHDs were cloned and expressed in Escherichia coli. Each cloned RHD was tested for activity against nine PAHs ranging in size from two to five rings. Despite differences in their predicted protein sequences, each of the six RHDs was capable of transforming phenanthrene and pyrene. Three RHDs could additionally transform naphthalene and fluorene, and these genotypes were also associated with the ability of the E. coli constructs to convert indole to indigo. Only one of the six cloned RHDs was capable of transforming anthracene and benz[a]anthracene. None of the tested RHDs were capable of significantly transforming fluoranthene, chrysene, or benzo[a]pyrene. PMID- 22427502 TI - Molecular epidemiology of Brucella abortus isolates from cattle, elk, and bison in the United States, 1998 to 2011. AB - A variable-number tandem repeat (VNTR) protocol targeting 10 loci in the Brucella abortus genome was used to assess genetic diversity among 366 field isolates recovered from cattle, bison, and elk in the Greater Yellowstone Area (GYA) and Texas during 1998 to 2011. Minimum spanning tree (MST) and unweighted-pair group method with arithmetic mean (UPGMA) analyses of VNTR data identified 237 different VNTR types, among which 14 prominent clusters of isolates could be identified. Cattle isolates from Texas segregated into three clusters: one comprised of field isolates from 1998 to 2005, one comprised of vaccination associated infections, and one associated with an outbreak in Starr County in January 2011. An isolate obtained from a feral sow trapped on property adjacent to the Starr County herd in May 2011 clustered with the cattle isolates, suggesting a role for feral swine as B. abortus reservoirs in Starr County. Isolates from a 2005 cattle outbreak in Wyoming displayed VNTR-10 profiles matching those of strains recovered from Wyoming and Idaho elk. Additionally, isolates associated with cattle outbreaks in Idaho in 2002, Montana in 2008 and 2011, and Wyoming in 2010 primarily clustered with isolates recovered from GYA elk. This study indicates that elk play a predominant role in the transmission of B. abortus to cattle located in the GYA. PMID- 22427503 TI - Cytoplasmic pH response to acid stress in individual cells of Escherichia coli and Bacillus subtilis observed by fluorescence ratio imaging microscopy. AB - The ability of Escherichia coli and Bacillus subtilis to regulate their cytoplasmic pH is well studied in cell suspensions but is poorly understood in individual adherent cells and biofilms. We observed the cytoplasmic pH of individual cells using ratiometric pHluorin. A standard curve equating the fluorescence ratio with pH was obtained by perfusion at a range of external pH 5.0 to 9.0, with uncouplers that collapse the transmembrane pH difference. Adherent cells were acid stressed by switching the perfusion medium from pH 7.5 to pH 5.5. The E. coli cytoplasmic pH fell to a value that varied among individual cells (range of pH 6.2 to 6.8), but a majority of cells recovered (to pH 7.0 to 7.5) within 2 min. In an E. coli biofilm, cells shifted from pH 7.5 to pH 5.5 failed to recover cytoplasmic pH. Following a smaller shift (from pH 7.5 to pH 6.0), most biofilm cells recovered fully, although the pH decreased further than that of isolated adherent cells, and recovery took longer (7 min or longer). Some biofilm cells began to recover pH and then failed, a response not seen in isolated cells. B. subtilis cells were acid shifted from pH 7.5 to pH 6.0. In B. subtilis, unlike the case with E. coli, cytoplasmic pH showed no "overshoot" but fell to a level that was maintained. This level of cytoplasmic pH post-acid shift varied among individual B. subtilis cells (range of pH, 7.0 to 7.7). Overall, the cytoplasmic pHs of individual bacteria show important variation in the acid stress response, including novel responses in biofilms. PMID- 22427504 TI - Longitudinal Poisson regression to evaluate the epidemiology of Cryptosporidium, Giardia, and fecal indicator bacteria in coastal California wetlands. AB - Fecal pathogen contamination of watersheds worldwide is increasingly recognized, and natural wetlands may have an important role in mitigating fecal pathogen pollution flowing downstream. Given that waterborne protozoa, such as Cryptosporidium and Giardia, are transported within surface waters, this study evaluated associations between fecal protozoa and various wetland-specific and environmental risk factors. This study focused on three distinct coastal California wetlands: (i) a tidally influenced slough bordered by urban and agricultural areas, (ii) a seasonal wetland adjacent to a dairy, and (iii) a constructed wetland that receives agricultural runoff. Wetland type, seasonality, rainfall, and various water quality parameters were evaluated using longitudinal Poisson regression to model effects on concentrations of protozoa and indicator bacteria (Escherichia coli and total coliform). Among wetland types, the dairy wetland exhibited the highest protozoal and bacterial concentrations, and despite significant reductions in microbe concentrations, the wetland could still be seen to influence water quality in the downstream tidal wetland. Additionally, recent rainfall events were associated with higher protozoal and bacterial counts in wetland water samples across all wetland types. Notably, detection of E. coli concentrations greater than a 400 most probable number (MPN) per 100 ml was associated with higher Cryptosporidium oocyst and Giardia cyst concentrations. These findings show that natural wetlands draining agricultural and livestock operation runoff into human-utilized waterways should be considered potential sources of pathogens and that wetlands can be instrumental in reducing pathogen loads to downstream waters. PMID- 22427505 TI - How is stroke thrombolysis portrayed in UK national and London local newspapers? A review and critical discourse analysis. AB - BACKGROUND: thrombolysis for stroke has been licensed in the UK since 2007 and needs to be administered within 4.5 h. Given this time critical factor, the media may have an important role in public awareness. METHODS: this review aimed to find out how stroke thrombolysis was reported in UK national and London local newspapers and how treatment risks and benefits were communicated. Newspapers published between 1 January 2007 and 31 March 2010 were searched for articles on thrombolysis. Fifty-six articles were included and dispositive analysis, a qualitative analysis method, was used to identify themes. RESULTS: four main themes were identified: inaccurate description of thrombolysis, stroke clinicians' involvement, presentation of risks and benefits and patient stories. Inaccuracies included the presentation of thrombolysis as a treatment for transient ischaemic attack. Clinicians were quoted to suggest that thrombolysis produced complete recovery but were not reported to discuss risks or broader stroke management. The articles reported little or no risks of treatment. Patients' stories were used to reinforce that thrombolysis produces full recovery. CONCLUSIONS: this review found that newspaper media provides the public with inaccurate perspectives on thrombolysis. Clinicians may wish to check press articles prior to publishing and to consider the impact of reporting thrombolysis as a treatment which produces complete recovery. PMID- 22427506 TI - The airflow resistance sensing threshold during tidal breathing rises in old age in patients with asthma. AB - BACKGROUND: in a previous study, we showed that the ability to detect a rise in airflow resistance at rest was reduced in some non-asthmatic subjects in old age. OBJECTIVE: to determine whether airflow resistance detection is attenuated in elderly subjects with asthma. METHODS: we studied 60 adult subjects with stable asthma (age range 20-88). Progressive external airflow resistance loading was used to measure the inspiratory load detection threshold (LDT) during tidal breathing at rest. RESULTS: the mean inspiratory LDT was 5.57 (4.33 SD) kPa.s/l in the 20-64 age group (n=32) and 15.6 (10.1 SD) kPa.s/l in those aged 65 and above (n=28) (P<0.0001). The inspiratory LDT was significantly correlated with age (r=0.5246, P<0.00008), mainly due to the effect of higher LDTs in about half of the subjects above the age of 65 years. Expiratory LDT values and correlations were very similar to inspiratory values. CONCLUSIONS: the threshold for detecting external resistive loads during tidal breathing rises in old age in some, but not all, asthmatic patients as was observed in non-asthmatic subjects. The finding has implications for treatment guidelines because some elderly subjects are likely to have reduced awareness of worsening airflow obstruction, and consequently delay their use of rescue treatments. PMID- 22427507 TI - Effects of a stepped-care intervention programme among older subjects who screened positive for depressive symptoms in general practice: the PROMODE randomised controlled trial. AB - OBJECTIVES: to determine (cost)-effectiveness of a stepped-care intervention programme among subjects >= 75 years who screened positive for depressive symptoms in general practice. DESIGN: the pragmatic cluster-randomised controlled trial with 12-month follow-up. SETTING: sixty-seven Dutch general practices. SUBJECTS: two hundred and thirty-nine subjects >= 75 years screened positive for untreated depressive symptoms (15-item Geriatric Depression Scale >= 5). METHODS: usual care (34 practices, 118 subjects) was compared with the stepped-care intervention (33 practices, 121 subjects) consisting of three steps: individual counselling; Coping with Depression course; and-if indicated-referral back to general practitioner to discuss further treatment. Measurements included severity of depressive symptoms [Montgomery-Asberg Depression Rating Scale (MADRS)], quality of life, mortality and costs. RESULTS: at baseline subjects mostly were mildly/moderately depressed. At 6 months MADRS scores had improved more in the usual care than the intervention group (-2.9 versus -1.1 points, P=0.032), but not at 12 months (-3.1 versus -4.6, P=0.084). No significant differences were found within two separate age groups (75-79 years and >= 80 years). In intervention practices, 83% accepted referral to the stepped-care programme, and 19% accepted course participation. The control group appeared to have received more psychological care. CONCLUSIONS: among older subjects who screened positive for depressive symptoms, an offered stepped-care intervention programme was not (cost)-effective compared with usual care, possibly due to a low uptake of the course offer. TRIAL REGISTRATION: www.controlled-trials.com/ISRCTN 71142851v. PMID- 22427508 TI - The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9. AB - The multifunctional CaMKII has been implicated in vascular smooth muscle cell (VSMC) migration, but little is known regarding its downstream targets that mediate migration. Here, we examined whether CaMKII regulates migration through modulation of matrix metalloproteinase 9 (MMP9). Using CaMKIIdelta(-/-) mice as a model system, we evaluated migration and MMP9 regulation in vitro and in vivo. After ligation of the common carotid artery, CaMKII was activated in the neointima as determined by oxidation and autophosphorylation. We found that MMP9 was robustly expressed in the neointima and adventitia of carotid-ligated wild type (WT) mice but was barely detectable in CaMKIIdelta(-/-) mice. The perimeter of the external elastic lamina, a correlate of migration-related outward remodeling, was increased in WT but not in CaMKIIdelta(-/-) mice. Migration induced by serum, platelet-derived growth factor, and tumor necrosis factor-alpha (TNF-alpha) was significantly decreased in CaMKIIdelta(-/-) as compared with WT VSMCs, but migration was rescued with adenoviral overexpression of MMP9 in CaMKIIdelta(-/-) VSMCs. Likewise, overexpression of CaMKIIdelta in CaMKIIdelta(-/ ) VSMCs increased migration, whereas an oxidation-resistant mutant of CaMKIIdelta did not. TNF-alpha strongly induced CaMKII oxidation and autophosphorylation as well as MMP9 activity, mRNA, and protein levels in WT, but not in CaMKIIdelta(-/ ) VSMC. Surprisingly, TNF-alpha strongly induced MMP9 promoter activity in WT and CaMKIIdelta(-/-) VSMC. However, the MMP9 mRNA stability was significantly decreased in CaMKIIdelta(-/-) VSMC. Our data demonstrate that CaMKII promotes VSMC migration through posttranscriptional regulation of MMP9 and suggest that CaMKII effects on MMP9 expression may be a therapeutic pathway in vascular injury. PMID- 22427509 TI - Mechanotransduction through fibronectin-integrin focal adhesion in microvascular smooth muscle cells: is calcium essential? AB - It is believed that increased transmural pressure exerts force on vascular smooth muscle cells (VSMCs) and triggers Ca(2+) signaling as an initiating event responsible for the arteriolar myogenic response. However, the mechanisms linking the pressure increase to Ca(2+) signaling are unclear. We have shown previously using atomic force microscopy (AFM) that mechanical force induces a VSMC contractile response when applied to single fibronectin (FN; Sun Z, Martinez Lemus LA, Hill MA, Meininger GA. Am J Physiol Cell Physiol 295; C268-C278, 2008) focal adhesion sites. This current study seeks to determine whether application of force to single focal adhesions can cause a change in VSMC Ca(2+). Experiments were performed in low passage (p3~10) as well as in freshly isolated skeletal muscle arteriole VSMCs. AFM-attached microbeads (5 MUm) were coated with FN or collagen type I (CN-I) or type IV (CN-IV) and placed on a VSMC for 20 min, resulting in formation of a focal adhesion between the cell and the microbead. In low passage VSMCs, mechanically pulling on the FN-coated beads (800~3000 pN) did not induce a Ca(2+) increase but did cause a contractile response. In freshly isolated VSMCs, application of an FN or CN-I-coated bead onto the cell surface induced global Ca(2+) increases. However, these Ca(2+) increases were not correlated with the application of AFM pulling force to the bead or with the VSMC contractile responses to FN-coupled pulling. Chelating cytosolic Ca(2+) using BAPTA loading had no negative effect on the focal adhesion-related contractile response in both freshly isolated and low passage VSMCs, while the Rho-kinase inhibitor Y27632 abolished the micromyogenic response in both cases. These observations suggest that, in freshly isolated and cultured VSMCs, application of mechanical force to a focal adhesion does not invoke an acute global Ca(2+) increase. On the other hand, our data support a role for Rho-linked signaling mechanism involved in mechanotransduction leading to focal contraction that is independent of the need for a global increase in VSMC Ca(2+). PMID- 22427510 TI - Expression and functional significance of NADPH oxidase 5 (Nox5) and its splice variants in human blood vessels. AB - The expression and functional significance of NADPH oxidase 5 (Nox5) and its five isoforms in vascular cells is poorly understood. The goal of this study was to determine whether Nox5-alpha, -beta, -delta, -gamma, and -epsilon (short) are expressed in human blood vessels and evaluate their respective functions. Nox5 mRNA and protein were detected in human blood vessels, cultured human vascular smooth muscle (HVSMC) and endothelium, but not fibroblasts. The most abundant isoforms were alpha and beta, whereas delta and gamma were not detected. Nox5 alpha and -beta produced reactive oxygen species (ROS), but -delta, -gamma, and epsilon were not catalytically active. Coexpression of the active Nox5 isoforms with inactive Nox5 variants suppressed ROS production, and coimmunoprecipitation revealed that Nox5-beta binds the inactive epsilon variant, which may account for reduced ROS production. In HVSMC, angiotensin II, endothelin-1 and TNF-alpha increased endogenous Nox5 mRNA levels, while adenovirus-mediated overexpression of Nox5 promoted p38 MAPK, JAK2, JNK, and ERK1/2 phosphorylation in endothelial cells (EC), but only increased ERK1/2 phosphorylation in HVSMC. At higher levels of Nox5, there was evidence of increased apoptosis in EC, but not in HVSMC, as detected by the presence of cleaved caspase-3 and cleaved poly(ADP ribose)polymerase. Although catalytically inactive, Nox5-epsilon potently activated ERK in HVSMC, and increased expression of Nox5-epsilon promoted HVSMC proliferation. Nox5 is expressed in human blood vessels. The Nox5-alpha and -beta splice variants are the major isoforms that are expressed and the only variants capable of ROS production. Nox5-epsilon can inhibit Nox5 activity and activate ERK and HVSMC proliferation. PMID- 22427512 TI - The "systolic volume balance" method for the noninvasive estimation of cardiac output based on pressure wave analysis. AB - Cardiac output (CO) monitoring is essential for the optimal management of critically ill patients. Several mathematical methods have been proposed for CO estimation based on pressure waveform analysis. Most of them depend on invasive recording of blood pressure and require repeated calibrations, and they suffer from decreased accuracy under specific conditions. A new systolic volume balance (SVB) method, including a simpler empirical form (eSVB), was derived from basic physical principles that govern blood flow and, in particular, a volume balance approach for the conservation of mass ejected into and flowed out of the arterial system during systole. The formulas were validated by a one-dimensional model of the systemic arterial tree. Comparisons of CO estimates between the proposed and previous methods were performed in terms of agreement and accuracy using "real" CO values of the model as a reference. Five hundred and seven different hemodynamic cases were simulated by altering cardiac period, arterial compliance, and resistance. CO could be accurately estimated by the SVB method as follows: CO = C * PP(ao)/(T - P(sm) * T(s)/P(m)) and by the eSVB method as follows: CO = k * C * PP(ao)/T, where C is arterial compliance, PP(ao) is aortic pulse pressure, T is cardiac period, P(sm) is mean systolic pressure, T(s) is systolic duration, P(m) is mean pressure, and k is an empirical coefficient. SVB applied on aortic pressure waves did not require calibration or empirical correction for CO estimation. An empirical coefficient was necessary for brachial pressure wave analysis. The difference of SVB-derived CO from model CO (for brachial waves) was 0.042 +/- 0.341 l/min, and the limits of agreement were -0.7 to 0.6 l/min, indicating high accuracy. The intraclass correlation coefficient and root mean square error between estimated and "real" CO were 0.861 and 0.041 l/min, respectively, indicating very good accuracy. eSVB also provided accurate estimation of CO. An in vivo validation study of the proposed methods remains to be conducted. PMID- 22427513 TI - Functional recovery of fluid drainage precedes lymphangiogenesis in acute murine foreleg lymphedema. AB - Secondary lymphedema in humans is a common consequence of axillary lymph node dissection (ALND) to treat breast cancer. It is commonly hypothesized that lymphatic growth is required to increase fluid drainage and ameliorate lymphedema. Although there is a pronounced alteration in the balance of interstitial forces regulating fluid transport that sustains the chronic form of lymphedema, it is presently unknown whether changes occur to the balance of interstitial forces during acute lymphedema that may play a role in the recovery of fluid drainage. Here, we compared the relative importance of lymphangiogenesis of lymphatic vessels and interstitial flows for restoring fluid drainage and resolving acute lymphedema in the mouse foreleg after ALND. We found that removal of the axillary lymph nodes reduced lymph drainage in the foreleg at days 0 and 5 postsurgery, with fluid tracer spreading interstitially through subcutaneous tissues. Interstitial fluid drainage returned to normal by day 10, whereas functional regrowth of lymphatic vessels was first detected by indocyanine green fluorescence lymphography at day 15, demonstrating that the recovery of interstitial fluid drainage preceded the regrowth of lymphatic vessels. This was confirmed by the administration of VEGF receptor-3-neutralizing antibodies, which completely blocks lymphatic regrowth. It was found that the recovery of interstitial fluid drainage and the natural resolution of acute lymphedema produced by ALND were not hindered by VEGF receptor-3 neutralization, demonstrating that interstitial fluid drainage recovery and the resolution of acute lymphedema are lymphangiogenesis independent. The data highlight the central role of the interstitial environment in adapting to lymphatic injury to increase fluid drainage. PMID- 22427511 TI - NADPH oxidase-derived ROS and the regulation of pulmonary vessel tone. AB - Pulmonary vessel constriction results from an imbalance between vasodilator and vasoconstrictor factors released by the endothelium including nitric oxide, endothelin, prostanoids, and reactive oxygen species (ROS). ROS, generated by a variety of enzymatic sources (such as mitochondria and NADPH oxidases, a.k.a. Nox), appear to play a pivotal role in vascular homeostasis, whereas elevated levels effect vascular disease. The pulmonary circulation is very sensitive to changes in the partial pressure of oxygen and differs from the systemic circulation in its response to this change. In fact, the pulmonary vessels contract in response to low oxygen tension, whereas systemic vessels dilate. Growing evidence suggests that ROS production and ROS-related pathways may be key factors that underlie this differential response to oxygen tension. A major emphasis of our laboratory is the role of Nox isozymes in cardiovascular disease. In this review, we will focus our attention on the role of Nox-derived ROS in the control of pulmonary vascular tone. PMID- 22427514 TI - Disruption of group IVA cytosolic phospholipase A(2) attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-alpha-mediated pathway. AB - Group IVA cytosolic phospholipase A(2) (cPLA(2)alpha), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-alpha, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)alpha activation. This study examined the potential role of cPLA(2)alpha and its mechanistic link with TNF-alpha in myocardial I/R injury using cPLA(2)alpha knockout (cPLA(2)alpha(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)alpha(+/+)) mice, cPLA(2)alpha(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-alpha inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)alpha(+/+) mice but not cPLA(2)alpha(-/-) mice. sTNFR:Fc also suppressed cPLA(2)alpha phosphorylation in the ischemic myocardium after I/R of cPLA(2)alpha(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)alpha(+/+) mice but not cPLA(2)alpha(-/-) cardiomyocytes. H/R and TNF alpha induced cPLA(2)alpha phosphorylation in cPLA(2)alpha(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)alpha(-/-) cardiomyocytes, TNF-alpha induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)alpha(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)alpha attenuates myocardial I/R injury partly through inhibition of TNF-alpha-mediated pathways. PMID- 22427515 TI - CREB critically regulates action potential shape and duration in the adult mouse ventricle. AB - The cAMP response element binding protein (CREB) belongs to the CREB/cAMP response element binding modulator/activating transcription factor 1 family of cAMP-dependent transcription factors mediating a regulation of gene transcription in response to cAMP. Chronic stimulation of beta-adrenergic receptors and the cAMP-dependent signal transduction pathway by elevated plasma catecholamines play a central role in the pathogenesis of heart failure. Ion channel remodeling, particularly a decreased transient outward current (I(to)), and subsequent action potential (AP) prolongation are hallmarks of the failing heart. Here, we studied the role of CREB for ion channel regulation in mice with a cardiomyocyte-specific knockout of CREB (CREB KO). APs of CREB KO cardiomyocytes were prolonged with increased AP duration at 50 and 70% repolarization and accompanied by a by 51% reduction of I(to) peak amplitude as detected in voltage-clamp measurements. We observed a 29% reduction of Kcnd2/Kv4.2 mRNA in CREB KO cardiomyocytes mice while the other I(to)-related channel subunits Kv4.3 and KChIP2 were not different between groups. Accordingly, Kv4.2 protein was reduced by 37% in CREB KO. However, we were not able to detect a direct regulation of Kv4.2 by CREB. The I(to)-dependent AP prolongation went along with an increase of I(Na) and a decrease of I(Ca,L) associated with an upregulation of Scn8a/Nav1.6 and downregulation of Cacna1c/Cav1.2 mRNA in CREB KO cardiomyocytes. Our results from mice with cardiomyocyte-specific inactivation of CREB definitively indicate that CREB critically regulates the AP shape and duration in the mouse ventricle, which might have an impact on ion channel remodeling in situations of altered cAMP dependent signaling like heart failure. PMID- 22427516 TI - Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats. AB - We investigated the hypothesis that repetitive hyperthermia (RHT) attenuates the progression of cardiac hypertrophy and delays the transition from hypertensive cardiomyopathy to heart failure in Dahl salt-sensitive (DS) hypertensive rats. Six-week-old DS rats were divided into the following five groups: a normal-salt diet (0.4% NaCl) (NS group), a normal-salt diet plus RHT by daily immersion for 10 min in 40 degrees C water (NS+RHT group), a high-salt diet (8% NaCl) (HS group), a high-salt diet (8% NaCl) plus RHT (HS+RHT group), and high-salt diet (8% NaCl) plus RHT with 17-DMAG (HSP90 inhibitor) administration (HS+RHT+17-DMAG group). All rats were killed at 10 wk. Cardiac hypertrophy and fibrosis were noted in the HS group, whereas RHT attenuated salt-induced cardiac hypertrophy, myocardial and perivascular fibrosis, and blood pressure elevation. The phosphorylated endothelial nitric oxide synthase (eNOS) and Akt were decreased in the HS group compared with the NS group, but these changes were not observed in the HS+RHT group. The levels of HSP60, 70, and 90 were elevated by RHT. Moreover, the increased levels of iNOS, nitrotyrosine, Toll-like receptor-4, BNP, PTX3, and TBARS in the HS group were inhibited by RHT. Telomeric DNA length, telomerase activity, and telomere reverse transcriptase (TERT) were reduced in the HS group; however, these changes were partially prevented by hyperthermia. In conclusion, RHT attenuates the development of cardiac hypertrophy and fibrosis and preserves telomerase, TERT activity and the length of telomere DNA in salt-induced hypertensive rats through activation of eNOS and induction of HSPs. PMID- 22427517 TI - Cardiac mitochondrial network excitability: insights from computational analysis. AB - In the heart, mitochondria form a regular lattice and function as a coordinated, nonlinear network to continuously produce ATP to meet the high-energy demand of the cardiomyocytes. Cardiac mitochondria also exhibit properties of an excitable system: electrical or chemical signals can spread within or among cells in the syncytium. The detailed mechanisms by which signals pass among individual elements (mitochondria) across the network are still not completely understood, although emerging studies suggest that network excitability might be mediated by the local diffusion and autocatalytic release of messenger molecules such as reactive oxygen species and/or Ca(2+). In this short review, we have attempted to described recent advances in the field of cardiac mitochondrial network excitability. Specifically, we have focused on how mitochondria communicate with each other through the diffusion and regeneration of messenger molecules to initiate and propagate waves or oscillations, as revealed by computational models of mitochondrial network. PMID- 22427518 TI - Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics. AB - The present study was conducted to determine the impact of suppressing trophoblast remodeling of the uterine spiral arteries by prematurely elevating estrogen levels in the first trimester of baboon pregnancy on uterine and umbilical blood flow dynamics. Uteroplacental blood flow was assessed by Doppler ultrasonography after acute administration of saline (basal state) and serotonin on days 60, 100, and 160 of gestation (term: 184 days) to baboons in which uterine spiral artery remodeling had been suppressed by the administration of estradiol on days 25-59 of gestation. Maternal blood pressure in the basal state was increased (P < 0.01), and uterine artery diastolic notching and the umbilical artery pulsatility index and systolic-to-diastolic ratio, reflecting downstream flow impedance, were increased (P < 0.01) after serotonin administration on day 160, but not earlier, in baboons treated with estradiol in early gestation. These changes in uteroplacental flow dynamics in serotonin-infused, estradiol-treated animals were accompanied by a decrease (P < 0.05) in uterine and umbilical artery volume flow and fetal bradycardia. The results of this study show that suppression of uterine artery remodeling by advancing the rise in estrogen from the second trimester to the first trimester disrupted uteroplacental blood flow dynamics and fetal homeostasis after vasochallenge late in primate pregnancy. PMID- 22427519 TI - Attenuation by sphingosine-1-phosphate of rat microvessel acute permeability response to bradykinin is rapidly reversible. AB - To evaluate the hypothesis that sphingosine-1-phosphate (S1P) and cAMP attenuate increased permeability of individually perfused mesenteric microvessels through a common Rac1-dependent pathway, we measured the attenuation of the peak hydraulic conductivity (L(p)) in response to the inflammatory agent bradykinin (BK) by either S1P or cAMP. We varied the extent of exposure to each agent (test) and measured the ratio L(p)(test)/L(p)(BK alone) for each vessel (anesthetized rats). S1P (1 MUM) added at the same time as BK (concurrent, no pretreatment) was as effective to attenuate the response to BK (L(p) ratio: 0.14 +/- 0.05; n = 5) as concurrent plus pretreatment with S1P for 30 min (L(p) ratio: 0.26 +/- 0.06; n = 11). The same pretreatment with S1P, but with no concurrent S1P, caused no inhibition of the BK response (L(p) ratio 1.07 +/- 0.11; n = 8). The rapid on and off action of S1P demonstrated by these results was in contrast to cAMP-dependent changes induced by rolipram and forskolin (RF), which developed more slowly, lasted longer, and resulted in partial inhibition when given either as pretreatment or concurrent with BK. In cultured endothelium, there was no Rac activation or peripheral cortactin localization at 1 min with RF, but cortactin localization and Rac activation were maximal at 1 min with S1P. When S1P was removed, Rac activation returned to control within 2 min. Because of such differing time courses, S1P and cAMP are unlikely to act through fully common effector mechanisms. PMID- 22427520 TI - Biaxial vasoactivity of porcine coronary artery. AB - The passive mechanical properties of blood vessel mainly stem from the interaction of collagen and elastin fibers, but vessel constriction is attributed to smooth muscle cell (SMC) contraction. Although the passive properties of coronary arteries have been well characterized, the active biaxial stress-strain relationship is not known. Here, we carry out biaxial (inflation and axial extension) mechanical tests in right coronary arteries that provide the active coronary stress-strain relationship in circumferential and axial directions. Based on the measurements, a biaxial active strain energy function is proposed to quantify the constitutive stress-strain relationship in the physiological range of loading. The strain energy is expressed as a Gauss error function in the physiological pressure range. In K(+)-induced vasoconstriction, the mean +/- SE values of outer diameters at transmural pressure of 80 mmHg were 3.41 +/- 0.17 and 3.28 +/- 0.24 mm at axial stretch ratios of 1.3 and 1.5, respectively, which were significantly smaller than those in Ca(2+)-free-induced vasodilated state (i.e., 4.01 +/- 0.16 and 3.75 +/- 0.20 mm, respectively). The mean +/- SE values of the inner and outer diameters in no-load state and the opening angles in zero stress state were 1.69 +/- 0.04 mm and 2.25 +/- 0.08 mm and 126 +/- 22 degrees , respectively. The active stresses have a maximal value at the passive pressure of 80-100 mmHg and at the active pressure of 140-160 mmHg. Moreover, a mechanical analysis shows a significant reduction of mean stress and strain (averaged through the vessel wall). These findings have important implications for understanding SMC mechanics. PMID- 22427521 TI - Modulation of SR Ca2+ release by the triadin-to-calsequestrin ratio in ventricular myocytes. AB - Calsequestrin (CSQ) is a Ca(2+) storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca(2+) signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TG(CSQ)) was associated with heart failure, attenuation of SR Ca(2+) release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TG(CxT)) could be beneficial for impaired intracellular Ca(2+) signaling and contractile function. Indeed, the depressed intracellular Ca(2+) concentration ([Ca](i)) peak amplitude in TG(CSQ) was normalized by co-overexpression in TG(CxT) myocytes. This effect was associated with changes in the expression of cardiac Ca(2+) regulatory proteins. For example, the protein level of the L-type Ca(2+) channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo)plasmic reticulum Ca(2+) ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared with TG(CSQ), whereas JUN expression and [(3)H]ryanodine binding were lower in both TG(CxT) and TG(CSQ) compared with wild-type hearts. As a result of these expressional changes, the SR Ca(2+) load was higher in both TG(CxT) and TG(CSQ) myocytes. In contrast to the improved cellular Ca(2+), transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TG(CxT) compared with TG(CSQ). Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca(2+) release compared with TG(CSQ) mice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to beta-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca(2+) signaling. PMID- 22427522 TI - Functional scaffold-free 3-D cardiac microtissues: a novel model for the investigation of heart cells. AB - To bridge the gap between two-dimensional cell culture and tissue, various three dimensional (3-D) cell culture approaches have been developed for the investigation of cardiac myocytes (CMs) and cardiac fibroblasts (CFs). However, several limitations still exist. This study was designed to develop a cardiac 3-D culture model with a scaffold-free technology that can easily and inexpensively generate large numbers of microtissues with cellular distribution and functional behavior similar to cardiac tissue. Using micromolded nonadhesive agarose hydrogels containing 822 concave recesses (800 MUm deep * 400 MUm wide), we demonstrated that neonatal rat ventricular CMs and CFs alone or in combination self-assembled into viable (Live/Dead stain) spherical-shaped microtissues. Importantly, when seeded simultaneously or sequentially, CMs and CFs self-sorted to be interspersed, reminiscent of their myocardial distribution, as shown by cell type-specific CellTracker or antibody labeling. Microelectrode recordings and optical mapping revealed characteristic triangular action potentials (APs) with a resting membrane potential of -66 +/- 7 mV (n = 4) in spontaneously contracting CM microtissues. Under pacing, optically mapped AP duration at 90% repolarization and conduction velocity were 100 +/- 30 ms and 18.0 +/- 1.9 cm/s, respectively (n = 5 each). The presence of CFs led to a twofold AP prolongation in heterogenous microtissues (CM-to-CF ratio of 1:1). Importantly, Ba(2+) sensitive inward rectifier K(+) currents and Ca(2+)-handling proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, were detected in CM-containing microtissues. Furthermore, cell type-specific adenoviral gene transfer was achieved, with no impact on microtissue formation or cell viability. In conclusion, we developed a novel scaffold-free cardiac 3-D culture model with several advancements for the investigation of CM and CF function and cross regulation. PMID- 22427523 TI - Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension. AB - Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventricle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca(2+) handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca(2+) transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(endo)plasmic reticular Ca(2+)-ATPase activity, increased sarcoplasmic reticular Ca(2+)-release fraction, and increased Ca(2+) spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca(2+) handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs. PMID- 22427524 TI - The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation. AB - The signaling complex consisting of the growth factor neuregulin-1 (NRG1) and its tyrosine kinase receptors ErbB2 and ErbB4 has a critical role in cardiac development and homeostasis of the structure and function of the adult heart. Recent research results suggest that targeting this signaling complex may provide a viable strategy for treating heart failure. Clinical trials are currently evaluating the effectiveness and safety of intravenous administration of recombinant NRG1 formulations in heart failure patients. Endogenous as well as administered NRG1 has multiple possible activities in the adult heart, but how these are related is unknown. It has recently been demonstrated that NRG1 administration can stimulate proliferation of cardiomyocytes, which may contribute to repair failing hearts. This review summarizes the current knowledge of how NRG1 and its receptors control cardiac physiology and biology, with special emphasis on its role in cardiomyocyte proliferation during myocardial growth and regeneration. PMID- 22427525 TI - Influence of age and sex on the pressor response following a spontaneous burst of muscle sympathetic nerve activity. AB - The sympathetic nervous system is critical for the beat-to-beat regulation of arterial blood pressure (BP). Although studies have examined age- and sex-related effects on BP control, findings are inconsistent and limited data are available in postmenopausal women. In addition, the majority of studies have focused on time-averaged responses without consideration for potential beat-to-beat alterations. Thus we examined whether the ability of muscle sympathetic nerve activity (MSNA) to modulate BP on a beat-to-beat basis is affected by age or sex. BP and MSNA were measured during supine rest in 40 young (20 men) and 40 older (20 men) healthy subjects. Beat-to-beat fluctuations in mean arterial pressure (MAP) were characterized for 15 cardiac cycles after each MSNA burst using signal averaging. The rise in MAP following an MSNA burst was similar between young men and women (+2.64 +/- 0.3 vs. +2.57 +/- 0.3 mmHg, respectively). However, the magnitude of the increase in MAP after an MSNA burst was reduced in older compared with young subjects (P < 0.05). Moreover, the attenuation of the pressor response was greater in older women (+1.20 +/- 0.1 mmHg) compared with older men (+1.72 +/- 0.2 mmHg; P < 0.05). Interestingly, in all groups, MAP consistently decreased after cardiac cycles without MSNA bursts (nonbursts) with the magnitude of fall greatest in older men. In summary, healthy aging is associated with an attenuated beat-to-beat increase in BP after a spontaneous MSNA burst, and this attenuation is more pronounced in postmenopausal women. Furthermore, our nonburst findings highlight the importance of sympathetic vasoconstrictor activity to maintain beat-to-beat BP, particularly in older men. PMID- 22427526 TI - Dual-energy micro-CT of the rodent lung. AB - The purpose of this work is to investigate the use of dual-energy micro-computed tomography (CT) for the estimation of vascular, tissue, and air fractions in rodent lungs using a postreconstruction three material decomposition method. Using simulations, we have estimated the accuracy limits of the decomposition for realistic micro-CT noise levels. Next, we performed experiments involving ex vivo lung imaging in which intact rat lungs were carefully removed from the thorax, injected with an iodine-based contrast agent, and then inflated with different volumes of air (n = 2). Finally, we performed in vivo imaging studies in C57BL/6 mice (n = 5) using fast prospective respiratory gating in end inspiration and end expiration for three different levels of positive end expiratory pressure (PEEP). Before imaging, mice were injected with a liposomal blood pool contrast agent. The three-dimensional air, tissue, and blood fraction maps were computed and analyzed. The results indicate that separation and volume estimation of the three material components of the lungs are possible. The mean accuracy values for air, blood, and tissue were 93, 93, and 90%, respectively. The absolute accuracy in determining all fraction materials was 91.6%. The coefficient of variation was small (2.5%) indicating good repeatability. The minimum difference that we could detect in material fractions was 15%. As expected, an increase in PEEP levels for the living mouse resulted in statistically significant increases in air fractions at end expiration but no significant changes at end inspiration. Our method has applicability in preclinical pulmonary studies where changes in lung structure and gas volume as a result of lung injury, environmental exposures, or drug bioactivity would have important physiological implications. PMID- 22427527 TI - In pursuit of scientific excellence: sex matters. PMID- 22427528 TI - Nerve growth factor modulates human rhinovirus infection in airway epithelial cells by controlling ICAM-1 expression. AB - Human rhinoviruses (HRV) are the most common agent of upper respiratory infections and an important cause of lower respiratory tract symptoms. Our previous research with other viral pathogens has shown that virus-induced airway inflammation and hyperreactivity involve neurotrophic pathways that also affect tropism and severity of the infection. The goals of this study were to analyze systematically the expression of key neurotrophic factors and receptors during HRV-16 infection of human airway epithelial cells and to test the hypothesis that neurotrophins modulate HRV infection by controlling the expression of a major cellular receptor for this virus, the intercellular adhesion molecule 1 (ICAM-1). Neurotrophins and ICAM-1 expression were analyzed at the mRNA level by real-time PCR and at the protein level by flow cytometry and immunocytochemistry. A small inhibitory RNA (siRNA) or a specific blocking antibody was utilized to suppress nerve growth factor (NGF) expression and measure its effects on viral replication and virus-induced cell death. Nasal and bronchial epithelial cells were most susceptible to HRV-16 infection at 33 degrees C and 37 degrees C, respectively, and a significant positive relationship was noted between expression of NGF and tropomyosin-related kinase A (TrkA) and virus copy number. ICAM-1 expression was dose dependently upregulated by exogenous NGF and significantly downregulated by NGF inhibition with corresponding decrease in HRV-16 replication. NGF inhibition also increased apoptotic death of infected cells. Our results suggest that HRV upregulates the NGF-TrkA pathway in airway epithelial cells, which in turn amplifies viral replication by increasing HRV entry via ICAM-1 receptors and by limiting apoptosis. PMID- 22427529 TI - Prenatal iodine deficiency results in structurally and functionally immature lungs in neonatal rats. AB - Maternal hypothyroidism affects postnatal lung structure. High prevalence of hypothyroxinemia (low T4, normal T3) in iodine-deficient pregnant women and associated risk for neuropsychological development along with high infant/neonatal mortality ascribed to respiratory distress prompted us to study the effects of maternal hypothyroxinemia on postnatal lung development. Female Sprague Dawley rats were given a low-iodine diet (LID) with 1% KClO(4) in drinking water for 10 days, to minimize thyroid hormone differences. Half of these rats were continued on iodine-deficient diet; ID (LID with 0.005% KClO(4)) for 3 mo, whereas the rest were switched to an iodine-sufficient diet; IS [LID + potassium iodide (10 MUg iodine/20 g of diet + normal drinking water)]. Pups born to ID mothers were compared with age-matched pups from IS mothers at postnatal days 8 (P8) and 16 (P16) (n = 6-8/group). ID pups had normal circulating T3 but significantly low T4 levels (P < 0.05) and concomitantly approximately sixfold higher thyroid hormone receptor-beta mRNA in alveolar epithelium. Lung histology revealed larger and irregularly shaped alveoli in ID pups relative to controls. Lung function was assessed at P16 using a double-chambered plethysmograph and observed reduced tidal volume, peak inspiratory and expiratory flow, and dynamic lung compliance in ID pups compared with IS pups. Significant lowering of surfactant protein (SP)-B and SP-C mRNA and protein found in ID pups at P16. ID pups had 16-fold lower matrix metalloproteinase-9 mRNA levels in their alveolar epithelium. In addition, mRNA levels of thyroid transcription factor-1 and SP-D were significantly higher (3-fold) compared with IS pups. At P16, significantly lower levels of SP-B and SP-C found in ID pups may be responsible for immature lung development and reduced lung compliance. Our data suggest that maternal hypothyroxinemia may result in the development of immature lungs that, through respiratory distress, could contribute to the observed high infant mortality in ID neonates. PMID- 22427530 TI - Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. AB - The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-alpha, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis. PMID- 22427531 TI - The p110delta subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice. AB - Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110delta subunit of PI3K (PI3K p110delta) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110delta inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and alpha4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110delta significantly attenuated eotaxin 1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110delta with siRNA in BM Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110delta inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110delta in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation. PMID- 22427532 TI - Community-based targeted case finding for tuberculosis and HIV in household contacts of patients with tuberculosis in South Africa. AB - RATIONALE: South Africa has a high prevalence of tuberculosis (TB) and HIV coinfected adults in whom TB is often diagnosed late in the course of disease. OBJECTIVES: Improved case-finding approaches for TB and HIV are needed to reduce mortality and prevent transmission. METHODS: We identified newly diagnosed index TB cases in a rural district and enrolled their households in a TB-HIV contact tracing study. A group of randomly selected control households were enrolled to determine community prevalence of undetected TB and HIV. Field teams screened participants for TB symptoms, collected sputum specimens for smear microscopy and culture, provided HIV counseling and testing, and collected blood for CD4 testing. Participants were referred to public clinics for TB treatment and antiretroviral therapy. MEASUREMENTS AND MAIN RESULTS: We evaluated 2,843 household contacts of 727 index patients with TB and 983 randomly selected control household members. The prevalence of TB in household contacts was 6,075 per 100,000 (95% confidence interval, 5,789-6,360 per 100,000), whereas the prevalence detected in randomly selected households was 407 per 100,000 (95% confidence interval, 0-912 per 100,000; prevalence difference, 5,668 per 100,000; P < 0.001). TB detected among contacts was less likely to be smear-positive than in the index patients (6% vs. 22%; P < 0.001). Most contacts with culture confirmed TB were asymptomatic. At least one case of undiagnosed TB was found in 141 (19%) of 727 contact versus 4 (1%) of 312 control households. HIV testing was positive in 166 (11%) of 1,568 contacts tested versus 76 (14%) of 521 control participants tested (odds ratio, 1.48; P = 0.02). CONCLUSIONS: Active case finding in TB contact households should be considered to improve TB and HIV case detection in high-prevalence settings, but sensitive diagnostic tools are necessary. PMID- 22427533 TI - The lung tissue microbiome in chronic obstructive pulmonary disease. AB - RATIONALE: Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), which have now been confirmed by others. OBJECTIVES: To extend these findings to human lung tissue samples. METHODS: DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD [GOLD] 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing. MEASUREMENT AND MAIN RESULTS: Total bacterial populations within lung tissue were small (20-1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007). CONCLUSIONS: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD. PMID- 22427534 TI - Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. AB - RATIONALE: Accurate prediction of mortality helps select patients for interventions aimed at improving outcome. OBJECTIVES: Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy. METHODS: A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers. MEASUREMENTS AND MAIN RESULTS: At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-alpha were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers. CONCLUSIONS: The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT00292552). PMID- 22427535 TI - Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. AB - Apolipoprotein A-I (apoA-I) is a key component of high-density lipoproteins that mediates reverse cholesterol transport from cells and reduces vascular inflammation. We investigated whether endogenous apoA-I modulates ovalbumin (OVA) induced airway inflammation in mice. We found that apoA-I expression was significantly reduced in the lungs of OVA-challenged, compared with saline challenged, wild-type (WT) mice. Next, to investigate the role of endogenous apoA I in the pathogenesis of OVA-induced airway inflammation, WT and apoA-I(-/-) mice were sensitized by intraperitoneal injections of OVA and aluminum hydroxide, followed by multiple nasal OVA challenges for 4 weeks. OVA-challenged apoA-I(-/-) mice exhibited a phenotype of increased airway neutrophils compared with WT mice, which could be rescued by an administration of a 5A apoA-I mimetic peptide. Multiple pathways promoted neutrophilic inflammation in OVA-challenged apoA-I(-/ ) mice, including the up-regulated expression of (1) proinflammatory cytokines (IL-17A and TNF-alpha), (2) CXC chemokines (CXCL5), (3) vascular adhesion molecules (i.e., vascular cell adhesion molecule-1), and (4) granulocyte colony stimulating factors (G-CSF). Because concentrations of G-CSF in bronchoalveolar lavage fluid (BALF) were markedly increased in OVA-challenged apoA-I(-/-) mice, we hypothesized that enhanced G-CSF expression may represent the predominant pathway mediating increased neutrophilic inflammation. This was confirmed by the intranasal administration of a neutralizing anti-G-CSF antibody, which significantly reduced BALF neutrophilia by 72% in OVA-challenged apoA-I(-/-) mice, compared with mice that received a control antibody. We conclude that endogenous apoA-I negatively regulates OVA-induced neutrophilic airway inflammation, primarily via a G-CSF-dependent mechanism. Furthermore, these findings suggest that apoA-I may play an important role in modulating the severity of neutrophilic airway inflammation in asthma. PMID- 22427536 TI - Syndecan-4 regulates early neutrophil migration and pulmonary inflammation in response to lipopolysaccharide. AB - Proteoglycans (PGs) and their associated glycosaminoglycan side chains are effectors of inflammation, but little is known about changes to the composition of PGs in response to lung infection or injury. The goals of this study were to identify changes to heparan sulfate PGs in a mouse model of gram-negative pneumonia, to identify the Toll-like receptor adaptor molecules responsible for these changes, and to determine the role of the heparan sulfate PG in the innate immune response in the lungs. We treated mice with intratracheal LPS, a component of the cell wall of gram-negative bacteria, to model gram-negative pneumonia. Mice treated with intratracheal LPS had a rapid and selective increase in syndecan-4 mRNA that was regulated through MyD88-dependent mechanisms, whereas expression of several other PGs was not affected. To determine the role of syndecan-4 in the inflammatory response, we exposed mice deficient in syndecan-4 to LPS and found a significant increase in neutrophil numbers and amounts of CXC chemokines and total protein in bronchoalveolar lavage fluid. In studies performed in vitro, macrophages and epithelial cells treated with LPS had increased expression of syndecan-4. Studies performed using BEAS-2B cells showed that pretreatment with heparin and syndecan-4 decreased the expression of CXCL8 mRNA in response to LPS and TNF-alpha. These findings indicate that the early inflammatory response to LPS involves marked up-regulation of syndecan-4, which functions to limit the extent of pulmonary inflammation and lung injury. PMID- 22427537 TI - Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury. AB - Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI. Obesity-associated effects on neutrophil chemoattractant response were examined in bone marrow neutrophils using chemotaxis and adoptive transfer; neutrophil surface levels of chemokine receptor CXCR2 were determined by flow cytometry. Airspace neutrophilia, capillary leak, and plasma IL-6 were all decreased in obese relative to lean mice in established lung injury (24 h). No difference in airspace inflammatory cytokine levels was found between obese and lean mice in both obesity models during the early phase of neutrophil recruitment (2-6 h), but early airspace neutrophilia was reduced in db/db obese mice. Neutrophils from uninjured obese mice demonstrated diminished chemotaxis to the chemokine keratinocyte cytokine compared with lean control mice, and adoptive transfer of obese mouse neutrophils into injured lean mice revealed a defect in airspace migration of these cells. Possibly contributing to this defect, neutrophil CXCR2 expression was significantly lower in obese db/db mice, and a similar but nonsignificant decrease was seen in diet-induced obese mice. ALI is attenuated in obese mice, and this blunted response is in part attributable to an obesity-associated abnormal neutrophil chemoattractant response. PMID- 22427538 TI - Human primary lung endothelial cells in culture. AB - Pulmonary endothelial functions are critical to maintain the low pressure of the pulmonary circulation and effective diffusion capacity of the lung. To investigate pulmonary endothelial cell biology in healthy or diseased lungs, we developed methods to harvest and culture pure populations of primary pulmonary arterial endothelial cells and microvascular endothelial cells from human lung explanted at time of transplantation or from donor lungs not used in transplantation. The purity and characteristics of cultured endothelial cells is ascertained by morphologic criteria using phase contrast and electron microscopy; phenotypic expression profile for endothelial specific proteins such as endothelial nitric oxide synthase, platelet/endothelial cell adhesion molecule, and von Willbrand factor; and endothelial function assays such as Dil-acetylated low-density lipoprotein uptake and tube formation. This detailed method provides researchers with the ability to establish cells for molecular, genetic, and biochemical investigation of human pulmonary vascular diseases. PMID- 22427539 TI - The SMART Platform: early experience enabling substitutable applications for electronic health records. AB - OBJECTIVE: The Substitutable Medical Applications, Reusable Technologies (SMART) Platforms project seeks to develop a health information technology platform with substitutable applications (apps) constructed around core services. The authors believe this is a promising approach to driving down healthcare costs, supporting standards evolution, accommodating differences in care workflow, fostering competition in the market, and accelerating innovation. MATERIALS AND METHODS: The Office of the National Coordinator for Health Information Technology, through the Strategic Health IT Advanced Research Projects (SHARP) Program, funds the project. The SMART team has focused on enabling the property of substitutability through an app programming interface leveraging web standards, presenting predictable data payloads, and abstracting away many details of enterprise health information technology systems. Containers--health information technology systems, such as electronic health records (EHR), personally controlled health records, and health information exchanges that use the SMART app programming interface or a portion of it--marshal data sources and present data simply, reliably, and consistently to apps. RESULTS: The SMART team has completed the first phase of the project (a) defining an app programming interface, (b) developing containers, and (c) producing a set of charter apps that showcase the system capabilities. A focal point of this phase was the SMART Apps Challenge, publicized by the White House, using http://www.challenge.gov website, and generating 15 app submissions with diverse functionality. CONCLUSION: Key strategic decisions must be made about the most effective market for further disseminating SMART: existing market-leading EHR vendors, new entrants into the EHR market, or other stakeholders such as health information exchanges. PMID- 22427540 TI - The effect of glaucoma on the optical attenuation coefficient of the retinal nerve fiber layer in spectral domain optical coherence tomography images. AB - PURPOSE: To demonstrate the effect of glaucoma on the optical attenuation coefficient of the retinal nerve fiber layer (RNFL) in Spectral Domain Optical Coherence Tomography (SD-OCT) images. METHODS: We analyzed images of the peripapillary areas in 10 healthy and 30 glaucomatous eyes (mild, moderate, and advanced glaucoma, 10 eyes each), scanned with the Spectralis OCT (Heidelberg Engineering GmbH, Dossenheim, Germany). To calculate the RNFL attenuation coefficient (MU(att)), determined by the scattering properties of the RNFL, we used a model that normalized the reflectivity of the RNFL by the retinal pigment epithelium. The analysis was performed at four preset locations at 1.3 and 1.7 mm from the center of the optic nerve head (ONH) (i.e., temporally, superiorly, nasally, and inferiorly) and on averages per eye. To assess the structure function relationship, we correlated the MU(att) to the mean deviation (MD) in standard automated perimetry. RESULTS: The MU(att) of the RNFL decreased up to 40% with increasing disease severity, on average as well as in each location around the ONH (Jonckheere-Terpstra test, P < 0.019 in all tests). The MU(att) of the RNFL depended significantly on the location around the ONH in all eyes (Kruskal-Wallis test, P < 0.014) and was lowest nasally from the ONH. The MU(att) correlated significantly with the MD in SAP (R(2) = 0.337). CONCLUSIONS: The measurements clearly demonstrated that the MU(att) of the RNFL decreased with increasing disease severity. The RNFL attenuation coefficient may serve as a new method to quantify glaucoma in SD-OCT images. PMID- 22427541 TI - Localization of hemodynamic responses to simple visual stimulation: an fNIRS study. AB - PURPOSE: The purpose of the study was to use functional near-infrared spectroscopy (fNIRS) to explore the extent of activation in occipito-parietal cortices to high-contrast checkerboard stimuli. The distributions of oxyhemoglobin (HbO), deoxyhemoglobin (Hb), and total hemoglobin (THb) concentrations were used as measures of cortical activation. METHODS: Data were collected sequentially using the Frequency Domain Multi-Distance oximeter to record absolute chromophore concentration. Responses to three presentation modes (static, pattern reversal, and ON/OFF stimulation) were compared over 15 locations in two participants. The most effective stimulus was used in 10 participants at the most responsive occipito-parietal sites. RESULTS: Pattern reversal stimulation evoked the largest increase in HbO, and this increase was greatest at O1 and O2 (5% to the right and left of the midline occipital location Oz) and diminished at recording locations over the posterior parietal regions in the vertical direction. Hb changes were smaller than those observed for HbO. Significantly smaller responses were recorded over the midline (Oz) compared with those at O1 and O2. Changes in hemoglobin concentration reflected the location of activated brain tissue. CONCLUSIONS: The authors have demonstrated the distribution of the hemodynamic response using absolute values of hemoglobin chromophores in response to simple but strong stimulation using checkerboard presentations. PMID- 22427542 TI - A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene. AB - Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD. PMID- 22427543 TI - Measurement of macular pigment optical density in a healthy Chinese population sample. AB - PURPOSE: Macular pigment may protect against age-related macular degeneration (AMD) by its capacity to absorb blue light and scavenge free radicals. Current information on human macular pigment density has been largely from studies on Caucasian populations. The purpose of this study was to assess macular pigment density and its determinant factors in a Chinese population sample. METHODS: Macular pigment optical density (MPOD) was measured in a healthy Chinese population using heterochromatic flicker photometry (HFP). Participants received a standard ophthalmic examination, and only subjects who were confirmed not to have any eye diseases except mild age-related cataract were included in the study. Demographic and lifestyle data and general health status were recorded by questionnaire. RESULTS: A total of 281 unrelated healthy Chinese individuals, including 96 males and 185 females, with ages ranging from 17 to 85 years, participated in the study. The mean and standard deviation of MPOD levels were 0.56 +/- 0.19, 0.49 +/- 0.18, 0.36 +/- 0.15, and 0.19 +/- 0.12, respectively, at 0.25 degrees , 0.5 degrees , 1.0 degrees , and 1.75 degrees eccentricity points. A significant age-related decline in MPOD was observed at 0.25 degrees (P = 0.014). Females tended to have relatively lower levels of MPOD than males at 0.25 degrees (P = 0.21), 0.5 degrees (P = 0.025), and 1.0 degrees (P = 0.16). No statistically significant association of MPOD was observed with body mass index or smoking status. CONCLUSIONS: Macular pigment density measured by HFP tended to decline with aging in this healthy Chinese population sample. Females may have lower levels of MPOD than males. PMID- 22427544 TI - Does increased blood pressure rather than aging influence retinal pulse wave velocity? AB - PURPOSE: It was demonstrated previously that retinal pulse wave velocity (rPWV) as a measure of retinal arterial stiffness is increased in aged anamnestically healthy volunteers compared with young healthy subjects. Using novel methodology of rPWV assessment this finding was confirmed and investigated whether it might relate to the increased blood pressure usually accompanying the aging process, rather than to the aging itself. METHODS: A total of 12 young 25.5-year-old (24.0 28.8) [median(1st quartile-3rd quartile)] and 12 senior 68.5-year-old (63.8-71.8) anamnestically healthy volunteers; and 12 senior 63.0-year-old (60.8-65.0) validated healthy volunteers and 12 young 33.0-year-old (29.5-35.0) hypertensive patients were examined. Time-dependent alterations of vessel diameter were assessed by the Dynamic Vessel Analyzer in a retinal artery of each subject. The data were filtered and processed using mathematical signal analysis and rPWVs were calculated. RESULTS: rPWV amounted to 1200 (990-1470) RU (relative units)/s in the hypertensive group and to 1040 (700-2230) RU/s in anamnestically healthy seniors. These differed significantly from rPWVs in young healthy group (410 [280 500] RU/s) and in validated healthy seniors (400 [320-510] RU/s). rPWV associated with age and mean arterial pressure (MAP) in the pooled cohort excluded validated healthy seniors. In a regression model these associations remain when alternately adjusted for MAP and age. When including validated healthy seniors in the pooled cohort only association with MAP remains. CONCLUSIONS: Both aging (with not excluded cardiovascular risk factors) and mild hypertension are associated with elevated rPWV. rPWV increases to a similar extent both in young mildly hypertensive subjects and in aged anamnestically healthy persons. Healthy aging is not associated with increased rPWV. PMID- 22427545 TI - An accurate method to determine Bowman's layer thickness in vivo in the human cornea. AB - PURPOSE: To determine an accurate value for Bowman's layer (BL) thickness in vivo in humans. METHODS: Seventeen corneal transplant patients were examined preoperatively by laser-scanning in vivo confocal microscopy (IVCM), and corneal buttons were removed postoperatively and sectioned for light microscopy (LM). Nine corneas with uniformly thick BL by LM were used for thickness measurement. In the uniformly thick samples, probable overestimation of BL thickness in vivo by a first in vivo method (Method 1) led to the development of a revised in vivo method (Method 2). Method 2 was used to measure BL thickness in 20 healthy volunteers. RESULTS: In nine patients, mean BL thickness prior to transplantation was 13.7 +/- 1.6 MUm by IVCM (Method 1) while BL thickness of the removed corneal button was 9.7 +/- 1.7 MUm by LM (P < 0.001). The correlation of BL thickness between IVCM (Method 1) and LM was poor (P = 0.226). In 20 right eyes of 20 normal corneas, both in vivo methods were used to determine BL thickness. Mean BL thickness by Method 1 was 13.2 +/- 1.6 MUm and by Method 2 was 9.1 +/- 1.4 MUm (P < 0.001). BL thickness measurements by both in vivo methods were highly correlated (P < 0.001). CONCLUSION: BL thickness by a revised in vivo method was close to LM values in this study and to values reported in fixed tissue in other studies. The authors believe this revised method provides the most accurate estimates of BL thickness in vivo to date. PMID- 22427546 TI - Stimulation of aquaporin-mediated fluid transport by cyclic GMP in human retinal pigment epithelium in vitro. AB - PURPOSE: The retinal pigment epithelium (RPE) expresses aquaporin-1 (AQP1) and components of the natriuretic peptide signaling pathway. We hypothesized that stimulation of the natriuretic signaling pathway in RPE with atrial natriuretic peptide (ANP) and with membrane-permeable analogs of cGMP would induce a net apical-to-basal transport of fluid. METHODS: The hypothesis was tested using human RPE cultures that retain properties seen in vivo. Confluent monolayers were treated with ANP or membrane-permeable cGMP analogs in the presence of anantin, H 8, and an AQP1 inhibitor, AqB013. Fluid movement from the apical to basal chambers was measured by weight and used to calculate net fluid transport. RESULTS: Our results demonstrated a 40% increase in net apical-to-basal fluid transport by ANP (5 MUM) that was inhibited completely by the ANP receptor antagonist anantin and a 60% increase in net apical-to-basal fluid transport in response to the extracellularly applied membrane-permeable cGMP analog pCPT-cGMP (50 MUM), which was not affected by the protein kinase G inhibitor H-8. The aquaporin antagonist AqB013 (20 MUM) inhibited the cGMP-stimulated RPE fluid flux. CONCLUSIONS: The effect of cGMP is consistent with an enhancement of the net fluid flux in RPE mediated by AQP1 channels. Pharmacologic activation of cGMP signaling and concomitant stimulation of fluid uptake from the subretinal space could offer insights into a new approach to treating or reducing the risk of retinal detachment. PMID- 22427547 TI - Nasal ciliary beat frequency and beat pattern in retinal ciliopathies. AB - PURPOSE: The cilium in photoreceptors appears ultrastructurally very similar to the nasal ciliated epithelium. The purpose of this study was to evaluate the nasal ciliary beat frequency and beat pattern in patients with retinitis pigmentosa (RP) and Usher syndrome type II and compare it with that of healthy control subjects. METHODS: A prospective, comparative control study. Fresh samples of nasal mucosa were obtained from 13 patients with typical forms of RP, and from 4 patients with Usher syndrome type II. The nasal ciliary beat frequency (CBF) and beat pattern were determined using high-resolution digital high-speed video imaging (DHSV). The control group included 32 fresh nasal mucosa samples from 32 healthy volunteers without any other confounding diseases. RESULTS: The nasal CBF was lower in patients with Usher syndrome than in control subjects (Mann-Whitney U test, P = 0.01). The nasal CBF was 9.28 +/- 0.4 (mean +/- SD) Hz in patients with Usher syndrome and 10.82 +/- 1.39 Hz in patients of the control group. No significant difference was observed in the nasal CBF between the RP (10.59 +/- 1.54 Hz) and control group (Mann-Whitney U test, P = 0.64). Normal ciliary beat pattern was observed in all the patients and healthy volunteers. CONCLUSIONS: The nasal CBF is diminished in patients with Usher syndrome type II, whereas it remains normal in simplex RP patients. These results add evidence to the fact that Usher syndrome could be a primary ciliary disorder. PMID- 22427548 TI - Important role of epiregulin in inflammatory responses during corneal epithelial wound healing. AB - PURPOSE: To investigate the role played by epiregulin in corneal epithelial wound healing in vivo in epiregulin-knockout (KO) mice and cultured mouse corneal epithelial cells (MCECs). METHODS: A 2-mm diameter central epithelial wound was created in epiregulin-KO and wild-type (WT) mouse corneas. The size of the unhealed area and the epithelial cell proliferation and migration were examined. Myeloperoxidase assay was performed to determine the number of polymorphonuclear (PMN) cells infiltrating corneal stroma. Real-time PCR was used to determine expression of the mRNA of inflammatory cytokines in the corneal epithelial cells. Expression of chemokine (C-X-C motif) ligand 2 (CXCL2) response to IL-1beta was examined in MCECs with or without recombinant mouse epiregulin. Repetitive injuries were created to determine the effect of inflammation in healing in epiregulin-KO mice. RESULTS: After a single injury, corneal epithelial wound healing and cell migration and proliferation were unimpaired. However, corneal opacities and a larger number of infiltrating PMN cells were observed in epiregulin-KO mice. Expression levels of IL-1beta, IL-6, CXCL1, and CXCL2 were higher in epiregulin-KO than in WT corneal epithelia cells. The addition of epiregulin significantly reduced the expression of CXCL2 in response to IL-1beta in MCECs. In response to repetitive injuries, a significant delay in healing and more severe opacities were observed in epiregulin-KO mice than in WT mice. CONCLUSIONS: Our results indicate that during wound healing, epiregulin may regulate the expression of cytokines and chemokines to reduce an excessive accumulation of PMN cells, which will cause corneal opacity and persistent epithelial defects. PMID- 22427550 TI - A one-step multiplex PCR for acanthamoeba keratitis diagnosis and quality samples control. AB - PURPOSE: As the number of cases of Acanthamoeba spp. keratitis (AK) is constantly growing, new diagnostic tools are needed to confirm and guide ophthalmologists in this clinically problematic diagnosis. Molecular diagnosis is particularly well adapted, although only a few real-time PCR techniques have been described recently. The aim of this study was to develop a new PCR technique for the diagnosis of AK by combining the detection of Acanthamoeba DNA with human DNA, thus allowing an accurate interpretation of the PCR result. METHODS: Different DNA extraction procedures were compared to ensure an optimized amplification of one Acanthamoeba genome. The analytical parameters of this new multiplex Acanthamoeba beta-globin PCR (MAB-PCR) were evaluated. Fourteen eye drops were tested as potential PCR inhibitors. A prospective series of 28 corneal scrapings was subjected to MAB-PCR. RESULTS: The best extraction procedure associated thermal-shock pretreatment followed by a manual extraction procedure. The MAB-PCR parameters displayed excellent specificity and sensitivity, with a detection of 0.02 genome of Acanthamoeba. No eye drops were total PCR inhibitors. Of 28 corneal scrapings, 18 were considered true negatives. Seven could not be interpreted because of insufficient scraping material. Three were considered true positives: every patient progressed favorably on specific and reliable treatment. CONCLUSIONS: The MAB-PCR is a new tool to diagnose AK. It allows rapid diagnosis and prompt treatment of this probably underestimated etiology of infectious keratitis. This optimized real-time PCR outperforms the gold standard for Acanthamoeba keratitis diagnosis and it allows a concomitant evaluation of the quality of the corneal scraping, which is necessary for a precise interpretation of the results. PMID- 22427549 TI - Structure/function studies and the effects of memantine in monkeys with experimental glaucoma. AB - Purpose. The scanning laser polarimetry with variable corneal compensation (GDx VCC) methodology was established and verified in monkeys with experimental glaucoma (ExpG). Terminal GDx parameters were correlated with axon counts and electrophysiologic measures. The effects of memantine on these parameters were investigated. Methods. ExpG was induced in monkeys and intraocular pressure monitored weekly. Some monkeys received memantine in their diet before and after ExpG induction (1-10 months). GDx VCC scans, stereophotographs, and multifocal visual evoked potential (mfVEP) data were collected at baseline and every 6 to 8 weeks until euthanasia. Optic nerves were prepared for axon counting and other morphologic analysis. Results. There was no difference in IOP elevation exposure between memantine-treated and no-memantine-treated monkeys. The percentage of the optic nerve area composed of connective tissue septa was significantly greater in ExpG eyes than in Fellow eyes. There was a strong positive correlation between axon counts and terminal GDx parameter measures. Animals not receiving memantine exhibited significantly lower mfVEP amplitudes in ExpG eyes compared with the ipsilateral baseline or the final value in the Fellow eye. ExpG eyes from memantine-treated animals had higher overall mean amplitudes that were not significantly different relative to the ipsilateral baseline and final amplitudes in the Fellow eye. Conclusions. The authors' studies confirm that GDx VCC can be utilized in monkey ExpG studies to detect early retinal structural changes and that these changes are highly correlated with optic nerve axon counts. These structural changes may or may not lead to central functional changes as shown by the mfVEP in response to investigational therapies. PMID- 22427551 TI - Dietary docosahexaenoic acid supplementation prevents age-related functional losses and A2E accumulation in the retina. AB - PURPOSE: With age, retina function progressively declines and A2E, a constituent of the toxin lipofuscin, accumulates in retinal pigment epithelial (RPE) cells. Both events are typically exacerbated in age-related retina diseases. We studied the effect of dietary docosahexaenoic acid (DHA, C22:6n-3) supplementation on these events, using a transgenic mouse model (mutant human ELOVL4; E4) displaying extensive age-related retina dysfunction and massive A2E accumulation. METHODS: Retina function was assessed with the electroretinogram (ERG) and A2E levels were measured in E4 and wildtype (WT) mice. Dietary DHA was manipulated from 1 to 3, 1 to 6, 6 to 12, and 12 to 18 months: 1% DHA over total fatty acids (E4+, WT+) or similar diet without DHA (E4-, WT-). RESULTS: Increased omega-3/6 ratios (DHA/arachidonic acid) in E4+ and WT+ retinas were confirmed for the 1- to 3 month and 1- to 6-month trials. Although 1- to 3-month intervention had no effects, when prolonged to 1 to 6 months, RPE function (ERG c-wave) was preserved in E4+ and WT+. Intervention from 6 to 12 months led to maintained outer and inner retina function (ERG a- and b-wave, respectively) in E4+. At 12 to 18 months, a similar beneficial effect on retina function occurred in WT+; A2E levels were reduced in E4+ and WT+. CONCLUSIONS: DHA supplementation was associated with: preserved retina function at mid-degenerative stages in E4 mice; prevention of age-related functional losses in WT mice; and reduced A2E levels in E4 and WT mice at the oldest age examined. These findings imply that dietary DHA could have broad preventative therapeutic applications (acting on pathologic and normal age-related ocular processes). PMID- 22427552 TI - A novel cyclosporin a aqueous formulation for dry eye treatment: in vitro and in vivo evaluation. AB - PURPOSE: The aim of the present study was the in vitro and in vivo evaluation of a novel aqueous formulation based on polymeric micelles for the topical delivery of cyclosporine A for dry eye treatment. METHODS: In vitro experiments were carried out on primary rabbit corneal cells, which were characterized by immunocytochemistry using fluorescein-labeled lectin I/isolectin B4 for the endothelial cells and mouse monoclonal antibody to cytokeratin 3+12 for the epithelial ones. Living cells were incubated for 1 hour or 24 hours with a fluorescently labeled micelle formulation and analyzed by fluorescence microscopy. In vivo evaluations were done by Schirmer test, osmolarity measurement, CyA kinetics in tears, and CyA ocular distribution after topical instillation. A 0.05% CyA micelle formulation was compared to a marketed emulsion (Restasis). RESULTS: The in vitro experiments showed the internalization of micelles in the living cells. The Schirmer test and osmolarity measurements demonstrated that micelles did not alter the ocular surface properties. The evaluation of the tear fluid gave similar CyA kinetics values: AUC = 2339 +/- 1032 min*MUg/mL and 2321 +/- 881.63; Cmax = 478 +/- 111 MUg/mL and 451 +/- 74; half-life = 36 +/- 9 min and 28 +/- 9 for the micelle formulation and Restasis, respectively. The ocular distribution investigation revealed that the novel formulation delivered 1540 +/- 400 ng CyA/g tissue to the cornea. CONCLUSIONS: The micelle formulation delivered active CyA into the cornea without evident negative influence on the ocular surface properties. This formulation could be applied for immune-related ocular surface diseases. PMID- 22427553 TI - Flt23k nanoparticles offer additive benefit in graft survival and anti-angiogenic effects when combined with triamcinolone. AB - PURPOSE: To determine if nanoparticles delivering plasmids expressing Flt23k (an anti-VEGF intraceptor) can enhance murine cornea transplant survival and whether their effect is synergistic with steroid therapy. METHODS: Biodegradable PLGA Flt23k loaded or blank nanoparticles were prepared using the emulsion solvent evaporation METHOD: Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among the Flt23k nanoparticles, blank nanoparticles, triamcinolone acetonide, and PBS groups following subconjunctival injection in mice that underwent penetrating keratoplasty. Graft survival, corneal neovascularization, and corneal lymphangiogenesis in a group treated with both nanoparticles and steroid therapy were also analyzed. RESULTS: The Flt23k nanoparticle group showed less neovascularization, lymphangiogenesis, and graft failure compared with the PBS control group (P < 0.01). The 2-month graft survival rate was 20% in the Flt23k nanoparticle group with no grafts surviving in the PBS group. When the Flt23k nanoparticle was combined with steroid therapy, a significant increase in graft survival was seen compared with both steroid treatment alone (P < 0.05) and steroid combined with blank nanoparticle treatment (P < 0.05). The 2-month graft survival rate was 91.6% in the combination group compared with 47.6% in the triamcinolone-only group and 42.4% in the triamcinolone plus blank nanoparticle group. CONCLUSIONS: Anti-VEGF nanoparticles (Flt23k) have a significant effect on decreasing neovascularization and lymphangiogenesis, resulting in increased graft survival in penetrating keratoplasty. This beneficial effect is synergistically enhanced with steroid treatment. PMID- 22427554 TI - Circadian changes in subfoveal choroidal thickness and the relationship with circulatory factors in healthy subjects. AB - PURPOSE: To investigate circadian changes in subfoveal choroidal thickness (SFCT) and the relation to systemic factors in healthy subjects. METHODS: Thirty-eight eyes of 19 healthy volunteers were enrolled. SFCT was measured by using prototype high-penetration optical coherence tomography. Intraocular pressure (IOP), systolic blood pressure (SBP), diastolic blood pressures (DBP), and heart rate (HR) were measured every 3 hours over a 24-hour period. Circadian changes in the mean arterial pressure (MAP) and mean ocular perfusion pressure (MOPP) were calculated. The difference between the maximal and minimal SFCTs was analyzed, and correlations between the SFCT and other systemic factors were evaluated. RESULTS: There was a significant circadian variation in SFCT (P < 0.0001). The total mean SFCT was 280.3 +/- 106.1 MUm. At 6 PM, the mean SFCT (271.9 +/- 103.5 MUm) was the thinnest and at 3 AM it was the thickest (290.8 +/- 110.8 MUm). The SFCTs in 32 of 38 eyes were thickest between 3 and 9 AM and in 27 of 38 eyes, thinnest between 3 and 9 PM. The mean SFCT was significantly negatively correlated with the mean SBP (R(2) = 0.59, P = 0.02) in all eyes. There were no significant correlations between the mean SFCT and the mean DBP, MAP, HR, IOP, and MOPP in all eyes. CONCLUSIONS: We investigated the circadian change of choroidal thickness using high-penetration optical coherence tomography in healthy volunteers. The significant diurnal change was found and the choroid was thicker at night and thinner in daytime. Fluctuations in the choroidal thickness may be related to SBP. PMID- 22427555 TI - Ophthalmic artery Doppler waveform changes associated with increased damage in glaucoma patients. AB - PURPOSE: To characterize Doppler waveform variables (early systolic acceleration [ESA] and systolic/diastolic mean velocity ratios [Sm/Dm]) of the Ophthalmic Artery (OA) by color Doppler imaging (CDI) in eyes with primary open-angle glaucoma (POAG). METHODS: Analysis of CDI examinations of the retrobulbar circulation of patients with POAG (n = 102), normal tension glaucoma (NTG, n = 89), and healthy controls (n = 59) by a condition-masked investigator. One-way ANOVA, chi-square, and Spearman's rank correlation tests were used to determine differences, establish comparisons, and to explore associations between variables, respectively. RESULTS: The overall Doppler waveform presented a shift to the right in the glaucoma groups, with significantly lower Sm/Dm ratios when compared to the control group (healthy: 2.94 +/- 0.86, POAG: 2.60 +/- 0.67, NTG: 2.63 +/- 0.84; P = 0.01). ESA was significantly lower in the glaucoma groups (healthy: 688.8 +/- 484 cm.s(-2), POAG: 548.1 +/- 419 cm.s(-2), NTG: 548.5 +/- 337 cm.s(-2); P = 0.03). No statistical differences were, however, detected in the OA velocities or resistance index (P ranged between 0.08 and 0.96). In the glaucoma groups, waveform parameters such as ESA, acceleration time, and systolic mean velocities correlated with systemic blood pressure variables (P < 0.05). In these groups, negative correlations were detected between Sm/Dm ratios and the degree of visual field defects (POAG: P = 0.01; r = -0.25) and retinal nerve fiber layer thickness (NTG: P = 0.02; r = -0.25). CONCLUSIONS: The pattern of blood flow velocities in the OA throughout the cardiac cycle seems to be altered in glaucoma patients. Further studies on how systemic blood pressure affects waveform variables in glaucoma patients may provide a better understanding of an underlying vascular dysfunction. PMID- 22427556 TI - Hypoxia regulated gene transcription in human optic nerve lamina cribrosa cells in culture. AB - PURPOSE: Vascular hypoperfusion, extracellular matrix remodeling and axon loss are pathological characteristics of the glaucomatous optic nerve head. We report a novel study demonstrating transcriptional responses in optic nerve lamina cribrosa (LC) cells exposed to in vitro hypoxic stress. METHODS: Primary cultures of human glial fibrillary acid protein (GFAP) negative LC cells were generated from four donors. Cells were exposed to 24 hours of hypoxic stress (1% O2) or normoxia (21% O2). Hypoxia responsive genes were identified using Affymetrix HG U133A microarrays (n = 3) and validated with real time PCR (n = 3). Secreted protein was measured by ELISA (n = 4) and cellular protein by Western blot (n = 4). Expression data were annotated with NIH DAVID software and putative transcription factor sites in hypoxia-responsive gene promoters were identified using Core_TF software. RESULTS: Hypoxia-sensitive genes included those involved in apoptosis (e.g., BNIP3), neurogenesis (e.g., STC1), extracellular matrix (e.g., MIF, DDR1/TrkE, and IGFR2), mitochondrion (e.g., CYP1B1) and angiogenesis (e.g., VEGF). Real time PCR for selected genes supported the expression changes identified by microarray. ELISA and Western blot validated corresponding changes in protein production. Promoter sequence interrogation revealed putative conserved transcription factor binding sites (e.g., HIF and CREB) in the promoters of the hypoxia responsive genes. CONCLUSIONS: Our data show that LC cell gene expression is sensitive to reduced oxygen levels in vitro and provides bioinformatic evidence of the potential transcriptional regulators of this response. PMID- 22427557 TI - Manual suction versus femtosecond laser trephination for penetrating keratoplasty: intraocular pressure, endothelial cell damage, incision geometry, and wound healing responses. AB - PURPOSE: To measure real-time intraocular pressure (IOP) during trephination with a manual suction trephine (MST) and the femtosecond laser (FSL), and to assess endothelial cell damage, incision geometry, and wound healing response with these procedures. METHODS: IOP was monitored with an intracameral sensor. Eight rabbits underwent manual suction trephination. Eight rabbits had FSL trephination (FSL T). Slit lamp photography, confocal microscopy, and anterior segment optical coherence tomography (AS-OCT) were performed at baseline and postoperatively. Animals were sacrificed at 4 hours and 3 days. Tissue was examined with scanning electron microscopy (SEM) and immunohistochemistry for an array of wound-healing markers. Separately, 6 human corneas had MST (3) and FSL-T (3). Incision geometry was imaged with high resolution Optovue AS-OCT. RESULTS: The average IOP during MST and FSL-T was similar (37 mm Hg). There was wider IOP fluctuation during the MST cutting phase (60 mm Hg maximum). There were 1-2 rows of endothelial loss on either side of the incision for FSL-T and 2-5 rows deep for MST. Immune cell responses at 4 hours (CD11b) were comparable, greater apoptosis with FSL-T (TUNEL) occurred at 4 hours, and there was increased keratocyte proliferation at 3 days (Ki67) with FSL-T. There was significantly greater undercutting of the cornea with MST (46.86 degrees versus 16.72 degrees). CONCLUSIONS: There is more IOP variation during MST. Average IOP is 37 mm Hg for both techniques. More endothelial damage and undercutting of the cornea occurs with MST. The wound healing response to FSL-T appears greater at 3 days. PMID- 22427558 TI - Randomized controlled trial on the effects of training in the use of closed circuit television on reading performance. AB - PURPOSE: To investigate the effectiveness of training in the use of closed circuit television (CCTV) on reading performance in visually impaired patients. METHODS: In a multicenter masked randomized controlled trial, 122 patients were randomized either to a treatment group that received usual delivery instructions from the CCTV supplier combined with concise outpatient standardized training, or to a control group that received delivery instructions only. The main outcome measure was reading performance, which was obtained by measuring reading acuity, reading speed, reading errors, column-tracking time, and technical reading, approximately two weeks after patients had received their CCTV and 3 months later. Videotapes of all measurements were rated by two investigators. Training effects were analyzed with linear mixed modeling. RESULTS: There were no statistically significant differences in results between the treatment and control group. However, introducing a CCTV increased reading acuity (mean difference [MD] 0.93 logRAD; P < 0.01) and maximum reading speed (MD 15 wpm; P < 0.01), and decreased the number of errors (MD 0.33; P = 0.04), compared to reading without CCTV. Average reading speed (P = 0.05), number of errors (P = 0.04), and column-tracking time (P = 0.01) improved over time. CONCLUSIONS: Prescribing a CCTV and the delivery instructions by the supplier seemed sufficient to improve reading performance. Additional training in the use of this device did not result in further improvement. Based on these results, outpatient low-vision rehabilitation centers may consider reallocating part of the training resources into other evidence-based rehabilitation programs. (trialregister.nl number, NTR1031.). PMID- 22427559 TI - Vascular endothelial growth factor gene polymorphisms and choroidal neovascularization in highly myopic eyes. AB - PURPOSE: To investigate a potential association between VEGF gene polymorphisms and the occurrence and/or the size of choroidal neovascularization (CNV) in highly myopic eyes. METHODS: In the case-control study for CNV occurrence, 327 highly myopic Japanese patients were enrolled. One hundred and eighty-four patients had CNV in at least one eye, and 143 did not have CNV in either eye. Of the 184 patients with CNV, 83 patients were used to evaluate an association with CNV size, and an additional 76 patients with CNV were used to confirm the association. We genotyped four tag single nucleotide polymorphisms (SNPs) and four functional SNPs previously reported to be correlated with VEGF gene expression to evaluate the associations of these eight SNPs with CNV occurrence and size. To confirm the association between CNV size and VEGF gene polymorphism, the associated SNP was genotyped in 76 additional patients with myopic CNV. RESULTS: There was no significant association between the occurrence of myopic CNV and the SNPs in the VEGF gene (P > 0.16). Of the eight SNPs evaluated, however, rs2010963 showed significant association with CNV area (P = 0.0047). This association was successfully replicated in the additional 76 eyes with myopic CNV, and pooled analysis revealed significant association of rs2010963 with CNV size (P = 0.00078). CONCLUSIONS: VEGF gene polymorphisms were not associated with CNV occurrence in highly myopic eyes but were significantly associated with the size of CNV, suggesting roles in the growth rather than the emergence of CNV. PMID- 22427560 TI - Pointwise rates of visual field progression cluster according to retinal nerve fiber layer bundles. AB - PURPOSE: To explore whether pointwise rates of visual field progression group together in patterns consistent with retinal nerve fiber layer (RNFL) bundles. METHODS: Three hundred eighty-nine eyes of 309 patients from the Advanced Glaucoma Intervention Study with >=6 years of follow-up and >=12 reliable visual field exams were selected. Linear and exponential regression models were used to estimate pointwise rates of change over time. Clustering of pointwise rates of progression was investigated with hierarchical cluster analysis using Pearson's correlation coefficients as distance measure and an average linkage scheme for building the hierarchy with cutoff value of r > 0.7. RESULTS: The average mean deviation (+/-SD) was -10.9 (+/-5.4). The average (+/-SD) follow-up time and number of visual field exams were 8.1 (+/-1.1) years and 15.7 (+/-3.0), respectively. Pointwise rates of progression across the visual field grouped into clusters consistent with anatomic patterns of RNFL bundles with both linear (10 clusters) and exponential (six clusters) regression models. One hundred forty four (37%) eyes progressed according to the two-omitting pointwise linear regression model. CONCLUSIONS: ointwise rates of change in glaucoma patients cluster into regions consistent with RNFL bundle patterns. This finding validates the clinical significance of such pointwise rates. The correlations among pointwise rates of change can be used for spatial filtering purposes, facilitating detection or prediction of glaucoma progression. PMID- 22427561 TI - Glucosamine modulates TNF-alpha-induced ICAM-1 expression and function through O linked and N-linked glycosylation in human retinal pigment epithelial cells. AB - PURPOSE: The purpose of this article was to investigate the effects of glucosamine (GlcN) on the TNF-alpha-induced expression of intercellular adhesion molecule 1 (ICAM-1) and the function of ICAM-1 in ARPE-19 cells in vitro. METHODS: We quantified protein levels of TNF-alpha-induced ICAM-1 in ARPE-19 cells with Western blotting. The effects of GlcN on O-linked glycosylation, and therefore on ICAM-1 expression, were compared after the addition of alloxan, an inhibitor of O-linked N-acetylglucosamine transferase (OGT), or O-(2-acetamido-2 deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), an inhibitor of N acetylglucosaminidase (O-GlcNAcase [OGA]), or after OGT gene overexpression. The effect of GlcN on the N-linked glycosylation of ICAM-1 was evaluated by the change in its molecular mass on Western blotting. The effect of O-linked glycosylation on the nuclear factor kappaB (NF-kappaB) signaling pathway was examined using an NF-kappaB reporter gene assay. The effect of GlcN on ICAM-1 adhesion activity was examined using an ICAM-1 adhesion assay. RESULTS: GlcN, PUGNAc, and OGT overexpression inhibited TNF-alpha-induced ICAM-1 expression and NF-kappaB activity in ARPE-19 cells. Alloxan increased ICAM-1 expression and NF kappaB activity in TNF-alpha-induced ARPE-19 cells. GlcN and tunicamycin reduced the molecular mass of TNF-alpha-induced ICAM-1 in ARPE-19 cells. The proteasome inhibitor MG-132 suppressed the GlcN-induced reduction in the molecular mass of TNF-alpha-induced ICAM-1. GlcN also attenuated the adhesion activity of TNF-alpha induced ICAM-1. CONCLUSIONS: GlcN inhibits ICAM-1 expression and functions by modulating the O-linked glycosylation of factors involved in NF-kappaB signaling and by reducing the N-linked glycosylation of TNF-alpha-induced ICAM-1 in ARPE-19 cells. These effects may contribute to the GlcN-mediated anti-inflammatory effects in the eye. PMID- 22427562 TI - Electrophysiological findings in a porcine model of selective retinal capillary closure. AB - PURPOSE: To determine the effects on the electroretinogram (ERG) of retinal capillary closure induced in the pig by embolization with microspheres. METHODS: Fourteen Yorkshine Landrace pigs of 25- to 45-kg body weight were used. With a customized cannula introduced into the external carotid artery, 10-MUm diameter microspheres were delivered to the origin of the vessel that supplies blood to the eye in the pig. Fundus fluorescein angiography and electroretinography were performed between days 7 and 28 post injection. The ERG responses of embolized eyes were compared with those of the contralateral nonembolized eyes. RESULTS: The amplitudes of the scotopic b-wave (P = 0.002), the maximal b-wave (P < 0.010), the photopic a-wave (P < 0.001) and b-wave (P < 0.001), and the scotopic oscillatory potentials (OPs) (P = 0.025) and photopic OPs (P = 0.036) were significantly reduced in embolized eyes. The reduction of these ERG amplitudes was significantly correlated with the number of microspheres in the retina. There was no significant difference in the combined rod-cone bright flash (maximal) ERG a-wave amplitude between eyes with and without microspheres. Implicit times, however, were similar in embolized and control eyes. CONCLUSIONS: In eyes embolized with microspheres, the amplitudes of most ERG components were significantly reduced without alteration of their implicit times. The magnitude of ERG amplitude reduction correlated with the number of microspheres in the retina. PMID- 22427563 TI - Fully automated montaging of laser scanning in vivo confocal microscopy images of the human corneal subbasal nerve plexus. AB - PURPOSE: Creating wide-field montages of the human corneal subbasal nerve plexus using laser scanning in vivo confocal microscopy (IVCM) requires considerable expertise and remains highly labor intensive. A typical montage contains several hundred images to be quality checked and manually arranged. The purpose of this study was to develop and validate software for off-line montaging of IVCM images of the living human cornea. METHODS: The software was developed and tested using four large data sets of IVCM images from normal human corneas. Two of the data sets were used for calibration purposes, the remaining images served as a validation set. Techniques utilized included image binarization, clustering, key point generation, and feature-based stitching. A range of tests involving computer processing and visual inspection were applied to audit and compare the automated montages with manually constructed montages. RESULTS: The original IVCM images (N = 2565) from four corneas were processed into image groups, reducing the number of effective images by 68% to 86%. Each data set contained a large primary grouping. A clustering strategy was used to reduce the total potential workload by 57%. Both programmatic and visual inspection confirmed the method was robust to errors, with a specificity of 100% (i.e., no falsely matched images). The time taken to complete the montage varied from 1.5 to 3 hours. METHODS: Computer-driven image stitching is a useful, effective, and time-saving tool for studies involving IVCM corneal nerve imaging. Further research will extend and optimize these PMID- 22427564 TI - Effect of berberine on proinflammatory cytokine production by ARPE-19 cells following stimulation with tumor necrosis factor-alpha. AB - PURPOSE: Berberine (BBR) is a well-known drug used in traditional medicine and has been shown to possess anti-inflammatory properties. Whether it can affect the production of inflammatory cytokines by RPE cells is not yet clear and was therefore the subject of our study. METHODS: ARPE-19 cells were cultured with TNF alpha in the presence or absence of BBR to different time points. Concentrations of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) in the supernatant were measured by using an ELISA. The mRNA expression of these cytokines was measured by real-time PCR. Phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and c-Jun N terminal kinase (JNK) was measured by Western blot assay. The signal transduction mechanisms involved in cytokine production were evaluated using various inhibitors for p38, ERK1/2, and JNK. RESULTS: TNF-alpha significantly increased the expression of IL-6, IL-8, and MCP-1 in ARPE-19 cells at both the protein and mRNA levels. It promoted the phosphorylation of p38, ERK1/2, and JNK. Inhibitory experiments showed that IL-6 was modulated by p38, whereas IL-8 and MCP-1 were modulated by p38, ERK1/2, and JNK signal pathways. BBR inhibited the expression of IL-6, IL-8, and MCP-1 remarkably at both protein and mRNA levels and down regulated the phosphorylation of p38, ERK1/2, and JNK upon stimulation with TNF alpha. CONCLUSIONS: The present results suggested that BBR significantly inhibits the expression of inflammatory cytokines in ARPE-19 cells and that the inhibitory effect is mediated by down-regulation of the p38, ERK1/2, and JNK pathways. PMID- 22427565 TI - Methods to estimate the size and shape of the unaccommodated crystalline lens in vivo. AB - PURPOSE: The purpose of this article was to present methods capable of estimating the size and shape of the human eye lens without resorting to phakometry or magnetic resonance imaging (MRI). METHODS: Previously published biometry and phakometry data of 66 emmetropic eyes of 66 subjects (age range [18, 63] years, spherical equivalent range [-0.75, +0.75] D) were used to define multiple linear regressions for the radii of curvature and thickness of the lens, from which the lens refractive index could be derived. MRI biometry was also available for a subset of 30 subjects, from which regressions could be determined for the vertex radii of curvature, conic constants, equatorial diameter, volume, and surface area. All regressions were compared with the phakometry and MRI data; the radii of curvature regressions were also compared with a method proposed by Bennett and Royston et al. RESULTS: The regressions were in good agreement with the original measurements. This was especially the case for the regressions of lens thickness, volume, and surface area, which each had an R(2) > 0.6. The regression for the posterior radius of curvature had an R(2) < 0.2, making this regression unreliable. For all other regressions we found 0.25 < R(2) < 0.6. The Bennett Royston method also produced a good estimation of the radii of curvature, provided its parameters were adjusted appropriately. CONCLUSIONS: The regressions presented in this article offer a valuable alternative in case no measured lens biometry values are available; however care must be taken for possible outliers. PMID- 22427566 TI - GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. AB - PURPOSE: Retinal pigment epithelium (RPE) expresses GPR109A, a receptor for the vitamin niacin and the ketone body beta-hydroxybutyrate (beta-HB). Because diabetes results in elevated levels of beta-HB, here we studied expression of the receptor in diabetic retina. We also investigated its functional relevance in RPE. METHODS: Retinal expression of GPR109A in diabetic mice and postmortem human eyes was evaluated by quantitative PCR (qPCR). ARPE-19 cells and primary wild type and Gpr109a(-/-) mouse RPE cells were exposed to TNF-alpha in the presence or absence of niacin or beta-HB, followed by analysis of IL-6 and Ccl2 expression via real-time qPCR and ELISA. RESULTS: GPR109A expression was increased in diabetic mouse and human retina. TNF-alpha increased the expression and secretion of IL-6 and Ccl2 in ARPE-19 cells. Niacin and beta-HB suppressed these effects, implicating GPR109A as the target responsible for mediation of the observed effects. Primary RPE cells from wild-type mice behaved similarly. In contrast, GPR109A ligands failed to suppress TNF-alpha-induced expression and secretion of IL-6 and Ccl2 in primary RPE cells from Gpr109a(-/-) mice, confirming that the observed anti-inflammatory effects were mediated specifically by Gpr109a. CONCLUSIONS: GPR109A plays an anti-inflammatory role in RPE and its expression is upregulated in diabetes. Inflammation is a key causative factor in the pathogenesis of diabetic retinopathy. We speculate that the increased expression of GPR109A and elevation of its ligand beta-HB in diabetes are mechanisms by which the tissue attempts to fight inflammation in this disease. Pharmacological activation of GPR109A may therefore have therapeutic potential in clinical management of diabetic retinopathy. PMID- 22427567 TI - Signal quality assessment of retinal optical coherence tomography images. AB - PURPOSE: The purpose of this article was to assess signal quality of retinal optical coherence tomography (OCT) images from multiple devices using subjective and quantitative measurements. METHODS: A total of 120 multiframe OCT images from 4 spectral domain OCT devices (Cirrus, RTVue, Spectralis, and 3D OCT-1000) were evaluated subjectively by trained graders, and measured quantitatively using a derived parameter, maximum tissue contrast index (mTCI). An intensity histogram decomposition model was proposed to separate the foreground and background information of OCT images and to calculate the mTCI. The mTCI results were compared with the manufacturer signal index (MSI) provided by the respective devices, and to the subjective grading scores (SGS). RESULTS: Statistically significant correlations were observed between the paired methods (i.e., SGS and MSI, SGS and mTCI, and mTCI and MSI). Fisher's Z transformation indicated the Pearson correlation coefficient rho >= 0.8 for all devices. Using the Deming regression, correlation parameters between the paired methods were established. This allowed conversion from the proprietary MSI values to SGS and mTCI that are universally applied to each device. CONCLUSIONS: The study suggests signal quality of retinal OCT images can be evaluated subjectively and objectively, independent of the devices. Together with the proposed histogram decomposition model, mTCI may be used as a standardization metric for OCT signal quality that would affect measurements. PMID- 22427568 TI - Collagenase-mediated tissue modeling of corneal ectasia and collagen cross linking treatments. AB - PURPOSE: Corneal collagen cross-linking (CXL) is a method for modifying the natural history of keratoconus and other corneal ectatic diseases. The authors evaluated the use of collagenase for generating an experimental model of ectasia to evaluate the topographic effects of CXL interventions. METHODS: Nine human corneoscleral specimens unsuitable for transplantation were used. After epithelial debridement, mounting, and pressurization on an artificial anterior chamber, a solution of 10 mg/mL collagenase type II with 15% dextran was applied to five corneas for three hours. Three of these corneas subsequently underwent riboflavin/UV-A CXL. Scheimpflug-based tomography was performed before collagenase exposure, after collagenase exposure, and after CXL to evaluate changes in maximum axial curvature of the anterior surface (K(max)) at three IOP levels. Results were compared to four control eyes exposed to dextran alone. RESULTS: A statistically significant increase in K(max) was seen across all IOP levels in the collagenase group compared to the control group (+6.6 +/- 1.1 diopters [D] and +0.3 +/- 0.8 D, respectively, at physiological IOP). After CXL, K(max) decreased (-7.6 +/- 2.0 D at physiological IOP). Anterior corneal aberrations increased after collagenase exposure and decreased after CXL. Light microscopy showed loss of normal stromal collagen architecture and localized edema after collagenase exposure. CONCLUSIONS: A method for generating topographic features of corneal ectasia in human tissue is demonstrated. No significant sensitivity of K(max) to IOP was observed. CXL caused regression of steepening and induced aberrations in this model, consistent with clinical trends. The model may be useful for testing modifications to standard CXL techniques. PMID- 22427569 TI - Replication analysis for severe diabetic retinopathy. AB - PURPOSE: The purpose of this study is to attempt to replicate the top single nucleotide polymorphism (SNP) associations from a previous genome-wide association study (GWAS) for the sight-threatening complications of diabetic retinopathy in an independent cohort of diabetic subjects from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). METHODS: This study included 469 type 1 diabetic, Caucasian subjects from WESDR. Cases (n = 208) were defined by prior laser treatment for either proliferative diabetic retinopathy or diabetic macular edema. Controls (n = 261) were all other subjects in the cohort. Three hundred eighty-nine SNPs were tested for association using the Illumina GoldenGate custom array. A retinopathy-only subanalysis was conducted in 437 subjects by removing those with end-stage renal disease. Evaluation for association between cases and controls was conducted by using chi-square tests. A combined analysis incorporated the results from WESDR with the prior GWAS. RESULTS: No associations were significant at a genome-wide level. The analysis did identify SNPs that can be pursued in future replication studies. The top association was at rs4865047, an intronic SNP, in the gene CEP135 (P value 2.06 * 10(-5)). The top association from the subanalysis was at rs1902491 (P value 2.81 * 10(-5)), a SNP that sits upstream of the gene NPY2R. CONCLUSIONS: This study nominates several novel genetic loci that may be associated with severe diabetic retinopathy. In order to confirm these findings, replication and extension in additional cohorts will be necessary as susceptibility alleles for diabetic retinopathy appear to be of modest effect. PMID- 22427570 TI - Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis. AB - Purpose. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. Methods. To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC. Results. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL 8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. Conclusions. These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies. PMID- 22427571 TI - Isolation and characterization of progenitor cells in uninjured, adult rat lacrimal gland. AB - PURPOSE: The purpose of this study was to investigate the presence of progenitor cells in the uninjured, adult rat lacrimal gland (LG). METHODS: The presence of progenitor cells was examined in LG sections from male rats using antibodies against selected stem cell markers and alpha-smooth muscle actin (SMA), which marks myoepithelial cells (MECs), by immunofluorescence microscopy (IF). Small, immature cells were isolated after digestion of LG with collagenase and culture in RPMI 1640 for 2 weeks. Immature cells were examined for expression of stem cell markers by IF. Immature cell were grown in neuronal, epithelial, and myoepithelial cell media, and examined by light morphology and IF using antibodies to markers of different cell lineages. RESULTS: In the intact LGs, MECs expressed the stem cell markers nestin, Musashi 1, ABCG2, Pax6, Chx 10, DeltaN p63, and Sox 2. All markers colocalized with SMA. Isolated immature cells contained Ki-67, nestin, Musashi 1, Pax 6, and CHX 10. In neuronal media, immature cells differentiated and assumed a neuronal cell morphology expressing neurofilament 200. In media for human corneal endothelial cells, immature cells differentiated, assumed cobblestone morphology, and labeled with the epithelial marker AE1/AE3. In RPMI media immature cells differentiated into cells with MEC like morphology, and expressed the MEC markers SMA, alpha-actinin, adenylate cyclase II, and vimentin. CONCLUSIONS: We conclude that uninjured, adult LG contains progenitor cells that may be MECs, which can be isolated and differentiated into multiple lineages. PMID- 22427572 TI - Differential lateral rectus compartmental contraction during ocular counter rolling. AB - PURPOSE: The lateral rectus (LR) and medial rectus (MR) extraocular muscles (EOMs) have largely nonoverlapping superior and inferior innervation territories, suggesting functional compartmental specialization. We used magnetic resonance imaging (MRI) in humans to investigate differential compartmental activity in the rectus EOMs during head tilt, which evokes ocular counter-rolling, a torsional vestibulo-ocular reflex (VOR). METHODS: MRI in quasi-coronal planes was analyzed during target-controlled central gaze in 90 degrees right and left head tilts in 12 normal adults. Cross sections and posterior partial volumes of the transverse portions of the four rectus EOMs were compared in contiguous image planes 2 mm thick spanning the orbit from origins to globe equator, and used as indicators of contractility. RESULTS: Horizontal rectus EOMs had significantly greater posterior volumes and maximum cross sections in their inferior compartments (P < 10(-8)). In orbit tilt up (extorted) compared with orbit tilt down (intorted) head tilts, contractile changes in LR maximum cross section (P < 0.0001) and posterior partial volume (P < 0.05) were significantly greater in the inferior but not in the superior compartment. These changes were not explainable by horizontal or vertical eye position changes. A weaker compartmental effect was suggested for MR. The vertical rectus EOMs did not exhibit significant compartmental contractile changes during head tilt. Mechanical modeling suggests that differential LR contraction may contribute to physiological cyclovertical effects. CONCLUSIONS: Selective activation of the two LR, and possibly MR, compartments correlates with newly recognized segregation of intramuscular innervation into distinct compartments, and probably contributes to noncommutative torsion during the VOR. PMID- 22427573 TI - Reliability and reproducibility of assessment of corneal epithelial thickness by fourier domain optical coherence tomography. AB - PURPOSE: To analyze the intra-user reliability and inter-user reproducibility of assessment of corneal epithelial thickness by Fourier domain optical coherence tomography. METHODS: In this consecutive cross-sectional case series performed at a tertiary ocular care institution, 210 eyes of 210 subjects underwent anterior segment Fourier domain optical coherence tomography (FDOCT). A caliper tool software was used to measure the corneal thickness. For the reproducibility measures, the examination was done by 2 examiners (user 1, user 2) within 30 minutes of each other. For the reliability measure, the retest was done by user 1 on the next day, within 30 minutes of the previous test's time. The total corneal thickness, epithelial thickness, and corneal thickness excluding the epithelium were measured. RESULTS: The mean corneal thickness of the population measured by user 1 was 519.5 +/- 31.1 MUm, 58.6 +/- 4.2 MUm, and 460.95 +/- 31.4 MUm for total cornea, epithelium, and non-epithelial cornea, respectively. The difference in results between user 2 and user 1 was 0.8 +/- 7.2 MUm, 0.23 +/- 3.3 MUm, and 0.7 +/- 8.2 MUm for total, epithelium, and non-epithelial cornea, respectively, and the difference in results between the repeated series by user 1 was 0.49 +/- 5.7 MUm, -0.13 +/- 2.7 MUm, 0.61 +/- 5.4 MUm total, epithelium, and non epithelial cornea, respectively (paired t-test, P > 0.05). Intraclass correlations ranged from 0.87 to 0.99, coefficients of repeatability from 4.5 to 14.11, and coefficient of variation from 2.3% to 11.1%. CONCLUSIONS: Fourier domain anterior segment optical coherence tomography is reproducible and reliable for the measurement of epithelial thickness at vertex. PMID- 22427574 TI - Higher percentage of FISH-determined monosomy 3 and 8q amplification in uveal melanoma cells relate to poor patient prognosis. AB - PURPOSE: To investigate the relation between patient survival and incrementally increasing percentages of fluorescence in situ hybridization-determined complete loss of chromosome 3 (monosomy 3) and gain of chromosome 8q in primary uveal melanoma cells. METHODS: Clinicopathological factors were related to disease-free survival. Fluorescence in situ hybridization was performed using probes on chromosomes 1, 3, 6, and 8. The percentages of UM cells with monosomy 3 or chromosome 8q gain were classified in groups with incrementally increasing percentages and related to disease-free survival. Correlations between clinical factors and cytogenetic aberrations were also analyzed. RESULTS: Two-hundred twenty choroidal and ciliary body melanomas were analyzed. The following proved to be significant predictors of survival in univariate analysis: older patient age (P = 0.003); large tumor diameter (P < 0.001); mixed cell type (P = 0.001); presence of closed microvascular loops (P < 0.001); loss of chromosome 1p (P = 0.006); monosomy 3 (P < 0.001); gain of 6p (P < 0.001); and gain of chromosome 8q (P < 0.001). Multivariate Cox analysis displayed monosomy 3 (Hazard ratio [HR] 2.83, P = 0.002) and gain of chromosome 8q (HR 3.13, P = 0.002) as the most important independent prognostic factors of poor survival, followed by older patient age (HR 1.02, P = 0.017). Increasing percentages of monosomy 3 and gain of chromosome 8q in tumor cells showed a correlation with worse prognosis (Log rank test 49.9 and 40.4, both P < 0.001) and increased number of additional copies of 8q correlated with shorter disease-free interval (Log-rank test 45.7, P < 0.001). CONCLUSIONS: A high percentage monosomy 3 and chromosome 8q gain in primary UM cells showed a strong relation with poor disease-free survival compared with low percentage aberrations. PMID- 22427575 TI - Even moderate visual impairments degrade drivers' ability to see pedestrians at night. AB - PURPOSE: To determine the effect of moderate levels of refractive blur and simulated cataracts on nighttime pedestrian conspicuity in the presence and absence of headlamp glare. METHODS: The ability to recognize pedestrians at night was measured in 28 young adults (M = 27.6 years) under three visual conditions: normal vision, refractive blur, and simulated cataracts; mean acuity was 20/40 or better in all conditions. Pedestrian recognition distances were recorded while participants drove an instrumented vehicle along a closed road course at night. Pedestrians wore one of three clothing conditions and oncoming headlamps were present for 16 participants and absent for 12 participants. RESULTS: Simulated visual impairment and glare significantly reduced the frequency with which drivers recognized pedestrians and the distance at which the drivers first recognized them. Simulated cataracts were significantly more disruptive than blur even though photopic visual acuity levels were matched. With normal vision, drivers responded to pedestrians at 3.6- and 5.5-fold longer distances on average than for the blur or cataract conditions, respectively. Even in the presence of visual impairment and glare, pedestrians were recognized more often and at longer distances when they wore a "biological motion" reflective clothing configuration than when they wore a reflective vest or black clothing. CONCLUSIONS: Drivers' ability to recognize pedestrians at night is degraded by common visual impairments, even when the drivers' mean visual acuity meets licensing requirements. To maximize drivers' ability to see pedestrians, drivers should wear their optimum optical correction, and cataract surgery should be performed early enough to avoid potentially dangerous reductions in visual performance. PMID- 22427576 TI - Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR). AB - PURPOSE: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder that disrupts the development of the retinal vasculature and can result in blindness. FEVR is genetically heterogeneous and mutations in four genes, NDP, FZD4, LRP5, and TSPAN12, encoding components of a novel ligand-receptor complex that activates the Norrin-beta-catenin signaling pathway, account for approximately 50% of cases. We recently identified mutations in TSPAN12 as a cause of dominant FEVR. The purpose of this study was to identify recessive TSPAN12 mutations in FEVR patients. METHODS: Mutation screening was performed by directly sequencing PCR products generated from genomic DNA with primers designed to amplify the coding sequence of TSPAN12. Splicing defects were verified by reverse transcriptase PCR of leukocyte cDNA. RESULTS: TSPAN12 screening in a large dominant FEVR family unexpectedly led to the identification of homozygous mutations in severely affected family members, whereas mildly affected family members were heterozygous. Further screening in a cohort of 10 retinal dysplasia/severe FEVR patients identified an additional three cases with recessive TSPAN12 mutations. In all examined cases, single mutation carriers were mildly affected compared to patients harboring two TSPAN12 mutations. CONCLUSIONS: We report for the first time recessive mutations in TSPAN12 and describe the first genetic cause for the clinical variation seen in FEVR families. Our data raise the possibility that patients with severe FEVR actually may harbor two mutant alleles, derived either from the same gene or potentially from other genes encoding components of the Norrin-beta-catenin signaling pathway. PMID- 22427577 TI - Predicting glaucomatous progression in glaucoma suspect eyes using relevance vector machine classifiers for combined structural and functional measurements. AB - PURPOSE: The goal of this study was to determine if glaucomatous progression in suspect eyes can be predicted from baseline confocal scanning laser ophthalmoscope (CSLO) and standard automated perimetry (SAP) measurements analyzed with relevance vector machine (RVM) classifiers. METHODS: Two hundred sixty-four eyes of 193 participants were included. All eyes had normal SAP results at baseline with five or more SAP tests over time. Eyes were labeled progressed (n = 47) or stable (n = 217) during follow-up based on SAP Guided Progression Analysis or serial stereophotograph assessment. Baseline CSLO measured topographic parameters (n = 117) and baseline total deviation values from the 24-2 SAP test-grid (n = 52) were selected from each eye. Ten-fold cross validation was used to train and test RVMs using the CSLO and SAP features. Receiver operating characteristic (ROC) curve areas were calculated using full and optimized feature sets. ROC curve results from RVM analyses of CSLO, SAP, and CSLO and SAP combined were compared to CSLO and SAP global indices (Glaucoma Probability Score, mean deviation and pattern standard deviation). RESULTS: The areas under the ROC curves (AUROCs) for RVMs trained on optimized feature sets of CSLO parameters, SAP parameters, and CSLO and SAP parameters combined were 0.640, 0.762, and 0.805, respectively. AUROCs for CSLO Glaucoma Probability Score, SAP mean deviation (MD), and SAP pattern standard deviation (PSD) were 0.517, 0.513, and 0.620, respectively. No CSLO or SAP global indices discriminated between baseline measurements from progressed and stable eyes better than chance. CONCLUSIONS: In our sample, RVM analyses of baseline CSLO and SAP measurements could identify eyes that showed future glaucomatous progression with a higher accuracy than the CSLO and SAP global indices. (ClinicalTrials.gov numbers, NCT00221897, NCT00221923.). PMID- 22427578 TI - Genome-wide identification of Chlamydia trachomatis antigens associated with trachomatous trichiasis. AB - PURPOSE: Chlamydia trachomatis is the leading infectious cause of blindness. The goal of the current study was to search for biomarkers associated with C. trachomatis-induced ocular pathologies. METHODS: We used a whole genome scale proteome array to systematically profile antigen specificities of antibody responses to C. trachomatis infection in individuals from trachoma-endemic communities with or without end-stage trachoma (trichiasis) in The Gambia. RESULTS: When 61 trichiasis patients were compared with their control counterparts for overall antibody reactivity with organisms of different chlamydial species, no statistically significant difference was found. Both groups developed significantly higher titers of antibodies against C. trachomatis ocular serovars A and B than ocular serovar C, genital serovar D, or Chlamydia psittaci, whereas the titers of anti-Chlamydia pneumoniae antibodies were the highest. When antisera from 33 trichiasis and 26 control patients (with relatively high titers of antibodies to C. trachomatis ocular serovars) were reacted with 908 C. trachomatis proteins, 447 antigens were recognized by at least 1 of the 59 antisera, and 10 antigens by 50% or more antisera, the latter being designated as immunodominant antigens. More importantly, four antigens were preferentially recognized by the trichiasis group, with antigens CT414, CT667, and CT706 collectively reacting with 30% of trichiasis antisera but none from the normal group, and antigen CT695 reacting with 61% of trichiasis but only 31% of normal antisera. On the other hand, eight antigens were preferentially recognized by the control group, with antigens CT019, CT117, CT301, CT553, CT556, CT571, and CT709 together reacting with 46% of normal antisera and none from the trichiasis group, whereas antigen CT442 reacted with 35% of normal and 19% of trichiasis antisera respectively. CONCLUSIONS: The current study, by mapping immunodominant C. trachomatis antigens and identifying antigens associated with both ocular pathology and protection, has provided important information for further understanding chlamydial pathogenesis and the development of subunit vaccines. PMID- 22427579 TI - Feedback via Ca2+-activated ion channels modulates endothelin 1 signaling in retinal arteriolar smooth muscle. AB - PURPOSE: To investigate the role of feedback by Ca2+-sensitive plasma-membrane ion channels in endothelin 1 (Et1) signaling in vitro and in vivo. Methods. Et1 responses were imaged from Fluo-4-loaded smooth muscle in isolated segments of rat retinal arteriole using two-dimensional (2-D) confocal laser microscopy. Vasoconstrictor responses to intravitreal injections of Et1 were recorded in the absence and presence of appropriate ion channel blockers using fluorescein angiograms imaged using a confocal scanning laser ophthalmoscope. Results. Et1 (10 nM) increased both basal [Ca2+](i) and the amplitude and frequency of Ca2+ waves in retinal arterioles. The Ca2+-activated Cl--channel blockers DIDS and 9 anthracene carboxylic acid (9AC) blocked Et1-induced increases in wave frequency, and 9AC also inhibited the increase in amplitude. Iberiotoxin, an inhibitor of large conductance (BK) Ca2+-activated K+-channels, increased wave amplitude in the presence of Et1 but had no effect on frequency. None of these drugs affected basal [Ca2+](i). The voltage-operated Ca2+-channel inhibitor nimodipine inhibited wave frequency and amplitude and also lowered basal [Ca2+](i) in the presence of Et1. Intravitreal injection of Et1 caused retinal arteriolar vasoconstriction. This was inhibited by DIDS but not by iberiotoxin or penitrem A, another BK channel inhibitor. Conclusions. Et1 evokes increases in the frequency of arteriolar Ca2+-waves in vitro, resulting in vasoconstriction in vivo. These responses, initiated by release of stored Ca2+, also require positive feedback via Ca2+-activated Cl--channels and L-type Ca2+-channels. PMID- 22427580 TI - Photochemical kinetics of corneal cross-linking with riboflavin. AB - PURPOSE: To model the photochemical kinetics of corneal cross-linking with riboflavin (Rf) and confirm the model through measured oxygen concentration experiments under varying energy input conditions by UV-A irradiance and temperature modulation in ex vivo porcine cornea. METHODS: A theoretical model was developed to describe the corneal cross-linking photochemical kinetics of Rf. After instillation with drops of Rf solution in distilled water, de epithelialized porcine corneas were exposed to 365-nm ultraviolet light (UV-A) under varying irradiance and temperature. Oxygen concentration in the cornea at a known depth was monitored during UV-A illumination with a dissolved oxygen fiberoptic microsensor. Data from the oxygen experiments were used to confirm the model. RESULTS: On the basis of the known chemical reactions and diffusion rates of Rf and oxygen into the cornea, the authors developed a theoretical model consistent with corneal oxygen consumption experimental results during UV-A irradiation under different conditions. Oxygen concentration in the cornea is modulated by UV-A irradiance and temperature and quickly decreased at the beginning of UV-A exposure. The time-dependence of both Type-I and Type-II photochemical mechanisms in corneal cross-linking with Rf are discussed. CONCLUSIONS: Using a chemical kinetics modeling approach, the authors developed a simple model that is in agreement with their experimental results on oxygen consumption in the cornea during corneal cross-linking with Rf. It is suggested that the main photochemical kinetics mechanism is the direct interaction between Rf triplets and reactive groups of corneal proteins, which leads to the cross linking of the proteins mainly through radical reactions. PMID- 22427581 TI - Enhancement of rAAV2-mediated transgene expression in retina cells in vitro and in vivo by coadministration of low-dose chemotherapeutic drugs. AB - PURPOSE: Recombinant adeno-associated viral vector serotype 2 (rAAV2) has been used with success to deliver retina-targeted gene therapeutics in retinal degeneration. However, one of the major limitations of this approach is the vector's low transduction efficiency. This study is designed to increase AAV2 transduction efficiency in vitro and in vivo. METHODS: Green fluorescence protein (GFP) or luciferase reporter gene-carried rAAV2 vectors were applied to cultured human RPE cells (ARPE-19) or animal eyes with or without chemotherapeutic agents. GFP transduction efficiency was evaluated by image, flow cytometry analysis, and Western blot. The ciliary neurotrophic factor (rAAV2-CNTF)-carried AAV2 vector was coinjected to subretinal space with or without chemotherapeutic agent. The therapeutic efficacy was evaluated by counting numbers of remaining photoreceptors in retina sections of treated or untreated eyes. RESULTS: Coadministration of 0.1 MUg/mL doxorubicin (DXR), 0.14 MUg/mL cytarabine (Ara-C), 1 MUg/mL etoposide (VP-16), or 20 MUg/mL cisplatin (DDP) significantly increased rAAV2-mediated GFP and/or luciferase expression in cultured hRPE cells without any detectable toxicity. Pretreatment with DXR for 24 h prior to infection was most effective in enhancing rAAV2 transgene expression in hRPE cells. In addition, subretinal coinjection of rAAV2-CMV-ciliary neurotrophic factor (rAAV2 CNTF) and DXR into the eyes of rats with inherited retinal degeneration resulted in an approximately 2-fold increase in photoreceptor layer thickness and cellular density of the outer nuclear layer (ONL) compared to rAAV2-CNTF alone, reflecting a pronounced protection effect mediated by the enhanced expression of CNTF. CONCLUSIONS: The method described here to improve rAAV2-based gene delivery is simple and feasible without any detectable toxicity. This strategy might be therapeutically exploited in the gene therapy of degenerative retinal diseases. PMID- 22427583 TI - Classification algorithms enhance the discrimination of glaucoma from normal eyes using high-definition optical coherence tomography. AB - PURPOSE: To evaluate the diagnostic performance of classification algorithms based on Linear Discriminant Analysis (LDA) and Classification And Regression Tree (CART) methods, compared with optic nerve head (ONH) and retinal nerve fiber layer (RNFL) parameters measured by high-definition optical coherence tomography (Cirrus HD-OCT) for discriminating glaucoma subjects. METHODS: Consecutive glaucoma subjects (Training data = 184; Validation data = 102) were recruited from an eye center and normal subjects (n = 508) from an ongoing Singaporean Chinese population-based study. ONH and RNFL parameters were measured using a 200 * 200 scan protocol. LDA and CART were computed and areas under the receiver operating characteristic curve (AUC) compared. RESULTS: Average RNFL thickness (AUC 0.92, 95% confidence interval [CI] 0.91, 0.93), inferior RNFL thickness (AUC 0.92, 95% CI 0.91, 0.93), vertical cup-disc ratio (AUC 0.91, 95% CI 0.90, 0.92) and rim area/disc area ratio (AUC 0.90, 95% CI 0.86, 0.93) discriminated glaucoma better than other parameters (P <= 0.033). LDA (AUC 0.96, 95% CI 0.95, 0.96) and CART (0.98, 95% CI 0.98, 0.99) outperformed all parameters for diagnostic accuracy (P <= 0.005). Misclassification rates in LDA (8%) and CART (5.6%) were found to be low. The AUC of LDA for the validation data was 0.98 (0.95, 0.99) and CART was 0.99 (0.99, 0.994). CART discriminated mild glaucoma from normal better than LDA (AUC 0.94 vs. 0.99, P < 0.0001). CONCLUSIONS: Classification algorithms based on LDA and CART can be used in HD-OCT analysis for glaucoma discrimination. The CART method was found to be superior to individual ONH and RNFL parameters for early glaucoma discrimination. PMID- 22427582 TI - Early neurodegeneration in the retina of type 2 diabetic patients. AB - PURPOSE: The purpose of this study was to determine whether diabetes type 2 causes thinning of retinal layers as a sign of neurodegeneration and to investigate the possible relationship between this thinning and duration of diabetes mellitus, diabetic retinopathy (DR) status, age, sex, and glycemic control (HbA1c). METHODS: Mean layer thickness was calculated for retinal layers following automated segmentation of spectral domain optical coherence tomography images of diabetic patients with no or minimal DR and compared with controls. To determine the relationship between layer thickness and diabetes duration, DR status, age, sex, and HbA1c, a multiple linear regression analysis was used. RESULTS: In the pericentral area of the macula, the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were thinner in patients with minimal DR compared to controls (respective difference 1.9 MUm, 95% confidence interval [CI] 0.3-3.5 MUm; 5.2 MUm, 95% CI 1.0-9.3 MUm; 4.5 MUm, 95% CI 2.2-6.7 MUm). In the peripheral area of the macula, the RNFL and IPL were thinner in patients with minimal DR compared to controls (respective difference 3.2 MUm, 95% CI 0.1-6.4 MUm; 3.3 MUm, 95% CI 1.2-5.4 MUm). Multiple linear regression analysis showed DR status to be the only significant explanatory variable (R = 0.31, P = 0.03) for this retinal thinning. CONCLUSIONS: This study demonstrated thinner inner retinal layers in the macula of type 2 diabetic patients with minimal DR than in controls. These results support the concept that early DR includes a neurodegenerative component. PMID- 22427584 TI - Repeatability and reproducibility of manual choroidal volume measurements using enhanced depth imaging optical coherence tomography. AB - PURPOSE: To evaluate the repeatability and reproducibility of manual choroidal volume (CV) measurements by spectral domain- optical coherence tomography (SD OCT) using enhanced depth imaging (EDI). METHODS: Sixty eyes of 32 patients with or without any ocular chorioretinal diseases were enrolled prospectively. Thirty one choroidal scans were performed on each eye, centered at the fovea, using a raster protocol. Two masked observers demarcated choroidal boundaries by using built-in automated retinal segmentation software on two separate sessions. Observers were masked to each other's and their own previous readings. A standardized grid centered on the fovea was positioned automatically by OCT software, and values for average CVs and total CVs in three concentric rings were noted. The agreement between the intraobserver measurements or interobserver measurements was assessed using the concordance correlation coefficient (CCC). Bland-Altman plots were used to assess the clinically relevant magnitude of differences between inter- and intraobserver measurements. RESULTS: The interobserver CCC for the overall average CV was very high, 0.9956 (95% confidence interval [CI], 0.991-0.9968). CCCs for all three Early Treatment Diabetic Retinopathy Study concentric rings between two graders was 0.98 to 0.99 (95% CI, 0.97-0.98). Similarly intraobserver repeatability of two graders also ranged from 0.98 to 0.99. The interobserver coefficient of reproducibility was approximately 0.42 (95% CI, 0.34-0.5 mm(3)) for the average CV. CONCLUSIONS: CV measurement by manual segmentation using built-in automated retinal segmentation software on EDI-SD-OCT is highly reproducible and repeatable and has a very small range of variability. PMID- 22427586 TI - Fenofibrate, an anti-dyslipidemia drug, elicits the dilation of isolated porcine retinal arterioles: role of nitric oxide and AMP-activated protein kinase. AB - PURPOSE: Although recent clinical trials have demonstrated that fenofibrate is effective for treating diabetic retinopathy, the mechanism of this beneficial effect remains unclear. In the current study, we examined the effect of the vasomotor action of fenofibrate on porcine retinal arterioles. METHODS: Porcine retinal arterioles (internal diameter, 60-90 MUm) were isolated, cannulated, and pressurized (55 cmH(2)O) without flow in vitro. Video-microscopic techniques recorded the diameter responses to fenofibrate. RESULTS: The retinal arterioles dilated in a dose-dependent manner in response to fenofibrate (10 nM to 30 MUM). This vasodilation significantly decreased after the endothelium was removed. N(omega)-nitro-L-arginine methyl ester (a nitric oxide [NO] synthase inhibitor), 1H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (a soluble guanylyl cyclase inhibitor), wortmannin (a phosphatidylinositol [PI] 3-kinase inhibitor), and compound C (an AMP-activated protein kinase inhibitor) attenuated the effect of fenofibrate-induced vasodilation to an extent comparable to that produced by denudation. Pretreatment with GW6471, a peroxisome proliferator-activated receptor-alpha blocker, did not significantly inhibit fenofibrate-induced vasodilation. CONCLUSIONS: Fenofibrate primarily elicited endothelium-dependent dilation of the retinal arterioles. The current findings suggested that fenofibrate-induced endothelium-dependent vasodilation is mediated by the release of NO, which probably mediates dilation via activation of guanylyl cyclase, the PI3-kinase pathway, and the AMP-activated protein kinase pathway. Understanding the vasodilatory effect of fenofibrate on the retinal microvasculature may improve potential therapy for diabetic retinopathy. PMID- 22427585 TI - Oligomerization with wt alphaA- and alphaB-crystallins reduces proteasome mediated degradation of C-terminally truncated alphaA-crystallin. AB - PURPOSE: We previously demonstrated that the ubiquitin-proteasome pathway (UPP) is a general protein quality control system that selectively degrades damaged or abnormal lens proteins, including C-terminally truncated alphaA-crystallin. The objective of this work was to determine the effects of wt alphaA- and alphaB crystallins on the degradation of C-terminally truncated alphaA-crystallin (alphaA(1-162)) and vice versa. METHODS: Recombinant wt alphaA, alphaB, and alphaA(1-162) were expressed in Escherichia coli and purified to homogeneity by chromatography. Subunit exchange and oligomerization were detected by fluorescence resonance energy transfer (FRET), multiangle-light scattering and coprecipitation assays. Protein substrates were labeled with (125)I and lens epithelial cell lysates were used as the source of the UPP for degradation assays. RESULTS: FRET, multiangle light scattering, and coprecipitation assays showed that alphaA(1-162) exchanged subunits with wt alphaA- or wt alphaB- crystallin to form hetero-oligomers. alphaA(1-162) was more susceptible than wt alphaA-crystallin to degradation by the UPP. When mixed with wt alphaA-crystallin at 1:1 or 1:4 (alphaA(1-162) : wt) ratios to form hetero-oligomers, the degradation of alphaA(1-162) was significantly decreased. Conversely, formation of hetero-oligomers with alphaA(1-162) enhanced the degradation of wt alphaA crystallin. The presence of alphaA(1-162), but not wt alphaA-crystallin, decreased the degradation of wt alphaB-crystallin. CONCLUSIONS: alphaA(1-162) forms hetero-oligomers with wt alphaA- and alphaB-crystallins. Oligomerization with wt alphaA- or alphaB-crystallins reduces the susceptibility of alphaA(1-162) to degradation by the UPP. In addition, the presence of alphaA(1-162) in the hetero-oligomers also affects the degradation of wt alphaA- and alphaB crystallins. PMID- 22427587 TI - Functional topography of rod and cone photoreceptors in macaque retina determined by retinal densitometry. AB - PURPOSE: The purpose of this study is to determine the topography of bleaching in rods, middle/long-wavelength (M/L) and short-wavelength (S) cones in the macaque retina by using a modified retinal densitometry technique. METHODS: A modified commercial digital fundus camera system was used to measure continuously the intensity of the light reflectance during bleaching with band pass lights in the ocular fundus of three adult Rhesus monkeys (Macaca mulatta) under general anesthesia. The topography of bleaching in rods, M/L-, and S-cones was obtained separately by considering the characteristic time course of the reflectance changes, depending on the wavelengths of light and retinal locations. RESULTS: The distribution of M/L-cones response had a steep peak at the foveal center and was elongated horizontally. The distribution of rod responses was minimum at the foveal center and maximum along a circular region at the eccentricity of the optic disc. The distribution of S-cone responses was highest at the fovea and was excavated centrally. There was a circular region with the maximal responses at 0.38 to 1.0 degrees from the foveal center. CONCLUSIONS: With the current imaging technique, not only the steep peak of the M/L-cone responses at the fovea, but the ring-shaped distribution of rod responses in the periphery and the central reduction of S-cone response could be determined with good resolution. PMID- 22427588 TI - Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts. AB - PURPOSE: Following the recent demonstration of increased mitochondrial DNA mutations in lymphocytes of POAG patients, the authors sought to characterize mitochondrial function in a separate cohort of POAG. METHODS: Using similar methodology to that previous applied to Leber's hereditary optic neuropathy (LHON) patients, maximal adenosine triphosphate (ATP) synthesis and cellular respiration rates, as well as cell growth rates in glucose and galactose media, were assessed in transformed lymphocytes from POAG patients (n = 15) and a group of age- and sex-matched controls (n = 15). RESULTS: POAG lymphoblasts had significantly lower rates of complex-I-driven ATP synthesis, with preserved complex-II-driven ATP synthesis. Complex-I driven maximal respiration was also significantly decreased in patient cells. Growth in galactose media, where cells are forced to rely on mitochondrial ATP production, revealed no significant differences between the control and POAG cohort. CONCLUSIONS: POAG lymphoblasts in the study cohort exhibited a defect in complex-I of the oxidative phosphorylation pathway, leading to decreased rates of respiration and ATP production. Studies in LHON and other diseases have established that lymphocyte oxidative phosphorylation measurement is a reliable indicator of systemic dysfunction of this pathway. While these defects did not impact lymphoblast growth when the cells were forced to rely on oxidative ATP supply, the authors suggest that in the presence of a multitude of cellular stressors as seen in the early stages of POAG, these defects may lead to a bioenergetic crisis in retinal ganglion cells and an increased susceptibility to cell death. PMID- 22427589 TI - Explaining the relationship between three eye diseases and depressive symptoms in older adults. AB - PURPOSE: The purpose of this study is to examine whether patients with age related eye diseases, like age-related macular degeneration (AMD), glaucoma, or Fuchs corneal dystrophy, are more likely to show signs of depression compared to a control group of older adults with good vision, and to determine whether reduced mobility mediates these relationships. METHODS: We recruited 315 eligible patients (81 with AMD, 55 with Fuchs, 91 with glaucoma, and 88 controls) from the ophthalmology clinics of a Montreal hospital from September 2009 until December 2011. Depressive symptoms were assessed using the Geriatric Depression Scale Short Form (GDS-15). Life space was measured using the Life Space Assessment. Logistic regression was used to adjust for demographic, health, and social factors, and mediation was assessed using the methods of Baron and Kenny. RESULTS: There were 78 people (25%) meeting the criteria for depression in the cohort. All three groups with eye disease were more likely to be depressed than the control group after adjusting for age, sex, ethnicity, education, cognitive score, limitations in activities of daily living, social support, and lens opacity (P < 0.05). Life space and limited activities due to a fear of falling appeared to mediate the relationship between eye disease and depression. CONCLUSIONS: Visually limiting eye disease is associated with depression in older adults. Further research on interventions to prevent depression in patients with eye disease is warranted and should consider strategies to alleviate mobility limitation. Greater attention from families, physicians, and society to the mental health needs and mobility challenges of patients with eye disease is needed. PMID- 22427590 TI - Evaluation of total and corneal wavefront high order aberrations for the detection of forme fruste keratoconus. AB - PURPOSE: To investigate the application of anterior corneal and ocular aberrations in detecting mildly ectatic corneas. METHODS: This study retrospectively reviewed the data of 220 eyes separated into three groups by the NIDEK Corneal Navigator System automated corneal classification software: normal (N) (n = 123); forme fruste keratoconus (N topography with contralateral KC) (n = 34); and KC (n = 63). Anterior corneal and ocular aberrations were obtained with the optical path difference scan and compared using a Kruskal-Wallis test. Evaluation of these data to discriminate between the three groups was assessed using a Receiver-Operating Characteristic curve analysis. RESULTS: Corneal and ocular tilt, vertical coma, and trefoil were significantly different in the FFKC as compared with the N group. The discriminant functions between the FFKC and the N group, and between the KC and the N group reached an area under the receiver operating characteristic curve of 0.98 and 0.96, respectively. CONCLUSION: Indices generated from corneal and ocular wavefront can identify very mild forms of ectasia that may be undetected by Placido-based neural network programs. PMID- 22427591 TI - Assessment of 180 degrees rotation of the choroid as a novel surgical treatment for age-related macular degeneration. AB - PURPOSE: Our objective was to examine the feasibility of rotating choriocapillaris, Bruch's membrane (BM), and retinal pigment epithelium (RPE) through 180 degrees on a vascular pedicle and to assess revascularization and tissue preservation postoperatively. Such an approach could be used in the treatment of age-related macular degeneration where there is focal disease at the macula with healthy tissues located peripherally. METHODS: Successful surgery was performed in six rhesus macaque monkeys, which have a very similar choroidal blood supply to humans. After inducing a retinal detachment, the recurrent branch of the long posterior ciliary artery was used as a pedicle around which a graft stretching to the temporal equator was rotated. Retina was reattached over the rotated graft and eyes were followed up for up to 6 months with repeated angiography and optical coherence tomography (OCT). The morphology of retinal cells and BM were assessed by immunohistochemistry and electron microscopy. RESULTS: Revascularization of the choroid was limited, with reestablishment of drainage to the vortex veins seen in only one case. There was a secondary loss of the RPE and outer retina evident on histological analysis three months after surgery. The underlying BM however remained intact. CONCLUSIONS: Pedicled choroidal rotation surgery is technically feasible in vivo with intraoperative control of bleeding. However, lack of graft revascularization with the technique in its current form leads to neuroretinal and RPE tissue loss, and graft shrinkage. We found no evidence that rotational grafts are likely to improve the outcomes presently achieved with free graft techniques. PMID- 22427592 TI - In vitro biocompatibility of various polymer-based microelectrode arrays for retinal prosthesis. AB - PURPOSE: The purpose of our study is to evaluate the biocompatibility of various polymers used as microelectrode arrays (MEAs) in retinal prostheses through in vitro cytotoxicity testing following a standardized METHOD: METHODS: Three types of polymer-based MEAs were examined: silicone-based platinum, polyimide-based gold and liquid crystal polymer (LCP)-based gold MEAs. The silicone/platinum MEAs were fabricated by a Nd:YAG laser, polyimide/gold MEAs by a semiconductor manufacturing technique, and LCP/gold MEAs by laser micromachining and thermal bonding process. All experimental procedures followed the International Organization for Standardization (ISO) 10993-5. To obtain the extracts of specimens, 4 g of each type of MEA were eluted by culture media, MEM, for 24 hours. Then, several diluents of extracts, including the original extracts, were applied to a cultured-cell monolayer, L929 fibroblasts. The morphologic changes of cells were analyzed by microscope after 24 and 48 hours of incubation. The quantitative evaluations of cell viability were performed by MTT assay after 24 hours of incubation. RESULTS: The microscopic evaluations revealed that extracts from polymer-based MEAs did not induce morphologic changes or reduction of cells compared with control irrespective of concentrations of extracts. The MTT assay showed high viability values of approximately 80 to 130% regardless of diluted ratio of extracts from polymer-based MEAs. None of the polymers demonstrated a significant reduction of cell viability when compared with control. CONCLUSIONS: All types of polymer-based MEAs, including silicone/platinum, polyimide/gold, and LCP/gold MEAs, meet the criteria of biocompatibility guided by international standards, ISO 10993-5. PMID- 22427593 TI - Are normally sighted, visually impaired, and blind pedestrians accurate and reliable at making street crossing decisions? AB - PURPOSE: The purpose of this study is to measure the accuracy and reliability of normally sighted, visually impaired, and blind pedestrians at making street crossing decisions using visual and/or auditory information. METHODS: Using a 5 point rating scale, safety ratings for vehicular gaps of different durations were measured along a two-lane street of one-way traffic without a traffic signal. Safety ratings were collected from 12 normally sighted, 10 visually impaired, and 10 blind subjects for eight different gap times under three sensory conditions: (1) visual plus auditory information, (2) visual information only, and (3) auditory information only. Accuracy and reliability in street crossing decision making were calculated for each subject under each sensory condition. RESULTS: We found that normally sighted and visually impaired pedestrians were accurate and reliable in their street crossing decision-making ability when using either vision plus hearing or vision only (P > 0.05). Under the hearing only condition, all subjects were reliable (P > 0.05) but inaccurate with their street crossing decisions (P < 0.05). Compared to either the normally sighted (P = 0.018) or visually impaired subjects (P = 0.019), blind subjects were the least accurate with their street crossing decisions under the hearing only condition. CONCLUSIONS: Our data suggested that visually impaired pedestrians can make accurate and reliable street crossing decisions like those of normally sighted pedestrians. When using auditory information only, all subjects significantly overestimated the vehicular gap time. Our finding that blind pedestrians performed significantly worse than either the normally sighted or visually impaired subjects under the hearing only condition suggested that they may benefit from training to improve their detection ability and/or interpretation of vehicular gap times. PMID- 22427594 TI - Comparison of formalin-fixed and snap-frozen samples analyzed by multiplex ligation-dependent probe amplification for prognostic testing in uveal melanoma. AB - PURPOSE: Survival of patients with uveal melanoma (UM) correlates strongly with chromosomal abnormalities, such as monosomy 3 and polysomy 8q. Studies have shown multiplex ligation-dependent probe amplification (MLPA) to detect reliably chromosomal aberrations in UM using frozen samples. To date, the concordance between MLPA data generated from frozen and fixed samples has not been investigated. Our study aimed to compare MLPA data obtained from fixed and frozen tissues to determine whether fixed samples can be used in UM genetic prognostic testing. METHODS: Adjacent samples were taken from 20 UM cases, with one sample being snap-frozen, and the second being formalin-fixed and paraffin-embedded (FFPE). MLPA analysis was performed using the P027.B1 assay. The chromosome arm copy numbers obtained for each pair of UM samples then were compared. RESULTS: Of the 20 UM cases 18 gave MLPA results from FFPE material that passed quality control thresholds. When chromosome 3 copy number was classified successfully (loss, disomy or gain) using FFPE material, the corresponding frozen sample showed concordance in 100% of cases. However, even when FFPE samples passed quality thresholds, chromosome arm copy numbers for 3p and 3q were "unclassifiable" in 28% and 11% of cases, respectively. This compared to "unclassifiable" cases in 0% and 6% of the frozen UM samples. CONCLUSIONS: Whenever possible, fresh or snap-frozen tissue should be used for UM genetic prognostic testing by MLPA. When only fixed tissue is available, MLPA can be used to determine reliably chromosome 3 copy number. However, some tumors will be unclassifiable where DNA quality is poor. PMID- 22427595 TI - Nanomechanical characterization of the stiffness of eye lens cells: a pilot study. AB - PURPOSE: The purpose of this study is to probe the mechanical properties of individual eye lens cells isolated from nucleus and cortex of adult sheep eye lens, and to characterize the effect of cytoskeletal drugs. METHODS: We used atomic force microscopy (AFM), featuring a spherical tip at the end of a soft cantilever, to indent single lens cells, and measure the Young's modulus of isolated nuclear and cortical lens cells. Measurements were performed under basal conditions, and after addition of drugs that disrupt actin filaments and microtubules. RESULTS: We found that single lens cells were able to maintain their shape and mechanical properties after being isolated from the lens tissue. The median Young's modulus value for nuclear lens cells (4.83 kPa) was ~ 20-fold higher than for cortical lens cells (0.22 kPa). Surprisingly, disruption of actin filaments and microtubules did not affect the measured Young's moduli. CONCLUSIONS: We found that single cells from the lens nucleus and cortex can be distinguished unambiguously using the elastic modulus as a criterion. The uncommon maintenance of shape and elastic properties after cell isolation together with the null effect of actin filaments and microtubules targeting drugs suggest that the mechanical stability of fiber cells is provided by cellular elements other than the usual cytoskeletal proteins. PMID- 22427596 TI - Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. AB - PURPOSE: To describe epidemiologic characteristics of asymptomatic and symptomatic meibomian gland dysfunction (MGD) in a general adult population in northwestern Spain. METHODS: A total of 1155 subjects aged 40 years and older were selected by an age-stratified random sample procedure in O Salnes, Spain. A standardized symptoms questionnaire was administered and a comprehensive ophthalmic evaluation, which included ocular surface tests, was carried out. Absent, viscous, or waxy white secretion upon digital expression, lid margin telangiectasia or plugging of the meibomian gland orifices was considered evidence of MGD. The prevalence and associations of asymptomatic and symptomatic MGD, and their effects on the ocular surface, were investigated. RESULTS: From 937 eligible subjects, 619 (66.1%) participated (mean age [SD], 63.4 [14.5] years; range, 40-96; 37.0% males). The prevalence of asymptomatic MGD was 21.9% (95% confidence interval [CI], 18.8-25.3). This prevalence increased with age (P = 0.000) and was higher in males than in females (P = 0.003). The prevalence of symptomatic MGD was 8.6% (95% CI, 6.7-10.9). This prevalence also increased with age (P = 0.000) but was not associated with sex. Abnormal tear breakup time and fluorescein staining prevalence estimates were higher among asymptomatic subjects. After controlling for age and sex, asymptomatic MGD was associated with diabetes (adjusted odds ratio [OR(a)] 2.23) and cardiovascular disease (OR(a) 1.80), and symptomatic MGD with rosacea (OR(a) 3.50) and rheumatoid arthritis (OR(a) 16.50). CONCLUSIONS: Asymptomatic MGD is more common than symptomatic MGD. Symptomatology is not associated with secondary damage to the ocular surface. Some systemic diseases may lower whereas others may raise the risk of developing symptoms. Symptom-based approaches do not seem appropriate for MGD estimation. PMID- 22427597 TI - Intervals between visual field tests when monitoring the glaucomatous patient: wait-and-see approach. AB - PURPOSE: Published recommendations suggest three visual field (VF) tests per year are required to identify rapid progression in a newly diagnosed glaucomatous patient over 2 years. This report aims to determine if identification of progression would be improved by clustering tests at the beginning and end of the 2-year period. METHODS: Computer-simulated "patients" were given a rapid VF (mean deviation [MD]) loss of -2 dB/year with added MD measurement variability. Linear regression of MD against time was used to estimate progression. One group of "patients" was measured every 6 months, another every 4 months, whereas the wait and-see group were measured either 2 or 3 times at both baseline and at the end of a 2-year period. Stable "patients" (0 dB/year) were generated to examine the effect of the follow-up patterns on false-positive (FP) progression identification. RESULTS: By 2 years, 58% and 82% of rapidly progressing patients were correctly detected using evenly spaced 6- and 4-month VFs, respectively. This power of detection significantly improved to 62% and 95% with the wait-and see approach (P < 0.001). When compared with evenly spaced VFs, the rate of MD loss was better estimated by the wait-and-see approach, but average detection time was slightly slower. Evenly spaced testing incurred a significantly higher FP rate: up to 5.9% compared with only 0.4% in wait-and-see (P < 0.001). CONCLUSIONS: Compared with an evenly spaced follow-up, wait-and-see identifies more "patients" with rapid VF progression with fewer FPs, making it particularly applicable to clinical trials. Modeling experiments, as reported here, are useful for investigating and optimizing follow-up schemes. PMID- 22427598 TI - The optic nerve head as a robust biomechanical system. AB - Purpose. Understanding the effects of IOP on the optic nerve head (ONH) is important in understanding glaucoma and ONH structure and function. The authors tested the hypothesis that the ONH is a robust biomechanical structure wherein various factors combine to produce a relatively stable response to IOP. Methods. The authors generated two populations of 100,000 ONH numerical models each with randomly selected values, but controlled distributions, either uniform or Gaussian, of ONH geometry and mechanical properties. The authors predicted the lamina cribrosa displacement (LCD), scleral canal expansion (SCE), and the stresses (forces) and deformations (strains) produced by a 10 mm Hg increase in IOP. The authors analyzed the distributions of the responses. Results. The responses were distributed nonuniformly, with the majority of the models having a response within a small region, often less than 30% of the size of the overall response region. This concentration of responses was more marked in the Gaussian population than in the uniform population. All the responses were positively skewed. Whether a particular case was typical or not depended on the response used for classification and on whether the decision was made using one dimensional or two-dimensional criteria. Conclusions. Despite wide variations in ONH characteristics and responses to IOP, some responses were much more common than others. This supports conceiving of the eye as a robust structure, particularly for LCD and SCE, which is tolerant to variations in tissue geometry and mechanical properties. The authors also provide the first estimates of the typical mechanical response of the ONH to variations in IOP over a large population of ONHs. PMID- 22427599 TI - Increased mortality risk among the visually impaired: the roles of mental well being and preventive care practices. AB - PURPOSE: Mechanisms by which visual impairment (VI) increases mortality risk are poorly understood. We estimated the direct and indirect effects of self-rated VI on risk of mortality through mental well-being and preventive care practice mechanisms. METHODS: Using complete data from 12,987 adult participants of the 2000 Medical Expenditure Panel Survey with mortality linkage through 2006, we undertook structural equation modeling using two latent variables representing mental well-being and poor preventive care to examine multiple effect pathways of self-rated VI on all-cause mortality. Generalized linear structural equation modeling was used to simultaneously estimate pathways including the latent variables and Cox regression model, with adjustment for controls and the complex sample survey design. RESULTS: VI increased the risk of mortality directly after adjusting for mental well-being and other covariates (hazard ratio [HR] = 1.25 [95% confidence interval: 1.01, 1.55]). Poor preventive care practices were unrelated to VI and to mortality. Mental well-being decreased mortality risk (HR = 0.68 [0.64, 0.74], P < 0.001). VI adversely affected mental well-being (beta = 0.54 [-0.65, -0.43]; P < 0.001). VI also increased mortality risk indirectly through mental well-being (HR = 1.23 [1.16, 1.30]). The total effect of VI on mortality including its influence through mental well-being was HR 1.53 [1.24, 1.90]. Similar but slightly stronger patterns of association were found when examining cardiovascular disease-related mortality, but not cancer-related mortality. CONCLUSIONS: VI increases the risk of mortality directly and indirectly through its adverse impact on mental well-being. Prevention of disabling ocular conditions remains a public health priority along with more aggressive diagnosis and treatment of depression and other mental health conditions in those living with VI. PMID- 22427600 TI - Theoretical, experimental, and optical coherence tomography (OCT) studies of graft apposition and adhesion in Descemets stripping automated endothelial keratoplasty (DSAEK). AB - PURPOSE: To investigate the effects of adhesion promoting surgical adjuncts in Descemets stripping automated endothelial keratoplasty (DSAEK). The effects of air-fill pressure, duration, use of venting incisions and stromal roughening on fluid dispersion, and donor adhesion strength were examined in theoretical, optical coherence tomography (OCT), and strain gauge models of DSAEK. METHODS: OCT analysis: DSAEK modeled using a microkeratome prepared lenticule inserted under a "recipient" corneo-scleral rim mounted on an artificial anterior chamber. Pressure of 18 mm Hg (n = 6) or 60 mm Hg (n = 6) was applied. The area of interface fluid was measured sequentially. The area of interface fluid before and after opening of venting incisions was measured (n = 6). Adhesion experiments: Direct measurement of adhesion force using a universal testing machine was performed. Peak adhesion after compression at 60 mm Hg/8 minutes, 60 mm Hg/1 minutes, 18 mm Hg/8 minutes, and 18 mm Hg/1 minutes (n = 8 each group) was measured. Subsequently, adhesion after complete removal of interface fluid and after stromal roughening was measured in separate samples (n = 12). RESULTS: Interface fluid diminishes with time during tamponade at both low and high pressures (P < 0.0001). Pressure had no effect on amount or rate of fluid dispersion. Venting incisions eliminated interface fluid in all samples when opened sufficiently. Adhesion is independent of anterior chamber air tamponade pressure (P = 0.38). Complete removal of interface fluid increases average adhesion (16.0 mN vs. 7.8 mN, P = 0.0001). Roughening of the host stroma increased adhesion (13.8 mN vs. 9.8 mN, P = 0.0034). CONCLUSIONS: Venting incisions and stromal roughening aid adhesion in DSAEK. Sustained high-pressure anterior chamber air tamponade has no demonstrable effect on measured fluid dispersion or adhesion strength. PMID- 22427601 TI - Constriction of retinal arterioles to endothelin-1: requisite role of rho kinase independent of protein kinase C and L-type calcium channels. AB - PURPOSE: Although endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in several retinal pathologies, the underlying mechanism of vasoconstriction is understood incompletely. We addressed this issue by assessing the contributions of extracellular calcium (Ca2+), L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) to ET-1 induced constriction of porcine retinal arterioles, all of which have been implicated commonly in vascular smooth muscle contraction. METHODS: Porcine retinal arterioles (~50-100 MUm) were isolated for vasomotor study and molecular assessment of ROCK isoforms. RESULTS: Isolated arterioles developed stable basal tone at 55 cmH2O luminal pressure and constricted to ET-1 (0.1 nM) with a 40 +/- 6% reduction in resting diameter in 20 minutes. In the absence of extraluminal Ca2+, arterioles lost basal tone and failed to constrict to ET-1. Although L-VOCC inhibitor nifedipine reduced basal tone and blocked vasoconstriction to PKC activator PDBu, vasoconstriction to ET-1 was unaffected. The broad-spectrum PKC inhibitor Go-6983 abolished vasoconstriction to PDBu, but did not alter ET-1 induced vasoconstriction or basal tone. Incubation of arterioles with ROCK inhibitor H-1152 abolished basal tone and vasoconstrictions to ET-1 and PDBu. Both ROCK1 and ROCK2 isoforms were expressed in the retinal arteriolar wall. CONCLUSIONS: Extracellular Ca2+ entry via L-VOCCs and basal ROCK activity play important roles in the maintenance of basal tones of porcine retinal arterioles. ET-1-induced constriction is mediated by extracellular Ca2+ entry independent of L-VOCCs and by ROCK activation without the involvement of PKC. However, direct PKC activation can cause vasoconstriction via L-VOCC and ROCK signaling. PMID- 22427602 TI - Larger therapeutic window for steroid versus VEGF-A inhibitor in inflammatory angiogenesis: surprisingly similar impact on leukocyte infiltration. AB - PURPOSE: The current treatments against inflammatory angiogenesis are steroids and anti-VEGF-A, such as dexamethasone and bevacizumab, respectively. However, the therapeutic windows for dexamethasone and bevacizumab against inflammatory angiogenesis are unknown. METHODS: To investigate the therapeutic windows for dexamethasone and bevacizumab, we used the corneal pocket assay. IL-1beta pellets were implanted in corneas of BALB/c mice that were then treated with dexamethasone or bevacizumab at different time points. Angiogenesis (area, number of vessels, and sprouting) was quantitated at various time points after implantation. Nuclear Factor-kappaB (NF-kappaB) signaling and leukocyte accumulation in inflammatory angiogenesis were examined by Western blotting, by immunohistochemistry, and in the authors' novel leukocyte transmigration assay. RESULTS: Dexamethasone inhibited IL-1beta-induced angiogenesis when treatment started 4 days after IL-1beta implantation, while bevacizumab only inhibited angiogenesis by day 2 after implantation. Both bevacizumab and dexamethasone inhibited angiogenic sprouting. Interestingly, bevacizumab did not affect NF kappaB activation, which is one of the main signaling targets for steroid action. The authors' new imaging approach revealed that bevacizumab and steroid treatment blocked leukocyte infiltration into implanted corneas. CONCLUSIONS: VEGF-A inhibition affected angiogenic sprouting, while it was not effective against matured vessels. Both dexamethasone and bevacizumab inhibited leukocyte transmigration from angiogenic vessels; however, dexamethasone had a larger therapeutic window. These insights improve the treatment strategy in angiogenic disorders. PMID- 22427603 TI - Modeling human choroidal melanoma xenograft growth in immunocompromised rodents to assess treatment efficacy. AB - PURPOSE: To evaluate potential treatments of primary uveal melanoma in rodent xenograft models, it is necessary to track individual tumor growth during treatment. Previously, high-frequency ultrasound (HF-US) was used to measure tumor volume in nude rats for up to 2 weeks. This study tests the hypothesis that HF-US can be used to repeatedly measure tumor volume for at least a month in both nude rat and severe combined immunodeficiency (SCID) mouse xenograft models of human uveal melanoma, with the goal of modeling tumor growth to evaluate treatment efficacy. METHODS: C918 human uveal melanoma spheroids were implanted in the choroids of six nude rats and six severe combined immunodeficiency mice. OCM-1 human uveal melanoma spheroids were implanted in six nude rats. Every 4-7 days thereafter for up to 5 weeks, HF-US images of the tumor-bearing eye were captured every 100 or 250 MUm. Tumor areas were measured on each image and integrated to calculate volume. Tumor growth was modeled using a logistic curve, and parameters characterizing growth, including the time to reach a target volume (t(T)), were evaluated as potential measures of treatment efficacy. RESULTS: Tumor volume could be measured for up to 5 weeks in all models, and the logistic curve described the growth well. The parameter t(T) was shown to be a suitable endpoint to evaluate treatments. CONCLUSIONS: HF-US is a practical method to track uveal melanoma growth in the same nude rat or SCID mouse for up to a month. Such growth data can be used to evaluate treatments in these xenograft models. PMID- 22427604 TI - Photo quiz: an 11-year-old with abdominal pain. PMID- 22427605 TI - Routine identification of clinical isolates of anaerobic bacteria: matrix assisted laser desorption ionization-time of flight mass spectrometry performs better than conventional identification methods. PMID- 22427606 TI - Bordetella holmesii in nasopharyngeal samples from Chilean patients with suspected Bordetella pertussis infection. PMID- 22427609 TI - Tools for innovative thinking in epidemiology. AB - Innovation is the engine of scientific progress. Concern has been raised by the National Academies of Science about how well America is sustaining its "creative ecosystem." In this commentary, the author argues that we can all improve our ability to think innovatively through instruction and practice. The author presents a series of tools that are currently being taught in a curriculum developed at the University of Texas, based on earlier evidence-based creativity training programs. The tools are these: 1) finding the right question; 2) enhancing observation; 3) using analogies; 4) juggling induction and deduction; 5) changing your point of view; 6) broadening the perspective; 7) dissecting the problem; 8) leveraging serendipity and reversal; 9) reorganization and combination of ideas; 10) getting the most out of groups; and 11) breaking out of habitual expectations and frames. Each tool is explained using examples from science and public health. It is likely that each of us will identify with and agree with the usefulness of one or two of the tools described. Broader mastery of many of these tools, particularly when used in combination, has provided our students with a powerful device for enhancing innovation. PMID- 22427610 TI - Methods for meta-analyses of genome-wide association studies: critical assessment of empirical evidence. AB - There has been a steep increase in the number of meta-analyses of genome-wide association (GWA) studies aimed at identifying genetic variants with increasingly smaller effects, but pressure to publish findings of new genetic associations has limited the time available for careful consideration of all of their methodological aspects. The authors surveyed the literature (2007-2010) to provide empirical evidence on the methods used in GWA meta-analyses, including their organization, requirements about the uniformity of methods used in primary studies, methods for data pooling, investigation of between-study heterogeneity, and quality of reporting. This review showed that a great variety of methods are being used, but the rationale for their choice is often unclear. It also highlights how important methodological aspects have received insufficient attention, potentially leading to missed opportunities for improving gene discovery and characterization. Evaluation of power to replicate findings was inadequate, and the number of variants selected for replication was not associated with replication sample size. A low proportion of GWA meta-analyses investigated the presence and magnitude of heterogeneity, even when there was little uniformity in methods used in primary studies. More methodological work is required before clear guidance can be offered as to optimal methods or tradeoffs between alternative methods. However, there is a clear need for guidelines for reporting the results of GWA meta-analyses. PMID- 22427611 TI - Adiposity, its related biologic risk factors, and suicide: a cohort study of 542,088 taiwanese adults. AB - Recent studies in Western nations have shown inverse associations between body mass index (BMI, measured as weight (kg)/height (m)(2)) and suicide. However, it is uncertain whether the association is similar in non-Western settings, and the biologic pathways underlying the association are unclear. The authors investigated these issues in a cohort of 542,088 Taiwanese people 20 years of age or older who participated in a health check-up program (1994-2008); there were 573 suicides over a mean 8.1 years of follow up. There was a J-shaped association between BMI and suicide risk (P for the quadratic term = 0.033) but limited evidence of a linear association (adjusted hazard ratio per 1-standard-deviation increase = 0.95 (95% confidence interval: 0.85, 1.06)); compared with individuals whose BMI was 18.5-22.9, adjusted hazard ratios for those with a BMI <18.5 or >=35 were 1.56 (95% confidence interval: 1.07, 2.28) and 3.62 (95% confidence interval: 1.59, 8.22), respectively. A high waist-to-hip ratio was associated with an increased risk of suicide. There was some evidence for a reverse J-shaped association of systolic blood pressure and high density lipoprotein cholesterol with suicide and an association of higher triglyceride level with increased suicide risk; these associations did not appear to mediate the associations of BMI and waist-to-hip ratio with suicide. PMID- 22427612 TI - Mortality prediction by surrogates of body composition: an examination of the obesity paradox in hemodialysis patients using composite ranking score analysis. AB - In hemodialysis patients, lower body mass index and weight loss have been associated with higher mortality rates, a phenomenon sometimes called the obesity paradox. This apparent paradox might be explained by loss of muscle mass. The authors thus examined the relation to mortality of changes in dry weight and changes in serum creatinine levels (a muscle-mass surrogate) in a cohort of 121,762 hemodialysis patients who were followed for up to 5 years (2001-2006). In addition to conventional regression analyses, the authors conducted a ranking analysis of joint effects in which the sums and differences of the percentiles of change for the 2 measures in each patient were used as the regressors. Concordant with previous body mass index observations, lower body mass, lower muscle mass, weight loss, and serum creatinine decline were associated with higher death rates. Among patients with a discordant change, persons whose weight declined but whose serum creatinine levels increased had lower death rates than did those whose weight increased but whose serum creatinine level declined. A decline in serum creatinine appeared to be a stronger predictor of mortality than did weight loss. Assuming residual selection bias and confounding were not large, the present results suggest that a considerable proportion of the obesity paradox in dialysis patients might be explained by the amount of decline in muscle mass. PMID- 22427613 TI - Expression and role of p53 in the retina. AB - Since it was identified in 1979, p53 has been widely studied for its role in tumor suppression. It is mutated in approximately half of all human cancers, leading to aberrant cell growth. In addition to its role as a tumor suppressor, p53 is activated in response to various cell stress signals, including DNA damage and hypoxia. This activation leads to alterations in target gene expression, giving p53 a regulatory role in diverse cellular functions such as apoptosis, senescence, and cell cycle arrest. Throughout life, the eye is exposed to a multitude of stressors including disease, light-induced damage, and oxidative stress, all of which can lead to debilitating loss of vision. This article examines the role of p53 during ocular development. Finally, the role of p53 is examined in ocular response to intense light exposure, ionizing radiation, oxidative stress, degenerative disorders, and retinoblastoma. PMID- 22427614 TI - Efficacy of posaconazole in a murine model of disseminated infection caused by Apophysomyces variabilis. AB - OBJECTIVES: We evaluated the in vitro activity of posaconazole and amphotericin B against several clinical strains of the mucoralean fungus Apophysomyces variabilis, and their efficacy in a murine model of disseminated infection caused by that fungus. METHODS: The in vitro susceptibility of seven strains of A. variabilis to posaconazole and amphotericin B was determined by using a broth microdilution method. The in vivo efficacy of both drugs, posaconazole at 20 mg/kg twice daily orally by gavage and amphotericin B at 0.8 mg/kg once daily intravenously, was evaluated against six of the strains previously tested in vitro using immunocompetent mice. RESULTS: In general, MICs of both drugs were within the range of susceptibility or intermediate susceptibility. Posaconazole and amphotericin B were able to significantly reduce the percentages of positive cultures in the affected tissues. However, in general, posaconazole significantly improved survival (median, 23 days; range, 7-30 days) compared with untreated controls (median, 6 days; range, 4-7 days) and, in some cases, with respect to the animals treated with amphotericin B (median, 15 days; range, 5-30 days). CONCLUSIONS: Our results demonstrate the efficacy of posaconazole in the treatment of a disseminated murine infection caused by A. variabilis. However, further clinical studies are required to ascertain the potential use in human infections caused by this fungus. PMID- 22427615 TI - Trends in cardiovascular health metrics and associations with all-cause and CVD mortality among US adults. AB - CONTEXT: Recent recommendations from the American Heart Association aim to improve cardiovascular health by encouraging the general population to meet 7 cardiovascular health metrics: not smoking; being physically active; having normal blood pressure, blood glucose and total cholesterol levels, and weight; and eating a healthy diet. OBJECTIVE: To examine time trends in cardiovascular health metrics and to estimate joint associations and population-attributable fractions of these metrics in relation to all-cause and cardiovascular disease (CVD) mortality risk. DESIGN, SETTING, AND PARTICIPANTS: Study of a nationally representative sample of 44,959 US adults (>=20 years), using data from the National Health and Nutrition Examination Survey (NHANES) 1988-1994, 1999-2004, and 2005-2010 and the NHANES III Linked Mortality File (through 2006). MAIN OUTCOME MEASURES: All-cause, CVD, and ischemic heart disease (IHD) mortality. RESULTS: Few participants met all 7 cardiovascular health metrics (2.0% [95% CI, 1.5%-2.5%] in 1988-1994, 1.2% [95% CI, 0.8%-1.9%] in 2005-2010). Among NHANES III participants, 2673 all-cause, 1085 CVD, and 576 IHD deaths occurred (median follow-up, 14.5 years). Among participants who met 1 or fewer cardiovascular health metrics, age- and sex-standardized absolute risks were 14.8 (95% CI, 13.2 16.5) deaths per 1000 person-years for all-cause mortality, 6.5 (95% CI, 5.5-7.6) for CVD mortality, and 3.7 (95% CI, 2.8-4.5) for IHD mortality. Among those who met 6 or more metrics, corresponding risks were 5.4 (95% CI, 3.6-7.3) for all cause mortality, 1.5 (95% CI, 0.5-2.5) for CVD mortality, and 1.1 (95% CI, 0.7 2.0) for IHD mortality. Adjusted hazard ratios were 0.49 (95% CI, 0.33-0.74) for all-cause mortality, 0.24 (95% CI, 0.13-0.47) for CVD mortality, and 0.30 (95% CI, 0.13-0.68) for IHD mortality, comparing participants who met 6 or more vs 1 or fewer cardiovascular health metrics. Adjusted population-attributable fractions were 59% (95% CI, 33%-76%) for all-cause mortality, 64% (95% CI, 28% 84%) for CVD mortality, and 63% (95% CI, 5%-89%) for IHD mortality. CONCLUSION: Meeting a greater number of cardiovascular health metrics was associated with a lower risk of total and CVD mortality, but the prevalence of meeting all 7 cardiovascular health metrics was low in the study population. PMID- 22427616 TI - Improving the cardiovascular health of the US population. PMID- 22427617 TI - Hyaluronan protects bovine articular chondrocytes against cell death induced by bupivacaine at supraphysiologic temperatures. AB - BACKGROUND: Bupivacaine and supraphysiologic temperature can independently reduce cell viability of articular chondrocytes. In combination, these 2 deleterious factors could further impair cell viability. HYPOTHESIS: Hyaluronan may protect chondrocytes from death induced by bupivacaine at supraphysiologic temperatures. STUDY DESIGN: Controlled laboratory study. METHODS: Bovine articular chondrocytes were treated with hyaluronan at physiologic (37 degrees C) and supraphysiologic temperatures (45 degrees C and 50 degrees C) for 1 hour and then exposed to bupivacaine for 1 hour at room temperature. Cell viability was assessed at 3 time points: immediately after treatment, 6 hours later, and 24 hours later using flow cytometry and fluorescence microscopy. The effects of hyaluronan on the levels of sulfated glycosaminoglycan in the chondrocytes were determined using Alcian blue staining. RESULTS: (1) Bupivacaine alone did not induce noticeable chondrocyte death at 37 degrees C; (2) bupivacaine and temperature synergistically increased chondrocyte death, that is, when the chondrocytes were conditioned to 45 degrees C and 50 degrees C, 0.25% and 0.5% bupivacaine increased the cell death rate by 131% to 383% in comparison with the phosphate-buffered saline control group; and (3) addition of hyaluronan reduced chondrocyte death rates to approximately 14% and 25% at 45 degrees C and 50 degrees C, respectively. Hyaluronan's protective effects were still observed at 6 and 24 hours after bupivacaine treatment at 45 degrees C. However, at 50 degrees C, hyaluronan delayed but did not prevent the cell death caused by bupivacaine. One-hour treatment with hyaluronan significantly increased sulfated glycosaminoglycan levels in the chondrocytes. CONCLUSION: Bupivacaine and supraphysiologic temperature synergistically increase chondrocyte death, and hyaluronan may protect articular chondrocytes from death caused by bupivacaine. CLINICAL RELEVANCE: This study provides a rationale to perform preclinical and clinical studies to evaluate whether intra-articular injection of a mixture of bupivacaine and hyaluronan after arthroscopic surgery may protect against bupivacaine's chondrotoxicity. PMID- 22427618 TI - Acceleration of tendon-bone healing of anterior cruciate ligament graft using autologous ruptured tissue. AB - BACKGROUND: It has been recently reported that human anterior cruciate ligament (ACL) ruptured tissue contains abundant vascular stem cells that contribute to tendon-bone healing in an immunodeficient rat model of ACL reconstruction. HYPOTHESIS: Autologous ruptured ACL tissue has an effect on the maturation of bone-tendon integration in anterior cruciate ligament reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty healthy adult beagle dogs underwent bilateral ACL reconstruction using the ipsilateral flexor digitorum superficialis tendon and were divided into 2 groups: right knee (a tissue-treated group) and left knee (a control group). The tissue-treated group received autologous ruptured ACL tissue, which was obtained 2 days after resection and sutured to the tibial side of the graft. Histological, radiographic, and biomechanical assessments were performed. In addition, immunohistochemical staining was performed to assess angiogenesis and osteogenesis. RESULTS: Histological assessment and staining for osteoblasts and endothelial cells at week 2 demonstrated early healing, inducing endochondral ossification-like integration with enhanced angiogenesis and osteogenesis in the tissue-treated group's grafts. Computed tomography at week 4 showed a significantly smaller tibial bone tunnel in the tissue-treated group (tissue, 19.0 +/- 4.4 mm(2); control, 42.6 +/- 4.7 mm(2); P = .009, n = 5). Furthermore, biomechanical testing of force during loading to ultimate failure at week 4 demonstrated a significantly higher strength in the tissue-treated group (tissue, 66.4 +/- 10.1 N; control, 30.5 +/- 10.3 N; P = .009, n = 5). CONCLUSION: In the present study, the authors elucidated that transplantation of ACL-ruptured tissue, which was sutured to the tibial side of the graft, contributed to early tendon-bone healing in a canine model of ACL reconstruction. CLINICAL RELEVANCE: Anterior cruciate ligament ruptured tissue has a therapeutic potential in promoting an appropriate environment for tendon-to-bone healing in bone tunnels of ACL reconstruction. PMID- 22427619 TI - Leg dominance is a risk factor for noncontact anterior cruciate ligament injuries in female recreational skiers. AB - BACKGROUND: In recreational alpine skiing, the knee joint accounts for about one third of all injuries in male and female skiers. However, female recreational skiers have twice the knee injury incidence of male skiers, and the anterior cruciate ligament (ACL) injury risk is 3 times greater in female skiers. PURPOSE: To evaluate whether leg dominance is a risk factor for noncontact ACL injuries in female recreational skiers. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The relationships between leg dominance, side of knee injury, and gender were analyzed in 65 male and 128 female skiers suffering from a noncontact ACL rupture. RESULTS: Anterior cruciate ligament ruptures of the left knee occurred more frequently in female than in male recreational skiers (68% vs 48%, P = .006). For both genders, in 90%, the right leg was the preferred kicking leg. With regard to leg dominance, female skiers suffered more often from ACL ruptures of their nondominant leg than male skiers (63% vs 45%, P = .020). An adjusted odds ratio of 2.0 (95% confidence interval, 1.0-3.8) was calculated. CONCLUSION: Female skiers showed a 2-fold higher risk of suffering from an ACL rupture on their nondominant leg. Therefore, leg dominance seems to be a risk factor for noncontact ACL injuries in female recreational skiers. PMID- 22427620 TI - All-inside repair for a root tear of the medial meniscus using a suture anchor. AB - BACKGROUND: There are no published articles reporting clinical outcomes after all inside meniscal repair using a suture anchor for a medial meniscal root tear. PURPOSE: To evaluate the subjective and objective outcomes after repair of medial meniscal root tears. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirteen patients with a root tear of the medial meniscus underwent all-inside repair using a suture anchor. Postoperative evaluation of meniscal status was performed using physical examination criteria, specifically joint line tenderness, McMurray test, and follow-up magnetic resonance imaging (MRI). Functional evaluations were performed using Tegner activity level and Lysholm knee score. Follow-up MRI scans were obtained 6 months postoperatively to evaluate healing of the root tear and measure extrusion of the midbody of the medial meniscus. RESULTS: The average follow-up was 30.8 months (range, 24-40 months). No patients had joint line tenderness or effusion. No patients demonstrated a positive McMurray test result postoperatively. The preoperative mean Tegner activity level was 1.9 (range, 1-6), and the mean Lysholm score was 69.1 (range, 53-91). At last follow-up, the mean Tegner activity level was 3.9 (range, 2-6), and the mean Lysholm score was 90.3 (range, 75-100). Improvements in both the Tegner activity level and Lysholm score were statistically significant (P = .001 and P = .000, respectively). Follow-up MRI was performed in 10 patients. Five (50%) patients showed complete healing; 2 of these 5 patients showed complete healing with isointense signal of a normal meniscus, and 3 showed intermediate signal tissue at the previous tear site without any high signal cleft or ghost sign. Four (40%) patients showed partial healing, and 1 (10%) showed no healing. Mean extrusion of the midbody of the medial meniscus was 3.9 mm (range, 2.2-7.1 mm) preoperatively and 3.5 mm (range, 1.2-6.1 mm) postoperatively. Extrusion was not significantly decreased. CONCLUSION: This study demonstrated symptomatic improvement after meniscal root repair using a suture anchor. However, follow-up MRI scans did not show complete healing of all repaired root tears. PMID- 22427621 TI - Forefoot running improves pain and disability associated with chronic exertional compartment syndrome. AB - BACKGROUND: Anterior compartment pressures of the leg as well as kinematic and kinetic measures are significantly influenced by running technique. It is unknown whether adopting a forefoot strike technique will decrease the pain and disability associated with chronic exertional compartment syndrome (CECS) in hindfoot strike runners. HYPOTHESIS: For people who have CECS, adopting a forefoot strike running technique will lead to decreased pain and disability associated with this condition. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Ten patients with CECS indicated for surgical release were prospectively enrolled. Resting and postrunning compartment pressures, kinematic and kinetic measurements, and self-report questionnaires were taken for all patients at baseline and after 6 weeks of a forefoot strike running intervention. Run distance and reported pain levels were recorded. A 15-point global rating of change (GROC) scale was used to measure perceived change after the intervention. RESULTS: After 6 weeks of forefoot run training, mean postrun anterior compartment pressures significantly decreased from 78.4 +/- 32.0 mm Hg to 38.4 +/ 11.5 mm Hg. Vertical ground-reaction force and impulse values were significantly reduced. Running distance significantly increased from 1.4 +/- 0.6 km before intervention to 4.8 +/- 0.5 km 6 weeks after intervention, while reported pain while running significantly decreased. The Single Assessment Numeric Evaluation (SANE) significantly increased from 49.9 +/- 21.4 to 90.4 +/- 10.3, and the Lower Leg Outcome Survey (LLOS) significantly increased from 67.3 +/- 13.7 to 91.5 +/- 8.5. The GROC scores at 6 weeks after intervention were between 5 and 7 for all patients. One year after the intervention, the SANE and LLOS scores were greater than reported during the 6-week follow-up. Two-mile run times were also significantly faster than preintervention values. No patient required surgery. CONCLUSION: In 10 consecutive patients with CECS, a 6-week forefoot strike running intervention led to decreased postrunning lower leg intracompartmental pressures. Pain and disability typically associated with CECS were greatly reduced for up to 1 year after intervention. Surgical intervention was avoided for all patients. PMID- 22427622 TI - The effect of proximal tibial slope on dynamic stability testing of the posterior cruciate ligament- and posterolateral corner-deficient knee. AB - BACKGROUND: Proximal tibial slope has been shown to influence anteroposterior translation and tibial resting point in the posterior cruciate ligament (PCL) deficient knee. The effect of proximal tibial slope on rotational stability of the knee is unknown. HYPOTHESIS: Change in proximal tibial slope produced via osteotomy can influence both static translation and dynamic rotational kinematics in the PCL/posterolateral corner (PLC)-deficient knee. STUDY DESIGN: Controlled laboratory study. METHODS: Posterior drawer, dial, and mechanized reverse pivot shift (RPS) tests were performed on hip-to-toe specimens and translation of the lateral and medial compartments measured utilizing navigation (n = 10). The PCL and structures of the PLC were then sectioned. Stability testing was repeated, and compartmental translation was recorded. A proximal tibial osteotomy in the sagittal plane was then performed achieving either +5 degrees or -5 degrees of tibial slope variation, after which stability testing was repeated (n = 10). Analysis was performed using 1-way analysis of variance (ANOVA; alpha = .05). RESULTS: Combined sectioning of the PCL and PLC structures resulted in a 10.5-mm increase in the posterior drawer, 15.5-mm increase in the dial test at 30 degrees , 14.5-mm increase in the dial test at 90 degrees , and 17.9-mm increase in the RPS (vs intact; P < .05). Increasing the posterior slope (high tibial osteotomy [HTO] +5 degrees ) in the PCL/PLC-deficient knee reduced medial compartment translation by 3.3 mm during posterior drawer (vs deficient; P < .05) but had no significant effect on the dial test at 30 degrees , dial test at 90 degrees , or RPS. Conversely, reversing the slope (HTO -5 degrees ) caused a 4.8-mm increase in medial compartment translation (vs deficient state; P < .05) during posterior drawer and an 8.6-mm increase in lateral compartment translation and 9.0-mm increase in medial compartment translation during RPS (vs deficient state; P < .05). CONCLUSION: Increasing posterior tibial slope diminished static posterior instability of the PCL/PLC-deficient knee as measured by the posterior drawer test but had little effect on rotational or dynamic multiplanar stability as assessed by the dial and RPS tests, respectively. Conversely, decreasing posterior slope resulted in increased posterior instability and a significant increase in the magnitude of the RPS. CLINICAL RELEVANCE: These results suggest that increasing posterior tibial slope may improve sagittal stability in the PCL/PLC-deficient knee. Moreover, a knee with diminished posterior tibial slope may demonstrate greater multiplanar instability in this setting. Consequently, proximal tibial slope should be considered when treating combined PCL/PLC injuries of the knee. PMID- 22427623 TI - Efficient decoding of the UAG triplet as a full-fledged sense codon enhances the growth of a prfA-deficient strain of Escherichia coli. AB - We previously reassigned the amber UAG stop triplet as a sense codon in Escherichia coli by expressing a UAG-decoding tRNA and knocking out the prfA gene, encoding release factor 1. UAG triplets were left at the ends of about 300 genes in the genome. In the present study, we showed that the detrimental effect of UAG reassignment could be alleviated by increasing the efficiency of UAG translation instead of reducing the number of UAGs in the genome. We isolated an amber suppressor tRNA(Gln) variant displaying enhanced suppression activity, and we introduced it into the prfA knockout strain, RFzero-q, in place of the original suppressor tRNA(Gln). The resulting strain, RFzero-q3, translated UAG to glutamine almost as efficiently as the glutamine codons, and it proliferated faster than the parent RFzero-q strain. We identified two major factors in this growth enhancement. First, the sucB gene, which is involved in energy regeneration and has two successive UAG triplets at the end, was expressed at a higher level in RFzero-q3 than RFzero-q. Second, the ribosome stalling that occurred at UAG in RFzero-q was resolved in RFzero-q3. The results revealed the importance of "backup" stop triplets, UAA or UGA downstream of UAG, to avoid the deleterious impact of UAG reassignment on the proteome. PMID- 22427624 TI - Biofilm research uncovers a novel nonenzymatic signal peptidase function in Bacillus. PMID- 22427625 TI - Inhibition of the sole type I signal peptidase of Mycobacterium tuberculosis is bactericidal under replicating and nonreplicating conditions. AB - Proteins secreted by bacteria perform functions vital for cell survival and play a role in virulence in Mycobacterium tuberculosis. M. tuberculosis lepB (Rv2903c) encodes the sole homolog of the type I signal peptidase (SPase). The lepB gene is essential in M. tuberculosis, since we could delete the chromosomal copy only when a second functional copy was provided elsewhere. By placing expression under the control of an anhydrotetracycline-inducible promoter, we confirmed that reduced lepB expression was detrimental to growth. Furthermore, we demonstrated that a serine-lysine catalytic dyad, characteristic for SPase function, is required for LepB function. We confirmed the involvement of LepB in the secretion of a reporter protein fused to an M. tuberculosis signal peptide. An inhibitor of LepB (MD3; a beta-aminoketone) was active against M. tuberculosis, exhibiting growth inhibition and bactericidal activity. Overexpression of lepB reduced the susceptibility of M. tuberculosis to MD3, and downregulation resulted in increased susceptibility, suggesting that LepB is the true target of MD3. MD3 lead to a rapid loss of viability and cell lysis. Interestingly, the compound had increased potency in nonreplicating cells, causing a reduction in viable cell numbers below the detection limit after 24 h. These data suggest that protein secretion is required to maintain viability under starvation conditions and that secreted proteins play a critical role in generating and surviving the persistent state. We conclude that LepB is a promising novel target for drug discovery in M. tuberculosis, since its inhibition results in rapid killing of persistent and replicating organisms. PMID- 22427626 TI - Induction of the Pho regulon suppresses the growth defect of an Escherichia coli sgrS mutant, connecting phosphate metabolism to the glucose-phosphate stress response. AB - Some bacteria experience stress when glucose-6-phosphate or analogues like alpha methyl glucoside-6-phosphate (alphaMG6P) accumulate in the cell. In Escherichia coli, the small SgrS RNA is vital to recovery from glucose-phosphate stress; the growth of sgrS mutants is strongly inhibited by alphaMG. SgrS helps to restore growth in part through inhibiting translation of the ptsG mRNA, which encodes the major glucose transporter EIICB(Glc). While the regulatory mechanism of SgrS has been characterized, little is known about how glucose-phosphate stress connects to other aspects of cell physiology. In the present study, we discovered that mutation of pitA, which encodes the low-affinity transporter of inorganic phosphate, partially suppresses the alphaMG growth defect of an sgrS mutant. Induction of the stress response was also reduced in the sgrS pitA mutant compared to its sgrS parent. Microarray analysis suggested that expression of phosphate (Pho) regulon genes is increased in the sgrS pitA mutant compared to the sgrS parent. Consistent with this, we found increased PhoA (alkaline phosphatase) activity in the sgrS pitA mutant compared to the sgrS strain. Further, direct induction of the Pho regulon (in a pitA(+) background) also resulted in partial suppression of the sgrS growth defect. The suppression was reversed when Pho induction was prevented by mutation of phoB, which encodes the Pho transcriptional activator. Deletion of individual Pho structural genes in suppressed strains did not identify a single gene responsible for suppression. Altogether, this work describes one of the first studies of glucose-phosphate stress physiology and suggests a novel connection of carbon and phosphate metabolism. PMID- 22427627 TI - The RNA chaperone Hfq regulates antibiotic biosynthesis in the rhizobacterium Pseudomonas aeruginosa M18. AB - The rhizosphere microbe Pseudomonas aeruginosa M18 shows strong antifungal activities, mainly due to the biosynthesis of antibiotics like pyoluteorin (Plt) and phenazine-1-carboxylic acid (PCA). The ubiquitous RNA chaperone Hfq regulates bacterial virulence and stress tolerance through global posttranscriptional regulation. Here, we explored the molecular mechanism by which Hfq controls antibiotic biosynthesis in P. aeruginosa M18. The robust downregulation of Plt biosynthesis by Hfq was mediated exclusively by the posttranscriptional downregulation of the plt transcriptional activator PltR. Hfq posttranscriptionally repressed phzM expression and consequently reduced the conversion of PCA to pyocyanin. However, Hfq positively controlled the phz2 operon and PCA biosynthesis through both QscR-mediated transcriptional regulation at the promoter and an unknown regulation at the operator. Also, Hfq was shown to directly bind at the mRNA 5' untranslated leaders of pltR, qscR, and phzM. These three negatively regulated target genes of Hfq shared a similar secondary structure with a short single-stranded AU-rich spacer (a potential Hfq-binding motif) linking two stem-loops. Taken together, these results indicate that Hfq, potentially in collaboration with unknown small noncoding RNAs (sRNAs), tightly controls antibiotic biosynthesis through both direct posttranscriptional inhibition and indirect transcriptional regulation. PMID- 22427628 TI - Alp7R regulates expression of the actin-like protein Alp7A in Bacillus subtilis. AB - Alp7A is a bacterial actin from Bacillus subtilis plasmid pLS20 that functions in plasmid segregation. Alp7A's function requires that it assemble into filaments that treadmill and exhibit dynamic instability. These dynamic properties require the two other components of the alp7A operon, the downstream alp7R gene and the upstream alp7C sequence, as does the ability of Alp7A to form filaments at its physiological concentration in the cell. Here, we show that these two other components of the operon also determine the amount of Alp7A that is produced in the cell. The deletion of alp7R leads to overproduction of Alp7A, which assembles into large, amorphous, static filaments that disrupt chromosome segregation and cell division. The product of the alp7R gene is a DNA-binding protein that represses transcription of the alp7A operon. Purified Alp7R protein binds specifically to alp7C, which contains two sigma(A) promoters embedded within a series of near-repeats of a 10-mer. Alp7R also shows the typical nonspecific binding activity of a DNA-binding protein: Alp7R-GFP (green fluorescent protein) associates with the chromosomes of cells that lack alp7C. When Alp7A-GFP is produced in B. subtilis along with untagged Alp7R, Alp7A-GFP also colocalizes with the chromosome, indicating that Alp7R associates with Alp7A. Hence Alp7R, determines both the activity and the cellular concentration of Alp7A, and it can associate with Alp7A even if it is not bound to alp7C. PMID- 22427629 TI - The FsrA sRNA and FbpB protein mediate the iron-dependent induction of the Bacillus subtilis lutABC iron-sulfur-containing oxidases. AB - The Bacillus subtilis ferric uptake regulator (Fur) protein regulates iron homeostasis and directly represses more than 20 operons. Fur indirectly regulates many more genes, including those controlled by the small, noncoding RNA FsrA. FsrA translationally represses numerous target genes and, for at least some targets, appears to function in conjunction with one or more of three small, basic proteins, known as FbpA, FbpB, and FbpC. The lactate-inducible lutABC operon encodes iron sulfur-containing enzymes required for growth on lactate. We here demonstrate that a fur mutant strain grows poorly on lactate due to FsrA dependent repression of LutABC synthesis. Growth is restored in an fsrA mutant and also partially restored by mutation of the fbpAB operon. Genetic studies indicate that the 48-amino-acid FbpB protein but not FbpA contributes to regulation of lutABC. FbpB may function, at least in part, by increasing the efficiency of FsrA targeting to the lutABC mRNA, since the role of FbpB can be bypassed by modest upregulation of FsrA. These results provide support for a model in which FbpB, and perhaps other Fbp proteins, contributes along with FsrA to the translational regulation of gene expression. PMID- 22427630 TI - Mfd is required for rapid recovery of transcription following UV-induced DNA damage but not oxidative DNA damage in Escherichia coli. AB - Transcription-coupled repair (TCR) is a cellular process by which some forms of DNA damage are repaired more rapidly from transcribed strands of active genes than from nontranscribed strands or the overall genome. In humans, the TCR coupling factor, CSB, plays a critical role in restoring transcription following both UV-induced and oxidative DNA damage. It also contributes indirectly to the global repair of some forms of oxidative DNA damage. The Escherichia coli homolog, Mfd, is similarly required for TCR of UV-induced lesions. However, its contribution to the restoration of transcription and to global repair of oxidative damage has not been examined. Here, we report the first direct study of transcriptional recovery following UV-induced and oxidative DNA damage in E. coli. We observed that mutations in mfd or uvrA reduced the rate that transcription recovered following UV-induced damage. In contrast, no difference was detected in the rate of transcription recovery in mfd, uvrA, fpg, nth, or polB dinB umuDC mutants relative to wild-type cells following oxidative damage. mfd mutants were also fully resistant to hydrogen peroxide (H(2)O(2)) and removed oxidative lesions from the genome at rates comparable to wild-type cells. The results demonstrate that Mfd promotes the rapid recovery of gene expression following UV-induced damage in E. coli. In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage. PMID- 22427631 TI - Phylogeny of the staphylococcal major autolysin and its use in genus and species typing. AB - The major staphylococcal autolysin Atl is an important player in cell separation and daughter cell formation. In this study, we investigated the amino acid sequences of Atl proteins derived from 15 staphylococcal and 1 macrococcal species representatives. The overall organization of the bifunctional precursor protein consisting of the signal peptide, a propeptide (PP), the amidase (AM), six repeat sequences (R(1) to R(6)), and the glucosaminidase (GL) was highly conserved in all of the species. The most-conserved domains were the enzyme domains AM and GL; the least-conserved regions were the PP and R regions. An Atl based phylogenetic tree for the various species representatives correlated well with the corresponding 16S rRNA-based tree and also perfectly matched the phylogenetic trees based on core genome analysis. The phylogenetic distance analysis of 18 AtlA proteins of various Staphylococcus aureus strains and 15 AtlE proteins of S. epidermidis revealed that both species representatives formed a relatively homogeneous cluster. Two S. epidermidis strains, M23864:W1 and VCU116, were identified by Atl typing that clustered far more distantly and belonged to either S. caprae and S. capitis or a new subspecies. Here we show that Atl typing is a useful tool for staphylococcal genus and species typing by using either the highly conserved AM domain or the less-conserved PP domain. PMID- 22427632 TI - Heat shock protein 90-mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by CD4(+) T cells. AB - Tumor Ag-specific CD4(+) T cells play important functions in tumor immunosurveillance, and in certain cases they can directly recognize HLA class II expressing tumor cells. However, the underlying mechanism of intracellular Ag presentation to CD4(+) T cells by tumor cells has not yet been well characterized. We analyzed two naturally occurring human CD4(+) T cell lines specific for different peptides from cytosolic tumor Ag NY-ESO-1. Whereas both lines had the same HLA restriction and a similar ability to recognize exogenous NY-ESO-1 protein, only one CD4(+) T cell line recognized NY-ESO-1(+) HLA class II expressing melanoma cells. Modulation of Ag processing in melanoma cells using specific molecular inhibitors and small interfering RNA revealed a previously undescribed peptide-selective Ag-presentation pathway by HLA class II(+) melanoma cells. The presentation required both proteasome and endosomal protease-dependent processing mechanisms, as well as cytosolic heat shock protein 90-mediated chaperoning. Such tumor-specific pathway of endogenous HLA class II Ag presentation is expected to play an important role in immunosurveillance or immunosuppression mediated by various subsets of CD4(+) T cells at the tumor local site. Furthermore, targeted activation of tumor-recognizing CD4(+) T cells by vaccination or adoptive transfer could be a suitable strategy for enhancing the efficacy of tumor immunotherapy. PMID- 22427633 TI - MARCKS as a negative regulator of lipopolysaccharide signaling. AB - Myristoylated alanine-rich C kinase substrate (MARCKS) is an intrinsically unfolded protein with a conserved cationic effector domain, which mediates the cross-talk between several signal transduction pathways. Transcription of MARCKS is increased by stimulation with bacterial LPS. We determined that MARCKS and MARCKS-related protein specifically bind to LPS and that the addition of the MARCKS effector peptide inhibited LPS-induced production of TNF-alpha in mononuclear cells. The LPS binding site within the effector domain of MARCKS was narrowed down to a heptapeptide that binds to LPS in an extended conformation as determined by nuclear magnetic resonance spectroscopy. After LPS stimulation, MARCKS moved from the plasma membrane to FYVE-positive endosomes, where it colocalized with LPS. MARCKS-deficient mouse embryonic fibroblasts (MEFs) responded to LPS with increased IL-6 production compared with the matched wild type MEFs. Similarly, small interfering RNA knockdown of MARCKS also increased LPS signaling, whereas overexpression of MARCKS inhibited LPS signaling. TLR4 signaling was enhanced by the ablation of MARCKS, which had no effect on stimulation by TLR2, TLR3, and TLR5 agonists. These findings demonstrate that MARCKS contributes to the negative regulation of the cellular response to LPS. PMID- 22427634 TI - Hypoxia triggers the expression of human beta defensin 2 and antimicrobial activity against Mycobacterium tuberculosis in human macrophages. AB - Low oxygen tension is a metabolic hallmark of chronic infection. To investigate the influence of hypoxia on macrophage biology, we analyzed the interaction between the intracellular pathogen Mycobacterium tuberculosis and primary human macrophages. Although the metabolic activity of extracellular M. tuberculosis was reduced at oxygen levels between 0.5 and 10%, the bacilli remained viable throughout the 4 d of culture. Phagocytosis of virulent M. tuberculosis and the pathogen-induced release of inflammatory cytokines by macrophages were not affected by oxygen levels as low as 1%. However, we detected the upregulation of an antimicrobial effector pathway mediated by the vitamin D receptor and human beta defensin 2. This finding was functionally relevant, because intracellular mycobacterial growth was inhibited by 58 +/- 8% at 1% O(2). We conclude that a hypoxic microenvironment, which is characteristic of infected tissue, supports the efficacy of antimicrobial immunity, in part by the upregulation of the antimicrobial peptide human beta defensin 2. PMID- 22427635 TI - Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation. AB - Negative regulation of innate immune responses is essential to prevent excess inflammation and tissue injury and promote homeostasis. Lysophosphatidic acid (LPA) is a pleiotropic lipid that regulates cell growth, migration, and activation and is constitutively produced at low levels in tissues and in serum. Extracellular LPA binds to specific G protein-coupled receptors, whose function in regulating innate or adaptive immune responses remains poorly understood. Of the classical LPA receptors belonging to the Edg family, lpa2 (edg4) is expressed by dendritic cells (DC) and other innate immune cells. In this article, we show that DC from lpa2(-/-) mice are hyperactive compared with their wild-type counterparts and are less susceptible to inhibition by different LPA species. In transient-transfection assays, we found that lpa2 overexpression inhibits NF kappaB-driven gene transcription. Using an adoptive-transfer approach, we found that allergen-pulsed lpa2(-/-) DC induced substantially more lung inflammation than did wild-type DC after inhaled allergen challenge. Finally, lpa2(-/-) mice develop greater allergen-driven lung inflammation than do their wild-type counterparts in models of allergic asthma involving both systemic and mucosal sensitization. Taken together, these findings identify LPA acting via lpa2 as a novel negative regulatory pathway that inhibits DC activation and allergic airway inflammation. PMID- 22427636 TI - The SWI/SNF-like BAF complex is essential for early B cell development. AB - During the process of B cell development, transcription factors, such as E2A and Ebf1, have been known to play key roles. Although transcription factors and chromatin regulators work in concert to direct the expression of B lineage specific genes, little is known about the involvement of regulators for chromatin structure during B lymphopoiesis. In this article, we show that deletion of Srg3/mBaf155, a scaffold subunit of the SWI/SNF-like BAF complex, in the hematopoietic lineage caused defects at both the common lymphoid progenitor stage and the transition from pre-pro-B to early pro-B cells due to failures in the expression of B lineage-specific genes, such as Ebf1 and Il7ra, and their downstream target genes. Moreover, mice that were deficient in the expression of Brg1, a subunit of the complex with ATPase activity, also showed defects in early B cell development. We also found that the expression of Ebf1 and Il7ra is directly regulated by the SWI/SNF-like BAF complex. Thus, our results suggest that the SWI/SNF-like BAF complex facilitates early B cell development by regulating the expression of B lineage-specific genes. PMID- 22427637 TI - Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. AB - Follicular helper CD4 T (Tfh) cells provide B cells with signals that are important for the generation of high-affinity Abs and immunological memory and, therefore, are critical for the protective immunity elicited by most human vaccines. Transcriptional regulators of human Tfh cell differentiation are poorly understood. In this article, we demonstrate that Bcl6 controls specific gene modules for human Tfh cell differentiation. The introduction of Bcl6 expression in primary human CD4 T cells resulted in the regulation of a core set of migration genes that enable trafficking to germinal centers: CXCR4, CXCR5, CCR7, and EBI2. Bcl6 expression also induced a module of protein expression critical for T-B interactions, including SAP, CD40L, PD-1, ICOS, and CXCL13. This constitutes direct evidence for Bcl6 control of most of these functions and includes three genes known to be loci of severe human genetic immunodeficiencies (CD40L, SH2D1A, and ICOS). Introduction of Bcl6 did not alter the expression of IL-21 or IL-4, the primary cytokines of human Tfh cells. We show in this article that introduction of Maf (c-Maf) does induce the capacity to express IL-21. Surprisingly, Maf also induced CXCR5 expression. Coexpression of Bcl6 and Maf revealed that Bcl6 and Maf cooperate in the induction of CXCR4, PD-1, and ICOS. Altogether, these findings reveal that Bcl6 and Maf collaborate to orchestrate a suite of genes that define core characteristics of human Tfh cell biology. PMID- 22427638 TI - Vigorous response of human innate functioning IgM memory B cells upon infection by Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae, the cause of the sexually transmitted infection gonorrhea, elicits low levels of specific Ig that decline rapidly after the bacteria are cleared. Reinfection with the same serovar can occur, and prior gonococcal infection does not alter the Ig response upon subsequent exposure, suggesting that protective immunity is not induced. The mucosal Ig response apparent during gonorrhea does not correlate with that observed systemically, leading to a suggestion that it is locally generated. In considering whether N. gonorrhoeae directly influences B cells, we observed that gonococcal infection prolonged viability of primary human B cells in vitro and elicited robust activation and vigorous proliferative responses in the absence of T cells. Furthermore, we observed the specific expansion of IgD(+)CD27(+) B cells in response to gonococcal infection. These cells are innate in function, conferring protection against diverse microbes by producing low-affinity, broadly reactive IgM without inducing classical immunologic memory. Although gonococcal infection of B cells produced small amounts of gonococcal-specific IgM, IgM specific for irrelevant Ags were also produced, suggesting a broad, polyspecific Ig response. The gonococci were effectively bound and engulfed by B cells. TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. To our knowledge, this is the first report of a bacterial pathogen having specific affinity for the human IgM memory B cells, driving their potent activation and polyclonal Ig response. This unfocused T-independent response explains the localized Ig response that occurs, despite an absence of immunologic memory elicited during gonorrhea. PMID- 22427639 TI - Innate immunity mediates follicular transport of particulate but not soluble protein antigen. AB - Ag retention on follicular dendritic cells (FDCs) is essential for B cell activation and clonal selection within germinal centers. Protein Ag is deposited on FDCs after formation of immune complexes with specific Abs. In this study, by comparing the same antigenic determinant either as soluble protein or virus-like particle (VLP), we demonstrate that VLPs are transported efficiently to murine splenic FDCs in vivo in the absence of prior immunity. Natural IgM Abs and complement were required and sufficient to mediate capture and transport of VLPs by noncognate B cells. In contrast, soluble protein was only deposited on FDCs in the presence of specifically induced IgM or IgG Abs. Unexpectedly, IgG Abs had the opposite effect on viral particles and inhibited FDC deposition. These findings identify size and repetitive structure as critical factors for efficient Ag presentation to B cells and highlight important differences between soluble proteins and viral particles. PMID- 22427640 TI - Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance. AB - Hepatic stellate cells (HSCs) may play an important role in hepatic immune regulation by producing numerous cytokines/chemokines and expressing Ag presenting and T cell coregulatory molecules. Due to disruption of the endothelial barrier during cold-ischemic storage and reperfusion of liver grafts, HSCs can interact directly with cells of the immune system. Endotoxin (LPS), levels of which increase in liver diseases and transplantation, stimulates the synthesis of many mediators by HSCs. We hypothesized that LPS-stimulated HSCs might promote hepatic tolerogenicity by influencing naturally occurring immunosuppressive CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Following their portal venous infusion, allogeneic CD4(+) T cells, including Tregs, were found closely associated with HSCs, and this association increased in LPS-treated livers. In vitro, both unstimulated and LPS-stimulated HSCs upregulated Fas (CD95) expression on conventional CD4(+) T cells and induced their apoptosis in a Fas/Fas ligand-dependent manner. By contrast, HSCs induced Treg proliferation, which required cell-cell contact and was MHC class II-dependent. This effect was augmented when HSCs were pretreated with LPS. LPS increased the expression of MHC class II, CD80, and CD86 and stimulated the production of IL-1alpha, IL-1beta, IL 6, IL-10 and TNF-alpha by HSCs. Interestingly, production of IL-1alpha, IL-1beta, IL-6, and TNF-alpha was strongly inhibited, but that of IL-10 enhanced in LPS pretreated HSC/Treg cocultures. Adoptively transferred allogeneic HSCs migrated to the secondary lymphoid tissues and induced Treg expansion in lymph nodes. These data implicate endotoxin-stimulated HSCs as important immune regulators in liver transplantation by inducing selective expansion of tolerance-promoting Tregs and reducing inflammation and alloimmunity. PMID- 22427641 TI - The Drosophila protein mustard tailors the innate immune response activated by the immune deficiency pathway. AB - In this study, we describe a Drosophila melanogaster transposon insertion mutant with tolerance to Vibrio cholerae infection and markedly decreased transcription of diptericin as well as other genes regulated by the immune deficiency innate immunity signaling pathway. We present genetic evidence that this insertion affects a locus previously implicated in pupal eclosion. This genetic locus, which we have named mustard (mtd), contains a LysM domain, often involved in carbohydrate recognition, and a TLDc domain of unknown function. More than 20 Mtd isoforms containing one or both of these conserved domains are predicted. We establish that the mutant phenotype represents a gain of function and can be replicated by increased expression of a short, nuclearly localized Mtd isoform comprised almost entirely of the TLDc domain. We show that this Mtd isoform does not block Relish cleavage or translocation into the nucleus. Lastly, we present evidence suggesting that the eclosion defect previously attributed to the Mtd locus may be the result of the unopposed action of the NF-kappaB homolog, Relish. Mtd homologs have been implicated in resistance to oxidative stress. However, to our knowledge this is the first evidence that Mtd or its homologs alter the output of an innate immunity signaling cascade from within the nucleus. PMID- 22427642 TI - CD16 regulates TRIF-dependent TLR4 response in human monocytes and their subsets. AB - Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF dependent genes as well as a selective expansion of CD16-expressing (CD16(+)) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R-associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16(+) monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis. PMID- 22427643 TI - Activated mouse B cells lack expression of granzyme B. AB - Recently, it has been reported that human B cells express and secrete the cytotoxic protease granzyme B (GrB) after stimulation with IL-21 and BCR cross linking. To date, there are few clues on the function of GrB in B cell biology. As experimental transgenic murine systems should provide insights into these issues, we assayed for GrB in C57BL/6 B cells using an extensive array of physiologically relevant stimuli but were unable to detect either GrB expression or its proteolytic activity, even when Ag-specific transgenic BCRs were engaged. Similar results were also obtained with B cells from DBA/2, CBA, or BALB/c mice. In vivo, infection with either influenza virus or murine gamma-herpesvirus induced the expected expression of GrB in CTLs, but not in B cell populations. We also investigated a possible role of GrB on the humoral immune response to the model Ag 4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin, but GrB deficient mice produced normal amounts of Ab with typical affinity maturation and a heightened secondary response, demonstrating conclusively the redundancy of GrB for Ab responses. Our results highlight the complex evolutionary differences that have shaped the immune systems of mice and humans. The physiological consequences of GrB expression in human B cells remain unclear, and the current study suggests that experimental mouse models will not be helpful in addressing this issue. PMID- 22427644 TI - The TIGIT/CD226 axis regulates human T cell function. AB - T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4(+) T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IFN regulatory factor 4, and retinoic acid-related orphan receptor c with inhibition of cytokine production, predominantly IFN-gamma. Knockdown of TIGIT expression by short hairpin RNA resulted in an increase of both T-bet and IFN-gamma mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFN-gamma with TIGIT knockdown could be overcome by blocking CD226 signaling, indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. Our results provide evidence for a novel role of this alternative costimulatory pathway in regulating human T cell responses associated with autoimmune disease. PMID- 22427645 TI - Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68. AB - Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment. PMID- 22427646 TI - Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure. AB - Matrix metalloproteinase 10 (MMP-10, stromelysin-2) is a secreted metalloproteinase with functions in skeletal development, wound healing, and vascular remodeling; its overexpression is also implicated in lung tumorigenesis and tumor progression. To understand the regulation of MMP-10 by tissue inhibitors of metalloproteinases (TIMPs), we have assessed equilibrium inhibition constants (K(i)) of putative physiological inhibitors TIMP-1 and TIMP-2 for the active catalytic domain of human MMP-10 (MMP-10cd) using multiple kinetic approaches. We find that TIMP-1 inhibits the MMP-10cd with a K(i) of 1.1 * 10(-9) M; this interaction is 10-fold weaker than the inhibition of the similar MMP-3 (stromelysin-1) catalytic domain (MMP-3cd) by TIMP-1. TIMP-2 inhibits the MMP 10cd with a K(i) of 5.8 * 10(-9) M, which is again 10-fold weaker than the inhibition of MMP-3cd by this inhibitor (K(i) = 5.5 * 10(-10) M). We solved the x ray crystal structure of TIMP-1 bound to the MMP-10cd at 1.9 A resolution; the structure was solved by molecular replacement and refined with an R-factor of 0.215 (R(free) = 0.266). Comparing our structure of MMP-10cd.TIMP-1 with the previously solved structure of MMP-3cd.TIMP-1 (Protein Data Bank entry 1UEA), we see substantial differences at the binding interface that provide insight into the differential binding of stromelysin family members to TIMP-1. This structural information may ultimately assist in the design of more selective TIMP-based inhibitors tailored for specificity toward individual members of the stromelysin family, with potential therapeutic applications. PMID- 22427647 TI - Formation of dAMP-glycerol and dAMP-Tris derivatives by Thermococcus kodakaraensis DNA primase. AB - In the presence of dATP, glycerol, and Tris buffer, the DNA primase isolated from Thermococcus kodakaraensis catalyzed the formation of dAMP and two products that were identified as dAMP-glycerol and dAMP-Tris. These products were formed by the T. kodakaraensis p41 catalytic subunit alone and the T. kodakaraensis p41-p46 complex in the absence of a DNA template. They were not formed with preparations containing the catalytically inactive p41 subunit. Similar glycerol and Tris derivatives as well as dNMPs were also formed with dGTP, dCTP, or dTTP. The mechanism contributing to the formation of these products and its implications in the initiation reaction catalyzed by the T. kodakaraensis primase are discussed. PMID- 22427648 TI - TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells. AB - The RNA-binding proteins TDP-43 and FUS form abnormal cytoplasmic aggregates in affected tissues of patients with amyotrophic lateral sclerosis and frontotemporal lobar dementia. TDP-43 and FUS localize mainly in the nucleus where they regulate pre-mRNA splicing, but they are also involved in mRNA transport, stability, and translation. To better investigate their cytoplasmic activities, we applied an RNA immunoprecipitation and chip analysis to define the mRNAs associated to TDP-43 and FUS in the cytoplasmic ribonucleoprotein complexes from motoneuronal NSC-34 cells. We found that they bind different sets of mRNAs although converging on common cellular pathways. Bioinformatics analyses identified the (UG)(n) consensus motif in 80% of 3'-UTR sequences of TDP-43 targets, whereas for FUS the binding motif was less evident. By in vitro assays we validated binding to selected target 3'-UTRs, including Vegfa and Grn for TDP 43, and Vps54, Nvl, and Taf15 for FUS. We showed that TDP-43 has a destabilizing activity on Vegfa and Grn mRNAs and may ultimately affect progranulin protein content, whereas FUS does not affect mRNA stability/translation of its targets. We also demonstrated that three different point mutations in TDP-43 did not change the binding affinity for Vegfa and Grn mRNAs or their protein level. Our data indicate that TDP-43 and FUS recognize distinct sets of mRNAs and differently regulate their fate in the cytoplasm of motoneuron-like cells, therefore suggesting complementary roles in neuronal RNA metabolism and neurodegeneration. PMID- 22427649 TI - Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy. AB - The sarco(endo)plasmic reticulum calcium ATPase (SERCA) and its regulatory partner phospholamban (PLN) are essential for myocardial contractility. Arg(9) -> Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with lethal dilated cardiomyopathy in humans. To better understand these mutations, we made a series of amino acid substitutions in the cytoplasmic domain of PLN and tested their ability to inhibit SERCA. R9C is a complete loss-of-function mutant of PLN, whereas R14del is a mild loss-of-function mutant. When combined with wild type PLN to simulate heterozygous conditions, the mutants had a dominant negative effect on SERCA function. A series of targeted mutations in this region of the PLN cytoplasmic domain ((8)TRSAIRR(14)) demonstrated the importance of hydrophobic balance in proper PLN regulation of SERCA. We found that Arg(9) -> Leu and Thr(8) -> Cys substitutions mimicked the behavior of the R9C mutant, and an Arg(14) -> Ala substitution mimicked the behavior of the R14del mutant. The results reveal that the change in hydrophobicity resulting from the R9C and R14del mutations is sufficient to explain the loss of function and persistent interaction with SERCA. Hydrophobic imbalance in the cytoplasmic domain of PLN appears to be a predictor for the development and progression of dilated cardiomyopathy. PMID- 22427650 TI - Calpain 2 regulates Akt-FoxO-p27(Kip1) protein signaling pathway in mammary carcinoma. AB - We investigated the role of the ubiquitously expressed calpain 2 isoform in breast tumor cell growth, migration, signaling, and tumorigenesis. RNAi-mediated knockdown of the capn2 transcript was used to manipulate expression of the catalytic subunit of calpain 2 in the AC2M2 mouse mammary carcinoma cell line. Stable knockdown of capn2 correlated with reduced in vitro proliferation rates, soft agar colony formation efficiency, and migration rates, indicating roles for calpain 2 in mitogenesis, survival, and motogenesis. Biochemical analysis showed increased levels of protein phosphatase 2A and reduced levels of activated Akt in calpain 2-deficient cells, and this correlated with increased levels of the FoxO3a target gene product p27(Kip1), a key regulator of cell proliferation. Calpain 2 deficiency in the AC2M2 cells correlated with enhanced nuclear localization of FoxO3a, consistent with it being in a derepressed state capable of regulating transcriptional targets. Orthotopically engrafted calpain 2 knockdown AC2M2 cells generated tumors with reduced growth rates and enhanced in vivo expression of p27(Kip1). In summary, calpain 2 deficiency correlated with reduced Akt activity, increased protein phosphatase 2A levels, derepression of FoxO3a, and enhanced expression of the p27(Kip1) tumor suppressor. These observations argue that calpain 2 promotes tumor cell growth both in vitro and in vivo through the PI3K-Akt-FoxO-p27(Kip1) signaling cascade. Inhibition of calpain 2 might therefore provide therapeutic benefits in the treatment of cancer. PMID- 22427651 TI - Design of a specific colonic mucus marker using a human commensal bacterium cell surface domain. AB - Imaging living cells and organs requires innovative, specific, efficient, and well tolerated fluorescent markers targeting cellular components. Such tools will allow proceeding to the dynamic analysis of cells and the adaptation of tissues to environmental cues. In this study, we have identified and synthesized a novel non-toxic fluorescent marker allowing a specific fluorescent staining of the human colonic mucus. Our strategy to identify a molecule able to specifically bind to the human colonic mucus was on the basis of the mucus adhesion properties of commensal bacteria. We identified and characterized the mucus-binding property of a 70-amino acid domain (MUB(70)) expressed on the surface of Lactobacillus strains. The chemical synthesis of MUB(70) was achieved using the human commensal bacterium Lactobacillus reuteri AF120104 protein as a template. The synthesized Cy5-conjugated MUB(70) marker specifically stained the colonic mucus on fixed human, rabbit, and guinea pig tissues. Interestingly, murine tissue was not stained, suggesting significant differences in the composition of the murine colonic mucus. In addition, this marker stained the mucus of living cultured human colonic cells (HT29-MTX) and human colonic tissue explants. Using a biotinylated derivative of MUB(70), we demonstrated that this peptide binds specifically to Muc2, the most abundant secreted mucin, through its glycosylated moieties. Hence, Cy5-MUB(70) is a novel and specific fluorescent marker for mammalian colonic mucus. It may be used for live imaging analysis but also, as demonstrated in this study, as a marker for the diagnosis and the prognosis of colonic mucinous carcinomas. PMID- 22427652 TI - Fungal ecdysteroid-22-oxidase, a new tool for manipulating ecdysteroid signaling and insect development. AB - Steroid hormones ecdysteroids regulate varieties of developmental processes in insects. Although the ecdysteroid titer can be increased experimentally with ease, its artificial reduction, although desirable, is very difficult to achieve. Here we characterized the ecdysteroid-inactivating enzyme ecdysteroid-22-oxidase (E22O) from the entomopathogenic fungus Nomuraea rileyi and used it to develop methods for reducing ecdysteroid titer and thereby controlling insect development. K(m) and K(cat) values of the purified E22O for oxidizing ecdysone were 4.4 MUM and 8.4/s, respectively, indicating that E22O can inactivate ecdysone more efficiently than other ecdysteroid inactivating enzymes characterized so far. The cloned E22O cDNA encoded a FAD-dependent oxidoreductase. Injection of recombinant E22O into the silkworm Bombyx mori interfered with larval molting and metamorphosis. In the hemolymph of E22O injected pupae, the titer of hormonally active 20-hydroxyecdysone decreased and concomitantly large amounts of inactive 22-dehydroecdysteroids accumulated. E22O injection also prevented molting of various other insects. In the larvae of the crambid moth Haritalodes basipunctalis, E22O injection induced a diapause-like developmental arrest, which, as in normal diapause, was broken by chilling. Transient expression of the E22O gene by in vivo lipofection effectively decreased the 20-hydroxyecdysone titer and blocked molting in B. mori. Transgenic expression of E22O in Drosophila melanogaster caused embryonic morphological defects, phenotypes of which were very similar to those of the ecdysteroid synthesis deficient mutants. Thus, as the first available simple but versatile tool for reducing the internal ecdysteroid titer, E22O could find use in controlling a broad range of ecdysteroid-associated developmental and physiological phenomena. PMID- 22427653 TI - The S-helix determines the signal in a Tsr receptor/adenylyl cyclase reporter. AB - A signaling or S-helix has been identified as a conserved, up to 50-residue-long segment in diverse sensory proteins. It is present in all major bacterial lineages and in euryarchea and eukaryotes. A bioinformatic analysis shows that it connects upstream receiver and downstream output domains, e.g. in histidine kinases and bacterial adenylyl cyclases. The S-helix is modeled as a two-helical parallel coiled coil. It is predicted to prevent constitutive activation of the downstream signaling domains in the absence of ligand-binding. We identified an S helix of about 25 residues in the adenylyl cyclase CyaG from Arthrospira maxima. Deletion of the 25 residue segment connecting the HAMP and catalytic domains in a chimera with the Escherichia coli Tsr receptor changed the response to serine from inhibition to stimulation. Further examination showed that a deletion of one to three heptads plus a presumed stutter, i.e. 1, 2, or 3 * 7 + 4 amino acids, is required and sufficient for signal reversion. It was not necessary that the deletions be continuous, as removal of separated heptads and presumed stutters also resulted in signal reversion. Furthermore, insertion of the above segments between the HAMP and cyclase catalytic domains similarly resulted in signal reversion. This indicates that the S-helix is an independent, segmented module capable to reverse the receptor signal. Because the S-helix is present in all kingdoms of life, e.g. in human retinal guanylyl cyclase, our findings may be significant for many sensory systems. PMID- 22427654 TI - Sulforaphane induction of p21(Cip1) cyclin-dependent kinase inhibitor expression requires p53 and Sp1 transcription factors and is p53-dependent. AB - Sulforaphane (SFN) is an important cancer preventive agent derived from cruciferous vegetables. We show that SFN treatment suppresses normal human keratinocyte proliferation via a mechanism that involves increased expression of p21(Cip1). SFN treatment produces a concentration-dependent increase in p21(Cip1) promoter activity via a mechanism that involves stabilization of the p53 protein leading to increased p53 binding to the p21(Cip1) promoter p53 response elements. The proximal p21(Cip1) promoter GC-rich Sp1 factor binding elements are also required, as the SFN-dependent increase is lost when these sites are mutated. SFN treatment increases Sp1 binding to these elements, and the response is enhanced in the presence of exogenous Sp1 and reduced in the presence of DeltaN-Sp3. CpG island methylation alters p21(Cip1) promoter activity some systems; however, expression in SFN-treated keratinocytes does not involve changes in proximal promoter methylation. The promoter is minimally methylated, and the methylation level is not altered by SFN treatment. This study indicates that SFN increases p21(Cip1) promoter transcription via a mechanism that involves SFN-dependent stabilization of p53 and increased p53 and Sp1 binding to their respective response elements in the p21(Cip1) promoter. These results are in marked contrast to the mechanisms observed in skin cancer cell lines and suggest that SFN may protect normal keratinocytes from damage while causing cancer cells to undergo apoptosis. PMID- 22427655 TI - Leucine-rich repeat and WD repeat-containing protein 1 is recruited to pericentric heterochromatin by trimethylated lysine 9 of histone H3 and maintains heterochromatin silencing. AB - Lrwd1, a protein containing a leucine-rich repeat and a WD40 repeat domain, interacts with the origin replication complex (ORC), a protein complex involved in both initiation of DNA replication and heterochromatin silencing. Lrwd1 and ORC are known to co-purify with repressive histone marks (trimethylated lysine 9 of histone H3 (H3K9me3) and trimethylated lysine 20 of histone H4 (H4K20me3)) and localize to pericentric heterochromatin. However, how the Lrwd1 is recruited to heterochromatin and the functional significance of the localization of Lrwd1 to the heterochromatin are not known. Here, we show that Lrwd1 preferentially binds to trimethylated repressive histone marks in vitro, which is dependent on an intact WD40 domain but independent of ORC proteins. The localization of Lrwd1 and Orc2 at pericentric heterochromatin in mouse cells is lost in cells lacking H3K9me3 but not in cells lacking H4K20me3. In addition, depletion of HP1alpha has little impact on the localization of Lrwd1 on pericentric heterochromatin. Finally, depletion of Lrwd1 and Orc2 in mouse cells leads to increased transcription of major satellite repeats. These results indicate that the Lrwd1 is recruited to pericentric heterochromatin through binding to H3K9me3 and that the association of Lrwd1 with pericentric heterochromatin is required for heterochromatin silencing and maintenance. PMID- 22427656 TI - Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-kappaB (NF-kappaB)-mediated interleukin-9 (IL-9) transactivation. AB - IL-9 regulates diverse inflammatory immune responses. Although the functional importance of IL-9 has been investigated in various pathophysiological conditions, molecular mechanisms by which TCR stimulation induced IL-9 gene expression are still unclear. In this study, we investigated the functional importance of the NFAT1 and NF-kappaB (p65) in IL-9 gene transcription in CD4(+) T cells. In vivo binding of NFAT1 and NF-kappaB (p65) to the IL-9 promoter was observed. NFAT1 binding induced a transcriptionally active chromatin configuration at the IL-9 promoter locus, whereas NF-kappaB (p65) binding transactivated the IL-9 promoter. Mouse deficient in NFAT1 shows a significant down-regulation of IL-9 expression that resulted from an inaccessible chromatin configuration at the IL-9 promoter. In parallel, knockdown of NF-kappaB (p65) also resulted in reduced IL-9 expression. In this process, NFAT1 plays a pivotal role as a core protein that creates an accessible platform for the assembly of transcription activators. The presence of NFAT1 correlates with recruitment of NF kappaB (p65), p300, and active histone markers on the IL-9 promoter, resulting in a transcriptionally competent promoter. NFAT1 deficiency significantly reduced the recruitment of the above activation complex to the IL-9 promoter. In summary, our data suggest that functional cooperation of NFAT1 and NF-kappaB synergistically enhances IL-9 transcription in CD4(+) T cells. PMID- 22427657 TI - Involvement of polo-like kinase 1 (Plk1) in mitotic arrest by inhibition of mitogen-activated protein kinase-extracellular signal-regulated kinase-ribosomal S6 kinase 1 (MEK-ERK-RSK1) cascade. AB - Cell division is controlled through cooperation of different kinases. Of these, polo-like kinase 1 (Plk1) and p90 ribosomal S6 kinase 1 (RSK1) play key roles. Plk1 acts as a G(2)/M trigger, and RSK1 promotes G(1) progression. Although previous reports show that Plk1 is suppressed by RSK1 during meiosis in Xenopus oocytes, it is still not clear whether this is the case during mitosis or whether Plk1 counteracts the effects of RSK1. Few animal models are available for the study of controlled and transient cell cycle arrest. Here we show that encysted embryos (cysts) of the primitive crustacean Artemia are ideal for such research because they undergo complete cell cycle arrest when they enter diapause (a state of obligate dormancy). We found that Plk1 suppressed the activity of RSK1 during embryonic mitosis and that Plk1 was inhibited during embryonic diapause and mitotic arrest. In addition, studies on HeLa cells using Plk1 siRNA interference and overexpression showed that phosphorylation of RSK1 increased upon interference and decreased after overexpression, suggesting that Plk1 inhibits RSK1. Taken together, these findings provide insights into the regulation of Plk1 during cell division and Artemia diapause cyst formation and the correlation between the activity of Plk1 and RSK1. PMID- 22427658 TI - How enzymes handle the energy derived from the cleavage of high-energy phosphate compounds. PMID- 22427659 TI - Mapping ultra-weak protein-protein interactions between heme transporters of Staphylococcus aureus. AB - Iron is an essential nutrient for the proliferation of Staphylococcus aureus during bacterial infections. The iron-regulated surface determinant (Isd) system of S. aureus transports and metabolizes iron porphyrin (heme) captured from the host organism. Transportation of heme across the thick cell wall of this bacterium requires multiple relay points. The mechanism by which heme is physically transferred between Isd transporters is largely unknown because of the transient nature of the interactions involved. Herein, we show that the IsdC transporter not only passes heme ligand to another class of Isd transporter, as previously known, but can also perform self-transfer reactions. IsdA shows a similar ability. A genetically encoded photoreactive probe was used to survey the regions of IsdC involved in self-dimerization. We propose an updated model that explicitly considers self-transfer reactions to explain heme delivery across the cell wall. An analogous photo-cross-linking strategy was employed to map transient interactions between IsdC and IsdE transporters. These experiments identified a key structural element involved in the rapid and specific transfer of heme from IsdC to IsdE. The resulting structural model was validated with a chimeric version of the homologous transporter IsdA. Overall, our results show that the ultra-weak interactions between Isd transporters are governed by bona fide protein structural motifs. PMID- 22427660 TI - Human cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is dimeric in its disulfide-reduced state, with natively disordered N-terminal region. AB - CDK2AP1 (cyclin-dependent kinase 2-associated protein 1), corresponding to the gene doc-1 (deleted in oral cancer 1), is a tumor suppressor protein. The doc-1 gene is absent or down-regulated in hamster oral cancer cells and in many other cancer cell types. The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G(1)-to-S phase transition. Here, we report the solution structure of CDK2AP1 by combined methods of solution state NMR and amide hydrogen/deuterium exchange measurements with mass spectrometry. The homodimeric structure of CDK2AP1 includes an intrinsically disordered 60-residue N-terminal region and a four-helix bundle dimeric structure with reduced Cys-105 in the C terminal region. The Cys-105 residues are, however, poised for disulfide bond formation. CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by IkappaB kinase epsilon. PMID- 22427661 TI - Reconstitution of glucosylceramide flip-flop across endoplasmic reticulum: implications for mechanism of glycosphingolipid biosynthesis. AB - Most glycosphingolipids are synthesized by the sequential addition of monosaccharides to glucosylceramide (GlcCer) in the lumen of the Golgi apparatus. Because GlcCer is synthesized on the cytoplasmic face of Golgi membranes, it must be flipped to the non-cytoplasmic face by a lipid flippase in order to nucleate glycosphingolipid synthesis. Halter et al. (Halter, D., Neumann, S., van Dijk, S. M., Wolthoorn, J., de Maziere, A. M., Vieira, O. V., Mattjus, P., Klumperman, J., van Meer, G., and Sprong, H. (2007) Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. J. Cell Biol. 179, 101-115) proposed that this essential flipping step is accomplished via a complex trafficking itinerary; GlcCer is moved from the cytoplasmic face of the Golgi to the endoplasmic reticulum (ER) by FAPP2, a cytoplasmic lipid transfer protein, flipped across the ER membrane, then delivered to the lumen of the Golgi complex by vesicular transport. We now report biochemical reconstitution studies to analyze GlcCer flipping at the ER. Using proteoliposomes reconstituted from Triton X-100-solubilized rat liver ER membrane proteins, we demonstrate rapid (t(1/2) < 20 s), ATP-independent flip-flop of N-(6-((7-nitro-2-1,3-benzoxadiazol 4-yl)amino)hexanoyl)-D-glucosyl-beta1-1'-sphingosine, a fluorescent GlcCer analog. Further studies involving protein modification, biochemical fractionation, and analyses of flip-flop in proteoliposomes reconstituted with ER membrane proteins from yeast indicate that GlcCer translocation is facilitated by well characterized ER phospholipid flippases that remain to be identified at the molecular level. By reason of their abundance and membrane bending activity, we considered that the ER reticulons and the related Yop1 protein could function as phospholipid-GlcCer flippases. Direct tests showed that these proteins have no flippase activity. PMID- 22427662 TI - Anti-inflammatory IgG production requires functional P1 promoter in beta galactoside alpha2,6-sialyltransferase 1 (ST6Gal-1) gene. AB - The anti-inflammatory properties associated with intravenous immunoglobulin therapy require the sialic acid modification of the N-glycan of the Fc domain of IgG. Sialylation of the Fc fragment is mediated by beta-galactoside alpha2,6 sialyltransferase 1 (ST6Gal-1), acting on the Gal(beta4)GlcNAc terminal structure of the biantennary N-glycans on the Fc domain. However, little is known regarding the in vivo regulation of Fc sialylation and its role in the progression of inflammatory processes. Here, we report that decreased Fc sialylation of circulatory IgG accompanies the acute phase response elicited by turpentine exposure or upon acute exposure to either nontypeable Haemophilus influenzae or ovalbumin. However, Fc sialylation was increased 3-fold from the base line upon transition to chronic inflammation by repeated exposure to challenge. The P1 promoter of the ST6Gal-1 gene is critical for Fc sialylation, but P1 does not drive ST6Gal-1 expression in B cells. The Siat1DeltaP1 mouse, with a dysfunctional P1 promoter, was unable to produce sialylated Fc in the systemic circulation, despite the presence of Gal(beta4)GlcNAc termini on the Fc glycans. The major contribution of P1 action is to synthesize ST6Gal-1 enzymes that are deposited into the systemic circulation. The data strongly indicate that this pool of extracellular ST6Gal-1 in the blood impacts the sialylation of IgG Fc and that defective Fc sialylation is likely a major contributing mechanism for the proinflammatory tendencies previously noted in Siat1DeltaP1 animals. PMID- 22427663 TI - N-glycoform diversity of cellobiohydrolase I from Penicillium decumbens and synergism of nonhydrolytic glycoform in cellulose degradation. AB - Four cellobiohydrolase I (CBHI) glycoforms, namely, CBHI-A, CBHI-B, CBHI-C, and CBHI-D, were purified from the cultured broth of Penicillium decumbens JU-A10. All glycoforms had the same amino acid sequence but displayed different characteristics and biological functions. The effects of the N-glycans of the glycoforms on CBH activity were analyzed using mass spectrum data. Longer N glycan chains at the Asn-137 of CBHI increased CBH activity. After the N-glycans were removed using site-directed mutagenesis and homologous expression in P. decumbens, the specific CBH activity of the recombinant CBHI without N glycosylation increased by 65% compared with the wild-type CBHI with the highest specific activity. However, the activity was not stable. Only the N-glycosylation at Asn-137 can improve CBH activity by 40%. rCBHI with N-glycosylation only at Asn-470 exhibited no enzymatic activity. CBH activity was affected whether or not the protein was glycosylated, together with the N-glycosylation site and N-glycan structure. N-Glycosylation not only affects CBH activity but may also bring a new feature to a nonhydrolytic CBHI glycoform (CBHI-A). By supplementing CBHI-A to different commercial cellulase preparations, the glucose yield of lignocellulose hydrolysis increased by >20%. After treatment with a low dose (5 mg/g substrate) of CBHI-A at 50 degrees C for 7 days, the hydrogen-bond intensity and crystalline degree of cotton fibers decreased by 17 and 34%, respectively. These results may provide new guidelines for cellulase engineering. PMID- 22427664 TI - Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-beta (TGF-beta)-induced suppressor effects in hepatocytes. AB - Transforming growth factor-beta (TGF-beta) plays a dual role in hepatocytes, mediating both tumor suppressor and promoter effects. The suppressor effects of the cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity. The aim of our work was to study the role of the protein-tyrosine phosphatase 1B (PTP1B) on the cellular responses to TGF-beta, using for this purpose immortalized neonatal hepatocytes isolated from both PTP1B(+/+) and PTP1B(-/-) mice. We have found that PTP1B deficiency conferred resistance to TGF-beta suppressor effects, such as apoptosis and growth inhibition, correlating with lower Smad2/Smad3 activation. Both responses were recovered in the presence of the general tyrosine kinase inhibitor genistein. PTP1B(-/-) cells showed elevated NF-kappaB activation in response to TGF-beta. Knockdown of the NF-kappaB p65 subunit increased cell response in terms of Smads phosphorylation and apoptosis. Interestingly, these effects were accompanied by inhibition of Smad7 up-regulation. In addition, lack of PTP1B promoted an altered NADPH oxidase (NOX) expression pattern in response to TGF-beta, strongly increasing the NOX1/NOX4 ratio, which was reverted by genistein and p65 knockdown. Importantly, NOX1 knockdown inhibited nuclear translocation of p65, promoted Smad phosphorylation, and decreased Smad7 levels. In summary, our results suggest that PTP1B deficiency confers resistance to TGF-beta through Smad inhibition, an effect that is mediated by NOX1-dependent NF-kappaB activation, which in turn, increases the level of the Smad inhibitor Smad7 and participates in a positive feedback loop on NOX1 up-regulation. PMID- 22427665 TI - Sublytic C5b-9 complexes induce apoptosis of glomerular mesangial cells in rats with Thy-1 nephritis through role of interferon regulatory factor-1-dependent caspase 8 activation. AB - The apoptosis of glomerular mesangial cells (GMC) in rat Thy-1 nephritis (Thy 1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by sublytic C5b-9 deposition, but the mechanism of sublytic C5b-9-mediated GMC apoptosis has not been elucidated. In the present study, the gene expression profiles both in the GMC stimulated by sublytic C5b-9 and the rat renal tissue of Thy-1N were detected using microarrays. Among the co-up-regulated genes, the up regulation of interferon regulatory factor-1 (IRF-1) was further confirmed. Increased caspase 8 and caspase 3 expression and caspase 8 promoter activity in the GMC were also identified. Meanwhile, overexpression or knockdown of IRF-1 not only enhanced or inhibited GMC apoptosis and caspase 8 and 3 induction but also increased or decreased caspase 8 promoter activity, respectively. The element of IRF-1 binding to the caspase 8 promoter was first revealed. Furthermore, silencing IRF-1 or repressing the activation of caspases 8 and 3 significantly reduced GMC apoptosis, including other pathologic changes of Thy-1N. These novel findings indicate that GMC apoptosis of Thy-1N is associated with the IRF-1 activated caspase 8 pathway. PMID- 22427666 TI - Hormone-induced 14-3-3gamma adaptor protein regulates steroidogenic acute regulatory protein activity and steroid biosynthesis in MA-10 Leydig cells. AB - Cholesterol is the sole precursor of steroid hormones in the body. The import of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroid biosynthesis, relies on the formation of a protein complex that assembles at the outer mitochondrial membrane called the transduceosome. The transduceosome contains several mitochondrial and cytosolic components, including the steroidogenic acute regulatory protein (STAR). Human chorionic gonadotropin (hCG) induces de novo synthesis of STAR, a process shown to parallel maximal steroid production. In the hCG-dependent steroidogenic MA-10 mouse Leydig cell line, the 14-3-3gamma protein was identified in native mitochondrial complexes by mass spectrometry and immunoblotting, and its levels increased in response to hCG treatment. The 14-3-3 proteins bind and regulate the activity of many proteins, acting via target protein activation, modification and localization. In MA-10 cells, cAMP induces 14-3-3gamma expression parallel to STAR expression. Silencing of 14-3-3gamma expression potentiates hormone-induced steroidogenesis. Binding motifs of 14-3-3gamma were identified in components of the transduceosome, including STAR. Immunoprecipitation studies demonstrate a hormone-dependent interaction between 14-3-3gamma and STAR that coincides with reduced 14-3-3gamma homodimerization. The binding site of 14-3-3gamma on STAR was identified to be Ser-194 in the STAR-related sterol binding lipid transfer (START) domain, the site phosphorylated in response to hCG. Taken together, these results demonstrate that 14-3-3gamma negatively regulates steroidogenesis by binding to Ser-194 of STAR, thus keeping STAR in an unfolded state, unable to induce maximal steroidogenesis. Over time 14-3-3gamma homodimerizes and dissociates from STAR, allowing this protein to induce maximal mitochondrial steroid formation. PMID- 22427667 TI - Chaperone insufficiency links TLR4 protein signaling to endoplasmic reticulum stress. AB - Inflammation plays an important pathogenic role in a number of metabolic diseases such as obesity, type 2 diabetes, and atherosclerosis. The activation of inflammation in these diseases depends at least in part on the combined actions of TLR4 signaling and endoplasmic reticulum stress, which by acting in concert can boost the inflammatory response. Defining the mechanisms involved in this phenomenon may unveil potential targets for the treatment of metabolic/inflammatory diseases. Here we used LPS to induce endoplasmic reticulum stress in the human monocyte cell-line, THP-1. The unfolded protein response, produced after LPS, was dependent on CD14 activity but not on RNA-dependent protein kinase and could be inhibited by an exogenous chemical chaperone. The induction of the endoplasmic reticulum resident chaperones, GRP94 and GRP78, by LPS was of a much lower magnitude than the effect of LPS on TLR4 and MD-2 expression. In face of this apparent insufficiency of chaperone expression, we induced the expression of GRP94 and GRP78 by glucose deprivation. This approach completely reverted endoplasmic reticulum stress. The inhibition of either GRP94 or GRP78 with siRNA was sufficient to rescue the protective effect of glucose deprivation on LPS-induced endoplasmic reticulum stress. Thus, insufficient LPS induced chaperone expression links TLR4 signaling to endoplasmic reticulum stress. PMID- 22427668 TI - Proline-proline-glutamic acid (PPE) protein Rv1168c of Mycobacterium tuberculosis augments transcription from HIV-1 long terminal repeat promoter. AB - Cells of the monocyte/macrophage lineage are shown to play a role in the pathogenesis of human immunodeficiency virus (HIV). The occurrence of HIV type 1 (HIV-1) infection is found to be accelerated in people infected with Mycobacterium tuberculosis, but the mechanism by which mycobacterial protein(s) induces HIV-1 LTR trans-activation is not clearly understood. We show here that the M. tuberculosis proline-proline-glutamic acid (PPE) protein Rv1168c (PPE17) can augment transcription from HIV-1 LTR in monocyte/macrophage cells. Rv1168c interacts specifically with Toll-like receptor-2 (TLR2) resulting in downstream activation of nuclear factor-kappaB (NF-kappaB) resulting in HIV-1 LTR trans activation. Another PPE protein, Rv1196 (PPE18), was also found to interact with TLR2 but had no effect on HIV-1 LTR trans-activation because of its inability to activate the NF-kappaB signaling pathway. In silico docking analyses and mutation experiments have revealed that the N-terminal domain of Rv1168c specifically interacts with LRR motifs 15-20 of TLR2, and this site of interaction is different from that of Rv1196 protein (LRR motifs 11-15), indicating that the site of interaction on TLR2 dictates the downstream signaling events leading to activation of NF-kappaB. This information may help in understanding the mechanism of pathogenesis of HIV-1 during M. tuberculosis co-infection. PMID- 22427669 TI - Mechanistic studies on activation of ubiquitin and di-ubiquitin-like protein, FAT10, by ubiquitin-like modifier activating enzyme 6, Uba6. AB - Uba6 is a homolog of the ubiquitin-activating enzyme, Uba1, and activates two ubiquitin-like proteins (UBLs), ubiquitin and FAT10. In this study, biochemical and biophysical experiments were performed to understand the mechanisms of how Uba6 recognizes two distinct UBLs and catalyzes their activation and transfer. Uba6 is shown to undergo a three-step activation process and form a ternary complex with both UBLs, similar to what has been observed for Uba1. The catalytic mechanism of Uba6 is further supported by inhibition studies using a mechanism based E1 inhibitor, Compound 1, which forms covalent adducts with both ubiquitin and FAT10. In addition, pre-steady state kinetic analysis revealed that the rates of UBL-adenylate (step 1) and thioester (step 2) formation are similar between ubiquitin and FAT10. However, distinct kinetic behaviors were also observed for ubiquitin and FAT10. FAT10 binds Uba6 with much higher affinity than ubiquitin while demonstrating lower catalytic activity in both ATP-PP(i) exchange and E1-E2 transthiolation assays. Also, Compound 1 is less potent with FAT10 as the UBL compared with ubiquitin in ATP-PP(i) exchange assays, and both a slow rate of covalent adduct formation and weak adduct binding to Uba6 contribute to the diminished potency observed for FAT10. Together with expression level analysis in IM-9 cells, this study sheds light on the potential role of cytokine-induced FAT10 expression in regulating Uba6 pathways. PMID- 22427670 TI - The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation. AB - The tumor suppressor, PTEN is key to the regulation of diverse cellular processes, making it a prime candidate to be tightly regulated. The PTEN level is controlled in a major way by E3 ligase-mediated degradation through the Ubiquitin Proteasome System (UPS). Nedd 4-1, XIAP, and WWP2 have been shown to maintain PTEN turnover. Here, we report that CHIP, the chaperone-associated E3 ligase, induces ubiquitination and regulates the proteasomal turnover of PTEN. It was apparent from our findings that PTEN transiently associates with the molecular chaperones and thereby gets diverted to the degradation pathway through its interaction with CHIP. The TPR domain of CHIP and parts of the N-terminal domain of PTEN are required for their interaction. Overexpression of CHIP leads to elevated ubiquitination and a shortened half-life of endogenous PTEN. On the other hand, depletion of endogenous CHIP stabilizes PTEN. CHIP is also shown to regulate PTEN-dependent transcription presumably through its down-regulation. PTEN shared an inverse correlation with CHIP in human prostate cancer patient samples, thereby triggering the prospects of a more complex mode of PTEN regulation in cancer. PMID- 22427671 TI - Excision of Trpv6 gene leads to severe defects in epididymal Ca2+ absorption and male fertility much like single D541A pore mutation. AB - Replacement of aspartate residue 541 by alanine (D541A) in the pore of TRPV6 channels in mice disrupts Ca(2+) absorption by the epididymal epithelium, resulting in abnormally high Ca(2+) concentrations in epididymal luminal fluid and in a dramatic but incomplete loss of sperm motility and fertilization capacity, raising the possibility of residual activity of channels formed by TRPV6(D541A) proteins (Weissgerber, P., Kriebs, U., Tsvilovskyy, V., Olausson, J., Kretz, O., Stoerger, C., Vennekens, R., Wissenbach, U., Middendorff, R., Flockerzi, V., and Freichel, M. (2011) Sci. Signal. 4, ra27). It is known from other cation channels that introducing pore mutations even if they largely affect their conductivity and permeability can evoke considerably different phenotypes compared with the deletion of the corresponding protein. Therefore, we generated TRPV6-deficient mice (Trpv6(-/-)) by deleting exons encoding transmembrane domains with the pore-forming region and the complete cytosolic C terminus harboring binding sites for TRPV6-associated proteins that regulate its activity and plasma membrane anchoring. Using this strategy, we aimed to determine whether the TRPV6(D541A) pore mutant still contributes to residual channel activity and/or channel-independent functions in vivo. Trpv6(-/-) males reveal severe defects in fertility and motility and viability of sperm and a significant increase in epididymal luminal Ca(2+) concentration that is mirrored by a lack of Ca(2+) uptake by the epididymal epithelium. Therewith, Trpv6 excision affects epididymal Ca(2+) handling and male fertility to the same extent as the introduction of the D541A pore mutation, arguing against residual functions of the TRPV6(D541A) pore mutant in epididymal epithelial cells. PMID- 22427672 TI - Substrate-selective and calcium-independent activation of CaMKII by alpha actinin. AB - Protein-protein interactions are thought to modulate the efficiency and specificity of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling in specific subcellular compartments. Here we show that the F-actin binding protein alpha-actinin targets CaMKIIalpha to F-actin in cells by binding to the CaMKII regulatory domain, mimicking CaM. The interaction with alpha actinin is blocked by CaMKII autophosphorylation at Thr-306, but not by autophosphorylation at Thr-305, whereas autophosphorylation at either site blocks Ca(2+)/CaM binding. The binding of alpha-actinin to CaMKII is Ca(2+)-independent and activates the phosphorylation of a subset of substrates in vitro. In intact cells, alpha-actinin selectively stabilizes CaMKII association with GluN2B containing glutamate receptors and enhances phosphorylation of Ser-1303 in GluN2B, but inhibits CaMKII phosphorylation of Ser-831 in glutamate receptor GluA1 subunits by competing for activation by Ca(2+)/CaM. These data show that Ca(2+)-independent binding of alpha-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity. PMID- 22427673 TI - Mutational analysis of the T4 gp59 helicase loader reveals its sites for interaction with helicase, single-stranded binding protein, and DNA. AB - Efficient DNA replication involves coordinated interactions among DNA polymerase, multiple factors, and the DNA. From bacteriophage T4 to eukaryotes, these factors include a helicase to unwind the DNA ahead of the replication fork, a single stranded binding protein (SSB) to bind to the ssDNA on the lagging strand, and a helicase loader that associates with the fork, helicase, and SSB. The previously reported structure of the helicase loader in the T4 system, gene product (gp)59, has revealed an N-terminal domain, which shares structural homology with the high mobility group (HMG) proteins from eukaryotic organisms. Modeling of this structure with fork DNA has suggested that the HMG-like domain could bind to the duplex DNA ahead of the fork, whereas the C-terminal portion of gp59 would provide the docking sites for helicase (T4 gp41), SSB (T4 gp32), and the ssDNA fork arms. To test this model, we have used random and targeted mutagenesis to generate mutations throughout gp59. We have assayed the ability of the mutant proteins to bind to fork, primed fork, and ssDNAs, to interact with SSB, to stimulate helicase activity, and to function in leading and lagging strand DNA synthesis. Our results provide strong biochemical support for the role of the N terminal gp59 HMG motif in fork binding and the interaction of the C-terminal portion of gp59 with helicase and SSB. Our results also suggest that processive replication may involve the switching of gp59 between its interactions with helicase and SSB. PMID- 22427674 TI - Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase C epsilon. AB - Synaptic loss is the earliest pathological change in Alzheimer disease (AD) and is the pathological change most directly correlated with the degree of dementia. ApoE4 is the major genetic risk factor for the age-dependent form of AD, which accounts for 95% of cases. Here we show that in synaptic networks formed from primary hippocampal neurons in culture, apoE3, but not apoE4, prevents the loss of synaptic networks produced by amyloid beta oligomers (amylospheroids). Specific activators of PKCepsilon, such as 8-(2-(2-pentyl-cyclopropylmethyl) cyclopropyl)-octanoic acid methyl ester and bryostatin 1, protected against synaptic loss by amylospheroids, whereas PKCepsilon inhibitors blocked this synaptic protection and also blocked the protection by apoE3. Blocking LRP1, an apoE receptor on the neuronal membrane, also blocked the protection by apoE. ApoE3, but not apoE4, induced the synthesis of PKCepsilon mRNA and expression of the PKCepsilon protein. Amyloid beta specifically blocked the expression of PKCepsilon but had no effect on other isoforms. These results suggest that protection against synaptic loss by apoE is mediated by a novel intracellular PKCepsilon pathway. This apoE pathway may account for much of the protective effect of apoE and reduced risk for the age-dependent form of AD. This finding supports the potential efficacy of newly developed therapeutics for AD. PMID- 22427675 TI - Association between Helicobacter pylori colonization and glycated hemoglobin levels: is this another reason to eradicate H. pylori in adulthood? PMID- 22427676 TI - Association between gastric Helicobacter pylori colonization and glycated hemoglobin levels. AB - BACKGROUND: Few studies have evaluated the potential influence of Helicobacter pylori on biomarkers for diabetes. METHODS: We conducted cross-sectional analyses using data from 7417 participants in the National Health and Nutrition Examination Survey (NHANES) III (aged >=18 years) and 6072 participants in NHANES 1999-2000 (aged >=3 years) to assess the association between H. pylori and levels of glycosylated hemoglobin (HbA1c). RESULTS: There was no association between H. pylori and history of self-reported diabetes. Helicobacter pylori seropositivity, especially H. pylori cagA positivity, was positively associated (P < .01, NHANES III; P = .02, NHANES 1999-2000) with HbA1c levels after excluding individuals with history of diabetes and controlling for potential confounders. There was also a synergistic interaction between H. pylori and higher body mass index (BMI), such that increased levels of HbA1c associated with having both H. pylori and higher BMI were greater than the sum of their individual effects (P for interaction < .01). This interaction was observed consistently in both NHANES III and NHANES 1999-2000 and for H. pylori cagA positivity in NHANES III. CONCLUSIONS: The findings indicate a role of H. pylori in impaired glucose tolerance in adults that may be potentiated by higher BMI level. PMID- 22427677 TI - Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue. AB - Regulatory T cells (Tregs) are potent immune modulators, but their role in human immunodeficiency virus type 1 (HIV-1) pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in a large cohort of HIV-1-infected individuals and HIV-1 negative controls. While HIV "elite controllers" and uninfected individuals had similar Treg numbers and frequencies, the absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue in patients with chronic progressive HIV-1 infection. Despite quantitative changes in Tregs, HIV-1 infection was not associated with an impairment of ex vivo suppressive function of flow-sorted Tregs in both HIV controllers and untreated chronic progressors. PMID- 22427678 TI - Relationships between HIV disease history and blood HIV-1 DNA load in perinatally infected adolescents and young adults: the ANRS-EP38-IMMIP study. AB - BACKGROUND: Our aim was to study the impact of lifelong human immunodeficiency virus (HIV) disease history on the current immune and virological status of perinatally infected patients reaching adulthood. We evaluated blood cell associated HIV DNA load as an indicator of cell-associated HIV reservoirs and an independent predictor of disease progression. METHODS: The ANRS-EP38-IMMIP Study included 93 patients aged 15-24 years who were infected with HIV during the perinatal period. HIV DNA load was quantified by real-time polymerase chain reaction. RESULTS: Eighty-five percent of patients were receiving highly active antiretroviral therapy (HAART), and HIV RNA was undetectable in the plasma of 75% of these patients. The median HIV DNA load was 2.84 (interquartile range, 2.51 3.16) log(10) copies per 10(6) peripheral blood mononuclear cells. In patients with viral suppression, HIV DNA load was independently associated with cumulative HIV RNA viremia over the last 5 years. HIV DNA load was negatively correlated with CD4 cell count in patients with active replication but not in those with undetectable HIV RNA. CONCLUSIONS: In perinatally infected youths who are successfully treated, sustained viral suppression is associated with a low HIV DNA load. The absence of association between current HIV DNA load and CD4 cell counts suggests that the unique physiological characteristics of pediatric infection persist after adolescence. CLINICAL TRIALS REGISTRATION: NCT01055873. PMID- 22427679 TI - Genital warts and risk of cancer: a Danish study of nearly 50 000 patients with genital warts. AB - BACKGROUND: We conducted a large national cohort study to examine the risk of cancer among men and women with genital warts (GW). METHODS: By use of the Danish National Patient Register, we identified 16,155 men and 32,933 women who received a diagnosis of GW during 1978-2008. Standardized incidence ratios (SIRs) were computed as estimates of the relative risk of specific cancers or sites. RESULTS: A diagnosis of GW was strongly related to anal (SIR for men, 21.5; SIR for women, 7.8), vulvar (SIR, 14.8), vaginal (SIR, 5.9), cervical (SIR, 1.5), penile (SIR, 8.2), and head and neck cancer (SIR, 2.8), including subsites of head and neck cancer with confirmed HPV association (SIR for men, 3.5; SIR for women, 4.8). The risks remained elevated for >10 years following GW diagnosis. In addition, we found moderately increased SIR estimates for nonmelanoma skin cancer, smoking related cancers, and Hodgkin and non-Hodgkin lymphoma. CONCLUSIONS: Individuals with GW have a long-term increased risk of anogenital cancers and head and neck cancers. The elevated risks of nonmelanoma skin cancers might indicate an association with HPV, while excess risks of other cancers could point to differences in other risk factors between individuals with GW and the general population. PMID- 22427680 TI - Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF-kappaB activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury. AB - Mer signaling participates in a novel inhibitory pathway in TLR activation. The purpose of the present study was to examine the role of Mer signaling in the down regulation of TLR4 activation-driven immune responses in mice, i.t.-treated with LPS, using the specific Mer-blocking antibody. At 4 h and 24 h after LPS treatment, expression of Mer protein in alveolar macrophages and lung tissue decreased, sMer in BALF increased significantly, and Mer activation increased. Pretreatment with anti-Mer antibody did not influence the protein levels of Mer and sMer levels. Anti-Mer antibody significantly reduced LPS-induced Mer activation, phosphorylation of Akt and FAK, STAT1 activation, and expression of SOCS1 and -3. Anti-Mer antibody enhanced LPS-induced inflammatory responses, including activation of the NF-kappaB pathway; the production of TNF-alpha, IL 1beta, and MIP-2 and MMP-9 activity; and accumulation of inflammatory cells and the total protein levels in BALF. These results indicate that Mer plays as an intrinsic feedback inhibitor of the TLR4- and inflammatory mediator-driven immune responses during acute lung injury. PMID- 22427681 TI - Role of IL-6 in the resolution of pancreatitis in obese mice. AB - Obesity increases severity of acute pancreatitis and risk of pancreatic cancer. Pancreatitis and obesity are associated with elevated IL-6, a cytokine involved in inflammation and tumorigenesis. We studied the role of IL-6 in the response of lean and obese mice to pancreatitis induced by IL-12 + IL-18. Lean and diet induced obese (DIO) WT and IL-6 KO mice and ob/ob mice pretreated with anti-IL-6 antibodies were evaluated at Days 1, 7, and 15 after induction of pancreatitis. Prolonged elevation of IL-6 in serum and visceral adipose tissue was observed in DIO versus lean WT mice, whereas circulating sIL-6R declined in DIO but not lean mice with pancreatitis. The severe inflammation and lethality of DIO mice were also observed in IL-6 KO mice. However, the delayed resolution of neutrophil infiltration; sustained production of CXCL1, CXCL2, and CCL2; prolonged activation of STAT-3; and induction of MMP-7 in the pancreas, as well as heightened induction of serum amylase A of DIO mice, were blunted significantly in DIO IL-6 KO mice. In DIO mice, production of OPN and TIMP-1 was increased for a prolonged period, and this was mediated by IL-6 in the liver but not the pancreas. Results obtained in IL-6 KO mice were confirmed in ob/ob mice pretreated with anti-IL-6 antibodies. In conclusion, IL-6 does not contribute to the increased severity of pancreatitis of obese mice but participates in delayed recovery from acute inflammation and may favor development of a protumorigenic environment through prolonged activation of STAT-3, induction of MMP-7, and sustained production of chemokines. PMID- 22427682 TI - Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression. AB - Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages. PMID- 22427683 TI - Bacterial reprogramming of PBMCs impairs monocyte phagocytosis and modulates adaptive T cell responses. AB - Septic diseases are characterized by an initial systemic, proinflammatory phase, followed by a period of anti-inflammation. In the context of the latter, monocytes have been described to display altered functions, including reduced TNF secretion and T cell-stimulating capacities in response to recall antigens. This hyporesponsiveness is supposed to be detrimental for coping with secondary infections. We here characterize bacterially reprogrammed PBMC-derived monocytes with special focus on their phagocytic activity. Hence, we have implemented a surrogate model of the early, postinflammatory period by exposing PBMCs to Escherichia coli on d0 and rechallenging them with bacteria on d2. This induced the emergence of a distinct monocytic phenotype with profound phagocytic impairments but a preserved ability for naive T cell stimulation. The compromising effects on phagocytosis required the presence of bacteria and were not mimicked by TLR4 ligation or exposure to isolated cytokines alone. Moreover, the impairments were specific for the engulfment of bacteria and were coupled to a selective down-regulation of FcgammaR and SR expression. Intriguingly, this monocytic phenotype contributed to the stimulation of a T(H)17-polarized adaptive immune response in the context of secondary infection. Our findings extend the current knowledge of monocytic reprogramming and identify the phagocytic capacity of monocytes as a putative sepsis biomarker. PMID- 22427684 TI - Changing concepts: Menopausal hormone therapy and breast cancer. AB - Hormone therapy is still used by millions of women for menopausal symptoms. Concerns regarding hormone therapy and breast cancer were initially based on case reports and retrospective case-control studies. However, recent results from large prospective cohort studies and the Women's Health Initiative (WHI) randomized placebo-controlled hormone therapy trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestin influence breast cancer. The preponderance of observational studies suggested that estrogen alone and estrogen plus progestin both increased the risk of breast cancer, with cancers commonly diagnosed at an early stage. However, substantially different results emerged from the WHI randomized hormone therapy trials. In the WHI trial evaluating estrogen plus progestin in postmenopausal women with an intact uterus, combined hormone therapy statistically significantly increased the risk of breast cancer and hindered breast cancer detection, leading to delayed diagnosis and a statistically significant increase in breast cancer mortality. By contrast, estrogen alone use by postmenopausal women with prior hysterectomy in the WHI trial did not substantially interfere with breast cancer detection and statistically significantly decreased the risk of breast cancer. Differential mammography usage patterns may explain differences between observational study and randomized trial results. In clinical practice, hormone therapy users have mammograms more frequently than nonusers, leading to more and earlier stage cancer detection. By contrast, in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups. Currently, the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely understood. PMID- 22427685 TI - Association tests of striatal DAT availability and SNPs that impact a novel splice variant in the DAT gene. PMID- 22427686 TI - Characterization of Mid1 domains for targeting and scaffolding in fission yeast cytokinesis. AB - Division-site selection and contractile-ring assembly are two crucial steps in cytokinesis. In fission yeast, the anillin-like Mid1 protein specifies the division site at the cell equator by assembling cortical nodes, the precursors of the contractile ring. Thus, Mid1 is essential for linking the positional cues for the cleavage site to contractile-ring formation. However, how Mid1 domains cooperate to regulate cytokinesis is poorly understood. Here we unravel the functions of different Mid1 domains (motifs) by a series of truncations. We report that the conserved PH domain stabilizes Mid1 in nodes by binding to lipids and is required for Mid1 cortical localization during interphase in the absence of Cdr2 kinase. Mid1 lacking an internal region that is approximately one third of the full-length protein has higher nuclear and cortical concentration and suppresses the division-site positioning defects in cells with a deletion of the dual-specificity tyrosine-regulated kinase Pom1. The N-terminus of Mid1 physically interacts with cytokinesis node proteins. When fused to cortical node protein Cdr2, Mid1(1-100) is sufficient to assemble cytokinesis nodes and the contractile ring. Collectively, our study recognizes domains regulating Mid1 cortical localization and reveals domains sufficient for contractile-ring assembly. PMID- 22427687 TI - Polo-like kinase is necessary for flagellum inheritance in Trypanosoma brucei. AB - Polo-like kinases play an important role in a variety of mitotic events in mammalian cells, ranging from centriole separation and chromosome congression to abscission. To fulfill these roles, Polo-like kinase homologs move to different cellular locations as the cell cycle progresses, starting at the centrosome, progressing to the spindle poles and then the midbody. In the protist parasite Trypanosoma brucei, the single polo-like kinase homolog T. brucei PLK (TbPLK) is essential for cytokinesis and is necessary for the correct duplication of a centrin-containing cytoskeletal structure known as the bilobe. We show that TbPLK has a dynamic localization pattern during the cell cycle. The kinase localizes to the basal body, which nucleates the flagellum, and then successively localizes to a series of cytoskeletal structures that regulate the position and attachment of the flagellum to the cell body. The kinase localizes to each of these structures as they are duplicating. TbPLK associates with a specialized set of microtubules, known as the microtubule quartet, which might transport the kinase during its migration. Depletion of TbPLK causes defects in basal body segregation and blocks the duplication of the regulators that position the flagellum, suggesting that its presence on these structures might be necessary for their proper biogenesis. TbPLK migrates throughout the cell in T. brucei, but the specific locations to which it targets and its functions are geared towards the inheritance of a properly positioned and attached flagellum. PMID- 22427688 TI - The SEC6 protein is required for contractile vacuole function in Chlamydomonas reinhardtii. AB - Contractile vacuoles (CVs) are essential for osmoregulation in many protists. To investigate the mechanism of CV function in Chlamydomonas, we isolated novel osmoregulatory mutants. Four of the isolated mutant cell lines carried the same 33,641 base deletion, rendering the cell lines unable to grow under strong hypotonic conditions. One mutant cell line (Osmo75) was analyzed in detail. The CV morphology was variable in mutant cells, and most cells had multiple small CVs. In addition, one or two enlarged CVs or no visible CVs at all, were observed by light microscopy. These findings suggest that the mutant is impaired in homotypic vacuolar and exocytotic membrane fusion. Furthermore the mutants had long flagella. One of the affected genes is the only SEC6 homologue in Chlamydomonas (CreSEC6). The SEC6 protein is a component of the exocyst complex that is required for efficient exocytosis. Transformation of the Osmo75 mutant with a CreSEC6-GFP construct rescued the mutant completely (osmoregulation and flagellar length). Rescued strains overexpressed CreSEC6 (as a GFP-tagged protein) and displayed a modified CV activity. CVs were larger, whereas the CV contraction interval remained unchanged, leading to increased water efflux rates. Electron microscopy analysis of Osmo75 cells showed that the mutant is able to form the close contact zones between the plasma membrane and the CV membrane observed during late diastole and systole. These results indicate that CreSEC6 is essential for CV function and required for homotypic vesicle fusion during diastole and water expulsion during systole. In addition, CreSEC6 is not only necessary for CV function, but possibly influences the CV cycle in an indirect manner and flagellar length in Chlamydomonas. PMID- 22427689 TI - TIG3 interaction at the centrosome alters microtubule distribution and centrosome function. AB - TIG3 is an important pro-differentiation regulator that is expressed in the suprabasal epidermis. We have shown that TIG3 activates selective keratinocyte differentiation-associated processes leading to cornified envelope formation. However, TIG3 also suppresses cell proliferation by an unknown mechanism. Our present studies suggest that cessation of growth is mediated through the impact of TIG3 on the centrosome and microtubules. The centrosome regulates microtubule function in interphase cells and microtubule spindle formation in mitotic cells. We show that TIG3 colocalizes with gamma-tubulin and pericentrin at the centrosome. Localization of TIG3 at the centrosome alters microtubule nucleation and reduces anterograde microtubule growth, increases acetylation and detyrosination of alpha-tubulin, increases insoluble tubulin and drives the formation of a peripheral microtubule ring adjacent to the plasma membrane. In addition, TIG3 suppresses centrosome separation, but not duplication, and reduces cell proliferation. We propose that TIG3 regulates the formation of the peripheral microtubule ring observed in keratinocytes of differentiated epidermis and also has a role in the cessation of proliferation in these cells. PMID- 22427690 TI - Various p53 mutant proteins differently regulate the Ras circuit to induce a cancer-related gene signature. AB - Concomitant expression of mutant p53 and oncogenic Ras, leading to cellular transformation, is well documented. However, the mechanisms by which the various mutant p53 categories cooperate with Ras remain largely obscure. From this study we suggest that different mutant p53 categories cooperate with H-Ras in different ways to induce a unique expression pattern of a cancer-related gene signature (CGS). The DNA-contact p53 mutants (p53(R248Q) and p53(R273H)) exhibited the highest level of CGS expression by cooperating with NFkappaB. Furthermore, the Zn(+2) region conformational p53 mutants (p53(R175H) and p53(H179R)) induced the CGS by elevating H-Ras activity. This elevation in H-Ras activity stemmed from a perturbed function of the p53 transcription target gene, BTG2. By contrast, the L3 loop region conformational mutant (p53(G245S)) did not affect CGS expression. Our findings were further corroborated in human tumor-derived cell lines expressing Ras and the aforementioned mutated p53 proteins. These data might assist in future tailor-made therapy targeting the mutant p53-Ras axis in cancer. PMID- 22427691 TI - Actin coating and compression of fused secretory vesicles are essential for surfactant secretion--a role for Rho, formins and myosin II. AB - Secretion of vesicular contents by exocytosis is a fundamental cellular process. Increasing evidence suggests that post-fusion events play an important role in determining the composition and quantity of the secretory output. In particular, regulation of fusion pore dilation and closure is considered a key regulator of the post-fusion phase. However, depending on the nature of the cargo, additional mechanisms might be essential to facilitate effective release. We have recently described that in alveolar type II (ATII) cells, lamellar bodies (LBs), which are secretory vesicles that store lung surfactant, are coated with actin following fusion with the plasma membrane. Surfactant, a lipoprotein complex, does not readily diffuse out of fused LBs following opening and dilation of the fusion pore. Using fluorescence microscopy, atomic force microscopy and biochemical assays, we present evidence that actin coating and subsequent contraction of the actin coat is essential to facilitate surfactant secretion. Latrunculin B prevents actin coating of fused LBs and inhibits surfactant secretion almost completely. Simultaneous imaging of the vesicle membrane and the actin coat revealed that contraction of the actin coat compresses the vesicle following fusion. This leads to active extrusion of vesicle contents. Initial actin coating of fused vesicles is dependent on activation of Rho and formin-dependent actin nucleation. Actin coat contraction is facilitated by myosin II. In summary, our data suggest that fusion pore opening and dilation itself is not sufficient for release of bulky vesicle cargos and that active extrusion mechanisms are required. PMID- 22427692 TI - TOR signaling regulates planarian stem cells and controls localized and organismal growth. AB - Target of Rapamycin (TOR) controls an evolutionarily conserved signaling pathway that modulates cellular growth and division by sensing levels of nutrients, energy and stress. As such, TOR signaling is a crucial component of tissues and organs that translates systemic signals into cellular behavior. The ubiquitous nature of TOR signaling, together with the difficulty of analyzing tissue during cellular turnover and repair, have limited our understanding of how this kinase operates throughout the body. Here, we use the planarian model system to address TOR regulation at the organismal level. The planarian TOR homolog (Smed-TOR) is ubiquitously expressed, including stem cells (neoblasts) and differentiated tissues. Inhibition of TOR with RNA interference severely restricts cell proliferation, allowing the study of neoblasts with restricted proliferative capacity during regeneration and systemic cell turnover. Strikingly, TOR signaling is required for neoblast response to amputation and localized growth (blastema). However, in the absence of TOR signaling, regeneration takes place only within differentiated tissues. In addition, TOR is essential for maintaining the balance between cell division and cell death, and its dysfunction leads to tissue degeneration and lack of organismal growth in the presence of nutrients. Finally, TOR function is likely to be mediated through TOR Complex 1 as its disruption recapitulates signs of the TOR phenotype. Our data reveal novel roles for TOR signaling in controlling adult stem cells at a systemic level and suggest a new paradigm for studying TOR function during physiological turnover and regeneration. PMID- 22427693 TI - The late endosomal adaptor p14 is a macrophage host-defense factor against Salmonella infection. AB - The outcome of an infection depends on the balance between host resistance and bacterial virulence. Here, we show that the late endosomal adaptor p14 (also known as LAMTOR2) is one of the components for cellular host defense against the intracellular pathogen Salmonella enterica serovar Typhimurium. During Salmonella infection, the complex of p14 and MP1 is required for the accurately timed transport of Salmonella through the endolysosomal system. Loss of p14 opens a time window that allows Salmonella to populate a replication niche, in which early and late antimicrobial effector systems, comprising NADPH phagocytic oxidase and inducible nitric oxide synthase, respectively, are inappropriately activated. Thus, p14 supports the accurate transport of Salmonella through the endolysosomal system, thereby limiting bacterial replication in both, professional phagocytes and in non-phagocytic cells in vitro, and helps mice to successfully battle Salmonella infection in vivo. PMID- 22427694 TI - Zds1 regulates PP2A(Cdc55) activity and Cdc14 activation during mitotic exit through its Zds_C motif. AB - At anaphase onset, highly active mitotic cyclin-dependent kinase (Cdk) is inactivated to promote exit from mitosis and completion of cytokinesis. The budding yeast Cdc14p phosphatase is a key mitotic regulator that counteracts cyclin-dependent kinase (Cdk) activity during mitotic exit. Separase, together with Zds1p, promotes the downregulation of the protein phosphatase 2A in conjunction with its Cdc55p regulatory subunit (PP2A(Cdc55)) in early anaphase, enabling accumulation of phosphorylated forms of Net1p and release of Cdc14p from the nucleolus. Here we show that the C-terminal domain of Zds1p, called the Zds_C motif, is required for Zds1-induced release of Cdc14p, and the N-terminal domain of the protein might be involved in regulating this activity. More interestingly, Zds1p physically interacts with Cdc55p, and regulates its localization through the Zds_C motif. Nevertheless, expression of the Zds_C motif at endogenous levels cannot induce timely release of Cdc14p from the nucleolus, despite the proper (nucleolar) localization of Cdc55p. Our results suggest that the activity of PP2A(Cdc55) cannot be modulated solely through regulation of its localization, and that an additional regulatory step is probably required. These results suggest that Zds1p recruits PP2A(Cdc55) to the nucleolus and induces its inactivation by an unknown mechanism. PMID- 22427695 TI - Associative learning of shape as a cue to appearance: a new demonstration of cue recruitment. AB - The perceived rotation direction of a wire-frame Necker cube at stimulus onset can be conditioned to be dependent on retinal location (B. T. Backus & Q. Haijiang, 2007; S. J. Harrison & B. T. Backus, 2010a). This phenomenon was proposed to be an example of the visual system learning new cues to visual appearance, by adaptation in response to new experiences. Here, we demonstrate recruitment of a new cue, object shape, for the appearance of rotating 3D objects. The cue was established by interleaving ambiguous and disambiguated instances of two shapes, cubes and spheres, at the same retinal location. Disambiguated cubes and spheres rotated in opposite directions. A significant bias was consequently introduced in the resolution of ambiguity, whereby the proportions of ambiguous shapes perceived as rotating clockwise differed, in the direction predicted by their disambiguated counterparts. This finding suggests that training led the visual system to distinguish between the two shapes. The association of rotation direction and shape was only achieved when monocular depth cues were used to depict rotation in depth; shapes disambiguated by binocular disparity did not lead to recruitment of the shape cue. We speculate that this difference may be the consequence of a difference in the neural pathways by which the disambiguating cues act. This new instance of the cue recruitment effect opens possibilities for further generalization of the phenomenon. PMID- 22427696 TI - The relative weight of shape and non-rigid motion cues in object perception: a model of the parameters underlying dynamic object discrimination. AB - Shape and motion are two dominant cues for object recognition, but it can be difficult to investigate their relative quantitative contribution to the recognition process. In the present study, we combined shape and non-rigid motion morphing to investigate the relative contributions of both types of cues to the discrimination of dynamic objects. In Experiment 1, we validated a novel parameter-based motion morphing technique using a single-part three-dimensional object. We then combined shape morphing with the novel motion morphing technique to pairs of multipart objects to create a joint shape and motion similarity space. In Experiment 2, participants were shown pairs of morphed objects from this space and responded "same" on the basis of motion-only, shape-only, or both cues. Both cue types influenced judgments: When responding to only one cue, the other cue could be ignored, although shape cues were more difficult to ignore. When responding on the basis of both cues, there was an overall bias to weight shape cues more than motion cues. Overall, our results suggest that shape influences discrimination more than motion even when both cue types have been made quantitatively equivalent in terms of their individual discriminability. PMID- 22427697 TI - Commentary: promoting health and well-being in pediatric primary care settings: using health and behavior codes at routine well-child visits. PMID- 22427698 TI - Multimethod assessment of children's distress during noninvasive outpatient medical procedures: child and parent attitudes and factors. AB - The present study assessed behavioral distress during noninvasive outpatient procedures in children ages 4-10 years using a multimethod approach. Factors hypothesized to exacerbate children's distress included parents' and children's attitudes toward healthcare, children's knowledge of medical settings, and parental anxiety. A total of 53 parent-child dyads were recruited from outpatient clinics, with procedural distress assessed via child report, parent report, and direct observation. Some differences emerged depending on the method used to gauge distress. Children's healthcare attitudes and knowledge were associated with observed and child-reported distress, but parent's personal anxiety was associated only with their own perceptions of children's procedural distress. Parents' attitudes toward healthcare were associated with their anxiety but not with children's behavioral distress or healthcare attitudes. Findings are discussed in terms of more consistent findings regarding children's healthcare knowledge and attitudes versus the potential need for additional research on more divergent findings regarding parents' anxiety and healthcare attitudes. PMID- 22427699 TI - Risky health behavior among adolescents in the childhood cancer survivor study cohort. AB - OBJECTIVE: To report the prevalence and comparison of cancer-linked health behaviors and identify risk factors associated with unhealthy behavior among adolescent siblings and cancer survivors. METHODS: The Child Health and Illness Profile--Adolescent Edition (CHIP--AE) was completed by 307 survivors and 97 sibling controls 14-20 years of age. RESULTS: Risky behavior ranged from 0.7% to 35.8% for survivors and 1.0% to 41.2% for siblings. Comparisons of sexual behavior, tobacco, alcohol, or illicit drug use utilizing continuous data revealed no differences between groups. Categorically, survivors were less likely to report past smokeless tobacco use or current use of beer/wine or binge drinking (p-values range from .01 to .04). Survivors with better mental health were at lower risk for poor behavioral outcomes. CONCLUSIONS: Adolescent survivors engage in risky health behaviors at rates generally equivalent to their siblings. Aggressive health education efforts should be directed toward this high risk population. PMID- 22427700 TI - Covert video monitoring in the assessment of medically unexplained symptoms in children. AB - OBJECTIVE: Diagnosis of medically unexplained symptoms (MUS) occurs after thorough evaluations have failed to identify a physiological cause for symptoms. However, families and providers may wonder if something has been missed, leading to reduced confidence in behavioral treatment. Confidence may be improved through the use of technology such as covert video monitoring to better assess functioning across settings. METHODS: A 12-year-old male presented with progressive neurological decline, precipitated by chronic pain. After thorough evaluation and the failure of standard treatments (medical, rehabilitative, and psychological) covert video monitoring revealed that the patient demonstrated greater abilities when alone in his room. Negative reinforcement was used to initiate recovery, accompanied by positive reinforcement and a rehabilitative approach. Covert video monitoring assisted in three subsequent cases over the following 3 years. RESULTS AND CONCLUSIONS: In certain complex cases, video monitoring can inform the assessment and treatment of MUS. Discussion includes ethical and practical considerations. PMID- 22427701 TI - Activation of nicotinic receptors can contribute to endothelium-dependent relaxations to acetylcholine in the rat aorta. AB - Acetylcholine causes endothelium-dependent relaxations in the rat aorta. Both muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs) are expressed in endothelial cells. It is generally accepted that mAChRs are responsible for the endothelium-dependent relaxations evoked by acetylcholine. The present study was designed to investigate whether nAChRs can also be involved in such responses evoked by the cholinergic transmitter. Rings with or without endothelium of aortae of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats were suspended in organ chambers for the measurement of isometric tension. In WKY aortae the muscarinic antagonist atropine abolished the relaxations to increasing concentrations of acetylcholine, confirming that mAChRs are responsible mainly for the response under control conditions. In SHR aortae, atropine caused only partial inhibition of the endothelium-dependent relaxations to acetylcholine; the remaining decreases in tension were inhibited by the nicotinic antagonist mecamylamine, which did not significantly affect the response in the absence of atropine in either SHR or WKY preparations. Thus, when mAChRs are inhibited, nAChRs mediate relaxation to the cholinergic transmitter in the SHR but not the WKY aorta. Nicotine, a direct agonist of the nicotinic receptor, induced endothelium-dependent relaxations in both SHR and WKY rats via the activation of alpha7-nAChRs, but not by mecamylamine-sensitive nicotinic receptors (alpha3 subtype). The acetylcholine induced, atropine-insensitive relaxations and those to nicotine both involve the phosphatidylinositol 3-kinase/AKT pathway. The present study demonstrates that the activation of nAChRs can contribute to acetylcholine-induced, endothelium dependent relaxations in the aortae of hypertensive animals and suggests that these receptors may contribute to the endothelium-dependent regulation of vascular tone. PMID- 22427702 TI - Carbon monoxide from neighbouring restaurants: the need for an integrated multi agency response. AB - BACKGROUND: Carbon monoxide (CO) is a colourless, odourless toxic gas produced during incomplete combustion of carbon-based fuels. Most CO incidents reported to the UK Health Protection Agency (HPA) are due to faulty gas appliances, and legislation exists to ensure gas appliances are properly installed. METHODS: We present three CO poisoning incidents of unusual origin reported to the HPA. In each, residents living above restaurants were poisoned after workers left charcoal smouldering overnight in specialist or traditional ovens whilst ventilation systems were turned off. This led to production of CO, which travelled through floorboards and built up to dangerous concentrations in the flats. RESULTS: Working with local authorities, these incidents were investigated and resolved, and work was conducted to prevent further occurrences. CONCLUSIONS: The novel nature of these CO incidents led to delays in recognition and subsequent remedial action. Although previously undescribed, it is likely that due to the number of residences built above restaurants and the rising popularity of traditional cooking methods, similar incidents may be occurring and could increase in frequency. Multi-agency response and reporting mechanisms could be strengthened. Awareness raising in professional groups and the public on the importance of correct ventilation of such appliances is vital. PMID- 22427703 TI - Quantitative proteomics reveals that only a subset of the endoplasmic reticulum contributes to the phagosome. AB - Phagosomes, by killing and degrading pathogens for antigen presentation, are organelles implicated in key aspects of innate and adaptive immunity. Although it has been well established that phagosomes consist of membranes from the plasma membrane, endosomes, and lysosomes, the notion that the endoplasmic reticulum (ER) membrane could play an important role in the formation of the phagosome is debated. However, a method to accurately estimate the contribution of potential source organelles and contaminants to the phagosome proteome has been lacking. Herein, we have developed a proteomic approach for objectively quantifying the contribution of various organelles to the early and late phagosomes by comparing these fractions to their total membrane and postnuclear supernatant of origin in the J774A.1 murine macrophage cell line. Using quantitative label-free mass spectrometry, the abundance of peptides corresponding to hundreds of proteins was estimated and attributed to one of five organelles (e.g. plasma membrane, endosomes/lysosomes, ER, Golgi, and mitochondria). These data in combination with a stable isotope labeling in cell culture method designed to detect potential contaminant sources revealed that the ER is part of the phagosomal membrane and contributes ~ 20% of the early phagosome proteome. In addition, only a subset of ER proteins is recruited to the phagosome, suggesting that a specific subdomain(s) of the ER might be involved in phagocytosis. Western blotting and immunofluorescence substantially validated this conclusion; we were able to demonstrate that the fraction of the ER in which the ER marker GFP-KDEL accumulates is excluded from the phagosomes, whereas that containing the mVenus Syntaxin 18 is recruited. These results highlight promising new avenues for the description of the pathogenic mechanisms used by Leishmania, Brucella, and Legionella spp., which thrive in ER-rich phagosomes. PMID- 22427704 TI - Modulation of neuronal pentraxin 1 expression in rat pancreatic beta-cells submitted to chronic glucotoxic stress. AB - Insulin secretory granules are beta-cell vesicles dedicated to insulin processing, storage, and release. The secretion of insulin secretory granule content in response to an acute increase of glucose concentration is a highly regulated process allowing normal glycemic homeostasis. Type 2 diabetes is a metabolic disease characterized by chronic hyperglycemia. The consequent prolonged glucose exposure is known to exert deleterious effects on the function of various organs, notably impairment of insulin secretion by pancreatic beta cells and induction of apoptosis. It has also been described as modifying gene and protein expression in beta-cells. Therefore, we hypothesized that a modulation of insulin secretory granule protein expression induced by chronic hyperglycemia may partially explain beta-cell dysfunction. To identify the potential early molecular mechanisms underlying beta-cell dysfunction during chronic hyperglycemia, we performed SILAC and mass spectrometry experiments to monitor changes in the insulin secretory granule proteome from INS-1E rat insulinoma beta-cells cultivated either with 11 or 30 mm of glucose for 24 h. Fourteen proteins were found to be differentially expressed between these two conditions, and several of these proteins were not described before to be present in beta-cells. Among them, neuronal pentraxin 1 was only described in neurons so far. Here we investigated its expression and intracellular localization in INS-1E cells. Furthermore, its overexpression in glucotoxic conditions was confirmed at the mRNA and protein levels. According to its role in hypoxia-ischemia-induced apoptosis described in neurons, this suggests that neuronal pentraxin 1 might be a new beta-cell mediator in the AKT/GSK3 apoptotic pathway. In conclusion, the modification of specific beta-cell pathways such as apoptosis and oxidative stress may partially explain the impairment of insulin secretion and beta-cell failure, observed after prolonged exposure to high glucose concentrations. PMID- 22427705 TI - Closing the translation gap for justice requirements in international research. AB - Bioethicists have long debated the content of sponsors and researchers' obligations of justice in international clinical research. However, there has been little empirical investigation as to whether and how obligations of responsiveness, ancillary care, post-trial benefits and research capacity strengthening are upheld in low- and middle-income country settings. In this paper, the authors argue that research ethics guidelines need to be more informed by international research practice. Practical guidance on how to fulfil these obligations is needed if research groups and other actors are to successfully translate them into practice because doing so is often a complicated, context specific process. Case study research methods offer one avenue for collecting data to develop this guidance. The authors describe how such methods have been used in relation to the Shoklo Malaria Research Unit's vivax malaria treatment (VHX) trial (NCT01074905). Relying on the VHX trial example, the paper shows how information can be gathered from not only international clinical researchers but also trial participants, community advisory board members and research funder representatives in order to: (1) measure evidence of responsiveness, provision of ancillary care, access to post-trial benefits and research capacity strengthening in international clinical research; and (2) identify the contextual factors and roles and responsibilities that were instrumental in the fulfilment of these ethical obligations. Such empirical work is necessary to inform the articulation of obligations of justice in international research and to develop guidance on how to fulfil them in order to facilitate better adherence to guidelines' requirements. PMID- 22427706 TI - Statistical guidelines for detecting past population shifts using ancient DNA. AB - Populations carry a genetic signal of their demographic past, providing an opportunity for investigating the processes that shaped their evolution. Our ability to infer population histories can be enhanced by including ancient DNA data. Using serial-coalescent simulations and a range of both quantitative and temporal sampling schemes, we test the power of ancient mitochondrial sequences and nuclear single-nucleotide polymorphisms (SNPs) to detect past population bottlenecks. Within our simulated framework, mitochondrial sequences have only limited power to detect subtle bottlenecks and/or fast post-bottleneck recoveries. In contrast, nuclear SNPs can detect bottlenecks followed by rapid recovery, although bottlenecks involving reduction of less than half the population are generally detected with low power unless extensive genetic information from ancient individuals is available. Our results provide useful guidelines for scaling sampling schemes and for optimizing our ability to infer past population dynamics. In addition, our results suggest that many ancient DNA studies may face power issues in detecting moderate demographic collapses and/or highly dynamic demographic shifts when based solely on mitochondrial information. PMID- 22427707 TI - Sequence evolution correlates with structural dynamics. AB - Biochemical activity and core stability are essential properties of proteins, maintained usually by conserved amino acids. Structural dynamics emerged in recent years as another essential aspect of protein functionality. Structural dynamics enable the adaptation of the protein to binding substrates and to undergo allosteric transitions, while maintaining the native fold. Key residues that mediate structural dynamics would thus be expected to be conserved or exhibit coevolutionary patterns at least. Yet, the correlation between sequence evolution and structural dynamics is yet to be established. With recent advances in efficient characterization of structural dynamics, we are now in a position to perform a systematic analysis. In the present study, a set of 34 enzymes representing various folds and functional classes is analyzed using information theory and elastic network models. Our analysis shows that the structural regions distinguished by their coevolution propensity as well as high mobility are predisposed to serve as substrate recognition sites, whereas residues acting as global hinges during collective dynamics are often supported by conserved residues. We propose a mobility scale for different types of amino acids, which tends to vary inversely with amino acid conservation. Our findings suggest the balance between physical adaptability (enabled by structure-encoded motions) and chemical specificity (conferred by correlated amino acid substitutions) underlies the selection of a relatively small set of versatile folds by proteins. PMID- 22427708 TI - Nuclear chromosome dynamics in the Drosophila male germ line contribute to the nonrandom genomic distribution of retrogenes. AB - The origin of RNA-based gene duplicates, that is, retrogenes, involves the reverse transcription of an mRNA derived from a parental gene to generate a cDNA copy, its insertion elsewhere in the genome, and the recruitment of regulatory sequences. Drosophila retrogenes are preferentially expressed in testis and a higher than expected number transpose to autosomal locations from the X chromosome. However, the influence of genomic context on the insertion preference of retrogenes remains poorly understood. We find that the distribution of retrogenes in the Drosophila melanogaster genome can be explained by an insertion bias toward chromosome domains containing testis-biased genes that are located at the nuclear periphery in somatic cells, but at inner positions in the male germ line. The lower fraction of these chromosome domains accessible in the male germ line on the X chromosome as compared with the autosomes also contributes to the scarcity of retrogenes on the X chromosome. PMID- 22427709 TI - Detecting patches of protein sites of influenza A viruses under positive selection. AB - Influenza A viruses are single-stranded RNA viruses capable of evolving rapidly to adapt to environmental conditions. Examples include the establishment of a virus in a novel host or an adaptation to increasing immunity within the host population due to prior infection or vaccination against a circulating strain. Knowledge of the viral protein regions under positive selection is therefore crucial for surveillance. We have developed a method for detecting positively selected patches of sites on the surface of viral proteins, which we assume to be relevant for adaptive evolution. We measure positive selection based on dN/dS ratios of genetic changes inferred by considering the phylogenetic structure of the data and suggest a graph-cut algorithm to identify such regions. Our algorithm searches for dense and spatially distinct clusters of sites under positive selection on the protein surface. For the hemagglutinin protein of human influenza A viruses of the subtypes H3N2 and H1N1, our predicted sites significantly overlap with known antigenic and receptor-binding sites. From the structure and sequence data of the 2009 swine-origin influenza A/H1N1 hemagglutinin and PB2 protein, we identified regions that provide evidence of evolution under positive selection since introduction of the virus into the human population. The changes in PB2 overlap with sites reported to be associated with mammalian adaptation of the influenza A virus. Application of our technique to the protein structures of viruses of yet unknown adaptive behavior could identify further candidate regions that are important for host-virus interaction. PMID- 22427710 TI - Exploring reservoir dynamics: a case study of rabies in the Serengeti ecosystem. AB - Knowledge of infection reservoir dynamics is critical for effective disease control, but identifying reservoirs of multi-host pathogens is challenging. Here, we synthesize several lines of evidence to investigate rabies reservoirs in complex carnivore communities of the Serengeti ecological region in northwest Tanzania, where the disease has been confirmed in 12 carnivore species.Long-term monitoring data suggest that rabies persists in high-density domestic dog Canis familiaris populations (> 11 dogs km(-2)) and occurs less frequently in lower density (< 5 dogs km(-2)) populations and only sporadically in wild carnivores.Genetic data show that a single rabies virus variant belonging to the group of southern Africa canid-associated viruses (Africa 1b) circulates among a range of species, with no evidence of species-specific virus-host associations.Within-species transmission was more frequently inferred from high resolution epidemiological data than between-species transmission. Incidence patterns indicate that spill-over of rabies from domestic dog populations sometimes initiates short-lived chains of transmission in other carnivores.Synthesis and applications. The balance of evidence suggests that the reservoir of rabies in the Serengeti ecosystem is a complex multi-host community where domestic dogs are the only population essential for persistence, although other carnivores contribute to the reservoir as non-maintenance populations. Control programmes that target domestic dog populations should therefore have the greatest impact on reducing the risk of infection in all other species including humans, livestock and endangered wildlife populations, but transmission in other species may increase the level of vaccination coverage in domestic dog populations necessary to eliminate rabies. PMID- 22427711 TI - Genetic influences on the development of childhood psychiatric disorders. AB - This review covers the key types of genetic research design, the methodology involved and emerging, and established findings in relation to child and adolescent psychiatry. Traditional family, twin, and adoption studies show that child and adolescent psychiatric disorders are familial and genetically influenced. Genes and environment contribute to all disorders. Genetic factors seem especially important for autism and attention deficit hyperactivity disorder. Twin and adoption study designs are now being used to examine gene environment interplay, the effects of environmental risk factors, co-morbidity, phenotype definition, and developmental change. Molecular genetic strategies are increasingly being adopted to identify gene variants that increase risk of specific disorders. The ways in which specific gene variants exert risk effects at cellular and biological system levels are proving to be highly complex. There is also interest in examining the brain mechanisms that may be involved in risk pathways that link gene variant to psychopathology. Finally, molecular genetic studies also highlight the importance of gene-environment interplay, which seems to be especially important in depression and antisocial behaviour. PMID- 22427712 TI - Everybody's Doin' It (Right?): Neighborhood Norms and Sexual Activity in Adolescence. AB - A neighborhood's normative climate is linked to, but conceptually distinct from, its structural characteristics such as poverty and racial/ethnic composition. Given the deleterious consequences of early sexual activity for adolescent health and well-being, it is important to assess normative influences on youth behaviors such as sexual debut, number of sex partners, and involvement in casual sexual experiences. The current study moves beyond prior research by constructing a measure of normative climate that more fully captures neighborhood norms, and analyzing the influence of normative climate on behavior in a longitudinal framework. Using recently geo-coded data from the Toledo Adolescent Relationships Study (TARS), we analyze the effect of normative climate on adolescents' sexual behaviors. Results indicate that variation in neighborhood normative climates increases adolescents' odds of sexual debut and casual sex, and is associated with their number of sex partners, even after accounting for neighborhood structural disadvantage and demographic risk factors. PMID- 22427713 TI - Open-ended and Open-door Treatment Groups for Young People with Mental Illness. AB - The concept of open-ended groups is expanded to include an open-door model (OEOD) wherein members with severe mental illnesses, including schizophrenia disorders and bi-polar, can join, leave, and re-enter groups as their life circumstances dictate their availability and willingness for treatment. This model is grounded on the work of Schopler and Galinsky's (1984/2006) and Galinsky and Schopler's (1989) theses on the value and processes of open-ended groups and includes perspectives on mutual aid and group development. Groupwork with the OEOD format is illustrated with examples taken from a group of 79 participants diagnosed with first-episode schizophrenia/schizoaffective disorders, 40 of who had co-occurring substance abuse. Of the 79 participants in the OEOD group program, 70 (89%) remained in treatment for the maximum of 3 years. The over-all value of group treatment for this population is reviewed along with the small number of available publications on open-ended and open-door-type groups. PMID- 22427714 TI - Methodological Issues in the Neuroscience of Moral Judgement. AB - Neuroscience and psychology have recently turned their attention to the study of the subpersonal underpinnings of moral judgment. In this article we critically examine an influential strand of research originating in Greene's neuroimaging studies of 'utilitarian' and 'non-utilitarian' moral judgement. We argue that given that the explananda of this research are specific personal-level states moral judgments with certain propositional contents-its methodology has to be sensitive to criteria for ascribing states with such contents to subjects. We argue that current research has often failed to meet this constraint by failing to correctly 'fix' key aspects of moral judgment, criticism we support by detailed examples from the scientific literature. PMID- 22427715 TI - I am going to gag: Disgust cognitions in spider and blood-injury-injection fears. AB - There is mounting evidence that disgust plays an important role in certain anxiety disorders, yet little is known about disgust's cognitive component. The current study introduces a measure of cognitions associated with disgust and contamination to assess the role of disgust-specific primary and secondary appraisals in phobic responding. A multi-modal assessment of blood-injury injection (BII) and spider phobia was conducted using BII (N=29) and spider (N=30) fearful groups, and a non-fearful control group (N=30). The Disgust Cognitions scale showed good reliability and validity, and distinguished among the groups. For example, relative to the other groups, the spider fear group reported higher disgust cognitions following presentation of a live spider, whereas the BII Fear group reported higher disgust cognitions following a surgery video. Moreover, the scale was associated with multiple phobic indicators (behavioral avoidance, subjective distress, symptom endorsement), suggesting cognitions may be critical to understanding how disgust contributes to anxiety disorders. PMID- 22427716 TI - Factors Influencing the Development of School Bonding Among Middle School Students. AB - The goal of this research is to examine the trajectory of school bonding over the middle school period and how factors such as gender, substance use, antisocial peers, delinquent behavior, and academic achievement affect this developmental process. Data from 4 waves of measurement of 2,902 adolescents are analyzed using hierarchical growth curve modeling. Results suggest that school bonding decreases in a non-linear fashion from Grade 6-8. However, school bonding development varies based on inter-individual differences. Boys have lower initial levels and greater decreases in school bonding than girls. Student deviant behavior, having antisocial peers, and low academic achievement are associated with lower levels of school bonding at Grade 6. Low grades and an increase in substance use are associated with a steeper decrease of school bonding over time. Increases in substance use and being male are also associated with a curvilinear pattern of school bonding. Implications for interventions are discussed. PMID- 22427717 TI - Technology Commercialization Effects on the Conduct of Research in Higher Education. AB - The objective of this study was to investigate the effects of technology commercialization on researcher practice and productivity at U.S. universities. Using data drawn from licensing contract documents and databases of university industry linkages and faculty research output, the study findings suggest that the common practice of licensing technologies exclusively to singular firms may have a dampening effect on faculty inventor propensity to conduct published research and to collaborate with others on research. Furthermore, faculty who are more actively engaged in patenting may be less likely to collaborate with outsiders on research while faculty at public universities may experience particularly strong norms to engage in commercialization vis-a-vis traditional routes to research dissemination. These circumstances appear to be hindering innovation via the traditional mechanisms (research publication and collaboration), questioning the success of policymaking to date for the purpose of speeding the movement of research from the lab bench to society. PMID- 22427718 TI - Challenges in Drug Discovery for Thiazolidinedione Substitute. AB - Thiazolidinedione (TZD) is a powerful insulin sensitizer in the treatment of type 2 diabetes. It acts as a ligand to the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor-gamma) and induces transcription of PPARgamma responsive genes. TZD controls lipid synthesis and storage in adipose tissue, liver and many other tissues through PPARgamma. Derivatives of TZD, such as rosiglitazone (Avandia) and pioglitazone (Actos), are more powerful than metformin or berberine in insulin sensitization. Although they have common side effects such as weight gain and edema, these did not influence the side effects in general. However, recent findings of risk for congestive heart failure and bladder cancer have indeed significantly impaired their future in many countries. European countries have prohibited those drugs and in 2011, US will terminate application of rosiglitazone in clinics and hospitals. The multiple country actions may mark the end of TZD era. As a result, there is a strong demand for identification of TZD substitute in the treatment of type 2 diabetes. In this regard, literature about PPARgamma ligands and potential TZD substitute are reviewed in this article. Histone deacetylase (HDAC) inhibitor is emphasized as a new class of insulin sensitizer here. Regulators of SIRT1, CREB, NO, p38, ERK and Cdk5 are discussed in the activation of PPARgamma. PMID- 22427720 TI - Metabolic modeling of Chlamydomonas reinhardtii: energy requirements for photoautotrophic growth and maintenance. AB - In this study, a metabolic network describing the primary metabolism of Chlamydomonas reinhardtii was constructed. By performing chemostat experiments at different growth rates, energy parameters for maintenance and biomass formation were determined. The chemostats were run at low irradiances resulting in a high biomass yield on light of 1.25 g mol(-1). The ATP requirement for biomass formation from biopolymers (K(x)) was determined to be 109 mmol g(-1) (18.9 mol mol(-1)) and the maintenance requirement (m(ATP)) was determined to be 2.85 mmol g(-1) h(-1). With these energy requirements included in the metabolic network, the network accurately describes the primary metabolism of C. reinhardtii and can be used for modeling of C. reinhardtii growth and metabolism. Simulations confirmed that cultivating microalgae at low growth rates is unfavorable because of the high maintenance requirements which result in low biomass yields. At high light supply rates, biomass yields will decrease due to light saturation effects. Thus, to optimize biomass yield on light energy in photobioreactors, an optimum between low and high light supply rates should be found. These simulations show that metabolic flux analysis can be used as a tool to gain insight into the metabolism of algae and ultimately can be used for the maximization of algal biomass and product yield. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10811-011-9674-3) contains supplementary material, which is available to authorized users. PMID- 22427719 TI - Molecular Genetics and Economics. PMID- 22427721 TI - Pelagostrobilidium neptuni (Montagnes and Taylor, 1994) and Strombidium biarmatum nov. spec. (Ciliophora, Oligotrichea): phylogenetic position inferred from morphology, ontogenesis, and gene sequence data. AB - Morphological data from life, protargol impregnation, and scanning electron microscopy were combined with genetic data not only to describe the marine plankton ciliates Pelagostrobilidium neptuni (Montagnes and Taylor, 1994) Petz, Song, and Wilbert, 1995 and Strombidium biarmatum nov. spec., but also to elucidate their phylogenetic relationships. Additionally, the ontogenesis of P. neptuni was studied and the diagnosis of the genus Pelagostrobilidium was improved due to further data from the newly affiliated species P. epacrum (Lynn and Montagnes, 1988) nov. comb. (basionym: Strobilidium epacrum Lynn and Montagnes, 1988). The phylogenetic analysis of the small subunit ribosomal RNA genes matched the morphologic and ontogenetic assigning of P. neptuni to the choreotrichid family Strobilidiidae. The considerable genetic distance of d = 0.074 between P. neptuni and Strobilidium caudatum corroborated the morphological differences and thus the maintenance of the genus Pelagostrobilidium. Strombidium biarmatum nov. spec. is a typical member of the genus, except for the two types of extrusomes ("trichites"): ~12 * 0.5 MUm, needle-shaped ones attached anterior to the girdle kinety and ~6 * 0.5 MUm, rod-shaped ones at the distal end of the intermembranellar ridges. Its flask-shaped resting cysts have several strong spines. In accordance with the morphologic data, S. biarmatum is placed within the order Oligotrichida by gene sequence analysis. The great genetic distances within the oligotrichids support the diversity found in morphologic and ontogenetic studies. PMID- 22427722 TI - Synthetic pH-Responsive Polymers for Protein Transduction. PMID- 22427723 TI - Searle's wager. AB - Nicholas Agar has recently argued that it would be irrational for future human beings to choose to radically enhance themselves by uploading their minds onto computers. Utilizing Searle's argument that machines cannot think, he claims that uploading might entail death. He grants that Searle's argument is controversial, but he claims, so long as there is a non-zero probability that uploading entails death, uploading is irrational. I argue that Agar's argument, like Pascal's wager on which it is modelled, fails, because the principle that we (or future agents) ought to avoid actions that might entail death is not action guiding. Too many actions fall under its scope for the principle to be plausible. I also argue that the probability that uploading entails death is likely to be lower than Agar recognizes. PMID- 22427724 TI - Cost-effectiveness study of oral hypoglycemic agents in the treatment of outpatients with type 2 diabetes attending a public primary care clinic in Mexico City. AB - INTRODUCTION: Worldwide, diabetes mellitus presents a high burden for individuals and society. In Latin America, many people with diabetes have limited access to health care, which means that indirect costs may exceed direct health care cost. Diabetes is Mexico's leading cause of death. PURPOSE: To evaluate the cost effectiveness ratios of the most used oral hypoglycemic agents (OHA) in the treatment of outpatients with type 2 diabetes attending a public primary care clinic in Mexico City. DESIGN: A cross-sectional and analytic study was conducted in Mexico City. METHODOLOGY: Twenty-seven adult outpatients with type 2 diabetes who were treated either with metformin or glibenclamide were included. Acarbose was used as an alternative strategy. The study was carried out from the perspective of Mexican society. Direct medical and nonmedical costs as well as indirect costs were evaluated using a structured questionnaire. Efficacies of all drug treatments were evaluated retrospectively. A systematic search was conducted to select published randomized clinical trials based on predetermined inclusion criteria, and treatment success was defined as glycosylated hemoglobin factor <= 7%. Efficacy data of each drug and/or combination were analyzed using meta analysis. The Monte Carlo Markov model was used. Quality-adjusted life-years (QALY) were used as the unit of effectiveness; incremental and sensitive analyses were performed and a 5% discount rate was calculated. A hypothetical cohort of 10,000 patients was modeled. RESULTS: The odds ratios of the success of each drug treatment were obtained from the meta-analyses, and were the following: 5.82 (glibenclamide), 3.86 (metformin), 3.5 (acarbose), and 6.76 (metformin glibenclamide). The cost-effectiveness ratios found were US$272.63/QALY (glibenclamide), US$296.48/QALY (metformin), and US$409.86/QALY (acarbose). Sensitivity analysis did not show changes for the most cost-effective therapy when the effectiveness probabilities or treatment costs were modified. CONCLUSION: Glibenclamide is the most cost-effective treatment for the present study outpatient population diagnosed with type 2 diabetes in the early stages. PMID- 22427725 TI - Cost considerations in the management of atrial fibrillation - impact of dronedarone. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is associated with significant morbidity and mortality. At the societal level, AF carries an enormous cost. Strategies aimed at reducing AF morbidity and mortality and containing the associated fiscal burden are of paramount importance. This review will discuss AF treatment strategies and economics, focusing on the impact of dronedarone, a novel antiarrhythmic agent. PMID- 22427726 TI - Differences in clinical outcomes among hepatitis C genotype 1-infected patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin: a meta-analysis. AB - BACKGROUND: With the development of new direct acting antiviral (DAA) therapy for hepatitis C, the backbone peginterferon alpha used may be of importance in maximizing treatment outcomes. To this end, the rates of sustained virologic response (SVR), relapse, and treatment discontinuation among hepatitis C genotype 1-infected patients given peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin were determined using a meta-analysis. METHODS: Randomized trials examining peginterferon alpha-2a or peginterferon alpha-2b co administered with ribavirin for 48 weeks were included. Data were extracted on SVR, relapse, and treatment discontinuations for treatment-naive and treatment experienced patients. Pooled proportions using fixed and random effects meta analysis were calculated. RESULTS: Twenty-six trials provided data on patients treated with peginterferon alpha-2a plus ribavirin, and 19 trials provided data on patients treated with peginterferon alpha-2b plus ribavirin. Five trials were direct head-to-head evaluations. In the subset of trials that included head-to head evaluations, no significant differences were observed between the two treatments for treatment-naive (relative risk [RR]: 1.07, 95% confidence intervals [CI]: 0.97-1.18) and treatment-experienced patients (RR: 1.27, 95% CI: 0.58-2.77). Using only active trial arms, a larger proportion of the treatment- naive patients who were provided peginterferon alpha-2a plus ribavirin achieved a SVR (47%), which is greater than that of treatment-naive patients who were provided peginterferon alpha- 2b plus ribavirin (40% SVR achievement); however, a larger proportion of treatment- experienced patients who were provided peginterferon alpha-2b plus ribavirin achieved a SVR (16%) when compared with treatment-experienced patients given peginterferon alpha-2a plus ribavirin (12% SVR achievement). A larger proportion of relapses occurred among both treatment naive and treatment-experienced patients given peginterferon alpha-2a plus ribavirin, when compared with treatment-naive and treatment-experienced patients taking peginterferon alpha-2b plus ribavirin. The proportion of patients discontinuing treatment was greater among treatment-naive patients taking peginterferon alpha-2a plus ribavirin, but smaller among treatment-experienced patients. CONCLUSION: There are small differences in treatment outcomes for different types of peginterferon- alpha. Patient status and complexity of administration may differentiate clinical outcomes. PMID- 22427727 TI - Chronic mandibular osteomyelitis with suspected underlying synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: a case report. AB - Chronic mandibular osteomyelitis is an intractable disease. In recent years, some case reports have related this disease process to synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, which is chronic with frequent remissions and exacerbations. This report describes a case of chronic mandibular osteomyelitis suspected to be SAPHO syndrome. A 68-year-old woman presented with pain on the left side of the mandible. On the basis of clinical and radiological findings, chronic mandibular diffuse sclerosing osteomyelitis was initially diagnosed. We administrated oral clarithromycin (400 mg daily) and levofloxacin (500 mg daily), and her pain subsequently resolved. On (99m)Tc-labeled methylene diphosphonate scintigraphy, tracer uptake in the asymptomatic mandible was unchanged, but there was increasing tracer uptake in the sternocostal and sternoclavicular joints, compared with (99m)Tc-labeled methylene diphosphonate scintigraphic findings of the first visit. We diagnosed SAPHO syndrome and administrated oral sodium risedronate hydrate (2.5 mg daily). Although there has been no pain or swelling in the area of the left mandibular lesion, we have followed up on other skin and osteoarticular manifestations in conjunction with other medical departments. PMID- 22427728 TI - Review of eprodisate for the treatment of renal disease in AA amyloidosis. AB - Secondary (AA) amyloidosis is a multisystem disorder complicating chronic infections or inflammatory diseases. It is characterized by extracellular deposit of fibrils composed of fragments of serum amyloid A (SAA), an acute phase reactant protein. The kidney is the most frequent organ involved, manifesting as progressive proteinuria and renal impairment. Attenuation of the level of circulating SAA protein by treating the underlying inflammatory condition remains the primary strategy in treating AA amyloidosis. However, at times, achieving adequate control of protein production can prove difficult. In addition, relapse of renal function often occurs rapidly following any subsequent inflammatory stimulus in patients with existing amyloidosis. Recently there has been an interest in finding other potential strategies targeting amyloid deposits themselves. Eprodisate is a sulfonated molecule with a structure similar to heparan sulfate. It competitively binds to the glycosaminoglycan-binding sites on SAA and inhibits fibril polymerization and amyloid deposition. Recent randomized clinical trial showed that it may slow down progressive renal failure in patients with AA amyloidosis. However confirmatory studies are needed and results of a second Phase III study are eagerly awaited to clarify whether or not eprodisate has a place in treating renal amyloid disease. PMID- 22427729 TI - Inherited variation in pattern recognition receptors and cancer: dangerous liaisons? AB - The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are carcinogenic, and they launch an immune response against them. Inherited structural variation in genes encoding these receptors and proteins of their signaling pathways may affect their function, modulating cancer risk and features of cancer progression. Relevant malignancies, valuable gene polymorphisms, prime questions about future directions, and answers to these questions are analyzed in this review. It is possible to suggest that polymorphisms of genes encoding pattern recognition receptors and proteins of their signaling pathways may be associated with almost all cancer types, particularly with those in which carcinogenic infectious agents are responsible for the substantial share of cases (namely gastric cancer, colorectal cancer, liver cancer, cervical cancer, and nasopharyngeal carcinoma). The concept of selection of polymorphisms for further oncogenomic investigation, based on a combination of results from basic and epidemiological studies, is proposed. PMID- 22427730 TI - C-type lectin receptors and RIG-I-like receptors: new points on the oncogenomics map. AB - The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are oncogenic, and they launch an immune response against them, normally promoting their eradication. Inherited variations in genes encoding these receptors and proteins and their signaling pathways may affect their function, possibly modulating cancer risk and features of cancer progression. There are numerous studies investigating the association of single nucleotide polymorphisms within or near genes encoding Toll-like receptors and NOD-like receptors, cancer risk, and features of cancer progression. However, there is an almost total absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. Nevertheless, there is some evidence supporting the hypothesis that inherited C type lectin receptor and RIG-I-like receptor variants can be associated with increased cancer risk. Certain C-type lectin receptors and RIG-I-like receptors recognize pathogen-associated molecular patterns of potentially oncogenic infectious agents, and certain polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors may have functional consequences at the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. Polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors thereby may be correlated with a risk of lung, oral, esophageal, gastric, colorectal, and liver cancer, as well as nasopharyngeal carcinoma, glioblastoma, multiple myeloma, and lymphoma. The list of the most promising polymorphisms for oncogenomic investigations may include rs1926736, rs2478577, rs2437257, rs691005, rs2287886, rs735239, rs4804803, rs16910526, rs36055726, rs11795404, and rs10813831. PMID- 22427731 TI - Time associated with intravenous zoledronic acid administration in patients with breast or prostate cancer and bone metastasis. AB - PURPOSE: Intravenous (IV) zoledronic acid (ZA) is commonly used to delay skeletal complications secondary to bone metastases. However, the time associated with ZA administration may represent a significant burden to healthcare providers and patients. This study assessed the time associated with IV ZA infusion in patients with bone metastases secondary to breast or prostate cancer (BC or PC) in the clinic setting. METHODS: Eligible BC or PC patients with bone metastases scheduled to receive IV ZA were observed at seven US-based oncology clinics. Trained observers recorded the time for preinfusion tasks, ZA drug preparation, intravenous infusion, and follow-up activities. RESULTS: Data are reported for 39 patients (BC: 24; PC: 15). Mean administration time was 69 (standard deviation [SD] 42) minutes for all patients combined, 72 (SD 47) minutes for BC, and 65 (SD 33) minutes for PC. Activity times were comparable between tumor types. Mean time for preinfusion tasks (eg, assessment of vital signs, blood draw) and ZA preparation were 12 (SD 20) minutes and 2 (SD 1) minutes, respectively. Mean time required for intravenous infusion (ZA infusion and hydration, when provided) and follow-up activities were 54 (SD 31) minutes and 2 (SD 1) minutes, respectively. CONCLUSION: Infusion time was the greatest time commitment associated with IV ZA administration, representing 78% of the total time on average. Time for preinfusion activities varied substantially. Overall, the mean time for ZA administration represents a notable time burden for healthcare providers and patients. PMID- 22427732 TI - Psychological and sexual disorders in long-term breast cancer survivors. AB - BACKGROUND: The progressive increase in the number of patients surviving long term after a diagnosis of malignant disease has led to a focus on the early and late complications of the disease and its treatment. The aim of this study was to investigate the prevalence of complications which may worsen quality of life and shorten long-term survival. METHODS: We identified 306 cancer patients who had been disease-free without treatment for at least three years. Of these, 167 with breast cancer were enrolled in this study. A detailed questionnaire-based interview was undertaken to investigate the characteristics of the patients (age, gender, marital status, education), the tumor (date of diagnosis, histology), and treatment. We also used the Beck Depression Inventory to screen for depression, Spitzer's Quality of Life Index to assess quality of life, and the International Index of Erectile Function and the Female Sexual Function Index to get precise information on sexual function. RESULTS: Psychological effects were reported by 121 (72.4%) subjects. Sexual disorders were identified in 60 (35.9%) subjects. A correlation between frequency of psychological disorders and severity of sexual disorders was reported. The proportion of psychological disorders was higher in younger patients, those who were married, and those with low education. CONCLUSION: In survivors of breast cancer, the incidences of psychological and sexual affective disorders are significant and frequently correlated, resulting in diminished quality of life. PMID- 22427733 TI - Reappraisal of the role of dolasetron in prevention and treatment of nausea and vomiting associated with surgery or chemotherapy. AB - Chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting are one of the most frequent but also very concerning consequences for patients undergoing chemotherapy or surgical procedures under general anesthesia. There are a variety of mechanisms involved in the activation of nausea and vomiting. Serotonin, a ubiquitous central and peripheral neurotransmitter, is thought to be the predominant mediator of the perception of nausea and triggering of the vomiting response in both the brain and the periphery via the 5-hydroxytryptamine type 3 (5-HT(3)) receptor pathways. 5-HT(3) receptor antagonists disrupt this pathway, largely at the level of the vagal afferent pathways, to decrease nausea and vomiting. This review will focus on dolasetron, an older but sill commonly used 5-HT(3) receptor antagonist and its multimodal mechanism of action, safety and tolerability, patient considerations, and a review of the current literature on its use to combat both chemotherapy-induced and postoperative nausea and vomiting in these two important patient populations. PMID- 22427734 TI - Phase 1 clinical study of the acute and subacute safety and proof-of-concept efficacy of carbohydrate-derived fulvic acid. AB - BACKGROUND: The purpose of this research was to determine the acute and subacute safety and proof-of-concept efficacy of carbohydrate-derived fulvic acid (CHD FA). METHODS: In this double-blind study, 30 male volunteers with predetermined atopy were randomly assigned to either Group A or Group B, each consisting of 15 participants. In part 1 of the study, the groups were administered increasing amounts of CHD-FA, ranging from 5 mL to 40 mL, provided that no adverse events had occurred at the previous dosage. In part 2, Group A participants received 20 mL of 3.8% CHD-FA twice daily for 3 days and were monitored for a week. Because no adverse events occurred, Group B received 40 mL of 3.8% CHD-FA twice daily for a period of 3 days. In part 3, both groups received either 40 mL of 3.8% CHD-FA or placebo twice daily for a period of one week, followed by a one-week washout period before crossover to the alternative treatment schedule. Parameters used to establish safety were electrocardiography, a physical examination, a health questionnaire, and hematology and biochemistry, determined at baseline, during regular calculated intervals, and at the end of each part of the study. A skin prick test was done as part of the screening process and, from the result, the allergen the participant was most allergic to was then selected, along with the positive histamine and negative control to be repeated at the start and end of each respective stage. RESULTS: Safety parameters remained constant throughout the trial. A significant decrease in skin prick test results was observed. CONCLUSION: No severe adverse events occurred, establishing that CHD-FA to be safe at doses up to 40 mL twice daily for a week and that at this dosage CHD-FA acts as an anti-inflammatory agent. These findings confirm earlier animal data. PMID- 22427735 TI - Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response. AB - BACKGROUND: The metabolic activation of clopidogrel is a two-step process. It has been suggested that paraoxonase-1 (PON1) is a rate-limiting enzyme in the conversion of 2-oxo- clopidogrel to an active thiol metabolite. Conflicting results have been reported in regard to (1) the association of a common polymorphism of PON1 (Q192R) with reduced rates of coronary stent thrombosis in patients taking clopidogrel and (2) its effects on platelet inhibition in patient populations of European descent. METHODS: Blood samples from 151 subjects of mixed racial background with established coronary artery disease and who received clopidogrel were analyzed. Platelet aggregation was determined with light transmittance aggregometry and VerifyNow((r)) P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)*2 and *3 and PON1 (Q192R) polymorphisms was performed. RESULTS: Carriers of CYP2C19*2 alleles exhibited lower levels of platelet inhibition and higher on-treatment platelet aggregation than noncarriers. There was no significant difference in platelet aggregation among PON1 Q192R genotypes. Homozygous carriers of the wild-type variant of PON1 (QQ192) had similar on-treatment platelet reactivity to carriers of increased function variant alleles during maintenance clopidogrel dosing, as well as after administration of a clopidogrel 600 mg loading dose. CONCLUSION: CYP2C19*2 allele is associated with impaired platelet inhibition by clopidogrel and high on treatment platelet aggregation. PON1 (Q192R) polymorphism does not appear to be a significant determinant of clopidogrel response. PMID- 22427736 TI - The role of self-help in the treatment of mild anxiety disorders in young people: an evidence-based review. AB - Anxiety disorders are the most common mental health problems experienced by young people, and even mild anxiety can significantly limit social, emotional, and cognitive development into adulthood. It is, therefore, essential that anxiety is treated as early and effectively as possible. Young people are unlikely, however, to seek professional treatment for their problems, increasing their chance of serious long-term problems such as impaired peer relations and low self-esteem. The barriers young people face to accessing services are well documented, and self-help resources may provide an alternative option to respond to early manifestations of anxiety disorders. This article reviews the potential benefits of self-help treatments for anxiety and the evidence for their effectiveness. Despite using inclusive review criteria, only six relevant studies were found. The results of these studies show that there is some evidence for the use of self help interventions for anxiety in young people, but like the research with adult populations, the overall quality of the studies is poor and there is need for further and more rigorous research. PMID- 22427738 TI - The first 10 years of the Universal Coverage Scheme in Thailand: review of its impact on health inequalities and lessons learnt for middle-income countries. AB - AIMS: We aim to assess the impacts of Thailand Universal Coverage Scheme (UCS) of health insurance on health service use and healthcare finance in the past 10 years. METHODS: We review the impacts of the UCS on preventive and health promotion including dental care and reproductive health as well as on vulnerable population subgroups. RESULTS: Three decades after the implementation of low income health insurance in the 1970s, Thailand finally introduced a UCS in 2001. It has brought under its umbrella the uninsured 30% of the Thai population. Many empirical studies of illness expenditure confirm that the Thai UCS substantially reduced the financial burden of healthcare among the poor. The Thai UCS mechanism boosts use of primary healthcare facilities and has substantially reduced catastrophic medical payments and consequent impoverishment. CONCLUSIONS: The UCS relies on a solid primary healthcare foundation. Continued investment into primary healthcare resources will help to ensure sustainable development of the UCS and reduced health inequity. The UCS development in Thailand can provide some valuable lessons for middle income countries pursuing the goal of equity in health and healthcare. PMID- 22427737 TI - Meningococcal disease serogroup C. AB - Despite current advances in antibiotic therapy and vaccines, meningococcal disease serogroup C (MDC) remains a serious threat to global health, particularly in countries in North and Latin America, Europe, and Asia. MDC is a leading cause of morbidity, mortality, and neurological sequelae and it is a heavy economic burden. At the individual level, despite advances in antibiotics and supportive therapies, case fatality rate remains nearly 10% and severe neurological sequelae are frequent. At the population level, prevention and control of infection is more challenging. The main approaches include health education, providing information to the public, specific treatment, chemoprophylaxis, and the use of vaccines. Plain and conjugate meningococcal C polysaccharide vaccines are considered safe, are well tolerated, and have been used successfully for over 30 years. Most high-income countries use vaccination as a part of public health strategies, and different meningococcal C vaccination schedules have proven to be effective in reducing incidence. This is particularly so with conjugate vaccines, which have been found to induce immunogenicity in infants (the age group with the highest incidence rates of disease), stimulate immunologic memory, have longer effects, not lead to hyporesponsiveness with repeated dosing, and decrease acquisition of nasopharyngeal carriage, inducing herd immunity. Antibiotics are considered a cornerstone of MDC treatment and must be administered empirically as soon as possible. The choice of which antibiotic to use should be made based on local antibiotic resistance, availability, and circulating strains. Excellent options for a 7-day course are penicillin, ampicillin, chloramphenicol, and third generation cephalosporins (ceftriaxone and cefotaxime) intravenously, although the latter are considerably more expensive than the others. The use of steroids as adjunctive therapy for MDC is still controversial and remains a topic of debate. A combination of all of the aforementioned approaches is useful in the prevention and control of MDC, and each country should tailor its public health policy to its own particular needs and knowledge of disease burden. PMID- 22427739 TI - Comparison of Two ESI MS Based H/D Exchange Methods for Extracting Protein Folding Energies. AB - In this report, the model proteins staphylococcal nuclease and ubiquitin were used to test the applicability of two new hydrogen/deuterium exchange (HX) electrospray ionization mass spectrometry (ESI-MS) methods for estimating protein folding energies. Both methods use the H/D exchange of globally protected amide protons (amide protons which are buried in the hydrophobic core) to elucidate protein folding energies. One method is a kinetic-based method and the other is equilibrium-based. The first method, the HX ESI-MS kinetic-based approach is conceptually identical to SUPREX (stability of unpurified proteins from rates of H/D exchange) method but is based on ESI-MS rather than MALDI-MS (matrix assisted laser desorption mass spectrometry). This method employs the time-dependence of H/D exchange using various denaturant concentrations to extract folding energies. Like SUPREX, this approach requires the assumption of EX2 exchange kinetics. The second method, which we call a protein equilibrium population snapshot (PEPS) by HX ESI-MS uses data collected only for a single time point (usually the shortest possible) to obtain a snapshot of the open and closed populations of the protein. The PEPS approach requires few assumptions in the derivation of the equations used for calculation of the folding energies. The extraction of folding energies from mass spectral data is simple and straightforward. The PEPS method is applicable for proteins that follow either EX1 or EX2 HX mechanisms. In our experiments the kinetic-based method produced less accurate DeltaG(H(2)O) and m(GdHCl) values for wild-type staphylococcal nuclease and mutants undergoing H/D exchange by EX1, as would be expected. Better results were obtained for ubiquitin which undergoes HX by an EX2 mechanism. Using the PEPS method we obtained DeltaG(H(2)O) and m(GdHCl) values that were in good agreement with literature values for both staphylococcal nuclease (EX1) and ubiquitin (EX2). We also show that the observation of straight lines in linear extrapolation method (LEM) plots is not a reliable indicator of the validity of the data obtained using the LEM approach. PMID- 22427740 TI - Laminin 332 expression in breast carcinoma. AB - Laminin 332 (LN332) is a basally expressed extracellular matrix protein that enhances the migration and invasion of breast carcinoma cells. The goal of this study was to examine LN332 expression breast carcinoma. Triple negative breast carcinomas lack estrogen receptor (ER), progesterone receptor (PR) expression and HER2 positivity. Immunohistochemistry for ER, PR, HER2, and dual silver in situ hybridization for the HER2 gene were used to define the phenotype of 243 breast cancers in biopsies or arrays. Immunohistochemistry for LN332 revealed that 70% of triple negative carcinomas stained for LN332. Cytokeratins 5/6 (CK5/6), epidermal growth factor receptor and p63 alone stained fewer triple negative breast carcinomas each, but the combination of LN332 and CK5/6 or epidermal growth factor receptor identified 92% of triple negative breast carcinoma. Of the 163 non-triple negative cases, LN332 was expressed in only 15%. The identification of LN332 in triple negative breast carcinomas is consistent with gene profiling studies showing its expression among breast carcinomas with a basal phenotype. The observation that a proinvasive protein such as LN332 is expressed in breast cancer suggests another mechanism by which the triple negative phenotype could be aggressive. PMID- 22427741 TI - Combinatorial activation and repression by seven transcription factors specify Drosophila odorant receptor expression. AB - The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system. PMID- 22427742 TI - Convergent evolution of escape from hepaciviral antagonism in primates. AB - The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV. PMID- 22427743 TI - Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal synaptic potentiation and pain hypersensitivity. AB - Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP. Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice). Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected. Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity. PMID- 22427744 TI - War archives: how some primates fought off ancient viruses. PMID- 22427745 TI - Uterine rupture by intended mode of delivery in the UK: a national case-control study. AB - BACKGROUND: Recent reports of the risk of morbidity due to uterine rupture are thought to have contributed in some countries to a decrease in the number of women attempting a vaginal birth after caesarean section. The aims of this study were to estimate the incidence of true uterine rupture in the UK and to investigate and quantify the associated risk factors and outcomes, on the basis of intended mode of delivery. METHODS AND FINDINGS: A UK national case-control study was undertaken between April 2009 and April 2010. The participants comprised 159 women with uterine rupture and 448 control women with a previous caesarean delivery. The estimated incidence of uterine rupture was 0.2 per 1,000 maternities overall; 2.1 and 0.3 per 1,000 maternities in women with a previous caesarean delivery planning vaginal or elective caesarean delivery, respectively. Amongst women with a previous caesarean delivery, odds of rupture were also increased in women who had >= two previous caesarean deliveries (adjusted odds ratio [aOR] 3.02, 95% CI 1.16-7.85) and <12 months since their last caesarean delivery (aOR 3.12, 95% CI 1.62-6.02). A higher risk of rupture with labour induction and oxytocin use was apparent (aOR 3.92, 95% CI 1.00-15.33). Two women with uterine rupture died (case fatality 1.3%, 95% CI 0.2-4.5%). There were 18 perinatal deaths associated with uterine rupture among 145 infants (perinatal mortality 124 per 1,000 total births, 95% CI 75-189). CONCLUSIONS: Although uterine rupture is associated with significant mortality and morbidity, even amongst women with a previous caesarean section planning a vaginal delivery, it is a rare occurrence. For women with a previous caesarean section, risk of uterine rupture increases with number of previous caesarean deliveries, a short interval since the last caesarean section, and labour induction and/or augmentation. These factors should be considered when counselling and managing the labour of women with a previous caesarean section. PMID- 22427746 TI - Guidance for evidence-informed policies about health systems: linking guidance development to policy development. PMID- 22427747 TI - A comparison of DSM-IV and DSM-5 panel members' financial associations with industry: a pernicious problem persists. PMID- 22427748 TI - To VBAC or not to VBAC. PMID- 22427749 TI - Planned vaginal birth or elective repeat caesarean: patient preference restricted cohort with nested randomised trial. AB - BACKGROUND: Uncertainty exists about benefits and harms of a planned vaginal birth after caesarean (VBAC) compared with elective repeat caesarean (ERC). We conducted a prospective restricted cohort study consisting of a patient preference cohort study, and a small nested randomised trial to compare benefits and risks of a planned ERC with planned VBAC. METHODS AND FINDINGS: 2,345 women with one prior caesarean, eligible for VBAC at term, were recruited from 14 Australian maternity hospitals. Women were assigned by patient preference (n = 2,323) or randomisation (n = 22) to planned VBAC (1,225 patient preference, 12 randomised) or planned ERC (1,098 patient preference, ten randomised). The primary outcome was risk of fetal death or death of liveborn infant before discharge or serious infant outcome. Data were analysed for the 2,345 women (100%) and infants enrolled. The risk of fetal death or liveborn infant death prior to discharge or serious infant outcome was significantly lower for infants born in the planned ERC group compared with infants in the planned VBAC group (0.9% versus 2.4%; relative risk [RR] 0.39; 95% CI 0.19-0.80; number needed to treat to benefit 66; 95% CI 40-200). Fewer women in the planned ERC group compared with women in the planned VBAC had a major haemorrhage (blood loss >= 1,500 ml and/or blood transfusion), (0.8% [9/1,108] versus 2.3% [29/1,237]; RR 0.37; 95% CI 0.17-0.80). CONCLUSIONS: Among women with one prior caesarean, planned ERC compared with planned VBAC was associated with a lower risk of fetal and infant death or serious infant outcome. The risk of major maternal haemorrhage was reduced with no increase in maternal or perinatal complications to time of hospital discharge. Women, clinicians, and policy makers can use this information to develop health advice and make decisions about care for women who have had a previous caesarean. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53974531 PMID- 22427750 TI - Transcriptional activation of the adenoviral genome is mediated by capsid protein VI. AB - Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents viral gene expression through the assembly of repressive chromatin remodeling complexes targeting incoming viral genomes. However, it has remained unclear how initial transcriptional activation of the adenoviral genome is achieved. Here we show that Daxx mediated repression of the immediate early Ad E1A promoter is efficiently counteracted by the capsid protein VI. This requires a conserved PPxY motif in protein VI. Capsid proteins from other DNA viruses were also shown to activate the Ad E1A promoter independent of Ad gene expression and support virus replication. Our results show how Ad entry is connected to transcriptional activation of their genome in the nucleus. Our data further suggest a common principle for genome activation of DNA viruses by counteracting Daxx related repressive mechanisms through virion proteins. PMID- 22427751 TI - Short-term variation in near-highway air pollutant gradients on a winter morning. AB - Quantification of exposure to traffic-related air pollutants near highways is hampered by incomplete knowledge of the scales of temporal variation of pollutant gradients. The goal of this study was to characterize short-term temporal variation of vehicular pollutant gradients within 200-400 m of a major highway (>150 000 vehicles/d). Monitoring was done near Interstate 93 in Somerville (Massachusetts) from 06:00 to 11:00 on 16 January 2008 using a mobile monitoring platform equipped with instruments that measured ultrafine and fine particles (6 1000 nm, particle number concentration (PNC)); particle-phase (>30 nm) [Formula: see text], [Formula: see text], and organic compounds; volatile organic compounds (VOCs); and CO(2), NO, NO(2), and O(3). We observed rapid changes in pollutant gradients due to variations in highway traffic flow rate, wind speed, and surface boundary layer height. Before sunrise and peak traffic flow rates, downwind concentrations of particles, CO(2), NO, and NO(2) were highest within 100-250 m of the highway. After sunrise pollutant levels declined sharply (e.g., PNC and NO were more than halved) and the gradients became less pronounced as wind speed increased and the surface boundary layer rose allowing mixing with cleaner air aloft. The levels of aromatic VOCs and [Formula: see text], [Formula: see text] and organic aerosols were generally low throughout the morning, and their spatial and temporal variations were less pronounced compared to PNC and NO. O(3) levels increased throughout the morning due to mixing with O(3)-enriched air aloft and were generally lowest near the highway reflecting reaction with NO. There was little if any evolution in the size distribution of 6-225 nm particles with distance from the highway. These results suggest that to improve the accuracy of exposure estimates to near-highway pollutants, short-term (e.g., hourly) temporal variations in pollutant gradients must be measured to reflect changes in traffic patterns and local meteorology. PMID- 22427752 TI - Pain after craniotomy - really a problem? PMID- 22427753 TI - Reduced tumourigenicity of EG7 after RANTES gene transfer and the underlying mechanism. AB - INTRODUCTION: Chemokine ligand 5, also known as CCL5 or regulated on activation normal T-cell expressed and secreted (RANTES), is a chemokine expressed in inflamed tissue and capable of inducing migration of immature dendritic cells (DCs) or Langerhans cells. In this study, we explored the effect of RANTES on EG7 cells. MATERIAL AND METHODS: In vivo, RANTES gene transfer reduced the tumourigenic capacity of EG7 and prolonged the survival of tumour-bearing mice. To reveal the underlying mechanism, we performed the following experiments and provided evidence to support our hypothesis of RANTES gene therapy for EG7. Higher natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activity was induced after RANTES gene transfer, accompanied by higher levels of Th1 type cytokines (IL-2 and IFN-gamma). RESULTS: Tumour necrosis was also markedly observed in the tumour tissues after RANTES gene transfer, which was attributed to reduced expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-2). CONCLUSIONS: We draw the conclusion that reduced tumourigenicity of EG7 after RANTES gene transfer can be attributed to higher NK cell and CTL activity, anti-angiogenesis and higher levels of Th1 type cytokines induced by RANTES. These results support the notion that higher chemokine expression in tumour tissue elicits potent anti-tumour immunity. PMID- 22427754 TI - The effects of prenatal and neonatal exposure to electromagnetic fields on infant rat myocardium. AB - INTRODUCTION: Electromagnetic fields (EMF) have adverse effects as a result of widespread use of electromagnetic energy on biological systems. The aim of this study was to investigate the effects of prenatal exposure to EMF on rat myocardium by biochemical and histopathological evaluations. MATERIAL AND METHODS: In this study, 10 pregnant Wistar rats were used. Half of the pregnant rats were exposed to EMF of 3 mT, and the other half to sham conditions during gestation. After parturition, rat pups in the 5 EMF-exposed litters from birth until postnatal day 20 were exposed to EMF of 3 mT for 4 h/day (EMF-exposed group, n = 30). Rat pups in sham litters from birth until postnatal day 20 were exposed to sham conditions (sham group, n= 20). RESULTS: In the EMF-exposed group, lipid peroxidation levels significantly increased compared to sham. Superoxide dismutase activities decreased significantly in the EMF-exposed group compared to sham. TUNEL staining showed that the number of TUNEL-positive cells increased significantly in EMF-exposed rats compared with sham. Under electron microscopy, there were mitochondrial degeneration, reduction in myofibrils, dilated sarcoplasmic reticulum and perinuclear vacuolization in EMF-exposed rats. CONCLUSIONS: In conclusion, the results show that prenatal exposure to EMF causes oxidative stress, apoptosis and morphological pathology in myocardium of rat pups. The results of our study indicate a probable role of free radicals in the adverse effects of prenatal exposure to EMF. Further studies are needed to demonstrate whether the EMF exposure can induce adverse effects on the myocardium. PMID- 22427755 TI - Effect of repeated ischaemic preconditioning on TLR4 and proinflammatory cytokines TNF-alpha and IL-1beta in myocardial ischaemia-reperfusion injury in a rat model. AB - INTRODUCTION: The role of TLR4 in ischaemic preconditioning is still unclear; we do not know the change of the expression of TLR4 in the process. In this study, we used ischaemic preconditioning models to observe the change of TLR4 expression and the level of proinflammatory cytokines TNF-alpha and IL-1beta to investigate the protective mechanism of TLR4 in ischaemic preconditioning for myocardial ischaemia-reperfusion injury (MI/RI) in rats. MATERIAL AND METHODS: Eighteen male Sprague-Dawley (SD) rats were randomly separated into sham, ischaemic reperfusion (IR) and ischaemic preconditioning (IP) groups (6/group). Peripheral blood and cardiac muscle with pathological changes were collected after the establishment of the above three animal models. We used ELISA to determine proinflammatory cytokines TNF-alpha and IL-1beta production in serum of these animals. RT-PCR and Western blot were used to assay the transcriptional level and protein level of TLR4 in cardiac muscle tissue with pathological changes, respectively. RESULTS: We found that compared with the IR group, ischaemic preconditioning could effectively reduce the expression levels of TNF-alpha and IL-1beta in sera of rats in the IP group (p < 0.01). Meanwhile, TLR4 mRNA and protein levels were down-regulated (p < 0.01 and p < 0.05, respectively). We also found that infarct size decreased in the IP group compared with the IR group (p < 0.05). CONCLUSIONS: Based on the results, we can conclude that the specific mechanism of ischaemic preconditioning for RI might be closely associated with decreasing expression levels of TLR4 and proinflammatory cytokines such as TNF-alpha and IL 1beta. PMID- 22427756 TI - The role of oxidative stress and effect of alpha-lipoic acid in reexpansion pulmonary edema - an experimental study. AB - INTRODUCTION: We investigated the role of oxidative stress in the pathogenesis of reexpansion pulmonary edema (RPE) and effect of alpha-lipoic acid (ALA) in the prevention of RPE. MATERIAL AND METHODS: There were 4 groups consisting of 10 rats in each group; control group (CG), alpha-lipoic acid group (ALAG), reexpansion pulmonary edema group (RPEG), reexpansion pulmonary edema plus alpha lipoic acid group (RPE + ALAG). In all the groups, all rats were sacrificed 2 hours after the reexpansion of lungs. To indicate oxidative stress malondialdehyde (MDA), and to indicate antioxidant status superoxide dismutase (SOD), catalase (CAT) and glutathione peroxides (GPx) were measured in the lungs of rats. RESULTS: Mean MDA value was lower in CG (7.02 +/-0.14) and in ALAG (6.95 +/-0.11) than the other groups (p = 0.001). It was highest in RPEG (8.89 +/-0.21) (p = 0.001). It was lower in RPE + ALA G (7.21 +/-0.32) than RPEG (p = 0.001). Antioxidant levels: GPx (37.21 +/-3.01), CAT (2.87 +/-0.14) and SOD (100.12 +/ 12.39) were lowest in RPEG among all groups (p = 0.001). These values were GPx (45.21 +/-3.54), CAT (3.24 +/-0.21) and SOD (172.36 +/-15.48) in RPE + ALA G and were greater than those of RPEG (p = 0.001). While normal pulmonary parenchyma was seen in 2 rats in RPE + ALAG, it was not seen in RPEG. Pulmonary edema was seen in 1 rat in RPE + ALAG; however, it was seen in 3 in RPEG. CONCLUSIONS: Oxidative stress might have an important role in the pathogenesis of RPE. In addition, ALA treatment might contribute in preventing RPE. PMID- 22427757 TI - Degree of genetic homozygosity and distribution of AB0 blood types among patients with spina bifida occulta and spina bifida aperta. AB - INTRODUCTION: Assuming that spina bifida (SB) is a genetically controlled disease, the aim of our study was to evaluate the degree of genetic homozygosity and the distribution of AB0 blood types among patients with SB occulta and SB aperta by the homozygously recessive characteristics (HRC) test. MATERIAL AND METHODS: Our study included an analysis of the presence, distribution and individual combination of 15 selected genetically controlled morpho-physiological traits in a sample of 100 patients with SB (SB occulta N = 50 and SB aperta N = 50) and a control group of individuals (N = 100). RESULTS: We found a statistically significant difference between the mean values for genetic homozygosity (SB 4.5 +/-0.3; control 3.0 +/-0.2, p < 0.001) and also differences in the presence of certain individual combinations of such traits. In 12 (80.0%) of the 15 observed characteristics, recessive homozygosity was expressed to a greater degree among the group of SB patients, while for 9 (60.0%) of the traits this level of difference was statistically significant (Sigma(chi) (2) = 266.3, p < 0.001). There was no difference in average homozygosity of such genetic markers between groups of SB occulta and SB aperta patients, but the type of individual variation in the two studied groups significantly differed. In the group of patients with SB the frequency of 0 blood group was significantly increased while B blood group was significantly decreased. CONCLUSIONS: Our results clearly show that there is a populational genetic difference in the degree of genetic homozygosity and variability between the group of patients with SB and individuals without clinical manifestations, indicating a possible genetic component in the aetiopathogenesis of spina bifida. PMID- 22427758 TI - Interleukin-6 and the IL-6 (-174) C/G polymorphism in breast pathologies and in HIV-infected patients. AB - INTRODUCTION: Breast cancer and acquired immunodeficiency syndrome (AIDS) are key issues for modern medicine. The aim of the current study was to present how cytokines, in the example of IL-6 and its polymorphism, can affect these two conditions. MATERIAL AND METHODS: Thirty-one women with benign breast tumours, 42 breast cancer patients and 40 HIV-infected females were enrolled in the study. Serum IL-6 levels were determined by ELISA. The IL-6 polymorphism was genotyped by PCR-RFLP. RESULTS: Serum IL-6 in patients with benign breast tumours was significantly lower than in females with breast cancer (p = 0.017) and HIV infected women (p = 0.032). We did not find statistically significant differences in serum IL-6 level between females with breast cancer and HIV-infected women (p = 0.749). Comparing the distribution of genotypes and frequency of the IL-6 ( 174) C/G polymorphism between the three study groups - breast cancer patients, patients with benign breast tumours, and HIV-infected patients - we did not find any statistically significant differences. CONCLUSIONS: IL-6 can play an important role in pathogenesis of breast cancer and HIV infection and its level is higher than in the control group irrespective of distribution of genotypes and frequency of the IL-6 (-174) C/G polymorphism. PMID- 22427759 TI - Effect of atorvastatin in patients with chronic heart failure - insights from randomized clinical trials. AB - INTRODUCTION: Recent large clinical trials have yielded disappointing results of rosuvastatin in the chronic heart failure (CHF) population. The question that remains is whether these results of rosuvastatin studies could be extended to other statins. Therefore, we performed a meta-analysis based on all currently available randomized controlled trials (RCTs) to evaluate the clinical efficacy of atorvastatin in CHF patients. MATERIAL AND METHODS: The published literature was scanned by formal searches of electronic databases up to January 2010. RCTs were eligible for inclusion if they compared atorvastatin versus placebo treatment in patients with CHF and reported the clinical outcomes. RESULTS: Pre specified criteria were met by 7 trials involving 540 patients. The primary endpoint, all-cause mortality, was significantly reduced with atorvastatin therapy compared with placebo in CHF patients (odds ratio [OR] 0.39, P = 0.002), with similar results in cardiovascular mortality (OR 0.28, P = 0.002) and sudden cardiac death (OR 0.24, P = 0.01). There was also a significant decrease in hospitalization for worsening CHF with atorvastatin therapy compared with placebo (OR 0.30, P < 0.001). CONCLUSIONS: This meta-analysis suggests the effectiveness of atorvastatin treatment in reducing the risks of all-cause mortality and worsening CHF hospitalization in patients with CHF. Further large, well-conducted randomized trials are needed to confirm the benefits of atorvastatin or other statins for CHF relative to placebo or rosuvastatin. PMID- 22427760 TI - Physical activity evaluation in Yugoslav Study of the Precursors of Atherosclerosis in School Children - YUSAD study. AB - INTRODUCTION: It is observed that there is a lack of physical activity and exercise in children, stressing higher prevalence of childhood obesity. The purpose of the study was to evaluate duration of physical activity in a child population and correlation of dynamics in physical activity during 5 years of follow-up in the same population. MATERIAL AND METHODS: We evaluated 3243 school children from 12 regional centres across Serbia. The first examination was done when the children were 10 years old (baseline group), while the second examination was done on the same population when children were 15 years old. Physical activity was classified as recreational activity after school. We analysed 3 groups regarding physical activity: a group of children who were physically active less than 1 hour per day (group I), a second group active from 1 hour to < 3 hours per day (group II), and a third group active >= 3 hours per day (group III). RESULTS: In our study we have found on examination that the majority of children were physically active between 1 and 3 hours per day. Our results indicate that there is significant movement from groups I and III toward group II on the second examination regarding the proportion in the baseline group. There is a significant increase in the number of children in group I as they get older. CONCLUSIONS: School children in Serbia are physically active predominantly between 1 and 3 hours per day at the age between 10 and 15 years. PMID- 22427761 TI - Postprandial metabolic heterogeneity in men with primary dyslipidaemia. AB - INTRODUCTION: Familial combined hyperlipidaemia (FCH) and familial hypercholesterolaemia (FH) have been strongly linked to premature coronary artery disease. Postprandial hypertriglyceridaemia is also associated with atherosclerotic disease. We evaluated the postprandial lipaemia in men with FCH and FH and compared them to a group of healthy men. MATERIAL AND METHODS: The study population consisted of 83 men: 34 FCH, 29 FH and 20 healthy. The FCH and FH groups were further divided into five subgroups, according to their lipid phenotype: FCH-IIA (n = 13), FCH-IIB (n = 10), FCH-IV (n = 11), FH-IIA (n = 21) and FH-IIB (n = 8). Postprandial lipaemia was evaluated by the areas under the curve for triglyceride (TG) concentrations (TG-AUC). RESULTS: The TG levels after oral fat tolerance test were significantly higher in FCH, compared to FH and healthy groups (TG-AUC in mg/dl/h; 2678 +/-1415 vs. 1503 +/-1147 and 1011 +/-652 respectively, p < 0.001). The postprandial response was higher in FCH-IV and FCH IIB, compared to FCH-IIA (TG-AUC in mg/dl/h; 3220 +/-824 or 3409 +/-770 vs. 1863 +/-577 respectively, p < 0.001, for both comparisons). The FCH-IIA group showed higher postprandial TG levels when compared to FH-IIA (TG-AUC in mg/dl/h; 1863 +/ 577 vs. 1374 +/-428 respectively, p = 0.008). There were no significant differences between FH-IIB and FCH-IIB subgroups. There was a significant correlation (r = 0.907, p < 0.001) between the postprandial TG-AUC and fasting TG levels in all FCH subjects. CONCLUSIONS: All phenotypes of FCH and the FH IIB phenotype demonstrate an exaggerated postprandial response that could partially contribute to the high cardiovascular risk. These patients should be identified and treated early with the appropriate hypolipidaemic agents. PMID- 22427762 TI - Persistent atrial fibrillation is not associated with thrombomodulin level increase in efficiently anticoagulated patients. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and leads to a five-fold increased risk of stroke compared to persons with sinus rhythm. A soluble form of thrombomodulin (sTM) is a recognized marker of endothelial dysfunction and may contribute to the hypercoagulable state in AF. The aim of the study was to evaluate plasma concentration of sTM in persistent AF patients before and after sinus rhythm recovery following direct current cardioversion (CV). MATERIAL AND METHODS: In 45 effectively anticoagulated consecutive patients, with persistent non-valvular AF, and normal left ventricular function, CV was performed. Blood samples for sTM assessment were collected twice: 24 hours before and 24 hours after CV. RESULTS: In 43 patients sinus rhythm was obtained. The mean plasma sTM level was significantly lower in AF patients compared to the control group with sinus rhythm and without anticoagulation (38.5 +/-9.9 ng/ml vs. 44.1 +/-9.1 ng/ml, p = 0.04). Plasma sTM levels did not change 24 hours after successful CV (36.7 +/-9.5 ng/ml vs. 38.5 +/-9.9 ng/ml, p = 0.16). CONCLUSIONS: Plasma sTM concentration was lower in patients with persistent AF and normal left ventricle systolic function than in patients with sinus rhythm, presumably due to chronic oral anticoagulant therapy in the AF group. CV has no impact on sTM plasma level evaluated 24 hours after sinus rhythm restoration. PMID- 22427763 TI - Left atrial and left atrial appendage systolic function in patients with post myocardial distal blocks. AB - INTRODUCTION: The study aimed to evaluate function of the left atrium (LA) and of the left atrial appendage (LAA) after myocardial infarction (MI) complicated by intracardiac conduction disturbances. MATERIAL AND METHODS: The study comprised 59 patients with persistent post-myocardial distal blocks, who were allocated to one of the three following subgroups: study group I - 20 patients with left bundle branch block (LBBB); study group II - 20 patients with right bundle branch block (RBBB), and study group III -19 pts with left anterior hemiblock (LAHB). The control groups included patients with MI in their history and no BBBs (19 pts - group IV) and clinically healthy people (16 patients - group V). The parameters of LA and LAA systolic function were determined by means of transthoracic (TTE) and transoesophageal echocardiography (TOE). RESULTS: We showed that patients who experienced myocardial infarction not complicated with conduction disturbances expressed compensatory LA systolic function enhancement. In patients with post myocardial RBBB and LAHB significant enhancement of LA systolic function was observed as well but it was expressed to a lesser degree. There was also a tendency towards deterioration of LA systolic function in patients with post myocardial LBBB. LBBB did not affect LAA systolic function negatively. CONCLUSIONS: Parameters of LAA systolic function showed its enhancement in all patients after myocardial infarction irrespective of whether it was complicated by conduction disturbances. PMID- 22427764 TI - Incidence of appropriate cardioverter-defibrillator shocks and mortality in patients with implantable cardioverter-defibrillators with ischemic cardiomyopathy versus nonischemic cardiomyopathy at 33-month follow-up. AB - INTRODUCTION: The aim of the study was to investigate at long-term follow-up the incidence of appropriate implantable cardioverter-defibrillator (ICD) shocks and of all-cause mortality in patients with ICDs with ischemic cardiomyopathy versus nonischemic cardiomyopathy. MATERIAL AND METHODS: ICDs were implanted in 485 patients with ischemic cardiomyopathy and in 299 patients with nonischemic cardiomyopathy, all of whom had coronary angiography. Baseline characteristics were not significantly different between the 2 groups. Follow-up was 965 days in patients with ischemic cardiomyopathy versus 1039 days in patients with nonischemic cardiomyopathy (p not significant). The ICDs were interrogated every 3 months to see if shocks occurred. RESULTS: Appropriate ICD shocks occurred in 179 of 485 patients (37%) with ischemic cardiomyopathy and in 93 of 299 patients (31%) with nonischemic cardiomyopathy (p not significant). All-cause mortality occurred in 162 of 485 patients (33%) with ischemic cardiomyopathy and in 70 of 299 patients (23%) with nonischemic cardiomyopathy (p = 0.002). CONCLUSIONS: The incidence of appropriate ICD shocks was not significantly different at 33-month follow-up in patients with ischemic cardiomyopathy versus nonischemic cardiomyopathy. However, patients with ischemic cardiomyopathy had a significantly higher incidence of all-cause mortality than patients with nonischemic cardiomyopathy (p = 0.002). PMID- 22427765 TI - Progression of diabetic retinopathy correlated with muscle perfusion disturbances of the lower limbs, with clinically important diagnostic recommendations. AB - INTRODUCTION: The objective of this study was to investigate the relationship between microvascular and macrovascular disturbances in patients with type 2 diabetes, as shown by results of ophthalmological examination and by vascular and perfusion examinations of the lower limbs. MATERIAL AND METHODS: A total of 85 patients with type 2 diabetes and an additional cardiovascular risk factor were enrolled in the study. All patients underwent complex ophthalmological examination, including fundus colour photography and fluorescein angiography, and were divided into two groups: group I with signs of diabetic non-proliferative retinopathy (NPDR), and group II with signs of diabetic proliferative retinopathy (P/PDR). After collection of the general medical history and analysis of medical data, patients underwent vascular and muscle perfusion examination of the lower limbs. RESULTS: In the P/PDR group, disturbances of lower-limb perfusion were more frequent than in the NPDR group. Analysis of the blood flow and results of lower-limb muscle perfusion for the two groups showed a significant relationship with the severity of microvascular complications observed in examination of the fundus. CONCLUSIONS: Ophthalmological assessment of the progression of diabetic retinopathy in patients with type 2 diabetes is a reliable indicator of the changes in peripheral vessel systems and perfusion defects in the lower limbs. PMID- 22427766 TI - Renal autoregulation in medical therapy of renovascular hypertension. AB - INTRODUCTION: Renovascular hypertension (RVH) is caused by renal ischaemia associated with haemodynamically significant renal artery stenosis (RAS). The choice of optimal treatment of atherosclerotic RAS is still controversial. Increase in the renal resistive index (RI) value after captopril administration is considered to indicate preserved renal autoregulation. The objective of the study was to assess the effect of medical therapy of RVH on renal autoregulation efficiency in patients with atherosclerotic RAS. MATERIAL AND METHODS: 19 persons (38 kidneys) in 2 groups: 1) study: with RVH and stenosis of 1 renal artery - 8 patients; 2) control: - 11 healthy volunteers. Doppler captopril test with RI measurements and estimation of creatinine clearance (CCr) were performed in both groups at baseline, and after a period of controlled medical therapy (CMT) only in the study group. ABPM was evaluated in controls at baseline, and in the study group at the end of CMT. RESULTS: In the study group the mean period of CMT was 8.3 +/-2.7 months, the number of antihypertensive drugs was 4.1 +/-1.0, and mean 24-hour blood pressure was 138/74 mmHg. Mean CCr was stable during the study. Significant increase of RI after captopril was found only in controls. At baseline, in the group of kidneys with a non-stenotic renal artery, significant lowering of RI was observed, and DeltaRI differed significantly from controls. After CMT, DeltaRI increased in non-stenotic kidneys in comparison to the baseline, and did not differ from controls. CONCLUSIONS: Adequate medical therapy of RVH preserved renal function and improved renal autoregulation efficiency in non-stenotic kidneys. PMID- 22427767 TI - Effect of different monotherapies on serum nitric oxide and pulmonary functions in children with mild persistent asthma. AB - INTRODUCTION: Common medications used to treat mild persistent asthma are glucocorticoids, leukotriene receptor antagonists and theophylline. The aim of the study was to evaluate monotherapy with either inhaled steroids, oral leukotriene receptor antagonist or theophylline in Egyptian children with mild persistent asthma by determining their clinical, laboratory and spirometric responses to treatment. MATERIAL AND METHODS: Thirty-nine mild asthmatic children between 8 and 13 years of age were included in the study. Patients were classified according to therapy received into four groups: oral leukotriene receptor antagonist (montelukast), inhaled corticosteroid (fluticasone propionate), sustained-release (SR) theophylline, and no treatment. Pulmonary function testing was performed at the start of therapy and 8 weeks later using spirometry. Eosinophil count and serum nitric oxide were estimated in the blood. Minitab statistical package was used for analysis of data. RESULTS: Follow-up after 8 weeks revealed significant improvement in FEV1% in groups 1 (p < 0.01) and 3 (p < 0.05), significant improvement in PEFR in groups 1 (p < 0.05) and 2 (p < 0.01), significant decline in serum NO levels in groups 1 (p < 0.05) and 2 (p < 0.05), as well as significant improvement in eosinophil count in groups 1, 2 and 3 (p < 0.01, < 0.001, < 0.01 respectively). There was a statistically significant positive correlation between the decline in serum NO and the decline in blood eosinophil % in group 2 (p < 0.05). CONCLUSIONS: Inhaled corticosteroids and montelukast have a significant role in controlling the pulmonary functions and the inflammatory process in children with mild persistent asthma, although inhaled corticosteroids seem to yield a better response. Children with mild persistent asthma should receive a controller medication, and SR theophylline may be a good cost-benefit alternative for low socio-economic groups of patients. PMID- 22427768 TI - Epidemiology of mesothelioma in Egypt. A ten-year (1998-2007) multicentre study. AB - INTRODUCTION: Mesothelioma is a cancer strongly linked to exposure to carcinogenic minerals, especially asbestos. The aim of the study was to detect the incidence of malignant pleural mesothelioma (MPM) in Egypt, to clarify the impact of occupational and environmental risk factors, and to characterise its demographic features. MATERIAL AND METHODS: They were 584 cases diagnosed as MPM detected in Cairo University Hospitals and National Cancer Institute from 1998 to 2007. Unfortunately, full epidemiological data were only available for 165 cases due to absence of a reliable registration system. RESULTS: A steady increase in the number of cases was detected, from 24 in 1998, peaking at 82 cases in 2005, followed by a gradual decline (though still high) with 68 cases in 2006 and 51 cases in 2007. Male/female ratio was 1.35/1 (p > 0.05). The occupational exposure to asbestos was 13.9%. Residential exposure plays a major role in two regions, Helwan and Shoubra (27.3% and 20.6% respectively), while in Upper and Lower Egypt the level was 12.7% and 17.5% respectively. Kaplan-Meier survival for sex, residence and the pathological types epithelioid, biphasic and sarcomatoid was insignificant. The median survival for different grades and treatment modalities was significant (P < 0.001). CONCLUSIONS: There was a steady increase in the incidence of MPM from 1998 to 2005 followed by a decline during 2006-2007. Mesothelioma in Egypt is mainly concentrated in areas of high environmental pollution. The decline within the last 2 years may be attributed to recent strict industrial preventive measures. However, a better environmental control programme would benefit Egypt. PMID- 22427769 TI - Is there any correlation between TNF-related apoptosis-inducing ligand (TRAIL) genetic variants and breast cancer? AB - INTRODUCTION: TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand and also a member of the TNF superfamily. We aimed to investigate the possible relationship between TRAIL and breast cancer. Here, we report the results of the first association study on genetic variation in the TRAIL gene and its effect on breast cancer susceptibility and prognosis. MATERIAL AND METHODS: A C/T polymorphism at 1595 position in exon 5 of the TRAIL gene was genotyped in a Turkish breast cancer case-control population including 53 cases (mean age: 55.09 +/-11.63 years) and 57 controls (mean age: 57.17 +/-17.48 years) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: There were no differences in the distribution of TRAIL genotypes and frequencies of the alleles in the breast cancer patients and controls. A heterozygous TRAIL CT polymorphism in exon 5 was present in 8.3% of tumour stage III-IV and 48.8% of stage I-II patients, and in 42.1% of controls. The reduced frequency of this genotype in patients who had advanced tumour stage was statistically significant (p = 0.017). CONCLUSIONS: Our findings indicate that genetic variants of TRAIL at position 1595 in exon 5 might be associated with progression of breast cancer. PMID- 22427770 TI - Long-term survival of endometrioid endometrial cancer patients. AB - INTRODUCTION: To establish risk factors for onset and progression of endometrioid endometrial cancer still remains the aim of scientists. The aim of the study was to determine disease-free survival (DFS) and overall survival (OS) in women with endometrioid endometrial cancer. MATERIAL AND METHODS: A retrospective review of 142 patients with endometrioid endometrial cancer after surgery treated with adjuvant radiotherapy and/or chemotherapy in the Regional Cancer Centre in Lodz between 2002 and 2004 was performed. Clinical and pathological data were correlated with clinical outcome and survival. RESULTS: In 3 patients (2.1%) clinical progression was diagnosed during the treatment. In 23 patients (16.7%) after primary remission, relapse was diagnosed 2-56 months after treatment. DFS and OS were 81.7% and 83.1% respectively. Better DFS significantly correlated with larger number of pregnancies (> 1), stage I of the disease and optimal surgery. Lower stage of disease, pelvic lymph node dissection, optimal surgery and depth of myometrial infiltration <= 50% were independent prognostic factors for better OS. CONCLUSIONS: The results of our study provided significant evidence that early detection of endometrioid endometrial cancer enables optimal surgery. It reduces the indications for adjuvant therapy in stage I of the disease, and makes the prognosis significantly better. Other clinical and pathological factors such as numerous pregnancies, pelvic lymphadenectomy, and depth of myometrial infiltration, although important, are of less significance. Further prospective, randomized studies are necessary to prove the role of these factors. PMID- 22427771 TI - Half-dose, long-acting gonadotropin-releasing hormone agonist (Diphereline) is comparable with daily injections of short-acting gonadotropin-releasing hormone agonist (Suprefact) in IVF/ICSI cycles. AB - INTRODUCTION: The aim of the study was to compare the efficacy of half-dose, long acting GnRH analogue (Diphereline) with Suprefact in IVF/ICSI (in vitro fertilization/intracytoplasmic sperm injection) cycles. MATERIAL AND METHODS: In this randomized clinical trial performed in Royan Institute, 126 infertile women who were first time candidates for IVF/ICSI were enrolled. Patients were randomly divided into two groups by using a random number table. In one group, 62 patients received a single half dose, 1.87 mg Diphereline, in mid-luteal phase. In the other group, 64 cases were treated with buserelin from the previous mid-luteal phase. P value less than 0.05 was considered significant. RESULTS: The mean age of patients in the Diphereline and Suprefact groups was 27.9 +/-3.6 and 29.6 +/ 3.5 years, respectively (p = 0.01). In the Diphereline group, the mean number of used gonadotropins was 25.6 +/-12.1 ampoules, while in the second group it was 25.9 +/-8.5 ampoules. Numbers of retrieved and MII oocytes were significantly higher in the Diphereline group (12.1 +/-6.3 and 9.6 +/-5.5) in comparison to the Suprefact group (9.4 +/-6.4 and 7.2 +/-5.1). Although the number of developed embryos in the Diphereline group was statistically higher than in the Suprefact group (6.1 +/-3.9 vs. 4.7 +/-3.4, p = 0.04) there was no significant difference in pregnancy rate (37.1%, 95% CI [26.16-49.54] vs. 37.5%, 95% CI [26.67-49.75]). CONCLUSIONS: A half-dose, long-acting GnRH agonist can be successfully used in ovarian stimulation and produces a higher number of MII oocytes and embryos. The pregnancy rates with this method are acceptable. PMID- 22427772 TI - Mixture of Arnebia euchroma and Matricaria chamomilla (Marhame-Mafasel) for pain relief of osteoarthritis of the knee - a two-treatment, two-period crossover trial. AB - INTRODUCTION: Osteoarthritis is the most prevalent chronic non-infective joint arthritis. Because of its chronic disease nature, local drugs are preferred due to lower complications. In the present study, the new herbal pomade Marhame Mafasel for knee osteoarthritis was used in a double-blind crossover trial. The aim of the study was to assess the efficacy and safety of Marhame-Mafasel pomade, which consists of several medical herbs including Arnebia euchroma and Matricaria chamomilla, in osteoarthritis of the knee. MATERIAL AND METHODS: This study was a placebo-controlled double-blind crossover trial. Forty-two patients with pain associated with osteoarthritis of the knee (diagnosed by criteria of the European League against Rheumatism and physical examination) were drawn from patients attending the Clinic of Mostafa-Khomeini Hospital. In this study we assessed efficacy (analgesic effect and improved function) of herbal pomade Marhame Mafasel, which was used locally in patients with primary osteoarthritis of the knee over three weeks. The instrument of the study was the Western Ontario and McMaster Universities (WOMAC) LK3.1 standard questionnaires. RESULTS: The participants in each group were 21 patients; 30 (71.4%) were women and 12 (28.6%) of them were men. The participants were between 40 and 76 years old. Six patients had mild arthritis, 15 had moderate arthritis and 21 had severe arthritis. The positive analgesic effect of the herbal pomade Marhame-Mafasel in primary knee osteoarthritis was proven. The herbal joint pomade Marhame-Mafasel had a significantly greater mean change in score compared to the placebo group for osteoarthritis severity (p < 0.05). CONCLUSIONS: Herbal pomade Marhame-Mafasel in comparison to placebo has more effect on reduction of pain of primary knee osteoarthritis. PMID- 22427773 TI - Randomized study assessing the influence of supervised exercises on ankle joint mobility in patients with venous leg ulcerations. AB - INTRODUCTION: The aim of the study was to assess the influence of a supervised programme of exercises on ankle joint mobility in patients with venous leg ulcerations. MATERIAL AND METHODS: The study was carried out between 2008 and 2009 at the Venous Ulcer Treatment Outpatient Clinic and Clinic of General and Vascular Surgery of the Dr Jan Biziel University Hospital no. 2 in Bydgoszcz. It was a randomized control study in which 32 patients with venous leg ulcerations were qualified. Patients with ulcerations were randomized to 2 groups - 16 patients were included in the group with a supervised programme of exercises and the other 16 patients were included in the control group performing physical exercises by themselves, without supervision. The ranges of ankle joint mobility were assessed before, during and after the end of the 9-week exercise programme. A 32 cm goniometer with a scale from 0 degrees to 180 degrees with accuracy to 1 degrees was used for measurements. RESULTS: In both groups a substantial increase of ankle joint mobility (p < 0.05) was observed. The total ankle joint mobility after completion of the exercises was significantly higher in the group performing exercises under the supervision of a nurse. Having a significant effect on the mobility of the ankle were the ulceration area, the extent of lipodermatosclerosis, and the intensity of symptoms and signs of CVI (p < 0.05). CONCLUSIONS: Supervised physical exercises broaden the range of ankle joint mobility. They should constitute an integral part of a holistic model of care for patients with venous leg ulcerations. PMID- 22427774 TI - Interleukin-18 expression and the response to treatment in patients with psoriasis. AB - INTRODUCTION: The aim of the study was to demonstrate Interleukin-18 (IL-18) expression in keratinocytes from psoriatic lesions in comparison to keratinocytes from uninvolved skin and to study the change of expression after therapeutic interventions. MATERIAL AND METHODS: This study included 16 patients of different clinical subtypes of psoriasis. IL-18 gene expression analysis was performed using real-time quantitative PCR. Three biopsies were obtained from each patient. Two were taken from the lesional psoriatic skin and from uninvolved skin before starting treatment. A third lesional skin biopsy was taken at the end of two months' treatment course. The treatment was in the form of topical steroids or oral systemic methotrexate. RESULTS: Of all 16 studied patients significantly increased IL-18 expression was noted in keratinocytes from psoriatic lesions before and after treatment when compared to keratinocytes from uninvolved skin (P = 0.001 and 0.002 respectively). The IL-18 expression in the skin lesions after treatment was significantly lower than lesional skin before treatment (P = 0.023). In psoriatic skin lesions of all studied patients IL-18 expression was significantly correlated with disease duration (r = 0.40 and P = 0.01) and clinical severity of psoriasis (r = 0.72 and P = 0.001). CONCLUSIONS: Increased IL-18 expression in keratinocytes from psoriatic lesions of our patients and its correlation with disease duration and severity supported the concept which views psoriasis as a T-cell-mediated autoimmune disease. This could establish therapeutic and preventive approaches for psoriasis that ultimately lead to improved outcomes for patients. PMID- 22427775 TI - Hemodynamic support with TandemHeart in tako-tsubo cardiomyopathy - a case report. AB - Tako-tsubo cardiomyopathy is characterized by chest pain, electrocardiographic abnormalities mimicking acute myocardial infarction, akinesis or dyskinesis of apical or mid left ventricular segments, and the absence of obstructive coronary artery disease. Tako-tsubo cardiomyopathy is usually a potentially reversible form of cardiac dysfunction. A careful literature search revealed no previous report of a patient requiring mechanical circulatory support in tako-tsubo cardiomyopathy. We report a patient with tako-tsubo cardiomyopathy, ventricular fibrillation, and hemodynamic instability requiring a left ventricular assist device (TandemHeart(TM)) followed by improvement of left ventricular ejection fraction to 45%. PMID- 22427776 TI - Combined percutaneous treatment of atrial septal defect and pulmonic or aortic stenosis in adult patients. AB - Combined atrial septal defect and pulmonic or aortic stenosis are relatively uncommon conditions in adult patients, with few reported cases of percutaneous treatment. We present two patients with secundum type atrial septal defect and concomitant pulmonic or aortic stenosis and their treatment by transcatheter techniques. PMID- 22427777 TI - Uncommon cause of obstruction in the left ventricular outflow tract by a metastasis of adenocarcinoma. AB - Cardiac metastases are rare diagnoses among cardiac disorders. This case demonstrates a unique presence of an obstruction in the left ventricular outflow tract caused by the metastasis of a renal carcinoma. Adequate diagnostic and therapeutic procedures were lifesaving in this potentially fatal diagnosis. PMID- 22427778 TI - Desflurane anaesthesia in a patient with multiple sclerosis in total hip replacement. AB - Multiple sclerosis (MS) is a progressive demyelinating disease presenting with a relapsing-remitting course and affects large areas of the brain and the spinal cord. Surgical stress often induces exacerbation of MS symptoms. It is mandatory to prepare the MS patient very carefully for the surgery and anaesthesia with an effective premedication and an effective postoperative analgesia following a safe and minimal-risk anaesthesia management. In recent reports, results of general and regional anaesthesia in MS patients have been discussed. To our knowledge this is the first case report of the use of desflurane anaesthesia in a patient with MS. In conclusion, desflurane anaesthesia is a safe and useful method for MS patients. PMID- 22427779 TI - A case of hyperosmolar hyperglycaemic state with involuntary movements - diagnostic dilemma and clinical considerations. AB - Hyperosmolar hyperglycaemic state (HHS) is a medical emergency which needs immediate medical intervention. A 37-year-old Chinese woman with a history of hypertension attended the Emergency Department. She had a two-day history of involuntary movement, i.e. chorea of the upper limbs, preceded by a one-week history of upper respiratory tract infection. She also had polyuria and polydipsia, although she was never diagnosed as diabetic. The main aim of reporting the present case was to highlight the importance of biochemical investigations involved in the diagnosis of involuntary movements. PMID- 22427780 TI - Percutaneous management of a saphenous vein graft perforation using a covered stent and final coil embolization technique. AB - Coronary artery perforation as a result of percutaneous coronary intervention is a rare complication which may result in cardiac tamponade, myocardial infarction and death. Perforation of a saphenous vein graft is unusual and generally requires surgical intervention. We describe a novel percutaneous approach that facilitated the successful management of a potentially catastrophic saphenous vein graft (SVG) perforation. PMID- 22427781 TI - A missing piece in the puzzle: HIV in mature adults in sub-Saharan Africa. AB - Healthcare and social needs for mature adults aged 50 years or older differ from those of younger adults due to stigma concerning HIV in older people, beliefs that engagement in sexual activity no longer applies, age driven comorbidities and responses to antiretroviral treatment, which complicate HIV diagnosis and management. In the face of a growing HIV epidemic in mature adults, mostly due to infected people aging with HIV, but also due to new infections in this age group, HIV services, which mostly cater for HIV in young adults and children, and HIV education messages and interventions, which mainly target young adults, leave the mature adult exposed and vulnerable to HIV transmission and to a lack of care and treatment thereafter. PMID- 22427782 TI - Panaortitis heralding giant cell temporal arteritis. PMID- 22427783 TI - Long term diarrhoea caused by simultaneous Crohn's disease and coeliac disease in the same patient. AB - Coeliac disease and Crohn's disease are among the most well known gastrointestinal disorders, with distinct pathogenic mechanisms. However, because of some overlapping features between these two conditions, there may be some inevitable misdiagnoses. In addition, diarrhoea and changes in bowel habit may lead the physician to misdiagnose more common disorders such as irritable bowel syndrome. There are a few cases reporting both coeliac and Crohn's disease in the same patient. Here we report a case of a 32-year-old woman suffering from long term diarrhoea who was eventually discovered to have coeliac disease and Crohn's disease simultaneously. PMID- 22427784 TI - Tubercular abscess of pons in a child with quadriparesis. AB - Tuberculous brain abscess is a rare manifestation of tuberculosis of the central nervous system. We report a case of a 6-year-old girl with a pontine tuberculous abscess, who presented with fever and quadriparesis and recovered completely after stereotactic aspiration and antituberculous treatment with four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol). Tuberculous abscess was confirmed based on findings of magnetic resonance imaging, a positive tuberculin test, and the presence of acid fast bacilli in smear and culture of abscess aspirate. PMID- 22427785 TI - Pyelocalyceal cysts with hydrotic nephritis of the kidney: case of a unilateral congenital developmental anomaly. AB - This report describes the diagnostic, morbid, anatomical and histopathological features of pyelocalyceal cysts with hydrotic nephritis of the kidney in a 3-year old boy, and discusses the pathogenesis. Calyceal cysts gave rise to a 'large blue cystic lobulated kidney' with microscopic changes in nephrons identifiable as 'hydrotic nephritic glomerulosclerosis'. Pelvic and calyceal cysts were identifiable by location, number, arrangement, and morbid anatomical and microscopic features of their lining walls. Such cysts may develop due to partial or complete obliterate adhesions at the uretero-pelvic and pyelocalyceal junctions. Patent calyceo-tubulonephric junctions in such cases may give rise to hydrotic nephritis. Pyelocalyceal cystic disease with hydrotic nephritis of the kidney needs to be distinguished from megacalycosis and hydronephrosis and deserves recognition. Observations in this case may provide the basis for future classifications of cystic renal diseases. PMID- 22427786 TI - Endocarditis presenting as acute abdomen. AB - Infective endocarditis remains an interesting and challenging disease in which the presenting features have been modified by medical progress. We report a case of a 63-year-old woman who presented with pyrexia, weight loss, night sweats and fatigue over a period of 7 weeks, at the end of which she developed severe right hypochondrial pain, mimicking acute abdomen. She was provisionally diagnosed with and treated for acute cholecystitis to no avail. An abdominal computed tomography scan was performed and revealed the presence of right kidney infarction, the source of which was later proven to originate from aortic valve endocarditis. The patient made a remarkable recovery following 6 weeks of treatment with intravenous antibiotics. This case demonstrates that endocarditis can present as an acute abdomen which is caused mainly by embolism in various organs (the kidney in our patient). PMID- 22427787 TI - The dilemma between efficacy as defined by regulatory bodies and effectiveness in clinical practice. PMID- 22427788 TI - New drugs: evidence relating to their therapeutic value after introduction to the market. AB - BACKGROUND: Drug approval is based on three criteria: quality, efficacy, and safety. We investigated the types of study design and statistical methods employed to demonstrate safety and efficacy of proprietary medicinal products (PMPs) that were approved for use in the European Union through the centralized procedure. METHODS: We retrospectively analyzed the European Public Assessment Reports of PMPs that the European Medicinal Agency approved, either initially or for extended indications, in 2009 and 2010. RESULTS: Data were analyzed for 39 PMPs: 64% of these were new active substances, and 36% were approved for extended indications. 46% of the PMPs had been studied in an active-control trial. In only 28%, superiority of the new PMPs compared to active control had been tested. 46% of the approvals included testing of a patient-relevant primary endpoint. The median size of population used to demonstrate safety was 1700 persons. CONCLUSION: The centralized procedure does not require comparative information from active-control trials. Accordingly, as our descriptive analysis revealed, this information is often not available at the time of market introduction. Pivotal studies only rarely clearly demonstrate an added therapeutic value of a new PMP compared to existing alternatives. PMID- 22427789 TI - Fertility in survivors of childhood cancer. PMID- 22427790 TI - Suspected infertility after treatment for leukemia and solid tumors in childhood and adolescence. AB - BACKGROUND: With improved cure rates of cancer in children and adolescents, the long-term effects of oncological treatment, including impaired fertility, have become an important clinical issue. METHODS: In 2008, we conducted a nationwide survey in Germany in which we asked 4689 female and male patients who had been treated for cancer in childhood or adolescence for information on menstruation, previous fertility testing (if any), attempts to conceive, and pregnancies. In a complementary study carried out in 2009, 748 former cancer patients in Berlin were offered hormone testing and sperm analysis. The defined criteria for suspected infertility were, in women, anti-muellerian hormone levels below 0.1 ng/mL; in men, FSH levels above 10 IU/L and inhibin B levels below 80 pg/mL, or azoospermia. RESULTS: The respondents to the nationwide survey included 1476 leukemia survivors and 1278 persons who had had a solid tumor. 104 former leukemia patients and 96 former solid tumor patients had already undergone fertility testing, leading to the suspicion of infertility in 26% and 34% of the persons in these respective groups (95% confidence intervals [CI], 18%-34% and 25%-43%). The patients who were tested in the Berlin study included 59 leukemia survivors and 104 persons who had had a solid tumor. The frequency of suspected infertility in these two groups was 25% and 27%, respectively (95% CI, 14%-36% and 18%-36%). CONCLUSION: Up to one-third of adults who undergo fertility testing after having been treated for cancer in childhood or adolescence have suspected infertility. Patients and their parents should be counseled about the possibility of infertility and about fertility-preserving measures. PMID- 22427791 TI - Congenital heart defects in adults. Organization not well enough explained. PMID- 22427793 TI - ESTIMATING WITHIN-HOUSEHOLD CONTACT NETWORKS FROM EGOCENTRIC DATA. AB - Acute respiratory diseases are transmitted over networks of social contacts. Large-scale simulation models are used to predict epidemic dynamics and evaluate the impact of various interventions, but the contact behavior in these models is based on simplistic and strong assumptions which are not informed by survey data. These assumptions are also used for estimating transmission measures such as the basic reproductive number and secondary attack rates. Development of methodology to infer contact networks from survey data could improve these models and estimation methods. We contribute to this area by developing a model of within household social contacts and using it to analyze the Belgian POLYMOD data set, which contains detailed diaries of social contacts in a 24-hour period. We model dependency in contact behavior through a latent variable indicating which household members are at home. We estimate age-specific probabilities of being at home and age-specific probabilities of contact conditional on two members being at home. Our results differ from the standard random mixing assumption. In addition, we find that the probability that all members contact each other on a given day is fairly low: 0.49 for households with two 0-5 year olds and two 19-35 year olds, and 0.36 for households with two 12-18 year olds and two 36+ year olds. We find higher contact rates in households with 2-3 members, helping explain the higher influenza secondary attack rates found in households of this size. PMID- 22427794 TI - Expression of Tas1 taste receptors in mammalian spermatozoa: functional role of Tas1r1 in regulating basal Ca2+ and cAMP concentrations in spermatozoa. AB - BACKGROUND: During their transit through the female genital tract, sperm have to recognize and discriminate numerous chemical compounds. However, our current knowledge of the molecular identity of appropriate chemosensory receptor proteins in sperm is still rudimentary. Considering that members of the Tas1r family of taste receptors are able to discriminate between a broad diversity of hydrophilic chemosensory substances, the expression of taste receptors in mammalian spermatozoa was examined. METHODOLOGY/PRINCIPAL FINDINGS: The present manuscript documents that Tas1r1 and Tas1r3, which form the functional receptor for monosodium glutamate (umami) in taste buds on the tongue, are expressed in murine and human spermatozoa, where their localization is restricted to distinct segments of the flagellum and the acrosomal cap of the sperm head. Employing a Tas1r1-deficient mCherry reporter mouse strain, we found that Tas1r1 gene deletion resulted in spermatogenic abnormalities. In addition, a significant increase in spontaneous acrosomal reaction was observed in Tas1r1 null mutant sperm whereas acrosomal secretion triggered by isolated zona pellucida or the Ca2+ ionophore A23187 was not different from wild-type spermatozoa. Remarkably, cytosolic Ca2+ levels in freshly isolated Tas1r1-deficient sperm were significantly higher compared to wild-type cells. Moreover, a significantly higher basal cAMP concentration was detected in freshly isolated Tas1r1-deficient epididymal spermatozoa, whereas upon inhibition of phosphodiesterase or sperm capacitation, the amount of cAMP was not different between both genotypes. CONCLUSIONS/SIGNIFICANCE: Since Ca2+ and cAMP control fundamental processes during the sequential process of fertilization, we propose that the identified taste receptors and coupled signaling cascades keep sperm in a chronically quiescent state until they arrive in the vicinity of the egg - either by constitutive receptor activity and/or by tonic receptor activation by gradients of diverse chemical compounds in different compartments of the female reproductive tract. PMID- 22427795 TI - Uncoupling protein-4 (UCP4) increases ATP supply by interacting with mitochondrial Complex II in neuroblastoma cells. AB - Mitochondrial uncoupling protein-4 (UCP4) protects against Complex I deficiency as induced by 1-methyl-4-phenylpyridinium (MPP(+)), but how UCP4 affects mitochondrial function is unclear. Here we investigated how UCP4 affects mitochondrial bioenergetics in SH-SY5Y cells. Cells stably overexpressing UCP4 exhibited higher oxygen consumption (10.1%, p<0.01), with 20% greater proton leak than vector controls (p<0.01). Increased ATP supply was observed in UCP4 overexpressing cells compared to controls (p<0.05). Although state 4 and state 3 respiration rates of UCP4-overexpressing and control cells were similar, Complex II activity in UCP4-overexpressing cells was 30% higher (p<0.05), associated with protein binding between UCP4 and Complex II, but not that of either Complex I or IV. Mitochondrial ADP consumption by succinate-induced respiration was 26% higher in UCP4-overexpressing cells, with 20% higher ADP:O ratio (p<0.05). ADP/ATP exchange rate was not altered by UCP4 overexpression, as shown by unchanged mitochondrial ADP uptake activity. UCP4 overexpression retained normal mitochondrial morphology in situ, with similar mitochondrial membrane potential compared to controls. Our findings elucidate how UCP4 overexpression increases ATP synthesis by specifically interacting with Complex II. This highlights a unique role of UCP4 as a potential regulatory target to modulate mitochondrial Complex II and ATP output in preserving existing neurons against energy crisis. PMID- 22427796 TI - Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease. AB - Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity.We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort.There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis. PMID- 22427797 TI - DNA methylation-independent reversion of gemcitabine resistance by hydralazine in cervical cancer cells. AB - BACKGROUND: Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase. PMID- 22427798 TI - Wolbachia induces male-specific mortality in the mosquito Culex pipiens (LIN strain). AB - BACKGROUND: Wolbachia are maternally inherited endosymbionts that infect a diverse range of invertebrates, including insects, arachnids, crustaceans and filarial nematodes. Wolbachia are responsible for causing diverse reproductive alterations in their invertebrate hosts that maximize their transmission to the next generation. Evolutionary theory suggests that due to maternal inheritance, Wolbachia should evolve toward mutualism in infected females, but strict maternal inheritance means there is no corresponding force to select for Wolbachia strains that are mutualistic in males. METHODOLOGY/PRINCIPAL FINDINGS: Using cohort life table analysis, we demonstrate that in the mosquito Culex pipiens (LIN strain), Wolbachia-infected females show no fitness costs due to infection. However, Wolbachia induces up to a 30% reduction in male lifespan. CONCLUSIONS/SIGNIFICANCE: These results indicate that the Wolbachia infection of the Culex pipiens LIN strain is virulent in a sex-specific manner. Under laboratory situations where mosquitoes generally mate at young ages, Wolbachia strains that reduce male survival could evolve by drift because increased mortality in older males is not a significant selective force. PMID- 22427799 TI - Coping with temperature at the warm edge--patterns of thermal adaptation in the microbial eukaryote Paramecium caudatum. AB - BACKGROUND: Ectothermic organisms are thought to be severely affected by global warming since their physiological performance is directly dependent on temperature. Latitudinal and temporal variations in mean temperatures force ectotherms to adapt to these complex environmental conditions. Studies investigating current patterns of thermal adaptation among populations of different latitudes allow a prediction of the potential impact of prospective increases in environmental temperatures on their fitness. METHODOLOGY/PRINCIPAL FINDINGS: In this study, temperature reaction norms were ascertained among 18 genetically defined, natural clones of the microbial eukaryote Paramecium caudatum. These different clones have been isolated from 12 freshwater habitats along a latitudinal transect in Europe and from 3 tropical habitats (Indonesia). The sensitivity to increasing temperatures was estimated through the analysis of clone specific thermal tolerances and by relating those to current and predicted temperature data of their natural habitats. All investigated European clones seem to be thermal generalists with a broad thermal tolerance and similar optimum temperatures. The weak or missing co-variation of thermal tolerance with latitude does not imply local adaptation to thermal gradients; it rather suggests adaptive phenotypic plasticity among the whole European subpopulation. The tested Indonesian clones appear to be locally adapted to the less variable, tropical temperature regime and show higher tolerance limits, but lower tolerance breadths. CONCLUSIONS/SIGNIFICANCE: Due to the lack of local temperature adaptation within the European subpopulation, P. caudatum genotypes at the most southern edge of their geographic range seem to suffer from the predicted increase in magnitude and frequency of summer heat waves caused by climate change. PMID- 22427800 TI - The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. AB - There is an increasing interest in using microRNAs (miRNA) as biomarkers in autoimmune diseases. They are easily accessible in many body fluids but it is controversial if they are circulating freely or are encapsulated in microvesicles, particularly exosomes. We investigated if the majority of miRNas in serum and saliva are free-circulating or concentrated in exosomes. Exosomes were isolated by ultracentrifugation from fresh and frozen human serum and saliva. The amount of selected miRNAs extracted from the exosomal pellet and the exosome-depleted serum and saliva was compared by quantitative RT-PCR. Some miRNAs tested are ubiquitously expressed, others were previously reported as biomarkers. We included miRNAs previously reported to be free circulating and some thought to be exosome specific. The purity of exosome fraction was confirmed by electronmicroscopy and western blot. The concentration of miRNAs was consistently higher in the exosome pellet compared to the exosome-depleted supernatant. We obtained the same results using an equal volume or equal amount of total RNA as input of the RT-qPCR. The concentration of miRNA in whole, unfractionated serum, was between the exosomal pellet and the exosome-depleted supernatant. Selected miRNAs, which were detectable in exosomes, were undetectable in whole serum and the exosome-depleted supernantant. Exosome isolation improves the sensitivity of miRNA amplification from human biologic fluids. Exosomal miRNA should be the starting point for early biomarker studies to reduce the probability of false negative results involving low abundance miRNAs that may be missed by using unfractionated serum or saliva. PMID- 22427801 TI - The JNK inhibitor XG-102 protects against TNBS-induced colitis. AB - The c-Jun N-terminal kinase (JNK)-inhibiting peptide D-JNKI-1, syn. XG-102 was tested for its therapeutic potential in acute inflammatory bowel disease (IBD) in mice. Rectal instillation of the chemical irritant trinitrobenzene sulfonic acid (TNBS) provoked a dramatic acute inflammation in the colon of 7-9 weeks old mice. Coincident subcutaneous application of 100 ug/kg XG-102 significantly reduced the loss of body weight, rectal bleeding and diarrhoea. After 72 h, the end of the study, the colon was removed and immuno-histochemically analysed. XG-102 significantly reduced (i) pathological changes such as ulceration or crypt deformation, (ii) immune cell pathology such as infiltration and presence of CD3- and CD68-positive cells, (iii) the production of tumor necrosis factor (TNF) alpha in colon tissue cultures from TNBS-treated mice, (iv) expression of Bim, Bax, FasL, p53, and activation of caspase 3, (v) complexation of JNK2 and Bim, and (vi) expression and activation of the JNK substrate and transcription factor c-Jun. A single application of subcutaneous XG-102 was at least as effective or even better depending on the outcome parameter as the daily oral application of sulfasalazine used for treatment of IBD.The successful and substantial reduction of the severe, TNBS-evoked intestinal damages and clinical symptoms render the JNK-inhibiting peptide XG-102 a powerful therapeutic principle of IBD. PMID- 22427802 TI - Small-animal PET imaging of amyloid-beta plaques with [11C]PiB and its multi modal validation in an APP/PS1 mouse model of Alzheimer's disease. AB - In vivo imaging and quantification of amyloid-beta plaque (Abeta) burden in small animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Abeta in mouse brain with [(11)C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Abeta at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [(11)C]PiB uptake in individual brain regions with Abeta deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Abeta pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [(11)C]PiB imaging of Abeta in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Abeta imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice. PMID- 22427803 TI - Towards prenatal biomonitoring in North Carolina: assessing arsenic, cadmium, mercury, and lead levels in pregnant women. AB - Exposure to toxic metals during the prenatal period carries the potential for adverse developmental effects to the fetus, yet such exposure remains largely unmonitored in the United States. The aim of this study was to assess maternal exposure to four toxic metals (arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb)) in a cohort of pregnant women in North Carolina. We analyzed blood samples submitted to the North Carolina Department of Health and Human Services for blood typing to assess toxic metal levels in pregnant women (n = 211) across six North Carolina counties. Whole blood metal concentrations were measured by inductively coupled plasma mass spectrometry. The association between maternal characteristics, including county of residence, age, and race, and metal exposure was analyzed using multiple linear regression analysis. A large fraction of the blood samples showed detectable levels for each of the four metals. Specifically, As (65.7%), Cd (57.3%), Hg (63.8%), and Pb (100%) were detected in blood samples. Moreover, compared with adult females participating in the Fourth National Report on Human Exposure to Environmental Chemicals and guidelines for pregnant women, some women in the sample population exceeded benchmark levels of Cd, Hg, and Pb. Evidence from this pilot study indicates that pregnant women in North Carolina are exposed to As, Cd, Hg, and Pb and suggests that factors related to maternal county of residence and race may impact maternal exposure levels. As increased levels of one or more of these metals in utero have been associated with detrimental developmental and reproductive outcomes, further study is clearly warranted to establish the impacts to newborns. PMID- 22427804 TI - Does consideration and assessment of effects on health equity affect the conclusions of systematic reviews? A methodology study. AB - INTRODUCTION: Tackling health inequities both within and between countries remains high on the agenda of international organizations including the World Health Organization and local, regional and national governments. Systematic reviews can be a useful tool to assess effects on equity in health status because they include studies conducted in a variety of settings and populations. This study aims to describe the extent to which the impacts of health interventions on equity in health status are considered in systematic reviews, describe methods used, and assess the implications of their equity related findings for policy, practice and research. METHODS: We conducted a methodology study of equity assessment in systematic reviews. Two independent reviewers extracted information on the reporting and analysis of impacts of health interventions on equity in health status in a group of 300 systematic reviews collected from all systematic reviews indexed in one month of MEDLINE, using a pre-tested data collection form. Any differences in data extraction were resolved by discussion. RESULTS: Of the 300 systematic reviews, 224 assessed the effectiveness of interventions on health outcomes. Of these 224 reviews, 29 systematic reviews assessed effects on equity in health status using subgroup analysis or targeted analyses of vulnerable populations. Of these, seven conducted subgroup analyses related to health equity which were reported in insufficient detail to judge their credibility. Of these 29 reviews, 18 described implications for policy and practice based on assessment of effects on health equity. CONCLUSION: The quality and completeness of reporting should be enhanced as a priority, because without this policymakers and practitioners will continue lack the evidence base they need to inform decision making about health inequity. Furthermore, there is a need to develop methods to systematically consider impacts on equity in health status that is currently lacking in systematic reviews. PMID- 22427805 TI - Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants. AB - Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5' promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRalpha isoform, the most abundant GRalpha isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC. PMID- 22427806 TI - Recurrent Plasmodium falciparum malaria infections in Kenyan children diminish T cell immunity to Epstein Barr virus lytic but not latent antigens. AB - Plasmodium falciparum malaria (Pf-malaria) and Epstein Barr Virus (EBV) infections coexist in children at risk for endemic Burkitt's lymphoma (eBL); yet studies have only glimpsed the cumulative effect of Pf-malaria on EBV-specific immunity. Using pooled EBV lytic and latent CD8+ T-cell epitope-peptides, IFN gamma ELISPOT responses were surveyed three times among children (10 months to 15 years) in Kenya from 2002-2004. Prevalence ratios (PR) and 95% confidence intervals (CI) were estimated in association with Pf-malaria exposure, defined at the district-level (Kisumu: holoendemic; Nandi: hypoendemic) and the individual level. We observed a 46% decrease in positive EBV lytic antigen IFN-gamma responses among 5-9 year olds residing in Kisumu compared to Nandi (PR: 0.54; 95% CI: 0.30-0.99). Individual-level analysis in Kisumu revealed further impairment of EBV lytic antigen responses among 5-9 year olds consistently infected with Pf malaria compared to those never infected. There were no observed district- or individual-level differences between Pf-malaria exposure and EBV latent antigen IFN-gamma response. The gradual decrease of EBV lytic antigen but not latent antigen IFN-gamma responses after primary infection suggests a specific loss in immunological control over the lytic cycle in children residing in malaria holoendemic areas, further refining our understanding of eBL etiology. PMID- 22427807 TI - Glycerol hypersensitivity in a Drosophila model for glycerol kinase deficiency is affected by mutations in eye pigmentation genes. AB - Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency. PMID- 22427808 TI - Uncovering the molecular machinery of the human spindle--an integration of wet and dry systems biology. AB - The mitotic spindle is an essential molecular machine involved in cell division, whose composition has been studied extensively by detailed cellular biology, high throughput proteomics, and RNA interference experiments. However, because of its dynamic organization and complex regulation it is difficult to obtain a complete description of its molecular composition. We have implemented an integrated computational approach to characterize novel human spindle components and have analysed in detail the individual candidates predicted to be spindle proteins, as well as the network of predicted relations connecting known and putative spindle proteins. The subsequent experimental validation of a number of predicted novel proteins confirmed not only their association with the spindle apparatus but also their role in mitosis. We found that 75% of our tested proteins are localizing to the spindle apparatus compared to a success rate of 35% when expert knowledge alone was used. We compare our results to the previously published MitoCheck study and see that our approach does validate some findings by this consortium. Further, we predict so-called "hidden spindle hub", proteins whose network of interactions is still poorly characterised by experimental means and which are thought to influence the functionality of the mitotic spindle on a large scale. Our analyses suggest that we are still far from knowing the complete repertoire of functionally important components of the human spindle network. Combining integrated bio-computational approaches and single gene experimental follow-ups could be key to exploring the still hidden regions of the human spindle system. PMID- 22427809 TI - A collaboratively-derived science-policy research agenda. AB - The need for policy makers to understand science and for scientists to understand policy processes is widely recognised. However, the science-policy relationship is sometimes difficult and occasionally dysfunctional; it is also increasingly visible, because it must deal with contentious issues, or itself becomes a matter of public controversy, or both. We suggest that identifying key unanswered questions on the relationship between science and policy will catalyse and focus research in this field. To identify these questions, a collaborative procedure was employed with 52 participants selected to cover a wide range of experience in both science and policy, including people from government, non-governmental organisations, academia and industry. These participants consulted with colleagues and submitted 239 questions. An initial round of voting was followed by a workshop in which 40 of the most important questions were identified by further discussion and voting. The resulting list includes questions about the effectiveness of science-based decision-making structures; the nature and legitimacy of expertise; the consequences of changes such as increasing transparency; choices among different sources of evidence; the implications of new means of characterising and representing uncertainties; and ways in which policy and political processes affect what counts as authoritative evidence. We expect this exercise to identify important theoretical questions and to help improve the mutual understanding and effectiveness of those working at the interface of science and policy. PMID- 22427810 TI - A novel thin NIPAM gel cassette dosimeter for photon-beam radiotherapy. AB - The response of thin polymer gel cassettes (called NIPAM gels) to ionizing radiation was investigated in this study. The NIPAM gels were prepared from gelatin, N-isopropyl acrylamide, tetrakis (hydroxymethyl) phosphoniumchloride, and N,N'-methylene-bis-acrylamide. Gel cassettes were irradiated in a phantom using a linear accelerator, and the polymerization morphology of irradiated NIPAM gel was characterized using scanning electron microscopy. The dose-response sensitivity of the NIPAM gels was evaluated using the differences in optical densities. The optical densities were obtained using a computer-controlled CCD camera that was connected to a planar illumination source for acquisition of optical transmission images. The central axis depth dose profiles of the phantom were extracted, and a comparison with ionization chamber measurements demonstrated similarities in profiles. The sensitivity, linearity of the response, accuracy, and reproducibility of the polymer gel cassettes were acceptable. However, the profiles of the half-blocked field irradiation showed no significant dispersion in the visible region. This study also extensively investigated the spatial stability of the NIPAM gel. The results showed that the gel cassette response remains stable for up to three months after irradiation. PMID- 22427811 TI - Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication. AB - BACKGROUND: Any strategy for curing HIV infection must include a method to eliminate viral-infected cells. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb) to gp41 viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development. METHODOLOGY/PRINCIPAL FINDINGS: Among the several human mAbs to gp41 tested, mAb 2556 was found to have high affinity, reactivity with multimeric forms of gp41 present on both the surface of virus particles and cells expressing HIV-1 Env, and recognition of a highly conserved epitope of gp41 shared by all HIV-1 subtypes. Also, mAb 2556 was the best in competition with HIV-1+ serum antibodies, which is an extremely important consideration for efficacy in the treatment of HIV patients. When radiolabeled with alpha-emitting radionuclide 213 Bismuth ((213)Bi) - (213)Bi-2556 efficiently and specifically killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs). The number of binding sites for (213)Bi-2556 on the surface of the infected cells was >10(6). The in vivo experiments were performed in two HIV-1 mouse models--splenic and intraperitoneal. In both models, the decrease in HIV-1 infected hPBMCs from the spleens and peritoneum, respectively, was dose-dependent with the most pronounced killing of hPBMCs observed in the 100 uCi (213)Bi-2556 group (P = 0.01). Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for (213)Bi-2556. CONCLUSIONS/SIGNIFICANCE: We describe the preclinical development of a novel radiolabeled mAb reagent that could potentially be part of an HIV eradication strategy that is ready for translation into the clinic as the next step in its development. As viral antigens are very different from "self" human antigens - this approach promises high selectivity, increased efficacy and low toxicity, especially in comparison to immunotoxins. PMID- 22427812 TI - Human cryptochrome-1 confers light independent biological activity in transgenic Drosophila correlated with flavin radical stability. AB - Cryptochromes are conserved flavoprotein receptors found throughout the biological kingdom with diversified roles in plant development and entrainment of the circadian clock in animals. Light perception is proposed to occur through flavin radical formation that correlates with biological activity in vivo in both plants and Drosophila. By contrast, mammalian (Type II) cryptochromes regulate the circadian clock independently of light, raising the fundamental question of whether mammalian cryptochromes have evolved entirely distinct signaling mechanisms. Here we show by developmental and transcriptome analysis that Homo sapiens cryptochrome--1 (HsCRY1) confers biological activity in transgenic expressing Drosophila in darkness, that can in some cases be further stimulated by light. In contrast to all other cryptochromes, purified recombinant HsCRY1 protein was stably isolated in the anionic radical flavin state, containing only a small proportion of oxidized flavin which could be reduced by illumination. We conclude that animal Type I and Type II cryptochromes may both have signaling mechanisms involving formation of a flavin radical signaling state, and that light independent activity of Type II cryptochromes is a consequence of dark accumulation of this redox form in vivo rather than of a fundamental difference in signaling mechanism. PMID- 22427813 TI - Migratory connectivity of the monarch butterfly (Danaus plexippus): patterns of spring re-colonization in eastern North America. AB - Each year, millions of monarch butterflies (Danaus plexippus) migrate up to 3000 km from their overwintering grounds in central Mexico to breed in eastern North America. Malcolm et al. (1993) articulated two non-mutually exclusive hypotheses to explain how Monarchs re-colonize North America each spring. The 'successive brood' hypothesis proposes that monarchs migrate from Mexico to the Gulf Coast, lay eggs and die, leaving northern re-colonization of the breeding range to subsequent generations. The 'single sweep' hypothesis proposes that overwintering monarchs continue to migrate northward after arriving on the Gulf coast and may reach the northern portion of the breeding range, laying eggs along the way. To examine these hypotheses, we sampled monarchs throughout the northern breeding range and combined stable-hydrogen isotopes (deltaD) to estimate natal origin with wing wear scores to differentiate between individuals born in the current vs. previous year. Similar to Malcolm et al. (1993), we found that the majority of the northern breeding range was re-colonized by the first generation of monarchs (90%). We also estimated that a small number of individuals (10%) originated directly from Mexico and, therefore adopted a sweep strategy. Contrary to Malcolm et al. (1993), we found that 62% of monarchs sampled in the Great Lakes originated from the Central U.S., suggesting that this region is important for sustaining production in the northern breeding areas. Our results provide new evidence of re-colonization patterns in monarchs and contribute important information towards identifying productive breeding regions of this unique migratory insect. PMID- 22427814 TI - Hierarchical information clustering by means of topologically embedded graphs. AB - We introduce a graph-theoretic approach to extract clusters and hierarchies in complex data-sets in an unsupervised and deterministic manner, without the use of any prior information. This is achieved by building topologically embedded networks containing the subset of most significant links and analyzing the network structure. For a planar embedding, this method provides both the intra cluster hierarchy, which describes the way clusters are composed, and the inter cluster hierarchy which describes how clusters gather together. We discuss performance, robustness and reliability of this method by first investigating several artificial data-sets, finding that it can outperform significantly other established approaches. Then we show that our method can successfully differentiate meaningful clusters and hierarchies in a variety of real data-sets. In particular, we find that the application to gene expression patterns of lymphoma samples uncovers biologically significant groups of genes which play key roles in diagnosis, prognosis and treatment of some of the most relevant human lymphoid malignancies. PMID- 22427815 TI - Molecular prognostic prediction for locally advanced nasopharyngeal carcinoma by support vector machine integrated approach. AB - BACKGROUND: Accurate prognostication of locally advanced nasopharyngeal carcinoma (NPC) will benefit patients for tailored therapy. Here, we addressed this issue by developing a mathematical algorithm based on support vector machine (SVM) through integrating the expression levels of multi-biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: Ninety-seven locally advanced NPC patients in a randomized controlled trial (RCT), consisting of 48 cases serving as training set and 49 cases as testing set of SVM models, with 5-year follow-up were studied. We designed SVM models by selecting the variables from 38 tissue molecular biomarkers, which represent 6 tumorigenesis signaling pathways, and 3 EBV-related serological biomarkers. We designed 3 SVM models to refine prognosis of NPC with 5-year follow-up. The SVM1 displayed highly predictive sensitivity (sensitivity, specificity were 88.0% and 81.9%, respectively) by integrating the expression of 7 molecular biomarkers. The SVM2 model showed highly predictive specificity (sensitivity, specificity were 84.0% and 94.5%, respectively) by grouping the expression level of 12 molecular biomarkers and 3 EBV-related serological biomarkers. The SVM3 model, constructed by combination SVM1 with SVM2, displayed a high predictive capacity (sensitivity, specificity were 88.0% and 90.3%, respectively). We found that 3 SVM models had strong power in classification of prognosis. Moreover, Cox multivariate regression analysis confirmed these 3 SVM models were all the significant independent prognostic model for overall survival in testing set and overall patients. CONCLUSIONS/SIGNIFICANCE: Our SVM prognostic models designed in the RCT displayed strong power in refining patient prognosis for locally advanced NPC, potentially directing future target therapy against the related signaling pathways. PMID- 22427816 TI - Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFbeta, and Wnt/beta-catenin signaling in adrenocortical carcinoma cells. AB - The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) beta and Wnt/beta-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma. PMID- 22427817 TI - Dextran sodium sulfate (DSS) induces colitis in mice by forming nano lipocomplexes with medium-chain-length fatty acids in the colon. AB - Inflammatory bowel diseases (IBDs), primarily ulcerative colitis and Crohn's disease, are inflammatory disorders caused by multiple factors. Research on IBD has often used the dextran sodium sulfate (DSS)-induced colitis mouse model. DSS induces in vivo but not in vitro intestinal inflammation. In addition, no DSS associated molecule (free glucose, sodium sulfate solution, free dextran) induces in vitro or in vivo intestinal inflammation. We find that DSS but not dextran associated molecules established linkages with medium-chain-length fatty acids (MCFAs), such as dodecanoate, that are present in the colonic lumen. DSS complexed to MCFAs forms nanometer-sized vesicles ~200 nm in diameter that can fuse with colonocyte membranes. The arrival of nanometer-sized DSS/MCFA vesicles in the cytoplasm may activate intestinal inflammatory signaling pathways. We also show that the inflammatory activity of DSS is mediated by the dextran moieties. The deleterious effect of DSS is localized principally in the distal colon, therefore it will be important to chemically modify DSS to develop materials beneficial to the colon without affecting colon-targeting specificity. PMID- 22427818 TI - The teacher, the physician and the person: how faculty's teaching performance influences their role modelling. AB - OBJECTIVE: Previous studies identified different typologies of role models (as teacher/supervisor, physician and person) and explored which of faculty's characteristics could distinguish good role models. The aim of this study was to explore how and to which extent clinical faculty's teaching performance influences residents' evaluations of faculty's different role modelling statuses, especially across different specialties. METHODS: In a prospective multicenter multispecialty study of faculty's teaching performance, we used web-based questionnaires to gather empirical data from residents. The main outcome measures were the different typologies of role modelling. The predictors were faculty's overall teaching performance and faculty's teaching performance on specific domains of teaching. The data were analyzed using multilevel regression equations. RESULTS: In total 219 (69% response rate) residents filled out 2111 questionnaires about 423 (96% response rate) faculty. Faculty's overall teaching performance influenced all role model typologies (OR: from 8.0 to 166.2). For the specific domains of teaching, overall, all three role model typologies were strongly associated with "professional attitude towards residents" (OR: 3.28 for teacher/supervisor, 2.72 for physician and 7.20 for the person role). Further, the teacher/supervisor role was strongly associated with "feedback" and "learning climate" (OR: 3.23 and 2.70). However, the associations of the specific domains of teaching with faculty's role modelling varied widely across specialties. CONCLUSION: This study suggests that faculty can substantially enhance their role modelling by improving their teaching performance. The amount of influence that the specific domains of teaching have on role modelling differs across specialties. PMID- 22427819 TI - Highly (H5N1) and low (H7N2) pathogenic avian influenza virus infection in falcons via nasochoanal route and ingestion of experimentally infected prey. AB - An experimental infection with highly pathogenic avian influenza (HPAI) and low pathogenic avian influenza (LPAI) viruses was carried out on falcons in order to examine the effects of these viruses in terms of pathogenesis, viral distribution in tissues and viral shedding. The distribution pattern of influenza virus receptors was also assessed. Captive-reared gyr-saker (Falco rusticolus x Falco cherrug) hybrid falcons were challenged with a HPAI H5N1 virus (A/Great crested grebe/Basque Country/06.03249/2006) or a LPAI H7N2 virus (A/Anas plathyrhynchos/Spain/1877/2009), both via the nasochoanal route and by ingestion of previously infected specific pathogen free chicks. Infected falcons exhibited similar infection dynamics despite the different routes of exposure, demonstrating the effectiveness of in vivo feeding route. H5N1 infected falcons died, or were euthanized, between 5-7 days post-infection (dpi) after showing acute severe neurological signs. Presence of viral antigen in several tissues was confirmed by immunohistochemistry and real time RT-PCR (RRT-PCR), which were generally associated with significant microscopical lesions, mostly in the brain. Neither clinical signs, nor histopathological findings were observed in any of the H7N2 LPAI infected falcons, although all of them had seroconverted by 11 dpi. Avian receptors were strongly present in the upper respiratory tract of the falcons, in accordance with the consistent oral viral shedding detected by RRT PCR in both H5N1 HPAI and H7N2 LPAI infected falcons. The present study demonstrates that gyr-saker hybrid falcons are highly susceptible to H5N1 HPAI virus infection, as previously observed, and that they may play a major role in the spreading of both HPAI and LPAI viruses. For the first time in raptors, natural infection by feeding on infected prey was successfully reproduced. The use of avian prey species in falconry husbandry and wildlife rehabilitation facilities could put valuable birds of prey and humans at risk and, therefore, this practice should be closely monitored. PMID- 22427820 TI - Adherence to self-administered tuberculosis treatment in a high HIV-prevalence setting: a cross-sectional survey in Homa Bay, Kenya. AB - BACKGROUND: Good adherence to treatment is crucial to control tuberculosis (TB). Efficiency and feasibility of directly observed therapy (DOT) under routine program conditions have been questioned. As an alternative, Medecins sans Frontieres introduced self-administered therapy (SAT) in several TB programs. We aimed to measure adherence to TB treatment among patients receiving TB chemotherapy with fixed dose combination (FDC) under SAT at the Homa Bay district hospital (Kenya). A second objective was to compare the adherence agreement between different assessment tools. METHODS: We conducted a cross-sectional survey amongst a series of new TB patients receiving 6 months of standard TB chemotherapy with FDC under SAT. Adherence was assessed at home with urine testing for Isoniazid (INH), pill count, interviewer-administered questionnaire and visual analogue scale (VAS). RESULTS: In November 2008 and in June 2009, 212 of 279 eligible patients were assessed for adherence. Overall, 95.2% [95%CI: 91.3 97.7] of the patients reported not having missed a tablet in the last 4 days. On the VAS, complete adherence was estimated at 92.5% [95%CI: 88.0-95.6]. INH urine test was positive for 97.6% [95%CI: 94.6-99.2] of the patients. Pill count could be assessed among only 70% of the interviewed patients. Among them, it was complete for 82.3% [95%CI: 75.1-88.1]. Among the 212 surveyed patients, 193 (91.0%) were successfully treated (cured or treatment completed). The data suggest a fair agreement between the questionnaire and the INH urine test (k = 0.43) and between the questionnaire and the VAS (k = 0.40). Agreement was poor between the other adherence tools. CONCLUSION: These results suggest that SAT, together with the FDC, allows achieving appropriate adherence to antituberculosis treatment in a high TB and HIV burden area. The use of a combination of a VAS and a questionnaire can be an adequate approach to monitor adherence to TB treatment in routine program conditions. PMID- 22427821 TI - Virologic failure of protease inhibitor-based second-line antiretroviral therapy without resistance in a large HIV treatment program in South Africa. AB - BACKGROUND: We investigated the prevalence of wild-type virus (no major drug resistance) and drug resistance mutations at second-line antiretroviral treatment (ART) failure in a large HIV treatment program in South Africa. METHODOLOGY/ PRINCIPAL FINDINGS: HIV-infected patients >= 15 years of age who had failed protease inhibitor (PI)-based second-line ART (2 consecutive HIV RNA tests >1000 copies/ml on lopinavir/ritonavir, didanosine, and zidovudine) were identified retrospectively. Patients with virologic failure were continued on second-line ART. Genotypic testing for drug resistance was performed on frozen plasma samples obtained closest to and after the date of laboratory confirmed second-line ART failure. Of 322 HIV-infected patients on second-line ART, 43 were adults with confirmed virologic failure, and 33 had available plasma for viral sequencing. HIV-1 RNA subtype C predominated (n = 32, 97%). Mean duration on ART (SD) prior to initiation of second-line ART was 23 (17) months, and time from second-line ART initiation to failure was 10 (9) months. Plasma samples were obtained 7(9) months from confirmed failure. At second-line failure, 22 patients (67%) had wild type virus. There was no major resistance to PIs found. Eleven of 33 patients had a second plasma sample taken 8 (5.5) months after the first. Median HIV-1 RNA and the genotypic resistance profile were unchanged. CONCLUSIONS/ SIGNIFICANCE: Most patients who failed second-line ART had wild-type virus. We did not observe evolution of resistance despite continuation of PI-based ART after failure. Interventions that successfully improve adherence could allow patients to continue to benefit from second-line ART therapy even after initial failure. PMID- 22427822 TI - Estimate of leaf area index in an old-growth mixed broadleaved-Korean pine forest in northeastern China. AB - Leaf area index (LAI) is an important variable in the study of forest ecosystem processes, but very few studies are designed to monitor LAI and the seasonal variability in a mixed forest using non-destructive sampling. In this study, first, true LAI from May 1(st) and November 15(th) was estimated by making several calibrations to LAI as measured from the WinSCANOPY 2006 Plant Canopy Analyzer. These calibrations include a foliage element (shoot, that is considered to be a collection of needles) clumping index measured directly from the optical instrument, TRAC (Tracing Radiation and Architecture of Canopies); a needle-to shoot area ratio obtained from shoot samples; and a woody-to-total area ratio. Second, by periodically combining true LAI (May 1(st)) with the seasonality of LAI for deciduous and coniferous species throughout the leaf-expansion season (from May to August), we estimated LAI of each investigation period in the leaf expansion season. Third, by combining true LAI (November 15(th)) with litter trap data (both deciduous and coniferous species), we estimated LAI of each investigation period during the leaf-fall season (from September to mid November). Finally, LAI for the entire canopy then was derived from the initial leaf expansion to the leaf fall. The results showed that LAI reached its peak with a value of 6.53 m(2) m(-2) (a corresponding value of 3.83 m(2) m(-2) from optical instrument) in early August, and the mean LAI was 4.97 m(2) m(-2) from May to November using the proposed method. The optical instrument method underestimated LAI by an average of 41.64% (SD = 6.54) throughout the whole study period compared to that estimated by the proposed method. The result of the present work implied that our method would be suitable for measuring LAI, for detecting the seasonality of LAI in a mixed forest, and for measuring LAI seasonality for each species. PMID- 22427823 TI - Testing the growth rate hypothesis in vascular plants with above- and below ground biomass. AB - The growth rate hypothesis (GRH) proposes that higher growth rate (the rate of change in biomass per unit biomass, MU) is associated with higher P concentration and lower C:P and N:P ratios. However, the applicability of the GRH to vascular plants is not well-studied and few studies have been done on belowground biomass. Here we showed that, for aboveground, belowground and total biomass of three study species, MU was positively correlated with N:C under N limitation and positively correlated with P:C under P limitation. However, the N:P ratio was a unimodal function of MU, increasing for small values of MU, reaching a maximum, and then decreasing. The range of variations in MU was positively correlated with variation in C:N:P stoichiometry. Furthermore, MU and C:N:P ranges for aboveground biomass were negatively correlated with those for belowground. Our results confirm the well-known association of growth rate with tissue concentration of the limiting nutrient and provide empirical support for recent theoretical formulations. PMID- 22427824 TI - Regulation of the vapBC-1 toxin-antitoxin locus in nontypeable Haemophilus influenzae. AB - Nontypeable Haemophilus influenzae (NTHi) are human-adapted commensal bacteria that can cause a number of chronic mucosal infections, including otitis media and bronchitis. One way for these organisms to survive antibiotic therapy and cause recurrent disease is to stop replicating, as most antimicrobials target essential biosynthetic pathways. Toxin-antitoxin (TA) gene pairs have been shown to facilitate entry into a reversible bacteriostatic state. Characteristically, these operons encode a protein toxin and an antitoxin that associate following translation to form a nontoxic complex, which then binds to and regulates the cognate TA promoter. Under stressful conditions, the labile antitoxin is degraded and the complex disintegrates, freeing the stable toxin to facilitate growth arrest. How these events affected the regulation of the TA locus, as well as how the transcription of the operon was subsequently returned to its normal state upon resumption of growth, was not fully understood. Here we show that expression of the NTHi vapBC-1 TA locus is repressed by a complex of VapB-1 and VapC-1 under conditions favorable for growth, and activated by the global transactivator Factor for Inversion Stimulation (Fis) upon nutrient upshift from stationary phase. Further, we demonstrate for the first time that the VapC-1 toxin alone can bind to its cognate TA locus control region and that the presence of VapB-1 directs the binding of the VapBC-1 complex in the transcriptional regulation of vapBC-1. PMID- 22427825 TI - Plasma heme oxygenase-1 concentration in relation to impaired glucose regulation in a non-diabetic Chinese population. AB - BACKGROUND: Our previous study has recently shown that plasma heme oxygenase-1 (HO-1), a stress-responsive protein, is elevated in individuals with type 2 diabetes. The current study aimed to examine the association between plasma HO-1 concentration and impaired glucose regulation (IGR) in non-diabetic individuals. METHODS: We conducted a case-control study including a total of 865 subjects (262 IGR individuals and 603 healthy controls) in a Chinese population. Basic characteristics were collected by questionnaire and standardized anthropometric measurements. Plasma HO-1 concentration was determined by ELISA. RESULTS: Plasma HO-1 concentration was significantly increased in IGR individuals compared with healthy controls (1.34 (0.81-2.29) ng/ml vs 0.98 (0.56-1.55) ng/ml, P<0.001). After adjustment for age, sex, and BMI, the ORs for IGR in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 3.42 (95% CI 2.11 5.54; P for trend <0.001). The trend remained significant even after additional adjustment for smoking, alcohol drinking, hypertension, family history of diabetes, lipid profiles and C-reactive protein. In the receiver-operating characteristic curve analysis, addition of plasma HO-1 concentration to a model with known risk factors yielded significantly improved discriminative value for IGR (area under the curves 0.75 (95% CI 0.71-0.78) vs. 0.72 (95% CI 0.69-0.76); P for difference = 0.026). CONCLUSIONS: Elevated plasma HO-1 concentration is significantly associated with increased ORs for IGR. However, its clinical utility should be validated in further studies, especially in prospective cohort studies. PMID- 22427826 TI - Robust framework for PET image reconstruction incorporating system and measurement uncertainties. AB - In Positron Emission Tomography (PET), an optimal estimate of the radioactivity concentration is obtained from the measured emission data under certain criteria. So far, all the well-known statistical reconstruction algorithms require exactly known system probability matrix a priori, and the quality of such system model largely determines the quality of the reconstructed images. In this paper, we propose an algorithm for PET image reconstruction for the real world case where the PET system model is subject to uncertainties. The method counts PET reconstruction as a regularization problem and the image estimation is achieved by means of an uncertainty weighted least squares framework. The performance of our work is evaluated with the Shepp-Logan simulated and real phantom data, which demonstrates significant improvements in image quality over the least squares reconstruction efforts. PMID- 22427827 TI - Non-enzymatic decomposition of collagen fibers by a biglycan antibody and a plausible mechanism for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. In RA cases, the immune response to inflammation causes synovial fibroblasts, monocytes and macrophages to produce cytokines and secrete matrix remodeling enzymes, whereas B cells are stimulated to produce immunoglobulins. The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo. PMID- 22427828 TI - Efficacy of vaccination against HPV infections to prevent cervical cancer in France: present assessment and pathways to improve vaccination policies. AB - BACKGROUND: Seventy percent of sexually active individuals will be infected with Human Papillomavirus (HPV) during their lifetime. These infections are incriminated for almost all cervical cancers. In France, 3,068 new cases of cervical cancer and 1,067 deaths from cervical cancer occurred in 2005. Two vaccines against HPV infections are currently available and vaccination policies aim to decrease the incidence of HPV infections and of cervical cancers. In France, vaccine coverage has been reported to be low. METHODS: We developed a dynamic model for the heterosexual transmission of Human Papillomavirus types 16 and 18, which are covered by available vaccines. A deterministic model was used with stratification on gender, age and sexual behavior. Immunity obtained from vaccination was taken into account. The model was calibrated using French data of cervical cancer incidence. RESULTS: In view of current vaccine coverage and screening, we expected a 32% and 83% reduction in the incidence of cervical cancers due to HPV 16/18, after 20 years and 50 years of vaccine introduction respectively. Vaccine coverage and screening rates were assumed to be constant. However, increasing vaccine coverage in women or vaccinating girls before 14 showed a better impact on cervical cancer incidence. On the other hand, performing vaccination in men improves the effect on cervical cancer incidence only moderately, compared to strategies in females only. CONCLUSION: While current vaccination policies may significantly decrease cervical cancer incidence, other supplementary strategies in females could be considered in order to improve vaccination efficacy. PMID- 22427829 TI - The homeodomain protein defective proventriculus is essential for male accessory gland development to enhance fecundity in Drosophila. AB - The Drosophila male accessory gland has functions similar to those of the mammalian prostate gland and the seminal vesicle, and secretes accessory gland proteins into the seminal fluid. Each of the two lobes of the accessory gland is composed of two types of binucleate cell: about 1,000 main cells and 40 secondary cells. A well-known accessory gland protein, sex peptide, is secreted from the main cells and induces female postmating response to increase progeny production, whereas little is known about physiological significance of the secondary cells. The homeodomain transcriptional repressor Defective proventriculus (Dve) is strongly expressed in adult secondary cells, and its mutation resulted in loss of secondary cells, mononucleation of main cells, and reduced size of the accessory gland. dve mutant males had low fecundity despite the presence of sex peptide, and failed to induce the female postmating responses of increased egg laying and reduced sexual receptivity. RNAi-mediated dve knockdown males also had low fecundity with normally binucleate main cells. We provide the first evidence that secondary cells are crucial for male fecundity, and also that Dve activity is required for survival of the secondary cells. These findings provide new insights into a mechanism of fertility/fecundity. PMID- 22427830 TI - Phylogeography of Sardinian cave salamanders (genus Hydromantes) is mainly determined by geomorphology. AB - Detecting the factors that determine the interruption of gene flow between populations is key to understanding how speciation occurs. In this context, caves are an excellent system for studying processes of colonization, differentiation and speciation, since they represent discrete geographical units often with known geological histories. Here, we asked whether discontinuous calcareous areas and cave systems represent major barriers to gene flow within and among the five species of Sardinian cave salamanders (genus Hydromantes) and whether intraspecific genetic structure parallels geographic distance within and among caves. We generated mitochondrial cytochrome b gene sequences from 184 individuals representing 48 populations, and used a Bayesian phylogeographic approach to infer possible areas of cladogenesis for these species and reconstruct historical and current dispersal routes among distinct populations. Our results show deep genetic divergence within and among all Sardinian cave salamander species, which can mostly be attributed to the effects of mountains and discontinuities in major calcareous areas and cave systems acting as barriers to gene flow. While these salamander species can also occur outside caves, our results indicate that there is a very poor dispersal of these species between separate cave systems. PMID- 22427831 TI - Robust and fast whole brain mapping of the RF transmit field B1 at 7T. AB - In-vivo whole brain mapping of the radio frequency transmit field B(1) (+) is a key aspect of recent method developments in ultra high field MRI. We present an optimized method for fast and robust in-vivo whole-brain B(1) (+) mapping at 7T. The method is based on the acquisition of stimulated and spin echo 3D EPI images and was originally developed at 3T. We further optimized the method for use at 7T. Our optimization significantly improved the robustness of the method against large B(1) (+) deviations and off-resonance effects present at 7T. The mean accuracy and precision of the optimized method across the brain was high with a bias less than 2.6 percent unit (p.u.) and random error less than 0.7 p.u. respectively. PMID- 22427832 TI - Menopausal status modifies breast cancer risk associated with the myeloperoxidase (MPO) G463A polymorphism in Caucasian women: a meta-analysis. AB - BACKGROUND: Breast cancer susceptibility may be modulated partly through polymorphisms in oxidative enzymes, one of which is myeloperoxidase (MPO). Association of the low transcription activity variant allele A in the G463A polymorphism has been investigated for its association with breast cancer risk, considering the modifying effects of menopausal status and antioxidant intake levels of cases and controls. METHODOLOGY/PRINCIPAL FINDINGS: To obtain a more precise estimate of association using the odds ratio (OR), we performed a meta analysis of 2,975 cases and 3,427 controls from three published articles of Caucasian populations living in the United States. Heterogeneity among studies was tested and sensitivity analysis was applied. The lower transcriptional activity AA genotype of MPO in the pre-menopausal population showed significantly reduced risk (OR 0.56-0.57, p = 0.03) in contrast to their post-menopausal counterparts which showed non-significant increased risk (OR 1.14; p = 0.34 0.36). High intake of antioxidants (OR 0.67-0.86, p = 0.04-0.05) and carotenoids (OR 0.68-0.86, p = 0.03-0.05) conferred significant protection in the women. Stratified by menopausal status, this effect was observed in pre-menopausal women especially those whose antioxidant intake was high (OR 0.42-0.69, p = 0.04). In post-menopausal women, effect of low intake elicited susceptibility (OR 1.19 1.67, p = 0.07-0.17) to breast cancer. CONCLUSIONS/SIGNIFICANCE: Based on a homogeneous Caucasian population, the MPO G463A polymorphism places post menopausal women at risk for breast cancer, where this effect is modified by diet. PMID- 22427833 TI - A novel serpin with antithrombin-like activity in Branchiostoma japonicum: implications for the presence of a primitive coagulation system. AB - Serine protease inhibitors, or serpins, are a group of widely distributed proteins with similar structures that use conformational change to inhibit proteases. Antithrombin (AT) is a member of the serine protease inhibitor superfamily and a major coagulation inhibitor in all vertebrates, but its evolutionary origin remains elusive. In this study we isolated for the first time a cDNA encoding an antithrombin homolog, BjATl, from the protochordate Branchiostoma japonicum. The deduced protein BjATl consisted of 338 amino acids sharing 36.7% to 41.1% identity to known vertebrate ATs. BjATl contains a potential N-linked glycosylation site, two potential heparin binding sites and the reactive center loop with the absolutely conserved sequence Gly-Arg-Ser; all of these are features characteristic of ATs. All three phylogenetic trees constructed using Neighbor-Joining, Maximum-Likelihood and Bayesian-Inference methods also placed BjATl together with ATs. Moreover, BjATl expressed in yeast cells was able to inhibit bovine thrombin activity by forming a SDS-stable BjATl thrombin complex. It also displays a concentration-dependent inhibition of thrombin that is accelerated by heparin. Furthermore, BjATl was predominantly expressed in the hepatic caecum and hind-gut, agreeing with the expression pattern of AT in mammalian species. All these data clearly demonstrate that BjATl is an ortholog of vertebrate ATs, suggesting that a primitive coagulation system emerged in the protochordate. PMID- 22427834 TI - Immune responses in pigs vaccinated with adjuvanted and non-adjuvanted A(H1N1)pdm/09 influenza vaccines used in human immunization programmes. AB - Following the emergence and global spread of a novel H1N1 influenza virus in 2009, two A(H1N1)pdm/09 influenza vaccines produced from the A/California/07/09 H1N1 strain were selected and used for the national immunisation programme in the United Kingdom: an adjuvanted split virion vaccine and a non-adjuvanted whole virion vaccine. In this study, we assessed the immune responses generated in inbred large white pigs (Babraham line) following vaccination with these vaccines and after challenge with A(H1N1)pdm/09 virus three months post-vaccination. Both vaccines elicited strong antibody responses, which included high levels of influenza-specific IgG1 and haemagglutination inhibition titres to H1 virus. Immunisation with the adjuvanted split vaccine induced significantly higher interferon gamma production, increased frequency of interferon gamma-producing cells and proliferation of CD4(-)CD8(+) (cytotoxic) and CD4(+)CD8(+) (helper) T cells, after in vitro re-stimulation. Despite significant differences in the magnitude and breadth of immune responses in the two vaccinated and mock treated groups, similar quantities of viral RNA were detected from the nasal cavity in all pigs after live virus challenge. The present study provides support for the use of the pig as a valid experimental model for influenza infections in humans, including the assessment of protective efficacy of therapeutic interventions. PMID- 22427835 TI - Regular patterns for proteome-wide distribution of protein abundance across species. AB - A proteome of the bio-entity, including cell, tissue, organ, and organism, consists of proteins of diverse abundance. The principle that determines the abundance of different proteins in a proteome is of fundamental significance for an understanding of the building blocks of the bio-entity. Here, we report three regular patterns in the proteome-wide distribution of protein abundance across species such as human, mouse, fly, worm, yeast, and bacteria: in most cases, protein abundance is positively correlated with the protein's origination time or sequence conservation during evolution; it is negatively correlated with the protein's domain number and positively correlated with domain coverage in protein structure, and the correlations became stronger during the course of evolution; protein abundance can be further stratified by the function of the protein, whereby proteins that act on material conversion and transportation (mass category) are more abundant than those that act on information modulation (information category). Thus, protein abundance is intrinsically related to the protein's inherent characters of evolution, structure, and function. PMID- 22427836 TI - Time to task failure and motor cortical activity depend on the type of feedback in visuomotor tasks. AB - The present study aimed to elucidate whether the type of feedback influences the performance and the motor cortical activity when executing identical visuomotor tasks. For this purpose, time to task failure was measured during position- and force-controlled muscular contractions. Subjects received either visual feedback about the force produced by pressing a force transducer or about the actual position between thumb and index finger. Participants were instructed to either match the force level of 30% MVC or the finger position corresponding to the thumb and index finger angle at this contraction intensity. Subjects demonstrated a shorter time to task failure when they were provided with feedback about their joint position (11.5 +/- 6.2 min) instead of force feedback (19.2 +/- 12.8 min; P = 0.01). To test differences in motor cortical activity between position- and force-controlled contractions, subthreshold transcranial magnetic stimulation (subTMS) was applied while executing submaximal (20% MVC) contractions. SubTMS resulted in a suppression of the first dorsal interosseus muscle (FDI) EMG in both tasks. However, the mean suppression for the position-controlled task was significantly greater (18.6 +/- 9.4% vs. 13.3 +/- 7.5%; P = 0.025) and lasted longer (13.9 +/- 7.5 ms vs. 9.3 +/- 4.3 ms; P = 0.024) compared to the force controlled task. The FDI background EMG obtained without stimulation was comparable in all conditions. The present results demonstrate that the presentation of different feedback modalities influences the time to task failure as well as the cortical activity. As only the feedback was altered but not the mechanics of the task, the present results add to the body of evidence that suggests that the central nervous system processes force and position information in different ways. PMID- 22427837 TI - Fast retinal vessel detection and measurement using wavelets and edge location refinement. AB - The relationship between changes in retinal vessel morphology and the onset and progression of diseases such as diabetes, hypertension and retinopathy of prematurity (ROP) has been the subject of several large scale clinical studies. However, the difficulty of quantifying changes in retinal vessels in a sufficiently fast, accurate and repeatable manner has restricted the application of the insights gleaned from these studies to clinical practice. This paper presents a novel algorithm for the efficient detection and measurement of retinal vessels, which is general enough that it can be applied to both low and high resolution fundus photographs and fluorescein angiograms upon the adjustment of only a few intuitive parameters. Firstly, we describe the simple vessel segmentation strategy, formulated in the language of wavelets, that is used for fast vessel detection. When validated using a publicly available database of retinal images, this segmentation achieves a true positive rate of 70.27%, false positive rate of 2.83%, and accuracy score of 0.9371. Vessel edges are then more precisely localised using image profiles computed perpendicularly across a spline fit of each detected vessel centreline, so that both local and global changes in vessel diameter can be readily quantified. Using a second image database, we show that the diameters output by our algorithm display good agreement with the manual measurements made by three independent observers. We conclude that the improved speed and generality offered by our algorithm are achieved without sacrificing accuracy. The algorithm is implemented in MATLAB along with a graphical user interface, and we have made the source code freely available. PMID- 22427838 TI - Invariant natural killer T cell agonist modulates experimental focal and segmental glomerulosclerosis. AB - A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis (FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro Th1 activity on invariant Natural Killer T (iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin(ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1alpha, IL-1beta, IL-17, TNF-alpha, and chemokines, such as RANTES and eotaxin. In addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-beta analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-beta could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-beta, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-beta through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. In conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM induced glomerulosclerosis and may provide an alternative approach to disease management. PMID- 22427839 TI - Identification of a new rhoptry neck complex RON9/RON10 in the Apicomplexa parasite Toxoplasma gondii. AB - Apicomplexan parasites secrete and inject into the host cell the content of specialized secretory organelles called rhoptries, which take part into critical processes such as host cell invasion and modulation of the host cell immune response. The rhoptries are structurally and functionally divided into two compartments. The apical duct contains rhoptry neck (RON) proteins that are conserved in Apicomplexa and are involved in formation of the moving junction (MJ) driving parasite invasion. The posterior bulb contains rhoptry proteins (ROPs) unique to an individual genus and, once injected in the host cell act as effector proteins to co-opt host processes and modulate parasite growth and virulence. We describe here two new RON proteins of Toxoplasma gondii, RON9 and RON10, which form a high molecular mass complex. In contrast to the other RONs described to date, this complex was not detected at the MJ during invasion and therefore was not associated to the MJ complex RON2/4/5/8. Disruptions of either RON9 or RON10 gene leads to the retention of the partner in the ER followed by subsequent degradation, suggesting that the RON9/RON10 complex formation is required for proper sorting to the rhoptries. Finally, we show that the absence of RON9/RON10 has no significant impact on the morphology of rhoptry, on the invasion and growth in fibroblasts in vitro or on virulence in vivo. The conservation of RON9 and RON10 in Coccidia and Cryptosporidia suggests a specific relation with development in intestinal epithelial cells. PMID- 22427840 TI - beta-sheet topology prediction with high precision and recall for beta and mixed alpha/beta proteins. AB - The prediction of the correct beta-sheet topology for pure beta and mixed alpha/beta proteins is a critical intermediate step toward the three dimensional protein structure prediction. The predicted beta sheet topology provides distance constraints between sequentially separated residues, which reduces the three dimensional search space for a protein structure prediction algorithm. Here, we present a novel mixed integer linear optimization based framework for the prediction of beta-sheet topology in beta and mixed alpha/beta proteins. The objective is to maximize the total strand-to-strand contact potential of the protein. A large number of physical constraints are applied to provide biologically meaningful topology results. The formulation permits the creation of a rank-ordered list of preferred beta-sheet arrangements. Finally, the generated topologies are re-ranked using a fully atomistic approach involving torsion angle dynamics and clustering. For a large, non-redundant data set of 2102 beta and mixed alpha/beta proteins with at least 3 strands taken from the PDB, the proposed approach provides the top 5 solutions with average precision and recall greater than 78%. Consistent results are obtained in the beta-sheet topology prediction for blind targets provided during the CASP8 and CASP9 experiments, as well as for actual and predicted secondary structures. The beta-sheet topology prediction algorithm, BeST, is available to the scientific community at http://selene.princeton.edu/BeST/. PMID- 22427841 TI - Chronic allergic inflammation causes vascular remodeling and pulmonary hypertension in BMPR2 hypomorph and wild-type mice. AB - Loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene have been identified in patients with heritable pulmonary arterial hypertension (PAH); however, disease penetrance is low, suggesting additional factors play a role. Inflammation is associated with PAH and vascular remodeling, but whether allergic inflammation triggers vascular remodeling in individuals with BMPR2 mutations is unknown. Our goal was to determine if chronic allergic inflammation would induce more severe vascular remodeling and PAH in mice with reduced BMPR-II signaling. Groups of Bmpr2 hypomorph and wild-type (WT) Balb/c/Byj mice were exposed to house dust mite (HDM) allergen, intranasally for 7 or 20 weeks to generate a model of chronic inflammation. HDM exposure induced similar inflammatory cell counts in all groups compared to controls. Muscularization of pulmonary arterioles and arterial wall thickness were increased after 7 weeks HDM, more severe at 20 weeks, but similar in both groups. Right ventricular systolic pressure (RVSP) was measured by direct cardiac catheterization to assess PAH. RVSP was similarly increased in both HDM exposed groups after 20 weeks compared to controls, but not after 7 weeks. Airway hyperreactivity (AHR) to methacholine was also assessed and interestingly, at 20 weeks, was more severe in HDM exposed Bmpr2 hypomorph mice versus WT. We conclude that chronic allergic inflammation caused PAH and while the severity was mild and similar between WT and Bmpr2 hypomorph mice, AHR was enhanced with reduced BMPR II signaling. These data suggest that vascular remodeling and PAH resulting from chronic allergic inflammation occurs independently of BMPR-II pathway alterations. PMID- 22427842 TI - Complete mitochondrial genomes reveal neolithic expansion into Europe. AB - The Neolithic transition from hunting and gathering to farming and cattle breeding marks one of the most drastic cultural changes in European prehistory. Short stretches of ancient mitochondrial DNA (mtDNA) from skeletons of pre Neolithic hunter-gatherers as well as early Neolithic farmers support the demic diffusion model where a migration of early farmers from the Near East and a replacement of pre-Neolithic hunter-gatherers are largely responsible for cultural innovation and changes in subsistence strategies during the Neolithic revolution in Europe. In order to test if a signal of population expansion is still present in modern European mitochondrial DNA, we analyzed a comprehensive dataset of 1,151 complete mtDNAs from present-day Europeans. Relying upon ancient DNA data from previous investigations, we identified mtDNA haplogroups that are typical for early farmers and hunter-gatherers, namely H and U respectively. Bayesian skyline coalescence estimates were then used on subsets of complete mtDNAs from modern populations to look for signals of past population expansions. Our analyses revealed a population expansion between 15,000 and 10,000 years before present (YBP) in mtDNAs typical for hunters and gatherers, with a decline between 10,000 and 5,000 YBP. These corresponded to an analogous population increase approximately 9,000 YBP for mtDNAs typical of early farmers. The observed changes over time suggest that the spread of agriculture in Europe involved the expansion of farming populations into Europe followed by the eventual assimilation of resident hunter-gatherers. Our data show that contemporary mtDNA datasets can be used to study ancient population history if only limited ancient genetic data is available. PMID- 22427843 TI - Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating pro-inflammatory pathways. AB - Prostate cancer is one of the leading causes of cancer death among men worldwide. In this study, using transgenic adenocarcinoma of mouse prostate (TRAMP) mice, the effect of diet enriched with 1% w/w ursolic acid (UA) was investigated to evaluate the stage specific chemopreventive activity against prostate cancer. We found that TRAMP mice fed with UA diet for 8 weeks (weeks 4 to 12) delayed formation of prostate intraepithelial neoplasia (PIN). Similarly, mice fed with UA diet for 6 weeks (weeks 12 to 18) inhibited progression of PIN to adenocarcinoma as determined by hematoxylin and eosin staining. Finally, TRAMP mice fed with UA diet for 12 weeks (weeks 24 to 36) demonstrated markedly reduced tumor growth without any significant effects on total body weight and prolonged overall survival. With respect to the molecular mechanism, we found that UA down regulated activation of various pro-inflammatory mediators including, NF-kappaB, STAT3, AKT and IKKalpha/beta phosphorylation in the dorsolateral prostate (DLP) tissues that correlated with the reduction in serum levels of TNF-alpha and IL-6. In addition, UA significantly down-regulated the expression levels of cyclin D1 and COX-2 but up-regulated the levels of caspase-3 as revealed by immunohistochemical analysis of tumor tissue sections. Finally, UA was detected in serum samples obtained from various mice groups fed with enriched diet in nanogram quantity indicating that it is well absorbed in the GI tract. Overall, our findings provide strong evidence that UA can be an excellent agent for both the prevention and treatment of prostate cancer. PMID- 22427844 TI - Time distribution of the onset of chest pain in subjects with acute ST-elevation myocardial infarction: an eight-year, single-center study in China. AB - OBJECTIVE: The objective of this study was to explore the time distribution patterns of the onset of chest pain in subjects with acute ST-elevation myocardial infarction in a Chinese population. METHODS: A total of 1467 patients with acute ST-elevation myocardial infarction were enrolled from 2003 to 2010. The hourly, daily, monthly, seasonal and day-of-week fluctuations in the prevalence of acute ST-elevation myocardial infarction were analyzed. RESULTS: A peak was found between the morning hours of 07:31 and 08:30. A second peak was observed between 14:31 and 15:30, and a third peak was found between 23:31 and 00:30 (p<0.001). The monthly maximum was recorded in November and the minimum was in April (p<0.001). The number of daily cases was greatest in autumn and lowest in the spring (p = 0.001). Day-of-the-week variations of ST-elevation acute myocardial infarction were not found, except in patients more than 75-years-old. CONCLUSIONS: Periodic variations in the frequency of ST-elevation acute myocardial infarction in Chinese patients showed significant differences with regard to diurnal, monthly and seasonal patterns. The exact mechanisms underlying these circadian variations require further study. PMID- 22427845 TI - Defects in the outer limiting membrane are associated with rosette development in the Nrl-/- retina. AB - The neural retinal leucine zipper (Nrl) knockout mouse is a widely used model to study cone photoreceptor development, physiology, and molecular biology in the absence of rods. In the Nrl(-/-) retina, rods are converted into functional cone like cells. The Nrl(-/-) retina is characterized by large undulations of the outer nuclear layer (ONL) commonly known as rosettes. Here we explore the mechanism of rosette development in the Nrl(-/-) retina. We report that rosettes first appear at postnatal day (P)8, and that the structure of nascent rosettes is morphologically distinct from what is seen in the adult retina. The lumen of these nascent rosettes contains a population of aberrant cells protruding into the subretinal space that induce infolding of the ONL. Morphologically adult rosettes do not contain any cell bodies and are first detected at P15. The cells found in nascent rosettes are photoreceptors in origin but lack inner and outer segments. We show that the adherens junctions between photoreceptors and Muller glia which comprise the retinal outer limiting membrane (OLM) are not uniformly formed in the Nrl(-/-) retina and thus allow protrusion of a population of developing photoreceptors into the subretinal space where their maturation becomes delayed. These data suggest that the rosettes of the Nrl(-/-) retina arise due to defects in the OLM and delayed maturation of a subset of photoreceptors, and that rods may play an important role in the proper formation of the OLM. PMID- 22427846 TI - Capillary electrophoresis separation of protein composition of gamma-irradiated food pathogens Listeria monocytogenes and Staphylococcus aureus. AB - BACKGROUND: A capillary electrophoresis method using UV detection was developed to analyse protein composition of the lysates of two foodborne pathogens, Listeria monocytogenes and Staphylococcus aureus which were previously treated at different irradiation doses. METHODOLOGY AND PRINCIPAL FINDINGS: Bacterial samples were gamma-irradiated at different doses to produce damage cells, to kill cells and to provoke viable but non culturable cells (VBNC) in order to evaluate the respective expression of stress proteins. In Listeria monocytogenes, two proteins (MW of 70.2 and 85.4 kDa) were significantly changed (P <= 0.05) at different doses of irradiation. In Staphyloccocus aureus, one protein (50 S ribosomal protein) with the MW of 16.3 kDa was significantly decreased at a low dose of irradiation treatment and the other protein (transcriptional regulator CtsR) with the MW of 17.7 kDa was increased significantly (P <= 0.05) at all doses of irradiation treatment compared to control. CONCLUSION: Expression of two proteins from the acyltransferase family in Listeria monocytogenes was statistically changed during irradiation treatment (P <= 0.05). In Staphylococcus aureus, expression of the 50 S ribosomal protein decreased and the transcriptional regulator CtsR espression increased significantly (P <= 0.05) following irradiation treatment. These expressed proteins do not belong to the well-known heat shock proteins family of Listeria monocytogenes and Staphylococcus aureus. The research further confirmed that capillary electrophoresis is a useful method to separate and analyse proteins expression which may be related to the resistance or sensitivity of food pathogens to gamma irradiation. PMID- 22427847 TI - Visual feature integration indicated by pHase-locked frontal-parietal EEG signals. AB - The capacity to integrate multiple sources of information is a prerequisite for complex cognitive ability, such as finding a target uniquely identifiable by the conjunction of two or more features. Recent studies identified greater frontal parietal synchrony during conjunctive than non-conjunctive (feature) search. Whether this difference also reflects greater information integration, rather than just differences in cognitive strategy (e.g., top-down versus bottom-up control of attention), or task difficulty is uncertain. Here, we examine the first possibility by parametrically varying the number of integrated sources from one to three and measuring phase-locking values (PLV) of frontal-parietal EEG electrode signals, as indicators of synchrony. Linear regressions, under hierarchical false-discovery rate control, indicated significant positive slopes for number of sources on PLV in the 30-38 Hz, 175-250 ms post-stimulus frequency time band for pairs in the sagittal plane (i.e., F3-P3, Fz-Pz, F4-P4), after equating conditions for behavioural performance (to exclude effects due to task difficulty). No such effects were observed for pairs in the transverse plane (i.e., F3-F4, C3-C4, P3-P4). These results provide support for the idea that anterior-posterior phase-locking in the lower gamma-band mediates integration of visual information. They also provide a potential window into cognitive development, seen as developing the capacity to integrate more sources of information. PMID- 22427848 TI - Specific versus non-specific immune responses in an invertebrate species evidenced by a comparative de novo sequencing study. AB - Our present understanding of the functioning and evolutionary history of invertebrate innate immunity derives mostly from studies on a few model species belonging to ecdysozoa. In particular, the characterization of signaling pathways dedicated to specific responses towards fungi and Gram-positive or Gram-negative bacteria in Drosophila melanogaster challenged our original view of a non specific immunity in invertebrates. However, much remains to be elucidated from lophotrochozoan species. To investigate the global specificity of the immune response in the fresh-water snail Biomphalaria glabrata, we used massive Illumina sequencing of 5'-end cDNAs to compare expression profiles after challenge by Gram positive or Gram-negative bacteria or after a yeast challenge. 5'-end cDNA sequencing of the libraries yielded over 12 millions high quality reads. To link these short reads to expressed genes, we prepared a reference transcriptomic database through automatic assembly and annotation of the 758,510 redundant sequences (ESTs, mRNAs) of B. glabrata available in public databases. Computational analysis of Illumina reads followed by multivariate analyses allowed identification of 1685 candidate transcripts differentially expressed after an immune challenge, with a two fold ratio between transcripts showing a challenge-specific expression versus a lower or non-specific differential expression. Differential expression has been validated using quantitative PCR for a subset of randomly selected candidates. Predicted functions of annotated candidates (approx. 700 unisequences) belonged to a large extend to similar functional categories or protein types. This work significantly expands upon previous gene discovery and expression studies on B. glabrata and suggests that responses to various pathogens may involve similar immune processes or signaling pathways but different genes belonging to multigenic families. These results raise the question of the importance of gene duplication and acquisition of paralog functional diversity in the evolution of specific invertebrate immune responses. PMID- 22427849 TI - Delayed mTOR inhibition with low dose of everolimus reduces TGFbeta expression, attenuates proteinuria and renal damage in the renal mass reduction model. AB - BACKGROUND: The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors are widely used in solid organ transplantation, but their effect on kidney disease progression is controversial. mTOR has emerged as one of the main pathways regulating cell growth, proliferation, differentiation, migration, and survival. The aim of this study was to analyze the effects of delayed inhibition of mTOR pathway with low dose of everolimus on progression of renal disease and TGFbeta expression in the 5/6 nephrectomy model in Wistar rats. METHODS: This study evaluated the effects of everolimus (0.3 mg/k/day) introduced 15 days after surgical procedure on renal function, proteinuria, renal histology and mechanisms of fibrosis and proliferation. RESULTS: Everolimus treated group (EveG) showed significantly less proteinuria and albuminuria, less glomerular and tubulointerstitial damage and fibrosis, fibroblast activation cell proliferation, when compared with control group (CG), even though the EveG remained with high blood pressure. Treatment with everolimus also diminished glomerular hypertrophy. Everolimus effectively inhibited the increase of mTOR developed in 5/6 nephrectomy animals, without changes in AKT mRNA or protein abundance, but with an increase in the pAKT/AKT ratio. Associated with this inhibition, everolimus blunted the increased expression of TGFbeta observed in the remnant kidney model. CONCLUSION: Delayed mTOR inhibition with low dose of everolimus significantly prevented progressive renal damage and protected the remnant kidney. mTOR and TGFbeta mRNA reduction can partially explain this anti fibrotic effect. mTOR can be a new target to attenuate the progression of chronic kidney disease even in those nephropathies of non-immunologic origin. PMID- 22427850 TI - The effect of maternal multiple micronutrient supplementation on cognition and mood during pregnancy and postpartum in Indonesia: a randomized trial. AB - Maternal caregiving capacity, which is affected in part by cognition and mood, is crucial for the health of mothers and infants. Few interventions aim to improve maternal and infant health through improving such capacity. Multiple micronutrient (MMN) supplementation may improve maternal cognition and mood, since micronutrients are essential for brain function. We assessed mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind cluster-randomized trial in Indonesia comparing MMN supplementation to iron and folic acid (IFA) during pregnancy and until three months postpartum. We adapted a set of well-studied tests of cognition, motor dexterity, and mood to the local context and administered them to a random sample of 640 SUMMIT participants after an average of 25 weeks (SD = 9) of supplementation. Analysis was by intention to treat. Controlling for maternal age, education, and socio-economic status, MMN resulted in a benefit of 0.12 SD on overall cognition, compared to IFA (95%CI 0.03-0.22, p = .010), and a benefit of 0.18 SD on reading efficiency (95%CI 0.02-0.35, p = .031). Both effects were found particularly in anemic (hemoglobin<110 g/L; overall cognition: B = 0.20, 0.00-0.41, p = .055; reading: B = 0.40, 0.02-0.77, p = .039) and undernourished (mid-upper arm circumference<23.5 cm; overall cognition: B = 0.33, 0.07-0.59, p = .020; reading: B = 0.65, 0.19-1.12, p = .007) mothers. The benefit of MMN on overall cognition was equivalent to the benefit of one year of education for all mothers, to two years of education for anemic mothers, and to three years of education for undernourished mothers. No effects were found on maternal motor dexterity or mood. This is the first study demonstrating an improvement in maternal cognition with MMN supplementation. This improvement may increase the quality of care mothers provide for their infants, potentially partly mediating effects of maternal MMN supplementation on infant health and survival. The study is registered as an International Standard Randomized Controlled Trial, number ISRCTN34151616. http://www.controlled-trials.com/ISRCTN34151616. PMID- 22427851 TI - An alternative theoretical approach to escape decision-making: the role of visual cues. AB - Escape enables prey to avoid an approaching predator. The escape decision-making process has traditionally been interpreted using theoretical models that consider ultimate explanations based on the cost/benefit paradigm. Ultimate approaches, however, suffer from inseparable extra-assumptions due to an inability to accurately parameterize the model's variables and their interactive relationships. In this study, we propose a mathematical model that uses intensity of predator-mediated visual stimuli as a basic cue for the escape response. We consider looming stimuli (i.e. expanding retinal image of the moving predator) as a cue to flight initiation distance (FID; distance at which escape begins) of incubating Mallards (Anas platyrhynchos). We then examine the relationship between FID, vegetation cover and directness of predator trajectory, and fit the resultant model to experimental data. As predicted by the model, vegetation concealment and directness of predator trajectory interact, with FID decreasing with increased concealment during a direct approach toward prey, but not during a tangential approach. Thus, we show that a simple proximate expectation, which involves only visual processing of a moving predator, may explain interactive effects of environmental and predator-induced variables on an escape response. We assume that our proximate approach, which offers a plausible and parsimonious explanation for variation in FID, may serve as an evolutionary background for traditional, ultimate explanations and should be incorporated into interpretation of escape behavior. PMID- 22427852 TI - Large-scale brain networks in board game experts: insights from a domain-related task and task-free resting state. AB - Cognitive performance relies on the coordination of large-scale networks of brain regions that are not only temporally correlated during different tasks, but also networks that show highly correlated spontaneous activity during a task-free state. Both task-related and task-free network activity has been associated with individual differences in cognitive performance. Therefore, we aimed to examine the influence of cognitive expertise on four networks associated with cognitive task performance: the default mode network (DMN) and three other cognitive networks (central-executive network, dorsal attention network, and salience network). During fMRI scanning, fifteen grandmaster and master level Chinese chess players (GM/M) and fifteen novice players carried out a Chinese chess task and a task-free resting state. Modulations of network activity during task were assessed, as well as resting-state functional connectivity of those networks. Relative to novices, GM/Ms showed a broader task-induced deactivation of DMN in the chess problem-solving task, and intrinsic functional connectivity of DMN was increased with a connectivity pattern associated with the caudate nucleus in GM/Ms. The three other cognitive networks did not exhibit any difference in task evoked activation or intrinsic functional connectivity between the two groups. These findings demonstrate the effect of long-term learning and practice in cognitive expertise on large-scale brain networks, suggesting the important role of DMN deactivation in expert performance and enhanced functional integration of spontaneous activity within widely distributed DMN-caudate circuitry, which might better support high-level cognitive control of behavior. PMID- 22427853 TI - The differential proliferative ability of satellite cells in Lantang and Landrace pigs. AB - Here, for the first time, we evaluate the hypothesis that the proliferative abilities of satellite cells (SCs) isolated from Lantang (indigenous Chinese pigs) and Landrace pigs, which differ in muscle characteristics, are different. SCs were isolated from the longissimus dorsi muscle of neonatal Lantang and Landrace pigs. Proliferative ability was estimated by the count and proliferative activity of viable cells using a hemocytometer and MTT assay at different time points after seeding, respectively. Cell cycle information was detected by flow cytometry. Results showed that there was a greater (P<0.05) number of SCs in Lantang pigs compared with Landrace pigs after 72 h of culture. The percentage of cell population in S phase and G(2)/M phases in Lantang pigs were higher (P<0.05), while in G(0)/G(1) phase was lower (P<0.05) in comparison with the Landrace pigs. The mRNA abundances of MyoD, Myf5, myogenin and Pax7 in SCs from Lantang pigs were higher (P<0.05), while those of myostatin, Smad3 and genes in the mammalian target of rapamycin (mTOR) pathway (with the exception of 4EBP1) were lower (P<0.05) than the Landrace pigs. Protein levels of MyoD, myogenin, myostatin, S6K, phosphorylated mTOR and phosphorylated eIF4E were consistent with the corresponding mRNA abundance. Collectively, these findings suggested that SCs in the two breeds present different proliferative abilities, and the proliferative potential of SCs in Lantang pigs is higher than in Landrace pigs. PMID- 22427854 TI - Comparative tuberculosis (TB) prevention effectiveness in children of Bacillus Calmette-Guerin (BCG) vaccines from different sources, Kazakhstan. AB - BACKGROUND: Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guerin (BCG) in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia) or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. METHODS/FINDINGS: We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan), the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. LIMITATIONS: Potential limitations included considerations that 1) the methodology used was retrospective, 2) multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3) most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4) small variations in reported population TB burden could have affected relative risk of exposure for cohorts. CONCLUSIONS/SIGNIFICANCE: All three BCG vaccines evaluated were protective against TB, and prevention effectiveness varied by manufacturer. When setting national immunization policy, consideration should be given to prevention effectiveness of BCG preparations. PMID- 22427855 TI - In vitro characterization of a nineteenth-century therapy for smallpox. AB - In the nineteenth century, smallpox ravaged through the United States and Canada. At this time, a botanical preparation, derived from the carnivorous plant Sarracenia purpurea, was proclaimed as being a successful therapy for smallpox infections. The work described characterizes the antipoxvirus activity associated with this botanical extract against vaccinia virus, monkeypox virus and variola virus, the causative agent of smallpox. Our work demonstrates the in vitro characterization of Sarracenia purpurea as the first effective inhibitor of poxvirus replication at the level of early viral transcription. With the renewed threat of poxvirus-related infections, our results indicate Sarracenia purpurea may act as another defensive measure against Orthopoxvirus infections. PMID- 22427856 TI - CRIM1 complexes with beta-catenin and cadherins, stabilizes cell-cell junctions and is critical for neural morphogenesis. AB - In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1) is a single-pass (type 1) transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using CRIM1 antisense morpholino oligonucleotides resulted in a failure of neural development. The CRIM1 knockdown phenotype was, in some cases, mild and resulted in perturbed neural fold morphogenesis. In severely affected embryos there was a dramatic failure of cell adhesion in the neural plate and complete absence of neural structures subsequently. Investigation of the mechanism of CRIM1 function revealed that it can form complexes with beta-catenin and cadherins, albeit indirectly, via the cytosolic domain. Consistent with this, CRIM1 knockdown resulted in diminished levels of cadherins and beta-catenin in junctional complexes in the neural plate. We conclude that CRIM1 is critical for cell-cell adhesion during neural development because it is required for the function of cadherin-dependent junctions. PMID- 22427857 TI - Hypertension in sub-Saharan Africa: cross-sectional surveys in four rural and urban communities. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of adult mortality in low-income countries but data on the prevalence of cardiovascular risk factors such as hypertension are scarce, especially in sub-Saharan Africa (SSA). This study aims to assess the prevalence of hypertension and determinants of blood pressure in four SSA populations in rural Nigeria and Kenya, and urban Namibia and Tanzania. METHODS AND FINDINGS: We performed four cross-sectional household surveys in Kwara State, Nigeria; Nandi district, Kenya; Dar es Salaam, Tanzania and Greater Windhoek, Namibia, between 2009-2011. Representative population-based samples were drawn in Nigeria and Namibia. The Kenya and Tanzania study populations consisted of specific target groups. Within a final sample size of 5,500 households, 9,857 non-pregnant adults were eligible for analysis on hypertension. Of those, 7,568 respondents >= 18 years were included. The primary outcome measure was the prevalence of hypertension in each of the populations under study. The age-standardized prevalence of hypertension was 19.3% (95%CI:17.3-21.3) in rural Nigeria, 21.4% (19.8-23.0) in rural Kenya, 23.7% (21.3 26.2) in urban Tanzania, and 38.0% (35.9-40.1) in urban Namibia. In individuals with hypertension, the proportion of grade 2 (>= 160/100 mmHg) or grade 3 hypertension (>= 180/110 mmHg) ranged from 29.2% (Namibia) to 43.3% (Nigeria). Control of hypertension ranged from 2.6% in Kenya to 17.8% in Namibia. Obesity prevalence (BMI >= 30) ranged from 6.1% (Nigeria) to 17.4% (Tanzania) and together with age and gender, BMI independently predicted blood pressure level in all study populations. Diabetes prevalence ranged from 2.1% (Namibia) to 3.7% (Tanzania). CONCLUSION: Hypertension was the most frequently observed risk factor for CVD in both urban and rural communities in SSA and will contribute to the growing burden of CVD in SSA. Low levels of control of hypertension are alarming. Strengthening of health care systems in SSA to contain the emerging epidemic of CVD is urgently needed. PMID- 22427858 TI - Effects of anesthetic agents on brain blood oxygenation level revealed with ultra high field MRI. AB - During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2)* weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine xylazine, medetomidine). We showed that the brain/vessels contrast in T(2)* weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation. PMID- 22427859 TI - Interferon-gamma release assay performance in pulmonary and extrapulmonary tuberculosis. AB - BACKGROUND: The diagnosis of tuberculosis remains difficult. This study aimed to assess performance of interferon-gamma release assay (IGRA) in diagnosis of active tuberculosis (ATB) with pulmonary and extrapulmonary involvements, and to determine the diagnostic role of IGRA (T-SPOT.TB) and tuberculin skin test (TST) in BCG-vaccinated population. METHODS AND FINDINGS: Two hundred twenty-six ATB suspects were recruited and examined with T-SPOT.TB. Among them, fifty-two and seventy-six subjects were simultaneously tested by TST with 5TU or 1TU of purified protein derivative (PPD). The sensitivity of T-SPOT.TB was 94.7% (71/75), comparable in pulmonary and extrapulmonary disease groups (95.6% vs. 93.3%, P>0.05), while the specificity was 84.10% (90/107) but differed in two groups (69.2% vs. 88.9%, P = 0.02). Compared to T-SPOT.TB, TST with 5TU-PPD showed less sensitivity (92.3% vs. 56.4%) and specificity (84.6% vs. 61.5%) (both P<0.01); the sensitivity of TST with 1TU-PPD was 27.8%, and despite its specificity identical to T-SPOT.TB (both 82.8%) positive predictive value (PPV) was only 33.3%. By combining T-SPOT.TB with TST (1TU), the specificity rose to 95%, but the PPV stayed unchanged. CONCLUSIONS: IGRA could function as a powerful immunodiagnostic test to explore pulmonary and extrapulmonary TB, while TST failed to play a reliable or auxiliary role in identifying TB disease and infection in the BCG-vaccinated population. PMID- 22427860 TI - Simulation and mechanistic investigation of the arrhythmogenic role of the late sodium current in human heart failure. AB - Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na(+) current (I(NaL)) is relevant and is currently under investigation. In this study we examined the role of I(NaL) in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I(NaL). A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I(NaL) and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I(NaL) in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca(2+) transient. A mechanistic investigation of intracellular Na(+) accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na(+)/K(+) pump, the Na(+)/Ca(2+) exchanger and I(NaL). The results of the simulations also showed that in failing myocytes, the enhancement of I(NaL) increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I(NaL) prolong APD and alter Ca(2+) transient facilitating the development of early afterdepolarizations. An enhanced I(NaL) appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca(2+)](i) homeostasis of failing myocytes. PMID- 22427861 TI - Reproductive factors and serum uric acid levels in females from the general population: the KORA F4 study. AB - OBJECTIVE: Hyperuricemia is associated with an increased risk of metabolic and cardiovascular diseases. There are pronounced sex differences in the levels of uric acid. It is largely unknown whether or not reproductive parameters which induce hormonal changes are responsible for this. We examined if there are associations between reproductive parameters and uric acid levels in a female population-based sample. METHODS: In this cross-sectional analysis, data of 1530 women aged 32 to 81 years participating in the KORA F4 study, conducted between 2006 and 2008 in Southern Germany were used. Reproductive parameters were obtained by standardized interviews. Uric acid levels were tested by the uricase method. The whole study sample and stratified in pre- and postmenopausal women was analyzed. RESULTS: Menopausal status and earlier age at menarche were associated with higher serum uric acid levels (age-adjusted: p-values 0.003, <0.001 respectively; after multivariable adjustment, including BMI: p-values 0.002, 0.036). A history of oral contraceptive use showed an association with uric acid levels only after multivariable adjustment (p-value 0.009). Hot flushes showed an association with uric acid levels only after age-adjustment (p-value 0.038), but lost significance after adding other confounders. Other reproductive factors, including parity, current or ever use of hormone replacement therapy, current use of oral contraceptives, hysterectomy, bilateral oophorectomy, or depressive mood related to menopausal transition were not associated with uric acid levels. CONCLUSIONS: Postmenopausal status, earlier age at menarche and a history of oral contraceptive use were independently associated with higher serum uric acid concentrations in women from the general population. Further studies, especially longitudinal population-based studies investigating the relationship of female reproductive parameters with uric acid levels are necessary to confirm our findings. PMID- 22427862 TI - Toxoplasma gondii chromodomain protein 1 binds to heterochromatin and colocalises with centromeres and telomeres at the nuclear periphery. AB - BACKGROUND: Apicomplexan parasites are responsible for some of the most deadly parasitic diseases afflicting humans, including malaria and toxoplasmosis. These obligate intracellular parasites exhibit a complex life cycle and a coordinated cell cycle-dependant expression program. Their cell division is a coordinated multistep process. How this complex mechanism is organised remains poorly understood. METHODS AND FINDINGS: In this study, we provide evidence for a link between heterochromatin, cell division and the compartmentalisation of the nucleus in Toxoplasma gondii. We characterised a T. gondii chromodomain containing protein (named TgChromo1) that specifically binds to heterochromatin. Using ChIP-on-chip on a genome-wide scale, we report TgChromo1 enrichment at the peri-centromeric chromatin. In addition, we demonstrate that TgChromo1 is cell cycle regulated and co-localised with markers of the centrocone. Through the loci specific FISH technique for T. gondii, we confirmed that TgChromo1 occupies the same nuclear localisation as the peri-centromeric sequences. CONCLUSION: We propose that TgChromo1 may play a role in the sequestration of chromosomes at the nuclear periphery and in the process of T. gondii cell division. PMID- 22427863 TI - Glucuronidated quercetin lowers blood pressure in spontaneously hypertensive rats via deconjugation. AB - BACKGROUND: Chronic oral quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, because it is rapidly metabolized into conjugated, mostly inactive, metabolites. The aim of the study is to analyze whether deconjugation of these metabolites is involved in the blood pressure lowering effect of quercetin. METHODOLOGY/PRINCIPAL FINDINGS: We have analyzed the effects on blood pressure and vascular function in vitro of the conjugated metabolites of quercetin (quercetin-3-glucuronide, Q3GA; isorhamnetin-3-glucuronide, I3GA; and quercetin-3'-sulfate, Q3'S) in spontaneously hypertensive rats (SHR). Q3GA and I3GA (1 mg/kg i.v.), but not Q3'S, progressively reduced mean blood pressure (MBP), measured in conscious SHR. The hypotensive effect of Q3GA was abolished in SHR treated with the specific inhibitor of beta-glucuronidase, saccharic acid 1,4 lactone (SAL, 10 mg/ml). In mesenteric arteries, unlike quercetin, Q3GA had no inhibitory effect in the contractile response to phenylephrine after 30 min of incubation. However, after 1 hour of incubation Q3GA strongly reduced this contractile response and this effect was prevented by SAL. Oral administration of quercetin (10 mg/Kg) induced a progressive decrease in MBP, which was also suppressed by SAL. CONCLUSIONS: Conjugated metabolites are involved in the in vivo antihypertensive effect of quercetin, acting as molecules for the plasmatic transport of quercetin to the target tissues. Quercetin released from its glucuronidated metabolites could be responsible for its vasorelaxant and hypotensive effect. PMID- 22427864 TI - Physiological state influences the social interactions of two honeybee nest mates. AB - Physiological state profoundly influences the expression of the behaviour of individuals and can affect social interactions between animals. How physiological state influences food sharing and social behaviour in social insects is poorly understood. Here, we examined the social interactions and food sharing behaviour of honeybees with the aim of developing the honeybee as a model for understanding how an individual's state influences its social interactions. The state of individual honeybees was manipulated by either starving donor bees or feeding them sucrose or low doses of ethanol to examine how a change in hunger or inebriation state affected the social behaviours exhibited by two closely-related nestmates. Using a lab-based assay for measuring individual motor behaviour and social behaviour, we found that behaviours such as antennation, willingness to engage in trophallaxis, and mandible opening were affected by both hunger and ethanol intoxication. Inebriated bees were more likely to exhibit mandible opening, which may represent a form of aggression, than bees fed sucrose alone. However, intoxicated bees were as willing to engage in trophallaxis as the sucrose-fed bees. The effects of ethanol on social behaviors were dose-dependent, with higher doses of ethanol producing larger effects on behaviour. Hungry donor bees, on the other hand, were more likely to engage in begging for food and less likely to antennate and to display mandible opening. We also found that when nestmates received food from donors previously fed ethanol, they began to display evidence of inebriation, indicating that ethanol can be retained in the crop for several hours and that it can be transferred between honeybee nestmates during trophallaxis. PMID- 22427865 TI - A novel betaproteobacterial agent of gill epitheliocystis in seawater farmed Atlantic salmon (Salmo salar). AB - Epitheliocystis, a disease characterised by cytoplasmic bacterial inclusions (cysts) in the gill and less commonly skin epithelial cells, has been reported in many marine and freshwater fish species and may be associated with mortality. Previously, molecular and ultrastructural analyses have exclusively associated members of the Chlamydiae with such inclusions. Here we investigated a population of farmed Atlantic salmon from the west coast of Norway displaying gill epitheliocystis. Although 'Candidatus Piscichlamydia salmonis', previously reported to be present in such cysts, was detected by PCR in most of the gill samples analysed, this bacterium was found to be a rare member of the gill microbiota, and not associated with the observed cysts as demonstrated by fluorescence in situ hybridization assays. The application of a broad range 16 S rRNA targeted PCR assay instead identified a novel betaproteobacterium as an abundant member of the gill microbiota. Fluorescence in situ hybridization demonstrated that this bacterium, tentatively classified as 'Candidatus Branchiomonas cysticola', was the cyst-forming agent in these samples. While histology and ultrastructure of 'Ca. B. cysticola' cysts revealed forms similar to the reticulate and intermediate bodies described in earlier reports from salmon in seawater, no elementary bodies typical of the chlamydial developmental cycle were observed. In conclusion, this study identified a novel agent of epitheliocystis in sea-farmed Atlantic salmon and demonstrated that these cysts can be caused by bacteria phylogenetically distinct from the Chlamydiae. PMID- 22427866 TI - Single-nucleotide polymorphism genotyping identifies a locally endemic clone of methicillin-resistant Staphylococcus aureus. AB - We developed, tested, and applied a TaqMan real-time PCR assay for interrogation of three single-nucleotide polymorphisms that differentiate a clade (termed 't003 X') within the radiation of methicillin-resistant Staphylococcus aureus (MRSA) ST225. The TaqMan assay achieved 98% typeability and results were fully concordant with DNA sequencing. By applying this assay to 305 ST225 isolates from an international collection, we demonstrate that clade t003-X is endemic in a single acute-care hospital in Germany at least since 2006, where it has caused a substantial proportion of infections. The strain was also detected in another hospital located 16 kilometers away. Strikingly, however, clade t003-X was not found in 62 other hospitals throughout Germany nor among isolates from other countries, and, hence, displayed a very restricted geographical distribution. Consequently, our results show that SNP-typing may be useful to identify and track MRSA clones that are specific to individual healthcare institutions. In contrast, the spatial dissemination pattern observed here had not been resolved by other typing procedures, including multilocus sequence typing (MLST), spa typing, DNA macrorestriction, and multilocus variable-number tandem repeat analysis (MLVA). PMID- 22427867 TI - Allelic analysis of sheath blight resistance with association mapping in rice. AB - Sheath blight (ShB) caused by the soil-borne pathogen Rhizoctonia solani is one of the most devastating diseases in rice world-wide. Global attention has focused on examining individual mapping populations for quantitative trait loci (QTLs) for ShB resistance, but to date no study has taken advantage of association mapping to examine hundreds of lines for potentially novel QTLs. Our objective was to identify ShB QTLs via association mapping in rice using 217 sub-core entries from the USDA rice core collection, which were phenotyped with a micro chamber screening method and genotyped with 155 genome-wide markers. Structure analysis divided the mapping panel into five groups, and model comparison revealed that PCA5 with genomic control was the best model for association mapping of ShB. Ten marker loci on seven chromosomes were significantly associated with response to the ShB pathogen. Among multiple alleles in each identified loci, the allele contributing the greatest effect to ShB resistance was named the putative resistant allele. Among 217 entries, entry GSOR 310389 contained the most putative resistant alleles, eight out of ten. The number of putative resistant alleles presented in an entry was highly and significantly correlated with the decrease of ShB rating (r = -0.535) or the increase of ShB resistance. Majority of the resistant entries that contained a large number of the putative resistant alleles belonged to indica, which is consistent with a general observation that most ShB resistant accessions are of indica origin. These findings demonstrate the potential to improve breeding efficiency by using marker-assisted selection to pyramid putative resistant alleles from various loci in a cultivar for enhanced ShB resistance in rice. PMID- 22427868 TI - TRAF6 mediates IL-1beta/LPS-induced suppression of TGF-beta signaling through its interaction with the type III TGF-beta receptor. AB - Transforming growth factor-beta1 (TGF-beta1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL 1beta must overcome the anti-inflammatory effects of TGF-beta to boost pro inflammatory responses in epithelial cells. Here we show that IL-1beta or Lipopolysaccharide (LPS) suppresses TGF-beta-induced anti-inflammatory signaling in a NF-kappaB-independent manner. TRAF6, a key molecule in IL-1beta signaling, mediates this suppressive effect through interaction with the type III TGF-beta receptor (TbetaRIII), which is TGF-beta-dependent and requires type I TGF-beta receptor (TbetaRI) kinase activity. TbetaRI phosphorylates TbetaRIII at residue S829, which promotes the TRAF6/TbetaRIII interaction and consequent sequestration of TbetaRIII from the TbetaRII/TbetaRI complex. Our data indicate that IL-1beta enhances the pro-inflammatory response by suppressing TGF-beta signaling through TRAF6-mediated sequestration of TbetaRIII, which may be an important contributor to the early stages of tumor progression. PMID- 22427869 TI - An observational cohort comparison of facilitators of retention in care and adherence to anti-eetroviral therapy at an HIV treatment center in Kenya. AB - BACKGROUND: Most HIV treatment programs in resource-limited settings utilize multiple facilitators of adherence and retention in care but there is little data on the efficacy of these methods. We performed an observational cohort analysis of a treatment program in Kenya to assess which program components promote adherence and retention in HIV care in East Africa. METHODS: Patients initiating ART at A.I.C. Kijabe Hospital were prospectively enrolled in an observational study. Kijabe has an intensive program to promote adherence and retention in care during the first 6 months of ART that incorporates the following facilitators: home visits by community health workers, community based support groups, pharmacy counseling, and unannounced pill counts by clinicians. The primary endpoint was time to treatment failure, defined as a detectable HIV-1 viral load; discontinuation of ART; death; or loss to follow-up. Time to treatment failure for each facilitator was calculated using Kaplan-Meier analysis. The relative effects of the facilitators were determined by the Cox Proportional Hazards Model. RESULTS: 301 patients were enrolled. Time to treatment failure was longer in patients participating in support groups (448 days vs. 337 days, P<0.001), pharmacy counseling (480 days vs. 386 days, P = 0.002), pill counts (482 days vs. 189 days, P<0.001) and home visits (485 days vs. 426 days, P = 0.024). Better adherence was seen with support groups (89% vs. 82%, P = 0.05) and pill counts (89% vs. 75%, P = 0.02). Multivariate analysis using the Cox Model found significant reductions in risk of treatment failure associated with pill counts (HR = 0.19, P<0.001) and support groups (HR = 0.43, P = 0.003). CONCLUSION: Unannounced pill counts by the clinician and community based support groups were associated with better long term treatment success and with better adherence. PMID- 22427870 TI - Environmental and demographic determinants of avian influenza viruses in waterfowl across the contiguous United States. AB - Outbreaks of avian influenza in North American poultry have been linked to wild waterfowl. A first step towards understanding where and when avian influenza viruses might emerge from North American waterfowl is to identify environmental and demographic determinants of infection in their populations. Laboratory studies indicate water temperature as one determinant of environmental viral persistence and we explored this hypothesis at the landscape scale. We also hypothesized that the interval apparent prevalence in ducks within a local watershed during the overwintering season would influence infection probabilities during the following breeding season within the same local watershed. Using avian influenza virus surveillance data collected from 19,965 wild waterfowl across the contiguous United States between October 2006 and September 2009 We fit Logistic regression models relating the infection status of individual birds sampled on their breeding grounds to demographic characteristics, temperature, and interval apparent prevalence during the preceding overwintering season at the local watershed scale. We found strong support for sex, age, and species differences in the probability an individual duck tested positive for avian influenza virus. In addition, we found that for every seven days the local minimum temperature fell below zero, the chance an individual would test positive for avian influenza virus increased by 5.9 percent. We also found a twelve percent increase in the chance an individual would test positive during the breeding season for every ten percent increase in the interval apparent prevalence during the prior overwintering season. These results suggest that viral deposition in water and sub-freezing temperatures during the overwintering season may act as determinants of individual level infection risk during the subsequent breeding season. Our findings have implications for future surveillance activities in waterfowl and domestic poultry populations. Further study is needed to identify how these drivers might interact with other host-specific infection determinants, such as species phylogeny, immunological status, and behavioral characteristics. PMID- 22427871 TI - A surveillance system to reduce transmission of pandemic H1N1 (2009) influenza in a 2600-bed medical center. AB - BACKGROUND: Concerns have been raised about how the transmission of emerging infectious diseases from patients to healthcare workers (HCWs) and vice versa could be recognized and prevented in a timely manner. An effective strategy to block transmission of pandemic H1N1 (2009) influenza in HCWs is important. METHODOLOGY/PRINCIPAL FINDINGS: An infection control program was implemented to survey and prevent nosocomial outbreaks of H1N1 (2009) influenza at a 2,600-bed, tertiary-care academic hospital. In total, 4,963 employees at Kaohsiung Chang Gung Memorial Hospital recorded their temperature and received online education on control practices for influenza infections. Administration records provided vaccination records and occupational characteristics of all HCWs. Early recognition of a pandemic H1N1 (2009) influenza case was followed by a semi structured questionnaire to analyze possible routes of patient contact, household contact, or unspecified contact. Surveillance spanned August 1, 2009 to January 31, 2010; 51 HCWs were confirmed to have novel H1N1 (2009) influenza by quantitative real-time reverse transcription polymerase chain reaction. Prevalence of patient contact, household contact, or unspecified contact infection was 13.7% (7/51), 13.7% (7/51), and 72.5% (37/51), respectively. The prevalence of the novel H1N1 infection was significantly lower among vaccinated HCWs than among unvaccinated HCWs (p<0.001). Higher viral loads in throat swabs were found in HCWs with patient and household contact infection than in those with unspecified contact infection (4.15 vs. 3.53 copies/mL, log(10), p = 0.035). CONCLUSION: A surveillance system with daily temperature recordings and online education for HCWs is important for a low attack rate of H1N1 (2009) influenza transmission before H1N1 (2009) influenza vaccination is available, and the attack rate is further decreased after mass vaccination. Unspecified contact infection rates were significantly higher than that of patient contact and household contact infection, highlighting the need for public education of influenza transmission in addition to hospital infection control. PMID- 22427872 TI - Perineuronal nets play a role in regulating striatal function in the mouse. AB - The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse. PMID- 22427873 TI - Seed spillage from grain trailers on road verges during oilseed rape harvest: an experimental survey. AB - CONTEXT: Anthropogenic vectors enhance the natural dispersal capacity of plant seeds significantly in terms of quantity and distance. Human-mediated seed dispersal (i.e. anthropochory) greatly increases the dispersal of crop species across agroecosystems. In the case of oilseed rape (OSR), spillage of seeds from grain trailers during harvest has never been quantified. METHODS: Our experimental approach involved establishing 85 seed trap-sites on the road verges of an agricultural area around the grain silo of Selommes (Loir-et-Cher, France). We recorded OSR spillage during harvest and applied a linear model to the data. RESULTS: The amount of seed spilled was related positively to the area of the OSR fields served by the road, whereas the amount of seed spilled decreased with other variables, such as distance from the trap-site to the verge of the road and to the nearest field. The distance to the grain silo, through local and regional effects, affected seed loss. Local effects from fields adjacent to the road resulted in a cumulative spillage on one-lane roads. On two-lane roads, spillage was nearly constant whatever the distance to the silo due to a mixture of these local effects and of grain trailers that joined the road from more distant fields. From the data, we predicted the number of seeds lost from grain trailers on one road verge in the study area. We predicted a total spillage of 2.05 * 10(6) seeds (+/- 4.76 * 10(5)) along the road length, which represented a mean of 404 +/- 94 seeds per m(2). CONCLUSION: Containment of OSR seeds will always be challenging. However, seed spillage could be reduced if grain trailers were covered and filled with less seed. Reducing distances travelled between fields and silos could also limit seed loss. PMID- 22427874 TI - Curvature of double-membrane organelles generated by changes in membrane size and composition. AB - Transient double-membrane organelles are key players in cellular processes such as autophagy, reproduction, and viral infection. These organelles are formed by the bending and closure of flat, double-membrane sheets. Proteins are believed to be important in these morphological transitions but the underlying mechanism of curvature generation is poorly understood. Here, we describe a novel mechanism for this curvature generation which depends primarily on three membrane properties: the lateral size of the double-membrane sheets, the molecular composition of their highly curved rims, and a possible asymmetry between the two flat faces of the sheets. This mechanism is evolutionary advantageous since it does not require active processes and is readily available even when resources within the cell are restricted as during starvation, which can induce autophagy and sporulation. We identify pathways for protein-assisted regulation of curvature generation, organelle size, direction of bending, and morphology. Our theory also provides a mechanism for the stabilization of large double-membrane sheet-like structures found in the endoplasmic reticulum and in the Golgi cisternae. PMID- 22427875 TI - CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3. AB - BACKGROUND: Genetic variability of the major subunit (CACNA1E) of the voltage dependent Ca(2+) channel Ca(V)2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: In 595 GAD-negative, drug naive patients (mean +/- SD; age: 58.5 +/- 10.2 yrs; BMI: 29.9 +/- 5 kg/m(2), HbA1c: 7.0+/-1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ~93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05-0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05). CONCLUSIONS/SIGNIFICANCE: In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment. PMID- 22427876 TI - Validity of thermal ramping assays used to assess thermal tolerance in arthropods. AB - Proper assessment of environmental resistance of animals is critical for the ability of researchers to understand how variation in environmental conditions influence population and species abundance. This is also the case for studies of upper thermal limits in insects, where researchers studying animals under laboratory conditions must select appropriate methodology on which conclusions can be drawn. Ideally these methods should precisely estimate the trait of interest and also be biological meaningful. In an attempt to develop such tests it has been proposed that thermal ramping assays are useful assays for small insects because they incorporate an ecologically relevant gradual temperature change. However, recent model-based papers have suggested that estimates of thermal resistance may be strongly confounded by simultaneous starvation and dehydration stress. In the present study we empirically test these model predictions using two sets of independent experiments. We clearly demonstrate that results from ramping assays of small insects (Drosophila melanogaster) are not compromised by starvation- or dehydration-stress. Firstly we show that the mild disturbance of water and energy balance of D. melanogaster experienced during the ramping tests does not confound heat tolerance estimates. Secondly we show that flies pre-exposed to starvation and dehydration have "normal" heat tolerance and that resistance to heat stress is independent of the energetic and water status of the flies. On the basis of our results we discuss the assumptions used in recent model papers and present arguments as to why the ramping assay is both a valid and ecologically relevant way to measure thermal resistance in insects. PMID- 22427877 TI - Two odorant-binding proteins mediate the behavioural response of aphids to the alarm pheromone (E)-beta-farnesene and structural analogues. AB - BACKGROUND: Aphids are agricultural pests of great economical interest. Alternatives to insecticides, using semiochemicals, are of difficult applications. In fact, sex pheromones are of little use as aphids reproduce partenogenetically most of the time. Besides, the alarm pheromone, (E)-beta farnesene for a great number of species, is difficult to synthesize and unstable in the environment. The search for novel semiochemicals to be used in population control can be efficiently approached through the study of the olfactory system at the biochemical level. Recently odorant-binding proteins (OBPs) have been shown to play a central role in olfactory recognition, thus becoming the target of choice for designing new semiochemicals. METHODOLOGY/PRINCIPAL FINDINGS: To address the question of how the alarm message is recognised at the level of OBPs, we have tested 29 compounds, including (E)-beta-farnesene, in binding assays with 6 recombinant proteins and in behaviour experiments. We have found that good repellents bind OBP3 and/or OBP7, while non repellents present different spectra of binding. These results have been verified with two species of aphids, Acyrthosiphon pisum and Myzus persicae, both using (E)-beta-farnesene as the alarm pheromone. CONCLUSIONS: Our results represent further support to the idea (so far convincingly demonstrated only in Drosophila) that OBPs are involved in decoding the chemical information of odorants and pheromones, and for the first time provide such evidence in other insect species and using wild-type insects. Moreover, the data offer guidelines and protocols for the discovery of potential alarm pheromones, using ligand-binding assays as a preliminary screening before subjecting selected compounds to behaviour tests. PMID- 22427878 TI - Ancient DNA assessment of tiger salamander population in Yellowstone National Park. AB - Recent data indicates that blotched tiger salamanders (Ambystoma tigrinum melanostictum) in northern regions of Yellowstone National Park are declining due to climate-related habitat changes. In this study, we used ancient and modern mitochondrial haplotype diversity to model the effective size of this amphibian population through recent geological time and to assess past responses to climatic changes in the region. Using subfossils collected from a cave in northern Yellowstone, we analyzed >700 base pairs of mitochondrial sequence from 16 samples ranging in age from 100 to 3300 years old and found that all shared an identical haplotype. Although mitochondrial diversity was extremely low within the living population, we still were able to detect geographic subdivision within the local area. Using serial coalescent modelling with Bayesian priors from both modern and ancient genetic data we simulated a range of probable population sizes and mutation rates through time. Our simulations suggest that regional mitochondrial diversity has remained relatively constant even through climatic fluctuations of recent millennia. PMID- 22427879 TI - Co-deletion of chromosome 1p/19q and IDH1/2 mutation in glioma subsets of brain tumors in Chinese patients. AB - OBJECTIVE: To characterize co-deletion of chromosome 1p/19q and IDH1/2 mutation in Chinese brain tumor patients and to assess their associations with clinical features. METHODS: In a series of 528 patients with gliomas, pathological and radiological materials were reviewed. Pathological constituents of tumor subsets, incidences of 1p/19q co-deletion and IDH1/2 mutation in gliomas by regions and sides in the brain were analyzed. RESULTS: Overall, 1p and 19q was detected in 339 patients by FISH method while the sequence of IDH1/2 was determined in 280 patients. Gliomas of frontal, temporal and insular origin had significantly different pathological constituents of tumor subsets (P<0.001). Gliomas of frontal origin had significantly higher incidence of 1p/19q co-deletion (50.4%) and IDH1/2 mutation (73.5%) than those of non-frontal origin (27.0% and 48.5%, respectively) (P<0.001), while gliomas of temporal origin had significantly lower incidence of 1p/19q co-deletion (23.9%) and IDH1/2 mutation (41.7%) than those of non-temporal origin (39.9% and 63.2%, respectively) (P = 0.013 and P = 0.003, respectively). Subgroup analysis confirmed these findings in oligoastrocytic and oligodendroglial tumors, respectively. Although the difference of 1p/19q co deletion was not statistically significant in temporal oligodendroglial tumors, the trend was marginally significant (P = 0.082). However, gliomas from different sides of the brain did not show significant different pathological constituents, incidences of 1p/19q co-deletion or IDH1/2 mutation. CONCLUSION: Preferential distribution of pathological subsets, 1p/19q co-deletion and IDH1/2 mutation were confirmed in some brain regions in Chinese glioma patients, implying their distinctive tumor genesis and predictive value for prognosis. PMID- 22427880 TI - Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. AB - Heat shock proteins (Hsps) are well appreciated as intrinsic protectors of cardiomyocytes against numerous stresses. Recent studies have indicated that Hsp20 (HspB6), a small heat shock protein, was increased in blood from cardiomyopathic hamsters. However, the exact source of the increased circulating Hsp20 and its potential role remain obscure. In this study, we observed that the circulating Hsp20 was increased in a transgenic mouse model with cardiac-specific overexpression of Hsp20, compared with wild-type mice, suggesting its origin from cardiomyocytes. Consistently, culture media harvested from Hsp20-overexpressing cardiomyocytes by Ad.Hsp20 infection contained an increased amount of Hsp20, compared to control media. Furthermore, we identified that Hsp20 was secreted through exosomes, independent of the endoplasmic reticulum-Golgi pathway. To investigate whether extracellular Hsp20 promotes angiogenesis, we treated human umbilical vein endothelial cells (HUVECs) with recombinant human Hsp20 protein, and observed that Hsp20 dose-dependently promoted HUVEC proliferation, migration and tube formation. Moreover, a protein binding assay and immunostaining revealed an interaction between Hsp20 and VEGFR2. Accordingly, stimulatory effects of Hsp20 on HUVECs were blocked by a VEGFR2 neutralizing antibody and CBO-P11 (a VEGFR inhibitor). These in vitro data are consistent with the in vivo findings that capillary density was significantly enhanced in Hsp20-overexpressing hearts, compared to non-transgenic hearts. Collectively, our findings demonstrate that Hsp20 serves as a novel cardiokine in regulating myocardial angiogenesis through activation of the VEGFR signaling cascade. PMID- 22427881 TI - Low level of low-density lipoprotein receptor-related protein 1 predicts an unfavorable prognosis of hepatocellular carcinoma after curative resection. AB - BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC). METHODS: LRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens. RESULTS: Low LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set. CONCLUSIONS: LRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy. PMID- 22427882 TI - Ribosomal history reveals origins of modern protein synthesis. AB - The origin and evolution of the ribosome is central to our understanding of the cellular world. Most hypotheses posit that the ribosome originated in the peptidyl transferase center of the large ribosomal subunit. However, these proposals do not link protein synthesis to RNA recognition and do not use a phylogenetic comparative framework to study ribosomal evolution. Here we infer evolution of the structural components of the ribosome. Phylogenetic methods widely used in morphometrics are applied directly to RNA structures of thousands of molecules and to a census of protein structures in hundreds of genomes. We find that components of the small subunit involved in ribosomal processivity evolved earlier than the catalytic peptidyl transferase center responsible for protein synthesis. Remarkably, subunit RNA and proteins coevolved, starting with interactions between the oldest proteins (S12 and S17) and the oldest substructure (the ribosomal ratchet) in the small subunit and ending with the rise of a modern multi-subunit ribosome. Ancestral ribonucleoprotein components show similarities to in vitro evolved RNA replicase ribozymes and protein structures in extant replication machinery. Our study therefore provides important clues about the chicken-or-egg dilemma associated with the central dogma of molecular biology by showing that ribosomal history is driven by the gradual structural accretion of protein and RNA structures. Most importantly, results suggest that functionally important and conserved regions of the ribosome were recruited and could be relics of an ancient ribonucleoprotein world. PMID- 22427883 TI - Speed-dependent cellular decision making in nonequilibrium genetic circuits. AB - Despite being governed by the principles of nonequilibrium transitions, gene expression dynamics underlying cell fate decision is poorly understood. In particular, the effect of signaling speed on cellular decision making is still unclear. Here we show that the decision between alternative cell fates, in a structurally symmetric circuit, can be biased depending on the speed at which the system is forced to go through the decision point. The circuit consists of two mutually inhibiting and self-activating genes, forced by two external signals with identical stationary values but different transient times. Under these conditions, slow passage through the decision point leads to a consistently biased decision due to the transient signaling asymmetry, whereas fast passage reduces and eventually eliminates the switch imbalance. The effect is robust to noise and shows that dynamic bifurcations, well known in nonequilibrium physics, are important for the control of genetic circuits. PMID- 22427884 TI - Contribution of climate and air pollution to variation in coronary heart disease mortality rates in England. AB - There are substantial geographic variations in coronary heart disease (CHD) mortality rates in England that may in part be due to differences in climate and air pollution. An ecological cross-sectional multi-level analysis of male and female CHD mortality rates in all wards in England (1999-2004) was conducted to estimate the relative strength of the association between CHD mortality rates and three aspects of the physical environment--temperature, hours of sunshine and air quality. Models were adjusted for deprivation, an index measuring the healthiness of the lifestyle of populations, and urbanicity. In the fully adjusted model, air quality was not significantly associated with CHD mortality rates, but temperature and sunshine were both significantly negatively associated (p<0.05), suggesting that CHD mortality rates were higher in areas with lower average temperature and hours of sunshine. After adjustment for the unhealthy lifestyle of populations and deprivation, the climate variables explained at least 15% of large scale variation in CHD mortality rates. The results suggest that the climate has a small but significant independent association with CHD mortality rates in England. PMID- 22427885 TI - Successful determination of larval dispersal distances and subsequent settlement for long-lived pelagic larvae. AB - Despite its importance, we still have a poor understanding of the level of connectivity between marine populations in most geographical locations. Taking advantage of the natural features of the southeast coast of New Zealand's North Island, we deployed a series of settlement stations and conducted plankton tows to capture recent settlers and planktonic larvae of the common intertidal gastropod Austrolittorina cincta (6-8 week larval period). Satellite image analysis and ground truthing surveys revealed the absence of suitable intertidal rocky shore habitat for A. cincta over a 100 km stretch of coastline between Kapiti Island to the south and Wanganui to the north. Fifteen settlement stations (3 replicates * 5 sites), which were used to mimic intertidal habitat suitable for A. cincta, were deployed for two months around and north of Kapiti Island (at 0.5, 1, 5, 15, 50 km). In addition, we also conducted plankton tows at each settlement station when the stations were first deployed to collect A. cincta larvae in the water column. On collection, all newly settled gastropods and larvae in the plankton samples were individually isolated, and a species-specific microsatellite marker was used to positively identify A. cincta individuals. Most of the positively identified A. cincta settlers and larvae were collected at the first three sampling stations (<5 km). However, low numbers of A. cincta settlers and larvae were also recorded at the two more distant locations (15 and 50 km). Dispersal curves modeled from our data suggested that <1% of gastropod larvae would travel more than 100 km. While our data show that most larvae are retained close to their natal populations (<5 km), a small proportion of larvae are able to travel much larger geographic distances. Our estimates of larval dispersal and subsequent settlement are one of only a few for marine species with a long-lived larva. PMID- 22427886 TI - Reproductive ecology and severe pollen limitation in the polychromic tundra plant, Parrya nudicaulis (Brassicaceae). AB - Pollen limitation is predicted to be particularly severe in tundra habitats. Numerous reproductive patterns associated with alpine and arctic species, particularly mechanisms associated with reproductive assurance, are suggested to be driven by high levels of pollen limitation. We studied the reproductive ecology of Parrya nudicaulis, a species with relatively large sexual reproductive investment and a wide range of floral pigmentation, in tundra habitats in interior montane Alaska to estimate the degree of pollen limitation. The plants are self-compatible and strongly protandrous, setting almost no seed in the absence of pollinators. Supplemental hand pollinations within pollinator exclusion cages indicated no cage effect on seed production. Floral visitation rates were low in both years of study and particularly infrequent in 2010. A diversity of insects visited P. nudicaulis, though syrphid and muscid flies composed the majority of all visits. Pollen-ovule ratios and levels of heterozygosity are consistent with a mixed mating system. Pollen limitation was severe; hand pollinations increased seed production per plant five-fold. Seed-to ovule ratios remained low following hand pollinations, indicating resource limitation is likely to also be responsible for curtailing seed set. We suggest that pollen limitation in P. nudicaulis may be the result of selection favoring an overproduction of ovules as a bet-hedging strategy in this environmental context of highly variable pollen receipt. PMID- 22427887 TI - Identification of cellular infiltrates during early stages of brain inflammation with magnetic resonance microscopy. AB - A comprehensive view of brain inflammation during the pathogenesis of autoimmune encephalomyelitis can be achieved with the aid of high resolution non-invasive imaging techniques such as microscopic magnetic resonance imaging (MUMRI). In this study we demonstrate the benefits of cryogenically-cooled RF coils to produce MUMRI in vivo, with sufficient detail to reveal brain pathology in the experimental autoimmune encephalomyelitis (EAE) model. We could visualize inflammatory infiltrates in detail within various regions of the brain, already at an early phase of EAE. Importantly, this pathology could be seen clearly even without the use of contrast agents, and showed excellent correspondence with conventional histology. The cryogenically-cooled coil enabled the acquisition of high resolution images within short scan times: an important practical consideration in conducting animal experiments. The detail of the cellular infiltrates visualized by in vivo MUMRI allows the opportunity to follow neuroinflammatory processes even during the early stages of disease progression. Thus MUMRI will not only complement conventional histological examination but will also enable longitudinal studies on the kinetics and dynamics of immune cell infiltration. PMID- 22427888 TI - Repeatability and reproducibility of decisions by latent fingerprint examiners. AB - The interpretation of forensic fingerprint evidence relies on the expertise of latent print examiners. We tested latent print examiners on the extent to which they reached consistent decisions. This study assessed intra-examiner repeatability by retesting 72 examiners on comparisons of latent and exemplar fingerprints, after an interval of approximately seven months; each examiner was reassigned 25 image pairs for comparison, out of total pool of 744 image pairs. We compare these repeatability results with reproducibility (inter-examiner) results derived from our previous study. Examiners repeated 89.1% of their individualization decisions, and 90.1% of their exclusion decisions; most of the changed decisions resulted in inconclusive decisions. Repeatability of comparison decisions (individualization, exclusion, inconclusive) was 90.0% for mated pairs, and 85.9% for nonmated pairs. Repeatability and reproducibility were notably lower for comparisons assessed by the examiners as "difficult" than for "easy" or "moderate" comparisons, indicating that examiners' assessments of difficulty may be useful for quality assurance. No false positive errors were repeated (n = 4); 30% of false negative errors were repeated. One percent of latent value decisions were completely reversed (no value even for exclusion vs. of value for individualization). Most of the inter- and intra-examiner variability concerned whether the examiners considered the information available to be sufficient to reach a conclusion; this variability was concentrated on specific image pairs such that repeatability and reproducibility were very high on some comparisons and very low on others. Much of the variability appears to be due to making categorical decisions in borderline cases. PMID- 22427889 TI - Nfkb1 inhibits LPS-induced IFN-beta and IL-12 p40 production in macrophages by distinct mechanisms. AB - BACKGROUND: Nfkb1-deficient murine macrophages express higher levels of IFN-beta and IL-12 p40 following LPS stimulation than control macrophages, but the molecular basis for this phenomenon has not been completely defined. Nfkb1 encodes several gene products including the NF-kappaB subunit p50 and its precursor p105. p50 is derived from the N-terminal of 105, and p50 homodimers can exhibit suppressive activity when overexpressed. The C-terminal region of p105 is necessary for LPS-induced ERK activation and it has been suggested that ERK activity inhibits both IFN-beta and IL-12 p40 following LPS stimulation. However, the contributions of p50 and the C-terminal domain of p105 in regulating endogenous IFN-beta(Ifnb) and IL-12 p40 (Il12b) gene expression in macrophages following LPS stimulation have not been directly compared. METHODOLOGY/PRINCIPAL FINDINGS: We have used recombinant retroviruses to express p105, p50, and the C terminal domain of p105 (p105DeltaN) in Nfkb1-deficient murine bone marrow derived macrophages at near endogenous levels. We found that both p50 and p105DeltaN inhibited expression of Ifnb, and that inhibition of Ifnb by p105DeltaN depended on ERK activation, because a mutant of p105DeltaN (p105DeltaNS930A) that lacks a key serine necessary to support ERK activation failed to inhibit. In contrast, only p105DeltaN but not p50 inhibited Il12b expression. Surprisingly, p105DeltaNS930A retained inhibitory activity for Il12b, indicating that ERK activation was not necessary for inhibition. The differential effects of p105DeltaNS930A on Ifnb and Il12b expression inversely correlated with the function of one of its binding partners, c-Rel. This raised the possibility that p105DeltaNS930A influences gene expression by interfering with the function of c-Rel. CONCLUSIONS: These results demonstrate that Nfkb1 exhibits multiple gene-specific inhibitory functions following TLR stimulation of murine macrophages. PMID- 22427890 TI - Forestry alters foraging efficiency and crop contents of aphid-tending red wood ants, Formica aquilonia. AB - Forest management alters species behaviours, distributions and interactions. To evaluate forestry effects on ant foraging performance, we compared the quality and quantity of honeydew harvested by ants among clear-cuts, middle-aged and mature spruce-dominated stands in boreal forests in Sweden. Honeydew quality was examined using honeydew collected by squeezing the gasters of laden Formica aquilonia workers. We used fifteen laden individuals at each study site (four replicates of each stand age) and analysed honeydew chemical composition with gas chromatography-mass spectroscopy. To compare the quantity of honeydew collected by individual ants, we collected and weighed five ants moving up and five ants moving down each of ten trees at the twelve sites (totally 1200 ants). The concentration of trehalose in honeydew was lower in clear-cuts compared with middle aged and mature stands, and similar trends were shown for sucrose, raffinose and melezitose, indicating poorer honeydew quality on clear cuts. Concentrations of the amino acid serine were higher on clear-cuts. The same trend occurred for glutamine, suggesting that increased N-uptake by the trees after clear cutting is reflected in the honeydew of aphids. Ants in mature stands had larger heads and carried proportionally more honeydew and may therefore be more efficient foragers. Human alternation of habitats through clear-cutting thus affects food quality and worker condition in F. aquilonia. This is the first study to show that honeydew quality is affected by anthropogenic disturbances, likely contributing to the reduction in size and abundance of F. aquilonia workers and mounds after clear cutting. PMID- 22427891 TI - Relating habitat and climatic niches in birds. AB - Predicting species' responses to the combined effects of habitat and climate changes has become a major challenge in ecology and conservation biology. However, the effects of climatic and habitat gradients on species distributions have generally been considered separately. Here, we explore the relationships between the habitat and thermal dimensions of the ecological niche in European common birds. Using data from the French Breeding Bird Survey, a large-scale bird monitoring program, we correlated the habitat and thermal positions and breadths of 74 bird species, controlling for life history traits and phylogeny. We found that cold climate species tend to have niche positions in closed habitats, as expected by the conjunction of the biogeographic history of birds' habitats, and their current continent-scale gradients. We also report a positive correlation between thermal and habitat niche breadths, a pattern consistent with macroecological predictions concerning the processes shaping species' distributions. Our results suggest that the relationships between the climatic and habitat components of the niche have to be taken into account to understand and predict changes in species' distributions. PMID- 22427892 TI - Conversion of t11t13 CLA into c9t11 CLA in Caco-2 cells and inhibition by sterculic oil. AB - BACKGROUND: Conjugated linoleic acids (CLA), and principally c9t11 CLA, are suspected to have numerous preventive properties regarding non-infectious pathologies such as inflammatory diseases, atherosclerosis and several types of cancer. C9t11 CLA is produced in the rumen during biohydrogenation of linoleic acid, but can also be synthesized in mammalian tissues from trans-vaccenic acid (C18:1 t11) through the action of delta-9 desaturase (D9D). For several years, it is also known that c9t11 CLA can be synthesized from conjugated linolenic acids (CLnA), i.e. c9t11c13 CLnA and c9t11t13 CLnA. This study aimed at investigating to which extent and by which route c9t11 CLA can be produced from another isomer of CLA, the t11t13 CLA that is structurally very similar to c9t11t13 CLnA, in Caco-2 cells. METHODOLOGY/PRINCIPAL FINDINGS: Caco-2 cells were incubated for 24 h with 20 umol/l of t11t13 CLA in the absence or presence of sterculic oil used as an inhibitor of D9D. Caco-2 cells were able to convert t11t13 CLA into c9t11 CLA, and c9t11t13 CLnA was formed as an intermediate compound. In the presence of sterculic oil, the production of this intermediate was decreased by 46% and the formation of c9t11 CLA was decreased by 26%. No other metabolite was detected. CONCLUSIONS/SIGNIFICANCE: These results not only highlight the conversion of t11t13 CLA into c9t11 CLA but demonstrate also that this conversion involves first a desaturation step catalysed by D9D to produce c9t11t13 CLnA and then the action of another enzyme reducing the double bond on the Delta13 position. PMID- 22427893 TI - Dynamics of envelope evolution in clade C SHIV-infected pig-tailed macaques during disease progression analyzed by ultra-deep pyrosequencing. AB - Understanding the evolution of the human immunodeficiency virus type 1 (HIV-1) envelope during disease progression can provide tremendous insights for vaccine development, and simian-human immunodeficiency virus (SHIV) infection of non human primate provides an ideal platform for such studies. A newly developed clade C SHIV, SHIV-1157ipd3N4, which was able to infect rhesus macaques, closely resembled primary HIV-1 in transmission and pathogenesis, was used to infect several pig-tailed macaques. One of the infected animals subsequently progressed to AIDS, whereas one remained a non-progressor. The viral envelope evolution in the infected animals during disease progression was analyzed by a bioinformatics approach using ultra-deep pyrosequencing. Our results showed substantial envelope variations emerging in the progressor animal after the onset of AIDS. These envelope variations impacted the length of the variable loops and charges of different envelope regions. Additionally, multiple mutations were located at the CD4 and CCR5 binding sites, potentially affecting receptor binding affinity, viral fitness and they might be selected at late stages of disease. More importantly, these envelope mutations are not random since they had repeatedly been observed in a rhesus macaque and a human infant infected by either SHIV or HIV-1, respectively, carrying the parental envelope of the infectious molecular clone SHIV-1157ipd3N4. Moreover, similar mutations were also observed from other studies on different clades of envelopes regardless of the host species. These recurring mutations in different envelopes suggest that there may be a common evolutionary pattern and selection pathway for the HIV-1 envelope during disease progression. PMID- 22427894 TI - Deep brain stimulation: eye movements reveal anomalous effects of electrode placement and stimulation. AB - One of the major difficulties in evaluating the efficacy of deep brain stimulation (DBS), or understanding its mechanism, is the need to distinguish the effects of stimulation itself from those of the lesion inevitably created during surgery. Recent work has shown that DBS of the subthalamic nucleus in Parkinson's disease greatly reduces the time it takes the eyes to make a saccade in response to a visual stimulus. Since this saccadic latency can be rapidly and objectively measured, we used it to compare the effects of surgery and of stimulation. We used a saccadometer to measure the saccadic latencies of 9 DBS patients (1) preoperatively, (2) the day after insertion of subthalamic nucleus electrodes, (3) three weeks later, prior to turning on the stimulator, and (4) after commencement of stimulation. Patients were on their anti-Parkinsonian medication throughout the study. It revealed an entirely unexpected and puzzling finding. As in previous studies an amelioration of symptoms is seen immediately after surgery, and then a further improvement when finally the stimulator is turned on, but in the case of saccadic latency the pattern is different: surgery produces a transient increase in latency, returning to baseline within three weeks, while subsequent stimulation reduced latency. Thus the differential effects of electrode placement and stimulation are completely different for saccades and for more general motor symptoms. This important finding rules out some over-simple interpretations of the mechanism of DBS, and needs to be taken into account in future attempts at modelling the neurophysiology of DBS. PMID- 22427895 TI - Effectiveness of IV cannulation skills laboratory training and its transfer into clinical practice: a randomized, controlled trial. AB - BACKGROUND: The effectiveness of skills laboratory training is widely recognized. Yet, the transfer of procedural skills acquired in skills laboratories into clinical practice has rarely been investigated. We conducted a prospective, randomised, double-blind, controlled trial to evaluate, if students having trained intravenous (IV) cannulation in a skills laboratory are rated as more professional regarding technical and communication skills compared to students who underwent bedside teaching when assessed objectively by independent video assessors and subjectively by patients. METHODOLOGY AND PRINCIPAL FINDINGS: 84 volunteer first-year medical students were randomly assigned to one of two groups. Three drop-outs occurred. The intervention group (IG; n = 41) trained IV cannulation in a skills laboratory receiving instruction after Peyton's 'Four Step Approach'. The control group (CG; n = 40) received a bedside teaching session with volunteer students acting as patients. Afterwards, performance of IV cannulation of both groups in a clinical setting with students acting as patients was video-recorded. Two independent, blinded video assessors scored students' performance using binary checklists (BC) and the Integrated Procedural Protocol Instrument (IPPI). Patients assessed students' performance with the Communication Assessment Tool (CAT) and a modified IPPI. IG required significantly shorter time needed for the performance on a patient (IG: 595.4 SD(188.1)s; CG: 692.7 SD(247.8)s; 95%CI 23.5 s to 45.1 s; p = 0.049) and completed significantly more single steps of the procedure correctly (IG: 64% SD(14) for BC items; CG: 53% SD(18); 95%CI 10.25% to 11.75%; p = 0.004). IG also scored significantly better on IPPI ratings (median: IG: 3.1; CG: 3.6; p = 0.015;). Rated by patients, students' performance and patient-physician communication did not significantly differ between groups. CONCLUSIONS: Transfer of IV cannulation-related skills acquired in a skills laboratory is superior to bedside teaching when rated by independent video raters by means of IPPI and BC. It enables students to perform IV cannulation more professionally on volunteer students acting as patients. PMID- 22427896 TI - Enabling large-scale design, synthesis and validation of small molecule protein protein antagonists. AB - Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. PMID- 22427897 TI - The evolution of pepsinogen C genes in vertebrates: duplication, loss and functional diversification. AB - BACKGROUND: Aspartic proteases comprise a large group of enzymes involved in peptide proteolysis. This collection includes prominent enzymes globally categorized as pepsins, which are derived from pepsinogen precursors. Pepsins are involved in gastric digestion, a hallmark of vertebrate physiology. An important member among the pepsinogens is pepsinogen C (Pgc). A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga). Although gene sequences with similarity to Pgc have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far. METHODOLOGY/PRINCIPAL FINDINGS: By combining phylogenetics and genomic analysis, we find an unexpected Pgc diversity in the vertebrate sub-phylum. We were able to reconstruct gene duplication timings relative to the divergence of major vertebrate clades. Before tetrapod divergence, a single Pgc gene tandemly expanded to produce two gene lineages (Pgbc and Pgc2). These have been differentially retained in various classes. Accordingly, we find Pgc2 in sauropsids, amphibians and marsupials, but not in eutherian mammals. Pgbc was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to Pgb and Pgc1. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. Pgb was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of Pgc2 and Pgbc have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation. CONCLUSIONS: We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats. PMID- 22427898 TI - Characterization of the promoter, MxiE box and 5' UTR of genes controlled by the activity of the type III secretion apparatus in Shigella flexneri. AB - Activation of the type III secretion apparatus (T3SA) of Shigella flexneri, upon contact of the bacteria with host cells, and its deregulation, as in ipaB mutants, specifically increases transcription of a set of effector-encoding genes controlled by MxiE, an activator of the AraC family, and IpgC, the chaperone of the IpaB and IpaC translocators. Thirteen genes carried by the virulence plasmid (ospB, ospC1, ospD2, ospD3, ospE1, ospE2, ospF, ospG, virA, ipaH1.4, ipaH4.5, ipaH7.8 and ipaH9.8) and five genes carried by the chromosome (ipaHa-e) are regulated by the T3SA activity. A conserved 17-bp MxiE box is present 5' of most of these genes. To characterize the promoter activity of these MxiE box containing regions, similar ~67-bp DNA fragments encompassing the MxiE box of 14 MxiE-regulated genes were cloned 5' of lacZ in a promoter probe plasmid; beta galactosidase activity detected in wild-type and ipaB strains harboring these plasmids indicated that most MxiE box-carrying regions contain a promoter regulated by the T3SA activity and that the relative strengths of these promoters cover an eight-fold range. The various MxiE boxes exhibiting up to three differences as compared to the MxiE box consensus sequence were introduced into the ipaH9.8 promoter without affecting its activity, suggesting that they are equally efficient in promoter activation. In contrast, all nucleotides conserved among MxiE boxes were found to be involved in MxiE-dependent promoter activity. In addition, we present evidence that the 5' UTRs of four MxiE-regulated genes enhance expression of the downstream gene, presumably by preventing degradation of the mRNA, and the 5' UTRs of two other genes carry an ancillary promoter. PMID- 22427899 TI - Innate immune deficiency of extremely premature neonates can be reversed by interferon-gamma. AB - BACKGROUND: Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. METHODOLOGY/PRINCIPAL FINDINGS: We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon gamma. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-gamma. CONCLUSION/SIGNIFICANCE: Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-gamma reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis. PMID- 22427900 TI - Resistance of Asian Cryptococcus neoformans serotype A is confined to few microsatellite genotypes. AB - BACKGROUND: Cryptococcus neoformans is a pathogenic yeast that causes cryptococcosis, a life threatening disease. The prevalence of cryptococcosis in Asia has been rising after the onset of the AIDS epidemic and estimates indicate more than 120 cases per 1,000 HIV-infected individuals per year. Almost all cryptococcal disease cases in both immunocompromised and immunocompetent patients in Asia are caused by C. neoformans var. grubii. Epidemiological studies on C. neoformans in pan-Asia have not been reported. The present work studies the genetic diversity of the fungus by microsatellite typing and susceptibility analysis of approximately 500 isolates from seven Asian countries. METHODOLOGY/PRINCIPAL FINDINGS: Genetic diversity of Asian isolates of C. neoformans was determined using microsatellite analysis with nine microsatellite markers. The analysis revealed eight microsatellite complexes (MCs) which showed different distributions among geographically defined populations. A correlation between MCs and HIV-status was observed. Microsatellite complex 2 was mainly associated with isolates from HIV-negative patients, whereas MC8 was associated with those from HIV-positive patients. Most isolates were susceptible to amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole, but 17 (3.4%) and 10 (2%) were found to be resistant to 5-flucytosine and fluconazole, respectively. Importantly, five Indonesian isolates (approximately 12.5% from all Indonesian isolates investigated and 1% from the total studied isolates) were resistant to both antifungals. The majority of 5-flucytosine resistant isolates belonged to MC17. CONCLUSIONS: The findings showed a different distribution of genotypes of C. neoformans var. grubii isolates from various countries in Asia, as well as a correlation of the microsatellite genotypes with the original source of the strains and resistance to 5-flucytosine. PMID- 22427901 TI - Measuring discrimination in South Korea: underestimating the prevalence of discriminatory experiences among female and less educated workers? AB - OBJECTIVES: To investigate the possibility that Koreans show different patterns in reporting discriminatory experiences based on their gender and education level, we analyzed the participants who answered "Not Applicable" for the questions of discriminatory experiences that they were eligible to answer. METHODS: Discriminatory experiences in eight social situations were assessed using the 7(th) wave of Korean Labor and Income Panel Study. After restricting the study population to waged workers, a logistic regression model was constructed to predict the probability that an individual has experienced discrimination based on the observed covariates for each of eight situations, using the data of participants who answered either Yes or No. With the model fit, the predicted logit score of discrimination (PLSD) was obtained for participants who answered Not Applicable (NA), as well as for those who answered Yes or No. The mean PLSD of the NA group was compared with those of the Yes group and the No group after stratification by gender and education level using an ANOVA model. RESULTS: On the questions of discrimination in getting hired and receiving income, the PLSD of the NA group was significantly higher than that of the No group and was not different from that of Yes group for female and junior high or less educated workers, suggesting that their NA responses were more likely to mean that they have experienced discrimination. For male and college or more educated workers, the NA group had a PLSD similar to that for the No group and had a significantly higher PLSD than the Yes group, implying that their NA responses would mean they that they have not experienced discrimination. CONCLUSIONS: Our findings suggest that the responses of NA on the discrimination questionnaire may need different interpretation based on the respondents' gender and education level in South Korea. PMID- 22427902 TI - Influenza a viruses from wild birds in Guatemala belong to the North American lineage. AB - The role wild bird species play in the transmission and ecology of avian influenza virus (AIV) is well established; however, there are significant gaps in our understanding of the worldwide distribution of these viruses, specifically about the prevalence and/or significance of AIV in Central and South America. As part of an assessment of the ecology of AIV in Guatemala, we conducted active surveillance in wild birds on the Pacific and Atlantic coasts. Cloacal and tracheal swab samples taken from resident and migratory wild birds were collected from February 2007 to January 2010.1913 samples were collected and virus was detected by real time RT-PCR (rRT-PCR) in 28 swab samples from ducks (Anas discors). Virus isolation was attempted for these positive samples, and 15 isolates were obtained from the migratory duck species Blue-winged teal. The subtypes identified included H7N9, H11N2, H3N8, H5N3, H8N4, and H5N4. Phylogenetic analysis of the viral sequences revealed that AIV isolates are highly similar to viruses from the North American lineage suggesting that bird migration dictates the ecology of these viruses in the Guatemalan bird population. PMID- 22427903 TI - Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment. AB - INTRODUCTION: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. METHODS: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through $800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base case and sensitivity analyses were performed. RESULTS: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of $400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost effective, with ICERs ranging from $714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of $50,000/QALY at all alendronate costs evaluated. CONCLUSIONS: Osteoporosis screening followed by alendronate treatment is effective and highly cost effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. PMID- 22427904 TI - Ex vivo stretch reveals altered mechanical properties of isolated dystrophin deficient hearts. AB - Duchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from beta-sarcoglycan-null and laminin-alpha(2) mutant mice, but not in dysferlin-null mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD. PMID- 22427905 TI - Effects of dopamine on sensitivity to social bias in Parkinson's disease. AB - Patients with Parkinson's disease (PD) sometimes develop impulsive compulsive behaviours (ICBs) due to their dopaminergic medication. We compared 26 impulsive and 27 non-impulsive patients with PD, both on and off medication, on a task that examined emotion bias in decision making. No group differences were detected, but patients on medication were less biased by emotions than patients off medication and the strongest effects were seen in patients with ICBs. PD patients with ICBs on medication also showed more learning from negative feedback and less from positive feedback, whereas off medication they showed the opposite effect. PMID- 22427906 TI - Zebrafish arl6ip1 is required for neural crest development during embryogenesis. AB - BACKGROUND: Although the embryonic expression pattern of ADP ribosylation factor like 6 interacting protein 1 (Arl6ip1) has been reported, its function in neural crest development is unclear. METHODS/PRINCIPAL FINDINGS: We found that knockdown of Arl6ip1 caused defective embryonic neural crest derivatives that were particularly severe in craniofacial cartilages. Expressions of the ectodermal patterning factors msxb, dlx3b, and pax3 were normal, but the expressions of the neural crest specifier genes foxd3, snai1b, and sox10 were greatly reduced. These findings suggest that arl6ip1 is essential for specification of neural crest derivatives, but not neural crest induction. Furthermore, we revealed that the streams of crestin- and sox10-expressing neural crest cells, which migrate ventrally from neural tube into trunk, were disrupted in arl6ip1 morphants. This migration defect was not only in the trunk neural crest, but also in the enteric tract where the vagal-derived neural crest cells failed to populate the enteric nervous system. We found that this migration defect was induced by dampened Shh signaling, which may have resulted from defective cilia. These data further suggested that arl6ip1 is required for neural crest migration. Finally, by double staining of TUNEL and crestin, we confirmed that the loss of neural crest cells could not be attributed to apoptosis. CONCLUSIONS/SIGNIFICANCE: Therefore, we concluded that arl6ip1 is required for neural crest migration and sublineage specification. PMID- 22427907 TI - Factors associated with height catch-up and catch-down growth among schoolchildren. AB - In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirao Preto (RP), a more developed city, and in Sao Luis (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score >= 0.67 was considered catch-up; a change in z-score <= -0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only (preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10(th) percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families (RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch down growth. PMID- 22427908 TI - HIV knowledge and associated factors among internet-using men who have sex with men (MSM) in South Africa and the United States. AB - BACKGROUND: We compared factors associated with low HIV/AIDS knowledge among internet-using MSM in South Africa and the United States. METHODS: 1,154 MSM in the US and 439 MSM in South Africa, recruited through Facebook.com, completed an online survey using a US-validated HIV knowledge scale (HIV-KQ-18). Separate multivariable logistic regression models were built, one for the US and one for South Africa, using a dichotomized variable of scoring less than and equal to 13/18 ("low knowledge") on the HIV-KQ-18 as outcome. RESULTS: Median knowledge scores were 16/18 for both groups of respondents. For South African MSM, factors associated with low knowledge were: a high school education or less (adjusted odds ratio [aOR]: 2.5, 95% confidence interval [CI]: 1.4-4.6), not using condom compatible lubrication during last anal sex with another man (aOR: 1.9, CI: 1.0 3.5), number of gay or bisexual acquaintances (aOR: 0.89, CI: 0.81-0.99), being unemployed (aOR: 2.2, CI: 1.0-4.6), and testing HIV negative (aOR: 0.30, CI: 0.16 0.59) or testing HIV positive (aOR: 0.15, CI: 0.03-0.74) compared to those never HIV tested. For US MSM, associated factors were: a high school education or less (aOR: 2.7, CI: 1.9-3.8), low pride and acceptance of homosexuality (aOR: 1.3, CI: 1.2-1.5), age 18-24 (aOR: 2.3, CI: 1.3-3.8) or age 50+ (aOR: 3.2, CI: 1.6-6.3) compared to age 25-29, Hispanic ethnicity compared to white non-Hispanic (aOR: 1.9, CI: 1.1-3.2), and testing HIV positive (aOR: 0.34, CI: 0.16-0.69) or testing HIV negative (aOR: 0.59, CI: 0.39-0.89) compared to those never HIV tested [corrected]. CONCLUSIONS: Those developing programs for MSM in South Africa should weigh these data and other relevant factors, and might consider focusing education services towards MSM with limited education, less integration into gay/bisexual communities, no HIV testing history, limited use of condom compatible lube, and the unemployed. In the United States, Hispanic MSM, those with limited education, no HIV testing history, low pride/acceptance of homosexuality, and those aged 18-24 or 50+ may be at risk for gaps in HIV knowledge. PMID- 22427909 TI - Effects of subthalamic nucleus lesions and stimulation upon corticostriatal afferents in the 6-hydroxydopamine-lesioned rat. AB - Abnormalities of striatal glutamate neurotransmission may play a role in the pathophysiology of Parkinson's disease and may respond to neurosurgical interventions, specifically stimulation or lesioning of the subthalamic nucleus (STN). The major glutamatergic afferent pathways to the striatum are from the cortex and thalamus, and are thus likely to be sources of striatal neuronally released glutamate. Corticostriatal terminals can be distinguished within the striatum at the electron microscopic level as their synaptic vesicles contain the vesicular glutamate transporter, VGLUT1. The majority of terminals which are immunolabeled for glutamate but are not VGLUT1 positive are likely to be thalamostriatal afferents. We compared the effects of short term, high frequency, STN stimulation and lesioning in 6-hydroxydopamine (6OHDA)-lesioned rats upon striatal terminals immunolabeled for both presynaptic glutamate and VGLUT1. 6OHDA lesions resulted in a small but significant increase in the proportions of VGLUT1 labeled terminals making synapses on dendritic shafts rather than spines. STN stimulation for one hour, but not STN lesions, increased the proportion of synapses upon spines. The density of presynaptic glutamate immuno-gold labeling was unchanged in both VGLUT1-labeled and -unlabeled terminals in 6OHDA-lesioned rats compared to controls. Rats with 6OHDA lesions+STN stimulation showed a decrease in nerve terminal glutamate immuno-gold labeling in both VGLUT1-labeled and -unlabeled terminals. STN lesions resulted in a significant decrease in the density of presynaptic immuno-gold-labeled glutamate only in VGLUT1-labeled terminals. STN interventions may achieve at least part of their therapeutic effect in PD by normalizing the location of corticostriatal glutamatergic terminals and by altering striatal glutamatergic neurotransmission. PMID- 22427910 TI - Uropathogenic Escherichia coli induces serum amyloid a in mice following urinary tract and systemic inoculation. AB - Serum amyloid A (SAA) is an acute phase protein involved in the homeostasis of inflammatory responses and appears to be a vital host defense component with protective anti-infective properties. SAA expression remains poorly defined in many tissues, including the urinary tract which often faces bacterial challenge. Urinary tract infections (UTIs) are usually caused by strains of uropathogenic Escherichia coli (UPEC) and frequently occur among otherwise healthy individuals, many of whom experience bouts of recurrent and relapsing infections despite the use of antibiotics. To date, whether SAA is present in the infected urothelium and whether or not the induction of SAA can protect the host against UPEC is unclear. Here we show, using mouse models coupled with immunofluorescence microscopy and quantitative RT-PCR, that delivery of UPEC either directly into the urinary tract via catheterization or systemically via intraperitoneal injection triggers the expression of SAA. As measured by ELISA, serum levels of SAA1/2 were also transiently elevated in response to UTI, but circulating SAA3 levels were only up-regulated substantially following intraperitoneal inoculation of UPEC. In in vitro assays, physiological relevant levels of SAA1/2 did not affect the growth or viability of UPEC, but were able to block biofilm formation by the uropathogens. We suggest that SAA functions as a critical host defense against UTIs, preventing the formation of biofilms both upon and within the urothelium and possibly providing clinicians with a sensitive serological marker for UTI. PMID- 22427911 TI - Electron tomography of fusiform vesicles and their organization in urothelial cells. AB - The formation of fusiform vesicles (FVs) is one of the most distinctive features in the urothelium of the urinary bladder. FVs represent compartments for intracellular transport of urothelial plaques, which modulate the surface area of the superficial urothelial (umbrella) cells during the distension-contraction cycle. We have analysed the three-dimensional (3D) structure of FVs and their organization in umbrella cells of mouse urinary bladders. Compared to chemical fixation, high pressure freezing gave a new insight into the ultrastructure of urothelial cells. Electron tomography on serial sections revealed that mature FVs had a shape of flattened discs, with a diameter of up to 1.2 um. The lumen between the two opposing asymmetrically thickened membranes was very narrow, ranging from 5 nm to 10 nm. Freeze-fracturing and immunolabelling confirmed that FVs contain two opposing urothelial plaques connected by a hinge region that made an omega shaped curvature. In the central cytoplasm, 4-15 FVs were often organized into stacks. In the subapical cytoplasm, FVs were mainly organized as individual vesicles. Distension-contraction cycles did not affect the shape of mature FVs; however, their orientation changed from parallel in distended to perpendicular in contracted bladder with respect to the apical plasma membrane. In the intermediate cells, shorter and more dilated immature FVs were present. The salient outcome from this research is the first comprehensive, high resolution 3D view of the ultrastructure of FVs and how they are organized differently depending on their location in the cytoplasm of umbrella cells. The shape of mature FVs and their organization into tightly packed stacks makes them a perfect storage compartment, which transports large amounts of urothelial plaques while occupying a small volume of umbrella cell cytoplasm. PMID- 22427912 TI - Quantifying neighbourhood socioeconomic effects in clustering of behaviour related risk factors: a multilevel analysis. AB - BACKGROUND: The extent to which neighbourhood characteristics explain accumulation of health behaviours is poorly understood. We examined whether neighbourhood disadvantage was associated with co-occurrence of behaviour-related risk factors, and how much of the neighbourhood differences in the co-occurrence can be explained by individual and neighbourhood level covariates. METHODS: The study population consisted of 60 694 Finnish Public Sector Study participants in 2004 and 2008. Neighbourhood disadvantage was determined using small-area level information on household income, education attainment, and unemployment rate, and linked with individual data using Global Positioning System-coordinates. Associations between neighbourhood disadvantage and co-occurrence of three behaviour-related risk factors (smoking, heavy alcohol use, and physical inactivity), and the extent to which individual and neighbourhood level covariates explain neighbourhood differences in co-occurrence of risk factors were determined with multilevel cumulative logistic regression. RESULTS: After adjusting for age, sex, marital status, and population density we found a dose response relationship between neighbourhood disadvantage and co-occurrence of risk factors within each level of individual socioeconomic status. The cumulative odds ratios for the sum of health risks comparing the most to the least disadvantaged neighbourhoods ranged between 1.13 (95% confidence interval (CI): 1.03-1.24) and 1.75 (95% CI, 1.54-1.98). Individual socioeconomic characteristics explained 35%, and neighbourhood disadvantage and population density 17% of the neighbourhood differences in the co-occurrence of risk factors. CONCLUSIONS: Co occurrence of poor health behaviours associated with neighbourhood disadvantage over and above individual's own socioeconomic status. Neighbourhood differences cannot be captured using individual socioeconomic factors alone, but neighbourhood level characteristics should also be considered. PMID- 22427913 TI - Structure-based high-throughput epitope analysis of hexon proteins in B and C species human adenoviruses (HAdVs). AB - Human adenoviruses (HAdVs) are the etiologic agent of many human infectious diseases. The existence of at least 54 different serotypes of HAdVs has resulted in difficulties in clinical diagnosis. Acute respiratory tract disease (ARD) caused by some serotypes from B and C species is particularly serious. Hexon, the main coat protein of HAdV, contains the major serotype-specific B cell epitopes; however, few studies have addressed epitope mapping in most HAdV serotypes. In this study, we utilized a novel and rapid method for the modeling of homologous proteins based on the phylogenetic tree of protein families and built three dimensional (3D) models of hexon proteins in B and C species HAdVs. Based on refined hexon structures, we used reverse evolutionary trace (RET) bioinformatics analysis combined with a specially designed hexon epitope screening algorithm to achieve high-throughput epitope mapping of all 13 hexon proteins in B and C species HAdVs. This study has demonstrated that all of the epitopes from the 13 hexon proteins are located in the proteins' tower regions; however, the exact number, location, and size of the epitopes differ among the HAdV serotypes. PMID- 22427914 TI - Rhodococcus bacteremia in cancer patients is mostly catheter related and associated with biofilm formation. AB - Rhodococcus is an emerging cause of opportunistic infection in immunocompromised patients, most commonly causing cavitary pneumonia. It has rarely been reported as a cause of isolated bacteremia. However, the relationship between bacteremia and central venous catheter is unknown. Between 2002 and 2010, the characteristics and outcomes of seventeen cancer patients with Rhodococcus bacteremia and indwelling central venous catheters were evaluated. Rhodococcus bacteremias were for the most part (94%) central line-associated bloodstream infection (CLABSI). Most of the bacteremia isolates were Rhodococcus equi (82%). Rhodococcus isolates formed heavy microbial biofilm on the surface of polyurethane catheters, which was reduced completely or partially by antimicrobial lock solution. All CLABSI patients had successful response to catheter removal and antimicrobial therapy. Rhodococcus species should be added to the list of biofilm forming organisms in immunocompromised hosts and most of the Rhodococcus bacteremias in cancer patients are central line associated. PMID- 22427915 TI - Identity negative priming: a phenomenon of perception, recognition or selection? AB - The present study addresses the problem whether negative priming (NP) is due to information processing in perception, recognition or selection. We argue that most NP studies confound priming and perceptual similarity of prime-probe episodes and implement a color-switch paradigm in order to resolve the issue. In a series of three identity negative priming experiments with verbal naming response, we determined when NP and positive priming (PP) occur during a trial. The first experiment assessed the impact of target color on priming effects. It consisted of two blocks, each with a different fixed target color. With respect to target color no differential priming effects were found. In Experiment 2 the target color was indicated by a cue for each trial. Here we resolved the confounding of perceptual similarity and priming condition. In trials with coinciding colors for prime and probe, we found priming effects similar to Experiment 1. However, trials with a target color switch showed such effects only in trials with role-reversal (distractor-to-target or target-to-distractor), whereas the positive priming (PP) effect in the target-repetition trials disappeared. Finally, Experiment 3 split trial processing into two phases by presenting the trial-wise color cue only after the stimulus objects had been recognized. We found recognition in every priming condition to be faster than in control trials. We were hence led to the conclusion that PP is strongly affected by perception, in contrast to NP which emerges during selection, i.e., the two effects cannot be explained by a single mechanism. PMID- 22427916 TI - Cellular phenotype-dependent and -independent effects of vitamin C on the renewal and gene expression of mouse embryonic fibroblasts. AB - Vitamin C has been shown to delay the cellular senescence and was considered a candidate for chemoprevention and cancer therapy. To understand the reported contrasting roles of vitamin C: growth-promoting in the primary cells and growth inhibiting in cancer cells, primary mouse embryonic fibroblasts (MEF) and their isogenic spontaneously immortalized fibroblasts with unlimited cell division potential were used as the model pair. We used microarray gene expression profiling to show that the immortalized MEF possess human cancer gene expression fingerprints including a pattern of up-regulation of inflammatory response related genes. Using the MEF model, we found that a physiological treatment level of vitamin C (10(-5) M), but not other unrelated antioxidants, enhanced cell growth. The growth-promoting effect was associated with a pattern of enhanced expression of cell cycle- and cell division-related genes in both primary and immortalized cells. In the immortalized MEF, physiological treatment levels of vitamin C also enhanced the expression of immortalization-associated genes including a down-regulation of genes in the extracellular matrix functional category. In contrast, confocal immunofluorescence imaging of the primary MEF suggested an increase in collagen IV protein upon vitamin C treatment. Similar to the cancer cells, the growth-inhibitory effect of the redox-active form of vitamin C was preferentially observed in immortalized MEF. All effects of vitamin C required its intracellular presence since the transporter-deficient SVCT2-/- MEF did not respond to vitamin C. SVCT2-/- MEF divided and became immortalized readily indicating little dependence on vitamin C for the cell division. Immortalized SVCT2-/- MEF required higher concentration of vitamin C for the growth inhibition compared to the immortalized wildtype MEF suggesting an intracellular vitamin C toxicity. The relevance of our observation in aging and human cancer prevention was discussed. PMID- 22427917 TI - Characterization of the active microbiotas associated with honey bees reveals healthier and broader communities when colonies are genetically diverse. AB - Recent losses of honey bee colonies have led to increased interest in the microbial communities that are associated with these important pollinators. A critical function that bacteria perform for their honey bee hosts, but one that is poorly understood, is the transformation of worker-collected pollen into bee bread, a nutritious food product that can be stored for long periods in colonies. We used 16S rRNA pyrosequencing to comprehensively characterize in genetically diverse and genetically uniform colonies the active bacterial communities that are found on honey bees, in their digestive tracts, and in bee bread. This method provided insights that have not been revealed by past studies into the content and benefits of honey bee-associated microbial communities. Colony microbiotas differed substantially between sampling environments and were dominated by several anaerobic bacterial genera never before associated with honey bees, but renowned for their use by humans to ferment food. Colonies with genetically diverse populations of workers, a result of the highly promiscuous mating behavior of queens, benefited from greater microbial diversity, reduced pathogen loads, and increased abundance of putatively helpful bacteria, particularly species from the potentially probiotic genus Bifidobacterium. Across all colonies, Bifidobacterium activity was negatively correlated with the activity of genera that include pathogenic microbes; this relationship suggests a possible target for understanding whether microbes provide protective benefits to honey bees. Within-colony diversity shapes microbiotas associated with honey bees in ways that may have important repercussions for colony function and health. Our findings illuminate the importance of honey bee-bacteria symbioses and examine their intersection with nutrition, pathogen load, and genetic diversity, factors that are considered key to understanding honey bee decline. PMID- 22427918 TI - FLASH knockdown sensitizes cells to Fas-mediated apoptosis via down-regulation of the anti-apoptotic proteins, MCL-1 and Cflip short. AB - FLASH (FLICE-associated huge protein or CASP8AP2) is a large multifunctional protein that is involved in many cellular processes associated with cell death and survival. It has been reported to promote apoptosis, but we show here that depletion of FLASH in HT1080 cells by siRNA interference can also accelerate the process. As shown previously, depletion of FLASH halts growth by down-regulating histone biosynthesis and arrests the cell cycle in S-phase. FLASH knockdown followed by stimulating the cells with Fas ligand or anti-Fas antibodies was found to be associated with a more rapid cleavage of PARP, accelerated activation of caspase-8 and the executioner caspase-3 and rapid progression to cellular disintegration. As is the case for most anti-apoptotic proteins, FLASH was degraded soon after the onset of apoptosis. Depletion of FLASH also resulted in the reduced intracellular levels of the anti-apoptotic proteins, MCL-1 and the short isoform of cFLIP. FLASH knockdown in HT1080 mutant cells defective in p53 did not significantly accelerate Fas mediated apoptosis indicating that the effect was dependent on functional p53. Collectively, these results suggest that under some circumstances, FLASH suppresses apoptosis. PMID- 22427919 TI - Transposable elements are a major cause of somatic polymorphism in Vitis vinifera L. AB - Through multiple vegetative propagation cycles, clones accumulate mutations in somatic cells that are at the origin of clonal phenotypic diversity in grape. Clonal diversity provided clones such as Cabernet-Sauvignon N degrees 470, Chardonnay N degrees 548 and Pinot noir N degrees 777 which all produce wines of superior quality. The economic impact of clonal selection is therefore very high: since approx. 95% of the grapevines produced in French nurseries originate from the French clonal selection. In this study we provide the first broad description of polymorphism in different clones of a single grapevine cultivar, Pinot noir, in the context of vegetative propagation. Genome sequencing was performed using 454 GS-FLX methodology without a priori, in order to identify and quantify for the first time molecular polymorphisms responsible for clonal variability in grapevine. New generation sequencing (NGS) was used to compare a large portion of the genome of three Pinot noir clones selected for their phenotypic differences. Reads obtained with NGS and the sequence of Pinot noir ENTAV-INRA(r) 115 sequenced by Velasco et al., were aligned on the PN40024 reference sequence. We then searched for molecular polymorphism between clones. Three types of polymorphism (SNPs, Indels, mobile elements) were found but insertion polymorphism generated by mobile elements of many families displayed the highest mutational event with respect to clonal variation. Mobile elements inducing insertion polymorphism in the genome of Pinot noir were identified and classified and a list is presented in this study as potential markers for the study of clonal variation. Among these, the dynamic of four mobile elements with a high polymorphism level were analyzed and insertion polymorphism was confirmed in all the Pinot clones registered in France. PMID- 22427920 TI - Population based model of human embryonic stem cell (hESC) differentiation during endoderm induction. AB - The mechanisms by which human embryonic stem cells (hESC) differentiate to endodermal lineage have not been extensively studied. Mathematical models can aid in the identification of mechanistic information. In this work we use a population-based modeling approach to understand the mechanism of endoderm induction in hESC, performed experimentally with exposure to Activin A and Activin A supplemented with growth factors (basic fibroblast growth factor (FGF2) and bone morphogenetic protein 4 (BMP4)). The differentiating cell population is analyzed daily for cellular growth, cell death, and expression of the endoderm proteins Sox17 and CXCR4. The stochastic model starts with a population of undifferentiated cells, wherefrom it evolves in time by assigning each cell a propensity to proliferate, die and differentiate using certain user defined rules. Twelve alternate mechanisms which might describe the observed dynamics were simulated, and an ensemble parameter estimation was performed on each mechanism. A comparison of the quality of agreement of experimental data with simulations for several competing mechanisms led to the identification of one which adequately describes the observed dynamics under both induction conditions. The results indicate that hESC commitment to endoderm occurs through an intermediate mesendoderm germ layer which further differentiates into mesoderm and endoderm, and that during induction proliferation of the endoderm germ layer is promoted. Furthermore, our model suggests that CXCR4 is expressed in mesendoderm and endoderm, but is not expressed in mesoderm. Comparison between the two induction conditions indicates that supplementing FGF2 and BMP4 to Activin A enhances the kinetics of differentiation than Activin A alone. This mechanistic information can aid in the derivation of functional, mature cells from their progenitors. While applied to initial endoderm commitment of hESC, the model is general enough to be applicable either to a system of adult stem cells or later stages of ESC differentiation. PMID- 22427921 TI - Fungal endophyte diversity in Sarracenia. AB - Fungal endophytes were isolated from 4 species of the carnivorous pitcher plant genus Sarracenia: S. minor, S. oreophila, S. purpurea, and S. psittacina. Twelve taxa of fungi, 8 within the Ascomycota and 4 within the Basidiomycota, were identified based on PCR amplification and sequencing of the internal transcribed spacer sequences of nuclear ribosomal DNA (ITS rDNA) with taxonomic identity assigned using the NCBI nucleotide megablast search tool. Endophytes are known to produce a large number of metabolites, some of which may contribute to the protection and survival of the host. We speculate that endophyte-infected Sarracenia may benefit from their fungal associates by their influence on nutrient availability from within pitchers and, possibly, by directly influencing the biota within pitchers. PMID- 22427922 TI - Genome-wide haplotype changes produced by artificial selection during modern rice breeding in Japan. AB - During the last 90 years, the breeding of rice has delivered cultivars with improved agronomic and economic characteristics. Crossing of different lines and successive artificial selection of progeny based on their phenotypes have changed the chromosomal constitution of the ancestors of modern rice; however, the nature of these changes is unclear. The recent accumulation of data for genome-wide single-nucleotide polymorphisms (SNPs) in rice has allowed us to investigate the change in haplotype structure and composition. To assess the impact of these changes during modern breeding, we studied 177 Japanese rice accessions, which were categorized into three groups: landraces, improved cultivars developed from 1931 to 1974 (the early breeding phase), and improved cultivars developed from 1975 to 2005 (the late breeding phase). Phylogenetic tree and structure analysis indicated genetic differentiation between non-irrigated (upland) and irrigated (lowland) rice groups as well as genetic structuring within the irrigated rice group that corresponded to the existence of three subgroups. Pedigree analysis revealed that a limited number of landraces and cultivars was used for breeding at the beginning of the period of systematic breeding and that 11 landraces accounted for 70% of the ancestors of the modern improved cultivars. The values for linkage disequilibrium estimated from SNP alleles and the haplotype diversity determined from consecutive alleles in five-SNP windows indicated that haplotype blocks became less diverse over time as a result of the breeding process. A decrease in haplotype diversity, caused by a reduced number of polymorphisms in the haplotype blocks, was observed in several chromosomal regions. However, our results also indicate that new haplotype polymorphisms have been generated across the genome during the breeding process. These findings will facilitate our understanding of the association between particular haplotypes and desirable phenotypes in modern Japanese rice cultivars. PMID- 22427923 TI - Single neurons in M1 and premotor cortex directly reflect behavioral interference. AB - Some motor tasks, if learned together, interfere with each other's consolidation and subsequent retention, whereas other tasks do not. Interfering tasks are said to employ the same internal model whereas noninterfering tasks use different models. The division of function among internal models, as well as their possible neural substrates, are not well understood. To investigate these questions, we compared responses of single cells in the primary motor cortex and premotor cortex of primates to interfering and noninterfering tasks. The interfering tasks were visuomotor rotation followed by opposing visuomotor rotation. The noninterfering tasks were visuomotor rotation followed by an arbitrary association task. Learning two noninterfering tasks led to the simultaneous formation of neural activity typical of both tasks, at the level of single neurons. In contrast, and in accordance with behavioral results, after learning two interfering tasks, only the second task was successfully reflected in motor cortical single cell activity. These results support the hypothesis that the representational capacity of motor cortical cells is the basis of behavioral interference and division between internal models. PMID- 22427924 TI - Cryptic bumblebee species: consequences for conservation and the trade in greenhouse pollinators. AB - Commercial greenhouse growers in both Japan and China are increasingly using reared orange-tailed bumblebees known previously as Bombus hypocrita Perez as pollinators. Phylogenetic analysis of the DNA (COI) barcodes with Bayesian methods shows that this "species" is a long-standing confusion of two cryptic species. We find that the orange-tailed bumblebees in North China are actually part of the widespread Russian (otherwise white-tailed) B. patagiatus Nylander (as B. patagiatus ganjsuensis Skorikov, n. comb.), whereas the orange-tailed bees in Japan are true B. hypocrita. This situation has been further complicated because two other cryptic species from North China that were previously confused with the Russian B. patagiatus are now recognised as separate: B. lantschouensis Vogt n. stat. and B. minshanensis Bischoff n. stat.. As demand for pollination services by greenhouse growers inevitably increases, these bees are more likely to be transported between countries. In order to conserve genetic resources of pollinator species for their option value for future food security, we advocate preventing trade and movement of B. patagiatus from China into Japan and of B. hypocrita from Japan into China. PMID- 22427925 TI - Not all are lost: interrupted laboratory monitoring, early death, and loss to follow-up (LTFU) in a large South African treatment program. AB - BACKGROUND: Many HIV treatment programs in resource-limited settings are plagued by high rates of loss to follow-up (LTFU). Most studies have not distinguished between those who briefly interrupt, but return to care, and those more chronically lost to follow-up. METHODS: We conducted a retrospective cohort study of 11,397 adults initiating antiretroviral therapy (ART) in 71 Southern African Catholic Bishops Conference/Catholic Relief Services HIV treatment clinics between January 2004 and December 2008. We distinguished among patients with early death, within the first 7 months on ART; patients with interruptions in laboratory monitoring (ILM), defined as missing visits in the first 7 months on ART, but returning to care by 12 months; and those LTFU, defined as missing all follow-up visits in the first 12 months on ART. We used multilevel logistic regression models to determine patient and clinic-level characteristics associated with these outcomes. RESULTS: In the first year on ART, 60% of patients remained in care, 30% missed laboratory visits, and 10% suffered early death. Of the 3,194 patients who missed laboratory visits, 40% had ILM, resuming care by 12 months. After 12 months on ART, patients with ILM had a 30% increase in detectable viremia compared to those who remained in care. Risk of LTFU decreased with increasing enrollment year, and was lowest for patients who enrolled in 2008 compared to 2004 [OR 0.49, 95%CI 0.39-0.62]. CONCLUSIONS: In a large community-based cohort in South Africa, nearly 30% of patients miss follow up visits for CD4 monitoring in the first year after starting ART. Of those, 40% have ILM but return to clinic with worse virologic outcomes than those who remain in care. The risk of chronic LTFU decreased with enrollment year. As ART availability increases, interruptions in care may become more common, and should be accounted for in addressing program LTFU. PMID- 22427926 TI - Induction of protective immunity against Chlamydia muridarum intravaginal infection with a chlamydial glycogen phosphorylase. AB - We evaluated 7 C. muridarum ORFs for their ability to induce protection against chlamydial infection in a mouse intravaginal infection model. These antigens, although encoded in C. muridarum genome, are transcriptionally regulated by a cryptic plasmid that is known to contribute to C. muridarum pathogenesis. Of the 7 plasmid-regulated ORFs, the chlamydial glycogen phosphorylase or GlgP, when delivered into mice intramuscularly, induced the most pronounced protective immunity against C. muridarum intravaginal infection. The GlgP-immunized mice displayed a significant reduction in vaginal shedding of live organisms on day 14 after infection. The protection correlated well with a robust C. muridarum specific antibody and a Th1-dominant T cell responses, which significantly reduced the severity but not overall incidence of hydrosalpinx. The GlgP-induced partial protection against upper genital tract pathology suggests that GlgP may be considered a component for a multi-subunit vaccine. These results have demonstrated that intramuscular immunization of mice with purified proteins can be used to identify vaccine antigens for preventing intravaginal infection with C. trachomatis in humans. PMID- 22427927 TI - Creating non-believed memories for recent autobiographical events. AB - A recent study showed that many people spontaneously report vivid memories of events that they do not believe to have occurred [1]. In the present experiment we tested for the first time whether, after powerful false memories have been created, debriefing might leave behind nonbelieved memories for the fake events. In Session 1 participants imitated simple actions, and in Session 2 they saw doctored video-recordings containing clips that falsely suggested they had performed additional (fake) actions. As in earlier studies, this procedure created powerful false memories. In Session 3, participants were debriefed and told that specific actions in the video were not truly performed. Beliefs and memories for all critical actions were tested before and after the debriefing. Results showed that debriefing undermined participants' beliefs in fake actions, but left behind residual memory-like content. These results indicate that debriefing can leave behind vivid false memories which are no longer believed, and thus we demonstrate for the first time that the memory of an event can be experimentally dissociated from the belief in the event's occurrence. These results also confirm that belief in and memory for an event can be independently occurring constructs. PMID- 22427928 TI - Calpain cleavage of brain glutamic acid decarboxylase 65 is pathological and impairs GABA neurotransmission. AB - Previously, we have shown that the GABA synthesizing enzyme, L-glutamic acid decarboxylase 65 (GAD65) is cleaved to form its truncated form (tGAD65) which is 2-3 times more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiological stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this communication, we examined the cleavage of fGAD65 under diverse pathological conditions including rats under ischemia/reperfusion insult as well as rat brain synaptosomes and primary neuronal cultures subjected to excessive stimulation with high concentration of KCl. We have shown that the formation of tGAD65 progressively increases with increasing stimulus concentration both in rat brain synaptosomes and primary rat embryo cultures. More importantly, direct cleavage of synaptic vesicle - associated fGAD65 by calpain was demonstrated and the resulting tGAD65 bearing the active site of the enzyme was detached from the synaptic vesicles. Vesicular GABA transport of the newly synthesized GABA was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate as indicated by microdialysis. Moreover, the levels of tGAD65 was also proportional to the degree of cell death when the primary neuronal cultures were exposed to high KCl. Based on these observations, we conclude that calpain mediated cleavage of fGAD65 is pathological, presumably due to decrease in the activity of synaptic vesicle - associated fGAD65 resulting in a decrease in the GABA synthesis - packaging coupling process leading to reduced GABA neurotransmission. PMID- 22427930 TI - Rapid, specific detection of alphaviruses from tissue cultures using a replicon defective reporter gene assay. AB - We established a rapid, specific technique for detecting alphaviruses using a replicon-defective reporter gene assay derived from the Sindbis virus XJ-160. The pVaXJ expression vector containing the XJ-160 genome was engineered to form the expression vectors pVaXJ-EGFP expressing enhanced green fluorescence protein (EGFP) or pVaXJ-GLuc expressing Gaussia luciferase (GLuc). The replicon-defective reporter plasmids pVaXJ-EGFPDeltansp4 and pVaXJ-GLucDeltansp4 were constructed by deleting 1139 bp in the non-structural protein 4 (nsP4) gene. The deletion in the nsP4 gene prevented the defective replicons from replicating and expressing reporter genes in transfected BHK-21 cells. However, when these transfected cells were infected with an alphavirus, the non-structural proteins expressed by the alphavirus could act on the defective replicons in trans and induce the expression of the reporter genes. The replicon-defective plasmids were used to visualize the presence of alphavirus qualitatively or detect it quantitatively. Specificity tests showed that this assay could detect a variety of alphaviruses from tissue cultures, while other RNA viruses, such as Japanese encephalitis virus and Tahyna virus, gave negative results with this system. Sensitivity tests showed that the limit of detection (LOD) of this replicon-defective assay is between 1 and 10 PFU for Sindbis viruses. These results indicate that, with the help of the replicon-defective alphavirus detection technique, we can specifically, sensitively, and rapidly detect alphaviruses in tissue cultures. The detection technique constructed here may be well suited for use in clinical examination and epidemiological surveillance, as well as for rapid screening of potential viral biological warfare agents. PMID- 22427929 TI - CXCL12 mediates trophic interactions between endothelial and tumor cells in glioblastoma. AB - Emerging evidence suggests endothelial cells (EC) play a critical role in promoting Glioblastoma multiforme (GBM) cell proliferation and resistance to therapy. The molecular basis for GBM-EC interactions is incompletely understood. We hypothesized that the chemokine CXCL12 and its receptor CXCR4 could mediate direct interactions between GBM cells and tumor-associated endothelial cells and that disruption of this interaction might be the molecular basis for the anti tumor effects of CXCR4 antagonists. We investigated this possibility in vivo and in an in vitro co-culture model that incorporated extracellular matrix, primary human brain microvascular ECs (HBMECs) and either an established GBM cell line or primary GBM specimens. Depletion of CXCR4 in U87 GBM cells blocked their growth as intracranial xenografts indicating that tumor cell CXCR4 is required for tumor growth in vivo. In vitro, co-culture of either U87 cells or primary GBM cells with HBMECs resulted in their co-localization and enhanced GBM cell growth. Genetic manipulation of CXCL12 expression and pharmacological inhibition of its receptors CXCR4 and CXCR7 revealed that the localizing and trophic effects of endothelial cells on GBM cells were dependent upon CXCL12 and CXCR4. These findings indicate that the CXCL12/CXCR4 pathway directly mediates endothelial cell trophic function in GBMs and that inhibition of CXCL12-CXCR4 signaling may uniquely target this activity. Therapeutic disruption of endothelial cell trophic functions could complement the structural disruption of anti-angiogenic regimens and, in combination, might also improve the efficacy of radiation and chemotherapy in treating GBMs. PMID- 22427931 TI - A model for how signal duration can determine distinct outcomes of gene transcription programs. AB - The reason why IL-6 induces a pro-inflammatory response, while IL-10 induces an anti-inflammatory response, despite both cytokines activating the same transcription factor, STAT3, is not well understood. It is known that IL-6 induces a transient STAT3 signal and that IL-10 induces a sustained STAT3 signal due to the STAT3-induced inhibitor SOCS3's ability to bind to the IL-6R and not the IL-10R. We sought to develop a general transcriptional network that is capable of translating sustained signals into one response, while translating transient signals into a second response. The general structure of such a network is that the transcription factor STAT3 can induce both an inflammatory response and an anti-inflammatory response by inducing two different genes. The anti inflammatory gene can bind to and inhibit the inflammatory gene's production and the inflammatory gene can bind to its own promoter and induce its own transcription in the absence of the signal. One prediction that can be made from such a network is that in SOCS3-/- mice, where IL-6 induces a sustained STAT3 signal, that IL-6 would act as an anti-inflammatory cytokine, which has indeed been observed experimentally in the literature. PMID- 22427932 TI - Inhibition of melanogenesis by the pyridinyl imidazole class of compounds: possible involvement of the Wnt/beta-catenin signaling pathway. AB - While investigating the role of p38 MAPK in regulating melanogenesis, we found that pyridinyl imidazole inhibitors class compounds as well as the analog compound SB202474, which does not inhibit p38 MAPK, suppressed both alpha-MSH induced melanogenesis and spontaneous melanin synthesis. In this study, we demonstrated that the inhibitory activity of the pyridinyl imidazoles correlates with inhibition of the canonical Wnt/beta-catenin pathway activity. Imidazole treated cells showed a reduction in the level of Tcf/Lef target genes involved in the beta-catenin signaling network, including ubiquitous genes such as Axin2, Lef1, and Wisp1 as well as cell lineage-restricted genes such as microphthalmia associated transcription factor and dopachrome tautomerase. Although over expression of the Wnt signaling pathway effector beta-catenin slightly restored the melanogenic program, the lack of complete reversion suggested that the imidazoles interfered with beta-catenin-dependent transcriptional activity rather than with beta-catenin expression. Accordingly, we did not observe any significant change in beta-catenin protein expression. The independence of p38 MAPK activity from the repression of Wnt/beta-catenin signaling pathway was confirmed by small interfering RNA knockdown of p38 MAPK expression, which by contrast, stimulated beta-catenin-driven gene expression. Our data demonstrate that the small molecule pyridinyl imidazoles possess two distinct and opposite mechanisms that modulate beta-catenin dependent transcription: a p38 inhibition dependent effect that stimulates the Wnt pathway by increasing beta-catenin protein expression and an off-target mechanism that inhibits the pathway by repressing beta-catenin protein functionality. The p38-independent effect seems to be dominant and, at least in B16-F0 cells, results in a strong block of the Wnt/beta-catenin signaling pathway. PMID- 22427933 TI - Embryonic diapause is conserved across mammals. AB - Embryonic diapause (ED) is a temporary arrest of embryo development and is characterized by delayed implantation in the uterus. ED occurs in blastocysts of less than 2% of mammalian species, including the mouse (Mus musculus). If ED were an evolutionarily conserved phenomenon, then it should be inducible in blastocysts of normally non-diapausing mammals, such as domestic species. To prove this hypothesis, we examined whether blastocysts from domestic sheep (Ovis aries) could enter into diapause following their transfer into mouse uteri in which diapause conditions were induced. Sheep blastocysts entered into diapause, as demonstrated by growth arrest, viability maintenance and their ED-specific pattern of gene expression. Seven days after transfer, diapausing ovine blastocysts were able to resume growth in vitro and, after transfer to surrogate ewe recipients, to develop into normal lambs. The finding that non-diapausing ovine embryos can enter into diapause implies that this phenomenon is phylogenetically conserved and not secondarily acquired by embryos of diapausing species. Our study questions the current model of independent evolution of ED in different mammalian orders. PMID- 22427934 TI - Acquired idiopathic ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in a population from Japan. AB - Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13 deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed. PMID- 22427935 TI - Capsaicin protects mice from community-associated methicillin-resistant Staphylococcus aureus pneumonia. AB - BACKGROUND: alpha-toxin is one of the major virulence factors secreted by most Staphylococcus aureus strains, which played a central role in the pathogenesis of S. aureus pneumonia. The aim of this study was to investigate the impact of capsaicin on the production of alpha-toxin by community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) strain USA 300 and to further assess its performance in the treatment of CA-MRSA pneumonia in a mouse model. METHODOLOGY/PRINCIPAL FINDINGS: The in vitro effects of capsaicin on alpha-toxin production by S. aureus USA 300 were determined using hemolysis, western blot, and real-time RT-PCR assays. The influence of capsaicin on the alpha-toxin mediated injury of human alveolar epithelial cells was determined using viability and cytotoxicity assays. Mice were infected intranasally with S. aureus USA300; the in vivo protective effects of capsaicin against S. aureus pneumonia were assessed by monitoring the mortality, histopathological changes and cytokine levels. Low concentrations of capsaicin substantially decreased the production of alpha-toxin by S. aureus USA 300 without affecting the bacterial viability. The addition of capsaicin prevented alpha-toxin-mediated human alveolar cell (A549) injury in co-culture with S. aureus. Furthermore, the in vivo experiments indicated that capsaicin protected mice from CA-MRSA pneumonia caused by strain USA 300. CONCLUSIONS/SIGNIFICANCE: Capsaicin inhibits the production of alpha toxin by CA-MRSA strain USA 300 in vitro and protects mice from CA-MRSA pneumonia in vivo. However, the results need further confirmation with other CA-MRSA lineages. This study supports the views of anti-virulence as a new antibacterial approach for chemotherapy. PMID- 22427936 TI - Ferredoxin containing bacteriocins suggest a novel mechanism of iron uptake in Pectobacterium spp. AB - In order to kill competing strains of the same or closely related bacterial species, many bacteria produce potent narrow-spectrum protein antibiotics known as bacteriocins. Two sequenced strains of the phytopathogenic bacterium Pectobacterium carotovorum carry genes encoding putative bacteriocins which have seemingly evolved through a recombination event to encode proteins containing an N-terminal domain with extensive similarity to a [2Fe-2S] plant ferredoxin and a C-terminal colicin M-like catalytic domain. In this work, we show that these genes encode active bacteriocins, pectocin M1 and M2, which target strains of Pectobacterium carotovorum and Pectobacterium atrosepticum with increased potency under iron limiting conditions. The activity of pectocin M1 and M2 can be inhibited by the addition of spinach ferredoxin, indicating that the ferredoxin domain of these proteins acts as a receptor binding domain. This effect is not observed with the mammalian ferredoxin protein adrenodoxin, indicating that Pectobacterium spp. carries a specific receptor for plant ferredoxins and that these plant pathogens may acquire iron from the host through the uptake of ferredoxin. In further support of this hypothesis we show that the growth of strains of Pectobacterium carotovorum and atrosepticum that are not sensitive to the cytotoxic effects of pectocin M1 is enhanced in the presence of pectocin M1 and M2 under iron limiting conditions. A similar growth enhancement under iron limiting conditions is observed with spinach ferrodoxin, but not with adrenodoxin. Our data indicate that pectocin M1 and M2 have evolved to parasitise an existing iron uptake pathway by using a ferredoxin-containing receptor binding domain as a Trojan horse to gain entry into susceptible cells. PMID- 22427937 TI - Identification of nucleic acid binding sites on translin-associated factor X (TRAX) protein. AB - Translin and TRAX proteins play roles in very important cellular processes such as DNA recombination, spatial and temporal expression of mRNA, and in siRNA processing. Translin forms a homomeric nucleic acid binding complex and binds to ssDNA and RNA. However, a mutant translin construct that forms homomeric complex lacking nucleic acid binding activity is able to form fully active heteromeric translin-TRAX complex when co-expressed with TRAX. A substantial progress has been made in identifying translin sites that mediate its binding activity, while TRAX was thought not to bind DNA or RNA on its own. We here for the first time demonstrate nucleic acid binding to TRAX by crosslinking radiolabeled ssDNA to heteromeric translin-TRAX complex using UV-laser. The TRAX and translin, photochemically crosslinked with ssDNA, were individually detected on SDS-PAGE. We mutated two motifs in TRAX and translin, designated B2 and B3, to help define the nucleic acid binding sites in the TRAX sequence. The most pronounced effect was observed in the mutants of B3 motif that impaired nucleic acid binding activity of the heteromeric complexes. We suggest that both translin and TRAX are binding competent and contribute to the nucleic acid binding activity. PMID- 22427938 TI - Analysis of microsatellite variation in Drosophila melanogaster with population scale genome sequencing. AB - Genome sequencing technologies promise to revolutionize our understanding of genetics, evolution, and disease by making it feasible to survey a broad spectrum of sequence variation on a population scale. However, this potential can only be realized to the extent that methods for extracting and interpreting distinct forms of variation can be established. The error profiles and read length limitations of early versions of next-generation sequencing technologies rendered them ineffective for some sequence variant types, particularly microsatellites and other tandem repeats, and fostered the general misconception that such variants are inherently inaccessible to these platforms. At the same time, tandem repeats have emerged as important sources of functional variation. Tandem repeats are often located in and around genes, and frequent mutations in their lengths exert quantitative effects on gene function and phenotype, rapidly degrading linkage disequilibrium between markers and traits. Sensitive identification of these variants in large-scale next-gen sequencing efforts will enable more comprehensive association studies capable of revealing previously invisible associations. We present a population-scale analysis of microsatellite repeats using whole-genome data from 158 inbred isolates from the Drosophila Genetics Reference Panel, a collection of over 200 extensively phenotypically characterized isolates from a single natural population, to uncover processes underlying repeat mutation and to enable associations with behavioral, morphological, and life-history traits. Analysis of repeat variation from next generation sequence data will also enhance studies of genome stability and neurodegenerative diseases. PMID- 22427939 TI - The homeostatic chemokine CCL21 predicts mortality and may play a pathogenic role in heart failure. AB - BACKGROUND: CCL19 and CCL21, acting through CCR7, are termed homeostatic chemokines. Based on their role in concerting immunological responses and their proposed involvement in tissue remodeling, we hypothesized that these chemokines could play a pathogenic role in heart failure (HF). METHODOLOGY/PRINCIPAL FINDINGS: Our main findings were: (i) Serum levels of CCL19 and particularly CCL21 were markedly raised in patients with chronic HF (n = 150) as compared with healthy controls (n = 20). A CCL21 level above median was independently associated with all-cause mortality. (ii) In patients with HF following acute myocardial infarction (MI; n = 232), high versus low CCL21 levels 1 month post-MI were associated with cardiovascular mortality, even after adjustment for established risk factors. (iii). Explanted failing human LV tissue (n = 29) had markedly increased expression of CCL21 as compared with non-failing myocardium (n = 5). (iv) Our studies in CCR7(-/-) mice showed improved survival and attenuated increase in markers of myocardial dysfunction and wall stress in post-MI HF after 1 week, accompanied by increased myocardial expression of markers of regulatory T cells. (v) Six weeks post-MI, there was an increase in markers of myocardial dysfunction and wall stress in CCR7 deficient mice. CONCLUSIONS/SIGNIFICANCE: High serum levels of CCL21 are independently associated with mortality in chronic and acute post-MI HF. Our findings in CCR7 deficient mice may suggest that CCL21 is not only a marker, but also a mediator of myocardial failure. However, while short term inhibition of CCR7 may be beneficial following MI, a total lack of CCR7 during long-term follow-up could be harmful. PMID- 22427940 TI - Carbon monoxide promotes respiratory hemoproteins iron reduction using peroxides as electron donors. AB - The physiological role of the respiratory hemoproteins (RH), hemoglobin and myoglobin, is to deliver O(2) via its binding to their ferrous (Fe(II)) heme iron. Under variety of pathological conditions RH proteins leak to blood plasma and oxidized to ferric (Fe(III), met) forms becoming the source of oxidative vascular damage. However, recent studies have indicated that both metRH and peroxides induce Heme Oxygenase (HO) enzyme producing carbon monoxide (CO). The gas has an extremely high affinity for the ferrous heme-iron and is known to reduce ferric hemoproteins in the presence of suitable electron donors. We hypothesized that under in vivo plasma conditions, peroxides at low concentration can assist the reduction of metRH in presence of CO. The effect of CO on interaction of metRH with hydrophilic or hydrophobic peroxides was analyzed by following Soret and visible light absorption changes in reaction mixtures. It was found that under anaerobic conditions and low concentrations of RH and peroxides mimicking plasma conditions, peroxides served as electron donors and RH were reduced to their ferrous carboxy forms. The reaction rates were dependent on CO as well as peroxide concentrations. These results demonstrate that oxidative activity of acellular ferric RH and peroxides may be amended by CO turning on the reducing potential of peroxides and facilitating the formation of redox-inactive carboxyRH. Our data suggest the possible role of HO/CO in protection of vascular system from oxidative damage. PMID- 22427941 TI - Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells. AB - Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes. PMID- 22427942 TI - Functional epitope core motif of the Anaplasma marginale major surface protein 1a and its incorporation onto bioelectrodes for antibody detection. AB - Anaplasmosis, a persistent intraerythrocytic infection of cattle by Anaplasma marginale, causes severe anemia and a higher rate of abortion, resulting in significant loss to both dairy and beef industries. Clinical diagnosis is based on symptoms and confirmatory laboratory tests are required. Currently, all the diagnostic assays have been developed with whole antigens with indirect ELISA based on multiple epitopes. In a pioneer investigation we demonstrated the use of critical motifs of an epitope as biomarkers for immunosensor applications. Mimotopes of the MSP1a protein functional epitope were obtained through Phage Display after three cycles of selection of a 12-mer random peptide library against the neutralizing monoclonal antibody 15D2. Thirty-nine clones were randomly selected, sequenced, translated and aligned with the native sequence. The consensus sequence SxSSQSEASTSSQLGA was obtained, which is located in C terminal end of the 28-aa repetitive motif of the MSP1a protein, but the alignment and sequences' variation among mimotopes allowed us to map the critical motif STSSxL within the consensus sequence. Based on these results, two peptides were chemically synthesized: one based on the critical motif (STSSQL, Am1) and the other based on the consensus sequence aligned with the native epitope (SEASTSSQLGA, Am2). Sera from 24 infected and 52 healthy animals were tested by ELISA for reactivity against Am1 and Am2, which presented sensitivities of 96% and 100%, respectively. The Am1 peptide was incorporated onto a biolectrode (graphite modified with poly-3-hydroxyphenylacetic acid) and direct serum detection was demonstrated by impedance, differential pulse voltammetry, and atomic force microscopy. The electrochemical sensor system proved to be highly effective in discriminating sera from positive and negative animals. These immunosensors were highly sensitive and selective for positive IgG, contaminants did not affect measurements, and were based on a simple, fast and reproducible electrochemical system. PMID- 22427943 TI - Influenza transmission in a community during a seasonal influenza A(H3N2) outbreak (2010-2011) in Mongolia: a community-based prospective cohort study. AB - BACKGROUND: Knowledge of how influenza viruses spread in a community is important for planning and implementation of effective interventions, including social distancing measures. Households and schools are implicated as the major sites for influenza virus transmission. However, the overall picture of community transmission is not well defined during actual outbreaks. We conducted a community-based prospective cohort study to describe the transmission characteristics of influenza in Mongolia. METHODS AND FINDINGS: A total of 5,655 residents in 1,343 households were included in this cohort study. An active search for cases of influenza-like illness (ILI) was performed between October 2010 and April 2011. Data collected during a community outbreak of influenza A(H3N2) were analyzed. Total 282 ILI cases occurred during this period, and 73% of the subjects were aged <15 years. The highest attack rate (20.4%) was in those aged 1-4 years, whereas the attack rate in those aged 5-9 years was 10.8%. Fifty one secondary cases occurred among 900 household contacts from 43 households (43 index cases), giving an overall crude household secondary attack rate (SAR) of 5.7%. SAR was significantly higher in younger household contacts (relative risk for those aged <1 year: 9.90, 1-4 years: 5.59, and 5-9 years: 6.43). We analyzed the transmission patterns among households and a community and repeated transmissions were detected between households, preschools, and schools. Children aged 1-4 years played an important role in influenza transmission in households and in the community at large. Working-age adults were also a source of influenza in households, whereas elderly cases (aged >= 65 years) had no link with household transmission. CONCLUSIONS: Repeated transmissions between households, preschools, and schools were observed during an influenza A(H3N2) outbreak period in Mongolia, where subjects aged 1-4 years played an important role in influenza transmission. PMID- 22427944 TI - Association of LMP/TAP gene polymorphisms with tuberculosis susceptibility in Li population in China. AB - BACKGROUND: Tuberculosis (TB) is a contagious disease affected by multiple genetic and environmental factors. Several association studies have suggested that cellular immune response is vital for controlling and preventing of tuberculosis infection. Low molecular weight polypeptides (LMPs) and transporters with antigen processing (TAPs) are the main molecules in the processing and presentation pathway for intracellular antigens. This study was performed to elucidate whether these antigen-processing genes (LMP/TAP) polymorphisms could be associated with the risk of tuberculosis infection in China. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 205 active pulmonary tuberculosis patients and 217 normal controls from Li population for this study. Four polymorphisms of LMP/TAP genes were determined by PCR-RFLP assay and haplotypes were constructed by software PHASE 1.0. Of the total four polymorphisms, genotype frequencies of LMP7 AA homozygote and CA heterozygote were significantly greater among cases compared to controls, with odds ratio of 3.77 (95% CI: 1.60-8.89; P = 0.002) and 2.97 (95% CI: 1.80-4.90; P<0.0001), respectively. The genotypes of TAP1-2 GG homozygote and AG heterozygote were more frequent in subjects with TB than in controls, with odds ratio of 3.94 (95% CI: 1.82-8.53; P = 0.001) and 2.87 (95% CI: 1.75-4.71; P<0.0001), respectively. Similarly, we found that haplotype B which carried LMP7 and TAP1-2 variations significantly increased the susceptibility to TB (OR = 3.674, 95% CI: 2.254-5.988; P<0.0001). Moreover, it is noteworthy that the homozygote of wild haplotype A (A/A) may be a strong protection for TB infection. CONCLUSIONS: Our findings suggested that LMP/TAP gene polymorphisms might be risk factors for TB infection among Li population in China. PMID- 22427946 TI - Position of the third Na+ site in the aspartate transporter GltPh and the human glutamate transporter, EAAT1. AB - Glutamate transport via the human excitatory amino acid transporters is coupled to the co-transport of three Na(+) ions, one H(+) and the counter-transport of one K(+) ion. Transport by an archaeal homologue of the human glutamate transporters, Glt(Ph), whose three dimensional structure is known is also coupled to three Na(+) ions but only two Na(+) ion binding sites have been observed in the crystal structure of Glt(Ph). In order to fully utilize the Glt(Ph) structure in functional studies of the human glutamate transporters, it is essential to understand the transport mechanism of Glt(Ph) and accurately determine the number and location of Na(+) ions coupled to transport. Several sites have been proposed for the binding of a third Na(+) ion from electrostatic calculations and molecular dynamics simulations. In this study, we have performed detailed free energy simulations for Glt(Ph) and reveal a new site for the third Na(+) ion involving the side chains of Threonine 92, Serine 93, Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also studied the transport properties of alanine mutants of the coordinating residues Threonine 92 and Serine 93 in Glt(Ph), and the corresponding residues in a human glutamate transporter, EAAT1. The mutant transporters have reduced affinity for Na(+) compared to their wild type counterparts. These results confirm that Threonine 92 and Serine 93 are involved in the coordination of the third Na(+) ion in Glt(Ph) and EAAT1. PMID- 22427945 TI - In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. AB - Manganese (Mn) is an essential metal for development and metabolism. However, exposures to high Mn levels may be toxic, especially to the central nervous system (CNS). Neurotoxicity is commonly due to occupational or environmental exposures leading to Mn accumulation in the basal ganglia and a Parkinsonian-like disorder. Younger individuals are more susceptible to Mn toxicity. Moreover, early exposure may represent a risk factor for the development of neurodegenerative diseases later in life. The present study was undertaken to investigate the developmental neurotoxicity in an in vivo model of immature rats exposed to Mn (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN12. Neurochemical analysis was carried out on PN14. We focused on striatal alterations in intracellular signaling pathways, oxidative stress and cell death. Moreover, motor alterations as a result of early Mn exposure (PN8-12) were evaluated later in life at 3-, 4- and 5-weeks-of-age. Mn altered in a dose dependent manner the activity of key cell signaling elements. Specifically, Mn increased the phosphorylation of DARPP-32-Thr-34, ERK1/2 and AKT. Additionally, Mn increased reactive oxygen species (ROS) production and caspase activity, and altered mitochondrial respiratory chain complexes I and II activities. Mn (10 and 20 mg/kg) also impaired motor coordination in the 3(rd), 4(th) and 5(th) week of life. TroloxTM, an antioxidant, reversed several of the Mn altered parameters, including the increased ROS production and ERK1/2 phosphorylation. However, TroloxTM failed to reverse the Mn (20 mg/kg)-induced increase in AKT phosphorylation and motor deficits. Additionally, Mn (20 mg/kg) decreased the distance, speed and grooming frequency in an open field test; TroloxTM blocked only the decrease of grooming frequency. Taken together, these results establish that short-term exposure to Mn during a specific developmental window (PN8-12) induces metabolic and neurochemical alterations in the striatum that may modulate later-life behavioral changes. Furthermore, some of the molecular and behavioral events, which are perturbed by early Mn exposure are not directly related to the production of oxidative stress. PMID- 22427947 TI - Topical application of activity-based probes for visualization of brain tumor tissue. AB - Several investigators have shown the utility of systemically delivered optical imaging probes to image tumors in small animal models of cancer. Here we demonstrate an innovative method for imaging tumors and tumor margins during surgery. Specifically, we show that optical imaging probes topically applied to tumors and surrounding normal tissue rapidly differentiate between tissues. In contrast to systemic delivery of optical imaging probes which label tumors uniformly over time, topical probe application results in rapid and robust probe activation that is detectable as early as 5 minutes following application. Importantly, labeling is primarily associated with peri-tumor spaces. This methodology provides a means for rapid visualization of tumor and potentially infiltrating tumor cells and has potential applications for directed surgical excision of tumor tissues. Furthermore, this technology could find use in surgical resections for any tumors having differential regulation of cysteine cathepsin activity. PMID- 22427948 TI - The level of DING proteins is increased in HIV-infected patients: in vitro and in vivo studies. AB - DING proteins constitute an interesting family, owing to their intriguing and important activities. However, after a decade of research, little is known about these proteins. In humans, at least five different DING proteins have been identified, which were implicated in important biological processes and diseases, including HIV. Indeed, recent data from different research groups have highlighted the anti-HIV activity of some DING representatives. These proteins share the ability to inhibit the transcriptional step of HIV-1, a key step of the viral cycle that is not yet targeted by the current therapies. Since such proteins have been isolated from humans, we undertook a comprehensive study that focuses on the relationship between these proteins and HIV-infection in an infectious context. Hence, we developed a home-made ELISA for the quantification of the concentration of DING proteins in human serum. Using this method, we were able to determine the concentration of DING proteins in healthy and HIV-infected patients. Interestingly, we observed a significant increase of the concentration of DING proteins in non treated and treated HIV-infected patients compared to controls. In addition, cell cultures infected with HIV also show an increased expression of DING proteins, ruling out the possible role of antiretroviral treatment in the increase of the expression of DING proteins. In conclusion, results from this study show that the organism reacts to HIV-infection by an overexpression of DING proteins. PMID- 22427949 TI - Perilipin 2 (PLIN2)-deficiency does not increase cholesterol-induced toxicity in macrophages. AB - Interventions on macrophages/foam cells to redirect intracellular cholesterol towards efflux pathways could become a very valuable addition to our therapeutic arsenal against atherosclerosis. However, certain manipulations of the cholesteryl ester cycle, such as the inhibition of ACAT1, an ER-resident enzyme that re-esterifies cholesterol, are not well tolerated. Previously we showed that targeting perilipin-2 (PLIN2), a major lipid droplet (LD)-associated protein in macrophages, prevents foam cell formation and protects against atherosclerosis. Here we have assessed the tolerance of PLIN2-deficient bone marrow derived macrophages (BMM) to several lipid loading conditions similar to the found during atherosclerosis development, including exposure to modified low-density lipoprotein (mLDL) and 7-ketocholesterol (7-KC), a free cholesterol (FC) metabolite, in media with or without cholesterol acceptors. BMM isolated from mice that do or do not express PLIN2 were tested for apoptosis (TUNEL and cleaved caspase-3), ER stress (CHOP induction and XBP-1 splicing), and inflammation (TNF alpha and IL-6 mRNA levels). Like in other cell types, PLIN2 deficiency impairs LD buildup in BMM. However, while most stress parameters were elevated in macrophages under ACAT inhibition and 7-KC loading, PLIN2 inactivation was well tolerated. The data support the safety of targeting PLIN2 to prevent foam cell formation and atherosclerosis. PMID- 22427950 TI - Acylsucrose-producing tomato plants forces Bemisia tabaci to shift its preferred settling and feeding site. AB - BACKGROUND: The whitefly Bemisia tabaci (Genn.) causes dramatic damage to plants by transmitting yield-limiting virus diseases. Previous studies proved that the tomato breeding line ABL 14-8 was resistant to B. tabaci, the vector of tomato yellow leaf curl disease (TYLCD). This resistance is based on the presence of type IV glandular trichomes and acylsucrose production. These trichomes deter settling and probing of B. tabaci in ABL 14-8, which reduces primary and secondary spread of TYLCD. METHODOLOGY/PRINCIPAL FINDINGS: Whitefly settlement preference was evaluated on the adaxial and abaxial leaf surfaces of nearly isogenic tomato lines with and without B. tabaci-resistance traits, 'ABL 14-8 and Moneymaker' respectively, under non-choice and free-choice conditions. In addition, the Electrical Penetration Graph technique was used to study probing and feeding activities of B. tabaci on the adaxial and abaxial leaf surfaces of the same genotypes. B. tabaci preferred to settle on the abaxial than on the adaxial surface of 'Moneymaker' leaves, whereas no such preference was observed on ABL 14-8 tomato plants at the ten-leaf growth stage. Furthermore, B. tabaci preferred to feed on the abaxial than on the adaxial leaf surface of 'Moneymarker' susceptible tomato plants as shown by a higher number of sustained phloem feeding ingestion events and a shorter time to reach the phloem. However, B. tabaci standard probing and feeding behavior patterns were altered in ABL 14-8 plants and whiteflies were unable to feed from the phloem and spent more time in non-probing activities when exposed to the abaxial leaf surface. CONCLUSIONS/SIGNIFICANCE: The distorted behavior of B. tabaci on ABL 14-8 protects tomato plants from the transmission of phloem-restricted viruses such as Tomato yellow leaf curl virus (TYLCV), and forces whiteflies to feed on the adaxial side of leaves where they feed less efficiently and become more vulnerable to natural enemies. PMID- 22427951 TI - PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis. AB - PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis. PMID- 22427952 TI - Cysteinyl-tRNA deacylation can be uncoupled from protein synthesis. AB - Aminoacyl-tRNA synthetases (ARSs) are critical components of protein translation, providing ribosomes with aminoacyl-tRNAs. In return, ribosomes release uncharged tRNAs as ARS substrates. Here, we show that tRNA deacylation can be uncoupled from protein synthesis in an amino acid specific manner. While tRNAs coupled to radiolabeled Met, Leu Lys, or Ser are stable in cells following translation inhibition with arsenite, radiolabeled Cys is released from tRNA at a high rate. We discuss possible translation independent functions for tRNA(Cys). PMID- 22427953 TI - Single-cell census of mechanosensitive channels in living bacteria. AB - Bacteria are subjected to a host of different environmental stresses. One such insult occurs when cells encounter changes in the osmolarity of the surrounding media resulting in an osmotic shock. In recent years, a great deal has been learned about mechanosensitive (MS) channels which are thought to provide osmoprotection in these circumstances by opening emergency release valves in response to membrane tension. However, even the most elementary physiological parameters such as the number of MS channels per cell, how MS channel expression levels influence the physiological response of the cells, and how this mean number of channels varies from cell to cell remain unanswered. In this paper, we make a detailed quantitative study of the expression of the mechanosensitive channel of large conductance (MscL) in different media and at various stages in the growth history of bacterial cultures. Using both quantitative fluorescence microscopy and quantitative Western blots our study complements earlier electrophysiology-based estimates and results in the following key insights: i) the mean number of channels per cell is much higher than previously estimated, ii) measurement of the single-cell distributions of such channels reveals marked variability from cell to cell and iii) the mean number of channels varies under different environmental conditions. The regulation of MscL expression displays rich behaviors that depend strongly on culturing conditions and stress factors, which may give clues to the physiological role of MscL. The number of stress induced MscL channels and the associated variability have far reaching implications for the in vivo response of the channels and for modeling of this response. As shown by numerous biophysical models, both the number of such channels and their variability can impact many physiological processes including osmoprotection, channel gating probability, and channel clustering. PMID- 22427955 TI - Skin lesions on common bottlenose dolphins (Tursiops truncatus) from three sites in the Northwest Atlantic, USA. AB - Skin disease occurs frequently in many cetacean species across the globe; methods to categorize lesions have relied on photo-identification (photo-id), stranding, and by-catch data. The current study used photo-id data from four sampling months during 2009 to estimate skin lesion prevalence and type occurring on bottlenose dolphins (Tursiops truncatus) from three sites along the southeast United States coast [Sarasota Bay, FL (SSB); near Brunswick and Sapelo Island, GA (BSG); and near Charleston, SC (CHS)]. The prevalence of lesions was highest among BSG dolphins (P = 0.587) and lowest in SSB (P = 0.380), and the overall prevalence was significantly different among all sites (p<0.0167). Logistic regression modeling revealed a significant reduction in the odds of lesion occurrence for increasing water temperatures (OR = 0.92; 95%CI:0.906-0.938) and a significantly increased odds of lesion occurrence for BSG dolphins (OR = 1.39; 95%CI:1.203 1.614). Approximately one-third of the lesioned dolphins from each site presented with multiple types, and population differences in lesion type occurrence were observed (p<0.05). Lesions on stranded dolphins were sampled to determine the etiology of different lesion types, which included three visually distinct samples positive for herpesvirus. Although generally considered non-fatal, skin disease may be indicative of animal health or exposure to anthropogenic or environmental threats, and photo-id data provide an efficient and cost-effective approach to document the occurrence of skin lesions in free-ranging populations. PMID- 22427954 TI - The personal and health service impact of falls in 85 year olds: cross-sectional findings from the Newcastle 85+ cohort study. AB - INTRODUCTION: Falls are common in older people and increase in prevalence with advancing old age. There is limited knowledge about their impact in those aged 85 years and older, the fastest growing age group of the population. We investigated the prevalence and impact of falls, and the overlap between falls, dizziness and blackouts, in a population-based sample of 85 year olds. METHODS: DESIGN: Cross sectional analysis of baseline data from Newcastle 85+ Cohort Study. SETTING: Primary care, North-East England. PARTICIPANTS: 816 men and women aged 85 years. MEASUREMENTS: Structured interview with research nurse. Cost-consequence analysis of fall-related healthcare costs. RESULTS: Over 38% (313/816) of participants had fallen at least once in the previous 12 months and of these: 10.6% (33/312) sustained a fracture, 30.1% (94/312) attended an emergency department, and 12.8% (40/312) were admitted to hospital. Only 37.2% (115/309) of fallers had specifically discussed their falls problem with their general practitioner and only 12.7% (39/308) had seen a falls specialist. The average annual healthcare cost per faller was estimated at L202 (inter-quartile range L174-L231) or US$329 ($284-$377). 'Worry about falling' was experienced by 42.0% (128/305) of fallers, 'loss of confidence' by 40.0% (122/305), and 'going out less often' by 25.9% (79/305); each was significantly more common in women, odds ratios (95% confidence interval) for women: men of 2.63 (1.45-4.55), 4.00 (2.27-7.14), and 2.86 (1.54-5.56) respectively. Dizziness and blackouts were reported by 40.0% (318/796) and 6.4% (52/808) of participants respectively. There was marked overlap in the report of falls, dizziness and blackouts. CONCLUSIONS: Falls in 85 year olds are very common, associated with considerable psychological and physical morbidity, and have high impact on healthcare services. Wider use of fall prevention services is needed. Significant expansion in acute and preventative services is required in view of the rapid growth in this age group. PMID- 22427956 TI - Reducing the medical cost of deliveries in Burkina Faso is good for everyone, including the poor. AB - Since 2007, Burkina Faso has subsidized 80% of the costs of child birth. Women are required to pay 20% (900 F CFA = 1.4 Euros), except for the indigent, who are supposed to be exempted. The objective of the policy is to increase service utilization and reduce costs for households. We analyze the efficacy of the policy and the distribution of its benefits.The study was carried out in Ouargaye district. The analysis was based on two distinct cross-sectional household surveys, conducted before (2006; n= 1170) and after (2010; n = 905) the policy, of all women who had had a vaginal delivery in a public health centre.Medical expenses for delivery decreased from a median of 4,060 F CFA in 2006 to 900 F CFA in 2010 (p<0.001). There was pronounced contraction in the distribution of expenses and a reduction in interquartile range. Total expenses for delivery went from a median of 7,366 F CFA in 2006 to 4,750 F CFA in 2010 (p = 0.001). There was no exacerbation of the initial inequalities of the share in consumption after the policy. The distribution of benefits for medical expenses showed a progressive evolution. The greatest reduction in risk of excessive expenses was seen in women in the bottom quintile living less than 5 km from the health centres. Only 10% of those in the poorest quintile were exempted. The subsidy policy was more effective in Burkina Faso than in other African countries. All categories of the population benefited from this policy, including the poorest. Yet despite the subsidy, women still carry a significant cost burden; half of them pay more than they should, and few indigents are fully exempted. Efforts must still be made to reach the indigent and to reduce geographic barriers for all women. PMID- 22427957 TI - Light-induced responses of slow oscillatory neurons of the rat olivary pretectal nucleus. AB - BACKGROUND: The olivary pretectal nucleus (OPN) is a small midbrain structure responsible for pupil constriction in response to eye illumination. Previous electrophysiological studies have shown that OPN neurons code light intensity levels and therefore are called luminance detectors. Recently, we described an additional population of OPN neurons, characterized by a slow rhythmic pattern of action potentials in light-on conditions. Rhythmic patterns generated by these cells last for a period of approximately 2 minutes. METHODOLOGY: To answer whether oscillatory OPN cells are light responsive and whether oscillatory activity depends on retinal afferents, we performed in vivo electrophysiology experiments on urethane anaesthetized Wistar rats. Extracellular recordings were combined with changes in light conditions (light-dark-light transitions), brief light stimulations of the contralateral eye (diverse illuminances) or intraocular injections of tetrodotoxin (TTX). CONCLUSIONS: We found that oscillatory neurons were able to fire rhythmically in darkness and were responsive to eye illumination in a manner resembling that of luminance detectors. Their firing rate increased together with the strength of the light stimulation. In addition, during the train of light pulses, we observed two profiles of responses: oscillation-preserving and oscillation-disrupting, which occurred during low- and high-illuminance stimuli presentation respectively. Moreover, we have shown that contralateral retina inactivation eliminated oscillation and significantly reduced the firing rate of oscillatory cells. These results suggest that contralateral retinal innervation is crucial for the generation of an oscillatory pattern in addition to its role in driving responses to visual stimuli. PMID- 22427958 TI - Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. AB - Tunneling nanotubes are long, non-adherent F-actin-based cytoplasmic extensions which connect proximal or distant cells and facilitate intercellular transfer. The identification of nanotubes has been limited to cell lines, and their role in cancer remains unclear. We detected tunneling nanotubes in mesothelioma cell lines and primary human mesothelioma cells. Using a low serum, hyperglycemic, acidic growth medium, we stimulated nanotube formation and bidirectional transfer of vesicles, proteins, and mitochondria between cells. Notably, nanotubes developed between malignant cells or between normal mesothelial cells, but not between malignant and normal cells. Immunofluorescent staining revealed their actin-based assembly and structure. Metformin and an mTor inhibitor, Everolimus, effectively suppressed nanotube formation. Confocal microscopy with 3-dimensional reconstructions of sectioned surgical specimens demonstrated for the first time the presence of nanotubes in human mesothelioma and lung adenocarcinoma tumor specimens. We provide the first evidence of tunneling nanotubes in human primary tumors and cancer cells and propose that these structures play an important role in cancer cell pathogenesis and invasion. PMID- 22427959 TI - Enteric infection with Citrobacter rodentium induces coagulative liver necrosis and hepatic inflammation prior to peak infection and colonic disease. AB - Acute and chronic forms of inflammation are known to affect liver responses and susceptibility to disease and injury. Furthermore, intestinal microbiota has been shown critical in mediating inflammatory host responses in various animal models. Using C. rodentium, a known enteric bacterial pathogen, we examined liver responses to gastrointestinal infection at various stages of disease pathogenesis. For the first time, to our knowledge, we show distinct liver pathology associated with enteric infection with C. rodentium in C57BL/6 mice, characterized by increased inflammation and hepatitis index scores as well as prominent periportal hepatocellular coagulative necrosis indicative of thrombotic ischemic injury in a subset of animals during the early course of C. rodentium pathogenesis. Histologic changes in the liver correlated with serum elevation of liver transaminases, systemic and liver resident cytokines, as well as signal transduction changes prior to peak bacterial colonization and colonic disease. C. rodentium infection in C57BL/6 mice provides a potentially useful model to study acute liver injury and inflammatory stress under conditions of gastrointestinal infection analogous to enteropathogenic E. coli infection in humans. PMID- 22427960 TI - Dendrimers bind antioxidant polyphenols and cisplatin drug. AB - Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4) with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2) groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2) M(-1) to 10(3) M(-1). The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (DeltaG = -4.75 kcal/mol) than curcumin-PAMAM-G4 ((DeltaG = -4.53 kcal/mol) and resveratrol-PAMAM-G4 ((DeltaG = -4.39 kcal/mol). Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs. PMID- 22427961 TI - In vivo depletion of lymphotoxin-alpha expressing lymphocytes inhibits xenogeneic graft-versus-host-disease. AB - Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic cell transplantation and is largely mediated by activated donor lymphocytes. Lymphotoxin (LT)-alpha is expressed by subsets of activated T and B cells, and studies in preclinical models demonstrated that targeted depletion of these cells with a mouse anti-LT-alpha monoclonal antibody (mAb) was efficacious in inhibiting inflammation and autoimmune disease. Here we demonstrate that LT alpha is also upregulated on activated human donor lymphocytes in a xenogeneic model of GVHD and targeted depletion of these donor cells ameliorated GVHD. A depleting humanized anti-LT-alpha mAb, designated MLTA3698A, was generated that specifically binds to LT-alpha in both the soluble and membrane-bound forms, and elicits antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Using a human peripheral blood mononuclear cell transplanted SCID (Hu-SCID) mouse model of GVHD, the anti-human LT-alpha mAb specifically depleted activated LT expressing human donor T and B cells, resulting in prolonged survival of the mice. A mutation in the Fc region, rendering the mAb incapable of mediating ADCC, abolished all in vitro and in vivo effects. These data support a role for using a depleting anti-LT-alpha antibody in treating immune diseases such as GVHD and autoimmune diseases. PMID- 22427962 TI - Antibiotic-induced change of bacterial communities associated with the copepod Nitocra spinipes. AB - Environmental pressures, such as physical factors, diet and contaminants may affect interactions between microbial symbionts and their multicellular hosts. Despite obvious relevance, effects of antimicrobial contaminants on host-symbiont relations in non-target aquatic organisms are largely unknown. We show that exposure to antibiotics had negative effects on survival and juvenile development of the copepod Nitocra spinipes and caused significant alterations in copepod associated bacterial communities. The significant positive correlations between indices of copepod development and bacterial diversity indicate that disruption of the microflora was likely to be an important factor behind retarded juvenile development in the experimental animals. Moreover, as evidenced by ribotype distribution in the bacterial clone libraries, the exposure to antibiotics caused a shift in dominance from Betaproteobacteria to Cardinium bacteria; the latter have been shown to cause reproductive manipulations in various terrestrial arthropods. Thus, in addition to providing evidence that the antibiotic-induced perturbation of the microbial community associates with reductions in fitness related traits of the host, this study is the first record of a copepod serving as a host for endosymbiotic Cardinium. Taken together, our results suggest that (1) antimicrobial substances and possibly other stressors can affect micobiome and symbiont-mediated interactions in copepods and other hosts, and (2) Cardinium endosymbionts may occur in other copepods and affect reproduction of their hosts. PMID- 22427963 TI - Audiovisual segregation in cochlear implant users. AB - It has traditionally been assumed that cochlear implant users de facto perform atypically in audiovisual tasks. However, a recent study that combined an auditory task with visual distractors suggests that only those cochlear implant users that are not proficient at recognizing speech sounds might show abnormal audiovisual interactions. The present study aims at reinforcing this notion by investigating the audiovisual segregation abilities of cochlear implant users in a visual task with auditory distractors. Speechreading was assessed in two groups of cochlear implant users (proficient and non-proficient at sound recognition), as well as in normal controls. A visual speech recognition task (i.e. speechreading) was administered either in silence or in combination with three types of auditory distractors: i) noise ii) reverse speech sound and iii) non altered speech sound. Cochlear implant users proficient at speech recognition performed like normal controls in all conditions, whereas non-proficient users showed significantly different audiovisual segregation patterns in both speech conditions. These results confirm that normal-like audiovisual segregation is possible in highly skilled cochlear implant users and, consequently, that proficient and non-proficient CI users cannot be lumped into a single group. This important feature must be taken into account in further studies of audiovisual interactions in cochlear implant users. PMID- 22427964 TI - Immuno-Golgi as a tool for analyzing neuronal 3D-dendritic structure in phenotypically characterized neurons. AB - Characterization of neuronal dendritic structure in combination with the determination of specific neuronal phenotype or temporal generation is a challenging task. Here we present a novel method that combines bromodioxyuridine (BrdU) immunohistochemistry with Golgi-impregnation technique; with this simple non-invasive method, we are able to determine the tridimensional structure of dendritic arborization and spine shape of neurons born at a specific time in the hippocampus of adult animals. This analysis is relevant in physiological and pathological conditions in which altered neurogenesis is implicated, such as aging or emotional disorders. PMID- 22427965 TI - Prevention and therapy of hepatocellular carcinoma by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex without carriers. AB - Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a CD4(+) cells- and Th1 differentiation dependent manner. The transmembrane 4 superfamily member 5 protein (TM4SF5) has gained attention as a target for hepatocellular carcinoma (HCC) therapy because it induces uncontrolled growth of human HCC cells via the loss of contact inhibition. Monoclonal antibodies specific to an epitope of human TM4SF5 (hTM4SF5R2-3) can recognize native mouse TM4SF5 and induce functional effects on mouse cancer cells. Pre-immunization with a complex of the hTM4SF5R2-3 epitope and Lipoplex(O) had prophylactic effects against tumor formation by HCC cells implanted in an mouse tumor model. Furthermore, therapeutic effects were revealed regarding the growth of HCC when the vaccine was injected into mice after tumor formation. These results suggest that our improved peptide vaccine technology provides a novel prophylaxis measure as well as therapy for HCC patients with TM4SF5-positive tumors. PMID- 22427966 TI - Comparative transcriptome analysis of the necrotrophic fungus Ascochyta rabiei during oxidative stress: insight for fungal survival in the host plant. AB - Localized cell death, known as the hypersensitive response (HR), is an important defense mechanism for neutralizing phytopathogens. The hallmark of the HR is an oxidative burst produced by the host plant. We aimed to identify genes of the necrotrophic chickpea blight fungus Ascochyta rabiei that are involved in counteracting oxidative stress. A subtractive cDNA library was constructed after menadione treatment, which resulted in the isolation of 128 unigenes. A reverse northern blot was used to compare transcript profiles after H(2)O(2), menadione and sodium nitroprusside treatments. A total of 70 unigenes were found to be upregulated by more than two-fold following menadione treatment at different time intervals. A large number of genes not previously associated with oxidative stress were identified, along with many stress-responsive genes. Differential expression patterns of several genes were validated by quantitative real-time PCR (qRT-PCR) and northern blotting. In planta qRT-PCR of several selected genes also showed differential expression patterns during infection and disease progression. These data shed light on the molecular responses of the phytopathogen A. rabiei to overcome oxidative and nitrosative stresses and advance the understanding of necrotrophic fungal pathogen survival mechanisms. PMID- 22427967 TI - Glass-(nAg, nCu) biocide coatings on ceramic oxide substrates. AB - The present work was focused on obtaining biocide coatings constituted by a glassy soda-lime matrix containing silver or copper nanoparticles on ceramic (alumina and zirconia based) substrates. Both glassy coatings showed a high biocide activity against Gram-, Gram+ bacteria and yeast, reducing cell numbers more than three logarithms. Silver nanoparticles had a significantly higher biocide activity than copper nanoparticles, since the lixiviation levels required to reduce cell numbers more than 3 logarithms was of almost 1-2 ug/cm(2) in the case of silver nanoparticles, and 10-15 ug/cm(2) for the copper nanoparticles. PMID- 22427968 TI - Two isoforms of the mRNA binding protein IGF2BP2 are generated by alternative translational initiation. AB - IGF2BP2 is a member of a family of mRNA binding proteins that, collectively, have been shown to bind to several different mRNAs in mammalian cells, including one of the mRNAs encoding insulin-like growth factor-2. Polymorphisms in the Igf2bp2 gene are associated with risk of developing type 2 diabetes, but detailed functional characterisation of IGF2BP2 protein is lacking. By immunoblotting with C-terminally reactive antibodies we identified a novel IGF2BP2 isoform with a molecular weight of 58 kDa in both human and rodents, that is expressed at somewhat lower levels than the full-length 65 kDa protein. We demonstrated by mutagenesis that this isoform is generated by alternative translation initiation at the internal Met69. It lacks a conserved N-terminal RNA Recognition Motif (RRM) and would be predicted to differ functionally from the canonical full length isoform. We further investigated IGF2BP2 mRNA transcripts by amplification of cDNA using 5'-RACE. We identified multiple transcription start sites of the human, mouse and rat Igf2bp2 genes in a highly conserved region only 50-90 nts upstream of the major translation start site, ruling out the existence of N terminally extended isoforms. We conclude that structural heterogeneity of IGF2BP2 protein should be taken into account when considering cellular function. PMID- 22427969 TI - Characterization of the effects of cross-linking of macrophage CD44 associated with increased phagocytosis of apoptotic PMN. AB - Control of macrophage capacity for apoptotic cell clearance by soluble mediators such as cytokines, prostaglandins and lipoxins, serum proteins, and glucocorticoids may critically determine the rate at which inflammation resolves. Previous studies suggested that macrophage capacity for clearance of apoptotic neutrophils was profoundly altered following binding of CD44 antibodies. We have used a number of different approaches to further define the mechanism by which CD44 rapidly and specifically augment phagocytosis of apoptotic neutrophils. Use of Fab' fragments unequivocally demonstrated a requirement for cross-linking of macrophage surface CD44. The molecular mechanism of CD44-augmented phagocytosis was shown to be opsonin-independent and to be distinct from the Mer/protein S pathway induced by glucocorticoids and was not functional for clearance of apoptotic eosinophils. CD44-cross-linking also altered macrophage migration and induced cytoskeletal re-organisation together with phosphorylation of paxillin and activation of Rac2. Investigation of signal transduction pathways that might be critical for CD44 augmentation of phagocytosis revealed that Ca(2+) signalling, PI-3 kinase pathways and altered cAMP signalling were not involved, but did implicate a key role for tyrosine phosphorylation events. Finally, although CD44 antibodies were able to augment phagocytosis of apoptotic neutrophils by murine peritoneal and bone marrow-derived macrophages, we did not observe a difference in the clearance of neutrophils following induction of peritonitis with thioglycollate in CD44-deficient animals. Together, these data demonstrate that CD44 cross-linking induces a serum opsonin-independent mechanism of macrophage phagocytosis of apoptotic neutrophils that is associated with reduced macrophage migration and cytoskeletal reorganisation. PMID- 22427970 TI - Polypyrimidine tract binding protein (hnRNP I) is possibly a conserved modulator of miRNA-mediated gene regulation. AB - MiRNAs can regulate gene expression through versatile mechanisms that result in increased or decreased expression of the targeted mRNA and it could effect the expression of thousands of protein in a particular cell. An increasing body of evidence suggest that miRNAs action can be modulated by proteins that bind to the same 3'UTRs that are targeted by miRNAs, suggesting that other factors apart from miRNAs and their target sites determine miRNA-modulation of gene expression. We applied an affinity purification protocol using biotinylated let-7 miRNA inhibitor to isolate proteins that are involved in let-7 mediated gene regulation that resulted in an affinity purification of Polypyrimidine Tract Binding protein (PTB). Here we show that PTB interacts with miRNAs and human Argonaute 2 (hAgo2) through RNA as well as identified potential mammalian cellular targets that are co-regulated by PTB and hAgo2. In addition, using genetic approach, we have demonstrated that PTB genetically interacts with Caenorhabditis elegans let-7 indicating a conserved role for PTB in miRNA-mediated gene regulation. PMID- 22427971 TI - The time window for generation of dendritic spikes by coincidence of action potentials and EPSPs is layer specific in somatosensory cortex. AB - The precise timing of events in the brain has consequences for intracellular processes, synaptic plasticity, integration and network behaviour. Pyramidal neurons, the most widespread excitatory neuron of the neocortex have multiple spike initiation zones, which interact via dendritic and somatic spikes actively propagating in all directions within the dendritic tree. For these neurons, therefore, both the location and timing of synaptic inputs are critical. The time window for which the backpropagating action potential can influence dendritic spike generation has been extensively studied in layer 5 neocortical pyramidal neurons of rat somatosensory cortex. Here, we re-examine this coincidence detection window for pyramidal cell types across the rat somatosensory cortex in layers 2/3, 5 and 6. We find that the time-window for optimal interaction is widest and shifted in layer 5 pyramidal neurons relative to cells in layers 6 and 2/3. Inputs arriving at the same time and locations will therefore differentially affect spike-timing dependent processes in the different classes of pyramidal neurons. PMID- 22427973 TI - The natural variation of a neural code. AB - The way information is represented by sequences of action potentials of spiking neurons is determined by the input each neuron receives, but also by its biophysics, and the specifics of the circuit in which it is embedded. Even the "code" of identified neurons can vary considerably from individual to individual. Here we compared the neural codes of the identified H1 neuron in the visual systems of two families of flies, blow flies and flesh flies, and explored the effect of the sensory environment that the flies were exposed to during development on the H1 code. We found that the two families differed considerably in the temporal structure of the code, its content and energetic efficiency, as well as the temporal delay of neural response. The differences in the environmental conditions during the flies' development had no significant effect. Our results may thus reflect an instance of a family-specific design of the neural code. They may also suggest that individual variability in information processing by this specific neuron, in terms of both form and content, is regulated genetically. PMID- 22427972 TI - Simulated-physiological loading conditions preserve biological and mechanical properties of caprine lumbar intervertebral discs in ex vivo culture. AB - Low-back pain (LBP) is a common medical complaint and associated with high societal costs. Degeneration of the intervertebral disc (IVD) is assumed to be an important causal factor of LBP. IVDs are continuously mechanically loaded and both positive and negative effects have been attributed to different loading conditions.In order to study mechanical loading effects, degeneration-associated processes and/or potential regenerative therapies in IVDs, it is imperative to maintain the IVDs' structural integrity. While in vivo models provide comprehensive insight in IVD biology, an accompanying organ culture model can focus on a single factor, such as loading and may serve as a prescreening model to reduce life animal testing. In the current study we examined the feasibility of organ culture of caprine lumbar discs, with the hypothesis that a simulated physiological load will optimally preserve IVD properties.Lumbar caprine IVDs (n = 175) were cultured in a bioreactor up to 21 days either without load, low dynamic load (LDL), or with simulated-physiological load (SPL). IVD stiffness was calculated from measurements of IVD loading and displacement. IVD nucleus, inner- and outer annulus were assessed for cell viability, cell density and gene expression. The extracellular matrix (ECM) was analyzed for water, glycosaminoglycan and total collagen content.IVD biomechanical properties did not change significantly with loading conditions. With SPL, cell viability, cell density and gene expression were preserved up to 21 days. Both unloaded and LDL resulted in decreased cell viability, cell density and significant changes in gene expression, yet no differences in ECM content were observed in any group.In conclusion, simulated-physiological loading preserved the native properties of caprine IVDs during a 21-day culture period. The characterization of caprine IVD response to culture in the LDCS under SPL conditions paves the way for controlled analysis of degeneration- and regeneration-associated processes in the future. PMID- 22427974 TI - Genome-wide evaluation of histone methylation changes associated with leaf senescence in Arabidopsis. AB - Leaf senescence is the orderly dismantling of older tissue that allows recycling of nutrients to developing portions of the plant and is accompanied by major changes in gene expression. Histone modifications correlate to levels of gene expression, and this study utilizes ChIP-seq to classify activating H3K4me3 and silencing H3K27me3 marks on a genome-wide scale for soil-grown mature and naturally senescent Arabidopsis leaves. ChIPnorm was used to normalize data sets and identify genomic regions with significant differences in the two histone methylation patterns, and the differences were correlated to changes in gene expression. Genes that showed an increase in the H3K4me3 mark in older leaves were senescence up-regulated, while genes that showed a decrease in the H3K4me3 mark in the older leaves were senescence down-regulated. For the H3K27me3 modification, genes that lost the H3K27me3 mark in older tissue were senescence up-regulated. Only a small number of genes gained the H3K27me3 mark, and these were senescence down-regulated. Approximately 50% of senescence up-regulated genes lacked the H3K4me3 mark in both mature and senescent leaf tissue. Two of these genes, SAG12 and At1g73220, display strong senescence up-regulation without the activating H3K4me3 histone modification. This study provides an initial epigenetic framework for the developmental transition into senescence. PMID- 22427975 TI - Cell-autonomous alterations in dendritic arbor morphology and connectivity induced by overexpression of MeCP2 in Xenopus central neurons in vivo. AB - Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Mutations in the MeCP2 gene have been linked to Rett syndrome, a severe X-linked progressive neurodevelopmental disorder, and one of the most common causes of mental retardation in females. MeCP2 duplication and triplication have also been found to affect brain development, indicating that both loss of function and gain in MeCP2 dosage lead to similar neurological phenotypes. Here, we used the Xenopus laevis visual system as an in vivo model to examine the consequence of increased MeCP2 expression during the morphological maturation of individual central neurons in an otherwise intact brain. Single cell overexpression of wild-type human MeCP2 was combined with time-lapse confocal microscopy imaging to study dynamic mechanisms by which MeCP2 influences tectal neuron dendritic arborization. Analysis of neurons co-expressing DsRed2 demonstrates that MeCP2 overexpression specifically interfered with dendritic elaboration, decreasing the rates of branch addition and elimination over a 48 hour observation period. Moreover, dynamic analysis of neurons co-expressing wt hMeCP2 and PSD95-GFP revealed that even though neurons expressing wt-hMeCP2 possessed significantly fewer dendrites and simpler morphologies than control neurons at the same developmental stage, postsynaptic site density in wt-hMeCP2 expressing neurons was similar to controls and increased at a rate higher than controls. Together, our in vivo studies support an early, cell-autonomous role for MeCP2 during the morphological differentiation of neurons and indicate that perturbations in MeCP2 gene dosage result in deficits in dendritic arborization that can be compensated, at least in part, by synaptic connectivity changes. PMID- 22427976 TI - Lipopolysaccharide O1 antigen contributes to the virulence in Klebsiella pneumoniae causing pyogenic liver abscess. AB - Klebsiella pneumoniae is the common cause of a global emerging infectious disease, community-acquired pyogenic liver abscess (PLA). Capsular polysaccharide (CPS) and lipopolysaccharide (LPS) are critical for this microorganism's ability to spread through the blood and to cause sepsis. While CPS type K1 is an important virulence factor in K. pneumoniae causing PLA, the role of LPS in PLA is not clear. Here, we characterize the role of LPS O antigen in the pathogenesis of K. pneumoniae causing PLA. NTUH-K2044 is a LPS O1 clinical strain; the presence of the O antigen was shown via the presence of 1,3-galactan in the LPS, and of sequences that align with the wb gene cluster, known to produce O-antigen. Serologic analysis of K. pneumoniae clinical isolates demonstrated that the O1 serotype was more prevalent in PLA strains than that in non-tissue-invasive strains (38/42 vs. 9/32, P<0.0001). O1 serotype isolates had a higher frequency of serum resistance, and mutation of the O1 antigen changed serum resistance in K. pneumoniae. A PLA-causing strain of CPS capsular type K2 and LPS serotype O1 (i.e., O1:K2 PLA strain) deleted for the O1 synthesizing genes was profoundly attenuated in virulence, as demonstrated in separate mouse models of septicemia and liver abscess. Immunization of mice with the K2044 magA-mutant (K(1) (-) O(1)) against LPS O1 provided protection against infection with an O1:K2 PLA strain, but not against infection with an O1:K1 PLA strain. Our findings indicate that the O1 antigen of PLA-associated K. pneumoniae contributes to virulence by conveying resistance to serum killing, promoting bacterial dissemination to and colonization of internal organs after the onset of bacteremia, and could be a useful vaccine candidate against infection by an O1:K2 PLA strain. PMID- 22427977 TI - CIBZ, a novel BTB domain-containing protein, is involved in mouse spinal cord injury via mitochondrial pathway independent of p53 gene. AB - Spinal cord injury (SCI) induces both primary uncontrollable mechanical injury and secondary controllable degeneration, which further results in the activation of cell death cascades that mediate delayed tissue damage. To alleviate its impairments and seek for an effective remedy, mRNA differential display was used to investigate gene mRNA expression profiling in mice following SCI. A specific Zinc finger and BTB domain-containing protein, CIBZ, was discovered to implicate in the SCI process for the first time. Further researches indicated that CIBZ was extensively distributed in various tissues, and the expression level was highest in muscle, followed by spinal cord, large intestine, kidney, spleen, thymus, lung, cerebrum, stomach, ovary and heart, respectively. After injury, the CIBZ expression decreased dramatically and reached the lowest level at 8 h, but it gradually increased to the maximal level at 7 d. Caspase-3 and C-terminal-binding protein (CtBP), two CIBZ-related proteins, showed similar tendency. Interestingly, p53 expression remained constant in all groups. Via flow cytometry (FCM) analysis, it was found that the cell death rate in SCI group markedly increased and reached the highest value 1 d after surgery and the mitochondrial transmembrane potential (DeltaPsim) at 1 d was the lowest in all groups. Taken together, it is suggested that: (i) in the presence of CtBP, CIBZ gene is involved in secondary injury process and trigger the activation of apoptotic caspase-3 and bax genes independent of p53; (ii) abrupt down-regulation of CtBP at 8 h is a sign of mitochondria dysfunction and the onset of cell death; (iii) it could be used as an inhibitor or target drug of caspase-3 gene to improve spinal cord function. PMID- 22427978 TI - High-resolution imaging of the retinal nerve fiber layer in normal eyes using adaptive optics scanning laser ophthalmoscopy. AB - PURPOSE: To conduct high-resolution imaging of the retinal nerve fiber layer (RNFL) in normal eyes using adaptive optics scanning laser ophthalmoscopy (AO SLO). METHODS: AO-SLO images were obtained in 20 normal eyes at multiple locations in the posterior polar area and a circular path with a 3-4-mm diameter around the optic disc. For each eye, images focused on the RNFL were recorded and a montage of AO-SLO images was created. RESULTS: AO-SLO images for all eyes showed many hyperreflective bundles in the RNFL. Hyperreflective bundles above or below the fovea were seen in an arch from the temporal periphery on either side of a horizontal dividing line to the optic disc. The dark lines among the hyperreflective bundles were narrower around the optic disc compared with those in the temporal raphe. The hyperreflective bundles corresponded with the direction of the striations on SLO red-free images. The resolution and contrast of the bundles were much higher in AO-SLO images than in red-free fundus photography or SLO red-free images. The mean hyperreflective bundle width around the optic disc had a double-humped shape; the bundles at the temporal and nasal sides of the optic disc were narrower than those above and below the optic disc (P<0.001). RNFL thickness obtained by optical coherence tomography correlated with the hyperreflective bundle widths on AO-SLO (P<0.001) CONCLUSIONS: AO-SLO revealed hyperreflective bundles and dark lines in the RNFL, believed to be retinal nerve fiber bundles and Muller cell septa. The widths of the nerve fiber bundles appear to be proportional to the RNFL thickness at equivalent distances from the optic disc. PMID- 22427979 TI - Differential interactions of sex pheromone and plant odour in the olfactory pathway of a male moth. AB - Most animals rely on olfaction to find sexual partners, food or a habitat. The olfactory system faces the challenge of extracting meaningful information from a noisy odorous environment. In most moth species, males respond to sex pheromone emitted by females in an environment with abundant plant volatiles. Plant odours could either facilitate the localization of females (females calling on host plants), mask the female pheromone or they could be neutral without any effect on the pheromone. Here we studied how mixtures of a behaviourally-attractive floral odour, heptanal, and the sex pheromone are encoded at different levels of the olfactory pathway in males of the noctuid moth Agrotis ipsilon. In addition, we asked how interactions between the two odorants change as a function of the males' mating status. We investigated mixture detection in both the pheromone specific and in the general odorant pathway. We used a) recordings from individual sensilla to study responses of olfactory receptor neurons, b) in vivo calcium imaging with a bath-applied dye to characterize the global input response in the primary olfactory centre, the antennal lobe and c) intracellular recordings of antennal lobe output neurons, projection neurons, in virgin and newly-mated males. Our results show that heptanal reduces pheromone sensitivity at the peripheral and central olfactory level independently of the mating status. Contrarily, heptanal-responding olfactory receptor neurons are not influenced by pheromone in a mixture, although some post-mating modulation occurs at the input of the sexually isomorphic ordinary glomeruli, where general odours are processed within the antennal lobe. The results are discussed in the context of mate localization. PMID- 22427980 TI - Decision, sensation, and habituation: a multi-layer dynamic field model for Inhibition of Return. AB - Inhibition of Return (IOR) is one of the most consistent and widely studied effects in experimental psychology. The effect refers to a delayed response to visual stimuli in a cued location after initial priming at that location. This article presents a dynamic field model for IOR. The model describes the evolution of three coupled activation fields. The decision field, inspired by the intermediate layer of the superior colliculus, receives endogenous input and input from a sensory field. The sensory field, inspired by earlier sensory processing, receives exogenous input. Habituation of the sensory field is implemented by a reciprocal coupling with a third field, the habituation field. The model generates IOR because, due to the habituation of the sensory field, the decision field receives a reduced target-induced input in cue-target-compatible situations. The model is consistent with single-unit recordings of neurons of monkeys that perform IOR tasks. Such recordings have revealed that IOR phenomena parallel the activity of neurons in the intermediate layer of the superior colliculus and that neurons in this layer receive reduced input in cue-target compatible situations. The model is also consistent with behavioral data concerning temporal expectancy effects. In a discussion, the multi-layer dynamic field account of IOR is used to illustrate the broader view that behavior consists of a tuning of the organism to the environment that continuously and concurrently takes place at different spatiotemporal scales. PMID- 22427981 TI - Studying language change using price equation and Polya-urn dynamics. AB - Language change takes place primarily via diffusion of linguistic variants in a population of individuals. Identifying selective pressures on this process is important not only to construe and predict changes, but also to inform theories of evolutionary dynamics of socio-cultural factors. In this paper, we advocate the Price equation from evolutionary biology and the Polya-urn dynamics from contagion studies as efficient ways to discover selective pressures. Using the Price equation to process the simulation results of a computer model that follows the Polya-urn dynamics, we analyze theoretically a variety of factors that could affect language change, including variant prestige, transmission error, individual influence and preference, and social structure. Among these factors, variant prestige is identified as the sole selective pressure, whereas others help modulate the degree of diffusion only if variant prestige is involved. This multidisciplinary study discerns the primary and complementary roles of linguistic, individual learning, and socio-cultural factors in language change, and offers insight into empirical studies of language change. PMID- 22427982 TI - Robust, integrated computational control of NMR experiments to achieve optimal assignment by ADAPT-NMR. AB - ADAPT-NMR (Assignment-directed Data collection Algorithm utilizing a Probabilistic Toolkit in NMR) represents a groundbreaking prototype for automated protein structure determination by nuclear magnetic resonance (NMR) spectroscopy. With a [(13)C,(15)N]-labeled protein sample loaded into the NMR spectrometer, ADAPT-NMR delivers complete backbone resonance assignments and secondary structure in an optimal fashion without human intervention. ADAPT-NMR achieves this by implementing a strategy in which the goal of optimal assignment in each step determines the subsequent step by analyzing the current sum of available data. ADAPT-NMR is the first iterative and fully automated approach designed specifically for the optimal assignment of proteins with fast data collection as a byproduct of this goal. ADAPT-NMR evaluates the current spectral information, and uses a goal-directed objective function to select the optimal next data collection step(s) and then directs the NMR spectrometer to collect the selected data set. ADAPT-NMR extracts peak positions from the newly collected data and uses this information in updating the analysis resonance assignments and secondary structure. The goal-directed objective function then defines the next data collection step. The procedure continues until the collected data support comprehensive peak identification, resonance assignments at the desired level of completeness, and protein secondary structure. We present test cases in which ADAPT-NMR achieved results in two days or less that would have taken two months or more by manual approaches. PMID- 22427983 TI - Trends in depression and antidepressant prescribing in children and adolescents: a cohort study in The Health Improvement Network (THIN). AB - BACKGROUND: In 2003, the Committee on Safety of Medicines (CSM) advised against treatment with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine in children, due to a possible increased risk of suicidal behaviour. This study examined the effects of this safety warning on general practitioners' depression diagnosing and prescription behaviour in children. METHODS AND FINDINGS: We identified a cohort of 1,502,753 children (<18 y; registered with GP for >6 m) in The Health Improvement Network (THIN) UK primary care database. Trends in incidence of depression diagnoses, symptoms and antidepressant prescribing were examined 1995-2009, accounting for deprivation, age and gender. We used segmented regression analysis to assess changes in prescription rates. Overall, 45,723 (3%) children had >= 1 depression-related entry in their clinical records. SSRIs were prescribed to 16,925 (1%) of children. SSRI prescription rates decreased from 3.2 (95%CI:3.0,3.3) per 1,000 person-years at risk (PYAR) in 2002 to 1.7 (95%CI:1.7,1.8) per 1,000 PYAR in 2005, but have since risen to 2.7 (95%CI:2.6,2.8) per 1,000 PYAR in 2009. Prescription rates for CSM contraindicated SSRIs citalopram, sertraline and especially paroxetine dropped dramatically after 2002, while rates for fluoxetine and amitriptyline remained stable. After 2005 rates for all antidepressants, except paroxetine and imipramine, started to rise again. Rates for depression diagnoses dropped from 3.0 (95%CI:2.8,3.1) per 1,000 PYAR in 2002 to 2.0 (95%CI:1.9,2.1) per 1,000 PYAR in 2005 and have been stable since. Recording of symptoms saw a steady increase from 1.0 (95%CI:0.8,1.2) per 1,000 PYAR in 1995 to 4.7 (95%CI:4.5,4.8) per 1,000 PYAR in 2009. CONCLUSIONS: The rates of depression diagnoses and SSRI prescriptions showed a significant drop around the time of the CSM advice, which was not present in the recording of symptoms. This could indicate caution on the part of GPs in making depression diagnoses and prescribing antidepressants following the CSM advice. PMID- 22427984 TI - Selection of diethylstilbestrol-specific single-chain antibodies from a non immunized mouse ribosome display library. AB - Single chain variable fragments (scFvs) against diethylstilbestrol (DES) were selected from the splenocytes of non-immunized mice by ribosome display technology. A naive library was constructed and engineered to allow in vitro transcription and translation using an E. coli lysate system. Alternating selection in solution and immobilization in microtiter wells was used to pan mRNA ribosome-antibody (ARM) complexes. After seven rounds of ribosome display, the expression vector pTIG-TRX containing the selected specific scFv DNAs were transformed into Escherichia coli BL21 (DE3) for expression. Twenty-six positive clones were screened and five clones had high antibody affinity and specificity to DES as evidenced by indirect competitive ELISA. Sequence analysis showed that these five DES-specific scFvs had different amino acid sequences, but the CDRs were highly similar. Surface plasmon resonance (SPR) analysis was used to determine binding kinetics of one clone (30-1). The measured K(D) was 3.79 uM. These results indicate that ribosome display technology can be used to efficiently isolate hapten-specific antibody (Ab) fragments from a naive library; this study provides a methodological framework for the development of novel immunoassays for multiple environmental pollutants with low molecular weight detection using recombinant antibodies. PMID- 22427985 TI - Symbionts as major modulators of insect health: lactic acid bacteria and honeybees. AB - Lactic acid bacteria (LAB) are well recognized beneficial host-associated members of the microbiota of humans and animals. Yet LAB-associations of invertebrates have been poorly characterized and their functions remain obscure. Here we show that honeybees possess an abundant, diverse and ancient LAB microbiota in their honey crop with beneficial effects for bee health, defending them against microbial threats. Our studies of LAB in all extant honeybee species plus related apid bees reveal one of the largest collections of novel species from the genera Lactobacillus and Bifidobacterium ever discovered within a single insect and suggest a long (>80 mya) history of association. Bee associated microbiotas highlight Lactobacillus kunkeei as the dominant LAB member. Those showing potent antimicrobial properties are acquired by callow honey bee workers from nestmates and maintained within the crop in biofilms, though beekeeping management practices can negatively impact this microbiota. Prophylactic practices that enhance LAB, or supplementary feeding of LAB, may serve in integrated approaches to sustainable pollinator service provision. We anticipate this microbiota will become central to studies on honeybee health, including colony collapse disorder, and act as an exemplar case of insect-microbe symbiosis. PMID- 22427986 TI - Loss and recovery of Mgat3 and GnT-III Mediated E-cadherin N-glycosylation is a mechanism involved in epithelial-mesenchymal-epithelial transitions. AB - BACKGROUND: N-acetylglucosaminyltransferase-III (GnT-III) is a glycosyltransferase encoded by Mgat3 that catalyzes the addition of beta1,4 bisecting-N-acetylglucosamine on N-glycans. GnT-III has been pointed as a metastases suppressor having varying effects on cell adhesion and migration. We have previously described the existence of a functional feedback loop between E cadherin expression and GnT-III-mediated glycosylation. The effects of GnT-III mediated glycosylation on E-cadherin expression and cellular phenotype lead us to evaluate Mgat3 and GnT-III-glycosylation role during Epithelial-Mesenchymal Transition (EMT) and the reverted process, Mesenchymal-Epithelial-Transition (MET). METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the expression profile and genetic mechanism controlling Mgat3 expression as well as GnT-III-mediated glycosylation, in general and specifically on E-cadherin, during EMT/MET. We found that during EMT, Mgat3 expression was dramatically decreased and later recovered when cells returned to an epithelial-like phenotype. We further identified that Mgat3 promoter methylation/demethylation is involved in this expression regulation. The impact of Mgat3 expression variation, along EMT/MET, leads to a variation in the expression levels of the enzymatic product of GnT-III (bisecting GlcNAc structures), and more importantly, to the specific modification of E-cadherin glycosylation with bisecting GlcNAc structures. CONCLUSIONS/SIGNIFICANCE: Altogether, this work identifies for the first time Mgat3 glycogene expression and GnT-III-mediated glycosylation, specifically on E cadherin, as a novel and major component of the EMT/MET mechanism signature, supporting its role during EMT/MET. PMID- 22427987 TI - Functional identification of dendritic cells in the teleost model, rainbow trout (Oncorhynchus mykiss). AB - Dendritic cells are specialized antigen presenting cells that bridge innate and adaptive immunity in mammals. This link between the ancient innate immune system and the more evolutionarily recent adaptive immune system is of particular interest in fish, the oldest vertebrates to have both innate and adaptive immunity. It is unknown whether dendritic cells co-evolved with the adaptive response, or if the connection between innate and adaptive immunity relied on a fundamentally different cell type early in evolution. We approached this question using the teleost model organism, rainbow trout (Oncorhynchus mykiss), with the aim of identifying dendritic cells based on their ability to stimulate naive T cells. Adapting mammalian protocols for the generation of dendritic cells, we established a method of culturing highly motile, non-adherent cells from trout hematopoietic tissue that had irregular membrane processes and expressed surface MHCII. When side-by-side mixed leukocyte reactions were performed, these cells stimulated greater proliferation than B cells or macrophages, demonstrating their specialized ability to present antigen and therefore their functional homology to mammalian dendritic cells. Trout dendritic cells were then further analyzed to determine if they exhibited other features of mammalian dendritic cells. Trout dendritic cells were found to have many of the hallmarks of mammalian DCs including tree-like morphology, the expression of dendritic cell markers, the ability to phagocytose small particles, activation by toll-like receptor-ligands, and the ability to migrate in vivo. As in mammals, trout dendritic cells could be isolated directly from the spleen, or larger numbers could be derived from hematopoietic tissue and peripheral blood mononuclear cells in vitro. PMID- 22427988 TI - Molecular phylogeny of the cyrtophorid ciliates (Protozoa, Ciliophora, Phyllopharyngea). AB - Evolutionary relationships of cyrtophorian ciliates are poorly known because molecular data of most groups within this subclass are lacking. In the present work, the SS rRNA genes belonging to 17 genera, 7 families of Cyrtophoria were sequenced and phylogenetic trees were constructed to assess their inter-generic relationships. The results indicated: (1) the assignment of cyrtophorians into two orders is consistently confirmed in all topologies; (2) the order Dysteriida is an outlined monophyletic assemblage while Chlamydodontida is paraphyletic with three separate monophyletic families; (3) Microxysma, which is currently assigned within the family Hartmannulidae, should be transferred to the family Dysteriidae; (4) the systematic position of Plesiotrichopidae remains unclear, yet the two genera that were placed in this family before, Pithites and Trochochilodon, should be transferred to Chlamydodontida; (5) a new family, Pithitidae n. fam., based on the type genus Pithites was suggested; and (6) the sequence of Isochona sp., the only available data of Chonotrichia so far, is probably from a misidentified species. In addition, three group I introns of SS rRNA gene were discovered in Aegyriana oliva, among which Aol.S516 is the first IE group intron reported in ciliates. PMID- 22427989 TI - MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. AB - BACKGROUND: Recent studies suggest that alterations in expression of genes, including those which regulate neural and structural plasticity, may be crucial in the pathogenesis of depression. MicroRNAs (miRNAs) are newly discovered regulators of gene expression that have recently been implicated in a variety of human diseases, including neuropsychiatric diseases. METHODOLOGY/PRINCIPAL FINDINGS: The present study was undertaken to examine whether the miRNA network is altered in the brain of depressed suicide subjects. Expression of miRNAs was measured in prefrontal cortex (Brodmann Area 9) of antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) using multiplex RT-PCR plates. We found that overall miRNA expression was significantly and globally down-regulated in prefrontal cortex of depressed suicide subjects. Using individual tests of statistical significance, 21 miRNAs were significantly decreased at p = 0.05 or better. Many of the down-regulated miRNAs were encoded at nearby chromosomal loci, shared motifs within the 5'-seeds, and shared putative mRNA targets, several of which have been implicated in depression. In addition, a set of 29 miRNAs, whose expression was not pairwise correlated in the normal controls, showed a high degree of co-regulation across individuals in the depressed suicide group. CONCLUSIONS/SIGNIFICANCE: The findings show widespread changes in miRNA expression that are likely to participate in pathogenesis of major depression and/or suicide. Further studies are needed to identify whether the miRNA changes lead to altered expression of prefrontal cortex mRNAs, either directly (by acting as miRNA targets) or indirectly (e.g., by affecting transcription factors). PMID- 22427990 TI - N-cadherin mediates neuronal cell survival through Bim down-regulation. AB - N-cadherin is a major adhesion molecule involved in the development and plasticity of the nervous system. N-cadherin-mediated cell adhesion regulates neuroepithelial cell polarity, neuronal precursor migration, growth cone migration and synaptic plasticity. In vitro, it has been involved in signaling events regulating processes such as cell mobility, proliferation and differentiation. N-cadherin has also been implicated in adhesion-dependent protection against apoptosis in non-neuronal cells. In this study, we investigated if the engagement of N-cadherin participates to the control of neuronal cells survival/death balance. We observed that plating either primary mouse spinal cord neurons or primary rat hippocampal neurons on N-cadherin recombinant substrate greatly enhances their survival compared to non-specific adhesion on poly-L-lysine. We show that N-cadherin engagement, in the absence of other survival factors (cell-matrix interactions and serum), protects GT1-7 neuronal cells against apoptosis. Using this cell line, we then searched for the signaling pathways involved in the survival effect of N-cadherin engagement. The PI3-kinase/Akt survival pathway and its downstream effector Bad are not involved, as no phosphorylation of Akt or Bad proteins in response to N-cadherin engagement was observed. In contrast, N-cadherin engagement activated the Erk1/2 MAP kinase pathway. Moreover, N-cadherin ligation mediated a 2-fold decrease in the level of the pro-apoptotic protein Bim-EL whereas the level of the anti-apoptotic protein Bcl-2 was unchanged. Inhibition of Mek1/2 kinases with U0126, and the resulting inhibition of Erk1/2 phosphorylation, induced the increase of both the level of Bim-EL and apoptosis of cells seeded on the N-cadherin substrate, suggesting that Erk phosphorylation is necessary for cell survival. Finally, the overexpression of a phosphorylation defective form of Bim-EL prevented N-cadherin-engagement induced cell survival. In conclusion, our results show that N-cadherin engagement mediates neuronal cell survival by enhancing the MAP kinase pathway and down regulating the pro-apoptotic protein Bim-EL. PMID- 22427991 TI - Angiotensin II requires zinc and downregulation of the zinc transporters ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells. AB - Senescence, a hallmark of mammalian aging, is associated with the onset and progression of cardiovascular disease. Angiotensin II (Ang II) signaling and zinc homeostasis dysfunction are increased with age and are linked to cardiovascular disease, but the relationship among these processes has not been investigated. We used a model of cellular senescence induced by Ang II in vascular smooth muscle cells (VSMCs) to explore the role of zinc in vascular dysfunction. We found that Ang II-induced senescence is a zinc-dependent pathway mediated by the downregulation of the zinc transporters ZnT3 and ZnT10, which work to reduce cytosolic zinc. Zinc mimics Ang II by increasing reactive oxygen species (ROS), activating NADPH oxidase activity and Akt, and by downregulating ZnT3 and ZnT10 and inducing senescence. Zinc increases Ang II-induced senescence, while the zinc chelator TPEN, as well as overexpression of ZnT3 or ZnT10, decreases ROS and prevents senescence. Using HEK293 cells, we found that ZnT10 localizes in recycling endosomes and transports zinc into vesicles to prevent zinc toxicity. Zinc and ZnT3/ZnT10 downregulation induces senescence by decreasing the expression of catalase. Consistently, ZnT3 and ZnT10 downregulation by siRNA increases ROS while downregulation of catalase by siRNA induces senescence. Zinc, siZnT3 and siZnT10 downregulate catalase by a post-transcriptional mechanism mediated by decreased phosphorylation of ERK1/2. These data demonstrate that zinc homeostasis dysfunction by decreased expression of ZnT3 or ZnT10 promotes senescence and that Ang II-induced senescence is a zinc and ROS-dependent process. Our studies suggest that zinc might also affect other ROS-dependent processes induced by Ang II, such as hypertrophy and migration of smooth muscle cells. PMID- 22427992 TI - Computational and serologic analysis of novel and known viruses in species human adenovirus D in which serology and genomics do not correlate. AB - In November of 2007 a human adenovirus (HAdV) was isolated from a bronchoalveolar lavage (BAL) sample recovered from a biopsy of an AIDS patient who presented with fever, cough, tachycardia, and expiratory wheezes. To better understand the isolated virus, the genome was sequenced and analyzed using bioinformatic and phylogenomic analysis. The results suggest that this novel virus, which is provisionally named HAdV-D59, may have been created from multiple recombination events. Specifically, the penton, hexon, and fiber genes have high nucleotide identity to HAdV-D19C, HAdV-D25, and HAdV-D56, respectively. Serological results demonstrated that HAdV-D59 has a neutralization profile that is similar yet not identical to that of HAdV-D25. Furthermore, we observed a two-fold difference between the ability of HAdV-D15 and HAdV-D25 to be neutralized by reciprocal antiserum indicating that the two hexon proteins may be more similar in epitopic conformation than previously assumed. In contrast, hexon loops 1 and 2 of HAdV D15 and HAdV-D25 share 79.13 and 92.56 percent nucleotide identity, respectively. These data suggest that serology and genomics do not always correlate. PMID- 22427993 TI - A putative cell surface receptor for white spot syndrome virus is a member of a transporter superfamily. AB - White spot syndrome virus (WSSV), a large enveloped DNA virus, can cause the most serious viral disease in shrimp and has a wide host range among crustaceans. In this study, we identified a surface protein, named glucose transporter 1 (Glut1), which could also interact with WSSV envelope protein, VP53A. Sequence analysis revealed that Glut1 is a member of a large superfamily of transporters and that it is most closely related to evolutionary branches of this superfamily, branches that function to transport this sugar. Tissue tropism analysis showed that Glut1 was constitutive and highly expressed in almost all organs. Glut1's localization in shrimp cells was further verified and so was its interaction with Penaeus monodon chitin-binding protein (PmCBP), which was itself identified to interact with an envelope protein complex formed by 11 WSSV envelope proteins. In vitro and in vivo neutralization experiments using synthetic peptide contained WSSV binding domain (WBD) showed that the WBD peptide could inhibit WSSV infection in primary cultured hemocytes and delay the mortality in shrimps challenged with WSSV. These findings have important implications for our understanding of WSSV entry. PMID- 22427994 TI - Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. AB - Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by a CTG trinucleotide repeat expansion (CTG(exp)) in the DMPK gene. In skeletal muscle, nuclear sequestration of the alternative splicing factor muscleblind-like 1 (MBNL1) explains the majority of the alternative splicing defects observed in the HSA(LR) transgenic mouse model which expresses a pathogenic range CTG(exp). In the present study, we addressed the possibility that MBNL1 sequestration by CUG(exp) RNA also contributes to splicing defects in the mammalian brain. We examined RNA from the brains of homozygous Mbnl1(DeltaE3/DeltaE3) knockout mice using splicing-sensitive microarrays. We used RT-PCR to validate a subset of alternative cassette exons identified by microarray analysis with brain tissues from Mbnl1(DeltaE3/DeltaE3) knockout mice and post-mortem DM1 patients. Surprisingly, splicing-sensitive microarray analysis of Mbnl1(DeltaE3/DeltaE3) brains yielded only 14 candidates for mis-spliced exons. While we confirmed that several of these splicing events are perturbed in both Mbnl1 knockout and DM1 brains, the extent of splicing mis-regulation in the mouse model was significantly less than observed in DM1. Additionally, several alternative exons, including Grin1 exon 4, App exon 7 and Mapt exons 3 and 9, which have previously been reported to be aberrantly spliced in human DM1 brain, were spliced normally in the Mbnl1 knockout brain. The sequestration of MBNL1 by CUG(exp) RNA results in some of the aberrant splicing events in the DM1 brain. However, we conclude that other factors, possibly other MBNL proteins, likely contribute to splicing mis-regulation in the DM1 brain. PMID- 22427995 TI - Grapevine aquaporins: gating of a tonoplast intrinsic protein (TIP2;1) by cytosolic pH. AB - Grapevine (Vitis vinifera L.) is one of the oldest and most important perennial crops being considered as a fruit ligneous tree model system in which the water status appears crucial for high fruit and wine quality, controlling productivity and alcohol level. V. vinifera genome contains 28 genes coding for aquaporins, which acting in a concerted and regulated manner appear relevant for plant withstanding extremely unfavorable drought conditions essential for the quality of berries and wine. Several Vv aquaporins have been reported to be expressed in roots, shoots, berries and leaves with clear cultivar differences in their expression level, making their in vivo biochemical characterization a difficult task. In this work V. vinifera cv. Touriga nacional VvTnPIP1;1, VvTnPIP2;2 and VvTnTIP2;1 were expressed in yeast and water transport activity was characterized in intact cells of the transformants. The three aquaporins were localized in the yeast plasma membrane but only VvTnTIP2;1 expression enhanced the water permeability with a concomitant decrease of the activation energy of water transport. Acidification of yeast cytosol resulted in loss of VvTnTIP2;1 activity. Sequence analysis revealed the presence of a His(131) residue, unusual in TIPs. By site directed mutagenesis, replacement of this residue by aspartic acid or alanine resulted in loss of pH(in) dependence while replacement by lysine resulted in total loss of activity. In addition to characterization of VvTn aquaporins, these results shed light on the gating of a specific tonoplast aquaporin by cytosolic pH. PMID- 22427996 TI - Divergent roles of Salmonella pathogenicity island 2 and metabolic traits during interaction of S. enterica serovar typhimurium with host cells. AB - The molecular mechanisms of virulence of the gastrointestinal pathogen Salmonella enterica are commonly studied using cell culture models of infection. In this work, we performed a direct comparison of the interaction of S. enterica serovar Typhimurium (S. Typhimurium) with the non-polarized epithelial cell line HeLa, the polarized cell lines CaCo2, T84 and MDCK, and macrophage-like RAW264.7 cells. The ability of S. Typhimurium wild-type and previously characterized auxotrophic mutant strains to enter host cells, survive and proliferate within mammalian cells and deploy the Salmonella Pathogenicity Island 2-encoded type III secretion system (SPI2-T3SS) was quantified. We found that the entry of S. Typhimurium into polarized cells was much more efficient than entry into non-polarized cells or phagocytic uptake. While SPI2-T3SS dependent intracellular proliferation was observed in HeLa and RAW cells, the intracellular replication in polarized cells was highly restricted and not affected by defective SPI2-T3SS. The contribution of aromatic amino acid metabolism and purine biosynthesis to intracellular proliferation was distinct in the various cell lines investigated. These observations indicate that the virulence phenotypes of S. Typhimurium are significantly affected by the cell culture model applied. PMID- 22427997 TI - Time-frequency analysis of chemosensory event-related potentials to characterize the cortical representation of odors in humans. AB - BACKGROUND: The recording of olfactory and trigeminal chemosensory event-related potentials (ERPs) has been proposed as an objective and non-invasive technique to study the cortical processing of odors in humans. Until now, the responses have been characterized mainly using across-trial averaging in the time domain. Unfortunately, chemosensory ERPs, in particular, olfactory ERPs, exhibit a relatively low signal-to-noise ratio. Hence, although the technique is increasingly used in basic research as well as in clinical practice to evaluate people suffering from olfactory disorders, its current clinical relevance remains very limited. Here, we used a time-frequency analysis based on the wavelet transform to reveal EEG responses that are not strictly phase-locked to onset of the chemosensory stimulus. We hypothesized that this approach would significantly enhance the signal-to-noise ratio of the EEG responses to chemosensory stimulation because, as compared to conventional time-domain averaging, (1) it is less sensitive to temporal jitter and (2) it can reveal non phase-locked EEG responses such as event-related synchronization and desynchronization. METHODOLOGY/PRINCIPAL FINDINGS: EEG responses to selective trigeminal and olfactory stimulation were recorded in 11 normosmic subjects. A Morlet wavelet was used to characterize the elicited responses in the time-frequency domain. We found that this approach markedly improved the signal-to-noise ratio of the obtained EEG responses, in particular, following olfactory stimulation. Furthermore, the approach allowed characterizing non phase-locked components that could not be identified using conventional time-domain averaging. CONCLUSION/SIGNIFICANCE: By providing a more robust and complete view of how odors are represented in the human brain, our approach could constitute the basis for a robust tool to study olfaction, both for basic research and clinicians. PMID- 22427998 TI - Locally administrated perindopril improves healing in an ovariectomized rat tibial osteotomy model. AB - Angiotensin-converting enzyme inhibitors are widely prescribed to regulate blood pressure. High doses of orally administered perindopril have previously been shown to improve fracture healing in a mouse femur fracture model. In this study, perindopril was administered directly to the fracture area with the goal of stimulating fracture repair. Three months after being ovariectomized (OVX), tibial fractures were produced in Sprague-Dawley rats and subsequently stabilized with intramedullary wires. Perindopril (0.4 mg/kg/day) was injected locally at the fractured site for a treatment period of 7 days. Vehicle reagent was used as a control. Callus quality was evaluated at 2 and 4 weeks post-fracture. Compared with the vehicle group, perindopril treatment significantly increased bone formation, increased biomechanical strength, and improved microstructural parameters of the callus. Newly woven bone was arranged more tightly and regularly at 4 weeks post-fracture. The ultimate load increased by 66.1 and 76.9% (p<0.01), and the bone volume over total volume (BV/TV) increased by 29.9% and 24.3% (p<0.01) at 2 and 4 weeks post-fracture, respectively. These findings suggest that local treatment with perindopril could promote fracture healing in ovariectomized rats. PMID- 22427999 TI - Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. AB - Infection of mice with murine gammaherpesvirus 68 (MHV68) provides a tractable small animal model to study various aspects of persistent gammaherpesvirus infection. We have previously utilized a transgenic MHV68 that expresses enhanced yellow fluorescent protein (EYFP) to identify infected cells. While this recombinant MHV68 has been useful for identifying infected cell populations by flow cytometry, it has been suboptimal for identification of infected cells in tissue sections due to the high solubility of EYFP. Efficient detection of EYFP expressed from the MHV68 genome in tissue sections requires fixation of whole organs prior to sectioning, which frequently leads to over-fixation of some cellular antigens precluding their detection. To circumvent this issue, we describe the generation and characterization of a transgenic MHV68 harboring a fusion gene composed of the EYFP coding sequence fused to the histone H2B open reading frame. Because the H2bYFP fusion protein is tightly bound in nucleosomes in the nucleus it does not freely diffuse out of unfixed tissue sections, and thus eliminates the need for tissue fixation. We have used the MHV68-H2bYFP recombinant virus to assess the location and distribution of virus infected B cells in germinal centers during the peak of MHV68 latency in vivo. These analyses show that the physical location of distinct populations of infected germinal center B cells correlates well with their surface phenotype. Furthermore, analysis of the distribution of virus infection within germinal center B cell populations revealed that ca. 70% of MHV68 infected GC B cells are rapidly dividing centroblasts, while ca. 20% have a clear centrocyte phenotype. Finally, we have shown that marking of infected cells with MHV68-H2bYFP is extended long after the onset of latency - which should facilitate studies to track MHV68 latently infected cells at late times post-infection. PMID- 22428000 TI - Common changes in global gene expression induced by RNA polymerase inhibitors in Shigella flexneri. AB - Characterization of expression profile of organisms in response to antimicrobials provides important information on the potential mechanism of action of the drugs. The special expression signature can be used to predict whether other drugs act on the same target. Here, the common response of Shigella flexneri to two inhibitors of RNA polymerase was examined using gene expression profiling. Consistent with similar effects of the two drugs, the gene expression profiles indicated that responses of the bacteria to these drugs were roughly the same, with 225 genes affected commonly. Of them, 88 were induced and 137 were repressed. Real-time PCR was performed for selected genes to verify the microarray results. Analysis of the expression data revealed that more than 30% of the plasmid-encoded genes on the array were up-regulated by the antibiotics including virF regulon, other virulence-related genes, and genes responsible for plasmid replication, maintenance, and transfer. In addition, some chromosome encoded genes involved in virulence and genes acquired from horizontal transfer were also significantly up-regulated. However, the expression of genes encoding the beta-subunit of RNA polymerase was increased moderately. The repressed genes include those that code for products associated with the ribosome, citrate cycle, glycolysis, thiamine biosynthesis, purine metabolism, fructose metabolism, mannose metabolism, and cold shock proteins. This study demonstrates that the two antibiotics induce rapid cessation of RNA synthesis resulting in inhibition of translation components. It also indicates that the production of virulence factors involved in intercellular dissemination, tissue invasion and inflammatory destruction may be enhanced through derepressing horizontal transfer genes by the drugs. PMID- 22428001 TI - Hypoxia reduces arylsulfatase B activity and silencing arylsulfatase B replicates and mediates the effects of hypoxia. AB - This report presents evidence of 1) a role for arylsulfatase B (ARSB; N acetylgalactosamine-4-sulfatase) in mediating intracellular oxygen signaling; 2) replication between the effects of ARSB silencing and hypoxia on sulfated glycosaminoglycan content, cellular redox status, and expression of hypoxia associated genes; and 3) a mechanism whereby changes in chondroitin-4-sulfation that follow either hypoxia or ARSB silencing can induce transcriptional changes through galectin-3. ARSB removes 4-sulfate groups from the non-reducing end of chondroitin-4-sulfate and dermatan sulfate and is required for their degradation. For activity, ARSB requires modification of a critical cysteine residue by the formylglycine generating enzyme and by molecular oxygen. When primary human bronchial and human colonic epithelial cells were exposed to 10% O(2) * 1 h, ARSB activity declined by ~41% and ~30% from baseline, as nuclear hypoxia inducible factor (HIF)-1alpha increased by ~53% and ~37%. When ARSB was silenced, nuclear HIF-1alpha increased by ~81% and ~61% from baseline, and mRNA expression increased to 3.73 (+/- 0.34) times baseline. Inversely, ARSB overexpression reduced nuclear HIF-1alpha by ~37% and ~54% from baseline in the epithelial cells. Hypoxia, like ARSB silencing, significantly increased the total cellular sulfated glycosaminoglycans and chondroitin-4-sulfate (C4S) content. Both hypoxia and ARSB silencing had similar effects on the cellular redox status and on mRNA expression of hypoxia-associated genes. Transcriptional effects of both ARSB silencing and hypoxia may be mediated by reduction in galectin-3 binding to more highly sulfated C4S, since the galectin-3 that co-immunoprecipitated with C4S declined and the nuclear galectin-3 increased following ARSB knockdown and hypoxia. PMID- 22428002 TI - Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. AB - Uterine leiomyomas (uterine fibroids) arise from smooth muscle tissue in the majority of women by age 45. It is common for these clonal tumors to develop from multiple locations within the uterus, leading to a variety of symptoms such as pelvic pain, abnormal uterine bleeding, and infertility. We performed whole exome sequencing on genomic DNA from five pairs of leiomyomas and corresponding normal myometrium to determine genetic variations unique to leiomyomas. Whole exome sequencing revealed that the gene encoding transcription factor MED12 (Mediator complex subunit 12) harbored heterozygous missense mutations caused by single nucleotide variants in highly conserved codon 44 of exon 2 in two of five leiomyomas. Sanger re-sequencing of MED12 among these five leiomyomas confirmed the two single nucleotide variants and detected a 42 base-pair deletion within exon 2 of MED12 in a third leiomyoma. MED12 was sequenced in an additional 143 leiomyomas and 73 normal myometrial tissues. Overall, MED12 was mutated in 100/148 (67%) of the genotyped leiomyomas: 79/148 (53%) leiomyomas exhibited heterozygous missense single nucleotide variants, 17/148 (11%) leiomyomas exhibited heterozygous in-frame deletions/insertion-deletions, 2/148 (1%) leiomyomas exhibited intronic heterozygous single nucleotide variants affecting splicing, and 2/148 (1%) leiomyomas exhibited heterozygous deletions/insertion deletions spanning the intron 1-exon 2 boundary which affected the splice acceptor site. Mutations were not detected in MED12 in normal myometrial tissue. MED12 mutations were equally distributed among karyotypically normal and abnormal uterine leiomyomas and were identified in leiomyomas from both black and white American women. Our studies show an association between MED12 mutations and leiomyomas in ethnically and racially diverse American women. PMID- 22428003 TI - Structure and dynamics of the G121V dihydrofolate reductase mutant: lessons from a transition-state inhibitor complex. AB - It is well known that enzyme flexibility is critical for function. This is due to the observation that the rates of intramolecular enzyme motions are often matched to the rates of intermolecular events such as substrate binding and product release. Beyond this role in progression through the reaction cycle, it has been suggested that enzyme dynamics may also promote the chemical step itself. Dihydrofolate reductase (DHFR) is a model enzyme for which dynamics have been proposed to aid in both substrate flux and catalysis. The G121V mutant of DHFR is a well studied form that exhibits a severe reduction in the rate of hydride transfer yet there remains dispute as to whether this defect is caused by altered structure, dynamics, or both. Here we address this by presenting an NMR study of the G121V mutant bound to reduced cofactor and the transition state inhibitor, methotrexate. NMR chemical shift markers demonstrate that this form predominantly adopts the closed conformation thereby allowing us to provide the first glimpse into the dynamics of a catalytically relevant complex. Based on (15)N and (2)H NMR spin relaxation, we find that the mutant complex has modest changes in ps-ns flexibility with most affected residues residing in the distal adenosine binding domain rather than the active site. Thus, aberrant ps-ns dynamics are likely not the main contributor to the decreased catalytic rate. The most dramatic effect of the mutation involves changes in us-ms dynamics of the F-G and Met20 loops. Whereas loop motion is quenched in the wild type transition state inhibitor complex, the F-G and Met20 loops undergo excursions from the closed conformation in the mutant complex. These excursions serve to decrease the population of conformers having the correct active site configuration, thus providing an explanation for the G121V catalytic defect. PMID- 22428004 TI - Old and new stories: revelations from functional analysis of the bovine mammary transcriptome during the lactation cycle. AB - The cow mammary transcriptome was explored at -30, -15, 1, 15, 30, 60, 120, 240, and 300 d relative to parturition. A total of 6,382 differentially expressed genes (DEG) at a false discovery rate <= 0.001 were found throughout lactation. The greatest number of DEG (>3,500 DEG) was observed at 60 and 120 d vs. -30 d with the largest change between consecutive time points observed at -15 vs. 1 d and 120 vs. 240 d. Functional analysis of microarray data was performed using the Dynamic Impact Approach (DIA). The DIA analysis of KEGG pathways uncovered as the most impacted and induced 'Galactose metabolism', 'Glycosylphosphatidylinositol (GPI)-anchor biosynthesis', and 'PPAR signaling'; whereas, 'Antigen processing and presentation' was among the most inhibited. The integrated interpretation of the results suggested an overall increase in metabolism during lactation, particularly synthesis of carbohydrates and lipid. A marked degree of utilization of amino acids as energy source, an increase of protein export, and a decrease of the protein synthesis machinery as well cell cycle also were suggested by the DIA analysis. The DIA analysis of Gene Ontology and other databases uncovered an induction of Golgi apparatus and angiogenesis, and the inhibition of both immune cell activity/migration and chromosome modifications during lactation. All of the highly-impacted and activated functions during lactation were evidently activated at the onset of lactation and inhibited when milk production declined. The overall analysis indicated that the bovine mammary gland relies heavily on a coordinated transcriptional regulation to begin and end lactation. The functional analysis using DIA underscored the importance of genes associated with lactose synthesis, lipid metabolism, protein synthesis, Golgi, transport, cell cycle/death, epigenetic regulation, angiogenesis, and immune function during lactation. PMID- 22428005 TI - Tracking the expression of excitatory and inhibitory neurotransmission-related proteins and neuroplasticity markers after noise induced hearing loss. AB - Excessive exposure to loud noise can damage the cochlea and create a hearing loss. These pathologies coincide with a range of CNS changes including reorganisation of frequency representation, alterations in the pattern of spontaneous activity and changed expression of excitatory and inhibitory neurotransmitters. Moreover, damage to the cochlea is often accompanied by acoustic disorders such as hyperacusis and tinnitus, suggesting that one or more of these neuronal changes may be involved in these disorders, although the mechanisms remain unknown. We tested the hypothesis that excessive noise exposure increases expression of markers of excitation and plasticity, and decreases expression of inhibitory markers over a 32-day recovery period. Adult rats (n = 25) were monaurally exposed to a loud noise (16 kHz, 1/10(th) octave band pass (115 dB SPL)) for 1-hour, or left as non-exposed controls (n = 5). Animals were euthanased at either 0, 4, 8, 16 or 32 days following acoustic trauma. We used Western Blots to quantify protein levels of GABA(A) receptor subunit alpha1 (GABA(A)alpha1), Glutamic-Acid Decarboxylase-67 (GAD-67), N-Methyl-D-Aspartate receptor subunit 2A (NR2A), Calbindin (Calb1) and Growth Associated Protein 43 (GAP-43) in the Auditory Cortex (AC), Inferior Colliculus (IC) and Dorsal Cochlear Nucleus (DCN). Compared to sham-exposed controls, noise-exposed animals had significantly (p<0.05): lower levels of GABA(A)alpha1 in the contralateral AC at day-16 and day-32, lower levels of GAD-67 in the ipsilateral DCN at day-4, lower levels of Calb1 in the ipsilateral DCN at day-0, lower levels of GABA(A)alpha1 in the ipsilateral AC at day-4 and day-32. GAP-43 was reduced in the ipsilateral AC for the duration of the experiment. These complex fluctuations in protein expression suggests that for at least a month following acoustic trauma the auditory system is adapting to a new pattern of sensory input. PMID- 22428006 TI - Caregiver recognition of childhood diarrhea, care seeking behaviors and home treatment practices in rural Burkina Faso: a cross-sectional survey. AB - INTRODUCTION: To design effective national diarrhea control programs, including oral rehydration solution (ORS) and therapeutic zinc supplementation, information is needed on local perceptions of illness, external care seeking behaviors, and home treatment practices. METHODS: A cross-sectional, community-based household survey was conducted in the Orodara Health District, Burkina Faso. Caregivers of 10,490 children <27 months were interviewed to assess child diarrhea prevalence and related care practices. Characteristics of households, caregivers, children, and reported illnesses were compared for those caregivers who did or did not recognize the presence of diarrhea, as defined according to clinical criteria (>= 3 liquid or semi-liquid stools/day). Multiple logistic regression models were used to examine factors associated with illness recognition and treatment. RESULTS: Clinically defined diarrhea was present in 7.6% (95% CI: 7.1-8.1%) of children during the 24 hours preceding the survey but recognized by only 55% of caregivers. Over half (55%) of the caregivers of 1,067 children with a clinically defined diarrhea episode in the past 14 days sought care outside the home; 78% of those seeking care attended a public sector clinic. Care was sought and treatment provided more frequently for children with fever, vomiting, anorexia, longer illness duration, and those living closer to the health center; and care was sought more frequently for male children. 80% of children with recent diarrhea received some form of treatment; only 24% received ORS, whereas 14% received antibiotics. Zinc was not yet available in the study area. CONCLUSIONS: Caregivers frequently fail to recognize children's diarrhea, especially among younger infants and when illness signs are less severe. Treatment practices do not correspond with international recommendations in most cases, even when caregivers consult with formal health services. Child caregivers need additional assistance to recognize diarrhea correctly, and both caregivers and health care providers need updated training on current diarrhea treatment recommendations. PMID- 22428007 TI - Identification of myeloid derived suppressor cells in dogs with naturally occurring cancer. AB - Dogs with naturally occurring cancer represent an important large animal model for drug development and testing novel immunotherapies. However, poorly defined immunophenotypes of canine leukocytes have limited the study of tumor immunology in dogs. The accumulation of myeloid derived suppressor cells (MDSCs) is known to be a key mechanism of immune suppression in tumor-bearing mice and in human patients. We sought to identify MDSCs in the blood of dogs with cancer. Peripheral blood mononuclear cells (PBMCs) from dogs with advanced or early stage cancer and from age-matched healthy controls were analyzed by flow cytometry and microscopy. Suppressive function was tested in T cell proliferation and cytokine elaboration assays. Semi-quantitative RT-PCR was used to identify potential mechanisms responsible for immunosuppression. PBMCs from dogs with advanced or metastatic cancer exhibited a significantly higher percentage of CD11b(+)CD14( )MHCII(-) cells compared to dogs diagnosed with early stage non-metastatic tumors and healthy dogs. These CD11b(+) CD14(-)MHCII(-) cells constitute a subpopulation of activated granulocytes that co-purify with PBMCs, display polymorphonuclear granulocyte morphology, and demonstrate a potent ability to suppress proliferation and IFN-gamma production in T cells from normal and tumor-bearing donors. Furthermore, these cells expressed hallmark suppressive factors of human MDSC including ARG1, iNOS2, TGF-beta and IL-10. In summary our data demonstrate that MDSCs accumulate in the blood of dogs with advanced cancer and can be measured using this three-marker immunophenotype, thereby enabling prospective studies that can monitor MDSC burden. PMID- 22428008 TI - Beta-amyloid peptides enhance the proliferative response of activated CD4CD28 lymphocytes from Alzheimer disease patients and from healthy elderly. AB - Alzheimer's disease (AD) is the most frequent form of dementia among elderly. Despite the vast amount of literature on non-specific immune mechanisms in AD there is still little information about the potential antigen-specific immune response in this pathology. It is known that early stages of AD include beta amyloid (Abeta)- reactive antibodies production and inflammatory response. Despite some evidence gathered proving cellular immune response background in AD pathology, the specific reactions of CD4(+) and CD8(+) cells remain unknown as the previous investigations yielded conflicting results. Here we investigated the CD4(+)CD28(+) population of human peripheral blood T cells and showed that soluble beta-amyloids alone were unable to stimulate these cells to proliferate significantly, resulting only in minor, probably antigen-specific, proliferative response. On the other hand, the exposure of in vitro pre-stimulated lymphocytes to soluble Abeta peptides significantly enhanced the proliferative response of these cells which had also lead to increased levels of TNF, IL-10 and IL-6. We also proved that Abeta peptide-enhanced proliferative response of CD4(+)CD28(+) cells is autonomous and independent from disease status while being associated with the initial, ex vivo activation status of the CD4(+) cells. In conclusion, we suggest that the effect of Abeta peptides on the immune system of AD patients does not depend on the specific reactivity to Abeta epitope(s), but is rather a consequence of an unspecific modulation of the cell cycle dynamics and cytokine production by T cells, occurring simultaneously in a huge proportion of Abeta peptide-exposed T lymphocytes and affecting the immune system performance. PMID- 22428009 TI - Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. AB - BACKGROUND: Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown. PRINCIPAL FINDINGS: We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels. CONCLUSIONS: These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women. PMID- 22428010 TI - Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction. AB - Liver-directed gene transfer is being investigated for the treatment of systemic or liver-specific diseases. Recombinant vectors based on adeno-associated virus serotype 8 (AAV2/8) efficiently transduce liver cells allowing long term transgene expression after a single administration in animal models and in patients.We evaluated the impact on AAV2/8-mediated rat liver transduction of the following variables: i) age at vector administration, ii) presence of lysosomal storage in liver cells, and iii) regulatory elements included in the transgene expression cassette. We found that systemic administration of AAV2/8 to newborn rats results in vector genome dilution and reduced transduction efficacy when compared to adult injected animals, presumably due to hepatocyte proliferation. Accumulation of glycosaminoglycans in lysosomes does not impact on levels and distribution of AAV2/8-mediated liver transduction. Transgene expression occurs in hepatocytes but not in Kupffer or liver endothelial cells when the liver specific thyroxine-binding-globulin promoter is used. However, extra-hepatic transduction is observed in the spleen and kidney of animals injected at birth. The use of target sequences for the hematopoietic-specific microRNA miR142-3p does not improve liver transduction efficacy neither reduce immune responses to the lysosomal enzyme arylsulfatase B. The inclusion of a variant of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE-m) decreases AAV2/8 mediated liver transduction levels.As AAV2/8-mediated liver gene transfer is entering in the clinical arena, these data will provide relevant information to the design of efficient AAV2/8-based therapeutic strategies. PMID- 22428011 TI - Characterization of a novel binding protein for Fortilin/TCTP--component of a defense mechanism against viral infection in Penaeus monodon. AB - The Fortilin (also known as TCTP) in Penaeus monodon (PmFortilin) and Fortilin Binding Protein 1 (FBP1) have recently been shown to interact and to offer protection against the widespread White Spot Syndrome Virus infection. However, the mechanism is yet unknown. We investigated this interaction in detail by a number of in silico and in vitro analyses, including prediction of a binding site between PmFortilin/FBP1 and docking simulations. The basis of the modeling analyses was well-conserved PmFortilin orthologs, containing a Ca(2+)-binding domain at residues 76-110 representing a section of the helical domain, the translationally controlled tumor protein signature 1 and 2 (TCTP_1, TCTP_2) at residues 45-55 and 123-145, respectively. We found the pairs Cys59 and Cys76 formed a disulfide bond in the C-terminus of FBP1, which is a common structural feature in many exported proteins and the "x-G-K-K" pattern of the amidation site at the end of the C-terminus. This coincided with our previous work, where we found the "x-P-P-x" patterns of an antiviral peptide also to be located in the C terminus of FBP1. The combined bioinformatics and in vitro results indicate that FBP1 is a transmembrane protein and FBP1 interact with N-terminal region of PmFortilin. PMID- 22428012 TI - Lithium impacts on the amplitude and period of the molecular circadian clockwork. AB - Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions. PMID- 22428013 TI - Functional connectivity of pain-mediated affect regulation in Borderline Personality Disorder. AB - Affective instability and self-injurious behavior are important features of Borderline Personality Disorder. Whereas affective instability may be caused by a pattern of limbic hyperreactivity paired with dysfunctional prefrontal regulation mechanisms, painful stimulation was found to reduce affective arousal at the neural level, possibly underlying the soothing effect of pain in BPD.We used psychophysiological interactions to analyze functional connectivity of (para-) limbic brain structures (i.e. amygdala, insula, anterior cingulate cortex) in Borderline Personality Disorder in response to painful stimulation. Therefore, we re-analyzed a dataset from 20 patients with Borderline Personality Disorder and 23 healthy controls who took part in an fMRI-task inducing negative (versus neutral) affect and subsequently applying heat pain (versus warmth perception).Results suggest an enhanced negative coupling between limbic as well as paralimbic regions and prefrontal regions, specifically with the medial and dorsolateral prefrontal cortex, when patients experienced pain in addition to emotional arousing pictures. When neutral pictures were combined with painful heat sensation, we found positive connectivity in Borderline Personality Disorder between (para-)limbic brain areas and parts of the basal ganglia (lentiform nucleus, putamen), as well areas involved in self-referential processing (precuneus and posterior cingulate).We found further evidence for alterations in the emotion regulation process in Borderline Personality Disorder, in the way that pain improves the inhibition of limbic activity by prefrontal areas. This study provides new insights in pain processing in BPD, including enhanced coupling of limbic structures and basal ganglia. PMID- 22428014 TI - Unique proteomic signatures distinguish macrophages and dendritic cells. AB - Monocytes differentiate into heterogeneous populations of tissue macrophages and dendritic cells (DCs) that regulate inflammation and immunity. Identifying specific populations of myeloid cells in vivo is problematic, however, because only a limited number of proteins have been used to assign cellular phenotype. Using mass spectrometry and bone marrow-derived cells, we provided a global view of the proteomes of M-CSF-derived macrophages, classically and alternatively activated macrophages, and GM-CSF-derived DCs. Remarkably, the expression levels of half the plasma membrane proteins differed significantly in the various populations of cells derived in vitro. Moreover, the membrane proteomes of macrophages and DCs were more distinct than those of classically and alternatively activated macrophages. Hierarchical cluster and dual statistical analyses demonstrated that each cell type exhibited a robust proteomic signature that was unique. To interrogate the phenotype of myeloid cells in vivo, we subjected elicited peritoneal macrophages harvested from wild-type and GM-CSF deficient mice to mass spectrometric and functional analysis. Unexpectedly, we found that peritoneal macrophages exhibited many features of the DCs generated in vitro. These findings demonstrate that global analysis of the membrane proteome can help define immune cell phenotypes in vivo. PMID- 22428015 TI - Habitat composition and connectivity predicts bat presence and activity at foraging sites in a large UK conurbation. AB - BACKGROUND: Urbanization is characterized by high levels of sealed land-cover, and small, geometrically complex, fragmented land-use patches. The extent and density of urbanized land-use is increasing, with implications for habitat quality, connectivity and city ecology. Little is known about densification thresholds for urban ecosystem function, and the response of mammals, nocturnal and cryptic taxa are poorly studied in this respect. Bats (Chiroptera) are sensitive to changing urban form at a species, guild and community level, so are ideal model organisms for analyses of this nature. METHODOLOGY/PRINCIPAL FINDINGS: We surveyed bats around urban ponds in the West Midlands conurbation, United Kingdom (UK). Sites were stratified between five urban land classes, representing a gradient of built land-cover at the 1 km(2) scale. Models for bat presence and activity were developed using land-cover and land-use data from multiple radii around each pond. Structural connectivity of tree networks was used as an indicator of the functional connectivity between habitats. All species were sensitive to measures of urban density. Some were also sensitive to landscape composition and structural connectivity at different spatial scales. These results represent new findings for an urban area. The activity of Pipistrellus pipistrellus (Schreber 1774) exhibited a non-linear relationship with the area of built land-cover, being much reduced beyond the threshold of ~60% built surface. The presence of tree networks appears to mitigate the negative effects of urbanization for this species. CONCLUSIONS/SIGNIFICANCE: Our results suggest that increasing urban density negatively impacts the study species. This has implications for infill development policy, built density targets and the compact city debate. Bats were also sensitive to the composition and structure of the urban form at a range of spatial scales, with implications for land-use planning and management. Protecting and establishing tree networks may improve the resilience of some bat populations to urban densification. PMID- 22428016 TI - Systemic IL-12 administration alters hepatic dendritic cell stimulation capabilities. AB - The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2-3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFNgamma expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections. PMID- 22428017 TI - Transcriptome sequencing and characterization for the sea cucumber Apostichopus japonicus (Selenka, 1867). AB - BACKGROUND: Sea cucumbers are a special group of marine invertebrates. They occupy a taxonomic position that is believed to be important for understanding the origin and evolution of deuterostomes. Some of them such as Apostichopus japonicus represent commercially important aquaculture species in Asian countries. Many efforts have been devoted to increasing the number of expressed sequence tags (ESTs) for A. japonicus, but a comprehensive characterization of its transcriptome remains lacking. Here, we performed the large-scale transcriptome profiling and characterization by pyrosequencing diverse cDNA libraries from A. japonicus. RESULTS: In total, 1,061,078 reads were obtained by 454 sequencing of eight cDNA libraries representing different developmental stages and adult tissues in A. japonicus. These reads were assembled into 29,666 isotigs, which were further clustered into 21,071 isogroups. Nearly 40% of the isogroups showed significant matches to known proteins based on sequence similarity. Gene ontology (GO) and KEGG pathway analyses recovered diverse biological functions and processes. Candidate genes that were potentially involved in aestivation were identified. Transcriptome comparison with the sea urchin Strongylocentrotus purpuratus revealed similar patterns of GO term representation. In addition, 4,882 putative orthologous genes were identified, of which 202 were not present in the non-echinoderm organisms. More than 700 simple sequence repeats (SSRs) and 54,000 single nucleotide polymorphisms (SNPs) were detected in the A. japonicus transcriptome. CONCLUSION: Pyrosequencing was proven to be efficient in rapidly identifying a large set of genes for the sea cucumber A. japonicus. Through the large-scale transcriptome sequencing as well as public EST data integration, we performed a comprehensive characterization of the A. japonicus transcriptome and identified candidate aestivation-related genes. A large number of potential genetic markers were also identified from the A. japonicus transcriptome. This transcriptome resource would lay an important foundation for future genetic or genomic studies on this species. PMID- 22428018 TI - Impact of dietary gluten on regulatory T cells and Th17 cells in BALB/c mice. AB - Dietary gluten influences the development of type 1 diabetes (T1D) and a gluten free (GF) diet has a protective effect on the development of T1D. Gluten may influence T1D due to its direct effect on intestinal immunity; however, these mechanisms have not been adequately studied. We studied the effect of a GF diet compared to a gluten-containing standard (STD) diet on selected T cell subsets, associated with regulatory functions as well as proinflammatory Th17 cells, in BALB/c mice. Furthermore, we assessed diet-induced changes in the expression of various T cell markers, and determined if changes were confined to intestinal or non-intestinal lymphoid compartments. The gluten-containing STD diet led to a significantly decreased proportion of gammadelta T cells in all lymphoid compartments studied, although an increase was detected in some gammadelta T cell subsets (CD8(+), CD103(+)). Further, it decreased the proportion of CD4(+)CD62L(+) T cells in Peyer's patches. Interestingly, no diet-induced changes were found among CD4(+)Foxp3(+) T cells or CD3(+)CD49b(+)cells (NKT cells) and CD3(-)CD49b(+) (NK) cells. Mice fed the STD diet showed increased proportions of CD4(+)CD45RB(high+) and CD103(+) T cells and a lower proportion of CD4(+)CD45RB(low+) T cells in both mucosal and non-mucosal compartments. The Th17 cell population, associated with the development of autoimmunity, was substantially increased in pancreatic lymph nodes of mice fed the STD diet. Collectively, our data indicate that dietary gluten influences multiple regulatory T cell subsets as well as Th17 cells in mucosal lymphoid tissue while fewer differences were observed in non-mucosal lymphoid compartments. PMID- 22428020 TI - A functional role for modality-specific perceptual systems in conceptual representations. AB - Theories of embodied cognition suggest that conceptual processing relies on the same neural resources that are utilized for perception and action. Evidence for these perceptual simulations comes from neuroimaging and behavioural research, such as demonstrations of somatotopic motor cortex activations following the presentation of action-related words, or facilitation of grasp responses following presentation of object names. However, the interpretation of such effects has been called into question by suggestions that neural activation in modality-specific sensorimotor regions may be epiphenomenal, and merely the result of spreading activations from "disembodied", abstracted, symbolic representations. Here, we present two studies that focus on the perceptual modalities of touch and proprioception. We show that in a timed object-comparison task, concurrent tactile or proprioceptive stimulation to the hands facilitates conceptual processing relative to control stimulation. This facilitation occurs only for small, manipulable objects, where tactile and proprioceptive information form part of the multimodal perceptual experience of interacting with such objects, but facilitation is not observed for large, nonmanipulable objects where such perceptual information is uninformative. Importantly, these facilitation effects are independent of motor and action planning, and indicate that modality specific perceptual information plays a functionally constitutive role in our mental representations of objects, which supports embodied assumptions that concepts are grounded in the same neural systems that govern perception and action. PMID- 22428019 TI - A functional genomics approach to establish the complement of carbohydrate transporters in Streptococcus pneumoniae. AB - The aerotolerant anaerobe Streptococcus pneumoniae is part of the normal nasopharyngeal microbiota of humans and one of the most important invasive pathogens. A genomic survey allowed establishing the occurrence of twenty-one phosphotransferase systems, seven carbohydrate uptake ABC transporters, one sodium:solute symporter and a permease, underlining an exceptionally high capacity for uptake of carbohydrate substrates. Despite high genomic variability, combined phenotypic and genomic analysis of twenty sequenced strains did assign the substrate specificity only to two uptake systems. Systematic analysis of mutants for most carbohydrate transporters enabled us to assign a phenotype and substrate specificity to twenty-three transport systems. For five putative transporters for galactose, pentoses, ribonucleosides and sulphated glycans activity was inferred, but not experimentally confirmed and only one transport system remains with an unknown substrate and lack of any functional annotation. Using a metabolic approach, 80% of the thirty-two fermentable carbon substrates were assigned to the corresponding transporter. The complexity and robustness of sugar uptake is underlined by the finding that many transporters have multiple substrates, and many sugars are transported by more than one system. The present work permits to draw a functional map of the complete arsenal of carbohydrate utilisation proteins of pneumococci, allows re-annotation of genomic data and might serve as a reference for related species. These data provide tools for specific investigation of the roles of the different carbon substrates on pneumococcal physiology in the host during carriage and invasive infection. PMID- 22428021 TI - Linkage of bacterial protein synthesis and presentation of MHC class I-restricted Listeria monocytogenes-derived antigenic peptides. AB - The processing and MHC class I-restricted presentation of antigenic peptides derived from the p60 protein of the facultative intracellular bacterium Listeria monocytogenes is tightly linked to bacterial protein synthesis. We used non linear regression analysis to fit a mathematical model of bacterial antigen processing to a published experimental data set showing the accumulation and decay of p60-derived antigenic peptides in L. monocytogenes-infected cells. Two alternative models equally describe the experimental data. The simulation accounting for a stable and a hypothetical rapidly degraded form of antigen predicts that the antigenic peptides p60 217-225 and p60 449-457 are derived from a putative instable form of p60 with an average intracellular half-life of approximately 3 minutes accounting for approximately 31% of all p60 molecules synthesized. The alternative model predicts that both antigenic peptides are processed from p60 degraded intracellularly with a half-life of 109 min and that antigen processing only occurs as long as bacterial protein synthesis is not inhibited. In order to decide between both models the intracellular accumulation of p60 in infected cells was studied experimentally and compared with model predictions. Inhibition of p60 degradation by the proteasome inhibitor epoxomicin revealed that during the first 3 h post infection approximately 30% of synthesized p60 molecules were degraded. This value is significantly lower than the approximately 50% degradation of p60 that would be expected in the presence of the predicted putative short-lived state of p60 and also fits precisely with the predictions of the alternative model, indicating that the tight connection of bacterial protein biosynthesis and antigen processing and presentation of L. monocyctogenes-derived antigenic peptides is not caused by the presence of a highly instable antigenic substrate. PMID- 22428022 TI - Top-down modulations from dorsal stream in lexical recognition: an effective connectivity FMRI study. AB - Both the ventral and dorsal visual streams in the human brain are known to be involved in reading. However, the interaction of these two pathways and their responses to different cognitive demands remains unclear. In this study, activation of neural pathways during Chinese character reading was acquired by using a functional magnetic resonance imaging (fMRI) technique. Visual-spatial analysis (mediated by the dorsal pathway) was disassociated from lexical recognition (mediated by the ventral pathway) via a spatial-based lexical decision task and effective connectivity analysis. Connectivity results revealed that, during spatial processing, the left superior parietal lobule (SPL) positively modulated the left fusiform gyrus (FG), while during lexical processing, the left SPL received positive modulatory input from the left inferior frontal gyrus (IFG) and sent negative modulatory output to the left FG. These findings suggest that the dorsal stream is highly involved in lexical recognition and acts as a top-down modulator for lexical processing. PMID- 22428023 TI - A role for phospholipase D3 in myotube formation. AB - Phospholipase D3 (PLD3) is a non-classical, poorly characterized member of the PLD superfamily of signaling enzymes. PLD3 is a type II glycoprotein associated with the endoplasmic reticulum, is expressed in a wide range of tissues and cells, and undergoes dramatic upregulation in neurons and muscle cells during differentiation. Using an in vitro skeletal muscle differentiation system, we define the ER-tethering mechanism and report that increased PLD3 expression enhances myotube formation, whereas a putatively dominant-negative PLD3 mutant isoform reduces myotube formation. ER stress, which also enhances myotube formation, is shown here to increase PLD3 expression levels. PLD3 protein was observed to localize to a restricted set of subcellular membrane sites in myotubes that may derive from or constitute a subdomain of the endoplasmic reticulum. These findings suggest that PLD3 plays a role in myogenesis during myotube formation, potentially in the events surrounding ER reorganization. PMID- 22428024 TI - Engineered protein nano-compartments for targeted enzyme localization. AB - Compartmentalized co-localization of enzymes and their substrates represents an attractive approach for multi-enzymatic synthesis in engineered cells and biocatalysis. Sequestration of enzymes and substrates would greatly increase reaction efficiency while also protecting engineered host cells from potentially toxic reaction intermediates. Several bacteria form protein-based polyhedral microcompartments which sequester functionally related enzymes and regulate their access to substrates and other small metabolites. Such bacterial microcompartments may be engineered into protein-based nano-bioreactors, provided that they can be assembled in a non-native host cell, and that heterologous enzymes and substrates can be targeted into the engineered compartments. Here, we report that recombinant expression of Salmonella enterica ethanolamine utilization (eut) bacterial microcompartment shell proteins in E. coli results in the formation of polyhedral protein shells. Purified recombinant shells are morphologically similar to the native Eut microcompartments purified from S. enterica. Surprisingly, recombinant expression of only one of the shell proteins (EutS) is sufficient and necessary for creating properly delimited compartments. Co-expression with EutS also facilitates the encapsulation of EGFP fused with a putative Eut shell-targeting signal sequence. We also demonstrate the functional localization of a heterologous enzyme (beta-galactosidase) targeted to the recombinant shells. Together our results provide proof-of-concept for the engineering of protein nano-compartments for biosynthesis and biocatalysis. PMID- 22428025 TI - Dopamine D1-D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2. AB - In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs) coexpress D1 and D2 receptors (D1R and D2R) along with the neuropeptides dynorphin (DYN) and enkephalin (ENK). These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1-D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R-D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc), ventral tegmental area (VTA), caudate putamen and substantia nigra (SN). Additionally, activation of the D1R-D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction. PMID- 22428026 TI - Generation of a convalescent model of virulent Francisella tularensis infection for assessment of host requirements for survival of tularemia. AB - Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of which immune components are required to survive infection. Defining these requirements for protection against virulent F. tularensis, such as strain SchuS4, has been difficult since experimentally infected animals typically die within 5 days after exposure to as few as 10 bacteria. Such a short mean time to death typically precludes development, and therefore assessment, of immune responses directed against virulent F. tularensis. To enable identification of the components of the immune system that are required for survival of virulent F. tularensis, we developed a convalescent model of tularemia in C57Bl/6 mice using low dose antibiotic therapy in which the host immune response is ultimately responsible for clearance of the bacterium. Using this model we demonstrate alphabetaTCR(+) cells, gammadeltaTCR(+) cells, and B cells are necessary to survive primary SchuS4 infection. Analysis of mice deficient in specific soluble mediators shows that IL 12p40 and IL-12p35 are essential for survival of SchuS4 infection. We also show that IFN-gamma is required for survival of SchuS4 infection since mice lacking IFN-gammaR succumb to disease during the course of antibiotic therapy. Finally, we found that both CD4(+) and CD8(+) cells are the primary producers of IFN gammaand that gammadeltaTCR(+) cells and NK cells make a minimal contribution toward production of this cytokine throughout infection. Together these data provide a novel model that identifies key cells and cytokines required for survival or exacerbation of infection with virulent F. tularensis and provides evidence that this model will be a useful tool for better understanding the dynamics of tularemia infection. PMID- 22428027 TI - Contrasting patterns of coral bleaching susceptibility in 2010 suggest an adaptive response to thermal stress. AB - BACKGROUND: Coral bleaching events vary in severity, however, to date, the hierarchy of susceptibility to bleaching among coral taxa has been consistent over a broad geographic range and among bleaching episodes. Here we examine the extent of spatial and temporal variation in thermal tolerance among scleractinian coral taxa and between locations during the 2010 thermally induced, large-scale bleaching event in South East Asia. METHODOLOGY/PRINCIPAL FINDINGS: Surveys to estimate the bleaching and mortality indices of coral genera were carried out at three locations with contrasting thermal and bleaching histories. Despite the magnitude of thermal stress being similar among locations in 2010, there was a remarkable contrast in the patterns of bleaching susceptibility. Comparisons of bleaching susceptibility within coral taxa and among locations revealed no significant differences between locations with similar thermal histories, but significant differences between locations with contrasting thermal histories (Friedman = 34.97; p<0.001). Bleaching was much less severe at locations that bleached during 1998, that had greater historical temperature variability and lower rates of warming. Remarkably, Acropora and Pocillopora, taxa that are typically highly susceptible, although among the most susceptible in Pulau Weh (Sumatra, Indonesia) where respectively, 94% and 87% of colonies died, were among the least susceptible in Singapore, where only 5% and 12% of colonies died. CONCLUSIONS/SIGNIFICANCE: The pattern of susceptibility among coral genera documented here is unprecedented. A parsimonious explanation for these results is that coral populations that bleached during the last major warming event in 1998 have adapted and/or acclimatised to thermal stress. These data also lend support to the hypothesis that corals in regions subject to more variable temperature regimes are more resistant to thermal stress than those in less variable environments. PMID- 22428028 TI - Pilot study of the association of the DDAH2 -449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis. AB - BACKGROUND: Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock. METHODOLOGY/PRINCIPAL FINDINGS: In a prospective study, blood and buccal swabs were obtained from 82 patients <= 18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the -871 6g/7 g insertion/deletion and 449G/C single nucleotide polymorphisms. Shock type ("warm" versus "cold") was characterized by clinical assessment. The -871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between -871 6g/7 g genotypes. While genotype frequencies also did not vary between groups for the -449G/C SNP (p = 0.75), septic patients with at least one 449G allele had lower ADMA (median, IQR 0.36, 0.30-0.41 umol/L) than patients with the -449CC genotype (0.55, 0.49-0.64 umol/L, p = 0.008) and exhibited a higher incidence of "cold" shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration. CONCLUSIONS/SIGNIFICANCE: The -449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with "cold" shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology. PMID- 22428029 TI - Downregulation of the AU-rich RNA-binding protein ZFP36 in chronic HBV patients: implications for anti-inflammatory therapy. AB - Inflammation caused by chronic hepatitis B virus (HBV) infection is associated with the development of cirrhosis and hepatocellular carcinoma; however, the mechanisms by which HBV infection induces inflammation and inflammatory cytokine production remain largely unknown. We analyzed the gene expression patterns of lymphocytes from chronic HBV-infected patients and found that the expression of ZFP36, an AU-rich element (ARE)-binding protein, was dramatically reduced in CD4(+) and CD8(+) T lymphocytes from chronic HBV patients. ZFP36 expression was also reduced in CD14(+) monocytes and in total PBMCs from chronic HBV patients. To investigate the functional consequences of reduced ZFP36 expression, we knocked down ZFP36 in PBMCs from healthy donors using siRNA. siRNA-mediated silencing of ZFP36 resulted in dramatically increased expression of multiple inflammatory cytokines, most of which were also increased in the plasma of chronic HBV patients. Furthermore, we found that IL-8 and RANTES induced ZFP36 downregulation, and this effect was mediated through protein kinase C. Importantly, we found that HBsAg stimulated PBMCs to express IL-8 and RANTES, resulting in decreased ZFP36 expression. Our results suggest that an inflammatory feedback loop involving HBsAg, ZFP36, and inflammatory cytokines may play a critical role in the pathogenesis of chronic HBV and further indicate that ZFP36 may be an important target for anti-inflammatory therapy during chronic HBV infection. PMID- 22428030 TI - The side population in human lung cancer cell line NCI-H460 is enriched in stem like cancer cells. AB - Lung cancer is among the most lethal malignancies with a high metastasis and recurrence rate. Recent studies indicate that tumors contain a subset of stem like cancer cells that possess certain stem cell properties. Herein, we used Hoechst 33342 dye efflux assay and flow cytometry to isolate and characterize the side population (SP) cells from human lung cancer cell line NCI-H460 (H460). We show that the H460 SP cells harbor stem-like cells as they can readily form anchorage-independent floating spheres, possess great proliferative potential, and exhibit enhanced tumorigenicity. Importantly, the H460 SP cells were able to self-renew both in vitro and in vivo. Finally, we show that the H460 SP cells preferentially express ABCG2 as well as SMO, a critical mediator of the Hedgehog (HH) signaling, which seems to play an important role in H460 lung cancer cells as its blockage using Cyclopamine greatly inhibits cell-cycle progression. Collectively, our results lend further support to the existence of lung cancer stem cells and also implicate HH signaling in regulating large-cell lung cancer (stem) cells. PMID- 22428031 TI - Evaluation of the role of Candida albicans agglutinin-like sequence (Als) proteins in human oral epithelial cell interactions. AB - The fungus C. albicans uses adhesins to interact with human epithelial surfaces in the processes of colonization and pathogenesis. The C. albicans ALS (agglutinin-like sequence) gene family encodes eight large cell-surface glycoproteins (Als1-Als7 and Als9) that have adhesive function. This study utilized C. albicans Deltaals mutant strains to investigate the role of the Als family in oral epithelial cell adhesion and damage, cytokine induction and activation of a MAPK-based (MKP1/c-Fos) signaling pathway that discriminates between yeast and hyphae. Of the eight Deltaals mutants tested, only the Deltaals3 strain showed significant reductions in oral epithelial cell adhesion and damage, and cytokine production. High fungal:epithelial cell multiplicities of infection were able to rescue the cell damage and cytokine production phenotypes, demonstrating the importance of fungal burden in mucosal infections. Despite its adhesion, damage and cytokine induction phenotypes, the Deltaals3 strain induced MKP1 phosphorylation and c-Fos production to a similar extent as control cells. Our data demonstrate that Als3 is involved directly in epithelial adhesion but indirectly in cell damage and cytokine induction, and is not the factor targeted by oral epithelial cells to discriminate between the yeast and hyphal form of C. albicans. PMID- 22428032 TI - Resveratrol inhibits KSHV reactivation by lowering the levels of cellular EGR-1. AB - In the field of herpesvirus research, the exact molecular mechanism by which such viruses reactivate from latency remains elusive. Kaposi's sarcoma-associated herpesvirus (KSHV) primarily exists in a latent state, while only 1-3% of cells support lytic infection at any specific time. KSHV reactivation from latency is an exceedingly intricate process mediated by the integration of viral and cellular factors. Previously, our lab has described early growth response-1 (Egr 1) as an essential component for the KSHV reactivation process via its ability to mediate transcription of KSHV ORF50, the gene encoding for replication and transcription activator (RTA), a viral component known to control the switch from latent to lytic infection. In here, electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) experiments revealed that Egr-1 binds KSHV ORF50 promoter (ORF50P) in at least two different GC-rich binding domains. Expression profiles of cellular egr-1 and KSHV-encoded ORF50 follow a similar pattern during de novo KSHV infection. Over-expressing Egr-1, a signaling component downstream of Raf>MEK>ERK1/2, in KSHV-infected cells activates KSHV lytic replication. Through performing more physiologically relevant experiments, we analyzed the effect of a dietary supplement containing resveratrol on KSHV infected cells. Our results, for the first time, demonstrate resveratrol to act in lowering ERK1/2 activity and expression of Egr-1 in KSHV-infected cells, resulting in the suppression of virus reactivation from latency. Taken together, these findings will undoubtedly contribute to future studies on not only combating KSHV related disease conditions, but also on other herpesviruses induced pathogenesis. PMID- 22428033 TI - A novel intravital method to evaluate cerebral vasospasm in rat models of subarachnoid hemorrhage: a study with synchrotron radiation angiography. AB - Precise in vivo evaluation of cerebral vasospasm caused by subarachnoid hemorrhage has remained a critical but unsolved issue in experimental small animal models. In this study, we used synchrotron radiation angiography to study the vasospasm of anterior circulation arteries in two subarachnoid hemorrhage models in rats. Synchrotron radiation angiography, laser Doppler flowmetry cerebral blood flow measurement, [(125)I]N-isopropyl-p-iodoamphetamine cerebral blood flow measurement and terminal examinations were applied to evaluate the changes of anterior circulation arteries in two subarachnoid hemorrhage models made by blood injection into cisterna magna and prechiasmatic cistern. Using synchrotron radiation angiography technique, we detected cerebral vasospasm in subarachnoid hemorrhage rats compared to the controls (p<0.05). We also identified two interesting findings: 1) both middle cerebral artery and anterior cerebral artery shrunk the most at day 3 after subarachnoid hemorrhage; 2) the diameter of anterior cerebral artery in the prechiasmatic cistern injection group was smaller than that in the cisterna magna injection group (p<0.05), but not for middle cerebral artery. We concluded that synchrotron radiation angiography provided a novel technique, which could directly evaluate cerebral vasospasm in small animal experimental subarachnoid hemorrhage models. The courses of vasospasm in these two injection models are similar; however, the model produced by prechiasmatic cistern injection is more suitable for study of anterior circulation vasospasm. PMID- 22428034 TI - Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. AB - Primary cilia, solitary microtubule-based structures that grow from the centriole and extend into the extracellular space, have increasingly been implicated as sensors of a variety of biochemical and biophysical signals. Mutations in primary cilium-related genes have been linked to a number of rare developmental disorders as well as dysregulation of cell proliferation. We propose that primary cilia are also important in mechanically regulated bone formation in adults and that their malfunction could play a role in complex multi-factorial bone diseases, such as osteoporosis. In this study, we generated mice with an osteoblast- and osteocyte specific knockout of Kif3a, a subunit of the kinesin II intraflagellar transport (IFT) protein; IFT is required for primary cilia formation, maintenance, and function. These Colalpha1(I) 2.3-Cre;Kif3a(fl/fl) mice exhibited no obvious morphological skeletal abnormalities. Skeletally mature Colalpha1(I) 2.3 Cre;Kif3a(fl/fl) and control mice were exposed to 3 consecutive days of cyclic axial ulna loading, which resulted in a significant increase in bone formation in both the conditional knockouts and controls. However, Colalpha1(I) 2.3 Cre;Kif3a(fl/fl) mice did exhibit decreased formation of new bone in response to mechanical ulnar loading compared to control mice. These results suggest that primary cilia act as cellular mechanosensors in bone and that their function may be critical for the regulation of bone physiology due to mechanical loading in adults. PMID- 22428035 TI - Wildfires in bamboo-dominated Amazonian forest: impacts on above-ground biomass and biodiversity. AB - Fire has become an increasingly important disturbance event in south-western Amazonia. We conducted the first assessment of the ecological impacts of these wildfires in 2008, sampling forest structure and biodiversity along twelve 500 m transects in the Chico Mendes Extractive Reserve, Acre, Brazil. Six transects were placed in unburned forests and six were in forests that burned during a series of forest fires that occurred from August to October 2005. Normalized Burn Ratio (NBR) calculations, based on Landsat reflectance data, indicate that all transects were similar prior to the fires. We sampled understorey and canopy vegetation, birds using both mist nets and point counts, coprophagous dung beetles and the leaf-litter ant fauna. Fire had limited influence upon either faunal or floral species richness or community structure responses, and stems <10 cm DBH were the only group to show highly significant (p = 0.001) community turnover in burned forests. Mean aboveground live biomass was statistically indistinguishable in the unburned and burned plots, although there was a significant increase in the total abundance of dead stems in burned plots. Comparisons with previous studies suggest that wildfires had much less effect upon forest structure and biodiversity in these south-western Amazonian forests than in central and eastern Amazonia, where most fire research has been undertaken to date. We discuss potential reasons for the apparent greater resilience of our study plots to wildfire, examining the role of fire intensity, bamboo dominance, background rates of disturbance, landscape and soil conditions. PMID- 22428036 TI - alpha-Mangostin induces apoptosis and suppresses differentiation of 3T3-L1 cells via inhibiting fatty acid synthase. AB - alpha-Mangostin, isolated from the hulls of Garcinia mangostana L., was found to have in vitro cytotoxicity against 3T3-L1 cells as well as inhibiting fatty acid synthase (FAS, EC 2.3.1.85). Our studies showed that the cytotoxicity of alpha mangostin with IC(50) value of 20 uM was incomplicated in apoptotic events including increase of cell membrane permeability, nuclear chromatin condensation and mitochondrial membrane potential (DeltaPsim) loss. This cytotoxicity was accompanied by the reduction of FAS activity in cells and could be rescued by 50 uM or 100 uM exogenous palmitic acids, which suggested that the apoptosis of 3T3 L1 preadipocytes induced by alpha-mangostin was via inhibition of FAS. Futhermore, alpha-mangostin could suppress intracellular lipid accumulation in the differentiating adipocytes and stimulated lipolysis in mature adipocytes, which was also related to its inhibition of FAS. In addition, 3T3-L1 preadipocytes were more susceptible to the cytotoxic effect of alpha-mangostin than mature adipocytes. Further studies showed that alpha-mangostin inhibited FAS probably by stronger action on the ketoacyl synthase domain and weaker action on the acetyl/malonyl transferase domain. These findings suggested that alpha mangostin might be useful for preventing or treating obesity. PMID- 22428037 TI - Extremely low genetic diversity indicating the endangered status of Ranodon sibiricus (Amphibia: Caudata) and implications for phylogeography. AB - BACKGROUND: The Siberian salamander (Ranodon sibiricus), distributed in geographically isolated areas of Central Asia, is an ideal alpine species for studies of conservation and phylogeography. However, there are few data regarding the genetic diversity in R. sibiricus populations. METHODOLOGY/PRINCIPAL FINDINGS: We used two genetic markers (mtDNA and microsatellites) to survey all six populations of R. sibiricus in China. Both of the markers revealed extreme genetic uniformity among these populations. There were only three haplotypes in the mtDNA, and the overall nucleotide diversity in the mtDNA was 0.00064, ranging from 0.00000 to 0.00091 for the six populations. Although we recovered 70 sequences containing microsatellite repeats, there were only two loci that displayed polymorphism. We used the approximate Bayesian computation (ABC) method to study the demographic history of the populations. This analysis suggested that the extant populations diverged from the ancestral population approximately 120 years ago and that the historical population size was much larger than the present population size; i.e., R. sibiricus has experienced dramatic population declines. CONCLUSION/SIGNIFICANCE: Our findings suggest that the genetic diversity in the R. sibiricus populations is the lowest among all investigated amphibians. We conclude that the isolation of R. sibiricus populations occurred recently and was a result of recent human activity and/or climatic changes. The Pleistocene glaciation oscillations may have facilitated intraspecies genetic homogeneity rather than enhanced divergence. A low genomic evolutionary rate and elevated inbreeding frequency may have also contributed to the low genetic variation observed in this species. Our findings indicate the urgency of implementing a protection plan for this endangered species. PMID- 22428038 TI - Activation of PI3K/AKT and MAPK pathway through a PDGFRbeta-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma. AB - BACKGROUND: Rapamycin is an attractive approach for the treatment and prevention of HCC recurrence after liver transplantation. However, the objective response rates of rapamycin achieved with single-agent therapy were modest, supporting that rapamycin resistance is a frequently observed characteristic of many cancers. Some studies have been devoted to understanding the mechanisms of rapamycin resistance, however, the mechanisms are cell-type-dependent and studies on rapamycin resistance in HCC are extremely limited. METHODOLOGY/PRINCIPAL FINDINGS: The anti-tumor sensitivity of rapamycin was modest in vitro and in vivo. In both human and rat HCC cells, rapamycin up-regulated the expression and phosphorylation of PDGFRbeta in a time and dose-dependent manner as assessed by RT-PCR and western blot analysis. Using siRNA mediated knockdown of PDGFRbeta, we confirmed that subsequent activation of AKT and ERK was PDGFRbeta-dependent and compromised the anti-tumor activity of rapamycin. Then, blockade of this PDGFRbeta-dependent feedback loop by sorafenib enhanced the anti-tumor sensitivity of rapamycin in vitro and in an immunocompetent orthotopic rat model of HCC. CONCLUSIONS: Activation of PI3K/AKT and MAPK pathway through a PDGFRbeta dependent feedback loop compromises the anti-tumor activity of rapamycin in HCC, and blockade of this feedback loop by sorafenib is an attractive approach to improve the anti-tumor effect of rapamycin, particularly in preventing or treating HCC recurrence after liver transplantation. PMID- 22428039 TI - A tightly controlled conditional knockdown system using the Tol2 transposon mediated technique. AB - BACKGROUND: Gene knockdown analyses using the in utero electroporation method have helped reveal functional aspects of genes of interest in cortical development. However, the application of this method to analyses in later stages of brain development or in the adult brain is still difficult because the amount of injected plasmids in a cell decreases along with development due to dilution by cell proliferation and the degradation of the plasmids. Furthermore, it is difficult to exclude the influence of earlier knockdown effects. METHODOLOGY/PRINCIPAL FINDINGS: We developed a tightly controlled conditional knockdown system using a newly constructed vector, pT2K-TBI-shRNAmir, based on a Tol2 transposon-mediated gene transfer methodology with the tetracycline inducible gene expression technique, which allows us to maintain a transgene for a long period of time and induce the knockdown of the gene of interest. We showed that expression of the endogenous amyloid precursor protein (APP) was sharply decreased by our inducible, stably integrated knockdown system in PC12 cells. Moreover, we induced an acute insufficiency of Dab1 with our system and observed that radial migration was impaired in the developing cerebral cortex. Such inhibitory effects on radial migration were not observed without induction, indicating that our system tightly controlled the knockdown, without any expression leakage in vivo. CONCLUSIONS/SIGNIFICANCE: Our system enables us to investigate the brain at any of the later stages of development or in the adult by utilizing a knockdown technique with the aid of the in utero electroporation gene transfer methodology. Furthermore, we can perform knockdown analyses free from the influence of undesired earlier knockdown effects. PMID- 22428040 TI - Identification and behavioral evaluation of sex pheromone components of the Chinese pine caterpillar moth, Dendrolimus tabulaeformis. AB - BACKGROUND: The Chinese pine caterpillar moth, Dendrolimus tabulaeformis Tsai and Liu (Lepidoptera: Lasiocampidae) is the most important defoliator of coniferous trees in northern China. Outbreaks occur over enormous areas and often lead to the death of forests during 2-3 successive years of defoliation. The sex pheromone of D. tabulaeformis was investigated to define its chemistry and behavioral activity. METHODOLOGY/PRINCIPAL FINDINGS: Sex pheromone was collected from calling female D. tabulaeformis by headspace solid phase microextraction (SPME) and by solvent extraction of pheromone glands. Extracts were analyzed by coupled gas chromatography/mass spectrometry (GC-MS) and coupled GC electroantennographic detection (GC-EAD), using antennae from male moths. Five components from the extracts elicited antennal responses. These compounds were identified by a combination of retention indices, electron impact mass spectral matches, and derivatization as (Z)-5-dodecenyl acetate (Z5-12:OAc), (Z)-5 dodecenyl alcohol (Z5-12:OH), (5Z,7E)-5,7-dodecadien-1-yl acetate (Z5,E7-12:OAc), (5Z,7E)-5,7-dodecadien-1-yl propionate (Z5,E7-12:OPr), and (5Z,7E)-5,7-dodecadien 1-ol (Z5,E7-12:OH). Behavioral assays showed that male D. tabulaeformis strongly discriminated against incomplete and aberrant blend ratios. The correct ratio of Z5,E7-12:OAc, Z5,E7-12:OH, and Z5,E7-12:OPr was essential for optimal upwind flight and source contact. The two monoenes, Z5-12:OAc and Z5-12:OH, alone or binary mixtures, had no effect on behavioral responses when added to the optimal three-component blend. CONCLUSIONS/SIGNIFICANCE: The fact that deviations from the optimal ratio of 100:100:4.5 of Z5,E7-12:OAc, Z5,EZ7-12:OH, and Z5,E7-12:OPr resulted in marked decreases in male responses suggests that biosynthesis of the pheromone components is precisely controlled. The optimal blend of the sex pheromone components of D. tabulaeformis worked out in this study should find immediate use in monitoring this pest in Chinese forests. PMID- 22428041 TI - High-dose chemotherapy followed by autologous stem cell transplantation as a first-line therapy for high-risk primary breast cancer: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Several trials have generated conflicting results about the results of high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) for primary breast cancer. This meta-analysis summarizes the available evidence from all suitable studies. DESIGN AND METHODS: Prospective, randomized trials with HDCT as a first-line therapy for primary breast cancer were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival and overall survival); secondary endpoints included treatment-related mortality (TRM) and second (non-breast) cancers. We used a median age of 47, a PR positive rate of 50% and a premenopausal rate of 70% as cutoff values to complete the subgroup analyses, which were pre-planned according to the prepared protocol. RESULTS: Fourteen trials with 5747 patients were eligible for the meta-analysis. Compared with non-HDCT, non-significant second (non-breast) cancers (RR = 1.28; 95% CI = 0.82-1.98) and higher TRM (RR = 3.42; 95% CI = 1.32-8.86) were associated with HDCT for primary breast cancer. A significant DFS benefit of HDCT was documented (HR = 0.89; 95% CI = 0.79-0.99). No difference in OS (overall survival) was found when the studies were pooled (HR = 0.91; 95% CI = 0.82-1.00, p = 0.062). In subgroup analysis, age and hormone receptor status had a significant interaction with prolonged DFS and OS. CONCLUSIONS: HDCT has a benefit on DFS and OS compared to SDC in some special patients with high-risk primary breast cancer. PMID- 22428042 TI - Common variants in CDKN2B-AS1 associated with optic-nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese. AB - BACKGROUND: To date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated. METHODS AND PRINCIPAL FINDINGS: We examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8 * 10(-10)). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)--POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)--and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients. CONCLUSIONS AND SIGNIFICANCE: In this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma. PMID- 22428043 TI - The action of D-dopachrome tautomerase as an adipokine in adipocyte lipid metabolism. AB - Adipose tissue is a critical exchange center for complex energy transactions involving triacylglycerol storage and release. It also has an active endocrine role, releasing various adipose-derived cytokines (adipokines) that participate in complex pathways to maintain metabolic and vascular health. Here, we found D dopachrome tautomerase (DDT) as an adipokine secreted from human adipocytes by a proteomic approach. DDT mRNA levels in human adipocytes were negatively correlated with obesity-related clinical parameters such as BMI, and visceral and subcutaneous fat areas. Experiments using SGBS cells, a human preadipocyte cell line, revealed that DDT mRNA levels were increased in an adipocyte differentiation-dependent manner and DDT was secreted from adipocytes. In DDT knockdown adipocytes differentiated from SGBS cells that were infected with the adenovirus expressing shRNA against the DDT gene, mRNA levels of genes involved in both lipolysis and lipogenesis were slightly but significantly increased. Furthermore, we investigated AMP-activated protein kinase (AMPK) signaling, which phosphorylates and inactivates enzymes involved in lipid metabolism, including hormone-sensitive lipase (HSL) and acetyl-CoA carboxylase (ACC), in DDT knockdown adipocytes. The AMPK phosphorylation of HSL Ser-565 and ACC Ser-79 was inhibited in DDT knockdown cells and recovered in the cells treated with recombinant DDT (rDDT), suggesting that down-regulated DDT in adipocytes brings about a state of active lipid metabolism. Furthermore, administration of rDDT in db/db mice improved glucose intolerance and decreased serum free fatty acids levels. In the adipose tissue from rDDT-treated db/db mice, not only increased levels of HSL phosphorylated by AMPK, but also decreased levels of HSL phosphorylated by protein kinase A (PKA), which phosphorylates HSL to promote its activity, were observed. These results suggested that DDT acts on adipocytes to regulate lipid metabolism through AMPK and/or PKA pathway(s) and improves glucose intolerance caused by obesity. PMID- 22428044 TI - Aging Kit mutant mice develop cardiomyopathy. AB - Both bone marrow (BM) and myocardium contain progenitor cells expressing the c Kit tyrosine kinase. The aims of this study were to determine the effects of c Kit mutations on: i. myocardial c-Kit(+) cells counts and ii. the stability of left ventricular (LV) contractile function and structure during aging. LV structure and contractile function were evaluated (echocardiography) in two groups of Kit mutant (W/Wv and W41/W42) and in wild type (WT) mice at 4 and 12 months of age and the effects of the mutations on LV mass, vascular density and the numbers of proliferating cells were also determined. In 4 month old Kit mutant and WT mice, LV ejection fractions (EF) and LV fractional shortening rates (FS) were comparable. At 12 months of age EF and FS were significantly decreased and LV mass was significantly increased only in W41/W42 mice. Myocardial vascular densities and c-Kit(+) cell numbers were significantly reduced in both mutant groups when compared to WT hearts. Replacement of mutant BM with WT BM at 4 months of age did not prevent these abnormalities in either mutant group although they were somewhat attenuated in the W/Wv group. Notably BM transplantation did not prevent the development of cardiomyopathy in 12 month W41/W42 mice. The data suggest that decreased numbers and functional capacities of c-Kit(+) cardiac resident progenitor cells may be the basis of the cardiomyopathy in W41/W42 mice and although defects in mutant BM progenitor cells may prove to be contributory, they are not causal. PMID- 22428045 TI - Expression and regulation of the Escherichia coli O157:H7 effector proteins NleH1 and NleH2. AB - BACKGROUND: E. coli O157 carries two genes encoding the effector proteins NleH1 and NleH2 which are 87% identical. Despite the similarity between the proteins, the promoter regions upstream of the genes encoding the effectors are more divergent suggesting that the actual expression of the genes may be differentially regulated. This was tested by creating reporter fusions and examining their expression in different genetic backgrounds, media and on contact with host cells. The function of the proteins was also tested following transfection into host cells. PRINCIPAL FINDINGS: Expression of both NleH1 and NleH2 was enhanced when cultured under conditions that stimulated expression of the Type Three Secretion System (T3SS) and was influenced by the regulators Ler and GrlA. Maximal expression of NleH1 required 531 bp of the upstream untranslated region but NleH2 required only 113 bp. Interestingly, contact with host cells strongly repressed expression of both NleH1 and NleH2. Following transfection, both proteins produced only minor effects on NF-kappaB activation when assessed using a NF-kappaB luciferase reporter assay, a result that is consistent with the recent report demonstrating the dependence on RPS3 for NleH1 modulation of NF-kappaB. SIGNIFICANCE: This study demonstrates the importance of considering gene regulation when studying bacterial effector proteins. Despite their sequence similarity, NleH1 and NleH2 are expressed differentially and may, therefore, be translocated at distinct times during an infection. PMID- 22428046 TI - Genome-wide linkage in a highly consanguineous pedigree reveals two novel loci on chromosome 7 for non-syndromic familial Premature Ovarian Failure. AB - BACKGROUND: The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10-15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients. METHODOLOGY/PRINCIPAL FINDINGS: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LOD(max) of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1) included within the largest region did not reveal any causal mutations. CONCLUSIONS/SIGNIFICANCE: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function. PMID- 22428047 TI - Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate induced HIF-1 activation and tumor angiogenesis. AB - Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF 1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities. PMID- 22428048 TI - Increase in muscle mitochondrial biogenesis does not prevent muscle loss but increased tumor size in a mouse model of acute cancer-induced cachexia. AB - Cancer-associated cachexia is a complex metabolic condition characterized by the progressive loss of body fat and deterioration of muscle mass. Although the cellular and molecular mechanisms of cachexia are incompletely understood, previous studies have suggested mitochondrial dysfunction in murine models of cancer cachexia. To better understand the metabolic shift in cancer-induced cachexia, we studied the effects of enhanced oxidative capacity on muscle wasting using transgenic mice over-expressing Peroxisome Proliferator-Activated Receptor gamma Co-activator-1alpha (PGC-1alpha) in skeletal muscle in a Lewis lung carcinoma-implanted model. Increased mitochondrial biogenesis was observed in the skeletal muscle of tumor-implanted mice. However, these increases did not prevent or reverse muscle wasting in mice harboring tumors. Moreover, tumor size was increased in muscle PGC-1alpha over-expressing mice. We found similar levels of circulating inflammatory cytokines in tumor-implanted animals, which was not affected by increased muscle expression of PGC-1alpha. Our data indicated that increased mitochondrial biogenesis in skeletal muscle is not sufficient to rescue tumor-associated, acute muscle loss, and could promote tumor growth, possibly through the release of myokines. PMID- 22428049 TI - RNA-binding protein Musashi1 modulates glioma cell growth through the post transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways. AB - Musashi1 (MSI1) is an RNA-binding protein that plays critical roles in nervous system development and stem-cell self-renewal. Here, we examined its role in the progression of glioma. Short hairpin RNA (shRNA)-based MSI1-knock down (KD) in glioblastoma and medulloblastoma cells resulted in a significantly lower number of self renewing colony on day 30 (a 65% reduction), compared with non-silencing shRNA-treated control cells, indicative of an inhibitory effect of MSI1-KD on tumor cell growth and survival. Immunocytochemical staining of the MSI1-KD glioblastoma cells indicated that they ectopically expressed metaphase markers. In addition, a 2.2-fold increase in the number of MSI1-KD cells in the G2/M phase was observed. Thus, MSI1-KD caused the prolongation of mitosis and reduced the cell survival, although the expression of activated Caspase-3 was unaltered. We further showed that MSI1-KD glioblastoma cells xenografted into the brains of NOD/SCID mice formed tumors that were 96.6% smaller, as measured by a bioluminescence imaging system (BLI), than non-KD cells, and the host survival was longer (49.3+/-6.1 days vs. 33.6+/-3.6 days; P<0.01). These findings and other cell biological analyses suggested that the reduction of MSI1 in glioma cells prolonged the cell cycle by inducing the accumulation of Cyclin B1. Furthermore, MSI1-KD reduced the activities of the Notch and PI(3) kinase-Akt signaling pathways, through the up-regulation of Numb and PTEN, respectively. Exposure of glioma cells to chemical inhibitors of these pathways reduced the number of spheres and living cells, as did MSI1-KD. These results suggest that MSI1 increases the growth and/or survival of certain types of glioma cells by promoting the activation of both Notch and PI(3) kinase/Akt signaling. PMID- 22428050 TI - Positive and purifying selection influence the evolution of doublesex in the Anastrepha fraterculus species group. AB - The gene doublesex (dsx) is considered to be under strong selective constraint along its evolutionary history because of its central role in somatic sex differentiation in insects. However, previous studies of dsx used global estimates of evolutionary rates to investigate its molecular evolution, which potentially miss signals of adaptive changes in generally conserved genes. In this work, we investigated the molecular evolution of dsx in the Anastrepha fraterculus species group (Diptera, Tephritidae), and test the hypothesis that this gene evolved solely by purifying selection using divergence-based and population-based methods. In the first approach, we compared sequences from Anastrepha and other Tephritidae with other Muscomorpha species, analyzed variation in nonsynonymous to synonymous rate ratios (dN/dS) in the Tephritidae, and investigated radical and conservative changes in amino acid physicochemical properties. We show a general selective constraint on dsx, but with signs of positive selection mainly in the common region. Such changes were localized in alpha-helices previously reported to be involved in dimer formation in the OD2 domain and near the C-terminal of the OD1 domain. In the population-based approach, we amplified a region of 540 bp that spanned almost all of the region common to both sexes from 32 different sites in Brazil. We investigated patterns of selection using neutrality tests based on the frequency spectrum and locations of synonymous and nonsynonymous mutations in a haplotype network. As in the divergence-based approach, these analyses showed that dsx has evolved under an overall selective constraint, but with some events of positive selection. In contrast to previous studies, our analyses indicate that even though dsx has indeed evolved as a conserved gene, the common region of dsx has also experienced bouts of positive selection, perhaps driven by sexual selection, during its evolution. PMID- 22428051 TI - Expression of Ixodes scapularis antifreeze glycoprotein enhances cold tolerance in Drosophila melanogaster. AB - Drosophila melanogaster experience cold shock injury and die when exposed to low non-freezing temperatures. In this study, we generated transgenic D. melanogaster that express putative Ixodes scapularis antifreeze glycoprotein (IAFGP) and show that the presence of IAFGP increases the ability of flies to survive in the cold. Male and female adult iafgp-expressing D. melanogaster exhibited higher survival rates compared with controls when placed at non-freezing temperatures. Increased hatching rates were evident in embryos expressing IAFGP when exposed to the cold. The TUNEL assay showed that flight muscles from iafgp-expressing female adult flies exhibited less apoptotic damage upon exposure to non-freezing temperatures in comparison to control flies. Collectively, these data suggest that expression of iafgp increases cold tolerance in flies by preventing apoptosis. This study defines a molecular basis for the role of an antifreeze protein in cryoprotection of flies. PMID- 22428052 TI - Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma. AB - Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases (n = 33/35 for MSP; n = 35/35 for PSQ; n = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p<0.001). Conclusively, taking into consideration prognostic value, cost effectiveness and ease of use, we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput settings and MSP for clinical routine diagnostics with low sample numbers. PMID- 22428053 TI - The Enterococcus faecalis exoproteome: identification and temporal regulation by Fsr. AB - Analysis of the culture supernatant exoproteins produced by two PFGE clusters of high-level gentamicin and ciprofloxacin-resistant clinical isolates of Enterococcus faecalis from the UK and Ireland revealed two distinct protein profiles. This grouping distinguished OG1RF and GelE metalloprotease-expressing isolates from JH2-2 and other GelE-negative isolates. The integrity of the fsrABDC operon was found to determine the exoproteome composition, since an fsrB mutant of strain OG1RF appeared very similar to that of strain JH2-2, and complementation of the latter with the fsrABDC operon produced an OG1RF-like exoproteome. The proteins present in the supernatant fraction of OG1RF were separated using 2D gels and identified by mass spectrometry and comprised many mass and pI variants of the GelE and SprE proteases. In addition cell wall synthesis and cell division proteins were identified. An OG1RF fsrB mutant had a distinct exoprotein fraction with an absence of the Fsr-regulated proteases and was characterised by general stress and glycolytic proteins. The exoproteome of the OG1RF fsrB mutant resembles that of a divIVA mutant of E. faecalis, suggestive of a stress phenotype. PMID- 22428054 TI - Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat. AB - Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa. PMID- 22428055 TI - Activation of NF-kappaB/p65 facilitates early chondrogenic differentiation during endochondral ossification. AB - BACKGROUND: NF-kappaB/p65 has been reported to be involved in regulation of chondrogenic differentiation. However, its function in relation to key chondrogenic factor Sox9 and onset of chondrogenesis during endochondral ossification is poorly understood. We hypothesized that the early onset of chondrogenic differentiation is initiated by transient NF-kappaB/p65 signaling. METHODOLOGY/PRINCIPAL FINDINGS: The role of NF-kappaB/p65 in early chondrogenesis was investigated in different in vitro, ex vivo and in vivo endochondral models: ATDC5 cells, hBMSCs, chicken periosteal explants and growth plates of 6 weeks old mice. NF-kappaB/p65 activation was manipulated using pharmacological inhibitors, RNAi and activating agents. Gene expression and protein expression analysis, and (immuno)histochemical stainings were employed to determine the role of NF kappaB/p65 in the chondrogenic phase of endochondral development. Our data show that chondrogenic differentiation is facilitated by early transient activation of NF-kappaB/p65. NF-kappaB/p65-mediated signaling determines early expression of Sox9 and facilitates the subsequent chondrogenic differentiation programming by signaling through key chondrogenic pathways. CONCLUSIONS/SIGNIFICANCE: The presented data demonstrate that NF-kappaB/p65 signaling, as well as its intensity and timing, represents one of the transcriptional regulatory mechanisms of the chondrogenic developmental program of chondroprogenitor cells during endochondral ossification. Importantly, these results provide novel possibilities to improve the success of cartilage and bone regenerative techniques. PMID- 22428056 TI - Genetic structure, linkage disequilibrium and signature of selection in Sorghum: lessons from physically anchored DArT markers. AB - Population structure, extent of linkage disequilibrium (LD) as well as signatures of selection were investigated in sorghum using a core sample representative of worldwide diversity. A total of 177 accessions were genotyped with 1122 informative physically anchored DArT markers. The properties of DArTs to describe sorghum genetic structure were compared to those of SSRs and of previously published RFLP markers. Model-based (STRUCTURE software) and Neighbor-Joining diversity analyses led to the identification of 6 groups and confirmed previous evolutionary hypotheses. Results were globally consistent between the different marker systems. However, DArTs appeared more robust in terms of data resolution and bayesian group assignment. Whole genome linkage disequilibrium as measured by mean r(2) decreased from 0.18 (between 0 to 10 kb) to 0.03 (between 100 kb to 1 Mb), stabilizing at 0.03 after 1 Mb. Effects on LD estimations of sample size and genetic structure were tested using i. random sampling, ii. the Maximum Length SubTree algorithm (MLST), and iii. structure groups. Optimizing population composition by the MLST reduced the biases in small samples and seemed to be an efficient way of selecting samples to make the best use of LD as a genome mapping approach in structured populations. These results also suggested that more than 100,000 markers may be required to perform genome-wide association studies in collections covering worldwide sorghum diversity. Analysis of DArT markers differentiation between the identified genetic groups pointed out outlier loci potentially linked to genes controlling traits of interest, including disease resistance genes for which evidence of selection had already been reported. In addition, evidence of selection near a homologous locus of FAR1 concurred with sorghum phenotypic diversity for sensitivity to photoperiod. PMID- 22428057 TI - The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells. AB - Insight into the normal function of PrP(C), and how it can be subverted to produce neurotoxic effects, is provided by PrP molecules carrying deletions encompassing the conserved central region. The most neurotoxic of these mutants, Delta105-125 (called DeltaCR), produces a spontaneous neurodegenerative illness when expressed in transgenic mice, and this phenotype can be dose-dependently suppressed by co-expression of wild-type PrP. Whether the toxic activity of DeltaCR PrP and the protective activity or wild-type PrP are cell-autonomous, or can be exerted on neighboring cells, is unknown. To investigate this question, we have utilized co-cultures of differentiated neural stem cells derived from mice expressing DeltaCR or wild-type PrP. Cells from the two kinds of mice, which are marked by the presence or absence of GFP, are differentiated together to yield neurons, astrocytes, and oligodendrocytes. As a surrogate read-out of DeltaCR PrP toxicity, we assayed sensitivity of the cells to the cationic antibiotic, Zeocin. In a previous study, we reported that cells expressing DeltaCR PrP are hypersensitive to the toxic effects of several cationic antibiotics, an effect that is suppressed by co-expression of wild type PrP, similar to the rescue of the neurodegenerative phenotype observed in transgenic mice. Using this system, we find that while DeltaCR-dependent toxicity is cell-autonomous, the rescuing activity of wild-type PrP can be exerted in trans from nearby cells. These results provide important insights into how DeltaCR PrP subverts a normal physiological function of PrP(C), and the cellular mechanisms underlying the rescuing process. PMID- 22428058 TI - Reconstruction of monocyte transcriptional regulatory network accompanies monocytic functions in human fibroblasts. AB - Transcriptional regulatory networks (TRN) control the underlying mechanisms behind cellular functions and they are defined by a set of core transcription factors regulating cascades of peripheral genes. Here we report SPI1, CEBPA, MNDA and IRF8 as core transcription factors of monocyte TRN and demonstrate functional inductions of phagocytosis, inflammatory response and chemotaxis activities in human dermal fibroblasts. The Gene Ontology and KEGG pathway analyses also revealed notable representation of genes involved in immune response and endocytosis in fibroblasts. Moreover, monocyte TRN-inducers triggered multiple monocyte-specific genes based on the transcription factor motif response analysis and suggest that complex cellular TRNs are uniquely amenable to elicit cell specific functions in unrelated cell types. PMID- 22428059 TI - Differential expression of Vegfr-2 and its soluble form in preeclampsia. AB - BACKGROUND: Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta. METHODOLOGY/PRINCIPAL FINDINGS: By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR 2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction. PMID- 22428060 TI - Aging, eye movements, and object-location memory. AB - This study investigated whether "intentional" instructions could improve older adults' object memory and object-location memory about a scene by promoting object-oriented viewing. Eye movements of younger and older adults were recorded while they viewed a photograph depicting 12 household objects in a cubicle with or without the knowledge that memory about these objects and their locations would be tested (intentional vs. incidental encoding). After viewing, participants completed recognition and relocation tasks. Both instructions and age affected viewing behaviors and memory. Relative to incidental instructions, intentional instructions resulted in more accurate memory about object identity and object-location binding, but did not affect memory accuracy about overall positional configuration. More importantly, older adults exhibited more object oriented viewing in the intentional than incidental condition, supporting the environmental support hypothesis. PMID- 22428061 TI - Cold physiology: postprandial blood flow dynamics and metabolism in the Antarctic fish Pagothenia borchgrevinki. AB - Previous studies on metabolic responses to feeding (i.e. the specific dynamic action, SDA) in Antarctic fishes living at temperatures below zero have reported long-lasting increases and small peak responses. We therefore hypothesized that the postprandial hyperemia also would be limited in the Antarctic fish Pagothenia borchgrevinki. The proportion of cardiac output directed to the splanchnic circulation in unfed fish was 18%, which is similar to temperate fish species. Contrary to our prediction, however, gastrointestinal blood flow had increased by 88% at twenty four hours after feeding due to a significant increase in cardiac output and a significant decrease in gastrointestinal vascular resistance. While gastric evacuation time appeared to be longer than in comparable temperate species, digestion had clearly commenced twenty four hours after feeding as judged by a reduction in mass of the administered feed. Even so, oxygen consumption did not increase suggesting an unusually slowly developing SDA. Adrenaline and angiotensin II was injected into unfed fish to investigate neuro humoral control mechanisms of gastrointestinal blood flow. Both agonists increased gastrointestinal vascular resistance and arterial blood pressure, while systemic vascular resistance was largely unaffected. The hypertension was mainly due to increased cardiac output revealing that the heart and the gastrointestinal vasculature, but not the somatic vasculature, are important targets for these agonists. It is suggested that the apparently reduced SDA in P. borchgrevinki is due to a depressant effect of the low temperature on protein assimilation processes occurring outside of the gastrointestinal tract, while the gastrointestinal blood flow responses to feeding and vasoactive substances resemble those previously observed in temperate species. PMID- 22428062 TI - A dominant negative ERbeta splice variant determines the effectiveness of early or late estrogen therapy after ovariectomy in rats. AB - The molecular mechanisms for the discrepancy in outcome of initiating estrogen therapy (ET) around peri-menopause or several years after menopause in women are unknown. We hypothesize that the level of expression of a dominant negative estrogen receptor (ER) beta variant, ERbeta2, may be a key factor determining the effectiveness of ET in post-menopausal women. We tested this hypothesis in ovariectomized nine month-old (an age when irregular estrous cycles occur) female Sprague Dawley rats. Estradiol treatment was initiated either 6 days (Early ET, analogous to 4 months post-menopause in humans), or 180 days (Late ET, analogous to 11 years post-menopause in humans) after ovariectomy. Although ERbeta2 expression increased in all OVX rats, neurogenic and neuroprotective responses to estradiol differed in Early and Late ET. Early ET reduced ERbeta2 expression in both hippocampus and white blood cells, increased the hippocampal cell proliferation as assessed by Ki-67 expression, and improved mobility in the forced swim test. Late ET resulted in either no or modest effects on these parameters. There was a close correlation between the degree of ERbeta2 expression and the preservation of neural effects by ET after OVX in rats, supporting the hypothesis that persistent elevated levels of ERbeta2 are a molecular basis for the diminished effectiveness of ET in late post-menopausal women. The correlation between the expression of ERbeta2 in circulating white blood cells and brain cells suggests that ERbeta2 expression in peripheral blood cells may be an easily accessible marker to predict the effective window for ET in the brain. PMID- 22428063 TI - The testicular and epididymal expression profile of PLCzeta in mouse and human does not support its role as a sperm-borne oocyte activating factor. AB - Phospholipase C zeta (PLCzeta) is a candidate sperm-borne oocyte activating factor (SOAF) which has recently received attention as a potential biomarker of human male infertility. However, important SOAF attributes of PLCzeta, including its developmental expression in mammalian spermiogenesis, its compartmentalization in sperm head perinuclear theca (PT) and its release into the ooplasm during fertilization have not been established and are addressed in this investigation. Different detergent extractions of sperm and head/tail fractions were compared for the presence of PLCzeta by immunoblotting. In both human and mouse, the active isoform of PLCzeta was detected in sperm fractions other than PT, where SOAF is expected to reside. Developmentally, PLCzeta was incorporated as part of the acrosome during the Golgi phase of human and mouse spermiogenesis while diminishing gradually in the acrosome of elongated spermatids. Immunofluorescence localized PLCzeta over the surface of the postacrosomal region of mouse and bull and head region of human spermatozoa leading us to examine its secretion in the epididymis. While previously thought to have strictly a testicular expression, PLCzeta was found to be expressed and secreted by the epididymal epithelial cells explaining its presence on the sperm head surface. In vitro fertilization (IVF) revealed that PLCzeta is no longer detectable after the acrosome reaction occurs on the surface of the zona pellucida and thus is not incorporated into the oocyte cytoplasm for activation. In summary, we show for the first time that PLCzeta is compartmentalized as part of the acrosome early in human and mouse spermiogenesis and is secreted during sperm maturation in the epididymis. Most importantly, no evidence was found that PLCzeta is incorporated into the detergent-resistant perinuclear theca fraction where SOAF resides. PMID- 22428064 TI - Local gene silencing of monocyte chemoattractant protein-1 prevents vulnerable plaque disruption in apolipoprotein E-knockout mice. AB - Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine (CCL2), has been demonstrated to play important roles in atherosclerosis and becoming an important therapeutic target for atherosclerosis. The present study was undertaken to test the hypothesis that local RNAi of MCP-1 by site-specific delivery of adenovirus mediated small hairpin RNA (shRNA) may enhance plaque stability and prevent plaque disruption in ApoE-/- mice. We designed an adenovirus-mediated shRNA against mouse MCP-1 (rAd5-MCP-1-shRNA). Male apolipoprotein E-knockout (ApoE-/-) mice (n = 120) were fed a high-fat diet and vulnerable plaques were induced by perivascular placement of constrictive collars around the carotid artery, intraperitoneal injection of lipopolysaccharide and stress stimulation. Mice were randomly divided into RNA interference (Ad-MCP-1i) group receiving local treatment of rAd5-MCP-1-shRNA suspension, Ad-EGFP group receiving treatment of rAd5-mediated negative shRNA and mock group receiving treatment of saline. Two weeks after treatment, plaque disruption rates were significantly lower in the Ad MCP-1i group than in the Ad-EGFP group (13.3% vs. 60.0%, P = 0.01), and local MCP 1 expression was significantly inhibited in the Ad-MCP-1i group confirmed by immunostaining, qRT-PCR and western blot (P<0.001). Compared with the Ad-EGFP group, carotid plaques in the Ad-MCP-1i group showed increased levels of collagen and smooth muscle cells, and decreased levels of lipid and macrophages. The expression of inflammatory cytokines and activities of matrix metalloproteinases (MMPs) were lower in the Ad-MCP-1i group than in the Ad-EGFP group. In conclusion, site-specific delivery of adenoviral-mediated shRNA targeting mouse MCP-1 downregulated MCP-1 expression, turned a vulnerable plaque into a more stable plaque phenotype and prevented plaque disruption. A marked suppression of the local inflammatory cytokine expression may be the central mechanism involved. PMID- 22428065 TI - Effect of RECK gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features. AB - BACKGROUND: The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) down-regulation has been confirmed in numerous human cancers and is clinically associated with metastasis. This study investigates the potential associations of RECK single-nucleotide polymorphisms (SNPs) with hepatocellular carcinoma (HCC) susceptibility and its clinicopathologic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: A total of 135 HCC cancer patients and 501 cancer-free controls were analyzed for four RECK SNPs (rs10814325, rs16932912, rs11788747, and rs10972727) using real-time PCR and PCR-RFLP genotyping analysis. After adjusting for other co-variants, the individuals carrying RECK promoter rs10814325 inheriting at least one C allele had a 1.85-fold [95% confidence interval (CI), 1.03-3.36] risk of developing HCC compared to TT wild type carriers. The HCC patients, who carried rs11788747 with at least one G allele, had a higher distant metastasis risk than wild type probands. CONCLUSIONS: RECK gene polymorphisms might be a risk factor increasing HCC susceptibility and distant metastasis in Taiwan. PMID- 22428066 TI - Topiramate treatment is neuroprotective and reduces oligodendrocyte loss after cervical spinal cord injury. AB - Excess glutamate release and associated neurotoxicity contributes to cell death after spinal cord injury (SCI). Indeed, delayed administration of glutamate receptor antagonists after SCI in rodents improves tissue sparing and functional recovery. Despite their therapeutic potential, most glutamate receptor antagonists have detrimental side effects and have largely failed clinical trials. Topiramate is an AMPA-specific, glutamate receptor antagonists that is FDA-approved to treat CNS disorders. In the current study we tested whether topiramate treatment is neuroprotective after cervical contusion injury in rats. We report that topiramate, delivered 15-minutes after SCI, increases tissue sparing and preserves oligodendrocytes and neurons when compared to vehicle treatment. In addition, topiramate is more effective than the AMPA-receptor antagonist, NBQX. To the best of our knowledge, this is the first report documenting a neuroprotective effect of topiramate treatment after spinal cord injury. PMID- 22428067 TI - Minim typing--a rapid and low cost MLST based typing tool for Klebsiella pneumoniae. AB - Here we report a single nucleotide polymorphism (SNP) based genotyping method for Klebsiella pneumoniae utilising high-resolution melting (HRM) analysis of fragments within the multilocus sequence typing (MLST) loci. The approach is termed mini-MLST or Minim typing and it has previously been applied to Streptococcus pyogenes, Staphylococcus aureus and Enterococcus faecium. Six SNPs were derived from concatenated MLST sequences on the basis of maximisation of the Simpsons Index of Diversity (D). DNA fragments incorporating these SNPs and predicted to be suitable for HRM analysis were designed. Using the assumption that HRM alleles are defined by G+C content, Minim typing using six fragments was predicted to provide a D = 0.979 against known STs. The method was tested against 202 K. pneumoniae using a blinded approach in which the MLST analyses were performed after the HRM analyses. The HRM-based alleles were indeed in accordance with G+C content, and the Minim typing identified known STs and flagged new STs. The tonB MLST locus was determined to be very diverse, and the two Minim fragments located herein contribute greatly to the resolving power. However these fragments are refractory to amplification in a minority of isolates. Therefore, we assessed the performance of two additional formats: one using only the four fragments located outside the tonB gene (D = 0.929), and the other using HRM data from these four fragments in conjunction with sequencing of the tonB MLST fragment (D = 0.995). The HRM assays were developed on the Rotorgene 6000, and the method was shown to also be robust on the LightCycler 480, allowing a 384 well high through-put format. The assay provides rapid, robust and low-cost typing with fully portable results that can directly be related to current MLST data. Minim typing in combination with molecular screening for antibiotic resistance markers can be a powerful surveillance tool kit. PMID- 22428068 TI - L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis. AB - Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis (UC), results in substantial morbidity and is difficult to treat. New strategies for adjunct therapies are needed. One candidate is the semi-essential amino acid, L-arginine (L-Arg), a complementary medicine purported to be an enhancer of immunity and vitality in the lay media. Using dextran sulfate sodium (DSS) as a murine colonic injury and repair model with similarities to human UC, we assessed the effect of L-Arg, as DSS induced increases in colonic expression of the y(+) cationic amino acid transporter 2 (CAT2) and L-Arg uptake. L-Arg supplementation improved the clinical parameters of survival, body weight loss, and colon weight, and reduced colonic permeability and the number of myeloperoxidase-positive neutrophils in DSS colitis. Luminex-based multi-analyte profiling demonstrated that there was a marked reduction in proinflammatory cytokine and chemokine expression with L-Arg treatment. Genomic analysis by microarray demonstrated that DSS-treated mice supplemented with L-Arg clustered more closely with mice not exposed to DSS than to those receiving DSS alone, and revealed that multiple genes that were upregulated or downregulated with DSS alone exhibited normalization of expression with L-Arg supplementation. Additionally, L-Arg treatment of mice with DSS colitis resulted in increased ex vivo migration of colonic epithelial cells, suggestive of increased capacity for wound repair. Because CAT2 induction was sustained during L-Arg treatment and inducible nitric oxide (NO) synthase (iNOS) requires uptake of L-Arg for generation of NO, we tested the effect of L-Arg in iNOS(-/-) mice and found that its benefits in DSS colitis were eliminated. These preclinical studies indicate that L-Arg supplementation could be a potential therapy for IBD, and that one mechanism of action may be functional enhancement of iNOS activity. PMID- 22428069 TI - Detection of PIGO-deficient cells using proaerolysin: a valuable tool to investigate mechanisms of mutagenesis in the DT40 cell system. AB - While isogenic DT40 cell lines deficient in DNA repair pathways are a great tool to understand the DNA damage response to genotoxic agents by a comparison of cell toxicity in mutants and parental DT40 cells, no convenient mutation assay for mutagens currently exists for this reverse-genetic system. Here we establish a proaerolysin (PA) selection-based mutation assay in DT40 cells to identify glycosylphosphatidylinositol (GPI)-anchor deficient cells. Using PA, we detected an increase in the number of PA-resistant DT40 cells exposed to MMS for 24 hours followed by a 5-day period of phenotype expression. GPI anchor synthesis is catalyzed by a series of phosphatidylinositol glycan complementation groups (PIGs). The PIG-O gene is on the sex chromosome (Chromosome Z) in chicken cells and is critical for GPI anchor synthesis at the intermediate step. Among all the mutations detected in the sequence levels observed in DT40 cells exposed to MMS at 100 uM, we identified that ~55% of the mutations are located at A:T sites with a high frequency of A to T transversion mutations. In contrast, we observed no transition mutations out of 18 mutations. This novel assay for DT40 cells provides a valuable tool to investigate the mode of action of mutations caused by reactive agents using a series of isogenic mutant DT40 cells. PMID- 22428070 TI - Effect of geographical access to health facilities on child mortality in rural Ethiopia: a community based cross sectional study. AB - BACKGROUND: There have been few studies that have examined associations between access to health care and child health outcomes in remote populations most in need of health services. This study assessed the effect of travel time and distance to health facilities on mortality in children under five years in a remote area of rural north-western Ethiopia. METHODS AND FINDINGS: This study involved a randomly selected cross sectional survey of 2,058 households. Data were collected during home visits to all resident women of reproductive age (15 49 years). A geographic information system (GIS) was used to map all households and the only health centre in the district. The analysis was restricted to 2,206 rural children who were under the age of five years during the five years before the survey. Data were analysed using random effects Poisson regression. 90.4% (1,996/2,206) of children lived more than 1.5 hours walk from the health centre. Children who lived >=1.5 hrs from the health centre had a two to three fold greater risk of death than children who lived <1.5 hours from the health centre (children with travel time 1.5-<2.5 hrs adjusted relative risk [adjRR] 2.3[0.95 5.6], travel time 2.5-<3.5 hrs adjRR 3.1[1.3-7.4] and travel time 3.5-<6.5 hrs adjRR 2.5[1.1-6.2]). CONCLUSION: Distance to a health centre had a marked influence on under five mortality in a poor, rural, remote area of Ethiopia. This study provides important information for policy makers on the likely impact of new health centres and their most effective location in remote areas. PMID- 22428071 TI - A reservoir species for the emerging Amphibian pathogen Batrachochytrium dendrobatidis thrives in a landscape decimated by disease. AB - Chytridiomycosis, a disease caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is driving amphibian declines and extinctions in protected areas globally. The introduction of invasive reservoir species has been implicated in the spread of Bd but does not explain the appearance of the pathogen in remote protected areas. In the high elevation (>1500 m) Sierra Nevada of California, the native Pacific chorus frog, Pseudacris regilla, appears unaffected by chytridiomycosis while sympatric species experience catastrophic declines. We investigated whether P. regilla is a reservoir of Bd by comparing habitat occupancy before and after a major Bd outbreak and measuring infection in P. regilla in the field, monitoring susceptibility of P. regilla to Bd in the laboratory, examining tissues with histology to determine patterns of infection, and using an innovative soak technique to determine individual output of Bd zoospores in water. Pseudacris regilla persists at 100% of sites where a sympatric species has been extirpated from 72% in synchrony with a wave of Bd. In the laboratory, P. regilla carried loads of Bd as much as an order of magnitude higher than loads found lethal to sympatric species. Histology shows heavy Bd infection in patchy areas next to normal skin, a possible mechanism for tolerance. The soak technique was 77.8% effective at detecting Bd in water and showed an average output of 68 zoospores per minute per individual. The results of this study suggest P. regilla should act as a Bd reservoir and provide evidence of a tolerance mechanism in a reservoir species. PMID- 22428072 TI - Phage display against corneal epithelial cells produced bioactive peptides that inhibit Aspergillus adhesion to the corneas. AB - Dissection of host-pathogen interactions is important for both understanding the pathogenesis of infectious diseases and developing therapeutics for the infectious diseases like various infectious keratitis. To enhance the knowledge about pathogenesis infectious keratitis, a random 12-mer peptide phage display library was screened against cultured human corneal epithelial cells (HCEC). Fourteen sequences were obtained and BLASTp analysis showed that most of their homologue counterparts in GenBank were for defined or putative proteins in various pathogens. Based on known or predicted functions of the homologue proteins, ten synthetic peptides (Pc-A to Pc-J) were measured for their affinity to bind cells and their potential efficacy to interfere with pathogen adhesion to the cells. Besides binding to HCEC, most of them also bound to human corneal stromal cells and umbilical endothelial cells to different extents. When added to HCEC culture, the peptides induced expression of MyD88 and IL-17 in HCEC, and the stimulated cell culture medium showed fungicidal potency to various extents. While peptides Pc-C and Pc-E inhibited Aspergillus fumigatus (A.f) adhesion to HCEC in a dose-dependent manner, the similar inhibition ability of peptides Pc-A and Pc-B required presence of their homologue ligand Alb1p on A.f. When utilized in an eyeball organ culture model and an in vivo A.f keratitis model established in mouse, Pc-C and Pc-E inhibited fungal adhesion to corneas, hence decreased corneal disruption caused by inflammatory infiltration. Affinity pull-down of HCEC membrane proteins with peptide Pc-C revealed several molecules as potential receptors for this peptide. In conclusion, besides proving that phage display selected peptides could be utilized to interfere with adhesion of pathogens to host cells, hence could be exploited for managing infectious diseases including infectious keratitis, we also proposed that the phage display technique and the resultant peptides could be used to explore host-pathogen interactions at molecular levels. PMID- 22428073 TI - The lasso segment is required for functional dimerization of the Plasmodium formin 1 FH2 domain. AB - Apicomplexan parasites, such as the malaria-causing Plasmodium species, utilize a unique way of locomotion and host cell invasion. This substrate-dependent gliding motility requires rapid cycling of actin between the monomeric state and very short, unbranched filaments. Despite the crucial role of actin polymerization for the survival of the malaria parasite, the majority of Plasmodium cellular actin is present in the monomeric form. Plasmodium lacks most of the canonical actin nucleators, and formins are essentially the only candidates for this function in all Apicomplexa. The malaria parasite has two formins, containing conserved formin homology (FH) 2 and rudimentary FH1 domains. Here, we show that Plasmodium falciparum formin 1 associates with and nucleates both mammalian and Plasmodium actin filaments. Although Plasmodium profilin alone sequesters actin monomers, thus inhibiting polymerization, its monomer-sequestering activity does not compete with the nucleating activity of formin 1 at an equimolar profilin-actin ratio. We have determined solution structures of P. falciparum formin 1 FH2 domain both in the presence and absence of the lasso segment and the FH1 domain, and show that the lasso is required for the assembly of functional dimers. PMID- 22428074 TI - Muscle hypertrophy in prepubescent tennis players: a segmentation MRI study. AB - PURPOSE: To asses if tennis at prepubertal age elicits the hypertrophy of dominant arm muscles. METHODS: The volume of the muscles of both arms was determined using magnetic resonance imaging (MRI) in 7 male prepubertal tennis players (TP) and 7 non-active control subjects (CG) (mean age 11.0 +/- 0.8 years, Tanner 1-2). RESULTS: TP had 13% greater total muscle volume in the dominant than in the contralateral arm. The magnitude of inter-arm asymmetry was greater in TP than in CG (13 vs 3%, P<0.001). The dominant arm of TP was 16% greater than the dominant arm of CG (P<0.01), whilst non-dominant arms had similar total muscle volumes in both groups (P = 0.25), after accounting for height as covariate. In TP, dominant deltoid (11%), forearm supinator (55%) and forearm flexors (21%) and extensors (25%) were hypertrophied compared to the contralateral arm (P<0.05). In CG, the dominant supinator muscle was bigger than its contralateral homonimous (63%, P<0.05). CONCLUSIONS: Tennis at prepubertal age is associated with marked hypertrophy of the dominant arm, leading to a marked level of asymmetry (+13%), much greater than observed in non-active controls (+3%). Therefore, tennis particpation at prepubertal age is associated with increased muscle volumes in dominant compared to the non-dominant arm, likely due to selectively hypertrophy of the loaded muscles. PMID- 22428075 TI - Constitutive expression of TNF-related activation-induced cytokine (TRANCE)/receptor activating NF-kappaB ligand (RANK)-L by rat plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) are a subset of DCs whose major function relies on their capacity to produce large amount of type I IFN upon stimulation via TLR 7 and 9. This function is evolutionary conserved and place pDC in critical position in the innate immune response to virus. Here we show that rat pDC constitutively express TNF-related activation-induced cytokine (TRANCE) also known as Receptor-activating NF-kappaB ligand (RANKL). TRANCE/RANKL is a member of the TNF superfamily which plays a central role in osteoclastogenesis through its interaction with its receptor RANK. TRANCE/RANK interaction are also involved in lymphoid organogenesis as well as T cell/DC cross talk. Unlike conventional DC, rat CD4(high) pDC were shown to constitutively express TRANCE/RANKL both at the mRNA and the surface protein level. TRANCE/RANKL was also induced on the CD4(low) subsets of pDC following activation by CpG. The secreted form of TRANCE/RANKL was also produced by rat pDC. Of note, levels of mRNA, surface and secreted TRANCE/RANKL expression were similar to that observed for activated T cells. TRANCE/RANKL expression was found on pDC in all lymphoid organs as well blood and BM with a maximum expression in mesenteric lymph nodes. Despite this TRANCE/RANKL expression, we were unable to demonstrate in vitro osteoclastogenesis activity for rat pDC. Taken together, these data identifies pDC as novel source of TRANCE/RANKL in the immune system. PMID- 22428076 TI - Evaluation of Colloids and Activation Agents for Determination of Melamine Using UV-SERS. AB - UV-SERS measurements offer a great potential for environmental or food (detection of food contaminats) analytics. Here, the UV-SERS enhancement potential of various kinds of metal colloids, such as Pd, Pt, Au, Ag, Au-Ag core-shell, and Ag Au core-shell with different shapes and sizes, were studied using melamine as a test molecule. The influence of different activation (KF, KCl, KBr, K(2)SO(4)) agents onto the SERS activity of the nanomaterials was investigated, showing that the combination of a particular nanoparticle with a special activation agent is extremely crucial for the observed SERS enhancement. In particular, the size dependence of spherical nanoparticles of one particular metal on the activator has been exploited. By doing so, it could be shown that the SERS enhancement increases or decreases for increasing or decreasing size of a nanoparticle, respectively. Overall, the presented results demonstrate the necessity to adjust the nanoparticle size and the activation agent for different experiments in order to achieve the best possible UV-SERS results. PMID- 22428077 TI - A transcriptomic view of the proteome variability of newborn and adult Bothrops jararaca snake venoms. AB - BACKGROUND: Snake bite is a neglected public health problem in communities in rural areas of several countries. Bothrops jararaca causes many snake bites in Brazil and previous studies have demonstrated that the pharmacological activities displayed by its venom undergo a significant ontogenetic shift. Similarly, the venom proteome of B. jararaca exhibits a considerable variation upon neonate to adult transition, which is associated with changes in diet from ectothermic prey in early life to endothermic prey in adulthood. Moreover, it has been shown that the Brazilian commercial antibothropic antivenom, which is produced by immunization with adult venom, is less effective in neutralizing newborn venom effects. On the other hand, venom gland transcripts of newborn snakes are poorly known since all transcriptomic studies have been carried out using mRNA from adult specimens. METHODS/PRINCIPAL FINDINGS: Here we analyzed venom gland cDNA libraries of newborn and adult B. jararaca in order to evaluate whether the variability demonstrated for its venom proteome and pharmacological activities was correlated with differences in the structure of toxin transcripts. The analysis revealed that the variability in B. jararaca venom gland transcriptomes is quantitative, as illustrated by the very high content of metalloproteinases in the newborn venom glands. Moreover, the variability is also characterized by the structural diversity of SVMP precursors found in newborn and adult transcriptomes. In the adult transcriptome, however, the content of metalloproteinase precursors considerably diminishes and the number of transcripts of serine proteinases, C-type lectins and bradykinin-potentiating peptides increase. Moreover, the comparison of the content of ESTs encoding toxins in adult male and female venom glands showed some gender-related differences. CONCLUSIONS/SIGNIFICANCE: We demonstrate a substantial shift in toxin transcripts upon snake development and a marked decrease in the metalloproteinase P-III/P-I class ratio which are correlated with changes in the venom proteome complexity and pharmacological activities. PMID- 22428078 TI - Addressing the neglected tropical disease podoconiosis in Northern Ethiopia: lessons learned from a new community podoconiosis program. AB - BACKGROUND: Despite its great public health importance, few control initiatives addressing podoconiosis (non-filarial elephantiasis, a geochemical neglected tropical disease) exist. In June 2010, the first podoconiosis program in Northern Ethiopia, consisting of prevention, awareness, and care and support activities, began in Debre Markos, Northern Ethiopia. This study aims to document and disseminate the lessons learned from a new community podoconiosis program in Debre Markos. METHODS/PRINCIPAL FINDINGS: We used a content analysis approach to examine and evaluate data from a series of sources. These sources include conducted interview transcripts, a focus group discussion transcript and secondary sources including monitoring and evaluation field reports, observation notes, and research obtained from a literature review. Themes were identified and grouped into matrix tables. Overall, sixteen program steps were identified and grouped into 6 domains: Initial preparation, training and sensitization, foundation building, treatment activity implementation, awareness, and follow-up. Emphasis is placed on the need for baseline data, effective training, local leadership, experience-sharing, mass-awareness, cross-cutting sector issues (i.e., water and waste management), and integration with government health systems. Related successes and challenges are also described, as are stakeholder roles and misconceptions and socio-cultural challenges affecting the program start-up. Many of the identified successes and challenges are relevant to the aim of the podoconiosis program to be sustainable and community-led. CONCLUSIONS/SIGNIFICANCE: Much of this information has already been used to improve the Debre Markos program. We also anticipate that the domains and steps identified will be useful in guiding new programs in other settings where podoconiosis is highly prevalent. We hope to encourage partnerships and collaboration among podoconiosis stakeholders in future growth and disease control expansion. PMID- 22428079 TI - Enhanced protective efficacy of a chimeric form of the schistosomiasis vaccine antigen Sm-TSP-2. AB - The large extracellular loop of the Schistosoma mansoni tetraspanin, Sm-TSP-2, when fused to a thioredoxin partner and formulated with Freund's adjuvants, has been shown to be an efficacious vaccine against murine schistosomiasis. Moreover, Sm-TSP-2 is uniquely recognised by IgG(1) and IgG(3) from putatively resistant individuals resident in S. mansoni endemic areas in Brazil. In the present study, we expressed Sm-TSP-2 at high yield and in soluble form in E. coli without the need for a solubility enhancing fusion partner. We also expressed in E. coli a chimera called Sm-TSP-2/5B, which consisted of Sm-TSP-2 fused to the immunogenic 5B region of the hookworm aspartic protease and vaccine antigen, Na-APR-1. Sm-TSP 2 formulated with alum/CpG showed significant reductions in adult worm and liver egg burdens in two separate murine schistosomiasis challenge studies. Sm-TSP-2/5B afforded significantly greater protection than Sm-TSP-2 alone when both antigens were formulated with alum/CpG. The enhanced protection obtained with the chimeric fusion protein was associated with increased production of anti-Sm-TSP-2 antibodies and IL-4, IL-10 and IFN-gamma from spleen cells of vaccinated animals. Sera from 666 individuals from Brazil who were infected with S. mansoni were screened for potentially deleterious IgE responses to Sm-TSP-2. Anti-Sm-TSP-2 IgE to this protein was not detected (also shown previously for Na-APR-1), suggesting that the chimeric antigen Sm-TSP-2/5B could be used to safely and effectively vaccinate people in areas where schistosomes and hookworms are endemic. PMID- 22428081 TI - A versatile telemetry system for continuous measurement of heart rate, body temperature and locomotor activity in free-ranging ruminants. AB - 1. Measuring physiological and behavioural parameters in free-ranging animals - and therefore under fully natural conditions - is of general biological concern but difficult to perform.2. We have developed a minimally invasive telemetry system for ruminants that is capable of measuring heart rate (HR), body temperature (T(b)) and locomotor activity (LA). A ruminal transmitter unit was per os placed into the reticulum and therefore located in close proximity to the heart. The unit detected HR by the use of an acceleration sensor and also measured T(b). HR and T(b) signals were transmitted via short-distance UHF link to a repeater system located in a collar unit. The collar unit decoded and processed signals received from the ruminal unit, measured LA with two different activity sensors and transmitted pulse interval-modulated VHF signals over distances of up to 10 km.3. HR data measured with the new device contained noise caused by reticulum contractions and animal movements that triggered the acceleration sensor in the ruminal unit. We have developed a software filter to remove this noise. Hence, the system was only capable of measuring HR in animals that showed little or no activity and in the absence of rumen contractions. Reliability of this 'stationary HR' measurement was confirmed with a second independent measurement of HR detected by an electrocardiogram in a domestic sheep (Ovis aries).4. In addition, we developed an algorithm to correctly classify an animal as 'active' or 'at rest' during each 3-min interval from the output of the activity sensors. Comparison with direct behavioural observations on free-ranging Alpine ibex (Capra ibex) showed that 87% of intervals were classified correctly.5. First results from applications of this new technique in free-ranging Alpine ibex underlined its suitability for reliable and long-term monitoring of physiological and behavioural parameters in ruminants under harsh field conditions. With the battery settings and measurement cycles used in this study, we achieved a system lifetime of approximately 2 years. PMID- 22428080 TI - Anopheles gambiae antiviral immune response to systemic O'nyong-nyong infection. AB - BACKGROUND: Mosquito-borne viral diseases cause significant burden in much of the developing world. Although host-virus interactions have been studied extensively in the vertebrate host, little is known about mosquito responses to viral infection. In contrast to mosquitoes of the Aedes and Culex genera, Anopheles gambiae, the principal vector of human malaria, naturally transmits very few arboviruses, the most important of which is O'nyong-nyong virus (ONNV). Here we have investigated the A. gambiae immune response to systemic ONNV infection using forward and reverse genetic approaches. METHODOLOGY/PRINCIPAL FINDINGS: We have used DNA microarrays to profile the transcriptional response of A. gambiae inoculated with ONNV and investigate the antiviral function of candidate genes through RNAi gene silencing assays. Our results demonstrate that A. gambiae responses to systemic viral infection involve genes covering all aspects of innate immunity including pathogen recognition, modulation of immune signalling, complement-mediated lysis/opsonisation and other immune effector mechanisms. Patterns of transcriptional regulation and co-infections of A. gambiae with ONNV and the rodent malaria parasite Plasmodium berghei suggest that hemolymph immune responses to viral infection are diverted away from melanisation. We show that four viral responsive genes encoding two putative recognition receptors, a galectin and an MD2-like receptor, and two effector lysozymes, function in limiting viral load. CONCLUSIONS/SIGNIFICANCE: This study is the first step in elucidating the antiviral mechanisms of A. gambiae mosquitoes, and has revealed interesting differences between A. gambiae and other invertebrates. Our data suggest that mechanisms employed by A. gambiae are distinct from described invertebrate antiviral immunity to date, and involve the complement-like branch of the humoral immune response, supressing the melanisation response that is prominent in anti-parasitic immunity. The antiviral immune response in A. gambiae is thus composed of some key conserved mechanisms to target viral infection such as RNAi but includes other diverse and possibly species-specific mechanisms. PMID- 22428082 TI - The effect of cholesterol domains on PEGylated liposomal gene delivery in vitro. AB - AIM: PEGylated components have been widely used to reduce particle aggregation in serum and extend circulation lifetime for lipid- and polymer-based gene-delivery systems. However, PEGylation is known to interfere with cell interaction and intracellular trafficking, resulting in decreased biological activity. In the present study, the effect of cholesterol domains on PEGylated liposome-mediated gene delivery was evaluated by PEGylating formulations with and without a cholesterol domain, and also by altering the location of PEG on the particle surface (i.e., within or excluded from the domain). MATERIALS AND METHODS: Lipoplexes formulated with PEG-cholesterol or PEG-diacyl lipid were used to transfect various cell lines, including human and mouse cancer cells. Cellular uptake of lipoplexes was also quantified and compared with the transfection results. RESULTS: Our findings are consistent with previous work demonstrating that PEGylation reduces transfection rates; however, formulations in which PEG was incorporated into the cholesterol domain did not exhibit this detrimental effect. In some cell lines, the incorporation of PEG into the domain actually increased transfection rates, despite no enhancement of cellular uptake. DISCUSSION: These results suggest that the adverse alterations in intracellular trafficking that are a consequence of PEGylation may be avoided by utilizing delivery vehicles that allow PEG to partition into a cholesterol domain. PMID- 22428083 TI - Incentives and barriers to neurological clinical research participation. AB - BACKGROUND: Understanding barriers and incentives to neurological research participation may improve clinical trial enrollment. RESULTS: Telephone-based focus groups were conducted with four neurological disorder patient groups (n = 22) and one caregiver group (n = 6). A total of 14 neurologists and neurosurgeons participated in structured interviews. Topics discussed included identifying ways in which health information is gathered and attitudes toward participation in medical research. Interestingly, 86% of physicians interviewed have referred patients to clinical trials and 82% of patients expressed interest in clinical trials participation. Patients cited their primary physician as the best source of health-related information, including information about clinical trials. Barriers to patients and physicians regarding clinical trials participation included compensation. Patients expressed concern about increased visit frequency and required treatment changes. CONCLUSION: Patients are willing to participate in clinical trials and physicians are willing to refer patients for participation with appropriate compensation for their time and sensitivity to change in care. PMID- 22428084 TI - Fetal radiofrequency radiation exposure from 800-1900 mhz-rated cellular telephones affects neurodevelopment and behavior in mice. AB - Neurobehavioral disorders are increasingly prevalent in children, however their etiology is not well understood. An association between prenatal cellular telephone use and hyperactivity in children has been postulated, yet the direct effects of radiofrequency radiation exposure on neurodevelopment remain unknown. Here we used a mouse model to demonstrate that in-utero radiofrequency exposure from cellular telephones does affect adult behavior. Mice exposed in-utero were hyperactive and had impaired memory as determined using the object recognition, light/dark box and step-down assays. Whole cell patch clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) revealed that these behavioral changes were due to altered neuronal developmental programming. Exposed mice had dose-responsive impaired glutamatergic synaptic transmission onto layer V pyramidal neurons of the prefrontal cortex. We present the first experimental evidence of neuropathology due to in-utero cellular telephone radiation. Further experiments are needed in humans or non-human primates to determine the risk of exposure during pregnancy. PMID- 22428085 TI - Evaluating the viscoelastic properties of tissue from laser speckle fluctuations. AB - Most pathological conditions such as atherosclerosis, cancer, neurodegenerative, and orthopedic disorders are accompanied with alterations in tissue viscoelasticity. Laser Speckle Rheology (LSR) is a novel optical technology that provides the invaluable potential for mechanical assessment of tissue in situ. In LSR, the specimen is illuminated with coherent light and the time constant of speckle fluctuations, tau, is measured using a high speed camera. Prior work indicates that tau is closely correlated with tissue microstructure and composition. Here, we investigate the relationship between LSR measurements of tau and sample mechanical properties defined by the viscoelastic modulus, G*. Phantoms and tissue samples over a broad range of viscoelastic properties are evaluated using LSR and conventional mechanical testing. Results demonstrate a strong correlation between tau and |G*| for both phantom (r = 0.79, p <0.0001) and tissue (r = 0.88, p<0.0001) specimens, establishing the unique capability of LSR in characterizing tissue viscoelasticity. PMID- 22428086 TI - Towards the understanding of microRNA and environmental factor interactions and their relationships to human diseases. AB - Increasing studies have shown that the interactions between microRNAs (miRNAs) and environmental factors (EFs) play critical roles in determining phenotypes and diseases. In this study, we revealed a number of important biological insights by analyzing and modeling of miRNA-EF interactions and their relationships with human diseases. We demonstrated that the miRNA signatures of EFs could provide new information on EFs. More importantly, we quantitatively showed that the miRNA signatures of drug/radiation could be used as indicators for evaluating the results of cancer treatments. Finally, we developed a computational model that could efficiently identify the possible relationship between EF and human diseases. Meanwhile, we provided a website (http://cmbi.hsc.pku.edu.cn/miren) for the main results of this study. This study elucidates the mechanisms of EFs, presents a framework for predicting the results of cancer treatments, and develops a model that illustrates the relationships between EFs and human diseases. PMID- 22428087 TI - Lifecourse Urbanization, Social Demography, and Health Outcomes among a National Cohort of 71,516 Adults in Thailand. AB - We examine the influence of urbanization on household structure, social networks, and health in Thailand. We compare lifetime urban or rural dwellers and those who were rural as children and urban as adults. Data derived from a large national cohort of 71,516 Sukhothai Thammathirat Open University adult students participating in an on-going longitudinal study of the health-risk transition in Thailand. The rural-urban group, one-third of cohort households, was significantly different from other groups (e.g., smaller households). The rural rural and the urban-urban groups often were the two extremes. Urbanization, after adjusting for covariates, was a risk factor for poor overall health and depression. Urbanization is a mediator of the health-risk transition underway in Thailand. Health programs and policies directed at transitional health outcomes should focus on the health risks of the urbanizing population, in particular smoking, drinking, low social trust, and poor psychological health. PMID- 22428090 TI - The mGluR5 Positive Allosteric Modulator CDPPB Does Not Alter Extinction or Contextual Reinstatement of Methamphetamine-Seeking Behavior in Rats. AB - Extinction of drug-seeking behavior is a form of new and active learning. Facilitation of extinction learning is of clinical interest since cue exposure therapies for the treatment of addiction have largely been unsuccessful in preventing relapse, primarily due to the context specificity of extinction learning. Recently, several studies have shown that potentiation of glutamatergic transmission can facilitate extinction learning in rodent models of cocaine addiction. In this study we investigated the effects of the type 5 metabotropic glutamate receptor (mGluR5) positive allosteric modulator (PAM) 3-cyano-N-(1,3 diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction and contextual reinstatement of methamphetamine-seeking behavior. Rats were trained and allowed to self-administer methamphetamine (0.1 mg/kg/infusion) in 2 hr daily sessions in Context A where self-administration chambers had distinct tactile, visual, auditory, and olfactory cues. Next, CDPPB (60 mg/kg) or vehicle was administered prior to subsequent extinction training sessions that were conducted in modified self-administration chambers (Context B) that were Context A. Following 16 days of extinction training in Context B, animals were placed back in Context A for assessment of contextual reinstatement of methamphetamine-seeking behavior. CDPPB failed to produce significant reductions in extinction responding or in the magnitude of contextual reinstatement of methamphetamine-seeking compared to vehicle treated controls. We postulate that numerous factors, including methamphetamine-induced changes in mGluR5 receptor expression or function, may have contributed to the observed lack of effects. Although these findings initially suggest that mGluR5 PAMs may be ineffective in facilitating extinction learning or preventing context-induced relapse in methamphetamine addiction, additional studies are warranted examining effects of other mGluR5 PAMs, particularly those with improved pharmacological properties and devoid of potential side effects at higher doses. PMID- 22428089 TI - Investigating Methamphetamine Craving Using the Extinction-Reinstatement Model in the Rat. AB - Like all other drugs of abuse, the primary therapeutic objective for treating methamphetamine addiction research is the maintenance of abstinence and prevention of relapse to habitual drug-taking. Compounds with the potential to prevent relapse are often investigated in rats that are trained to self administer intravenous methamphetamine, subjected to extinction training where responding is no longer reinforced, and then given tests for reinstatement of drug-seeking behavior triggered by methamphetamine injections or re-exposure to drug-paired cues. Experimental compounds are administered to the animals prior to the reinstatement tests to evaluate their potential for attenuating or preventing drug-seeking behavior. This article describes the common procedures of the extinction-reinstatement model in studies of this type, and identifies areas of discrepancy. This is followed by a comprehensive overview of the currently published anti-reinstatement effects of pharmacological compounds, classified by the most relevant neurological systems associated with these compounds. The article concludes with a brief discussion of how the study of anti-reinstatement effects can be expanded to further verify existing positive results or to find novel neurobiological targets. PMID- 22428091 TI - Size-dependent phase diagrams of metallic alloys: A Monte Carlo simulation study on order-disorder transitions in Pt-Rh nanoparticles. AB - Nanoparticles of Pt-Rh were studied by means of lattice-based Monte Carlo simulations with respect to the stability of ordered D0(22)- and 40-phases as a function of particle size and composition. By thermodynamic integration in the semi-grand canonical ensemble, phase diagrams for particles with a diameter of 7.8 nm, 4.3 nm and 3.1 nm were obtained. Size-dependent trends such as the lowering of the critical ordering temperature, the broadening of the compositional stability range of the ordered phases, and the narrowing of the two phase regions were observed and discussed in the context of complete size dependent nanoparticle phase diagrams. In addition, an ordered surface phase emerges at low temperatures and low platinum concentration. A decrease of platinum surface segregation with increasing global platinum concentration was observed, when a second, ordered phase is formed inside the core of the particle. The order-disorder transitions were analyzed in terms of the Warren-Cowley short range order parameters. Concentration-averaged short-range order parameters were used to remove the surface segregation bias of the conventional short-range order parameters. Using this procedure, it was shown that the short-range order in the particles at high temperatures is bulk-like. PMID- 22428092 TI - X-ray spectroscopy characterization of self-assembled monolayers of nitrile substituted oligo(phenylene ethynylene)s with variable chain length. AB - Self-assembled monolayers (SAMs) of nitrile-substituted oligo(phenylene ethynylene) thiols (NC-OPEn) with a variable chain length n (n ranging from one to three structural units) on Au(111) were studied by synchrotron-based high resolution X-ray photoelectron spectroscopy and near-edge absorption fine structure spectroscopy. The experimental data suggest that the NC-OPEn molecules form well-defined SAMs on Au(111), with all the molecules bound to the substrate through the gold-thiolate anchor and the nitrile tail groups located at the SAM ambient interface. The packing density in these SAMs was found to be close to that of alkanethiolate monolayers on Au(111), independent of the chain length. Similar behavior was found for the molecular inclination, with an average tilt angle of ~33-36 degrees for all the target systems. In contrast, the average twist of the OPEn backbone (planar conformation) was found to depend on the molecular length, being close to 45 degrees for the films comprising the short OPE chains and ~53.5 degrees for the long chains. Analysis of the data suggests that the attachment of the nitrile moiety, which served as a spectroscopic marker group, to the OPEn backbone did not significantly affect the molecular orientation in the SAMs. PMID- 22428093 TI - Effect of the tip state during qPlus noncontact atomic force microscopy of Si(100) at 5 K: Probing the probe. AB - BACKGROUND: Noncontact atomic force microscopy (NC-AFM) now regularly produces atomic-resolution images on a wide range of surfaces, and has demonstrated the capability for atomic manipulation solely using chemical forces. Nonetheless, the role of the tip apex in both imaging and manipulation remains poorly understood and is an active area of research both experimentally and theoretically. Recent work employing specially functionalised tips has provided additional impetus to elucidating the role of the tip apex in the observed contrast. RESULTS: We present an analysis of the influence of the tip apex during imaging of the Si(100) substrate in ultra-high vacuum (UHV) at 5 K using a qPlus sensor for noncontact atomic force microscopy (NC-AFM). Data demonstrating stable imaging with a range of tip apexes, each with a characteristic imaging signature, have been acquired. By imaging at close to zero applied bias we eliminate the influence of tunnel current on the force between tip and surface, and also the tunnel-current-induced excitation of silicon dimers, which is a key issue in scanning probe studies of Si(100). CONCLUSION: A wide range of novel imaging mechanisms are demonstrated on the Si(100) surface, which can only be explained by variations in the precise structural configuration at the apex of the tip. Such images provide a valuable resource for theoreticians working on the development of realistic tip structures for NC-AFM simulations. Force spectroscopy measurements show that the tip termination critically affects both the short-range force and dissipated energy. PMID- 22428094 TI - Octadecyltrichlorosilane (OTS)-coated ionic liquid drops: Micro-reactors for homogenous catalytic reactions at designated interfaces. AB - An ionic liquid (IL), 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) can assemble on prefabricated carboxylic acid-terminated chemical patterns on octadecyltrichlorosilane (OTS) film. The chemical pattern controls the position, shape and size of the IL on the surface. After the IL assembly - by incubating IL drops assembled on sample surface in an OTS silane vapor - an OTS layer was coated on the IL drop surface which encapsulated the IL drop. The OTS-coated capsule can exist stably under aqueous solution. The OTS coating protected the IL drops from being instantaneously dissolved by other solutions. We found that a homogenous catalyst (FeCl(3)) dissolved in [Bmim]Cl can be assembled together on the chemical patterns and subsequently encapsulated together with [Bmim]Cl by OTS coating. The pinhole defects within the vapor-coated silane layer provide space for the catalyst inside the capsule and reactants outside the capsule to meet and react. When the OTS-coated capsule containing a FeCl(3)/IL mixture was soaked under H(2)O(2) solution, the Fe(3+) ions catalyzed the decomposition reaction of hydrogen peroxide at the vapor-coated OTS-water interface. Since the shape and position of the interface is defined by the underneath chemical pattern, our findings show that the OTS-coated IL drops assembled on chemical patterns can be used as novel micro-reactors. This allows homogenous catalytic reactions to occur at the designated interfaces. PMID- 22428095 TI - Transmission eigenvalue distributions in highly conductive molecular junctions. AB - BACKGROUND: The transport through a quantum-scale device may be uniquely characterized by its transmission eigenvalues tau(n). Recently, highly conductive single-molecule junctions (SMJ) with multiple transport channels (i.e., several tau(n) > 0) have been formed from benzene molecules between Pt electrodes. Transport through these multichannel SMJs is a probe of both the bonding properties at the lead-molecule interface and of the molecular symmetry. RESULTS: We use a many-body theory that properly describes the complementary wave-particle nature of the electron to investigate transport in an ensemble of Pt-benzene-Pt junctions. We utilize an effective-field theory of interacting pi-electrons to accurately model the electrostatic influence of the leads, and we develop an ab initio tunneling model to describe the details of the lead-molecule bonding over an ensemble of junction geometries. We also develop a simple decomposition of transmission eigenchannels into molecular resonances based on the isolated resonance approximation, which helps to illustrate the workings of our many-body theory, and facilitates unambiguous interpretation of transmission spectra. CONCLUSION: We confirm that Pt-benzene-Pt junctions have two dominant transmission channels, with only a small contribution from a third channel with tau(n) << 1. In addition, we demonstrate that the isolated resonance approximation is extremely accurate and determine that transport occurs predominantly via the HOMO orbital in Pt-benzene-Pt junctions. Finally, we show that the transport occurs in a lead-molecule coupling regime where the charge carriers are both particle-like and wave-like simultaneously, requiring a many body description. PMID- 22428096 TI - Direct-write polymer nanolithography in ultra-high vacuum. AB - Polymer nanostructures were directly written onto substrates in ultra-high vacuum. The polymer ink was coated onto atomic force microscope (AFM) probes that could be heated to control the ink viscosity. Then, the ink-coated probes were placed into an ultra-high vacuum (UHV) AFM and used to write polymer nanostructures on surfaces, including surfaces cleaned in UHV. Controlling the writing speed of the tip enabled the control over the number of monolayers of the polymer ink deposited on the surface from a single to tens of monolayers, with higher writing speeds generating thinner polymer nanostructures. Deposition onto silicon oxide-terminated substrates led to polymer chains standing upright on the surface, whereas deposition onto vacuum reconstructed silicon yielded polymer chains aligned along the surface. PMID- 22428097 TI - Impact of cell shape in hierarchically structured plant surfaces on the attachment of male Colorado potato beetles (Leptinotarsa decemlineata). AB - Plant surfaces showing hierarchical structuring are frequently found in plant organs such as leaves, petals, fruits and stems. In our study we focus on the level of cell shape and on the level of superimposed microstructuring, leading to hierarchical surfaces if both levels are present. While it has been shown that epicuticular wax crystals and cuticular folds strongly reduce insect attachment, and that smooth papillate epidermal cells in petals improve the grip of pollinators, the impact of hierarchical surface structuring of plant surfaces possessing convex or papillate cells on insect attachment remains unclear. We performed traction experiments with male Colorado potato beetles on nine different plant surfaces with different structures. The selected plant surfaces showed epidermal cells with either tabular, convex or papillate cell shape, covered either with flat films of wax, epicuticular wax crystals or with cuticular folds. On surfaces possessing either superimposed wax crystals or cuticular folds we found traction forces to be almost one order of magnitude lower than on surfaces covered only with flat films of wax. Independent of superimposed microstructures we found that convex and papillate epidermal cell shapes slightly enhance the attachment ability of the beetles. Thus, in plant surfaces, cell shape and superimposed microstructuring yield contrary effects on the attachment of the Colorado potato beetle, with convex or papillate cells enhancing attachment and both wax crystals or cuticular folds reducing attachment. However, the overall magnitude of traction force mainly depends on the presence or absence of superimposed microstructuring. PMID- 22428098 TI - Substrate-mediated effects in photothermal patterning of alkanethiol self assembled monolayers with microfocused continuous-wave lasers. AB - In recent years, self-assembled monolayers (SAMs) have been demonstrated to provide promising new approaches to nonlinear laser processing. Most notably, because of their ultrathin nature, indirect excitation mechanisms can be exploited in order to fabricate subwavelength structures. In photothermal processing, for example, microfocused lasers are used to locally heat the substrate surface and initiate desorption or decomposition of the coating. Because of the strongly temperature-dependent desorption kinetics, the overall process is highly nonlinear in the applied laser power. For this reason, subwavelength patterning is feasible employing ordinary continuous-wave lasers. The lateral resolution, generally, depends on both the type of the organic monolayer and the nature of the substrate. In previous studies we reported on photothermal patterning of distinct types of SAMs on Si supports. In this contribution, a systematic study on the impact of the substrate is presented. Alkanethiol SAMs on Au-coated glass and silicon substrates were patterned by using a microfocused laser beam at a wavelength of 532 nm. Temperature calculations and thermokinetic simulations were carried out in order to clarify the processes that determine the performance of the patterning technique. Because of the strongly temperature-dependent thermal conductivity of Si, surface temperature profiles on Au/Si substrates are very narrow ensuring a particularly high lateral resolution. At a 1/e spot diameter of 2 um, fabrication of subwavelength structures with diameters of 300-400 nm is feasible. Rapid heat dissipation, though, requires high laser powers. In contrast, patterning of SAMs on Au/glass substrates is strongly affected by the largely distinct heat conduction within the Au film and in the glass support. This results in broad surface temperature profiles. Hence, minimum structure sizes are larger when compared with respective values on Au/Si substrates. The required laser powers, though, are more than one order of magnitude lower. Also, the laser power needed for patterning decreases with decreasing Au layer thickness. These results demonstrate the impact of the substrate on the overall patterning process and provide new perspectives in photothermal laser patterning of ultrathin organic coatings. PMID- 22428099 TI - Improvement of the oxidation stability of cobalt nanoparticles. AB - In order to enhance the resistance of cobalt nanoparticles to oxidation in air, the impact of different stabilization strategies on the isothermal oxidation of particle dispersions and powders was kinetically investigated and compared to as prepared particle preparations. A post-synthesis treatment with different alcohols was employed, and we also investigate the influence of two different polymer shells on the oxidation process. We found a parabolic decrease of the magnetization for all particle charges, indicating that the process is dominated by a diffusion of oxygen to the cobalt core and a radial growth of the oxide layer from the particle surface to the core. A significant deceleration of the oxidation process was observed for all alcohol-passivated particle preparations, and this resulted finally in a stagnation effect. The stabilizing effect increases in the sequence Co@OA/MeOH < Co@OA/EtOH < Co@OA/iPrOH. For polymer coated particle preparations Co@PCL and Co@PS, the deceleration was even more pronounced. The results demonstrate that cobalt nanoparticles can effectively be protected against oxidation in order to improve their mid- to longterm stability. PMID- 22428100 TI - Surface functionalization of aluminosilicate nanotubes with organic molecules. AB - The surface functionalization of inorganic nanostructures is an effective approach for enriching the potential applications of existing nanomaterials. Inorganic nanotubes attract great research interest due to their one-dimensional structure and reactive surfaces. In this review paper, recent developments in surface functionalization of an aluminosilicate nanotube, "imogolite", are introduced. The functionalization processes are based on the robust affinity between phosphate groups of organic molecules and the aluminol (AlOH) surface of imogolite nanotubes. An aqueous modification process employing a water soluble ammonium salt of alkyl phosphate led to chemisorption of molecules on imogolite at the nanotube level. Polymer-chain-grafted imogolite nanotubes were prepared through surface-initiated polymerization. In addition, the assembly of conjugated molecules, 2-(5''-hexyl-2,2':5',2''-terthiophen-5-yl)ethylphosphonic acid (HT3P) and 2-(5''-hexyl-2,2':5',2''-terthiophen-5-yl)ethylphosphonic acid 1,1-dioxide (HT3OP), on the imogolite nanotube surface was achieved by introducing a phosphonic acid group to the corresponding molecules. The optical and photophysical properties of these conjugated-molecule-decorated imogolite nanotubes were characterized. Moreover, poly(3-hexylthiophene) (P3HT) chains were further hybridized with HT3P modified imogolite to form a nanofiber hybrid. PMID- 22428101 TI - Electron-beam patterned self-assembled monolayers as templates for Cu electrodeposition and lift-off. AB - Self-assembled monolayers (SAMs) of 4'-methylbiphenyl-4-thiol (MBP0) adsorbed on polycrystalline gold substrates served as templates to control electrochemical deposition of Cu structures from acidic solution, and enabled the subsequent lift off of the metal structures by attachment to epoxy glue. By exploiting the negative-resist behaviour of MBP0, the SAM was patterned by means of electron beam lithography. For high deposition contrast a two-step procedure was employed involving a nucleation phase around -0.7 V versus Cu(2+)/Cu and a growth phase at around -0.35 V versus Cu(2+)/Cu. Structures with features down to 100 nm were deposited and transferred with high fidelity. By using substrates with different surface morphologies, AFM measurements revealed that the roughness of the substrate is a crucial factor but not the only one determining the roughness of the copper surface that is exposed after lift-off. PMID- 22428102 TI - Self-assembly of octadecyltrichlorosilane: Surface structures formed using different protocols of particle lithography. AB - Particle lithography offers generic capabilities for the high-throughput fabrication of nanopatterns from organosilane self-assembled monolayers, which offers the opportunity to study surface-based chemical reactions at the molecular level. Nanopatterns of octadecyltrichlorosilane (OTS) were prepared on surfaces of Si(111) using designed protocols of particle lithography combined with either vapor deposition, immersion, or contact printing. Changing the physical approaches for applying molecules to masked surfaces produced OTS nanostructures with different shapes and heights. Ring nanostructures, nanodots and uncovered pores of OTS were prepared using three protocols, with OTS surface coverage ranging from 10% to 85%. Thickness measurements from AFM cursor profiles were used to evaluate the orientation and density of the OTS nanostructures. Differences in the thickness and morphology of the OTS nanostructures are disclosed based on atomic force microscopy (AFM) images. Images of OTS nanostructures prepared on Si(111) that were generated by the different approaches provide insight into the self-assembly mechanism of OTS, and particularly into the role of water and solvents in hydrolysis and silanation. PMID- 22428103 TI - Mesoporous MgTa(2)O(6) thin films with enhanced photocatalytic activity: On the interplay between crystallinity and mesostructure. AB - Ordered mesoporous, crystalline MgTa(2)O(6) thin films with a mesoscopic nanoarchitecture were synthesized by evaporation-induced self-assembly (EISA) in combination with a sol-gel procedure. Utilization of novel templates, namely the block copolymers KLE (poly(ethylene-co-butylene)-b-poly(ethylene oxide)) and PIB6000 (CH(3)C(CH(3))(2)(CH(2)C(CH(3))(2))(107)CH(2)C(CH(3))(2)C(6)H(4)O(CH(2)CH(2)O)(10 )H), was the key to achieving a stable ordered mesoporous structure even upon crystallization of MgTa(2)O(6) within the mesopore walls. The effect of the calcination temperature on the ability of the mesoporous films to assist the photodegradation of rhodamine B in water was studied. As a result, two maxima in the photocatalytic activity were identified in the calcination temperature range of 550-850 degrees C, peaking at 700 degrees C and 790 degrees C, and the origin of this was investigated by using temperature-dependent X-ray scattering. Optimal activity was obtained when the mesoporous film was heated to 790 degrees C; at this temperature, crystallinity was significantly high, with MgTa(2)O(6) nanocrystals of 1.6 nm in size (averaged over all reflections), and an ordered mesoporous structure was maintained. When considering the turnover frequency of such photocatalysts, the optimized activity of the present nanoarchitectured MgTa(2)O(6) thin film was ca. four times that of analogous anatase TiO(2) films with ordered mesopores. Our study demonstrated that high crystallinity and well developed mesoporosity have to be achieved in order to optimize the physicochemical performance of mesoporous metal-oxide films. PMID- 22428104 TI - Parallel- and serial-contact electrochemical metallization of monolayer nanopatterns: A versatile synthetic tool en route to bottom-up assembly of electric nanocircuits. AB - Contact electrochemical transfer of silver from a metal-film stamp (parallel process) or a metal-coated scanning probe (serial process) is demonstrated to allow site-selective metallization of monolayer template patterns of any desired shape and size created by constructive nanolithography. The precise nanoscale control of metal delivery to predefined surface sites, achieved as a result of the selective affinity of the monolayer template for electrochemically generated metal ions, provides a versatile synthetic tool en route to the bottom-up assembly of electric nanocircuits. These findings offer direct experimental support to the view that, in electrochemical metal deposition, charge is carried across the electrode-solution interface by ion migration to the electrode rather than by electron transfer to hydrated ions in solution. PMID- 22428105 TI - Current-induced forces in mesoscopic systems: A scattering-matrix approach. AB - Nanoelectromechanical systems are characterized by an intimate connection between electronic and mechanical degrees of freedom. Due to the nanoscopic scale, current flowing through the system noticeably impacts upons the vibrational dynamics of the device, complementing the effect of the vibrational modes on the electronic dynamics. We employ the scattering-matrix approach to quantum transport in order to develop a unified theory of nanoelectromechanical systems out of equilibrium. For a slow mechanical mode the current can be obtained from the Landauer-Buttiker formula in the strictly adiabatic limit. The leading correction to the adiabatic limit reduces to Brouwer's formula for the current of a quantum pump in the absence of a bias voltage. The principal results of the present paper are the scattering-matrix expressions for the current-induced forces acting on the mechanical degrees of freedom. These forces control the Langevin dynamics of the mechanical modes. Specifically, we derive expressions for the (typically nonconservative) mean force, for the (possibly negative) damping force, an effective "Lorentz" force that exists even for time-reversal invariant systems, and the fluctuating Langevin force originating from Nyquist and shot noise of the current flow. We apply our general formalism to several simple models that illustrate the peculiar nature of the current-induced forces. Specifically, we find that in out-of-equilibrium situations the current-induced forces can destabilize the mechanical vibrations and cause limit-cycle dynamics. PMID- 22428106 TI - Analysis of fluid flow around a beating artificial cilium. AB - Biological cilia are found on surfaces of some microorganisms and on surfaces of many eukaryotic cells where they interact with the surrounding fluid. The periodic beating of the cilia is asymmetric, resulting in directed swimming of unicellular organisms or in generation of a fluid flow above a ciliated surface in multicellular ones. Following the biological example, externally driven artificial cilia have recently been successfully implemented as micropumps and mixers. However, biomimetic systems are useful not only in microfluidic applications, but can also serve as model systems for the study of fundamental hydrodynamic phenomena in biological samples. To gain insight into the basic principles governing propulsion and fluid pumping on a micron level, we investigated hydrodynamics around one beating artificial cilium. The cilium was composed of superparamagnetic particles and driven along a tilted cone by a varying external magnetic field. Nonmagnetic tracer particles were used for monitoring the fluid flow generated by the cilium. The average flow velocity in the pumping direction was obtained as a function of different parameters, such as the rotation frequency, the asymmetry of the beat pattern, and the cilium length. We also calculated the velocity field around the beating cilium by using the analytical far-field expansion. The measured average flow velocity and the theoretical prediction show an excellent agreement. PMID- 22428107 TI - Noncontact atomic force microscopy. PMID- 22428108 TI - qPlus magnetic force microscopy in frequency-modulation mode with millihertz resolution. AB - Magnetic force microscopy (MFM) allows one to image the domain structure of ferromagnetic samples by probing the dipole forces between a magnetic probe tip and a magnetic sample. The magnetic domain structure of the sample depends on the alignment of the individual atomic magnetic moments. It is desirable to be able to image both individual atoms and domain structures with a single probe. However, the force gradients of the interactions responsible for atomic contrast and those causing domain contrast are orders of magnitude apart, ranging from up to 100 Nm(-1) for atomic interactions down to 0.0001 Nm(-1) for magnetic dipole interactions. Here, we show that this gap can be bridged with a qPlus sensor, with a stiffness of 1800 Nm(-1) (optimized for atomic interaction), which is sensitive enough to measure millihertz frequency contrast caused by magnetic dipole-dipole interactions. Thus we have succeeded in establishing a sensing technique that performs scanning tunneling microscopy, atomic force microscopy and MFM with a single probe. PMID- 22428109 TI - Quantitative multichannel NC-AFM data analysis of graphene growth on SiC(0001). AB - Noncontact atomic force microscopy provides access to several complementary signals, such as topography, damping, and contact potential. The traditional presentation of such data sets in adjacent figures or in colour-coded pseudo three-dimensional plots gives only a qualitative impression. We introduce two dimensional histograms for the representation of multichannel NC-AFM data sets in a quantitative fashion. Presentation and analysis are exemplified for topography and contact-potential data for graphene grown epitaxially on 6H-SiC(0001), as recorded by Kelvin probe force microscopy in ultrahigh vacuum. Sample preparations by thermal decomposition in ultrahigh vacuum and in an argon atmosphere are compared and the respective growth mechanisms discussed. PMID- 22428110 TI - Molecular-resolution imaging of pentacene on KCl(001). AB - The growth of pentacene on KCl(001) at submonolayer coverage was studied by dynamic scanning force microscopy. At coverages below one monolayer pentacene was found to arrange in islands with an upright configuration. The molecular arrangement was resolved in high-resolution images. In these images two different types of patterns were observed, which switch repeatedly. In addition, defects were found, such as a molecular vacancy and domain boundaries. PMID- 22428111 TI - Preconditions of Voluntary Tax Compliance: Knowledge and Evaluation of Taxation, Norms, Fairness, and Motivation to Cooperate. AB - Taxpayers' willingness to cooperate with the state and its institutions in general, and their willingness to pay taxes in particular, depend on a variety of variables. While economists stress the relevance of external variables such as tax rate, income and probability of audits and severity of fines, psychological research shows that internal variables are of similar importance. We present a comprehensive review on the relevance of citizens' knowledge of tax law, their attitudes towards the government and taxation, personal norms, perceived social norms and fairness, as well as motivational tendencies to comply, and discuss possibilities for strategic intervention to increase tax compliance. PMID- 22428112 TI - Spectroscopy analysis for simultaneous determination of lycopene and beta carotene in fungal biomass of Blakeslea trispora. AB - Blakeslea trispora is a good alternative source for producing such carotenoids as lycopene and beta-carotene. The objective of this research was to elaborate a method for the simultaneous determination of lycopene and beta-carotene in Blakeslea trispora products using a usual UV-vis spectrophotometer. The standard solutions of the mixture of different concentrations of beta-carotene and lycopene were measured with the UV-vis method and correlation formula for the extinction coefficients of 1% standard solution of lycopene in the solvent (hexane) and the ratios of the optical densities at the character peaks of 470 and 502 nm was elaborated. This gives a possibility to calculate the concentrations of lycopene and beta-carotene in the mixture. The prediction quality of the UV-vis method was sufficient and the obtained results were very close to the ones, being measured with the HPLC technique. The proposed method can be used for both routine industrial work and academic research, providing the rapid analysis for simultaneous measurements of lycopene and beta-carotene. PMID- 22428113 TI - Synthesis of highly 13C enriched carotenoids: access to carotenoids enriched with 13C at any position and combination of positions. AB - Carotenoids and their metabolites are essential factors for the maintenance of important life processes such as photosynthesis. Animals cannot synthesize carotenoids de novo, they must obtain them via their food. In order to make intensive animal husbandry possible and maintain human and animal health synthetic nature identical carotenoids are presently commercially available at the multi-tonnes scale per year. Synthetically accessible (13)C enriched carotenoids are essential to apply isotope sensitive techniques to obtain information at the atomic level without perturbation about the role of carotenoids in photosynthesis, nutrition, vision, animal development, etc. Simple highly (13)C enriched C(1), C(2) and C(3) building blocks are commercially available via 99% (13)CO. The synthetic routes for the preparation of the (13)C enriched building blocks starting from the commercially available systems are discussed first. Then, how these building blocks are used for the synthesis of the various (13)C enriched carotenoids and apocarotenoids are reviewed next. The synthetic Schemes that resulted in (13)C enriched beta-carotene, spheroidene, beta-cryptoxanthin, canthaxanthin, astaxanthin, (3R,3'R)-zeaxanthin and (3R,3'R,6'R)-lutein are described. The Schemes that are reviewed can also be used to synthetically access any carotenoid and apocarotenoid in any (13)C isotopically enriched form up to the unitarily enriched form. PMID- 22428114 TI - Superlative carotenoids. AB - A selection of carotenoids beyond normal appearance or properties has been presented at the 16(th) International Symposium on Carotenoids. Some of the exceptional compounds shown at the conference cannot be reproduced in this proceeding since they have not yet been published. In addition, editorial space limitation does not allow illustrating all of the previously mentioned carotenoids. PMID- 22428115 TI - Are lycopene metabolites metabolically active? AB - Lycopene is the most abundant carotenoid found in tomatoes and thus has been touted as the bioactive component for the reduced risk of chronic diseases such as prostate cancer. We and others hypothesize that lycopene metabolites are responsible for positively modulating biomarkers and risk factors for the prevention of chronic diseases. Lycopene metabolites circulate in serum and accumulate in tissues at concentrations equivalent to bioactive retinoids. Recent studies report that lycopene metabolites reduce the proliferation of cancer cells, induce apoptosis, enhance gap junction communication between cells, alter normal cell cycle progression, and modulate androgen signaling pathways. Here we review recent literature and provide new evidence to suggest that lycopene metabolites may be bioactive at physiological concentrations. PMID- 22428116 TI - A multicarotenoid beadlet for human nutrition - proof of concept of in vitro timed release. AB - Since the 1980's when the predominate focus of study and use of carotenoids in human nutritional formulations was solely on beta-carotene, there has been a steady increase in research aimed to understand the role of a wide variety of carotenoids in human health. This work has increasingly demonstrated the benefits of a number of carotenoids, and there has been a corresponding increase in the number of carotenoids provided in nutritional supplements (multicarotenoids). Numerous published observations in both human and animal studies suggest significant interaction and competition between various carotenoids during absorption and metabolism, resulting in the inhibition of uptake of one over the other. This competition has the end result of reducing the beneficial effects of the inhibited carotenoid. To limit such competition and maximize carotenoid uptakes, a layered beadlet was designed to release a defined ratio of carotenoids sequentially. Preliminary dissolution testing is presented showing the release profile in simulated digestive conditions of a combination of beta-carotene, alpha carotene, lutein, zeaxanthin, lycopene and astaxanthin derived from natural sources. Comparison is made to an immediate release beadlet formulation using the same combination of carotenoids. These results will be used to guide proof of concept clinical testing for effectiveness in humans. PMID- 22428117 TI - Unique carotenoid lactoside, P457, in Symbiodinium sp. of dinoflagellate. AB - The dinoflagellates are a large group of unicellular alge in marine and fresh water. Some are an endosymbiont of marine animals. Photosynthetic dinoflagellates have peridinin, a light-harvesting carotenoid. In addition, a unique carotenoid, P457, was found from Amphinidium. The presence of P457 in Symbiodinium derived from marine animals has not been reported. We reconfirmed the molecular structure of P457, a neoxanthin-like carotenoid with an aldehyde group and a lactoside, from Symbiodinium sp. NBRC 104787 isolated from a sea anemone. In addition, we investigated the distribution of P457 and peridinin in various Symbiodinium and scleractinian coral species, and possible biosynthetic pathways of these carotenoids are proposed. PMID- 22428118 TI - alpha-Carotene and its derivatives have a sole chirality in phototrophic organisms? AB - Carotenoids in eukaryotic phototrophic organisms can be classified into two groups; beta-carotene and its derivatives, and alpha-carotene and its derivatives. We re-examined distribution of alpha-carotene and its derivatives among various taxa of aquatic algae (17 classes) and land plants. alpha-carotene and its derivatives were found from Rhodophyceae (macrophytic type), Cryptophyceae, Euglenophyceae, Chlorarachniophyceae, Prasinophyceae, Chlorophyceae, Ulvophyceae, Charophyceae, and land plants, while they could not be detected from Glaucophyceae, Rhodophyceae (unicellular type), Chryosophyceae, Raphidophyceae, Bacillariophyceae, Phaeophyceae, Xanthophyceae, Eustigmatophyceae, Haptophyceae, and Dinophyceae. We also analyzed the chirality of alpha-carotene and/or its derivatives, such as lutein and siphonaxanthin, and found all of them had only (6'R)-type, not (6'S)-type. PMID- 22428119 TI - Light distributions on the retina: relevance to macular pigment photoprotection. AB - Light exposure has been implicated in age-related macular degeneration (AMD). This study was designed to measure cumulative light distribution on the retina to determine whether it peaked in the macula. An eye-tracker recorded the subject's field of view and pupil size, and superimposed the gaze position. Fifteen naive subjects formed a test group; 5 formed a control group. In phase 1, all subjects viewed a sequence of photographic images. In phase 2, the naive subjects observed a video; in phase 3, they performed computer tasks; in phase 4, the subjects walked around freely. In phase 1, control subjects were instructed to gaze at bright features in the field of view and, in a second test, at dark features. Test group subjects were allowed to gaze freely for all phases. Using the subject's gaze coordinates, we calculated the cumulative light distribution on the retina. As expected for control subjects, cumulative retinal light distributions peaked and dipped in the fovea when they gazed at bright or dark features respectively in the field of view. The light distribution maps obtained from the test group showed a consistent tendency to peak in the macula in phase 3, a variable tendency in phase 4, but little tendency in phases 1 and 2. We conclude that a tendency for light to peak in the macula is a characteristic of some individuals and of certain tasks. In these situations, risk of AMD could be increased but, at the same time, mitigated by the presence of macular carotenoids. PMID- 22428120 TI - Exceptional molecular organization of canthaxanthin in lipid membranes. AB - Canthaxanthin (beta,beta-carotene 4,4' dione) used widely as a drug or as a food and cosmetic colorant may have some undesirable effects on human health, caused mainly by the formation of crystals in the macula lutea membranes of the retina of an eye. Experiments show the exceptional molecular organization of canthaxanthin and a strong effect of this pigment on the physical properties of lipid membranes. The most striking difference between canthaxanthin and other macular pigments is that the effects of canthaxanthin at a molecular level are observed at much lower concentration of this pigment with respect to lipid (as low as 0.05 mol%). An analysis of the molecular interactions of canthaxanthin showed molecular mechanisms such as: strong van der Waals interactions between the canthaxanthin molecule and the acyl chains of lipids, restrictions to the segmental molecular motion of lipid molecules, modifications of the surface of the lipid membranes, effect on the membrane thermotropic properties and finally interactions based on the formation of the hydrogen bonds. Such interactions can lead to a destabilization of the membrane and loss of membrane compactness. In the case of the retinal vasculature, it can lead to an increase in the permeability of the retinal capillary walls and the development of retinopathy. PMID- 22428121 TI - Femtosecond stimulated Raman spectroscopy of the dark S1 excited state of carotenoid in photosynthetic light harvesting complex. AB - Vibrational dynamics of the excited state in the light-harvesting complex (LH1) have been investigated by femtosecond stimulated Raman spectroscopy (FSRS). The native and reconstituted LH1 complexes have same dynamics. The nu(1) (C=C stretching) vibrational mode of spirilloxanthin in LH1 shows ultrafast high frequency shift in the S(1) excited state with a time constant of 0.3 ps. It is assigned to the vibrational relaxation of the S(1) state following the internal conversion from the photoexcited S(2) state. PMID- 22428122 TI - Polarization angle dependence of stark absorption spectra of spirilloxanthin bound to the reconstituted LH1 complexes using LH1-subunits isolated from the purple photosynthetic bacterium Rhodospirillum rubrum. AB - Reconstituted LH1 complexes were prepared using the LH1 subunit-type complexes, isolated from the purple photosynthetic bacterium Rhodospirillum (Rs.) rubrum, and purified all-trans spirilloxanthin. Stark absorption spectra of spirilloxanthin bound to both the native and reconstituted LH1 complexes were compared in different polarization angles (chi) against the external electric field. From the polarization angle dependence of the Stark absorption spectra, two angles were determined in reference to the direction of transition dipole moment (m) of spirilloxanthin: one is the change in polarizability upon photoexcitation (Deltaalpha), theta(Deltaalpha) and the other is the change in static dipole moment upon photoexcitation (DeltaMU), theta(DeltaMU). Despite the symmetric molecular structure of all-trans spirilloxanthin, its Stark absorption spectra show pronounced values of DeltaMU. This large DeltaMU values essentially caused by the effect of induced dipole moment through Deltaalpha both in the cases for native and reconstituted LH1 complexes. However, slightly different values of theta(Deltaalpha) and theta(DeltaMU) observed for the native LH1 complex suggest that spirilloxanthin is asymmetrically distorted when bound to the native LH1 complex and gives rise to intrinsic DeltaMU value. PMID- 22428123 TI - Carotenoid composition and in vitro pharmacological activity of rose hips. AB - The aim of the present study was to compare carotenoid extracts of Rose hips (Rosa canina L.) with regard to their phytochemical profiles and their in vitro anti-Helicobacter pylori (H. pylori), cytotoxic, multidrug resistance (MDR) reversal and radical scavenging activity. Carotenoid composition was investigated in the different fractionation of rose hips, using extraction methods. Six main carotenoids - epimers of neochrome, lutein, zeaxanthin, rubixanthin, lycopene, beta,beta-carotene - were identified from Rose hips by their chromatographic behavior and UV-visible spectra, which is in accordance with other studies on carotenoids in this plant material. The active principles in the carotenoid extract might differ, depending upon the extraction procedures. PMID- 22428124 TI - Modulation of the human preadipocyte mitochondrial activity by beta-carotene. AB - Increased ROS generation by the overload by metabolic substrates mitochondria paralleled by decrease of antioxidant activity are typical events found in metabolic syndrome and diabetes type 2. Metabolites of beta-carotene (BC) such as retinoic acid (RA), as well as low concentration of reactive oxygen species (ROS) modify the mitochondrial bioenergetic function. The aim of the study was to investigate the effect of beta-carotene on mitochondrial activity in human preadipocytes. BC used in concentrations, 10 or 30 uM, decreased mitochondrial membrane potential, inhibited mitochondrial respiration and decreased cellular ATP content. We conclude, that BC, the known antioxidant may decrease oxidative phosphorylation capacity of mitochondria. PMID- 22428125 TI - Application of resonance raman microscopy to in vivo carotenoid. AB - The high antioxidant activity of astaxanthin has been attracted considerable attention in these days. One of the major antioxidant activities of this carotenoid is anti-photoaging. We have been focusing our attention on this particular issue. The anti-photoaging activity should be functioning in inner skin. In this study we tried to find out the fact that astaxanthin that has been swabbed on the outer surface of the skin has really passed through and reached to the inner skin. For this purpose resonance Raman microscopy was applied to the rat skin sample on which astaxanthin was swabbed on its outer surface. Astaxanthin gives rise to a unique Raman spectrum that is characteristic of its molecular structure. Therefore, we can easily identify the presence or absence of astaxanthin in the area of the rat skin that is subjected to this spectroscopic measurement. We used 532 nm laser light for probing the resonance Raman scattering of astaxanthin. Astaxanthin shows three strong Raman lines at 1508, 1145, and 993 cm(-1). These three lines are ascribable to the C=C stretching, C-C stretching, and C-CH(3) in-plane rocking vibrational modes, respectively. We have constructed confocal Raman microscope that has the spatial resolution of ca. 500 nm. Three-dimensional mapping of the Raman spectrum of astaxanthin has been performed in order to determine its distribution in the rat skin. PMID- 22428126 TI - Northern berries as a source of carotenoids. AB - Carotenoids are bioactive substances in human diet. The aim of the study was to determine beta-carotene and xanthophylls in four berries species. An HPLC gradient elution system were used for separation and quantification of the carotenoids. The highest total carotenoid content among the berries studied was found in cloudberry (2840 MUg/100g dw), followed by blueberry (2140 MUg/100 g). All berries had lutein but it was a predominant carotenoid in blueberry. The highest beta-carotene levels were found in cloudberry (83% of total Car content). Cranberry and cowberry were the poorest sources of carotenoids. Our data will be included in the regional database of resources with the increased nutritional value. PMID- 22428127 TI - Seasonal changes of violaxanthin cycle pigment de-epoxidation in wintergreen and evergreen plants. AB - We studied carotenoids composition and the activities of the xanthophylls pigments in evergreen conifers (Abies sibirica, Juniperus communis, Picea obovata) and dwarf-shrub (Vaccinium vitis-idaea), and in wintergreen herbaceous plants (Ajuga reptans, Pyrola rotundifolia) growing near Syktyvkar (61 degrees 67(/) N 50 degrees 77(/) E). The carotenoid pool consisted mainly of following xanthophylls: lutein (70%), neoxanthin (7-10%) and a xanthophylls cycle component - violaxanthin (3-15%). Zeaxanthin and antheraxanthin were found in conifer samples collected in December-March while in other species - during all year. A direct connection between xanthophyll pigment de-epoxidation level and light energy thermal dissipation was shown only for boreal conifer species. It is proposed that zeaxanthin plays a central role in the dissipation of excess excitation energy (nonphotochemical quenching) in the antenna of photosystem II (PSII). We conclude that the increase in the extent of de-epoxidation is beneficial for the retention of PSII activity for conifers in early spring and for herbs in summer. PMID- 22428128 TI - Lycopene recovery from tomato peel under mild conditions assisted by enzymatic pre-treatment and non-ionic surfactants. AB - The tomato processing industry generates large quantities of tomato peel residues, usually creating environmental problems. These residues are a significant source of lycopene, thus providing an attractive alternative for profitable handling of these otherwise problematic by-products. The enzymatic pretreatment of these residues for lycopene recovery has already been employed, although the use of surfactants for enhancing the recovery has not been examined so far. The enzymatic pretreatment of tomato peels, using two commercially available pectinolytic enzyme preparations, was evaluated suggesting that there is an optimum pretreatment time of about 1 h, enzyme amount 250 Units/mL and no significant pH influence. Lycopene surfactant - assisted extraction was further investigated, showing that, among eight surfactants used, the most suitable was "Span 20", with an optimum ratio of 6-7 surfactant molecules per lycopene molecule. Sequential enzymatic pretreatment and surfactant-assisted extraction (30 min for each step) was evaluated leading to an improved lycopene extraction yield, with a somewhat smaller surfactant molar ratio (i.e. 4-5). In the latter case, the yield of lycopene recovery was almost four times greater compared to just 1 hr enzymatic pretreatment, and was approximately ten times greater compared to the recovery from untreated peels. Furthermore, such lipophilic compound recovery, avoiding the use of organic solvents, is environmentally attractive and ensures direct lycopene use in the food and cosmetics industries. PMID- 22428129 TI - Antioxidant capacity of crude extracts containing carotenoids from the berries of various cultivars of Sea buckthorn (Hippophae rhamnoides L.). AB - Comparative analysis of antioxidant capacity was performed using FRAP and DPPH methods on extracts containing carotenoids acquired from fruits of Sea buckthorn. The examination included nine varieties of Sea buckthorn growing in the comparative cultivation. Conducted analysis allowed to compare the antioxidant capacity with carotenoids content measured with spectrophotometric and HPLC methods. Three of the examined cultivars indicating high antioxidant activity in both, FRAP and DPPH methods, also revealed highest ('Aromatnaya') and high ('Botanicheskaya', 'Arumnyj') total carotenoids content in HPLC analysis. PMID- 22428130 TI - Content of carotenoids in roots of seventeen cultivars of Daucus carota L. AB - The aim of this study was to compare the content of carotenoids in seventeen cultivars of carrots grown in Poland. Conventional orange cultivars with rarely grown were compared: white, yellow and purple with yellow core cultivars. To determine the content of carotenoids, extracts from lyophilized carrot roots were prepared and analyzed by spectrophotometric as well as HPLC methods with DAD detector. The highest content of carotenoids was found in cultivars: 'Korund F(1)' (48 mg/100g of fresh weight) and 'Salsa F(1)' (36 mg/100g of fresh weight). The antioxidant properties of selected cultivars were compared using the DPPH method. PMID- 22428131 TI - Lycopene as a guardian of redox signalling. AB - It has been suggested that lycopene, the major carotenoid found in tomato, exhibits health-beneficial effects by virtue of its antioxidant activity. However, recent literature suggests that lycopene can actually "perform" roles independent of such capacity and involving a direct modulation of redox signalling. Reactive oxygen species are known to act as second messengers in the modulation of cellular signalling leading to gene expression changes and pharmacological responses. Lycopene may control redox-sensitive molecular targets, affecting enzyme activities and expressions and modulating the activation of MAPKs and transcription factors, such as NF-kappaB and AP-1, Nrf2. PMID- 22428132 TI - Synthesis of carotenoid-cysteine conjugates. AB - Isozeaxanthin under acidic conditions forms an allylic cation which reacts readily with thiol nucleophiles. With N-acetylcysteine as a nucleophile the products obtained are carotenoid-cysteine conjugates in which the amino acid moiety is attached to the carotenoid via sulphur in position 4. The water solubility of the products can be increased by deprotection of the amino group. The antioxidant activity of the products were examined on human liver cells under conditions of hydrogen-peroxide induced oxidative stress. PMID- 22428133 TI - Agro-food wastes utilization by Blakeslea trispora for carotenoids production. AB - The all-trans-beta-carotene is a natural pigment used in various industrial fields (food, cosmetics, pharmaceuticals, etc) and possesses the higher provitamin A activity, in respect to other carotenoids. All-trans-beta-carotene is produced industrially by chemical and biotechnological means. For beta carotene biotechnological production in industrial scale mated cultures of Blakeslea trispora, a heterothallic fungus, are mainly used. Despite the intense research for beta-carotene production by B. trispora, natural substrate utilization has not been extensively studied. Solid agro-food wastes such as cabbage, watermelon husk and peach peels from northern Greece as main carbon source into submerged B. trispora cultures for carotenoids production, was examined. The media containing only the agro-food waste (2-4) gave a biomass accumulation 7.77 +/- 0.4 g/L, while a reference medium 1 with glucose (10 g/L) gave 4.65 +/- 0.21 g/L. In another experiments series agro-food wastes were used with corn steep liquor and thiamine (media 6-8), giving a biomass accumulation and total carotenoid volumetric production 10.2 +/- 2.41 g/L and 230.49 +/- 22.97 mg/L, respectively. These are the higher values reported for solid wastes so far in respect to those obtained from a synthetic medium, with higher glucose concentration of 50 g/L where the correspondent values were 9.41 +/- 1.18 g/L and 45.63 mg/L respectively. The results support that B. trispora is able to utilize, almost equivalently, different origin agro-food wastes for carotenoids production. Furthermore, beta-carotene percentage in all examined cases was over 76%, as it was estimated by HPLC analysis, suggesting that these agro food wastes may be used for high purity, large scale beta carotene production. PMID- 22428134 TI - Violaxanthin and diadinoxanthin de-epoxidation in various model lipid systems. AB - The xanthophyll cycle is an important photoprotective process functioning in plants. One of its forms, the violaxanthin (Vx) cycle, involves interconversion between: Vx, antheraxanthin (Ax) and zeaxanthin (Zx). Another kind of the xanthophyll cycle is the diadinoxanthin (Ddx) cycle in which interconversion between Ddx and diatoxanthin (Dtx) occurs. In this study an information on molecular mechanism and regulation of these two types of the xanthophyll cycle is presented. The influence of lipids on the de-epoxidation of the xanthophyll cycle pigments was investigated, with special focus put on the significance of physical properties of the aggregates formed by inverted lipid micelles, which are necessary for activity of the xanthophyll cycle enzymes. In particular, thickness of the hydrophobic fraction of the aggregates, size of the inverted micelles, suggested by mathematical description of the structures and solubility of Vx and Ddx in various kind of lipids were studied. Obtained results show that the rate of de-epoxidation is strongly dependent on the physicochemical properties of the lipids used. The key role for enzyme activation play non-bilayer lipids and the parameters of inverted micelles such as thickness, fluidity of hydrophobic core and their diameter. The presented results show that MGDG and other non-lamellar lipids like different forms of phosphatidylethanolamine are necessary for the Vx and Ddx de-epoxidation because they provide the three-dimensional structures, which are needed for the binding of de-epoxidases and for the accessibility of Vx and Ddx to these enzymes. PMID- 22428135 TI - Zeaxanthin epoxidation - an in vitro approach. AB - Zeaxanthin epoxidase (ZE) is an enzyme operating in the violaxanthin cycle, which is involved in photoprotective mechanisms. In this work model systems to study zeaxanthin (Zx) epoxidation were developed. Two assay systems are presented in which epoxidation of Zx was observed. In these assays two mutants of Arabidopsis thaliana which have active only one of the two xanthophyll cycle enzymes were used. The npq1 mutant possesses an active ZE and is thus able to convert Zx to violaxanthin (Vx) but the violaxanthin de-epoxidase (VDE) is inactive, so that Vx cannot be converted to Zx. The other mutant, npq2, possesses an active VDE and can convert exogenous Vx to Zx under strong light conditions but reverse reaction is not possible. The first assay containing thylakoids from npq1 and npq2 mutants of A. thaliana gave positive results and high efficiency of epoxidation reaction was observed. The amount of Zx was reduced by 25%. To optimize high efficiency of epoxidation reaction additional factors facilitating both fusion of the two types of thylakoids and incorporation of Zx to their membranes were also studied. The second kind of assay contained npq1 mutant thylakoids of A. thaliana supplemented with exogenous Zx and monogalactosyldiacylglycerol (MGDG). Experiments with different proportions of Zx and MGDG showed that their optimal ratio is 1:60. In such system, due to epoxidation, the amount of Zx was reduced by 38% of its initial level. The in vitro systems of Zx epoxidation described in this paper enable analysis some properties of the ZE without necessity of its isolation. PMID- 22428136 TI - Biosynthesis of alpha- and beta-ionone, prominent scent compounds, in flowers of Osmanthus fragrans. AB - Carotenoid derived volatiles are important fragrance compounds, which contribute to the scents of flowers from diverse taxa. A famous example is represented by the flowers of Osmanthus fragrans where apocarotenoids account for more than 20% of all volatiles. In the recent years, bio-degradation of carotenoids has been shown to be an important route for apocarotenoids formation. Here, we report on the contribution the O. fragrans carotenoid cleavage dioxygenase 1 to the synthesis of the two predominant C(13)-apocarotenoids, alpha- and beta-ionone, derived from alpha-and beta-carotene, respectively. PMID- 22428137 TI - Cosmetic benefits of astaxanthin on humans subjects. AB - Two human clinical studies were performed. One was an open-label non-controlled study involving 30 healthy female subjects for 8 weeks. Significant improvements were observed by combining 6 mg per day oral supplementation and 2 ml (78.9 MUM solution) per day topical application of astaxanthin. Astaxanthin derived from the microalgae, Haematococcus pluvialis showed improvements in skin wrinkle (crow's feet at week-8), age spot size (cheek at week-8), elasticity (crow's feet at week-8), skin texture (cheek at week-4), moisture content of corneocyte layer (cheek in 10 dry skin subjects at week-8) and corneocyte condition (cheek at week 8). It may suggest that astaxanthin derived from H. pluvialis can improve skin condition in all layers such as corneocyte layer, epidermis, basal layer and dermis by combining oral supplementation and topical treatment. Another was a randomized double-blind placebo controlled study involving 36 healthy male subjects for 6 weeks. Crow's feet wrinkle and elasticity; and transepidermal water loss (TEWL) were improved after 6 mg of astaxanthin (the same as former study) daily supplementation. Moisture content and sebum oil level at the cheek zone showed strong tendencies for improvement. These results suggest that astaxanthin derived from Haematococcus pluvialis may improve the skin condition in not only in women but also in men. PMID- 22428138 TI - Carotenoid-binding proteins; accessories to carotenoid function. AB - Understanding of the widespread biological importance of carotenoids is increasing. Accompanying this is the developing recognition that the interaction of carotenoids with other molecules, such as proteins, is also essential. Here the significance of carotenoid-protein interactions with respect to biological function is reviewed for three well characterised carotenoprotein complexes; crustacyanin, the orange carotenoid protein and glutathione-S-transferase P1. In addition a preliminary report is made on the recent partial purification of an echinenone-binding protein extracted from a New Zealand sea urchin, Evechinus chloroticus. PMID- 22428139 TI - Photoprotection by carotenoids of Plantago media photosynthetic apparatus in natural conditions. AB - The study of daily changes in photosynthetic rate, of energy used in photochemical and non-photochemical processes, and of carotenoid composition aimed at evaluating the role of xanthophyll cycle (XC) in protection of hoary plantain plants (Plantago media) in nature. The leaves of sun plants differed from shade plants in terms of CO(2) exchange rate and photosynthetic pigments content. The total pool XC pigments and the conversion state increased from morning to midday in sun plants. An increase in zeaxanthin content occurred concomitantly with the violaxanthin decrease. About 80% violaxanthin was involved in conversion. The maximum of zeaxanthin in XC pigments pool was 60%. The conversion state of XC was twice as lower in shade plants than that in sun plants. The photosynthesis of sun leaves was depressed strongly at midday, but changes of maximum quantum yield of PS2 (F(v)/F(m)) were not apparent at that time. The coefficient qN (non-photochemical quenching) in the sun leaves changed strongly, from 0.3 to 0.9 as irradiance increased. The direct relation between heat dissipation and the conversion state of XC in plantain leaves was revealed. Thus, plantain leaves were found to be resistant to excess solar radiation due to activation of qN mechanisms associated with the XC de-epoxidation. PMID- 22428140 TI - Extraction and analysis of carotenoids from the New Zealand sea urchin Evechinus chloroticus gonads. AB - Sea urchin gonad (roe) is a highly valued food in Japan and North America. Gonad price is strongly influenced by quality, with appearance, especially colour being a major determinant. Previous attempts to extract a carotenoid profile from the New Zealand sea urchin species Evechinus chloroticus have been challenging due to the large amount of lipid present in the gonad. A carotenoid extraction and high performance liquid chromatography (HPLC) analysis method was developed to reduce lipid contamination by incorporating a saponification and lipid cold precipitation in the extraction procedure. This method enabled greater carotenoid purity and enhanced analysis by HPLC. Echinenone was found to be the main carotenoid present in all E. chloroticus gonads. Dark coloured gonads contained higher levels of fucoxanthin/fucoxanthinol, beta-carotene and xanthophylls such as astaxanthin and canthaxanthin. This information on the modification and deposition of carotenoids will help in the development of diets to enhance gonad colour. PMID- 22428141 TI - Excited-state dynamics of overlapped optically-allowed 1B(u)+ and optically forbidden 1B(u)- or 3A(g)- vibronic levels of carotenoids: possible roles in the light-harvesting function. AB - Pump-probe spectroscopy after selective excitation of all-trans Cars (n = 9-13) in nonpolar solvent identified a symmetry selection rule of diabatic electronic mixing and diabatic internal conversion, i.e., '1B(u)(+)-to-1B(u)(-) is allowed but 1B(u)(+)-to-3A(g)(-) is forbidden'. Kerr-gate fluorescence spectroscopy showed that this selection rule breaks down, due to the symmetry degradation when the Car molecules are being excited, and, as a result, the 1B(u)(+)-to-3A(g)(-) diabatic electronic mixing and internal conversion become allowed. On the other hand, pump-probe spectroscopy after coherent excitation of the same set of Cars in polar solvent identified three stimulated-emission components (generated by the quantum-beat mechanism), consisting of the long-lived coherent cross term from the 1B(u)(+) + 1B(u)(-) or 1B(u)(+) + 3A(g)(-) diabatic pair and incoherent short-lived 1B(u)(+) and 1B(u)(-) or 3A(g)(-) split incoherent terms. The same type of stimulated-emission components were identified in Cars bound to LH2 complexes, their lifetimes being substantially shortened by the Car-to-BChl singlet-energy transfer. Each diabatic pair and its split components appeared with high intensities in the first component. The low-energy shifts of the 1B(u)(+)(0), 1B(u)(-)(0) and 3A(g)(-)(0) levels and efficient triplet generation were also found. PMID- 22428142 TI - Can macular xanthophylls replace cholesterol in formation of the liquid-ordered phase in lipid-bilayer membranes? AB - Lateral organization of membranes made from binary mixtures of dimyristoylphosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC) and macular xanthophylls (lutein or zeaxanthin) was investigated using the saturation-recovery (SR) EPR spin-labeling discrimination by oxygen transport (DOT) method in which the bimolecular collision rate of molecular oxygen with the nitroxide spin label is measured. This work was undertaken to examine whether or not lutein and zeaxanthin, macular xanthophylls that parallel cholesterol in its function as a regulator of both membrane fluidity and hydrophobicity, can parallel other structural functions of cholesterol, including formation of the liquid-ordered phase in membranes. The DOT method permits discrimination of different membrane phases when the collision rates (oxygen transport parameter) differ in these phases. Additionally, membrane phases can be characterized by the oxygen transport parameter in situ without the need for separation, which provides information about the dynamics of each phase. In gel-phase membranes, two coexisting phases were discriminated in the presence of macular xanthophylls namely, the liquid-ordered-like and solid-ordered-like phases. However, in fluid phase membranes, xanthophylls only induce the solitary liquid-ordered-like phase, while at similar concentrations, cholesterol induces coexisting liquid-ordered and liquid-disordered phases. No significant differences between the effects of lutein and zeaxanthin were found. PMID- 22428143 TI - Variations in xanthophyll composition in etiolated seedlings of Arabidopsis thaliana correlate with protochlorophyllide accumulation. AB - Protochlorophyllide (Pchlide) accumulation and xantophyll composition were studied in 5-day old etiolated seedlings of three ecotypes of Arabidopsis thaliana: Columbia (Col-0), Landsberg erecta (Ler) and Wassiliewska (Ws). The total Pchlide level as measured by fluorescence spectroscopy varied significantly between ecotypes. A rapid HPLC method revealed quantitative differences in carotenoid composition. It was found that in the Ler ecotype any enhanced accumulation of Pchlide correlates with an increased level of lutein, suggesting the role of enzymes involved in lutein synthesis in cross-regulation between chlorophyll and carotenoid biosynthetic pathways. The function of the dark accumulated carotenoid pool in seedling de-etiolation is discussed. PMID- 22428144 TI - Comparison of dietary supplementation with lutein diacetate and lutein: a pilot study of the effects on serum and macular pigment. AB - The responses of subjects taking a 20 mg/day lutein diacetate supplement were compared with that for a 20 mg/day crystalline lutein or a placebo. Ten subjects, assigned to each of three groups, lutein diacetate (group 1), lutein (group 2), and a placebo (group 3), were supplemented for 24 weeks. Groups 1 and 2 consumed a dose equivalent to 20 mg per day of free lutein. Serum samples, collected at baseline, and at weeks 6, 12, 18, and 24 were analyzed by HPLC. Macular Pigment Optical Density (MPOD) was obtained by heterochromatic flicker photometry at baseline and weeks 6, 12, 18 and 24. RESULTS: The average serum lutein concentrations for weeks 6 to 24 expressed as a ratio to the baseline value (+/ S.D.) were 5.52 +/- 2.88 for group 1, 4.43 +/- 1.61 for group 2, and 1.03 +/- 0.25 for group 3. The median rate of macular pigment increase (milli-absorbance units/week) for groups 1, 2, and 3 were 2.35, 1.55, and 0.19 mAU/wk, respectively. P-values for these serum and MPOD increases are both highly significant when compared to placebo. The average serum response was about 25% higher for group 1 compared with group 2 and, the median MPOD response was 52% higher for group 1 than group 2. P-values calculated for the differences in these increases were, p = 0.066, marginally significant, for serum, and p = 0.09 approaching significance, for MPOD. PMID- 22428145 TI - EPR study of thylakoid membrane dynamics in mutants of the carotenoid biosynthesis pathway of Synechocystis sp. PCC6803. AB - EPR spectroscopy using 5-doxylstearic acid (5-SASL) and 16-doxylstearic acid (16 SASL) spin probes was used to study the fluidity of thylakoid membranes. These were isolated from wild type Synechocystis and from several mutants in genes encoding selected enzymes of the carotenoid biosynthesis pathway and/or acyl lipid desaturases. Cyanobacteria were cultivated at 25 degrees C and 35 degrees C under different light regimes: photoautotrophically (PAG) and/or in light activated heterotrophic conditions (LAHG). The relative fluidity of membranes was estimated from EPR spectra based on the empirical outermost splitting parameter in a temperature range from 15 degrees C to 40 degrees C. Our findings demonstrate that in native thylakoid membranes the elimination of xanthophylls decreased fluidity in the inner membrane region under optimal growth conditions (25 degrees C) and increased it under sublethal heat stress (35 degrees C). This indicated that the overall fluidity of native photosynthetic membranes in cyanobacteria may be influenced by the ratio of polar to non-polar carotenoid pools under different environmental conditions. PMID- 22428146 TI - Orientation of lutein in a lipid bilayer - revisited. AB - Lutein is present in the human retina and lens, where it plays a protective role. As lutein is associated with the lipid matrix of biomembranes, the role depends on its membrane location. Experimental studies predicted two orientations of lutein in a phosphatidylcholine (PC) bilayer: vertical and horizontal. Using a molecular dynamics simulation, we observed, in two different PC bilayers, both orientations of lutein, and in each bilayer, a single change from vertical to horizontal orientation or vice versa. Both orientations were stabilized by hydrogen bonding of lutein OH groups with mainly carbonyl but also phosphate oxygen atoms of PC. PMID- 22428147 TI - Partial synthesis of serum carotenoids and their metabolites. AB - Human serum and tissues contain in excess of 12 dietary carotenoids and several metabolites that originate from consumption of fruits and vegetables. Among these are hydroxycarotenoids: (3R,3'R,6'R)-lutein (1), (3R,3'R)-zeaxanthin (2), (3R,6'R)-alpha-cryptoxanthin (3), and (3R)-beta-cryptoxanthin (4). In addition, several dehydration products of 1 have also been identified in human serum, these are: (3R,6'R)-3-hydroxy-3',4'-didehydro-beta,gamma-carotene (5), (3R,6'R)-3 hydroxy-2',3'-didehydro-beta,epsilon-carotene (6), and (3R)-3-hydroxy-3',4' didehydro-beta,beta-carotene (7). Several metabolites of 1 and/or 2, namely, (3R,3'S,6'R)-lutein (3'-epilutein, 8) and (3R,3'S;meso)-zeaxanthin (9) have also been characterized in human serum and ocular tissues. Semi-synthetic processes have been developed that separately transform commercially available 1 into 4 via 7 as well as 1 into 8. While 8 is converted into 2 by base-catalyzed isomerization, 7 is transformed into 2 and its (3R,3'S;meso)-stereoisomer (9) by regioselective hydroboration. PMID- 22428148 TI - Structural aspects of the antioxidant activity of lutein in a model of photoreceptor membranes. AB - It was shown that in membranes containing raft domains, the macular xanthophylls lutein and zeaxanthin are not distributed uniformly, but are excluded from saturated raft domains and about ten times more concentrated in unsaturated bulk lipids. The selective accumulation of lutein and zeaxanthin in direct proximity to unsaturated lipids, which are especially susceptible to lipid peroxidation, could be very important as far as their antioxidant activity is concerned. Therefore, the protective role of lutein against lipid peroxidation was investigated in membranes made of raft-forming mixtures and in models of photoreceptor outer segment membranes and compared with their antioxidant activity in homogeneous membranes composed of unsaturated lipids. Lipid peroxidation was induced by photosensitized reactions using rose Bengal and monitored by an MDA-TBA test, an iodometric assay, and oxygen consumption (using EPR spectroscopy and the mHCTPO spin label as an oxygen probe). The results show that lutein protects unsaturated lipids more effectively in membranes made of raft-forming mixtures than in homogeneous membranes. This suggests that the selective accumulation of macular xanthophylls in the most vulnerable regions of photoreceptor membranes may play an important role in enhancing their antioxidant properties and ability to prevent age-related macular diseases (such as age related macular degeneration (AMD)). PMID- 22428149 TI - Antioxidant effects of carotenoids in a model pigment-protein complex. AB - The effect of carotenoids on stability of model photosynthetic pigment-protein complexes subjected to chemical oxidation with hydrogen peroxide or potassium ferricyanide was investigated. The oxidation of carotenoid-less and carotenoid containing complexes was conducted in the presence or absence of ascorbic acid. The progress of the reactions was monitored by use of absorption and fluorescence spectroscopy. Our results show that carotenoids may significantly enhance the stability of photosynthetic complexes against oxidation and their protective (antioxidant) effect depends on the type of the oxidant. PMID- 22428150 TI - Atomic force microscopy studies of the adhesive properties of DPPC vesicles containing beta-carotene. AB - A role of carotenoids as modulators of physical properties of model and biological membranes has been already postulated. However, there is a lack of information on the influence of these pigments on interactions between the lipids which form such membranes. This paper applies atomic force microscopy (AFM) in to study the effects of beta-carotene on the adhesion properties of DPPC multilamellar liposomes. This allowed us to gain, for the first time, a direct insight into the interactions between the components in model systems on a molecular level. We observe that the adhesive forces in DPPC multilamellar liposomes containing 1mol% of beta-carotene decrease exponentially with increasing temperature, and that at about 37 degrees C they diminish. In the case of pure liposomes the decline in adhesion is of a different nature and the adhesive forces disappear at 34 degrees C. The adhesive forces are about 5 times higher at 31 degrees C in the presence of beta-carotene than in its absence. However, measurements using differential scanning calorimetry (DSC) showed a shift of the lamellar-to-undulled-lamellar phase transition toward lower temperatures by about 0.8 +/- 0.2 degrees C in a system containing beta-carotene. The enthalpy changes (DeltaH) of this transition are similar for both systems. For the main transition, gel-to-liquid crystalline, the peak is shifted by about 0.5 +/- 0.1 degrees C, and DeltaH decreases by about 30% in liposomes treated with beta-carotene in comparison to pure liposomes. Our results suggest increased cooperation between liposome components in a system with enriched beta-carotene, which cause a change in phase transition temperatures. Moreover, these interactions are very sensitive to temperature. PMID- 22428151 TI - Interactions of dietary carotenoids with singlet oxygen (1O2) and free radicals: potential effects for human health. AB - The dietary carotenoids provide photoprotection to photosynthetic organisms, the eye and the skin. The protection mechanisms involve both quenching of singlet oxygen and of damaging free radicals. The mechanisms for singlet oxygen quenching and protection against free radicals are quite different - indeed, under some conditions, quenching of free radicals can lead to a switch from a beneficial anti-oxidant process to damaging pro-oxidative situation. Furthermore, while skin protection involves beta-carotene or lycopene from a tomato-rich diet, protection of the macula involves the hydroxyl-carotenoids (xanthophylls) zeaxanthin and lutein. Time resolved studies of singlet oxygen and free radicals and their interaction with carotenoids via pulsed laser and fast electron spectroscopy (pulse radiolysis) and the possible involvement of amino acids are discussed and used to (1) speculate on the anti- and pro-oxidative mechanisms, (2) determine the most efficient singlet oxygen quencher and (3) demonstrate the benefits to photoprotection of the eye from the xanthophylls rather than from hydrocarbon carotenoids such as beta-carotene. PMID- 22428152 TI - Detection and quantification of traces of bisphenol A and bisphenol S in paper samples using analytical pyrolysis-GC/MS. AB - In this paper a simplified method based on analytical pyrolysis gas chromatography mass spectrometry (Py-GC/MS) for the detection and quantification of bisphenol A and bisphenol S in paper samples is presented. The method enables a direct analysis of the samples without tedious sample preparation. As the analytes are thermally desorbed, a solvent extraction is not needed. The method is applicable to small samples of ~120 MUg. The limits of detection are below 1 mg kg(-1) for bisphenol A and for bisphenol S. The limits of quantification are about 1.3 mg kg(-1). Several validation characteristics of the method developed like standard error of calibration, limit of determination, linearity, and accuracy are given. To prove the accuracy of the method, interferences and matrix dependencies were also investigated. The influence of the pyrolysis crucibles, a special effect of analytical pyrolysis, was additionally investigated. It was found that the impact of the crucibles on the results is significant and one cause for matrix effects. PMID- 22428153 TI - Size-exclusion SPR sensor chip: application to detection of aggregation and disaggregation of biological particles. AB - We propose a novel surface plasmon resonance (SPR) sensor chip with a microfabricated slit array. The microslit excludes micrometre-size objects larger than its slit size from the SPR sensing area, so that it functions as an in situ filter. We demonstrated the sensing of microparticles of different diameters using the chip, and the results show a successful size-exclusion effect. As a demonstration of the biological application, we performed the detection of aggregation and disaggregation of biological particles using sugar-chain immobilized gold nanoparticles as a test sample. PMID- 22428154 TI - Comprehensive HILIC * RPLC with mass spectrometry detection for the analysis of saponins in Panax notoginseng. AB - A comprehensive off-line two-dimensional liquid chromatography (2D-LC) method coupling hydrophilic interaction liquid chromatography (HILIC) and reversed phase liquid chromatography (RPLC) was developed in this study to detect as many saponins as possible in extracts of Panax notoginseng. The orthogonality of the 2D HILIC * RPLC was up to 81%, and the peak capacity was 10200. In total, 224 saponins were found, and some of them were trace amounts. Besides, a screening table designed by adding molecular weights of possible aglycones and sugars was constructed to help rapidly characterize the saponins using MS information. Unfortunately, the structure of saponins could not be identified by using only MS information. PMID- 22428155 TI - Ultrasensitive electrochemiluminescence immunosensor using PtAg@carbon nanocrystals composites as labels and carbon nanotubes-chitosan/gold nanoparticles as enhancer. AB - An ultrasensitive electrochemiluminescence (ECL) immunosensor was developed using PtAg@carbon nanocrystals (CNCs) as excellent labels based on carbon nanotubes chitosan/AuNPs (CNT-CHIT/AuNPs) composite modified screen-printed carbon electrodes (SPCEs) for prostate protein antigen (PSA) detection. The CNCs were obtained simply by electro-oxidation of graphite with abundant carboxyl groups at their surfaces. The PtAg bimetallic nanocomposites with hierarchically hollow structures were fabricated through simple replacement reaction using dealloyed nanoporous silver (NPS) as both a template and reducing agent. Structure characterization was obtained by means of transmission electron microscope (TEM) and scanning electron microscope (SEM) images. The PtAg@CNCs composites exhibit a 6 times higher ECL intensity than the pure CNCs labeled anti-PSA. The as-prepared CNT-CHIT/AuNPs composite can attach more antibody than pure CNTs. Due to the dual amplification techniques, the concentrations of PSA were obtained in the range from 1 pg mL(-1) to 50 ng mL(-1) with a detection limit of 0.6 pg mL(-1). Finally, the as-proposed ECL immunosensor has the advantages of high sensitivity, specificity and stability and could become a promising technique for tumor marker detection. PMID- 22428156 TI - Targeting carbon nanotubes against cancer. AB - The use of carbon nanotubes (CNTs) as polyvalent tools for cancer treatment is progressing at a very fast pace. The most promising approach is the targeted delivery of drugs, designed to selectively direct the therapeutic treatment towards the tumours. CNTs may offer several advantages to overcome one of the main limitations of most existing anticancer therapies, namely the lack of selectivity. Herein, an account of the existing literature on CNT-based nanomedicine for cancer treatment is given. The most significant results obtained so far in the field of drug delivery are presented for many anticancer chemotherapeutics (doxorubicin, methotrexate, taxanes, platinum analogues, camptothecine and gemcitabine), but also for immunotherapeutics and nucleic acids. Moreover, the alternative anticancer therapies based on thermal ablation and radiotherapy are discussed. The attention throughout the review is focused on the different targeting strategies proposed so far, mainly based on antibodies, but also on other specifically recognised molecules or on the application of an external magnetic field. PMID- 22428157 TI - High-spin versus spin-crossover versus low-spin: geometry intervention in cooperativity in a 3D polymorphic iron(II)-tetrazole MOFs system. AB - Reported here are three 3D metal-organic framework (MOF) polymorphs with the chemical formula [Fe(2)(H(0.67)bdt)(3)].xH(2)O (H(2)bdt = 5,5'-(1,4 phenylene)bis(1H-tetrazole)), all of which are constructed from similar Fe(II) tetrazole rod secondary building units (SBUs) via covalent links, but exhibit diverse spin states regulated by inter-chain cooperativity. PMID- 22428158 TI - Toward highly-effective and sustainable hydrogen production: bio-ethanol oxidative steam reforming coupled with water splitting in a thin tubular membrane reactor. AB - Highly-effective sustainable hydrogen production from ethanol and water was achieved in a tubular dense mixed-conducting oxygen permeable membrane reactor, in which water splitting took place at the tube side of the membrane and oxidative steam reforming of ethanol occurred at the shell side simultaneously. PMID- 22428159 TI - Potent divalent inhibitors with rigid glucose click spacers for Pseudomonas aeruginosa lectin LecA. AB - The synthesis of a new rigid spacer based on carbohydrate-triazole repeating units and their incorporation into divalent systems is described. Inhibition studies showed that a well-matched system with a rigid spacer with flexible ends leads to the most potent inhibition of Pseudomonas aeruginosa lectin LecA. PMID- 22428160 TI - Unique nanoscale {Cu(II)36Ln(III)24} (Ln = Dy and Gd) metallo-rings. AB - Two unprecedented 3d-4f hexagonal metallo-rings {Ln(24)Cu(36)} (Ln = Dy and Gd) with a diagonal dimension of about 4.6 nm were facilely synthesized by self assembly of Cu(II), Ln(III) nitrates and benzoate in the presence of triethylamine. Magnetic studies show slow relaxation behaviour for the dysprosium analogue and a large magnetocaloric effect (MCE) for the gadolinium analogue. PMID- 22428161 TI - Concatenation of reversible electronic energy transfer and photoinduced electron transfer to control a molecular piston. AB - Reversible electronic energy transfer and photoinduced electron transfer conspire in the light-driven dethreading of a molecular piston, showing the potential of combining these processes in supramolecular systems. PMID- 22428162 TI - Rapid determination of the optical and redox properties of a metal-organic framework via in situ solid state spectroelectrochemistry. AB - The optical properties of [Zn(2)(NDC)(2)(DPNI)](0/-/2-) (NDC = 2,7-naphthalene dicarboxylate, DPNI = N,N'-di(4-pyridyl)-1,4,5,8-naphthalenetetracarboxydiimide), a redox-active metal-organic framework, have been examined using a simple and robust in situ solid state UV-Vis-NIR spectroelectrochemical technique. PMID- 22428163 TI - Mapping the location of grafted PNIPAAM in mesoporous SBA-15 silica using gas adsorption analysis. AB - The thermoresponsive polymer poly-N-isopropylacrylamide (PNIPAAM) was grafted in mesoporous SBA-15 silica. The grafting process consists of three steps: (i) increasing the amount of surface silanol groups of SBA-15 by hydroxylation, (ii) attachment of an anchor (1-(trichlorosilyl)-2-(m/p-(chloromethylphenyl)ethane) and finally (iii) the polymerization of the monomers (NIPAAM) onto the anchor. After each step, the materials were characterized regarding the porosity, using inert gas (argon, nitrogen) physisorption measurements. Also, the structure was investigated by small-angle X-ray diffraction analysis and thermogravimetric analysis was used for determination of the amount of grafted material. A total of 17% by weight of organic material was introduced in the porous host and the structure was preserved during the grafting process. Physisorption measurements revealed that the anchor is mainly located in the intrawall pores present in SBA 15. Consequently, the polymer is preferentially located in the intrawall pores or in the vicinity thereof. The final mesopore volume is 0.47 cm(3) g(-1) as compared to 0.96 cm(3) g(-1) for the pure SBA-15. The surprisingly large loss of mesopore volume and an almost constant mesopore diameter is consistent with a partial sealing of the mesopore volume in the composite materials. The potential thermocontrol combined with the large mesoporosity and the possible "storage space" provided by the sealed mesopore volume leads to a material with possibilities for various applications. PMID- 22428164 TI - The science of dispersing carbon nanotubes with surfactants. AB - Self-assembled structures adsorbed on carbon nanotubes and other nanofibres offer a plethora of opportunities to endow them with new functions and to integrate them into devices and materials. At the same time they are key to solve the greatest problem in carbon nanotube utilisation--debundling and individualisation. Success will inevitably require an understanding of the underlying structure-function relationship of the adsorbed surfactant layer. Computer simulations are ideally suited to develop this understanding as they enable us to study the structure-function relationship in great detail. Combining the results from mesoscale and atomistic simulations we begin to develop this understanding and derive a number of recommendations for optimal dispersion design. PMID- 22428165 TI - A modified two-sphere model for solvent reorganization energy in electron transfer. AB - In this work, the solvent reorganization energy is formulated within the framework of classical thermodynamics, by adding some external charges to construct a constrained equilibrium state. The derivation clearly shows that the reorganization energy is exactly the polarization cost for the inertial part of the polarization. We perform our derivation just within the framework of the first law of thermodynamics, and the final form of the reorganization energy is completely the same as that we gave in our recent work by defining a nonequilibrium solvation free energy. With the two-sphere model approximation, our solvent reorganization energy is derived as lambda(0) = Deltaq(2)/2[1/r(D) + 1/r(A) - 2/d][(epsilon(-1)(op) - epsilon(-1)(s))/(1 - epsilon(-1)(s))]. This amends Marcus' model by a factor of (epsilon(-1)(op) - epsilon(-1)(s))/(1 - epsilon(-1)(s)), which is coupled with the solvent polarity. Making use of the modified expression of solvent reorganization energy, two recently reported electron transfer processes are investigated in representative solvents. The results show that our formula can well reproduce the experimental observations. PMID- 22428166 TI - In situ X-ray Raman spectroscopy of LiBH4. AB - X-Ray Raman Spectroscopy (XRS) is used to study the electronic properties of bulk lithium borohydride (LiBH(4)) and LiBH(4) in porous carbon nano-composites (LiBH(4)/C) during dehydrogenation. The lithium (Li), boron (B) and carbon (C) K edges are studied and compared with calculations of the starting material and intermediate compounds. Comparison of the B and C K-edge XRS spectra of the as prepared samples with rehydrogenated samples shows that the B and C electronic structure is largely regained after rehydrogenation. Both Li and C K-edge spectra show that during dehydrogenation, part of the Li intercalates into the porous carbon. This study shows that XRS in combination with calculations is a promising tool to study the electronic properties of nano-crystalline light-weight materials for energy storage. PMID- 22428167 TI - Physicochemical perspective of cyclodextrin nano and microaggregates. AB - ''Chemistry beyond the molecule'' is the nickname for supramolecular chemistry. This branch of study is based on molecular recognition that is host-guest chemistry. A number of potential hosts have been defined and applied in scores of studies. Among all potential hosts, cyclodextrins occupy a high position due to their characteristic solubilisation capability and biocompatibility. In the present article we are revisiting the host-guest aspects of cyclodextrins from a physicochemical perspective. We present details of formation and applications of cyclodextrin nanoaggregates induced by guest molecules, the concerned thermodynamics behind the process and also the effect of concentration of the guest molecules on the morphology of the aggregates. This article reviews the topic mainly from the spectroscopic point of view. PMID- 22428168 TI - AFTD: Making Connections and Building Resources. PMID- 22428169 TI - Introduction to Papers of the Caregiver Session. PMID- 22428170 TI - Coercing bisphosphonates to kill cancer cells with nanoscale coordination polymers. AB - Nanoscale coordination polymers containing exceptionally high loadings of bisphosphonates were coated with single lipid bilayers to control the drug release kinetics and functionalized with a targeting ligand to endow cell targeting capability, leading to much enhanced cytotoxicity against human lung and pancreatic cancer cells. PMID- 22428171 TI - The challenge of dyskinetic cerebral palsy. PMID- 22428172 TI - The Dyskinesia Impairment Scale: a new instrument to measure dystonia and choreoathetosis in dyskinetic cerebral palsy. AB - AIM: The aim of this study was to examine the reliability and validity of the Dyskinesia Impairment Scale (DIS). The DIS consists of two subscales: dystonia and choreoathetosis. It measures both phenomena in dyskinetic cerebral palsy (CP). METHOD: Twenty-five participants with dyskinetic CP (17 males; eight females; age range 5-22y; mean age 13y 6mo; SD 5y 4mo), recruited from special schools for children with motor disorders, were included. Exclusion criteria were changes in muscle relaxant medication within the previous 3 months, orthopaedic or neurosurgical interventions within the previous year, and spinal fusion. Interrater reliability was verified by two independent raters. For interrater reliability, intraclass correlation coefficients were assessed. Standard error of measurement, the minimal detectable difference, and Cronbach's alpha for internal consistency were determined. For concurrent validity of the DIS dystonia subscale, the Barry-Albright Dystonia Scale was administered. RESULTS: The intraclass correlation coefficient for the total DIS score and the two subscales ranged between 0.91 and 0.98 for interrater reliability. The reliability of the choreoathetosis subscale was found to be higher than that of the dystonia subscale. The standard error of the measurement and minimal detectable difference values were adequate. Cronbach's alpha values ranged from 0.89 to 0.93. Pearson's correlation between the dystonia subscale and Barry-Albright Dystonia Scale was 0.84 (p<0.001). INTERPRETATION: Good to excellent reliability and validity were found for the DIS. The DIS may be promising for increasing insights into the natural history of dyskinetic CP and evaluating interventions. Future research on the responsiveness of the DIS is warranted. PMID- 22428173 TI - Protein-protein interactions and selection: yeast-based approaches that exploit guanine nucleotide-binding protein signaling. AB - For elucidating protein-protein interactions, many methodologies have been developed during the past two decades. For investigation of interactions inside cells under physiological conditions, yeast is an attractive organism with which to quickly screen for hopeful candidates using versatile genetic technologies, and various types of approaches are now available.Among them, a variety of unique systems using the guanine nucleotide-binding protein (G-protein) signaling pathway in yeast have been established to investigate the interactions of proteins for biological study and pharmaceutical research. G-proteins involved in various cellular processes are mainly divided into two groups: small monomeric G proteins,and heterotrimeric G-proteins. In this minireview, we summarize the basic principles and applications of yeast-based screening systems, using these two types of G-protein, which are typically used for elucidating biological protein interactions but are differentiated from traditional yeast two-hybrid systems. PMID- 22428174 TI - Clearing the air around cloud computing. PMID- 22428176 TI - The TWEAK-FN14 axis: opening new doors. PMID- 22428177 TI - Letter from the chairman & CEO. PMID- 22428178 TI - Letters to the editor. PMID- 22428179 TI - Letter to editor. PMID- 22428180 TI - Unfinished business. PMID- 22428181 TI - Retigabine: fewer drug interactions. AB - There are already about a dozen antiepileptic drugs with acceptable harm-benefit balances that can be used in combination therapy for adult patients whose partial epilepsy is not adequately controlled by successive single-agent regimens. Retigabine (Trobalt, GlaxoSmithKline) has now been authorised in the European Union in this indication. Clinical evaluation is based on 3 double-blind randomised controlled trials in which either retigabine or placebo was added to an ineffective ongoing treatment. An additional 30% of patients treated with retigabine (in absolute numbers) had at least a 50% reduction in the monthly frequency of seizures. This translates to approximately 50% of patients with a reduced seizure rate as compared with about 20% of patients on placebo. Based on indirect comparisons, which must be interpreted with care, this efficacy seems similar to that of other antiepileptic drugs. Retigabine shares several adverse effects with other antiepileptic drugs, especially neuropsychiatric disorders. Retigabine can also cause urinary disorders (5%), psychotic disorders (about 6%) and urolithiasis. It also appears to prolong the QT interval. Retigabine does not interfere with major cytochrome P450 isoenzymes or with P-glycoprotein-mediated drug transport. About 30% of the ingested dose is excreted unchanged in urine. The risk of pharmacokinetic interactions is low in patients with normal renal function. In practice, retigabine is another option for second-line combination therapy in patients at high risk of drug interactions. PMID- 22428182 TI - Rituximab maintenance therapy for follicular lymphoma: no better than watchful waiting. AB - Chemotherapy is the first-choice treatment for patients with advanced follicular lymphoma (Ann Arbor stage III or IV) who qualify for therapy, but there is no consensus protocol. Adding rituximab (Mabthera, Roche) to chemotherapy moderately improves survival time. Rituximab is now authorised for long-term maintenance therapy in patients with follicular lymphoma in whom first-line chemotherapy induces a response. Clinical evaluation of rituximab in this setting is based on two unblinded randomised trials comparing rituximab maintenance therapy with watchful waiting in 1193 and 401 patients. Neither trial showed that rituximab had an impact on mortality or quality of life. Rituximab prolonged progression free survival, based on unblinded assessment of radiological, laboratory or clinical criteria. These trials suffer from biases that make it difficult to interpret the results, including the lack of blinding, premature termination and too short follow-up in the larger trial, and in the other trial, heterogeneous patient recruitment and use of a different dose regimen from that recommended in the summary of product characteristics. Both trials confirmed the adverse effect profile of rituximab, which includes haematological disorders, infections, and cardiac and digestive disorders. These adverse effects are severe in about 7% of patients. There is also a riskof musculoskeletal and neuropsychiatric disorders. Questions still persist abouta possible oncogenic effect. In practice, the benefits of long-term rituximab maintenance therapy after a first line of chemotherapy remain to be demonstrated in terms of the length or quality of survival in patients with follicular lymphoma, while adverse effects are noteworthy. Pending further data, rituximab should only be used in clinical trials in this specific setting. PMID- 22428183 TI - Rituximab maintenance therapy of relapsed or refractory follicular lymphoma, with longer follow-up: no proven impact on survival. AB - Long-term follow-up data from a clinical trial including 334 patients that compared single-agent maintenance therapy with rituximab versus watchful waiting showed no statistically significant increase in survival time among patients with relapsed or refractory follicular lymphoma. PMID- 22428184 TI - Bendamustine: inadequate or outdated data. AB - Chronic lymphocytic leukaemia (the most common form of leukaemia in adults), non Hodgkin's lymphoma and multiple myeloma are haematological malignancies. Their clinical course varies from one patient to another. Bendamustine (Levact, MA holder Astellas, French representative: Mundipharma), an alkylating agent, was authorised for first-line treatment of chronic lymphocytic leukaemia and multiple myeloma, and for second-line single-agent treatment of indolent non-Hodgkin's lymphoma. Most data on the efficacy of bendamustine as first-line treatment for chronic lymphocytic leukaemia come from a randomised unblinded trial comparing bendamustine versus chlorambucil in 312 patients. The trial was stopped prematurely (which tends to overestimate the benefits) after a median follow-up of 35 months. Median overall survival did not differ between the groups but the length of follow-up was inadequate, given the slow course of the disease. Median progression-free survival was statistically significantly longer with bendamustine (21.5 months versus 8.3 months). The overall response rate was also statistically significantly higher with bendamustine (68% versus 31%). An indirect comparison (there are no head-to-head comparisons) suggests that these results are similar to those obtained with fludarabine. In indolent non-Hodgkin's lymphoma, assessment of bendamustine is mainly based on a single uncontrolled trial. No data on overall survival were reported, ruling out conclusions as to the possible benefits of bendamustine. In multiple myeloma, assessment of bendamustine is based on an unblinded trial of bendamustine + prednisone versus melphalan + prednisone in 131 patients. This trial took place before the value of thalidomide in this setting had been shown. In addition, it suffered from many methodological flaws (study population, endpoints, etc.). Bendamustine had no advantages over melphalan. Bendamustine has many serious and potentially life threatening adverse effects, including frequent myelosuppression, infections, and secondary cancers. In practice, the efficacy of bendamustine in non-Hodgkin's lymphoma and multiple myeloma is uncertain, while its adverse effects are numerous, varied and often severe. Further trials are needed to determine the value of bendamustine in chronic lymphocytic leukaemia. PMID- 22428185 TI - Ranibizumab and diabetic macular oedema: after laser therapy. AB - Diabetic retinopathy is sometimes accompanied by macular oedema, leading to a marked decline in visual acuity. The standard treatment, in addition to glycaemic and blood pressure control, is laser photocoagulation, despite its modest efficacy. Ranibizumab (Lucentis, Novartis), a VEGF (vascular endothelial growth factor) inhibitor, was initially authorised for age-related macular degeneration (AMD) in the European Union. It is now also approved for the treatment of visual loss due to macular oedema in diabetic patients. In this setting, clinical evaluation of ranibizumab is mainly based on two double-blind randomised trials comparing ranibizumab + laser photocoagulation versus placebo + laser photo coagulation in a total of about 1000 patients. Compared with placebo, addition of ranibizumab to laser therapy led to a marked improvement in visual acuity in approximately 15% of patients after 12 months of treatment. The improvement appeared to persist after 24 months of treatment. In a trial that included a group treated with ranibizumab alone, efficacy did not differ from that of the ranibizumab + laser combination. Uncertainties remain concerning the long-term efficacy of ranibizumab and its benefits in patients with poorly controlled diabetes or proliferative retinopathy. The adverse effect profile of ranibizumab in patients with diabetic macular oedema is similar to that reported in patients with AMD, and mainly includes ocular adverse effects such as pain, bleeding and increased intraocular pressure. A risk of systemic adverse effects, particularly cardiovascular disorders, should be kept in mind in case of long-term treatment. Ranibizumab can cause birth defects, even after intravitreal injection during pregnancy. Monthly treatment with ranibizumab is inconvenient, difficult and expensive. In practice, laser therapy remains the standard treatment for diabetic patients with significantly reduced visual acuity due to macular oedema. Ranibizumab, which requires intravitreal injections, should be restricted to second-line use. PMID- 22428186 TI - Common stem: -mustine. PMID- 22428187 TI - In France, healthcare products are involved in about half of all serious adverse events related to healthcare. AB - These adverse events generally involve a drug, sometimes a medical device, and more rarely a labile blood product. PMID- 22428188 TI - NSAIDs, corticosteroids and atrial fibrillation? AB - Evidence that a number of drugs can cause atrial fibrillation has been accumulating since the 2000s. A case-control analysis of a UK general medicine database showed statistically significant increases in the risk of chronic atrial fibrillation in patients taking NSAIDs, after as little as one month of treatment. When NSAID treatment lasted more than 30 days, the incidence was 9.4%, versus 4.7% in the control group, corresponding to a relative risk (RR) of 1.57 (95% confidence interval (95% CI): 1.15 to 2.15). Similar results were found in patients with no history of heart failure. A Danish case-control study yielded similar results. In the UK case-control study, a statistically significant increase in the risk of chronic atrial fibrillation was found in patients taking corticosteroids (5% versus 1.4% in the control group, RR=2.5, 95% CI: 1.6 to 4). The risk increased with the dose. Another Danish case-control study showed that hospitalisation for atrial fibrillation or flutter was twice as frequent among patients exposed to corticosteroids. In contrast, trials in which corticosteroids were given shortly after cardiac surgery, a highly specific setting, showed a decreased risk of atrial fibrillation. In practice, the risk of atrial fibrillation should be taken into account before deciding whether or not to prescribe a corticosteroid or an NSAID, especially to a patient with known risk factors for atrial fibrillation. The heart rate of treated patients should be closely monitored. PMID- 22428189 TI - Mephenesin: anaphylactic shock and acute generalised exanthematous pustulosis. PMID- 22428190 TI - Perinatal lopinavir + ritonavir: adrenal insufficiency. PMID- 22428191 TI - Orlistat: hepatitis and oxalate nephropathy. PMID- 22428192 TI - Hypoglycaemia due to tramadol. PMID- 22428193 TI - Tramadol withdrawal symptoms in infants exposed in utero. PMID- 22428194 TI - Thalidomide and lenalidomide: overview of the French pharmacovigilance database. AB - Mainly neurological disorders associated with thalidomide, and haematological, cutaneous and respiratory disorders with lenalidomide. PMID- 22428195 TI - Strontium ranelate: too many adverse effects. PMID- 22428196 TI - Fluconazole: teratogenicity. PMID- 22428197 TI - Bleeding from ruptured oesophageal varices: propranolol for primary prevention. PMID- 22428198 TI - Oesophageal varices: a complication of portal hypertension. PMID- 22428199 TI - [Medical treatment of diabetic patients in high risk pregnancy clinic improves glycemic control prior to fertility treatment]. AB - INTRODUCTION: Diabetic women are at increased risk for spontaneous abortions and congenital anomalies. Preconception care can improve pregnancy outcome. AIM: To evaluate glycemic control in diabetic women undergoing fertility treatment, and compare between women who were treated in high risk pregnancy (HRP) clinics prior to fertility treatment and those who received usuaL care. METHODS: Retrospective study on diabetic women undergoing fertility treatment during 2008-2009 in Haifa and Western Galilee District of Clalit Health Services (CHS). Data on fertility treatments, prescription fillings, HBA1C Levels and demographic data was extracted from CHS computer Data on medical treatment in HRP clinic was retrieved from visits in the researcher clinic. We evaluated measurement and Level of HBA1C within 3 months of fertility treatment; and compared it between the two groups. RESULTS: There were 230 fertility treatment cycles in 83 diabetic women; 10 women were treated in the HRP clinic. Median HBA C was significantly lower 6.1% in the HRP group compared to 7.1% in women who received usual care (P < 0.05]. HBA1C Level was recorded within 3 months of fertility treatment in 84.2% of cycles in the HRP group compared to 52.6% of cycles in the usual care group (P < 0.05). Furthermore, HBA1C < 7.0% was found in 68.4% of cycles in women in the HRP clinic compared to only 24.0% of cycles in the other group [P < 0.05). CONCLUSIONS: The medical care of diabetic women undergoing fertility treatment needs improvement. Many women undergo fertility treatment despite poor glycemic control. Referral to HRP clinic improves diabetic control and can improve pregnancy outcome. PMID- 22428200 TI - [The impact of changing the approach of performing episiotomy on perineal trauma in primiparous: a comparison between two periods with different episiotomy rates]. AB - BACKGROUND: The purpose of this study was to evaluate the impact of changing the approach of performing episiotomy on immediate delivery complications in primiparous women by comparing two periods of time with different episiotomy rates. MATERIALS AND METHODS: A retrospective population-based study comparing singleton vaginaL deliveries of nulliparous women for immediate delivery complications during two periods of time: 9192 women during 1994-1999 (period A) with episiotomy rates of 80%-90% and 11,150 women during 2002-2009 (period B) with episiotomy rates of 20%-30%. RESULTS: The study included 20,342 vaginal deliveries. First and second degree perineal tears rate was significantly higher during period B than period A (37.5% vs. 5.8%, p < 0.00). Third degree perineal tears were four times more prevalent in period B than in period A [0.4% vs. 0.1%, p < 0.0001). First and second degree perineal tears rate was significantly higher in women not undergoing episiotomy in both periods. Multiple logistic regression analysis reveals that episiotomy is a significant predictor for first and second degree perineal tears (OR = 0.1, p < 0.001) but not for third degree perineal tears. CONCLUSIONS: Since spontaneous first and second degree perineal tears entail no significant morbidity, it is better to manage uncomplicated deLiveries in primiparous women without the use of episiotomy. PMID- 22428201 TI - [Characteristics of pregnancy and delivery of fetuses affected by either central nervous system malformations or chromosomal abnormalities]. AB - OBJECTIVE: To determine whether fetuses affected by either chromosomal abnormalities or central nervous system (CNS) malformations are prone to complications during pregnancy and delivery. STUDY DESIGN: In this study, 320 singleton pregnancies with CNS malformations and 133 singleton pregnancies with chromosomal abnormaLities were compared with 149,112 singleton births without any known congenital anomalies. Exclusion criteria were: births with other congenital anomalies or malformations, pregnancies Lacking prenatal care and multiple pregnancies. Data was obtained using the computerized birth discharge records. The statistical analysis was performed with the SPSS package. RESULTS: There were no statistically significant differences in maternal age, ethnicity, uterine anomalies or parity. The ratio of general anesthesia was almost double in the study groups compared to the control group: 25% in the CNS malformation group (RR 2.617, CI 2.031-3.372) and 25.6% in the chromosomal abnormality group (RR 2.696, CI 1.825-3.982) and 11.3% in the control group (p < 0.001). There were nearly double cesarean sections (CS) rates in both study groups: 21.5% in the CNS malformation group, 20.3% in the chromosomal abnormaLity group and 12% in the control group. A logistic regression model that included previous CS, maLpresentation, non-reassuring fetal heart monitor (NRFHR) and presence of a malformation, concluded that the presence of a malformation was not an independent risk factor for CS. However, indirect causes, such as malpresentation (4.34 OR), were independently associated with the malformations. CONCLUSION: Fetuses affected by either CNS malformations or chromosomal abnormalities have a higher rate of pregnancy and delivery complications, including those which increase the risk of maternal morbidity and mortality. PMID- 22428202 TI - [In vitro maturation of oocytes: a novel method of treatment of patients with polycystic ovarian syndrome undergoing in vitro fertilization]. AB - BACKGROUND: In vitro maturation of oocytes (IVM) was developed to make in vitro fertilization (IVF) safer and simpler mainly for women with poLycystic ovarian syndrome (PCOS). The major benefits of IVM treatment include avoidance of hormone administration and risk of ovarian hyperstimulation syndrome (OHSS). OBJECTIVE: Results of IVM from our unit in patients with PCOS. METHODS: In this study 85 PCOS patients underwent 102 IVF cycles of IVM and were treated with one of the following protocols: (1) Priming with 150 units of recombinant FSH for 3 days, from the 3rd day of menses, following follicle development up to 10-12 mm. (2) Administration of 17beta estradiol (estrofem) on second day of menses, followed by ultrasound endometrial measurement up to > or =6 mm. thickness. Oocytes were collected 38 hours post recombinant human chorionic gonadotropin (rhCG) administration. Luteal phase support was achieved by estrofem and progesterone. Oocytes were matured either 6-30 hours (protocol 1) or 24-48 hours (protocol 2) in IVM medium and fertilized by intracytoplasmatic sperm injection (ICSI). Mean number of immature oocytes collected, maturation, fertilization, cleavage and pregnancy rates were assessed. RESULTS: Total number of retrieved oocytes was 1224 (mean 12 +/- 6.2 per cycle); 820 (64.9%) underwent maturation after 6-48 hours of culture while 128 of them (15.6%) after 6 hours and 20.2% of transferred embryos originated from those oocytes. FertiLization rate was 47.2%. Pregnancy and implantation rates were 28.4% and 11.25% respectively. CONCLUSIONS: IVM appears to be a simpler and tolerable treatment method in patients with PCOS undergoing IVF treatment. Favorable results were obtained. PMID- 22428204 TI - [Advances and updates in obstetrics, gynecology and infertility]. PMID- 22428203 TI - [Human papillomavirus types in women with cervical cancer in Haifa District]. AB - BACKGROUND: Human papillomavirus (HPV) is recognized as the absolute cause of cervical cancer and is found in 99% of the Lesions. HPV 16 and 18 are detected in 70% of the cases. Two vaccines against HPV 16 and 18 were approved for use in Israel in recent years. PURPOSE: To determine the prevalence of human papillomavirus (HPV) in women with invasive cervical cancer in the Haifa district, and to see if the vaccine is suitable for our population. METHODS: The study population included 65 women from the Haifa District who were diagnosed with invasive cervical cancer in the Cervix Clinic of Carmel Medical Center. Samples for HPV typing were obtained during the evaluation of those patients. DNA was extracted from brush samples and HPV genotype was determined by nested-PCR followed by sequencing. RESULTS: Out of 65 patients with cervical carcinoma, 64 were found positive for HPV. The main HPV types in our patients were HPV 16 in 53.8% of the patients, HPV 18 in 12.3% of the patients and HPV type 45 in 13.8% of the patients. HPV type 33 was found in 4.6% of the patients, and HPV types 31 and 66 in 3.1% of the patients. Each of HPV types 54, 56, 58 and 59 were found in one patient. The main complaint was postmenopausal bleeding or menometrorrhagia in 24 patients (36.9%), post coital bleeding in 18 patients (27.7%) and 14 patients (21.5%) were evaluated due to an abnormal cytological smear Squamous cell carcinoma was diagnosed in 83% of the patients and cervical adenocarcinoma in 15.1% of them. CONCLUSIONS: The prevalence of HPV types in Haifa district is similar to world prevalence of HPV's, where HPV 16 and 18 cause 66.1% of cervical cancer, while in our study HPV45 and HPV 66 were found in higher proportions of cases than reported worldwide. In our population the vaccine against HPV 16/18 can prevent almost 70% of cases of cervical cancer, but a multicenter study should be performed in order to obtain larger numbers. PMID- 22428205 TI - [Medical evaluation prior to fertility treatment--time for reconsideration?]. AB - The aim of modern obstetrics is to bring a healthy child to a healthy mother. Preconception counseling is a form of preventive medicine that consists of three main components: risk assessment, health promotion and intervention, in order to improve pregnancy outcome. A large proportion of women, who need assisted reproductive technologies (ART) due to infertility, are older than the average pregnant women. The risk for chronic maternal disease such as obesity, diabetes mellitus, chronic hypertension, cardiovascular diseases and malignant disease greatly increases with maternal age. Chronic maternal illness might increase the risk of in vitro fertilization procedure and is also associated with increased obstetrics risk and even death. A previous study has shown that most maternal deaths in the USA, due to chronic maternal disease, are potentially preventable through better medical care from preconception, yet most studies that deal with preconception care in infertility patients only address the problems of infertility. Therefore, similar to the recommendations of the American Heart Association before non-competitive physical activity, and the American Society of Anesthesiologists before an elective surgery, we suggest a pre-ART medical assessment. Our objective is to outline the potential risks for older women who undergo ART procedure and potentially, pregnancy, and to characterize guidelines for evaluation prior to enrolling them in ART programs. Pre-ART assessment should include a thorough medical questionnaire and medical examination. Appropriate treatment for women with medical conditions prior to ART procedure and optimizing disease control in preparation for pregnancy including changing a potentially teratogenic treatment, can improve women's health status prior to pregnancy and reduce pregnancy related complications. At the end of the evaluation, and before ART treatment, the women should be consulted, based on the results of tests, on the possible risks that might accompany the ART procedure, pregnancy and delivery. PMID- 22428206 TI - [Upper extremity deep vein thrombosis following ovarian stimulation]. AB - Upper extremity deep venous thrombosis (UEDVT) is uncommon as a spontaneous event in the general population and is associated with well-defined risk factors. Thromboembotic events are serious, but fortunately rare, complications following ovarian stimulation for IVF. A review of the Literature indicates that thromboembolic events after ovarian stimulation are usually associated with ovarian hyperstimulation syndrome (OHSS). The incidence of UEDVT is higher in women undergoing assisted reproductive technology (ART) compared to the general population. The incidence of this condition is estimated to be 0.08%-0.11% of treatment cycles. While lower extremity DVT may be considered a natural consequence of OHSS, given the diminished venous return secondary to enlarged ovaries and ascites, it is unclear why there appears to be a predilection for thrombi in the upper extremities in women undergoing ART. Early diagnosis and treatment is crucial for both maternal and fetal well-being. Since infertility treatment is becoming commonplace in today's society, women undergoing treatment and their clinicians should be better informed of the presentation and clinical course of UEDVT to enable early diagnosis and start treatment. Consideration must be given to screening patients at risk for OHSS for thrombophilias, as well as administrating prophylactic anticoagulation therapy to patients who develop OHSS. PMID- 22428207 TI - [Recurrent pregnancy loss--evaluation and treatment]. AB - Women with recurrent spontaneous pregnancy loss (RPLJ are in a complex scenario, due to the work-up evaLuation that is negative in about 50% of the cases, and the stress associated with the outcome of the next pregnancy. Therefore, these patients experience psychoLogicaL conditions including anxiety and depression. The basic examination includes: parental karyotype, anatomical evaluation of the uterus, hormonal profile (including TSH, prolactin level and glucose) and APLA evaLuation. In recent years, several changes had been reported in the recurrent pregnancy loss definition, the preferred mode of the uterine cavity evaluation and the need for anti-thrombotic treatment in idiopathic RPL. In addition, new concepts in the pathophysiology and the etiology of RPL have been described as well as the extent of the evaluation. It is important to emphasize that those women with RPL in general and those with idiopathic RPL specifically, will experience about a 75% live birth rate in the next pregnancy when they are in a specialized RPL clinic. In this review, we will discuss these issues according to the recent studies incLuding the evaluation and treatment that are implicated in the RPL clinic in the Soroka University Medical Center. PMID- 22428208 TI - [Predicting pregnancy outcomes based on first trimester screening]. AB - Pregnancy surveillance in the western world focuses on the second and third trimesters. Recently, a few studies demonstrated that several pregnancy outcomes can be predicated by first trimester screening, especially in the time period between 11 + 0 to 13 + 6 weeks of gestation. These outcomes include the risk of developing preeclampsia, small for gestational age (SGA) and macrosomic fetuses, risk of abortion or intrauterine fetal death, risk of preterm labor and the risk of developing gestational diabetes. This review focuses on these findings and examines if it is feasible to expand the nuchal translucency and first trimester biochemical screening that is customary in Israel, so it may include additional parameters to predict those pregnancy outcomes. PMID- 22428209 TI - [Trial of labor after two cesarean sections: the policy in Israel and four years experience]. AB - INTRODUCTION: Trial of vaginal birth after caesarean is considered acceptable after one caesarean section. However, trial of vaginal birth after more than one caesarean section is still unaccepted by most clinicians. Birth rates in Israel are within the highest in the western world and many women are interested in a trial of labor after two previous caesarean sections. Therefore, it is crucial to establish evidence based guidelines for this issue. OBJECTIVE: To perform a systematic review of literature on success rate of vaginal birth after two caesarean sections and to present our experience in trial of labor after two caesarean sections. METHODS: We searched MEDLINE, using search terms "Caesarean section", "caesarian", "C*rean", "C*rian", "Vaginal birth after caesarean section", "Trial of labor". RESULTS: The literature revealed a success rate of 60 80%. The main complication is rupture of the uterus and its rate is 0-3%. During the years 2006-2009, 67 trials of labor after two caesarean sections were performed in our medical center. Our success rate is 88%. There were no cases of rupture of the uterus. CONCLUSION: A trial of labor after two caesarean sections is possible for carefully selected women and when appropriate medical resources are available. PMID- 22428210 TI - [Non-indicated cesarean section--does the "Golem" counteract?]. AB - Cesarean section rate is steadily increasing and in Israel it has risen to 20%. MultipLe and different reasons have led to this phenomenon, among them are non indicated cesarean sections. Although health care providers disagree whether this development is medically, ethically and publically justified, national associations allow it, while respecting those obstetricians who decline to do so. In Israel there are some hospitals which allow non-indicated cesarean sections, whereas others reject them. When discussing this issue with the patients, documentation is advised concerning the reasons for approval or rejection of the patients' request in order to avoid future complaints in the case of adverse outcome. Low risk vaginal delivery should be regarded as a natural process and not as a medical treatment and keeping balanced and reasonable decisions may help to contain the phenomenon and avoid a situation in which the "Golem" created by the medical system, counteracts. PMID- 22428211 TI - [Intractable pediatric infectious disease: examining the ability of a new drug, tosufloxacin tosilate hydrate for pediatric (discussion)]. PMID- 22428212 TI - [Efficacy and safety of sitafloxacin for lower respiratory tract infections]. AB - We investigated the efficacy and safety of sitafloxacin (STFX) in patients with mild to moderate community-acquired pneumonia or secondary infections of chronic respiratory tract diseases. The results showed that the efficacy rate was 96.5% (111/115) in patients analyzed for efficacy. The efficacy rate by STFX administration method was 93.9% (46/49) at 50mg b.i.d., 100% (37/37) at 100 mg q.d. and 96.6% (28/29) at 100mg b.i.d. In chest X-rays, the image improvement rate in 102 patients with shadows before treatment was 94.1% (96/102). The image improvement rate by STFX administration method was 90.5% (38/42) at 50 mg b.i.d., 97.1% (33/34) at 100mg q.d. and 96.2% (25/26) at 100mg b.i.d. Side effects occurred in five out of 115 patients (4.3%). Abnormalities in hepatic function test values appeared in two patients and abnormalities in renal function test values appeared in three patients. In four cases, the abnormalities were very mild and STFX administration was continued without any treatment. In the other patient, the abnormal value rapidly returned to normal after STFX administration was discontinued. These findings indicated that STFX can be used safety in routine practice by adjusting the administration within the approved dose based on patient characteristics. Good therapeutic effects can be expected in patients with respiratory tract infections. PMID- 22428213 TI - [Current clinical practice in the treatment of febrile neutropenia (FN)]. AB - Because of the refractory and recurrent nature of febrile neutropenia (FN), definite diagnosis and early empiric treatment with antibiotics are important for FN patients. With this background, guidelines for FN treatment have been published in Japan and overseas, although a treatment method appropriate for clinical practice in Japan has not yet been established. Therefore, we conducted a survey of actual practice, including trends in prescription of antibiotics for FN, in the hope that it would help establish a definitive treatment for FN in Japan. The survey results confirmed that FN patients under care of hematology departments accounted for the largest proportion, followed by pediatrics (hematology), pulmonary medicine, medical oncology, and respiratory surgery, and the proportions of patients diagnosed with FN and those receiving antibiotics in hematology departments are larger than in other departments. Across all departments, cefepime (CFPM) is most frequently used as the initial treatment of choice, accounting for 35.9% of prescriptions, followed by meropenem (MEPM) (24.3%). These drugs are selected because they exhibit high potency and wide coverage against organisms that are presumed to cause FN, and their costs are covered by insurance, while the existence of insurance coverage is the major determining factor for treatment in Japan. Among second-line drugs, MEPM is most frequently used, accounting for 46.3% of prescriptions. The guidelines are commonly used as the basis for treatment, accounting for 52.0% of all departments, especially the guidelines established by the Japan Febrile Neutropenia Study Group. On the other hand, the percentage of departments that have introduced a hospital protocol and clinical path is only 13.0% in total. To provide appropriate treatment for FN patients, insurance coverage and introduction of a hospital protocol and clinical path based on guidelines and evidence are essential. The current situation, in which these are not implemented, is not desirable. The survey results show that the guidelines need to be revised to more closely reflect the actual situation in Japan and hospital protocols and clinical paths need to be introduced. PMID- 22428214 TI - [Retrospective analysis of the safety of four hours administration of liposomal amphotericin B in patients with chronic necrotizing pulmonary aspergillosis]. AB - We have retrospectively analyzed the safety of 4 hours administration of liposomal amphotericin B (L-AMB) compared to less than or equal to 3 hours administration in patients with chronic necrotizing pulmonary aspergillosis (CNPA). The elevation of serum creatinine in the group with 4 hours administration of L-AMB in patients with CNPA was equal to the group with shorter administration time (less than or equal to three hours). During the administration of L-AMB, the group with 4 hours administration of LAMB had significantly a safer profile in relation to hypokalemia during L-AMB treatment than the group with shorter administration time. Additionally, white cell counts, platelet counts, serum creatinine, AST, ALT were not significantly different between L-AMB 4 hours administration group and less than or equal to 3 hours administration group. As the group with 4 hours administration of L-AMB had significantly a safer profile in relation to hypokalemia during L-AMB treatment, this modality can be one of the safer ways in the treatment of CNPA. As L-AMB is one of the fungicidal agents, 4 hours administration of L-AMB can be an optimal way of treating CNPA. PMID- 22428215 TI - [Study on the safety and efficacy of sitafloxacin--results of the use-results survey]. AB - Sitafloxacin (STFX, Gracevit 50 mg, fine granules 10%), a new quinolone antibacterial agent, was approved in January 2008, and the use-results survey was performed for 2 years from December 2008 to November 2010. In total, 3558 case cards were collected from 287 medical institutions and 3331 cases were subjected to a safety evaluation and 3225 were subjected to an efficacy evaluation. Incidence of adverse drug reactions (ADRs) was 4.44% (148/3331 cases). Major ADRs were diarrhea (55 cases) and hepatic function disorders (39 cases), and the incidences were 1.65% and 1.17%, respectively. Serious ADRs were observed in 5 cases (7 episodes); gastrointestinal haemorrhage, hepatic function abnormal, white blood cell count decreased, drug eruption, hypoglycemia, pneumonia, and superinfection in one case each. Efficacy rate was 92.9% (2997/3225 patients) in total with a range of 91.4 to 97.8% by type of infection such as respiratory tract and urinary tract. Eradication rate of indicated strains was 91.5% (808/883 strains) including Gram-positive bacteria at 92.3% (310/336 strains), Gram negative bacteria at 90.7% (458/505 strains), anaerobes at 100.0% (28/28 strains) and atypical bacteria at 85.7% (12/14 strains). In conclusion, this use-results survey confirmed that STFX is a useful antibacterial agent with no serious problems in its safety profile and efficacy rates of over 90% against all infections. PMID- 22428216 TI - The administration of aerosolised medications in bronchiectasis: the rediscovery of an old method. PMID- 22428217 TI - Prevalence of airflow obstruction according GOLD, ATS and ERS criteria in symptomatic ever-smokers referring to a pulmonary rehabilitation department. AB - AIM: To evaluate in a Pulmonary Rehabilitation (PR) setting the prevalence of airflow obstruction (AO) in either current or former smokers > or = 45 years old both with dyspnoea and with chronic productive cough, using European Respiratory society (ERS) statement (FEV1/SVC < 88 and < 89% predicted in men and women, respectively), American Thoracic Society (ATS) statement (FEV1/FVC < 75%), and Global Initiative for Chronic Obstructive Lung Disease (GOLD) statement (FEV1/FVC < 70%). METHODS: Lung function tests were performed in each patient who was referred to our PR department due to respiratory diagnosis or symptoms. For analysis, in patients showing AO we used post-bronchodilator lung function values. RESULTS: In 184 ever-smoker patients with symptoms of chronic obstructive pulmonary disease (COPD), the prevalence rates of AO were as follows: ERS = 89.7%, ATS = 76.6%, and GOLD = 63.6%. Patients with AO according ERS criteria showing moderate to severe (M/S) obstruction (i.e., FEV1 < 70% predicted) were 119. Patients with ERS M/S AO but without AO using either ATS or GOLD criteria were 8.4% and 19.3%, respectively. CONCLUSIONS: Prevalence of AO is highly dependent on which guidelines it is based. ATS and particularly GOLD statement can cause a large under-diagnosis even of moderate to severe COPD. Diagnosis of COPD may be overlooked if SVC is not performed. PMID- 22428218 TI - Validation of lung densitometry threshold at CT for the distinction between senile lung and emphysema in elderly subjects. AB - BACKGROUND AND AIMS: An ageing lung is characterised by distal airspace enlargement without alveolar wall destruction: therefore the anatomical distinction between senile lung and emphysema is clear-cut. In clinical settings the definition of precise boundaries between normalcy and pathology is more difficult with the risk of overdiagnosis. CT is an important diagnostic advancement in the field of COPD. Most methods for the evaluation of emphysema are based on the detection and measurement of areas characterised by a density level below a threshold assumed to characterize parenchymal destruction. METHODS: Our retrospective study included 47 healthy subjects (65-91 years), 36 never smokers and 11 former smokers. As a reference sample we recruited 9 patients with emphysema (69-81 years). Thoracic scan was performed by single slice spiral CT and acquired without contrast enhancement. For each scan and on both lungs we sampled eighteen regions of interest in the upper, middle and lower field. Mean lung density (MLD) and lower limit of normal (LLN) of density distribution were calculated. RESULTS: MLD for the whole study sample was -846 +/- 41 HU. -901 HU was the LLN of density distribution in the study sample. No significant correlation was noted between age and MLD. In the emphysematous sample the average lung density was -946 +/- 18 HU. The mean coefficient of variation was 3% in the healthy sample and 2% in the emphysematous one. The difference between groups was significant (p < 0.0001). In one healthy subject only we measured a value slightly below the threshold reported in literature for conventional CT; no emphysematous value fell above the LLN. CONCLUSIONS: This study highlights the fact that in the elderly the threshold level of lung density commonly adopted in diagnostic algorithms of emphysema is fully applicable. When applying this method to older subjects the risk of misinterpreting areas of physiologic non destructive reduction of density as emphysema is low. PMID- 22428219 TI - Hyaluronic acid levels are increased in complicated parapneumonic pleural effusions. AB - BACKGROUND AND AIM: Hyaluronic acid (HA) is a component of extracellular matrix and may play a role in the pleural inflammation which is implicated in parapneumonic effusions.The aim of the current study was to investigate HA levels in serum and pleura in patients with parapneumonic effusions. METHODS: We prospectively studied pleural and serum levels of HA in 58 patients with pleural effusions due to infection (complicated and uncomplicated parapneumonic effusions), malignant effusions and transudative effusions due to congestive heart failure. In addition to HA, TNF-alpha and IL-beta levels were determined in pleural fluid and serum by ELISA. RESULTS: The median +/- SD HA levels (pg/ml) in pleural fluid of patients with complicated effusions (39.058 +/- 11.208) were significantly increased (p < 0.005), compared to those with uncomplicated parapneumonic effusions (11.230 +/- 1.969), malignant effusions (10.837 +/- 4.803) or congestive heart failure (5.392 +/- 3.133). There was no correlation between pleural fluid and serum HA values. Pleural fluid TNF-alpha levels (146 +/ 127 pg/mL) and IL-1beta levels (133.4 +/- 156 pg/mL) were significantly higher in patients with complicated parapneumonic effusions compared to patients with other types of effusion (p < 0.05). No significant association between HA and TNF alpha or IL-1beta was found. CONCLUSIONS. HA may play a significant role in the inflammatory process which characterises exudative infectious pleuritis. Further investigation might reveal whether HA is a useful marker in the management of parapneumonic effusions. PMID- 22428220 TI - Failure of noninvasive prediction of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Pulmonary hypertension (PH) in patients with advanced idiopathic pulmonary fibrosis (IPF) is a complication connected with unfavorable prognosis. Great efforts have been made in attempting to establish a reliable non-invasive method which would enable detection of this complication. In this context a formula using pulmonary function parameters was published with outstanding results. METHODS: We tested the formula in 27 IPF patients who underwent a lung function examination, cardiac ultrasonography and catheterisation on the same day. RESULTS: Pulmonary hypertension was detected by catheterisation in 17 patients (63%). In our group, contrary to the published data, the aforementioned formula was neither useful for detecting patients with a high probability of PH nor as a means of calculating the mean pulmonary artery pressure in individual patients (p = 0.502 and p = 0.833, respectively). Ultrasound examination reached borderline correlation with the values measured by catheterisation when we compare patients with relevant results (r = 0.531, p = 0.051). However, the examination gave no usable results in 13 patients (48%). CONCLUSION: Our data suggests that no reliable, noninvasive method is currently available for detecting and confirming PH in IPF patients. We did not confirm the usefulness of the published formula. Further carefully organised studies will be necessary to verify or refute it. PMID- 22428221 TI - Adult cystic fibrosis care in the 21st century. AB - Cystic fibrosis (CF) is the most common autosomal recessive inherited disease of Caucasian populations. As a result of a variety of diagnostic and therapeutic strategies there has been a dramatic increase in the life expectancy of patients with CF in the last decades and 50% of patients are now adults. This review will focus on the disease in adults and the provision of appropriate care. The complex care required to improve the survival and quality of life in the adult patients can best be provided in a dedicated adult cystic fibrosis unit. These units currently exist in many European countries, but more are needed in Italy. PMID- 22428222 TI - Use of aerosols in bronchiectasis patients. AB - Bronchiectasis is a chronic respiratory disease which recognises different etiologies, and characterised by persistent cough, bronchial hypersecretion, airway colonisation with Gram-negative pathogens; frequent infectious exacerbations; progressive lung function decline, and poor quality of life. Several therapeutic strategies are used for managing bronchiectasis, and nebulised medications are regarded with great and ever increasing interest because they allow the direct medication of targets airway structures, higher concentrations of the drug employed, and much less systemic effects. In general terms, the available therapeutic strategies lead to different results depending of whether bronchiectasis are related to cystic fibrosis or not. The effects of the main classes of drugs for aerosol delivery in bronchiectasis patients have been reviewed and updated. Further research is needed in order to ameliorate therapeutic interventions in bronchiectasis, both in terms of new molecules and aerosol formulations to use, and of systems able to optimize drug delivery and drug effectiveness. PMID- 22428223 TI - Bronchial glomus tumor mimicking a COPD exacerbation. AB - We report the case of a glomus tumor originating in the left main bronchus diagnosed in a 79 year old Caucasian man. A glomus tumor is an extremely rare neoplasm in the bronchi with nonspecific clinical features. Bronchoscopy allows the diagnosis through biopsy and subsequent histopathological examination of the tissue and in selected cases may represent a valid alternative to surgery permitting a radical tumor excision. PMID- 22428224 TI - Nurse practitioners... the good news. PMID- 22428225 TI - Eliminating disruptive behavior: it takes an interdisciplinary team. PMID- 22428226 TI - Supporting a nurse's re-entry to practice after treatment for addiction. PMID- 22428227 TI - New iridoid from aerial parts of Mussaenda roxburghii. AB - A new iridoid, shanzhiol (1), was isolated from the aerial parts of Mussaenda roxburghii. The structure was established by spectroscopic (including 2D NMR) and chemical methods. Shanzhiol (1) showed mild antibacterial activity against both Staphylococcus aureus and Escherichia coli with a MIC of 100 microg/mL by the broth dilution method. PMID- 22428228 TI - A new megastigmane glycoside, phoenixoside A, from Phoenix dactylifera. AB - A new megastigmane glycoside, phoenixoside A (1), has been isolated from the n butanol--soluble fraction of seeds of Phoenix dactylifera. The structure was characterized as (6S,7Z,9R)-hydroxy-3-oxo-ionol-9-O-beta-D-glucopyranosyl-(1" --> 6')-beta-D-glucopyranoside on the basis of 1D and 2D NMR spectroscopy, high resolution mass spectrometry, and CD spectroscopy. PMID- 22428229 TI - New 3,4-seco-ent-kaurene dimers from Croton micans. AB - From the stems of Croton micans Sw., five new 3,4-seco-ent-kaurene dimers: micansinoic acid (1), isomicansinoic acid (2), and the dimethyl (3), monomethyl (4) and monoethyl ester (5) of micansinoic acid were isolated. The structures of the new compounds were elucidated by spectroscopic data interpretation, mainly 1D and 2D NMR experiments and MS. These compounds are the first 3,4-seco-ent-kaurene dimers from a Croton species. PMID- 22428230 TI - Diacarperoxide S, new norterpene cyclic peroxide from the sponge Diacarnus megaspinorhabdosa. AB - Re-investigation of the methanolic extract of the sponge Diacarnus megaspinorhabdosa afforded one new norsesterpene cyclic peroxide diacarperoxide S (2), in addition to two known compounds sigmosceptrellin B (1) and nebularine (3). The structures of the isolated compounds were established on the basis of one and two dimensional NMR spectroscopic studies (1H, 13C, DEPT, COSY, HMQC, HMBC, and ROESY) as well as on mass spectral analysis. The isolated compounds were evaluated for their cytotoxic as well as antimicrobial activities. PMID- 22428231 TI - Constituents of Kenyan Gardenia volkensii. AB - A new triterpenoid, 3-oxo-22alpha-hydroxy-olean-12-en-28-oic acid (1), oleanolic acid (2) and a known iridoid, 10-hydroxy-1-oxo-7-iriden-11-oic acid methyl ester (3) have been isolated from the dichloromethane extract of the dried seeds of Gardenia volkensii. Their structures were established by 1D and 2D NMR spectroscopic and MS methods. PMID- 22428232 TI - Oral administration of Cimicifuga racemosa extract attenuates immobilization stress-induced reactions. AB - Dried rhizomes of Cimicifuga racemosa (CR), known as black cohosh, have been widely used as a herbal dietary supplement in the treatment of menopausal symptoms. Here we used experimental mouse stress models to investigate the role of anti-stress food factors, and found that a CR extract had stress-relieving effects. A single oral administration of CR extract (1,000 mg/kg) significantly attenuated plasma corticosterone and aspartate aminotransferase (AST) levels that had increased as a result of enforced immobilization. Bioassay-guided fractionation of the CR extract resulted in the isolation of 10 triterpenes, among which actein, 23-epi-26-deoxyactein, and cimiracemoside F (100 mg/kg, per os) were shown to contribute to the anti-stress effects. Furthermore, the CR extract significantly prevented the development of water immersion stress-induced gastric mucosal ulcers in rats. We propose that the CR extract might be suitable for the prevention and treatment of stress-related disorders. PMID- 22428233 TI - Complete NMR assignments of tubulosine. AB - This article reports the structural elucidation of the Alangium alkaloid, tubulosine (1) on the basis of systematic 2D-NMR analyses (DEPT, COSY, TOCSY, NOESY, ROESY, HMQC and HMBC). The data obtained allowed the unambiguous assignment of all proton and carbon signals in 1 for the first time. PMID- 22428234 TI - Application of mixture analysis to crude materials from natural resources (III): NMR spectral studies to analyze chalcones from Angelica keiskei. AB - This study presents the application of the NMR-based analyses, DOSY and ROSY, to the chalcones, xanthoangelol (1) and 4-hydroxyderricin (2) from Angelica keiskei. We investigated whether virtual separation and structural information from each compound can be obtained. DOSY displays spectra of (1) and (2) in one dimension and diffusion spectra in the other. And the 1H slice spectra were analyzed in detail by comparison with authentic samples previously isolated from the same material. The resulting ROSY spectrum clearly showed two distinct peaks in the 1H T1 dimension. Each slice of the ROSY spectrum along the 13C dimension contains over-lapped signals, which are difficult to assign at this time. PMID- 22428235 TI - A validated chromatographic method for the determination of flavonoids in Copaifera langsdorffii by HPLC. AB - Hydroethanolic extracts of C. langsdorffii leaves have therapeutic potential. This work reports a validated chromatographic method for the quantification of polar compounds in the hydroethanolic extract of C. langsdorffii leaves. A reliable HPLC method was developed using two monolithic columns linked in series (100 x 4.6 mm - C18), with nonlinear gradient elution, and UV detection set at 257 nm. A procedure for the extraction of flavonols was also developed, which involved the use of 70% aqueous ethanol and the addition of benzophenone as the internal standard. The developed method led to a good detection response as the values for linearity were between 10.3 and 1000 microg/mL, and those for recovery between 84.2 and 111.1%. The detection limit ranged from 0.02 to 1.70 microg/mL and the quantitation limit from 0.07 to 5.1 microg/mL, with a maximum RSD of 5.24%. Five compounds, rutin, quercetin-3-O-alpha-L-rhamnopyranoside, kaempferol 3-O-alpha-L-rhamnopyranoside, quercetin and kaempferol, were quantified. This method could, therefore, be used for the quality control of hydroethanolic extracts of Copaifera leaves and their cosmetic and pharmaceutical products. PMID- 22428236 TI - Luteolin induces mitochondria-dependent apoptosis in human lung adenocarcinoma cell. AB - The effects of luteolin on the proliferation of A549 cells were evaluated by MTT and clone formation assays. DNA ploidy and apoptotic cell percentage were calculated by flow cytometry. The expression of Bax, Bcl-xl, Bcl-2, Mcl-1, caspase-9, caspase-3, and PARP was analyzed by Western blotting. The membrane potential of mitochondria was detected by JC-1 fluorescence microscopy assay. Our results demonstrated that luteolin could inhibit the proliferation of A549 cells via induction of apoptosis, with the evidence of characteristic morphological changes of apoptosis in the nucleus. Furthermore, DNA flow cytometric analysis indicated that luteolin induced a S phase arrest of the cell cycle. The membrane potential of mitochondria was decreased. The protein levels of Bax, Bcl-xl, Bcl 2, Mcl-1, caspase-9, caspase-3, and PARP were activated after treatment with luteolin. Luteolin can inhibit the proliferation of A549 cells and trigger mitochondria- dependent apoptosis in them. PMID- 22428237 TI - Diuretic activity of Lophophytum leandri. AB - A bioassay-oriented study was carried-out in order to validate the traditional uses of Lophophytum leandri, a parasitic plant used as a diuretic in traditional medical practices of Argentina. Four known flavonoids have been isolated from the active fraction. Quercetin-3-O-beta-D-glucopyranoside was identified as the active principle of the fraction. However, the diuretic activity of the extract and of the most active fraction had greater activity than that of the pure isolated compounds. PMID- 22428238 TI - Evaluation of the hypocholesterolemic effect and phytochemical screening of the hydroethanolic extract of Crataegus aronia from Jordan. AB - Chemical screening of the leaves and flowers of Crataegus aronia resulted in the isolation of hyperoside, quercetin, rutin and beta-sitosterol for the first time from this plant. The effects of the hydroethanolic extract of C. aronia (CAHE) on hypercholesterolemic rats were investigated. The rats, treated orally for four weeks with 400 mg/kg/day CAHE, exhibited significant decreases in serum total cholesterol (TC) and low-density lipoprotein (LDL). The results were compared with those obtained after oral administration of atorvastatin (10 mg/kg/day). Furthermore, 10-week daily co-administration of a high cholesterol diet and CAHE (200 mg/kg/day) prevented the increase in TC and LDL. These observations indicate that CAHE has a hypocholesterolemic effect. PMID- 22428239 TI - Secondary metabolites, cytotoxic response by neutral red retention and protective effect against H2O2 induced cytotoxicity of Sedum caespitosum. AB - The EtOAc, n-BuOH and H20 subextracts of the crude MeOH extract of the aerial parts of Sedum caespitosum (cav.) Dc. were screened for cytotoxicity using the neutral red assay in Chinese hamster ovary cells as well as their protective effect against H2O2 induced cytotoxicity in human red blood cells. While the extracts did not show cytotoxicity, they displayed a protective effect compared to a blank and ascorbic acid. Gallic acid (1), kaempferol 3-O-alpha rhamnopyranoside (2), quercetin 3-O-beta-glucopyranoside (3), quercetin 3-O-alpha rhamnopyranoside (4) and myricetin 3-O-alpha-rhamnopyranoside (5) were isolated from the EtOAc extract and identified by 1D- and 2D-NMR. The protective effects of the isolated compounds against H2O2 induced cytotoxicity in human red blood cells were evaluated and 5 was the most active. PMID- 22428240 TI - Effect of Hibiscus sabdariffa and its anthocyanins on some reproductive aspects in rats. AB - An aqueous extract of Hibiscus sabdariffa L. is a common beverage in many parts of the world. Reports on its effect on reproduction are conflicting, with anecdotal evidence that the plant is an aphrodisiac, while others report that it is estrogenic, and adversely affects spermatogenesis in rats. We have studied the effect of different concentrations of aqueous extracts of H. sabdariffa calyces (10%, 15% and 20%) used as drinking water for 10 consecutive weeks, and its anthocyanins (50, 100, 200 mg/kg for 5 days, orally) on the weight and histology of the testis, and on some biochemical constituents in testicular homogenates, in addition to the plasma concentrations of testosterone, luteinizing hormone and estradiol. The possible presence of an estrogenic effect of the extract and anthocyanins on the uteri of immature female rats was also tested. Neither the H. sabdariffa extract nor the anthocyanins significantly altered either testicular weight and histology, or uterus weight. Plasma concentrations of the three hormones studied, the testicular concentrations of protein, reduced glutathione and total cholesterol, and superoxide dismutase activity were all insignificantly affected by either the extract or the anthocyanins, except for a slight, but statistically significant, decrease in testicular protein concentration caused by the 15% aqueous extract when compared with controls. These results suggest that H. sabdariffa exerts no adverse effect on the male reproductive system. Consumption of H. sabdariffa aqueous extract inhibited the growth of the rats compared with the controls. PMID- 22428241 TI - New galloyl derivative from winged sumac (Rhus copallinum) fruit. AB - Twelve compounds were isolated from Winged Sumac (Rhus copallinum) fruit and their structures were elucidated on the basis of NMR and mass spectral data. The isolates included a new galloyl derivative, (R)-galloyl malic acid dimethyl ester (1), and eleven known compounds, gallic acid (2), methyl gallate (3), glucogallin (4), methyl m-digallate (5), methyl p-digallate (6), quercetin (7), myricetin (8), rhamnazin (9), kaempferol (10), betulinic acid (11), and oleanolic acid (12). All of the compounds were evaluated for antiproliferative effects against human colon tumorigenic (HCT-116, Caco-2) and nontumorigenic (CCD18-Co) cell lines. PMID- 22428242 TI - Phytochemical analysis and antioxidant capacity of BM-21, a bioactive extract rich in polyphenolic metabolites from the sea Grass Thalassia testudinum. AB - The aqueous ethanol extract of Thalassia testudinum leaves (BM-21) is now being developed in Cuba as an herbal medicine due to its promising pharmacological properties. Although some interesting biological activities of BM-21 have already been reported, its chemical composition remains mostly unknown. Thus, we now describe the qualitative and quantitative analyzes of BM-21 using standard phytochemical screening techniques, including colorimetric quantification, TLC and HPLC analyses. Phytochemical investigation of BM-21 resulted in the isolation and identification of a new phenolic sulfate ester (1), along with ten previously described phenolic derivatives (2-11), seven of which have never been previously reported from the genus Thalassia. The structures of these compounds were established by analysis of their spectroscopic (1D and 2D NMR) and spectrometric (HRMS) data, as well as by comparison of these with those reported in the literature. Furthermore, BM-21 was found to exhibit strong antioxidant activity in four different free radical scavenging assays (HO*, RO2*, O2-* and DPPH*). Consequently, this is the first study which highlights the phytochemical composition of BM-21 and demonstrates that this product is a rich source of natural antioxidants with potential applications in pharmaceutical, cosmetic and food industries. PMID- 22428243 TI - Herbicidal activity of curvuiinic acid isolated from Nimbya alternantherae. AB - A phytotoxic compound, identified as 2-(2-acetyl-3,5-dihydroxyphenyl) acetic acid (curvulinic acid), was isolated from liquid cultures of the phytopathogenic fungus Nimbya alternantherae. The activity of curvulinic acid on seed germination and seedling growth of Capsella bursa-pastoris was evaluated. Percentage seed germination of C. bursa-pastoris was decreased with increasing concentrations of curvulinic acid. The compound had stronger inhibitory effects on root length than shoot length. At a concentration of 600 microg x mL(-1), curvulinic acid caused 73.5% and 66.7% growth inhibition on roots and shoots with IC50 values of 204.7 and 281.1 microg x mL(-1), respectively. The finding of curvulinic acid in N. alternantherae and its herbicidal activity are reported here for the first time. PMID- 22428244 TI - Xanthones with antiproliferative effects on prostate cancer cells from the stem bark of Garcinia xanthochymus. AB - Investigations of the constituents of the stem barks of Garcinia xanthochymus have yielded two new compounds, garcinenones X (1) and Y (2), along with five known xanthones, 1,4,5,6-tetrahydroxy-7-(3-methylbut-2-enyl)xanthone (3), 1,4,6 trihydroxy-5-methoxy-7-(3-methylbut-2-enyl)xanthone (4), 1,4,5,6-tetrahydroxy-7,8 di(3-methylbut-2-enyl)xanthone (5), 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methylbut-2 enyl)xanthone (6), and 1,5,6-trihydroxy-7,8-di(3-methylbut-2-enyl) 6',6'dimethylpyrano(2',3':3,4)xanthone (7). The structures of the compounds were determined by spectroscopic methods. The cell growth inhibitory activity of the isolated compounds against the PC-3 cell line was measured. Among them, compounds 2, 3, 5, and 6 exhibited significant inhibitory effects with IG50 values of 14.3, 15.5, 11.1, and 6.8 microM, respectively. PMID- 22428245 TI - Aromatic hydroxyl group plays a critical role in antibacterial activity of the curcumin analogues. AB - The aim of this study was to investigate the role of the aromatic substituents of the curcumin scaffold on the antibacterial activity of the resulting curcumin analogues. Six curcumin analogues with different aromatic substituents were prepared and their antibacterial activities were evaluated against two Gram positive and four Gram-negative bacteria. The structure-activity relationship study demonstrated that antibacterial activity of the curcumin analogues was critically dependent upon the aromatic hydroxyl group. Thus, hydroxycurcumin with an additional aromatic hydroxyl group on the curcumin scaffold showed antibacterial activity against all six pathogens tested and it remained effective even against ampicillin-resistant Enterobacter cloacae. Along with the previously reported antioxidative effect, the broad-spectrum antibacterial activity of the hydroxycurcumin warrants further investigation of its biological activity as well as extensive structure-activity relationship study of the curcumin analogues with various aromatic substituents. PMID- 22428246 TI - Analysis of Danshen and twelve related Salvia species. AB - Danshen is a commonly used traditional Chinese herb, but over twenty Salvia species are used as Danshen by local herbalists. In this study, twelve Salvia species from the plateau of Sichuan and Yunnan Provinces were collected, analyzed and compared with Danshen by HPLC. The results showed that most of the Salvia species were good sources of rosmarinic acid and tanshinones. The highest amount of both rosmarinic acid and tanshinone IIA were found in S. przewalskii Maxim. These results pave the way for a better therapeutic exploitation of these plants. PMID- 22428247 TI - Meliloester, a new melilotic ester from Melilotus alba. AB - A new melilotic ester, meliloester [2-ethyl-hexyl-3-(2-hydroxyphenyl) propionate], was isolated from the whole plant of Melilotus alba. Its structure was elucidated on the basis of spectroscopic and mass spectrometric analyses, including EI-MS, HR-MS, and UV, IR, 1D and 2D-NMR spectroscopic studies. PMID- 22428248 TI - A new long-chain unsaturated ester and other constituents of Hypericum tomentosum. AB - Three long-chain unsaturated esters (1-3), a fatty acid (4), a fatty ester (5), phytone (6) and a phloroglucinol (hyperfoliatin) (7) were isolated from the light petroleum extract of the endemic species Hypericum tomentosum L. (Clusiaceae). Compound 2, 8,10,13-trimethyltetradecanoic acid (2E)-3-methylhexadec-2-enyl ester, which we named tomentosate, is reported for the first time. The structures of the identified compounds were established on the basis of physical and spectroscopic analysis, and by comparison with literature data. PMID- 22428249 TI - Microbial conversion of tomato by a plant pathogenic bacterium Pectobacterium atrosepticum: a plant-microbial approach to control pathogenic Candida species. AB - This study was carried out to produce bioconverted products by microbial fermentation of tomato using a plant pathogenic bacterium Pectobacterium atrosepticum and to evaluate their in vitro antimycotic effect against pathogenic Candida species. The bioconverted products (500 microg/disc) provoked promising antimycotic effects against pathogenic isolates of Candida species as shown by the diameters of zones of inhibition (9 +/- 0.6 to 14 +/- 0.4 mm), along with their respective minimum inhibitory and minimum fungicidal concentration values, which increased from 250 to 1000 and 250 to 2000 microg/mL, respectively. With the viable counts of the tested fungal pathogens, exposure of the bioconverted products revealed a remarkable antimycotic effect. In addition, the morphology of a clinical isolate of C. glabrata KBN06P00368, visualized by scanning electron microscopy, showed a severe detrimental effect produced by the bioconverted products at the minimum inhibitory concentration (250 microg/mL). The bioconverted products significantly inhibited the in vitro growth of all the tested clinical and pathogenic laboratory isolates of Candida species. This study confirmed the potent antimycotic efficacy of the bioconverted products of tomato, hence justifying the therapeutic uses of bioconverted products in pharmaceutical preparations as an alternative approach to support the antifungal activity of conventional antimycotics. PMID- 22428250 TI - Antibacterial and antiparasitic effects of Bothropoides lutzi venom. AB - The therapeutic potential of toxins has aroused great interest in the scientific community. Microbial resistance is a serious current public health problem, in part because of the wide use of antimicrobial drugs. Furthermore, there are several problems in the treatment of parasitic diseases such as leishmaniosis and Chagas' disease, including the low efficacy in some clinical phases of the diseases and the loss of effectiveness of benzonidazole in the chronic phase of Chagas' disease. In this context, the aim of this work was to study the antimicrobial and antiparasitic effects of Bothropoides lutzi total venom (BltTV). The venom exerted an antibacterial effect on S. aureus, with MIC=MLC=200 microg/mL. The inhibitory effects of BltTV on promastigote forms of Leishmania amazonensis and L. chagasi were assessed by counting of viable cells after incubation with BltTV. IC50 values of 234.6 microg/mL and 61.2 microg/mL, were obtained, respectively. Furthermore, the venom repressed epimastigote forms of Trypanosoma cruzi growth. Finally, BltTV was verified to affect murine peritoneal macrophages, causing a cytotoxic effect at the highest concentrations (100 and 50 microg/mL). In conclusion, Bothropoides lutzi venom demonstrated antibacterial and antiparasite effects, suggesting that the venom contains some substance(s) of therapeutic value. PMID- 22428251 TI - Ternary liquid-liquid equilibria measurement for epoxidized soybean oil + acetic acid + water. AB - Liquid-liquid equilibria (LLE) data were measured for ternary system epoxidized soybean oil (ESO) + acetic acid + water at 313.15, 323.15 and 333.15 K, respectively. The consistency of the measured LLE data was tested, using Othmer Tobias correlation and root-mean-square deviation (sigma) in mass fraction of water in the lower phase and average value of the absolute difference (AAD) between experimental mass fraction of epoxidized soybean oil in the upper phase and that calculated using Othmer-Tobias correlation. PMID- 22428252 TI - Chemical constituents of the essential oil from aerial parts and fruit of Anisosciadium orientale. AB - The essential oils from aerial parts and fruits of Anisosciadium orientale DC. growing wild in Iran were obtained by hydrodistillation and analyzed by GC and GC/MS. Seventy-one compounds were identified in the fruit oil and fifteen in the oil from the aerial parts. The main oil components of the fruits and aerial parts were myristicin (33.5%-33.7%), alpha-terpinolene (22%-25.8%) and limonene (19.5% 19.7%). Some compounds, such as geranyl butyrate and germacrene-D, were only detected in the fruit oil. PMID- 22428253 TI - GC-MS analysis of Ziziphora clinopodioides essential oil from North Xinjiang, China. AB - The essential oils of Ziziphora clinopodioide Lam. from four different production areas (Banfang ditch; Altay mountains; Tuoli; Terks) were investigated. The oils were extracted by hydro-distillation and analyzed by gas chromatography-mass spectrometry (GC-MS). Seventeen constituents were identified in the essential oil from Banfang ditch, 20 in that from the Altay mountains, 12 in the Tuoli essential oil, and 9 in the Terks sample. The major components of the oils were pulegone (67.6%, 32.5%, 86.4%, and 82.1%) and p-menthanone (14.8%, 43.7%, 3.2%, and 8.2% from the Banfang ditch, Tuoli, Altay mountains, and Terks samples, respectively). PMID- 22428254 TI - Analysis of the essential oil of Teucrium polium ssp. capitatum from the Balkan Peninsula. AB - The chemical composition of the essential oil of the aerial parts of Teucrium polium ssp. capitatum collected during the flowering period from rocky places and dry pastures, (Serbia, Nis, Kamenica), and dunes along the sea-side, (Bulgaria, Burgas, Primorsko) has been studied by GC and GC/MS. The identified compounds, 45 for the oil from Serbia and 44 for that from Bulgaria, amounted to 97.3% and 96.4% of the oils, respectively. The dominant constituents of the Serbian oil were sesquiterpenes {59.6%, the most abundant components being germacrene D (31.8%), trans-caryophyllene (8.8%) and bicyclogermacrene (6.2%)}, while monoterpenes accounted for 37.5% {the most abundant components being linalool (14.0%) and beta-pinene (10.7%)}. The essential oil from Bulgaria was characterized by a high percentage of monoterpenes, amounting to 62.9% {the most abundant components being beta-pinene (26.8%), alpha-pinene (9.3%) and limonene (6.4%)}, while sesquiterpenes accounted for 33.5% (the most abundant component was germacrene D 17.7%)}. PMID- 22428255 TI - Composition of the essential oil of Pogostemon travancoricus var. travancoricus. AB - The essential oil of Pogostemon travancoricus Bedd. var. travancoricus collected from the Agasthyamalai region of Tamil Nadu, India was analyzed by GC and GC-MS. The major components of the oil were bicyclogermacrene (16.0%), cis-calamenene (6.3%), germacrene B (11.1%), spathulenol (7.6%), viridiflorol (5.8%), alpha cadinol (4.2%) and pogostone (9.9%). PMID- 22428256 TI - Liquid CO2 extraction of Jasminum grandiflorum and comparison with conventional processes. AB - The concrete (0.35%) of Jasminum grandiflorum L. flowers was prepared by extraction in n-pentane, and the absolute (0.27%) by fractionation of the n pentane extract (concrete) with cold methanol. Direct extraction of flowers with liquid CO2 gave a relatively fat-free product in 0.26% yield. The liquid CO2 extract was enriched with terpenoids and benzenoids, thus providing the organoleptically accepted product. The major compounds, such as benzyl acetate, (E,E)-alpha-farnesene and (Z)-3-hexenyl benzoate, along with compounds like indole, methyl anthranilate, (Z)-jasmone, (Z)-methyl jasmonoate and (Z)-methyl epi-jasmonoate, are responsible for the high diffusivity of the jasmine fragrance. These compounds have been obtained with improved recoveries in the liquid CO2 extract. On the other hand, the yield of the essential oil was poor (0.05%), and some polar compounds (oxygenated terpenoids) were recovered in less amounts in comparison with either the n-pentane or liquid CO2 extract. PMID- 22428257 TI - Chemical composition of volatile oils from the pericarps of Indian sandalwood (Santalum album) by different extraction methods. AB - The chemical composition of volatile compounds from pericarp oils of Indian sandalwood, Santalum album L., isolated by hydrodistillation and solvent extraction, were analyzed by GC and GC-MS. The pericarps yielded 2.6 and 5.0% volatile oil by hydrodistillation and n-hexane extraction, and they were colorless and yellow in color, respectively. A total of 66 volatile components were detected. The most prominent compounds were palmitic and oleic acids, representing about 40-70% of the total oil. Many fragrant constituents and biologically active components, such as alpha- and beta-santalol, cedrol, esters, aldehydes, phytosterols, and squalene were present in the pericarp oils. This is the first report of the volatile composition of the pericarps of any Santalum species. PMID- 22428258 TI - Fast quality assessment of German chamomile (Matricaria chamomilla L.) by headspace solid-phase microextraction: influence of flower development stage. AB - For an adequate quality evaluation of aromatic plants grown under different conditions, a rapid, simple and sensitive method for the analysis of volatile constituents is indispensable. The main objective of the present study was to compare fast screening of German chamomile (Matricaria chamomilla L.) by means of headspace solid-phase microextraction (HS-SPME) with conventional isolation of the essential oil (steam distillation-solvent extraction (SDSE)) for the differentiation of chamomile essential oil constituents. Flowers were harvested at two distinct development stages: stage I, when ligulate flowers start to develop and tubular flowers are still closed, and stage II, when tubular flowers are partially to completely opened. Dried chamomile flowers at two development stages were extracted by means of both SDSE and HS-SPME, followed by GC-MS analysis. Among 30 compounds detected, (E)-beta-farnesene (49%), artemisia ketone (10%) and germacrene D (9%) were the predominant volatile components in the HS SPME-extract, while alpha-bisabolol oxide A (42%), chamazulene (21%) and (Z) spiroether (8%) were the main essential oil constituents among the 13 compounds obtained by SDSE. After statistical analysis of the data, both techniques enabled the same conclusion: (E)-beta-farnesene was the only compound which showed significant differences between the two flower development stages. These results suggest that HS-SPME-GC-MS can be used as a sensitive technique for the rapid screening and quality assessment of M. chamomilla. PMID- 22428259 TI - Floral scent composition of Plumeria tuberculata analyzed by HS-SPME. AB - The headspace volatile compounds of the flowers of Plumeria tuberculata Lodd. were analyzed by solid phase microextraction coupled with capillary gas chromatography/mass spectrometry. Twenty-five compounds were identified, representing 100% of the total composition. The volatile fraction was characterized by oxygenated monoterpenes (79.6%), oxygenated sesquiterpenes (8.4%), sesquiterpene hydrocarbons (7.6%), and benzenoid esters (2.6%). The major components were geraniol (34.9%), citronelol (21.5%) and geranial (16.2%), and they were found to make the major contribution to the typical scent of this flower. PMID- 22428260 TI - Identification and quantification of the antimicrobial components of a citrus essential oil vapor. AB - The anti-bacterial components of a citrus essential oil vapor were identified as linalool, citral and beta-pinene using a bioautography method and quantified by GC-MS. Essential oil vapor release, monitored in real-time with Atmospheric Pressure Chemical Ionization - MS (APCI-MS), showed differences in the vapor release profile oflimonene, beta-pinene and linalool over 24 hours, while Solid Phase Micro-extraction (SPME) GC-MS demonstrated changes in composition of the vapor at 35 degrees C. Fourteen isolates were tested in vitro for their susceptibility to the EO vapor and to linalool, citral and beta-pinene vapors, both separately and in a mixture containing the three components in the amounts at which they occur in the EO vapor. All eleven Gram-positive strains tested were susceptible to the EO vapor, linalool, citral and beta-pinene vapors separately and the mixture with zones of inhibition of 4.34 cm, 5.32 cm, 5.58 cm, 4.86 cm and 4.68 cm, respectively. Of the three Gram-negative strains tested, Pseudomonas aeruginosa 10145 was resistant to all the vapors. When bacteria inoculated onto stainless steel surfaces were exposed to either the EO vapor or a linalool/citral/beta-pinene vapor mixture there was no significant difference in reduction for the Gram-positive isolates, while the Gram-negative isolates were resistant to both EO vapor and the linalool/citral/beta-pinene mixture. PMID- 22428261 TI - Composition, antioxidant and antimicrobial activities of the leaf essential oil of Machilus japonica from Taiwan. AB - The chemical composition, and antioxidant and antimicrobial activities of the essential oil isolated from the leaf of Machilus japonica from Taiwan have been investigated. The essential oil from the fresh leaves was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. A total of 97 compounds were identified, representing 100% of the oil. The main components identified were alpha-phellandrene (14.5%), alpha-pinene (12.8%), thymol (12.6%), beta-pinene (8.3%), alpha-terpineol (6.5%) and carvacrol (6.0%). The antioxidant activity of the oil was tested by the DPPH (2,2-diphenyl-1 picrylhydrazyl) free radical scavenging capability test. The results showed that the IC50 was 51.8 microg/mL. The antimicrobial activity of the oil was tested by the disc diffusion and micro-broth dilution methods against ten microbial species. The oil exhibited strong growth suppression against Gram-positive bacteria and yeast, with inhibition zones of 48-54 mm and MIC values of 16.12 32.25 microg/mL, respectively. For the antioxidant and antimicrobial activities of the oil, the active source compounds were determined to be thymol and carvacrol. PMID- 22428262 TI - Chemical composition, antimicrobial, antiradical and anticholinesterase activity of the essential oil of Pulicaria stephanocarpa from Soqotra. AB - The chemical composition of the hydrodistilled leaf essential oil from Pulicaria stephanocarpa Balf. Fil was determined by GC-MS analysis, and its antimicrobial, antioxidant and anticholinesterase (AChE) activities were evaluated. Eighty-three compounds were identified representing 97.2% of the total oil. (E)-Caryophyllene 13.4%, (E)-nerolidol 8.5%, caryophyllene oxide 8.5%, alpha-cadinol 8.2% spathulenol 6.8% and tau-cadinol 4.7%, were the main components. Antimicrobial activity of the oil, evaluated using the disc diffusion and broth dilution methods, demonstrated the highest susceptibility on Gram-positive bacteria and Candida albicans. The free radical scavenging ability of the oil was assessed by the DPPH assay to show antiradical activity with IC50 of 330 microg/mL. Moreover, the oil revealed an AChE inhibitory activity of 47% at a concentration of 200 microg/mL using Ellman's method. PMID- 22428263 TI - Composition of the essential oils and antibacterial activities of Hymenocrater yazdianus, Stachys obtusicrena and Nepeta asterotricha three Labiatae herbs growing wild in Iran. AB - Water-distilled essential oils from leaves of Hymenocrater yazdianus Rech.f., flowers of Stachys obtusicrena Boiss., and stems and flowers of Nepeta asterotricha Rech.f., which are endemic to Iran, were analyzed by GC and GC/MS. Fifty-five components of the leaf oil of H. yazdianus were characterized, representing 95.1% of the total components detected. The major constituents were identified as 1,8-cineole (17.6%), beta-caryophyllene (13.9%), alpha-pinene (10.6%) and caryophyllene oxide (10.4%). Germacrene-D (37.5%) and alpha-bisabolol (23.5%) were the main components among the twenty constituents characterized in the flower oil of S. obtusicrena, representing 90.8% of the total components detected. Thirty-five compounds representing 93.0% of the stem oil of N. asterotrica were identified among which terpinen-4-ol (22.8%) and gamma-terpinene (14.1%) were the major ones. The flower oil of the species was characterized by higher amounts of terpinen-4-ol (24.8%), 4a alpha, 7a beta-nepetalactone (18.2%) and 1,8-cineole (11.6%) among the thirty-three components comprising 98.5% of the total oil detected. The antibacterial activity of the stem, leaf and flower oils of Hymenocrater yazdianus, Stachys obtusicrena and Nepeta asterotricha against seven Gram-positive and Gram-negative bacteria were determined using the MIC method. The growth inhibitory zone (mm) was also measured. PMID- 22428264 TI - Antibacterial activities of essential oils extracted from leaves of Murraya koenigii by solvent-free microwave extraction and hydro-distillation. AB - Solvent-free microwave extraction (SFME) for the isolation of essential oil from leaves of Murraya koenigii L. (Rutaceae) has been compared with the conventional hydro-distilled oil (HD) in terms of yield, composition, antioxidant activity, and antibacterial activity against Listeria innocua. The yield of essential oil obtained from 30 min of SFME was similar to that of HD for 180 min. By GC-MS analysis, the major compounds of the essential oil extracted by SFME, which were obtained in somewhat lower amounts than in the essential oil obtained by HD, were alpha-copaene (44.3%), beta-gurjunene (25.5%), isocaryophyllene (12.1%), beta caryophyllene (8.7%) and germacrene D (2.9%). The content of oxygenated terpenes, slightly higher for the SFME-essential oil (2.3%) than the HD-essential oil (1.4%), were much lower than that of nonoxygenated terpenes in both oils. DPPH radical scavenging activities of both essential oils were relatively low (10% 24%). Complete inhibition of growth of L. innocua was observed with both SFME and HD essential oils, at 400 and 600 microg/mL (minimum inhibitory concentration), respectively. The SFME-essential oil at 300 microg/mL provided 92% inhibition, indicating its potential as a natural antimicrobial agent. PMID- 22428265 TI - Chemical composition, antifungal and herbicidal effects of essential oil isolated from Chersodoma Argentina (Asteraceae). AB - Analysis of the hydrodistilled essential oil of the aerial parts of Chersodoma argentina Cabrera by GC-MS and NMR spectroscopy revealed that over 80% consisted of monoterpene hydrocarbons such as alpha-thujene, alpha-pinene and beta-pinene. Contact and headspace volatile exposure assays of the essential oil demonstrated antifungal activity against Sclerotinia sclerotiorum, Sclerotium rolfsii and Rhizoctonia solani with the contact assay showing greater activity than the headspace assay. Herbicidal activity was shown by reduced root growth of Allium porrum, Solanum lycopersicon and Sorghum halepense in both assays. PMID- 22428266 TI - Essential oil composition and acaricidal activity of Schinus terebinthifolius from Atlantic Forest of Pernambuco, Brazil against Tetranychus urticae. AB - The compositions of the essential oils from unripe (UFr) and ripe (RFr) fruits of Schinus terebinthifolius were analyzed by GC and GC/MS. The major compound identified in both oils was limonene (UFr = 44.1 +/- 1.3%; RFr = 31.8 +/- 1.2%), followed by alpha-phellandrene (15.7 +/- 0.4%) in the UFr oil and thujene (21.7 +/- 0.9%) in the RFr oil. Repellent and toxicity activities of the two oils were also evaluated, and the results compared with eugenol. The UFr oil was more active in the fumigation tests (LC50 = 1.46 microL/L of air), whereas the RFr oil was more active in the sealed dishes (SD) than open dishes (OD) contact assay (LC50 = 3.04 microL/cm2) and not significantly different from eugenol. Both oils exhibited significant repellent activity comparable with that of eugenol. The results suggest that the repellent activity of these oils in association with its toxicity could be a great advantage for the integrated management of T. urticae. PMID- 22428267 TI - Evaluation of the anti-Leishmania major activity of Satureja bakhtiarica essential oil in vitro. AB - Leishmaniasis is a painless chronic skin disease that is caused by the protozoan parasite Leishmania. Due to the importance of this disease and the side effects of chemical drugs, use of drugs of plant origin to treat Leishmaniasis is very important. In the present study, the chemical composition and the anti-Leishmania major activity of the essential oils obtained from Satureja bakhtiarica were evaluated in vitro. The oils were extracted using a Clevenger apparatus and then the chemical composition was analyzed by GC-MS. Promastigotes of L. major were cultured in both N.N.N and RPMI1640 media. GC-MS analysis showed 13 compounds, in which the major components were the phenolic (37.4%) compounds, thymol (22.6%) and p-cymene (19.3%). The essential oil of S. bakhtiarica showed higher activity against L. major than the standard anti-Leishmania drug, glucantime,. Perhaps because of the high concentration of phenolic compounds in the essential oil, all the parasites were killed after 24 hours. The essential oil from S. bakhtiarica is a potential plant drug against leishmaniasis. Further studies are necessary to evaluate this oil in animal models (in vivo) for future drug applications. PMID- 22428268 TI - Spartium junceum aromatic water: chemical composition and antitumor activity. AB - The purpose of this study was to analyse the chemical composition of Spartium junceum L. (also known as Spanish Broom) aromatic water and to evaluate its cytotoxic activity against a series of human cancer cell lines (melanoma: RPMI 7932; leukemia: K562; breast cancer cell: MCF7-Bart and MCF7-ICLC, colon adenocarcinoma: SW480). The results show that the aromatic water was cytotoxic toward the tumor cell lines analyzed (RPMI 7932, K562, MCF7-Bart, MCF7-ICLC, SW480), while it did not appreciably alter the viability of normal keratinocytes (NCTC 2544) suggesting its potential use as an antitumor agent for cancer treatment and/or prevention. PMID- 22428269 TI - [3-D technology]. PMID- 22428270 TI - [Radiographs for the assessment of bone loss around implants. Exploring the potential]. AB - Twelve per cent of oral implants fail due to the loss of bone within 15 years after implantation. If bone loss is detected early, measures can be taken which increase the success rate of implants. To monitor implants, radiographs are made regularly. Generally, the loss of marginal bone level is measured on the radiographs. An alternative method is based on the subtraction ofradiographs. The authors applied subtraction to non-standardized panoramic radiographs of patients with implants. Bone loss around the implants could be rendered visible, at least on the level of patient groups. For individuals, no accurate method exists to render bone loss around implants visible. For the early recognition of bone loss around implants, intra-oral radiographs are preferred above panoramic radiographs. It is also important to maintain the same exposure time and projection geometry. PMID- 22428271 TI - [Rontgen and his discovery of 'X-rays']. PMID- 22428272 TI - [Diabetes mellitus]. AB - Currently there are over 740,000 patients with diabetes mellitus in the Netherlands, and this number will increase further in the coming years. Approximately 90% of patients has type 2 diabetes, a metabolic disorder that is often associated with obesity, hypertension and increased cholesterol levels. Treatment of diabetes mellitus is essential to reduce the risk of severe complications with irreversible organ damage in the long-term. Gingivitis and periodontitis are more common in patients with diabetes mellitus and are now also considered as complications of diabetes. Collaboration among healthcare professionals is important for effective diabetes care. PMID- 22428273 TI - [A peripheral osteoma]. AB - A 43-year-old man appeared with a painless, asymptomatic swelling on the left side of his neck, which had existed for years and had slowly been progressing. After surgical removal, it became clear that it had to do with a peripheral osteoma. This is a benign lesion with a low incidence. Generally, complete surgical removal leads to cure, although recurrence is possible. A peripheral osteoma is mostly located in the mandible, although peripheral osteomata in the frontal or maxillary sinus have been described. The aetiology is unknown. Trauma in the patient's history has been described on occasion. The presence of multiple osteomata in the jawbones is characteristic of Gardner's syndrome. PMID- 22428274 TI - [Validity and reliability of digital diagnostic measurements on digital three dimensional dental models]. AB - Digital three-dimensional dental models are widely used for orthodontic diagnosis. The aim of this clinical study was to assess the validity and reliability of digital diagnostic measurements on digital three-dimensional dental models. Two types of digital three-dimensional dental models and a plaster dental model were made of 10 volunteers. Digital measurements of the tooth width were compared with the physical measurements of the plaster models. None of the digital diagnostic measurements appeared to differ significantly from the physical measurements. PMID- 22428275 TI - [Dissertations 25 years after date 32. Physiological aspects of mastication]. AB - Mastication is the first phase of the digestive process. It serves to reduce the size ofsolid food and to mix it with saliva so that it can be swallowed. The degree to which food is reduced in size depends on various factors, such as the masticatory force generated by the jaw muscles, the number and form of the (pre )molars, the neuro-muscular control of the movements of the mandible and the quantity and composition of the saliva. If the mastication is to operate efficiently, form and function have to be properly balanced. Disturbances in function and abnormalities inform can lead to complaints and are often accompanied by a diminished fragmentation of the food. By investigating the fundamental mechanisms of the functional process, abnormalities can clinically be better understood. PMID- 22428276 TI - Applications up yet places down. PMID- 22428277 TI - "Every nursing contact counts for improving public health". PMID- 22428278 TI - Carter: "NHS faces toughest year yet". Interview by Nick Golding. PMID- 22428279 TI - "This year's resolution is to see the power in the little things". PMID- 22428280 TI - "Technology can transform the quality of clinical practice". PMID- 22428281 TI - Managing obesity in primary care. AB - Obesity is a complex problem and often difficult to tackle in primary care. A year-long pilot of a practice nurse-led scheme that used a holistic approach towards self-care in obesity management was set up to reduce the cardiovascular risk of patients who were obese and improve their quality of life. This person centred approach may offer an important tool in the management of these patients in the GP surgery. PMID- 22428282 TI - Self-management of obesity. PMID- 22428283 TI - Why do students fail to disclose health problems? AB - BACKGROUND: At the university where this study took place, pre-qualifying healthcare students had previously been enrolled on programmes and were found to have pre-existing and ongoing health problems, which caused difficulties for some students during clinical placements. AIM: To develop a web-based information zone dealing with students' concerns about fitness-to-practise issues. METHOD: A three stage study involving an online student survey, in-depth student interviews and development of a university web-based information zone was carried out. RESULTS: The web zone's content is based on key areas of importance identified by students who participated in the study. CONCLUSION: Early indications show that prospective and current students regularly use the web zone, demonstrated by the number of site hits. PMID- 22428284 TI - Effect of recording site on pulse oximetry readings. AB - BACKGROUND: Ambulatory oxygen requirements are routinely assessed and titrated using portable finger pulse oximetry. However, movement artefacts from hands moving or reduced circulation may adversely affect the accuracy of measurement. At Wythenshawe Hospital, we decided to use an ear oximeter routinely in addition to the finger oximeter. AIM: To evaluate and compare the use of portable oximetry measurements taken from the ear and finger during ambulatory assessments. METHOD: Before, during and after a six-minute walking test, 304 patients had ear and finger pulse oximetry measurements recorded. RESULTS: There was a significant difference between ear and finger measurements before and after exercise (p=<0.001 for both). The differences would have altered the clinical outcome in 27% of those assessed. PMID- 22428285 TI - Healing hands. PMID- 22428286 TI - Do you know how to identify and deal with stress? PMID- 22428287 TI - [Cornea in diabetus mellitus]. AB - Diabetus mellitus is associated with numerous ocular complications. Diabetic keratopathy occurs in response to a neuropathy of the ophthalmic division of the trigeminal nerve, but also as a result of epithelial subclinical abnormalities, limbal vasculopathy and decrease in tear production. It comprises several symptomatic corneal conditions inducing superficial punctate keratopathy and persistent corneal epithelial erosions; the latter can progress to corneal ulceration and is often resistant to routine clinical management. PMID- 22428288 TI - [Normal corneal wound healing]. AB - Corneal wound healing is divided into several phases that, in reality are part of a continuous process, involving the corneal epithelium and stroma, corneal nerves, inflammatory cells, lacrimal glands. The layers of the cornea interact through autocrine and paracrine modulation, mediated by cytokines, growth factors, proteolytic enzymes. Corneal healing is affected by many factors, including: wound size and depth, causative agent, age, medication, preexisting diseases. PMID- 22428289 TI - [Specular microscopy and clinical correlations]. AB - Specular microscope displays images of reflected light at an optical interface. Allows qualitative, quantitative and morphometric analysis of corneal endothelium in a noninvasive way using specular reflection. This can be achieved by: Slit Lamp or Specular Microscope. Confocal Microscope is a category of Specular Microscope where the objective and condensor lens have the same focal point. It has a higher resolution and unlike conventional microscope this can scan all corneal layers. PMID- 22428290 TI - [Headache--from an ophthalmic point of view]. AB - The authors approach a subject keen to neuroophthalmologists, which is becoming more and more frequent with the overuse of VTU (videoterminal unit). They hope to better understand the headache (from an ophthalmic point of view), and how to diagnose it better and faster. PMID- 22428291 TI - [Azarga, a new and useful fixed combination in glaucoma treatment]. AB - Azarga is a new fixed combination product that consists of the carbonic anhydrase inhibitor brinzolamide 1% and the betablocker timolol 0,5%. Its efficacy in lowering intraocular pressure is similar to that of Cosopt, a fixed combination that combines another carbonic anhydrase inhibitor (eg dorzolamide 2%) with the betablocker timolol 0,5%. The main difference between these two ocular hypotensive agents lies in their safety profiles with Cosopt causing more ocular discomfort to appear while instilling (burning,stinging and smarting sensations) probably due to the differences between the pH of these two fixed combinations agents. Its similar efficacy and enhanced tolerability compared with Cosopt make Azarga represent a resonable alternative for the patients who do not achieve an adequate intraocular pressure control while treating with a monotherapeutic agent. PMID- 22428292 TI - [Specific aspects in diabetic cataract]. AB - Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Prevention of eye complications by removing metabolic risk factors and good control of the disease is the most efficient step, because no effective treatments in the absence of optimal glycemic control through diet and medication. Diabetic cataract is a condition that benefits from surgery with good functional recovery. This recovery depends on the detection and treatment of diabetic retinopathy with photocoagulation correct laser. PMID- 22428293 TI - [The latest developments in glaucoma therapy using fixed combination products]. AB - Modern fixed-combination products simplify medication dose regimen without sacrificing their effectiveness.Potential benefits of the therapy with fixed combination products are enhanced tolerability increased convenience,better compliance,cost and time economy and removal of the wash out effect. Regarding intraocular pressure lowering effect, fixed-combination agents are superior to monotherapy with the two medication components, with the exception of Duotrav that is not superior to travoprost action.Fixed-combination products are noninferior to concomitant administration of the two components of medication (nonfixed-combination agents) relative to their ocular hypotensive efficacy with the exception of Ganfort that is however inferior to concurrent administration of both the bimatoprost and timolol. PMID- 22428294 TI - [Pseudo-internuclear ophthalmoplegia in myasthenia gravis]. AB - Myasthenia Gravis is an organ-specific autoimmune disorder generaly thought to be caused by an antibody-mediated attack against the skeletal muscle nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Not infrequently there may be other diseases accompanying myasthenia, that can give different neuro-ophtalmological manifestations or neurological syndromes with autoimmune substrate. By these autoimmmune diseases we note:Autoimmune thyroiditis, Systemic lupus erythematous, Dermatomyositis, i.e. The extraocular muscle weakness is present at 90% of myastenia patients. While anti-AChR are detectable in the majority of patients with generalized myasthenia, at patients with ocular myasthenia these antibodies are nearly undetectable. On the another hand, epidemiological, clinical and immunoserological studies, suggests that the ocular myasthenia and generalized myasthenia are two separate disorders. Both Myasthenia Gravis forms could be associated with other autoimmune disturbances with ocular impact, for example such as Autoimmune thyroiditis Ophtalmopathy. PMID- 22428295 TI - Mathematical models of human retina. AB - To describe the human retina, due the absence of complete topographical data, mathematical models are required. The mathematical formula permits a relatively simple representation to explore the physical and optical characteristics of the retina, with particular parameters. Advanced mathematical models are applied for human vision studies, solid modelling and biomechanical behavior of the retina. The accurate modelling of the retina is important in the development of visual prostheses. The objective of this paper is to present an overview of researches for human retina modelling using mathematical models. PMID- 22428296 TI - [Fixed combination of topical prostaglandin analogue in glaucoma treatment]. AB - The purpose of glaucoma treatment is to prevent progressive loss of optic nerve fibers and thereby to preserve the visual field. Because increased IOP is a primary risk factor in developing glaucoma, descrease its value below which may affect the optic is the antiglaucoma treatment target. This paper provides an overview of glaucoma treatment and the use of fixed combinations of topical prostaglandin analogues (PGA). PMID- 22428297 TI - [Progresses in antiinflamatory treatment in cataract surgery]. AB - Anti-inflamatory medication is commonly used to reduce inflammation, edema and symptoms associated with allergies, trauma and infections diseases. Topical nonsteroidial anti-inflammatory (NSAIDs) and topical corticosteroids are overview of the role of topical NSAIDs and the progress of their use in eye surgery PMID- 22428298 TI - [Ocular surface in glaucoma patients with topical treatment]. AB - PURPOSE: Our study is trying to establish the prevalence of Dry Eye Syndrome in glaucoma patients treated with topical medication. MATERIAL AND METHOD: We investigated 40 patients (21 females and 19 males), age over 50, treated with topical antiglaucoma medication for at least one year. The control group was consisted of 40 healthy adults, 20 female and 20 males, age over 50, who didn't took any ocular treatment in the last three months. Each patient completed an Ocular Surface Disease Index questionnaire (OSDI) and underwent evaluation by Schirmer test and tear break-up time (TBUT). RESULTS: In the control group we diagnose 9 patients (23%) with Dry Eye Syndrome. In glaucoma group 25 patients (63%) had Dry Eye Syndrome. Tear break-up time showed abnormal tear quality in all of those 25 patients. Schirmer testing showed 23 patients with decrease in tear production. Using Ocular Surface Disease Index 22 patients reported ocular symptoms. Unlike the control group, at the glaucoma patients we didn't notice any difference between the two genders. Regarding the age, we found at the control group the Dry Eye Syndrome at patients over 70 years old, and at the glaucoma group the average age was 55 years old. CONCLUSIONS: In general population the prevalence of Dry Eye Syndrome is about 20%, mainly affecting females over 60 years old. In our study 63% of glaucoma patients had Dry Eye Syndrome--as a result of long term topical therapy that affects the integrity of the tear film and the ocular surface. PMID- 22428299 TI - [Perimetric changes in advanced glaucoma]. AB - AIM: The evaluation of various perimetric aspects in advanced glaucoma stages correlated to morpho-functional changes. MATHERIAL AND METHOD: Retrospective clinical trial over a 10 months time period that included patients with advanced glaucoma stages, for which there have been recorded several computerised visual field tests (central 24-2 strategy, 10-2 strategy with either III or V--Goldman stimulus spot size) along with other morpho-funtional ocular paramaters: VA, lOP optic disk analysis. RESULTS: We included in our study 56 eyes from 45 patients. In most cases 89% it was an open angle glaucoma (either primary or secondary) Mean visual acuity was 0.45 +/- 0.28. Regarding the perimetric deficit 83% had advanced deficit, 9% moderate and 8% early visual changes. As perimetric type of defect we found a majority with general reduction of sensitivity (33 eyes) + ring shape scotoma. In 6 eyes (10.7%) having left only a central isle of vision we performed the central 10-2 strategy with III or V Goldmann stimulus spot size. Statistic analysis showed scarce correlation between the visual acuity and the quantitative perimetric parameters (MD and PSD), and variance analysis found present a multiple correlation parameter p = 0.07 that proves there is no liniary correspondence between the morpho-functional parameters: VA-MD(PSD) and C/D ratio. CONCLUSIONS: In advanced glaucoma stages, the perimetric changes are mostly severe. Perimetric evaluation is essential in these stages and needs to be individualised. PMID- 22428300 TI - Mating types in Paramecium and a molecular approach to their determination. AB - Mating types are expressed in ciliates for the duration of the mature period of their clonal cycle. During cell conjugation the reciprocal fertilization of complementary mating types takes place. Models of mating type determination in the Paramecium aurelia species complex based on classical genetics are reviewed including molecular aspects of the studies. PMID- 22428301 TI - Comparative cytogenetic analysis of sex chromosomes in several Canidae species using zoo-FISH. AB - Sex chromosome differentiation began early during mammalian evolution. The karyotype of almost all placental mammals living today includes a pair of heterosomes: XX in females and XY in males. The genomes of different species may contain homologous synteny blocks indicating that they share a common ancestry. One of the tools used for their identification is the Zoo-FISH technique. The aim of the study was to determine whether sex chromosomes of some members of the Canidae family (the domestic dog, the red fox, the arctic fox, an interspecific hybrid: arctic fox x red fox and the Chinese raccoon dog) are evolutionarily conservative. Comparative cytogenetic analysis by Zoo-FISH using painting probes specific to domestic dog heterosomes was performed. The results show the presence of homologous synteny covering the entire structures of the X and the Y chromosomes. This suggests that sex chromosomes are conserved in the Canidae family. The data obtained through Zoo-FISH karyotype analysis append information obtained using other comparative genomics methods, giving a more complete depiction of genome evolution. PMID- 22428302 TI - Genetic variability and changes of elemental concentrations in cells of Tetrix tenuicornis (orthoptera: tetrigidae) from polluted and unpolluted areas. AB - Genetic variability between populations of the orthopteran insect Tetrix tenuicornis, collected from six locations in Poland, was assayed by using the random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) method. The results show that insects in a population from metal polluted areas in Boleslaw have reduced genetic variability in contrast to five other populations located in unpolluted areas. The insects from polluted sites also showed significant changes in elemental concentrations in nerve and muscle cells, measured by X-ray spectroscopy, when compared to insects of the same species collected from unpolluted sites. PMID- 22428303 TI - Prenatal exposure to antiandrogen flutamide affects androgen receptor (AR) expression in postnatal ovarian development in pig. AB - The following study was undertaken to localize androgen receptors (ARs) in various structures of the porcine ovary after prenatal exposure to antiandrogen flutamide. In utero treatment by antiandrogens may have adverse effects on reproductive function in immature and adult animals. Flutamide was injected into pregnant swines between days 20 and 28 (GD20) or 80 to 88 (GD80) of gestation. The ovaries were collected from treated animals and from control ones (non treated) at two different points of development: from immature and adult pigs. Immunoexpression of AR was determined for preantral and antral follicles and for stroma cells. Immunostaining showed that AR expression in immature animals was unaffected in the primary follicles, while in the preantral and antral follicles the AR level fluctuated depending on day of treatment as well as on analyzed tissue. In adult animals, the immunoexpression of AR slightly decreased in antral follicles independently on the day of flutamide treatment. Therefore, AR expression in postnatal life may be affected by in utero exposure to antiandrogen flutamide. PMID- 22428304 TI - Comparative effects of new generation oxazaphosphorines on the size and viability of human acute myeloblastic leukemia cells. AB - Mafosfamide cyclohexylamine salt (D-17272), 4-hydro-peroxy-cyclophosphamide (D 18864), and beta-D-glucose-isophosphoramide mustard (D-19575, glufosfamide) are three new generation oxazaphosphorine agents. The aim of the present study was to compare the cell response to the action of these three oxazaphosphorines. The experiments were performed in vitro on human acute myeloblastic leukemia ML-1 cells. After exposure of ML-1 cells to the oxazaphosphorines, the size, viability and count of these cells were determined. The research was conducted using the spectrophotometric MTT assay and the electronic Beckman Coulter method. The temporary changes in the ML-1 cell size, viability and count, were dependent on the oxazaphosphorine agent tested, its dose, and the time intervals after its application. Among the three oxazaphosphorine agents, D-18864 proved to be the most cytotoxic, and D-19575 was characterized by the lowest cytotoxicity. The results suggest the possibility of using the electronic sizing and counting method and the MTT assay as a rapid in vitro test for assessing leukemic cell sensitivity to the action of new potential chemotherapeutic agents. PMID- 22428305 TI - Morphological characteristics of neonatal adipose tissue. AB - The aim of the present work was to study the morphological characteristics of neonatal adipose tissue using rats as an animal model. The results revealed that the subcutaneous adipose tissue of newborns consists of packets of unilocular adipose cells (one large lipid drop occupying the whole cell and pushing the cytoplasm and the nucleus to the cell periphery) and some multilocular fat cells (several lipid droplets of different size and an almost centrally located nucleus). All the adipocytes demonstrated positive immunohistochemical expression for leptin, whereas the multilocular adipose cells were positive for cyclin D1. These findings suggest that the multilocular adipose cells are preadipocytes that have not yet finished proliferation and differentiation and could under some external and/or internal stimuli conclude their development and become mature unilocular adipocytes, thus increasing fat mass. PMID- 22428306 TI - Effect of age and sex on digestive tract morphometry of guinea fowl (Numida meleagris L.). AB - As guinea fowl age, their body weights and length of the esophagus and crop increased significantly, and relative length (cm x 100 g b.w(-1)) of the small intestine, caeca and total intestine decreased significantly (P < or = 0.05) in males and females. In addition, 52-week-old males had a significantly higher percentage length of rectum and heart weight, and females a significantly higher gizzard weight compared to 13-week-old birds. Compared to females, adult males differed significantly (P < or = 0.05) in the length of caeca and also in the proportion of the gizzard, proventriculus, heart and liver in total weight. PMID- 22428307 TI - Skeletal muscle-derived fibroblast-like cells fail to enable HeLa cells to induce bone in the murine kidney. AB - HeLa cells fail to induce bone in murine kidneys, despite being highly chondro/osteogenic when implanted into thigh muscles. Bone induction in the kidneys failed also when HeLa cells were grafted together with skeletal-muscle derived cell cultures. It is postulated that kidney parenchyma releases unidentified factcor(s) which prevent activation by inducer of cells termed Friedenstein's (1976) "inducible osteoprogenitor cells", while this hypothetical factor does not prevent further differentiation of"determined osteoprogenitor cells", thus allowing bone to form in the renal parenchyma. PMID- 22428308 TI - Pathological changes in the microstructure of longissimus lumborum muscle from five breeds of pigs. AB - The aim of the study was to determine the extent of histopathological changes in m. longissimus lumborum of PL, PLW, Duroc, Pietrain, and Pulawska pigs (N = 30 per breed) aged 210 days. Changes in fibre size (atrophy, hypertrophy - giant fibres), changes in fibre shape (angular fibres), degenerative lesions (necrosis with phagocytosis) and connective tissue hypertrophy were evaluated. The percentage of individual pathological changes in m. longissimus lumborum of the analysed pig breeds was relatively low. Significantly more normal fibres were found in the muscles of Pulawska compared to Pietrain pigs. Muscle fibre atrophy was the most frequent and extensive histopathological change. The muscles of Pulawska pigs had significantly fewer atrophic, giant and angular fibres, significantly less necrosis with phagocytosis, and less animals with connective tissue hypertrophy compared to the other pig breeds. On the other hand, Pietrain pigs were characterized by a greater number of animals with giant fibres and a significantly higher proportion of giant fibres compared to the other breeds. Also the diameter of giant fibres was the largest in Pietrain, intermediate in PL and PLW, and the smallest in Duroc and Pulawska pigs. Moreover, current findings indicate that giant fibres may arise from each muscle fibre type (I, IIA and IIB). It is concluded that selection of pigs for increased leanness contributes to the incidence of histopathological changes, which may decrease pork quality. PMID- 22428309 TI - Prevalence of Toxoplasma gondii infection diagnosed by PCR in farmed red foxes, arctic foxes and raccoon dogs. AB - The aim of this study was to compare Toxoplasma gondii infection in three canid species: red fox Vulpes vulpes, arctic fox Vulpes lagopus and raccoon dog Nyctereutesprocyonoides kept at the same farm. Anal swabs were taken from 24 adult and 10 juvenile red foxes, 12 adult arctic foxes, three adult and seven juvenile raccoon dogs. Additionally, muscle samples were taken from 10 juvenile red foxes. PCR was used to detect T. gondii DNA. T. gondii infection was not detected in any of the arctic foxes; 60% ofraccoon dogs were infected; the prevalence of the parasite in material from red fox swabs was intermediate between the prevalence observed in arctic foxes and raccoon dogs. It is possible that susceptibility and immune response to the parasite differ between the three investigated canid species. T. gondii DNA was detected in muscle tissue of five young foxes. The results of this study suggest that T. gondii infection is not rare in farmed canids. PMID- 22428310 TI - The level of major proteins and minerals in the blood serum of chickens fed diets with pure cellulose. AB - The aim of the research was to determine the concentration of total protein and its fractions as well as the concentration of selected mineral components in the blood serum of male broiler chickens Cobb 500 fed diets with different cellulose content. Blood samples were collected for examination from the birds' pterygoid canal veins on their 42 day of age. There was no influence of cellulose preparation on the content of total protein and its fractions: albumins, alfa1-, alfa2-, beta-, gamma-globulins, albumin to globulin ratio, inorganic phosphorus, sodium, potassium, chloride and iron concentrations in blood serum. The highest calcium concentration (P < 0.05) was detected in the blood serum of males fed a diet with the highest cellulose content (0.75-0.95%). Simultaneously, a tendency of increased calcium content was observed along with an increased amount of pure cellulose in diets. The lowest magnesium level (P < 0.05) was observed in the blood of birds fed diets with the lowest amount of cellulose (0.25-0.45%). The magnesium level in the blood of birds fed a diet with higher amounts of cellulose did not considerably differ from the control group. Results from the current study suggest that introduction of a limited amount of pure cellulose into the diet of broiler chickens does not affect total protein concentration and protein fractions but can influence the mineral content in the blood serum. PMID- 22428311 TI - In vitro contractility of normal and aneurysmal abdominal aorta muscle coat sections in human and animal material. AB - The objective of the study was to demonstrate spontaneous contractile activity of the smooth muscle coat of the aorta in human and animal material. Spontaneous contractility of smooth muscle tissue, or tonus, is essential for the proper function of many internal organs as observed in the many types of muscle cells which make up the internal structures. The spontaneous contractile activity of the muscle tissue in blood vessels is particularly marked in resistance vessels, regulating circulation within organs or tissues. It can also be observed in large blood vessels such as arteries and veins. The contractile activity of muscular tissue isolated from arteries is the result of a number of factors, including endogenous paracrine substances, neurotransmitters released at postganglionic endings (mostly within the sympathetic system), cells capable of spontaneously generation of functional potentials (pacemaking cells) and the vascular endothelium. Pacemaking cells present in the aortic wall are an important factor in the development of the spontaneous contractility of the muscular coat of the aorta. They are capable of generating functional potentials, resulting in the constant tonus of the smooth muscular coat (comprising the aortic wall) due to tonic contraction. In vitro studies were carried out on abdominal aortic sections collected from 30 New Zealand rabbits with a body mass of 3-4 kilograms each and also on aneurysmal abdominal aortic sections collected during elective aneurysm repair procedures in humans (10 abdominal aortic sections). The 1.5 cm-long sections were mounted in chambers of an automated water bath. The sections were oriented in a transverse and longitudal fashion in order to compare contractility. The incubation medium consisted of Krebs-Henseleit buffer. Spontaneous contractile activity was observed during the study, characterized by rhythmic contractions of the muscular layer of the aorta. The contractile tension within the sections was 0.15 mN in the case of rabbit sections and 0.8 mN in the case of human sections. The average duration of a single contraction was 38.3 +/- 15.05 seconds. The average contraction frequency, i.e. the average number of contractions per minute, was 1.61 +/- 0.54 contractions per minute. The spontaneous contraction is modulated by many factors like endogenous paracrine substances, neurotransmitters or vascular endothelium. PMID- 22428312 TI - Body weight and some biometrical traits of ring-necked pheasants (Phasianus colchicus) at different ages. AB - Although the growth of pheasants is an important issue, there are few publications providing information on body weight and morphometrics of pheasants at different ages. The aim of this study was to investigate body weight, tarsus length, wing length and wingspan in farmed pheasants aged 3-16 weeks. The study was carried out on 50 pheasants (31 females and 19 males). All one-day old birds were marked and kept until the 16th week of life. In the 3rd 8 h 12th and 16th weeks of life all pheasants were weighted and tarsus length, wing length and wingspan were measured. Male chicks appeared to be significantly heavier than females (P< or = 0.01) already in the third week of life. Also their wings were longer and their wingspan attained higher values (P < or = 0.05). Absolute gains of the majority of traits also differed between sexes (being larger in males) in all studied periods. Values of body weight, tarsus length and wingspan noted in the third week of life were significantly correlated with all later measurements. Thus body weight and some biometrical traits of pheasant chicks measured already at the 3rd week of life could be applied as predictors of future body weight and size. PMID- 22428313 TI - The effect of sperm concentration in the ejaculate on morphological traits of bull spermatozoa. AB - Experiments were performed on 75 ejaculates obtained from 19 bulls representing different cattle breeds used at the Masovian Centre for Animal Breeding and Reproduction in Lowicz. Fresh ejaculates were measured in respect to their volume and sperm count in the ejaculates was determined. The ejaculates were classified based on the criterion of sperm concentration and divided into five groups. Sperm morphometric measurements were taken from each bull and assessment of semen morphology was done on the basis of examination under a microscope using preparations made from fresh ejaculates. For each slide, morphometric measurements were taken of 15 randomly selected spermatozoa characterised by normal morphology and well visible under the microscope. Additionally, in each preparation morphometry of 500 spermatozoa was evaluated, numbers of spermatozoa with normal morphology and morphological abnormalities were recorded and these were categorized into spermatozoa with major and minor defects. An insignificant correlation was observed between the sperm concentration in the ejaculate and morphological traits, dimensions and shapes of bull spermatozoa. The less concentrated ejaculates contained spermatozoa with a slightly larger head circumference and a more elongated head shape in comparison with the spermatozoa in the more concentrated ejaculates. The highest frequency of morphologically malformed spermatozoa, both in the case of primary and secondary alterations, was observed in ejaculates with sperm concentration of no more than 1000 x 10(3)/mm3. PMID- 22428314 TI - Effect of in ovo injection of vitamin C during incubation on hatchability of chickens and ducks. AB - The aim of the investigation was to ascertain the influence of different doses of vitamin C injected at selected dates of incubation into the eggs of broiler breeders and Pekin ducks on hatchability. The injected vitamin C doses were administered into the air cell on the 13th, 15th and 17th days (3 and 6 mg- chickens) and on the 12th and 20th days (4 and 8 mg--ducks) of incubation. In the case of chickens, no significant differences were recorded between the control and experimental groups with regard to hatchability, although the highest value of hatchability from fertilized eggs was determined in the group injected with 6 mg of vitamin C on the 15th day of incubation. On the other hand, in ducks, significant differences were found between the control and experimental groups (4 mg of vitamin C administered on days 12 and 20 and 8 mg of vitamin C injected on day 20 of incubation) regarding hatchability. The value of this trait was higher in the group of eggs injected with ascorbic acid in comparison with the eggs which were not treated. On average, the difference amounted to 32.5 percentage points. Similarly, in the case of the number of dead embryos and unhatched chicks, better results were observed in the above-mentioned experimental groups. In summary, vitamin C injected into chicken eggs failed to influence hatchability. In the case of duck eggs, it was demonstrated that their injection on the 20th day of incubation with selected doses of vitamin C (4 and 8 mg/egg) improved hatchability by decreasing the proportions of dead and unhatched embryos. PMID- 22428315 TI - Discrete movements of foot epithelium during adhesive locomotion of a land snail. AB - During the adhesive locomotion of land snails a series of short dark transverse bands, called pedal or foot waves, is visible ifa moving snail's ventral surface is observed through a sheet of glass. Moreover, the mucus secreted from the pedal glands and some pedal epithelial cells forms a thin layer which acts as a glue augmenting adherence, while also acting as a lubricant under the moving parts of the snail's foot. The relationships between velocity and the frequency of pedal waves as well as changes in the volume of small air bubbles under foot waves were analyzed by means of digital recordings made through a glass sheet on which the snails were moving. On the ventral surface of a moving snail foot, the adhering parts of the foot constituted about 80% of the total area, while several moving parts only about 20%. The single moving region of the foot (the pedal wave) amounted to about 3% of snail length. The epithelium in the region of the pedal wave was arched above the substrate and was also more wrinkled than the stationary epithelium, which enabled the forward motion of each specific point of epithelium during the passage of a pedal wave above it. The actual area of epithelium engaged by a pedal wave was at least 30% greater than the area of the epithelium as recorded through a glass sheet. In the region of the pedal wave, the tiny subepithelial muscles acting on the epithelium move it up in the front part of the wave, and then down at the end of the wave, operating vertically in relation to the substrate. In the middle part of the wave, the epithelium only moves forward. In summary, during the adhesive locomotion of snails, the horizontal movement of the ventral surface epithelium proceeds as temporally separate phases of upward, forward and downward movement. PMID- 22428316 TI - Technical advisors serving the profession. PMID- 22428317 TI - Sneakers and spokes: an assessment of the walkability and bikeability of U.S. postsecondary institutions. AB - The purpose of the study described in this article was to assess the walkability and bikeability of 15 U.S. postsecondary education campuses. The Centers for Disease Control and Prevention's evidence-based Healthier Worksite Initiative Walkability Audit was modified to rate campus walking and biking path segments for path safety, quality, and comfort. Universities (n = 13) assessed an average of 44 path segments, which earned a mean score of 72.71 +/- 10.77 SD (possible range 0 to 100). Postsecondary technical schools (n = 2) assessed 20 path segments, which received an average score of 76.56 +/- 13.15. About 70% of path segments received a grade A or B, but almost 1 in 10 received a failing or poor support score for walking and biking. Nearly half or more campus environments scored significantly below an acceptable score on many path safety and quality criteria. Postsecondary education campuses that are supportive of walking and biking offer numerous benefits to the environment and people. Findings from environmental assessments like the data reported here can provide valuable input to campus planners. PMID- 22428318 TI - Lead in drinking water: sampling in primary schools and preschools in south central Kansas. AB - Studies in Philadelphia, New York City, Houston, Washington, DC, and Greenville, North Carolina, have revealed high lead levels in drinking water. Unlike urban areas, lead levels in drinking water in suburban and rural areas have not been adequately studied. In the study described in this article, drinking water in primary schools and preschools in five suburban and rural south central Kansas towns was sampled to determine if any exceeded the U.S. Environmental Protection Agency (U.S. EPA) guidance level for schools and child care facilities of 20 parts per billion (ppb). The results showed a total of 32.1% of the samples had detectable lead levels and 3.6% exceeded the U.S. EPA guidance level for schools and child care providers of 20 ppb. These results indicate that about one-third of the drinking water consumed by children age six and under in the five suburban and rural south central Kansas towns studied has some lead contamination, exposing these children to both short-term and long-term health risks. The authors suggest a need for increased surveillance of children's drinking water in these facilities. PMID- 22428319 TI - The potential for community exposures to pathogens from an urban dairy. AB - The objectives of the study described in this article were to evaluate the variation and transport of fungal and bacterial concentrations in the air of a northern Mexico dairy cattle confined animal feeding operation (CAFO) and to determine the concentration and incidence of antibiotic-resistant Staphylococcus aureus isolates. Two-stage viable cascade impactors were used to measure the culturable airborne fungal organisms and bacteria. S. aureus resistant to penicillin, ampicillin, or cefaclor was identified. Samples were collected at three locations that were designated as on site, upwind of the cattle, and downwind of the cattle. The highest concentrations of culturable bacterial bioaerosols were consistently recovered from the on-site location. More than half of the organisms were antibiotic resistant at the on-site location. Elevated levels of culturable bacterial bioaerosols were recovered from the upwind site that may have been associated with the surrounding community. Bioaerosol concentrations were found in higher amounts than in a facility in the southwestern U.S. examined in the authors' previous study. The urban setting of the CAFO resulted in a higher potential for immediate community exposures. PMID- 22428320 TI - ATSDR in the 21st century. PMID- 22428321 TI - Evaluating local and state food and water safety programs. PMID- 22428322 TI - 12 laws of the future. PMID- 22428323 TI - The story of CanSAR. PMID- 22428324 TI - Think future--introducing Thomas Frey. PMID- 22428325 TI - MNA tells Congressmen Camp and Upton to "listen up!" Supercommittee members have not responded to requests for public town halls. PMID- 22428326 TI - Nurses in the vanguard. PMID- 22428327 TI - The Main Street Contract--ongoing. PMID- 22428328 TI - Hard-fought gains. PMID- 22428329 TI - The hitting stops now! PMID- 22428330 TI - Task Force on Nursing Practice overview. PMID- 22428331 TI - De$killing. PMID- 22428332 TI - [Deglutition disorders: whistling after eating. Zenker's diverticulum]. PMID- 22428333 TI - [Waiting room television watching: bringing your IGeL to the patient]. PMID- 22428334 TI - [Early intervention for stuttering]. PMID- 22428335 TI - [Heart risk patient before surgical intervention: how to keep him safe through the operation?]. PMID- 22428336 TI - [Sports and cancer: on the ergometer during chemotherapy? (interview by Dr. Christine Sarostzik)]. PMID- 22428337 TI - [Prevention and therapy of hypertension: let us take advantage of the new chances]. PMID- 22428338 TI - [Hypertension as a model for prevention]. PMID- 22428339 TI - [Errors in diagnosis and therapy of hypertension]. PMID- 22428340 TI - [Asthma--what is to do in general practice?]. PMID- 22428341 TI - The contribution of culture to Korean American women's cervical cancer screening behavior: the critical role of prevention orientation. AB - BACKGROUND: Despite the proven benefits of Pap testing, Korean American women have one of the lowest cervical cancer screening rates in the United States. This study examined how cultural factors are associated with Pap test utilization among Korean American women participants. METHODS: Quota sampling was used to recruit 202 Korean American women participants residing in New York City. Hierarchical logistic regression was used to assess the association of cultural variables with Pap test receipt. RESULTS: Overall, participants in our study reported significantly lower Pap test utilization; only 58% reported lifetime receipt of this screening test. Logistic regression analysis revealed one of the cultural variables--prevention orientation--was the strongest correlate of recent Pap test use. Older age and married status were also found to be significant predictors of Pap test use. CONCLUSION: Findings suggest cultural factors should be considered in interventions promoting cervical cancer screening among Korean American women. Furthermore, younger Korean American women and those not living with a spouse/partner should be targeted in cervical cancer screening efforts. PMID- 22428342 TI - Physical activity reduces breast cancer risk in African American women. AB - OBJECTIVE: To examine the relationship between physical activity and breast cancer in African American women. DESIGN: A population-based case-control study was conducted with 199 women (97 cases and 102 controls) from the Washington, DC metro area. A physical activity questionnaire elicited responses on frequency of walking for exercise and vigorous physical activity (eg, running, aerobics) in the past year. Responses were used to calculate a metabolic equivalent (MET) score (MET-hours/week = hours/week vigorous activity x 7 + hours/week walking x 3). The MET score was categorized into low, medium, and high tertiles. Multivariate logistic regression examined the association between physical activity and breast cancer. RESULTS: African American women who engaged in vigorous physical activity (> or = 2 hours/week in the past year) had a 64% reduced risk of breast cancer compared to those who did not participate in any vigorous activity (odds ratio, OR = .36; 95% confidence interval, CI = .17-.75). We also found a 64% reduced breast cancer risk in women with a high vs low tertile of total activity (OR = .36; 95% CI = .16-.79). For postmenopausal women, vigorous physical activity and total activity (high vs low tertile) also had an inverse relationship with breast cancer (P<.05). CONCLUSION: Data regarding the association of physical activity and breast cancer have been equivocal and lacking for African American women. This study found that modest levels of physical activity reduced breast cancer risk in this group. Targeted efforts are needed to encourage more African American women to engage in physical activity. PMID- 22428343 TI - Safety and efficacy of colonoscopy in the elderly: experience in an innercity community hospital serving African American and Hispanic patients. AB - Data regarding safety and efficacy of colonoscopy in elderly African American and Hispanic patients is scarce. We designed our study to determine the safety and efficacy of colonoscopy in this population. We retrospectively reviewed records of 1530 patients, who underwent colonoscopy over a nine-year period. The population included the elderly group (age>65 years) comprising 780 patients and control group (aged < or = 65 years) comprising 750 patients. Data about cancer prevalence, complications and 30 day mortality were abstracted. The median age was 77 years (range 66-101, 61% females) for the elderly group and 57 years (range 18-65, 51% females) for controls. The elderly group required lower doses of medications for conscious sedation (P<.0001). The crude completion rate was lower for the elderly group (79.5% vs 89.7%), however the adjusted completion rate was similar in both groups (90.3% elderly vs 90.9% control). There was no significant difference in outcome between the two ethnic groups. Diagnostic yield was higher in the elderly group (69% vs 49%, P<.0001), with a significantly higher rate of cancer detection (7.9% vs 1.8%, P<.0001). There was no statistical difference in complication rate between the two groups (P=.35). There were 2 deaths within 30 days of colonoscopy: one in the elderly group, and one in the control group. Our results suggest that colonoscopy in our elderly patients was safe and effective and resulted in a high diagnostic yield. Therefore, old age alone should not deter colonoscopic evaluation when indicated. PMID- 22428344 TI - HPV vaccine readiness among American Indian college students. AB - INTRODUCTION: Young adults experience high rates of human papillomavirus (HPV) infection. This article reports on American Indian (AI) university students' HPV vaccine readiness and female vaccine decision-making. METHODS: Eight focus groups were held with AI students attending four universities. A questionnaire was also administered. Fifty-seven students, 23 males and 34 females, aged 19 to 26 participated. Audio-recorded sessions were transcribed. Common themes were coded and categorized following grounded theory procedures. Statistical tests included chi-square and two sample independent t tests. RESULTS: A significant difference was observed between sexes and HPV risk status (P=.008). Females perceived a higher risk and were more knowledgeable about HPV and the vaccine than males, however, they did not know where to seek information and were less likely to recommend the vaccine to friends. Fifty-two percent of males reported perceived low risk of contracting HPV. Six explanatory factors were identified: low knowledge, access barriers, fear of side effects, culture, adverse historical events, and poor risk perception. DISCUSSION: American Indian female college students are not at a stage of readiness to comply with HPV vaccine recommendations, and need improved access to the HPV vaccine. PMID- 22428345 TI - Risk factors for acute non-ST-segment elevation myocardial infarction in a population sample of predominantly African American patients with chest pain and normal coronary arteries. AB - BACKGROUND: We sought to investigate the relationship between echocardiographic left ventricular hypertrophy (LVH) and acute non-ST-elevation segment myocardial infarction (NSTE-MI) in patients with chest pain and angiographically normal coronary arteries. METHODS: Retrospective analysis of patients admitted for acute chest pain in a large urban hospital serving predominantly African American patients. RESULTS: 131 (of 700) patients had normal coronary arteries or only minimal luminal irregularities (ie, <10% luminal narrowing) on cardiac angiography and available cardiac biomarker data to define the presence or absence of MI. Mean age was 53 +/- 10 years, 76% were African Americans, 88% had a history of hypertension (49% uncontrolled) and 74% had LVH by echocardiography. Of these 131 patients, 22 (17%) had an acute NSTE-MI by creatine kinase MB criteria. The mean systolic blood pressure (BP) was significantly higher in patients with NSTE-MI compared with non-NSTE-MI group (156 +/- 30 vs 143 +/- 25 mm Hg, P=.04). Patients with NSTE-MI were more likely to have LVH (95% vs 70%, P=.03). NSTE-MI was present in 22% of patients with LVH compared with 3% without LVH (P=.02). The in-hospital course of NSTE-MI patients with LVH was not benign: 19% had persistent angina and positive stress thallium suggestive of recurrent myocardial ischemia and 48% had congestive heart failure. The results of multivariable model after adjusting for selected variables revealed that these two preexisting conditions were independently associated with NSTE-MI: LVH (OR=4.0, CI 1.06-10.05) and elevated systolic BP (OR=3.7, CI 1.01-10.64). CONCLUSION: These findings provide preliminary evidence that LVH and uncontrolled hypertension predispose to NSTE-MI in this patient group. PMID- 22428346 TI - Racial/ethnic disparities on self-reported hypertension in New York City: examining disparities among Hispanic subgroups. AB - OBJECTIVES: To investigate differences in self-reported hypertension among Hispanic subgroups as they compare to Asian, non-Hispanic Black and non-Hispanic White groups; and whether these differences depend on nativity status in the New York City Community Health Survey 2006-2008. DESIGN: Cross-sectional. SETTING: New York City. MAIN OUTCOME MEASURE: Self-reported hypertension. METHODS: Log binomial regression was used to estimate the strength of the association between race/ethnicity and self-reported hypertension before and after adjusting for selected covariates. RESULTS: In adjusted analyses, Puerto Ricans, Dominicans and Blacks had 17%, 28% and 34% greater probability of reporting hypertension than Whites. The association between race/ethnicity and self-reported hypertension appears to vary with nativity status/length of stay in the United States. (P=.08). CONCLUSIONS: These findings underscore the need to investigate the prevalence of hypertension among subgroups of the Hispanic population. This issue is also relevant to Asians and Blacks, who are very heterogeneous populations regarding subgroups and nativity status. PMID- 22428347 TI - Racial residential segregation and stroke mortality in Atlanta. AB - OBJECTIVE: To assess the association between neighborhood-level racial residential segregation and stroke mortality using a spatially derived segregation index. DESIGN: Cross-sectional study SETTING: Atlanta Metropolitan Statistical Area METHODS: The study population consisted of non-Hispanic Black and White residents of the Atlanta Metropolitan Statistical Area during the time period Jan 1, 2000 to December 31, 2006. Census tract-level stroke death rates for Blacks and Whites were modeled as a function of the segregation index while controlling for two neighborhood-level chronic stressors (poverty, low education). RESULTS: Racial segregation was positively associated with stroke mortality for both Blacks and Whites aged 35-64 years. Among Blacks and Whites aged 65 or older, segregation was negatively associated with stroke mortality after controlling for the two stressors, suggesting that they were pathways between segregation and stroke death rates. CONCLUSION: Future studies are needed to identify additional pathways between residential segregation and other health outcomes, and to collect data that support a life course approach to understanding the impact of residential segregation on health. PMID- 22428348 TI - A comparison of the arthritis foundation self-help program across three race/ethnicity groups. AB - OBJECTIVE: Despite high prevalence rates of pain among older adults, relatively few studies have examined the impact of the Arthritis Foundation Self-Help Program (ASHP) in this age group, particularly older minority groups. DESIGN: This study compared the effects of the ASHP on groups of Hispanic, African American and non-Hispanic White older adults. SETTING: Three senior centers in New York City. PARTICIPANTS: Data are presented for 112 (37 African American, 38 Hispanic and 37 non-Hispanic White) participants (mean age= 75 years) age 60 and over with diverse noncancer pain disorders. INTERVENTION: Participants enrolled in the 6-week Arthritis Self Help Course. MAIN OUTCOME MEASURES: Participants were surveyed before and after course completion (in person) and at 18 weeks (by telephone). Demographic and clinical data were collected at baseline; outcomes included pain, mood, self-efficacy, and number of days per week spent exercising. RESULTS: All three groups experienced significant decreases in pain intensity (P< or =.05). Significant improvements were also found in mood scores for non Hispanic White (P=.01) and Hispanic participants (P=.03). Hispanic participants also evidenced significant improvement in their confidence to self-manage pain (P=.003) and reported fewer arthritis-related symptoms (P=.02). All three race/ethnicity groups reported substantial increases in the number of days spent doing stretching, endurance and relaxation exercises (P< or =.01). CONCLUSION: Positive results were noted for all three race/ethnicity groups, particularly in the areas of pain reduction and uptake of stretching, endurance and relaxation exercises. Our findings support efforts to disseminate broadly the ASHP in community settings that serve older African American, Hispanic and non-Hispanic white adults. PMID- 22428349 TI - Racial differences in pain reports between Black and White participants with chronic venous disorders treated with cryotherapy compared to usual care. AB - OBJECTIVE: To evaluate racial differences in pain and pain medication use in response to cryotherapy or usual care (UC) for leg skin inflamed by chronic venous disorders (CVDs). DESIGN: Randomized clinical trial. SETTING: Academic medical center in Charleston, South Carolina. PARTICIPANTS: Sixty Black and White participants with severe CVDs randomized to receive cryotherapy or UC during the one-month study. INTERVENTION: Cryotherapy consisted of 30-minutes of cooling the most severely affected lower leg skin with a gel wrap while receiving UC (ie, elevating the legs and wearing compression stockings during the day). MAIN OUTCOME MEASURE: Pain measured with the Leg Pain Questionnaire-Composite Score. RESULTS: 56 participants (n=27 cryotherapy; n=29 UC) completed the study: 52% African Americans (Blacks). Blacks in the usual care group (n=15) reported lower pain after 30 days compared to Blacks in the cryotherapy group (n=15) (P=.02). In Whites, there were no differences between cryotherapy (n=13) and usual care (n=14) (P=.78). CONCLUSIONS: No statistically significant differences in pain were found between the cryotherapy group or UC group. Usual care in the Black group was found to reduce pain. PMID- 22428351 TI - Street foods and fast foods: how much do South Africans of different ethnic groups consume? AB - OBJECTIVE: To assess consumption of street food (sold by vendors) and fast food (from fast food outlets) by different ethnic groups in South Africa. DESIGN: A national cross-sectional survey representative of adults (> or = 16 years, N=3827) from different ethnic groups, provinces, geographic localities, and socio economic strata was undertaken. METHODS: Trained interviewers visited participants at their homes during October 2009. Specific questions relating to street food and fast food consumption were asked. RESULTS: At the national level, 11.3% of the population bought food from street vendors and 6.8% from fast food outlets frequently (> or = 2 times a week). Black Africans were the most frequent consumers of street food with nearly one out of five (19%) consuming such foods at least twice a week. By contrast, Indians (1.9%) and Whites (2.9%) had the lowest street food consumption. Indians (14%) and Whites (12.5%) had the highest fast food consumption with the lowest percentages found in the Black (5.4%) and Euro-Afr-Malay groups. The highest consumption of street food took place in urban informal (19.4%) and urban formal areas (16.7%). The lowest percentage of respondents buying street food was recorded in rural areas (4.7%). CONCLUSIONS: Both street foods and fast foods are commonly consumed by South Africans with Black Africans being the most frequent consumers of street foods and Whites of fast foods. This first national survey on street food and fast food consumption identifies this business sector as a potential area for health and nutrition education intervention. PMID- 22428350 TI - Physical inactivity, but not sedentary behavior or energy intake, is associated with higher fat mass in Latina and African American girls. AB - BACKGROUND: Minority girls are disproportionately affected by overweight and obesity. The independent effects of physical activity (PA), sedentary behavior (SB), and diet are not well understood. OBJECTIVE: This study examined the individual influences of PA, SB and diet on fat mass in Latina and African American (AA) girls, aged 8-11. METHODS: Baseline data from a longitudinal cohort study in minority girls is presented. Multiple linear regression analysis assessed the effects of PA, SB, and energy intake on fat mass, adjusting for lean mass, age, Tanner stage and ethnicity. RESULTS: Participants were 53 Latina and AA girls (77% Latina; M age=9.8 +/- .9; M(BMI%)=80.8 +/- 23.1). Moderate-to vigorous physical activity (MVPA) by accelerometry (beta= -.13, P<.01) and lean mass (beta=.69, P<.001) were associated with fat mass (Model R2=.63; P<.0001). MVPA by 3-day-physical-activity-recall (beta=-.04, P=.01) and lean mass (beta=.75, P<.001) were associated with fat mass (Model R2=.61; P<.0001). SB and energy intake were not associated with fat mass in any model. CONCLUSION: Using both objective and subjective measures of PA, MVPA, but not SB or diet, was associated with higher fat mass in Latina and AA girls, independent of lean mass, age, Tanner stage, and ethnicity. Prospective studies are needed to clarify the differential impact of diet and activity levels on adiposity in this population. PMID- 22428352 TI - Commentary: A social-ecological perspective on obesity among Latinos. AB - The Southeast United States has experienced rapid growth in the Latino population - mostly Mexican immigrants - with the number of Latinos in the region nearly quadrupling over the past decade. These states, known as new settlement areas, are not as well prepared to meet the health needs of Spanish-speaking immigrants compared to traditional settlement states like Florida, Texas, and California. Unfortunately for these families, immigration to the United States is often associated with becoming obese, or having children at a higher risk for obesity. Rates of obesity have risen dramatically among all racial and ethnic groups in the past few decades, however, Latinos of all ages have the highest rates of overweight and obesity compared to other racial and ethnic groups. One explanation is that although adjustment to a new environment and culture takes considerable time, the adoption of a more sedentary lifestyle and unhealthy diet occurs more rapidly, leading to significant increases in obesity between first and subsequent generations. Families are important referents in establishing health behaviors in children, and there are broader social and physical environmental factors that have strong associations with the development of obesity as well. Moreover, immigrant families must strive to be healthy while coping with acculturative stressors. Relationships between all of these factors are typically studied in isolation. This article explores obesity among new settlement Latino families and provides an integrated conceptual model anchored in the social ecological perspective. PMID- 22428353 TI - Diabetes care and language discordance among Chinese and Latino primary care patients. AB - OBJECTIVES: To assess differences in diabetes processes of care among Chinese and Latino patients across medical interpreting methods. DESIGN AND SETTING: This is a nested cohort study of patients with diabetes, comparing interpreting methods and their impact on medical outcomes at the primary care clinic of a New York City municipal hospital. PARTICIPANTS: 54 Spanish and Chinese-speaking language discordant diabetic patients were enrolled and followed for one year. INTERVENTION: Language discordant patients received either Remote Simultaneous Medical Interpreting (RSMI), or usual and customary (U&C) interpreting. MAIN OUTCOME MEASURES: Composite medical care scores were calculated for physician ordering and patient completion of diabetes care measures. RESULTS: RSMI patients, compared with U&C patients, had trends towards higher mean patient completion (.29 vs .25) and physician ordering (.41 vs .37) scores. Overall rates of completion of diabetes care measures in both groups were very low. CONCLUSIONS: Overall rates of physician ordering and patient completion of diabetes care measures were distressingly low in our study. Further studies are needed to explore the potential role of RSMI in addressing the language barrier and improving diabetes care for Chinese- and Spanish-speaking patients. PMID- 22428354 TI - Family support is associated with success in achieving weight loss in a group lifestyle intervention for diabetes prevention in Arab Americans. AB - OBJECTIVE: We have recently shown the feasibility of a community-based, culturally-specific, Diabetes Prevention Program-adapted, goal-oriented group lifestyle intervention targeting weight loss in Arab Americans. The objective of this study was to examine factors associated with weight-loss goal attainment at 24-weeks of the lifestyle intervention. METHODS: We assessed the relationship among demographic, psychosocial, and behavioral measures and the attainment of > or =7% decrease of initial body weight among 71 lifestyle intervention participants. RESULTS: Weight loss goal of > or = 7% of body weight was achieved by 44% of study participants. Demographic and psychosocial factors were not associated with weight loss. Individuals attaining the weight loss goal were more likely to have family support during the core curriculum sessions (70% vs 30%; P=.0023). Decrease in body weight was positively correlated with attendance at sessions (r=.46; P=.0016) and physical activity minutes (r=.66; P<.0001) and negatively correlated with reported caloric intake (r=-.49; P=.0023), fat intake (r=-.52; P=.0010), and saturated fat intake (r=-.39; P=.0175) in women; these trends were similar but not significant in men. CONCLUSIONS: Family support was an important predictor of attainment of the weight loss goal. Family-centered lifestyle interventions are likely to succeed in curtailing the rising epidemic of diabetes in the Arab-American Community. PMID- 22428355 TI - Diabetes knowledge in a high risk urban population. AB - This study explored the impact of an intensive educational intervention to patients on their knowledge and understanding of diabetes. This study was a hypothesis-testing, prospective study, with an experimental two-by-two factorial design. The educational programs were offered to physicians only, patients only, or both patients and their physicians. In the fourth arm, neither patients nor their physicians received any education. Patients with uncontrolled diabetes were enrolled in the study. The outcome was the changes in the score of patients on the diabetes knowledge test. The knowledge test was administered at the time of enrollment and every six months thereafter. The study showed that a total of 622 (75%) patients took the diabetes knowledge test. The mean diabetes knowledge test score increased over time for both insulin and non-insulin users. The mean diabetes knowledge score in patients with patient education only was 11 points higher compared to those in the group of patients and their physicians without education (P=.0104). The study indicated that patients who are exposed to the educational program end up with better knowledge on all counts, than patients who just go through the health care system in the course of usual care for diabetes. PMID- 22428356 TI - The TG/HDL-C ratio does not predict insulin resistance in overweight women of African descent: a study of South African, African American and West African women. AB - Women of African descent have a high prevalence of diseases caused by insulin resistance. To positively impact cardiometabolic health in Black women, effective screening tests for insulin resistance must be identified. Recently, the TG/HDL-C ratio has been recommended as a tool to predict insulin resistance in overweight people. While the ratio predicts insulin resistance in White women, it is ineffective in African American women. As there are no data for African women, we tested the ability of the TG/HDL-C ratio to predict insulin resistance in Black women from South Africa, West Africa and the United States. For comparison, the ratio was also tested in White women from South Africa. Participants were 801 women (157 Black South African, 382 African American, 119 West African, 143 White South African, age 36 +/- 9y [mean +/- SD]). Standardized scores were created from log-transformed homeostasis model assessment-insulin resistance values from each population. Participants in the upper third of their population distribution were classified as insulin-resistant. To predict insulin resistance by the TC/HDL C ratio, area under the receiver operating characteristic (AUC-ROC) curve was used and criteria were: 0.50 for no discrimination and > or = 0.70 for acceptable. Seventy-one percent of the Black women were overweight vs 51% of White women (P<.01). In overweight White women, AUC-ROC curve for prediction of insulin resistance by TG/HDL-C was 0.76 +/- 0.06, but below the 0.70 threshold in each group of overweight Black women (Black South African: 0.64 +/- 0.06, African American: 0.66 +/- 0.03, and West African: 0.63 +/- 0.07). Therefore, TG/HDL-C does not predict insulin resistance in overweight African American women and this investigation extends that finding to overweight Black South African and West African women. Resources to identify effective markers of insulin resistance are needed to improve cardiometabolic health in women of African descent. PMID- 22428357 TI - The impact of social communication on perceived HPV vaccine effectiveness in a low-income, minority population. AB - OBJECTIVES: Perceived vaccine effectiveness is linked to vaccine-uptake. This study aims to determine if hearing about the HPV vaccine from family/friends (social source) or discussing the vaccine with family/friends (social discussion) is associated with perceived HPV vaccine effectiveness among female ethnic minority, medical-decision-makers of vaccine-eligible girls. METHODS: Data come from a cross-sectional HPV vaccine telephone-survey administered by the Los Angeles County Office of Women's Health (OWH) hotline operators between January November 2009. Among survey participants who reported awareness of the HPV vaccine (n=294), two logistic regression models of perceived HPV vaccine effectiveness were conducted; a source of information model with social source as the main predictor, and a discussion model with social discussion as the main predictor. These were adjusted for medical source and medical discussion, and covariates affecting interaction with the health care system. RESULTS: Women who heard about the HPV vaccine from a social source were more likely to perceive the vaccine as effective compared to those who did not report a social source of information (adjusted OR 4.78, 95% CI 1.76-12.98). Medical source of information was also associated with perceived vaccine effectiveness (adjusted OR 2.07, 95% CI 1.06-4.05). Those who reported social discussion, but not those who discussed the vaccine with a medical provider, had increased odds of perceived vaccine effectiveness (adjusted OR 1.98, 95% CI 1.04-3.78). CONCLUSIONS: Social source of information and social discussion were associated with perceived HPV vaccine effectiveness; this highlights the value of social communication among low-income minority women, and the need for vaccine-messaging interventions that utilize a social network approach.(Ethn Dis. 2011;21(4):495-501) PMID- 22428359 TI - Mesoscopic biochemical basis of isogenetic inheritance and canalization: stochasticity, nonlinearity, and emergent landscape. AB - Biochemical reaction systems in mesoscopic volume, under sustained environmental chemical gradient(s), can have multiple stochastic attractors. Two distinct mechanisms are known for their origins: (a) Stochastic single-molecule events, such as gene expression, with slow gene on-off dynamics; and (b) nonlinear networks with feedbacks. These two mechanisms yield different volume dependence for the sojourn time of an attractor. As in the classic Arrhenius theory for temperature dependent transition rates, a landscape perspective provides a natural framework for the system's behavior. However, due to the nonequilibrium nature of the open chemical systems, the landscape, and the attractors it represents, are all themselves emergent properties of complex, mesoscopic dynamics. In terms of the landscape, we show a generalization of Kramers' approach is possible to provide a rate theory. The emergence of attractors is a form of self-organization in the mesoscopic system; stochastic attractors in biochemical systems such as gene regulation and cellular signaling are naturally inheritable via cell division. Delbruck-Gillespie's mesoscopic reaction system theory, therefore, provides a biochemical basis for spontaneous isogenetic switching and canalization. PMID- 22428358 TI - Adapting the everyday discrimination scale to medical settings: reliability and validity testing in a sample of African American patients. AB - OBJECTIVE: Despite evidence that discrimination within the health care system may play an important role in perpetuating health disparities, instruments designed to measure discrimination within the health care setting have not been adequately tested or validated. Consequently, we sought to test the psychometric properties of a modified version of the Everyday Discrimination scale, adapted for medical settings. DESIGN: Cross-sectional study. SETTING: Academic medical center in Chicago. PARTICIPANTS: Seventy-four African American patients. OUTCOME MEASURES: We measured factor analysis, internal consistency, test-retest reliability, convergent validity and discriminant validity. RESULTS: Seventy-four participants completed the baseline interviews and 66 participants (89%) completed the follow up interviews. Eighty percent were women. The Discrimination in Medical Settings (DMS) Scale had a single factor solution (eigenvalue of 4.36), a Cronbach's alpha of 0.89 and test-retest reliability of .58 (P<.0001). The DMS was significantly correlated with an overall measure of societal discrimination (EOD) (r=.51, P<.001) as well as two of its three subscales (unfair: r=-.04, P=.76; discrimination: r=.45, P<0.001; worry: r=-.36, P=.002). The DMS was associated with the overall African American Trust in Health Care Scale (r=.27, P=.02) as well as two key subscales (racism: r=.31, P<.001; disrespect: r=.44, P<.001). The DMS scale was inversely associated with the Social Desirability Scale (r=.18, P=.13). The DMS scale was not correlated with the Center for Epidemiologic Studies Depression Scale (r=.03, P=.80). CONCLUSIONS: The Discrimination in Medical Settings Scale has excellent internal consistency, test-retest reliability, convergent validity and discriminant validity among our sample of African American patients. Further testing is warranted among other racial/ethnic groups. PMID- 22428360 TI - Transient bioheat simulation of the laser-tissue interaction in human skin using hybrid finite element formulation. AB - This paper presents a hybrid finite element model for describing quantitatively the thermal responses of skin tissue under laser irradiation. The model is based on the boundary integral-based finite element method and the Pennes bioheat transfer equation. In this study, temporal discretization of the bioheat system is first performed and leads to the well-known modified Helmholtz equation. A radial basis function approach and the boundary integral based finite element method are employed to obtain particular and homogeneous solutions of the laser tissue interaction problem. In the boundary integral based finite element formulation, two independent fields are assumed: intra-element field and frame field. The intra-element field is approximated through a linear combination of fundamental solutions at a number of source points outside the element domain. The frame temperature field is expressed in terms of nodal temperature and the corresponding shape function. Numerical examples are considered to verify and assess the proposed numerical model. Sensitivity analysis is performed to explore the thermal effects of various control parameters on tissue temperature and to identify the degree of burn injury due to laser heating. PMID- 22428361 TI - The effect of collagenase on the critical buckling pressure of arteries. AB - The stability of arteries is essential to normal arterial functions and loss of stability can lead to arterial tortuosity and kinking. Collagen is a main extracellular matrix component that modulates the mechanical properties of arteries and collagen degradation at pathological conditions weakens the mechanical strength of arteries. However, the effects of collagen degradation on the mechanical stability of arteries are unclear. The objective of this study was to investigate the effects of collagen degradation on the critical buckling pressure of arteries. Arterial specimens were subjected to pressurized inflation testing and fitted with nonlinear thick-walled cylindrical model equations to determine their stress strain relationships. The arteries were then tested for the critical buckling pressure at a set of axial stretch ratios. Then, arteries were divided into three groups and treated with Type III collagenase at three different concentrations (64, 128, and 400 U/ml). Mechanical properties and buckling pressures of the arteries were determined after collagenase treatment. Additionally, the theoretical buckling pressures were also determined using a buckling equation. Our results demonstrated that the buckling pressure of arteries was lower after collagenase treatment. The difference between pre- and post- treatment was statistically significant for the highest concentration of 400U/ml but not at the lower concentrations. The buckling equation was found to yield a fair estimation to the experimental critical pressure measurements. These results shed light on the role of matrix remodeling on the mechanical stability of arteries and developments of tortuous arteries. PMID- 22428362 TI - IVUS-based computational modeling and planar biaxial artery material properties for human coronary plaque vulnerability assessment. AB - Image-based computational modeling has been introduced for vulnerable atherosclerotic plaques to identify critical mechanical conditions which may be used for better plaque assessment and rupture predictions. In vivo patient specific coronary plaque models are lagging due to limitations on non-invasive image resolution, flow data, and vessel material properties. A framework is proposed to combine intravascular ultrasound (IVUS) imaging, biaxial mechanical testing and computational modeling with fluid-structure interactions and anisotropic material properties to acquire better and more complete plaque data and make more accurate plaque vulnerability assessment and predictions. Impact of pre-shrink-stretch process, vessel curvature and high blood pressure on stress, strain, flow velocity and flow maximum principal shear stress was investigated. PMID- 22428363 TI - SPRIX (ketorolac tromethamine) nasal spray: a novel nonopioid alternative for managing moderate to moderately severe dental pain. AB - In summary, SPRIX is a nonopioid alternative for the management of moderate to moderately severe pain. SPRIX offers dentists, physicians, and patients a new non opioid option to control acute moderate to moderately severe pain in situations in which use of an IM or IV access is not feasible or not wanted. SPRIX is a valuable treatment option for patients with nausea or vomiting, those unable to take oral medications, and those unable to tolerate the side effects of opioids. In ambulatory acute pain settings, use of SPRIX will allow patients who need to remain alert to receive effective pain control. Currently, there are no nonopioid alternatives for the treatment of moderate to moderately severe pain other than ketorolac. In patients with more severe pain states, the combination of opioids and SPRIX provides unique advantages in maximizing analgesia while minimizing the unwanted adverse effects of both classes of drugs (referred to as multimodal or "balanced analgesia"). PMID- 22428364 TI - Narrative medicine, or a sense of story. PMID- 22428365 TI - Narrative poetry and narrative medicine rounds. PMID- 22428366 TI - Terminology and praxis: clarifying the scope of narrative in medicine. PMID- 22428367 TI - Narrative medicine in the literature classroom: ethical pedagogy and Mark Haddon's The curious incident of the dog in the night-time. PMID- 22428368 TI - When the photograph speaks: photo-analysis in narrative medicine. PMID- 22428369 TI - Positive wrongdoings: reading doctors' narratives on ordinary ethics. PMID- 22428370 TI - Guiding our learners in reflective writing: a practical approach. PMID- 22428371 TI - Making a case for narrative competency in the field of fetal cardiology. PMID- 22428372 TI - Primum non nocere: on accountability in narrative-based medicine. PMID- 22428373 TI - Father locus of control and child emotional and behavioral outcomes: a prospective study. AB - In a prospective longitudinal study the authors examined the associations between parent locus of control of reinforcement (LOCR), measured before the birth of a child, and behavioral-emotional outcomes in that child at age 7 years. A total of 307 couples completed questionnaires regarding their emotional status and LOCR at their first prenatal care appointment. When their children turned 7 years old, teachers completed questionnaires regarding each participating child's behavior. Findings indicate significant associations between fathers' prenatal LOCR and child outcomes, particularly hyperactivity in sons. Hyperactivity and behavioral emotional problems in girls, in contrast, were better predicted by maternal prenatal emotional distress. Results provide evidence that paternal and maternal characteristics that predate the birth of a child relate to later behavioral outcomes in that child. Implications for prevention of child psychopathology are discussed. PMID- 22428374 TI - Predicting feelings of cognitive competence in head start preschoolers. AB - Little is known about what predicts the budding sense of self-competence in preschoolers. This is particularly true of cognitive competence, which may have implications for later schooling. Based on previous research with older children, it was expected that feelings of self-competence would be influenced by attitudes of significant others as well as intrapersonal dispositions. Forty-five Head Start preschoolers (M age = 4.36 years) served as participants. As expected, high effortful control and language competence, as well as teachers' ratings of competence, predicted positive feelings about cognitive competence in children. Further analysis revealed that the teachers' ratings were predicted by maternal education and language competence. The findings suggest that the development of cognitive self-concept in preschoolers is predicted by contextual and constitutional factors. PMID- 22428375 TI - Comparing measures of attachment: "To whom one turns in times of stress", parental warmth, and partner satisfaction. AB - The Attachment and Clinical Issues Questionnaire (ACIQ; M. A. Lindberg & S. W. Thomas, 2011), was developed over an 18-year period containing 29 scales. The purpose of the present study was to test (a) the validity of the attachment scales in terms of how they predict to whom one turns in times of stress and for affective sharing, and (b) how the attachment scales compared with the Experiences in Close Relationship Questionnaire (ECR) in terms of concurrent, convergent, and discriminant evidence. The relevant secure scales of the ACIQ predicted to whom one turned in study 1, and study 2 demonstrated good convergent evidence with the ECR, but superior concurrent evidence in predicting partner satisfaction, and superior discriminant evidence in differentially correlating with mother and father warmth. Thus, the ACIQ passed essential validity and psychometric tests and was a more robust measure than the ECR with these defining characteristics of attachment. PMID- 22428376 TI - Functions, targets, and outcomes of specific forms of social aggression: a daily diary study. AB - The authors investigated 8 specific forms of social aggression (SA) in terms of the functions they serve, the characteristics of the peers targeted by them, and the outcomes associated with using the behaviors. Two hundred and seventeen fifth and seventh-grade boys and girls completed a structured daily diary for 5 consecutive days in their English classes. Participants reported on their own acts of SA. Girls reported using SA overall more frequently than boys, but most specific forms of SA were used equally often by both genders. Consistent with study hypotheses, different forms of SA were associated with different functions, targets, and outcomes. Gender and grade moderated many of these associations. The need for greater understanding of the underlying processes associated with SA, including the role of gender, are highlighted. PMID- 22428377 TI - Searching for the self: an identity control theory approach to triggers of occupational exploration. AB - Identity control theory researchers have found evidence for two processes of identity development (identity defense and identity change) and have theorized a third process (identity exploration). College students (N = 123) self-rated as high or low in occupational identity certainty and importance received self discrepant feedback to induce identity disturbance, and dependent measures of identity defense, identity change, and identity exploration were obtained. As predicted, high certainty about identity standards led to identity defense, while low certainty led to identity change. Although an interaction between certainty and importance was hypothesized to predict identity exploration, results showed that the two operated independently. Low certainty predicted exploration of additional occupational areas, whereas high importance predicted exploration of self, environment, and additional occupational areas. PMID- 22428378 TI - Heritability in cognitive performance: evidence using computer-based testing. AB - There is overwhelming evidence of genetic influence on cognition. The effect is seen in general cognitive ability, as well as in specific cognitive domains. A conventional assessment approach using face-to-face paper and pencil testing is difficult for large-scale studies. Computerized neurocognitive testing is a suitable alternative. A total of 267 parent-child dyads were selected from a larger database of computerized neurocognitive test results. Correlations were determined between parent-child dyads, as well as matched parent-child dyads. Univariate regression analyses were estimated to determine the extent to which children's performance could be accounted for by that of their parents, compared with matched control parents. Multiple significant positive correlations in neurocognitive test performance were found in parent-child dyads. Parent performance accounted for a greater proportion of variability in every case. These findings indicated that a computerized neurocognitive battery is an effective tool for studying heritability in cognitive performance in a large sample. PMID- 22428379 TI - [Bariatric surgery and reproductive health]. AB - Obesity is associated with metabolic complications such as insulin-resistance, type 2 diabetes, dyslipidemia, hypertension and polycystic ovary syndrome. Obesity adversely impacts fecundability and IVF outcomes through a variety of mechanisms, however even modest weight loss can improve situation. Pregnancy may be a significant health risk for morbidly obese women (BMI over 40 kg/m2) and fertility treatments are not recommended before weight loss. The fertile age of women is limited, therefore an efficient treatment of obesity should be chosen. For morbid obesity bariatric surgery combined with lifestyle changes is more efficient treatment than conservative treatment alone. Weight loss is associated with significant improvement in many parameters of reproductive function, chance to get pregnant improves and gestational risks decrease. PMID- 22428380 TI - [The effectiveness of psychotherapy on depression in the long term]. AB - Different short-term therapies, mainly with short follow-ups, seem equally effective treatments of mood disorders. The Helsinki Psychotherapy Study is the only published randomized trial on the effectiveness of short-term and long-term therapies during a longer follow-up. During a 5-year follow-up, patients' recovery from symptoms and improvement in work ability were greater in long-term therapy than in two, equally effective, short-term therapies. The short-term therapies were, however, more cost-effective, but many patients in them did not recover. More randomized clinical trials and cohort studies with long follow-ups on the efficacy, sufficiency and suitability of short- and long-term therapy are thus needed. PMID- 22428381 TI - [Eosinophilic diseases of the gastrointestinal tract]. AB - Eosinophilic esophagitis, gastroenteritis and colitis are very likely underdiagnosed conditions, and their actual incidence may be increasing. The diagnosis and treatment remain, however, fairly poorly established and are based on inadequate scientific evidence. Differential diagnosis is broad, mainly conditions causing secondary eosinophilia, such as allergies. If the secondary causes have been carefully excluded, the possibility of rare hypereosinophilic syndrome should be considered in prolonged eosinophilia. PMID- 22428382 TI - [New challenges in the biological weapons convention]. AB - Microbes and their toxins are biological weapons that can cause disease in humans, animals or plants, and which can be used with hostile intent in warfare and terrorism. Biological agents can be used as weapons of mass destruction and therefore, immense human and social and major economical damage can be caused. Rapid development of life sciences and technologies during the recent decades has posed new challenges to the Biological Weapons Convention. The Convention states that the States Parties to the BWC strive to ensure that the Convention remains relevant and effective, despite changes in science, technology or politics. PMID- 22428383 TI - [Treatment of eye allergies]. AB - Seasonal atopic conjunctivitis is treated with antihistamines, cromoglycate and short courses of corticosteroids, in severe cases with subcutaneous or sublingual immunotherapy. Chronic conjunctivitis requires year-round treatment with mast cell stabilizers, antihistamines or topical corticosteroids. Long-term treatment of atopic blepharoconjunctivitis consists of tacrolimus or pimecrolimus cream. For atopic keratoconjunctivitis corticosteroid and, if necessary, cyclosporine eye drops are needed. First-line therapy of vernal conjunctivitis involves mast cell stabilizers and, if necessary, corticosteroid eye drops. Treatment of non allergic eosinophilic conjunctivitis involves mast cell stabilizers, corticosteroid and, if necessary, cyclosporine eye drops. PMID- 22428384 TI - [Chest, skin and joint symptoms of a middle-aged man]. AB - A middle-aged male patient was examined due to chest pain. At the same time blisters appeared on his palms and soles of the foot. Radiologic examinations revealed lesions in the thoracic vertebral bodies, in the first rib and in the sternum. Inflammatory markers were elevated in the blood. The patient subsequently developed arthritis in a previously injured knee. PMID- 22428385 TI - [Myelitis following vaccination against tick-borne encephalitis]. AB - Tick-borne encephalitis is a significant concern in endemic regions, and in rare cases it may even be fatal. There is no specific treatment for the disease. Vaccines from two manufacturers are available against tick-borne encephalitis, both considered effective and safe. Severe adverse effects due to tick-borne encephalitis vaccine are rare. We describe the first severe myelitis detected in Finland following vaccination against tick-borne encephalitis. PMID- 22428386 TI - [Update on current care guidelines: tobacco dependence and cessation]. AB - Of teenagers in Finland aged 14 to 18 years, one in six smoke. Of adults, one in five smoke. All health care workers should register smoking among patients, urge them to quit and offer help in cessation. Tobacco cessation groups should be available to all smokers and all central hospitals should have a smoking cessation unit. Cessation medication or nicotine replacement therapy should be offered actively together with counselling. The cessation plan takes account of personal needs like pregnancy, age and medication. PMID- 22428387 TI - Restrictions of the sale of pharmaceuticals and medical devices such as contact lenses over the internet and the free movement of goods. AB - In the light of new case law development, this article examines whether national restrictions on the online sale of pharmaceuticals and medical devices such as contact lenses are consistent either with EU secondary law, either with Article 34 TFEU that prohibits measures having equivalent effect to quantitative restrictions on imports. In particular, this article focuses on an analysis of two judgments on this important issue delivered by the Court of Justice of the European Union in 2003 and 2010, namely the Deutscher Apothekerverband decision and the Ker-Optika decision. PMID- 22428388 TI - Free movement of patients: Directive 2011/24 on the application of patients' rights in cross-border healthcare. AB - This contribution comments on Directive 2011/24, providing a legal framework for cross border healthcare 13 years after the famous Kohll and Decker case law. The Directive contains provisions concerning the reimbursement of costs, the responsibilities of the Member States and their mutual cooperation in healthcare. Analysing the (potential) impact of the Directive 2011/24 on EU healthcare systems, patients and healthcare providers, it becomes clear that the impact of the Directives reaches far beyond patient mobility. The Directive creates patients' rights, pays attention to the quality and safety of healthcare services and creates an excessive structure of cooperation in the field of healthcare. The European Union seems ready to use its economies of scale to improve healthcare for all European patients. PMID- 22428389 TI - Surrogate decision-making for incompetent elderly patients: the role of informal representatives. AB - Informal or unofficial representation refers to the practice (more common in some European jurisdictions than in others), that persons not designed by a court or by the patient himself, make medical decisions on the patient's behalf in case of their incompetence. If the law provides for this, it is usually next of kin (spouse, children, brothers and sisters, etc.) who are allowed to act in such a capacity. Informal representation raises several questions. Are family members always familiar with what their relative would have wished, ready to take responsibility, and not too much reigned by their emotions? The basic legal concern is whether there are sufficient procedural and other safeguards to protect the incompetent patient from representatives who do not serve their best interests. In addressing these issues, after a brief survey of the law in the Netherlands as compared with that in Belgium, Germany and England/Wales, we will argue that informal representation as such is not at variance with international and European standards. However, an 'informal' approach to surrogate decision making should always go together with sufficient protection of the incompetent patient, including procedural safeguards with regard to the decision that the patient is incompetent, limits to the decision-making power of informal representatives and effective forms of conflict resolution. PMID- 22428390 TI - Obesity in Europe: the strategy of the European Union from a public health law perspective. AB - In 2007 the European Commission published a White Paper on a "Strategy on nutrition, overweight and obesity", proposing measures to impede the current trend towards a steady gain in weight by Union citizens. In this article, these ideas are discussed critically in the light of the competences of the Union and from a public health law perspective, in order to scrutinise the effectiveness of the measures and to identify shortcomings in the White Paper. One focus of this article will be European food legislation, as food is one of the leading causes of people being overweight or obese. PMID- 22428391 TI - European Court of Human Rights: ECHR 2012/1 Case of S. v. Estonia, 4 October 2011, no. 17779/08 (First Section). PMID- 22428392 TI - European Court of Human Rights: ECHR 2012/2 Case of Gorobet v. Moldova, 11 October 2011, no. 30951/10 (Third Section). PMID- 22428393 TI - European Court of Human Rights: ECHR 2012/3 Case of Sosinowska v. Poland, 18 October 2011, no. 10247/09 (Fourth Section). PMID- 22428394 TI - European Court of Human Rights: ECHR 2012/4 Case of X and Y v. Croatia, 3 November 2011, no. 5193/09 (First Section). PMID- 22428395 TI - European Court of Justice: ECJ 2011/01, Oliver Brustle v. Greenpeace e. V., 18 October 2011 (Case C-34/10). PMID- 22428397 TI - Worry grows as chiefs flee NMC. PMID- 22428396 TI - European Court of Justice: ECJ 2011/02, European Commission v. Portuguese Republic, 27 October 2011 (Case C-255/09). PMID- 22428398 TI - "Further strike action is still on the table if pension talks fail". PMID- 22428399 TI - "NHS shouldn't be safety net for irresponsible cosmetic clinics". PMID- 22428400 TI - "If data isn't used, it just takes nurses away from the bedside". PMID- 22428401 TI - Leading change: 1--identifying the issue. AB - To enable sustainable change, nurses need to take the lead in managing it. Recent national initiatives have emphasised the importance of frontline staff in service improvement. The ability to influence and manage change has been identified as an essential skill for delivering new models of care. This article is the first in a three-part series designed to help nurses at all levels develop the knowledge and skills they will need to initiate and manage change. This article focuses on identifying what needs to be changed and why. PMID- 22428402 TI - Pressure ulcer risk assessment. AB - The Department of Health wants to reduce harm caused by pressure ulcers dramatically. Identifying which patients are at risk is an important part of prevention. This article discusses the most common risk factors, the advantages and disadvantages of risk assessment tools, and challenges in prevention. PMID- 22428403 TI - Foreign body ingestion in children. PMID- 22428404 TI - Care in the home. PMID- 22428405 TI - Motivate your team to embrace change. PMID- 22428406 TI - C. H. McCloy lecture: fifty years of advancements in fitness and activity research. AB - Over the past 50 years progress in fitness and activity research has been influenced by social events, technical innovations, and changes in the field of physical education and kinesiology. The conventional wisdom of the 1950s yielded to a new wisdom based on research evidence. The author's research, as well as the research of others, from 1960 to the present is discussed. The new wisdom focuses on health-related fitness and physical activity promotion based on health behavior change strategies. PMID- 22428407 TI - BMI group-related differences in physical fitness and physical activity in preschool-age children: a cross-sectional analysis. AB - In the Ballabeina study, we investigated age- and BMI-group-related differences in aerobic fitness (20 m shuttle run), agility (obstacle course), dynamic (balance beam) and static balance (balance platform), and physical activity (PA, accelerometers) in 613 children (M age = 5.1 years, SD = 0.6). Normal weight (NW) children performed better than overweight (OW) children in aerobic fitness, agility, and dynamic balance (all p <.001), while OWchildren had a better static balance (p < .001). BMI-group-related differences in aerobic fitness and agility were larger in older children (p for interaction with age = .01) in favor of the NW children. PA did not differ between NW and OW (p > or = .1), but did differ between NW and obese children (p < .05). BMI-group-related differences in physical fitness can already be present in preschool-age children. PMID- 22428408 TI - Correlates of school-day physical activity in preschool students. AB - This study examined the relationship among sex, body mass index, motor skill competence (MSC), perceived physical competence (PPC), and school-day physical activity in preschool students (N = 34). Physical activity was assessed by steps accumulated during the school day, while MSC and PPC were assessed with the Test of Gross Motor Development-2nd edition (Ulrich, 2000) and the Pictorial Scale of Perceived Competence and Social Acceptance (Harter & Pike, 1984). Regression analyses revealed that preschool students' locomotor ability accounted for 21 % (p = .007) of the variance associated with school-day physical activity. The findings support an association between participants' ability to locomote and be physically active. The findings warrant future investigations to examine the relationship between locomotor skills and physical activity behaviors. PMID- 22428409 TI - Self-control of task difficulty during training enhances motor learning of a complex coincidence-anticipation task. AB - The aim of the present work was to analyze the influence of self-controlled task difficulty on motor learning. Participants had to intercept three targets falling at different velocities by displacing a stylus above a digitizer Task difficulty corresponded to racquet width. Half the participants (self-control condition) could choose the racquet width at the beginning of each trial. Each was paired with a participant from the yoked group. The self-control condition resulted in better performances and accuracy during immediate and delayed retention tests. These results confirm the advantage of a self-control condition on motor learning. They are discussed with reference to the challenge point hypothesis (Guadagnoli & Lee, 2004). PMID- 22428410 TI - Are K-12 learners motivated in physical education? A meta-analysis. AB - Previous studies devoted to K-12 learner motivation in physical education share a general assumption that students may lack motivation. This meta-analytic study examined published original studies (n = 79) to determine students' motivation level and the association between motivation and outcomes. Original means of motivation measures were converted and aggregated to determine motivation levels. Correlation effect sizes were calculated to determine the association between motivation and outcome measures. The analyses revealed that K-12 students are motivated regardless of the theoretical constructs used in the studies (M > 50). The correlation effect sizes (r = .20-.30, p < .05) indicate a weak association between motivation and outcome. The findings suggest a need to involve meaningful learning and pedagogy variables in motivation research. PMID- 22428411 TI - Changes in bone alkaline phosphatase and procollagen type-1 C-peptide after static and dynamic exercises. AB - We investigated the effects of two types of nonweight-bearing exercise on changes in bone-specific alkaline phosphatase (BAP) and procollagen type 1 C-peptide (PIP). BAP is a specific marker of bone synthesis, whereas P1P reflects synthesis of type 1 collagen in other organs as well as bone. Eight participants performed static and dynamic unilateral knee extensions. BAP and PIP were measured before, and at 1, 2, 24, 48, and 72 hr after exercise. PIP increased at 24 hr after a static knee extension exercise, whereas BAP did not change during the experimental period. We found no changes in these markers after dynamic exercise. These results imply that type I collagen synthesis in tendons increases after static exercise. PMID- 22428412 TI - Path analysis examining self-efficacy and decision-making performance on a simulated baseball task. AB - The purpose of this study was to examine the relationship between decision-making self-efficacy and decision-making performance in sport. Undergraduate students (N = 78) performzed 10 trials of a decision-making task in baseball. Self-efficacy was measured before performing each trial. Decision-making performance was assessed by decision speed and decision accuracy. Path analyses examined the relationships between self-efficacy, residualized past performance, and current performance. The results indicated that self-efficacy was a significant and consistent predictor of decision speed (eight of nine trials), but not decision accuracy (four of nine trials). It was also found that experience does not have a meaningful effect on the relationship between self-efficacy and decision-making performance in sport. PMID- 22428413 TI - Resilient excellence: challenges faced by trailblazing women in U.S. sport psychology. AB - Consistent with other sciences (e.g, Kass-Simon, 1993; Tang 2006), the field of kinesiology has been called a "masculine domain," which has an institutionalized culture biased against women (Brackenridge, Mutrie, & Choi, 2005). This paper represents the second part of a larger project that examined the life histories of eight trailblazing women in sport and exercise psychology. In the first paper (Krane & Whaley, 2010) we made the case for replacing these women into the history of sport psychology, based on their contributions to research, teaching and service to the field. In this study, we explored the experiences of these women with regard to the challenges they faced and how they overcame or coped with them. The specific themes emerging from the data analysis were the trailblazers' graduate school and early professional experiences, general campus climates, departmental politics, gender or discipline, coping and the cost of caring and giving back and moving forward. PMID- 22428414 TI - Implementation planning and progress on physical activity goals: the mediating role of life-management strategies. AB - This 4-week prospective study examined whether the use of life-management strategies mediates the relationship between implementation planning and short term progress on physical activity goals. In particular the strategies of elective selection, compensation, and loss-based selection were disentangled to assess their specific mediating effects. Results from a sample of 131undergraduate students showed that, as a composite, life-management strategies fully mediated the relationship between planning and goal progress. More specifically, decomposing the effects demonstrated that only elective selection and compensation mediated the association between planning and greater progress on a personal physical activity goal. Results are discussed in light of their practical implications and contributions to the personal goal literature. PMID- 22428415 TI - Differences in motor imagery time when predicting task duration in alpine skiers and equestrian riders. AB - Athletes' ability to use motor imagery (MI) to predict the speed at which they could perform a motor sequence has received little attention. In this study, 21 alpine skiers and 16 equestrian riders performed MI based on a prediction of actual performance time (a) after the course inspection, (b) before the start, and (c) after the actual performance. MI and physical times were similar in expert skiers during each imagery session, while novice skiers and novice and expert riders underestimated the actual course duration. These findings provide evidence that the temporal accuracy of an imagery task prediction depends on the performer's expertise level and characteristics of the motor skill. PMID- 22428416 TI - Social inequalities in body weight and physical activity: exploring the role of fitness centers. AB - Fitness centers are a viable option for physical activity, particularly in climates with significant weather variation. Due to variation in economic and social expressions ofexclusivity, fitness centers may have some relation to social inequalities in physical inactivity and related health outcomes; thus, our objective was to explore this relation. Using publicly available data and guided by Bourdieu's theory of habitus, we classified fitness centers in Calgary, Canada, on three dimensions of exclusivity (economic, social, and appearance). We found that, although some highly exclusive centers exist, most demonstrated low exclusivity based on our dimensions. An overall contribution of centers to inequalities appears to be limited; however, caution is warranted in light of cutbacks to municipal budgets that can have an impact on publicly funded facilities. PMID- 22428417 TI - Children's in-school and out-of-school physical activity during two seasons. PMID- 22428418 TI - Evaluation of thetrackstick super GPS tracker for use in walking research. PMID- 22428419 TI - Age-related differences in bilateral asymmetry in cycling performance. PMID- 22428420 TI - Prevalence of disordered eating and pathogenic weight control behaviors among NCAA division I female collegiate gymnasts and swimmers. PMID- 22428421 TI - 125 years of the American Journal of Psychology: a historical overview. AB - The American journal of Psychology celebrates 125 years of publication this year. From its inception, the Journal has attempted to record and communicate the results of research conducted in laboratories of psychology. It has also provided its readers with laboratory plans and designs for apparatus for research and demonstrations and described experimental procedures to facilitate the conduct of research. Its attention to reviews of books over a wide range of psychological topics and its inclusion of articles that provide historical perspectives on the development of psychology and its concerns broaden the context in which laboratory research is carried out. This brief overview of the Journal's history offers a perspective on the role of the Journal in, and its contributions to, the development of scientific psychology. PMID- 22428422 TI - 125 years of perceptual-motor skill research. AB - This article celebrates the contribution that the American Journal of Psychology (AJP) has made to the area of perceptual-motor skill over its 125-year history. We highlight the articles published in AJP and trace the technical and theoretical developments that stem from this groundbreaking work. Included in our overview are AJP articles on the excitability of the motor system, motor learning, adaptation to visual rearrangement, the ecological approach to perception and action, and the measurement of human handedness. We conclude by identifying a number of areas associated with perceptual-motor skill where AJP continues to make an important contribution. PMID- 22428423 TI - The higher mental processes in the American Journal of Psychology. AB - Research on the higher mental processes throughout the history of The American Journal of Psychology is reviewed. The domains covered include reasoning, judgment and decision, problem solving, and metacognition. Within each domain, the earliest contributions to the Journal are discussed, as is the development of the research domain over time. The increasing refinement of research methods and theoretical tools over time is accompanied by much consistency in research questions. PMID- 22428424 TI - Nocturnal emissions: a failure to replicate. AB - A time series of nocturnal emissions was presented in The American Journal of Psychology in 1904. The anonymous author of this remarkable article provided the time series to support his contention that his nocturnal emissions exhibited a seasonal pattern of variation. Specifically, he claimed to have heightened emissions during spring and summer, with dampened emissions later. The basis for this claim was a time series graph of average emissions by month across an 8-year period. The purpose of this article is to reanalyze these data with statistical procedures developed in the past century to validate the original conclusion drawn by the author. After analyses of the data with several state-of-the-art methods, no statistical support was found for a seasonal pattern of nocturnal emissions. PMID- 22428425 TI - When violations of perfect duties do not cause strong trait attributions. AB - It is well documented that violations of perfect duties (duties that can never be violated by moral agents) cause strong trait attributions. Brown, Trafimow, and Gregory (2005) found an exception to this general principle when the violation is performed under extreme circumstances. In the present research, we hypothesized that extreme circumstances are not necessary to weaken the attributional effect of violations of perfect duties provided that the violations were performed to help another person. Two experiments were performed in which target people violated perfect or imperfect duties for an unspecified reason or to help a third party. As expected, perfect duty violations did not result in strong trait attributions when they were performed to help someone, although they did result in strong trait attributions otherwise. Thus, the data support that the motive to help is sufficient to eliminate correspondent inferences to perfect duty violations. PMID- 22428426 TI - An apparent-motion confound causes the negative exogenous cuing effect at SOAs with larger numbers of target locations. AB - Salient but irrelevant stimuli seem to cause an automatic orienting of covert attention, facilitating the detection of targets at the cued location for a brief period of time. However, this finding is highly dependent on the number of possible target locations, at least when the simple detection of targets is all that the task requires. Whereas small numbers of possible target locations (e.g., 2 or 3) produce the well-known advantage in response time for valid cue trials (i.e., a positive cuing effect), larger numbers of possible target locations (e.g., 6 or 8) produce a negative cuing effect. If not explained in terms of a nonattentional mechanism, this latter finding raises serious questions about the standard interpretation of positive cuing effects. The present experiment tested a particular nonattentional mechanism: that a confound between target presence and apparent motion, which occurs only on invalid cue trials, is responsible for negative cuing effect. We reduced or eliminated this confound by the use of a new type of catch trial and eliminated the negative cuing effect with large numbers of target locations. PMID- 22428427 TI - Affective orientation influences memory for emotional and neutral words. AB - Memory is better for emotional words than for neutral words, but the conditions contributing to emotional memory improvement are not entirely understood. Elsewhere, it has been observed that retrieval of a word is easier when its attributes are congruent with a property assessed during an earlier judgment task. The present study examined whether affective assessment of a word matters to its remembrance. Two experiments were run, one in which only valence assessment was performed, and another in which valence assessment was combined with a running recognition for list words. In both experiments, some participants judged whether each word in a randomized list was negative (negative monitoring), and others judged whether each was positive (positive monitoring). We then tested their explicit memory for the words via both free recall and delayed recognition. Both experiments revealed an affective congruence effect, such that negative words were more likely to be recalled and recognized after negative monitoring, whereas positive words likewise benefited from positive monitoring. Memory for neutral words was better after negative monitoring than positive monitoring.Thus, memory for both emotional and neutral words is contingent on one's affective orientation during encoding. PMID- 22428428 TI - Modality and variability of synesthetic experience. AB - In synesthesia, stimulation of one sensory or cognitive pathway leads to additional, involuntary experiences in a second sensory or cognitive pathway. We here review previous surveys on this neurologically based phenomenon and report the results of 63 synesthetes who completed our Internet and paper questionnaire on synesthesia. In addition to asking for personal data and information on the participant's synesthesia, the questionnaire focused on the components of the inducer that elicit or modulate synesthesia. Synesthesia was most often developmental (92%) and of the grapheme-color type (86%). Sixty-two percent of the participants perceived time-related words in a spatial configuration. Music color synesthesia was common (41%), and synesthesia for natural and artificial sounds (33%) was higher than in previous estimates. Eighty-one percent of participants experienced more than one form of synesthesia. Multimodal synesthesia, in which inducer and concurrent belong to 2 different sensory modalities, occurred in 92% of the participants. Overall, auditory stimuli were most often reported as inducers, and visual concurrents were most common. Modulations of the synesthetic experiences such as changes of the concurrent color, expansion within the same or to a different sensory modality, or reduction of the number of inducers over time were reported by 17% of participants. This challenges the presumed consistency of synesthesia and the adequacy of the test retest consistency score still most commonly used to assess the veracity of reported synesthesia. Implications of the high prevalence of cross-modal synesthesia and the variability of synesthesia are discussed. PMID- 22428429 TI - [Glucose monitoring in children with type 1 diabetes mellitus. New insights]. PMID- 22428430 TI - Short review about Helicobacter pylori infection in pediatric age: epidemiological and clinical findings, diagnosis, therapy and role of probiotics. AB - Helicobacterpylori (Hp) is mainly acquired during childhood and causes one of the most widespread infections worldwide; it is recognised as a cause of gastritis and peptic ulcer and it has been classified as a group A carcinogen by World Health Organization. This infection can be diagnosed by invasive techniques requiring endoscopy and biopsy (histological examination, rapid urease test, culture) and by non invasive tests (serology, urea breath test, detection of Hp antigen stool specimen). The gold standard in the eradication of Hp is one-week triple therapy: one proton pump inhibitor (PPI) and two antibiotics (mainly nitromidazoles, macrolides and beta-lactames). It is possible the use of probiotics during this therapy to reduce the adverse effects, to improve tolerability and compliance of multiple antibiotics regimens. PMID- 22428431 TI - [Ultrasound and MRI measurements investigation in juvenile idiopatic arthritis]. AB - The juvenile idiopatic arthritis (JIA) is the childhood most common rheumatologic disorder. The JIA diagnosis is not based on specific clinical and serological markers, but mainly on the ultrasound and magnetic resonance imaging investigations. The use of both these imaging techniques seem to be very promising, especially for the ultrasound. In fact, the improvement in both the ultrasound methods (power e colour Doppler, high resolution technique) and the operator knowledge could give the same results of the MRI imaging leading to a better cost-benefit ratio. PMID- 22428432 TI - Postoperative nutrition of neonates undergoing heart surgery. AB - OBJECTIVE: Postoperative nutrition of newborns undergoing heart surgery (HS) is ill-defined. We compared the postoperative growth rates (grams/day) of neonates with congenital heart defects (CHDs) fed with their own mothers' milk (HU), a starting formula (SF; 67 kcal/100 mL), or a "preterm formula" (PF; 80 kcal/100 mL). PATIENTS AND METHODS: We studied 122 newborns undergoing HS: 81 underwent corrective surgery (group A), and 41 palliative surgery (group B). RESULTS: No statistically significant differences were found in the growth rate between group A and B. Moreover, in both groups, no differences in terms of growth rate between infants fed HU, SF, or PF were observed. This was also true when analyses were limited to infants undergoing HS either with or without cardiopulmonary bypass. CONCLUSIONS: In neonates undergoing HS, human milk allowed a growth rate similar to that observed with starting formulas and "preterm formulas". This effect may depend on the particular features of human milk and its protective properties for the intestinal mucosa. PMID- 22428433 TI - Early metabolic, functional and histological changes in a rat ileal-augmented bladder model. AB - OBJECTIVE: An animal model of female Wistar species of rats was developed to study the early effects of ileocystoplasty. MATERIALS AND METHODS: Bladder augmentation using ileum and a sham operation (cistostomy) were performed in 14 and 6 female Wistar rats, rispectively. Urine was obtained for culture and urinalysis in all rats at the time of operation and at the time of the sacrifice. Seven rats underwent ileocystoplasty and three shams were sacrificed after one and three months. In all rats sacrificed three months after ileocystoplasty, blood sample drawn for serum electrolytes, blood urea, nitrogen creatine and bicarbonate was performed. Post mortem histopathological examination of the ileal patch and of kidneys was performed. RESULTS: The cultures of the urine were positive in 1 out 7 (14.3%) and in 4 out 7 (57%) after one and three months after ileocystoplasty, respectively. Urinary pH of the augmented group was significantly higher in treated rats than in shams (p < 0.05). At sacrifice three months post operatively, the serum chloride concentration was significantly higher in augmented than shams (p < 0.05). Bladder calculi were formed in 28.6% of ileocystoplasty. Histopathological examination of the enteropatch showed urothelialization of the graft and kidneys showed a significant glomerular depletion. CONCLUSION: Our data confirm an early significant enhancement of urinary pH in rats underwent ileocystoplasty and the stone formation is a frequent event. Already three months after ileocystoplasty urothelialization extended from the side of anastomosis towards the central portion of the ileal graft. Moreover, a significant improvement of serum creatine, sign of glomerular overload and progressive glomerular depletion were recorded in treated rats, probably as a consequence of water and electrolyte resoption through the intestinal graft. PMID- 22428434 TI - [Gartner's duct cyst: report of three cases]. AB - Gartner's duct cyst is a rare condition consequent to an unfinished disappearance of the mesonephric duct in females. In this report we present three cases of mesonephric duct remnants cysts: two of these were originated from its proximal part ,paraooforon, whereas in the third case the cyst was originated from its paraurethral distal end. These lesions are an uncommon and extremely rare manifestations in paediatric age and more in neonatal age: therefore we believe very interesting and useful to report these cases, describe their clinical data, debate the embryogenic origins, discuss diagnostic and therapeutic problems according to international literature. PMID- 22428435 TI - Usefulness of lung ultrasound in a newborn with pulmonary atelectasis. AB - The use of ultrasound for the evaluation of the lung is relatively recent. We describe the case of a newborn with pulmonary atelectasis and shift of the mediastinum underlining both advantages and limits of lung ultrasound (LUS). The baby, 1 month of age, was admitted to our hospital for tachypnoea, vomiting and poor weight gain. Chest X-ray (CXR) showed displacement of the heart to the right, suggesting the presence of atelectasis of the right lung. LUS confirmed the displacement of the mediastinum to the right and atelectasis of the right lung, clearly visible as a consolidation with the presence of air bronchograms. The computed tomography image showed that the lung parenchyma displayed in the right hemithorax could be attributed to the hyperexpanded left lung. However, once this information was acquired, and compared to the ultrasound picture, we were able to monitor the patient by LUS until normalization, thus avoiding further exposure to ionizing radiation. Our case, in accordance with the recent Literature, indicates that LUS can be adopted as a simple and non-invasive method for evaluating children with lung disease. It is easy to perform at bedside, allows a close follow-up and avoids the use of ionizing radiation. PMID- 22428436 TI - [Pediatric steatohepatitis: is it only obesity?]. AB - We describe the case of an 11-year-old obese child with nonalcoholic steatohepatitis and Wilson's disease. Nonalcoholic steatohepatitis, although frequently found in patients with obesity, can also be caused by other etiologies, including Wilson's disease, which must therefore always be ruled out in the obese child. PMID- 22428437 TI - www.unique global first: World Wide Web window opens to Missouri Medicine! PMID- 22428438 TI - Routine vaccination: a growing crisis of public confidence. PMID- 22428439 TI - "I've heard some things that scare me". Responding with empathy to parents' fears of vaccinations. AB - The Lancet's 1998 publication of "Ileal-lymphoid-nodular hyperplasia, non specific colitis, and pervasive developmental disorder in children" by Andrew Wakefield, et. al., positing a causal relationship between MMR vaccine and autism in children, set off a media storm and galvanized the anti-vaccine movement. In this paper, centuries-old fears of vaccination and the history of autism as a medical diagnosis are considered, and an affective, family-centered approach to dealing with parental fears by physicians is proposed. PMID- 22428440 TI - The thimerosal insinuation. PMID- 22428441 TI - Escalating medication shortages: a public health and patient care crisis. PMID- 22428442 TI - Solving the growing Rx shortages. PMID- 22428443 TI - It all started with Harry. PMID- 22428444 TI - Estate and business planning for the retiring physician. AB - Retiring physicians have much to think about for estate planning purposes. The authors stand ready to help physicians sell or close their medical practice, navigate the 2010 Tax Act, take advantage of current planning opportunities, and prepare appropriate estate planning documents. Every estate is unique, so it is important to contact an estate planning advisor before taking any action. PMID- 22428445 TI - Kansas horse & buggy doctor receives letter from Albert Einstein. PMID- 22428446 TI - Rheumatology updates for the primary care physician. PMID- 22428447 TI - New directions in fibromyalgia. AB - Fibromyalgia is a common disorder causing pain, fatigue and sleep disturbances. The differential diagnosis includes rheumatic diseases and a variety of other conditions. New diagnostic guidelines emphasize the multiple somatic symptoms that may be seen. Pharmacological and nonpharmacological treatment options are available. Three new medications were recently approved for treatment. PMID- 22428448 TI - Ophthalmic manifestations of rheumatologic disease: diagnosis and management. AB - Rheumatologic diseases are often associated with ophthalmic findings. Familiarity with and recognition of these ophthalmic presentations are important in the management of both the systemic and ocular manifestations of the disease. Identification of ocular signs and symptoms of rheumatologic disease will allow a more comprehensive approach to treatment of patients with rheumatic conditions. PMID- 22428449 TI - Rational use of blood tests in the evaluation of rheumatic diseases. AB - Many blood tests used in the evaluation of rheumatic diseases are non-specific and should not be ordered and interpreted in isolation. False positive results can lead to inappropriate therapies with serious adverse events while false negatives may steer the provider to incorrect diagnoses. Relying on blood tests alone without considering the clinical context should be avoided. PMID- 22428450 TI - The forgotten crystal arthritis: calcium pyrophosphate deposition. AB - Calcium pyrophosphate crystals are related to a variety of articular manifestations known as calcium pyrophosphate deposition (CPPD) arthritis. Acute CPPD arthritis is commonly known as pseudogout, but there are many other presentations. Diverse endocrine and metabolic diseases may be related to CPPD arthritis. Septic arthritis is in the differential diagnosis of acute CPPD arthritis. The treatment options for CPPD arthritis include non-steroidal anti inflammatories and steroids. PMID- 22428451 TI - Spondyloarthropathies: new directions in etiopathogenesis, diagnosis and treatment. AB - The spondyloarthropathies (SpA) are a group of inflammatory rheumatic diseases affecting the spine, peripheral joints and nonarticular structures. Often referred to as "seronegative" due to the absence of rheumatoid factor, SpA include ankylosing spondylitis (AS), reactive arthritis (ReA), enteropathic (IBD) associated arthritis, psoriatic arthritis (PsA), as well as undifferentiated, and juvenile SpA. A broad and overlapping spectrum of disease presentations creates difficulties in determining an initial diagnosis. In the last 10 years treatment options have expanded. PMID- 22428452 TI - Economic impact of a smoke-free ordinance on bars and restaurants in a small, rural, Missouri community. AB - The purpose of this study was to analyze the economic impact of a city-wide smoke free ordinance in the small, relatively isolated, rural, Northeast Missouri community of Kirksville. A model similar to prior studies was applied to the taxable sales revenues of eating and drinking establishment data prior to and following enactment of a smoke-free ordinance. It was found that there was a significant positive change in eating and drinking establishment taxable sales revenues post-enactment. PMID- 22428453 TI - Patients overestimate the potential benefits of elective percutaneous coronary intervention. AB - OBJECTIVE: Although percutaneous coronary intervention (PCI) reduces mortality in the setting of myocardial infarction (MI), recent studies suggest that the benefits of PCI for chronic Coronary Artery Disease (CAD) are predominantly related to angina relief and improved quality of life. Whether patients in the current era understand these benefits of elective PCI, or perceive that they also derive protection against death and MI is unknown. PATIENTS & METHODS: We surveyed 498 consecutive elective PCI patients a mean of 13.7 months after being treated between 1/06-10/07, 2007, at two hospitals. We used a one-page questionnaire quantifying their perceptions of the benefits from PCI. RESULTS: Of 498 eligible subjects, 350 responded (70%). The mean age was 67.8 +/- 10.9 years, and 76% were male. One-third believed that their PCI was emergent (despite the fact that all were elective), 71% believed the procedure would prevent future heart attacks, 66% thought it would extend their life, 42% reported that it saved their life, 42% stated that it would improve abnormalities on their stress test, and only 31'% believed it would decrease their angina. CONCLUSION: Although considerable attention is given to facilitating informed consent at our center, patients' perceived benefits of elective PCI do not match existing evidence, as they overestimated both the benefits and urgency of their procedures. These findings suggest that an even greater effort at patient education is needed prior to elective PCI to facilitate fully informed decision-making. PMID- 22428454 TI - Involvement of TLR4 in diazinon-induced neurotoxicity in mice. AB - Our laboratory recently reported that Toll-like receptor (TLR) 4 may play a role in the neurotoxic effects in mice exposed to the environmental toxic chemical toluene. To investigate the role of TLR4 in hippocampal neurotrophin expression, C3H/HeN (TLR4 intact) and C3H/HeJ (TLR4 defective) male adult mice were administered diazinon (0, 0.05, 0.5 or 5 mg/kg) intraperitoneally once a week for three weeks. Twenty-four hours after the final diazinon injection, the hippocampus was collected from each mouse to detect mRNA expression of neurotrophins (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) by the real-time RT-PCR method. There was no difference between groups in neurotrophin expression in the C3H/HeN mice. However, the expression of NGF and BDNF mRNAs was suppressed significantly in the diazinon-injected C3H/HeJ mice compared with their control group. We also found an increased tendency of proinflammatory chemokine CCL3 mRNA and a marked increase in the proapoptotic gene Bax mRNA in the diazinon-injected C3H/HeJ mice. Our findings indicate that diazinon injection affects neurotrophin expression in the hippocampus in TLR4 defective mice but not in TLR4 intact mice. These results suggest that a defective TLR4 signaling pathway in the mouse hippocampus can be easily affected by diazinon administration. PMID- 22428455 TI - The effects of static trunk flexion on oxygenation and electromyographic activity of erector spinae muscles. AB - In the workplace, localized muscle fatigue can be a limiting factor for prolonged static work. It is important to study the etiology of fatigue in the muscle to prevent discomfort and potential muscle injury. The purpose of this study was to investigate the effect of sustained trunk flexion and loading on the erector spinae muscles (ESM) fatigue using electromyography (EMG) and muscle oxygenation (Mox) changes. Twelve healthy male volunteers, aged between 19 and 28 years (mean age 23 +/- 2.6), participated in this study. The subjects held a load (5, 10 and 15 kg) and no load in their hands whilst sustaining trunk flexion at 60 degrees and also in an upright standing posture for 30 seconds. Five minutes rest was given between the conditions, and each condition was randomly repeated three times. Surface EMG and near-infrared spectroscopy were recorded. Root mean square and median frequency (MF) of EMG, and Mox were calculated. The results showed a greater decrease in Mox with an increase in loads over time (P = 0.015). Using unloaded trunk flexion as a control to ascertain load effect resulted in a significant difference in Mox in the unloaded condition and in the 15 kg condition (P = 0.027). EMG results showed a significant decrease in the MF over time in trunk flexion while holding a load (P < 0.001). These results show objectively that trunk flexion while holding loads causes ESM fatigue. PMID- 22428456 TI - Peroxiredoxin 4: critical roles in inflammatory diseases. AB - We review the critical roles of peroxiredoxin (PRDX) 4 in inflammatory diseases. The PRDX family, a new family of proteins with an antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. The function of these enzymes, which include at least six distinct PRDX genes expressed in mammals, still remains unclear. Especially, in contrast to the intracellular localization of other family members, PRDX4 is the only known secretory form located in the extracellular space and exerts its protective function against oxidative damage by scavenging reactive oxygen species in the vascular vessels. To date, however, it is not clear whether or how PRDX4 expression affects various diseases in vivo. More recently, we generated human PRDX4 (hPRDX4) transgenic (Tg) mice, and, for the first time, established a type 1 diabetes mellitus model induced by a single high dose of streptozotocin on Tg mice. Our published data demonstrate that streptozotocin-treated Tg mice, which overexpress hPRDX4 in pancreatic islets, can protect pancreatic beta-cells against streptozotocin-induced injury (insulitis) by suppressing increased oxidative stress and inflammatory signaling activation. These observations indicate that Tg mice could become a useful animal model to study the relevance of oxidative stress to inflammation, and that a specific accelerator of PRDX4 might prove to be a potential therapeutic agent for ameliorating various chronic inflammatory diseases. PMID- 22428457 TI - [Clinical characteristics of pulmonary hamartoma resected surgically as undiagnosed pulmonary nodule]. AB - Pulmonary hamartoma is the most common tumor in benign lung neoplasm. We reviewed the clinical characteristics of 9 patients who had undergone surgical resection for pulmonary hamartoma between 2000 and 2009. There were 1 male and 8 female patients. The age of the patients ranged from 42 to 77 years old (mean 59). Calcification was not observed by computed tomography scan except in 1 patient. Although transbronchial lung biopsy (TBLB) was performed in 5 patients, no definitive diagnosis was obtained. Six patients underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography, and none of them showed any accumulation of FDG except for 1 patient. Concerning the operative procedures, a sleeve lobectomy was performed in 1 patient, a segmentectomy in 1, a lobectomy in 2, a partial resection of the lung in 3, and a nucleation in 2 patients. The postoperative courses were uneventful, and no findings of recurrence were observed in any of the patients after surgery. As a preoperative diagnosis of pulmonary hamartoma is often difficult in TBLB, it is necessary to perform surgical resection in the differential diagnosis of lung cancer or metastatic lung tumor, unless there are typical findings of pulmonary hamartoma in clinical imaging. PMID- 22428458 TI - [Relationship between performance rating and risk of low back pain in manufacturing line workers]. AB - It is possible that the performance rating of line workers is affected by the risk factors for musculoskeletal disorders that are included in their work more so than by the actual takt time. To investigate whether performance rating relates to the risk factors for musculoskeletal disorders, we analyzed a dataset obtained from a self-administered questionnaire answered by assembly line workers (n=1579). As a result, performance rating had a significant association with unsuitable work environments, poor working postures and handling of heavy loads. The workers who reported the fastest rating had a higher exposure than others to the risk factors for occupational low back pain. The results of our study support the effectiveness of performance rating as an index of work burden. PMID- 22428459 TI - [Hazard assessment of manufactured nanoparticles: association of in vitro and in vivo examinations]. AB - Nanoparticles are defined as particles whose diameter is 1-100 nm. Many investigations about the toxicology of nanoparticles have been reported recently. The toxicity of nanoparticles has been examined both in vivo and in vitro and many results are being achieved. However, the results of in vivo and in vitro examinations are sometimes different. According to the in vitro examinations, it is suggested that solubility, adsorption ability and surface activity are involved in the cytotoxicity of nanoparticles. On the other hand, in in vivo, clearance is an important factor in the lung toxicity of nanoparticles. In the hazard assessment of nanoparticles, in vivo and in vitro examinations are necessary for an accurate evaluation of their biological influences, including the toxic mechanisms. PMID- 22428460 TI - [Biological effect of fullerene (C60) to lung by inhalation or instillation]. AB - Fullerene (C60) is a newly generated nanoparticle that has a soccer-ball structure with 60 carbon atoms. Fullerenes are expected to have a multitude of uses, for example as energy device materials or information technology materials. The biological effects of nanoparticles are now being discussed, and there are ongoing animal studies using various nanoparticles. Here we review some reports about the toxicity of C60, and in addition we present the results of our 2-year follow up studies of instillation and inhalation of C60 via the trachea. PMID- 22428461 TI - [The biological role of UVB-induced cutaneous immunosuppression]. AB - Skin is a large organ which protects our inner body from external stresses. Skin serves not only as a physical barrier but also as an important immune system. Ultraviolet rays B (UVB) activate melanin synthesis by melanocytes in the skin. Melanin, in turn, absorbs UVB and protects the skin from overexposure to UVB. In addition, it is generally known that UVB suppresses immune reaction in the skin. This phenomenon is applied to the treatment of cutaneous diseases such as psoriasis and vitiligo. UVB-induced immunosuppression is mediated by regulatory T cells (Tregs). We and other groups have figured out the mechanism of UVB-induced antigen specific immunosuppression. Here we propose that the role of UVB-mediated immunosuppression is the inhibition of self-destruction against external stresses. PMID- 22428462 TI - [Wheat dependent exercise induced anaphylaxis possibly sensitized by the hydrolyzed wheat proteins in a facial cleansing soap]. AB - There are increasing cases of wheat dependent exercise-induced anaphylaxis (WDEIA) with transcutaneous or transmucosal sensitization. Hydrolyzed wheat included in a certain brand of soap was identified as a cause of sensitization. The useful clues to detect this disorder consist of the patient's past usage of a soap containing hydrolyzed wheat, the appearance of cutaneous or mucosal symptoms after the intake of wheat or washing with this soap, and a high level of specific IgE for wheat gluten. Because hydrolyzed wheat is used as an additive in a wide variety of cosmetics, we should pay careful attention to the ingredients of cosmetics when observing WDEIA. PMID- 22428463 TI - [A questionnaire survey about public's image of radiation after the Fukushima Daiichi nuclear power plant accident]. AB - A questionnaire survey about the public's image of radiation was performed after the Fukushima Daiichi nuclear power plant (FDNPP) accident. The survey was taken by general citizens (200 and 1640 in Fukushima and 52 outside of Fukushima) and doctors (63 in Fukushima and 1942 outside of Fukushima (53 in Oita, 44 in Sagamihara and 1,845 in Kitakyushu)) in and outside of Fukushima and second year medical students in the University of Occupational and Environmental Health, Japan. The questionnaire surveys were performed during lectures about radiation. The response rates were 86% for the general citizens in Fukushima, 91% for the general citizens outside of Fukushima, 86% for doctors in Fukushima, and 85% and 86% for doctors in Sagamihara and Oita, respectively. The questionnaire surveys were sent to clinics and hospitals in Fukushima where the general citizens answered with a response rate of 50%. When the questionnaire surveys were sent to clinics and hospitals in Kitakyushu, doctors answered, with a response rate of 17%. The percentages of anxiety about future radiation effects after the FDNPP accident were the highest among the general citizens (71.6% in Fukushima and 40.4% outside of Fukushima), in the middle among the doctors (30.2% in Fukushima and 26.2% outside of Fukushima) and the lowest among the medical students (12.2%). The doctors in Fukushima and the medical students were anxious about food and soil pollution. The general citizens and the doctors outside of Fukushima were anxious about health problems and food and soil pollution. We concluded that a high level of education about radiation decreased the anxiety about the radiation effects. It is important to spread knowledge about radiation. PMID- 22428464 TI - Regulation of blood flow by aspirin following muscle ischemia. AB - BACKGROUND: The vascular endothelium secretes a balance of dilator and constrictor substances which regulate vascular tone. During ischemic stress, this balance changes. After a short period of ischemia, a protective mechanism known as reactive hyperemia (RH) contributes to a post-ischemic increase in blood flow. The agents regulating this phenomenon remain controversial. AIM: The purpose of this study was to examine whether aspirin regulates vascular endothelial function following ischemia. METHODS: Sixteen healthy volunteers presented for two visits, each serving as their own control, and randomized to receive 500 mg aspirin or placebo. Forearm blood flow (FBF) was measured at baseline and during reactive hyperemia (RH) which was induced by five minutes of arterial occlusion. Blood samples were analyzed for vWF and lipids. RESULTS: After ischemia, RH was attenuated when subjects were pre-medicated with 500 mg aspirin compared to placebo: AUC[aspirin] = 1450 +/- 201 mL/100 mL tissue/min vs. AUC[pIacebo] = 2207 +/- 294 mL/100 mL tissue/min; (p < 0.05). Separation of the subjects with high HDL or low HDL levels resulted in a similar peak FBF response with placebo, but in the high-HDL group only, aspirin ingestion attenuated peak FBF after ischemia compared to the placebo condition (22.6 +/- 1.7 m/100 mL tissue/min vs. 33.5 +/- 3.2 mL/100 mL tissue/min, respectively) (p < 0.05). CONCLUSIONS: Aspirin partially regulates the RH response following ischemia compared to placebo, and this effect appears to be more profound when adjusting for plasma HDL concentration in healthy individuals. This suggests that the post-ischemic RH response may be partially mediated by arachidonic acid-derived mediators such as the prostaglandins. PMID- 22428465 TI - Psidium guajava Linn confers gastro protective effects on rats. AB - BACKGROUND AND OBJECTIVES: The best alternatives to synthetic medicines, available, for the treatment of gastric ulcer disorders, are the natural products found in plants. They are known to exhibit a variety of activities. The present study is aimed at the screening of Psidium (P.) guajava Linn for its gastro protective effect. MATERIAL AND METHODS: The methanol extracts of the leaves of P. guajava were tested in three different ulcer models viz. aspirin (ASP), pyloric ligation (PL) and ethanol (EtoH) induced ulcer models in rats. RESULTS AND DISCUSSION: The treatment of P. guajava at varying doses (100 mg/kg and 200 mg/kg) significantly (p < 0.001) inhibited the gastric lesions induced by ASP (70.5%), PL (65.07%) and EtoH (70.4%) respectively and the potency was found to be equivalent as compared to the standard drug, omeprazole. Reduction in the gastric secretory volume, acid secretion and increased gastric pH were the factors observed in treated rats. The presence of volatile oil, flavonoids and saponins present in the extracts of P. guajava may be responsible for the anti ulcer property exhibited. CONCLUSIONS: The results further suggest that P. guajava possess gastro protective as well as ulcer healing properties which might also be due to its anti-secretory properties. PMID- 22428466 TI - Purification and optimization of production conditions of a marine-derived antibiotic and ultra-structural study on the effect of this antibiotic against MRSA. AB - OBJECTIVES: In this study we have attempted to partially purify, characterize and optimize the fermentation condition for the antimicrobial compound production with anti-MRSA (Methicillin Resistant Staphylococcus aureus) activity produced by Pseudoalteromonas piscicida PG-02 bacterium, isolated from the Persian Gulf, and finally understand the morphological changes in MRSA due to this antibiotic. MATERIALS AND METHODS: Optimization process of antibacterial compound production was studied based on the sources of carbon and nitrogen, optimum temperature, optimum pH and optimum incubation time. The purification of intended antibiotic was done using TLC and also thermostability and enzymatic stability treatment was studied. Ultrastructural study on the effect of intended antibacterial compound on MRSA was done using a Transmission Electron Microscopy (TEM). RESULTS: The optimized bioprocess conditions for the maximum production were at temperature 28 degrees C, pH 7, NaCI 0.5% (w/v), 96 hrs (incubation time), glucose and tryptone as carbon source and nitrogen source, respectively. The antibacterial component showed thermal sensitivity but it was sensitive to proteinase K, so this compound may have proteinaceous nature. The results of sonication revealed that this compound is accumulated in both intra- and extra-cellular locations. TEM pictures showed disorganization of cytoplasmic membrane upon the extract treatment comparing to control so, it can be said that this antibacterial compound can be considered as a bactericidal agent against MRSA. CONCLUSION: On the basis of obtained results, this bacterium can be regarded as a valuable strain for discovery of new weapon as bactericidal agent in fighting against multi-drug resistant bacteria especially MRSA. PMID- 22428467 TI - Hypoglycemic effect and mechanism of a proteoglycan from ganoderma lucidum on streptozotocin-induced type 2 diabetic rats. AB - BACKGROUND AND OBJECTIVES: Diabetes mellitus inducing a leading cause of morbidity are widespread in the entire globe. The present study was to investigate the antidiabetic potency and mechanism of a proteoglycan extract, named FYGL (Fudan-Yueyang-G. lucidum), from the fruiting bodies of Ganoderma Lucidum as published recently, using streptozotocin-induced type 2 diabetic mellitus (T2DM) rats. MATERIAL AND METHODS: The T2DM model rats were treated with FYGL as well as metformin and rosiglitazone. The levels of plasma glucose and insulin were measured, and the expression and activity of the protein tyrosine phosphatase 1B (PTP1B) and the tyrosine phosphorylation level of the insulin receptor (IR) 3-subunit in the livers and skeletal muscles of the T2DM rats were analyzed by immunoprecipitation and Western blotting methods. In addition, the levels of free fatty acid and serum lipid profile were measured using commercial kits for those trailed rats. RESULTS: The decrease in fasting plasma glucose and the increase in insulin concentration dose- and time-dependently in the T2DM rats treated by FYGL, comparable with that by the clinical drugs, metformin and rosiglitazone. The levels of the PTP1B expression and activity were decreased, and the tyrosine phosphorylation level of the IR 1-subunit was increased in the skeletal muscles of the T2DM rats. Furthermore, FYGL significantly decreased the levels of free fatty acid, triglyceride, total cholesterol and low density lipoprotein-cholesterol as well as increased the level of high density lipoprotein-cholesterol. DISCUSSION: It is suggested that the hypoglycemic mechanisms of FYGL are caused by inhibition of the PTP1B expression and activity, consequently, regulation of the tyrosine phosphorylation level of the IR 13 subunit. As those results, FYGL also controlled the plasma biochemistry indexes relative to the type 2 diabetes-accompanied metabolic disorders. This is possibly the first report on the underlying mechanisms responsible for the antidiabetic effect of Ganoderma lucidum. PMID- 22428468 TI - Study of the role of interleukin-6 and highly sensitive C-reactive protein in diabetic nephropathy in type 1 diabetic patients. AB - BACKGROUND: Diabetes Mellitus (DM) is becoming an increasingly common disease which is the leading cause of chronic renal failure. The pathogenesis of diabetic nephropathy is still a matter of debate. There are conflicting results regarding the relation of C reactive protein (CRP), interleukin-6 (IL-6) and diabetic nephropathy in type 1 diabetes. OBJECTIVES: This study was aiming to determine the association between higly sensitive (Hs)-CRP and IL6 with nephropathy in a sample of type 1 diabetic Egyptian patients. MATERIALS AND METHODS: The study was conducted on forty type-1 diabetic patients (Group I), who subdivided into three subgroups according to their urine albumin excretion rate (AER); Group IA: 10 patients with AER <20 microg/min, Group IB: 15 patients with AER ranges from 20 200 microg/min. Group IC: 15 patients with AER is > 200 microg/min and 10 healthy subjects as a control (Group II). RESULTS: There were high statistical significant difference (p < 0.001) between group I with group II regarding HsCRP (4.39 +/- 1.94, 1.32 +/- 0.39), and IL-6 (2.82 +/- 0.76, 1.95 +/- 0.35). In group I, we found a positive significant correlation (p < 0 .001) between UAE and levels of Hs-CRP (r = 0.927), and IL-6 (r = 0.838), respectively. Also, a positive significant correlation between Hs-CRP and IL-6 (r = 0.728, p < 0.001) was found. Fasting plasma glucose (FPG) level and HbA1c showed a significant positive correlation (p < 0.001) with Hs-CRP (r = 0.531) (r = 0.750), and IL-6 (r = 0. 490) (r = 0.680) respectively. CONCLUSION: Hs-CRP and IL-6 are sensitive markers for diabetic nephropathy predicting its progression and severity in type 1 diabetics. PMID- 22428469 TI - Treatment of acute exacerbations with non-invasive ventilation in chronic hypercapnic COPD patients with pulmonary hypertension. AB - BACKGROUND AND OBJECTIVES: Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive airways disorder characterized by not fully reversible airflow obstruction, often presenting exacerbations of respiratory symptoms requiring hospitalization. Non-Invasive Ventilation (NIV) has been shown to be an effective adjunct to standard medical therapy in the treatment of acute respiratory failure. Secondary pulmonary hypertension leads to a rapid progression of the disease. AIM: To evaluate the effect of NIV treatment in patients with acute exacerbation of COPD, with or without respiratory acidosis, and its effect in patients with pulmonary hypertension. PATIENTS AND METHODS: We enrolled 61 consecutive subjects (M 41; F 20) with COPD admitted to our respiratory ward for acute respiratory exacerbation. Patients were divided into two groups on the basis of arterial pH (group A: 26 individuals with pH <7.35; group B: 35 with pH > or =7.35) and treated with optimal medical therapy (oxygen-therapy, systemic corticosteroids, bronchodilators, antibiotics) and NIV. Moreover, we evaluated functional autonomy thought Six Minute Walking Test (6 mWT), and pulmonary arterial pressure (by transthoracic echocardiography). RESULTS: In group A NIV treatment was associated to a total regression of uncompensated respiratory acidosis (pH 7.36 vs. 7.29). In both groups we observed a significant reduction of PaCO2 (group A: 77.14 +/- 10.4 vs. 45.1 +/- 2.8 mmHg; group B: 70.1 vs. 44 +/- 3.9 mmHg) and an improvement in PaO2 (group A: 51.2 +/- 10.3 vs 84.2 mmHg; group B: 59 +/- vs. 87 +/- 3.3 mmHg). Total average duration of NIV administration was longer in Group A than in Group B (81.14 hours vs 55.83 hours). At the end of NIV treatment, we observed improvement in the autonomy of walking (175.1 meters vs 118.4 meters) in both groups. Patients with severe pulmonary hypertension (PASP > or =55 mmHg) showed a lower reduction of PaCO2 (47.8 vs. 43.7 mmHg) and a minor improvement of arterial pH (7.37 vs. 7.41) compared to patients with a lower value of pulmonary hypertension. CONCLUSIONS: In this study we showed that NIV is useful in patients with or without uncompensated respiratory acidosis, through the improvement of symptoms, blood gases parameters, and walking autonomy. Patients with severe pulmonary hypertension are associated with poorer response to NIV treatment. PMID- 22428470 TI - Diet and pancreatic cancer: many questions with few certainties. AB - BACKGROUND, OBJECTIVES: Pancreatic cancer ranks fourth for cancer mortality for men and women in the United States. This is a particularly devastating cancer since the case-fatality proportion approaches 90% within 12 months following diagnosis. Therefore, understanding the etiology and identifying the risk factors are essential for the primary prevention of this deadly disease. Of the few potentially modifiable risk factors that have been identified, cigarette smoking, history of diabetes mellitus, and obesity seem to be among the most consistent, but the effect of dietary factors is still unclear. The aim of our study is to review of the literature examining the potential role of carbohydrates, fatty acids, meat, fruit and vegetables, alcohol. DISCUSSION: Although large prospective cohort studies with questionnaire based analyses will continue to have much to offer in defining predisposing factors for difficult diseases, such as pancreatic cancer, unfortunately dietary questionnaires do not reflect the bioavailability of the nutrients from various foods, the level of absorption from the digestive tract, or individual differences in metabolism. CONCLUSIONS: Greater use of participant-derived biological samples, banked plasma, germline DNA, and tumour tissue samples may help to the understanding of pancreatic cancer pathogenesis. PMID- 22428471 TI - Single intrathecal fentanyl for combined spinal epidural anesthesia confers no advantage over hemodynamic effects in elderly patients. AB - BACKGROUND: Neuroaxial blockade for ambulatory transurethral resection of the prostate is a well established technique. Patients in this group are often at high risk for perioperative complications from concurrent diseases. The purpose of this study was to compare the elderly patients who received intrathecal fentanyl alone or intrathecal fentanyl plus bupivacaine or epidural anesthesia for transurethral resection of prostate surgery. MATERIAL AND METHODS: Ninety nine patients were prospectively randomized to receive fentanyl 25 microg (Group F), fentanyl 25 microg plus hyperbaric bupivacaine 2.5 mg (Group BF), or epidural anesthesia adding fentanyl 50 microg (Group E) by combined spinal epidural anesthesia technique. RESULTS: The amount of local anesthetics used until when the sensorial block reached the level of T10 was significantly lower in the Group BF than in the Group E and the Group F (p < 0.001). Maximum level of sensory block was significantly lower in the Group BF than in the Group E and the Group F (p = 0.01). The time elapsed until the sensory block reached T10, the regression of sensory block to L5 level were significantly lower in the Group BF than in the Group E and the Group F (p = 0.005, p < 0.001, respectively). Compared to the basal values, mean arterial pressures were significantly lower in the Group BF than in the Group E and the Group F (p < 0.05). The occurrence of hypotension was significantly lower in the Group BF (9.4%) than in the Group E (18.2%) and the Group F (24.2%). CONCLUSIONS: Intrathecal hyperbaric bupivacaine 2.5 mg plus fentanyl 25 microg administration provides shorter motor block onset time, less local anesthetic usage and adequate hemodynamic stability in elderly patients. PMID- 22428472 TI - Congenital ureteropelvic junction obstruction: physiopathology, decoupling of tout court pelvic dilatation-obstruction semantic connection, biomarkers to predict renal damage evolution. AB - The widespread use of fetal ultrasonography results in a frequent antenatally observation of hydronephrosis, ureteropelvic junction obstruction (UPJO) accounting for the greatest fraction of congenital obstructive nephropathy. UPJO may be considered, in most cases, as a functional obstructive condition, depending on defective fetal smooth muscle/nerve development at this level, with lack of peristaltic wave propagation--aperistaltic segment--and, therefore, poor urine ejection from the renal pelvis into the ureter. The UPJO-related physiopathologic events are, at first, the compliant dilatation of renal pelvis that, acting as hydraulic buffer, protects the renal parenchyma from the rising intrapelvic pressure-related potential damages, and, subsequently, beyond such phase of dynamic balance, the tubular cell stretch-stress induced by increased intratubular pressure and following parenchymal inflammatory lesions: inflammatory infiltrates, fibroblast proliferation, activation of myofibroblasts, tubulo-interstitial fibrosis. Reactive oxygen species (ROS), nitric oxide (NO), several chemo- and cytokines, growth factors, prostaglandins and eicosanoids, angiotensin-II are the main pathogenetic mediators of the obstructive nephropathy. Apoptosis of tubular cells is the major cause of the tubular atrophy, together with epithelial-mesenchymal transdifferentiation. Some criticisms on tout court semantic renal pelvis dilatation-obstruction connection have been raised considering that the renal pelvis expansion isn't, in any case, linked to an ostructive condition, as it may be verified by diuretic (furosemide) renogram together with scintiscan-based evaluation of differential renal function. In this regard, rather than repetitive invasive nuclear procedures that expose the children to ionizing radiations, an intriguing noninvasive strategy, based on the evaluation of urinary biomarkers and urinary proteome, can define the UPJO-related possible progress of parenchymal lesions, thus predicting which patients must require an obstruction correcting surgery and in which patients, instead, the hydronephrosis will spontaneously resolve. PMID- 22428473 TI - The role of high frequency tympanometry in newborn hearing screening programme. AB - BACKGROUNDS AND OBJECTIVE: The hearing assessment of the newborns ideally should detect both middle and inner ear functions. The aim of this study is to control the association between otoscopic evaluation, multifrequency tympanometry and TEOAE results. METHODS: Fifty new-borns otherwise healthy were tested after the otolaryngological evaluation by 226 and 1000 Hz tympanometries and transient evoked otoacoustic emissions (TEOAE's). The study was performed in three steps and 17 babies that could not pass from the first step they were tested in the second step with the same tests (226 Hz and 1000 Hz tympanometry and TEOAE) The babies that could not pass from the second step were evaluated by multifrequency tympanometries, TEOAE and acoustic brainstem responses (ABR) at the third step. RESULTS: The association between the results obtained from otoscopic evaluation, multifrequency tympanometry and TEOAE were assessed. We found that 1000 Hz tympanometry results were more sensitive and gives more correlated with TEOAE and otoscopic evaluation. CONCLUSIONS: Multifrequency tympanometry can detect the middle ear pathologies of the infants sensitively and should be a part of neonatal hearing screening test battery. PMID- 22428474 TI - Prospective randomised comparison of rubber band ligation (RBL) and combined hemorrhoidal radiocoagulation (CHR). AB - BACKGROUND: In this prospective randomized study we compared two groups of patients with grade II hemorrhoids treated with standard Rubber Band Ligation (RBL) and Combined Hemorrhoidal Radiocoagulation (CHR), respectively. METHODS: Out of 90 patients initially randomized, a total of 75 patients regularly returned to visit controls at least for 6 months of follow-up. Consequently, two groups of patients were considered: Group A, represented by 36 individuals treated with RBL, and Group B, consisting of 39 patients treated with CHR. In this study primary endpoints were determined as evaluation of the grade of pain felt immediately after the procedure and at the first evacuation (score from 1 to 10), bleeding, patient's satisfaction after 15 days and after 6 months from the treatment (score from 1 to 10), appearance of failures. RESULTS: Comparing two techniques, the mean pain score reported immediately after the procedure was 2.08 +/- 1.1 for Group A and 2.13 +/- 1.26 or Group B. At the first evacuation, the mean pain score for Group A and for Group B was 2.69 +/- 1.12 vs. 2.38 +/- 1.18, respectively. The satisfaction score during the first 15 days from the procedure was 6.61 +/- 2.35 for patients treated with RBL and 6.72 +/- 2.28 for patients who received CHR, while the mean score on overall satisfaction after 6 months was 7.11 +/- 2.11 (Group A) vs. 7.31 +/- 2.04 (Group B). At 6 months of follow-up, we observed remission of symptoms in 25 patients in Group A (69.4%) and 31 patients in Group B (79.5%). CONCLUSIONS: Satisfactory results were reported in both groups of patients after different treatments, which confirm the validity and efficacy of the two techniques used in this study. At least all patients reported positive results in terms of immediate and long-term comfort after both procedures. CHR showed better results than standard RBL, but further studies are required to evaluate the validity of these methods. PMID- 22428475 TI - Comparison of levonorgestrel and copper releasing intrauterine contraceptive device on body iron stores and menstrual bleeding patterns: experience on Indian women. AB - INTRODUCTION: The search for an ideal contraceptive device most suited for women of developing countries with anemia poses a challenge. AIM: This study was conducted to compare the effects of levonorgestrel releasing (LNG) and copper releasing (Cu T) intrauterine contraceptive devices (IUCD) on body iron stores and menstrual bleeding patterns. METHODS: Hundred women desiring contraception were divided into two groups of fifty each where either LNG or Cu T 200 IUCD was inserted. Outcome parameters evaluated were change in menstrual bleeding patterns, serum ferritin and hemoglobin level post insertion at three, six and twelve months. Main outcome measures were change in serum ferritin, hemoglobin concentration, menstrual bleeding and spotting days 12 months after insertion. RESULTS: Menstrual bleeding days increased initially at three month for both IUCD's, but by 12 months, mean number of bleeding days reduced from preinsertion 4.96 +/- 1.61 to 3.14 +/- 1.72 days (p < 0.05) in the LNG group while in Cu T number of bleeding days remained higher at 12 months (4.76 +/- 0.96 days) compared to pre-insertion level (4.46 +/- 0.91 days, p = NS). At 12 months, 60% women developed hypomenorrhoea and 20% had amenorrhea in LNG group. Higher (p < 0.05) serum ferritin (24.17 + 5.97 vs. 20.80 + 5.78) and hemoglobin (12.45 + 0.46 vs. 11.95 + 11.042 gm/dl) concentration was noted in the LNG group as compared to Cu T by the end of 1 year. CONCLUSION: LNG reduced the number of menstrual bleeding days and increased the hemoglobin and serum ferritin levels, thus preventing loss of body iron. This may be especially important for women in developing countries like India where decrease in blood loss may improve iron deficient situations. PMID- 22428476 TI - Effect of HMG-CoA reductase inhibitors on blood pressure in hypertensive patients treated with blood pressure-lowering agents: retrospective study using an anti hypertensive drug database. AB - BACKGROUND AND OBJECTIVES: We used a Japanese antihypertensive drug database to investigate the blood pressure-lowering effect of statins in hypertensive patients receiving antihypertensive medication. We also examined the class effect of antihypertensive drugs on blood pressure lowering by statins. MATERIAL AND METHODS: The Risk/Benefit Assessment of Drugs-Analysis and Response (RAD-AR) Council has developed an antihypertensive drug database which contains the results of post-marketing surveillance for various antihypertensive agents from 143,509 antihypertensive users in clinical settings. Antihypertensive patients in the database with concurrent hyperlipidemia were grouped into statin users and non-users, and changes in systolic and diastolic blood pressure over a three month period were compared. Further, the class effects of antihypertensive drugs on the lipid lowering effects of statins were also investigated. RESULTS: A total of 1070 statin users and 1974 non-users were analyzed. Changes in systolic blood pressure were significantly greater in the statin user than in the non-user group (mean difference: 1.63 mmHg, p = 0.03). In contrast, no significant effect of statin use was observed on the change in diastolic blood pressure (DBP) (0.87 mmHg, p = 0.08). When stratified by antihypertensive class, reductions in blood pressure were greater in statin user groups for all antihypertensive classes without statistical significance, except for a significant change in DBP in those receiving beta-blockers (mean difference: 2.98 mmHg, p = 0.03). DISCUSSION: The present study documented that statin's effect on blood pressure in hypertensive patients with hyperlipidemia in clinical setting is statistically significant but has a minimal significance. With regard to class differences among antihypertensive agents, the decrease was greatest in the DBP of patients treated with beta-blockers. In contrast, no significant changes were seen in the ACE inhibitor or Ca antagonist subgroups. One possible explanation for the differential effects of antihypertensive class in our study might be the lack of a vasodilatation effect. PMID- 22428477 TI - Atrial fibrillation and the pharmacological treatment: the role of propafenone. AB - BACKGROUND: Atrial fibrillation is the most frequent cardiac rhythm disturbance, with prevalence increasing with age. This disease is a major risk factor for ischaemic stroke. The costs resulting from atrial fibrillation are really impressive. Pharmacological agents are the first line therapy for the management of atrial fibrillation. Antiarrhythmic drugs are used to terminate arrhythmias, as acute treatment for conversion of recent onset atrial fibrillation, and to maintain sinus rhythm, as chronic therapy for prevention of atrial fibrillation recurrences. Among antiarrhythmic agents, drugs that inhibit early sodium current (as propafenone) are proven effective in atrial fibrillation. In this review, the most relevant data on propafenone are provided. DISCUSSION: The development of a sustained-release formulation of propafenone allowed to reduce the wide fluctuations in plasma levels observed with the immediate release preparation, improving compliance and adherence to therapy, by simplifying the dosing regimen from 3 to 2 daily doses. Propafenone resulted an effective measure as acute treatment for conversion of recent onset atrial fibrillation, and to maintain sinus rhythm, as chronic therapy for prevention of atrial fibrillation recurrences. In several clinical studies, strong increases of arrhythmia-free periods as well as marked increases in time to recurrence of symptomatic atrial fibrillation, such as paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation were observed. In particular, well-designed clinical studies demonstrated in large patient populations the efficacy of propafenone at several doses. At the suggested doses propafenone is usually well tolerated. CONCLUSION: The risk of increased occurrence of regular supraventricular arrhythmia or paroxysmal supraventricular tachycardia has been overestimated for propafenone, because this adverse event was seen in all treatment groups, including placebo, with the same (and low) frequency. PMID- 22428478 TI - Correlation of cardiac MRI T2* with echocardiography in thalassemia major. AB - BACKGROUND AND OBJECTIVE: Myocardial iron deposition and cardiac failure in thalassemia major (TM) is the most serious reason of morbidity and mortality. Cardiac magnetic resonance imaging (MRI T2*) can indirectly quantified myocardial iron content. Moreover echocardiographic left ventricular diastolic evaluation in comparison to systolic evaluation is more sensitive to detect early myocardial dysfunction secondary to iron overload. The aim was to determine some diastolic and tissue Doppler echo indices correlated with cardiac MRI T2* to predict iron load. PATIENTS AND METHODS: Thirty three TM patients (17F/16M) with history of 15 years transfusion or more were selected. They did cardiac MRI (CMR) with measurement of relaxation time of T2* and also echocardiographic examination with systolic and diastolic evaluation and tissue Doppler imaging. RESULTS: The mean value of cardiac T2* was 20.41 +/- 12.1 ms. Patients with abnormal T2* (< 20 ms) had abnormal ejection fraction (EF) in 10 (53.6%), and abnormal diastolic indices including deceleration time (DT), early (E) and late (A) transmitral peak flow velocity ratio (E/A), E/Em and Tei- index in 13 (72.2%), 12 (66.7%), 18 (100%) and 14 (77.8%) patients respectively. There was a good correlation between DT, Tei index and E/Em index with cardiac T2* values (p < 0.05, r = 0.70-0.81), poor correlation between E/A with T2* (p < 0.05, r = -0.44) and no significant correlation of liver T2* with cardiac T2* (p = 0.819). CONCLUSIONS: In unequipped centres which CMR is not available because of good correlation between diastolic echocardiographic parameters and CMR T2*, the use of echocardiographic diastolic parameters for evaluation of cardiac state could be a replacing tool. In equipped centres we suggest doing CMR T2* as a first step examination in high risk patients, and then doing regular F/U with echocardiographic evaluation of diastolic and tissue Doppler echocardiographic parameters especially DT, E/Em and Tei index. PMID- 22428479 TI - Catheter ablation of atrial tachycardia after interatrial defect repair with patch apposition. AB - A 54-year-old woman with history of septal atrial mixoma surgically treated and drug-refractory supraventricular tachyarrhythmia underwent catheter ablation of macro-reentry areas near the pericardial patch placed to repair an interatrial defect. The use of ablative therapy has been successful to cure this arrhythmia. PMID- 22428480 TI - Human parvovirus B 19 and Epstein-Barr virus co-infection in a child with hereditary spherocytosis. AB - BACKGROUND: In patients with chronic congenital haemolytic disorders, human Parvovirus B19 (HPV B19) is frequently involved in pure red-cell aplastic crises. Furthermore, it may inhibit three-lineage haematopoiesis in the bone marrow, causing severe pancytopenia. In such patients, Epstein Barr virus (EBV) infection also seems to share the same mechanism as HPV B19 in inducing bone marrow aplasia, but at present the clinical effect of an infection sustained by both viruses is unknown. CLINICAL REPORT: We present a 7-year-old boy affected by hereditary spherocytosis (HS) who suffered from transient aplastic crisis, in whom laboratory findings revealed a double HPV B19 and EBV infection. CONCLUSIONS: To our knowledge, this is the first report of a case of HPV B19 and EBV co-infection diagnosis in a paediatric patient. Despite underlying HS, no signs of haemolytic anaemia were detected, but the infection only produced transient pancytopenia. Nevertheless, the reason why there was no additive effect of the two viruses on the aplastic crisis is still unclear. PMID- 22428481 TI - Psychiatric disorders and mitochondrial dysfunctions. AB - BACKGROUND: Mitochondria play a key role in the production of the cell energy. The final product of this process is adenosine triphosphate (ATP), used as a source of chemical energy. Besides this major role, mithocondria have been shown to be involved in other functions, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. The aim of this paper is to highlight the relationships between psychiatric disorders, especially schizophrenia, bipolar disorder (BD), autism, attention deficit hyperactivity disorder (ADHD) and Alzheimer's dementia. RESULTS: The review of the available literature indicate that different mitochondrial dysfunctions may accompany and/or be part of the clinical picture of some neuropsychiatric disorders. CONCLUSIONS: Different data would indicate that mitochondrial dysfunctions may be involved in the pathophysiology of different neuropsychiatric disorders, given their key role in the cell energy metabolism. Moreover, they would greatly contribute to the process of neural apoptosis that should be at the basis of neurodegenerative disorders, such as schizophrenia, Alzheimer's dementia and the most severe forms of BD. In addition, data are available that mithocondrial abnormalities are present also in developmental disorders, such as autism and ADHD, although the studies aiming at elucidating the role of mithocondria in the onset and pathophysiology of all these conditions should be considered preliminary. In any case, taken together, these scattered findings would suggest novel drugs targeting protecting mitochondria from oxidative stress. PMID- 22428482 TI - Role of sexual abuse in development of conversion disorder: case report. AB - Described case report speaks in favour of the relation between childhood sexual abuse with the development of conversion disorder. Following Salmonella poisoning, adolescent, at the age of 16, develops series of severe somatic symptoms. Results of diagnostic procedures excluded organic foundation of the symptoms; diagnosis of conversion disorder is established. Soon, patient's problems stop abruptly and spontaneously, and the aetiology of the mental disorder remains unexplained. Six years later, adolescent reveals for the first time data about the childhood sexual abuse during the forensic evaluation (within the court process related to the request for compensation for the complications which occurred following the Salmonella infection). During the forensic evaluation, we had insight into the previous medical history, while an interview, psychological and psychiatric exploration was conducted with the examinee. Data about the sexual abuse retrospectively explain the dynamics of the development of conversion disorder. The described case indicates that sexual abuse of children and adolescents frequently remains unrecognized, which has sequels for treatment and prevention of subsequent consequences for mental health. It is important to emphasize the significance of examining history of abuse during the diagnostic of certain mental disorders. Forensic implications of the case have not been discussed in details for the needs of this report. PMID- 22428483 TI - Palatal fistula resulting from cocaine abuse: a case report. AB - Cocaine blocks the reuptake of norepinephrine and dopamine of the sympathetic nervous system. It has a psychomotor stimulating effect that provokes euphoria, motor activity and an amplification of a well being sensation similar to the effect of amphetamines. Well known are the systemic effects of cocaine abuse (acute myocardial infarction, cardiac arrhythmias, aortic ruptures, cerebrovascular accidents). Several local effects are also documented involving above all palatal mucosa and central midface structures. The most common palatal lesions are fistulae resulting from ischemia caused by the constricting effect of cocaine on small vessels, mucosal breakdown, loss of palatal bone, and loss of nasal mucosa. IF cocaine use becomes chronic and compulsive, wider lesions may cause extensive destruction of the osteocartilagineous structures of the nose, sinus and palate, a syndrome called CIMDL (cocaine-induced midline destructive lesion). Many techniques have been described to treat these defects depending on the size and the involved structures of the face. These techniques range from local flaps to complex free flaps. The authors describe a case of a median hard and soft palatal fistula resulting from cocaine abuse treated with local bilateral palatal flaps, and analyze the most common therapeutic options described in literature. PMID- 22428484 TI - Succinylcholine "the gold standard" for rapid-sequence induction of anesthesia. PMID- 22428485 TI - Prospective, randomized study to assess the role of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. AB - BACKGROUND: Preliminary data on the perioperative use of dexmedetomidine in patients undergoing craniotomy for brain tumor under general anaesthesia indicate that the intraoperative administration of dexmedetomidine is opioid-sparing, results in less need for antihypertensive medication, and may offer greater hemodynamic stability at incision and emergence. Dexmedetomidine, alpha 2 adrenoceptor agonist used as adjuvant to anaesthetic agents. Relatively recent studies have shown that dexmedetomidine is able to decrease circulating plasma norepinephrine and epinephrine concentration in approximately 50%, decreases brain blood flow by directly acting on post-synaptic alpha 2 receptors, decreases CSF pressure without ischemic suffering and effectively decrease brain metabolism and intracranial pressure and also, able to decrease injury caused by focal ischemia. PURPOSE: This prospective, randomized, double-blind study was designed to assess the perioperative effect of intraoperative infusion of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. METHODS: Forty patients with CT- scanning proof of supratentorial tumors. The patients were classified equally into 2 groups (twenty patients in each group). Group A:--The dexmedetomidine was given as a bolus dose of 1 microg/kg in 20 minutes before induction of anaesthesia, followed by a maintenance infusion of 0.4 microg/kg/hr. The infusion was discontinued when surgery ended. Group B:--The patients received similar volumes of saline. RESULTS: The heart rate and mean arterial blood pressure, decreased in patients of group A (dexmedetomidine group) more than group B (placebo group) with significant statistical difference between the two groups (P-value <0.05). No significant statistical difference between the two groups regarding the central venous pressure and arterial partial pressure of Carbon Dioxide (P-value >0.05). The intraoperative end-tidal sevoflurane (%) in patients of group A less than in patients of group B (P-value <0.05).The intracranial pressure decreased in patients of Group A more than group B (P-value <0.05). The Glasgow coma scale (GCS) improved in patients of group A and deteriorated in patients of Group B with significant statistical difference between the two groups (P-value <0.05). The total fentanyl requirements from induction to extubation of patients increased in patients of group B more than in patients of group A (P-value <0.05). The total postoperative patients' requirements for antiemetic drugs within the 2 hours after extubation decreased in patients of group A more than group B (P-value <0.05). The postoperative duration from the end of surgery to extubation decreased significantly in patients of group A more than group B (P value <0.05). The total urine output during the duration from drug administration to extubation of patients increased in patients of group A more than group B (P value <0.05). CONCLUSIONS: Continuous intraoperative infusion of dexmedetomidine during craniotomy for supratentorial tumors under general anaesthesia maintained the haemodynamic stability, reduced sevoflurane and fentanyl requirements, decreased intracranial pressure, and improved significantly the outcomes. PMID- 22428486 TI - Anesthetic challenges in oro-facial cleft repair in Ile-Ife, Nigeria. AB - BACKGROUND AND METHODS: A retrospective review of all patients with oro-facial lip defects operated at the Obafemi Awolowo University Teaching Hospital, Ile Ife, Nigeria over an 18 month period was undertaken with a view to determine: the pattern of presentation; associated clinical problems and congenital anomalies; perioperative complications; anaesthetic techniques used and outcomes; and the determinants of outcome. RESULTS: Of the 80 patients treated, 74 were managed under general anaesthesia but the case records of only 60 (81%) of these patients were available for review. The ages ranged between 3 months and 59 years. The male to female ratio was 1:1. Eighty percent of all cases studied were cleft lip (CL) +/- cleft palate (CP). Of these, 65% were left sided CL, 23% were right sided while 12% were bilateral. All patients had ASA score 1 or 2 at the time of surgery. Halothane in O2 induction was employed in 60% of the patients while 40% had IV induction. Intubation was facilitated with muscle relaxant in 63.3% of these patients. Naso-tracheal intubation was performed in 82% of all cleft palate repairs. Preoperative complications were encountered in 18% of the patients. Associated congenital anomalies were noted in 5% of the cases. One case each of difficult intubation and failed intubation were encountered. Intra-operative dysrrhythmia was noted in 5% of cases; no life-threatening complication was encountered peri-operatively. CONCLUSIONS: There is a dramatic increase in the number of patients presenting for care due to improved awareness of the population. Peri-operative attention to detail is essential in handling the challenges posed by the condition. PMID- 22428487 TI - Comparison between ropivacaine 1.5 mg ml(-1) plus fentanyl 2 mg ml(-1) and ropivacaine 1.5 mg ml(-1) plus clonidine 1 mg ml(-1) as analgesic solution after anterior cruciate ligament reconstruction: a randomized clinical trial. AB - BACKGROUND: Ropivacaine is commonly used as local anesthetic for postoperative analgesia through an epidural catheter. Data show that several adjuvants influence the analgesic effect of local anesthetic potency. OBJECTIVE: The aim of the study was to compare fentanyl and clonidine as adjuvants to 1.5 mg ml(-1) ropivacaine in terms of motor blockade, pain relief and side effects. METHODS: In this single center, randomized, clinical trial, 52 patient scheduled for arthroscopic anterior cruciate ligament reconstruction were radomly allocated in two groups. At twenty-six patient a solution with ropivacaine 1.5 mg ml(-1) plus fentanyl 2 microg ml(-1) (group F) was administered through patient controlled epidural analgesia (PCEA) as postoperative analgesia and ropivacaine 1.5 mg ml( 1) plus clonidine 1 microg ml(-1) (group C) was administered at the remaining twenty-six patients. The VAS score, the Bromage scale and total solution consumption were documented and compared between the two groups for 24 hours after the end of the operation. RESULTS: The mean patient control consumption of the solution was higher at group C respect group F (p = 0.007). At the 8th hour after the operation we register a statistical significant difference at the mean VAS score between the two groups (p < 0.05) with clonidine group achieving a higher score. At the 8th and 12th hour clonidine group register a lower Bromage score than fentanyl group (p < 0.005 and p = 0.002). CONCLUSION: Ropivacaine 1.5 mg ml(-1) plus fentanyl 2 microg ml(-1) administred through PCEA compared with ropivacaine 1.5 mg ml(-1) plus clonidine 1 microg ml(-1) h guarantee higher quality analgesia after ACL reconstruction. PMID- 22428488 TI - The influence of simulation-based physiology labs taught by anesthesiologists on the attitudes of first-year medical students towards anesthesiology. AB - BACKGROUND: The development of medical students' perceptions of different medical specialties is based on many factors and influences their career choices and appreciation of other practitioners' knowledge and skills. The goal of this study was to determine if participation in a series of anesthesiologist-run, simulation based physiology labs changed first year medical students' perceptions of anesthesiologists. METHODS: One hundred first-year medical students were surveyed at random three months before completion of a simulation-based physiology lab run by anesthesiologists. All participants received the same survey instrument, which employed a 5-point Rating Scale to rate the appropriateness of several descriptive terms as they apply to a particular specialist or specialty. A post simulation survey was performed to track changes in attitudes. RESULTS: Response rates to the survey before and after the simulation labs were 75% and 97% (ofthe initial cohort responding), respectively. All students who filled out the post simulation surveys had been exposed to anesthesiologists in the prior three months whereas none had interacted with surgeons in the interim. Nearly all had interacted with internal medicine specialists in that time period. No changes in the medical students' perceptions of surgeons or internal medicine specialists were evident. Statistically significant changes were found for most descriptors of anesthesiologists, with a trend towards a more favorable perception after the simulation program. CONCLUSIONS: Using a survey instrument containing descriptors of different medical specialists and specialties, we found an improved attitude towards anesthesiology after medical students participated in an anesthesiologist run simulation-based physiology lab series. Given the importance of providing high quality medical education and attracting quality applicants to the field, integrati-on of anesthesiology staff into medical student courses at the non clinical level appears useful. PMID- 22428489 TI - Preemptive analgesic effect of diclofenac: experimental study in rats. AB - BACKGROUND: Preemptive analgesia is an antinociceptive treatment that prevents central sensitization. Antinociceptive effects of diclofenac are well-known. The aim of this study was to investigate preemptive analgesic effects of intraperitoneally administrated diclofenac, before and after acute and inflammatory induced pain in rat model. METHODS: Forty eight male Sprague Dawley rats were included in the study. The rats are divided in five groups (n=8 per each group); Group A, diclofenac at 10 mg/kg given ip, 30 min before the nociceptive stimulus realized with hot plate test; Group B, diclofenac at 10 mg/kg given ip, 5 min after the nociceptive stimulus, realized with hot plate test; Group C, diclofenac at 10 mg/kg given ip, 30 min before the nociceptive stimulus realized with formalin test, and; Group D, diclofenac at 10 mg/kg given ip, 5 min after the nociceptive stimulus, realized with formalin test. Saline was used as a control. Paw movements in response to induced pain with hot plate test and formalin test were measured during 60 minutes. RESULTS: Preemptive analgesic effect was significant in both groups when diclofenac was administrated before the pain stimuli (P < 0.01 and P < 0.001). The significant decrease in paw movements started in 15 min after pain stimuli in group A and in 25 min, in group C. CONCLUSION: Intraperitoneally administered diclofenac had preemptive analgesic effects on acute thermal, and inflammatory induced pain in rats. Our results contain the preemptive analgesic effect of systematically administrated diclofenac. PMID- 22428490 TI - Comparison between two phenylephrine infusion rates with moderate co-loading for the prevention of spinal anaeshtesia-induced hypotension during elective caesarean section. AB - BACKGROUND: Phenylephrine induces maternal bradycardia in 50% of mothers when used for prevention and treatment of spinal anaesthesia-induced hypotension during caesarean delivery. Rapid fluid administration immediately after initiation of the spinal block (co-loading) may have a vasopressor sparing effect. The aim of this study was to evaluate the hypothesis that when using rapid crystalloid co-loading, an infusion of 50 mcg/minute of PE could be as effective as 100 mcg/minute in preventing maternal hypotension but with minimal maternal bradycardia and an acceptable fetal outcome. METHODS: 117 mothers scheduled for elective caesarean section were recruited in this randomized controlled trial. Co-loading with 10 ml/kg of Hartmann's solution started immediately after a standard spinal anaesthesia. Parturients were then randomly allocated into two groups. Group 50 (n = 54) received phenylephrine infusion at 50 microg/min, and group 100 (n=63) 100 microg/min. Rescue phenylephrine boluses (50 mcg) were administered if needed to maintain systolic blood pressure between 80-100% of its baseline values. RESULTS: Systolic blood pressure was not different between mothers in both groups during the study period. All neonatal Apgar scores at 1 minute were > or =7 and at 5 minutes were > or =9. No mother had umbilical arterial pH <7.2. Umbilical arterial and venous blood gas and acid base values were not different between both groups except the umbilical arterial PCO2 that was significantly higher in group 100. There were more frequent episodes of maternal bradycardia in Group 100 than in Group 50 (eleven and one parturients respectively). There was no difference in the incidence of nausea and vomiting in both groups. CONCLUSION: In combination with rapid co-loading, an infusion rate of 50 microg/min of PE is as adequate as 100 microg/min in prevention of spinal anaesthesia-induced hypotension during elective caesarean section. Both infusions are associated with a similar neonatal outcome. PE infusion of 50 microg/min is associated with significantly less maternal bradycardia than 100 microg/min. PMID- 22428491 TI - Evaluation of an intraoperative algorithm based on near-infrared refracted spectroscopy monitoring, in the intraoperative decision for shunt placement, in patients undergoing carotid endarterectomy. AB - BACKGROUND: We evaluated whether the use of an intraoperative algorithm based on cerebral oximetry with near-infrared refracted spectroscopy (NIRS) monitoring, could aid in the intraoperative decision for shunt placement, in patients undergoing carotid endarterectomy (CEA). METHODS: In this prospective, randomized, controlled study were included 253 patients who underwent CEA under general anesthesia. They were randomly allocated in Group A (n=83) using NIRS monitoring and the suggested algorithm, Group B (n=84) using NIRS monitoring without the algorithm and Group C (n=86) who served as controls. Shunt placement criterion for Group A and B was 20% drop in ipsilateral regional saturation from the baseline value recorded before surgery. Primary endpoint of the study was to evaluate the use of the intraoperative algorithm based on NIRS monitoring, in the intraoperative decision for shunt placement, in patients undergoing carotid endarterectomy. Additionally, we examined whether this might affect the rate of postoperative neurologic deficits. RESULTS: When compared with Group A, Group B and Group C had 3.7 times (99% c.i. 1.5-9.5) and 70.6 times (99% c.i. 15-724.3) respectively, greater likelihood of having a shunt placed. When compared with Group B, Group C had 19.4 times (99% c.i. 4.3-191.2) greater likelihood of having a shunt placed. Regarding the rate of postoperative neurologic deficits no significant difference was found between the three groups. CONCLUSIONS: The use of a specific algorithm based on NIRS monitoring, in patients undergoing CEA, may aid in the intraoperative decision for shunt placement. PMID- 22428492 TI - Effects of preoperative oral carbohydrates and trace elements on perioperative nutritional status in elective surgery patients. AB - PURPOSE: In order to enhance postoperative recovery, preoperative consumption of carbohydrate (CHO) drinks has been used to suppress metabolic fluctuations. Trace elements such as zinc and copper are known to play an important role in postoperative recovery. Here, we examined the effects of preoperatively consuming a CHO drink containing zinc and copper. METHODS: Subjects were 122 elective surgery patients divided into two groups (overnight fasting and CHO groups); each group was further divided into morning or afternoon surgery groups. Subjects in the CHO group consumed 300 mL of a CHO drink the night before surgery, followed by 200 ml before morning surgery or 700 ml before afternoon surgery (> or =2 hours before anesthesia induction). Blood levels of glucose, nonesterified fatty acids (NEFA), retinol-binding protein, zinc, and copper were determined. RESULTS: One subject in the CHO group was excluded after refusing the drink. There were no adverse effects from the CHO drink. NEFA levels increased in the fasting groups. Although zinc levels increased in the CHO group immediately after anesthesia induction, no group differences were observed the day after surgery. CONCLUSION: Preoperative consumption of a CHO drink containing trace elements suppressed preoperative metabolic fluctuations without complications and prevented trace element deficiency. Further beneficial effects during the perioperative period can be expected by adding trace elements to CHO supplements. PMID- 22428493 TI - Reduced hemodynamic responses to tracheal intubation by the Bonfils retromolar fiberscope: a randomized controlled study. AB - The Bonfils retromolar intubation fiberscope is a rigid endoscope designed to enable glottic visualization and facilitate intubation under endoscopic vision. Theoretically, avoiding direct-vision laryngoscopy and thus could produce less stimulation during intubation than the conventional direct laryngoscopic procedure. This prospective randomized study was designed to compare the effect of tracheal intubation with direct vision laryngoscopy (Macintosh blade) and the Bonfils retromolar intubation fiberscope on the hemodynamic responses in ASA I patients. Forty patients scheduled for elective surgery and requiring endotracheal intubation were randomly allocated to one of two groups according to the intubating tool under sevoflurane nitrous oxide Anaesthesia (n=20 each). The retromolar group received tracheal intubation with the Bonfils retromolar fiberscope, while the direct laryngoscopy group received tracheal intubation by the direct vision laryngoscope (Macintosh blade). Heart rate and arterial blood pressure (systolic BP, diastolic BP, mean ABP) were recorded before induction of Anaesthesia, 3 minutes after induction of Anaesthesia (before intubation) and 5 successive recordings at one-minute interval after intubation. All the systolic BP, diastolic Bp, mean ABP and heart rate values in the direct laryngoscopy group were significantly higher in the 5 successive minutes after intubation in comparison with the retromolar group (P = 0.00). This might be attributed to the gentle intubating technique, by the Bonfils retromolar fiberscope, which allows quick endotracheal intubation without manipulations of the base of the tongue or epiglottis. PMID- 22428494 TI - Effect of ketamine on bispectral index during propofol--fentanyl anesthesia: a randomized controlled study. AB - BACKGROUND: The Bispectral Index (BIS) helps in the assessment of the depth of hypnosis. N-methyl-D-aspartic acid antagonist, ketamine, has been used in various doses to decrease postoperative morphine consumption. The purpose of our study was to compare the effects of two different doses (0.5 mg/kg and 0.2 mg/kg) of ketamine on BIS values. METHODS: Forty-five ASA I or II patients undergoing general anesthesia were included in this double-blind, prospective, control trial and randomly allocated into three groups. After induction of anesthesia and tracheal intubation, a propofol infusion was started and titrated to attain BIS values of around 40. After five minutes of stable BIS values and in the absence of any surgical stimulus, patients received either 0.5 mg/kg of ketamine (Group K1) or 0.2 mg/kg of ketamine (Group K2) or normal saline (Group N) as bolus intravenously. BIS values were recorded for the next 15 minutes, at five-minutes interval. RESULTS: Mean BIS values were significantly increased in Group K1 (63.5) while Group K2 (42.0) failed to show any significant rise. BIS values in Group K2 were comparable to those in Group N. CONCLUSION: Thus, under stable propofol anesthesia, a bolus ofketamine 0.5 mg/kg increases BIS values while ketamine 0.2 mg/kg does not. PMID- 22428495 TI - Effect of prophylactic dexamethasone on nausea and vomiting after laparoscopic gynecological operation: meta-analysis. AB - BACKGROUND: Sex of female and laraproscopic surgery are both risk factors related to postoperative nausea and vomiting, and dexamethasone is used as anti-emetic in some operations. A meta-analysis of randomized trials was performed to determine the effect of prophylactic dexamethasone administration on postoperative nausea and vomiting, pain and complications in patients undergoing laparoscopic gynecological operation. METHODS: A systematic literature search was conducted to identify all randomized clinical trials. The primary outcome was the incidence and severity of postoperative nausea and vomiting. The secondary outcomes include postoperative pain and complications. RESULTS: Totally 1801 patients were enrolled in 11 eligible randomized trials comparing effect of prophylactic dexamethasone administration on postoperative nausea and vomiting with placebo. The pooled incidence of nausea, vomiting, nausea and vomiting, and rescue anti emetic was significantly lower in dexamethasone group than placebo group during post-anesthesia care unit (10.5% vs. 18.2%, OR 0.51, 95% CI 0.31-0.84; 6.5% vs. 17.1%, OR 0.31, 95% CI 0.17-0.56; 17.0% vs. 35.4%, OR 0.33, 95% CI 0.21-0.50; 6.7% vs. 23.3%, OR 0.22, 95% CI 0.10-0.49, P < 0.00001) and within the first postoperative 24 hours (25.2% vs. 40.3%, OR 0.46, 95% CI 0.32-0.66; 14.4% vs 36.6%, OR 0.27, 95% CI 0.19-0.40; 33.0% vs. 69.0%, OR 0.18, 95% CI 0.13-0.26; 21.0% vs 51.1%, OR 0.26, 95% CI 0.16-0.41, P < 0.00001). No significant difference was found about the incidence of rescue analgesia between dexamethasone group and placebo group (48.5% vs 56.4%, OR 0.68, 95% CI 0.40-1.18, P = 0.17). CONCLUSION: Prophylactic dexamethasone administration decreases the incidence of nausea and vomiting after laparoscopic gynecological operations during post-anesthesia care unit and within the first postoperative 24 hours. (286 words) Postoperative nausea and vomiting are the most common complications after anesthesia and surgery, and both sex of female and type of laparoscopic operation are risk factors. It is certain of a remarkably high incidence after laparoscopic gynecological surgery, which is reported as nearly 70% within the first postoperative 24 hours. It is very important to find an effective treatment to alleviate postoperative nausea and vomiting. PMID- 22428496 TI - Ventilation difficulty due to herniation of inflating tube of the cuff inside the endotracheal tube. PMID- 22428497 TI - Anesthesia for cesarian section in pregnant woman with acute intermittent porphyria and hypothyroidism--case report. AB - Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder' affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme hydroxymethylbilane synthase; without this cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphobilinogen accumulates in the cytoplasm. Some additional factors must also be present such as drugs, hormones, dietary changes, infections diseases and surgery that trigger the appearance of symptoms, which include neurological disorders, abdominal pain, constipation, and muscle weakness. We present a perioperative course of a pregnant woman with porphyria in association with hypothyroidism and its anesthetic management. PMID- 22428498 TI - "Crime scene investigation" at an anesthetic cocktail party with atrioventricular dissociation. AB - A healthy 21-year-old female patient received midazolam, propofol, fentanyl, rocuronium, nitrous oxide in oxygen, ranitidine, diclofenac, neostigmine and glycopyrrolate during the anesthetic process for elective knee arthroscopy and developed a complete AV dissociation with a P-wave frequency of 40 and a "small" QRS-complex frequency of 55 beats/min. Based on this typical case of poly pragmatic anesthetic drug administration causing a complete atrioventricular dissociation in a young healthy patient we will discuss the possible pharmacodynamic mechanisms of all used drugs with regard to the cardiac conduction system. PMID- 22428499 TI - Left atrial myxoma with coronary artery disease: an unexpected preoperative finding--case report. AB - We describe the case of a 54-year-old man with no symptoms of a cardiac disease who, in the preoperative assessment for eye surgery was diagnosed to have a left atrial myxoma coupled with coronary artery disease. After thorough investigations, the patient underwent resection of the left atrial tumor and coronary artery bypass grafting with a succesful outcome. The histopathological examination revealed a myxoma. This case report highlights the importance of preoperative evaluation in patients with unsuspected coexisting cardiac diseases, treatment options and the anesthetic concerns. PMID- 22428500 TI - Post-operative respiratory complications after palatoplasty in a 19-month-old female with Cornelia de Lange syndrome--a case report. AB - Cornelia De Lange syndrome is a rare genetically heterogeneous and sporadic syndrome, with an estimated prevalence of 1 in 10,000 to 30,000. The disorder may present many complications during anesthesia due to cardiac, gastrointestinal and airway anomalies. We report a case of an ex premature toddler presenting for repair of a cleft palate. Postoperatively she had respiratory distress, successfully treated by the anesthetic care team Causes for the complication are discussed. PMID- 22428501 TI - What if the epidural catheter needs to be fixed more than fifteen centimetres at skin? PMID- 22428502 TI - Extreme intraoperative hyperkalemia in a non dialysis patient undergoing kidney transplantation. AB - The majority of patients who present for kidney transplantation have end stage renal disease and are on dialysis. Those patients are known to be at risk for the development of hyperkalemia. A patient who has not required dialysis, and with stable potassium levels would not be expected to acutely develop intraoperative hyperkalemia. Presented here is an unusual case in which a 61-year-old man with chronic renal disease but no history of dialysis developed severe intraoperative hyperkalemia during a renal transplant. PMID- 22428503 TI - Successful treatment of early ropivacaine toxicity with intralipid in a patient with attention deficit hyperactivity disorder. PMID- 22428504 TI - Chronic use of oxybutynin and spinal anesthesia: a case of postoperative urinary retention and hematuria. PMID- 22428505 TI - Infiltrative angiolipoma of the neck. PMID- 22428506 TI - Cardiac arrest during elective orthopedic surgery due to moderate hypokalemia. AB - We report the case of a perioperative cardiac arrest (ventricular fibrillation) of a patient undergoing elective orthopedic surgery due to moderate hypokalemia (serum potassium 2.8 mmol/l), whereas preoperative levels were normal. He was successfully resuscitated without neurological deficits and underwent postoperative intensive care monitoring. In times of increasing populations of elderly people presenting with considerable co-morbidity, clinicians should be aware of possible rapid changes of electrolyte levels resulting in perioperative cardiac arrhythmia. PMID- 22428507 TI - The anesthetic management of a patient with Dorfman-Chanarin syndrome. AB - Dorfman-Chanarin syndrome (DCS), which is also known as neutral lipid storage disease, is a rare autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma. Since the Dorfman-Chanarin syndrome is a multisystemic disease the choice of drugs and the conduct of anesthesia in these patients are important. Preoperative evaluation should be performed in detail and anesthetic method and drugs to be used should be chosen carefully in accordance with affected system, overall state of patient and characteristics of the operation, in order to decrease perioperative morbidity rates in these patients. We report the anesthetic management of a child with DCS operated for correction of strabismus under general anesthesia. PMID- 22428508 TI - Lingual thyroid: a rare cause of difficult intubation. AB - This case report is about a patient with an oropharyngeal mass presenting to our hospital for biopsy under general anesthesia. Because of the great risk of failure of mask ventilation and direct laryngoscopy, an awake fiberoptic intubation was performed successfully. The biopsy revealed a thyroid tissue leading to the diagnosis of ectopic lingual thyroid. PMID- 22428509 TI - Should surgery be cancelled when surreptitious cocaine use is discovered before elective non-cardiac surgery? PMID- 22428510 TI - Automatic endotracheal tube cuff inflator and continuous pressure monitor/controller. PMID- 22428511 TI - Palmar and digital dermatoglyphic patterns in the Ndokwas of Delta State, Nigeria. AB - We determined asymmetry, complexity and pattern polarization of dermal ridges and palmar variables of atd angle, a - b ridge count and total finger ridge count of dermal ridges among the Ndokwa people of Nigeria. 400 healthy students who are Ndokwas were studied. Ink prints of their fingers and palms were obtained. Counting and classifying of Palmar and digital ridge pattern configurations of arches, loops and whorls was based on standard techniques. Ulnar loops polarized preferentially to digits III, IV and V and radial loops to digit II. Female subjects had higher counts of radial loops (p < 0.001) than the males. Male subjects had a higher whorl count than the females (p < 0.05). Our findings form useful baseline data for subsequent longitudinal cytogenetic studies on the Ndokwa people. PMID- 22428512 TI - Endurance exercise effect on quality of life and menopausal symptoms in Nigerian women. AB - INTRODUCTION: Women in the menopausal stage of life usually have climacteric symptoms of hot flashes, back pain, sleeplessness, night sweats and increased risk of cardiovascular disorders. Although physical exercises have been documented to favourably alleviate some of these problems, there's a paucity of knowledge of their effects on menopausal women in Nigeria. OBJECTIVES: This study investigated the effect of a twelve-week Endurance Exercise Programme (EEP) on quality of life(QOL) and menopausal symptoms in these women. METHODS: Participants were purposively recruited and assigned into perimenopausal and postmenopausal groups based on history of thier last menstrual period and from each of these groups randomized into: perimenopausal exercise group (PEMEG), postmenopausal exercise group (POMEG), perimenopausal control group (PEMCG) postmenopausal control group (POMCG). Quality of life (QOL), Menopausal symptoms Back Pain (BP) and hot flashes (HF) among other variables, were evaluated at baseline and 4 weekly intervals. EEP consisted of a 10-station circuit of muscular and cardiovascular endurance, flexibility, coordination, abdominal and pelvic floor muscle exercises. RESULTS: One hundred and seventy five menopausal women, mean age 52.3 +/- 4.1 years. Significant changes occurred between baseline and end of 12th week mean values of PEMEG for QOL: 565.9 +/- 108.8 vs 725.0 +/- 42.9 and BP 4.42 +/- 1.7 vs 1.00 +/- 0.0. (p= 0.000). Also, in POMEG: QOL 558.3 +/- 127.7 vs 736.5 +/- 44.8; and BP 5.37 +/- 1.48 vs 1.88 +/- 1.18 (p=0.000). Significant changes in QOL and BP did not occur in the control groups. CONCLUSION: Routine participation in endurance exercise programme is recommended for menopausal women for improved QOL. PMID- 22428513 TI - Maternal weight gain and pregnancy outcome in adolescent girls in Ibadan, Nigeria. AB - BACKGROUND: Maternal weight gain is an important predictor of pregnancy outcome. Pregnancy in adolescence is a major health challenge because it is associated with high risk. Few studies have been carried out on the influence of weight gain in adolescent pregnancy outcome in Nigeria. OBJECTIVE: This study determines the influence of maternal weight gain on the pregnancy outcome of adolescent mothers in Ibadan, Oyo state, Nigeria. MATERIALS AND METHODS: A retrospective review of case notes of 785 adolescents < or = 19 years and 1300 adult mothers who delivered atAdeoyo and Oluyoro maternity hospitals from January 2003 to December 2006 was carried out. Anthropometric information such as weight at second and third trimester, and infant birth weight and length were collected using a record review proforma. The data were analyzed using chi-square, ANOVA, Pearson's and Spearman's correlation. RESULTS: Adolescent mothers had a significantly lower weight gain (6.1 +/- 2.9 kg) compared to the control whose mean weight gain was 6.7 +/- 3.6 kg (p<0.05). There was also a significant difference in the proportion of the adolescent mothers (77.3%) and the adult mothers (57.6%) with packed cell volume below normal levels (p<0.05). The mean infant birth weight and length among adolescents (2.8 +/- 0.5 kg and 46.6 +/- 4.0cm) were significantly lower than 3.1 +/- 0.5 kg and 47.9 +/- 3.5cm of adult mothers respectively (p<0.05). The prevalence of low birth weight was significantly higher among the adolescent mothers (12.2%) than in the adult mothers (7.9%) (p<0.05). A significant positive relationship was found between infant birth weight and maternal weight gain in pregnancy (r(s)= 0.18, p<0.05). Caesarean section was siignificantly higher among adolescent mothers (21.0%) than adult mothers (10.7%) (p<0.05). Complications of pregnancy were more common among adolescent mothers (35.8%) than adult mothers (15.5%). CONCLUSION: The adolescent mothers had significantly lower weight gain in pregnancy and higher rates of low birth weight compared to the adult mothers (p<0.05). Strategies to reduce incidence of adolescent pregnancies and improve access to nutrition information that will promote weight gain among pregnant adolescents should be instituted. PMID- 22428514 TI - Descriptive analysis of blood pressure control among treated hypertensive patients in a tertiary hospital in Nigeria. AB - BACKGROUND: Blood pressure (BP) is poorly controlled in sub-Saharan Africa and this is due to poor utilization of antihypertensive drugs among other factors. Evaluation BP control will provide basis for recommendation for appropriate therapeutic measures for achieving target BP. AIM: To determine the pattern of BP control as a measure of impact of antihypertensive usage among treated hypertensive patients in University of Ilorin Teaching Hospital in Nigeria. METHODOLOGY: This is a descriptive-analytical study of 605 treated adult hypertensive patients who have been attending our specialist clinics for at least one year. Definition of blood pressure control was according to the World Health Organization criteria. RESULTS: The results showed that the mean age was 58.48 +/ 11.65 with 211 (34.9%) males (M:F =1:1.87). Median duration of follow up was 4(1 27) years. 152 (25%) were diabetic, 381 (63%) were taking antiplatelet aspirin and 213 (35.2%) had cardiovascular events. There was a significant difference between the first visit BP (initial BP) and last BP observed during the study (SBP[initial])=154 +/- 28mmHg, SBP(last)=133 +/- 21 mmHg (p<0.01); DBP[initial]=95 +/- 17mmHg, DBP[last]=80 +/- 12mmHg (p<0.001)).The pattern of BP control was: SBP+DBP controlled 322(53.3%); SBP+DBP uncontrolled 149 (24.6%); SBP controlled/DBP uncontrolled 39 (6.4%); DBP controlled/SBP uncontrolled 95 (15.7%).The control rate among the diabetic subgroup was 23.7%. CONCLUSION: BP control rate among treated hypertensive patients in our institution is significantly higher than reports from similar patient populations in similar healthcare centres in Nigeria and sub-Saharan Africa which reflects an improved and appropriate usage of antihypertensive drugs recently observed in our institution. The rate of control among diabetics is still very poor. PMID- 22428515 TI - Effects of intrathecally administered fentanyl on duration of analgesia in patients undergoing spinal anaesthesia for elective caesarean section. AB - BACKGROUND: Intrathecal opioids have gained popularity in obstetrics; they augment the analgesia produced by local anaesthetic agents. The aim of this study is to determine the duration of analgesia following addition of fentanyl to bupivacaine during elective Caesarean section. METHOD: This is a prospective randomized study comparing the effect of addition of 25 microg of fentanyl to 2.5 mls of 0.5% hyperbaric bupivacaine intrathecally on sixty healthy women of American Society ofAnaesthesiologist (ASA) physical status I scheduled for elective Caesarean section at the UCH, Ibadan. Patients were randomized to group B, n=30 and group FB, n=30. Maternal heart rate, blood pressure, respiratory rate, sensory level, motor block, pain score (NRS) and side effects were observed every 2 minutes for first 15 minutes, then at 5 minutes interval for the remainder of the operation. Thereafter at 30 minutes interval until the first complaint of pain. RESULTS: Complete analgesia (time from injection of intrathecal drug to first report of pain) lasted longer in group FB (240 +/- 29 minutes) than group B (99 +/- 12 minutes) with a p-value of 0.002. The duration of effective analgesia (time from injection of intrathecal drug to first request for analgesic) in group FB (276 +/- 26 minutes) while group B was (121 +/- 10 minutes) with a p-value of 0.001. Both were statistically significant. CONCLUSION: We conclude that the addition of 25 microg of fentanyl to bupivacaine intrathecally for elective Caesarean section increases the duration of complete and effective analgesia thereby reducing the need for early postoperative use of analgesics. PMID- 22428516 TI - Laparoscopic cholecystectomy in Ile-Ife, Nigeria. AB - BACKGROUND: Laparoscopic cholecystectomy is not yet routinely performed in most public tertiary hospitals in Nigeria. OBJECTIVES: To assess the feasibility and early outcoe of laparoscopic cholecystectoy in Ile-ife, Nigeria. METHOD: Consecutive patients who were selected for the procedure from June 2009 through December 2010 at the Ife State Hospital of the ObafemiAwolowo University Teaching Hospitals Complex, Ile-Ife were prospectively studied. RESULTS: Eighteen female (75%) and six male patients had laparoscopic cholecystectomy within the study period. They were aged 19-83 years with a mean age of 33.4 years. Six (25%) patients had acute calculous cholecystitis while the rest presented with chronic calculous cholecystitis. Their Body Mass Indices ranged from 21 to 32kg/m2. Operation time ranged from 65 to 105 minutes. One procedure (4%) was converted to open due to bleeding from the gallbladder bed. Another patient who had a minor common bile duct injury presented with generalized dull abdominal pain on the sixth postoperative day. She had open repair of the injury over a T-tube. Three patients (12.5%) were discharged on the first postoperative day while 15 (62.5%) others were discharged on the second postoperative day. No mortality was recorded. CONCLUSION: Laparoscopic cholecystectomy is feasible in our setting with outcome comparable to previous pioneering experiences in other African countries centre in spite of resource limitations. PMID- 22428517 TI - Effect of adrenaline on glucose uptake in the rabbit small intestine. AB - OBJECTIVES: Previous study had shown that nicotine acts on blood glucose through release of adrenaline. While there are reports on the hyperglyceic effect of adrenaline in rabbits, there is no information on the effect of adrenaline on intestinal glucose uptake of rabbits. The present study was carried out to find out if adrenaline has any effect on glucose uptake in the rabbit small intestine. MATERIALS AND METHODS: Experiments were carried out on fasted anaesthetized male rabbits. Five groups of rabbits (6 rabbits per group) were studied. A vein draining a segment of the upper jejunum was cannulated for blood flow and venous glucose measurements. The left femoral artery and vein were cannulated for arterial blood sampling and drug infusion respectively. Glucose uptake was calculated as a product of jejunal blood flow and the glucose difference between arterial (A) and venous (V) blood. RESULTS: The fasting venous blood glucose levels were 151.8 +/- 4.4mg/dl and 164.0 + 2.3mg/dl in Groups I and V that were not given adrenoceptor blockers. The upper jejunum had a resting (or basal) glucose uptake of 38.3 +/- 1.6mg/min in the control group. When adrenaline (2ug/kg) was injected intravenously, arterial blood glucose rose from a basal value of 245.5 +/- 4.6mg/dl to 307.5+4.7mg/dl at the peak of response while venous glucose rose from 151.8+4.4mg/dl to 275.8 +/- 4.2mg/dl at the peak of response. Glucose uptake increased to 107.4 +/- 2.5mg/ min at the peak of response. The hyperglycaemic response to adrenaline injection was abolished by propranolol but not by prazosin indicating that this effect of adrenaline is mediated through beta adrenoceptor. Both prazosin and propranolol reduced considerably adrenaline-induced increase in blood flow and glucose uptake, prazosin being more potent in flow reduction. CONCLUSION: This study showed that the resting small intestine of rabbits took up large amounts of glucose. The intestinal glucose uptake was markedly increased by adrenaline injection. The response to adrenaline was mediated through alpha and beta adrenoceptors. The responses to adrenaline are different in many respects from those induced by nicotine in rabbits in our earlier study. The reason for the differences is obscure. PMID- 22428518 TI - Antibiotic resistance pattern of uropathogenic Escherichia coli in South West Nigeria. AB - BACKGROUND: Various studies have indicated Escherichia coli to be the most prevalent pathogen isolated in urine specimens. OBJECTIVES: This study was therefore conducted to find out whether the same holds in this environment. The study will also determine the resistance pattern of uropathogenic Escherichia coli isolates to available antibiotics. METHODS: Two hundred consecutive urine samples collected from patients with clinical diagnosis of urinary tract infections (UTI) and which have significant bacteriuria were included in this study. These were analysed using standard bacteriological techniques. Escherichia coli isolated from the urine specimens were subjected to antibiotic susceptibility testing because many cases of resistance to commonly available antibiotics here have been encountered in the course of management of patients with UTI. RESULTS: Klebsiella species (40%) were found to be the most prevalent uropathogen in this environment, followed by E. coli (25%), Staphylococcus aureus (25%), Proteus species (4%), Pseudomonas aeruginosa (2.5%), and Enterococcus faecalis (3.5%). Resistance of E. coli to antibiotics commonly used in our environment for UTI, namely, amoxicillin/ clavulanate, cotrimoxazole and amoxicillin were 100% each. Resistance rates to other antibiotics such as ofloxacin, gentamycin, nalidixic acid and tetracycline were 70%, 92%, 96% and 88% respectively. CONCLUSION: The high antibiotic resistance rates recorded in this study therefore calls for urgent review of existing and implementation of effective antibiotic policy in this community. PMID- 22428519 TI - Predictors of early seizure remission in Nigerian children with newly diagnosed epilepsy. AB - BACKGROUND: It is important to predict as soon as possible after diagnosis and starting treatment, the likely clinical course of childhood-onset epilepsy, both in terms of seizure control and even more pertinently, seizure intractability. Little is known about the factors predictive of seizure control in African children. METHODS: All consecutive cases of newly-diagnosed childhood epilepsy seen over a period of two years in the Paediatric Neurology clinic, University College Hospital, Ibadan, Nigeria were prospectively followed for a period of three years to determine seizure outcomes. Remission was defined as being seizure free for at least two consecutive years. RESULTS: A total of 170 children were enrolled but 54 defaulted and were excluded from further analysis. Twenty nine (25%) attained remission while 20 (17.2%) showed signs of intractability. The remaining 67 (57.8%) showed some response to anti-epileptic drug (AED) therapy. Primary generalized epilepsy was found to be significantly associated with seizure remission and successful discontinuation of AED. Factors associated with reduced likelihood of seizure remission were remote symptomatic/cryptogenic aetiology, slow waves on electroencephalography (EEG), high seizure frequency of at least one attack/ month at presentation, failure of response to the initial AED and presence of associated neurological deficits. On logistic regression, high seizure frequency and presence of slow waves on EEG remained independent negative predictors of seizure remission. CONCLUSION: About one-quarter of Nigerian children with newly diagnosed epilepsy attain early seizure remission within the first three years ofAED therapy. The major predictors of poor seizure control and failure of seizure remission include high seizure frequency at presentation and presence of slow waves on EEG. PMID- 22428520 TI - Social profile and habits of oral cancer patients in Ibadan. AB - OBJECTIVES: The aim of this study was to compare the socioeconomic profile and social habits of oral cancer patients and those of control subjects in order to investigate the relative importance of these risk factors in the occurrence of oral cancer. STUDY DESIGN: Thirty-two histologically diagnosed oral carcinoma patients and 30 normal patients were recruited at the dental centre University College Hospital, Ibadan. A 33-item questionnaire was administered to the two groups. The data obtained was analyzed using student t test and chi square as appropriate as well as odds ratio. RESULTS: Incomes less than 50,000 naira per annum, absence of fruit in every diet and tobacco use, were associated with 5.7, 3.0 and 4.05 increased risk of oral cancer respectively. CONCLUSION: Low income, fruit depleted diet and tobacco use seems to be the most important risk factors for oral cancer development in the studied environment. PMID- 22428521 TI - Quinolizidine alkaloids: the bioactive principles in Cnestis ferruginea (de Candolle) with male antifertility activities. AB - OBJECTIVES: The reproductive activities of purified fractions from the root extract of Cnestis ferruginea was evaluated in rats. Phytochemical screening of the extract revealed the presence of alkaloids, tannins and anthraquinones. MATERIALS AND METHODS: Column chromatography produced 20 fractions which were reduced to 6 by thin layer chromatography. Nuclear magnetic resonance spectroscopy revealed quinolizidine alkaloids (fractions 3 and 4) as the active principles in the extract of Cnestis ferruginea. Each fraction of Cnestis ferruginea (0.1, 1 and 2 mgkg(-1)bw) was administered to rats by gavages for 60 days. RESULTS: All fractions caused significant reduction (p<0.05) in sperm counts, motility, viability, morphology and plasma levels of testosterone, luteinizing hormone and follicle stimulating hormone. Fractions 3 and 4 caused the highest reduction (p<0.001) in fertility, FSH and LH levels comparable to those of quinine sulphate. There was recovery after 60 days of withdrawal from the extracts. CONCLUSION: The results suggest that Cnestis ferruginea possesses reversible male antifertility effects. The active principles with these activities appear to be quinolizidine alkaloids. PMID- 22428522 TI - Standard of care for HIV prevention technology research: a consensus document from Nigeria. AB - AIM: A framework of care includes the notion that care is that received from outside an individual and nurtures its body and soul. Defining care and the context of providing it is difficult especially with the ever changing and evolving field like that found operational in the HIV and AIDS research field. The standard of care for HIV and AIDS prevention trials continues to evolve and countries/communities are encouraged to define locally relevant standard of care guidelines. The paper reports on the consensus reached by stakeholders in Nigeria on the standard of care to be provided during HIV prevention research. It is an attempt by the community of stakeholders involved with New HIV Prevention Technology trials in Nigeria to define the standard of care for HIV prevention research in Nigeria. METHOD: Four consultative meetings involving policy makers, the national government and government agencies, representatives of donor communities, regulatory agencies in the country, community advocates, people living with HIV/AIDS, sex workers, people who engage in sae sex practices, researchers, women, youths, journalists and organizations that serve these various communities, were held. This is a report of the consensus reached on the standard of care for HIV prenvention in Nigeria. RESULTS: Such obligations include the provision of counselling and testing for trial participants throughout the trial and during the post trial period using the most sensitive and specific test kits for the most prevalent HIV strains in the country. ART provision should also be provided for trial participants who seroconvert during the trial by the sponsors after which the trial participants are rolled unto the national governments' ART programme. Researchers and sponsors also have defined obligatory responsibilities to volunteers who screen out of the trial and to trial participants' spouse. The report also defines good research practice with respect to access to health care services as well as moral obligatory responsibilities of researchers and sponsors to trial participants. CONCLUSION: The consensus on standard of care for HIV prevention research in Nigeria is a step forward with respect to mapping the path for future HIV prevention research in Nigeria is a step forward with respect to mapping the path for future HIV preventive research in the country. As emerging issues emerge, there will be a need to review and define these standards again. PMID- 22428523 TI - Valsartan, an angiotensin receptor blocker treats sexual dysfunction in a female hypertensive: a case report. AB - INTRODUCTION: Hypertension and its treatment cause sexual dysfunction (SD), impairing quality of life; and adversely affecting compliance and blood pressure control. SD is reported more often by men than women in most cultures especially ours. This has tended to affect the attitude of clinicians towards SD in female hypertensives. METHODS: A woman who for over 15 years of hypertension and its treatment faced difficulties in all domains of sexual function is hereby reported. On reporting this, the beta blocker in her regimen was replaced by an angiotensin receptor blocker (ARB). RESULTS: Gradually she regained libido and began to enjoy intercourse once again. This change obviated the need for a 5 phosphodiesterase inhibitor which would have added to cost of treatment. DISCUSSION/CONCLUSION: SD occurs in female hypertensives and should be sought. When found, ARB use can reverse the problem with all its attendant benefit on quality of life and blood pressure control. PMID- 22428524 TI - Melanin pigmented periradicular lesions of extracted teeth: a report of 3 cases and review of the literature. AB - This article reports 3 cases of melanin pigmented lesions among 75 histologically diagnosed periradicular lesions of extracted teeth. Case 1 was a 25-year old male who presented with one week history of toothache involving a tender carious left mandibular second molar tooth (37), with periapical radiolucency and diagnosed clinically as acute apical periodontitis. The lesion was diagnosed histologically (using Haematoxylin and Eosin) as periapical granuloma, while histochemical examination (using Masson-Fontana technique) showed the presence of round/oval shaped melanin pigmented macrophages (melanophage) in the lesion. Case 2 was a 54 year old male with one week history of toothache associated with tender carious right maxillary first molar tooth (16) with periapical radiolucency. A clinical diagnosis of acute apical periodontitis was made, but histological and histochemical examination showed a melanin pigmented periapical granuloma with spindle shaped melanophage. Case 3 was a 28-year old female who presented with 4 days history of toothache, involving the tender left mandibular first molar tooth (36). The lesion had periapical radiolucency and a clinical diagnosis of acute apical periodontitis. On examination histologically and histochemically, the lesion was diagnosed as an intraosseous melanocytic naevi with dark-brown nests of round naevus cells. In conclusion, this article shows the rarity of melanin pigmented periradicular lesions in the jaws. The cases reported suggest that the trigger for formation of melanin-pigmented cells in the periradicular lesions may be related to the acute phase of the lesions. Further study is recommended to determine if the remnants of the migratory neural crest cells are the precursors of melanin-pigmented cells in the periradicular region. PMID- 22428525 TI - Management of mandibular chronic osteomyelitis using Belfast technique. AB - Chronic osteomyelitis is still common in developing countries like Nigeria due to the fact that conditions associated with the lowering of resistance to infections like malnutrition, malaria, anaemia, and acute eruptive fever are still prevalent in our society. Various operative techniques have been described for the treatment of chronic osteomyelitis with various outcomes. A case of chronic osteomyelitis of the mandible managed using the Belfast technique is presented. The Patient was followed up for 2 years with no evidence of recurrence of infection and a repeat radiograph at the end of follow-up revealed new bone formation. The Belfast technique is effective in the treatment of chronic osteomyelitis of the mandible and is recommended in the management of this condition. PMID- 22428526 TI - Adsorption of Cd2+ on carboxyl-terminated superparamagnetic iron oxide nanoparticles. AB - The affinity of Cd(2+) toward carboxyl-terminated species covalently bound to monodisperse superparamagnetic iron oxide nanoparticles, Fe(3)O(4)(np)-COOH, was investigated in situ in aqueous electrolytes using rotating disk electrode techniques. Strong evidence that the presence of dispersed Fe(3)O(4)(np)-COOH does not affect the diffusion limiting currents was obtained using negatively and positively charged redox active species in buffered aqueous media (pH = 7) devoid of Cd(2+). This finding made it possible to determine the concentration of unbound Cd(2+) in solutions containing dispersed Fe(3)O(4)(np)-COOH, 8 and 17 nm in diameter, directly from the Levich equation. The results obtained yielded Cd(2+) adsorption efficiencies of ~20 MUg of Cd/mg of Fe(3)O(4)(np)-COOH, which are among the highest reported in the literature employing ex situ methods. Desorption of Cd(2+) from Fe(3)O(4)(np)-COOH, as monitored by the same forced convection method, could be accomplished by lowering the pH, a process found to be highly reversible. PMID- 22428528 TI - Planting mangroves in mudflats: is it the way of the world? PMID- 22428527 TI - Enhanced self-association of mucins possessing the T and Tn carbohydrate cancer antigens at the single-molecule level. AB - Mucins are linear O-glycosylated glycoproteins involved in inflammation, cell adhesion, and tumorigenesis. Cancer-associated mucins often possess increased expression of the T (Galbeta1,3GalNAcalphaThr/Ser) and Tn (GalNAcalphaThr/Ser) cancer antigens, which are diagnostic markers for several cancers, including colon cancer. We have used AFM based single-molecule forced unbinding under near physiological conditions to investigate the self-interactions between porcine submaxillary mucin (PSM) as well as between PSM analogs possessing various carbohydrates including the T- and Tn-antigen. Distributions of unbinding forces and corresponding force loading rates were determined for force loading rates from 0.18 nN/s to 39 nN/s, and processed to yield most probable unbinding forces f* and lifetimes of the interactions. Parameter f* varied in the range 27 to 50 pN at force loading rates of about 2 nN/s among the various mucins. All mucin samples investigated showed self-interaction, but the tendency was greatest for PSM displaying only the Tn-antigen (Tn-PSM) or a mixture of Tn-, T-antigen, and the trisaccharide Fucalpha1,2Galbeta1,3GalNAc (Tri-PSM). Weaker self-interactions were observed for native PSM (Fd-PSM), which consists of a nearly equal mixture of the longer core 1 blood group A tetrasaccharide (GalNAcalpha1,3(Fucalpha1,2)Galbeta1,3GalNAcalphaSer/Thr) and Tn-antigen. The data are consistent with the truncated Tn and T glycans enhancing self interaction of the mucins. These carbohydrate cancer antigens may, thus, play an active role in the disease by constitutively activating mucin and mucin-type receptors by self-association on cells. PMID- 22428529 TI - Impact of impaired renal function and metabolic syndrome on the recurrence of atrial fibrillation after catheter ablation: a long term follow-up. AB - BACKGROUND: The goal of this study was to analyze impact of metabolic syndrome (MetS) and impaired renal function on long-term follow-up after catheter ablation of atrial fibrillation (AF). METHODS AND RESULTS: A total of 702 consecutive patients with AF (age = 58 year, history of AF = 5 year, male = 478, paroxysmal atrial fibrillation = 416, coronary artery disease = 62, hypertension = 487) considered for catheter ablation were enrolled in the study. The MetS was diagnosed at admission in 276 patients. The renal function was estimated by glomerular filtration rate (eGFR). Pulmonary vein isolation (PVI) was performed either with cryoballoon technique (n = 260) or circumferential PVI (n = 442) with a 3.5-mm irrigated tip catheter. A 7-day-Holter electrocardiogram was performed at each follow-up visit. Any episode of documented AF after an initial 3-month blanking period was considered as clinical endpoint. Out of 702 patients, 370 (52.7%) were free of AF recurrences at median follow-up of 15 six interquartile range (12.7-42.3) months. The patients with MetS had significantly lower success rate than those without (128/276 (46.4%) vs 242/426 (56.8%), P = 0.006). Among 103 patients with eGFR < 68 mL/min only 35 (34%) were free of recurrences compared with 335/599 (55.9%) in patients with GFR >= 68 mL/min (P = 0.001). Both parameters were revealed in multivariate analysis to be independent predictors for outcome after catheter ablation. CONCLUSION: The results of our study clearly demonstrated that outcome after 1st catheter ablation of AF is poor in patients with MetS and/or impaired renal function. This observation has a potential clinical impact for the follow up management of these patients. PMID- 22428530 TI - Discovery of a phosphine-mediated cycloisomerization of alkynyl hemiketals: access to spiroketals and dihydropyrazoles via tandem reactions. AB - Reported here are details on the discovery of a phosphine-catalyzed isomerization of hemiketals and subsequent reactions of the cyclic keto enol ether products. The new cycloisomerization complements a previously reported amine-catalyzed process that gave oxepinones from the same hemiketal starting materials. In the absence of functionality (R(2)) on the cyclic keto enol ether, a rapid and facile dimerization occurs, giving spiroketal products. When the enone is substituted (i.e., R(2) = Ph), the cyclic keto enol ether is sufficiently stable so that it can be isolated; it can then be further reacted in the same pot to provide the corresponding dihydropyrazoles. Both the spiroketal and dihydropyrazole products arise by a tandem reaction that begins with the novel cycloisomerization. The method allows for the rapid introduction of complexity in the products from relatively simple starting materials. It should find application in the synthesis of natural product-like molecules. PMID- 22428531 TI - Analysis of the Fusarium mycotoxin moniliformin in cereal samples using 13C2 moniliformin and high-resolution mass spectrometry. AB - Moniliformin is a mycotoxin produced by fungi of the Fusarium genus and occurs as a contaminant of different cereals worldwide. This study describes the first application of isotopically labeled (13)C(2)-moniliformin for the analysis of moniliformin in cereals. Moniliformin is a small and ionic molecule that forms only a single sensitive fragment ion in the collision cell of a tandem mass spectrometer. Therefore, the methods described in the literature for this kind of instrument observe only a single mass transition and show a relatively poor sensitivity. The use of high-resolution mass spectrometry was described to be a suitable alternative technique for the detection of this compound and was therefore applied in this study. The developed method is based on the use of strong anion exchange columns for cleanup prior to HPLC analysis and has a recovery rate of 75.3%, a limit of detection (LOD) of 0.7 MUg/kg, and a limit of quantitation (LOQ) of 2.5 MUg/kg. Twenty-three different cereal samples were analyzed for their moniliformin content. Twenty of them showed positive results with levels up to 126 +/- 12.2 MUg/kg. PMID- 22428533 TI - Carbohydrate but not fat is associated with elevated aminotransferases. AB - BACKGROUND: Recently, many studies reported that high carbohydrate and simple sugar intake increase a risk of obesity and metabolic syndrome significantly. AIM: To investigate the effect of carbohydrate on aminotransferase levels in Korea, where the proportion of carbohydrate in meals is extremely high but fat is low. METHODS: We used the data of Korean National Health and Nutrition Examination Surveys (KNHANES). A total of 19 749 people were included. Amounts and types of consumed foods were examined by the 24 h recall method. RESULTS: Mean carbohydrate and fat proportions in total energy intake were 67.7% and 17.4%, respectively. Aminotransferase activity increased according to the rise of the proportion of carbohydrate in the energy intake. A high carbohydrate intake (>70% of energy) was associated with abnormal aminotransferase activity and metabolic syndrome. After adjusting for covariates, such as age, energy intake and body mass index, abnormal aminotransferase activity was significantly associated with carbohydrate proportion. There was a negative correlation between fat proportion in the total energy intake and aminotransferase activity (P < 0.01). The relation between aminotransferase activity and carbohydrate composition showed a J-shaped curve. The lowest point (the J point) was located at 50-60% carbohydrate. CONCLUSIONS: The proportion of carbohydrate in energy intake but not fat is positively correlated with abnormal aminotransferase activity in Koreans. This finding may be useful in planning a strategy of nutrition education for NAFLD in countries where the proportion of carbohydrate in most meals is extremely high. PMID- 22428532 TI - Dihydroceramide accumulation and reactive oxygen species are distinct and nonessential events in 4-HPR-mediated leukemia cell death. AB - 4-(Hydroxyphenyl)retinamide (4-HPR) is a synthetic retinoid with a strong apoptotic effect towards different cancer cell lines in vitro, and it is currently tested in clinical trials. Increases of reactive oxygen species (ROS) and modulation of endogenous sphingolipid levels are well-described events observed upon 4-HPR treatment, but there is still a lack of understanding of their relationship and their contribution to cell death. LC-MS analysis of sphingolipids revealed that in human leukemia CCRF-CEM and Jurkat cells, 4-HPR induced dihydroceramide but not ceramide accumulation even at sublethal concentrations. Myriocin prevented the 4-HPR-induced dihydroceramide accumulation, but it did not prevent the loss of viability and increase of intracellular ROS production. On the other hand, ascorbic acid, Trolox, and vitamin E reversed 4-HPR effects on cell death but not dihydroceramide accumulation. NDGA, described as a lipoxygenase inhibitor, exerted a significantly higher antioxidant activity than vitamin E and abrogated 4-HPR mediated ROS. It did not however rescue cellular viability. Taken together, this study demonstrates that early changes observed upon 4-HPR treatment, i.e., sphingolipid modulation and ROS production, are mechanistically independent events. Furthermore, the results indicate that 4-HPR-driven cell death may occur even in the absence of dihydroceramide or ROS accumulation. These observations should be taken into account for an improved design of drug combinations. PMID- 22428534 TI - First detection of Hb Taybe [alpha38(C3) or alpha39(C4) Thr->0 (alpha1)] in an Italian child. AB - Hb Taybe [alpha38(C3) or alpha39(C4) Thr->0 (alpha1)] is an unstable hemoglobin (Hb) variant caused by a deletion of a threonine residue at codon 39 of the alpha1-globin chain. Usually asymptomatic or with minimal hematological abnormalities in the heterozygous state, Hb Taybe becomes clinically evident in compound heterozygosity with alpha-thalassemia (alpha-thal) or in homozygous patients. To date, Hb Taybe has been described in Israeli-Arab and Greek individuals. We report, for the first time, a patient with chronic hemolytic anemia due to the presence of Hb Taybe in trans to the alpha2 initiation codon mutation ATG>ACG in an Italian child. Hb Taybe was not evident at Hb analysis with cellulose acetate electrophoresis and high performance liquid chromatography (HPLC). Globin biosynthetic studies revealed an alpha/beta-globin ratio in the range of beta-thal trait. Consequently, an investigation of the alpha- and beta globin genes was requested in order to avoid missing any rare globin chain variant and to offer accurate genetic counseling. PMID- 22428536 TI - Developmental immunotoxicity (DIT) testing of pharmaceuticals: current practices, state of the science, knowledge gaps, and recommendations. AB - The development and regulatory approval of immunomodulatory pharmaceuticals to treat many human diseases has increased significantly over the last two decades. As discussed by FDA and ICH guidelines, all human pharmaceuticals in development should be evaluated for potential adverse effects on the immune system. Developmental immunotoxicology (DIT) focuses on the concern that early-life (during pre-/post-natal development) exposure to agents which target the immune system may result in enhanced susceptibility to immune-related disease (e.g., infection, autoimmunity, and cancer, particularly leukemia) compared to adults, unique effects not observed in adults, or more persistent effects in comparison to those following adult exposure. This article provides a substantive review of the literature and presents detailed considerations for DIT testing strategies with a specific focus on pharmaceuticals and biopharmaceuticals. In this regard, differences between small molecule and large molecule therapeutics will be considered, along with recommendations for best practices in the assessment of DIT during drug development. In addition, gaps in the DIT knowledge base and current testing strategies are identified. Finally, a summary of an ILSI-HESI-ITC sponsored Workshop conducted in 2010, entitled 'Developmental Immunotoxicity Testing of Pharmaceuticals' will be presented. This Workshop consisted of participants from the pharmaceutical, biotechnology, academic, and regulatory sectors, where many of the issues relating to DIT outlined in this review were discussed, key points of consensus reached, and current gaps in the science identified. PMID- 22428535 TI - Receipt of monitoring of diabetes mellitus in older adults with comorbid dementia. AB - OBJECTIVES: To examine the extent to which receipt of recommended monitoring of diabetes mellitus (DM) differed for participants with and without comorbid dementia, as well as the effect of other comorbidities on monitoring of DM in individuals with comorbid dementia. DESIGN: Retrospective cohort study. SETTING: Secondary analysis of 2005/2006 claims and enrollment data for a 5% national random sample of Medicare beneficiaries. PARTICIPANTS: Two hundred eighty-eight thousand eight hundred five Medicare fee-for-service beneficiaries with a diagnosis of DM before 2006, 44,717 (16%) of whom had evidence of comorbid dementia in claims. MEASUREMENTS: Established algorithms were used to determine whether patients received at least one glycosylated hemoglobin (HbA1c) test, one low-density lipoprotein cholesterol (LDL-C) test, and one annual eye examination in 2006 and to construct variables representing comorbidities common in DM, sociodemographic characteristics, and patterns of healthcare utilization. RESULTS: In unadjusted and fully adjusted models, the presence of dementia reduced the likelihood of receiving HbA1c tests, LDL-C tests, and eye examinations, with effects being smallest for HbA1c tests. The effects of other comorbidities on DM monitoring in participants with dementia varied according to the nature of the comorbidity and the specific test. CONCLUSION: Dementia reduces the likelihood that individuals with DM will receive recommended annual monitoring for DM. More research is needed to understand reasons for lower monitoring in this subgroup and how this affects functioning, adverse events, and quality of life. PMID- 22428537 TI - Synthesis and rapid characterization of amine-functionalized silica. AB - Amine-functionalized colloidal silica finds use in a variety of applications and fundamental investigations. To explore convenient methods of synthesis and characterization of research-grade materials in relatively large quantities, nearly monodisperse colloidal silica particles were prepared by base-catalyzed hydrolysis of reagent-grade tetraethyl orthosilicate (TEOS) without the traditional time- and energy-consuming distillation step. Radius was varied reliably from 30 to 125 nm by changing the water/TEOS ratio. Asymmetric flow field flow fractionation (AF4) methods with online light scattering detection proved effective in assessing the uniformity of the various preparations. Even highly uniform commercial standards were resolved by AF4. The surface of the colloidal silica was decorated with amino groups using (3-aminopropyl) trimethoxysilane and spacer methyl groups from methyl-trimethoxysilane. The surface density of amino groups was quantified spectrophotometrically after reaction with ninhydrin; the nature of this analysis avoids interference from sample turbidity. As an alternative to the ninhydrin test, an empirical relationship between surface density of amino groups and zeta potential at low pH was found. The size of the colloidal silica was predictably decreased by etching with HF; this method will be effective for some preparations, despite a modest reduction in size uniformity. PMID- 22428538 TI - Endogenous ACh effects on NMDA-induced interictal-like discharges along the septotemporal hippocampal axis of adult rats and their modulation by an early life generalized seizure. AB - PURPOSE: Our earlier findings of the modulation of cholinergic neurotransmission by an early life generalized seizure and the reported interaction between muscarinic and N-methyl-d-aspartate (NMDA) receptors prompted us to investigate the effects of endogenous acetylcholine (ACh) on the frequency (Hz) of the epileptiform discharges following NMDA-receptor activation in the hippocampal slice. METHODS: A sustained (>20 min) generalized convulsion was induced in Sprague-Dawley juvenile rats by intraperitoneal injection with pentylenetetrazole (PTZ, 70-90 mg/kg) at postnatal day (P) 20. Temporal and septal hippocampal slices were prepared of normal (N) and PTZ-treated (PTZ) adult (>=P60) rats, and CA3 field potentials were recorded during perfusion with Mg(2+) -free artificial cerebrospinal fluid (ACSF) or with ACSF containing 50 MUm 4 aminopyridine (4-AP). KEY FINDINGS: In Mg(2+) -free ACSF, spontaneous interictal-like epileptiform discharges (IEDs) were recorded in all slices, with significantly higher frequencies in temporal (0.46 +/- 0.03 Hz, n = 85) versus septal slices (0.20 +/- 0.02 Hz, n = 47, p < 0.000001) but no consistent differences in any other group (i.e., male vs. female or N vs. PTZ). The anticholinesterase eserine (10 MUm) increased their frequencies by 150-200% in N septal and in all temporal slices and by 300% in PTZ-septal slices (p = 0.0028). In 60% of the slices the excitatory effect persisted throughout drug perfusion, whereas in the remaining ones it was distinguished in two phases: an early "transient" and a late "steady state." The steady-state frequencies resembled the predrug ones in N slices but remained significantly elevated in PTZ slices, especially in the septal group. The muscarinic antagonist atropine (1 MUm) decreased IED frequency in all slices (n = 36, p = 0.005) and also fully reversed the eserine effect (n = 38, p < 0.0001). In 4-AP ACSF, eserine increased spontaneous IED frequency (n = 21) in N and PTZ slices alike; IEDs were subsequently abolished by addition of the NMDA-receptor antagonist D(-)-2-amino-5 phosphonopentanoic acid (AP5; 50 MUm, n = 6). SIGNIFICANCE: These results demonstrate an intrinsic tonic positive muscarinic acetylcholine receptor (mAChR) contribution to the frequency of NMDA receptor-dependent epileptiform discharges that is amplified following an elevation of endogenous ACh and is more pronounced in the septal hippocampus. Moreover, this positive mAChR contribution to the frequency of IEDs is even more pronounced and persistent in the septal extremity after an early life generalized sustained convulsion. This cholinergic enhancement of the excitatory septal hippocampal output may influence cognitive function and performance, and possibly the adult seizure threshold. PMID- 22428539 TI - A Chinese family carrying novel mutations in SEC23B and HFE2, the genes responsible for congenital dyserythropoietic anaemia II (CDA II) and primary iron overload, respectively. PMID- 22428540 TI - Testing the effects of social anxiety disorder on friendship quality across gender and ethnicity. AB - Previous research suggests that social anxiety disorder (SAD) has a specific relationship with impairment in friendship quality; however, potential moderators of this relationship have not been tested. The current study examines whether the specific effect of SAD on friendship quality is stable or varies across gender and ethnicity in a large epidemiological dataset. Results indicate that the underlying construct of friendship quality differed slightly but significantly between men and women; as a result, effects of SAD were tested in men and women separately. After partially constraining friendship quality across ethnic groups, our results indicated that the relationship between SAD and friendship quality remained robust in all groups. In addition to replicating the finding that SAD specifically relates to perceived friendship quality, the current study highlights the need to test whether underlying constructs such as friendship quality are consistent across the groups that make up heterogeneous samples. PMID- 22428541 TI - Critical analysis of consecutive unilateral cleft lip repairs: determining ideal sample size. AB - Objective : Cleft surgeons often show 10 consecutive lip repairs to reduce presentation bias, however the validity remains unknown. The purpose of this study is to determine the number of consecutive cases that represent average outcomes. Secondary objectives are to determine if outcomes correlate with cleft severity and to calculate interrater reliability. Design : Consecutive preoperative and 2-year postoperative photographs of the unilateral cleft lip nose complex were randomized and evaluated by cleft surgeons. Parametric analysis was performed according to chronologic, consecutive order. The mean standard deviation over all raters enabled calculation of expected 95% confidence intervals around a mean tested for various sample sizes. Setting : Meeting of the American Cleft Palate-Craniofacial Association in 2009. Patients, Participants : Ten senior cleft surgeons evaluated 39 consecutive lip repairs. Main Outcome Measures : Preoperative severity and postoperative outcomes were evaluated using descriptive and quantitative scales. Results : Intraclass correlation coefficients for cleft severity and postoperative evaluations were 0.65 and 0.21, respectively. Outcomes did not correlate with cleft severity (P = .28). Calculations for 10 consecutive cases demonstrated wide 95% confidence intervals, spanning two points on both postoperative grading scales. Ninety-five percent confidence intervals narrowed within one qualitative grade (+/-0.30) and one point (+/-0.50) on the 10-point scale for 27 consecutive cases. Conclusions : Larger numbers of consecutive cases (n > 27) are increasingly representative of average results, but less practical in presentation format. Ten consecutive cases lack statistical support. Cleft surgeons showed low interrater reliability for postoperative assessments, which may reflect personal bias when evaluating another surgeon's results. PMID- 22428542 TI - Synthesis of a wide range of thioethers by indium triiodide catalyzed direct coupling between alkyl acetates and thiosilanes. AB - An indium triiodide-catalyzed substitution of the acetoxy group in alkyl acetates with thiosilanes provides access to a variety of thioethers. The method is efficient for a wide scope of acetates such as primary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic, and propargylic acetates. PMID- 22428543 TI - Occupational contact allergy to monomeric isocyanates. AB - BACKGROUND: The monomeric isocyanates diphenylmethane diisocyanate (MDI), 2,4 toluene diisocyanate (TDI), isophorone diisocyanate (IPDI) and 1,6-hexamethylene diisocyanate (HDI) are used in polyurethane products and sometimes cause contact allergy. OBJECTIVES: To describe patients with isocyanate contact allergy in an occupational dermatology clinic. METHODS: Test files were screened for allergic reactions to isocyanates and 4,4'-diaminodiphenylmethane (MDA). Patients with allergic reactions to some of the allergens were analysed for occupation, exposure, concomitant reactions to other allergens, and diagnosis. RESULTS: Over a period of almost 13 years, 54 patients reacted to isocyanates (9 to IPDI, 12 to MDI, 6 to TDI, and 1 to HDI) or MDA (44 patients). The motor vehicle, electronics and paint industries, and painting and construction work, were among the most significant occupational fields. An in-house polymeric MDI (PMDI) test substance was superior to commercial MDI preparations. About half of the occupational cases related to MDI products were diagnosed by testing MDA. The most prominent cause of IPDI allergy comprised polyurethane paint hardeners. Some of the IPDI reactions could be explained by cross-allergy to isophoronediamine in epoxy products. Specific exposure to MDA was difficult to trace. CONCLUSIONS: MDA and PMDI test substances were significant in the diagnosis of MDI contact allergy. PMID- 22428544 TI - CARM1/PRMT4 is necessary for the glycogen gene expression programme in skeletal muscle cells. AB - CARM1 (co-activator-associated arginine methyltransferase 1)/PRMT4 (protein arginine methyltransferase 4), functions as a co-activator for transcription factors that are regulators of muscle fibre type and oxidative metabolism, including PGC (peroxisome-proliferator-activated receptor gamma co-activator) 1alpha and MEF2 (myocyte enhancer factor 2). We observed significantly higher Prmt4 mRNA expression in comparison with Prmt1-Prmt6 mRNA expression in mouse muscle (in vitro and in vivo). Transfection of Prmt4 siRNA (small interfering RNA) into mouse skeletal muscle C2C12 cells attenuated PRMT4 mRNA and protein expression. We subsequently performed additional qPCR (quantitative PCR) analysis (in the context of metabolism) to examine the effect of Prmt4 siRNA expression on >200 critical genes that control (and are involved in) lipid, glucose and energy homoeostasis, and circadian rhythm. This analysis revealed a strikingly specific metabolic expression footprint, and revealed that PRMT4 is necessary for the expression of genes involved in glycogen metabolism in skeletal muscle cells. Prmt4 siRNA expression selectively suppressed the mRNAs encoding Gys1 (glycogen synthase 1), Pgam2 (muscle phosphoglycerate mutase 2) and Pygm (muscle glycogen phosphorylase). Significantly, PGAM, PYGM and GYS1 deficiency in humans causes glycogen storage diseases type X, type V/McArdle's disease and type 0 respectively. Attenuation of PRMT4 was also associated with decreased expression of the mRNAs encoding AMPK (AMP-activated protein kinase) alpha2/gamma3 (Prkaa2 and Prkag3) and p38 MAPK (mitogen-activated protein kinase), previously implicated in Wolff-Parkinson-White syndrome and Pompe Disease (glycogen storage disease type II). Furthermore, stable transfection of two PRMT4-site-specific (methyltransferase deficient) mutants (CARM1/PRMT4 VLD and CARM1E267Q) significantly repressed the expression of Gys1, Pgam2 and AMPKgamma3. Finally, in concordance, we observed increased and decreased glycogen levels in PRMT4 (native)- and VLD (methylation deficient mutant)-transfected skeletal muscle cells respectively. This demonstrated that PRMT4 expression and the associated methyltransferase activity is necessary for the gene expression programme involved in glycogen metabolism and human glycogen storage diseases. PMID- 22428545 TI - Transient 100 nM dexamethasone treatment reduces inter- and intraindividual variations in osteoblastic differentiation of bone marrow-derived human mesenchymal stem cells. AB - The development of in vitro culturing techniques for osteoblastic differentiation of human mesenchymal stem cells (hMSC) is important for cell biology research and the development of tissue-engineering applications. Dexamethasone (Dex) is a commonly used supplement, but the optimal use of Dex treatment is still unclear. By adjusting the timing of Dex supplementation, the negative effects of long-term Dex treatment could be overcome. Transient Dex treatment could contribute toward minimizing broad donor variation, which is a major challenge. We compared the two most widely used Dex concentrations of 10 and 100 nM as transient or continuous treatment and studied inter- and intraindividual variations in osteoblastic differentiation of hMSC. Characterized bone marrow-derived hMSC from 17 female donors of different age groups were used. During osteoblastic induction, the cells were treated with 10 or 100 nM Dex either transiently for different time periods or continuously. Differentiation was evaluated by measuring alkaline phosphatase (ALP) activity and staining for ALP, von Kossa, collagen type I, and osteocalcin. Cell proliferation, cell viability, and apoptosis were also monitored. The strongest osteoblastic differentiation was observed when 100 nM Dex was present for the first week. In terms of inter- and intraindividual coefficients of variations, transient treatment with 100 nM Dex was superior to the other culture conditions and showed the lowest variations in all age groups. This study demonstrates that the temporary presence of 100 nM Dex during the first week of induction culture promotes hMSC osteoblastic differentiation and reduces inter- and intraindividual variations. With this protocol, we can reproducibly produce functional osteoblasts in vitro from the hMSC of different donor populations. PMID- 22428546 TI - Gene therapy approaches for lysosomal storage disorders, a good model for the treatment of mendelian diseases. AB - This review describes the different gene therapy technologies applied to approach lysosomal storage disorders, monogenic conditions, with known genetic and biochemical defects, for many of which animal models are available. Both viral and nonviral procedures are described, underlying the specific needs that the treatment of genetic disorders requires. CONCLUSIONS: Lysosomal storage disorders represent a good model of study of gene therapeutic procedures that are, or could be, relevant to the treatment of several other mendelian diseases. PMID- 22428547 TI - Covariation of learning and "reasoning" abilities in mice: evolutionary conservation of the operations of intelligence. AB - Contemporary descriptions of human intelligence hold that this trait influences a broad range of cognitive abilities, including learning, attention, and reasoning. Like humans, individual genetically heterogeneous mice express a "general" cognitive trait that influences performance across a diverse array of learning and attentional tasks, and it has been suggested that this trait is qualitatively and structurally analogous to general intelligence in humans. However, the hallmark of human intelligence is the ability to use various forms of "reasoning" to support solutions to novel problems. Here, we find that genetically heterogeneous mice are capable of solving problems that are nominally indicative of inductive and deductive forms of reasoning, and that individuals' capacity for reasoning covaries with more general learning abilities. Mice were characterized for their general learning ability as determined by their aggregate performance (derived from principal component analysis) across a battery of five diverse learning tasks. These animals were then assessed on prototypic tests indicative of deductive reasoning (inferring the meaning of a novel item by exclusion, i.e., "fast mapping") and inductive reasoning (execution of an efficient search strategy in a binary decision tree). The animals exhibited systematic abilities on each of these nominal reasoning tasks that were predicted by their aggregate performance on the battery of learning tasks. These results suggest that the coregulation of reasoning and general learning performance in genetically heterogeneous mice form a core cognitive trait that is analogous to human intelligence. PMID- 22428548 TI - Metabolism of gamma-hydroxybutyrate in perfused rat livers. AB - GHB (gamma-hydroxybutyrate) is both a neurotransmitter and a drug of abuse (date rape drug). We investigated the catabolism of this compound in perfused rat livers. Using a combination of metabolomics and mass isotopomer analysis, we showed that GHB is metabolized by multiple processes, in addition to its previously reported metabolism in the citric acid cycle via oxidation to succinate. A substrate cycle operates between GHB and gamma-aminobutyrate via succinic semialdehyde. Also, GHB undergoes (i) beta-oxidation to glycolyl CoA+acetyl-CoA, (ii) two parallel processes which remove C-1 or C-4 of GHB and form 3-hydroxypropionate from C-2+C-3+C-4 or from C-1+C-2+C-3 of GHB, and (iii) degradation to acetyl-CoA via 4-phosphobutyryl-CoA. The present study illustrates the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery. PMID- 22428549 TI - Mesio-Distal and Buccal-Lingual Tooth Dimensions are Part of the Cleft Spectrum: A Pilot for Future Genetic Studies. AB - Objective : Considering that oral clefts and tooth dimensions may be part of the same phenotypic spectrum, the aim of this study was to investigate tooth dimensions in permanent dentition and dental malformations, including tooth size discrepancies, of subjects born with clefts compared with individuals without clefts. Design : Cross-sectional study. Participants : The cleft group was composed of 66 subjects, and the noncleft group consisted of 66 healthy unrelated subjects. Main Outcome Measures : The mesio-distal and buccal-lingual crown diameter of fully erupted permanent teeth outside the cleft area was measured using a digital caliber. Clinical records and radiographs were used to evaluate the type of clefts and dental anomalies. Results : The lower second premolar was significantly reduced in the CLP and CP groups. The upper lateral incisor was found to be significantly smaller in the CP group, only for mesio-distal dimensions (P < .05). Dental agenesis was found in eight (12%) cleft subjects and supernumerary teeth in two (3%). Conclusions : Subjects born with oral clefts presented size reduction in specific dental groups. PMID- 22428550 TI - Absence of unspecific innate immune cell activation by GATA-3-specific DNAzymes. AB - DNAzymes of the 10-23 family represent an important class of antisense molecules with implications for therapeutic treatment of diseases. These molecules are single-stranded oligodeoxynucleotides combining the high specificity of oligonucleotide base pairing with an inherent RNA-cleaving enzymatic activity. However, like other oligonucleotide-based molecules these substances might exert so-called off-target effects, which have not been investigated so far for this molecule class. Therefore, the present study investigates putative off-target effects of DNAzymes on innate immune mechanisms using GATA-3-specific DNAzymes that have recently been developed as novel therapeutic approach for the treatment of allergic diseases including allergic asthma. The conserved catalytic domain of 10-23 DNAzymes contains a CpG motif that may stimulate innate immune cells via Toll-like receptor 9 (TLR-9). Therefore, potential TLR-9-mediated as well as TLR 9 independent cell activation was investigated using TLR-9-transfected HEK293 cells, macrophage cell lines and primary innate immune cells. Furthermore, putative effects of GATA-3-specific DNAzymes on the activation of neutrophil granulocytes and degranulation of mast cells/basophils were analyzed. In summary, no innate immune cell-stimulating activities of the tested DNAzymes were observed in any of the systems. Consequently, use of GATA-3-specific DNAzymes may represent a novel and highly specific approach for the treatment of allergic diseases. PMID- 22428551 TI - Engaging patients via mobile phone technology to assist follow-up after hospitalization in Quito, Ecuador. AB - OBJECTIVE: Disease management following hospital discharge is difficult in most low-resourced areas, posing a major obstacle to health equity. Although mobile phones are a ubiquitous and promising technology to facilitate healthcare access, few studies have tested the acceptability and feasibility of patients themselves using the devices for assisting linkages to healthcare services. We hypothesized that patients would use mobile phones to help manage postdischarge problems, if given a communication protocol. We developed a mobile phone-based program and investigated its acceptability and feasibility as a method of delivering posthospitalization care. SUBJECTS AND METHODS: A consecutive cohort of adult patients in a public hospital in Quito, Ecuador was enrolled over a 1-month period. A hospital-based nurse relayed patients' discharge instructions to a community-based nurse. Patients corresponded with this nurse via text messaging and phone calls according to a protocol to initiate and participate in follow-up. RESULTS: Eighty-nine percent of eligible patients participated. Ninety-seven percent of participants completed at least one contact with the nurse; 81% initiated contact themselves. Nurses completed 262 contacts with 32 patients, clarifying discharge instructions, providing preventive education, and facilitating clinic appointments. By this method, 87% of patients were successfully linked to follow-up appointments. CONCLUSIONS: High levels of patient participation and successful delivery of follow-up services indicate the mobile phone program's acceptability and feasibility for facilitating posthospitalization follow-up. Patients actively used mobile phones to interact with nurses, enabling the provision of posthospitalization medical advice and facilitate community-based care via mobile phone. PMID- 22428552 TI - NHS connecting for health: healthcare professionals, mobile technology, and infection control. AB - BACKGROUND: Mobile phones improve the efficiency of clinical communication and are increasingly involved in all areas of healthcare delivery. Despite this, healthcare workers' mobile phones provide a known reservoir of pathogenic bacteria, with the potential to undermine infection control efforts aimed at the reducing bacterial cross-contamination in hospitals. This potential could be amplified further when employers require doctors to carry additional electronic devices for communication, without concurrently providing appropriate guidance on decontamination or use. METHODS: Eighty-seven on-call doctors' mobile phones were sampled for bacterial growth prior to, and 12 h after, a cleaning intervention involving 70% isopropyl alcohol. RESULTS: Seventy-eight percent of doctors were aware that mobile phones could carry pathogenic bacteria, but only 8% cleaned their phones regularly. The cleaning intervention reduced the number of phones that grew bacteria by 79% (55% [48 of 87] before versus 16% [14 of 87] after cleaning). Eight percent of the phones grew Staphyloccus aureus, and 44.8% of phones grew Gram-positive cocci. All S. aureus isolates were methicillin sensitive. Bacterial contamination was not associated with gender, specialty, or seniority of the phone user (p>0.05). CONCLUSIONS: Simple cleaning interventions can reduce the surface bioburden of hospital-provided doctors' mobile phones and therefore the potential for cross-contamination. This cleaning intervention is inexpensive, easily instituted, and effective. Healthcare workers should carry the minimum number of electronic devices on their person, maintain good hand hygiene, and clean their device appropriately in order to minimize the potential for cross-contamination in the work place. PMID- 22428553 TI - Differential protein and mRNA expression of CaMKs during osteoclastogenesis and its functional implications. AB - The calmodulin-dependent kinase (CaMK) family has been recently recognized to participate in the regulation of osteoclastogenesis. However, there are some controversial reports regarding the mRNA expression patterns of CaMKs during osteoclastogenesis, although the protein expression pattern of most CaMKs during osteoclastogenesis have not been studied. In the present study, we attempted to address this issue by using a mouse bone marrow monocyte model and parallel Western blotting and quantitative real-time PCR. Our results revealed some interesting expression patterns of CaMKs during the process. Among all CaMKs examined, only CaMKIIdelta exhibited consistent expression patterns between its mRNA and protein with both rising remarkably during osteoclastogenesis. CaMKIV protein was not detectable during the first three days of cell culture, but it rose on Day 5. The CaMK inhibitor, KN93, subdued osteoclastogenesis during the first three days of cell culture, a time when CaMKIV was absent while other KN93 sensitive CaMKs presented. In addition, KN93 was found to inhibit the expression of some early receptor activator of NF-kappaB (RANK) signaling intermediates (extracellular signal-regulated kinase (ERK) and Akt) in the non-differentiated mouse bone marrow monocytes. Collectively, these data reveal differential expression patterns of KN93-sensitive CaMK proteins and their mRNAs during osteoclastogenesis, supporting a CaMKII-RANK signaling interaction in the regulation of early osteoclastogenesis. PMID- 22428554 TI - Effects of pioglitazone and/or simvastatin on circulating TNFalpha and adiponectin levels in insulin resistance. AB - The current study investigated the effects of 14-day pioglitazone (PIO) and/or simvastatin (SIM) treatments on serum adiponectin (Adp) and TNFalpha levels (markers of adipocyte dysfunction), as well as on metabolic perturbations that arise from prolonged (8 week) consumption of a high fructose (HFD; 60%) diet in a rat model of pre-diabetic insulin resistance. The HFD induced a deranged lipid profile that was associated with adipose tissue hypertrophy, increased ratios of visceral and epididymal fats to body weight, and fatty liver. These perturbations were associated with hypo-adiponectinemia (50.8%) and increased serum TNFalpha (6.5-fold) levels. Treatment with PIO ameliorated the altered blood and hepatic glucose metabolism via an Adp-dependent mechanism; PIO also mitigated the changes in blood TNFalpha and led to a hyperelevation of Adp levels. SIM amended hepatic and overall lipid metabolism, regulated TNFalpha, but failed to alter the glucose intolerance or significantly impact on the HFD-altered Adp levels. Coadministration of SIM + PIO was superior in improving overall metabolic parameters compared to each monotherapy. Cotreatment was optimal in reestablishing insulin resistance, most efficacious in improving serum lipid profiles, normalizing percentage ratios of epididymal and visceral fats to body weight, and augmenting Adp/reducing TNFalpha levels relative to that in the HFD group or with HFD + each drug alone. The results here show that use of either monotherapy or a combined SIM + PIO approach might, from a clinical perspective, provide an ability to delay progression to Type 2 diabetes and its associated inflammatory/cardiovascular effects. PMID- 22428556 TI - A neutral face is not neutral even if you have not seen it: social anxiety disorder and affective priming with facial expressions. AB - Cognitive theories suggest that social anxiety disorder (SAD) is characterized by biased processing of negative facial expressions. Recently, however, it has been proposed that the fear of positive evaluation may play an additional, important role. In order to investigate which specific expressions evoke biased processing, 15 patients diagnosed with SAD and 15 non-anxious controls (NACs) completed an affective priming procedure: they rated neutral symbols which were preceded by sub-optimally presented primes of angry, neutral, and smiling faces. Patients with SAD rated the symbols significantly more negatively than NACs when they were primed with a neutral face. In addition, SAD patients tended to rate all symbols significantly more negatively suggesting that all faces (negative, positive, and neutral) are threatening to SAD patients. PMID- 22428557 TI - Influence of familiar features on diagnosis: instantiated features in an applied setting. AB - Medical diagnosis can be viewed as a categorization task. There are two mechanisms whereby humans make categorical judgments: "analytical reasoning," based on explicit consideration of features and "nonanalytical reasoning," an unconscious holistic process of matching against prior exemplars. However, there is evidence that prior experience can also operate at the level of individual "instantiated" features (Brooks & Hannah, 2006). The present studies examined instantiated features in medical diagnosis. Four "pseudopsychiatric" conditions, each described by four characteristic features, were taught to undergraduate psychology students. They practiced on additional cases, then were tested on new cases with features from two conditions. In Experiment 1, diagnoses associated with familiar features presented one or three times during practice were assigned a higher probability than those with novel features. Experiment 2 showed that the impact of feature frequency was dependent on its consistency with the case diagnosis. Experiment 3 showed that the effect of feature familiarity was not confined to cases with two equiprobable diagnoses. Experiment 4 showed that the effect remained after a 24 hour delay. These four studies demonstrated that features seen in practice have a greater influence on diagnosis than novel synonyms. In fact, seeing a feature once within the appropriate context (a patient case in which it is a member of the primary diagnosis) was sufficient to form a diagnostic association equivalent to instantiations seen four times in a different context. The results of these studies have implications for theories of categorization and for teaching clinical reasoning. PMID- 22428558 TI - Re-fraction: a machine learning approach for deterministic identification of protein homologues and splice variants in large-scale MS-based proteomics. AB - A key step in the analysis of mass spectrometry (MS)-based proteomics data is the inference of proteins from identified peptide sequences. Here we describe Re Fraction, a novel machine learning algorithm that enhances deterministic protein identification. Re-Fraction utilizes several protein physical properties to assign proteins to expected protein fractions that comprise large-scale MS-based proteomics data. This information is then used to appropriately assign peptides to specific proteins. This approach is sensitive, highly specific, and computationally efficient. We provide algorithms and source code for the current version of Re-Fraction, which accepts output tables from the MaxQuant environment. Nevertheless, the principles behind Re-Fraction can be applied to other protein identification pipelines where data are generated from samples fractionated at the protein level. We demonstrate the utility of this approach through reanalysis of data from a previously published study and generate lists of proteins deterministically identified by Re-Fraction that were previously only identified as members of a protein group. We find that this approach is particularly useful in resolving protein groups composed of splice variants and homologues, which are frequently expressed in a cell- or tissue-specific manner and may have important biological consequences. PMID- 22428559 TI - Stable isotope-labelling analysis of the impact of inhibition of the mammalian target of rapamycin on protein synthesis. AB - mTORC1 [mTOR (mammalian target of rapamycin) complex 1] regulates diverse cell functions. mTORC1 controls the phosphorylation of several proteins involved in mRNA translation and the translation of specific mRNAs, including those containing a 5'-TOP (5'-terminal oligopyrimidine). To date, most of the proteins encoded by known 5'-TOP mRNAs are proteins involved in mRNA translation, such as ribosomal proteins and elongation factors. Rapamycin inhibits some mTORC1 functions, whereas mTOR-KIs (mTOR kinase inhibitors) interfere with all of them. mTOR-KIs inhibit overall protein synthesis more strongly than rapamycin. To study the effects of rapamycin or mTOR-KIs on synthesis of specific proteins, we applied pSILAC [pulsed SILAC (stable isotope-labelling with amino acids in cell culture)]. Our results reveal, first, that mTOR-KIs and rapamycin differentially affect the synthesis of many proteins. Secondly, mTOR-KIs inhibit the synthesis of proteins encoded by 5'-TOP mRNAs much more strongly than rapamycin does, revealing that these mRNAs are controlled by rapamycin-insensitive outputs from mTOR. Thirdly, the synthesis of certain other proteins shows a similar pattern of inhibition. Some of them appear to be encoded by 'novel' 5'-TOP mRNAs; they include proteins which, like known 5'-TOP mRNA-encoded proteins, are involved in protein synthesis, whereas others are enzymes involved in intermediary or anabolic metabolism. These results indicate that mTOR signalling may promote diverse biosynthetic processes through the translational up-regulation of specific mRNAs. Lastly, a SILAC-based approach revealed that, although rapamycin and mTOR-KIs have little effect on general protein stability, they stabilize proteins encoded by 5'-TOP mRNAs. PMID- 22428560 TI - An image processing approach for blind mobility facilitated through visual intracortical stimulation. AB - This article presents an image processing approach dedicated for a blind mobility aid facilitated through visual intracortical electrical stimulation. The method examines a display framework based on the distances related to a scene. The distances of objects to the walker are measured using a size perspective method which uses only one camera without any occlusion effect. The method extracts the information of the closest object to the camera and transfers a sense of distance to a blind walker. The proposed image processing method can estimate the distances of objects within 7.5 m of the walker, and alert the presence of the closest object to the person. This new method offers the advantages of information reduction and scene understanding suitable for visual prosthesis. PMID- 22428561 TI - Neuronal polarization is impaired in mice lacking RhoE expression. AB - Proper development of neuronal networks relies on the polarization of the neurons, thus the establishment of two compartments, axons and dendrites, whose formation depends on cytoskeletal rearrangements. Rnd proteins are regulators of actin organization and they are important players in several aspects of brain development as neurite formation, axon guidance and neuron migration. We have recently demonstrated that mice lacking RhoE/Rnd3 expression die shortly after birth and have neuromotor impairment and neuromuscular alterations, indicating an abnormal development of the nervous system. In this study, we have further investigated the specific role played by RhoE in several aspects of neuronal development by using hippocampal neuron cultures. Our findings show that neurons from a mice lacking RhoE expression exhibit a decrease in the number and the total length of the neurites. We also show that RhoE-deficient neurons display a reduction in axon outgrowth and a delay in the process of neuronal polarization. In addition, our results suggest an involvement of the RHOA/ROCK/LIMK/COFILIN signaling pathway in the neuronal alterations induced by the lack of RhoE. These findings support our previous report revealing the important role of RhoE in the normal development of the nervous system and may provide novel therapeutic targets in neurodegenerative disorders. PMID- 22428562 TI - Depressive symptoms and subjective and objective sleep in community-dwelling older women. AB - OBJECTIVES: To examine the relationship between depressive symptoms and subjective and objective sleep in older women. DESIGN: Cross-sectional. SETTING: Four U.S. clinical centers. PARTICIPANTS: Three thousand forty-five community dwelling women aged 70 and older. MEASUREMENTS: Depressive symptoms were assessed using the Geriatric Depression Scale, categorizing participants as normal (0-2, reference), some depressive symptoms (3-5), or depressed (>= 6). Subjective sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Objective sleep measures were assessed using wrist actigraphy. RESULTS: In multivariable-adjusted models, there were graded associations between greater level of depressive symptoms and worse subjective sleep quality and more subjective daytime sleepiness (P-trends < .001). Women with some depressive symptoms (odds ratio (OR) = 1.82, 95% confidence interval (CI) = 1.48-2.24) and depressed (OR = 2.84, 95% CI = 2.08 3.86) women had greater odds of reporting poor sleep (PSQI>5). Women with some depressive symptoms (OR = 1.97, 95% CI = 1.47-2.64) and depressed women (OR = 1.70, 95% CI = 1.12-2.58) had greater odds of reporting excessive daytime sleepiness (ESS>10). There were also graded associations between greater level of depressive symptoms and objectively measured wake after sleep onset (WASO) (P trend = .03) and wake episodes longer than 5 minutes (P-trend = .006). Depressed women had modestly higher odds of WASO of 1 hour or longer (OR = 1.37, 95% CI = 1.03-1.83). Women with some depressive symptoms (OR = 1.49, 95% CI = 1.19-1.86) and depressed women (OR = 2.04, 95% CI = 1.52-2.74) had greater odds of being in the highest quartile for number of nap episodes longer than 5 minutes. No associations between depressive symptom level and prolonged sleep latency, poor sleep efficiency, or short or long total sleep time were found. CONCLUSION: Greater depressive symptom levels were associated with more subjective sleep disturbance and objective evidence of sleep fragmentation and napping. PMID- 22428563 TI - Phenolic compounds from Nicotiana tabacum and their biological activities. AB - Three new phenolic compounds, nicotphenols A-C (1-3), together with 14 known phenols (4-17), were isolated from the leaves of Nicotiana tabacum. Their structures were established by means of spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were tested for their anti-HIV 1 activities and cytotoxicities. They all showed significant cytotoxic abilities and modest anti-HIV-1 activities, respectively. PMID- 22428564 TI - Dual effect of Mesorhizobium loti T3SS functionality on the symbiotic process. AB - Mesorhizobium loti MAFF303099 has a functional type III secretory system (T3SS) involved in the nodulation process on Lotus tenuis and Lotus japonicus. Four putative M. loti T3SS effectors (Mlr6358, Mlr6331, Mlr6361, and Mlr6316) have been previously described, and it has been demonstrated that the N-terminal regions of Mlr6361 and Mlr6358 mediate the secretion via a T3SS. Here, we demonstrate the capacity of Mlr6316 and Mlr6331 N-terminal regions to direct the secretion of a translational fusion to a reporter peptide through T3SS. By using single, double, and triple mutants, we demonstrated the positive and negative participation of some of these proteins in the determination of competitiveness on Lotus spp. Low competitiveness values correlated with low nodulation efficiency for a mutant deficient in three of the putative M. loti effectors. Our data suggest that the net effect of M. loti T3SS function on symbiotic process with Lotus results from a balance between positive and negative effects. PMID- 22428565 TI - Review article: intestinal lymphoid nodular hyperplasia in children--the relationship to food hypersensitivity. AB - BACKGROUND: Lymphoid aggregates are normally found throughout the small and large intestine. Known as lymphoid nodular hyperplasia (LNH), these aggregates are observed especially in young children and are not associated with clinical symptoms being considered 'physiological'. In children presenting with gastrointestinal symptoms the number and size of the lymphoid follicles are increased. Patients suffering from gastrointestinal symptoms (i.e. recurrent abdominal pain) should systematically undergo gastroduodenoscopy and colonoscopy. With these indications LNH, especially of the upper but also of the lower gastrointestinal tract has been diagnosed, and in some children it may reflect a food hypersensitivity (FH) condition. AIM: To review the literature about the relationship between LNH and FH, particularly focusing on the diagnostic work-up for LNH related to FH. METHODS: We reviewed literature using Pubmed and Medline, with the search terms 'lymphoid nodular hyperplasia', 'food hypersensitivity', 'food allergy' and 'food intolerance'. We overall examined 10 studies in detail, selecting articles about the prevalence of LNH in FH patients and of FH in LNH patients. RESULTS: Collected data showed a median of 49% (range 32-67%) LNH in FH patients and a median of 66% (range 42-90%) FH in LNH patients. Literature review pointed out that the most important symptom connected with LNH and/or FH was recurrent abdominal pain, followed by diarrhoea and growth retardation. Both LNH and FH are associated with an increase in lamina propria gamma/delta+ T cells, but the mechanisms by which enhanced local immune responses causing gastrointestinal symptoms still remain obscure. CONCLUSIONS: When assessing FH, we rely on clinical evaluation, including elimination diet and challenge tests, and endoscopic and immunohistochemical findings. Considering the possible co existence of duodenal and ileo-colonic LNH, upper endoscopy can be recommended in children with suspected FH, especially in those presenting with additional upper abdominal symptoms (i.e. vomiting). Likewise, lower endoscopy might be additionally performed in patients with suspected FH and LNH of the duodenal bulb, also presenting with lower abdominal symptoms (i.e. recurrent abdominal pain). PMID- 22428566 TI - Comprehensive profiling of coal tar and crude oil to obtain mass spectra and retention indices for alkylated PAH shows why current methods err. AB - Investigators use C(1) to C(4) substituted polycyclic aromatic hydrocarbons (PAH) to assess ecological risk and to track fossil fuels and related pollutants in the environment. To quantify these compounds gas chromatography/mass spectrometry (GC/MS) is used. This work demonstrates single ion monitoring (SIM) or extraction (SIE) of full scan data produces inaccurate and imprecise concentration estimates due to incorrect homologue peak assignments. Profiling of coal tar and crude oil by automated sequential GC-GC/MS provided the retention windows and spectral patterns for each homologue to correctly quantify these compounds. Simultaneous pulsed flame photometric (sulfur-specific) detection differentiated PAH from polycyclic aromatic sulfur heterocycles and their alkylated homologues when they eluted within the same retention windows and had common ions. Differences between SIE and spectral deconvolution of GC/MS data based on multiple fragmentation patterns per homologue ranged from a few percent for C(1) compounds to hundreds of percent for the higher alkylated homologues. Findings show current methods produce poor quality data adversely affecting forensic investigations, risk assessments, and weathering studies. PMID- 22428567 TI - Targeted testing with diethylthiourea often reveals clinically relevant allergic contact dermatitis caused by neoprene rubber. AB - BACKGROUND: Diethylthiourea is widely used in the rubber industry, particularly in neoprene rubber, and may cause allergic contact dermatitis. However, as thiourea allergens are not part of the European baseline series, the diagnosis of allergic contact dermatitis caused by thiourea compounds depends on clinical suspicion and aimed testing. OBJECTIVES: The aims of this study were to evaluate the occurrence of sensitization to diethylthiourea during a 19-year period by using data from the Allergen Bank database at the Department of Dermatology and Allergy Centre, Odense University Hospital, and to evaluate whether the yield of aimed patch tests with diethylthiourea differed between the dermatologists in practice and those working in the dermatology department. PATIENTS AND METHODS: A total of 239 patients were patch tested with diethylthiourea 1% in petrolatum obtained from the Allergen Bank. The records for patients with positive reactions were evaluated retrospectively. RESULTS: One hundred and fifty-one patients were tested by 27 different dermatologists in private practice, and positive reactions were found in 16% (24/151) of the patients; 88 patients were tested at the dermatology department, and positive reactions were found in 15% (13/88). Thus, 15% (37/239) had positive patch test reactions to diethylthiourea, all with current clinical relevance and all strong. CONCLUSION: Clinical suspicion of neoprene rubber allergy and subsequent aimed patch testing with diethylthiourea give a high yield of clinically relevant allergic patch test reactions for both dermatologists in practice and dermatologists in the hospital department. PMID- 22428568 TI - Developing an anti-Campylobacter jejuni vaccine. AB - The proteomics era allows for the definition of biological organisms at the protein level, offering new opportunities for delimiting the self- and non-self boundaries between microbes and the human host. Here, we apply proteomics to design a vaccine against the major pathogenic factor of Campylobacter jejuni, i.e. cytolethal distending toxin (CDT). We used the scientific rationale that only peptide sequences not represented in the host proteome have the potential to evoke powerful, non-cross-reactive immune responses, thereby guaranteeing effectiveness and safety. PMID- 22428569 TI - Fluorescence-based experimental model to evaluate the concomitant effect of drugs on the tumour microenvironment and cancer cells. AB - The response of the tumour microenvironment to anti-cancer drugs can influence treatment efficacy. Current drug-screening methodologies fail to distinguish and quantify simultaneously the concomitant effect of drugs on the tumour stroma and cancer cells. To overcome this limitation we have developed a fluorescence-based experimental model that employs mCherry-labelled stromal cells (e.g. bone marrow fibroblastic stromal cells) co-cultured in direct contact with enhanced green fluorescent protein-labelled tumour cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumour cells. Additionally, we used fluorescence-based image analysis to determine morphological changes that correlate with cell function (e.g. morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with multiple myeloma cells via a process involving Src/c-Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone mediated by HS5 cells and osteoclasts was reversed by treatment with the Src/c-Abl inhibitor dasatinib but not with bortezomib. This new experimental platform provides a more precise screening of new therapeutics for improved efficacy of tumour cell killing within the bone marrow microenvironment. PMID- 22428571 TI - Lactogenesis failure following successful delivery of advanced abdominal pregnancy. AB - Abdominal pregnancy is a rare condition with significant risk of maternal and fetal morbidity and mortality. Because of the vascular involvement, the placenta is often left in situ. Prior reports have neglected to discuss the implications of leaving the placenta in situ on breastfeeding and lactation. We present a case of failure of lactogenesis II following the successful delivery of an advanced abdominal pregnancy in which the placenta was left in situ. This is the first report to discuss the effects on lactation of leaving the placenta in situ as a conservative management option in advanced abdominal pregnancy. PMID- 22428570 TI - Hydrophilic gold nanoparticles adaptable for hydrophobic solvents. AB - Surface ligand molecules enabling gold nanoparticles to disperse in both polar and nonpolar solvents through changes in conformation are presented. Gold nanoparticles coated with alkyl-head-capped PEG derivatives were initially well dispersed in water through exposure of the PEG residue (bent form). When chloroform was added to the aqueous solution of gold nanoparticles, the gold nanoparticles were transferred from an aqueous to a chloroform phase through exposure of the alkyl-head residue (straight form). The conformational change (bent to straight form) of immobilized ligands in response to the polarity of the solvents was supported by NMR analyses and water contact angles. PMID- 22428572 TI - An all-purpose nipple ointment versus lanolin in treating painful damaged nipples in breastfeeding women: a randomized controlled trial. AB - BACKGROUND: The negative outcomes associated with painful and damaged nipples have been widely documented in the breastfeeding literature. Numerous studies have been conducted evaluating topical preparations to treat nipple pain and damage with equivocal findings. No studies have evaluated the effectiveness of the increasingly popular all-purpose nipple ointment (APNO). The purpose of this trial is to evaluate the effect of the APNO versus lanolin on nipple pain among breastfeeding women with damaged nipples. SUBJECTS AND METHODS: A double-blind, randomized controlled trial was conducted in a large single-site, tertiary-care hospital in Toronto, ON, Canada. Breastfeeding women (n=151) identified as having damage to one or both nipples were randomized to apply either APNO (intervention group) or lanolin (control group) to their nipples according to the trial protocol. The primary outcome was nipple pain at 1 week after randomization measured using the Short Form McGill Pain Questionnaire. Additional outcomes at 1 week after randomization and 12 weeks postpartum included nipple yeast symptoms and/or mastitis, rates of breastfeeding duration and exclusivity, and maternal satisfaction with infant feeding method and treatment ointment. RESULTS: There were no significant group differences in mean pain scores at 1 week after randomization. Women in the lanolin group reported significantly greater satisfaction with their infant feeding method and had nonsignificantly higher breastfeeding duration and exclusivity rates at 12 weeks postpartum. CONCLUSION: Results suggest that APNO is not superior to lanolin in treating painful, damaged nipples. PMID- 22428573 TI - Tooth lengths of the permanent upper incisors in patients with cleft lip and palate determined with cone beam computed tomography. AB - Objective : To measure the tooth lengths of fully developed permanent upper incisors and to qualitatively evaluate the root shapes of the incisors in patients with cleft lip and palate (CLP). Design : Cross-sectional, noninterventional, case-control imaging study. Setting : Hospital and Stomatology Unit of Peking University, Beijing, China (institutional tertiary care). Participants : Sixty consecutive nonsyndromic CLP patients (including 40 unilateral [UCLP] and 20 bilateral [BCLP]), and 53 age- and sex-matched controls were selected for this study. Main Outcome Measure : Crown heights and root lengths of permanent upper incisors were measured from cone beam computed tomography scans, and the root shapes of upper incisors were evaluated. Results : Compared with controls, the crown heights of upper incisors in CLP patients were reduced by 9.7% to 22.5% (p < .05), and the root lengths were reduced by 15.8% to 31.7% (p < .05). BCLP patients had greater reductions than the UCLP cases (p < .05). There were no significant differences between incisors and their antimeres in controls and BCLP patients. However, measurements on the cleft side in UCLP patients were lower than those of the noncleft side (p < .05). The prevalence of atypical root shape was higher in CLP than in the control group (p = .002); of these, 83.3% (30/36) occurred in central incisors near the cleft. Conclusion : The permanent upper incisors in nonsyndromic CLP patients are underdeveloped. Incisor developmental deficiency was greater in teeth adjacent to the cleft. PMID- 22428574 TI - The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels. AB - Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; North American adopted name), a first-in-class antiepileptic drug (AED) that reduces neuronal excitability primarily by enhancing the activity of KCNQ2/3 (K(v)7.2/7.3) potassium channels, has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. Much of the RTG/EZG safety profile will be familiar to health care professionals who are experienced with the clinical use of AEDs. RTG/EZG, as a potassium channel opener, also has a pharmacologic effect on smooth muscle of the urinary bladder. Consequently, the adverse event (AE) profile of RTG/EZG includes a potential risk of effects on the urinary system. This review summarizes the urinary safety profile and any secondary renal effects of RTG/EZG using data from patients in the pivotal controlled trials and the overall phase 2/3 clinical development program. Urinary AEs were reported more frequently in patients receiving RTG/EZG compared with placebo, although most patients were able to continue with treatment. Specifically, there is an increased risk of urinary retention with RTG/EZG, with urinary hesitation representing the most frequently reported urinary retention-related AE. Potential secondary renal effects, which may be caused by an inability to empty the bladder, were evaluated. Crystals with a bilirubin-like appearance were detected in the urine of patients receiving RTG/EZG. Although investigations indicated that these crystals were not bilirubin, their composition remains undetermined. There was no causal association with urinary tract infections, and nephrolithiasis was uncommon. The reported clinical effects of RTG/EZG are consistent with its documented effects on bladder smooth muscle in preclinical studies. RTG/EZG should be used with caution in patients at risk of urinary retention. PMID- 22428576 TI - Could diastereoselectivity in the presence of O-2 chiral nonparticipating groups be an indicator of glycopyranosyl oxacarbenium ions in glycosylation reactions? AB - Although long postulated, the existence of glycopyranosyl oxacarbenium ions as intermediates or transition states (TS) in chemical glycosylation reactions has not been convincingly demonstrated experimentally. It is anticipated that elucidation of such reactive species will greatly assist synthetic chemists to control the alpha/beta stereoselectivity by rational means. Previous density functional theory (DFT) calculations from our group found that the torsion potential about C-2-O-2 in protected glycopyranosyl donors changed from a conventional 3-fold rotor to a 2-fold rotor with a strong syn (CH-2-C-2-O-2-CPg) preference once the donor was ionized to its oxacarbenium ion. This suggested to us that if CPg of the protecting group was a chiral carbon, then diastereoselectivity might be observed in glycosylation reactions that proceed through oxacarbenium ions. The hypothesis to test is as follows: if a nonparticipating O-2 racemic chiral protecting group exhibits diastereoselectivity in glycosylation reactions, then the reaction probably proceeds through an oxacarbenium ion intermediate or TS. We present data for O-2 ether-protected d-glucopyranosyl donors where the racemic protecting group 1 methyl 1'-methylcyclopropylmethyl (MCPM) provides the chirality. MCPM proves to be more activating than the O-2-benzyl ether, and in cases where the donor is otherwise deactivated, several examples of moderate diastereoselectivity are found. These results can be interpreted to indicate that a continuum of reactivity exists where some glycosyl donors form oxacarbenium ions in glycosylation reactions but more reactive donors do not. The strongly activating properties of the cyclopropylmethyl ether functionality and the ability to induce diastereoselectivity with chiral derivatives strongly suggest widespread applications. PMID- 22428577 TI - Controlled release of ionic drugs from complex micelles with charged channels. AB - Oral administration of ionic drugs generally encounters with significant fluctuation in plasma concentration due to the large variation of pH value in the gastrointestinal tract and the pH-dependent solubility of ionic drugs. Polymeric complex micelles with charged channels on the surface provided us with an effective way to reduce the difference in the drug release rate upon change in pH value. The complex micelles were prepared by self-assembly of PCL-b-PAsp and PCL b-PNIPAM in water at room temperature with PCL as the core and PAsp/PNIPAM as the mixed shell. With an increase in temperature, PNIPAM collapsed and enclosed the PCL core, while PAsp penetrated through the PNIPAM shell, leading to the formation of negatively charged PAsp channels on the micelle surface. Release behavior of ionic drugs from the complex micelles was remarkably different from that of usual core-shell micelles where diffusion and solubility of drugs played a key role. Specifically, it was mainly dependent on the conformation of the PAsp chains and the electrostatic interaction between PAsp and drugs, which could partially counteract the influence of pH-dependent diffusion and solubility of drugs. As a result, the variation of drug release rate with pH value was suppressed, which was favorable for acquiring relatively steady plasma drug concentration. PMID- 22428578 TI - Unexpected copper(II) catalysis: catalytic amine base promoted beta-borylation of alpha,beta-unsaturated carbonyl compounds in water. AB - Using bis(pinacolato)diboron, catalytic amounts of Cu(II), and various amine bases in water under atmospheric conditions at rt, acyclic and cyclic alpha,beta unsaturated ketones and esters are beta-borylated in up to 98% yield. Mechanistic investigations using UV-vis spectroscopy, (11)B NMR, and solvent kinetic isotope effect suggest that the role of the amine is not only to coordinate to Cu(II) but also to activate a nucleophilic water molecule to form the reactive sp(2)-sp(3) diboron complex. PMID- 22428579 TI - Motions on the millisecond time scale and multiple conformations of HIV-1 capsid protein: implications for structural polymorphism of CA assemblies. AB - The capsid protein (CA) of human immunodeficiency virus 1 (HIV-1) assembles into a cone-like structure that encloses the viral RNA genome. Interestingly, significant heterogeneity in shape and organization of capsids can be observed in mature HIV-1 virions. In vitro, CA also exhibits structural polymorphism and can assemble into various morphologies, such as cones, tubes, and spheres. Many intermolecular contacts that are critical for CA assembly are formed by its C terminal domain (CTD), a dimerization domain, which was found to adopt different orientations in several X-ray and NMR structures of the CTD dimer and full-length CA proteins. Tyr145 (Y145), residue two in our CTD construct used for NMR structure determination, but not present in the crystallographic constructs, was found to be crucial for infectivity and engaged in numerous interactions at the CTD dimer interface. Here we investigate the origin of CA structural plasticity using solid-state NMR and solution NMR spectroscopy. In the solid state, the hinge region connecting the NTD and CTD is flexible on the millisecond time scale, as evidenced by the backbone motions of Y145 in CA conical assemblies and in two CTD constructs (137-231 and 142-231), allowing the protein to access multiple conformations essential for pleimorphic capsid assemblies. In solution, the CTD dimer exists as two major conformers, whose relative populations differ for the different CTD constructs. In the longer CTD (144-231) construct that contains the hinge region between the NTD and CTD, the populations of the two conformers are likely determined by the protonation state of the E175 side chain that is located at the dimer interface and within hydrogen-bonding distance of the W184 side chain on the other monomer. At pH 6.5, the major conformer exhibits the same dimer interface as full-length CA. In the short CTD (150-231) construct, no pH-dependent conformational shift is observed. These findings suggest that the presence of structural plasticity at the CTD dimer interface permits pleiotropic HIV-1 capsid assembly, resulting in varied capsid morphologies. PMID- 22428580 TI - Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction. AB - Mitochondrial dysfunction represents a critical event during the pathogenesis of Parkinson's disease (PD) and expanding evidences demonstrate that an altered balance in mitochondrial fission/fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction/degeneration. In this study, we investigated whether DJ-1 is involved in the regulation of mitochondrial dynamics and function in neuronal cells. Confocal and electron microscopic analysis demonstrated that M17 human neuroblastoma cells over-expressing wild-type DJ-1 (WT DJ-1 cells) displayed elongated mitochondria while M17 cells over-expressing PD-associated DJ-1 mutants (R98Q, D149A and L166P) (mutant DJ-1 cells) showed significant increase of fragmented mitochondria. Similar mitochondrial fragmentation was also noted in primary hippocampal neurons over-expressing PD associated mutant forms of DJ-1. Functional analysis revealed that over expression of PD-associated DJ-1 mutants resulted in mitochondria dysfunction and increased neuronal vulnerability to oxidative stress (H(2) O(2)) or neurotoxin. Further immunoblot studies demonstrated that levels of dynamin-like protein (DLP1), also known as Drp1, a regulator of mitochondrial fission, was significantly decreased in WT DJ-1 cells but increased in mutant DJ-1 cells. Importantly, DLP1 knockdown in these mutant DJ-1 cells rescued the abnormal mitochondria morphology and all associated mitochondria/neuronal dysfunction. Taken together, these studies suggest that DJ-1 is involved in the regulation of mitochondrial dynamics through modulation of DLP1 expression and PD-associated DJ 1 mutations may cause PD by impairing mitochondrial dynamics and function. PMID- 22428582 TI - Dissemination of therapist-assisted internet cognitive behaviour therapy: development and open pilot study of a workshop. AB - There is considerable research suggesting that therapist-assisted Internet cognitive behaviour therapy (ICBT) is efficacious in the treatment of depression and anxiety. Given this research, there is a growing interest in training students in therapist-assisted ICBT in order to assist with the dissemination of this emerging modality into routine clinical practice. In this study, we developed, delivered, and evaluated a therapist-assisted ICBT workshop for clinical psychology graduate students (n=20). The workshop provided both research evidence and practical information related to the delivery of therapist-assisted ICBT. The workshop also incorporated an experiential component with students working on and discussing responses to client e-mails. Before and after the workshop, we measured knowledge of therapist-assisted ICBT research and professional practice issues, as well as attitudes towards and confidence in delivering therapist-assisted ICBT. Statistically significant changes were observed in all areas. Eighty-five per cent of students are now offering therapist-assisted ICBT under supervision. We conclude by discussing future research directions related to disseminating therapist-assisted ICBT. PMID- 22428583 TI - Functional status after colon cancer surgery in elderly nursing home residents. AB - OBJECTIVES: To determine functional status and mortality rates after colon cancer surgery in older nursing home residents. DESIGN: Retrospective cohort study. SETTING: Nursing homes in the United States. PARTICIPANTS: Six thousand eight hundred twenty-two nursing home residents aged 65 and older who underwent surgery for colon cancer in the United States between 1999 and 2005. MEASUREMENTS: Changes in functional status were assessed before and after surgery using the Minimum Data Set Activity of Daily Living (MDS-ADL) summary scale, a 28-point scale in which score increases as functional dependence increases. Regression techniques were used to identify patient characteristics associated with mortality and functional decline 1 year after surgery. RESULTS: On average, residents who underwent colectomy had a 3.9-point worsening in MDS-ADL score at 1 year. One year after surgery, rates of mortality and sustained functional decline were 53% and 24%, respectively. In multivariate analysis, older age (>= 80 vs 65 69, adjusted relative risk (ARR) = 1.53, 95% confidence interval (CI) = 1.15 2.04, P < .001), readmission after surgical hospitalization (ARR = 1.15, 95% CI = 1.03-1.29, P = .02), surgical complications (ARR = 1.11, 95% CI = 1.02-1.21, P = .01), and functional decline before surgery (ARR = 1.21, 95% CI = 1.11-1.32, P < .001) were associated with functional decline at 1 year. CONCLUSION: Mortality and sustained functional decline are common after colon cancer surgery in nursing home residents. Initiatives aimed at improving surgical outcomes are needed in this vulnerable population. PMID- 22428584 TI - Discovery of a compound which acts as a bacterial UMP kinase PyrH inhibitor. AB - PyrH is a member of the UMP kinase family that catalyses the conversion of UMP to UDP, an essential step in the pyrimidine metabolic pathway in a variety of bacteria including those causing community-acquired respiratory tract infections (RTIs). In this study, we have developed a luminescence-based kinase assay of PyrH and evaluated the inhibitory activity of PYRH-1 (sodium {3-[4-tert-butyl-3 (9H-xanthen-9-ylacetylamino)phenyl]-1 cyclohexylmethylpropoxycarbonyloxy}acetate). PYRH-1 inhibits PyrH derived from both Streptococcus pneumoniae and Haemophilus influenzae with IC(50) (concentration of inhibitor giving a 50% decrease in enzyme activity) values of 48 and 75 MUM, respectively, whose inhibitory activity against S. pneumoniae PyrH was far higher compared with that of UTP (IC(50) = 710 MUM), an allosteric PyrH inhibitor. The molecular interaction analysis by surface plasmon resonance suggested that PYRH-1 directly interacts with S. pneumoniae PyrH at one-to-one molar ratio. Finally, PYRH-1 was shown to have antimicrobial activity against several different bacteria causing RTIs, such as S. pneumoniae, Staphylococcus aureus, H. influenzae (acrA knockout strain), suggesting that PYRH-1 is a prototype chemical compound that can be harnessed as an antimicrobial drug with a novel mode of action by targeting bacterial PyrH. PMID- 22428585 TI - Contact allergy to metals in adolescents: nickel release from metal accessories 7 years after the implementation of the EU Nickel Directive in Poland. AB - BACKGROUND: Contact allergy among adolescents is an important issue. OBJECTIVES: To assess the prevalence of contact allergy to metals in adolescents aged 15 years and nickel release from metal accessories that are in direct contact with the skin. METHODS: Three hundred and nine females and 219 males, all 15 years old, from randomly selected secondary schools were examined and patch tested with nickel sulfate, cobalt chloride, palladium chloride, and potassium dichromate. Three hundred and ninety-nine metal accessories were tested with the dimethylglyoxime (DMG) test. RESULTS: 'Metal dermatitis' was reported by 19.4% of females and 0.5% of males. Positive patch test reactions were found in 8.5% of the adolescents (12.9% in females; 2.3% in males), namely to: nickel (12.3% of females; 1.4% of males); palladium (5.2% of females; 0.5% of males); cobalt (3.2% of females; 1.4% of males); and chromium (1.3% of females; 0.9% of males). Allergic contact dermatitis caused by metals was diagnosed in 9.7% of females and in 0.5% of males. Of the metal items, 26.1% gave positive DMG test results: 10.0% of earrings, 11.4% of snaps, and 56.2% of belt buckles. CONCLUSIONS: Despite the implementation of the Nickel Directive in Poland, nickel still remains an important causal factor for allergic contact dermatitis. Numerous metal accessories do not comply with the Directive. PMID- 22428586 TI - Mapping microclimate pH distribution inside protein-encapsulated PLGA microspheres using confocal laser scanning microscopy. AB - The pH in the aqueous pores of poly(lactide-co-glycolide) (PLGA) matrix, also referred to as microclimate pH (MUpH), is often uncontrolled, ranging from highly acidic to neutral pH range. The MUpH distribution inside protein-encapsulated PLGA microspheres was quantitatively evaluated using confocal laser scanning microscopy. The fluorescent response of Lysosensor yellow/blue dextran used to map MUpH in PLGA was influenced by the presence of encapsulated protein. The nonprotonated form of pyridyl group on the fluorescence probe at neutral pH was responsible for the interference, which was dependent on the type and concentration of protein. A method for correction of this interference based on estimating protein concentration inside the microspheres was established and validated. After correction of the influence, the MUpH distribution kinetics inside microspheres was evaluated for different PLGA 50/50 microsphere formulations under physiological conditions for 4 weeks. Generally, the MUpH acidity increased with the progression of incubation time. The coincorporation of poorly soluble base, magnesium carbonate, in the microspheres prolonged the appearance of detectable acidity for up to 3 weeks. Co-addition of an acetate buffer was able to control the MUpH over a slightly acidic range (around pH 4.7) after two week incubation. Microspheres prepared from a lower polymer concentration exhibited a higher MUpH, likely owing to reduced diffusional resistance to acidic degradation products. The stability of protein was enhanced by addition of MgCO(3), acetate buffer, or by reduced polymer concentration in the preparation, as evidenced by more soluble protein recovered after incubation. Hence, the MUpH imaging technique developed can be employed in the future for optimization of formulation strategies for controlling MUpH and stabilizing encapsulated proteins. PMID- 22428587 TI - Highly efficient synthesis and antitumor activity of monosaccharide saponins mimicking components of Chinese folk medicine Cordyceps sinensis. AB - Ergosterol 3-O-beta-D-glucopyranoside (1a) and ergosterol 3-O-beta-D galactopyranoside (1b) were highly efficiently synthesized and evaluated for their inhibitory activities against two tumor cell lines. The structures of these compounds were extensively confirmed by (1)H, (13)C NMR, IR, and HRMS. Compounds 1a and 1b exhibited interesting cytotoxic profiles. The antitumor activity of compound 1a was higher than that of 1b. PMID- 22428588 TI - Effectiveness of combining plasma exchange with continuous hemodiafiltration on acute Fatty liver of pregnancy complicated by multiple organ dysfunction. AB - Acute fatty liver of pregnancy (AFLP) is a rare disease of progressive hepatic insufficiency and secondary systemic complications that induce significant maternal risk. The application of combining plasma exchange (PE) and continuous hemodiafiltration (CHDF) is a novel concept for patients with AFLP. Since 2002, we have utilized the combination of PE with CHDF as adjunctive medical therapy for 11 AFLP patients with multiple organ dysfunction. Before PE and CHDF initiation, four patients had signs and symptoms of encephalopathy, four required ventilatory support, and all 11 were developing liver failure, significant renal compromise, and coagulopathy. PE combined with CHDF for patients was initiated a mean of 2 days postpartum (range, days 0-3). Daily or every other day PE combined with CHDF was undertaken on two to eight occasions for each of the 11 patients. Ten patients responded with composite clinical and laboratory improvement and were discharged to the ward, then cured and discharged from hospital; one patient died of septic shock. Average duration of hospitalization was 17 days (range, days 9-38) from time of admission to discharge; the average duration of intensive care unit was 10 days (range, days 4-23). No significant PE- and CHDF-related complications occurred. These results indicate that combing PE and CHDF in a series-parallel circuit is an effective and safe treatment for patients with severe AFLP. This finding may have important implications for the development of an effective treatment for patients with AFLP suffering multiple organ dysfunction. PMID- 22428589 TI - Proteomic analysis of endothelial lipid rafts reveals a novel role of statins in antioxidation. AB - As inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins have pleiotropic vascular-protective effects, such as anti-inflammatory and antioxidative effects. We investigated the short-term beneficial effects of statins on modulating the translocation of lipid-raft-related proteins in endothelial cells (ECs). Human umbilical vein ECs were treated with atorvastatin for 30 min or 2 h; lipid-raft proteins were isolated and examined by quantitative proteome assay. Functional classification of identified proteins in lipid rafts revealed upregulated antioxidative proteins; downregulated proteins were associated with inflammation and cell adhesion. Among proteins verified by Western blot analysis, endoplasmic reticulum protein 46 (ERp46) showed increased level in lipid rafts with atorvastatin. Further, atorvastatin inhibited the activation of membrane-bound NADPH oxidase in both untreated and angiotensin II treated ECs, as shown by reduced reactive oxygen species production. Co immunoprecipitation and immunofluorescence experiments revealed that atorvastatin increased the association of ERp46 and Nox2, an NADPH oxidase isoform, in lipid rafts, thereby inhibiting Nox2 assembly with its regulatory subunits, such as p47phox and p67phox. Our results reveal a novel antioxidative role of atorvastatin by promoting the membrane translocation of ERp46 and its binding with Nox2 to inhibit Nox2 activity in ECs, which may offer another insight into the pleiotropic functions of statins. PMID- 22428590 TI - A neurocomputational approach to prepositional phrase attachment ambiguity resolution. AB - A neurocomputational model based on emergent massively overlapping neural cell assemblies (CAs) for resolving prepositional phrase (PP) attachment ambiguity is described. PP attachment ambiguity is a well-studied task in natural language processing and is a case where semantics is used to determine the syntactic structure. A large network of biologically plausible fatiguing leaky integrate and-fire neurons is trained with semantic hierarchies (obtained from WordNet) on sentences with PP attachment ambiguity extracted from the Penn Treebank corpus. During training, overlapping CAs representing semantic similarities between the component words of the ambiguous sentences emerge and then act as categorizers for novel input. The resulting average resolution accuracy of 84.56% is on par with known machine learning algorithms. PMID- 22428591 TI - Dynamic state and parameter estimation applied to neuromorphic systems. AB - Neuroscientists often propose detailed computational models to probe the properties of the neural systems they study. With the advent of neuromorphic engineering, there is an increasing number of hardware electronic analogs of biological neural systems being proposed as well. However, for both biological and hardware systems, it is often difficult to estimate the parameters of the model so that they are meaningful to the experimental system under study, especially when these models involve a large number of states and parameters that cannot be simultaneously measured. We have developed a procedure to solve this problem in the context of interacting neural populations using a recently developed dynamic state and parameter estimation (DSPE) technique. This technique uses synchronization as a tool for dynamically coupling experimentally measured data to its corresponding model to determine its parameters and internal state variables. Typically experimental data are obtained from the biological neural system and the model is simulated in software; here we show that this technique is also efficient in validating proposed network models for neuromorphic spike based very large-scale integration (VLSI) chips and that it is able to systematically extract network parameters such as synaptic weights, time constants, and other variables that are not accessible by direct observation. Our results suggest that this method can become a very useful tool for model-based identification and configuration of neuromorphic multichip VLSI systems. PMID- 22428592 TI - Variation in the local motion statistics of real-life optic flow scenes. AB - Optic flow motion patterns can be a rich source of information about our own movement and about the structure of the environment we are moving in. We investigate the information available to the brain under real operating conditions by analyzing video sequences generated by physically moving a camera through various typical human environments. We consider to what extent the motion signal maps generated by a biologically plausible, two-dimensional array of correlation-based motion detectors (2DMD) not only depend on egomotion, but also reflect the spatial setup of such environments. We analyzed the local motion outputs by extracting the relative amounts of detected directions and comparing the spatial distribution of the motion signals to that of idealized optic flow. Using a simple template matching estimation technique, we are able to extract the focus of expansion and find relatively small errors that are distributed in characteristic patterns in different scenes. This shows that all types of scenes provide suitable motion information for extracting ego motion despite the substantial levels of noise affecting the motion signal distributions, attributed to the sparse nature of optic flow and the presence of camera jitter. However, there are large differences in the shape of the direction distributions between different types of scenes; in particular, man-made office scenes are heavily dominated by directions in the cardinal axes, which is much less apparent in outdoor forest scenes. Further examination of motion magnitudes at different scales and the location of motion information in a scene revealed different patterns across different scene categories. This suggests that self-motion patterns are not only relevant for deducing heading direction and speed but also provide a rich information source for scene structure and could be important for the rapid formation of the gist of a scene under normal human locomotion. PMID- 22428593 TI - Identification of directed influence: Granger causality, Kullback-Leibler divergence, and complexity. AB - Detecting and characterizing causal interdependencies and couplings between different activated brain areas from functional neuroimage time series measurements of their activity constitutes a significant step toward understanding the process of brain functions. In this letter, we make the simple point that all current statistics used to make inferences about directed influences in functional neuroimage time series are variants of the same underlying quantity. This includes directed transfer entropy, transinformation, Kullback-Leibler formulations, conditional mutual information, and Granger causality. Crucially, in the case of autoregressive modeling, the underlying quantity is the likelihood ratio that compares models with and without directed influences from the past when modeling the influence of one time series on another. This framework is also used to derive the relation between these measures of directed influence and the complexity or the order of directed influence. These results provide a framework for unifying the Kullback-Leibler divergence, Granger causality, and the complexity of directed influence. PMID- 22428594 TI - Fisher and Shannon information in finite neural populations. AB - The precision of the neural code is commonly investigated using two families of statistical measures: Shannon mutual information and derived quantities when investigating very small populations of neurons and Fisher information when studying large populations. These statistical tools are no longer the preserve of theorists and are being applied by experimental research groups in the analysis of empirical data. Although the relationship between information-theoretic and Fisher-based measures in the limit of infinite populations is relatively well understood, how these measures compare in finite-size populations has not yet been systematically explored. We aim to close this gap. We are particularly interested in understanding which stimuli are best encoded by a given neuron within a population and how this depends on the chosen measure. We use a novel Monte Carlo approach to compute a stimulus-specific decomposition of the mutual information (the SSI) for populations of up to 256 neurons and show that Fisher information can be used to accurately estimate both mutual information and SSI for populations of the order of 100 neurons, even in the presence of biologically realistic variability, noise correlations, and experimentally relevant integration times. According to both measures, the stimuli that are best encoded are those falling at the flanks of the neuron's tuning curve. In populations of fewer than around 50 neurons, however, Fisher information can be misleading. PMID- 22428595 TI - Simple deterministically constructed cycle reservoirs with regular jumps. AB - A new class of state-space models, reservoir models, with a fixed state transition structure (the "reservoir") and an adaptable readout from the state space, has recently emerged as a way for time series processing and modeling. Echo state network (ESN) is one of the simplest, yet powerful, reservoir models. ESN models are generally constructed in a randomized manner. In our previous study (Rodan & Tino, 2011), we showed that a very simple, cyclic, deterministically generated reservoir can yield performance competitive with standard ESN. In this contribution, we extend our previous study in three aspects. First, we introduce a novel simple deterministic reservoir model, cycle reservoir with jumps (CRJ), with highly constrained weight values, that has superior performance to standard ESN on a variety of temporal tasks of different origin and characteristics. Second, we elaborate on the possible link between reservoir characterizations, such as eigenvalue distribution of the reservoir matrix or pseudo-Lyapunov exponent of the input-driven reservoir dynamics, and the model performance. It has been suggested that a uniform coverage of the unit disk by such eigenvalues can lead to superior model performance. We show that despite highly constrained eigenvalue distribution, CRJ consistently outperforms ESN (which has much more uniform eigenvalue coverage of the unit disk). Also, unlike in the case of ESN, pseudo-Lyapunov exponents of the selected optimal CRJ models are consistently negative. Third, we present a new framework for determining the short-term memory capacity of linear reservoir models to a high degree of precision. Using the framework, we study the effect of shortcut connections in the CRJ reservoir topology on its memory capacity. PMID- 22428596 TI - Conditional association. AB - Estimating conditional dependence between two random variables given the knowledge of a third random variable is essential in neuroscientific applications to understand the causal architecture of a distributed network. However, existing methods of assessing conditional dependence, such as the conditional mutual information, are computationally expensive, involve free parameters, and are difficult to understand in the context of realizations. In this letter, we discuss a novel approach to this problem and develop a computationally simple and parameter-free estimator. The difference between the proposed approach and the existing ones is that the former expresses conditional dependence in terms of a finite set of realizations, whereas the latter use random variables, which are not available in practice. We call this approach conditional association, since it is based on a generalization of the concept of association to arbitrary metric spaces. We also discuss a novel and computationally efficient approach of generating surrogate data for evaluating the significance of the acquired association value. PMID- 22428598 TI - Neural information processing with feedback modulations. AB - Descending feedback connections, together with ascending feedforward ones, are the indispensable parts of the sensory pathways in the central nervous system. This study investigates the potential roles of feedback interactions in neural information processing. We consider a two-layer continuous attractor neural network (CANN), in which neurons in the first layer receive feedback inputs from those in the second one. By utilizing the intrinsic property of a CANN, we use a projection method to reduce the dimensionality of the network dynamics significantly. The simplified dynamics allows us to elucidate the effects of feedback modulation analytically. We find that positive feedback enhances the stability of the network state, leading to an improved population decoding performance, whereas negative feedback increases the mobility of the network state, inducing spontaneously moving bumps. For strong, negative feedback interaction, the network response to a moving stimulus can lead the actual stimulus position, achieving an anticipative behavior. The biological implications of these findings are discussed. The simulation results agree well with our theoretical analysis. PMID- 22428600 TI - The disordered N-terminal region of dengue virus capsid protein contains a lipid droplet-binding motif. AB - Dengue is the major arthropod-borne human viral disease, for which no vaccine or specific treatment is available. We used NMR, zeta potential measurements and atomic force microscopy to study the structural features of the interaction between dengue virus C (capsid) protein and LDs (lipid droplets), organelles crucial for infectious particle formation. C protein-binding sites to LD were mapped, revealing a new function for a conserved segment in the N-terminal disordered region and indicating that conformational selection is involved in recognition. The results suggest that the positively charged N-terminal region of C protein prompts the interaction with negatively charged LDs, after which a conformational rearrangement enables the access of the central hydrophobic patch to the LD surface. Taken together, the results allowed the design of a peptide with inhibitory activity of C protein-LD binding, paving the way for new drug development approaches against dengue. PMID- 22428601 TI - True volumetric method for flow cytometric enumeration of CD34 + stem cells and its agreement with a standard bead-based single-platform protocol. AB - BACKGROUND AIMS: Stem cells are commonly enumerated with bead-based methods in blood and marrow progenitor cell transplantation centers. We compared the International Society of Hematotherapy and Graft Engineering (ISHAGE) bead-based method with a true volumetric one that obviates the use of fluorescent beads for enumeration. METHODS: From 31 samples, including 15 peripheral blood samples and 16 leukapheresis products, CD34 (+) cells were enumerated with the single platform bead-based ISHAGE method and a true volumetric method. After exclusion of two outliers, one from the peripheral blood group and the other from the leukapheresis group, the results were compared. RESULTS: In the peripheral blood category, no significant difference was observed. However, a proportional systematic error was seen in the leukapheresis group. The systematic error was corrected in the leukapheresis group using a regression line equation. The 95% confidence interval of differences was [-5.83, 2.18] for the peripheral blood and [-38.40, 38.77] for the leukapheresis group after correction of the systematic error. CONCLUSIONS: The true volumetric method is a simple and reliable approach that can be used instead of the more popular bead-based procedures. PMID- 22428602 TI - Preparation of water-soluble maleimide-functionalized 3 nm gold nanoparticles: a new bioconjugation template. AB - We present an efficient methodology to prepare maleimide-tethered, water-soluble gold nanoparticles (maleimide-AuNPs). The maleimide-AuNPs were prepared in the protected form and are readily recovered via a retro-Diels-Alder reaction. The maleimide-AuNPs were fully characterized by (1)H NMR, TGA, TEM, and XPS and were determined to have a gold core with an average size of 3.2 +/- 0.8 nm; each core contains about 1000 gold atoms and is surrounded by 30 maleimide-terminated ligands and 60 thiolated PEG ligands. The maleimide-AuNPs efficiently react with rhodamine 123 and cysteine and are a promising template for biological applications. PMID- 22428603 TI - Exhaled nitric oxide and atherosclerosis. AB - BACKGROUND: Fractional exhaled nitric oxide concentration (FENO) measurement has been proposed to be an important adjunct in the diagnosis and management of asthma, pulmonary hypertension and cystic fibrosis. But do we understand how other diseases influence the FENO values? In particular, atherosclerosis is one of the pathological conditions, in which nitric oxide (NO) production is inhibited and its degradation enhanced. Therefore, hypothesis of the current study was that FENO is inversely associated with risk markers of atherosclerosis and with diseases leading secondarily to the progression of atherosclerosis. MATERIALS AND METHODS: A long-term FENO value (median of biweekly measurements over a 24-week period) of 53 patients with ischaemic heart disease (IHD) was compared with the results of clinical and biochemical analyses. RESULTS: Fractional exhaled NO was inversely associated with the plasma concentration of triglycerides (P = 0.01) and with the blood concentration of glycated haemoglobin A1c (P = 0.03). It also tended to be inversely associated with the plasma glucose concentration (P = 0.10). However, there were no statistically significant associations with inflammatory or other biochemical markers, health status, lifestyle or other personal determinants. CONCLUSIONS: In accordance with the hypothesis, FENO is inversely associated with some of risk markers of atherosclerosis in patients with stable IHD (triglycerides and haemoglobin A1c, a marker of hyperglycaemic metabolism). A potential explanation is that, at hyperglycaemia and with higher triglyceride concentrations, atherosclerosis leads to endothelial dysfunction and, subsequently, to decreased production and increased degradation of NO. PMID- 22428604 TI - Diacetyl exposure at a food flavoring production facility. PMID- 22428605 TI - The impact of ulcerative colitis on the long-term outcome of patients with primary sclerosing cholangitis. AB - BACKGROUND: The impact of ulcerative colitis (UC) on the outcome of primary sclerosing cholangitis (PSC) outcome remains unclear. AIM: To investigate whether the presence of UC is associated with a worse clinical of associated PSC. METHODS: A total of 222 patients with PSC (167 with UC and 55 without UC) seen and followed at a single centre from 1985 to 2011 were included. Clinical and demographic variables were obtained and patients were followed until the date of their last clinic visit. RESULTS: The median age at presentation of PSC with associated UC was 38 vs. 47 years without UC (P < 0.001). At presentation, median serum bilirubin (2.1 vs. 4.5, P < 0.001) and the Mayo PSC Risk Score (0.95 vs. 1.69, P < 0.001) were lower in those with UC vs. those without UC. A total of 55 of 167 (32.9%) patients with PSC-UC developed colon neoplasia in contrast to 1 of the 55 (1.8%) patients with PSC. (P < 0.001) On proportional hazards analysis, UC (hazard ratio (HR) = 0.90 [95% confidence interval (CI): 0.60-1.34, P = 0.60] was not associated with death or orthotopic liver transplantation (OLT), when adjusting for gender, Mayo risk score and year of PSC diagnosis; whereas the revised Mayo risk score [HR = 5.08, 95% CI: (2.62-9.86), P < 0.001] was associated with a greater risk of OLT or death. CONCLUSIONS: Primary sclerosing cholangitis often is recognised at an early stage in patients with concurrent ulcerative colitis; ulcerative colitis has no impact on long-term prognosis in terms of liver-related outcomes when adjusted for the severity of liver disease. PMID- 22428606 TI - Mechanisms of calpain mediated proteolysis of voltage gated sodium channel alpha subunits following in vitro dynamic stretch injury. AB - Although enhanced calpain activity is well documented after traumatic brain injury (TBI), the pathways targeting specific substrate proteolysis are less defined. Our past work demonstrated that calpain cleaves voltage gated sodium channel (NaCh) alpha-subunits in an in vitro TBI model. In this study, we investigated the pathways leading to NaCh cleavage utilizing our previously characterized in vitro TBI model, and determined the location of calpain activation within neuronal regions following stretch injury to micropatterned cultures. Calpain specific breakdown products of alpha-spectrin appeared within axonal, dendritic, and somatic regions 6 h after injury, concurrent with the appearance of NaCh alpha-subunit proteolysis in both whole cell or enriched axonal preparations. Direct pharmacological activation of either NMDA receptors (NMDArs) or NaChs resulted in NaCh proteolysis. Likewise, a chronic (6 h) dual inhibition of NMDArs/NaChs but not L-type voltage gated calcium channels significantly reduced NaCh proteolysis 6 h after mechanical injury. Interestingly, an early, transient (30 min) inhibition of NMDArs alone significantly reduced NaCh proteolysis. Although a chronic inhibition of calpain significantly reduced proteolysis, a transient inhibition of calpain immediately after injury failed to significantly attenuate NaCh proteolysis. These data suggest that both NMDArs and NaChs are key contributors to calpain activation after mechanical injury, and that a larger temporal window of sustained calpain activation needs consideration in developing effective treatments for TBI. PMID- 22428607 TI - Safety and efficacy of targeting platelet proteinase-activated receptors in combination with existing anti-platelet drugs as antithrombotics in mice. AB - BACKGROUND AND PURPOSE: Developing novel anti-platelet strategies is fundamental to reducing the impact of thrombotic diseases. Thrombin activates platelets via proteinase-activated receptors (PARs), and PAR antagonists are being evaluated in clinical trials for prevention of arterial thrombosis. However, one such trial was recently suspended due to increased bleeding in patients receiving a PAR1 antagonist in addition to anti-platelet drugs that most often included both aspirin and clopidogrel. Therefore, it remains unclear how to best manipulate PARs for safe antithrombotic activity. To address this, we have examined potential interactions between existing anti-platelet drugs and strategies that target PARs. EXPERIMENTAL APPROACH: We used in vivo mouse models in which interactions between various anti-platelet strategies could be evaluated. We examined the effects on thrombosis and haemostasis in PAR4 -/- mice (platelets unresponsive to thrombin) treated with therapeutic doses of either aspirin or clopidogrel. KEY RESULTS: Using a model in which occlusive thrombosis occurred in PAR4 -/- mice or wild-type mice treated with aspirin or clopidogrel, PAR4 -/- mice treated with either anti-platelet agent showed marked protection against thrombosis. This antithrombotic effect occurred without any effect on haemostasis with aspirin, but not clopidogrel. Furthermore, specifically targeting thrombin induced platelet activation (via PARs) improved the therapeutic window of non specifically inhibiting thrombin functions (via anticoagulants). CONCLUSIONS AND IMPLICATIONS: Our results indicate that PAR antagonists used in combination with aspirin provide a potent yet safe antithrombotic strategy in mice and provide insights into the safety and efficacy of using PAR antagonists for the prevention of acute coronary syndromes in humans. PMID- 22428608 TI - Would corrected QT dispersion predict left ventricular hypertrophy in hypertensive patients? AB - AIMS: We explored whether QT corrected dispersion (QTcD) can identify left ventricular hypertrophy (LVH) in hypertensives. METHODS: We enrolled 100 hypertensive patients (study group) and 30 normotensive subjects (control group). Echocardiography was performed to measure left ventricular mass and left ventricular mass index. Electrocardiogram was performed to measure QTcD. RESULTS: LVH was present in 42 patients (42%) of the study group, none among controls. Hypertensive patients had significantly greater indices of LVH and QTcD compared with controls (p <0.001 for all). Similarly, among hypertensive patients, those with LVH had a significantly greater QTcD compared with those without (p <0.001). Pearson's correlation coefficient test demonstrated strongly positive correlations between QTcD and the indices of LVH (p <0.001 for all). Analysis of the receiver operating characteristic curves identified 60 ms as the optimal cut off value of QTcD that best predicts LVH in hypertensives. Using this value, QTcD was able to predict LVH with a sensitivity of 92.9% and specificity 98.2%. CONCLUSIONS: QTcD is significantly increased in hypertensive patients with LVH compared with those without, being strongly correlated with the indices of LVH. A QTcD cut-off value of 60 ms predicted LVH in hypertensive patients with a high sensitivity and specificity. PMID- 22428609 TI - Exhaustive syntheses of naphthofluoresceins and their functions. AB - Naphthofluorescein and/or seminaphthofluorescein derivatives possessing the additional benzene units to one or both sides of fluorescein were exhaustively constructed through Friedel-Crafts type reactions between corresponding aroylbenzoic acids and dihydroxynaphthalenes. Compound 4 works as a one-dye pH indicator, which shows red in strong acid condition and blue in basic solution. Compound 23 (diacetate of compound 4) shows good transitivity to the HEK 293 cells and acts as a fluorescent pigment for the living cell imaging. Compounds 5, 6, and 9 show fluorescent emission in the NIR region (>700 nm) and imply the potentialities of NIR fluorescent probes. PMID- 22428610 TI - Belimumab: a guide to its use in systemic lupus erythematosus. AB - Belimumab (Benlysta(r)), a fully human recombinant IgG1lambda monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells, is indicated for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity despite receiving standard therapy. In multinational trials, significantly more belimumab recipients than placebo recipients achieved an SLE Responder Index response at 52 weeks. PMID- 22428611 TI - Exposure and kinetics of polycyclic aromatic hydrocarbons (PAHs) in cigarette smokers. AB - Our study objectives were (1) to investigate the selectivity of polycyclic aromatic hydrocarbon (PAH) metabolites for tobacco smoke exposure and (2) to determine half-lives of PAH metabolites in smokers. There were 622 participants from the United States (US) and Poland, and of these, 70% were smokers. All subjects provided spot urine samples, and 125 smokers provided blood samples. Urinary PAH metabolite half-lives were determined in 8 smokers. In controlled hospital studies of 18 smokers, the associations between various measures of nicotine intake and urinary excretion of PAH metabolites were investigated. Plasma nicotine was measured by GC. LC-MS/MS was used to measure the plasma levels of cotinine and trans-3'-hydroxycotinine, and urine levels of nicotine and its metabolites, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and PAH metabolites (2-naphthol, 1-, 2-, and 3-hydroxyfluorenes, 1-, 2-, 3-, and 4 hydroxyphenanthrenes, and 1-hydroxypyrene). Regardless of smoking status, PAH metabolite excretion was higher in Polish subjects than in US subjects (p-values <0.001). 1-Hydroxyfluorene exhibited the greatest difference between smokers and nonsmokers, with a 5-fold difference in Polish subjects and a 25-fold difference in US subjects, followed by 3- and 2-hydroxyfluorenes, 2-naphthol, and 1 hydroxypyrene. The differences for hydroxyphenanthrenes were small or nonsignificant. 1-Hydroxyfluorene had the highest correlation with urine nicotine equivalents (r = 0.77) and urine NNAL (r = 0.64). While the half-lives of PAH metabolites were <10 h in smokers, 1-hydroxyfluorene had the largest ratio of initial to terminal urine concentration (58.4 +/- 38.6, mean +/- SD) after smoking. Receiver Operating Characteristic (ROC) analysis of PAHs among Polish and US subjects further showed that hydroxyfluorenes are most highly discriminative of smokers from nonsmokers followed by 2-naphthol and 1 hydroxypyrene. In conclusion, hydroxyfluorenes, particularly 1-hydroxyfluorene, and 2-naphthol are more selective of tobacco smoke than 1-hydroxypyrene and hydroxyphenanthrenes. Characterization of hydroxyfluorene and 2-naphthol metabolites in urine may improve the characterization of PAHs from tobacco smoke and related disease risks among smokers and nonsmokers. PMID- 22428612 TI - Contextual modulation of mirror and countermirror sensorimotor associations. AB - Automatic imitation-the unintended copying of observed actions-is thought to be a behavioral product of the mirror neuron system (MNS). Evidence that the MNS develops through associative learning comes from previous research showing that automatic imitation is attenuated by countermirror training, in which the observation of one action is paired contingently with the execution of a different action. If the associative account of the MNS is correct, countermirror training should show context specificity, because countermirror associations render action stimuli ambiguous, and ambiguity promotes contextual control. Two experiments that confirm this prediction are reported. In Experiment 1 we found less residual automatic imitation when human participants were tested in their countermirror training context. In Experiment 2, sensorimotor training where participants made action responses to novel abstract stimuli was insensitive to the same context manipulation, confirming that the former result was not a procedural artifact. Contextual modulation may enable the MNS to function effectively in spite of the fact that action observation often excites multiple conflicting MNS responses. PMID- 22428613 TI - When does a good working memory counteract proactive interference? Surprising evidence from a probe recognition task. AB - It is often proposed that individuals with high working memory span overcome proactive interference (PI) from previous trials, saving working memory for task relevant items. We examined this hypothesis in word-list probe recognition. We found no difference in PI related to span. Instead, ex-gaussian analysis of reaction time showed speed advantages for high spans specific to short lists (3 or 4 items) but absent from longer lists (6 or 8 items). We suggest that high span advantages in reaction time are based on finesse during easy trials, not on overcoming PI. PMID- 22428614 TI - Silver-mediated oxidative C-H/C-H functionalization: a strategy to construct polysubstituted furans. AB - A novel silver-mediated highly selective oxidative C-H/C-H functionalization of 1,3-dicarbonyl compounds with terminal alkynes for the creation of polysubstituted furans and pyrroles in one step has been demonstrated. Promoted by the crucial silver species, perfect selectivity and good to excellent yields could be achieved. This protocol represents an extremely simple and atom-economic way to construct polysubstituted furans and pyrroles from basic starting materials under mild conditions. PMID- 22428615 TI - The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro. AB - BACKGROUND AND PURPOSE: Clopidogrel is a prodrug bioactivated by cytochrome P450s (CYPs). More recently, paraoxonase-1 (PON1) has been proposed as a major contributor to clopidogrel metabolism. The purpose of this study was to assess the relative contribution of CYPs and PON1 to clopidogrel metabolism in vitro. EXPERIMENTAL APPROACH: Clopidogrel metabolism was studied in human serum, recombinant PON1 enzyme (rePON1), pooled human liver microsomes (HLMs), HLMs with the CYP2C19*1/*1 genotype and HLMs with the CYP2C19*2/*2 genotype. Inhibition studies were also performed using specific CYP inhibitors and antibodies. Clopidogrel and its metabolites were measured using LC/MS/MS method. KEY RESULTS: PON1 activity was highest in the human serum and there was no difference in PON1 activity between any of the HLM groups. The production of clopidogrel's active metabolite (clopidogrel-AM) from 2-oxo-clopidogrel in pooled HLMs was approximately 500 times that in serum. When 2-oxo-clopidogrel was incubated with rePON1, clopidogrel-AM was not detected. Clopidogrel-AM production from 2-oxo clopidogrel was lower in CYP2C19*2/*2 HLMs compared with CYP2C19*1/*1 HLMs, while PON1 activity in HLMs with both genotypes was similar. Moreover, incubation with inhibitors of CYP3A, CYP2B6 and CYP2C19 significantly reduced clopidogrel bioactivation while a PON1 inhibitor, EDTA, had only a weak inhibitory effect. CONCLUSION AND IMPLICATIONS: This in vitro study shows that the contribution of PON1 to clopidogrel metabolism is limited at clinically relevant concentrations. Moreover, CYP2C19, CYP2B6 and CYP3A play important roles in the bioactivation of clopidogrel. PMID- 22428616 TI - Neurotrophic effect of bone marrow mesenchymal stem cells for erectile dysfunction in diabetic rats. AB - It has been demonstrated that intracavernous injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) had beneficial effects on improving erectile function in type-1 diabetic rats. This study was designed to investigate the neurotrophic effect of BM-MSCs for type-1 diabetic rats. Streptozocin-induced type-1 diabetic rats were randomly divided into three groups: diabetic group, BM MSCs-treated group and BM-MSCs-conditioned medium-treated group. At the 3d, 1 and 2w time points after BM-MSCs injection, three randomly selected rats in MSCs group were sacrificed and penile samples were harvested to detect BM-MSCs in penile tissue. Four weeks after intracavernous injection of BM-MSCs or BM-MSCs conditioned medium, intracavernous pressure (ICP) was assessed to evaluate the erectile function. Immunohistochemistry was used to track labelled BM-MSCs in penile tissue and to detect neuronal nitric oxide synthase (nNOS) and neurofilament (NF) positive fibres in penile dorsal nerve. Enzyme lined immunosorbent assay (ELISA) was used to measure the concentrations of vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in BM-MSCs-conditioned medium. BM- MSCs secreted detectable levels of VEGF, BDNF and NGF. Intracavernous injection of BM-MSCs improved erectile function in diabetic rats. The functional improvement was accompanied by promoted nNOS and NF positive nerve fibres within penile dorsal nerve in type-1 diabetic rats. Histological data revealed a time-dependent decrease in the number of BM-MSCs in the corpus cavernosum following injection. Furthermore, the beneficial effect of BM-MSCs was partially repeated by BM-MSCs conditioned medium. Intracavernous injection of BM-MSCs is effective in improving nerve regeneration in diabetic rats. Paracrine effects of BM-MSCs are probably involved in the improvement. PMID- 22428617 TI - Involvement of TSSA (trypomastigote small surface antigen) in Trypanosoma cruzi invasion of mammalian cells. AB - TSSA (trypomastigote small surface antigen) is a polymorphic mucin-like molecule displayed on the surface of Trypanosoma cruzi trypomastigote forms. To evaluate its functional properties, we undertook comparative biochemical and genetic approaches on isoforms present in parasite stocks from extant evolutionary lineages (CL Brener and Sylvio X-10). We show that CL Brener TSSA, but not the Sylvio X-10 counterpart, exhibits dose-dependent and saturable binding towards non-macrophagic cell lines. This binding triggers Ca(2+)-based signalling responses in the target cell while providing an anchor for the invading parasite. Accordingly, exogenous addition of either TSSA-derived peptides or specific antibodies significantly inhibits invasion of CL Brener, but not Sylvio X-10, trypomastigotes. Non-infective epimastigote forms, which do not express detectable levels of TSSA, were stably transfected with TSSA cDNA from either parasite stock. Although both transfectants produced a surface-associated mucin like TSSA product, epimastigotes expressing CL Brener TSSA showed a ~2-fold increase in their attachment to mammalian cells. Overall, these findings indicate that CL Brener TSSA functions as a parasite adhesin, engaging surface receptor(s) and inducing signalling pathways on the host cell as a prerequisite for parasite internalization. More importantly, the contrasting functional features of TSSA isoforms provide one appealing mechanism underlying the differential infectivity of T. cruzi stocks. PMID- 22428618 TI - Rate of oxygen isotope exchange between selenate and water. AB - The rate of oxygen isotope exchange between selenate and water was investigated at conditions of 10 to 80 degrees C and pH -0.6 to 4.4. Oxygen isotope exchange proceeds as a first-order reaction, and the exchange rate is strongly affected by reaction temperature and pH, with increased rates of isotope exchange at higher temperature and lower pH. Selenate speciation (HSeO(4)(-) vs SeO(4)(2-)) also has a significant effect on the rate of isotope exchange. The half-life for isotope exchange at example natural conditions (25 degrees C and pH 7) is estimated to be significantly in excess of 10(6) years. The very slow rate of oxygen isotope exchange between selenate and water under most environmental conditions demonstrates that selenate-delta(18)O signatures produced by biogeochemical processes will be preserved and hence that it will be possible to use the value of selenate-delta(18)O to investigate the biogeochemical behavior of selenate, in an analogous fashion to the use of sulfate-delta(18)O to study the biogeochemical behavior of sulfate. PMID- 22428619 TI - Mesoporous nanostructured Nb-doped titanium dioxide microsphere catalyst supports for PEM fuel cell electrodes. AB - Crystalline microspheres of Nb-doped TiO(2) with a high specific surface area were synthesized using a templating method exploiting ionic interactions between nascent inorganic components and an ionomer template. The microspheres exhibit a porosity gradient, with a meso-macroporous kernel, and a mesoporous shell. The material has been investigated as cathode electrocatalyst support for polymer electrolyte membrane (PEM) fuel cells. A uniform dispersion of Pt particles on the Nb-doped TiO(2) support was obtained using a microwave method, and the electrochemical properties assessed by cyclic voltammetry. Nb-TiO(2) supported Pt demonstrated very high stability, as after 1000 voltammetric cycles, 85% of the electroactive Pt area remained compared to 47% in the case of commercial Pt on carbon. For the oxygen reduction reaction (ORR), which takes place at the cathode, the highest stability was again obtained with the Nb-doped titania-based material even though the mass activity calculated at 0.9 V vs RHE was slightly lower. The microspherical structured and mesoporous Nb-doped TiO(2) is an alternative support to carbon for PEM fuel cells. PMID- 22428621 TI - Continuous glucose monitoring--a study of the Enlite sensor during hypo- and hyperbaric conditions. AB - BACKGROUND: The performance and accuracy of the Enlite(TM) (Medtronic, Inc., Northridge, CA) sensor may be affected by microbubble formation at the electrode surface during hypo- and hyperbaric conditions. The effects of acute pressure changes and of prewetting of sensors were investigated. MATERIALS AND METHODS: On Day 1, 24 sensors were inserted on the right side of the abdomen and back in one healthy individual; 12 were prewetted with saline solution, and 12 were inserted dry. On Day 2, this procedure was repeated on the left side. All sensors were attached to an iPro continuous glucose monitoring (CGM) recorder. Hypobaric and hyperbaric tests were conducted in a pressure chamber, with each test lasting 105 min. Plasma glucose values were obtained at 5-min intervals with a HemoCue((r)) (Angelholm, Sweden) model 201 glucose analyzer for comparison with sensor glucose values. RESULTS: Ninety percent of the CGM systems operated during the tests. The mean absolute relative difference was lower during hyperbaric than hypobaric conditions (6.7% vs. 14.9%, P<0.001). Sensor sensitivity was slightly decreased (P<0.05) during hypobaric but not during hyperbaric conditions. Clarke Error Grid Analysis showed that 100% of the values were found in the A+B region. No differences were found between prewetted and dry sensors. CONCLUSIONS: The Enlite sensor performed adequately during acute pressure changes and was more accurate during hyperbaric than hypobaric conditions. Prewetting the sensors did not improve accuracy. Further studies on type 1 diabetes subjects are needed under various pressure conditions. PMID- 22428620 TI - Controlling the surface chemistry of graphite by engineered self-assembled peptides. AB - The systematic control over surface chemistry is a long-standing challenge in biomedical and nanotechnological applications for graphitic materials. As a novel approach, we utilize graphite-binding dodecapeptides that self-assemble into dense domains to form monolayer-thick long-range-ordered films on graphite. Specifically, the peptides are rationally designed through their amino acid sequences to predictably display hydrophilic and hydrophobic characteristics while maintaining their self-assembly capabilities on the solid substrate. The peptides are observed to maintain a high tolerance for sequence modification, allowing control over surface chemistry via their amino acid sequence. Furthermore, through a single-step coassembly of two differently designed peptides, we predictably and precisely tune the wettability of the resulting functionalized graphite surfaces from 44 degrees to 83 degrees . The modular molecular structures and predictable behavior of short peptides demonstrated here give rise to a novel platform for functionalizing graphitic materials that offers numerous advantages, including noninvasive modification of the substrate, biocompatible processing in an aqueous environment, and simple fusion with other functional biological molecules. PMID- 22428622 TI - The history of the prolonged depolarizing afterpotential (PDA) and its role in genetic dissection of Drosophila phototransduction. AB - In invertebrate photoreceptors, the photopigment exhibits a long-lived and physiologically active photoproduct, called metarhodopsin (M). The long life of invertebrate M implies that under physiological conditions, M and the original pigment state rhodopsin, R, are in photoequilibrium. In many invertebrates, the absorption spectra of R and M states are different, allowing large photopigment conversion between R and M states. These net pigment molecules conversions between R and M are the basis of the prolonged depolarizing afterpotential (PDA) phenomenology, which is the main subject of this review. A large net conversion of R to M disrupts phototransduction termination at the photopigment level, which in turn results in sustained excitation long after the light is turned off. Throughout this period, the photoreceptors are partially desensitized and are insensitive (or less sensitive) to subsequent test lights. In Drosophila, the PDA tests the maximal capacity of the photoreceptor cell to maintain excitation for an extended period and is strictly dependent on the presence of high concentrations of rhodopsin and the transient receptor potential (TRP) channels. Therefore, it detects even minor defects in rhodopsin or TRP biogenesis and easily scores deficient replenishment of phototransduction components, which results in temporary desensitization of the phototransduction process. Indeed, the introduction and use of PDA to screen for phototransduction-defective Drosophila mutants by Pak and colleagues yielded a plethora of new and most interesting visual mutants. Remarkably, to this day, the PDA mutants that Pak and his colleagues isolated are the main source of mutants for analysis of the Drosophila visual system. PMID- 22428623 TI - Green biosynthesis of floxuridine by immobilized microorganisms. AB - This work describes an efficient, simple, and green bioprocess for obtaining 5 halogenated pyrimidine nucleosides from thymidine by transglycosylation using whole cells. Biosynthesis of 5-fluoro-2'-deoxyuridine (floxuridine) was achieved by free and immobilized Aeromonas salmonicida ATCC 27013 with an 80% and 65% conversion occurring in 1 h, respectively. The immobilized biocatalyst was stable for more than 4 months in storage conditions (4 degrees C) and could be reused at least 30 times without loss of its activity. This microorganism was able to biosynthesize 2.0 mg L(-1) min(-1) (60%) of 5-chloro-2'-deoxyuridine in 3 h. These halogenated pyrimidine 2'-deoxynucleosides are used as antitumoral agents. PMID- 22428624 TI - Testing compliance with occupational exposure limits: development of the British Dutch guidance. AB - The Yant Award was established in 1964 to honor the contributions of William P. Yant, the first president of the American Industrial Hygiene Association. It is presented annually for outstanding contributions in industrial hygiene or allied fields to an individual residing outside the United States. The 2011 award recipient is Dr. Trevor Ogden, chief editor of the Annals of Occupational Hygiene. PMID- 22428625 TI - Nerve injury increases brain-derived neurotrophic factor levels to suppress BK channel activity in primary sensory neurons. AB - Abnormal hyperexcitability of primary sensory neurons contributes to neuropathic pain development after nerve injury. Nerve injury profoundly reduces the expression of big conductance Ca(2+) -activated K(+) (BK) channels in the dorsal root ganglion (DRG). However, little is known about how nerve injury affects BK channel activity in DRG neurons. In this study, we determined the changes in BK channel activity in DRG neurons in a rat model of neuropathic pain and the contribution of brain-derived neurotrophic factor (BDNF) to reduced BK channel activity. The BK channel activity was present predominantly in small and medium DRG neurons, and ligation of L5 and L6 spinal nerves profoundly decreased the BK current density in these neurons. Blocking BK channels significantly increased neuronal excitability in sham control, but not in nerve-injured, rats. The BDNF concentration in the DRG was significantly greater in nerve-injured rats than in control rats. BDNF treatment largely reduced BK currents in DRG neurons in control rats, which was blocked by either anti-BDNF antibody or K252a, a Trk receptor inhibitor. Furthermore, either anti-BDNF antibody or K252a reversed reduction in BK currents in injured DRG neurons. BDNF treatment reduced the mRNA levels of BKalpha1 subunit in DRG neurons, and anti-BDNF antibody attenuated the reduction in the BKalpha1 mRNA level in injured DRG neurons. These findings suggest that nerve injury primarily diminishes the BK channel activity in small and medium DRG neurons. Increased BDNF levels contribute to reduced BK channel activity in DRG neurons through epigenetic and transcriptional mechanisms in neuropathic pain. PMID- 22428626 TI - Metabonomics reveals plasma metabolic changes and inflammatory marker in polycystic ovary syndrome patients. AB - Polycystic ovary syndrome (PCOS) is a common, clinically heterogeneous endocrine disorder affecting women of reproductive age, associated with endocrinopathy and metabolic abnormalities. Although some metabolic parameters have been investigated, very little information has been reported on the changes of small metabolites in biofluids. The aim of this study was to establish the metabolic profile of PCOS and compare it with that of controls. In this cross-sectional study of 34 women with PCOS and 36 controls, contents of small metabolites and lipids in plasma samples were measured using nuclear magnetic resonance (NMR) based techniques and analyzed using multivariate statistical methods. Significant decrease (P < 0.05) in the levels of amino acids (leucine, isoleucine, methionine, glutamine, and arginine), citrate, choline, and glycerophosphocholine/phosphocholine (GPC/PC), and increase (P < 0.05) in the levels of lactate, dimethylamine (DMA), creatine, and N-acetyl glycoproteins were observed in PCOS patients compared with the controls. Subgroups of patients with obesity, metabolic syndrome, or hyperandrogenism exhibited greater metabolic deviations than their corresponding subgroups without these factors. PCOS patients have perturbations in amino acid metabolism, the tricarboxylic acid (TCA) cycle, and gut microflora, as well as mild disturbances in glucose and lipid metabolism. The elevated level of N-acetyl glycoproteins demonstrates the existence of low-grade chronic inflammation in PCOS patients. PMID- 22428627 TI - Clinical development of new treatments for diabetic macular oedema. AB - The benchmark treatment for diabetic macular oedema, the major cause of visual impairment in patients with diabetes mellitus, has traditionally been laser photocoagulation; however, as laser treatment does not always improve vision or even prevent further loss in many cases, several new pharmacotherapies that are injected into the vitreous for diabetic macular oedema have been successfully trialled over the past decade. Others are currently being evaluated. The two major classes of these drugs are steroids and vascular endothelial growth factor antagonists. In this article we briefly review the major clinical studies recently conducted in this field. PMID- 22428628 TI - 4(R/S)-Guanidinylprolyl collagen peptides: on-resin synthesis, complexation with plasmid DNA, and the role of peptides in enhancement of transfection. AB - Chimeric collagen peptides containing cationic 4(R/S)-guanidinylproline are synthesized by in situ amidinylation of 4(R/S)-aminoproline residues. These peptides uniquely enhance the transfection efficiency of GFP-encoded plasmid DNA (pRmHa3-GFP) into cells through efficient DNA condensation resulting from nonspecific electrostatic interactions of cationic guanidino groups and localize in subcytoplasmic organelles. PMID- 22428630 TI - Frontlines: making a difference. PMID- 22428631 TI - Interoperability 'is here to stay'. PMID- 22428632 TI - Using caution around ethylene oxide. PMID- 22428633 TI - A patient's story. PMID- 22428637 TI - The next generation: what will it take to succeed? PMID- 22428639 TI - 'An obligation to join forces'. PMID- 22428640 TI - Managing recalls: responsibility, adaptability are key to effective process. PMID- 22428641 TI - Reverse mentorships: younger workers can help veterans stay on right track. PMID- 22428642 TI - Overview: HTM professionals and electronic health records. AB - Revolutionary changes in healthcare delivery systems are impacting every facet of healthcare itself, including clinical engineering. While basic equipment services will always be needed, more time and human resources must be dedicated to emerging markets within health IT as a part of a large delivery team. Now is the time to initiate the changes necessary to promote the evolution of health IT. PMID- 22428643 TI - Ethnographic field research for medical-device design. PMID- 22428644 TI - A team approach: a look at ways biomeds can improve patient safety. PMID- 22428645 TI - Deploying medical devices in both wi-fi bands. PMID- 22428646 TI - Safety advocate sees progress, but 'frustrating' problems persist. PMID- 22428647 TI - Finding an upside in system downtime. PMID- 22428648 TI - CMS maintenance update is a giant step backwards. PMID- 22428649 TI - The fudamental of ... cell washing centrifuges. PMID- 22428650 TI - A 'game changer' for computer networks. PMID- 22428651 TI - Blanket warmers revisited and temporal thermometers. PMID- 22428653 TI - Are you ready for the future? PMID- 22428654 TI - Time for a new standard in developing standards. PMID- 22428655 TI - 6 months of "temporary" support by Levitronix left ventricular assist device. AB - An otherwise healthy 47-year-old man presented to the emergency department in cardiogenic shock after suffering a massive myocardial infarction due to left main occlusion. He was initially supported by extracorporeal membrane oxygenation and subsequently was converted to paracorporeal support with a Levitronix left ventricular assist device. He experienced multiple postoperative complications including renal failure, respiratory failure, retroperitoneal hematoma requiring suspension of anticoagulation, and fungal bloodstream infection precluding transition to an implantable device. He was reconditioned and successfully underwent orthotopic heart transplant 183 days after presentation. A discussion of the relevant issues is included. PMID- 22428656 TI - Self-plagiarism. PMID- 22428657 TI - Multilevel X-Pol: a fragment-based method with mixed quantum mechanical representations of different fragments. AB - The explicit polarization (X-Pol) method is a fragment-based quantum mechanical model, in which a macromolecular system or other large or complex system in solution is partitioned into monomeric fragments. The present study extends the original X-Pol method, where all fragments are treated using the same electronic structure theory, to multilevel representations, called multilevel X-Pol, in which different electronic structure methods are used to describe different fragments. The multilevel X-Pol method has been implemented into a locally modified version of Gaussian 09. A key ingredient that is used to couple interfragment electrostatic interactions at different levels of theory is the use of the response density for the post-self-consistent-field energy. (The response density is also called the generalized density.) The method is useful for treating fragments in a small region of the system such as a solute molecule or the substrate and amino acids in the active site of an enzyme with a high-level theory, and the fragments in the rest of the system by a lower-level and computationally more efficient method. Multilevel X-Pol is illustrated here by applications to hydrogen bonding complexes in which one fragment is treated with the hybrid M06 density functional, Moller-Plesset perturbation theory, or coupled cluster theory, and the other fragments are treated by Hartree-Fock theory or the B3LYP or M06 hybrid density functionals. PMID- 22428658 TI - Colon-targeted cell-permeable NFkappaB inhibitory peptide is orally active against experimental colitis. AB - For the purpose of development of orally active peptide therapeutics targeting NFkappaB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFkappaB inhibitory peptides (NIP). Suppression of NFkappaB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPP-NIP FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFkappaB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD. PMID- 22428659 TI - Combination pharmacological therapies for the management of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a highly prevalent condition of older men caused by unregulated growth of the prostate gland. Clinical trials of medical therapy for BPH have consistently demonstrated that combined therapy with an alpha(1)-adrenergic receptor (AR) antagonist and a 5alpha-reductase inhibitor is superior to either agent alone. The addition of anticholinergic therapy to a treatment regimen could effectively improve symptoms in men with persistent storage lower urinary tract symptoms (LUTS) who have not seen a benefit with an alpha(1)-AR antagonist or 5alpha-reductase inhibitor. Among alpha(1)-AR antagonists, doxazosin, terazosin, tamsulosin, and alfuzosin, although with slight differences in adverse event profiles, are equivalent in effectiveness and efficacy. No data in the form of direct comparator trials exist to suggest a difference in clinical efficacy of finasteride and dutasteride, the two 5alpha reductase inhibitors currently available. Current American Urological Association guidelines do not recommend phytotherapy or dietary supplements in any combination for the medical management of BPH. The current literature supports the safety and efficacy of the combination of an alpha(1)-AR antagonist and a 5alpha-reductase inhibitor in the treatment of symptomatic BPH and, in select patients, the use of an alpha(1)-AR antagonist and anticholinergic medication in the treatment of LUTS suggestive of BPH. PMID- 22428660 TI - Assessment of concordance of symptom reflux association tests in ambulatory pH monitoring. AB - BACKGROUND: Both simple proportions and statistical tests are utilised for symptom-reflux association. We systematically compared three such tests in a clinical setting. AIM: To compare the three commonly used symptom reflux association tests in a large cohort of patients undergoing ambulatory pH monitoring for the evaluation of oesophageal symptoms. METHODS: Ambulatory pH data from 772 symptomatic subjects (49.1 +/- 0.5 years; 479 F) tested off therapy were assessed for acid exposure time (AET, elevated when pH <4 for >=4%), symptom index (SI, >=50% when positive), and symptom association probability (SAP) and Ghillebert probability estimate (GPE, P < 0.05 when positive). Test concordance and discordance were individually assessed; discordance between statistical tests was minor if one had P < 0.1 while the other was positive. Logistic regression determined independent predictors of test discordance. RESULTS: The SAP, GPE and SI were positive in 42.7%, 39.3% and 33.9% respectively. GPE performed extremely well compared to SAP (sensitivity 0.95, specificity 0.91), with major discordance in only 2.8%. Positive concordance was significantly higher when AET was abnormal. GPE underestimated symptom association compared to SAP, whereas SAP was subject to symptom over-counting in 33.3% of discordant cases. GPE-SAP discordance was associated with higher AET (7.5% vs. 5.1%) and more symptoms (19.3 vs. 10.7, P > 0.001 for each comparison with concordant tests); both remained significant on logistic regression analysis (P <= 0.003). SI was discordant with SAP when symptoms were extremely frequent (median 19, IQR 10-32) or limited (median 1, IQR 1-2), and concordant when median 6 symptoms (IQR 3-12) were recorded. CONCLUSIONS: The GPE can be used interchangeably with SAP in symptom reflux association. SI has uncertain value with very high and very low symptom counts. PMID- 22428661 TI - Hospital transfers of nursing home residents with advanced dementia. AB - OBJECTIVES: To describe diagnoses and factors associated with hospital transfer in nursing home (NH) residents with advanced dementia. DESIGN: Prospective cohort study. SETTING: Twenty-two Boston, Massachusetts-area NHs. PARTICIPANTS: Three hundred twenty-three NH residents with advanced dementia. MEASUREMENTS: Data were collected quarterly for up to 18 months. Data regarding transfers were collected with regard to hospitalization or emergency department (ED) visit, diagnosis, and duration of inpatient admission. Information on the occurrence of any acute medical event (pneumonia, febrile episode, or other acute illness) in the prior 90 days was obtained quarterly. Logistic regression conducted at the level of the acute medical event identified characteristics associated with hospital transfer. RESULTS: The entire cohort experienced 74 hospitalizations and 60 ED visits. Suspected infections were the most common reason for hospitalization (44, 59%), most frequently attributable to a respiratory source (30, 41%). Feeding tube related complications accounted for 47% of ED visits. In adjusted analysis conducted on acute medical events, younger resident age, event type (pneumonia or other event vs febrile episode), chronic obstructive pulmonary disease, and the lack of a do-not-hospitalize (DNH) order (adjusted odds ratio = 5.22, 95% confidence interval = 2.31-11.79) were associated with hospital transfer. CONCLUSION: The majority of hospitalizations of NH residents with advanced dementia were due to infections and thus were potentially avoidable, because infections are often treatable in the NH. Feeding tube-related complications accounted for almost half of all ED visits, representing a common but underrecognized burden of this intervention. Advance care planning in the form of a DNH order was the only identified modifiable factor associated with avoiding hospitalization. PMID- 22428662 TI - Social anxiety and emotion regulation in daily life: spillover effects on positive and negative social events. AB - To minimize the possibility of scrutiny, people with social anxiety difficulties exert great effort to manage their emotions, particularly during social interactions. We examined how the use of two emotion regulation strategies, emotion suppression and cognitive reappraisal, predict the generation of emotions and social events in daily life. Over 14 consecutive days, 89 participants completed daily diary entries on emotions, positive and negative social events, and their regulation of emotions. Using multilevel modeling, we found that when people high in social anxiety relied more on positive emotion suppression, they reported fewer positive social events and less positive emotion on the subsequent day. In contrast, people low in social anxiety reported fewer negative social events on days subsequent to using cognitive reappraisal to reduce distress; the use of cognitive reappraisal did not influence the daily lives of people high in social anxiety. Our findings support theories of emotion regulation difficulties associated with social anxiety. In particular, for people high in social anxiety, maladaptive strategy use contributed to diminished reward responsiveness. PMID- 22428663 TI - Cell cycle regulation by carboxylated multiwalled carbon nanotubes through p53 independent induction of p21 under the control of the BMP signaling pathway. AB - This report describes how carboxylated multiwalled carbon nanotubes (MWCNTs) induce p53-independent p21 expression and cell cycle arrest. MWCNTs suppress BMP signaling and lead to the downregulation of Id protein production and the upregulation of p21 because p21 expression is directly controlled by Id proteins through their regulation of the E-box motifs in the p21 promoter. The overexpressed p21 protein then binds to the cyclin D/cdk4,6 complexes and inhibits the phosphorylation of Rb protein. Hypophosphorylation of Rb prevents the release of E2F factors and causes cell cycle arrest. These findings provide valuable insight into a mechanistic understanding of carbon nanotubes' effects on cellular functions. PMID- 22428664 TI - Cannabinoid CB(2) receptor attenuates morphine-induced inflammatory responses in activated microglial cells. AB - BACKGROUND AND PURPOSE: Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems. Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states. In the present study, we characterized the signal transduction pathways mediated by cannabinoid CB(2) and u-opioid receptors in quiescent and LPS-stimulated murine microglial cells. EXPERIMENTAL APPROACH: We examined the effects of u-opioid and CB(2) receptor stimulation on phosphorylation of MAPKs and Akt and on IL-1beta, TNF alpha, IL-6 and NO production in primary mouse microglial cells. KEY RESULTS: Morphine enhanced release of the proinflammatory cytokines, IL-1beta, TNF-alpha, IL-6, and of NO via u-opioid receptor in activated microglial cells. In contrast, CB(2) receptor stimulation attenuated morphine-induced microglial proinflammatory mediator increases, interfering with morphine action by acting on the Akt-ERK1/2 signalling pathway. CONCLUSIONS AND IMPLICATIONS: Because glial activation opposes opioid analgesia and enhances opioid tolerance and dependence, we suggest that CB(2) receptors, by inhibiting microglial activity, may be potential targets to increase clinical efficacy of opioids. PMID- 22428665 TI - Detection of endocrine disruptors - from simple assays to whole genome scanning. AB - Endocrine disruptors frequently bear little structural relationship to the hormone whose actions they disrupt. Consequently, the threat of an uninvestigated chemical cannot easily be assessed. Here three different approaches to assessment are discussed. The first presumes an endocrine-disrupting property, following which a cell model capable of responding to such a hormone is used. Although simple and cheap, it provides limited data. A second approach involves multiple assays to detect multiple hormones. Increasing the amount of data increased the difficulty in assessing the significance of results. To meet this problem, cluster analysis based on a simple mathematical matrix was adopted. The matrix was used to determine (i) a limited number of assays to identify a maximum number of endocrine disruptors and (ii) the chemicals with the most wide-ranging effects. A third approach was a whole genome expression analysis based on expression of mRNAs in human TE671 medulloblastoma cells. Expression of individual mRNAs was assessed using the Affymetrix GeneChip((r)) Human Genome U133 Plus 2.0 chip. The significance of differential expressed genes was assessed based on gene ontology and pathways analyses using DAVID and GenMaPP programs. The results illustrated the very wide-ranging effects of these chemicals across the genome. PMID- 22428666 TI - Two new phenolic glycosides from the rhizome of Gastrodia elata. AB - Two new phenolic glycosides, named parishins F-G (1-2), together with known parishin E, were isolated from the rhizome of Gastrodia elata. The new structures were established as 1,3-di-[4-O-(beta-D-glucopyranosyl) benzyl]-2-{4-O-[beta-D glucopyranosyl-(1 -> 6)-beta-D-glucopyranosyl] benzyl} citrate (1) and 2-[4-O (beta-D-glucopyranosyl)benzyl] citrate (2), by means of MS, 1D, and 2D NMR spectral analyses, as well as chemical methods. PMID- 22428667 TI - Nonfluorescent quenchers to correlate single-molecule conformational and compositional dynamics. AB - Single-molecule Forster resonance energy transfer (smFRET) is a powerful method for studying the conformational dynamics of a biomolecule in real-time. However, studying how interacting ligands correlate with and regulate the conformational dynamics of the biomolecule is extremely challenging because of the availability of a limited number of fluorescent dyes with both high quantum yield and minimal spectral overlap. Here we report the use of a nonfluorescent quencher (Black Hole Quencher, BHQ) as an acceptor for smFRET. Using a Cy3/BHQ pair, we can accurately follow conformational changes of the ribosome during elongation in real time. We demonstrate the application of single-color FRET to correlate the conformational dynamics of the ribosome with the compositional dynamics of tRNA. We use the normal Cy5 FRET acceptor to observe arrival of a fluorescently labeled tRNA with a concomitant transition of the ribosome from the locked to the unlocked conformation. Our results illustrate the potential of nonfluorescent quenchers in single-molecule correlation studies. PMID- 22428668 TI - Temporal target integration underlies performance at Lag 1 in the attentional blink. AB - When two targets follow each other directly in rapid serial visual presentation (RSVP), they are often identified correctly but reported in the wrong order. These order reversals are commonly explained in terms of the rate at which the two targets are processed, the idea being that the second target can sometimes overtake the first in the race toward conscious awareness. The present study examined whether some of these order reversals might alternatively be due to a mechanism of temporal integration whereby targets appearing closely in time may be merged into a single representation. To test this integration account, we used an attentional blink task in which the two targets could be combined perceptually in a meaningful way such that the conjunction of the two target elements constituted a possible target stimulus itself. The results showed that when targets appeared at Lag 1, observers frequently reported seeing only a single merged target stimulus, and these reports occurred up to approximately three times as often as (real) order reversals. When the possibility to report the integrated percept was removed, order reversals consequently tripled. These results suggest that integration may actually be the primary cause of order reversals in dual-target RSVP tasks. PMID- 22428669 TI - Evidence for delayed parafoveal-on-foveal effects from word n+2 in reading. AB - During reading information is acquired from word(s) beyond the word that is currently looked at. It is still an open question whether such parafoveal information can influence the current viewing of a word, and if so, whether such parafoveal-on-foveal effects are attributable to distributed processing or to mislocated fixations which occur when the eyes are directed at a parafoveal word but land on another word instead. In two display-change experiments, we orthogonally manipulated the preview and target difficulty of word n+2 to investigate the role of mislocated fixations on the previous word n+1. When the eyes left word n, an easy or difficult word n+2 preview was replaced by an easy or difficult n+2 target word. In Experiment 1, n+2 processing difficulty was manipulated by means of word frequency (i.e., easy high-frequency vs. difficult low-frequency word n+2). In Experiment 2, we varied the visual familiarity of word n+2 (i.e., easy lower-case vs. difficult alternating-case writing). Fixations on the short word n+1, which were likely to be mislocated, were nevertheless not influenced by the difficulty of the adjacent word n+2, the hypothesized target of the mislocated fixation. Instead word n+1 was influenced by the preview difficulty of word n+2, representing a delayed parafoveal-on foveal effect. The results challenge the mislocated-fixation hypothesis as an explanation of parafoveal-on-foveal effects and provide new insight into the complex spatial and temporal effect structure of processing inside the perceptual span during reading. PMID- 22428670 TI - Perceptual grouping allows for attention to cover noncontiguous locations and suppress capture from nearby locations. AB - A salient stimulus may interrupt visual search because of attentional capture. It has been shown that attentional capture occurs with a wide, but not with a small attentional window. We tested the hypothesis that capture depends more strongly on the shape of the attentional window than on its size. Search elements were arranged in two nested rings. The ring containing the search target remained fixed, while a salient color singleton occurred either in the same or in the other ring. We observed that color singletons only disrupted search when shown in the same ring as the search target. It is important to note that, when focusing on the outer array, which presumably required a larger attentional window, singletons on the inner array did not capture attention. In contrast to the original attentional window hypothesis, our results show that attentional capture does not always occur with a large attentional window. Rather, attention can be flexibly allocated to the set of relevant stimulus locations and attentional capture is confined to the attended locations. Further experiments showed that attention was allocated to search elements that were perceptually grouped into "whole" or "Gestalt"-like objects, which prevented attentional capture from nearby locations. However, when attention was allocated to noncontiguous locations that did not form a perceptual Gestalt, nearby locations elicited attentional capture. Perceptual grouping could be based on a combination of color and position, but not on color alone. Thus, the allocation of attention to Gestalt-like objects that were jointly defined by similarity and proximity prevented attentional capture from nearby locations. PMID- 22428671 TI - It is not what you expect: dissociating conflict adaptation from expectancies in a Stroop task. AB - In conflict tasks, congruency effects are modulated by the sequence of preceding trials. This modulation effect has been interpreted as an influence of a proactive mechanism of adaptation to conflict (Botvinick, Nystrom, Fissell, Carter, & Cohen, 1999), but the possible contribution of explicit expectancies to this adaptation effect remains unclear. The present study shows that it is possible to dissociate explicit expectancies from sequential adaptation effects in a Stroop task, in conditions in which feature repetitions are avoided, and in which the response-to-stimulus interval is set to 0 ms. We found a progressive adaptation effect that depends on the congruency of the previous series of trials, rather than exclusively on the preceding trial. This effect is independent from explicit expectancies (Experiment 1), and can even contradict these expectancies when participants are presented with informative patterns favoring either repeating or alternating congruency (Experiments 2a and 2b). The existence of a progressive adaptation effect independent from explicit expectancies and from repetition priming challenges the idea that conflict adaptation acts always on a top-down basis (Notebaert, Gevers, Verbruggen, & Liefooghe, 2006), and it rather indicates the existence of automatic sources of sequential adaptation, including the adaptation to the lack of conflict. Implications of these results on current understanding of some empirical phenomena of cognitive control, such as that of proportion of congruency, will be highlighted. PMID- 22428672 TI - The social psychology of perception experiments: hills, backpacks, glucose, and the problem of generalizability. AB - Experiments take place in a physical environment but also a social environment. Generalizability from experimental manipulations to more typical contexts may be limited by violations of ecological validity with respect to either the physical or the social environment. A replication and extension of a recent study (a blood glucose manipulation) was conducted to investigate the effects of experimental demand (a social artifact) on participant behaviors judging the geographical slant of a large-scale outdoor hill. Three different assessments of experimental demand indicate that even when the physical environment is naturalistic, and the goal of the main experimental manipulation was primarily concealed, artificial aspects of the social environment (such as an explicit requirement to wear a heavy backpack while estimating the slant of a hill) may still be primarily responsible for altered judgments of hill orientation. PMID- 22428673 TI - Multiple spatial mappings in numerical cognition. AB - A recent cross-cultural comparison (Shaki, Fischer, & Petrusic, 2009) suggested that spatially consistent processing habits for words and numbers are a necessary condition for the spatial representation of numbers (Spatial-Numerical Association of Response Codes; SNARC effect). Here we reexamine the SNARC in Israelis who read text from right to left but numbers from left to right. We show that, despite these spatially inconsistent processing habits, a SNARC effect still emerges when the response dimension is spatially orthogonal to the conflicting processing dimension. These results clarify the cognitive conditions for spatial-numerical mappings. PMID- 22428674 TI - Aesthetic issues in spatial composition: effects of vertical position and perspective on framing single objects. AB - Aesthetic preference for the vertical composition of single-object pictures was studied through a series of two-alternative forced-choice experiments. The results reveal the influence of several factors, including spatial asymmetries in the functional properties of the object and the typical position of the object relative to the observer. With asymmetric side views of objects, people generally prefer objects typically located below the observer's viewpoint (e.g., a bowl or swimming stingray) to be below the center of the frame and objects typically located above the observer's viewpoint (e.g., a light fixture or flying eagle) to be above the center of the frame. In addition, people generally prefer symmetric views of those same objects from directly above or directly below to be closer to the center of the frame. We suggest that these results can be unified by the hypothesis that people prefer the object's "affordance space" to be centered within the frame. PMID- 22428675 TI - Rapid acquisition but slow extinction of an attentional bias in space. AB - Substantial research has focused on the allocation of spatial attention based on goals or perceptual salience. In everyday life, however, people also direct attention using their previous experience. Here we investigate the pace at which people incidentally learn to prioritize specific locations. Participants searched for a T among Ls in a visual search task. Unbeknownst to them, the target was more often located in one region of the screen than in other regions. An attentional bias toward the rich region developed over dozens of trials. However, the bias did not rapidly readjust to new contexts. It persisted for at least a week and for hundreds of trials after the target's position became evenly distributed. The persistence of the bias did not reflect a long window over which visual statistics were calculated. Long-term persistence differentiates incidentally learned attentional biases from the more flexible goal-driven attention. PMID- 22428676 TI - The learning of visually guided action: an information-space analysis of pole balancing. AB - In cart-pole balancing, one moves a cart in 1 dimension so as to balance an attached inverted pendulum. We approached perception-action and learning in this task from an ecological perspective. This entailed identifying a space of informational variables that balancers use as they perform the task and demonstrating that they improve by traversing the space to the loci of more useful variables. We presented a novel information space-including fractional derivatives of pendulum angle (e.g., halfway between angle and angular velocity) as possible information for balancing. Fourteen college students tried to meet a criterion of balancing the pole for 30 s on 3 of 5 successive trials, up to a maximum of 150 attempts. Loci in the fractional derivative space predicted the time series of force production well. Systematic differences were seen in loci as a function of success, and systematic changes in locus were seen with learning. The fractional derivatives were shown to predict pole angles a short time interval into the future, allowing balancers to prospectively control the action and thereby nullify visuomotor delay. In addition to loci in the information space, we analyzed loci in a calibration space, reflecting the gain relating force to information. PMID- 22428677 TI - Saccade preparation is required for exogenous attention but not endogenous attention or IOR. AB - Covert attention is tightly coupled with the control of eye movements, but there is controversy about how tight this coupling is. The premotor theory of attention proposes that activation of the eye movement system is necessary to produce shifts of attention. In this study, we experimentally prevented healthy participants from planning or executing eye movements and observed the effect on exogenous attention, inhibition of return (IOR), and endogenous attention. The participants experienced a deficit of exogenous attentional facilitation that was specific to locations that were inaccessible by saccade. In contrast, their ability to endogenously orient attention was preserved, as was IOR. These results show that (a) exogenous attention depends on motor preparation, (b) IOR is independent of motor preparation and exogenous attention, and (c) endogenous attention is independent of motor preparation. Although these data are consistent with a weak version of the premotor theory, we believe they can be better explained by a biased competition account of visual attention. PMID- 22428678 TI - Eye movements blink the attentional blink. AB - When presented with a sequence of visual stimuli in rapid succession, participants often fail to detect a second salient target, a phenomenon referred as the attentional blink (AB; Raymond, Shapiro, & Arnell, 1992; Shapiro, Raymond, & Arnell, 1997). On the basis of a vast corpus of experiments, several cognitive theories suggest that the blink results from a discrete structuring of attention, sampling information from temporal episodes during which several items can access encoding process (Wyble, Bowman, & Nieuwenstein, 2009; Wyble, Potter, Bowman, & Nieuwenstein, 2011). The objective of this work is to explore the AB when multiple items are presented at the fovea during ocular movements. The authors reasoned that each fixation may cohesively form an episode and hence expected that the blink may vanish within a single fixation. In turn, they expected saccades to accentuate episodic borders and hence shorten the regime of interference when 2 targets are presented fovealy in successive fixations. Evidence is provided in favor of this hypothesis, showing that the blink vanishes when both targets are presented in the core of a single fixation (far from the saccadic boundaries) and that it recovers more rapidly in successive fixations. These studies support current views that episodes should have an effect on the AB and provide evidence that eye movements play an important role in the formation of episodes. PMID- 22428679 TI - On the fate of distractor representations. AB - Research on the topic of distractor inhibition has used different empirical approaches to study how the human mind selects relevant information from the environment, and the results are controversially discussed. One key question that typically arises is how selection deals with the irrelevant information. We used a new selection task, in which participants sometimes had to respond to the distractors instead of the target. Importantly, we varied the time interval between stimuli onset and the cue that signaled participants to respond to the distractors. We analyzed RTs and error rates from responses to distractors as a function of how long the target had been processed (and the distractor ignored) before the cue required a response to the distractor (i.e., stimulus-cue SOA). The data are compatible with selection models assuming that distractor stimuli are initially activated and then deactivated. Thus, we argue for selection models assuming top down deactivation of distractor representations that work in parallel with top down activation of target representations. PMID- 22428680 TI - HLA-A*31:56 and HLA-A*31:59 were identified by polymerase chain reaction sequence based typing in Chinese individuals. AB - Compared with HLA-A*31:01:02, HLA-A*31:56 shows one nucleotide difference at position 706 G>A and HLA-A*31:59 has a single nucleotide polymorphism at position 626 C>T. PMID- 22428681 TI - Pressure-sensitive adhesion system using acrylate block copolymers in response to photoirradiation and postbaking as the dual external stimuli for on-demand dismantling. AB - We have demonstrated the validity of a new type of pressure-sensitive adhesion system using block copolymers containing a poly(2-ethylhexyl acrylate) (P2EHA) segment as the low glass transition temperature polymer and a poly(tert-butyl acrylate) (PtBA) or poly(isobornyl acrylate) (PIBoA) segment as the reacting polymer in the presence of a photoacid generator (PAG). This adhesion system can be easily debonded because of a change in the polymer properties of the adhesives by acid-catalyzed deprotection uniquely occurring during the photoirradiation followed by postbaking. We investigated the transformation of PtBA and PIBoA into poly(acrylic acid) using IR spectroscopy and a thermogravimetric analysis in the presence of p-toluenesulfonic acid and the PAGs. The block copolymers with a well defined molecular structure were then synthesized by atom transfer radical polymerization, and their adhesive properties were evaluated using the 180 degrees peel test. The block copolymers showed superior adhesion property than a random copolymer and polymer blends, due to the microphase separation of the block copolymers. A drastic change in the adhesive strength of the block copolymers was observed in response to the dual external stimuli consisting of UV irradiation and the subsequent heating. PMID- 22428682 TI - Investigations into the bending constant and edge energy of bilayers of salt-free catanionic vesicles. AB - Using molecular dynamics simulation, we performed theoretical calculations on the curvature constant and edge energy of bilayers of salt-free, zero-charged, cationic and anionic (catanionic) surfactant vesicles composed of alkylammonium cations (C(m)(+)) and fatty acid anions (C(n)(-)). Both the minimum size and edge energy of vesicles were calculated to examine the relation between the length of the surfactant molecules and the mechanical properties of the catanionic bilayers. Our simulation results clearly demonstrate that, when the chain lengths of the cationic and anionic surfactants are equal, both the edge energy and the rigidity of the catanionic bilayers increase dramatically, changing from around 0.36 to 2.77 kBT.nm(-1) and around 0.86 to 6.51 kBT.nm(-1), respectively. For the smallest catanionic vesicles, the curvature is not uniform and the surfactant molecules adopt a multicurvature arrangement in the vesicle bilayers. We suspect that the multicurvature bending of bilayers of catanionic vesicles is a common phenomenon in rigid bilayer systems, which could aid understanding of ion transport through bilayer membranes. PMID- 22428683 TI - Western Canadian Arctic ringed seal organic contaminant trends in relation to sea ice break-up. AB - The association between changing sea ice conditions and contaminant exposure to Arctic animals interests Inuvialuit harvesters, communities, and researchers. We examined organochlorine contaminant (OC) concentrations in the blubber of 90 male adult ringed seals (Phoca hispida) sampled from the subsistence harvest in Ulukhaktok (formerly Holman), NT, Canada, just prior to break-up of the sea ice (1993-2008). OC blubber concentrations were assessed with respect to year and sea ice break-up date. HCB and age- and blubber-adjusted concentrations of p,p'-DDT and SigmaCHB (chlorobornane) significantly decreased over the study period. With respect to the timing of the spring break-up, highly lipophlic OCs, such as p,p' DDE and PCB 153, were higher during years of early ice clearing (at least 12 days earlier than the mean annual break-up date), whereas no trends were observed for alpha, beta, and gamma isomers of HCH, trans- and cis-chlordane, oxychlordane, or SigmaCHB. The higher contaminant concentrations found in earlier break-up years is likely due to earlier and/or increased foraging opportunities. This situation also has potential for enhancing bioaccumulation and biomagnification of contaminants over the long-term if projected changes continue to result in lighter and earlier ice conditions. PMID- 22428685 TI - Synthesis and evaluation of biodegradable PCL/PEG nanoparticles for neuroendocrine tumor targeted delivery of somatostatin analog. AB - PURPOSE: Neuroendocrine tumors often present a diagnostic and therapeutic challenge. We have aimed to synthesize and develop biodegradable nanoparticles of somatostatin analogue, octreotide for targeted therapy of human neuroendocrine pancreatic tumor. METHODS: Direct solid phase peptide synthesis of octreotide was done. Octreotide loaded PCL/PEG nanoparticles were prepared by solvent evaporation method and characterized for transmission electron microscopy, differential scanning calorimetery (DSC), Zeta potential measurement studies. The nanoparticles were evaluated in vitro for release studies and peptide content. For biological evaluations, receptor binding & cytotoxicity studies were done on BON-1 neuroendocrine tumor cell line. Biodistribution of radiolabeled peptide and nanoparticles, tumor regression studies were performed on tumor-bearing mouse models. RESULTS: We have synthesized and purified octreotide with the purity of 99.96% in our laboratory. PEG/PCL nanoparticles with an average diameter of 130 195 nm having peptide loading efficiency of 66-84% with a negative surface charge were obtained with the formulation procedure. Octreotide nanoparticles have a negative action on the proliferation of BON-1 cells. In vivo biodistribution studies exhibited major accumulation of octreotide nanoparticles in tumor as compared to plain octreotide. Octreotide nanoparticles inhibited tumor growth more efficiently than free octreotide. CONCLUSIONS: Thus, it was concluded that the PCL/PEG nanoformulation of octreotide showed high tumor uptake due to the enhanced permeation and retention (EPR) effect and then peptide ligand imparts targetability to the sst2 receptor and there by showing increase tumor growth inhibition. Selective entry of nanoparticles to the tumor also give the reduce side effects both in vivo and in vitro. PMID- 22428686 TI - Preparation and cytotoxicity of poly (DL-lactide-co-glycolide) microspheres encapsulating 2-methoxyestradiol. AB - Injectable implant would be a potential way for 2-methoxyestradiol (2-ME) for the therapy of breast cancer because of its water-insolubility, short half-life, and low oral bioavailability. So 2-ME microspheres based on poly (DL-lactide-co glycolide) were prepared by emulsion solvent extraction method and characterized for morphology, particle size, drug physical state, entrapment efficiency and drug release in vitro and in vivo. Their cytotoxicity on MCF-7 cells was evaluated by sulforhodamine B (SRB) method. The 2-ME was successfully entrapped in the interior of microspheres with particle size of 55.44 +/- 12.21 MUm and could exist in an amorphism. In vitro and in vivo release of 2-ME from the microspheres occurred in a Ritger-Peppas and zero-order manner with a slow release over 46 days, respectively, and their better correlation was found. The 2 ME even with very low concentration in the microspheres could efficiently inhibit the growth of MCF-7 cells compared to the equivalent amount of drug in free solution, which indicated that the release rate from the microspheres and local water-solubility of 2-ME could maintain effective drug concentration in target site. The above results indicated that the microspheres prepared could not only control prolonged release of 2-ME in vitro and in vivo but also maintain effective drug concentration in target site. So 2-ME microspheres are acceptable for controlled release devices for effective treatment of breast cancer. PMID- 22428688 TI - Ipso-Nitration of calix[6]azacryptands: intriguing effect of the small rim capping pattern on the large rim substitution selectivity. AB - The ipso-nitration of calix[6]arene-based molecular receptors is a important synthetic pathway for the elaboration of more sophisticated systems. This reaction has been studied for a variety of capped calixarenes, and a general trend for the regioselective nitration of three aromatic units out of six in moderate to high yield has been observed. This selectivity is, in part, attributed to the electronic connection between the protonated cap at the small rim and the reactive sites at the large rim. In addition, this work highlights the fact that subtle conformational properties can drastically influence the outcome of this reaction. PMID- 22428690 TI - Cervical cancer screening in the United States and the Netherlands: a tale of two countries. AB - CONTEXT: This article compares cervical cancer screening intensity and cervical cancer mortality trends in the United States and the Netherlands to illustrate the potential of cross-national comparative studies. We discuss the lessons that can be learned from the comparison as well as the challenges in each country to effective and efficient screening. METHODS: We used nationally representative data sources in the United States and the Netherlands to estimate the number of Pap smears and the cervical cancer mortality rate since 1950. The following questions are addressed: How do differences in intensity of Pap smear use between the countries translate into differences in mortality trends? Can population coverage rates (the proportion of eligible women who had a Pap smear within a specified period) explain the mortality trends better than the total intensity of Pap smear use? FINDINGS: Even though three to four times more Pap smears per woman were conducted in the United States than in the Netherlands over a period of three decades, the two countries' mortality trends were quite similar. The five-year coverage rates for women aged thirty to sixty-four were quite comparable at 80 to 90 percent. Because screening in the Netherlands was limited to ages thirty to sixty, screening rates for women under thirty and over sixty were much higher in the United States. These differences had consequences for age specific mortality trends. The relatively good coverage rate in the Netherlands can be traced back to a nationwide invitation system based on municipal population registries. While both countries followed a "policy cycle" involving evidence review, surveillance of screening practices and outcomes, clinical guidelines, and reimbursement policies, the components of this cycle were more systematically linked and implemented nationwide in the Netherlands than in the United States. To a large extent, this was facilitated by a public health model of screening in the Netherlands, rather than a medical services model. CONCLUSIONS: Cross-country studies like ours are natural experiments that can produce insights not easily obtained from other types of study. The cervical cancer screening system in the Netherlands seems to have been as effective as the U.S. system but used much less screening. Adequate coverage of the female population at risk seems to be of central importance. PMID- 22428691 TI - Opportunities to improve cervical cancer screening in the United States. PMID- 22428692 TI - Too much of a good thing? PMID- 22428693 TI - Theory! The missing link in understanding the performance of neonate/infant home visiting programs to prevent child maltreatment: a systematic review. AB - CONTEXT: Home-visiting programs have been offered for more than sixty years to at risk families of newborns and infants. But despite decades of experience with program delivery, more than sixty published controlled trials, and more than thirty published literature reviews, there is still uncertainty surrounding the performance of these programs. Our particular interest was the performance of home visiting in reducing child maltreatment. METHODS: We developed a program logic framework to assist in understanding the neonate/infant home-visiting literature, identified through a systematic literature review. We tested whether success could be explained by the logic model using descriptive synthesis and statistical analysis. FINDINGS: Having a stated objective of reducing child maltreatment-a theory or mechanism of change underpinning the home-visiting program consistent with the target population and their needs and program components that can deliver against the nominated theory of change-considerably increased the chance of success. We found that only seven of fifty-three programs demonstrated such consistency, all of which had a statistically significant positive outcome, whereas of the fifteen that had no match, none was successful. Programs with a partial match had an intermediate success rate. The relationship between program success and full, partial or no match was statistically significant. CONCLUSIONS: Employing a theory-driven approach provides a new way of understanding the disparate performance of neonate/infant home-visiting programs. Employing a similar theory-driven approach could also prove useful in the review of other programs that embody a diverse set of characteristics and may apply to diverse populations and settings. A program logic framework provides a rigorous approach to deriving policy-relevant meaning from effectiveness evidence of complex programs. For neonate/infant home-visiting programs, it means that in developing these programs, attention to consistency of objectives, theory of change, target population, and program components is critical. PMID- 22428694 TI - Health insurance coverage and take-up: lessons from behavioral economics. AB - CONTEXT: Millions of uninsured Americans ostensibly have insurance available to them-many at very low cost-but do not take it up. Traditional economic analysis is based on the premise that these are rational decisions, but it is hard to reconcile observed enrollment patterns with this view. The policy prescriptions that the traditional model generates may thus fail to achieve their goals. Behavioral economics, which integrates insights from psychology into economic analysis, identifies important deviations from the traditional assumptions of rationality and can thus improve our understanding of what drives health insurance take-up and improved policy design. METHODS: Rather than a systematic review of the coverage literature, this article is a primer for considering issues in health insurance coverage from a behavioral economics perspective, supplementing the standard model. We present relevant evidence on decision making and insurance take-up and use it to develop a behavioral approach to both the policy problem posed by the lack of health insurance coverage and possible policy solutions to that problem. FINDINGS: We found that evidence from behavioral economics can shed light on both the sources of low take-up and the efficacy of different policy levers intended to expand coverage. We then applied these insights to policy design questions for public and private insurance coverage and to the implementation of the recently enacted health reform, focusing on the use of behavioral insights to maximize the value of spending on coverage. CONCLUSIONS: We concluded that the success of health insurance coverage reform depends crucially on understanding the behavioral barriers to take-up. The take up process is likely governed by psychology as much as economics, and public resources can likely be used much more effectively with behaviorally informed policy design. PMID- 22428695 TI - What we talk about when we talk about risk: refining surgery's hazards in medical thought. AB - CONTEXT: Current efforts to improve the cost-effectiveness of health care focus on assessing accurately the value of technologically complex, costly medical treatments for individual patients and society. These efforts universally acknowledge that the determination of such value should incorporate information regarding the risks posed by a given treatment for an individual, but they typically overlook the implications for medical decision making that inhere in how notions of risk are understood and used in contemporary medical discourse. To gain perspective on how the hazards of surgery have been defined and redefined in medical thought, we examine changes over time in notions of risk related to operative care. METHODS: We reviewed historical writings on risk assessment and patient selection for surgical procedures published between 1957 and 1997 and conducted informal interviews with experts. To examine changes attributable to advances in research on risk assessment, we focused on the period surrounding the 1977 publication of an influential surgical risk-stratification index. FINDINGS: Writings before 1977 demonstrate a summative, global approach to patients as "good" or "poor" risks, without quantifying the likelihood of specific postoperative events. Beginning in the early 1980s, assessments of operative risk increasingly emphasized quantitative estimates of the probability of dysfunction of a specific organ system after surgery. This new approach to establishing surgical risk was consistent with concurrent trends in other domains of medicine. In particular, it emphasized a more "scientific," standardized approach to medical decision making over an earlier focus on individual physicians' judgment and professional authority. CONCLUSIONS: Recent writings on operative risk reflect a viewpoint that is more specific and, at the same time, more generic and fragmented than earlier approaches. By permitting the separation of multiple component hazards implicit in surgical interventions, such a viewpoint may encourage a distinct, permissive standard for surgical interventions that conflicts with larger policy efforts to promote cost-effective decision making by physicians and patients. PMID- 22428696 TI - Impact of nurse staffing mandates on safety-net hospitals: lessons from California. AB - CONTEXT: California is the first and only state to implement a patient-to-nurse ratio mandate for hospitals. Increasing nurse staffing is an important organizational intervention for improving patient outcomes. Evidence suggests that staffing improved in California hospitals after the mandate was enacted, but the outcome for hospitals bearing a disproportionate share of uncompensated care safety-net hospitals-remains unclear. One concern was that California's mandate would burden safety-net hospitals without improving staffing or that hospitals would reduce their skill mix, that is, the proportion of registered nurses of all nursing staff. We examined the differential effect of California's staffing mandate on safety-net and non-safety-net hospitals. METHODS: We used a time series design with Annual Hospital Disclosure data files from the California Office of Statewide Health Planning and Development (OSHPD) for the years 1998 to 2007 to assess differences in the effect of California's mandate on staffing outcomes in safety-net and non-safety-net hospitals. FINDINGS: The mandate resulted in significant staffing improvements, on average nearly a full patient per nurse fewer (-0.98) for all California hospitals. The greatest effect was in those hospitals with the lowest staffing levels at the outset, both safety-net and non-safety-net hospitals, as the legislation intended. The mandate led to significantly improved staffing levels for safety-net hospitals, although there was a small but significant difference in the effect on staffing levels of safety net and non-safety-net hospitals. Regarding skill mix, a marginally higher proportion of registered nurses was seen in non-safety-net hospitals following the mandate, while the skill mix remained essentially unchanged for safety-net hospitals. The difference between the two groups of hospitals was not significant. CONCLUSIONS: California's mandate improved staffing for all hospitals, including safety-net hospitals. Furthermore, improvement did not come at the cost of a reduced skill mix, as was feared. Alternative and more targeted designs, however, might yield further improvement for safety-net hospitals and reduce potential disparities in the staffing and skill mix of safety-net and non safety-net hospitals. PMID- 22428697 TI - Metropolitan fragmentation and health disparities: is there a link? AB - CONTEXT: This article explores the relationship between metropolitan fragmentation, as defined by the total number of governmental units within a metropolitan statistical area (local municipalities, special service districts, and school districts), and racial disparities in mortality among blacks and whites in the 1990s. The presence of numerous governmental jurisdictions in large metropolitan areas in the United States can shape the geography of opportunity, with adverse consequences for health. METHODS: We conducted a regression analysis using U.S. Census of Government data and Compressed Mortality File data for the country's largest 171 metropolitan statistical areas. FINDINGS: We found a link between increased metropolitan area fragmentation and greater racial differences in mortality between blacks and whites for both children and working-age adults. Although increasing fragmentation is associated with a higher mortality rate for blacks, it is not associated with a higher mortality rate for whites. These findings suggest that research is needed to understand how governance can positively or negatively influence a population's health and create conditions that generate or exacerbate health disparities. CONCLUSIONS: We need to understand the extent to which metropolitan fragmentation contributes to racial segregation, whether racism contributes to both, and the role of poverty and antipoverty policies in reducing or exacerbating the consequences of metropolitan fragmentation. The exact pathways by which metropolitan fragmentation contributes to differences between blacks' and whites' mortality rates are unknown. Uncovering how institutions influence the social, economic, and environmental conditions, which in turn contribute to the current racial and ethnic health disparities in the largest metropolitan areas, is key. Understanding these "upstream" determinants of a population's health and the disparities in health between subgroups in the overall population must be at the core of any attempt to reduce disparities in health. Building bridges between urban planning and public health can be critical to these efforts. PMID- 22428698 TI - How do rootstocks control shoot water relations? PMID- 22428699 TI - Missing nodes and links in mycorrhizal networks. PMID- 22428700 TI - From pure to applied: legume research reports from Down Under. PMID- 22428701 TI - Effect of different lysis treatments on the characteristics of yeast derivatives for winemaking. AB - The effects of three preparation techniques on the oenological properties of a yeast autolysate were investigated: enzymatic autolysis, thermolysis, and the combination of a slow freezing-defrosting and mechanical disruption were carried out on a commercial formulation of active dry yeasts (Saccharomyces cerevisiae). The powders obtained by freeze drying, were characterized: volatile compounds were analyzed by SPME-GC with mass spectrometric (MS) and olfactometric detection (O); the release of colloids in winelike solution was studied by SDS-PAGE and size exclusion chromatography (SEC). Finally, the effects of the powders addition on the aroma composition of a white wine were investigated by SPME-GC-MS, SPME-GC O, and sensory evaluation. The products obtained were quite different from each other. In particular, enzymatic autolysis led to higher contents of nonglycosilated soluble proteins in the powders and determined a higher retention of wine aroma compounds. On the contrary, thermal autolysate was richer in glycoproteins, and it was able to increase the wine aroma intensity; nevertheless, in the wines treated with such preparation, a slight yeastlike olfactory note was perceived. PMID- 22428702 TI - Reliability and construct validity of three health-related self-report scales in HIV-positive adults in rural Rwanda. AB - Depression, low health-related quality of life, and low perceived social support have been shown to predict poor health outcomes, including HIV-related outcomes. Mental health morbidity and HIV are important public health concerns in Rwanda, where approximately half of the current population is estimated to have survived the genocide and 3% is living with HIV. We examined the reliability and construct validity of the Hopkins Symptom Checklist-15 (HSCL-15), the Medical Outcomes Study HIV Health Survey (MOS-HIV), and the Duke/UNC Functional Social Support Questionnaire (DUFSSQ), which were used to assess depression, health-related quality of life, and perceived social support, respectively, among HIV-infected adults in rural Rwanda. We also studied whether scale reliability differed by gender, literacy status, or antiretroviral therapy (ART) delivery strategy. The Kinyarwanda versions of the HSCL-15, MOS-HIV, and DUFSSQ performed well in the study population. Reliability was favorable (Cronbach's alpha coefficients >=0.75 or above) for the scales overall and across subgroups of gender, literacy, and mode of ART delivery. The scales also demonstrated good convergent, discriminant, and known-group validity. PMID- 22428703 TI - Synthesis and gene transfer activities of novel serum compatible reducible tocopherol-based cationic lipids. AB - The molecular structure of the cationic lipids greatly influences their transfection efficiency. High transfection efficiencies of tocopherol-based simple monocationic transfection lipids with hydroxylethyl headgroups were recently reported by us (Kedika, B., et al. J. Med. Chem.2011, 54 (2), 548-561). Toward enhancing the transfection efficiency of tocopherol-based lipids, we have synthesized two tocopherol-based dicationic lipids (1 and 2) using simple cystine in the headgroup region. The efficiency of tocopherol-based lipids (1 and 2) were compared with nontocopherol-based lipids (3 and 4) with cystine in the headgroup region. We report also a comprehensive structure-activity relationship study that identified tocopherol-based gemini cationic lipid 1 is a better transfecting agent than its monomeric lipid counterpart 2 and two other nontocopherol-based gemini cationic lipids (3 and 4). The transfection efficiency of lipid 1 was also greater than that of commercial formulation in HepG2 cell lines. A major characteristic feature of this investigation is that serum does not inhibit the transfection activity of tocopherol-based lipids (1 and 2) in general and in particular lipid 1 which is found to be highly serum-compatible even at higher concentrations of serum when compared to its monomeric counterpart lipid 2 and the other two control lipid analogues 3 and 4. PMID- 22428704 TI - Health-related quality of life in different stages of renal failure. AB - Measures of health-related quality of life (HRQoL) have a significant predictive value on patient survival and hospitalizations, especially in patients with chronic kidney disease (CKD). In this review, some of the major studies performed in patients with different stages of renal failure are presented. The most used instrument for measuring HRQoL is the Short form health survey questionnaire (SF 36). Patients with predialysis CKD had higher SF-36 scores than a large cohort of hemodialysis (HD) or peritoneal dialysis (PD) patients, but lower scores than those reported for the adult population. Kidney transplantation offers better HRQoL than dialysis. Hemoglobin level predicted both physical and mental domain scores of the SF-36. HRQoL of HD and PD patients were compared in only a few studies, mostly because these studies are difficult to interpret. PD patients generally have lower comorbidity scores at the onset of end-stage renal disease (ESRD), independent of other factors influencing modality selection. Comorbid medical conditions are common in patients with ESRD, and are an important contributing factor to clinical outcomes and quality of life. Depression occurs in about 20-30% of dialysis patients. This is important because of the negative impact depression has on quality of life, but also because depression is now established as a factor that can significantly affect morbidity and mortality in ESRD patients. Sexual life satisfaction showed marked deterioration in all age groups. Patients aged over 65 scored significantly better than younger patients on dialysis stress scales, and were generally more satisfied with life. Longitudinal studies are needed to define periods at risk for decline in HRQoL during progression of CKD. PMID- 22428705 TI - Small non-coding RNA SraG regulates the operon YPK_1206-1205 in Yersinia pseudotuberculosis. AB - Small non-coding RNAs (sRNAs) are important post-transcriptional regulators in prokaryotes and have been demonstrated to participate in most of the cellular processes. SraG is an sRNA found in several enterobacterial species, but its targets have not been characterized. Here, we compared the protein expression patterns between the wild-type and an sraG-depleted mutant of Yersinia pseudotuberculosis by proteomic analysis. Sixteen proteins were up- or downregulated, and the negative regulatory role of SraG associated with the YPK_1206-1205 operon was confirmed. A region in the coding sequence of YPK_1206 was further demonstrated to be required for this negative regulation. PMID- 22428707 TI - Listening to many voices. PMID- 22428706 TI - Platelet-derived growth factor-BB induces cystathionine gamma-lyase expression in rat mesangial cells via a redox-dependent mechanism. AB - BACKGROUND AND PURPOSE: So far, there is only limited information about the regulation of the endogenous synthesis of hydrogen sulfide (H(2) S), an important gaseous signalling molecule. This study was done to evaluate the redox-dependent signalling events that regulate the expression of the H(2) S synthesising enzyme cystathionine-gamma-lyase (CSE) in rat mesangial cells. EXPERIMENTAL APPROACH: The effects of platelet-derived growth factor (PDGF)-BB and antioxidants on CSE expression and activity in cultured rat renal mesangial cells were assessed. Activity of nuclear factor erythroid-2-related factor-2 (Nrf2) was measured as the binding capacity to a radiolabelled consensus element by electrophoretic mobility shift assay (EMSA). Furthermore, CSE and Nrf2 expression was analysed in a rat model of anti-Thy-1-induced glomerulonephritis by immunohistochemistry. KEY RESULTS: Treatment of mesangial cells with PDGF-BB resulted in a marked time- and dose-dependent up-regulation of CSE mRNA and protein levels, as well as CSE activity accompanied with increased formation of reactive oxygen species. Remarkably, co-administration of antioxidants, such as N-acetylcysteine, ebselen or diphenylene iodonium chloride, drastically reduced PDGF-BB-induced CSE expression. PDGF-BB induced binding of Nrf2 to a corresponding consensus antioxidant element in a redox-dependent manner. Furthermore, PDGF-BB-induced CSE expression in mouse mesangial cells was completely abolished in Nrf2 knockout mice compared with wild-type mice. In a rat model of anti-Thy-1-induced proliferative glomerulonephritis, we observed a marked up-regulation of CSE protein paralleled by a stabilization of Nrf2 protein. CONCLUSIONS AND IMPLICATIONS: PDGF-BB regulated CSE via a redox-mediated activation of Nrf2. Such action would aid the resolution of glomerular inflammatory diseases. LINKED ARTICLE: This article is commented on by Gallyas, pp. 2228-2230 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01976.x. PMID- 22428708 TI - Collaborative relationships and dialogic conversations: ideas for a relationally responsive practice. AB - The author presents a set of philosophical assumptions that provide a different language for thinking about and responding to the persistent questions: "How can our therapy practices have relevance for people's everyday lives in our fast changing world, what is this relevance, and who determines it?" "Why do some shapes of relationships and forms of talk engage while others alienate? Why do some invite possibilities and ways forward not imagined before and others imprison us?" The author then translates the assumptions to inform a therapist's philosophical stance: a way of being. Next, she discusses the distinguishing features of the stance and how it facilitates collaborative relationships and dialogic conversations that offer fertile means to creative ends for therapists and their clients. PMID- 22428709 TI - Producing evidence of a miracle: exemplars of therapy conversation with a survivor of torture. AB - This article illustrates the termination sessions of a therapy case with a survivor of torture, displaced to the United States after facing targeted persecution in his home country. Using methods of qualitative research in the naturalistic paradigm, I examine the case of the client's torture rehabilitation experience through his descriptions and evaluation of the therapy process. Excerpts from the dialogue of the final 2 sessions, during which we discussed the client's past and future through the miracle question, are highlighted in this article. A case is made for further multimodal qualitative analyses of therapy conversation with this population. PMID- 22428710 TI - Scaffolding a community of competent practitioners: positioning and agency in a training program for narrative counseling. AB - This article explores the scaffolding of learning experiences in a postgraduate program in New Zealand that offers training in narrative counseling. The authors draw on positioning theory to identify student shifts in learning, and in agency, that help build an increasingly skilled and peer-generated context for learning. We describe a selection of exercises and one key assignment, introduced in the course in a particular order, that we believe enable students to step into positions of agency which ultimately allow a competent community of learner practitioners to emerge. We also describe a dance of positioning for ourselves as teachers in this program. We suggest that, at any given time, our own positioning is tied up with possibilities for student positioning. Acknowledging relationships of power in classrooms, we explore ways to align poststructuralist counseling practices and the teaching of these practices. PMID- 22428711 TI - Culturally adapting an evidence-based parenting intervention for Latino immigrants: the need to integrate fidelity and cultural relevance. AB - Latinos constitute the largest ethnic minority group in the United States. However, the cultural adaptation and dissemination of evidence-based parenting interventions among Latino populations continues to be scarce despite extensive research that demonstrates the long-term positive effects of these interventions. The purpose of this article is threefold: (1) justify the importance of cultural adaptation research as a key strategy to disseminate efficacious interventions among Latinos, (2) describe the initial steps of a program of prevention research with Latino immigrants aimed at culturally adapting an evidence-based intervention informed by parent management training principles, and (3) discuss implications for advancing cultural adaptation prevention practice and research, based on the initial feasibility and cultural acceptability findings of the current investigation. PMID- 22428712 TI - Parenting as relationship: a framework for assessment and practice. AB - Parenting tends to be framed as a set of actions directed toward the child rather than as a relationship. This article helps therapists, parent-educators, and researchers conceptualize parenting as a socioculturally embedded relationship. The authors apply the relational orientations typology (Silverstein, Bass, Tuttle, Knudson-Martin, & Huenergardt, 2006) to parent-child relationships. The typology addresses two dimensions: whether the focus is on the child's meeting parental expectations or on expectations of mutuality and whether power between parent and child is expected to be symmetrical or asymmetrical. Four relational orientations are described: (1) rule directed, (2) position directed, (3) independence directed, and (4) relationship directed. These relational orientations describe the nature of the reciprocal relationship between parent and child and offer a framework from which to address parenting issues. A case illustration shows how the relational orientations framework helps therapists incorporate a larger systems/relational perspective into what was originally framed primarily as a child behavior problem. PMID- 22428713 TI - Parent training in nonviolent resistance for adult entitled dependence. AB - "Adult entitled dependence" is a condition characterized by the extreme dependence of grown children on their family and by levels of dysfunction, seemingly excessive in light of their apparent capacity to function. The family and the dependent adult become involved in an interaction in which the very attempts to alleviate the problem may aggravate it. Parent-training in nonviolent resistance (NVR) is an intervention that has been shown to be helpful to parents of behaviorally disturbed youth. Parent training in NVR offers parents means to shift away from a stance of helplessness toward realistic goals that are accomplishable without the collaboration of their offspring. We report on the parents of 27 entitled dependent grown children who participated in parent training in NVR. Additionally, we present 2 detailed case studies that exemplify the problem and the therapeutic process. Before treatment, the dependent adults were not working or studying, drew heavily on parental services (financial or otherwise), and were resistant to parental attempts to change the situation. Most parents succeeded in overcoming their helplessness and reducing the provision of parental services. In a considerable proportion of cases, the grown children started working or studying or moved to independent lodgings. PMID- 22428714 TI - We-talk, communal coping, and cessation success in a couple-focused intervention for health-compromised smokers. AB - We investigated first-person plural pronoun use (we-talk) by health-compromised smokers and their spouses as a possible implicit marker of adaptive, problem resolving communal processes. Twenty couples in which one or both partners used tobacco despite one of them having a heart or lung problem participated in up to 10 sessions of a smoking cessation intervention designed to promote communal coping, where partners define smoking as "our" problem, rather than "your" problem or "my" problem, and take collaborative action to solve it. We used the Linguistic Inquiry Word Count automatic text analysis program to tabulate first person pronoun use by both partners from transcripts of a pretreatment marital interaction task and later intervention sessions. Results indicated that pretreatment we-talk by the patient's spouse predicted whether the patient remained abstinent 12 months after quitting, and residualized change in we-talk by both partners during the course of intervention (controlling for baseline levels) predicted cessation outcomes as well. These findings add to evidence regarding the prognostic significance of partner we-talk for patient health and provide preliminary documentation of communal coping as a possible mechanism of change in couple-focused intervention. PMID- 22428715 TI - Adding a baby to the equation. married and cohabiting women's relationship satisfaction in the transition to parenthood. AB - The trajectory of relationship satisfaction among married and cohabiting women in their transition to parenthood was compared in a potential sample of 71,504 women taking part in the Norwegian Mother and Child Cohort Study (MoBa). Prospective longitudinal data were collected in 4 waves over a 2-year period starting 6 months prebirth. Results from latent curve models suggested that married and cohabiting women experience similar negative change in relationship satisfaction during the transition to parenthood. However, cohabiting women start off and stay less satisfied throughout the transition period, suggesting the presence of a negative cohabitation effect that prevailed after controlling for various covariates. Extending investigation on the cohabitation effect to the transition to parenthood, and replicating it in a Scandinavian context, is discussed in relation to the understanding of what causes the cohabitation effect, and its clinical implications. PMID- 22428716 TI - Development and dissemination of collaborative family-oriented services: the case of community/day residential care in Israel. AB - The initiation, development, and dissemination of family-oriented programs are a unifying thread that highlights family therapy's contribution to the fields of mental/physical health and social services. These demanding tasks require an ecosystemic vision, a supportive larger context, and a range of skills. This article delineates the evolution of community and day residential care in Israel by examining processes at different ecological levels: the formulation and implementation of national social policy, the follow-up of two family-oriented facilities, one of which thrived while the other eventually closed, and the residential care provided to 1 family with 3 children. The analysis of this multilevel data highlights 4 facilitating/obstructing factors that have had major impact on family-oriented programs: support by both national and local sociopolitical-professional administration, program's management autonomy, staff training, support and development, and effective facility leadership that establishes and nurtures family-oriented organizational structure and culture. PMID- 22428717 TI - Two new sesquiterpene lactones from the supercritical fluid extract of Centipeda minima. AB - Two new sesquiterpene lactones, minimolides G(1) and H(2), were isolated from the supercritical fluid extract of Centipeda minima. Their structures were elucidated on the basis of extensive analyses of spectroscopic data including IR, HR-ESI-MS, 1D and 2D NMR. Compounds 1 and 2 displayed inhibitory activity against human nasopharyngeal cancer cell line (CNE) with IC50 values of 61.4 and 28.7 MUM, respectively. PMID- 22428718 TI - Mechanism-based approach to the economic evaluation of pharmaceuticals: pharmacokinetic/pharmacodynamic/pharmacoeconomic analysis of rituximab for follicular lymphoma. AB - BACKGROUND AND OBJECTIVES: Economic value is an important consideration during all phases of the drug development process. We previously published an article in PharmacoEconomics in which we described a mechanism-based economic modelling approach that incorporates data obtained during phase II clinical studies on the relationships between dose, exposure and response. We now describe case studies of rituximab for the treatment of follicular non-Hodgkin's lymphoma based on this methodology. METHODS: We utilized a population pharmacokinetic and pharmacodynamic model linking serum rituximab concentration to progression-free survival, to simulate the effectiveness of rituximab in various clinical contexts. These served as inputs to economic models of follicular lymphoma, based on National Institute for Health and Clinical Excellence (NICE) appraisals, to assess the cost effectiveness of rituximab. Our results were compared with trial based estimates from the NICE appraisals. In a further analysis, we simulated the results of an ongoing trial to generate predictions of cost effectiveness. RESULTS: Our analyses suggest an acceptable degree of concordance between simulation- and trial-based estimates of cost effectiveness. For first-line and maintenance therapy, deviations of L2,099 and L1,355 per QALY, respectively, from trial-based incremental cost-effectiveness ratio estimates of L8,290 and L7,721 per QALY gained would not affect reimbursement decisions. The probability of rituximab-containing regimens being cost effective at L20,000 and L30,000 per QALY thresholds was 1 for both first-line and maintenance therapy in both simulated and trial-based analyses. CONCLUSIONS: Our analyses demonstrate the feasibility of mechanism-based economic analyses, which may have applications during drug development to the following: (i) directing future research based on the cost of reducing uncertainty; (ii) assessing subgroups, dosing schedules and protocol deviations; and (iii) informing strategic research and development and pricing decisions. PMID- 22428719 TI - Cognitive control: a role for implicit learning? AB - We investigated the influence of implicit learning on cognitive control. In a sequential Stroop task, participants implicitly learned a sequence placed on the color of the Stroop words. In Experiment 1, Stroop conflict was lower in sequenced than in random trials (learning-improved control). However, as these results were derived from an interaction between learning and conflict, they could also be explained by improved implicit learning (difference between random and sequenced trials), under incongruent compared with congruent trials (control improved learning). Therefore, we further unraveled the direction of the interaction in 2 additional experiments. In Experiment 2, participants who learned the color sequence were no better at resolving conflict than participants who did not undergo sequence training. This shows that implicit knowledge does not directly reduce conflict (no learning-improved control). In Experiment 3, the amount of conflict did not directly improve learning either (no control-improved learning). However, conflict had a significant impact on the expression of implicit learning, as most knowledge was expressed under the highest amount of conflict. Thus, task-optimization was accomplished by an increased reliance on implicit sequence knowledge under high conflict. These findings demonstrate that implicit learning processes can be flexibly recruited to support cognitive control functions. PMID- 22428720 TI - Lack of association of ACP1 gene with inflammatory bowel disease: a case-control study. AB - The red cell acid phosphatease (ACP1) gene, which encodes a low molecular weight phosphotyrosine phosphatase (LMW-PTP), has been suggested as a common genetic factor of autoimmunity. In the present study, we aimed to investigate the possible influence of ACP1 polymorphisms in the susceptibility of inflammatory bowel disease (IBD). A total of 1271 IBD Spanish patients [720 Crohn's disease (CD) and 551 ulcerative colitis (UC)] and 1877 healthy subjects were included. Four single-nucleotide polymorphisms (SNPs), rs10167992, rs11553742, rs7576247 and rs3828329, were genotyped using TaqMan SNP genotyping assays. Common ACP1 alleles (i.e. ACP1*A, ACP1*B and ACP1*C) were determined by two of these SNPs. After the analysis, no evidence of association of the ACP1 genetic variants was found with CD or UC. Therefore, our results suggest that the ACP1 gene may not play a relevant role in the development of IBD. PMID- 22428721 TI - Buprenorphine exposure in infants of opioid-dependent mothers at birth. AB - BACKGROUND: Buprenorphine, a partial opioid agonist used in treating opioid dependence, is not approved in Australia for use in pregnancy. Nevertheless, many pregnant women choose to remain on the drug. AIM: To investigate cord/maternal transfer ratios for buprenorphine and norbuprenorphine in women at delivery. METHODS: Maternal and cord serum samples were collected from 10 maternal-infant pairs at delivery. Drug concentrations were measured by liquid chromatography tandem mass spectrometry. Maternal and infant demographic information was collected. Linear regression was used to assess the relationship between maternal and cord measurements. RESULTS: Median (interquartile range) maternal age was 27 (23.8-32) years, with 90% of the women on buprenorphine before pregnancy. Median infant birthweight was 3148 (3088-3545) g and 60% of infants had neonatal abstinence requiring admission to a neonatal intensive care unit for a median of 8.5 (2.5-16.3) days. Median maternal buprenorphine daily dose was 8.5 mg (range 1 28 mg). Mean (95% confidence interval) cord serum concentrations of buprenorphine and norbuprenorphine were 0.4 (0.3-0.5) MUg/L and 1.2 (0.9-1.4) MUg/L, respectively. Mean maternal concentrations of buprenorphine and norbuprenorphine were 1.0 (0.6-1.4) MUg/L and 1.2 (0.9-1.4) MUg/L, respectively. Mean cord/maternal ratios were 0.43 (0.36-0.5) for buprenorphine and 0.53 (0.43-0.63) for norbuprenorphine. Maternal buprenorphine and norbuprenorphine concentrations and ratio of buprenorphine/norbuprenorphine explained 85.7, 69.6 and 94.4%, respectively, of variation in the corresponding cord concentrations. CONCLUSION: Usual therapeutic doses of buprenorphine administered to pregnant women resulted in low concentrations of buprenorphine and norbuprenorphine in maternal serum and a low transfer to the fetal circulation (cord plasma) at birth. PMID- 22428722 TI - Biological therapies for von Willebrand disease. AB - INTRODUCTION: von Willebrand factor (VWF)-related disorders are generally distinguished as either acquired (von Willebrand Syndrome; VWS) or congenital (von Willebrand Disease; VWD). VWD is the most common inherited bleeding disorder and is due to deficiencies and/or defects in VWF. VWS arises from a large variety of causes. AREAS COVERED: The current report briefly overviews the diagnosis of VWD and VWS, but primarily covers the management of these disorders, as reflected by differential processes applied within different centers worldwide, also focusing on emerging trends in biological therapies. Most developed countries currently use standard therapy to manage bleeding, employing desmopressin wherever possible, factor concentrate in other situations and additional (e.g., antifibrinolytic) therapy when required. With regards to factor concentrates, there are differences in content between those available in relation to levels and composition of VWF and factor VIII, and only selective concentrates are available in different localities. EXPERT OPINION: All these aspects reflect important but sometimes overlooked issues when using replacement therapy, or attempting to follow expert guidelines. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may change the VWD management landscape in the near future. PMID- 22428723 TI - Stimuli responsive release of metalic nanoparticles on semiconductor substrates. AB - Optically active metal nanoparticles have been of recent and broad interest for applications to biomarker detection because of their ability to enable high sensitivity enhancements in various optical detection techniques. Here, we report stimuli responsive release of metallic nanoparticles on a semiconductor thin film array structure based on pH change. The metallic nanoparticles are obtained by a simple redox procedure on the semiconductor surface. This approach allows controlling nanoparticle surface coatings in situ for biomolecule conjugation, such as DNA probes on nanoparticles, and rapid stimuli responsive release of these nanoparticles upon pH change. PMID- 22428724 TI - Facile synthesis of main-chain degradable block copolymers for performance enhanced dismantlable adhesion. AB - Block copolymers consisting of readily degradable polyperoxides and non degradable vinyl polymers as the block segments were successfully synthesized by reversible chain transfer catalyzed polymerization, which is one of living radical polymerization techniques. The block copolymers showed characteristic morphology and wettability being different from the polymer blends. When block copolymers containing polyperoxide and polymethacrylate blocks were heated below 150 degrees C, the polyperoxide blocks were completely degraded and the polymethacrylate blocks were recovered without degradation. Block copolymers containing a poly(2-ethylhexyl methacrylate) block were then investigated as a dismantlable adhesion material, which requires adequate bonding strength during use and easy debonding on demand. Among the several block copolymers, the one consisting of poly(2-ethylhexyl methacrylate) and polyperoxide from methyl sorbate (PPMS) (M(n) = 4900) exhibited good performance as a pressure-sensitive adhesive (PSA). After heating the test specimens in a temperature range from 60 to 100 degrees C, PSA performance, which was evaluated by 180 degrees peel strength and shear holding power measurements, was significantly diminished. Especially, after heating at 100 degrees C for 1 h, spontaneous debonding of some test specimens was observed because of the evolution of volatile acetaldehyde from PPMS. PMID- 22428725 TI - Generation, characterization, and potential therapeutic applications of cardiomyocytes from various stem cells. AB - Heart failure is one of the leading causes of death worldwide. Myocardial cell transplantation emerges as a novel therapeutic strategy for heart failure, but this approach has been hampered by severe shortage of human cardiomyocytes. We have recently induced mouse embryonic stem cells to differentiate into embryoid bodies and eventually, cardiomyocytes. Here, we address recent advancements in cardiomyocyte differentiation from cardiac stem cells and pluripotent stem cells. We highlight the methodologies, using growth factors, endoderm-like cell cocultures, small molecules, and biomaterials, in directing the differentiation of pluripotent stem cells into cardiomyocytes. The characterization and identification of pluripotent stem cell-derived cardiomyocytes by morphological, phenotypic, and functional features are also discussed. Notably, increasing evidence demonstrates that cardiomyocytes may be generated from the stem cells of several tissues outside the cardiovascular system, including skeletal muscles, bone marrow, testes, placenta, amniotic fluid, and adipose tissues. We further address the potential applications of cardiomyocytes derived from various kinds of stem cells. The differentiation of stem cells into functional cardiomyocytes, especially from an extra-cardiac stem cell source, would circumvent the scarcity of heart donors and human cardiomyocytes, and, most importantly, it would offer an ideal and promising cardiomyocyte source for cell therapy and tissue engineering in treating heart failure. PMID- 22428726 TI - Antioxidant status in hyperthyroid cats before and after radioiodine treatment. AB - BACKGROUND: Reversible antioxidant depletion is found in hyperthyroid humans, and antioxidant depletion increases the risk of methimazole toxicosis in rats. OBJECTIVES: To determine whether abnormalities in concentrations of blood antioxidants or urinary isoprostanes were present in hyperthyroid cats, and were reversible after radioiodine treatment. To determine whether or not antioxidant abnormalities were associated with idiosyncratic methimazole toxicosis. ANIMALS: Hyperthyroid cats presented for radioiodine treatment (n = 44) and healthy mature adult control cats (n = 37). METHODS: Prospective, controlled, observational study. Red blood cell glutathione (GSH), plasma ascorbate (AA), plasma free retinol (vitamin A), alpha-tocopherol (vitamin E), and urinary free 8 isoprostanes in hyperthyroid cats were compared to healthy cats and to hyperthyroid cats 2 months after treatment. RESULTS: Blood antioxidants were not significantly different in hyperthyroid cats (mean GSH 1.6 +/- 0.3 mM; AA 12.8 +/ 4.9 MUM, and vitamin E, 25 +/- 14 MUg/mL) compared to controls (GSH 1.4 +/- 0.4 mM; AA 15.0 +/- 6.6 MUM, and vitamin E, 25 +/- 17 MUg/mL). Urinary isoprostanes were increased in hyperthyroid cats (292 +/- 211 pg/mg creatinine) compared to controls (169 +/- 82 pg/mg; P = .006), particularly in hyperthyroid cats with a USG < 1.035. Plasma free vitamin A was higher in hyperthyroid cats (0.54 +/- 0.28 MUg/mL versus 0.38 +/- 0.21 in controls; P = .007). Both abnormalities normalized after radioiodine treatment. No association was found between oxidative status and prior idiosyncratic methimazole toxicosis. CONCLUSION AND CLINICAL IMPORTANCE: Increased urinary isoprostane could reflect reversible renal oxidative stress induced by hyperthyroidism, and this requires additional evaluation. PMID- 22428727 TI - Exploiting transport activity of p-glycoprotein at the blood-brain barrier for the development of peripheral cannabinoid type 1 receptor antagonists. AB - Although the CB1 receptor antagonist/inverse agonist rimonabant has positive effects on weight loss and cardiometabolic risk factors, neuropsychiatric side effects have prompted researchers to develop peripherally acting derivatives. Here, we investigated for a series of 3,4-diarylpyrazoline CB1 receptor antagonists if transport by the brain efflux transporter P-gp could be used as a selection criterion in the development of such drugs. All 3,4-diarylpyrazolines and rimonabant inhibited P-gp transport activity in membrane vesicles isolated from HEK293 cells overexpressing the transporter, but only the 1,1-dioxo thiomorpholino analogue 23 exhibited a reduced accumulation (-38 +/- 2%) in these cells, which could be completely reversed by the P-gp/BCRP inhibitor elacridar. In addition, 23 appeared to be a BCRP substrate, whereas rimonabant was not. In rats, the in vivo brain/plasma concentration ratio of 23 was significantly lower than for rimonabant (0.4 +/- 0.1 vs 6.2 +/- 1.6, p < 0.001). Coadministration of elacridar resulted in an 11-fold increase of the brain/plasma ratio for 23 (p < 0.01) and only 1.4-fold for rimonabant (p < 0.05), confirming the involvement of P-gp and possibly BCRP in limiting the brain entrance of 23 in vivo. In conclusion, these data support the conception that efflux via transporters such as P-gp and BCRP can limit the brain penetration of CB1 receptor antagonists, and that this property could be used in the development of peripheral antagonists. PMID- 22428728 TI - Polyatomic anion assistance in the assembly of [2]pseudorotaxanes. AB - We describe the use of polyatomic anions for the quantitative assembly of ion paired complexes displaying pseudorotaxane topology. Our approach exploits the unique ion-pair recognition properties exhibited by noncovalent neutral receptors assembled through hydrogen-bonding interactions between a bis-calix[4]pyrrole macrocycle and linear bis-amidepyridyl-N-oxides. The complexation of bidentate polyatomic anions that are complementary in size and shape to the receptor's cavity, in which six NH hydrogen-bond donors converge, induces the exclusive formation of four particle-threaded assemblies. PMID- 22428729 TI - Visible-light-driven photocatalytic inactivation of E. coli K-12 by bismuth vanadate nanotubes: bactericidal performance and mechanism. AB - Bismuth vanadate nanotube (BV-NT), synthesized by a template-free solvothermal method, was used as an effective visible-light-driven (VLD) photocatalyst for inactivation of Escherichia coli K-12. The mechanism of photocatalytic bacterial inactivation was investigated by employing multiple scavengers combined with a simple partition system. The VLD photocatalytic bacterial inactivation by BV-NT did not allow any bacterial regrowth. The photogenerated h(+) and reactive oxidative species derived from h(+), such as OH(ads), H(2)O(2) and HO(2)/O(2)(-), were the major reactive species for bacterial inactivation. The inactivation by h(+) and OH(ads) required close contact between the BV-NT and bacterial cells, and only a limited amount of H(2)O(2) could diffuse into the solution to inactivate bacterial cells. The direct oxidation effect of h(+) to bacterial cells was confirmed by adopting F(-) surface modification and anaerobic experiments. The bacterial cells could trap e(-) in order to minimize e(-)-h(+) recombination, especially under anaerobic condition. Transmission electron microscopic study indicated the destruction process of bacterial cell began from the cell wall to other cellular components. The OH(ads) was postulated to be more important than OH(bulk) and was not supposed to be released very easily in the BV NT bacterial inactivation system. PMID- 22428730 TI - Synthesis and properties of fluorescence dyes: tetracyclic pyrazolo[3,4 b]pyridine-based coumarin chromophores with intramolecular charge transfer character. AB - Two series of new tetracyclic pyrazolo[3,4-b]pyridine-based coumarin chromophores were synthesized through a facile reaction between 3-aldehyde-7 diethylaminocoumarin (5) or 3-acetyl-7-diethylaminocoumarin (6) and 5 aminopyrazole derivatives (7) in a one-pot procedure. Different condensed products were obtained from compounds 5 and 6, and the potential reaction mechanism was studied using the reaction of 5 with 5-amino-1-phenylpyrazole (7a). The molecular structures were characterized by NMR and HRMS and confirmed by X ray diffraction. The photophysical, electrochemical, and thermal properties of these compounds were investigated by absorption spectroscopy, fluorescence spectroscopy, single photon counting technique, cyclic voltammetry, thermogravimetric analysis, etc. Results show that the compounds exhibited high fluorescence quantum yields and good electrochemical, thermal, and photochemical stabilities. In addition, the application of these highly fluorescent compounds in living cell imaging was also explored by laser scanning confocal microscopy. PMID- 22428731 TI - The effects of liver transplantation on the clinical course of colitis in ulcerative colitis patients with primary sclerosing cholangitis. AB - BACKGROUND: The course of ulcerative colitis (UC) following orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) is unclear. AIM: To investigate the clinical course of UC, before and after OLT for PSC. METHODS: From a historical cohort of 86 patients with PSC-UC who underwent OLT, 77 patients who were followed up at our institution both before and after OLT from 1985 to 2011 were included. RESULTS: Ulcerative colitis was diagnosed in 77 (97.5%) patients before OLT. Nineteen of 77 (24.7%) patients underwent colectomy before OLT. In the other 58 patients, the course of UC after OLT when compared to the last 5 years before OLT was quiescent in 48 patients (82.8%) while 9/58 (15.5%) of patients underwent colectomy post-OLT. There was a total of 97 colitis flares over a total of 621 years of follow-up from PSC/UC diagnosis to OLT (0.156 flares per patient year) whereas post-OLT, there were 31 flares over a total of 511 years of post-OLT follow-up (0.061 flares per patient year) (P < 0.001). On univariable analysis, the number of UC flares [Odds ratio (OR) 1.52; 95% Confidence interval (1.02-2.27), P = 0.04] and dysplasia [OR 47.00; 95% CI (6.48 340.66), P < 0.001] increased the risk of colectomy following OLT; the use of corticosteroids [OR 0.07; 95% CI (0.01-0.63), P = 0.008] and 5-aminosalicylate [OR 0.18; 95% CI (0.04-0.83), P = 0.04] was protective. CONCLUSIONS: Ulcerative colitis in the presence of primary sclerosing cholangitis remains quiescent, and may improve in most patients after orthotopic liver transplantation. PMID- 22428733 TI - Hemodiafiltration in infants with complications during peritoneal dialysis. AB - End-stage renal disease (ESRD) in neonates still has a high mortality, particularly in the first year of life. We present the combination of peritoneal dialysis (PD) with intermittent hemodiafiltration (iHDF) in neonates with ESRD. Four infants younger than 28 days were treated with PD and iHDF. Renal diagnoses leading to ESRD were cortical necrosis, prune belly syndrome, neonatal hemolytic uremic syndrome, and autosomal recessive polycystic kidney disease. Initially, three patients were on iHDF until PD was started. At the time when complications occurred during PD, patients were switched back to iHDF. iHDF was used five times as a bridge to PD in case of abdominal surgery. Two of the four patients were switched to iHDF because of peritoneal ultrafiltration failure due to recurrent peritoneal leaks. Once, iHDF became necessary due to refractory peritonitis. All four patients survived the first year of life. Two patients were transplanted successfully at an age of 35 and 22 months, respectively. The others are on renal replacement therapy, one on PD at the age of 28 months and one on iHDF at the age of 25 months, respectively. In case of PD complications, iHDF may be an appropriate bridge to achieve long-term survival until kidney transplantation. PMID- 22428734 TI - The life and times of Thomas Willis and his impact on contemporary medicine. AB - Thomas Willis made numerous contributions to the neurosciences that were broad in scope. In an age of scientific breakthroughs and intellectual revolutions, Willis bestowed upon medical research the clinical rigor that set the stage for subsequent medical breakthroughs. In Cerebri Anatome, Willis introduced a measure of empiricism hitherto unknown in medieval times. By coupling the delineation of brain and neural anatomy with functional studies, Willis brought the science of clinical neurology into fruition. Psychiatry, too, benefited from Willis' elucidation of mental illness and intellectual disability, and modern behavioral psychologists claim Willis as one their early, most ardent champions. PMID- 22428735 TI - Ramon y Cajal erroneously identified as Camillo Golgi on a souvenir postage stamp. AB - Focusing on a philatelic oddity that erringly identifies a picture of Santiago Ramon y Cajal as that of Camillo Golgi, this brief article examines official and unofficial stamp issues honoring the two great neuroanatomists, one from Spain and the other from Italy, who were early Nobel Prize winners in Physiology or Medicine. PMID- 22428736 TI - The woman of Pritschoena: an example of the German neolithic neurosurgery in Saxony-Anhalt. AB - We present an outstanding example of successful prehistoric double trephination dating between 2700 and 2200 BC, most likely to the Corded Ware culture, at the end of the Neolithic Age. The particularity of this case is the presence of a double trephination, one frontal over the sinus sagittal superior and one parietal right. There is evidence that the patient survived months to years after the operations. The purpose of the procedure is not known. The case confirms the astonishing degree of technical skills reached in Saxony-Anhalt over 4500 years ago without anesthetic, antiseptic, or technologic aids. PMID- 22428737 TI - Historical essay: electroconvulsive therapy, memory, and self in America. AB - Electroconvulsive Therapy (ECT) practitioners and anti-ECT activists have divergent interpretations of both the treatment and its history. Despite claims by ECT opponents that practitioners do not acknowledge memory side effects, the published literature on the procedure demonstrates psychiatrists' awareness of this issue. And though current ECT practitioners claim that memory side effects were mostly the result of outmoded methods, investigators continue to publish studies that indicate ongoing memory problems. This article explores the conflict between pro- and anti-ECT groups around the issue of memory side effects in the broader context of changes in American psychiatry and society. PMID- 22428738 TI - An old hypothesis and new tools: Alfred Fessard's approach to the problem of consciousness. AB - In 1954, a symposium was held in Canada on "Brain Mechanisms and Consciousness." It was a time for the promotion of international and interdisciplinary scientific cooperation, of new technological expectation, and of speculating about complex human behavior. Alfred Fessard's lecture on "Mechanisms of Nervous Integration and Conscious Experience" was one of the outstanding presentations, rich in critical analysis of the then available experimental data and in working hypothesis proposals. Reading the concept expressed by Fessard, it was found that several of his ideas had anticipated data obtained in modern research with new technologies. PMID- 22428739 TI - From brain to neuro: the brain research association and the making of British neuroscience, 1965-1996. AB - This article explores the short history of "neuroscience" as a discipline in its own right as opposed to the much longer past of the brain sciences. It focuses on one historical moment, the formation of the first British "neuroscience" society, the Brain Research Association (BRA), renamed in 1996 to the British Neuroscience Association (BNA). It outlines the new thinking brought about by this new science of brain, mind, and behavior, it sketches the beginnings of the BRA and the institutionalization of neuroscience in the British context, and it further explores the ambiguous relation the association had towards some of the ethical, social, and political implications of this new area of research. PMID- 22428740 TI - Memories of John Eccles. AB - This article contains an account of the career of John Eccles that can be divided into two parts. The first extends from 1925, when he won a Rhodes scholarship to Magdalen College Oxford, to 1975, when he took voluntary retirement from the State University of New York at Buffalo. During this period, he set up six different laboratories in which he carried out research on synaptic mechanisms that provide the basis of neuroscience. The second period is the 20 years between his retirement and death in Switzerland, which he spent on the problem of the relationship between mind and brain. PMID- 22428741 TI - Neurognostics question. Howard Andrew Knox. PMID- 22428742 TI - Is poetry a disease of the Brain, as Alfred de Vigny said? PMID- 22428745 TI - Is quality of life poorer for older adults with HIV/AIDS? International evidence using the WHOQOL-HIV. AB - Increasingly older adults are being diagnosed with HIV/AIDS. In 2002, UNAIDS indicated that 13 aspects of quality of life (QoL) were poorer for older adults, but only sparse, inconsistent cross-cultural evidence is available. This statement was investigated using a reliable, valid measure (the WHOQOL-HIV) distributed in nine cultures (eight countries). HIV positive and well adults (n = 2089) were assessed across 30 QoL facets; 403 were 40+ years. It was confirmed that sleep, fatigue and sex-life were poorer areas of QoL for older HIV adults than younger. Furthermore, they could be misinterpreted as normal ageing signs. Moreover, older people reported greater dependency on medication. However, older HIV adults had better QoL than expected on 11 dimensions; negative feelings, social inclusion, and several environmental and spiritual facets. This highlights the extent of poor QoL in younger adults. After accounting for culture and gender, overall QoL and health in older HIV adults was explained by eight facets comprising 61.3% of the variance. Social relationships were paramount, especially personal relationships (41%), but support and sex-life also. Energy, negative feelings, cognitions, financial resources and HIV symptoms also contributed. Social interventions for ageing communities would improve well-being. This evidence could support global ageing and HIV policy. PMID- 22428746 TI - Perinatal ethinyl oestradiol alters mammary gland development in male and female Wistar rats. AB - Increased attention is being paid to human mammary gland development because of concerns for environmental influences on puberty onset and breast cancer development. Studies in rodents have showed a variety of changes in the mammary glands after perinatal exposure to endocrine disrupting chemicals, indicating progressed development of mammary glands when exposed to oestrogens early in life. However, laboratories use different parameters to evaluate the development of mammary glands, making studies difficult to compare. Moreover, studies of whole mounts in Wistar rats are lacking. In the present study, Wistar rats were exposed to 0, 5, 15 or 50 MUg/kg of ethinyl oestradiol per day during gestation and lactation. A wide range of morphological parameters were evaluated in whole mounts of mammary glands from male and female offspring PD21-22. This study showed that in both male and female pre-pubertal Wistar rats, mammary gland development was accelerated after perinatal oestrogen exposure with increase in size, density and number of terminal end buds (TEBs). In female rats, the most sensitive parameters were the distance to the fifth gland, the relative growth towards the lymph node and the overall density. The sensitive endpoints in male rats were TEB numbers, both in the whole gland and in the zone C, the overall- and the highest density. The overall density was sensitive in both male and female rats and was considered a good representative of both branching and budding of the gland. The number of TEBs in zone C was representative of the number of TEBs in the whole gland. Further studies in older Wistar rats and with weak oestrogenic compounds could be performed to validate mammary gland examination as an endpoint in reproductive toxicity studies and to examine how early life environmental exposures may alter mammary gland development, disrupt lactation and alter susceptibility to breast cancer. PMID- 22428747 TI - Culturable gut microbiota diversity in zebrafish. AB - The zebrafish (Danio rerio) is an increasingly used laboratory animal model in basic biology and biomedicine, novel drug development, and toxicology. The wide use has increased the demand for optimized husbandry protocols to ensure animal health care and welfare. The knowledge about the correlation between culturable zebrafish intestinal microbiota and health in relation to environmental factors and management procedures is very limited. A semi-quantitative level of growth of individual types of bacteria was determined and associated with sampling points. A total of 72 TAB line zebrafish from four laboratories (Labs A-D) in the Zebrafish Network Norway were used. Diagnostic was based on traditional bacterial culture methods and biochemical characterization using commercial kits, followed by 16S rDNA gene sequencing from pure subcultures. Also selected Gram-negative isolates were analyzed for antibiotic susceptibility to 8 different antibiotics. A total of 13 morphologically different bacterial species were the most prevalent: Aeromonas hydrophila, Aeromonas sobria, Vibrio parahaemolyticus, Photobacterium damselae, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas luteola, Comamonas testosteroni, Ochrobactrum anthropi, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus capitis, and Staphylococcus warneri. Only Lab B had significantly higher levels of total bacterial growth (OR=2.03), whereas numbers from Lab C (OR=1.01) and Lab D (OR=1.12) were found to be similar to the baseline Lab A. Sexually immature individuals had a significantly higher level of harvested total bacterial growth than mature fish (OR=0.82), no statistically significant differences were found between male and female fish (OR=1.01), and the posterior intestinal segment demonstrated a higher degree of culturable bacteria than the anterior segment (OR=4.1). Multiple antibiotic (>3) resistance was observed in 17% of the strains. We propose that a rapid conventional diagnostic bacteriological assay on the culturable microbiota profiles can be designed and used as quality measure of the husbandry routines of a zebrafish facility to ensure a bacterial standard safeguarding the zebrafish health and welfare. PMID- 22428748 TI - ZeBase: an open-source relational database for zebrafish laboratories. AB - Abstract ZeBase is an open-source relational database for zebrafish inventory. It is designed for the recording of genetic, breeding, and survival information of fish lines maintained in a single- or multi-laboratory environment. Users can easily access ZeBase through standard web-browsers anywhere on a network. Convenient search and reporting functions are available to facilitate routine inventory work; such functions can also be automated by simple scripting. Optional barcode generation and scanning are also built-in for easy access to the information related to any fish. Further information of the database and an example implementation can be found at http://zebase.bio.purdue.edu. PMID- 22428749 TI - An inexpensive, efficient method for regular egg collection from zebrafish in a recirculating system. AB - Zebrafish in our laboratory are usually bred by removing the fish from the recirculating aquatic system and placing them into 1-2 L spawning tanks. These spawning tanks consist of a bottom reservoir, a lid, and an insert that fits in closely into the bottom reservoir. When the fish breed, the eggs fall through holes of the insert and into the reservoir, thus preventing them from being cannibalized. Because fish in these spawning tanks are not fed and do not get fresh water, they are bred only once a week. During a period where we had high demand for embryos, we instead tried breeding the fish for multiple consecutive days on the recirculating system. Fish were placed into the spawning insert as usual, but the insert was placed into the home tank instead of into the bottom reservoir. We found that there was no significant difference in the number of fertilized eggs produced between the spawning tank and home tank breeding methods. Further, the fish in the home tanks regularly produced fertile embryos over a 28-day time course, with the highest number of eggs per pair produced by the tank with only one pair of adult fish. This method is time-saving as fish bred in home tanks only require to be set up once. It is also an effective way to collect embryos over long periods from the same pair or group of fish and to more easily obtain embryos from stocks with low spawning frequency. PMID- 22428751 TI - Spatial patterns of soil pathogens in declining Mediterranean forests: implications for tree species regeneration. AB - Soil-borne pathogens are a key component of the belowground community because of the significance of their ecological and socio-economic impacts. However, very little is known about the complexity of their distribution patterns in natural systems. Here, we explored the patterns, causes and ecological consequences of spatial variability in pathogen abundance in Mediterranean forests affected by oak decline. We used spatially explicit neighborhood models to predict the abundance of soil-borne pathogen species (Phytophthora cinnamomi, Pythium spiculum and Pythium spp.) as a function of local abiotic conditions (soil texture) and the characteristics of the tree and shrub neighborhoods (species composition, size and health status). The implications of pathogen abundance for tree seedling performance were explored by conducting a sowing experiment in the same locations in which pathogen abundance was quantified. Pathogen abundance in the forest soil was not randomly distributed, but exhibited spatially predictable patterns influenced by both abiotic and, particularly, biotic factors (tree and shrub species). Pathogen abundance reduced seedling emergence and survival, but not in all sites or tree species. Our findings suggest that heterogeneous spatial patterns of pathogen abundance at fine spatial scale can be important for the dynamics and restoration of declining Mediterranean forests. PMID- 22428752 TI - Patient and public involvement in patient-reported outcome measures: evolution not revolution. AB - This paper considers the potential for collaborative patient and public involvement in the development, application, evaluation, and interpretation of patient-reported outcome measures (PROMs). The development of PROMs has followed a well trodden methodological path, with patients contributing as research subjects to the content of many PROMs. This paper argues that the development of PROMs should embrace more collaborative forms of patient and public involvement with patients as research partners in the research process, not just as those individuals who are consulted or as subjects, from whom data are sourced, to ensure the acceptability, relevance, and quality of research. We consider the potential for patients to be involved in a much wider range of methodological activities in PROM development working in partnership with researchers, which we hope will promote paradigmal evolution rather than revolution. PMID- 22428753 TI - Estimation of the kinetic-optimized stimulus intensity envelope for drop foot gait rehabilitation. AB - The purpose of present study is to estimate the optimal stimulus intensity envelope for drop foot rehabilitation based on a kinetic perspective. The voluntary and electric-stimulated elicited dorsiflexion torque responses of 11 healthy subjects were measured. During dorsiflexion, we recorded the tibialis anterior (TA) electromyography (EMG) or the stimulation intensity at four angles of the ankle joint. From these measurements, we derived two approximate equations that estimate dorsiflexion produced by either voluntary contraction or by electrical stimulation using a sigmoid function and a stepwise-regression analysis. We then tested the predictive capability of the model using Pearson correlation. Both equations indicated high correlation coefficients. Finally, we derived a relation between the TA EMG amplitude and stimulation intensity. From the obtained equation, we determined the optimal stimulus amplitude. We assume that the derived stimulus intensity envelope, calculated from EMG amplitude and angle of ankle joint, satisfies kinetic demand. PMID- 22428754 TI - Matrix metalloproteinase-2, -9, -12, and tissue inhibitor of metalloproteinase 2 gene polymorphisms and cutaneous expressions in patients with Behcet's disease. AB - Matrix metalloproteinases (MMPs) induce leukocyte migration into inflammation sites that lead to either promotion or repression of inflammation by activating or inactivating cytokines. An increased level of MMP-9 and a decreased level of MMP-2 have been observed in Behcet's disease (BD). This study was performed to analyze the relationship between MMP-2, -9, -12 and the tissue inhibitor of metalloproteinase-2 (TIMP-2) promoter polymorphisms in developing BD. The expression of MMP-2 and -9 was also evaluated in the skin of BD. The MMPs and TIMP-2 polymorphisms were confirmed by using polymerase chain reaction restriction fragment length polymorphism in 251 BD and 312 controls. Cutaneous expression of MMP-2 and -9 in 17 BD patients with erythema nodosum (EN) or EN like lesion was compared with 14 patients with idiopathic EN by immunohistochemical stains. The frequency of MMP-2-1575*G/*G and MMP-2-735*C/*C genotypes was shown to be lower in BD, whereas MMP-9-1562*C/*C was significantly higher in BD compared with the controls. The frequency of common haplotype MMP-2 1575*G -735*C was significantly lower in BD patients than in controls (P = 0.0046, permutation P = 0.009). No significant differences were observed between BD and controls in the allele and genotype frequencies of MMP-12-82A>G or TIMP-2 418G>C polymorphisms. The tissue expression of MMP-2, shown by immunohistochemistry, was significantly lower in BD compared with the controls. However, the expression of MMP-9 was significantly higher in BD. These results suggest that MMP-2 and -9 could each modulate the development of BD in opposite directions. Major genotypes of the MMP-2-1575*G/*G and MMP-2-735*C/*C and the common MMP-2-1575*G -735*C haplotype may provide some protection against development of BD, while MMP-9-1562*C/*C may promote the disease. The reciprocal expression of MMP-2 and -9 in the skin tissue of BD was also confirmed. PMID- 22428755 TI - Three new cycloartane glycosides from Nervilia fordii. AB - From the water-soluble extract of the aerial part of herbal plant Nervilia fordii, three new cycloartane glycosides, named as nervisides A (1), B (2), and C (3), were isolated. Their structures were elucidated through a combination of spectroscopic analysis and hydrolysis. At the same time, the new compounds were tested for their cytotoxicities in vitro against human tumor cell lines (CNE, Hep 2, and HepG2) using MTT method. PMID- 22428757 TI - Effective and selective bisphenol A synthesis on a layered silicate with spatially arranged sulfonic acid. AB - The silylated derivatives of a layered alkali silicate, magadiite, modified with propylsulfonic or arylsulfonic acid were synthesized and used as catalysts for an acid-catalyzed condensation of phenol with acetone. The propylsulfonated magadiites with a different amount of the attached silyl group were synthesized by the silylation of the dodecylammonium-exchanged magadiite with the tuned amount of 3-(mercaptopropyl)trimethoxysilane and the subsequent oxidation of the attached thiol to sulfonic acid. The arylsulfonated magadiite was synthesized by the silylation of the dodecylammonium-exchanged magadiite with 2-(4 chlorosulfonylphenyl)ethyltrimethoxysilane and the subsequent hydrolysis of the attached sulfonyl chloride to sulfonic acid. The X-ray diffraction (XRD) patterns and elemental mappings of the products, and the photoluminescent spectra of the Eu(3+)-exchanged products suggested that propylsulfonic or arylsulfonic acid was homogeneously distributed in the interlayer space. When all the sulfonated materials were used as an acid catalyst for condensation between phenol and acetone, p,p' bisphenol A selectively formed over the o,p' isomer, and higher yield and selectivity were attained on the catalysts with larger amount of the attached sulfonic acid. When the interlayer space of the propylsulfonated magadiite was expanded by the co-attachment of octadecylsilyl group, lower selectivity was obtained. The arylsulfonated magadiite showed considerably higher p,p' bisphenol A yield than the propylsulfonated magadiites. PMID- 22428756 TI - Monoacylglycerol lipase - a target for drug development? AB - The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. 'Drugable' selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2-arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents. PMID- 22428758 TI - Can shoulder dystocia be reliably predicted? AB - AIMS: To evaluate factors reported to increase the risk of shoulder dystocia, and to evaluate their predictive value at a population level. METHODS: The South Australian Pregnancy Outcome Unit's population database from 2005 to 2010 was accessed to determine the occurrence of shoulder dystocia in addition to reported risk factors, including age, parity, self-reported ethnicity, presence of diabetes and infant birth weight. Odds ratios (and 95% confidence interval) of shoulder dystocia was calculated for each risk factor, which were then incorporated into a logistic regression model. Test characteristics for each variable in predicting shoulder dystocia were calculated. RESULTS: As a proportion of all births, the reported rate of shoulder dystocia increased significantly from 0.95% in 2005 to 1.38% in 2010 (P = 0.0002). Using a logistic regression model, induction of labour and infant birth weight greater than both 4000 and 4500 g were identified as significant independent predictors of shoulder dystocia. The value of risk factors alone and when incorporated into the logistic regression model was poorly predictive of the occurrence of shoulder dystocia. CONCLUSIONS: While there are a number of factors associated with an increased risk of shoulder dystocia, none are of sufficient sensitivity or positive predictive value to allow their use clinically to reliably and accurately identify the occurrence of shoulder dystocia. PMID- 22428759 TI - Different cardiac loading conditions and haemodynamic monitoring in animal models. AB - OBJECTIVE: To develop models of various cardiac loading conditions in an experimental study. MATERIALS AND METHODS: A total of 78 piglets, average weight 24 kg were divided into 4 groups under different cardiac loading conditions: Group A were spontaneously breathing pigs without haemodynamic changes, Group B were ventilated animals with increased left ventricular afterload, Group C ventilated with increased right ventricular preload and Group D ventilated with increased afterload of both heart ventricles. Haemodynamic parameters were invasively measured at 60 and 120 minutes. RESULTS: Groups B, C and D demonstrated higher preload of both ventricles, compared with Group A. Group C demonstrated higher preload and afterload of both ventricles in comparison with Groups B and D. CONCLUSION: Haemodynamic measured data confirmed the expected changes in cardiac loading and corresponded to human clinical situations. These models may be used for future experimental haemodynamic studies (Tab. 1, Fig. 3, Ref. 8). PMID- 22428760 TI - Does vitamin C prevent the effects of high dose dexmedetomidine on rat erythrocyte deformability? AB - PURPOSE: Dexmedetomidine is an anesthetic agent frequently used for sedation at the intensive care units and during general anesthesia. The purpose of our study was to investigate whether vitamin C prevents the effect of high dose dexmedetomidine on erythrocyte deformability in rats. METHODS: The study was performed on 21 male rats, with 7 rats in each study groups and the control group. The rats in the study groups were treated with intraperitoneal dexmedetomidine (10 ug/kg) and intraperitoneal dexmedetomidine plus Vitamin C (ascorbic acid) (100 mg/kg ascorbic acid administered 1 hour before administration of 10 ug/kg dexmedetomidine), respectively. Intraperitoneal physiological saline was administered in the control group. Erythrocyte packs were prepared using heparinized total blood samples. Deformability measurements were done by erythrocyte suspensions in phosphate buffered saline (PBS) buffer. A constant flow filtrometer system was used to measure erythrocyte deformability and the relative resistance was calculated. RESULTS: Erythrocyte deformability was significantly higher in dexmedetomidine group than in control and vitamin C plus dexmedetomidine groups (p=0.003, p=0.013, respectively). Erythrocyte deformability indexes were found similar in the control group and in the vitamin C plus dexmedetomidine group (p=0.383). CONCLUSIONS: High dose dexmedetomidine may cause functional deterioration in blood flow and tissue perfusion with negative effects in erythrocyte deformability. Vitamin C supplementation seems to reverse those negative effects and variations in erythrocyte deformability. However, our preliminary results should be confirmed in wider serious of experimental and clinical trials (Fig. 1, Ref. 27). PMID- 22428761 TI - The protective effects of ketamine and propofol in obstructive jaundice: an experimental study. AB - OBJECTIVE: In this study, we investigated the protective effects of frequently used intravenous anesthetics (ketamine, propofol, thiopental, and fentanyl) in oxidative stress in a rat liver model of obstructive jaundice. MATERIALS AND METHODS: Thirty-two Wistar albino rats were divided into four groups in a randomized fashion. All rats were subjected to laparotomy, common bile duct ligation and severance on day 0. Following 7 days, laparotomy was again performed using ketamine, propofol, pentobarbital, or fentanyl anesthesia. After 2 hours, the animals were sacrificed and tissue specimens were acquired for histopathological scoring and determination of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activities. RESULTS: All rats demonstrated enlargement in the bile duct, obstructive jaundice, and histopathologic ductal proliferation. MDA and SOD levels were significantly lower in the ketamine group compared with the thiopental and fentanyl groups. CAT was significantly increased in the ketamine group compared with the other groups. The best portal polymorphonuclear leukocyte and necrosis scores were in the ketamine group, but this difference was not statistically significant ( p=0.07). CONCLUSION: Ketamine and propofol were observed to cause the least amount of oxidative stress in this rat model of induced oxidative stress generated by ligation of the common bile duct. This experiment is the first study on this subject in the literature (Tab. 3, Ref. 65). PMID- 22428763 TI - Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms. AB - OBJECTIVES: The aim of our study was to evaluate impact of CYP2D6 and MDR1 polymorphisms on the analgesic efficacy of tramadol in patients after a knee arthroscopy. BACKGROUND: Pharmacokinetics of tramadol and its metabolites is stereoselective and displays high interindividual variability correlating with polymorphic CYP2D6 in the population. Available data provide controversial results regarding the analgesic efficacy of tramadol in subjects with different CYP2D6 genotypes. METHODS: Pain intensity was assessed using visual analogue scale at 2 and 24 hours after the knee arthroscopy in 156 patients. Polymorphisms CYP2D6*3,*4,*5,*6, and gene duplication and C3435T in MDR1 gene were analyzed by PCR - RFLP. RESULTS: Mean VAS2h value in the whole study group was 44.0 +/- 16.5 mm. Mean pain difference, was lowest in the UM group and highest in the PM group. The pain difference varied significantly among the CYP2D6 subgroups (F = 4.29; p = 0.006) with significant differences between homEM vs hetEM, homEM vs PM, and UM vs PM subgroups. There were no significant differences among MDR1 subgroups with regards of pain difference. Mean tramadol consumption was 2.47 +/- 1.17 mg/kg during the 24 h period. There were no significant differences in the drug consumption, reporting of adverse reactions, need for rescue analgesic medication or verbal description of pain among the CYP2D6 or MDR1 genotype subgroups. CONCLUSION: CYP2D6 plays a significant role in tramadol analgesic efficacy. The non-opioid analgesia in PMs was associated with better subjective pain relief in patients after a knee arthroscopy (Tab. 3, Ref. 18). PMID- 22428762 TI - The comparison of the effects of hepatic regeneration after partial hepatectomy, silybum marinaum, propofol, N-acetylcysteine and vitamin E on liver. AB - AIM: We investigated the comparison of the effects of N-acetylcysteine, silybum marinaum, propofol, and vitamin E on liver hepatic regeneration after partial hepatectomy. METHOD: Forty-eight rats were randomized into 6 different groups of the same age and weight. After partial hepatectomy, all animals were resuscitated with 5 ml of isotonic sodium chloride solution administered subcutaneously while group 1 (sham) did not receive any injection, group 2 (control) received serum physiologic intraperitoneally, group 3 received 25 mg /kg of propofol intraperitoneally, group 4 received 20 mg/kg of N-acetylcysteine intraperitoneally, group 5 received 400 mg/kg of vitamin E intraperitoneally, and group 6 received 10 mg/kg of silybum intraperitoneally. None of these groups were given antibitotics. On the third day, a half of the rats, and on the seventh day, the other half of rats were reoperated and sacrificed. RESULTS: Blood samples were used for biochemical parameters (AST, ALT). Ki-67 proliferation index was used for histopathologic parameters. A statistically meaningful difference was detected in silybum, vitamin E, N-acetylcysteine, and propofol groups for AST, ALT levels when compared to control and sham groups (p<0.05). Ki-67 regeneration proliferation index of all groups, which were given agents on the third and seventh days were statistically higher than the control and sham groups (p<0.05). During the evaluation, AST, ALT, Ki-67, Ro (regeneration value) levels of silybum group displayed a statistically significant difference according to other groups (p<0.05). CONCLUSION: Our experimental study indicates that hepatic regeneration after partial hepatectomy was meaningful and significant in groups with intraperitoneal administration of silybum marinaum,vitamin E, N-acetylcysteine and propofol. Hepatic regeneration rate was particularly higher in silybum group compared to other groups (Fig. 16, Ref. 26). PMID- 22428764 TI - A pilot randomized trial comparing long-term effects of red and white wines on biomarkers of atherosclerosis (in vino veritas: IVV trial). AB - BACKGROUND: Since early 90', growing body of evidence indicates that the Mediterranean diet with mild to moderate consumption of wine, mostly red wine, has a protective effect on cardiovascular diseases. Several mechanisms have been discussed to participate in the beneficial effect of red wine, such as antioxidant or vasodilating activity. However, later it has been shown that also other alcoholic beverages have a protective effect on atherosclerosis. Up to now, data from the prospective, long-term, head-to-head comparisons of the effects of different drinks on markers of atherosclerosis are insufficient. METHODS: The IVV (in vino veritas) study is a long-term, prospective, multicenter, randomized trial comparing the effect of red and white wines on the markers of atherosclerosis. One hundred and twenty healthy subjects with mild to moderate risk of atherosclerosis will be randomized to regular consumption of red wine (Pinot Noir) or white wine (Chardonnay-Pinot) for one year. The primary endpoint is the level of HDL-cholesterol at one year, while secondary endpoints are levels of other markers of atherosclerosis (LDL-cholesterol, C-reactive protein, myeloperoxidase, advanced oxidation protein product, interleukins 6 and 18, matrix metalloproteinases, glutathione s-transferase, monocyte chemoattractant protein 1, soluble CD40L). CONCLUSION: The IVV trial is the first study focusing on the long-term prospective comparison of the effects of red and white wines consumption on HDL-cholesterol and other markers of atherosclerosis. Results of the IVV trial may extend our understanding of the widely discussed "French paradox" (Tab. 1, Ref. 21) PMID- 22428765 TI - Abnormal cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVE: Clinical cardiac complications in oncologic patients may develop from subclinical myocardial damage. Biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and troponin T (cTnT) have been hypothesized to reflect preclinical cardiotoxicity earlier than echocardiography. The aim of this study was to assess prospectively the serial values of these cardiomarkers in leukemia patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS: Twenty-one patients who were treated with allogeneic HSCT for acute leukemia at mean age of 32.8 years (range: 19-58) were studied. The conditioning regimen included high-dose cyclophosphamide in combination with total body irradiation (TBI) or busulphan. All patients were treated with anthracyclines earlier (median cumulative dose 250 mg/m, range: 150-580). METHODS: Cardiomarkers were measured before the preparative regimen (PR) and on days 1, 14 and 30 after HSCT. Their cardiac systolic function was assessed before PR, and 1-2 months after HSCT by echocardiography. RESULTS AND CONCLUSION: The differences in NT proBNP before PR and after HSCT were statistically significant (p<0.001). The values of cTnT before and after HSCT were also significantly different (p=0.005). Persistent abnormalities (30 days after HSCT) of NT-proBNP levels were found in 19/21 patients (90.5 %) and of cTnT levels in 10/21 patients (47.6 %). The median cTnT concentrations were higher in patients treated with TBI than in patients without TBI (p=0.013). The median NT-proBNP values were higher in patients pretreated with higher cumulative doses of anthracyclines (>250 mg/m vs <=250 mg/m) Cardiac symptoms developed in 3/21 (14.3 %) patients (Tab. 1, Fig. 3, Ref. 36). PMID- 22428766 TI - HMGB1 and its physiological and pathological roles. AB - HMGB1 has been formerly known for its intracellular function - as the intranuclear non-histone DNA binding protein, which contributes to stabilization of nucleosomes, mediation of DNA bending and is regarded to have an essential position in DNA repair. Lately, its participation in innate and specific immune responses has been revealed. Passively released from necrotic cells or actively produced by various cell types it acts as an alarmin and is responsible for production of pro-inflammaory cytokines. HMGB1 is able to interact with RAGE and TLRs, receptors that belong into family of pattern recognition receptors and are involved in activation of pathways leading to production of pro-inflammatory cytokines. Its key role has been revealed in mediation of sepsis and as it is released later than other pro-inflammatory cytokines it became known as a "late mediator of sepsis". HMGB1 also contributes to the development of atherosclerosis and autoimmune diseases, e.g. its association with immunopathogenesis of SLE and RA has been suggested. Beside its negative function, HMGB1 protein seems to be able to attract stem cells to the area of inflammation and thus promotes regeneration processes. This paradoxical function of HMGB1 protein has also been revealed in growth and spread of many types of tumours. HMGB1 represents a potential target in therapy of various disorders related to inflammation (Fig. 2, Ref. 137). PMID- 22428767 TI - The bases of the inflammatory acute abdomen. AB - Vermiform appendix is an anatomical structure, which due to its topographical relations usually causes many complications, especially in inflammation such as appendicitis. One of the manifestations of the inflammatory processes is pain, which may have different location. It could be probably a result of the neuron stimulation. The nerve formation and distribution of the vermiform appendix is still unknown in fine details and is a subject of further studies (Fig. 8, Ref.12). PMID- 22428768 TI - Granulocyte transfusions. AB - Neutrophils play an essential role in the defense of the body against bacterial and fungal infections. Disorders of their number or function significantly increase the risk of life-threatening infection. In spite of the development of growth factors, new broad spectrum antibiotics and antifungal drugs against nearly all known pathogens, severe neutropenia associated with bacterial or invasive fungal infections remains a major cause of morbidity and mortality in patients undergoing aggressive cancer chemotherapy or hematopoietic stem cell transplantation. Lately, an interest about granulocyte transfusions was renewed, what is a logical approach in the management of patients with prolonged 'reversible' severe neutropenia and severe infection, which is not controlled with appropriate antimicrobial and supportive treatment, including recombinant hematopoietic growth factors. It was a consequence of advances in the field of apheresis science, use of sedimenting agents and especially advances in mobilization of granulocytes to the peripheral blood. It became now possible to collect large numbers of neutrophils. Therefore, the clinical use of granulocyte transfusions, as a potential life saving treatment option in patients with severe neutropenia and uncontrolled infection in spite of appropriate antimicrobial therapy should be considered, with regard to possible benefits and risks (Ref. 74). PMID- 22428769 TI - Rare conditions of gastrointestinal bleeding. AB - The aim of this paper is to analyze and discuss an infrequent topic, i. e. rare conditions of gastrointestinal bleeding.Bleeding from gastrointestinal system is a common cause of acute abdomen and the most frequent causes are generally known.Clinicians, first of all emergency medicine staff, surgeons and internists (gastroenterology specialists), general practitioners, or less frequently other specialists, sometimes meet with less common causes of acute or chronic bleeding from gastrointestinal organs. It is quite important to be aware of the possibility the bleeding being caused by some rare condition, which is not so often met in medical practice, because of their great diagnostic and therapeutic problem. The low index of expectation of such a rare etiological unit could be the reason why destiny of such patients can be extremely problematic and why clinicians may fail at management of these patients (Fig. 4, Ref. 8). PMID- 22428770 TI - Small bowel obstruction due to anomalous congenital peritoneal bands - case series in adults. AB - BACKGROUND: Congenital bands cause 3 % of all intestinal obstruction and almost always lead to small bowel obstruction. In adults, obstruction due to bands is even rarer. MATERIALS AND METHODS: A multicenter study in Turkey. From January 2000 to December 2010 inclusive - a period of 10 years - all adult patients admitted to the emergency departments with a clinical diagnosis of acute intestinal obstruction due to congenital peritoneal band were included in the study. Surgery was defined as emergency. Recorded operative findings included the site of obstruction, and the operative procedure to relieve it. In the present study, the findings in adult patients with congenital band reported in the literature together with findings in ten cases operated at four center were retrospectively assessed with respect to their demographic, preoperative, peroperative, and postoperative characteristics. RESULTS: There were 8 males and 2 females aged between 18 and 72 year. There were no history of abdominal or inguinal surgery. Plain abdominal X-rays radiography revealed air- fluid levels in all patients. All the bands were ligated and divided. On histopathological examination, the bands were composed of loose connective tissue containing blood vessels. There were no calcification in the bands. CONCLUSION: an anomalous congenital band could be included in the differential diagnosis of intestinal obstruction. This clinical situation requires early surgical intervention that will be diagnostic and therapeutic (Tab. 1, Fig. 4, Ref. 21). PMID- 22428771 TI - Mediterranean diet and cardiovascular disease: the penalty for neglecting the benefit. AB - This brief review strongly suggests that the traditional mediterranean diet with its pyramid of nutrients, high fish consumption and an adequate physical activity is a desirable component of a life style model for the world being rapidly transformed by the effects of globalization (Fig. 1, Ref. 7). PMID- 22428772 TI - Methods for preserving fertility in young women suffering from cancer: some aspects of ovarian tissue cryopreservation. PMID- 22428773 TI - Randomised clinical trial: the effect of baclofen in patients with gastro oesophageal reflux--a randomised prospective study. AB - BACKGROUND: Baclofen, a GABA(B) agonist, has been shown to reduce transient lower oesophageal sphincter relaxations (TLESRs), a major cause of gastro-oesophageal reflux disease (GERD). AIM: To examine the effect and tolerability of baclofen in GERD patients over a 2-week period. METHODS: Forty-three GERD patients with abnormal 24-h pH tests were prospectively randomised to receive baclofen or placebo in a double-blind fashion for 2 weeks. Oesophageal manometry, 24-h pH monitoring, and a standard questionnaire was administered, before and after treatment. RESULTS: Thirty-four patients completed the study. In the baclofen group there were significant decreases in 24-h pH score (P = 0.020), percent of upright reflux episodes (P = 0.016), percent total time pH <4 (P = 0.003), number of reflux episodes (P = 0.018), number of reflux episodes longer than 5 min (P = 0.016), number of postprandial reflux episodes (P = 0.045), and percentage of time pH <4 (P = 0.003). No significant changes in reflux parameters were noted in the placebo group. Patients receiving baclofen had significantly less belching (P = 0.038), regurgitation (P = 0.036) and overall symptom score (P = 0.004) whereas placebo patients had less heartburn (P = 0.001), chest pain (P = 0.002), regurgitation (P = 0.017) and overall symptom score (P = 0.000). However, there were no significant differences in changes of reflux parameters or symptoms when comparing the two groups. Drowsiness did not limit baclofen use. CONCLUSIONS: Baclofen was associated with a significant decrease in percent upright reflux by 24-h pH monitoring and a significant improvement in belching, regurgitation and overall symptom score. Baclofen may be more effective in patients with predominantly upright reflux and belching. PMID- 22428774 TI - Pericardial patch tracheoplasty for the repair of a long, multisegmental postintubation tracheal damage. AB - A 64-year-old man was admitted with a postintubation, multisegmental tracheal damage comprising of two stenotic lesions, below and above a tracheotomy. The patient underwent resection of the damaged anterolateral tracheal wall through a combined collar-cuff and median sternotomy incision and tracheoplasty with autologous pericardium around a Silastic T-tube that was fixed to the cricoid cartilage, healthy distal trachea, and the remaining membranous wall. The postoperative period was complicated with a deep sternal wound infection that was successfully treated with vacuum-assisted closure for 2 weeks. Removal of the T tube 9 months later resulted in a patent and well-functioning airway. Pericardial patch tracheoplasty and T-tube stenting of the repair for several months is a good alternative to extended tracheal resection for the treatment of the rare long, postintubation multisegmental tracheal damage. The pericardial patch is highly resistant to infection and allows the formation of a neotrachea. PMID- 22428775 TI - Synthesis of triangular metallodendrimers via coordination-driven self-assembly. AB - A new family of 60 degrees dendritic di-Pt(II) acceptor tectons have been successfully designed and synthesized, from which a series of novel "three component" triangular metallodendrimers were prepared via [3 + 3] coordination driven self-assembly. The structures of newly designed triangular metallodendrimers are characterized by multinuclear NMR ((1)H and (31)P), (1)H DOSY NMR, mass spectrometry (CSI-TOF-MS), and elemental analysis. The shape and size of all supramolecular dendritic triangles were investigated with PM6 semiempirical molecular orbital methods. PMID- 22428776 TI - Past, present, and future exceedance of critical loads of acidity for surface waters in Finland. AB - A critical load is a deposition limit below which harmful effects for a given ecosystem do not occur; the approach has underpinned European sulfur (S) and nitrogen (N) effects-based emission reduction policies during the last two decades. Surface waters are an important resource in Finland, as such the development of models and determination of critical loads has played a central role in supporting their recovery from acidification or preservation of ecosystem health. Critical loads of acidity for Finnish lakes were determined using the steady-state First-order Acidity Balance (FAB) model in conjunction with comprehensive national surveys of surface waters (headwater lakes; n = 1066) and soils. In the 1980s almost 60% of the study lakes were exceeded, impacting brown trout and perch populations. The steep decline in emissions and acidic (S and N) deposition during the last two decades has reduced exceedance to <10%, and by 2020 exceedance is predicted to reach preindustrial (1880) levels. In concert with these reductions, chemical and biological recovery has been observed. The critical load approach has been instrumental in assessing impacts to surface waters in Finland and directing effects-based emission reduction policies. PMID- 22428777 TI - Child and young adult-headed households in the context of the AIDS epidemic in Zimbabwe, 1988-2006. AB - The emergence of child-headed households (CHH) is considered an indicator of the erosion of the traditional safety nets in sub-Saharan African countries and a direct consequence of the increasing number of orphans in the region. Using four available waves of the Zimbabwe Demographic and Health Surveys (1988, 1994, 1999, 2005/2006), we find that the proportion of households with no adults remained stable in the last years, although the number of orphans increased significantly. In fact, a large number of children living in CHH are nonorphans, which suggests that this kind of living arrangement is not always a direct consequence of parental death. Moreover, our analysis shows that children living in CHH and young adult households are less likely to have unmet basic needs than children in households headed by working-age adults and in other vulnerable households. PMID- 22428778 TI - Presentation and validation of the multiple sclerosis depression rating scale: a test specifically devised to investigate affective disorders in multiple sclerosis patients. AB - Accurate diagnosis of depression in patients affected by MS is important, as it may be a cause of reduced quality of life and increased suicide risk. We present a new scale, the Multiple Sclerosis Depression Rating Scale (MSDRS), and assess its diagnostic accuracy in comparison to the Beck Depression Inventory (BDI). A total of 94 MS participants were classified as non-depressed (N = 44) or affected by mood disorder associated to MS with depressive manifestations (MSD-MDDM; N = 37) or with a major depression-like episode (MSD-MDL; N = 13). Each participant underwent a psychiatric interview, MSDRS, and BDI; diagnostic accuracy was evaluated using area under the ROC curve (AROC). The diagnostic accuracy of MSDRS and BDI was comparable when diagnosing both MSD-MDDM and MSD-MDL (AROC respectively 0.8998 and 0.8659); the MSDRS showed higher accuracy for the diagnosis of MSD-MDL (AROC respectively 0.9278 and 0.8314; p = .038). The MSDRS may be a reliable tool for the diagnosis of depression in MS. PMID- 22428779 TI - Klebsiella pneumoniae secretes outer membrane vesicles that induce the innate immune response. AB - Outer membrane vesicles (OMVs) derived from pathogenic Gram-negative bacteria are an important vehicle for delivery of effector molecules to host cells, but the production of OMVs from Klebsiella pneumoniae, an opportunistic pathogen of both nosocomial and community-acquired infections, and their role in bacterial pathogenesis have not yet been determined. In the present study, we examined the production of OMVs from K. pneumoniae and determined the induction of the innate immune response against K. pneumoniae OMVs. Klebsiella pneumoniae ATCC 13883 produced and secreted OMVs during in vitro culture. Proteomic analysis revealed that 159 different proteins were associated with K. pneumoniae OMVs. Klebsiella pneumoniae OMVs did not inhibit cell growth or induce cell death. However, these vesicles induced expression of proinflammatory cytokine genes such as interleukin (IL)-1beta and IL-8 in epithelial cells. An intratracheal challenge of K. pneumoniae OMVs in neutropenic mice resulted in severe lung pathology similar to K. pneumoniae infection. In conclusion, K. pneumoniae produces OMVs like other pathogenic Gram-negative bacteria and K. pneumoniae OMVs are a molecular complex that induces the innate immune response. PMID- 22428780 TI - The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells. AB - Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen-associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro-inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient-based clinical research in this area of human and veterinary medicine. PMID- 22428781 TI - Chronic psychological stress induces vascular inflammation in rabbits. AB - Psychological stress is associated with a systemic inflammatory response. It is unclear, however, whether psychological stress contributes to vascular inflammation. Here, we examined the effects of unpredictable chronic mild stress (UCMS) on vascular inflammation in rabbits. One hundred rabbits were randomly divided into control and stress groups. UCMS was induced by a set of defined adverse conditions applied in a shuffled order for 4, 8, 12, or 16 weeks, and rabbits were killed 24 h after the end of the UCMS protocol. Expression of different inflammatory molecules was analyzed by real-time polymerase chain reaction, immunohistochemistry, or enzyme-linked immunosorbent assay. UCMS resulted in depression-like behaviors, decreased body weight gain, and hypertension with no significant effects on serum lipids. Aortic mRNA and protein expression for tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor, and expression of intercellular adhesion molecule-1 (ICAM-1) protein were increased. UCMS increased circulating concentrations of corticosterone, TNF alpha, and CRP throughout. Moreover, stress downregulated the expression of endothelial nitric oxide synthase. At 16 weeks of UCMS, macrophage infiltration and lipid accumulation in the subendothelial space were detected in the aorta. In cultured murine vascular smooth muscle cells, treatment with serum from stressed rabbits significantly increased phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and upregulated expression of MCP-1 and ICAM-1 mRNAs, in which the effect was blunted by a TNF-alpha neutralizing antibody or p38 and JNK inhibitors. Our results indicate that chronic psychological stress induces vascular inflammation via TNF-alpha and p38/JNK pathways, which may contribute to the development of atherosclerosis. PMID- 22428782 TI - Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy. AB - Fabry disease is a multisystem, X-linked, lysosomal storage disorder caused by a mutation in the GLA gene on chromosome Xq22 resulting in alpha-galactosidase A enzyme (alpha-Gal A) deficiency. Neurological manifestations other than cerebrovascular accidents include small fibre neuropathy and dysautonomic disorders, which may be the presenting clinical features in a proportion of patients. An atypical disease onset may be misdiagnosed until the emergence of a more typical clinical picture, characterized by chronic renal and cardiac failure. Thus, neurologists should consider Fabry disease in differential diagnosis and provide an appropriate diagnostic work up. This review focuses on central and peripheral nervous system involving available diagnostic tools and diagnostic work up in Fabry disease. It also covers the most recent evidence regarding enzyme replacement therapy. PMID- 22428783 TI - Enhancing the melting properties of small molecule-DNA hybrids through designed hydrophobic interactions: an experimental-computational study. AB - Detailed experimental and computational studies revealed the important role that hydrophobic interactions play in the aqueous assembly of rigid small molecule-DNA hybrid (rSMDH) building blocks into nanoscale cage and face-to-face (ff) dimeric structures. In aqueous environments, the hydrophobic surfaces of the organic cores in these nanostructures are minimized by interactions with the core in another rSMDHs, with the bases in the attached DNA strands, and/or with the base pairs in the final assembled structures. In the case that the hydrophobic surfaces of the cores could not be properly isolated in the assembly process, an ill-defined network results instead of dimers, even at low concentration of DNA. In contrast, if ff dimers can be formed with good minimization of the exposed hydrophobic surfaces of the cores, they are highly stable structures with enhanced melting temperatures and cooperative melting behavior. PMID- 22428785 TI - Obinutuzumab (GA101)--a different anti-CD20 antibody with great expectations. PMID- 22428786 TI - High urinary phthalate concentration associated with delayed pubarche in girls. AB - Phthalates are a group of chemicals present in numerous consumer products. They have anti-androgenic properties in experimental studies and are suspected to be involved in human male reproductive health problems. A few studies have shown associations between phthalate exposure and changes in pubertal timing among girls, although controversies exist. We determined the concentration of 12 phthalate metabolites in first morning urine samples from 725 healthy Danish girls (aged 5.6-19.1 years) in relation to age, pubertal development (breast and pubic hair stage) and reproductive hormone levels (luteinizing hormone, oestradiol and testosterone). Furthermore, urinary phthalates were determined in 25 girls with precocious puberty (PP). In general, the youngest girls with less advanced pubertal development had the highest first morning urinary concentration of the monobutyl phthalate isoforms (?MBP((i+n))), monobenzyl phthalate (MBzP), metabolites of di-(2-ethylhexyl) phthalate (?DEHPm) and of di-iso-nonyl phthalate (?DINPm). After stratification of the urinary phthalate excretion into quartiles, we found that the age at pubarche was increasing with increasing phthalate metabolite quartiles (except for MEP). This trend was statistically significant when all phthalate metabolites (except MEP) were summarized and expressed as quartiles. No association between phthalates and breast development was observed. In addition, there were no differences in urinary phthalate metabolite levels between girls with PP and controls. We demonstrated that delayed pubarche, but not thelarche, was associated with high phthalate excretion in urine samples from 725 healthy school girls, which may suggest anti-androgenic actions of phthalates in our study group of girls. PMID- 22428787 TI - Source monitoring and olfactory hallucinations in schizophrenia. AB - People with schizophrenia who experience auditory-verbal hallucinations experience difficulty in determining the source (self vs. other) of verbal information, and those with visual hallucinations experience a conceptually similar problem with visual information. In this study, we examined whether such source monitoring deficits extend to olfaction for olfactory hallucinators and whether they are selective to the modality in which the hallucination is experienced. To test these claims, three groups were formed: normal controls (NC), people with schizophrenia who experience olfactory hallucinations (OH), and people with schizophrenia who experience auditory-verbal hallucinations (AVH). These three groups were then tested on both an olfactory and an auditory-verbal source-monitoring task. We found evidence of a modality-specific impairment. The OH group was less accurate in determining whether an odor had been imagined or smelled relative to NC and AVH groups. In contrast, the AVH group was least accurate in determining the source of a word, relative to the OH and NC groups. These findings provide the first evidence of a source-monitoring impairment in schizophrenic participants with OHs and suggest that this impairment is modality specific. PMID- 22428788 TI - Frontal brain asymmetry in depression with comorbid anxiety: a neuropsychological investigation. AB - The approach-withdrawal model posits that depression and anxiety are associated with a relative right asymmetry in frontal brain activity. Most studies have tested this model using measures of cortical brain activity such as electroencephalography. However, neuropsychological tasks that differentially use left versus right frontal cortical regions can also be used to test hypotheses from the model. In two independent samples (Study 1 and 2), the present study investigated the performance of currently depressed individuals with or without a comorbid anxiety disorder and healthy controls on neuropsychological tasks tapping primarily left (verbal fluency) or right (design fluency) frontal brain regions. Across both samples, results indicated that comorbid participants performed more poorly than depressed only and control participants on design fluency, while all groups showed equivalent performance on verbal fluency. Moreover, comorbid participants showed "asymmetrical" performance on these two tasks (i.e., poorer design [right frontal] relative to verbal [left frontal] fluency), whereas depressed only and control participants showed approximately symmetrical profiles of performance. Results from these two samples suggest an abnormal frontal asymmetry in neurocognitive performance driven primarily by right frontal dysfunction among anxious-depressed individuals and highlight the importance of considering comorbid anxiety when examining frontal brain functioning in depression. PMID- 22428789 TI - Expanding stress generation theory: test of a transdiagnostic model. AB - Originally formulated to understand the recurrence of depressive disorders, the stress generation hypothesis has recently been applied in research on anxiety and externalizing disorders. Results from these investigations, in combination with findings of extensive comorbidity between depression and other mental disorders, suggest the need for an expansion of stress generation models to include the stress generating effects of transdiagnostic pathology as well as those of specific syndromes. Employing latent variable modeling techniques to parse the general and specific elements of commonly co-occurring Axis I syndromes, the current study examined the associations of transdiagnostic internalizing and externalizing dimensions with stressful life events over time. Analyses revealed that, after adjusting for the covariation between the dimensions, internalizing was a significant predictor of interpersonal dependent stress, whereas externalizing was a significant predictor of noninterpersonal dependent stress. Neither latent dimension was associated with the occurrence of independent, or fateful, stressful life events. At the syndrome level, once variance due to the internalizing factor was partialed out, unipolar depression contributed incrementally to the generation of interpersonal dependent stress. In contrast, the presence of panic disorder produced a "stress inhibition" effect, predicting reduced exposure to interpersonal dependent stress. Additionally, dysthymia was associated with an excess of noninterpersonal dependent stress. The latent variable modeling framework used here is discussed in terms of its potential as an integrative model for stress generation research. PMID- 22428790 TI - A longitudinal transactional risk model for early eating disorder onset. AB - The presence of binge eating behavior in early middle school predicts future diagnoses and health difficulties. We showed that this early binge eating behavior can be predicted by risk factors assessed in elementary school. We tested the acquired preparedness model of risk, which involves transactions among personality, psychosocial learning, and binge eating. In a sample of 1,906 children assessed in the spring of fifth grade (the last year of elementary school), the fall of sixth grade, and the spring of sixth grade, we found that fifth grade negative urgency (the personality tendency to act rashly when distressed) predicted subsequent increases in the expectancy that eating helps alleviate negative affect, which in turn predicted subsequent increases in binge eating behavior. This transactional risk process appeared to continue to occur at later time points. Negative urgency in the fall of sixth grade was predicted by fifth grade pubertal onset, binge eating behavior, and expectancies. In turn, it predicted increases in high-risk eating expectancies by the spring of sixth grade, and thus heightened risk. PMID- 22428791 TI - Can DSM-IV borderline personality disorder be diagnosed via dimensional personality traits? Implications for the DSM-5 personality disorder proposal. AB - The proposal for the diagnosis of personality disorders (PDs) in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5;American Psychiatric Association, in preparation) involves, in part, the use of elevated scores on dimensional personality traits. For instance, the diagnosis of borderline personality disorder (BPD) in the DSM-5 will require evidence of self- and interpersonal impairment as well as elevated scores on traits of emotional lability, anxiousness, separation insecurity, depressivity, impulsivity, risk taking, and hostility. Using a sample of individuals from the community (N = 134), half of whom were receiving psychiatric treatment, we tested whether the summation of relevant personality trait scores, using data derived from a measure of the Five-Factor Model of personality (FFM), would result in a construct that corresponds to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV, American Psychiatric Association, 2000) BPD construct as scored by expert consensus ratings. The DSM-IV and FFM BPD scores were significantly correlated (r = .60) and generated highly similar patterns of relations (ricc = .84) with key constructs from BPD's nomological network. These data should serve to allay concerns that the DSM-5's new diagnostic approach will be detrimental to the identification of BPD. PMID- 22428792 TI - Lightening the load: perceptual load impairs visual detection in typical adults but not in autism. AB - Autism spectrum disorder (ASD) research portrays a mixed picture of attentional abilities with demonstrations of enhancements (e.g., superior visual search) and deficits (e.g., higher distractibility). Here we test a potential resolution derived from the Load Theory of Attention (e.g., Lavie, 2005). In Load Theory, distractor processing depends on the perceptual load of the task and as such can only be eliminated under high load that engages full capacity. We hypothesize that ASD involves enhanced perceptual capacity, leading to the superior performance and increased distractor processing previously reported. Using a signal-detection paradigm, we test this directly and demonstrate that, under higher levels of load, perceptual sensitivity was reduced in typical adults but not in adults with ASD. These findings confirm our hypothesis and offer a promising solution to the previous discrepancies by suggesting that increased distractor processing in ASD results not from a filtering deficit but from enhanced perceptual capacity. PMID- 22428793 TI - Evaluating vigilance deficits in ADHD: a meta-analysis of CPT performance. AB - We meta-analytically review 47 between-groups studies of continuous performance test (CPT) performance in children with attention-deficit/hyperactivity disorder (ADHD). Using a random effects model and correcting for both sampling error and measurement unreliability, we found large effect sizes (delta) for overall performance, but only small to moderate delta for performance over time in the handful of studies that reported that data. Smaller deltas for performance over time are likely attributable, in part, to the extensive use of stimuli for which targets and distractors are quite easily differentiated. Artifacts accounted for a considerable proportion of variance among observed deltas. Effect sizes reported in previous reviews were significantly attenuated because of the presence of uncorrected artifacts and highlight the necessity of accounting for artifactual variance in future work to determine the amount of true neurocognitive heterogeneity within ADHD. Signal detection theory and diffusion modeling analyses indicated that the ADHD-related deficits were because of decreased perceptual sensitivity (d') and slower drift rates (v). Results are interpreted the context of several recent models of ADHD. PMID- 22428794 TI - Efficient incorporation of quantum dots into porous microspheres through a solvent-evaporation approach. AB - Quantum dot (QD)-encoded microspheres play an important role in suspension arrays by acting as supports for various reactions between biomolecules. With regard to QD-encoded microspheres utilized in suspension arrays, three key requirements are controllable size, abundant surface functional groups, and especially excellent fluorescence properties. In this paper, narrowly dispersed poly(styrene-co divinylbenzene-co-methylacrylic acid) (PSDM) microspheres with specific size, surface carboxyl groups, and porous structures were synthesized by seeded copolymerization. In order to improve the incorporation efficiency of QDs within microspheres, we developed a swelling-evaporation approach in which the swelling process was combined with gradual evaporation of the solvent and thus gradual concentration of QDs in the dispersion solution. This approach was demonstrated to be an efficient method for improving the fluorescence intensity of resultant microspheres compared with the use of swelling alone. Moreover, the porous structure was shown to aid the penetration of QDs into the interiors of the microspheres. Through this approach, microspheres encoded with either single or multiple wavelength-emitting QDs were fabricated effectively. The suspension immunoassays were then founded based on the QD-encoded microspheres, by coating mouse antihuman chorionic gonadotropin as the probe for goat antimouse IgG detection. The positive results determined by Luminex 100 and the low cytotoxicity of the QD-encoded microspheres demonstrated their great potential in suspension arrays. PMID- 22428795 TI - Revisiting the risk of celiac disease in children born small for gestational age: a sibling design perspective. AB - OBJECTIVE: An association between small for gestational age (SGA) and risk for celiac disease (CD) in childhood has previously been reported. However, this association may reflect residual confounding by genetic or environmental factors. For example, presence of subclinical CD in the mother might be a common cause of both SGA and CD in the offspring. We investigate whether SGA is causally associated with CD before age six years by applying both conventional population based regression models and sibling analysis that investigates the association in siblings discordant for SGA. MATERIAL AND METHODS: Using the Swedish Medical Birth Registry, we identified all singleton children born in Sweden during 1987 1993 (792,401). Of these we included 681,954 children in the study and identified 2641 cases of CD using the Swedish National In-Hospital Registry. We applied both conventional Cox regression analysis and a quasi-experimental sibling design that to some extent simulates a counterfactual situation of exposure, reducing possible confounding effects of genetic and shared environmental factors. RESULTS: We identified an increased risk of CD in both boys (hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.25-2.32) and girls (HR 1.30, 95% CI 0.99 1.70) using conventional Cox regression models. Using sibling analysis, the association between SGA and CD was confirmed in boys (HR 4.23, 95% CI 1.19-15.04) but not in girls (HR 1.00, 95% CI 0.45-2.20). CONCLUSIONS: Our results support a causal association between SGA and CD risk in boys but not in girls, although the mechanisms underlying this difference are still unclear. PMID- 22428796 TI - Diffusion tensor imaging in the human spinal cord: development, limitations, and clinical applications. AB - Diffusion tensor imaging (DTI) is currently the only non-invasive in vivo assessment of white matter tract integrity. Capitalizing on the diffusion properties of water within an axon, DTI enables the visualization of tissue structure at a microscopic scale. Furthermore, measurements of anisotropy and diffusivity enable the detection of subtle details of the effects of injury that cannot be detected using conventional magnetic resonance techniques. Recently, DTI has been applied to the spinal cord, and results have demonstrated it to be a valuable tool for assessing the extent of white matter damage in numerous spinal cord-related conditions including multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, myelitis, and spinal cord tumors. The purpose of this review is to discuss the technical limitations of the imaging method within the spinal cord, review possible solutions, and highlight the current uses and the potential clinical application of this technique. PMID- 22428798 TI - Etiology and biomechanics of first metatarsophalangeal joint sprains (turf toe) in athletes. AB - Sprains of the first metatarsophalangeal (MTP) joint, referred to colloquially as "turf toe," are a debilitating sports injury because the hallux is pivotal to an athletes' ability to accelerate and cut. Severe sprains may require weeks to full recovery, and injuries requiring surgery may prevent an athlete from full athletic participation for months. Whereas the diagnosis and treatment of turf toe are well documented in the literature, less is known about the biomechanics of this joint and the mechanical properties of the structures that compose it. Nevertheless, this information is vital to those, such as equipment designers, who attempt to develop athletic footwear and surfaces intended to reduce the likelihood of injury. To that end, this review summarizes the literature on the anatomy of the first MTP joint, on biomechanical studies of the first MTP joint, and on the incidence, mechanisms, and treatment of turf toe. Furthermore, gaps in the literature are identified and opportunities for future research are discussed. Only through a thorough synthesis of the anatomic, biomechanical, and clinical knowledge regarding first MTP joint sprains can appropriate countermeasures be designed to reduce the prevalence and severity of these injuries. PMID- 22428797 TI - Nanoscale drug delivery systems for enhanced drug penetration into solid tumors: current progress and opportunities. AB - Poor penetration of anticancer drags into solid tumors significantly limits their efficacy. This phenomenon has long been observed for small-molecule chemotherapeutics, and it can be even more pronounced for nanoscale therapies. Nanoparticles have enormous potential for the treatment of cancer due to their wide applicability as drug delivery and imaging vehicles and their size-dependent accumulation into solid tumors by the enhanced permeability and retention (EPR) effect. Further, synthetic nanoparticles can be engineered to overcome barriers to drag delivery. Despite their promise for the treatment of cancer, relatively little work has been done to study and improve their ability to diffuse into solid tumors following passive accumulation in the tumor vasculature. In this review, we present the complex issues governing efficient penetration of nanoscale therapies into solid tumors. The current methods available to researchers to study nanoparticle penetration into malignant tumors are described, and the most recent works studying the penetration of nanoscale materials into solid tumors are summarized. We conclude with an overview of the important nanoparticle design parameters governing their tumor penetration, as well as by highlighting critical directions in this field. PMID- 22428799 TI - Pathological speech signal analysis using time-frequency approaches. AB - Acoustical measures of vocal function are important in the assessments of disordered voice, and for monitoring patients' progress over the course of voice therapy. In the last 2 decades, a variety of techniques for automatic pathological voice detection have been proposed, ranging from traditional temporal or spectral approaches to advanced time-frequency techniques. However, comparison of these methods is a difficult task because of the diversity of approaches. In this article, we explain a framework that holds the existing methods. In the light of this framework, the methodologic principles of disordered voice analysis schemes are compared and discussed. In addition, this article presents a comprehensive review to demonstrate the advantages of time frequency approaches in analyzing and extracting pathological structures from speech signals. This information may have an important role in the development of new approaches to this problem. PMID- 22428800 TI - Electrorheology of polystyrene filler/polyhedral silsesquioxane suspensions. AB - An important challenge in the field of electrorheology is identifying low viscosity fluids that would exhibit significant changes in viscosity, or a yield stress, upon the application of an external electric field. Our recent research showed that optimal compositions of mixtures, 10 wt % sulfonated polyhedral oligomeric silsesquioxanes (s-POSS) mixed with polydimethyl siloxane (PDMS), exhibited significant electrorheological activity. Here we show that s-POSS/PDMS mixtures containing polystyrene (PS) fillers, of micrometer-sized dimensions, containing as little as ~1 wt % s-POSS, exhibited an increase in ER activity by an order of magnitude, beyond that of s-POSS/PDMS mixtures. The dynamic yield stress was found to scale with the particle diameter, a, as tau(y) is proportional to a(0.5) and with the electric field as tau(y) is proportional to E(1.5-2.5); this behavior is reasonably well understood within the context of dielectric electrorheological theory. PMID- 22428801 TI - Supragastric belches are the main determinants of troublesome belching symptoms in patients with gastro-oesophageal reflux disease. AB - BACKGROUND: Patients with gastro-oesophageal reflux disease (GERD) frequently report excessive belching but it is not known what determines the severity of these complaints. AIM: To determine what causes troublesome belching symptoms in GERD patients. METHODS: We included 90 consecutive patients who were referred for ambulatory 24-h pH-impedance measurement as part of the analysis of reflux symptoms. Overall severity of belching was reported by the patients using a 3 point scale. Furthermore, each belch perceived during the ambulatory measurement was reported by the patients using a symptom diary. RESULTS: No significant differences in frequency of gastric belches or combined liquid reflux and gastric belches were observed. However, the number of supragastric belches was significantly higher in patients with severe belching complaints compared to patients with moderate and none to mild complaints. Moreover, the number of supragastric belches which coincided with a liquid reflux episode was significantly higher in patients with severe complaints than in those with moderate and none to mild complaints. Per-patient analysis showed that belches coinciding with a liquid reflux event were more often symptomatic than isolated belches. CONCLUSIONS: The type of belch determines the burden of belching complaints in patients with GERD. Supragastric belches, not gastric belches determine the severity of belching complaints. PMID- 22428802 TI - In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy. AB - BACKGROUND: Skin ageing is a complex process due to intrinsic chronological factors (chronoageing) and extrinsic environmental factors. The primary extrinsic factor is cumulative ultraviolet (UV) exposure, and is therefore termed photoageing. The current standards for measuring cumulative sun damage are biopsy histology and skin microtopography. However, skin biopsies are too invasive for population studies and skin replicas render only superficial skin architecture data. Reflectance confocal microscopy (RCM) is a noninvasive imaging tool that allows for in vivo imaging of the skin at quasihistological resolution. OBJECTIVES: To define and identify RCM features associated with chronological ageing and photoageing on the forearm in two age groups with different skin phototypes and to assess whether these results agree with previous findings. METHODS: We obtained RCM images of dorsal and volar nonlesional skin of the lower forearm of 75 individuals with skin Fitzpatrick phototypes I-III in two age groups (20-30 years and 50-60 years). From each participant and body site, 21 RCM features were assessed and statistically significant differences between the two age groups and different forearm sites determined. RESULTS: RCM enabled identification of changes in architecture, cell morphology and extracellular matrix (collagen) at the level of the epidermis, dermoepidermal junction and papillary dermis. Changes that were correlated with chronological ageing and which were aggravated on the UV-exposed dorsal forearm were: loss of small skin furrows resulting in wider and less intersecting furrows; irregularity of the epidermal honeycomb pattern; irregularly distributed (mottled) pigmented keratinocytes/melanocytes; irregularity of the papillary rings and/or effacement of the rete ridges; and loss of thin collagen fibres and presence of collagen clods. CONCLUSION: We have tested previously reported and new parameters for skin ageing evaluation by RCM, and identified 15 statistically significant RCM features that can be used to quantify ageing and photoageing in forearm skin noninvasively. PMID- 22428803 TI - Improvement of inhibitor identification for heat shock protein 90alpha by utilizing a red-shifted fluorescence polarization probe. AB - Heat shock protein-90 (HSP90) is an ATP-dependent molecular chaperone with intrinsic ATPase activity. HSP90 is required for the stability and function of client proteins, many of which are involved in oncogenesis. Thus, identification of HSP90 inhibitors would potentially lead to the discovery of cancer therapeutics. Here, we present a high-throughput screening campaign utilizing two geldanamycin (GM)-labeled probes in a fluorescence polarization (FP) assay. For the primary screen, a previously reported green BODIPY-labeled GM (GM-BODIPY) was used to evaluate a library collection of about 400,000 compounds. From this screen, 3058 compounds showed >30% inhibition. To distinguish true positives from compound interference, a confirmatory screen was deemed necessary. Accordingly, a red-shifted FP binding assay was developed using GM labeled with red BODIPY. This tool enabled reliable identification of promising HSP90alpha inhibitors. PMID- 22428804 TI - An automated electrophysiological assay for differentiating Ca(v)2.2 inhibitors based on state dependence and kinetics. AB - Ca(V)2.2 (N-type) calcium channels are key regulators of neurotransmission. Evidence from knockout animals and localization studies suggest that Ca(V)2.2 channels play a critical role in nociceptive transmission. Additionally, ziconotide, a selective peptide inhibitor of Ca(V)2.2 channels, is clinically used to treat refractory pain. However, the use of ziconotide is limited by its low therapeutic index, which is believed, at least in part, to be a consequence of ziconotide inhibiting Ca(V)2.2 channels regardless of the channel state. Subsequent efforts have focused on the discovery of state-dependent inhibitors that preferentially bind to the inactivated state of Ca(V)2.2 channels in order to achieve an improved safety profile relative to ziconotide. Much less attention has been paid to understanding the binding kinetics of these state-dependent inhibitors. Here, we describe a novel electrophysiology-based assay on an automated patch platform designed to differentiate Ca(V)2.2 inhibitors based on their combined state dependence and kinetics. More specifically, this assay assesses inactivated state block, closed state block, and monitors the kinetics of recovery from block when channels move between states. Additionally, a use dependent assay is described that uses a train of depolarizing pulses to drive channels to a similar level of inactivation for comparison. This use-dependent protocol also provides information on the kinetics of block development. Data are provided to show how these assays can be utilized to screen for kinetic diversity within and across chemical classes. PMID- 22428805 TI - Time-resolved fluorescence resonance energy transfer as a versatile tool in the development of homogeneous cellular kinase assays. AB - Homogeneous cellular assays can streamline product detection in the drug discovery process. One commercially available assay employing time-resolved fluorescence resonance energy transfer (TR-FRET) that detects phosphorylated products was used to evaluate inhibitors of the receptor tyrosine kinase AXL in a cell line expressing an AXL-green fluorescent protein fusion protein. This TR FRET assay was modified to evaluate the phosphorylation state of the AXL family member MER in a cell line expressing MER with a V5 tag by adding a fluorescein labeled anti-V5 antibody. This homogeneous cellular assay was further modified to evaluate the nonreceptor tyrosine kinase focal adhesion kinase (FAK) in cell lines that expressed an untagged kinase by the inclusion of a commercially available anti-FAK antibody conjugated with an acceptor dye. The methods described here can be further adapted for TR-FRET detection of other cellular kinase activities. PMID- 22428806 TI - Validation of the comprehensive ICF core set for multiple sclerosis from the perspective of occupational therapists. AB - OBJECTIVE: The comprehensive ICF core set for multiple sclerosis (MS) is an application of the international classification of functioning, disability and health (ICF) and represents the typical spectrum of problems in functioning of people with MS (PwMS). The objective of this study was to validate this ICF core set from the perspective of occupational therapists (OTs). METHOD: In a three round Delphi study, OTs were asked about problems and resources of PwMS, as well as environmental aspects treated by OTs. Statements were linked to the ICF and compared with the categories included in the comprehensive ICF core set for MS. RESULTS: Sixty-one OTs from 21 countries agreed on 71 categories that are included in the comprehensive ICF core set for MS (19 body functions, 40 categories of activities and participation, 12 environmental factors). Eleven ICF categories were identified as not-yet-included ICF categories in the comprehensive ICF core set for MS (6 body functions, 2 categories of Activities and participation, 3 environmental factors). CONCLUSION: This study contributes to the validity of the ICF categories included in the comprehensive ICF core set. It outlines which areas of functioning and health are relevant for PwMS from the perspective of OTs and consequently should be assessed. PMID- 22428807 TI - Use of urinary biomarkers of renal ischemia in a lamb preclinical left ventricular assist device model. AB - Evaluation of thrombogenicity is a critical component in the preclinical testing and development of blood pumps. Left ventricular assist devices (LVADs), because of their device routing, can produce thromboembolic showers to the kidney resulting in renal cortical ischemia or infarctions. Although postmortem evaluation of renal pathology can confirm ischemic events and infarctions, there are no validated and highly sensitive real-time measures of renal ischemia in the preclinical models. In this article, we report the evaluation of urinary biomarkers of ischemic tubular damage in a lamb preclinical LVAD model. We found that urinary excretion of glutathione-S-transferase-pi, heat shock protein 1B, and hepatitis A virus cellular receptor 1 homologue precursor (HAVCR1/kidney injury molecule 1) were upregulated in toxic ischemic renal injury as well as in the immediate postoperative period in an LVAD-implanted lamb. These markers were consistent with both gross and histologic pathology, and proved far more sensitive for renal injury than serum blood urea nitrogen or creatinine concentrations. PMID- 22428808 TI - Effect of disinfection and accelerated ageing on dimensional stability and detail reproduction of a facial silicone with nanoparticles. AB - The aim of the present study was to evaluate the effect of disinfection and accelerated ageing on the dimensional stability and detail reproduction of a facial silicone with different types of nanoparticle. A total of 60 specimens were fabricated with Silastic MDX 4-4210 silicone and they were divided into three groups: colourless and pigmented with nanoparticles (make-up powder and ceramic powder). Half of the specimens of each group were disinfected with Efferdent tablets and half with neutral soap for 60 days. Afterwards, all specimens were subjected to accelerated ageing. Both dimensional stability and detail reproduction tests were performed after specimen fabrication (initial period), after chemical disinfection, and after accelerated ageing periods (252, 504 and 1008 hours). The dimensional stability test was conducted using AutoCAD software, while detail reproduction was analysed using a stereoscope magnifying glass. Dimensional stability values were statistically evaluated by analysis of variance (ANOVA) followed by Tukey's test (p < 0.01). Detail reproduction results were compared using a score. Chemical disinfection and also accelerated ageing affected the dimensional stability of the facial silicone with statistically significant results. The silicone's detail reproduction was not affected by these two factors regardless of nanoparticle type, disinfection and accelerated ageing. PMID- 22428809 TI - HealthCall: technology-based extension of motivational interviewing to reduce non injection drug use in HIV primary care patients - a pilot study. AB - To reduce non-injection drug use (NIDU) among HIV primary care patients, more than a single brief intervention may be needed, but clinic resources are often too limited for extended interventions. To extend brief motivational interviewing (MI) to reduce NIDU, we designed and conducted a pilot study of "HealthCall," consisting of brief (1-3 minutes) daily patient calls reporting NIDU and health behaviors to a telephone-based interactive voice response (IVR) system, which provided data for subsequent personalized feedback. Urban HIV adult clinic patients reporting >=4 days of NIDU in the previous month were randomized to two groups: MI-only (n=20) and MI+HealthCall (n=20). At 30 and 60 days, patients were assessed and briefly discussed their NIDU behaviors with their counselors. The outcome was the number of days patients used their primary drug in the prior 30 days. Medical marijuana issues precluded HealthCall with patients whose primary substance was marijuana (n=7); excluding these, 33 remained, of whom 28 patients (MI-only n=17; MI+HealthCall n=11) provided post-treatment data for analysis. Time significantly predicted reduction in "days used" in both groups (p<0.0001). At 60 days, between-group differences approached trend level, with an effect size of 0.62 favoring the MI+HealthCall arm. This pilot study suggests that HealthCall is feasible and acceptable to patients in resource-limited HIV primary care settings and can extend patient involvement in brief intervention with little additional staff time. A larger efficacy trial of HealthCall for NIDU-reduction in such settings is warranted. PMID- 22428810 TI - Therapeutic apheresis for nephrologists: an introduction. PMID- 22428811 TI - Therapeutic apheresis for renal disorders. AB - This review summarizes the clinical evidence and practical details for the use of plasmapheresis and other apheresis modalities for each indication in nephrology. Updated information on the molecular biology and immunology of each renal disease is discussed in relation to the rationale for apheresis therapy and its place amid other available treatments. Autoantibody-mediated diseases, such as anti-GBM (anti-glomerular basement membrane) glomerulonephritis (GN), ANCA (antineutrophil cytoplasmic antibody)-related GN and the antibody-mediated type of TTP (thrombotic thrombocytopenic purpura), and alloantibody-mediated diseases such as kidney transplant sensitization and humoral rejection, can be treated by various plasmapheresis methods. These include standard plasmapheresis with a replacement volume, or plasmapheresis with online plasma purification using adsorption columns or secondary filtration. However, it should be noted that the pathogenic molecules implicated in FSGS (focal segmental glomerulosclerosis), myeloma cast nephropathy, and perhaps other diseases are too small to be removed by most online purification methods. A great majority of controlled trials and series on which evidence-based treatment recommendations are made were performed using centrifugal plasmapheresis; it is presumed that membrane-separation plasmapheresis is equally efficacious. For some rarer diseases, such as MPGN (membranoproliferative GN) type 2 with factor H abnormalities or C3Nef (C3 nephritic factor) autoantibodies, there are only a few case reports, but enough scientific understanding to warrant a trial of plasmapheresis in severe cases. Photopheresis, which is effective for cell-mediated rejection in heart and lung transplantation, has not yet found a place in the routine treatment of kidney transplant rejection. PMID- 22428812 TI - Beyond dialysis: current and emerging blood purification techniques. AB - Extracorporeal blood purification using various techniques and hardware is a major part of the modern day practice of clinical nephrology. Although the various modalities of hemodialysis and hemofiltration are the most commonly used extracorporeal therapies in clinical nephrology, blood purification using other techniques have become necessary to remove pathogenic, toxic, or waste substances not easily cleared by hemodialysis or hemofiltration due to factors such as molecular size, protein binding, and lipid solubility. The following review is an up to date summary of extracorporeal therapies, beyond hemodialysis and hemofiltration, in current clinical use as practiced by nephrologists and others in the United States and beyond. This comprises therapeutic apheresis (plasma exchange and cytapheresis), plasma adsorption, hemoperfusion, and the bio artificial devices. PMID- 22428814 TI - Programs that incorporate active drug users as change agents for promoting their own goals and those of public health. Preface. PMID- 22428815 TI - Drug user organizations in the Nordic countries--local, national, and international dimensions. AB - The article focuses on drug user organizations that represent and advocate for active "hard drug" users in the Nordic countries. It discusses the opportunities and challenges that these organizations face in their search for legitimacy and political influence. The comparative perspective points at similarities and differences in national contexts that both support and challenges the existence of drug user organizations, including drug policy, social welfare policy, trends in drug use, and organizational conditions. The article also discusses the importance of international network and transnational organizations that support drug user organizations. PMID- 22428816 TI - A social network approach to demonstrate the diffusion and change process of intervention from peer health advocates to the drug using community. AB - Project RAP (Risk Avoidance Partnership) trained 112 active drug users to become peer health advocates (PHAs). Six months after baseline survey (N(bl) = 522), 91.6% of PHAs and 56.6% of community drug users adopted the RAP innovation of giving peer intervention, and 59.5% of all participants (N(6m) = 367) were exposed to RAP innovation. Sociometric network analysis shows that adoption of and exposure to RAP innovation was associated with proximity to a PHA or a highly active interventionist (HAI), being directly linked to multiple PHAs/HAIs, and being located in a network sector where multiple PHAs/HAIs were clustered. RAP innovation has diffused into the Hartford drug-using community. PMID- 22428817 TI - The Injection Support Team: a peer-driven program to address unsafe injecting in a Canadian setting. AB - In 2005, members of the Vancouver Area Network of Drug Users (VANDU) formed the Injection Support Team (IST). A community-based research project examined this drug-user-led intervention through observation of team activities, over 30 interviews with team members, and 9 interviews with people reached by the team. The IST is composed of recognized "hit doctors," who perform outreach in the open drug scene to provide safer injecting education and instruction regarding safer assisted-injection. The IST represents a unique drug-user-led response to the gaps in local harm reduction efforts including programmatic barriers to attending the local supervised injection facility. PMID- 22428818 TI - Collective empowerment while creating knowledge: a description of a community based participatory research project with drug users in Bangkok, Thailand. AB - In light of growing concerns regarding the ongoing drug war in Thailand and a lack of support for people who inject drugs in this setting, in 2008, we undertook a community-based participatory research project involving a community of active drug users at a peer-run drop-in center in Bangkok. This case study describes a unique research partnership developed between academic and active drug users and demonstrates that participatory approaches can help empower this vulnerable population while generating valid research. Further research is needed to explore ways of optimizing community-based participatory research methods when applied to drug-using populations. PMID- 22428819 TI - In control?: Ukrainian opiate substitution treatment patients strive for a voice in their treatment. AB - This article explores the burgeoning advocacy movement for methadone and buprenorphine treatment by patients, parents, and doctors in Ukraine, and their efforts to remake a system that infantilizes and controls patients into one where patients have a voice in their treatment. Through a review of gray literature and in-depth interviews with 28 patient-advocates and doctors in five Ukrainian cities between October 2009 and July 2010, this piece chronicles the emergence of opiate substitution treatment in Ukraine, describes successes toward patient friendly treatment, and explores the institutionalized barriers that have pushed the patients to become advocates for their own treatment. PMID- 22428820 TI - Agents of change: peer mentorship as HIV prevention among HIV-positive injection drug users. AB - This paper presents a qualitative investigation of peer mentoring among HIV seropositive injection drug users in a randomized controlled trial, the INSPIRE study. Qualitative analyses of 68 in-depth open-ended interviews conducted in 2005 in Baltimore, New York, Miami, and San Francisco revealed that these individuals conceptualized themselves as change agents through the identity of peer mentor at the three related domains of individual, interpersonal, and community-level change. Implications for program development and future research of peer mentoring as a mechanism for HIV prevention are discussed. This study was funded by the Centers for Disease Control and Prevention and Health Resources and Services Administration (HRSA). PMID- 22428821 TI - Implementation of harm reduction toward crack users in Brazil: barriers and achievements. AB - From 2002 to 2005, we evaluated five Brazilian harm reduction programs ran by active drug users who distributed pipes, condoms, educational material, and provided referral to crack users. System-wide barriers identified: funds discontinuation and legislation barriers toward fieldwork. Major achievements: increased access to health, social, and psychological support. Crack-cocaine users experience a plethora of health/social problems, attenuated by low threshold and user-friendly interventions, particularly those developed by other drug users. However, a stronger political commitment is needed to face a fast growing crack-cocaine epidemic in Brazil, aiming to ensure availability/continuity of funds, implementation of large-scale interventions, outreach workers training, and proper evaluation. PMID- 22428822 TI - The "translators": engaging former drug users as key research staff to design and implement a risk reduction program for rural cocaine users. AB - This manuscript describes lessons learned in the development and implementation of a clinical behavioral trial to reduce sexual risk among African-American cocaine users in rural Arkansas, from the perspectives of a multidisciplinary investigative team and community staff members with a history as local drug users who served as "translators." Recommendations for investigators doing community based research with active substance users are provided in the following domains: (a) engaging the community during formative research, (b) establishing bidirectional trust, (c) ensuring community voices are heard, and (d) managing conflict. The "translator's" role is critical to the success of such projects. PMID- 22428823 TI - Street-level research on street-level interventions among drug users: commentary on papers by Frank et al., Hayashi et al., Small et al., and Domanico and Malta. PMID- 22428824 TI - Caught between the "soft" and "hard" arms of the state: a conceptual apparatus for situating the formative role of drug user organizations in national policy making and local service delivery--a commentary. PMID- 22428825 TI - People who use drugs as agents of change: peer-to-peer education as a force for positive change. PMID- 22428826 TI - What we do not know about organizations of people who use drugs. AB - In this paper, we present some brief thoughts about drug users' organizations. After a brief discussion of users groups' history, we suggest a number of issues that require further research. PMID- 22428827 TI - "Peer workers/health counselors": a new label for a labeled population. A work-in progress which may not progress. AB - The relatively new labels, "peer workers," "peer health counselors," etc., are explored in terms of a selected number of their implications--few, if any, of which have been or are positive for this targeted population. PMID- 22428829 TI - Views: Active drug users as social change agents a straw for the pilgrim: beyond specialization. PMID- 22428830 TI - The proactivity of people who use drugs as a political and ethical imperative. PMID- 22428831 TI - Drug users as social change agents: example of Austria. PMID- 22428832 TI - Creative drug consumption and production in Medellin, Colombia. PMID- 22428833 TI - Active drug users as social change agents: some ethical dimensions. PMID- 22428834 TI - Drug use research: drug users as subjects or agents of change. PMID- 22428835 TI - Active drug users as agents of change. PMID- 22428836 TI - Committeeville and drug users as social change agents. PMID- 22428837 TI - Drug users as social change agents in Asia: the diversity of experience and challenges. PMID- 22428838 TI - Drug users as social change agents: increasing but limited possibilities in Sweden. PMID- 22428841 TI - Probing affinity and ubiquitin linkage selectivity of ubiquitin-binding domains using mass spectrometry. AB - Non-covalent interactions between ubiquitin (Ub)-modified substrates and Ub binding domains (UBDs) are fundamental to signal transduction by Ub receptor proteins. Poly-Ub chains, linked through isopeptide bonds between internal Lys residues and the C-terminus of Ub, can be assembled with varied topologies to mediate different cellular processes. We have developed and applied a rapid and sensitive electrospray ionization-mass spectrometry (ESI-MS) method to determine isopeptide linkage-selectivity and affinity of poly-Ub.UBD interactions. We demonstrate the technique using mono-Ub and poly-Ub complexes with a number of alpha-helical and zinc-finger (ZnF) UBDs from proteins with roles in neurodegenerative diseases and cancer. Affinities in the 2-200 MUM range were determined to be in excellent agreement with data derived from other biophysical techniques, where available. Application of the methodology provided further insights into the poly-Ub linkage specificity of the hHR23A-UBA2 domain, confirming its role in Lys48-linked poly-Ub signaling. The ZnF UBP domain of isopeptidase-T showed no linkage specificity for poly-Ub chains, and the Rabex-5 MIU also exhibited little or no specificity. The discovery that a number of domains are able to bind cyclic Lys48 di-Ub with affinities similar to those for the acyclic form indicates that cyclic poly-Ub may be capable of playing a role in Ub-signaling. Detection of a ternary complex involving Ub interacting simultaneously with two different UBDs demonstrated the co-existence of multi site interactions, opening the way for the study of crosstalk between individual Ub-signaling pathways. PMID- 22428842 TI - CinA is regulated via ComX to modulate genetic transformation and cell viability in Streptococcus mutans. AB - The Streptococcus mutans ComX-regulon encompasses > 200 mostly uncharacterized genes, including cinA. Here we report that cinA is regulated by ComX in the presence of the competence stimulating peptide (CSP), wherein loss of CinA (strain SmuCinA) results in reduced transformability with or without added CSP by 74- and 15-fold, respectively (P < 0.003). In CSP-supplemented cultures, a two fold increase in cell viability was noted for SmuCinA relative to UA159 (P < 0.002), suggesting CinA's involvement in the CSP-modulated cell killing response. Relative to UA159, loss of CinA also rendered the mutant hypersensitive to killing by methyl methanesulfonate (MMS), which impairs homologous recombination. Despite our use of a non-polar mutagenesis strategy to knockout cinA, which is the first gene of the multicistronic operon harboring cinA, we noted a drastic reduction in recA expression. By using a CinA-complemented mutant, we were able to partially, but not completely restore all phenotypes to UA159 levels. Complementation results suggested that although cinA participates in modulating competence, viability and MMS tolerance, genes downstream of the cinA transcript may also regulate these phenotypes, a finding that warrants further examination. This is the first report that describes a role for S. mutans' CinA in contending with DNA damage, genetic transformation and cell survival. PMID- 22428843 TI - Ignoring emissions of Hg from coal ash and desulfurized gypsum will lead to ineffective mercury control in coal-fired power plants in China. PMID- 22428844 TI - MicroRNA as a novel drug target for cancer therapy. AB - INTRODUCTION: MicroRNAs (miRNAs), a class of small, regulatory and non-coding RNA molecules, display aberrant expression patterns and functional abnormalities in all kinds of human diseases including cancers. As important emerging modulators in cellular pathways, miRNAs play a key role in tumorigenesis. Correcting these miRNA deficiencies by either up-regulating or down-regulating miRNA function may provide a therapeutic benefit. AREAS COVERED: We herein provide a brief review of miRNA in the following aspects: their possible role of miRNA as oncogenes or tumor suppressors in the pathogenesis of cancer, the abnormally expressed miRNAs in various types of human common cancers, novel drug targets and therapeutic tools for diagnosis, prognosis and treatments of human cancers was also discussed. Finally, we comment on the difficulties and challenges of miRNAs in clinical practice, and the bright perspective for future application. EXPERT OPINION: Targeting of these ectopically miRNAs could provide an important diagnostic or therapeutic strategy for human cancer in the future. PMID- 22428845 TI - Early predictors of non-response to interferon in multiple sclerosis. AB - OBJECTIVE: To identify early clinical and MRI predictors of non-response to interferon (IFN) treatment in multiple sclerosis (MS). METHODS: In 172 patients with relapsing-remitting MS treated with IFNbeta, we evaluated prediction of future treatment non-response. Candidate predictors comprised disability and its sustained progression, relapse score (combining frequency and severity of relapses), brain volume change, brain parenchymal fraction, number of new T2 lesions, and T2 and T1 lesion volume within the initial year of treatment. Treatment non-response was evaluated as confirmed disability progression or overall average annual relapse score exceeding 1 over the following 5 years. Logistic regression model was adjusted for patient age, gender, disease duration and changes in treatment. RESULTS: Ninety patients (52%) reached the status of IFN non-responders in years 2-6. Patients with >=1 new T2 lesion and relapse score >=2 (odds ratio >=5.7) or those with >=3 new T2 lesions regardless of the relapse score (odds ratio = 3) were in a significantly higher risk of future treatment non-response. CONCLUSIONS: In patients with MS treated with IFNbeta for 1 year, number of new T2 lesions and annualized relapse score predict individual risk of treatment non-response over the following 5 years. PMID- 22428847 TI - pH-Sensitive surfactants from lysine: assessment of their cytotoxicity and environmental behavior. AB - The toxicity and environmental behavior of new pH-sensitive surfactants from lysine are presented. Three different chemical structures are studied: surfactants with one amino acid and one alkyl chain, surfactants with two amino acids on the polar head and one alkyl chain, and gemini surfactants. The pH sensitivity of these compounds can be tuned by modifying their chemical structures. Cytotoxicity has been evaluated using erythrocytes and fibroblast cells. The toxic effects against these cells depend on the hydrophobicity of the molecules as well as their cationic charge density. The effect of hydrophobicity and cationic charge density on toxicity is different for each type of cells. For erythrocytes, the toxicity increases as hydrophobicity and charge density increases. Nevertheless, for fibroblasts cationic charge density affects cytotoxicity in the opposite way: the higher charge density, the lower the toxicity. The effect of the pH on hemolysis has been evaluated in detail. The aquatic toxicity was established using Daphnia magna . All surfactants yielded EC(50) values considerably higher than that reported for cationic surfactants based on quaternary ammonium groups. Finally, their biodegradability was evaluated using the CO(2) headspace test (ISO 14593). These lysine derivatives showed high levels of biodegradation under aerobic conditions and can be classified as "readily biodegradable compounds". PMID- 22428846 TI - The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us? AB - Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the u-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the kappa-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse. PMID- 22428849 TI - Ceramic pore channels with inducted carbon nanotubes for removing oil from water. AB - Water contaminated with tiny oil emulsions is costly and difficult to treat because of the colloidal stability and deformable nature of emulsified oil. This work utilizes carbon nanotubes (CNTs) in macro/mesopore channels of ceramic membrane to remove tiny oil droplets from water. The CNTs were implanted into the porous ceramic channels by means of chemical vapor deposition. Being hydrophobic in nature and possessing an interfacial curvature at nanoscale, CNTs enabled tiny oil emulsion in submicrometer and nano scales to be entrapped while permeating through the CNTs implanted pore channels. Optimizing the growth condition of the CNTs resulted in a uniform distribution of CNT grids, which allowed the development of lipophilic layers during filtration. These lipo-layers drastically enhanced the separation performance. The filtration capability of CNT-ceramic membrane was assessed by the purification of a dilute oil-in-water (o/w) emulsion containing ca. 210 ppm mineral oil 1600 ppm emulsifier, and a trace amount of dye, a proxy polluted water source. The best CNT-tailored ceramic membrane, prepared under the optimized CNT growth condition, claimed 100% oil rejection rate and a permeation flux of 0.6 L m(-2) min(-1), driven by a pressure drop of ca. 1 bar for 3 days on the basis of UV measurement. The CNT-sustained adsorption complements the size-exclusion mechanism in removing soluble oil. PMID- 22428850 TI - Size-controlled synthesis of Au/Pd octopods with high refractive index sensitivity. AB - Au/Pd octopods, nanostructures with eight branches and a primarily Au interior, have been synthesized as size-controlled samples through the manipulation of seed mediated co-reduction. The position of their localized surface plasmon resonance can be controllably tuned throughout the visible and near-infrared regions, and this response is correlated with the structural features (branch length and tip width) of the octopods. These Au/Pd octopods were also found to be highly sensitive to changes in the local refractive index of the surrounding media and suitable substrates for surface enhanced Raman spectroscopy. These findings, coupled with their unique composition, highlight the multifunctional capabilities of the Au/Pd octopods and provide insight into the optical properties of architecturally controlled bimetallic nanostructures. PMID- 22428851 TI - 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies. AB - The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior. PMID- 22428852 TI - The unique features of Th9 cells and their products. AB - Although it was discovered more than two decades ago, new information concerning the biological activities of IL-9 has been provided in recent years, after the isolation of cells that selectively produce this cytokine, designated "Th9." Th9 cells are generated in vitro by polarization, mainly by TGF-beta and IL-4, during activation with the specific antigen, or with anti-CD3/CD28 antibodies. This review deals mainly with Th9 generated by the former, "physiological" mode of activation. Of particular interest is the unique production kinetics of IL-9: the cytokine is produced very rapidly, but after reaching its peak (day 3 in our studies), it declines sharply to trace levels. In addition to IL-9, Th9 cells also produce similar amounts of another cytokine, IL-10, but the production kinetics of these two cytokines are strikingly different. Antigen-activated Th9 in our studies also developed pathogenic capacity, but only during the short time period of peak IL-9 production. Interestingly, no IL-9-producing cells were detected in sites of inflammation induced by Th9, in contrast to Thl and Thl7. The unique features of Th9 cells and their products are discussed with regards to the known and assumed functions of the cytokine. PMID- 22428853 TI - Functions of fascin in dendritic cells. AB - Fascin-1 is an actin-bundling protein that shares no homology with other actin bundling proteins. It is greatly induced upon maturation of dendritic cells (DCs). However, fascin-1 is not expressed in other primary blood cells, including macrophages and neutrophils, indicating a unique role of fascin-1 in the function of DCs upon maturation. An increasing body of evidence has shown that fascin-1 plays critical roles in maturation-associated DC functions, including dynamic assembly of veil-like membrane protrusions, disassembly of podosomes, migration to lymph nodes, and the assembly of the immunological synapse. Pathological analyses of fascin-1 expression revealed that fascin-1 is a useful marker of diseases of immune cells, including Langerhans cell histiocytosis and Hodgkin diseases. Furthermore, attempts have been made to explore the use of a fascin-1 promoter for DNA vaccination because it is strong and specific to DCs. PMID- 22428856 TI - Genetic requirements for the development and differentiation of interleukin-17 producing gammadelta T cells. AB - Most effector T cells are generated in the periphery following an encounter with a foreign antigen and exposure to soluble and membrane-bound mediators. There are, however, some T cell subsets, such as gammadelta T cells and natural killer T cells, that acquire their effector potential in the thymus before their emigration to the periphery. This developmental preprogramming enables these cells to differentiate rapidly into cytokine-producing effectors during the host immune response. This review focuses on murine interleukin (IL)-17-producing gammadelta T (gammadelta-17) cells, which have been shown, through their early production of IL-17, to have a critical role in multiple infectious and autoimmune diseases. Specifically, we discuss what is currently known about the genetic requirements for their generation and compare it with what is known about that of the more extensively studied IL-17-producing helper T (Thl7) cells. Based on this comparison, we propose a model for murine gammadelta-17 development and differentiation. PMID- 22428857 TI - Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan. AB - WHAT IS KNOWN AND OBJECTIVE: Concern about the drug lag, the delay in marketing approval between one country and another, for anticancer drugs has increased in Japan. Although a number of studies have investigated the drug lag, none has investigated it in relation to the transition of anticancer therapy from traditional cytotoxic drugs to molecularly targeted agents. Our aim was to investigate current trend in oncology drug lag between the US and Japan and identify oncology drugs approved in only one of the two countries. METHODS: Publicly and commercially available data sources were used to identify drugs approved in the US and Japan as of 31 December 2010 and the data used to calculate the drug lag for individual drugs. RESULTS AND DISCUSSION: Fifty-one drugs were approved in both the US and Japan, whereas 34 and 19 drugs were approved only in the US or Japan, respectively. Of the 19 drugs approved only in Japan, 12 had not been subject to development for a cancer indication in the US, and all were approved before 1996 in Japan. Of the 34 drugs approved only in the US, 20 had not been subject to development in Japan, and none was in the top 25 by annual US anticancer drug-class sales. For drugs approved in both countries, the mean approval lag of the molecularly targeted drugs (MTDs) was significantly shorter than that of the non-molecularly targeted drugs (non-MTDs) (3.3 vs. 5.4 years). Further, mean R&D time of the MTDs was significantly shorter than that of non-MTDs (10.0 vs. 13.7 years). The price of MTDs had increased on average by 6.6% annually in the US, whereas it had decreased on average by 4.3% biyearly in Japan. WHAT IS NEW AND CONCLUSION: The emergence of new molecularly targeted agents has contributed to reducing the approval lag, most likely due to improvements in R&D strategy. PMID- 22428855 TI - Regulation generation: the suppressive functions of human regulatory T cells. AB - Proper regulation of immune homeostasis is necessary to limit inflammation and prevent autoimmune and chronic inflammatory diseases. Many autoimmune diseases, such as psoriasis, are driven by vicious cycles of activated T cells that are unable to be suppressed by regulatory T cells. Effective suppression of auto reactive T cells by regulatory T cells (Treg) is critical for the prevention of spontaneous autoimmune disease. Psoriatic Treg cells have been observed to a defect in their capacity to regulate, which clearly contributes to psoriasis pathogenesis. A challenge for translational research is the development of novel therapeutic interventions for autoimmune diseases that will result in durable remissions. Understanding the mechanism(s) of dysregulated T cell responses in autoimmune disease will allow for the development of future therapeutic strategies that may be employed to specifically target pathogenic, proinflammatory cells. Several reports have demonstrated a pathogenic role for Thl and Thl7 cells in psoriasis as well as other autoimmune diseases. Similarly, several laboratories have independently demonstrated functional defects in regulatory T cells isolated from patients with numerous divergent autoimmune diseases. One primary challenge of research in autoimmune diseases is therefore to restore the balance between chronic T cell activation and impairment of Treg suppressor mechanisms. To this end, it is critical to develop an understanding of the many suppressive mechanisms employed by Treg cells in hopes of developing more targeted therapeutic strategies for Treg-mediated autoimmune diseases. PMID- 22428859 TI - Incidence, etiology and mortality of cirrhosis: a population-based cohort study. AB - OBJECTIVE: Knowledge on the prognosis among patients with cirrhosis is mainly based on clinical trials with selected patient groups as well as population-based register studies with suboptimal diagnostic reliability. The aim of the study was to describe incidence, etiology, and mortality of well-validated cirrhotic cases in a population-based cohort at Funen (population 470,000) between 1996 and 2006. MATERIALS AND METHODS: A population-based cohort study with case identification from discharge diagnosis followed by manual validation of patient records with inclusion of cases that fulfilled predefined diagnostic criteria. RESULTS: 4010 possible cases were identified. 1369 patients were included, 67% males, mean age 56.4 years, 75% had cirrhotic complications at entry. Mean follow-up was 3.6 years with a total of 4976 years of follow-up. The incidence was 33/100,000 person-years (95% confidence interval CI 28-40). Stratified for age and sex, the incidence was twice as high for men compared with women in all age groups. The five-year mortality was 62% (95% CI 59-65). A multivariate analysis showed a high mortality associated with male gender (HR 1.24, 95% CI 1.08-1.42), ages above 70 years (HR 2.01 95% CI 1.65-2.47) compared with ages 50-59 years, complications present at diagnosis (HR 1.28, 95% CI 1.09-1.50) and etiology of alcoholic disease or cryptogenic cirrhosis (HR 2.38, 95% CI 1.22-4.67 and 2.26, 95% CI 1.13 4.53). CONCLUSIONS: Incidence of cirrhosis is higher among men than among women. High age, male gender, alcoholic cirrhosis, cryptogenic cirrhosis, and complications at the time of diagnosis increased mortality. PMID- 22428854 TI - Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. AB - Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis. Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases. Thus a fundamental understanding of IL-10 gene expression is critical for our comprehension of disease progression and resolution of host inflammatory response. In this review, we discuss modes of regulation of IL-10 gene expression in immune effector cell types, including signal transduction, epigenetics, promoter architecture, and post-transcriptional regulation, and how aberrant regulation contributes to immunopathology and disease progression. PMID- 22428860 TI - Influence of surface characteristics on the adhesion of Candida albicans to various denture lining materials. AB - OBJECTIVE: This study evaluated the influence of surface characteristics of various denture lining materials on the adherence of Candida albicans. MATERIALS AND METHODS: Four different types of materials (tissue conditioners, acrylic and silicone soft liners and hard reline materials) were selected. Disk-shaped material specimens were prepared and their surface roughness values (R(a) ) measured using a profilometer. The contact angles of four reference liquids were measured on the material surfaces and surface energy parameters (total surface energy, acid and base components, degree of hydrophobicity/hydrophilicity) of the materials were calculated in accordance with acid-base theory. Specimens were incubated with C. albicans and adhering fungi quantified using the colony counting method. Data were statistically analyzed using a one-way ANOVA with Games-Howell post-hoc test (alpha = 0.05). Pearson correlation analysis was applied to detect correlations between surface characteristics and Candida adhesion. RESULTS: Significant differences in the surface roughness of the materials were found (p < 0.001). The acrylic soft liners were more hydrophilic than the other materials. Overall, the acrylic soft liners and tissue conditioners showed significantly greater Candida adhesion than silicone soft liners and hard reline materials (p < 0.05). The Pearson correlation analysis indicated that the base component and degree of hydrophobicity/hydrophilicity of the materials (p = 0.005/0.008), rather than the total surface energy and the surface roughness (p = 0.093/0.057), affected C. albicans adherence in a statistically significant way. CONCLUSIONS: The adhesion of C. albicans to denture lining materials can be accounted for in terms of interfacial acid-base interactions. PMID- 22428861 TI - Do conduct problems and sensation seeking moderate the association between ADHD and three types of stimulant use in a college population? AB - Evidence suggests that ADHD symptoms predict increased risk for misusing stimulant medication, which may extend to misuse of over-the-counter (OTC) stimulants and illicit stimulants. Conduct-problem (CP) symptoms and sensation seeking (SS) also predict substance use and may enhance risk for stimulant use among college students with ADHD symptoms. Participants, who were undergraduate students aged 18 to 25 years (N = 660; average age = 20.23 years, SD = 1.40; 30% male; 49% non-European American), completed an online survey regarding ADHD symptoms, CP symptoms, SS, and stimulant use (i.e., OTC stimulants, misuse of stimulant medication, and illicit stimulants). Results of logistic regression indicated that SS moderated the association between ADHD symptoms and OTC stimulants. Also, CP moderated the relation between ADHD symptoms and misuse of stimulant medication. Disinhibition, a subscale of SS, also moderated the association between ADHD symptoms and misuse of stimulant medication. Only CP symptoms predicted illicit stimulants. These results suggest that college students with ADHD symptoms display risk for using OTC stimulants, and that disinhibition and CP symptoms increase their risk for misuse of stimulant medication. Implications of these findings are discussed. PMID- 22428862 TI - Efficacy of expectancy challenge interventions to reduce college student drinking: a meta-analytic review. AB - Interventions challenging alcohol expectancies may lead to reductions in alcohol consumption. We conducted a meta-analysis to examine the efficacy of alcohol expectancy challenge (EC) interventions for college alcohol abuse prevention. Included were 14 studies (19 EC interventions) that measured alcohol expectancies and consumption, provided sufficient information to calculate effect sizes, and were available as of June 2010 (N=1,415; M age=20 years; 40% women; 88% White). Independent raters coded participant characteristics, design and methodological features, and intervention content, and calculated weighted mean effect sizes at first follow-up, using both fixed and random effects models. Compared with controls, EC participants reported lower positive alcohol expectancies, reduced their alcohol use, and reduced their frequency of heavy drinking (d+s ranged from 0.23 to 0.28). Within-group improvements in alcohol expectancies and consumption emerged for the EC group only; relative to their own baseline, EC participants reported lower positive alcohol expectancies, reduced their alcohol use, and reduced their frequency of heavy drinking (d+s ranged from 0.13 to 0.36). Supplemental analyses found improvements in specific alcohol expectancies (social, sexual, tension, and arousal) both between groups and within group. The short-term effects of EC interventions on college student drinking are not maintained at follow-ups greater than 4 weeks. PMID- 22428863 TI - I drink therefore I am: validating alcohol-related implicit association tests. AB - There is an imperative to predict hazardous drinking among college students. Implicit measures have been useful in predicting unique variance in drinking and alcohol-related problems. However, they have been developed to test different theories of drinking and have rarely been directly compared with one another. Thus, their comparative utility is unclear. The current study examined five alcohol-related variants of the Implicit Association Test (IAT) in a sample of 300 undergraduates and sought to establish their predictive validity. Results indicated that the Drinking Identity IAT, which measured associations of "drinker" with "me," was the most consistent predictor of alcohol consumption, alcohol problems, and alcohol cravings. It also had the highest internal consistency and test-retest reliability scores. The results for the Alcohol Excitement and Alcohol Approach IATs were also promising, but their psychometric properties were less consistent. Although the two IATs were positively correlated with all of the drinking outcome variables, they did not consistently predict unique variance in those variables after controlling for explicit measures. They also had relatively lower internal consistencies and test-retest reliabilities. Ultimately, results suggested that implicit drinking identity may be a useful tool for predicting alcohol consumption, problems, and cravings and a potential target for prevention and intervention efforts. PMID- 22428864 TI - Successful and long-lasting treatment of solar urticaria with ultraviolet A rush hardening therapy. AB - BACKGROUND: Solar urticaria (SU) is a photodermatosis that is thought to be caused through the effects of mast cell mediators released because of an altered chromophore, possibly a photoallergen recognized by IgE. Phototherapy for SU to induce a tolerant state appears to be most effective, but is often time consuming and provides only short-lived remission. Ultraviolet (UV) A rush hardening has been successful and less time consuming in serum factor-negative patients with SU. However, the mechanism of action and long-lasting effects of UVA rush hardening therapy remain unclear. OBJECTIVES: We aimed to evaluate whether UVA rush hardening exhibits long-lasting therapeutic effects in serum factor-positive patients with SU and to examine the action mechanism of tolerance. METHODS: Two serum factor-positive patients with SU were exposed to multiple UVA irradiations at 1-h intervals per day for 2 or 3 days. Intradermal injection of their in vitro irradiated autologous serum or compound 48/80 and a prick test for histamine were performed before and after UVA rush hardening. RESULTS: The two serum factor positive patients with SU benefited greatly from UVA rush hardening, as documented by a marked increase in minimal wealing dose, and remained symptom free without using sunscreen in their daily life. Intradermal injection of in vitro-irradiated autologous serum induced wealing before hardening, but not in tolerized skin after hardening. The responses to compound 48/80 and histamine were unaltered. CONCLUSIONS: UVA rush hardening is an effective and long-lasting treatment even in serum factor-positive patients with SU. The mechanism of tolerance may involve continued blockade of photoallergen binding to IgE on mast cells, rather than depletion of mast cell mediators or histamine tachyphylaxis. PMID- 22428865 TI - HIV diagnosis and sexual risk behavior intentions among couple VCT clients in Ethiopia. AB - This research examines whether members of HIV affected couples are more likely to change their abstinence and condom intentions than members of HIV- couples during couple voluntary counseling and testing (VCT). A total of 1260 couple VCT clients in Ethiopia were asked about their sexual risk behavior intentions for the next two months after pre-test and post-test counseling. Multinomial logistic regression was used to determine whether the couple's HIV status was associated with changed intentions to abstain or use condoms between pre-test and post-test. Individuals belonging to male HIV+ serodiscordant couples (aRRR = 7.98, p < 0.001), female HIV+ serodiscordant couples (aRRR = 5.85, p < 0.001), and HIV+ concordant couples (aRRR = 3.12, p = 0.05) were more likely to have increased their intentions to abstain or use condoms in the next two months than individuals in HIV- concordant relationships. The couple's HIV status was not associated with decreased intentions to abstain or use condoms in the next two months. Counseling for all HIV affected couples should include practical information on obtaining and using condoms. This includes HIV affected couples who intend to abstain from sex, whether for a short or long period of time, so that they are prepared to have protected sex if their intentions change. PMID- 22428866 TI - Mycoplasma pulmonis Vsa proteins and polysaccharide modulate adherence to pulmonary epithelial cells. AB - The Mycoplasma pulmonis Vsa proteins are a family of size- and phase-variable lipoproteins that shield the mycoplasmas from complement and modulate attachment to abiotic surfaces. Mycoplasmas producing a long Vsa protein hemadsorb poorly and yet are proficient at colonizing rats and mice. The effect of the length of the Vsa protein on the attachment of mycoplasmas to epithelial cells has not been previously explored. We find that independent of Vsa isotype, mycoplasmas producing a long Vsa protein with many tandem repeats adhere poorly to murine MLE 12 cells compared with mycoplasmas producing a short Vsa. We also find that mutants lacking the EPS-I polysaccharide of M. pulmonis exhibited decreased adherence to MLE-12 cells, even though it has been shown previously that such mutants have an enhanced ability to form a biofilm. PMID- 22428868 TI - Tranexamic acid increases hemoglobin and ferritin levels in women with heavy menstrual bleeding. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is the most common cause of iron deficiency anemia (IDA) in women. A novel, modified-release oral formulation of tranexamic acid (TA) designed to reduce gastrointestinal side effects was approved recently for treatment of HMB. We assessed improvements in objective laboratory measures of IDA in women with self-reported HMB who received long-term TA therapy. METHODS: Women enrolled in a long-term, open-label, multicenter study self-medicated with TA 3.9 g/day administered as 1.3 g orally up to three times daily for 5 days/menstrual cycle for 27 cycles. Oral iron therapy was required if serum hemoglobin (Hgb) levels decreased to <11 g/dL. RESULTS: A total of 723 women (mean age 38.3 years) were included in the intent-to-treat (ITT) population. Significant increases in mean serum Hgb and ferritin were observed throughout the study (p<0.01). Among 191 patients with low Hgb (<12 g/dL) at baseline, mean serum Hgb increased by >=0.71 g/dL after the third cycle and all subsequent assessments (p<0.001). After 3 and 27 cycles, 34.1% and 45.7%, respectively, of patients with low Hgb at baseline shifted to within normal range, respectively. Among 233 patients with low ferritin (<10 ng/mL) at baseline, mean serum ferritin increased by >5.38 ng/mL after cycles 15 and 27. After 6 and 27 cycles, 35.2% and 58% of patients, respectively, with low ferritin levels at baseline shifted to within normal range. CONCLUSIONS: Long-term self medication with this novel TA formulation improved Hgb and ferritin levels in women with self-reported HMB. PMID- 22428867 TI - In vitro selection of highly modified cyclic peptides that act as tight binding inhibitors. AB - There is a great demand for the discovery of new therapeutic molecules that combine the high specificity and affinity of biologic drugs with the bioavailability and lower cost of small molecules. Small, natural-product-like peptides hold great promise in bridging this gap; however, access to libraries of these compounds has been a limitation. Since ribosomal peptides may be subjected to in vitro selection techniques, the generation of extremely large libraries (>10(13)) of highly modified macrocyclic peptides may provide a powerful alternative for the generation and selection of new useful bioactive molecules. Moreover, the incorporation of many non-proteinogenic amino acids into ribosomal peptides in conjunction with macrocyclization should enhance the drug-like features of these libraries. Here we show that mRNA-display, a technique that allows the in vitro selection of peptides, can be applied to the evolution of macrocyclic peptides that contain a majority of unnatural amino acids. We describe the isolation and characterization of two such unnatural cyclic peptides that bind the protease thrombin with low nanomolar affinity, and we show that the unnatural residues in these peptides are essential for the observed high-affinity binding. We demonstrate that the selected peptides are tight-binding inhibitors of thrombin, with K(i)(app) values in the low nanomolar range. The ability to evolve highly modified macrocyclic peptides in the laboratory is the first crucial step toward the facile generation of useful molecular reagents and therapeutic lead molecules that combine the advantageous features of biologics with those of small-molecule drugs. PMID- 22428869 TI - Statin therapy and hemodialysis vascular access--were we bringing a knife to a gunfight and were hoping to win? AB - Vascular access dysfunction is a major contributor to end stage renal disease patient morbidity, and the cost of maintaining it is staggering. Any intervention able to improve the vascular access maturation rate and/or patency would be significant progress. Based on the anti-inflammatory and vascular beneficial effects demonstrated in non-end stage renal disease patients, we were hoping that statin use might provide the much needed improvement in the hemodialysis vascular access outcome. The reality proved disappointing. The statins failed to improve every aspect of hemodialysis vascular access studied. The present editorial discusses the current data regarding the effect of statins on vascular access and attempts to explain their lack of success. PMID- 22428870 TI - Molten salt synthesis of a mixed-valent lanthanide(III/IV) oxychloride with an unprecedented Sillen X(2)(4) structure: Ce1.3Nd0.7O3Cl. AB - A new cerium neodymium oxychloride, Ce1.3Nd0.7O3Cl, has been synthesized by precipitation in a LiCl-CaCl2 molten salt by humid argon sparging. Chemical and structure characterization have been undertaken by powder X-ray diffraction, scanning electron microscopy, high-temperature X-ray diffraction, thermogravimetric analysis, and X-ray photoelectron scattering. This oxychloride crystallizes in space group P4/nmm, a = 3.9848(3) A and c = 12.467(2) A, in a new Sillen-type phase represented by the symbol X(2)(4) where "quadruple" fluorite type layers [M4O6], containing Ce(IV) in "inner" sublayers and both CeIII and NdIII in "outer" sublayers, alternate with double-halide ion sheets. The structure is also described as a stacking of LnOCl and fluorite-type blocks and constitutes the term n = 2 of a possible series (MO2)n(NdOCl)2. PMID- 22428871 TI - Perturbation of the electron transport mechanism by proton intercalation in nanoporous TiO2 films. AB - This study addresses a long-standing controversy about the electron-transport mechanism in porous metal oxide semiconductor films that are commonly used in dye sensitized solar cells and related systems. We investigated, by temperature dependent time-of-flight measurements, the influence of proton intercalation on the electron-transport properties of nanoporous TiO(2) films exposed to an ethanol electrolyte containing different percentages of water (0-10%). These measurements revealed that increasing the water content in the electrolyte led to increased proton intercalation into the TiO(2) films, slower transport, and a dramatic change in the dependence of the thermal activation energy (E(a)) of the electron diffusion coefficient on the photogenerated electron density in the films. Random walk simulations based on a microscopic model incorporating exponential conduction band tail (CBT) trap states combined with a proton-induced shallow trap level with a long residence time accounted for the observed effects of proton intercalation on E(a). Application of this model to the experimental results explains the conditions under which E(a) dependence on the photoelectron density is consistent with multiple trapping in exponential CBT states and under which it appears at variance with this model. PMID- 22428872 TI - A high-throughput screen for the engineered production of beta-lactam antibiotics. AB - High-throughput screens and selections have had profound impact on our ability to engineer proteins possessing new, desired properties. These methods are especially useful when applied to the modification of existing enzymes to create natural and unnatural products. In an advance upon existing methods we developed a high-throughput, genetically regulated screen for the in vivo production of beta-lactam antibiotics using a green fluorescent protein (gfp) reporter. This assay proved reliable and sensitive and presents a dynamic range under which a wide array of beta-lactam architectural subclasses can be detected. Moreover, the graded response elicited in this assay can be used to rank mutant activity. The utility of this development was demonstrated in vivo and then applied to the first experimental investigation of a putative catalytic residue in carbapenem synthase (CarC). Information gained about the mutability of this residue defines one parameter for enzymatic activity and sets boundaries for future mechanistic and engineering efforts. PMID- 22428873 TI - A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. PMID- 22428874 TI - Investigation of the sunscreen octocrylene's interaction with amino acid analogs in the presence of UV radiation. AB - Octocrylene is an organic UV filter, commonly used in sunscreens and cosmetics, which can give rise to both contact and photocontact allergy. Our aim was to investigate octocrylene's interaction with amino acid analogs in the presence of UV radiation to better understand the reason for octocrylene's photoallergenic capacity. The amino acid analogs were photolysed in presence and absence of octocrylene for 1 h in cyclohexane. The rate of degradation was considerably slower for all amino acid analogs when octocrylene was present in the mixture. Benzylamine, the lysine analog, did react with octocrylene during the photolysis and the corresponding amide was formed in an acylation reaction. By varying the benzylamine concentration and keeping the octocrylene concentration fixed the reaction rate was shown to be independent of the amine concentration. The same type of acylation reaction took place when octocrylene alone was photolysed in ethanol in which the ethyl ester was formed from octocrylene and ethanol. Our results suggest that octocrylene's ability to cause photocontact allergy could be due to its photoinduced reactivity toward primary amines and alcohols. PMID- 22428875 TI - Bevacizumab in endometrial cancer treatment. AB - INTRODUCTION: There is a critical need to develop effective new strategies for the management of patients with advanced or recurrent endometrial cancer (EC) and molecular targeted therapies; in particular, antiangiogenic drugs represent an interesting field of pharmacological research. One of the most interesting of these agents is bevacizumab, a monoclonal antivascular endothelial growth factor antibody. AREAS COVERED: Mechanism of action and clinical trials of bevacizumab in EC, and suggestions for its future use are reviewed. The most relevant papers and the meeting abstracts published up to December 2011 were used as sources for this review. The purposes of this manuscript are to discuss the rationale of interfering with the process of tumor angiogenesis in EC, to help readers in understanding the mechanism of action of bevacizumab, and to provide a comprehensive summary of initial preclinical and clinical results of this drug in EC patients. EXPERT OPINION: Recent advances in the understanding of the molecular biology of EC have led to development of targeted therapies. Among these, antiangiogenic agents are one of the most promising therapies. PMID- 22428876 TI - The effect of P-glycoprotein on methadone hydrochloride flux in equine intestinal mucosa. AB - Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P-glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P-glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapamil. Electrical measurements demonstrated tissue viability for 120 min, and the flux of methadone across the jejunal membrane (mucosal to submucosal direction) was calculated based on the relative drug concentration measured by ELISA. The flux of methadone was significantly higher only in the presence of verapamil. P-glycoprotein was immunolocalized in the apical membrane of the jejunal epithelial cells (enterocytes), mainly located in the tip of the villi compared to cells of the crypts. P-glycoprotein is present in the equine jejunum and may possibly mediate the intestinal transport of methadone. This study suggests that P-glycoprotein may play a role in the poor intestinal absorption of methadone in vivo. PMID- 22428877 TI - Evaluating the electrochemical capacitance of surface-charged nanoparticle oxide coatings. AB - While transition metal oxides have been thoroughly investigated as coatings for electrochemical capacitors due to their pseudocapacitance, little work has been done investigating other oxide coatings. There exists a whole class of nanoporous oxides typically synthesized by sol-gel chemistry techniques that have very high differential capacitance. This high differential capacitance has been attributed to the surface potential of these materials and the close approach of counterions near the surface of these oxides. This study focuses on investigating the electrochemical capacitance of non-transition metal oxide nanoparticle coatings when deposited on supporting electrodes. Here, we show that, by adding coatings of SiO(2), AlOOH, TiO(2), and ZrO(2) nanoparticles to graphite support electrodes, we can increase the electrochemical capacitance. We also show that the measured electrochemical capacitance of these oxide-coated electrodes directly relates to the electrophoretic mobility of these materials with the lowest values in capacitance occurring at or near the respective isoelectric pH (pH(IEP)) of each oxide. PMID- 22428879 TI - Optimal cutoff value of the serum pepsinogen level for prediction of gastric cancer incidence: the Hisayama Study. AB - BACKGROUND: Serum pepsinogen (sPG) levels have been established as a good marker of chronic atrophic gastritis and the sequential occurrence of gastric cancer. However, there have been few prospective investigations which investigated the predictive performance of sPG for future gastric cancer incidence. SUBJECTS AND METHODS: We prospectively followed-up a total of 2446 community-dwelling Japanese aged >= 40 years for 10 years and used the Youden's index to determine the cutoff values of the pepsinogen I level and pepsinogen I/II ratio to accurately discriminate gastric cancer events. Predictive performance of sPG was assessed by ROC curve. RESULTS: During the follow-up, 69 subjects developed gastric cancer. The most predictive sPG test criteria were determined to be a pepsinogen I level <= 59 ng/ml and pepsinogen I/II ratio <= 3.9. The sensitivity and specificity of these criteria to discriminate the actual occurrence of gastric cancer were 71.0% and 69.2%, respectively. The area under the ROC curve for gastric cancer occurrence increased significantly by adding the sPG test to the model that included the status of Helicobater pylori infection and other potential risk factors (from 0.742 to 0.809; p for difference in the area < 0.001). CONCLUSIONS: This study determined the optimal sPG test criteria for predicting gastric cancer occurrence over 10 years in a general Japanese population. These criteria would be effective to screen for individuals at high risk of this disease. PMID- 22428880 TI - Mechanisms of protein kinase Sch9 regulating Bcy1 in Saccharomyces cerevisiae. AB - In this study, we investigated the mechanisms of Sch9 regulating the localization and phosphorylation of Bcy1. Our research indicated that Sch9 regulated localization of Bcy1 via Zds1 for the following reasons: (1) deletions of SCH9 or ZDS1 both caused nuclear localization of Bcy1; (2) Sch9 and Zds1 interacted physically; (3) overexpression of ZDS1 led to a significantly increased cytoplasmic localization of Bcy1 in sch9Delta cells, whereas overexpression of SCH9 had no visible effect on cytoplasmic localization of Bcy1 in zds1Delta cells. Our study also suggested that Sch9 regulated phosphorylation of Bcy1 via Yak1. PMID- 22428881 TI - Primary cicatricial alopecias: a U.K. survey. PMID- 22428882 TI - Overcoming clopidogrel resistance: discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent. AB - A series of optically active 2-hydroxytetrahydrothienopyridine derivatives were designed and synthesized as prodrugs of clopidogrel thiolactone in order to overcome clopidogrel resistance. The final compounds were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. Compound 9a was selected for further in vitro and in vivo metabolism studies, since its potency was comparable to that of prasugrel and was much higher than that of clopidogrel. Preliminary pharmacokinetic study results showed that the bioavailability of clopidogrel thiolactone generated from 9a was 6-fold higher than that generated from clopidogrel, implying a much lower clinically effective dose for 9a in comparison with clopidogrel. In summary, 9a (vicagrel) holds great promise as a more potent and a safer antiplatelet agent that might have the following advantages over clopidogrel: (1) no drug resistance for CYP2C19 poor metabolizers; (2) lower dose-related toxicity due to a much lower effective dose; (3) faster onset of action. PMID- 22428883 TI - Pharmacodynamic bioequivalence testing. AB - WHAT IS KNOWN AND OBJECTIVE: The assessment of bioequivalence of drugs intended for local action/targeted delivery and with poor systemic absorption presents unique challenges. Approaches such as pharmacodynamic (PD) bioequivalence testing have been proposed as alternatives to pharmacokinetic (PK) bioequivalence studies. Our objective is to comment on when PD bioequivalence testing might be considered appropriate and whether the acceptance criteria for bioequivalence could be adjusted based on observed variability in PD response. COMMENT: Pharmacokinetic bioequivalence studies are generally conducted to evaluate the rate and extent of drug absorption of a test drug as compared to a reference drug. However, this may not be appropriate for locally acting drugs, when the plasma drug concentrations, if measurable, are not correlated with the clinical therapeutic effect. Systemic absorption may in fact be undesirable for such drugs. The US Food and Drug Administration (FDA) recommends alternative approaches for evaluating the bioequivalence of acarbose, including a bioequivalence study with a PD endpoint. For the evaluation of therapeutic equivalence of highly variable drugs, adjusting the acceptance interval for the PK parameters has been discussed by the FDA and the European Medicines Agency (EMEA). However, it is still not clear whether the newly proposed methodology is applicable to PD bioequivalence testing. WHAT IS NEW AND CONCLUSION: Although no consensus has been reached on the criteria for PD bioequivalence testing, various approaches are currently being investigated. Further studies should be performed to assess whether an adjustment of the acceptance intervals is appropriate based on the within-subject variability of PD responses. This may potentially minimize the unnecessary exposure of a large number of subjects to the test drugs. PMID- 22428885 TI - Dissipation of sulfamethoxazole and trimethoprim antibiotics from manure-amended soils. AB - In this study, the dissipation of two antibiotics, sulfamethoxazole (SMX) and trimethoprim (TRM), in three soils under both aerobic and anaerobic conditions are evaluated. Under aerobic conditions, SMX dissipated rapidly through biodegradation but TRM was more persistent. Within the first 20 days in biologically active soils, >50% of the SMX was lost from the clay loam and loamy sand soils, and >80% loss was noted in the loam soil. Anaerobic dissipation of both compounds was more rapid than aerobic dissipation. The addition of manure to the soil only slightly increased the initial dissipation rate of the two compounds. Little effect was found on glucose mineralisation in soil following the addition of SMX and TRM, even as mixtures at high concentrations. PMID- 22428884 TI - Assays of dioxins and dioxin-like compounds in actually contaminated soils using transgenic tobacco plants carrying a recombinant mouse aryl hydrocarbon receptor mediated beta-glucuronidase reporter gene expression system. AB - The transgenic tobacco plant XD4V-26 carrying the recombinant mouse aryl hydrocarbon receptor XD4V-mediated beta-glucuronidase (GUS) reporter gene expression system was used for assay of dioxins and dioxin-like compounds consisting of polychlorodibenzo-p-dioxins, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls (Co-PCBs) in actually contaminated soils. The transgenic tobacco plant XD4V-26 showed a significant dose-dependent induced GUS activity when cultured on MS medium containing PCB126 [toxic equivalency factor (TEF) = 0.1]. In contrast, PCB169 and PCB180, which have 0.03 of TEF and unassigned TEF values, respectively, did not significantly induce GUS activity under the same conditions as with PCB126. When the tobacco plants were cultivated for up to 5 weeks on actually contaminated soils with dioxins and dioxin-like compounds collected from the periphery of an incinerator used for disposal of life and industrial wastes, GUS activity in the leaves was dose-dependently increased. The plants clearly detected 360 pg-TEQ g(-1) of dioxins and dioxin like compounds in this assay. There was a positive correlation between GUS activity and TEQ value of dioxins and dioxin-like compounds in the plants. This assay does not require any extraction and purification processes for the actually contaminated soil samples. PMID- 22428886 TI - Agricultural pesticide residues of farm runoff in the Okanagan Valley, British Columbia, Canada. AB - The objectives of this study were to determine environmental occurrence and concentrations of selected currently-used-pesticides and some transformation products in agricultural farms in the Okanagan Valley (OKV), and to conduct a simple risk assessment of environmental pesticides levels detected in OKV on non target aquatic organisms. The OKV is the tree fruit country of the Province of British Columbia where considerable amount of pesticides are applied annually. Water, sediment and soil samples were collected at eleven sites in early June and late September following rainfall events and/or extended periods of irrigation from drainage ditches and/or from small streams. Undisturbed reference sites were also sampled. Study results showed that forty of the eighty chemicals analyzed, including organochlorine, nitrogen-containing and organophosphate pesticides commonly used for OKV crops, were detected in runoff and small stream water samples. Among which, endosulfan-sulfate was the most frequently detected chemical. Also, azinophos-methyl (0.699-25.5 ng/L), diazinon (0.088-214 ng/L) exceeded, and alpha-, beta- endosulfan, endosulfan sulphate approached the guidelines for the protection of aquatic life. PMID- 22428887 TI - Cytotoxic effect of fenitrothion and lambda-cyhalothrin mixture on lipid peroxidation and antioxidant defense system in rat kidney. AB - A mixture of pyrethroids plus organophosphates was assessed for their potential effects on lipid peroxidation, the antioxidant defense system and lactate dehydrogenase (LDH) in rat kidney in vitro. Various insecticide concentrations were incubated with kidney homogenate at 37 degrees C for different incubation times. Treatment with fenitothion (FNT) plus lambda-cyhalothrin (LC) caused a significant induction (P < 0.05) in thiobarbituric acid reactive substances (TBARS), which might be associated to decreased levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) activities and protein content in rat kidney. However, a significant induction of lactate dehydrogenase (LDH) activity was observed. The effect was concentration and time dependent. It can be concluded that depletion of GSH might indicate that reactive oxygen species (ROS) could be involved in the toxic effects of FNT plus LC which lead to marked perturbations in antioxidant defense system. PMID- 22428888 TI - Comparison of nitroethane, 2-nitro-1-propanol, lauric acid, Lauricidin(r) and the Hawaiian marine algae, Chaetoceros, for potential broad-spectrum control of anaerobically grown lactic acid bacteria. AB - The gastrointestinal tract of bovines often contains bacteria that contribute to disorders of the rumen, and may also contain foodborne or opportunistic human pathogens as well as bacteria capable of causing mastitis in cows. Thus there is a need to develop broad-spectrum therapies that are effective while not leading to unacceptably long antibiotic withdrawal times. The effects of the CH(4) inhibitors nitroethane (2 mg/mL), 2-nitro-1-propanol (2 mg/mL), lauric acid (5 mg/mL), the commercial product Lauricidin(r) (5 mg/mL), and a finely ground product of the Hawaiian marine algae, Chaetoceros (10 mg/mL), were compared in pure cultures of Streptococcus agalactia, Enterococcus faecium, Streptococcus bovis, and in a mixed lactic acid rumen bacterial culture. Lauricidin(r) and lauric acid exhibited the most bactericidal acidity against all bacteria. These results suggest potential animal health benefits from supplementing cattle diets with lauric acid or Lauricidin(r) to improve the health of the rumen and help prevent shedding of human pathogens. PMID- 22428889 TI - The aqueous solubility of some herbicidal by-side toxic impurities: predicted data of the 399 chlorinated trans-azoxybenzene congeners. AB - The quantitative structure - property relationship (QSPR) and the artificial neural networks (ANNs) methods were used to estimate aqueous solubility (log S and MUg/L) of polychlorinated trans-azoxybenzenes (PCt-ABs). These QSPR and ANN models are based on geometry optimalization and quantum-chemical structural descriptors, which were computed on the level of density functional theory (DFT) using B3LYP functional and 6-311++G** basis set in Gaussian 03 software and the semi-empirical quantum chemistry method for property parameterization (RM1) in the molecular orbital package (MOPAC) software. The predicted solubility of PCt AOBs by RM1 and DFT models and depending on a congener varied within a homologue class between 47-19498 and 371-1738 MUg/L for Mono-; 33-11481 and 7.9-3630 MUg/L for Di-; 6.1-4786 and 4.7-12882 MUg/L for Tri-; 1.3-1174 and 0.3-14791 MUg/L for Tetra-; 0.4-646 and 0.1-38904 MUg/L for Penta-; 0.1-155 and 0.2-63096 MUg/L for Hexa-; 0.2-27 and 0.1-646 MUg/L for Hepta-; < 0.1-6.2 and 0.8-282 MUg/L for Octa ; 0.6-2.6 and 0.8-12 MUg/L for NonaCt-AOBs; and 1.2 and 0.5 MUg/L for DecaCt-AOB, respectively. Both computational models used were characterized by good predictive abilities and small errors, while calculations by RM1 method were highly competitive compared to a much more time-consuming and expensive method by DFT. PMID- 22428890 TI - Biological degradation and microbial function effect of norfloxacin in a soil under different conditions. AB - This paper investigated the degradation kinetics of norfloxacin in a soil, and its effects on soil respiration and nitrogen transformation under different conditions. Compared to the sterile control, the degradation rates of norfloxacin in the non-sterile soil were greatly enhanced, suggesting that microorganisms played a major role in the degradation. Accelerated degradation for norfloxacin in the soil was observed with decreasing concentrations (30 mg/kg to 5 mg/kg) with its half-life decreasing from 62 days to 31 days. Amending swine manure into the soil and increasing the soil moisture level enhanced the biological degradation of norfloxacin. No obvious inhibition of norfloxacin on soil respiration was observed in the soil, while only slight effect on nitrogen transformation was found. The results suggested that norfloxacin at the reported environmental concentrations (<100 mg/kg) would have little effect on microbial activity and functions in the soils. PMID- 22428891 TI - Metals in edible fish from Vistula River and Dead Vistula River channel, Baltic Sea. AB - Metals including Al, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, Pb, Sr and Zn were determined in muscle tissue of 12 fish species by inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and cold vapour-atomic absorption spectroscopy (CV-AAS). Fish were collected from Vistula River at lower course and Dead Vistula River channel in south of Baltic Sea in Poland. The fish species examined include Round Goby (Neogobius melanostomus), Crucian Carp (Carassius carassius), Bull-rout (Myoxocephalus scorpius), Tench (Tinca tinca), Bream (Abramis brama), Burbot (Lota lot), Perch (Perca perca), Roach (Rutilus rutilus), Silver Carp (Hypophthalmichthys molitrix), Pikeperch (Stizostediun lucioperca), Brown salmon (Salmo trutta m. Trutta) and Eel (Anguilla anguilla). The median values of metal concentrations in fresh muscle tissue of 11 fish species varied as follows: Al < 0.5-60; Ba < 0.05-0.31; Ca 120-1800; Cd < 0.05-0.096; Co < 0.10; Cr < 0.10-0.50; Cu < 0.15-0.77; Fe 1.5-21; Hg 0.0058-0.65; K 1800-4200; Mg 130 560; Mn 0.12-0.59; Na 350-840; Ni < 0.2-0.31; Pb < 0.75; Sr 0.079-2.9; Zn 3.3-23 MUg/g fresh weight. The Target Hazard Quotient (THQ) values calculated in this study for Cd and Hg from muscles of fish species collected from Vistula River were low in the range of 0.4 for Hg and 0.8 for Cd. PMID- 22428892 TI - Deleterious effects of cypermethrin on rat liver and kidney: protective role of sesame oil. AB - The involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides. Our study was designed to investigate the induction of oxidative stress by cypermethrin; a Type II pyrethroid in rat liver and kidney. In addition, the protective role of sesame oil against the toxicity of cypermethrin was investigated. Animals were divided into four equal groups; the first group used as control while groups 2, 3 and 4 were treated with sesame oil (5 mL/kg b.w), cypermethrin (12 mg/kg b.w) and the combination of both sesame oil (5 mL/kg b.w) plus cypermethrin (12 mg/kg b.w), respectively. Rats were daily administered with their respective doses for 30 days by gavage. Repeated oral administration of cypermethrin was found to reduce the level of glutathione (GSH) and the activities of the antioxidant enzymes. While, the level of TBARS was elevated indicating the presence of oxidative stress. The activities of LDH, AST and ALT were decreased in the liver extract while increased in the plasma of the cypermethrin-treated group. Also, the levels of urea and creatinine were significantly increased after treatment with cypermethrin. Liver and kidney injury was confirmed by the histological changes. In conclusion, the administration of sesame oil provided significant protection against cypermethrin induced oxidative stress, biochemical changes, histopathological damage and genomic DNA fragmentation. PMID- 22428893 TI - PCR-RAPD profiling of Fusarium spp. causing guava wilt disease in India. AB - Wilt is a serious disease of the guava crop in India. Fusarium oxysporum f. sp. psidii and F. solani have been reported as causative agents of this disease. In this study, 42 isolates each of F. oxysporum f. sp. psidii and F. solani, were isolated from guava cultivars and characterized by randomly amplified polymorphic DNA (RAPD) method. Thirty RAPD primers were tested in the genome of Fusarium spp. and the number of scorable bands for corresponding primer ranged from 1-8 with an average of 5 bands per individual. DNA band size ranged from 200 bp to 5090 bp. A 0.21 per cent polymorphism was found in individual isolates of F. solani indicating that the 42 isolates were similar. However, a 2.58 percent polymorphism among individual isolates of F. oxysporum f.sp. psidii showed a higher level of genetic diversity. Cluster analysis of the RAPD band patterns clearly separated the isolates of F. oxysporum f.sp. psidii into three clusters. Two clusters were formed with F. solani isolates, showing a higher degree of similarity. Unique fingerprint profiles generated by the PCR-RAPD can be exploited for genetic characterization purposes. PMID- 22428894 TI - Synthesis of 2-furyl-4-arylidene-5(4H)-oxazolones as new potent antibacterial agents against phyto-pathogenic and nitrifying bacteria. AB - Crop losses due to bacterial pathogens are a major global concern. Most of the available pesticides for these pathogens suffer from various drawbacks such as complicated synthesis, high cost, high toxicity, pesticide resistance and environmental hazards. To overcome these drawbacks, the present study was undertaken to find a potent bactericide. Therefore, a series of compounds comprising bioactive furyl and oxazolone rings was synthesized under microwave irradiation and screened for in vitro antibacterial activity. The reactions were completed in fewer than 2 minutes with minimal use of solvents and resulted in high yields. These compounds were screened for antibacterial activity against plant pathogens, Xanthomonas oryzae, Ralstonia solanacearum and nitrifying bacteria, Nitrosomonas species under laboratory conditions. Five compounds were active as antibacterial agents against Xanthomonas oryzae and Ralstonia solanacearum. However, all compounds were effective against the Nitrosomonas species and the best one was 2-furyl-4-(3-methoxy-4-hydroxybenzylidene)-5(4H) oxazolone. The study revealed the fast and environmentally friendly synthesis of bioactive title compounds, which also hold promise to be used as prototypes for the discovery of potent analogues. PMID- 22428895 TI - Sorption of tebuconazole onto selected soil minerals and humic acids. AB - The aim of the present study was to investigate tebuconazole sorption on common soil minerals (birnessite, ferrihydrite, goethite, calcite and illite) and humic acids (representing soil organic matter). Tebuconazole was used (i) in the commercial form Horizon 250 EW and (ii) as an analytical grade pure chemical. In the experiment with the commercially available tebuconazole, a significant pH dependent sorption onto the oxides was observed (decreasing sorption with increasing pH). The highest sorption was found for ferrihydrite due to its high specific surface area, followed by humic acids, birnessite, goethite and illite. No detectable sorption was found for calcite. The sorption of analytical grade tebuconazole on all selected minerals was significantly lower compared to the commercial product. The sorption was the highest for humic acids, followed by ferrihydrite and illite and almost negligible for goethite and birnessite without any pH dependence. Again, no sorption was observed for calcite. The differences in sorption of the commercially available and analytical grade tebuconazole can be attributed to the additives (e.g., solvents) present in the commercial product. This work proved the importance of soil mineralogy and composition of the commercially available pesticides on the behavior of tebuconazole in soils. PMID- 22428896 TI - Comparison of organochlorine pesticides and polychlorinated biphenyls residues in vegetables, grain and soil from organic and conventional farming in Poland. AB - Organic and conventional crops were studied by identifying the relationship between persistent organic pollutants in cereals, vegetables and soil. The residues of organochlorine pesticides and polychlorinated biphenyls (PCBs) were determined in grains (rye and wheat), vegetables (carrots and beets) and soil collected from the fields. PCB residues recorded in the beets from organic farming were as high as 3.71 ppb dry weight (dry wt.), while in the soil from conventional farming of beets 0.53 ppb dry wt. Among vegetables, higher concentrations of pesticides were detected in organically grown beets (190.63 ppb dry wt.). Soil samples from the organic farming contained lower levels of organochlorine pesticide residues compared to the conventional farming. Taking into account toxicity equivalent (TEQ), the conventionally grown carrots accumulated the most toxic PCBs. Non-ortho and mono-ortho PCBs were also noted in the grain of conventionally grown rye and amounted to 3.05 pg-TEQ/g wet wt. PMID- 22428897 TI - The efficiency of electrocoagulation in treating wastewater from a dairy industry, part I: iron electrodes. AB - Iron electrodes were used for electrocoagulation (EC) treatment of wastewater from a dairy plant. Electrolysis time, pH, current density and distance between electrodes were considered to assess the removal efficiency of chemical oxygen demand (COD), total solids (TS) and their fractions and turbidity. Samples were collected from the effluent of a dairy plant using a sampling methodology proportional to the flow. The treatments were applied according to design factorial of half fraction with two levels of treatments and three repetitions at the central point. The optimization of parameters for treating dairy industry effluent by electrocoagulation using iron electrodes showed that electric current application for 15 minutes, an initial sample pH close to neutral (pH 7.0) and a current density of 50 A (.)(m-2) resulted in a significant reduction in COD by 58 %; removal of turbidity, suspended solids and volatile suspended solids by 95 %; and a final treated effluent pH of approximately 9.5. Negative consequences of the type of electrode used were the emergence of an undesirable color and an increase in the proportion of dissolved solids in the treated effluent. PMID- 22428898 TI - Microwave enhanced advanced oxidation process for treating dairy manure at low pH. AB - This study investigated the treatment of dairy manure using the microwave enhanced advanced oxidation process (MW-AOP) at pH 2. An experimental design was developed based on a statistical program using response surface methodology to explore the effects of temperature, hydrogen peroxide dosage and heating time on sugar production, nutrient release and solids destruction. Temperature, hydrogen peroxide dosage and acid concentration were key factors affecting reducing sugar production. The highest reducing sugar yield of 7.4% was obtained at 160 degrees C, 0 mL, 15 min heating time, and no H(2)O(2) addition. Temperature was a dominant factor for an increase of soluble chemical oxygen demand (SCOD) in the treated dairy manure. The important factors for volatile fatty acids (VFA) production were microwave temperature and hydrogen peroxide dosage. Temperature was the most important parameter, and heating time, to a lesser extent affecting orthophosphate release. Heating time, hydrogen peroxide dosage and temperature were significant factors for ammonia release. There was a maximum of 96% and 196% increase in orthophosphate and ammonia concentration, respectively at 160 degrees C, 0.5 mL H(2)O(2) and 15 min heating time. The MW-AOP is an effective method in dairy manure treatment for sugar production, nutrient solubilisation, and solids disintegration. PMID- 22428899 TI - Perceived dental needs and attitudes toward dental treatments in HIV-infected Thais. AB - Despite the advancement in highly active antiretroviral therapy and improved health status of HIV-infected individuals, dental problems are still affecting their life and well-beings. We aimed to establish the prevalence of oral and dental complaints among HIV-infected patients, the prevalence of delayed access to dental service, and factors related with delayed access to dental service. A cross-sectional study using self-report questionnaire completed by the HIV positive subjects was conducted at the largest HIV research clinic in Thailand during 2009-2010. Of all 299 subjects (28.6% males, 71% females, and 0.4% sex change from male to female: ages ranged from 22 to 59 years [mean 36.7+/-5.53)]), 84.3% reported of having past or present illnesses or problems related to the dental or oral conditions. The most reported problems were dental hypersensitivity (93.3%), bleeding from the gum (92.1%), and having dental caries (65.9%). Two-hundred and forty-two subjects (80.9%) would not disclose their HIV status when seeing a dentist. The most cited reasons of such behavior were their personal right whether to reveal or not, and being afraid of not receiving dental treatment from the dentists or staffs (51.7 and 40.9%, respectively). It is important to note that HIV-subjects admitted to having fear of being discriminated by the dental staffs even if they trusted their dentists as having high morality. In conclusion, our HIV-subjects had good basic knowledge of oral health with regard to HIV infection, experienced common dental problems, and wished to have accesses to HIV-dental specialist services, if possible. PMID- 22428900 TI - Validity of patient skin cancer report among organ transplant recipients. AB - Skin cancer is a common, potentially life-threatening malignancy in organ transplant recipients (OTR), and it is important for transplant physicians to be aware of patient history of skin cancer. Patient self-report represents a quick method of obtaining past medical history of skin cancer but no study has validated the self-report of skin cancer among OTR. Among 339 OTR with a history of skin cancer, the sensitivity and specificity of self-report of non-melanoma skin cancer (NMSC) were 1.00 and 0.92, with a correct classification rate of 0.92. Breakdown of NMSC into squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) resulted in a decrease in correct classification, to 0.83 for SCC and 0.74 for BCC. For SCC, sensitivity was 0.81 and specificity was 0.83, while BCC had a sensitivity of 0.52 and specificity of 0.86. Melanoma self-report had a sensitivity of 0.90 and specificity of 0.86, with a correct classification rate of 0.90. Overall, OTR have comparable accuracy of self-report with the general population. Owing to the high prevalence and increased risk of metastatic potential of skin cancer in this population, the ability to distinguish between cancer types is an important consideration in the dermatologic care of OTR. PMID- 22428902 TI - Palladium(II) containing gamma-Keggin silicodecatungstate that efficiently catalyzes hydration of nitriles. AB - A mixture of Pd(OAc)(2) and TBA(4)[gamma-SiW(10)O(34)(H(2)O)(2)] (TBA-SiW10, TBA = [(n-C(4)H(9))(4)N](+)) showed high catalytic activities for hydration of various kinds of structurally diverse nitriles including aromatic, aliphatic, heteroaromatic, and double bond-containing ones. For hydration of 3 cyanopyridine, the turnover frequency was 860 h(-1), and the turnover number reached up to 670. A dipalladium-substituted gamma-Keggin silicodecatungstate, [gamma-H(2)SiW(10)O(36)Pd(2)(OAc)(2)](4-) (I), was successfully synthesized by the reaction of [gamma-SiW(10)O(34)(H(2)O)(2)](4-) with Pd(OAc)(2) in a mixed solvent of acetone and water. The crystal structure of I was a monomeric, dipalladium-substituted, gamma-Keggin silicodecatungstate with bidentate acetate ligands. Compound I showed similar activities and selectivities to those of a simple mixture of Pd(OAc)(2) and TBA-SiW10. The kinetic, mechanistic, and density functional theory calculation studies show that the dipalladium site plays an important role in the present hydration, and the nucleophilic attack of a hydroxide or water to the nitrile carbon atom is included in the rate-determining step. PMID- 22428901 TI - Reduced palatability in drug-induced taste aversion: I. Variations in the initial value of the conditioned stimulus. AB - Like illness-inducing agents (e.g., lithium chloride), drugs of abuse also suppress intake of a taste solution. To explore the nature of this drug-induced intake reduction, in the current study three aqueous stimuli with different initial values served as the conditioned stimuli (CSs) that were paired with a standard dose of amphetamine in a voluntary intake procedure and lick patterns were analyzed. Consistent with earlier studies, amphetamine significantly reduced intake of all three CSs (quinine, sodium chloride, and orange odor). In contrast to studies that analyze orofacial responses, we found that lick cluster size was significantly lowered by amphetamine, indicating that the psychoactive drug induced a conditioned reduction in taste palatability. PMID- 22428903 TI - Cusp radius measurement through digital image analysis. AB - OBJECTIVE: Dental anatomy has been extensively described in numerous textbooks. Nevertheless, there are very few details about the value of the cusp radius of posterior teeth. This in vitro study used a laser profilometer to scan the occlusal surfaces of 21 molar teeth. MATERIALS AND METHODS: The images were analysed with uScan software and the approximate radius of curvature was measured. RESULTS: The values varied between 0.6-2.5 mm. The radius average value was 1.25 mm bucco-lingually and 1.61 mm mesio-distally. CONCLUSIONS: These findings might serve as a guide for different dental biomechanics studies and the conception, design and manufacturing of dental prosthetics. PMID- 22428904 TI - Synthesis, structure, and magnetic properties of regular alternating MU-bpm/di-MU X copper(II) chains (bpm = 2,2'-bipyrimidine; X = OH, F). AB - The preparation and X-ray crystal structure of four 2,2'-bipyrimidine (bpm) containing copper(II) complexes of formula {[Cu(2)(MU-bpm)(H(2)O)(4)(MU OH)(2)][Mn(H(2)O)(6)](SO(4))(2)}(n) (1), {[Cu(2)(MU-bpm)(H(2)O)(4)(MU OH)(2)]SiF(6)}(n) (2), {Cu(2)(MU-bpm)(H(2)O)(2)(MU-F)(2)F(2)}(n) (3), and [Cu(bpm)(H(2)O)(2)F(NO(3))][Cu(bpm)(H(2)O)(3)F]NO(3).2H(2)O (4) are reported. The structures of 1-3 consist of chains of copper(II) ions with regular alternation of bis-bidentate bpm and di-MU-hydroxo (1 and 2) or di-MU-fluoro (3) groups, the electroneutrality being achieved by either hexaaqua manganese(II) cations plus uncoordinated sulfate anions (1), uncoordinated hexafluorosilicate anions (2), or terminally bound fluoride ligands (3). Each copper(II) ion in 1-4 is six coordinated in elongated octahedral surroundings. 1 and 2 show identical, linear chain motifs with two bpm-nitrogen atoms and two hydroxo groups building the equatorial plane at each copper(II) ion and the axial position being filled by water molecules. In the case of 3, the axial sites at the copper atom are occupied by a bpm-nitrogen atom and a bis-monodentate fluoride anion, producing a "step-like" chain motif. The values of the angle at the hydroxo and fluoro bridges are 94.11(6) (1), 94.75(4) (2), and 101.43(4) degrees (3). In each case, the copper-copper separation through the bis-bidentate bpm [5.428(1) (1), 5.449(1) (2), and 5.9250(4) A (3)] is considerably longer than that through the di-MU-hydroxo [2.8320(4) (1) and 2.824(1) A (2)] or di-MU-fluoro [3.3027(4) A (3)] bridges. Compound 4 is a mononuclear species whose structure is made up of neutral [Cu(bpm)(H(2)O)(2)F(NO(3))] units, [Cu(bpm)(H(2)O)(3)F](+) cations, uncoordinated nitrate anions, and crystallization water molecules, giving rise to a pseudo-helical, one-dimensional (1D) supramolecular motif. The magnetic properties of 1-3 have been investigated in the temperature range 1.9-300 K. Relatively large, alternating antiferro- [J = -149 (1) and -141 cm(-1) (2) across bis-bidentate bpm] and ferromagnetic [alphaJ = +194 (1) and +176 cm(-1) (2) through the dihydroxo bridges] interactions occur in 1 and 2 [the Hamiltonian being defined as H = -J?(i=1)(n/2) (S(2i).S(2i-1) - alphaS(2i).S(2i+1))]. These values compare well with those previously reported for parent examples. Two weak intrachain antiferromagnetic interactions [J = -0.30 and alphaJ = -8.1 cm(-1) across bpm and the di-MU-fluoro bridges, respectively] whose values were substantiated by density functional theory (DFT)-type calculations occur in 3. PMID- 22428906 TI - Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades? AB - Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as 'cascade screening'. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks. PMID- 22428905 TI - Retinal photodamage mediated by all-trans-retinal. AB - Accumulation of all-trans-retinal (all-trans-RAL), reactive vitamin A aldehyde, is one of the key factors in initiating retinal photodamage. This photodamage is characterized by progressive retinal cell death evoked by light exposure in both an acute and chronic fashion. Photoactivated rhodopsin releases all-trans-RAL, which is subsequently transported by ATP-binding cassette transporter 4 and reduced to all-trans-retinol by all-trans-retinol dehydrogenases located in photoreceptor cells. Any interruptions in the clearing of all-trans-RAL in the photoreceptors can cause an accumulation of this reactive aldehyde and its toxic condensation products. This accumulation may result in the manifestation of retinal dystrophy including human retinal degenerative diseases such as Stargardt's disease and age-related macular degeneration. Herein, we discuss the mechanisms of all-trans-RAL clearance in photoreceptor cells by sequential enzymatic reactions, the visual (retinoid) cycle, and potential molecular pathways of retinal photodamage. We also review recent imaging technologies to monitor retinal health status as well as novel therapeutic strategies preventing all-trans-RAL-associated retinal photodamage. PMID- 22428907 TI - Role of anisotropy in electrodynamically induced colloidal aggregates. AB - We investigate the assembly of spherical and anisotropic colloidal particles with the shape of peanuts when subjected to an external alternating electric field. By varying the strength and frequency of the applied field, we observe that both types of particles form clusters at low frequencies due to attractive electrohydrodynamic interactions or disperse into a liquidlike phase at high frequencies due to repulsive dipolar interactions. We characterize the observed structures via pair correlation functions and radius of gyration, and observe a clear difference in the ordering process between the isotropic and anisotropic colloids. Further on, we interpret the cluster formation kinetics in terms of dynamic scaling theory, and observe a faster aggregation of the anisotropic colloids with respect to the isotropic ones. PMID- 22428909 TI - Low rate of sustained virological response in an outbreak of acute hepatitis C in HIV-infected patients. AB - Recent reports have suggested an increased risk of acute hepatitis C (AHC) infection in homosexual HIV-infected men and that early treatment with interferon alfa, alone or associated with ribavirin, significantly reduces the risk of chronic evolution. A retrospective analysis of 38 HIV-infected patients who were consecutively diagnosed as developing AHC, defined by both seroconversion of anti hepatitis C virus (HCV) antibodies and detection of serum HCV-RNA in those with previous negative results. Thirty-six patients were men with history of unprotected sexual intercourse with men and two were women with sexual and nosocomial risk factors. AHC infection was asymptomatic in 26 patients; asthenia and jaundice were the most frequent symptoms. HCV genotype 1 was present in 19 patients and genotype 4 in 14 patients. Thirty-five patients received early antiviral treatment with pegylated interferon-alfa associated with ribavirin; 15 of the 32 patients who completed the follow-up (47%) achieved a sustained virological response, as defined by undetectable HCV-RNA 6 months after the end of therapy. There is a risk of sexual transmission of HCV in HIV-infected men who have sex with men. In our experience, early treatment of AHC with pegylated interferon-alfa plus ribavirin in HIV patients achieves poor results. PMID- 22428908 TI - Nucleic acid delivery: the missing pieces of the puzzle? AB - The delivery of genes or RNA interference (RNAi) agents can increase or decrease the expression of virtually any protein in a cell, and this process opens the path for cures to most diseases that afflict humans. However, the high molecular weight, anionic nature, and instability of nucleic acids in the presence of enzymes pose major obstacles to their delivery and frustrates their use as human therapies. This Account describes current ideas about the mechanisms in nonviral nucleic acid delivery and how lipidic and polymeric carriers can overcome some of the critical barriers to delivery. Over the last 20 years, researchers have developed a multitude of polymeric and lipidic vectors, but only a small fraction of these have progressed into clinical trials. None of these vectors has received FDA approval, which indicates that the current vectors do not yet have suitable properties for effective in vivo nucleic acid delivery. Nucleic acid delivery is a multistep process and inefficiencies at any stage result in a dramatic decrease in gene delivery or gene silencing. However, the majority of studies investigating synthetic vectors focus solely on optimization of endosomal escape. A small number of studies address how to improve uptake via targeted delivery, and an even smaller fraction examine the intracellular fate of the delivery systems and nucleic acid cargo. The internalization of genes into the cell nucleus remains an inefficient and mysterious process. In the case of DNA delivery, strategies are needed to increase and accelerate the migration of DNA through the cytoplasm and transport it through the nuclear membrane. siRNA delivery involves fewer barriers. siRNA is more readily released from the carrier and more resistant to enzymatic degradation, and its target is in the cytoplasm; hence, siRNA delivery systems are becoming a clinical reality. With regard to siRNA therapy, the exact cytoplasmic location of RNA-induced silencing complex (RISC) formation and activity is unknown, which makes specific targeting of the RISC for more efficient delivery difficult. Furthermore, we would like to identify the factors that favor the binding of siRNA to Ago-2. If we could understand how the half-life of siRNA and Ago-2/siRNA complex in the cytoplasm can be modulated without interfering with RISC functions that are essential for normal cell activity, we could increase siRNA delivery efficiency. In this Account, we review the current synthetic vectors and propose alternative strategies in a few cases. We also suggest how certain cellular mechanisms might be exploited to improve gene transfection and silencing. Finally, we discuss whether some carriers that deliver the siRNA to cells could also repackage the siRNA into exosomes. The exosomes would then transport the siRNA into a subsequent population of cells that manifest the siRNA effect. This piggy-back mechanism may be responsible for reported deep tissue siRNA effects using certain carriers. PMID- 22428910 TI - Nonhematotoxic naphthalene diimide modified by polyamine: synthesis and biological evaluation. AB - With the aim of up-regulating antitumor efficacy and down-regulating adverse effects, three types of aromatic imide and diimides were designed to couple with different polyamines. The in vitro assays revealed that two naphthalene diimide polyamine conjugates could inhibit the growth of multiple cancer cell lines more potently than amonafide. 9f, the most potent compound, was verified to efficiently induce apoptosis via a ROS mediated mitochondrial pathway in a preliminary mechanistic study. The comprehensive in vivo trials on three H22 tumor transplant models demonstrated that 9f improved the indexes in terms of inhibitive effect and lifespan extension and reduced the hematotoxicity which is one of main drawbacks of amonafide. More importantly, the obviously elevated ability in preventing lung cancer metastasis was observed, which increased the value of 9f as a promising lead compound. This work supported that the versatile function of polyamines may endow some intriguing biological features to the parent drugs. PMID- 22428911 TI - Nonscarring skin blistering disease and mucosal lesions with IgA autoantibodies reactive with collagen VII and IgG reactivity with laminin gamma2. PMID- 22428912 TI - Effect of the pasteurization process on the contents of ascorbigen, indole-3 carbinol, indole-3-acetonitrile, and 3,3'-diindolylmethane in fermented cabbage. AB - The aim of the study was to investigate the effect of the pasteurization process on the content of ascorbigen, indole-3-carbinol, indole-3-acetonitrile, and 3,3' diindolylmethane in fermented cabbage. Pasteurization was run at a temperature of 80 degrees C for 5-30 min. Significant changes were only observed in contents of ascorbigen and 3,3'-diindolylmethane. The total content of the compounds analyzed in cabbage pasteurized for 10-30 min was found to be decreased by ca. 20%, and the losses were due to thermal degradation of the predominating ascorbigen. Pasteurization was found not to exert any considerable effect on contents of indole-3-acetonitrile and indole-3-carbinol in cabbage nor did it affect contents of the compounds analyzed in juice. PMID- 22428913 TI - ABCC2 transporter gene polymorphisms, diet and risk of colorectal cancer: a Danish prospective cohort study. PMID- 22428914 TI - Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets. AB - WHAT IS KNOWN AND OBJECTIVE: Acarbose, an alpha-glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. METHODS: This investigation consisted of a pilot study and a main study. The pilot study had an open, single-dose, single-sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay((r)) 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two-period, two-sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100-mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G(max)) and the area under the serum glucose concentration-time profile (AUC(gluc)) were determined and compared. RESULTS AND DISCUSSION: Five subjects completed the pilot study. The AUC(gluc) from dosing until 1 h post-dose (AUC(gluc,1 h)) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G(max) (DeltaG(max)) and AUC(gluc,1 h) (DeltaAUC(gluc,1 h)) for the reference formulation compared with placebo were 22.0 +/- 18.3 mg/dL and 928.2 +/- 756.0 mg min/dL, respectively. The corresponding values for the test formulation were 23.3 +/- 21.2 mg/dL and 923.0 +/- 991.4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for DeltaG(max) and DeltaAUC(gluc, 1 h) were 1.06 and 1.00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0.79-1.39 and 0.64-1.36, respectively. WHAT IS NEW AND CONCLUSION: The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0.80-1.25). PMID- 22428915 TI - Perceptions of health and environmental impacts of e-waste management in Ghana. AB - This paper explores the perception of health and environmental concerns of workers and residents living close to e-waste recycling sites in Ghana using both qualitative and quantitative research techniques. The social constructionist approach and a logit regression model were adopted to examine the rationale of their claims and concerns which have hitherto been unknown and unexplored. We find that workers' environmental and health perceptions were seriously downplayed and do not match those of epidemiological studies, revealing a lack of convergence between lay and expert knowledge. This study further shows a respondent-specificity rationale; the perception of those directly involved in the processes was mainly influenced by economic considerations, while some at best displayed "genuine" ignorance. We recommend that all policy interventions incorporate approaches that have a better chance of arriving at conclusions economically meaningful to participants and that facilitate greater understanding of health and environmental issues. PMID- 22428917 TI - Brentuximab vedotin in systemic T-cell lymphoma. AB - INTRODUCTION: Brentuximab vedotin is an antibody-drug conjugate which consists of the anti-CD30 monoclonal antibody cAC10 conjugated with the cytotoxic agent monomethyl auristatin E (MMAE). Brentuximab vedotin has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory Hodgkin's lymphoma (HL) and anaplastic large cell lymphoma (ALCL). The efficacy of brentuximab vedotin in other CD30(+) lymphomas is currently being investigated. AREAS COVERED: In this paper, we review the currently available treatment options for systemic peripheral T-cell lymphomas (PTCL) and the role of brentuximab vedotin in relapsed or refractory ALCL. In addition, ongoing clinical trial of brentuximab vedotin in relapsed PTCL and combination therapy with other chemotherapies for initial treatment of CD30 lymphoma will also be reviewed. EXPERT OPINION: Brentuximab vedotin has established its role in the treatment of relapsed or refractory HL and ALCL. In the next few years, the efficacy of this agent in other CD30(+) lymphomas will be described. The safety and efficacy of several brentuximab-based combination regimens, including use as frontline chemotherapy is under investigation. PMID- 22428918 TI - Voice disorders in teachers: occupational risk factors and psycho-emotional factors. AB - BACKGROUND: Teaching is a high-risk occupation for developing voice disorders. The purpose of this study was to investigate previously described vocal risk factors as well as to identify new risk factors related to both the personal life of the teacher (fluid intake, voice-demanding activities, family history of voice disorders, and children at home) and to environmental factors (temperature changes, chalk use, presence of curtains, carpet, or air-conditioning, acoustics in the classroom, and noise in and outside the classroom). METHODS: The study group comprised 994 teachers (response rate 46.6%). All participants completed a questionnaire. Chi-square tests and logistic regression analyses were performed. RESULTS: A total of 51.2% (509/994) of the teachers presented with voice disorders. Women reported more voice disorders compared to men (56.4% versus 40.4%, P < 0.001). Vocal risk factors were a family history of voice disorders (P = 0.005), temperature changes in the classroom (P = 0.017), the number of pupils per classroom (P = 0.001), and noise level inside the classroom (P = 0.001). Teachers with voice disorders presented a higher level of psychological distress (P < 0.001) compared to teachers without voice problems. CONCLUSION: Voice disorders are frequent among teachers, especially in female teachers. The results of this study emphasize that multiple factors are involved in the development of voice disorders. PMID- 22428919 TI - A cross-sectional analysis of the prevalence of dental anxiety and its relation to the oral health-related quality of life in patients with dental treatment needs at a university clinic in Switzerland. AB - OBJECTIVES: The aim of this observational, cross-sectional study was to analyse the relationship between dental anxiety (DA) and health-related quality of life aspects associated with oral conditions of a population with dental treatment needs in Switzerland. METHODS: The measurements of DA were collected by means of two questionnaires, the Dental Anxiety Scale (DAS) and a Visual Analogue Scale (VAS). Oral health-related quality of life (OHRQoL) was assessed with the Oral Health Impact Profile (OHIP). The sample included 223 patients enrolled at a university clinic which specialises in oral prosthetic rehabilitation and temporomandibular disorders. Of them, 78.9% were at or above the age of 50. RESULTS: No gender or age dependencies were observed. A comparison of answers regarding OHRQoL and DA revealed a significant interdependence (p = 0.0118); highly anxious patients were 3.55 times more likely to suffer from poor quality of life compared with less anxious ones. CONCLUSION: This cross-sectional study of mostly elderly patients seeking dental treatment in Switzerland found that increased DA was associated with an impaired OHRQoL. The average DA was slightly higher than the results of other industrialised countries and the average OHRQoL was reduced. PMID- 22428920 TI - The natural compound trans-chalcone induces programmed cell death in Arabidopsis thaliana roots. AB - Chalcone (1,3-diphenyl-2-propen-1-one) is an aromatic ketone precursor of important molecules in plants such as flavonoids or anthocyanins. Its phytotoxicity has been demonstrated on different plant species, but to date little is known about the mechanisms of action of this secondary metabolite at plant cellular level. Detailed analysis by light and transmission electron microscopy (TEM) was conducted to examine the root meristems' ultrastructure of control and chalcone-treated Arabidopsis seedlings. Mitochondrial dysfunction was analysed by measuring mitochondrial membrane potential with JC-1 fluorochrome. Finally, acridine orange/ethidium bromide staining was used for the detection of programmed cell death. Microscopy revealed tissue alterations, inhibition of root hair formation and important changes after 7 and 14 d at the chalcone IC(50) value. Chalcone-treated cells showed signs of programmed cell death such as mitochondrial condensation, disruption of organelles and chromatin fragmentation. Acridine orange/ethidium bromide staining confirmed the programmed cell death, which could be induced by the reduction of mitochondrial transmembrane potential (DeltaPsi(m)) that was detected after chalcone treatment. These results confirm the phytotoxic activity of chalcone on Arabidopsis seedlings, the alteration of mitochondrial membrane potential and the induction of programmed cell death. PMID- 22428922 TI - Author's reply. PMID- 22428921 TI - Engineering de novo membrane-mediated protein-protein communication networks. AB - Mechanical properties of biological membranes are known to regulate membrane protein function. Despite this, current models of protein communication typically feature only direct protein-protein or protein-small molecule interactions. Here we show for the first time that, by harnessing nanoscale mechanical energy within biological membranes, it is possible to promote controlled communication between proteins. By coupling lipid-protein modules and matching their response to the mechanical properties of the membrane, we have shown that the action of phospholipase A(2) on acyl-based phospholipids triggers the opening of the mechanosensitive channel, MscL, by generating membrane asymmetry. Our findings confirm that the global physical properties of biological membranes can act as information pathways between proteins, a novel mechanism of membrane-mediated protein-protein communication that has important implications for (i) the underlying structure of signaling pathways, (ii) our understanding of in vivo communication networks, and (iii) the generation of building blocks for artificial protein networks. PMID- 22428923 TI - Infantile bilateral glaucoma in a child with ectodermal dysplasia. AB - Ectodermal dysplasia is a rare disease which affects at least two ectodermal derived structures such as hair, nails, skin, sweat glands and teeth. Approximately 200 different conditions have been classified as an ectodermal dysplasia and X-linked hypohidrotic ectodermal dysplasia (XHED) represents the commonest form. Clinically, XHED is characterized by hypotrichosis, hypohidrosis and hypodontia. A variety of ocular manifestations have been reported in XHED, the most common being dryness of eyes due to tear deficiency and instability of the film secondary to the absence of meibomian gland function. Here we report a child with the distinctive clinical features of XHED confirmed with molecular diagnosis who presented with infantile bilateral glaucoma, in addition to the classical ocular involvement in XHED. PMID- 22428924 TI - Placental mesenchymal dysplasia and an estimation of the population incidence. AB - Placental mesenchymal dysplasia (PMD) is a rare placental malformation of as yet undetermined etiology. We report a single center's experience of this diagnosis and present an estimation of the population incidence. Within our institution, all placentae are examined within a pathology department that provides a dedicated perinatal service. In this study, we evaluated the incidence of PMD over a period of 18 years following the description and recognition of PMD as a pathological diagnosis. During the period 1991-2009, only two cases were identified amongst over 95 000 deliveries at our institution. This series of placental examinations is by far the largest in a normal population within which the occurrence of PMD is reported, and the resulting incidence of only 0.02 per 1000 deliveries is some 10 times less than that which has previously been estimated. PMID- 22428925 TI - Combination of magnetic susceptibility and electron paramagnetic resonance to monitor the 1D to 2D solid state transformation in flexible metal-organic frameworks of Co(II) and Zn(II) with 1,4-bis(triazol-1-ylmethyl)benzene. AB - Two families of coordination polymers, {[M(btix)(2)(OH(2))(2)].2NO(3).2H(2)O}(n) [M = Co (1), Zn (2), Co-Zn (3); btix = 1,4-bis(triazol-1-ylmethyl)benzene] and {[M(btix)(2)(NO(3))(2)]}(n) [M = Co (4), Zn (5), Co-Zn (6)], have been synthesized and characterized. The two conformations of the ligand, syn and anti, lead to one-dimensional (1D) cationic chains or two-dimensional (2D) neutral grids. Extrusion of the water molecules of the 1D compounds results in an irreversible transformation into the 2D compounds, which involves a change in conformation of the btix ligands and a rearrangement in the metal environment with cleavage and reformation of covalent bonds. This structural transformation has been followed by electron paramagnetic resonance (EPR) and magnetic susceptibility measurements to monitor the minor modifications that the metal centers suffer. PMID- 22428926 TI - Relationship between mortality and fine particles during Asian dust, smog-Asian dust, and smog days in Korea. AB - This study examined the association between all-cause/cardiovascular mortality and PM(2.5) as related to Asian dust (AD), smog-AD, smog, and nonevent days and evaluated the differential risks according to specific events for mortality. The daily records of all-cause/cardiovascular mortality and PM(2.5) from March to May 2003-2006 in Seoul, Korea, were used as independent and dependent variables. Differences in the event effects were assessed using a time-series analysis. Both all-cause and cardiovascular mortalities were significantly associated with PM(2.5) during smog-AD and AD days only. Differences in chemical composition emerging during long-range transport to Korea may explain these observations, especially as regards secondary aerosol, metal-sulfate/or nitrate, and metallic components. These results suggest that exposure to PM(2.5) during specific events is differentially associated with human mortality and that changes in the chemical composition of PM(2.5), occurring during long-range transport, represent important factors in such differential effects on health. PMID- 22428927 TI - Safflomide increases the expression of adiponectin in vitro and in vivo: potential implication for hypoadiponectemia, visceral obesity, and insulin resistance. AB - Safflomide (N-caffeoyltryptamine) is a phenolic amide with serotonin receptor antagonist and antioxidant activities. We investigated the potential effects of safflomide on the expression of adipokines in vitro and in vivo. Safflomide did not affect the expressions of TNF-alpha, IL-6, and MCP-1/CCL2 in hypertrophic 3T3 L1 cells but upregulated adiponectin mRNA 1-5-fold at concentrations between 1 and 20 MUM (p < 0.05). Because safflomide is a non-selective 5-HT receptor antagonist and because the expression of 5-HT2A receptor is often inversely correlated to adiponectin expression, the potential effects of 5-HT receptor antagonist activity of safflomide on the expression of adiponectin was further investigated in 3T3-L1 cells. At the concentration of 10 MUM, safflomide was able to increase adiponectin protein production in 3T3-L1 cells more than 4-fold (p < 0.05), which was greater than the 5-HT2A antagonist ketanserin. The upregulation was partially suppressed by treatment with 5-HT2A agonists (serotonin and alpha Me-5-HT), suggesting that safflomide may upregulate adiponectin expression more than by blocking 5-HT2A receptors in 3T3-L1 cells. Likely, the upregulation was also attributed to the antioxidant activity of safflomide because two safflomide analogues (N-cinnamoyltryptamine and N-coumaroyltryptamine) with less antioxidant activity were not as potent as safflomide. Rats supplemented with safflomide (3 mg/day) in a high-fat diet showed a significant plasma adiponectin increase (more than 30%) with a significant reduction in body weight, visceral fat, and improved insulin resistance compared to non-supplemented rats, demonstrating the in vivo activity of safflomide. These data suggest that safflomide may have beneficial effects on obesity-related conditions, such as low adiponectin, visceral obesity, and insulin resistance. PMID- 22428928 TI - Risk factors and chemoprevention in Barrett's esophagus--an update. AB - OBJECTIVE: Barrett's esophagus (BO) is a precursor of esophageal adenocarcinoma (OAC), a cancer with a poor prognosis and an increasing incidence. Hence there is an interest in mapping causal factors underlying BO and finding strategies to reduce the risk of dysplasia progression in patients with BO. Here we review current knowledge on established as well as less risk factors for the development of BO. Additionally, we summarize today's status on the use of chemoprevention aiming to reduce the risk of cancer progression in BO patients. METHODS: We searched Medline and the Cochrane Library using the MeSH terms "Barrett's esophagus" and "Barrett esophagus," both alone and combined with the terms "risk factor," "aetiology," "diet," or "prevention." Focus was on original contributions, systematic reviews, and meta-analyses. RESULTS: Established risk factors for the development of BO include gastro-esophageal reflux, obesity, male gender, Caucasian ethnicity, and increasing age. Smoking might increase the risk of BO, while aspirin/NSAIDs, Helicobacter pylori infection, and specific "healthy" dietary factors may lower the risk. The potential value of using chemoprevention with proton pump inhibitors, aspirin/NSAIDs, or statins is still uncertain. CONCLUSIONS: There is today a substantial knowledge of risk factors of BO. Certain diet may be protective of BO, albeit yet to be proven. The efficiency of chemoprevention in BO is currently addressed further in randomized clinical trials. PMID- 22428929 TI - A comparison of qualitative and quantitative fecal immunochemical tests in the Korean national colorectal cancer screening program. AB - OBJECTIVE: The National Cancer Screening Program (NCSP) has since 2004 provided annual colorectal cancer screening using the fecal immunochemical test (FIT) for individuals aged 50 years or older. The aim of this study was to examine the positivity and detection rates of the FIT and to compare the detection rates of the qualitative and quantitative FITs in participants in the 2009 NCSP. METHODS: We analyzed positivity and detection rates according to FIT type (qualitative and quantitative). We used a multinomial logistic regression to analyze the odds ratio of "benign" or "suspicious cancer and cancer" compared to "normal," adjusted for gender, age, health insurance type, region of residence, hospital type, and FIT type. RESULTS: Of the 1,181,904 participants, 72.8% received a qualitative and 27.2% a quantitative FIT. The positivity rates were 8.1% for the qualitative and 2.5% for the quantitative FIT. The detection rate was 5.2% for the qualitative and 14.4% for the quantitative FIT. The odds ratio of a "suspicious cancer and cancer" versus a "normal" result was 2.73 (95% CI = 2.22 3.35) for the quantitative compared to qualitative FIT, after adjustment. CONCLUSIONS: The positivity rate of the qualitative FIT was around three times higher than that of the quantitative FIT. However, the odds ratio for detection of "suspicious cancer and cancer" versus "normal" of the quantitative FIT was about three times higher than that of the qualitative FIT. These findings suggest that quality control may be important, particularly for the qualitative FIT. PMID- 22428930 TI - Supramolecular assemblies of lipid-coated polyelectrolytes. AB - We reveal the existence of a general class of supramolecular assemblies made up of lipid-coated polyelectrolytes including the celebrated lipid-nucleic acid complexes. With the aid of high-resolution cryo-electron microscopy, we unveil the nanoscale internal organization of assemblies generated with a wide range of synthetic and biological polyelectrolytes, several of them being investigated in this context for the first time, namely, poly(styrene sulfonic acid), carboxylmethylcellulose, and filamentous actin. Using an original coarse-grained model representing lipid-coated polyelectrolytes as semiflexible tubes, we thoroughly explored the morphologies resulting from the self-assembly process as a function of tube lengths and rigidities; the computed structures are fully consistent with the experimental observations. In particular, we found a strong extension of the correlation range of the order parameter as the rigidity of the lipid-coated polyelectrolytes increases. Electrostatic interactions provide a stabilizing mechanism leading to finite-size equilibrium assemblies. These assemblies may constitute a generic route for interfacing polyelectrolytes to living cells to perform gene delivery, for instance. PMID- 22428932 TI - Modification of risk for cancer as a coincidental finding in DNA array investigation. AB - The high resolution of modern DNA arrays has the implification of unintended coincidental detection of gene deletions predisposing to late-onset neurological and oncological disorders. Here, we report the case of an 18-year-old girl with mild intellectual disability, facial dysmorphisms, and a microdeletion of approximately 6.3 Mb on 22q12.1q12.3 including NF2, the gene for neurofibromatosis type 2, and CHEK2, a modifier gene for breast cancer. Subsequent magnetic resonance imaging of the brain showed she had already developed bilateral vestibular schwannomas. The challenge of DNA arrays and the consequences for genetic counselling and informed consent will be discussed in the light of this unique case with a microdeletion including both a high risk and a moderate risk cancer predisposition gene. PMID- 22428931 TI - Tamoxifen subcellular localization; observation of cell-specific cytotoxicity enhancement by inhibition of mitochondrial ETC complexes I and III. AB - Recently, a nongenomic cytotoxic component of the chemotherapeutic agent tamoxifen (TAM) has been identified that predominantly triggers mitochondrial events. The present study delineates the intracellular fate of TAM and studies its interaction with a spectrum of cell homeostasis modulators primarily relevant to mitochondria. The subcellular localization of TAM was assessed by confocal fluorescence microscopy. The effect of the modulators on TAM cytotoxicity was assessed by standard MTT assays. Our findings show that in estrogen receptor positive MCF7 breast adenocarcinoma cells and DU145 human prostate cancer cells, TAM largely accumulates in the mitochondria and endoplasmic reticulum, but not lysosomes. Our results further demonstrate that in MCF7, but not in DU145 cells, mitochondrial electron transport chain complex I and III inhibitors exacerbate TAM toxicity with an order of potency of myxothiazol >= stigmatellin > rotenone > antimycin A, suggesting a cell-specific cytotoxic interplay between mitochondrial complex I and III function and TAM action. PMID- 22428933 TI - Development and morphogenesis of human wrist joint during embryonic and early fetal period. AB - The development of the human wrist joint has been studied widely, with the main focus on carpal chondrogenesis, ligaments and triangular fibrocartilage. However, there are some discrepancies concerning the origin and morphogenetic time-table of these structures, including nerves, muscles and vascular elements. For this study we used serial sections of 57 human embryonic (n = 30) and fetal (n = 27) specimens from O'Rahilly stages 17-23 and 9-14 weeks, respectively. The following phases in carpal morphogenesis have been established: undifferentiated mesenchyme (stage 17), condensated mesenchyme (stages 18 and 19), pre-chondrogenic (stages 19 and 20) and chondrogenic (stages 21 and over). Carpal chondrification and osteogenic processes are similar, starting with capitate and hamate (stage 19) and ending with pisiform (stage 22). In week 14, a vascular bud penetrates into the lunate cartilaginous mold, early sign of the osteogenic process that will be completed after birth. In stage 18, median, ulnar and radial nerves and thenar eminence appear in the hand plate. In stage 21, there are indications of the interosseous muscles, and in stage 22 flexor digitorum superficialis, flexor digitorum profundus and lumbrical muscles, transverse carpal ligament and collateral ligaments emerge. In stage 23, the articular disc, radiocarpal and ulnocarpal ligaments and deep palmar arterial arch become visible. Radiate carpal and interosseous ligaments appear in week 9, and in week 10, dorsal radiocarpal ligament and articular capsule are evident. Finally, synovial membrane is observed in week 13. We have performed a complete analysis of the morphogenesis of the structures of the human wrist joint. Our results present new data on nervous and arterial elements and provide the basis for further investigations on anatomical pathology, comparative morphology and evolutionary anthropology. PMID- 22428934 TI - Is there any way to protect from tacrolimus-induced renal and pancreas injury? AB - BACKGROUND: The aim of this study was to explore effects of erythropoietin and pentoxifylline in tacrolimus-induced pancreatic beta cell and renal injury in rats. METHODS: Rats in group I were given saline; rats in group II were injected with tacrolimus; rats in group III were received erythropoietin (Epo) and tacrolimus; while rats in group IV were injected pentoxifylline (Ptx) plus tacrolimus for nine d. On 10th day, blood and tissue samples were taken for biochemical and pathological evaluations. RESULTS: Tacrolimus-injected animals exhibited significant elevation in blood urea nitrogen (BUN), and serum BUN levels were improved in rats pretreated with Ptx. Significantly more apoptotic nuclei were observed in kidneys of tacrolimus group. In rats subjected to tacrolimus and pretreated with Epo, there was significant decrease in apoptotic nuclei staining than those in tacrolimus group. Blood trough levels of tacrolimus were significantly higher in erythropoietin-pretreated group, although same amount of tacrolimus was injected with other groups. CONCLUSION: Results of our study demonstrated significant antiapoptotic effects of erythropoietin on renal tubules, increasing effect of erythropoietin on tacrolimus blood levels, and insignificant antioxidant effects of both erythropoietin and pentoxifylline on renal and pancreas tissues. Study with clinically greater tacrolimus levels may be useful to confirm these findings. PMID- 22428935 TI - Malignancies developing in obese patients with psoriasis while on antitumour necrosis factor-alpha therapies: a case series. PMID- 22428936 TI - CAl2Be3(2-) and its salt complex LiCAl2Be3-: anionic global minima with planar pentacoordinate carbon. AB - Following the isoelectronic relationship in global minima planar pentacoordinate carbon (ppC) species (cationic CAl(5)(+), neutral CAl(4)Be, and monoanionic CAl(3)Be(2)(-)), we designed a dianionic ppC species C(2v) CAl(2)Be(3)(2-) (1a) and its salt complex C(2v) LiCAl(2)Be(3)(-) (2a) in this work. In combination with DFT and high-level ab initio calculations (CCSD(T)), the extensive exploration on their potential energy surfaces indicates that they are the global minima. Their kinetic stability was proved by two sets of 100 ps ab initio Born Oppenheimer molecular dynamic simulations at the B3LYP/6-31+G(d) level. The detailed analyses indicate that the introduction of Li(+) into 1a only influences the electrovalent bonding (through changing of the charge distribution) and the sigma aromaticity (through changing of the in-plane ring current), while the structures, the bonding properties, the pi aromaticity, and so forth are almost unchanged. Nevertheless, the MO energy levels, the HOMO-LUMO gaps, and the values of vertical detachment energies (VDEs) all verify that the lithiation significantly improves the stability. We think the ppC dianion 1a is possible to detect directly in the gas-phase experiments, but it can be detected as its salt complex 2a more easily. PMID- 22428939 TI - Severity of mental health impairment and trajectories of improvement in an integrated primary care clinic. AB - OBJECTIVE: To model typical trajectories for improvement among patients treated in an integrated primary care behavioral health service, multilevel models were used to explore the relationship between baseline mental health impairment level and eventual mental health functioning across follow-up appointments. METHOD: Data from 495 primary care patients (61.1% female, 60.7% Caucasian, 37.141 +/- 12.21 years of age) who completed the Behavioral Health Measure (Kopta & Lowry, 2002) at each primary care appointment were used for the analysis. Three separate models were constructed to identify clinical improvement in terms of number of appointments attended, baseline impairment severity level, and the interaction of these 2 variables. RESULTS: The data showed that 71.5% of patients improved across appointments, 56.8% of which (40.5% of the entire sample) was clinically meaningful and reliable. Number of appointments and baseline severity of impairment significantly accounted for variability in clinical outcome, with trajectories of change varying across appointments as a function of baseline severity. Patients with more severe impairment at baseline improved faster than patients with less severe baseline impairment. CONCLUSIONS: Patients treated within an integrated primary care behavioral health service demonstrate significant improvements in clinical status, even those with the most severe levels of distress at baseline. PMID- 22428938 TI - The liposomal daunorubicin plus tamoxifen: improving the stability, uptake, and biodistribution of carriers. AB - The synergistic effects of tamoxifen on the sensitivity of MCF-7 cells to daunorubicin have been reported. Whether the effects of daunorubicin on MCF-7/adr cells can be improved by tamoxifen in liposomes and how tamoxifen changes daunorubicin's behavior in vivo remains unclear. The aim of this study was to investigate the effects of tamoxifen on the uptake and biodistribution of daunorubicin liposomes by breast-cancer-resistant MCF-7/adr cells in vitro and in vivo. The uptake of liposomes by MCF-7/adr cells in vitro studies was measured using flow cytometry and laser confocal microscopy. The biodistributions of carriers and free drugs were evaluated by DiR dye using in vivo imaging. Tamoxifen obviously enhanced the cellular uptake of liposomes by MCF-7/adr cells in time-dependent manners. According to the results from in vivo imaging analysis, the mean fluorescence intensity of DiR liposomes with tamoxifen in the tumor regions of MCF-7/adr tumor-bearing nude mice was much stronger than that of DiR liposomes alone (16,450 +/- 1,331 versus 3,666 +/- 321; n = 3). Pegylated liposomes elongated the existence of daunorubicin in the circulatory system and the enhanced permeability and retention effect enhanced its concentration in local tumor tissues, which may provide the precondition for tamoxifen further promoting the uptake by MCF-7/Adr cells in vivo. Using daunorubicin liposomes and tamoxifen together generates better biodistribution profiles in tumor tissue than using daunorubicin liposomes only, which contributes to improving the therapeutic effect of breast cancer treatment. PMID- 22428940 TI - Treating depressed and anxious smokers in smoking cessation programs. AB - OBJECTIVE: Cigarette smoking is the leading cause of preventable death in the United States. In addition, smoking rates among depressed and anxious smokers are higher than in the population at large. Furthermore, treating depressed and anxious smokers effectively is particularly challenging because of their significant negative affect, dysfunctional emotional regulation, severe withdrawal symptoms, and numerous institutional barriers to successful treatment. Previous reviews in this area have typically focused on depression or anxiety disorders, whereas this review focuses on both disorders. METHOD: This article presents a brief review of the literature on treating depressed and anxious smokers in smoking cessation programs. We also discuss treatment issues, challenges, and guidelines regarding effective interventions for depressed and anxious smokers who wish to stop smoking. RESULTS: The potential benefits for better health and improved functioning are quite large. Moreover, the merit of pursuing evidence-based interventions with these comorbid populations of depressed and anxious smokers-including practical, multidisciplinary, and cost effective smoking cessation programs-is compelling. CONCLUSIONS: A sensible time for an aggressive approach to this health promotion effort is now. PMID- 22428941 TI - Teacher consultation and coaching within mental health practice: classroom and child effects in urban elementary schools. AB - OBJECTIVE: To examine effects of a teacher consultation and coaching program delivered by school and community mental health professionals on change in observed classroom interactions and child functioning across one school year. METHOD: Thirty-six classrooms within 5 urban elementary schools (87% Latino, 11% Black) were randomly assigned to intervention (training + consultation/coaching) and control (training only) conditions. Classroom and child outcomes (n = 364; 43% girls) were assessed in the fall and spring. RESULTS: Random effects regression models showed main effects of intervention on teacher-student relationship closeness, academic self-concept, and peer victimization. Results of multiple regression models showed levels of observed teacher emotional support in the fall moderated intervention impact on emotional support at the end of the school year. CONCLUSIONS: Results suggest teacher consultation and coaching can be integrated within existing mental health activities in urban schools and impact classroom effectiveness and child adaptation across multiple domains. PMID- 22428942 TI - Childhood maltreatment and differential treatment response and recurrence in adult major depressive disorder. AB - OBJECTIVE: A substantial number of patients with major depressive disorder (MDD) do not respond to treatment, and recurrence rates remain high. The purpose of this study was to examine a history of severe childhood abuse as a moderator of response following a 16-week acute treatment trial, and of recurrence over a 12 month follow-up. METHOD: Participants included 203 adult outpatients with MDD (129 women; age 18-60). The design was a 16-week single-center randomized, open label trial of interpersonal psychotherapy, cognitive-behavioral therapy, or antidepressant medication, with a 12-month naturalistic follow-up, conducted at a university psychiatry center in Canada. The main outcome measure was Hamilton Depression Rating Scale scores at treatment end point. Childhood maltreatment was assessed at the completion of treatment using an interview-based contextual measure of childhood physical, sexual, and emotional abuse. Multiple imputation was adopted to estimate missing values. RESULTS: Patients with severe maltreatment were significantly less likely to respond to interpersonal psychotherapy than to cognitive-behavioral therapy or medication (OR = 3.61), whereas no differences among treatments were found in those with no history of maltreatment (ORs < 1.50). Furthermore, maltreatment significantly predicted a shorter time to recurrence over follow-up across treatment conditions (OR = 3.04). These findings were replicated in the sample with complete case data. CONCLUSIONS: Patients with a history of childhood abuse may benefit more from antidepressant medication or cognitive-behavioral therapy than from interpersonal psychotherapy. However, these patients remain vulnerable to recurrence regardless of treatment modality. PMID- 22428943 TI - Reliability of subjective, linear, ratio and area cephalometric measurements in assessing adenoid hypertrophy among different age groups. AB - OBJECTIVE: To test the validity of four different types of lateral cephalometric radiograph (LCR) measurements as a diagnostic test of adenoid hypertrophy in different age groups of mouth-breathing children. MATERIALS AND METHODS: Eighty six mouth-breathing children (male 54.65%, mean age 7.0 +/- 2.2 years) were randomly selected from a hospital population. Adenoid obstruction of the nasopharynx was evaluated by subjective, linear, ratio, and area LCR measurements. Each measurement was compared with flexible fiberoptic endoscopy diagnosis. RESULTS: Kendall correlation coefficients for agreement between tests were >= 0.67 and kappa scores were substantial (>= 0.64). Higher correlation coefficients and agreement values were found in older age groups. When the sample was stratified by age, the 3- to 5-year-old age group showed lower correlation coefficients and agreement strength for subjective, linear, and ratio measurements. The sensitivity of LCR varied from 71% (ratio) to 84% (linear). The specificity varied from 83% (linear) to 97% (ratio). The positive predictive value varied from 88% (linear) to 97% (ratio). The negative predictive value varied from 70% (ratio) to 78% (linear). The validity of each measure was different among the age groups. CONCLUSIONS: LCR is a valid method for measuring adenoid hypertrophy in children from 6 to 12 years old. The diagnosis of adenoid hypertrophy, based on LCR measurements, in children with primary dentition (3-5 years old) should be made with caution. The combination of linear and ratio LCR measurements is a reliable screening tool to determine the need for an ear, nose, and throat evaluation. PMID- 22428944 TI - Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes. AB - As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3 yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance. PMID- 22428945 TI - Exceptional electrochemical performance of Si-nanowires in 1,3-dioxolane solutions: a surface chemical investigation. AB - The effect of 1,3-dioxolane (DOL) based electrolyte solutions (DOL/LiTFSI and DOL/LiTFSI-LiNO(3)) on the electrochemical performance and surface chemistry of silicon nanowire (SiNW) anodes was systematically investigated. SiNWs exhibited an exceptional electrochemical performance in DOL solutions in contrast to standard alkyl carbonate solutions (EC-DMC/LiPF(6)). Reduced irreversible capacity losses, enhanced and stable reversible capacities over prolonged cycling, and lower impedance were identified with DOL solutions. After 1000 charge-discharge cycles (at 60 degrees C and a 6 C rate), SiNWs in DOL/LiTFSI LiNO(3) solution exhibited a reversible capacity of 1275 mAh/g, whereas only 575 and 20 mAh/g were identified in DOL/LiTFSI and EC-DMC solutions, respectively. Transmission electron microscopy (TEM) studies demonstrated the complete and uniform lithiation of SiNWs in DOL-based electrolyte solutions and incomplete, nonuniform lithiation in EC-DMC solutions. In addition, the formation of compact and uniform surface films on SiNWs cycled in DOL-based electrolyte solutions was identified by scanning electron microscopic (SEM) imaging, while the surface films formed in EC-DMC based solutions were thick and nonuniform. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy were employed to analyze the surface chemistry of SiNWs cycled in EC DMC and DOL based electrolyte solutions. The distinctive surface chemistry of SiNWs cycled in DOL based electrolyte solutions was found to be responsible for their enhanced electrochemical performances. PMID- 22428946 TI - Oral health-related quality of life of older people from three South American cities. AB - OBJECTIVE: To describe subjective oral health status and its association with overall health conditions and socioeconomic factors in the elderly (60 years and older) living in the capital cities with the oldest average populations in South America. BACKGROUND: Oral diseases are a public health problem, frequently neglected in older adults. In recent years, the subjective assessment of psychological and social consequences of the problems related to oral health has been valued. One of the instruments used to estimate the Oral Health-Quality of Life is the Geriatric Oral Health Assessment (GOHAI). MATERIAL AND METHODS: Representative samples from SABE study (1999-2000) of Santiago (n = 1301), Buenos Aires (n = 1043), and Montevideo (n = 1450) aged 60 and over community-dwelling people. We assessed OH-QoL (GOHAI), self-reported missing teeth, denture use, and self-rated-health, among other indicators. Logistic regression models(GOHAI < 58) for each city, adjusted by sex and age, were applied. RESULTS: GOHAI average scores were higher in Montevideo (54.8 +/- 6.1) than in Buenos Aires (53.1 +/- 7.4) and Santiago (49.9 +/- 8.6). A pronounced gradient of the oral condition and GOHAI scores were observed within the three-cities. Denture use -less prevalent in Santiago and more common among women- is a protective factor against a poor OH QoL. CONCLUSION: Socioeconomic inequalities in oral health status and OH-QoL are observed in the three cities. The increasing life expectancy emphasizes the need to integrate prevention and treatment efforts, as a way to improve OH-QoL over the course of a lifetime. PMID- 22428947 TI - A field-compatible method for measuring alternative respiratory pathway activities in vivo using stable O2 isotopes. AB - Plants can alter rates of electron transport through the alternative oxidase (AOX) pathway in response to environmental cues, thus modulating respiratory efficiency, but the (18)O discrimination method necessary for measuring electron partitioning in vivo has been restricted to laboratory settings. To overcome this limitation, we developed a field-compatible analytical method. Series of plant tissue subsamples were incubated in 12 mL septum-capped vials for 0.5-4 h before aliquots of incubation air were injected into 3.7 mL evacuated storage vials. Vials were stored for up to 10 months before analysis by mass spectrometry. Measurements were corrected for unavoidable contamination. Additional mathematical tools were developed for detecting and addressing non-linearity (whether intrinsic or due to contamination) in the data used to estimate discrimination values. Initial contamination in the storage vials was 0.03 +/- 0.01 atm; storing the gas samples at -17 degrees C eliminated further contamination effects over 10 months. Discrimination values obtained using our offline incubation and computation method replicated previously reported results over a range of 10-310/00, with precision generally better than +/-0.50/00. Our method enables large-scale investigations of plant alternative respiration along natural environmental gradients under field conditions. PMID- 22428948 TI - Optical coherence tomography in optic nerve head avulsion. AB - Early diagnosis of optic nerve head (ONH) avulsion may be difficult due to an obscured fundus view. Although B-scan ultrasonography is more useful than MRI and CT imaging, it has limited sensitivity and specificity. Optical coherence tomography (OCT) can be used to identify optic nerve pathology. Utilization of OCT has not been widely reported in the diagnosis of ONH avulsion. Two cases OCT use in ONH avulsion are reported. The utility of OCT in the diagnosis of ONH avulsion is of limited value. PMID- 22428949 TI - Occurrence and antibiotic susceptibility profiles of Burkholderia cepacia complex in coastal marine environment. AB - During an environmental study of bacterial resistance to antibiotics in coastal waters of the Kastela Bay, Adriatic Sea, Croatia, 47 Burkholderia cepacia complex (Bcc) isolates were recovered from seawater and mussel (Mytilus galloprovincialis) samples. All isolates showed multiple antibiotic resistance. Among the isolates, two Burkholderia cenocepacia isolates produced chromosomally encoded TEM-116 extended-spectrum beta-lactamase (ESBL). Analysis of outer membrane proteins revealed that decreased expression of a 36-kDa protein could be associated with a high level of beta-lactam resistance in both isolates. Phenotypic study of efflux system also indicated an over-expression of Resistance Nodulation-Cell Division (RND) efflux-mediated mechanism in one of the isolates. This study demonstrated the presence of Bcc in seawater and M. galloprovincialis, which gives evidence that coastal marine environment, including mussels, could be considered as a reservoir for Bcc species. Detection of ESBL-encoding genes indicates the potential role of these bacteria in the maintenance and dispersion of antibiotic resistance genes. PMID- 22428950 TI - Abiotic factors influence microbial diversity in permanently cold soil horizons of a maritime-associated Antarctic Dry Valley. AB - The McMurdo Dry Valleys collectively comprise the most extensive ice-free region in Antarctica and are considered one of the coldest arid environments on Earth. In low-altitude maritime-associated valleys, mineral soil profiles show distinct horizontal structuring, with a surface arid zone overlying a moist and biologically active zone generated by seasonally melted permafrost. In this study, long-term microenvironmental monitoring data show that temperature and soil humidity regimes vary in the soil horizons of north- and south-facing slopes within the Miers Valley, a maritime valley in the McMurdo Dry Valleys. We found that soil bacterial communities varied from the north to the south. The microbial assemblages at the surface and shallow subsurface depths displayed higher metabolic activity and diversity compared to the permafrost soil interface. Multivariate analysis indicated that K, C, Ca and moisture influenced the distribution and structure of microbial populations. Furthermore, because of the large % RH gradient between the frozen subsurface and the soil surface we propose that water transported to the surface as water vapour is available to microbial populations, either as a result of condensation processes or by direct adsorption from the vapour phase. PMID- 22428951 TI - Long-term outcome after obstetric injury: a retrospective study. AB - OBJECTIVE: To examine problems experienced by women after vaginal delivery with and without a sphincter tear and compare those with less and more severe injuries. DESIGN: Retrospective questionnaire study. Setting. Regional hospital in Sweden. SAMPLE: A total of 324 women with and 309 without sphincter tears. METHODS: Questionnaires were sent out four to eight years after delivery enquiring about the existence and time course of gas incontinence, fecal incontinence, dyspareunia and perineal pain. A question about vacuum delivery was also included. MAIN OUTCOME MEASURES: Prevalence of persisting symptoms. RESULTS: The reply rate was 77%. About 10% of the women with a sphincter tear had fecal incontinence initially, compared with 3% among those without a sphincter tear. In women with moderate or severe tears, 20 and 31%, respectively, had gas incontinence, compared with 6% of women without a tear. Dyspareunia and perineal pain were present 18-23% of women in the tear groups compared with 9-12% of those without a tear. Almost 45% of women with initial symptoms had remaining problems after four to eight years. There was a significantly higher risk for symptoms after vacuum extraction (p < 0.001). CONCLUSIONS: Gas incontinence, fecal incontinence, dyspareunia and perineal pain were common problems after delivery. The prevalence of persisting symptoms was high even among women without a tear. The higher prevalence after vacuum extraction delivery indicates that there are more complications associated with this mode of delivery than previously thought. PMID- 22428952 TI - Biofortification of rice with zinc: assessment of the relative bioavailability of zinc in a Caco-2 cell model and suckling rat pups. AB - Staple foods, such as rice, can now be enriched in micronutrients through conventional breeding (i.e., biofortification) to enhance dietary intake of vulnerable populations. The objectives of this study were (1) to establish a rapid, high capacity Caco-2 cell model to determine the relative bioavailability of zinc (Zn) from samples of staple food breeding lines for potential use as a guideline for selection/breeding and (2) to determine the relative bioavailability of Zn from conventional rice varieties and one Zn-biofortified type. Polished or undermilled, parboiled rice samples were digested in vitro with pepsin and pH adjustment, and by pancreatic enzymes. Zn uptake from digested samples was measured in Caco-2 cells in culture. A previously validated rat pup model was also used to assess Zn absorption in vivo, using gastric intubation and (65)Zn labeling. Pups were killed after 6 h, and radioactivity in tissues and in small intestine perfusate and cecum-colon contents was used to measure Zn bioavailability. A biofortified rice variety contained substantially more Zn than conventional varieties, with no change in phytate content. Absorbed Zn (MUg/g rice) was significantly higher from the new variety in both the in vitro Caco-2 cell model (2.1-fold) and the rat pup model (2.0-fold). Results from the two models were highly correlated, particularly for the polished samples. Biofortification of rice with Zn results in significantly increased Zn uptake in both models. Since results from the Caco-2 cell model correlated well with those from rat pups, this cell model is likely to predict results in human populations and can be used for screening purposes. PMID- 22428953 TI - Exposure of black-legged kittiwakes to Lyme disease spirochetes: dynamics of the immune status of adult hosts and effects on their survival. AB - 1. Despite a growing interest in wildlife disease ecology, there is a surprising lack of knowledge about the exposure dynamics of individual animals to naturally circulating infectious agents and the impact of such agents on host life-history traits. 2. The exploration of these questions requires detailed longitudinal data on individual animals that can be captured multiple times during their life but also requires being able to account for several sources of uncertainty, notably the partial observation or recapture of individuals at each sampling occasion. 3. We use a multi-year dataset to (i) assess the potential effect of exposure to the tick-borne agent of Lyme disease, Borrelia burgdorferi sensu lato (Bbsl), on adult apparent survival for one of its natural long-lived hosts, the Black-legged kittiwake (Rissa tridactyla), and (ii) investigate the temporal dynamics of individual immunological status in kittiwakes to infer the rate of new exposure and the persistence of the immune response. Using a multi-event modelling approach, potential uncertainties arising from partial observations were explicitly taken into account. 4. The potential impact of Bbsl on kittiwake survival was also evaluated via an experimental approach: the apparent survival of a group of breeding birds treated with an antibiotic was compared with that of a control group. 5. No impact of exposure to Bbsl was detected on adult survival in kittiwakes, in either observational or experimental data. 6. An annual seroconversion rate (from negative to positive) of 1.5% was estimated, but once an individual became seropositive, it remained so with a probability of 1, suggesting that detectable levels of anti-Bbsl antibodies persist for multiple years. 7. These results, in combination with knowledge on patterns of exposure to the tick vector of Bbsl, provide important information for understanding the spatio-temporal nature of the interaction between this host and several of its parasites. Furthermore, our analyses highlight the utility of capture-mark recapture approaches handling state uncertainty for disease ecology studies. PMID- 22428954 TI - Defibrotide for the prevention of hepatic veno-occlusive disease after hematopoietic stem cell transplantation: a systematic review. AB - Prophylactic use of defibrotide (DF) to prevent veno-occlusive disease (VOD), a relatively common and high-risk complication of hematopoietic stem cell transplantation (HSCT), may be an encouraging modality to reduce morbidity and mortality from VOD. However, conclusions remain unclear. We carried out a systematic review to summarize the state of knowledge. One randomized controlled trial (RCT), four cohort studies and eight case series studies were found, including a total of 1230 patients. The overall mean incidence of VOD in patients using DF was 4.7% (95% CI, 3.3-6.1) which was significantly lower than the data 13.7% (95% CI, 13.3-14.1) across 135 studies using no VOD prophylaxis (p < 0.005). The meta-analysis of the incidence of VOD in controlled trials revealed a statistical reduction in VOD incidence in the DF group (RR = 0.47, 95% CI, 0.31 0.73). The overall mean incidence of severe VOD was 0.8% (95% CI, 0.2-1.4). The RR was 0.31 (95% CI, 0.09-1.06). However, the lack of RCTs and the methodological weaknesses of the studies may preclude making generalizable conclusions. Our review described that DF appears promising for VOD prevention and large RCT is needed for further confirmation. PMID- 22428955 TI - Iron complex-catalyzed ammonia-borane dehydrogenation. A potential route toward B N-containing polymer motifs using earth-abundant metal catalysts. AB - Ammonia-borane (NH(3)BH(3), AB) has garnered interest as a hydrogen storage material due to its high weight percent hydrogen content and ease of H(2) release relative to metal hydrides. As a consequence of dehydrogenation, B-N-containing oligomeric/polymeric materials are formed. The ability to control this process and dictate the identity of the generated polymer opens up the possibility of the targeted synthesis of new materials. While precious metals have been used in this regard, the ability to construct such materials using earth-abundant metals such as Fe presents a more economical approach. Four Fe complexes containing amido and phosphine supporting ligands were synthesized, and their reactivity with AB was examined. Three-coordinate Fe(PCy(3))[N(SiMe(3))(2)](2) (1) and four-coordinate Fe(DEPE)[N(SiMe(3))(2)](2) (2) yield a mixture of (NH(2)BH(2))(n) and (NHBH)(n) products with up to 1.7 equiv of H(2) released per AB but cannot be recycled (DEPE = 1,2-bis(diethylphosphino)ethane). In contrast, Fe supported by a bidentate P-N ligand (4) can be used in a second cycle to afford a similar product mixture. Intriguingly, the symmetric analogue of 4 (Fe(N-N)(P-P), 3), only generates (NH(2)BH(2))(n) and does so in minutes at room temperature. This marked difference in reactivity may be the result of the chemistry of Fe(II) vs Fe(0). PMID- 22428956 TI - Polymer compatibility in two dimensions. Modeling of phase behavior of mixed polymethacrylate Langmuir films. AB - We analyze the possibility of polymer blends undergoing phase separation in two dimensions. To this end, we investigate a model system consisting of water supported Langmuir monolayers, obtained from binary polyalkyl-methacrylate mixtures (PXMA, where X stands for any of the type of ester side groups used: M, methyl-; E, ethyl-; B, butyl-; H, hexyl-; O, octyl-; L, lauryl-methacrylate), by means of self consistent field (SCF) calculations. In particular, we address the conditions which determine demixing and phase separation in the two-dimensional system, showing that a sufficient chain length mismatch in the ester side group moieties is able to drive the polymer demixing. When the difference in length of the alkyl chain of the ester moieties on the two types of polymers is progressively reduced, from 11 carbon atoms (PMMA/PLMA) to 4 carbons only (POMA/PLMA), the demixing tendency is also reduced. The polymer/subphase interactions affect more the distribution of the polymer coils in the POMA/PLMA blend monolayer. Mixing of the two polymers is observed, but also a partial layering along the vertical direction. We also add, to a PMMA/PLMA blended monolayer, a third component, namely, a symmetrical diblock copolymer of the type PLMA-b-PMMA. We observe adsorption of the diblock copolymer exclusively at the contact line between the two homopolymer domains, and a concomitant lowering of the line tension. The line tension varies with the chemical potential of the diblock copolymer according to Gibbs' law, which demonstrates that PLMA-b-PMMA can act as a "lineactant" (the equivalent of a surfactant in two-dimensional systems) in the binary demixed PMMA/PLMA Langmuir monolayer. PMID- 22428957 TI - Cold spray metal embedment: an innovative antifouling technology. AB - The study demonstrates that embedment of copper particles into thermoplastic polymers (polymers) using cold spray technology is an effective deterrent against fouling organisms. Two polymers, high-density polyethylene (HDPE) and nylon were metallised with copper powder using cold spray technology. After 250 days in the field, Cu-embedded HDPE and copper plate controls were completely free of hard foulers compared to Cu-embedded nylon and polymer controls which were heavily fouled with both soft and hard fouling. Antifouling (AF) success is related to the interaction between the properties of the polymers (elastic modulus and hardness) and the cold spray process which affect particle embedment depth, and subsequently, the release of copper ions as determined by analytical techniques. Embedding metal using cold spray equipment is shown to be an effective AF technology for polymers, in particular those that are difficult to treat with standard AF coatings, with efficacy being a function of the interaction between the cold spray metal and the polymer recipient. PMID- 22428958 TI - Sensitivity and specificity of time-domain and spectral-domain optical coherence tomography in differentiating optic nerve head drusen and optic disc oedema. AB - PURPOSE: To evaluate the efficacy of time-domain optical coherence tomography (TD OCT) and spectral-domain optical coherence tomography (SD-OCT) in differentiating between optic nerve head drusen (ONHD) and optic disc oedema (ODE). METHODS: We studied 66 patients with ONHD, 31 patients with ODE, and 70 controls using TD-OCT and SD-OCT. We analysed two aspects of the tomographic findings: (i) quantitative, through measurement of the retinal nerve fibre layer (RNFL) and papillary elevation; and (ii) qualitative, through assessment of the hyporeflective space, morphology of the internal contour, focal papillary mass and RNFL increases in seven contiguous clock hours. We evaluated the sensitivity, specificity, intra-class correlation coefficient (ICC), and inter-observer agreement (kappa). RESULTS: The quantitative analysis of the RNFL revealed an average thickness of the RNFL <124MUm with TD-OCT (sensitivity=91%; specificity=94%) and <116MUm with SD-OCT (sensitivity=91%; specificity=97%). The thickness of the nasal quadrant was <108MUm with TD-OCT (sensitivity=89%; specificity=87%) and with SD-OCT was <92MUm (sensitivity=88%; specificity=94%), however without significant differences between the nasal, superior and inferior quadrants' and average thickness. The measurement of papillary elevation was 0.85mm with TD-OCT (sensitivity=96%; specificity=84% [ICC=0.96]) and was <0.80 mm with SD-OCT (sensitivity=86%; specificity=87% [ICC=0.94]). The abrupt termination of the hyporeflective space measured with TD-OCT had sensitivity=79% and specificity=90% (kappa=0.60) and with SD-OCT had sensitivity=88% and specificity=89% (kappa=0.75); the irregularity of the internal contour with TD OCT had sensitivity=80% and specificity=90% (kappa=0.70) and with SD-OCT had sensitivity=88% and specificity=90% (kappa=0.75); and the absence of seven contiguous clock hours had values of sensitivity=97% and specificity=77% with TD OCT and had sensitivity=98% and specificity=77% with SD-OCT. CONCLUSIONS: Optical coherence tomography allowed for differentiation between ONHD and ODE, yielding similar results with TD-OCT and SD-OCT. The new quantitative parameters of papillary elevation and RNFL measurements showed greater sensitivity and specificity than the qualitative criteria. PMID- 22428964 TI - Moving forward: exercise as an intervention to improve bone health in children with disabilities. PMID- 22428965 TI - Excised melanocytic lesions in children and adolescents - a 10-year survey. AB - BACKGROUND: Early recognition and prompt excision is to date the only available strategy for reducing mortality from melanoma. Little is known about the accuracy of melanoma detection in children and adolescents. OBJECTIVES: To assess the accuracy of melanoma detection in a paediatric population. METHODS: From the Department of Dermatology, Medical University of Graz, Austria, we reviewed the dermatopathology reports of naevi and melanomas excised in patients younger than 20 years over a 10-year period (1998-2007). Patients were subdivided into four age groups: 0-4, 5-9, 10-14 and 15-19 years. RESULTS: Accuracy in melanoma detection was tested using the number needed to excise (NNE) value that is obtained by dividing the total number of excised lesions by the number of melanomas. A total of 22564 lesions were reviewed, disclosing 22526 naevi and 38 melanomas, for an overall NNE value of 593.8. Five melanomas were excised in children aged 10-14 years (NNE 1141) and 33 in children aged 15-19 years (NNE 479.8), whereas no melanomas were found among 1026 lesions excised in children younger than 10 years. In children aged 0-4 years, congenital and Spitz/Reed naevi accounted for 34.5% and 20% of lesions, respectively. These percentages decreased progressively when moving to older age groups (P<0.0001). In contrast, the percentage of dermal and compound naevi rose in direct proportion with age, being 3.4% and 20.7%, respectively, in the youngest age group, and 36.7% and 31.9%, respectively, among the oldest patients (P<0.0001). CONCLUSIONS: The overall NNE value in paediatric patients over the 10-year study period was 593.8, meaning that about 594 lesions were excised to find one melanoma. This value is 20 times higher than the rates found in adult patients. PMID- 22428966 TI - Analysis of gemcitabine liposome injection by HPLC with evaporative light scattering detection. AB - Gemcitabine liposome injection (i.e., stealth liposomes) has facilitated the targeting of gemcitabine for cancer treatment. We systemically reviewed liposome based drug-delivery systems, which can improve pharmacokinetics, reduce side effects, and potentially increase tumor uptake, for pancreatic cancer therapy. A novel liposomal formulation, which allows for higher tumor-targeting efficiencies and can be used in current clinical trials to treat this challenging disease, has gained great popularity and attention. In this work, a simple, rapid high performance liquid chromatography (HPLC) method was developed for the simultaneous determination of N-(carbonyl-methoxypolyethylene glycol 2000)-1, 2 distearoyl-sn-glycero-3-phosphoethanolamine sodium salt and neutral colipids cholesterol and hydrogenated soy phosphatidylcholine or distearoyl phosphatidylcholine. Because of the poor ultraviolet absorbance of the lipids, evaporative light-scattering detection (ELSD) was used to monitor the separation. The separation was carried out on a YMC-Pack column (YMC Co., Ltd., Kyoto, Japan). Lipids were eluted using binary linear gradients starting from a mixture of 80% A and 20% B to 100% B in 10 minutes, followed by a 6-minute plateau at 100% B, where A is chloroform/isopropyl alcohol/diethylamine/trifluoroacetic acid (TFA) (50:50:0.01:0.0025) and B is chloroform/isopropyl alcohol/H2O/diethylamine/TFA (41:50:9:0.01:0.0025). The mobile phase composition was then changed back to initial solvent mixture in 1 minute, and the column was equilibrated for 13 minutes before every subsequent run. Then, 0.025% (v/v) TFA was added into the mobile phase to enhance the retaining of the stealth lipids. This newly developed method enabled direct analysis of liposomes without solvent lipid extraction and was validated to be linear, precise, accurate, specific, and sensitive. The method has been successfully employed in a wide range of lipid based formulation screening, process development, and stability testing. Further, we describe the simple, rapid HPLC-ELSD method for the simultaneous determination of all the lipids and active pharmaceutical ingredients in various liposome-based drug formulations. The method can quantitate all the lipids of active targeting liposomes, which bond with folic acid. PMID- 22428967 TI - What else can we learn from the anesthesia specialty application? PMID- 22428968 TI - Demand in pediatric dentistry for sedation and general anesthesia by dentist anesthesiologists: a survey of directors of dentist anesthesiologist and pediatric dentistry residencies. AB - This study describes what training programs in pediatric dentistry and dental anesthesiology are doing to meet future needs for deep sedation/general anesthesia services required for pediatric dentistry. Residency directors from 10 dental anesthesiology training programs in North America and 79 directors from pediatric dentistry training programs in North America were asked to answer an 18 item and 22-item online survey, respectively, through an online survey tool. The response rate for the 10 anesthesiology training program directors was 9 of 10 or 90%. The response rate for the 79 pediatric dentistry training program directors was 46 of 79 or 58%. Thirty-seven percent of pediatric dentistry programs use clinic-based deep sedation/general anesthesia for dental treatment in addition to hospital-based deep sedation/general anesthesia. Eighty-eight percent of those programs use dentist anesthesiologists for administration of deep sedation/general anesthesia in a clinic-based setting. Pediatric dentistry residency directors perceive a future change in the need for deep sedation/general anesthesia services provided by dentist anesthesiologists to pediatric dentists: 64% anticipate an increase in need for dentist anesthesiologist services, while 36% anticipate no change. Dental anesthesiology directors compared to 2, 5, and 10 years ago have seen an increase in the requests for dentist anesthesiologist services by pediatric dentists reported by 56% of respondents (past 2 years), 63% of respondents (past 5 years), and 88% of respondents (past 10 years), respectively. Predicting the future need of dentist anesthesiologists is an uncertain task, but these results show pediatric dentistry directors and dental anesthesiology directors are considering the need, and they recognize a trend of increased need for dentist anesthesiologist services over the past decade. PMID- 22428969 TI - The use of office-based sedation and general anesthesia by board certified pediatric dentists practicing in the United States. AB - The purpose of this study is to explore the use of office-based sedation by board certified pediatric dentists practicing in the United States. Pediatric dentists have traditionally relied upon self-administered sedation techniques to provide office-based sedation. The use of dentist anesthesiologists to provide office based sedation is an emerging trend. This study examines and compares these two models of office-based sedations. A survey evaluating office-based sedation of diplomates of the American Board of Pediatric Dentistry (ABPD) based on gender, age, years in practice, practice types, regions, and years as a diplomate of the ABPD was completed by 494 active members. The results were summarized using frequencies and percentages. Relationships of dentist age, gender, and number of years in practice with the use of intravenous (IV) sedation was completed using two-way contingency tables and Mantel-Haenszel tests for ordered categorical data. Relationships of office-based sedation use and the type of one's practice were examined using Pearson chi-square tests. Of the 1917 surveys e-mailed, 494 completed the survey for a response rate of 26%. Over 70% of board-certified US pediatric dentists use some form of sedation in their offices. Less than 20% administer IV sedation, 20 to 40% use a dentist anesthesiologist, and 60 to 70% would use dentist anesthesiologists if one were available. PMID- 22428970 TI - Oral mucosal injection of a local anesthetic solution containing epinephrine enhances muscle relaxant effects of rocuronium. AB - The purpose of this study was to examine how submucosal injection of a clinically relevant dose of a lidocaine hydrochloride solution containing epinephrine affects the muscle relaxant effects of rocuronium bromide. Sixteen patients scheduled for orthognathic surgery participated in this study. All patients were induced with fentanyl citrate, a target-controlled infusion of propofol and rocuronium bromide. Anesthesia was maintained by total intravenous anesthesia. After nasotracheal intubation, an infusion of rocuronium bromide was started at 7 ug/kg/min, and the infusion rate was then adjusted to maintain a train of four (TOF) ratio at 10 to 15%. The TOF ratio just prior to oral mucosal injection of a 1% lidocaine hydrochloride solution containing 10 ug/mL epinephrine (LE) was taken as the baseline. TOF ratio was observed for 20 minutes, with 1-minute intervals following the start of injection. Mean epinephrine dose was 85.6 +/- 18.6 ug and mean infusion rate of rocuronium bromide was 6.3 +/- 1.6 ug/kg/min. TOF ratio began to decrease 2 minutes after the injection of LE, reached the minimum value at 3.1 +/- 3.6% 12 minutes after the injection, and then began to recover. We conclude that oral mucosal injection of LE enhances the muscle relaxant effects of rocuronium bromide. PMID- 22428971 TI - Transient delayed facial nerve palsy after inferior alveolar nerve block anesthesia. AB - Facial nerve palsy, as a complication of an inferior alveolar nerve block anesthesia, is a rarely reported incident. Based on the time elapsed, from the moment of the injection to the onset of the symptoms, the paralysis could be either immediate or delayed. The purpose of this article is to report a case of delayed facial palsy as a result of inferior alveolar nerve block, which occurred 24 hours after the anesthetic administration and subsided in about 8 weeks. The pathogenesis, treatment, and results of an 8-week follow-up for a 20-year-old patient referred to a private maxillofacial clinic are presented and discussed. The patient's previous medical history was unremarkable. On clinical examination the patient exhibited generalized weakness of the left side of her face with a flat and expressionless appearance, and she was unable to close her left eye. One day before the onset of the symptoms, the patient had visited her dentist for a routine restorative procedure on the lower left first molar and an inferior alveolar block anesthesia was administered. The patient's medical history, clinical appearance, and complete examinations led to the diagnosis of delayed facial nerve palsy. Although neurologic occurrences are rare, dentists should keep in mind that certain dental procedures, such as inferior alveolar block anesthesia, could initiate facial nerve palsy. Attention should be paid during the administration of the anesthetic solution. PMID- 22428972 TI - Pharmacodynamic considerations for moderate and deep sedation. AB - Moderate and deep sedation can be provided using various classes of drugs, each having unique mechanisms of action. While drugs within a given classification share similar mechanisms and effects, certain classes demonstrate superior efficacy but added concern regarding safety. This continuing education article will highlight essential principles of pharmacodynamics and apply these to drugs commonly used to produce moderate and deep sedation. PMID- 22428975 TI - Systemic errors in quantitative polymerase chain reaction titration of self complementary adeno-associated viral vectors and improved alternative methods. AB - Self-complementary AAV (scAAV) vector genomes contain a covalently closed hairpin derived from a mutated inverted terminal repeat that connects the two monomer single-stranded genomes into a head-to-head or tail-to-tail dimer. We found that during quantitative PCR (qPCR) this structure inhibits the amplification of proximal amplicons and causes the systemic underreporting of copy number by as much as 10-fold. We show that cleavage of scAAV vector genomes with restriction endonuclease to liberate amplicons from the covalently closed terminal hairpin restores quantitative amplification, and we implement this procedure in a simple, modified qPCR titration method for scAAV vectors. In addition, we developed and present an AAV genome titration procedure based on gel electrophoresis that requires minimal sample processing and has low interassay variability, and as such is well suited for the rigorous quality control demands of clinical vector production facilities. PMID- 22428976 TI - Priming of hepatocytes enhances in vivo liver transduction with lentiviral vectors in adult mice. AB - Lentiviral vectors are promising tools for liver disease gene therapy, because they can achieve protracted expression of transgenes in hepatocytes. However, the question as to whether cell division is required for optimal hepatocyte transduction has still not been completely answered. Liver gene-transfer efficiency after in vivo administration of recombinant lentiviral vectors carrying a green fluorescent protein reporter gene under the control of a liver specific promoter in mice that were either hepatectomized or treated with cholic acid or phenobarbital was compared. Phenobarbital is known as a weak inducer of hepatocyte proliferation, whereas cholic acid has no direct effect on the cell cycle. This study shows that cholic acid is able to prime hepatocytes without mitosis induction. Both phenobarbital and cholic acid significantly increased hepatocyte transduction six- to ninefold, although cholic acid did not modify the mitotic index or cell-cycle entry. However, the effect of either compound was weaker than that observed after partial hepatectomy. In no cases was there a correlation between the expression of cell-cycle marker and transduction efficiency. We conclude that priming of hepatocytes should be considered a clinically applicable strategy to enhance in vivo liver gene therapy with lentiviral vectors. PMID- 22428977 TI - Universal real-time PCR for the detection and quantification of adeno-associated virus serotype 2-derived inverted terminal repeat sequences. AB - Viral vectors based on various naturally occurring adeno-associated virus (AAV) serotypes are among the most promising tools in human gene therapy. For the production of recombinant AAV (rAAV) vectors, researchers are focusing predominantly on cross-packaging an artificial AAV genome based on serotype 2 (AAV2) into capsids derived from other serotypes. Within the packaged genome the inverted terminal repeats (ITRs) are the only cis-acting viral elements required for rAAV vector generation and depict the lowest common denominator of all AAV2 derived vector genomes. Up to now, no quantitative PCR (qPCR) for the detection and quantification of AAV2 ITRs could be established because of their extensive secondary hairpin structure formation. Current qPCR-based methods are therefore targeting vector-encoded transgenes or regulatory elements. Herein we establish a molecular biological method that allows accurate and reproducible quantification of AAV2 genomes on the basis of an AAV2 ITR sequence-specific qPCR. Primers and labeled probe are located within the ITR sequence and have been designed to detect both wild-type AAV2 and AAV2-based vectors. This method is suitable for detecting single-stranded DNA derived from AAV2 vector particles and double stranded DNA derived from vector plasmids. The limit of detection has been determined as 50 ITR sequence copies per reaction, by comparison with a plasmid standard. In conclusion, this method describes the first qPCR system facilitating the detection and quantification of AAV2 ITR sequences. Because this method can be used universally for all AAV2 genome-based vectors, it will significantly simplify rAAV2 vector titrations in the future. PMID- 22428978 TI - Single tyrosine mutation in AAV8 and AAV9 capsids is insufficient to enhance gene delivery to skeletal muscle and heart. AB - Site-directed mutations of tyrosine (Y) to phenylalanine (F) on the surface of adeno-associated viral (AAV) capsids have been reported as a simple method to greatly enhance gene transfer in vitro and in vivo. To determine whether the Y-to F mutation could also enhance AAV8 and AAV9 gene transfer in skeletal muscle and heart to facilitate muscular dystrophy gene therapy, we investigated four capsid mutants of AAV8 (Y447F or Y733F) and AAV9 (Y446F or Y731F). The mutants and their wild-type control AAV8 and AAV9 capsids were used to package reporter genes (luciferase or beta-galactosidase) resulting in similar vector yields. To evaluate gene delivery efficiencies, especially in muscle and heart, the vectors were compared side by side in a series of experiments in vivo in two different strains of mice, the outbred ICR and the inbred C57BL/6. Because AAV8 and AAV9 are among the most effective in systemic gene delivery, we first examined the mutant and wild-type vectors in neonatal mice by intraperitoneal injection, or in adult mice by intravenous injection. To our surprise, no statistically significant differences in transgene expression were observed between the mutant and wild-type vectors, regardless of the reporter genes, vector doses, and the ages and strains of mice used. In addition, quantitative analyses of vector DNA copy number in various tissues from mice treated with mutant and wild-type vectors also showed similar results. Finally, direct intramuscular injection of the above-described vectors with the luciferase gene into the hind limb muscles revealed the same levels of gene expression between mutant and wild-type vectors. Our results thus demonstrate that a single mutation of Y447F or Y733F on capsids of AAV8, and of Y446F or Y731F on AAV9, is insufficient to enhance gene delivery to the skeletal muscle and heart. PMID- 22428979 TI - Identity, potency, in vivo viability, and scaling up production of lentiviral vector-induced dendritic cells for melanoma immunotherapy. AB - SmartDCs (Self-differentiated Myeloid-derived Antigen-presenting-cells Reactive against Tumors) consist of highly viable dendritic cells (DCs) induced to differentiate with lentiviral vectors (LVs) after an overnight ex vivo transduction. Tricistronic vectors co-expressing cytokines (granulocyte macrophage-colony stimulating factor [GM-CSF], interleukin [IL]-4) and a melanoma antigen (tyrosine related protein 2 [TRP2]) were used to transduce mouse bone marrow cells or human monocytes. Sixteen hours after transduction, the cells were dispensed in aliquots and cryopreserved for identity, potency, and safety analyses. Thawed SmartDCs readily differentiated into highly viable cells with a DC immunophenotype. Prime/boost subcutaneous administration of 1*10(6) thawed murine SmartDCs into C57BL/6 mice resulted into TRP2-specific CD8(+) T-cell responses and protection against lethal melanoma challenge. Human SmartDC-TRP2 generated with monocytes obtained from melanoma patients secreted endogenous cytokines associated with DC activation and stimulated TRP2-specific autologous T cell expansion in vitro. Thawed human SmartDCs injected subcutaneously in NOD.Rag1(-/-).IL2rgamma(-/-) mice maintained DC characteristics and viability for 1 month in vivo and did not cause any signs of pathology. For development of good manufacturing practices, CD14(+) monocytes selected by magnetic-activated cell separation were transduced in a closed bag system (multiplicity of infection of 5), washed, and cryopreserved. Fifty percent of the monocytes used for transduction were recovered for cryopreservation. Thawed SmartDCs produced in two independent runs expressed the endogenous cytokines GM-CSF and IL-4, and the resulting homogeneous SmartDCs that self-differentiated in vitro contained approximately 1.5-3.0 copies of integrated LVs per cell. Thus, this method facilitates logistics, standardization, and high recovery for the generation of viable genetically reprogrammed DCs for clinical applications. PMID- 22428980 TI - Analysis of particle content of recombinant adeno-associated virus serotype 8 vectors by ion-exchange chromatography. AB - Advances in adeno-associated virus (AAV)-mediated gene therapy have brought the possibility of commercial manufacturing of AAV vectors one step closer. To realize this prospect, a parallel effort with the goal of ever-increasing sophistication for AAV vector production technology and supporting assays will be required. Among the important release assays for a clinical gene therapy product, those monitoring potentially hazardous contaminants are most critical for patient safety. A prominent contaminant in many AAV vector preparations is vector particles lacking a genome, which can substantially increase the dose of AAV capsid proteins and lead to possible unwanted immunological consequences. Current methods to determine empty particle content suffer from inconsistency, are adversely affected by contaminants, or are not applicable to all serotypes. Here we describe the development of an ion-exchange chromatography-based assay that permits the rapid separation and relative quantification of AAV8 empty and full vector particles through the application of shallow gradients and a strong anion exchange monolith chromatography medium. PMID- 22428981 TI - Using Pulmozyme DNase treatment in lentiviral vector production. AB - In the production of lentiviral vector for clinical studies the purity of the final product is of vital importance. To remove plasmid and producer cell line DNA, investigators have incubated the vector product with Benzonase, a bacterially derived DNase. As an alternative we investigated the use of Pulmozyme, a U.S. Food and Drug Administration-approved human DNase for the treatment of cystic fibrosis, by comparing the efficiency of DNA removal from lentiviral vector preparations. A green fluorescent protein-expressing lentiviral vector was prepared by transient calcium phosphate transfection of HEK 293T cells and DNA removal was compared when treating vector after harvest or immediately after transfection. The effectiveness of DNase treatment was measured by quantitative PCR using primers for vesicular stomatitis virus glycoprotein G viral envelope plasmid. When treating the final product, 1-hr incubations (37 degrees C) with Pulmozyme at 20 U/ml reduced plasmid DNA to undetectable levels. Longer incubations (up to 4 hr) did not improve DNA removal at lower concentrations and the effectiveness was equivalent to or better than Benzonase at 50 U/ml. Attempting to use Pulmozyme immediately after transfection, but before final medium change, as a means to decrease Pulmozyme concentration in the final product provided a 2-log reduction in DNA but was inferior to treatment at the end of production. Pulmozyme, at concentrations up to 100 U/ml, had no measurable effect on infectious titer of the final vector product. The use of Pulmozyme is likely to increase the cost of DNase treatment when preparing vector product and should be considered when generating clinical-grade vector products. PMID- 22428982 TI - Change detection by rhesus monkeys (Macaca mulatta) and pigeons (Columba livia). AB - Two monkeys (Macaca mulatta) learned a color change-detection task where two colored circles (selected from a 4-color set) were presented on a 4 * 4 invisible matrix. Following a delay, the correct response was to touch the changed colored circle. The monkeys' learning, color transfer, and delay transfer were compared to a similar experiment with pigeons. Monkeys, like pigeons (Columba livia), showed full transfer to four novel colors, and to delays as long as 6.4 s, suggesting they remembered the colors as opposed to perceptual based attentional capture process that may work at very short delays. The monkeys and pigeons were further tested to compare transfer with other dimensions. Monkeys transferred to shape and location changes, unlike the pigeons, but neither species transferred to size changes. Thus, monkeys were less restricted in their domain to detect change than pigeons, but both species learned the basic task and appear suitable for comparative studies of visual short-term memory. PMID- 22428983 TI - Reversal learning in rats (Rattus norvegicus) and pigeons (Columba livia): qualitative differences in behavioral flexibility. AB - Research has shown that pigeons given a simultaneous visually based discrimination reversal, in which a single reversal occurs at the midpoint of each session, consistently show anticipation prior to the reversal as well as perseveration after the reversal, suggesting that they use a less effective cue (time or trial number into the session) than what would be optimal to maximize reinforcement (local feedback from the most recent trials). In the present research, pigeons (Columba livia) and rats (Rattus norvegicus) were tested with a simultaneous spatial discrimination midsession reversal. Pigeons showed remarkably similar errors in anticipation and perseveration as with visual stimuli, thereby continuing to show the suboptimal use of time as a cue, whereas rats showed no anticipatory errors and very few perseverative errors, suggesting that they used local feedback as a cue, thus more nearly optimizing reinforcement. To further test the rats' flexibility, they were then tested with a variable point of reversal and then with multiple points of reversal within a session. Results showed that the rats effectively maximized reinforcement by developing an approximation to a win-stay/lose-shift rule. The greater efficiency shown by rats with this task suggests that they are better able to use the feedback from their preceding choice as the basis of their future choice. The difference in cue preference further suggests a qualitative difference in acquisition of the midsession reversal task between pigeons and rats. PMID- 22428984 TI - Pharmacokinetics of recombinant bifunctional fusion proteins. AB - INTRODUCTION: The development of biotechnology has enabled the creation of various recombinant fusion proteins as a new class of biotherapeutics. The uniqueness of fusion proteins lies in their ability to fuse two or more protein domains, providing vast opportunities to generate novel combinations of functions. Pharmacokinetic (PK) studies, which are critical components in preclinical and clinical drug development, have not been fully explored for fusion proteins. The lack of general PK models and study guidelines has become a bottleneck for translation of fusion proteins from basic research to the clinic. AREAS COVERED: This article reviews the current status of PK studies for fusion proteins, covering the processes that affect PK. According to their PK properties, a classification of fusion proteins is suggested along with examples from the clinic or under development. Current limitations and future perspectives for PK of fusion proteins are also discussed. EXPERT OPINION: A PK model for bifunctional fusion proteins is presented to highlight the importance of mechanistic studies for a thorough understanding of the PK properties of fusion proteins. The model suggests investigating the receptor binding and subsequent intracellular disposition of individual domains, which can have dramatic impact on the PK of fusion proteins. PMID- 22428985 TI - Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis. AB - Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses. PMID- 22428986 TI - The gonadotropin-releasing hormone antagonist protocol--the protocol of choice for the polycystic ovary syndrome patient undergoing controlled ovarian stimulation. AB - Polycystic ovary syndrome (PCOS) patients are prone to develop ovarian hyperstimulation syndrome (OHSS), a condition which can be minimized or completely eliminated by the use of a gonadotropin-releasing hormone agonist (GnRHa) trigger. In this commentary paper, we maintain that the gonadotropin releasing hormone antagonist protocol should be the protocol of choice for the PCOS patient undergoing ovarian stimulation with gonadotropins for in vitro fertilization. If an excessive ovarian response is encountered, the clinician will always have two options: either to trigger final oocyte maturation with a bolus of GnRHa and supplement the luteal phase with a small bolus of human chorionic gonadotropin in addition to the standard luteal phase support and transfer in the fresh cycle or, alternatively, to trigger with GnRHa and perform a total freeze, resulting in a complete elimination of OHSS and high ongoing pregnancy rates in the subsequent frozen-thawed transfer cycles. PMID- 22428987 TI - Heat shock-induced biphasic Ca(2+) signature and OsCaM1-1 nuclear localization mediate downstream signalling in acquisition of thermotolerance in rice (Oryza sativa L.). AB - We investigated heat shock (HS)-triggered Ca(2+) signalling transduced by a Ca(2+) sensor, calmodulin (CaM), linked to early transcriptome changes of HS responsive genes in rice. We observed a biphasic [Ca(2+) ](cyt) signature in root cells that was distinct from that in epicotyl and leaf cells, which showed a monophasic response after HS. Treatment with Ca(2+) and A23187 generated an intense and sustained increase in [Ca(2+) ](cyt) in response to HS. Conversely, treatment with Ca(2+) chelator, L-type Ca(2+) channel blocker and CaM antagonist, but not intracellular Ca(2+) release inhibitor, strongly inhibited the increased [Ca(2+) ](cyt) . HS combined with Ca(2+) and A23187 accelerated the expression of OsCaM1-1 and sHSPC/N genes, which suggests that the HS-induced apoplastic Ca(2+) influx is responsible for the [Ca(2+) ](cyt) response and downstream HS signalling. In addition, the biphasic response of OsCaM1-1 in the nucleus followed the Ca(2+) signature, which may provide the information necessary to direct HS-related gene expression. Overexpression of OsCaM1-1 induced the expression of Ca(2+) /HS-related AtCBK3, AtPP7, AtHSF and AtHSP at a non-inducing temperature and enhanced intrinsic thermotolerance in transgenic Arabidopsis. Therefore, HS-triggered rapid increases in [Ca(2+) ](cyt) , together with OsCaM1 1 expression and its nuclear localization, are important in mediating downstream HS-related gene expression for the acquisition of thermotolerance in rice. PMID- 22428988 TI - Prevalence of removable partial dentures users treated at the Aracatuba Dental School-UNESP. AB - OBJECTIVES: The aim of this study was to evaluate the frequency of removable partial dentures (RPD) at the Aracatuba Dental School. METHODS: The study was conducted by analysing 412 clinical history of patients attended at the RPD clinics in the period from 2000 to 2007. RESULTS: 412 charts were analysed: 148 (35.9%) men and 264 (64.1%) women. The mean age was 53.8 years (men) and 52.4 years (women). A total of 556 dentures were made; of these, 233 (41.90%) were maxillary and 323 (58.09%) were mandibular dentures. The most frequent Kennedy classification found was Class III (maxilla) and Class I (mandible). In the maxilla, 55% (126) of the major connectors were of the anterior-posterior palatal bar, while in the mandible, 64% (202) were the lingual bar. As regards the claps, 401 were circumferential and 318 were bar claps. CONCLUSION: The mean age of the patients was 52.9 years with higher prevalence of female patients; the most frequent Kennedy's classification was Class I in mandible and Class III in maxilla; the most common major connector was anterior-posterior palatal bar for maxilla and lingual bar for mandible; the circumferential clasps were the most common retainer used in both jaws. PMID- 22428989 TI - Beyond rose colored glasses: the adaptive role of depressive and anxious symptoms among individuals with heart failure who were evaluated for transplantation. AB - The prospect of and the evaluative period for transplantation can be stressful for individuals with heart failure (HF). Little is known about the impact of psychosocial factors on service utilization and health outcomes. The current study examined the impact of depression, dysthymia, and anxiety on two-yr hospitalization and mortality among 96 individuals with HF who were evaluated for transplantation. Results revealed that only a small percentage of individuals endorsed sufficient symptomatology to meet criteria for a psychiatric, Axis I disorder (3.1% = anxiety; 2.1% = depression; 1.0% = dysthymia) although a significant proportion of the sample was prescribed an antidepressant or an anxiolytic (37%). Multivariable regression analysis was conducted to examine the association between significant independent demographic, medical, and psychiatric predictors and total duration of hospitalizations; logistic regression analysis was used to examine the relation between predictors and mortality. An increase in anxious symptoms was associated with a decrease in total number of days hospitalized during the two-yr period following the initial evaluation. Similarly, as depressive symptoms increased, risk of two-yr mortality decreased. Future research should assess communication between the patient and providers to further elucidate the potential relationship between psychiatric symptoms, service utilization/hospitalization, and mortality in this patient population. PMID- 22428990 TI - Characterization of a new Acidobacteria-derived moderately thermostable lipase from a Brazilian Atlantic Forest soil metagenome. AB - A clone (LP001) expressing a new lipase gene was isolated from a metagenomic library of the Brazilian Atlantic Forest soil. The DNA insert of LP001 was fully sequenced, and 38 ORFs were identified. Comparison of ORFs, %G + C content and gene organization with sequenced bacterial genomes suggested that the fosmid DNA insert belongs to an organism of the Acidobacteria phylum. Protein domain analysis and inactivation by transposon insertion showed that the protein encoded by ORF29 was responsible for the lipase activity and was named LipAAc. The purified LipAAc lipase was capable of hydrolyzing a broad range of substrates, showing the highest activity against p-nitrophenol (pNP) decanoate. The lipase was active over a pH range of 5.0-10.0 and was insensitive to divalent cations. LipAAc is moderately thermostable with optimum temperature between 50 and 60 degrees C and was thermally activated (80% activity increase) after 1 h incubation at 50 degrees C. Phylogenetic analysis suggested that the LipAAc is a member of family I of bacterial lipases and clusters with other moderately thermostable lipases of this group. Comparisons of the DNA insert of fosmid LP001 with other acidobacterial genomes and sequence database suggest that lipAAc gene has a fungal origin and was acquired by horizontal transfer. PMID- 22428991 TI - Enzymatic biotransformation of ginsenoside Rb1 to compound K by recombinant beta glucosidase from Microbacterium esteraromaticum. AB - We cloned and characterized a beta-glucosidase (bgp3) gene from Microbacterium esteraromaticum isolated from ginseng field. The bgp3 gene consists of 2,271 bp encoding 756 amino acids which have homology to the glycosyl hydrolase family 3 protein domain. The molecular mass of purified Bgp3 was 80 kDa, as determined by SDS-PAGE. The enzyme (Bgp3) catalyzed the conversion of ginsenoside Rb1 to the more pharmacologically active minor ginsenoside Rd and compound K. The Bgp3 hydrolyzed the outer glucose moiety attached to the C-20 position of ginsenoside Rb1, followed by hydrolysis of the inner glucose moiety attached to the C-3 position. Using 0.1 mg mL(-1) enzyme in 20 mM sodium phosphate buffer at 40 degrees C and pH 7.0, 1.0 mg mL(-1) ginsenoside Rb1 was transformed into 0.46 mg mL(-1) compound K within 60 min with a corresponding molar conversion yield of 77%. Bgp3 hydrolyzed the ginsenoside Rb1 along the following pathway: Rb1 -> Rd > compound K. PMID- 22428992 TI - H5N1 influenza virus-like particles produced by transient expression in mammalian cells induce humoral and cellular immune responses in mice. AB - Vaccination is an effective way to protect from influenza virus infection. Among the new candidates of influenza vaccines, influenza virus-like particles (VLPs) seem to be promising. Here, we generated 2 types of H5N1 influenza VLPs by co expressing influenza virus Env (envelope protein) and murine leukemia virus (MLV) Gag-Pol. VLPs generated by co-transfection of pHCMV-wtH5 or pHCMV-mtH5 with pSV Mo-MLVgagpol and pHCMV-N1 were named as wtH5N1 VLPs or mtH5N1 VLPs. The plasmid of pHCMV-wtH5 encoded the wild-type hemagglutinin (HA) (wtH5) from A/swine/Anhui/ca/2004 (H5N1) with a multibasic cleavage site, while pHCMV-mtH5 encoded the modified mutant-type (mtH5) with a monobasic cleavage site. Influenza virus HA VLPs were characterized and equal amounts of them were used to immunize mice subcutaneously, intraperitoneally, or intramuscularly. The levels of HA specific IgG1, IFN-gamma, and neutralization antibodies were significantly induced in mice immunized with wtH5N1 VLPs or mtH5N1 VLPs via all 3 routes, while HA-specific IgG2a was barely detectable. IL-4 secretion was detected in mice subcutaneously immunized with wtH5N1 VLPs or mtH5N1 VLPs, or intramuscularly immunized with mtH5N1 VLPs. Our results indicated that both H5N1 influenza VLPs could induce specific humoral and cellular immune responses in immunized mice. In conclusion, our study provides helpful information for designing new candidate vaccines against H5N1 influenza viruses. PMID- 22428993 TI - Context modulates attention to social scenes in toddlers with autism. AB - BACKGROUND: In typical development, the unfolding of social and communicative skills hinges upon the ability to allocate and sustain attention toward people, a skill present moments after birth. Deficits in social attention have been well documented in autism, though the underlying mechanisms are poorly understood. METHODS: In order to parse the factors that are responsible for limited social attention in toddlers with autism, we manipulated the context in which a person appeared in their visual field with regard to the presence of salient social (child-directed speech and eye contact) and nonsocial (distractor toys) cues for attention. Participants included 13- to 25-month-old toddlers with autism (autism; n = 54), developmental delay (DD; n = 22), and typical development (TD; n = 48). Their visual responses were recorded with an eye-tracker. RESULTS: In conditions devoid of eye contact and speech, the distribution of attention between key features of the social scene in toddlers with autism was comparable to that in DD and TD controls. However, when explicit dyadic cues were introduced, toddlers with autism showed decreased attention to the entire scene and, when they looked at the scene, they spent less time looking at the speaker's face and monitoring her lip movements than the control groups. In toddlers with autism, decreased time spent exploring the entire scene was associated with increased symptom severity and lower nonverbal functioning; atypical language profiles were associated with decreased monitoring of the speaker's face and her mouth. CONCLUSIONS: While in certain contexts toddlers with autism attend to people and objects in a typical manner, they show decreased attentional response to dyadic cues for attention. Given that mechanisms supporting responsivity to dyadic cues are present shortly after birth and are highly consequential for development of social cognition and communication, these findings have important implications for the understanding of the underlying mechanisms of limited social monitoring and identifying pivotal targets for treatment. PMID- 22428994 TI - Preparation and evaluation of polymer based microcarriers for all-trans-retinoic acid. AB - Polymeric biomaterials are being investigated for the last several years because of their controllable properties. In this study, it was aimed to prepare and evaluate the atRA carrying system using Poly(lactide-co-glycolide) (PLGA). Microparticles were characterized in terms of morphology and encapsulation efficiency. Release studies were performed for the evaluation of drug release rates. Cytotoxicity tests were implemented on MCF-7 Human breast cancer cell line for the investigation of drug and polymer toxicity. The microparticles were found smooth and spherical in shape. However, as the loaded drug amount increased, the sizes of microparticles also increased and the size distribution became less uniform. The sizes of atRA-loaded microparticles ranged between 1-10 um. The encapsulation efficiency of atRetinoic acid (all-trans-Retinoic acid) was achieved approximately %90. Approximately, 45% of atRA was released from atRA loaded microparticles by the end of 4-5 days. Cell growth inhibition was observed after 4 days of incubation of cells with PLGA microparticles. PMID- 22428995 TI - A novel IL36RN/IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis. PMID- 22428996 TI - Antioxidant activity of polyphenol and ultrasonic extracts from fruits of Crataegus pentagyna subsp. elburensis. AB - The effects of two extracting methods on the total phenolic and total flavonoid contents of Crataegus pentagyna subsp. elburensis Waldst. & Kit. ex Willd fruit extracts were investigated. Antioxidant activities of polyphenol (PP) fraction and ultrasonic (US) extraction were evaluated with four different in vitro antioxidant tests. IC(50) for DPPH radical-scavenging activity was 32.2 +/- 1.6 for PP fraction and 36.7 +/- 1.5 ug mL(-1) for US extract. Reducing powers of extracts increased with the increase of their concentrations. PP fraction exhibited high reducing power at 2-32 ug mL(-1). Extracts exhibited good H(2)O(2) radical scavenging and Fe(2+) chelating ability. Their high phenolic and flavonoid contents could be responsible for their antioxidant activity and pharmacologic actions. PMID- 22428997 TI - Cross-cultural temperamental differences in infants, children, and adults in the United States of America and Finland. AB - Cross-cultural differences in temperament were investigated between infants (n = 131, 84 Finns), children (n = 653, 427 Finns), and adults (n = 759, 538 Finns) from the United States of America and Finland. Participants from both cultures completed the Infant Behavior Questionnaire, Childhood Behavior Questionnaire and the Adult Temperament Questionnaire. Across all ages, Americans received higher ratings on temperamental fearfulness than Finnish individuals, and also demonstrated higher levels of other negative affects at several time points. During infancy and adulthood, Finns tended to score higher on positive affect and elements of temperamental effortful control. Gender differences consistent with prior studies emerged cross-culturally, and were found to be more pronounced in the US during childhood and in Finland during adulthood. PMID- 22428998 TI - High-throughput production and structural characterization of libraries of self assembly lipidic cubic phase materials. AB - A protocol is presented for the high-throughput (HT) production of lyotropic liquid crystalline phases from libraries of lipids and lipid mixtures using standard liquid dispensing robotics, implementing methods that circumvent the problems traditionally associated with handling the highly viscous cubic phase. In addition, the ability to structurally characterize lipidic phases and assess functionality for membrane proteins contained within cubic phases, in a HT manner, is demonstrated. The techniques are combined and exemplified using the application of membrane protein crystallization within lipidic cubic phases. PMID- 22428999 TI - Rational nanoconjugation improves biocatalytic performance of enzymes: aldol addition catalyzed by immobilized rhamnulose-1-phosphate aldolase. AB - Gold nanoparticles (AuNPs) are attractive materials for the immobilization of enzymes due to several advantages such as high enzyme loading, absence of internal diffusion limitations, and Brownian motion in solution, compared to the conventional immobilization onto porous macroscopic supports. The affinity of AuNPs to different groups present at the protein surface enables direct enzyme binding to the nanoparticle without the need of any coupling agent. Enzyme activity and stability appear to be improved when the biocatalyst is immobilized onto AuNPs. Rhamnulose-1-phosphate aldolase (RhuA) was selected as model enzyme for the immobilization onto AuNPs. The enzyme loading was characterized by four different techniques: surface plasmon resonance (SPR) shift and intensity, dynamic light scattering (DLS), and transmission electron microscopy (TEM). AuNPs RhuA complexes were further applied as biocatalyst of the aldol addition reaction between dihydroxyacetone phosphate (DHAP) and (S)-Cbz-alaninal during two reaction cycles. In these conditions, an improved reaction yield and selectivity, together with a fourfold activity enhancement were observed, as compared to soluble RhuA. PMID- 22429000 TI - Gene expression profiles of phaeochromocytomas with ERBB2 overexpression reveal a new molecular mechanism tumourigenicity. AB - OBJECTIVE: Phaeochromocytomas (PHEO) and functional paragangliomas (PGLs) are catecholamine-secreting neuroendocrine tumours. Although most PHEO/PGLs are benign, 10-35% present as (or develop into) malignant tumours with a poor prognosis. Overexpression of ERBB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has been reported to be associated with malignant PHEO. We used gene expression profiling of PHEO/PGLs to gain a better understanding of the tumourigenic pathways associated with ERBB2. METHODS: We used the Affymetrix Gene Chip U133 Plus 2.0 genome-wide gene expression cDNA microarray of 18 PHEO/PGLs (12 benign and six malignant, divided into two groups depending on ERBB2 expression levels) to analyse the gene expression patterns. RESULTS: Unsupervised hierarchical cluster analysis of transcription profiles of 18 samples identified two dominant expression clusters corresponding to samples belonging to the ERBB2+ and ERBB2- groups. According to the gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases, the differentially expressed genes were classified into diverse functional categories and signalling pathways. In particular, the focal adhesion signalling pathway showed significant differences between the groups; specifically, the FAK-Src-MAPK pathway was prominently activated in the ERBB2+ group. CONCLUSIONS: In summary, ERBB2+ PHEO/PGLs have a distinct expression pattern compared with the ERBB2- group. The focal adhesion signalling pathway may participate in ERBB2-induced tumourigenesis in PHEO/PGLs. PMID- 22429001 TI - Association of dietary quercetin with reduced risk of proximal colon cancer. AB - Quercetin is a flavonol that appears to be protective against several cancers, but its possible role in prevention of colorectal cancer is not yet well studied. We evaluated dietary intakes of quercetin and risk of colorectal cancer in a large case-control study conducted in metropolitan Detroit, Michigan (N = 2664). The protective effects of quercetin intake, as assessed by a food frequency questionnaire, were confined to risk of proximal colon cancer. Stratified analyses showed that the protective effects of quercetin on risk of proximal colon cancer were significant only when fruit intake or the Healthy Eating Index score was high, or when tea intake was low, with odds ratios (OR) for the highest vs. the lowest quartile of 0.49, 0.44, and 0.51, respectively. Increased quercetin intake had no protective effects when tea intake was high. Interestingly, increased intake of quercetin was associated with increased risk of distal colon cancer when total fruit intake was low (OR for the highest vs. the lowest quartile = 1.99). These results suggest that quercetin can have disparate effects on colon cancer risk depending on whether dietary intakes of fruit or tea are high, and that quercetin had protective effects only on proximal, not distal, colon cancer. PMID- 22429002 TI - Impact of intensive upper limb rehabilitation on quality of life: a randomized trial in children with unilateral cerebral palsy. AB - AIM: The aim of this study was to determine whether constraint-induced movement therapy is more effective than bimanual training in improving the quality of life of children with unilateral cerebral palsy (CP). METHOD: Sixty-three children (mean age 10y 2mo [SD 2y 6mo]; 33 males, 30 females) with CP of the spastic motor type (n=59) or with spasticity and dystonia (n=4) were randomly allocated to two groups. The children were assessed as Manual Ability Classification System level I (n=16), II (n=46), or III (n=1). Each group received 6 hours of daily intervention (either constraint-induced movement therapy [CIMT] or bimanual training [BIM]) for 10 days over a 2-week period (total intervention time 60h). Children aged 9 years and older completed the Cerebral Palsy Quality of Life Questionnaire for Children (CPQOL-Child) and those aged 8 years and older completed the KIDSCREEN-52. All parents completed proxy versions of each measure. Assessments were made at baseline and at 3, 26, and 52 weeks after the end of the intervention. RESULTS: Thirty-five children completed the CPQOL-Child and 41 completed the KIDSCREEN-52. No changes in social or emotional well-being were reported by children in either group. Children and parents from both groups reported a significant improvement in their or their child's feelings about functioning as well as participation and physical health on the CPQOL-Child. The parents of children receiving CIMT reported positive and sustained changes in their child's social well-being (CPQOL-Child). The CIMT group showed significant improvements in physical well-being, psychological well-being, and moods and emotions (KIDSCREEN-52) at 3 weeks post intervention, which were maintained over the study period. INTERPRETATION: Intensive goal-directed upper limb training programmes using either CIMT or BIM achieved domain-specific changes in quality of life relating to feelings about functioning and participation and physical health. A condition-specific quality of life compared with a generic measure may be better able to detect changes in quality of life in children with unilateral CP. PMID- 22429003 TI - Young age predicts poor antiretroviral adherence and viral load suppression among injection drug users. AB - Previous studies of adherence to antiretroviral therapy (ART) for HIV among young injection drug users (IDU) have been limited because financial barriers to care disproportionately affect youth, thus confounding results. This study examines adherence among IDU in a unique setting where all medical care is provided free of-charge. From May 1996 to April 2008, we followed a prospective cohort of 545 HIV-positive IDU of 18 years of age or older in Vancouver, Canada. Using generalized estimating equations (GEE), we studied the association between age and adherence (obtaining ART>=95% of the prescribed time), controlling for potential confounders. Using Cox proportional hazards regression, we also studied the effect of age on time to viral load suppression (<500 copies per milliliter), and examined adherence as a mediating variable. Five hundred forty-five participants were followed for a median of 23.8 months (interquartile range [IQR]=8.5-91.6 months). Odds of adherence were significantly lower among younger IDU (adjusted odds ratio [AOR]=0.76 per 10 years younger; 95% confidence interval [CI], 0.65-0.89). Younger IDU were also less likely to achieve viral load suppression (adjusted hazard ratio [AHR]=0.75 per 10 years younger; 95% CI, 0.64 0.88). Adding adherence to the model eliminated this association with age, supporting the role of adherence as a mediating variable. Despite absence of financial barriers, younger IDU remain less likely to adhere to ART, resulting in inferior viral load suppression. Interventions should carefully address the unique needs of young HIV-positive IDU. PMID- 22429004 TI - Longitudinal associations between mothers' and fathers' sense of competence and children's externalizing problems: the mediating role of parenting. AB - This longitudinal study examined the bidirectional associations between parents' sense of competence and children's externalizing problems, mediation of these associations by parenting behaviors, and differences between mothers and fathers concerning these associations. A sample of 551 families with children (49.9% girls; mean age = 7.83 years, SD = 1.08) participated. We found children's externalizing problems to predict parents' sense of competence 6 years later, both directly and, for mothers but not for fathers, indirectly through inept discipline. Parents' sense of competence did not predict children's externalizing problems, either directly or indirectly via parenting behaviors. Some differences were found between mothers and fathers in the associations between parenting behaviors and sense of competence. PMID- 22429005 TI - Does being an older parent attenuate the intergenerational transmission of parenting? AB - Evidence that the transition to parenthood is occurring at older ages in the Western world, that older parents provide more growth-facilitating care than do younger ones, and that most prospective studies of the intergenerational transmission of parenting have focused on relatively young parents led us to evaluate whether parental age might moderate-and attenuate-the intergenerational transmission of parenting. On the basis of the seemingly commonsensical assumption that as individuals age they often become more psychologically mature and have more opportunity to reflect upon and free themselves from the legacy of childhood experiences, we hypothesized that deferring parenting would weaken links between rearing experiences in the family of origin and parenting in the family of procreation. To test this proposition we repeated analyses reported by Belsky, Jaffee, Sligo, Woodward, and Silva (2005) on 227 parents averaging 23 years of age linking rearing experiences repeatedly measured from 3 to 15 years of age with observed parenting in adulthood; we added 273 participants who became parents at older ages than did those in the original sample. Although previously reported findings showing that rearing history predicted mothering but not fathering reemerged, parental age generally failed to moderate the intergenerational transmission of parenting. Other investigators prospectively following children and adults into adulthood and studying the intergenerational transmission process should determine whether these null results vis-a-vis the attenuation of transmission with age obtain when parents with older children are studied or when other methods are used. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22429006 TI - Furoxans (1,2,5-oxadiazole-N-oxides) as novel NO mimetic neuroprotective and procognitive agents. AB - Furoxans (1,2,5-oxadiazole-N-oxides) are thiol-bioactivated NO-mimetics that have not hitherto been studied in the CNS. Incorporation of varied substituents adjacent to the furoxan ring system led to modulation of reactivity toward bioactivation, studied by HPLC-MS/MS analysis of reaction products. Attenuated reactivity unmasked the cytoprotective actions of NO in contrast to the cytotoxic actions of higher NO fluxes reported previously for furoxans. Neuroprotection was observed in primary neuronal cell cultures following oxygen glucose deprivation (OGD). Neuroprotective activity was observed to correlate with thiol-dependent bioactivation to produce NO(2)(-), but not with depletion of free thiol itself. Neuroprotection was abrogated upon cotreatment with a sGC inhibitor, ODQ, thus supporting activation of the NO/sGC/CREB signaling cascade by furoxans. Long-term potentiation (LTP), essential for learning and memory, has been shown to be potentiated by NO signaling, therefore, a peptidomimetic furoxan was tested in hippocampal slices treated with oligomeric amyloid-beta peptide (Abeta) and was shown to restore synaptic function. The novel observation of furoxan activity of potential therapeutic use in the CNS warrants further studies. PMID- 22429007 TI - Colonization and distribution of segmented filamentous bacteria (SFB) in chicken gastrointestinal tract and their relationship with host immunity. AB - Uncultivable segmented filamentous bacteria (SFB) reside in the gastrointestinal (GI) tract of mammals and can boost the host immunity. Immunoglobulin A (IgA) from mother's milk has been previously shown to be a key factor in regulating SFB colonization. Because neonatal chicken cannot acquire IgA from maternal milk, they are a good model to examine the role of IgA in SFB colonization. Here, we used the fluorescent in situ hybridization (FISH) and quantitative PCR (qPCR) to monitor the colonization and distribution of SFB in chickens aged from 2-day-old to 6-week-old. Early SFB colonization, which primarily occurred in the ileal mucosa (< 13 days old), was IgA independent. From the age of 17-42 days, there was an increase in IgA in the gut mucosa, which was correlated with a decrease in SFB. To examine the effect of probiotics and immunosuppression on SFB colonization, we treated the chickens by feeding them Lactobacillus delbrueckii or giving them a subcutaneous injection of cyclophosphamide (CTX). Feeding lactobacilli at birth rendered SFB colonization occurring 4 days earlier, while CTX treatment increases the SFB colonization through reducing the other non-SFB bacteria. Altogether, our data suggest that early colonization of SFB in chicken occurs independently of IgA and the population of SFB in the GI tract of chicken may be manipulated from birth via probiotic or CTX treatment. PMID- 22429008 TI - The effect of immersion cleansers on gloss, colour and sorption of acetal denture base material. AB - OBJECTIVE: To study the effect of peroxide and hypochlorite cleansers on gloss, colour and sorption of acetal denture resins. MATERIALS AND METHODS: Pink acetal and thermoplastic acrylic resins were evaluated. Thirty-five specimens 39 * 39* 1.8 mm of each resin were prepared. Each group of specimens (n = 7) was then immersed into cleansers for 100 days. Group I immersed in tap water, Group II in Corega Extradent for 5 min, Group III in Corega Extradent for 8 h, Group IV in NitrAdineTM Seniors for 15 min and Group V in NaOCl 5.25%. Gloss, colour and weight measurements were taken initially and after 100 days. Data subjected to two-way anova and Tukey's test at alpha = 0.05. RESULTS: Acrylic resin showed reductions of glossiness from -5 to -15 and acetal from -0.2 to -6. Colour changes (DeltaEpsilon*) ranged from 2.64 to 7.64 for acrylic and 2.77 to 26.54 for acetal resin. Sorption for acrylic ranged from 11.64 to 17.06 MUg/mm(3) and 9.18 to 24.79 MUg/mm(3) for acetal resin. The results of (DeltaEpsilon*) and sorption showed an interaction between denture resins and cleansers. CONCLUSIONS: The gloss of acetal resin was less affected by water, peroxides and NaOCl 5.25% compared with acrylic resin. Acetal resin showed clinically acceptable (DeltaEpsilon*) whereas acrylic resin unacceptable ones for water and peroxide solutions. The immersion of acetal resin in NaOCl 5.25% showed clinically unacceptable (DeltaEpsilon*) and higher sorption and should be avoided or should be managed with care. PMID- 22429009 TI - Effect of enamel matrix derivative and of proline-rich synthetic peptides on the differentiation of human mesenchymal stem cells toward the osteogenic lineage. AB - With the aim of discovering new molecules for induction of bone formation and biomineralization, combination of bioinformatics and simulation methods were used to design the structure of artificial peptides based on proline-rich domains of enamel matrix proteins. In this study, the effect of such peptides on the differentiation toward the osteogenic lineage of human umbilical cord mesenchymal stem cells (hUCMSCs) was evaluated with or without osteogenic supplements (hydrocortisone, beta-glycerol phosphate, and ascorbic acid) and compared to the effect of the commercially available enamel matrix derivative (EMD). It was hypothesized that the differentiation toward the osteogenic lineage of hUCMSCs would be promoted by the treatment with the synthetic peptides when combined with differentiation media, or it could even be directed exclusively by the synthetic peptides. Osteoinductivity was assessed by cell proliferation, bone morphogenetic protein-2 secretion, and gene expression of osteogenic markers after 1, 3, and 14 days of treatment. All peptides were safe with the dosages used, showing lower cell toxicity. P2, P4, and P6 reduced cell proliferation with growing media by 10%-15%. Higher expression of early osteoblast markers was found after 3 days of treatment with EMD in combination with osteogenic supplements, while after 14 days of treatment, cells treated by the different synthetic peptides in combination with osteogenic supplements showed higher osteocalcin mRNA levels. We can conclude that osteogenic differentiation of hUCMSCs is promoted by short-term EMD treatment in combination with osteogenic supplements and by long-term treatment by the synthetic peptides in combination with osteogenic supplements, showing similar results for all the peptide variants analyzed in this study. PMID- 22429010 TI - Telmisartan in the management of diabetic nephropathy: a contemporary view. AB - Diabetic nephropathy, a complex disorder with heterogeneous etiologies, remains one of the most threatening diseases worldwide. There were around 177 million people with diabetes mellitus worldwide, and it has been estimated to be increased to 360 million by 2030. Given that about 20-30% of these people develop diabetic nephropathy, the present treatment protocols primarily aim for an efficient glucose and blood pressure control to arrest the initiation and progression of diabetic nephropathy. The treatment of diabetic nephropathy near the beginning at microalbuminuria stage with angiotensin-II-AT1 receptor blockers (ARBs) improves blood pressure control and halts disease progression of diabetic nephropathy. In fact, ARBs exert renoprotective effects independently of their blood pressure lowering effect, as they have direct defensive action on the diabetic kidney. Indubitably, it would be better if an ARB has both glucose lowering and blood pressure controlling potentials efficiently. Intriguingly, telmisartan has such possessions considering its dual role of AT1 receptor blocking action and peroxisome proliferator-activated receptor gamma (PPARgamma) partial agonistic property. The additional PPARgamma agonistic potential of telmisartan could make it a distinctive intervention in the ARB class to prevent the progression of diabetic nephropathy through activation of PPARgamma-mediated insulin sensitization, and renal anti-inflammatory and anti-oxidant actions. Indeed, telmisartan reduced insulin resistance and glucose intolerance, and halted the progressive renal dysfunction associated with diabetic nephropathy by inhibiting the incidence of albuminuria, and preventing the progression of glomerulosclerosis, renal interstitial inflammation and fibrosis. This review will discuss the current status of therapeutic potentials of telmisartan in treating diabetic nephropathy. PMID- 22429011 TI - An update in incretin-based therapy: a focus on dipeptidyl peptidase--4 inhibitors. AB - Dipeptidyl peptidase -4 inhibitors represent a novel way to augment the incretin system and one of the newest class of medications in the treatment of type 2 diabetes mellitus. Their mechanism of action is to decrease the inactivation of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, both of which are involved in maintaining euglycemia subsequent to carbohydrate intake. Currently investigated agents include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. Each agent has been shown to provide significant improvements in glycemic control compared to placebo. They are effective when added to other oral diabetes agents and in the cases of sitagliptin, vildagliptin, and alogliptin in addition to insulin. These agents may not provide as significant improvement in glucose concentrations as some other medications including metformin, thiazolidinediones, or glucagon-like peptide 1 agonists. The lack of head to head clinical data comparing the various dipeptidyl peptidase 4 inhibitors does not allow for specific recommendations if one agent is more effective or safer than another within the class. Their side effect profile suggests they are very well tolerated and have few drug interactions. For patients with mildly elevated glucose concentrations, they are therapeutic options in both drug-naive patients as well as those not optimally controlled on other diabetes medications. PMID- 22429012 TI - The diabetic Charcot foot. AB - Charcot neuroarthropathy (CN) is a devastating condition affecting the feet in patients with diabetes. The pathophysiology of (CN) is still incompletely understood, although main etiological components have been identified. The cornerstone of treatment of acute CN is immediate effective offloading, typically with total contact casting, and reduction in weight-bearing. The main current targets of pharmacological intervention are the inhibition of excess osteoclast activation and suppression of an excess pro-inflammatory cytokine response. Anti resorption therapy, especially with bisphosphonates, has been used in randomized trials. The trials so far have demonstrated improved symptom control, a more rapid decline in foot temperature and a significant decrease in bone turnover markers. An understanding of the molecular pathways of bone resorption will help in the development of novel adjunctive pharmacological therapies which might further improve the outcome in patients with CN. PMID- 22429013 TI - Advances in the topical treatment of diabetic foot ulcers. AB - The diabetic foot remains a major cause of morbidity worldwide. Even though considerable progress has been achieved over the past years, there is still an urgent need for improvement. While established therapeutic modalities (revascularization, casting and debridement) remain the mainstay of management, there is, therefore, continuous development of new treatment options. This review provides an outlook of advances in topical treatment, including bioengineered skin substitutes (such as Dermagraft, Apligraf, HYAFF, OASIS and Graftjacket), extracellular matrix proteins (such as Hyalofill and E-matrix), as well as miscellaneous further therapeutic adjuncts. Although promising, new therapies should not, for the time being, constitute the basis of management, since clinical experience has not yet confirmed their effectiveness in hard-to-heal diabetic foot ulcers. Furthermore, their cost-effectiveness merits further investigation. Instead, they should only be considered in combination with established treatments or be attempted when these have not been successful. Moreover, we should not be oblivious to the fact that established and emerging treatments need to be practised in the setting of multidisciplinary foot clinics to reduce the number of amputations. PMID- 22429014 TI - Effective management of the type 2 diabetes patient with cardiovascular and renal disease: secondary prevention strategies after a myocardial infarction. AB - The prevalence of type 2 diabetes mellitus has reached epidemic proportions and continues to grow in nations throughout the world. This disease is typically accompanied by other related conditions that each pose a hazard to the health of these patients and exacerbate the risk associated with diabetes for cardiovascular morbidity and mortality. Despite guideline recommendations for assessment and treatment of all of these related conditions, many patients do not achieve treatment goals. In this article, an archetypal case study is presented based on patient characteristics and conditions typically encountered in the clinic. After sustaining a myocardial infarction, the patient undergoes comprehensive evaluation and is noted to have multiple poorly controlled risk factors for cardiovascular disease and nephropathy. A multidisciplinary approach is advocated, not only to address blood glucose levels, but also to treat risk factors and comorbid conditions commonly associated with type 2 diabetes mellitus (adverse lifestyle behaviors, obesity, hypertension, albuminuria, and dyslipidemia) and complications resulting from this disease (secondary cardiovascular events, as well as nephropathy, retinopathy, and neuropathy). This comprehensive approach helps to maximize both the likelihood of reaching treatment targets for blood glucose, blood pressure, and serum lipids, and reducing the long-term risk of diabetes-related morbidity and mortality. PMID- 22429015 TI - Update on the imaging techniques in the diagnosis of diabetic retinopathy. AB - Diabetic retinopathy is one of the leading causes of vision loss worldwide. Fluorescein angiogram still plays a primary role in its diagnosis but new non invasive technologies as optical coherence tomography, fundus autofluorescence and microperimetry are gaining popularity in the last years. Anatomical changes found with these devices have been widely described but their correlation with visual function needs to be assessed and several features have been proposed as indicators of visual prognosis. The aim of this paper is to give a scope of the actual role of these techniques in the evaluation of retinal impairment secondary to diabetes. PMID- 22429016 TI - Photobiomodulation of aqueous interfaces as selective rechargeable bio-batteries in complex diseases: personal view. AB - OBJECTIVE: In this personal view, we propose that the modulation of the structure and function of water by light may come to embody a new mechanistic approach for the treatment of complex diseases. BACKGROUND DATA: Long considered an innocuous medium, water has increasingly been found to be a key player in numerous mechanisms, including first-contact events in which cells decide between survival and apoptosis. Consequently, externally applied electromagnetic energy (light) may selectively target the organization of water to steer biological function. METHODS: We survey light-water research with particular emphasis on the quasi crystalline exclusion zone (EZ), part of the cell's aqueous interface that is just now beginning to be decoded. The current state of research, the technical challenges involved in obtaining evidence in biological systems, and some potential uses and implications of EZ water in medicine are presented. RESULTS: Though existing data have not yet proven the role of EZ water in photobiomodulation, research shows that EZ water can store charge and can later return it in the form of current flow, with as much as 70% of the input charge being readily obtainable. Macroscopic separation of charges can be stable for days to weeks and has unusual electric potential. Water is, thus, an unexpectedly effective charge separation and storage medium. CONCLUSIONS: We propose that the EZ may be selectively targeted in photobiomodulation as an efficient energy reservoir, which cells can use expeditiously to fuel cellular work, triggering signaling pathways and gene expression in the presence of injury-induced redox potentials. PMID- 22429017 TI - Identification and characterization of complex bioactive oligosaccharides in white and red wine by a combination of mass spectrometry and gas chromatography. AB - Over forty-five complex free oligosaccharides (of which several are novel) have been isolated and chemically characterized by gas chromatography and high resolution and high mass accuracy matrix-assisted laser desorption/ionization mass spectrometry (MALDI-FTICR MS) in red and white wines, Grignolino and Chardonnay, respectively. Oligosaccharides with a degree of polymerization between 3 and 14 were separated from simple monosaccharides and disaccharides by solid-phase extraction. The concentrations of free oligosaccharides were over 100 mg/L in both red and white wines. The free oligosaccharides-characterized for the first time in the present study-include hexose-oligosaccharides, xyloglucans, and arabinogalactans and may be the natural byproduct of the degradation of cell wall polysaccharides. The coupled gas chromatography and accurate mass spectrometry approach revealed an effective method to characterize and quantify complex functional oligosaccharides in both red and white wine. PMID- 22429018 TI - Kinetics of regulatory dendritic cells in inflammatory responses during Trypanosoma evansi infection. AB - Trypanosoma evansi (T. evansi) causes a wasting disease in almost all mammals. Trypanosoma evansi infection gives rise to the inflammatory responses that contribute to the development of inflammation-associated tissue injury. To determine what kinds of inflammatory molecules play roles in the pathogenicity of T. evansi infection, polymerase chain reaction array analysis was performed on samples from the infected and uninfected mice. The inflammatory cytokine and chemokine storm, caused mainly by macrophages, was observed. On the other hand, the expression levels of Ccl8 and Il10 in splenocytes were also markedly increased. These results suggested an augmentation in the number and activity of regulatory dendritic cells (DCs). Therefore, the kinetics of regulatory DCs in T. evansi-infected mice were investigated. During T. evansi infection, the regulatory DCs became prevalent, with reducing the amount of inflammatory DCs. Interestingly, when the regulatory DCs were implanted into T. evansi-infected mice, the survival was prolonged, and the expression levels of inflammatory molecules were suppressed. Taken together, these results showed that a subset of regulatory DCs acted as a potential regulator of the inflammatory responses. PMID- 22429019 TI - Computational analysis of intersubject variability and thrombin generation in dilutional coagulopathy. AB - BACKGROUND: Blood dilution is a frequent complication of massive transfusion during trauma and surgery. This article investigates the quantitative effects of blood plasma dilution on thrombin generation in the context of intersubject variability. STUDY DESIGN AND METHODS: A thoroughly validated computational model was used to simulate thrombin generation curves for 472 healthy subjects in the Leiden Thrombophilia Study. Individual thrombin curves were calculated for undiluted blood and for different dilution scenarios. For every such curve, five standard quantitative parameters of thrombin generation were calculated and analyzed. RESULTS: Thrombin generation parameters in diluted blood plasma displayed significant intersubject variability (with a coefficient of variation up to approx. 28%). Nevertheless, dilutional effects in the majority (or all) of the subjects in the study group were characterized by persistent patterns. In particular, the largest dilution-induced change typically occurred in the maximum slope (MS) of the thrombin curve, followed by a change in thrombin peak height (PH), whereas the smallest change often occurred in the area under the curve. The identified patterns demonstrated considerable robustness to variations in dilution scenario and tissue factor concentration. CONCLUSION: Dilutional effects on thrombin generation in a human population can be predicted from trends identified for the "average" subject and then refined by performing an analysis of actual subjects in the study group. The MS and PH are dilution indicators that are both sensitive and reliable across a large subject group and could potentially be used as disease markers in the diagnosis of coagulopathic conditions. PMID- 22429020 TI - Impact of electronic coupling, symmetry, and planarization on one- and two-photon properties of triarylamines with one, two, or three diarylboryl acceptors. AB - We have performed a study of the one- and two-photon absorption properties of a systematically varied series of triarylamino-compounds with one, two, or three attached diarylborane arms arranged in linear dipolar, bent dipolar, and octupolar geometries. Two-photon fluorescence excitation spectra were measured over a wide spectral range with femtosecond laser pulses. We found that on going from the single-arm to the two- and three-arm systems, the peak in two-photon absorption (2PA) cross-section is suppressed by factors of 3-11 for the lowest excitonic level associated with the electronic coupling of the arms, whereas it is enhanced by factors of 4-8 for the higher excitonic level. These results show that the coupling of arms redistributes the 2PA cross-section between the excitonic levels in a manner that strongly favors the higher-energy excitonic level. The experimental data on one- and two-photon cross-sections, ground- and excited-state transition dipole moments, and permanent dipole moment differences between the ground and the lowest excited states were compared to the results obtained from a simple Frenkel exciton model and from highly correlated quantum chemical calculations. It has been found that planarization of the structure around the triarylamine moiety leads to a sizable increase in peak 2PA cross section for the lowest excitonic level of the two-arm system, whereas for the three-arm system, the corresponding peak was weakened and shifted to lower energy. Our studies show the importance of the interarm coupling, number of arms, and structural planarity on both the enhancement and the suppression of two photon cross-sections in multiarm molecules. PMID- 22429021 TI - Differential expression of TRPM7 in rat hepatoma and embryonic and adult hepatocytes. AB - TRPM7 channels are implicated in cellular survival, proliferation, and differentiation. However, a profile of TRPM7 activity in a specific cell type has not been determined from embryonic to terminally differentiated state. Here, we characterized TRPM7 expression in a spectrum of rat liver cells at different developmental stages. Using the whole-cell patch clamp technique, TRPM7-like Na(+) currents were identified in RLC-18 cells, a differentiated, proliferating hepatocellular line derived from day 17 embryonic rat liver. Currents were outwardly rectifying, enhanced in divalent-free solutions, and inhibited by intracellular Mg(2+). Reverse transcription - polymerase chain reaction (RT-PCR) revealed that RLC-18 cells express both TRPM6 and TRPM7. However, mean currents were reduced almost 80% by 1 mmol/L 2-aminoethoxyphenylborate (2-APB) and were abolished in RLC-18 cells heterologously expressing a dominant negative TRPM7 construct, suggesting that TRPM7 is the major current carrier in these cells. Functional comparison showed that relative to terminally differentiated adult rat hepatocytes, currents were 1.8 and 3.9 times higher in, respectively, RLC-18 and WIF-B cells, a rat hepatoma - human fibroblast cross. Our results demonstrate that plasma membrane TRPM7 channels are more highly expressed in proliferating cells as compared with terminally differentiated and nondividing rat hepatocytes and suggest that downregulation of this channel is associated with hepatocellular differentiation. PMID- 22429022 TI - A puzzling mutation in congenital erythropoietic porphyria and an association with beta-thalassaemia trait. PMID- 22429023 TI - Quantitative measurement of the near-field enhancement of nanostructures by two photon polymerization. AB - The quantitative determination of the strength of the near-field enhancement in and around nanostructures is essential for optimizing and using these structures for applications. We combine the gaussian intensity distribution of a laser profile and two-photon-polymerization of SU-8 to a suitable tool for the quantitative experimental measurement of the near-field enhancement of a nanostructure. Our results give a feedback to the results obtained by finite difference time-domain (FDTD) simulations. The structures under investigation are gold nanotriangles on a glass substrate with 85 nm side length and a thickness of 40 nm. We compare the threshold fluence for polymerization for areas of the gaussian intensity profile with and without the near-field enhancement of the nanostructures. The experimentally obtained value of the near-field intensity enhancement is 600 +/- 140, independent of the laser power, irradiation time, and spot size. The FDTD simulation shows a pointlike maximum of 2600 at the tip. In a more extended area with an approximate size close to the smallest polymerized structure of 25 nm in diameter, we find a value between 800 and 600. Using our novel approach, we determine the threshold fluence for polymerization of the commercially available photopolymerizable resin SU-8 by a femtosecond laser working at a wavelength of 795 nm and a repetition rate of 82 MHz to be 0.25 J/cm(2) almost independent of the irradiation time and the laser power used. This finding is important for future applications of the method because it enables one to use varying laser systems. PMID- 22429024 TI - Extraction and separation of volatile and fixed oils from seeds of Myristica fragrans by supercritical CO2: chemical composition and cytotoxic activity on Caco-2 cancer cells. AB - Isolation of volatile and fixed oils from nutmeg have been obtained by supercritical fractioned extraction with carbon dioxide. Extraction experiments were carried out at pressures of 90 and 250 bar and temperature of 40 degrees C. The extraction step performed at 90 bar produced a volatile fraction mainly formed by myristicin (32.8%), sabinene (16.1%), alpha-pinene (9.8%), beta-pinene (9.4%), beta-phellandrene (4.9%), safrole (4.1%) and terpinen-4-ol (3.6%). The oil yield relative to this step of the process was 1.4% by weight of the charge. The last extraction step at 250 bar produced a butter-like material (nutmeg butter). The yield of this step was 14.4% by weight. The most represented fatty acids of fixed oil from nutmeg were 14:0 (79.2%), 18:1 n-9 (7.4%) and 16:0 (6.1%), and in particular the unsaturated fatty acids 18:1 n-9 averaged 32.96 MUg/mg of oil. The level of myristicin in the nutmeg essential and fixed oils was also directly quantified by reversed HPLC-DAD. Moreover, the essential oil obtained from nutmeg, as well as myristicin, showed a significant in vitro inhibitory effect on the growth of a colon cancer cell line (undifferentiated Caco-2 cells). PRACTICAL APPLICATION: In this study, the chemical characterization and the anticancer activity of nutmeg oils obtained by supercritical extraction with carbon dioxide were investigated. This is important for their potential application in food and pharmaceutical industries. PMID- 22429025 TI - Changes in glucose metabolism and metabolites during the epileptogenic process in the lithium-pilocarpine model of epilepsy. AB - PURPOSE: The metabolic and biochemical changes that occur during epileptogenesis remain to be determined. (18) F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and proton magnetic resonance spectroscopy ((1) H MRS) are noninvasive techniques that provide indirect information on ongoing pathologic changes. We, therefore, utilized these methods to assess changes in glucose metabolism and metabolites in the rat lithium-pilocarpine model of epilepsy as markers of epileptogenesis from baseline to chronic spontaneous recurrent seizures (SRS). METHODS: PET and MRS were performed at baseline, and during the acute, subacute, silent, and chronic periods after lithium-pilocarpine induced status epilepticus (SE). Sequential changes in glucose metabolism on (18) F-FDG PET using SPM2 and the ratios of percent injected dose per gram (%ID)/g of regions of interest (ROIs) in the bilateral amygdala, hippocampus, basal ganglia with the thalamus, cortex, and hypothalamus normalized to the pons were determined. Voxels of interest (VOIs) on (1) H MRS were obtained at the right hippocampus and the basal ganglia. NAA/Cr levels and Cho/Cr at various time points were compared to baseline values. KEY FINDINGS: Of 81 male Sprague Dawley rats, 30 progressed to SRS. (18) F-FDG PET showed widespread global hypometabolism during the acute period, returning to baseline level during the subacute period. Glucose metabolism, however, declined in part of the hippocampus during the silent period, with the hypometabolic area progressively expanding to the entire limbic area during the chronic period. (1) H MRS showed that the NAA/Cr levels in the hippocampus and basal ganglia were reduced during the acute period and were not restored subsequently from the subacute to the chronic period without any significant change in the Cho/Cr ratio throughout the entire experiment. SIGNIFICANCE: Serial metabolic and biochemical changes in the lithium-pilocarpine model of epilepsy indirectly represent the process of human epileptogenesis. Following initial irreversible neural damage by SE, global glucose metabolism transiently recovered during the subacute period without neuronal recovery. Progressive glucose hypometabolism in the limbic area during the silent and chronic periods may reflect the important role of the hippocampus in the formation of ongoing epileptic network during epileptogenesis. PMID- 22429026 TI - Cytokine reporter mice: the special case of IL-10. AB - IL-10 is one of the key cytokines preventing inflammation-mediated tissue damage. In an attempt to identify IL-10-producing cells in vivo, several groups have recently developed IL-10 reporter mouse strains. Up until now, in total, eight IL 10 reporter strains have been published. This incomparable interest in IL-10 reporter mice emphasizes the importance and difficulties in tracking and subsequently investigating the role of IL-10-producing cells in infectious, inflammatory, autoimmune and cancer diseases. In this review, I summarize and compare the properties of those published IL-10 reporter mouse models. I also discuss the necessity to develop new strategies to generate 'multi-cytokine' reporter mouse models enabling highly sensitive in/ex vivo detection of many cytokines in the same single cell. Such 'multi-cytokine' reporter mice will enable to reconsider the dichotomy 'T-effector versus T-regulatory' paradigm and to provide an accurate revised model for cellular sources of cytokines. Finally, I propose to launch cooperative, international initiatives to promote and coordinate the generation of accurate, combinatorial, reporter mice for every individual murine cytokine. PMID- 22429027 TI - Two new triterpenoid saponins from the husks of Xanthoceras sorbifolia. AB - Two new oleanane triterpenoid saponins, xanthohuskisides A (1) and B (2), were isolated from the husks of Xanthoceras sorbifolia. The structures of these two compounds were established as 3-O-beta-D-glucopyranosyl (1->6)-[beta-D glucopyranosyl (1->2)]-beta-D-glucopyranosyl, 28-O-beta-D-glucopyranosyl (1->6) [alpha-L-rhamnopyranosyl (1->2)]-beta-D-glucopyranosyl 16-deoxybarringtogenol C (1) and 3-O-beta-D-glucopyranosyl (1->6)-[beta-D-glucopyranosyl (1->2)]-beta-D glucopyranosyl, 28-O-beta-D-glucopyranosyl (1->6)-beta-D-glucopyranosyl 16 deoxybarringtogenol C (2), respectively, based on the analysis on their spectral data including NMR and HR-ESI-MS. The growth inhibitory activities of compounds 1 and 2 were assayed, and 2 showed moderate activity against U937 cell line with the IG(50) value of 82.85 +/- 1.58 uM. PMID- 22429028 TI - Low molecular weight apple polysaccharides induced cell cycle arrest in colorectal tumor. AB - Dietary components play an important role in cancer prevention. Many ingredients from apples have been proven to have antitumor potency. We thus made low molecular weight apple polysaccharides (LMWAP) and evaluated the effects of it on colorectal cancer (CRC). The effects of LMWAP on human colon carcinoma cells (HT 29) were evaluated using a microarray. Then, cell-cycle distribution was measured by flow cytometric analysis. A colitis-associated colorectal cancer mouse model was used to assess the effect of LMWAP on in vivo CRC prevention. Treatment of HT 29 cells with LMWAP resulted in 333 genes expression over cutoff values (>=2 fold). Further analysis demonstrated that pathways of cell cycle were mainly influenced. At the concentrations from 0.001 to 0.1 mg/mL, LMWAP induced a G(0)/G(1) phase block in HT-29 cells in a dose-dependent way. In vivo studies revealed that administration of LMWAP could protect ICR mice against CRC effectively. The results of Western blot suggested LMWAP induced cell-cycle arrest in a p53 independent manner. These data indicate that LMWAP could inhibit the development of CRC through affecting cell cycle, and it has potential for clinical prevention for colon cancer. PMID- 22429029 TI - Implicit and explicit theory of mind: state of the art. PMID- 22429030 TI - 2.5-year-olds succeed at a verbal anticipatory-looking false-belief task. AB - Recent research suggests that infants and toddlers succeed at a wide range of non elicited-response false-belief tasks (i.e., tasks that do not require children to answer a direct question about a mistaken agent's likely behaviour). However, one exception to this generalization comes from verbal anticipatory-looking tasks, which have produced inconsistent findings with toddlers. One possible explanation for these findings is that toddlers succeed when they correctly interpret the prompt as a self-addressed utterance (making the task a non-elicited-response task), but fail when they mistakenly interpret the prompt as a direct question (making the task an elicited-response task). Here, 2.5-year-old toddlers were tested in a verbal anticipatory-looking task that was designed to help them interpret the anticipatory prompt as a self-addressed utterance: the experimenter looked at the ceiling, chin in hand, during and after the prompt. Children gave evidence of false-belief understanding in this task, but failed when the experimenter looked at the child during and after the prompt. These results reinforce claims of robust continuity in early false-belief reasoning and provide additional support for the distinction between non-elicited- and elicited response false-belief tasks. Three accounts of the discrepant results obtained with these tasks - and of early false-belief understanding more generally - are discussed. PMID- 22429031 TI - Where will the triangle look for it? Attributing false beliefs to a geometric shape at 17 months. AB - Prior research on implicit mind-reading skills has focussed on how infants anticipate other persons' actions. This study investigated whether 11- and 17 month-olds spontaneously attribute false beliefs (FB) even to a simple animated geometric shape. Infants were shown a triangle chasing a disk through a tunnel. Using an eye-tracker, we found that 17-month-olds in a change-of-location true belief (TB) task anticipated that the triangle would search for the disk in the correct place while in a FB test they anticipated that it would search for it in the wrong, belief congruent place. These results suggest that 17-month-olds' psychological-reasoning system is applied to the actions of unfamiliar agents and it is employed to anticipate agents' actions even in the absence of any morphological features that are typical of natural agents. These findings provide support for theoretical accounts that emphasize continuity in the development of theory of mind core concepts and belief reasoning skills. PMID- 22429032 TI - A cue-based approach to 'theory of mind': re-examining the notion of automaticity. AB - The potential utility of a distinction between 'automatic (or spontaneous) and implicit' versus 'controlled and explicit' processes in theory of mind (ToM) is undercut by the fact that the terms can be employed to describe different but related distinctions within cognitive systems serving that function. These include distinctions in the underlying cognitive systems, processes, or representations involved in ToM, distinctions among methodologies or task procedures used to measure ToM, and distinctions among behavioural signatures evaluated as evidence for the engagement of ToM. We propose an approach in which rather than continued dispute over whether or not ToM 'is' or 'is not' automatic, researchers focus instead on discovering what the range of stimulus conditions and task contexts are that give rise to various signatures of the ToM system. These input-output relations will constrain theorizing about the kinds of representations employed, the types of processing operating over those representations, and the overall architecture of ToM mechanisms. PMID- 22429033 TI - Do infants have a theory of mind? AB - The central question debated in current research on infant social cognition is 'do infants have a theory of mind?' It is argued here that this question is understood and treated in radically different ways by different participants of the debate arguing either for (e.g., Onishi & Baillargeon, 2005) or against early competence in theory of mind (e.g., Perner & Ruffman, 2005). As a consequence, there is considerable talking past each other, both sides make claims that appear incompatible but are actually answers to different questions and framed at different levels of description. Some conceptual distinctions from the philosophy of mind are therefore introduced to describe the different interpretations of the question and the misunderstandings based thereupon, with the aim of providing some conceptual clarification as groundwork for future debates. PMID- 22429034 TI - Direct and indirect measures of Level-2 perspective-taking in children and adults. AB - Studies with infants show divergence between performance on theory of mind tasks depending on whether direct or indirect measures are used. It has been suggested that direct measures assess a flexible but cognitively demanding ability to reason about the minds of others, whereas indirect measures assess distinct processes which afford more efficient but less flexible theory of mind abilities (Apperly & Butterfill, 2009). This leads to the prediction that performance on indirect measures should be subject to signature limits. The current study tested whether the Level-1/Level-2 distinction might constitute one such limit. The study adapted a task that has shown evidence of Level-1 perspective-taking on both direct and indirect measures (Samson, Apperly, Braithwaite, Andrews, & Bodley-Scott, 2010). The aim was to test Level-2 perspective-taking in a sample of 6- to 11-year-olds (N = 80) and adults (N = 20). Participants were able to make Level-2 judgements on the direct measure. In contrast with the findings from Level-1 perspective-taking, there was no evidence of automatic processing of Level-2 perspectives on the indirect measure. This finding is consistent with the view that theory of mind abilities assessed by indirect measures are subject to signature limits. The Level-1/Level-2 distinction, suitably refined, marks one way in which efficient but inflexible theory of mind abilities are limited. PMID- 22429035 TI - Statistical learning as a basis for social understanding in children. AB - Many authors have argued that infants understand goals, intentions, and beliefs. We posit that infants' success on such tasks might instead reveal an understanding of behaviour, that infants' proficient statistical learning abilities might enable such insights, and that maternal talk scaffolds children's learning about the social world as well. We also consider which skills and insights are likely to be innate, and why it is difficult to say exactly when children understand mental states as opposed to behaviours. PMID- 22429036 TI - Bridging the gap between implicit and explicit understanding: how language development promotes the processing and representation of false belief. AB - Recent advancements in the field of infant false-belief reasoning have brought into question whether performance on implicit and explicit measures of false belief is driven by the same level of representational understanding. The success of infants on implicit measures has also raised doubt over the role that language development plays in the development of false-belief reasoning. In the current paper, we argue that children's performance on disparate measures cannot be used to infer similarities in understanding across different age groups. Instead, we argue that development must continue to occur between the periods when children can reason implicitly and then explicitly about false belief. We then propose mechanisms by which language associated with false-belief tasks facilitates this transition by assisting with both the processes of elicited response selection and the formation of metarepresentational understanding. PMID- 22429037 TI - Chinese preschoolers' implicit and explicit false-belief understanding. AB - Mandarin-speaking preschoolers in Mainland China (3- to 4-year-olds; N= 192) were tested for dissociations between anticipatory looking (AL) and verbal judgments on false-belief tasks. The dissociation between the two kinds of understanding was robust despite direct false-belief test questions using a Mandarin specific think-falsely verb and despite participants living in a culture that promotes early self-control. Children showed coherent AL across different belief-formation scenarios. Manipulation of inhibitory demand in the false-belief task did not affect preschoolers' verbal judgments any more than their AL, and yet separate measures executive function correlated only with direct judgments and not looking responses. The findings are discussed in terms of an implicit-explicit cognitive systems account of false-belief understanding. PMID- 22429038 TI - Self-knowledge and knowing other minds: the implicit/explicit distinction as a tool in understanding theory of mind. AB - Holding content explicitly requires a form of self-knowledge. But what does the relevant self-knowledge look like? Using theory of mind as an example, this paper argues that the correct answer to this question will have to take into account the crucial role of language-based deliberation but warns against the standard assumption that explicitness is necessary for ascribing awareness. It argues in line with Bayne that intentional action is at least an equally valid criterion for awareness. This leads to a distinction between different levels of implicitness. Postulating these different levels, it is argued, allows us to make better sense of the empirical literature on early false-belief task abilities. PMID- 22429039 TI - Breaking the rules: do infants have a true understanding of false belief? AB - It has been suggested that infants' performance on the false belief task can be explained by the use of behavioural rules. To test this hypothesis, 18-month-old infants were trained to learn the new rule that an object that disappeared in location A could be found in location B. Infants were then administered a false belief task based on the violation of expectation (VOE) paradigm, an intention understanding task, and a modified detour-reaching task. Results revealed that infants looked significantly longer at the display when the experimenter looked for the toy in the full box (box with the toy) compared to infants who observed the experimenter search in the empty box (box without the toy). Results also revealed significant correlations between infants' looking time at the display and their scores on the intention task and on the detour-reaching task. Taken together, these findings suggest that infants possess an implicit understanding of false belief. In addition, they challenge the view that success on the implicit false belief task does not require executive functioning abilities. PMID- 22429040 TI - Continuity from an implicit to an explicit understanding of false belief from infancy to preschool age. AB - An implicit understanding of false belief indicated by anticipatory looking has been shown to be significantly correlated with performance on explicit false belief tasks in 3- and 4-year-old children (Low, 2010). Recent evidence from infant research indicates, however, that implicit false-belief understanding guides infants' expectations about goal-directed actions even in the second year of life. The present study presents data from a sample of N= 70 infants who were tested longitudinally at 15, 18, 30, 36 and 48 months with implicit and explicit Theory of Mind measures, as well as an assessment of verbal IQ. Belief-based anticipatory looking in the false-belief task at 18 months significantly predicted verbal false-belief reasoning at 48 months, after controlling for verbal IQ. These findings indicate developmental continuity and conceptual specificity in belief reasoning from infancy to preschool age. They are discussed with respect to competing accounts of infants' understanding of the mind. PMID- 22429041 TI - Deception dissociates from false belief reasoning in deaf children: implications for the implicit versus explicit theory of mind distinction. AB - Deception is a controversial aspect of theory of mind, and researchers disagree about whether it entails an understanding of the false beliefs of one's opponent. The present study asks whether children with delayed language and delayed explicit false belief reasoning can succeed on explicit deception tasks. Participants were 45 orally taught deaf children with varying language delays aged 4.5-8 years and 45 hearing children aged 3.5-6 years. Participants received a battery of language, executive function, deception, and both verbal and low verbal false belief tasks. The result reveal a dissociation of deception and false belief tasks: the deaf children are on par with their hearing peers on deception games, but show significant delays in false belief tasks even when the language demands are made minimal. Furthermore, different skills are predictors of success for the two types of task in the deaf children: language, and in particular complement syntax, is the best predictor of false belief reasoning; but executive function skills, especially inhibitory control, are the best predictors of deception. It is argued that deception at this level can be handled by behaviour rules without reference to mental states. PMID- 22429042 TI - Do actions speak louder than words? A comparative perspective on implicit versus explicit meta-cognition and theory of mind. AB - Research in non-human animal (hereafter, animal) cognition has found strong evidence that some animal species are capable of meta-cognitively monitoring their mental states. They know when they know and when they do not know. In contrast, animals have generally not shown robust theory of mind (ToM) capabilities. Comparative research uses methods that are non-verbal, and thus might easily be labelled 'implicit' using the terminology of traditional human cognition. However, comparative psychology has developed several non-verbal methods that are designed to test for aspects of meta-cognition that - while perhaps not fully explicit - go beyond the merely implicit or associative. We believe similar methods might be useful to developmental researchers who work with young children, and may provide a sound empirical alternative to verbal reports. Comparative psychology has moved away from all-or-none categorical labels (e.g., 'implicit' vs. 'explicit') towards a theoretical framework that contains a spectrum of mental abilities ranging from implicit to explicit, and from associative to cognitive to fully conscious. We discuss how this same framework might be applied to developmental psychology when it comes to implicit versus explicit processing and ToM. PMID- 22429044 TI - Communication behavior and relationship satisfaction among American and Chinese newlywed couples. AB - Most research on couple communication patterns comes from North America and Europe and suggests cross-cultural universality in effects, but emerging studies suggest that couple communication takes different forms depending on the cultural context in which it occurs. The current study addressed this discrepancy by comparing the observed social support behaviors of 50 newlywed American couples and 41 newlywed Mainland Chinese couples, first on mean levels of positivity and negativity and second on behavior-satisfaction associations. Consistent with predictions derived from observational work by Tsai and Levenson (1997), Chinese couples were observed displaying significantly more negative behavior than American couples, even after controlling for relationship satisfaction; the 2 groups did not differ in observed positive behaviors. Tests of the moderating role of culture on behavior-satisfaction associations showed that positivity was significantly related to relationship satisfaction only for American husbands, whereas negativity was significantly associated with relationship satisfaction only for Chinese husbands. We speculate that cultural contexts may influence the display and evaluation of behavior in intimate relationships, suggesting the need for caution when generalizing models and associated interventions to non-Western couples. PMID- 22429045 TI - Response of tufted angiomas to low-dose aspirin. AB - Tufted angioma (TA), also known as angioblastoma of Nakagawa, is an uncommon vascular tumor. Clinical presentation and evolution of TA can vary. There are many treatment modalities, but none are uniformly effective. We present two patients with TA without Kasabach-Merritt phenomenon (KMP) treated with low dose aspirin, which resulted in improved appearance, decreased bulk, and resolution of symptoms. Low-dose aspirin should be considered as a treatment option for large or symptomatic TA that are not associated with KMP. PMID- 22429046 TI - Spinal curvature and characteristics of postural change in pregnant women. AB - OBJECTIVE: Pregnant women often report complaints due to physiological and postural changes. Postural changes during pregnancy may cause low back pain and pelvic girdle pain. This study aimed to compare the characteristics of postural changes in pregnant compared with non-pregnant women. DESIGN: Prospective case control study. SETTING: Pregnancy care center. POPULATION: Fifteen women at 17-34 weeks pregnancy comprised the study group, while 10 non-pregnant female volunteers comprised the control group. METHODS: Standing posture was evaluated in the sagittal plane with static digital pictures. Two angles were measured by image analysis software: (1) between the trunk and pelvis; and (2) between the trunk and lower extremity. Spinal curvature was measured with Spinal Mouse(r) to calculate the means of sacral inclination, thoracic and lumbar curvature and inclination. MAIN OUTCOME MEASURES: The principal components were calculated until eigenvalues surpassed 1. RESULTS: Three distinct factors with eigenvalues of 1.00-2.49 were identified, consistent with lumbosacral spinal curvature and inclination, thoracic spine curvature, and inclination of the body. These factors accounted for 77.2% of the total variance in posture variables. Eleven pregnant women showed postural characteristics of lumbar kyphosis and sacral posterior inclination. Body inclination showed a variety of patterns compared with those in healthy women. CONCLUSIONS: Spinal curvature demonstrated a tendency for lumbar kyphosis in pregnant women. Pregnancy may cause changes in spinal curvature and posture, which may in turn lead to relevant symptoms. Our data provide a basis for investigating the effects of spinal curvature and postural changes on symptoms during pregnancy. PMID- 22429047 TI - Socio-demographic, clinical and treatment characteristics of relapsing schizophrenic patients. AB - AIMS: To define the clinical profile of relapsing patients with schizophrenia attended in daily practice. METHOD: Patients with schizophrenia/schizoaffective disorder admitted to short-stay/acute-care psychiatric units were eligible provided that data for the previous 3 years and for the next 12 months after discharge were collected. RESULTS: Remarking features in 1646 patients (68% men) included low family support (34%), primary education (48%), schizophrenia as the main diagnosis (77%), duration of illness > 10 years (60%), mean number of previous hospitalizations of 2.74, non-adherence as the main reason of hospitalization (58.6%), treatment with a mean of two different antipsychotics and differences in adherence according to antipsychotic medication (P < 0.0001) (highest rates for depot atypical antipsychotics). The relapse rate was 38.6%. There were no differences in the number of relapsing patients according to antipsychotic drugs. DISCUSSION AND CONCLUSION: The profile of relapsing schizophrenic patients may be defined as a male subject, aged 30-45 years, with primary education level, more than 10 years of disease' duration, low family support, moderately and severely ill, treated with multiple antipsychotic drugs, and poor to moderate adherence. Differences in relapse according to antipsychotic types were not observed but long-acting second generation antipsychotic drugs showed the highest percentage of maximum adherence. PMID- 22429048 TI - The non-human primate model of tuberculosis. AB - Non-human primates (NHPs) are used to model human disease owing to their remarkably similar genomes, physiology, and immune systems. Recently, there has been an increased interest in modeling tuberculosis (TB) in NHPs. Macaques are susceptible to infection with different strains of Mycobacterium tuberculosis (Mtb), producing the full spectrum of disease conditions, including latent infection, chronic progressive infection, and acute TB, depending on the route and dose of infection. Clearly, NHPs are an excellent model of human TB. While the initial aim of the NHP model was to allow preclinical testing of candidate vaccines and drugs, it is now also being used to study pathogenesis and immune correlates of protection. Recent advances in this field are discussed in this review. Key questions such as the effect of hypoxia on the biology of Mtb and the basis of reactivation of latent TB can now be investigated through the use of this model. PMID- 22429049 TI - Schistosoma haematobium infection levels determine the effect of praziquantel treatment on anti-schistosome and anti-mite antibodies. AB - Field studies show an association between schistosome infection and atopy, but the effects of anti-helminthic treatment on this association have not yet been investigated in human populations with different schistosome endemicity levels. This study aimed to compare the effects of anti-helminthic treatment on responses directed against the house dust mite Dermatophagoides pteronyssinus (Derp1) and Schistosoma haematobium in Zimbabwean populations living in high and low schistosome infection areas. Derp1- and schistosome-specific IgE and IgG4 antibodies were quantified by ELISA before and 6 weeks after anti-helminthic treatment. Following treatment, there were changes in the immune responses, which varied with place of residence. After allowing for the effects of sex, age and baseline infection intensity, there was no significant treatment effect on the change in anti-schistosome IgE and IgG4 in the high infection area. However, the anti-schistosome IgE/IgG4 ratio increased significantly, while anti-Derp1 IgE responses decreased as a result of treatment. In the low infection area, treatment resulted in a significant increase in anti-worm IgE levels, but there was no significant treatment effect on anti-schistosome or anti-Derp1 IgE/IgG4 ratios. Thus, the study shows that the level of schistosome endemicity affects the host responses to schistosome and mite antigens following anti-helminthic treatment. PMID- 22429050 TI - Prevalence of nephrolithiasis in human immunodeficiency virus infected patients on the highly active antiretroviral therapy. AB - BACKGROUND AND PURPOSE: Protease inhibitors, specifically indinavir, have historically been implicated as a cause of nephrolithiasis in the human immunodeficiency virus (HIV) infected patients. There is a paucity of data, however, on stone disease with nonindinavir etiologies since the introduction of highly active antiretroviral therapy (HAART). We sought to describe the prevalence of nephrolithiasis in the HIV population since the use of HAART. PATIENTS AND METHODS: We retrospectively reviewed HIV-positive patients currently receiving HAART treatment in whom image proven kidney and/or ureteral urolithiasis developed, between 1998 and 2010. A detailed analysis of patients' current treatment, surgical intervention, and metabolic studies was performed. RESULTS: A total of 436 HIV-positive patients were included and 46 (11%) patients had nephrolithiasis. Each patient included in this study was receiving nonindinavir-based antiretroviral therapy. There were 41 men of whom 36 were Caucasian. Eleven (24%) patients underwent 24-hour urine collections with 11 metabolic abnormalities identified. Stone analysis was available for seven patients (four calcium oxalate monohydrate, one cystine, one uric acid, and one atazanavir). CONCLUSIONS: We report the largest series of nephrolithiasis in an HIV population since the introduction of HAART and highlight not only the similar prevalence of nephrolithiasis to the non-HIV population but also the lack of consistent comprehensive metabolic evaluations in HIV patients with recurrent nephrolithiasis. PMID- 22429051 TI - Molecular modeling of the structural and dynamical properties of secondary plant cell walls: influence of lignin chemistry. AB - A modeling of lignified secondary plant cell walls adapted to grass has been achieved, using molecular dynamics for time up to 180 ns, applied to systems composed of cellulose, xylan, water, and lignin. The overall model, which was 70 nm thick for a volume of 74.4 nm(3), consisted of two crystalline cellulose layers, each being two molecules deep, separated by an interlayer space where the three other components were located. Whereas the cellulose and xylan chemistry was fixed, 18 lignin systems were considered that varied not only in guaiacyl, syringyl, and p-hydroxyphenyl composition, but also in chain length, linkage types, and the presence or absence of coumaryl units. The stabilized models showed a well-defined interface between xylan and cellulose, but some interpenetration of xylan into the lignin part of the models. A survey of the 18 models showed that their lignin component was amorphous and that their density profile was very variable and essentially model dependent. This variability was also reflected in the co-orientation of the lignin phenyl rings with respect to the cellulose surfaces, some systems showing some orientation whereas others did not. The pattern of void distribution accessible to water varied from one system to the next, but the overall void volume was systematically established at around 3%, accepting around 200 water molecules. The estimated mobility of the water molecules interacting with lignin was 1.5 times greater than that interacting with carbohydrates. PMID- 22429052 TI - Bioactive diterpenes from Callicarpa longissima. AB - Investigation of the leaves and twigs of Callicarpa longissima resulted in the isolation of four new compounds (1-4), callilongisins A-D, and five known compounds, ursolic acid, 3-oxoanticopalic acid, (E)-6beta-hydroxylabda-8(17),13 dien-15-oic acid, 5-hydroxy-3,6,7,4'-tetramethoxyflavone, and artemetin. Compounds 1-3 are 3,4-seco-abietane-type diterpenoids, and compound 4 is an analogue of a labdenoic-type diterpene. The structure of compound 1 was confirmed by X-ray crystallographic analysis. Cytotoxicity against a human prostate cancer cell line (PC3) and anti-inflammatory activities of the isolated compounds were evaluated. PMID- 22429053 TI - Probing dynamically tunable localized surface plasmon resonances of film-coupled nanoparticles by evanescent wave excitation. AB - The localized surface plasmon resonance (LSPR) spectrum associated with a gold nanoparticle (NP) coupled to a gold film exhibits extreme sensitivity to the nanogap region where the fields are tightly localized. The LSPR of an ensemble of film-coupled NPs can be observed using an illumination scheme similar to that used to excite the surface plasmon resonance (SPR) of a thin metallic film; however, in the present system, the light is used to probe the highly sensitive distance-dependent LSPR of the gaps between NPs and film rather than the delocalized SPR of the film. We show that the SPR and LSPR spectral contributions can be readily distinguished, and we compare the sensitivities of both modes to displacements in the average gap between a collection of NPs and the gold film. The distance by which the NPs are suspended in solution above the gold film is fixed via a thin molecular spacer layer and can be further modulated by subjecting the NPs to a quasistatic electric field. The observed LSPR spectral shifts triggered by the applied voltage can be correlated with angstrom scale displacements of the NPs, suggesting the potential for chip-scale or flow-cell plasmonic nanoruler devices with extreme sensitivity. PMID- 22429054 TI - Biogenic amine profile in unripe Arabica coffee beans processed according to dry and wet methods. AB - Immature coffee fruit processing contributes to a high amount of defective beans, which determines a significant amount of low-quality coffee sold in the Brazilian internal market. Unripe bean processing was tested, taking the levels of bioactive amines as criteria for evaluating the extent of fermentation and establishing the differences between processing methods. The beans were processed by the dry method after being mechanically depulped immediately after harvest or after a 12 h resting period in a dry pile or immersed in water. Seven bioactive amines were quantified: putrescine, spermine, spermidine, serotonin, cadaverine, histamine, and tyramine, with global amounts ranging from 71.8 to 80.3 mg/kg. The levels of spermine and spermidine were lower in the unripe depulped coffee than in the natural coffee. The specific conditions of dry and wet processing also influenced cadaverine levels, and histamine was reduced in unripe depulped coffee. A resting period of 12 h does not induce significant alteration on the beans and can be improved if performed in water. These results confirm that peeling immature coffee can decrease fermentation processes while providing more uniform drying, thus reducing the number of defects and potentially increasing beverage quality. PMID- 22429055 TI - Three requirements for justifying an educational neuroscience. AB - BACKGROUND: Over the past quarter century, efforts to bridge between research in the neurosciences and research, theory, and practice in education have grown from a mere hope to noteworthy scholarly sophistication. Many dedicated educational researchers have developed the secondary expertise in the necessary neurosciences and related fields to generate both empirical research and theoretical syntheses of noteworthy promise. Nonetheless, thoughtful and critical scholars in education have expressed concern about both the intellectual coherence and ethical dangers of this new area. It is still an open question whether educational neuroscience is for some time yet to remain only a formative study area for adventurous scholars or is already a fully fledged field of educational scholarship. AIMS: In this paper, I suggest that to be a worthy field of educational research, educational neuroscience will need to address three issues: intellectual coherence, mutually informing and respected scholarly expertise, and an ethical commitment to the moral implications and obligations shared within educational research generally. I shall set forth some examples of lapses in this regard, focusing primarily on work on reading development, as that is my area of expertise, and make recommendations for due diligence. Arguments. First, intellectual coherence requires both precision in definition of technical terms (so that diverse scholars and professionals may communicate findings and insights consistently across fields), and precision in the logical warrants by which educational implications are drawn from empirical data from the neurosciences. Both needs are facilitated by careful attention to categorical boundary and avoidance of category error. Second, educational neuroscientists require focused and broad expertise in both the neurosciences and educational scholarship on teaching and learning in classrooms (and/or ancillary fields). If history is our guide, neuroscience implications for practice will prove unlikely in practice without expertise on practice. Additionally, respect for the expertise of others in this hybrid and necessarily collaborative enterprise is required. Third, educational neuroscience must take seriously the heightened moral and ethical concerns and commitments of educational professionals generally and educational researchers particularly. This means keeping a vigilant eye towards preserving the integrity of empirical and theoretical findings against rhetorical misuse by educational marketers, policy makers, and polemicists targeting the general public. CONCLUSIONS: I conclude that educational neuroscience is more than a hybrid patchwork of individual interests constituting a study area, and is perhaps ready to stand as a legitimate field of educational inquiry. It will not be accepted as such, however, nor should it be, unless the need to demonstrate a capacity for consistent intellectual coherence, scholarly expertise, and ethical commitment is met. PMID- 22429056 TI - Mathematical and cognitive predictors of the development of mathematics. PMID- 22429057 TI - Longitudinal study of low and high achievers in early mathematics. AB - BACKGROUND: Longitudinal studies allow us to identify, which specific maths skills are weak in young children, and whether there is a continuing weakness in these areas throughout their school years. AIMS: This 2-year study investigated whether certain socio-demographic variables affect early mathematical competency in children aged 5-7 years. SAMPLE: A randomly selected sample of 127 students (64 female; 63 male) participated. At the start of the study, the students were approximately 5 years old (M= 5.2; SD= 0.28; range = 4.5-5.8). METHOD: The students were assessed using the Early Numeracy Test and then allocated to a high (n= 26), middle (n= 76), or low (n= 25) achievers group. The same children were assessed again with the Early Numeracy Test at 6 and 7 years old, respectively. Eight socio-demographic characteristics were also evaluated: family model, education of the parent(s), job of the parent(s), number of family members, birth order, number of computers at home, frequency of teacher visits, and hours watching television. RESULTS: Early Numeracy Test scores were more consistent for the high-achievers group than for the low-achievers group. Approximately 5.5% of low achievers obtained low scores throughout the study. A link between specific socio-demographic characteristics and early achievement in mathematics was only found for number of computers at home. CONCLUSIONS: The level of mathematical ability among students aged 5-7 years remains relatively stable regardless of the initial level of achievement. However, early screening for mathematics learning disabilities could be useful in helping low-achieving students overcome learning obstacles. PMID- 22429058 TI - Domain-specific and domain-general precursors of mathematical achievement: a longitudinal study from kindergarten to first grade. AB - BACKGROUND: Many contributing factors, both domain specific and domain general, influence children's performance in school achievement. AIMS: This research aims to verify the importance of kindergarten measures of cognitive abilities and numerical competence in the role of predicting mathematical school achievement at the end of first grade. SAMPLE AND METHODS: A total of 70 children (38 females and 32 males) took part in the study. We tested the children at the beginning of their last year of kindergarten (time 1) on the following cognitive abilities: IQ, phonology, counting skills, verbal short-term memory, visuo-spatial short term memory, working memory, and processing speed. Then, we tested the same children at end of their last year of kindergarten (time 2) on a measure of numerical competence and at the end of their first year of primary school (time 3) on a test of math achievement. RESULTS: Path analysis models revealed the direct influence of working memory and processing speed on predicting numerical competence in pre-schoolers and the influence of processing speed and verbal IQ on predicting math achievement in first graders. Moreover, this study found a direct link between numerical competence and math achievement. CONCLUSIONS: Both domain-specific and domain-general factors contribute to determining math achievement at the end of first grade. PMID- 22429059 TI - The cognitive underpinnings of emerging mathematical skills: executive functioning, patterns, numeracy, and arithmetic. AB - BACKGROUND: Exposure to mathematical pattern tasks is often deemed important for developing children's algebraic thinking skills. Yet, there is a dearth of evidence on the cognitive underpinnings of pattern tasks and how early competencies on these tasks are related to later development. AIMS: We examined the domain-specific and domain-general determinants of performances on pattern tasks by using (a) a standardized test of numerical and arithmetic proficiency and (b) measures of executive functioning, respectively. SAMPLE: Participants were 163 6-year-olds enrolled in primary schools that typically serve families from low to middle socioeconomic backgrounds. METHOD: Children were administered a battery of executive functioning (inhibitory, switching, updating), numerical and arithmetic proficiency (the Numerical Operations task from the Wechsler Individual Achievement Test-II), and three types of pattern tasks. RESULTS: Contrary to findings from the adult literature, we found all the executive functioning measures coalesced into two factors: updating and an inhibition/switch factor. Only the updating factor predicted performances on the pattern tasks. Although performance on the pattern tasks were correlated with numerical and arithmetic proficiency, findings from structural equation modelling showed that there were no direct or independent relationships between them. CONCLUSIONS: The findings suggest that the bivariate relationships between pattern, numeracy, and arithmetic tasks are likely due to their shared demands on updating resources. Unlike older children, these findings suggest that for 6-year olds, better numerical and arithmetic proficiency, without accompanying advantages in updating capacities, will no more likely lead to better performance on the pattern tasks. PMID- 22429060 TI - The development of executive functions and early mathematics: a dynamic relationship. AB - BACKGROUND: The relationship between executive functions and mathematical skills has been studied extensively, but results are inconclusive, and how this relationship evolves longitudinally is largely unknown. AIM: The aim was to investigate the factor structure of executive functions in inhibition, shifting, and updating; the longitudinal development of executive functions and mathematics; and the relation between them. SAMPLE: A total of 211 children in grade 2 (7-8 years old) from 10 schools in the Netherlands. METHOD: Children were followed in grade 1 and 2 of primary education. Executive functions and mathematics were measured four times. The test battery contained multiple tasks for each executive function: Animal stroop, local global, and Simon task for inhibition; Animal Shifting, Trail Making Test in Colours, and Sorting Task for shifting; and Digit Span Backwards, Odd One Out, and Keep Track for updating. The factor structure of executive functions was assessed and relations with mathematics were investigated using growth modelling. RESULTS: Confirmatory factor analysis (CFA) showed that inhibition and shifting could not be distinguished from each other. Updating was a separate factor, and its development was strongly related to mathematical development while inhibition and shifting did not predict mathematics in the presence of the updating factor. CONCLUSIONS: The strong relationship between updating and mathematics suggest that updating skills play a key role in the maths learning process. This makes updating a promising target for future intervention studies. PMID- 22429061 TI - Cognitive correlates of mathematical achievement in children with cerebral palsy and typically developing children. AB - BACKGROUND: Remarkably few studies have investigated the nature and origin of learning difficulties in children with cerebral palsy (CP). AIMS: To investigate math achievement in terms of word-problem solving ability in children with CP and controls. Because of the potential importance of reading for word-problem solving, we investigated reading as well. SAMPLE: Children with CP attending either special (n= 41) or mainstream schools (n= 16) and a control group of typically developing children in mainstream schools (n= 16). METHOD: Group differences in third grade math and reading, controlled for IQ, were tested with analyses of co-variance (ANCOVAs). Hierarchical regression was used to investigate cognitive correlates of third grade math and reading. Predictors included verbal and non-verbal IQ measured in first grade, components of working memory (WM) and executive function (EF) measured in second grade, and arithmetic fact fluency and reading measured in third grade. RESULTS: Children with CP in special schools performed significantly worse than their peers on word-problem solving and reading. There was a trend towards worse performance in children with CP in mainstream schools compared to typically developing children. CONCLUSIONS: Impairments of non-verbal IQ and WM updating predicted future difficulties in both word-problem solving and reading. Impairments of visuospatial sketchpad and inhibition predicted future word-problem, but not reading difficulty. Conversely, deficits of phonological loop predicted reading but not word-problem difficulty. Concurrent arithmetic fact fluency and reading ability were both important for word-problem solving ability. These results could potentially help to predict which children are likely to develop specific learning difficulties, facilitating early intervention. PMID- 22429062 TI - The relative importance of two different mathematical abilities to mathematical achievement. AB - BACKGROUND: Two distinct abilities, mathematical reasoning and arithmetic skill, might make separate and specific contributions to mathematical achievement. However, there is little evidence to inform theory and educational practice on this matter. AIMS: The aims of this study were (1) to assess whether mathematical reasoning and arithmetic make independent contributions to the longitudinal prediction of mathematical achievement over 5 years and (2) to test the specificity of this prediction. SAMPLE: Data from Avon Longitudinal Study of Parents and Children (ALSPAC) were available on 2,579 participants for analyses of KS2 achievement and on 1,680 for the analyses of KS3 achievement. METHOD: Hierarchical regression analyses were used to assess the independence and specificity of the contribution of mathematical reasoning and arithmetic skill to the prediction of achievement in KS2 and KS3 mathematics, science, and English. Age, intelligence, and working memory (WM) were controls in these analyses. RESULTS: Mathematical reasoning and arithmetic did make independent contributions to the prediction of mathematical achievement; mathematical reasoning was by far the stronger predictor of the two. These predictions were specific in so far as these measures were more strongly related to mathematics than to science or English. Intelligence and WM were non-specific predictors; intelligence contributed more to the prediction of science than of maths, and WM predicted maths and English equally well. CONCLUSIONS: There is clear justification for making a distinction between mathematical reasoning and arithmetic skills. The implication is that schools must plan explicitly to improve mathematical reasoning as well as arithmetic skills. PMID- 22429063 TI - Cognitive correlates of performance in advanced mathematics. AB - BACKGROUND: Much research has been devoted to understanding cognitive correlates of elementary mathematics performance, but little such research has been done for advanced mathematics (e.g., modern algebra, statistics, and mathematical logic). AIMS: To promote mathematical knowledge among college students, it is necessary to understand what factors (including cognitive factors) are important for acquiring advanced mathematics. SAMPLES: We recruited 80 undergraduates from four universities in Beijing. METHODS: The current study investigated the associations between students' performance on a test of advanced mathematics and a battery of 17 cognitive tasks on basic numerical processing, complex numerical processing, spatial abilities, language abilities, and general cognitive processing. RESULTS: The results showed that spatial abilities were significantly correlated with performance in advanced mathematics after controlling for other factors. In addition, certain language abilities (i.e., comprehension of words and sentences) also made unique contributions. In contrast, basic numerical processing and computation were generally not correlated with performance in advanced mathematics. CONCLUSIONS: Results suggest that spatial abilities and language comprehension, but not basic numerical processing, may play an important role in advanced mathematics. These results are discussed in terms of their theoretical significance and practical implications. PMID- 22429065 TI - Patient empowerment and optimal glycemic control. AB - OBJECTIVE: This review updates the clinician on strategies of insulin use and educational approaches to empower their patients to use insulin correctly in self management treatment plans. DESIGN AND METHODS: A PubMed literature search was conducted to identify peer-reviewed clinical trials published in English in the last 10 years. Search terms used were 'glycemic control', 'insulin', and 'type 2 diabetes'. An additional search to include the terms 'patient empowerment' and 'self-management' was also conducted. Some articles relevant to this review may not have been identified using these terms. Oral antidiabetes agents in conjunction with insulin are not addressed. RESULTS: A total of 562 articles were initially identified. Papers that did not provide data pertinent to the efficacy and tolerance of insulin types for treatment of type 2 diabetes mellitus (T2DM) were excluded. Based on methodology, results, and clinical implications, 12 clinical trials were included for discussion in this review. CONCLUSIONS: Patients with T2DM who are empowered with knowledge about their disease and treatment can take an active role in their diabetes care, and therefore, are more likely to achieve blood glucose and A1C goals, which can slow progression of their disease and the onset of complications. Although concentrating solely on medical information and physiological facts does not guarantee patient empowerment and self-management, educational strategies such as interactive teaching, problem solving and individualized education can have a positive impact. Insulin titration algorithms can empower patients to manage their therapy, and such algorithms are simple to use for patients treated with insulin analogs. As patients with T2DM become empowered by knowledge and gain more control of their disease, their physicians must then serve as their advisors rather than as their directors or prescribers. PMID- 22429066 TI - Short-term (2-week) effects of discontinuing milnacipran in patients with fibromyalgia. AB - OBJECTIVE: To examine the effects of abruptly withdrawing milnacipran during the 2-week discontinuation phase of a study in which FM patients had received 12 weeks of stable-dose treatment with milnacipran at 100 mg/day. RESEARCH DESIGN AND METHODS: The effects of withdrawing milnacipran were evaluated prospectively over a 2-week period (Weeks 12 to 14) using a randomized, placebo-controlled withdrawal design. Patients who had originally received milnacipran 100 mg/d for 12 weeks were re-randomized to continue milnacipran (n = 178) or switch directly to placebo (n = 178); patients originally receiving placebo continued placebo (n = 359). CLINICAL TRIAL REGISTRATION: Clinicalstrials.gov (NCT00314249). MAIN OUTCOME MEASURES: Loss of efficacy was evaluated by mean changes in pain and functional measures and by percentage of composite responders, defined as patients with simultaneous improvements in pain, global status, and physical functioning. Newly emergent adverse events and changes in vital signs were also recorded. RESULTS: Within 2 weeks,patients switched from milnacipran to placebo had greater mean worsening in pain, functioning, and global status measures when compared with patients continuing treatment. In addition, significantly fewer composite responders were found in patients who discontinued active treatment than in patients who continued receiving milnacipran (22.0% vs 32.3%, p < 0.05). Incidences of newly emergent adverse events were 16.3% and 18.0% in patients discontinuing and continuing treatment, respectively. Mean vital sign changes decreased or returned to baseline within 2 weeks of discontinuation. CONCLUSIONS: Patients discontinuing milnacipran experienced worsening in multiple efficacy parameters within 2 weeks. Vital sign changes observed with milnacipran during the 12-week stable-dose period decreased or returned to baseline values within 2 weeks after discontinuation of treatment. No new safety concerns were found during this discontinuation period with milnacipran. PMID- 22429067 TI - Effect of dosing frequency on chronic cardiovascular disease medication adherence. AB - BACKGROUND: Many cardiovascular diseases (CVDs) require patients to take one or more long term medications, often administered multiple times a day. We sought to determine the effect of chronic CVD medication dosing frequency on medication adherence. METHODS: A search of Medline and Embase from 1986 to December 2011 was performed. Included studies used a prospective design, assessed adults with chronic CVDs, evaluated scheduled oral medications administered one to four times daily, and measured adherence for >=1 month using an electronic monitoring device. Mixed linear model meta-regression was used to determine how dosing frequency affected adherence using three definitions of increasing strictness: taking, regimen and timing adherence. RESULTS: A total of 29 studies, comprising 41, 29, and 27 dosing frequency arms for the taking, regimen and timing adherence definitions were included. Crude pooled adherence estimates were highest when the lenient taking definition was assessed (range for dosing frequencies: 80.1% 93.1%), and lowest when the strictest timing definition was assessed (range: 57.1%-76.3%). Upon meta-regression, the adjusted weighted mean percentage adherence for twice and three times daily dosing regimens (no studies evaluated four times daily regimens), were 6.9% and 13.7% lower than once daily regimens for the taking, 14.0% and 27.5% lower for the regimen, and 22.9% and 30.4% lower for the timing adherence definition (p < 0.01 for all). LIMITATIONS: The presence of residual confounding and publication bias cannot be ruled out. CONCLUSION: Patients appear to be more adherent with once daily dosing compared with more frequently scheduled chronic CVD medication regimens. This finding is magnified when more stringent definitions of adherence are used. PMID- 22429068 TI - Bimolecular rate constant and product branching ratio measurements for the reaction of C2H with ethene and propene at 79 K. AB - The reactions of the ethynyl radical (C(2)H) with ethene (C(2)H(4)) and propene (C(3)H(6)) are studied under low temperature conditions (79 K) in a pulsed Laval nozzle apparatus. Ethynyl radicals are formed by 193 nm photolysis of acetylene (C(2)H(2)) and the reactions are studied in nitrogen as a carrier gas. Reaction products are sampled and subsequently photoionized by the tunable vacuum ultraviolet radiation of the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory. The product ions are detected mass selectively and time resolved by a quadrupole mass spectrometer. Bimolecular rate coefficients are determined under pseudo-first-order conditions, yielding values in good agreement with previous measurements. Photoionization spectra are measured by scanning the ALS photon energy while detecting the ionized reaction products. Analysis of the photoionization spectra yields-for the first time-low temperature isomer resolved product branching ratios. The reaction between C(2)H and ethene is found to proceed by H-loss and yields 100% vinylacetylene. The reaction between C(2)H and propene results in (85 +/- 10)% C(4)H(4) (m/z = 52) via CH(3)-loss and (15 +/- 10)% C(5)H(6) (m/z = 66) by H-loss. The C(4)H(4) channel is found to consist of 100% vinylacetylene. For the C(5)H(6) channel, analysis of the photoionization spectrum reveals that (62 +/- 16)% is in the form of 4-penten-1-yne, (27 +/- 8)% is in the form of cis- and trans-3-penten-1-yne and (11 +/- 10)% is in the form of 2-methyl-1-buten-3-yne. PMID- 22429069 TI - Broad-band near-infrared plasmonic nanoantennas for higher harmonic generation. AB - We propose a broad-band near-infrared trapezoidal plasmonic nanoantenna, analyze it numerically using finite integration and difference time domain techniques, and explain qualitatively its performance via a multidipolar scenario as well as a conformal transformation. The plasmonic nanoantenna reported here intercepts the incoming light as if it were of cross-sectional area larger than double its actual physical size for a 1500 nm bandwidth expanding from the near-infrared to the visible spectrum. Within this bandwidth, it also confines the incoming light to its center with more than 1 order of magnitude field enhancement. This wide band operation is achieved due to the overlapping of the different dipole resonances excited across the nanoantenna. We further demonstrate that the broad band field enhancement leads to efficient third harmonic generation in a simplified wire trapezoidal geometry when a Kerr medium is introduced, due to the lightning rod effect at the fundamental and the Purcell effect at the induced third harmonic. PMID- 22429070 TI - Synthesis of Ag nanobars in the presence of single-crystal seeds and a bromide compound, and their surface-enhanced Raman scattering (SERS) properties. AB - This Article describes the synthesis of Ag nanobars with different aspect ratios using a seed-mediated method and evaluation of their use for surface-enhanced Raman scattering (SERS). The formation of Ag nanobars was found to critically depend on the introduction of a bromide compound into the reaction system, with ionic salts being more effective than covalent molecules. We examined single crystal seeds with both spherical and cubic shapes and found that Ag nanobars grown from spherical seeds had much higher aspect ratios than those grown from cubic seeds. The typical product of a synthesis contained nanocrystals with three different morphologies: nanocubes, nanobars with a square cross section, and nanobars with a rectangular cross section. Their formation can be attributed to the difference in growth rates along the three orthogonal <100> directions. The SERS enhancement factor of the Ag nanobar was found to depend on its aspect ratio, its orientation relative to the laser polarization, and the wavelength of excitation. PMID- 22429071 TI - Obstetrical situations with a high risk of anal sphincter laceration in vacuum assisted deliveries. AB - OBJECTIVE: To determine risk factors for anal sphincter laceration and define situations with a high risk for such trauma in vacuum-assisted deliveries. DESIGN: Retrospective observational study of 1961 vacuum-assisted deliveries over a period of 5 years. SETTING: French university hospital. POPULATION: All women who delivered with vacuum assistance. METHODS: Third- and fourth-degree perineal tears were reviewed. The factors studied through univariate and multivariate logistic regression were the mother's age, parity, history of assisted delivery, cesarean section, gestational age, uterine fundal height, duration of the second stage of labor, head position at expulsion, epidural anesthesia, episiotomy, biparietal diameter and birthweight. MAIN OUTCOME MEASURES: Third- and fourth degree perineal tears. RESULTS: There were 1.9% third-degree and no fourth-degree perineal tears. Risk factors identified were occipito-posterior position (odds ratio 4.7, p < 0.001), biparietal diameter (odds ratio 2.0 for each 5 mm increase, p= 0.004), duration of second stage (only significant when parity was >= 1; odds ratio 1.3 for each 10 min increase, p= 0.004) and nulliparity (decreasing effect according to duration of the second stage). The patterns of the association between these factors and the risk of perineal tears were different for nulli- and multiparous women. CONCLUSIONS: In a targeted population of women having vacuum-assisted deliveries, the association of specific risk factors allows clinicians to identify women who are at high risk of anal sphincter laceration. PMID- 22429072 TI - DNA/amphiphilic block copolymer nanospheres reduce asthmatic response in a mouse model of allergic asthma. AB - Asthma is a chronic, inflammatory, respiratory disease caused by an abnormal reactivity against allergens. The most promising treatments for asthma are based on specific immunotherapies, but they lack efficiency and can induce deleterious side effects. Among new modalities of immunotherapy currently in development, DNA vaccination presents a promising approach, as it enables targeted immunotherapy in association with reduced allergenicity. We have developed an innovative, DNA based vaccine against Dermatophagoides farinae 1 allergen (Der f 1), one of the allergens most commonly encountered by asthma patients in Europe. Intramuscular administration of a Der f 1-encoding plasmid formulated with the block copolymer 704 in healthy mice induced a strong humoral and cellular response with a pro helper T cell type 1 bias. Administration of the same formulation in asthmatic mice, according to an early vaccination protocol, led to a reduction of airway hyperresponsiveness and a significant decrease in the level of inflammatory cytokines in the bronchoalveolar lavage of Der f 1-vaccinated mice. PMID- 22429073 TI - Imaging language networks before and after anterior temporal lobe resection: results of a longitudinal fMRI study. AB - PURPOSE: Anterior temporal lobe resection (ATLR) controls seizures in up to 70% of patients with intractable temporal lobe epilepsy (TLE) but, in the language dominant hemisphere, may impair language function, particularly naming. Functional reorganization can occur within the ipsilateral and contralateral hemispheres. We investigated reorganization of language in left-hemisphere dominant patients before and after ATLR; whether preoperative functional magnetic resonance imaging (fMRI) predicts postoperative naming decline; and efficiency of postoperative language networks. METHODS: We studied 44 patients with TLE due to unilateral hippocampal sclerosis (24 left) on a 3T GE-MRI scanner. All subjects performed language fMRI and neuropsychological testing preoperatively and again 4 months after left or right ATLR. KEY FINDINGS: Postoperatively, individuals with left TLE had greater bilateral middle/inferior frontal fMRI activation and stronger functional connectivity from the left inferior/middle frontal gyri to the contralateral frontal lobe than preoperatively, and this was not observed in individuals with right TLE. Preoperatively, in left and right TLE, better naming correlated with greater preoperative left hippocampal and left frontal activation for verbal fluency (VF). In left TLE, stronger preoperative left middle frontal activation for VF was predictive of greater decline in naming after ATLR. Postoperatively, in left TLE with clinically significant naming decline, greater right middle frontal VF activation correlated with better postoperative naming. In patients without postoperative naming decline, better naming correlated with greater activation in the remaining left posterior hippocampus. In right TLE, naming ability correlated with left hippocampal and left and right frontal VF activation postoperatively. SIGNIFICANCE: In left TLE, early postoperative reorganization to the contralateral frontal lobe suggests multiple systems support language function. Postoperatively, ipsilateral recruitment involving the posterior hippocampal remnant is important for maintaining language, and reorganization to the contralateral hemisphere is less effective. Preoperative left middle frontal activation for VF was predictive of naming decline in left TLE after ATLR. PMID- 22429074 TI - Pharmacological treatment and adherence one week prior to acute psychiatric admissions. AB - BACKGROUND AND AIMS: To describe use of and adherence to psychotropic medication 1 week prior to acute admission to a psychiatric inpatient department. METHODS: All acute inpatient admissions to a department serving a catchment area were included. RESULTS AND CONCLUSIONS: Of the 227 admissions, 158 were prescribed psychotropic medication and 129 of the 158 had taken at least 75% of the prescribed dose. Among 59 patients with affective disorders, 23 were not prescribed medication prior to admission and two refused medication, while the rest were adherent. CONCLUSION: The high adherence to medication 1 week prior to admission might be related to increased experience of serious symptoms. Lack of opportunity to receive pharmacological treatment is a major problem. PMID- 22429075 TI - Inorganic polyphosphate stimulates cartilage tissue formation. AB - Clinical utilization of tissue-engineered cartilage constructs has been limited by their inferior mechanical properties compared to native articular cartilage. A number of strategies have been investigated to increase the accumulation of major extracellular matrix components within in vitro-formed cartilage, including the administration of growth factors and mechanical stimulation. In this study, the anabolic effect of inorganic polyphosphates, a linear polymer of orthophosphate residues linked by phosphoanhydride bonds, was demonstrated in both chondrocyte cultures and native articular cartilage cultured ex vivo. Compared to untreated controls, polyphosphate treatment of three-dimensional primary chondrocyte cultures induced increased glycosaminoglycan and collagen accumulation in a concentration- and chain length-dependent manner. This effect was transient, because chondrocytes express exopolyphosphatases that hydrolyze polyphosphate. The anabolic effect of polyphosphates was accompanied by a lower rate of DNA increase within the chondrocyte cultures treated with inorganic polyphosphate. Inorganic polyphosphate enhances cartilage matrix accumulation and is a promising approach to improve the quality of tissue-engineered cartilage constructs. PMID- 22429076 TI - Enhancing maternal depression recognition in health care settings: a review of strategies to improve detection, reduce barriers, and reach mothers in need. AB - Maternal depression is a major public health concern in the United States affecting mothers, children, and families. Many mothers experience depression, and exposure to maternal depression can put children at increased risk for psychopathology and poor psychosocial development. Early recognition of maternal depression is a critical step in promoting healthy development and preventing adverse outcomes in children and families. In this review, we examine some of the major barriers that mothers face in seeking help for depression; discuss optimal settings in which to implement maternal depression screening; review available depression screening tools for identifying mothers in need of care; discuss steps providers can take after screening; examine barriers to screening; and present information about promising initiatives developed to address these barriers. PMID- 22429077 TI - Toward a new understanding of risk perception among young female BRCA1/2 "previvors". AB - The quantitative risk of cancer among BRCA1/2 gene mutation carriers is generally well-understood, and can be communicated clearly to potential and known mutation carriers during the genetic risk assessment, education, and testing process. The extent to which individual mutation carriers feel vulnerable to cancer is a more complex dynamic with a powerful effect on risk-management decision-making; however, these decisions are not the products of straightforward personal assessment of one's quantitative probability of being diagnosed with cancer. We undertook this National Cancer Institute study to broaden understanding of the lived experiences of women who learn early in the life course that they carry a BRCA1/2 mutation. Our data indicate that the relationship between perceived risk and risk-management decisions is not direct, that is, several nononcologic components of risk are also integral to women's management decision-making. High risk women commonly utilize self-perceived cancer risk to shape their decision making and communication about various tasks of young adulthood, including differentiation from family of origin, establishing a permanent couple relationship, and family formation. Risk-management is also an important domain in which they strive to take control of their lives by actively participating in management choices. By understanding how these complex dynamics fit together, care providers can better guide, counsel, and support high-risk women as they struggle to balance legitimate risk-reduction needs with the desire to live a normal life. Here we present data from our qualitative research to aid in this effort. PMID- 22429078 TI - Paternal involvement in pediatric Type 1 diabetes: fathers' and mothers' psychological functioning and disease management. AB - Psychological functioning in fathers of children with Type 1 diabetes has received relatively little attention compared to mothers. This study examined fathers' perceived involvement in their children's diabetes care as it related to mothers' and fathers' pediatric parenting stress, depression, anxiety, marital satisfaction, and sleep, and to their children's diabetes regimen adherence and glycemic control. Eighty-two mothers and 43 fathers completed questionnaires. Multivariate linear regressions were conducted separately for mothers and fathers to determine the relationships between the perceived amount and the perceived helpfulness of father involvement in child diabetes care on parental psychosocial functioning and child diabetes control. Maternal perceptions of father helpfulness and amount of involvement in illness care were related to improved marital satisfaction and fewer depressive symptoms in mothers. In fathers, perception of their own amount of involvement was related to increased pediatric parenting stress and anxiety. Better child regimen adherence was associated with maternal perceptions of father helpfulness but not the amount of their involvement, while paternal perceptions of their own helpfulness were related to poorer glycemic control. These findings suggest that fathers and mothers may react differently to their roles in childhood illness and that perceptions of their involvement may be differently associated with children's glycemic control and regimen adherence. PMID- 22429079 TI - Collaboration in the presence of an electronic health record. AB - Recent laws in the United States incent healthcare practices to adopt electronic health records (EHRs). While there is extensive research related to EHRs generally, there is a dearth of EHR research specific to collaborative care settings. This study reports responses from 101 collaborative care offices who completed a 13-question online survey. The mixed-methods analysis provides insights as to the satisfaction, obstacles, and solutions to interdisciplinary collaboration in the presence of an EHR. Respondents reported highest satisfaction with medical billing, interdisciplinary communication, and scheduling. Satisfaction was lower as it relates to time consumption, difficult learning curve, creation of appointment notes, and health registries. This research reveals varied and conflicting approaches to addressing confidentiality and HIPAA within the EHR. Recommendations for improving EHR to better support collaborative care include the addition of modules common in mental health specific EHR, enhanced tracking of mental health outcomes, templates for joint appointments, and improvements in population-based registry functions. PMID- 22429083 TI - Integrating the common risk factor approach into a social determinants framework. AB - The common risk factor approach (CRFA) has been highly influential in integrating oral health into general health improvement strategies. However, dental policy makers and oral health promoters have interpreted the CRFA too narrowly. They have focussed too heavily on the common behavioural risks, rather than on the broader shared social determinants of chronic diseases. A behavioural preventive approach alone will have minimal impact in tackling oral health inequalities and indeed may widen inequalities across the population. Based on recent WHO policy recommendations, this study presents the case for updating the CRFA in accordance with the social determinants agenda. The theoretical basis for a social determinants framework for oral health inequalities is presented, and implications for oral health improvement strategies are highlighted. Future action to address oral health inequalities in middle- and high-income countries requires a radical policy reorientation towards tackling the structural and environmental determinants of chronic diseases. In more equal and fairer societies, all sections of the social hierarchy experience better health and social well-being. PMID- 22429084 TI - Mental workload and stress perceived by novice operators in the laparoscopic and robotic minimally invasive surgical interfaces. AB - BACKGROUND AND PURPOSE: High levels of mental workload and stress are experienced by surgeons in the laparoscopic environment. The da Vinci((r)) surgical robot was developed to provide surgeons a more user-friendly interface while maintaining the patient benefits associated with laparoscopy. This study examined whether the da Vinci robot reduces mental workload and stress in novice medical students. A detailed understanding of trainees' mental workload and mental stress experiences can aid in the development of training programs that are aimed at facilitating the acquisition of laparoscopic and robotic surgery skills. MATERIALS AND METHODS: Fifteen novice first-year medical students performed a standard peg transfer task at a laparoscopic simulator and the da Vinci Surgical System. Mental workload and stress were assessed with the Multiple Resources Questionnaire (MRQ) and the Dundee Stress State Questionnaire (DSSQ), respectively. RESULTS: Students' mental workload profiles were identical with the two surgical systems and replicated previous MRQ results reported with the laparoscopic system showing high levels of workload. Students experienced a better stress profile with the robotic system, however, when compared wih the laparoscopic system. CONCLUSION: Our study shows that novice medical students perceive less stress when working with the robotic surgical interface than with the laparoscopic surgery interface. The MRQ and the DSSQ are valuable tools for identifying mental workload and mental stress in the laparoscopic and robotic surgery environments. This information may be useful for facilitating the acquisition of laparoscopic and robotic surgery skills. PMID- 22429085 TI - Effect of maturity stage and storage on flavor compounds and sensory description of berrycactus (Myrtillocactus geometrizans). AB - Descriptive sensory analysis combined with a chemical analysis, provided insight regarding sensory significance for a better understanding of berrycactus' flavor. This study was based on the volatile components derived from the gas chromatography-olfactometry (GC-O) analysis. Four different ripening stages were used for the experiments: unripe, red, transition, and over-ripe. Besides red and transition stages were stored in sealed plastic bags for 7 d at 5 degrees C as an additional treatment in order to establish comparisons with fresh samples. GC O analysis was performed following OSME (time-intensity) method. Moreover, chemical characterization was achieved through GC-MS analysis, each compound was tentatively identified by comparing its mass spectra with the spectra from the library NIST02, by its aroma notes and Kovats Index. The aroma descriptors found were: caramel, fruity, acetic acid, fresh, citrus, floral, and phenolics. Nine volatile compounds are among the most important in flavor of berrycactus: furfural, 5-methyl-2-furancarboxaldehyde, 2(5H)-furanone, 5-acetoxymethyl-2 furaldehyde, 2-cyclohexen-1-ol, octanoic acid ethyl ester, decanoic acid ethyl ester, octanoic acid, and phenylethyl alcohol. To better reflect the real responses of these compounds, the regression analysis of concentrations to ripening stages were performed. The 2,3-dihydro-3,5-dihydroxy-6-methyl-(4H)-pyran 4-one was found in berrycactus, it has been reported in chemical profile of other berries as a product of heat-induced reactions, however, this compound has no aroma activity. The data suggest that both furanones and esters contribute to the aroma of berrycactus. On the other hand, solid phase microextraction was found to be more useful in detecting esters and acids whereas solvent extraction was more effective in detecting furanones and ketones. PRACTICAL APPLICATION: This information could contribute to setting up favorable processing conditions; in order to retain the best sensory characteristics of berrycactus along with functional properties that would enhance commercialization and exploitation of this fruit and to promote berrycactus cultivation programs. PMID- 22429086 TI - Detection of wall motion abnormalities during ambulatory echocardiography using a novel ultrasound transducer. AB - BACKGROUND: This investigation was designed to determine whether transient wall motion abnormalities due to myocardial ischemia induced by walking could be detected by ambulatory echocardiography. METHODS: Two groups were studied. Group 1 consisted of 10 males (mean age 34 years) who had no symptoms of angina. Group 2 consisted of eight selected patients (mean 61 years) with angina and angiographic evidence of coronary artery disease. The 2.5 MHz transducer is spherical in its distal part and mounted in an external housing to permit steering in 360 degrees . The external housing was attached to the chest wall using an adhesive patch. The transducer was placed in the 3rd or 4th intercostal space at the left sternal border to permit imaging of the left ventricle (LV) in its short axis and attached to the chest wall. The transducer was interfaced with an Acuson Cypress echocardiography system which was placed on a mobile cart. To permit portability, the echocardiography system was powered by a capacitor (UPS device). The subjects were asked to walk along the corridor as fast as possible for 10 minutes or until the onset of symptoms while pushing the cart. The short axis of the LV was displayed on a monitor and recorded on optical disks. RESULTS: The heart rate, systolic blood pressure (SBP), and double product of Group 1 at rest were 77 +/- 3 beats/min, 119 +/- 13 mmHg, and 9,150 +/- 868, respectively, and increased to 106 +/- 8 beats/min, 129 +/- 15 mmHg, and 1,3793 +/- 2,176 with walking. The baseline heart rate, SBP, and double product were 71 +/- 12 beats/min, 130 +/- 14 mmHg, and 8,555 +/- 1,928 in Group 2 and increased to 94 +/ 14 beats/min, 135 +/- 20 mmHg, and 12,480 +/- 3,830 with walking. All patients in Group 1 had normal wall motion at rest and during walking. Patients in Group 2 had normal wall motion during rest and new wall motion abnormalities were noted in all subjects during walking (anterior septum and/or anterolateral wall in seven, posterolateral wall in one). The wall motion abnormalities resolved shortly after discontinuation of walking. CONCLUSION: Ambulatory echocardiography permitted the detection of transient wall motion abnormalities in patients with coronary artery disease (CAD). This technique could be potentially useful in evaluating selected patients for myocardial ischemia. PMID- 22429087 TI - Interactions between immune system and mesenchymal stem cells in dental pulp and periapical tissues. AB - The recent isolation and characterization of mesenchymal stem cells (MSCs) in dental tissues constitutes a major step forward in the development of new treatment strategies. MSCs are essential for dental pulp repair and the success of regenerative endodontic procedures. It is important to understand that immune cells and cytokines can affect stem cell function, which can impact their healing potential. On the other hand, stem cells are immunoprivileged and have the ability to modulate immune and inflammatory responses, which can be utilized to improve treatments outcome. This review addresses both aspects of this interaction and suggests that any change on both sides can tip the balance in favour of either persistence of inflammation or healing. Finally, the therapeutic relevance of the interaction between MSCs and immune system relative to current treatments is discussed, and future research and treatment perspectives are suggested. PMID- 22429088 TI - Role of denaturation in maltose binding protein translocation dynamics. AB - We present a computational study on the driven transport of the Maltose Binding Protein (MBP) across nanochannels in the framework of coarse-grained modeling. The work is motivated by recent experiments on voltage-driven transport of MBP across nanopores exploring the influence of denaturation on translocation pathways. Our simplified approach allows a statistical mechanical interpretation of the process which may be convenient also to the experiments. Specifically, we identify and characterize short and long channel blockades, associated to the translocation of denaturated and folded MBP conformations, respectively. We show that long blockades are related to long stall events where MBP undergoes specific and reproducible structural rearrangements. To clarify the origin of the stalls, the stick-and-slip translocation is compared to mechanical unfolding pathways obtained via steered molecular dynamics. This comparison clearly shows the translocation pathway to significantly differ from free-space unfolding dynamics and strongly suggests that stalling events are preferentially determined by the MBP regions with higher density of long-range native interactions. This result might constitute a possible criterion to predict a priori some statistical features of protein translocation from the structural analysis. PMID- 22429089 TI - Angiotensin II and oxidative stress in the failing heart. AB - SIGNIFICANCE: Despite recent medical advances, cardiovascular disease and heart failure (HF) continue to be major health concerns, and related mortality remains high. As a result, investigation of the mechanisms involved in the development of HF continues to be an active field of study. RECENT ADVANCES: The renin angiotensin system (RAS) and its effector molecule, angiotensin (Ang) II, affect cardiac function through both systemic and local actions, and have been shown to play a major role in cardiac remodeling and dysfunction in the failing heart. Many of the downstream effects of AngII signaling are mediated by elevated levels of reactive oxygen species (ROS) and oxidative stress, which have also been implicated in the pathology of HF. CRITICAL ISSUES: Inhibitors of the RAS have proven beneficial in the treatment of patients at risk for and suffering from HF, but remain only partially effective. ROS can be generated from several different sources, and the oxidative state is normally tightly regulated in the heart. How AngII increases ROS levels and causes dysregulation of the cardiac oxidative state has been the subject of considerable interest in recent years. FUTURE DIRECTIONS: A better understanding of this process and the mechanisms involved should lead to the development of more effective HF therapies and improved outcomes. PMID- 22429090 TI - Lactobacillus and Pediococcus species richness and relative abundance in the vagina of rhesus monkeys (Macaca mulatta). AB - BACKGROUND: The rhesus monkey is an important animal model to study human vaginal health to which lactic acid bacteria play a significant role. However, the vaginal lactic acid bacterial species richness and relative abundance in rhesus monkeys is largely unknown. METHODS: Vaginal swab samples were aseptically obtained from 200 reproductive-aged female rhesus monkeys. Following Rogosa agar plating, single bacterial colonies representing different morphotypes were isolated and analyzed for whole-cell protein profile, species-specific polymerase chain reaction, and 16S rRNA gene sequence. RESULTS: A total of 510 Lactobacillus strains of 17 species and one Pediococcus acidilactici were identified. The most abundant species was Lactobacillus reuteri, which colonized the vaginas of 86% monkeys. Lactobacillus johnsonii was the second most abundant species, which colonized 36% of monkeys. The majority of monkeys were colonized by multiple Lactobacillus species. CONCLUSIONS: The vaginas of rhesus monkeys are frequently colonized by multiple Lactobacillus species, dominated by L. reuteri. PMID- 22429091 TI - Aerosol synthesis of cargo-filled graphene nanosacks. AB - Water microdroplets containing graphene oxide and a second solute are shown to spontaneously segregate into sack-cargo nanostructures upon drying. Analytical modeling and molecular dynamics suggest the sacks form when slow-diffusing graphene oxide preferentially accumulates and adsorbs at the receding air-water interface, followed by capillary collapse. Cargo-filled graphene nanosacks can be nanomanufactured by a simple, continuous, scalable process and are promising for many applications where nanoscale materials should be isolated from the environment or biological tissue. PMID- 22429092 TI - Scleromyxoedema due to a plasma cell neoplasm: rapid remission with bortezomib, thalidomide and dexamethasone. PMID- 22429094 TI - Hesperetin upregulates ABCA1 expression and promotes cholesterol efflux from THP 1 macrophages. AB - ABCA1, a member of the ATP-binding cassette transporter family, regulates high density lipoprotein (HDL) metabolism and cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR). Since ABCA1 plays a pivotal role in cholesterol and HDL metabolism, identification of a compound capable of increasing its expression may be beneficial for the prevention and therapy of atherosclerosis. Firefly luciferase reporter assays were developed for human ABCA1 promoters and LXR enhancers, and an in-house phytochemical library was screened. It was found that a citrus flavonoid, hesperetin (1), increased ABCA1 promoter and LXR enhancer activities in THP-1 macrophages. It was also found that this flavonoid promoted PPAR-enhancing activity. In accordance with these findings, 1 increased mRNA and protein expression of ABCA1 and consequently upregulated ApoA-I-mediated cholesterol efflux. These results provide evidence that 1 promotes ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression through the activation of LXRalpha and PPARgamma. PMID- 22429093 TI - A combined pulmonary-radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation. AB - The purposes of this study were: to describe chest CT findings in normal non smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. METHODS: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9-11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. RESULTS: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. CONCLUSIONS: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation. PMID- 22429095 TI - Acaricidal toxicity of 2'-hydroxy-4'-methylacetophenone isolated from Angelicae koreana roots and structure-activity relationships of its derivatives. AB - The acaricidal activities of 2'-hydroxy-4'-methylacetophenone derived from Angelica koreana roots and its derivatives against Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Tyrophagus putrescentiae were examined by vapor phase and contact toxicity bioassays. In the vapor phase toxicity bioassay, 2'-methylacetophenone (1.25 MUg/cm(2)) was 8.0 times more toxic against D. farinae than benzyl benzoate (10.00 MUg/cm(2)), followed by 3'-methylacetophenone (1.26 MUg/cm(2)), 4'-methylacetophenone (1.29 MUg/cm(2)), 2'-hydroxy-4' methylacetophenone (1.75 MUg/cm(2)), and 2'-hydroxy-5'-methylacetophenone (1.96 MUg/cm(2)). In the contact toxicity bioassay, 3'-methylacetophenone (0.58 MUg/cm(2)) was 17.24 times more effective against D. farinae than benzyl benzoate (7.52 MUg/cm(2)), followed by 2'-methylacetophenone (0.64 MUg/cm(2)), 2'-hydroxy 4'-methylacetophenone (0.76 MUg/cm(2)), 4'-methylacetophenone (0.77 MUg/cm(2)), and 2'-hydroxy-5'-methylacetophenone (1.16 MUg/cm(2)). The acaricidal activities of 2'-hydroxy-4'-methylacetophenone derivatives against D. pteronyssinus and T. putrescentiae were similar to those against D. farinae. In terms of structure activity relationships, acaricidal activity against the three mite species changed with the introduction of hydroxyl and methyl functional groups onto the acetophenone skeleton. Furthermore, some of 2'-hydroxy-4'-methylacetophenone derivatives could be useful for natural acaricides against three mite species. PMID- 22429096 TI - Mitochondrial disturbances, tryptophan metabolites and neurodegeneration: medicinal chemistry aspects. AB - Neurodegenerative disorders, e.g. Parkinson's, Huntington's and Alzheimer's diseases are distinct clinical and pathological entities sharing a number of leading features in their underlying processes. These common features involve the disturbances in the normal functioning of the mitochondria and the alterations in the delicate balance of tryptophan metabolism. The development of agents capable of halting the progression of these diseases is in the limelight of neuroscience research. This review highlights the role of mitochondria in the development of neurodegenerative processes with special focus on the involvement of neuroactive kynurenines both as pathological agents and potential targets and tools for future therapeutic approaches by providing a comprehensive summary of the main streams of rational drug design and giving an insight into present clinical achievements. PMID- 22429097 TI - Syntheses and in-vitro evaluation of novel adamantane based gamma-secretase inhibitors. AB - Abnormal processing of amyloid precursor protein (APP) by beta - and gamma secretases to produce excess amyloid-beta-peptide is believed to contribute to the pathophysiological cascade that results in Alzheimer's disease. gamma Secretase inhibition or modulation therefore represents a rational approach to the prevention and/or management of AD. Here, we present the discovery and SAR of a class of novel adamantanyl sulfonamide based gamma -secretase inhibitors. Activity evaluation was conducted on cell lines overexpressing APP (wild type and Swedish mutation). Our results suggest size threshold and hydrogen bond formation are necessary for inhibitory activity. There was no correlation between compound activity, Log P, and the electronic effect of substituents on the aromatic ring. These compounds possess desirable drug like properties and results of the study can guide a pharmacophore based design of gamma -secretase inhibitors. PMID- 22429098 TI - Recent advances in the research of 2,3-diaryl-1,3-thiazolidin-4-one derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - Derived from the structure of 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), 2,3 diaryl-1,3-thiazolidin-4-one derivatives became a novel class of HIV-1 non nucleoside reverse transcriptase inhibitors (NNRTIs). Under the guidance of continuous structure-activity relationship (SAR) analysis and molecular modeling, various structural modifications were carried out on nearly all the positions of the thiazolidin-4-one nucleus. Some of the derivatives proved to be highly effective against HIV-1 replication at 10-40 nanomolar concentration ranges with minimal cytotoxicities. In this article, the whole development of 2,3-diaryl-1,3 thiazolidin-4-one series from the discoveries to recent advances, their panoramic SAR studies and binding modes based on molecular modeling were reviewed, and also some enlightenments for further investigation were presented. PMID- 22429099 TI - Preventing delirium in older adults with recent hip fracture through multidisciplinary geriatric consultation. AB - OBJECTIVES: To evaluate the effect of inpatient geriatric consultation teams (IGCTs), which have been introduced to improve the quality of care of older persons hospitalized on nongeriatric wards, on delirium and overall cognitive functioning in older adults with hip fracture. DESIGN: Controlled trial. SETTING: Two trauma wards in a university hospital setting. PARTICIPANTS: One-hundred seventy-one people with hip fracture aged 65 and older assigned to a multidisciplinary geriatric intervention (n = 94) or usual care (n = 77). MEASUREMENTS: Incidence and duration of delirium were measured using the Confusion Assessment Method, severity of delirium using the Delirium Index, and cognitive status using the 12-item Mini-Mental State Examination. RESULTS: Significantly more controls (53.2%; n = 41) than intervention group participants (37.2%; n = 35; P = .04; odds ratio (OR) = 1.92, 95% confidence interval (CI) = 1.04-3.54) were delirious at any point after surgery. No significant difference was found between the groups for duration or severity of delirium episodes. The proportion of participants with cognitive decline at discharge was higher in controls than in those assigned to geriatric intervention (38.7% vs 22.6%; P = .02; OR = 2.16, 95% CI = 1.10-4.24). CONCLUSION: Delirium episodes and cognitive decline during hospitalization were found to be common in older adults with hip fracture, as expected, but an IGCT intervention reduced the incidence of these adverse outcomes. In participants who developed delirium, a geriatric consultation had no effect on severity or duration of the delirium episode. PMID- 22429100 TI - Cooperative effect in receptor-mediated endocytosis of multiple nanoparticles. AB - The uptake of nanoparticles (NPs) by a cellular membrane is known to be NP size dependent, but the pathway and kinetics for the endocytosis of multiple NPs still remain ambiguous. With the aid of computer simulation techniques, we show that the internalization of multiple NPs is in fact a cooperative process. The cooperative effect, which in this work is interpreted as a result of membrane curvature mediated NP interaction, is found to depend on NP size, membrane tension, and NP concentration on the membranes. While small NPs generally cluster into a close packed aggregate on the membrane and internalize, as a whole, NPs with intermediate size tend to aggregate into a linear pearl-chain-like arrangement, and large NPs are apt to separate from each other and internalize independently. The cooperative wrapping process is also affected by the size difference between neighboring NPs. Depending on the size difference of neighboring NPs and inter-NP distance, four different internalization pathways, namely, synchronous internalization, asynchronous internalization, pinocytosis like internalization, and independent internalization, are observed. PMID- 22429101 TI - Coalescence in double emulsions. AB - Coalescence processes in double emulsions, water-in-oil-in-water, are studied by optical microscopy. The time evolution of such systems is determined by the interplay of two coalescence processes, namely, between inner water droplets and between the inner water droplets and the continuous external water phase. The predominance of one of those processes over the other, regulated by the relative amount of hydrophilic and lipophilic surfactants, leads to different evolutions of the system. We present here results for a class of systems whose evolution follows a master behavior. We also implemented a computer simulation where the system is modeled as a spherical cavity filled with smaller Brownian spheres. Collisions between spheres allow coalescence between them with probability P(i), whereas collisions between a sphere and the wall of the cavity allow coalescence with the external phase with probability P(e). The phenomenology observed in the experimental systems is well reproduced by the computer simulation for suitable values of the probability parameters. PMID- 22429102 TI - Structural basis for NHERF1 PDZ domain binding. AB - The Na(+)/H(+) exchange regulatory factor-1 (NHERF1) is a scaffolding protein that possesses two tandem PDZ domains and a carboxy-terminal ezrin-binding domain (EBD). The parathyroid hormone receptor (PTHR), type II sodium-dependent phosphate cotransporter (Npt2a), and beta2-adrenergic receptor (beta2-AR), through their respective carboxy-terminal PDZ-recognition motifs, individually interact with NHERF1 forming a complex with one of the PDZ domains. In the basal state, NHERF1 adopts a self-inhibited conformation, in which its carboxy-terminal PDZ ligand interacts with PDZ2. We applied molecular dynamics (MD) simulations to uncover the structural and biochemical basis for the binding selectivity of NHERF1 PDZ domains. PDZ1 uniquely forms several contacts not present in PDZ2 that further stabilize PDZ1 interactions with target ligands. The binding free energy (DeltaG) of PDZ1 and PDZ2 with the carboxy-terminal, five-amino acid residues that form the PDZ-recognition motif of PTHR, Npt2a, and beta2-AR was calculated and compared with the calculated DeltaG for the self-association of NHERF1. The results suggest that the interaction of the PTHR, beta2-adrenergic, and Npt2a involves competition between NHERF1 PDZ domains and the target proteins. The binding of PDZ2 with PTHR may also compete with the self-inhibited conformation of NHERF1, thereby contributing to the stabilization of an active NHERF1 conformation. PMID- 22429103 TI - Unfavorable health conditions associated with high social anxiety in the elderly: a community-based study. AB - BACKGROUND: There is little knowledge concerning unfavorable health conditions (UHC) associated with high level of social phobia/anxiety symptoms (SPAS) in the elderly. AIMS: This cross-sectional community-based study examines five categories of UHC related to high SPAS in individuals aged 75/76 years compared with controls with lower SPAS. METHODS: The study was based on data from the Oslo Health Study. Based on self-rating of the MINI-SPIN screening instrument, 246 individuals (9%) had high SPAS (cases) and 2464 (91%) had lower SPAS (controls). The socio-demographic, somatic, lifestyle, social and mental categories of UHC were compared between cases and controls. RESULTS: A significantly higher proportion of cases were in non-paired relationships, had low level of education and low income compared with controls. Among cases, a significantly higher proportion had poor self-rated health, more somatic morbidity, regular use of analgesics and frequent drinking. All indicators of social UHC, except low community activism, were significantly more common among cases compared with controls. Except for use of hypnotics, the same was true for the indicators of mental UHC. Stepwise multivariate logistic regression analysis showed that the socio-demographic, somatic, social and mental UHC steps were significantly associated with high SPAS. CONCLUSIONS: Individuals aged 75/76 years with high level of SPAS showed multiple UHC within several areas. Identification and interventions like exposure and though modification geared at such anxiety should be considered. PMID- 22429104 TI - Boundary work of dentists in everyday work. AB - OBJECTIVE: The Swedish policy objectives in dental care provision - to meet public demands for dental care and to increase the cost-effectiveness of the service - require dentists to work in teams with dental hygienists and dental nurses. This study focused on the role of dentists in the distribution of work tasks within teams in one Swedish Public Dental Service organisation. Dental clinics were viewed as micro-political arenas in which dentists attempt to demarcate professional boundaries in response to teamwork. METHODS: Semi structured interviews, observations and documents were used. The interviewed individuals were seven dentists employed at two clinics, the managers of each clinic and the general manager. The dentists were interviewed to investigate how they defend or blur professional boundaries. They were also observed at work. The clinic managers and the general manager were interviewed to identify their expectations of dentists concerning work division. The documents comprised organisational plans and annual reports. RESULTS: Dentists demarcated professional boundaries by utilising various power resources: treatment responsibility, specialist knowledge, discretion, and avoidance of work considered to be low status work. The dentists also contributed to blurred boundaries between themselves and the other dental professionals by discussing patient treatment, giving and receiving advice, and assisting the others in skill development. CONCLUSION: Although dentists' boundary work could obstruct implementation of policy objectives, dentists' behaviour contributed to effective collaboration within the teams. PMID- 22429105 TI - Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. AB - INTRODUCTION: Insomnia is common among the elderly. The use of hypnotic drugs in elderly patients is frequently criticized owing to dependency, cognitive impairments, falls and withdrawal effects. The production of melatonin, a physiological sleep and circadian rhythm regulator, declines with age. Prolonged release melatonin (Circadin(r)), designed to mimic the endogenous pattern of melatonin production, is licensed for insomnia in patients aged >= 55 years. AREAS COVERED: This review summarizes published studies on Circadin's efficacy and safety (Summary of Product Characteristics and Medline search on 'Circadin' and 'insomnia'). EXPERT OPINION: The main significant and clinically relevant benefits are improvements in sleep quality and latency, next-day morning alertness and quality of life. The responses may develop over several days. An oral 2-mg dose once daily, for 3 months, has generally been well tolerated with no rebound, withdrawal or 'hangover' effects and no safety concerns on concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti inflammatory drugs. Untoward effects of hypnotics on cognition, memory, postural stability and sleep structure are not seen with Circadin. Given as a first-line prescription, with 13 weeks' posology and the lack of rebound effects, Circadin has the potential to improve quality of life in insomnia patients aged 55 years and older and avoid long-term use of hypnotics. PMID- 22429106 TI - Assessment of daily exposure of endodontic personnel to extremely low frequency magnetic fields. AB - AIM: To measure daily exposure levels to extremely low frequency magnetic fields (ELF MFs) in endodontic clinics. METHODOLOGY: In total, 10 subjects (five endodontic trainees, five hygienists) participated. Each volunteer wore a 60-Hz MF measurement device on the left upper arm during working hours. Measurements were taken continuously throughout the working day except at lunch time. Separate measurements were taken for specific items of equipment at several distances. RESULTS: The average MF exposure for the 10 personnel was 0.03+/-0.04micro-Tesla (MUT) (range, 0.01-6.4MUT). The average MF exposure of endodontic personnel was lower than that of other hospital personnel according to the literature. Furthermore, all monitored exposure levels were well below the maximum acute exposure level, 500MUT, recommended by the International Committee on Non ionizing Radiation Protection for the protection of workers against ELF MFs. However, relatively high levels of exposure occurred in an operating room and X ray room, presumably as a result of the use of surgical equipment such as microscopes and monitors, various motors and power cables of X-ray machines with large current flows. CONCLUSIONS: The total average MF exposure level of 0.03MUT was lower than the typical background level at home. Although high levels of exposure were measured in an operating room and X-ray room, the MF exposure level to dental personnel was minimal during routine endodontic clinical work. PMID- 22429107 TI - Reduction of PAH and soot precursors in benzene flames by addition of ethanol. AB - A one-dimensional premixed flame model (PREMIX) and schemes resulting from the merging of validated kinetic schemes for the oxidation of the components of the present mixtures (benzene and ethanol) were used to investigate the effect of oxygenated additives on aromatic species, which are known to be soot precursors, in fuel-rich benzene combustion. The specific flames were low-pressure (45 mbar), laminar, premixed flames at an equivalence ratio of 2.0. The blended fuels were formed by incrementally adding 4% wt of oxygen (ethanol) to the neat benzene flame and by keeping the inert mole fraction (argon) and the equivalence ratio constants. Special emphasis was directed toward the causes for the concentration dependent influence of the blends on the amount of polycyclic aromatic hydrocarbons (PAHs) formed. The effects of oxygenate addition to the benzene base flame were seen to result in interesting differences, especially regarding trends to form PAH. The modeling results indicated that the concentration of acetylene and propargyl radicals, the main PAH precursors, as well as the PAH amounts were lower in the flame of the ethanol-benzene fuel mixture than in the pure benzene flame and that all of the formed PAHs were issued from the phenyl radical. Finally, the modeling results provided evidence that the PAH reduction was a result of simply replacing "sooting" benzene with "nonsooting" ethanol without influencing the combustion chemistry of the benzene. PMID- 22429109 TI - Authentication of pure camellia oil by using near infrared spectroscopy and pattern recognition techniques. AB - Total of 4 pattern recognition methods for the authentication of pure camellia oil applying near infrared (NIR) spectroscopy were evaluated in this study. Total of 115 samples were collected and their authenticities were confirmed by gas chromatography (GC) in according to China Natl. Standard (GB). A preliminary study of NIR spectral data was analyzed by unsupervised methods including principal component analysis (PCA) and hierarchical cluster analysis (HCA). Total of 2 supervised classification techniques based on discriminant analysis (DA) and radical basis function neural network (RBFNN) were utilized to build calibration model and predict unknown samples. In the wavenumber range of 6000 to 5750 cm-1, correct classification rate of both supervised and unsupervised solutions all can reach 98.3% when smoothing, first derivative, and autoscaling were used. The good performance showed that NIR spectroscopy with multivariate calibration models could be successfully used as a rapid, simple, and nondestructive method to discriminate pure camellia oil. PMID- 22429108 TI - Zinc finger protein designed to target 2-long terminal repeat junctions interferes with human immunodeficiency virus integration. AB - Integration of the human immunodeficiency virus type 1 (HIV-1) genome into the host chromosome is a vital step in the HIV life cycle. The highly conserved cytosine-adenine (CA) dinucleotide sequence immediately upstream of the cleavage site is crucial for integrase (IN) activity. As this viral enzyme has an important role early in the HIV-1 replication cycle, interference with the IN substrate has become an attractive strategy for therapeutic intervention. We demonstrated that a designed zinc finger protein (ZFP) fused to green fluorescent protein (GFP) targets the 2-long terminal repeat (2-LTR) circle junctions of HIV 1 DNA with nanomolar affinity. We report now that 2LTRZFP-GFP stably transduced into 293T cells interfered with the expression of vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped lentiviral red fluorescent protein (RFP), as shown by the suppression of RFP expression. We also used a third-generation lentiviral vector and pCEP4 expression vector to deliver the 2LTRZFP-GFP transgene into human T-lymphocytic cells, and a stable cell line for long-term expression studies was selected for HIV-1 challenge. HIV-1 integration and replication were inhibited as measured by Alu-gag real-time PCR and p24 antigen assay. In addition, the molecular activity of 2LTRZFP-GFP was evaluated in peripheral blood mononuclear cells. The results were confirmed by Alu-gag real time PCR for integration interference. We suggest that the expression of 2LTRZFP GFP limited viral integration on intracellular immunization, and that it has potential for use in HIV gene therapy in the future. PMID- 22429110 TI - Car-Parrinello simulation of the vibrational spectrum of a medium strong hydrogen bond by two-dimensional quantization of the nuclear motion: application to 2 hydroxy-5-nitrobenzamide. AB - The nature of medium strong intra- and intermolecular hydrogen bonding in 2 hydroxy-5-nitrobenzamide in the crystal phase was examined by infrared spectroscopy and Car-Parrinello molecular dynamics simulation. The focal point of our study was the part of the infrared spectra associated with the O-H and N-H stretching modes that are very sensitive to the strength of hydrogen bonding. For spectra calculations we used an isolated dimer and the fully periodic crystal environment. We calculated the spectra by using harmonic approximation, the time course of the dipole moment function as obtained from the Car-Parrinello simulation, and the quantization of the nuclear motion of the proton for an instantaneous snapshot of the structures in one and two dimensions. Although quantitative assessment of the agreement between the computed and experimental band contour is difficult due to the fact that the experimental band is very broad, we feel that the most reasonable qualitative agreement with the experiment is obtained from snapshot structures and two-dimensional quantization of the proton motion. We have also critically examined the methods of constructing the one-dimensional proton potential. Perspectives are given for the treatment of nuclear quantum effects in biocatalysis. PMID- 22429111 TI - A hybrid silk/RADA-based fibrous scaffold with triple hierarchy for ligament regeneration. AB - While silk-based microfibrous scaffolds possess excellent mechanical properties and have been used for ligament tissue-engineering applications, the microenvironment in these scaffolds is not biomimetic. We hypothesized that coating a hybrid silk scaffold with an extracellular matrix (ECM)-like network of self-assembling peptide nanofibers would provide a biomimetic three-dimensional nanofibrous microenvironment and enhance ligament tissue regeneration after bone marrow-derived mesenchymal stem cell (BMSC)-seeding. A novel scaffold possessing a triple structural hierarchy comprising macrofibrous knitted silk fibers, a silk microsponge, and a peptide nanofiber mesh was developed by coating self-assembled RADA16 peptide nanofibers on a silk microfiber-reinforced-sponge scaffold. Compared with the uncoated control, RADA-coated scaffolds showed enhanced BMSC proliferation, metabolism, and fibroblastic differentiation during the 3 weeks of culture. BMSC-seeded RADA-coated scaffolds showed an increasing temporal expression of key fibroblastic ECM proteins (collagen type I and III, tenascin C), with a significantly higher tenascin-C expression compared with the controls. BMSC-seeded RADA-coated scaffolds also showed a temporal increase in total collagen and glycosaminoglycan production (the amount produced being higher than in control scaffolds) during 3 weeks of culture, and possessed 7% higher maximum tensile load compared with the BMSC-seeded control scaffolds. The results indicate that the BMSC-seeded RADA-coated hybrid silk scaffold system has the potential for use in ligament tissue-engineering applications. PMID- 22429112 TI - Secondarily generalized seizures in temporal lobe epilepsy. AB - PURPOSE: Secondarily generalized tonic-clonic seizure (SGTCS) may occur rarely in temporal lobe epilepsy (TLE), but SGTCS is the major risk factor for sudden death and for seizure-related fatal injuries. Our aim was to investigate clinical factors associated with the occurrence of SGTCS in TLE by addressing two questions: (1) What clinical features differentiate patients with TLE who regularly had SGTCS from those who did not? (2) Is there an association of secondarily generalized seizures with preceding seizure elements and clinical data? METHODS: We included 171 patients with TLE (mean age 34.4 +/- 10) who participated in our presurgical evaluation program, which included continuous video-electroencephalography (EEG) and magnetic resonance imaging (MRI). Patients had a temporal lobectomy as a result of mesial or neocortical TLE. To reevaluate the archived seizures, we selected the consecutively recorded seizures of each patient. If the patient had more than three recorded seizures, then we reevaluated only the first three. Altogether video-recorded seizures of 402 patients were reanalyzed. KEY FINDINGS: A positive association between the presence of hippocampal sclerosis on the MRI and SGTCS in the patient history was found, whereas ictal speech and pedal automatism showed a negative association with a SGTCS history. The age of patients showed a positive association, whereas patient's reactivity before and during the seizure, oral/pedal automatisms, and vocalizations showed a negative association with secondary generalization of a focal-onset seizure during video-EEG monitoring. SIGNIFICANCE: Clinical features associated with SGTCS may help clinicians during presurgical monitoring identify high-risk patients for SGTCS. Our study may help in understanding the pathophysiology of secondary generalization. PMID- 22429113 TI - Ultra performance liquid chromatography-tandem quadrupole mass spectrometry profiling of anthocyanins and flavonols in cowpea (Vigna unguiculata) of varying genotypes. AB - The structure of flavonoids in food plants affects bioactivity and important nutritional attributes, like micronutrient bioavailability. This study investigated flavonol and anthocyanin compositions of cowpea (Vigna unguiculata) of varying genotypes. Black, red, green, white, light brown, and golden brown cowpea phenotypes were analyzed for anthocyanins and flavonols using ultra performance liquid chromatography-tandem quadrupole mass spectrometry. Eight anthocyanins and 23 flavonols (15 newly identified in cowpea) were characterized. Mono-, di-, and tri(acyl)glycosides of quercetin were predominant in most phenotypes; myricetin and kaempferol glycosides were present only in specific phenotypes. The red phenotypes had the highest flavonol content (880-1060 MUg/g), whereas green and white phenotypes had the lowest (270-350 MUg/g). Only black (1676-2094 MUg/g) and green (875 MUg/g) phenotypes had anthocyanins, predominantly delphinidin and cyanidin 3-O-glucosides. Cowpea phenotype influenced the type and amount of flavonoids accumulated in the seed; this may have implications in selecting varieties for nutrition and health applications. PMID- 22429114 TI - Invasive aspergillosis in a putty-nosed monkey (Cercopithecus nictitans) with adrenocortical Cushing's syndrome. AB - BACKGROUND: An 18-year-old captive female putty-nosed-monkey (Cercopithecus nictitans) with a history of long-term infertility and hyperglucocorticism was euthanized because of perforating thoracic trauma induced by group members and subsequent development of neurological signs. METHODS: Complete necropsy and histopathological examination of formalin-fixed tissue samples was carried out. RESULTS: The monkey showed invasive pulmonary and cerebral infection with Aspergillus fumigatus together with adrenocortical neoplasia and signs of Cushing's syndrome, such as alopecia with atrophic skin changes, evidence for diabetes mellitus and marked immunosuppression. CONCLUSIONS: Spontaneous endocrinopathies are rarely described in non-human primates. Here we report the first case of spontaneous adrenocortical hyperglucocorticism predisposing to systemic aspergillosis in a putty-nosed monkey. PMID- 22429115 TI - Visualizing electrical breakdown and ON/OFF states in electrically switchable suspended graphene break junctions. AB - Narrow gaps are formed in suspended single- to few-layer graphene devices using a pulsed electrical breakdown technique. The conductance of the resulting devices can be programmed by the application of voltage pulses, with voltages of 2.5 to ~4.5 V, corresponding to an ON pulse, and ~8 V, corresponding to an OFF pulse. Electron microscope imaging of the devices shows that the graphene sheets typically remain suspended and that the device conductance tends to zero when the observed gap is large. The switching rate is strongly temperature dependent, which rules out a purely electromechanical switching mechanism. This observed switching in suspended graphene devices strongly suggests a switching mechanism via atomic movement and/or chemical rearrangement and underscores the potential of all-carbon devices for integration with graphene electronics. PMID- 22429116 TI - PCOS and peripheral AMH levels in relation to FSH receptor gene single nucleotide polymorphisms. AB - OBJECTIVES: To determine if an association exists between the follicle stimulating hormone receptor (FSHR) gene p.Asn680Ser polymorphism and polycystic ovary syndrome (PCOS) or with high anti-mullerian hormone (AMH) levels without PCOS. PATIENTS: Fifty-eight women with PCOS, 24 women with high AMH (>44.5 pmol/L) without PCOS and 80 healthy ethnically matched female controls. MAIN OUTCOME MEASURES: Prevalence of the FSHR p.Asn680Ser polymorphism, baseline serum AMH levels and response to ovulation induction with clomiphene citrate. RESULTS: The frequency of FSHR p.Asn680Ser genotypes were not significantly different between PCOS patients, patients with high AMH without PCOS and controls (p = 0.88). Of the women with PCOS, 34/58 were on clomiphene citrate treatment and 12/34 were resistant. There was no association between sensitivity or resistance to clomiphene and p.Asn680Ser genotypes (p = 0.38). CONCLUSIONS: There is no evidence that FSHR p.Asn680Ser genotypes are associated with PCOS, high AMH levels or response to clomiphene citrate. PMID- 22429118 TI - Attitudes and expectations regarding exercise in the hospital of hospitalized older adults: a qualitative study. AB - OBJECTIVES: To describe expectations of, and perceived motivators and barriers to, in-hospital exercise of hospitalized older adults. DESIGN: Qualitative study using the framework theory. SETTING: Public hospital general medical wards. PARTICIPANTS: Twenty-eight English- or Spanish-speaking inpatients aged 65 to 103. MEASUREMENTS: Semistructured interviews were conducted at the bedside. Questions explored attitudes and expectations regarding in-hospital exercise. Interviews were tape recorded and transcribed, and content analysis was performed to identify major themes. RESULTS: For most participants (71%), exercise in the hospital meant walking. Only 29% of participants expected to be exercising in the hospital, although three-quarters perceived it to be appropriate. Major themes included motivating factors and barriers to in-hospital exercise. Motivating factors included avoiding the negative effects of prolonged bed rest, promoting a sense of well-being, promoting functional recovery, and being asked to exercise. Barriers included symptoms related to one's illness, institutional barriers, and fear of injury. Most respondents (85%) felt that if the physician suggested exercise, it would influence their decision to do so, yet few (27%) reported that they had spoken to their physician about exercise. CONCLUSION: Hospitalized older adults have positive perceptions about in-hospital exercise, although they must overcome significant barriers to do so. Medical professionals have a strong influence over the exercise behavior of elderly adults in the hospital yet infrequently address the issue. Incorporating motivating factors and removing barriers may increase the effectiveness of in-hospital exercise programs. PMID- 22429119 TI - Angiotensin-generated reactive oxygen species in brain and pathogenesis of cardiovascular diseases. AB - SIGNIFICANCE: Overproduction of angiotensin II (Ang II) in brain contributes to the pathogenesis of cardiovascular diseases. One of the most promising theses that emerged during the last decade is that production of reactive oxygen species (ROS) and activation of redox-dependent signaling cascades underlie those Ang II actions. This review summarizes our status of understanding on the roles of ROS and redox-sensitive signaling in brain Ang II-dependent cardiovascular diseases, using hypertension and heart failure as illustrative examples. RECENT ADVANCES: ROS generated by NADPH oxidase, mitochondrial electron transport chain, and proinflammatory cytokines activates mitogen-activated protein kinases and transcription factors, which in turn modulate ion channel functions and ultimately increase neuronal activity and sympathetic outflow in brain Ang II dependent cardiovascular diseases. Antioxidants targeting ROS have been demonstrated to be beneficial to Ang II-induced hypertension and heart failure via protection from oxidative stress in brain regions that subserve cardiovascular regulation. CRITICAL ISSUES: Intra-neuronal signaling and the downstream redox-sensitive proteins involved in controlling the neuronal discharge rate, the sympathetic outflow, and the pathogenesis of cardiovascular diseases need to be identified. The cross talk between Ang II-induced oxidative stress and neuroinflammation in neural mechanisms of cardiovascular diseases also warrants further elucidation. FUTURE DIRECTIONS: Future studies are needed to identify new redox-based therapeutics that work not only in animal models, but also in patients suffering from the prevalent diseases. Upregulation of endogenous antioxidants in the regulation of ROS homeostasis is a potential therapeutic target, as are small molecule- or nanoformulated conjugate-based antioxidant therapy. PMID- 22429120 TI - Bolaamphiphiles bearing bipyridine as mesogenic core: rational exploitation of molecular architectures for controlled self-assembly. AB - A bolaamphiphile (5,5-B2NBr8) bearing a functional bipyridine moiety as the mesogenic core is reported for the first time. 5,5-B2NBr8 was found to self assemble into uniform fibrous structure in aqueous solution, when the concentration was higher than cmc. Analogues of 5,5-B2NBr8 with structural differences in chain length, headgroup, mesogenic core, and substituted position were synthesized, elucidating that small variances of the molecular structure could lead to dramatic changes of the resulting assemblies. For example, compound 4,4-B2NBr8 showed only spherical colloidal aggregates rather than fibers as 5,5 B2NBr8 did, while the only difference between them was the position at which the alkyl chains were attached onto bipyridine. A probable model for the fibrous structure of 5,5-B2NBr8 was proposed. Moreover, exploiting the coordination capacity of bipyridine, assembly and disassembly of 5,5-B2NBr8 could be reversibly controlled through the addition of EDTA and Cu(II), respectively. PMID- 22429121 TI - Mature B-cell acute lymphoblastic leukaemia associated with a rare MLL-FOXO4 fusion gene. PMID- 22429122 TI - Selection of promising fungal biological control agent of the western flower thrips Frankliniella occidentalis (Pergande). AB - AIMS: Larval stages of Frankliniella occidentalis are known to be refractory to fungal infection compared with the adult stage. The objective of this study was to identify promising fungal isolate(s) for the control of larval stages of F. occidentalis. METHODS AND RESULTS: Ten isolates of Metarhizium anisopliae and eight of Beauveria bassiana were screened for virulence against second-instar larvae of F. occidentalis. Conidial production and genetic polymorphism were also investigated. Metarhizium anisopliae isolates ICIPE 7, ICIPE 20, ICIPE 69 and ICIPE 665 had the shortest LT(50) values of 8.0-8.9 days. ICIPE 69, ICIPE 7 and ICIPE 20 had the lowest LC(50) values of 1.1 * 10(7), 2.0 * 10(7) and 3.0 * 10(7) conidia ml(-1), respectively. Metarhizium anisopliae isolate ICIPE 69 produced significantly more conidia than M. anisopliae isolates ICIPE 7 and ICIPE 20. Internally transcribed spacers sequences alignment showed differences in nucleotides composition, which can partly explain differences in virulence. CONCLUSION: These results coupled with the previous ones on virulence and field efficacy against other species of thrips make M. anisopliae isolate ICIPE 69 a good candidate. SIGNIFICANCE AND IMPACT OF THE STUDY: Metarhizium anisopliae isolate ICIPE 69 can be suggested for development as fungus-based biopesticide for thrips management. PMID- 22429123 TI - Site-saturation mutagenesis of position V117 in OXA-1 beta-lactamase: effect of side chain polarity on enzyme carboxylation and substrate turnover. AB - Class D beta-lactamases pose an emerging threat to the efficacy of beta-lactam therapy for bacterial infections. Class D enzymes differ mechanistically from other beta-lactamases by the presence of an active-site N-carboxylated lysine that serves as a general base to activate the serine nucleophile for attack. We have used site-saturation mutagenesis at position V117 in the class D beta lactamase OXA-1 to investigate how alterations in the environment around N carboxylated K70 affect the ability of that modified residue to carry out its normal function. Minimum inhibitory concentration analysis of the 20 position 117 variants demonstrates a clear pattern of charge and polarity effects on the level of ampicillin resistance imparted on Escherichia coli (E. coli). Substitutions that introduce a negative charge (D, E) at position 117 reduce resistance to near background levels, while the positively charged K and R residues maintain the highest resistance levels of all mutants. Treatment of the acidic variants with the fluorescent penicillin BOCILLIN FL followed by SDS-PAGE shows that they are active for acylation by substrate but deacylation-deficient. We used a novel fluorescence anisotropy assay to show that the specific charge and hydrogen bonding potential of the residue at position 117 affect CO(2) binding to K70, which in turn correlates to deacylation activity. These conclusions are discussed in light of the mechanisms proposed for both class D beta-lactamases and BlaR beta-lactam sensor proteins and suggest a reason for the preponderance of asparagine at the V117-homologous position in the sensors. PMID- 22429124 TI - Unrealistic optimism is associated with subclinical atherosclerosis. AB - OBJECTIVE: Unrealistic optimism-typically conceptualized as underestimation of comparative risk-has been previously associated with poorer health behaviors and outcomes, but no research to date has examined the association between unrealistic optimism and subclinical or clinical disease endpoints. Here, cross sectional data from one time point in the Pittsburgh Healthy Heart study are used to examine whether unrealistic optimism about risk of heart disease is associated with carotid artery intima-media thickness (IMT), a subclinical marker of atherosclerosis. METHODS: Participants were 148 adults aged 57-77. Objective risk score was calculated using the Framingham calculator, and IMT was regressed on risk score and perceived risk. Controlling for the Framingham risk score effectively equated risk across the sample, meaning that lower risk perceptions represented unrealistic optimism. RESULTS: When controlling for the risk score, risk perceptions were negatively associated with IMT (beta = -.21, p < .01, t = 2.79, d = .46), a finding that was not moderated by gender. The risk score was also associated with IMT (beta = .42, p < .001, t = 5.55, d = .91). CONCLUSIONS: Unrealistic optimism was associated with subclinical atherosclerosis. Future longitudinal research is necessary to evaluate the temporal sequence as well as to examine putative explanatory mechanisms. PMID- 22429125 TI - Contextual and individual predictors of physical activity: Interactions between environmental factors and health cognitions. AB - OBJECTIVE: Although health behavior theories assume a role of the context in health behavior self-regulation, this role is often weakly specified and rarely examined. The two studies in this article test whether properties of the environment (districts) affect if and how health-related cognitions are translated into physical activity. METHODS: Multilevel modeling was used to examine the assumed cross-level interactions. Study 1 is a large-scale survey representative of the German adult population (N = 6,201). Gross domestic product (GDP) on the level of administrative districts was used to indicate environmental opportunities and barriers. Study 2 examined cross-level interactions of proximal predictors of physical activity (intentions, action planning, and coping planning) in older adults with multiple illnesses (N = 309), a high-risk group for health deteriorations. RESULTS: Study 1 showed that on the individual level, health attitudes (B = .11) and education (B = .71) were significantly associated with physical activity. GDP moderated the attitudes-behavior relation (B = .01), with higher attitude-behavior relations in districts with higher GDP. Study 2 finds that intention (B = .16), action planning (B = .17), and coping planning (B = .13) significantly predict activity. In addition, district-level GDP significantly moderated the relations between action planning and coping planning, but not intention, on physical activity. CONCLUSIONS: Results suggest that the effects of health attitudes and planning on physical activity are moderated by environmental factors. Districts with higher GDP provide better contextual opportunities for the enactment of concrete if-then plans for physical activity. This has implications for both theory and health promotion. PMID- 22429126 TI - Examining physical activity trajectories for people with spinal cord injury. AB - OBJECTIVE: It is crucial to understand long-term leisure time physical activity (LTPA) patterns of persons with spinal cord injury (SCI) as the challenges of living with this disability heavily influence LTPA levels. The purpose of this study was to explore emerging LTPA patterns in a sample of persons with SCI over an 18-month period. In addition, the study aimed to investigate the influence of pressure ulcers, demographic variables, and theory of planned behavior (TPB) constructs on the emerging LTPA trajectories. METHOD: Participants (N = 541) were enrolled in the SHAPE-SCI study and responded to questionnaires assessing LTPA, TPB constructs and demographic variables. Latent Class Growth Modeling was used to detect emerging LTPA patterns and to test the influence of important demographic and theoretical variables. RESULTS: Four LTPA patterns emerged: inactive, increaser, decreaser, and stable active, representing 22%, 14%, 32%, and 32% of the sample, respectively. The presence of pressure ulcers resulted in a decline in LTPA among participants with a stable active trajectory. Finally, LTPA intentions were higher in all patterns compared to the inactive group. Injury severity, age, and years postinjury also distinguished the trajectories. CONCLUSION: Interventions should focus on increasing individuals' intentions and should be directed toward people who are older, have more severe injuries and have been injured for longer. PMID- 22429127 TI - Change in health and self-perceptions of aging over 16 years: the role of psychological resources. AB - OBJECTIVE: Self-perceptions of aging (SPA) are argued to be an indicator of the ability to adapt to heath decline in late life. Our objective was to examine the influence of psychological resources in maintaining positive self-perceptions of aging in the face of declining health in older adults. METHODS: Time-varying change in health (medical conditions), physical functioning (ADLs), and psychological resources (expectancy of control and self-esteem) on change in SPA were examined over 16 years (5 waves) in a large representative sample (N = 1569) of older adults (65 + years at baseline) from the Australian Longitudinal Study of Aging. RESULTS: Multilevel structural equation models revealed mediating effects of psychological resources at the within-person level for the relationship between decline in ADLs and SPA. At the between-person level, the relationship between medical conditions and SPA was not mediated by psychological resources, whereas ADLs and SPA were shown to be indirectly associated through self-esteem and expectancy of control. CONCLUSIONS: Results demonstrate that maintaining self-esteem and an expectancy of personal control can buffer the effects of declining ADLs on perceptions of aging. Findings have clinical implications regarding psychological interventions aimed at improving resilience in older adults, which may ultimately increase health outcomes and quality of life. PMID- 22429128 TI - Effects of a single topical doxycycline administration adjunctive to mechanical debridement in patients with persistent/recurrent periodontitis but acceptable oral hygiene during supportive periodontal therapy. AB - OBJECTIVES: To evaluate the efficacy of a slow release doxycycline gel (SRD) adjunctively administered to non-surgical therapy in subjects with recurrent or persistent periodontitis but acceptable oral hygiene during supportive periodontal care. MATERIAL & METHODS: In this single blind, parallel group, multicentre study, 202 of 203 recruited periodontal maintenance subjects with recurrent or persistent periodontitis were randomly assigned to subgingival ultrasonic/sonic instrumentation (USI) with (test) or without (control) subsequent administration of SRD in all residual periodontal pockets >=4 mm. Intergroup differences in probing depth, BOP reductions, treatment time, probing attachment levels were evaluated at 3, 6 and 12 months. The primary outcome was the inter-group difference in absolute change of probing pocket depth (PPD) 3, 6 and 12 months after intervention. RESULTS: At baseline, the two groups were comparable. At 3 months, the test group showed a significantly higher decrease in mean probing depth than the control group at 3 months (mean difference = 0.11 mm, 95% CI 0.03-0.19 mm, p = 0.003). Administration of SRD resulted in significantly greater odds of transition of bleeding pockets >=5 mm to a category of non bleeding sites with PPD <=4 mm at 3 and 6 months (O.R. = 1.4, 95% CI 1.2-1.8 at 3 months). At 6 months, SRD benefit was observed only in the deeper pockets. 7.5% of subjects (no significant difference between test and control) showed disease progression (attachment loss >=2 mm) and were exited from the study. No difference in the incidence of adverse events was observed between groups. CONCLUSION: The trial results show that topically administered SRD may provide short-term benefit in controlling inflammation and deep pockets in treated periodontal patients participating in a secondary prevention programme and able to maintain a satisfactory level of oral hygiene. PMID- 22429129 TI - Psychiatry in Latvia: a journey through the past three centuries. AB - BACKGROUND: While there is close contact established between Latvia and the Nordic psychiatric community now, there are many pages of our history we have not had opportunity to share. The aim of this article is to highlight the most important facts of more than 200 years of history of psychiatry in Latvia. RESULTS: The development of the psychiatric services in Latvia started with the building of an asylum-type establishment at the end of the 1700s. To address the increasing needs, psychiatric hospitals of various size and quality were gradually opened all over the country. Psychiatry as a field of science emerged in Latvia after the Declaration of Independence in 1918. Active and progressive development of services and the academic environment took place between the World Wars. During the Soviet regime, psychiatric services were rebuilt within the frameworks and guidelines of the existing system. Following the restoration of Independence in 1991, a number of rapid and positive changes took place. There was a gradual decrease in the number of hospital beds, outpatient services were developed and modern treatment methods were established. Policy documents in the field of mental health were developed and legislation improved. Active collaboration with other, particularly Scandinavian, countries was developed. Academic education continued and specialist training was provided following European standards. The role of the psychiatric professional organization was strengthened. CONCLUSIONS: Many positive changes in the mental healthcare in Latvia have taken place, but there are still some aspects to be addressed. The strengthening of our regional collaboration could be crucial for our future development. PMID- 22429130 TI - Foreword: "new targets and new drugs: from in silico planning to in vivo testing". PMID- 22429131 TI - Allosteric inhibitors of Bcr-Abl: towards novel myristate-pocket binders. AB - Among the currently available options for the treatment of chronic myeloid leukemia (CML), ATP-competitive tyrosine kinases inhibitors (Gleevec((r)), Dasatinib((r)) and Nilotinib((r))) represent one of the most promising therapeutic approaches developed in the last 10-15 years. However, the initial enthusiasm generated by the high response rate to these drugs has been dampened by the development of resistance. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, such as the recent development of more selective non-ATP competitive inhibitors targeting sites outside the ATP-binding cleft. Some of these allosteric inhibitors alter the kinase conformation, while others directly compete with the protein substrates. Another interesting family of allosteric inhibitors is represented by those compounds targeting the myristate-pocket of Bcr-Abl (myristate-pocket binders). The binding of these inhibitors blocks the Bcr-Abl kinase in the inactive conformation and provides an advantage in overcoming drug resistance due to kinase mutations. This review reports the last findings in the development of novel myristate-pocket binders of Bcr-Abl as promising anti leukemia agents. PMID- 22429132 TI - Therapeutic genes for anti-HIV/AIDS gene therapy. AB - The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future. PMID- 22429133 TI - Peptides as drugs: from screening to application. AB - Peptides are ideally suited to mimic natural ligands and thereby function in an antagonistic or agonistic way. Furthermore they are able to physiologically disrupt functional complexes due to their small size and specific binding properties. Proteins form homo- or heteromeric (macro)molecular complexes and intricate networks by interacting with small molecules, peptides, nucleic acids or other proteins. On average, five interaction partners have been estimated for any given cellular protein, illustrating the complexity of the formed 'interactomes' and the impact of their investigation. Many protein-protein interactions are mediated by hot-spots, which comprise only a small part of the large binding interface but account for 80% of the binding energy. Thus, these hot spots provide an 'Achilles heel' for pharmaceutical interventions aiming at the disruption of functional protein-protein complexes. Methods to select peptides for defined target structures include display technologies on phages, ribosomes or yeast, and the yeast-two-hybrid system. Once selected, these peptides can be optimized for their binding affinity using peptide arrays. Stabilization of biologically unstable peptides is achieved by the introduction of non-natural amino acids to form so-called peptidomimetics that are resistant to cellular proteases. Moreover, lipocalins and peptide aptamers represent scaffolded binding structures with unique binding characteristics and enhanced stability. In case of extracellular targets, like cell surface receptors or pathogens in patients' plasma, peptide inhibitors have direct access. Addressing intracellular targets with peptides is more difficult since short hydrophilic peptides generally do not cross plasma membranes on their own. However, intracellular uptake of peptides can be achieved by coupling to carrier systems like liposomes or nanoparticles or upon fusion to a protein transduction domain. Alternatively, peptides may be expressed within cells after transduction with viral vectors in a gene therapy setting. This review will summarize the broad potential of peptides as drugs, with special emphasis on peptides which inhibit protein-protein interactions. PMID- 22429134 TI - Capsid assembly as a point of intervention for novel anti-viral therapeutics. AB - In general, drug discovery in the therapeutic field of infectious disease has a stellar track record. And yet, subsets of pathogens, for example many classes of viruses other than HIV, HSV, influenza, and HCV, have been poorly addressed. In addition, the development of resistance remains a specter of great concern for almost all current chemotherapy directed against infectious diseases, including viruses. Within the viral lifecycle, capsid assembly stands out as a step occurring in all viruses, which has not been the subject of extensive drug discovery programs. Until recently, the common view of assembly was that all the necessary information for assembly was contained in the sequence of the viral protein, in other words, the capsid self-assembles. In the last few years, a body of data has opened new opportunities for antiviral pharmaceutical research. Evidence that host proteins may play catalytic or essential structural roles in viral capsid assembly suggests that these host proteins and their functions are novel targets for small molecule therapeutics. Here we review the current understanding of the capsid assembly process with emphasis on recent data that demonstrate the essential role of host proteins in capsid assembly. Furthermore, this dependency of assembly on host factors appears quite sensitive to small molecule intervention. Implications of this alternate mechanism of capsid assembly are also considered. For example, the dependency on host factors could impose a potent barrier to development of viral resistance to a host-targeted anti-capsid chemotherapeutic. Finally, we give specific examples of the current state of drug discovery programs that have focused on therapeutic inhibition of host-assisted viral capsid assembly. PMID- 22429135 TI - Poly(ADP-ribosylation) and neoplastic transformation: effect of PARP inhibitors. AB - Poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribosylation) play essential roles in several biological processes, among which neoplastic transformation and telomere maintenance. In this paper, we review the poly(ADP-ribosylation) process together with the highly appealing use of PARP inhibitors for the treatment of cancer. In addition, we report our results concerning poly(ADP-ribosylation) in a cellular model system for neoplastic transformation developed in our laboratory. Here we show that PARP-1 and PARP-2 expression increases during neoplastic transformation, together with the basal levels of poly(ADP-ribosylation). Furthermore, we demonstrate a greater effect of the PARP inhibitor 3 aminobenzamide (3AB) on cellular viability in neoplastically transformed cells compared to normal fibroblasts and we show that prolonged 3AB administration to tumorigenic cells causes a decrease in telomere length. Taken together, our data support an active involvement of poly(ADP-ribosylation) in neoplastic transformation and telomere length maintenance and confirm the relevant role of poly(ADP-ribosylation) inhibition for the treatment of cancer. PMID- 22429136 TI - X-ray crystallography as a tool for mechanism-of-action studies and drug discovery. AB - Knowledge of three-dimensional structures of biological macromolecules is essential for a complete understanding of many biological processes. X-ray crystallography is the most widely used technique in structural biology and can provide highly detailed structures of proteins, nucleic acids or macromolecular complexes without any size limit. In the past decade, several recent advances in biological crystallography and automation of data collection and structure solution allowed extraordinary progresses and now more than 93 000 crystal structures have been deposited into the Protein Data Bank. This wealth of structural data significantly helped the elucidation of many biological processes and led to the development of new drugs. In this review we will show how of X-ray crystallography can provide insights into the mechanism of action of biological processes and can contribute to the rationale development of ligands through structure-based drug design. PMID- 22429137 TI - The power of enzyme kinetics in the drug development process. AB - Drug development is a long and expensive process. It starts from the identification of a small molecule (hit compound) endowed with the ability to suppress a cellular or viral enzyme essential for the development of a given disease and proceeds through subsequent rounds of structural changes and optimization until the desired pharmacological properties are reached (lead compound). At any point of the hit-to-lead optimization process, it is of essence to monitor the behavior of the intermediate molecules with respect to their molecular targets. This involves precise mechanism of action studies as well as quantitative measurement of the performance of the compound against its target. Enzyme kinetic studies are thus an essential component of the drug development process. Relevant examples of the power of enzyme kinetics in the antiviral drug development process will be discussed in the context of anti-HIV chemotherapy. PMID- 22429138 TI - Simple and general criterion for "in silico" screening of candidate HIV drugs. AB - Highly active antiretroviral therapy (HAART) dramatically has changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor. This broad spectrum of anti HIV agents recently was extended with compounds inhibiting HIV integrase and vital entry. But these advances did not come without a cost: there were the short and long-term drug toxicities, emergence of drug resistance, and persistence of viral reservoirs. For these reasons, there is a pressing need for novel anti-HIV drugs, particularly those that have a novel action mechanism, as these might be less likely to show cross-resistance with current therapies. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of the time and money consuming process of the drug development. Here we review the application of the EIIP/AQVN (Electron-Ion Interaction Potential, EIIP; Average Quasi Valence Number, AQVN) bioinformatics concept in the development of new anti-HIV drugs and propose a simple theoretical criterion for a virtual screening of molecular libraries for promising lead anti-HIV compounds and refinement of selected lead compounds in order to increase their biological activity. PMID- 22429140 TI - Treatment options for chronic myeloid leukemia. AB - INTRODUCTION: The bcr-abl tyrosine kinase inhibitors (TKIs) are the cornerstone treatment for chronic myeloid leukemia (CML). However, there are many topics related to therapy that remain debated. AREAS COVERED: The aim of this paper is to give the reader a comprehensive review of how to treat CML at diagnosis, how to monitor the disease and a brief read of special populations and case scenarios. It describes the first-line (imatinib) and second-line (nilotinib and dasatinib) TKIs currently used for the treatment of CML, including landmark studies proving their efficacy, side effect profile, dosage and use in special populations. It also reviews the current guidelines regarding treatment and monitoring of the disease while on TKIs, along with an overview of treatment in advanced stages, the role of allogeneic stem cell transplantation and investigational drugs. EXPERT OPINION: Although imatinib represented a mayor therapeutic advancement over conventional chemotherapy, second-generation TKIs offer higher rates of optimal response and should be used as the frontline therapy. Patients with the T315I mutation carry a worse prognosis and should be offered allogeneic stem cell transplantation. The treatment in advanced stages of CML remains suboptimal and bench, translational and clinical research is encouraged. PMID- 22429139 TI - Conformational sampling of peptides in the presence of protein crowders from AA/CG-multiscale simulations. AB - Macromolecular crowding is recognized as an important factor influencing folding and conformational dynamics of proteins and nucleic acids. Previous views of crowding have focused on the mostly entropic volume exclusion effect of crowding, but recent studies are indicating the importance of enthalpic effects, in particular, changes in electrostatic interactions due to crowding. Here, temperature replica exchange molecular dynamics simulations of trp-cage and melittin in the presence of explicit protein crowders are presented to further examine the effect of protein crowders on peptide dynamics. The simulations involve a three-component multiscale modeling scheme where the peptides are represented at an atomistic level, the crowder proteins at a coarse-grained level, and the surrounding aqueous solvent as implicit solvent. This scheme optimally balances a physically realistic description for the peptide with computational efficiency. The multiscale simulations were compared with simulations of the same peptides in different dielectric environments with dielectric constants ranging from 5 to 80. It is found that the sampling in the presence of the crowders resembles sampling with reduced dielectric constants between 10 and 40. Furthermore, diverse conformational ensembles are generated in the presence of crowders including partially unfolded states for trp-cage. These findings emphasize the importance of enthalpic interactions over volume exclusion effects in describing the effects of cellular crowding. PMID- 22429141 TI - Elemental composition of ferruginous bodies and occupational categories: analyses and case studies in Mexico. AB - Inorganic fibers form part of the complex mixture of environmental pollutants in Mexico City and in general locations. Upon entering the lungs, some of those fibers are transformed into ferruginous bodies (FB) that can be used as biological markers of exposure to fibers. Hence, the objectives of this study were, first, to describe the most frequent types of FB found in the lungs, and second, to determine the elemental composition of the cores of some of those FB. A total of 264 lung samples collected from autopsies performed at the National Institutes of Health in Mexico City were analyzed. The FB were obtained by digesting the samples in commercial bleach and all the FB were then collected in 0.45 um Millipore membranes. All the FB obtained from each case were counted directly under bright field microscopy, and then classified by morphology. Results showed from 14.5 FB/g in Category 1 (housewives), to 50.2 FB/g for samples from Category 5 (construction workers), and 152 FB/g for Category 6 (miners). Significant differences were found upon comparing samples from Categories 5/6 to Category 1 (p < 0.05). Type 1 FB were the most frequent ones seen in the samples from Categories 1 to 5. Elemental analyses of the cores of several FB found aluminosilicates, fiberglass, tremolite and amosite asbestos among others. In conclusion, residents of Mexico show exposures to a variety of fibers that induce FB including asbestos. PMID- 22429142 TI - Acute inhalation study of allyl alcohol for derivation of acute exposure guideline levels. AB - An acute, whole-body inhalation study for allyl alcohol in Sprague-Dawley rats was designed to support derivation of AEGL values, with emphasis on establishing NOAELs for irreversible effects of different exposure concentrations and durations. Groups of 10 rats were exposed for 1 hour (0, 50, 200, or 400 ppm), 4 hours (0, 20, 50, or 100 ppm), or 8 hours (0, 10, 20, or 50 ppm). Clinical evaluations were performed during exposure and in an open field within 22-71 minutes after termination of exposure. Clinical pathology, gross necropsy, and histopathology (nasal tissues, larynx, trachea, lungs/bronchi, liver, and kidneys) were evaluated 14 days after exposure. Mortality was limited to 1 male exposed for 8 hours to 50 ppm. Clinical findings of gasping, rales, increased respiration noted at higher exposure levels were rapidly reversed. No treatment related findings were observed in the liver and kidneys, or in the lungs of surviving animals. Histopathology in the nasal cavity was noted at all exposure levels following 1, 4, or 8 hours of exposure. Mild nasal inflammation was found at the lowest exposure levels (50-ppm/1-hour, 20-ppm/4-hour, and 10-ppm/8-hour). These effects were considered reversible and were not associated with related clinical signs. Severe, irreversible nasal olfactory epithelial lesions were present in 50 ppm/8-hour males. The NOELs for irreversible effects were 400-ppm/1 hour, 100-ppm/4-hour, and 20-ppm/8-hour. The incidence of severe findings was positively dependent on both concentration and the exposure duration. In contrast, the incidence of mild reversible findings did not appear to be dependent on duration. PMID- 22429143 TI - Does the use of ingredients added to tobacco increase cigarette addictiveness?: a detailed analysis. AB - The possibility that ingredients added to tobacco contribute to the addictiveness of cigarette smoking was evaluated by comparing cessation rates of smokers of traditional blended cigarettes to those of smokers of flue-cured cigarettes. Such a comparison is a valid means of assessing cigarette ingredients as traditional blended cigarettes contain ingredients (>20), whereas flue-cured cigarettes contain no or very few ingredients. Separate analysis of 108 treatment groups and 108 control groups from randomized clinical trials of nicotine replacement therapy (NRT) were performed by multiple logistic regressions. The results of these analyses demonstrated slightly higher quit rates for smokers of blended cigarettes (OR = 1.90, 95% CI 1.70-2.13 and OR = 1.32, 95% CI 1.14-1.53 for treatment and control groups, respectively). The control groups were also investigated using classification tree analysis from which no difference in quit rates were observed for smokers of either type of cigarette. Further analyses showed that studies that utilized a high level of psychological support in conjunction with NRT produced at least a two-fold increase in quit rates compared to studies that utilized a low level of psychological support. It was also demonstrated that there is a large difference when results were reported by sustained abstinence compared to point prevalence. Additional meta-analyses found the pooled OR for NRT treatment to be in exact agreement with a recent review that assessed the effectiveness of NRT. Overall these results strongly suggest that ingredients used in the manufacture of traditional blended cigarettes do not increase the inherent addictiveness of cigarettes. PMID- 22429144 TI - Coexistence of psoriasis and bullous pemphigoid: remission with low-dose methotrexate. AB - The coexistence of psoriasis vulgaris and bullous pemphigoid is rare. Here, we report a 90-year-old patient with a 20-year history of psoriasis. She developed vesicles and bullae suddenly and was diagnosed as bullous pemphigoid. Low-dose methotrexate therapy quickly cleared both psoriatic and bullous lesions. PMID- 22429146 TI - B cells in allergic diseases: bad or better? AB - IgE-producing B cells are always considered as 'bad' guys in allergic diseases, as they play a direct role in promoting inflammatory responses against inhaled or ingested allergens and contribute to the development of subsequent clinical symptoms. During the past decade, mouse studies have shown that B cells may also have a 'better' side, producing IL-10 and suppressing inflammatory responses; those cells are called regulatory B (Breg) cells. There is evidence now that impairment of Breg cell activity may play a role in the development of inflammatory diseases. New transgenic models and renewed interest have expanded our knowledge on different B cell phenotypes, signals to promote their activity and their function in health and disease. This review will highlight the current knowledge on disease-promoting or disease-protecting activities of B cells and discuss its potential for therapeutic applications in allergies. PMID- 22429147 TI - Modeling the effect of time and temperature on respiration rate of pomegranate arils (cv. "Acco" and "Herskawitz"). AB - Understanding the effect of time and temperature on the respiration rate (RR) of fresh-cut produce, towards the design of a suitable modified atmosphere packaging (MAP) system, requires an adequate mathematical model for prediction of RR as a function of both time and temperature. This study investigated the effect of temperature (5, 10, and 15 degrees C) and storage time (1 to 5 d) on the RR (R(O2) and R(CO2)) of 2 pomegranate cultivars (cv. "Acco" and "Herskawitz") fresh arils. R(O2) and R(CO2) were 3 to 4 folds significantly higher with increased temperature from 5 to 15 degrees C and were within the range of 2.51 to 7.59 mL/kg h and 2.72 to 9.01 mL/kg h, respectively, for both cultivars. At 15 degrees C R(CO2) increased significantly from 8.4 to 25.96 mL/kg h from day 1 to 5, respectively, while at 5 degrees C R(CO2) changed from 2.9 to 2.05 mL/kg h from day 1 to 5. Temperature had the greatest influence on RR and the interaction of time and temperature also significantly affected R(O2) and R(CO2). The respiratory quotient (RQ) estimated by linear regression was 0.98 at 95% significant level. The dependence of RR on temperature and time was accurately described with a combination of an Arrhenius-type and power equation model for and of fresh pomegranate arils. PMID- 22429148 TI - Near field of strongly coupled plasmons: uncovering dark modes. AB - Strongly coupled plasmons in a system of individual gold nanoparticles placed at subnanometer distance to a gold film (nanoparticle-on-plane, NPOP) are investigated using two complementary single particle spectroscopy techniques. Optical scattering spectroscopy exclusively detects plasmon modes that couple to the far field via their dipole moment (bright modes). By using photoemission electron microscopy (PEEM), we detect in the identical NPOPs near-field modes that do not couple to the scattered far field (dark modes) and are characterized by a strongly enhanced nonlinear electron emission process. To our knowledge, this is the first time that both far- and near-field spectroscopy are carried out for identical individual nanostructures interacting via a subnanometer gap. Strongly resonant electron emission occurs at excitation wavelengths far off resonant in the scattering spectra. PMID- 22429149 TI - Empty-level structure and reactive species produced by dissociative electron attachment to tert-butyl peroxybenzoate. AB - The energy and nature of the gas-phase temporary anion states of tert butylperoxybenzoate in the 0-6 eV energy range are determined for the first time by means of electron transmission spectroscopy (ETS) and appropriate theoretical calculations. The first anion state, associated with electron capture into a delocalized pi* MO with mainly ring and carbonyl character, is found to lie close to zero energy, i.e., sizably more stable (about 2 eV) than the ground (sigma*) anion state of saturated peroxides. Dissociative decay channels of the unstable parent molecular anions are detected with dissociative attachment spectroscopy (DEAS), as a function of the incident electron energy, in the 0-14 eV energy range. A large DEA cross-section, with maxima at zero energy, 0.7 and 1.3 eV, is found for production of the (m/e = 121) PhCOO(-) anion fragment, together with the corresponding tert-butoxy neutral radical, following cleavage of the O-O bond. Although with much smaller intensities, a variety of other negative currents are observed and assigned to the corresponding anion fragments with the support of density functional theory calculations. PMID- 22429150 TI - Inflammation and Toll-like receptor ligation differentially affect the osteogenic potential of human mesenchymal stromal cells depending on their tissue origin. AB - Mesenchymal stromal cells (MSCs) can be isolated not only from bone marrow (BM) but also from other tissues, including adipose tissue (AT) and umbilical cord Wharton's Jelly (WJ). Thanks to their ability to differentiate into various cell types, MSC are considered attractive candidates for cell-based regenerative therapy. In degenerative clinical settings, inflammation or infection is often involved. In the present work, we hypothesized that an inflammatory environment and/or Toll-like receptor (TLR) ligation could affect the MSC differentiation potential. MSC were isolated from BM, AT, and WJ. Inflammation was mimicked by a cytokine cocktail, and TLR activation was induced through TLR3 and TLR4 ligation. Osteogenesis was chosen as a model for differentiation. Osteogenic parameters were evaluated by measuring Ca2+ deposits and alkaline phosphatase (ALP) activity at day 7, 14, and 21 of the culture in an osteogenic medium. Our results show that WJ-MSC exhibit a much lower osteogenic potential than the other two MSC types. However, inflammation was able to strongly increase the osteogenic differentiation of WJ-MSC as calcification, and ALP activity appeared as early as day 7. However, this latter enzymatic activity remained much lower than that disclosed by BM-MSC. TLR3 or TLR4 triggering increased the osteogenesis in AT- and, to lesser extent, in BM-MSC. In conclusion, WJ-MSC constitutively disclose a lower osteogenic potential as compared with BM and AT-MSC, which is not affected by TLR triggering but is strongly increased by inflammation, then reaching the level of BM-MSC. These observations suggest that WJ-MSC could constitute an alternative of BM-MSC for bone regenerative applications, as WJ is an easy access source of large amounts of MSC that can effectively differentiate into osteoblasts in an inflammatory setting. PMID- 22429151 TI - Large deletion in the Factor VIII gene (F8) involving segmental duplications in int22h shows no haematological phenotype in female carriers, but may be embryonic lethal in males. PMID- 22429152 TI - Radiological diagnosis of periapical bone tissue lesions in endodontics: a systematic review. AB - This systematic review evaluates the diagnostic accuracy of radiographic methods employed to indicate presence/absence and changes over time of periapical bone lesions. Also investigated were the leads radiographic images may give about the nature of the process and the condition of the pulp in nonendodontically treated teeth. Electronic literature search included the databases PubMed, Embase and CENTRAL from January 1950 to June 2011. All languages were accepted provided there was an abstract in English. The MeSH terms were 'Cone beam computed tomography (CBCT)', 'Radiography, panoramic', 'Periapical diseases', 'Dental pulp diseases', 'Sensitivity and specificity', 'receiver operating characteristics (ROC) curve', 'Cadaver', 'Endodontics' and 'Radiography dental'. Two reviewers independently assessed abstracts and full text articles. An article was read in full text if at least one of the two reviewers considered an abstract to be potentially relevant. Altogether, 181 articles were read in full text. The GRADE approach was used to assess the quality of evidence of each radiographic method based on studies of high or moderate quality. Twenty-six studies fulfilled criteria set for inclusion. None was of high quality; 11 were of moderate quality. There is insufficient evidence that the digital intraoral radiographic technique is diagnostically as accurate as the conventional film technique. The same applies to CBCT. No conclusions can be drawn regarding the accuracy of radiological examination in identifying various forms of periapical bone tissue changes or about the pulpal condition. PMID- 22429153 TI - Reduction in Listeria monocytogenes and spoilage bacteria on smoked catfish using X-ray treatments. AB - AIMS: To determine the efficacy of X-ray processes in inactivating L. monocytogenes levels in smoked catfish during storage at 5 degrees C and to determine the effects of X-ray doses on controlling the growth of spoilage bacteria on smoked catfish during storage at 5 degrees C for up to 5 weeks. METHODS AND RESULTS: Smoked catfish fillets inoculated with L. monocytogenes were treated with 0.0-2.0 kGy X-ray and stored at 5 degrees C for 5 weeks. The negative controls (uninoculated/untreated) and uninoculated samples treated with the lowest (0.1 kGy) and highest (2.0 kGy) doses were stored at 5 degrees C and tested for psychrotrophs count during the 5 weeks of storage. The initial L. monocytogenes population on smoked catfish was significantly (P < 0.05) reduced to undetectable level by a treatment of 1.0 kGy or higher. The initial psychrotrophs count on smoked catfish was significantly reduced from 4.7 CFU g( 1) to below the detectable level by a treatment with 2.0 kGy. CONCLUSIONS: Smoked catfish treated with 2.0 kGy X-ray had no detectable L. monocytogenes throughout 35 days of storage at 5 degrees C. A treatment with 2.0 kGy X-ray also kept the levels of psychrotrophs in the smoked catfish within the acceptable level until 35 days. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this investigation indicate that X-ray at 2.0 kGy can eliminate L. monocytogenes and extend the shelf life of smoked catfish stored at refrigeration temperature. PMID- 22429154 TI - Comparison of angiogenic and anti-angiogenic factors in maternal and umbilical cord blood in early- and late-onset pre-eclampsia. AB - PURPOSE: The aim of this study was to compare maternal and umbilical cord serum levels of the angiogenic and anti-angiogenic factors in early- and late-onset pre eclamptic pregnancies as well as in normal pregnancies, which might have significant importance in the etiology of pre-eclampsia. MATERIALS AND METHODS: This prospective case-control study was carried out with pre-eclamptic (early onset, <= 34 weeks and late-onset, >34 weeks) and normal pregnant women. VEGF, PIGF, sFlt-1 and sEng levels in maternal and umbilical cord serum were measured before delivery and the findings were compared. RESULTS: The study was conducted with 15 early- and 15 late-onset pre-eclampsia patients, and 17 patients with normal pregnancies. It was found that sEng levels were higher in the umbilical cord serum in the early-onset and in the maternal serum in the late-onset pre eclampsia group than the control group (p < 0.05). No significant difference in any factor was observed between the early- and late-onset pre-eclampsia groups. CONCLUSION: In this study, the results showed that angiogenic and anti-angiogenic factor levels in maternal serum and umbilical cord serum may not be related to the time of onset of pre-eclampsia. PMID- 22429155 TI - Gastrointestinal disease outbreak detection using multiple data streams from electronic medical records. AB - BACKGROUND: Passive reporting and laboratory testing delays may limit gastrointestinal (GI) disease outbreak detection. Healthcare systems routinely collect clinical data in electronic medical records (EMRs) that could be used for surveillance. This study's primary objective was to identify data streams from EMRs that may perform well for GI outbreak detection. METHODS: Zip code-specific daily episode counts in 2009 were generated for 22 syndromic and laboratory-based data streams from Kaiser Permanente Northern California EMRs, covering 3.3 million members. Data streams included outpatient and inpatient diagnosis codes, antidiarrheal medication dispensings, stool culture orders, and positive microbiology tests for six GI pathogens. Prospective daily surveillance was mimicked using the space-time permutation scan statistic in single and multi stream analyses, and space-time clusters were identified. Serotype relatedness was assessed for isolates in two Salmonella clusters. RESULTS: Potential outbreaks included a cluster of 18 stool cultures ordered over 5 days in one zip code and a Salmonella cluster in three zip codes over 9 days, in which at least five of six cases had the same rare serotype. In all, 28 potential outbreaks were identified using single stream analyses, with signals in outpatient diagnosis codes most common. Multi-stream analyses identified additional potential outbreaks and in one example, improved the timeliness of detection. CONCLUSIONS: GI disease-related data streams can be used to identify potential outbreaks when generated from EMRs with extensive regional coverage. This process can supplement traditional GI outbreak reports to health departments, which frequently consist of outbreaks in well-defined settings (e.g., day care centers and restaurants) with no laboratory-confirmed pathogen. Data streams most promising for surveillance included microbiology test results, stool culture orders, and outpatient diagnoses. In particular, clusters of microbiology tests positive for specific pathogens could be identified in EMRs and used to prioritize further testing at state health departments, potentially improving outbreak detection. PMID- 22429156 TI - Dual photonic-electrochemical lab on a chip for online simultaneous absorbance and amperometric measurements. AB - A dual lab on a chip (DLOC) approach that enables simultaneous optical and electrochemical detection working in a continuous flow regime is presented. Both detection modes are integrated for the first time into a single detection volume and operate simultaneously with no evidence of cross-talk. The electrochemical cell was characterized amperometrically by measuring the current in ferrocyanide solutions at +0.4 V vs gold pseudoreference electrode, at a flow rate of 200 MUL min(-1). The experimental results for ferrocyanide concentrations ranging from 0.005 to 2 mM were in good agreement with the values predicted by the Levich equation for a microelectrode inside a rectangular channel, with a sensitivity of 2.059 +/- 0.004 MUA mM(-1) and a limit of detection (LoD) of (2.303 +/- 0.004) * 10(-3) mM. Besides, optical detection was evaluated by measuring the absorbance of ferricyanide solutions at 420 nm. The results obtained therein coincide with those predicted by the Beer-Lambert law for a range of ferricyanide concentrations from 0.005 to 0.3 mM and showed an estimated LoD of (0.553 +/- 0.001) * 10(-3) mM. The DLOC was finally applied to the analysis of L-lactate via a bienzymatic reaction involving lactate oxidase (LOX) and horseradish peroxidase (HRP). Here, the consumption of the reagent of the reaction (ferrocyanide) was continuously monitored by amperometry whereas the product of the reaction (ferricyanide) was recorded by absorbance. The DLOC presented good performance in terms of sensitivity and limit of detection, comparable to other fluidic systems found in the literature. Additionally, the ability to simultaneously quantify enzymatic reagent consumption and product generation confers the DLOC a self verifying capability which in turn enhances its robustness and reliability. PMID- 22429157 TI - In vivo antitumor effects of 4,7-dimethoxy-5-methyl-1,3-benzodioxole isolated from the fruiting body of Antrodia camphorata through activation of the p53 mediated p27/Kip1 signaling pathway. AB - In this study, 4,7-dimethoxy-5-methyl-1,3-benzodioxole (SY-1) was isolated from three different sources of dried Antrodia camphorata (AC) fruiting bodies. AC is a medicinal mushroom that grows on the inner heartwood wall of Cinnamomum kanehirai Hay (Lauraceae), which is an endemic species that is used in Chinese medicine for its antitumor properties. We demonstrated that SY-1 [given as a 1-30 mg/kg body weight intraperitoneal (ip) injection three times per week] profoundly decreased the growth of COLO-205 human colon cancer cell tumor xenografts in an athymic nude mouse model. We further demonstrated that significant AC extract mediated antitumor effects were observed at the highest concentration (5 g/kg body weight/day). No gross toxicity signs were observed (i.e., body weight changes, general appearance, or individual organ effects). Frozen COLO-205 xenograft tumors were pulverized in liquid N(2), and the expression of cell cycle regulatory proteins was detected by immunoblotting. We found that the p53 mediated p27/Kip1 protein was significantly induced in the low-dose (1 mg/kg body weight) SY-1-treated tumors, whereas the p21/Cip1 protein levels did not change. The G0/G1 phase cell cycle regulators induced by SY-1 were also associated with a significant decrease in cyclins D1, D3, and A. These results provide further evidence that SY-1 may have significance for cancer chemotherapy. PMID- 22429158 TI - The antidepressants citalopram and reboxetine reduce seizure frequency in rats with chronic epilepsy. AB - PURPOSE: For a long time, antidepressants have been thought to possess proconvulsant properties. This assumption, however, remains controversial, since anticonvulsant effects have been attributed to certain antidepressants. To date, it remains unclear which antidepressants can be used for the treatment of depression in patients with epilepsy. In this respect, studies investigating the convulsant liability of antidepressants in a chronic epilepsy model can give valuable information. The present study was designed to determine the seizure liability of citalopram and reboxetine in the kainic acid-induced post-status epilepticus model for temporal lobe epilepsy. METHODS: Two months after the induction of status epilepticus, chronic epileptic rats (n = 16) were video electroencephalography (EEG) monitored during seven consecutive weeks. Weeks 1, 3, 5, and 7 served as sham weeks during which the rats received intraperitoneal saline injections for four consecutive days, followed by a 3-day sham washout period during which no injections were given. During weeks 2, 4, and 6, rats received intraperitoneal injections with either citalopram (5, 10, and 15 mg/kg, once daily, n = 8) or reboxetine (10, 20, and 30 mg/kg, twice daily, n = 8) for 4 days, again followed by a washout period of 3 days. Drugs were administered in a randomly assigned fixed-dose regimen per week. Each rat served as its own control. The drug doses were selected based on the doses reported to have antidepressant effects in rats. KEY FINDINGS: Citalopram significantly decreased the spontaneous seizure frequency at the highest dose tested, that is, the mean number of seizures decreased from 12.8 seizures to 8.8 seizures per week (31%) after treatment with 15 mg/kg citalopram. This dose also significantly decreased the cumulative seizure duration. Administration of 5 and 10 mg/kg citalopram did not alter the seizure frequency. The two highest doses of reboxetine significantly decreased the spontaneous seizure frequency, that is, 20 mg/kg reboxetine decreased the seizure frequency from 14.1 to 7.9 (44%) and 30 mg/kg reboxetine decreased the seizure frequency from 11.8 to 7.2 (39%). In addition, both doses significantly decreased the cumulative seizure duration. Administration of 10 mg/kg reboxetine did not alter seizure frequency. Citalopram and reboxetine had no effect on seizure severity and seizure duration in any of the doses tested. SIGNIFICANCE: In general we can conclude that antidepressant doses of citalopram and reboxetine have, depending on the dose, an anticonvulsant effect or no effect on spontaneous seizures in the kainic acid-induced post status epilepticus rat model. PMID- 22429159 TI - How society shapes the health gradient: work-related health inequalities in a comparative perspective. AB - Analyses in comparative political economy have the potential to contribute to understanding health inequalities within and between societies. This article uses a varieties of capitalism approach that groups high-income countries into coordinated market economies (CME) and liberal market economies (LME) with different labor market institutions and degrees of employment and unemployment protection that may give rise to or mediate work-related health inequalities. We illustrate this approach by presenting two longitudinal comparative studies of unemployment and health in Germany and the United States, an archetypical CME and LME. We find large differences in the relationship between unemployment and health across labor-market and institutional contexts, and these also vary by educational status. Unemployed Americans, especially of low education or not in receipt of unemployment benefits, have the poorest health outcomes. We argue for the development of a broader comparative research agenda on work-related health inequalities that incorporates life course perspectives. PMID- 22429160 TI - A review of spatial methods in epidemiology, 2000-2010. AB - Understanding the impact of place on health is a key element of epidemiologic investigation, and numerous tools are being employed for analysis of spatial health-related data. This review documents the huge growth in spatial epidemiology, summarizes the tools that have been employed, and provides in-depth discussion of several methods. Relevant research articles for 2000-2010 from seven epidemiology journals were included if the study utilized a spatial analysis method in primary analysis (n = 207). Results summarized frequency of spatial methods and substantive focus; graphs explored trends over time. The most common spatial methods were distance calculations, spatial aggregation, clustering, spatial smoothing and interpolation, and spatial regression. Proximity measures were predominant and were applied primarily to air quality and climate science and resource access studies. The review concludes by noting emerging areas that are likely to be important to future spatial analysis in public health. PMID- 22429161 TI - Early intervention to reduce the global health and economic burden of major depression in older adults. AB - Randomized trials for selective and indicated prevention of depression in both mixed-aged and older adult samples, conducted in high-income countries (HICs), show that rates of incident depression can be reduced by 20-25% over 1-2 years through the use of psychoeducational and psychological interventions designed to increase protective factors. Recurrence of major depression can also be substantially reduced through both psychological and psychopharmacological strategies. Additional research is needed, however, to address the specific issues of depression prevention in older adults in low- and middle-income countries (LMICs). The growing number of older adults globally, as well as workforce issues and the expense of interventions, makes it important to develop rational, targeted, and cost-effective risk-reduction strategies. In our opinion, one strategy to address these issues entails the use of lay health counselors (LHCs), a form of task shifting already shown to be effective in the treatment of common mental disorders in LMICs. We suggest in this review that the time is right for research into the translation of depression-prevention strategies for use in LMICs. PMID- 22429162 TI - Advertising of prescription-only medicines to the public: does evidence of benefit counterbalance harm? AB - Since the global withdrawal of rofecoxib (Vioxx) in 2004, concerns about public health effects of direct-to-consumer advertising (DTCA) have grown. A systematic review of the research evidence on behavioral, health, and cost effects, published in 2005, found four studies meeting inclusion criteria, which showed that DTCA increases prescribing volume and patient demand, and shifts prescribing. From 2005 to 2010, nine studies met similar criteria. These largely confirm previous results. Additional effects include a shift to less appropriate prescribing, differential effects by patient price sensitivity and drug type, switches to less cost-effective treatment, and sustained sales despite a price increase. Claimed effects on adherence do not stand up to scrutiny and are based mainly on negative trials. There is no evidence of improved treatment quality or early provision of needed care. If policy is to be informed by evidence, the strength of research methods and ability to assess causality need to be considered. PMID- 22429163 TI - Remodeling of ventricular repolarization in a chronic doxorubicin cardiotoxicity rat model. AB - Doxorubicin, one of the most effective anticancer drugs, is characterized by severe cardiotoxic effects, which induce cardiac remodeling and congestive heart failure. The aim of the study was to evaluate remodeling of ventricular repolarization heterogeneity in chronic doxorubicin cardiotoxicity in rats. Doxorubicin cardiotoxicity was produced by six equal intraperitoneal injections of the drug in a cumulative dose of 15 mg/kg in a 2-week period. Electrophysiological mapping of the ventricular epicardium in situ was performed 6 weeks after the last injection of doxorubicin. Activation-recovery intervals (ARIs) were used for the evaluation of the heterogeneity in repolarization durations. The major findings were as follows: (1) ARIs on the ventricular epicardium of both ventricles were significantly prolonged in the doxorubicin group and (2) this inhomogeneous prolongation of ARIs on the ventricular epicardium resulted in (i) the increase in the dispersion of repolarization across the ventricular epicardium and (ii) the inhomogeneous alterations of the regional ARI gradients on the ventricular epicardium. These changes in repolarization could explain the electrocardiographic alterations, that is, the prolongation of the QT interval and flattening of the T wave. PMID- 22429164 TI - Does fludarabine increase the incidence of sinusoidal obstruction syndrome when combined with Bu/Cy during conditioning? PMID- 22429166 TI - Conversations with medical education. PMID- 22429167 TI - Nurturing resiliency in medical trainees. PMID- 22429168 TI - Teaching and learning resilience: a new agenda in medical education. PMID- 22429169 TI - Shining light on competence. PMID- 22429170 TI - Towards an understanding of resilience and its relevance to medical training. AB - OBJECTIVES: This article explores the concept of resilience and its potential relevance to medicine. It also looks at the dimensions of resilience and its ethical importance for effective professional practice, and considers whether a focus on resilience might be useful in medical training. METHODS: An applied literature search was conducted across the domains of education, ethics, psychology and sociology to answer the research question: 'What is resilience and what might it mean for professional development in medical education?' This article predominantly considers the findings in relation to training in undergraduate and postgraduate settings, although the literature is wide-ranging and findings may be applicable elsewhere. RESULTS: Resilience is a dynamic capability which can allow people to thrive on challenges given appropriate social and personal contexts. The dimensions of resilience (which include self efficacy, self-control, ability to engage support and help, learning from difficulties, and persistence despite blocks to progress) are all recognised as qualities that are important in clinical leaders. Much of what is deemed good practice in modern pedagogical approaches to medical training may support the development of resilience in adulthood, but this concept has rarely been used as a goal of professional development. More research is needed on the ways in which resilience can be recognised, developed and supported during and after clinical training. CONCLUSIONS: Resilience is a useful and interesting construct which should be further explored in medical education practice and research. PMID- 22429171 TI - Varying conceptions of competence: an analysis of how health sciences educators define competence. AB - CONTEXT: Current debate in medical education focuses on the nature of 'competency-based medical education' (CBME) and whether or not it should be adopted. Many medical schools claim to run 'competency-based' curricula, but the structure of their programmes can differ radically. A review of the existing CBME literature reveals that little attention has been paid to defining the concept of competence. A straightforward examination of what is meant by the term 'competence' is noticeably missing from the literature, despite its impact on medical training. OBJECTIVES: This paper aims to illustrate the varying conceptions of 'competence' by comparing and contrasting definitions provided in the health sciences education literature and discussing their respective impacts on medical education. METHODS: A systematic review of recent publications in medical education journals published in English and French was conducted to extract definitions of competence or, if definitions were not explicitly stated, to derive the authors' implicit conception of competence. A sample of 14 definitions from articles in the health sciences education field was studied using thematic analysis. RESULTS: There is agreement that competence is composed of knowledge, skills and other components. Although agreement about the nature of these other components is lacking, attitudes and values are suggested to be essential ingredients of competence. Furthermore, a clear divergence in conceptions of how a competent person utilises these components is apparent. One view specifies that competence involves selecting components according to specific situations, as required. A second view places greater emphasis on the synergy that results from the use of a combination of components in a given situation. CONCLUSIONS: These conceptual distinctions have many implications for the way CBME is implemented. A conception of competence as the selection of components may lead to a greater emphasis, in a training setting, on the mastery of each component separately. A conception of competence as the use of a combination of components leads to greater emphasis on the synergy that results as they are deployed in clinical situations. PMID- 22429172 TI - From test validity to construct validity ... and back? AB - CONTEXT: Major changes in thinking about validity have occurred during the past century, shifting the focus in thinking from the validity of the test to the validity of test score interpretations. These changes have resulted from the 'new' thinking about validity in which construct validity has emerged as the central or unifying idea of validity today. Construct validity was introduced by Cronbach and Meehl in the mid-1950s in an attempt to address the validity of those many psychological concepts that have no clear referent in reality. To do this, construct validity theory required a nomological network--an elaborate theoretical network of constructs and observations connected by scientific laws- to validate the constructs. However, nomological networks are hard to come by and none that would do the job required by construct validity has been forthcoming to date. Thus, the current construct validity approach has retreated to one of simply 'interpretation and argument', but this seems to be too general to tie down the constructs in the way a nomological network would do to give credibility to the validity of the construct. As a result, the concept of validity seems to have been watered down and the credibility of validity claims weakened. OBJECTIVES: The purpose of this paper is to encourage a discussion of the use of construct validity in medical education, and to suggest that test developers and users reconsider the use of abstract theoretical constructs that have no referent apart from theory. METHODS: We present a critical review of these concerns about construct validity and provide for contrast a brief overview of a recently proposed view of measurement based on scientific realism and causality analysis. PMID- 22429173 TI - Working with words: exploring textual analysis in medical education research. AB - CONTEXT: Text is familiar to us all. This paper offers an introduction to, and an exploration of, the range of methodological possibilities open to the education researcher who has chosen to use text as a research data source. It encourages a purposeful deliberation of the different textual sources available as data, the range of methodological approaches possible and the types of interpretation that can be adopted when embarking on an empirical study using textual data. METHODS: Approaches to interpreting text are varied and utilise a range of analytical and interpretative strategies. To illustrate the theoretical points raised within this paper, two contrasting methods were applied to the same text. Tag cloud analysis and performative narrative analysis (PNA) were employed to analyse Chapter 4 of the UK government's 2010 White Paper Equity and excellence: Liberating the NHS. RESULTS: The adoption of these contrasting methodologies, which are not currently used extensively in medical education research, revealed that some common issues were identified by both tag clouds and PNA, but, in addition, each approach was able to unveil something unique about the text. CONCLUSIONS: These two methods highlight the range of affordances, or possibilities, that textual analysis will have on the results. We suggest that medical education researchers should be encouraged to move away from the current dominant and privileged methodologies that seek to provide answers and explore other methods and approaches to textual data that encourage us to question and reflect more deeply. PMID- 22429174 TI - Factors influencing residents' evaluations of clinical faculty member teaching qualities and role model status. AB - OBJECTIVES: Evaluations of faculty members are widely used to identify excellent or substandard teaching performance. In order to enable such evaluations to be properly interpreted and used in faculty development, it is essential to understand the factors that influence resident doctors' (residents) evaluations of the teaching qualities of faculty members and their perceptions of faculty members as role-model specialists. METHODS: We carried out a cross sectional survey within a longitudinal study of the System for Evaluation of Teaching Qualities (SETQ) of clinical teachers. The study sample included 889 residents and 1014 faculty members in 61 teaching programmes spanning 22 specialties in 20 hospitals in the Netherlands. Main outcome measures included residents' (i) global and (ii) specific ratings of faculty member teaching qualities, and (iii) global ratings of faculty members as role-model specialists. Statistical analysis was conducted using adjusted multivariable logistic generalised estimating equations. RESULTS: In total, 690 residents (77.6%) completed 6485 evaluations of 962 faculty members, 848 (83.6%) of whom also self evaluated. More recently certified faculty members, those who had attended a teacher training programme, and those who spent more time teaching than seeing patients or conducting research were more likely to score highly on most teaching qualities. However, faculty members who had undergone teacher training were less likely to be seen as role models (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.59-0.88). In addition, faculty members were evaluated slightly higher by male than female residents on core teaching domains and overall teaching quality, but were less likely to be seen as role models by male residents (OR 0.80, 95% CI 0.67-0.97). Lastly, faculty members had higher odds of receiving top scores in specific teaching domains from residents in the first 4 years of residency and were less likely to be considered as role models by more senior residents. CONCLUSIONS: Younger faculty members who dedicated more time to teaching, had attended a teacher training programme, and were evaluated by male residents in the early years of residency were more likely to receive higher scores for teaching performance. PMID- 22429175 TI - How lead consultants approach educational change in postgraduate medical education. AB - CONTEXT: Consultants in charge of postgraduate medical education (PGME) in hospital departments ('lead consultants') are responsible for the implementation of educational change. Although difficulties in innovating in medical education are described in the literature, little is known about how lead consultants approach educational change. OBJECTIVES: This study was conducted to explore lead consultants' approaches to educational change in specialty training and factors influencing these approaches. METHODS: From an interpretative constructivist perspective, we conducted a qualitative exploratory study using semi-structured interviews with a purposive sample of 16 lead consultants in the Netherlands between August 2010 and February 2011. The study design was based on the research questions and notions from corporate business and social psychology about the roles of change managers. Interview transcripts were analysed thematically using template analysis. RESULTS: The lead consultants described change processes with different stages, including cause, development of content, and the execution and evaluation of change, and used individual change strategies consisting of elements such as ideas, intentions and behaviour. Communication is necessary to the forming of a strategy and the implementation of change, but the nature of communication is influenced by the strategy in use. Lead consultants differed in their degree of awareness of the strategies they used. Factors influencing approaches to change were: knowledge, ideas and beliefs about change; level of reflection; task interpretation; personal style, and department culture. CONCLUSIONS: Most lead consultants showed limited awareness of their own approaches to change. This can lead them to adopt a rigid approach, whereas the ability to adapt strategies to circumstances is considered important to effective change management. Interventions and research should be aimed at enhancing the awareness of lead consultants of approaches to change in PGME. PMID- 22429176 TI - Evaluating cognitive ability, knowledge tests and situational judgement tests for postgraduate selection. AB - OBJECTIVES: This study aimed to evaluate the validity and utility of and candidate reactions towards cognitive ability tests, and current selection methods, including a clinical problem-solving test (CPST) and a situational judgement test (SJT), for postgraduate selection. METHODS; This was an exploratory, longitudinal study to evaluate the validities of two cognitive ability tests (measuring general intelligence) compared with current selection tests, including a CPST and an SJT, in predicting performance at a subsequent selection centre (SC). Candidate reactions were evaluated immediately after test administration to examine face validity. Data were collected from candidates applying for entry into training in UK general practice (GP) during the 2009 recruitment process. Participants were junior doctors (n = 260). The mean age of participants was 30.9 years and 53.1% were female. Outcome measures were participants' scores on three job simulation exercises at the SC. RESULTS: Findings indicate that all tests measure overlapping constructs. Both the CPST and SJT independently predicted more variance than the cognitive ability test measuring non-verbal mental ability. The other cognitive ability test (measuring verbal, numerical and diagrammatic reasoning) had a predictive value similar to that of the CPST and added significant incremental validity in predicting performance on job simulations in an SC. The best single predictor of performance at the SC was the SJT. Candidate reactions were more positive towards the CPST and SJT than the cognitive ability tests. CONCLUSIONS: In terms of operational validity and candidate acceptance, the combination of the current CPST and SJT proved to be the most effective administration of tests in predicting selection outcomes. In terms of construct validity, the SJT measures procedural knowledge in addition to aspects of declarative knowledge and fluid abilities and is the best single predictor of performance in the SC. Further research should consider the validity of the tests in this study in predicting subsequent performance in training. PMID- 22429177 TI - The role of collaborative interactivity in the observational practice of clinical skills. AB - CONTEXT: Video-based observational practice can extend simulation-based learning outside the training space. This study explores the value of collaborative feedback provided during observational practice to the acquisition of clinical skills. METHODS: Nursing students viewed a video demonstrating the proper ventrogluteal injection technique before performing a videotaped pre-test trial on a simulator. They were then assigned randomly to one of three observational practice groups: a group that observed the expert demonstration (EO group); a group that viewed the expert demonstration, self-assessed their individual pre-test and contrasted their self-assessments with expert feedback (ESO group), and a group that observed the expert demonstration, self-assessed and contrasted their assessments with those of an expert, and formed a community that engaged in peer-to-peer feedback (ESPO group). The observation of all videos, the provision of assessments and all networking occurred via an Internet mediated network. After 2 weeks, participants returned for post-tests and transfer tests. RESULTS: The pre-test-post-test analyses revealed significant interactions (global rating scale: F((2,22)) =4.00 [p =0.033]; checklist: F((2,22)) =4.31 [p =0.026]), which indicated that post-test performance in the ESPO group was significantly better than pre-test performance. The transfer analyses revealed main effects for both the global rating scale (F((2,23)) =6.73; p =0.005) and validated checklist (F((2,23)) =7.04; p =0.004) measures. Participants in the ESPO group performed better on the transfer test than those in the EO group. CONCLUSIONS: The results suggest that video-based observational practice can be effective in extending simulation-based learning, but its effectiveness is mediated by the amount of time the learner spends engaged in the practice and the type of learning activities the learner performs in the observational practice environment. We speculate that increasing collaborative interactivity supports observational learning by increasing the extent to which the educational environment can accommodate learners' specific needs. PMID- 22429178 TI - Integrating virtual patients into courses: follow-up seminars and perceived benefit. AB - CONTEXT: The use of virtual patients (VPs) suggests promising effects on student learning. However, currently empirical data on how best to use VPs in practice are scarce. More knowledge is needed regarding aspects of integrating VPs into a course, of which student acceptance is one key issue. Several authors call for looking beyond technology to see VPs in relation to the course context. The follow-up seminar is proposed as an important aspect of integration that warrants investigation. METHODS: A cross-sectional explanatory study was performed in a clinical clerkship introduction course at four teaching hospitals affiliated to the same medical faculty. The VP-related activities were planned collaboratively by teachers from all four settings. However, each setting employed a different strategy to follow up the activity in the course. Sixteen questionnaire items were grouped into three scales pertaining to: perceived benefit of VPs; wish for more guidance on using VPs, and wish for assessment and feedback on VPs. Scale scores were compared across the four settings, which were ranked according to the level of intensity of students' processing of cases during VP follow-up activities. RESULTS: The perceived benefit of VPs and their usage were higher in the two intense-use settings compared with the moderate- and low-intensity settings. The wish for more guidance was high in the low- and one of the high-intensity settings. Students in all settings displayed little interest in more assessment and feedback regarding VPs. CONCLUSIONS: High case processing intensity was related to positive perceptions of the benefit of VPs. However, the low interest in more assessment and feedback on the use of VPs indicates the need to clearly communicate the added value of the follow-up seminar. The findings suggest that a more intense follow-up pays off in terms of the benefit perceived by students. This study illustrates the need to consider VPs from the perspective of a holistic course design and not as isolated add-ons. PMID- 22429179 TI - Video-based cases disrupt deep critical thinking in problem-based learning. AB - CONTEXT: Video is a popular tool in problem-based learning (PBL), although its production requires resources and time. Few studies have examined the impact of the use of video in PBL upon cognitive processes and critical thinking. Those that have done focused on cases involving physical signs, where video has natural advantages. OBJECTIVES: This study aimed to investigate preferences for video- or text-based cases and the effects of each format upon medical students' deep thinking in PBL. Tutorials were based on material portraying interviews with patients with conditions that include psychosocial elements but no physical signs. METHODS: Four tutorial groups of students in a Year 2 endocrine and reproductive pathophysiology course participated in a crossover study using one video-based and one text-based case. Transcripts of tutorials were coded for depth of thinking by a blinded coder. A generalised estimating equation model was used to adjust for potential differences among groups, cases, and tutor participation. The distribution of cognitive activity within the crossover groups and the adjusted odds ratios (ORs) for deep versus superficial thinking were calculated. A prior cohort of 165 students and 18 tutors completed a survey of learning preferences. RESULTS: Of 5224 student utterances, the majority referred to problem exploration (2622, 50%) and description (1479, 28%). Overall, the odds of deep thinking versus superficial thinking were significantly lower using video-based cases compared with text-based cases (2045 deep/2454 for video versus 1961 deep/2218 for text; OR 0.663, 95% confidence interval [CI] 0.582 0.754; p < 0.0001). This was also true for the problem exploration domain (1217 deep/1365 for video versus 1178 deep/1257 for text; OR 0.559, 95% CI 0.355-0.882; p = 0.0125). The majority of students (59%) and tutors (78%) indicated a preference for video-based cases over text-based cases. CONCLUSIONS: Students and their tutors prefer video-based cases in PBL. However, compared with text based material, the use of video-based material that refers to cases without dynamic physical signs is associated with a reduction in deep thinking. PMID- 22429180 TI - Making sense of work-based assessments. PMID- 22429181 TI - Arts-based learning: is it worthwhile? PMID- 22429182 TI - Synthesis and properties of semiconducting iron pyrite (FeS2) nanowires. AB - We report the growth and structural, electrical, and optical characterization of vertically oriented single-crystalline iron pyrite (FeS(2)) nanowires synthesized via thermal sulfidation of steel foil for the first time. The pyrite nanowires have diameters of 4-10 nm and lengths greater than 2 MUm. Their crystal phase was identified as cubic iron pyrite using high-resolution transmission electron microscopy, Raman spectroscopy, and powder X-ray diffraction. Electrical transport measurements showed the pyrite nanowires to be highly p-doped, with an average resistivity of 0.18 +/- 0.09 Omega cm and carrier concentrations on the order of 10(21) cm(-3). These pyrite nanowires could provide a platform to further study and improve the physical properties of pyrite nanostructures toward solar energy conversion. PMID- 22429184 TI - Corticospinal adaptations and strength maintenance in the immobilized arm following 3 weeks unilateral strength training. AB - Cross-education strength training has being shown to retain strength and muscle thickness in the immobilized contralateral limb. Corticospinal mechanisms have been proposed to underpin this phenomenon; however, no transcranial magnetic stimulation (TMS) data has yet been presented. This study used TMS to measure corticospinal responses following 3 weeks of unilateral arm training on the contralateral, immobilize arm. Participants (n = 28) were randomly divided into either immobilized strength training (Immob + train) immobilized no training (Immob) or control. Participants in the immobilized groups had their nondominant arm rested in a sling, 15 h/day for 3 weeks. The Immob + train group completed unilateral arm curl strength training, while the Immob and control groups did not undertake training. All participants were tested for corticospinal excitability, strength, and muscle thickness of both arms. Immobilization resulted in a group x time significant reduction in strength, muscle thickness and corticospinal excitability for the untrained limb of the Immob group. Conversely, no significant change in strength, muscle thickness, or corticospinal excitability occurred in the untrained limb of the Immob + train group. These results provide the first evidence of corticospinal mechanisms, assessed by TMS, underpinning the use of unilateral strength training to retain strength and muscle thickness following immobilization of the contralateral limb. PMID- 22429183 TI - B cells as effectors and regulators of sex-biased arthritis. AB - B cells have been implicated both with pathogenic as well as protective capabilities in induction and regulation of autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune disease that occurs more often in women than men. A significant role of B cells as antibody producing and antigen-presenting cells has been demonstrated in RA. Predisposition to RA is associated with the presence of certain HLA class II alleles that share sequences with DRB1*0401. To determine the role of HLA genes and B cells in vivo, we have generated transgenic mice carrying HLA genes, DRB1*0401 and DQ8, known to be associated with susceptibility to RA. Humanized mice can be induced to develop arthritis that mimics human disease in clinical, histopathological and sex bias. Effect of hormones on immune cells and their function has been described in humans and mice and has been suggested to be the major reason for female bias of autoimmune diseases. An immune response to an antigen requires presentation by HLA molecules thus suggesting a critical role of MHC in combination with sex hormones in susceptibility to develop rheumatoid arthritis. Based on our observations, we hypothesize that modulation of B cells by estrogen, presentation of modified antigens by DR4 and production of antigen-specific B cell modulating cytokines leads to autoreactivity in females. These data suggest that considering patient's sex may be crucial in selecting the optimal treatment strategy. Humanized mice expressing RA susceptible and resistant haplotype provide a means to investigate mechanism sex-bias of arthritis and future strategies for therapy. PMID- 22429185 TI - Family history of exceptional longevity is associated with lower serum uric acid levels in Ashkenazi Jews. AB - OBJECTIVES: To test whether lower serum uric acid (UA) levels are associated with longevity independent of renal function. DESIGN: Cross-sectional cohort study. SETTING: Ashkenazi Jewish individuals with exceptional longevity (Longevity Genes Project at Albert Einstein College of Medicine). PARTICIPANTS: Long-lived individuals (LLI) of Ashkenazi Jewish ethnicity (mean age +/- standard deviation 97.7 +/- 2.9, n = 365), their offspring (mean age +/- standard deviation 68.2 +/- 8.2, n = 593) and controls (without family history of longevity, mean age +/- standard deviation 72.5 +/- 9.9, n = 356). MEASUREMENTS: Association between UA levels and estimated glomerular filtration rate (eGFR) as well as chronic kidney disease (CKD) stage, and correlation of UA levels of LLI and offspring were determined. Because LLI lack an appropriate control group, UA levels, eGFR, and prevalence of hyperuricemia and CKD stages were compared between offspring and controls. RESULTS: Offspring were less likely to have hyperuricemia and had lower UA levels than controls. Despite negative correlation between UA levels and eGFR and positive correlation between UA levels and CKD stages, eGFR and the prevalence of CKD stage III to V were not found to be different between offspring and controls. Furthermore, significant association between UA levels in LLI and their offspring (beta estimate 0.1544, 95% confidence interval = 0.08-0.23, P < .001) has been observed. CONCLUSION: Offspring had lower UA levels than controls despite similar renal function, suggesting that other factors such as UA metabolism or renal tubular transport determine UA levels. The association between UA levels and longevity is particularly intriguing because UA levels are potentially modifiable with diet and drugs. PMID- 22429186 TI - Mini-BEAM is effective as a bridge to transplantation in patients with refractory or relapsed Hodgkin lymphoma who have failed to respond to previous lines of salvage chemotherapy but not in patients with salvage-refractory DLBCL. AB - Patients with relapsed or refractory lymphoma can be cured with stem cell transplantation if they are shown to have disease that is responsive to salvage chemotherapy. Patients who fail to respond to first-line salvage chemotherapy tend to do very poorly. Here we report on 39 such patients who received mini-BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy as second or subsequent-line salvage chemotherapy. Fifty-six percent of these patients had primary refractory disease and a further 28% had responses to first-line therapy that lasted <12 months. Seventy-two percent had progressive disease following the salvage chemotherapy administered immediately prior to mini-BEAM and the remaining 28% had stable disease. Overall there was a 38% response to mini-BEAM (complete response = 28%, partial response = 10%). Patients with Hodgkin lymphoma (HL) had a higher response rate compared to those with diffuse large B cell lymphoma (DLBCL) (63% vs. 20%). Seventy-four percent of HL patients were able to proceed to transplantation compared with 30% of patients with DLBCL. Mini-BEAM is a very effective bridge to transplantation in very poor risk patients with HL who have failed to respond to first-line salvage chemotherapy. Its efficacy in non Hodgkin lymphoma is more modest. PMID- 22429188 TI - Preferential formation of the different hydrogen bonds and their effects in tetrahydrofuran and tetrahydropyran microhydrated complexes. AB - The role of cycloether-water (c-w) and water-water (w-w) hydrogen bonds (H-bonds) on the stability of the tetrahydrofuran THF/(H(2)O)(n) and the tetrahydropyran THP/(H(2)O)(n) complexes with n = 1-4 was investigated herein using the density functional and ab initio methods and the atoms in molecules theory. Geometry optimizations for these complexes were carried out with various possible initial guess structures. It was revealed that the major contributions of the mono and dihydrated complexes came from c-w H-bonds. A competition between c-w and w-w H bonds contribution was observed for trihydrated complexes. For most of tetrahydrated complexes, the inter-water H-bonds provided the greatest contribution, whereas the c-w contributions were small but not negligible. It was confirmed that to produce a hydrophobic hydration of cycloethers, the C-H...O(w) H-bond should be associated with a network of H-bonds that connects both portions of the solute, through the formation of a bifunctional H-bond. A linear correlation is obtained for the sum of electron density at the bond critical points (rho(b)) with the interaction energy (DeltaE) and with the solute-solvent interaction energy (DeltaE(s-w)) of the microhydrated complexes. In addition, a new way to estimate the energetic contribution as well as the preferential formation of the different H-bonds based completely on rho(b) was found. Even more, it allows to differentiate the contribution from c-w interactions in both hydrophilic and hydrophobic contributions, it is therefore a useful tool for studying the hydration of large biomolecules. The analysis of the modifications in the atomic and group properties brought about by successive addition of H(2)O molecules allowed to pinpoint the atoms or molecular groups that undergo the greatest changes in electron population and energetic stabilization. It was identified that the remarkable stabilization of the water oxygen atoms is crucial for the stabilization of the complexes. PMID- 22429187 TI - Fatty acid profile and sensory characteristics of table eggs from laying hens fed hempseed and hempseed oil. AB - Hempseed (HS) is rich in omega-3 polyunsaturated fatty acids, with approximately 17% of total fatty acids as alpha-linolenic acid. As such, HS and its oil may be used in hen diet formulations to produce eggs enriched in essential fatty acids. Because omega-3 eggs have the potential for unpleasant aromas and flavors, the current study was designed to assess the fatty acid profile and sensory attributes of eggs procured from hens consuming diets containing hempseed oil (HO) or HS. A total of 48 individually caged White Bovan hens received 1 of 6 diets containing 4%, 8%, 12% HO, 10%, 20% HS or 0% hemp (w/w) for 12 wk. Total omega-3 polyunsaturated fatty acid content was highest in the 12% HO group (15.3 mg/g of yolk) compared to the control (2.4 mg/g of yolk). Trained panellists (n= 8) found no significant differences (P>= 0.05) in aroma or flavor between cooked eggs from different dietary treatments, with the exception of sweet flavor. The 4% HO group yielded the least sweet eggs compared to the 20% HS group, which was highest. For yolk color, L*, a*, and b* values (Mean +/- SEM) for control eggs were 61.2 +/- 0.10, 1.1 +/- 0.05, and 43.0 +/- 0.22, respectively. Addition of hemp led to significant (P < 0.001) reductions in L*, and significant increases in a* and b*, with the largest changes observed in the 20% HS treatment (L*= 58.7 +/- 0.10; a*= 5.8 +/- 0.05; b*= 60.5 +/- 0.22). The results show that hemp use in hen diets leads to increased omega-3 polyunsaturated fatty acid content and color intensity of egg yolks, but does not have adverse effects on the sensory profiles of the cooked eggs. PRACTICAL APPLICATION: This study provides evidence that HS and hempseed oil (HO) can safely be utilized as feed ingredients for laying hens to produce table eggs that are enriched in essential fatty acids. Additionally, the eggs procured from these hens had similar aroma and flavor compared to eggs from hens not fed any hemp. The greater the dietary hemp inclusion, the more pigmented the resulting yolks became in terms of darkness, redness, and yellowness. PMID- 22429189 TI - Agreement between psychophysical tuning curves and the threshold equalizing noise test in dead region identification. AB - OBJECTIVE: Identification of dead regions is currently based on the results of psychophysical tuning curves (PTC) and the threshold equalizing noise (TEN) test. Summers et al (2003) found poor agreement (56%) between PTC- and TEN test results. Kluk and Moore (2005) argued that these results are explained by beat- and/or combination tone detection. The purpose of this study was to examine the diagnostic dead region relationship between PTCs, modified for beats and/or combination tone detection, and the TEN test with levels calibrated in hearing levels (HL), i.e., TEN[HL]. DESIGN: Twenty-four hearing-impaired ears were evaluated using PTCs and the TEN[HL] test. RESULTS: The results show an agreement of about 75%, depending on the criteria applied, between PTC and the TEN[HL] test. Results also show that PTC probe levels affected diagnostic results in PTCs. CONCLUSIONS: Recommended criteria based on the highest agreement score included a PTC shift of 20% and an 8-dB probe elevation above TEN masking levels for the TEN[HL] test. Low agreement scores and level dependent effects in PTCs and the TEN[HL] test suggest that identification of dead regions using a single test is not reliable. PMID- 22429190 TI - Systematic review: the prognostic role of alpha-fetoprotein following liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Liver transplantation (LT) offers a possible cure for carefully selected patients with hepatocellular carcinoma (HCC). Studies report that preoperative alpha-fetoprotein (AFP) is a prognostic indicator that can predict survival and recurrence in these patients. AIM: To undertake a systematic review of available literature on preoperative AFP as a predictor of survival and recurrence following LT for HCC. METHODS: A literature search was performed using Medline, Embase, Cochrane Library, CINAHL and Google scholar databases to identify studies reporting AFP as a prognostic marker in LT for HCC. Primary outcomes of interest were overall survival and recurrence. Secondary outcomes were correlation of pre-LT AFP with vascular invasion and grade of tumour differentiation. RESULTS: A total of 13 studies met the inclusion criteria (12,159 patients). The majority were male (9603, 78.9%). All were observational studies and only one prospective. Methodological quality was rated as poor for all studies, with selection and observer bias apparent for most cohorts. Reported survival rates and recurrence rates varied widely between the studies although overall demonstrated better outcomes for those with lower (<1000 ng/mL) pre-LT AFP levels. Similarly, rates of vascular invasion and poor tumour differentiation were higher in those with high pre-LT AFP levels. CONCLUSIONS: A quantity of AFP >1000 ng/mL is associated with poorer outcomes from liver transplantation for hepatocellular carcinoma. The quality of studies was generally poor and precluded valid statistical meta-analysis. There is a need to improve the performance and reporting of primary prognostic studies to facilitate high quality systematic review and meta-analysis. PMID- 22429191 TI - Detection of Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia in primary endodontic infections in a Chinese population. AB - AIM: To assess the prevalence of three black-pigmented bacterial species (Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia) using microarray technology in root canals of teeth associated with primary endodontic infections in a Chinese population. METHODOLOGY: Microbial samples were taken from root canals of 80 teeth with pulp necrosis and primary endodontic infections in a Chinese population. DNA extracted from the samples was amplified by PCR with universal bacterial primers based on 16S rRNA gene sequences, and the products hybridized with the microarrays in which the specific oligonucleotide probes were added. The results of hybridization were screened by a confocal laser scanner. Pearson chi-square test and the two-sided Fisher exact test were used to analyse whether a significant association existed between the species and symptoms as well as in co-existence of two target organisms by a statistical software package (SAS 8.02). RESULTS: The 16S rRNA gene microarray detected at least one of the three test species in 76% of the study teeth. P. endodontalis, P. gingivalis and P. intermedia were found in 50%, 33% and 45%, respectively. A significant association was found in the presence of the pair P. endodontalis / P. gingivalis (P < 0.005). Both P. endodontalis (P <0.05) and P. gingivalis (P <0.005) had a statistically significant association with the presence of a sinus tract. The simultaneous presence of P. endodontalis and P. gingivalis was also associated with the presence of a sinus tract (P<0.005) and abscess formation (P<0.05). CONCLUSIONS: The three black-pigmented bacteria were prevalent in teeth with pulp necrosis and primary endodontic infections in a Chinese population. P. gingivalis and P. endodontalis were associated with the presence of sinus tract and abscess formation. PMID- 22429192 TI - A randomized controlled trial of the GnRH antagonist ganirelix in Chinese normal responders: high efficacy and pregnancy rates. AB - Gonadotropin-releasing hormone (GnRH) antagonists for controlled ovarian stimulation (COS) were only recently introduced into China. The efficacy and safety of the GnRH antagonist ganirelix was assessed in a multicenter, controlled, open-label study, in which Chinese women were randomized to either ganirelix (n = 113) or a long GnRH agonist protocol of triptorelin (n = 120). The primary end point was the amount of recombinant follicle-stimulating hormone (rFSH) required to meet the human chorionic gonadotropin criterion (three follicles >=17 mm). The amount of rFSH needed was significantly lower for ganirelix (1272 IU) vs. triptorelin (1416 IU; P< 0.001). Ongoing pregnancy rates per started cycle were 39.8% (ganirelix) and 39.2% (triptorelin). Although both treatments were well tolerated, cancellation due to risk of ovarian hyperstimulation syndrome (OHSS) was less frequent with ganirelix (1.8%) than triptorelin (7.5%) (P = 0.06). Less rFSH was needed in the ganirelix protocol than the long GnRH agonist protocol, with fewer reported cases of OHSS and similar pregnancy rates. PMID- 22429193 TI - A comparison of methods for estimating quadratic effects in nonlinear structural equation models. AB - Two Monte Carlo simulations were performed to compare methods for estimating and testing hypotheses of quadratic effects in latent variable regression models. The methods considered in the current study were (a) a 2-stage moderated regression approach using latent variable scores, (b) an unconstrained product indicator approach, (c) a latent moderated structural equation method, (d) a fully Bayesian approach, and (e) marginal maximum likelihood estimation. Of the 5 estimation methods, it was found that overall the methods based on maximum likelihood estimation and the Bayesian approach performed best in terms of bias, root-mean square error, standard error ratios, power, and Type I error control, although key differences were observed. Similarities as well as disparities among methods are highlight and general recommendations articulated. As a point of comparison, all 5 approaches were fit to a reparameterized version of the latent quadratic model to educational reading data. PMID- 22429194 TI - Decrease of MMP-9 activity improves soleus muscle regeneration. AB - The regeneration of skeletal muscles relies on the function of satellite cells that are quiescent myogenic precursors associated with adult skeletal muscle fibers. Upon injury, the satellite cells are activated, divide extensively, and differentiate into new myofibers. These events are accompanied by the remodeling of the surrounding extracellular matrix, which is mediated by variety of factors, including matrix metalloproteinases (MMPs). Regeneration of certain type of muscles, such as Soleus slow twitch muscle, is often inefficient and hindered by the development of fibrosis. Here, we studied the effect of inhibition of MMP-9 and MMP-2 activity on the Soleus muscle regeneration in vivo and on the in vitro differentiation of myoblasts derived from this muscle. Using in situ and in-gel zymography, we tested the activity of these two MMPs in vivo, during regeneration of the muscle, and in vitro, during differentiation of the myoblasts. We also analyzed the histology of regenerating muscles and morphology of differentiating myoblasts. All these analyses showed that treatment with doxycycline and anti-MMP 9, but not MMP-2 antibody, significantly improved Soleus muscle regeneration and ameliorated development of excessive fibrosis, as well as delayed myoblast proliferation and differentiation in vitro. PMID- 22429195 TI - The Inaugural Digestive Disorders Federation Meeting: a collaborative and multidisciplinary approach to medical and nutrition education? PMID- 22429196 TI - Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation. AB - Recent study has shown that mutations in the alpha-II-spectrin (SPTAN1) gene cause early onset intractable seizures, severe developmental delay, diffuse hypomyelination, and widespread brain atrophy. We report a Slovene girl with hypotonia, lack of visual attention, early onset epileptic encephalopathy, and severe developmental delay. The patient presented with segmental myoclonic jerks at the age of 6 weeks, and infantile spasms at the age of 3.5 months. Her seizures were resistant to treatment. Multiple electroencephalography recordings showed deterioration of the background activity, followed by multifocal abnormalities before progressing to hypsarrhythmia. Ophthalmologic examination revealed bilateral dysplastic, coloboma-like optic discs. Brain magnetic resonance imaging showed diffusely reduced white matter and brainstem volumes with hypomyelination. A de novo heterozygous in-frame deletion was detected in SPTAN1: c.6619_6621delGAG (p.E2270del). This report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain volume reduction. Coloboma-like optic discs might be an additional feature observed in patients with SPTAN1 mutations. PMID- 22429197 TI - Limited aggregation behavior of beta-conglycinin and its terminating effect on glycinin aggregation during heating at pH 7.0. AB - In this work, different thermal aggregation behaviors of soy beta-conglycinin and glycinin at pH 7.0 were characterized with size exclusion chromatography and low angle light scattering. Limited aggregation that grew via the consumption of "monomers" was detected in beta-conglycinin, forming soluble aggregates. For glycinin, the association between the aggregates that led to the appearance of insoluble materials was observed. Heated with beta-conglycinin, the assembly between the glycinin aggregates was terminated and its solubility was recovered. The structure of the soluble and insoluble aggregates was analyzed by small-angle X-ray scattering and dynamic light scattering. Unlike the beta-conglycinin soluble aggregates that possessed limited size and less compact conformation, particles with a denser core and a less dense outer shell were found in the glycinin insoluble aggregates. Evidence is presented to reveal the transition between the soluble and insoluble aggregates and the role of beta-conglycinin in the solubilization of the soy protein aggregates during heating. PMID- 22429198 TI - "I can't just follow any particular textbook": immigrants in cardiac rehabilitation. AB - AIM: The study purpose was to examine how and under what circumstances immigrants combine diabetes self-care with cardiac rehabilitation recommendations. BACKGROUND: Cardiac rehabilitation can improve and lengthen life in people with coronary heart disease as it promotes healthy physical and psychosocial behaviours and outcomes. This study is the first to examine the convergence of two common issues on participation: (1) the problems posed when cardiac rehabilitation patients must also contend with type II diabetes and (2) the experiences of immigrants in cardiac rehabilitation. DESIGN: A critical ethnographic approach was employed. METHODS: Two in depth interviews were conducted with 18 immigrants (eight men, ten women) enrolled in cardiac rehabilitation. Data were collected from 2008-2010. FINDINGS: Threaded throughout immigrant participants' descriptions were biographical accounts of crossing geographical borders, establishing a sense of belonging in their adopted country and trying to feel 'at home' in cardiac rehabilitation. Participants described creative hybridization of transnationally informed knowledges and particularized practices to manage diabetes self-care and to reduce cardiac risk. Participants judiciously considered, assessed and blended knowledges from cardiac rehabilitation, experience with their own bodies and general 'wisdoms' passed on within their own and other immigrant communities. CONCLUSION: These findings suggest that migration constitutes an important social positioning that contextualizes individual efforts to activate diabetes self-care and cardiac rehabilitation. Support to immigrants may improve when nurses recognize the significance of such experiences. Efforts are needed in practice and research to recognize and explore immigrants' creative efforts to engage in cardiac rehabilitation. PMID- 22429199 TI - Color consilience: color through the lens of art practice, history, philosophy, and neuroscience. AB - Paintings can be interpreted as the product of the complex neural machinery that translates physical light signals into behavior, experience, and emotion. The brain mechanisms responsible for vision and perception have been sculpted during evolution and further modified by cultural exposure and development. By closely examining artists' paintings and practices, we can discover hints to how the brain works, and achieve insight into the discoveries and inventions of artists and their impact on culture. Here, I focus on an integral aspect of color, color contrast, which poses a challenge for artists: a mark situated on an otherwise blank canvas will appear a different color in the context of the finished painting. How do artists account for this change in color during the production of a painting? In the broader context of neural and philosophical considerations of color, I discuss the practices of three modern masters, Henri Matisse, Paul Cezanne, and Claude Monet, and suggest that the strategies they developed not only capitalized on the neural mechanisms of color, but also influenced the trajectory of western art history. PMID- 22429200 TI - Adaptation with gene flow across the landscape in a dune sunflower. AB - Isolation by adaptation increases divergence at neutral loci when natural selection against immigrants reduces the rate of gene flow between different habitats. This can occur early in the process of adaptive divergence and is a key feature of ecological speciation. Despite the ability of isolation by distance (IBD) and other forms of landscape resistance to produce similar patterns of neutral divergence within species, few studies have used landscape genetics to control for these other forces. We have studied the divergence of Helianthus petiolaris ecotypes living in active sand dunes and adjacent non-dune habitat, using landscape genetics approaches, such as circuit theory and multiple regression of distance matrices, in addition to coalescent modelling. Divergence between habitats was significant, but not strong, and was shaped by IBD. We expected that increased resistance owing to patchy and unfavourable habitat in the dunes would contribute to divergence. Instead, we found that landscape resistance models with lower resistance in the dunes performed well as predictors of genetic distances among subpopulations. Nevertheless, habitat class remained a strong predictor of genetic distance when controlling for isolation by resistance and IBD. We also measured environmental variables at each site and confirmed that specific variables, especially soil nitrogen and vegetation cover, explained a greater proportion of variance in genetic distance than did landscape or the habitat classification alone. Asymmetry in effective population sizes and numbers of migrants per generation was detected using coalescent modelling with Bayesian inference, which is consistent with incipient ecological speciation being driven by the dune habitat. PMID- 22429201 TI - Editorial: Radiopharmaceuticals: pre-clinical evaluation. PMID- 22429202 TI - Enhanced carrier transport along edges of graphene devices. AB - The relation between macroscopic charge transport properties and microscopic carrier distribution is one of the central issues in the physics and future applications of graphene devices (GDs). We find strong conductance enhancement at the edges of GDs using scanning gate microscopy. This result is explained by our theoretical model of the opening of an additional conduction channel localized at the edges by depleting accumulated charge by the tip. PMID- 22429203 TI - Atypical left atrial flutter following aortic valve surgery. PMID- 22429204 TI - Antinuclear antibodies predicts a poor IVF-ET outcome: impaired egg and embryo development and reduced pregnancy rate. AB - To investigate the impact of anti-nuclear antibodies (ANAs) on the outcome of in vitro fertilization-embryo transfer (IVF-ET), 66 (96 cycles) infertile women positive for anti-nuclear antibodies (ANA+ group), and 233(285 cycles) infertile women negative for ANAs (ANA- group) were enrolled. The clinical characteristics and IVF outcome were compared between the two groups. In the ANA+ group, the proportion of MII oocytes and two-pronuclear zygotes (2PN), cleavage rate, number of available embryos and proportion of available embryos, number of high-quality embryos and proportion of high-quality embryos were significantly lower than those in the ANA- group. In addition, the pregnancy rate and implantation rate in patients positive for ANA was markedly lower than the ANA- patients (28.1% vs 46.4%, 15% vs 25.7%, respectively). Thus, our findings suggest that the presence of ANAs significantly interfere with the oocyte and embryo development, as well as reduce implantation and pregnancy rate in patients undergoing IVF treatment. PMID- 22429205 TI - GH/IGF-I axis and matrix adaptation of the musculotendinous tissue to exercise in humans. AB - Exercise is not only associated with adaptive responses within skeletal muscle fibers but also with induction of collagen synthesis both in muscle and adjacent connective tissue. Additionally, exercise and training leads to activation of the systemic growth hormone/insulin-like growth factor I axis (GH/IGF-I), as well as increased local IGF-I expression. Studies in humans with pathologically high levels of GH/IGF-I, and in healthy humans who receive either weeks of GH administration or acute injection of IGF-I into connective tissue, demonstrate increased expression and synthesis of collagen in muscle and tendon. These observations support a stimulatory effect of GH/IGF-I on the connective tissue in muscle and tendon, which appears far more potent than the effect on contractile proteins of skeletal muscle. However, GH/IGF-I may play an additional role in skeletal muscle by regulation of stem cells (satellite cells), as increased satellite cell numbers are found in human muscle with increased GH/IGF-I levels, despite no change in myofibrillar protein synthesis. Although advanced age is associated with both a reduction in the GH/IGF-I axis activity, and in skeletal muscle mass (sarcopenia) as well as in tendon connective tissue, there is no direct proof linking age-related changes in the musculotendinous tissue to an impaired GH/IGF-I axis. PMID- 22429206 TI - Are culturally specific measures of trauma-related anxiety and depression needed? The case of Sri Lanka. AB - The hypothesis that psychometric instruments incorporating local idioms of distress predict functional impairment in a non-Western, war-affected population above and beyond translations of already established instruments was tested. Exploratory factor analysis was conducted on the War-Related Psychological and Behavioral Problems section of the Penn/RESIST/Peradeniya War Problems Questionnaire (PRPWPQ; N. Jayawickreme, Jayawickreme, Goonasekera, & Foa, 2009), a measure that incorporates local idioms of distress, using data from 197 individuals living in Northern and Eastern Sri Lanka. Three subscales--Anxiety, Depression, and Negative Perception--were identified. Regression analyses were conducted to test whether these 3 subscales better predicted functional impairment than the PTSD Symptom Scale-Self Report (PSS; Foa, Riggs, Dancu, & Rothbaum, 1993) and the Beck Depression Inventory (BDI; Beck & Steer, 1987), both widely used self-report measures of posttraumatic stress disorder and depression, respectively. Two of the 3 subscales from the PRPWPQ--Anxiety and Depression- were significantly associated with higher rates of functional impairment after controlling for age, the PSS and the BDI. After the inclusion of PRPWPQ, the PSS and the BDI did not significantly contribute to the final regression model predicting functional impairment. These findings suggest that the scores of measures with local idioms of distress have incremental validity in non-Western war-affected populations, predicting functional impairment above and beyond translations of established self-report measures that have been developed in the Western world. PMID- 22429207 TI - The role of anger in generalized anxiety disorder. AB - Little is known about the role of anger in the context of anxiety disorders, particularly with generalized anxiety disorder (GAD). The aim of study was to examine the relationship between specific dimensions of anger and GAD. Participants (N=381) completed a series of questionnaires, including the Generalized Anxiety Disorder Questionnaire (GAD-Q-IV; Newman et al., 2002, Behavior Therapy, 33, 215-233), the State-Trait Anger Expression Inventory (STAXI 2; Spielberger 1999, State-Trait Anger Expression Inventory-2: STAXI-2 professional manual, Odessa, FL: Psychological Assessment Resources) and the Aggression Questionnaire (AQ; Buss & Perry 1992, Journal of Personality and Social Psychology, 63, 452-459). The GAD-Q-IV identifies individuals who meet diagnostic criteria for GAD (i.e. GAD analogues) and those who do not (non-GAD). The STAXI-2 includes subscales for trait anger, externalized anger expression, internalized anger expression, externalized anger control and internalized anger control. The AQ includes subscales for physical aggression, verbal aggression, anger and hostility. The GAD-Q-IV significantly correlated with all STAXI-2 and AQ subscales (r's ranging from .10 to .46). Multivariate analyses of variance revealed that GAD analogues significantly differed from non-GAD participants on the combined STAXI-2 subscales (eta2=.098); high levels of trait anger and internalized anger expression contributed the most to GAD group membership. GAD analogue participants also significantly differed from non-GAD participants on the combined AQ subscales (eta2=.156); high levels of anger (affective component of aggression) and hostility contributed the most to GAD group membership. Within the GAD analogue group, the STAXI-2 and AQ subscales significantly predicted GAD symptom severity (R2=.124 and .198, respectively). Elevated levels of multiple dimensions of anger characterize individuals who meet diagnostic criteria for GAD. PMID- 22429208 TI - Digital methods in pathology - the future is already here. PMID- 22429209 TI - Reconciliation of diverse telepathology system designs. Historic issues and implications for emerging markets and new applications. AB - Telepathology, the distant service component of digital pathology, is a growth industry. The word "telepathology" was introduced into the English Language in 1986. Initially, two different, competing imaging modalities were used for telepathology. These were dynamic (real time) robotic telepathology and static image (store-and-forward) telepathology. In 1989, a hybrid dynamic robotic/static image telepathology system was developed in Norway. This hybrid imaging system bundled these two primary pathology imaging modalities into a single multi modality pathology imaging system. Similar hybrid systems were subsequently developed and marketed in other countries as well. It is noteworthy that hybrid dynamic robotic/static image telepathology systems provided the infrastructure for the first truly sustainable telepathology services. Since then, impressive progress has been made in developing another telepathology technology, so-called "virtual microscopy" telepathology (also called "whole slide image" telepathology or "WSI" telepathology). Over the past decade, WSI has appeared to be emerging as the preferred digital telepathology digital imaging modality. However, recently, there has been a re-emergence of interest in dynamic-robotic telepathology driven, in part, by concerns over the lack of a means for up-and-down focusing (i.e., Z-axis focusing) using early WSI processors. In 2010, the initial two U.S. patents for robotic telepathology (issued in 1993 and 1994) expired enabling many digital pathology equipment companies to incorporate dynamic-robotic telepathology modules into their WSI products for the first time. The dynamic robotic telepathology module provided a solution to the up-and-down focusing issue. WSI and dynamic robotic telepathology are now, rapidly, being bundled into a new class of telepathology/digital pathology imaging system, the "WSI-enhanced dynamic robotic telepathology system". To date, six major WSI processor equipment companies have embraced the approach and developed WSI-enhanced dynamic-robotic digital telepathology systems, marketed under a variety of labels. Successful commercialization of such systems could help overcome the current resistance of some pathologists to incorporate digital pathology, and telepathology, into their routine and esoteric laboratory services. Also, WSI-enhanced dynamic robotic telepathology could be useful for providing general pathology and subspecialty pathology services to many of the world's underserved populations in the decades ahead. This could become an important enabler for the delivery of patient centered healthcare in the future. PMID- 22429210 TI - Digital image analysis: a review of reproducibility, stability and basic requirements for optimal results. AB - Digital image analysis (DIA) is increasingly implemented in histopathological research to facilitate truly quantitative measurements, decrease inter-observer variation and reduce hands-on time. Originally, efforts were made to enable DIA to reproduce manually obtained results on histological slides optimized for light microscopy and the human eye. With improved technical methods and the acknowledgement that computerized readings are different from analysis by human eye, recognition has been achieved that to really empower DIA, histological slides must be optimized for the digital 'eye', with reproducible results correlating with clinical findings. In this review, we focus on the basic expectations and requirements for DIA to gain wider use in histopathological research and diagnostics. With a reference to studies that specifically compare DIA with conventional methods, this review discusses reproducibility, application of stereology-based quantitative measurements, time consumption, optimization of histological slides, regions of interest selection and recent developments in staining and imaging techniques. PMID- 22429211 TI - A travel report of the implementation of virtual whole slide images in routine surgical pathology. AB - Virtual microscopy is the terminology used to indicate the use of digitized images of whole slides for inspection of cells and tissue sections on computer screens as an add-on or replacement for conventional microscopy using bright field or other types of illumination in combination with a wide variety of microscope brands. Although technically there is no longer a limit in the size and colour composition of the images, the logistics of embedding virtual microscopy in daily routine of a diagnostic process are still a relatively open area where new pitfalls and opportunities can be found. In this article, we described various aspects in the process. None of them had been planned in advance, but mostly originated from observations done during the different steps towards implementation of virtual microscopy in daily routine, for example, the choice between the different scanner types and their (dis)advantages, issues on storing and retrieval and at last, the effect of digitalization on the diagnostic process. This approach resulted in a manuscript that in a way has more the appearance of a story than of a scientific study with strict protocols, with a clear cut question in advance, a research plan and expected outcome. Depending on the purpose of the virtual slides in a given situation, different solutions must be found locally. PMID- 22429212 TI - Utility of whole slide imaging and virtual microscopy in prostate pathology. AB - Whole slide imaging (WSI) has been used in conjunction with virtual microscopy (VM) for training or proficiency testing purposes, multicentre research, remote frozen section diagnosis and to seek specialist second opinion in a number of organ systems. The feasibility of using WSI/VM for routine surgical pathology reporting has also been explored. In this review, we discuss the utility and limitations of WSI/VM technology in the histological assessment of specimens from the prostate. Features of WSI/VM that are particularly well suited to assessment of prostate pathology include the ability to examine images at different magnifications as well as to view histology and immunohistochemistry side-by-side on the screen. Use of WSI/VM would also solve the difficulty in obtaining multiple identical copies of small lesions in prostate biopsies for teaching and proficiency testing. It would also permit annotation of the virtual slides, and has been used in a study of inter-observer variation of Gleason grading to facilitate precise identification of the foci on which grading decisions had been based. However, the large number of sections examined from each set of prostate biopsies would greatly increase time required for scanning as well as the size of the digital file, and would also be an issue if digital archiving of prostate biopsies is contemplated. Z-scanning of glass slides, a process that increases scanning time and file size would be required to permit focusing a virtual slide up and down to assess subtle nuclear features such as nucleolar prominence. The common use of large blocks to process prostatectomy specimens would also be an issue, as few currently available scanners can scan such blocks. A major component of proficiency testing of prostate biopsy assessment involves screening of the cores to detect small atypical foci. However, screening virtual slides of wavy fragmented prostate cores using a computer mouse aided by an overview image is very different from screening glass slides using a microscope stage. Hence, it may be more appropriate in this setting to mark the lesional area and focus only on the interpretation component of competency testing. Other issues limiting the use of digital pathology in prostate pathology include the cost of high quality slide scanners for WSI and high resolution monitors for VM as well as the requirement for fast Internet connection as even a subtle delay in presentation of images on the screen may be very disturbing for a pathologist used to the rapid viewing of glass slides under a microscope. However, these problems are likely to be overcome by technological advances in the future. PMID- 22429213 TI - Virtual microscopy and digital pathology in training and education. AB - Traditionally, education and training in pathology has been delivered using textbooks, glass slides and conventional microscopy. Over the last two decades, the number of web-based pathology resources has expanded dramatically with centralized pathological resources being delivered to many students simultaneously. Recently, whole slide imaging technology allows glass slides to be scanned and viewed on a computer screen via dedicated software. This technology is referred to as virtual microscopy and has created enormous opportunities in pathological training and education. Students are able to learn key histopathological skills, e.g. to identify areas of diagnostic relevance from an entire slide, via a web-based computer environment. Students no longer need to be in the same room as the slides. New human-computer interfaces are also being developed using more natural touch technology to enhance the manipulation of digitized slides. Several major initiatives are also underway introducing online competency and diagnostic decision analysis using virtual microscopy and have important future roles in accreditation and recertification. Finally, researchers are investigating how pathological decision-making is achieved using virtual microscopy and modern eye-tracking devices. Virtual microscopy and digital pathology will continue to improve how pathology training and education is delivered. PMID- 22429214 TI - State-of-the-art of visualization in post-mortem imaging. AB - Autopsies constitute a valuable feedback to the healthcare chain to achieve improvements in quality of care and cost effectiveness. This review describes post-mortem imaging, which has emerged as an important part of the pathology toolbox. A broad range of visualization aspects within post-mortem imaging are covered. General state-of-the-art overviews of the components in the visualization pipeline are complemented by in-depth descriptions of methods developed by the authors and our collaborators. The forensic field is represented and related to, as it is spearheading much development in post-mortem imaging. Other topics are workflow, imaging data acquisition, and visualization rendering technology. All in all, this review shows the mature state of visual analysis for a non- or minimal-invasive investigation of the deceased patient. PMID- 22429215 TI - Digital stereology in neuropathology. AB - Two-dimensional quantitative methods have frequently been used to address questions in neuropathological research; however, they face important limitations which design-based stereology may overcome by offering a set of methods to quantify two-dimensional histological sections into three-dimensional structural knowledge. Accordingly, stereology is a science based on statistical sampling principles and geometric measures. The application of stereology to neuropathological studies allows the researcher to efficiently obtain a precise estimate of various structural quantities. This neuropathological review will therefore present the relevant stereological estimators for obtaining reliable quantitative structural data from brains and peripheral nerves when using digital light microscopy. It is discussed how to obtain brain and nerve fibre samples to fulfil the requirements for the estimators. A presentation of design-based stereological probes for obtaining global volume, total number, local volume, total length, total surface area, cross-sectional area and diameter will be followed by discussion of the error variances of the methods. No mathematical equations or calculations are shown in this review. PMID- 22429216 TI - Implementation of TMA and digitalization in routine diagnostics of breast pathology. AB - To ensure optimal treatment of breast cancer patients, breast tumours are classified based on clinico-pathological features. As part of this process, routine diagnostics of breast tumours includes histological typing and grading, as well as profiling by use of an immunohistochemistry panel of antibodies, probes and in situ hybridization. This will, as a minimum, include assessment of oestrogen receptor (OR) and HER2. The individual preparation and staining of many breast tumours in a large laboratory with this standard panel is thus time consuming and costly. Herein, we show that in breast cancer routine diagnostics the use of the tissue microarray technique in combination with digitalization of the stained multi-slides is not only economical, with a considerable cost reduction, but it also enhances standardization of tumour profiling. We demonstrate that 2 mm breast tumour cores correlate with the corresponding tumour on whole mount slides, regarding staining/hybridizing results with the biomarkers in our panel consisting of human epidermal growth factor receptor 2, OR and Topiomerase IIa. Furthermore, we show that simultaneous staining/hybridizing of multiple breast tumour specimens reduces variation of staining/hybridizing quality, hereby increasing reliability of interpretation. By scanning and digitalization of the stained and hybridized multi-slides, we could optimize documentation and filing of the results. Our work is an example of translational research by implementing a tool in daily diagnostics originally developed for high throughput analyses in the search for prognostic and predictive markers in targeted medicine. PMID- 22429217 TI - Detection of ricin contamination in liquid egg by electrochemiluminescence immunosorbent assay. AB - A monoclonal antibody-based electrochemical luminescence method was developed for detecting and quantifying ricin in liquid egg, with a limit of detection of 0.2 ng/mL. Because this highly toxic protein, present in the seeds of Ricinus communis (castor), has been used for intentional poisoning in the past, it is important to have sensitive and reliable analytical methodology to detect ricin in food matrices such as liquid egg. The detection of this quantity of pure or crude ricin spiked into commercial samples of liquid egg provides approximately 50000-fold greater sensitivity than required to detect a toxic dose of ricin (>1 mg) in a 100 g sample. PRACTICAL APPLICATION: Because ricin has been used for intentional poisoning, there is a need for analytical methodology to detect ricin in food matrices to assure a safe food supply. Using monoclonal antibodies to ricin developed in our laboratory, we explored an assay readout system known as electrochemiluminescence. This technique afforded sensitive and specific analysis of ricin intentionally added to liquid egg and could potentially be used to monitor egg-based vaccine production. PMID- 22429218 TI - Anticonvulsive effect of atorvastatin on pentylenetetrazole-induced seizures in mice: the role of nitric oxide pathway. AB - Atorvastatin has shown to possess neuroprotective, antiexcitotoxic, and antiepileptic effects besides its cholesterol-lowering properties. Nitric oxide (NO) may be responsible for a group of these effects. In the present study, a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice was used to investigate the anticonvulsive effects of atorvastatin through NO dependent pathways. Atorvastatin (5 mg/kg) significantly increased the seizure threshold (P < 0.001). Moreover, L-arginine (a precursor of NO) significantly (P < 0.01) potentiated the anticonvulsive effects of subeffective doses of atorvastatin (1 mg/kg). Finally, L-NAME [L-arginine methyl ester dihydrochloride], a nonspecific NO synthase inhibitor, completely abolished the anticonvulsive properties of atorvastatin. Our findings demonstrated the role of atorvastatin as an anticonvulsive agent and showed the effects to be mediated through NO-related pathways. PMID- 22429219 TI - Reactive uptake of HONO to TiO2 surface: "dark" reaction. AB - The interaction of HONO with TiO(2) solid films was studied under dark conditions using a low pressure flow reactor (1-10 Torr) combined with a modulated molecular beam mass spectrometer for monitoring of the gaseous species involved. The reactive uptake of HONO to TiO(2) was studied as a function of HONO concentration ([HONO)(0) = (0.3-3.3) * 10(12) molecules cm(-3)), water concentration (RH = 3 * 10(-4) to 13%), and temperature (T = 275-320 K). TiO(2) surface deactivation upon exposure to HONO was observed. The measured initial uptake coefficient of HONO on TiO(2) surface was independent of the HONO concentration and showed slight negative temperature dependence (activation factor = -1405 +/- 110 K). In contrast, the relative humidity (RH) was found to have a strong impact on the uptake coefficient: gamma(0) = 1.8 * 10(-5) (RH)(-0.63) (calculated using BET surface area, 40% uncertainty) at T = 300 K. NO(2) and NO were observed as products of the HONO reaction with TiO(2) surface with sum of their yields corresponding to nearly 100% of the nitrogen mass balance. The yields of the NO and NO(2) products were found to be 42 +/- 7% and 60 +/- 9%, respectively, independent of relative humidity, temperature, and concentration of HONO under experimental conditions used. The contribution of aerosol to the total HONO loss in the boundary layer (calculated with initial uptake data for HONO on TiO(2) surface) showed the unimportance of this process in the atmosphere. In addition, the diffusion coefficient of HONO in He was determined to be D(HONO-He) = 490 +/- 50 Torr cm(2) s(-1) at T = 300 K. PMID- 22429220 TI - Porous membrane substrates offer better niches to enhance the Wnt signaling and promote human embryonic stem cell growth and differentiation. AB - Human embryonic stem cells (hESCs) require specific niches for adhesion, expansion, and lineage-specific differentiation. In this study, we showed that a membrane substrate offers better tissue niches for hESC attachment, spreading, proliferation, and differentiation. The cell doubling time was shortened from 46.3+/-5.7 h for hESCs grown on solid substrates to 25.6+/-2.6 h for those on polyester (PE) membrane substrates with pore size of 0.4 MUm. In addition, we observed an increase of approximately five- to ninefold of definitive endoderm marker gene expression in hESCs differentiated on PE or polyethylene terephthalate membrane substrates. Global gene expression analysis revealed upregulated expressions of a number of extracellular matrix and cell adhesion molecules in hESCs grown on membrane substrates. Further, an enhanced nuclear translocation of beta-catenin was detected in these cells. These observations suggested the augmentation of Wnt signaling in hESCs grown on membrane substrates. These results also demonstrated that a membrane substrate can offer better physicochemical cues for enhancing in vitro hESC attachment, proliferation, and differentiation. PMID- 22429221 TI - Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs. AB - BACKGROUND Acotiamide hydrochloride (acotiamide), a novel selective acetylcholinesterase (AChE) inhibitor, has proven significantly effective in treating functional dyspepsia (FD) in clinical trials, particularly in alleviating meal-related symptoms. In the present study, we examined the gastrointestinal prokinetic effects of acotiamide administered orally or intraduodenally in conscious dogs and investigated in vivo and ex vivo anti-AChE activity of acotiamide to clarify its mechanism of prokinetic action. METHODS: Gastrointestinal motility was measured in conscious dogs with chronically implanted force transducers. KEY RESULTS: Oral administration of acotiamide stimulated postprandial gastroduodenal and colonic motor activities. Measurement of gastrointestinal motility showed that acotiamide, like itopride and mosapride, enhanced gastric antral motility. Further, acotiamide markedly improved clonidine (an alpha(2) -adrenoceptor agonist)-induced hypomotility in a dog model of gastric motor dysfunction. The postprandial gastric antral motility enhanced by acotiamide was completely abolished on treatment with the muscarinic receptor antagonist atropine. Results of an in vivo experiment on anti-AChE activity showed clearly increased acetylcholine-induced gastric motility on intraduodenal administration of acotiamide, just as observed with the AChE inhibitor neostigmine. Further, in ex vivo experiment, intraduodenal administration of acotiamide significantly inhibited AChE activity in canine gastric antrum. CONCLUSIONS & INFERENCES: Our findings revealed that acotiamide administered through the alimentary tract exerts gastroprokinetic action via cholinergic pathways by inhibiting AChE activity. These results may also confirm the mechanism of action in clinical efficacy of acotiamide on FD. PMID- 22429222 TI - The impact of erythrocyte age on eryptosis. AB - Mature, circulating erythrocytes undergo senescence, which limits their life span to approximately 120 d. Upon injury, erythrocytes may undergo suicidal erythrocyte death or eryptosis, which may accelerate senescence and shorten their survival. Eryptosis is defined as cell shrinkage and exposure of phosphatidylserine at the cell surface. Triggers of eryptosis include oxidative stress. The present study addresses the impact of erythrocyte age on the relative susceptibility to eryptosis. Erythrocytes were separated into five fractions, based on age-associated differences in density and volume. Cell membrane scrambling was estimated from binding of annexin V to phosphatidylserine at the erythrocyte surface, the cell volume from forward scatter, and the Ca(2+) level from Fluo-3-dependent fluorescence. In addition, glutathione (GSH) concentrations were measured by an enzymatic/colourimetric method. After 48 h incubation in Ringer solution, Annexin V binding increased significantly with erythrocyte age. The differences were not accompanied by altered GSH concentrations, but were reversed by addition of the antioxidant N-acetyl-L-cysteine in vitro. Also, N acetyl-L-cysteine significantly prolonged the half-life of circulating mouse erythrocytes in vivo. Thus, the susceptibility to eryptosis increases with the age of the erythrocytes, and this effect is at least partially due to enhanced sensitivity to oxidative stress. PMID- 22429223 TI - Recent advances in Toll-like receptors and anterior uveitis. AB - Uveitis involves acute, recurrent or chronic inflammation of the uvea, and occurs when the normal state of ocular immune privilege has broken down. Accumulating evidence implicates the role of microbial triggers in the development of various forms of immune-mediated uveitis in addition to its causative role in infectious uveitis. Toll-like receptors (TLRs) are the most important pattern-recognition receptors of the innate immune system that recognize pathogen-associated molecular patterns of microbes. Activation of TLRs by pathogen-associated molecular patterns leads to the induction of an inflammatory cascade and activation of both innate and adaptive arms of the immune response. TLRs have been implicated in the pathogenesis of various inflammatory diseases, including uveitis. This review provides an update on recent progress in TLR research and uveitis, specifically summarizing new evidence for the role of TLRs in anterior uveitis. There have been important observations from studies involving human ocular tissue, clinical uveitis and from experimental animal models of uveitis, such as endotoxin-induced uveitis. The 'Toll rush' has certainly gained momentum, and future advances in this field have the potential for selectively targeting the TLR pathway and ultimately translating into better therapies for patients with sight-threatening uveitis. PMID- 22429224 TI - Medical and commercial ethics in altitude trekking. PMID- 22429227 TI - Refractive surgery safety at altitude. AB - Over the years, many climbers and other visitors to high altitude have been attracted to refractive surgery in hopes of lessening their dependence on glasses. Although there has been a gradual refinement of these procedures over time, they continue to have the potential for visual changes with altitude exposure. The goal of this review is to provide guidance to clinicians as to how to better advise their patients on the pros and cons of these procedures. PMID- 22429228 TI - Prevalence and determinants of hyperlipidemia in moderate altitude areas of the Yunnan-Kweichow plateau in Southwestern China. AB - The objective of the current study was to determine the prevalence and determinants of hyperlipidemia among the populations living at moderate altitude on the Yunnan-Kweichow Plateau in Southwestern China. We randomly recruited 1415 people for this study. These subjects underwent a physical examination and a comprehensive questionnaire regarding their daily habits and diets. Furthermore, blood samples from the participants were collected for assessing the lipid profile. We found that 49.3% of participants (95% CI: 46.7-51.9%) suffered from hyperlipidemia. The prevalence in men was significantly higher than that in women (53.6% vs. 44.7%, p<0.01). The prevalence of hypercholesterolemia was 23.3% and of hypertriglyceridemia was 34.1%. Low HDL-C showed a prevalence of 17.5% and high LDL-C of 9.0%. The prevalence of hyperlipidemia also increased with age, as did the prevalence of high TC, TG, and LDL-C. Hyperlipidemic subjects tended to be older and have a higher BMI and WHR than the normolipidemic subjects in the study cohort (p<0.05). The hyperlipidemic subjects, both men and women, tended to dine out often and consume more animal-based foods and alcohol. In addition, the hyperlipidemic men in our cohort consumed more salted food then their normolipidemic counterparts (p<0.01). Normolipidemic subjects of both sexes were also found to prefer a vegetarian diet (p<0.01). Age, alcohol consumption, a preference for meat and animal products, regular dining out, and BMI were found to be the main determinants of hyperlipidemia in women, whereas a prevalence of salted food was observed to be related to hyperlipidemia in men from the Yunnan Kweichow Plateau subpopulation under study (p<0.05). The average daily energy, and protein and fat intakes of the sampled subjects were also higher than the levels set by the Chinese Recommendation Nutrient Intakes (RNI), while hyperlipidemic subjects had an even higher average daily intake of total fat, cholesterol, and lower dietary fiber compared with the normolipidemic subjects in the study group (p<0.05). In conclusion, this study reveals a higher prevalence of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, increased BMI and WHR values in men, as well as a slightly higher prevalence of low HDL-C and high LDL-C in women from Yunnan-Kweichow Plateau. The incidence of hyperlipidemia also increased with age, as did the prevalence of an abnormal TC, TG, LDL-C, and WHR in our study cohort. A high BMI, and less healthy living habits and dietary preferences thus play significant roles in the onset of hyperlipidemia. PMID- 22429229 TI - Carbohydrate supplementation and exercise performance at high altitude: a randomized controlled trial. AB - Acute carbohydrate supplementation decreases effort perception and increases endurance exercise capacity at sea level. It also improves laboratory-based endurance performance at altitude. However, the effect of chronic carbohydrate supplementation at altitude, when acclimatization may attenuate carbohydrate effects, achieved doses are lower and metabolic effects may be different, is unknown and was therefore focused on in the present study. Forty-one members of a 22-day high altitude expedition were randomized in a double-blind design to receive either placebo or carbohydrate supplementation. Diet was manipulated with commercially available energy drinks consumed ad libitum throughout the expedition. Participants performed a mountaineering time trial at 5192 m, completed submaximal incremental exercise step tests to assess cardiovascular parameters before, during, and after the expedition, and recorded spontaneous physical activity by accelerometer on rest days. Compared to placebo, compliant individuals of the carbohydrate-supplemented group received daily an additional 3.5+/-1.4 g carbohydrate.kg body mass(-1). Compliant individuals of the carbohydrate supplemented group reported 18% lower ratings of perceived exertion during the time trial at altitude, and completed it 17% faster than the placebo group (both p<0.05 by t-test). However, cardiovascular parameters obtained during submaximal exercise and spontaneous physical activity on rest days were similar between the two groups (all p>0.05 by analysis of variance). This study utilized testing protocols of specific relevance to high altitude sojourners, including the highest mountaineering time trial completed to date at altitude. Chronic carbohydrate supplementation reduced ratings of perceived exertion and improved physical performance, especially during prolonged and higher intensity exercise tasks. PMID- 22429230 TI - The effect of a sleep high-train low regimen on the finger cold-induced vasodilation response. AB - The present study evaluated the effect of a sleep high-train low regimen on the finger cold-induced vasodilation (CIVD) response. Seventeen healthy males were assigned to either a control (CON; n=9) or experimental (EXP; n=8) group. Each group participated in a 28-day aerobic training program of daily 1-h exercise (50% of peak power output). During the training period, the EXP group slept at a simulated altitude of 2800 meters (week 1) to 3400 m (week 4) above sea level. Normoxic (CIVD(NOR); CON and EXP groups) and hypoxic (CIVD(HYPO); F(I)O(2)=0.12; EXP group only) CIVD characteristics were assessed before and after the training period during a 30-min immersion of the hand in 8 degrees C water. After the intervention, the EXP group had increased average finger skin temperature (CIVD(NOR): +0.5 degrees C; CIVD(HYPO): +0.5 degrees C), number of waves (CIVD(NOR): +0.5; CIVD(HYPO): +0.6), and CIVD amplitude (CIVD(NOR): +1.5 degrees C; CIVD(HYPO): +3 degrees C) in both CIVD tests (p<0.05). In contrast, the CON group had an increase in only the CIVD amplitude (+0.5 degrees C; p<0.05). Thus, the enhancement of aerobic performance combined with altitude acclimatization achieved with the sleep high-train low regimen contributed to an improved finger CIVD response during cold-water hand immersion in both normoxic and hypoxic conditions. PMID- 22429231 TI - Hypobaric versus normobaric hypoxia: same effects on postural stability? AB - AIMS: To test the hypothesis that postural stability would be more affected during acute exposure in hypobaric (HH) than in normobaric (NH) hypoxia. METHODS: In separate trials, 12 subjects stood on a posturographic platform for two successive 25.6 sec tests in three conditions: eyes open (EO), eyes closed (EC), and verbal dual task (DT). Ambient pressure in O(2) was matched between HH and NH at 1700 and 3000 m, respectively. RESULTS: Compared to NH, the length of Centre of Pression trajectory in Y-axis was increased (p<0.05) in HH for EO at 1700 m, EC at 1700 and 3000 m, and for DT at 1700 m, whereas the variance of speed of CoP was decreased (p<0.05) in EO, EC, and DT at 1700 m. Compared to normobaric normoxia (NN; 400 m), the surface of CoP trajectory was increased (p<0.05) in HH in EO and EC at 3000 m. CONCLUSIONS: HH deteriorated postural stability in the antero-posterior plane, for the variance of speed and the surface of CoP in 3 conditions, whereas no difference was observed between NH and NN. These results suggest that hypobaria instead of hypoxia per se plays an important role to the altered balance classically reported in altitude. PMID- 22429232 TI - Body composition and somatotype of experienced mountain climbers. AB - AIMS: In order to evaluate body composition and somatotype, 10 Italian experienced mountain climbers were assessed from an anthropometric point of view, before a high altitude ascent. Body mass, height, girths, skinfolds, and bone breadths were gathered and used to calculate body composition and somatotype of each subject. RESULTS: Means and standard deviations of the subjects' anthropometric characteristics were calculated. Mesomorphism (5.28+/-1.10) is the dominant somatotype component in all but one the participants, endomorphism (1.55+/-0.49) is low, and body fat percentage (11.76%+/-2.93) is low. Comparisons with athletes involved in other climbing subdisciplines highlight the specificity of elite mountain climbers anthropometry. CONCLUSIONS: The elite mountain climbers in our sample were predominantly mesomorphic with somatotype attitudinal mean values lower than reported for male athletes participating in free-climbing, volleyball, gymnastics, and soccer. Anthropometric characteristics may therefore play a role in mountain climbing, even though the trainable components may be more relevant than the nontrainable ones. PMID- 22429233 TI - A tale of two climbers: hypothermia, death, and survival on Mount Everest. AB - Hypothermia is an acknowledged risk for those who venture into high altitude regions. There is however little quantitative information on this risk that can be used to implement mitigation strategies. Here we provide an analysis of the meteorological and hypothermic risk parameters, wind chill temperature, and facial frostbite time, during the spring 2006 Mount Everest climbing season. This season was marked by two high profile events where a solo climber was forced to spend the night in highly exposed conditions near the summit. One climber survived, while the other did not. Although this retrospective examination of two individual cases has admittedly a small sample size, and there are other factors that undoubtedly contributed to the difference in outcomes, we show that wind chill temperature and facial frostbite time experienced by the two climbers were dramatically different. In particular, the climber who did not survive experienced conditions that were approximately one standard deviation more severe that usual for that time of the year; while the climber who survived experienced conditions that were approximately one standard deviation less severe then usual. This suggests that the environmental conditions associated with hypothermia played an important role in the outcomes. This report confirms the importance of providing quantitative guidance to climbers as the risk of hypothermia on high mountains. PMID- 22429234 TI - High altitude medicine education in China: exploring a new medical education reform. AB - China has the largest plateau in the world, which includes the whole of Tibet, part of Qinghai, Xinjiang, Yunnan, and Sichuan. The plateau area is about 257.2*10(4) km(2), which accounts for about 26.8% of the total area of China. According to data collected in 2006, approximately twelve million people were living at high altitudes, between 2200 to 5200 m high, on the Qinghai-Tibetan Plateau. Therefore, there is a need for medical workers who are trained to treat individuals living at high altitudes. To train undergraduates in high altitude medicine, the College of High Altitude Military Medicine was set up at the Third Military Medical University (TMMU) in Chongqing in 1999. This is the only school to teach high altitude medicine in China. Students at TMMU study natural and social sciences, basic medical sciences, clinical medical sciences, and high altitude medicine. In their 5(th) year, students work as interns at the General Hospital of Tibet Military Command in Lhasa for 3 months, where they receive on site teaching. The method of on-site teaching is an innovative approach for training in high altitude medicine for undergraduates. Three improvements were implemented during the on-site teaching component of the training program: (1) standardization of the learning progress; (2) integration of formal knowledge with clinical experience; and (3) coaching students to develop habits of inquiry and to engage in ongoing self-improvement to set the stage for lifelong learning. Since the establishment of the innovative training methods in 2001, six classes of high altitude medicine undergraduates, who received on-site teaching, have graduated and achieved encouraging results. This evidence shows that on-site teaching needs to be used more widely in high altitude medicine education. PMID- 22429235 TI - Cerebral venous sinus thrombosis at high altitude. AB - Cerebral venous sinus thrombosis (CVST) is a rare but potentially life threatening medical condition. We describe a case of a 47-year-old woman who presented with headache, speech defects, and visual disturbances, and was later diagnosed with cerebral venous sinus thrombosis. The article describes a possible risk of such thrombotic events with exposure to high altitude environment in patients with coagulation defects such as Factor V Leiden mutation. Besides, such neurological conditions can occur independent of altitude illness and need to be recognized as their management differs. PMID- 22429236 TI - The impact of hypoxia on cells, mice, and men. PMID- 22429237 TI - Pre-hospital wrist block for digital frostbite injuries. PMID- 22429238 TI - Dehydropyrrolizidine alkaloids, including monoesters with an unusual esterifying acid, from cultivated Crotalaria juncea (Sunn Hemp cv.'Tropic Sun'). AB - Cultivation of Crotalaria juncea L. (Sunn Hemp cv. 'Tropic Sun') is recommended as a green manure crop in a rotation cycle to improve soil condition, help control erosion, suppress weeds, and reduce soil nematodes. Because C. juncea belongs to a genus that is known for the production of toxic dehydropyrrolizidine alkaloids, extracts of the roots, stems, leaves, and seeds of 'Tropic Sun' were analyzed for their presence using HPLC-ESI/MS. Qualitative analysis identified previously unknown alkaloids as major components along with the expected macrocyclic dehydropyrrolizidine alkaloid diesters, junceine and trichodesmine. The dehydropyrrolizidine alkaloids occurred mainly as the N-oxides in the roots, stems, and, to a lesser extent, leaves, but mainly as the free bases in the seeds. Comprehensive spectrometric and spectroscopic analysis enabled elucidation of the unknown alkaloids as diastereoisomers of isohemijunceine, a monoester of retronecine with an unusual necic acid. The dehydropyrrolizidine alkaloid contents of the roots, stems, and leaves of immature plants were estimated to be 0.05, 0.12, and 0.01% w/w, respectively, whereas seeds were estimated to contain 0.15% w/w. PMID- 22429239 TI - Interictal psychotic episodes in epilepsy: duration and associated clinical factors. AB - PURPOSE: There have been few reports showing the distribution of the duration of interictal psychosis (IIP) episodes and their association with clinical characteristics. To clarify the nature of IIP, we studied the duration of IIP episodes and their related factors. METHODS: One hundred fifty-five patients with epilepsy exhibited 320 IIP episodes during our follow-up period (mean 16.9 years). The duration of all the episodes and the longest episode in each patient during the follow-up periods were studied. Characteristics of the patients (e.g., epilepsy type, age of onset, and family history of psychosis) and episode specific factors (e.g., age of the episode, seizure frequency, administrations of antiepileptic drugs [AEDs] and antipsychotic drugs [APDs]) were analyzed in association with the duration of the episodes. KEY FINDINGS: Mean duration of the 320 IIP episodes was 82.7 weeks and that of the longest IIP episodes was 150.1 weeks. During the follow-up period, 17 patients (11.0%) showed all episodes remitting within a month and 54 (34.8%) showed all episodes lasting for 6 months or longer. The IIP episodes that occurred at a younger age were often prolonged. Patients with a family history of psychosis or with early onset of psychosis tended to have more prolonged IIP episodes. Among the episodes treated with APDs, early administration of APDs was significantly associated with shorter IIP duration. SIGNIFICANCE: The distribution of the duration of IIP episodes indicated the broad spectrum and heterogeneity of the IIP phenomena. The individual vulnerability to psychosis may be associated with prolonged episodes. Administration of APDs soon after onset of the episodes appeared to be effective in controlling them. These findings support empirical treatment principles for IIP to administer APDs at an early stage of its development. PMID- 22429240 TI - Synthesis of inositol phosphate ligands of plant hormone-receptor complexes: pathways of inositol hexakisphosphate turnover. AB - Reduction of phytate is a major goal of plant breeding programs to improve the nutritional quality of crops. Remarkably, except for the storage organs of crops such as barley, maize and soybean, we know little of the stereoisomeric composition of inositol phosphates in plant tissues. To investigate the metabolic origins of higher inositol phosphates in photosynthetic tissues, we have radiolabelled leaf tissue of Solanum tuberosum with myo-[2-3H]inositol, undertaken a detailed analysis of inositol phosphate stereoisomerism and permeabilized mesophyll protoplasts in media containing inositol phosphates. We describe the inositol phosphate composition of leaf tissue and identify pathways of inositol phosphate metabolism that we reveal to be common to other kingdoms. Our results identify the metabolic origins of a number of higher inositol phosphates including ones that are precursors of cofactors, or cofactors of plant hormone-receptor complexes. The present study affords alternative explanations of the effects of disruption of inositol phosphate metabolism reported in other species, and identifies different inositol phosphates from that described in photosynthetic tissue of the monocot Spirodela polyrhiza. We define the pathways of inositol hexakisphosphate turnover and shed light on the occurrence of a number of inositol phosphates identified in animals, for which metabolic origins have not been defined. PMID- 22429241 TI - Cyclic fatigue analysis of twisted file rotary NiTi instruments used in reciprocating motion. AB - AIM: To evaluate the cyclic fatigue fracture resistance of engine-driven twisted file (TF) instruments under reciprocating movement. METHODOLOGY: A sample of 30 size 25, 0.08 taper NiTi TF instruments was tested in a simulated canal with 60 angle of curvature and a 3 mm radius. During mechanical testing, different movement kinematics were used at a constant speed, which resulted in three experimental groups (each group n = 10). The instruments from the first group (G1) were rotated until fracture occurred. The instruments in the second (G2) and third group (G3) were driven under reciprocating movement with different angles of reciprocation. The time of fracture for each instrument was measured, and statistical analysis was performed using one-way analysis of variance followed by Tukey's Honestly Significant Different test. RESULTS: Reciprocating movement resulted in a significantly longer cyclic fatigue life (P < 0.0001) when compared with continuous rotation. No difference was found between reciprocation 150 degrees clockwise/30 degrees counterclockwise (CW/CCW) and 30 degrees CW/150 degrees CCW. CONCLUSIONS: The reciprocating movement was associated with an extended cyclic fatigue life of the TF size 0.25, 0.08 taper instruments in comparison with conventional rotation. PMID- 22429243 TI - Parvalbumin-producing cortical interneurons receive inhibitory inputs on proximal portions and cortical excitatory inputs on distal dendrites. AB - To examine inputs to parvalbumin (PV)-producing interneurons, we generated transgenic mice expressing somatodendritic membrane-targeted green fluorescent protein specifically in the interneurons, and completely visualized their dendrites and somata. Using immunolabeling for vesicular glutamate transporter (VGluT)1, VGluT2, and vesicular GABA transporter, we found that VGluT1-positive terminals made contacts 4- and 3.1-fold more frequently with PV-producing interneurons than VGluT2-positive and GABAergic terminals, respectively, in the primary somatosensory cortex. Even in layer 4, where VGluT2-positive terminals were most densely distributed, VGluT1-positive inputs to PV-producing interneurons were 2.4-fold more frequent than VGluT2-positive inputs. Furthermore, although GABAergic inputs to PV-producing interneurons were as numerous as VGluT2-positive inputs in most cortical layers, GABAergic inputs clearly preferred the proximal dendrites and somata of the interneurons, indicating that the sites of GABAergic inputs were more optimized than those of VGluT2-positive inputs. Simulation analysis with a PV-producing interneuron model compatible with the present morphological data revealed a plausible reason for this observation, by showing that GABAergic and glutamatergic postsynaptic potentials evoked by inputs to distal dendrites were attenuated to 60 and 87%, respectively, of those evoked by somatic inputs. As VGluT1-positive and VGluT2 positive axon terminals were presumed to be cortical and thalamic glutamatergic inputs, respectively, cortical excitatory inputs to PV-producing interneurons outnumbered the thalamic excitatory and intrinsic inhibitory inputs more than two fold in any cortical layer. Although thalamic inputs are known to evoke about two fold larger unitary excitatory postsynaptic potentials than cortical ones, the present results suggest that cortical inputs control PV-producing interneurons at least as strongly as thalamic inputs. PMID- 22429244 TI - Distinct cortical networks support the planning and online control of reaching-to grasp in humans. AB - A number of brain imaging studies have identified regions involved in the planning and control of complex actions. Here we attempt to contrast activity related to planning and online control in the human brain during simple reaching and grasping movements. In four conditions, participants did one of the following: passively observed a grasp target; planned a grasping movement without executing; planned and then executed a grasp; or immediately executed a grasp. Neural activity was measured using functional magnetic resonance imaging and activity in the various conditions compared. Two large, independent networks of brain activity were identified: (i) a planning network including the premotor cortex, basal ganglia, anterior cingulate, posterior medial parietal area, superior parietal occipital cortex and middle intraparietal sulcus; and (ii) a control network including sensorimotor cortex, the cerebellum, the supramarginal gyrus and the superior parietal lobule. These findings provide evidence that the planning and control of even simple reaching and grasping actions use different brain regions, including different parts of the frontal and parietal lobes. PMID- 22429242 TI - Exploration and modulation of brain network interactions with noninvasive brain stimulation in combination with neuroimaging. AB - Much recent work in systems neuroscience has focused on how dynamic interactions between different cortical regions underlie complex brain functions such as motor coordination, language and emotional regulation. Various studies using neuroimaging and neurophysiologic techniques have suggested that in many neuropsychiatric disorders, these dynamic brain networks are dysregulated. Here we review the utility of combined noninvasive brain stimulation and neuroimaging approaches towards greater understanding of dynamic brain networks in health and disease. Brain stimulation techniques, such as transcranial magnetic stimulation and transcranial direct current stimulation, use electromagnetic principles to alter brain activity noninvasively, and induce focal but also network effects beyond the stimulation site. When combined with brain imaging techniques such as functional magnetic resonance imaging, positron emission tomography and electroencephalography, these brain stimulation techniques enable a causal assessment of the interaction between different network components, and their respective functional roles. The same techniques can also be applied to explore hypotheses regarding the changes in functional connectivity that occur during task performance and in various disease states such as stroke, depression and schizophrenia. Finally, in diseases characterized by pathologic alterations in either the excitability within a single region or in the activity of distributed networks, such techniques provide a potential mechanism to alter cortical network function and architectures in a beneficial manner. PMID- 22429245 TI - Pitting binding against selection--electrophysiological measures of feature-based attention are attenuated by Gestalt object grouping. AB - Humans have limited cognitive resources to process the nearly limitless information available in the environment. Endogenous, or 'top-down', selective attention to basic visual features such as color or motion is a common strategy for biasing resources in favor of the most relevant information sources in a given context. Opposing this top-down separation of features is a 'bottom-up' tendency to integrate, or bind, the various features that constitute objects. We pitted these two processes against each other in an electrophysiological experiment to test if top-down selective attention can overcome constitutive binding processes. Our results demonstrate that bottom-up binding processes can dominate top-down feature-based attention even when explicitly detrimental to task performance. PMID- 22429246 TI - Plasticity of cortical inhibition in dystonia is impaired after motor learning and paired-associative stimulation. AB - Artificial induction of plasticity by paired associative stimulation (PAS) in healthy volunteers (HV) demonstrates Hebbian-like plasticity in selected inhibitory networks as well as excitatory networks. In a group of 17 patients with focal hand dystonia and a group of 19 HV, we evaluated how PAS and the learning of a simple motor task influence the circuits supporting long-interval intracortical inhibition (LICI, reflecting activity of GABA(B) interneurons) and long-latency afferent inhibition (LAI, reflecting activity of somatosensory inputs to the motor cortex). In HV, PAS and motor learning induced long-term potentiation (LTP)-like plasticity of excitatory networks and a lasting decrease of LAI and LICI in the motor representation of the targeted or trained muscle. The better the motor performance, the larger was the decrease of LAI. Although motor performance in the patient group was similar to that of the control group, LAI did not decrease during the motor learning as it did in the control group. In contrast, LICI was normally modulated. In patients the results after PAS did not match those obtained after motor learning: LAI was paradoxically increased and LICI did not exhibit any change. In the normal situation, decreased excitability in inhibitory circuits after induction of LTP-like plasticity may help to shape the cortical maps according to the new sensorimotor task. In patients, the abnormal or absent modulation of afferent and intracortical long-interval inhibition might indicate maladaptive plasticity that possibly contributes to the difficulty that they have to learn a new sensorimotor task. PMID- 22429247 TI - Beech roots are simultaneously colonized by multiple genets of the ectomycorrhizal fungus Laccaria amethystina clustered in two genetic groups. AB - In this study, we characterize and compare the genetic structure of aboveground and belowground populations of the ectomycorrhizal fungus Laccaria amethystina in an unmanaged mixed beech forest. Fruiting bodies and mycorrhizas of L. amethystina were mapped and collected in four plots in the Swietokrzyskie Mountains (Poland). A total of 563 fruiting bodies and 394 mycorrhizas were successfully genotyped using the rDNA IGS1 (intergenic spacer) and seven simple sequence repeat markers. We identified two different genetic clusters of L. amethystina in all of the plots, suggesting that a process of sympatric isolation may be occurring at a local scale. The proportion of individuals belonging to each cluster was similar among plots aboveground while it significantly differed belowground. Predominance of a given cluster could be explained by distinct host preferences or by priority effects and competition among genets. Both aboveground and belowground populations consisted of many intermingling small genets. Consequently, host trees were simultaneously colonized by many L. amethystina genets that may show different ecophysiological abilities. Our data showed that several genets may last for at least 1 year belowground and sustain into the next season. Ectomycorrhizal species reproducing by means of spores can form highly diverse and persistent belowground genets that may provide the host tree with higher resilience in a changing environment and enhance ecosystem performance. PMID- 22429248 TI - Bilateral testicular germ cell tumours: a systematic review. AB - What's known on the subject? and What does the study add? Bilateral testicular germ cell tumours (BTGCTs) are rare neoplasms. Most previously published studies consist of case reports or small retrospective case series. Little is known about their epidemiological and clinicopathological characteristics. BTGCT corresponded to 1.82% of testicular tumours. Metachronous disease was about twice as frequent as synchronous disease. The primary tumour histology, chemotherapy use and the interval between metachronous tumours influenced the histology of the second tumour. Overall, synchronous tumours were associated with more advanced disease and presented less favourable survival rates than metachronous tumours. Testicular cancer is the most common tumour in young men. It is known that a second primary contralateral testis tumour may occur in up to 5% of men with a proior tumour. About 35% of these men present with synchronous tumours, and 65% present with metachronous tumours. However there is little data about bilateral testicular germ cell tumours (BTGCT) in the literature and the most published articles are case reports on a small series of men, which makes it difficult to draw conclusions about therapeutic strategies for the treatment of BTGCTs. In fact, current guidelines for the treatment of testicular cancer contain little information related to bilateral disease. Therefore, the aim of our study is to provide a broad overview of BTGCT and to update data focusing on incidence, pathological features, and clinical outcomes of men with BTGCTs. Thus, an extensive review containing 94 studies and more than 50,000 patients was conducted. PMID- 22429249 TI - Biomass production and alcoholic fermentation performance of Saccharomyces cerevisiae as a function of nitrogen source. AB - Nitrogen limitation is one of the most common causes for stuck or sluggish fermentation. A broad range of values have been reported as the minimum nitrogen concentration necessary for the completion of alcoholic fermentation. We have analyzed the minimum nitrogen concentration required to yield the maximum biomass (nitrogen reference value) using a microwell plate reader to monitor fermentation with different nitrogen sources and sugar concentrations. The biomass yield was dependent on the amount of available nitrogen, the nature of nitrogen source, and the sugar concentration in the medium. Nevertheless, achieving the maximum biomass was not sufficient to ensure the completion of the alcoholic fermentation, because the fermentation of 280 g sugar L(-1) stuck, regardless of the nature and concentration of nitrogen source. However, a mixture of five amino acids (Leu, Ile, Val, Phe and Thr) as the nitrogen source allowed for maximum sugar consumption. Analysis of cell vitality by impedance showed a significant improvement in the vitality for cells fermenting using this amino acid combination. PMID- 22429250 TI - Nurses' use of situation awareness in decision-making: an integrative review. AB - AIM: To critically review the literature related to situation awareness and clinical decision-making by nurses. BACKGROUND: International recognition that situation awareness positively contributes to clinical decision-making has led to a growing body of healthcare literature. To date, research has predominately focused on anaesthetists and surgeons using measurement frameworks from the aviation industry. The evidence focussing directly on situation awareness in decision-making by nurses remains limited. DATA SOURCES: Databases: PROQUEST, Web of Science, CINAHL, and PUBMED. REVIEW METHODS: An integrative review was undertaken following an extensive literature search with the date range January 1965 - March 2011. English language literature reviews, primary qualitative, quantitative and mixed method studies describing situation awareness in decision making by or including nurses were included. RESULTS: Five empirical studies of nurses' situation awareness were reviewed. Of these, three included decision making and situation awareness by nurses in inter-professional teams; two related solely to situation awareness and decision-making by nurses. Findings from the five studies could be grouped under three themes: individual factors influencing situation awareness, interpersonal behaviours influencing situation awareness and situation awareness improving working relationships and patient care. CONCLUSION: Further investigation is needed to identify the situation awareness skills that are vital to decision-making by nurses. Elucidating essential skills sets associated with situation awareness may inform the development of education and training to enhance clinical decision-making by nurses. PMID- 22429251 TI - Efficacy of cardiac autonomic denervation for atrial fibrillation: a meta analysis. AB - INTRODUCTION: Adjunctive complex fractionated atrial electrograms (CFAE) ablation or ganglionated plexi (GP) ablation have been proposed as new strategies to increase the elimination of AF, but the difference between CFAE/GP ablation and pulmonary vein isolation (PVI), as well as the combined effect of CFAE/GP plus PVI ablation were unclear. This meta-analysis was designed to determine whether adjunctive cardiac autonomic denervation (CAD) was effective for the elimination of AF, and whether CAD alone was superior to PVI in AF patients. METHODS: A systemic literature search in MEDLINE, EMBASE, and Cochrane Controlled Trials Register (CCRT) was performed and controlled trials comparing the effect of PVI plus CFAE/GP ablation with PVI, as well as CFAE/GP ablation with PVI were collected. RESULTS: A total of 15 trials including 1,147 patients with AF were qualified for this meta-analysis. CAD plus PVI significantly increased the freedom from AF/ATs (OR 1.85, 95% CI: 1.33-2.59, P = 0.29). Subgroup analysis showed that additional CAD increased the ratio of sinus rhythm maintenance in both paroxysmal AF (OR 1.69; 95% CI: 1.09-2.62, P = 0.41) and nonparoxysmal AF (OR 2.11, 95% CI: 1.14-3.90, P = 0.14). Besides, when compared respectively, adjunctive CAD was not superior to PVI (OR 0.31; 95% CI: 0.11-0.86, P = 0.002). CONCLUSION: This study suggested that CAD plus PVI significantly increase the freedom from recurrence of AF both in paroxysmal and nonparoxysmal patients. However, when compared alone, the benefit of CAD was not superior to PVI. PMID- 22429252 TI - Association of PTPN22 C1858T polymorphism and type 1 diabetes: a meta-analysis. AB - Recently, protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism has been identified as a susceptibile gene for type 1 diabetes (T1D), but studies are inconsistence, In order to assess the association between PTPN22C1858T polymorphism and T1D based on different ethnicities, a meta-analysis was performed, including 26 studies, total of 16,240 patients and 17,997 controls. Meta-analysis was performed on T versus C, T/T+T/C versus C/C (dominant model) and T/T versus T/C+C/C (recessive model) in a fixed/random effects model. The results indicated an association between the PTPN22 C1858T polymorphism and T1D in all subjects. The overall odds ratio (OR) of T versus C using the fixed effects model was 1.948 (95% CI = 1.859~2.041, P < 0.001). After stratification by ethnicity, analysis revealed that the PTPN22 C1858T polymorphism T allele was significantly associated with T1D in Europeans, Americans (OR = 1.946, 95% CI = 1.852~2.045, P < 0.001; OR = 1.946, 95% CI = 1.690~2.242, P < 0.001, respectively). Meta-analysis of the T/T+T/C genotype and the T/T genotypes showed the same results as that shown by the PTPN22 C1858T polymorphism T allele. This meta-analysis suggests a possible association between the PTPN22 C1858T polymorphism and T1D, especially in European and American populations. PMID- 22429253 TI - Pd(II)-catalyzed dehydrogenative olefination of vinylic C-H bonds with allylic esters: general and selective access to linear 1,3-butadienes. AB - This work demonstrates a general and efficient method to prepare conjugated dienes by Pd(II)-catalyzed direct olefination of unactivated alkenes with allylic esters and acrylates via vinylic C-H activation. Various aryl and heteroaryl alkenes as well as aliphatic alkenes all give the desired linear 1,3-butadienes with retention of the traditional leaving groups such as OAc and other carboxylic acid ester groups. PMID- 22429254 TI - Training and bone - from health to injury. AB - Mechanical load through physical activity has been shown to be one of the best stimuli to increase the bone strength. This effect of mechanical load accounts for both the accrual of bone mineral and structural skeletal adaptations. Exercise prescription also includes a "window of opportunity" in the late pre- and early peri-pubertal period, where exercise is supposed to insert the most obvious beneficial effects, even if physical activity provides recordable skeletal benefits during all growth. There is also evidence that benefits in bone mass and bone structure obtained by mechanical load during growth may be maintained at advanced age. The notion that former male athletes have lower fracture risk than expected by age, support this view. Physical activity could therefore to be recommended at growth and adolescence as one possible strategy to reduce the future burden of fragility fractures. PMID- 22429255 TI - Understanding naltrexone mechanism of action and pharmacogenetics in Asian Americans via behavioral economics: a preliminary study. AB - A behavioral economic approach to understanding the relative value of alcohol may be useful for advancing medication development for alcoholism. Naltrexone is a heavily researched and moderately effective treatment for alcohol dependence making it a good candidate for a proof-of-concept study of behavioral economics and alcoholism pharmacotherapy. This study examines naltrexone efficacy and pharmacogenetics in terms of the relative value of alcohol, assessed via demand curve analysis. Participants were 35 heavy drinking (AUDIT >=8) Asian Americans. A within-subjects cross-over medication design was used along with an intravenous alcohol challenge completed after 4 days of both naltrexone and placebo. At baseline and BrAC = 0.06g/dl, participants completed an Alcohol Purchase Task, which assessed estimated alcohol consumption along escalating prices. Behavioral economic demand curve analysis yielded measures of intensity, elasticity, maximum expenditure (O(max)), proportionate price insensitivity (P(max)) and breakpoint. Compared to placebo, naltrexone significantly reduced intensity, O(max) and breakpoint. There were also trend-level medication effects on P(max). BrAC was associated with increases in P(max) and breakpoint. A significant naltrexone * OPRM1 genotype interaction was observed for intensity of demand. The present study extends the literature on naltrexone's mechanisms through the application of a novel behavioral economic paradigm. These results indicate that naltrexone reduces several indices of demand for alcohol. This preliminary report provides further evidence for the effectiveness of naltrexone and supports the utility of a behavioral economic approach to alcoholism pharmacotherapy development. PMID- 22429257 TI - Alcohol and substance abuse identified during pregnancy: maternal morbidity, child morbidity and welfare interventions. AB - AIM: To study the relations between postnatal maternal morbidity, child morbidity and welfare interventions in families with prenatal alcohol or substance abuse. METHODS: A register-based longitudinal retrospective cohort study. The exposed cohort included 638 children born to 524 women followed-up during pregnancy for alcohol or substance abuse 1992-2001. Non-exposed children (n = 1914) born to control women were matched for maternal age, parity, number of foetuses, month of birth and delivery hospital of the index child. Perinatal and follow-up data of both cohorts were collected from national registers until 2007. RESULTS: Postnatal maternal abuse-related healthcare utilization and use of medication were associated with child out-of-home care. Significant differences were in particular observed in the categories of maternal mental and behavioural disorders caused by psychoactive substance use as well as injury and poisoning. Maternal inpatient care for mental and behavioural disorders peaked at the time of child out-of-home care. Maternal abuse-related healthcare utilization was associated with early child healthcare utilization and use of medication for mental and behavioural disorders. These associations were largely explained by the association with child out-of-home care. CONCLUSIONS: Postnatal maternal abuse-related morbidity is associated with significant early child morbidity, use of medication and timing of out-of-home care. PMID- 22429258 TI - Effect of chemico-physical parameters on the histidine decarboxylase (HdcA) enzymatic activity in Streptococcus thermophilus PRI60. AB - In this study the activity of the histidine decarboxylase (HdcA) of Streptococcus thermophilus PRI60 was determined during growth and in crude enzyme preparations to evaluate its hazardousness in dairy products. The effect of different pH values, lactose availability, NaCl concentration, and growth temperature on histamine production was evaluated in M17 medium during 168 h incubation. In each case, the production of histamine increased concomitantly with the cell number with a relatively small further rise during the stationary phase. In all cultures the maximum histamine levels were reached at the end of active growth. Histamine was detectable (10 to 55 mg/L) even when growth was strongly inhibited. The HdcA enzyme in crude cell-free extracts was mostly active at acidic pH values common in dairy products. NaCl concentrations lower than 5% did not affect its activity. The enzyme was quite resistant to heat treatments resembling low pasteurization, but was inactivated at 75 degrees C for 2 min. Given the features of the enzyme studied, efforts must be dedicated to a thorough risk analysis and development of strategies to contrast the presence of histaminogenic S. thermophilus strains in products from raw or mildly heat-treated milk. PRACTICAL APPLICATION: During its growth Streptococcus thermophilus can produce histamine over a wide range of conditions encountered in cheesemaking and cheese ripening. The histidine decarboxylase is even more active in cell-free extract and histamine can be accumulated independently of cell viability. PMID- 22429260 TI - Abstracts of the Annual Meeting of the Danish Pathology Society. March 22-24, 2012. Copenhagen, Denmark. PMID- 22429259 TI - Acquired haemophilia A. First line treatment with calcineurin inhibitors and steroid pulses: a 10-year follow-up study. AB - Acquired haemophilia A (AH) is defined as the presence of autoantibodies or inhibitors against factor VIII (FVIII) with a clinical bleeding onset that can be life-threatening. Immunosuppressant therapy must be initiated rapidly to eradicate the inhibitor. Current treatments based on steroids plus cyclophosphamide or rituximab are quite effective, but with significant side effects. Based on previous described AH cases treated with cyclosporine, with a good side-effect profile, we aimed at assessing prospectively a first-line calcineurin inhibitor based immunosuppressive therapy. We included a total of 11 patients affected with AH. Once diagnosed, pulse steroids and calcineurin inhibitors were started. Time to achieve sustained response (SR), defined as testing negative for inhibitor and with stable FVIII level >50%, immunosuppressant side-effects, and relapse of AH were evaluated. Eight patients received cyclosporine and three patients received tacrolimus. SR was achieved in 10 of 11 patients (90.9%) in a median time of 3 weeks (range 2-8 weeks), and none of them relapsed during a median follow-up time of 14 months (range 4-120). One major side-effect appeared (posterior encephalopathy) that forced to discontinue cyclosporine. Overall 5-year survival rate was 54.5%, with a total of five patients dying during the follow-up (mortality rate of 45.5%). These five patients had achieved SR and died because of complications of basal morbidities and/or senescence, not related to AH (bleeding) or to immunosuppressant's (infection) side-effects. Combination therapy of calcineurin inhibitors and pulse steroids seems clinically effective as a first-line treatment of AH. PMID- 22429261 TI - Charge transfer in model bioinspired carotene-porphyrin dyads. AB - We present a computational study based on accurate DFT and TD-DFT methods on model bioinspired donor-acceptor dyads, formed by a carotenoid covalently linked to a tetraphenylporphyrin (TPP) at the ortho position of one of the TPP phenyl rings. Dyadic systems can be used in the construction of organic solar cells and development of efficient photocatalytic systems for the solar energy conversion, due to the unique advantages they offer in terms of synthetic feasibility. This study aims to describe the influence of chemical modifications on the absorption spectra, in particular on the lowest energy charge transfer bands. Effects of different metals of biological interest, i.e., Mg, Fe, Ni, and Zn, and of H(2)O and histidine molecules coordinated to the metals in different axial positions are rationalized. PMID- 22429262 TI - A comparison of the functionality and in vivo phenotypic stability of cartilaginous tissues engineered from different stem cell sources. AB - Joint-derived stem cells are a promising alternative cell source for cartilage repair therapies that may overcome many of the problems associated with the use of primary chondrocytes (CCs). The objective of this study was to compare the in vitro functionality and in vivo phenotypic stability of cartilaginous tissues engineered using bone marrow-derived stem cells (BMSCs) and joint tissue-derived stem cells following encapsulation in agarose hydrogels. Culture-expanded BMSCs, fat pad-derived stem cells (FPSCs), and synovial membrane-derived stem cells (SDSCs) were encapsulated in agarose and maintained in a chondrogenic medium supplemented with transforming growth factor-beta3. After 21 days of culture, constructs were either implanted subcutaneously into the back of nude mice for an additional 28 days or maintained for a similar period in vitro in either chondrogenic or hypertrophic media formulations. After 49 days of in vitro culture in chondrogenic media, SDSC constructs accumulated the highest levels of sulfated glycosaminoglycan (sGAG) (~2.8% w/w) and collagen (~1.8% w/w) and were mechanically stiffer than constructs engineered using other cell types. After subcutaneous implantation in nude mice, sGAG content significantly decreased for all stem cell-seeded constructs, while no significant change was observed in the control constructs engineered using primary CCs, indicating that the in vitro chondrocyte-like phenotype generated in all stem cell-seeded agarose constructs was transient. FPSCs and SDSCs appeared to undergo fibrous dedifferentiation or resorption, as evident from increased collagen type I staining and a dramatic loss in sGAG content. BMSCs followed a more endochondral pathway with increased type X collagen expression and mineralization of the engineered tissue. In conclusion, while joint tissue-derived stem cells possess a strong intrinsic chondrogenic capacity, further studies are needed to identify the factors that will lead to the generation of a more stable chondrogenic phenotype. PMID- 22429263 TI - The DISC (Diabetes in Social Context) Study-evaluation of a culturally sensitive social network intervention for diabetic patients in lower socioeconomic groups: a study protocol. AB - BACKGROUND: Compared to those in higher socioeconomic groups, diabetic patients in lower socioeconomic groups have less favourable metabolic control and experience more diabetes-related complications. They encounter specific barriers that hinder optimal diabetes self-management, including a lack of social support and other psychosocial mechanisms in their immediate social environments. Powerful Together with Diabetes is a culturally sensitive social network intervention specifically targeted to ethnic Dutch, Moroccan, Turkish, and Surinamese diabetic patients in lower socioeconomic groups. For ten months, patients will participate in peer support groups in which they will share experiences, support each other in maintaining healthy lifestyles, and learn skills to resist social pressure. At the same time, their significant others will also receive an intervention, aimed at maximizing support for and minimizing the negative social influences on diabetes self-management. This study aims to test the effectiveness of Powerful Together with Diabetes. METHODS/DESIGN: We will use a quasi-experimental design with an intervention group (Group 1) and two comparison groups (Groups 2 and 3), N = 128 in each group. Group 1 will receive Powerful Together with Diabetes. Group 2 will receive Know your Sugar, a six-week group intervention that does not focus on the participants' social environments. Group 3 receives standard care only. Participants in Groups 1 and 2 will be interviewed and physically examined at baseline, 3, 10, and 16 months. We will compare their haemoglobin A1C levels with the haemoglobin A1C levels of Group 3. Main outcome measures are haemoglobin A1C, diabetes-related quality of life, diabetes self-management, health-related, and intermediate outcome measures. We will conduct a process evaluation and a qualitative study to gain more insights into the intervention fidelity, feasibility, and changes in the psychosocial mechanism in the participants' immediate social environments. DISCUSSION: With this study, we will assess the feasibility and effectiveness of a culturally sensitive social network intervention for lower socioeconomic groups. Furthermore, we will study how to enable these patients to optimally manage their diabetes. PMID- 22429264 TI - The effect of left ventricular (LV) remodeling on ventricular arrhythmia in cardiac resynchronization therapy (CRT-D) patients (antiarrhythmic effect of CRT). AB - BACKGROUND: In patients with low ejection fraction and ventricular dyssynchrony, cardiac resynchronization therapy (CRT) is an accepted therapeutic modality. In these patients, CRT can improve the quality of life and exercise tolerance in addition to improved survival. On the other hand, antiarrhythmic effects of CRT is a place of debate. METHOD: In this study, we evaluated the effect of CRT induced reverse remodeling on ventricular arrhythmia in heart failure patients. Patients with CRT were divided to two groups of responders and nonresponders. Responders were those with reduction of LVESD of more than 10% or increase in LVEF of more than 5%. They were visited and device analysis was performed during the follow-up. RESULTS: One hundred and nineteen patients were enrolled in this study. Those with reverse remodeling experienced fewer ventricular arrhythmias after two years of follow-up (N = 2 vs 11, P = 0.001). CONCLUSION: Reverse remodeling associated with CRT implantation can result in decreased frequency of ventricular arrhythmias. PMID- 22429265 TI - Exercise therapy - the public health message. AB - Non-communicable chronic diseases (NCDs), such as cardiovascular disease, diabetes, and cancer, are currently responsible for 65% of all deaths worldwide and are projected to cause over 75% of all deaths by 2030. A substantial accumulation of epidemiological and experimental evidence has established a causal relationship between NCDs and well-known yet preventable risk factors (e.g., physical inactivity and obesity). Given that physical activity has both direct and indirect effects on the mortality and morbidity of NCDs via other risk factors (e.g., obesity, diabetes, and hypertension), it is now undeniable that sedentary lifestyles are one of the most significant public health problems of the 21st century. In 2007, the American College of Sports Medicine (ACSM) and American Medical Association (AMA) launched the Exercise is Medicine(r) (EIM) initiative in recognition of the fundamental importance of physical activity to health and well-being. EIM is on the forefront of a global movement to reduce sedentary lifestyles, foster implementation of exercise counseling into clinical practice, and disseminate exercise therapy on a global scale. If the devastating human losses and financial burden of inactivity-induced chronic disease are to be ameliorated, the wide-ranging cost-effective health benefits and financial feasibility of physical activity interventions must be appreciated and promoted. PMID- 22429266 TI - On the evolution of morphogenetic models: mechano-chemical interactions and an integrated view of cell differentiation, growth, pattern formation and morphogenesis. AB - In the 1950s, embryology was conceptualized as four relatively independent problems: cell differentiation, growth, pattern formation and morphogenesis. The mechanisms underlying the first three traditionally have been viewed as being chemical in nature, whereas those underlying morphogenesis have usually been discussed in terms of mechanics. Often, morphogenesis and its mechanical processes have been regarded as subordinate to chemical ones. However, a growing body of evidence indicates that the biomechanics of cells and tissues affect in striking ways those phenomena often thought of as mainly under the control of cell-cell signalling. This accumulation of data has led to a revival of the mechano-transduction concept in particular, and of complexity in general, causing us now to consider whether we should retain the traditional conceptualization of development. The researchers' semantic preferences for the terms 'patterning', 'pattern formation' or 'morphogenesis' can be used to describe three main 'schools of thought' which emerged in the late 1970s. In the 'molecular school', the term patterning is deeply tied to the positional information concept. In the 'chemical school', the term 'pattern formation' regularly implies reaction diffusion models. In the 'mechanical school', the term 'morphogenesis' is more frequently used in relation to mechanical instabilities. Major differences among these three schools pertain to the concept of self-organization, and models can be classified as morphostatic or morphodynamic. Various examples illustrate the distorted picture that arises from the distinction among differentiation, growth, pattern formation and morphogenesis, based on the idea that the underlying mechanisms are respectively chemical or mechanical. Emerging quantitative approaches integrate the concepts and methods of complex sciences and emphasize the interplay between hierarchical levels of organization via mechano-chemical interactions. They draw upon recent improvements in mathematical and numerical morphogenetic models and upon considerable progress in collecting new quantitative data. This review highlights a variety of such models, which exhibit important advances, such as hybrid, stochastic and multiscale simulations. PMID- 22429267 TI - Unmyelinated nerve fibers in the human dental pulp express markers for myelinated fibers and show sodium channel accumulations. AB - BACKGROUND: The dental pulp is a common source of pain and is used to study peripheral inflammatory pain mechanisms. Results show most fibers are unmyelinated, yet recent findings in experimental animals suggest many pulpal afferents originate from fibers that are myelinated at more proximal locations. Here we use the human dental pulp and confocal microscopy to examine the staining relationships of neurofilament heavy (NFH), a protein commonly expressed in myelinated afferents, with other markers to test the possibility that unmyelinated pulpal afferents originate from myelinated axons. Other staining relationships studied included myelin basic protein (MBP), protein gene product (PGP) 9.5 to identify all nerve fibers, tyrosine hydroxylase (TH) to identify sympathetic fibers, contactin-associated protein (caspr) to identify nodal sites, S-100 to identify Schwann cells and sodium channels (NaChs). RESULTS: Results show NFH expression in most PGP9.5 fibers except those with TH and include the broad expression of NFH in axons lacking MBP. Fibers with NFH and MBP show NaCh clusters at nodal sites as expected, but surprisingly, NaCh accumulations are also seen in unmyelinated fibers with NFH, and in fibers with NFH that lack Schwann cell associations. CONCLUSIONS: The expression of NFH in most axons suggests a myelinated origin for many pulpal afferents, while the presence of NaCh clusters in unmyelinated fibers suggests an inherent capacity for the unmyelinated segments of myelinated fibers to form NaCh accumulations. These findings have broad implications on the use of dental pulp to study pain mechanisms and suggest possible novel mechanisms responsible for NaCh cluster formation and neuronal excitability. PMID- 22429268 TI - Bleb vascularity following post-trabeculectomy subconjunctival bevacizumab: a pilot study. AB - BACKGROUND: To determine whether postoperative subconjunctival bevacizumab significantly alters bleb vascularity. DESIGN: A randomized, prospective interventional study. PARTICIPANTS: Forty-three eyes from 39 patients were recruited, with 21 eyes randomized to subconjunctival injections of 5 fluorouracil, and 22 eyes to combined 5-fluorouracil/bevacizumab. METHODS: All patients who underwent uncomplicated primary antimetabolite augmented trabeculectomy who subsequently required postoperative subconjunctival 5 fluorouracil injection within 4 weeks of surgery were eligible. Patients were randomized to receive subconjunctival 5-fluorouracil only (7.5 mg/0.15 mL) or 5 fluorouracil plus bevacizumab (1.25 mg/0.05 mL). MAIN OUTCOME MEASURES: Primary outcome was bleb vascularity with secondary endpoints including visual acuity, intraocular pressure, bleb morphology, complications and total numbers of 5 fluorouracil injections were recorded at baseline, week 12 and 18 months. RESULTS: At week 12, there was no significant difference between groups for visual acuity, intraocular pressure, bleb vascularity and morphology, or total number of 5-fluorouracil injections. By 18 months, 47.4% of the 5 fluorouracil/bevacizumab group exhibited central bleb avascularity compared with 21.1% of the 5-fluorouracil group (Fisher's exact test, P = 0.17). Two bleb complications (one blebitis; one suture abscess) recorded in the 5 fluorouracil/bevacizumab group. CONCLUSIONS: After a single combined injection, a trend for increased central bleb avascularity was observed, although this effect was not sufficient to reach statistical significance. This, in addition to the occurrence of two bleb-related complications in the bevacizumab group, suggests the need for a larger clinical trial to further evaluate the safety and efficacy of bevacizumab as a modulating agent in glaucoma filtration surgery. PMID- 22429269 TI - Predictors of seizures during pregnancy in women with epilepsy. AB - We aimed to characterize the seizure pattern during pregnancy in a large cohort of women with epilepsy (WWE) and identify possible predictors of seizure relapse during pregnancy. We recorded the antiepileptic drug (AED) use and seizure frequency for WWE during the prepregnancy month and pregnancy. The seizure profile was correlated with the clinical details and seizure type as abstracted from the clinical records maintained in the registry. Of the 1,297 pregnancies in WWE with complete seizure data, 47.8% were seizure-free during pregnancy. Seizure relapse was highest during the three peripartum days. Women with partial seizures had higher risk of relapse (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.2 2.0) than those with generalized seizures. They had two peaks of seizure relapse (second to third month and sixth month). Those with generalized seizures had one peak at first trimester. Those who were on polytherapy had increased risk of seizures (OR 2.98, 95% CI 2.3-3.9) when compared to those on monotherapy. Those who had seizures in the prepregnancy month had higher risk (OR 15, 95% CI 9-25.1) of seizures during pregnancy when compared to those who were seizure-free during that period. On multiple logistic regression, prepregnancy seizure was the most important predictor of seizures during pregnancy. PMID- 22429270 TI - Effects of nonsystemic ventricular pacing in patients with transposition of the great arteries and atrial redirection. AB - INTRODUCTION: Ventricular pacing may add additional risk for right ventricular (RV) dysfunction in patients with transposition of the great arteries (TGA) and atrial redirection. The aim of our study was to evaluate the effects of long-term nonsystemic ventricular pacing on cardiac function, dyssynchrony, and clinical performance in patients with systemic RV. METHODS AND RESULTS: Forty-six adults with TGA and atrial redirection, of whom 11 were permanently paced at the nonsystemic ventricle, underwent assessment of clinical status and exercise stress testing, as well as echocardiography to assess parameters of RV function and dyssynchrony. In paced patients, median NYHA functional class was II, which was significantly higher than in nonpaced patients (median class I; P = 0.002). Maximum performance and peak oxygen consumption on exercise testing were significantly lower in paced patients when compared with nonpaced patients (100 +/- 30 vs 120 +/- 32 W and 22 +/- 6 vs 27 +/- 7 mLO(2)/kg/min, respectively; P < 0.05 for both). On echocardiography, RV shortening fraction (27 +/- 11 vs 33 +/- 10%), RV ejection fraction (39 +/- 7 vs 44 +/- 10%) and RV dP/dt(max) (891 +/- 470 vs 1,024 +/- 318 mmHg/s) were significantly lower (P < 0.05 for all) in paced versus nonpaced patients. Inter- and intraventricular dyssynchrony was most pronounced in the paced group (99 +/- 10 vs 25 +/- 9 ms and 70 +/- 29 vs 21 +/- 15 ms, respectively; P < 0.001 for both). CONCLUSIONS: Long-term pacing of the nonsystemic ventricle in patients with atrial switch for TGA was associated with significantly impaired functional status, exercise capacity, and systemic ventricular function. PMID- 22429271 TI - Primed interference: the cognitive and behavioral costs of an incongruity between chronic and primed motivational orientations. AB - Research has shown that temporarily primed motivational orientations have essentially the same effects on how people pursue their goals as their chronic orientations. This article shows that, despite the interchangeability of temporary and chronic motivations, primed motivational orientations that are incongruent with chronic orientations create interference, requiring the deployment of cognitive resources and thus undermining performance on subsequent tasks that rely on these resources. Across 6 studies, we primed motivational orientations that were either congruent or incongruent with participants' chronic orientations and then assessed their performance on subsequent tasks that required cognitive resources. Consistent with the primed interference hypothesis, we found that incongruity between temporary and chronic motivational orientations undermined participants' (a) inhibition of incorrect but highly accessible responses, (b) mental arithmetic, (c) analytical reasoning, and (d) resistance to temptation. These results--which were observed following the activation of motivations for promotion or prevention (Studies 1-2 and 5-6), high or low need for belonging (Study 3), and high or low power orientations (Study 4)--illustrate the broad implications of holding incongruent chronic and primed orientations. PMID- 22429272 TI - Effects of self-other decision making on regulatory focus and choice overload. AB - A growing stream of research is investigating how choices people make for themselves are different from choices people make for others. In this paper, I propose that these choices vary according to regulatory focus, such that people who make choices for themselves are prevention focused, whereas people who make choices for others are promotion focused. Drawing on regulatory focus theory, in particular work on errors of omission and commission, I hypothesize that people who make choices for others experience a reversal of the choice overload effect. In 6 studies, including a field study, I found that people who make choices for themselves are less satisfied after selecting among many options compared to few options, yet, people who make choices for others are more satisfied after selecting among many options compared to few options. Implications and suggestions for other differences in self-other decision making are discussed. PMID- 22429273 TI - Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial. AB - BACKGROUND: Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use. METHODS: This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 MUg, levonorgestrel [LV] 150 MUg [Microgynon 30(r)]). Thirty-two healthy female subjects participated in an open label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 MUg BID from Days 1 through 4 and at 10 MUg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period. RESULTS: Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial. CONCLUSIONS: The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00254800. PMID- 22429274 TI - Relationship between depression, clinical and biochemical parameters in patients undergoing haemodialysis. AB - In this paper, we investigated the incidence of depression and its relation to clinical, laboratory parameters and sleep disorders in 45 haemodialysis (HD) patients. They were divided into two groups. Group A (n = 29) had no depression, whereas Group B (n = 16) had clinically assessed depression. Subjects were compared in terms of socioeconomic, clinical, laboratory parameters and presence of sleep disorders. Groups were matched for age, sex, family status, education, self-esteem, coffee and alcohol consumption, psychiatric history, time on HD and laboratory (serum urea, creatinine, electrolytes, iron, albumin and lipids) parameters. Group B demonstrated significantly lower haemoglobin levels (11.13 +/ 1.69 and 12.23 +/- 1.31 g/dl, respectively; p < 0.01) and higher C-Reactive Protein (CRP) levels (1.82 +/- 1.73 and 0.83 +/- 0.6 mg/dl, respectively; p < 0.005) compared to Group A. Additionally, strong correlation was observed when Hamilton Depression Scale scores were related to haemoglobin (r =-0.30, p < 0.05), CRP (r = 0.38, p < 0.001) and AIS scores (r = 0.54, p < 0.0001). In conclusion, depression seems to be related to high CRP, low haemoglobin levels and sleep disorders. PMID- 22429275 TI - Opsin gene sequence variation across phylogenetic and population histories in Mysis (Crustacea: Mysida) does not match current light environments or visual pigment absorbance spectra. AB - The hypothesis that selection on the opsin gene is efficient in tuning vision to the ambient light environment of an organism was assessed in 49 populations of 12 Mysis crustacean species, inhabiting arctic marine waters, coastal littoral habitats, freshwater lakes ('glacial relicts') and the deep Caspian Sea. Extensive sequence variation was found within and among taxa, but its patterns did not match expectations based on light environments, spectral sensitivity of the visual pigment measured by microspectrophotometry or the history of species and populations. The main split in the opsin gene tree was between lineages I and II, differing in six amino acids. Lineage I was present in marine and Caspian Sea species and in the North American freshwater Mysis diluviana, whereas lineage II was found in the European and circumarctic fresh- and brackish-water Mysis relicta, Mysis salemaai and Mysis segerstralei. Both lineages were present in some populations of M. salemaai and M. segerstralei. Absorbance spectra of the visual pigment in nine populations of the latter three species showed a dichotomy between lake (lambda(max) =554-562 nm) and brackish-water (Baltic Sea) populations (lambda(max) = 521-535 nm). Judged by the shape of spectra, this difference was not because of different chromophores (A2 vs. A1), but neither did it coincide with the split in the opsin tree (lineages I/II), species identity or current light environments. In all, adaptive evolution of the opsin gene in Mysis could not be demonstrated, but its sequence variation did not conform to a neutral expectation either, suggesting evolutionary constraints and/or unidentified mechanisms of spectral tuning. PMID- 22429276 TI - Investigation of the interaction between the MIR-503 and CD40 genes in irradiated U937 cells. AB - BACKGROUND: MicroRNAs (miRNAs) are a group of small noncoding RNAs that take part in diverse biological processes by suppressing target gene expression. Relatively few miRNAs have been studied in detail, especially miR-503, and hence the biological relevance of majority remains to be uncovered. Whether altered expression of miRNA-503 affects the immunity response to radiotherapy has yet to be addressed. RESULTS: In the present study, we applied ionizing radiation with a dose of either 0.1 Gy or 5 Gy to irradiate U937 cells to confirm CD40 as a miR 503 target, which was identified using a bioimformatics tool. In high dose (5 Gy) ionizing-irradiated U937 cells, expression of miR-503 was up regulated while the expression of CD40 gene was down regulated. Using the transfection of the miR-503 gene into U937 cells and Luciferase assay, we confirmed that miR-503 suppressed the expression of CD40, and was a negtive regulator of CD40. CONCLUSIONS: To our knowledge, we are the first to describe involvement of miR-503 in radiobiological effect at a molecular level. This initial finding suggested the evidence that ionizing radiation could alter the expression of miR-503 and its target gene CD40, and may be very important to shed light on a possible mechanism regarding regulation of immune responses to irradiation. PMID- 22429277 TI - Sustained rheumatoid arthritis remission is uncommon in clinical practice. AB - INTRODUCTION: Remission is an important goal of therapy in rheumatoid arthritis (RA), but data on duration of remission are lacking. Our objective was to describe the duration of remission in RA, assessed by different criteria. METHODS: We evaluated patients from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) not in remission at baseline with at least 2 years of follow-up. Remission was assessed according to the Disease Activity Score 28-C reactive protein (DAS28-CRP4), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) scores, and the recently proposed American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for remission. Analyses were performed by using Kaplan-Meier survival curves. RESULTS: We identified 871 subjects with >= 2 years of follow-up. Of these subjects, 394 were in remission at one or more time-points and not in remission at baseline, according to at least one of the following criteria: DAS28-CRP < 2.6 (n = 309), DAS28-CRP < 2.3 (n = 275), SDAI (n = 168), CDAI (n = 170), and 2010 ACR/EULAR (n = 158). The median age for the 394 subjects at entrance to BRASS was 56 years; median disease duration was 8 years; 81% were female patients; and 72% were seropositive. Survival analysis performed separately for each remission criterion demonstrated that < 50% of subjects remained in remission 1 year later. Median remission survival time was 1 year. Kaplan-Meier curves of the various remission criteria did not significantly differ (P = 0.29 according to the log rank test). CONCLUSIONS: This study shows that in clinical practice, a minority of RA patients are in sustained remission. PMID- 22429278 TI - Effect of roasting conditions on color and volatile profile including HMF level in sweet almonds (Prunus dulcis). AB - Microwave, oven, and oil roasting of almonds were used to promote almond flavor and color formation. Raw pasteurized almonds were roasted in a microwave for 1 to 3 min, in an oven at 177 degrees C for 5, 10, 15, and 20 min; and at 135 and 163 degrees C for 20 min, and in oil at 135, 163, and 177 degrees C for 5 min and 177 degrees C for 10 min. Volatile compounds were quantified in the headspace of ground almonds, both raw and roasted, by selected ion flow tube mass spectrometry. Strong correlations were found between L value, chroma, and 5 (hydroxy methyl)-2- furfural; and were independent of roasting method. Raw almonds had lower concentrations of most volatiles than roasted almonds. Conditions that produced color equivalent to commercial samples were 2 min in the microwave, 5 min at 177 degrees C in the oven, and 5 min at 135 degrees C in oil. Microwave heating produced higher levels of most volatiles than oven and oil roasting at commercial color. Sensory evaluation indicated that microwave-roasted almonds had the strongest aroma and were the most preferred. Oil-roasted almonds showed significantly lower levels of volatiles than other methods, likely due to loss of these volatiles into the oil. Alcohols such as benzyl alcohols and strecker aldehydes including benzaldehyde and methional were at higher concentrations than other volatiles in roasted almonds. The oxidation of lipids to form alkanals such as nonanal and degradation of sugars to form furan type compounds was also observed. The Maillard reaction contributed to the formation of more of the total volatiles in almonds than the lipid oxidation reaction. PRACTICAL APPLICATION: The level of 5-(hydroxy methyl)-2- furfural (HMF), color, volatile profile, and sensory perception can be used to develop the best roasting method, time, and temperature for almonds. The rate of color development and the production of volatiles differ under different roasting conditions. Based on the color, volatile, and sensory assessments of the 3 almonds, the use of microwave technology as a process for roasting almonds reduces processing time and leads to an almond product with better flavor than oven or oil roasting. PMID- 22429279 TI - Evaluation of the anti-resorptive ability of an experimental acetazolamide paste for the treatment of late replanted teeth: a study in rats. AB - When late replantation is performed, the root surface and root canal should be treated. Notwithstanding failures still occur, because of the high rates of root resorption, evidencing the need to search for substances that may inhibit root resorption. The acetazolamide is a known anti-resorptive agent, and its use as root canal dressing may increase the success rates in the treatment of root resorption. Therefore, this study evaluated the effect of an acetazolamide paste used as root canal dressing in late replanted teeth. The study was conducted on 24 maxillary right incisors of rats, which were avulsed and divided in two groups. In group I, the teeth were kept dry for 30 min, had their root surfaces rubbed with a blade, and were treated with 2% sodium fluoride at pH 5.5 for 20 min; the root canals were instrumented and filled with acetazolamide paste; and then the teeth were replanted. In group II, the treatment was similar to group I, except for the root canal dressing, with utilization of calcium hydroxide in group II. At 15 and 60 days after replantation, the animals were killed and the specimens were processed in a histotechnical laboratory for microscopic and morphometric analysis. The results demonstrated the ability of both intracanal substances to limit root resorption, yet they were unable to completely inhibit the root resorption. Replacement resorption lacunae were present in greater proportion in group II, at 60 days. It was concluded that the acetazolamide paste was effective to limit the root resorption, being more effective in limiting the replacement resorption compared with calcium hydroxide. PMID- 22429280 TI - Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging. AB - The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 MUL, 0.007 to 0.02 M) or intravenously (300 MUL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-MUL subcutaneous dose of Au DENPs with [Au] >= 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT. PMID- 22429281 TI - Duration and morbidity of chronic immune thrombocytopenic purpura in children: five-year follow-up of a Nordic cohort. AB - AIM: To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP). METHODS: Prospective 5-year follow-up of 96 children with ITP lasting more than 6 months, with reporting of hospital admissions, severity of bleeding episodes and stabilization of platelet counts above 20, 50 and 150 * 10(9) /L. RESULTS: The estimated 5-year recovery rate was 52%; exclusion of 12 splenectomized children did not change the estimate. Events eliciting admission to hospital occurred in 39 (41%). Major haemorrhages occurred in eight children (8%), including a nonfatal intracranial haemorrhage in one child (1%). The overall admission rate was 0.4/year of thrombocytopenia, decreasing during follow up as thrombocytopenia converted to milder degrees. Early recovery within 2 years of diagnosis occurred in 35%, was associated with low morbidity and was more likely in young children with abrupt onset of symptoms. CONCLUSION: In a Nordic cohort of children with chronic ITP, one half had recovered 5 years after diagnosis, more than half never required hospitalization and <10% experienced serious bleeding episodes, always with a platelet count <20 * 10(9) /L. Aggressive management can be restricted to the minority of children with continuing severe thrombocytopenia and frequent, clinically significant bleeding events. PMID- 22429282 TI - The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in different serum testosterone levels. AB - INTRODUCTION: In addition to a depletion of androgen, attenuated action of androgen receptor (AR) might also contribute to andropausal symptoms. AIM: To evaluate the interaction of AR cytosine adenine guanine (CAG) repeat polymorphism and serum testosterone levels and their effect on andropausal symptoms in aging Taiwanese men. METHODS: From August 2007 to April 2008, a free health screening for men older than 40 years was conducted by a medical center in Kaohsiung City, Taiwan. All participants received physical examination, answered questionnaires to collect their demographic information and medical histories, completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire, and provided 20-cm(3) whole blood samples for biochemical and genetic evaluation. MAIN OUTCOME MEASURES: The ADAM questionnaire was used to evaluate andropausal symptoms. Serum albumin, total testosterone (TT), and sex hormone-binding globulin levels were measured. Free testosterone level was calculated. AR gene CAG repeat polymorphism was determined by direct sequencing. RESULTS: Seven hundred two men with the mean age of 57.2 +/- 6.5 years were included. There was no significant association between TT levels and the distribution of AR CAG repeat polymorphism. When TT levels were above 340 ng/dL, subjects with AR CAG repeat lengths ~25 showed significantly higher risk of developing andropausal symptoms, as compared with those with AR CAG repeat lengths ~22 (P = 0.006), but this was not observed when TT levels were 340 ng/dL or below. Age and number of comorbidities were also independent risk factors for andropausal symptoms. CONCLUSION: In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing andropausal symptoms. Age and number of comorbidities can also influence the appearance of andropausal symptoms. In clinical practice, a multifactorial approach to evaluate andropausal symptoms and the interactions between those risk factors is suggested. PMID- 22429284 TI - Haematocytopathology: why? PMID- 22429285 TI - Effects of BmKIT 3 R gene transfer on pupal development of Bombyx mori Linnaeus using a Gal4/UAS binary transgenic system. AB - The pupal stage of the silkworm Bombyx mori Linnaeus lasts for approximately two weeks. However, prolongation of pupal duration would reduce the labor required to process and dry fresh cocoons. This study investigated the effects of BmKIT(3)(R) gene (from the Chinese scorpion Buthus martensii Karsch) transfer on the pupal development of B. mori using a Gal4/UAS binary transgenic system. Gal4 driven by a pupa-specific promoter BmWCP4 (from a B. mori wing-cuticle protein gene) or PDP (from a B. mori cocoonase gene), and BmKIT(3)(R) driven by a UAS cis-acting element were used to construct novel piggyBac-derived plasmids containing a neomycin-resistance gene (neo) controlled by the Bombyx mori nucleopolyhedrovirus (BmNPV) ie-1 (immediate-early gene) promoter and a green fluorescent protein gene (gfp) under the control of the B. mori actin 3 (A3) promoter. The vector was transferred into silkworm eggs by sperm-mediated gene transfer. Transgenic silkworms were produced after screening for neo and gfp genes, and gene transfer was verified by polymerase chain reaction and dot-blot hybridization. The larval development of the hybrid progeny of Gal4- and UAS transgenic silkworms was similar to that of normal silkworms, but some pupae failed to metamorphose into moths, and the development of surviving pupae was arrested as a result of BmKIT(3)(R) expression. Moreover, Gal4 driven by the BmWCP4 promoter delayed pupal development more effectively than that driven by the PDP promoter in the Gal4/UAS binary transgenic system. Pupal durations of hybrid transgenic silkworm progeny with BmWCP4 and PDP promoters were approximately 5, 2, and 4 days longer, respectively, compared to corresponding normal silkworms, BmWCP4/Gal4, and UAS/BmKIT(3)(R) transgenic silkworms, respectively. These results suggest new avenues of research for prolonging the pupal duration of silkworms. PMID- 22429286 TI - Response to editorial comment to effect of constipation on serum total prostate specific antigen levels in men. PMID- 22429287 TI - The effect of the duration of mechanical stimulation and post-stimulation culture on the structure and properties of dynamically compressed tissue-engineered menisci. AB - This study investigated the hypothesis that timing and duration of dynamic compression are integral to regulating extracellular matrix (ECM) assembly of tissue-engineered (TE) menisci. The goal of this study was to examine the effects of varying load and static culture duration on structure, composition, and mechanical properties of TE menisci. We accomplished this by varying the duration of dynamic loading over 4 weeks of culture, and by examining increasing periods of static culture after 2 weeks of dynamic loading. Bovine meniscal fibrochondrocytes were seeded into 2% w/v alginate, crosslinked with CaSO(4), injected into anatomical micro-computed tomography-based molds, and post crosslinked with CaCl(2). Meniscal constructs were dynamically compressed three times a week via a custom bioreactor for a total of 2 h, with an hour of rest between loading cycles, for 1, 2, or 4 weeks. They were then placed in static culture. After 4 weeks of culture, increased load duration was found to be beneficial to matrix formation and mechanical properties, with superior mechanical and biochemical properties in samples loaded for 2 or 4 weeks. Further, the mechanical properties of these constructs were similar, suggesting that the additional 2 weeks of loading may not be necessary. Samples loaded for 2 weeks followed by a 4-week static culture period yielded the most mature matrix with significant improvements in collagen bundle formation, 2.8-fold increase in the glycosaminoglycan content, 2-fold increase in the collagen content, and 4.3 fold increase in the compressive equilibrium modulus. Overall, this study demonstrated the importance of timing and duration of loading. By switching to prolonged static culture after 2 weeks of loading, we decreased the amount of ECM lost to the media, while significantly increasing biochemical and mechanical properties of TE menisci. PMID- 22429288 TI - Population-based study of presbyopia in Shahroud, Iran. AB - BACKGROUND: There is limited information regarding the prevalence of presbyopia in different parts of the world. The add power and the prevalence of presbyopia by age and gender in general population of Shahroud, north of Iran, were studied. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Using random cluster sampling, 6311 people from the 40- to 64-year-old population of Shahroud were invited. Of the invited population, 5190 individuals (82.2%) participated in the study. METHODS: Presbyopia was defined as the correction of near vision to logMAR 1 (N8 point) with at least 1 D of add power. MAIN OUTCOME MEASURES: Near visual acuity of participants was evaluated with a logMAR chart at a distance of 40 cm. RESULTS: Mean add power in the age groups of 40-44, 45-49, 50-54, 55-59 and 60-64 years was 0.65, 1.30, 1.70, 1.87 and 2.08 D, respectively. For each 5 year increase in age, a 0.35 D increase in add power was noted. The prevalence of presbyopia was 58.15% (95% confidence interval: 56.46-59.84). Presbyopia was more prevalent in women (P < 0.001) and increased with ageing more in women than in men (P < 0.001). Furthermore, in the 60-64-year-old age group, 11% of men and 23% of women were not presbyopic. CONCLUSIONS: Compared with other reports, the add power in different age groups was 0.5 D less, and presbyopia was less prevalent. More than 50% of the over 45-year-old individuals were presbyopic and 17% of the over 60 individuals were free of this condition. PMID- 22429289 TI - Psychiatric disorders in patients with end-stage renal disease. AB - Psychiatric disorders in patients with end-stage renal disease are associated with poor prognosis and quality of life. The goal of this study is to investigate the association between psychiatric disorders and renal disease in patients undergoing dialysis treatment, compared with other chronic diseases, appreciating the demographic status of these patients. Sixty-nine patients participated in a diagnostic interview and gave socio-demographic data. The population was composed of 55% men aged 19-77 years with an average age of 50 years (95% CI = 47-54 years). The prevalence of psychiatric disorders found in this study (46.6%) was compared with that found in patients with asthma, polycystic ovary syndrome and HIV-positive. Moreover, the prevalence of the four most common psychiatric disorders which were identified among patients on dialysis were also the subject of comparison between them and others. These results demonstrate the relationship between the various psychiatric disorders and are compatible with other research studies. PMID- 22429290 TI - Comparison of the structural changes in two cellobiohydrolases, CcCel6A and CcCel6C, from Coprinopsis cinerea--a tweezer-like motion in the structure of CcCel6C. AB - The basidiomycete Coprinopsis cinerea produces five cellobiohydrolases belonging to glycoside hydrolase family 6 (GH6). Among these enzymes, C. cinerea cellulase 6C (CcCel6C), but not C. cinerea cellulase 6A (CcCel6A), can efficiently hydrolyze carboxymethyl cellulose and is constitutively expressed in C. cinerea. In contrast, CcCel6A possesses a cellulose-binding domain, and is strongly induced by cellobiose. Here, we determined the crystal structures of the CcCel6A catalytic domain complexed with a Hepes buffer molecule, with cellobiose, and with p-nitrophenyl beta-D-cellotrioside (pNPG3). A notable feature of the GH6 cellobiohydrolases is that the active site is enclosed by two loops to form a tunnel, and the loops have been demonstrated to open and close in response to ligand binding. The enclosed tunnel of CcCel6A-Hepes is seen as the open form, whereas the tunnels of CcCel6A-cellobiose and CcCel6A-pNPG3 adopt the closed form. pNPG3 was not hydrolyzed by CcCel6A, and bound in subsites +1 to +4. On the basis of this observation, we constructed two mutants, CcCel6A D164A and CcCel6C D102A. Neither CcCel6A D164A nor CcCel6C D102A hydrolyze phosphoric acid-swollen cellulose. We have previously determined the crystal structures of CcCel6C unbound and in complex with ligand, both of which adopt the open form. In the present study, both CcCel6A and CcCel6C mutants were identified as the closed form. However, the motion angle of CcCel6C was more than 10-fold greater than that of CcCel6A. The width of the active site cleft of CcCel6C was narrowed, owing to a tweezer-like motion. PMID- 22429291 TI - Self-report use-of-time tools for the assessment of physical activity and sedentary behaviour in young people: systematic review. AB - Regular physical activity and limiting extended periods of sitting are two behaviours critical for the prevention of obesity in young people. The purpose of the systematic review was to synthesize the psychometric evidence for self-report use-of-time tools that assess these behaviours. Articles were retrieved that reported reliability and/or validity for use-of-time tools in participants aged 18 years or under. Outcome variables were physical activity, sedentary behaviour and energy expenditure. Study quality was appraised, and the results summarized narratively. Sixteen studies and six different tools were identified. The tools were the Previous Day Physical Activity Recall, the Three-Day Physical Activity Recall, the Physical Activity Interview, the Computerized Activity Recall, the Activitygram, and the Multimedia Activity Recall for Children and Adolescents. Overall, tools indicated moderate validity compared with objective and criterion comparison methods. Generally, validity correlation coefficients were in the range of 0.30-0.40. Correlation coefficients for test-retest reliability ranged widely from 0.24 to 0.98. CONCLUSION: Use-of-time tools have indicated moderate reliability and validity for the assessment of physical activity and energy expenditure. Future research should focus on using criterion methods and on validating specifically for sedentary behaviour outcomes. Implementation of these tools for population surveillance should be considered. PMID- 22429292 TI - Optic disc size and retinal vein occlusions. PMID- 22429293 TI - Successful surgical repair of iatrogenic pulmonary vein stenosis. AB - Pulmonary vein stenosis can complicate ablation procedures for atrial fibrillation and often presents with severe respiratory symptoms. Described in this case report is a 21-year-old male who underwent a bilateral surgical augmentation of the pulmonary veins for severe occlusive pulmonary vein stenosis. The occluded left lower and right upper lobe veins were surgically modified to regain flow to the left atrium. Follow-up computed tomogram imaging showed patency of the veins intervened upon and an exercise test demonstrated an oxygen saturation of 98% at peak stress.This case report marks the first-ever surgical intervention for acquired pulmonary vein stenosis. PMID- 22429294 TI - Regenerative capability of dental pulp cells after crown fracture. AB - The purpose of this study was to evaluate the characteristics of dental pulp cells for tissue engineering derived from the fractured incisal portion of tooth crowns. Thirty Sprague-Dawley rats were used for histological and immunohistochemical analysis of nestin protein expression and to measure levels of mRNAs encoding osteocalcin, osteopontin, bone sialoprotein (BSP), dentin sialoprotein (DSP), heat shock protein (HSP) 27, vascular endothelial growth factor (VEGF), ATP-binding cassette transporter G2 (ABCG2), nestin, and p57(Kip2) . Odontoblasts at the incisal portion in the control group were oriented in a regular pattern, but those in the experimental group were randomly stratified. Immunohistochemically, only a few odontoblasts were positive for nestin at the incisal portion in the experimental group at 2 days. Some cells in the inner area in the control group were positive for nestin, but nestin-positive cells in the experimental group at the incisal portion were not observed. The mRNA expression for osteogenic or odontogenic markers in the experimental group was higher than in the control group. HSP27 mRNA expression in the experimental group at 2 days was higher than in the control group and in the experimental group at 7 days. mRNA expression of stem cell markers, such as ABCG2 and nestin, in the experimental group tended to decrease compared with the control. In conclusion, this study demonstrates that dental pulp stem cells derived from fractured teeth differentiate to osteogenic or odontogenic cells. PMID- 22429295 TI - The correlations between alteration of p16 gene and clinicopathological factors and prognosis in squamous cell carcinomas of the buccal mucosa. AB - OBJECTIVE: To evaluate relationships between the alteration of p16 gene and the clinical status and prognosis of the patients with squamous cell carcinoma of the buccal mucosa. METHODS: Thirty buccal cancers were included in the analysis. Deletion analysis was performed by PCR. Point mutation analysis was used by PCR SSCP and direct sequencing. Methylation-specific PCR methods were adopted for the evaluation of p16 methylation. The correlation between alteration of p16 gene and clinicopathological factors buccal cancer was evaluated by Fisher's exact test. Kaplan-Meier and Cox regression were used to investigate the relationship between p16 alteration and survival time. RESULTS: The frequency of p16 alteration was 63.3% in buccal carcinomas. P16 deletion was associated significantly with tumor size (P = 0.01). P16 point mutation was associated significantly with differentiation (P = 0.006). P16 methylation was associated significantly with nodes metastasis (P = 0.027). The overall survival rate of 30 buccal carcinomas was 53.3%. The Log-rank test (P = 0.021) and univariate Cox regression analysis (P = 0.030) revealed that p16 methylation was significantly associated with the overall survival rate. Multivariate analysis showed that p16 deletion, p16 mutation, and p16 methylation were not statistically significant. CONCLUSIONS: The alterations of p16 gene may play a major role in malignancy and development and metastases of buccal carcinoma and may be an excellent marker of aggressive clinical behavior. P16 methylation has a prognostic value in buccal carcinoma but not an independent prognosis factor. P16 point mutation and p16 deletion have not prognostic significance in buccal carcinoma. PMID- 22429296 TI - Industry challenge to best practice risk communication. AB - Effective food safety and food defense risk communication helps to inform consumers without causing panic and alarm. The Risk Communication Team of the Natl. Center for Food Protection and Defense has developed a list of 11 best practices recommended for effective risk communication. These practices, designed for a food defense crisis, are currently applied to food safety issues, since fortunately a food defense crisis has yet to occur. IFT examined the utility of these best practices and the limitations on their use during food safety and food defense crises by academics, trade associations, and the government. It was hypothesized that legal and business considerations as well as the nature of the event would determine the implementation of the best practices. Through the use of focus group meetings, it was discovered that there was a low level of awareness of the best practices. However, stakeholders practiced some aspects of the recommended practices. Participants felt some of the practices were related and could be consolidated. They also agreed that a food defense event will increase the urgency of the communication and include players not typically involved in food safety issues. The challenges reported by the stakeholders varied, but legal liability, as well as the impact their communications could have on an industry, were often cited. From the government perspective, their need to act within their authorities drove some of their actions with respect to communication. Determining the differences in communication limitations during food safety against food defense events can provide key information to further developing and refining risk communications and specific messages targeted for a food defense incident. PRACTICAL APPLICATION: Effective food safety and food defense risk communication helps to inform consumers without causing panic and alarm. Determining the differences in communication limitations during food safety against food defense events can provide key information to further developing and refining risk communications and specific messages targeted for a food defense incident. PMID- 22429297 TI - Additive effects of clofibric acid and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) deficiency on hepatic steatosis in mice fed a high saturated fat diet. AB - Although improving glucose metabolism by inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may prove beneficial in the treatment of type 2 diabetes or diet induced obesity, it may have detrimental effects by inhibiting fatty acid oxidation. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists are often used to treat dyslipidemia in patients, especially in type 2 diabetes. Combinational treatment using a PDK4 inhibitor and PPARalpha agonists may prove beneficial. However, PPARalpha agonists may be less effective in the presence of a PDK4 inhibitor because PPARalpha agonists induce PDK4 expression. In the present study, the effects of clofibric acid, a PPARalpha agonist, on blood and liver lipids were determined in wild-type and PDK4 knockout mice fed a high-fat diet. As expected, treatment of wild-type mice with clofibric acid resulted in less body weight gain, smaller epididymal fat pads, greater insulin sensitivity, and lower levels of serum and liver triacylglycerol. Surprisingly, rather than decreasing the effectiveness of clofibric acid, PDK4 deficiency enhanced the beneficial effects of clofibric acid on hepatic steatosis, reduced blood glucose levels, and did not prevent the positive effects of clofibric acid on serum triacylglycerols and free fatty acids. The metabolic effects of clofibric acid are therefore independent of the induction of PDK4 expression. The additive beneficial effects on hepatic steatosis may be due to induction of increased capacity for fatty acid oxidation and partial uncoupling of oxidative phosphorylation by clofibric acid, and a reduction in the capacity for fatty acid synthesis as a result of PDK4 deficiency. PMID- 22429298 TI - Sexual dysfunctions in men affected by autoimmune Addison's disease before and after short-term gluco- and mineralocorticoid replacement therapy. AB - INTRODUCTION: There is evidence suggesting that autoimmune Addison's disease (AD) could be associated with sexual dysfunctions probably caused by gluco- and mineralocorticoid deficiency; however, no study has yet treated this subject in males. AIM: To evaluate male sexuality and psychological correlates in autoimmune AD before and after gluco- and mineralocorticoid replacement therapy. METHODS: Twelve subjects with a first diagnosis of autoimmune AD were studied before (baseline) and 2 months after (recovery phase) initiating hormone replacement therapy. MAIN OUTCOME MEASURES: Erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), overall satisfaction (OS), depression, and anxiety were studied using a number of questionnaires (International Index of Erectile Function, Beck Depression Inventory, and Spielberger State-Trait Anxiety Inventory); clinical, biochemical, and hormone data were included in the analysis. RESULTS: At baseline, low values were found for EF, OF, SD, IS, and OS and high values for depression and anxiety; all of these parameters improved significantly in the recovery phase compared with baseline. EF variation between the two phases correlated significantly and positively with the variation of serum cortisol, urinary free cortisol, systolic blood pressure, and diastolic blood pressure and inversely with that of upright plasma renin activity. Multiple linear regression analysis using EF variation as dependent variable confirmed the relationship of the latter with variation of serum cortisol, urinary free cortisol, and upright plasma renin activity but not with variation of systolic and diastolic blood pressure. CONCLUSIONS: Our study showed that onset of autoimmune AD in males is associated with a number of sexual dysfunctions, all reversible after initiating replacement hormone therapy; cortisol and aldosterone deficiency seems to play an important role in the genesis of erectile dysfunction although the mechanism of their activity is not clear. PMID- 22429299 TI - Histologic work-up of non-palpable breast lesions classified as probably benign at initial mammography and/or ultrasound (BI-RADS category 3). AB - PURPOSE: To determine the accuracy of a probably benign assessment of non palpable breast lesions (BI-RADS category 3) at mammography and/or ultrasound with immediate histological work-up. MATERIALS AND METHODS: Stereotactic or ultrasound guided core needle breast biopsy (NBB) was performed to evaluate 288 lesions, which were prospectively assessed as BI-RADS category 3. Imaging findings included 195 masses, 73 calcification cases, 16 focal asymmetries, and four architectural distortion cases. After NBB, patients underwent either open surgical biopsy (OSB) (n=204) or mammographic follow-up (n=84) for at least 24 months. Histological results of NBB were compared with those of OSB. RESULTS: Three of the 288 lesions (1.0%) proved to be malignant at histological work-up, two of them were ductal carcinoma in situ (DCIS) and one of them was an invasive carcinoma. NBB revealed invasive carcinoma in 1/288 (0.35%) and atypical ductal hyperplasia (ADH) in 13/288 (4.5%) lesions. OSB revealed DCIS in 2/204 (1%) and invasive carcinoma in 1/204 (0.5%) lesions. The two DCIS were underestimated as ADH by NBB. The remaining 285 (99%) lesions proved to be benign at OSB or remained stable during follow-up. CONCLUSION: Confirmed by tissue diagnosis, the low likelihood of malignancy of prospectively assessed probably benign lesions is below the 2% threshold established for BI-RADS category 3. Imaging follow-up is a safe and effective alternative to immediate histological work-up for such lesions. PMID- 22429300 TI - Performance-based parameter tuning method of model-driven PID control systems. AB - In this paper, performance-based parameter tuning method of model-driven Two Degree-of-Freedom PID (MD TDOF PID) control system has been proposed to enhance the control performances of a process. Known for its ability of stabilizing the unstable processes, fast tracking to the change of set points and rejecting disturbance, the MD TDOF PID has gained research interest recently. The tuning methods for the reported MD TDOF PID are based on internal model control (IMC) method instead of optimizing the performance indices. In this paper, an Integral of Time Absolute Error (ITAE) zero-position-error optimal tuning and noise effect minimizing method is proposed for tuning two parameters in MD TDOF PID control system to achieve the desired regulating and disturbance rejection performance. The comparison with Two-Degree-of-Freedom control scheme by modified smith predictor (TDOF CS MSP) and the designed MD TDOF PID tuned by the IMC tuning method demonstrates the effectiveness of the proposed tuning method. PMID- 22429301 TI - Phosphorus and DOC availability influence the partitioning between bacterioplankton production and respiration in tidal marsh ecosystems. AB - The organic carbon consumed by aquatic bacteria (BCC) is partitioned between bacterial production (BP) and respiration (BR), but the factors that determine BCC and its partition into BP and BR are not well understood. We explored the coupling between BR, BR and BCC, and their links to dissolved organic carbon (DOC) and nutrient availability in natural and restored tidal marshes and in the adjoining waters of Delaware Bay estuary. Labile DOC (LDOC) ranged from 3% to 22% of the DOC pool, and explained more of the variance in both BR and BCC than did bulk DOC. Bacterial growth efficiency (BGE) was highly variable (0.09-0.58), and natural Spartina alterniflora marshes had consistently higher BGE than both restoration marshes and tidal floodwaters. BGE was negatively related to the ratio of LDOC to total dissolved phosphorous, which was highest in natural marshes. The enhancement of BP observed in the marshes relative to the estuarine floodwaters had different origins: In natural marshes it was mostly due to increases in BGE, whereas in restored marshes it followed increased BCC. These results highlight the importance of P in regulating microbial metabolism in coastal areas, and the need to understand the pathways that lead to BP in these systems. PMID- 22429302 TI - Women's preferences regarding options for management of atypical, borderline and low-grade cervical abnormalities. PMID- 22429303 TI - The significance of Mg in prebiotic geochemistry. AB - Magnesium plays a special role in biochemistry because of its ability to coordinate six oxygen atoms efficiently in its first coordination shell. Such oxygen atoms may be part of one or two charged oxyanions, which means that Mg2+ can, for instance, tie together two different phosphate groups that are located at distance from each other in a macromolecule, and in this way be responsible for the folding of molecules like RNA. This property of Mg2+ also helps the stabilization of diphosphate and triphosphate groups of nucleotides, as well as promoting the condensation of orthophosphate to oligophosphates, like pyrophosphate and trimetaphosphate. Borates, on the other hand, are known to promote the formation of nucleobases and carbohydrates, ribose in particular, which is yet another constituent of nucleotides. The oldest borate minerals that we find on Earth today are magnesium borates. Dissolved borate stabilizes pentose sugars by forming complexes with cis-hydroxyl groups. In the furanose form of ribose, the preferential binding occurs to the 2 and 3 carbon, leaving the 5 carbon free for phosphorylation. The central role of Mg2+ in the function of ribozymes and its 'archaic' position in ribosomes, and the fact that magnesium generally has coordination properties different from other cations, suggests that the inorganic chemistry of magnesium had a key position in the first chemical processes leading to the origin and early evolution of life. PMID- 22429304 TI - Temperature treatments during larval development reveal extensive heritable and plastic variation in gene expression and life history traits. AB - Little is known about variation in gene expression that affects life history traits in wild populations of outcrossing species. Here, we analyse heritability of larval development traits and associated variation in gene expression in the Glanville fritillary butterfly (Melitaea cinxia) across three ecologically relevant temperatures. We studied the development of final-instar larvae, which is greatly affected by temperature, and during which stage larvae build up most of the resources for adult life. Larval development time and weight gain varied significantly among families sampled from hundreds of local populations, indicating substantial heritable variation segregating in the large metapopulation. Global gene expression analysis using common garden-reared F2 families revealed that 42% of the >8000 genes surveyed exhibited significant variation among families, 39% of the genes showed significant variation between the temperature treatments, and 18% showed a significant genotype-by-environment interaction. Genes with large family and temperature effects included larval serum protein and cuticle-binding protein genes, and the expression of these genes was closely correlated with the rate of larval development. Significant expression variation in these same categories of genes has previously been reported among adult butterflies originating from newly established versus old local populations, supporting the notion of a life history syndrome put forward based on ecological studies and involving larval development and adult dispersal capacity. These findings suggest that metapopulation dynamics in heterogeneous environments maintain heritable gene expression variation that affects the regulation of life history traits. PMID- 22429305 TI - Clinical reproductive immunology in critical demand. PMID- 22429306 TI - Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. AB - Earlier, we have shown that the increased cartilage production in pellet co cultures of chondrocytes and bone marrow-derived mesenchymal stem cells (BM-MSCs) is due to a trophic role of the MSC in stimulating chondrocyte proliferation and matrix production rather than MSCs actively undergoing chondrogenic differentiation. These studies were performed in a culture medium that was not compatible with the chondrogenic differentiation of MSCs. In this study, we tested whether the trophic role of the MSCs is dependent on culturing co-culture pellets in a medium that is compatible with the chondrogenic differentiation of MSCs. In addition, we investigated whether the trophic role of the MSCs is dependent on their origins or is a more general characteristic of MSCs. Human BM MSCs and bovine primary chondrocytes were co-cultured in a medium that was compatible with the chondrogenic differentiation of MSCs. Enhanced matrix production was confirmed by glycosaminoglycans (GAG) quantification. A species specific quantitative polymerase chain reaction demonstrated that the cartilage matrix was mainly of bovine origin, indicative of a lack of the chondrogenic differentiation of MSCs. In addition, pellet co-cultures were overgrown by bovine cells over time. To test the influence of origin on MSCs' trophic effects, the MSCs isolated from adipose tissue and the synovial membrane were co-cultured with human primary chondrocytes, and their activity was compared with BM-MSCs, which served as control. GAG quantification again confirmed increased cartilage matrix production, irrespective of the source of the MSCs. EdU staining combined with cell tracking revealed an increased proliferation of chondrocytes in each condition. Irrespective of the MSC source, a short tandem repeat analysis of genomic DNA showed a decrease in MSCs in the co-culture over time. Our results clearly demonstrate that in co-culture pellets, the MSCs stimulate cartilage formation due to a trophic effect on the chondrocytes rather than differentiating into chondrocytes, irrespective of culture condition or origin. This implies that the trophic effect of MSCs in co-cultures is a general phenomenon with potential implications for use in cartilage repair strategies. PMID- 22429307 TI - Pre- and post-transplant care: nursing management of the renal transplant recipient: part 2. AB - This is the second article in a three part continuing education series on renal transplantation which addresses the specialised knowledge and skills required in order to prepare a patient admitted to hospital for renal transplantation and then how to care for that patient afterwards. The first article in this series addressed patient health and well-being while waiting for a renal transplant. The third article will look at the long-term care of kidney recipients. PMID- 22429308 TI - Effectiveness of a web-based health risk assessment with individually-tailored feedback on lifestyle behaviour: study protocol. AB - BACKGROUND: Physical inactivity, unhealthy dietary habits, smoking and high alcohol consumption are recognized risk factors for cardiovascular disease and cancer. Web-based health risk assessments with tailored feedback seem promising in promoting a healthy lifestyle. This study evaluates the effectiveness of a web based health risk assessment with individually-tailored feedback on lifestyle behaviour, conducted in a worksite setting. METHODS/DESIGN: The web-based health risk assessment starts with a questionnaire covering socio-demographic variables, family and personal medical history, lifestyle behaviour and psychological variables. Prognostic models are used to estimate individual cardiovascular risks. In case of high risk further biometric and laboratory evaluation is advised. All participants receive individually-tailored feedback on their responses to the health risk assessment questionnaire. The study uses a quasi experimental design with a waiting list control group. Data are collected at baseline (T0) and after six months (T1). Within each company, clusters of employees are allocated to either the intervention or the control group. Primary outcome is lifestyle behaviour, expressed as the sum of five indicators namely physical activity, nutrition, smoking behaviour, alcohol consumption, and symptoms of burnout. Multilevel regression analysis will be used to answer the main research question and to correct for clustering effects. Baseline differences between the intervention and control group in the distribution of characteristics with a potential effect on lifestyle change will be taken into account in further analyses using propensity scores. DISCUSSION: This study will increase insight into the effectiveness of health risk assessments with tailored feedback and into conditions that may modify the effectiveness. This information can be used to design effective interventions for lifestyle behaviour change among employees. TRIAL REGISTRATION: Dutch Trial Register NTR8148. PMID- 22429309 TI - Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. AB - The natural history for patients with de novo donor-specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation with serologic data is limited. We studied 315 consecutive renal transplants without pretransplant DSA, with a mean follow up of 6.2 +/- 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA posttransplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 +/- 3.0 years posttransplant. Independent predictors of dnDSA were HLA-DRbeta1 MM > 0 (OR 5.66, p < 0.006); and nonadherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p = 0.061). The median 10-year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody-mediated injury can occur and progress in patients with dnDSA in the absence of graft dysfunction and furthermore, nonadherence and cellular rejection contribute to dnDSA development and progression to graft loss. PMID- 22429311 TI - Strong coupling between surface plasmon polaritons and Sulforhodamine 101 dye. AB - We demonstrate a strong coupling between surface plasmon polaritons and Sulforhodamine 101 dye molecules. Dispersion curves for surface plasmon polaritons on samples with a thin layer of silver covered with Sulforhodamine 101 molecules embedded in SU-8 polymer are obtained experimentally by reflectometry measurements and compared to the dispersion of samples without molecules. Clear Rabi splittings, with energies up to 360 and 190 meV, are observed at the positions of the dye absorption maxima. The split energies are dependent on the number of Sulforhodamine 101 molecules involved in the coupling process. Transfer matrix and coupled oscillator methods are used to model the studied multilayer structures with a great agreement with the experiments. Detection of the scattered radiation after the propagation provides another way to obtain the dispersion relation of the surface plasmon polaritons and, thus, provides insight into dynamics of the surface plasmon polariton/dye interaction, beyond the refrectometry measurements.PACS: 42.50.Hz, 33.80.-b, 78.67.-n. PMID- 22429310 TI - Chestnut resistance to the blight disease: insights from transcriptome analysis. AB - BACKGROUND: A century ago, Chestnut Blight Disease (CBD) devastated the American chestnut. Backcross breeding has been underway to introgress resistance from Chinese chestnut into surviving American chestnut genotypes. Development of genomic resources for the family Fagaceae, has focused in this project on Castanea mollissima Blume (Chinese chestnut) and Castanea dentata (Marsh.) Borkh (American chestnut) to aid in the backcross breeding effort and in the eventual identification of blight resistance genes through genomic sequencing and map based cloning. A previous study reported partial characterization of the transcriptomes from these two species. Here, further analyses of a larger dataset and assemblies including both 454 and capillary sequences were performed and defense related genes with differential transcript abundance (GDTA) in canker versus healthy stem tissues were identified. RESULTS: Over one and a half million cDNA reads were assembled into 34,800 transcript contigs from American chestnut and 48,335 transcript contigs from Chinese chestnut. Chestnut cDNA showed higher coding sequence similarity to genes in other woody plants than in herbaceous species. The number of genes tagged, the length of coding sequences, and the numbers of tagged members within gene families showed that the cDNA dataset provides a good resource for studying the American and Chinese chestnut transcriptomes. In silico analysis of transcript abundance identified hundreds of GDTA in canker versus healthy stem tissues. A significant number of additional DTA genes involved in the defense-response not reported in a previous study were identified here. These DTA genes belong to various pathways involving cell wall biosynthesis, reactive oxygen species (ROS), salicylic acid (SA), ethylene, jasmonic acid (JA), abscissic acid (ABA), and hormone signalling. DTA genes were also identified in the hypersensitive response and programmed cell death (PCD) pathways. These DTA genes are candidates for host resistance to the chestnut blight fungus, Cryphonectria parasitica. CONCLUSIONS: Our data allowed the identification of many genes and gene network candidates for host resistance to the chestnut blight fungus, Cryphonectria parasitica. The similar set of GDTAs in American chestnut and Chinese chestnut suggests that the variation in sensitivity to this pathogen between these species may be the result of different timing and amplitude of the response of the two to the pathogen infection. Resources developed in this study are useful for functional genomics, comparative genomics, resistance breeding and phylogenetics in the Fagaceae. PMID- 22429312 TI - Balance of human choline kinase isoforms is critical for cell cycle regulation: implications for the development of choline kinase-targeted cancer therapy. AB - The enzyme choline kinase (CK), which catalyzes the phosphorylation of choline to phosphorylcholine in the presence of ATP, has an essential role in the biosynthesis of phosphatidylcholine, the major constituent of all mammalian cell membranes. CK is encoded by two separate genes expressing the three isoforms CKalpha1, CKalpha2 and CKbeta that are active as homodimeric or heterodimeric species. Metabolic changes observed in various cancer cell lines and tumors have been associated with differential and marked up-regulation of the CKalpha genes, and specific inhibition of CKalpha activity has been proposed as a potential anti cancer strategy. As a result, less attention has been given to CKbeta and its interaction with CKalpha. With the aim of profiling the intracellular roles of CKalpha and CKbeta, we used RNA interference (RNAi) as a molecular approach to down-regulate the expression of CK in HeLa cells. Individual and simultaneous RNAi-based silencing of the CK alpha and beta isoforms was achieved using different combinations of knockdown strategies. Efficient knockdown was confirmed by immunodetection using our isoform-specific antibodies and by quantitative real time PCR. Our analyses of the phenotypic consequences of CK depletion showed the expected lethal effect of CKalpha knockdown. However, CKbeta- and CKalpha + CKbeta-silenced cells had no aberrant phenotype. Therefore, our results support the hypothesis that the balance of the alpha and beta isoforms is critical for cancer cell survival. The suppression of the cancer cell killing effect of CKalpha silencing by simultaneous knockdown of both isoforms implies that a more effective CK-based anti-cancer strategy can be achieved by reducing cross reactivity with CKbeta. PMID- 22429313 TI - Current approaches to the management of Her2-negative metastatic breast cancer. AB - While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while maintaining quality of life and physical function. Optimal management of MBC balances a multitude of factors, including a woman's performance status, social support, symptoms, disease burden, prior therapies, and surrogates for tumor biology. Choosing the most appropriate initial therapy and subsequent sequence of treatments demands flexibility as goals and patient preferences may change. Knowledge of the estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor status of the metastatic tumor has become critical to determining the optimal treatment strategy in the metastatic setting as targeted therapeutic approaches are developed. Patients with ER+ or PR+ breast cancer or both have a wide array of hormonal therapy options that can forestall the use of cytotoxic therapies, although rapidly progressive phenotypes and the emergence of resistance may ultimately lead to the need for chemotherapy in this setting. So called 'triple-negative' breast cancer - lacking ER, PR, and Her2 overexpression remains a major challenge. These tumors have an aggressive phenotype, and clear targets for therapy have not yet been established. Chemotherapy remains the mainstay of treatment in this group, but biologically based clinical trials of new agents are critical to developing a more effective set of therapies for this patient population. PMID- 22429314 TI - Bacterial water quality and network hydraulic characteristics: a field study of a small, looped water distribution system using culture-independent molecular methods. AB - AIMS: To determine the spatial and temporal variability in the abundance, structure and composition of planktonic bacterial assemblages sampled from a small, looped water distribution system and to interpret results with respect to hydraulic conditions. METHODS AND RESULTS: Water samples were collected from five sampling points, twice a day at 06:00 h and 09:00 h on a Monday (following low weekend demand) and a Wednesday (higher midweek demand). All samples were fully compliant with current regulated parameter standards. This study did not show obvious changes in bacterial abundance (DAPI count) or community structure Denaturing gradient gel electrophoresis analysis with respect to sample site and hence to water age; however, the study did show temporal variability with respect to both sampling day and sample times. CONCLUSIONS: Data suggests that variations in the bacterial assemblages may be associated with the local system hydraulics: the bacterial composition and numbers, over short durations, are governed by the interaction of the bulk water and the biofilm influenced by the hydraulic conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates general stability in bacterial abundance, community structure and composition within the system studied. Trends and patterns supporting the transfer of idealized understanding to the real world were evident. Ultimately, such work will help to safeguard potable water quality, fundamental to public health. PMID- 22429315 TI - Transient rise of serum testosterone level after single sildenafil treatment of adult male rats. AB - INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors have been established in therapy for a variety of physiological disorders including erectile dysfunction. Despite its popularity and wide usage in erectile dysfunction treatment, the short-term effect of PDE5 inhibition on Leydig cell functionality and testosterone dynamics is missing. AIM: This study was designed to assess the acute in vivo effects of sildenafil citrate (Viagra) treatment on testosterone production. METHODS: Male adult rats were given sildenafil (1.25 mg/kg BW) per os, and testosterone production were analyzed 30, 60, 120, and 180 minutes after treatment. Additionally, in vitro effect of sildenafil extract on Leydig cell steroidogenesis was estimated. MAIN OUTCOME MEASURES: The formation of testicular interstitial fluid (TIF), and testosterone, cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) content was followed. Occurrence and phosphorylation of mature steroidogenic acute regulatory protein (StAR) and interaction with protein kinase G 1 (PRKG1) were assessed by immunoprecipitation and Western blot. RESULTS: Serum testosterone was increased 60 and 120 minutes after sildenafil treatment. In 60 minutes, TIF volume was doubled and stayed increased till the end of the experimental period. cGMP and testosterone content in TIF were increased 30 minutes after treatment, and cAMP decreased in 60 minutes. Further, sildenafil-induced stimulation of testosterone production was abolished by ex vivo addition of PRKG1 inhibitor but not by protein kinase A inhibitor. Sildenafil treatment increased the level of phosphorylated and total StAR protein. Moreover, co-immunoprecipitation of StAR and PRKG1 was increased following sildenafil treatment suggesting the active role of this kinase in initiation of testosterone synthesis. Additionally, sildenafil extract applied in vitro on primary Leydig cell culture increased cGMP accumulation and testosterone production in time- and dose-dependent manner without effect on cAMP level. CONCLUSION: Acute sildenafil treatment enlarged TIF volume but also stimulated testosterone production which may be significant considering the positive testosterone effect in regulation of sexual activity. PMID- 22429316 TI - The use of prisms for vision rehabilitation after macular function loss: an evidence-based review. AB - To determine the efficacy of prisms used for redirection of incoming images towards the peripheral retina in cases with macular function loss. Meta-analysis of published work reporting outcomes from interventions using prisms was performed. The primary outcome measure selected for analysis was visual acuity (VA) used for viewing distance targets. Pooled data from 449 cases where prisms were prescribed for wearing in distance glasses were analysed. Visual acuity was better after using prisms (1.05 versus 0.89 logMAR units, p < 0.044). Mean effect size for improving VA was 79 bigger than the effect size calculated for the control group (0.158 versus 0.002). Most patients (76%) reported compliance with the therapy and also reported other benefits directly derived from the realized VA improvement. Published studies collectively offer positive evidence in support of using prisms for low vision rehabilitation after macular function loss. Further research is required to reach definitive binding conclusions. PMID- 22429317 TI - Do medical student attitudes towards patients with chronic low back pain improve during training? a cross-sectional study. AB - BACKGROUND: Health care professionals with positive attitudes towards the functional abilities of patients with low back pain are more likely to encourage activity and avoidance of rest as per recommended guidelines. This study investigated whether medical student training fosters positive attitudes towards patients with back pain and their ability to function. METHODS: First (n = 202) and final (n = 146) year medical students at the University of Glasgow completed the Health Care Professionals' Pain and Impairment Relationship Scale (HC-PAIRS) questionnaire. This measures attitudes of clinicians towards the functional ability of patients with back pain. A group of first (n = 62) and final year (n = 61) business students acted as non-health care controls. Attitudes were compared using two-way ANOVA with year of study and discipline of degree as independent variables. RESULTS: Both year of study [F(1,465) = 39.5, p < 0.01] and discipline of degree [F(1,465) = 43.6, p < 0.01] had significant effects on total HC-PAIRS scores and there was a significant interaction effect [F(1,465) = 9.5, p < 0.01]. Medical students commenced their course with more positive attitudes than non health care students (65.7 vs. 69.2 respectively; p < 0.01)--lower scores translating into more positive attitudes. In their final year, the difference between the two student groups had widened (56.4 vs. 65.3; p < 0.01). CONCLUSIONS: Undergraduate medical training promotes positive attitudes towards the functional ability of patients with back pain, suggesting that students may be more likely to develop an evidence-based approach to this patient group after qualification. Some adjustments to training may be warranted to encourage a more positive shift in attitudes. PMID- 22429318 TI - Improving surface functional properties of tofu whey-derived peptides by chemical modification with fatty acids. AB - Effect of acylation with saturated fatty acids on surface functional properties of tofu whey-derived peptides was investigated. Tofu whey (TW) and soy proteins (7S, 11S, and acid-precipitated soy protein [APP]) were hydrolyzed by Protease M 'Amano' G, and resulting peptide mixtures were acylated with esterified fatty acids of different chain length (6C to 18C) to form a covalent linkage between the carboxyl group of fatty acid and the free amino groups of peptide. Acylation significantly (P < 0.05) increased emulsifying properties of 7S, 11S, and APP peptides independent of fatty acid chain length. Acylation decreased water binding capacity although oil binding capacity of acylated tofu whey ultra filtered fraction (UFTW < 3 kDa), 7S- and 11S-peptides were improved compared to native peptides. 7S peptides acylated with long chain fatty acids had shown significant higher surface hydrophobicity as in contrast with acylated UFTW < 3 kDa and APP peptides. Fluorescence spectra studies revealed structural conformation of acylated soy peptides as compared to native peptides. This study shows that chemical modification with fatty acids can further affect functional properties of soy proteins. PMID- 22429319 TI - Signet-ring cell adenocarcinoma of rectum with breast metastases diagnosed on FNA cytology: case report and literature review. PMID- 22429320 TI - Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration. AB - Articular cartilage is difficult to heal once injury or disease occurs. Autologous chondrocyte transplantation is a biological treatment with good prognosis, but donor site morbidity and limited cell source are disadvantages. Currently, mesenchymal stem cells (MSCs) are a promising approach for cartilage regeneration. Despite there being various sources, the best candidate for cartilage regeneration is the one with the greatest chondrogenic potential and the least hypertrophic differentiation. These properties are able to insure that the regenerated tissue is hyaline cartilage of high quality. This review article will summarize relevant literature to justify synovium-derived stem cells (SDSCs) as a tissue-specific stem cell for chondrogenesis by comparing synovium and cartilage with respect to anatomical location and functional structure, comparing the growth characterization and chondrogenic capacity of SDSCs and MSCs, evaluating the application of SDSCs in regenerative medicine and diseases, and discussing potential future directions. PMID- 22429321 TI - Immunogenicity study of plasmid DNA encoding mouse cysteine-rich secretory protein-1 (mCRISP1) as a contraceptive vaccine. AB - PROBLEM: To examine the immunocontraceptive properties of the plasmid pcDNA mCRISP1 and compare them to the corresponding recombinant mCRISP1 (r-mCRISP1). METHOD OF STUDY: RT-PCR and indirect immunofluorescence were performed to observe the mCRISP1 protein expression in COS-7 cells. Three groups of mice received three injections of r-mCRISP1, pcDNA-mCRISP1 or pcDNA vector, respectively. ELISA and Western blot were used to examine the immune responses and immunoreactivity of antisera. Sperm-egg penetration assay was performed to examine the effect of anti-mCRISP1 antibodies in vitro fertilization of mouse oocytes. Fertility and mean litter size were analysed by natural mating. Histological analysis was carried out to look for potential immunopathologic effects of the antibodies. RESULTS: COS-7 cells transfected with pcDNA-mCRISP1 present the expression of mCRISP1. Both r-mCRISP1 and pcDNA-mCRISP1 raised an immune response against r mCRISP1 protein and native CRISP1 in mouse sperm. The titres of anti-mCRISP1 antibodies from DNA immunized mice were significantly lower than that of r mCRISP1 immunized mice, but it lasted relatively longer. Male and female pcDNA mCRISP1 injected animals presented a statistically significant reduction in their fertility with no signs of immunopathologic effects. CONCLUSION: These studies demonstrated the feasibility of generating an immune response to mCRISP1 protein by DNA vaccine and pcDNA-mCRISP1 plasmid causing significant anti-fertility potential. PMID- 22429322 TI - Tracking nickel-adaptive biomarkers in Pisolithus albus from New Caledonia using a transcriptomic approach. AB - The fungus Pisolithus albus forms ectomycorrhizal (ECM) associations with plants growing on extreme ultramafic soils, which are naturally rich in heavy metals such as nickel. Both nickel-tolerant and nickel-sensitive isolates of P. albus are found in ultramafic soils in New Caledonia, a biodiversity hotspot in the Southwest Pacific. The aim of this work was to monitor the expression of genes involved in the specific molecular response to nickel in a nickel-tolerant P. albus isolate. We used pyrosequencing and quantitative polymerase chain reaction (qPCR) approaches to investigate and compare the transcriptomes of the nickel tolerant isolate MD06-337 in the presence and absence of nickel. A total of 1,071,375 sequencing reads were assembled to infer expression patterns of 19,518 putative genes. Comparison of expression levels revealed that 30% of the identified genes were modulated by nickel treatment. The genes, for which expression was induced most markedly by nickel, encoded products that were putatively involved in a variety of biological functions, such as the modification of cellular components (53%), regulation of biological processes (27%) and molecular functions (20%). The 10 genes that pyrosequencing analysis indicated were induced the most by nickel were characterized further by qPCR analysis of both nickel-tolerant and nickel-sensitive P. albus isolates. Five of these genes were expressed exclusively in nickel-tolerant isolates as well as in ECM samples in situ, which identified them as potential biomarkers for nickel tolerance in this species. These results clearly suggest a positive transcriptomic response of the fungus to nickel-rich environments. The presence of both nickel-tolerant and nickel-sensitive fungal phenotypes in ultramafic soils might reflect environment-dependent phenotypic responses to variations in the effective concentrations of nickel in heterogeneous ultramafic habitats. PMID- 22429323 TI - Microbiological evaluation of ten French archives and link to occupational symptoms. AB - Fungi that damage documents in archives may harm workers' health, depending on which mold species are inhaled, the concentrations of fungal species inhaled, and individual factors. Our aim was to identify and quantify fungi in archives and to investigate possible links with the symptoms experienced by workers. Ten French archives were sampled using an air impactor and electrostatic dust collectors. Allergies and general symptoms felt by 144 workers were reported using a self report questionnaire. Utilizing culture-based analysis methods along with qPCR, Penicillium chrysogenum, Cladosporium sphaerospermum, and Aspergillus versicolor were the three main fungi in air and dust in terms of quantity and frequency. Median fungal concentrations in storage areas, ranged from 30 to 465 CFU/m(3). People working in the most contaminated archives did not report more symptoms of allergy than others. However, workers in contact with moldy documents reported more headaches (odds ratio, 2.4; 95% confidence interval, 1.1-5.3), fatigue (OR, 2.9; 95% CI, 1.2-6.7), eye irritation (OR, 5.4; 95% CI, 1.9-14.9), throat irritation (OR, 2.4; 95% CI, 1.0-5.7), coughing (OR, 3.2; 95% CI, 1.2-8.4), and rhinorrhea (OR, 2.6; 95% CI, 1.0-6.4) than others. Other parameters such as dust levels and concentrations of metabolites and chemical substances should be considered as confounding factors in further investigations to isolate the role of molds. PRACTICAL IMPLICATIONS: Most studies about fungi and archives deal with the conservation of manuscripts and documents, and few discuss workers' health problems. Our study shows that archives do not represent a highly contaminated environment. Symptoms felt by workers were more often linked to direct contact with moldy documents than to high concentrations of mold in the air of archive storage areas. This study provides data on concentration levels in archives that could be used to interpret microbiological investigations in this type of environment in the future. PMID- 22429324 TI - Reply to increased levels of COX-2 and oral lichen planus by P.D. Pigatto, F. Spaderi, G.P. Bombeccari, G. Guzzi by Danielsson et al. PMID- 22429325 TI - Effect of a self-efficacy promotion training programme on the body weight changes in patients undergoing haemodialysis. AB - INTRODUCTION: Haemodialysis is the most common form of medical management of patients affected by end-stage renal disease (ESRD). For haemodialysis to be successful, strict fluid and weight control is recommended. Education, in terms of self-care activities, is an important intervention for improving patients' outcomes. A self-efficacy promotion training programme can be an effective strategy to bring about behavioural change. The aim of this study was to investigate the effect of a self-efficacy promotion training programme on the body weight changes in patients undergoing haemodialysis. METHODS: In this single blind quasi-experimental study, we recruited a convenience sample of 63 patients undergoing haemodialy-sis from two teaching hospitals and allocated them randomly to the experimental or control group. Patients in the experimental group received a six-session self-efficacy promotion training programme while the control group received the routine care of the institute. Mean body weight gain and self efficacy were measured before, immediately and two months after the study. FINDINGS: The groups did not differ significantly regarding the study variable before the study. However, immediately and two months after the study, the mean body weight gain and self-efficacy in the experimental group were significantly lower and higher, respectively, than the control group (p < 0.05). CONCLUSION: Implementing a self-efficacy promotion training programme is effective in decreasing weight gain and increasing self-efficacy in patients undergoing haemodialysis. Nurses in haemodialysis units can use self-efficacy promotion training programmes as an effective intervention for improving patients' outcomes. PMID- 22429326 TI - DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity. AB - BACKGROUND: Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process. METHODS: A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of gammaH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry. RESULTS: Pretreatment with psammaplin A, 5-aza-2' deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of gammaH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone. CONCLUSIONS: Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair. PMID- 22429327 TI - Involvement of thermophilic archaea in the biocorrosion of oil pipelines. AB - Two thermophilic archaea, strain PK and strain MG, were isolated from a culture enriched at 80 degrees C from the inner surface material of a hot oil pipeline. Strain PK could ferment complex organic nitrogen sources (e.g. yeast extract, peptone, tryptone) and was able to reduce elemental sulfur (S degrees ), Fe(3+) and Mn(4+) . Phylogenetic analysis revealed that the organism belonged to the order Thermococcales. Incubations of this strain with elemental iron (Fe degrees ) resulted in the abiotic formation of ferrous iron and the accumulation of volatile fatty acids during yeast extract fermentation. The other isolate, strain MG, was a H(2) :CO(2) -utilizing methanogen, phylogenetically affiliated with the genus Methanothermobacter family. Co-cultures of the strains grew as aggregates that produced CH(4) without exogenous H(2) amendment. The co-culture produced the same suite but greater concentrations of fatty acids from yeast extract than did strain PK alone. Thus, the physiological characteristics of organisms both alone and in combination could conceivably contribute to pipeline corrosion. The Thermococcus strain PK could reduce elemental sulfur to sulfide, produce fatty acids and reduce ferric iron. The hydrogenotrophic methanogen strain MG enhanced fatty acid production by fermentative organisms but could not couple the dissolution Fe degrees with the consumption of water-derived H(2) like other methanogens. PMID- 22429328 TI - PEP-1-heat shock protein 27 protects from neuronal damage in cells and in a Parkinson's disease mouse model. AB - Heat shock proteins (HSPs) are a highly conserved family of proteins that are induced in response to various environmental stressors including reactive oxygen species. HSP27 is a chaperone protein with the ability to increase cell survival in response to oxidative stress. Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Although the mechanism of PD remains unclear, oxidative stress is known to be important in its pathogenesis. This study investigated the protective effects of PEP-1-HSP27 on neuronal damage induced by 1-methyl-4-phenyl pyridinium (MPP(+) ) in SH-SY5Y cells and in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. PEP-1-HSP27 rapidly entered the cells and protected them against MPP(+) -induced toxicity by inhibiting the reactive oxygen species levels and DNA fragmentation. Furthermore, transduced PEP-1-HSP27 prevented dopaminergic neuronal cell death in the substantia nigra of MPTP-induced PD mouse models. These results demonstrate that PEP-1-HSP27 provides a potential strategy for therapeutic delivery against various diseases and is a potential tool for the treatment of PD. PMID- 22429329 TI - Human cytomegalovirus infection leads to elevated levels of transplant arteriosclerosis in a humanized mouse aortic xenograft model. AB - Recent findings emphasized an important role of human cytomegalovirus (HCMV) infection in the development of transplant arteriosclerosis. Therefore, the aim of this study was to develop a human peripheral blood lymphocyte (hu-PBL)/Rag-2( /-) gammac(-/-) mouse-xenograft-model to investigate both immunological as well as viral effector mechanisms in the progression of transplant arteriosclerosis. For this, sidebranches from the internal mammary artery were recovered during coronary artery bypass graft surgery, tissue-typed and infected with HCMV. Then, size-matched sidebranches were implanted into the infrarenal aorta of Rag-2(-/-) gammac(-/-) mice. The animals were reconstituted with human peripheral blood mononuclear cells (PBMCs) 7 days after transplantation. HCMV-infection was confirmed by Taqman-PCR and immunofluorescence analyses. Arterial grafts were analyzed by histology on day 40 after transplantation. PBMC-reconstituted Rag-2( /-) gammac(-/-) animals showed splenic chimerism levels ranging from 1-16% human cells. After reconstitution, Rag-2(-/-) gammac(-/-) mice developed human leukocyte infiltrates in their grafts and vascular lesions that were significantly elevated after infection. Cellular infiltration revealed significantly increased ICAM-1 and PDGF-R-beta expression after HCMV-infection of the graft. Arterial grafts from unreconstituted Rag-2(-/-) gammac(-/-) recipients showed no vascular lesions. These data demonstrate a causative relationship between HCMV-infection as an isolated risk factor and the development of transplant-arteriosclerosis in a humanized mouse arterial transplant-model possibly by elevated ICAM-1 and PDGF-R-beta expression. PMID- 22429330 TI - Relevance of PTEN loss in brain metastasis formation in breast cancer patients. AB - INTRODUCTION: With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer. METHODS: Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations. RESULTS: The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P < 0.01; false discovery rate (fdr) < 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases. CONCLUSIONS: These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation. PMID- 22429331 TI - A new, innovative, lengthening surgical procedure for Peyronie's disease by penile prosthesis implantation with double dorsal-ventral patch graft: the "sliding technique". AB - INTRODUCTION: Peyronie's disease is the result of the formation of fibrous plaques in the tunica albuginea of the penis; typical presentations of the disease are represented by pain during erection, erectile dysfunction, and penile deformities, such as curvature, narrowing, and penile shortening. The most complex treatment is related to penile shortening. AIM: To find a safe procedure in penile shortening due to Peyronie's disease providing a satisfactory lengthening, allowing an early stabilization of the penis, and preventing axial tension on the neurovascular bundles during dilation. METHODS: We describe a new lengthening surgical procedure based on a ventro-dorsal incision of the tunica albuginea, penile prosthesis implantation, and double dorsal-ventral patch grafting with porcine small intestinal submucosa. Three patients, affected by Peyronie's disease with penile shortening and erectile dysfunction, underwent this procedure with approval of our local ethical committee. We evaluated the penis lengthening, intraoperative and postoperative complications, patient's preoperative and postoperative sexual life satisfaction (International Index of Erectile Function [IIEF] questionnaire). RESULTS: The average operative time was 2 hours and 50 minutes. No major intraoperative nor postoperative complications occurred. No significant bleedings were recorded. Patients were discharged after 48-72 hours. The average increase in length obtained was 3.2 cm. All patients resumed sexual intercourses with satisfaction; no significant loss of sensitivity or any sign of vascular distress of the glans was recorded. The follow-up is 13 months. The average IIEF score is 60. CONCLUSIONS: The lengthening of the penis by a double dorsal-ventral patch graft is an innovative procedure that is based on current techniques of plaque incision and grafting, and that can easily resolve severe shortening of the penis due to Peyronie's disease. In the cases presented, this procedure resulted easily, effectively, and safely. Nevertheless, the technique proposed in this article shall be validated through prospective studies with larger samples. PMID- 22429332 TI - Irradiation alters MMP-2/TIMP-2 system and collagen type IV degradation in brain. AB - PURPOSE: Blood-brain barrier (BBB) disruption is one of the major consequences of radiation-induced normal tissue injury in the central nervous system. We examined the effects of whole-brain irradiation on matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and extracellular matrix (ECM) degradation in the brain. METHODS AND MATERIALS: Animals received either whole brain irradiation (a single dose of 10 Gy gamma-rays or a fractionated dose of 40 Gy gamma-rays, total) or sham-irradiation and were maintained for 4, 8, and 24 h following irradiation. mRNA expression levels of MMPs and TIMPs in the brain were analyzed by real-time reverse transcriptase-polymerase chain reaction (PCR). The functional activity of MMPs was measured by in situ zymography, and degradation of ECM was visualized by collagen type IV immunofluorescent staining. RESULTS: A significant increase in mRNA expression levels of MMP-2, MMP-9, and TIMP-1 was observed in irradiated brains compared to that in sham-irradiated controls. In situ zymography revealed a strong gelatinolytic activity in the brain 24 h postirradiation, and the enhanced gelatinolytic activity mediated by irradiation was significantly attenuated in the presence of anti-MMP-2 antibody. A significant reduction in collagen type IV immunoreactivity was also detected in the brain at 24 h after irradiation. In contrast, the levels of collagen type IV were not significantly changed at 4 and 8 h after irradiation compared with the sham-irradiated controls. CONCLUSIONS: The present study demonstrates for the first time that radiation induces an imbalance between MMP-2 and TIMP-2 levels and suggests that degradation of collagen type IV, a major ECM component of BBB basement membrane, may have a role in the pathogenesis of brain injury. PMID- 22429333 TI - Mitigating errors in external respiratory surrogate-based models of tumor position. AB - PURPOSE: To investigate the effect of tumor site, measurement precision, tumor surrogate correlation, training data selection, model design, and interpatient and interfraction variations on the accuracy of external marker-based models of tumor position. METHODS AND MATERIALS: Cyberknife Synchrony system log files comprising synchronously acquired positions of external markers and the tumor from 167 treatment fractions were analyzed. The accuracy of Synchrony, ordinary least-squares regression, and partial-least-squares regression models for predicting the tumor position from the external markers was evaluated. The quantity and timing of the data used to build the predictive model were varied. The effects of tumor-surrogate correlation and the precision in both the tumor and the external surrogate position measurements were explored by adding noise to the data. RESULTS: The tumor position prediction errors increased during the duration of a fraction. Increasing the training data quantities did not always lead to more accurate models. Adding uncorrelated noise to the external marker based inputs degraded the tumor-surrogate correlation models by 16% for partial least-squares and 57% for ordinary-least-squares. External marker and tumor position measurement errors led to tumor position prediction changes 0.3-3.6 times the magnitude of the measurement errors, varying widely with model algorithm. The tumor position prediction errors were significantly associated with the patient index but not with the fraction index or tumor site. Partial least-squares was as accurate as Synchrony and more accurate than ordinary-least squares. CONCLUSIONS: The accuracy of surrogate-based inferential models of tumor position was affected by all the investigated factors, except for the tumor site and fraction index. PMID- 22429334 TI - Osteonecrosis of the jaw in a patient with advanced non-small-cell lung cancer receiving bevacizumab. PMID- 22429335 TI - Molecular analysis of the bacterial communities in the live Pacific oyster (Crassostrea gigas) and the influence of postharvest temperature on its structure. AB - AIMS: To evaluate the effect of postharvest temperature on bacterial communities in live Pacific oysters (Crassostrea gigas) using nonculture-based methods. METHODS AND RESULTS: Live oysters were compared before and after storage at 4, 6, 15, 20 and 30 degrees C using terminal restriction fragment length polymorphism (T-RFLP). Bacterial communities in freshly harvested (control) vs stored oysters were significantly different. Changes in bacterial communities at 4, 15 and 30 degrees C observed by T-RFLP were further investigated by clone library analysis. Members of the Proteobacteria predominated (43.0-57.0% of clones) in control oysters, while storage altered the bacterial profile. At 4 degrees C, Psychrilyobacter spp. (phylum Fusobacteria) predominated (43.8% of clones), while at 15 and 30 degrees C, members of the phylum Bacteroidetes represented 63.0 and 60.2% of clones, respectively. High microbial diversity in oysters was observed, with at least 73 different genera-related clones among all samples. CONCLUSIONS: Changes in the overall bacterial community of Pacific oysters were influenced by storage temperature and would likely not be detected by standard culture-based methods currently used to assess oyster quality. Certain dominant genera, such as Psychrilyobacter, Polynucleobacter and a bacterial group related to Alkaliflexus, should be further studied as possible indicators for postharvest temperature control. SIGNIFICANCE AND IMPACT OF THE STUDY: This work is the first report describing the effect of different storage temperatures on bacterial diversity in postharvest live Pacific oysters using molecular-based methods. PMID- 22429336 TI - On the structure and oxygen transmission rate of biodegradable cellulose nanobarriers. AB - Cellulose nanofibrils have been proposed for novel barrier concepts, based on their capability to form smooth, strong and transparent films, with high oxygen barrier properties. A series of cellulose-based films were manufactured and tested with respect to their oxygen transmission rate (OTR) capabilities. The obtained OTR levels were considerably better than the levels recommended for packaging applications. Part of the nanofibrillated material applied in this study was produced with 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) mediated oxidation as pretreatment. Films made of TEMPO-pretreated samples yielded lower OTR values. The minimum obtained OTR value was 3.0 mL m-2 day-1 atm-1 with a corresponding oxygen permeability of 0.04 mL mm m-2 day-1 atm-1, tested at 50% relative humidity. The good barrier properties are due to the compact and dense structure of the films, as revealed by field-emission scanning electron microscopy. A relationship between OTR and the structure of the corresponding nanofibril-based films was confirmed. PMID- 22429337 TI - Helical assembly in the death domain (DD) superfamily. AB - Death domain (DD) superfamily members play a central role in apoptotic and inflammatory signaling through formation of oligomeric molecular scaffolds. These scaffolds promote the activation of proinflammatory and apoptotic initiator caspases, as well as Ser/Thr kinases. Interactions between DDs are facilitated by a conserved set of interaction surfaces, type I, type II, and type III. Recently structural information on a ternary complex containing the DDs of MyD88, IRAK4, and IRAK2 and a binary complex containing Fas and FADD DDs has become available. This review will focus on how the three DD interaction surfaces cooperate to facilitate the assembly of these oligomeric signaling complexes. PMID- 22429338 TI - Multimorbidity prevalence and patterns across socioeconomic determinants: a cross sectional survey. AB - BACKGROUND: Studies on the prevalence of multimorbidity, defined as having two or more chronic conditions, have predominantly focused on the elderly. We estimated the prevalence and specific patterns of multimorbidity across different adult age groups. Furthermore, we examined the associations of multimorbidity with socio demographic factors. METHODS: Using data from the Health Quality Council of Alberta (HQCA) 2010 Patient Experience Survey, the prevalence of self reported multimorbidity was assessed by telephone interview among a sample of 5010 adults (18 years and over) from the general population. Logistic regression analyses were performed to determine the association between a range of socio-demographic factors and multimorbidity. RESULTS: The overall age- and sex-standardized prevalence of multimorbidity was 19.0% in the surveyed general population. Of those with multimorbidity, 70.2% were aged less than 65 years. The most common pairing of chronic conditions was chronic pain and arthritis. Age, sex, income and family structure were independently associated with multimorbidity. CONCLUSIONS: Multimorbidity is a common occurrence in the general adult population, and is not limited to the elderly. Future prevention programs and practice guidelines should take into account the common patterns of multimorbidity. PMID- 22429340 TI - Efficacy and safety of angiotensin II type 1 receptor blocker/calcium channel blocker combination therapy for hypertension: focus on a single-pill fixed-dose combination of valsartan and amlodipine. AB - Adequate lowering of blood pressure reduces the risk of hypertension-induced cardiovascular events. Worldwide, blood pressure is not optimally controlled and more effective management is needed. The efficacy and tolerability of angiotensin II type 1 receptor blockers (ARBs) have led to their widespread use. Calcium channel blockers (CCBs) are highly effective antihypertensives and amlodipine has a long half-life in the circulation. The combination of an ARB with a CCB as a single-pill, fixed-dose treatment is emerging as possibly the best therapy for preventing cardiovascular disease. Although many kinds of ARB are used in such combinations, amlodipine is mainly used as the CCB. Thus, differences in safety and efficacy among single-pill ARB/CCBs depend mainly on the ARB. Not all ARBs have the same effects and some of these may be molecular (or differential) rather than class (or common) effects. This review discusses the safety and efficacy of ARB/CCB combination therapy, with particular focus on a single-pill, fixed-dose combination of valsartan/amlodipine. PMID- 22429339 TI - Differential effects of environment on potato phenylpropanoid and carotenoid expression. AB - BACKGROUND: Plant secondary metabolites, including phenylpropanoids and carotenoids, are stress inducible, have important roles in potato physiology and influence the nutritional value of potatoes. The type and magnitude of environmental effects on tuber phytonutrients is unclear, especially under modern agricultural management that minimizes stress. Understanding factors that influence tuber secondary metabolism could facilitate production of more nutritious crops. Metabolite pools of over forty tuber phenylpropanoids and carotenoids, along with the expression of twenty structural genes, were measured in high-phenylpropanoid purple potatoes grown in environmentally diverse locations in North America (Alaska, Texas and Florida). RESULTS: Phenylpropanoids, including chlorogenic acid (CGA), were higher in samples from the northern latitudes, as was the expression of phenylpropanoid genes including phenylalanine ammonia lyase (PAL), which had over a ten-fold difference in relative abundance. Phenylpropanoid gene expression appeared coordinately regulated and was well correlated with metabolite pools, except for hydroxycinnamoyl-CoA:quinatehydroxcinnamoyl transferase (HQT; r = -0.24). In silico promoter analysis identified two cis-acting elements in the HQT promoter not found in the other phenylpropanoid genes. Anthocyanins were more abundant in Alaskan samples and correlated with flavonoid genes including DFR (r = 0.91), UFGT (r = 0.94) and F3H (r = 0.77). The most abundant anthocyanin was petunidin-3 coum-rutinoside-5-glu, which ranged from 4.7 mg g-1 in Alaska to 2.3 mg g-1 in Texas. Positive correlations between tuber sucrose and anthocyanins (r = 0.85), suggested a stimulatory effect of sucrose. Smaller variation was observed in total carotenoids, but marked differences occurred in individual carotenoids, which had over a ten-fold range. Violaxanthin, lutein or zeaxanthin were the predominant carotenoids in tubers from Alaska, Texas and Florida respectively. Unlike in the phenylpropanoid pathway, poor correlations occurred between carotenoid transcripts and metabolites. CONCLUSION: Analysis of tuber secondary metabolism showed interesting relationships among different metabolites in response to collective environmental influences, even under conditions that minimize stress. The variation in metabolites shows the considerable phenotypical plasticity possible with tuber secondary metabolism and raises questions about to what extent these pathways can be stimulated by environmental cues in a manner that optimizes tuber phytonutrient content while protecting yields. The differences in secondary metabolites may be sufficient to affect nutritional quality. PMID- 22429341 TI - Angiotensin receptor blockers in clinical practice--implications of the ONTARGET study. AB - Hypertension and cardiovascular disease remain the major causes of premature morbidity and mortality. Following a diagnosis of hypertension, treatment with antihypertensive medication will almost invariably be lifelong. Even when prescribed treatment, many patients remain above blood pressure goals, and this is particularly common in patients at high risk of cardiovascular events due to the presence of other risk factors such as diabetes mellitus. An important cause of this failure is medication nonadherence, which is particularly common with treatments that have side-effects. Antihypertensive drugs do not make the patient feel better in the short term, but side-effects often occur immediately. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is highly relevant to clinical practice because it demonstrated that the angiotensin receptor blocker (ARB) telmisartan is as effective as the proven angiotensinconverting enzyme inhibitor ramipril in preventing cardiovascular events in high-risk patients, while being better tolerated. Evidence of the advantages of telmisartan in the management of cardiovascular morbidity suggest, therefore, that it might be a better treatment option for hypertensive patients and that switching to generic ARBs may not always be best. PMID- 22429342 TI - Angioplasty with stenting for intracranial atherosclerosis: a systematic review. AB - OBJECTIVE: Intracranial artery stenosis can be fatal, requiring fast, safe and effective intervention. The introduction of the WingspanTM stent system with GatewayTM percutaneous transluminal angioplasty balloon catheter has made intracranial intervention possible in a clinical trial setting. This systematic review planned to identify and review all randomized controlled trials comparing angioplasty and stenting of intracranial arteries with standard medical care. METHODS: Electronic databases and relevant records were examined for possible trials using predefined inclusion and exclusion criteria. RESULTS: A total of 3661 records were identified by searching several English language databases and other sources including Chinese academic journals. The recently discontinued Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial was the single qualifying study and showed clear advantage of medical management over percutaneous transluminal angioplasty and stenting (PTAS). CONCLUSIONS: The SAMPRASS trial indicated that PTAS is associated with high complication and morbidity rates. Definitive recommendations cannot be made until convincing results from additional robustly designed randomized trials become available. PMID- 22429343 TI - A combination of high-dose vitamin C plus zinc for the common cold. AB - Vitamin C and zinc play important roles in nutrition, immune defence and maintenance of health. Intake of both is often inadequate, even in affluent populations. The common cold continues to place a great burden on society in terms of suffering and economic loss. After an overview of the literature on the effects of the separate administration of either vitamin C or zinc against the common cold, this article presents data from two preliminary, double-blind, randomized, placebo-controlled trials, conducted with a combination of 1000 mg vitamin C plus 10 mg zinc in patients with the common cold. In both studies, a nonsignificant reduction of rhinorrhoea duration (range 9-27%) was seen. In pooled analyses of both studies (n=94), vitamin C plus zinc was significantly more efficient than placebo at reducing rhinorrhoea over 5 days of treatment. Furthermore, symptom relief was quicker and the product was well tolerated. In view of the burden associated with the common cold, supplementation with vitamin C plus zinc may represent an efficacious measure, with a good safety profile, against this infectious viral disease. PMID- 22429344 TI - Anaemia and prognosis in acute coronary syndromes: a systematic review and meta analysis. AB - OBJECTIVE: This meta-analysis was conducted to summarize the association between anaemia and outcomes in patients with acute coronary syndromes (ACS). METHODS: MEDLINE(r), Cochrane Library, OVID and EMBASE databases were searched to identify studies that examined the effect of anaemia on mortality or other adverse events (heart failure, cardiogenic shock or major bleeding). RESULTS: Nineteen studies met the final inclusion criteria (total number of patients 241 293). The risks of shortterm mortality (odds ratio [OR] 2.77; 95% confidence interval [CI] 2.09, 3.65), long-term mortality (OR 2.03; 95% CI 1.52, 2.71), heart failure (OR 1.96; 95% CI 1.47, 2.62), cardiogenic shock (OR 1.95; 95% CI 1.04, 2.64) and major bleeding (OR 4.28; 95% CI 1.05, 17.14) were increased in patients with anaemia, compared with patients without anaemia. Anaemia was also associated with a higher risk of mortality (adjusted hazard ratio 1.49, 95% CI 1.24, 1.79). CONCLUSIONS: These study findings suggest that anaemia can be used to identify patients with ACS who are at a high risk of death or adverse events, and it may become a promising risk stratification factor in ACS. PMID- 22429345 TI - Celecoxib radiosensitizes the human cervical cancer HeLa cell line via a mechanism dependent on reduced cyclo-oxygenase-2 and vascular endothelial growth factor C expression. AB - OBJECTIVE: The effects of celecoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor, on HeLa cervical cancer cell growth and radiosensitivity were investigated. METHODS: Cytotoxicity was quantified using a 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium assay and effects on radiosensitivity were assessed using the lethal dose, quasithreshold dose, fraction surviving after 2 Gy irradiation and the radiosensitization ratio (SER, based on average lethal dose) determined using a single-hit multitarget model. RESULTS: Celecoxib inhibited HeLa cell proliferation in a concentration- and time-dependent manner, with a half-maximal inhibitory concentration at 72 h of 44 MUmol/l. Treatment with 20 MUmol/l celecoxib for 72 h before irradiation was associated with an SER of 2.01. The SER of irradiated cells was 2.41 when treated with 40 MUmol/l celecoxib before irradiation, 1.89 when treated simultaneously and 1.44 when treated after irradiation. Celecoxib downregulated COX-2 and vascular endothelial growth factor C (VEGF-C) expression evaluated immunohistochemically. CONCLUSION: Celecoxib pretreatment radiosensitizes HeLa cells via a mechanism dependent on down-regulation of COX-2 and VEGF-C. PMID- 22429346 TI - Targeted drug regulation on methylation of p53-BAX mitochondrial apoptosis pathway affects the growth of cholangiocarcinoma cells. AB - OBJECTIVE: To study the mechanism of 5-aza-2-deoxycytidine (DAC; a methylation inhibitor) on growth of the human cholangiocarcinoma QBC939 cell line. METHODS: A colourimetric assay was used to detect growth of QBC939 cells treated with DAC (0.1-100 MUmol/l) over 24 h, 48 h and 72 h. Cell morphology was observed by transmission electron microscopy (TEM). The cell cycle and apoptosis were analysed by flow cytometry. Hypermethylation of the promoters of the p53-BAX mitochondrial apoptosis genes cyclin-dependent kinase inhibitor 2A (CDKN2A), death-associated protein kinase 1 (DAPK1) and PYD and CARD domain containing (PYCARD) was detected by methylation-specific polymerase chain reaction, with and without DAC treatment. RESULTS: DAC inhibited QBC939 cell growth with a half maximal inhibitory concentration of 5 MUmol/l at 72 h. After DAC treatment, apoptosis was observed by TEM. Flow cytometric analysis of propidium iodide positive cells demonstrated increased apoptosis of DAC-treated QBC939 cells (43.04%) compared with untreated cells (4.31%). DAC treatment resulted in demethylation of the gene promoters of CDKN2A and DAPK1 in QBC939 cells. CONCLUSIONS: DAC induces apoptosis of QBC939 cells by reactivation of hypermethylated p53-BAX mitchondrial apoptosis genes in cholangiocarcinoma cells. PMID- 22429347 TI - Noninvasive evaluation of cerebral glioma grade by using diffusion-weighted imaging-guided single-voxel proton magnetic resonance spectroscopy. AB - OBJECTIVE: To investigate the usefulness of diffusion-weighted imaging (DWI) guided, single-voxel proton magnetic resonance spectroscopy (SVS) for preoperative evaluation of cerebral glioma grade. METHODS: For SVS, placement of volume-of-interest was guided by the minimal apparent diffusion coefficient value obtained from DWI. Spectral data for N-acetylaspartate (NAA), choline (Cho), and phosphocreatine (Cr) were analysed in 33 patients with primary gliomas. RESULTS: Cho/Cr and Cho/NAA ratios were significantly higher in high grade than in low-grade gliomas; NAA/Cr ratios were significantly lower in high grade than in low-grade gliomas. Receiver operating characteristic curve analysis demonstrated a threshold value of 2.01 for Cho/Cr for sensitivity, specificity, positive predictive and negative predictive values of 86.36%, 90.00%, 95.00% and 75.00%, respectively. Threshold values of 2.49 and 0.97 were obtained for Cho/NAA and NAA/Cr, respectively. Despite no significant difference in diagnostic accuracy between the metabolite ratios, diagnostic accuracy using the Cho/Cr ratio was slightly better than that of Cho/NAA or NAA/Cr. CONCLUSION: DWI-guided SVS has potential value for the preoperative prediction of glioma grade. PMID- 22429348 TI - Growth inhibition of malignant melanoma by intermediate frequency alternating electric fields, and the underlying mechanisms. AB - OBJECTIVE: This study investigated the antitumour effects of intermediate frequency alternating electric fields (IF-AEF) in a murine melanoma cell line (B16F10) and a mouse tumour model. METHODS: IF-AEF was applied at 100 kHz. Proliferation of B16F10 cells in vitro was assessed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. IF-AEF was applied in vivo to mice bearing B16F10 tumours. Terminal deoxy nucleotidyl transferase mediated dUTP nick end labelling (TUNEL) assay for apoptosis, and immunohistochemical detection of CD34 and vascular endothelial growth factor (VEGF), were performed. RESULTS: IF-AEF inhibited the proliferation of B16F10 cells in an electrical intensity and time-dependent manner. Treatment with IF-AEF for 7 days significantly inhibited the growth of tumours compared with untreated controls. IF-AEF induced apoptosis in vivo and reduced CD34-positive cell numbers; CD34 is a special marker of microvessel density. CONCLUSION: IF-AEF reduced microvessel density related to tumour growth and may serve as a therapeutic strategy for cancer treatment. PMID- 22429349 TI - A primary proteomic analysis of serum from patients with nonfunctioning pituitary adenoma. AB - OBJECTIVE: The early diagnosis of nonfunctioning pituitary adenoma (NFPA) is difficult. The objective of this study was to find specific protein biomarkers to aid in the early detection of NFPA. METHODS: Serum samples from 34 patients with NFPA and 34 age- and sex-matched healthy control subjects were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. The spectra were generated, protein peak clustering was performed and classification analyses were carried out using a decision tree classification algorithm. RESULTS: Nine differentially expressed serum proteins were identified in the patients with NFPA compared with the control subjects. Both the sensitivity and specificity of the decision tree classification algorithm were 82.4% for NFPA. CONCLUSIONS: Nine new serum protein biomarkers for NFPA were identified. SELDI-TOF-MS coupled with data mining tools might provide a novel approach for the early diagnosis of NFPA and population screening for the disease. PMID- 22429350 TI - Association between cardiac function and pulmonary function in hypertensive patients. AB - OBJECTIVE: This study examined the association between cardiac function and pulmonary function in hypertensive patients. METHODS: Hypertensive patients without overt cardiovascular disease were enrolled (n=43; mean+/-SD age 71+/-9 years). Pulmonary function was measured by the percentage of predicted forced vital capacity (%FVC) and the ratio of 1 s forced expiratory volume (FEV1) to FVC (FEV1/FVC ratio). Left ventricular ejection fraction (LVEF) and the ratio of peak early diastolic transmitral flow (E) to peak early diastolic mitral annular velocity (e') (E/e' ratio) were assessed using echocardiography. RESULTS: Multiple linear regression analysis revealed that E/e' was independently associated with %FVC and that LVEF was independently associated with FEV1/FVC ratio. Both LVEF and FEV1/FVC ratio were significantly lower in hypertensive former or current smokers than in hypertensive never smokers. CONCLUSIONS: Subclinical cardiac dysfunction was independently associated with reduced pulmonary function in hypertensive patients. Hypertensive patients with decreased pulmonary function may need preventive care to prevent the progression of heart failure. PMID- 22429351 TI - Vaporized perfluorocarbon confers protection against acute lung injury by inhibiting MMP-9 expression without protective effects in other organs. AB - OBJECTIVE: Vaporized perfluorocarbon (PFC) is a treatment for lung injury; this study investigated its mode of action and potential protective effects on other organs, which are unclear. METHODS: Acute lung injury was induced by lung lavage with artificial seawater in 32 female New Zealand White rabbits. Animals received either conventional mechanical ventilation (CMV), positive end-expiratory pressure under CMV (PEEP), vaporized PFC ventilation, or positive end-expiratory pressure with vaporized PFC ventilation (PEEP+PFC). Histopathology of the lung, small intestine, liver and kidney were investigated. Matrix metalloproteinase (MMP)-9 mRNA levels in the lung were analysed. RESULTS: Pathological injury of the lung was significantly alleviated in the PEEP, PFC and PEEP+PFC groups compared with the CMV group. Tissue damage in the liver, kidney and small intestine was similar between all groups. MMP-9 mRNA levels in the PEEP, PFC and PEEP+PFC groups were significantly lower than those in the CMV group. CONCLUSIONS: Vaporized PFC ventilation can significantly alleviate lung injury but has no significant protective effect on other organs. Alleviation of lung injury may be associated with MMP-9 inhibition. PMID- 22429352 TI - Diffusion tensor imaging for predicting hand motor outcome in chronic stroke patients. AB - OBJECTIVE: Previous studies have indicated that diffusion tensor imaging (DTI) values are related to clinical outcome in stroke patients. This prospective study explored whether DTI values were predictive for hand function outcome in chronic stroke patients. METHODS: The DTI parameters (rlambda1, rlambda23, fractional anisotropy [rFA] and mean diffusivity [rMD]) were investigated in patients with completely paralysed hands (CPH; n=10) or partially paralysed hands (PPH; n=10), by two methods of analysis: segment of the corticospinal tract [sCST] analysis; pure region of interest [ROI] analysis. Spearman's correlation coefficient was used to assess the correlation between the DTI parameters and the following clinical measures: Fugl-Meyer Assessment [FMA]; National Institutes of Health Stroke Scale [NIHSS]. RESULTS: Significant differences were found between CPH and PPH for rFA and rlambda23 (sCST analysis) and for rMD and rlambda23 (ROI analysis). The rlambda23 (sCST analysis) correlated with the NIHSS; the rMD (sCST analysis) correlated with the FMA (hand). CONCLUSION: The three parameters, rFA, rlambda23 and rMD may have predictive value for evaluating hand function outcome in chronic stroke patients. PMID- 22429353 TI - Serum levels of calcitonin gene-related peptide and substance P are decreased in patients with diabetes mellitus and coronary artery disease. AB - OBJECTIVE: This study evaluated serum levels of the neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP) in coronary artery disease (CAD) patients with and without a history of diabetes mellitus (DM). METHODS: Patients undergoing coronary angiography for suspected myocardial ischaemia were divided into four groups depending on their clinical status: control group (no CAD or DM; n=44), DM group (DM without CAD; n=46), CAD group (stable CAD without DM; n=44) and DM+CAD group (stable CAD with DM; n=50). Serum levels of CGRP and SP were determined using radioimmunoassays. RESULTS: CGRP and SP levels in the DM and CAD groups were significantly lower than in the control group. The lowest levels of CGRP and SP were observed in the DM+CAD group. There were no significant differences in CGRP and SP levels between the DM group and the CAD group. CONCLUSION: CGRP and SP may have a role in the pathogenesis of CAD in patients with diabetes. PMID- 22429354 TI - Selective neurogenic blockade and perioperative immune reactivity in patients undergoing lung resection. AB - OBJECTIVE: This double-blind, prospective, randomized, controlled trial examined the effects of thoracic epidural block and intravenous clonidine and opioid treatment on the postoperative Th1/Th2 cytokine ratio after lung surgery. The primary endpoint was the interferon gamma (IFN-gamma; Th1 cytokine)/interleukin 4 (IL-4; Th2 cytokine) ratio. Secondary endpoints were reductions in pain and incidence of pneumonia. METHODS: Sixty patients were randomized into three groups to receive remifentanil intravenously (remifentanil group, n=20), remifentanil and clonidine intravenously (clonidine group, n=20), or ropivacaine epidurally (ropivacaine group, n=20). Pain was assessed using a numerical rating scale (NRS). Cytokines were measured using a cytometric bead array. RESULTS: Patients in the ropivacaine group (thoracic epidural block) had a significantly lower IFN gamma/IL-4 ratio at the end of surgery than those in the remifentanil group and clonidine group. There were no significant between-group differences in the IFN gamma/IL-4 ratio at other time-points. There were no differences in NRS scores at any time-point. No patient developed pneumonia. CONCLUSION: Intraoperative thoracic epidural block decreased the IFN-gamma/IL-4 ratio immediately after lung surgery, indicating less inflammatory stimulation during surgery. PMID- 22429355 TI - Association of sterol regulatory element-binding transcription factor gene polymorphisms with ischaemic stroke. AB - OBJECTIVE: To explore the association between polymorphisms of the sterol regulatory element-binding transcription factor (SREBF) gene and ischaemic stroke. METHODS: The SREBF1c 54G>C and SREBPF2 1784G>C genotypes were assessed using restriction fragment length polymorphism analysis in 446 Han Chinese ischaemic stroke patients and 355 Han Chinese control subjects without cerebrovascular disease. RESULTS: The frequencies of the SREBF2 1784G>C CC genotype and the C allele were significantly higher in the ischaemic stroke group than in controls. Patients with ischaemic stroke who had the SREBF2 1784G>C CC genotype had significantly lower high-density lipoprotein (HDL) levels, compared with ischaemic stroke patients and control subjects with the GC or GG genotypes. Multivariate logistic regression analysis revealed a significant positive association between SREBF2 1784G>C and ischaemic stroke; an inverse association was observed between HDL level and risk of ischaemic stroke. CONCLUSIONS: The CC genotype of the SREBF2 1784G>C polymorphism was associated with an increased risk of ischaemic stroke, possibly through decreasing the HDL level, which was inversely associated with the risk of ischaemic stroke. PMID- 22429356 TI - Role of oxidative stress in the clinical outcome of patients with multiple blunt trauma. AB - OBJECTIVE: This prospective study evaluated serum total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI), along with the Revised Trauma Score (RTS) and Injury Severity Score (ISS), as predictors of clinical outcome in the early post-traumatic period in patients with multiple blunt trauma (MBT). METHODS: The study included 52 patients admitted to the emergency department with MBT and 40 age- and sex-matched healthy control subjects. RESULTS: The overall MBT patient mortality was 32.7% (17/52). There was no significant association between age and mortality in MBT patients, but there was a negative correlation between mortality and RTS, and a positive correlation between mortality and ISS. TOS levels were significantly higher in nonsurvivors compared with survivors. There was no correlation between TAS or OSI and survival. ISS and RTS showed positive and negative correlations with TOS level, respectively, but neither was significantly related to TAS or OSI. CONCLUSIONS: These findings suggest that TOS, as an early oxidative stress biomarker, may be an objective alternative criterion to the ISS and RTS for managing patients with MBT during the early period following traumatic injury. PMID- 22429357 TI - Comparison of the optimal effect-site concentrations of remifentanil for preventing cough during emergence from desflurane or sevoflurane anaesthesia. AB - OBJECTIVE: To compare the effect-site concentrations of remifentanil target controlled infusion (TCI) that produced 50% and 95% of the maximal effect (EC50 and EC95, respectively) for preventing cough during emergence from desflurane or sevoflurane anaesthesia, in patients undergoing elective thyroidectomy. METHODS: Adults undergoing elective thyroidectomy were randomized to receive anaesthesia with desflurane or sevoflurane. The EC50 and EC95 values for remifentanil TCI were determined using Dixon's up-and-down method and probit analysis with sigmoid curve. RESULTS: In total, 48 patients aged 20-64 years were enrolled in the study. The EC50+/-SD of remifentanil TCI, determined by Dixon's up-and-down method, were 1.54+/-0.70 and 1.11+/-0.24 ng/ml for desflurane and sevoflurane, respectively. The EC95 of remifentanil TCI, analysed by probit analysis, were 2.88 ng/ml and 2.29 ng/ml for desflurane and sevoflurane, respectively. The effect-site concentration of remifentanil TCI for preventing cough during emergence from desflurane anaesthesia was not significantly higher than that observed for sevoflurane. CONCLUSIONS: During emergence from anaesthesia, variations in effect-site concentrations of remifentanil for preventing cough are of limited importance as they do not generate significant differences in results. PMID- 22429358 TI - The diagnostic value of a multivariate logistic regression analysis model with transvaginal power Doppler ultrasonography for the prediction of ectopic pregnancy. AB - OBJECTIVE: A multivariate logistic regression analysis model for predicting ectopic pregnancy in women with pregnancy of unknown location was designed and evaluated clinically. METHODS: Endometrial thickness, symmetry, resonance, pattern of echogenicity, helicine artery blood flow and blood flow resistance index (RI) in 129 patients with suspected early ectopic pregnancy were assessed by transvaginal power Doppler ultrasonography. Variables significant in univariate logistic regression analysis were included in a multivariate predictive logistic regression analysis model. RESULTS: The final predictive model included three factors: endometrial thickness<=9 mm; a multilayered endometrial echogenicity pattern with prominent outer and midline hyperechogenic lines and an inner hypoechogenic region; and visible endometrial arterial blood flow. The area under the receiver operating characteristic curve of the model was 0.980. When RI was >0.65 and the predictive probability>0.50, diagnostic accuracy was high. The model correctly diagnosed 52/55 (94.5%) clinically confirmed ectopic pregnancy cases. CONCLUSION: This multivariate predictive logistic regression analysis model has clinical value for the differential diagnosis of early ectopic pregnancy when the pregnancy location is unknown. PMID- 22429359 TI - Oral fluid testing for illicit substance use in preanaesthetic care. AB - OBJECTIVE: Due to specific risks associated with illicit drug use, the preanaesthetic detection of illicit substances is essential. This prospective observational study evaluated oral fluid testing and self reporting of illicit drug use compared with confirmatory blood testing. METHODS: Consecutively enrolled preanaesthetic and emergency room patients (n=939) completed a paper based lifestyle questionnaire. An oral fluid sample was obtained and analysed for illicit substance use by a point-of-care testing device (Drager Drugtest(r) 5000). Patients who tested positive by self reporting or oral fluid testing underwent confirmatory blood testing (n=117). RESULTS: Self reporting revealed more overall illicit substance use and more users of cannabinoids, amphetamines, opioids, cocaine and benzodiazepines than oral fluid testing. Self reporting was more sensitive than blood testing for the detection of overall illicit substance use, and for use of cannabinoids and benzodiazepines. CONCLUSIONS: Self reporting revealed higher rates of illicit substance use than oral fluid testing in preanaesthetic patients, and may lead to more interventions and more appropriately tailored treatment and anaesthesia compared with oral fluid testing. PMID- 22429360 TI - The value of eliminating foods according to food-specific immunoglobulin G antibodies in irritable bowel syndrome with diarrhoea. AB - OBJECTIVE: This study investigated the role of food intolerance in irritable bowel syndrome with diarrhoea (D-IBS). METHODS: Specific immunoglobulin G (IgG) antibodies against 14 common food antigens in the serum were measured in 77 patients with D-IBS and 26 healthy controls. Food-specific IgG antibodies were identified in 39 (50.65%) patients with D-IBS patients compared with four (15.38%) controls. For 12 weeks following the serological testing, 35 patients with D-IBS and food intolerance consumed diets that excluded the identified food. Changes in the main symptoms of D-IBS were evaluated before treatment and regularly during treatment in these patients. RESULTS: After 4 weeks' dietary therapy, most symptoms of D-IBS had improved. By 12 weeks, all symptom scores had decreased significantly compared with the baseline scores. CONCLUSIONS: The 12 week specific-food exclusion diets resulted in significant improvements in abdominal pain (bloating level and frequency), diarrhoea frequency, abdominal distension, stool shape, general feelings of distress and total symptom score compared with baseline in patients with D-IBS. PMID- 22429361 TI - Impact of a resistant dextrin on intestinal ecology: how altering the digestive ecosystem with NUTRIOSE(r), a soluble fibre with prebiotic properties, may be beneficial for health. AB - OBJECTIVES: The prebiotic potential of NUTRIOSE(r)--a sugar-free, digestion resistant dextrin--was evaluated in two randomized, placebo-controlled trials that included 48 and 40 healthy volunteers, respectively. METHODS: In study 1, the effect on colonic bacteria of NUTRIOSE(r) 10, 15 or 20 g/day administered for 14 days was examined; in study 2, gut microbial changes in response to NUTRIOSE(r) 8 g/day for 14 days were monitored using real-time polymerase chain reaction analysis. RESULTS: NUTRIOSE(r) increased proliferation of Bacteroides and inhibited Clostridum perfringens in both studies, increased beta-glucosidase activity (at 10 and 15 g/day) and decreased colonic pH (at 20 g/day). The increase in short-chain fatty acid production with NUTRIOSE(r) consumption was not statistically significant. There were no indications of gastrointestinal intolerance at any dose. CONCLUSIONS: According to commonly accepted definitions, NUTRIOSE(r) is a prebiotic soluble fibre that provides a beneficial effect on colonic ecology while preserving digestive comfort. PMID- 22429362 TI - Perioperative assessment of terlipressin infusion during living donor liver transplantation. AB - OBJECTIVE: To investigate the safety and efficacy of infusion of terlipressin during living donor liver transplantation (LDLT). METHODS: Patients undergoing LDLT with low systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) (n=41) were randomly allocated into control (n=20) and terlipressin groups (n=21). Terlipressin was infused at 1.0-4.0 MUg/kg per h in the terlipressin group during surgery. Controls received generally accepted inotropic and vasopressor agents. RESULTS: Terlipressin infusion induced significantly higher SVRI and PVRI at 60 min after drug infusion, produced significantly greater hourly urine output during the anhepatic phase, and was related to significantly shorter stays in the postoperative intensive care unit (ICU) compared with control treatment (mean+/-SD ICU stay 5.7+/-1.5 versus 6.9+/ 1.5 days, respectively). Patients given a terlipressin infusion>2.0 MUg/kg per h during the preanhepatic phase had a median ICU stay of <6 days (sensitivity 90.0%; specificity 89.0%). CONCLUSIONS: Terlipressin infusion improved low SVRI and PVRI during LDLT and may have contributed to better renal function and shorter ICU stays. PMID- 22429363 TI - A new molecular diagnostic approach to assess Y chromosome microdeletions in infertile men. AB - OBJECTIVE: A key cause of spermatogenetic failure in infertile males is microdeletions in the azoospermia factor (AZF) regions of the Y chromosome. This study screened for microdeletions in the AZF regions using suspension array technology and compared the results with those from polymerase chain reaction (PCR). METHODS: Patients with spermatogenetic failure (n=507) and healthy control sperm donors (n=100) were recruited. DNA samples were analysed using both multiplex PCR with gel electrophoresis and suspension array technology. RESULTS: The suspension array method identified 45 infertile males with Y chromosome microdeletions, while none was found in the controls. Amongst the AZF subregions, two cases had deletions in AZFa, three in AZFb, 35 in AZFc, three in AZFbc and two in AZFabc. The results from 507 patients were identical when analysed with either suspension array or multiplex PCR, however suspension array technology offered improved sensitivity, may be more accurate and could give time and cost savings. CONCLUSIONS: Suspension array technology offers a rapid and high throughput method for Y chromosome microdeletion screening in infertile men. PMID- 22429364 TI - Oxidative stress and antioxidant enzyme activities in newborns with oesophageal atresia and their mothers. AB - OBJECTIVE: To measure the oxidant/antioxidant status of newborn babies with oesophageal atresia and their mothers, compared with healthy control subjects. METHODS: This case-control study included 40 participants: 10 newborns with oesophageal atresia and their mothers, and 10 healthy newborns and their mothers. Whole blood malondialdehyde (MDA) levels and the activities of antioxidant enzymes (catalase, carbonic anhydrase [CA], glucose-6-phosphate dehydrogenase [G-6-PD], and superoxide dismutase [SOD]) were measured. RESULTS: MDA levels and CA activity were significantly higher, and catalase, SOD and G-6 PD activities were significantly lower, in newborns with oesophageal atresia and their mothers than in healthy newborns and their mothers. Although CA activity was similar between the newborns and mothers in the patient group, it was significantly lower in newborns than in mothers in the healthy group. CONCLUSIONS: Increased lipid peroxidation might play an important role in the pathogenesis of oesophageal atresia. Impairment of the free radical/antioxidant balance may lead to increased free radical and decreased antioxidant levels in oesophageal atresia. PMID- 22429365 TI - DAOA variants on diagnosis and response to treatment in patients with major depressive disorder and bipolar disorder. AB - OBJECTIVE: This study investigated whether selected D-amino acid oxidase activator (DAOA) gene single nucleotide polymorphisms (SNPs; rs3916966, rs3916967, rs2391191, rs3916968, rs7139958, rs9558571, rs778293) are associated with major depressive disorder (MDD) and bipolar disorder (BD), and whether they can predict clinical outcomes in Korean in-patients treated with antidepressants and mood stabilizers, respectively. METHODS: In total, 145 patients with MDD, 132 patients with BD and 170 psychiatrically healthy controls were genotyped for the DAOA SNPs. Baseline and final clinical assessments included the Montgomery Asberg Depression Rating Scale and Young Mania Rating Scale for patients with MDD and BD, respectively. RESULTS: There was no association between DAOA SNP genotypes or alleles with diagnosis, clinical improvement, response rates or remission rates for MDD and BD. Haplotype analyses found no association with MDD or BD diagnosis or clinical outcomes. CONCLUSIONS: The findings suggest that the DAOA SNPs investigated may not affect MDD or BD phenotype, clinical symptoms or other clinical factors, and are unlikely to be involved in MDD or BD development and treatment outcomes. Given the study's limitations, further investigation should be carried out. PMID- 22429366 TI - Alleviation of ferric chloride-induced seizures and retarded behaviour in epileptic rats by cortical electrical stimulation treatment. AB - OBJECTIVE: To study the effects of low-frequency cortical electrical stimulation (CES) on seizures and behaviour in a rat model of epilepsy induced by ferric chloride (FeCl3). METHODS: Rats were randomly assigned into four groups (n=8 per group): normal healthy rats; saline-treated control rats; FeCl3-induced epileptic rats; CES-treated FeCl3-induced epileptic rats. Behavioural tests, analysis of the levels of brain-derived neurotrophic factor (BDNF) protein in brain tissue, and ultrastructural studies using transmission electron microscopy (TEM) were undertaken. RESULTS: CES significantly decreased the number and grade of seizures, and improved rat behaviour, compared with untreated epileptic rats. CES reduced levels of BDNF protein in the forebrain and increased levels of BDNF protein in the hippocampus compared with untreated epileptic rats. TEM showed less damage and ultrastructural changes in the neurons of CES-treated epileptic rats. CONCLUSIONS: CES inhibited seizures in FeCl3-induced epileptic rats and improved their behaviour. These effects might be mediated by altering BDNF protein levels in the brain. PMID- 22429367 TI - Aspirin resistance: clinical significance and genetic polymorphism. AB - OBJECTIVE: To determine the prevalence, clinical implications and underlying mechanism of aspirin resistance in Chinese patients. METHODS: Platelet aggregation was determined by light transmission aggregometry (LTA) using four different inducers. Patients were divided into aspirin-resistant (AR), aspirin semi responder (ASR) and aspirin-sensitive (AS) groups, according to their LTA results. Aspirin resistance was assessed by thrombo elastography (TEG, with arachidonic acid [AA] or adenosine diphosphate as inducers), serum/urinary 11 dehydrothromboxane B2 (11-DH-TXB2) assay, platelet function analyser-100 assay and P-selectin assay. Polymorphisms in the prostaglandin endoperoxide synthase 1 (PTGS1) gene (A842G, C50T, C22T, G128A, C644A and C714A), the PTGS2 gene (G765C) and the integrin beta3 (ITGB3) gene (C196T) were examined. RESULTS: The study included 360 aspirin-treated patients and 314 healthy controls. AS patients had significantly lower levels of 11-DH-TXB2 than AR and ASR patients, and significantly lower levels of P-selectin than AR patients. TEG-AA was more sensitive, specific and consistent than P-selectin in detecting aspirin resistance. The frequency of the PTGS2 G765C mutation was significantly higher in the AR/ASR groups versus the AS group. CONCLUSIONS: TEG-AA was more sensitive, specific and consistent than the P-selectin assay for detecting aspirin resistance, and the PTGS2 G765C mutation may be related to aspirin resistance. PMID- 22429368 TI - Detection and clinical significance of lymph node micrometastasis in gastric cardia adenocarcinoma. AB - OBJECTIVES: Lymph node micro metastasis was investigated in gastric cardia adenocarcinoma (GCA) patients without lymph node metastasis on routine pathological examination. The relationship between micrometastasis and clinicopathological features was also evaluated. METHODS: A total of 349 lymph nodes were obtained from 45 patients with GCA. Micrometastases were detected by immunohistochemical staining for the markers cytokeratin 19 (CK19) and CD44 variant 6 (CD44v6). RESULTS: A total of 33 lymph nodes (9.5%) from 15 patients (33.3%) were positive for CK19. Of these, 27 lymph nodes (7.7%) from 12 patients (26.7%) were also positive for CD44v6. Micrometastasis was significantly related to depth of tumour invasion and Lauren classification (intestinal or diffuse). The recurrence rate was significantly higher and 2-year survival rate significantly lower in patients with than in those without lymph node micrometastasis, showing the necessity of detecting micrometastasis in GCA patients who test negative for lymph node metastasis on routine examination. CONCLUSION: CK19 and CD44v6 were shown to be good markers for micrometastasis detection. PMID- 22429369 TI - Detection of breast lesions using an automated breast volume scanner system. AB - OBJECTIVE: This study investigated the clinical utility of an automated breast volume scanner (ABVS) system for the detection of breast lesions. METHODS: The breasts of 81 patients referred for ultrasonographic examination were scanned using the ABVS system and hand-held ultrasonography independently by two experienced examiners. The ABVS was used to perform scans of the breast in three directions (anteroposterior, lateral and medial), with the addition of further inferior and superior scans if necessary. The scanning data were then stored and automatically reconstructed. For hand-held ultrasonography the whole breast was scanned radially from the outside to the centre of the nipple. RESULTS: The numbers of lesions reported by the two examiners were 89 and 99, respectively, using the ABVS (not statistically significant), compared with 60 and 85, respectively, using hand-held ultrasonography (statistically significant). CONCLUSIONS: The ABVS system is an operator-independent method for automated breast scanning. It detected more breast lesions and provided additional information for the diagnosis of intraductal and malignant lesions compared with hand-held ultrasonography. PMID- 22429370 TI - Decreased CD27 on B lymphocytes in patients with primary hepatocellular carcinoma. AB - OBJECTIVES: Hepatitis B virus (HBV) replicates in the liver and can lead to hepatocellular carcinoma (HCC). The B lymphocytes may provide a means for HBV to persist although the mechanism remains unknown. This study aimed to characterize B lymphocyte subset phenotypes and measure levels of B lymphocyte-related cytokines in HCC patients. METHODS: The study population included 38 HCC patients and 30 healthy control subjects. Phenotyping of B lymphocytes was performed by flow cytometry. Serum cytokine levels were measured using a cytometric bead array immunoassay. RESULTS: The ratio of naive (CD29+CD27-) to memory (CD19+CD27+) B lymphocytes was significantly higher in HCC patients compared with healthy controls. The percentage of memory B lymphocytes decreased with the progression of HCC. Levels of interleukin (IL)-6 and IL-10 were significantly increased in HCC patients compared with healthy controls. CONCLUSIONS: The depletion of memory B lymphocytes may contribute to unresponsiveness to HBV or to HCC. This humoral defect might be related to raised production of IL-6 and IL-10. PMID- 22429371 TI - Mesenchymal stem cells modified to express interferon-beta inhibit the growth of prostate cancer in a mouse model. AB - OBJECTIVE: This study investigated use of mesenchymal stem cells (MSCs) genetically engineered to produce interferon-beta (IFN-beta) as a gene delivery system to treat prostate cancer in an animal model. METHODS: To measure the effects on tumour cell growth in vitro, IFN-beta-producing MSCs (IFN-beta-MSCs) were co-cultured with the prostate cancer cell line PC-3. The in vivo migration of intravenously injected fluorescently-labelled MSCs to healthy tissues and PC-3 xenograft tumours grown in immuno-deficient mice was determined by fluorescence microscopy. The antitumour effects of intravenously injected IFN-beta-MSCs on PC 3 xenograft growth and animal survival were also investigated. RESULTS: IFN-beta MSCs inhibited the growth of PC-3 cells in vitro. Fluorescently-labelled MSCs migrated to the margins and centre of tumour masses but not into healthy tissues. Intravenously injected IFN-beta-MSCs significantly reduced PC-3 xenograft tumour weight and increased animal survival compared with controls. CONCLUSIONS: Intravenously injected IFN-beta-MSCs inhibited PC-3 xenograft growth. This could be an effective gene delivery system for treatment of solid human tumours. PMID- 22429372 TI - Evaluation of biventricular myocardial performance index in patients with Behcet's disease. AB - OBJECTIVE: The global function of both left ventricular (LV) and right ventricular (RV) functions were compared in patients with Behcet's disease (BD) versus healthy controls. METHODS: Biventricular function was evaluated by measurement of the myocardial performance index (MPI) evaluated from tissue Doppler echocardiographic measurements in 24 BD patients and was compared with measurements in 24 age- and sex-matched healthy controls. RESULTS: Significantly higher MPI values were associated with ventricular dysfunction. The study demonstrated impaired RV function in patients with BD compared with healthy controls, whereas normal LV function was observed both in patients with BD and in healthy controls. CONCLUSION: Early noninvasive evaluation of the properties of BD during the asymptomatic phase of this inflammatory disease may have prognostic value in the management of patients. PMID- 22429373 TI - Reduction of postoperative haemorrhage with the use of a haemostatic thrombin matrix in patients who underwent decortication. AB - OBJECTIVE: To assess the efficacy of two measures for the control of postoperative haemorrhage in patients with fibrothoracic disease secondary to symptomatic extraparenchymal restrictive disease (e.g.empyema, haematoma) undergoing decortication. METHODS: This randomized, prospective study was performed in 50 adult patients with fibrothoracic disease secondary to symptomatic extraparenchymal restrictive disease who were scheduled to undergo decortication. Patients were randomized to receive either electrocautery plus hot compressor application or a thrombin-added haemostatic matrix (THM) for intraoperative haemostasis (n=25 per group). Control of postoperative haemorrhage was compared between groups by evaluation of pre- and postoperative blood characteristics and mean postoperative drainage volume and blood transfusion requirements. RESULTS: Mean postoperative drainage and blood transfusion volumes were significantly lower in the THM group versus the electrocautery plus hot compress group. There was no difference in preoperative and postoperative blood tests in the THM group, whereas significant differences were observed in the electrocautery plus hot compress group. There were no infections, systemic allergies or sensitization, or reoperations in either group. CONCLUSIONS: Compared with electro cautery plus hot compress, the use of a THM significantly reduced postoperative haemorrhage and blood transfusion requirements in patients who underwent decortication. PMID- 22429374 TI - Asymmetric dimethylarginine: a novel cardiovascular risk factor in end-stage renal disease. AB - OBJECTIVE: This cross-sectional study explored the association between carotid intima-media thickness (CIMT) and the oxidative stress markers asymmetric dimethylarginine (ADMA) and homo cysteine in patients with end-stage renal disease who were on haemodialysis. METHODS: A total of 30 patients undergoing chronic haemodialysis treatment were recruited to this study. Homocysteine and ADMA levels were determined using a fluorescence polarization immunoassay and an enzyme-linked immunosorbent assay, respectively. CIMT was measured as a marker of atherosclerosis using high-resolution ultrasonography and was performed after haemodialysis. RESULTS: Significant positive correlations were found between CIMT and ADMA, and CIMT and duration of haemodialysis. Linear regression analysis showed that ADMA level and age were significant independent determinants of CIMT, whereas homo cysteine was not. CONCLUSIONS: The relationship demonstrated between plasma ADMA and carotid artery thickening suggests that ADMA may be a novel marker of atherosclerosis in patients on haemodialysis. PMID- 22429375 TI - Correlation between thyroid nodule calcification morphology on ultrasound and thyroid carcinoma. AB - OBJECTIVE: This study investigated the detection of thyroid nodule calcifications on ultrasound and their relationship to thyroid carcinoma. METHODS: Microcalcifications (<=2 mm) and macro calcifications (>2 mm) on preoperative ultrasound examination of thyroid and lymph nodes were compared with postoperative pathological diagnoses in 4186 patients undergoing thyroid surgery. RESULTS: Higher incidences of micro- and macrocalcifications were found in patients with thyroid carcinoma than in those with benign disease. The incidence of malignant disease was significantly higher in patients with microcalcifications than those with macrocalcifications, suggesting that the presence of microcalcifications is a better predictor of malignant thyroid carcinoma than other calcification types. The specificity of microcalcifications for a diagnosis of malignant thyroid carcinoma was 96.5%. Microcalcifications were significantly more frequent in patients aged<=45 years, but there was no difference between genders. The incidence of malignancy was significantly higher in patients with single nodule calcifications than in those with multiple nodule calcifications. Lymph node calcifications were seen in 12 patients, all of whom had papillary carcinoma. CONCLUSIONS: Thyroid microcalcifications are strongly associated with thyroid carcinoma, especially micropapillary carcinoma. When cervical lymph node calcification is present, immediate surgery is required. PMID- 22429376 TI - The effects of surgery type and duration of tourniquet inflation on body temperature. AB - OBJECTIVE: To identify factors related to the decrease in core body temperature after deflation of a pneumatic tourniquet during unilateral knee surgery under general anaesthesia. METHODS: This observational study recruited 30 patients scheduled for arthroscopic surgery (group A) and 30 patients scheduled for open surgery (group O). Intraoperative oesophageal temperature was measured during tourniquet inflation and every minute for 10 min after deflation. RESULTS: Core temperature decreased significantly after tourniquet deflation in both groups, the decrease being significantly greater in group A than in group O. Duration of tourniquet inflation and type of surgery were correlated with the temperature decrease. CONCLUSIONS: In knee surgery using a tourniquet, the decrease in core body temperature after tourniquet deflation was closely related to the duration of tourniquet inflation and to arthroscopic rather than open surgery. Further studies are required to determine the effect of surgery type on temperature changes, independently of the duration of tourniquet inflation. PMID- 22429377 TI - Could vital signs predict carbon monoxide intoxication? AB - OBJECTIVE: This retrospective study examined the correlation between carboxy haemoglobin (COHb) levels and vital signs in patients with carbon monoxide (CO) intoxication. METHODS: Over a 10-year period, patients>16 years of age who presented to the emergency department due to CO intoxication were included. Age, gender, comorbidities, month/year of presentation, presenting symptoms, vital signs, blood pH, COHb level, treatment and outcome were recorded. RESULTS: In total, 476 patients were included. The mean+/-SD age was 36.22+/-13.65 years; 96.4% of the patients had a normal Glasgow Coma Scale score, 91.0% had normal blood pressure and 80.0% had a normal heart rate. COHb levels were stratified into three groups: <10% (n=39), 10-20% (n=106) and >20% (n=205); levels could not be obtained in the remaining 126 patients. In patients with COHb levels>20%, 34 (16.6%) had alkalosis and nine (4.4%) had acidosis. Among patients with COHb levels>20%, 140 (68.3%) had normal vital signs. CONCLUSIONS: Vital signs cannot be used as a prognostic marker of CO intoxication and, therefore, patients must be monitored closely. PMID- 22429378 TI - Prognostic value of a mitochondrial functional score in prostate cancer. AB - OBJECTIVE: To evaluate the utility of a mitochondrial functional score in predicting the progress of prostate cancer. METHODS: This retrospective study included 72 patients (mean age 70.1 years) with prostate cancer who were treated by radical prostatectomy between October 2006 and March 2007. The epithelioglandular mitochondrial functional scores were assessed according to the Flameng grading. Patients were divided into six groups (groups 1-6) according to their Gleason score (Gleason score 2-7, respectively). The correlation between Gleason score and mitochondrial functional score was examined using Pearson's correlation coefficient. RESULTS: The mean mitochondrial functional score was significantly lower in group 6 compared with group 1. An inverse correlation was found between the Gleason and mitochondrial functional scores. At 1 year, significantly fewer patients in group 1 had died (0/15 patients) than in group 6 (2/10 patients); the deaths were cancer-related. CONCLUSIONS: Mitochondrial dysfunction exists in patients with prostate cancer, particularly in cases with a higher degree of malignancy. The mitochondrial functional score, combined with the Gleason score, is beneficial for predicting the progress of prostate cancer. PMID- 22429379 TI - HLA-B*1502 allele is associated with a cross-reactivity pattern of cutaneous adverse reactions to antiepileptic drugs. AB - The US Food and Drug Administration has recommended genetic screening for the human leucocyte antigen-B (HLA-B)*1502 allele in patients of Asian ethnicity before starting carbamazepine therapy, to avoid the fatal adverse treatment related events associated with this drug. The association between cross reactivity to antiepileptic drugs (AEDs) and the HLA-B*1502 allele has been only rarely reported. Here, two cases of cross-reactivity to AEDs, where cutaneous adverse drug reactions (cADRs) developed in female Han Chinese patients with epilepsy who tested positive for the HLA-B*1502 allele, are described. If the genetic association could be confirmed in larger studies, the HLA-B*1502 allele should be tested for in any patient experiencing cADRs, to avoid crossreactivity to AEDs. PMID- 22429380 TI - Wegener's granulomatosis with pulmonary fungal infection: a case report and brief review. AB - Wegener's granulomatosis (WG) is an autoimmune, necrotizing granulomatous disease of unknown aetiology that affects small and medium blood vessels, and is usually recurrent. Infection is the most frequent cause of death in patients with WG. A case of WG with pulmonary fungal infection in a 50-year-old man is reported. The patient was hospitalized following a 2-month history of haemoptysis and a 1-month history of intermittent fever. Examination and pathology results confirmed a diagnosis of WG with associated pulmonary fungal infection. The patient's condition was complicated by a septic pneumothorax and sinus formation after lung biopsy, and preexisting diabetes and hypertension, which worsened rapidly due to his critical condition. He was treated with glucocorticoids and cyclophosphamide therapy with the goal of controlling these complications, and had no recurrence within the 4-year follow-up period. This case demonstrated the utility of combined glucocorticoid and cyclophosphamide therapy for the treatment of infection in WG. PMID- 22429381 TI - Imprisonment-associated sperm clumping and male infertility. AB - OBJECTIVE: This observational, retrospective study investigated infertility among Iraqi men who had been long-term prisoners of war. METHODS: Routine seminal fluid analyses were undertaken in former prisoners with suspected infertility attending the Ramadi Infertility Clinic, Ramadi, Iraq; semen samples were also microscopically evaluated in these patients. RESULTS: In 16 out of 38 patients (42%), male infertility was found to be associated with the formation of unusually large clumps of sperm. These sperm clumps contained large numbers of sperm; clumping led to sperm immobilization and infertility. CONCLUSIONS: The causes of sperm clumping are unclear. It is possible that the sperm clumping observed in the present study might be a result of developmental defects, possibly related to stress or other undiscovered factors, although this requires further investigation. PMID- 22429382 TI - Predictive-focus illumination for reducing photodamage in live-cell microscopy. AB - Due to photobleaching and phototoxicity induced by high-intensity excitation light, the number of fluorescence images that can be obtained in live cells is always limited. This limitation becomes particularly prominent in multidimensional recordings when multiple Z-planes are captured at every time point. Here we present a simple technique, termed predictive-focus illumination (PFI), which helps to minimize cells' exposure to light by decreasing the number of Z-planes that need to be captured in live-cell 3D time-lapse recordings. PFI utilizes computer tracking to predict positions of objects of interest (OOIs) and restricts image acquisition to small dynamic Z-regions centred on each OOI. Importantly, PFI does not require hardware modifications and it can be easily implemented on standard wide-field and spinning-disc confocal microscopes. PMID- 22429383 TI - Comparison of haemoglobin F detection by the acid elution test, flow cytometry and high-performance liquid chromatography in maternal blood samples analysed for fetomaternal haemorrhage. AB - BACKGROUND AND OBJECTIVE: All pregnant women undergoing blood grouping at Southmead Hospital are offered haemoglobinopathy screening by high-performance liquid chromatography (HPLC). RhD-negative women who deliver RhD-positive infants are tested for fetomaternal haemorrhage (FMH) by acid elution (AE). The effectiveness of these two assays for quantitation of FMH was compared with flow cytometry (FC). MATERIALS AND METHODS: The relationship between expression of haemoglobin F (HbF) in individual cells by AE and FC and quantitation of HbF in haemolysates by HPLC was investigated, using maternal samples with unusually high levels of HbF-positive maternal cells (F cells) or with large FMH (fetal cells). Standard anti-D FC was performed to quantitate fetal D-positive cells in D negative women and compared with FMH estimated by AE and HbF FC. RESULTS: AE overestimated FMH when maternal F cells were increased. HbF FC distinguished F cells from fetal cells. Values of HbF determined by HPLC were less than the level of 5% used for investigation of raised fetal haemoglobin, even in the maternal samples with elevated F cells or massive FMH. CONCLUSIONS: To quantitate FMH, measurement of HbF using FC was more sensitive and accurate than AE or HPLC. HbF FC is the method of choice when results from routine investigation using AE or standard anti-D FC are discrepant or when there is maternal and fetal RhD compatibility. PMID- 22429384 TI - Decision aids for respite service choices by carers of people with dementia: development and pilot RCT. AB - BACKGROUND: Decision aids are often used to assist individuals confronted with a diagnosis of a serious illness to make decisions about treatment options. However, they are rarely utilised to help those with chronic or age related conditions to make decisions about care services. Decision aids should also be useful for carers of people with decreased decisional capacity. These carers' choices must balance health outcomes for themselves and for salient others with relational and value-based concerns, while relying on information from health professionals. This paper reports on a study that both developed and pilot tested a decision aid aimed at assisting carers to make evaluative judgements of community services, particularly respite care. METHODS: A mixed method sequential study, involving qualitative development and a pilot randomised controlled trial, was conducted in Tasmania, Australia. We undertook 13 semi-structured interviews and three focus groups to inform the development of the decision aid. For the randomised control trial we randomly assigned 31 carers of people with dementia to either receive the service decision aid at the start or end of the study. The primary outcome was measured by comparing the difference in carer burden between the two groups three months after the intervention group received the decision aid. Pilot data was collected from carers using interviewer-administered questionnaires at the commencement of the project, two weeks and 12 weeks later. RESULTS: The qualitative data strongly suggest that the intervention provides carers with needed decision support. Most carers felt that the decision aid was useful. The trial data demonstrated that, using the mean change between baseline and three month follow-up, the intervention group had less increase in burden, a decrease in decisional conflict and increased knowledge compared to control group participants. CONCLUSIONS: While these results must be interpreted with caution due to the small sample size, all intervention results trend in a direction that is beneficial for carers and their decisional ability. Mixed method data suggest the decision aid provides decisional support that carers do not otherwise receive. Decision aids may prove useful in a community health services context. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN32163031. PMID- 22429385 TI - Cataract surgery in West Africa: is couching still a choice? PMID- 22429386 TI - Microvascular flow modeling using in vivo hemodynamic measurements in reconstructed 3D capillary networks. AB - OBJECTIVE: We describe a systematic approach to modeling blood flow using reconstructed capillary networks and in vivo hemodynamic measurements. Our goal was to produce flow solutions that represent convective O(2) delivery in vivo. METHODS: Two capillary networks, I and II (84 * 168 * 342 and 70 * 157 * 268 MUm(3)), were mapped using custom software. Total network red blood cell supply rate (SR) was calculated from in vivo data and used as a target metric for the flow model. To obtain inlet hematocrits, mass balances were applied recursively from downstream vessels. Pressure differences across the networks were adjusted to achieve target SR. Baseline flow solutions were used as inputs to existing O(2) transport models. To test the impact of flow redistribution, asymmetric flow solutions (Asym) were generated by applying a +/- 20% pressure change to network outlets. RESULTS: Asym solutions produced a mean absolute difference in SR per capillary of 27.6 +/- 33.3% in network I and 33.2 +/- 40.1% in network II vs. baseline. The O(2) transport model calculated mean tissue PO(2) of 28.2 +/- 4.8 and 28.1 +/- 3.5 mmHg for baseline and 27.6 +/- 5.2 and 27.7 +/- 3.7 mmHg for Asym. CONCLUSIONS: This outcome illustrates that moderate changes in flow distribution within a capillary network have little impact on tissue PO(2) provided that total SR remains unchanged. PMID- 22429387 TI - Reliability and failure modes of internal conical dental implant connections. AB - OBJECTIVE: Biological and mechanical implant-abutment connection complications and failures are still present in clinical practice, frequently compromising oral function. The purpose of this study was to evaluate the reliability and failure modes of anterior single-unit restorations in internal conical interface (ICI) implants using step-stress accelerated life testing (SSALT). MATERIALS AND METHODS: Forty-two ICI implants were distributed in two groups (n = 21 each): group AT-OsseoSpeed(TM) TX (Astra Tech, Waltham, MA, USA); group SV-Duocon System Line, Morse Taper (Signo Vinces Ltda., Campo Largo, PR, Brazil). The corresponding abutments were screwed to the implants and standardized maxillary central incisor metal crowns were cemented and subjected to SSALT in water. Use level probability Weibull curves and reliability for a mission of 50,000 cycles at 200 N were calculated. Differences between groups were assessed by Kruskal Wallis along with Bonferroni's post-hoc tests. Polarized-light and scanning electron microscopes were used for failure analyses. RESULTS: The Beta (beta) value derived from use level probability Weibull calculation was 1.62 (1.01-2.58) for group AT and 2.56 (1.76-3.74) for group SV, indicating that fatigue was an accelerating factor for failure of both groups. The reliability for group AT was 0.95 and for group SV was 0.88. Kruskal-Wallis along with Bonferroni's post-hoc tests showed no significant difference between the groups tested (P > 0.27). In all specimens of both groups, the chief failure mode was abutment fracture at the conical joint region and screw fracture at neck's region. CONCLUSIONS: Reliability was not different between investigated ICI connections supporting maxillary incisor crowns. Failure modes were similar. PMID- 22429388 TI - The relationship of major depressive disorder and gender to changes in smoking for current and former smokers: longitudinal evaluation in the US population. AB - AIMS: Although depression and smoking are correlated highly, the relationship of major depressive disorder (MDD) to smoking cessation and relapse remains unclear. This study compared changes in smoking for current and former smokers with and without current and life-time MDD over a 3-year period. DESIGN: Analysis of two waves of longitudinal data from the National Institute on Alcohol Abuse and Alcoholism's National Epidemiologic Survey on Alcohol and Related Conditions (wave 1, 2001-02; wave 2, 2004-05). SETTING: Data were collected through face-to face interviews from non-institutionalized United States civilians, aged 18 years and older, in 50 states and the District of Columbia. PARTICIPANTS: A total of 11 973 adults (54% male) classified as current or former daily smokers at wave 1 and completed wave 2. MEASUREMENTS: Classification as current or former smokers at wave 1 and wave 2. FINDINGS: Smoking status remained stable for most participants. Wave 1 current daily smokers with current MDD [odds ratio (OR) = 1.38, 95% confidence interval (CI): 1.03, 1.85] and life-time MDD (OR = 1.52, 95% CI: 1.15, 2.01) were more likely than those without the respective diagnosis to report continued smoking at wave 2. Wave 1 former daily smokers with current MDD (OR = 0.44, 95% CI: 0.26, 0.76) were less likely to report continued abstinence at wave 2. None of the gender * MDD diagnosis interactions were significant. Patterns of results remained similar when analyses were limited to smokers with nicotine dependence. CONCLUSIONS: Current and life-time major depressive disorders are associated with a lower likelihood of quitting smoking and current major depressive disorder is associated with greater likelihood of smoking relapse. PMID- 22429389 TI - Is conjunctival mucous involvement a marker of severity in pemphigus vulgaris? PMID- 22429390 TI - The future of trauma care. PMID- 22429391 TI - Identification at the species and symbiovar levels of strains nodulating Phaseolus vulgaris in saline soils of the Marrakech region (Morocco) and analysis of the otsA gene putatively involved in osmotolerance. AB - Salinity is an increasing problem in Africa affecting rhizobia-legume symbioses. In Morocco, Phaseolus vulgaris is cultivated in saline soils and its symbiosis with rhizobia depends on the presence of osmotolerant strains in these soils. In this study, 32 osmotolerant rhizobial strains nodulating P. vulgaris were identified at the species and symbiovar levels by analysing core and symbiotic genes, respectively. The most abundant strains were closely related to Rhizobium etli and R. phaseoli and belonged to symbiovar phaseoli. A second group of strains was identified as R. gallicum sv gallicum. The remaining strains, identified as R. tropici, belonged to the CIAT 899(T) nodC group, which has not yet been described as a symbiovar. In representative strains, the otsA gene involved in the accumulation of trehalose and putatively in osmotolerance was analysed. The results showed that the phylogeny of this gene was not completely congruent with those of other core genes, since the genus Ensifer was more closely related to some Rhizobium species than others. Although the role of the otsA gene in osmotolerance is not well established, it can be a useful protein coding gene for phylogenetic studies in the genus Rhizobium, since the phylogenies of otsA and other core genes are coincident at the species level. PMID- 22429392 TI - Ceramide profiles in the brain of rats with diabetes induced by streptozotocin. AB - Diabetes is associated with disturbances of brain activity and cognitive impairment. We hypothesize that ceramides may constitute an important contribution to diabetes-linked neuro-dysfunction. In our study we used rats injected with streptozotocin (STZ) as a model of severe hyperglycemia. Using the gas-liquid chromatography technique we found a significant increase of ceramide content in brains and a decrease in plasma of diabetic rats. The inhibitor of serine palmitoyltransferase, myriocin, reduced ceramide generation in hyperglycemic brains, although injected alone it exerted a paradoxical effect of ceramide upregulation. Myriocin had no impact on ceramide concentration in the plasma of either control or diabetic rats. The level of ceramide saturated fatty acids was elevated whereas the level of ceramide poly-unsaturated fatty acids was downregulated in brains of all experimental groups. The concentration of ceramide mono-unsaturated fatty acids remained unchanged. The pattern of individual ceramide species was altered depending on treatment. We noted an STZ-evoked increase of brain ceramide C16:0, C18:0 and C20:0 and a strong decline in ceramide C18:2 fatty acid levels. Some changes of brain ceramide pattern were modified by myriocin. We found a decreased amount of total ceramide-omega-6 fatty acids in STZ-treated rat brains and no changes in ceramide-omega-3 concentration. We conclude that ceramides may be important mediators of diabetes-accompanied brain dysfunction. PMID- 22429393 TI - Pulmonary langerhans cell histiocytosis. AB - Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic hallmark of PLCH is the accumulation of Langerhans and other inflammatory cells in small airways, resulting in the formation of nodular inflammatory lesions. While the overwhelming majority of patients are smokers, mechanisms by which smoking induces this disease are not known, but likely involve a combination of events resulting in enhanced recruitment and activation of Langerhans cells in small airways. Bronchiolar inflammation may be accompanied by variable lung interstitial and vascular involvement. While cellular inflammation is prominent in early disease, more advanced stages are characterized by cystic lung destruction, cicatricial scarring of airways, and pulmonary vascular remodeling. Pulmonary function is frequently abnormal at presentation. Imaging of the chest with high resolution chest CT scanning may show characteristic nodular and cystic abnormalities. Lung biopsy is necessary for a definitive diagnosis, although may not be required in instances were imaging findings are highly characteristic. There is no general consensus regarding the role of immunosuppressive therapy in smokers with PLCH. All smokers must be counseled on the importance of smoking cessation, which may result in regression of disease and obviate the need for systemic immunosuppressive therapy. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Complications like pneumothoraces and secondary pulmonary hypertension may shorten life expectancy. Patients with progressive disease may require lung transplantation. PMID- 22429395 TI - Randomized trial of short-course high-dose erythropoietin in donation after cardiac death kidney transplant recipients. AB - Eryhropoiesis-stimulating agents have demonstrated tissue-protective effects in experimental models of ischemia-reperfusion injury. PROTECT was a 12-month, randomized, double-blind, placebo-controlled, single center study with high-dose recombinant human erythropoietin-beta (Epoetin) in 92 donation after cardiac death (DCD) kidney transplant recipients. Patients were randomized to receive an intravenous bolus of Epoetin (3.3 * 10(4) international unit (IU); n = 45) or placebo (saline 0.9% solution; n = 47) on 3 consecutive days, starting 3-4 h before the transplantation and 24 h and 48 h after reperfusion. The immunosuppressive regimen included an anti-CD25 antibody, steroids, mycophenolate mofetil and delayed introduction of cyclosporine. Primary end point was a composite of the incidence of primary nonfunction and delayed graft function, either defined by spontaneous functional recovery or need for dialysis in the first week. Secondary objectives included duration of delayed function, renal function and proteinuria up to 1 year and thrombotic adverse events. Results showed no differences in the incidence or duration of delayed graft function and/or primary nonfunction (Epoetin 77.8 vs. placebo 78.7%, p = 1.00). Epoetin treatment significantly increased the risk of thrombotic events at 1 month and 1 year (Epoetin 24.4% vs. placebo 6.4%, p = 0.02). PMID- 22429394 TI - Identification of functionally active aerobic methanotrophs in sediments from an arctic lake using stable isotope probing. AB - Arctic lakes are a significant source of the greenhouse gas methane (CH(4) ), but the role that methane oxidizing bacteria (methanotrophs) play in limiting the overall CH(4) flux is poorly understood. Here, we used stable isotope probing (SIP) techniques to identify the metabolically active aerobic methanotrophs in upper sediments (0-1 cm) from an arctic lake in northern Alaska sampled during ice-free summer conditions. The highest CH(4) oxidation potential was observed in the upper sediment (0-1 cm depth) with 1.59 umol g wet weight(-1) day(-1) compared with the deeper sediment samples (1-3 cm, 3-5 cm and 5-10 cm), which exhibited CH(4) oxidation potentials below 0.4 umol g wet weight(-1) day(-1) . Both type I and type II methanotrophs were directly detected in the upper sediment total communities using targeted primer sets based on 16S rRNA genes. Sequencing of 16S rRNA genes and functional genes (pmoA and mxaF) in the (13) C DNA from the upper sediment indicated that type I methanotrophs, mainly Methylobacter, Methylosoma, Methylomonas and Methylovulum miyakonense, dominated the assimilation of CH(4) . Methylotrophs, including the genera Methylophilus and/or Methylotenera, were also abundant in the (13) C-DNA. Our results show that a diverse microbial consortium acquired carbon from CH(4) in the sediments of this arctic lake. PMID- 22429396 TI - Persistent sexual dysfunction and 5 alpha reductase inhibitors. PMID- 22429397 TI - Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells. AB - INTRODUCTION: Acquisition of mesenchymal characteristics confers to breast cancer (BC) cells the capability of invading tissues different from primary tumor site, allowing cell migration and metastasis. Regulators of the mesenchymal-epithelial transition (MET) may represent targets for anticancer agents. Accruing evidence supports functional implications of choline phospholipid metabolism in oncogene activated cell signaling and differentiation. We investigated the effects of D609, a xanthate inhibiting phosphatidylcholine-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS), as a candidate regulator of cell differentiation and MET in the highly metastatic BC cell line MDA-MB-231. METHODS: PC-PLC expression and activity were investigated using confocal laser scanning microscopy (CLSM), immunoblotting and enzymatic assay on human MDA-MB 231 compared with MCF-7 and SKBr3 BC cells and a nontumoral immortalized counterpart (MCF-10A). The effects of D609 on PC-PLC and SMS activity, loss of mesenchymal markers and changes in migration and invasion potential were monitored in MDA-MB-231 cells by enzymatic assays, CLSM, immunoblotting and transwell chamber invasion combined with scanning electron microscopy examinations. Cell proliferation, formation and composition of lipid bodies and cell morphology were investigated in D609-treated BC cells by cell count, CLSM, flow-cytometry of BODIPY-stained cells, nuclear magnetic resonance and thin-layer chromatography. RESULTS: PC-PLC (but not phospholipase D) showed 2- to 6-fold activation in BC compared with nontumoral cells, the highest activity (up to 0.4 pmol/MUg protein/min) being detected in the poorly-differentiated MDA-MB-231 cells. Exposure of the latter cells to D609 (50 MUg/mL, 24-72 h) resulted into 60 80% PC-PLC inhibition, while SMS was transiently inhibited by a maximum of 21%. These features were associated with progressive decreases of mesenchymal traits such as vimentin and N-cadherin expression, reduced galectin-3 and milk fat globule EGF-factor 8 levels, beta-casein formation and decreased in vitro cell migration and invasion. Moreover, proliferation arrest, changes in cell morphology and formation of cytosolic lipid bodies typical of cell differentiation were induced by D609 in all investigated BC cells. CONCLUSIONS: These results support a critical involvement of PC-PLC in controlling molecular pathways responsible for maintaining a mesenchymal-like phenotype in metastatic BC cells and suggests PC-PLC deactivation as a means to promote BC cell differentiation and possibly enhance the effectiveness of antitumor treatments. PMID- 22429398 TI - Use of a public telephone hotline to detect urban plague cases. AB - Current methods for vector-borne disease surveillance are limited by time and cost. To avoid human infections from emerging zoonotic diseases, it is important that the United States develop cost-effective surveillance systems for these diseases. This study examines the methodology used in the surveillance of a plague epizootic involving tree squirrels (Sciurus niger) in Denver Colorado, during the summer of 2007. A call-in centre for the public to report dead squirrels was used to direct animal carcass sampling. Staff used these reports to collect squirrel carcasses for the analysis of Yersinia pestis infection. This sampling protocol was analysed at the census tract level using Poisson regression to determine the relationship between higher call volumes in a census tract and the risk of a carcass in that tract testing positive for plague. Over-sampling owing to call volume-directed collection was accounted for by including the number of animals collected as the denominator in the model. The risk of finding an additional plague-positive animal increased as the call volume per census tract increased. The risk in the census tracts with >3 calls a month was significantly higher than that with three or less calls in a month. For tracts with 4-5 calls, the relative risk (RR) of an additional plague-positive carcass was 10.08 (95% CI 5.46-18.61); for tracts with 6-8 calls, the RR = 5.20 (2.93 9.20); for tracts with 9-11 calls, the RR = 12.80 (5.85-28.03) and tracts with >11 calls had RR = 35.41 (18.60-67.40). Overall, the call-in centre directed sampling increased the probability of locating plague-infected carcasses in the known Denver epizootic. Further studies are needed to determine the effectiveness of this methodology at monitoring large-scale zoonotic disease occurrence in the absence of a recognized epizootic. PMID- 22429399 TI - 'What ever I do it's a lost cause.' The emotional and behavioural experiences of individuals who are ulcer free living with the threat of developing further diabetic foot ulcers: a qualitative interview study. AB - OBJECTIVE: Individuals who have had one diabetic foot ulcer (DFU) are at high risk for developing further DFUs. This study was designed to examine the emotional and behavioural consequences of living with this heightened risk of re ulceration. PARTICIPANTS AND SETTING: Fifteen women and men living in south-west England were interviewed at home or at the university by an academic psychologist. DESIGN: Interviews were audiotaped and transcribed verbatim. Thematic analysis using the constant comparative method was employed for data analysis. RESULTS: Participants reported having little perceived control in preventing further DFUs. This lack of control was associated with a range of negative emotions including fears and worries about developing further foot ulcers, amputation and guilt for the past neglect. Tensions were present between participants' beliefs and reported behaviours, that is, what they felt they ought to be doing and what they were actually doing to care for their feet; most engaged in 'strategic adherence', that is, conducting a trade-off between living a normal life and following foot-care advice. CONCLUSION: A lack of perceived control appears central to the emotional and behavioural responses of individuals living with the threat of re-ulceration. We propose that these responses may serve to increase individuals' risk of re-ulceration and that these 'risk factors' should be considered part of the management of this patient group. PMID- 22429400 TI - Characterization of a GH family 3 beta-glycoside hydrolase from Chrysosporium lucknowense and its application to the hydrolysis of beta-glucan and xylan. AB - The Bxl5-gene encoding a GH3 glycoside hydrolase of Chrysosporium lucknowense C1 was successfully cloned, the homologous recombinant product was secreted, purified and characterized. Bxl5 (120 +/- 5 kDa) was able to hydrolyze low molecular weight substrates and polysaccharides containing beta-glucosidic as well as beta-xylosidic residues. The K(m) and V(max)/E values were found to be 0.3mM and 88 s(-1) on p-nitrophenyl-beta-d-glucopyranoside (PNPG), and 13.5mM and 1.8s(-1) on p-nitrophenyl-beta-d-xylopyranoside (PNPX). Optimal pH and temperature for Bxl5 were 4.6 and 75 degrees C for the PNPG hydrolysis, and 5.0 5.5 and 70 degrees C for PNPX hydrolysis. The enzyme was quite stable when incubated at elevated temperatures up to 65 degrees C. Bxl5 hydrolyzes polymeric beta-glucans by the exo-mechanism allowing their complete conversion to d-glucose and is effective for xylan hydrolysis in combination with endo-acting xylan degrading enzymes. The enzyme seems to be a very promising for bioconversion purposes. PMID- 22429401 TI - Conversion of fructose and glucose into 5-hydroxymethylfurfural with lignin derived carbonaceous catalyst under microwave irradiation in dimethyl sulfoxide ionic liquid mixtures. AB - 5-Hydroxymethylfurfural (5-HMF) was successfully produced by the dehydration of fructose and glucose using lignin-derived solid acid catalyst in DMSO-[BMIM][Cl] (dimethyl sulfoxide and 1-butyl-3-methylimidazolium chloride) mixtures. Six solid acid catalysts were synthesized by carbonization and sulfonation of raw biomass materials, i.e., glucose, fructose, cellulose, lignin, bamboo and Jatropha hulls. It was found that lignin-derived solid acid catalyst (LCC) was the most active one in the dehydration of sugars. LCC coupled with microwave irradiation was used for the 5-HMF production, 84% 5-HMF yield with 98% fructose conversion rate was achieved at 110 degrees C for 10 min. Furthermore, 99% glucose was converted with 68% 5-HMF yield under severer condition (160 degrees C for 50 min). LCC was recycled for five times, 5-HMF yield declined only 7%. Use of LCC combined with DMSO-[BMIM][Cl] solution and microwave irradiation is a novel method for the effective production of 5-HMF. PMID- 22429402 TI - Regulation of G protein-coupled receptors by palmitoylation and cholesterol. AB - Due to their membrane location, G protein-coupled receptors (GPCRs) are subject to regulation by soluble and integral membrane proteins as well as membrane components, including lipids and sterols. GPCRs also undergo a variety of post translational modifications, including palmitoylation. A recent article by Zheng et al. in BMC Cell Biology demonstrates cooperative roles for receptor palmitoylation and cholesterol binding in GPCR dimerization and G protein coupling, underlining the complex regulation of these receptors. PMID- 22429403 TI - The mitochondrial alternative oxidase pathway protects the photosynthetic apparatus against photodamage in Rumex K-1 leaves. AB - BACKGROUND: It is known that excess reducing equivalents in the form of NADPH in chloroplasts can be transported via shuttle machineries, such as the malate oxaloacetate (OAA) shuttle, into the mitochondria, where they are efficiently oxidised by the mitochondrial alternative oxidase (AOX) respiratory pathway. Therefore, it has been speculated that the AOX pathway may protect plants from photoinhibition, but the mechanism by which this protection occurs remains to be elucidated. RESULTS: The observation that the malate-OAA shuttle activity and the AOX pathway capacity increased markedly after intense light treatment in Rumex K 1 leaves indicates that excess NADPH was transported from the chloroplasts and oxidised by the AOX pathway. The inhibition of the AOX pathway by salicylhydroxamic acid (SHAM) caused the over-reduction of the photosystem I (PSI) acceptor side, as indicated by the increases in the extent of reduction of P700+. Furthermore, the photosynthetic linear electron flow was restricted, which was indicated by the decreases in the PSII electron transport rate (ETR) and the photosynthetic O2 evolution rate. The restriction of the photosynthetic linear electron flow, which generates the thylakoid DeltapH, inevitably decreased the de epoxidation of the xanthophyll cycle (DeltaPRI). Therefore, the induction of non photochemical quenching (NPQ) was suppressed when the AOX pathway was inhibited. The effect of the inhibition of the AOX pathway on NPQ induction was less at 20 mM NaHCO3 than at 1 mM NaHCO3. The suppression of NPQ induction by the inhibition of the AOX pathway was also observed during the induction phase of photosynthesis. In addition, the inhibition of the AOX pathway increased the accumulation of hydrogen peroxide (H2O2), suggesting that the AOX pathway functions as an antioxidant mechanism. CONCLUSIONS: The inhibition of the AOX pathway resulted in the rapid accumulation of NADPH in the chloroplasts, which caused the over-reduction of the PSI acceptor side. Furthermore, the restriction of the photosynthetic linear electron flow due to the inhibition of the AOX pathway limited the generation of the thylakoid DeltapH and suppressed the induction of NPQ. Therefore, the mitochondrial AOX pathway protected the photosynthetic apparatus against photodamage by alleviating the over-reduction of the PSI acceptor side and accelerating the induction of NPQ in Rumex K-1 leaves. PMID- 22429404 TI - Protocol for the "four steps to control your fatigue (4-STEPS)" randomised controlled trial: a self-regulation based physical activity intervention for patients with unexplained chronic fatigue. AB - BACKGROUND: Unexplained Chronic Fatigue is a medical condition characterized by the presence of persistent, severe and debilitating medically unexplained fatigue, leading to impaired functioning and lower quality of life. Research suggests that physical activity can contribute to the reduction of fatigue and other somatic symptoms and can thus significantly improve physical functioning and quality of life in these patients. Based on the self-regulation (SR) theory of behaviour change, we developed a brief physical activity program for patients suffering from unexplained chronic fatigue which focuses on the training of self regulation skills, the "4-STEPS to control your fatigue" program. METHODS/DESIGN: This is a multi-centre, randomised controlled trial (RCT) that will be carried out in local primary care centres and at the Portuguese Fibromyalgia and Chronic Fatigue Syndrome Patients Association. Patients aged between 18 and 65 and fulfilling operationalized criteria for Idiopathic Chronic Fatigue (ICF) and Chronic Fatigue Syndrome (CFS) will be recruited and randomly allocated to standard care (SC) or standard care plus a self-regulation based physical activity program (4-STEPS). Patients will be assessed at baseline, after the intervention (3 months) and at 12 months follow-up. The primary outcome is fatigue severity. DISCUSSION: The results of the RCT will provide information about the effectiveness of a brief self-regulation intervention for promoting physical activity in patients with unexplained chronic fatigue. If the program proves to be effective, it may be considered as an adjunctive treatment for these patients. TRIAL REGISTRATION: ISRCTN: ISRCTN70763996. PMID- 22429405 TI - Automatic cell counting in vivo in the larval nervous system of Drosophila. AB - Identification and counting of cells is necessary to test biological hypotheses, for instance of nervous system formation, disease, degeneration, injury and regeneration, but manual counting is time consuming, tedious, and subject to bias. The fruit fly Drosophila is a widely used model organism to analyse gene function, and most research is carried out in the intact animal or in whole organs, rather than in cell culture. Inferences on gene function require that cell counts are known from these sample types. Image processing and pattern recognition techniques are appropriate tools to automate cell counting. However, counting cells in Drosophila is a complex task: variations in immunohistochemical markers and developmental stages result in images of very different properties, rendering it challenging to identify true cells. Here, we present a technique for counting automatically larval glial cells in three dimensions, from confocal microscopy serial optical sections. Local outlier thresholding and domes are combined to find the cells. Shape descriptors extracted from a data set are used to characterize cells and avoid oversegmentation. Morphological operators are employed to divide cells that could otherwise be missed. The method is accurate and very fast, and treats all samples equally and objectively, rendering all data comparable across specimens. Our method is also applicable to identify cells labelled with other nuclear markers and in sections of mouse tissues. PMID- 22429406 TI - Commentary on Keidan 2012: routine antenatal anti-D prophylaxis - is the protection adequate? PMID- 22429407 TI - Integrating a health-related-quality-of-life module within electronic health records: a comparative case study assessing value added. AB - BACKGROUND: Health information technology (HIT) applications that incorporate point-of-care use of health-related quality of life (HRQL) assessments are believed to promote patient-centered interactions between seriously ill patients and physicians. However, it is unclear how willing primary care providers are to use such HRQL HIT applications. The specific aim of this study was to explore factors that providers consider when assessing the value added of an HRQL application for their geriatric patients. METHODS: Three case studies were developed using the following data sources: baseline surveys with providers and staff, observations of staff and patients, audio recordings of patient-provider interactions, and semi-structured interviews with providers and staff. RESULTS: The primary factors providers considered when assessing value added were whether the HRQL information from the module was (1) duplicative of information gathered via other means during the encounter; (2) specific enough to be useful and/or acted upon, and; (3) useful for enough patients to warrant time spent reviewing it for all geriatric patients. Secondary considerations included level of integration of the HRQL and EHR, impact on nursing workflow, and patient reluctance to provide HRQL information. CONCLUSIONS: Health-related quality of life modules within electronic health record systems offer the potential benefit of improving patient centeredness and quality of care. However, the modules must provide benefits that are substantial and prominent in order for physicians to decide that they are worthwhile and sustainable. Implications of this study for future research include the identification of perceived "costs" as well as a foundation for operationalizing the concept of "usefulness" in the context of such modules. Finally, developers of these modules may need to make their products customizable for practices to account for variation in EHR capabilities and practice workflows. PMID- 22429408 TI - Editor's briefing. PMID- 22429409 TI - Competition and integration: the NHS Future Forum's confused consensus. PMID- 22429410 TI - Calling time on the 10-minute consultation. PMID- 22429411 TI - Genetic advances in medicine: has the promise been fulfilled in general practice? PMID- 22429413 TI - Obesity and chronic disease in younger people. PMID- 22429414 TI - How to afford a just health service. PMID- 22429415 TI - Predictive effect of heartburn and indigestion and risk of upper gastro intestinal malignancy. PMID- 22429416 TI - Is healthy eating for obese children necessarily more costly for families? PMID- 22429417 TI - Thirty-minute compared to standardised office blood pressure measurement in general practice. PMID- 22429418 TI - Tips for GP trainees working in general medicine. PMID- 22429419 TI - Waterpipe tobacco smoking and cigarette equivalence. PMID- 22429420 TI - A new meaning for 'going Dutch'. PMID- 22429421 TI - Touch in the consultation. PMID- 22429422 TI - Word cloud analysis of the BJGP. PMID- 22429423 TI - A day in the life. PMID- 22429424 TI - Clinicians' perceptions of reporting methods for back pain trials: a qualitative study. AB - BACKGROUND: How outcomes of clinical trials are reported alters the way treatment effectiveness is perceived: clinicians interpret the outcomes of trials more favourably when results are presented in relative (such as risk ratio) rather than absolute terms (such as risk reduction). However, it is unclear which methods clinicians find easiest to interpret and use in decision making. AIM: To explore which methods for reporting back pain trials clinicians find clearest and most interpretable and useful to decision making. DESIGN AND SETTING: Indepth interviews with clinicians at clinical practices/research centre. METHOD: Clinicians were purposively sampled by professional discipline, sex, age, and practice setting. They were presented with several different summaries of the results of the same hypothetical trial. Each summary used a different reporting method, and the study explored participants' preferences for each method and how they would like to see future trials reported. RESULTS: The 14 clinicians interviewed (comprising GPs, manual therapists, psychologists, a rheumatologist, and surgeons) stated that clinical trial reports were not written with them in mind. They were familiar with mean differences, proportion improved, and numbers needed to treat (NNT), but unfamiliar with standardised mean differences, odds ratios, and relative risks (RRs). They found the proportion improved, RR, and NNT most intuitively understandable, and thought reporting between-group mean differences, RRs, and odds ratios could mislead. CONCLUSION: Clinicians stated that additional reporting methods facilitate the interpretation of trial results, and using a variety of methods would make results easier to interpret in context and incorporate into practice. Authors of future back pain trials should report data in a format that is accessible to clinicians. PMID- 22429426 TI - The training capacity of general practice revisited: advanced training practices. PMID- 22429430 TI - Making an impact: research, publications, and bibliometrics in the BJGP. PMID- 22429431 TI - Power and powerlessness: GPs' narratives about lifestyle counselling. AB - BACKGROUND: Power in doctor-patient relationships is asymmetrically distributed. The doctor holds resources the patient needs and has a mandate to promote healthy living. Power may benefit or harm the patients' health, and the doctor-patient relationship. AIM: To identify aspects of power and powerlessness in GPs' narratives about lifestyle counselling. DESIGN AND SETTING: A qualitative study using focus groups from peer-group meetings of Norwegian GPs attending continuing medical education. METHOD: GPs discussed case stories about lifestyle counselling in focus groups. The discussions were transcribed and the text analysed using systematic text condensation. RESULTS: Aspects of power concerning the framework of the consultation and the GPs' professional role were found. Also identified were: power expressed by opportunistic approaches to change patients' lifestyle; rhetoric communication; paternalism; and disclosure. GPs reported powerlessness in complex communication, when there were difficulties reaching goals, and when patients resisted or ignored their proposals. CONCLUSION: Case-study discussions in peer groups disclose several aspects of power and powerlessness that occur in consultations. Consciousness about aspects of power may facilitate counselling that benefits the patient and the doctor-patient relationship. PMID- 22429432 TI - Management of hypertension in adults in primary care: NICE guideline. PMID- 22429433 TI - Detection of patient psychological distress and longitudinal patient-doctor relationships: a cross-sectional study. AB - BACKGROUND: Psychological distress in patients who attend their GP is thought to be under-recognised. However, it is likely that both disclosure and detection are influenced by how well the patient and doctor know each another. AIM: To examine whether patient-doctor depth of relationship is associated with identification of psychological distress. DESIGN AND SETTING: Cross-sectional study in general practices in and around Bristol, England. METHOD: Patients (aged >=16 years) were asked to complete a questionnaire and consent to their electronic medical records being reviewed. Study GPs independently assessed patient psychological distress. Multivariable logistic regression was used to look for associations between patient-doctor depth of relationship and GP detection of patient psychological distress (defined according to the 12-item General Health Questionnaire, GHQ-12). RESULTS: There were 643 eligible appointments with 31 GPs. In total, 541 (84.1%) patients returned questionnaires and 490 (76.2%) consented to their records being reviewed. Patient-doctor depth of relationship was not associated with GP detection of mild to severe patient psychological distress (adjusted odds ratio [OR] 0.94, 95% CI = 0.87 to 1.02) but, in secondary analyses, it was associated with the identification of moderate to severe distress (adjusted OR 1.13, 95% CI = 1.02 to 1.26). GPs reported more patient psychological distress in patients who reported a greater depth of relationship but this did not relate to patients' GHQ-12 scores. CONCLUSION: Evidence to support an association between patient-doctor depth of relationship and improved GP detection of patients with psychological distress was weak, except in those patients who GPs thought were more distressed. GPs may overestimate emotional distress in patients who report deeper patient-doctor relationships. PMID- 22429434 TI - Therapeutic identification of depression in young people: lessons from the introduction of a new technique in general practice. AB - BACKGROUND: Mild-to-moderate depression in young people is associated with impaired social functioning and high rates of affective disorder in adult life. Earlier recognition of depression in young people has the potential to reduce the burden of depression in adulthood. However, depression in teenagers is underdiagnosed and undertreated. AIM: To assess the usability and usefulness of a cognitive-behavioural-therapy-based technique for Therapeutic Identification of Depression in Young people (TIDY). DESIGN AND SETTING: A qualitative study of four group practices in northwest London. METHOD: Face-to-face semi-structured interviews were conducted with practitioners who had been trained in the use of the TIDY technique. RESULTS: Twenty-five GPs and six nurses were interviewed. The key themes that emerged from the interviews were: practitioners were 'making sense of teenage depression' when interpreting signs and symptoms; the training in the technique was variable in its impact on practitioners' attitudes and practice; and time factors constrained practitioners in the application of the technique. CONCLUSION: The TIDY technique is usable in routine practice, but only if practitioners are allowed to use it selectively. This need for selectivity arises partly from concerns about time management, and partly to avoid medicalisation of psychological distress in young people. The perceived usefulness of the TIDY technique depends on the practitioner's prior knowledge, experience, and awareness. PMID- 22429435 TI - Service users' views of moving on from early intervention services for psychosis: a longitudinal qualitative study in primary care. AB - BACKGROUND: The role of primary care for young people with psychosis, and transitions between specialist mental health services and primary care, are underexplored areas, both clinically and in research terms. AIM: To explore service users' perspectives of early intervention services and primary care, in depth and over time. DESIGN AND SETTING: Longitudinal qualitative methodology in five geographically diverse sites across England. METHOD: Semi-structured interviews with 21 young people with first-episode psychosis at two time points. RESULTS: Early intervention services are highly prized by service users; however, the 'gold standard' nature of the care is difficult to replicate in other services and may lead to unrealistic expectations. Flexibility in terms of the timing of discharge does appear to be happening in practice, but continuity is not always well established before discharge. Primary care seems to be under utilised, both as a location of care during time with the early intervention service and as a skill set, particularly for physical health problems. Service users expected GPs to advocate for and navigate the health system, particularly at times of crisis or relapse. CONCLUSION: Early intervention services should focus on actively establishing relationships between service users and either the community mental health team or the GP in the months leading up to discharge, and ensuring that service users' expectations about access and availability of care are 'realistic'. Primary care could be better utilised, even when service users are actively engaged with early intervention services, to help ensure physical health needs are met from the start of treatment. PMID- 22429436 TI - A primary care specialist genetics service: a cluster-randomised factorial trial. AB - BACKGROUND: GPs do not have the confidence to identify patients at increased genetic risk. A specialist primary care clinical genetics service could support GPs with referral and provide local clinics for their patients. AIM: To test whether primary care genetic-led genetics education improves both non-cancer and cancer referral rates, and primary care-led genetics clinics improve the patient pathway. DESIGN AND SETTING: Cluster-randomised factorial trial in 73 general practices in the south of England. METHOD: Practices randomised to receive case scenario based seminar (intervention) or not (control), and referred patients a primary (intervention) or secondary (control) care genetic counsellor (GC)-led appointment. OUTCOME MEASURES: GP referral and clinic attendance rates (primary), appropriate cancer and case scenario referral rates, patient satisfaction, clinic costs, and case management (secondary). RESULTS: Eighty-nine and 68 referrals made by 36 intervention and 37 control practices respectively. There was a trend towards an overall higher referral rate among educated GPs (referral rate ratio [RRR] 1.34, 95% confidence interval [CI] = 0.89 to 2.02; P = 0.161), and they made more appropriate cancer referrals (RRR 2.36, 95% CI = 1.07 to 5.24; P = 0.035). No indication of difference in clinic attendance rates (odds ratio 0.91, 95% CI = 0.43 to 1.95; P = 0.802) or patient satisfaction (P = 0.189). Patients spent 49% less travelling (L3.60 versus L6.62; P<0.001) and took 33% less time (39.7 versus 57.7 minutes; P<0.001) to attend a primary than secondary care appointment; 83% of GC-managed appointments met the 18-week referral to treatment, NHS target. CONCLUSION: An integrated primary care genetics service both supports GPs in appropriate cancer referral and provides care in the right place by the right person. PMID- 22429437 TI - Family functioning style and health: opportunities for health prevention in primary care. AB - BACKGROUND: The relationship between family and health has not been studied in detail in primary care. AIM: To evaluate the association between family functioning style and health problems among families receiving primary care. DESIGN AND SETTING: Cross-sectional study in an underserved primary care clinic in Santiago, Chile. METHOD: Families registered at the Juan Pablo II Primary Care Clinic in Santiago, Chile from 2006 to 2010 formed the study sample. Each family selected an adult family member to answer a questionnaire to provide data on: family sociodemographics; health problems among family members; and the family functioning style, as assessed with the Family Functioning Style Scale (FFSS). The t-test was used to assess differences in family functioning styles between families with and without health problems, and analysis of variance was used to study the relationship between the family functioning style and the number of health problems present. RESULTS: A total of 6202 families, comprising 25 037 people, were assessed. The following diseases and conditions were examined: in children--asthma or recurrent bronchitis, delayed development, enuresis or encopresis, behavioural problems, overweight; in adolescents and adults--teenage pregnancy, asthma or chronic obstructive pulmonary disease, smoking, hypertension, type 2 diabetes, major depression, alcohol or drug abuse, and frailty. Families with health problems had a significantly lower FFSS score than families without health conditions. Mental health diseases had the strongest association with family functioning style. An inverse relationship between the number of health problems and the FFSS score was also observed. CONCLUSION: A better family functioning style was associated with a lower prevalence of health problems in families. Bases for further research considering the family as a target for clinical interventions are provided. PMID- 22429438 TI - Influences on the uptake of diabetes screening: a qualitative study in primary care. AB - BACKGROUND: To address the increasing global prevalence of type 2 diabetes healthcare organisations have been contemplating different screening and intervention strategies. Patient acceptability is a key criterion of a screening programme. AIM: To explore the perspectives of those invited to attend the MY WAIST screening study for type 2 diabetes, particularly explanations for attending or not, and views on the specific screening strategy. DESIGN AND SETTING: Qualitative study of 11 general practices in Leicestershire, UK. METHOD: Semi-structured interviews were conducted with 24 individuals (40-69 years) invited to attend the MY-WAIST screening study, comprising 13 who attended and 11 who did not attend the screening. Additional data included reply slips from 73 individuals who declined the offer of screening. Analysis was informed by the constant comparative method. RESULTS: Two categories of influence on the decision about attending screening emerged. 1) Beliefs about type 2 diabetes candidacy and type 2 diabetes was more common among those who had attended; lack of perceived severity of type 2 diabetes was more common among those who did not attend. 2) Practical aspects about the screening strategy: the lengthy, early morning screening appointments were a barrier to uptake; screening attendees found the procedure largely acceptable. Pre-screening waist self-measurement was more memorable than the remainder of the risk-score calculation; neither impacted on uptake. CONCLUSION: The barriers to screening uptake highlighted contribute to current debates about different screening and diagnostic tests for type 2 diabetes and future risk of type 2 diabetes. The findings are useful for those contemplating implementation of screening programmes for identifying type 2 diabetes and pre-diabetes. PMID- 22429439 TI - Follow-up of mild alanine aminotransferase elevation identifies hidden hepatitis C in primary care. AB - BACKGROUND: Hepatitis C (HCV) and hepatitis B (HBV) virus infection can lead to serious complications if left untreated, but often remain undetected in primary care. Mild alanine aminotransferase (ALT) elevations (30-100 IU/l) are commonly found and could be associated with viral hepatitis; unfortunately, these findings frequently remain without follow-up. AIM: To determine if and how mild ALT elevation can be used to identify hidden HCV and HBV infection in primary care. DESIGN AND SETTING: Primary care patients referred for liver enzyme testing were selected by a large primary care Diagnostic Centre (Saltro). METHOD: First, 750 anonymous samples were collected in three categories of ALT elevation (30-50 IU/l, 50-70 IU/l, and 70-100 IU/l) and tested for HCV and HBV. Second, the national prevalence of each ALT elevation was estimated by analysing all annual ALT tests performed at Saltro. RESULTS: HCV prevalence was 1.6% and 1.2% in patients with an ALT of 50-70 IU/l and 70-100 IU/l respectively. In patients with an ALT of 30-50 IU/l, HCV prevalence was normal (<=0.1%). HBV prevalence was normal (<=0.4%) in all groups. The estimated number of ALT tests performed nationally each year in primary care was 1.1 million. An ALT of 30-50 IU/l was found in 21.1%, an ALT of 50-70 IU/l in 5.6%, and 2.6% had an ALT of 70-100 IU/l. CONCLUSION: In primary care patients with an ALT level of 50-100 IU/l, HCV prevalence is tenfold the population prevalence, whereas HBV prevalence is not elevated. Therefore, diagnostic follow-up for HCV is indicated in these patients, even when other explanations for ALT elevation are present. PMID- 22429440 TI - Payment for performance and the QOF: are we doing the right thing? PMID- 22429441 TI - Against all odds? Improving the understanding of risk reporting. PMID- 22429442 TI - Point-of-care testing for the analysis of lipid panels: primary care diagnostic technology update. PMID- 22429443 TI - Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula. AB - BACKGROUND: Gaucher disease (GD) is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics. METHODS: We evaluated the distribution, and clinical and genetic characteristics of GD patients in the Iberian Peninsula (IP). We analysed geographical distribution, demographic, genetic and clinical data, age at diagnosis, type, and years of therapy in 436 GD patients from the IP. RESULTS: The prevalence of GD was 1/149,000 inhabitants; 88.3% were type 1, 6.7% type 2, and 5.0% type 3. The mean age at diagnosis in type 1 was 28.7 years. A total of 72.7% were classified as having mild forms, 25.5% moderate, and 1.7% severe. Anemia and thrombocytopenia were present in 56% and 55%, respectively. Bone disease and hepatomegaly were reported in 62% and 68%, respectively, and were more likely in asplenic than in non-splenectomized patients. Sixty-nine mutant alleles were identified, and five mutations accounted for 75% of the GBA alleles. Several patients described in our series had interesting phenotypes. A total of 58.7% of patients had received enzyme replacement therapy and 12.6% were treated with miglustat. CONCLUSIONS: A broad spectrum of GBA mutations is present in the IP, with 98.2% of type 1 GD being mild and 23.0% never treated. These data highlight genetic and phenotypic heterogeneities among geographic populations. PMID- 22429444 TI - Is processing speed a valid cognitive endophenotype for bipolar disorder? AB - OBJECTIVES: The current study investigated whether a single brief cognitive assessment, processing speed, could be considered as a valid endophenotype for bipolar disorder (BD). METHODS: Processing speed was assessed using the Digit Symbol Test (DST) in 53 euthymic BD probands (BD-P), 50 unaffected first-degree relatives (UFDR) and 60 unrelated healthy controls (HC). RESULTS: Euthymic BD-P and the UFDR were significantly more impaired on DST performance even after controlling for demography and current mood symptoms (effect sizes 0.89 and 0.52). Clinically significant performance impairment was present in about 30% BD P and 25% UFDR. LIMITATIONS: Pharmacotherapy was not controlled for. CONCLUSIONS: Processing speed, as measured with the DST, is a brief reliable measure that could be used in clinical assessments of at risk populations. Our findings support the hypothesis that processing speed may be a valid endophenotype, highly specific for differentiating both euthymic BD-P and UFDR, from HC. PMID- 22429445 TI - Simultaneous consumption and production of fluorescent dissolved organic matter by lake bacterioplankton. AB - Recent evidence suggests a key role of bacterioplankton in shaping the composition of the dissolved organic matter (DOM) pool in aquatic systems, not only through consumption but also through production of specific compounds, but the latter process is still not well understood. We used a bioassay approach to assess the patterns in bacterial production and consumption of five fluorescent DOM pools in seven lakes and two streams in Southeastern Quebec, Canada, and the links these patterns may have with key aspects of bacterial metabolism, DOM origin and nutrients availability. Total dissolved organic C declined by 3-15% during these incubations, whereas the specific DOM pools had very different dynamics: Two humic-like fractions accumulated in all incubations, with rates of production increasing as a function of bacterial growth efficiency, which itself increased with phosphorus concentrations. In contrast, two protein-like fractions and a third humic-like fraction either increased or declined over the course of the experiments. The net production or consumption of these pools appeared to be a function of the contribution of terrestrial C to bulk DOM (derived from delta(13) C of the DOM) and of total bacterial activity. Our results suggest that lake bacterioplankton play a dual role in DOM dynamics, as consumers and also producers, and that the interplay between DOM origin and nutrient availability appears to determine the net outcome of bacterial DOM processing, thus influencing the bulk DOM composition and its fate in these aquatic systems. PMID- 22429446 TI - Preface: Immunoaffinity methods and related methods. PMID- 22429447 TI - Increased serum hepcidin levels in patients with porphyria cutanea tarda. AB - BACKGROUND: Increased iron stores- are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down-regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. OBJECTIVE: To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. METHODS: Hepcidin levels were measured by a competitive enzyme-linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). RESULTS: The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin-6 (IL-6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. CONCLUSION: Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse. PMID- 22429448 TI - Perceived service quality, perceived value, overall satisfaction and happiness of outlook for long-term care institution residents. AB - OBJECTIVE: To investigate the psychometric properties and relationships of perceived service quality, perceived value and overall satisfaction for residents with respect to their long-term care institutions. DESIGN: The five-point Likert scale questionnaire administered through facetoface interviews. SETTING: Fourteen long-term care institutions located in central and southern Taiwan stratified according to services and accommodation population. PARTICIPANTS: One hundred and eighty long-term institutional care residents. MAIN OUTCOME MEASURES: Perceived service quality (the SERVPERF model), perceived value and overall satisfaction (models based on the literature on perceived value and satisfaction). RESULTS: Student's t-test on institutional location shows a significant difference between overall satisfaction for central and southern institution long-term care recipients. The correlation test revealed that the higher a resident's level of education, the higher the scores for perceived value. The factor loading results of confirmation factor analysis show acceptable levels of reliability and index of-model fits for perceived service, perceived value and overall satisfaction. In addition, the results suggest that an additional construct, a positive attitude (happiness of outlook) towards long-term care institutions, is also an important factor in residents' overall satisfaction. CONCLUSION: The primary goal of long term institutional care policy in Taiwan, as in other countries, is to provide residents with practical, cost-effective but high-quality care. On the basis of the results of in-depth interviews with long-term institutional care residents, this study suggests long-term care institutions arrange more family visit days to increase the accessibility and interaction of family and residents and thereby increase the happiness of outlook of the residents. PMID- 22429449 TI - The plastidial glucan, water dikinase (GWD) catalyses multiple phosphotransfer reactions. AB - The plant genome encodes at least two distinct and evolutionary conserved plastidial starch-related dikinases that phosphorylate a low percentage of glucosyl residues at the starch granule surface. Esterification of starch favours the transition of highly ordered alpha-glucans to a less ordered state and thereby facilitates the cleavage of interglucose bonds by hydrolases. Metabolically most important is the phosphorylation at position C6, which is catalysed by the glucan, water dikinase (GWD). The reactions mediated by recombinant wild-type GWD from Arabidopsis thaliana (AtGWD) and from Solanum tuberosum (StGWD) were studied. Two mutated proteins lacking the conserved histidine residue that is indispensible for glucan phosphorylation were also included. The wild-type GWDs consume approximately 20% more ATP than is required for glucan phosphorylation. Similarly, although incapable of phosphorylating alpha-glucans, the two mutated dikinase proteins are capable of degrading ATP. Thus, consumption of ATP and phosphorylation of alpha-glucans are not strictly coupled processes but, to some extent, occur as independent phosphotransfer reactions. As revealed by incubation of the GWDs with [gamma-(33) P]ATP, the consumption of ATP includes the transfer of the gamma-phosphate group to the GWD protein but this autophosphorylation does not require the conserved histidine residue. Thus, the GWD proteins possess two vicinal phosphorylation sites, both of which are transiently phosphorylated. Following autophosphorylation at both sites, native dikinases flexibly use various terminal phosphate acceptors, such as water, alpha-glucans, AMP and ADP. A model is presented describing the complex phosphotransfer reactions of GWDs as affected by the availability of the various acceptors. PMID- 22429450 TI - Disruption of Type-I IFN pathway ameliorates preservation damage in mouse orthotopic liver transplantation via HO-1 dependent mechanism. AB - Ischemia/reperfusion injury (IRI) remains unresolved problem in clinical organ transplantation. We analyzed the role of Type-I interferon (IFN) pathway in a clinically relevant murine model of extended hepatic cold preservation followed by orthotopic liver transplantation (OLT). Livers from Type-I IFN receptor (IFNAR) knockout (KO) or wild-type (WT) mice (C57/BL6) were harvested, preserved at 4 degrees C in UW solution for 20 h and transplanted to groups of syngeneic IFNAR KO or WT recipients. Liver graft but not recipient IFNAR deficiency was required to consistently ameliorate IRI in OLTs. Indeed, disruption of Type-I IFN signaling decreased serum alanine aminotransferase (sALT) levels (p < 0.001), diminished Suzuki's score of histological OLT damage (p < 0.01) and improved 14 day survival (from 42%[5/12] in WT to 92%[11/12] in IFNAR KO; p < 0.05). Unlike in WT group, IFNAR deficiency attenuated OLT expression of TNF-alpha, IL-1beta, IL-6, MCP-1, CXCL-10, ICAM-1; diminished infiltration by macrophages/PMNs; and enhanced expression of antioxidant HO-1/Nrf2. The frequency of TUNEL+ apoptotic cells and caspase-3 activity/expression selectively decreased in IFNAR KO group. Small interfering (si)RNA-directed targeting of HO-1 restored cardinal features of liver IRI in otherwise resistant IFNAR-deficient OLTs. Thus, intact Type-I IFN signaling is required for hepatic IRI, whereas HO-1 is needed for cytoprotection against innate immunity-dominated organ preservation damage in IFNAR-deficient liver transplants. PMID- 22429451 TI - Randomized controlled trial comparing treatment outcome of two compression bandaging systems and standard care without compression in patients with venous leg ulcers. AB - BACKGROUND: Compression therapy is not common for venous leg ulcer patients in Hong Kong. METHODS: This randomized controlled trial compared the clinical effectiveness of compression bandaging using four-layer bandaging (4LB) or short stretch bandaging (SSB) and usual care (moist wound healing dressing without compression). The 24-week study looked at venous leg ulcer patients aged >60 years in a community setting. The primary parameter was time to ulcer healing. Secondary parameters were ulcer area and pain reduction comparing week 0 (start) vs week 24 (end), measuring results per group and between groups. Intention-to treat analysis involved descriptive statistics, survival analysis, and repeated measures analysis of variance. The log-rank test was used for univariable analysis. All withdrawn patients had a negative outcome score over the whole study duration. RESULTS: Of 321 patients who received randomized treatment, 45 (14%) did not complete the 24-week study period. At 24 weeks, Kaplan-Meier analysis on healing time was statistically significant (P < .001) in favor of the compression groups. The mean (SD) healing time in the SSB group (9.9 [0.77]) was shorter than that of the 4LB group (10.4 [0.80]) and the usual care group (18.3 [0.86]). Pain reduction was significant (P < .001) for the compression-treated groups only. CONCLUSIONS: Compression bandaging was more effective than usual care without compression. Both compression systems were safe and feasible for venous ulcer patients in a community setting in Hong Kong. PMID- 22429452 TI - Diminished aversive classical conditioning in pathological gamblers. AB - AIMS: Impaired ability to form associations between negative events in gambling and aversive somatic reactions may be a predisposing factor for pathological gambling. The current study investigated whether a group of pathological gamblers and a control group differed in aversive classical conditioning. DESIGN: A differential aversive classical conditioning paradigm, which consisted of three phases. In the habituation phase, one 850-Hz tone stimulus and one 1500-Hz tone stimulus were presented three times each in random order. In the acquisition phase, the two tones were presented 10 times each in random order, and one was always followed by a 100-dB burst of white noise. In the extinction phase the two tones were presented three times each without the white noise. SETTING: University laboratory testing facilities and out-patient treatment facilities. PARTICIPANTS: Twenty pathological gamblers and 20 control participants. MEASUREMENTS: Duration of seven cardiac interbeat-intervals (IBIs) following tone offset, gambling severity, tobacco and alcohol use, anxiety and depression. FINDINGS: No group differences were found in the habituation and acquisition phases. However, a significant group * stimuli * trials * IBIs interaction effect was found in the extinction phase (P < 0.049). Follow-up analysis indicated that the pathological gamblers did not show aversive classical conditioning, but that the control group did. CONCLUSIONS: Pathological gamblers have a diminished capacity to form associations between aversive events and stimuli that predict aversive events. Aversion learning is likely to be an ineffective treatment for pathological gamblers. PMID- 22429453 TI - Dynamics of cell attachment: adhesion time and force. AB - Due to its biological significance, cell adhesion to biomaterial surfaces or scaffolds is the key step in biomedical applications. Here, we describe two sensitive and facile methods that quantify the kinetic and mechanic properties of the entire cell attachment process characterized by two parameters: Adhesion Time T(Ad) and Adhesion Force F(Ad). We demonstrate that both methods can be applied to any adherent cell type (e.g., stem or cancer cells), tissue-engineered substrate, and culture condition in a fast, effective, and reproducible manner. Additional investigations about the role of the extracellular matrix and the formation of focal contacts help in acquiring further interpretations of these parameters from biological and mechanical points of view. PMID- 22429454 TI - Smoking and health-related quality of life in English general population: implications for economic evaluations. AB - BACKGROUND: Little is known as to how health-related quality of life (HRQoL) when measured by generic instruments such as EQ-5D differ across smokers, ex-smokers and never-smokers in the general population; whether the overall pattern of this difference remain consistent in each domain of HRQoL; and what implications this variation, if any, would have for economic evaluations of tobacco control interventions. METHODS: Using the 2006 round of Health Survey for England data (n = 13,241), this paper aims to examine the impact of smoking status on health related quality of life in English population. Depending upon the nature of the EQ-5D data (i.e. tariff or domains), linear or logistic regression models were fitted to control for biology, clinical conditions, socio-economic background and lifestyle factors that an individual may have regardless of their smoking status. Age- and gender-specific predicted values according to smoking status are offered as the potential 'utility' values to be used in future economic evaluation models. RESULTS: The observed difference of 0.1100 in EQ-5D scores between never smokers (0.8839) and heavy-smokers (0.7739) reduced to 0.0516 after adjusting for biological, clinical, lifestyle and socioeconomic conditions. Heavy-smokers, when compared with never-smokers, were significantly more likely to report some/severe problems in all five domains--mobility (67%), self-care (70%), usual activity (42%), pain/discomfort (46%) and anxiety/depression (86%). 'Utility' values by age and gender for each category of smoking are provided to be used in the future economic evaluations. CONCLUSION: Smoking is significantly and negatively associated with health-related quality of life in English general population and the magnitude of this association is determined by the number of cigarettes smoked. The varying degree of this association, captured through instruments such as EQ-5D, may need to be fed into the design of future economic evaluations where the intervention being evaluated affects (e.g. tobacco control) or is affected (e.g. treatment for lung cancer) by individual's (or patients') smoking status. PMID- 22429455 TI - Caloric restriction prevents visceral adipose tissue accumulation and maintains erectile function in aging rats. AB - INTRODUCTION: Increased adiposity is an important risk factor for erectile dysfunction (ED) and cardiovascular disease (CVD). Although accumulation of visceral adipose tissue (VAT) is recognized as a key mediator in the pathogenesis of CVD, its role in ED has not been elucidated. AIM: To determine whether caloric restriction (CR) could prevent VAT accumulation and thereby prevent the onset of ED in normotensive rats. METHODS: Male Sprague Dawley rats (10 weeks) were randomized into three dietary groups: ad libitum control (CON), mild CR (CR(MI)), and moderate CR (CR(MOD)). Body weight (BW), body length abdominal girth (AG), and VAT (g-magnetic resonance imaging based) were assessed longitudinally. Erections were assessed using the apomorphine bioassay (80 ug/kg, SQ) after 20 weeks of CR. Excised VAT (mesenteric, epididymal, omental, and retroperitoneal), the internal pudendal artery (IPA) and serum were collected postmortem. Structure and function of the IPA was assessed at study end. MAIN OUTCOME MEASURES: Erectile responses, adiposity (VAT), abdominal girth, serum analysis. RESULTS: BW (CON = 653 +/- 58.6 g; CR(MI) = 535 +/- 47.4 g; CR(MOD) = 409 +/- 17.4 g) and VAT (CON = 39 +/- 9.0 g; CR(MI) = 30 +/- 9.9 g; CR(MOD) = 14 +/- 3.5 g) were markedly different between the three groups. AG significantly correlated with longitudinal changes in VAT (R(2) = 0.61) and excised VAT (R(2) = 0.87). CR preserved erectile responses (CON = 0.6 +/- 0.45, CR(MI) = 1.2 +/- 0.77 g, CR(MOD) = 2.5 +/- 0.43 g). A strong inverse correlation between VAT (%) and erectile function was found (R(2) = 0.74) whereas BW was less predictive of ED (R(2) = 0.48). There were no changes in traditional biomarkers (glucose, lipids) which could account for the ED. IPA structure was not different between groups, while CR(MOD) preserved endothelial function. CONCLUSIONS: CR effectively prevented VAT accumulation in normotensive rats. Independently of changes in other metabolic markers, this intervention ameliorated the negative impact on erectile responses that occurs with age. Functional changes of the IPA may be a key mechanism by which erections are preserved with CR. AG was shown to be a strong index of VAT in rats. PMID- 22429456 TI - Scabies in the developing world--its prevalence, complications, and management. AB - Scabies remains one of the commonest of skin diseases seen in developing countries. Although its distribution is subject to a cycle of infection, with peaks and troughs of disease prevalence, this periodicity is often less obvious in poor communities. Scabies is a condition that affects families, particularly the most vulnerable; it also has the greatest impact on young children. Largely through the association with secondary bacterial infection caused by group A streptococci and Staphylococcus aureus, the burden of disease is compounded by nephritis, rheumatic fever and sepsis in developing countries. However, with a few notable exceptions, it remains largely neglected as an important public health problem. The purpose of this review is to provide an update on the current position of scabies with regard to its complications and control in resource-poor countries. PMID- 22429457 TI - Taxonomy of lice and their endosymbiotic bacteria in the post-genomic era. AB - Recent studies of molecular and genomic data from the parasitic lice of birds and mammals, as well as their mutualistic endosymbiotic bacteria, are changing the phylogenetic relationships and taxonomy of these organisms. Phylogenetic studies of lice suggest that vertebrate parasitism arose multiple times from free-living book and bark lice. Molecular clocks show that the major families of lice arose in the late Mesozoic and radiated in the early Cenozoic, following the radiation of mammals and birds. The recent release of the human louse genome has provided new opportunities for research. The genome is being used to find new genetic markers for phylogenetics and population genetics, to understand the complex evolutionary relationships of mitochondrial genes, and to study genome evolution. Genomes are informing us not only about lice, but also about their obligate endosymbiotic bacteria. In contrast to lice and their hosts, lice and their endosymbionts do not share common evolutionary histories, suggesting that endosymbionts are either replaced over time or that there are multiple independent origins of symbiosis in lice. Molecular phylogenetics and whole genome sequencing have recently provided the first insights into the phylogenetic placement and metabolic characteristics of these distantly related bacteria. Comparative genomics between distantly related louse symbionts can provide insights into conserved metabolic functions and can help to explain how distantly related species are fulfilling their role as mutualistic symbionts. In lice and their endosymbionts, molecular data and genome sequencing are driving our understanding of evolutionary relationships and classification, and will for the foreseeable future. PMID- 22429458 TI - Insecticide resistance in head lice: clinical, parasitological and genetic aspects. AB - Insecticide treatment resistance is considered to be a major factor in the increasing number of infestations by head lice. The large insecticide selection pressure induced by conventional topical pediculicides has led to the emergence and spread of resistance in many parts of the world. Possible mechanisms of resistance include accelerated detoxification of insecticides by enzyme-mediated reduction, esterification, oxidation that may be overcome by synergistic agents such as piperonyl butoxide, alteration of the binding site, e.g. altered acetylcholinesterase or altered nerve voltage-gated sodium channel, and knockdown resistance (kdr). Clinical, parasitological and molecular data on resistance to conventional topical pediculicides show that treatments with neurotoxic insecticides have suffered considerable loss of activity worldwide. In particular, resistance to synthetic pyrethroids has become prominent, probably because of their extensive use. As other treatment options, including non insecticidal pediculicides such as dimeticone, are now available, the use of older insecticides, such as lindane and carbaryl, should be minimized, owing to their loss of efficacy and safety concerns. The organophosphorus insecticide malathion remains effective, except in the UK, mostly in formulations that include terpineol. PMID- 22429460 TI - Rapid detection, differentiation and typing of methicillin-resistant Staphylococcus aureus harbouring either mecA or the new mecA homologue mecA(LGA251). AB - The recent finding of a new mecA homologue, mecA(LGA251) , with only 70% nucleotide homology to the conventional mecA gene has brought the routine testing for mecA as a confirmatory test for methicillin-resistant Staphylococcus aureus (MRSA) into question. A multiplex PCR was designed to differentiate mecA(LGA251) from the known mecA together with detection of lukF-PV and the spa gene fragments, enabling direct spa typing by sequencing of the PCR amplicons. The PCR analysis and subsequent spa typing were validated on a large collection (n=185) of contemporary MRSA and methicillin-sensitive S. aureus isolates, including 127 isolates carrying mecA(LGA251) . The mecA(LGA251) gene was situated in staphylococcal cassette chromosome mec type XI elements, and sequence variation within a 631-bp fragment of mecA(LGA251) in 79 isolates indicated a very conserved gene sequence. Following a successful validation, the multiplex PCR strategy was implemented in the routine testing of MRSA for national surveillance. Over a 2-month period, among 203 samples tested, 12 new MRSA cases caused by isolates carrying mecA(LGA251) were identified, emphasizing the clinical importance of testing for these new MRSA isolates. PMID- 22429461 TI - Morphea-like lesion following topical endectocide application in a cat. AB - BACKGROUND: Scleroderma is a rare chronic disease of connective tissues that may affect the skin in humans. Although still unclear, its aetiology may be related to drug reactions. To date, scleroderma has been reported in only a few dogs and one cat. CASE REPORT: Localized (morphea-like) scleroderma was diagnosed in a 3 year-old intact male Persian cat that developed a nonpruritic, well-demarcated alopecic plaque a few days after topical application of a 'spot-on' solution containing praziquantel and emodepside. The lesion occurred at the site of application at the dorsal cervical region, and was characterized histologically by fibrosing dermatitis. There was no response to systemic treatment with pentoxifylline. Following topical therapy with minoxidil 5% for 30 days, hair regrowth occurred, and the lesion had completely disappeared after 60 days. CONCLUSIONS AND CLINICAL IMPORTANCE: The relationship between the alopecic plaque and the topical application of the spot-on solution cannot be proved; however, according to the Naranjo scale, which estimates the probability of adverse drug reactions, this case could be classified as a 'possible' reaction to one of the components of the product. Sclerodermoid reactions have not been described as a cutaneous drug eruption in veterinary medicine, so this case may possibly represent the first such idiosyncratic reaction to one of the applied substances. Furthermore, to the best of the authors' knowledge, this is the second report of a morphea-like lesion in a cat. PMID- 22429462 TI - In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol 5-ol in human liver microsomes. AB - Bazedoxifene is a selective estrogen receptor modulator (SERM) that has been developed for use in post-menopausal osteoporosis. However, it contains a potentially toxic 5-hydroxy-3-methylindole moiety. Previous studies on the 5 hydroxyindole and the 3-alkylindole-containing drugs indometacine, zafirlukast and MK-0524 structural analogs have shown that they are bioactivated by cytochrome P450s through a dehydrogenation process to form quinoneimine or 3 methyleneindolenine electrophilic species. In the present study, bazedoxifene was synthesized and then evaluated, together with raloxifene and 2-(4-hydroxyphenyl) 3-methyl-1H-indol-5-ol (13), a 3-methyl-5-hydroxyindole-based structural fragment of bazedoxifene, for its ability to form reactive electrophilic species when incubated with human liver microsomes (HLMs) or recombinant CYP isozymes. We showed that bazedoxifene was bioactivated only in trace amounts with recombinant CYP isozymes. In contrast, the N-dealkylated fragment of bazedoxifene (2-(4 hydroxyphenyl)-3-methyl-1H-indol-5-ol) was bioactivated in considerable amounts to an electrophilic intermediate, which was trapped with glutathione and identified by LC-MS/MS. This suggests that bazedoxifene would require initial N dealkylation, which could subsequently lead to the formation of the reactive intermediate. However, such an N-dealkylated metabolite of bazedoxifene was not detected after the incubation of bazedoxifene in HLM or recombinant CYP isozymes. PMID- 22429463 TI - Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients. AB - INTRODUCTION: A gene expression signature indicative of activated wound responses is common to more than 90% of non-neoplastic tissues adjacent to breast cancer, but these tissues also exhibit substantial heterogeneity. We hypothesized that gene expression subtypes of breast cancer microenvironment can be defined and that these microenvironment subtypes have clinical relevance. METHODS: Gene expression was evaluated in 72 patient-derived breast tissue samples adjacent to invasive breast cancer or ductal carcinoma in situ. Unsupervised clustering identified two distinct gene expression subgroups that differed in expression of genes involved in activation of fibrosis, cellular movement, cell adhesion and cell-cell contact. We evaluated the prognostic relevance of extratumoral subtype (comparing the Active group, defined by high expression of fibrosis and cellular movement genes, to the Inactive group, defined by high expression of claudins and other cellular adhesion and cell-cell contact genes) using clinical data. To establish the biological characteristics of these subtypes, gene expression profiles were compared against published and novel tumor and tumor stroma-derived signatures (Twist-related protein 1 (TWIST1) overexpression, transforming growth factor beta (TGF-beta)-induced fibroblast activation, breast fibrosis, claudin low tumor subtype and estrogen response). Histological and immunohistochemical analyses of tissues representing each microenvironment subtype were performed to evaluate protein expression and compositional differences between microenvironment subtypes. RESULTS: Extratumoral Active versus Inactive subtypes were not significantly associated with overall survival among all patients (hazard ratio (HR) = 1.4, 95% CI 0.6 to 2.8, P = 0.337), but there was a strong association with overall survival among estrogen receptor (ER) positive patients (HR = 2.5, 95% CI 0.9 to 6.7, P = 0.062) and hormone-treated patients (HR = 2.6, 95% CI 1.0 to 7.0, P = 0.045). The Active subtype of breast microenvironment is correlated with TWIST-overexpression signatures and shares features of claudin low breast cancers. The Active subtype was also associated with expression of TGF beta induced fibroblast activation signatures, but there was no significant association between Active/Inactive microenvironment and desmoid type fibrosis or estrogen response gene expression signatures. Consistent with the RNA expression profiles, Active cancer-adjacent tissues exhibited higher density of TWIST nuclear staining, predominantly in epithelium, and no evidence of increased fibrosis. CONCLUSIONS: These results document the presence of two distinct subtypes of microenvironment, with Active versus Inactive cancer-adjacent extratumoral microenvironment influencing the aggressiveness and outcome of ER positive human breast cancers. PMID- 22429464 TI - Maternal malaria status and metabolic profiles in pregnancy and in cord blood: relationships with birth size in Nigerian infants. AB - BACKGROUND: Malaria is more common in pregnant than in non-pregnant Nigerian women, and is associated with small birth size and the attendant short- and long term health risks. The influence of malaria on maternal metabolic status in pregnancy and in cord blood and how this relates to birth size has not been studied. The study objective was to define relationships between maternal and cord serum metabolic markers, maternal malaria status and birth size. METHODS: During pregnancy, anthropometric measurements, blood film for malaria parasites and assays for lipids, glucose, insulin and TNF were obtained from 467 mothers and these analytes and insulin-like growth factor-I (IGF-I) were obtained from cord blood of 187 babies. RESULTS: Overall prevalence of maternal malaria was 52%, associated with younger age, anaemia and smaller infant birth size. Mothers with malaria had significantly lower cholesterol (total, HDL and LDL) and higher TNF, but no difference in triglyceride. In contrast, there was no effect of maternal malaria on cord blood lipids, but the median (range) cord IGF-I was significantly lower in babies whose mothers had malaria: 60.4 (24, 145) MUg/L, versus no malaria: 76.5 (24, 150) MUg/L, p = 0.03. On regression analysis, the key determinants of birth weight included maternal total cholesterol, malarial status and cord insulin and IGF-I. CONCLUSIONS: Malaria in pregnancy was common and associated with reduced birth size, lower maternal lipids and higher TNF. In the setting of endemic malaria, maternal total cholesterol during pregnancy and cord blood insulin and IGF-I levels are potential biomarkers of foetal growth and birth size. PMID- 22429465 TI - Adjunctive antibiotics in the treatment of acute bacterial endophthalmitis following cataract surgery. PMID- 22429466 TI - Inhibition of tumor suppressor protein p53-dependent transcription by a tetramerization domain peptide via hetero-oligomerization. AB - Tumor suppressor protein p53 induces cell cycle arrest, apoptosis, and senescence in response to cellular stresses. The p53 tetramer formation is essential for its functions. Despite of these crucial functions of p53 for integrity of genome, activation of the p53 signal pathway causes low induced pluripotent stem (iPS) cell generation efficiency. In this study, we report transient inhibition of p53 dependent transcription using a p53 tetramerization domain peptide that contains cell penetrating and nuclear localization signals. The peptide was efficiently introduced into cells and inhibited p21 expression via hetero-tetramerization with endogenous p53 protein. This method can be applied towards safe and efficient iPS cell generation. PMID- 22429467 TI - Medicinal chemistry approaches to avoid aldehyde oxidase metabolism. AB - Aldehyde oxidase (AO) is a molybdenum-containing enzyme distributed throughout the animal kingdom and capable of metabolising a wide range of aldehydes and N heterocyclic compounds. Although metabolism by this enzyme in man is recognised to have significant clinical impact where human AO activity was not predicted by screening in preclinical species, there is very little reported literature offering real examples where drug discoverers have successfully designed away from AO oxidation. This article reports on some strategies adopted in the Pfizer TLR7 agonist programme to successfully switch off AO metabolism that was seen principally in the rat. PMID- 22429468 TI - Indole-propionic acid derivatives as potent, S1P3-sparing and EAE efficacious sphingosine-1-phosphate 1 (S1P1) receptor agonists. AB - Novel indole-propionic acid derivatives were developed as sphingosine-1-phosphate (S1P) receptor agonists through a systematic SAR study. The optimized and S1P(3) selective S1P(1) agonist 9f induced peripheral blood lymphocyte reduction in vivo and has an excellent efficacy in mouse experimental autoimmune encephalomyelitis (EAE). PMID- 22429469 TI - Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active gamma-secretase modulators. AB - We report the discovery and optimization of a novel series of dihydrobenzofuran amides as gamma-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Abeta42 lowering activity at 100 mg/kg po dose. PMID- 22429470 TI - Calcitonin gene-related peptide (CGRP) receptor antagonists: pyridine as a replacement for a core amide group. AB - In our continuing efforts to identify CGRP receptor antagonists that can be dosed orally for the treatment of migraine headache, we have investigated a pyridine bioisosteric replacement of a polar amide portion of a previous lead compound, BMS-694153. Pyridine derivatives were discovered and their SAR was studied. Some of them showed excellent binding potency. However, oral bioavailability was low, even for compounds with good Caco-2 cell permeability. PMID- 22429471 TI - Calcitonin gene-related peptide (CGRP) receptor antagonists: novel aspartates and succinates. AB - Novel aspartate and succinate CGRP full antagonists were identified through core modification of a potent lead CGRP antagonist, BMS-694153. While aspartates were much less active and had a flat SAR, some of the succinates were very potent CGRP full antagonists and matched the potency of BMS-694153. The most potency resides in the S enantiomer as demonstrated through an asymmetric synthesis. PMID- 22429472 TI - Therapeutic targeting of Kruppel-like factor 4 abrogates microglial activation. AB - BACKGROUND: Neuroinflammation occurs as a result of microglial activation in response to invading micro-organisms or other inflammatory stimuli within the central nervous system. According to our earlier findings, Kruppel-like factor 4 (Klf4), a zinc finger transcription factor, is involved in microglial activation and subsequent release of proinflammatory cytokines, tumor necrosis factor alpha, macrophage chemoattractant protein-1 and interleukin-6 as well as proinflammatory enzymes, inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-treated microglial cells. Our current study focuses on finding the molecular mechanism of the anti-inflammatory activities of honokiol in lipopolysaccharide-treated microglia with emphasis on the regulation of Klf4. METHODS: For in vitro studies, mouse microglial BV-2 cell lines as well as primary microglia were treated with 500 ng/mL lipopolysaccharide as well as 1 MUM and 10 MUM of honokiol. We cloned full-length Klf4 cDNA in pcDNA3.1 expression vector and transfected BV-2 cells with this construct using lipofectamine for overexpression studies. For in vivo studies, brain tissues were isolated from BALB/c mice treated with 5 mg/kg body weight of lipopolysaccharide either with or without 2.5 or 5 mg/kg body weight of honokiol. Expression of Klf4, cyclooxygenase-2, inducible nitric oxide synthase and phospho-nuclear factor kappa B was measured using immunoblotting. We also measured the levels of cytokines, reactive oxygen species and nitric oxide in different conditions. RESULTS: Our findings suggest that honokiol can substantially downregulate the production of proinflammatory cytokines and inflammatory enzymes in lipopolysaccharide-stimulated microglia. In addition, honokiol downregulates lipopolysaccharide-induced upregulation of both Klf4 and phospho-nuclear factor kappa B in these cells. We also found that overexpression of Klf4 in BV-2 cells suppresses the anti-inflammatory action of honokiol. CONCLUSIONS: Honokiol potentially reduces inflammation in activated microglia in a Klf4-dependent manner. PMID- 22429473 TI - Factors associated with dementia care practices among community health nurses: results of a postal survey. AB - BACKGROUND: The incremental prevalence of dementia is making dementia management a worldwide issue. The role of community health nurses must grow along with the increasing aging population and the resulting increase in dementia cases. OBJECTIVES: Explore the factors related to dementia care practices among the different types of community health nurses in Taiwan. DESIGN: Cross-sectional study. SETTING: Primary care centers or institutions in New Taipei City. PARTICIPANTS: Community health nurses who work in health care centers (district nurses), long-term care centers (care managers), or home care institutions (home health care nurses). METHODS: Self-completion questionnaires sent by mail. RESULTS: A total of 195 participants returned the questionnaires (response rate 81.9%). Although 65.8% of participants had experience in case finding, just 34.6% of them reported using validated cognitive testing tools. Only 15% of participants provided case management following dementia case findings. The regression models showed that the different types of community health nurses, number of years working as a nurse, and their level of confidence was significantly related to their dementia care practice. District nurses identified significantly less suspected dementia cases and provided less nursing care to caregivers of dementia patients than care managers and home health care nurses. Among community health nurses, the care managers most often used formal cognitive instruments. District nurses provided the least amount of supportive resources information, had the most negative attitude and the lowest level of confidence toward dementia care than care managers and home health care nurses. CONCLUSIONS: This study presented the profiles of dementia care practice in Taiwan. It showed the considerable variation in knowledge, attitude, confidence and dementia care practices among the different community health nurses. The professional roles regarding dementia care in Taiwan remain blurred. Future training must focus on promoting the level of confidence of community health nurses to identify and manage people with dementia and raise awareness about demented person's and their caregiver's need. The priority of the policy on dementia care in the community must be raised to high, and the professional responsibilities and roles of the different types of community health nurses for the ever increasing dementia population in Taiwan must be redefined and optimized. PMID- 22429474 TI - Clinical outcomes after treatment of multiple lesions with zotarolimus-eluting versus sirolimus-eluting coronary stents (a SORT OUT III substudy). AB - BACKGROUND: Data on clinical outcomes among patients treated with the zotarolimus eluting EndeavorTM stent versus the sirolimus-eluting CypherTM stent favor the sirolimus-eluting stent. However, a separate comparison of clinical outcome among patients treated for multiple lesions with these stents is lacking. We performed this comparison within the SORT OUT III trial data set. METHODS: Among 2332 patients randomized in SORT OUT III, 695 were treated for multiple lesions with zotarolimus-eluting (n = 350) or sirolimus-eluting (n = 345) stents and followed for 18 months. Major adverse cardiac events (MACE); composite of cardiac death, myocardial infarction, or target vessel revascularization (TVR); was the primary endpoint. RESULTS: Zotarolimus-eluting compared to sirolimus-eluting stent treatment was associated with increased MACE rate (13.2% vs. 2.6%; hazard ratio 5.29 with 95% confidence interval: 2.59-10.8). All secondary endpoints; all cause death, cardiac death, myocardial infarction, TVR, target lesion revascularization, in-stent restenosis, and definite stent thrombosis; were observed more frequently among zotarolimus-eluting stent treated patients. For all endpoints, hazard ratios were 1.6 to 4.6 times higher than in the overall results of the SORT OUT III trial. CONCLUSIONS: We observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent. PMID- 22429475 TI - An inter-laboratory comparative study of serological tools employed in the diagnosis of Besnoitia besnoiti infection in bovines. AB - Bovine besnoitiosis is considered an emerging chronic and debilitating disease in Europe. Many infections remain subclinical, and the only sign of disease is the presence of parasitic cysts in the sclera and conjunctiva. Serological tests are useful for detecting asymptomatic cattle/sub-clinical infections for control purposes, as there are no effective drugs or vaccines. For this purpose, diagnostic tools need to be further standardized. Thus, the aim of this study was to compare the serological tests available in Europe in a multi-centred study. A coded panel of 241 well-characterized sera from infected and non-infected bovines was provided by all participants (SALUVET-Madrid, FLI-Wusterhausen, ENV-Toulouse, IPB-Berne). The tests evaluated were as follows: an in-house ELISA, three commercial ELISAs (INGEZIM BES 12.BES.K1 INGENASA, PrioCHECK Besnoitia Ab V2.0, ID Screen Besnoitia indirect IDVET), two IFATs and seven Western blot tests (tachyzoite and bradyzoite extracts under reducing and non-reducing conditions). Two different definitions of a gold standard were used: (i) the result of the majority of tests ('Majority of tests') and (ii) the majority of test results plus pre-test information based on clinical signs ('Majority of tests plus pre test info'). Relative to the gold standard 'Majority of tests', almost 100% sensitivity (Se) and specificity (Sp) were obtained with SALUVET-Madrid and FLI Wusterhausen tachyzoite- and bradyzoite-based Western blot tests under non reducing conditions. On the ELISAs, PrioCHECK Besnoitia Ab V2.0 showed 100% Se and 98.8% Sp, whereas ID Screen Besnoitia indirect IDVET showed 97.2% Se and 100% Sp. The in-house ELISA and INGEZIM BES 12.BES.K1 INGENASA showed 97.3% and 97.2% Se; and 94.6% and 93.0% Sp, respectively. IFAT FLI-Wusterhausen performed better than IFAT SALUVET-Madrid, with 100% Se and 95.4% Sp. Relative to the gold standard 'Majority of test plus pre-test info', Sp significantly decreased; this result was expected because of the existence of seronegative animals with clinical signs. All ELISAs performed very well and could be used in epidemiological studies; however, Western blot tests performed better and could be employed as a posteriori tests for control purposes in the case of uncertain results from valuable samples. PMID- 22429476 TI - Environmental conditions that influence toxin biosynthesis in cyanobacteria. AB - Over the past 15 years, the genetic basis for production of many cyanobacterial bioactive compounds has been described. This knowledge has enabled investigations into the environmental factors that regulate the production of these toxins at the molecular level. Such molecular or systems level studies are also likely to reveal the physiological role of the toxin and contribute to effective water resource management. This review focuses on the environmental regulation of some of the most relevant cyanotoxins, namely the microcystins, nodularin, cylindrospermopsin, saxitoxins, anatoxins and jamaicamides. PMID- 22429477 TI - Accuracy of blood transfusion in postpartum hemorrhage to assess maternal morbidity. AB - OBJECTIVE: To measure the accuracy of blood transfusion (timing and number of blood units) in postpartum hemorrhage (PPH) in a perinatal network. STUDY DESIGN: (1) The ANONYMAT software system was used for anonymization and linkage of two large stand-alone databases, the Burgundy Perinatal Network (BPN) and the National Blood Centre (EFS) databases, which contain, respectively, clinical data from hospital discharges and information concerning any blood transfusion in France (considered as the gold standard database for identifying any transfusion). (2) Identification of prescriptions of at least one red blood cell (RBC) unit at the day of delivery (>=22 weeks) and up to 42 days, with manual reviewing of medical records in case of discordant recording. (3) Assessing the sensitivity and positive predictive value of data from the BPN database. RESULTS: Among the 9736 women receiving at least one blood product dispensed between 01/01/2006 and 12/31/2007 and the 35,779 women who delivered, 233 women (0.65% of deliveries) received at least one RBC unit for post partum hemorrhage. In the BPN database according to the type of hospital stay in our perinatal network (delivery stay only, delivery and post-delivery stays), sensitivity and positive predictive value for RBC transfusion ranged from 61.4% (55.1-67.6) to 67.8% (61.8 73.8) and 82.2% (76.5-87.9) to 83.2% (77.8-88.5), respectively. Linkage of both BPN and EFS databases allowed accurate recording of all but one RBC transfusion. CONCLUSION: Our approach allowed 100% electronic recording of PPH requiring blood transfusion, making it an important sentinel event of maternal morbidity to assess the perinatal network. PMID- 22429478 TI - FE65 as a link between VLDLR and APP to regulate their trafficking and processing. AB - BACKGROUND: Several studies found that FE65, a cytoplasmic adaptor protein, interacts with APP and LRP1, altering the trafficking and processing of APP. We have previously shown that FE65 interacts with the ApoE receptor, ApoER2, altering its trafficking and processing. Interestingly, it has been shown that FE65 can act as a linker between APP and LRP1 or ApoER2. In the present study, we tested whether FE65 can interact with another ApoE receptor, VLDLR, thereby altering its trafficking and processing, and whether FE65 can serve as a linker between APP and VLDLR. RESULTS: We found that FE65 interacted with VLDLR using GST pull-down and co-immunoprecipitation assays in COS7 cells and in brain lysates. This interaction occurs via the PTB1 domain of FE65. Co-transfection with FE65 and full length VLDLR increased secreted VLDLR (sVLDLR); however, the levels of VLDLR C-terminal fragment (CTF) were undetectable as a result of proteasomal degradation. Additionally, FE65 increased cell surface levels of VLDLR. Moreover, we identified a novel complex between VLDLR and APP, which altered trafficking and processing of both proteins. Furthermore, immunoprecipitation results demonstrated that the presence of FE65 increased the interaction between APP and VLDLR in vitro and in vivo. CONCLUSIONS: These data suggest that FE65 can regulate VLDLR trafficking and processing. Additionally, the interaction between VLDLR and APP altered both protein's trafficking and processing. Finally, our data suggest that FE65 serves as a link between VLDLR and APP. This novel interaction adds to a growing body of literature indicating trimeric complexes with various ApoE Receptors and APP. PMID- 22429479 TI - Serum cortisol concentration in patients with major depression after treatment with fluoxetine. AB - Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels is characteristic of the pathophysiology of major depressive disorder (MDD). The aim of this study was to determine whether increased plasma cortisol levels appear in patients with major depression and if effective antidepressant treatment by fluoxetine leads to regulation of cortisol level. This aim was realized by describing and validation of methods of determining fluoxetine and cortisol in serum and searching for correlation between their concentrations in patients with endogenous depression, the therapeutic effect as assessed in Hamilton Depression Rating Scale (HDRS), age and sex of patients. Plasma cortisol and fluoxetine levels were measured using high performance liquid chromatography (HPLC) methods with applying Shimadzu chromatograph with UV detection. Plasma cortisol and fluoxetine levels were measured at time zero (before therapy) and after 6h, 24h, 2, 4, 6 and 8 weeks of fluoxetine administration in patients with major depression qualified for therapeutic drug monitoring (TDM). The study included 21 patients (14 women, 7 men; mean age 29-75 years) and 24 healthy comparison subjects. The patients had a mean score on the 21-item HDRS. As the effect of fluoxetine administration the decrease of the level of cortisol was observed in patients who responded to the therapy (the reduction of points in HDRS scale in at least 50%). The validation parameters of HPLC method of fluoxetine and cortisol determination indicate the possibility of applying them for determination of both: the level of concentration of the drug in therapeutic drug monitoring and the level of cortisol in serum of patients with endogenous depression. PMID- 22429480 TI - Genetic association study of individual symptoms in depression. AB - The heritability of some individual depressive symptoms has been well established. However, the causal genes related to individual depressive symptoms and genetic effects on the courses of individual depressive symptoms are still unclear. We examined these issues in 241 Korean patients who met the DSM-IV-TR criteria for major depression. Patients entered a 12-week clinical trial with antidepressants. A total of 1399 single-nucleotide polymorphisms (SNPs) of 79 candidate genes were assessed. The rs557762 and the TT haplotype in the 11th haplotype block of the GRIA3 gene were associated with feelings of guilt in females. The GGCCGGGC haplotype in the first haplotype block of TPH1 was significantly associated with middle insomnia. The ACAG haplotype in the 13th haplotype block of the GRIK2 gene was associated with somatic anxiety. Moreover, the effect of the rs557762 on guilt significantly varied across times. Our results indicate that there are associations between particular gene polymorphisms and some individual depressive symptoms. These results could contribute to understanding the biological mechanisms of depression. PMID- 22429481 TI - Effects of lithium and valproate on oxidative stress and behavioral changes induced by administration of m-AMPH. AB - In the last years our research group has studied and validated the animal model of mania induced by dextroamphetamine (d-AMPH). Considering the lack of animal models of mania reported in the literature; this study evaluated the possibilities to validate the animal model induced by methamphetamine (m-AMPH). Then, we evaluated the effects of lithium (Li), valproate (VPA) on the behavior and parameters of oxidative damage in rat brain after administration of m-AMPH. In the prevention treatment, Wistar rats were pretreated with Li, VPA or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with m-AMPH (1, 0.5 or 0.25 mg/kg) or Sal. In the reversal treatment, rats were first given m AMPH (0.25 mg/kg) or Sal. Locomotor behavior was assessed using the open-field task and parameters of oxidative damage were measured in brain structures. Our results show that the hyperactivity was prevented and reverted by Li and VPA only when m-AMPH was administered in the dose of 0.25mg/kg. In addition, the m-AMPH in all doses administrated induced oxidative damage in both structures tested in two models. Li and VPA reversed and prevented this impairment, however in a way dependent of cerebral area, the dose of m-AMPH and technique. PMID- 22429482 TI - Impairment in associative memory in healthy aging is distinct from that in other types of episodic memory. AB - There is evidence that age related changes in episodic memory are heterogeneous and result from diverse pathologies. To test this, we examined performance of healthy high-functioning younger (N=41, ages 18-60 y) and older (N=58, ages 61-83 y) individuals in tests of associative memory, logical memory and memory in executive and object-recognition domains. We compared their relationships to each other and to other cognitive functions, including, psychomotor speed and verbal and spatial working memory. Older individuals showed significantly greater reduction in an index of the ability to learn new associations (NAL) than for memory in executive and object-recognition domains. Age-related reduction in NAL and in logical memory was of similar severity, but the two measures showed only moderate correlation when age and other cognitive functions were controlled for. NAL shows an age-related pattern of change distinct from memory in executive and object-recognition domains and from logical (item) memory. We propose that in healthy well-functioning individuals, NAL taps processes which support binding of newly learned association in context of accumulating information, a key function of the hippocampus. NAL may thus serve as a selective marker of complex, hippocampus-based, cognitive functions in studies of normal cognitive aging and of its possible relationship to early dementia. PMID- 22429483 TI - Impaired monocyte activation in schizophrenia. AB - An inflammatory process is hypothesized in schizophrenia. Innate immunity, in particular the monocyte/macrophage system, has rarely been studied in this disorder, although alterations in microglia indicate a role for this system. Increased monocyte numbers have repeatedly been described. Toll-like receptors (TLRs) mediate the activation of monocytes. We studied the expression of the toll like receptors TLR-2, TLR-3 and TLR-4 on CD14(+) monocytes in 31 schizophrenia patients and 31 sex- and age-matched healthy controls. Blood samples were taken and stimulated with either lipopolysaccharides (LPS), to mimic a bacterial infection, or polyI:C, to mimic a viral infection. Moreover, the intracellular concentration of interleukin-1beta (IL-1beta) in CD33(+) monocytes was estimated before and after stimulation. The intracellular concentrations of IL-1beta and the TLR surface markers were analyzed by flow cytometry. Receptor expression of TLR-3 and TLR-4, but not of TLR-2, was significantly higher in the schizophrenia patients. After stimulation, patients showed less increase in the expression of TLR-3 and TLR-4 than controls did. The IL-1beta concentration was significantly lower in patients both before and after stimulation with polyI:C, and there was a trend towards a lower concentration after LPS stimulation. The higher expression of TLR-3 and TLR-4 receptors might compensate for a functional deficit, and the lower intracellular concentrations of IL-1beta might reflect the blunted monocytic function in schizophrenia. The immunological dysfunctions might be associated with a poor clearance of pathogens in schizophrenia, which in turn could lead to a low-grade inflammatory process. PMID- 22429484 TI - Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation. AB - Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently >= 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of >= 600mg/day for >= 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of >= 4 on the Clinical Global Impression (CGI) Severity and a score of <= 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or <= 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of <= 2, a >= 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of >= 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials. PMID- 22429485 TI - Oxidative stress rather than triglyceride accumulation is a determinant of mitochondrial dysfunction in in vitro models of hepatic cellular steatosis. AB - BACKGROUND/AIMS: There is still debate about the relationship between fat accumulation and mitochondrial function in nonalcoholic fatty liver disease. It is a critical question as only a small proportion of individuals with steatosis progress to steatohepatitis. In this study, we focused on defining (i) the effects of triglyceride accumulation and reactive oxygen species (ROS) on mitochondrial function (ii) the contributions of triglyceride, ROS and subsequent mitochondrial impairment on the metabolism of energy substrates. METHODS: Human hepatoblastoma C3A cells, were treated with various combinations of oleate, octanoate, lactate (L), pyruvate (P) and ammonia (N) acutely or for 72 h, before measurements of triglyceride concentration, cell respiration, ROS production, mitochondrial membrane potential, ketogenesis and gluconeogenesis, TCA cycle metabolite analysis and electron microscopy. RESULTS: Acutely, LPON treatment enhanced mitochondrial respiration and ROS formation. After 72 h, despite the similarities in triglyceride accumulation, LPON treatment, but not oleate, dramatically affected mitochondrial function as evidenced by decreased respiration, increased mitochondrial membrane potential and ROS formation with concomitant enhanced ketogenesis. By comparison, respiration and ROS formation remained unperturbed with oleate. Importantly, this was accompanied by an increased gluconeogenesis and ketogenesis. The addition of the antioxidant N acetyl-L-cysteine prevented mitochondrial dysfunction and reversed metabolic changes seen with LPON, strongly suggesting ROS involvement in mediating mitochondrial impairment. CONCLUSIONS: Our data indicate that ROS formation, rather than cellular steatosis per se, impairs mitochondrial function. Thus, reduction in cellular steatosis may not always be the desired outcome without concomitant improvement in mitochondrial function and/or reducing of ROS formation. PMID- 22429486 TI - Characteristics of hospitalised US veterans with nosocomial pressure ulcers. AB - The objective of this study was to describe demographic and clinical characteristics of hospitalised US veterans with nosocomial pressure ulcer (NPU) referred to a certified Wound, Ostomy & Continence Nurse (WOCN). We conducted a retrospective review of electronic records at a Veterans Affairs Medical Center in the northwestern USA. Records of veterans with NPU referred to a WOCN (n = 29) from May 2005 to June 2006 were reviewed. Location and stage of pressure ulcer(s), Braden score on admission and when the ulcer was first noted, day of hospital stay when the ulcer was first noted, medical diagnoses and clinical conditions and events such as surgery, hypoxemia, hypoalbuminemia and hypotension were recorded. Mean age of the patients was 69.8. The most common location was the sacrum/coccyx. Most ulcers were stage 1 when identified. Braden score during admission classified half of the sample at risk, but 81% of Braden scores at ulcer occurrence were <18. Ninety percent of the sample had three or more comorbidities. Over half had died in the 1-14 months after the reviewed hospitalisation. Hospitalised veterans referred for WOCN consultation had multiple risk factors and comorbid conditions, including hypoxemia, serum albumin depletion, anaemia and hypotension. Veterans cared for in Veterans Affairs Medical Centers are known to have multiple health problems, and those in this sample not only had nosocomial pressure ulcer, but also other physiological derangements that may shorten survival. PMID- 22429487 TI - The use of rpoB sequence analysis in the differentiation of Mycobacterium abscessus and Mycobacterium chelonae: a critical judgement in cystic fibrosis? AB - Individuals suffering from fibrocystic disease may acquire non-tuberculous mycobacteria as colonizing or infecting organisms. Mycobacterium abscessus is of particular concern because it may be very difficult to eradicate and may mitigate against lung transplantation. However, this species may be difficult to reliably differentiate from the closely related M. chelonae. We have developed a rapid, low-cost, short sequence-based technique to confirm species identity by analysis of a segment of the RNA Polymerase B (rpoB) gene. PMID- 22429488 TI - Private peer group settings as an environmental determinant of alcohol use in Dutch adolescents: results from a representative survey in the region of Twente. AB - This study supports the hypothesis that the drinking setting can be an environmental risk factor for hazardous alcohol use. In a survey of Dutch adolescents (n = 1516), alcohol consumption and participation in private peer group settings (PPSs), environments where adolescents meet and drink alcohol without direct adult supervision, were measured. After controlling for demographic variables, adolescents visiting PPSs as compared to non-visitors, appeared to have a significantly higher lifetime prevalence of alcohol use, average weekly consumption, and frequency of heavy episodic drinking. Moreover, accounting for school clustering, the frequency of PPS visits was associated with increased alcohol consumption. PMID- 22429489 TI - Does cultural context make a difference to women's experiences of maternity care? A qualitative study comparing the perspectives of breast-feeding women of Bangladeshi origin and health practitioners. AB - BACKGROUND: Maternity services struggle to provide culturally appropriate care that meets the needs of women from diverse populations. Problems include simplistic understandings of ethnicity and the role of culture in women's lives, and stereotypes held by health practitioners. OBJECTIVE: To explore the extent to which cultural context makes a difference to experiences of breast-feeding support for women of Bangladeshi origin and to consider the implications for the provision of culturally appropriate care. METHODS: The study comprised individual interviews with 23 women of Bangladeshi origin and four health service managers, and focus group discussions with 28 health practitioners between February and December 2008. Participants were recruited from four localities in northern England. RESULTS: Women's rich descriptions of various facets of their identities were in contrast to practitioners' representations of women of Bangladeshi origin as homogenous. Practitioners did not recognize when the needs of women of Bangladeshi origin were similar to those of the majority white population, or where cultural context made a difference to their experiences of breast-feeding and breast-feeding support. Some practitioners used cultural stereotypes which, combined with organizational constraints, resulted in services not meeting many of the women's needs. CONCLUSIONS: Implications for education, policy and practice include the need for training of health practitioners to work with diverse populations, implementing evidence-based practice and providing an organizational context which supports practitioners to respond to diversity without using cultural stereotypes. PMID- 22429490 TI - The association between drinking motives and alcohol-related consequences - room for biases and measurement issues? AB - AIMS: To investigate whether the predominant finding of generalized positive associations between self-rated motives for drinking alcohol and negative consequences of drinking alcohol are influenced by (i) using raw scores of motives that may weight inter-individual response behaviours too strongly, and (ii) predictor-criterion contamination by using consequence items where respondents attribute alcohol use as the cause. DESIGN: Cross-sectional study within the European School Survey Project on Alcohol and other Drugs (ESPAD). SETTING: School classes. PARTICIPANTS: Students, aged 13-16 (n = 5633). MEASUREMENTS: Raw, rank and mean-variance standardized scores of the Drinking Motives Questionnaire--Revised (DMQ-R); four consequences: serious problems with friends, sexual intercourse regretted the next day, physical fights and troubles with the police, each itemized with attribution ('because of your alcohol use') and without. FINDINGS: As found previously in the literature, raw scores for all drinking motives had positive associations with negative consequences of drinking, while transformed (rank or Z) scores showed a more specific pattern: external reinforcing motives (social, conformity) had negative and internal reinforcing motives (enhancement, coping) had non-significant or positive associations with negative consequences. Attributed consequences showed stronger associations with motives than non-attributed ones. CONCLUSION: Standard scoring of the Drinking Motives Questionnaire (Revised) fails to capture motives in a way that permits specific associations with different negative consequences to be identified, whereas use of rank or Z-scores does permit this. Use of attributed consequences overestimates the association with drinking motives. PMID- 22429492 TI - The chemical tuning of a weak zinc binding motif for histone deacetylase using electronic effects. AB - The hydroxamic acid moiety is an effective metal-binding warhead for a variety of metalloenzyme targets of interest in drug-discovery. For the zinc-containing histone deacetylase enzymes in particular, this chemical group has been widely incorporated and studied in the clinic. An alternative chemical functionality for binding zinc is the alpha-aminocarbonyl motif, which has been shown to bind to histone deacetylase enzymes. The current article explores the minimal binding site theoretical approach combined with structural knowledge to explore the ideal chemical substitution pattern of the alpha-aminocarbonyl motif within HDAC8. The metal-binding strength of the group is predicted to be highly tunable to chemical substitution at the carbonyl and the alpha-amino carbon. A fixed receptor model approach with a dispersion-corrected density functional, clearly discerned the effect of different substituents at both these positions using either a flexible or partially fixed ligand optimized in the presence of a fixed receptor model of the HDAC8 binding site. An electron donating substituent such as methyl at the C(alpha) in combination with NMe(2) substitution at the carbonyl position, similar to observed crystal structures, result in the optimal energetic profile for binding the zinc atom in the HDAC8 enzyme. PMID- 22429491 TI - Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro apoptotic protein Bim. AB - INTRODUCTION: In this pre-clinical in vitro study conducted in estrogen receptor positive (ER+) breast cancer cells, we have characterized the effects of insulin like growth factor I (IGF-1) on the cytostatic and cytotoxic action of antiestrogen treatment when used as a single agent or in combination with the antiprogestin mifepristone (MIF). Our goal was to identify new molecular targets to improve the efficacy of hormonal therapy in breast cancer patients that have a poor response to hormonal therapy, in part, due to high circulating levels of unbound insulinIGF-1. METHODS: IGF-1-mediated effects on cytostasis and apoptotic cell death were determined with cell counts conducted in the presence and absence of trypan blue; enzyme-linked immunosorbent assays to determine the intracellular levels of cleaved cytokeratin 18, a marker of epithelial cancer cell apoptosis; and immunoblot analysis to determine the levels of cleaved poly-ADP ribose polymerase (PARP) and lamin A that result from caspase-dependent apoptosis. Cytotoxicity was further characterized by determination of the levels of reactive oxygen species (ROS) and the percent of mitochondrial membrane depolarization in cell populations treated with the different hormones in the presence and absence of IGF-1. Small molecule inhibitors of the dual-specificity protein kinase MEK1, MEK1 siRNA, Bim siRNA, and vectors overexpressing MEK1 wild type and mutant, dominant negative cDNA were used to identify key IGF-1 downstream prosurvival effectors. RESULTS: IGF-1, at physiologically relevant levels, blocked the cytotoxic action(s) of the antiestrogens 4-hydroxytamoxifen (4-OHT) and tamoxifen (TAM) when used as single agents or in combination with the antiprogestin MIF. The antiapoptotic action of IGF-1 was mediated primarily through the action of MEK1. MEK1 expression reduced the levels of ROS and mitochondrial membrane depolarization induced by the hormonal treatments via a mechanism that involved the phosphorylation and proteasomal turnover of the proapoptotic BH3-only Bcl-2 family member Bim. Importantly, small-molecule inhibitors of MEK1 circumvented the prosurvival action of IGF-1 by restoring Bim to levels that more effectively mediated apoptosis in ER+ breast cancer cells. CONCLUSION: his study provides strong support for the use of MEK1 inhibitors in combination with hormonal therapy to effectively affect cytostasis and activate a Bim-dependent apoptotic pathway in ER+ breast cancer cells. We discuss that MEK1 blockade may be a particularly effective treatment for women with high circulating levels of IGF-1, which have been correlated to a poor prognosis. PMID- 22429493 TI - LIN28 expression and prognostic value in hepatocellular carcinoma patients who meet the Milan criteria and undergo hepatectomy. AB - Stem cell marker LIN28, related closely with SOX2 and OCT4, has been studied as a biomarker for the maintainance of pluripotent cells in several malignancies. Our previous study showed that SOX2 and OCT4 were negative predictors for hepatocellular carcinoma (HCC). However, the predictive value of LIN28 in HCC outcome is still undetermined. We hypothesized that LIN28 may also play a role as a biomarker for HCC. To test this hypothesis, we examined the expression of LIN28 in 129 radically resected HCC tissues using reverse transcription-polymerase chain reaction and analyzed the association of LIN28 expression with clinicopathologic features and prognosis. Our study showed that LIN28 was expressed at a higher frequency in tumor tissues than in non-HCC tissues (45.0% vs. 21.7%, P = 0.020). Moreover, LIN28 expression was significantly increased in cases with large tumor size (P = 0.010). Univariate analysis did not reveal a significant correlation between LIN28 expression and overall survival or recurrence-free survival. For HCC patients who met the Milan criteria, stratified analysis revealed shorter overall survival (P = 0.007) and recurrence-free survival (P < 0.001) in those with detectable LIN28 expression compared to those with no detectable LIN28 expression. Furthermore, multivariate analysis revealed that LIN28 was a negative independent predictor for both overall survival (hazard ratio= 7.093, P = 0.017) and recurrence-free survival (hazard ratio=5.518, P = 0.004) in patients who met the Milan criteria. Taken together, our results suggest that LIN28 identifies low-risk and high-risk subsets of HCC patients meeting the Milan criteria who undergo hepatectomy. PMID- 22429494 TI - Application of mesenchymal stem cells as a vehicle to deliver replication competent adenovirus for treating malignant glioma. AB - Although gene therapy was regarded as a promising approach for glioma treatment, its therapeutic efficacy was often disappointing because of the lack of efficient drug delivery systems. Mesenchymal stem cells(MSCs) have been reported to have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. Therefore, in this study, we attempted to treat glioma by using MSCs as a vehicle for delivering replication-competent adenovirus. We firstly compared the infectivity of type 3, type 5, and type 35 fiber-modified adenoviruses in MSCs. We also determined suitable adenovirus titer in vitro and then used this titer to analyze the ability of MSCs to deliver replication-competent adenovirus into glioma in vivo. Our results indicated that type 35 fiber-modified adenovirus showed higher infectivity than did naked type 3 or type 5 fiber-modified adenovirus. MSCs carrying replication-competent adenovirus significantly inhibited tumor growth in vivo compared with other control groups. In conclusion, MSCs are an effective vehicle that can successfully transport replication competent adenovirus into glioma, making it a potential therapeutic strategy for treating malignant glioma. PMID- 22429495 TI - Predictors of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study. AB - AIM: To assess the risk of re-operation due to post-surgical bleeding after initial breast cancer surgery and to identify predictors of re-operation. METHODS: We conducted a population-based study in Denmark. Patients were categorized according to age group, surgery type, and glucocorticoid use before surgery: never, current (0-90 days), and former (>90 days). We calculated the risk of re-operation due to post-surgical bleeding within 14 days after surgery, risk differences, and risk ratios of re-operation associated with age group, surgery type, and glucocorticoid use. RESULTS: 19,919 women were studied; 508 were re-operated. 3573 of the 19,919 women ever used glucocorticoids. Older age and mastectomy increased the risk of post-surgical bleeding compared with breast conserving surgery and younger age among both ever and never users of glucocorticoids. The crude risk of re-operation was 2.5% among never users of glucocorticoids, 2.6% among ever users and 4.0% among current users. Women aged >=80 who were ever users of glucocorticoids and who had a mastectomy had 8.1% risk of re-operation due to post-surgical bleeding, whereas women <80 years old who never used glucocorticoids and who had breast conserving surgery had a 1.7% risk of re-operation. CONCLUSIONS: Older age, mastectomy, and - in some women - glucocorticoid use add an extra risk of re-operation due to bleeding. Clinicians and their patients can use this information to evaluate the patient-specific risk of this complication. PMID- 22429496 TI - Use of an injectable, 25-gauge shape-memory clip to fixate an encircling silicone band: a laboratory model. PMID- 22429497 TI - Left lobe living donor liver transplantation in adults. AB - Adult left lobe (LL) living donor liver transplantation (LDLT) has not generally been recognized as a feasible procedure because of the problem of graft size. The objectives of this study were to assess the feasibility and short- and long-term results of adult LL LDLT in comparison with right lobe (RL) LDLT. Data on 200 consecutive LL LDLTs, including five retransplants, were retrospectively compared with those of 112 RL LDLTs, in terms of survival, complications and donor morbidity. The mean graft weight to standard volume ratio of LL grafts was 38.7% whereas that of RL grafts was 47.6% (p < 0.0001). The 1-, 5- and 10-year patient survival rates of LL LDLT were 85.6%, 77.9% and 69.5%, respectively, which were comparable to those of RL LDLT (89.8%, 71.3% and 70.7%, respectively). The incidence of small-for-size syndrome was higher in LL LDLT (19.5%) than in RL LDLT (7.1%) (p < 0.01). The overall donor morbidity rates were comparable between LL (36.0%) and RL (34.8%), whereas postoperative liver function tests and hospital stay were significantly better (p < 0.0001) in LL donors. In conclusion, adult LL LDLT has comparable outcomes to that of RL LDLT. LL LDLT is viable and is the first choice in adult LDLT. PMID- 22429498 TI - Sexual behaviours, knowledge and attitudes regarding safe sex, and prevalence of non-viral sexually transmitted infections among attendees of youth clinics in St. Petersburg, Russia. AB - BACKGROUND: Adolescents and young adults are at increased risk of sexually transmitted infections (STIs). Knowledge of STI prevalence and risk factors are essential tools to elaborate preventive strategies. However, internationally reported studies on epidemiology of STIs among the youth in Russia are mainly lacking. OBJECTIVES: To ascertain sexual behaviours, knowledge and attitudes about safe sex and prevalence and correlates with STIs in attendees of youth clinics in St. Petersburg, Russia. METHODS: A total of 301 women and 131 men, who self-referred for STI testing, completed a questionnaire and were screened for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis using nucleic acid amplification tests. RESULTS: The overall STI prevalence was 16.9%, and similar in the female patients and male patients (15.6% and 19.8% respectively). C. trachomatis, N. gonorrhoeae, M. genitalium and T. vaginalis were detected in 13%, 2.5%, 4.6% and 1.2% of the attendees respectively. The men displayed riskier sexual behaviours and worse knowledge and attitudes regarding safe sex compared to the women, with the most distinguishing features being younger age at first intercourse (P < 0.0005), higher numbers of sex partners during lifetime (P = 0.001) and latest 6 months (P < 0.0005), more frequently consuming alcohol (P < 0.0005), poorer knowledge of STI/HIV prevention measures (P < 0.0005), and less positive attitudes towards safe sex (P = 0.001). However, no significant predictors of STI positivity were found in the men. In the women, the strongest predictors of STI positivity were young age (15-19 years) and multiple sex partners (>= 2) during latest 6 months. CONCLUSIONS: The overall prevalence of STIs among users of STI services at youth clinics in St. Petersburg was high. Comprehensive epidemiological data on STI prevalence and sexual behaviour correlates are necessary to initiate new and strengthen existing STI prevention programmes for the youth, in Russia as well as in many other settings. PMID- 22429499 TI - Protective effect of recombinant staphylococcal enterotoxin A entrapped in polylactic-co-glycolic acid microspheres against Staphylococcus aureus infection. AB - Staphylococcus aureus is an important cause of nosocomial and community-acquired infections in humans and animals, as well as the cause of mastitis in dairy cattle. Vaccines aimed at preventing S. aureus infection in bovine mastitis have been studied for many years, but have so far been unsuccessful due to the complexity of the bacteria, and the lack of suitable vaccine delivery vehicles. The current study developed an Escherichia coli protein expression system that produced a recombinant staphylococcal enterotoxin A (rSEA) encapsulated into biodegradable microparticles generated by polylactic-co-glycolic acid (PLGA) dissolved in methylene chloride and stabilized with polyvinyl acetate. Antigen loading and surface properties of the microparticles were investigated to optimize particle preparation protocols. The prepared PLGA-rSEA microspheres had a diameter of approximately 5 MUm with a smooth and regular surface. The immunogenicity of the PLGA-rSEA vaccine was assessed using mice as an animal model and showed that the vaccine induced a strong humoral immune response and increased the percent survival of challenged mice and bacterial clearance. Histological analysis showed moderate impairment caused by the pathogen upon challenge afforded by immunization with PLGA-rSEA microspheres. Antibody titer in the sera of mice immunized with PLGA-rSEA microparticles was higher than in vaccinated mice with rSEA. In conclusion, the PLGA-rSEA microparticle vaccine developed here could potentially be used as a vaccine against enterotoxigenic S. aureus. PMID- 22429500 TI - Genetic population structure of the malaria vector Anopheles baimaii in north east India using mitochondrial DNA. AB - BACKGROUND: Anopheles baimaii is a primary vector of human malaria in the forest settings of Southeast Asia including the north-eastern region of India. Here, the genetic population structure and the basic population genetic parameters of An. baimaii in north-east India were estimated using DNA sequences of the mitochondrial cytochrome oxidase sub unit II (COII) gene. METHODS: Anopheles baimaii were collected from 26 geo-referenced locations across the seven north east Indian states and the COII gene was sequenced from 176 individuals across these sites. Fifty-seven COII sequences of An. baimaii from six locations in Bangladesh, Myanmar and Thailand from a previous study were added to this dataset. Altogether, 233 sequences were grouped into eight population groups, to facilitate analyses of genetic diversity, population structure and population history. RESULTS: A star-shaped median joining haplotype network, unimodal mismatch distribution and significantly negative neutrality tests indicated population expansion in An. baimaii with the start of expansion estimated to be ~0.243 million years before present (MYBP) in north-east India. The populations of An. baimaii from north-east India had the highest haplotype and nucleotide diversity with all other populations having a subset of this diversity, likely as the result of range expansion from north-east India. The north-east Indian populations were genetically distinct from those in Bangladesh, Myanmar and Thailand, indicating that mountains, such as the Arakan mountain range between north-east India and Myanmar, are a significant barrier to gene flow. Within north-east India, there was no genetic differentiation among populations with the exception of the Central 2 population in the Barail hills area that was significantly differentiated from other populations. CONCLUSIONS: The high genetic distinctiveness of the Central 2 population in the Barail hills area of the north-east India should be confirmed and its epidemiological significance further investigated. The lack of genetic population structure in the other north east Indian populations likely reflects large population sizes of An. baimaii that, historically, were able to disperse through continuous forest habitats in the north-east India. Additional markers and analytical approaches are required to determine if recent deforestation is now preventing ongoing gene flow. Until such information is acquired, An. baimaii in north-east India should be treated as a single unit for the implementation of vector control measures. PMID- 22429501 TI - Postcoital vaginal rupture in a young woman with no prior pelvic surgery. AB - INTRODUCTION: Reports of postcoital vaginal rupture in the literature are limited to cases involving women who are postmenopausal, have recently undergone pelvic surgery, or have suffered genitourinary trauma. AIM: We report a case of postcoital vaginal rupture in a 23-year-old woman with no prior surgical history who complained of acute onset, severe vaginal pain after consensual intercourse. RESULTS: Examination under anesthesia revealed a 6-cm laceration of the posterior fornix, which extended into the abdominal cavity. The laceration was repaired using a combined vaginal and laparoscopic approach. CONCLUSIONS: Coitus-induced vaginal rupture in a reproductive aged woman with no prior pelvic surgery or other risk factors is a rare clinical presentation. Prior reports of rupture in premenopausal women have recommended repair via laparotomy. This case documents successful transvaginal and laparoscopic repair, and reviews the etiological mechanisms for coitus-induced injury. PMID- 22429502 TI - Hepatocellular adenoma subtypes: the impact of overweight and obesity. AB - BACKGROUND: Hepatocellular adenomas (HCA) are rare benign tumours occurring mainly in women using oral contraceptives. With the appearance of a generation of new oral contraceptives, the number of HCA cases was anticipated to decrease, but in fact this was not observed in our practice. The influence of obesity was therefore suspected as a new co-factor. AIMS: The aim of this study was to analyze the impact of overweight/obesity in our cohort of HCA patients classified according to their subtypes. RESULTS: The number of HCA noticeably increased faster in the 2001-2011 period compared to the 1990-2000 period. This phenomenon concurred with an increasing number of patients overweight or obese. Females still represented the great majority of overweight/obese patients presenting HCA, however, overweight/obese male patients constituted a new entity in the inflammatory HCA and beta-catenin activated- inflammatory HCA subgroups. CONCLUSION: We propose that overweight/obesity may soon represent a major risk of malignant transformation of HCA, possibly via the IL-6 pathway. PMID- 22429503 TI - Flavonols intake and the risk of coronary heart disease: a meta-analysis of cohort studies. AB - OBJECTIVE: Prospective cohort are inconsistent regarding the association between flavonols intake and the risk of coronary heart disease (CHD). The aim was to perform a meta-analysis to determine whether an association exists between them in observational studies. METHODS: We searched PUBMED and EMBASE databases for studies conducted from 1966 through January 2012. Data were independently abstracted by 2 investigators using a standardized protocol. Study-specific risk estimates were combined by using a random-effects model. RESULTS: A total of nine general population cohorts with 216,908 participants and more than 5249 CHD cases were included in the meta-analysis. The summary relative risk (RR) did not indicate a significant association between the highest flavonols intake and reduced risk of CHD (summary RR: 0.91; 95% CI: 0.83, 1.01). Furthermore, no significant association was found through the dose-response analysis (an increment of 20mg/day, summary RR: 0.96; 95% CI: 0.90, 1.03). CONCLUSIONS: Our results do not support a protective role of flavonols intake against CHD. PMID- 22429504 TI - Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece. AB - OBJECTIVE: To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether this GRS also predicts incident stroke. METHODS: Genotypes at nine CHD-relevant SNPs were determined in 494 cases of incident CHD, 320 cases of incident stroke and 1345 unaffected controls drawn from the population-based Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. An additive GRS was calculated for each study participant by adding one unit for the presence of each high-risk allele multiplied by the estimated effect size of that allele in the discovery samples. Statistical analysis was performed using logistic regression. RESULTS: The GRS was significantly associated with the incidence of CHD where the odds of CHD incidence in the highest quintile of the GRS were 1.74 times higher (95% confidence interval [CI]=1.25-2.43, p for trend=0.0004), compared to the lowest quintile. With respect to stroke, a weaker and non-significant positive association with GRS was apparent as the odds of stroke incidence in the highest quintile of the GRS were 1.36 times higher (95% CI=0.90-2.06, p for trend=0.188), compared to the lowest quintile. CONCLUSION: A GRS relying on nine documented "CHD-specific" SNPs is significantly predictive of CHD but it was not found to be statistically significantly associated with incident stroke. PMID- 22429505 TI - Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats. AB - This study investigated the effect of the bark extract of Bathysa cuspidata on paraquat (PQ)-induced extra-pulmonary acute lung injury (ALI) and mortality in rats. ALI was induced with a single dose of PQ (30 mg/kg, i.p.), and animals were treated with B. cuspidata extract (200 and 400 mg/kg). Analyses were conducted of survival, cell migration, lung oedema, malondialdehyde, proteins carbonyls, catalase, superoxide dismutase, histopathology and the stereology of lung tissue. Rats exposed to PQ and treated with 200 and 400 mg of the extract presented lower mortality (20% and 30%), compared with PQ alone group (50%). Furthermore, lung oedema, septal thickening, alveolar collapse, haemorrhage, cell migration, malondialdehyde and proteins carbonyl levels decreased, and catalase and superoxide dismutase activity were maintained. These results show that the bark extract of B. cuspidata reduced PQ-induced extra-pulmonary ALI and mortality in rats and suggest that these effects may be associated with the inhibition of oxidative damage. PMID- 22429507 TI - Synthesis and biological evaluation of pyrethroid insecticide-derivatives as a chemical inducer for Bdnf mRNA expression in neurons. AB - Brain-derived neurotrophic factor (BDNF) plays a fundamental role in neuronal synaptic plasticity. A decrease of plasticity in the brain may be related to the pathogenesis of neurodegenerative or psychiatric disorders. Pyrethroid insecticides, which affect sodium channels in neurons, are widely used to control insect pests in agriculture and in the home. We previously found that deltamethrin (DM), a type II pyrethroid, increased Bdnf mRNA expression in cultured rat cortical neurons. However, the cyano group at the alpha-position of type II pyrethroids is likely susceptible to hydrolytic degradation and, its degraded product, hydrogen cyanide, could generate a cellular toxicity in the human body. To determine if the cyano group is required for the Bdnf exon IV-IX (Bdnf eIV-IX) mRNA expression induced by type II pyrethroids, for this study we synthesized a series of derivatives, in which the cyano group at the alpha position was replaced with an ethynyl group. Then we added various substituents at the terminal position of the ethynyl group, and biologically evaluated the effects of these derivatives on Bdnf eIV-IX mRNA expression. These ethynyl derivatives induced the Bdnf eIV-IX mRNA expression in a concentration-dependent manner, at varying levels but lower levels than that evoked by DM. The mechanisms for the Bdnf induction and the morphological changes of neurons were the same whether the cyano or ethynyl group was included in the compounds. PMID- 22429506 TI - Variable effect of co-infection on the HIV infectivity: within-host dynamics and epidemiological significance. AB - BACKGROUND: Recent studies have implicated viral characteristics in accounting for the variation in the HIV set-point viral load (spVL) observed among individuals. These studies have suggested that the spVL might be a heritable factor. The spVL, however, is not in an absolute equilibrium state; it is frequently perturbed by immune activations generated by co-infections, resulting in a significant amplification of the HIV viral load (VL). Here, we postulated that if the HIV replication capacity were an important determinant of the spVL, it would also determine the effect of co-infection on the VL. Then, we hypothesized that viral factors contribute to the variation of the effect of co infection and introduce variation among individuals. METHODS: We developed a within-host deterministic differential equation model to describe the dynamics of HIV and malaria infections, and evaluated the effect of variations in the viral replicative capacity on the VL burden generated by co-infection. These variations were then evaluated at population level by implementing a between-host model in which the relationship between VL and the probability of HIV transmission per sexual contact was used as the within-host and between-host interface. RESULTS: Our within-host results indicated that the combination of parameters generating low spVL were unable to produce a substantial increase in the VL in response to co-infection. Conversely, larger spVL were associated with substantially larger increments in the VL. In accordance, the between-host model indicated that co infection had a negligible impact in populations where the virus had low replicative capacity, reflected in low spVL. Similarly, the impact of co infection increased as the spVL of the population increased. CONCLUSION: Our results indicated that variations in the viral replicative capacity would influence the effect of co-infection on the VL. Therefore, viral factors could play an important role driving several virus-related processes such as the increment of the VL induced by co-infections. These results raise the possibility that biological differences could alter the effect of co-infection and underscore the importance of identifying these factors for the implementation of control interventions focused on co-infection. PMID- 22429508 TI - Influence of conformationally restricted pyrimidines on the activity of 10-23 DNAzymes. AB - The catalytic core of a 10-23 DNAzyme was modified introducing conformationally restricted nucleosides such as (2'R)-, (2'S)-2'-deoxy-2'-C-methyluridine, (2'R)-, (2'S)-2'-deoxy-2'-C-methylcytidine, 2,2'-anhydrouridine and LNA-C, in one, two or three positions. Catalytic activities under pseudo first order conditions were compared at different Mg(2+) concentrations using a short RNA substrate. At low Mg(2+) concentrations, triple modified DNAzymes with similar kinetic performance to that displayed by the non-modified control were identified. In the search for a partial explanation of the obtained results, in silico studies were carried out in order to explore the conformational behavior of 2'-deoxy-2'-C methylpyrimidines in the context of a loop structure, suggesting that at least partial flexibility is needed for the maintenance of activity. Finally, the modified 2'-C-methyl DNAzyme activity was tested assessing the inhibition of Stat3 expression and the decrease in cell proliferation using the human breast cancer cell line T47D. PMID- 22429509 TI - Synthesis and biological evaluation of bifendate-chalcone hybrids as a new class of potential P-glycoprotein inhibitors. AB - Overexpression of P-glycoprotein (P-gp) is one of the major problems to successful cancer chemotherapy. To find novel effective P-gp inhibitors, a series of bifendate-chalcone hybrids were synthesized and evaluated. Among them, the most active compound 8g had little intrinsic cytotoxicity (IC(50)>200 MUM), and could increase accumulation of Rhodamine 123 in K562/A02 cells more potently than bifendate and verapamil (VRP) by inhibiting P-gp efflux function. And 8g displayed potent chemo-sensitizing effect and persisted for much longer time (>24h) compared with VRP (<6h). In addition, 8g, unlike VRP, showed no stimulation on the P-gp ATPase activity, suggesting it is not a P-gp substrate. Therefore, 8g may represent a promising lead to develop MDR reversal agents for cancer chemotherapy. PMID- 22429510 TI - Synthesis of novel 7-oxo and 7-hydroxy trifluoroallocolchicinoids with cytotoxic effect. AB - The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-beta-phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory effect towards the polymerization of tubulin. The results yielded some potent cytotoxic compounds with correlated partial antitubulin effect. PMID- 22429511 TI - Segregation of a new mutation in SLC26A4 and p.E47X mutation in GJB2 within a consanguineous Tunisian family affected with Pendred syndrome. AB - OBJECTIVE: Recessive mutations of the SLC26A4 (PDS) gene on chromosome 7q31 can cause sensorineural hearing loss with goiter (Pendred syndrome) or non-syndromic autosomal recessive hearing loss (DFNB4). Furthermore, mutations in the GJB2 gene results in autosomal recessive (DFNB1) and dominant (DFNA3) non-syndromic hearing loss. The aim of the present study was to characterize a family with Pendred syndrome affected by severe to profound HL and presenting goiter. METHODS: Affected members underwent detailed audiologic examination and characterization. DNA samples from family members were genotyped with polymorphic microsatellite markers and sequencing of the SLC26A4 and GJB2 genes was performed. A total of 25 families with non-syndromic hearing loss were screened for the common p.E47X mutation in the GJB2 gene by direct dideoxy sequencing. RESULTS: Genetic microsatellite analysis showed linkage to the 7q22-q31 chromosomal region and mutation analysis revealed a novel frameshift mutation (c.451delG) in the SLC26A4 gene. Screening of the GJB2 gene in one patient, displayed a homozygous p.E47X mutation, together with a heterozygous c.451delG mutation. Screening of 25 families with HL showed frequent segregation of the p.E47X mutation, which was homozygous in five of these families. Haplotype analysis using microsatellite markers and single nucleotide polymorphisms (SNPs) closely flanking the GJB2 gene, revealed the presence of two disease-associated-haplotypes suggesting the presence of at least, two founder effects carrying the p.E47X non-sense mutation in the Tunisian population. CONCLUSIONS: The segregation of both SLC26A4 and GJB2 mutations in the family illustrates once again the unexpected intra-familial genetic heterogeneity in consanguineous families and highlights the difficulty of genetic counselling in such families. In addition, our results disclose the existence of founder effects in the Tunisian population. PMID- 22429512 TI - Ambulatory blood pressure monitoring in children with obstructive sleep apnea and primary snoring. AB - OBJECTIVE: To evaluate the systemic blood pressure (BP) during daytime and nighttime in children with sleep breathing disorders (SBD) and compare parameters of BP in children with diagnosis of obstructive sleep apnea syndrome (OSA) to those one with primary snoring (PS). METHODS: Children, both genders, aged from 8 to 12 years, with symptoms of SBD realized an overnight polysomnography followed by a 24h recording of ambulatory BP. RESULTS: All subjects presented with a history of snoring 7 nights per week. Children who have apnea/hipoapnea index >= four or a apnea index >= one presented a mean BP of 93+/-7mmHg and 85+/-9mmHg diurnal and nocturnal respectively whereas children who have a apnea/hipoapnea < four or a apnea index < one presented 90+/-7mmHg and 77+/-2mmHg. Eight children out of fourteen, from OSA group, lost the physiologic nocturnal dipping of the blood pressure. Among OSA children 57% were considered non-dippers. Two (16%) have presented absence of nocturnal dipping among children with primary snoring. The possibility of OSA children loosing physiologic blood pressure dipping was 6.66 higher than the possibilities of patients from PS group. DISCUSSION: Our results indicate that children with sleep apnea syndrome exhibit a higher 24h blood pressure when compared with those of primary snoring in form of decreased degree of nocturnal dipping and increased levels of diastolic and mean blood pressure, according to previous studies in literature. OSA in children seems to be associated to the development of hypertension or other cardiovascular disease. PMID- 22429513 TI - Randomised comparative study of adenotonsillectomy by conventional and coblation method for children with obstructive sleep apnoea. AB - INTRODUCTION: Adenotonsillectomy is one of the most common surgical procedures throughout the world for children in otolaryngology. One of the current indications for adenotonsillectomy is adenotonsillar hypertrophy causing Obstructive Sleep Apnoea (OSA). The choice of surgical tools and technique affects the outcome and morbidity due to adenotonsillectomy. AIM OF THE STUDY: To assess the efficacy and safety of coblation adenotonsillectomy as compared to dissection method. To evaluate the morbidity and to study complications associated with each procedure. MATERIALS AND METHODS: This prospective and comparative study of dissection and coblation method of adenotonsillectomy was conducted in our institute, Madras ENT Research Foundation, Chennai over a period of 6 months. 50 cases of children with OSA age group between 5 and 12 years were randomly selected for each group and studied. Duration of surgical procedure, blood loss, post operative pain, post operative reactionary and secondary bleeding was noted and compared. OBSERVATION AND RESULTS: Operative time was more in dissection method compared to coblation technique. Blunt dissection tonsillectomy was associated with greater blood loss than coblation tonsillectomy. Post operative pain was more in dissection method and it was less in coblation technique. Post operative bleeding in both the techniques were found to be minimal. CONCLUSION: We conclude that the use of coblation for adenotonsillectomy may have several advantages over standard methods for the treatment of children with Obstructive Sleep Apnoea. It is highly efficacious, practical and safe with less morbidity and less complications. PMID- 22429514 TI - Is it possible to estimate the minimal clinically important treatment effect needed to change practice in preterm birth prevention? Results of an obstetrician survey used to support the design of a trial. AB - BACKGROUND: Sample sizes for obstetrical trials are often based on the opinion of investigators about clinically important effect size. We surveyed Canadian obstetricians to investigate clinically important effect sizes required before introducing new treatments into practice to prevent preterm birth. METHODS: Questionnaires were mailed to practicing obstetricians, asking the magnitude of pregnancy prolongation required to introduce treatments into practice. The three prophylactic treatments were of increasing invasiveness: vaginal progesterone, intramuscular progesterone, and cervical cerclage. We also asked about the perceived most relevant outcome measures for obstetrical trials and current obstetrical practice in preterm birth prevention. RESULTS: 544/1293(42.1%) completed questionnaires were received. The majority of respondents required one or two weeks' increase in length of gestation before introducing vaginal (372,77.1%), and intramuscular progesterone(354,67.9%). At least three weeks increase was required before introducing prophylactic cervical cerclage(326,62.8%). Clinicians who already used a treatment required a smaller difference before introducing it into practice. Decreasing neonatal morbidity was cited as the most important outcome for obstetrical trials (349,72.2%). CONCLUSION: Obstetricians would require a larger increase in treatment effect before introducing more invasive treatments into practice. Although infant morbidity was perceived as a more important outcome, clinicians appeared willing to change practice on the basis of prolongation of pregnancy, a surrogate outcome. We found that there is not a single minimum clinically important treatment effect that will influence all practising clinicians: rather the effect size that will influence physicians is affected by the nature of the treatment, the reported outcome measure and the clinician's own current clinical practice. PMID- 22429515 TI - Global asthma prevalence in adults: findings from the cross-sectional world health survey. AB - BACKGROUND: Asthma is a major cause of disability, health resource utilization and poor quality of life world-wide. We set out to generate estimates of the global burden of asthma in adults, which may inform the development of strategies to address this common disease. METHODS: The World Health Survey (WHS) was developed and implemented by the World Health Organization in 2002-2003. A total of 178,215 individuals from 70 countries aged 18 to 45 years responded to questions related to asthma and related symptoms. The prevalence of asthma was based on responses to questions relating to self-reported doctor diagnosed asthma, clinical/treated asthma, and wheezing in the last 12 months. RESULTS: The global prevalence rates of doctor diagnosed asthma, clinical/treated asthma and wheezing in adults were 4.3%, 4.5%, and 8.6% respectively, and varied by as much as 21-fold amongst the 70 countries. Australia reported the highest rate of doctor diagnosed, clinical/treated asthma, and wheezing (21.0%, 21.5%, and 27.4%). Amongst those with clinical/treated asthma, almost 24% were current smokers, half reported wheezing, and 20% had never been treated for asthma. CONCLUSIONS: This study provides a global estimate of the burden of asthma in adults, and suggests that asthma continues to be a major public health concern worldwide. The high prevalence of smoking remains a major barrier to combating the global burden of asthma. While the highest prevalence rates were observed in resource-rich countries, resource-poor nations were also significantly affected, posing a barrier to development as it stretches further the demands of non communicable diseases. PMID- 22429516 TI - NTproBNP as a marker of rejection in pediatric heart transplant recipients. AB - Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject's serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value. PMID- 22429517 TI - Random and cyclical deletion of large DNA segments in the genome of Pseudomonas putida. AB - Cumulative site-directed mutagenesis is of limited suitability for the global analysis of the gene functions in the microbe's cellular network. In order to simplify and stabilize the genome of the soil bacterium Pseudomonas putida, we developed a recyclable three-step excision method based on the combination of customized mini-transposons and the FLP-FRT site-specific recombination system. To demonstrate the powerful potential of these tools, we first established insertion mutant libraries that allow users to study gene functions with respect either to phenotypic characteristics (single insertions) or to their involvement in predicted networks (double insertions). Based on these libraries, we generated as a proof-of-principle, single-deletion mutants lacking ~4.1% of the genome (~3.7% of the gene repertoire). A cyclical application of the method generated four double-deletion mutants of which a maximum of ~7.4% of the chromosome (~6.9% of the gene count) was excised. This procedure demonstrates a new strategy for rapid genome streamlining and gain of new insights into the molecular interactions and regulations. PMID- 22429518 TI - Factors associated with cerebral white matter hyperintensities in haemodialysis patients. AB - AIM: Cerebral white matter hyperintensities (WMHs), comprising periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH) on magnetic resonance imaging (MRI), have been reported to be markers of ischaemic cerebral small-vessel disease and risk factors for future stroke, cognitive impairment and dementia in the general population. However, there have been only a few reports describing WMHs in haemodialysis (HD) patients and these previous studies have been relatively small population studies with little investigation on prevalence and risk factors according to the regional subtypes of WMHs. METHODS: Cranial MRI was performed on 179 HD patients and 58 healthy control subjects and we investigated the prevalence of WMHs (PVH and/or DSWMH) and the clinical factors associated with the presence of WMHs. RESULTS: The prevalence of WMHs was significantly higher in the HD patients than in the healthy subjects. In the HD patients, multiple logistic regression analysis showed that independent and significant factors associated with the presence of PVH were age, female gender and systolic blood pressure and those associated with the presence of DSWMH were age, female gender, systolic blood pressure and body mass index. CONCLUSIONS: These findings indicated a high prevalence of WMHs in HD patients. Older age, female gender and high blood pressure were strong factors associated with the presence of both PVH and DSWMH. Moreover, excess body weight was a significant factor associated with the presence of DSWMH only, indicating that there may be differences in risk factors according to the subtype of WMHs. PMID- 22429519 TI - The relationship between adipose tissue and bone metabolism. AB - OBJECTIVES: The authors have set out to evaluate the literature relevant to the dynamic regulation of adipogenesis and osteogenesis. DESIGN AND METHODS: A detailed search of the past and recent literature was conducted on Pubmed using a combination of keywords including: adipogenesis, bone marrow, hematopoiesis, mesenchymal stromal/stem cell, and osteogenesis. RESULTS: Throughout one's lifespan, the bone marrow microenvironment provides a unique niche for mesenchymal stromal/stem cells (BMSCs) and hematopoietic stem cells (HSCs). The marrow changes as a function of biological age and pathophysiology. Historically, clinical biochemistry has observed these changes from an HSC and hematological perspective. Nevertheless, these changes also reflect the balance between BMSC adipogenic and osteogenic processes which can display an inverse or reciprocal relationship. Multiple hormonal factors and nuclear hormone receptor ligands and drugs are responsible for BMSC lineage selection. Data from a number of laboratories now implicates endocrine feedback loops between extramedullary adipose depots and the central nervous system. CONCLUSIONS: This concise review provides a perspective on the mechanisms regulating BMSC differentiation in the context of biological aging, obesity, and osteoporosis. PMID- 22429520 TI - Diagnostic and prognostic significance of human kallikrein 11 (KLK11) mRNA expression levels in patients with laryngeal cancer. AB - OBJECTIVES: Human kallikrein 11 gene (KLK11) encodes a secreted serine protease. In view of its diagnostic and prognostic strength in many malignancies, we investigated the mRNA expression levels of KLK11 in laryngeal tissues in order to unveil its clinical usefulness in laryngeal cancer. DESIGN AND METHODS: KLK11 expression was quantified in 163 tissue samples from 105 laryngeal cancer patients with the development of a highly sensitive real-time PCR methodology, using SYBR Green(r) chemistry. RESULTS: KLK11 expression in laryngeal cancer specimens of primary or recurrent nature was significantly inferior compared with their non-malignant counterparts (P<0.001 and P=0.026, respectively), a finding of immense diagnostic value as illustrated in the ROC curve analyses (P<0.001). Survival analysis showed that patients harboring KLK11-positive tumors had a significantly decreased risk of death (HR=0.26, P=0.042). CONCLUSIONS: Our data recommend KLK11 mRNA expression as a novel and independent biomarker in laryngeal cancer for diagnostic and prognostic purposes. PMID- 22429521 TI - Laboratory detection of macro-aspartate aminotransferase: case report and evaluation of the PEG-precipitation method. AB - BACKGROUND: Chronic elevated AST without other signs of liver disease, cardiac or skeletal abnormalities, is suggestive for macro-AST. Laboratory detection can be performed by gel filtration chromatography, ultrafiltration or precipitation with polyethylene glycol (PEG). PATIENT AND METHODS: A healthy 27 year-old female was referred because of chronic elevated AST (116-704U/L) without other abnormalities. Macro-AST positivity was suspected since AST was no longer measurable in the supernatant of a serum sample (<3U/L) after PEG precipitation. Optimization of this method included analysis of proteins and lipids precipitated, testing the effect of different PEG concentrations and centrifugation times. 25% (m/v) PEG solution gave the most reliable results. No significant difference was seen between 10 and 30 min centrifugation time. A reference range was obtained by analysis of 31 normal patient samples (mean % PEG precipitation activity 35.1% with 95% confidence limits of 14.5-62.5%). Retrospective analysis of 1371 patient samples with elevated AST revealed one other positive patient sample. CONCLUSION: Early recognition of macro-AST, proven by simple PEG precipitation, can avoid time-consuming and invasive investigations. PMID- 22429522 TI - Clinical measurement of mechanical ankle instability. AB - Clinicians commonly use the anterior draw test (ligament laxity) and distal fibular position (lateral malleolus displacement), to measure ankle instability. The purpose of this study was to establish intra-rater and inter-rater reliability for the anterior draw test and distal fibular position in a clinical setting. The anterior draw test (AD) was measured with a plastic Goniometer, and was defined as the linear displacement of the foot as it is drawn anteriorly with the ankle held in 20 degrees of plantar-flexion. Distal fibular position (DFP) was measured in standing using a digital vernier caliper and was the relative linear distance between the lateral and the medial malleoli. 20 participants aged 21-28 volunteered for the study and were measured on both ankles. It was found that Intra-tester reliability (ICC) ranged from 0.88 to 0.97 for AD and DFP; while inter-tester reliability (ICC) was 0.6 for AD and 0.77 for DFP. In addition for measures across trials, the standard error of the measurement (SEM) was, on average 0.66 mm for AD and 1.7 mm for DFP. While the limits of agreement (LOA) was +/-0.17 mm for AD and +/-4.03 mm for DFP. However, the SEM and LOA between testers was 2.27 mm and +/-2.27 mm respectively for AD; and for 3.1 mm and +/ 10.4 mm for DFP. Overall the results suggest that both measures, as defined in this study exhibit moderate to good reliability and low standard error of measurement, suggesting a high degree of repeatability across trials. PMID- 22429523 TI - Effect of mineral-enriched diet and medicinal herbs on Fe, Mn, Zn, and Cu uptake in chicken. AB - BACKGROUND: The goal of our study was to evaluate the effects of different medicinal herbs rich in polyphenol (Lemon balm, Sage, St. John's wort and Small flowered Willowherb) used as dietary supplements on bioaccumulation of some essential metals (Fe, Mn, Zn and Cu) in different chicken meats (liver, legs and breast). RESULTS: In different type of chicken meats (liver, legs and breast) from chickens fed with diets enriched in minerals and medicinal herbs, beneficial metals (Fe, Mn, Zn and Cu) were analysed by flame atomic absorption spectrometry. Fe is the predominant metal in liver and Zn is the predominant metal in legs and breast chicken meats. The addition of metal salts in the feed influences the accumulations of all metals in the liver, legs and breast chicken meat with specific difference to the type of metal and meat. The greatest influences were observed in legs meat for Fe and Mn. Under the influence of polyphenol-rich medicinal herbs, accumulation of metals in the liver, legs and breast chicken meat presents specific differences for each medicinal herb, to the control group that received a diet supplemented with metal salts only. Great influence on all metal accumulation factors was observed in diet enriched with sage, which had significantly positive effect for all type of chicken meats. CONCLUSIONS: Under the influence of medicinal herbs rich in different type of polyphenol, accumulation of metals in the liver, legs and breast chicken meat presents significant differences from the group that received a diet supplemented only with metal salts. Each medicinal herb from diet had a specific influence on the accumulation of metals and generally moderate or poor correlations were observed between total phenols and accumulation of metals. This may be due to antagonism between metal ions and presence of other chelating agents (amino acids and protein) from feeding diets which can act as competitor for complexation of metals and influence accumulation of metals in chicken meat.Graphical abstract. PMID- 22429524 TI - Antimalarial activity of newly synthesized chalcone derivatives in vitro. AB - Twenty-seven novel chalcone derivatives were synthesized using Claisen-Schmidt condensation and their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Antiplasmodial IC(50) (half-maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4 dimethoxy-phenyl)-propen-1-one with IC(50) of 1.1 MUg/mL, while that of the natural phytochemical, licochalcone A is 1.43 MUg/mL. The presence of methoxy groups at position 2 and 4 in chalcone derivatives appeared to be favorable for antimalarial activity as compared to other methoxy-substituted chalcones. Furthermore, 3, 4, 5-trimethoxy groups on chalcone derivative probably cause steric hindrance in binding to the active site of cysteine protease enzyme, explaining the relative lower inhibitory activity. PMID- 22429525 TI - Workaholism and mental health among Polish academic workers. AB - The aim of this study was to examine the relationship between workaholism and mental health among 126 Polish academic workers. The participants' mean age was 45.9 years, 51.6% of them were women. The participants completed 2 questionnaires: the work addiction risk test and the general health questionnaire. Even though 66% of the subjects were classified in the group of moderate-to-high risk of workaholism, the overall state of mental health was categorized as average. The results revealed that workaholism was associated with poorer mental health. Employees with higher levels of workaholism had worse state of health, i.e., more somatic symptoms, higher levels of anxiety, insomnia, social dysfunction and symptoms of depression. Emotional arousal/perfectionism was the strongest predictor of the state of general health and was mostly responsible for harmful effects on mental health. However, the general effect of workaholism on health was not as strong as expected. PMID- 22429526 TI - Validity and reliability of a job factors questionnaire related to the work tasks of physical therapists. AB - Physical therapists engage in work tasks that expose them to occupational risk factors related to musculoskeletal disorders. Due to the gap in the literature on instruments focused on those workers, this study adapted a job factors questionnaire to physical therapists, and assessed its psychometric properties. The questionnaire was adapted and its content validity was established. The psychometric properties were evaluated among 142 physical therapists. Reliability was verified using the temporal-stability design and internal consistency. Construct validity was assessed with the known-groups technique. Test-retest results demonstrated intraclass correlation coefficients between .82 and .90 (p < .001). Cronbach's alpha of .91 verified the reliability of the questionnaire. The known-groups technique demonstrated a statistically significant difference on the scores of the items when physical therapists were compared to office workers. The results indicated that the adapted questionnaire had acceptable psychometric properties for assessing problematic job factors among physical therapists working in hospitals. PMID- 22429527 TI - Motivating ergonomic computer workstation setup: sometimes training is not enough. AB - Musculoskeletal disorders lead to pain and suffering and result in high costs to industry. There is evidence to suggest that whereas conventional ergonomics training programs result in knowledge gains, they may not necessarily translate to changes in behavior. There were 11 participants in an ergonomics training program, and a subsample of participants received a motivational intervention in the form of incentives for correct workstation setup. Training did not yield any changes in ergonomics measures for any participant. Incentives resulted in marked and durable changes in targeted workstation measures. The data suggest that improving worker knowledge about ergonomically correct workstation setup does not necessarily lead to correct workstation setup, and that motivational interventions may be needed to achieve lasting behavior change. PMID- 22429528 TI - The influence of age and type of force on muscle strength capabilities in women. AB - The aim of this study was to assess handgrip and 5 other types of force in 52 women and to determine if handgrip force reflected general upper limb force capabilities correlated with age. The women were divided into subgroups according to age: 20-25, 45-50 and 55-65 years. Maximum forces of the right upper limb were measured in 6 types of force activities. In most tests the values of force showed statistically significant differences between the 20-25 group and the groups aged 45-50 and 55-64 years. The results did not show any differences related to age or to force activities that involved the small muscles of the forearms and hands. Thus handgrip force cannot always be considered an indicator of total force capabilities. PMID- 22429529 TI - Research on simultaneous impact of hand-arm and whole-body vibration. AB - This article presents the results of laboratory tests on the combined effect of whole-body vibration (WBV) and hand-arm vibration (HAV). The reactions of subjects exposed to various combinations of vibration were recorded. The vibrotactile perception threshold (VPT) test identified changes caused by exposure to vibration. Ten male subjects met the criteria of the study. There were 4 series of tests: a reference test and tests after exposure to HAV, WBV, and after simultaneous exposure to HAV and WBV. An analysis of the results (6000 ascending and descending VPTs) showed that the changes in VPTs were greatest after simultaneous exposure to both kinds of vibration. The increase in VPT, for all stimulus frequencies, was then higher than after exposure to HAV or WBV only. PMID- 22429530 TI - Postural evaluation in a poultry farm for broiler chickens. AB - The goal of this study was to evaluate working postures in 9 operations of poultry farming for broiler chickens for 14 body segments with 4 categories, and for fingers with 14 categories. Overall, the farmers commonly bent almost all their body segments and used power grips. The operations of cleaning with water wand and inspecting chickens seemed light work because the farmers walked around most of their working time. The operations of detaching base from hanging feeder and attaching base to hanging feeder had the farmers continue squatting to handle the feeders close to the floor. The farmers also repeatedly bent their trunks in shoveling feces, unloading a box of chicks, and releasing chicks. A power grip was frequently observed due to using tools with round handles. Workplace design to raise working height would be necessary for a better working environment for broiler farmers. PMID- 22429531 TI - Measuring coupling forces woodcutters exert on saws in real working conditions. AB - Prolonged exposure to hand-arm vibration (HAV) generated by chainsaws can cause HAV syndrome, i.e., disorders in the upper extremities of forestry workers. Progress of HAV syndrome depends on the intensity of mechanical vibration transmitted throughout the body, which is directly proportional to coupling forces applied by the woodcutter to a vibrating tool. This study aimed to establish a method of measuring coupling forces exerted by chainsaw workers in real working conditions. Coupling forces exerted by workers with their right and left hands were measured with a hydro-electronic force meter. Wood hardness, the type of chainsaw and the kind of forest operation, i.e., felling, cross-cutting or limbing, were considered. PMID- 22429532 TI - Development of prolonged standing strain index to quantify risk levels of standing jobs. AB - Many occupations in industry such as metal stamping workers, electronics parts assembly operators, automotive industry welders, and lathe operators require working in a standing posture for a long time. Prolonged standing can contribute to discomfort and muscle fatigue particularly in the back and legs. This study developed the prolonged standing strain index (PSSI) to quantify the risk levels caused by standing jobs, and proposed recommendations to minimize the risk levels. Risk factors associated with standing jobs, such as working posture, muscles activity, standing duration, holding time, whole-body vibration, and indoor air quality, were the basis for developing the PSSI. All risk factors were assigned multipliers, and the PSSI was the product of those multipliers. Recommendations for improvement are based on the PSSI; however, extensive studies are required to validate their effectiveness. multipliers, and the PSSI was the product of those multipliers. Recommendations for improvement are based on the PSSI; however, extensive studies are required to validate their effectiveness. PMID- 22429533 TI - Health effects associated with long-term occupational exposure of employees of a chlor-alkali plant to mercury. AB - This study aimed to evaluate possible health effects associated with long-term occupational exposure to low levels of mercury vapors. Forty-six subjects exposed to mercury and 65 healthy unexposed employees were studied. The subjects were administered a questionnaire on experienced symptoms and underwent clinical examinations as well as routine biochemical tests. Atmospheric and urinary concentrations of mercury were measured, too. Environmental concentrations of mercury were estimated to be 3.97 +/- 6.28 MUg/m(3) and urinary concentrations of mercury in exposed and referent groups were 34.30 +/- 26.77 and 10.15 +/- 3.82 MUg/dm(3), respectively. Additionally, symptoms such as somatic fatigue, anorexia, loss of memory, erethism, blurred vision and teeth problems were significantly more common among exposed individuals. These observations indicate that occupational exposure to mercury vapors, even at low levels, is likely to be associated with neurological and psychological symptoms. PMID- 22429534 TI - Effect of simultaneous exposure to benzene and ethanol on urinary thioether excretion. AB - The toxicity of benzene is not an issue of the past, especially in developing countries. Bone marrow toxicity is demonstrated among workers. In this study, the effect of simultaneous exposure to benzene and ethanol on benzene metabolism in mice was investigated by measuring the excretion of thioethers in urine. Urinary thioether excretion significantly decreased in the mice receiving both benzene and ethanol compared with the animals receiving benzene only. The assay of determining thioethers in urine samples in this study is a simple and low-cost method, thus suitable for routine use, especially in developing countries, not only for benzene, but also for other alkilating agents, which can be found during occupational exposure. Our results suggest that further research is needed to elucidate the mechanisms of decreased urinary excretion of thioether after simultaneous exposure to benzene and ethanol. PMID- 22429535 TI - Safety management in a relationship-oriented culture. AB - A relationship-oriented culture predominates in the Greater China region, where it is more important than in Western countries. Some characteristics of this culture influence strongly the organizational structure and interactions among members in an organization. This study aimed to explore the possible influence of relationships on safety management in relationship-oriented cultures. We hypothesized that organizational factors (management involvement and harmonious relationships) within a relationship-oriented culture would influence supervisory work (ongoing monitoring and task instructions), the reporting system (selective reporting), and teamwork (team communication and co-ordination) in safety management at a group level, which would in turn influence individual reliance complacency, risk awareness, and practices. We distributed a safety climate questionnaire to the employees of Taiwanese high-risk industries. The results of structural equation modeling supported the hypothesis. This article also discusses the findings and implications for safety improvement in countries with a relationship-oriented culture. PMID- 22429536 TI - Human albumin in the management of complications of liver cirrhosis. PMID- 22429537 TI - Vitreomacular traction in a case of exudative age-related macular degeneration resistant to anti-VEGF therapy. PMID- 22429538 TI - Cloud BioLinux: pre-configured and on-demand bioinformatics computing for the genomics community. AB - BACKGROUND: A steep drop in the cost of next-generation sequencing during recent years has made the technology affordable to the majority of researchers, but downstream bioinformatic analysis still poses a resource bottleneck for smaller laboratories and institutes that do not have access to substantial computational resources. Sequencing instruments are typically bundled with only the minimal processing and storage capacity required for data capture during sequencing runs. Given the scale of sequence datasets, scientific value cannot be obtained from acquiring a sequencer unless it is accompanied by an equal investment in informatics infrastructure. RESULTS: Cloud BioLinux is a publicly accessible Virtual Machine (VM) that enables scientists to quickly provision on-demand infrastructures for high-performance bioinformatics computing using cloud platforms. Users have instant access to a range of pre-configured command line and graphical software applications, including a full-featured desktop interface, documentation and over 135 bioinformatics packages for applications including sequence alignment, clustering, assembly, display, editing, and phylogeny. Each tool's functionality is fully described in the documentation directly accessible from the graphical interface of the VM. Besides the Amazon EC2 cloud, we have started instances of Cloud BioLinux on a private Eucalyptus cloud installed at the J. Craig Venter Institute, and demonstrated access to the bioinformatic tools interface through a remote connection to EC2 instances from a local desktop computer. Documentation for using Cloud BioLinux on EC2 is available from our project website, while a Eucalyptus cloud image and VirtualBox Appliance is also publicly available for download and use by researchers with access to private clouds. CONCLUSIONS: Cloud BioLinux provides a platform for developing bioinformatics infrastructures on the cloud. An automated and configurable process builds Virtual Machines, allowing the development of highly customized versions from a shared code base. This shared community toolkit enables application specific analysis platforms on the cloud by minimizing the effort required to prepare and maintain them. PMID- 22429539 TI - In vivo assessment of the host reactions to the biodegradation of the two novel magnesium alloys ZEK100 and AX30 in an animal model. AB - BACKGROUND: Most studies on biodegradable magnesium implants published recently use magnesium-calcium-alloys or magnesium-aluminum-rare earth-alloys.However, since rare earths are a mixture of elements and their toxicity is unclear, a reduced content of rare earths is favorable. The present study assesses the in vivo biocompatibility of two new magnesium alloys which have a reduced content (ZEK100) or contain no rare earths at all (AX30). METHODS: 24 rabbits were randomized into 4 groups (AX30 or ZEK100, 3 or 6 months, respectively) and cylindrical pins were inserted in their tibiae. To assess the biodegradation MUCT scans and histological examinations were performed. RESULTS: The MUCT scans showed that until month three ZEK100 degrades faster than AX30, but this difference is leveled out after 6 months. Histology revealed that both materials induce adverse host reactions and high numbers of osteoclasts in the recipient bone. The mineral apposition rates of both materials groups were high. CONCLUSIONS: Both alloys display favorable degradation characteristics, but they induce adverse host reactions, namely an osteoclast-driven resorption of bone and a subsequent periosteal formation of new bone. Therefore, the biocompatibility of ZEK100 and AX30 is questionable and further studies, which should focus on the interactions on cellular level, are needed. PMID- 22429540 TI - The challenges of the scholarship in the field of disability and health. PMID- 22429541 TI - Parental psychological distress and quality of life after a prenatal or postnatal diagnosis of congenital anomaly: a controlled comparison study with parents of healthy infants. AB - BACKGROUND: Parental early adjustment to a prenatal or postnatal diagnosis of congenital anomaly has been studied mainly within a pathological and deterministic perspective, giving us an inadequate view of the impact of the diagnosis. OBJECTIVES: Adopting a comprehensive approach on parental adjustment, we aimed to characterise the impact of the diagnosis on psychological distress and quality of life, in the early postdiagnosis stage. The effects of gender and the timing of the diagnosis were also examined. METHODS: In this cross-sectional study, 42 couples with healthy infants and 42 couples whose infants were prenatal or postnatally diagnosed with a congenital anomaly responded to the Brief Symptom Inventory-18 and to the World Health Organization Quality of Life-Brief instrument. RESULTS: In the early postdiagnosis stage, parents whose infants were diagnosed with a congenital anomaly presented higher levels of psychological distress than did the parents of healthy infants (F(2,79) = 6.23, p = .003), although they displayed similar levels of quality of life (F(4,78) = 0.62, p = .647). Mothers reported more adjustment difficulties than fathers in both groups. Receiving the diagnosis in the prenatal period was associated with higher maternal psychological quality of life (Z = -2.00, p = .045). CONCLUSION: The occurrence of a diagnosis of congenital anomaly during the transition to parenthood adds to an accumulation of stress-inducing events and manifests itself in psychopathological symptoms. Maintaining a positive evaluation of well-being may be understood as a parental resource to deal with the diagnosis. The importance of adopting a comprehensive perspective on parental adjustment is highlighted. PMID- 22429542 TI - Tax subsidization of personal assistance services. AB - BACKGROUND: Personal assistance services (PAS) is the term used to describe the range of assistance, services, and supports many people with disabilities and older Americans need to remain in their homes and communities. The Americans with Disabilities Act requires that people with disabilities receive essential services in the communities of their choice rather than in institutional settings. PAS availability often determines whether persons with disabilities become institutionalized or remain in their communities. PAS, however, are not inexpensive or broadly available. Strategies are needed to improve their availability to people with disabilities and the elderly. We sought to analyze 8 provisions of the Internal Revenue Code for their utility to make PAS more affordable and available. METHODS: The authors conducted a legal analysis of 8 statutory provisions, as interpreted by regulations, court decisions, and other authoritative sources. RESULTS: Each of the tax provisions analyzed covers some PAS expenses incurred by an individual or family. Favorable tax treatment is impacted by the nature and amount of expenses and by the location and conditions of services. The current limitations and complexities of legal interpretations and the fact that many individuals with disabilities are uninformed about these tax provisions present challenges and opportunities. CONCLUSIONS: As the need for PAS grows, reform of tax policy is an important complement to health care and long-term services and supports for people with disabilities. To increase utilization of current beneficial tax provisions that subsidize the cost of PAS, individuals with disabilities and tax preparers must become better informed about using these provisions. PMID- 22429543 TI - Built environment instruments for walkability, bikeability, and recreation: disability and universal design relevant? AB - BACKGROUND: Despite a plethora of instruments that measure the built environment with respect to its effect on potential physical activity, little is known about how relevant these instruments are for people with disabilities (PWDs). OBJECTIVE: This review comprises an in-depth review of instruments related to the built environment and physical activity, as well as an examination of such instruments to determine their applicability for PWDs. METHODS: In this paper, the term "built environment" refers to human-made structures (e.g., urban and rural design characteristics, recreational structures) that may facilitate or impede an individual's ability to be physically active. A content analysis was conducted on 95 instruments measuring walkability, bikeability, and recreation with respect to disability and universal design (UD) relevance. Instruments were also cataloged according to other dimensions, including psychometric properties, data collection modalities, and impact or use. RESULTS: Roughly one third of all instruments include some disability-specific items, and only a few UD principles are consistently demonstrated across all instruments. Psychometric information is available for approximately one half of the instruments. Most instruments use objective/audit methods of data collection, with less using subjective/perceived and Geographic Information System (GIS) methods. With respect to instrument impact/use, just over one half of the instruments have articles cited in the peer reviewed literature. CONCLUSIONS: Recommendations for new and revised built environment instruments include more focus on specific disability populations, incorporation of all UD principles, as well as attention to psychometric quality and measurement specificity. PMID- 22429544 TI - Physical ill health, disability, dependence and depression: results from the 2007 national survey of psychiatric morbidity among adults in England. AB - BACKGROUND: The relationship between physical ill health, disability, and depression is not straightforward. Both cross-sectional and longitudinal studies have clearly shown that medical illness and physical disability are strongly associated with depression. OBJECTIVE: To test the hypothesis that disability is associated with an increased prevalence of depression irrespective of physical health problems and that this is proportionate to the severity of disability (measured in terms of the number of difficulties in daily activities and the degree of dependence on others). METHODS: Using a random probability sample design, 7460 respondents were interviewed for the third national survey of psychiatric morbidity of adults in the private household population in England. Fieldwork was carried out throughout 2007. The prevalence of depression was established by the administration of the revised Clinical Interview Schedule (CIS R), while disability was measured by reported difficulties in activities of daily living (ADL) and instrumental activities of daily living (IADL). RESULTS: Disability was associated with depression even after adjustment for physical ill health. The number of ADL/IADL difficulties was directly related to the likelihood of respondents having depression. Dependence on others was not associated with depression once severity of disability had been accounted for. CONCLUSION: All ADL/IADL limitations are significantly associated with depression and there seems to be a cumulative effect irrespective of whether the limitation is in personal care or in instrumental activities such as mobility problems. PMID- 22429545 TI - Association of total serum cholesterol with functional outcome following home care rehabilitation in Italian patients with stroke. AB - BACKGROUND: Stroke is a disabling disease. In elderly populations, stroke is the third leading cause of death and the primary cause of reduction in or loss of functional ability and personal autonomy. Possible associations between levels of total serum cholesterol (TC) and both incidence of stroke and functional outcomes after rehabilitation are still under study. OBJECTIVE: To detect positive and negative prognostic factors associated with functional outcomes in first-time stroke patients admitted to an integrated home care rehabilitative program. METHODS: This study enrolled 141 patients with a first-time stroke who were admitted to a home care rehabilitation program. Primary outcome measures were the Barthel activities of daily living (ADL) and mobility indices at the beginning and end of the rehabilitative treatment. The impact of TC and other demographic and clinical variables was analyzed using bivariate and multivariate logistic regression analyses. RESULTS: Age and Short Portable Mental Status Questionnaire (SPMSQ) score were negatively associated with functional outcome. In contrast, elevated TC was positively associated with a better home rehabilitative treatment outcome. Barthel index score at admission was negatively associated with outcomes assessed by the Barthel ADL index and age with outcomes assessed by the Barthel mobility index. In a multivariate logistic regression analysis, SPMSQ score and elevated TC were significantly associated with outcome. Specifically, higher SPMSQ scores were negatively associated with better rehabilitative treatment outcomes, whereas elevated TC was positively associated. CONCLUSIONS: Elevated TC seems to be associated with better functional outcomes in patients with first time stroke. PMID- 22429546 TI - What barriers to physical activity do individuals with a recent brain injury face? AB - BACKGROUND AND OBJECTIVE: Traumatic brain injury (TBI) is a serious public health issue that challenges professionals to develop effective health promotion strategies to meet individual's diverse and unique needs. One effective health promotion strategy is physical activity (PA), although barriers to activity frequently prevent participation. Thus, there is a need to identify the barriers to participation, amount of weekly PA completed, and readiness to be active if effective health promotion programs are to be implemented. METHODS: A convenience sample of 28 outpatients with a TBI completed a questionnaire before discharge from a comprehensive outpatient program and descriptive statistics were reported. In addition independent t tests and effect sizes were calculated between amount of PA and stage of change. RESULTS: Our results indicated that participants only faced an average of 2.25 barriers (range 0-9), completed a mean of 46 minutes of PA each week, and reported being in the "action" stage of PA participation. Individuals in the action and maintenance stage completed significantly more PA (21.67; t [25] = -15.43; p < .001; Cohen's D effect size = 4.39) than precontemplators or contemplators. CONCLUSIONS: Individuals with a TBI face many different barriers that prevent them from being active, placing them at further risk of experiencing secondary and chronic conditions. Practitioners should acknowledge that each individual faces a unique set of barriers emphasizing the importance of individualized health promotion programs. PMID- 22429547 TI - Cationic cyclodextrin as versatile chiral selector for enantiomeric separation in capillary electrophoresis. AB - A novel cationic cyclodextrin, mono-6(A)-(3-methoxypropan-1-ammonium)-6(A)-beta cyclodextrin chloride, has been developed and used as chiral selector in capillary electrophoresis (CE). This chiral selector has three recognition sites: beta-CD, ammonium cation and methoxy group in the sidearm to contribute three corresponding driving forces including inclusion complexation, electrostatic interaction and hydrogen bonding. This elegantly designed CD exhibits outstanding enantioselectivities in CE for a wide range of acidic and ampholytic racemates due to the extra hydrogen bonding for the chiral recognition. Under optimum pH 6.0, chiral resolutions over 10 can be readily achieved for acidic racemates with CD concentration below 10 mM. This cationic CD exhibits great potential for versatile chiral separation in CE. The finding in this study may be applied to construct new host-guest systems for practical applications. PMID- 22429548 TI - Characterization of carboxylate-terminated carbosilane dendrimers and their evaluation as nanoadditives in capillary electrophoresis for vegetable protein profiling. AB - Protein profiles are becoming an important tool to differentiate and classify varieties of several cultivars and to obtain a specific fingerprint for them. The use of protein profiles for these purposes needs to achieve high separation efficiencies to obtain a high number of well resolved peaks. In this work, carbosilane dendrimers with interior carbon-silicon bonds and negatively charged in the dendrimer surface with carboxylic acid as functional groups were employed as nanoadditives to separate soybean and olive seeds proteins. First, these dendrimers were characterized using CE to evaluate their possible impurities. A potentiometric titration was later carried out to determine their pK(a) values. Afterwards, the characterized dendrimers were used to improve the protein profiles obtained by EKC for vegetable proteins. Different dendrimer generations (G1, G2, and G3) and concentrations (0.01-1% m/v) were tested. The highest dendrimer generation G3 at 0.1% (m/v) allowed observing the best protein profiles for soybean and olive seeds. These results demonstrate that carboxylate terminated carbosilane dendrimers are attractive nanoadditives in EKC for the effective separation of vegetable proteins. PMID- 22429549 TI - Thermodynamic study of molecularly imprinted polymer used as the stationary phase in high performance liquid chromatography. AB - Molecularly imprinted polymer (MIP) and non-imprinted polymer (NIP) on the base of methacrylic acid prepared by a bulk polymerization were used as stationary phases for the HPLC analysis. The thermodynamic processes were carried out to investigate the temperature effects during sorption processes of potential local anaesthetics - morpholinoethyl esters of alkoxy-substituted phenylcarbamic acid (MEsP), local anaesthetic - diperodon, flavonoid - quercetin in methanol, acetonitrile and toluene (porogen) as mobile phases. Mobile phases and corresponding solvents were selected according to the solubility of each analyte. The template was chosen from the set of homologous of MEsP - 2-(morpholin-4 yl)ethyl (2-methoxyphenyl)carbamate. Values of retention factors were measured over the temperature range of 20-60 degrees C. There were determined van't Hoff curves - dependences between logarithms of the retention factors (lnk) and the inverse value of the temperature (1/T). Observed graphs were linear directly indicating that there were no changes of interaction mechanisms in the studied range of temperature. Selectivities (evaluated by the separation factors, alpha) and sorption selectivities (evaluated by the imprinting factors, IFs) of the MIP and the NIP toward template, related and not-related structures with the template were evaluated chromatographically. The highest separation factors and the imprinting factors (IF=4.73 +/- 0.35 for the template) were observed in methanol, not in porogen. Only in the case of quercetin the highest IF was observed in ACN (1.88 +/- 0.13). Contrary to expectations, the driving force for the affinity of the target molecules for both of polymers was enthalpic term (with an average of 54%, 82% and 84% contribution of enthalpic term for MeOH, ACN and toluene, respectively on the MIP and 53%, 57% and 65% for MeOH, ACN and toluene, respectively on the NIP). The MIP and NIP were also characterized by attenuated total reflectance analysis Fourier transform infrared spectroscopy (ATR-FTIR) and thermogravimetric analysis (TGA). PMID- 22429551 TI - The effect of mouthrinses on oral malodor: a systematic review. AB - OBJECTIVE: The objective of this study is to systematically review the literature regarding the impact of mouthrinses on oral malodor and present evidence for the treatment effects of mouthrinses on oral malodor. MATERIAL AND METHODS: PubMed MEDLINE, the Cochrane-CENTRAL and EMBASE were searched through February 10, 2012 to identify appropriate studies. Volatile sulphur compound measurements, organoleptic measurements and tongue coating were selected as outcome variables. SEARCH RESULTS: The independent screenings of 333 unique titles and paper abstracts revealed 12 publications (12 experiments) that met the eligibility criteria. Means and standard deviations were extracted. The results were separated into short-term (<3 weeks) and longer-term (>=3 weeks) studies. CONCLUSION: In this review, nearly all mouthwashes with active ingredients had beneficial effects in reducing oral malodor in both short- and longer-term studies. The most compelling evidence was provided for chlorhexidine mouthwashes, and those that contained a combination of cetyl pyridinum chloride and zinc provided the best evidence profile on oral malodor. Little data with respect to tongue coating were available, and none of the studies showed a beneficial effect for this parameter. PMID- 22429552 TI - TLR2 and TLR4 gene polymorphisms in Turkish vitiligo patients. AB - BACKGROUND: It has been shown that toll like receptors (TLR) may be involved in some inflammatory skin diseases such as psoriasis, atopic dermatitis. Vitiligo is an acquired pigmentation disorder of unknown aetiology. A number of genes playing a role in inflammatory response may be associated with development of vitiligo. OBJECTIVES: To investigate whether there is an association between TLR 2 and TLR4 gene polymorphisms in Turkish patients with vitiligo. METHODS: A total of 100 patients (59 women and 41 men) with vitiligo and 100 controls (58 women and 42 men) were included in the study. The TLR2 gene Arg753Gln and TLR4 gene Asp299Gly and Thr399Ile polymorphisms were genotyped by using polymerase chain reaction and restriction fragment length polymorphism method. The data were analysed by Mann Whitney U-test, chi-squared test and logistic regression analysis. RESULTS: Significant difference was found in the distribution of TLR2 Arg753Gln genotype and in the allele frequencies TLR2 753Gln between vitiligo patients and healthy subjects (P < 0.05). The distribution of TLR4 Asp299Gly genotype was significantly higher in the patient group (10%) than in the control group (%2) (P < 0.05). The TLR4 Thr399Ile distribution did not show any difference in both vitiligo and healthy groups. CONCLUSIONS: Our findings suggest that Toll-like receptor 2 gene Arg753Gln and Toll-like receptor 4 Asp299Gly gene polymorphisms are associated with vitiligo susceptibility in Turkish patients. PMID- 22429553 TI - Sexual abuse history in GI illness, how do gastroenterologists deal with it? AB - INTRODUCTION: Data support an increased prevalence of sexual abuse (SA) among patients with gastrointestinal (GI) complaints. Sexual abuse causes multiple symptoms related to pelvic floor and stress mediated brain-gut dysfunctions. Treating these patients asks for a holistic approach, using centrally targeted interventions. However, gastroenterologists have never been surveyed regarding their practice patterns and constraints about inquiring into SA. AIM: To evaluate whether gastroenterologists address SA in their daily practice and to evaluate their knowledge regarding the implications of SA in GI illness. METHODS: A 42 item anonymous questionnaire was mailed to all 402 members of the Dutch Society of Gastroenterology (gastroenterologists and fellows in training). The questionnaire addressed SA and pelvic-floor-related complaints. MAIN OUTCOME MEASURES: The results of this survey. RESULTS: One hundred eighty-three of the 402 (45.2%) questionnaires were returned. Overall, 4.7% of the respondents asked their female patients regularly about SA; in males, this percentage was 0.6%. Before performing a colonoscopy, these percentages were even smaller (2.4% and 0.6%, respectively). When patients presented with specific complaints, such as chronic abdominal pain or fecal incontinence, 68% of the gastroenterologists asked females about SA and 29% of the males (P < 0.01). The majority of respondents stated it as rather important to receive more training on how to inquire about SA and its implications for treatment. CONCLUSION: Gastroenterologists do not routinely inquire about a history of SA and they rarely ask about it before performing colonoscopy. There is a need for training to acquire the skills and knowledge to deal with SA. PMID- 22429554 TI - Activity determination and nuclear decay data of 177Lu. AB - The activity concentration of a (177)Lu solution was measured within the scope of the international comparison CCRI(II)-K2.Lu-177, starting in 2009. At PTB, the solution was measured by means of 4pibeta-gamma coincidence counting using a proportional counter and a NaI detector. In addition, liquid scintillation counting using the CIEMAT/NIST efficiency tracing method as well as the triple-to double coincidence ratio (TDCR) method was applied. The efficiency computation for the TDCR method was realized by means of the MICELLE2 program, applying a stochastic model for the computation of electron emission spectra. The activity concentrations derived from the three methods were found to be in good agreement and the relative standard uncertainty of the combined result was found to be 0.19%. At PTB, the combined result was used to calibrate a 4pi ionization chamber for future calibrations of this isotope which is frequently used in nuclear medicine. In addition, activity standardizations were combined with gamma-ray spectrometry to determine photon emission probabilities. To this end, the comparison solution as well as another (177)Lu solution was used. The results are in good agreement with previous measurements at PTB but show a considerable discrepancy to recently published values from Deepa et al. (2011). The decay curve of a third solution was followed by liquid scintillation counting for about 66 days to determine the half-life of (177)Lu, which was found to be T(1/2)=6.639(9) d. PMID- 22429555 TI - Simplified methods for coincidence summing corrections in HPGe efficiency calibration. AB - Simple and practical coincidence summing corrections for n-type HPGe detectors are presented for the common calibration nuclides (57)Co and (60)Co using a defined "virtual peak" and accounting for the summing of gamma photons with x rays having energies up to 40 keV ((88)Y and (139)Ce). These corrections make it possible to easily and effectively establish peak and total efficiency curves suitable for subsequent summing corrections in routine gamma spectrometry analyses. Experimental verification of the methods shows excellent agreement for measurements of different reference solutions. PMID- 22429556 TI - Laboratories new to the ICRM. AB - The Scientific Committee of the ICRM decided, for the 2011 Conference, to present laboratories that are at a key developmental stage in establishing, expanding or applying radionuclide metrology capabilities. The expansion of radionuclide metrology capabilities is crucial to meet evolving and emerging needs in health care, environmental monitoring, and nuclear energy. Five laboratories (from Greece, Lithuania, Indonesia, Norway and Turkey) agreed to participate. Each laboratory is briefly introduced, and examples of their capabilities and standardization activities are discussed. PMID- 22429557 TI - Comparison of experimental and calculated calibration coefficients for a high sensitivity ionization chamber. AB - The response of a Vacutec 70129 ionization chamber was calculated using the PENELOPE-2008 Monte Carlo code and compared to experimental data. The filling gas mixture composition and its pressure have been determined using IC simulated response adjustment to experimental results. The Monte Carlo simulation revealed a physical effect in the detector response to photons due to the presence of xenon in the chamber. A very good agreement is found between calculated and experimental calibration coefficients for 17 radionuclides. PMID- 22429558 TI - A simple and versatile data acquisition system for software coincidence and pulse height discrimination in 4pibeta-gamma coincidence experiments. AB - A simple but versatile data acquisition system for software coincidence experiments is described, in which any time stamping and live time controller are not provided. Signals from beta- and gamma-channels are fed to separately two fast ADCs (16 bits, 25 MHz clock maximum) via variable delay circuits and pulse height stretchers, and also to pulse-height discriminators. The discriminating level was set to just above the electronic noise. Two ADCs were controlled with a common clock signal, and triggered simultaneously by the logic OR pulses from both discriminators. Paired digital signals for each sampling were sent to buffer memories connected to main PC with a FIFO (First-In, First-Out) pipe via USB. After data acquisition in list mode, various processing including pulse-height analyses was performed using MS-Excel (version 2007 and later). The usefulness of this system was demonstrated for 4pibeta(PS)-4pigamma coincidence measurements of (60)Co, (134)Cs and (152)Eu. Possibilities of other extended applications will be touched upon. PMID- 22429559 TI - Community responses to communication campaigns for influenza A (H1N1): a focus group study. AB - BACKGROUND: This research was a part of a contestable rapid response initiative launched by the Health Research Council of New Zealand and the Ministry of Health in response to the 2009 influenza A pandemic. The aim was to provide health authorities in New Zealand with evidence-based practical information to guide the development and delivery of effective health messages for H1N1 and other health campaigns. This study contributed to the initiative by providing qualitative data about community responses to key health messages in the 2009 and 2010 H1N1 campaigns, the impact of messages on behavioural change and the differential impact on vulnerable groups in New Zealand. METHODS: Qualitative data were collected on community responses to key health messages in the 2009 and 2010 Ministry of Health H1N1 campaigns, the impact of messages on behaviour and the differential impact on vulnerable groups. Eight focus groups were held in the winter of 2010 with 80 participants from groups identified by the Ministry of Health as vulnerable to the H1N1 virus, such as people with chronic health conditions, pregnant women, children, Pacific Peoples and Maori. Because this study was part of a rapid response initiative, focus groups were selected as the most efficient means of data collection in the time available. For Maori, focus group discussion (hui) is a culturally appropriate methodology. RESULTS: Thematic analysis of data identified four major themes: personal and community risk, building community strategies, responsibility and information sources. People wanted messages about specific actions that they could take to protect themselves and their families and to mitigate any consequences. They wanted transparent and factual communication where both good and bad news is conveyed by people who they could trust. CONCLUSIONS: The responses from all groups endorsed the need for community based risk management including information dissemination. Engaging with communities will be essential to facilitate preparedness and build community resilience to future pandemic events. This research provides an illustration of the complexities of how people understand and respond to health messages related to the H1N1 pandemic. The importance of the differences identified in the analysis is not the differences per se but highlight problems with a "one size fits all" pandemic warning strategy. PMID- 22429560 TI - Sexual behavior of HIV-positive adults not accessing HIV treatment in Mombasa, Kenya: Defining their prevention needs. AB - BACKGROUND: HIV spread continues at high rates from infected persons to their sexual partners. In 2009, an estimated 2.6 million new infections occurred globally. People living with HIV (PLHIV) receiving treatment are in contact with health workers and therefore exposed to prevention messages. By contrast, PLHIV not receiving ART often fall outside the ambit of prevention programs. There is little information on their sexual risk behaviors. This study in Mombasa Kenya therefore explored sexual behaviors of PLHIV not receiving any HIV treatment. RESULTS: Using modified targeted snowball sampling, 698 PLHIV were recruited through community health workers and HIV-positive peer counsellors. Of the 59.2% sexually-active PLHIV, 24.5% reported multiple sexual partners. Of all sexual partners, 10.2% were HIV negative, while 74.5% were of unknown HIV status. Overall, unprotected sex occurred in 52% of sexual partnerships; notably with 32% of HIV-negative partners and 54% of partners of unknown HIV status in the last 6 months. Multivariate analysis, controlling for intra-client clustering, showed non-disclosure of HIV status (AOR: 2.38, 95%CI: 1.47-3.84, p < 0.001); experiencing moderate levels of perceived stigma (AOR: 2.94, 95%CI: 1.50-5.75, p = 0.002); and believing condoms reduce sexual pleasure (AOR: 2.81, 95%CI: 1.60 4.91, p < 0.001) were independently associated with unsafe sex. Unsafe sex was also higher in those using contraceptive methods other than condoms (AOR: 5.47, 95%CI: 2.57-11.65, p < 0.001); or no method (AOR: 3.99, 95%CI: 2.06-7.75, p < 0.001), compared to condom users. CONCLUSIONS: High-risk sexual behaviors are common among PLHIV not accessing treatment services, raising the risk of HIV transmission to discordant partners. This population can be identified and reached in the community. Prevention programs need to urgently bring this population into the ambit of prevention and care services. Moreover, beginning HIV treatment earlier might assist in bringing this group into contact with providers and HIV prevention services, and in reducing risk behaviors. PMID- 22429561 TI - The impact of early emergency department allied health intervention on admission rates in older people: a non-randomized clinical study. AB - BACKGROUND: This study sought to determine whether early allied health intervention by a dedicated Emergency Department (ED) based team, occurring before or in parallel with medical assessment, reduces hospital admission rates amongst older patients presenting with one of ten index problems. METHODS: A prospective non-randomized trial in patients aged sixty five and over, conducted in two Australian hospital EDs. Intervention group patients, receiving early comprehensive allied health input, were compared to patients that received no allied health assessment. Propensity score matching was used to compare the two groups due to the non-randomized nature of the study. The primary outcome was admission to an inpatient hospital bed from the ED. RESULTS: Of five thousand two hundred and sixty five patients in the trial, 3165 were in the intervention group. The admission rate in the intervention group was 72.0% compared to 74.4% in the control group. Using propensity score probabilities of being assigned to either group in a conditional logistic regression model, this difference was of borderline statistical significance (p = 0.046, OR 0.88 (0.76-1.00)). On subgroup analysis the admission rate in patients with musculoskeletal symptoms and angina pectoris was less for those who received allied health intervention versus those who did not. This difference was significant. CONCLUSIONS: Early allied health intervention in the ED has a significant but modest impact on admission rates in older patients. The effect appears to be limited to a small number of common presenting problems. PMID- 22429562 TI - A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. AB - BACKGROUND: An early and proper diagnosis of acute on chronic liver failure (ACLF), together with the identification of indicators associated with disease severity is critical for outcome prediction and therapy. OBJECTIVE: To systematically identify and summarize prognostic indicators for patients with ACLF and to evaluate the predictive value of these indicators. METHODS: Embase and Ovid-Medline were searched for English-language articles. The search criteria focused on identifying clinical trials and observational studies reporting on indicators used for prediction of mortality in patients with ACLF. RESULTS: Of 2382 studies identified, 19 were included for detailed analysis. Thirteen different definitions of ACLF were found. The main differences were related to acute deterioration in liver function, coagulopathy and hyperbilirubinaemia/jaundice. Seventy three prognostic indicators and their association with mortality were extracted and categorized into seven categories: general markers (n = 13), viral markers (n = 6), bio-markers (n = 22), hemodynamics (n = 1), morphology/histology (n = 17), scoring systems (n = 10) and treatments (n = 4). CONCLUSIONS: The ambiguity and variability in the definition of ACLF and in its predictive indicators hampers comparability among studies. There is a need for a single uniform definition of ACLF. Also absence of a gold standard is an obstacle to render one indicator superior to another. The age, hepatic encephalopathy, model for end-stage liver disease score, total bilirubin and International normalized ratio (prothrombin time) appeared to be promising candidates for evaluation in future studies. The result of this review may be useful as a starting point in developing a standard list of indicators for clinical outcome that concur with the clinicians' subjective views on prognosis in ACLF. PMID- 22429563 TI - The impact of perioperative transfusion of blood products on survival after pediatric liver transplantation. AB - Intraoperative transfusion of red blood cells (RBC) is associated with adverse outcome after LT in adult patients. This relationship in pediatric patients has not been studied in depth, and its analysis is the scope of this study. Forty-one variables associated with outcome, including blood product transfusions, were studied in a cohort of 243 pediatric patients undergoing a cadaveric LT between 2002 and 2009 at the General Hospital of Bergamo. Multivariate stepwise Cox proportional hazards models were adopted with adjustment by propensity scores to minimize factors associated with the use of blood products. Median age at transplant was 1.37 yr. In uni- and multivariate analyses, perioperative transfusion of FFP and RBC was an independent risk factor for predicting one-yr patient and graft survival. The effect on one-yr survival was dose-related with a hazard ratio of 3.15 for three or more units of RBC (p = 0.033) and 3.35 for three or more units of FFP (p = 0.021) when compared with 1 or no units transfused. The negative impact of RBC and FFP transfusion was confirmed by propensity score-adjusted analysis. These findings may have important implications for transfusion practice in the LT pediatric recipients. PMID- 22429564 TI - Combinations of favipiravir and peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. AB - Favipiravir, an influenza virus RNA polymerase inhibitor, and peramivir, an influenza virus neuraminidase inhibitor, were evaluated alone and in combination against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Infected mice were treated twice daily for 5 d starting 4 h after virus challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100 mg/kg/d. Peramivir was 30% protective at 0.5 mg/kg/d, but ineffective at lower doses when used as monotherapy. Combinations of favipiravir and peramivir increased the numbers of survivors by 10-50% when the 0.025, 0.05, and 0.1 mg/kg/d doses of peramivir were combined with 20 mg/kg/d favipiravir and when all doses of peramivir were combined with 40 mg/kg/d favipiravir. Three-dimensional analysis of drug interactions using the MacSynergy method indicates strong synergy for these drug combinations. In addition, an increase in lifespan for groups of mice treated with drug combinations, compared to the most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1 mg/kg/d doses of peramivir combined with favipiravir at the 20 mg dose level. Therefore, the 20 mg/kg/d dose of favipiravir was selected for further combination studies. Increased survival was exhibited when this dose was combined with peramivir doses of 0.1, 0.25 and 0.5 mg/kg/d (1 mg/kg/d of peramivir alone was 100% protective in this experiment). Improved body weight relative to either compound alone was evident using 0.25, 0.5, and 1 mg/kg/d of peramivir. Significant reductions in lung hemorrhage score and lung weight were evident on day 6 post-infection. In addition, virus titers were reduced significantly on day 4 post-infection by combination therapy containing favipiravir combined with peramivir at 0.25 and 0.5 mg/kg/d. These data demonstrate that combinations of favipiravir and peramivir perform better than suboptimal doses of each compound alone for the treatment of influenza virus infections in mice. PMID- 22429565 TI - Crossed synkinesia associated with long-term, intensive tennis playing. PMID- 22429566 TI - Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: a double blind randomized clinical trial. AB - OBJECTIVE: We compared the efficacy and safety of two biosimilar forms of interferon beta-1a in the treatment of multiple sclerosis: Avonex (Biogen Idec, USA) and CinnoVex (CinnaGen, Iran). METHODS: In a double blind randomized clinical trial study 84 patients with relapsing remitting multiple sclerosis (RRMS) with Expanded Disability Status Scale (EDSS) score of 0-5.5 were randomly allocated to two groups of 42 subjects. RESULTS: Twenty-four patients lost to follow-up. Finally, 31 patients (mean+/-SD of age=33.7+/-7.0; 7 males and 24 females) in the Avonex and 29 patients (mean+/-SD of age=32.2+/-9.2; 8 males and 21 females) in the CinnoVex group completed full 24 months of study period. Decrease in EDSS was 1.05+/-0.24, p=0.62 in the Avonex and 0.16+/-0.88, p=1.0 in the CinnoVex group after 12 months and 0.27+/-1.05, p=0.46 in the Avonex and 0.16+/-1.06, p=1.0 in the CinnoVex group after 24 months. There was no statistically significant difference in attack number between two groups (1.0+/ 1.2 in Avonex and 1.2+/-1.3 in CinnoVex; p=0.46). Volume of T2-weighted lesions on MRI showed a progressive significant increase in the 12th month (28056+/ 23693) in Avonex treated patients compared with first image (16353+/-11172) (p=0.01). But number of gadolinium-enhancing lesions in CinnoVex showed statistically significant decrease after 12 months (0.08+/-0.28 vs. 1.00+/-1.22; p=0.03). However, there were no significant differences between groups after 24 months. There were no significant differences between 2 groups regarding frequency and duration of most considerable side effects, as well. Neutralizing antibodies were not positive in any patients. CONCLUSION: CinnoVex can be used as a safe and effective alternative to Avonex in treatment of RRMS. PMID- 22429567 TI - Antimicrobial peptides and their potential application in inflammation and sepsis. PMID- 22429568 TI - Effect of statins on chronic inflammation and nutrition status in renal dialysis patients: a systematic review and meta-analysis. AB - AIM: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may have an adjunctive effect on chronic inflammation and nutrition status in renal dialysis patients. Therefore, we performed a systematic review of randomized controlled trials to assess the effect of statins on chronic inflammation and nutrition status in dialysis patients. METHODS: The randomized controlled trials (RCTs) of statins versus placebo or no treatment for renal dialysis patients were searched from PubMed, EMbase and Cochran Central Register of Controlled Trials. We screened relevant studies according to predefined inclusion and exclusion criteria, evaluated the quality of the included studies, and performed meta-analyses by using the Cochrane Collaboration's Revman 5.1 software. RESULTS: We identified nine trials including 3098 patients. Meta analysis showed statins can significantly decrease the serum C-reactive protein (CRP) (SMD, -0.54; 95% confidence interval (CI), -1.04 to -0.05; P = 0.03) and high sensitivity CRP (hs-CRP) level (SMD, -0.72; 95% CI, -1.14 to -0.31; P = 0.0007) of dialysis patients compared with that of the control group. However, statins did not differ significantly from the control group in increasing the serum Alb level (SMD, -0.13; 95% CI, -0.42 to 0.15; P = 0.37). CONCLUSIONS: Statins can improve the chronic inflammation status reflected by the decreasing of serum CRP and hs-CRP levels, whereas there is no conclusive evidence that it can improve the nutrition status. However, this result needs to be further confirmed in more high-quality randomized clinical trials. PMID- 22429569 TI - Controlling the simultaneous production of laccase and lignin peroxidase from Streptomyces cinnamomensis by medium formulation. AB - BACKGROUND: Use of crude ligninase of bacterial origin is one of the most promising ways to improve the practical biodegradation of lignocellulosic biomass. However, lignin is composed of diverse monolignols with different abundance levels in different plant biomass and requires different proportions of ligninase to realize efficient degradation. To improve activity and reduce cost, the simultaneous submerged fermentation of laccase and lignin peroxidase (LiP) from a new bacterial strain, Streptomyces cinnamomensis, was studied by adopting formulation design, principal component analysis, regression analysis and unconstrained mathematical programming. RESULTS: The activities of laccase and LiP from S. cinnamomensis cultured with the optimal medium formulations were improved to be five to eight folders of their initial activities, and the measured laccase:LiP activity ratios reached 0.1, 0.4 and 1.7 when cultured on medium with formulations designed to produce laccase:LiP complexes with theoretical laccase:LiP activity ratios of 0.05 to 0.1, 0.5 to 1 and 1.1 to 2. CONCLUSION: Both the laccase and LiP activities and also the activity ratio of laccase to LiP could be controlled by the medium formulation as designed. Using a crude laccase-LiP complex with a specially designed laccase:LiP activity ratio has the potential to improve the degradation of various plant lignins composed of diverse monolignols with different abundance levels. PMID- 22429570 TI - Discovery of novel acyl coenzyme a: cholesterol acyltransferase inhibitors: pharmacophore-based virtual screening, synthesis and pharmacology. AB - The present study describes ligand-based pharmacophore modeling of a series of structurally diverse acyl coenzyme A cholesterol acyltransferase inhibitors. Quantitative pharmacophore models were generated using HypoGen module of Discovery Studio 2.1, whereby the best pharmacophore model possessing two hydrophobic, one ring aromatic, and one hydrogen bond acceptor feature for inhibition of acyl coenzyme A cholesterol acyltransferase showed a very good correlation coefficient (r = 0.942) along with satisfactory cost analysis. Hypo1 was also validated by test set and cross-validation methods. Developed models were found to be predictive as indicated by low error values for test set molecules. Virtual screening against Maybridge database using Hypo1 was performed. The two most potent compounds (47 and 48; predicted IC50 = 1 nM) of the retrieved hits were synthesized and biologically evaluated. These compounds showed 86% and 88% inhibition of acyl coenzyme A cholesterol acyltransferase (at 10 MUg/mL) with IC50 value of 3.6 and 2.5 nM, respectively. As evident from the close proximity of biological data to the predicted values, it can be concluded that the generated model (Hypo1) is a reliable and useful tool for lead optimization of novel acyl coenzyme A cholesterol acyltransferase inhibitors. PMID- 22429571 TI - Signal transduction pathway for L-ascorbic acid- and L-ascorbic acid 2-glucoside induced DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes. AB - We examined the effects of L-ascorbic acid and its analogues on DNA synthesis and cell proliferation. We also investigated the signal transduction pathways involved in the induction of mitogenesis by L-ascorbic acid and its analogues using primary cultures of adult rat hepatocytes. Following a 4-h serum-free cultivation, both L-ascorbic acid and its stable analogue, L-ascorbic acid 2 glucoside, time- and dose-dependently stimulated hepatocyte DNA synthesis and cell proliferation, with EC50 values of 6.46*10-8 M and 3.34*10-8 M, respectively. Dehydroascorbic acid (10-6 M-10-5 M) weakly stimulated hepatocyte mitogenesis, whereas isoascorbic acid (10-9 M-10-5 M) had no effect. Hepatocyte mitogenesis induced by L-ascorbic acid or L-ascorbic acid 2-glucoside was dose dependently abolished by treatment with monoclonal antibodies against insulin like growth factor (IGF)-I receptor, but not by treatment with monoclonal antibodies against insulin receptor or IGF-II receptor. Western blot analysis showed that both L-ascorbic acid and L-ascorbic acid 2-glucoside significantly stimulated IFG-I receptor tyrosine kinase activity within 3 min, and mitogen activated protein (MAP) kinase activity within 5 min. These results demonstrate that both L-ascorbic acid and L-ascorbic acid 2-glucoside induce DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes by interacting with the IGF-I receptor site and by activating the receptor tyrosine kinase/MAP kinase pathway. PMID- 22429572 TI - Involvement of the peroxisome proliferator-activated receptor (PPAR) alpha in vascular response of endocannabinoids in the bovine ophthalmic artery. AB - Endocannabinoids regulate vascular tone in a variety of vascular tissues. This study aimed to investigate the role of peroxisome proliferators-activated receptors (PPARs) in anandamide- and palmitoylethanolamide-induced relaxant responses on the bovine ophthalmic artery and to evaluate the mechanisms involved. The effects of anandamide and palmitoylethanolamide were examined under myographic conditions on arterial rings pharmacologically pre-contracted with 5 HT. Anandamide and palmitoylethanolamide relaxed the ophthalmic artery rings in time- and concentration-dependent manner stimulating the PPAR alpha (PPARalpha). The vasorelaxation to endocannabinoids was inhibited by PPARalpha antagonist GW6471 (1MUM), but not the PPAR gamma (PPARgamma) antagonist GW9662 (1 MUM). Anandamide-induced relaxation was attenuate during the first 60 min by AM251, a selective antagonist of cannabinoid CB(1) receptors, and Pertussis toxin, an inhibitor of G(i/o) protein; by the contrast, the palmitoylethanolamide-induced vasorelaxation was unaffected by cannabinoid antagonists and Pertussis toxin. Endothelium removal decreases slightly the potency and efficacy to endocannabinoids. The relaxant effect to anandamide and palmitoylethanolamide was inhibited by L-NMMA (300 MUM), an inhibitor of nitric oxide synthase, and iberiotoxin (200 nM), a selective blocker of large conductance Ca2+-activated K+ (BK(Ca)). These data support the view that anandamide and palmitoylethanolamide relax the ophthalmic artery in a time-dependent manner via the transcription factors PPARalpha suggesting a function for them in the physiological mechanisms of vascular regulation. PMID- 22429573 TI - Antisense oligonucleotide knockdown of mGlu5 receptor attenuates the antinociceptive tolerance and up-regulated expression of spinal protein kinase C associated with chronic morphine treatment. AB - Spinal metabotropic glutamate receptor 5 (mGlu5 receptor) is known to influence the development of intrathecal morphine antinociceptive tolerance. However, the signaling mechanisms remain unknown. We carried out intrathecal administration of an antisense oligodeoxynucleotide (ODN), which results in reduced expression of spinal mGlu5 receptor, to determine its effects on morphine tolerance and spinal protein kinase C (PKC) expression. Rats were treated intrathecally with saline, morphine, mGlu5 receptor antisense ODN or mGlu5 receptor mismatched ODN. Behavioral tests were used to test the thermal and mechanical pain thresholds. Eight days later, rats were sacrificed and spinal cords were harvested to assess the expression of spinal PKC (alpha, gamma and epsilon) by Western blotting and real-time polymerase chain reaction (PCR). Compared to control, intrathecal mGlu5 receptor antisense ODN resulted in a ~53.9% reduction of spinal mGlu5 receptor after 8days treatment. The mGlu5 receptor antisense ODN prevented the development of morphine tolerance. Expression of spinal PKC (alpha, gamma and epsilon) was up regulated at the mRNA and protein levels during the development of tolerance. Meanwhile, antisense ODN but not mismatched ODN reduced the spinal dorsal horn levels of PKC (alpha, gamma and epsilon) which had been up-regulated after morphine exposure. We conclude that mGlu5 receptor participates in the development of morphine tolerance. Expression of spinal PKC (alpha, gamma and epsilon) at the mRNA and protein levels increased during morphine tolerance. Antisense ODN of mGlu5 receptor prevented the tolerance and inhibited the altered expression of spinal PKC (alpha, gamma and epsilon) during the development of tolerance. PMID- 22429574 TI - Participant demographics reported in "Table 1" of randomised controlled trials: a case of "inverse evidence"? AB - INTRODUCTION: Data supporting external validity of trial results allows clinicians to assess the applicability of a study's findings to their practice population. Socio-economic status (SES) of trial participants may be critical to external validity given the relationship between social and economic circumstances and health. We explored how this is documented in reports of RCTs in four major general medical journals. METHODS: The contents lists of four leading general medical journals were hand searched to identify 25 consecutive papers reporting RCT results in each journal (n = 100). Data on demographic characteristics were extracted from each paper's Table 1 only (or equivalent). RESULTS: Authors infrequently reported key demographic characteristics relating to SES of RCT participants. Age and gender of participants were commonly reported. Less than 10% reported occupational group, employment status, income or area based measures of disadvantage. CONCLUSIONS: Without adequate reporting of key indicators of SES in trial participants it is unclear if lower SES groups are under-represented. If such groups are systematically under-recruited into trials, this may limit the external validity and applicability of study findings to these groups. This is in spite of the higher health-care need in more disadvantaged populations. Under-representation of low SES groups could underestimate the reported effect of an intervention for those with a higher baseline risk. The marginal benefit identified in a trial with poor or no representation of lower SES participants could significantly underestimate the potential benefit to a low SES community. More transparency in this reporting and greater attention to the impact of SES on intervention outcomes in clinical trials is needed. This could be considered in the next revision of the CONSORT statement. PMID- 22429575 TI - [Sequence-dependent effect of docetaxel with gefitinib on the proliferation and apoptosis of lung adenocarcinoma cell H1975]. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib show promising therapeutic effects in patients with advanced non-small cell lung cancer (NSCLC). However, despite an initial response to EGFR-TKIs treatment among responsive patients, most inevitably acquire resistance after a progression-free period of about 10 months. The percentage of T790M in TKI acquired-resistant patients in most studies is around 50%. The aim of this study is to assess the effects of the sequential administration of docetaxel and gefitinib on cell proliferation and apoptosis of lung adenocarcinoma cell H1975. METHODS: An MTT assay was used to measure cell proliferation. The potency of the sequential administration of docetaxel and gefitinib were determined by isobolograms and combination index (CI). Cell apoptosis and cycle distribution were determined by flow cytometry. The Hoechst 33258 method was used to observe the apoptotic morphology. Chemical colorimetric luminescence was used to measure the caspase activity. RESULTS: The isobolograms and CI showed that the sequential administration of docetaxel following gefitinib remarkably inhibits cell proliferation and cell apoptosis compared with other sequential administration models. The cycle distribution results indicate that sequential docetaxel administration following gefitinib blocked the cells in the G2/M phase but not in the G0/G1. The activation of the Caspase-8/Caspase-3 cascade is mainly involved in the apoptotic pathway of lung adenocarcinoma cell H1975 in all sequential administration models. CONCLUSIONS: The docetaxel administration following gefitinib might be a new stratagy for lung cancer with T790M mutation after having EGFR-TKIs resistance. PMID- 22429576 TI - [Lentivirus-mediated stable silencing of nm23-H1 gene in lung cancer cells and the influence on biological behavior]. AB - BACKGROUND AND OBJECTIVE: The nm23-H1 gene is an important tumor metastatic suppressor gene. Our previous study showed that the downregulation of nm23-H1 gene expression using small interfering RNA (siRNA) in NL9980 lung cancer cells greatly enhanced their invasiveness. To further explore the molecular mechanisms after nm23-H1 gene knockdown, we established transgene NL9980 and A549 lung cancer cell lines with stable nm23-H1 gene silencing through the lentivirus mediated short hairpin RNA (shRNA) method. METHODS: The human large cell lung cancer NL9980 and human lung adenocarcinoma A549 cells were transfected with shRNA lentiviral particles specific for the nm23-H1 gene, and were then selected through puromycin. Puromycin-resistant clones were generated and screened using reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time polymerase chain reaction (qPCR), and Western blot analysis. shRNA rescue experiments were performed to restore the nm23-H1 gene expression in the shRNA expressing cells. Invasiveness was determined through a Boyden chamber assay. RESULTS: The puromycin-resistant clones (NL9980-99 and A549-99) showed very low levels of nm23-H1 mRNA and protein expression under RT-PCR, qPCR, and Western blot analysis. Meanwhile, the shRNA rescue experiment restored the nm23-H1 expression in the NL9980-99 and A549-99 cells detected by Western blot. Downregulation of nm23-H1 gene expression enhanced the invasiveness of the NL9980 99 and A549-99 cells compared with the controls. CONCLUSIONS: The lung cancer cell lines NL9980-99 and A549-99 with stable nm23-H1 gene silencing were successfully established and their invasiveness was greatly increased after nm23 H1 gene knockdown. PMID- 22429577 TI - [Establishment of animal model of a human lung adenocarcinoma drug-resistant?cell line Anip973/NVB and investigation on mechanism of drug resistance]. AB - BACKGROUND AND OBJECTIVE: Multidrug resistance (MDR) is the main cause of chemotherapeutic failure in lung cancer, and vinorelbine (NVB) is one of the most efficient drugs that threaten non-small cell lung cancer (NSCLC). The current study aims to establish tumor xenografts and investigate the molecular mechanisms involved in the resistance of NVB in lung adenocarcinoma. METHODS: Nude mice were implanted with Anip973 and Anip973/NVB, and tumor-bearing mice were divided into the Anip973 treatment, Anip973 control, Anip973/NVB treatment, and Anip973/NVB control groups, respectively. The current study observes tumor growth, draws growth curves, and calculates inhibitory rates. The morphological changes in cell tumor were observed through the immunohistochemical method using an electron microscope to detect the expressions of MRP3 and Bcl-2 and to investigate the molecular mechanisms of Anip973/NVB cells. RESULTS: The tumor inhibitory rates of the Anip973 and Anip973/NVB cells treated with NVB were 60.00% and 4.65%, respectively, compared with the control group. The growth inhibition in the Anip973/NVB cell transplantation tumor had no significant difference. Apoptosis was observed using TEM when the Anip973 transplantation tumor was treated with NVB. On the other hand, no apoptosis was found in the Anip973/NVB transplantation tumor using TEM. Immunohistochemical staining (SP) shows the positive expressions of Bcl-2 and MRP3 proteins in Anip973/NVB transplantation tumor, which were observed to be higher than those in the Anip973 transplantation tumor. CONCLUSIONS: The overexpression of Bcl-2 and MRP3 might be one of the major mechanisms of the MDR of Anip973/NVB. PMID- 22429578 TI - [Establishment of the cell line that human lung adenocarcinoma can stably express luciferase which is absent of nm23-H1 expression and detecting its luminescence?in vitro and in vivo]. AB - BACKGROUND AND OBJECTIVE: On the condition that laboratory animals survive, we can detect the distribution of tumor cells by in vivo imaging that were labeled with firefly- luciferase (luc) gene. The purpose of this study is to establish a light-emitting cell line A549/nm23-H1-shRNA-luc which could express nm23-H1 shRNA and firefly-luciferase stably, and detect its bioluminescence in vitro and in vivo. It will provide the preparation for the next related experimental research in vivo. METHODS: The optimal concentration of hygromycin B for screening A549/nm23-H1-shRNA cells was determined by concentration gradient method. We firstly transfected the plasmid (PGL4.50) with luc gene into A549/nm23-H1-shRNA cells and then screened the monoclonal cell line A549/nm23-H1-shRNA-luc with hyhromycin B. The positive monoclonal cell line was identified with an in vivo imaging system, thereafter the expression stability of luciferase was analyzed in the strongest light-emitting positive monoclonal cell line. The A549/nm23-H1 shRNA-luc cells were inoculated subcutaneously into right-hind groin of nude mice and then observed by the in vivo imaging system. RESULTS: The optimal concentration of hygromycin B used in screening A549/nm23-H1-shRNA cells was 300 MUg/mL. After screening, the A549/nm23-H1-shRNA-luc cells established can express luciferase stably in vitro, a great linear correlation existed between the amount of cells (x) and bioluminescence values (y), with an equation of y=3,699.9x+992,237, and the square of the correlation coefficient (R2) was 0.975,1. To evaluate the stability of bioluminescence in vivo, 10 nude mice were randomly divided into two groups that the same number of cells were implanted into. The variation of bioluminescence values detected in vivo between the two groups of the same cells was not statistically significant (P>0.05). CONCLUSIONS: We have successfully established the cell line A549/nm23-H1-shRNA-luc which can express luciferase persistently and stably. PMID- 22429579 TI - [Descriptive study of the environmental epidemiology of high lung cancer?incidence rate in Qujing, Yunnan, China]. AB - BACKGROUND AND OBJECTIVE: Qujing, located in Southwest China, is an area with an extremely high lung cancer incidence. Combustion of coal has exposed local people to great health hazards. The aim of this study is to achieve a thorough understanding of the relationship between environmental pollution and the high incidence of lung cancer in Qujing, Yunnan Province, China. The results would provide a scientific basis and support for the etiology of lung cancer, as well as suggestions on improving the environmental conditions in the area. METHODS: A total of 280 rural villages were selected through stratified cluster random sampling. Environmental background and pollution were investigated, including details on fuel type, coking plant, metal smelting, and chemical plant, among others. Logistic regression analysis was used to analyze the investigated factors. RESULTS: Out of the total number of local villages studied, 78.1% of those with high incidence often use smoky coal and coking. On the other hand, 78.8% of the low-incidence areas use smokeless coal or wood. Logistic regression analysis indicated that the coal type used for everyday life was a main risk factor related to lung cancer (P<0.05). Using smoky and coking coals create an alarmingly high risk for developing lung cancer. Meanwhile, smokeless coals and wood seemed to have no significant relationship to the lung cancer incidence. CONCLUSIONS: The fuel type used for everyday life is an important factor in the high incidence of lung cancer in Qujing. Evidently, the use of smoky coal and coke increased the incidence of lung cancer, whereas smokeless coal and wood seem to bring about the contrary. PMID- 22429580 TI - [Clinical significance of T lymphocyte subset changes after first line chemotherapy in peripheral blood from patients with advanced stage adenocarcinoma cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: The immune function disorder relates closely to the occurrence, metastasis, and prognosis of cancer. T lymphocyte subsets take an important role in immune function. We identified the dynamic changes of the immune system by investigating the levels of T lymphocyte subsets in peripheral blood of lung cancer patients with advanced stage adenocarcinoma undergoing first line chemotherapy. The results aided the search for rational chemo-immunotherapy strategies in lung cancer treatment. METHODS: Samples from 49 patients with pathologically demonstrated advanced stage adenocarcinoma cell lung cancer were compared with those from 33 healthy donors. Subsequently, the patients were separately treated with Docetaxol-based or Pemetrexed-based therapy. Peripheral blood samples at different time points after therapy were analyzed by flowcytometry. The lymphocyte subsets of the total lymphocytes were compared. Independent sample t test was used for the quantitative data analysis. RESULTS: The percentage of CD3+, CD3+CD4+, CD4+CD25+ cells of the lung cancer patients significantly varied from those of the healthy donors, the P values are 0.012, 0.034 and 0.006 separately. The CD3+ and CD3+CD4+ levels increased significantly on the 4th and 7th-10th day post-chemotherapy, which return to normal levels on the 21th day. The CD3+ level increased significantly both in the treatment group on all time points, while the CD3+, CD3+CD4+, CD4+/CD8+ levels significantly increased and the CD3+CD8+, CD8+CD28- levels significantly decreased on the 4th day in Pemetrexed group. The CD3+CD4+ levels increased significantly on the 4th and 7th-10th day and the CD3+CD8+, CD8+CD28- levels decreased on the 4th day in partial response group. CONCLUSIONS: The immune function of advanced stage adenocarcinoma cell lung cancer patients was evidently suppressed, and was restored at the 4th day, followed by a reduction at the 21st day after chemotherapy. On the 4th day, Pemetrexed showed better effect on the immune system. The change of immune system post-chemotherapy could be related with the prognosis. PMID- 22429581 TI - [Vandetanib for advanced non-small cell lung cancer: a meta-analysis]. AB - BACKGROUND AND OBJECTIVE: Vandetanib is a small molecule inhibitor against vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). The aim of this study is to evaluate the efficacy and safety of vandetanib as a second-line treatment for advanced non-small cell lung cancer (NSCLC). METHODS: We selected randomized controlled trials (RCTs) on vandetanib for NSCLC from PubMed, Medline, Embase, VIP and CNKI. Meta-analysis was completed using software Review Manager 5.0. RESULTS: Compared with the control group (single other targeted therapy or chemotherapy group), there were statistical differences in progression free survival (PFS) (OR=1.23, 95%CI: 1.05-1.45), partial response (PR) (OR=2.15, 95%CI: 1.59-2.93), disease control (DC) (OR=1.22, 95%CI: 1.06-1.40), diarrhea (OR=1.59, 95%CI: 1.38-1.83), nausea (OR=0.69, 95%CI: 0.57-0.83), rash (OR=2.07, 95%CI: 1.71- 2.49), constipation (OR=0.81, 95%CI: 0.67 0.97), and vomiting (OR=0.72, 95%CI: 0.60-0.87) in the vandetanib group, but there were no differences in overall survival (OS), stable disease (SD), fatigue, cough, anorexia and dyspnea. CONCLUSIONS: Vandetanib might have more superior efficacy as a second-line treatment for NSCLC, but its advantages in terms of safety were not demonstrated. PMID- 22429582 TI - [Efficacy of pemetrexed as second-line therapy or beyond in patients with advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Pemetrexed is a standard second-line therapy in advanced non-small cell lung cancer (NSCLC). Currently, cytotoxic treatments beyond second-line therapy are not available. This study evaluated the efficacy and safety of pemetrexed as a salvage regimen in heavily pretreated patients with NSCLC. METHODS: Clinical data on 37 patients with advanced NSCLC who received pemetrexed as second-line therapy or beyond in Cancer Hospital of Peking Union Medical College from Feb 2005 to Sep 2009 were reviewed and analyzed retrospectively. RESULTS: Thirteen patients (35.1%) received pemetrexed as second line treatment, whereas 24 (64.9%) received it as third-line treatment or beyond. Complete response, partial response, stable disease and progressive disease were noted in 1 (2.7%), 2 (5.4%), 17 (45.9%) and 12 (32.4%) of the patients, respectively, with the disease control rate being 54.1%. The median duration of progression free survival was 8.05 months, whereas that of overall survival was 19.29 months. CONCLUSIONS: Pemetrexed is efficacious and tolerable as second-line therapy or beyond for advanced NSCLC and should thus be recommended for patients with this disease. PMID- 22429583 TI - [Mutation of the BRAF genes in non-small cell lung cancer]. AB - BRAF mutations have been found to be a driver mutation and maybe a therapy target in patients with non-small cell lung cancer. This article reviews the current understanding of BRAF gene, its structure, expression, the signal pathway, as well as its relationship with cancer especially the targeted therapies for non small cell lung cancer. PMID- 22429584 TI - [Side population cells and lung cancer stem cells]. AB - Side population (SP) cells are a rare subset of cells, which can be isolated by dual-wavelength flow cytometry because of their capacity to efflux Hoechst 33342, found in various tissues and cell lines that are highly enriched for stem cell activity. As recent studies have identified stem-cell-like SP cells in many lung cancer tissues and cell lines, this review is intended to find out the relationship between lung cancer SP cells and lung cancer stem cells. PMID- 22429585 TI - [Study advance of relationship between HPV and lung cancer]. AB - Lung cancer is one of malignant tumors harming human health. Over the past five decades, there is increasing morbidity and mortality of lung cancer which is the leading cause of cancer morbidity and mortality worldwide. Risk factors of lung cancer are versatile and smoking is among the important ones, but there are some non-smoking men, especially for women, some of whom developed lung cancer. Many studies showed that human papillomavirus (HPV) was the risk factor of lung cancer, however, which was less comprehensive or seriously estimated. The results of research on relationship between HPV infection and lung cancer are different because of the difference of detection methods, geographical distribution and sample size. Recently, the relationship of HPV and lung cancer is increasingly thought highly with deep study. Study advance of relationship between HPV and lung cancer in the recent years is briefly reviewed. PMID- 22429586 TI - Long-term outcomes of interruption and retreatment vs. continuous therapy with adalimumab for psoriasis: subanalysis of REVEAL and the open-label extension study. AB - BACKGROUND: REVEAL was a 52-week study of adalimumab for moderate to severe psoriasis. At Week 33, adalimumab-treated patients with sustained responses (PASI >=75 at Weeks 16 and 33) were re-randomized to receive adalimumab or placebo. Subsequently, they could receive adalimumab in an open-label extension (OLE) study. OBJECTIVE: To compare long-term efficacy and safety of adalimumab 40 mg every other week (eow), given as continuous treatment or with one period of interruption followed by retreatment. METHODS: Patients who were re-randomized to adalimumab or placebo at REVEAL Week 33 and received >= 1 dose of OLE adalimumab were analysed as the continuous and retreatment groups, respectively, for >2 years of OLE treatment with adalimumab 40 mg eow. LOCF was used for missing efficacy data. RESULTS: At OLE Weeks 0, 12 and 24, PASI 75 response rates were 84%, 84%, 86% with continuous treatment (N = 233) vs. 45%, 71%, 79% with retreatment (N = 227). Thereafter, efficacies were slightly greater for continuous treatment but similar between groups, with PASI 75 response rates at OLE Week 108 of 75% vs. 73% respectively. Retreatment was most effective for patients with >= PASI 50 responses when retreatment was initiated. Adverse event rates for retreatment were equal to or lower than those for continuous treatment. CONCLUSIONS: In psoriasis patients with sustained PASI 75 responses to adalimumab, long-term efficacy of retreatment after a <= 19-week interruption was similar to efficacy achieved with > 3 years continuous treatment. Adalimumab retreatment provided the best results when initiated before responses had declined below PASI 50. PMID- 22429587 TI - Alternating current electrophoretic deposition (EPD) of TiO2 nanoparticles in aqueous suspensions. AB - TiO(2)-nanostructured coatings from aqueous suspensions have been successfully prepared by the application of alternating current (AC) instead of direct current (DC) during electrophoretic deposition (EPD). No organic additives in suspension were required for successful EPD. The quality of the AC-EPD TiO(2) coatings in terms of homogeneity and extent of microcracking, upon drying, observed by SEM, was superior to that of DC-EPD coatings made from the same type of suspensions. The main difference between AC- and DC-EPD was the suppression of bubble formation. The absence of water electrolysis at the electrodes can be explained by the particular distribution of the electric field during AC mode, which prevents the nucleation of bubbles. The preparation of TiO(2) coatings from aqueous suspension and without the aid of organic stabilizers opens the possibility for co-deposition of sensitive materials such as biomolecules and even cells for biomedical applications, given the high biocompatibility of TiO(2). The deposition of TiO(2) coatings from aqueous suspensions is also attractive from environmental and economical points of view. PMID- 22429588 TI - Atmospheric pressure plasma induced grafting of poly(ethylene glycol) onto silicone elastomers for controlling biological response. AB - This study investigates the role that surface functionalisation of silicone elastomer (SE) by atmospheric pressure plasma induced graft immobilisation of poly(ethylene glycol) methyl ether methacrylate (PEGMA) plays in the attendant biological response. SE is used in modern ophthalmic medical devices and samples of the material were initially plasma treated using a dielectric barrier discharge reactor (DBD) to introduce reactive oxygen functionalities, prior to in situ grafting of two molecular weights of PEGMA (MW 1000 Da: PEGMA(1000), MW 2000 Da: PEGMA(2000)). The variously processed surfaces were characterised by water contact angle analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry and atomic force microscopy. Lens epithelial cells were then cultured on the PEGMA grafted SE surfaces. It was found that cells on the pristine surface were not well spread and had shrunken morphology. On the DBD pre-treated surfaces, the cells were well spread. On the PEGMA(1000) surface, the cells displayed evidence of shrinkage and were on the verge of detaching. Remarkably, on the PEGMA(2000) surface, no cell adhesion was detection. Bacterial adhesion to the surfaces was studied using Staphylococcus aureus NTC8325. There was no difference in the number of bacteria adhering to any of the surfaces studied. PMID- 22429589 TI - Palmitoylation and membrane cholesterol stabilize MU-opioid receptor homodimerization and G protein coupling. AB - BACKGROUND: A cholesterol-palmitoyl interaction has been reported to occur in the dimeric interface of the beta2-adrenergic receptor crystal structure. We sought to investigate whether a similar phenomenon could be observed with MU-opioid receptor (OPRM1), and if so, to assess the role of cholesterol in this class of G protein-coupled receptor (GPCR) signaling. RESULTS: C3.55(170) was determined to be the palmitoylation site of OPRM1. Mutation of this Cys to Ala did not affect the binding of agonists, but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex. In addition, both attenuation of receptor palmitoylation (by mutation of C3.55[170] to Ala) and inhibition of cholesterol synthesis (by treating the cells with simvastatin, a HMG-CoA reductase inhibitor) impaired receptor signaling, possibly by decreasing receptor homodimerization and Galphai2 coupling; this was demonstrated by co immunoprecipitation, immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) analyses. A computational model of the OPRM1 homodimer structure indicated that a specific cholesterol-palmitoyl interaction can facilitate OPRM1 homodimerization at the TMH4-TMH4 interface. CONCLUSIONS: We demonstrate that C3.55(170) is the palmitoylation site of OPRM1 and identify a cholesterol-palmitoyl interaction in the OPRM1 complex. Our findings suggest that this interaction contributes to OPRM1 signaling by facilitating receptor homodimerization and G protein coupling. This conclusion is supported by computational modeling of the OPRM1 homodimer. PMID- 22429590 TI - Effectiveness of 3D-CT in an accurate preoperative diagnosis and improving safety of vitrectomy for intraocular foreign body. PMID- 22429591 TI - Manganese superoxide dismutase: a regulator of T cell activation-induced oxidative signaling and cell death. AB - Mitochondrial reactive oxygen species (ROS) are indispensible for T cell activation-induced expression of interleukin 2 (IL-2) and CD95 ligand (CD95L, FasL/Apo-1L) genes, and in turn, for CD95L-mediated activation-induced cell death (AICD). Here, we show that manganese superoxide dismutase (MnSOD/SOD2), a major mitochondrial antioxidative enzyme, constitutes an important control switch in the process of activation-induced oxidative signal generation in T cells. Analysis of the kinetics of T cell receptor (TCR)-triggered ROS production revealed a temporal association between higher MnSOD abundance/activity and a shut-down phase of oxidative signal generation. Transient or inducible MnSOD overexpression abrogated T cell activation-triggered mitochondrial ROS production as well as NF-kappaB- and AP-1-mediated transcription. Consequently, lowered expression of IL-2 and CD95L genes resulted in decreased IL-2 secretion and CD95L dependent AICD. Moreover, upregulation of the mitochondrial MnSOD level is dependent on oxidation-sensitive transcription and not on the increase of mitochondrial mass. Thus, MnSOD-mediated negative feedback regulation of activation-induced mitochondrial ROS generation exemplifies a process of retrograde mitochondria-to-nucleus communication. Our finding underlines the critical role for MnSOD and mitochondria in the regulation of human T cell activation. PMID- 22429593 TI - Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints. AB - Similar to other vascular tumors, epithelioid hemangioendothelioma (EHE) can have multifocal presentation in up to 50% of cases. However, whether multifocal EHE represents an unusual pattern of metastasis or multiple separate primary tumors remains to be elucidated. Our recent identification of a WWTR1-CAMTA1 fusion as the genetic hallmark of EHE irrespective of anatomic location was used to clarify this question by comparing the similarity of translocation breakpoints. In our previous study, we found variability of the fusion transcripts of the t(1;3)(p36;q25) translocation among different patients with EHE. Thus, we undertook a molecular analysis of six samples from two patients with multicentric hepatic EHE to test our hypothesis that the presence of identical breakpoints in WWTR1 and CAMTA1 support the monoclonal nature of multifocal EHE. Using reverse transcription-polymerase chain reaction (RT-PCR) and subsequent sequencing, we confirmed an identical WWTR1-CAMTA1 fusion transcript product from different nodules in each patient. Our results confirm that multifocal EHE are monoclonal and thus represent metastatic implants of the same neoplastic clone rather than a "field-effect" or synchronous occurrence of multiple neoplastic clones. PMID- 22429592 TI - Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. AB - Pheochromocytomas and paragangliomas (PCC/PGL) are tumors derived from the adrenal medulla or extra-adrenal ganglia, respectively. They are rare and often benign tumors that are associated with high morbidity and mortality due to mass effect and high circulating catecholamines. Although most PCCs and PGLs are thought to be sporadic, over one third are associated with 10 known susceptibility genes. Mutations in three genes causing well characterized tumor syndromes are associated with an increased risk of developing PCCs and PGLs, including VHL (von Hippel-Lindau disease), NF1 (Neurofibromatosis Type 1), and RET (Multiple Endocrine Neoplasia Type 2). Mutations in any of the succinate dehydrogenase (SDH) complex subunit genes (SDHA, SDHB, SDHC, SDHD) can lead to PCCs and PGLs with variable penetrance, as can mutations in the subunit cofactor, SDHAF2. Recently, two additional genes have been identified, TMEM127 and MAX. Although these tumors are rare in the general population, occurring in two to eight per million people, they are more commonly associated with an inherited mutation than any other cancer type. This review summarizes the known germline and somatic mutations leading to the development of PCC and PGL, as well as biochemical profiling for PCCs/PGLs and screening of mutation carriers. PMID- 22429594 TI - Microarray CGH analyses of chromosomal 20q deletions in patients with hematopoietic malignancies. AB - The chromosomal abnormality del(20q) is mostly found in various myeloid disorders, including myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemia. Here, microarray comparative genomic hybridization (aCGH) analyses of 14 patients cytogenetically confirmed to carry the del(20q) aberration in their bone marrow demonstrated that all deletions were interstitial and both the proximal and distal breakpoints varied among individuals. The centromeric breakpoints were located in the 20q11.21-12 region, and the telomeric breakpoints, in the 20q13.13-13.33 region. The extent of the deletion ranged from 11.2 to 27.3 Mb, and the commonly deleted region (CDR) was estimated to be 7.2 Mb in size. Two commonly retained regions were present, the proximal region adjacent to the centromere (20q11.1-11.21) and a subtelomeric one (20q13.33). The CDR of our study was more distal than reported previously. Furthermore, in three patients fluorescence in situ hybridization (FISH) demonstrated that del(20q) cells were detected at a higher frequency in the karyotype analyses than by interphase FISH and aCGH analyses. As the size and breakpoints of del(20q) have been reported to vary among patients, the presence of one or more tumor suppressor genes in the CDR has been suggested. Our study will contribute to the identification of candidate tumor suppressor genes on 20q. PMID- 22429595 TI - Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583. AB - Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans. PMID- 22429596 TI - Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival. AB - Previous studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared with that of sporadic EOC, but few studies have evaluated differences between BRCA genotypes. We compared characteristics and outcome by genotype in BRCA-associated EOC. Patients with BRCA-associated EOC who were diagnosed between January 30,1981, and December 30, 2008, were retrospectively identified through institutional review board-approved registry studies. We examined clinical characteristics, including event-free survival (EFS) and overall survival (OS), for BRCA1 versus BRCA2 patients. We identified 197 cases (148 BRCA1 cases; 49 BRCA2 cases); the median follow-up period was 63 months. BRCA2 patients were older (55.4 vs. 51.1 y; P < 0.01) and had fewer poorly differentiated tumors (67% vs. 82%; P < 0.05). No difference in EFS was observed. OS at 5 years was 75% in BRCA2 patients versus 61% in BRCA1 patients; this was not statistically significant. A non-significant trend toward improved OS was observed in BRCA2 patients with advanced-stage disease (hazard ratio = 0.59; 95% confidence interval 0.32-1.08). Age and grade differed significantly between BRCA1 and BRCA2 carriers in our study population. Whereas no overall differences in EFS or OS were observed, there was a trend toward improved OS in BRCA2 carriers with advanced-stage disease. This may reflect important differences between BRCA genotypes and should be validated in larger studies. PMID- 22429597 TI - Clinical utilization of high-resolution single nucleotide polymorphism based oligonucleotide arrays in diagnostic studies of pediatric patients with solid tumors. AB - High-resolution single nucleotide polymorphism (SNP) arrays have been effectively implemented as a first tier test in clinical cytogenetics laboratories for the detection of constitutional chromosomal abnormalities in patients with suspected genomic disorders. We recently published our experience utilizing SNP array analysis of bone marrow aspirates as a clinical test for patients with suspected leukemia or lymphoma in the Clinical Cancer Cytogenetics Laboratory at The Children's Hospital of Philadelphia. In the present report we summarize our clinical experience using the Illumina HumanHap610 BeadChip array (Illumina, San Diego, CA) for whole genome analysis of pediatric solid tumors. A total of 168 DNA samples isolated from a variety of solid tumors, including brain tumors, sarcomas, neuroblastomas, and Wilms tumors, as well as benign neoplasms and reactive processes, were analyzed over a 2 1/2 year period. One hundred thirty seven of 168 (82%) specimens had at least one copy number alteration or region of loss of heterozygosity detected by the SNP array. Thirty-three of 168 (20%) of cases had a normal karyotype or targeted fluorescence in situ hybridization (FISH) study, but had an abnormal finding by the array analysis. Sixty-three of 168 (37%) samples for which cytogenetic studies were unsuccessful or not performed demonstrated an abnormal array result. In 44 of 168 cases (26%) the array and karyotype or FISH were abnormal, but each demonstrated alterations not detected by the other methodology. Based on our experience in the last 2 1/2 years, we suggest that SNP array analysis can be used as a first tier clinical test for the majority of pediatric solid tumors. PMID- 22429598 TI - A t(17;22)(q21;q12) with partial ETV4 deletion in a soft tissue Ewing sarcoma. AB - Cytogenetic analysis of a lumbar soft tissue Ewing sarcoma (ES) in a 7-month-old female child showed a t(17;22)(q21;q12), a rare translocation leading to an EWSR1 ETV4 chimeric transcript. These findings were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) techniques. The breakpoints were characterized by direct sequencing of the chimeric fusion gene. Tumor genotyping using the Affymetrix Genome-Wide Human single nucleotide polymorphism (SNP) array 6.0 Genechip identified deletions of both chromosomal regions involved in the translocation, resulting in partial deletion of ETV4, but an uninvolved EWSR1 gene. The creation of a fusion between EWSR1 and an ETS family gene consecutive to a chromosomal translocation is characteristic of the Ewing family of tumors (EFT). This is the first report of a deletion involving the two breakpoints in an EWS-ETS translocation. To date, only two cases of t(17;22)(q21;q12) in Ewing sarcoma have been reported, with no associated deletion. Interestingly, both cases had also occurred in soft tissue tumors, which are less common than their bone-involving counterparts. PMID- 22429599 TI - The effect of partial acclimatization to high altitude on loop gain and central sleep apnoea severity. AB - BACKGROUND AND OBJECTIVE: Loop gain is an engineering term that predicts the stability of a feedback control system, such as the control of breathing. Based on earlier studies at lower altitudes, it was hypothesized that acclimatization to high altitude would lead to a reduction in loop gain and thus central sleep apnoea (CSA) severity. METHODS: This study used exposure to very high altitude to induce CSA in healthy subjects to investigate the effect of partial acclimatization on loop gain and CSA severity. Measurements were made on 12 subjects (age 30 +/- 10 years, body mass index 22.8 +/- 1.9, eight males, four females) at an altitude of 5050 m over a 2-week period upon initial arrival (days 2-4) and following partial acclimatization (days 12-14). Sleep was studied by full polysomnography, and resting arterial blood gases were measured. Loop gain was measured by the 'duty cycle' method (duration of hyperpnoea/cycle length). RESULTS: Partial acclimatization to high-altitude exposure was associated with both an increase in loop gain (duty cycle fell from 0.60 +/- 0.05 to 0.55 +/- 0.06 (P = 0.03)) and severity of CSA (apnoea-hypopnoea index increased from 76.8 +/- 48.8 to 115.9 +/- 20.2 (P = 0.01)), while partial arterial carbon dioxide concentration fell from 29 +/- 3 to 26 +/- 2 (P = 0.01). CONCLUSIONS: Contrary to the results at lower altitudes, at high-altitude loop gain and severity of CSA increased. PMID- 22429600 TI - Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term: 12-month findings from the Walking for Wellbeing in the west study. AB - BACKGROUND: Pedometers provide a simple, cost effective means of motivating individuals to increase walking yet few studies have considered if short term changes in walking behaviour can be maintained in the long-term. The role of physical activity consultations in such interventions is unclear. The purpose of this study was to assess the sustainability of pedometer-based interventions and empirically examine the role of physical activity consultations using long-term results of a community-based walking study. METHODS: 79 low active Scottish men and women (63 women and 16 men) from the Walking for Wellbeing in the West intervention study were randomly assigned to receive either: Group 1; pedometer based walking programme plus physical activity consultations or Group 2; pedometer-based walking programme and minimal advice. Step counts (Omron HJ-109E Step-O-Meter pedometer), 7 day recall of physical activity (IPAQ long), mood (PANAS) and quality of life (EuroQol EQ-5D) were assessed pre-intervention and 12, 24 and 48 weeks after receiving the intervention. Body mass, body mass index and waist and hip circumference were assessed pre-intervention and 12 and 24 weeks after receiving the intervention. Analyses were performed on an intention to treat basis (baseline value carried forward for missing data) using mixed factorial ANOVAs and follow-up t-tests. RESULTS: A significant main effect of time (p < 0.001) was found for step-counts attributable to significant increases in steps/day between: pre-intervention (M = 6941, SD = 3047) and 12 weeks (M = 9327, SD = 4136), t(78) = - 6.52, p < 0.001, d = 0.66; pre-intervention and 24 weeks (M = 8804, SD = 4145), t(78) = - 4.82, p < 0.001, d = 0.52; and pre intervention and 48 weeks (M = 8450, SD = 3855), t(78) = - 4.15, p < 0.001, d = 0.44. Significant effects were found for several variables of self-reported physical activity, mood and quality of life and are discussed. No other significant effects in health related outcomes were found. CONCLUSION: Both interventions successfully increased and maintained step counts over 12 months. Physical activity consultations may encourage individuals to be active in other ways beyond walking and to reduce sitting time. TRIAL REGISTRATION NUMBER: Current Controlled Trials Ltd ISRCTN88907382. PMID- 22429602 TI - Parkinson's disease: considerations for dental hygienists. AB - The prevalence of Parkinson's disease (PD) is expected to double over the next 20 years owing to the increase in life expectancy. This progressive disease has several implications relating to oral health, and many are manageable with proper awareness and knowledge about the disease. This article reviews the epidemiology, pathophysiology, and characteristics of PD, as well as the treatments and oral health considerations to enable dental hygienists to undertake an informed approach to patient management strategies and provide optimal care. PMID- 22429601 TI - Burden of community-acquired and nosocomial rotavirus gastroenteritis in the pediatric population of Western Europe: a scoping review. AB - BACKGROUND: Rotavirus affects 95% of children worldwide by age 5 years and is the leading cause of severe dehydrating diarrhea. The objective of this review was to estimate the burden of rotavirus gastroenteritis (RVGE) in the Western European pediatric population. METHODS: A comprehensive literature search (1999-2010) was conducted in PubMed and other sources (CDC; WHO, others). Data on the epidemiology and burden of RVGE among children < 5 years-old in Western Europe - including hospital-acquired disease--were extracted. RESULTS: 76 studies from 16 countries were identified. The mean percentage of acute gastroenteritis (AGE) cases caused by rotavirus ranged from 25.3%-63.5% in children < 5 years of age, peaking during winter. Incidence rates of RVGE ranged from 1.33-4.96 cases/100 person- years. Hospitalization rates for RVGE ranged from 7% to 81% among infected children, depending on the country. Nosocomial RVGE accounted for 47% 69% of all hospital-acquired AGE and prolonged hospital stays by 4-12 days. Each year, RVGE incurred $0.54- $53.6 million in direct medical costs and $1.7-$22.4 million in indirect costs in the 16 countries studied. Full serotyping data was available for 8 countries. G1P[8], G2P[4], G9P[8], and G3P[8] were the most prevalent serotypes (cumulative frequency: 57.2%- 98.7%). Serotype distribution in nosocomial RVGE was similar. CONCLUSIONS: This review confirms that RVGE is a common disease associated with significant morbidity and costs across Western Europe. A vaccine protecting against multiple serotypes may decrease the epidemiological and cost burden of RVGE in Western Europe. PMID- 22429603 TI - Is oral sex really a dangerous carcinogen? Let's take a closer look. AB - INTRODUCTION: Questions have recently arisen in the popular press about the association between specific sexual behaviors, namely, fellatio and cunnilingus, with head and neck cancers. Although there has been an overall decline in the incidence of head and neck cancers over the past 25 years, there has been a shift in the distribution of these cancers toward a particular type known as oral squamous cell carcinomas (OSCCs), and a younger demographic. These particular cancers, OSCCs, have been shown to be associated with the human papillomavirus (HPV). Several researchers have suggested that this shift in the epidemiology of head and neck cancers might be attributable to changing sexual practices. While this speculation has caught on in the popular press, there are several interesting contradictions in the existing evidence that suggest this conclusion might be premature and overreached. AIM: The intent of this article is to help clarify the issues so that sexual medicine professionals can give accurate and up to-date information to their patients. MAIN OUTCOME MEASURES: This is a review article; no outcome data are reported. This is a review article; no measures were collected. METHODS: Pubmed search on HPV, oral sex, oral cancers, and OSCCs. RESULTS: One hundred ninety-six articles on HPV were found; 63 articles on oral sex, 55 on oral cancer, and 5 articles on OSCCs were identified as relevant. CONCLUSIONS: HPV infections occur commonly and are usually cleared within 18 months, thus HPV infection should not be a cause for concern among monogamous couples with a rich and varied sex life as long as the sexual system remains closed and other immune compromising factors are not present. HPV becomes a concern in the context of immune system compromise and infection persistence. Factors contributing to immune system compromise, HPV persistence, and oncogenesis are reviewed. PMID- 22429604 TI - The rise and fall of beta-agonists in the treatment of ARDS. PMID- 22429605 TI - Theoretical studies of QSAR and molecular design on a novel series of ethynyl-3 quinolinecarbonitriles as SRC inhibitors. AB - A theoretical study on the two-dimensional, three-dimensional quantitative structure-activity relationships and docking analysis of a novel series of ethynyl-3-quinolinecarbonitriles acting as Src inhibitors has been carried out. To correlate the c-Src kinase-inhibition activity of these compounds with the two dimensional and three-dimensional structural properties for 39 known compounds, some excellent quantitative structure-activity relationships models with satisfying internal and external predictive abilities were established. A combined method of the density functional theory, molecular mechanics and statistics as well as the comparative molecular field analysis was applied to develop two-dimensional- and three-dimensional-quantitative structure-activity relationship models. The leave-one-out cross-validation q2 values of two dimensional-quantitative structure-activity relationship and comparative molecular field analysis models are 0.834 and 0.812, respectively. The predictive abilities of these models were further validated by the test set including 10 compounds, and the predicted IC50 values were in a good agreement with the experimental ones. The appropriate binding orientations and conformations of these compounds interacting with c-Src kinase were also revealed by the docking study. Based on two-dimensional- and three-dimensional-quantitative structure activity relationship results along with docking analysis, some important factors responsible for inhibitory activity of this series of compounds were discussed in detail. These factors can be summarized as follows: selecting certain large-size substituent R2, increasing the negative charge of the first atom of substituent R1 and the net charge of the C15 atom on ring-C will enhance the activity. Meanwhile, the interaction information between protein and ligand was also revealed in detail. These results help to understand the action mechanism and designing novel potential Src inhibitors. Based on the established models and some designing considerations, three new compounds with rather high predicted Src inhibitory activity have been theoretically designed and presented to experimenters for reference. PMID- 22429606 TI - Causal diagrams in systems epidemiology. AB - Methods of diagrammatic modelling have been greatly developed in the past two decades. Outside the context of infectious diseases, systematic use of diagrams in epidemiology has been mainly confined to the analysis of a single link: that between a disease outcome and its proximal determinant(s). Transmitted causes ("causes of causes") tend not to be systematically analysed.The infectious disease epidemiology modelling tradition models the human population in its environment, typically with the exposure-health relationship and the determinants of exposure being considered at individual and group/ecological levels, respectively. Some properties of the resulting systems are quite general, and are seen in unrelated contexts such as biochemical pathways. Confining analysis to a single link misses the opportunity to discover such properties.The structure of a causal diagram is derived from knowledge about how the world works, as well as from statistical evidence. A single diagram can be used to characterise a whole research area, not just a single analysis - although this depends on the degree of consistency of the causal relationships between different populations - and can therefore be used to integrate multiple datasets.Additional advantages of system-wide models include: the use of instrumental variables - now emerging as an important technique in epidemiology in the context of mendelian randomisation, but under-used in the exploitation of "natural experiments"; the explicit use of change models, which have advantages with respect to inferring causation; and in the detection and elucidation of feedback. PMID- 22429607 TI - Decreased oligodendrocyte nuclear diameter in Alzheimer's disease and Lewy body dementia. AB - To better understand the pathogenesis of dementia, it is important to understand histopathologic changes in neurodegenerative diseases because they might highlight key aspects of the degenerative process. In this study, the nuclear diameter of neurons and oligodendrocytes in selected temporal lobe areas were determined in autopsy tissue sections from patients with Alzheimer's disease (AD), Lewy body dementia (LBD) and controls. Our morphometric studies targeted neurons in the CA4 region of the pyramidal cell layer of the hippocampus, neurons in the granular layer of the dentate gyrus and oligodendrocytes in parahippocampal white matter. Mean neuronal nuclear diameters were not different among the studied groups. However, our studies revealed a statistically significant reduction of mean oligodendrocyte nuclear diameter in AD and LBD relative to controls. The reduction of the mean nucleus diameter of oligodendrocytes in LBD was independent of the presence of associated AD pathology in LBD. These findings for the first time identify decreased oligodendrocyte nucleus diameter as a morphologic feature of AD and LBD and may lead to a better understanding of the role of oligodendrocytes in AD and LBD pathogenesis. PMID- 22429608 TI - Postoperative stability following maxillary downward movement with Le Fort I inclined osteotomy at the lateral nasal cavity wall. AB - Downward movement of the maxilla is regarded as one of the less stable long-term orthognathic surgical procedures. To increase postoperative stability with direct bone contact, the conventional Le Fort I osteotomy was modified with an inclined osteotomy at the lateral nasal cavity wall. The aim of this study was to evaluate the postoperative stability of the new method for Le Fort I inclined osteotomy for downward maxillary movement. The study included 27 patients with anterior vertical deficiency of the maxilla who underwent Le Fort I inclined osteotomy for downward maxillary movement. Patients were classified into two groups according to the amount of downward movement. The amounts of relapse (cephalometric changes) of the two groups were compared and statistically analyzed. The mean amount of relapse was about 1 mm. The tendency of relapse was not increased by a large initial downward movement with Le Fort I inclined osteotomy. Le Fort I inclined osteotomy was used safely for downward movement in order to increase bone height at the piriform aperture area and resulted in direct bone contact, suggesting it is a useful technique for maintaining postoperative stability. A further study with a larger number of patients is necessary. PMID- 22429609 TI - Dexrazoxane shows cytoprotective effects in zoledronic acid-treated human cells in vitro and in the rabbit tibia model in vivo. AB - INTRODUCTION: Bisphosphonates are important and effective drugs in oncology and osteoporosis therapy. They accumulate in the bone matrix becoming released and active by bone resorption. This leads to effective inhibition of tumor cells and bone degradation. A side effect of bisphosphonates similar to other drugs like denosumab is osteonecrosis of the jaws (ONJ). This problem mostly occurs after tooth extraction. We studied the cytoprotectant dexrazoxane known from anthracycline chemotherapy for cytoprotection in nitrogen-containing bisphosphonate treated cells and in the rabbit tibia model to evaluate a possible value in ONJ management. MATERIALS & METHODS: Human osteoblasts (HOB) P2 cells and Human ginigiva fibroblasts (HGF) P2 cells were treated with zoledronic acid (50 MUmol/L) and the cytoprotectant dexrazoxane (600 MUmol/L). Analysis included cell viability testing with MTT assay and morphology analysis using CellTrackerTM Green CMFDA. A biomaterial carrier (Bio-Oss Collagen) was implanted in the rabbit tibia of 6 female chinchilla bastard rabbits on both sides with drill hole defects (d: 3.2mm). Implants were loaded with 25 nmol zoledronic acid, with and without 300 nmol dexrazoxane and unloaded in a control group. Analysis included histological examination of undecalcified samples with toloudine blue staining after 10 days. RESULTS: In vitro experiments showed a significantly higher MTT activity in cells treated with zoledronic acid together with dexrazoxane compared to the same cells treated with the bisphosphonate alone in t-test (HOB: p=0.0003; HGF: p below 0.0001) and one-way ANOVA. Cell morphology changes were consistent with these results. In vivo results showed newly formed bone trabeculae directly growing towards the implanted hydroxylapatite particles and cortical bone interface resorption activities in the control and the experimental group only. CONCLUSION: The study suggests a possible value of this patented technology for ONJ therapy and prevention with local or systemic application. PMID- 22429610 TI - Ethical questions raised by the first allotransplantations of the face: a survey of French surgeons. AB - INTRODUCTION: More than any other allograft, the allotransplantation of the face has a symbolic character, which raises a large number of questions. The objective of this article is to make an analysis through a survey carried out among French surgeons. METHODS: A file of 909 e-mail addresses of surgeons was created so as to send out a questionnaire regarding 10 ethical issues. RESULTS: Beyond the technical prowess, the surgeons ethical reflection initially focused on the notion of consent to donation and care. They attached equal importance to all ethical questions. They spontaneously raised the issue of over-mediatization of these first transplants and the place of the transplant surgeons and their patients in the medical information. CONCLUSION: Over two thirds of the surgeons attached importance to ethical issues regarding the donor and recipient of a facial allograft. Some of the principal questions facing facial transplantation is of an ethical nature as it is an unprecedented procedure that is challenged by the axiom to first do no harm and the need of modern medicine to limit risk to as close to zero as possible. For the non-specialist, accepting psychologically the face of another individual appears to be a real issue. Contrary to that, the main demand expressed by the facial transplant recipients appears to be related to facial functions rather than appearance. PMID- 22429611 TI - Susceptibility testing of Atopobium vaginae for dequalinium chloride. AB - BACKGROUND: Atopobium vaginae and Gardnerella vaginalis are major markers for bacterial vaginosis. We aimed to determine the MIC and MBC range of the broad spectrum anti-infective and antiseptic dequalinium chloride for 28 strains, belonging to 4 species of the genus Atopobium, i.e. A. vaginae, A. minutum, A. rimae and A. parvulum. METHODS: The MIC was determined with a broth microdilution assay. RESULTS: The MIC and MBC for Atopobium spp. for dequalinium chloride ranged between < 0.0625 and 2 MUg/ml. CONCLUSIONS: This study demonstrated that dequalinium chloride inhibits and kills clinical isolates of A. vaginae at concentrations similar to those of clindamycin and lower than those of metronidazole. PMID- 22429612 TI - Characterization of FimA in Porphyromonas gingivalis genotype IV. AB - It has been reported that a large majority of periodontitis patients carry organisms with either type II or IV-fimA, while type I is the most prevalent fimA genotype among Porphyromonas gingivalis-positive healthy adults. Here we report characterization of recombinant fimbrial protein (rFimA) produced in Escherichia coli from genotype IV-fimA. In SDS-PAGE and immunoblot analysis after partial dissociation, type IV-rFimA showed a ladder-like pattern representing oligomeric/polymeric forms of native fimbrial structure. Unlike anti-type I native fimbriae which can only recognize conformational epitopes of the respective proteins, both anti-type IV-native fimbriae and anti-type IV-rFimA antibodies recognized conformational as well as linear epitopes in type IV fimbriae. These results suggest that the type IV-rFimA proteins retain the native fimbrial antigenicity and the antigenicity of type IV-fimbriae is different from that of type I-fimbriae. PMID- 22429613 TI - MicroRNA profiling of hepatocarcinogenesis identifies C19MC cluster as a novel prognostic biomarker in hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Progressive hepatocarcinogenesis is a stepwise process that drives liver transformation. However, the molecular mechanisms of early liver transformation are far from clear. A role for microRNAs (miRNA) as diagnostic and prognostic factors in human tumours, including hepatocellular carcinoma (HCC), is promising. We aimed to identify novel miRNA as biomarkers for differential diagnosis and predictors of disease progression. METHODS: We used a low-density array platform to profile the expression of 664 mature miRNA in a cohort of 60 hepatitis C virus-positive liver lesions representative of all stages of progressive hepatocarcinogenesis. We validated selected miRNA in two independent patient series by qPCR and we characterized the genomic status of the miRNA cluster C19MC by fluorescent in situ hybridization and copy-number variation analyses. RESULTS: A 18-miRNA signature distinguished cirrhosis, dysplastic nodules and HCC lesions. Four miRNAs overexpressed in HCCs belonged to chromosome 19 miRNA cluster (C19MC). Significant overexpression of C19MC in early HCC compared to dysplastic nodules could be confirmed in a second series of hepatitis B virus-related liver lesions (n = 30). In a third series of 61 HCCs, C19MC cluster was overexpressed in HCCs compared to matched cirrhotic parenchyma and regardless of the type of viral infection. High C19MC miRNA levels were correlated with poor clinico-pathological features, increased risk of tumour recurrence and shorter overall survival time. HCCs overexpressing the C19MC cluster showed genetic amplification of the corresponding locus. CONCLUSIONS: C19MC cluster is a novel molecular alteration characteristic of liver cancer and predictor of poor prognosis. C19MC is an attractive candidate for novel HCC therapies. PMID- 22429614 TI - Microvascular blood flow responses to muscle contraction are not altered by high fat feeding in rats. AB - AIM: Exercise and insulin each increase microvascular blood flow and enhance glucose disposal in skeletal muscle. We have reported that insulin-mediated microvascular recruitment in a diet-induced model of insulin resistance (high-fat feeding for 4 weeks) is markedly impaired; however, the effect of muscle contraction in this model has not been previously explored. METHODS: We fed rats either normal (ND, 10% calories from fat) or high-fat (HFD, 60% calories from fat) diets ad libitum for 4-8 weeks. Animals were then anaesthetized and one hindlimb electrically stimulated to contract at 0.05, 0.1 and 2 Hz (field stimulation, 30 V, 0.1 ms duration) in 15 min stepwise increments. Femoral artery blood flow (Transonic flow probe), muscle microvascular blood flow (hindleg metabolism of 1-methylxanthine and contrast-enhanced ultrasound) and muscle glucose disposal (uptake of radiolabelled 2-deoxy-d-glucose and hindleg glucose disappearance) were measured. RESULTS: Both ND and HFD rats received the same voltage across the leg and consequently developed the same muscle tension. Femoral artery blood flow in the contracting leg increased during 2 Hz contraction, but not during the lower frequencies and these effects were similar between ND and HFD rats. Muscle microvascular blood flow significantly increased in a contraction frequency-dependent manner, and preceded increases in total limb blood flow and these effects were similar between ND and HFD rats. Muscle glucose disposal was markedly elevated during 2 Hz contraction and was comparable between ND and HFD rats. CONCLUSION: Contraction-mediated muscle microvascular recruitment and glucose uptake are not impaired in the HFD insulin resistant rat. PMID- 22429615 TI - Taking action on the social determinants of health: improving health access for the urban poor in Mongolia. AB - INTRODUCTION: In recent years, the country of Mongolia (population 2.8 million) has experienced rapid social changes associated with economic growth, persisting socio-economic inequities and internal migration. In order to improve health access for the urban poor, the Ministry of Health developed a "Reaching Every District" strategy (RED strategy) to deliver an integrated package of key health and social services. The aim of this article is to present findings of an assessment of the implementation of the RED strategy, and, on the basis of this assessment, articulate lessons learned for equitable urban health planning. METHODS: Principal methods for data collection and analysis included literature review, barrier analysis of health access and in-depth interviews and group discussions with health managers and providers. FINDINGS: The main barriers to health access for the urban poor relate to interacting effects of poverty, unhealthy daily living environments, social vulnerability and isolation. Implementation of the RED strategy has resulted in increased health access for the urban poor, as demonstrated by health staff having reached new clients with immunization, family planning and ante-natal care services, and increased civil registrations which enable social service provision. Organizational effects have included improved partnerships for health and increased motivation of the health workforce. Important lessons learned from the early implementation of the RED strategy include the need to form strong partnerships among stakeholders at each level of the health system and in the community, as well as the need to develop a specific financing strategy to address the needs of the very poor. The diverse social context for health in an urban poor setting calls for a decentralized planning and partnership strategy, but with central level commitment towards policy guidance and financing of pro-poor urban health strategies. CONCLUSIONS: Lessons from Mongolia mirror other international studies which point to the need to measure and take action on the social determinants of health at the local area level in order to adequately reduce persistent inequities in health care access for the urban poor. PMID- 22429616 TI - Diagnostic accuracy of 320-slice computed-tomography for detection of significant coronary artery stenosis in patients with various heart rates and heart rhythms compared with conventional coronary-angiography. AB - PURPOSE: To evaluate the diagnostic accuracy of 320-slice CT for detection of significant coronary artery stenosis in patients with various heart rates (HR) and heart rhythms, including tachycardia and chronic atrial-fibrillation (CAF) compared with conventional-coronary-angiography (CAG). MATERIALS AND METHODS: One hundred-six consecutive patients underwent both 320-slice CT and CAG within 3 months (normal-sinus-rhythm [NSR] 91.5%, CAF 8.5%, mean HR 65 +/- 15 beats/min). There were no cardiac events between the 2 procedures. Patients were divided in 2 groups: Group 1 (HR <65 with NSR at CT scan, n=62), and Group 2 (HR >64 with NSR or heart rhythm irregularities at CT scan, n=44). Patients with >50% or >75% luminal stenosis on CT were compared with those with >50% or >75% stenosis on CAG, respectively. RESULTS: In a segment-by-segment analysis, in all patients, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of >50% stenosis on CT for predicting >50% stenosis on CAG were 69, 98, 78, and 97%, respectively, and those of >75% stenosis on CT for predicting >75% stenosis on CAG were 78, 98, 64, and 99%, respectively. Sensitivity, specificity, PPV, and NPV of >50% and 75% stenosis on CT for predicting >50% and >75% stenosis, respectively, on CAG were comparable. Diagnostic accuracy was essentially the same in both groups. CONCLUSION: 320-slice CT had high diagnostic accuracy for the detection of significant coronary artery stenosis compared with CAG. Even though the numbers were small, patients with high HR or heart rhythm irregularities might have essentially equivalent results to those with low HR with NSR. PMID- 22429617 TI - Isoforms of protein 4.1 are differentially distributed in heart muscle cells: relation of 4.1R and 4.1G to components of the Ca2+ homeostasis system. AB - The 4.1 proteins are cytoskeletal adaptor proteins that are linked to the control of mechanical stability of certain membranes and to the cellular accumulation and cell surface display of diverse transmembrane proteins. One of the four mammalian 4.1 proteins, 4.1R (80 kDa/120 kDa isoforms), has recently been shown to be required for the normal operation of several ion transporters in the heart (Stagg MA et al. Circ Res, 2008; 103: 855-863). The other three (4.1G, 4.1N and 4.1B) are largely uncharacterised in the heart. Here, we use specific antibodies to characterise their expression, distribution and novel activities in the left ventricle. We detected 4.1R, 4.1G and 4.1N by immunofluorescence and immunoblotting, but not 4.1B. Only one splice variant of 4.1N and 4.1G was seen whereas there are several forms of 4.1R. 4.1N, like 4.1R, was present in intercalated discs, but unlike 4.1R, it was not localised at the lateral plasma membrane. Both 4.1R and 4.1N were in internal structures that, at the level of resolution of the light microscope, were close to the Z-disc (possibly T tubules). 4.1G was also in intracellular structures, some of which were coincident with sarcoplasmic reticulum. 4.1G existed in an immunoprecipitable complex with spectrin and SERCA2. 80 kDa 4.1R was present in subcellular fractions enriched in intercalated discs, in a complex resistant to solubilization under non-denaturing conditions. At the intercalated disc 4.1R does not colocalise with the adherens junction protein, beta-catenin, but does overlap with the other plasma membrane signalling proteins, the Na/K-ATPase and the Na/Ca exchanger NCX1. We conclude that isoforms of 4.1 proteins are differentially compartmentalised in the heart, and that they form specific complexes with proteins central to cardiomyocyte Ca(2+) metabolism. PMID- 22429618 TI - Intracameral acetylcholine effectively contracts pupils after dilatation with intracameral mydriatics. AB - PURPOSE: To determine whether intracameral acetylcholine can contract pupils dilated with intracameral mydriatics in phacoemulsification cataract surgery. METHODS: A total of 60 patients were included in this prospective randomized masked study performed at Ornskoldsviks Hospital Eye Clinic. The patients were randomized and were given either topical placebo and an intracameral mydriatic solution (ICM) (cyclopentolate 0.1%, phenylephrine 1.5% and xylocaine 1%) (n = 30) or topical mydriatics (TM) (cyclopentolate 0.85% and phenylephrine 1.5%) and xylocaine 1% intracamerally (n = 30) at the start of surgery. After intraocular lens (IOL) implantation, 0.15 ml 1% acetylcholine was given intracamerally in all cases. The pupil size was registered preoperatively, 45 seconds after intracameral injection, after ophthalmic viscosurgical device (OVD) evacuation, 30 seconds after acetylcholine injection, 2 min after acetylcholine injection and the day after surgery. RESULTS: The pupil contraction and pupil size after acetylcholine injection showed no significant differences at 30 seconds (contraction 1.0 +/- 0.4 in ICM group versus 0.9 +/- 0.4 in TM group; p = 0.75; size 4.8 +/- 1.1 in the ICM group versus 5.2 +/- 1.1 in the TM group; p = 0.24) or at 2 min (contraction 1.5 +/- 0.6 in the ICM group versus 1.4 +/- 0.6 in the TM group; p = 0.63; size 4.3 +/- 0.9 in the ICM group versus 4.7 +/- 1.0 in the TM group; p = 0.13). No difference in baseline pupil size after ophthalmic viscosurgical device (OVD) evacuation was seen between the two groups (5.8 +/- 0.9 in the ICM group versus 6.1 +/- 1.2 in the TM group; p = 0.28). CONCLUSION: We here show that intracameral acetylcholine contracts pupils as effectively after dilatation with intracameral mydriatics as after dilatation with topical mydriatics. Cataract surgeons can feel comfortable and safe when using intracameral mydriatics, even if pupil contraction with acetylcholine should be required. PMID- 22429619 TI - Intravenous fat emulsion therapy: can it be tried without sufficient first-line treatment modalities? PMID- 22429620 TI - Assessment of phylogenetic sensitivity for reconstructing HIV-1 epidemiological relationships. AB - Phylogenetic analysis has been extensively used as a tool for the reconstruction of epidemiological relations for research or for forensic purposes. It was our objective to assess the sensitivity of different phylogenetic methods and various phylogenetic programs to reconstruct epidemiological links among HIV-1 infected patients that is the probability to reveal a true transmission relationship. Multiple datasets (90) were prepared consisting of HIV-1 sequences in protease (PR) and partial reverse transcriptase (RT) sampled from patients with documented epidemiological relationship (target population), and from unrelated individuals (control population) belonging to the same HIV-1 subtype as the target population. Each dataset varied regarding the number, the geographic origin and the transmission risk groups of the sequences among the control population. Phylogenetic trees were inferred by neighbor-joining (NJ), maximum likelihood heuristics (hML) and Bayesian methods. All clusters of sequences belonging to the target population were correctly reconstructed by NJ and Bayesian methods receiving high bootstrap and posterior probability (PP) support, respectively. On the other hand, TreePuzzle failed to reconstruct or provide significant support for several clusters; high puzzling step support was associated with the inclusion of control sequences from the same geographic area as the target population. In contrary, all clusters were correctly reconstructed by hML as implemented in PhyML 3.0 receiving high bootstrap support. We report that under the conditions of our study, hML using PhyML, NJ and Bayesian methods were the most sensitive for the reconstruction of epidemiological links mostly from sexually infected individuals. PMID- 22429621 TI - Influence of amino acid at position 132 in VPg on replication and systemic infection of Barley yellow mosaic virus. AB - A substitution of Lys with Asn or His at the amino-acid position 132 in VPg (VPg132) correlates with overcoming rym4-gene resistance by European strain 2 of Barley yellow mosaic virus (BaYMV-2). From the full-length cDNA clones for a Japanese BaYMV isolate JK05 (BaYMV-JK05) we generated virus mutants with Tyr, Lys, Asn, and Ala substituted for wild-type His at the VPg132. Only Tyr and Asn mutants replicated efficiently in protoplasts from barley varieties that are susceptible to wild-type virus. The Tyr mutant also infected susceptible barley plants systemically with the emergence of virus populations with partial or complete reversion to His, whereas the Asn mutant did not cause systemic infection. Thus, the VPg132 amino acid is essential for both efficient replication and systemic infection. Neither wild-type virus nor any of the mutants replicated in protoplasts from a rym4 barley genotype. Therefore, substitution of the VPg132 amino acid alone cannot enable breaking rym4-mediated resistance in the BaYMV-JK05 background. PMID- 22429622 TI - Fabrication of novel magnetic chitosan grafted with graphene oxide to enhance adsorption properties for methyl blue. AB - A novel magnetic composite bioadsorbent composed of magnetic chitosan and graphene oxide (MCGO) was prepared as the magnetic adsorbent. The morphology, chemical structure and magnetic property of the MCGO were characterized by Fourier transform infrared spectrometer (FT-IR), X-ray diffraction (XRD) and Scanning electronic microscope (SEM), respectively. Adsorption of methyl blue (MB) onto MCGO was investigated with respect to pH, adsorption time, initial MB concentration and temperature. Kinetics data and adsorption isotherm, obtained at the optimum pH 5.3, were better fitted by pseudo-second-order kinetic model and by Langmuir isotherm, respectively. The values of activation parameters such as free energy (DeltaG, -0.74~-1.46kJmol(-1)), enthalpy (DeltaH, -10.28kJmol(-1)) and entropy (DeltaS, -36.35Jmol(-1)K(-1)) were determined, respectively, indicating that the adsorption was spontaneous, favorable and exothermic process in nature. Moreover, the MCGO was stable and easily recovered, the adsorption capacity was about 90% of the initial saturation adsorption capacity after being used four times. PMID- 22429623 TI - Degradation of organics in reverse osmosis concentrate by electro-Fenton process. AB - The present work studied, for the first time, the removal of organic pollutants from a high-salinity reverse osmosis (RO) concentrate by electro-Fenton approach using a graphite-felt as cathode. To gain insights into the process, the in situ generation of hydrogen peroxide was also investigated. The COD removal efficiency and energy consumption were optimized by investigating the effects of some important operating parameters such as ferric ion concentration, initial pH and cathodic potential. Under the conditions of cathodic potential at -0.72V and Fe(3+) concentration 0.2mM, more than 62% COD could be removed in 3h treatment, meeting the local wastewater discharge requirement (COD <50mg/L). It confirmed the feasibility of electro-Fenton process for the treatment of RO concentrate accounting for its cost-effectiveness in wide pH ranges. PMID- 22429624 TI - Optimization of photocatalytic degradation of methyl blue using silver ion doped titanium dioxide by combination of experimental design and response surface approach. AB - Photocatalytic degradation of methyl blue (MYB) was studied using Ag(+) doped TiO(2) under UV irradiation in a batch reactor. Catalytic dose, initial concentration of dye and pH of the reaction mixture were found to influence the degradation process most. The degradation was found to be effective in the range catalytic dose (0.5-1.5g/L), initial dye concentration (25-100ppm) and pH of reaction mixture (5-9). Using the three factors three levels Box-Behnken design of experiment technique 15 sets of experiments were designed considering the effective ranges of the influential parameters. The results of the experiments were fitted to two quadratic polynomial models developed using response surface methodology (RSM), representing functional relationship between the decolorization and mineralization of MYB and the experimental parameters. Design Expert software version 8.0.6.1 was used to optimize the effects of the experimental parameters on the responses. The optimum values of the parameters were dose of Ag(+) doped TiO(2) 0.99g/L, initial concentration of MYB 57.68ppm and pH of reaction mixture 7.76. Under the optimal condition the predicted decolorization and mineralization rate of MYB were 95.97% and 80.33%, respectively. Regression analysis with R(2) values >0.99 showed goodness of fit of the experimental results with predicted values. PMID- 22429625 TI - Toward understanding the role of individual fluorescent components in DOM-metal binding. AB - Knowledge on the function of individual fractions in dissolved organic matter (DOM) is essential for understanding the impact of DOM on metal speciation and migration. Herein, fluorescence excitation-emission matrix quenching and parallel factor (PARAFAC) analysis were adopted for bulk DOM and chemically isolated fractions from landfill leachate, i.e., humic acids (HA), fulvic acids and hydrophilic (HyI) fraction, to elucidate the role of individual fluorescent components in metal binding (Cu(II) and Cd(II)). Three components were identified by PARAFAC model, including one humic substance (HS)-like, one protein-like and one component highly correlated with the HyI fraction. Among them, the HS-like and protein-like components were responsible for Cu(II) binding, while the protein-like component was the only fraction involved in Cd(II) complexation. It was further identified that the slight quenching effect of HA fraction by Cd(II) was induced by the presence of proteinaceous materials in HA. Fluorescent substances in the HyI fraction of landfill leachate did not play as important a role as HS did. Therefore, it was suggested that the potential risk of aged leachate (more humified) as a carrier of heavy metal should not be overlooked. PMID- 22429626 TI - Testes-specific hemoglobins in Drosophila evolved by a combination of sub- and neofunctionalization after gene duplication. AB - BACKGROUND: For a long time the presence of respiratory proteins in most insects has been considered unnecessary. However, in recent years it has become evident that globins belong to the standard repertoire of the insect genome. Like most other insect globins, the glob1 gene of Drosophila melanogaster displays a conserved expression pattern in the tracheae, the fat body and the Malpighian tubules. RESULTS: Here we show that the recently discovered D. melanogaster globin genes glob2 and glob3 both display an unusual male-specific expression in the reproductive tract during spermatogenesis. Both paralogs are transcribed at equivalent mRNA levels and largely overlap in their cellular expression patterns during spermatogenesis. Phylogenetic analyses showed that glob2 and glob3 reflect a gene duplication event that occurred in the ancestor of the Sophophora subgenus at least 40 million years ago. Therefore, flies of the Drosophila subgenus harbor only one glob2/3-like gene. CONCLUSIONS: Phylogenetic and sequence analyses indicate an evolution of the glob2 and glob3 duplicates by a combination of sub- and neofunctionalization. Considering their restricted, testes-specific expression, an involvement of both globins in alleviating oxidative stress during spermatogenesis is conceivable. PMID- 22429627 TI - Factors affecting commencement and cessation of smoking behaviour in Malaysian adults. AB - BACKGROUND: Tobacco consumption peak in developed countries has passed, however, it is on the increase in many developing countries. Apart from cigarettes, consumption of local hand-rolled cigarettes such as bidi and rokok daun are prevalent in specific communities. Although factors associated with smoking initiation and cessation has been investigated elsewhere, the only available data for Malaysia is on prevalence. This study aims to investigate factors associated with smoking initiation and cessation which is imperative in designing intervention programs. METHODS: Data were collected from 11,697 adults by trained recording clerks on sociodemographic characteristics, practice of other risk habit and details of smoking such as type, duration and frequency. Smoking commencement and cessation were analyzed using the Kaplan-Meier estimates and log rank tests. Univariate and multivariate Cox proportional hazard regression models were used to calculate the hazard rate ratios. RESULTS: Males had a much higher prevalence of the habit (61.7%) as compared to females (5.8%). Cessation was found to be most common among the Chinese and those regularly consuming alcoholic beverages. Kaplan-Meier plot shows that although males are more likely to start smoking, females are found to be less likely to stop. History of betel quid chewing and alcohol consumption significantly increase the likelihood of commencement (p < 0.0001), while cessation was least likely among Indians, current quid chewers and kretek users (p < 0.01). CONCLUSIONS: Gender, ethnicity, history of quid chewing and alcohol consumption have been found to be important factors in smoking commencement; while ethnicity, betel quid chewing and type of tobacco smoked influences cessation. PMID- 22429628 TI - [Change in publishing company for the Revista Espanola de Anestesiologia, Reanimacion (Spanish Journal of Anesthesiology and Critical Care)]. PMID- 22429629 TI - [Information technologies in the field of anaesthesiology]. PMID- 22429630 TI - [Levosimendan reduces mortality in cardiac surgery: a systematic review and meta analysis]. AB - OBJECTIVES: To evaluate whether Levosimendan has any impact on peri-operative mortality in cardiac surgery. MATERIAL AND METHODS: A literature search was performed with the main purpose of looking for mortality in cardiac surgery. Data tabulated by both the fixed effects model and the random effects model were analysed based on the method by Peto. The statistical heterogeneity and inconsistency was estimated and quantified, as well as performing a sensitivity analysis to test the influence of individual studies on the overall result. All the calculations and statistical analyses were performed using the software; "Comprehensive Meta-Analysis" V2.0 and "StatsDirect statistical software" V 2.7.8. At the same time, possible publication bias was also determined. RESULTS: A total of 169 articles were found, from which 13 studies were finally included in the meta-analysis; 12 randomised and one of them retrospective with paired data. The global analysis showed that the use of levosimendan was associated with a significant reduction in postoperative mortality. CONCLUSIONS: The meta analysis showed that the use of Levosimendan was associated with a reduction in mortality in patients subjected to cardiac surgery, although there is still no definitively clear evidence. Additional randomised and multicentre clinical studies, with a much larger number of patients are required, in which hospital mortality and mortality at 6 months are analysed as the primary outcomes. PMID- 22429631 TI - [Thoracic paravertebral block compared to thoracic paravertebral block plus pectoral nerve block in reconstructive breast surgery]. AB - INTRODUCTION: Major breast surgery was usually performed under general anaesthesia until the first patient series with thoracic paravertebral block was published. This block was introduced into our Hospital, and with the purpose of obtaining a more comfortable perioperative period, it was combined with blocking the pectoral nerves. In this study, both anaesthetic techniques are compared, as regards control of postoperative pain, incidence of postoperative nausea and vomiting, and sedation requirements. MATERIAL AND METHODS: An observational study was conducted with 60 patients scheduled for breast surgery with subpectoral implants (augmentation and /or prosthesis). Two groups were studied. The first (Group I) was randomly selected from a patient records data base to have thoracic paravertebral block and sedation. In the second (Group II), a pectoral nerve block was performed combined with a thoracic paravertebral block. RESULTS: In Group I, 33.3% of the patients had a score of <= 3 on the visual analogue scale (VAS) at 8 hours, and 66.7% had a VAS score of >= 4 at 24h, compared to 80% of the Group II patients who had a VAS score of <= 3 at 8 hours and 20% with a VAS score >= 4 at 24h. The mean difference in the VAS scores at 8 hours between the two groups was statistically significant: mean VAS score at 8 hours in Group I, 4.23 +/- 2.4 compared to 1.77 +/- 2.2 in Group II. There was no difference in the VAS scores at 24 hours. No statistically significant differences were found between the two groups in the incidence of postoperative nausea and vomiting. The need for intra-operative sedation supplements with propofol boluses was less in Group II, 40% compared to 90% in Group II. CONCLUSIONS: Pectoral nerve block is a technique that improves the results obtained with thoracic paravertebral block in reconstructive breast surgery, with better post-operative analgesic control in the immediate post-operative period and a lower requirement for sedation. PMID- 22429632 TI - [Multicentre epidemiological study of anaesthetic techniques in inguinal hernia surgery in Spain]. AB - OBJECTIVE: Despite renewed interest in the management of anaesthesia during inguinal hernia surgery, there is a lack of data on trends in anaesthesia in Spain. The purpose of this study was to analyse the different anaesthetic techniques used in inguinal hernia surgery and their association with recovery, hospital stay, complications, and satisfaction with the technique. PATIENTS AND METHODS: Ours was a multicentre, descriptive, cross-sectional epidemiological study performed at 20 Spanish hospitals. Each centre included 12 patients who underwent elective inguinal hernia repair. Data were collected on patient characteristics, clinical history, anaesthetic technique, post-operative recovery, and complications. RESULTS: Data were collected on 238 patients, most of whom (91%) were ASA I or II, with a mean age of 57 years (25-84). Day surgery was performed in 47% of cases; 26% as one-day surgery, and the rest as inpatient surgery. Spinal anaesthesia was the most widely used technique (60%), followed by general anaesthesia (27%), and local anaesthesia with sedation (13%) (pP<.0001). Discharge was within 6 hours with general anaesthesia and local anaesthesia in 94% and 100% of cases, respectively, compared with 68% for spinal anaesthesia (001). No differences were observed between anaesthetic techniques in terms of adverse effects, except for urinary retention in 10 male patients (mean age 68 years) all of whom had received spinal anaesthesia. CONCLUSIONS: Spinal anaesthesia is the most commonly used technique in Spain for inguinal hernia repair, although it is associated with a longer hospital stay (greater than 6h in 32% of cases) and a high incidence of urinary retention than other anaesthetic methods, in particular those with local infiltration. These techniques should be more vigorously implemented in daily practice. PMID- 22429633 TI - [Quality of postoperative analgesia protocols in a local hospital]. AB - OBJECTIVES: To demonstrate that the introduction of a nursing based Acute Pain Service (APS) leads to better postoperative pain management and a decrease in treatment-related adverse events. To assess the quality criteria of postoperative pain control and discuss their compliance. MATERIALS AND METHODS: A total of 116 major elective surgeries were assessed between November and December 2010 and compared to those collected between November and December 2007 before the introduction of the APS. The following variables were studied: sociodemographic data, type of surgery and postoperative analgesia, pain ratings (numeric verbal scale- NVS) per nursing shift (48 hours), compliance of quality criteria in pain management, and a patient satisfaction survey. RESULTS AND CONCLUSIONS: Despite there being a higher number of surgeries related to expected moderate-intense pain, better scores in pain ratings were obtained both at rest (86.1% +/- 11.2 vs 50.7% +/- 12.1 NVS <= 3, p=.0001) and during activity (73.9% +/- 10.8 vs 50.1% +/ 12.1 NVS <= 5, p=.0026) in surgical wards, but treatment-related side effects did not decrease with the analgesics and there was no increase treatment-related patient satisfaction. The data analysis showed that there is still a deficiency in the recording of the pain scores by nursing shift (70 +/- 6.1 vs 40 +/- 11.9, p=.0002). PMID- 22429634 TI - [Resuscitation damage control in the patient with severe trauma]. AB - Severe trauma is the principle cause of death among young people in developed countries, with the main causes being due to road traffic accidents and accidents at work. The principle cause of death in severe trauma is the massive uncontrolled loss of blood. Most of the severe traumas with a massive haemorrhage develop coagulopathy, with some controversy over what is the best treatment for this. Patients with severe trauma are complex patients; they have a high mortality, they consume a significant amount of sources and can require rapid, intensive and multidisciplinary treatment encompassed within the concept of resuscitation damage control. In this article we attempt to present a current view of the pathophysiology of severe trauma and resuscitation damage control that may be applied to these types of patients. PMID- 22429635 TI - [Review: effect of preventive analgesia on postoperative pain]. AB - Preventive analgesia (administration of a technique or analgesic drug with the aim of reducing postoperative pain, hyperalgesia and allodynia) has shown to be effective in experimental studies. However, the results in patients have been controversial. A review has been made of the clinical trials published during the last 5 years to test the efficacy of preventive analgesia on postoperative pain. A search was made of the published literature in Medline, with the terms "pre emptive analgesia", "preventive analgesia" and "postoperative pain", selecting prospective, controlled, randomised and double blind studies that compared analgesic regimens before and after the incision or the same or very similar postoperative conditions. A total of 27 studies were found during the period 2005 2010 that complied with the inclusion criteria. Analgesia measurement variables were analysed, such as postoperative pain, time passed until the first rescue, and total analgesic requirements. Preventive analgesia was effective in 15 of the 27 studies, with pre-incisional epidural drug administration being the most effective (local anaesthetics with or without opioids, clonidine). The possible effectiveness of preventive analgesia in humans is still controversial, partly due to the wide heterogeneity in the inclusion criteria, types of patients, or the analgesia measurement parameters analysed by the studies. More studies are required with common criteria and objectives. PMID- 22429636 TI - [Giant omphalocele correction in a patient with pentalogy of Cantrell]. AB - Pentalogy of Cantrell is a rare congenital malformation characterised by a large defect in the lower region of the sternum, diaphragm, and lower abdominal region. It is also characterised by the migration of organs, and its prognosis depends on the presence of cardiac malformations. We present the case of an 18 year-old male subjected to a scheduled giant omphalocele correction. Invasive monitoring, including cardiac output, was used to avoid episodes of instability due to the increase in abdominal pressure and the increase in venous return (as had happened on two previous operations). The prognosis depends on multiple factors, with good haemodynamic and respiratory control being the most important. Mortality is high despite the advances in monitoring. PMID- 22429637 TI - [Mandibular fracture in a patient with pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome)]. PMID- 22429638 TI - [Orotracheal intubation with an Airtraq optical laryngoscope in a child with Smith-Lemli-Opitz syndrome and a difficult airway]. PMID- 22429639 TI - [Patient with Madelung syndrome and difficult-to-treat airway]. PMID- 22429640 TI - [Airway treatment management in a case of Madelung disease or cervical lipomatosis]. PMID- 22429641 TI - Repair after acute lung injury: molecular mechanisms and therapeutic opportunities. PMID- 22429642 TI - Condyle and mandibular bone change after unilateral condylar neck fracture in growing rats. AB - Unilateral fracture of the condylar neck in immature subjects might lead to mandible asymmetry and condyle remodelling. A rat model was used to investigate mandibular deviation and condylar remodelling associated with condyle fracture. 72 4-week-old male rats were randomly divided into three groups: an experimental group (unilateral transverse condylar fracture induced surgically), a sham operation group (surgical exposure but no fracture), and a non-operative control group (no operation). The rats were killed at intervals up to 9weeks after surgery, and outcomes were assessed using various measures of mandible deviation, histological and X-ray observation, and immunohistochemical measures of expression levels of connective tissue growth factor (CTGF) and type II collagen (Col II). The fracture led to the degeneration of mandibular size, associated with atrophy of fractured condylar process. Progressive remodelling of cartilage and increasing expression levels of CTGF and Col II were found. The authors conclude that condylar fracture can lead to asymmetries in mandible and condyle remodelling and expression of CTGF and Col II in condylar cartilage on both the ipsilateral and the contralateral sides. PMID- 22429643 TI - Usefulness of health registries when estimating vaccine effectiveness during the influenza A(H1N1)pdm09 pandemic in Norway. AB - BACKGROUND: During the 2009-2010 pandemic in Norway, 12 513 laboratory-confirmed cases of pandemic influenza A(H1N1)pdm09, were reported to the Norwegian Surveillance System for Communicable Diseases (MSIS). 2.2 million persons (45% of the population) were vaccinated with an AS03-adjuvanted monovalent vaccine during the pandemic. Most of them were registered in the Norwegian Immunisation Registry (SYSVAK). Based on these registries, we aimed at estimating the vaccine effectiveness (VE) and describing vaccine failures during the pandemic in Norway, in order to evaluate the role of the vaccine as a preventive measure during the pandemic. METHODS: We conducted a population-based retrospective cohort study, linking MSIS and SYSVAK with pandemic influenza vaccination as exposure and laboratory-confirmed pandemic influenza as outcome. We measured VE by week and defined two thresholds for immunity; eight and 15 days after vaccination. RESULTS: The weekly VE ranged from 77% to 96% when considering 15 days or more after vaccination as the threshold of immunity and from 73% to 94% when considering eight days or more. Overall, 157 individuals contracted pandemic influenza eight or more days after vaccination (8.4/100,000 vaccinated), of these 58 had onset 15 days or more after vaccination (3.0/100,000 vaccinated). Most of the vaccine failures occurred during the first weeks of the vaccination campaign. More than 30% of the vaccine failures were found in people below 10 years of age. CONCLUSIONS: Having available health registries with data regarding cases of specific disease and vaccination makes it feasible to estimate VE in a simple and rapid way. VE was high regardless the immunity threshold chosen. We encourage public health authorities in other countries to set up such registries. It is also important to consider including information on underlying diseases in registries already existing, in order to make it feasible to conduct more complete VE estimations. PMID- 22429644 TI - Premature ejaculation and erectile dysfunction prevalence and attitudes in the Asia-pacific region-a comment. PMID- 22429645 TI - Ramsay Hunt syndrome. AB - Ramsay Hunt syndrome is defined as herpes zoster oticus associated with an acute peripheral facial nerve paresis and quite often with other cranial nerve lesions. The combination of motor, sensory and autonomic involvement leads to a variety of neurological damage patterns, i. e. facial muscle paresis, hearing and balance disorders, sensory problems and disturbances of taste as well as lacrimal and nasal secretion. Additional variability of the clinical picture of Ramsay Hunt syndrome is produced by varying patterns of skin involvement explained by individual anastomoses between cranial and cervical nerves. Knowledge of these findings and an early diagnosis of Ramsay Hunt syndrome are important as prognosis of cranial nerve damage depends on the time at which acyclovir corticosteroid therapy is started. PMID- 22429646 TI - Tertiary paediatric refugee health clinic in Western Australia: analysis of the first 1026 children. AB - AIM: Children account for approximately half of the humanitarian refugees currently resettled in Australia. A multidisciplinary refugee health clinic (RHC) was established at the tertiary paediatric hospital in Western Australia to address burgeoning referrals of refugee children following voluntary post resettlement health assessment. The aim of this study is to describe the epidemiology of common conditions in resettled paediatric refugees attending a tertiary multidisciplinary RHC. METHODS: Standardised clinical and demographic data were routinely collected during first visit clinical assessment at the RHC. Descriptive analyses of the first 1026 children are presented. RESULTS: One thousand twenty-six refugee children from 475 families and over 30 different ethnicities were described. Nine hundred twenty-seven (90.4%) children were referred following post-resettlement health assessment. Median age was 7.8 years. Common reasons for referral were: vitamin D deficiency (400, 39%), iron deficiency (226, 22%), positive Helicobacter pylori serology (206, 21%), poor appetite (175, 17.1%), and schistosomiasis (170, 16.6%). Comorbidities identified by the RHC included tinea capitis and corporis (297, 28.9%), and dental disease (228, 22.2%). Two-thirds of children (680, 66.3%) had at least one abnormal finding on clinical examination that identified pathologies that were not evident from the history. Three hundred eighty children (37%) were referred to sub specialty services. CONCLUSIONS: A multidisciplinary paediatric RHC facilitated and strengthened the management of refugee children with multiple and complex health needs. Evidenced-based culturally appropriate methods to identify developmental delay, psychological morbidity and quantify social needs of this vulnerable population remain uncertain. These findings are relevant to the continuing evolution of paediatric refugee health care in Australia and other high income countries. PMID- 22429647 TI - Progesterone produces antinociceptive and neuroprotective effects in rats with microinjected lysophosphatidic acid in the trigeminal nerve root. AB - BACKGROUND: In our present study, we studied the role of demyelination of the trigeminal nerve root in the development of prolonged nociceptive behavior in the trigeminal territory. RESULTS: Under anesthesia, the Sprague-Dawley rats were mounted onto a stereotaxic frame and 3 MUL of lysophosphatidic acid (LPA, 1 nmol) was injected into the trigeminal nerve root to produce demyelination. This treatment decreased the air-puff thresholds, persisted until postoperative day 130, and then returned to the preoperative levels 160 days after LPA injection. The LPA-treated rats also showed a significant hyper-responsiveness to pin-prick stimulation. We further investigated the antinociceptive and neuroprotective effects of progesterone in rats undergoing demyelination of the trigeminal nerve root. Progesterone (8, 16 mg/kg/day) was administered subcutaneously, beginning on the operative day, for five consecutive days in the LPA-treated rats. Treatment with progesterone produced significant early anti-allodynic effects and delayed prolonged anti-allodynic effects. The expression of protein zero (P0) and peripheral myelin protein 22 (PMP22) were significantly down-regulated in the trigeminal nerve root on postoperative day 5 following LPA injection. This down regulation of the P0 and PMP22 levels was blocked by progesterone treatment. CONCLUSIONS: These results suggest that progesterone produces antinociceptive effects through neuroprotective action in animals with LPA-induced trigeminal neuropathic pain. Moreover, progesterone has potential utility as a novel therapy for trigeminal neuropathic pain relief at an appropriate managed dose and is therefore a possible future treatment strategy for improving the recovery from injury. PMID- 22429648 TI - nMAT1, a nuclear-encoded maturase involved in the trans-splicing of nad1 intron 1, is essential for mitochondrial complex I assembly and function. AB - Mitochondrial genomes (mtDNAs) in angiosperms contain numerous group II-type introns that reside mainly within protein-coding genes that are required for organellar genome expression and respiration. While splicing of group II introns in non-plant systems is facilitated by proteins encoded within the introns themselves (maturases), the mitochondrial introns in plants have diverged and have lost the vast majority of their intron-encoded ORFs. Only a single maturase gene (matR) is retained in plant mtDNAs, but its role(s) in the splicing of mitochondrial introns is currently unknown. In addition to matR, plants also harbor four nuclear maturase genes (nMat 1 to 4) encoding mitochondrial proteins that are expected to act in the splicing of group II introns. Recently, we established the role of one of these proteins, nMAT2, in the splicing of several mitochondrial introns in Arabidopsis. Here, we show that nMAT1 is required for trans-splicing of nad1 intron 1 and also functions in cis-splicing of nad2 intron 1 and nad4 intron 2. Homozygous nMat1 plants show retarded growth and developmental phenotypes, modified respiration activities and altered stress responses that are tightly correlated with mitochondrial complex I defects. PMID- 22429650 TI - Metabolomics in cancer: a bench-to-bedside intersection. AB - The field of oncology is a rapidly evolving science mostly due to extensive basic, translational and clinical research which have provided more insights into the tumor biology and set grounds for the development of new therapies. Metabolomics is the upcoming new science in the omics field with the potential to further increment our knowledge of cancer biology. In this review we intend to explore the potential role of metabolomics in understanding cancer process, improving cancer staging, refining tumor characterization and in the search for predictive biomarkers of response and toxicity. PMID- 22429651 TI - Disturbed sleep among COPD patients is longitudinally associated with mortality and adverse COPD outcomes. AB - OBJECTIVE: To investigate the cross-sectional association between COPD severity and disturbed sleep and the longitudinal association between disturbed sleep and poor health outcomes. METHODS: Ninety eight adults with spirometrically-confirmed COPD were recruited through population-based, random-digit telephone dialing. Sleep disturbance was evaluated using a 4-item scale assessing insomnia symptoms as: difficulty falling asleep, nocturnal awakening, morning tiredness, and sleep duration adequacy. COPD severity was quantified by: FEV(1) and COPD Severity Score, which incorporates COPD symptoms, requirement for COPD medications and oxygen, and hospital-based utilization. Subjects were assessed one year after baseline to determine longitudinal COPD exacerbations and emergency utilization and were followed for a median 2.4 years to assess all-cause mortality. RESULTS: Sleep disturbance was cross-sectionally associated with cough, dyspnea, and COPD Severity Score, but not FEV(1). In multivariable logistic regression, controlling for sociodemographics and body-mass index, sleep disturbance longitudinally predicted both incident COPD exacerbations (OR=4.7; p=0.018) and respiratory related emergency utilization (OR=11.5; p=0.004). In Cox proportional hazards analysis, controlling for the same covariates, sleep disturbance predicted poorer survival (HR=5.0; p=0.013). For all outcomes, these relationships persisted after also controlling for baseline FEV(1) and COPD Severity Score. CONCLUSIONS: Disturbed sleep is cross-sectionally associated with worse COPD and is longitudinally predictive of COPD exacerbations, emergency health care utilization, and mortality. PMID- 22429652 TI - Sleep instability and cognitive status in drug-resistant epilepsies. AB - OBJECTIVE: The aims of this study were to evaluate the sleep habits of children with drug resistant epilepsy and to correlate sleep abnormalities with epilepsy and level of intelligence. SUBJECTS AND METHODS: Twenty five subjects with drug resistant epilepsy (14 males, age range 2-16.4 years) were recruited for this study. A control group was formed by 23 normal children. Two instruments to assess sleep habits were administered to the patients with epilepsy: a questionnaire on sleep habits (to preschool children) and a questionnaire on sleep behavior (for children aged more than seven years old); a cognitive test (Wechsler Intelligence Scale for Children-WISC) was also performed. Patients underwent a complete polysomnographic study and sleep parameters, including CAP, were analyzed and correlated according to cognitive-behavioral measures in children with epilepsy. RESULTS: Children with drug-resistant epilepsy and severe mental retardation showed sleep abnormalities such as low sleep efficiency, high percentage of wakefulness after sleep onset, reduced slow wave sleep, and reduced REM sleep. Sleep microstructure evaluated by means of CAP analysis showed a decrease in A1 index during N3 in patients with more severe cognitive impairment. Children with epilepsy and cognitive impairment (n=10) had higher Sleep Behavior Questionnaire for Children (SBQC) total scores (65.60 +/- 18.56) compared to children with epilepsy and normal IQ (50.00 +/- 10.40), p<0.05. CONCLUSIONS: Children with drug-resistant epilepsy have a greater incidence of sleep problems regarding qualitative aspects, macrostructure, and CAP. The decrease of CAP rate and of A1, mainly during slow wave sleep (associated to REM sleep reduction), might represent a sleep microstructural pattern of intellectual disability. PMID- 22429653 TI - Prevalence of Coxiella burnetii in clinically healthy German sheep flocks. AB - BACKGROUND: Current epidemiological data on the situation of Coxiella (C.) burnetii infections in sheep are missing, making risk assessment and the implementation of counteractive measures difficult. Using the German state of Thuringia as a model example, the estimated sero-, and antigen prevalence of C. burnetii (10% and 25%, respectively) was assessed at flock level in 39/252 randomly selected clinically healthy sheep flocks with more than 100 ewes and unknown abortion rate. RESULTS: The CHECKITTM Q-fever Test Kit identified 11 (28%) antibody positive herds, whereas real-time PCR revealed the presence of C. burnetii DNA in 2 (5%) of the flocks. Multiple-locus variable number of tandem repeats analysis of 9 isolates obtained from one flock revealed identical profiles. All isolates contained the plasmid QpH1. CONCLUSIONS: The results demonstrate that C. burnetii is present in clinically inconspicuous sheep flocks and sporadic flare-ups do occur as the notifications to the German animal disease reporting system show. Although C. burnetii infections are not a primary veterinary concern due to the lack of significant clinical impact on animal health (with the exception of goats), the eminent zoonotic risk for humans should not be underestimated. Therefore, strategies combining the interests of public and veterinary public health should include monitoring of flocks, the identification and culling of shedders as well as the administration of protective vaccines. PMID- 22429654 TI - Combination of microscopic techniques reveals a comprehensive visual impression of biofilm structure and composition. AB - Bacterial biofilms are imaged by various kinds of microscopy including confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). One limitation of CLSM is its restricted magnification, which is resolved by the use of SEM that provides high-magnification spatial images of how the single bacteria are located and interact within the biofilm. However, conventional SEM is limited by the requirement of dehydration of the samples during preparation. As biofilms consist mainly of water, the specimen dehydration might alter its morphology. High magnification yet authentic images are important to understand the physiology of biofilms. We compared conventional SEM, Focused Ion Beam (FIB)-SEM and CLSM with SEM techniques [cryo-SEM and environmental-SEM (ESEM)] that do not require dehydration. In the case of cryo-SEM, the biofilm is not dehydrated but kept frozen to obtain high-magnification images closer to the native state of the sample. Using the ESEM technique, no preparation is needed. Applying these methods to biofilms of Pseudomonas aeruginosa showed us that the dehydration of biofilms substantially influences its appearance and that a more authentic biofilm image emerges when combining all methods. PMID- 22429655 TI - PMPs and Rx drug abuse--encouraging signs but is it every man for himself? PMID- 22429657 TI - Effect of vaginal delivery and ageing on the anatomy of the female anal canal assessed by three-dimensional anorectal ultrasound. AB - AIM: The effect of vaginal delivery and ageing on the anatomy of the anal canal was assessed using three-dimensional anorectal ultrasound to determine the interobserver reliability. METHOD: One-hundred and eighteen asymptomatic women without sphincter damage were grouped according to parity and mode of delivery. They were then stratified by age (<=50 years vs >50 years). Group I consisted of 35 nulliparous women, of mean ages 36 years (n = 20) and 62 years (n = 15), Group II consisted of multiparous women, having one or more vaginal deliveries (n = 43), of mean ages 43 years (n = 20) and 60 years (n = 23) and Group III consisted of women who had a Caesarean section (n = 40) of mean ages 41 years (n = 20) and 56 years (n = 20). The groups were compared with regard to the length and the thickness of the external anal sphincter, the internal anal sphincter, the posterior external sphincter and the puborectalis in all quadrants and the anterior gap. Interobserver variability was assessed. RESULTS: In women having vaginal delivery the length of the anterior external sphincter was shorter (P = 0.0004) and the gap was longer (P = 0.0306). The external sphincter tended to be thinner in individuals having vaginal delivery (P = 0.0677) and in those subjects over 50 years of age having had a vaginal delivery (P = 0.0164). In nulliparous women, the internal sphincter was thicker in subjects over 50 years of age (P = 0.0229). The intraclass correlation coefficient was 0.755-0.916 for sphincter muscle and gap length and 0.446-0.769 for muscle thickness. CONCLUSION: Vaginal delivery was associated with a shorter anterior external sphincter, a longer gap and a thinner anterior external sphincter in asymptomatic women. Age was correlated with sphincter thickness, and nulliparous women >50 years of age had a thicker internal sphincter. Three-dimensional ultrasound was found to be a reliable method for measuring anal structures. PMID- 22429658 TI - Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds. AB - BACKGROUND: Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence. METHODS: We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years). RESULTS: In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively. CONCLUSIONS: The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%. PMID- 22429659 TI - High incidence of adverse reactions to locoregional anaesthesia containing hyaluronidase after uneventful ophthalmic surgery. PMID- 22429660 TI - Effects of infection by larvae of Angiostrongylus cantonensis (Nematoda, Metastrongylidae) on the metabolism of the experimental intermediate host Biomphalaria glabrata. AB - The effect of infection by Angiostrongylus cantonensis on the activity of the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the concentration of total proteins, uric acid and urea in the hemolymph of Biomphalaria glabrata were investigated. The snails were dissected after 1, 2 and 3 weeks of infection to collect the hemolymph. The infection by A. cantonensis induced severe changes in the host snail's metabolism, triggering physiological mechanisms to minimize the deleterious effects caused by the larvae. There was a significant decrease in the concentration of total proteins in the infected snails, which occurred gradually as the infection advanced. This change was accompanied by an increase in the concentrations of urea and a decrease in the levels of uric acid in the hemolymph, suggesting that in this model the infection induces proteolysis and inversion of the excretion pattern of the infected snails. Besides this, variations in the activities of the aminotransferases were observed, with significantly higher levels in the infected groups than in the control group. These results indicate an increase in the protein metabolism of the infected snails, since there was an increase in nitrogen catabolites such as urea. PMID- 22429661 TI - Acute effects of ethanol on glutamate receptors. AB - Several studies have revealed that acute ethanol inhibits the function of glutamate receptors. Glutamate receptor-mediated synaptic plasticity, such as N methyl-D-aspartate-dependent long-term potentiation, is also inhibited by ethanol. However, the inhibition seems to be restricted to certain brain areas such as the hippocampus, amygdala and striatum. Ethanol inhibition of glutamate receptors generally requires relatively high concentrations and may therefore explain consequences of severe ethanol intoxication such as impairment of motor performance and memory. Effects of ethanol on glutamate system of developing nervous system may have a role in causing foetal alcohol syndrome. Newly found regulatory proteins of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA receptors seem to affect ethanol inhibition thus opening new lines of research. PMID- 22429663 TI - Local delivery of small and large biomolecules in craniomaxillofacial bone. AB - Current state of the art reconstruction of bony defects in the craniomaxillofacial (CMF) area involves transplantation of autogenous or allogenous bone grafts. However, the inherent drawbacks of this approach strongly urge clinicians and researchers to explore alternative treatment options. Currently, a wide interest exists in local delivery of biomolecules from synthetic biomaterials for CMF bone regeneration, in which small biomolecules are rapidly emerging in recent years as an interesting adjunct for upgrading the clinical treatment of CMF bone regeneration under compromised healing conditions. This review highlights recent advances in the local delivery small and large biomolecules for the clinical treatment of CMF bone defects. Further, it provides a perspective on the efficacy of biomolecule delivery in CMF bone regeneration by reviewing presently available reports of pre-clinical studies using various animal models. PMID- 22429662 TI - Gene therapy approaches to regenerating bone. AB - Bone formation and regeneration therapies continue to require optimization and improvement because many skeletal disorders remain undertreated. Clinical solutions to nonunion fractures and osteoporotic vertebral compression fractures, for example, remain suboptimal and better therapeutic approaches must be created. The widespread use of recombinant human bone morphogenetic proteins (rhBMPs) for spine fusion was recently questioned by a series of reports in a special issue of The Spine Journal, which elucidated the side effects and complications of direct rhBMP treatments. Gene therapy - both direct (in vivo) and cell-mediated (ex vivo) - has long been studied extensively to provide much needed improvements in bone regeneration. In this article, we review recent advances in gene therapy research whose aims are in vivo or ex vivo bone regeneration or formation. We examine appropriate vectors, safety issues, and rates of bone formation. The use of animal models and their relevance for translation of research results to the clinical setting are also discussed in order to provide the reader with a critical view. Finally, we elucidate the main challenges and hurdles faced by gene therapy aimed at bone regeneration as well as expected future trends in this field. PMID- 22429664 TI - Fellow travellers: a concordance of colonization patterns between mice and men in the North Atlantic region. AB - BACKGROUND: House mice (Mus musculus) are commensals of humans and therefore their phylogeography can reflect human colonization and settlement patterns. Previous studies have linked the distribution of house mouse mitochondrial (mt) DNA clades to areas formerly occupied by the Norwegian Vikings in Norway and the British Isles. Norwegian Viking activity also extended further westwards in the North Atlantic with the settlement of Iceland, short-lived colonies in Greenland and a fleeting colony in Newfoundland in 1000 AD. Here we investigate whether house mouse mtDNA sequences reflect human history in these other regions as well. RESULTS: House mice samples from Iceland, whether from archaeological Viking Age material or from modern-day specimens, had an identical mtDNA haplotype to the clade previously linked with Norwegian Vikings. From mtDNA and microsatellite data, the modern-day Icelandic mice also share the low genetic diversity shown by their human hosts on Iceland. Viking Age mice from Greenland had an mtDNA haplotype deriving from the Icelandic haplotype, but the modern-day Greenlandic mice belong to an entirely different mtDNA clade. We found no genetic association between modern Newfoundland mice and the Icelandic/ancient Greenlandic mice (no ancient Newfoundland mice were available). The modern day Icelandic and Newfoundland mice belong to the subspecies M. m. domesticus, the Greenlandic mice to M. m. musculus. CONCLUSIONS: In the North Atlantic region, human settlement history over a thousand years is reflected remarkably by the mtDNA phylogeny of house mice. In Iceland, the mtDNA data show the arrival and continuity of the house mouse population to the present day, while in Greenland the data suggest the arrival, subsequent extinction and recolonization of house mice--in both places mirroring the history of the European human host populations. If house mice arrived in Newfoundland with the Viking settlers at all, then, like the humans, their presence was also fleeting and left no genetic trace. The continuity of mtDNA haplotype in Iceland over 1000 years illustrates that mtDNA can retain the signature of the ancestral house mouse founders. We also show that, in terms of genetic variability, house mouse populations may also track their host human populations. PMID- 22429665 TI - Children, parents, and pets exercising together (CPET) randomised controlled trial: study rationale, design, and methods. AB - BACKGROUND: Objectively measured physical activity is low in British children, and declines as childhood progresses. Observational studies suggest that dog walking might be a useful approach to physical activity promotion in children and adults, but there are no published public health interventions based on dog walking with children. The Children, Parents, and Pets Exercising Together Study aims to develop and evaluate a theory driven, generalisable, family-based, dog walking intervention for 9-11 year olds. METHODS/DESIGN: The Children, Parents, and Pets Exercising Together Study is an exploratory, assessor-blinded, randomised controlled trial as defined in the UK MRC Framework on the development and evaluation of complex interventions in public health. The trial will follow CONSORT guidance. Approximately 40 dog-owning families will be allocated randomly in a ratio of 1.5:1 to receive a simple behavioural intervention lasting for 10 weeks or to a 'waiting list' control group. The primary outcome is change in objectively measured child physical activity using Actigraph accelerometry. Secondary outcomes in the child, included in part to shape a future more definitive randomised controlled trial, are: total time spent sedentary and patterning of sedentary behaviour (Actigraph accelerometry); body composition and bone health from dual energy x-ray absorptiometry; body weight, height and BMI; and finally, health-related quality of life using the PedsQL. Secondary outcomes in parents and dogs are: changes in body weight; changes in Actigraph accelerometry measured physical activity and sedentary behaviour. Process evaluation will consist of assessment of simultaneous child, parent, and dog accelerometry data and brief interviews with participating families. DISCUSSION: The Children, Parents, and Pets Exercising Together trial should be the first randomised controlled study to establish and evaluate an intervention aimed at dog-based physical activity promotion in families. It should advance our understanding of whether and how to use pet dogs to promote physical activity and/or to reduce sedentary behaviour in children and adults. The trial is intended to lead to a subsequent more definitive randomised controlled trial, and the work should inform future dog-based public health interventions such as secondary prevention interventions in children or adults. TRIAL REGISTRATION NUMBER: ISRCTN85939423. PMID- 22429666 TI - Microembolism, silent brain infarcts and dementia. AB - Cognitive decline becomes more prevalent than ever in parallel with the increasing life expectancy of the population. Alzheimer' disease (AD) and cerebral vascular lesions are common in the elderly and represent, with increased age, the most frequent contributors to cognitive decline. It is now believed that these pathologies frequently coexist in the same brain. The border discriminating vascular dementia from AD is blurred and challenges our understanding of these clinical entities. Further research, at both basic and clinical levels, is mandatory in order to better understand the interactions of vascular ischemic injury and primary degenerative physiopathologies of the brain, in order to prevent and better manage patients with cognitive decline. We review recent published clinical evidence of silent brain ischemia as a contributor to cognitive decline and dementia. Microemboli, from both cardiac and vascular origins, have been shown to be associated with structural changes in the brain. The role of transcranial Doppler as an objective tool for detecting and quantifying microemboli is discussed in light of recent clinical evidence. PMID- 22429667 TI - Meta-analysis of association between PITX3 gene polymorphism and Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Several studies had researched the association between the PITX3 gene polymorphism and Parkinson's disease. However, the results were inconsistent. To evaluate whether PITX3 gene polymorphism is involved in the risk of PD we conducted this meta-analysis. All the eligible studies were searched from the databases of Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index EXPANDED in any languages up to May 2011. Finally ten studies about PITX3 gene including 5172 patients and 7290 controls were identified for meta-analysis. Meta-analysis was carried out to evaluate whether PITX3 gene polymorphism was associated with PD, and subgroup analysis was also performed when necessary. This meta-analysis finds that rs4919621 allele A was significantly associated with PD in the Caucasian population (P=0.04,). Subgroup analysis of early onset PD (EOPD) and late onset PD (LOPD) revealed that the rs2281983 allele C and rs4919621 allele A were significantly associated with the risk of PD (all of the P values were <= 0.0001) in EOPD population. This research indicated that the presence of the rs4919621 allele A significantly increased the risk of PD patients in Caucasian population while rs2281983 allele C and rs4919621 allele A were both risk factors in EOPD. PMID- 22429668 TI - Novel preventive strategies for ventilator-associated pneumonia. PMID- 22429669 TI - Extracorporeal life support for cardiogenic shock or cardiac arrest due to acute coronary syndrome. AB - BACKGROUND: Few data are available on the clinical outcome of patients with acute coronary syndrome (ACS) complicated by refractory cardiogenic shock or cardiac arrest who receive percutaneous extracorporeal life support (ECLS). We investigated the in-hospital outcome and predictors of mortality in these patients. METHODS: The investigation was a single-center, retrospective cohort study of 98 ACS patients who received ECLS to reverse hemodynamic collapse refractory to conventional treatment. RESULTS: Circulatory status before ECLS introduction was cardiogenic shock in 34, ventricular fibrillation or pulseless ventricular tachycardia in 23, and asystole or pulseless electrical activity in 41. Ninety-four patients (95.9%) underwent emergency revascularization, including 92 who received percutaneous coronary intervention and 2 who received isolated coronary artery bypass grafting. Successful angioplasty was achieved in 65 of 92 patients (70.7%). Fifty-four patients (55.1%) were weaned from ECLS, and ECLS related complications occurred in 35 (35.7%). All-cause in-hospital mortality rate was 67.3%, and the survival rate to hospital discharge was 32.7%. Multivariate analysis revealed that independent predictors of in-hospital mortality were unsuccessful angioplasty, asystole or pulseless electrical activity before ECLS introduction, and ECLS-related complications. CONCLUSIONS: Despite hemodynamic support with ECLS, patients with ACS complicated by cardiogenic shock or cardiac arrest refractory to conventional treatment had high mortality. However, the higher than 30% in-hospital survival rate in this extremely critical population indicates that ECLS might improve outcomes in ACS by saving the lives of patients in this specialized category. Unsuccessful angioplasty, asystole or pulseless electrical activity before ECLS introduction, and ECLS-related complications were predictors of in-hospital mortality. PMID- 22429670 TI - Risk factors for early death in patients bridged to transplant with continuous flow left ventricular assist devices. AB - BACKGROUND: Recent evidence suggests patients bridged to heart transplant (BTT) have equivalent outcomes as those undergoing conventional orthotopic heart transplantation (OHT). However, data on risk factors for early death in BTT patients are limited. METHODS: We retrospectively reviewed the United Network for Organ Sharing database of all patients bridged to OHT with a HeartMate II from January 2005 to December 2010. The primary outcome was all-cause 90-day mortality. Additional postoperative outcomes were cerebrovascular accident and need for renal replacement therapy. Kaplan-Meier analysis assessed survival. Preoperative variables associated with 90-day death on univariate analysis (p<0.2) were included in a multivariable Cox proportional hazards regression. RESULTS: A HeartMate II was used to bridge 1,312 patients (average age, 52+/-12 years) to OHT, most commonly for idiopathic cardiomyopathy (50.7%). During the study, 171 patients (13.0%) died. The unadjusted 90-day survival was 92.3%. The highest annual average center volume in this cohort, examining for BTT recipients only, was 28 BTT procedures yearly. Postoperative cerebrovascular accident occurred in 29 patients (2.2%), and 106 (8.3%) required renal replacement therapy. Cox regression revealed age, glomerular filtration rate, African American race, human leukocyte antigen mismatch, serum bilirubin, need for mechanical ventilation, donor age, and prolonged ischemia time were associated with 90-day death. Early survival was improved for patients who underwent OHT at high-volume centers (p=0.01). CONCLUSIONS: This study examining risk factors for early death in patients bridged to OHT using HeartMate II mechanical assistance will aid in identifying patients best suited to benefit from this technology. PMID- 22429671 TI - Functional health status of adults with tetralogy of Fallot: matched comparison with healthy siblings. AB - BACKGROUND: Survival prospects for adults with repaired tetralogy of Fallot (TOF) are now excellent. Attention should therefore shift to assessing and improving functional health status and quality of life. We aimed to assess late functional health status of adults surviving TOF repair by matched comparison to their healthy siblings. METHODS: All 1,693 TOF repairs performed at our institution between 1946 and 1990 were reviewed. A matched comparison was undertaken whereby presumed survivors and their healthy sibling were contacted and asked to complete the Ontario Health Survey 1990 and the 36-Item Short Form Health Survey (SF-36) questionnaire. RESULTS: Both questionnaires were completed by 224 adult survivors and their sibling closest in age. Adults with repaired TOF had lower scores for self-perceived general health status (p < 0.001), were less likely to rate their health as good or excellent (p < 0.001), and had lower SF-36 scores for physical functioning and general health (p = 0.001) than their siblings. However, patients reported similar satisfaction with their lives, similar levels of social participation and support, and were as likely to be in long-term partnerships. Worse physical and mental health scores were associated with older age at surgery and at time of questionnaire completion and recent requirement for noncardiac medication. CONCLUSIONS: Although reporting lower functional health status then their siblings, quality of life and life satisfaction for adults who underwent surgery for TOF during childhood is comparable to that of their siblings without heart defects. Follow-up of younger adults is required to understand current health outcomes attributable to improvements in the management of TOF. PMID- 22429672 TI - The effect of a high dose of atorvastatin on the occurrence of atrial fibrillation after coronary artery bypass grafting. AB - BACKGROUND: Recent studies have suggested that statins reduce the incidence of atrial fibrillation (AF) after cardiac operations. Statin therapy at intensive doses, however, has yet to be thoroughly investigated. METHODS: We retrospectively studied 1,839 consecutive patients (1,177 men [73.2%]) who underwent isolated coronary artery bypass grafting and had no history of previous AF, pacemaker implantation, or antiarrhythmic medication. Data recorded included the atorvastatin dose during hospitalization, demographic, echocardiographic, and angiographic data, medical history, drug treatment, and procedural characteristics. Continuous telemonitoring during the first 72 postoperative hours assessed for AF, which was defined as episodes lasting more than 5 minutes. The dose-related effect of atorvastatin on postoperative AF was investigated by logistic analysis in 1,607 patients: 75 (4.7%) did not receive atorvastatin vs 1,047 (65.1%) and 485 (30.2%) who received 40 mg/d or 80 mg/d, respectively, for at least 3 days before the operation. RESULTS: The study population was a mean age of 60.6 +/- 9.5 years. Multivariate logistic regression demonstrated that a lack of atorvastatin pretreatment along with older age, enlarged left atrium, and male sex, and not taking beta-blockers, tended to be associated with an increased risk of postoperative AF. There was no significant difference between the effect of a higher (80 mg/d) and a lower dose (40 mg/d) in reducing postoperative AF. CONCLUSIONS: Atorvastatin pretreatment significantly reduced the occurrence of AF after bypass grafting; nonetheless, the difference between the beneficial effects of intensive and routine atorvastatin treatments on postoperative AF was not significant. PMID- 22429673 TI - Sublobar resection versus definitive radiation in patients with stage IA non small cell lung cancer. AB - BACKGROUND: Many patients with resectable non-small cell lung cancer (NSCLC) are unfit for lobectomy owing to comorbidity. Surgical outcomes are biased by preoperative selection factors and upstaging that occurs during surgery. This study compares outcomes between sublobar pulmonary resection and traditional external beam radiation therapy. METHODS: This cohort study utilizes Surveillance, Epidemiology, and End Results-Medicare data (1998 to 2005). Patients with stage IA NSCLC treated with either radiotherapy or sublobar resection were compared. The bias of clinical staging in the radiation group versus pathologic staging in the surgical group was addressed by including only sublobar resections without lymph node sampling. Medicare claims data were used to calculate a modified Charlson comorbidity score for each patient. RESULTS: In all, 878 patients received radiotherapy and 657 underwent sublobar resection without lymph node sampling. Radiation patients were older (77.0 versus 75.5 years, p<0.0001) and had larger tumors (22.8 versus 17.9 mm, p<0.0001). There was no difference in comorbidity scores between groups (p=0.21). Three-year overall survival favored sublobar resection (56% versus 35%; p<0.0001). Predictors of earlier death were radiation, age, comorbidity score, tumor size, male sex, and prior malignancy (all p<0.05). Propensity analysis matched 319 radiation patients and 319 sublobar resection patients. In this subgroup, 3-year overall survival favored sublobar resection (52% versus 41%; p<0.001). CONCLUSIONS: Sublobar resection without lymph node sampling appears to be superior to radiotherapy for clinical stage IA NSCLC. For patients with prohibitive risk for lobectomy, sublobar resection may be preferable to radiotherapy. Radiotherapy results in current and future patients are likely to be better. PMID- 22429674 TI - Tyrosine-protein phosphatase nonreceptor type 12 is a novel prognostic biomarker for esophageal squamous cell carcinoma. AB - BACKGROUND: Tyrosine-protein phosphatase nonreceptor type 12 (PTPN12) is considered to be a tumor suppressor. It plays a significant role in human cancer, but its clinicopathologic and prognostic significance in esophageal squamous cell carcinoma (ESCC) has not yet been elucidated. METHODS: Using Western blot, we evaluated the PTPN12 expression in 20 pairs of surgically resected esophageal tissues. The PTPN12 was detected by immunochemistry in a tissue microarray from 260 surgically resected ESCCs, of which 260 were from primary cancer sites and 60 were from matched paracancerous normal tissues. Statistical analyses were applied to test the associations between PTPN12 expression, clinicopathologic factors, and prognosis. RESULTS: Western blots showed that the expression level of PTPN12 was higher in normal paracancerous esophageal tissues than in ESCC tissues. By immunohistochemical analysis, high and low expression of PTPN12 was found in 62.1% and 37.9% of ESCCs, respectively. After multivariate analysis, along with pN status and tumor grade, the protein expression level of PTPN12 was an independent and significant predictive factor (p<0.001). Patients with PTPN12 high tumors had a longer disease-free survival and overall survival (p=0.002 and p=0.001, respectively), especially for those with stage II disease (both p<0.001). CONCLUSIONS: Our study suggests that PTPN12 protein expression is a valuable biomarker for ESCC patients. High expression of PTPN12 is associated with favorable disease-free survival and overall survival in ESCC patients. PMID- 22429675 TI - Surgical resection should be considered for stage I and II small cell carcinoma of the lung. AB - BACKGROUND: Small cell lung carcinoma (SCLC) is rarely treated with resection, either alone or combined with other modalities. This study evaluated the role of surgical resection in the treatment of stage I and II SCLC. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database for patients from 1988 to 2007 with SCLC. Survival was determined by Kaplan-Meier analysis and compared using the log-rank test. A Cox proportional hazard model identified relevant survival variables. RESULTS: We identified 3,566 patients with stage I or II SCLC. Lung resection was performed in 895 (25.1%), wedge resection in 251 (28.0%), lobectomy or pneumonectomy in 637 (71.2%), and lung resection not otherwise specified in 7 (0.78%). Median survival was 34.0 months (95% confidence interval [CI], 29.0 to 39.0 months) vs 16.0 months (95% CI, 15.3 to 16.7; p<0.001) in nonsurgical patients. Median survival after lobectomy or pneumonectomy was 39.0 months (95% CI, 30.7 to 40.3) and significantly longer than after wedge resection (28.0 months; 95% CI, 23.2 to 32.8; p=0.001). However, survival after wedge resection was still significantly longer than survival in nonsurgical patients (p<0.001). Sex (p=0.013), age, stage at diagnosis, radiotherapy, and operation (all p<0.001) significantly affected survival. In the surgical patients, sex (p=0.001), age (p<0.001), final stage (p<0.001), and type of resection (p=0.01) were important determinants of survival. CONCLUSIONS: Surgical resection as a component of treatment for stage I or II SCLC is associated with significantly improved survival and should be considered in the management of early-stage SCLC. PMID- 22429676 TI - Fusion positron emission/computed tomography underestimates the presence of hilar nodal metastases in patients with resected non-small cell lung cancer. AB - BACKGROUND: The 5-year survival for patients with resected stage II (N1) non small cell lung cancer ranges from 40% to 55%. No data exist addressing the benefit of neoadjuvant therapy for patients with stage II disease. This is largely in part due to the lack of a reliable, minimally invasive method to assess hilar nodes. This study is aimed at determining the ability of fusion positron emission/computed tomography (PET/CT) to identify hilar metastases in patients with resected non-small cell lung cancer. METHODS: A retrospective review of surgically resected patients with fusion PET/CT within 30 days of resection was performed. The sensitivity, specificity, positive predictive value, and negative predictive value for PET/CT in detecting hilar nodal metastases was calculated for a range of maximum standardized uptake values (SUVmax). Hilar nodes from patients with falsely positive PET/CT scans were analyzed for the presence of histoplasmosis. Additionally, the impact of hilar node size greater than 1 centimeter on the calculated values was assessed. RESULTS: There were 119 patients evaluated. The number of lymph nodes resected ranged from 1 to 12 (X=2.98). There was decreased sensitivity and increased specificity with higher SUVmax cutoff values. At the standard SUVmax value of 2.5, the sensitivity and specificity were only 48.5% and 80.2%. The addition of size of hilar node by CT led to a modest improvement in sensitivity at all SUVmax cutoff values. CONCLUSIONS: Fusion PET/CT lacks sensitivity and specificity in identifying hilar nodal metastasis in patients with resected non-small cell lung cancer. Further prospective studies assessing the utility of PET/CT versus alternative sampling techniques are warranted. PMID- 22429678 TI - A novel approach to endovascular treatment of severe hepatic vein stenoses following liver transplant in children. AB - Hepatic vein stenoses are a rare but serious complication of liver transplants in children. Restoration of flow by radiological methods often provides a viable treatment option. This technique relies on the interventional radiologist's ability to advance a guide wire across the obstruction, thus allowing for balloon dilatation and other necessary interventions. Failure to cross the stenosis reduces graft survival and increases patient morbidity. We report two cases with tight hepatic vein stenosis where the guide wire could not be advanced in a conventional approach across the upper end of the stenosis. Utilizing prominent intrahepatic collateral vessels, the stenoses were able to be crossed, facilitating successful PTA with good clinical outcome. PMID- 22429679 TI - Evaluation of the impact of atrial fibrillation on rehospitalization events in heart failure patients in recent years. AB - BACKGROUND: Although we have previously reported that the presence of paroxysmal atrial fibrillation (AF) is an independent risk factor for rehospitalization in patients with congestive heart failure (CHF) in a population from 1996 to 2002, the impact of AF configuration as a risk factor in a more recent population remains to be clarified. METHODS AND RESULTS: 319 patients with CHF admitted to our institute in 2006-2007 were retrospectively evaluated. The patients were divided into 3 groups in accordance with their basic cardiac rhythm, i.e. sinus rhythm (n=210), chronic AF (n=68), and paroxysmal AF (n=41). During the follow-up period of 19 +/- 17 months, there was no significant difference in mortality or rehospitalization events among the 3 groups (p=0.542). In the multivariate analysis, no administration of beta-blockers was the only independent risk factor for rehospitalization due to CHF exacerbation. CONCLUSIONS: The clinical impact of AF configuration as a risk factor of rehospitalization due to CHF exacerbation was considered to be decreased in recent years. PMID- 22429680 TI - High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort. AB - BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. METHODOLOGY: In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population. RESULTS: HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations. CONCLUSIONS: HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations. PMID- 22429681 TI - Learning contexts at two UK medical schools: a comparative study using mixed methods. AB - INTRODUCTION: The context in which learning takes place exerts a powerful effect on the approach learners take to their work. In some instances learners will be forced by the nature of a task to adopt a less-favoured approach.In this study, we used a combination of qualitative and quantitative methods to compare the effect of context on learning at different UK medical schools. We compared schools with conventional, and problem-based curricula. METHOD: We had collected data from 30 interviews with third year medical students in one UK medical school with a conventional, lecture-based curriculum in relation to a previous study. The interview guide had explored effects of context and approach to learning. We used the same guide to interview 6 students in another UK medical school with a problem-based curriculum.We then put together a pack of validated questionnaires, which measured the phenomena that had emerged in the interviews. In particular we selected questionnaires which measured the criteria on which students from the different schools appeared to demonstrate greatest variance. RESULTS: There were two areas where students from schools with differing curricula differed - basic learning activity and assessment. Students at the lecture-based school attended lectures where they received information while students at the Problem-based school attended tutorials where they stimulated prior knowledge and identified new learning objectives. Progress -testing at the problem-based school helped students gain a sense of accumulating a body of knowledge needed for their life in medicine while students' at the lecture-based school directed their learning towards passing the next set of exams.The findings from quantitative, questionnaire data correlated with the interview findings. They showed that students at a school with a PBL curriculum scored significantly higher for reflection in learning, self-efficacy in self-directed learning and for deep approach to learning. CONCLUSION: We set out to determine whether students at different medical schools approach their learning differently. We have succeeded in demonstrating that this is the case.The differences that we detected in learning context and approaches to learning in medical students at the two schools predict that learning at the non PBL school is likely to be via a surface approach and not integrated. These differences have major implications for the outcomes of medical student learning at the two schools in terms of accessibility and sustainability of learning. PMID- 22429682 TI - Young women's perceived health and lifetime sexual experience: results from the national survey of family growth. AB - INTRODUCTION: Sexuality is a component of health and well-being for all women, including adolescents. Yet relationships between young women's health perceptions and sexual behavior are unclear. AIM: We examined associations between perceived health and lifetime sexual experiences among young U.S. women. METHODS: We used data from 4,413 young women ages 15-24 years in the National Survey of Family Growth, 2002-2008. Descriptive, bivariate, and multivariate statistics estimated relationships between categories of perceived health and types of lifetime sexual experience. MAIN OUTCOME MEASURES: A self-rated health Likert item and sexual history questions were administered with a computer-assisted survey instrument. RESULTS: Young women reported excellent (30%), very good (41%), good (23%), and fair-poor (6%) health. Sexual experiences included vaginal (64%), oral (64%), and anal (20%) sex. Negative experiences included involuntary sex (11%) and sexually transmitted infection (STI) history (8%). In multivariate logistic regression models, lower perceived health ("good" rather than "excellent") was positively associated with vaginal (odds ratio [OR] 1.5, confidence interval [CI] 1.1-2.1, P = 0.02), oral (OR 1.5, CI 1.1-2.1, P = 0.005), and anal (OR 1.4, CI 1.0-2.0, P = 0.03) sex. In models stratified by age, point estimates for vaginal (OR 1.8, CI 1.2-2.6, P = 0.002) and oral (OR 1.9, CI 1.4-2.6, P < 0.001) sex were higher among adolescents ages 15-19 years, but associations were insignificant among young adults ages 20-24 years. When controlling for negative sexual experiences, point estimates were stable in models including STI history but statistically insignificant when including involuntary sexual experience. Other characteristics associated with sexual experiences varied by type of experience and included age, race/ethnicity, employment situation, poverty level, insurance status, childhood family situation, religious service participation, cohabitation/marital experience, and body mass index. CONCLUSIONS: Further investigation is warranted to disentangle potentially negative relationships between perceived health (as well as response bias and more objective health outcomes), sociodemographic factors, and diverse sexual experiences among young women in the United States. PMID- 22429683 TI - Experimental selective elevation of renal medullary blood flow in hypertensive rats: evidence against short-term hypotensive effect. AB - AIM: Renal medullary blood flow (MBF) can be selectively increased by intrarenal or systemic infusion of bradykinin (Bk) in anaesthetized normotensive rats. We reproduced this effect in a number of rat models of arterial hypertension and examined whether increased perfusion of the renal medulla can cause a short-term decrease in blood pressure (BP) that is not mediated by increased renal excretion and depletion of body fluids. METHODS: In uninephrectomized Sprague-Dawley rats, BP was elevated to approx. 145 mmHg by acute i.v. infusion of noradrenaline (NA) or angiotensin II (Ang II) (groups 1, 2), 2-week exposure to high-salt diet (3), high-salt diet + chronic low-dose infusion of Ang II using osmotic minipumps (4) or chronic high-dose Ang II infusion on normal diet (5). Uninephrectomized spontaneous hypertensive rats (SHR) were also examined (6,7). To selectively increase medullary perfusion, in anaesthetized rats, bradykinin was infused during 30-75 min into the renal medullary interstitium or intravenously. RESULTS AND CONCLUSION: Bradykinin increased outer- and inner-medullary blood flow (laser Doppler fluxes) by 10-20% in groups (1, 2), by 30-50% in groups (3, 4, 5) and approx. 20% in SHR (6, 7). The concurrent increase in total renal blood flow (Transonic probe) was < 3%. A minor (<3%) decrease in BP was seen only in rats acutely rendered hypertensive by NA or Ang II infusions; however, the decreases in BP and increases in medullary perfusion were not correlated. Thus, there was no evidence that in hypertensive rats, substantial selective increases in medullary perfusion can cause a short-term decrease in BP. PMID- 22429684 TI - Environmental exposure to dioxin-like compounds and the mortality risk in the U.S. population. AB - BACKGROUND: Little is known about the mortality risk associated with chronic dioxin exposure in the general U.S. populations. OBJECTIVE: To explore the association between dioxin-like chemicals and mortality risk in a large population-based cohort study. METHODS: The analysis included 2361 subjects aged 40 years or older from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Exposure to a mixture of dioxin-like chemicals, including dibenzo-p-dioxins, dibenzofurans, and polychlorinated biphenyls was estimated using toxic equivalency values (TEQs) calculated with 2005 World Health Organization toxic equivalency factors. All-cause and cause-specific mortalities were obtained from the NHANES-linked follow-up data through December 31, 2006. Cox proportional-hazards models were applied to assess the associations of interest. RESULTS: A total of 242 deaths occurred during the follow-up period, including 75 from cardiovascular disease and 72 from cancer. There was an increased mortality risk associated with logarithmically expressed dioxin TEQs for all-cause deaths (hazard ratio=1.19, 95% confidence interval=1.02-1.39, p=0.02). Similar graded dose-response trends were found for cardiovascular and cancer mortality which did not reach statistical significance. CONCLUSIONS: In general, higher dioxin exposure is associated with an increased mortality risk among subjects aged 40 and above. The cause-specific analyses and responsible mechanisms will require further investigation. PMID- 22429685 TI - Maximum voltage-guided catheter ablation of typical atrial flutter: making a good procedure even better? PMID- 22429686 TI - Ursodeoxycholic acid decreases sodium-glucose cotransporter (SGLT2) expression and oxidative stress in the kidney of diabetic rats. AB - Oxidative stress has been associated with diabetic complications like nephropathies. Recent studies indicate that ursodeoxycholic acid (UDCA) may be beneficial preventing diabetes-induced oxidative stress and secondary complications. Thus, we study if the UDCA-treatment decreases the expression of sodium-glucose cotransporter (SGLT2) and the oxidative stress in the kidney of diabetic rats. METHODS: The diabetes model was established by intraperitoneal injection of streptozotocin (50mg/kg). SGLT2 expression was evaluated by western blot and RT-PCR. Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase activities (SOD) and immunohistochemical analysis of 3-nitrotyrosine (3-NT). RESULTS: Streptozotocin induced diabetes caused hyperglycemia and lower body weight. The SGLT2 expression and mRNA levels increased in cortex of kidney from diabetic rats. The CAT activity decreased in cortex and medulla from diabetic rats, otherwise the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The UDCA treatment was able to decrease hyperglycemia and prevents the SGLT2 over-expression, restores the CAT and GPX activities and decreases 3-NT staining. CONCLUSION: The UDCA treatment prevents the over-expression of SGLT2 and oxidative stress in kidney of diabetic rats. PMID- 22429687 TI - A dual task priming investigation of right hemisphere inhibition for people with left hemisphere lesions. AB - BACKGROUND: During normal semantic processing, the left hemisphere (LH) is suggested to restrict right hemisphere (RH) performance via interhemispheric suppression. However, a lesion in the LH or the use of concurrent tasks to overload the LH's attentional resource balance has been reported to result in RH disinhibition with subsequent improvements in RH performance. The current study examines variations in RH semantic processing in the context of unilateral LH lesions and the manipulation of the interhemispheric processing resource balance, in order to explore the relevance of RH disinhibition to hemispheric contributions to semantic processing following a unilateral LH lesion. METHODS: RH disinhibition was examined for nine participants with a single LH lesion and 13 matched controls using the dual task paradigm. Hemispheric performance on a divided visual field lexical decision semantic priming task was compared over three verbal memory load conditions, of zero-, two- and six-words. Related stimuli consisted of categorically related, associatively related, and categorically and associatively related prime-target pairs. Response time and accuracy data were recorded and analyzed using linear mixed model analysis, and planned contrasts were performed to compare priming effects in both visual fields, for each of the memory load conditions. RESULTS: Control participants exhibited significant bilateral visual field priming for all related conditions (p < .05), and a LH advantage over all three memory load conditions. Participants with LH lesions exhibited an improvement in RH priming performance as memory load increased, with priming for the categorically related condition occurring only in the 2- and 6-word memory conditions. RH disinhibition was also reflected for the LH damage (LHD) group by the removal of the LH performance advantage following the introduction of the memory load conditions. CONCLUSIONS: The results from the control group are consistent with suggestions of an age related hemispheric asymmetry reduction and indicate that in healthy aging compensatory bilateral activation may reduce the impact of inhibition. In comparison, the results for the LHD group indicate that following a LH lesion RH semantic processing can be manipulated and enhanced by the introduction of a verbal memory task designed to engage LH resources and allow disinhibition of RH processing. PMID- 22429688 TI - Oxidative stress in the in vivo DMBA rat model of breast cancer: suppression by a voltage-gated sodium channel inhibitor (RS100642). AB - Breast cancer (BCa) was induced in vivo in female rats with 7,12 dimethylbenz(a)anthracene (DMBA). Two main questions were addressed. Firstly, would the carcinogenesis be accompanied by oxidative stress as signalled by superoxide dismutase, glutathione peroxidase, malondialdehyde and total nitrate? Secondly, would treating the rats additionally with a blocker of voltage-gated sodium channel (VGSC) activity, shown previously to promote BCa progression, affect the oxidative responses? The DMBA-induced increases in the antioxidant systems were completely blocked by the VGSC inhibitor RS100642, which also significantly prolonged the lifespan. We conclude that VGSC inhibition in vivo can significantly protect against oxidative stress and improve survival from tumour burden. PMID- 22429689 TI - Lobomycosis: an emerging disease in humans and delphinidae. AB - Lobomycosis, a disease caused by the uncultivable dimorphic onygenale fungi Lacazia loboi, remains to date as an enigmatic illness, both due to the impossibility of its aetiological agent to be cultured and grown in vitro, as well as because of its unresponsiveness to specific antifungal treatments. It was first described in the 1930s by Brazilian dermatologist Jorge Lobo and is known to cause cutaneous and subcutaneous localised and widespread infections in humans and dolphins. Soil and vegetation are believed to be the chief habitat of the fungus, however, increasing reports in marine mammals has shifted the attention to the aquatic environment. Infection in humans has also been associated with proximity to water, raising the hypothesis that L. loboi may be a hydrophilic microorganism that penetrates the skin by trauma. Although its occurrence was once thought to be restricted to New World tropical countries, its recent description in African patients has wrecked this belief. Antifungals noted to be effective in the empirical management of other cutaneous/subcutaneous mycoses have proven unsuccessful and unfortunately, no satisfactory therapeutic approach for this cutaneous infection currently exists. PMID- 22429690 TI - Chromosome painting in three-toed sloths: a cytogenetic signature and ancestral karyotype for Xenarthra. AB - BACKGROUND: Xenarthra (sloths, armadillos and anteaters) represent one of four currently recognized Eutherian mammal supraorders. Some phylogenomic studies point to the possibility of Xenarthra being at the base of the Eutherian tree, together or not with the supraorder Afrotheria. We performed painting with human autosomes and X-chromosome specific probes on metaphases of two three-toed sloths: Bradypus torquatus and B. variegatus. These species represent the fourth of the five extant Xenarthra families to be studied with this approach. RESULTS: Eleven human chromosomes were conserved as one block in both B. torquatus and B. variegatus: (HSA 5, 6, 9, 11, 13, 14, 15, 17, 18, 20, 21 and the X chromosome). B. torquatus, three additional human chromosomes were conserved intact (HSA 1, 3 and 4). The remaining human chromosomes were represented by two or three segments on each sloth. Seven associations between human chromosomes were detected in the karyotypes of both B. torquatus and B. variegatus: HSA 3/21, 4/8, 7/10, 7/16, 12/22, 14/15 and 17/19. The ancestral Eutherian association 16/19 was not detected in the Bradypus species. CONCLUSIONS: Our results together with previous reports enabled us to propose a hypothetical ancestral Xenarthran karyotype with 48 chromosomes that would differ from the proposed ancestral Eutherian karyotype by the presence of the association HSA 7/10 and by the split of HSA 8 into three blocks, instead of the two found in the Eutherian ancestor. These same chromosome features point to the monophyly of Xenarthra, making this the second supraorder of placental mammals to have a chromosome signature supporting its monophyly. PMID- 22429691 TI - Elongation-related functions of LEAFY COTYLEDON1 during the development of Arabidopsis thaliana. AB - The transcription factor LEAFY COTYLEDON1 (LEC1) controls aspects of early embryogenesis and seed maturation in Arabidopsis thaliana. To identify components of the LEC1 regulon, transgenic plants were derived in which LEC1 expression was inducible by dexamethasone treatment. The cotyledon-like leaves and swollen root tips developed by these plants contained seed-storage compounds and resemble the phenotypes produced by increased auxin levels. In agreement with this, LEC1 was found to mediate up-regulation of the auxin synthesis gene YUCCA10. Auxin accumulated primarily in the elongation zone at the root-hypocotyl junction (collet). This accumulation correlates with hypocotyl growth, which is either inhibited in LEC1-induced embryonic seedlings or stimulated in the LEC1-induced long-hypocotyl phenotype, therefore resembling etiolated seedlings. Chromatin immunoprecipitation analysis revealed a number of phytohormone- and elongation related genes among the putative LEC1 target genes. LEC1 appears to be an integrator of various regulatory events, involving the transcription factor itself as well as light and hormone signalling, especially during somatic and early zygotic embryogenesis. Furthermore, the data suggest non-embryonic functions for LEC1 during post-germinative etiolation. PMID- 22429692 TI - Age-related change in contrast sensitivity among Australian male adults: Florey Adult Male Ageing Study. AB - PURPOSE: To describe the age-related change in contrast sensitivity seen in 35- to 80-year-old men in an Australian population. METHODS: The Florey Adelaide Male Ageing Study (FAMAS) is a prospective population-based study of men aged 35-80 years randomly selected from the north-west suburbs of Adelaide. We conducted a nested ophthalmic substudy of these men. Contrast sensitivity (CS) was measured at four spatial frequencies (3, 6, 12 and 18 cycles/degree [cpd]) using the Vectorvision CSV-1000 contrast sensitivity test chart (Vectorvision, Dayton, OH, USA), and results were statistically analysed relative to age and cataract type. RESULTS: There were 2650 eligible subjects in the FAMAS and 1195 participated (45.1%); 472 of those participated in the ophthalmic substudy. A statistically significant decrease in contrast sensitivity was seen with advancing age at each spatial frequency tested [Generalized estimating equations (GEE) multiple linear regression: p <= 0.01]. The decline with age was greatest in the highest spatial frequency (18 cpd) and least in the lowest spatial frequency (3 cpd). Posterior subcapsular cataract caused the greatest reduction in contrast sensitivity at all spatial frequencies, while nuclear cataract caused significant reduction only in the intermediate (12 cpd) and high (18 cpd) spatial frequencies. Cortical cataract failed to reach statistical significance in contrast sensitivity reduction at all spatial frequencies tested. CONCLUSION: Contrast sensitivity declines with age in all spatial frequencies tested with a greater decline occurring in the higher spatial frequencies. Age and cataracts are independently associated with contrast sensitivity decline, and posterior subcapsular cataracts caused the greatest reduction at all spatial frequencies. PMID- 22429693 TI - The effectiveness of a health promotion with group intervention by clinical trial. Study protocol. AB - BACKGROUND: The promotion of health and the interventions in community health continue to be one of the pending subjects of our health system. The most prevalent health problems (cardiovascular diseases, cancer, diabetes...) are for the most part related to life habits. We propose a holistic and integral approach as the best option for tackling behavior and its determinants. The research team has elaborated the necessary educational material to realize group teaching, which we call "Health Workshops". The goal of the present study is to evaluate the effectiveness of these Health Workshops in the following terms: Health Related Quality of Life (HRQOL), incorporate and maintain a balanced diet, do physical activity regularly, maintain risk factors such as tension, weight, cholesterol within normal limits and diminish cardiovascular risk. METHODS/DESIGN: Controlled and random clinical testing, comparing a group of persons who have participated in the Health Workshops with a control group of similar characteristics who have not participated in the Health Workshops.Field of study: the research is being done in Health Centers of the city of Barcelona, Spain. POPULATION STUDIED: The group is composed of 108 persons that are actually doing the Health Workshops, and 108 that are not and form the control group. They are assigned at random to one group or the other. DATA ANALYSIS: With Student's t distribution test to compare the differences between numerical variables or their non parametric equivalent if the variable does not comply with the criteria of normality. (Kolmogorov-Smirnof test). Chi-square test to compare the differences between categorical variables and the Logistic Regression Model to analyze different meaningful variables by dichotomous analysis related to the intervention. DISCUSSION: The Health Workshop proposed in the present study constitutes an innovative approach in health promotion, placing the emphasis on the person's self responsibility for his/her own health.The rhythm of a weekly session during 8 weeks with recommended activities to put into practice, as well as the support of the group is an opportunity to incorporate healthy habits and make a commitment to self-care. The sheets handed out are a Health Manual that can always be consulted after the workshop ends. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01440738. PMID- 22429694 TI - Suicidal ideation and perceived burdensomeness in patients with chronic pain. AB - There is a clear relationship between suicide risk and chronic pain conditions. However, the exact nature of this link has been poorly understood, with risk attribution often limited to comorbid depression. Perceived burdensomeness has already been confirmed as a risk factor for suicidal ideation (SI) and suicide attempt in the general population. Self-perceived burden, studied among medically and terminally ill medical populations, has begun to receive a great deal of attention as a suicide risk factor. However, this risk has not been considered in an outpatient chronic pain population, a group likely to experience perceived burdensomeness as a particular problem. Guidelines recommend routine suicide risk screening in medical settings, but many questionnaires are time-consuming and do not allow for the assessment of the presence of newly identified risk constructs, such as perceived burdensomeness. This retrospective study examined the relationship between depression, perceived burdensomeness, and SI in a patient sample seeking behavioral treatment for chronic pain management. A logistic regression model was developed, with preliminary results indicating perceived burdensomeness was the sole predictor of SI, even in the presence of other well established risk factors such as age, gender, depressive symptoms, and pain severity. Findings highlight the potential utility of a single-item screening question in routine clinical care as an incrementally superior predictor of SI in a chronic pain population. PMID- 22429695 TI - Polymorphism in the vascular endothelial growth factor A (VEGFA) gene is associated with serum VEGF-A level and disease activity in rheumatoid arthritis: differential effect of cigarette smoking. AB - OBJECTIVE: To assess the impact of common genetic variants in the vascular endothelial growth factor A (VEGFA) gene on circulating VEGF-A levels and disease activity in patients with rheumatoid arthritis (RA). METHODS: A cohort (n=419) of consecutively recruited RA patients of Caucasian origin was studied. Disease activity (DAS28) was recorded on a regular basis (0, 12 and 24 months). Smoking history (never, past and current) was obtained. PCR-RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578 (rs699947), -460 (rs833061), +405 (rs2010963) and +936 (rs3025039). Circulating levels of VEGF-A were measured in serum samples using a fluorescent bead-based assay system (Luminex(r)). Associations were analyzed using univariate and multivariate statistics. RESULTS: VEGFA-2578 AA genotype was associated with lower serum VEGF-A levels, as was the most frequent haplotype (A(-2578)-C(-460) G(+405), 48.1%) within the 5'-flanking region of the gene. The same genotype and haplotype were also associated with decreased disease activity in RA. This was seen only in patients who had never smoked. In multivariate multiple regression models, the VEGFA-2578 SNP was shown to be associated with disease activity at presentation (p=0.029) and over time (p=0.016) in patients who never smoked, independent of serum VEGF-A levels and other confounding factors. CONCLUSION: Genetic variation in the VEGFA gene is associated with serum VEGF-A levels in RA, and shows an association with disease activity in RA patients who have never smoked, independent of serum VEGF-A levels. PMID- 22429696 TI - Could successful cryoballoon ablation of paroxysmal atrial fibrillation prevent progressive left atrial remodeling? AB - BACKGROUND: Radiofrequency catheter ablation of atrial fibrillation (AF) has been proved to be effective and to prevent progressive left atrial (LA) remodeling. Cryoballoon catheter ablation (CCA), using a different energy source, was developed to simplify the ablation procedure. Our hypothesis was that successful CCA can also prevent progressive LA remodeling. METHODS: 36 patients selected for their first CCA because of nonvalvular paroxysmal AF had echocardiography before and 3, 6 and 12 months after CCA. LA diameters, volumes (LAV) and LA volume index (LAVI) were evaluated. LA function was assessed by: early diastolic velocities of the mitral annulus (Aa(sept), Aa(lat)), LA filling fraction (LAFF), LA emptying fraction (LAEF) and the systolic fraction of pulmonary venous flow (PVSF). Detailed left ventricular diastolic function assessment was also performed. RESULTS: Excluding recurrences in the first 3-month blanking period, the clinical success rate was 64%. During one-year of follow-up, recurrent atrial arrhythmia was found in 21 patients (58%). In the recurrent group at 12 months after ablation, minimal LAV (38 +/- 19 to 44 +/- 20 ml; p < 0.05), maximal LAV (73 +/- 23 to 81 +/- 24 ml; p < 0.05), LAVI (35 +/- 10 to 39 +/- 11 ml/m2; p = 0.01) and the maximal LA longitudinal diameter (55 +/- 5 to 59 +/- 6 mm; p < 0.01) had all increased. PVSF (58 +/- 9 to 50 +/- 10%; p = 0.01) and LAFF (36 +/- 7 to 33 +/- 8%; p = 0.03) had decreased. In contrast, after successful cryoballoon ablation LA size had not increased and LA function had not declined. In the recurrent group LAEF was significantly lower at baseline and at follow-up visits. CONCLUSIONS: In patients whose paroxysmal atrial fibrillation recurred within one year after cryoballoon catheter ablation left atrial size had increased and left atrial function had declined. In contrast, successful cryoballoon catheter ablation prevented progressive left atrial remodeling. PMID- 22429697 TI - Neurogenic pulmonary edema. PMID- 22429698 TI - Results of Schirmer tear test in clinically normal llamas (Lama glama). AB - PURPOSE: To determine the normal reference range for Schirmer tear test (STT) values in clinically normal llamas (Lama glama) ANIMALS: Nine captive llamas (Lama glama) (seven females and two males) were used in this study. PROCEDURE: Complete ophthalmic examinations were performed without chemical restraint. STT I values were evaluated in both eyes of all llamas using a commercial STT strip of a single lot number (Schirmer-Tranentest((r)), Germany). STT II value was also measured in both eyes of seven female llamas. RESULTS: No statistically significant differences among ages or between right and left eyes were found for any of the results. The mean +/- SD STT I of 18 eyes of nine llamas was 17.3 +/- 1.1 mm/min (Range 15-19 mm/min). The mean +/- SD STT II of 14 eyes of seven llamas was 15.4 +/- 1.7 mm/min (Range 12.5-17.5 mm/min). A paired samples t-test demonstrated that there was a significant difference between the STT I and II values (P = 0.001). CONCLUSION: This study provides novel data for normal reference ranges of STT I and II values in healthy llamas. Results of this study may assist veterinarians in the diagnosis of ocular surface disease and syndromes affecting the tear film in these species. PMID- 22429699 TI - Lack of evidence for perinatal transmission of Cytauxzoon felis in domestic cats. AB - Cytauxzoon felis is a hemoprotozoan parasite of cats capable of causing severe, often fatal disease during acute infection, but cats that survive the acute stage of disease become chronic carriers. These otherwise healthy carriers are capable of transmitting the infection to other cats via the bite of a vector tick. A variety of other hematoprotozoan parasites are capable of vertical transmission from mother to offspring. If this were possible for C. felis, it could be an important part of the explanation for the apparent emergence of this disease with an increased incidence in an expanding geographic area. We investigated the possibility of perinatal transmission of C. felis from chronically infected cats to their offspring. Two queens produced a total of 14 healthy kittens in three litters. All kittens tested negative for C. felis by microscopic slide review and PCR until they were adopted to private homes at approximately 12 weeks of age. While this does not rule out the possibility of perinatal transmission, it is unlikely to be a common phenomenon. PMID- 22429700 TI - Influence of Pluronic 85 and ketoconazole on disposition and efficacy of ivermectin in sheep infected with a multiple resistant Haemonchus contortus isolate. AB - Non-specific mechanisms involving ATP-binding cassette drug efflux transporters may play an important role in xenobiotic clearance in ovine gastro-intestinal nematodes. By using transporter inhibitors, the aim of this trial was to assess the possibility of increasing drug bioavailability in the host in an attempt to improve treatment efficacy. Thirty-six lambs were infected with 5000 multiple drug resistant Haemonchus contortus third stage larvae and separated into six groups (n=6): ivermectin alone (IVM; 0.2 mg/kg body-weight, BW), ketoconazole alone (KET; 10 mg/kg BW), Pluronic 85 alone (P85; 4 mg/kg BW), IVM+KET, IVM+P85 or untreated control. Ivermectin was administered once on day 28 post-infection for all appropriate groups, whereas KET and P85 were administered as five separate doses on day 26-30 post-infection inclusive. The resultant data showed that concomitant administration of KET or P85 with IVM induced increases in plasma and tissue concentrations of IVM in treated animals, resulting in a two fold increase in the area under the time-concentration curve (p<0.05). Faecal egg counts and worm burdens of the IVM+KET and IVM+P85 groups were lower than in the untreated, KET and P85 alone control animals. Worm burdens were reduced by between 16% and 51% with IVM+KET and IVM+P85 respectively compared to untreated control animals. The co-administration of P85 with IVM increased the efficacy by 34%, compared with IVM alone, in terms of worm count reduction of the multi resistant isolate of H. contortus. PMID- 22429701 TI - Evaluation of different extracts and synthesised silver nanoparticles from leaves of Euphorbia prostrata against Haemaphysalis bispinosa and Hippobosca maculata. AB - The present study was based on assessments of the antiparasitic activity to determine the efficacies of hexane, chloroform, ethyl acetate, acetone, methanol and aqueous leaf extracts of Euphorbia prostrata Ait. (Euphorbiaceae) and synthesised Ag nanoparticles (NPs) using aqueous leaf extract against the adult cattle tick Haemaphysalis bispinosa Neumann (Acarina: Ixodidae) and the haematophagous fly Hippobosca maculata Leach (Diptera: Hippoboscidae). Synthesised Ag NPs were characterised with ultraviolet-vis (UV-vis) spectrum, scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) support the biosynthesis of Ag NPs. Parasites were exposed to varying concentrations of plant extracts and synthesised silver NPs for 24 h. All extracts showed the maximum toxic effect on parasites; however, the highest mortality was found in the hexane, chloroform, ethyl acetate, acetone, methanol and aqueous leaf extracts of E. prostrata and synthesised Ag NPs against the adult of H. bispinosa (LC(50)=45.24, 40.07, 21.91, 25.32, 19.30, 10.16 and 2.30 ppm; LC(90)=86.95, 88.66, 70.92, 83.22, 48.28, 70.27 and 8.28 ppm) and against H. maculata (LC(50)=39.37, 41.98, 19.92, 27. 93, 21.97, 9.79 and 2.55 ppm; LC(90)=89.44, 98.52, 76.59, 90.18, 55.07, 54.35 and 9.03 ppm), respectively. Mortality of 100% was found in synthesised Ag NPs at a concentration of 10 mg l( 1). UV-vis spectrograph of the colloidal solution of Ag NPs has been recorded as a function of time. The absorption spectrum of E. prostrata leaf extracts at different wavelengths ranging from 300 to 600 nm revealed a peak at 420 nm after 6 h. The FTIR spectra of Ag NPs exhibited prominent peaks at 3431; 1616; 1381; 1045; 818; 509; and 420 cm(-1). SEM analyses of the synthesised Ag NPs were rod shaped and measured 25-80 nm with an average size of 52.4 nm. The chemical composition of aqueous leaf extract was analysed by gas chromatography-mass spectrometry (GC-MS). The major chemical constituent was identified as 2 phenylethanol. These results suggest that the leaf methanol, aqueous extracts of E. prostrata and green synthesis of Ag NPs have the potential to be used as an ideal eco-friendly approach for the control of H. bispinosa and H. maculata. In addition, toxicity tests were conducted to analyse the toxicological effects of particle size on Daphnia magna and Ceriodaphnia dubia, and the animal model test was evaluated against Bos indicus for 24-h treatment. No toxicity on daphnids and no adverse effects were noted on animals after exposure to solvent extracts and synthesised Ag NPs. PMID- 22429702 TI - Histological localization of aluminum in topical aluminum chloride treatment for palmar hyperhidrosis. PMID- 22429703 TI - Fatal Burkholderia gladioli infection misidentified as Empedobacter brevis in a lung transplant recipient with cystic fibrosis. AB - Data describing the risk of lung transplantation (LT), clinical features, and outcomes of patients with cystic fibrosis (CF) infected with Burkholderia gladioli are limited. Herein, we report a case of disseminated B. gladioli infection characterized by bacteremia, necrotizing pneumonia, lung abscess, and empyema in a lung transplant recipient with CF, highlight the importance of accurate microbiological identification, and review published outcomes of LT in CF patients infected with B. gladioli, which include cases of pneumonia, tracheobronchitis, bacteremia, and abscesses, and demonstrate an all-cause 1-year mortality of approximately 23%, often after combined medical and surgical treatment. PMID- 22429704 TI - Impact of delay in diagnosis on survival to head and neck carcinomas: a systematic review with meta-analysis. AB - OBJECTIVE: To address the contradictory information on the role of delay in diagnosis on head and neck cancer survival. STUDY DESIGN: Systematic review and meta-analysis. SEARCH STRATEGY: Search on MEDLINE (1966 to March 2011), EMBASE (1980 to March 2011) and ISI proceedings (from inception to March 2011). The terms used were ('Head and neck cancers') AND ('delay'OR'prognostic'OR'survival') both in MeSH terms and free-text words. The reference lists of the retrieved articles were also revised manually to identify other potentially relevant papers. All searches were independently undertaken by two clinicians and one epidemiologist, and the results merged. SETTING: Primary and specialised care levels. PARTICIPANTS: Meta-analysis of data from papers on the subject published from 1966 to 2011. MAIN OUTCOME MEASURES: Survival. METHODS: After search in Medline and other databases, we computed pooled relative risks (RR) and 95% confidence interval (95%CI) from the 10 studies retrieved. RESULTS: The estimate of the relative risk of mortality related to any diagnostic delay (either patient or professional delay) was 1.34 (95%CI 1.12-1.61). Referral delay was associated with a three-fold increase in mortality. Total delay was marginally related to mortality (RR: 1.04, 95%CI: 1.01-1.07). By anatomic location, pharynx cancer shows the highest association (RR: 1.68, 95%CI: 1.22-2.31). CONCLUSIONS: Diagnostic delay is a moderate risk factor of mortality from head and neck cancer. However, part of the effect observed may be due to residual confounding (confounding from unknown variables that are not eliminated by adjustment). PMID- 22429706 TI - Potential for false positive HIV test results with the serial rapid HIV testing algorithm. AB - BACKGROUND: Rapid HIV tests provide same-day results and are widely used in HIV testing programs in areas with limited personnel and laboratory infrastructure. The Uganda Ministry of Health currently recommends the serial rapid testing algorithm with Determine, STAT-PAK, and Uni-Gold for diagnosis of HIV infection. Using this algorithm, individuals who test positive on Determine, negative to STAT-PAK and positive to Uni-Gold are reported as HIV positive. We conducted further testing on this subgroup of samples using qualitative DNA PCR to assess the potential for false positive tests in this situation. RESULTS: Of the 3388 individuals who were tested, 984 were HIV positive on two consecutive tests, and 29 were considered positive by a tiebreaker (positive on Determine, negative on STAT-PAK, and positive on Uni-Gold). However, when the 29 samples were further tested using qualitative DNA PCR, 14 (48.2%) were HIV negative. CONCLUSION: Although this study was not primarily designed to assess the validity of rapid HIV tests and thus only a subset of the samples were retested, the findings show a potential for false positive HIV results in the subset of individuals who test positive when a tiebreaker test is used in serial testing. These findings highlight a need for confirmatory testing for this category of individuals. PMID- 22429705 TI - Choosing to live with home dialysis-patients' experiences and potential for telemedicine support: a qualitative study. AB - BACKGROUND: This study examines the patients' need for information and guidance in the selection of dialysis modality, and in establishing and practicing home dialysis. The study focuses on patients' experiences living with home dialysis, how they master the treatment, and their views on how to optimize communication with health services and the potential of telemedicine. METHODS: We used an inductive research strategy and conducted semi-structured interviews with eleven patients established in home dialysis. Our focus was the patients' experiences with home dialysis, and our theoretical reference was patients' empowerment through telemedicine solutions. Three informants had home haemodialysis (HHD); eight had peritoneal dialysis (PD), of which three had automated peritoneal dialysis (APD); and five had continuous ambulatory peritoneal dialysis (CAPD). The material comprises all PD-patients in the catchment area capable of being interviewed, and all known HHD-users in Norway at that time. RESULTS: All of the interviewees were satisfied with their choice of home dialysis, and many experienced a normalization of daily life, less dominated by disease. They exhibited considerable self-management skills and did not perceive themselves as ill, but still required very close contact with the hospital staff for communication and follow-up. When choosing a dialysis modality, other patients' experiences were often more influential than advice from specialists. Information concerning the possibility of having HHD, including knowledge of how to access it, was not easily available. Especially those with dialysis machines, both APD and HHD, saw a potential for telemedicine solutions. CONCLUSIONS: As home dialysis may contribute to a normalization of life less dominated by disease, the treatment should be organized so that the potential for home dialysis can be fully exploited. Pre-dialysis information should be unbiased and include access to other patients' experiences. Telemedicine may potentially facilitate a communication-based follow-up and improve safety within the home setting, making it easier to choose and live with home dialysis. PMID- 22429707 TI - The CB(1) receptor antagonist, AM281, improves recognition loss induced by naloxone in morphine withdrawal mice. AB - Morphine withdrawal leads to the activation of endocannabinoid system and cognitive deficits. The aim of this study was to evaluate the effects of AM281, a cannabinoid antagonist/inverse agonist, on memory deficit following naloxone precipitated morphine withdrawal in mice. Male mice were made dependent by increasing doses of morphine (30-90 mg/kg) twice daily for 3 days. The object recognition task was used to evaluate memory dysfunction. The test comprised three sections: habituation for 15 min., first trial for 12 min. and test trial for 5 min. In this learning paradigm, the difference in exploration between a previously seen object and a new object is taken as an index of memory performance (recognition index). The recognition index was assessed on the third day of morphine treatment by the injection of 0.1 mg/kg naloxone 3 hr after the last dose of morphine. Chronic administration of AM281 at 2.5 mg/kg significantly improved the memory impairment, producing a recognition index of 36.0 +/- 3.9 as compared with vehicle-treated data (recognition index = -3.1 +/- 8.2%). A single dose of AM281 at 5 mg/kg improved the recognition index from -1.5 +/- 3.9% in morphine withdrawal animals to 18.5 +/- 11.6%. Concurrent administration of AM281 with morphine proved to be more effective in protecting the animals from losing their memory compared to acute action of AM281. These results indicate that the contribution of the cannabinoid system to memory deficit is attributable to morphine withdrawal. By blocking cannabinoid receptors, AM281 may become useful in preventing memory deficit after morphine withdrawal. PMID- 22429708 TI - Activation of gastrin-releasing peptide receptors in the lumbosacral spinal cord is required for ejaculation in male rats. AB - INTRODUCTION: Ejaculation is a complex reflex mediated by a spinal ejaculation generator located in the lumbosacral spinal cord and consisting of a population of lumbar spinothalamic (LSt) neurons. LSt neurons and their intraspinal axonal projections contain several neuropeptides, including gastrin-releasing peptide (GRP). AIM: To test the hypothesis that GRP is critically involved in mediating ejaculation by acting in autonomic and motor areas of the lumbosacral spinal cord, utilizing a physiological paradigm to investigate ejaculatory reflexes in isolation of supraspinal inputs. METHODS: Dual immunohistochemistry for GRP and galanin was performed to investigate co-expression of GRP in LSt cells of control male rats. Next, anesthetized, spinalized male rats received intrathecal infusions of either GRP antagonist RC-3095 (0, 10, or 20 nmol/10 uL) or GRP (0, 0.2, 0.5 nmol/10 uL). Ejaculatory reflexes were induced by electrical stimulation of the dorsal penile nerve (DPN) which reliably triggers rhythmic increases in seminal vesicle pressure (SVP) and contractions of the bulbocavernosus muscle (BCM), indicative of the emission and expulsion phases of ejaculation, respectively. MAIN OUTCOME MEASURES: GRP in LSt cells was expressed as percentages of co-expression. SVP and electromyographic recording (EMG) of BCM activity following drug treatment and DPN stimulation were recorded and analyzed for numbers of SVP increases, BCM events and bursts. RESULTS: GRP was exclusively expressed in LSt cells and axons. Intrathecal infusion of RC-3095, but not saline, blocked SVP increases and BCM bursting induced by DPN stimulation. Intrathecal infusions of GRP, but not saline, triggered SVP increases and BCM bursting in 43-66% of animals and facilitated SVP increases and BCM bursting induced by subthreshold DPN stimulation in all animals. CONCLUSION: These data support a critical role for GRP for control of the emission and expulsion phases of ejaculation in male rats by acting in LSt target areas in the lumbosacral spinal cord. PMID- 22429710 TI - Polymorphism of ventricular tachycardia due to variable exit from a single arrhythmogenic focus in the right ventricular outflow tract. PMID- 22429709 TI - Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience. AB - The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 MUg ml(-1) (range <0.20-13.47 MUg ml(-1)). Significant inter- and intra patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice. PMID- 22429711 TI - The suppressive function of the rice DELLA protein SLR1 is dependent on its transcriptional activation activity. AB - When the gibberellin (GA) receptor GIBBERELLIN INSENSITIVE DWARF 1 (GID1) binds to GA, GID1 interacts with DELLA proteins, repressors of GA signaling. This interaction inhibits the suppressive function of DELLA protein and thereby activates the GA response. However, how DELLA proteins exert their suppressive function and how GID1s inhibit suppressive function of DELLA proteins is unclear. By yeast one-hybrid experiments and transient expression of the N-terminal region of rice DELLA protein (SLR1) in rice callus, we established that the N-terminal DELLA/TVHYNP motif of SLR1 possesses transactivation activity. When SLR1 proteins with various deletions were over-expressed in rice, the severity of dwarfism correlated with the transactivation activity observed in yeast, indicating that SLR1 suppresses plant growth through transactivation activity. This activity was suppressed by the GA-dependent GID1-SLR1 interaction, which may explain why GA responses are induced in the presence of GA. The C-terminal GRAS domain of SLR1 also exhibits a suppressive function on plant growth, possibly by directly or indirectly interacting with the promoter region of target genes. Our results indicate that the N-terminal region of SLR1 has two roles in GA signaling: interaction with GID1 and transactivation activity. PMID- 22429712 TI - Occupational health issues in marine and freshwater research. AB - Marine and freshwater scientists are potentially exposed to a wide variety of occupational hazards. Depending on the focus of their research, risks may include animal attacks, physiological stresses, exposure to toxins and carcinogens, and dangerous environmental conditions. Many of these hazards have been investigated amongst the general population in their recreational use of the environment; however, very few studies have specifically related potential hazards to occupational exposure. For example, while the incidence of shark and crocodile attacks may invoke strong emotions and the occupational risk of working with these animals is certainly real, many more people are stung by jellyfish or bitten by snakes or dogs each year. Furthermore, a large proportion of SCUBA related injuries and deaths are incurred by novice or uncertified divers, rather than professional divers using aquatic environments. Nonetheless, marine and freshwater research remains a potentially risky occupation, and the likelihood of death, injury and long-term health impacts still needs to be seriously considered. PMID- 22429713 TI - Diabetes mellitus type 2 in urban Ghana: characteristics and associated factors. AB - BACKGROUND: Sub-Saharan Africa faces a rapid spread of diabetes mellitus type 2 (DM2) but its potentially specific characteristics are inadequately defined. In this hospital-based study in Kumasi, Ghana, we aimed at characterizing clinical, anthropometric, socio-economic, nutritional and behavioural parameters of DM2 patients and at identifying associated factors. METHODS: Between August 2007 and June 2008, 1466 individuals were recruited from diabetes and hypertension clinics, outpatients, community, and hospital staff. Fasting plasma glucose (FPG), serum lipids and urinary albumin were measured. Physical examination, anthropometry, and interviews on medical history, socio-economic status (SES), physical activity and nutritional behaviour were performed. RESULTS: The majority of the 675 DM2 patients (mean FPG, 8.31 mmol/L) was female (75%) and aged 40-60 years (mean, 55 years). DM2 was known in 97% of patients, almost all were on medication. Many had hypertension (63%) and microalbuminuria (43%); diabetic complications occurred in 20%. Overweight (body mass index > 25 kg/m2), increased body fat (> 20% (male), > 33% (female)), and central adiposity (waist-to-hip ratio > 0.90 (male), > 0.85 (female)) were frequent occurring in 53%, 56%, and 75%, respectively. Triglycerides were increased (>= 1.695 mmol/L) in 31% and cholesterol (>= 5.17 mmol/L) in 65%. Illiteracy (46%) was high and SES indicators generally low. Factors independently associated with DM2 included a diabetes family history (adjusted odds ratio (aOR), 3.8; 95% confidence interval (95%CI), 2.6-5.5), abdominal adiposity (aOR, 2.6; 95%CI, 1.8-3.9), increased triglycerides (aOR, 1.8; 95%CI, 1.1-3.0), and also several indicators of low SES. CONCLUSIONS: In this study from urban Ghana, DM2 affects predominantly obese patients of rather low socio-economic status and frequently is accompanied by hypertension and hyperlipidaemia. Prevention and management need to account for a specific risk profile in this population. PMID- 22429714 TI - Anterior segment fluorescein angiography of the normal canine eye using a dSLR camera adaptor. AB - PURPOSE: To describe anterior segment fluorescein angiography (ASFA) of the normal canine eye using two different sedation/anesthetic protocols and a digital single lens-reflex (dSLR) camera adaptor. METHODS: Dogs free of ocular and systemic disease were used for this study. Dogs received maropitant citrate (1.0 mg/kg SQ) and diphenhydramine (2.0mg/kg SQ) 20min prior to butorphanol [n = 6] (0.2 mg/kg IV) or propofol [n=6] (4 mg/kg IV bolus, 0.2 mg/kg/min CRI). Standard color and red-free images were obtained prior to administration of 10% sodium fluorescein (20 mg/kg IV). Image acquisition was performed using a dSLR camera (Canon 7D), dSLR camera adaptor, camera lens (Canon EF-S 60 mm f/2.8 macro), and an accessory flash (Canon 580EXII). Imaging occurred at a rate of 1/s immediately following bolus for a total of 30 s, then at 1, 2, 3, 4, 5, and 10 min. RESULTS: Twelve dogs with a combined mean age of 5.1 years and various iris colors were imaged. Arterial, capillary, and venous phases were identified and time sequences recorded. Visibility of the vascular pattern was inversely related to iris pigmentation. Complete masking of blood flow was noted with heavily pigmented irises. Vessel leakage was noted in some eyes. Proper patient positioning and restricted ocular movements were critical in acquiring quality images. No adverse events were noted. CONCLUSION: This study demonstrated that quality high resolution ASFA images were obtainable using a novel dSLR camera adaptor. ASFA of the normal canine eye is limited to irises, which are moderately to poorly pigmented. Use of general anesthesia produced higher quality images and is recommended for ASFA in the dog. PMID- 22429715 TI - Diagnosis of the vertebral level from which low back or leg pain originates. A comparison of clinical evaluation, MRI and epiduroscopy. AB - BACKGROUND: The precise localization of painful structures in the spine of patients with low back pain and/or pain radiating (LBP/RP) to the lower extremities is important for targeted therapeutic intervention. The aim of the study reported here was to determine and compare the spinal segment(s) where pain was elicited via endoscopic evaluation vs. the vertebral level from where the pain was thought to originate as determined by clinical evaluation and by MRI. METHODS: Observational cohort study of 143 patients 19 to 88 years of age undergoing spinal canal endoscopy (epiduroscopy) in a combined academic and private practice setting January 2008 to December 2008. Patients were asked whether pain generated by pressure upon epidural structures with the tip of an endoscope was similar in character and distribution (concordant) to the pain for which patients sought treatment. Notes from clinical evaluation and MRI reports were reviewed, and segmental level determined to be the locus of pathology was tabulated. RESULTS: One hundred twenty-five (87%) patients reported maximal reproducible pain at a specific level during epiduroscopy. The most common level was at L4 to L5 (87 patients). The least common level was L5 to S1 (2 patients). In only 40 patients did the level determined by clinical evaluation correlate with the level at which pain could be reproduced during epiduroscopy. MRI indicated a specific vertebral level that corresponded to the level at which pain could be reproduced during epiduroscopy in 28 of 143 (20%) patients. The results of the 3 diagnostic methods were significantly different (P < 0.01). CONCLUSION: Results of this study indicate that epiduroscopy is more reliable than is either clinical evaluation or MRI for determining the vertebral level where clinically significant spinal pathology occurs in patients with LBP/RP. PMID- 22429716 TI - Is there still a place for vasopressors in the treatment of cardiac arrest? PMID- 22429717 TI - No relationship between left ventricular radial wall motion and longitudinal velocity and the extent and severity of noncompaction cardiomyopathy. AB - BACKGROUND: Noncompaction cardiomyopathy (NCCM) is characterized by a prominent trabecular meshwork and deep intertrabecular recesses. Although systolic dysfunction is common, limited information is available on differences in wall motion of the normal compacted and noncompacted segments. The purpose of this study was to assess radial wall motion and longitudinal wall velocity in patients with NCCM, according to the extent and severity of noncompaction. METHODS: The study comprised 29 patients in sinus rhythm (age 41 +/- 15 years, 15 men), who fulfilled stringent diagnostic criteria for NCCM and compared to 29 age and gender matched healthy controls. Segmental radial wall motion of all compacted and noncompacted segments was assessed with the standard visual wall motion score index and longitudinal systolic (Sm) wall velocity with tissue Doppler imaging of the mitral annulus. For each LV wall a normalized Sm value was calculated. The extent and severity of NC in each LV segment was assessed both in a qualitative and quantitative manner. RESULTS: Heart failure was the primary clinical presentation in half of the patients. NCCM patients had a wall motion score index of 1.68 +/- 0.43 and a normalized Sm of 82 +/- 20%. The total and maximal noncompaction scores were not related to the wall motion score index and the normalized Sm. NCCM patients with and without heart failure had similar total and maximal noncompaction scores. CONCLUSIONS: In NCCM patient's radial wall motion and longitudinal LV wall velocity is impaired but not related to the extent or severity of noncompaction. PMID- 22429718 TI - A common, non-optimal phenotypic endpoint in experimental adaptations of bacteriophage lysis time. AB - BACKGROUND: Optimality models of evolution, which ignore genetic details and focus on natural selection, are widely used but sometimes criticized as oversimplifications. Their utility for quantitatively predicting phenotypic evolution can be tested experimentally. One such model predicts optimal bacteriophage lysis interval, how long a virus should produce progeny before lysing its host bacterium to release them. The genetic basis of this life history trait is well studied in many easily propagated phages, making it possible to test the model across a variety of environments and taxa. RESULTS: We adapted two related small single-stranded DNA phages, PhiX174 and ST-1, to various conditions. The model predicted the evolution of the lysis interval in response to host density and other environmental factors. In all cases the initial phages lysed later than predicted. The PhiX174 lysis interval did not evolve detectably when the phage was adapted to normal hosts, indicating complete failure of optimality predictions. PhiX174 grown on slyD-defective hosts which initially entirely prevented lysis readily recovered to a lysis interval similar to that attained on normal hosts. Finally, the lysis interval still evolved to the same endpoint when the environment was altered to delay optimal lysis interval. ST-1 lysis interval evolved to be ~2 min shorter, qualitatively in accord with predictions. However, there were no changes in the single known lysis gene. Part of ST-1's total lysis time evolution consisted of an earlier start to progeny production, an unpredicted phenotypic response outside the boundaries of the optimality model. CONCLUSIONS: The consistent failure of the optimality model suggests that constraint and genetic details affect quantitative and even qualitative success of optimality predictions. Several features of ST-1 adaptation show that lysis time is best understood as an output of multiple traits, rather than in isolation. PMID- 22429719 TI - A mouse model of tuberculosis reinfection. AB - Recent clinical observations shows that individuals treated with chemotherapy for tuberculosis who live in endemic areas are four times more likely to develop secondary disease, often as not caused by exogenous reinfection. In a mouse model described here, we show that mice infected with the virulent W-Beijing Mycobacterium tuberculosis strain HN878, then given chemotherapy to clear the infection, were resistant to re-challenge with the same organism thereafter. This resistance, which was mediated by rapid expression of CD4 T cells expressing markers consistent with both central and effector memory immunity, was only transient however. After 20-30 days of the reinfection the numbers of these cells steadily declined, the bacterial load in the lungs surged up, and the lung tissues became increasingly consolidated. No evidence was found for a regulatory T cell response in these mice, but many T cells harvested from the lungs showed evidence of increased PD-1 expression, indicating exhaustion. These data indicate that the memory T cell response to reinfection may not be as stable and long lived as previously thought, a finding with obvious implications for vaccine development. PMID- 22429720 TI - Optimizations of the naive-Bayes classifier for the prognosis of B-Chronic Lymphocytic Leukemia incorporating flow cytometry data. AB - Prognosis of B-Chronic Lymphocytic Leukemia (B-CLL) remains a challenging problem in medical research and practice. While the parameters obtained by flow cytometry analysis form the basis of the diagnosis of the disease, the question whether these parameters offer additional prognostic information still remains open. In this work, we attempt to provide computer-assisted support to the clinical experts of the field, by deploying a classification system for B-CLL multiparametric prognosis that combines various heterogeneous (clinical, laboratory and flow cytometry) parameters associated with the disease. For this purpose, we employ the naive-Bayes classifier and propose an algorithm that improves its performance. The algorithm discretizes the continuous classification attributes (candidate prognostic parameters) and selects the most useful subset of them to optimize the classification accuracy. Thus, in addition to the high classification accuracy achieved, the proposed approach also suggests the most informative parameters for the prognosis. The experimental results demonstrate that the inclusion of flow cytometry parameters in our system improves prognosis. PMID- 22429721 TI - Donor cornea transfer from Optisol GS to organ culture storage: a two-step procedure to increase donor tissue lifespan. AB - PURPOSE: Storage time for donor corneas in Optisol GS is limited compared to Eye Bank Organ Culture (EBOC). We here examine the epithelium on donor corneoscleral rims after primary storage in Optisol GS and subsequent incubation in EBOC. METHODS: Morphology was monitored by light and electron microscopy, expression of phenotypic and genotypic markers by immunohistochemistry and RT-PCR and changes in oxidative lipid and DNA damage by ELISA and COMET assay. RESULTS: A prominent loss of cells was observed after storage in Optisol GS. After maintenance in EBOC, spreading apical cells were Occludin(+) , while the staining for E-cadherin and Connexin-43 was less intense. There were an upregulation of Occludin and a downregulation of E-cadherin and Connexin-43. Eye Bank Organ Culture was associated with an ongoing proliferative activity and a downregulation of putative progenitor/stem cell marker ABCG2 and p63. Staining for 8-OHdG and Caspase-3 did not increase, while levels of malondialdehyde and number of DNA strand breaks and oxidized bases increased. CONCLUSIONS: This dual procedure should be pursued as an option to increase the storage time and the pool of available donor corneas. The observed downregulation of markers associated with stemness during EBOC is relevant considering the potential use of donor epithelium in the treatment of ocular surface disorders. PMID- 22429722 TI - Cancer treatment-induced bone loss in premenopausal women: a need for therapeutic intervention? AB - Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <-2.0 or Z-score <=-1.0 and/or a 5-10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements. PMID- 22429723 TI - In vitro activities of amphotericin B and AmBisome against Aspergillus isolates recovered from Italian patients treated for haematological malignancies. AB - Although there is evidence that liposomal amphotericin B (AmBisome) is non inferior to amphotericin B (AmB) in terms of in vivo efficacy, in vitro data regarding the activity of AmBisome against clinical isolates of Aspergillus are rare. In this study, the susceptibilities to AmB and AmBisome of 103 Aspergillus complex isolates (48 Aspergillus flavus, 33 Aspergillus fumigatus, 13 Aspergillus terreus and 9 Aspergillus niger) recovered from haematological patients with invasive infection were compared. Minimum inhibitory concentrations (MICs) were determined by the broth microdilution (BMD) method according to the Clinical and Laboratory Standards Institute (CLSI), whilst AmB susceptibility was also determined by Etest. Using a susceptible/resistant MIC cut-off of 1mg/L, all A. fumigatus and A. niger complexes isolates were susceptible to both AmB and AmBisome. In contrast, 38.5% and 30.8% of the A. terreus complex isolates were resistant to AmB and AmBisome, respectively, with good agreement between BMD and Etest methods. With respect to A. flavus complex isolates, 43.7% and 16.7% were resistant by the BMD method to AmBisome and AmB, respectively. For isolates with discrepant results, AmB MICs obtained by Etest were higher than those obtained for AmB by the BMD method and they were closer to those obtained for AmBisome by BMD. Aspergillus flavus AmB MICs ranged from 0.5 mg/L to 2 mg/L by the BMD method and from 1 mg/L to >16 mg/L by the Etest method, and AmBisome MICs ranged from 0.06 mg/L to >16 mg/L by the BMD method. Etest appears to be superior to the CLSI BMD method using AmB in detecting AmB resistance of Aspergillus spp., although the CLSI BMD method might be a suitable procedure if AmBisome is used as the test drug. PMID- 22429724 TI - Current treatment guidelines for Trypanosoma cruzi infection in pregnant women and infants. PMID- 22429725 TI - Association between corneal biomechanical properties and optic nerve head morphology in newly diagnosed glaucoma patients. AB - BACKGROUND: To investigate the association between corneal biomechanics and optic nerve head morphology in newly diagnosed primary open-angle glaucoma patients. DESIGN: Hospital based prospective study. PARTICIPANTS: Forty-two untreated newly diagnosed primary open-angle glaucoma patients. METHODS: Patients underwent corneal hysteresis measurement using the Ocular Response Analyzer and confocal scanning laser ophthalmoscopy for optic nerve head topography evaluation. One eye was selected randomly for analysis. Data collected included age, race, gender, intraocular pressure and central corneal thickness. MAIN OUTCOME MEASURES: Multiple regression analysis (controlling for baseline intraocular pressure and disc area) was used to investigate factors associated with the following optic nerve head topographic parameters: linear cup-to-disc ratio and mean cup depth. RESULTS: Mean age of participants was 66.7 +/- 11.8 years. Corneal hysteresis was the only factor significantly associated with both mean cup depth (correlation coefficient [r] = -0.34, P = 0.03) and cup-to-disc ratio (r = -0.41, P = 0.01). Central corneal thickness was significantly associated with mean cup depth (r = -0.35, P = 0.02), but not with cup-to-disc ratio (r = -0.25, P = 0.13). Although a trend towards a positive association between age and cup-to-disc ratio was identified (r = 0.26, P = 0.08), age was not significantly associated with mean cup depth (r = 0.06, P = 0.72). When comparing fellow eyes of patients with bilateral glaucoma, the eye with higher corneal hysteresis had smaller cup-to-disc ratio in 75% of the cases. CONCLUSIONS: In untreated newly diagnosed primary open-angle glaucoma patients, those with thinner corneas and mainly lower corneal hysteresis values had a larger cup-to-disc ratio and deeper cup, independently of intraocular pressure values and disc size. PMID- 22429726 TI - Isolation, modulatory functions on murine B cell development and antigen-specific immune responses of BP11, a novel peptide from the chicken bursa of Fabricius. AB - The bursa of Fabricius (BF) is the central humoral immune organ unique to birds which plays important roles in B lymphocyte differentiation. Here, a new bursal peptide (BP11) with the amino acid sequence DVAGKLPDNRT was identified and characterized from BF. It was proved that BP11 promoted CFU pre-B formation, and regulated B cell differentiation, including increase the percentage of immature and mature B cells in BM cells co-cultured with IL-7. BP11 also exerted immunomodulatory function on antigen-specific immune responses in BALB/c mice immunized with inactivated influence virus (AIV, H9N2 subtype) vaccine, including enhancing AIV-specific antibody and cytokine production. Furthermore, it was noteworthy that BP11 stimulated antibody productions and potentiates the Th1 and Th2-type immune responses in dose-dependent manner in chicken. These results suggested that BP11 might be highly relevant for the development of avian immune system. PMID- 22429727 TI - Role of catecholestrogens on ovarian prostaglandin secretion in vitro in the catfish Heteropneustes fossilis and possible mechanism of regulation. AB - Seasonal, periovulatory and 2-hydroxyestradiol-17beta (2-OHE(2))-induced changes on ovarian prostaglandin (PG) E(2) and F(2alpha) were investigated under in vivo or in vitro in the female catfish Heteropneustes fossilis. Both PGE(2) and PGF(2alpha) increased significantly during ovarian recrudescence with the peak levels in spawning phase. The PGs showed periovulatory changes with the peak levels at 16 h after the hCG treatment. Incubation of postvitellogenic ovary fragments with estradiol-17beta (E(2)), 2-OHE(2) or 2-methoxyE(2) produced concentration-dependent increases in PG levels; 2-OHE(2) was more effective. In order to identify the receptor mechanism involved in the 2-OHE(2)-induced PG stimulation, the ovarian pieces were incubated with phentolamine (an alpha adrenergic antagonist), propranolol (a beta-adrenergic antagonist) or tamoxifen (an estrogen receptor blocker) alone or in combination with 2-OHE(2). The incubation of the tissues with the receptor blockers alone did not produce any significant effect on basal PG levels. However, co- and pre-incubation of the tissues with the blockers resulted in inhibition of the stimulatory effect of 2 OHE(2) on the PGs. Phentolamine was more effective than propranolol. The signal transduction pathway(s) involved in the 2-OHE(2)-induced PG secretion was investigated. The incubation of the ovarian pieces with 3-isobutyl-1 methylxanthine (IBMX, a phosphodiesterase inhibitor), chelerythrine (a protein kinase C inhibitor) and PD098059 (a mitogen-activated protein kinase inhibitor) significantly lowered the basal secretion of PGF(2alpha) and PGE(2). In contrast, H89 (a protein kinase A inhibitor) increased the basal secretion of PGs at 1 and 5 MUM concentration and decreased it at 10 MUM concentration. The co- or pre incubation with IBMX, H89, chelerythrine and PD098059 significantly inhibited the stimulatory effect of 2-OHE(2) on PGF(2alpha) and PGE(2) levels. The inhibition was higher in the pre-incubation groups. Chelerythrine was the most effective followed by PD098059, IBMX and H89. The results suggest that 2-OHE(2) may employ both adrenergic and estrogen receptors, or a novel receptor mechanism having properties of both adrenergic and estrogen receptors. PMID- 22429728 TI - Ecological correlates of cortisol levels in two bat species with contrasting feeding habits. AB - The immediate release of adrenal glucocorticoids can be crucial for an animal's survival when facing a stressor, but constantly elevated or exceptionally high glucocorticoid levels are usually detrimental for health. Although baseline and maximal secretion of glucocorticoids are regulated within narrow ranges within species, plasma glucocorticoid levels vary largely across vertebrates. We asked what ecological factors affect baseline plasma cortisol levels (CortI) and maximum levels (CortMax) following a physiological challenge through administration of adrenocorticotropic hormone (ACTH). Specifically, we studied whether seasonal fluctuations in food abundance correlate with the capacity of cortisol increases in two phyllostomid bat species with contrasting feeding habits: the sanguinivorous vampire bat (Desmodus rotundus) and the frugivorous short-tailed fruit bat (Carollia perspicillata). Both species coexist in habitats with various levels of seasonality (dry and rainforest). On a seasonal basis, resource abundance is more stable for vampire than for fruit bats, but previous studies suggested that daily foraging success may vary more for vampire than for fruit bats. CortI and CortMax varied seasonally in C. perspicillata from dry and rainforests, with the exception of CortMax in rainforest bats. Although we expected food availability to be stable year-round for vampire bats, we found CortI and CortMax of vampires to be higher during the rainy season than during the dry season. Also, we found CortMax to be higher in vampires from the rainforest than in those from the dry forest. CortMax of vampires were among the highest measured for a free-ranging mammal; a pattern that could be related to the species' vulnerability to starvation. We conclude that food availability modulates cortisol levels in free-ranging species that face seasonally fluctuating resources; in species, however, that benefit from food which is constantly abundant, other factors than food may become more important in modulating cortisol levels. PMID- 22429729 TI - Plasma leptin and growth hormone levels in the fine flounder (Paralichthys adspersus) increase gradually during fasting and decline rapidly after refeeding. AB - In fish, recent studies have indicated an anorexigenic role of leptin and thus its possible involvement in regulation of energy balance and growth. In the present study, the effects of fasting and refeeding periods on plasma leptin levels were studied in the fine flounder, a flatfish with remarkably slow growth. To further assess the endocrine status of the fish during periods of catabolism and anabolism, plasma growth hormone (GH) levels were also analyzed. Under normal feeding condition, plasma leptin and GH levels remained stable and relatively high in comparison with other teleost species. For the three separate groups of fish, fasted for 2, 3, and 4 weeks, respectively, plasma leptin levels increase gradually, becoming significantly elevated after 3 weeks, and reaching highest levels after 4-week fasting. Plasma GH levels were significantly elevated after 2 week fasting. At the onset of refeeding, following a single meal, leptin levels decline rapidly to lower than initial levels within 2 h, irrespective of the length of fasting. Plasma GH also decline, the decrease being significant after 4, 24 and 2 h for the 2, 3 and 4-week fasted groups, respectively. This study shows that plasma leptin levels in the fine flounder are strongly linked to nutritional status and suggests that leptin secretion is regulated by fast-acting mechanisms. Elevated leptin levels in fasted fish may contribute to a passive survival strategy of species which experience natural food shortage periods by lowering appetite and limiting physical foraging activity. PMID- 22429730 TI - Extremely low risk for acquisition of a respiratory viral infection in the emergency room of a large pediatric hospital during the winter season. AB - The aim of this study was to investigate the rate of transmission of respiratory viral infections to children visiting the emergency room of a large pediatric hospital during winter. A total of 615 children were prospectively studied. Twenty-two (3.6%) children developed at least one symptom compatible with a respiratory viral infection within 1-7 days after the visit, including cough (12 children), fever (8), rhinorrhea (7), and/or respiratory distress (1). Three children (0.49%) developed an influenza-like illness. These findings indicate that transmission of respiratory viral infections to children visiting an emergency room during the winter season is extremely low. PMID- 22429731 TI - Community based weighing of newborns and use of mobile phones by village elders in rural settings in Kenya: a decentralised approach to health care provision. AB - BACKGROUND: Identifying every pregnancy, regardless of home or health facility delivery, is crucial to accurately estimating maternal and neonatal mortality. Furthermore, obtaining birth weights and other anthropometric measurements in rural settings in resource limited countries is a difficult challenge. Unfortunately for the majority of infants born outside of a health care facility, pregnancies are often not recorded and birth weights are not accurately known. Data from the initial 6 months of the Maternal and Neonatal Health (MNH) Registry Study of the Global Network for Women and Children's Health study area in Kenya revealed that up to 70% of newborns did not have exact weights measured and recorded by the end of the first week of life; nearly all of these infants were born outside health facilities. METHODS: To more completely obtain accurate birth weights for all infants, regardless of delivery site, village elders were engaged to assist in case finding for pregnancies and births. All elders were provided with weighing scales and mobile phones as tools to assist in subject enrollment and data recording. Subjects were instructed to bring the newborn infant to the home of the elder as soon as possible after birth for weight measurement.The proportion of pregnancies identified before delivery and the proportion of births with weights measured were compared before and after provision of weighing scales and mobile phones to village elders. Primary outcomes were the percent of infants with a measured birth weight (recorded within 7 days of birth) and the percent of women enrolled before delivery. RESULTS: The recorded birth weight increased from 43 +/- 5.7% to 97 +/- 1.1. The birth weight distributions between infants born and weighed in a health facility and those born at home and weighed by village elders were similar. In addition, a significant increase in the percent of subjects enrolled before delivery was found. CONCLUSIONS: Pregnancy case finding and acquisition of birth weight information can be successfully shifted to the community level. PMID- 22429732 TI - Poly(ADP-ribose) polymerase inhibition improves erectile function by activation of nitric oxide/cyclic guanosine monophosphate pathway in diabetic rats. AB - INTRODUCTION: Endothelial dysfunction-induced abnormalities of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the corpus cavernosum are thought to be the main factors involved in the pathogenesis of diabetes-induced erectile dysfunction (ED). Recent studies have shown that the poly(adenosine diphosphate ribose) polymerase (PARP) pathway plays a critical role in diabetic endothelial dysfunction. AIM: The aim of this study is to determine whether activation of the PARP pathway is involved in diabetic cavernosal endothelial dysfunction and abnormalities of the NO/cGMP pathway. METHODS: Male Sprague-Dawley rats were randomly divided into three groups: age matched controls, diabetic controls (DM), and the 3-aminobenzamide (3-AB, a PARP inhibitor)-treated diabetic group (DM+3-AB). Diabetes was induced by intraperitoneal injection of streptozotocin. Eight weeks after inducing diabetes, the DM+3-AB group was treated with 3-AB for 4 weeks. MAIN OUTCOME MEASURES: Erectile function was assessed at 12 weeks after inducing diabetes by stimulating the cavernous nerve. Expression of poly(ADP-ribose), protein kinase B (Akt), phospho-Akt, endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neuronal nitric oxide synthase (nNOS) were evaluated by Western blot. Cavernous NO generation and cGMP levels were also determined. RESULTS: The DM group showed impaired erectile function and significantly increased PARP activity. Expression of total eNOS and nNOS, phospho-Akt, and eNOS decreased significantly in the DM group compared with those in the control group. In addition, cavernous NO generation and cGMP levels decreased significantly in the DM group compared with those in the control group. Treatment with 3-AB restored erectile function and significantly reversed all molecular alterations except decreased nNOS expression. CONCLUSION: Overactivation of the PARP pathway in the corpus cavernosum of diabetic rats was involved in cavernosal endothelial dysfunction and abnormalities of the NO/cGMP pathway resulting in ED. These findings may be applied to develop novel therapies for patients with diabetic ED. PMID- 22429733 TI - NINJ2 SNP may affect the onset age of first-ever ischemic stroke without increasing silent cerebrovascular lesions. AB - BACKGROUND: To investigate if single nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 would be associated with earlier-onset (vs. late-onset) first-ever ischemic stroke and increase silent cerebrovascular lesions prior to the manifestation of the stroke. METHODS: We prospectively enrolled 164 patients (67.6 +/- 12.9 years, 92 men) admitted with first-ever ischemic strokes. All patients underwent genotyping of rs11833579 and rs12425791 as well as systemic investigations including magnetic resonance (MR) imaging and other vascular workup. Stroke-related MR lesions were registered on a brain template-set using a custom-built software package 'Image_QNA': high-signal intensity ischemic lesions on diffusion, T2-weighted, or fluid attenuation inversion recovery (FLAIR) MR images, and low signal intensity hemorrhagic lesions on gradient-echo MR images. RESULTS: The rs11833579 A/A or G/A genotype was independently associated with the first-ever ischemic stroke before the age 59 vs. 59 or over, after adjusting for cardiovascular risk factors and prior medication of antiplatelet or anticoagulant drugs, increasing the risk by about 2.5 fold. In the quantitative MR lesion maps from age-sex matched subgroups (n = 124 or 126), there was no difference between the patients with the rs11833579 A/A or G/A genotype and those with the G/G genotype. Unexpectedly, the extent of leukoaraiosis on FLAIR-MR images tended to be smaller in the corona radiata and centrum semiovale of the patients with the rs12425791 A/A or G/A genotype than in those with the G/G genotype (P = 0.052). Neither the rs11833579 nor the rs12425791 genotype significantly affected initial stroke severity; however the latter was associated with relatively low modified Rankin scale scores at 1 year after stroke. CONCLUSIONS: The rs11833579 A/A or G/A genotype may bring forward the onset age of first-ever ischemic stroke without increasing silent cerebrovascular lesions prior to the stroke. Further studies are required to confirm our preliminary findings. PMID- 22429734 TI - A catalog of magnetic resonance imaging compatibility of penile prostheses. AB - INTRODUCTION: Erectile dysfunction has been successfully treated with penile prosthesis implantation for over 50 years. Ferromagnetic implants or devices may create a potentially hazardous or painful situation during magnetic resonance imaging (MRI). A modern catalog of the MRI compatibility of penile prostheses is not available. AIM: Evaluate the safety profile of implanted, penile prostheses during MRI. MAIN OUTCOME MEASURE: Review available in vitro safety data and reported patient complications experienced during MRI with a penile prosthesis in place. METHODS: A search of PubMedTM for articles documenting a penile prosthesis present during MRI was performed. Radiology texts and product information from manufacturers' producing a penile prosthesis were reviewed. Direct discussion with product manufacturers was also performed to obtain additional safety and compatibility information. RESULTS: Nine clinical articles noted the presence of a penile prosthesis at the time of magnetic resonance imaging. No articles documented a complication from MRI of a man with a penile prosthesis. A single patient with an unnamed malleable prosthesis was noted to have twisting of the device during MRI which did not result in discomfort or malfunction of the device. In vitro studies support the safety of most prostheses during MRI. CONCLUSION: The available data suggests there is little risk for most patients with a penile prosthesis who undergo MRI. Notable exceptions include Dacomed's Omniphase and Duraphase device and the MRI-conditional Spectra device manufactured by AMS. Current manufacturers of penile implants provide wallet cards and medical letters to support safety when undergoing an MRI. Prior prosthesis implantation should not preclude patients from having an MRI. PMID- 22429735 TI - A prospective, multicentre survey on antifungal therapy in neutropenic paediatric haematology patients. AB - Invasive fungal infections are a frequent complication after intensive chemotherapy. The aims of this prospective study were to describe the use of antifungal therapy and to report which strategy was routinely adopted to guide the introduction of antifungal therapy. A total of 321 febrile episodes in 160 paediatric patients affected by acute leukaemia or non-Hodgkin-lymphoma were investigated. Antifungal therapy was used in 100 of 321 febrile episodes (31%), and classified as empiric in 73 episodes, diagnostic-driven in 25 episodes and targeted in 2 episodes. Switching to a second-line antifungal therapy was needed in 28 of 100 episodes (28%) and was classified as empiric in 10 episodes (36%), diagnostic-driven in 17 episodes (61%) and targeted in 1 episode (4%). In 9 of 28 episodes (32%), switching to a third-line antifungal therapy was performed and was classified as empiric in 2 episodes (22%), diagnostic-driven in 6 episodes (67%) and targeted in 1 episode (11%). Invasive fungal infections was reported in 23 of 100 episodes: confirmed in 4 episodes, probable in 8 episodes, and possible in 11 episodes. Attributable mortality was 2.8%. Antifungal therapy was still used mostly empirically, whereas as fever persisted, its modification was guided by a diagnostic-driven approach. PMID- 22429736 TI - Nocturnal peak in atrial tachyarrhythmia occurrence as a function of arrhythmia burden. AB - INTRODUCTION: We examined circadian periodicity of atrial tachyarrhythmias (AT/AF) in a large group of patients with implantable devices, which allow continuous collection of the event data over prolonged periods of time. METHODS AND RESULTS: A total of 16,130 AT/AF events were recorded in 236 patients (age: 63 +/- 12 years, 27% female, 90% had a history of cardiovascular disease, 33% ischemic, LVEF: 49 +/- 18%) over a period of 12 months. To exclude interactions with therapy, the patterns of arrhythmia occurrence were examined for all events and for those episodes that were preceded by at least 1, 6, and 24 hours of sinus rhythm. To prevent biasing toward patients with more frequent episodes, the patterns of AT/AF onset were analyzed both in absolute and patient-normalized (i.e., divided by the total number of events in each patient) units per hour per patient and then summarized for the entire group. In patients with <4 AT/AF events, the onset times were randomly distributed over 24-hour period. However, as the number of AT/AF events increased, a nocturnal pattern of occurrence (determined by the occurrence of a trough around noon) gradually emerged and became highly statistically significant (P < 10(-4) ). The magnitude of nocturnal peak of AT/AF events was well explained by a single-exponential function (R(2) = 0.97, P < 10(-2) ). CONCLUSION: Patients with more frequent atrial tachyarrhythmias are more likely to develop AT/AF at night. Knowledge of patient specific circadian patterns of arrhythmia occurrence can be useful for personalized management of individuals with significant arrhythmia burden. PMID- 22429737 TI - Epidemiology of tobacco use and dependence in adults in a poor peri-urban community in Lima, Peru. AB - BACKGROUND: Tobacco smoking is an important public health concern worldwide leading to both chronic disease and early death. In Latin America, smoking prevalence is estimated at approximately 30% and prior studies suggest that the prevalence in Peru is 22% to 38%. We sought to determine the prevalence of daily smoking in a poor peri-urban community in Lima, Peru. METHODS: We conducted a cross-sectional survey in a random sample of adults >=40 years of age living in Pampas de San Juan de Miraflores, Lima, Peru. We asked participants to respond to a survey that included questions on sociodemographics, tobacco use and dependence. RESULTS: We enrolled 316 participants. Average monthly household income was <= 400 USD and nearly all homes had running water, sewage, and electricity. Most individuals had not completed high school. Smoking prevalence was 16% overall, yet daily smoking prevalence was 1.9%. Former daily smokers comprised 3.8% of current nonsmokers and 9.1% current occasional smokers. Average scores for the Fagerstrom Test for Nicotine Dependence for daily smokers and occasional smokers were 1.5 and 0, respectively. CONCLUSIONS: Daily use of tobacco is uncommon among adults in peri-urban communities of Lima, Peru, unlike their counterparts in Lima and other Latin American capital cities. Tobacco dependence is also low. Hence, efforts aimed at primary prevention are of utmost importance in these communities. This study provides an accurate baseline using an internationally recognized assessment tool (Global Adult Tobacco Survey), allowing for accurate assessment of tobacco control interventions over time. PMID- 22429738 TI - Clinical case-study describing the use of skin-perichondrium-cartilage graft from the auricular concha to cover large defects of the nose. AB - BACKGROUND: The composite graft from the conchal cartilage is a graft that is often used, especially in surgery on the nose, due to its capacity to resolve problems of cover and tissue deficit, arising from the removal of neoplasms or as the result of trauma, burns or following over-aggressive rhinoplasty. We have started to use skin-perichondrium-cartilage graft from the ear to cover large areas of the nose with very satisfying results as well as we describe in the reported clinical case. METHODS: The operation consisted of reconstruction of the cartilaginous nasal septum, which had previously been removed, using two vestibular labial mucosa flaps to reconstruct the mucosa, and cartilage from the ear conch for the cartilaginous septum. After this, the skin edges of the fistula were turned to recreate the inner lining of the nose and form a vascular base of wide area to accept the composite graft. The case concerns a female 74-year old patient who had undergone several oncological surgery for a relapsing basal cell carcinoma on the dorsum of the nose. The operation consisted of reconstruction of the cartilaginous nasal septum using two vestibular labial mucosa flaps to reconstruct the mucosa, and cartilage from the ear conch for the cartilaginous septum. RESULTS: The perichondrial cutaneous graft has shown in this surgical case very favorable peculiarities that make it usable even in facial plastic surgery. CONCLUSIONS: We believe that the positive experience that we achieved in the use of composite grafts for the reconstruction of large areas of the nose could be interesting for others surgeons. PMID- 22429739 TI - Child protection training, experience, and personal views of dentists in the prefecture of Attica, Greece. AB - BACKGROUND: The abuse and neglect of children constitutes a social phenomenon that unfortunately is widespread irrespective of geographic, ethnic, or social background. Dentists may be the first health professionals to recognize signs of child maltreatment (CM) and have an important role in dealing with such incidents. AIM: To describe the training, experience, and personal views of dentists practicing in the Prefecture of Attica regarding the recognition and referral of abused and neglected children. DESIGN: A random sample was drawn from a target population of dentists registered with two of the largest dental associations in Greece. The dental practitioners were interviewed by two paediatric dentists using a specially designed questionnaire. Information was collected regarding their awareness on child maltreatment, the frequency of suspected incidents as well as the reasons for not reporting them. RESULTS: With a response rate of 83%, findings are reported from 368 interviews (54% male, mean age 43 years). Only 21% of respondents had received training on child protection at undergraduate level. Suspected abuse was 13% and suspected neglect was 35%. Only six of the 368 respondents made an official report of a suspected case of child maltreatment. The most common reason that might prevent a dentist from reporting a case was doubt over the diagnosis (44%). Ninety-seven per cent of dentists believed that recognition and referral of incidents should be part of undergraduate training. CONCLUSIONS: Dental practitioners did not feel adequately informed on recognizing and referring child abuse and neglect cases. The low percentage of reported incidents and the lack of legislation indicate a great need for continuously educating dentists on child maltreatment as well as for setting up an organized system in Greece for reporting such incidents to protect the dentist referring the case as well as the child being victimized. PMID- 22429740 TI - Platelet transfusion for reversal of dual antiplatelet therapy in patients requiring urgent surgery: a pilot study. PMID- 22429741 TI - Outbreak of Philophthalmus gralli in four greater rheas (Rhea americana). AB - Using slit-lamp biomicroscopy, conjunctival biopsy, and morphological identification, a flock of four Greater rheas (Rhea americana) in Arizona were diagnosed with conjunctivitis secondary to Philophthalmus gralli (P. gralli) infection. Aquatic snails from the exhibit's water source were identified as Melanoides tuberculatus, a known vector for P. gralli. Comparison of partial sequences of DNA regions from P. gralli adults removed from the rheas and metacercariae from the aquatic snails demonstrated a 100% match, confirming the source of infection. The flock was divided into two treatment groups: the most severely affected rheas received both manual removal of trematodes and praziquantel 1% ointment OU q12 h and the least severely affected rheas were only given praziquantel 1% ointment OU q12 h. The rheas were permanently relocated away from the infected water source and aquatic snails. Initial resolution was seen at 17 weeks in the most severely affected rhea, which had 675 adult P. gralli removed and topical praziquantel. The two rheas that only received topical praziquantel showed resolution within 3 and 15 weeks. Current recommendations for treating P. gralli include: manual removal of trematodes, topical praziquantel 1% ointment, and relocation away from infected water sources and aquatic snails. PMID- 22429742 TI - Serum profiling by MALDI-TOF mass spectrometry as a diagnostic tool for domoic acid toxicosis in California sea lions. AB - BACKGROUND: There are currently no reliable markers of acute domoic acid toxicosis (DAT) for California sea lions. We investigated whether patterns of serum peptides could diagnose acute DAT. Serum peptides were analyzed by MALDI TOF mass spectrometry from 107 sea lions (acute DAT n = 34; non-DAT n = 73). Artificial neural networks (ANN) were trained using MALDI-TOF data. Individual peaks and neural networks were qualified using an independent test set (n = 20). RESULTS: No single peak was a good classifier of acute DAT, and ANN models were the best predictors of acute DAT. Performance measures for a single median ANN were: sensitivity, 100%; specificity, 60%; positive predictive value, 71%; negative predictive value, 100%. When 101 ANNs were combined and allowed to vote for the outcome, the performance measures were: sensitivity, 30%; specificity, 100%; positive predictive value, 100%; negative predictive value, 59%. CONCLUSIONS: These results suggest that MALDI-TOF peptide profiling and neural networks can perform either as a highly sensitive (100% negative predictive value) or a highly specific (100% positive predictive value) diagnostic tool for acute DAT. This also suggests that machine learning directed by populations of predictive models offer the ability to modulate the predictive effort into a specific type of error. PMID- 22429743 TI - CD226 interaction with CD155 impacts on retention and negative selection of CD8 positive thymocytes as well as T cell differentiation to follicular helper cells in Peyer's Patches. AB - The immunoglobulin-like glycoprotein CD226 represents a receptor activating cytotoxic T and NK cells taking part in tumour surveillance. In addition, CD226 is involved in the differentiation of naive CD4(+) T cells into effector cells. CD155 that is widely over-expressed on tumour cells, was identified as a counter receptor of CD226 rendering many cancer cells sensitive to NK driven elimination. However, CD155 was also assigned a role in the establishment of follicular helper T cells in the small intestine and the final maturation of CD8 positive thymocytes. Here we show that mice lacking CD226 are distinguished by virtually identical phenotypes as already reported for CD155 deficient mice: a paucity of follicular helper T cells in Peyer's Patches and of terminally matured CD8 T cells in thymus. Moreover, like CD155, CD226 is involved in negative selection of CD8 thymocytes. These observations establish a firm link between the functions of CD155 and CD226 in several T cell differentiation steps. PMID- 22429745 TI - Characterization of the RNA-binding protein Musashi1 in zebrafish. AB - Musashi (Msi) is an evolutionarily conserved gene family of RNA-binding proteins (RBPs) that is preferentially expressed in the nervous system. The first member of the Msi family was identified in Drosophila. Drosophila Msi plays an important role in regulating asymmetric cell division of the sensory organ precursor cells. The mammalian orthologs, including human and mouse Musashi1 (Msi1), are neural RBPs that are strongly expressed in fetal and adult neural stem/progenitor cells (NS/PCs). Mammalian Msi1 contributes to self renewal of NS/PCs through translational regulation of several target mRNAs. In this study, the zebrafish Msi ortholog zMsi1 was identified and characterized. The normal spatial and temporal expression profiles for both protein and mRNA were determined. A series of splice variants were detected. Overall, zMsi1 was strongly expressed in neural tissue in early stages of development and exhibited similarity to mammalian Msi1 expression patterns. To reveal the in vivo function of zMsi1, morpholinos against Msi1 were introduced into one-cell stage zebrafish embryos. Knock down of zmsi1 frequently resulted in aberrant formation of the Central Nervous System (CNS). These results suggest that Msi1 plays roles in CNS development in vertebrates. This article is part of a Special Issue entitled "RNA-Binding Proteins". PMID- 22429746 TI - Schizotypy trait and striatal dopamine receptors in healthy volunteers. AB - Individuals with schizotypal features exhibit cognitive, perceptual and social deficits that are similar to but less prominent than those seen in patients with schizophrenia. Dopaminergic hyperactivity in the striatum has been related to the positive symptoms of schizophrenia, and brain-imaging studies of dopamine uptake in the striatum are thought to be linked to the pathophysiological mechanisms underlying schizophrenia. The aim of this study was to investigate whether the increased availability of striatal dopamine (DA) D(2/3) receptors is related to elevated levels of schizotypal features in healthy individuals. The Schizotypal Personality Questionnaire (SPQ) was administered to 55 healthy volunteers. The availability of their striatal DA D(2/3) receptors was analysed using [(123)I] iodobenzamide single photon emission computed tomography (SPECT). Although the SPQ total scores showed no correlation with the availability of total (left and right) striatal DA D(2) receptors, the SPQ disorganised subscale scores were positively correlated with the availability of right striatal DA D(2/3) receptors. Our findings demonstrated that the availability of striatal DA D(2/3) receptors may be associated with schizotypal features in healthy volunteers. PMID- 22429747 TI - Effects of victory and defeat on testosterone and cortisol response to competition: evidence for same response patterns in men and women. AB - In this study, we report evidence from sport competition that is consistent with the biosocial model of status and dominance. Results show that testosterone levels rise and drop following victory and defeat in badminton players of both sexes, although at lower circulating levels in women. After losing the match, peak cortisol levels are observed in both sexes and correlational analyses indicate that defeat leads to rises in cortisol as well as to drops in testosterone, the percent change in hormone levels being almost identical in both sexes. In conclusion, results show the same pattern of hormonal responses to victory and defeat in men and women. PMID- 22429748 TI - Cortisol serum levels in familial longevity and perceived age: the Leiden longevity study. AB - BACKGROUND: Cortisol levels are strongly associated with a person's health. Familial longevity and age assessment of facial photographs (perceived age) are both associated with morbidity and mortality. The present study aimed to investigate morning cortisol levels in familial longevity and the association of these levels with perceived age. METHODS: Perceived age and serum morning cortisol levels were measured for 138 offspring from long-lived families and 138 partners from the Leiden Longevity Study. Considered confounding factors were chronological age, gender, body mass index, current smoking habits, antidepressant drug use, antihypertensive drugs and diabetes medication. RESULTS: In the fully adjusted model, which was restricted to participants who did not use antidepressant drugs, offspring had similar serum cortisol levels compared to their partners (0.54 and 0.55MUmol/L, respectively; p=0.54). Using a similar model taking offspring and partners together, an increase of 0.1MUmol/L in morning cortisol levels was associated with an 0.42 (95% CI 0.0-0.84, p=0.048) year increase in perceived age. This association was significantly attenuated in the offspring group (0.01, 95% CI -0.58 to 0.59, p=0.98) compared to the partner group (0.81, 95% CI 0.20-1.41, p=0.009 year increase in perceived age per 0.1MUmol/L increase in cortisol respectively) (p for interaction=0.042). CONCLUSION: This study demonstrates that high levels of cortisol are associated with a higher perceived age. This association was attenuated in offspring from long-lived families compared to their partners, suggesting enhanced stress resistance in these subjects. Future research will be aimed at elucidating potential mechanisms underlying the observations in this study. PMID- 22429750 TI - Dormancy in the stem cell niche. AB - Tissues characterized by constant turnover contain post-mitotic, terminally differentiated cells originating from highly proliferative progenitors, which in turn derive from a relatively small population of stem cells. At the population level, self-renewal and differentiation are the possible outcomes of stem cell proliferation; overall, however, stem cells are quiescent if compared with their direct progeny. The recent discovery of a particularly quiescent, or dormant, subpopulation of hematopoietic stem cells (HSCs) raises a number of fundamental questions. As stem cell fate is influenced by the signals integrated by the stem cell niche, will dormant HSCs reside in specific dormant niches? Is the mechanism of dormancy common to multiple regenerating tissues or specific to the hematopoietic system? If cancer is maintained by a few cancer stem cells, do they also contain a subpopulation of dormant cells, and could this be exploited for therapeutic purposes? PMID- 22429751 TI - Role of Demodex folliculorum in the pathogenesis of blepharitis. PMID- 22429752 TI - Role of leukocytes in the pathogenesis of acute kidney injury. PMID- 22429753 TI - Imported malaria and dengue fever in returned travelers in Japan from 2005 to 2010. AB - Malaria and dengue are important problems in Japan particularly since international travel to developing countries has become increasingly popular. To describe the clinical features of malaria and dengue cases in Japan, a retrospective study was conducted on 50 malaria cases and 40 dengue cases presented to the National Centre for Global Health and Medicine of Japan between 2005 and 2010. The most frequent area of acquisition for cases of malaria was Africa (76.0%), and for dengue fever was Asia (90.0%). Although the immigrant population is very small in Japan, patients categorized as visiting friends and relatives were relatively high in proportion, which is similar to Western reports. Confirmed cases of malaria and dengue account for less than 10% of the all travelers returning with any health problems according to the National Centre for Global Health and Medicine. Careful observation of symptoms and signs helps the differential diagnosis of malaria and dengue. PMID- 22429754 TI - Frequency and expression of ALS and HWP1 genotypes in Candida albicans strains isolated from Mexican patients suffering from vaginal candidosis. AB - To detect the frequency and expression of eight ALS (agglutinin-like sequence) genes and the HWP1 genotype in a group of Candida albicans strains isolated from Mexican women suffering from vaginal candidosis. A group of 264 women (age 15-57 years) with vaginal infections were evaluated. C. albicans was identified by PCR amplification of the rRNA internal transcribed spacer regions ITS1 and ITS2. The ALS and HWP1 genes were identified by conventional PCR, and their expression levels were determined by real-time PCR after growing C. albicans strains in reconstituted human vaginal epithelium (RHVE). C. albicans was identified in 50 women (18.9%). The genotypic frequencies were ALS1 100%, ALS2 60%, ALS3 36%, ALS4 54%, ALS5 70%, ALS6 56%, ALS7 64%, ALS9 66% and HWP1 92%. The most frequently expressed genes in the strains harbouring all of the genes were ALS4 (100%), ALS1 (87.5%), ALS2 (87.5%), ALS3 (87.5%), ALS5 (87.5%), ALS7 (87.5%) and HWP1 (75.0%). Nineteen per cent of the vaginal infections were caused by C. albicans, and a high proportion of the strains carried genes encoding proteins involved in adhesion to epithelia. The ALS and HWP1 genes were expressed in RHVE, suggesting that the Als and Hwp1 proteins play an important role in the pathogenesis of the infection. PMID- 22429755 TI - Atypical forms of Guillain-Barre syndrome and H1N1-influenza vaccination. AB - Recent epidemiological studies established extremely rare incidence of Guillain Barre syndrome (GBS) after contemporary H1N1-influenza vaccine. We saw five patients with 'atypical' GBS variants that started within four weeks of 2010/2011 H1N1-influenza vaccine. There was no evidence for other etiologies of GBS. The patients presented with sensory ataxia, areflexia, extremity and oropharyngeal paresthesias, numbness, pain, weakness, sphincteric disturbances, and dysautonomia. One patient had Miller Fisher syndrome. All had elevated cerebrospinal fluid protein, and classic electrodiagnostic finding suggestive of GBS. All received the treatment with intravenous immunoglobulin with variable response. These pilot observations suggest that H1N1-influenza vaccine may be associated with rare and atypical variants of GBS. However, epidemiological studies with large cohorts are necessary to confirm excess cases of atypical GBS after H1N1-influenza vaccination. PMID- 22429756 TI - Invasive meningococcal disease in England and Wales: implications for the introduction of new vaccines. AB - A number of meningococcal vaccines have either been recently licensed or are in late-phase clinical trials. To inform national vaccination policy, it is important to define the burden of disease and the potential impact of any new vaccine. This study describes the epidemiology of invasive meningococcal disease across all age groups in England and Wales for recent epidemiological years between 2006 and 2010. The Health Protection Agency (HPA) conducts enhanced national meningococcal surveillance through a combination of clinical and laboratory reporting. Between 2006/07 and 2010/11, the average annual incidence of invasive meningococcal disease across all age groups was 2.0/100,000. Capsular group B (MenB) accounted for 87% (4777/5471) cases, with an overall incidence of 1.8/100,000. The highest MenB incidence observed among infants (36.2/100,000) where cases increased from birth to 5 months of age then gradually declined. An annual average of 245 MenB cases occurred in infants (135 in those aged <= 6 months) representing 26% (and 14%) of all MenB cases, respectively. After infancy, MenB rates declined until the age of 12 years, rising to a second smaller peak at 18 years. MenB case fatality ratio (CFR) was 5.2% (247/4777 cases) overall and was highest among >= 65 year-olds (28/161; 17.4%). The largest number of deaths (n=125), however, occurred among <5 year-olds. Clonal complexes cc269 and cc41/44 each accounted for around a third of cases across the age groups. Other capsular groups rarely caused invasive disease, although capsular group Y (MenY) cases more than doubled from 35 in 2006/07 to 86 in 2010/11. Thus, universal meningococcal vaccination with an effective broad-spectrum formulation has potential to prevent most disease, particularly if the vaccine is immunogenic early in infancy, but, there is currently little justification for routine quadrivalent ACWY conjugate vaccination in the UK, although the increase in MenY disease warrants continued surveillance. PMID- 22429757 TI - Watershed boundaries and geographic isolation: patterns of diversification in cutthroat trout from western North America. AB - BACKGROUND: For wide-ranging species, intraspecific variation can occur as a result of reproductive isolation from local adaptive differences or from physical barriers to movement. Cutthroat trout (Oncorhynchus clarkii), a widely distributed fish species from North America, has been divided into numerous putative subspecies largely based on its isolation in different watersheds. In this study, we examined mtDNA sequence variation of cutthroat trout to determine the major phylogenetic lineages of this polytypic species. We use these data as a means of testing whether geographic isolation by watershed boundaries can be a primary factor organizing intraspecific diversification. RESULTS: We collected cutthroat trout from locations spanning almost the entire geographic range of this species and included samples from all major subspecies of cutthroat trout. Based on our analyses, we reveal eight major lineages of cutthroat trout, six of which correspond to subspecific taxonomy commonly used to describe intraspecific variation in this species. The Bonneville cutthroat trout (O. c. utah) and Yellowstone cutthroat trout (O. c. bouvieri) did not form separate monophyletic lineages, but instead formed an intermixed clade. We also document the geographic distribution of a Great Basin lineage of cutthroat trout; a group typically defined as Bonneville cutthroat trout, but it appears more closely related to the Colorado River lineage of cutthroat trout. CONCLUSION: Our study indicates that watershed boundaries can be an organizing factor isolating genetic diversity in fishes; however, historical connections between watersheds can also influence the template of isolation. Widely distributed species, like cutthroat trout, offer an opportunity to assess where historic watershed connections may have existed, and help explain the current distribution of biological diversity across a landscape. PMID- 22429758 TI - Biosynthesis of tetraoxygenated phenylphenalenones in Wachendorfia thyrsiflora. AB - The biosynthetic origin of 1,2,5,6-tetraoxygenated phenylphenalenones and the sequence according to which their oxygen functionalities are introduced during the biosynthesis in Wachendorfia thyrsiflora were studied using two approaches. (1) Oxygenated phenylpropanoids were probed as substrates of recombinant W. thyrsiflora polyketide synthase 1 (WtPKS1), which is involved in the diarylheptanoid and phenylphenalenone biosynthetic pathways, (2) Root cultures of W. thyrsiflora were incubated with (13)C-labelled precursors in an (18)O2 atmosphere to observe incorporation of the two isotopes at defined biosynthetic steps. NMR- and HRESIMS-based analyses were used to unravel the isotopologue composition of the biosynthetic products, lachnanthoside aglycone and its allophanyl glucoside. Current results suggest that the oxygen atoms decorating the phenalenone tricycle are introduced at different biosynthetic stages in the sequence O-1->O-2->O-5. In addition, the incubation of W. thyrsiflora root cultures with (13)C-labelled lachnanthocarpone established a direct biosynthetic precursor-product relationship with 1,2,5,6-tetraoxygenated phenylphenalenones. PMID- 22429759 TI - Perspective: what does the term functional mean in the context of epiphora? AB - The term 'functional block' is used to encompass the concept of lacrimal drainage dysfunction in the presence of anatomical patency. There is significant variability in the nomenclature, clinical and investigative criteria used in the literature to define this entity. This has led to confusion and lack of comparability of studies looking at this group. The clinical features, investigative findings and treatment options in this group of patients are described. In addition, the need to differentiate between nasolacrimal stenosis and 'functional block' is emphasized, as evidence suggest patients with nasolacrimal duct stenosis have better outcomes with dacryocystorhinostomy. To better define the disease entity and enable comparability of future studies, it was proposed that this entity be replaced by the term functional epiphora with no delay, pre- or post-sac delay. PMID- 22429760 TI - A randomized open-label trial with a crossover comparison of sexual self confidence and other treatment outcomes following tadalafil once a day vs. tadalafil or sildenafil on-demand in men with erectile dysfunction. AB - AIM: To compare Sexual Self-Confidence and other treatment outcomes following 8 weeks of treatment with tadalafil 5 mg once a day (OaD) vs. tadalafil 20 mg or sildenafil 100 mg as needed (pro re nata [PRN]) in patients with erectile dysfunction (ED). METHODS: A randomized, open-label, crossover study in men >=18 years of age with history of ED and satisfactory response to current oral phosphodiesterase 5 (PDE5) inhibitor PRN. Data were analyzed with a mixed effects model for crossover design. MAIN OUTCOME MEASURES: The primary outcome measure was the Sexual Self-Confidence domain of the Psychological and Interpersonal Relationship Scales (PAIRS) between tadalafil OaD and sildenafil PRN. SECONDARY OUTCOMES INCLUDED: Time Concerns and Spontaneity domains of PAIRS, and the Self Esteem and Relationship (SEAR) scale. RESULTS: Men naive to tadalafil OaD were enrolled (N = 378), with 61-69% prior PDE5 inhibitor use. There were improvements in all PAIRS domains from baseline when comparing tadalafil OaD and PRN with sildenafil PRN (P < 0.001). The Sexual Self-Confidence domain improved from baseline and was 0.50 +/- 0.78 following tadalafil OaD, 0.5 +/- 0.72 for tadalafil PRN, and 0.39 +/- 0.67 for sildenafil PRN. The difference in least squares mean was 0.12 +/- 0.04 (confidence interval [CI] = 0.04, 0.19; P = 0.001) between tadalafil OaD and sildenafil PRN and 0.01 +/- 0.04 (CI = -0.06, 0.08; P = 0.872) between tadalafil OaD and tadalafil PRN. The Time Concerns domain score was lower with tadalafil OaD than tadalafil PRN (P < 0.001). There were no differences in SEAR scores between treatments. CONCLUSIONS: Tadalafil OaD and tadalafil PRN compared with sildenafil PRN demonstrated greater improvements in Sexual Self-Confidence, Time Concerns, and Spontaneity. There was no significant difference in Sexual Self-Confidence between tadalafil OaD and tadalafil PRN. Changes in SEAR, the erectile function domain of the International Index of Erectile Function, and the Erectile Dysfunction Inventory of Treatment Satisfaction scores from baseline to end point were similar. PMID- 22429761 TI - Restoring insulin production for type 1 diabetes. AB - Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new beta-cells by ectopic expression of key transcription factors in endogenous non-beta-cells. Finally, engineering surrogate beta-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production. PMID- 22429762 TI - Capture and commercialization of blue land crabs ("guaiamum") Cardisoma guanhumi (Lattreille, 1825) along the coast of Bahia State, Brazil: an ethnoecological approach. AB - BACKGROUND: Blue Land Crab (Cardisoma guanhumi) is one of the most important crustacean species captured and commercialized in Brazil. Although this species is not considered to be threatened with extinction, populations of C. guanhumi are known to be rapidly diminishing due to heavy harvesting pressures and degradation of their natural habitats, highlighting the necessity of developing and implanting management and protection strategies for their populations. There have been no ethnozoological publications that have focused specifically on C. guanhumi, in spite of importance of this type of information for developing efficient management plans of resource utilization. So, the present work describes the ethnoecological aspects of the capture and commercialization of C. guanhumi by a fishing community in northeastern Brazil. METHODS: Field work was carried out in the municipality of Mucuri, Bahia in Brazil, between the months of January and March/2011 through the use of open semi-structured interviews with all of the crustacean harvesters in city who acknowledged their work in capturing this species, totaling 12 interviewees. The informants were identified through the use of the "snowball" sampling technique. In addition to the interviews themselves, the "guided tour" technique and direct observations was employed. RESULTS: According all the interviewees, the C. guanhumi is popularly called "guaiamum" and is collected in "apicum" zones. They recognize sexual dimorphism in the species based on three morphological characteristics and the harvesters also pointed two stages in the reproductive cycle during the year and another phase mentioned by the interviewees was ecdysis. All of the interviewed affirmed that the size and the quantities C. guanhumi stocks in Mucuri have been diminishing. All of the interviewees agreed that the species and other mangrove resources constituted their principal source of income. The harvesters dedicated three to five days a week to collect Blue Land Crabs and the principal technique utilized for capturing is a trap called a "ratoeira" (rat-trap). CONCLUSIONS: The results of the present work demonstrated that the community retains a vast and important volume of knowledge about C. guanhumi that could subsidize both scientific studies and the elaboration of viable management and conservation strategies for this species. PMID- 22429763 TI - Hypoxia induces apoptosis and autophagic cell death in human periodontal ligament cells through HIF-1alpha pathway. AB - OBJECTIVES: Oxygen deficiency caused by occlusal trauma and smoking can be present in patients with periodontitis. However, biochemical events important in periodontal tissues during hypoxia remain unclear. The aim of this study was to investigate effects of hypoxia on apoptosis and autophagy of human periodontal ligament cells (PDLCs) in vitro. MATERIALS AND METHODS: Human PDLCs were obtained and cultured in vitro. Cell viability, apoptosis, autophagy and gene and protein expression were measured in presence and absence of cobalt chloride (CoCl(2)). RESULTS: CoCl(2) induced cytotoxicity of human PDLCs in a concentration-dependent manner dependent on macromolecular synthesis, and resulted in apoptosis and mitochondrial dysfunction. CoCl(2) also induced redistribution of autophagy marker LC3, increased ratio of LC3-IIto LC3-Iand function of lysosomes. Furthermore, CoCl(2) promoted expression of HIF-1alpha following upregulation of expressions of Bnip3. Significant increases in expression of IL-1beta and MMP-8 were also observed. All these results were reversed by pre-treatment with antioxidant N-acetylcysteine. CONCLUSIONS: Our data showed that CoCl(2) could induce cytotoxicity through mitochondria- apoptotic and autophagic pathways involved in HIF-1alpha. CoCl(2 -treated PDLCs may serve as an in vitro model for studies of molecular mechanisms in periodontitis. PMID- 22429764 TI - Psychopathology and symptoms of atrial fibrillation: implications for therapy. AB - INTRODUCTION: Current guidelines recommend that the choice of AF management strategy be guided by the symptomatic status of the patient when in AF. However, little is known regarding what drives AF symptoms. Several limited studies suggest that psychological distress may be linked with AF symptom severity. METHODS: A total of 300 patients with documented AF completed a questionnaire assessing general health and well-being, including a comprehensive psychological assessment as well as disease-specific measures of AF symptom severity. AF burden was determined by 1-week continuous looping monitor in a subset of patients. Analysis of covariance was used to determine the association between individual measures of depression, anxiety, and somatization disorder symptom severity with measures of general health status and AF-specific symptom severity, adjusting for important confounders. RESULTS: Patients with worsened severity of depression, anxiety, or somatization disorder symptoms had an associated increase in the severity of symptoms attributed to AF regardless of AF severity scale used (P < 0.0001 for each measure of psychological distress). This association persisted after adjusting for important confounders. Increasing severity of depression and anxiety symptoms were also associated with increased visits to medical care for AF management. CONCLUSIONS: Our study demonstrates the consequence of psychological distress on AF-specific symptom severity and healthcare resource utilization. Psychological well-being may strongly influence symptom severity and healthcare utilization. An assessment of psychological distress may be an important adjunct to standard AF management that warrants further study, particularly if symptom relief is the primary goal. PMID- 22429765 TI - Effects of a combined strengthening, stretching and functional training program versus usual-care on gait biomechanics and foot function for diabetic neuropathy: a randomized controlled trial. AB - BACKGROUND: Polyneuropathy is a complication of diabetes mellitus that has been very challenging for clinicians. It results in high public health costs and has a huge impact on patients' quality of life. Preventive interventions are still the most important approach to avoid plantar ulceration and amputation, which is the most devastating endpoint of the disease. Some therapeutic interventions improve gait quality, confidence, and quality of life; however, there is no evidence yet of an effective physical therapy treatment for recovering musculoskeletal function and foot rollover during gait that could potentially redistribute plantar pressure and reduce the risk of ulcer formation. METHODS/DESIGN: A randomised, controlled trial, with blind assessment, was designed to study the effect of a physiotherapy intervention on foot rollover during gait, range of motion, muscle strength and function of the foot and ankle, and balance confidence. The main outcome is plantar pressure during foot rollover, and the secondary outcomes are kinetic and kinematic parameters of gait, neuropathy signs and symptoms, foot and ankle range of motion and function, muscle strength, and balance confidence. The intervention is carried out for 12 weeks, twice a week, for 40-60 min each session. The follow-up period is 24 weeks from the baseline condition. DISCUSSION: Herein, we present a more comprehensive and specific physiotherapy approach for foot and ankle function, by choosing simple tasks, focusing on recovering range of motion, strength, and functionality of the joints most impaired by diabetic polyneuropathy. In addition, this intervention aims to transfer these peripheral gains to the functional and more complex task of foot rollover during gait, in order to reduce risk of ulceration. If it shows any benefit, this protocol can be used in clinical practice and can be indicated as complementary treatment for this disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01207284. PMID- 22429766 TI - Non-steroidal anti-inflammatory drug use and the risk of benign prostatic hyperplasia-related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. AB - Study Type - Therapy (cohort) Level of Evidence 4. What's known on the subject? and What does the study add? Accumulating evidence suggests that inflammation may contribute to the development of BPH and LUTS. Therefore, it is plausible that anti-inflammatory agents, such as aspirin and other NSAIDs, may reduce the risk of BPH/LUTS, as was observed in a recent analysis of daily aspirin use and BPH/LUTS risk in the Olmsted County Study of Urinary Symptoms and Health Status in Men. The present study, conducted in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, found no association for recent aspirin or ibuprofen use with the risk of BPH/LUTS. OBJECTIVE: To investigate the relationship between non-steroidal anti-inflammatory drug (NSAID) use and the incidence of benign prostatic hyperplasia (BPH)-related outcomes and nocturia, a lower urinary tract symptom (LUTS) of BPH, in light of accumulating evidence suggesting a role for inflammation in BPH/LUTS development. PATIENTS AND METHODS: At baseline, participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial completed questions on recent, regular aspirin and ibuprofen use, BPH surgery, diagnosis of an enlarged prostate/BPH, and nocturia. Participants in the intervention arm also underwent a digital rectal examination (DRE), from which prostate dimensions were estimated, as well as a prostate-specific antigen (PSA) test. Only participants in the intervention arm without BPH/LUTS at baseline were included in the analysis (n= 4771). * During follow-up, participants underwent annual DREs and PSA tests, provided annual information on finasteride use, and completed a supplemental questionnaire in 2006-2008 that included additional questions on diagnosis of an enlarged prostate/BPH and nocturia. * Information collected was used to investigate regular aspirin or ibuprofen use in relation to the incidence of six BPH/LUTS definitions: diagnosis of an enlarged prostate/BPH, nocturia (waking two or more times per night to urinate), finasteride use, any self-reported BPH/LUTS, prostate enlargement (estimated prostate volume >=30 mL on any follow-up DRE) and elevation in PSA level (>1.4 ng/mL on any follow-up PSA test). RESULTS: Generally, null results were observed for any recent, regular aspirin or ibuprofen use (risk ratio = 0.92 1.21, P= 0.043-0.91) and frequency of use (risk ratios for one category increase in NSAID use = 0.98-1.11, P-trends = 0.10-0.99) with incident BPH/LUTS. CONCLUSION: The findings obtained in the present study do not support a protective role for recent NSAID use in BPH/LUTS development. PMID- 22429767 TI - Giardia lamblia Nek1 and Nek2 kinases affect mitosis and excystation. AB - The NIMA-related serine/threonine kinases (Neks) function in the cell cycle and regulate ciliary and flagellar length. The Giardia lamblia genome encodes 198 Neks, of which 56 are predicted to be active. Here we believe that we report the first functional analysis of two G. lamblia Neks. The GlNek1 and GlNek2 kinase domains share 57% and 43% identity to the kinase domains of human Nek1 and Nek2, respectively. Both GlNeks are active in vitro, have dynamic relocalisation during the cell cycle, and are expressed throughout the life cycle, with GlNek1 being upregulated in cysts. Over-expression of inactive GlNek1 delays disassembly of the parental attachment disc and cytokinesis, whilst over-expression of either wild type GlNek1 or inactive mutant GlNek2 inhibits excystation. PMID- 22429768 TI - Effect of deer density on tick infestation of rodents and the hazard of tick borne encephalitis. II: population and infection models. AB - Tick-borne encephalitis is an emerging vector-borne zoonotic disease reported in several European and Asiatic countries with complex transmission routes that involve various vertebrate host species other than a tick vector. Understanding and quantifying the contribution of the different hosts involved in the TBE virus cycle is crucial in estimating the threshold conditions for virus emergence and spread. Some hosts, such as rodents, act both as feeding hosts for ticks and reservoirs of the infection. Other species, such as deer, provide important sources of blood for feeding ticks but they do not support TBE virus transmission, acting instead as dead-end (i.e., incompetent) hosts. Here, we introduce an eco-epidemiological model to explore the dynamics of tick populations and TBE virus infection in relation to the density of two key hosts. In particular, our aim is to validate and interpret in a robust theoretical framework the empirical findings regarding the effect of deer density on tick infestation on rodents and thus TBE virus occurrence from selected European foci. Model results show hump-shaped relationships between deer density and both feeding ticks on rodents and the basic reproduction number for TBE virus. This suggests that deer may act as tick amplifiers, but may also divert tick bites from competent hosts, thus diluting pathogen transmission. However, our model shows that the mechanism responsible for the dilution effect is more complex than the simple reduction of tick burden on competent hosts. Indeed, while the number of feeding ticks on rodents may increase with deer density, the proportion of blood meals on competent compared with incompetent hosts may decrease, triggering a decline in infection. As a consequence, using simply the number of ticks per rodent as a predictor of TBE transmission potential could be misleading if competent hosts share habitats with incompetent hosts. PMID- 22429769 TI - Phylogeny and evolution of the Piroplasmida as inferred from 18S rRNA sequences. AB - The order Piroplasmida consists of several genera of tick-borne parasites that infect mammals, and to a lesser extent birds, and are therefore of medical and economic importance. Despite their importance, considerable confusion exists concerning the relationship among piroplasmid species, specifically concerning the number of genera and the intergeneric relationships. To examine evolutionary relationships among piroplasmids, we conducted phylogenetic analyses of 192 18S rDNA sequences from the genera Theileria, Babesia and Cytauxzoon. Our analyses revealed eight clades potentially representing distinct genera, and we distinguish the Duncani Group and Microti Group as genetically distinct groups of species requiring detailed analysis of morphology and life-history to allow formal generic description. The piroplasmid phylogeny revealed considerable host diversity and limited host specificity, suggesting piroplasmids have undergone frequent host switches during their evolution. Our analyses provide the first reported evolutionary timescale for piroplasmids independent of the assumption of parasite-host cospeciation, which is invalid for piroplasmids. Evolutionary rate analyses revealed considerable substitution rate heterogeneity, which we attribute to host switching and diversification. Finally, we call for a comprehensive phylogenetic, morphological and life-history analysis for these medically relevant taxa to resolve relationships and understand host specificity. PMID- 22429770 TI - Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST), one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRalpha mutations) and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies) types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival. METHODS: This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P < 0.05 used to identify independent factors. RESULTS: Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRalpha mutations, and shorter survival times. The pediatric group (< age 18 at diagnosis) was also as previously reported with predominantly stomach tumors, females, wild-type GIST or SDH mutations, and extended survival. "Young adults" however formed a third group aged 18-35 at diagnosis, and were a clear mix of these two previously reported distinct sub types. CONCLUSIONS: Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each from a diverse real-world cohort. Additionally, these findings suggest that extra diligence be taken with "young adults" (aged 18-35 at diagnosis) as pediatric-type GIST may present well beyond adolescence, particularly as these distinct sub-types have different causes, and consequently respond differently to treatments. PMID- 22429771 TI - Substrate specificity of the recombinant alginate lyase from the marine bacteria Pseudomonas alginovora. AB - The gene coding for an alginate lyase from the marine bacteria Pseudomonas alginovora X017 was cloned and heterologously expressed in Escherichia coli strains. The protein was produced in inclusion bodies and the active form was obtained by applying a refolding protocol based upon dilution. The biochemical characterization was performed on the active, refolded form of the alginate lyase. The substrate specificity was monitored by NMR. The degradation products were size-fractioned by size exclusion chromatography. The fractions were subsequently analyzed by ESI-MS to determine the molecular weight of the compounds. The structures of the different oligosaccharides were then elucidated by NMR. The enzyme was shown to be only acting on M-M diads. No enzymatic hydrolysis occurred between M-MG, G-MM or G-MG blocks proving that the sequence accounting for the generated oligomers by enzymatic hydrolysis is M-MM. The unsaturated oligosaccharides produced by the alginate lyase were DeltaM, DeltaMM, DeltaMMM, and DeltaMMMM indicating that the minimum structure recognized by the enzyme is the M6 oligosaccharide. PMID- 22429772 TI - Light fluorous synthesis of glucosylated glycerol teichoic acids. AB - We here describe the synthesis of glucosylated teichoic acid (TA) fragments using two complementary fluorous scaffolds. The use of a perfluorooctylpropylsulfonylethyl (F-Pse) linker in combination with (glucosyl)glycerol phosphoramidite building blocks allows for the assembly of TA fragments with a terminal phosphate mono-ester, whereas the use of a perfluorooctylsuccinyl spacer delivers TA oligomers featuring a terminal alcohol functionality. These complementary linker systems have been developed because the nature of the TA chain terminus can play a role in the biological activity of the synthetic TAs. A novel alpha-glucosylated glycerolphosphoramidite building block is introduced to allow for a robust light fluorous synthetic protocol. PMID- 22429773 TI - An efficient synthesis of the polar part of sulfamisterin and its analogs. AB - An efficient synthesis of the polar part of sulfamisterin and its analogs starting from d-xylose is described. The corresponding allylic thiocyanates and trichloroacetimidates were subjected to aza-Claisen rearrangement that effectively generated a quaternary carbon having an amino group as one of the substituents. Subsequent functional group interconversions afforded the highly functionalized branched aminopolyol 29 that is expected to have the crucial application in the construction of sulfamisterin. On the other hand, the second diastereoisomer 34 would be transformed to 2-epi-congener. With respect to the appropriate stereochemical arrangement, the prepared polar segments 29 and 34 can also be utilized for the synthesis of mycestericins (E, G) and their analogs. PMID- 22429774 TI - Structure of the O-antigen of Budvicia aquatica 20186, a new bacterial polysaccharide that contains 3,6-dideoxy-4-C-[(S)-1-hydroxyethyl]-D-xylo-hexose (yersiniose A). AB - The following structure of the O-specific polysaccharide (O-antigen) of Budvicia aquatica 20186 was elucidated by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy: ->4)-alpha-L-Rhap-(1->3)-alpha-D-Galp-(1->2)-alpha-Yerp (1->3)-beta-D-GalpNAc-(1-> where Yer stands for 3,6-dideoxy-4-C-[(S)-1 hydroxyethyl]-D-xylo-hexose (yersiniose A). PMID- 22429775 TI - Augmented production of alginate oligosaccharides by the Pseudomonas mendocina NK 01 mutant. AB - Pseudomonas mendocina NK-01 can simultaneously synthesize medium-chain-length polyhydroxyalkanoate (PHA(MCL)) and alginate oligosaccharides (AO) from glucose under conditions of limited nitrogen. In this study, the PHA(MCL) synthesis pathway was blocked by a deletion of approximately 57% of the sequence of PHA synthase operon mediated by the suicide plasmid, pEX18TcC1ZC2Amp. Deletion of the PHA synthase operon in P. mendocina NK-01 was confirmed by polymerase chain reaction (PCR) and antibiotic resistance assays to form the gene knockout mutant, P. mendocina C7. Shake-flask and 30 L fermentor cultures of P. mendocina C7 showed a 2.21-fold and 2.64-fold accumulation of AO from glucose, respectively, compared with the wild-type strain. Mass spectrometry and gel permeation chromatography characterization revealed that P. mendocina C7 and P. mendocina NK 01 produced AO were identical in terms of monomer composition and average molecular weight (M(W)). Thus, the mutant P. mendocina C7 has potential use in large scale fermentation of AO. Furthermore, it was demonstrated that the PHA(MCL) and AO synthesis pathways compete for the use of carbon sources in P. mendocina NK-01. PMID- 22429776 TI - Insecticide susceptibility status of Phlebotomus (Paraphlebotomus) sergenti and Phlebotomus (Phlebotomus) papatasi in endemic foci of cutaneous leishmaniasis in Morocco. AB - BACKGROUND: In Morocco, cutaneous leishmaniasis is transmitted by Phlebotomus sergenti and Ph. papatasi. Vector control is mainly based on environmental management but indoor residual spraying with synthetic pyrethroids is applied in many foci of Leishmania tropica. However, the levels and distribution of sandfly susceptibility to insecticides currently used has not been studied yet. Hence, this study was undertaken to establish the susceptibility status of Ph. sergenti and Ph. papatasi to lambdacyhalothrin, DDT and malathion. METHODS: The insecticide susceptibility status of Ph. sergenti and Ph. papatasi was assessed during 2011, following the standard WHO technique based on discriminating dosage. A series of twenty-five susceptibility tests were carried out on wild populations of Ph. sergenti and Ph. papatasi collected by CDC light traps from seven villages in six different provinces. Knockdown rates (KDT) were noted at 5 min intervals during the exposure to DDT and to lambdacyhalothrin. After one hour of exposure, sandflies were transferred to the observation tubes for 24 hours. After this period, mortality rate was calculated. Data were analyzed by Probit analysis program to determine the knockdown time 50% and 90% (KDT50 and KDT90) values. RESULTS: Study results showed that Ph.sergenti and Ph. papatasi were susceptible to all insecticides tested. Comparison of KDT values showed a clear difference between the insecticide knockdown effect in studied villages. This effect was lower in areas subject to high selective public health insecticide pressure in the framework of malaria or leishmaniasis control. CONCLUSION: Phlebotomus sergenti and Ph. papatasi are susceptible to the insecticides tested in the seven studied villages but they showed a low knockdown effect in Azilal, Chichaoua and Settat. Therefore, a study of insecticide susceptibility of these vectors in other foci of leishmaniasis is recommended and the level of their susceptibility should be regularly monitored. PMID- 22429777 TI - Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination. AB - The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24 100 +/- 3560 vs 108 +/- 25 ng/mL, respectively; P < 0.001), as was the area under the concentration-time curve from 0 to 48 h (191 000 +/- 32 100 vs 1500 +/- 108 ng.h/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation. PMID- 22429778 TI - Expression of 12 cytokines in aqueous humour of uveal melanoma before and after combined Ruthenium-106 brachytherapy and transpupillary thermotherapy. AB - PURPOSE: To determine the aqueous humour levels of 12 cytokines in eyes with uveal melanoma and whether their expression changes after combined Ru-106 brachytherapy and transpupillary thermotherapy (TTT). METHODS: Aqueous humour samples were collected from 20 patients with previously untreated uveal melanoma undergoing combined Ru-106 brachytherapy and TTT, both at the time of plaque placement and removal. Using multiplex biochip array technology, 12 different cytokines were measured, including interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, epidermal growth factor (EGF) and monocyte chemoattractant protein (MCP)-1. Aqueous humour from 20 patients undergoing cataract surgery was used as control. RESULTS: IL-6, IL-8, IFN-gamma and MCP-1 were highly expressed in uveal melanoma, whereas IL-2, IL-10 and TNF- alpha were low in expression. There was a positive correlation between tumour height and IL-8 level (p = 0.020). Vascular endothelial growth factor tends to be highly expressed in melanoma-containing eyes (p = 0.056). Levels of IL-6, IL-8 and IL-1beta increased after the mean 117 +/- 38 hrs of brachytherapy and adjunctive TTT with a tumour apex dose of 61 +/- 28 Gy and a scleral contact dose of 786 +/- 226 Gy. Increase in levels of IL-6 (p = 0.003) and IL-8 (p = 0.046) positively correlated with scleral contact dose. CONCLUSIONS: Cytokines such as IL-6, IL-8, IFN-gamma and MCP-1 may be implicated in the progression of uveal melanoma. Ocular irradiation from a Ru-106 plaque promoted an increase in the levels of IL-6, IL-8 and IL-1beta, modulation of which could be useful in managing radiation-related side effects. PMID- 22429779 TI - Prenatal stress exposure hypothesis for infantile spasms. AB - Infantile spasms (IS) are an age-specific epileptic syndrome associated with diverse etiological factors. In recent years, several hypotheses and animal models have been proposed to explain the pathogenesis of IS, but none has elucidated the pathophysiology of IS. In the current case-control study, prenatal stress degree was identified to be higher among the mothers of IS patients than those among the control group. The onset risk of IS increased with the degree of prenatal stress within a certain range. We have recently exposed pregnant rats to forced cold swimming and have given intraperitoneal injection of N-methyl-d aspartate (NMDA) to rat pups with prenatal stress exposure. Prenatal stress exposure was found to alter the hormonal levels and neurotransmitter receptor expression of developing rats, sensitizing rat pups to develop NMDA-induced spasms and rendering the spasms to be sensitive to adrenocorticotropic hormone therapy. The studies above indicate that prenatal stress plays an important role in the onset of IS. Based on previous hypotheses and the current findings, we propose a prenatal stress exposure hypothesis for IS (also called Zou's hypothesis). PMID- 22429780 TI - Mentholated cigarettes and smoking-related cancers revisited: an ecologic examination. AB - The US Food and Drug Administration is assessing whether menthol should be banned as an additive to cigarettes. An important part of this determination concerns the health effects of mentholated relative to non-mentholated cigarettes. We examined the ecologic association between sales of mentholated cigarettes for the period 1950-2007, menthol preference by race and sex, and incidence rates of four tobacco-related cancers during 1973-2007. Total sales of mentholated cigarettes (market share) increased from about 3% in 1950 to slightly less than 30% in 1980 and remained fairly stable thereafter. Additional data show consistently that, compared to White smokers, Black smokers favor mentholated cigarettes by roughly a 3-fold margin. Differences in the incidence of lung cancer, squamous cell cancer of the esophagus, oropharyngeal cancer, and laryngeal cancer by race and sex and trends over a 35-year period, during which menthol sales were relatively stable and during which Black smokers were much more likely to smoke mentholated cigarettes compared to Whites, are not consistent with a large contribution of menthol, over and above the effect of smoking per se. PMID- 22429781 TI - Salicylic acid is involved in the regulation of starvation stress-induced flowering in Lemna paucicostata. AB - The short-day plant, Lemna paucicostata (synonym Lemna aequinoctialis), was induced to flower when cultured in tap water without any additional nutrition under non-inductive long-day conditions. Flowering occurred in all three of the tested strains, and strain 6746 was the most sensitive to the starvation stress conditions. For each strain, the stress-induced flowering response was weaker than that induced by short-day treatment, and the stress-induced flowering of strain 6746 was completely inhibited by aminooxyacetic acid and l-2-aminooxy-3 phenylpropionic acid, which are inhibitors of phenylalanine ammonia-lyase. Significantly higher amounts of endogenous salicylic acid (SA) were detected in the fronds that flowered under the poor-nutrition conditions than in the vegetative fronds cultured under nutrition conditions, and exogenously applied SA promoted the flowering response. The results indicate that endogenous SA plays a role in the regulation of stress-induced flowering. PMID- 22429782 TI - Influence of the type of phospholipid head and of the conformation of the polyelectrolyte on the growth of calcium carbonate thin films on LB/LbL matrices. AB - Calcium carbonate is one of the most important biominerals, and it is the main constituent of pearls, seashells, and teeth. The in vitro crystallization of calcium carbonate using different organic matrices as templates has been reported. In this work, the growth of calcium carbonate thin films on special organic matrices consisting of layer-by-layer (LbL) polyelectrolyte films deposited on a pre-formed phospholipid Langmuir-Blodgett (LB) film has been studied. Two types of randomly coiled polyelectrolytes have been used: lambda carrageenan and poly(acrylic acid). A precoating comprised of LB films has been prepared by employing a negatively charged phospholipid, the sodium salt of dimyristoilphosphatidyl acid (DMPA), or a zwitterionic phospholipid, namely dimyristoilphosphatidylethanolamine (DMPE). This approach resulted in the formation of particulate calcium carbonate continuous films with different morphologies, particle sizes, and roughness, as revealed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The crystalline structure of the calcium carbonate particles was analyzed by Raman spectroscopy. The randomly coiled conformation of the polyelectrolytes seems to be the main reason for the formation of continuous films rather than CaCO(3) isolated crystals. PMID- 22429783 TI - Phase behavior study of amphiphilic drugs: effect of pharmaceutical excipients. AB - Effect of various additives, like conventional as well as gemini cationic surfactants, non-ionic surfactants, hydrotropes, bile salts, fatty acid salts and beta-cyclodextrin on the cloud point (CP) of two amphiphilic drugs promethazine (PMT) and promazine (PMZ) hydrochlorides was investigated. These additives are generally used as pharmaceutical excipients. The CP variation with the additive concentration has been determined and the energetic parameters of the process have been estimated. All the surfactants increase the CP, while hydrotropes, bile salts and fatty acid salts, when added in low concentrations, increase or decrease, depending the added concentration, increase or decrease the CP. beta cyclodextrin is found to decrease the CP of the drug solutions. PMID- 22429784 TI - Temperature-dependent structural changes on DDAB surfactant assemblies evidenced by energy dispersive X-ray diffraction and dynamic light scattering. AB - Cationic amphiphile DDAB (dimethyl-dioctadecyl-ammonium-bromide) can spontaneously form water-dispersed and solid supported mimicking biomembrane structures as well as valuable DNA delivery vehicles whose shape, stability and transfection efficiency can be easily optimized on varying temperature, water content and chemical composition. In this framework, disclosing the thermotropic behavior of DDAB assemblies can be considered as an essential step in conceiving and developing new non-viral vector systems. Our work has been focused primarily on understanding the mesophase structure of silicon supported DDAB thin film on varying temperature at constant relative humidity by energy dispersive X-ray diffraction (EDXD). Diffraction results have then been employed in providing a more comprehensive dynamic light scattering (DLS) analysis of corresponding thermotropic water dispersed vesicles made up of DDAB alone and in combination with helper lecithin DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) liposomes. We found that above 55 degrees C silicon-supported DDAB films undergo a significant thinning effect, whilst DDAB-water vesicles exhibit a reduction in size polydispersity. Upon cooling to 25 degrees C a distinct silicon supported DDAB mesophase, exhibiting a relative humidity-dependent spacing, has been pointed out, and modeled in terms of a lyotropic metastable gel-crystalline phase.DDAB/DOPC-water vesicles show a temperature-dependent switching in size distribution, leading to promising biomedical applications. PMID- 22429785 TI - Low fibronectin concentration overcompensates for reduced initial fibroblasts adhesion to a nanoscale topography: single-cell force spectroscopy. AB - Using single-cell force spectroscopy, we compared the initial adhesion of L929 fibroblasts to planar and nanostructured silicon substrates as a function of fibronectin concentration. The nanostructures were periodically grooved with a symmetric groove-summit period of 180 nm and a groove depth of 120 nm. Cell adhesion strength to the bare nanostructure was lower (79%+/- 13%) than to the planar substrate, which we attribute to reduced contact area. After pre incubation with a low fibronectin concentration (5 MUg/ml) the adhesion strengths to both surfaces increased, with adhesion strength on the nanostructure outweighing that of the planar substrate by 133%+/- 14%. At a high fibronectin concentration (25 MUg/ml) the adhesion strengths on both surfaces further increased and showed wide variations. In parallel, the nanostructure lost its clear advantage over the planar substrate. Our results demonstrate that cell adhesion is influenced by substrate topography and fibronectin, which mediate the interplay between specific interactions, non-specific interactions, and cell mechanics. Two parallel processes govern the initial adhesion strength: the detachment of the cell body from the substrate and the extraction of tethers from the cell membrane. The duration of the latter process is determined by tether lifetimes, and is a major contributor to the overall work required for cell substrate detachment. Cell body detachment and tether lifetimes are affected by surface topography and may be strongly modulated by the presence of adsorbed proteins, whereas the tether extraction forces remained unchanged by these factors. PMID- 22429786 TI - Vaginal microbicides to prevent human immunodeficiency virus infection in women: perspectives on the female genital tract, sexual maturity and mucosal inflammation. AB - Topically applied vaginal microbicides to protect against human immunodeficiency (HIV) virus infection offer an important female-controlled prevention strategy. Microbicides have been in development for more than 2 decades, and have included various agents that disrupt cellular and microbial membranes (surfactants), restore the natural acidic protective pH of the vagina (acid buffers), and those that interfere with interactions between HIV envelope proteins and cellular receptors (anionic polymers). Although none of these candidate microbicides have shown significant protection against HIV in clinical trials, a topical gel, including the antiretroviral drug tenofovir (TFV) 1% was the first microbicide to be tested to show some protection against HIV infection. This review explores the effect of female genital tract biology and anatomy, mucosal inflammation, and age on the effectiveness of microbicides to prevent HIV infection. PMID- 22429787 TI - Best timing for energy provision during critical illness. PMID- 22429788 TI - Assessment of the genetic diversity of the Tunisian citrus rootstock germplasm. AB - BACKGROUND: Citrus represents a substantial income for farmers in the Mediterranean Basin. However, the Mediterranean citrus industry faces increasing biotic and abiotic constraints. Therefore the breeding and selection of new rootstocks are now of the utmost importance. In Tunisia, in addition to sour orange, the most widespread traditional rootstock of the Mediterranean area, other citrus rootstocks and well adapted to local environmental conditions, are traditionally used and should be important genetic resources for breeding. To characterize the diversity of Tunisian citrus rootstocks, two hundred and one local accessions belonging to four facultative apomictic species (C. aurantium, sour orange; C. sinensis, orange; C. limon, lemon; and C. aurantifolia, lime) were collected and genotyped using 20 nuclear SSR markers and four indel mitochondrial markers. Multi-locus genotypes (MLGs) were compared to references from French and Spanish collections. RESULTS: The differentiation of the four varietal groups was well-marked. The groups displayed a relatively high allelic diversity, primarily due to very high heterozygosity. Sixteen distinct MLGs were identified. Ten of these were noted in sour oranges. However, the majority of the analysed sour orange accessions corresponded with only two MLGs, differentiated by a single allele, likely due to a mutation. The most frequent MLG is shared with the reference sour oranges. No polymorphism was found within the sweet orange group. Two MLGs, differentiated by a single locus, were noted in lemon. The predominant MLG was shared with the reference lemons. Limes were represented by three genotypes. Two corresponded to the 'Mexican lime' and 'limonette de Marrakech' references. The MLG of 'Chiiri' lime was unique. CONCLUSIONS: The Tunisian citrus rootstock genetic diversity is predominantly due to high heterozygosity and differentiation between the four varietal groups. The phenotypic diversity within the varietal groups has resulted from multiple introductions, somatic mutations and rare sexual recombination events. Finally, this diversity study enabled the identification of a core sample of accessions for further physiological and agronomical evaluations. These core accessions will be integrated into citrus rootstock breeding programs for the Mediterranean Basin. PMID- 22429789 TI - Rates of visual field progression in distinct optic disc phenotypes. AB - BACKGROUND: To determine if optic disc phenotype is correlated with the rate of glaucomatous visual field progression. DESIGN: Retrospective cohort. PARTICIPANTS OR SAMPLES: Treated glaucoma patients. METHODS: The optic disc stereophotographs of glaucoma patients were reviewed by two investigators masked to all clinical and perimetric data. Each disc was classified as focal ischaemic, myopic, senile sclerotic and generalized enlargement. Visual field progression (defined as at least two adjacent test points in the same hemifield progressing by more than 1.0 dB/year at P < 0.01) was evaluated using automated pointwise linear regression. MAIN OUTCOME MEASURES: Association between optic disc phenotypes and other clinical variables and rates of visual field progression. RESULTS: 264 optic disc stereophotographs (127 generalized enlargement, 41 focal ischaemic, 54 myopic and 42 senile sclerotic) were evaluated. In the univariate analyses, it was found that patients with senile sclerotic discs were older (p = 0.002) and those with generalized enlargement had better baseline visual field mean deviation (p < 0.001) and higher intraocular pressure (p = 0.006) compared with the other groups. More disc haemorrhages were detected in the focal ischaemic and senile sclerotic groups (p = 0.010). After adjusting for other risk factors (intraocular pressure, age, central corneal thickness, disc haemorrhage), there were no differences among groups regarding the risk (p = 0.58) and velocity (p = 0.21) of visual field progression. CONCLUSIONS: Visual field progression was similar among the four optic disc phenotypes in treated glaucoma after adjusting for other known risk factors. The division of disc appearance into clinical phenotypes does not appear to provide independent information regarding the risk of progression in clinical practice. PMID- 22429790 TI - Extensive proteolysis of head and inner body proteins by a morphogenetic protease in the giant Pseudomonas aeruginosa phage phiKZ. AB - Encased within the 280 kb genome in the capsid of the giant myovirus phiKZ is an unusual cylindrical proteinaceous 'inner body' of highly ordered structure. We present here mass spectrometry, bioinformatic and biochemical studies that reveal novel information about the phiKZ head and the complex inner body. The identification of 39 cleavage sites in 19 phiKZ head proteins indicates cleavage of many prohead proteins forms a major morphogenetic step in phiKZ head maturation. The phiKZ head protease, gp175, is newly identified here by a bioinformatics approach, as confirmed by a protein expression assay. Gp175 is distantly related to T4 gp21 and recognizes and cleaves head precursors at related but distinct S/A/G-X-E recognition sites. Within the phiKZ head there are six high-copy-number proteins that are probable major components of the inner body. The molecular weights of five of these proteins are reduced 35-65% by cleavages making their mature form similar (26-31 kDa), while their precursors are dissimilar (36-88 kDa). Together the six abundant proteins sum to the estimated mass of the inner body (15-20 MDa). The identification of these proteins is important for future studies on the composition and function of the inner body. PMID- 22429791 TI - Paternal investment and status-related child outcomes: timing of father's death affects offspring success. AB - Recent work in human behavioural ecology has suggested that analyses focusing on early childhood may underestimate the importance of paternal investment to child outcomes since such investment may not become crucial until adolescence or beyond. This may be especially important in societies with a heritable component to status, as later investment by fathers may be more strongly related to a child's adult status than early forms of parental investment that affect child survival and child health. In such circumstances, the death or absence of a father may have profoundly negative effects on the adult outcomes of his children that cannot be easily compensated for by the investment of mothers or other relatives. This proposition is tested using a multigenerational dataset from Bangalore, India, containing information on paternal mortality as well as several child outcomes dependent on parental investment during adolescence and young adulthood. The paper examines the effects of paternal death, and the timing of paternal death, on a child's education, adult income, age at marriage and the amount spent on his or her marriage, along with similar characteristics of spouses. Results indicate that a father's death has a negative impact on child outcomes, and that, in contrast to some findings in the literature on father absence, the effects of paternal death are strongest for children who lose their father in late childhood or adolescence. PMID- 22429792 TI - Integrated programs for mothers with substance abuse issues: A systematic review of studies reporting on parenting outcomes. AB - BACKGROUND: Integrated treatment programs (those that include on-site pregnancy-, parenting-, or child-related services with addiction services) were developed to break the intergenerational cycle of addiction, dysfunctional parenting, and poor outcomes for mothers and children, yet there has been no systematic review of studies of parenting outcomes. OBJECTIVES: As part of larger systematic review to examine the effectiveness of integrated programs for mothers with substance abuse issues, we performed a systematic review of studies published from 1990 to 2011 with data on parenting outcomes. METHODS: Literature search strategies included online bibliographic database searches, checking printed sources, and requests to researchers. Studies were included if all participants were mothers with substance abuse problems at baseline, the treatment program included at least one specific substance use treatment and at least one parenting or child service, and there were quantitative data on parenting outcomes. We summarized data on parenting skills and capacity outcomes. RESULTS: There were 24 cohort studies, 3 quasi-experimental studies, and 4 randomized trials. In the three randomized trials comparing integrated programs to addiction treatment-as-usual (N = 419), most improvements in parenting skills favored integrated programs and most effect sizes indicated that this advantage was small, ds = -0.02 to 0.94. Results for child protection services involvement did not differ by group. In the three studies that examined factors associated with treatment effects, parenting improvements were associated with attachment-based parenting interventions, children residing in the treatment facility, and improvements in maternal mental health. CONCLUSIONS: This is the first systematic review of studies evaluating the effectiveness of integrated programs on parenting. The limited available evidence supports integrated programs, as findings suggest that they are associated with improvements in parenting skills. However, more research is required comparing integrated programs to addiction treatment-as-usual. This review highlights the need for improved methodology, study quality, and reporting to improve our understanding of how best to meet the parenting needs of women with substance abuse issues. PMID- 22429794 TI - A case-control analysis on the association between erectile dysfunction and sudden sensorineural hearing loss in Taiwan. AB - INTRODUCTION: Although the cause of sudden sensorineural hearing loss (SSNHL) is yet to be elucidated, many theories have been proposed regarding potentially contributory etiologies. One increasingly well-supported theory purports an underlying vascular pathomechanism. If this is the case, SSNHL may also associate with conditions comorbid with vascular diseases, such as erectile dysfunction (ED). However, no studies to date have investigated the association between ED and SSNHL. AIM: This study set out to estimate a putative association between ED and having been previously diagnosed with SSNHL using a population-based dataset with a case-control design. METHODS: This study used administrative claim data from the Taiwan National Health Insurance program. We identified 4,504 patients with ED as the study group and randomly selected 22,520 patients as the comparison group. Conditional logistic regression was used to examine the association between ED and having previously received a diagnosis of SSNHL. MAIN OUTCOME MEASURE: The prevalence and risk of SSNHL between cases and controls were calculated. RESULTS: Of the sampled patients, 41 (0.15%) had been diagnosed with SSNHL before the index date; 22 (0.49% of the cases) were from the study group and 19 (0.08% of controls) were from the control group. Conditional logistic regression analysis revealed that after adjusting for the patient's monthly income, geographic location, hypertension, diabetes, hyperlipidemia, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome status, patients with ED were more likely than controls to have been diagnosed with SSNHL before the index date (odds ratio = 6.06, 95% confidence interval = 3.25-11.29). CONCLUSIONS: There was an association between ED and prior SSNHL. The results of this study add to the evidence supporting an underlying vascular pathomechanism regarding the development of SSNHL and highlight a need for clinicians dealing with SSNHL patients to be alert to the development of ED. PMID- 22429795 TI - Establishment and characterization of a differentiated epithelial cell culture model derived from the porcine cervix uteri. AB - BACKGROUND: Cervical uterine epithelial cells maintain a physiological and pathogen-free milieu in the female mammalian reproductive tract and are involved in sperm-epithelium interaction. Easily accessible, differentiated model systems of the cervical epithelium are not yet available to elucidate the underlying molecular mechanisms within these highly specialized cells. Therefore, the aim of the study was to establish a cell culture of the porcine cervical epithelium representing in vivo-like properties of the tissue. RESULTS: We tested different isolation methods and culture conditions and validated purity of the cultured cells by immunohistochemistry against keratins. We could reproducibly culture pure epithelial cells from cervical tissue explants. Based on a morphology score and the WST-1 Proliferation Assay, we optimized the growth medium composition. Primary porcine cervical cells performed best in conditioned Ham's F-12, containing 10% FCS, EGF and insulin. After cultivation in an air-liquid interface for three weeks, the cells showed a discontinuously multilayered phenotype. Finally, differentiation was validated via immunohistochemistry against beta catenin. Mucopolysaccharide production could be shown via alcian blue staining. CONCLUSIONS: We provide the first suitable protocol to establish a differentiated porcine epithelial model of the cervix uteri, based on easily accessible cells using slaughterhouse material. PMID- 22429796 TI - End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome. AB - INTRODUCTION: Genetic variants represent benign single-nucleotide polymorphisms, disease causing mutations or variants of unknown significance (VUS). Resting, exercise, and recovery QTc intervals have been utilized to detect long-QT syndrome (LQTS) mutations. We sought to provide clinical data that may assist in classifying the presented VUS as disease causing/benign and to determine whether resting and/or end-recovery QT parameters can evaluate the significance of VUS. METHODS AND RESULTS: Twenty-six patients with a VUS in genes associated with LQTS (15 females, age 38 +/- 16 years) and 26 age and gender matched controls (age 37 +/- 20 years) were included. There were 10 VUS (5 KCNQ1, 4 KCNH2, 1 KCNE1) in 12 families. All but 1 VUS was associated with sudden cardiac death (SCD), aborted SCD or Torsade de pointes. A Schwartz score of >=3.5 was observed in at least 1 family member with each VUS. Resting QTc was marginally longer in VUS patients compared with controls (458 +/- 48 vs 437 +/- 25, P = 0.052). A prolonged resting QTc (>470 ms males, >480 ms females) identified 6 VUS carriers and 1 control. VUS carriers had a substantially longer end-recovery QTc (502 +/- 68 vs 427 +/- 17, P < 0.01) with an end-recovery QTc > 445 ms in 20/26 VUS patients compared to 2/26 controls (P < 0.01). The area under the receiver operating characteristic curve for resting QTc was 0.68 (95% CI, 0.53-0.83, P = 0.03) compared to the end recovery QTc of 0.88 (95% CI, 0.76-0.99, P < 0.0001). CONCLUSION: Variants in the current study appear to be disease causing. The end-recovery QTc is a useful metric when interpreting LQT VUS. PMID- 22429797 TI - Ex vivo expansion of cord blood progenitors impairs their short-term and long term repopulating activity associated with transcriptional dysregulation of signalling networks. AB - OBJECTIVES: Cord blood (CB) has been established to be an alternative source of haematopoietic stem/progenitor cells (HPC) for transplantation. The number of HPC per CB unit is limited, which results in engraftment delay. Ex vivo expansion of HPC improvement must overcome this. MATERIALS AND METHODS: Flow cytometry was used to extensively phenotype HPC pre- and post-expansion and CFDA-SE staining was used to track cell divisions. The NSG mouse model was employed in transplantation studies to determine long and short term repopulation in human cells. Gene array analysis was used to evaluate signalling pathways regulated following ex vivo expansion of HPC. RESULTS: expansion of CD34(+) HPC impaired their regenerative function. In this xenograft transplantation model we showed that repopulating activity of CB cells declined following expansion. Expanded HPC had delayed engraftment at early and late stages post-transplant. High resolution division tracking revealed that the cultured HPC had reduced expansion and self renewal probability and increased differentiation rate compared to non-expanded cells. Gene expression analysis exposed significant modulation of a complex network of genes and pathways that normally maintain HPC proliferation and limit their differentiation. CONCLUSIONS: The decline in short-term engraftment is consistent with the loss of rapid SCID repopulating ability r(SRA) by expanded CD34(+) CD38(+) cells recently reported. Our data raise concerns for future clinical applications of expanded HPC alone in transplantation. PMID- 22429798 TI - Trends in incidence and outcomes of revision total hip arthroplasty in Spain: a population based study. AB - BACKGROUND: To analyze changes in incidence and outcomes of patients undergoing revision total hip arthroplasty (RTHA) over an 8-year study period in Spain. METHODS: We selected all surgical admissions in individuals aged >= 40 years who underwent RTHA (ICD-9-CM procedure code 81.53) between 2001 and 2008 from the Spanish National Hospital Discharge Database. Age- and sex-specific incidence rates, Charlson co-morbidity index, length of stay (LOS), costs and in-hospital mortality (IHM) were estimated for each year. Multivariate analyses were conducted to asses time trends. RESULTS: 32,280 discharges of patients (13, 391 men/18, 889 women) having undergone RTHA were identified. Overall crude incidence showed a small but significant increase from 20.2 to 21.8 RTHA per 100, 000 inhabitants from 2001 to 2008 (p < 0.01).The incidence increased for men (17.7 to 19.8 in 2008) but did not vary for women (22.3 in 2001 and 22.2 in 2008). Greater increments were observed in patients older than 84 years and in the age group 75 84. In 2001, 19% of RTHA patients had a Charlson Index >= 1 and this proportion rose to 24.6% in 2008 (p < 0.001). The ratio RTHA/THA remained stable and around 20% in Spain along the entire period. The crude overall in-hospital mortality (IHM) increased from 1.16% in 2001 to 1.77% (p = 0.025) in 2008. For both sexes the risk of death was higher with age, with the highest mortality rates found among those aged 85 or over. After multivariate analysis no change was observed in IHM over time. The mean inflation adjusted cost per patient increased by 78.3%, from 9, 375 to 16, 715 Euros from 2001 to 2008.After controlling for possible confounders using Poisson regression models, we observed that the incidence of RTHA hospitalizations significantly increased for men and women over the period 2001 to 2008 (IRR 1.10, 95% CI 1.03-1.18 and 1.08, 95% CI 1.02-1.14 respectively). CONCLUSIONS: The crude incidence of RTHA in Spain showed a small but significant increase from 2001 to 2008 with concomitant reductions in LOS, significant increase in co-morbidities and cost per patient. PMID- 22429799 TI - Robotic paediatric urology. AB - What's known on the subject? and What does the study add? Robot assisted laparoscopic surgery (RALS) is slowly gaining acceptance in the field of paediatric urology. Accumulating data on safety and efficacy when performing paediatric robotic urologic procedures has led paediatric urologists to gradually embrace increasingly more complex reconstructive surgeries. Indeed, the unique and delicate movements generated by the robotic system make this technology ideal for children who often require reconstructive procedures. We critically review the current role of RALS in paediatric urology and to analyse the published data, with a special emphasis on the most common applications. We also propose a structured plan to expedite training and the surgical 'learning curve'. OBJECTIVES: To critically review the current role of robot-assisted laparoscopic surgery (RALS) in paediatric urology and to analyse the published data, with a special emphasis on the most common applications. One of the greatest benefits of RALS has been the ability to truly spread the application of minimally invasive surgery to paediatric surgical patients. The unique attributes of the robotic interface make this technology ideal for children with congenital anomalies, who often require reconstructive procedures. We also propose a structured plan to expedite training and the surgical 'learning curve'. PATIENTS AND METHODS: Currently, almost all urological surgical procedures in children have been performed with the assistance of the robotic interface. The most commonly performed procedures include pyeloplasty, nephrectomy/hemi-nephrectomy and surgery for vesico-ureteric reflux. Initial series of bladder augmentation and appendicovesicostomy are available. RESULTS: Initial results with RALS are encouraging and have shown safety similar to open procedures, and outcomes at least equivalent to standard laparoscopy. Accumulating data have consistently shown that postoperative analgesia requirements and overall hospital stay are decreased. However, operative durations are significantly longer than their open counterparts, but this is decreasing as experience accumulates. CONCLUSIONS: RALS is already part of paediatric urological surgery. Larger single-institution case series and comparative studies with the open approach and multi-institutional meta-analyses will help to identify the benefits of RALS in paediatric urology. PMID- 22429802 TI - Radiotherapy studies and extra-nodal non-Hodgkin lymphomas, progress and challenges. AB - Extra-nodal lymphomas may arise in any organ, and different histological subtypes occur in distinct patterns. Prognosis and treatment depend not only on the histological subtype and disease extent, but also on the particular involved extra-nodal organ. The clinical course and response to treatment for the more common extra-nodal organs, e.g. stomach, Waldeyer's ring, skin and brain, are fairly well known and show significant variation. A few randomised trials have been carried out testing the role of radiotherapy in these lymphomas. However, for most extra-nodal lymphomas, randomised trials have not been carried out, and treatment decisions are made on small patient series and extrapolations from nodal lymphomas. Hopefully, wide international collaboration will make controlled clinical trials possible in the less common extra-nodal lymphomas. Modern highly conformal radiotherapy allows better coverage of extra-nodal lymphomatous involvement with better sparing of normal tissues. The necessary radiation doses and volumes need to be defined for the different extra-nodal lymphoma entities. The challenge is to optimise the use of radiotherapy in the modern multimodality treatment of extra-nodal lymphomas. PMID- 22429801 TI - EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. AB - BACKGROUND: The epithelial to mesenchymal transition (EMT) is a molecular process through which an epithelial cell undergoes transdifferentiation into a mesenchymal phenotype. The role of EMT in embryogenesis is well-characterized and increasing evidence suggests that elements of the transition may be important in other processes, including metastasis and drug resistance in various different cancers. METHODS: Agilent 4 * 44 K whole human genome arrays and selected reaction monitoring mass spectrometry were used to investigate mRNA and protein expression in A2780 cisplatin sensitive and resistant cell lines. Invasion and migration were assessed using Boyden chamber assays. Gene knockdown of snail and slug was done using targeted siRNA. Clinical relevance of the EMT pathway was assessed in a cohort of primary ovarian tumours using data from Affymetrix GeneChip Human Genome U133 plus 2.0 arrays. RESULTS: Morphological and phenotypic hallmarks of EMT were identified in the chemoresistant cells. Subsequent gene expression profiling revealed upregulation of EMT-related transcription factors including snail, slug, twist2 and zeb2. Proteomic analysis demonstrated up regulation of Snail and Slug as well as the mesenchymal marker Vimentin, and down regulation of E-cadherin, an epithelial marker. By reducing expression of snail and slug, the mesenchymal phenotype was largely reversed and cells were resensitized to cisplatin. Finally, gene expression data from primary tumours mirrored the finding that an EMT-like pathway is activated in resistant tumours relative to sensitive tumours, suggesting that the involvement of this transition may not be limited to in vitro drug effects. CONCLUSIONS: This work strongly suggests that genes associated with EMT may play a significant role in cisplatin resistance in ovarian cancer, therefore potentially leading to the development of predictive biomarkers of drug response or novel therapeutic strategies for overcoming drug resistance. PMID- 22429803 TI - Do all the consumers accept marbling in the same way? The relationship between eating and visual acceptability of pork with different intramuscular fat content. AB - Several reports show that intramuscular fat (IMF) and/or marbling affect the sensory acceptability of meat. The aim of the present work was to (1) investigate using Spanish consumers the eating and visual acceptability of pork with different levels of IMF, (2) understand more about this acceptability by studying segments of consumers and (3) determine which fresh pork characteristics are important at the point of purchase. Loin section (n = 40) were sorted into four IMF groups: 0.96 +/- 0.30% (G1), 2.11 +/- 0.07% (G2), 3.72 +/- 0.26% (G3), and 5.78 +/- 0.19% (G4). Consumers (n = 200) evaluated the acceptability, tenderness and juiciness of cooked loin chops from each IMF group and then ranked raw chops according to visual preference. Two groups of consumers--'lean loin lovers' (55.5%) and 'marbled loin lovers' (44.5%)--were identified based on their visual preferences; however, according to their eating acceptability scores, all the consumers preferred loins with higher IMF levels. Accordingly, the minimum IMF content recommended to ensure a good taste is between 2.2% and 3.4%. PMID- 22429804 TI - Application of the SPE reversed phase HPLC/MS technique to determine vitamin B12 bio-active forms in beef. AB - Vitamin B12 is an animal origin nutrient of a substantial importance in human diet. Its concentration in foodstuffs is low and its chemical forms are diverse, which significantly hampers its precise determination. The determination method of choice is HPLC (high performance liquid chromatography) coupled with inductively-coupled-plasma mass spectrometry (ICP-MS). The main disadvantage of this method is high instrumentation cost and complexity of handling. The aim of this work was to develop a novel approach for determination of vitamin B12 bio active forms in beef and beef liver. The proposed method comprises the following steps: (i) vitamin B12 is cleaved off from peptides using thermal denaturation in a weakly acidic environment; (ii) sample is cleaned-up using liquid-liquid extraction and reversed phase solid phase extraction; and finally (iii) vitamin B12 is determined using HPLC and single-quadrupole mass spectrometer with ESI source. Vitamin B12 concentrations in various beef meats were in the 2.84-3.95 MUg 100g(-1) range. Average B12 concentration in beef liver was 153,60 MUg 100g( 1) (n = 15). Major forms of B12 present in beef meat include adenosine cobalamin (AdoCbl) and in smaller quantities hydroxycobalamin (OHCbl). Major forms of vitamin B12 present in beef liver include OHCbl (48.2%), AdoCbl (33.8%), methylocobalamin (MeCbl, 16.3%), and cyanocobalamin (CNCbl, 1.7%). Thermal treatment noticeably decreases B12 the content in meat. Depending on conditions of treatment, B12 concentrations in the 1.04-2.20 MUg 100g(-1) range were found in processed meats. PMID- 22429800 TI - Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE. AB - BACKGROUND: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. OBJECTIVES: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). PATIENTS/METHODS: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). RESULTS: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. CONCLUSIONS: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles. PMID- 22429805 TI - Genomic survey, expression profile and co-expression network analysis of OsWD40 family in rice. AB - BACKGROUND: WD40 proteins represent a large family in eukaryotes, which have been involved in a broad spectrum of crucial functions. Systematic characterization and co-expression analysis of OsWD40 genes enable us to understand the networks of the WD40 proteins and their biological processes and gene functions in rice. RESULTS: In this study, we identify and analyze 200 potential OsWD40 genes in rice, describing their gene structures, genome localizations, and evolutionary relationship of each member. Expression profiles covering the whole life cycle in rice has revealed that transcripts of OsWD40 were accumulated differentially during vegetative and reproductive development and preferentially up or down regulated in different tissues. Under phytohormone treatments, 25 OsWD40 genes were differentially expressed with treatments of one or more of the phytohormone NAA, KT, or GA3 in rice seedlings. We also used a combined analysis of expression correlation and Gene Ontology annotation to infer the biological role of the OsWD40 genes in rice. The results suggested that OsWD40 genes may perform their diverse functions by complex network, thus were predictive for understanding their biological pathways. The analysis also revealed that OsWD40 genes might interact with each other to take part in metabolic pathways, suggesting a more complex feedback network. CONCLUSIONS: All of these analyses suggest that the functions of OsWD40 genes are diversified, which provide useful references for selecting candidate genes for further functional studies. PMID- 22429807 TI - Correlation between optic nerve head parameters and retinal nerve fibre layer thickness measured by spectral-domain optical coherence tomography in myopic eyes. AB - BACKGROUND: To evaluate the correlation between optic nerve head parameters and retinal nerve fiber layer thickness measured by Cirrus HD spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec) in healthy myopic eyes. DESIGN: Cross-sectional study. PARTICIPANTS: One hundred and sixty-one right eyes from 161 healthy young myopic subjects. METHODS: Optic nerve head parameters and retinal nerve fiber layer thickness were measured with the Cirrus HD-OCT. The distance between optic disc margin and scan circle (disc margin-to scan distance) was measured on the Cirrus HD-OCT en-face optic nerve head image with aid of National Institutes of Health ImageJ image-analysis software (developed by Wayne Rasbands, National Institutes of Health, Bethesda, MD). MAIN OUTCOME MEASURES: The correlations among optic nerve head parameters, retinal nerve fibre layer thickness and the disc margin-to-scan distance were evaluated with and without adjustment of the magnification effect. RESULTS: Without correction of the magnification effect, the thicker average retinal nerve fiber layer was correlated with greater rim area and lower degree of myopia (P < 0.001). When the magnification effect was corrected, thicker average retinal nerve fibre layer was associated with greater disc area and greater rim area in univariate and multivariate analyses (P <= 0.028); however, degrees of myopia and the disc margin-to-scan distance were not significantly associated with average RNFL thickness (P >= 0.104). CONCLUSIONS: Thicker average retinal nerve fibre layer thickness was associated with greater rim and disc areas. Disc margin-to scan distance was not significantly correlated with average retinal nerve fibre layer thickness in healthy myopic eyes. PMID- 22429809 TI - Quantitative EEG for the detection of brain ischemia. PMID- 22429808 TI - Multiple ABC transporters are involved in the acquisition of petrobactin in Bacillus anthracis. AB - In Bacillus anthracis the siderophore petrobactin is vital for iron acquisition and virulence. The petrobactin-binding receptor FpuA is required for these processes. Here additional components of petrobactin reacquisition are described. To identify these proteins, mutants of candidate permease and ATPase genes were generated allowing for characterization of multiple petrobactin ATP-binding cassette (ABC)-import systems. Either of two distinct permeases, FpuB or FatCD, is required for iron acquisition and play redundant roles in petrobactin transport. A mutant strain lacking both permeases, DeltafpuBDeltafatCD, was incapable of using petrobactin as an iron source and exhibited attenuated virulence in a murine model of inhalational anthrax infection. ATPase mutants were generated in either of the permease mutant backgrounds to identify the ATPase(s) interacting with each individual permease channel. Mutants lacking the FpuB permease and FatE ATPase (DeltafpuBDeltafatE) and a mutant lacking the distinct ATPases FpuC and FpuD generated in the DeltafatCD background (DeltafatCDDeltafpuCDeltafpuD) displayed phenotypic characteristics of a mutant deficient in petrobactin import. A mutant lacking all three of the identified ATPases (DeltafatEDeltafpuCDeltafpuD) exhibited the same growth defect in iron depleted conditions. Taken together, these results provide the first description of the permease and ATPase proteins required for the import of petrobactin in B. anthracis. PMID- 22429810 TI - Retinal oximetry in central retinal artery occlusion. PMID- 22429811 TI - Morphophenotypic characteristics of intralymphatic cancer and stromal cells susceptible to lymphogenic metastasis. AB - The intravessel microenvironment has significant effects on cancer metastasis. The aim of the present study was to determine how the morphologic and immunophenotypic features of cancer cells and infiltrating stromal cells within the permeated lymphatic vessels are associated with lymphogenic metastasis. A total of 137 primary lung adenocarcinoma patients with extratumoral lymphatic permeations were examined. Morphologically, the floating cancer nests within the permeated lymphatic vessels were divided into two types: Type A, consisting of a single large cancer nest; and Type B, consisting of multiple small cancer nests. We compared the clinicopathologic characteristics and the immunophenotypes of the cancer cells and infiltrating stromal cells between the Type A and Type B nests. Eleven of 54 Type A patients (20%) had intrapulmonary metastases, compared with 36 of 83 Type B patients (43%; P = 0.006). Immunohistochemically, Type B cancer cells expressed significantly higher levels of CD44 than Type A cancer cells (mean scoresAUTHOR: Scores - what is this score? Is it the number of cells expressing CD44 or the concentration of CD44 or some other type of scoring system? 43.0 vs 20.5, respectively) and E-cadherin (60.5 vs 31.5, respectively), but lower levels of Geminin (11.9% vs 20.3%, respectively) and cleaved caspase 3 (2.4% vs 7.8%AUTHOR: 11.9% vs 20.3%, respectively) and cleaved caspase 3 (2.4% vs 7.8%, - what do the percentages here refer to? The number of cells expressing geminin and caspase 3? The levels of these factors? Please clarify., respectively). Moreover, a significantly larger number of CD204-positive macrophages were present within the cancer-permeated lymphatic vessels in Type B patients than in Type A patients (mean number 9.5 vs 4.6, respectively). The present study reveals that intralymphatic cancer cell and stromal cell phenotypes are susceptible to lymphogenic metastasis, suggesting that lymphogenic metastasis may be affected by the intralymphatic microenvironment they create. PMID- 22429812 TI - An integrated analysis of miRNA and gene copy numbers in xenografts of Ewing's sarcoma. AB - BACKGROUND: Xenografts have been shown to provide a suitable source of tumor tissue for molecular analysis in the absence of primary tumor material. We utilized ES xenograft series for integrated microarray analyses to identify novel biomarkers. METHOD: Microarray technology (array comparative genomic hybridization (aCGH) and micro RNA arrays) was used to screen and identify copy number changes and differentially expressed miRNAs of 34 and 14 passages, respectively. Incubated cells used for xenografting (Passage 0) were considered to represent the primary tumor. Four important differentially expressed miRNAs (miR-31, miR-31*, miR-145, miR-106) were selected for further validation by real time polymerase chain reaction (RT-PCR). Integrated analysis of aCGH and miRNA data was performed on 14 xenograft passages by bioinformatic methods. RESULTS: The most frequent losses and gains of DNA copy number were detected at 9p21.3, 16q and at 8, 15, 17q21.32-qter, 1q21.1-qter, respectively. The presence of these alterations was consistent in all tumor passages. aCGH profiles of xenograft passages of each series resembled their corresponding primary tumors (passage 0). MiR-21, miR-31, miR-31*, miR-106b, miR-145, miR-150*, miR-371-5p, miR-557 and miR 598 showed recurrently altered expression. These miRNAS were predicted to regulate many ES-associated genes, such as genes of the IGF1 pathway, EWSR1, FLI1 and their fusion gene (EWS-FLI1). Twenty differentially expressed miRNAs were pinpointed in regions carrying altered copy numbers. CONCLUSION: In the present study, ES xenografts were successfully applied for integrated microarray analyses. Our findings showed expression changes of miRNAs that were predicted to regulate many ES associated genes, such as IGF1 pathway genes, FLI1, EWSR1, and the EWS-FLI1 fusion genes. PMID- 22429813 TI - Detection of fatigue-induced micro-cracks in a pipe by using time-reversed nonlinear guided waves: a three-dimensional model study. AB - Localization of fatigue-related micro-cracks in pipelines is of increasing importance in industrial applications. A three-dimensional (3D) fatigue-crack imaging technique combining nonlinear guided waves with time reversal is proposed in this paper for potential applications in pipeline inspections. By using this method, the non-classical nonlinear guided waves generated from micro-cracks with hysteretic behavior are recorded, and the third harmonic waves are used to reconstruct the fatigue-crack images in a pipe by using a time reversal (TR) process. The feasibility of this method is examined by the imaging simulations for a steel pipe with varied defect areas. A finite-difference time-domain (FDTD) code is programmed to solve the wave equations under cylindrical coordinates, and simulate the experimental process of wave propagation. The results show that: (1) the proposed technique has excellent spatial retrofocusing capability; (2) the accuracy of defect localization and sizing depends on the crack orientation and the adopted guided wave mode; and (3) different displacement/stress components have varied sensitivities to the crack orientation. PMID- 22429814 TI - Antidiabetic and antihyperlipidemic effects of the stem of Musa sapientum Linn. in streptozotocin-induced diabetic rats. AB - BACKGROUND: Musa sapientum Linn. is a herbaceous plant of the Musaceae family. It has been used in India for the treatment of gastric ulcer, hypertension, diarrhea, dysentery, and diabetes. The antidiabetic effect of the fruit, root, and flower has been demonstrated. The aim of the present study was to assess the antidiabetic and antihyperlipidemic effects of the stem of M. sapientum Linn. METHODS: Diabetes was induced in rats by streptozotocin injection (45 mg/kg, i.p.). Diabetic rats were treated for 2 weeks with different doses of lyophilized stem juice of M. sapientum Linn. (25, 50, and 100 mg/kg) to select the most effective dose. The effects of 4 weeks treatment with this dose (50 mg/kg) on fasting and postprandial plasma glucose (FPG, PPG) levels, body weight, lipid profile, HbA1c, insulin, liver enzymes (i.e. glucokinase, glucose-6-phosphatase and 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase) and muscle and liver glycogen were evaluated. RESULTS: The most effective dose of lyophilized stem juice of M. sapientum Linn. was 50 mg/kg. Four weeks treatment with this dose resulted in significant decreases in FPG and PPG (P < 0.05). Serum insulin increased (P < 0.05) whereas HbA1c decreased (P < 0.05). Diabetes-induced changes to the lipid profile, muscle and liver glycogen, and enzyme activity (i.e. glucokinase, glucose-6-phosphatase, and HMG-CoA reductase) were restored near to normal levels (P < 0.05). CONCLUSION: Diabetic rats responded favorably to treatment with lyophilized stem juice of M. sapientum Linn., which exhibits antidiabetic and antihyperlipidemic effects. PMID- 22429815 TI - Association between epilepsy and erectile dysfunction: evidence from a population based study. AB - INTRODUCTION: Although the association between epilepsy and sexual disorders has long been known, very few studies have attempted to explore the association between epilepsy and erectile dysfunction (ED). AIM: This population-based case control study aimed to investigate the association between ED and a prior diagnosis with epilepsy. METHODS: This study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. The cases comprised 6,427 patients with a diagnosis of ED and 32,135 controls who were frequency matched with cases based on 10-year age groups and index year. Conditional logistic regression was used to calculate the odds ratios (ORs) for prior epilepsy. MAIN OUTCOME MEASURE: The prevalence and risk of epilepsy between cases and controls. RESULTS: Of the sampled patients, 3,861 (14%) were diagnosed before the index date: 1,358 individuals (19.7%) were cases and 2,503 (12.1%) were controls. After adjusting for hypertension, diabetes, hyperlipidemia, renal disease, coronary heart disease, obesity, alcohol abuse/alcohol dependence syndrome, and socioeconomic status, conditional logistic regression analysis revealed that patients with ED were more likely to have been diagnosed with prior epilepsy than controls (OR = 1.83, 95% CI = 1.51-2.21). Compared with controls, the adjusted ORs for prior generalized epilepsy and partial epilepsy for cases were 2.13 (95% CI = 1.52 3.00) and 1.64 (95% CI = 1.31-2.06), respectively. The most pronounced associations were detected in ED cases aged between 30 and 39 who were 3.04 (95% CI = 1.67-5.50) times more likely than controls to have been previously diagnosed with epilepsy. CONCLUSIONS: Our findings suggest a positive correlation between ED and a prior diagnosis with epilepsy. PMID- 22429816 TI - Impact of seminal trace element and glutathione levels on semen quality of Tunisian infertile men. AB - BACKGROUND: Growing evidence indicates that oxidative stress can be a primary cause of male infertility. Non-enzymatic antioxidants play an important protective role against oxidative damages and lipid peroxidation. Human seminal plasma is a natural reservoir of antioxidants. The aim of this study was to determine glutathione (GSH) concentrations, trace element levels (zinc and selenium) and the lipid peroxidation end product, malondialdehyde (MDA), in the seminal plasma of men with different fertility potentials. METHODS: Semen samples from 60 fertile men (normozoospermics) and 190 infertile patients (74 asthenozoospermics, 56 oligozoospermics, and 60 teratozoospermics) were analyzed for physical and biochemical parameters. Zinc (Zn) and selenium (Se) levels were estimated by atomic absorption spectrophotometry. Total GSH (GSHt), oxidized GSH (GSSG), reduced GSH (GSHr) and MDA concentrations were measured spectrophotometrically. RESULTS: Zn and Se concentrations in seminal plasma of normozoospermics were more elevated than the three abnormal groups. Nevertheless, only the Zn showed significant differences. On the other hand, Zn showed positive and significant correlations with sperm motility (P = 0.03, r = 0.29) and count (P < 0.01, r = 0.49); however Se was significantly correlated only with sperm motility (P < 0.01, r = 0.36). GSHt, GSSG and GSHr were significantly higher in normozoospermics than in abnormal groups. We noted a significant association between seminal GSHt and sperm motility (P = 0.03). GSSG was highly correlated to sperm motility (P < 0.001) and negatively associated to abnormal morphology (P < 0.001). GSHr was significantly associated to total sperm motility (P < 0.001) and sperm count (P = 0.01). MDA levels were significantly higher in the three abnormal groups than in normozoospermics. Rates of seminal MDA were negatively associated to sperm motility (P < 0.01; r = -0.24) and sperm concentration (P = 0.003; r = -0.35) Meanwhile, there is a positive correlation between seminal lipid peroxidation and the percentage of abnormal morphology (P = 0.008). CONCLUSIONS: This report revealed that decreased seminal GSH and trace element deficiencies are implicated in low sperm quality and may be an important indirect biomarker of idiopathic male infertility. Our results sustain that the evaluation of seminal antioxidant status in infertile men is necessary and can be helpful in fertility assessment from early stages. PMID- 22429817 TI - Long-term administration of fasudil improves cardiomyopathy in streptozotocin induced diabetic rats. AB - Inhibition of Rho kinase (ROCK) has been shown to improve diabetic-related disorders. In this study, the cardio-protective effects and potential mechanisms of fasudil, a selective ROCK inhibitor, on diabetic cardiomyopathy were investigated in a streptozotocin (STZ)-induced diabetic rat model. Eight weeks after diabetes was induced by a single tail vein injection of 60 mg/kg STZ, rats were administered long-term fasudil or captopril as a control over a four-week period. Similar to the effect of captopril, fasudil treatment significantly protected against STZ-induced hemodynamic, histopathologic changes and decreased serum lactate dehydrogenase and creatine phosphokinase. Moreover, fasudil significantly down-regulated ROCK I mRNA expression and ROCK activity, reduced cardiac collagen deposition, and decreased the incidence of apoptosis and ratio of Bax/Bcl-2 protein expression. Additionally, fasudil potently elevated superoxide dismutase activity and suppressed the extent of lipid peroxidation in sera and hearts of diabetic rats. Our findings indicated that long-term treatment with fasudil could improve cardiac dysfunction, attenuate myocardial injury and prevent pathological changes in a rat model of diabetic cardiomyopathy. These effects could be attributed to regulation of antioxidative activities, suppression of myocardial hypertrophy, apoptosis, fibrosis and subsequent cardiac remodeling. These results may help to expand the clinical application of fasudil for diabetic cardiomyopathy. PMID- 22429818 TI - Inhibitory effects of lycopene on HMGB1-mediated pro-inflammatory responses in both cellular and animal models. AB - High mobility group box 1 (HMGB1) mediates proinflammatory responses in inflammatory diseases. Lycopene found in tomatoes and tomato products has anti oxidant, anti-cancer and antiinflammatory effects. The potential anti inflammatory roles of lycopene in HMGB1-mediated proinflammatory responses in both primary human umbilical vein endothelial cells (HUVECs) and animal were investigated. The anti-inflammatory effects of lycopene were determined including permeability, monocyte adhesion and migration, and activation of proinflammatory proteins and HMGB1 receptors on HMGB1 activated HUVECs. In the in vivo model, the anti-inflammatory effect of lycopene was assessed by monitoring vascular permeability and migration of leukocytes to the peritoneal cavity of mice injected with lycopene. Lycopene inhibited lipopolysaccharide (LPS)-mediated release of HMGB1, expression of HMGB1-mediated tumor necrosis factor (TNF) secretory phospholipase A2 (sPLA2)-IIA, and HMGB1-mediated pro-inflammatory signaling responses in endothelial cells. It did this through down-regulation of cell surface expression of cell adhesion molecules (CAMs), HMGB1 receptors, toll like receptor (TLR)-2, and -4, and receptors for advanced glycation end products (RAGE). These findings suggest that lycopene promotes barrier integrity, inhibits monocyte adhesion and migration to HMGB1 activating HUVECs by blocking activation of proinflammatory cytokines and expression of CAMs and HMGB1 receptors, thereby showing its usefulness as a therapy for vascular inflammatory diseases. PMID- 22429819 TI - Acute and subacute toxicity and genotoxicity of schizonepetin, a naturally occurring monoterpene with antiviral activity. AB - In the present study, the acute, subacute and genetic toxicity of schizonepetin was assessed. The median lethal dose (LD(50)) of schizonepetin after oral administration was 478 mg/kg body weight in mice. Studies on dose toxicity were repeatedly conducted at 0, 60, 120, and 240 mg/kg bw/day in rats for 35 days after oral administration. Based on the results of this study, a dose level of 120 mg/kg bw/day is considered the no-observed-adverse-effect-level (NOAEL) in rats. Schizonepetin was negative in Salmonella typhimurium tester strains TA97, TA98, TA100, TA102 and TA1535, nonclastogenic in Chinese hamster lung (CHL) cells in the mammalian chromosome aberration test, and micronucleus formation were observed and no clinical signs or adverse effects were detected, and our results illustrated that schizonepetin is not genotoxic. PMID- 22429820 TI - Sterigmatocystin alters the number of FoxP3+ regulatory T cells and plasmacytoid dendritic cells in BALB/c mice. AB - Sterigmatocystin (ST), a mycotoxin with mutagenic, cytotoxic and carcinogenic properties, is commonly found as the contaminant in grains and animal feeds. Of particular interest is the capacity of ST to alter normal immune function when presented in foods. As part of an on-going investigation of ST toxicological effects, we attempt to explore the short-term immunotoxic effects of ST, specifically on FoxP3(+) regulatory T cells (FoxP3(+) Tregs) and plasmacytoid dendritic cells (pDCs), by observing changes in number/expression of FoxP3(+) Tregs, pDCs and CD4(+), CD8(+) T cells in BALB/c mice 24h after a single intraperitoneal administration of ST at different dosages (3, 30, 300 and 3000 MUg/kg body weight). The present study showed that 24h after ST treatment, the proportion of CD8(+) T cells was decreased in the thymus in ST 3 MUg/kg group, while that of CD4(+) and CD8(+) T cells was increased in the spleen in two treatment groups (3 and 30 MUg/kg). The proportion of FoxP3(+) Tregs and FoxP3 expressions were all significantly increased in mPBMCs, the thymus and the spleen. It is noteworthy that the population of pDCs significantly decreased in the thymus as we expected but increased in the spleen as compared with control, which we suspect is resulted from a temporary immune response triggered by the ST inhibition. We believe that ST may exert its immunotoxic effects by stimulating Treg, but inhibiting pDCs in the long-term to contribute its carcinogenic effects. PMID- 22429821 TI - Criminal charges prior to and after initiation of office-based buprenorphine treatment. AB - BACKGROUND: There is little data on the impact of office-based buprenorphine therapy on criminal activity. The goal of this study was to determine the impact of primary care clinic-based buprenorphine maintenance therapy on rates of criminal charges and the factors associated with criminal charges in the 2 years after initiation of treatment. METHODS: We collected demographic and outcome data on 252 patients who were given at least one prescription for buprenorphine. We searched a public database of criminal charges and recorded criminal charges prior to and after enrollment. We compared the total number of criminal cases and drug cases 2 years before versus 2 years after initiation of treatment. RESULTS: There was at least one criminal charge made against 38% of the subjects in the 2 years after initiation of treatment; these subjects were more likely to have used heroin, to have injected drugs, to have had any prior criminal charges, and recent criminal charges. There was no significant difference in the number of subjects with any criminal charge or a drug charge before and after initiation of treatment. Likewise, the mean number of all cases and drug cases was not significantly different between the two periods. However, among those who were opioid-negative for 6 or more months in the first year of treatment, there was a significant decline in criminal cases. On multivariable analysis, having recent criminal charges was significantly associated with criminal charges after initiation of treatment (adjusted odds ratio 3.92); subjects who were on opioid maintenance treatment prior to enrollment were significantly less likely to have subsequent criminal charges (adjusted odds ratio 0.52). CONCLUSIONS: Among subjects with prior criminal charges, initiation of office-based buprenorphine treatment did not appear to have a significant impact on subsequent criminal charges. PMID- 22429822 TI - Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer. AB - The caspase family is well characterized as playing a crucial role in modulation of programmed cell death (PCD), which is a genetically regulated, evolutionarily conserved process with numerous links to many human diseases, most notably cancer. In this review, we focus on summarizing the intricate relationships between some members of the caspase family and their key apoptotic mediators, involving tumour necrosis factor receptors, the Bcl-2 family, cytochrome c, Apaf 1 and IAPs in cancer initiation and progression. We elucidate new emerging types of cross-talk between several caspases and autophagy-related genes (Atgs) in cancer. Moreover, we focus on presenting several PCD-modulating agents that may target caspases-3, -8 and -9, and their substrates PARP-1 and Beclin-1, which may help us harness caspase-modulated PCD pathways for future drug discovery. PMID- 22429823 TI - Spinal manipulation epidemiology: systematic review of cost effectiveness studies. AB - BACKGROUND: Spinal manipulative therapy (SMT) is frequently used by health professionals to manage spinal pain. With many treatments having comparable outcomes to SMT, determining the cost-effectiveness of these treatments has been identified as a high research priority. OBJECTIVE: To investigate the cost effectiveness of SMT compared to other treatment options for people with spinal pain of any duration. METHODS: We searched eight clinical and economic databases and the reference lists of relevant systematic reviews. Full economic evaluations conducted alongside randomised controlled trials with at least one SMT arm were eligible for inclusion. Two authors independently screened search results, extracted data and assessed risk of bias using the CHEC-list. RESULTS: Six cost effectiveness and cost-utility analysis were included. All included studies had a low risk of bias scoring >=16/19 on the CHEC-List. SMT was found to be a cost effective treatment to manage neck and back pain when used alone or in combination with other techniques compared to GP care, exercise and physiotherapy. CONCLUSIONS: This review supports the use of SMT in clinical practice as a cost-effective treatment when used alone or in combination with other treatment approaches. However, as this conclusion is primarily based on single studies more high quality research is needed to identify whether these findings are applicable in other settings. PMID- 22429824 TI - Obesity, inflammation and the immune system. AB - Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications. PMID- 22429825 TI - Reduced von Willebrand factor secretion is associated with loss of Weibel-Palade body formation. AB - BACKGROUND: von Willebrand disease (VWD) is caused by mutations in von Willebrand factor (VWF) that have different pathophysiologic effect in causing low plasma VWF levels. Type 1 VWD includes quantitative plasma VWF deficiency with normal VWF structure and function. OBJECTIVES: We report three novel type 1 VWF mutations (A1716P, C2190Y and R2663C) located in different VWF domains that are associated with reduced secretion and reduced formation of elongated Weibel Palade body (WPB)-like granules. METHODS: Transient expression of recombinant mutant full-length VWF in 293 EBNA cells was performed and secretion, collagen binding and GpIb binding assessed in comparison with wild-type VWF. Expression was also examined in HEK293 cells that form WPB-like granules when transfected with wild-type VWF. RESULTS: Laboratory results and multimer analysis of plasma VWF was compatible with type 1 VWD. Expression experiments demonstrated slightly reduced VWF synthesis and drastically impaired secretion upon homozygous expression. In HEK293 cells, homozygous expression of A1716P and C2190Y VWF variants failed to form elongated WPB-like granules, while R2663C was capable of WPB-like granules. Heterozygous expression of VWF variants had a negative impact on wild-type VWF with a reduction in elongated WPB-like granules in co transfected cells. CONCLUSIONS: Our results demonstrate that homozygous and heterozygous quantitative VWF deficiency caused by missense VWF mutations in different VWF domains can be associated with inability to form endothelial WPB like granules. PMID- 22429826 TI - The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action. AB - BACKGROUND: The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated. METHODS: We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments. RESULTS: The N-arachidonoylethanolamine (anandamide, AEA), 2 arachidonoylglycerol and N- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor. CONCLUSIONS: This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors. This may contribute to the improvement of long term palliation or cure of melanoma. PMID- 22429827 TI - Morphometric analysis of hepatocellular nodular lesions in HCV cirrhosis. AB - We generated a computerized morphometric model to evaluate and quantify the morphological features in large regenerative nodules (LRN), high-grade dysplastic nodules (HGDN) and hepatocellular carcinoma (HCC). Sixteen LRN, 10 HGDN and 16 HCC in HCV-cirrhotic livers were stained with H&E, smooth muscle actin, CD34, CD31 and reticulin to evaluate volume and surface fractions. On H&E stains, the most discriminatory features between LRN, HGDN and HCC were volume fraction and the number of hepatocyte nuclei in unit volume and hepatocyte nuclear/cytoplasmic ratio. On immunohistochemistry, volume fractions of capillarised sinusoids, capillary units and isolated arteries were significantly different among all groups and highest in HCC; surface fraction of reticulin was markedly decreased in HCC. Our morphometric model is an objective method for quantification of the morphological changes of the nodular lesions, and it could be applied to studies involving histological evaluation of the spectrum of nodular lesions arising in the cirrhotic liver. PMID- 22429828 TI - Disparate activation of the coronary sinus and inferior left atrium during atrial tachycardia after persistent atrial fibrillation ablation: prevalence, pitfalls, and impact on mapping. AB - INTRODUCTION: Persistent atrial fibrillation (AF) ablation may lead to partial disconnection of the coronary sinus (CS). As a result, disparate activation sequences of the local CS versus contiguous left atrium (LA) may be observed during atrial tachycardia (AT). We aimed to evaluate the prevalence of this phenomenon and its impact on activation mapping. METHODS: AT occurring after persistent AF ablation were investigated in 74 consecutive patients. Partial CS disconnection during AT was suspected when double potentials with disparate activation sequences were observed on the CS catheter. Endocardial mapping facing CS bipoles was performed to differentiate LA far-field from local CS potentials. RESULTS: A total of 149 ATs were observed. Disparate LA-CS activations were apparent in 20 ATs after magnifying the recording scale (13%). The most common pattern (90%) was distal to proximal endocardial LA activation against proximal to distal CS activation, the latter involving the whole CS or its distal part. Perimitral macroreentry was more common when disparate LA-CS activations were observed (67% vs 29%; P = 0.002). Partial CS disconnection also resulted in "pseudo" mitral isthmus (MI) block during LA appendage pacing in 20% of patients as local CS activation was proximal to distal despite distal to proximal activation of the contiguous LA. CONCLUSION: Careful analysis of CS recordings during AT following persistent AF ablation often reveals disparate patterns of activation. Recognizing when endocardial LA activation occurs in the opposite direction to the more obvious local CS signals is critical to avoid misleading interpretations during mapping of AT and evaluation of MI block. PMID- 22429829 TI - The discriminative power of the EuroQol visual analog scale is sensitive to survey language in Singapore. AB - BACKGROUND: Existing evidence for validity of the visual analog scale of the EQ 5D-3L questionnaire (EQ-VAS) is weak in Chinese-speaking respondents in Singapore. We therefore investigated the validity of the Chinese (Singapore) version of EQ-VAS in patients with diabetes. METHODS: In a cross-sectional survey, patients with type 2 diabetes seen in a primary care facility completed an identical Chinese or English questionnaire containing the EQ-5D-3L and questions assessing other health and disease-related characteristics. Convergent and known-groups validity of the EQ-VAS was examined for Chinese- and English speaking respondents separately. RESULTS: The EQ-VAS was correlated with the EQ 5D-3L health index and a 5-point Likert-type scale for assessing global health in both Chinese-speaking (N = 335) and English-speaking respondents (N = 298), suggesting convergent validity. The mean EQ-VAS scores differed between English speaking patients with differing duration of diabetes (< 10 years versus >= 10 years), comorbidity status (absence versus presence), and complications of diabetes (absence versus presence), providing evidence for known-groups validity. However, the EQ-VAS scores for Chinese-speaking respondents known to differ in these characteristics were similar, even among subgroups of relatively younger patients or those with formal school education. CONCLUSIONS: Chinese- and English speaking Singaporeans respond differently to the EQ-VAS. The Chinese version of EQ-VAS appears less sensitive than its English version for measuring global health in patient populations in Singapore. PMID- 22429830 TI - The in vitro effects of zearalenone and T-2 toxins on Vero cells. AB - The aim of the present study was to investigate in vitro, whether cytolethality and oxidative damage is enhanced by combination of both mycotoxins as compared to their individual effect. In our paper, we applied a tiered in vitro experimental approach in order to predict the possible health risk effects of two interactive fusarial toxins. Considering the concomitant production of zearalenone (ZEN) and T-2 toxin, it is very likely that humans and animals are always exposed to the mixture rather than to individual compounds. Our results clearly showed that cultured renal cells respond to individual (ZEN) or T-2 toxin exposure by a moderate inhibition of cell proliferation, respectively. However, when combined, they exert a more significant decrease in cell viability. Similar results were found for the investigated oxidative status endpoints. When combined, ZEN and T-2 toxin increased ROS production and heat shock protein (Hsp) 70 expression as compared to the effect of each mycotoxin taken alone. We can conclude that the mixture of ZEN and T-2 toxin increased their toxic effects. The health risk is heightened by the interactions between co-occurring mycotoxins. PMID- 22429831 TI - Quantitative molecular assessment of chimerism across tissues in marmosets and tamarins. AB - BACKGROUND: Marmosets are playing an increasingly large and important role in biomedical research. They share genetic, anatomical, and physiological similarities with humans and other primate model species, but their smaller sizes, reproductive efficiency, and amenability to genetic manipulation offer an added practicality. While their unique biology can be exploited to provide insights into disease and function, it is also important that researchers are aware of the differences that exist between marmosets and other species. The New World monkey family Callitrichidae, containing both marmoset and tamarin species, typically produces dizygotic twins that show chimerism in the blood and other cells from the hematopoietic lineage. Recently, a study extended these findings to identify chimerism in many tissues, including somatic tissues from other lineages and germ cells. This has raised the intriguing possibility that chimerism may play an increasingly pervasive role in marmoset biology, ranging from natural behavioral implications to increased variability and complexity in biomedical studies. RESULTS: Using a quantitative PCR based methodology, Y chromosomes can be reliably detected in the females with male fraternal twins allowing for a relative quantification of chimerism levels between individuals and tissues. With this approach in common marmosets (Callithrix jacchus) and cotton-top tamarins (Saguinus oedipus), chimerism was detected across a broad array of tissues. Chimerism levels were significantly higher in tissues primarily derived from the hematopoietic lineage, while they were lower, though still detectable, in tissues with other origins. Interestingly, animals with a characteristic marmoset wasting disease show higher levels of chimerism in those tissues affected. Fibroblast cell lines from chimeric individuals, however, are not found to be chimeric themselves. CONCLUSION: Taken together, the levels of chimerism in tissues of different origins coupled with other lines of evidence suggest that indeed only hematopoietic cell lineages are chimeric in callitrichids. The chimerism detected in other tissues is likely the result of blood or lymphocytic infiltration. Using molecular methods to detect chimerism in a tissue sample seems to have allowed a substantial increase in the ability to detect these minor cell populations. PMID- 22429832 TI - Diseases of wild and cultured juvenile crustaceans: Insights from below the minimum landing size. AB - Decapod crustaceans (i.e., lobsters, crabs, and shrimps) are all subject to disease, both in the wild and in culture. No life stage appears to be immune to some form of pathogen or parasite. However, juveniles appear to be the targets of some of the most pervasive and consequential diseases. It is therefore surprising, given the enormous economic value of adult decapods, that we know so little about the effects of pathogens on their vulnerable life stage. Here I review the significant diseases reported for juvenile decapods that support fisheries and aquaculture, and highlight research that demonstrates the advantage of incorporating juveniles and ecology in studies of disease. PMID- 22429833 TI - Nucleic-acid based antivirals: augmenting RNA interference to 'vaccinate'Litopenaeus vannamei. AB - The Pacific white shrimp, Litopenaeus vannamei (Penaeidae: Litopenaeus) has emerged as the dominant farmed shrimp species globally in tropical countries. Rearing animals at high density in semi-intensive or intensive culture systems, and translocating animals across the globe, have created optimum conditions for devastating epizootics. Of the various pathogens that impact shrimp culture, viruses are arguably the most important infectious disease agents that exact devastating economic losses to the industry. Augmenting the RNA interference (RNAi) capacity of shrimp is a promising, emerging solution to prevent disease caused by a variety of highly pathogenic shrimp viruses. Indeed RNAi functions as a primary mechanism of antiviral RNA in arthropods, as was revealed initially in studies of mosquito-virus interactions. Double-stranded RNA (dsRNA) or small interfering RNA (siRNA) can be used as RNAi triggers in vivo in L. vannamei to reduce the pathology associated with virus infection. We explored the efficacy of those triggers as a function of the target gene in the virus genome and show that efficacy is virus-specific and cannot be predicted based on the target gene function or transcript level in an infected cell. Further, we show that carefully designed RNAi triggers provide an immune stimulus that results in specific, long term protection and therefore suggest that these dsRNA antivirals can function as vaccines in controlling disease. PMID- 22429834 TI - Historic emergence, impact and current status of shrimp pathogens in Asia. AB - It is estimated that approximately 60% of disease losses in shrimp aquaculture have been caused by viral pathogens and 20% by bacterial pathogens. By comparison, losses to fungi and parasites have been relatively small. For bacterial pathogens, Vibrio species are the most important while for viral pathogens importance has changed since 2003 when domesticated and genetically selected stocks of the American whiteleg shrimp Penaeus (Litopenaeus) vannamei (Boone 1931) replaced the formerly dominant giant tiger or black tiger shrimp Penaeus (Penaeus) monodon (Fabricius 1798) as the dominant cultivated species. For both species, white spot syndrome virus (WSSV) and yellow head virus (YHV) are the most lethal. Next most important for P. vannamei is infectious myonecrosis virus (IMNV), originally reported from Brazil, but since 2006 from Indonesia where it was probably introduced by careless importation of shrimp aquaculture stocks. So far, IMNV has not been reported from other countries in Asia. Former impacts of Taura syndrome virus (TSV) and infectious hypodermal and hematopoietic necrosis virus (IHHNV) on this species have dramatically declined due to the introduction of tolerant stocks and to implementation of good biosecurity practices. Another problem recently reported for P. vannamei in Asia is abdominal segment deformity disease (ASDD), possibly caused by a previously unknown retrovirus-like agent. Next most important after WSSV and YHV for P. monodon is monodon slow growth syndrome (MSGS) for which component causes appear to be Laem Singh virus (LSNV) and a cryptic integrase containing element (ICE). Hepatopancreatic parvovirus (HPV) and monodon baculovirus (MBV) may be problematic when captured P. monodon are used to produce larvae, but only in the absence of proper preventative measures. Since 2009 increasing losses with P. vannamei in China, Vietnam and now Thailand are associated with acute hepatopancreatic necrosis syndrome (AHPNS) of presently unknown cause. Despite these problems, total production of cultivated penaeid shrimp from Asia will probably continue to rise as transient disease problems are solved and use of post larvae originating from domesticated SPF shrimp stocks in more biosecure settings expands. PMID- 22429835 TI - Small intraretinal haemorrhage as the initial manifestation of pheochromocytoma. PMID- 22429836 TI - Enhanced age-related cataract in copper-zinc superoxide dismutase null mice. AB - BACKGROUND: As the lens is constantly exposed to light and oxygen that generate harmful reactive oxygen species, the importance of the intracellular antioxidant enzyme copper-zinc superoxide dismutase for the protection against age-related cataract development was explored. METHODS: The development of lens opacities and the lens oxidative status were studied in different age groups of mice lacking copper-zinc superoxide dismutase and in wild-type mice. The lens opacities were quantified from lens photographs using digital image analysis. Thereafter, the lenses were homogenized and analysed regarding their contents of reduced glutathione and protein carbonyls suggestive of protein oxidation. RESULTS: The 18-week-old mice of both genotypes had clear lenses. At 1 year of age, the copper zinc superoxide dismutase null mice had developed cortical lens opacities, whereas the wild-type mice did not show equivalent changes until 2 years of age. The lens contents of glutathione decreased only in the 2-year-old wild-type mice, whereas the carbonyls increased over time without any differences between the two genotypes. CONCLUSIONS: This study indicates that the lack of copper-zinc superoxide dismutase may accelerate age-related lens opacity development and that intracellular superoxide-derived oxidative stress may be damaging to the lens during ageing. Participation of the anti-oxidant enzyme copper-zinc superoxide dismutase in the protection against age-related cataract was thus suggested. PMID- 22429837 TI - Optimizing the care of patients with advanced prostate cancer in the UK: current challenges and future opportunities. AB - What's known on the subject? and What does the study add? Treatment options in the UK for men with metastatic castration-resistant prostate cancer (mCRPC) have been limited, and there is no standard approach, particularly in the second-line setting. The absence of a standard approach is further confounded by the differing definitions and terminologies still used in clinical practice to describe this group of patients (e.g. androgen-independent prostate cancer, hormone refractory prostate cancer, CRPC). With multiple new treatment options emerging, it will be critical to identify key considerations in our decision making process and to establish an optimum, standardized approach to treatment so that new therapies can be assimilated into an mCRPC treatment algorithm and our routine clinical practice. Most UK oncologists consider patients with advanced, symptomatic prostate cancer as eligible for chemotherapy, although a poor performance status, significant co-morbid factors, advancing age, and the presence of asymptomatic disease with slowly rising prostate-specific antigen levels would prevent chemotherapy use. The decision to retreat with chemotherapy is largely driven by prior response to first-line chemotherapy. Many UK oncologists feel that UK clinical practice is likely to change over the next 5 years, with abiraterone acetate, MDV3100 and cabazitaxel likely to have the most positive impacts in the treatment of mCRPC. OBJECTIVES: To evaluate the current management of patients with advanced prostate cancer by UK oncologists. To gain insights into the future role of emerging therapies. MATERIALS AND METHODS: A semi-structured questionnaire was issued by the British Uro-oncology Group to society members during a closed meeting in September 2010. Emerging therapies evaluated were: abiraterone acetate, aflibercept, bevacizumab, cabazitaxel, custirsen, MDV3100, sipuleucel-T and zibotentan. RESULTS: Eighty of 98 (82%) surveys were completed. Responders had on average 189 new referrals, and treated 126 patients with advanced prostate cancer each year. Chemotherapy was used by 86% of responders for patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC), although poor performance status, advancing age and slowly rising prostate-specific antigen levels would prevent chemotherapy use. The decision to retreat with chemotherapy was largely driven by prior response to first-line chemotherapy, with docetaxel preferred for those responding. Many (78%) felt that UK clinical practice was likely to change over the next 5 years, and that abiraterone acetate, MDV3100 and cabazitaxel would have the most positive impact. Opinions regarding the future use of aflibercept and custirsen were mixed. Few (<=3%) would use zibotentan or bevacizumab in the future based on recent negative phase III study results, or because of cost and complexity for sipuleucel-T. CONCLUSIONS: Although emerging therapies for mCRPC mean that the future is bright, guidelines are needed to ensure optimum use and sequencing of treatments. Additional costs and anticipated workload associated with new agents will require careful consideration. PMID- 22429838 TI - Synthetic disulfide-bridged cyclic peptides mimic the anti-angiogenic actions of chondromodulin-I. AB - Chondromodulin-I (ChM-I) is a 25-kDa glycoprotein in cartilage matrix that inhibits angiogenesis. It contains two distinctive structural domains: the N terminal third of the molecule is a hydrophilic domain that contains O-linked and N-linked oligosaccharide chains, and the C-terminal two-thirds is a hydrophobic domain that contains all of the cysteine residues. In the present study, we have attempted to further uncover the structural requirements for ChM-I to exert anti angiogenic activity by monitoring its inhibition of the vascular endothelial growth factor (VEGF)-A-induced migration of HUVEC in vitro. Site-directed mutagenesis experiments revealed that the cyclic structure formed by the disulfide bridge between Cys(83) and Cys(99) in human ChM-I is indispensable for its anti-angiogenic function. Moreover, the C-terminal hydrophobic tail (from Trp(111) to Val(120) ) was found to play an important role in ensuring the effectiveness of ChM-I activity on HUVEC. A synthetic cyclic peptide corresponding to the ChM-I region between Ile(82) to Arg(100) also inhibited the migration of HUVEC, while replacing the Cys(83) and Cys(99) residues in this peptide with Ser completely negated this inhibitory activity. An additional synthetic cyclic peptide harboring the hydrophobic C-terminal tail of ChM-I clearly mimicked the inhibitory action of this protein on the migration of HUVEC and successfully inhibited tumor angiogenesis and growth in a xenograft mouse model of human chondrosarcoma. PMID- 22429839 TI - Cloning of two members of the calcitonin-family receptors from stingray, Dasyatis akajei: possible physiological roles of the calcitonin family in osmoregulation. AB - In cartilaginous fish, two cDNAs encoding calcitonin-family receptors were isolated for the first time from the stingray brain. The open reading frame of one receptor cDNA coded a 525-amino acid protein. The amino acid identity of this receptor to human calcitonin-receptor-like receptor (CRLR) is 64.5%, frog CRLR is 64.7%, and flounder CRLR is 61.2% and this was higher than to human calcitonin receptor (CTR) (46.1%), frog CTR (54.7%), and flounder CTR (48.9%). We strongly suggested that this receptor is a ray CRLR based on phylogenetic analysis. In case of the second receptor, amino acid identity among CRLRs (human 50.5%, frog 50.7%, flounder 48.0%) and CTRs (human 43.2%, frog 49.1%, flounder 41.8%) was similar. From phylogenetic analysis of both CRLRs and CTRs, we believe that this receptor is ray CTR. The expression of ray CRLR mRNA was predominantly detected in the nervous system (brain) and vascular system (atrium, ventricle, and gill), which reflects the similar localization of CGRP in the nervous and vascular systems as mammals. It was observed that the second receptor was expressed in several tissues, namely cartilage, brain, pituitary gland, gill, atrium, ventricle, pancreas, spleen, liver, gall bladder, intestine, rectal gland, kidney, testis and ovary. This localization pattern was very similar to flounder CTR. Both receptor mRNAs were strongly expressed in the gill. This suggests that the calcitonin-family members are involved in the osmoregulation of stingray as this fish is known to be euryhaline. When a stingray was transferred to diluted seawater (20% seawater), the expression of both receptors significantly decreased in the gill. Similar results were obtained in the kidney of the stingray. Thus, our cloning and isolation of both receptors in the stingray will be helpful for elucidation of their physiological role(s) such as osmoregulation including calcium metabolism of cartilaginous fish. PMID- 22429840 TI - 'Cooperative sedation': optimizing comfort while maximizing systemic and neurological function. PMID- 22429841 TI - Acral peeling skin syndrome in two East-African siblings: case report. AB - BACKGROUND: Acral peeling skin syndrome is a rare autosomal recessive genodermatosis due to a missense mutation in transglutaminase 5. The skin peeling occurs at the separation of the stratum corneum from the stratum granulosum. CASE PRESENTATION: We present a case of two siblings who developed continuous peeling of the palms and soles from the first year of life. This peeling was more severe on the soles than palms and on younger sibling than elder sibling. Peeling is worsened by occlusion and sweating. CONCLUSIONS: Sporadic cases of Acral Peeling Skin Syndrome occur in African population. There is variability in time of presentation and clinical severity even within families. PMID- 22429842 TI - Transforming growth factor beta and apoptosis in leprosy skin lesions: possible relationship with the control of the tissue immune response in the Mycobacterium leprae infection. AB - The course of leprosy depends of the host immune response which ranges from the lepromatous pole (LL) to the tuberculoid pole (TT). A comparative study was conducted in 60 patients with the LL and TT. The results showed a mean expression of TGF-beta of 339 +/- 99.4 cells/field for TT and of 519.2 +/- 68.2 cells/field for LL. Frequency of apoptosis was 6.3 +/- 1.8 in TT and 14.0 +/- 6.1 in LL. A correlation (p = 0.0251) between TGF-beta and caspase-3 in the LL was found. This finding indicates a role of TGF-beta and apoptosis in the immune response in leprosy. PMID- 22429843 TI - Copper toxicity to Lemna minor modelled using humic acid as a surrogate for the plant root. AB - Humic acids are chemically analogous to plant root cell walls in that their surface sites are principally comprised of carboxylic and phenolic acids which bind both metals and protons. Based on this analogy, we developed a biotic-ligand type of model to predict Cu toxicity to Lemna minor, using particulate humic acid (HA(part)) of the Windermere Humic Aqueous Model (WHAM), and 7d static-renewal exposures with five surface waters and one nutrient media which varied in DOC (1 10 mg L(-1)), pH (6.9-8.7), and water hardness (35-236 mg equivalent CaCO(3)L( 1)). Although the range of waters tested resulted in a 36-fold variation in 50% inhibitory concentration (IC50) values, the calculated concentration of Cu bound to HA(part) using this framework was highly correlated with pooled percent net root elongation (%NRE) (R(2)=0.95). Ten and fifty percent IC values based on [Cu HA(part)] were additionally within a factor of +/-1.5 and +/-1.4, respectively, inclusive of 95% confidence limits. This model construct, which defines the free metal ion and the first hydrolysis product (but not metal carbonate complexes) as being bioavailable, provides an alternative means of defining the binding surface in bioavailability models, whereby a heterogeneous mixture of ligands collectively influence root-metal sorption and toxicity. PMID- 22429844 TI - Effects of excited-state structures and properties on photochemical degradation of polybrominated diphenyl ethers: a TDDFT study. AB - This study presents new insight into the photochemical degradation of polybrominated diphenyl ethers (PBDEs), and it provides details about the structures and properties of 27 PBDE congeners in the electronically excited state using the time-dependent density functional theory method. Each PBDE congener exhibited remarkably different geometries in the ground state and the excited state. The significant lengthening of C-Br bond in each PBDE congener was observed in the excited state for the first time by theoretical calculation, which is directly involved in the photochemistry reductive debromination of n-BDE to (n-1)-BDE. Generally, the lengthening of C-Br bonds cannot occur at the para position. Furthermore, the calculated results demonstrated that the photoreactivity of PBDEs increased with an increase of bromination degree. It was also found that the pattern of Br substituents had an effect upon the photoreactivity of PBDEs. These findings suggest that the information obtained in the excited state is crucial to the mechanism explanation of the photochemical degradation of PBDEs. PMID- 22429845 TI - Sorption and desorption of carbamazepine, naproxen and triclosan in a soil irrigated with raw wastewater: estimation of the sorption parameters by considering the initial mass of the compounds in the soil. AB - In conventional sorption studies, the prior presence of contaminants in the soil is not considered when estimating the sorption parameters because this is only a transient state. However, this parameter should be considered in order to avoid the under/overestimation of the soil sorption capacity. In this study, the sorption of naproxen, carbamazepine and triclosan was determined in a wastewater irrigated soil, considering the initial mass of the compounds. Batch sorption desorption tests were carried out at two soil depths (0-10 cm and 30-40 cm), using either 10 mM CaCl(2) solution or untreated wastewater as the liquid phase. Data were satisfactorily fitted to the initial mass model. For the two soils, release of naproxen and carbamazepine was observed when the CaCl(2) solution was used, but not in the soil/wastewater system. The compounds' release was higher in the topsoil than in the 30-40 cm soil. Sorption coefficients (K(d)) for CaCl(2) solution tests showed that in the topsoil, triclosan (64.9 L kg(-1)) is sorbed to a higher extent than carbamazepine and naproxen (5.81 and 2.39 L kg(-1), respectively). In the 30-40 cm soil, carbamazepine and naproxen K(d) values (11.4 and 4.41 L kg(-1), respectively) were higher than those obtained for the topsoil, while the triclosan K(d) value was significantly lower than in the topsoil (19.2 L kg(-1)). Differences in K(d) values were found when comparing the results obtained for the two liquid phases. Sorption of naproxen and carbamazepine was reversible for both soils, while sorption of triclosan was found to be irreversible. This study shows the sorption behavior of three pharmaceuticals in a wastewater irrigated soil, as well as the importance of considering the initial mass of target pollutants in the estimation of their sorption parameters. PMID- 22429846 TI - In-vivo passive sampling to measure elimination kinetics in bioaccumulation tests. AB - The application of in-tissue passive sampling to quantify chemical kinetics in fish bioconcentration experiments was investigated. A passive sampler consisting of an acupuncture needle covered with a PDMS tube was developed together with a method for its deployment in rainbow trout. The time to steady state for chemical uptake into the passive sampler was >1d, so it was employed as a kinetically limited sampler with a deployment time of 2 h. The passive sampler was employed in parallel with the established whole tissue extraction method to study the elimination kinetics of 10 diverse chemicals in rainbow trout. 4-n-nonylphenol and 2,4,6-tri-tert-butylphenol were close to or below the limit of quantification in the sampler. For chlorpyrifos, musk xylene, hexachlorobenzene, 2,5 dichlorobiphenyl and p,p'-DDT, the elimination rate constants determined with the passive sampler method and the established method agreed within 18%. Poorer agreement (35%) was observed for 2,3,4-trichloroanisole and p-diisopropylbenzene because fewer data were obtained with the passive sampling method due to its lower sensitivity. The work shows that in-tissue passive sampling can be employed to measure contaminant elimination kinetics in fish. This opens up the possibility of studying contaminant kinetics in individual fish, thereby reducing the fish requirements and analytical costs for the determination of bioconcentration factors. PMID- 22429847 TI - Alkbh2 protects against lethality and mutation in primary mouse embryonic fibroblasts. AB - Alkylating agents modify DNA and RNA forming adducts that disrupt replication and transcription, trigger cell cycle checkpoints and/or initiate apoptosis. If left unrepaired, some of the damage can be cytotoxic and/or mutagenic. In Escherichia coli, the alkylation repair protein B (AlkB) provides one form of resistance to alkylating agents by eliminating mainly 1-methyladenine and 3-methylcytosine, thereby increasing survival and preventing mutation. To examine the biological role of the mammalian AlkB homologs Alkbh2 and Alkbh3, which both have similar enzymatic activities to that of AlkB, we evaluated the survival and mutagenesis of primary Big Blue mouse embryonic fibroblasts (MEFs) that had targeted deletions in the Alkbh2 or Alkbh3 genes. Both Alkbh2- and Alkbh3-deficient MEFs were ~2-fold more sensitive to methyl methanesulfonate (MMS) induced cytotoxicity compared to the wild type control cells. Spontaneous mutant frequencies were similar for the wild type, Alkbh2-/- and Alkbh3-/- MEFs (average--1.3*10(-5)). However, despite the similar survival of the two mutant MEFs after MMS treatment, only the Alkbh2-deficient MEFs showed a statistically significant increase in mutant frequency compared to wild type MEFs after MMS treatment. Therefore, although both Alkbh2 and Alkbh3 can protect against MMS-induced cell death, only Alkbh2 shows statistically significant protection of MEF DNA against mutations following treatment with this exogenous methylating agent. PMID- 22429848 TI - Registered nurses' attention to and perceptions of pressure ulcer prevention in hospital settings. AB - AIM: To describe how registered nurses perform, document and reflect on pressure ulcer prevention in a specific nurse-patient care situation, as well as generally, on hospital wards. BACKGROUND: Registered nurses should provide safe and qualified pressure ulcer prevention, but pressure ulcers remain a problem. Compliance with evidence-based guidelines impedes pressure ulcer formation. DESIGN: A descriptive design with a multimethods approach. METHOD: Nine registered nurses at three wards and hospitals participated. The registered nurses were observed in a specific nurse-patient care situation with patients at risk for pressure ulcers. Interviews followed and patients' records were reviewed. Quantitative and qualitative data analysis methods were used. RESULTS: Pressure ulcer prevention performed by the registered nurses was dependent on the cultural care, which ranged from planned to unplanned prevention. Diversity was found in compliance with evidence-based guidelines across the wards. Although all patients involved were at risk and the nurses described pressure ulcer prevention as basic care, the nurses' attention to prevention was lacking. Few prevention activities and no structured risk assessments using risk assessment tools were observed, and few care plans were identified. The lack of attention was explained by registered nurses' trust in assistant nurses' knowledge, and prevention was seen as an assistant nurse task. CONCLUSION: Registered nurses paid little attention to pressure ulcer prevention among patients at risk. The planned and unplanned care structures affected the prevention. The nurses trusted and largely delegated their responsibility to the assistant nurses. RELEVANCE TO CLINICAL PRACTICE: Evidence-based pressure ulcer prevention is fundamental to patient safety. Care quality is created in situations where patients and care providers meet. How registered nurses work with pressure ulcer prevention, their role and communication, particularly with assistant nurses, should be of major concern to them as well as to healthcare managers. PMID- 22429849 TI - Regulation of interferon pathway in 2-methoxyestradiol-treated osteosarcoma cells. AB - BACKGROUND: Osteosarcoma is a bone tumor that often affects children and young adults. Although a combination of surgery and chemotherapy has improved the survival rate in the past decades, local recurrence and metastases still develop in 40% of patients. A definite therapy is yet to be determined for osteosarcoma. Anti- tumor compound and a metabolite of estrogen, 2-methoxyestradiol (2-ME) induces cell death in osteosarcoma cells. In this report, we have investigated whether interferon (IFN) pathway is involved in 2-ME-induced anti-tumor effects in osteosarcoma cells. METHODS: 2-ME effects on IFN mRNA levels were determined by Real time PCR analysis. Transient transfections followed by reporter assays were used for investigating 2-ME effects on IFN-pathway. Western blot analyses were used to measure protein and phosphorylation levels of IFN-regulated eukaryotic initiation factor-2 alpha (eIF-2alpha). RESULTS: 2-ME regulates IFN and IFN-mediated effects in osteosarcoma cells. 2 -ME induces IFN gene activity and expression in osteosarcoma cells. 2-ME treatment induced IFN-stimulated response element (ISRE) sequence-dependent transcription and gamma-activated sequence (GAS)-dependent transcription in several osteosarcoma cells. Whereas, 2 ME did not affect IFN gene and IFN pathways in normal primary human osteoblasts (HOB). 2-ME treatment increased the phosphorylation of eIF-2alpha in osteosarcoma cells. Furthermore, analysis of osteosarcoma tissues shows that the levels of phosphorylated form of eIF-2alpha are decreased in tumor compared to normal controls. CONCLUSIONS: 2-ME treatment triggers the induction and activity of IFN and IFN pathway genes in 2-ME-sensitive osteosarcoma tumor cells but not in 2-ME resistant normal osteoblasts. In addition, IFN-signaling is inhibited in osteosarcoma patients. Thus, IFN pathways play a role in osteosarcoma and in 2-ME mediated anti-proliferative effects, and therefore targeted induction of IFN signaling could lead to effective treatment strategies in the control of osteosarcoma. PMID- 22429850 TI - Awareness of time distortions and its relation with time judgment: a metacognitive approach. AB - The perception of time cannot be reduced to a simple percept produced by an internal clock. The aim of the present study was therefore to investigate the role of the individual consciousness of time on temporal judgments. In the present study, the participants' awareness of attention-related time distortions was assessed using a metacognitive questionnaire. The participants were also required to verbally judge a series of stimulus durations in a single or a dual task condition. The results revealed that time was underestimated in the dual task compared to the single task. However, the accuracy of time judgments improved in line with the participants' individual awareness of attentional time distortion: The more aware they were of the role of attention in time perception, the lower the time distortions they exhibited. Conscious awareness of time therefore plays a role in the accuracy of the time judgments made by human beings. PMID- 22429851 TI - The AID dilemma: infection, or cancer? AB - Activation-induced cytidine deaminase (AID), which is both essential and sufficient for forming antibody memory, is also linked to tumorigenesis. AID is found in many B lymphomas, in myeloid leukemia, and in pathogen-induced tumors such as adult T cell leukemia. Although there is no solid evidence that AID causes human tumors, AID-transgenic and AID-deficient mouse models indicate that AID is both sufficient and required for tumorigenesis. Recently, AID's ability to cleave DNA has been shown to depend on topoisomerase 1 (Top1) and a histone H3K4 epigenetic mark. When the level of Top1 protein is decreased by AID activation, it induces irreversible cleavage in highly transcribed targets. This finding and others led to the idea that there is an evolutionary link between meiotic recombination and class switch recombination, which share H3K4 trimethyl, topoisomerase, the MRN complex, mismatch repair family proteins, and exonuclease 3. As Top1 has recently been shown to be involved in many transcription associated genome instabilities, it is likely that AID took advantage of basic genome instability or diversification to evolve its mechanism for immune diversity. AID targets are therefore not highly specific to immunoglobulin genes and are relatively abundant, although they have strict requirements for transcription-induced H3K4 trimethyl modification and repetitive sequences prone to forming non-B structures. Inevitably, AID-dependent cleavage takes place in nonimmunoglobulin targets and eventually causes tumors. However, battles against infection are waged in the context of acute emergencies, while tumorigenesis is rather a chronic, long-term process. In the interest of survival, vertebrates must have evolved AID to prevent infection despite its long-term risk of causing tumorigenesis. PMID- 22429852 TI - The microRNA regulatory network in normal- and HTLV-1-transformed T cells. AB - Recent efforts to understand the molecular networks governing normal T cell development and driving the neoplastic transformation of T cells have brought to light the involvement of microRNAs (miRNAs), a class of noncoding RNAs of approximately 22 nucleotides that regulate gene expression at the posttranscriptional level. In the present review, we compare the expression profiles of miRNAs in normal T cell development to that of transformed T cells using as a model adult T cell leukemia/lymphoma, an aggressive malignancy of mature CD4+ T cells that is caused by infection with human T cell leukemia virus type 1. PMID- 22429853 TI - The multifaceted oncoprotein Tax: subcellular localization, posttranslational modifications, and NF-kappaB activation. AB - The human T-cell lymphotropic virus type-I (HTLV-I) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and of tropical spastic paraparesis/HTLV-I associated myelopathy. Constitutive NF-kappaB activation by the viral oncoprotein Tax plays a crucial role in the induction and maintenance of cellular proliferation, transformation, and inhibition of apoptosis. In an attempt to provide a general view of the molecular mechanisms of constitutive Tax-induced NF kappaB activation, we summarize in this review the recent body of literature that supports a major role for Tax posttranslational modifications, chiefly ubiquitination, and SUMOylation, in the NF-kappaB activity of Tax. These modifications indeed participate in the control of Tax subcellular localization and modulate its protein-protein interaction potential. Tax posttranslational modifications, which highlight the ability of HTLV-I to optimize its limited viral genome size, might represent an attractive target for the design of new therapies for ATL. PMID- 22429854 TI - Lynch or not Lynch? Is that always a question? AB - The familial cancer syndrome referred to as Lynch I and II was renamed hereditary nonpolyposis colorectal cancer (HNPCC) only to revert later to Lynch syndrome (LS). LS is the most frequent human predisposition for the development of colorectal cancer (CRC), and probably also for endometrial and gastric cancers, although it has yet to acquire a consensus name. Its estimated prevalence ranges widely from 2% to 7% of all CRCs due to the fact that tumors from patients with LS are difficult to recognize at both the clinical and molecular level. This review is based on two assumptions. First, all LS patients inherit a predisposition to develop CRC (without polyposis) and/or other tumors from the Lynch spectrum. Second, all LS patients have a germline defect in one of the DNA mismatch repair (MMR) genes. When a somatic second hit inactivates the relevant MMR gene, the consequence is instability of DNA repeat sequences such as microsatellites and the tumors are referred to as having the microsatellite instability (MSI) phenotype. However, some of the inherited predisposition to develop CRC without concurrent polyposis, termed HNPCC, is found in non-LS patients, while not all MSI tumors are from LS cases. LS tumors are therefore at the junction of inherited and MSI cases. We describe here the defining characteristics of LS tumors that differentiate them from inherited non-MSI tumors and from non-inherited MSI tumors. PMID- 22429856 TI - Opportunities and challenges in tumor angiogenesis research: back and forth between bench and bed. AB - Angiogenesis is essential for tumor growth and metastasis. Many signaling pathways are involved in regulating tumor angiogenesis, with the vascular endothelial growth factor pathway being of particular interest. The recognition of the heterogeneity in tumor vasculature has led to better predictions of prognosis through differential analyses of the vasculature. However, the clinical benefits from antiangiogenic therapy are limited, because many antiangiogenic agents cannot provide long-term survival benefits, suggesting the development of drug resistance. Activation of the hypoxia and c-Met pathways, as well as other proangiogenic factors, has been shown to be responsible for such resistance. Vessel co-option could be another important mechanism. For future development, research to improve the efficacy of antiangiogenic therapy includes (a) using tumor-derived endothelial cells for drug screening; (b) developing the drugs focusing on specific tumor types; (c) developing a better preclinical model for drug study; (d) developing more accurate biomarkers for patient selection; (e) targeting the c-Met pathway or other pathways; and (f) optimizing the dose and schedule of antiangiogenic therapy. In summary, the future of antiangiogenic therapy for cancer patients depends on our efforts to develop the right drugs, select the right patients, and optimize the treatment conditions. PMID- 22429855 TI - Activation-induced cytidine deaminase in antibody diversification and chromosome translocation. AB - DNA damage, rearrangement, and mutation of the human genome are the basis of carcinogenesis and thought to be avoided at all costs. An exception is the adaptive immune system where lymphocytes utilize programmed DNA damage to effect antigen receptor diversification. Both B and T lymphocytes diversify their antigen receptors through RAG1/2 mediated recombination, but B cells undergo two additional processes--somatic hypermutation (SHM) and class-switch recombination (CSR), both initiated by activation-induced cytidine deaminase (AID). AID deaminates cytidines in DNA resulting in U:G mismatches that are processed into point mutations in SHM or double-strand breaks in CSR. Although AID activity is focused at Immunoglobulin (Ig) gene loci, it also targets a wide array of non-Ig genes including oncogenes associated with lymphomas. Here, we review the molecular basis of AID regulation, targeting, and initiation of CSR and SHM, as well as AID's role in generating chromosome translocations that contribute to lymphomagenesis. PMID- 22429857 TI - Molecular logic underlying chromosomal translocations, random or non-random? AB - Chromosomal translocations serve as essential diagnostic markers and therapeutic targets for leukemia, lymphoma, and many types of solid tumors. Understanding the mechanisms of chromosomal translocation generation has remained a central biological question for decades. Rather than representing a random event, recent studies indicate that chromosomal translocation is a non-random event in a spatially regulated, site-specific, and signal-driven manner, reflecting actions involved in transcriptional activation, epigenetic regulation, three-dimensional nuclear architecture, and DNA damage-repair. In this review, we will focus on the progression toward understanding the molecular logic underlying chromosomal translocation events and implications of new strategies for preventing chromosomal translocations. PMID- 22429858 TI - Survey of methadone-drug interactions among patients of methadone maintenance treatment program in Taiwan. AB - BACKGROUND: Although methadone has been used for the maintenance treatment of opioid dependence for decades, it was not introduced in China or Taiwan until 2000s. Methadone-drug interactions (MDIs) have been shown to cause many adverse effects. However, such effects have not been scrutinized in the ethnic Chinese community. METHODS: The study was performed in two major hospitals in southern Taiwan. A total of 178 non-HIV patients aged >= 20 years who had participated in the Methadone Maintenance Treatment Program (MMTP) >= 1 month were recruited. An MDI is defined as concurrent use of drug(s) with methadone that may result in an increase or decrease of effectiveness and/or adverse effect of methadone. To determine the prevalence and clinical characteristics of MDIs, credible data sources, including the National Health Insurance (NHI) database, face-to-face interviews, medical records, and methadone computer databases, were linked for analysis. Socio-demographic and clinical factors associated with MDIs and co medications were also examined. RESULTS: 128 (72%) MMTP patients took at least one medication. Clinically significant MDIs included withdrawal symptoms, which were found among MMTP patients co-administered with buprenorphine or tramadol; severe QTc prolongation effect, which might be associated with use of haloperidol or droperidol; and additive CNS and respiratory depression, which could result from use of methadone in combination with chlorpromazine or thioridazine. Past amphetamine use, co-infection with hepatitis C, and a longer retention in the MMTP were associated with increased odds of co-medication. Among patients with co medication use, significant correlates of MDIs included the male gender and length of co-medication in the MMTP. CONCLUSIONS: The results demonstrate clinical evidence of significant MDIs among MMTP patients. Clinicians should check the past medical history of MMTP clients carefully before prescribing medicines. Because combinations of methadone with other psychotropic or opioid medications can affect treatment outcomes or precipitate withdrawal symptoms, clinicians should be cautious when prescribing these medications to MMTP patients and monitor the therapeutic effects and adverse drug reactions. Although it is difficult to interconnect medical data from different sources for the sake of privacy protection, the incumbent agency should develop pharmacovigilant measures to prevent the MDIs from occurring. Physicians are also advised to check more carefully on the medication history of their MMTP patients. PMID- 22429859 TI - Superiority of gold versus platinum irrigated tip catheter ablation of the pulmonary veins and the cavotricuspid isthmus: a randomized study comparing tip temperatures and cooling flow requirements. AB - INTRODUCTION: In order to optimize power delivery into the myocardium during radiofrequency ablation (RFA) without overheating the electrode tip, active cooling of the tip electrode as well as electrode tips made of gold have evolved. Recently, an externally irrigated gold tip electrode ablation catheter has been developed to combine the advantages of these 2 technologies. We sought to investigate the procedural parameters tip temperature, delivered power and cooling flow requirements of the irrigated gold tip catheter in comparison to the conventional irrigated platinum iridium (Pt) tip catheter in pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. METHODS AND RESULTS: Sixty patients referred for first PVI were randomized into ablation with irrigated gold tip catheter versus irrigated Pt tip catheter. Forty-nine patients received ablation of CTI following PVI. Mean and standard deviation from all measurements were calculated for each patient. During RFA of pulmonary veins, mean catheter tip temperature was significantly lower in the gold group (35.4 +/- 0.9 degrees C vs 38.2 +/- 0.8 degrees C, P < 0.001), and total amount of delivered energy was higher (1303.1 +/- 81.1 W vs 1223.7 +/- 115.6 W, P = 0.004). During CTI ablation, necessary saline flow was almost 2.5-fold lower in the gold group (22.5 +/- 5.9 mL/min vs 52.5 +/- 9.7 mL/min, P < 0.001), accompanied by significantly lower tip temperature (39.1 +/- 0.6 degrees C vs 40.5 +/- 1.4 degrees C, P < 0.001). CONCLUSION: The irrigated gold tip electrode allows to deliver significantly more energy at a lower electrode tip temperature in RFA of PV and CTI in comparison to the irrigated Pt tip electrode. The required saline flow during CTI ablation is much lower than in Pt. PMID- 22429860 TI - Treatment of corneal defects with delayed re-epithelization with a medical device/drug delivery system for epidermal growth factor. AB - BACKGROUND: Human recombinant epidermal growth factor has been shown to be effective in corneal healing when applied topically. The purpose of this preliminary study was to observe whether re-epithelization occurred in patients with non-healing corneal defects treated with a bandage contact lenses impregnated with epidermal growth factor. DESIGN: Prospective non-comparative interventional case series study. Epidermal growth factor-impregnated bandage contact lenses (created through passive transfer of epidermal growth factor into hydrogel contact lenses of high water content) were used to passively release epidermal growth factor to the corneal surface of the damaged eye. PARTICIPANTS: Nine clinical patients who presented for tertiary care at the University of British Columbia Eye Care Centre at Vancouver General Hospital. METHODS: All patients had clinically significant delayed corneal re-epithelization that had not healed despite standard treatments including conventional bandage contact lenses and topical medications. Causes of delayed re-epithelization varied from corneal injuries (e.g. alkali burns, recurrent corneal erosions) to recent corneal surgery (photorefractive keratectomy, phototherapeutic keratectomy, penetrating keratoplasty). MAIN OUTCOME MEASURES: Closure of wounds. RESULTS: Re-epithelialization was seen in the corneas of seven of the nine patients within 8 days after insertion of the epidermal growth factor-treated bandage contact lens into the damaged eye. The drug delivery system appeared to be most effective in non-inflamed corneas. CONCLUSIONS: Preliminary results indicate that bandage contact lenses impregnated with epidermal growth factor may be helpful in promoting re-epithelization in corneas with delayed healing. Efficacy appears to be reduced for vascularized and significantly inflamed corneas. PMID- 22429861 TI - The effects of male age on sperm analysis by motile sperm organelle morphology examination (MSOME). AB - BACKGROUND: This study aimed to investigate the influence of age on sperm quality, as analysed by motile sperm organelle morphology examination (MSOME). METHODS: Semen samples were collected from 975 men undergoing evaluation or treatment for infertility. Sperm cells were evaluated at 8400* magnification using an inverted microscope equipped with Nomarski (differential interference contrast) optics. Two forms of spermatozoa were considered: normal spermatozoa and spermatozoa with large nuclear vacuoles (LNV, defined as vacuoles occupying > 50% of the sperm nuclear area). At least 200 spermatozoa per sample were evaluated, and the percentages of normal and LNV spermatozoa were determined. The subjects were divided into three groups according to age: Group I, less than or equal to 35 years; Group II, 36-40 years; and Group III, greater than or equal to 41 years. RESULTS: There was no difference in the percentages of normal sperm between the two younger (I and II) groups (P >0.05). The percentage of normal sperm in the older group (III) was significantly lower than that in the younger (I and II) groups (P < 0.05). There was no difference in the percentage of LNV spermatozoa between the younger (I and II) groups (P >0.05). The percentage of LNV spermatozoa was significantly higher in the older group (III) than in the younger (I and II) groups (P < 0.05). Regression analysis demonstrated a significant decrease in the incidence of normal sperm with increasing age (P < 0.05; r = -0.10). However, there was a significant positive correlation between the percentage of spermatozoa with LNV and male age (P < 0.05, r = 0.10). CONCLUSION: The results demonstrated a consistent decline in semen quality, as reflected by morphological evaluation by MSOME, with increased age. Considering the relationship between nuclear vacuoles and DNA damage, these age-related changes predict that increased paternal age should be associated with unsuccessful or abnormal pregnancy as a consequence of fertilisation with damaged spermatozoa. Given that sperm nuclear vacuoles can be evaluated more precisely at high magnification, these results support the routine use of MSOME for ICSI as a criterion for semen analysis. PMID- 22429862 TI - Robotic paediatric urology. PMID- 22429863 TI - A new RNASeq-based reference transcriptome for sugar beet and its application in transcriptome-scale analysis of vernalization and gibberellin responses. AB - BACKGROUND: Sugar beet (Beta vulgaris sp. vulgaris) crops account for about 30% of world sugar. Sugar yield is compromised by reproductive growth hence crops must remain vegetative until harvest. Prolonged exposure to cold temperature (vernalization) in the range 6 degrees C to 12 degrees C induces reproductive growth, leading to bolting (rapid elongation of the main stem) and flowering. Spring cultivation of crops in cool temperate climates makes them vulnerable to vernalization and hence bolting, which is initiated in the apical shoot meristem in processes involving interaction between gibberellin (GA) hormones and vernalization. The underlying mechanisms are unknown and genome scale next generation sequencing approaches now offer comprehensive strategies to investigate them; enabling the identification of novel targets for bolting control in sugar beet crops. In this study, we demonstrate the application of an mRNA-Seq based strategy for this purpose. RESULTS: There is no sugar beet reference genome, or public expression array platforms. We therefore used RNA-Seq to generate the first reference transcriptome. We next performed digital gene expression profiling using shoot apex mRNA from two sugar beet cultivars with and without applied GA, and also a vernalized cultivar with and without applied GA. Subsequent bioinformatics analyses identified transcriptional changes associated with genotypic difference and experimental treatments. Analysis of expression profiles in response to vernalization and GA treatment suggested previously unsuspected roles for a RAV1-like AP2/B3 domain protein in vernalization and efflux transporters in the GA response. CONCLUSIONS: Next generation RNA-Seq enabled the generation of the first reference transcriptome for sugar beet and the study of global transcriptional responses in the shoot apex to vernalization and GA treatment, without the need for a reference genome or established array platforms. Comprehensive bioinformatic analysis identified transcriptional programmes associated with different sugar beet genotypes as well as biological treatments; thus providing important new opportunities for basic scientists and sugar beet breeders. Transcriptome-scale identification of agronomically important traits as used in this study should be widely applicable to all crop plants where genomic resources are limiting. PMID- 22429864 TI - Analysis of CNTNAP2 polymorphisms in Polish population with pseudoexfoliation syndrome. PMID- 22429865 TI - A new manual method for assessing elbow valgus laxity. AB - BACKGROUND: A screening of ulnar collateral ligament insufficiency is required for overhead throwers, since secondary pathologic changes result from an increased elbow valgus laxity. We developed a new manual method for assessing elbow valgus laxity and investigated the reliability of this method and its correlation with ultrasonographic assessment. METHODS: We defined elbow valgus laxity as the difference between the shoulder external rotation angle (ER angle) measured with the elbow in 90 degrees flexion and that measured with the elbow in extension because ER angle measured with the elbow in 90 degrees flexion includes elbow valgus laxity and ER angle with the elbow in extension does not include it. ER angle measurement with the elbow in extension involved the use of a custom arm holder. Three examiners each measured elbow valgus laxity by the new method in 5 healthy volunteers. Intraobserver and interobserver reliability was evaluated by calculating the intraclass correlation coefficient. We then assessed 19 high school baseball players with no complaints of shoulder or elbow pain. Elbow ultrasonography was performed with a 10-MHz linear transducer with the elbow in 90 degrees flexion, and the forearm in the neutral position, and the width of the medial joint space at the level of the anterior bundle was measured. Elbow valgus laxity assessed by ultrasonography was defined as the difference between the medial joint space width with gravity stress and that without gravity stress. Increased elbow valgus laxity assessed by both our method and ultrasonography was defined as the difference between the laxity of the elbow on the throwing side and that on the contralateral side. Pearson's correlation coefficient (r) was calculated to evaluate the relationship between increased elbow valgus laxity obtained by our manual method and that by ultrasonography. RESULTS: Intraobserver reliability ranged from 0.92 to 0.98, and interobserver reliability was 0.70. The increased elbow valgus laxity assessed by our method was significantly correlated with that assessed by ultrasonographic assessment (P = 0.019, r = 0.53). CONCLUSIONS: Elbow valgus laxity can be assessed by our method. This method may be useful for screening for insufficiency of the ulnar collateral ligament. PMID- 22429866 TI - Detection of vascular endothelial growth factor (VEGF) in moderate osteoarthritis in a rabbit model. AB - INTRODUCTION: Vascular endothelial growth factor (VEGF) is detectable in later stages of human osteoarthritis (OA), but not in the healthy articular cartilage. Due to its capacity to increase matrix metalloproteinases and to decrease their inhibitors (tissue inhibitors of metalloproteinases or TIMPs) VEGF seems to play an important role in the development of osteoarthrosis. In late stages of osteoarthritis, invasion of blood vessels from the subchondral growth plate, synovitis with angiogenesis and osteophyte growth is observable. Several studies have revealed a central role for VEGF in all these phenomena. In order to investigate whether VEGF participates in early changes of OA or may even possess characteristics of a marker of OA, we developed an experimental posttraumatic OA New Zealand White rabbit animal model. MATERIALS AND METHODS: In four skeletally mature New Zealand White rabbits, OA was induced by joint instability after transsection of the anterior cruciate ligament in both knees. After eight weeks the animals were killed. OA was verified histologically using the Mankin scale. Expression of VEGF was detected by immunohistochemistry and RT-PCR. Proteoglycans were evaluated by using HE and safranin-O staining. Four non-surgically treated animals acted as a control. RESULTS: The mean Mankin score was 5.11 (+/-2.14), corresponding to a moderate OA. VEGF and VEGF transcripts were detectable in the cartilage of early experimental posttraumatic OA rabbits. Control samples remained negative for VEGF mRNA and protein. DISCUSSION: The results of this study are promising concerning the role of VEGF as a diagnostic marker. VEGF could further be participated in early changes of OA. A therapeutic approach by modulation of VEGF production could be a possibility for the future. PMID- 22429867 TI - Differences in 5 anatomic parameters of mandibular body morphology by gonial angle size in dentulous Japanese subjects. AB - This study aimed to determine the differences in 5 anatomical parameters of the mandibular body on dental panoramic radiographs (DPRs) of 234 dentulous Japanese subjects (21-78years; mean, 25.76; median, 27 teeth) according to gender and gonial angle (GA) size, and to analyse the correlations between GA size and each variable by gender. The subjects were divided into low (LGA<=120 degrees ) and high gonial angle (HGA>=125 degrees ) groups. Linear, angular, and morphological measurements were obtained using the DPRs. Statically significant differences were determined using the Mann-Whitney U and chi(2) tests and simple regression analysis. Mandibular cortical width - MCW, antegonial notch depth - AD and angle AA, and panoramic mandibular index - PMI in the LGA group were significantly larger than those of the HGA group. In men, a significant difference was observed in the distribution of the 3 mandibular cortical index categories between both GAs. Sexual dimorphism for MCW and AD was significantly greater in men than in women. There were significantly negative low correlations between the GA and variables of the MCW, AD, and PMI. These results suggest that the MCW and AD can show significantly different morphology according to gender and GA size. PMID- 22429868 TI - Material parameters of the reindeer antler for use in dental implant biomechanics. AB - The survival of dental implants, in particular immediately loaded implants, critically depends on the biomechanical properties of the bone bed surrounding them. In experimental animal investigations of immediately loaded implants the initial stability, implant design as well as stress and strain distributions in the surrounding bone have been extensively studied. It was the aim of this study to investigate the biomechanical properties of the reindeer antler used as a bony tissue surrounding dental implants, in particular the Young's modulus, Poisson's ratio, and further numerical parameters such as mesh density, friction models and the corresponding frictional coefficients and relative velocities for establishing a novel animal model that can be used in the numerical analyses of experimentally investigated antler specimens. The sensitivity of the investigated parameters was analysed based on the close correlation of numerical and experimental results. No obvious influence of the frictional coefficient and/or relative velocity was observed on the implant displacement using a finite element model. Moreover, nearly identical numerical and experimental results were observed for two kinds of implants concerning implant deflection in the x-axis and implant rotation around the y-axis. PMID- 22429869 TI - Simultaneous anabolic and catabolic responses of human chondrocytes seeded in collagen hydrogels to long-term continuous dynamic compression. AB - Cartilage repair strategies increasingly focus on the in vitro development of cartilaginous tissues that mimic the biological and mechanical properties of native articular cartilage. However, current approaches still face problems in the reproducible and standardized generation of cartilaginous tissues that are both biomechanically adequate for joint integration and biochemically rich in extracellular matrix constituents. In this regard, the present study investigated whether long-term continuous compressive loading would enhance the mechanical and biological properties of such tissues. Human chondrocytes were harvested from 8 knee joints (n=8) of patients having undergone total knee replacement and seeded into a collagen type I hydrogel at low density of 2*10(5)cells/ml gel. Cell seeded hydrogels were cut to disks and subjected to mechanical stimulation for 28 days with 10% continuous cyclic compressive loading at a frequency of 0.3 Hz. Histological and histomorphometric evaluation revealed long-term mechanical stimulation to significantly increase collagen type II and proteoglycan staining homogenously throughout the samples as compared to unstimulated controls. Gene expression analyses revealed a significant increase in collagen type II, collagen type I and MMP-13 gene expression under stimulation conditions, while aggrecan gene expression was decreased and no significant changes were observed in the collagen type II/collagen type I mRNA ratio. Mechanical propertywise, the average value of elastic stiffness increased in the stimulated samples. In conclusion, long-term mechanical preconditioning of human chondrocytes seeded in collagen type I hydrogels considerably improves biological and biomechanical properties of the constructs, corroborating the clinical potential of mechanical stimulation in matrix-associated autologous chondrocyte transplantation (MACT) procedures. PMID- 22429870 TI - Exogenous markers for the characterization of human diseases associated with oxidative stress. AB - Many human conditions, including neurological diseases, atherosclerosis, cancer, diabetic complications and aging, are thought to be associated with oxidative stress (OS). The development of reliable and informative markers for the characterization of OS in humans is thus highly important. Various endogenous markers are known, but their accumulation with increasing OS and with time is not certain, and most of them do not provide information on the type or source of the stress, or on the kinetics of their formation. The aim of the present overview is to present exogenous markers, designed and synthesized by our group, which are sensitive to OS and can identify its presence, the type of reactive oxygen and nitrogen species involved ex vivo, and potential damage incurred by bio macromolecules, in real time. A microdialysis technique is used in animals for evaluation of OS in vivo. The designed probes are composed of several endogenous subunits, attached together covalently to form molecules that do not exist as such in humans. The subunits include an amino acid (tyrosine), an unsaturated fatty acid (linoleic acid), a nucleic acid (2'-deoxyribose guanosine) and cholesterol, representing the major macromolecules of the body, i.e. proteins, lipids, DNA and sterols, respectively. Incubation of these markers in a biological sample ex vivo, such as blood/serum, urine, saliva, cells or tissues under OS, alters their subunits, which are then analyzed and identified by LC/MS. This review demonstrates the potential of these markers to identify OS in samples taken from humans and animals suffering from, for example, atherosclerosis, hypertension, or Alzheimer's or Parkinson's disease. PMID- 22429871 TI - A 43 kD protein from the leaves of the herb Cajanus indicus L. modulates doxorubicin induced nephrotoxicity via MAPKs and both mitochondria dependent and independent pathways. AB - Doxorubicin (Dox), a chemotherapeutic drug, is used for the treatment of different types of cancers. Application of this drug has now been made limited because of its several acute and chronic side effects. The aim of this work is to investigate the nephroprotecive role of a 43 kD protein (CI protein) isolated from the leaves of Cajanus indicus L, against Dox-induced oxidative impairment and kidney tissue damage. Administration of Dox (20 mg/kg body weight, once) significantly enhanced levels of blood urea nitrogen (BUN), creatinine, uric acid, TNF-alpha, urinary gamma-glutamyl transpeptidase (gamma-GT) activity, total urinary protein and urinary glucose level. Moreover, Dox exposure increased intracellular ROS production, lipid peroxidation, protein carbonylation and ATPases (like Na(+)/K(+), Mg(2+).) activities. On the other hand, the same exposure decreased GSH level and the activities of antioxidant enzymes; indicating that Dox-induced renal damage was mediated via oxidative stress. Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential, disturbed Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased levels of Apaf1, caspase-9/3/8, FAS, cleaved PARP protein and ultimately led to apoptotic cell death. In addition, Dox distinctly increased the phosphorylation of p38, JNK and ERK MAPKs. Post treatment with CI protein (3 mg/kg body weight, once daily for 4 days), however, reduced Dox-induced oxidative stress and suppressed all these apoptotic events. Histological studies also support the beneficial role of the CI protein in this organ pathophysiology. Combining, results suggest that CI protein might act as a beneficial agent in Dox-induced renal dysfunctions. PMID- 22429872 TI - Citalopram is a more potent platelet function inhibitor than paroxetine in a case control study. PMID- 22429873 TI - Long-term effects of an inpatient weight-loss program in obese children and the role of genetic predisposition-rationale and design of the LOGIC-trial. AB - BACKGROUND: The prevalence of childhood obesity has increased worldwide, which is a serious concern as obesity is associated with many negative immediate and long term health consequences. Therefore, the treatment of overweight and obesity in children and adolescents is strongly recommended. Inpatient weight-loss programs have shown to be effective particularly regarding short-term weight-loss, whilst little is known both on the long-term effects of this treatment and the determinants of successful weight-loss and subsequent weight maintenance.The purpose of this study is to evaluate the short, middle and long-term effects of an inpatient weight-loss program for children and adolescents and to investigate the likely determinants of weight changes, whereby the primary focus lies on the potential role of differences in polymorphisms of adiposity-relevant genes. METHODS/DESIGN: The study involves overweight and obese children and adolescents aged 6 to 19 years, who participate in an inpatient weight-loss program for 4 to 6 weeks. It started in 2006 and it is planned to include 1,500 participants by 2013. The intervention focuses on diet, physical activity and behavior therapy. Measurements are taken at the start and the end of the intervention and comprise blood analyses (DNA, lipid and glucose metabolism, adipokines and inflammatory markers), anthropometry (body weight, height and waist circumference), blood pressure, pubertal stage, and exercise capacity. Physical activity, dietary habits, quality of life, and family background are assessed by questionnaires. Follow-up assessments are performed 6 months, 1, 2, 5 and 10 years after the intervention: Children will complete the same questionnaires at all time points and visit their general practitioner for examination of anthropometric parameters, blood pressure and assessment of pubertal stage. At the 5 and 10 year follow-ups, blood parameters and exercise capacity will be additionally measured. DISCUSSION: Apart from illustrating the short, middle and long-term effects of an inpatient weight-loss program, this study will contribute to a better understanding of inter-individual differences in the regulation of body weight, taking into account the role of genetic predisposition and lifestyle factors. TRIAL REGISTRATION: NCT01067157. PMID- 22429874 TI - Assessment of human deoxynivalenol exposure using an LC-MS/MS based biomarker method. AB - The Fusarium toxin deoxynivalenol (DON) is one of the most abundant mycotoxins worldwide and poses many adverse health effects to human and animals. Consequently, regulatory limits and a provisional maximum tolerable daily intake (PMTDI) for this important type B-trichothecene were assigned. We conducted a pilot survey to investigate the level of DON exposure in Austrian adults by measurements of DON and its glucuronide conjugates (DON-GlcA's), as biomarkers of exposure, in first morning urine. The average concentration of total DON (free DON+DON-GlcA's) was estimated to be 20.4+/-2.4 MUg L-1 (max. 63 MUg L-1). Surprisingly, we found that one third of the volunteers (n=27) exceeded the established PMTDI when consuming regular diet. DON-GlcA's were directly quantified by LC-MS/MS and the results were compared with indirect quantification after enzymatic hydrolysis and confirmed the suitability of the direct method. Moreover, we investigated the in vivo metabolism of DON in humans and were able to determine two closely eluting DON-GlcA's in naturally contaminated urine samples for the first time. In contrast to previous findings we have tentatively identified DON-15-glucuronide as a major DON metabolite in human urine based on the analysis of these samples. About 75% of total glucuronides were derived from this metabolite while DON-3-glucuronide accounted for approximately 25%. The reported new findings clearly demonstrate the great potential of suitable biomarkers to critically assess exposure of humans and animals to DON. PMID- 22429875 TI - Comparison of three derivatization reagents for the simultaneous determination of highly hydrophilic pyrimidine antitumor agents in human plasma by LC-MS/MS. AB - A comparison of three derivatization reagents (dansyl chloride, diazomethane and p-bromophenacyl bromide) for the simultaneous quantitation of three anticancer chemicals (tegafur, 5-fluorouracil and gimeracil) and endogenous uracil in plasma using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and evaluated. Through a comprehensive consideration, p bromophenacyl bromide (p-BPB) was finally selected as the derivatization reagent. Because it essentially changed the chromatographic behavior of the aforementioned highly hydrophilic compounds and significantly enhanced their sensitivities. The method was validated over the concentration ranges of 5-5000 ng/ml for tegafur, 0.6-700 ng/ml for 5-fluorouracil, 3-700 ng/ml for gimeracil and 6-2000 ng/ml for uracil. The method was successfully applied to the pharmacokinetics study of tegafur, 5-fluorouracil, gimeracil and uracil in cancer patients. PMID- 22429876 TI - A rapid and sensitive LC/ESI-MS/MS method for quantitative analysis of docetaxel in human plasma and its application to a pharmacokinetic study. AB - Docetaxel is a taxane family antineoplastic agent widely employed in cancer chemotherapy. We developed a liquid chromatography/tandem mass spectrometry method for the determination of docetaxel in human plasma. Plasma samples were deproteinized by acetonitrile containing internal standard paclitaxel. Chromatographic separation was performed on a TSKgel ODS-100 V 3 MUm (50 mm * 2.0 mm i.d.) column using a mobile phase composed of acetonitrile-methanol-water formic acid (50:5:45:0.1, v/v/v/v). Detection was performed on a triple quadrupole tandem mass spectrometer with multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. This method covered a linearity range of 5-5000 ng/mL with the lower limit of quantification of 5 ng/mL. The intra-day precision and inter-day precision (R.S.D.) of analysis were less than 6.7%, and the accuracy (R.E.) was within +/- 9.0% at the concentrations of 5, 20, 200, and 2000 ng/mL. The total run time was 5.0 min. This method was successfully applied for clinical pharmacokinetic investigation. PMID- 22429877 TI - Development of a highly sensitive method for the quantification of estrone and estradiol in serum by liquid chromatography tandem mass spectrometry without derivatization. AB - Measurement of estrone (E1) and estradiol (E2) values <1 pg/mL (3.7 pmol/L) is necessary for postmenopausal, pediatric and male serum samples. Until now this was rarely reached and only through derivatization which can present problems for estradiol. A very sensitive LC-MS/MS method was developed avoiding derivatization, convenient for large-scale studies. The desired sensitivity and specificity were achieved using ESI negative mode, LLE and a 2D chromatography consisting of a trapping column and a second dimension reverse-phase C8 analytical column. A mixture of an aqueous solution of ammonium fluoride at 0.2mM and methanol was used on the analytical column to further increase the sensitivity. Serum LOQ was <0.5 pg/mL (1.9 pmol/L) for E2 and E1 and recoveries ranged from 95 to 105%. No carry-over was detectable. Inter assay CV's were 4.0% at 21 pg/mL (77 pmol/L) for E2, 7.6% at 25 pg/mL (93 pmol/L) for E1. Comparison with commercial direct estrogen assays (Roche Diagnostics E170 for E2, Bioline RIA for E1) exposed analytical unsuitability (due to a combined lack of sensitivity and specificity) for the assay of male, postmenopausal or pediatric samples. PMID- 22429879 TI - Nutrition and sarcopenia: evidence for an interaction. AB - Nutritional interventions that might influence sarcopenia, as indicated by literature reporting on sarcopenia per se as well as dynapenia and frailty, are reviewed in relation to potential physiological aetiological factors, i.e. inactivity, anabolic resistance, inflammation, acidosis and vitamin D deficiency. As sarcopenia occurs in physically active and presumably well-nourished populations, it is argued that a simple nutritional aetiology is unlikely and unequivocal evidence for any nutritional influence is extremely limited. Dietary protein is probably the most widely researched nutrient but only for frailty is there one study showing evidence of an aetiological influence and most intervention studies with protein or amino acids have proved ineffective with only a very few exceptions. Fish oil has been shown to attenuate anabolic resistance of muscle protein synthesis in one study. There is limited evidence for a protective influence of antioxidants and inducers of phase 2 proteins on sarcopenia, dynapenia and anabolic resistance in human and animal studies. Also fruit and vegetables may protect against acidosis-induced sarcopenia through their provision of dietary potassium. While severe vitamin D deficiency is associated with dynapenia and sarcopenia, the evidence for a beneficial influence of increasing vitamin D status above the severe deficiency level is limited and controversial, especially in men. On this basis there is insufficient evidence for any more specific nutritional advice than that contained in the general healthy lifestyle-healthy diet message: i.e. avoiding inactivity and low intakes of food energy and nutrients and maintain an active lifestyle with a diet providing a rich supply of fruit and vegetables and frequent oily fish. PMID- 22429878 TI - Serum metabolomic profiles from patients with acute kidney injury: a pilot study. AB - Low sensitivity of current clinical markers (serum creatinine and blood urea nitrogen (BUN)) in early stages of the development of acute kidney injury (AKI) limits their utility. Rapid LC/MS-based metabolic profiling of serum demonstrated in a pilot study that metabolomics could provide novel indicators of AKI. Metabolic profiles of serum samples from seventeen hospitalized patients with newly diagnosed AKI were compared with the profiles of serum from age-matched subjects with normal kidney function. Increases in acylcarnitines and amino acids (methionine, homocysteine, pyroglutamate, asymmetric dimethylarginine (ADMA), and phenylalanine) and a reduction in serum levels of arginine and several lysophosphatidyl cholines were observed in patients with AKI compared to healthy subjects. Increases in homocysteine, ADMA and pyroglutamate have been recognized as biomarkers of cardiovascular and renal disease, and acylcarnitines represent biomarkers of defective fatty acid oxidation. The results of this pilot study demonstrate the utility of metabolomics in the discovery of novel serum biomarkers that can facilitate the diagnosis and determine prognosis of AKI in hospitalized patients. PMID- 22429880 TI - Expression of a splicing variant of the CADM1 specific to small cell lung cancer. AB - CADM1, a member of the immunoglobulin superfamily cell adhesion molecule, acts as a tumor suppressor in a variety of human cancers. CADM1 is also ectopically expressed in adult T-cell leukemia (ATL), conferring an invasive phenotype characteristic to ATL. Therefore, CADM1 plays dual roles in human oncogenesis. Here, we investigate the roles of CADM1 in small cell lung cancer (SCLC). Immunohistochemistry demonstrates that 10 of 35 (29%) primary SCLC tumors express CADM1 protein. Western blotting and RT-PCR analyses reveal that CADM1 is significantly expressed in 11 of 14 SCLC cells growing in suspension cultures but in neither of 2 SCLC cells showing attached growth to plastic dishes, suggesting that CADM1 is involved in anchorage-independent growth in SCLC. In the present study, we demonstrate that SCLC expresses a unique splicing variant of CADM1 (variant 8/9) containing additional extracellular fragments corresponding to exon 9 in addition to variant 8, a common isoform in epithelia. Variant 8/9 of CADM1 is almost exclusively observed in SCLC and testis, although this variant protein localizes along the membrane and shows similar cell aggregation activity to variant 8. Interestingly, both variant 8/9 and variant 8 of CADM1 show enhanced tumorigenicity in nude mice when transfected into SBC5, a SCLC cell lacking CADM1. Inversely, suppression of CADM1 expression by shRNA reduced spheroid-like cell aggregation of NCI-H69, an SCLC cell expressing a high amount of CADM1. These findings suggest that CADM1 enhances the malignant features of SCLC, as is observed in ATL, and could provide a molecular marker specific to SCLC. PMID- 22429881 TI - Restrained eaters preserve top-down attentional control in the presence of food. AB - This study investigated the attentional control of restrained eaters when exposed to food. Restrained (N=55) and unrestrained eaters (N=56) completed a color word Stroop task. Top-down attentional control was assessed by adaptation effects (the Stroop effect is smaller when the previous trial is an incongruent color word than a congruent color word). Adaptation effects differed between restrained and unrestrained eaters according to the type of background image presented (high-fat food vs. non-food). Specifically, in restrained eaters adaptation effects did not differ as a function of image. In contrast, adaptation effects in unrestrained eaters were not observed with high-fat food. Motivation to either approach or avoid food may explain these differences. PMID- 22429882 TI - Intracellular redox equilibrium is essential for the constitutive expression of AP-1 dependent genes in resting cells: studies on TGF-beta1 regulation. AB - The mechanisms involved in the continuous expression of constitutive genes are unclear. We hypothesize that steady state intracellular reactive oxygen species (ROS), which their levels are tightly maintained, could be regulating the expression of these constitutive genes in resting cells. We analyzed the regulation of an important constitutive gene, TGF-beta1, after decreasing intracellular ROS concentration in human mesangial cells. Decreased intracellular hydrogen peroxide by catalase addition reduced TGF-beta1 protein, mRNA expression and promoter activity. Furthermore, catalase decreased the basal activity of Activated Protein-1 (AP-1) that regulates TGF-beta1 promoter activity. This effect disappeared when AP-1 binding site was removed. Similar results were observed with another protein containing AP-1 binding sites in its promoter, such as eNOS, but it was not the case in other constitutive genes without any AP-1 binding site, as COX1 or PKG1. The pharmacological inhibition of the different ROS synthesis sources by blocking NADPH oxidase, the mitochondrial respiratory chain or xanthine oxidase, or the use of human fibroblasts with genetically deficient mitochondrial activity, induced a similar, significant reduction of steady state ROS concentration as the one observed with catalase. Moreover, there was decreased TGF-beta1 expression in all the cases excepting the xanthine oxidase blockade. These findings suggest a novel role for the steady state intracellular ROS concentration, where the compartmentalized, different systems involved in the intracellular ROS production, could be essential for the expression of constitutive AP1-dependent genes, as TGF-beta1. PMID- 22429883 TI - Palms, peccaries and perturbations: widespread effects of small-scale disturbance in tropical forests. AB - BACKGROUND: Disturbance is an important process structuring ecosystems worldwide and has long been thought to be a significant driver of diversity and dynamics. In forests, most studies of disturbance have focused on large-scale disturbance such as hurricanes or tree-falls. However, smaller sub-canopy disturbances could also have significant impacts on community structure. One such sub-canopy disturbance in tropical forests is abscising leaves of large arborescent palm (Arececeae) trees. These leaves can weigh up to 15 kg and cause physical damage and mortality to juvenile plants. Previous studies examining this question suffered from the use of static data at small spatial scales. Here we use data from a large permanent forest plot combined with dynamic data on the survival and growth of > 66,000 individuals over a seven-year period to address whether falling palm fronds do impact neighboring seedling and sapling communities, or whether there is an interaction between the palms and peccaries rooting for fallen palm fruit in the same area as falling leaves. We tested the wider generalisation of these hypotheses by comparing seedling and sapling survival under fruiting and non-fruiting trees in another family, the Myristicaceae. RESULTS: We found a spatially-restricted but significant effect of large arborescent fruiting palms on the spatial structure, population dynamics and species diversity of neighbouring sapling and seedling communities. However, these effects were not found around slightly smaller non-fruiting palm trees, suggesting it is seed predators such as peccaries rather than falling leaves that impact on the communities around palm trees. Conversely, this hypothesis was not supported in data from other edible species, such as those in the family Myristicaceae. CONCLUSIONS: Given the abundance of arborescent palm trees in Amazonian forests, it is reasonable to conclude that their presence does have a significant, if spatially-restricted, impact on juvenile plants, most likely on the survival and growth of seedlings and saplings damaged by foraging peccaries. Given the abundance of fruit produced by each palm, the widespread effects of these small-scale disturbances appear, over long time-scales, to cause directional changes in community structure at larger scales. PMID- 22429884 TI - A modest start, but a steady rise in research use: a longitudinal study of nurses during the first five years in professional life. AB - BACKGROUND: Newly graduated nurses are faced with a challenging work environment that may impede their ability to provide evidence-based practice. However, little is known about the trajectory of registered nurses' use of research during the first years of professional life. Thus, the aim of the current study was to prospectively examine the extent of nurses' use of research during the first five years after undergraduate education and specifically assess changes over time. METHOD: Survey data from a prospective cohort of 1,501 Swedish newly graduated nurses within the national LANE study (Longitudinal Analyses of Nursing Education and Entry in Worklife) were used to investigate perceived use of research over the first five years as a nurse. The dependent variables consisted of three single items assessing instrumental, conceptual, and persuasive research use, where the nurses rated their use on a five-point scale, from 'never' (1) to 'on almost every shift' (5). These data were collected annually and analyzed both descriptively and by longitudinal growth curve analysis. RESULTS: Instrumental use of research was most frequently reported, closely followed by conceptual use, with persuasive use occurring to a considerably lower extent. The development over time showed a substantial general upward trend, which was most apparent for conceptual use, increasing from a mean of 2.6 at year one to 3.6 at year five (unstandardized slope +0.25). However, the descriptive findings indicated that the increase started only after the second year. Instrumental use had a year one mean of 2.8 and a year five mean of 3.5 (unstandardized slope +0.19), and persuasive use showed a year one mean of 1.7 and a year five mean of 2.0 (unstandardized slope +0.09). CONCLUSION: There was a clear trend of increasing research use by nurses during their first five years of practice. The level of the initial ratings also indicated the level of research use in subsequent years. However, it took more than two years of professional development before this increase 'kicked in.' These findings support previous research claiming that newly graduated nurses go through a 'transition shock,' reducing their ability to use research findings in clinical work. PMID- 22429885 TI - beta-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis. AB - Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble beta amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble beta-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the beta amyloid(1-42)/beta-amyloid(1-40) ratio was increased, due primarily to reduced soluble beta-amyloid(1-40), and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical beta-amyloid(1-42)/beta-amyloid(1-40) ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD. PMID- 22429886 TI - Effects of age and beta-amyloid on cognitive changes in normal elderly people. AB - Age-related decline is common in multiple cognitive domains. beta-amyloid (Abeta) deposition, a pathological hallmark of Alzheimer's disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Abeta on cognition during aging. Using positron emission tomography (PET) imaging with the radiotracer Pittsburgh Compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequential multivariate analyses (i.e., principal components analysis [PCA] and discriminant analysis) to obtain summary measures of cognitive tests encompassing multiple cognitive domains. Among 5 cognitive components, a significant age effect was observed in component scores of visual memory and executive functions, regardless of the level of Abeta. Discriminant scores (weighted scores of the 5 cognitive components) revealed a significant effect of both age and Abeta and were further associated with quantitative PIB counts. The results of the current study highlight both effects of age and Abeta on cognitive changes in normal elderly. PMID- 22429887 TI - Structural and functional neural correlates of visuospatial information processing in normal aging and amnestic mild cognitive impairment. AB - Our understanding of cognitive changes related to human aging and their underlying neural processes is challenged by the distinction between normal and pathological aging. In our study, the neural correlates of visuospatial working memory (VSWM) in young persons (YC), healthy older adults (HC) and patients with amnestic mild cognitive impairment (aMCI) were investigated. Effects of the genetic risk factor apolipoprotein E (ApoE) epsilon4 on a VSWM task were analyzed for HC and aMCI patients. Higher cortical activation in extrastriate occipital regions and significantly decreased brain volumes in frontoparietal areas were observed in HC compared with young persons. Also, reduced cortical activation in the right middle frontal gyrus and superior frontal gyrus was observed in aMCI patients compared with HC. Thus, attenuated cortical activation during VSWM tasks is related to the formation of aMCI and may serve as an early marker for cognitive decline. In contrast to previous studies, no significant apolipoprotein E-linked differences were found between HC and aMCI groups. PMID- 22429888 TI - Thermochemical and spectroscopic studies on the supramolecular complex of PAMAM NH2 G4 dendrimer and 5-fluorouracil in aqueous solution. AB - The equilibrium of the formation of polyamidoamine dendrimer (PAMAM-NH(2) G4) and an oncological drug, 5-fluorouracil (FU) in water at room temperature has been examined. Using calorimetric titration, the number of active sites in the dendrimer combining the drug molecules and the equilibrium constant of the dendrimer-drug complex were estimated. The addition of the drug to the dendrimer active sites is an exothermic process. This process is accompanied by a beneficial change in entropy. The number of drug molecules combined by the polymer was confirmed by means of (1)H NMR spectroscopy. (1)HNMR measurements show that the dendrimer macromolecule binds the drug molecules with superficial protonated or unprotonated amine groups. PMID- 22429889 TI - The effect of Tween((r)) 20 on silicone oil-fusion protein interactions. AB - There is evidence in the literature that silicone oil, a lubricant, can induce aggregation in protein formulations delivered through prefilled syringes. Surfactants are commonly used to minimize protein-silicone oil and protein container interactions; however, these interactions are not well characterized and understood. The purpose of this manuscript was to understand the competitive interactions of a fusion protein with the silicone oil in the presence of Tween((r)) 20. An adsorption isotherm for Tween((r)) 20 at the silicone oil/water interface, using silicone oil coated quartz crystals, was generated at 25 degrees C to identify surface saturation concentrations. A concentration of Tween((r)) 20 providing interfacial saturation was selected for protein adsorption studies at the silicone oil/water interface. The surfactant molecules adsorbed at the interface in a monolayer with a reduced viscoelastic character in comparison to the bound protein layer. A significant reduction in protein adsorption was observed when the surfactant was present at the interface. No desorption of the pre-adsorbed protein molecules was observed when Tween((r)) 20 was introduced, suggesting that the protein has strong interactions with the interface. However, both, Tween((r)) 20 and protein, adsorbed to the silicone oil/water interface when adsorption was carried out from a mixture of protein and Tween((r)) 20. PMID- 22429890 TI - Transdermal iontophoresis of ranitidine: an opportunity in paediatric drug therapy. AB - The objective of this study was to examine the use of transdermal iontophoresis for the delivery of ranitidine hydrochloride in children. Constant, direct current, anodal iontophoresis of ranitidine was performed in vitro across dermatomed pig skin. The effect of donor vehicle, current intensity, and drug concentration were first examined using aqueous solutions. It was found that drug delivery was higher at pH 7 (donor: 5mM Tris) than pH 5.6 (donor: water). In the presence of low levels of competing background electrolyte, ranitidine delivery increased linearly with applied current but was independent of the donor drug concentration. The second part of the study evaluated two Pluronic((r)) F-127 gels as potential vehicles for ranitidine delivery. The formulations were characterised in terms of apparent viscosity, conductivity and passive permeation measurements. Iontophoretic delivery of ranitidine was only slightly affected when delivered from the gels relative to aqueous solutions. Overall the results demonstrated that therapeutic paediatric doses of ranitidine (neonates: 0.09-0.17 MUmol/kg h; 1 month to 12 years: 0.36-0.71 MUmol/kg h) could be easily achieved by transdermal iontophoresis with simple gel patches of practical surface area (0.2-1.5 cm(2)/kg). PMID- 22429891 TI - Liberating tumor immunity. PMID- 22429892 TI - Cost effectiveness of community-based and in-patient therapeutic feeding programs to treat severe acute malnutrition in Ethiopia. AB - BACKGROUND: This study estimated the cost effectiveness of community-based therapeutic care (CTC) for children with severe acute malnutrition (SAM) in Sidama Zone, Ethiopia compared to facility based therapeutic feeding center (TFC). METHODS: A cost effectiveness analysis comparing costs and outcomes of two treatment programmes was conducted. The societal perspective, which considers costs to all sectors of the society, was employed. Outcomes and health service costs of CTC and TFC were obtained from Save the Children USA (SC/USA) CTC and TFC programme, government health services and UNICEF(in kind supplies) cost estimates of unit costs. Parental costs were estimated through interviewing 306 caretakers. Cost categories were compared and a single cost effectiveness ratio of costs to treat a child with SAM in each program (regardless of outcome) was computed and compared. RESULTS: A total of 328 patient cards/records of children treated in the programs were reviewed; out of which 306 (157 CTC and 149 TFC) were traced back to their households to interview their caretakers. The cure rate in TFC was 95.36% compared to 94.30% in CTC. The death rate in TFC was 0% and in CTC 1.2%. The mean cost per child treated was $284.56 in TFC and $134.88 in CTC. The institutional cost per child treated was $262.62 in TFC and $128.58 in CTC. Out of these institutional costs in TFC 46.6% was personnel cost. In contrast, majority (43.2%) of the institutional costs in CTC went to ready to use therapeutic food (RUTF). The opportunity cost per caretaker in the TFC was $21.01 whereas it was $5.87 in CTC. The result of this study shows that community based CTC was two times more cost effective than TFC. CONCLUSION: CTC was found to be relatively more cost effective than TFC in this setting. This indicates that CTC is a viable approach on just economic grounds in addition to other benefits such improved access, sustainability and appropriateness documented elsewhere. If costs of RUTF can be reduced such as through local production the CTC costs per child can be further reduced as RUTF constitutes the highest cost in these study settings. PMID- 22429893 TI - Comparison of health-related quality-of-life outcomes for African-American and Caucasian-American men after radical prostatectomy. AB - What's known on the subject? and What does the study add? In addition to a higher prevalence and biological aggressiveness of prostate cancer, African-Americans tend towards narrower pelvises than Caucasians resulting in a potentially more difficult surgical dissection doing radical prostatectomy and increased positive surgical margins. In this study, there was no difference in urinary or sexual HRQL or overall satisfaction between African-Americans and Caucasians 2 years after radical prostatectomy, suggesting that the potential technical challenges of a narrower pelvis do not translate into poorer outcomes for African-Americans. OBJECTIVE: To determine if any differences exist in postoperative health-related quality-of-life (HRQL) outcomes, e.g. erectile function and continence, after radical prostatectomy (RP) in African-American (AA) vs Caucasian-American (CA) men. PATIENTS AND METHODS: Between October 2000 and July 2008, 1338 CA and 56 AA men underwent open RP by a single surgeon and signed informed consent to participate in a prospective longitudinal outcomes study. The American Urological Association Symptom Score (AUA-SS) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) and a global assessment of satisfaction were self-administered at baseline and after RP 24 months. Urinary, sexual, and satisfaction outcomes were compared at 24 months. RESULTS: AA men had significantly higher rates of hypertension and diabetes. There were no other significant baseline differences in age, co-morbidities, body mass index, phosphodiesterase type 5 inhibitor use, preoperative prostate-specific antigen level, AUA-SS, and UCLA-PCI scores. There were no differences in the percentage of men undergoing nerve-sparing procedures, estimated blood loss, transfusion rates, or complication rates between the groups. At 24 months after RP the mean UCLA-PCI urinary and sexual function and bother scores and global satisfaction scores were similar between the groups. CONCLUSION: AA and CA men experience no significant differences in urinary and sexual HRQL or overall satisfaction after open RP when performed by a single experienced surgeon. PMID- 22429894 TI - Multiple thoracoabdominal impalement injuries. AB - A 20-year-old male was impaled through the chest, abdomen, and right upper thigh by three 1.5 cm (0.59 in) diameter rods, each 2 m (6.56 ft) in length. The first rod entered below his right nipple, the second through the right hypochondrium, and the third through the right upper thigh. He was transported to the hospital with the rods in situ. This paper provides insight as to how these unusual injuries were managed in a limited-resource environment. Even in a developing country, the challenges posed by multiple impalement injuries can be managed successfully by rapid prehospital transfer, along with an adequate and coordinated hospital team effort. PMID- 22429895 TI - Role of the vein of Marshall in atrial fibrillation recurrences after catheter ablation: therapeutic effect of ethanol infusion. AB - Vein of Marshall Ethanol in Recurrent AF. INTRODUCTION: Atrial fibrillation (AF) or flutter can recur after pulmonary vein (PV) antral isolation (PVAI). The vein of Marshall (VOM) has been linked to the genesis of AF. We hypothesized that the VOM may play a role in AF recurrences and that VOM ethanol infusion may have therapeutic value in this setting. METHODS AND RESULTS: Sixty-one patients with recurrent AF or flutter after PVAI were studied. The VOM was successfully cannulated in 54; VOM and PV electrograms were recorded, and differential PV-VOM pacing was performed. VOM signals were present in all patients; however, VOM triggers of AF could not be demonstrated. VOM tachycardia was present in 1 patient. Left inferior (LIPV) and left superior (LSPV) reconnection was present in 32 and 30 patients, respectively. Differential pacing in VOM and LIPV showed VOM-mediated LIPV reconnection in 5/32 patients. In others, VOM and PV connected indirectly via left atrial tissues. Up to four 1 cc infusions of 98% ethanol were delivered in the VOM. Regardless of the reconnection pattern, ethanol infusion eliminated LIPV and LSPV reconnection in 23/32 and 13/30 patients, respectively. Ethanol terminated VOM and LIPV tachycardias in 2 patients. There were no acute procedural complications. CONCLUSIONS: VOM signals are consistently present in recurrent AF. VOM may rarely play a role in PV reconnection. However, VOM ethanol infusion can be useful in patients with recurrent AF after PVAI, assisting in achieving redisconnection of reconnected left PVs. PMID- 22429896 TI - Paying for personalized care: cancer biomarkers and comparative effectiveness. AB - Genomic-based diagnostics can play a key role in creating a more efficient healthcare system by directing patients toward beneficial therapies and away from therapies that pose substantial risk or are unlikely to improve outcomes for the patient. We outline how the value provided by diagnostics is closely linked to a range of factors including magnitude of health outcome improvement, avoiding adverse effect, diagnostic parameters, process of care, resource utilization, and costs. Comparative effectiveness approaches to evidence generation, including health outcome measurements, quality of life, economic analyses, decision modeling, and pragmatic clinical trials, can be used to provide stakeholders with a range of information to inform treatment, guidelines, coverage, and reimbursement decisions. Evidence of comparative effectiveness can also help support value-based reimbursement of cancer biomarkers and treatment strategies as means of paying for personalized medicine. PMID- 22429897 TI - Histochemical and morphometric characterization of broncho-pneumonia in calves caused by infection with Mycoplasma bovis. AB - The aim of this study was to identify morphometric histological features of pneumonia caused by Mycoplasma bovis in calves. Eight three-month-old calves were infected with M. bovis and samples of their lung tissue, three weeks after exposure, compared to samples from four uninfected calves. In the uninfected animals the goblet cells were clustered in the crypt area of the epithelial folds, while in the infected calves they had migrated towards the tips of the folds and were distributed evenly throughout the folds. In infected lung tissue there was goblet cell hyperplasia and metaplasia in the bronchioles and an increased epithelial height. Goblet cell mucin in uninfected calves was acidic, but in infected calves most goblet cells contained neutral mucins. These morphometric and histochemical bronco-epithelial changes may be able to be used as markers of the severity of bovine respiratory mycoplasmosis. PMID- 22429898 TI - Crystal structures from the Plasmodium peroxiredoxins: new insights into oligomerization and product binding. AB - BACKGROUND: Plasmodium falciparum is the protozoan parasite primarily responsible for more than one million malarial deaths, annually, and is developing resistance to current therapies. Throughout its lifespan, the parasite is subjected to oxidative attack, so Plasmodium antioxidant defences are essential for its survival and are targets for disease control. RESULTS: To further understand the molecular aspects of the Plasmodium redox system, we solved 4 structures of Plasmodium peroxiredoxins (Prx). Our study has confirmed PvTrx-Px1 to be a hydrogen peroxide (H2O2)-sensitive peroxiredoxin. We have identified and characterized the novel toroid octameric oligomer of PyTrx-Px1, which may be attributed to the interplay of several factors including: (1) the orientation of the conserved surface/buried arginine of the NNLA(I/L)GRS-loop; and (2) the C terminal tail positioning (also associated with the aforementioned conserved loop) which facilitates the intermolecular hydrogen bond between dimers (in an A C fashion). In addition, a notable feature of the disulfide bonds in some of the Prx crystal structures is discussed. Finally, insight into the latter stages of the peroxiredoxin reaction coordinate is gained. Our structure of PyPrx6 is not only in the sulfinic acid (RSO2H) form, but it is also with glycerol bound in a way (not previously observed) indicative of product binding. CONCLUSIONS: The structural characterization of Plasmodium peroxiredoxins provided herein provides insight into their oligomerization and product binding which may facilitate the targeting of these antioxidant defences. Although the structural basis for the octameric oligomerization is further understood, the results yield more questions about the biological implications of the peroxiredoxin oligomerization, as multiple toroid configurations are now known. The crystal structure depicting the product bound active site gives insight into the overoxidation of the active site and allows further characterization of the leaving group chemistry. PMID- 22429899 TI - Fragrance material review on isojasmone. AB - A toxicologic and dermatologic review of isojasmone when used as a fragrance ingredient is presented. Isojasmone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand alone document. Available data for isojasmone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22429900 TI - The pattern of relapse and survival of elective irradiation of the upper neck for stage N0 nasopharyngeal carcinoma. AB - BACKGROUND: To investigate patterns of failure and survival rates of elective irradiation of upper neck in N0 nasopharyngeal carcinoma patients. METHODS: From February 1996 to November 2002, 97 patients without cervical lymph node involvement were admitted for radiotherapy alone. Before treatment, each patient underwent enhanced CT of nasopharynx and neck. All patients received radiotherapy to the nasopharynx, skull base, and upper neck drainage areas (including levels II, III, and VA). The upper neck was irradiated to a total dose of 50-56 Gy/25-28 fractions/5-5.6 weeks. For the primary tumor, 22 patients used conventional fractionation for a total dose of 70 Gy/35 fractions/7 weeks, and 75 patients used an accelerated hyperfractionationated schedule for a total dose of 78 Gy/60 fractions/6 weeks. RESULTS: The median follow-up of these 97 patients was 7.75 years. 10 patients had recurrences in the nasopharynx, 8 had distant metastasis, and 5 had recurrences in the cervical lymph nodes. Among the cervical lymph node failures, the areas of recurrence were in the II drainage areas in 4 patients who had neck dissections afterwards, and in IA drainage areas in 1 patient who also had recurrence in the nasopharynx. The causes of death were recurrence in the nasopharynx for 8 patients, 1 of these also had recurrence in the neck, distant metastases in 8 patients, and non-neoplastic diseases in 3 patients. CONCLUSIONS: The causes of failure of N0 patients with nasopharyngeal carcinoma after radiotherapy alone to the nasopharynx and upper neck were nasopharyngeal recurrence, distant metastasis, and cervical recurrence in order of frequency. Elective irradiation of upper neck (II, III, VA) is advised for stage N0 patients diagnosed by enhanced CT of neck. Cervical recurrence alone is rare, which did not greatly affect the long-term survival after salvage neck dissection. PMID- 22429901 TI - Long-term risk of intraocular pressure elevation and glaucoma escalation after deep anterior lamellar keratoplasty. AB - BACKGROUND: To determine the prevalence and severity of intraocular pressure changes after deep anterior lamellar keratoplasty and its effect on visual function. DESIGN: Retrospective cohort study. PARTICIPANTS: All patients undergoing deep anterior lamellar keratoplasty procedures at a tertiary referral centre (Leeds University Hospitals, UK) using a manual dissection technique. METHODS: Case note review of all cases between the 1st of January 2000 and the 31st of December 2005. MAIN OUTCOME MEASURES: Raised intraocular pressure, glaucoma incidence or escalation. RESULTS: Data were collected for 69 of eyes of 58 patients. The mean period of follow-up was 54.9 months (median 60, range 6-95 months). The initial diagnosis was keratoconus in 56 cases (81%), corneal scarring in four cases (5.8%), herpes simplex keratitis in four cases (5.8%), lattice dystrophy in four cases (5.8%) and one case of corneal dermoid. Temporarily intraocular pressure was thought to be related to topical steroid use occurred in 12 (17%) cases. Ocular hypertension requiring treatment occurred in three eyes. None of these eyes had progressive disc changes or visual field defects suggestive of glaucoma, and all had well-controlled intraocular pressure on topical, single-drug therapy. Overall, there was a small insignificant rise in intraocular pressure after deep anterior lamellar keratoplasty (P = 0.11). CONCLUSIONS: The long-term risk of glaucoma following deep anterior lamellar keratoplasty using the manual dissection technique appears to be low. Ocular hypertension after deep anterior lamellar keratoplasty is infrequent and can be controlled on topical medication alone. PMID- 22429902 TI - Impact of scanning density on spectral domain optical coherence tomography assessments in neovascular age-related macular degeneration. AB - PURPOSE: To determine the effect of optical coherence tomography (OCT) B-scan density on the qualitative assessment of neovascular age-related macular degeneration (AMD). METHODS: Data were collected from 59 patients imaged with Topcon 3D OCT-1000 (128 B-scans * 512 A-scans). Custom software was used to generate less dense subsets of scans: 1/16 (eight B-scans), 1/8 (16 B-scans), 1/4 (32 B-scans) and 1/2 (64 B-scans). At each B-scan density, scans were assessed for cystoid spaces, subretinal fluid (SRF), subretinal tissue (SRT) and pigment epithelium detachment (PED). For each sampling density, sensitivity, specificity and predictive values were calculated using the full volume scan (128 B-scans) as the reference standard. RESULTS: For cystoid spaces, the detection sensitivity was 76.3% at 1/16 density; this rose to 89.5% with a 1/4 density. For SRF, the detection sensitivity was 75.0% at a 1/16 density; this increased to 91.1% with 1/4 density. For PED, even at the lowest sampling density (1/16) the detection sensitivity was 86.4%; this rose to 94.9% at 1/4 density. For SRT, detection sensitivity at a 1/16 density was 64.7% and only rose above 90% with the densest sampling subset (1/2). CONCLUSIONS: Use of scanning protocols with reduced sampling densities resulted in decreased detection of key features of neovascular AMD; despite this, a sampling density reduced to 1/4 appeared to allow accurate assessment for most features. Current management of neovascular AMD is dependent on qualitative assessment of OCT images; with the recent proliferation of OCT systems, optimization and standardization of scanning protocols may be of value. PMID- 22429903 TI - Daily rhythms of clock gene expression, glycaemia and digestive physiology in diurnal/nocturnal European seabass. AB - Seabass is a fish species with dual (diurnal/nocturnal) feeding behavior, although little is known about changes in its molecular clock, physiology and metabolism linked to this dual behavior. In the research described here possible differences in clock gene expression in central (brain) and peripheral (liver) oscillators, and in physiology (blood glucose and amylase activity in mid intestine) were studied in seabass with diurnal or nocturnal self-feeding patterns under LD 12:12h (light:dark) (lights on=Zeitgeber Time (ZT) 00:00h). The results revealed that per1 expression in brain shows daily rhythmicity with the acrophase (Phi) around the lights offset (ZT 12:00h, Cosinor, p<0.01) in both diurnal and nocturnal seabass. In liver, per 1 daily levels of expression were higher in diurnal fish (univariate GML, p<0.02). Daily blood glucose variations were observed in both groups (ANOVA I, p<0.01), with higher glucose levels occurring at night in nocturnal as well as in diurnal fish, although only diurnal seabass displayed a significant daily rhythm (Phi=ZT 16:52h, Cosinor, p<0.02). The highest values of amylase activity coincided with the feeding-phase of fish; that is, in nocturnal seabass the maximum was reached at ZT 18:00h (ANOVA I, p<0.01), whereas in diurnal seabass the Phi was ZT 03:39h (Cosinor, p<0.02). In short, our findings indicated that the feeding rhythm (diurnal vs. nocturnal) strongly influenced the daily patterns of digestive function and clock gene expression in the liver (feeding-entrained clock), but not in the brain (light entrained clock). PMID- 22429906 TI - A recurrent fusion gene in high-grade endometrial stromal sarcoma: a new tool for diagnosis and therapy? AB - High-grade endometrial stromal sarcomas (ESSs) are an aggressive group of endometrial stromal tumors. A recent study described a recurrent chromosomal translocation (t(10;17)) occurring in ESS, which joins the gene 14-3-3epsilon with either FAM22A or FAM22B. Expression of the resulting fusion gene leads to malignant transformation, and silencing of its expression reverses the malignant phenotype. Because the fusion can be readily detected in diagnostic samples using fluorescent in situ hybridization, this chromosomal aberration could be used to differentiate high-grade ESS from the low-grade, less aggressive form. Discovery of the new oncoprotein could also provide entry points for targeted therapies. PMID- 22429904 TI - Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. AB - The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the MU opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the ventrolateral periaqueductal gray to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation. PMID- 22429907 TI - Multichannel fNIRS assessment of overt and covert confrontation naming. AB - Confrontation naming tasks assess cognitive processes involved in the main stage of word production. However, in fMRI, the occurrence of movement artifacts necessitates the use of covert paradigms, which has limited clinical applications. Thus, we explored the feasibility of adopting multichannel functional near-infrared spectroscopy (fNIRS) to assess language function during covert and overt naming tasks. Thirty right-handed, healthy adult volunteers underwent both naming tasks and cortical hemodynamics measurement using fNIRS. The overt naming task recruited the classical left-hemisphere language areas (left inferior frontal, superior and middle temporal, precentral, and postcentral gyri) exemplified by an increase in the oxy-Hb signal. Activations were bilateral in the middle and superior temporal gyri. However, the covert naming task recruited activation only in the left-middle temporal gyrus. The activation patterns reflected a major part of the functional network for overt word production, suggesting the clinical importance of fNIRS in the diagnosis of aphasic patients. PMID- 22429905 TI - Impact of antibiotic treatments on the expression of the R plasmid tra genes and on the host innate immune activity during pRAS1 bearing Aeromonas hydrophila infection in zebrafish (Danio rerio). AB - BACKGROUND: The transfer of R plasmids between bacteria has been well studied under laboratory conditions and the transfer frequency has been found to vary between plasmids and under various physical conditions. For the first time, we here study the expression of the selected plasmid mobility genes traD, virB11 and virD4 in the 45 kb IncU plasmid, pRAS1, conferring resistance to tetracycline, trimethoprim and sulphonamide, using an in vivo zebrafish infection- treatment model. RESULTS: Three days after oral infection of adult zebrafish with Aeromonas hydrophila harboring pRAS1, elevated expression of pro-inflammatory cytokine (TNF alpha, IL-1beta and IL-8) and complement C3 genes in the intestine coincided with disease symptoms. Tetracycline, trimethoprim and an ineffective concentration of flumequine given 48 h prior to sampling, strongly increased expression of plasmid mobility genes, whereas an effective dosage of flumequine resulted in lower levels of mRNA copies of these genes relative to placebo treatment. Following effective treatment with flumequine, and ineffective treatments with a low concentration of flumequine, with trimethoprim or with sulphonamide, the intestinal expression of immune genes was strongly induced compared to placebo treated control fish. CONCLUSIONS: Treatment of zebrafish infected with an antibiotic resistant (TcR, TmR, SuR) A. hydrophila with ineffective concentrations of flumequine or the ineffective antimicrobials tetracycline and trimethoprim strongly induced expression of genes mediating conjugative transfer of the R-plasmid pRAS1. Simultaneously, there was a strong induction of selected inflammatory and immune response genes, which was again evident in fish subjected to ineffective treatment protocols. Our findings point to the essential role of therapeutic practices in escalation or control of antibiotic resistance transfer, and suggest that antibiotic substances, even in sub-inhibitory concentrations, may stimulate innate defenses against bacterial infections. PMID- 22429908 TI - Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies. AB - BACKGROUND: The management strategies for symptomatic isolated superficial vein thrombosis (SVT) (without concomitant deep vein thrombosis [DVT] or pulmonary embolism [PE]) have yet to achieve widespread consensus. Concerns have been raised regarding the usefulness of prescribing anticoagulant treatments to all patients with isolated SVT. Determining the isolated SVT subgroups who have the highest risks of venous thromboembolism (VTE) recurrence (composite of DVT, PE, and new SVT) may facilitate the identification of patients who are likely to benefit from anticoagulant treatment. DESIGN AND METHODS: We performed a pooled analysis on individual data from two observational, multicenter, prospective studies, to determine predictors for VTE recurrence and their impact in an unselected population of symptomatic isolated SVT patients. RESULTS: One thousand and seventy-four cases of symptomatic isolated SVT were followed up at 3 months. VTE recurrence was observed in 3.9% of the patients; 16.2% of the patients did not receive anticoagulants, and 0.6% experienced a VTE recurrence. Cancer, personal history of VTE and saphenofemoral/popliteal involvement significantly increased the risk of subsequent VTE or DVT/PE in univariate analyses. Only male sex significantly increased the risk of VTE or DVT/PE recurrence in multivariate analyses. Twelve percent of the patients had cancer or saphenofemoral junction involvement, and were at higher risk of DVT/PE recurrence than patients without those characteristics (4.7% vs. 1.9%, P= 0.06). CONCLUSIONS: In patients with symptomatic SVT, only male sex significantly and independently increased the risk of VTE recurrence. Cancer or saphenofemoral junction involvement defined a population at high risk for deep VTE recurrence. Some SVTs might be safely managed without anticoagulants. PMID- 22429909 TI - [NM23, an example of a metastasis suppressor gene]. AB - Metastasis suppressor genes - unlike tumor suppressor genes - are defined by their capacity to control metastatic dissemination in vivo without affecting growth of the primary tumor. The first of these metastasis suppressor genes, NM23, was identified in 1988. Since then, expression of NM23 has been studied widely in human tumor cohorts, often with contradictory results. Not only is NM23 overexpressed in most human solid tumors when compared to healthy tissues, but also low expression of NM23 correlates with metastasis and poor clinical prognosis in the advanced stages of a number of epithelial cancer types, including melanoma, breast, colon, and liver carcinoma. This does not hold true, however, for other cancer types such as neuroblastoma and hematological malignancies, in which high NM23 expression correlates with more aggressive disease. Genetic alterations in the NM23 gene - loss of heterozygosity, spontaneous mutations and polymorphisms - are rarely found in tumors; thus, the metastatic potential of tumor cells is probably affected by NM23 protein levels. Three lines of evidence demonstrate the anti-metastatic activity of NM23: first, overexpression of NM23 in metastatic cell lines reduces their metastatic potential in xenograft models; second, the incidence of lung metastases is elevated in NM23 knockout mice prone to develop hepatocellular carcinoma, and, third, silencing NM23 by RNA interference confers a "metastatic phenotype" on non invasive human epithelial liver and colon cancer cell lines. It appears that NM23 is crucial for inhibiting invasive migration, so acting at early stages of metastatic dissemination. The mechanistic basis of the metastasis suppressor function of NM23 and its regulated expression still remains obscure, however. Reactivation of expression of the endogenous NM23 gene in tumor cells, or stimulation of the pathways it controls, constitutes a promising avenue for anti metastatic therapy. PMID- 22429910 TI - Height, weight and BMI percentiles and nutritional status relative to the international growth references among Pakistani school-aged children. AB - BACKGROUND: Child growth is internationally recognized as an important indicator of nutritional status and health in populations. This study was aimed to compare age- and gender-specific height, weight and BMI percentiles and nutritional status relative to the international growth references among Pakistani school aged children. METHODS: A population-based study was conducted with a multistage cluster sample of 1860 children aged five to twelve years in Lahore, Pakistan. Smoothed height, weight and BMI percentile curves were obtained and comparison was made with the World Health Organization 2007 (WHO) and United States' Centers for Disease Control and Prevention 2000 (USCDC) references. Over- and under nutrition were defined according to the WHO and USCDC references, and the International Obesity Task Force (IOTF) cut-offs. Simple descriptive statistics were used and statistical significance was considered at P < 0.05. RESULTS: Height, weight and BMI percentiles increased with age among both boys and girls, and both had approximately the same height and a lower weight and BMI as compared to the WHO and USCDC references. Mean differences from zero for height-, weight- and BMI-for-age z score values relative to the WHO and USCDC references were significant (P < 0.001). Means of height-for-age (present study: 0.00, WHO: 0.19, USCDC: -0.24), weight-for-age (present study: 0.00, WHO: -0.22, USCDC: 0.48) and BMI-for-age (present study: 0.00, WHO: -0.32, USCDC: -0.53) z score values relative to the WHO reference were closer to zero and the present study as compared to the USCDC reference. Mean differences between weight-for-age (0.19, 95% CI 0.10-0.30) and BMI-for-age (0.21, 95% CI 0.11-0.30) z scores relative to the WHO and USCDC references were significant. Over-nutrition estimates were higher (P < 0.001) by the WHO reference as compared to the USCDC reference (17% vs. 15% overweight and 7.5% vs. 4% obesity) while underweight and thinness/wasting were lower (P < 0.001) by the WHO reference as compared to the USCDC reference (7% vs. 12% underweight and 10% vs. 13% thinness). Significantly lower overweight (8%) and obesity (5%) prevalence and higher thinness grade one prevalence (19%) was seen with use of the IOTF cut-offs as compared to the WHO and USCDC references. Mean difference between height-for-age z scores and difference in stunting prevalence relative to the WHO and USCDC references was not significant. CONCLUSION: Pakistani school-aged children significantly differed from the WHO and USCDC references. However, z score means relative to the WHO reference were closer to zero and the present study as compared to the USCDC reference. Overweight and obesity were significantly higher while underweight and thinness/wasting were significantly lower relative to the WHO reference as compared to the USCDC reference and the IOTF cut-offs. New growth charts for Pakistani children based on a nationally representative sample should be developed. Nevertheless, shifting to use of the 2007 WHO child growth reference might have important implications for child health programs and primary care pediatric clinics. PMID- 22429911 TI - Synthesis and antitumor activity of 5,6-dihydro-17-hydroxy icogenin analogs. AB - Four 5,6-dihydro-17-hydroxy icogenin analogs were designed and synthesized. Their in vitro antitumor activities were tested by the standard MTT assay. Compound 22 (IC(50) = 3.38-8.30 MUM) and compound 23 (IC(50) = 1.90-9.69 MUM) showed potential antitumor activities against the entire tested seven cancer cell lines. The SAR (structure activity relationship) research showed that the introduction of 17-hydroxy lowered the antitumor activity to an extent. PMID- 22429912 TI - Cobalt, nickel, copper and zinc complexes with 1,3-diphenyl-1H-pyrazole-4 carboxaldehyde Schiff bases: antimicrobial, spectroscopic, thermal and fluorescence studies. AB - Two new Schiff bases of 1,3-diphenyl-1H-pyrazole-4-carboxaldehyde and 4-amino-5 mercapto-3-methyl/H-1,2,4-triazole [HL(1-2)] and their Cobalt, Nickel, Copper and Zinc complexes have been synthesized and characterized by elemental analyses, spectral (UV-vis, IR, (1)H NMR, Fluorescence) studies, thermal techniques and magnetic measurements. A square planar geometry for Cu(II) and octahedral geometry for Co(II), Ni(II) and Zn(II) complexes have been proposed. In order to evaluate the biological activity of Schiff bases and to assess the role of metal ion on biological activity, the pyrazole Schiff bases and their metal complexes have been studied in vitro antibacterial against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and antifungal against Aspergillus niger, and Aspergillus flavus. In most of the cases higher activity was exhibited upon coordination with metal ions. PMID- 22429913 TI - Multiple endocrine neoplasias type 2B and RET proto-oncogene. AB - Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities. PMID- 22429914 TI - How accurate are parental responses concerning their fourth-grade children's school-meal participation, and what is the relationship between children's body mass index and school-meal participation based on parental responses? AB - BACKGROUND: This article investigated (1) parental response accuracy of fourth grade children's school-meal participation and whether accuracy differed by children's body mass index (BMI), sex, and race, and (2) the relationship between BMI and school-meal participation (based on parental responses). METHODS: Data were from four cross-sectional studies conducted from fall 1999 to spring 2003 with fourth-grade children from 13 schools total. Consent forms asked parents to report children's usual school-meal participation. As two studies' consent forms did not ask about lunch participation, complete data were available for breakfast on 1,496 children (51% Black; 49% boys) and for lunch on 785 children (46% Black; 48% boys). Researchers compiled nametag records (during meal observations) of meal participation on randomly selected days during children's fourth-grade school year for breakfast (average nametag days across studies: 7-35) and for lunch (average nametag days across studies: 4-10) and categorized participation as "usually" (>= 50% of days) or "not usually" (< 50% of days). Weight and height were measured. Concerning parental response accuracy, marginal regression was used with agreement between parental responses and nametag records as the dependent variable; independent variables were BMI, age, sex, race, and study. Concerning a relationship between BMI and school-meal participation, marginal regression was used with BMI as the dependent variable; independent variables were breakfast participation, lunch participation, age, sex, race, and study. RESULTS: Concerning breakfast participation and lunch participation, 74% and 92% of parents provided accurate responses, respectively. Parental response accuracy was better for older children for breakfast and lunch participation, and for Black than White children for lunch participation. Usual school-meal participation was significantly related to children's BMI but in opposite directions -- positively for breakfast and inversely for lunch. CONCLUSIONS: Parental response accuracy of children's school-meal participation was moderately high; however, disparate effects for children's age and race warrant caution when relying on parental responses. The BMI results, which showed a relationship between school-meal participation (based on parental responses) and childhood obesity, conflict with results from a recent article that used data from the same four studies and found no significant relationship when participation was based on nametag records compiled for meal observations. PMID- 22429915 TI - Signaling and gradients: what's going down? PMID- 22429916 TI - Shifting behaviour: epigenetic reprogramming in eusocial insects. AB - Epigenetic modifications are ancient and widely utilised mechanisms that have been recruited across fungi, plants and animals for diverse but fundamental biological functions, such as cell differentiation. Recently, a functional DNA methylation system was identified in the honeybee, where it appears to underlie queen and worker caste differentiation. This discovery, along with other insights into the epigenetics of social insects, allows provocative analogies to be drawn between insect caste differentiation and cellular differentiation, particularly in mammals. Developing larvae in social insect colonies are totipotent: they retain the ability to specialise as queens or workers, in a similar way to the totipotent cells of early embryos before they differentiate into specific cell lineages. Further, both differentiating cells and insect castes lose phenotypic plasticity by committing to their lineage, losing the ability to be readily reprogrammed. Hence, a comparison of the epigenetic mechanisms underlying lineage differentiation (and reprogramming) between cells and social insects is worthwhile. Here we develop a conceptual model of how loss and regain of phenotypic plasticity might be conserved for individual specialisation in both cells and societies. This framework forges a novel link between two fields of biological research, providing predictions for a unified approach to understanding the molecular mechanisms underlying biological complexity. PMID- 22429917 TI - Are quit attempts among U.S. female nurses who smoke different from female smokers in the general population? An analysis of the 2006/2007 tobacco use supplement to the current population survey. AB - BACKGROUND: Smoking is a significant women's health issue. Examining smoking behaviors among occupational groups with a high prevalence of women may reveal the culture of smoking behavior and quit efforts of female smokers. The purpose of this study was to examine how smoking and quitting characteristics (i.e., ever and recent quit attempts) among females in the occupation of nursing are similar or different to those of women in the general population. METHODS: Cross sectional data from the Tobacco Use Supplement of the Current Population Survey 2006/2007 were used to compare smoking behaviors of nurses (n = 2, 566) to those of non-healthcare professional women (n = 93, 717). Smoking characteristics included years of smoking, number of cigarettes, and time to first cigarette with smoking within the first 30 minutes as an indicator of nicotine dependence. Logistic regression models using replicate weights were used to determine correlates of ever and previous 12 months quit attempts. RESULTS: Nurses had a lower smoking prevalence than other women (12.1% vs 16.6%, p < 0.0001); were more likely to have ever made a quit attempt (77% vs 68%, p = 0.0002); but not in the previous 12 months (42% vs 43%, p = 0.77). Among those who ever made a quit attempt, nurses who smoked within 30 minutes of waking, were more likely to have made a quit attempt compared to other women (OR = 3.1, 95% CI: 1.9, 5.1). When considering quit attempts within the last 12 months, nurses whose first cigarette was after 30 minutes of waking were less likely to have made a quit attempt compared to other females (OR = 0.69, 95% CI: 0.49, 0.98). There were no other significant differences in ever/recent quitting. CONCLUSIONS: Smoking prevalence among female nurses was lower than among women who were not in healthcare occupations, as expected. The lack of difference in recent quit efforts among female nurses as compared to other female smokers has not been previously reported. The link between lower level of nicotine dependence, as reflected by the longer time to first cigarette, and lower quit attempts among nurses needs further exploration. PMID- 22429918 TI - Hypofractionated stereotactic radiotherapy for brain metastases larger than three centimeters. AB - BACKGROUND: To evaluate the efficacy and outcomes of hypofractionated stereotactic radiotherapy (HSRT) for brain metastases > 3 cm. METHODS: From March 2003 to October 2009, 40 patients with brain metastases larger than 3 cm were treated by HSRT. HSRT was applied in 29 patients for primary treatment and in 11 patients for rescue. Single brain metastasis was detected in 21 patients. Whole brain radiotherapy was incorporated into HSRT in 10 patients for primary treatment. HSRT boosts were applied in 23 patients. The diameters of the brain metastases ranged from 3.1 to 5.5 cm (median, 4.1 cm). The median prescribed dose (not including HSRT boosts) was 40 Gy (range, 20-53 Gy) with a median of 10 fractions (range, 4-15 fractions) to the 90% isodose line. The median dose of the boost was 20 Gy (range, 10-35 Gy) in 4 fractions (range, 2-10 fractions). RESULT: The median overall survival time was 15 months. The overall survival and local control rate at 12 months was 55.3% and 94.2%, respectively. Four patients experienced local progression of large brain metastases. Nine patients died of intracranial disease progression. One patient died of radiation necrosis with brain edema. CONCLUSION: HSRT was a safe and effective treatment for patients with brain metastases ranged from 3.1 to 5.5 cm. Dose escalation of HSRT boost may improve local control with an acceptable toxicity. PMID- 22429919 TI - Rule-based induction method for haplotype comparison and identification of candidate disease loci. AB - There is a need for methods that are able to identify rare variants that cause low or moderate penetrance disease susceptibility. To answer this need, we introduce a rule-based haplotype comparison method, Haplous, which identifies haplotypes within multiple samples from phased genotype data and compares them within and between sample groups. We demonstrate that Haplous is able to accurately identify haplotypes that are identical by descent, exclude common haplotypes in the studied population and select rare haplotypes from the data. Our analysis of three families with multiple individuals affected by lymphoma identified several interesting haplotypes shared by distantly related patients. PMID- 22429920 TI - Exploring the information practices of people with end-stage kidney disease. AB - This small exploratory study sought to understand how people with End-Stage Kidney Disease (ESKD) experience the information environment and what information practices they employ in order to inform the decisions they make in relation to treatment and care. Using a constructivist methodology, in-depth interviews were conducted with five people who were receiving haemodialysis in two small satellite dialysis units located in regional and rural communities in New South Wales, Australia. Thematic analysis revealed two types of patients. The first type appears to adopt a received view of information, who do not question their condition; and passively accept information. In the other type, patients were found to be engaged; they actively identified their information needs and quickly learned what that they needed to ask and who to ask. Knowing the information practices of people with ESKD is useful for nephrology nurses when providing patient education. PMID- 22429922 TI - Distribution of allele frequencies of 20 STRs loci in a population sample from Calabria, Southern Italy. PMID- 22429923 TI - Allele frequencies of 20 STRs from Northwest Spain (Galicia). PMID- 22429924 TI - Dietary green and white teas suppress UDP-glucuronosyltransferase UGT2B17 mediated testosterone glucuronidation. AB - The anabolic steroid testosterone can be used by athletes to enhance athletic performance and muscle growth. UDP-glucuronosyltransferase (UGT2B17) is the key enzyme involved in the glucuronidation of testosterone to testosterone glucuronide, which also serves as a marker for the testosterone/epitestosterone (T/E) ratio used to detect testosterone abuse in sport. Inhibitors of testosterone glucuronidation could have an impact on circulating testosterone levels, thus aiding performance, as well as potentially affecting the urinary T/E ratio and therefore masking testosterone abuse. Previous reports have revealed that non-steroidal, anti-inflammatory drugs, diclofenac and ibuprofen, inhibit the UGT2B17 enzyme. The aim of this study is to analyse dietary tea samples for inhibition of testosterone glucuronidation and, where inhibition is present, to identify the active compounds. Analysis of testosterone glucuronidation was conducted by performing UGT2B17 assays with detection of un-glucuronidated testosterone using high performance liquid chromatography. The results from this study showed that testosterone glucuronidation was inhibited by the green and white tea extracts, along with specific catechin compounds, notably: epicatechin, epigallocatechin gallate (EGCG) and catechin gallate. The IC50 inhibition value for EGCG was determined, using a Dixon plot, to be 64 MUM, equalling the most active NSAID inhibitor diclofenac. Thus, common foodstuffs and their constituents, for the first time, have been identified as inhibitors of a key enzyme involved in testosterone glucuronidation. Whilst these common compounds are not substrates of the UGT2B17 enzyme, we showed that they inhibit testosterone glucuronidation which may have implications on current doping control in sport. PMID- 22429925 TI - Validation and application of a highly specific and sensitive ELISA for the estimation of cortisone in saliva, urine and in vitro cell-culture media by using a novel antibody. AB - It is generally acknowledged that local tissue concentrations of cortisol and cortisone are modulated by site-specific actions of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isoenzymes 1 and 2. Cortisone, the inactive metabolite of cortisol is produced by 11betaHSD type 2. To assess 11beta-HSD types 1 and 2 activities, the cortisol/cortisone ratio has to be accurately determined. Immunoassays to measure cortisone levels are not widely available and tend to lack specificity. The aim of this project was to develop a highly specific and sensitive ELISA method for the estimation of free cortisone levels in urine, saliva and in vitro media samples without chromatographic separation. Antibodies against cortisone were raised in rabbits using cortisone-3-CMO-KLH as immunogen. HRP-goat anti-rabbit IgG conjugate was used as enzyme tracer. Cross-reactivities of the untreated cortisone antiserum with major interfering steroids were minimal except for cortisol (3.15%). However, following an immune-affinity purification of the antibodies using CNBr-activated sepharose-cortisol-3-CMO-BSA, cross reactivity of the purified cortisone antibody with cortisol was reduced to 0.27%. The minimum detection limit of cortisone ELISA was 28 pg/mL (77.7 pM). The validity of the cortisone ELISA was confirmed by the excellent correlation obtained before and after an HPLC fractionation step (Y=1.09X-0.21, R2=0.98). Intra-assay and inter-assay imprecision were 5.5-11.7% and 8.7-12.8% CV, respectively. Using this assay, salivary cortisone levels showed a circadian rhythm in men and women (11.2+/-7.3 nM at 08.00 h and 5.1+/-3.6 nM at 18.00 h), and the levels were reduced following liquorice ingestion. In media of adrenocortical H295 cell line incubations, basal cortisone levels were 4.24+/ 0.22 nM that increased to 8.6+/-1.2 nM post forskolin treatment. Urinary free cortisone excretion levels in healthy subjects were 56.66+/-36.9 nmol/day. In human volunteers following ingestion of green coffee bean extract for 2 weeks, urinary free cortisol excretion reduced significantly from 66.67+/-22.3 to 42.66+/-17.5 nmol/day (p=0.02) and the cortisol/cortisone ratio from 2.04+/-1.33 to 1.49+/-1.13, p=0.05. In conclusion, a simple and highly specific and sensitive ELISA has been developed and applied to estimate cortisone levels in biological fluids and culture media. PMID- 22429926 TI - Two-year bond strengths of "all-in-one" adhesives to dentine. AB - OBJECTIVES: To test the long-term in vitro bonding performance of "all-in-one" self-etch adhesives to dentine. METHODS: Adper Prompt (3M ESPE), Bond Force (Tokuyama), Brush & Bond (Parkell), iBond Self Etch (Heraeus Kulzer), OptiBond All-In-One (Kerr), and Xeno IV (Dentsply Caulk) were tested. The two-step self etch adhesive Clearfil SE Bond (Kuraray) served as the control. Extracted human teeth were assigned to groups after creation of smear layer on occlusal dentine. Adhesives were applied according to manufacturers' instructions, and resin composite (Filtek Z250, 3M ESPE) build-ups were placed. The bonded specimens were sectioned into beams after 24h of storage in water. Microtensile bond strengths (MUTBS) was determined at baseline, and following one and two years of water storage using an EZ-Test device (Shimadzu). Representative specimens were examined under field emission scanning electron microscope. Fracture mode was recorded. The data were analyzed using linear mixed effects and least square means analyses. The significance level was set at 0.01 for the pairwise comparisons and at 0.05 for the overall model effects. RESULTS: The mean MUTBS decreased significantly over time for Adper Prompt, iBond Self Etch, and OptiBond All-In-One. After two years of water ageing, Bond Force, Brush & Bond, OptiBond All-In-One, and Xeno IV had mean MUTBS values not statistically different from Clearfil SE Bond. CONCLUSIONS: After two years of water ageing, Clearfil SE Bond outperformed two of six all-in-one adhesives. That indicates that the composition of the adhesives rather than their application approach is accountable for their performance. CLINICAL SIGNIFICANCE: Despite the data available suggesting that most all-in-one adhesives are severely affected by hydrolytic degradation, results of the present in vitro study suggest that some may perform as well as the clinically proven Clearfil SE Bond in the longer term. PMID- 22429927 TI - Detection of proximal secondary caries at cervical class II-amalgam restoration margins in vitro. AB - OBJECTIVES: To compare the performance of LFpen (DIAGNOdent pen) with two different wedge-shaped tips to conventional bitewing radiography (BW) for detecting proximal secondary caries at the cervical margin of amalgam restorations in vitro. METHODS: Seventy-five molars with class II amalgam restorations were selected. Depending on the marginal filling extension, data was subdivided into a crown group (C), when the filling ended in enamel, and into a root group (R), when the filling ended beyond the cementum-enamel junction. Bayesian analysis including calculation of the area under the receiver operating curve (AUC) was performed. Furthermore, Spearman correlations between caries and cofactors, such as presence of plaque or stain, occlusal ditching, marginal gap size, filling overhangs, and shortfalls, were calculated. Additionally, for group R the correlation coefficient between LFpen measurements and lesion depth was calculated. Histology served as gold standard. RESULTS: In group C both at the D1 and D3 levels, LFpen with two different tips showed a better performance than bitewing radiography (AUC at D1: 0.83/0.79 (LFpen) and 0.63 (BW); at D3: 0.66/0.66 (LFpen) and 0.53 (BW)). In group R, the respective AUC values were 0.53/0.56 (LF) and 0.59 (BW). A significant medium correlation was observed for occlusal ditching and proximal caries. Stain accumulation at the restoration margins especially in combination with filling overhangs interfered with LFpen readings, resulting in false positive measurements. CONCLUSIONS: Compared to BW, LFpen enhances the detection of secondary caries lesions at the cervical margin of amalgam restorations that do not extend below the cementum-enamel junction. PMID- 22429928 TI - Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice. AB - The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression of one arylacetamide deacetylase (Aadac) and 11 carboxylesterases (Cess) by 15 microsomal enzyme inducers (MEIs) was examined in livers of male C57BL/6 mice. The data demonstrated that Aadac mRNA expression was suppressed by three aryl hydrocarbon receptor (AhR) ligands, two constitutive androstane receptor (CAR) activators, two pregnane X receptor (PXR) ligands, and one nuclear factor erythroid 2-related factor 2 (Nrf2) activator. Ces1 subfamily mRNA expression was not altered by most of the MEIs, whereas Ces2 subfamily mRNA was readily induced by the activators of CAR, PXR, and Nrf2 but not by peroxisome proliferator-activated receptor alpha activators. Studies using null mice demonstrated that 1) AhR was required for the 2,3,7,8-tetrachlorodibenzo-p-dioxin mediated suppression of Aadac and Ces3a; 2) CAR was involved in the 1,4-bis[2 (3,5-dichloropyridyloxy)]benzene-mediated induction of Aadac, Ces2c, Ces2a, and Ces3a; 3) PXR was required for the pregnenolone-16alpha-carbonitrile-mediated induction of Aadac, Ces2c, and Ces2a; 4) Nrf2 was required for the oltipraz mediated induction of Ces1g and Ces2c; and 5) PXR was not required for the DEX mediated suppression of Cess in livers of mice. In conclusion, the present study systematically investigated the regulation of Cess by MEIs in livers of mice and demonstrated that MEIs modulated mRNA expression of mouse hepatic Cess through the activation of AhR, CAR, PXR, and/or Nrf2 transcriptional pathways. PMID- 22429929 TI - Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFkappaB pathways. AB - BACKGROUND: H. pylori infection may trigger Smad7 and NFkappaB expression in the stomach, whereas probiotics promote gastrointestinal health and improve intestinal inflammation caused by pathogens. This study examines if probiotics can improve H. pylori-induced gastric inflammation by inactivating the Smad7 and NFkappaB pathways. RESULTS: Challenge with H. pylori increased IL-8 and TNF-alpha expressions but not TGF-beta1 in MKN45 cells. The RNA levels of Smad7 in AGS cells increased after H. pylori infection in a dose-dependent manner. A higher dose (MOI 100) of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-beta1. Such anti-inflammatory effect was mediated via increased cytoplasmic IkappaBalpha and depletion of nuclear NFkappaB. L. acidophilus also inhibited H. pylori-induced Smad7 transcription by inactivating the Jak1 and Stat1 pathways, which might activate the TGF-beta1/Smad pathway. L. acidophilus pre-treatment ameliorated IFN-gamma-induced Smad7 translation level and subsequently reduced nuclear NF-kappaB production, as detected by western blotting. CONCLUSIONS: H. pylori infection induces Smad7, NFkappaB, IL-8, and TNF alpha production in vitro. Higher doses of L. acidophilus pre-treatment reduce H. pylori-induced inflammation through the inactivation of the Smad7 and NFkappaB pathways. PMID- 22429930 TI - Developmental diversity in free-living flatworms. AB - Flatworm embryology has attracted attention since the early beginnings of comparative evolutionary biology. Considered for a long time the most basal bilaterians, the Platyhelminthes (excluding Acoelomorpha) are now robustly placed within the Spiralia. Despite having lost their relevance to explain the transition from radially to bilaterally symmetrical animals, the study of flatworm embryology is still of great importance to understand the diversification of bilaterians and of developmental mechanisms. Flatworms are acoelomate organisms generally with a simple centralized nervous system, a blind gut, and lacking a circulatory organ, a skeleton and a respiratory system other than the epidermis. Regeneration and asexual reproduction, based on a totipotent neoblast stem cell system, are broadly present among different groups of flatworms. While some more basally branching groups - such as polyclad flatworms retain the ancestral quartet spiral cleavage pattern, most flatworms have significantly diverged from this pattern and exhibit unique strategies to specify the common adult body plan. Most free-living flatworms (i.e. Platyhelminthes excluding the parasitic Neodermata) are directly developing, whereas in polyclads, also indirect developers with an intermediate free-living larval stage and subsequent metamorphosis are found. A comparative study of developmental diversity may help understanding major questions in evolutionary biology, such as the evolution of cleavage patterns, gastrulation and axial specification, the evolution of larval types, and the diversification and specialization of organ systems. In this review, we present a thorough overview of the embryonic development of the different groups of free-living (turbellarian) platyhelminths, including the Catenulida, Macrostomorpha, Polycladida, Lecithoepitheliata, Proseriata, Bothrioplanida, Rhabdocoela, Fecampiida, Prolecithophora and Tricladida, and discuss their main features under a consensus phylogeny of the phylum. PMID- 22429931 TI - Rethinking the regulation of cellular metabolism. AB - Most biologists working today have not considered the problem of how signal transduction events, which commit cells to energetically demanding processes such as growth and division, are connected to cellular metabolism. The primary reason for this is that we have believed for the last 30 or more years that the metabolism of cells is a homeostatic, self-regulating process that does not depend on any extracellular input. The traditional view is that a mammalian cell decides to take up nutrients whenever its bioenergetic and synthetic reserves are depleted. However, a considerable body of evidence now exists that challenges the notion that the nutrient uptake and metabolism of metazoan cells are cell autonomous. PMID- 22429932 TI - The structure of stress: confirmatory factor analysis of a Chinese version of the stressors in Nursing Students Scale (SINS). AB - BACKGROUND: Stress is a feature of the life of nursing students and this had been well studied. However, there are very few instruments to measure stress in nursing students specifically. One such instrument, the Stressors in Nursing Students Scale has been developed in Scotland and applied in studies in Hong Kong and Australia and proved useful alongside other measures of individual differences and psychological distress. OBJECTIVES: To translate the Stressors in Nursing Students Scale into Chinese, test it with Chinese nursing students and explore the psychometric structure of stress in this population. DESIGN: Cross sectional survey using a self-administered questionnaire. SETTING: A large teaching hospital in Southwest Mainland China. PARTICIPANTS: Nursing students (n=1090) participated (1000 in the classroom and 90 on clinical placement); 862 from the classroom and 79 from clinical placements returned questionnaires (n=914) representing a return rate of 86.3%. METHODS: Principal component analysis and confirmatory factor analysis using structural equation modelling. RESULTS: A four-factor structure was obtained from principal component analysis. This was confirmed (fit indices>0.9 and RMSEA<0.06) using structural equation modelling. The stress-related factors were: Clinical (0.83), Finance (0.81), Confidence (0.82), and Education (0.70). CONCLUSIONS: The original structure of the SINS in English was confirmed in this large sample of Chinese nursing students. This will allow cross-cultural studies of stress in nursing students. PMID- 22429933 TI - Epidemiology and seasonality of respiratory viral infections in hospitalized children in Kuala Lumpur, Malaysia: a retrospective study of 27 years. AB - BACKGROUND: Viral respiratory tract infections (RTI) are relatively understudied in Southeast Asian tropical countries. In temperate countries, seasonal activity of respiratory viruses has been reported, particularly in association with temperature, while inconsistent correlation of respiratory viral activity with humidity and rain is found in tropical countries. A retrospective study was performed from 1982-2008 to investigate the viral etiology of children (<= 5 years old) admitted with RTI in a tertiary hospital in Kuala Lumpur, Malaysia. METHODS: A total of 10269 respiratory samples from all children <= 5 years old received at the hospital's diagnostic virology laboratory between 1982-2008 were included in the study. Immunofluorescence staining (for respiratory syncytial virus (RSV), influenza A and B, parainfluenza types 1-3, and adenovirus) and virus isolation were performed. The yearly hospitalization rates and annual patterns of laboratory-confirmed viral RTIs were determined. Univariate ANOVA was used to analyse the demographic parameters of cases. Multiple regression and Spearman's rank correlation were used to analyse the correlation between RSV cases and meteorological parameters. RESULTS: A total of 2708 cases were laboratory-confirmed using immunofluorescence assays and viral cultures, with the most commonly detected being RSV (1913, 70.6%), parainfluenza viruses (357, 13.2%), influenza viruses (297, 11.0%), and adenovirus (141, 5.2%). Children infected with RSV were significantly younger, and children infected with influenza viruses were significantly older. The four main viruses caused disease throughout the year, with a seasonal peak observed for RSV in September-December. Monthly RSV cases were directly correlated with rain days, and inversely correlated with relative humidity and temperature. CONCLUSION: Viral RTIs, particularly due to RSV, are commonly detected in respiratory samples from hospitalized children in Kuala Lumpur, Malaysia. As in temperate countries, RSV infection in tropical Malaysia also caused seasonal yearly epidemics, and this has implications for prophylaxis and vaccination programmes. PMID- 22429934 TI - Effects of gaseous NH(3) and SO(2) on the concentration profiles of PCDD/F in flyash under post-combustion zone conditions. AB - The influence of gaseous ammonia and sulphur dioxide on the formation of 2378 substituted PCDD/F on a reference flyash from a municipal waste incinerator has been investigated using a laboratory scale fixed-bed reactor. The reference flyash samples (BCR-490) was reacted under a simulated flue gas stream at temperatures of 225 and 375 degrees C for 96h. The experiments were carried out in two series: first with simulated flue gas alone, and then with injection of NH(3) or SO(2) gas into the flue gas just before the reactor inlet. It was found that the injection of gaseous ammonia into the flue gas could decrease the concentration of both PCDD and PCDF by 34-75% from the solid phase and by 21-40% from the gas phase. Converting the results to I-TEQ values, it could reduce the total I-TEQ values of PCDD and PCDF in the sum of the flyash and exhaust flue gas by 42-75% and 24-57% respectively. The application of SO(2) led to 99% and 93% reductions in the PCDD and PCDF average congener concentrations, respectively in the solid phase. In the gas phase, the total reductions were 89% and 76% for PCDD and PCDF, respectively. Moreover, addition of SO(2) reduced the total I-TEQ value of PCDD and PCDF in the flyash and exhaust flue gas together by 60-86% and 72-82% respectively. Sulphur dioxide was more effective than ammonia in suppressing PCDD/F formation in flyash under the conditions investigated. PMID- 22429935 TI - Capacitated location of collection sites in an urban waste management system. AB - Urban waste management is becoming an increasingly complex task, absorbing a huge amount of resources, and having a major environmental impact. The design of a waste management system consists in various activities, and one of these is related to the location of waste collection sites. In this paper, we propose an integer programming model that helps decision makers in choosing the sites where to locate the unsorted waste collection bins in a residential town, as well as the capacities of the bins to be located at each collection site. This model helps in assessing tactical decisions through constraints that force each collection area to be capacitated enough to fit the expected waste to be directed to that area, while taking into account Quality of Service constraints from the citizens' point of view. Moreover, we propose an effective constructive heuristic approach whose aim is to provide a good solution quality in an extremely reduced computational time. Computational results on data related to the city of Nardo, in the south of Italy, show that both exact and heuristic approaches provide consistently better solutions than that currently implemented, resulting in a lower number of activated collection sites, and a lower number of bins to be used. PMID- 22429936 TI - [What management for the asymptomatic men carriers of BRCA1 or 2 mutation? Results of a survey in the French oncogenetic centers]. AB - The aim of this survey of practice was to define, in the absence of guideline, the management in France of asymptomatic men bearing a mutation of BRCA1 or 2 genes. A questionnaire was addressed to 90 oncogenetics centers. We obtained the answers of 34 practitioners working in 58 centers. Among the responders, 85.3% offered a systematic genetic test in all cases to determine the risk of transmission to the children and to offer a personal follow-up in 79.4 % of cases. This screening was directed towards prostate cancer, breast cancer and pancreatic cancer in respectively 94.1, 67.6 and 47.1% of cases. The screening of prostate cancer was mainly proposed to men bearing a BRCA2 mutation and from the age of 40 years. It was based on clinical examination and testing of prostate specific antigen. The screening of breast cancer was mainly proposed to men bearing a BRCA2 mutation and based on clinical examination and self-palpation without stating a started age. The screening of pancreatic cancer was mainly proposed to men with familial history of pancreatic cancer and from the age of 40 years. It was based on tomography and MRI. For the majority of answerers, the general practitioner was the best to perform all these screenings. These experts' opinions can help to establish guidelines for the global management of asymptomatic men carriers of BRCA1 or 2 mutations. PMID- 22429937 TI - Nanocomposite containing CaF(2) nanoparticles: thermal cycling, wear and long term water-aging. AB - OBJECTIVES: Fluoride (F) releasing dental restoratives are promising to promote remineralization and combat caries. The objectives of this study were to develop nanocomposite containing calcium fluoride nanoparticles (nCaF(2)), and to investigate the long-term mechanical durability including wear, thermal-cycling and long-term water-aging behavior. METHODS: Two types of fillers were used: nCaF(2) with a diameter of 53 nm, and glass particles of 1.4 MUm. Four composites were fabricated with fillers of: (1) 0% nCaF(2)+65% glass; (2) 10% nCaF(2)+55% glass; (3) 20% nCaF(2)+45% glass; (4) 30% nCaF(2)+35% glass. Three commercial materials were also tested. Specimens were subjected to thermal-cycling between 5 degrees C and 60 degrees C for 10(5) cycles, three-body wear for 4*10(5) cycles, and water-aging for 2 years. RESULTS: After thermal-cycling, the nCaF(2) nanocomposites had flexural strengths in the range of 100-150 MPa, five times higher than the 20-30 MPa for resin-modified glass ionomer (RMGI). The wear scar depth showed an increasing trend with increasing nCaF(2) filler level. Wear of nCaF(2) nanocomposites was within the range of wear for commercial controls. Water-aging decreased the strength of all materials. At 2 years, flexural strength was 94 MPa for nanocomposite with 10% nCaF(2), 60 MPa with 20% nCaF(2), and 48 MPa with 30% nCaF(2). They are 3-6 fold higher than the 15 MPa for RMGI (p<0.05). SEM revealed air bubbles and cracks in a RMGI, while composite control and nCaF(2) nanocomposites appeared dense and solid. SIGNIFICANCE: Combining nCaF(2) with glass particles yielded nanocomposites with long-term mechanical properties that were comparable to those of a commercial composite with little F release, and much better than those of RMGI controls. These strong long-term properties, together with their F release being comparable to RMGI as previously reported, indicate that the nCaF(2) nanocomposites are promising for load-bearing and caries-inhibiting restorations. PMID- 22429938 TI - Characterization of the effects of the FineView algorithm for full field digital mammography. AB - The aim of this study was to characterize the effect of an image processing algorithm (FineView) on both quantitative image quality parameters and the threshold contrast detail response of the GE Senographe DS full-field digital mammography system. The system was characterized using signal transfer property, pre-sampling modulation transfer function (MTF), normalized noise power spectrum (NNPS) and detective quantum efficiency (DQE) of the system. An algorithmic modulation transfer function (MTF(a)) was calculated from images acquired at a reduced detector air kerma (DAK) and with the FineView algorithm enabled. Two sets of beam conditions were used: Mo/Mo/28 kV and Rh/Rh/29 kV, both with 2 mm added Al filtration at the x-ray tube. Images were acquired with and without FineView at four DAK levels from 14 to 378 uGy. The threshold contrast detail response was assessed using the CDMAM contrast-detail test object which was imaged under standard clinical conditions with and without FineView at three DAK levels from 24 to 243 uGy. The images were scored by both human observers and by automated scoring software. Results indicated an improvement of up to 125% at 5 mm-1 in MTF(a) when FineView was activated, particularly at high DAK levels. A corresponding increase of up to 425% at 5 mm-1 was also seen in the NNPS, again with the same DAK dependence. FineView did not influence DQE, an indication that the signal to noise ratio transfer of the system remained unchanged. FineView did not affect the threshold contrast detectability of the system, a result that is consistent with the DQE results. PMID- 22429939 TI - Prognostic value of gross tumor volume delineated by FDG-PET-CT based radiotherapy treatment planning in patients with locally advanced pancreatic cancer treated with chemoradiotherapy. AB - BACKGROUND: We aimed to assess whether gross tumor volume (GTV) determined by fusion of contrast-enhanced computerized tomography (CT) and 18F-fluoro-deoxy-D glucose positron emission tomography-CT (FDG-PET-CT) based radiotherapy planning could predict outcomes, namely overall survival (OS), local-regional progression free survival (LRPFS), and progression-free survival (PFS) in cases with locally advanced pancreas cancer (LAPC) treated with definitive concurrent chemoradiotherapy. METHODS: A total of 30 patients with histological proof of LAPC underwent 50.4 Gy (1.8 Gy/28 fractions) of radiotherapy concurrent with continuously infused 5-FU followed by 4 to 6 courses of maintenance gemcitabine. Target volume delineations were performed on FDG-PET-CT-based RTP. Patients were stratified into 2 groups: GTV lesser (GTVL) versus greater (GTVG) than cut off value determined by receiver operating characteristic (ROC) analysis, and compared in terms of OS, LRPFS and PFS. RESULTS: Median GTV delineated according to the FDG-PET-CT data was 100.0 cm3. Cut off GTV value determined from ROC curves was 91.1 cm3. At a median follow up of 11.2 months, median OS, LRPFS and PFS for the entire population were 10.3, 7.8 and 5.7 months, respectively. Median OS, LRPFS and PFS for GTVL and GTVG cohorts were 16.3 vs. 9.5 (p = 0.005), 11.0 vs. 6.0 (p = 0.013), and 9.0 vs. 4.8 months (p = 0.008), respectively. CONCLUSIONS: The superior OS, LRPFS and PFS observed in GTVL patients over GTVG ones suggests a potential for FDG-PET-CT-defined GTV size in predicting outcomes of LAPC patients treated with definitive C-CRT, which needs to be validated by further studies with larger cohorts. PMID- 22429940 TI - 22q11.2 microduplication syndrome with congenital aural atresia: a family report. AB - 22q11.2 microduplication syndrome is characterized by a large phenotypic variability including facial dysmorphism, developmental delay, and hearing loss. We describe a family in whom 5 of 11 children were affected by a unilateral or bilateral congenital aural atresia. Four of these 5 carried a 22q11.2 microduplication and had typical dysmorphic features. Computed tomography with 3 D reconstructions allowed for a detailed examination of the middle ear structures and classification of the atresia type. Audiometry revealed a moderately severe conductive hearing loss in accordance with the clinical and computed tomography findings. CONCLUSION: Detailed examination of the ear is warranted in patients with a 22q11.2 microduplication. When outer ear abnormalities are encountered, an additional workup including audiometry and computed tomography with 3-D reconstructions is required. PMID- 22429941 TI - Is it the middle ear disease or the reconstruction material that determines the functional outcome in ossicular chain reconstruction? AB - OBJECTIVES: To evaluate the effects and the predictive value of environmental risk factors on the success of different reconstruction materials used in ossiculoplasty. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral university hospital. PATIENTS: Between January 2007 and October 2010, 110 patients who underwent ossiculoplasty with or without mastoidectomy due to chronic otitis media were enrolled in the study. All patients were classified into 1 of the 3 risk groups (mild, moderate, and severe) according to their measured Middle Ear Risk Index score. INTERVENTIONS: The patients underwent exploratory tympanotomy, tympanoplasty, or tympanomastoidectomy (canal wall-up or wall-down), all with ossicular reconstruction. The ossicular reconstructions were performed using either bone cement, autologous bone interposition, or allograft material. MAIN OUTCOME MEASURES: For each patient, the air-conduction threshold and air-bone gap (ABG) were measured at the 12th month after ossiculoplasty. The ABG gain and air-conduction improvement were compared with preoperative values. The correlation of the success of ossiculoplasty with the middle ear risk group of patients was investigated. Moreover, the efficacy of different types of reconstruction material on the success of ossiculoplasty in the same risk group was evaluated. RESULTS: In the mild- and moderate-risk groups, the ABG gain (p = 0.001 and p = 0.014) and air-conduction improvement (p < 0.001 for both) were statistically significant, whereas those changes were found to be insignificant in the severe-risk group. Moreover, the ABG gain and air-conduction improvement in none of the risk groups revealed a significance in favor of any of the used reconstruction materials. CONCLUSION: The results of this study revealed that none of the reconstruction materials or specific techniques have a superiority in the functional outcomes in patients from the same middle ear risk group. We conclude that the success of ossiculoplasty is highly correlated with the pathophysiological status of the middle ear and is independent of the type of replacement material. PMID- 22429942 TI - Malleostapedotomy prosthesis size and shape: key measurements from a temporal bone study. AB - HYPOTHESIS: By determining the dimensions of middle ear anatomic relationships pertinent to malleostapedotomy (MS), a simplified, yet optimized scheme for sizing, shaping, and placing a prosthesis can be generated. METHODS: Surgical dissection of 20 fresh (nonpreserved) cadaveric temporal bones was undertaken. Needlepoint calipers were used to manually measure pertinent distances between the ossicles. These measurements were then used to calculate the dimensions of anatomic triangles within the middle ear that were applied to the process of MS prosthesis sizing, shaping, and placement. RESULTS: Mean distances were 6.3 mm (range, 5.75-7.0 mm) between the usual MS crimp site and stapedotomy site, 3.6 mm (range, 3.00-4.25 mm) between the crimp site and the lateral edge of the distal incus long process, 4.9 mm (range, 4.50-5.00) between the lateral edge of the distal incus long process and the stapedotomy site, 3.7 mm (range, 3.25-4.00) between the crimp site and the umbo, and 3.3 mm (range, 2.75-3.75) between the umbo and lateral edge of the distal incus long process. CONCLUSION: A total crimped prosthesis length of at least 7.75 mm is required to accommodate the range of interossicular measurements, yet production of longer prostheses is wise owing to the limited number of temporal bones studied. Furthermore, the use of a single-length prosthesis for all MS cases will not suffice except when cutting a sufficiently long prosthesis to its desired length. Understanding of the ossicular anatomy can be used to bend the MS piston to favorably affect the orientation of the prosthesis barrel into the vestibule. PMID- 22429943 TI - Comparison of different grafting techniques in type I tympanoplasty in cases of significant middle ear granulation. AB - OBJECTIVE: To assess anatomical and hearing results after different reconstruction methods of tympanic membrane in cases of severe middle ear granulation. STUDY DESIGN: Retrospective review. SETTING: Secondary care medical center. PATIENTS: Forty patients with severe middle ear granulation were included. INTERVENTIONS: Canal wall-up mastoidectomy with Type I tympanoplasty. Temporalis fascia was used in 22 patients, cartilage island flap was used in 10 patients, and cartilage palisade was used in 8 patients. MAIN OUTCOME MEASURES: Graft take, air-bone gap, and air-bone gap closure ratio of 50% or more. RESULTS: In the fascia group, the graft take rate was 91%, whereas the graft take rate for the cartilage island group and the cartilage palisades group was 100% (p = 0.617). Mean +/- SD preoperative air-bone gaps for the fascia, island flap, and cartilage palisades were 30 +/- 9.4, 26 +/- 11.7, and 25 +/- 10.8 dB, respectively. Postoperative air-bone gaps were 17 +/- 10.2, 14 +/- 8.4, and 19 +/ 7.5 dB, respectively, in the same order. The cartilage palisades group failed to show statistically significant difference between preoperative and postoperative air-bone gaps (p = 0.195). Air-bone gap closure ratio of 50% or more was found in 11 cases (50%) of the fascia group, in 5 cases (50%) of the island flap group, and in 1 case (13%) of the cartilage palisades group. CONCLUSION: Cartilage palisades showed reliable graft take but slightly poor hearing results. Thus, fascia or cartilage island grafting might be better for tympanoplasty in cases of severe middle ear granulation tissue. PMID- 22429944 TI - Corticosteroid treatment of idiopathic sudden sensorineural hearing loss: randomized triple-blind placebo-controlled trial. AB - OBJECTIVE: To compare the effect of Prednisolone and placebo on the recovery of unilateral idiopathic sudden sensorineural hearing loss. STUDY DESIGN: Prospective, randomized, triple-blind, placebo-controlled multicenter trial. SETTING: Four tertiary and 10 secondary referral centers. PATIENTS: Of 103 patients randomly assigned, 93 were included in the modified intention-to-treat analysis. The patients, aged 18 to 80 years, were seeking care within 1 week after onset of acute unilateral sensorineural hearing loss with a mean decrease of 30 dB or greater in the 3 most affected contiguous frequencies. INTERVENTION: Patients were randomly assigned in permuted blocks of 10 to receive Prednisolone or placebo in tapering doses from 60 mg for 3 days and, thereafter, 10 mg less each day until Day 8. If complete recovery, no more medication given, otherwise medication continued at 10 mg per day until Day 30. Final follow-up was after 3 months with audiogram; 47 patients received Prednisolone and 46 placebo. MAIN OUTCOME MEASURE: The primary endpoint was efficacy of treatment on recovery at Day 90. Secondary endpoints were prognostic factors for hearing recovery. Analyses were by modified intention-to-treat and per protocol. RESULTS: Hearing improvement for 47 Prednisolone-treated patients was 25.5 +/- 27.1 dB compared to 26.4 +/- 26.2 dB for 46 placebo-treated patients at Day 8 and 39 +/- 20.1 dB versus 35.1 +/- 38.3 dB after 3 months. Vertigo had significant negative effect on hearing improvement and inflammatory signs in the laboratory workup-a positive prognostic effect, irrespective of treatment. CONCLUSION: Prednisolone in customary dosage does not seem to influence recovery of idiopathic sudden sensorineural hearing loss. PMID- 22429945 TI - Spontaneous tegmen defect and semicircular canal dehiscence: same etiopathogenic entity? AB - OBJECTIVES: To describe the clinical and radiologic features of associated spontaneous tegmen defects (STDs) with semicircular canal dehiscences (SCCDs) and to postulate a novel etiopathogenic hypothesis of these pathologic conditions. METHODS: Medical records of all patients with surgically confirmed STD between 2001 and May 2010 were reviewed. We excluded all secondary tegmen defects. Clinical, audiological, and radiologic data were analyzed. RESULTS: Twenty-three patients matched the inclusion criteria. Semicircular canal dehiscence was associated to STD in 13 patients. Of these patients, 12 (95%) had protruding superior semicircular canals in the middle cranial fossa versus only 3 (30%) of 10 patients for the nondehiscent cases. Twenty-two patients complained of hearing loss. Cerebrospinal fluid leak was found in 13 patients. Four patients had history of meningitis. Vestibular symptoms were present in 8 patients. CONCLUSION: This is the largest series of reported coexistence of STD and SCCD in the literature. Protrusion of the superior semicircular canal in the middle cranial fossa is probably an additional factor underlying STD and SCCD etiopathogeny. Semicircular canal dehiscence should always be looked for when STD is present. PMID- 22429946 TI - Efficacy and safety of bilateral posterior canal occlusion in patients with refractory benign paroxysmal positional vertigo: case report series. AB - OBJECTIVE: To highlight the effectiveness, safety, and adverse effects of treating intractable posterior canal benign paroxysmal positional vertigo (BPPV) with bilateral posterior canal occlusions. PATIENTS: Included in this study are 6 patients diagnosed with bilateral BPPV refractory to medical treatment and particle repositioning maneuvers (PRMs) who underwent bilateral posterior semicircular canal occlusions. Patients were selected from tertiary hospital referral centers in London, Ontario, Canada, and St. Louis, Missouri, USA. INTERVENTIONS: This study used the following interventions: preoperative and postoperative audiogram testing to monitor long-term changes in hearing, computed tomography of the head to rule out central lesions and confirm normal inner ear anatomy before surgery, magnetic resonance imaging of the head as needed to rule out posterior fossa lesions causing persistent vertigo, Dix-Hallpike maneuver to diagnose BPPV, PRM and physiotherapy vestibular rehabilitation to attempt treating BPPV before surgical intervention, and sequential transmastoid posterior semicircular canal occlusion for treatment of intractable BPPV. MAIN OUTCOME MEASURES: Postoperative resolution of vertigo induced by head movement and hearing preservation by audiometric testing and postural stability. RESULTS: All patients with severe debilitating bilateral BPPV refractory to medical treatment and PRM had complete resolution of their positional vertigo after bilateral sequential posterior semicircular canal occlusion. Hearing was preserved at the preoperative level in all but 1 patient who developed bilateral postoperative, mild, high-tone sensorineural loss. Residual postoperative adverse effects included transient imbalance in all patients and episodic, nonpositional vertigo in 1 patient. When stressed by extreme head motion, some patients had mild residual instability. There were no other significant long-term complications. CONCLUSION: Bilateral sequential posterior semicircular canal occlusion is a definitive, effective, and safe treatment modality for intractable bilateral BPPV, providing patients with resolution of their vertiginous symptoms. All 6 patients stated that the alleviation of their BPPV symptoms far out-weighed the residual motion sensitivity resulting from the occluded canals. PMID- 22429947 TI - A new vibroplasty coupling technique as a treatment for conductive and mixed hearing losses: a report of 4 cases. AB - OBJECTIVE: The primary objective was to report on experiences regarding the safety and efficacy of the Vibrant Soundbridge (VSB) using a floating mass transducer (FMT)-partial/total ossicular replacement prosthesis (PORP/TORP) assembly as a treatment for conductive and mixed hearing losses of mild-to moderate/severe degree. The secondary objective was to gather information regarding device fitting, as well as to refine surgical procedures. PATIENTS: Five German-speaking adults from 2 European study sites were implanted with a VSB using an FMT-PORP/TORP assembly and evaluated before and after surgery for air and bone-conduction thresholds and speech recognition performance. MAIN OUTCOME MEASURES: Evaluating the safety and efficacy of the VSB in combination with a PORP or TORP to treat conductive and mixed hearing loss. RESULTS: Residual cochlear hearing was unaffected by implantation with the device. Functional gain (measured as the difference between preoperative unaided and postoperative VSB aided thresholds) could be calculated in 2 of 5 subjects, demonstrating that the VSB is effective in treating bone-conduction hearing losses of moderate/severe degree. Word recognition tests in quiet and noise showed good improvement in 3 of the cases. One patient experienced several other medical problems, making her audiological outcomes limited. One patient was excluded from the study owing to insufficient benefit and subsequently underwent revision surgery with FMT placement at the round window. CONCLUSION: The use of the VSB, implanted using the FMT-PORP/TORP assembly, was safe in all and efficacious in 3 of the 5 cases in this study. These are patients who may have few, if any, other options to manage their hearing loss. PMID- 22429948 TI - Witnessing social injustice downstream and advocating for health equity upstream: "the trombone slide" of nursing. AB - Two aspects of a study examining the congruence of critical caring theory with public health nursing practice are reported. They confirm a congruence between expert public health nursing practice and the theory in terms of (a) a caring/social justice ethics that underpins practice and (b) the relevance to their practice of the carative health promoting process of contributing to the creation of supportive and sustainable physical, social, political, and economic environments. Public health nurse participants encountered many barriers to a practice underpinned by a caring/social justice ethic, some of which limited their moral agency. PMID- 22429951 TI - Gallbladder: Cftr affects gallbladder function and bile acid homeostasis. PMID- 22429953 TI - Microbiota: manipulating the microbiota in obesity. PMID- 22429955 TI - Endoscopy: no need for submucosal injection with 'underwater' EMR of large sessile colorectal polyps. PMID- 22429956 TI - Therapy: Probiotic-enriched artichokes for abdominal discomfort. PMID- 22429957 TI - The neighborhood social environment and body mass index among youth: a mediation analysis. AB - BACKGROUND: This study aimed to examine associations between aspects of the neighborhood social environment and body mass index (BMI) in youth both cross sectionally and prospectively; and whether this association was mediated by physical activity, screen-time and sedentary time. METHODS: Data were collected in 2004 and 2006 in high and low socio-economic areas of Melbourne, Australia. In 2004, 185 children aged 8-9 years (47% boys) and 359 children aged 13-15 years (45% boys) participated. Parents reported their perceptions of aspects of the social environment (i.e. social networks and social trust/cohesion), and physical activity (i.e. time spent outdoors by their children; and their younger children's walking and cycling trips) and screen-time (i.e. TV viewing, computer use). The older children self-reported their walking and cycling trips and their screen-time. All children wore an accelerometer to objectively assess outside school hours moderate- to-vigorous physical activity and sedentary time. BMI was calculated from height and weight measured in 2004 and 2006. Multilevel linear regression analyses were conducted to examine associations between the social environment and BMI. Mediation analyses using the products of coefficient method were conducted to determine whether associations between the social environment and BMI were mediated by the time spent in a range of physical activity and sedentary behaviors. RESULTS: Cross-sectional and prospective regression analyses showed that a more positive social network and higher social trust/cohesion was related to lower BMI among children. There was no evidence that time spent in physical activity or sedentary behaviors mediated this relation, despite significant associations between social networks and screen-time and between screen-time and BMI. CONCLUSIONS: The findings suggest that the neighborhood social environment may be important for preventing overweight and obesity in children. Further research investigating the mechanisms through which the neighborhood social environment exerts its effect on BMI is needed. PMID- 22429958 TI - Sensitivity of spatial integration to perceptual cues is preserved in healthy aging. AB - Spatial integration has been shown to substantially decline with age. We examined the mechanism underlying this age-related impairment. Young and older adults were tested on the ability to integrate contour elements across variations in the collinearity of the target elements, their spatial proximity, and the relative spacing of the target elements to the background noise elements (Delta). The results show that although contour integration generally declines with age, tolerating less noise (higher Delta) than in young adulthood, its mechanism is preserved over the years, critically depending on the relations between collinearity and spatial proximity of the contour elements. The results suggest that while spatial integration in childhood is limited by the absolute contour spacing, lacking the ability to use collinearity in order to overcome poor proximity among the elements, no changes occur in the sensitivity of contour integration to these perceptual cues at the other end of the lifespan. This suggests that the sensitivity of spatial integration to the statistics of natural scenes is preserved in aging. PMID- 22429959 TI - Non-linear global pooling in the discrimination of circular and non-circular shapes. AB - The ability to discriminate minute deviations from circularity is dependent upon global summation mechanisms integrating information along entire contours. The aim of this study was to determine how the strength of global summation depends on various stimulus features. To determine if the strength of global summation differs between shapes, contour discrimination for various contour shapes, generated by applying a sinusoidal modulation to the radius of a circle (radial frequency - RF - patterns), was measured. Shapes differed in frequency (number of lobes RF3, RF5 and RF20) and amplitude ('sharpness' of the lobes ranged between 0 and 20* thresholds for detecting deviation from a circle). Low amplitudes test discrimination against a circle while high amplitudes measure sensitivity for highly non-circular shapes (e.g. five-pointed star-shapes). The ability to integrate information along contours was assessed by comparing the effect of applying radial deformations to the entire contour or to only fractions (various number of cycles). Results show that discrimination thresholds remain in the hyperacuity range for low amplitudes, but increase for higher amplitudes. Concerning signal integration, discrimination, expressed as a function of the amount of contour deformed, exhibits a shallow and a steep regime. Discrimination improves only slowly as more contour cycles are deformed until the point when the entire pattern is modulated, when sensitivity increases substantially. The initial shallow regime is well captured by probability summation. The increase in sensitivity when the entire pattern is modulated compared to a single cycle provides evidence for global pooling. The pattern of integration and the existence of global pooling is dependent on shape frequency. The two-part behavior is independent of shape amplitude but is only seen for low RFs (3 and 5). Data for RF20 follow the prediction of probability summation. We next investigated various stimulus characteristics and their effect on integration strength. Global pooling exceeding probability summation is evident for different pattern sizes, presentation times and for high as well as low absolute contrasts. Only if the contrasts of different fractions of a contour shape are individually scaled to match their respective visibilities is integration strength below the level of probability summation. This explains the lack of apparent global pooling in previous studies employing mixed contrasts. The marked increase in performance for discriminating completely modulated RF patterns argues in favor of highly specialized, global shape mechanisms that are seen over a wide range of stimulus configurations. The results indicate global, non-linear mechanisms, which respond most strongly when stimulated by the entire pattern and comparatively weakly when only stimulated by parts of it. PMID- 22429960 TI - In-cage and out-of-cage combinations of benzylic radical pairs in the glassy and melted states of poly(alkyl methacrylate)s. AB - Norrish type 1 reactions of 1-(4-methylphenyl)-3-phenyl-2-propanone (ACOB(1)) have been used to probe structural and morphological properties of a series of poly(alkyl methacrylate)s (PAMAs, where the alkyl is ethyl, butyl, isobutyl, cyclohexyl, and hexadecyl) below and above their glass transition (or melting) temperatures. The PAMAs investigated cover a wide range of glass transition temperatures and structure types. The ratio of in-cage to the sum of in-cage and out-of-cage recombinations of the triplet benzylic radical-pairs generated upon irradiation of ACOB(1) (F(c)) have been calculated from relative photoproduct yields at different temperatures and are compared with the free hole volumes within the polymers as calculated from positronium annihilation lifetime spectroscopy. Laser flash photolysis experiments to follow the growth and decay of the radicals have also been conducted in order to correlate the steady-state irradiation results with the radical pair recombination processes (i.e., in-cage and out-of-cage). The changes in F(c) as a function of PAMA type and phase (temperature) can be correlated with chain relaxation rates and the nature of the polymer side chains, but not hole free volumes. These results are compared with those from our previous work, conducted in polyethylenes with differing degrees of crystallinity, where hole free volume was the primary factor in controlling F(c). PMID- 22429961 TI - Label-free reflectometric interference microchip biosensor based on nanoporous alumina for detection of circulating tumour cells. AB - In this report, a label-free reflectometric interference spectroscopy (RIfS) based microchip biosensor for the detection of circulating tumour cells (CTCs) is demonstrated. Highly ordered nanoporous anodic aluminium oxide (AAO) fabricated by electrochemical anodization of aluminium foil was used as the RIfS sensing platform. Biotinylated anti-EpCAM antibody that specifically binds to human cancer cells of epithelial origin such as pancreatic cancer cells (PANC-1) was covalently attached to the AAO surface through multiple surface functionalization steps. Whole blood or phosphate buffer saline spiked with low numbers of pancreatic cancer cells were successfully detected by specially designed microfluidic device incorporating an AAO RIfS sensor, without labour intensive fluorescence labelling and/or pre-enhancement process. Our results show that the developed device is capable of selectively detecting of cancer cells, within a concentrations range of 1000-100,000 cells/mL, with a detection limit of <1000 cells/mL, a response time of <5 min and sample volume of 50 MUL of. The presented RIfS method shows considerable promise for translation to a rapid and cost effective point-of-care diagnostic device for the detection of CTCs in patients with metastatic cancer. PMID- 22429962 TI - Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into the pathogenesis of IPF, we reanalyzed our previously published gene expression data profiling IPF lungs. Cytokine receptor like factor 1 (CRLF1) was among the most highly up-regulated genes in IPF lungs, compared with normal controls. The protein product (CLF-1) and its partner, cardiotrophin-like cytokine (CLC), function as members of the interleukin 6 (IL 6) family of cytokines. Because of earlier work implicating IL-6 family members in IPF pathogenesis, we tested whether CLF-1 expression contributes to inflammation in experimental pulmonary fibrosis. In IPF, we detected CLF-1 expression in both type II alveolar epithelial cells and macrophages. We found that the receptor for CLF-1/CLC signaling, ciliary neurotrophic factor receptor (CNTFR), was expressed only in type II alveolar epithelial cells. Administration of CLF-1/CLC to both uninjured and bleomycin-injured mice led to the pulmonary accumulation of CD4(+) T cells. We also found that CLF-1/CLC administration increased inflammation but decreased pulmonary fibrosis. CLF-1/CLC leads to significantly enriched expression of T-cell-derived chemokines and cytokines, including the antifibrotic cytokine interferon-gamma. We propose that, in IPF, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung. PMID- 22429963 TI - Promotion of a functional B cell germinal center response after Leishmania species co-infection is associated with lesion resolution. AB - Co-infection of C3HeB/FeJ (C3H) mice with both Leishmania major and Leishmania amazonensis leads to a healed footpad lesion, whereas co-infection of C57BL/6 (B6) mice leads to non-healing lesions. This inability to heal corresponds to a deficiency in B cell stimulation of the macrophage-mediated killing of L. amazonensis in vitro and a less robust antibody response. The mechanism that leads to healing of these lesions is not completely known, although our studies implicate the B cell response as having an important effector function in killing L. amazonensis. To understand more completely this disparate clinical outcome to the same infection, we analyzed the draining lymph node germinal center B cell response between co-infected C3H and B6 mice. There were more germinal center B cells, more antibody isotype-switched germinal center B cells, more memory B cells, and more antigen-specific antibody-producing cells in co-infected C3H mice compared to B6 mice as early as 2 weeks postinfection. Interleukin (IL)-21 production and IL-21 receptor expression in both mouse strains, however, were similar at 2 weeks, suggesting that the difference in the anti-Leishmania response in these mouse strains may be due to differences in T follicular cell commitment or intrinsic B cell differences. These data support the idea that functional B cells are important for healing L. amazonensis in this infectious disease model. PMID- 22429964 TI - Heparan sulfate subdomains that are degraded by Sulf accumulate in cerebral amyloid beta plaques of Alzheimer's disease: evidence from mouse models and patients. AB - Alzheimer's disease (AD) is characterized by extracellular cerebral accumulation of amyloid beta peptide (Abeta). Heparan sulfate (HS) is a glycosaminoglycan that is abundant in the extracellular space. The state of sulfation within the HS chain influences its ability to interact with a variety of proteins. Highly sulfated domains within HS are crucial for Abeta aggregation in vitro. Here, we investigated the expression of the sulfated domains and HS disaccharide composition in the brains of Tg2576, J20, and T41 transgenic AD mouse models, and patients with AD. RB4CD12, a phage display antibody, recognizes highly sulfated domains of HS. The RB4CD12 epitope is abundant in the basement membrane of brain vessels under physiological conditions. In the cortex and hippocampus of the mice and patients with AD, RB4CD12 strongly stained both diffuse and neuritic amyloid plaques. Interestingly, RB4CD12 also stained the intracellular granules of certain hippocampal neurons in AD brains. Disaccharide compositions in vessel enriched and nonvasculature fractions of Tg2576 mice and AD patients were found to be comparable to those of non-transgenic and non-demented controls, respectively. The RB4CD12 epitope in amyloid plaques was substantially degraded ex vivo by Sulf-1 and Sulf-2, extracellular HS endosulfatases. These results indicate that formation of highly sulfated HS domains may be upregulated in conjunction with AD pathogenesis, and that these domains can be enzymatically remodeled in AD brains. PMID- 22429965 TI - Co-expression of XIAP and cyclin D1 complex correlates with a poor prognosis in patients with hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Despite improved diagnosis and treatment, the prognosis for HCC patients remains poor. The goal of this study was to identify key regulatory proteins and signaling pathways important for cell apoptosis and proliferation as biomarkers for prognostication and targeted therapy. Protein Pathway Array was applied to screen 38 signaling proteins and phosphoproteins in 12 paired HCC tumors and surrounding benign tissues and found that 20 of them, including XIAP, CDK4, CDK6, and Cyclin D1, were overexpressed in HCC tissues. Immunostaining results of XIAP, CDK4, and Cyclin D1 in an additional 59 HCC tissues showed that the expression of XIAP correlated with the expression of CDK4/Cyclin D1, and that the increased expression of these proteins correlated with poor overall survival in these patients. Further studies using the HCC Huh7 cell line transfected with XIAP siRNA or expression vector demonstrated that XIAP regulated the expression of CDK4, CDK6, and Cyclin D1 via NF-eB and PTEN pathways. Finally, inhibition of XIAP using embelin, a XIAP-specific small molecule, leads to an increased apoptosis and decreased cell proliferation via arrest at G1 phase. Taken together, XIAP is a central modulator regulating cell apoptosis and cell cycle progression. Therefore, XIAP together with cell cycle regulatory proteins can be used as prognostic markers and therapeutic targets. PMID- 22429966 TI - Aberrant calreticulin expression is involved in the dedifferentiation of dedifferentiated liposarcoma. AB - Liposarcomas are a representative group of soft tissue sarcomas with variably hampered adipogenesis, which is most exemplified by its dedifferentiated subtype. However, the factor(s) responsible for inhibiting adipocyte differentiation remains unknown. A recent gene expression profiling study identified several unique genes that were highly expressed in dedifferentiated liposarcoma, and the gene encoding calreticulin (CALR), a major Ca(2+)-buffering protein that can inhibit adipocyte differentiation, was found to be overexpressed. Thus, we investigated the expression of calreticulin in 45 cases of liposarcomas, including 15 dedifferentiated tumors, at both the protein and mRNA levels. Immunohistochemically, calreticulin was consistently expressed in the dedifferentiated areas of dedifferentiated liposarcomas and commonly observed in atypical stromal cells and/or lipoblasts in the well-differentiated areas (87%), whereas large vacuolated adipocytic cells in either the tumors or normal fat were essentially negative. These results were further supported by the findings of Western blot and quantitative RT-PCR analyses. Although abnormalities in 19p13.1 13.2 where CALR is localized were uncommon in the dedifferentiated liposarcomas examined by fluorescence in situ hybridization, expression of miR-1257, a putative microRNA that targets calreticulin, was suppressed in the dedifferentiated subtype. The down-regulation of calreticulin by small interfering RNA could induce adipogenesis in dedifferentiated liposarcoma cells and reduce cell proliferation. Our results therefore suggest that aberrantly expressed calreticulin in dedifferentiated liposarcoma is involved in its dedifferenitation and/or tumor progression. PMID- 22429967 TI - Evidence for baseline retinal pigment epithelium pathology in the Trp1-Cre mouse. AB - The increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies. PMID- 22429968 TI - MicroRNA 15a, inversely correlated to PKCalpha, is a potential marker to differentiate between benign and malignant renal tumors in biopsy and urine samples. AB - NF-kappaB signal transduction is a potential therapeutic target in many malignant tumors. We have recently shown, in malignant renal proximal tumor cells, that a transcription complex, consisting of NF-kappaB p65 and mitogen-activated protein kinase p38alpha, joined by protein kinase C (PKC) alpha, transmigrates into the nucleus. There, PKCalpha suppresses the nuclear release of primary microRNA (pri miRNA) 15a. Induced by endothelin (ET)-1, a decrease in PKCalpha levels leads to increased miRNA 15a (miR-15A) expression. An identical system can be identified in renal carcinomas, in which, after nuclear transmigration, PKCalpha binds directly to pri-miRNA 15a in the nucleus. However, the pattern of PKC isoforms differs between malignant renal cell carcinoma (RCC) and benign oncocytoma. PKCalpha, a component of the transcription complex in tumors, is up-regulated in benign oncocytoma but down-regulated in RCC. Conversely, miRNA 15a is up regulated in RCC and down-regulated in oncocytoma. A similar behavior is observed in chromophobe carcinoma, whereas differences are less pronounced in papillary RCC (type I): NF-kappaB target gene expression (ie, ET-1, ET-A and ET-B receptors, vascular cell adhesion molecule-1, IL-6, and fractalkine) is particularly high in malignant RCCs. Up-regulated miRNA 15a can be measured in urine from patients with RCC but is nearly undetectable in oncocytoma, other tumors, and urinary tract inflammation. Thus, the up-regulation of miRNA 15a may be an important marker to help identify malignant clear-cell RCCs in both biopsy and urine samples. PMID- 22429969 TI - Dynamic effects of adrenaline (epinephrine) in out-of-hospital cardiac arrest with initial pulseless electrical activity (PEA). AB - BACKGROUND: In cardiac arrest, pulseless electrical activity (PEA) is a challenging clinical syndrome. In a randomized study comparing intravenous (i.v.) access and drugs versus no i.v. access or drugs during advanced life support (ALS), adrenaline (epinephrine) improved return of spontaneous circulation (ROSC) in patients with PEA. Originating from this study, we investigated the time dependent effects of adrenaline on clinical state transitions in patients with initial PEA, using a non-parametric multi-state statistical model. METHODS AND RESULTS: Patients with available defibrillator recordings were included, of whom 101 received adrenaline and 73 did not. There were significantly more state transitions in the adrenaline group than in the no-adrenaline group (rate ratio = 1.6, p<0.001). Adrenaline markedly increased the rate of transition from PEA to ROSC during ALS and slowed the rate of being declared dead; e.g. by 20 min 20% of patients in the adrenaline group had been declared dead and 25% had obtained ROSC, whereas 50% in the no-adrenaline group have been declared dead and 15% had obtained ROSC. The differential effect of adrenaline could be seen after approx. 10 min of ALS for most transitions. For both groups the probability of deteriorating from PEA to asystole was highest during the first 15 min. Adrenaline increased the rate of transition from PEA to ventricular fibrillation or -tachycardia (VF/VT), and from ROSC to VF/VT. CONCLUSIONS: Adrenaline has notable clinical effects during ALS in patients with initial PEA. The drug extends the time window for ROSC to develop, but also renders the patient more unstable. Further research should investigate the optimal dose, timing and mode of adrenaline administration during ALS. PMID- 22429970 TI - Comparison of GlideScope((r)) versus Macintosh laryngoscope for the removal of a hypopharyngeal foreign body: a randomized cross-over cadaver study. AB - OBJECTIVE: This study aimed to evaluate whether GlideScope((r)) is an effective and acceptable method for the removal of a hypopharyngeal foreign body. METHODS: This was a prospective study conducted in 28 first year emergency residents with little prior airway management experience. Participants extracted hypopharyngeal foreign bodies using a Macintosh laryngoscope and GlideScope((r)) with Magill and Sponge forceps. The primary endpoints were extraction time and success rate with each device. Participant preferences were also assessed. RESULTS: The cumulative success rate in relation to time to extraction was significantly higher with the Macintosh laryngoscope than with the GlideScope((r)) (p<0.001) regardless of the extraction device. Significantly fewer attempts were required for the first successful extraction with the Macintosh laryngoscope versus GlideScope((r)) with Magill forceps (p=<0.001) and Sponge forceps (p=<0.001). The time for successful foreign body extraction using GlideScope((r)) was significantly lower when using Magill (median 46 s, IQR 28-75 s) forceps than Sponge forceps (median 79 s, IQR 41-88 s). CONCLUSIONS: In this cadaver model, the Macintosh laryngoscope appeared to be more efficient and preferred than GlideScope((r)) for extracting hypopharyngeal airway foreign bodies that are associated with fatal asphyxiation. PMID- 22429971 TI - Can drugs ever improve outcome after cardiac arrest? PMID- 22429972 TI - Endothelial damage after cardiac arrest--"endotheliitis". PMID- 22429973 TI - The factors associated with successful paediatric endotracheal intubation on the first attempt in emergency departments: a 13-emergency-department registry study. AB - BACKGROUND: We investigated which factors are associated with successful paediatric endotracheal intubation (ETI) on the first attempt in emergency department (EDs) from multicentre emergency airway registry data. METHODS: We created a multicentre registry of intubations at 13 EDs and performed surveillance over 5 years. Each intubator filled out a data form after an intubation. We defined "paediatric patients" as patients younger than 10 years of age. We assessed the specialty and level of training of intubator, the method, the equipment, and the associated adverse events. We analysed the intubation success rates on the first attempt (first-pass success, FPS) based on these variables. RESULTS: A total of 430 ETIs were performed on 281 children seen in the ED. The overall FPS rate was 67.6%, but emergency medicine (EM) physicians showed a significantly greater success rate of 74.4%. In the logistic regression analysis, the intubator's specialty was the only independent predictive factor for paediatric FPS. In the subgroup analysis, the EM physicians used the rapid sequence intubation/intubation (RSI) method and Macintosh laryngoscope more frequently than physicians of other specialties. ETI-related adverse events occurred in 21 (7.2%) out of the 281 cases. The most common adverse event in the FPS group was mainstem bronchus intubation, and vomiting was the most common event in the non-FPS group. The incidence of adverse events was lower in the FPS group than in the non-FPS group, but this difference was not statistically significant. CONCLUSIONS: The intubator's specialty was the major factor associated with FPS in emergency department paediatric ETI, The overall ETI FPS rate among paediatric patients was 67.6%, but the EM physicians had a FPS rate of 74.4%. A well structured airway skill training program, and more actively using the RSI method are important and this could explain this differences. PMID- 22429974 TI - Video-based CPR training--the importance of quality assurance. PMID- 22429975 TI - Duration of hospital participation in Get With the Guidelines-Resuscitation and survival of in-hospital cardiac arrest. AB - BACKGROUND: Get With the Guidelines (GWTG-R) is a data registry and quality improvement program for in-hospital cardiac arrest (IHCA). It is unknown if duration of hospital participation in GWTG-R is associated with IHCA outcomes. METHODS: We analyzed adults with IHCA from 362 hospitals participating in GWTG-R between 2000 and 2009. Using logistic regression with generalized estimating equations to account for clustering on hospital, we determined the association between duration of hospital participation in GWTG-R and patient outcomes after IHCA, adjusted for patient and arrest characteristics and secular trend. Using these methods, we also evaluated the association between duration of participation and factors previously correlated with survival after IHCA, including ECG monitored status, after-hours arrest, and time to defibrillation. RESULTS: Of 104,732 patients with IHCA, 17,646 patients (16.9%) survived to discharge. Duration of hospital participation in GWTG-R was associated with IHCA event survival (per year of participation, odds ratio [OR] 1.02; 95% CI 1.00 1.04; p=0.046) but not survival to discharge (OR 1.02; 95% CI 0.99-1.04; p=0.18). Among factors previously correlated with IHCA survival, duration of participation was associated with time to defibrillation <=2 min (per year of participation, OR 1.06; 95% CI 1.03-1.10; p<0.001), but not ECG monitored status (OR 1.00; 95% CI 0.93-1.06; p=0.90) or survival of after-hours arrest (OR 1.01; 95% CI 0.99-1.03; p=0.41). Among ventricular tachycardia or ventricular fibrillation (VT/VF) arrests, time to defibrillation attenuated the association between duration of hospital participation and outcomes. CONCLUSION: Duration of hospital participation in GWTG-R was significantly associated with survival of the IHCA event, but not with survival to discharge. In VT/VF arrests, this association may have been mediated by improvements in time to defibrillation. PMID- 22429976 TI - Predictive scores, friend or foe for the cardiac arrest patient. PMID- 22429977 TI - Successful treatment of refractory cardiac arrest by emergency physicians using pre-hospital ECLS. PMID- 22429978 TI - Socioeconomic inequality in domains of health: results from the World Health Surveys. AB - BACKGROUND: In all countries people of lower socioeconomic status evaluate their health more poorly. Yet in reporting overall health, individuals consider multiple domains that comprise their perceived health state. Considered alone, overall measures of self-reported health mask differences in the domains of health. The aim of this study is to compare and assess socioeconomic inequalities in each of the individual health domains and in a separate measure of overall health. METHODS: Data on 247,037 adults aged 18 or older were analyzed from 57 countries, drawn from all national income groups, participating in the World Health Survey 2002-2004. The analysis was repeated for lower- and higher-income countries. Prevalence estimates of poor self-rated health (SRH) were calculated for each domain and for overall health according to wealth quintiles and education levels. Relative socioeconomic inequalities in SRH were measured for each of the eight health domains and for overall health, according to wealth quintiles and education levels, using the relative index of inequality (RII). A RII value greater than one indicated greater prevalence of self-reported poor health among populations of lower socioeconomic status, called pro-rich inequality. RESULTS: There was a descending gradient in the prevalence of poor health, moving from the poorest wealth quintile to the richest, and moving from the lowest to the highest educated groups. Inequalities which favor groups who are advantaged either with respect to wealth or education, were consistently statistically significant in each of the individual domains of health, and in health overall. However the size of these inequalities differed between health domains. The prevalence of reporting poor health was higher in the lower-income country group. Relative socioeconomic inequalities in the health domains and overall health were higher in the higher-income country group than the lower income country group. CONCLUSIONS: Using a common measurement approach, inequalities in health, favoring the rich and the educated, were evident in overall health as well as in every health domain. Existent differences in averages and inequalities in health domains suggest that monitoring should not be limited only to overall health. This study carries important messages for policy making in regard to tackling inequalities in specific domains of health. Targeting interventions towards individual domains of health such as mobility, self-care and vision, ought to be considered besides improving overall health. PMID- 22429979 TI - An anti-cancer Smurf. AB - A novel, cancer-fighting function was recently discovered for Smad ubiquitination regulatory factor 2 (Smurf2). PMID- 22429980 TI - Antitumor efficacy following the intracellular and interstitial release of liposomal doxorubicin. AB - pH-triggered lipid-membranes designed from biophysical principles are evaluated in the form of targeted liposomal doxorubicin with the aim to ultimately better control the growth of vascularized tumors. We compare the antitumor efficacy of anti-HER2/neu pH-triggered lipid vesicles encapsulating doxorubicin to the anti HER2/neu form of an FDA approved liposomal doxorubicin of DSPC/cholesterol-based vesicles. The HER2/neu receptor is chosen due to its abundance in human breast cancers and its connection to low prognosis. On a subcutaneous murine BT474 xenograft model, superior control of tumor growth is demonstrated by targeted pH triggered vesicles relative to targeted DSPC/cholesterol-based vesicles (35% vs. 19% decrease in tumor volume after 32 days upon initiation of treatment). Superior tumor control is also confirmed on SKBR3 subcutaneous xenografts of lower HER2/neu expression. The non-targeted form of pH-triggered vesicles encapsulating doxorubicin results also in better tumor control relative to the non-targeted DSPC/cholesterol-based vesicles (34% vs. 41% increase in tumor volume). Studies in BT474 multicellular spheroids suggest that the observed efficacy could be attributed to release of doxorubicin directly into the acidic tumor interstitium from pH-triggered vesicles extravasated into the tumor but not internalized by cancer cells. pH-triggered liposome carriers engineered from gel phase bilayers that reversibly phase-separate with lowering pH, form transiently defective interfacial boundaries resulting in fast release of encapsulated doxorubicin. Our studies show that pH-triggered liposomes release encapsulated doxorubicin intracellularly and intratumorally, and may improve tumor control at the same or even lower administered doses relative to FDA approved liposomal chemotherapy. PMID- 22429981 TI - Extrahepatic bile duct regeneration in pigs using collagen scaffolds loaded with human collagen-binding bFGF. AB - Extrahepatic bile duct defects and their complications are benign lesions but with malignant outcomes. Extrahepatic bile duct regeneration at the injury site could be important for the repair. In our previous work, a human basic fibroblast growth factor (bFGF) fused with a collagen-binding domain (CBD) was produced to activate the collagen membrane to obtain targeted tissue regeneration. This collagen/growth factor functional biomaterial could promote the regeneration of skin, bladder and full-thickness abdominal wall by accelerating vascularization and cellularization of autologous tissues. We speculate that the functional biomaterial could also provide the repairing effect on extrahepatic bile duct injuries. Using a pig extrahepatic bile duct injury model, we found that the collagen/CBD-bFGF composite biomaterial could significantly promote the extrahepatic bile duct regeneration at the injury site without causing structure deformation or hepatic dysfunction during both short- and long-time observations. PMID- 22429982 TI - Towards personalized medicine with a three-dimensional micro-scale perfusion based two-chamber tissue model system. AB - A three-dimensional micro-scale perfusion-based two-chamber (3D-MUPTC) tissue model system was developed to test the cytotoxicity of anticancer drugs in conjunction with liver metabolism. Liver cells with different cytochrome P450 (CYP) subtypes and glioblastoma multiforme (GBM) brain cancer cells were cultured in two separate chambers connected in tandem. Both chambers contained a 3D tissue engineering scaffold fabricated with biodegradable poly(lactic acid) (PLA) using a solvent-free approach. We used this model system to test the cytotoxicity of anticancer drugs, including temozolomide (TMZ) and ifosfamide (IFO). With the liver cells, TMZ showed a much lower toxicity to GBM cells under both 2D and 3D cell culture conditions. Comparing 2D, GBM cells cultured in 3D had much high viability under TMZ treatment. IFO was used to test the CYP-related metabolic effects. Cells with different expression levels of CYP3A4 differed dramatically in their ability to activate IFO, which led to strong metabolism-dependent cytotoxicity to GBM cells. These results demonstrate that our 3D-MUPTC system could provide a more physiologically realistic in vitro environment than the current 2D monolayers for testing metabolism-dependent toxicity of anticancer drugs. It could therefore be used as an important platform for better prediction of drug dosing and schedule towards personalized medicine. PMID- 22429983 TI - Surface modified magnetic nanoparticles for immuno-gene therapy of murine mammary adenocarcinoma. AB - Cancer immuno-gene therapy is an introduction of nucleic acids encoding immunostimulatory proteins, such as cytokine interleukin 12 (IL-12), into somatic cells to stimulate an immune response against a tumor. Various methods can be used for the introduction of nucleic acids into cells; magnetofection involves binding of nucleic acids to magnetic nanoparticles with subsequent exposure to an external magnetic field. Here we show that surface modified superparamagnetic iron oxide nanoparticles (SPIONs) with a combination of polyacrylic acid (PAA) and polyethylenimine (PEI) (SPIONs-PAA-PEI) proved to be safe and effective for magnetofection of cells and tumors in mice. Magnetofection of cells with plasmid DNA encoding reporter gene using SPIONs-PAA-PEI was superior in transfection efficiency to commercially available SPIONs. Magnetofection of murine mammary adenocarcinoma with plasmid DNA encoding IL-12 using SPIONs-PAA-PEI resulted in significant antitumor effect and could be further refined for cancer immuno-gene therapy. PMID- 22429984 TI - Commentary on 'Selection, thirty day outcome and costs for Short Stay Endovascular Aortic Aneurysm Repair (SEVAR)'. PMID- 22429985 TI - Net effect of lymphaticovenous anastomosis on volume reduction of peripheral lymphoedema after complex decongestive physiotherapy. PMID- 22429987 TI - Employing UMLS for generating hints in a tutoring system for medical problem based learning. AB - While problem-based learning has become widely popular for imparting clinical reasoning skills, the dynamics of medical PBL require close attention to a small group of students, placing a burden on medical faculty, whose time is over taxed. Intelligent tutoring systems (ITSs) offer an attractive means to increase the amount of facilitated PBL training the students receive. But typical intelligent tutoring system architectures make use of a domain model that provides a limited set of approved solutions to problems presented to students. Student solutions that do not match the approved ones, but are otherwise partially correct, receive little acknowledgement as feedback, stifling broader reasoning. Allowing students to creatively explore the space of possible solutions is exactly one of the attractive features of PBL. This paper provides an alternative to the traditional ITS architecture by using a hint generation strategy that leverages a domain ontology to provide effective feedback. The concept hierarchy and co-occurrence between concepts in the domain ontology are drawn upon to ascertain partial correctness of a solution and guide student reasoning towards a correct solution. We describe the strategy incorporated in METEOR, a tutoring system for medical PBL, wherein the widely available UMLS is deployed and represented as the domain ontology. Evaluation of expert agreement with system generated hints on a 5-point likert scale resulted in an average score of 4.44 (Spearman's rho=0.80, p<0.01). Hints containing partial correctness feedback scored significantly higher than those without it (Mann Whitney, p<0.001). Hints produced by a human expert received an average score of 4.2 (Spearman's rho=0.80, p<0.01). PMID- 22429988 TI - Co-administration of calcium gluconate and magnesium acetate effectively blocks the signs of morphine withdrawal in mice. AB - The present study was conducted to investigate the effect of oral administration of calcium gluconate and magnesium acetate on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of increasing doses of morphine. Mice were observed for 30 minutes for the withdrawal signs (jumping or standing events, diarrhea, piloerection, tremor and ptosis). Separate oral administration of magnesium (50, 75 and 100 mg/kg) and calcium (500, 750 and 1,000 mg/kg) significantly decreased the jumping, without affecting standing in animals withdrawn from morphine. Co-administration of magnesium (at a fixed dose of 100 mg/kg) and calcium (at a range of doses from 250 to 1,000 mg/kg) resulted in a significant reduction in jumping and standing events (P<0.05). In a similar fashion, the qualitative signs of withdrawal were also reduced when the above combination of calcium and magnesium was administered. Co-administration of calcium/magnesium at 500/50, 750/75 and 1,000/100 mg/kg significantly reduced the number of jumps in morphine-dependent animals without affecting the number of standing events. This study demonstrates the potential activity of the co administration calcium and magnesium in preventing the signs associated with morphine withdrawal syndrome. PMID- 22429989 TI - Evaluation of chamber response function influence on IMRT verification using 2D commercial detector arrays. AB - This work is devoted to studying the influence of chamber response functions on the standard IMRT verification for the different detector technologies available on commercial devices. We have tested three of the most used 2D detector arrays for radiotherapy dosimetry verification, based on air-ionization chambers and diode detectors. The response function has been carefully simulated using the Monte Carlo method and measured through slit and pinhole collimators. Although the response function of air-ionization detectors is considerably different with respect to that of standard diodes, the impact on a verification based in the gamma function with tolerances 3 mm and 3% is quite limited. The results show that the standard air-ionization detector arrays perform in a similar way whenever the tolerances for the gamma function are not lowered below 1.5 mm and 1.5%. Additionally, the sensitivity of these devices to fluence perturbations was measured by intentionally modifying some leaf positions in the multileaf collimator. The wider response function of air-ionization chamber arrays made them slightly more sensitive to random fluence perturbations, although silicon diode arrays are more accurate to describe the dose distribution in a point by point basis. PMID- 22429990 TI - Cylindrospermopsin, a blue-green algal toxin, inhibited human luteinised granulosa cell protein synthesis in vitro. AB - The blue-green algal toxin cylindrospermopsin (CYN) inhibits protein synthesis, and CYP450 enzymes metabolise CYN to cytotoxic endproducts. Human chorionic gonadotrophin (hCG) stimulates the de novo synthesis of StAR and CYP450 aromatase. Human IVF-derived granulosa cells (GC) (n=7) were exposed to 0-5MUM CYN+/-1IU/ml hCG for 2-24h. After 24h pre-culture GC responded to hCG by increasing estradiol 17beta (E(2)) and progesterone (P(4)) synthesis. Three micromolar of CYN+/-1IU/ml hCG for 24h was not cytotoxic and did not affect basal or hCG-stimulated E(2) or P(4) production, but did inhibit protein synthesis (p<0.05, n=4). hCG-stimulated steroidogenesis was not reduced by CYN, suggesting a lack of effect on StAR or CYP450 aromatase protein synthesis. hCG enhanced the effects of CYN on GC protein synthesis. Twenty four hours exposure to 0.1MUM CYN did not affect GC, supporting the establishment of a 0.0024MUM Guideline level for CYN in public water supplies. PMID- 22429991 TI - Efficient differentiation of AR42J cells towards insulin-producing cells using pancreatic transcription factors in combination with growth factors. AB - The AR42J-B13 rat pancreatic acinar cell line was used to identify pancreatic transcription factors and exogenous growth factors (GFs) that might facilitate the reprogramming of exocrine cells into islets. Adenoviruses were used to induce exogenous expression of the pancreatic transcription factors (TFs) Pdx1, MafA, Ngn3 and Pax4. Individually Pdx1, MafA and Pax4 had no effect on the expression of endocrine markers, whilst adeno-Ngn3 on its own increased the expression of Pax4, Ngn3 and NeuroD. In combination the four TFs had a significant effect on the expression of insulin 1 and 2 that was associated with a change in cell morphology from a rounded to a spindle-like shape. Amongst a range of growth factors, Betacellulin and Nicotinamide were shown to enhance the effects of the four TFs. The presence of adeno-Pax4 in the differentiation cocktail was important in limiting the expression of glucagon and in generating glucose sensitive insulin secretion. Further experiments asked whether the adenoviral TFs could be replaced by protein transduction domain (PTD)-containing TFs. The results showed that the PTD-TFs could mimic in part the effects of the adeno-TFs, but the resultant cells did not undergo the important morphological change associated with differentiation to endocrine lineages and levels of endogenous markers were very much lower. In summary, the results describe a cocktail of four TFs and two GFs that can be used to induce formation of glucose sensitive insulin secreting cells from ARJ42 cells, and demonstrate that it would be difficult to replace adenoviral transduction with PTD-TFS. PMID- 22429992 TI - Sex-specific antidepressant effects of dietary creatine with and without sub acute fluoxetine in rats. AB - The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. PMID- 22429993 TI - The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol preferring (P) rats. AB - The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH)-seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n=11-14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration. PMID- 22429994 TI - Antioxidant defence of colostrum and milk in consecutive lactations in sows. AB - BACKGROUND: Parturition is supposed to be related to oxidative stress, not only for the mother, but also for the newborn. Moreover, it is not clear whether consecutive pregnancies, parturitions, and lactations are similar to each other in regards to intensity of metabolic processes or differ from each other. The aim of the study was to compare dynamic changes of antioxidative parameters in colostrum and milk of sows taken during 72 h postpartum from animals in consecutive lactations. Activities of glutathione peroxidase (GSH-Px), glutathione transferase (GSH-Tr), and superoxide dismutase (SOD), and amount of vitamin A and C were measured. Healthy pregnant animals were divided into 4 groups according to the assessed lactation: A -1st lactation (n = 10), B - 2nd and 3rd lactation (n = 7), C - 4th and 5th lactation (n = 11), D - 6th - 8th lactation (n = 8). The colostrum was sampled immediately after parturition and after 6, 12, 18 and 36 h while the milk was assessed at 72 h after parturition. Spectrophotometric methods were used for measurements. RESULTS: The activity of antioxidative enzymes and the concentration of vitamin A increased with time postpartum. The concentration of vitamin C was the highest between the 18th and 36th h postpartum. CONCLUSIONS: Dynamic changes in the values of antioxidant parameters measured during the study showed that sows milk provides the highest concentration of antioxidants in the 2nd and 3rd and 4th and 5th lactation giving the best defence against reactive oxygen species to newborns and mammary glands. PMID- 22429995 TI - Heterologous mesenchymal stem cells successfully treat femoral pseudarthrosis in rats. AB - BACKGROUND: This study evaluated the effectiveness of treating pseudarthrosis in rats by using bone marrow cell suspensions or cultures of bone marrow mesenchymal stromal cells METHODS: Thirty-eight specific pathogen-free (SPF) animals were randomly assigned to four groups: Group 1, Control, without surgical intervention; Group 2 (Placebo), experimental model of femoral pseudarthrosis treated only with saline solution; Group 3, experimental model of femoral pseudarthrosis treated with heterologous bone marrow cells suspension; Group 4, experimental model of femoral pseudarthrosis treated with cultures of heterologous mesenchymal stromal cells from bone marrow. When pseudarthrosis was confirmed by simple radiological studies, digital radiography and histopathology after a 120-day postoperative period, Groups 2, 3 and 4 were treated as above. At 30, 60 and 90 days after the treatment, all animals were evaluated by simple radiological studies, and at the end of the experiment, the animals were assessed by computed axial tomography and anatomopathological and histomorphometric examinations. RESULTS: Injected cells were detected in the areas affected by pseudarthrosis using scintigraphy within the first 24 hours after their administration. After 60 days, the animals of Group 3 showed callus formation while the animals of Group 4 presented periosteal reaction and had some consolidated areas. In contrast, Group 2 showed a predominance of fibro-osteoid tissue. After 90 days, bone consolidation and remodeling was observed in all animals from Group 3 whereas animals from Group 4 exhibited partial consolidation and those ones from Group 2 persisted with pseudarthrosis. CONCLUSION: The treatment with heterologous bone marrow cells suspension proved to be effective in the treatment of pseudarthrosis whereas cultures of heterologous bone marrow mesenchymal stromal cells did not show the same potential to aid bone healing. PMID- 22429996 TI - Perfluoroalkyl acids: recent research highlights. PMID- 22429997 TI - Strain specific induction of pyometra and differences in immune responsiveness in mice exposed to 17alpha-ethinyl estradiol or the endocrine disrupting chemical bisphenol A. AB - Pyometra is an inflammatory disease of the uterus that can be caused by chronic exposure to estrogens. It is unknown whether weakly estrogenic endocrine disruptors can cause pyometra. We investigated whether dietary exposures to the estrogenic endocrine disruptor bisphenol A (BPA) induced pyometra. Pyometra did not occur in CD1 mice exposed to different dietary doses of BPA ranging from 4.1 to >4000MUg/kg-d or 17alpha-ethinyl estradiol (EE; 1.2 to >150MUg/kg-d). In the C57BL/6 strain, pyometra occurred in the 15MUg/kg-d EE and 33MUg/kg-d BPA treatment groups. At the effective concentration of BPA, histological analysis revealed pathological alterations of uterine morphology associated with a >5.3 fold increase in macrophage numbers in non-pyometra uteri of C57BL/6 mice exposed to BPA. These results suggest that BPA enhances immune responsiveness of the uterus and that heightened responsiveness in C57BL/6 females is related to increased susceptibility to pyometra. PMID- 22429998 TI - Inhibition of LDH-A by lentivirus-mediated small interfering RNA suppresses intestinal-type gastric cancer tumorigenicity through the downregulation of Oct4. AB - Many tumors metabolise the majority of the glucose that they take up through glycolysis even in the presence of an adequate oxygen supply. Lactate dehydrogenase A (LDH-A) is the critical enzyme that catalyses the transformation of pyruvate to lactate. We demonstrate that LDH-A reduction can suppress the tumorigenicity of intestinal-type gastric cancer (ITGC) cells by downregulating Oct4 both in vitro and in vivo. A statistical analysis of 661 ITGC specimens showed a significant correlation between LDH-A and Oct4 expression. Moreover, patients with low LDH-A/negative Oct4 expression exhibited better overall survival than patients with other combinations. We conclude that the close correlation of LDH-A and Oct4 may offer a promising therapeutic strategy for ITGC. PMID- 22429999 TI - Regulation of apoptosis pathways in cancer stem cells. AB - Cancer stem cell are considered to represent a population within the bulk tumor that share many similarities to normal stem cells as far as their capacities to self-renew, differentiate, proliferate and to reconstitute the entire tumor upon serial transplantation are concerned. Since cancer stem cells have been shown to be critical for maintaining tumor growth and have been implicated in treatment resistance and tumor progression, they constitute relevant targets for therapeutic intervention. Indeed, it has been postulated that eradication of cancer stem cells will be pivotal in order to achieve long-term relapse-free survival. However, one of the hallmarks of cancer stem cells is their high resistance to undergo cell death including apoptosis in response to environmental cues or cytotoxic stimuli. Since activation of apoptosis programs in tumor cells underlies the antitumor activity of most currently used cancer therapeutics, it will be critical to develop strategies to overcome the intrinsic resistance to apoptosis of cancer stem cells. Thus, a better understanding of the molecular mechanisms that are responsible for the ability of cancer stem cells to evade apoptosis will likely open new avenues to target this critical pool of cells within the tumor in order to develop more efficient treatment options for patients suffering from cancer. PMID- 22430000 TI - 'As a clinician, you are not managing lab results, you are managing the patient': how the enactment of malaria at health facilities in Cameroon compares with new WHO guidelines for the use of malaria tests. AB - In response to widespread overuse of antimalarial drugs, the World Health Organisation changed guidelines in 2010 to restrict the use of antimalarials to parasitologically confirmed malaria cases. Malaria rapid diagnostic tests (RDTs) have been presented as a means to realize the new guidelines, and National Malaria Control Programmes, including that of Cameroon, are developing plans to introduce the tests to replace microscopy or clinical diagnosis at public health facilities across the country. We aimed to understand how malaria tests and antimalarial drugs are currently used as part of social interactions between health workers and patients at public and mission health facilities in Yaounde and Bamenda and surrounding districts in the Northwest region of Cameroon. In May to June 2010, we held 17 focus group discussions with 146 health workers involved in clinical care from 49 health facilities. Clinicians enacted malaria as a 'juggling' exercise, involving attention to pathophysiology of the patient as well as their desires and medical reputations, utilising tests and medicines for their therapeutic effects as symbols in the process of care. Parasites were rarely mentioned in describing diagnostic decisions. These enactments of malaria contrast with evidence-based guidelines emanating from WHO, which assume the parasite is the central driver of practice. If RDTs are to be taken up in practice, public health practitioners need to pay careful attention to the values and priorities of health workers and patients if they are to work with them to improve diagnosis and treatment of febrile illnesses. PMID- 22430001 TI - A scoring system for the foot and ankle that is acceptable, reliable, valid and responsive. AB - We read with interest the recent paper by Groarke et al. (Quality of life in individuals with chronic foot conditions: a cross sectional observational study. The Foot (2012) doi:10.1016/i.foot.2011.11.007). The paper ended by stating that 'there is no scoring system for the foot and ankle that is valid, repeatable and reliable'. This statement is misleading. The authors could have made reference to the patient-reported Manchester-Oxford Foot Questionnaire (MOXFQ). The MOXFQ has been subjected to more rigorous testing of its measurement properties than is the case for most instruments, and has been demonstrated to be acceptable, reliable, valid and responsive in the context of foot or ankle surgery. PMID- 22430002 TI - Evolving P450pyr hydroxylase for highly enantioselective hydroxylation at non activated carbon atom. AB - Directed evolution of a monooxygenase to achieve very high enantioselectivity for hydroxylation at non-activated carbon atoms is demonstrated for the first time, where a triple mutant of P450pyr hydroxylase is obtained via determination of enzyme structure, iterative saturation mutagenesis, and high-throughput screening with a MS-based ee assay to increase the product ee from 53% to 98% for the hydroxylation of N-benzyl pyrrolidine to (S)-N-benzyl 3-hydroxypyrrolidine. PMID- 22430004 TI - [Advances in the prevention, diagnosis and therapy of vascular diseases]. AB - Atherosclerosis is a systemic disease affecting the coronary, carotid, intracerebral, renal and peripherial arteries. The early morphological and functional impairments could be detected in the second or third decades of life and their progression depend on the number and severity of risk factors and individual susceptility. Although the vascular risk factors (smoking, overweight, age, unhealthy diet, lack of physical exercise, hypertension, diabetes mellitus, chronic kidney disease and dyslipidemia) are the same and common in the different vascular diseases, the present clinical routine artificially classifies the diagnosis and therapy of different vascular diseases into different subfields of medicine with the negative impact of possible polypragmasia. Recently, worldwide health surveys (e.g. REACH registry) have proven the usefulness of a holistic approach in the diagnosis and therapy of multiorgan-affected vascular patients. This review summarizes the multidisciplinary advances and future perspective of vascular diseases. PMID- 22430005 TI - [The potential use of cannabidiol in the therapy of metabolic syndrome]. AB - Cannabidiol, a cannabinoid and serotonin receptor antagonist, may alleviate hyperphagia without the side effects of rimonabant (for example depression and reduced insulin sensitivity). Similar to the peroxisome proliferator-activated receptor-gamma agonists, it may also help the differentation of adipocytes. Cannabidiol has an immunomodulating effect, as well, that helps lessen the progression of atherosclerosis induced by high glucose level. It may also be effective in fighting ischaemic diseases, the most harmful complications of metabolic syndrome. However, it can only be administered as an adjuvant therapy because of its low binding potency, and its inhibiting effect of cytochrome P450 enzymes should also be considered. Nevertheless, it may be beneficially used in adjuvant therapy because of its few side effects. PMID- 22430006 TI - [Factors affecting influenza vaccine uptake among health care workers at the Medical and Health Sciences Center of Debrecen University, Hungary]. AB - Influenza vaccination is the most effective way of influenza prevention. The vaccination rate is low worldwide. In Hungary, the vaccine is free of charge to health care workers and, therefore, the low vaccination rate is unaccountable. AIMS: In this study, the authors wanted to explore those factors which influence the refusal of vaccination. METHODS: The Health Science Center of Debrecen University has about 4000 employees. The authors adjusted a questionnaire with 45 questions and sent it to 525 randomly selected health care workers, 294 of whom responded (response rate, 56%). The Epiinfo software was used for statistical evaluation. RESULTS: The respondents strongly agreed that the vaccine is free and easy to obtain at the workplace. Official recommendations of the occupational health, the Medical Association of Hungary and advice of the family doctors failed to influence the decision. However, a significant impact of communication with family members, friends and colleagues on the decision was documented. CONCLUSIONS: The results indicate that the most important tool in decision making of influenza vaccination is the internal communication, but this effect is not a permanent one. International data show highly variable vaccination rates (between 2.1% and 82%). A better vaccination rate (98% or above) may be achieved with a mandatory influenza vaccination program among health care workers. PMID- 22430007 TI - [Carbohydrate-deficient transferrin in doping and non-doping athletes]. AB - The determination of carbohydrate deficient transferrin (CDT) concentration is primarily used in social security studies as a proof of regular alcohol consumption exceeding the amount of 60 grams per day. AIMS: The present study was performed to investigate into how carbohydrate deficient transferrin CDT values in serum are affected by the so-called food supplements and chemicals included in doping lists. METHODS: The investigation was carried out in 15 bodybuilders of two sport clubs and in 10 boxers. All sportsmen were males. In both groups serum carbohydrate deficient transferrin (CDT%), median red blood cell volume and (MCV) gamma-glutamyl-transpeptidase (GGT) values were measured. RESULTS: The authors found a significant difference between the two groups only in carbohydrate deficient transferrin CDT% that was the CDT% value in bodybuilders was twice as high as in boxers. CONCLUSION: Not all the details of the specificity of carbohydrate deficient transferrin (CDT) concentration are known, however, the remarkably high sensitivity of the method makes it suitable and probably economically effective as a pre-screening tool in doping tests. PMID- 22430009 TI - Facial soft tissue thicknesses of the mid-face for Slovak population. AB - Forensic facial approximation is used as a tool for recreating the antemortem appearance of unknown dead and thus facilitates their identification. Several approaches to facial approximation are based on data on facial soft tissue thicknesses (FSTTs). The availability of sex-, age- and population-specific data contributes to the accuracy of the resulting facial approximation model. In this paper, first data set on FSTTs for a Central European population are presented. Soft tissue thicknesses of the mid-face were measured on 160 head CT-scans of 80 males and 80 females aged from 18 to 87 years. These CT-scans were made available after being a part of the diagnostic procedure concerning the paranasal sinuses of the patients. Basic descriptive statistics (i.e. mean, SD, median, range) for the FSTTs at 14 facial landmarks is reported separately by sex and age. Such information allows the forensic artist to choose the most suitable values for the FSTT considering the previous physiological and osteological analysis of the human remains. PMID- 22430010 TI - Terraskin(r) the paper made from stone: a study of a new writing support for forensic purposes. AB - Can a mineral paper be called paper? Until now all known writing supports have been ancient stones and tablets, parchment, and paper of vegetable origin, such as papyrus and fiber pulp paper. Some years ago polymeric banknotes appeared in Australia, and in 2004 mineral paper (stone plus polymer) emerged as an ecological alternative to pulp paper. In this article we study the physical and elemental features of a mineral paper such as the behavior of Terraskin(r) paper. We also study its behavior as a writing support, either for handwriting or printing, and compare these results with those usually obtained for paper made from pulp. PMID- 22430012 TI - A heterogeneous human tissue mimicking phantom for RF heating and MRI thermal monitoring verification. AB - This paper describes a heterogeneous phantom that mimics a human thigh with a deep-seated tumor, for the purpose of studying the performance of radiofrequency (RF) heating equipment and non-invasive temperature monitoring with magnetic resonance imaging (MRI). The heterogeneous cylindrical phantom was constructed with an outer fat layer surrounding an inner core of phantom material mimicking muscle, tumor and marrow-filled bone. The component materials were formulated to have dielectric and thermal properties similar to human tissues. The dielectric properties of the tissue mimicking phantom materials were measured with a microwave vector network analyzer and impedance probe over the frequency range of 80-500 MHz and at temperatures of 24, 37 and 45 degrees C. The specific heat values of the component materials were measured using a differential scanning calorimeter over the temperature range of 15-55 degrees C. The thermal conductivity value was obtained from fitting the curves obtained from one dimensional heat transfer measurement. The phantom was used to verify the operation of a cylindrical four-antenna annular phased array extremity applicator (140 MHz) by examining the proton resonance frequency shift (PRFS) thermal imaging patterns for various magnitude/phase settings (including settings to focus heating in tumors). For muscle and tumor materials, MRI was also used to measure T1/T2* values (1.5 T) and to obtain the slope of the PRFS phase change versus temperature change curve. The dielectric and thermal properties of the phantom materials were in close agreement to well-accepted published results for human tissues. The phantom was able to successfully demonstrate satisfactory operation of the tested heating equipment. The MRI-measured thermal distributions matched the expected patterns for various magnitude/phase settings of the applicator, allowing the phantom to be used as a quality assurance tool. Importantly, the material formulations for the various tissue types may be used to construct customized phantoms that are tailored for different anatomical sites. PMID- 22430014 TI - The mitochondrial Na(+)/Ca(2+) exchanger. AB - Powered by the steep mitochondrial membrane potential Ca(2+) permeates into the mitochondria via the Ca(2+) uniporter and is then extruded by a mitochondrial Na(+)/Ca(2+) exchanger. This mitochondrial Ca(2+) shuttling regulates the rate of ATP production and participates in cellular Ca(2+) signaling. Despite the fact that the exchanger was functionally identified 40 years ago its molecular identity remained a mystery. Early studies on isolated mitochondria and intact cells characterized the functional properties of a mitochondrial Na(+)/Ca(2+) exchanger, and showed that it possess unique functional fingerprints such as Li(+)/Ca(2+) exchange and that it is displaying selective sensitivity to inhibitors. Purification of mitochondria proteins combined with functional reconstitution led to the isolation of a polypeptide candidate of the exchanger but failed to molecularly identify it. A turning point in the search for the exchanger molecule came with the recent cloning of the last member of the Na(+)/Ca(2+) exchanger superfamily termed NCLX (Na(+)/Ca(2+)/Li(+) exchanger). NCLX is localized in the inner mitochondria membrane and its expression is linked to mitochondria Na(+)/Ca(2+) exchange matching the functional fingerprints of the putative mitochondrial Na(+)/Ca(2+) exchanger. Thus NCLX emerges as the long sought mitochondria Na(+)/Ca(2+) exchanger and provide a critical molecular handle to study mitochondrial Ca(2+) signaling and transport. Here we summarize some of the main topics related to the molecular properties of the Na(+)/Ca(2+) exchanger, beginning with the early days of its functional identification, its kinetic properties and regulation, and culminating in its molecular identification. PMID- 22430015 TI - Learning and memory: adult-born neurons change jobs. PMID- 22430016 TI - The many faces of insulin-like peptide signalling in the brain. AB - Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis - they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation. PMID- 22430018 TI - Ethnobotanical survey of medicinal plants used by Bapedi healers to treat diabetes mellitus in the Limpopo Province, South Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bapedi phytomedicine employ a range of plant species to treat diabetes mellitus (DM). Existing literature partially support the use of certain species for this purpose. AIM OF THE STUDY: To report on Bapedi medicinal plants employed to treat DM. MATERIALS AND METHODS: A semi structured questionnaire was employed to conduct a survey on medicinal plants used by Bapedi traditional healers in their DM management protocol. Fifty-two traditional healers from 16 municipalities, covering three districts, were interviewed during the first half of 2011. RESULTS: A total of 24 plant species belonging to 20 families, mostly from the Asteraceae (13%), Cucurbitaceae and Sapotaceae (8%), were used to treat diabetes mellitus. Plant parts mostly preferred were roots and leaves. A decoction of these is most commonly used to make extracts, which are then taken orally for a period of one week. Mimusops zeyheri (29%), Helichrysum caespititium (25%), Plumeria obtusa (21%), Aloe marlothii subsp. marlothii, Hypoxis iridifolia and Moringa oleifera (17% each), were repeatedly mentioned by the traditional healers as most used for the management of diabetes mellitus in the study area. Plumeria obtusa and Momordica balsamina are exclusively used to treat diabetes mellitus, and only in the Sekhukhune District. CONCLUSION: It is concluded that Bapedi traditional healers do have a basic understanding of the causes and remedial action required in the treatment of diabetes mellitus. PMID- 22430017 TI - Optogenetic investigation of neural circuits underlying brain disease in animal models. AB - Optogenetic tools have provided a new way to establish causal relationships between brain activity and behaviour in health and disease. Although no animal model captures human disease precisely, behaviours that recapitulate disease symptoms may be elicited and modulated by optogenetic methods, including behaviours that are relevant to anxiety, fear, depression, addiction, autism and parkinsonism. The rapid proliferation of optogenetic reagents together with the swift advancement of strategies for implementation has created new opportunities for causal and precise dissection of the circuits underlying brain diseases in animal models. PMID- 22430019 TI - Direct carboxamidation of indoles by palladium-catalyzed C-H activation and isocyanide insertion. AB - A selective C3 carboxamidation of indoles including free (N-H) ones by palladium catalyzed sequential C-H activation-isocyanide insertion has been developed. PMID- 22430020 TI - Cognitive improvement following treatment in late-life depression: relationship to vascular risk and age of onset. AB - OBJECTIVES: To test the hypothesis that the degree of vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late-life depression. DESIGN: Measurement of cognition both before and following 12 weeks of treatment with sertraline. SETTING: University medical centers (Washington University and Duke University). PARTICIPANTS: One hundred sixty-six individuals with late-life depression. INTERVENTION: Sertraline treatment. MEASUREMENTS: The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2-based white matter hyperintensities using the Fazekas criteria. RESULTS: Both episodic memory and executive function demonstrated significant improvement among adults with late-life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental State Examination scores predicted less change in working memory. Furthermore, older age, later age of onset, and higher vascular risk scores predicted less change in executive function. CONCLUSIONS: These results have important clinical implications in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life. PMID- 22430021 TI - Synthesis of enzyme mimics of iron telluride nanorods for the detection of glucose. AB - Iron telluride nanorods (FeTe NRs, length 45 +/- 11 nm) prepared from tellurium nanowires (Te NWs, length 785 +/- 170) have been used to detect H(2)O(2) and glucose with a limit of detection (LOD) of 55 nM (linear range = 0.1-5 MUM) and 0.38 MUM (linear range = 1-100 MUM) respectively. PMID- 22430022 TI - Functional roles for redox genes in ethanol sensitivity in Drosophila. AB - Whilst the effects and associated costs of excessive alcohol consumption in the human population are obvious at one level, the roles played by genetic factors at the molecular level are still unclear. Drosophila melanogaster has an alcohol response comparable to humans and is used as a genetic model to study the functional roles of genes regulated in response to ethanol. In the current study, the biological processes associated with behavioural responses to acute alcohol exposure in Drosophila have been analysed using whole genome expression profiling. Ethanol response genes differentially expressed (a) at a single time point (2 h) and (b) in a time series (0-4 h) were identified using microarrays. In addition, a subset of differentially expressed genes was validated using behavioural sedation and recovery assays. The study shows that genes involved in redox processes, neuron development, and specific signalling and metabolic pathways (including glutathione metabolism) form part of the response to ethanol in Drosophila. Biological processes for the regulation of oxidative stress are the common functional denominator of many of the ethanol response genes identified. These upregulated genes work to rescue cells from oxidative stress and its consequences such as protein misfolding, apoptosis and ageing. In the current study, an enrichment of Drosophila genes linked to ageing is observed for the first time. The functional genomics data revealed by such studies can be used to predict transcription networks of ethanol response genes, but the future lies in mapping these networks to the human population, with the ultimate aim of identifying genetic factors for alcohol use disorders. PMID- 22430023 TI - Effect of adjuvant drugs on the action of local anesthetics in isolated rat sciatic nerves. AB - BACKGROUND AND OBJECTIVES: There is increasing clinical use of adjuvant drugs to prolong the duration of local anesthetic-induced block of peripheral nerves. However, the mechanistic understanding regarding drug interactions between these compounds in the periphery is quite limited. Accordingly, we undertook this study to determine whether selected adjuvant drugs are efficacious in blocking action potential propagation in peripheral nerves at concentrations used clinically and whether these drugs influence peripheral nerve block produced by local anesthetics. METHODS: Isolated rat sciatic nerves were used to assess (1) the efficacy of buprenorphine, clonidine, dexamethasone, or midazolam, alone and in combination, on action potential propagation; and (2) their influence on the blocking actions of local anesthetics ropivacaine and lidocaine. Compound action potentials (CAPs) from A- and C-fibers were studied before and after drug application. RESULTS: At estimated clinical concentrations, neither buprenorphine nor dexamethasone affected either A- or C-waves of the CAP. Clonidine produced a small but significant attenuation of the C-wave amplitude. Midazolam attenuated both A- and C-wave amplitudes, but with greater potency on the C-wave. The combination of clonidine, buprenorphine, and dexamethasone had no influence on the potency or duration of local anesthetic- or midazolam-induced block of A- and C-waves of the CAP. CONCLUSIONS: These results suggest that the reported clinical efficacy of clonidine, buprenorphine, and dexamethasone influences the actions of local anesthetics via indirect mechanisms. Further identification of these indirect mechanisms may enable the development of novel approaches to achieve longer-duration, modality-specific peripheral nerve block. PMID- 22430024 TI - Primary payer status is associated with the use of nerve block placement for ambulatory orthopedic surgery. AB - INTRODUCTION: Although more than 30 million patients in the United States undergo ambulatory surgery each year, it remains unclear what percentage of these patients receive a perioperative nerve block. We reviewed data from the 2006 National Survey of Ambulatory Surgery to determine the demographic, socioeconomic, geographic, and clinical factors associated with the likelihood of nerve block placement for ambulatory orthopedic surgery. The primary outcome of interest was the association between primary method of payment and likelihood of nerve block placement. In addition, we examined the association between type of surgical procedures, patient demographics, and hospital characteristics with the likelihood of receiving a nerve block. METHODS: This cross-sectional study reviewed 6000 orthopedic anesthetics from the 2006 National Survey of Ambulatory Surgery data set, which accounted for more than 3.9 million orthopedic anesthetics when weighted. The primary outcome of this study addressed the likelihood of receiving a nerve block for orthopedic ambulatory surgery according to the patient's primary method of payment. Secondary end points included differences in demographics, surgical procedures, adverse effects, complications, recovery profile, anesthesia staffing model, and total perioperative charges in those with and without nerve block. RESULTS: Overall, 14.9% of anesthetics in this sample involved a peripheral nerve block. Length of time in postoperative recovery, total perioperative time, and total charges were less for those receiving nerve blocks. Patients were more likely to receive a nerve block if their procedures were performed in metropolitan service areas (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.19-2.91; P = 0.007) or in freestanding surgical facilities (OR, 2.27; 95% CI, 1.74-2.96; P < 0.0001) and if payment for their surgery was supported by government programs (OR, 2.5; 95% CI, 1.01-6.21; P = 0.048) or private insurance (OR, 2.62; 95% CI, 1.12-6.13; P = 0.03) versus self pay or charity care. CONCLUSIONS: For patients receiving ambulatory orthopedic surgery in the United States, our results suggest that geographic and socioeconomic factors are associated with different likelihoods of perioperative peripheral nerve block placement. PMID- 22430025 TI - Randomized controlled trial comparing pudendal nerve block under ultrasound and fluoroscopic guidance. AB - BACKGROUND: Although fluoroscopy is an established imaging modality for pudendal nerve block, ultrasound (US) technique allows physicians better visualization of anatomic structures. This study aimed to compare the effectiveness and safety between the US- and fluoroscopy-guided techniques. METHODS: A randomized, single blind, split-plot design was used to conduct the study. Twenty-three patients undergoing bilateral pudendal nerve blocks received US-guided injections to either the left or right side, whereas the contralateral side received a fluoroscopic-guided injection in randomized sequence. Injections consisted of 4 mL of 0.5% bupivacaine and 40 mg methylprednisone. The primary outcome was the success of the block in the distribution of the pudendal nerve along the perineum, rated as either absent, moderate, or strong. Secondary outcomes were the time to administer the blocks, quality of visualization of anatomic structures using US and fluoroscopy, distance of the final US-guided needle position from the ischial spine, and incidence of adverse effects. RESULTS: No differences in the degree of neural blockade were noted between US- or fluoroscopic-guided techniques for either temperature or pinprick blockade. Time to complete the procedure was significantly longer using US compared with fluoroscopy (219 [SD, 65] and 428 [SD, 151] secs, P < 0.0001). No significant differences were noted regarding the occurrence of adverse effects between the 2 techniques. CONCLUSIONS: Ultrasound-guided pudendal nerve blockade is as accurate as fluoroscopically guided injections when performed by an experienced clinician. However, the former took a longer time to perform. PMID- 22430026 TI - Comparison of oral robenacoxib and ketoprofen for the treatment of acute pain and inflammation associated with musculoskeletal disorders in cats: a randomised clinical trial. AB - The objective of the study was to evaluate the efficacy and tolerability of robenacoxib, a selective cyclooxygenase-2 inhibitor, for the treatment of acute pain and inflammation associated with musculoskeletal disorders in cats. The study was a prospective, multi-centre, randomised, blinded, non-inferiority design clinical trial comparing robenacoxib to ketoprofen. A total of 68 cats presenting with pain and inflammation associated with acute musculoskeletal disorders were recruited and allocated randomly to receive, orally once daily for 5-6 days, either 1.0-2.4 mg/kg robenacoxib (n=47) or 1mg/kg ketoprofen (n=21). The primary efficacy endpoint was the total clinician score, which was the sum of clinician numerical rating scale scores for pain, inflammation and mobility. Assessments were made at baseline, on day 2, and day 4 or 5. For the total clinician score, non-inferior efficacy of robenacoxib was demonstrated with a relative efficacy of 1.151 (95% confidence interval 0.872-1.494). Non-inferior efficacy of robenacoxib was also demonstrated for the secondary endpoint of the total owner score. Robenacoxib was superior (P<0.05) to ketoprofen for the owner's assessment of activity and human/animal relationship. The tolerability of both treatments was good as assessed by monitoring adverse events, clinical signs and haematology and serum biochemistry variables. PMID- 22430027 TI - Sleep-dependent memory consolidation--what can be learnt from children? AB - Extensive research has been accumulated demonstrating that sleep is essential for processes of memory consolidation in adults. In children and infants, a great capacity to learn and to memorize coincides with longer and more intense sleep. Here, we review the available data on the influence of sleep on memory consolidation in healthy children and infants, as well as in children with attention-deficit/hyperactivity disorder (ADHD) as a model of prefrontal impairment, and consider possible mechanisms underlying age-dependent differences. Findings indicate a major role of slow wave sleep (SWS) for processes of memory consolidation during early development. Importantly, longer and deeper SWS during childhood appears to produce a distinctly superior strengthening of hippocampus-dependent declarative memories, but concurrently prevents an immediate benefit from sleep for procedural memories, as typically observed in adults. Studies of ADHD children point toward an essential contribution of prefrontal cortex to the preferential consolidation of declarative memory during SWS. Developmental studies of sleep represent a particularly promising approach for characterizing the supra-ordinate control of memory consolidation during sleep by prefrontal-hippocampal circuitry underlying the encoding of declarative memory. PMID- 22430028 TI - Inactivation of the basolateral amygdala during opiate reward learning disinhibits prelimbic cortical neurons and modulates associative memory extinction. AB - RATIONALE: Neurons within the basolateral amygdala (BLA) and prelimbic cortex (PLC) are involved in associative learning during morphine reward memory recall and extinction. However, the nature by which the BLA regulates PLC neuronal encoding of associative opiate reward learning is not presently understood. OBJECTIVE: The purpose of this study was to examine the functional effects of reversible inactivation of the BLA on behavioral and neuronal activity patterns in the PLC during either the acquisition or extinction phases of opiate reward memory processing. METHODS: Using a combination of in vivo neuronal population recordings in the rat PLC and pharmacological inactivation of the BLA during a place conditioning procedure, we examined the functional impact of BLA inactivation during the acquisition, recall, and extinction of opiate reward memory. RESULTS: Inactivation of the BLA caused an increase in the spontaneous firing and bursting activity of PLC neurons. Inactivation of the BLA during the acquisition phase of opiate reward conditioning caused a subsequent acceleration in the extinction of the previously learned opiate reward memory and behavioral aversions to morphine-paired environments. While BLA inactivation during extinction training led to a delay in extinction memory recall. CONCLUSIONS: Our findings demonstrate a functional link between the BLA and neuronal populations in the PLC specifically during the acquisition and extinction phases of opiate reward memory and suggest that BLA input to the PLC modulates the processing of opiate-related extinction memory. PMID- 22430029 TI - Obesity and carotid atherosclerosis in African black and Caucasian women with established rheumatoid arthritis: a cross-sectional study. AB - INTRODUCTION: Reported findings on the relationship between adiposity and atherosclerotic cardiovascular disease (ACVD) risk in rheumatoid arthritis (RA) are contradictory and originate in developed populations. Approximately 80% of ACVD now occurs in developing countries. We aimed to ascertain the associations of clinical obesity measures with metabolic cardiovascular risk and atherosclerosis in African women with RA from a developing black and developed Caucasian population. METHODS: The associations of body mass index (BMI) as an indicator of overall adiposity and waist circumference and waist-to-height and waist-to-hip ratios as abdominal obesity indices with metabolic risk factors and high resolution B-mode ultrasound-determined carotid artery atherosclerosis were assessed in multivariate regression models in 203 African women with established RA; 108 were black and 95 Caucasian. RESULTS: BMI and waist-to-height ratio were higher in African black compared to Caucasian women (29.9 (6.6) versus 25.3 (4.9) kg/m2, P = 0.002 and 0.59 (0.09) versus 0.53 (0.08), P = 0.01, respectively). Interactions between population origin and anthropometric measures were not related to metabolic risk factors but were associated with atherosclerosis, independent of confounders and individual terms. In all patients, BMI was related to systolic and diastolic blood pressure but not with serum lipid concentrations whereas abdominal obesity indices were associated with serum lipid concentrations but not with blood pressure values; obesity measures that were associated with plasma glucose concentrations comprised BMI, waist circumference and waist-to height ratio (P < 0.05 in multiple confounder adjusted analysis). In African Caucasian women, BMI was associated with common carotid artery intima-media thickness (standardized beta (95% confidence interval (CI)) = 0.21 (0.03 to 0.38)) and waist-to-hip ratio with plaque (odds ratio (OR) (95% CI) = 1.83 (1.03 to 3.25) for one standard deviation (SD) increase). These relationships were independent of multiple non-metabolic risk factors and explained by metabolic risk factors. In African black women with RA, none of the obesity measures was related to atherosclerosis. CONCLUSIONS: Obesity in women with RA from developing groups of black African descent does not as yet translate into atheroma. In Caucasian women with RA that belong to developed populations, BMI and waist-to hip ratio should be considered in ACVD risk assessment. PMID- 22430030 TI - Characteristics and classification of hippocampal theta rhythm induced by passive translational displacement. AB - Theta rhythms in the hippocampus are believed to be the "metric" relating to various behavior patterns for free roaming rats. In this study, the theta rhythms were studied while rats either walked or were passively translated by a toy car on a linear track (referred to as WALK and TRANS respectively). For the similar running speeds in WALK and TRANS conditions, theta frequency and amplitude were both reduced during TRANS. Theta modulation of pyramidal cells during TRANS was reduced compared to that during WALK. Theta frequency was positively correlated with translation speed during TRANS. Theta rhythm remained apparent during TRANS and WALK after large dose of atropine sulfate (blocking the cholinergic pathway) was injected compared to still states. The present study demonstrated the patterns of theta rhythm induced by passive translation in rats and suggested that the Type I theta rhythm could occur during non-voluntary locomotion. We further argued that the perception of actual self-motion may be the underlying mechanism that initiates and modulates type I theta. PMID- 22430031 TI - Long-term survival of solid embryonic cerebellar grafts in Lurcher mice. AB - Lurcher mutant mice represent a natural model of olivocerebellar degeneration. They serve as a tool to study pathogenesis, the functional impact of the degeneration as well as therapeutic approaches. Wild type littermates are used as healthy controls. Neurotransplantation may be a promising method of therapy for neurodegenerative diseases. The aim of this work was to compare the long-term survival rate of the solid embryonic cerebellar graft in adult Lurcher mutant and wild type mice of the B6CBA strain and to assess the fundamental structural features of the graft. The graft was obtained from 12-day-old GFP mouse embryos. The brains of host mice were examined histologically 6 months after the transplantation. The graft was identified according to its GFP fluorescence. The graft presence and structure was assessed. The graft survived in all 14 Lurcher mice and in 12 of the 14 wild type mice. Cell migration and fibre sprouting from the graft were poor. No marked differences in the graft morphology between Lurcher mutant and wild type mice were found. The graft survival and appearance were similar to those after a shorter period described in a previous study. This suggests that during the 6 months, no intensive or commonly occurring processes changing the graft had proceeded and that the Lurcher mutant cerebellum niche had no strong influence over the fate of the solid cerebellar graft. PMID- 22430032 TI - A SNP site in pri-miR-124 changes mature miR-124 expression but no contribution to Alzheimer's disease in a Mongolian population. AB - Increasing evidence shows that single nucleotide polymorphisms (SNPs) or mutations in microRNAs (miRNAs) sequence may affect the processing and function of miRNAs and participate in the occurrence of diseases. Although many SNPs of miRNAs were found, their functions in the pathological process of nerve cells were only just emerging. In the present study, the effect of the SNP of one neuronal miRNA, miR-124, on miRNA biogenesis and human genetic disease was investigated using in vitro cell line model and Alzheimer's disease (AD) in the Mongolian population. Bioinformatics prediction showed that a common G/C polymorphism designated rs531564 was found in the pri-miR-124 and the G allele changed the formation of a ring-shaped structure in the predicted secondary structure of the pri-miRNA for miR-124-1. Northern blot and real-time PCR analysis showed that the amount of mature miR-124 from the C/G heterozygosity of rs531564 was increased compared with the CC or GG homozygosity of rs531564. The expression of mature miR-124 from GG homozygosity was also higher than that from CC homozygosity. But in an association study of AD patients and controls, neither genotype nor allele distribution difference was found in AD patients compared with controls. Collectively, the present study is the first to evaluate the relationship between miR-124 and AD in the Mongolian population. SNP rs531564 of miR-124 may not represent a risk factor in the development of AD among Mongolian population. PMID- 22430033 TI - Photovoltaic and electrocatalytic properties of novel ball-type phthalocyanines bridged with four dicumarol. AB - The new ball-type metallo bisphthalocyanines (Co(2)Pc(2) and Zn(2)Pc(2)) were synthesized from the corresponding [4,4'-bis(dicoumaroylphthalonitrile)] which can be obtained from the reaction of 3,3'-methylenebis(4-hydroxy-2H-chromen-2 one) and 4-nitrophthalonitrile. The structures of the newly synthesized compounds have been confirmed and characterized by elemental analysis, UV/Vis, IR and (1)H NMR spectroscopies and MALDI-TOF mass spectrometry. Solar cells of the configuration ITO/Co(2)Pc(2)/C60/Al and ITO/Zn(2)Pc(2)/C60/Al were fabricated. The effect of the thickness of the active Pc layer--the thickness of the Pc layer was varied from 15 to 80 nm--on solar cells parameters has been investigated. A nearly thickness independent open circuit voltage was observed in both structures. The maximum photovoltaic conversion efficiency, short circuit current and fill factor were observed in ITO/Zn(2)Pc(2)/C60/Al cell with 80 nm Pc layer to be 0.255%, 1 mA cm(-2) and 0.38, respectively. The redox properties of the ball-type complexes were investigated by cyclic voltammetry, controlled-potential coulometry and in situ spectroelectrochemistry in DMSO-TBAP. The electrochemical measurements showed that the complexes form ring-based and/or metal-based mixed valence species, due to the remarkable intramolecular interactions between the two metal phthalocyanine units. The Vulcan XC-72(VC)/Nafion(Nf)/Co(2)Pc(2) modified glassy carbon electrode showed much higher catalytic performance towards oxygen reduction, compared to the VC/Nf/Zn(2)Pc(2) modified one. It was found that the VC/Nf/Co(2)Pc(2) catalyst is nearly insensitive to the presence of methanol. In the presence of 1 M methanol in the electrolyte, the catalytic performance of the Co(2)Pc(2)-based catalyst in oxygen reduction was much better than that of the Pt-based one. Thus, it was shown that the VC/Nf/Co(2)Pc(2) catalyst can be a good alternative to VC/Nf/Pt as a cathode catalyst in direct methanol fuel cells. PMID- 22430034 TI - Necrotizing fasciitis of the neck after total laryngectomy. AB - Necrotizing fasciitis (NF) is an unusual, life threatening, rapidly advancing infection characterized by widespread fascial and subcutaneous tissue necrosis and gangrene of the skin. It most commonly affects the extremities, abdominal wall and perineum, whereas cervical NF is rare. NF of the head and neck is often caused by both aerobic and anaerobic microorganisms found in the upper aerodigestive tract. Usually, cervical NF originates from odontogenic, tonsillar and pharyngeal infection, and it is very rarely a complication of surgical procedure. Without immediate surgical treatment, cervical NF leads to mediastinitis and fatal sepsis. There is only one case of cervical NF after total laryngectomy described in the literature. We report two cases of cervical NF after total laryngectomy, selective neck dissection and primary vocal prosthesis insertion. In both cases, the infection spreads to thoracic region and in one of them NF was associated with Lemierre's syndrome, i.e., thrombosis of the internal jugular vein. In both patients, vocal prosthesis was inserted during the infection and did not influence the healing process. PMID- 22430035 TI - Anionic lipid-induced conformational changes in human phagocyte flavocytochrome b precede assembly and activation of the NADPH oxidase complex. AB - Phagocyte NADPH oxidases generate superoxide at high rates in defense against infectious agents, a process regulated by second messenger anionic lipids using incompletely understood mechanisms. We reconstituted the catalytic core of the human neutrophil NADPH oxidase, flavocytochrome b (Cyt b) in 99% phosphatidylcholine vesicles in order to correlate anionic lipid-dependent conformational changes in membrane-bound Cyt b and oxidase activity. The anionic lipid 10:0 phosphatidic acid (10:0 PA) specifically induced conformational changes in Cyt b as measured by a combination of fluorescence resonance energy transfer methods and size exclusion chromatography. The fluorescence lifetime of a complex between Cyt b and Cascade Blue-derivatized anti-p22(phox) antibody (CCB CS9), increased after exposure to 10:PA by ~50% of the change observed when the complex is dissociated, indicating a structural rearrangement of p22(phox) and/or the Cyt b heme prosthetic groups. Half of the quenching relaxation occurred at 10:0 PA concentrations permissive to less than 10% full NADPH oxidase activity, but saturated near the saturation in activity in a matched cell-free oxidase assay. We conclude that anionic lipids modulate the conformation of Cyt b in the membrane and suggest they may serve to modulate the structure of Cyt b as a control mechanism for the NADPH oxidase. PMID- 22430036 TI - Twitchin can regulate the ATPase cycle of actomyosin in a phosphorylation dependent manner in skinned mammalian skeletal muscle fibres. AB - The effect of twitchin, a thick filament protein of molluscan muscles, on the actin-myosin interaction at several mimicked sequential steps of the ATPase cycle was investigated using the polarized fluorescence of 1.5-IAEDANS bound to myosin heads, FITC-phalloidin attached to actin and acrylodan bound to twitchin in the glycerol-skinned skeletal muscle fibres of mammalian. The phosphorylation dependent multi-step changes in mobility and spatial arrangement of myosin SH1 helix, actin subunit and twitchin during the ATPase cycle have been revealed. It was shown that nonphosphorylated twitchin inhibited the movements of SH1 helix of the myosin heads and actin subunits and decreased the affinity of myosin to actin by freezing the position and mobility of twitchin in the muscle fibres. The phosphorylation of twitchin reverses this effect by changing the spatial arrangement and mobility of the actin-binding portions of twitchin. In this case, enhanced movements of SH1 helix of the myosin heads and actin subunits are observed. The data imply a novel property of twitchin incorporated into organized contractile system: its ability to regulate the ATPase cycle in a phosphorylation dependent fashion by changing the affinity and spatial arrangement of the actin binding portions of twitchin. PMID- 22430037 TI - Statistical image reconstruction from limited projection data with intensity priors. AB - The radiation dose generated from x-ray computed tomography (CT) scans and its responsibility for increasing the risk of malignancy became a major concern in the medical imaging community. Accordingly, investigating possible approaches for image reconstruction from low-dose imaging protocols, which minimize the patient radiation exposure without affecting image quality, has become an issue of interest. Statistical reconstruction (SR) methods are known to achieve a superior image quality compared with conventional analytical methods. Effective physical noise modeling and possibilities of incorporating priors in the image reconstruction problem are the main advantages of the SR methods. Nevertheless, the high computation cost limits its wide use in clinical scanners. This paper presents a framework for SR in x-ray CT when the angular sampling rate of the projection data is low. The proposed framework is based on the fact that, in many CT imaging applications, some physical and anatomical structures and the corresponding attenuation information of the scanned object can be a priori known. Therefore, the x-ray attenuation distribution in some regions of the object can be expected prior to the reconstruction. Under this assumption, the proposed method is developed by incorporating this prior information into the image reconstruction objective function to suppress streak artifacts. We limit the prior information to only a set of intensity values that represent the average intensity of the normal and expected homogeneous regions within the scanned object. This prior information can be easily computed in several x-ray CT applications. Considering the theory of compressed sensing, the objective function is formulated using the l(1) norm distance between the reconstructed image and the available intensity priors. Experimental comparative studies applied to simulated data and real data are used to evaluate the proposed method. The comparison indicates a significant improvement in image quality when the proposed method is used. PMID- 22430038 TI - Notification about influenza vaccination in Belgium: a descriptive study of how people want to be informed. AB - BACKGROUND: Influenza causes a substantial socioeconomic burden. In Belgium, only 54% of the target group receives an annual vaccination. Patient reminder/recall systems are effective in improving vaccination rates in primary care, but little is known about patients' preferences on notification of influenza vaccination. AIMS: To evaluate whether general practice patients wish to be notified of the possibility of receiving influenza immunisation, and how. METHODS: In January 2008, 750 questionnaires were handed out to all consecutive patients aged >18 years in three Belgian general practices. Main outcome measures were the percentage wanting to be notified, demographic and medical factors influencing the information needs of the patients and the specific way in which patients wanted to be notified. RESULTS: About 80% of respondents wanted to be notified of the possibility of influenza vaccination. Logistic regression analysis showed that those who had previously been vaccinated particularly wished to be notified, both in the total population (OR 4.45; 95% CI 2.87 to 6.90; p<0.0001) and in the subgroup of high-risk individuals (OR 9.05; 95% CI 4.47 to 18.33; p<0.0001). More than 85% of the participants wanted to be informed by their family physician, mostly during a consultation regardless of the reason for the encounter. The second most preferred option was a letter sent by the family physician enclosing a prescription. CONCLUSIONS: The majority of general practice patients want to be notified of the possibility of influenza vaccination. More than 85% of participants who wanted to be notified preferred to receive this information from their family physician, mostly by personal communication during a regular visit. However, since a large minority preferred to be addressed more proactively (letter, telephone call, e-mail), GPs should be encouraged to combine an opportunistic approach with a proactive one. PMID- 22430039 TI - Spirometrically-defined restrictive ventilatory defect: population variability and individual determinants. AB - BACKGROUND: A spirometrically-defined restrictive ventilatory defect is a common finding when performing spirometry. AIMS: We aimed to determine the frequency, geographical variation, individual consequences, and 'severity' of the restrictive ventilatory defect. METHODS: A population-based study was conducted in Spain. The response rate from 11 participating centres was 88.9%, totalling 3,802 participants. A restrictive ventilatory defect was defined according to pre bronchodilator spirometry as forced expiratory volume in 1s/forced vital capacity (FEV1/FVC) >0.70 and a predicted FVC <80%, in accordance with current American Thoracic Society/European Respiratory Society guidelines. RESULTS: The prevalence of a restrictive ventilatory defect was 12.7% (95% CI 9.7% to 15.7%), with the highest in Seville (19.4%) and Burgos (18.5%) and the lowest in Oviedo (5.2%) and Madrid-La Princesa (5.7%) (p<0.000). Although most of the participants (97.1%) with a restrictive ventilatory defect were objectively considered 'mild' by spirometry (%predicted FVC 50-80%), they reported more phlegm, dyspnoea, and wheezing than healthy control participants (p<0.000), and scored worse in all St George's Respiratory Questionnaire domains of quality of life and activities of daily living (p<0.000). Interestingly, they scored similarly to participants with chronic obstructive pulmonary disease (COPD) in both (p=0.102 and p=0.217). In a multivariate analysis, older age, male gender, heavy smoking, low education, and high body mass index were independently associated with having a restrictive ventilatory defect. CONCLUSIONS: A restrictive ventilatory defect in spirometry is a common finding (12.7%) with a highly variable geographical distribution (range 3.7) whose population burden is important in terms of quality of life and activities of daily living and similar to that of an obstructive pattern compatible with COPD. PMID- 22430040 TI - A centralised respiratory diagnostic service for primary care: a 4-year audit. AB - BACKGROUND: The literature shows that delayed or erroneous diagnosis of respiratory conditions may be common in primary care due to underuse of spirometry or poor spirometric technique. The Community Respiratory Assessment Unit (CRAU) was established to optimise diagnosis and treatment of respiratory disease by providing focused history-taking, quality-assured spirometry, and evidence-based guideline-derived management advice. AIMS: To review the service provided by the CRAU to primary care health professionals. METHODS: Data from 1,156 consecutive GP referrals over 4 years were analysed. RESULTS: From the 1,156 referrals, 666 were referred for one of five common reasons: suspected asthma, confirmed asthma, suspected chronic obstructive pulmonary disease (COPD), confirmed COPD, or unexplained breathlessness. COPD was the most prevalent referral indication (445/666, 66.8%), but one-third of suggested diagnoses of COPD by the GP were found to be incorrect (161/445, 36%) with inappropriate prescribing of inhaled therapies resulting from this misdiagnosis. Restrictive pulmonary defects (56/666, 8% of referrals) were overlooked and often mistaken for obstructive conditions. The potential for obesity to cause breathlessness may not be fully appreciated. CONCLUSIONS: Misdiagnosis has significant financial, ethical, and safety implications. This risk may be minimised by better support for primary care physicians such as diagnostic centres (CRAU) or alternative peripatetic practice-based services operating to quality-controlled standards. PMID- 22430042 TI - Regimens with intraperitoneal cisplatin plus intravenuous cyclophosphamide and intraperitoneal carboplatin plus intravenuous cyclophosphamide are equally effective in second line intraperitoneal chemotherapy for advanced ovarian cancer. AB - PURPOSE: We compared response, survival and side effects of regiments with intravenous cyclophosphamide followed by intraperitoneal cisplatin versus intravenous cyclophosphamide followed by intraperitoneal carboplatin as second line treatment in one center retrospective study. MATERIAL AND METHODS: Inclusion criteria were: relapse or recurrence of the disease after surgery and first line treatment; stage III histologicaly documented serous epithelial ovarian cancer after one or more prior regiments of chemotherapy. Recurrence were confirmed throughout restaging laparotomy or second look laparotomy. Patients from one of the groups received 90 mg/m(2) cisplatin on the first day and 750 mg/m(2) cyclophosphamide intravenously, while the second group members AUC 6 carboplatin intraperitoneally and 750 mg/m(2) cyclophosphamide intravenously. Four courses were administrated for each patient. RESULTS: Of the 49 patients in the cisplatin group the response rates were 21 (43%), 10 (20%) and 18 (37%) in the groups of pathologic complete response, pathologic partial response and progressive disease, respectively. The median survival from the initiation of intraperitoneal chemotherapy was 59 months. Of the 25 patients in the carboplatin group the response rates were 10 (40%), 4 (16%) and 11 (44%) respectively. The median survival -51 months. The differences between the groups were not statistically significant p>0.05 either in response or in toxicity. CONCLUSIONS: The results of our research including relatively long survival from intraperotoneal chemotherapy initiation confirm that carboplatin treatment is as good as cisplatin in second line intraperitoneal chemotherapy for ovarian cancer. PMID- 22430043 TI - HBV mutations and their clinical significance. AB - PURPOSE: The launch of the vaccine against HBV in 1983 significantly reduced the number of HBV infections in the world. But there still remain a large group of people with chronic hepatitis B who were infected before beginning of vaccination programs or in whom the vaccine was - for various reasons - ineffective. Current therapy of HBV infection based on PEG-IFN alpha-2a or nucleotide/nucleoside analogues does not guarantee sustained virologic response in the large majority of chronically infected persons. Treatment with some nucleoside analogues is associated with mutations and subsequent selection of resistant strains resulting with therapeutic failure, risk of cross-resistance to other drugs and finally selection of mutants with oncogenic properties. PMID- 22430044 TI - Effect of DHEA supplementation on serum IGF-1, osteocalcin, and bone mineral density in postmenopausal, glucocorticoid-treated women. AB - PURPOSE: DHEA therapy increases bone formation in postmenopausal women. We have found only a few reports of dehydroepiandrosterone replacement therapy in women receiving long-term glucocorticoid medication. The purpose of this study was to establish whether DHEA replacement therapy may be useful in the treatment of steroid-induced osteoporosis in postmenopausal women. MATERIALS AND METHODS: Nineteen women, aged 50-78 years, treated at least for three years with average daily doses of more than 7.5 mg prednisone, with T-score L2/L4<-1.5 and bisphosphonates intolerance, were enrolled to the study. For the first year of the study the patients were given calcium, vitamin D3 and thiazide diuretics. For another year the patients received orally micronized DHEA 25-50 mg daily. Before the study, after twelve months of Calcium/D3 therapy, then after six weeks and six months of DHEA therapy, serum concentrations of DHEAS, androstenedione, testosterone, estradiol, FSH, IGF-1 and osteocalcin were assessed. Bone mineral density (BMD) in lumbar spine and femoral neck was measured before the treatment, after a year on Calcium/D3 and after six and twelve months of DHEA replacement therapy. RESULTS: In all treated women, DHEA significantly increased serum DHEAS, androstenedione and testosterone concentrations. A significant elevation of serum IGF-1 and osteocalcin concentrations was found as early as after six weeks of DHEA treatment. A significant increase of bone mineral density in the lumbar spine and femoral neck was observed after six and twelve months of DHEA treatment. CONCLUSION: Our results suggest a beneficial role of DHEA replacement therapy in the treatment of steroid-induced osteoporosis. PMID- 22430045 TI - "Should all eligible patients with multiple myeloma receive autologous stem-cell transplant as part of initial treatment?". PMID- 22430046 TI - Blood simple: transfusion at home for patients with MDS. PMID- 22430047 TI - J-4: a novel and typical preclinical anticancer drug targeting protein kinase C zeta. AB - Metastasis is the major cause of morbidity and mortality from breast cancer. Cell motility and chemotaxis play important roles in the metastatic cascade of cancer cells. Protein kinase C zeta (PKCzeta) mediates cancer cell chemotaxis by regulating cytoskeleton rearrangement and cell adhesion. In the current study, we investigated the inhibitory effect of a compound called J-4 targeting PKCzeta. J 4 was tested with inhibitory concentration (IC(50)) of 10 umol/l using a Z' LYTETM Kinase Assay-Ser/Thr 7 Peptide Kit. Our results show that J-4 inhibited spontaneous migration and epidermal growth factor (EGF)-induced chemotaxis of human breast cancer cell MDA-MB-231. Through an 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, the drug designated as J-4 had no obvious cytotoxicity in vitro. Meanwhile, in the presence of J-4, the cells showed defects in EGF-induced actin polymerization and adhesion. Furthermore, J-4 dampened EGF-induced phosphorylation and recycling of cofilin. Taken together, our data demonstrate that J-4 is a new and typical inhibitor that blocks the PKCzeta pathway. Moreover, a better understanding of the mechanism of action of J 4 may provide a novel medical therapeutic strategy for cancer treatment that would block metastasis, thereby reducing the proliferation and dissemination of cancer cells and increasing patient survival. PMID- 22430048 TI - Impressive long-term disease stabilization by nilotinib in two pretreated patients with KIT/PDGFRA wild-type metastatic gastrointestinal stromal tumours. AB - KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumours (GISTs) showed a response rate to imatinib ranging from 0 to 25%. Nilotinib is a new-generation tyrosine kinase inhibitor that has demonstrated clinical activity in pretreated GIST patients. At present, no correlation between nilotinib activity and clinical/pathological/molecular features is available. We report on two WT GIST patients resistant to imatinib and sunitinib, and enrolled in the CAMN107A2201 study who achieved an impressive disease control by nilotinib. Both patients have germ-line mutations in the SDHA gene. In April 2004, a 39-year-old woman presented gastric GIST with multiple liver metastases and was treated with imatinib 400 mg/day, followed by imatinib 800 mg/day and then sunitinib. In August 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. In March 2005, a 27-year-old woman started imatinib 600 mg/day and then sunitinib for gastric GIST with multiple liver and lung metastases. In October 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. One patient still showed stable disease after 46 months of treatment according to the Response Evaluation Criteria In Solid Tumors, and a partial response after 9 months according to Choi's criteria. The other patient still showed stable disease after 42 months according to Response Evaluation Criteria In Solid Tumors. At present, they continue to receive nilotinib. We report very long-term disease stabilization under nilotinib treatment in two pretreated WT GIST patients. In-vitro studies and clinical analyses are warranted to evaluate a potential correlation between nilotinib activity and WT genotype or other clinical/pathological features. PMID- 22430049 TI - Full genome characterization of a porcine-like human G9P[6] rotavirus strain isolated from an infant in Belgium. AB - Interspecies transmissions of group A rotavirus (RVA) strains among animals and humans are thought to take place frequently. During a RVA surveillance study in Belgium we isolated an unusual G9P[6] RVA strain, RVA/human wt/BEL/BE2001/2009/G9P[6], from a 1month old boy, which did not cluster with other G9 or P[6] strains isolated in Belgium. In this study we sequenced and characterized the complete genome of this unusual G9P[6] strain BE2001. Phylogenetic analyses of all 11 genes revealed a unique genotype constellation: G9-P[6]-I5-R1-C1-M1-A8-N1-T7-E1-H1. The VP6 and NSP1 genotypes I5 and A8 are genotypes commonly found in porcine RVA strains, while the VP7 and VP4 genes clustered only distantly to human lineages of G9 and P[6], respectively. The VP1, VP2, VP3, NSP2, NSP4 and NSP5 genes all belonged to Wa-like genotypes, but clustered more closely to porcine strains than to human strains. NSP3 belonged to the rare T7 genotype. Thus far, T7 genotypes have only been detected in one porcine-like human strain (RVA/human-tc/CHN/R479/2004/G4P[6]), one bovine-like human strain (RVA/human-xx/IND/mani-265/2007/G10P[6]) and one bovine RVA strain (RVA/cow-tc/GBR/UK/1973/G6P7[5]). Sequence analysis of the BE2001 NSP5 gene segment revealed a 300 nucleotide duplication in the 3' end non-coding region. BE2001 is most likely a direct interspecies transmission between a pig and a human. Inquiry with the patient's physician revealed that the father of the patient had been working on a pig farm in the week the patient became ill, providing a plausible route of transmission. PMID- 22430050 TI - Molecular typing of the recently expanding subtype B HIV-1 epidemic in Romania: evidence for local spread among MSMs in Bucharest area. AB - HIV-1 subtype B is predominant in Europe except in some countries from Eastern Europe which are characterized by a high prevalence of non-B subtypes and circulating recombinant forms (CRFs). Romania is a particular case: the HIV-1 epidemic started with subtype F1 which is still the most prevalent. Previous studies have shown an increasing prevalence of subtype B which is the second most frequent one among the newly diagnosed individuals, followed by subtype C and several CRFs as well as unique recombinant forms (URFs). Our objective was to analyze in detail the characteristics (way of dispersal, association with transmission risk groups) of the subtype B infections in Romania by means of phylogenetic analysis. Among all the individuals sampled during 2003-2010, 71 out of 1127 patients (6.3%) have been identified to be infected with subtype B strains. The most frequent route of infection identified in HIV-1 subtype B patients in Romania was MSM transmission (39.6%), followed by the heterosexual route (35.2%). Many of the patients acquired the infection abroad, mainly in Western European countries. Phylogenetic analysis indicated the existence of a local transmission network (monophyletic clade) including 14 patients, mainly MSM living in the Bucharest area. We estimate the origin of the local transmission network that dates at the beginning of the 90s; the introduction of the F1 and C subtypes occurred earlier. The rest of the sequences were intermixed with reference strains sampled across Europe suggesting that single infection were not followed by subsequent dispersal within the local population. Although HIV-1 subtype B epidemic in Romania is recent, there is evidence for local spread among the MSMs, in addition to multiple introductions. PMID- 22430051 TI - Development and validation of a quality of life instrument for Kashin-Beck disease: an endemic osteoarthritis in China. AB - OBJECTIVES: To develop and validate a disease-specific Quality of Life (QOL) measure for a specialized osteoarthritis (OA)-Kashin-Beck disease (KBD). METHODS: The standard methodology used for developing QOL instruments was employed. In phase 1, initially a group of health care professionals (HCPs) and KBD patient defined the overall concept of KBDQOL. It was followed by generation of an item pool through literature review, in-depth interview of 20 KBD patients and eight KBD HCPs and four focus group discussions. In phase 2, 368 KBD patients were interviewed and the reinterview of 95 participants, 10-14 days later assessed the reproducibility of the KBDQOL instrument. RESULTS: A 37 items draft instrument was devised during phase 1. Principal Component Analysis (PCA) revealed six domains: physical function, activity limitation, social support, economics, mental health, and general health. Cronbach's alphas of six domains ranged from 0.77 to 0.90. The test-retest reliability (intraclass co-relation coefficient) of six domains was satisfactory, and ranged from 0.73 to 0.90. The smallest detectable change ranged from 13.2 to 30.2 points at the individual level and from 1.4 to 3.1 points at the group level for different domains. The construct validity was adequate when co-related with the EQ-5D (spearman co-relation coefficients: 0.49-0.61) and WHOQOL-BREF (spearman co-relation coefficients: 0.53 0.68). This resulted into the final version of KBDQOL instrument having 28 items and six domains. CONCLUSIONS: The KBDQOL is a simple and easy to use 28-item six dimensional questionnaire. The measure has been developed as a true patient-based questionnaire and demonstrates good measurement properties. PMID- 22430052 TI - Cross-sectional DXA and MR measures of tibial periarticular bone associate with radiographic knee osteoarthritis severity. AB - OBJECTIVE: We evaluated the relationship of medial proximal tibial periarticular areal bone mineral density (paBMD) and trabecular morphometry and determined whether these bone measures differed across radiographic medial joint space narrowing (JSN) scores. METHODS: 482 participants of the Osteoarthritis Initiative (OAI) Bone Ancillary Study had knee dual X-ray absorptiometry (DXA) and trabecular bone 3T magnetic resonance imaging (MRI) exams assessed at the same visit. Medial proximal tibial paBMD was measured on DXA and apparent trabecular bone volume fraction (aBV/TV), thickness (aTb.Th), number (aTb.N), and spacing (aTb.Sp) were determined from MR images. Radiographs were assessed for medial JSN scores (0-3). We evaluated associations between medial paBMD and trabecular morphometry. Whisker plots with notches of these measures versus medial JSN scores were generated and presented. RESULTS: Mean age was 63.9 (9.2) years, BMI 29.6 (4.8) kg/m(2), and 53% were male. The Spearman correlation coefficients between DXA-measured medial paBMD and aBV/TV was 0.61 [95% confidence interval (CI) 0.55-0.66]; between paBMD and aTb.Th was 0.38 (95%CI 0.30-0.46); paBMD and aTb.N was 0.65 (95%CI 0.60-0.70); paBMD and aTb.Sp was 0.65 (95%CI -0.70 to -0.59). paBMD and the trabecular metrics were associated with medial JSN scores. CONCLUSION: The moderate associations between periarticular trabecular bone density and morphometry and their relationship with greater severity of knee OA support hypotheses of remodeling and/or microscopic compression fractures in the natural history of OA. Longitudinal studies are needed to assess whether knee DXA will be a predictor of OA progression. Further characterization of the periarticular bone in OA utilizing complementary imaging modalities will help clarify OA pathophysiology. PMID- 22430053 TI - Prevalence and predictors of health care use in patients with early hip or knee osteoarthritis: two-year follow-up data from the CHECK cohort. AB - OBJECTIVE: To describe health care utilization (HCU) and predict analgesic use and health professional (HP) contact at baseline and 2 years in individuals with early symptomatic hip and/or knee osteoarthritis (OA). DESIGN: Baseline and two year data on HCU of the 1002 participants from the multi-centre Cohort Hip & Cohort Knee study were used. Six forms of health care services were described: analgesic use, supplement use, contact with a General Practitioner (GP), contact with a HP, contact in secondary care, and alternative medicine use. Multivariable logistic regression was performed in order to identify predisposing, enabling and disease-related variables that predict analgesic use and HP contact at 2 years; treatment modalities of first choice in early OA. RESULTS: For the hip (n=170), the knee (n=414) and the hip and knee (n=418) group analgesic use (38%, 29% and 47%, respectively), contact with a GP (32%, 38% and 36%, respectively) and contact with a HP (26%, 18% and 20%, respectively), were reported most often at baseline. Contact with a GP significantly decreased, supplement use increased (to about one third), and other treatment modalities remained stable at 2 years. In all three groups, analgesic use at baseline was the strongest predictor for analgesic use at 2 years, whereas contact with a HP at baseline was the strongest predictor of contact with a HP after 2 years. Belonging to a first generation minority was a predisposing risk factor [Odds Ratio (95%-CI), 8.72 (1.55-48.97)] for analgesic use in the hip and knee group. CONCLUSIONS: In early OA, familiarity with HCU and other predisposing factors are, apart from disease related factors strongly associated with HCU at 2 years. Further research is necessary to examine whether our findings reflect sub-optimal management of early OA in terms of efficacy and equity. PMID- 22430054 TI - Study warns of burgeoning health burden of CKD in China. PMID- 22430055 TI - The Declaration of Istanbul--early impact and future potential. AB - The Declaration of Istanbul on Organ Trafficking and Transplant Tourism was adopted at an international meeting held in 2008. The Declaration has been published globally and consists of a preamble, a set of principles and a series of proposals to improve the ethics and expand the benefits of the international organ transplantation endeavor. To promote and monitor the implementation of the Declaration, a Declaration of Istanbul Custodian Group (DICG) has been created. The DICG has provided support for official efforts to ban the sale of organs, restrict transplant tourism and prosecute those who persist in violating the law. Substantial progress has been made thus far in countries that have been the source of transplant tourists and in countries that have been the source of donor organs for trafficking. In China, however, the use of organs from executed prisoners for transplantation purposes continues despite widespread condemnation of this practice. PMID- 22430057 TI - Kidney donation does not increase cardiovascular risk. PMID- 22430058 TI - Surfactant-free single-nano-sized colloidal Cu nanoparticles for use as an active catalyst in Ullmann-coupling reaction. AB - Surfactant-free, single-nano-sized copper nanoparticles (Cu NPs) (size: about 2 nm) were prepared by the DMF reduction method. The Cu NPs showed high catalytic activity (with a turnover number (TON) of up to 2.2 * 10(4)) in Ullmann-type cross-coupling of aryl halides with phenols under ligand-free conditions. PMID- 22430056 TI - Pathogenesis of IgA nephropathy. AB - Since its first description in 1968, IgA nephropathy has remained the most common form of idiopathic glomerulonephritis leading to chronic kidney disease in developed countries. The exact pathogenesis of IgA nephropathy is still not well defined. Current data implicate an important genetic factor, especially in promoting the overproduction of an aberrant form of IgA1. The immunochemical aberrancy of IgA nephropathy is characterized by the undergalactosylation of O glycans in the hinge region of IgA1. However, such aberrant glycosylation alone does not cause renal injury. The next stage of disease development requires the formation of glycan-specific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule. These antibodies often have reactivity against antigens from extrinsic microorganisms and might arise from recurrent mucosal infection. B cells that respond to mucosal infections, particularly tonsillitis, might produce the nephritogenic IgA1 molecule. With increased immune-complex formation and decreased clearance owing to reduced uptake by the liver, IgA1 binds to the glomerular mesangium via an as yet unidentified receptor. Glomerular IgA1 deposits trigger the local production of cytokines and growth factors, leading to the activation of mesangial cells and the complement system. Emerging data suggest that mesangial-derived mediators following glomerular deposition of IgA1 lead to podocyte and tubulointerstitial injury via mesangio-podocytic tubular crosstalk. This Review summarizes the latest findings in the pathogenesis of IgA nephropathy. PMID- 22430059 TI - Biodegradation of bensulfuron-methyl and its effect on bacterial community in paddy soils. AB - Bensulfuron-methyl (BSM) is a new kind of sulfonylurea herbicide widely used to control broad-leaf weeds in rice paddies. The aim of this work was to study BSM biodegradation in paddy soils with BSM-degrading bacteria Bacillus megaterium L1 and Brevibacterium sp. BH and its effect on the structures of soil bacterial community. More than 90 % of BSM could be degraded in paddy soils with 0.0355 mg kg-1 BSM concentration. Addition of BSM-degrading bacterial strains Bacillus megaterium L1 into BSM contaminated paddy soil could have the half-life time of BSM compared to treatment without Bacillus megaterium L1 inoculation. Denaturing gradient gel electrophoresis and principle component analysis indicated that the diversity of the soil microbial community structure changed along with the addition of BSM, which recovered at the end of the experiment (5 weeks). Addition of BSM-degrading bacteria Bacillus megaterium L1 enriched the diversity of soil microbial community structure in paddy soils. This study provides information on the biodegradation of BSM and BSM's influences on the soil bacteria microbial community structures. PMID- 22430060 TI - Construction, in vitro and in vivo evaluation of an in-house conductance meter for measurement of skin hydration. AB - Different probes are used in dermato-cosmetic research to measure the electrical properties of the skin. The principle governing the choice of the geometry and material of the measuring probe is not well defined in the literature and some device's measuring principles are not accessible for the scientific community. The purpose of this work was to develop a simple inexpensive conductance meter for the objective in vivo evaluation of skin hydration. The conductance meter probe was designed using the basic equation governing wave propagation along Transverse Electromagnetic transmission lines. It consisted of two concentric copper circular electrodes printed on FR4 dielectric material. The performance of the probe was validated by evaluating its measurement depth, its ability to monitor in vitro water sorption-desorption and in vivo skin hydration effect in comparison to that of the Corneometer CM 825. The measurement depth of the probe, 15 MUm, was comparable to that of CM 825. The in vitro readings of the probe correlated strongly with the amount of water adsorbed on filter paper. Skin hydration after application of a moisturizer was monitored effectively by the new probe with good correlation to the results of CM 825. In conclusion, a simple probe for evaluating skin hydration was made from off-the-shelf materials and its performance was validated in comparison to a commercially available probe. PMID- 22430061 TI - Biomechanical stress maps of an artificial femur obtained using a new infrared thermography technique validated by strain gages. AB - Femurs are the heaviest, longest, and strongest long bones in the human body and are routinely subjected to cyclic forces. Strain gages are commonly employed to experimentally validate finite element models of the femur in order to generate 3D stresses, yet there is little information on a relatively new infrared (IR) thermography technique now available for biomechanics applications. In this study, IR thermography validated with strain gages was used to measure the principal stresses in the artificial femur model from Sawbones (Vashon, WA, USA) increasingly being used for biomechanical research. The femur was instrumented with rosette strain gages and mechanically tested using average axial cyclic forces of 1500 N, 1800 N, and 2100 N, representing 3 times body weight for a 50 kg, 60 kg, and 70 kg person. The femur was oriented at 7 degrees of adduction to simulate the single-legged stance phase of walking. Stress maps were also obtained using an IR thermography camera. Results showed good agreement of IR thermography vs. strain gage data with a correlation of R(2)=0.99 and a slope=1.08 for the straight line of best fit. IR thermography detected the highest principal stresses on the superior-posterior side of the neck, which yielded compressive values of -91.2 MPa (at 1500 N), -96.0 MPa (at 1800 N), and 103.5 MPa (at 2100 N). There was excellent correlation between IR thermography principal stress vs. axial cyclic force at 6 locations on the femur on the lateral (R(2)=0.89-0.99), anterior (R(2)=0.87-0.99), and posterior (R(2)=0.81 0.99) sides. This study shows IR thermography's potential for future biomechanical applications. PMID- 22430062 TI - Diorganodiselenides and zinc(II) organoselenolates containing (imino)aryl groups of type 2-(RN=CH)C6H4. AB - Several new diorganodiselenides containing (imino)aryl groups, [2-(RN[double bond, length as m-dash]CH)C(6)H(4)](2)Se(2) [R = Me(2)NCH(2)CH(2) (4), O(CH(2)CH(2))(2)NCH(2)CH(2) (5), PhCH(2) (6), 2',6'-(i)Pr(2)C(6)H(3) (7)] were obtained by reacting [2-{(O)CH}C(6)H(4)](2)Se(2) (3) with RNH(2). Treatment of the diselenides 6 and 7 with stoichiometric amounts of K-selectride or Na resulted in isolation of the selenolates K[SeC(6)H(4)(CH[double bond, length as m dash]NCH(2)Ph)-2] (9) and Na[SeC(6)H(4)(CH[double bond, length as m dash]NC(6)H(3)(i)Pr(2)-2',6')-2] (10), respectively. The reaction of potassium selenolates with anhydrous ZnCl(2) (2:1 molar ratio) gave Zn[SeC(6)H(4)(CH=NCH(2)Ph)-2](2) (11) and Zn[SeC(6)H(4)(CH[double bond, length as m-dash]NC(6)H(3)(i)Pr(2)-2',6')-2](2) (12). When the dark green solution obtained from diselenide 7 and an excess of Na (after removal of the unreacted metal) was reacted with anhydrous ZnCl(2) a carbon-carbon coupling reaction occurred and the 9,10-(2',6'-(i)Pr(2)C(6)H(3)NH)(2)C(14)H(10) (8) species was obtained. The compounds were investigated in solution by multinuclear NMR ((1)H, (13)C, (77)Se, including 2D and variable temperature experiments) and by mass spectrometry. The molecular structures of 6, 8, 11 and 12 were established by single-crystal X-ray diffraction. All compounds are monomeric in the solid state. In the diselenide 6 the (imino)aryl group acts as a (C,N)-ligand resulting in a distorted T-shaped coordination geometry of type (C,N)SeX (X = Se). For the zinc complexes 11 and 12 the (Se,N) chelate pattern of the selenolato ligands results in tetrahedral Zn(Se,N)(2) cores. PMID- 22430063 TI - Induction of chirality in porphyrin-(bis)calixarene assemblies: a mixed covalent non-covalent vs a fully non-covalent approach. AB - CD and UV-vis measurements were carried out to demonstrate chirality induction promoted by chiral covalently linked groups and non-covalently bound Delta- and Lambda-[Ru(phen)(3)](2+) enantiomers-in metallo-porphyrin-calixarene and metallo porphyrin-bis-calixarene non-covalent assemblies, respectively. PMID- 22430064 TI - Subtype-specific statistical causalities in parkinsonian tremor. AB - Tremor is one of the cardinal symptoms of Parkinson's disease. Up to now, however, its pathophysiology remains poorly understood. Previously, oscillatory coupling at tremor frequency between the subthalamic nucleus und affected muscles was shown. In these studies, however, causality of coupling could not be demonstrated. Thus, we analyzed the statistical causality between intraoperatively recorded local field potentials in the subthalamic area and affected arm muscles during tremor episodes, using squared partial directed coherence, a recently developed causality measure. The analysis identified differential statistical causality patterns for Parkinson's disease patients of the akinetic-rigid subtype during tremor episodes (n=6) versus patients of the tremor-dominant subtype (n=8): for the akinetic-rigid Parkinson's disease patients significantly more cases of the subthalamic region were found to be statistically causal for electromyographic-tremor activity, a result in accordance with the standard basal ganglia model. In contrast, for the tremor dominant patients, significantly more instances of electromyographic tremor activity turned out to be causal for activity of the subthalamic region. Furthermore, the clinical effective stimulation site coincided with the location of most input causalities from the periphery in seven out of eight tremor dominant patients. The data suggest that, although tremor activity in tremor dominant and akinetic-rigid Parkinson's disease patients was clinically similar, statistical causality between tremor electromyogram (EMG) and the subthalamic nucleus was fundamentally different. Therefore, we hypothesize different pathophysiological mechanisms to underlie the generation of tremor in the two subtypes of Parkinson's disease. PMID- 22430066 TI - Spontaneous crystalline-to-amorphous phase transformation of organic or medicinal compounds in the presence of porous media, part 3: effect of moisture. AB - PURPOSE: Amorphization of crystalline compounds using mesoporous media is a promising technique to improve the solubility and drug release of poorly-soluble compounds. The objective of this paper is to understand the effect of moisture on the capacity and performance of vapor-phase mediated amorphization. METHODS: Mesoporous silicon dioxide (SiO(2)) and crystalline naphthalene were used as the model system. The effect of moisture on the amorphization capacity of naphthalene was determined using adsorption chambers with various levels of relative humidity. Enthalpy and capacity of water vapor adsorption on SiO(2) were measured using isothermal microcalorimetry and thermogravimetry. RESULTS: Moisture not only suppressed the amorphization capacity of naphthalene, but reversed an already-amorphized formulation as well. On the other hand, through the same competitive interaction, improved drug release and enhanced solubility were obtained. The initial supersaturation was followed by an entropy-driven crystallization. In addition, moisture-induced siloxane bond fracture was found at normal processing conditions, which led to the changes in silica surface chemistry. However, the implication in amorphization has not reached a definitive conclusion. CONCLUSIONS: Humidity during processing and storage must be carefully controlled for this type of amorphous formulation. Further investigation is needed to better understand the moisture-induced changes of silica. PMID- 22430067 TI - Hepatitis B-positive donors in renal transplantation: increasing the deceased donor pool. AB - It is reasonable to transplant HbsAg-positive kidneys into recipients who are themselves hepatitis B surface antigen (HbsAg) positive with appropriate antiviral treatment after transplantation. Although there are limited data regarding the hepatitis B virus (HBV) transmission risk following transplantation of kidneys from HbsAg-positive donors into HBV-immune recipients, current literature suggests that the risk of chronic infection in the recipient can be prevented by using antiviral agents or by boosting protective anti-HBs titers. The risk of chronic HBV infection following transplantation of kidneys from HbsAg positive donors for HBV-naive recipients is high but can be minimized by administering lifelong antiviral therapy. Such a policy could be considered in an urgent situation. The most cost-effective antiviral prophylaxis strategy is lifelong lamivudine. Kidneys from HBsAg neg/anti-HBcore pos recipients are associated with a low rate of chronic HBV infection in the recipient and therefore can no longer be regarded as marginal donors. Booster vaccination to achieve protective HBV immunity or lifelong lamivudine therapy should prevent posttransplant HBV infection. Hence, we believe that strategies allowing transplantation of kidneys from donors with HBV can be undertaken safely with careful selection and matching of donors and recipients increasing access to kidney transplantation. PMID- 22430068 TI - Atrazine does not induce pica behavior at doses that increase hypothalamic pituitary-adrenal axis activation and cause conditioned taste avoidance. AB - Previous work has shown that a single oral administration of atrazine (ATR), a chlorotriazine herbicide, causes rapid increases in plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT) and progesterone. The mechanism for these effects is unknown. To test whether administration of ATR causes hypothalamic-pituitary-adrenal (HPA) axis activation through the production of a generalized stress response resulting from gastrointestinal distress, we conducted both conditioned taste avoidance (CTA) and pica behavior experiments. Body temperature data were also collected to detect the presence of stress induced hyperthermia. Adult male Wistar rats were given a single oral dose of ATR (0, 5, 25, 50, 100, or 200 mg/kg) or the primary ATR metabolite diamino-s chlorotriazine (DACT; 135 mg/kg). Increases were observed in ACTH (LOEL, 12.5 mg/kg), CORT (LOEL, 5 mg/kg) and progesterone (LOEL, 5 mg/kg) 15 min following a single dose of ATR. DACT (135 mg/kg) increased ACTH (1.3-fold), CORT (2.9-fold) and progesterone (1.9-fold) above vehicle control concentrations, but the magnitude of the responses was much lower than that observed for an equal molar dose of ATR (200 mg/kg; 7.0, 9.0 and 11.0-fold above ACTH, CORT, progesterone controls, respectively). CTA results demonstrated conditioned taste avoidance to ATR, with a NOEL of 5 mg/kg. Animals dosed with DACT developed avoidance responses comparable to the highest dose of ATR. In the pica experiment, lower doses (5-50 mg/kg) of ATR had no effect on pica behavior, as measured 6 and 24 h post-dosing, nor did DACT. However, the highest dose of ATR (200 mg/kg) did induce pica behavior at both time points. No differences in body temperature were observed. Overall, results indicate that increases in ACTH and CORT secretion following administration of ATR occur at doses that are without effect on the display of pica behavior, indicating that the HPA-axis activation caused by ATR is not likely the result of gastrointestinal distress. PMID- 22430069 TI - Research in higher surgical training: which rotation? AB - BACKGROUND: Orthopaedic higher surgical trainees in Ireland are allocated to one of eight training rotations. Each trainee is expected to publish at least one research paper per year during training. AIM: To assess the research productivity of each training rotation over a 10-year period. METHODS: A PubMed search was performed for each orthopaedic unit affiliated to higher surgical training (HST) in order to identify full-text research papers published between 2001 and 2010. The results were analysed to determine which training rotations are most productive in terms of research. RESULTS: We identified 267 papers published from 16 units over the 10-year period. There were substantial differences in the number of papers published from each unit, and substantial differences between the eight set trainee rotations. CONCLUSIONS: It is essential that each trainee makes an honest assessment of their potential for conducting and producing valuable and relevant research, and chooses an HST rotation that is appropriate to their needs. Publication of research articles is easier to achieve on some HST rotations than on others. PMID- 22430070 TI - The natural history of injecting drug use: a 25-year longitudinal study of a cohort of injecting drug users in inner city Dublin. AB - BACKGROUND: Injecting drug use is associated with increased morbidity and mortality. This is the first longitudinal study of a community-based population of injecting drug users (IDUs) in the Republic of Ireland. AIM: To establish the natural history of IDUs in a deprived Dublin community. METHODS: Eighty-two IDUs (heroin) were recruited over the summer months of 1985. The prevalence of drug use in this district electoral area was established in 1985 and followed-up over a 25-year period with two formal interviews in 1995 and 2010. RESULTS: It is a descriptive study of a cohort of IDUs established in 1985 prior to human immunodeficiency virus (HIV) testing being available. The majority of the cohort recruited included single, unemployed males aged 20 to 29 years, who had served a prison sentence. Fifty-one (63 %) of the cohort had died by 2010, of which 26 were attributed to HIV disease. The mean age of death was 35.9 years of age (standard deviation 4.1 years). Fifty-two (63 %) of the cohort tested positive for HIV and 58 (71 %) for hepatitis B between 1985 and 2010. The median survival time for those with a positive HIV status was 17 years (95 % CI 14.0-20.0) and for those with a positive hepatitis C status, 21 years (95 % CI 15.5-26.5). CONCLUSIONS: The lifestyle of IDUs, as demonstrated by the experience of this cohort, has hazardous consequences resulting in high levels of morbidity and mortality. A relatively stable picture of HIV associated with IDUs is now emerging in Ireland, as is the case throughout most of the EU. HIV is a more manageable chronic disease, posing challenges for primary care in its treatment of former and existing IDUs who are ageing and now have other chronic diseases. PMID- 22430072 TI - Development of a streamlined rat whole embryo culture assay for classifying teratogenic potential of pharmaceutical compounds. AB - This study describes a novel rat whole embryo culture (rWEC) teratogenicity assay that applies a simplified experimental design and statistical prediction model, resulting in reduced animal requirements and increased throughput with low prediction error rate for classifying teratogenic potential of compounds. A total of 70 compounds (38 teratogens and 32 nonteratogens) were evaluated, and the prediction model was generated from a dataset of 59 compounds. The rWEC assay requires only one test concentration (1MUM) and three structural endpoints (group average morphological scores of spinal cord, heart, and number of somite pairs), which are used in a recursive partition model for classifying teratogenic liability. The model fitting concordance between the WEC assay and in vivo outcome was 83% with a standard deviation (SD) of 4.9%. The predictivity for future compounds was evaluated by using two statistical methods. Fivefold cross validation estimated the predictivity of this model at 73% (SD 5.8%). A second estimation of predictivity was obtained from an independent test set of 11 compounds that were not used to build the prediction model and reached 82% (SD 11.6%). The overall estimate for prediction concordance is 74% (SD 5.2%). There is no statistically significant difference (p value > 0.50) in the predictivity between this model and the model supporting European Center for the Validation of Alternative Methods WEC assay with predictivity of 80% (SD 10.6%). Overall, the streamlined WEC assay is estimated to reduce animal use and operational costs by more than 50%. It substantially improves results turnaround with no loss of predictivity. PMID- 22430071 TI - A proteomic analysis of MCLR-induced neurotoxicity: implications for Alzheimer's disease. AB - Cyanobacteria-derived microcystin-leucine-arginine (MCLR), commonly characterized as a hepatotoxin, has recently been found to show neurotoxicity, but the exact mechanism is still unknown. To further our understanding of the neurotoxic effects of MCLR and the mechanisms behind it, we used two-dimensional gel electrophoresis and mass spectrometry analysis to identify global protein profiles associated with MCLR-induced neurotoxicity. MCLR-treated hippocampi showed alterations in proteins involved in cytoskeleton, neurodegenerative disease, oxidative stress, apoptosis, and energy metabolism. After validation by Western blot and quantitative real-time PCR, the expressions of three proteins related to neurodegenerative disease, septin 5, alpha-internexin, and alpha synuclein, were identified to be altered by MCLR exposure. Based on our proteomic analysis that MCLR toxicity might be linked to neurodegeneration, we examined the activity of serine/threonine-specific protein phosphatases (PPs), which are markers of neurodegenerative disease. MCLR was found to induce inhibition of PPs and abnormal hyperphosphorylation of the neuronal microtubule-associated protein tau. This was found to lead to impairment of learning and memory, accompanied by severe histological damage and neuronal apoptosis in the hippocampal CA1 regions of rats. Our results support the hypothesis that MCLR could induce neurotoxic effects, the reason for which could be attributed to the disruption of the cytoskeleton, oxidative stress, and inhibition of PPs in the hippocampus. Moreover, MCLR was found to induce tau hyperphosphorylation, spatial memory impairment, neuronal degenerative changes, and apoptosis, suggesting that this cyanotoxin may contribute to Alzheimer's disease in humans. PMID- 22430073 TI - Tissue distribution of inhaled micro- and nano-sized cerium oxide particles in rats: results from a 28-day exposure study. AB - In order to obtain more insight into the tissue distribution, accumulation, and elimination of cerium oxide nanoparticles after inhalation exposure, blood and tissue kinetics were investigated during and after a 28-day inhalation study in rats with micro- and nanocerium oxide particles (nominal primary particle size: < 5000, 40, and 5-10 nm). Powder aerosolization resulted in comparable mass median aerodynamic diameter (1.40, 1.17, and 1.02 MUm). After single exposure, approximately 10% of the inhaled dose was measured in lung tissue, as was also estimated by a multiple path particle dosimetry model (MPPD). Though small differences in pulmonary deposition efficiencies of cerium oxide were observed, no consistent differences in pulmonary deposition between the micro- and nanoparticles were observed. Each cerium oxide sample was also distributed to tissues other than lung after a single 6-h exposure, such as liver, kidney, and spleen and also brain, testis, and epididymis. No clear particle size-dependent effect on extrapulmonary tissue distribution was observed. Repeated exposure to cerium oxide resulted in significant accumulation of the particles in the (extra)pulmonary tissues. In addition, tissue clearance was shown to be slow, and, overall, insignificant amounts of cerium oxide were eliminated from the body at 48- to 72-h post-exposure. In conclusion, no clear effect of the primary particle size or surface area on pulmonary deposition and extrapulmonary tissue distribution could be demonstrated. This is most likely explained by similar aerodynamic diameter of the cerium oxide particles in air because of the formation of aggregates and irrespective possible differences in surface characteristics. The implications of the accumulation of cerium oxide particles for systemic toxicological effects after repeated chronic exposure via ambient air are significant and require further exploration. PMID- 22430074 TI - Critical role of microsomal prostaglandin E synthase-1 in the hydronephrosis caused by lactational exposure to dioxin in mice. AB - Hydronephrosis induced in the kidney of neonatal mice exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) via lactation is a sensitive and characteristic hallmark of TCDD teratogenicity. We previously found that cyclooxygenase-2 (COX-2) activity induced in mouse neonate kidneys by lactational TCDD exposure is required for this toxicity. COX-2 is an inducible form of cyclooxygenase and is responsible for producing prostaglandins (PGs) and thromboxane. PGE(2), a prostaglandin, is elevated in TCDD-exposed mouse pups. In this study, we investigated the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible form of PGE(2) synthase, in TCDD-induced hydronephrosis. A dose of 10 MUg TCDD/kg to dams increased mPGES-1 messenger RNA abundance, urinary PGE(2) levels, and the incidence of hydronephrosis in mPGES-1 wild-type pups. In homozygous mPGES-1 knockout (KO) mice, in contrast, TCDD-induced hydronephrosis was suppressed, demonstrating an essential role of mPGES-1 in the response. Lack of the mPGES-1 gene also suppressed urinary PGE(2) level to near the basal level in TCDD-exposed pups. In conclusion, mPGES-1 upregulation upon lactational TCDD exposure is a causal factor for TCDD-induced hydronephrosis in mouse neonates. PMID- 22430075 TI - Asymmetric synthesis of alpha-amino boronate esters via organocatalytic pinacolboryl addition to tosylaldimines. AB - Organocatalytic nucleophilic pinacolboryl addition from in situ generated MeO(-) > B(2)pin(2) to C=N double bond can be performed enantioselectively with the aid of chiral phosphines, which promote enantiofacial differentiation in the course of the C-B bond formation. PMID- 22430076 TI - The effect of rest breaks on time to injury - a study on work-related ladder-fall injuries in the United States. AB - OBJECTIVES: Rest breaks and other work-related temporal factors, such as time spent on task, influence the accumulation of fatigue, and thus impact occupational injury risk. The aim of this study was to investigate the effect of rest breaks on "time to injury" (the time between start of work and injury) for injured workers treated in a nationally representative sample of US emergency departments. METHODS: Using the National Electronic Injury Surveillance System (NEISS), we identified 629 workers who had experienced a work-related ladder fall. Of these, 306 were interviewed by telephone using a standardized questionnaire about the circumstances surrounding the injury. Survival analyses were used to estimate time to injury, and hazard ratios (HR) for time to injury were compared between workers who reported no rest break (reference) and workers who reported rest break(s) prior to the injury (accumulated break time categorized into 0, 1-15, 16-30, and >30 minutes). Age, gender, time of work start, injury time of day, and workload were included as covariates to control for demographic, circadian, and work-related factors, respectively. RESULTS: A clear dose-response relation indicated that longer accumulated break time was associated with a significantly longer time to injury when compared to workers without rest breaks [total break time 1-15 minutes: HR 0.60, 95% confidence interval (95% CI) 0.44-0.83; 16-30 minutes: HR 0.50, 95% CI 0.33-0.75; >30 minutes: HR 0.34, 95% CI 0.23-0.51], adjusted for all covariates. CONCLUSIONS: The results showed that longer total rest break time allowed for a significantly prolonged time spent on task without an injury. These findings suggest that rest break design could be used as a tool to enhance fatigue management and workplace safety. PMID- 22430077 TI - Veterinary medical education in transition? PMID- 22430078 TI - Developments in undergraduate teaching of small-animal soft-tissue surgical skills at the University of Sydney. AB - This article discusses recent developments in soft-tissue surgery teaching at the University of Sydney, Faculty of Veterinary Science. An integrated teaching program was developed for Bachelor of Veterinary Science (BVSc) students with the aim of providing them with optimal learning opportunities to meet "Day One" small animal soft-tissue surgical competencies. Didactic lectures and tutorials were introduced earlier into the curriculum to prepare students for live-animal surgery practical. In addition to existing clinics, additional spay/neuter clinics were established in collaboration with animal welfare organizations to increase student exposure to live-animal surgery. A silicon-based, life-like canine ovariohysterectomy model was developed with the assistance of a model making and special effects company. The model features elastic ovarian pedicles and suspensory ligaments, which can be stretched and broken like those of an actual dog. To monitor the volume and type of student surgical experience, an E portfolio resource was established. This resource allows for the tracking of numbers of live, student-performed desexing surgeries and incorporates competency based assessments and reflective tasks to be completed by students. Student feedback on the integrated surgical soft-tissue teaching program was assessed. Respondents were assessed in the fourth year of the degree and will have further opportunities to develop Day One small-animal soft-tissue surgical competencies in the fifth year. Ninety-four percent of respondents agreed or strongly agreed that they were motivated to participate in all aspects of the program, while 78% agreed or strongly agreed that they received an adequate opportunity to develop their skills and confidence in ovariohysterectomy or castration procedures through the fourth-year curriculum. PMID- 22430079 TI - Using focus groups to engage veterinary students in course redesign and development. AB - Students' perceptions about the quality of teaching have been shown to influence their approaches to learning and studying. The literature suggests that understanding student perceptions is critical to making informed decisions about curriculum development so that courses meet objectives, enhance engagement, and, ultimately, improve learning. However, the assessment of students' perceptions of their courses and the quality of teaching is frequently limited to an end-of-term course evaluation survey. While these course evaluations may be useful in providing a summative assessment, they do not typically provide insight into the reasons and influences that underlie student ratings. Achieving this type of understanding can be accomplished through qualitative methodology, which is a process of investigation used to reveal the depth, complexity, and nuances of perceptions and experiences. In the current article, we report the use of focus groups as a method of gaining in-depth understanding of student perceptions for course redesign. We present the redesign of the Art of Veterinary Medicine II course, a second-year core offering within the Doctor of Veterinary Medicine curriculum at the Ontario Veterinary College in Guelph, Canada. A series of student focus groups were held to gain greater insight into student perceptions of the course objectives, format, and content. Findings were then considered in the redevelopment of the course to better engage students and their various learning styles. Summative course evaluations as well as informal feedback before and after the focus groups indicate a notable improvement in student experiences and perceptions of the course format and content following the focus-group informed course redesign. PMID- 22430080 TI - Criterion-referenced evaluation of day one clinical competencies of veterinary students: VOLES-the VMTH (Veterinary Medicine Teaching Hospital) Online Evaluation System. AB - This article describes an extensive online criterion-referenced evaluation system for the assessment of veterinary students' achievement during their final year's Doctor of Veterinary Medicine (or equivalent) clinical education. Data are reported for the 2001 to 2009 University of California at Davis veterinary graduates, for a total of more than 1,100 students. These criterion-referenced evaluations extensively document the level of clinical skills attained and demonstrated during the individual clinical rotations that comprise the fourth year curriculum. On average, in each of the 17,500 clinical rotations undertaken during this time period, student performance was assessed in at least 11 separate areas of skills, knowledge, and professional attributes. This provided more than 200,000 criterion-referenced judgments of the individual clinical attributes of graduates over nine years. The system is based on a previously detailed and validated definition of the skills, knowledge, and professional attributes that students should have demonstrated before graduation. The extensive database that this system has provided has established that this system, termed VOLES (VMTH [Veterinary Medicine Teaching Hospital] On-Line Evaluation System), is an effective tool to assess the clinical capabilities of veterinary students and their achievement of the "Day One" skills required for entering clinical practice. These expected proficiencies are balanced according to the differing expectations that each area of veterinary clinical practice demands. PMID- 22430082 TI - Reactive intermediates-induced potential responses of a polymeric membrane electrode for ultrasensitive potentiometric biosensing. AB - Reactive intermediates rather than stable reactants or products have been found to induce large potential responses on an appropriately formulated polymeric membrane electrode, which provides a novel methodology for ultrasensitive potentiometric biosensing based on the horseradish peroxidase-H(2)O(2) oxidation reaction. PMID- 22430083 TI - Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism. AB - It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD), and inborn errors of metabolism (IEM) return to rates observed in the general population, matched for age, sex, and nationality. We studied patients with SCID (n = 201), non-SCID PIDD (n = 405), and IEM (n = 348) who survived for at least 2 years after transplantation with normal T cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rate was significantly higher in these patients compared with the general population for several years after transplantation. The rate decreased toward the normal rate in patients with SCID and non-SCID PIDD beyond 6 years after transplantation, but not in patients with IEM. Active chronic graft versus-host disease at 2 years was associated with increased risk of late mortality for all diseases (hazard ratio [HR], 1.87; P = .05). In addition, late mortality was higher in patients with non-SCID PIDD who received T cell-depleted grafts (HR 4.16; P = .007) and in patients with IEM who received unrelated donor grafts (HR, 2.72; P = .03) or mismatched related donor grafts (HR, 3.76; P = .01). The finding of higher mortality rates in these long-term survivors for many years after transplantation confirms the need for long-term surveillance. PMID- 22430084 TI - Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation. AB - The use of a neutropenic diet (ND) after hematopoietic stem cell transplantation (HSCT) was instituted more than 30 years ago as a means of preventing infection from organisms colonizing the gastrointestinal tract. Evidence supporting this practice is lacking, however, and the actual efficacy of the ND remains unknown. Institutional policy at Northwestern Memorial Hospital discontinued the use of ND in 2006. We conducted a retrospective study of 726 consecutive HSCT recipients, 363 who received an ND and 363 who received a general hospital diet, to determine the incidence of microbiologically confirmed infections during and after transplantation. Our findings indicate a higher rate of infections in the HSCT recipients who received an ND. PMID- 22430085 TI - Radiation-free allogeneic conditioning with fludarabine, carmustine, and thiotepa for acute lymphoblastic leukemia and other hematologic malignancies necessitating enhanced central nervous system activity. AB - Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days -6 to 4), carmustine (400 mg/m2 on day -6), and thiotepa (5 mg/kg twice daily on days 5 and -4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58 1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system-active conditioning. PMID- 22430086 TI - Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: a retrospective analysis of the registry data of the Japanese Society for Hematopoietic Cell Transplantation. AB - To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P = .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT. PMID- 22430087 TI - Prognostic impact of serum immunoglobulin heavy/light chain ratio in patients with multiple myeloma in complete remission after autologous stem cell transplantation. AB - Immunoglobulin heavy/light chain (HLC) ratios were studied in 37 patients with multiple myeloma in complete remission after autologous hematopoietic stem cell transplantation. Increased IgAkappa/IgAlambda and IgMkappa/IgMlambda ratios were associated with longer progression-free survival (P = .006 and .01, respectively). A statistical trend toward a longer overall survival was also observed for the IgAkappa/IgAlambda ratio (P = .068). Considering the original immunoglobulin isotype, our results indicate that an increased kappa/lambda ratio of the uninvolved isotype is associated with longer progression-free survival and overall survival. This is the first report demonstrating the association between the HLC ratio and sustained complete remission in patients with multiple myeloma. Our results suggest that the HLC ratio is a surrogate marker of immune recovery after myeloablative transplantation, rather than as a marker of minimal residual disease. PMID- 22430088 TI - Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. AB - Data on pretransplantation minimal residual disease (MRD) and outcomes of umbilical cord blood transplantation (UCBT) are limited. Out of the 143 patients with acute lymphoblastic leukemia (ALL) who underwent UCBT at the University of Minnesota between 2004 and 2010, we evaluated 86 patients with available MRD assessment data by 4- and 8-color flow cytometry analysis immediately before transplantation. Ten patients (11.6%) were MRD-positive, and 76 were MRD-negative (88.4%). Most of the patients (82%) received myeloablative conditioning. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. In multivariate analysis, age, disease status (complete remission [CR] 1 versus CR2/CR3), disease group (precursor B cell ALL versus Philadelphia chromosome-positive ALL versus T cell ALL), and time to transplantation had no impact on relapse. Patients with MRD before UCBT had a greater incidence of relapse at 2 years (relapse rate, 30%; 95% confidence interval [CI], 4%-56%) and lower 3-year disease-free survival (30%; 95% CI, 7%-58%) compared with those without MRD (relapse rate, 16%; 95% CI, 8%-25%; P = .05; disease-free survival, 55%; 95% CI, 43%-66%; P = .02). Our data suggest that in patients with ALL, achieving an MRD-negative state before UCBT improves outcomes. PMID- 22430089 TI - Metabolic consequences of NDUFS4 gene deletion in immortalized mouse embryonic fibroblasts. AB - Human mitochondrial complex I (CI) deficiency is associated with progressive neurological disorders. To better understand the CI pathomechanism, we here studied how deletion of the CI gene NDUFS4 affects cell metabolism. To this end we compared immortalized mouse embryonic fibroblasts (MEFs) derived from wildtype (wt) and whole-body NDUFS4 knockout (KO) mice. Mitochondria from KO cells lacked the NDUFS4 protein and mitoplasts displayed virtually no CI activity, moderately reduced CII, CIII and CIV activities and normal citrate synthase and CV (F(o)F(1) ATPase) activity. Native electrophoresis of KO cell mitochondrial fractions revealed two distinct CI subcomplexes of ~830kDa (enzymatically inactive) and ~200kDa (active). The level of fully-assembled CII-CV was not affected by NDUFS4 gene deletion. KO cells exhibited a moderately reduced maximal and routine O(2) consumption, which was fully inhibited by acute application of the CI inhibitor rotenone. The aberrant CI assembly and reduced O(2) consumption in KO cells were fully normalized by NDUFS4 gene complementation. Cellular [NAD(+)]/[NADH] ratio, lactate production and mitochondrial tetramethyl rhodamine methyl ester (TMRM) accumulation were slightly increased in KO cells. In contrast, NDUFS4 gene deletion did not detectably alter [NADP(+)]/[NADPH] ratio, cellular glucose consumption, the protein levels of hexokinases (I and II) and phosphorylated pyruvate dehydrogenase (P-PDH), total cellular adenosine triphosphate (ATP) level, free cytosolic [ATP], cell growth rate, and reactive oxygen species (ROS) levels. We conclude that the NDUFS4 subunit is of key importance in CI stabilization and that, due to the metabolic properties of the immortalized MEFs, NDUFS4 gene deletion has only modest effects at the live cell level. This article is part of a special issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22430090 TI - Positional dyspnea and tracheal compression as indications for goiter resection. AB - HYPOTHESES: Goiter is a surgically reversible cause of positional dyspnea (PD). Substernal tracheal compression (TC) predicts PD relief after thyroidectomy (Tx). DESIGN: Retrospective analysis of a prospective structured management algorithm. SETTING: Endocrine surgery academic center. METHODS: Before Tx, 1081 patients were queried about PD. Those patients with substernal goiter underwent computed tomography, and their degree of TC was estimated as greatest percent reduction of transverse tracheal diameter. For 197 patients with PD, TC, or both, surgical outcomes were examined with a mean follow- up of 12.6 months. After Tx, patients who carried the diagnosis of obstructive sleep apnea were referred for repeat sleep study evaluation. RESULTS: Positional dyspnea was reported by 188 of 1081 patients, and after Tx the PD improved or resolved in 82.4%. In the 151 patients with substernal goiter, TC was present on imaging in 97.2%; the mean (range) TC was 34% (5%-90%). Patients with TC had a high likelihood of PD (93.5%). After substernal goiter resection, PD improved in stepwise association with total resected thyroid gland weight. Improvement in PD was strongly predicted by both gland weight of 100 g or more (P.001) and by TC of 35% or more (P.01). After Tx, 59 of 77 snorers (76.6%) reported improvement in snoring, 77.1% of patients with obstructive sleep apnea reported improved PD, and 2 of 3 retested patients with obstructive sleep apnea demonstrated objective improvement in sleep study apnea hypopnea index. CONCLUSIONS: Resection of bulky goiter frequently improves PD, which in substernal goiter is highly associated with TC. Either PD or TC of 35% or more prompt Tx. Goiter should be considered when obstructive sleep apnea is diagnosed. PMID- 22430091 TI - Risk factors for anastomotic leak and mortality in diabetic patients undergoing colectomy: analysis from a statewide surgical quality collaborative. AB - OBJECTIVES: To determine the risk factors in diabetic patients that are associated with increased postcolectomy mortality and anastomotic leak. DESIGN: A prospectively acquired statewide database of patients who underwent colectomy was reviewed. Primary risk factors were diabetes mellitus, hyperglycemia (glucose level >= 140 mg/dL), steroid use, and emergency surgery. Categorical analysis, univariate logistic regression, and multivariate regression were used to evaluate the effects of these risk factors on outcomes. SETTING: Participating hospitals within the Michigan Surgical Quality Collaborative. PATIENTS: Database review of patients from hospitals within the Michigan Surgical Quality Collaborative. MAIN OUTCOME MEASURES: Anastomotic leak and 30- day mortality rate. RESULTS: Of 5123 patients, 153 (3.0%) had leaks and 153 (3.0%) died. Preoperative hyperglycemia occurred in 15.6% of patients, only 54% of whom were known to have diabetes. Multivariate analysis showed that the risk of leak for patients with and without diabetes increased only by preoperative steroid use (P<.05). Mortality among diabetic patients was associated with emergency surgery (P<.01) and anastomotic leak (P<.05); it was not associated with hyperglycemia. Mortality among nondiabetic patients was associated with hyperglycemia (P<.005). The presence of an anastomotic leak was associated with increased mortality among diabetic patients (26.3% vs 4.5%; P<.001) compared with nondiabetic patients (6.0% vs 2.5%; P<.05). CONCLUSIONS: The presence of diabetes did not have an effect on the presence of an anastomotic leak, but diabetic patients who had a leak had more than a 4-fold higher mortality compared with nondiabetic patients. Preoperative steroid use led to increased rates of anastomotic leak in diabetic patients. Mortality was associated with hyperglycemia for nondiabetic patients only. Improved screening may identify high-risk patients who would benefit from perioperative intervention. PMID- 22430092 TI - Influence of rescrubbing before laparotomy closure on abdominal wound infection after colorectal cancer surgery: results of a multicenter randomized clinical trial. AB - OBJECTIVE: To test the hypothesis that strict asepsis in closing wounds following laparotomy reduces the risk for surgical wound infection in elective colorectal cancer surgery. DESIGN: Multicenter randomized clinical trial conducted from June 1, 2009, through June 1, 2010. SETTINGS: Colorectal surgery units of 9 Spanish hospitals. PATIENTS: A total of 969 patients who underwent elective colorectal cancer surgery were eligible for randomization. In closing the laparotomy wound, the patients were randomized to 2 groups: conventional (n=516) and new operation (n=453). In the conventional group, a new set of instruments was used, surgical staff changed their gloves, and the surgical drapes surrounding the laparotomy were covered by a new set of drapes. The new operation group involved removing all drapes, the surgical staff scrubbed again, and a new set of drapes and instruments was used. MAIN OUTCOME MEASURES: Incisional (superficial and deep) surgical site infection 30 days after the operation and risk factors for postoperative wound infections. RESULTS: A total of 146 incisional surgical site infections (15.1%) were diagnosed. Of these, 96 (9.9%) were superficial and 50 (5.1%) were deep infections. On an intent-to-treat basis, significant differences were found between both groups (66 [12.8%] in the conventional group vs 80 [17.7%] in the new operation group [P=.04]). CONCLUSION: This study does not support the use of rescrubbing to reduce the incidence of incisional surgical site infection. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN19463413 PMID- 22430093 TI - Comparative analysis of diaphragmatic hernia repair outcomes using the nationwide inpatient sample database. AB - OBJECTIVE: To determine the comparative effectiveness of various approaches to diaphragmatic hernia (DH) repair, including open abdominal, laparoscopic abdominal, and thoracotomy. DESIGN, SETTING, AND PATIENTS: Using the Nationwide Inpatient Sample from 1999 to 2008, a comprehensive cohort of 38 764 patients (mean [SD] age, 60.8 [19.5] years) hospitalized with a primary diagnosis of DH who underwent repair was identified. MAIN OUTCOMES MEASURES: Morbidity and mortality of patients who underwent DH repair. RESULTS: Open approaches were the most common, performed in 91% of patients (open abdominal, n=28 824 [74.4%]; thoracotomy, n=6573 [17.0%]). Hospital mortality was 1.1% or less for each of the approaches. However, patients who underwent a laparoscopic DH repair had a shorter length of stay (mean [SD], 4.5 [0.10] days) and fewer discharges to skilled nursing facilities than those who underwent open abdominal or thoracotomy repair approaches. Patients who underwent a DH repair through a thoracotomy approach had the longest length of stay (mean [SD], 7.8 [0.11] days) and a higher need for postoperative mechanical ventilation than those undergoing open or laparoscopic abdominal approaches (5.6% vs 3.2% vs 2.3%, respectively; P.001). In addition, the thoracotomy approach was found to be an independent predictor for the development of a pulmonary embolism. CONCLUSIONS: This large national study demonstrates that most DH repairs are performed through open abdominal and thoracic approaches. Laparoscopic approaches are associated with decreased length of stay and more routine discharges than open abdominal and thoracotomy approaches. PMID- 22430095 TI - "A Culture of Safety" or "The Pursuit of Excellence"? PMID- 22430094 TI - Comparison of hospital performance in trauma vs emergency and elective general surgery: implications for acute care surgery quality improvement. AB - HYPOTHESES: As emergency general surgery (EMGS) and trauma care are increasingly being provided by the same personnel with overlapping resources, we postulated that the quality of care provided to EMGS and trauma patients would be similar. We also evaluated the relationship between trauma and elective general surgery (ELGS) care, believing that performance would be similar across these services as it reflects institutional culture. DESIGN: Retrospective cohort study comparing hospital performance in trauma and EMGS care and in trauma and ELGS care. Regression models for mortality and serious morbidity were constructed for trauma, EMGS, and ELGS hospitals contributing to both the National Trauma Data Bank (2007) and American College of Surgeons National Surgical Quality Improvement Program (2005-2008). SETTING: Forty-six hospitals. MAIN OUTCOME MEASURES: Correlations of observed to expected ratios were examined. Outlier status (hospitals with CIs of observed to expected ratios excluding 1.0) was compared using weighted . RESULTS: There was no significant relationship between trauma and EMGS mortality (r=-0.01, P=.94; =-0.10, P=.61) or between trauma and ELGS mortality (r=0.23, P=.12; =0.07, P=.62). There was no significant relationship between trauma and EMGS morbidity (r=0.21, P=.17; =0.04, P=.63) or between trauma and ELGS morbidity (r=0.16, P=.30; =0.11, P=.37). No hospitals were consistently low or high outliers across all 3 groups. CONCLUSIONS: Trauma performance improvement programs are well established compared with those for EMGS. Although EMGS patients use similar structures and processes as trauma patients, there is a lack of correlation between the quality of care provided to trauma and EMGS patients; EMGS should be incorporated into trauma performance improvement programs. PMID- 22430096 TI - The best method to repair diaphragmatic hernias: only the first chapter of the story. PMID- 22430097 TI - Risky business? Collaborative databases and quality improvement. PMID- 22430098 TI - "Doctor, my thyroid is choking me": common sense and scientific inquiry. PMID- 22430099 TI - Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. AB - Suppression of interleukin (IL)-6 production has beneficial effects against various inflammatory diseases. Through a rapid screening system, we found that nitazoxanide, or 2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide, which is a well known antiparasitic agent, suppressed lipopolysaccharide (LPS)-induced production of IL-6 from RAW 264.7 cells and mouse peritoneal macrophages, with 50% inhibitory concentrations (IC(50)s) of 1.54 mM and 0.17 mM, respectively. Nitazoxanide also inhibited the LPS-induced expression of IL-6 mRNA in RAW 264.7 cells. To investigate the effects of nitazoxanide in vivo, we orally administered nitazoxanide at a dose of 100mg/kg to mice 2h before a 1-mL intraperitoneal injection of 4% thioglycollate (TG). Six hours after TG injection, plasma IL-6 levels were markedly lower (by 90%) than the levels in vehicle-treated mice. These data suggest that nitazoxanide could be a promising lead compound for agents against various diseases associated with overproduction of IL-6. PMID- 22430100 TI - Parkinson disease: Tai chi improves balance in Parkinson disease. PMID- 22430102 TI - Parkinson disease: Proteomic tools identify dementia biomarkers in PD. PMID- 22430106 TI - Neuro-oncology: Glioblastoma--community adjusts to new standard of care. PMID- 22430112 TI - Multiple sclerosis: Multiple sclerosis therapy--vitamin D under spotlight. PMID- 22430107 TI - Diagnosis of dystonic syndromes--a new eight-question approach. AB - Dystonia is a syndrome of abnormal involuntary movements that are repetitive, twisting or patterned, and can result in abnormal postures. Dystonia may be generalized or focal, and can occur as a primary syndrome or secondary to another disease--over 50 clinical conditions are reported to cause dystonia. Classification of dystonia is based on genetic background, anatomical distribution, age at onset, and neurodegenerative processes. In many cases, manifestations of dystonia are identical regardless of the aetiology, which makes accurate diagnosis challenging, if not impossible, without additional investigations. Exhaustive lists of the causes of dystonia are not practical to aid clinicians when attempting to determine if a hyperkinetic movement can be diagnosed as dystonic. The existing diagnostic algorithms for dystonic syndromes rely on the clinician's experience, without a streamlined diagnostic pathway. Non specialist clinicians and neurologists may, therefore, find diagnosis of dystonic syndromes difficult. In this Review, an eight-question approach is proposed, with a summary of the evidence for investigations that enable successful diagnosis of dystonic syndromes. The aim of this approach is to inform both specialists and general neurologists on the appropriate diagnostic test for each patient who presents with a possible dystonic syndrome. PMID- 22430113 TI - Stroke: Neuroprotection for patients with stroke moves one step closer to the clinic. PMID- 22430115 TI - Triterpene saponins from the roots of Dipsacus asper and their protective effects against the Abeta(25-35) induced cytotoxicity in PC12 cells. AB - Three new triterpene saponins, named asperosaponin A-C (1-3), together with seven known triterpene saponins (4-10) were isolated from the roots of Dipsacus asper. The structures of compounds 1-3 were elucidated on the basis of detailed spectroscopic analysis and chemical methods. Compounds 1-3, 6-10 had significantly protective effects in PC12 cells against the Abeta(25-35) induced cytotoxicity. All the compounds isolated showed no cytotoxic activity against three human cancer cell lines, A-549, Bel-7402 and BGC-823. PMID- 22430114 TI - Is histidine dissociation a critical component of the NO/H-NOX signaling mechanism? Insights from X-ray absorption spectroscopy. AB - The H-NOX (Heme-Nitric oxide/OXygen binding) family of diatomic gas sensing hemoproteins has attracted great interest. Soluble guanylate cyclase (sGC), the well-characterized eukaryotic nitric oxide (NO) sensor is an H-NOX family member. When NO binds sGC at the ferrous histidine-ligated protoporphyrin-IX, the proximal histidine ligand dissociates, resulting in a 5-coordinate (5c) complex; formation of this 5c complex is viewed as necessary for activation of sGC. Characterization of other H-NOX family members has revealed that while most also bind NO in a 5c complex, some bind NO in a 6-coordinate (6c) complex or as a 5c/6c mixture. To gain insight into the heme pocket structural differences between 5c and 6c Fe(ii)-NO H-NOX complexes, we investigated the extended X-ray absorption fine structure (EXAFS) of the Fe(II)-unligated and Fe(II)-NO complexes of H-NOX domains from three species, Thermoanaerobacter tengcongensis, Shewanella woodyi, and Pseudoalteromonas atlantica. Although the Fe(II)-NO complex of TtH NOX is formally 6c, we found the Fe-N(His) bond is substantially lengthened. Furthermore, although NO binds to SwH-NOX and PaH-NOX as a 5c complex, consistent with histidine dissociation, the EXAFS data do not exclude a very weakly associated histidine. Regardless of coordination number, upon NO-binding, the Fe N(porphyrin) bond lengths in all three H-NOXs contract by ~0.07 A. This study reveals that the overall heme structure of 5c and 6c Fe(II)-NO H-NOX complexes are substantially similar, suggesting that formal histidine dissociation may not be required to trigger NO/H-NOX signal transduction. The study has refined our understanding of the molecular mechanisms underlying NO/H-NOX signaling. PMID- 22430116 TI - The biosynthetic products of Chinese insect medicine, Aspongopus chinensis. AB - A new oxazole (1) was obtained from Chinese insect medicine Aspongopus chinensis, along with three known N-acetyldopamine derivatives (2-4). Their structures were determined on the basis of NMR and ESI-MS analyses. The possible biosynthetic pathways of the isolated compounds are discussed. Cytotoxicities of those compounds against 10 selected cancer cells were measured in vitro. PMID- 22430117 TI - Synthesis and structural determination of novel 5-arylidene-3-N(2-alkyloxyaryl)-2 thioxothiazolidin-4-ones. AB - As part of our project devoted to the synthesis of heterocycles including thiazole rings, some new 5-arylidene-2-thioxo-3-N-arylthiazolidin-4-ones were synthesized by Knoevenagel condensation. An interesting feature of these compounds is that their chirality is induced by that of their 3-N-(2 alkyloxyaryl)-2-thioxothiazolidin-4-one precursors, which in turn is due to the presence of a C2 axis of chirality. These new compounds were characterized by spectroscopic methods (IR, 1H-NMR, 13C-NMR). The structure of compound (Z)-(2g) was further determined by X-ray diffraction. PMID- 22430118 TI - Enrichment and purification of deoxyschizandrin and gamma-schizandrin from the extract of Schisandra chinensis fruit by macroporous resins. AB - In present study, the performance and separation characteristics of 21 macroporous resins for the enrichment and purification of deoxyschizandrin and gamma-schizandrin, the two major lignans from Schisandra chinensis extracts, were evaluated. According to our results, HPD5000, which adsorbs by the molecular tiers model, was the best macroporous resin, offering higher adsorption and desorption capacities and higher adsorption speed for deoxyschizandrin and gamma schizandrin than other resins. Columns packed with HPD5000 resin were used to perform dynamic adsorption and desorption tests to optimize the technical parameters of the separation process. The results showed that the best adsorption time is 4 h, the rate of adsorption is 0.85 mL/min (4 BV/h) and the rate of desorption is 0.43 mL/min (2 BV/h). After elution with 90% ethanol, the purity of deoxy-schizandrin increased 12.62-fold from 0.37% to 4.67%, the purity of gamma schizandrin increased 15.8-fold from 0.65% to 10.27%, and the recovery rate was more than 80%. PMID- 22430119 TI - Terpenoids as potential anti-Alzheimer's disease therapeutics. AB - Alzheimer's disease (AD) is one of the most well-known neurodegenerative diseases and explains 50-60% of dementia in patients. The prevalence rate of AD is positively correlated with age and AD affects >= 40% of those over 85 years old. The major AD therapeutics available on the market are acetylcholinesterase inhibitors, such as tacrine and donepezil. New therapeutic agents that can block the disease-inducing mechanisms are essential. Diverse efforts have been made to discover anti-AD agents from natural sources. In this review article, we describe some representative terpenoids such as ginsenosides, gingkolides, and canabinoids as potential anti-AD agents. These compounds exhibit promising in vitro and in vivo biological activities, but are still waiting clinical trials. Additionally, we also discuss some terpenoids including cornel iridoid glycoside, oleanolic acid, tenuifolin, cryptotanshinone, and ursolic acid, which are under investigation for their in vitro and in vivo animal studies. PMID- 22430120 TI - A new norisoprenoid and other compounds from Fuzhuan brick tea. AB - Fuzhuan brick tea, a kind of dark tea consumed mainly in the border regions of Southwestern and Northwestern China since the 1860s, is produced from the leaves of Camellia sinensis var. sinensis by microbial fermentation. From this special fermented tea, a new norisoprenoid, 3R,9R-oxido-5-megastigmene, was isolated, together with alpha-linolenic acid, strictin, isovitexin, astragalin, (+) catechin, (-)-epicatechin, (-)-epicatechin gallate, (+)-gallocatechin, (-) epigallocatechin, (-)-epigallocatechin gallate and gallic acid. The structures of the compounds were identified by spectroscopic means. The new compound didn't show any inhibition activity against the tested enteric pathogenic microorganisms at a concentration of 800 MUg/mL by the hole plate diffusion method. PMID- 22430121 TI - Pneumoscrotum as the presenting symptom of pneumothorax and pneumoperitoneum after jet ventilation. PMID- 22430122 TI - Influence of smoking and snuff cessation on risk of preterm birth. AB - The mechanisms by which antenatal smoking exposure increases the risk of preterm birth remain unknown. Swedish oral moist snuff contains quantities of nicotine comparable to those typically absorbed from cigarette smoking, but does not result in exposure to the products of combustion, for example carbon monoxide. In a nation-wide study of 776,836 live singleton births in Sweden from 1999 to 2009, the authors used multiple logistic regression models to examine associations between cessation of smoking and Swedish snuff use early in pregnancy and risk of preterm birth (before 37 weeks). Compared with non-tobacco users both before and in early pregnancy, the adjusted odds ratios (OR), 95% confidence interval (CI) were OR=0.92, 95% CI 0.84-1.01, for women who stopped using snuff, and OR=0.90, 95% CI 0.87-0.94, for women who stopped smoking. In contrast, continued snuff use and smoking were associated with increased risks of preterm birth (adjusted OR=1.29, 95% CI 1.17-1.43, adjusted OR=1.30, 95% CI 1.25-1.36, respectively). The snuff and smoking-related risks were, if anything, higher for very (before 32 weeks) than moderately (32-36 weeks) preterm birth, and also higher for spontaneous than induced preterm birth. These findings suggest that antenatal exposure to nicotine is involved in the mechanism by which tobacco use increase the risk of preterm birth. PMID- 22430123 TI - L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury. AB - BACKGROUND: Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of L-arginine to L-citrulline in endothelial cells. We investigated whether administering L-citrulline by raising the serum levels of L-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury. METHODS: Newborn rats were exposed to FiO(2) = 0.6 or room air for 14 days to induce lung derangement and then were administered L-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed. RESULTS: Serum L-arginine rose in the L-citr + hyperoxia group (p = 0.05), as well as the Von Willebrand factor stained vessels count (p = 0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the L-citr + hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham treated groups compared with the groups reared in room air or treated with L citrulline under exposure to hyperoxia (p = 0.0001). Lung VEGF and eNOS increased in the L-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p = 0.003). CONCLUSIONS: We conclude that administering L: -citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups. PMID- 22430124 TI - Successful management of plastic bronchitis in a child post Fontan: case report and literature review. AB - PURPOSE: Plastic bronchitis is the occlusion of the major bronchial airways by a firm, gelatinous mucoid cast. It is a rare condition, which while classically described in asthma and sickle cell disease has greater mortality in patients with congenital heart disease. The management of this disease is obscure given the lack of clinical data regarding treatment therapies. METHODS: We describe a case of an 11-year-old female status after Fontan surgery who presented with respiratory distress secondary to atelectasis of the right lung. RESULTS: A bronchoscopy was performed demonstrating an obstructing bronchial cast with successful extraction. The plastic bronchitis continued to recur and she was placed on multiple inhaled mucolytics as well as inhaled tissue plasminogen activator with temporary resolution. Further evaluation of the etiology of her casts revealed that she had elevated pulmonary arterial pressures. Repeated bronchoscopic removal of the casts was utilized as well as continuation of the aggressive airway clearance. Ultimately fenestration of her Fontan was performed along with treatment of pulmonary vasodilators sildenafil and bosentan. Although there was improvement of the cast formation, her airway clearance could only be weaned to four times a day therapy with which she was discharged home after a 3 month hospitalization. She continues to remain on this therapy and has not required hospitalization since the initial incident over 1 year ago. CONCLUSIONS: Plastic bronchitis in a patient with Fontan physiology presents a treatment dilemma that may require comprehensive therapy in severe cases such as described. PMID- 22430125 TI - Dickkopf-1 (DKK-1) interrupts FAK/PI3K/mTOR pathway by interaction of carbonic anhydrase IX (CA9) in tumorigenesis. AB - Recently, we found that carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasion, and then identified dickkopf-1 (DKK-1) as a novel CA9-interacting protein. In this study, we have determined the binding regions that are required for interaction between CA9 and DKK-1 through in vitro and in vivo. The N-terminal domain of CA9 is participated to interact with the Val(60) Tyr(168) site of DKK-1. We also observed that DKK-1 inhibits endothelial cell angiogenesis of CA9 in tumorigenesis. Furthermore, induction of CA9-mediated mTOR phosphorylation and angiogenesis was significantly inhibited by over-expression of DKK-1. Taken together, these findings identify DKK-1 as a potential factor in the regulation of CA9 cellular homeostasis and also suggest a new possible role for DKK1-1 in tumorigenesis. PMID- 22430126 TI - ROCK1 feedback regulation of the upstream small GTPase RhoA. AB - Rho-associated coiled-coil containing protein kinase 1 (ROCK1) is a key downstream effector of the small GTPase RhoA. Targeting ROCK1 has shown promising clinical potential in cancer, cardioprotection, hypertension, diabetes, neuronal regeneration, and stem cell biology. General working hypothesis in previous studies has centered on the function of ROCK1 as a downstream sequence in the RhoA signaling pathway. In this study, the effects of the direct inhibition of ROCK1 on the activity of upstream RhoA and Rac1 were examined using a combined pharmacological and genetic approach. We report an intriguing mechanism by which the inhibition of ROCK1 indirectly diminishes the activity of upstream RhoA through the stimulation of Tiam1-induced Rac1 activity. This novel feedback mechanism, in which ROCK1 mediates upstream Rac1 and RhoA activity, offers considerable insight into the diverse effects of ROCK1 on the functional balance of the Rho family of small GTPases, which regulates actin cytoskeleton reorganization processes and the resulting overall behavior of cells. PMID- 22430127 TI - Surgical management of ventral and ventrolateral foramen magnum meningiomas: report on a 64-case series and review of the literature. AB - Foramen magnum meningioma poses a challenge for neurosurgeons. Prognosis has generally improved with diagnostic and surgical advances over the past two decades; however, it may ultimately depend more on the surgeon's ability to tailor the approach and interpret intraoperative risks in single cases. The series comprised 64 patients operated on for ventral and ventrolateral foramen magnum meningioma. All patients underwent preoperative magnetic resonance imaging and received surgery via the dorsolateral route, rendering the series homogeneous in neuroradiological workup and surgical treatment. Particular to this series was that the majority of patients were of advanced age (n = 29; age, >65 years), had serious functional impairment (n = 30, Karnofski score <70), and large tumors (mean diameter, 3.5 cm). Total tumor removal was achieved in 52 (81 %) patients; operative mortality was nil. Early outcome varied depending on difficulties encountered at surgery (cranial nerve position and type of involvement in particular) and type of preoperative dysfunction. Long-tract signs and cerebellar deficits improved in 74 and 77 % of cases, respectively, but only 27 % of cranial nerve deficits did so. Surgical complications most often involved the cranial nerves: cranial nerve impairment, especially of the 9th through the 12th cranial nerves, due to stretching or encasement was noted in 44 cases. At final outcome assessment, two thirds of the cranial nerve deficits cleared, and all but two patients returned to a normal productive life. One patient was reoperated on during the follow-up period. Foramen magnum meningiomas behave like clival or spinal tumors depending on their prevalent extension. A dorsolateral approach tailored to tumor position and extension and meticulous surgical technique allow for definitive control of surgical complications. Scrupulous postoperative care may prevent dysphagia, a major persistent complication of surgery. Long-term observation of indolent tumor behavior at follow-up suggests that incomplete resection may be a viable surgical treatment option. PMID- 22430128 TI - Unveiling the three-dimensional structure of the green pigment of nitrite-cured meat. AB - The 1.70 A-resolution X-ray crystal structure of the green pigment occasionally present in nitrite-cured meat reveals a regiospecific nitration of the heme at the 2-vinyl position; the regiospecificity is favored on steric grounds, and results in movement of the 2-nitrovinyl moiety into the plane of the 24-atom heme macrocycle. PMID- 22430130 TI - Basic mathematics and physics for undergraduate chemistry students according to the Eurobachelor(r) curriculum. PMID- 22430129 TI - Nonlinear optical absorption of photosynthetic pigment molecules in leaves. AB - A mathematical formulation of the relationship between optical absorption coefficient of photosynthetic pigment molecules and light intensity was developed. It showed that physical parameters of photosynthetic pigment molecule (i.e., light absorption cross-section of photosynthetic pigment molecule, its average lifetime in the excited state, total photosynthetic pigment molecules, the statistical weight, or degeneracy of energy level of photosynthetic pigment molecules in the ground state and in the excited state) influenced on both the light absorption coefficient and effective light absorption cross-section of photosynthetic pigment molecules. Moreover, it also showed that both the light absorption coefficient and effective light absorption cross-section of photosynthetic pigment molecules were not constant, they decreased nonlinearly with light intensity increasing. The occupation numbers of photosynthetic pigment molecules in the excited states increased nonlinearly with light intensity increasing. PMID- 22430131 TI - Multivariate statistics for the differentiation of erythropoietin preparations based on intact glycoforms determined by CE-MS. AB - Owing to the increasing number of erythropoietin biosimilars being approved, the comparison of different erythropoietin preparations in the pharmaceutical area is gaining in importance. Erythropoietin has a distinct natural heterogeneity arising from its glycosylation, which shows strong composition variations. This heterogeneity increases the complexity of the analysis of erythropoietin considerably, but may also be used to distinguish different preparations. Here, a method is presented for the differentiation of various erythropoietin preparations by capillary electrophoresis-mass spectrometry and the subsequent application of multivariate statistics. Relative peak areas of selected intact erythropoietin isoforms were used as variables in principal component analysis and hierarchical agglomerative clustering. Both of these strategies were suited for the clear differentiation of all erythropoietin preparations, including marketed products and preproduction preparations, which differ in the manufacturer, the production cell line, and the batch number. By this means, even closely related preparations were distinguished on the basis of the combined information on the antennarity, the sialoform, and the acetylation of the observed isoforms. PMID- 22430132 TI - The expansion and advancement of cancer biomarkers. PMID- 22430133 TI - Somatic mutation analysis of EGFR, KRAS, BRAF and PIK3CA in 861 patients with non small cell lung cancer. AB - The prevalence of EGFR, KRAS, BRAF and PIK3CA somatic mutations in 861 randomly selected Chinese patients with non-small cell lung cancer (NSCLC) was assayed by the SurPlex(r)-xTAG70plex platform and analyzed. The results showed that the occurrence rates were 41.0, 8.0, 0.7 and 3.7%, respectively. The mutation rates significantly correlated with gender, histology and smoking history. The EGFR exon 19, 20 and 21 mutations were higher in females compared to males (p< 0.001, exon 19 and 21; p=0.018, exon 20), higher in adenocarcinomas compared to other forms of lung cancers (p< 0.001, exon 19 and 21; p=0.035, exon 20), and higher in non-smokers compared to smokers (p< 0.001, exon 19 and 21; p=0.029, exon 20). Conversely, the KRAS mutations were higher in males compared to females (p=0.004), higher in adenocarcinomas compared to other forms of lung cancers (p< 0.001), and higher in smokers compared to non-smokers (p< 0.001). The PIK3CA mutation rate was lower in adenocarcinomas compared to other forms of lung cancers (p=0.003). PMID- 22430134 TI - MicroRNA-21 is a new marker of circulating tumor cells in gastric cancer patients. AB - The detection of circulating tumor cells (CTCs) has received great attention. MicroRNA-21 (miR-21) plays crucial roles in carcinogenesis and is considered as one of the most studied oncomiRNAs. We determined if miR-21 could be used a marker for the detection of CTCs in gastric cancer patients. Peripheral blood samples were collected from 53 preoperative patients with gastric cancer and 20 healthy volunteers. Real-time reverse transcription-polymerase chain reaction was used to detect the level of miR-21. Receiver operator characteristic curves (ROC) were constructed. Patients with gastric cancer display a significantly higher level of miR-21 in peripheral blood than those from controls. The miR-21 level was associated with the tumor node metastasis (TNM) stage, tumor size and tissue categories. The area under ROC curve was up to 0.853 +/- 0.086. This study highlights the potential of the detection of miR-21 in peripheral blood as a novel tool for monitoring CTCs in gastric cancer patients. PMID- 22430135 TI - CXCR4 and CXCL12 immunoreactivities differentiate primary non-small-cell lung cancer with or without brain metastases. AB - Synchronous or metachronous brain metastases (BMs) occur in about 33% of patients affected by non-small-cell lung cancer (NSCLC). To date, no reliable biological marker is able to identify patients who will develop BMs. In the present study, using a quantitative double-labeling immunofluorescence analysis, we evaluated the expression of chemokine CXCL12 and its receptor, CXCR4, in primary NSCLC histological specimens of patients with and without BMs. The immunoreactivity of CXCL12 and CXCR4 was significantly higher in NSCLC samples of patients with BMs. We performed Receiver Operating Characteristics (ROC) analysis in order to define optimal cut-off values for CXCL12 and CXCR4 immunoreactivity that could discriminate between NSCLC patients without and with BMs. ROC curves showed a good diagnostic accuracy and adequate predictive power for both CXCL12 and CXCR4. These findings suggest a possible role for the CXCL12/CXCR4 axis in the metastatic evolution of NSCLC, and its potential use as prognostic markers and drug targets. PMID- 22430136 TI - Tumoral C-reactive protein and nuclear factor kappa-B expression are associated with clinical outcome in patients with prostate cancer. AB - Prostate cancer (Pca) is the most common form of cancer affecting men, despite recent advances in PCa treatments, one third of patients diagnosed each year succumb to this disease. The inflammatory response has been implicated in prostate cancer progression. The pro-inflammatory transcription factor, NFkappaB/p65 has been implicated in PCa progression. Few studies have examined the involvement of NFkappaB and inflammatory signalling in PCa.Immunohistochemistry was employed to investigate the expression of NFkappaB/p65, C-reactive protein and Ki67 in 61 clinical samples. Tumours expressing high levels of p65 (p=0.004), CRP (p=0.011) and Ki67 (p=0.0003) had a shorter disease specific survival. Upon combining p65 and CRP status it was observed that those tumours with low expression of both proteins had a median survival of 11 years compared to 3.9 years for those with tumours with high expression of both (p=0.005). CRP expression was significantly higher in the 21 patients who died of their disease and on multivariate analysis CRP expression retained independent significance (p=0.005). This study suggests CRP and NFkappaB may function collectively to drive prostate cancer progression in a subset of patients. Tumoral CRP is a significant independent predictor of cancer specific survival. The relationship between tumour CRP and signalling pathways warrants further investigation in a larger cohort. PMID- 22430137 TI - Serum AGR2 as an early diagnostic and postoperative prognostic biomarker of human lung adenocarcinoma. AB - In the present study, the human orthologue of the secreted Xenopus laevis anterior gradient 2 (AGR2) protein was evaluated as a potential serum biomarker of lung adenocarcinoma. AGR2 protein levels were preoperatively measured in the serum of 111 primary lung adenocarcinoma patients and in 46 non-cancer controls with subsequent calculation of sensitivity and specificity in comparison with serum CEA levels. Correlations with clinicopathological variables were also assessed and survival analyses were performed according to the Kaplan-Meier method and differences determined with the log-rank test. The mean serum AGR2 level of lung adenocarcinoma patients in each stage, even Stage I, was significantly higher than in non-cancer controls (P < 0.001 for all stages, Mann Whitney U test). The sensitivity was 65.8% (52.9% for stage IA), even higher than that of CEA, which was 45.0% (29.4% for stage IA), and the specificity was 87.0% according to the ROC curve (AUC=0.858). Positive serum AGR2 expression was significantly associated with the incidence of recurrence after surgery (P=0.025) and with a poor prognosis (P=0.037 for overall survival and P=0.004 for disease free survival). Preoperative serum AGR2 might become a clinically useful biomarker for early detection, prediction of recurrence and prognosis with lung adenocarcinomas. PMID- 22430138 TI - Biomarker research and some deduction in superficial bladder cancer cells combined with corresponding stroma. AB - AIMS: To facilitate biomarker discovery and improve cancer biology research of superficial bladder transitional cell carcinoma (SBTCC). MATERIALS AND METHODS: Laser capture microdissection and two-dimensional liquid chromatography tandem mass spectrometry was used to identified the proteome expression profile of purified normal urothelial cells (cancer cells)/normal stromal cells (cancer stromal cells). Based on the expression profile, biomarker discovery and the mechanisms of multi-step carcinogenesis were discussed. RESULTS: 775/792 proteins commonly appeared in 4 paired cancer/normal tissue. 339 differential proteins located at the well-known biological KEGG pathways and defined as potential biomarkers. 53/31 proteins specific repeat expression in cancer tissue/normal tissue and thought to play important role in tumor--stroma interactions. CONCLUSION: Proteins origin from cancer or stromal cells have the same probability to be a biomarker. The significant altered pathways mainly include metabolic pathways, spliceosome, endocytosis, oxidative phosphorylation, etc. Most of the specific repeat expression proteins act important role in cancer biology. PMID- 22430139 TI - Effects of beta-(1,3-1,6)-D-glucan on irritable bowel syndrome-related colonic hypersensitivity. AB - Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain associated with altered bowel habits. Since the prevalence of IBS is very high and thus, involves elevated health-care costs, treatment of this condition by methods other than prescribed medicines could be beneficial. beta-(1,3)-D-glucan with beta-(1,6) branches (beta-glucan) has been used as a nutritional supplement for many years. In this study, we examined the effect of beta-glucan on fecal pellet output and visceral pain response in animal models of IBS. Oral administration of beta-glucan suppressed the restraint stress- or drug induced fecal pellet output. beta-Glucan also suppressed the visceral pain response to colorectal distension. These results suggest that beta-glucan could be beneficial for the treatment and prevention of IBS. PMID- 22430140 TI - A regulatory role of Kruppel-like factor 4 in endothelial argininosuccinate synthetase 1 expression in response to laminar shear stress. AB - Endothelial argininosuccinate synthetase 1 (ASS1) regulates the provision of l arginine to nitric oxide synthase 3 (NOS3). Previous studies demonstrated that endothelial ASS1 expression was induced by laminar shear stress (LSS) and that this enzyme plays a role in maintaining anti-inflammatory microenvironments through enhancing NO production. However, differently from the case of NOS3, the regulatory mechanism for the endothelial ASS1 expression in response to LSS is not well understood. This study addressed a specific issue whether endothelial ASS1 expression is regulated by Kruppel-like factors (KLFs) that are presumed to coordinate endothelial gene expressions in response to LSS. The cDNA microarray data indicated that LSS stimulated the expression of numerous KLFs in human umbilical vein endothelial cells. KLF4 showed the highest fold increase and LSS dependent increases of KLF4 and most other KLFs were similar in young versus senescent endothelial cells. LSS-induced KLF4 expression was verified by RT-PCR and Western blotting. LSS-induced ASS1 expression and NO production were suppressed by a small interfering RNA for KLF4. The ectopic expression of KLF4 led to the increase of ASS1 expression and NO production. The present study demonstrated a key regulatory role of KLF4 in the endothelial ASS1 expression and NO production in response to LSS. PMID- 22430141 TI - The effects of designed angiopoietin-1 variant on lipid droplet diameter, vascular endothelial cell density and metabolic parameters in diabetic db/db mice. AB - Metabolic syndrome consists of metabolic abnormality with central obesity, hypertriglyceridemia, insulin resistance and hypertension. Adipose tissue has been known as a primary site of insulin resistance and its adipocyte size may be correlated with the degree of insulin resistance. A designed angiopoietin-1, COMP Angiopoietin-1 (COMP-Ang1), mitigated high-fat diet-induced insulin resistance in skeletal muscle. In this study, we examined effects of COMP-Ang1 on adipocyte droplet size, vascular endothelial cell density in adipose tissue and metabolic parameters in db/db mice by administering COMP-Ang1 or LacZ (as a control) adenovirus. Administration of COMP-Ang1 decreased fat droplet diameter in epididymal and abdominal visceral adipocyte and visceral fat content in db/db mice. The density of vascular endothelial cell in adipose tissue was increased in db/db mice after treatment with COMP-Ang1. Serum resistin and tumor necrosis factor-alpha level was lower after treatment with COMP-Ang1 in db/db mice. COMP Ang1 caused a restoration of fasting glycemic control in db/db mice and decreased serum insulin level and insulin resistance measured by HOMA index. These findings indicate that COMP-Ang1 regulates adipocyte fat droplet diameter, vascular endothelial cell density and metabolic parameters in db/db mice. PMID- 22430142 TI - NAMPT pathway is involved in the FOXO3a-mediated regulation of GADD45A expression. AB - Nicotinamide-phosphoribosyltransferase (NAMPT), induced under stress, converts nicotinamide (NA) to nicotinamide mononucleotide (NMN), which then reacts with ATP to regenerate NAD(+). Despite the pivotal role of NAD(+) in metabolic reactions, the molecular pathways triggered by the intracellular changes in NAD(+) level in cancer cells are largely unknown. Growth Arrest and DNA Damage inducible Gene (GADD45A) is regulated by multiple cellular factors which play an important role in the control of cell-cycle checkpoint, DNA repair process and signal transduction. The present study was designed to assess the significance of intracellular NAD(+) levels on the regulation of GADD45A expression. The results of this study demonstrate an inverse relationship between NAMPT expression and the regulation of GADD45A gene. Thus, an overexpression of NAMPT led to a decreased expression of GADD45A, whereas, the inhibition of NAMPT by the known chemical inhibitor FK866 increased the expression of GADD45A in cells. Inhibition of SIRT1, an NAD(+)-dependent deacetylase, using shRNA also led to an increased expression of GADD45A gene. In further experiments we could show that the increased expression of GADD45A under the above experimental conditions, NAMPT inhibition by FK866, involves acetylation of FOXO3a, a member of the important family of forkhead (FOXO) proteins. This knowledge should contribute to our understanding of the role played by NAMPT and SIRT1 in the regulation of GADD45A expression by FOXO3a. PMID- 22430143 TI - Inhibition of fatty acid translocase cluster determinant 36 (CD36), stimulated by hyperglycemia, prevents glucotoxicity in INS-1 cells. AB - The purpose of the present study was to determine whether exposure of pancreatic islets to glucotoxic conditions changes fatty acid translocase cluster determinant 36 (CD36) and examine the role of CD36 on the induction of glucotoxicity. We measured the changes of CD36 and insulin secretion in high glucose (30 mM) exposed INS-1 cells and CD36 suppressed INS-1 cells by transfection of CD36 siRNA. The intracellular peroxide level of INS-1 cells increased in the high glucose media compared to normal glucose (5.6mM) media. The mRNA levels of insulin and PDX-1, as well as glucose stimulated insulin secretion (GSIS) were decreased in INS-1 cells exposed to high glucose media compared to normal glucose media, while CD36 and palmitate uptake were significantly elevated with exposure to high glucose media for 12h. The inhibition of CD36 reversed the decreased GSIS and intracellular peroxide level in INS-1 cells. These results suggest that high glucose may exacerbate glucotoxicity via increasing fatty acid influx by elevation of CD36 expression, and that CD36 may be a possible target molecule for preventing glucotoxicity in pancreatic beta-cells. PMID- 22430144 TI - The role of the Cx43 C-terminus in GJ plaque formation and internalization. AB - Connexin 43 (Cx43) is a major gap junction (GJ) protein found in many mammalian cell types. The C-terminal (CT) domain of Cx43 has unique characteristics in terms of amino acid (aa) sequence and its length differs from other connexins. This CT domain can be associated with protein partners to regulate GJ assembly and degradation, which results in the direct control of gap junction intercellular communication (GJIC). However, the essential roles of the CT regions involved in these mechanisms have not been fully elucidated. In this study, we aimed to investigate the specific regions of Cx43CT involved in GJ formation and internalization. Wild type Cx43((382aa)) and 10 CT truncated mutants were stably expressed in HeLa cells as GFP or DsRed tagged proteins. First, we found that the deletion of 235-382aa from Cx43 resulted in failure to make GJ and establish GJIC. Second, the Cx43 with 242-382aa CT deletion could form functional GJs and be internalized as annular gap junctions (AGJs). However, the plaques consisting of Cx43 with CT deletions (Delta242-382aa to Delta271 382aa) were longer than the plaques consisting of Cx43 with CT deletions (Delta302-382aa). Third, co-culture experiments of cells expressing wild type Cx43((382)) with cells expressing Cx43CT mutants revealed that the directions of GJ internalization were dependent on the length of the respective CT. Moreover, a specific region, 325-342aa residues of Cx43, played an important role in the direction of GJ internalization. These results showed the important roles of the Cx43 C-terminus in GJ expression and its turnover. PMID- 22430145 TI - A stereological study of the numbers of neurons and glia in the primary visual cortex across the lifespan of male and female rhesus monkeys. AB - Mild age-related declines in visual function occur in humans and monkeys, independent of ocular pathology, suggesting involvement of central visual pathways (Spear [1993] Vision Res 33:2589-2609). Although many factors might account for this decline, a loss of neurons in primary visual cortex (V1) could be a contributing factor. Previous studies of neuron numbers in V1 reported stability across age, but were limited in the ages and genders studied and sampled only limited parts of V1 or limited cell types, allowing for the possibility of a subtle loss of neurons. We pursued this question in 26 behaviorally tested adult male and female rhesus monkeys ranging from 7.4 to 31.0 years of age by using design-based stereology to estimate numbers of NeuN-labeled neurons and thionin-stained glia within three laminar zones, supragranular (layers II-IVB), granular (IVC), and infragranular (V-VI), across the entirety of V1. There were no significant differences between males and females on any measures, except for total brain weight (P = 0.0038). There was an average of 416,000,000 neurons in V1, but no effect of age on this total or numbers within any laminar zone. Similarly, there was an average of 184,000,000 glia in V1 (44% of the number of neurons), but no effect of age on this total. However, there was a significant age-related increase in numbers of glia in the infragranular zone, perhaps reflecting a glial response to pathology in myelinated projection fibers. This study provides further evidence that in normal aging neurons are not lost and hence cannot account for age-related dysfunction. PMID- 22430146 TI - Role of physical training in heart failure with preserved ejection fraction. AB - About 50% or more of heart failure (HF) patients living in the community have preserved left ventricular ejection fraction (HFpEF), and the proportion is higher among women and the very elderly. A cardinal feature of HFpEF is reduced aerobic capacity, measured objectively as peak exercise pulmonary oxygen uptake (peak VO(2)), that results in decreased quality of life. Specifically, peak VO(2) of HFpEF patients is 30-70% lower than age-, sex-, and comorbidity-matched control patients without HF. The mechanisms for the reduced peak VO(2) are due to cardiovascular and skeletal muscle dysfunction that results in reduced oxygen delivery to and/or utilization by the active muscles. Currently, four randomized controlled exercise intervention trials have been performed in HFpEF patients. These studies have consistently demonstrated that 3-6 months of aerobic training performed alone or in combination with strength training is a safe and effective therapy to increase aerobic capacity and endurance and quality of life in HFpEF patients. Despite these benefits, the physiologic mechanisms underpinning the improvement in peak exercise performance have not been studied; therefore, future studies are required to determine the role of physical training to reverse the impaired cardiovascular and skeletal muscle function in HFpEF patients. PMID- 22430147 TI - Skeletal muscle abnormalities in chronic heart failure. AB - Skeletal muscle abnormalities are well-established in patients with heart failure from an early stage in the progression of the disease and contribute to their symptoms and the limitation of physical activity. Heart failure-induced skeletal muscle pathology includes morphologic, histologic, and enzymatic changes along with derangements in skeletal muscle metabolism and autonomic function. These alterations influence both peripheral and ventilatory muscles, are present at rest, and deteriorate during exercise and their occurrence depends upon the severity and the duration of CHF syndrome. Future studies will be needed to elucidate the origin of skeletal "myopathy" and its reversibility, which is associated with improvement in exercise capacity, observed after physical training programs. PMID- 22430148 TI - Early development in the velvet worm Euperipatoides kanangrensis Reid 1996 (Onychophora: Peripatopsidae). AB - We present here a description of early development in the onychophoran Euperipatoides kanangrensis with emphasis on processes that are ambiguously described in older literature. Special focus has been on the pattern of early cleavage, blastoderm and germinal disc development and gastrulation. The formation of the blastopore, stomodeum and proctodeum is described from sectioned material using light and transmission electron microscopy as well as whole-mount material stained for nuclei and gene expression. The early cleavages were found to be superficial, contrary to earlier descriptions of cleavage in yolky, ovoviviparous onychophorans. Also, contrary to earlier descriptions, the embryonic anterior-posterior axis is not predetermined in the egg. Our data support the view of a blastopore that becomes elongated and slit-like, resembling some of the earliest descriptions. From gene expression data, we concluded that the position of the proctodeum is the most posterior pit in the developing embryo. This description of early development adds to our knowledge of the staging of embryonic development in onychophorans necessary for studies on the role of developmental changes in evolution. PMID- 22430149 TI - The role of LRRK2 in inflammatory bowel disease. PMID- 22430150 TI - Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor. AB - SRC-3/AIB1 (steroid receptor coactivator 3/amplified in breast cancer 1) is an authentic oncogene that contributes to the development of drug resistance and poor disease-free survival in cancer patients. Autophagy is also an important cell death mechanism that has tumor suppressor function. In this study, we identified macrophage migration inhibitory factor (MIF) as a novel target gene of SRC-3 and demonstrated its importance in cell survival. Specifically, we showed that MIF is a strong suppressor of autophagic cell death. We further showed that suppression of MIF, in turn, induced autophagic cell death, enhanced chemosensitivity and inhibited tumorigenesis in a xenograft mouse tumorigenesis model. Our study demonstrated that regulation of MIF expression and suppression of autophagic cell death is a potent mechanism by which SRC-3 contributes to increased chemoresistance and tumorigenicity. PMID- 22430151 TI - Laminin/beta1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization. AB - Axon specification during neuronal polarization is closely associated with increased microtubule stabilization in one of the neurites of unpolarized neuron, but how this increased microtubule stability is achieved is unclear. Here, we show that extracellular matrix (ECM) component laminin promotes neuronal polarization via regulating directional microtubule assembly through beta1 integrin (Itgb1). Contact with laminin coated on culture substrate or polystyrene beads was sufficient for axon specification of undifferentiated neurites in cultured hippocampal neurons and cortical slices. Active Itgb1 was found to be concentrated in laminin-contacting neurites. Axon formation was promoted and abolished by enhancing and attenuating Itgb1 signaling, respectively. Interestingly, laminin contact promoted plus-end microtubule assembly in a manner that required Itgb1. Moreover, stabilizing microtubules partially prevented polarization defects caused by Itgb1 downregulation. Finally, genetic ablation of Itgb1 in dorsal telencephalic progenitors caused deficits in axon development of cortical pyramidal neurons. Thus, laminin/Itgb1 signaling plays an instructive role in axon initiation and growth, both in vitro and in vivo, through the regulation of microtubule assembly. This study has established a linkage between an extrinsic factor and intrinsic cytoskeletal dynamics during neuronal polarization. PMID- 22430152 TI - A non-coding RNA locus mediates environment-conditioned male sterility in rice. PMID- 22430154 TI - A clinical approach to arterial ischemic childhood stroke: increasing knowledge over the last decade. AB - Childhood stroke is increasingly being recognized as an important burden not only for affected children and families, but also for socioeconomic reasons. A primary problem is delayed diagnosis, due to the many mimics of childhood stroke, and the variety of manifesting symptoms. The most important is hemiparesis (with/without dysphasia or facial palsy), but ataxia, seizures, and many more are also possible. Suspicion of stroke has to be ascertained by neuroimaging, gold standard being (diffusion weighted) magnetic resonance. Risk factors are multiple, but their presence might help to increase the suspicion of stroke. The most important factors are infectious/parainfectious etiologies, frequently possibly manifesting by transient focal cerebral arteriopathy (FCA). Cardiological underlying problems are the second most important. Arteriopathies can be detected in about half of the children, besides FCA and dissection and MoyaMoya disease are the most important. Hereditary coagulopathies increase the risk of stroke. There is still a controversy on best treatment in children: platelet antiaggregation and heparinization are used about equally. Thrombolysis is being discussed increasingly. Severity of symptoms at manifestation and on follow-up are not less significant in children than in young adults. About two third of the children have significant residual neurological problems and a majority cognitive and behavior problems. PMID- 22430153 TI - Misfolded Gbeta is recruited to cytoplasmic dynein by Nudel for efficient clearance. AB - The Gbetagamma heterodimer is an important signal transducer. Gbeta, however, is prone to misfolding due to its requirement for Ggamma and chaperones for proper folding. How cells dispose of misfolded Gbeta (mfGbeta) is not clear. Here, we showed that mfGbeta was able to be polyubiquitinated and subsequently degraded by the proteasome. It was sequestered in aggresomes after the inhibition of the proteasome activity with MG132. Sustained activation of Gbetagamma signaling further elevated cellular levels of the ubiquitinated Gbeta. Moreover, Nudel, a regulator of cytoplasmic dynein, the microtubule minus end-directed motor, directly interacted with both the unubiquitinated and ubiquitinated mfGbeta. Increasing the levels of both mfGbeta and Nudel promoted the association of Gbeta with both Nudel and dynein, resulting in robust aggresome formation in a dynein dependent manner. Depletion of Nudel by RNAi reduced the dynein-associated mfGbeta, impaired the MG132-induced aggresome formation, and markedly prolonged the half-life of nascent Gbeta. Therefore, cytosolic mfGbeta is recruited to dynein by Nudel and transported to the centrosome for rapid sequestration and degradation. Such a process not only eliminates mfGbeta efficiently for the control of protein quality, but may also help to terminate the Gbetagamma signaling. PMID- 22430155 TI - Development of somatosensory perception in children: a longitudinal QST-study. AB - Cross-sectional studies on somatosensory perception in children demonstrate lower pain thresholds for children compared with adolescents. The aim of the present longitudinal study was to replicate these age-related differences in a longitudinal design. Total 38 children and adolescents aged 6 to 16 years (two girls and two boys within each year) participated in this study. Quantitative sensory testing (QST) according to the protocol of the German research network on neuropathic pain (DFNS) was assessed twice with an interval of 15.8 +/- 3.0 months. Bland-Altman analyses describe the short-term reliability of the measurements. Intraindividual sensory development was measured using paired t test and quantified by effect sizes Cohen's d between the two measurements. QST parameters showed good short-term reliability. Over a period of 1 year, children became less sensitive to painful stimuli, especially to cold pain, pressure pain, and mechanical pain. No systematic developmental changes were observed in response to the other somatosensory stimuli. QST is reliable over short retest intervals. In line with previous results from cross-sectional studies, we find a decrease in pain sensitivity with increasing age but no differences in nonnociceptive somatosensory processing over a period of 1 year in children between 6 and 16 years of age. Taken together, these results highlight the importance of a reference-based interpretation of the individual QST data. PMID- 22430156 TI - Bromide in patients with SCN1A-mutations manifesting as Dravet syndrome. AB - We report a retrospective analysis of bromide therapy in 32 patients suffering from Dravet syndrome with SCN1A-mutations who received bromide. After 3 months of bromide treatment, 26 patients (81%) showed a relevant improvement with a reduction of seizure frequency by >50% (>75%) in 18 (12) patients (56 and 37%, respectively). After 12 months, we observed a reduction of >50% (>75%) in 15 (9) patients (47 and 28%, respectively). Long-term response was noted in 18 patients (56%). Adverse reactions were mainly mild or moderate leading to treatment termination in 5/32 patients; no aggravation was reported. We conclude that bromide holds promise in patients with SCN1A-mutations suffering from Dravet syndrome. PMID- 22430157 TI - Characteristics of early MRI in children and adolescents with vanishing white matter. AB - OBJECTIVE: MRI in vanishing white matter typically shows diffuse abnormality of the cerebral white matter, which becomes increasingly rarefied and cystic. We investigated the MRI characteristics preceding this stage. DESIGN: In a retrospective observational study, we evaluated all available MRIs in our database of DNA-confirmed VWM patients and selected MRIs without diffuse cerebral white matter abnormalities and without signs of rarefaction or cystic degeneration in patients below 20 years of age. A previously established scoring list was used to evaluate the MRIs. RESULTS: An MRI of seven patients fulfilled the criteria. All had confluent and symmetrical abnormalities in the periventricular and bordering deep white matter. In young patients, myelination was delayed. The inner rim of the corpus callosum was affected in all patients. CONCLUSIONS: In early stages of VWM, MRI does not necessarily display diffuse cerebral white matter involvement and rarefaction or cystic degeneration. If the MRI abnormalities do not meet the criteria for VWM, it helps to look at the corpus callosum. If the inner rim (the callosal-septal interface) is affected, VWM should be considered. PMID- 22430158 TI - Botulinum toxin type A and B for the reduction of hypersalivation in children with neurological disorders: a focus on effectiveness and therapy adherence. AB - Botulinum toxin (BoNT) is an established treatment option to reduce hypersalivation in children with chronic neurological disorders. Objective of this study was (1) to discriminate differences in efficacy and safety of repeated interventions using BoNT with a focus on different preparations used and (2) to look for effectiveness and treatment adherence from a qualitative research perspective in this single-center cohort study. We prospectively assessed goal attainment scaling, drooling severity and frequency score and the number of towels/day before, and 4 to 8 weeks after intervention. A parent questionnaire assessed therapy-related effects on quality of life retrospectively. A total of 19 out of 34 patients received repeated injections of BoNT (106 total). Mean dose: 95 units onabotulinumtoxinA (Botox(r)), 2383 units rimabotulinumtoxinB (Neuro-/Myobloc(r)). Outcome parameters showed a distinct reduction in all treatment groups with a higher efficacy of riB. The child's need for care was reduced in 79% and social interaction improved in 84%. Main reason for discontinuation was "not enough effect" and "formation of antibodies." riB showed to be more effective in reducing hypersalivation, but antibody-formation seems to be clinically relevant. Despite clinical efficacy treatment adherence is influenced by personal and environmental factors of parents and caretakers balancing the short-term clinical benefit versus the burden of intervention. PMID- 22430159 TI - Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases. AB - Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. RESULTS: Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. CONCLUSIONS: The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant. PMID- 22430160 TI - Chudley-McCullough syndrome: case report and review of the neuroimaging spectrum. AB - We report on a child with Chudley-McCullough syndrome and re-evaluate the spectrum of imaging findings (in 15 previously reported patients) which appear to be variable and, to some extent, ambiguous in the literature. Magnetic resonance imaging of the brain revealed asymmetric colpocephaly with agenesis of the splenium corporis callosi, ribbon-like subcortical gray matter heterotopia along the cingulate gyri, malrotation of both hippocampi, and dysplasia of the cerebellum. Macrocrania together with sensorineural hearing loss, colpocephaly, and posterior or complete agenesis of the corpus callosum can be considered the hallmarks of the autosomal recessive Chudley-McCullough syndrome. These may be variably associated with interhemispheric arachnoid cyst, cortical dysplasia, gray matter heterotopia, and cerebellar dysplasia. While early support with hearing aids may lead to improved language and cognitive outcome, shunting of ventricular dilatation is not indicated in the Chudley-McCullough syndrome. PMID- 22430161 TI - Failure of repeated cyclophosphamide pulse therapy in childhood cerebral X-linked adrenoleukodystrophy. AB - Childhood cerebral X-linked adrenoleukodystrophy (ALD) remains one of the most devastating neurological diseases of childhood. Cardinal features are inflammatory cerebral demyelination that coincides with an advancing zone of gadolinium enhancement on brain MRI. Therapeutic options, including the role of antiinflammatory therapy, are limited and poorly understood. We report the failure of repeated cyclophosphamide pulse therapy to halt the clinical progression or alter the gadolinium accumulation in two cases of childhood cerebral ALD. PMID- 22430162 TI - Measurements of elastic moduli of pharmaceutical compacts: a new methodology using double compaction on a compaction simulator. AB - The elastic properties of pharmaceutical powders play an important role during the compaction process. The elastic behavior can be represented by Young's modulus (E) and Poisson's ratio (v). However, during the compaction, the density of the powder bed changes and the moduli must be determined as a function of the porosity. This study proposes a new methodology to determine E and v as a function of the porosity using double compaction in an instrumented compaction simulator. Precompression is used to form the compact, and the elastic properties are measured during the beginning of the main compaction. By measuring the axial and radial pressure and the powder bed thickness, E and v can be determined as a function of the porosity. Two excipients were studied, microcrystalline cellulose (MCC) and anhydrous calcium phosphate (aCP). The values of E measured are comparable to those obtained using the classical three-point bending test. Poisson's ratio was found to be close to 0.24 for aCP with only small variations with the porosity, and to increase with a decreasing porosity for MCC (0.23 0.38). The classical approximation of a value of 0.3 for nu of pharmaceutical powders should therefore be taken with caution. PMID- 22430163 TI - Using a "genomics tool" to develop disease prevention strategy in a low-income setting: lessons from the podoconiosis research project. PMID- 22430165 TI - Prostate cancer: periprostatic fat is a risk factor for prostate cancer detection. PMID- 22430169 TI - BPH: 5alpha-reductase inhibition does not adversely affect muscle mass. PMID- 22430168 TI - Kidney cancer: assessing the management of localized kidney cancer. PMID- 22430171 TI - Urothelial cancer: therapeutic potential of KiSS-1 peptide in UTUC. PMID- 22430172 TI - Nanocrystal ligand exchange with 1,2,3,4-thiatriazole-5-thiolate and its facile in situ conversion to thiocyanate. AB - The 1,2,3,4-thiatriazole-5-thiolate anion (TTT(-)) was found to be a strongly binding ligand for CdSe nanocrystals, quantitatively exchanging various long chain ligands to yield stable colloidal suspensions in common polar solvents. The TTT(-) ligand thermolyzes at <100 degrees C to produce thiocyanate in situ, resulting in reduced quantum confinement in nanocrystal films. CdSe(TTT) possesses far higher colloidal stability than CdSe(SCN), and that, together with the facile synthesis of TTT(-), implies that this is a useful ligand for nanocrystal applications as a masked thiocyanate. PMID- 22430173 TI - Aortic annuloplasty ring: coronet or flat or not or what? PMID- 22430174 TI - Editorial comment: inflationary pressures. PMID- 22430175 TI - Editorial analysis: impact of perfusion strategy on stroke risk for minimally invasive cardiac surgery. PMID- 22430176 TI - Editorial comment: Reconstruction of the right ventricular outflow tract: short term solutions, long-term problems. PMID- 22430177 TI - Impact of ascending aortic wall thickness and atherosclerosis on the intermediate survival after coronary artery bypass surgery. AB - OBJECTIVES: We investigated the prognostic impact of atherosclerosis and wall thickness of the ascending aorta in patients undergoing coronary artery bypass grafting (CABG). METHODS: A series of 781 patients who underwent CABG and in whom epiaortic ultrasound was performed to assess the status of the ascending aorta and to measure the thickness of its anterior and lateral walls were the subjects of the present analysis. RESULTS: At multivariate analysis, thickness of the ascending aortic wall, but not atherosclerosis, was an independent predictor of all-cause intermediate mortality [relative risk (RR): 1.628; 95% confidence interval (CI): 1.219-2.176]. Five-year overall survival rates in patients with an aortic wall thickness >=1.8 mm and less were 82.2 and 92.6%, respectively (log rank test: P < 0.0001). Ascending aortic wall thickness (RR: 1.629; 95% CI: 1.135 2.339), but not atherosclerosis, was also an independent predictor of cardiovascular mortality. Aortic wall thickness >=1.8 mm combined with the presence of atherosclerosis of the ascending aorta was associated with a rather dismal overall survival compared with patients with normal findings at epiaortic ultrasound (at 5 years, 77.0 vs. 93.2%; adjusted analysis: P = 0.010). CONCLUSIONS: Ascending aortic wall thickness, but not the presence of atherosclerosis of any extent, is an independent predictor of intermediate all cause and cardiovascular mortality. Thickened aortic wall is associated with significantly higher hazard of all cause and cardiovascular mortality and can be considered an important surrogate marker of aggressive atherosclerosis. PMID- 22430178 TI - Repair versus replacement of the aortic valve in active infective endocarditis. AB - OBJECTIVES: Aortic valve repair has advantages over replacement in stable aortic regurgitation. It is unclear whether this is similar in active endocarditis. METHODS: From January 2000 to July 2009, 100 patients (age 54.9+/-15.1 years) underwent surgery for aortic valve endocarditis. Thirty-three patients were treated by valve repair (I) and 67 underwent valve replacement (II: 51 biologic, 10 mechanical valves, 6 Ross operations). In Group I, cusp and root lesions were treated by autologous pericardial patches. A root abscess was present in 32 cases (I: 27%, II 34%; P=0.82). Concomitant procedures (n=49) were mitral repair (I: 10, II: 11; P=0.12) and coronary bypass (I: 4, II: 11; P=0.77). All patients were followed. Cumulative follow-up was 268 patient-years (mean 2.7+/-3.0 years). In a retrospective analysis, we analysed the outcome. RESULTS: Hospital mortality was 15% (I: 9%, II: 18%; P=0.37). Survival at 5 years was significantly better after repair (I: 88%, II 65%; P=0.047). Ten patients were reoperated (I: 35%, II: 10%; P=0.021) between 1 month and 5 years postoperatively. Actuarial freedom from aortic regurgitation of grade II or higher was 80% at 5 years (I: 66%, II: 87%; P=0.066). In Group I, this was influenced by aorto-ventricular (AV) morphology (tricuspid 80%, bicuspid 50%; P=0.0045). Freedom from reoperation in reconstructed tricuspid valves (n=20) was 87% at 5 years, which was identical to Group II (P=0.40). At 5 years, freedom from thromboembolic events was 93% (I: 100%, II: 90%; P=0.087) and that from bleeding complications was 100%. CONCLUSIONS: AV repair for active endocarditis seems to lead to better survival compared with replacement. The use of large patches in combination with bicuspid anatomy results in increased risk of late failure. PMID- 22430179 TI - Editorial comment: the primary entry tear location in acute type B aortic dissection as an adjunct in therapeutic decision-making. PMID- 22430180 TI - Quantitative impurity analysis of monoclonal antibody size heterogeneity by CE LIF: example of development and validation through a quality-by-design framework. AB - This paper describes the framework of quality by design applied to the development, optimization and validation of a sensitive capillary electrophoresis sodium dodecyl sulfate (CE-SDS) assay for monitoring impurities that potentially impact drug efficacy or patient safety produced in the manufacture of therapeutic MAb products. Drug substance or drug product samples are derivatized with fluorogenic 3-(2-furoyl)quinoline-2-carboxaldehyde and nucleophilic cyanide before separation by CE-SDS coupled to LIF detection. Three design-of-experiments enabled critical labeling parameters to meet method requirements for detecting minor impurities while building precision and robustness into the assay during development. The screening design predicted optimal conditions to control labeling artifacts while two full factorial designs demonstrated method robustness through control of temperature and cyanide parameters within the normal operating range. Subsequent validation according to the guidelines of the International Committee of Harmonization showed the CE-SDS/LIF assay was specific, accurate, and precise (RSD <= 0.8%) for relative peak distribution and linear (R > 0.997) between the range of 0.5-1.5 mg/mL with LOD and LOQ of 10 ng/mL and 35 ng/mL, respectively. Validation confirmed the system suitability criteria used as a level of control to ensure reliable method performance. PMID- 22430181 TI - Psychological comorbidity in patients with chronic tinnitus: analysis and comparison with chronic pain, asthma or atopic dermatitis patients. AB - PURPOSE: To determine the prevalence and severity of psychological comorbidity in patients with chronic tinnitus in comparison with other chronic illnesses, namely chronic pain, chronic asthma and atopic dermatitis. METHODS: Psychological diagnoses were done according to ICD-10 Chapter V(F). Subjective impairment was evaluated using 5 psychometric questionnaires: tinnitus questionnaire, Berlin mood questionnaire, sense of coherence (SOC-L9) and perceived stress questionnaire. Sleep disturbance was measured by the subdomain 'exhaustion' of the Giessen physical complaints inventory. RESULTS: Somatoform or affective disorders were most frequent in all disease groups. Patients with chronic tinnitus had a stronger SOC and better subjective mood, stronger commitment, and less anger and anxious depression than the patients with chronic pain, chronic asthma or atopic dermatitis. However, in patients with higher tinnitus annoyance, psychological comorbidity was similar to that found in patients with other chronic diseases. CONCLUSIONS: Besides collecting medical and social history, special psychometric instruments should be used for the diagnosis of tinnitus patients. Based on relative high frequency of psychological comorbidity, we recommend interdisciplinary cooperation between otorhinolaryngologists and other specialists (psychosomatic medicine, psychology or psychiatry) during the treatment of tinnitus patients, especially when high degree of tinnitus annoyance is involved. PMID- 22430182 TI - Modulatory actions of dopamine and serotonin on insect antennal lobe neurons: insights from studies in vitro. AB - Biogenic amines play diverse roles in the development and modulation of invertebrate neurons and ultimately also, in the regulation of animal behaviour. Here we examine the contribution that analyses of antennal lobe neurons in vitro have made towards our understanding of the mechanisms through which dopamine and serotonin operate in primary olfactory centres of the brain of the moth, Manduca sexta and the honey bee, Apis mellifera. This chapter reviews evidence suggesting that these biogenic amines function as regulators of neuronal development and as mediators of cellular and behavioural plasticity, in part at least, through the modulation of K(+) conductances in the cells. Insect neurons in vitro provide an excellent model for exploring basic principles of amine function and their impact on neuronal excitability. PMID- 22430183 TI - Impaired savings despite intact initial learning of motor adaptation in Parkinson's disease. AB - In motor adaptation, the occurrence of savings (faster relearning of a previously learned motor adaptation task) has been explained in terms of operant reinforcement learning (Huang et al. in Neuron 70(4):787-801, 2011), which is thought to associate an adapted motor command with outcome success during repeated execution of the adapted movement. There is some evidence for deficient savings in Parkinson's Disease (PD), which might result from deficient operant reinforcement processes. However, this evidence is compromised by limited adaptation training during initial learning and by multi-target adaptation, which reduces the number of reinforced movement repetitions for each target. Here, we examined savings in PD patients and controls following overlearning with a single target. PD patients showed less savings than controls after successive adaptation and deadaptation blocks within the same test session, as well as less savings across test sessions separated by a 24-h delay. It is argued that impaired blunted dopaminergic signals in PD impairs the modulation of dopaminergic signals to the motor cortex in response to rewarding motor outcomes, thus impairing the association of the adapted motor command with rewarding motor outcomes. Consequently, the previously adapted motor command is not preferentially selected during relearning, and savings is impaired. PMID- 22430184 TI - Acquiring functional object knowledge through motor imagery? AB - A widely investigated question in the research on the acquisition of novel functional object representations is the role of the action system. Whereas most studies so far have investigated the role of active action training on the acquisition of object representation, we investigated whether people are able to acquire object representations by just imagining the use of novel objects, given that previous findings suggested that executed and imagined actions share a common representational format. To this end, participants trained the use of novel objects in a motor imagery condition. Training comprised the particular grip applied to the objects and the objects' typical end location. Subsequently, participants' object representations were assessed by means of an object detection task. The results show that participants responded slower when the novel objects were presented at functionally incorrect end locations, indicating that the participants had acquired functional knowledge about object use. Yet, there was no effect of correct versus incorrect grip. Altogether, the findings suggest that motor imagery can facilitate the acquisition of novel object representations, but point also to differences between first-hand action training and training by imagery. PMID- 22430185 TI - Local contextual processing of abstract and meaningful real-life images in professional athletes. AB - We investigated the effect of abstract versus real-life meaningful images from sports on local contextual processing in two groups of professional athletes. Local context was defined as the occurrence of a short predictive series of stimuli occurring before delivery of a target event. EEG was recorded in 10 professional basketball players and 9 professional athletes of individual sports during three sessions. In each session, a different set of visual stimuli were presented: triangles facing left, up, right, or down; four images of a basketball player throwing a ball; four images of a baseball player pitching a baseball. Stimuli consisted of 15 % targets and 85 % of equal numbers of three types of standards. Recording blocks consisted of targets preceded by randomized sequences of standards and by sequences including a predictive sequence signaling the occurrence of a subsequent target event. Subjects pressed a button in response to targets. In all three sessions, reaction times and peak P3b latencies were shorter for predicted targets compared with random targets, the last most informative stimulus of the predictive sequence induced a robust P3b, and N2 amplitude was larger for random targets compared with predicted targets. P3b and N2 peak amplitudes were larger in the professional basketball group in comparison with professional athletes of individual sports, across the three sessions. The findings of this study suggest that local contextual information is processed similarly for abstract and for meaningful images and that professional basketball players seem to allocate more attentional resources in the processing of these visual stimuli. PMID- 22430186 TI - After-training emotional interference may modulate sequence awareness in a serial reaction time task. AB - The purpose of the present experiment was to investigate the effects of emotional interference on consolidation of sequential learning. In different sessions, 6 groups of subjects were initially trained on a serial reaction time task (SRTT). To modulate consolidation of the newly learned skill, subjects were exposed, after the training, to 1 of 3 (positive, negative or neutral) different classes of emotional stimuli which consisted of a set of emotional pictures combined with congruent emotional musical pieces or neutral sound. Emotional intervention for each subject group was done in 2 different time intervals (either directly after the training session or 6 h later). After a 72 h post-training interval, each group was retested on the SRTT. Re-test performance was evaluated in terms of response times and accuracy during execution of a target sequence. Emotional intervention did not influence either response times or accuracy of re-testing SRTT target task performance, both variables sensitive to implicit knowledge acquired during SRTT training. However, explicit awareness of sequence knowledge after 72 h was enhanced when negative stimuli had been applied at 0 h after training. These findings suggest that consolidation of explicit aspects of procedural learning may be more responsive toward emotional interference than implicit aspects. PMID- 22430187 TI - Two potential biomarkers identified in mesenchymal stem cells and leukocytes of patients with sporadic amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder caused by degeneration of motor neurons. The cause for most cases of ALS is multi factorial,this enhances the need to characterize and isolate specific biomarkers found in biological samples from ALS patients. To this end we use human mesenchymal stem cells (hMSC) derived from the bone marrow of six ALS patients (ALS hMSC) and identified two genes, Cytoplasmic FMR Interacting Protein 2 (CyFIP2) and Retinoblastoma (Rb) Binding Protein 9 (RbBP9) with a significant decrease in post transcriptional A to I RNA editing compared to hMSC of healthy individuals. At the transcriptional level we show abnormal expression of these two genes in ALS hMSC by quantitative real time-PCR (qRT-PCR) and Western blot suggesting a problem in the regulation of these genes in ALS. To strengthen this view we tested by qRT-PCR the expression of these genes in peripheral blood leukocytes (PBL) isolated from blood samples of 17 ALS patients and found that CyFIP2 and RbBP9 levels of expression were significantly different compared to the levels of expression of these two genes in 19 normal PBL samples. Altogether we found two novel ALS potential biomarkers in non-neural tissues from ALS patients that may have direct diagnostic and therapeutic implications to the disease. PMID- 22430188 TI - Association between the miRNA signatures in plasma and bronchoalveolar fluid in respiratory pathologies. AB - The identification of new less invasive biomarkers is necessary to improve the detection and prognostic outcome of respiratory pathological processes. The measurement of miRNA expression through less invasive techniques such as plasma and serum have been suggested to analysis of several lung malignancies including lung cancer. These studies are assuming a common deregulated miRNA expression both in blood and lung tissue. The present study aimed to obtain miRNA representative signatures both in plasma and bronchoalveolar cell fraction that could serve as biomarker in respiratory diseases. Ten patients were evaluated to assess the expression levels of 381 miRNAs. We found that around 50% miRNAs were no detected in both plasma and bronchoalveolar cell fraction and only 20% of miRNAs showed similar expression in both samples. These results show a lack of association of miRNA signatures between plasma and bronchoalveolar cytology in the same patient. The profiles are not comparable; however, there is a similarity in the relative expression in a very small subset of miRNAs (miR-17, miR-19b, miR 195 and miR-20b) between both biological samples in all patients. This finding supports that the miRNAs profiles obtained from different biological samples have to be carefully validated to link with respiratory diseases. PMID- 22430189 TI - Replication of relevant SNPs associated with cardiovascular disease susceptibility obtained from GWAs in a case-control study in a Canarian population. AB - Recent genome-wide single nucleotide polymorphism (SNP) association studies (GWAS) have identified a number of SNPs that were significantly associated with coronary artery disease (CAD) and myocardial infarction (MI). We tested for replication of the previously described association with CAD in our case-control datasets of SNPs variants located at 1p13.1, 2q33.1, 10q11.1, 9p21, and 21q22. We observed a small significant risk associated of the SNP rs10757274 with CAD in the PROCAGENE study. Besides, the multilocus combination rs10757274 and rs1333048 gave a near significant result. We confirmed that the SNP rs10757274 showed association with CAD in the PROCAGENE study, although after applying the Bonferroni correction was not longer significant. Independent replication studies in other populations are needed to unequivocally confirm the association. PMID- 22430190 TI - Poly thymidine polymorphism and cystic fibrosis in a non-Caucasian population. AB - BACKGROUND: Cystic fibrosis is a monogenic recessive disorder found predominantly in Caucasian population. This disease arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In this study we consider poly T polymorphism c.1210-12T[5], c.1210-12T[7], c.1210-12T[9] (T{5}, T{7}, T{9}) in the intron 8 of CFTR gene in normal individuals and cystic fibrosis patients in the north of Iran. MATERIAL AND METHODS: 40 CF patients and 40 normal individuals were screened for poly T polymorphism in intron 8 of CFTR gene using Reverse Dot Blot method which was also used to detect p.Phe508del among CF patients. RESULTS: T{7} allele is the most prevalent in both normal and CF patients. Its abundance is approximately 75%. T{9} and T{5} represent approximately 20% and 5% of alleles respectively. T{7}/T{7} genotype is the most present in both normal and CF patients with 72.5% and 60% prevalence respectively. p.Phe508del was present in 13 CFTR alleles belonging to 7 patients with either homozygote T{9}/ T{9}, T{7}/ T{7} or compound heterozygote T{7}/ T{9} genotypes. CONCLUSION: Contrary to the Caucasians, T{7} allele is more frequent in Northern Iranian CF patients. The presence of p.Phe508del and T{7} allele in the same framework is reported for the first time in this part of the world. Further investigations of other populations will help to understand whether p.Phe508del arose by selection pressure in this part of the world or was imported from European countries. The abundance of T{5}, T{7}, T{9} alleles indicates that this polymorphism can be used as one of the informative markers for detection of normal and mutant alleles in prenatal diagnosis or carrier assessment in families with previous history of the disease in regions with high degree of CFTR mutation heterogeneity. PMID- 22430191 TI - Population analysis of pharmacogenetic polymorphisms related to acute lymphoblastic leukemia drug treatment. AB - This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL), and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes. PMID- 22430192 TI - Serological biomarkers of hepatocellular carcinoma in Egyptian patients. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. In Egypt, the disease is usually detected in an advanced stage at which no treatment may be effective including surgery. Early detection of the disease is thus an important goal allowing the patient to be treated before the enlargement of the tumor or its metastasis to distant organs. Tumor markers are serological agents which serum level may be useful in predicting the presence of the tumor at early stages. Alpha fetoprotein (AFP) which is the golden marker for HCC is of low sensitivity, therefore, additional markers such as alpha-L-fucosidase (AFU), transforming growth factors alpha and beta (TGF-alpha and TGF-beta) and interleukin-8 (IL-8) are suggested to be simultaneously evaluated in order to enhance the detection of HCC. A total of 96 patients with different liver diseases such as HCC, hepatitis C virus (HCV), hepatitis B virus (HBV) and cirrhotic patients are included in this study. Sixteen healthy volunteers are used as a control group. In patients with HCC each of AFP, AFU, TGF-alpha and TGF beta recorded significantly higher levels than the other patient groups and controls. HCC patients recorded significantly lower level of IL-8 compared to the other patient groups but significantly higher than the control. For AFP, AFU, TGF alpha, TGF-beta and IL-8, at the optimal cut-off values (obtained from the receiver operating characteristic (ROC) curves), the calculated sensitivities are 46%, 72.97%, 67.56%, 54.05% and 83.8%, respectively. The simultaneous evaluation using all of the suggested markers resulted in increasing the sensitivity up to 100%. It thus recommended that, if patients with cirrhosis, as high risk patients, are subjected to regular examination using these markers in addition to AFP, HCC may be detected by 100% sensitivity in an early stage and as a consequence an effective treatment can be achieved. PMID- 22430193 TI - Combined analysis of AFP and HCCR-1 as an useful serological marker for small hepatocellular carcinoma: a prospective cohort study. AB - Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors in the world. The only serological marker widely used for the diagnosis of HCC is alpha-fetoprotein (AFP). Despite that AFP is widely used for the diagnosis of HCC, it has a limit as a serological marker due to its low sensitivity and specificity. The human cervical cancer proto-oncogene 1 (HCCR-1) was previously reported as a new biomarker for HCC. To further evaluate the HCCR-1 as a biomarker for HCC, we conducted the prospective cohort study. We evaluated the significance of simultaneous measurement of 2 tumor markers in the diagnosis of HCC in China, Japan and Korea. Two markers for HCC, AFP and HCCR-1, were measured in the sera obtained from 1,338 patients at the time of initial diagnosis of HCC. Of the 1338 HCC patients, 616 (46%) and 686 (51.3%) were sero-positive for AFP and HCCR-1, respectively. The positive rate for HCC was increased up to 74.1% in combined use of AFP and HCCR-1. Many cases (54%) for AFP-negative HCC were positive for HCCR-1 and vice versa. More importantly, the diagnostic rate for small HCC (< 2 cm) was significantly improved in the combined analysis of AFP and HCCR-1 to 56.9% although it was only 40.1% and 23.4% in the single analysis of HCCR-1 and AFP, respectively. Our result suggests that the HCCR-1 could be an useful biomarker for HCC while the diagnostic rate could be significantly improved in the combined use of HCCR-1 and AFP. PMID- 22430194 TI - E3B1/ABI-1 isoforms are down-regulated in cancers of human gastrointestinal tract. AB - The expression of E3B1/ABI-1 protein and its role in cancer progression and prognosis are largely unknown in the majority of solid tumors. In this study, we examined the expression pattern of E3B1/ABI-1 protein in histologically confirmed cases of esophageal (squamous cell carcinoma and adenocarcinoma), gastro esophageal junction, colorectal cancers and corresponding normal tissues freshly resected from a cohort of 135 patients, by Western Blotting and Immunofluorescence Staining. The protein is present in its phosphorylated form in cells and tissues. Depending on the extent of phosphorylation it is either present in hyper-phosphorylated (M. Wt. 72 kDa) form or in hypo-phosphorylated form (M. Wt. 68 kDa and 65 kDa). A thorough analysis revealed that expression of E3B1/ABI-1 protein is significantly decreased in esophageal, gastro-esophageal junction and colorectal carcinomas irrespective of age, gender, dietary and smoking habits of the patients. The decrease in expression of E3B1/ABI-1 was consistently observed for all the three isoforms. However, the decrease in the expression of isoforms varied with different forms of cancers. Down-regulation of E3B1/ABI-1 expression in human carcinomas may play a critical role in tumor progression and in determining disease prognosis. PMID- 22430195 TI - An aryloxypropanolamine hbeta3-adrenoceptor agonist as bladder smooth muscle relaxant. AB - The relaxant effect of an aryloxypropanolamine beta3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy 3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2 (hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as hbeta3-AR agonists have been evaluated and discussed thoroughly. A ranking of hbeta3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such. PMID- 22430196 TI - "ON-OFF" switching of europium complex luminescence coupled with a ligand redox process. AB - A triarylamine-functionalized terpyridine ligand formed a highly coordinated complex with europium tris(beta-diketonate), which displayed reversible ''ON OFF'' luminescence switching coupled with a ligand redox process of triarylamine/triarylaminium cations. PMID- 22430197 TI - Fifteen non-CODIS autosomal short tandem repeat loci multiplex data from nine population groups living in Taiwan. AB - The analysis of autosomal short tandem repeat (STR) loci is a powerful tool in forensic genetics. We developed a multiplex system in which 15 non-Combined DNA Index System autosomal STRs (D3S1744, D4S2366, D8S1110, D10S2325, D12S1090, D13S765, D14S608, Penta E, D17S1294, D18S536, D18S1270, D20S470, D21S1437, Penta D, and D22S683) could be amplified in one single polymerase chain reaction. DNA samples from 1,098 unrelated subjects of nine population groups living in Taiwan, including Taiwanese Han, indigenous Taiwanese of Taiwan Island, Tao, mainland Chinese, Filipinos, Thais, Vietnamese, Indonesians, and Caucasians, were collected and analyzed using this system. The distributions of the allelic frequencies and the forensic parameters of each population group were presented. The combined discrimination power and the combined power of exclusion were high in all population groups tested in this study. A multidimensional scaling plot of these nine population groups based on the Reynolds' genetic distances calculated from 15 autosomal STRs was constructed, and the genetic substructure in this area was presented. In conclusion, this 15 autosomal STR multiplex system provides highly informative STR data and appears useful in forensic casework and parentage testing in different populations. PMID- 22430199 TI - Does long-term treatment with Doxil(r) predispose patients to oral cancer? AB - We present a possible adverse reaction related to long-term use of Doxil((r)) in female patients. We believe that long-term use of Doxil((r)) may predispose female patients to oral squamous cell carcinoma. The patients in this report were not exposed to the common risk factors related to oral cancer formation such as smoking or alcohol consumption. Both patients were 59-year-old females. The first patient was diagnosed in 2001 with stage IIIC ovarian cancer. Seven years following treatment with Doxil((r)), she was diagnosed with stage III squamous cell carcinoma of the right maxilla. The second patient was diagnosed with Kaposi's sarcoma with evidence of spread to the lungs. Four years following treatment with Doxil((r)) she was diagnosed with stage I squamous cell carcinoma of the left maxilla. A literature review did not reveal any report on Doxil((r)) and predisposition to oral cancer; however, we found an abstract that was presented at the last annual meeting of the American Society of Clinical Oncology (ASCO) by Cannon et al. When we combine the data from Cannon et al. and the data presented here, a total of six female patients developed an epithelial carcinoma of the oral cavity following long-term treatment with Doxil((r)). We believe that a large-scale study should be initiated on patients that were treated with Doxil((r)) for more than 3 years, since these patients might be at risk for developing secondary cancer of the oral cavity. PMID- 22430200 TI - A non-canonical UBA-UBL interaction forms the linear-ubiquitin-chain assembly complex. AB - HOIL-1L and its binding partner HOIP are essential components of the E3-ligase complex that generates linear ubiquitin (Ub) chains, which are critical regulators of NF-kappaB activation. Using crystallographic and mutational approaches, we characterize the unexpected structural basis for the specific interaction between the Ub-like domain (UBL) of HOIL-1L and the Ub-associated domain (UBA) of HOIP. Our data indicate the functional significance of this non canonical mode of UBA-UBL interaction in E3 complex formation and subsequent NF kappaB activation. This study highlights the versatility and specificity of protein-protein interactions involving Ub/UBLs and their cognate proteins. PMID- 22430201 TI - Antipsychotic drugs predominate in pharmacotherapy of nursing home residents with dementia. AB - INTRODUCTION: The aim of this study was to investigate the frequency of benzodiazepines, antidementia and antipsychotic drug prescriptions in nursing home residents (NHR).Data of a German health insurance company were retrospectively analyzed for the year 2008. METHODS: The study cohort comprised 13,042 NHR (82% women, mean age 83.6 +/- 7 years). Following analgetics, antipsychotic drugs were the second most frequently prescribed drug group with 13.3% of all prescriptions. Dementia was diagnosed in 8 017 (61.5%) NHR. Thereof 51.6% received an antipsychotic, 17.3% a benzodiazepine and 15.2% an antidementia pharmaceutical, respectively. 18.1% of NHR with dementia and antipsychotic drug prescriptions were in combined treatment with antidementia pharmaceuticals. The rate of antipsychotic drug prescribing was significantly doubled in NHR with dementia compared to those without this diagnosis (p<0.01); the most frequently prescribed antipsychotics were melperone, risperidone and pipamperone. DISCUSSION: This study demonstrates the wide-spread use of psychotropic drugs in NHR. Moreover, dementia in NHR was associated with antipsychotic drug prescribing in every second patient. This highlights the need for further studies analyzing alternative treatments for dementia-related symptoms. PMID- 22430202 TI - Toxicology and "one health": opportunities for multidisciplinary collaborations. PMID- 22430203 TI - Controllable synthesis and tunable luminescence properties of Y2(WO4)3:Ln3+ (Ln = Eu, Yb/Er, Yb/Tm and Yb/Ho) 3D hierarchical architectures. AB - Yttrium tungstate precursors with novel 3D hierarchical architectures assembled from nanosheet building blocks were successfully synthesized by a hydrothermal method with the assistance of sodium dodecyl benzenesulfonate (SDBS). After calcination, the precursors were easily converted to Y(2)(WO(4))(3) without an obvious change in morphology. The as-prepared precursors and Y(2)(WO(4))(3) were characterized by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and high-resolution transmission electron microscopy (HRTEM), and photoluminescence (PL) spectra, respectively. The results reveal that the morphology and dimensions of the as-prepared precursors can be effectively tuned by altering the amounts of organic SDBS and the reaction time, and the possible formation mechanism was also proposed. Upon ultraviolet (UV) excitation, the emission of Y(2)(WO(4))(3):x mol% Eu(3+) microcrystals can be tuned from white to red, and the doping concentration of Eu(3+) has been optimized. Furthermore, the up-conversion (UC) luminescence properties as well as the emission mechanisms of Y(2)(WO(4))(3):Yb(3+)/Ln(3+) (Ln = Er, Tm, Ho) microcrystals were systematically investigated, which show green (Er(3+), (4)S(3/2), (2)H(11/2)->(4)I(15/2)), blue (Tm(3+), (1)G(4)->(3)H(6)) and yellow (Ho(3+), (5)S(2)->(5)I(8)) luminescence under 980 nm NIR excitation. Moreover, the doping concentration of the Yb(3+) has been optimized under a fixed concentration of Er(3+) for the UC emission of Y(2)(WO(4))(3):Yb(3+)/Er(3+). PMID- 22430204 TI - Crosstalk between the DNA damage response pathway and microRNAs. AB - MicroRNAs (miRNAs) are a family of small, non-coding RNAs that control gene expression at the post-transcriptional level by destabilizing and inhibiting translation of their target messenger RNAs. MiRNAs are involved in the regulation of a number of fundamental biological processes, and their dysregulation is thought to contribute to several disease processes. Emerging evidence suggests that miRNAs also play a critical role in protecting the heritable genome by contributing to the regulation of the DNA damage response. Consequently, much recent investigative effort has been directed towards an improved understanding of how miRNAs are regulated in response to DNA damage. In this review, we discuss the most recent findings regarding the regulation of miRNA expression and the functional roles of miRNAs in the DNA damage response. PMID- 22430205 TI - The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis. AB - Rac1b, an alternative splice form of Rac1, has been previously shown to be upregulated in colon and breast cancer cells, suggesting an oncogenic role for Rac1b in these cancers. Our analysis of NSCLC tumor and matched normal tissue samples indicates Rac1b is upregulated in a significant fraction of lung tumors in correlation with mutational status of K-ras. To directly assess the oncogenic potential of Rac1b in vivo, we employed a mouse model of lung adenocarcinoma, in which the expression of Rac1b can be conditionally activated specifically in the lung. Although expression of Rac1b alone is insufficient to drive tumor initiation, the expression of Rac1b synergizes with an oncogenic allele of K-ras resulting in increased cellular proliferation and accelerated tumor growth. Finally, we show that in contrast to our previous findings demonstrating a requirement for Rac1 in K-ras-driven cell proliferation, Rac1b is not required in this context. Given the partially overlapping spectrum of downstream effectors regulated by Rac1 and Rac1b, our findings further delineate the signaling pathways downstream of Rac1 that are required for K-ras driven tumorigenesis. PMID- 22430206 TI - Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor. AB - The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR antibody that has been approved for use in oncology. Previously we investigated mechanisms of resistance to cetuximab using a model derived from the non-small cell lung cancer line NCI H226. We demonstrated that cetuximab-resistant clones (Ctx(R)) had increased nuclear localization of the EGFR. This process was mediated by Src family kinases (SFKs), and nuclear EGFR had a role in resistance to cetuximab. To better understand SFK-mediated nuclear translocation of EGFR, we investigated which SFK member(s) controlled this process as well as the EGFR tyrosine residues that are involved. Analyses of mRNA and protein expression indicated upregulation of the SFK members Yes (v-Yes-1 yamaguchi sarcoma viral oncogene) and Lyn (v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog) in all Ctx(R) clones. Further, immunoprecipitation analysis revealed that EGFR interacts with Yes and Lyn in Ctx(R) clones, but not in cetuximab-sensitive (Ctx(S)) parental cells. Using RNAi interference, we found that knockdown of either Yes or Lyn led to loss of EGFR translocation to the nucleus. Conversely, overexpression of Yes or Lyn in low nuclear EGFR-expressing Ctx(S) parental cells led to increased nuclear EGFR. Chromatin immunoprecipitation (ChIP) assays confirmed nuclear EGFR complexes associated with the promoter of the known EGFR target genes B-Myb and iNOS. Further, all Ctx(R) clones exhibited upregulation of B-Myb and iNOS at the mRNA and protein levels. siRNAs directed at Yes or Lyn led to decreased binding of EGFR complexes to the B-Myb and iNOS promoters based on ChIP analyses. SFKs have been shown to phosphorylate EGFR on tyrosines 845 and 1101 (Y845 and Y1101), and mutation of Y1101, but not Y845, impaired nuclear entry of the EGFR. Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101, which influences EGFR nuclear translocation in this model of cetuximab resistance. PMID- 22430207 TI - Minor cell-death defects but reduced tumor latency in mice lacking the BH3-only proteins Bad and Bmf. AB - Proapoptotic Bcl-2 family members of the Bcl-2 homology (BH)3-only subgroup are critical for the establishment and maintenance of tissue homeostasis and can mediate apoptotic cell death in response to developmental cues or exogenously induced forms of cell stress. On the basis of the biochemical experiments as well as genetic studies in mice, the BH3-only proteins Bad and Bmf have been implicated in different proapoptotic events such as those triggered by glucose- or trophic factor-deprivation, glucocorticoids, or histone deacetylase inhibition, as well as suppression of B-cell lymphomagenesis upon aberrant expression of c-Myc. To address possible redundancies in cell death regulation and tumor suppression, we generated compound mutant mice lacking both genes. Our studies revealed lack of redundancy in most paradigms of lymphocyte apoptosis tested in tissue culture. Only spontaneous cell death of thymocytes kept in low glucose or that of pre-B cells deprived of cytokines was significantly delayed when both genes were lacking. Of note, despite these minor apoptosis defects we observed compromised lymphocyte homeostasis in vivo that affected mainly the B cell lineage. Long-term follow-up revealed significantly reduced latency to spontaneous tumor formation in aged mice when both genes were lacking. Together our study suggests that Bad and Bmf co-regulate lymphocyte homeostasis and limit spontaneous transformation by mechanisms that may not exclusively be linked to the induction of lymphocyte apoptosis. PMID- 22430208 TI - Phosphorylation of Mps1 by BRAFV600E prevents Mps1 degradation and contributes to chromosome instability in melanoma. AB - Activating BRAF mutations that deregulate the mitogen-activated protein kinase (MAPK) pathway commonly occur in cancer. BRAF(V600E) induces centrosome amplification and spindle abnormalities that result in aneuploidy. We find modification of Mps1 is critical for contributing to centrosome amplification and chromosome instability induced by BRAF(V600E). Phosphorylation of Mps1 at residue S281 induced by BRAF(V600E) stabilizes Mps1 protein by preventing its ubiquitination by APC/C and subsequent degradation, allowing the non-degraded protein to accumulate at centrosomes. Cells in which endogenous Mps1 was replaced with a phospho-mimetic Mps1 mutant are viable but amplify centrosomes and missegregate chromosomes frequently. Importantly, analysis of tumor micro arrays revealed that phospho-MAPK and S281-phosphorylated Mps1 were highly correlated in human melanoma tissues, implying that MAPK contributes to defects in the degradation of Mps1 in situ. We propose that continuously activated BRAF(V600E) signaling may be a possible mechanism for the deregulation of Mps1 stability and kinase activity in human tumors, and that persistent phosphorylation of Mps1 through BRAF(V600E) signaling is a key event in disrupting the control of centrosome duplication and chromosome stability that may contribute to tumorigenesis. Our findings raise the possibility that targeting the oncogenic BRAF and S281-phosphorylated Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment. PMID- 22430209 TI - PIK3CA mutation spectrum in urothelial carcinoma reflects cell context-dependent signaling and phenotypic outputs. AB - Although activating mutations of PIK3CA are frequent in urothelial carcinoma (UC), no information is available on their specific effects in urothelial cells or the basis for the observed mutation spectrum, which has a large excess of helical domain mutations. We investigated the phenotypic and signaling consequences of hotspot and UC-specific rare PIK3CA mutations in immortalized normal human urothelial cells (NHUC) and mouse fibroblasts (NIH3T3). Our results indicate that in NHUC, rare mutant forms and all three hotspot mutant forms of PIK3CA can activate the PI3K/AKT pathway. The relative frequency at which helical domain and kinase domain mutations are found in UC is related to their potency in inducing signaling downstream of AKT and to the phenotypic effects induced in this cell type (E545K>E542K>H1047R). Helical domain mutations E542K and E545K conferred a significant proliferative advantage at confluence and under conditions of nutrient depletion, and increased cellular resistance to anoikis. Both helical and kinase domain mutants induced increased NHUC cell motility and migration towards a chemoattractant, though no significant differences were found between the mutant forms. In NIH3T3 cells, the kinase domain mutant H1047R induced high levels of AKT activation, but helical domain mutants were significantly less potent and this was reflected in their relative abilities to confer anchorage-independent growth. Our findings indicate that the effects of mutant PIK3CA are both cell type- and mutation-specific. Helical domain mutations in PIK3CA may confer a selective advantage in the urothelium in vivo by overcoming normal contact-mediated inhibitory signals and allowing proliferation in nutrient-limiting conditions. Mutant forms of PIK3CA may also stimulate intraepithelial cell movement, which could contribute to spread of cells within the urothelium. PMID- 22430210 TI - Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells. AB - Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction. PMID- 22430211 TI - Endometrial carcinoma: molecular alterations involved in tumor development and progression. AB - In the western world, endometrial carcinoma (EC) is the most common cancer of the female genital tract. The annual incidence has been estimated at 10-20 per 100,000 women. Two clinicopathological variants are recognized: the estrogen related (type I, endometrioid) and the non-estrogen related (type II, non endometrioid).The clinicopathological differences are paralleled by specific genetic alterations, with type I showing microsatellite instability and mutations in phosphatase and tensin homologue deleted on chromosome 10, PIK3CA, K-RAS and CTNNB1 (beta-catenin), and type II exhibiting TP53 mutations and chromosomal instability. Some non-endometrioid carcinomas probably arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological and molecular levels. In EC, apoptosis resistance may have a role in tumor progression. Understanding pathogenesis at the molecular level is essential in identifying biomarkers for successful targeted therapies. In this review, the genetic changes of endometrial carcinogenesis are discussed in the light of the morphological features of the tumors and their precursors. PMID- 22430212 TI - The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. AB - Anti-mitotic agents such as paclitaxel and docetaxel are widely used for the treatment of breast, ovarian and lung cancers. Although paclitaxel induces apoptosis, this drug also modulates autophagy. How autophagy affects paclitaxel activity, is unclear. We discovered that paclitaxel inhibited autophagy through two distinct mechanisms dependent on cell cycle stage. In mitotic cells, paclitaxel blocked activation of the class III phosphatidyl inositol 3 kinase, Vps34, a critical initiator of autophagosome formation. In non-mitotic paclitaxel treated cells, autophagosomes were generated but their movement and maturation was inhibited. Chemically or genetically blocking autophagosome formation diminished paclitaxel-induced cell death suggesting that autophagosome accumulation sensitized cells to paclitaxel toxicity. In line with these observations, we identified that primary breast tumors that expressed diminished levels of autophagy-initiating genes were resistant to taxane therapy, identifying possible mechanisms and prognostic markers of clinical chemotherapeutic resistance. PMID- 22430213 TI - N-(phosphonacetyl)-L-aspartate induces TAp73-dependent apoptosis by modulating multiple Bcl-2 proteins: potential for cancer therapy. AB - p53 is essential for the cellular responses to DNA damage that help to maintain genomic stability. However, the great majority of human cancers undergo disruption of the p53-network. Identification and characterization of molecular components important in both p53-dependent and -independent apoptosis might be useful in developing novel therapies for cancers. In the complete absence of p53, cells treated with N-(phosphonacetyl)-L-aspartate (PALA) continue to synthesize DNA slowly and eventually progress through S-phase, suffering severe DNA damage that in turn triggers apoptosis, whereas cells with functional p53 undergo growth arrest. In this study, we investigated apoptotic signaling in response to PALA and the role of p53 expression in this pathway. We found that treatment of cells lacking p53 with PALA induced TAp73, Noxa and Bim and inactivation of these proteins with dominant-negative plasmids or small interfering RNAs significantly inhibited apoptosis, suggesting that PALA-induced apoptosis was mediated via TAp73-dependent expression of Noxa and Bim. However, PALA treatment inhibited the expression of DeltaNp73 only in cells lacking p53 but not in cells expressing p53. In addition, PALA treatment inhibited Bcl-2, and overexpression of Bcl-2 significantly inhibited PALA-induced apoptosis. Moreover, expression of p53 in these cells protected them from PALA-induced apoptosis by activating p21, sustaining the expression of DeltaNp73 and inhibiting the induction of Noxa and Bim. Taken together, our study identifies novel but opposing roles for the p53 and TAp73 in the induction of Noxa and Bim and regulation of apoptosis. Our data will help to develop strategies to eliminate cancer cells lacking p53 while protecting normal cells with wild-type p53. PMID- 22430214 TI - Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs. AB - Little is known about metastatic pathways that are specific to the lung rather than other organs. We previously showed that antioxidant proteins such as peroxiredoxins were specifically upregulated in lung metastatic breast cancer cells. We hypothesize that cancer cells that live under aerobic conditions, as might be the case in lungs, protect themselves against the damage caused by reactive oxygen species (ROS). To examine this hypothesis, we studied the role of peroxiredoxin-2 (PRDX2) in lung vs bone metastasis formation. A metastatic variant of MDA-MB-435 breast cancer cells that specifically metastasize to lungs (435-L3) was transduced with short hairpin RNAs to specifically silence PRDX2. Conversely, a bone metastatic variant of MDA-MB-231 cells (BO2) was stably transfected to overexpress PRDX2. The 435-L3 cells silenced for PRDX2 were significantly more sensitive to H(2)O(2)-induced oxidative stress than the parental and scrambled transfected cells. BO2/PRDX2 cells produced less ROS than BO2/green fluorescent protein control cells under oxidative stress. Moreover, PRDX2 knockdown inhibited the growth of 435-L3 cells in the lungs, whereas lymph node metastasis remained unaffected. In contrast, PRDX2 overexpression in bone metastatic BO2 breast cancer cells led to drastic inhibition of the skeletal tumor burden and reduction of bone destruction. Furthermore, PRDX2 expression in breast cancer cells was associated with a glucose-dependent phenotype, different from bone metastatic cells. Overall, our results strongly suggest that PRDX2 is a targetable 'metabolic adaptor' driver protein implicated in the selective growth of metastatic cells in the lungs by protecting them against oxidative stress. PMID- 22430215 TI - Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition. AB - Gain-of-function mutations in KRAS and BRAF genes are found in up to 50% of colorectal cancers. These mutations result in the activation of the BRAF/MEK signaling pathway culminating in the stimulation of ERK1/2 mitogen-activated protein kinases. Upon activation, ERK1/2 translocate from the cytoplasm to the nucleus. This process has been shown to be required for the induction of many cellular responses, although the molecular mechanisms regulating ERK nuclear function, especially under oncogenic stimulation, remain to be explored. Herein, we examined the spatiotemporal regulation of ERK1/2 activity upon oncogenic activation of KRAS(G12V) and BRAF(V600E) in normal intestinal epithelial crypt cells (IECs). Results demonstrate that expression of these oncogenes markedly stimulated ERK1/2 activities and morphologically transformed IECs. Importantly however, ERK phosphorylation was not observed in the nucleus, but restricted to the cytoplasm of KRAS(G12V)- and BRAF(V600E)-transformed IECs. The absence of nuclear ERK phosphorylation was due to a vanadate-sensitive phosphatase activity. Nuclear ERK dephosphorylation was found to be tightly correlated with the rapid expression of DUSP4 phosphatase induced in an MEK-dependent manner. In addition, MEK-dependent phosphorylation of T361, T363, S390 and S395 residues highly stabilized DUSP4 protein. Finally, in human colorectal cancer cells, ERK1/2 activities were also confined to the cytoplasm and treatment with pervanadate reactivated ERK1/2 in the nucleus. Accordingly, DUSP4 mRNAs were found to be highly expressed, in an MEK-dependent manner, in all colorectal cancer cells analyzed. These findings indicate that DUSP4 functions as part of a negative feedback mechanism in the control of the duration and magnitude of nuclear ERK activation during intestinal tumorigenesis. PMID- 22430216 TI - Insulin-like growth factor-I regulates GPER expression and function in cancer cells. AB - Functional cross talk between insulin-like growth factor-I (IGF-I) system and estrogen signaling has been largely reported, although the underlying molecular mechanisms remain to be fully elucidated. As GPR30/GPER mediates rapid cell responses to estrogens, we evaluated the potential of IGF-I to regulate GPER expression and function in estrogen receptor (ER)alpha-positive breast (MCF-7) and endometrial (Ishikawa) cancer cells. We found that IGF-I transactivates the GPER promoter sequence and upregulates GPER mRNA and protein levels in both cells types. Similar data were found, at least in part, in carcinoma-associated fibroblasts. The upregulation of GPER expression by IGF-I involved the IGF IR/PKCdelta/ERK/c-fos/AP1 transduction pathway and required ERalpha, as ascertained by specific pharmacological inhibitors and gene-silencing. In both MCF-7 and Ishikawa cancer cells, the IGF-I-dependent cell migration required GPER and its main target gene CTGF, whereas the IGF-I-induced proliferation required both GPER and cyclin D1. Our data demonstrate that the IGF-I system regulates GPER expression and function, triggering the activation of a signaling network that leads to the migration and proliferation of cancer cells. PMID- 22430217 TI - In vivo photoprotective and anti-inflammatory effect of hyperforin is associated with high antioxidant activity in vitro and ex vivo. AB - Hyperforin, a major constituent of St. John's Wort (Hypericum perforatum, HP), provides anti-inflammatory, anti-tumor, and anti-bacterial properties. Previous studies have shown anti-oxidative properties of St. John's Wort extracts; however, its free radical scavenging activity in skin cells or skin has not been assessed in detail so far. Therefore, the free radical scavenging activity of hyperforin was tested in the H(2)DCFDA-assay in vitro in HaCaT keratinocytes irradiated with solar simulated radiation. Hyperforin (EC(50) 0.7 MUM corresponding to 0.42 MUg/ml) was much more effective compared to Trolox (EC(50) 12 MUg/ml) and N-acetylcysteine (EC(50) 847 MUg/ml) without showing phototoxicity. The radical protection factor of a cream containing 1.5%w/w of a hyperforin-rich HP extract was determined to be 200 * 10(14) radicals/mg, indicating a high radical scavenging activity. The cream was further applied ex vivo on porcine ear skin and significantly reduced radical formation after infrared irradiation. Finally, the UV-protective effect of the HP cream was tested on 20 volunteers in a randomized, double-blind, vehicle-controlled study. HP cream significantly reduced UVB-induced erythema as opposed to the vehicle. Occlusive application of HP cream on non-irradiated test sites did not cause any skin irritation. Taken together, these results demonstrate that hyperforin is a powerful free radical scavenger. PMID- 22430218 TI - Petri net applications in molecular biology. Preface. PMID- 22430219 TI - Cell Illustrator 4.0: a computational platform for systems biology. AB - Cell Illustrator is a software platform for Systems Biology that uses the concept of Petri net for modeling and simulating biopathways. It is intended for biological scientists working at bench. The latest version of Cell Illustrator 4.0 uses Java Web Start technology and is enhanced with new capabilities, including: automatic graph grid layout algorithms using ontology information; tools using Cell System Markup Language (CSML) 3.0 and Cell System Ontology 3.0; parameter search module; high-performance simulation module; CSML database management system; conversion from CSML model to programming languages (FORTRAN, C, C++, Java, Python and Perl); import from SBML, CellML, and BioPAX; and, export to SVG and HTML. Cell Illustrator employs an extension of hybrid Petri net in an object-oriented style so that biopathway models can include objects such as DNA sequence, molecular density, 3D localization information, transcription with frame-shift, translation with codon table, as well as biochemical reactions. PMID- 22430220 TI - Modeling of cell-to-cell communication processes with Petri nets using the example of quorum sensing. AB - The understanding of the molecular mechanism of cell-to-cell communication is fundamental for system biology. Up to now, the main objectives of bioinformatics have been reconstruction, modeling and analysis of metabolic, regulatory and signaling processes, based on data generated from high-throughput technologies. Cell-to-cell communication or quorum sensing (QS), the use of small molecule signals to coordinate complex patterns of behavior in bacteria, has been the focus of many reports over the past decade. Based on the quorum sensing process of the organism Aliivibrio salmonicida, we aim at developing a functional Petri net, which will allow modeling and simulating cell-to-cell communication processes. Using a new editor-controlled information system called VANESA (http://vanesa.sf.net), we present how to combine different fields of studies such as life-science, database consulting, modeling, visualization and simulation for a semi-automatic reconstruction of the complex signaling quorum sensing network. We show how cell-to-cell communication processes and information-flow within a cell and across cell colonies can be modeled using VANESA and how those models can be simulated with Petri net network structures in a sophisticated way. PMID- 22430221 TI - On determining firing delay time of transitions for Petri net based signaling pathways by introducing stochastic decision rules. AB - Parameter determination is important in modeling and simulating biological pathways including signaling pathways. Parameters are determined according to biological facts obtained from biological experiments and scientific publications. However, such reliable data describing detailed reactions are not reported in most cases. This prompted us to develop a general methodology of determining the parameters of a model in the case of that no information of the underlying biological facts is provided. In this study, we use the Petri net approach for modeling signaling pathways, and propose a method to determine firing delay times of transitions for Petri net models of signaling pathways by introducing stochastic decision rules. Petri net technology provides a powerful approach to modeling and simulating various concurrent systems, and recently have been widely accepted as a description method for biological pathways. Our method enables to determine the range of firing delay time which realizes smooth token flows in the Petri net model of a signaling pathway. The availability of this method has been confirmed by the results of an application to the interleukin-1 induced signaling pathway. PMID- 22430222 TI - Impact of delays and noise on dopamine signal transduction. AB - Dopamine is a critical neurotransmitter for the normal functioning of the central nervous system. Abnormal dopamine signal transmission in the brain has been implicated in diseases such as Parkinson's disease (PD) and schizophrenia, as well as in various types of drug addition. It is therefore important to understand the dopamine signaling dynamics in the presynaptic neuron of the striatum and the synaptic cleft, where dopamine synthesis, degradation, compartmentalization, release, reuptake, and numerous regulatory processes occur. The biochemical and biological processes governing this dynamics consist of interacting discrete and continuous components, operate at different time scales, and must function effectively in spite of intrinsic stochasticity and external perturbations. Not fitting into the realm of purely deterministic phenomena, the hybrid nature of the system requires special means of mathematical modeling, simulation and analysis. We show here how hybrid functional Petri-nets (HFPNs) and the software Cell Illustrator(r) facilitate computational analyses of systems that simultaneously contain deterministic, stochastic, and delay components. We evaluate the robustness of dopamine signaling in the presence of delays and noise and discuss implications for normal and abnormal states of the system. PMID- 22430223 TI - Role of mRNA gestation and senescence in noise reduction during the cell cycle. AB - Recent innovations in experimental techniques on single molecule detection resulted in advances in the quantification of molecular noise in several systems, and provide suitable data for defining stochastic computational models of biological processes. Some of the latest stochastic models of cell cycle regulation analyzed the effect of noise on cell cycle variability. In their study, Kar et al. (Proc. Natl. Acad. Sci. USA 106, 6471-6476, 2009) found that the observed variances of cell cycle time and cell division size distributions cannot be matched with the measured long half-lives of mRNAs. Here, we investigate through modeling and simulation how the noise created by the transcription and degradation processes of a key cell cycle controller mRNA affect the statistics of cell cycle time and cell size at division. Our model consists of an encoding of the model of Kar et al. into a stochastic Petri net, with the extensions necessary to represent multiple synthesis (gestation) and degradation (senescence) steps in the regulation of mRNAs. We found that few steps of gestation and senescence of mRNA are enough to give a good match for both the measured half-lives and variability of cell cycle-statistics. This result suggests that the complex process of transcription can be more accurately approximated by multi-step linear processes. PMID- 22430224 TI - Exhaustive analysis of the modular structure of the spliceosomal assembly network: a Petri net approach. AB - Spliceosomes are macro-complexes involving hundreds of proteins with many functional interactions. Spliceosome assembly belongs to the key processes that enable splicing of mRNA and modulate alternative splicing. A detailed list of factors involved in spliceosomal reactions has been assorted over the past decade, but, their functional interplay is often unknown and most of the present biological models cover only parts of the complete assembly process. It is a challenging task to build a computational model that integrates dispersed knowledge and combines a multitude of reaction schemes proposed earlier.Because for most reactions involved in spliceosome assembly kinetic parameters are not available, we propose a discrete modeling using Petri nets, through which we are enabled to get insights into the system's behavior via computation of structural and dynamic properties. In this paper, we compile and examine reactions from experimental reports that contribute to a functional spliceosome. All these reactions form a network, which describes the inventory and conditions necessary to perform the splicing process. The analysis is mainly based on system invariants. Transition invariants (T-invariants) can be interpreted as signaling routes through the network. Due to the huge number of T-invariants that arise with increasing network size and complexity, maximal common transition sets (MCTS) and T-clusters were used for further analysis. Additionally, we introduce a false color map representation, which allows a quick survey of network modules and the visual detection of single reactions or reaction sequences, which participate in more than one signaling route. We designed a structured model of spliceosome assembly, which combines the demands on a platform that i) can display involved factors and concurrent processes, ii) offers the possibility to run computational methods for knowledge extraction, and iii) is successively extendable as new insights into spliceosome function are reported by experimental reports. The network consists of 161 transitions (reactions) and 140 places (reactants). All reactions are part of at least one of the 71 T-invariants. These T-invariants define pathways, which are in good agreement with the current knowledge and known hypotheses on reaction sequences during spliceosome assembly, hence contributing to a functional spliceosome. We demonstrate that present knowledge, in particular of the initial part of the assembly process, describes parallelism and interaction of signaling routes, which indicate functional redundancy and reflect the dependency of spliceosome assembly initiation on different cellular conditions. The complexity of the network is further increased by two switches, which introduce alternative routes during A-complex formation in early spliceosome assembly and upon transition from the B-complex to the C complex. By compiling known reactions into a complete network, the combinatorial nature of invariant computation leads to pathways that have previously not been described as connected routes, although their constituents were known. T-clusters divide the network into modules, which we interpret as building blocks in spliceosome maturation. We conclude that Petri net representations of large biological networks and system invariants, are well-suited as a means for validating the integration of experimental knowledge into a consistent model. Based on this network model, the design of further experiments is facilitated. PMID- 22430225 TI - Modelling the molecular interactions in the flower developmental network of Arabidopsis thaliana. AB - We present a dynamical model of the gene network controlling flower development in Arabidopsis thaliana. The network is centered at the regulation of the floral organ identity genes (AP1, AP2, AP3, PI and AG) and ends with the transcription factor complexes responsible for differentiation of floral organs. We built and simulated the regulatory interactions that determine organ specificity using an extension of hybrid Petri nets as implemented in Cell Illustrator. The network topology is characterized by two main features: (1) the presence of multiple autoregulatory feedback loops requiring the formation of protein complexes, and (2) the role of spatial regulators determining floral patterning. The resulting network shows biologically coherent expression patterns for the involved genes, and simulated mutants produce experimentally validated changes in organ expression patterns. The requirement of heteromeric higher-order protein complex formation for positive autoregulatory feedback loops attenuates stochastic fluctuations in gene expression, enabling robust organ-specific gene expression patterns. If autoregulation is mediated by monomers or homodimers of proteins, small variations in initial protein levels can lead to biased production of homeotic proteins, ultimately resulting in homeosis. We also suggest regulatory feedback loops involving miRNA loci by which homeotic genes control the activity of their spatial regulators. PMID- 22430227 TI - Mechanisms underlying the developmental origins of disease. AB - It is well established that there is a relationship between patterns of early growth and subsequent risk of development of metabolic diseases such as type 2 diabetes and cardiovascular disease. Studies in both humans and in animal models have provided strong evidence that the early environment plays an important role in mediating these relationships. The concept of the developmental origins of health and disease is therefore widely accepted. The mechanisms by which an event in very early life can have a permanent effect on the long-term health of an individual are still relatively poorly understood. However a growing body of evidence has implicated a number of candidate mechanisms. These include permanent changes in an organ structure, programmed changes in gene expression through epigenetic modifications and persistent effects on regulation of cellular ageing. Understanding the extent and nature of these processes may enable the identification of individuals at risk of metabolic disease as well as providing insight into potential preventative and intervention strategies. PMID- 22430228 TI - Maternal micronutrient restriction programs the body adiposity, adipocyte function and lipid metabolism in offspring: a review. AB - Fetal growth is a complex process which depends both on the genetic makeup and intrauterine environment. Maternal nutrition during pregnancy is an important determinant of fetal growth. Adequate nutrient supply is required during pregnancy and lactation for the support of fetal/infant growth and development. Macro- and micronutrients are both important to sustain pregnancy and for appropriate growth of the fetus. While macronutrients provide energy and proteins for fetal growth, micronutrients play a major role in the metabolism of macronutrients, structural and cellular metabolism of the fetus. Discrepancies in maternal diet at different stages of foetal growth / offspring development can have pronounced influences on the health and well-being of the offspring. Indeed intrauterine growth restriction induced by nutrient insult can irreversibly modulate the endocrine/metabolic status of the fetus that leads to the development of adiposity and insulin resistance in its later life. Understanding the role of micronutrients during the development of fetus will provide insights into the probable underlying / associated mechanisms in the metabolic pathways of endocrine related complications. Keeping in view the modernized lifestyle and food habits that lead to the development of adiposity and world burden of obesity, this review focuses mainly on the role of maternal micronutrients in the foetal origins of adiposity. PMID- 22430229 TI - Managing Severe Community-Acquired Pneumonia Due to Community Methicillin Resistant Staphylococcus aureus (MRSA). AB - Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is a rare, but significant cause of community-acquired pneumonia (CAP). A number of virulence determinants have been implicated in the development of severe community MRSA pneumonia, characterized by multilobar cavitating necrosis in patients without usual risk-factors for pneumonia. Optimal management is uncertain, and is extrapolated from anecdotal experiences with small case series, randomized studies of hospital-acquired pneumonia, and laboratory investigations using in vitro experiments and animal models of MRSA pneumonia. Adequate clinical suspicion, early diagnosis and administration of appropriate antibiotics are necessary for best patient outcomes, although some patients will still do badly even with early anti-MRSA therapy. Vancomycin or linezolid have been recommended as first-line therapy, possibly in combination with other antibiotics. Newer antibiotics such as ceftaroline are still being evaluated. PMID- 22430230 TI - Elevated plasma platelet activating factor, platelet activating factor acetylhydrolase levels and risk of coronary heart disease or blood stasis syndrome of coronary heart disease in Chinese: a case control study: a case control study. AB - The purpose of the study was to explore the association between plasma platelet activating factor (PAF) and platelet activating factor acetylhydrolase (PAF-AH) levels and risk of coronary heart disease (CHD) or blood stasis syndrome (BSS) of CHD. Questionnaire, routine clinical assays and plasma levels of PAF, PAF-AH and inflammatory factors hs-CRP and IL-6 were investigated or measured for 120 controls and 150 CHD patients (66 non-BSS and 84 BSS). Plasma PAF levels were higher in CHD patients [49.7 (34.8-73.2 pg/mL)] than in controls [23.8 (14.9-42.3 pg/mL)] (P < 0.001), and in BSS [56.0 (40.1-86.1 pg/mL)] than in non-BSS [47.4 (29.0-67.4 pg/mL)] (P = 0.027). Similarly, plasma PAF-AH levels were higher in CHD patients [11.5 (7.5-15.6 MUmol/L)] than in controls [8.1 (5.4-12.6 MUmol/L)] (P < 0.001), and in BSS [13.4 (8.7-18.5 MUmol/L)] than in non-BSS [9.5 (7.3-14.3 MUmol/L)] (P = 0.014). After adjustment for the confounded effects of inflammatory factors or conventional risk factors, plasma PAF and PAF-AH levels still had a significant difference between CHD patients and controls, but plasma PAF-AH rather than PAF levels had a significant difference between BSS and non BSS. Elevated plasma PAF level contributed to the risk of CHD rather than BSS, and elevated plasma PAF-AH level was an independent risk factor of CHD and BSS. PMID- 22430231 TI - Plasma melatonin and urinary 6-hydroxymelatonin levels in patients with pulmonary tuberculosis. AB - Tuberculosis (TB) is the second most frequent cause of death in the world, after AIDS. Delay in diagnosing TB is an important worldwide problem. It seriously threatens public health. Cell-mediated immune responses play an important role in the pathogenesis of TB infection. The course of Mycobacterium tuberculosis (MTb) infection is regulated by two distinct T cell cytokine patterns. Melatonin is a biomolecule (mainly secreted by the pineal gland) with free radical scavenging, antioxidant and immunoregulatory properties. Melatonin has both its direct and indirect immunomodulatory effects on the immune system. In this study, we measured plasma melatonin and urine 6-hydroxy melatonin sulphate (6-HMS) concentrations in patients with newly diagnosed TB for the purpose of investigating whether there was a relationship between their levels and MTb infection. Thirty-one newly diagnosed patients presenting with active TB and 31 healthy subjects as the control group were included in this study. Blood and 24-h urine samples were collected from all individuals. Plasma melatonin levels and urine 6-HMS were measured. Our results show that in patients with TB, mean melatonin and 6-HMS concentrations were significantly lower than in the control subjects (p = 0.037, p < 0.001, respectively). We believe that the treatment of TB patients with melatonin might result in a wide range of health benefits including improved quality of life and reduced severity of infection in these patients. Supplementation with melatonin may be considered as an adjunctive therapy to classic treatment of pulmonary TB, especially during the acute phase of infection. PMID- 22430232 TI - Effects of chromium and nitrogen content on the microstructures and mechanical properties of as-cast Co-Cr-Mo alloys for dental applications. AB - The microstructure and mechanical properties of as-cast Co-(20-33)Cr-5Mo-N alloys were investigated to develop ductile Co-Cr-Mo alloys without Ni addition for dental applications that satisfy the requirements of the type 5 criteria in ISO 22674. The effects of the Cr and N contents on the microstructure and mechanical properties are discussed. The microstructures were evaluated using scanning electron microscopy with energy-dispersive X-ray spectroscopy (EDS), X-ray diffractometry (XRD), and electron back-scattered diffraction pattern analysis. The mechanical properties were evaluated using tensile testing. The proof strength and elongation of N-containing 33Cr satisfied the type 5 criteria in ISO 22674. epsilon-phase with striations was formed in the N-free (20-29)Cr alloys, while there was slight formation of epsilon-phase in the N-containing (20-29)Cr alloys, which disappeared in N-containing 33Cr. The lattice parameter of the gamma-phase increased with increasing Cr content (i.e. N content) in the N containing alloys, although the lattice parameter remained almost the same in the N-free alloys because of the small atomic radius difference between Co and Cr. Compositional analyses by EDS and XRD revealed that in the N-containing alloys Cr and Mo were concentrated in the cell boundary, which became enriched in N, stabilizing the gamma-phase. The mechanical properties of the N-free alloys were independent of the Cr content and showed low strength and limited elongation. Strain-induced martensite was formed in all the N-free alloys after tensile testing. On the other hand, the proof strength, ultimate tensile strength, and elongation of the N-containing alloys increased with increasing Cr content (i.e. N content). Since formation of epsilon-phase after tensile testing was confirmed in the N-containing alloys the deformation mechanism may change from strain induced martensite transformation to another form, such as twinning or dislocation slip, as the N content increases. Thus the N-containing 33Cr alloy with large elongation is promising for use in dentures with adjustable clasps through one piece casting. PMID- 22430233 TI - Controlled pauses at the initiation of sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitate neurological and cardiac recovery after 15 mins of untreated ventricular fibrillation. AB - OBJECTIVE: A multipronged approach to improve vital organ perfusion during cardiopulmonary resuscitation that includes sodium nitroprusside, active compression-decompression cardiopulmonary resuscitation, an impedance threshold device, and abdominal pressure (sodium nitroprusside-enhanced cardiopulmonary resuscitation) has been recently shown to increase coronary and cerebral perfusion pressures and higher rates of return of spontaneous circulation vs. standard cardiopulmonary resuscitation. To further reduce reperfusion injury during sodium nitroprusside-enhanced cardiopulmonary resuscitation, we investigated the addition of adenosine and four 20-sec controlled pauses spread throughout the first 3 mins of sodium nitroprusside-enhanced cardiopulmonary resuscitation. The primary study end point was 24-hr survival with favorable neurologic function after 15 mins of untreated ventricular fibrillation. DESIGN: Randomized, prospective, blinded animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Thirty-two female pigs (four groups of eight) 32+/-2 kg. INTERVENTIONS: After 15 mins of untreated ventricular fibrillation, isoflurane-anesthetized pigs received 5 mins of either standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine. After 4 mins of cardiopulmonary resuscitation, all animals received epinephrine (0.5 mg) and a defibrillation shock 1 min later. Sodium nitroprusside-enhanced cardiopulmonary resuscitation-treated animals received sodium nitroprusside (2 mg) after 1 min of cardiopulmonary resuscitation and 1 mg after 3 mins of cardiopulmonary resuscitation. After 1 min of sodium nitroprusside-enhanced cardiopulmonary resuscitation, adenosine (24 mg) was administered in two groups. MEASUREMENTS AND MAIN RESULTS: A veterinarian blinded to the treatment assigned a cerebral performance category score of 1-5 (normal, slightly disabled, severely disabled but conscious, vegetative state, or dead, respectively) 24 hrs after return of spontaneous circulation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside enhanced cardiopulmonary resuscitation+adenosine, and controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine resulted in a significantly higher 24-hr survival rate compared to standard cardiopulmonary resuscitation (7 of 8, 8 of 8, and 8 of 8 vs. 2 of 8, respectively p<.05). The mean cerebral performance category scores for standard cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation, sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine, or controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine were 4.6+/-0.7, 3+/-1.3, 2.5+/-0.9, and 1.5+/-0.9, respectively (p<.01 for controlled pauses-sodium nitroprusside-enhanced cardiopulmonary resuscitation+adenosine compared to all other groups). CONCLUSIONS: Reducing reperfusion injury and maximizing circulation during cardiopulmonary resuscitation significantly improved functional neurologic recovery after 15 mins of untreated ventricular fibrillation. These results suggest that brain resuscitation after prolonged cardiac arrest is possible with novel, noninvasive approaches focused on reversing the mechanisms of tissue injury. PMID- 22430234 TI - Statin therapy as prevention against development of acute respiratory distress syndrome: an observational study. AB - OBJECTIVES: The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") have anti-inflammatory properties and are associated with improved outcomes in critically ill patients. We investigated whether previous statin therapy affects outcomes in patients at risk for acute respiratory distress syndrome. DESIGN: Patients were followed-up for the primary outcome of acute respiratory distress syndrome and secondary outcomes of intensive care unit and 60-day mortality, organ dysfunction, and ventilator-free days in a secondary analysis of a prospective cohort study. Receipt of statin therapy was recorded. Propensity score matching was used to adjust for confounding by indication. SETTING: Intensive care units at a tertiary care academic medical center. PATIENTS: Critically ill patients (2,743) with acute respiratory distress syndrome risk factors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome developed in 738 (26%) patients; 413 patients (15%) received a statin within 24 hrs of intensive care unit admission. Those who had received a statin within 24 hrs had a lower rate of development of acute respiratory distress syndrome (odds ratio 0.56; 95% confidence interval 0.43 0.73; p<.0001). After multivariate adjustment for potential confounders, this association remained significant (odds ratio 0.69; 95% confidence interval 0.51 0.92; p=.01). However, after propensity score matching, the association was not statistically significant (odds ratio 0.79; 95% confidence interval 0.57-1.10; p=.16). Statin use was not associated with reduced acute respiratory distress syndrome mortality, organ dysfunction, or ventilator-free days. Results of the study were presented in accordance with STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. CONCLUSIONS: Statin therapy at the time of intensive care unit admission was not associated with a lower rate of development of acute respiratory distress syndrome after matching for patient propensity to receive statins. Statin therapy was not associated with improvements in acute respiratory distress syndrome mortality, organ failure, or days free from mechanical ventilation. PMID- 22430235 TI - Antibiotic strategies in severe nosocomial sepsis: why do we not de-escalate more often? AB - OBJECTIVES: To assess the use of antibiotic de-escalation in patients with hospital-acquired severe sepsis in an academic setting. DESIGN: We reviewed all episodes of severe sepsis treated over a 1-yr period in the department of intensive care. Antimicrobial therapy was considered as appropriate when the antimicrobial had in vitro activity against the causative microorganisms. According to the therapeutic strategy in the 5 days after the start of antimicrobial therapy, we classified patients into four groups: de-escalation (interruption of an antimicrobial agent or change of antibiotic to one with a narrower spectrum); no change in antibiotherapy; escalation (addition of a new antimicrobial agent or change in antibiotic to one with a broader spectrum); and mixed changes. SETTING: A 35-bed medico-surgical intensive care department in which antibiotic strategies are reviewed by infectious disease specialists three times per week. PATIENTS: One hundred sixty-nine patients with 216 episodes of severe sepsis attributable to a hospital-acquired infection who required broad spectrum beta-lactam antibiotics alone or in association with other anti infectious agents. MEASUREMENTS AND MAIN RESULTS: The major sources of infection were the lungs (44%) and abdomen (38%). Microbiological data were available in 167 of the 216 episodes (77%). Initial antimicrobial therapy was inappropriate in 27 episodes (16% of culture-positive episodes). De-escalation was applied in 93 episodes (43%), escalation was applied in 22 episodes (10%), mixed changes were applied in 24 (11%) episodes, and there was no change in empirical antibiotic therapy in 77 (36%) episodes. In these 77 episodes, the reasons given for maintaining the initial antimicrobial therapy included the sensitivity pattern of the causative organisms and previous antibiotic therapy. The number of episodes when the chance to de-escalate may have been missed was small (4 episodes [5%]). CONCLUSION: Even in a highly focused environment with close collaboration among intensivists and infectious disease specialists, de-escalation may actually be possible in <50% of cases. PMID- 22430236 TI - Angiopoietin-2 in acute liver failure. AB - OBJECTIVE: Angiopoietin-2, an antagonistic ligand of the endothelial Tie2 receptor, has been identified as a gatekeeper of endothelial activation. We examined whether the release of Angiopoietin-2 correlates with surrogates of organ dysfunction and outcome in patients with acute liver failure. DESIGN: Retrospective clinical and immunohistological study. SETTING: Intensive care unit of a university hospital. PATIENTS: Thirty-seven patients with acute liver failure and 20 healthy control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Angiopoietin-2 levels were measured in sera from 37 patients with acute liver failure on admission and from 20 healthy control subjects. Median age of patients with acute liver failure was 34 yrs, 29 were female, and 21 developed encephalopathy grade 3 or greater. Nine patients survived to day 28 without transplantation, five died without transplantation, and 23 received a transplant. Median (interquartile range) Angiopoietin-2 serum concentrations steadily increased across the following groups: healthy control subjects (1.4 [0.9-1.7] ng/mL), patients with transplant-free recovery (10.0 [4.7-12.1] ng/mL), and patients who reached the composite end point of death or emergency liver transplantation (16.8 [11.3-39.5] ng/mL). Angiopoietin-2 release correlated strongly with surrogate markers of organ dysfunction and disease severity measures (lactate, platelet count, Sequential Organ Failure Assessment score, and Simplified Acute Physiology Score III). Angiopoietin-2 levels were higher in patients with acute kidney injury and patients on mechanical ventilation. Furthermore, Angiopoietin-2 levels were closely associated with Bilirubin-Lactate Etiology score but not with other liver-specific markers. Unadjusted and adjusted Cox's proportional hazards analyses identified Angiopoietin-2 as a predictor of the composite end point of death or transplantation. Finally, immunohistological studies showed that Angiopoietin-2 protein was upregulated in acute liver failure explants compared with matched liver biopsies obtained at baseline. CONCLUSIONS: Collectively, our data show that circulating Angiopoietin-2, which potentially originates from the injured liver, correlates with several features of multiple organ dysfunction syndrome and independently predicts outcome. Tie2 agonists may have potential as an endothelium-targeted therapy to ameliorate multiple organ dysfunction syndrome and improve outcome in acute liver failure. PMID- 22430237 TI - Occurrence and impact of intracranial pressure elevation during treatment of severe intraventricular hemorrhage. AB - OBJECTIVES: Elevated intracranial pressure is one of the proposed mechanisms leading to poor outcomes in patients with intraventricular hemorrhage. We sought to characterize the occurrence and significance of intracranial hypertension in severe intraventricular hemorrhage requiring extraventricular drainage. DESIGN: Prospective analysis from two randomized, multicenter, clinical trials. SETTING: Intensive care units of 23 academic hospitals. PATIENTS: One hundred patients with obstructive intraventricular hemorrhage and intracerebral hemorrhage volume <30 mL requiring emergency extraventricular drainage from two randomized multicenter studies comparing intraventricular recombinant tissue plasminogen activator (n=78) to placebo (n=22). INTERVENTIONS: Intracranial pressure was recorded every 4 hrs in all patients and before and after a 1-hr extraventricular drainage closure period after injection. Intracranial pressure readings were analyzed at predefined thresholds and compared between treatment groups, before and after injection of study agent, and before and after opening of third and fourth ventricles on computed tomography. Impact on 30-day outcomes was assessed. MEASUREMENTS AND MAIN RESULTS: Initial intracranial pressure ranged from -2 to 60 mm Hg (median; interquartile range, 11;10). Of 2576 intracranial pressure readings, 91.5% (2359) were <=20 mm Hg, 1.6% were >30, 0.5% were >40, and 0.2% were >50 mm Hg. In a multivariate analysis, threshold events>20 mm Hg and >30 mm Hg were more frequent in placebo vs. recombinant tissue plasminogen activator treated groups (p=.03 and p=.08, respectively). Intracranial pressure elevation>20 mm Hg occurred during a required 1-hr extraventricular drainage closure interval in 207 of 868 (23.8%) injections of study agent, although early reopening of the extraventricular drainage only occurred in 7.9%. After radiographic opening of the lower ventricular system, intracranial pressure events>20 mm Hg remained significantly associated with initial intraventricular hemorrhage volume (p=.002) and extraventricular drainage placement ipsilateral to the largest intraventricular hemorrhage volume (p=.001), but not with thrombolytic treatment (p=.05) or intracerebral hemorrhage volume (p=.14). Ventriculoperitoneal shunts were required in 13.6% of placebo and 6.4% of recombinant tissue plasminogen activator-treated patients (p=.37). Percentage of intracranial pressure readings per patient>30 mm Hg and initial intracerebral hemorrhage and intraventricular hemorrhage volumes were independent predictors of 30-day mortality after adjustment for other outcome predictors (p=.003, p=.03, and p<.001, respectively). Independent predictors of poor modified Rankin Scale score at 30 days were percent of intracranial pressure events>30 mm Hg per patient (p=.01; but not >20 mm Hg), both intracerebral hemorrhage and intraventricular hemorrhage volume, and pulse pressure. CONCLUSIONS: Intracranial pressure is not frequently elevated during monitoring and drainage with an extraventricular drainage in patients with severe intraventricular hemorrhage, although intracranial pressure >30 mm Hg predicts higher short-term mortality. Thrombolytic therapy may reduce the frequency of high intracranial pressure events. Intracranial pressure elevation appears to be significantly correlated with extraventricular drainage placement in the ventricle with greatest clot volume. PMID- 22430238 TI - Role of receptor for advanced glycation end products in cardiogenic shock. AB - OBJECTIVES: Activation of the receptor for advanced glycation end products by its ligands promotes inflammatory processes and tissue injury. The available evidence suggests that soluble forms of receptor for advanced glycation end products circulating in the plasma may neutralize the ligand-mediated damage by acting as a decoy. Thus, it is hypothesized that receptor for advanced glycation end products expression might be deleterious, whereas soluble receptor for advanced glycation end products might be beneficial in cardiogenic shock. However, until now, no data exist regarding the role of soluble receptor for advanced glycation end products and receptor for advanced glycation end products in humans with cardiogenic shock complicating myocardial infarction. DESIGN: Prospective observational cohort study. SETTING: Intensive critical care unit of a university hospital. PATIENTS: Forty patients with cardiogenic shock complicating acute myocardial infarction, 20 age-matched patients with acute uncomplicated myocardial infarction and, 20 age-matched healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocytic receptor for advanced glycation end products expression assessed by flow cytometry was significantly increased in cardiogenic shock nonsurvivors (137.02+/-7.48 mean fluorescence intensity; n=13) compared to survivors (67.80+/-8.33 mean fluorescence intensity; n=17; p<.001). Conversely, nonsurvivors had significantly decreased plasma soluble receptor for advanced glycation end products levels (79.87+/-10.62 arbitrary units; n=13; p=.004) compared to survivors (127.65+/-10.52 arbitrary units; n=17) as assessed by Western blotting. Receptor for advanced glycation end products expression and soluble receptor for advanced glycation end products levels were determined as independent predictors for 28-day mortality in cardiogenic shock confirmed by receiver-operator characteristics and multivariate analysis (receptor for advanced glycation end products: area under the curve, 0.943+/-0.05; p<.001; soluble receptor for advanced glycation end products: area under the curve, 0.815+/-0.08; p<.01). Both receptor for advanced glycation end products>103.6 mean fluorescence intensity or soluble receptor for advanced glycation end products<76.88 arbitrary units independently predicted a 27.87-fold (p<.001) and a 3.97-fold (p=.019) increase in 28-day mortality in cardiogenic shock. CONCLUSIONS: Enhanced monocytic receptor for advanced glycation end products expression and decreased plasma soluble receptor for advanced glycation end products levels play a central role in patients with cardiogenic shock associated with proinflammatory and destroying pathways, resulting in an enhanced 28-day mortality-rate. Receptor for advanced glycation end products and soluble receptor for advanced glycation end products may be prognostic biomarkers for survival in cardiogenic shock and might represent a novel therapeutic target in cardiogenic shock. PMID- 22430239 TI - Lip-reading and the ventilated patient. AB - OBJECTIVE: To present a clinical ethics case report that illustrates the benefits of using lip-reading interpreters for ventilated patients who are capable of mouthing words. DESIGN: Case report. SETTING: The burn unit of a university teaching hospital in New York City. PATIENT: A 75-yr-old man was admitted to the burn unit with 50% total body surface area burns. He was awake, alert, ventilator dependent via a tracheostomy, and able to mouth words. INTERVENTIONS: A deaf lip reading interpreter and a hearing American sign language interpreter worked together in a circuit formation to provide verbal voice for the patient. CONCLUSION: For the ventilated patient who can mouth words, lip-reading interpretation offers an opportunity for communication. It is time we routinely provide lip-reading interpreters as well as recognize the need for prospective studies examining the role of lip-reading in medical settings. PMID- 22430240 TI - Acute lung inflammatory response and injury after hemorrhagic shock are more severe in postpartum rabbits. AB - OBJECTIVE: The acute respiratory distress syndrome may complicate postpartum hemorrhagic shock and resuscitation, but its mechanisms are not yet well defined. We studied the lung inflammatory response to postpartum hemorrhagic shock and resuscitation in a rabbit model and the role of the nuclear factor-kappaB pathway. DESIGN: Randomized, controlled, prospective study. SETTING: University hospital laboratory. SUBJECTS: Nonobstetric (not pregnant nor postpartum) and obstetrical (within 2 hrs postpartum) rabbits. INTERVENTIONS: Nonobstetric and obstetric female New Zealand white rabbits underwent fixed-pressure or fixed volume hemorrhagic shock for 30 mins and then were rapidly resuscitated with the shed blood and Ringer's solution. Finally, they were either monitored for survival time or euthanized by exsanguination for lung tissue examination 24 hrs after hemorrhage. MEASUREMENTS AND MAIN RESULTS: After hemorrhagic shock and resuscitation, median survival time in obstetric rabbits (3 days) was significantly shorter (p<.05) than that in nonobstetric rabbits (5 days). Compared with nonobstetric rabbits, obstetric rabbits had more severe lung injury as indicated by alveolar and interstitial fluid accumulation and marked neutrophil sequestration and greater lung injury score, myeloperoxidase activity, expression of intercellular adhesion molecule-1, serum tumor necrosis factor alpha levels, and nuclear factor-kappaB activation, and lower serum interleukin 10 levels (p<.05 for all). CONCLUSIONS: After hemorrhage and resuscitation, obstetric rabbits had significantly shorter survival time and more severe lung injury than nonobstetric rabbits. The mechanism may be through upregulation of the signal transductions of the nuclear factor-kappaB pathways. PMID- 22430241 TI - Spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury. AB - OBJECTIVE: We investigated whether potentially injurious transpulmonary pressure could be generated by strong spontaneous breathing and exacerbate lung injury even when plateau pressure is limited to <30 cm H2O. DESIGN: Prospective, randomized, animal study. SETTING: University animal research laboratory. SUBJECTS: Thirty-two New Zealand White rabbits. INTERVENTIONS: Lavage-injured rabbits were randomly allocated to four groups to receive low or moderate tidal volume ventilation, each combined with weak or strong spontaneous breathing effort. Inspiratory pressure for low tidal volume ventilation was set at 10 cm H2O and tidal volume at 6 mL/kg. For moderate tidal volume ventilation, the values were 20 cm H2O and 7-9 mL/kg. The groups were: low tidal volume ventilation+spontaneous breathingweak, low tidal volume ventilation+spontaneous breathingstrong, moderate tidal volume ventilation+spontaneous breathingweak, and moderate tidal volume ventilation+spontaneous breathingstrong. Each group had the same settings for positive end-expiratory pressure of 8 cm H2O. MEASUREMENTS AND RESULTS: Respiratory variables were measured every 60 mins. Distribution of lung aeration and alveolar collapse were histologically evaluated. Low tidal volume ventilation+spontaneous breathingstrong showed the most favorable oxygenation and compliance of respiratory system, and the best lung aeration. By contrast, in moderate tidal volume ventilation+spontaneous breathingstrong, the greatest atelectasis with numerous neutrophils was observed. While we applied settings to maintain plateau pressure at <30 cm H2O in all groups, in moderate tidal volume ventilation+spontaneous breathingstrong, transpulmonary pressure rose >33 cm H2O. Both minute ventilation and respiratory rate were higher in the strong spontaneous breathing groups. CONCLUSIONS: Even when plateau pressure is limited to <30 cm H2O, combined with increased respiratory rate and tidal volume, high transpulmonary pressure generated by strong spontaneous breathing effort can worsen lung injury. When spontaneous breathing is preserved during mechanical ventilation, transpulmonary pressure and tidal volume should be strictly controlled to prevent further lung injury. PMID- 22430243 TI - Quantitative assessment of the microcirculation in healthy volunteers and in patients with septic shock. AB - OBJECTIVE: The microcirculation of septic patients has been characterized only semiquantitatively. Our goal was to characterize the sublingual microcirculation in healthy volunteers and patients with septic shock quantitatively. Our hypotheses were that 1) hyperdynamic blood flow is absent in septic shock; 2) nonsurvivors show more severe alterations than survivors; and 3) quantitative and semiquantitative microcirculatory parameters have a similar performance. DESIGN: Prospective, observational study. SETTING: Teaching intensive care unit in a university-affiliated hospital. SUBJECTS: Twenty-five normal volunteers and 25 patients with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The sublingual microcirculation was evaluated by means of sidestream dark field imaging. Semiquantitative and quantitative microcirculatory parameters were determined through the use of applied software. Septic patients showed decreased perfused capillary density (13.2+/-4.4 mm/mm2 vs. 16.6+/-1.6 mm/mm2), proportion of perfused capillaries (0.78+/-0.23 vs. 1.00+/-0.01), microvascular flow index (2.15+/-0.61 vs. 2.97+/-0.03), and red blood cell velocity (830+/-183 um/sec vs. 1332+/-187 um/sec) along with increased heterogeneity flow index (1.64+/-1.14 vs. 0.25+/-0.19) compared with controls. No differences were found in total capillary density (16.9+/-2.2 vs. 16.7+/-1.6). Only 4% of capillaries analyzed showed red blood cell velocities>75th percentile of the velocities of the normal volunteers. The nonsurvivors exhibited decreased perfused capillary density, proportion of perfused capillaries, and microvascular flow index along with increased heterogeneity flow index compared with the survivors. The correlations between microvascular flow index and proportion of perfused capillaries, total capillary density and number of grid-crossing capillaries, and red blood cell velocities and microvascular flow index gave high R values (0.92, 0.65, and 0.52, respectively; p<.0001 for all). CONCLUSIONS: The main characteristics of sublingual microcirculation in patients with septic shock are hypoperfusion and increased flow heterogeneity. Hyperdynamic microvascular blood flow was not found. Nonsurvivors showed more severe alterations than survivors. Quantitative and semiquantitative microcirculatory variables displayed similar behaviors. PMID- 22430242 TI - Patterns of depressive symptoms in caregivers of mechanically ventilated critically ill adults from intensive care unit admission to 2 months postintensive care unit discharge: a pilot study. AB - OBJECTIVE: To examine trajectories of depressive symptoms in caregivers of critically ill adults from intensive care unit admission to 2 months postintensive care unit discharge and explore patient and caregiver characteristics associated with differing trajectories. DESIGN: Longitudinal descriptive study. SETTING: Medical intensive care unit in a tertiary university hospital. SUBJECTS: Fifty caregivers and 47 patients on mechanical ventilation for >=4 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Caregivers completed measures assessing depressive symptoms (Short version Center for Epidemiologic Studies-Depression Scale 10-items), burden (Brief Zarit Burden Interview), and health risk behaviors (caregiver health behaviors) during intensive care unit admission, at intensive care unit discharge, and 2 months postintensive care unit discharge. Group-based trajectory analysis was used to identify patterns of change in shortened Center for Epidemiologic Studies Depression Scale scores over time. Two trajectory groups emerged: 1) caregivers who had clinically significant depressive symptoms (21.0+/-4.1) during intensive care unit admission that remained high (13.6+/-5) at 2 months postintensive care unit discharge (high trajectory group, 56%); and 2) caregivers who reported scores that were lower (10.6+/-5.7) during intensive care unit admission and decreased further (5.7+/-3.6) at 2 months postintensive care unit discharge (low trajectory group, 44%). Caregivers in the high trajectory group tended to be younger, female, an adult child living with financial difficulty, and less likely to report a religious background or preference. More caregivers in the high trajectory group reported greater burden and more health risk behaviors at all time points; patients tended to be male with poorer functional ability at intensive care unit discharge. Caregivers' responses during intensive care unit admission did not differ in regard to number of days patients were on mechanical ventilation before enrollment. CONCLUSION: Findings suggest two patterns of depressive symptom response in caregivers of critically ill adults on mechanical ventilation from intensive care unit admission to 2 months postintensive care unit discharge. Future studies are necessary to confirm these findings and implications for providing caregiver support. PMID- 22430244 TI - Survey of determination of death after cardiac arrest by intensive care physicians. AB - OBJECTIVE: The controversy regarding death determination in the context of organ donation after cardiocirculatory death requires investigation. We sought to describe the manner in which Canadian adult and pediatric intensive care physicians report death determination after cardiac arrest. DESIGN: Pilot-tested paper survey. SETTING: Mail out between June and November 2009. SUBJECTS: Canadian adult and pediatric intensive care physicians. INTERVENTION: Paper-based survey. MAIN RESULTS: Forty-nine percent of 501 Canadian intensive care physicians responded. Eighty-five percent practiced in tertiary care, university affiliated centers, and 26% were from pediatric centers. Physicians had a median of 10 yrs (range 0-35) experience. Physicians reported that they performed determination of death after cardiac arrest a median of seven (range 0-60) times per year. Of 11 tests or procedures used, the absence of heart sounds by auscultation, palpable pulse, and breath sounds were the most common, although there was high variability in practice. No diagnostic test/procedure was uniformly performed or omitted. Sixty-five percent of respondents believed autoresuscitation exists and 37% of physicians reported to have seen a possible case during their career. Forty-eight percent had formal training for determining death after cardiac arrest and 22% used guidelines. The majority of respondents agreed that standardized methods for determination of death after cardiac arrest are required in general (69%) and specifically for donation after cardiocirculatory death (91%). CONCLUSIONS: Intensive care physicians in Canada report: 1) variability in the practice of determining death after cardiac arrest; 2) the existence of autoresuscitation; and 3) a need for standardization of practice. The results of this survey support the need to develop more robust education, guidelines, and standards for the determination of death after cardiac arrest, in general, as well as within the context of donation after cardiocirculatory death. PMID- 22430245 TI - Impact of telephone dispatcher assistance on the outcomes of pediatric out-of hospital cardiac arrest. AB - OBJECTIVE: Most previous studies of pediatric out-of-hospital cardiac arrest have typically examined relatively small datasets from small study regions. Although several studies have reported the impact on adult out-of-hospital cardiac arrest, little information is available on the impact of telephone dispatcher assistance on the outcomes of pediatric out-of-hospital cardiac arrest. We set out to examine the impact of cardiopulmonary resuscitation instruction by telephone dispatcher on the outcomes of pediatric out-of-hospital cardiac arrest. DESIGN: Population-based, observational study. SETTING: Japan-wide population-based setting. PATIENTS: We identified 1,780 pediatric out-of-hospital cardiac arrest patients (67.8% male) with witnessed collapse from a nationwide, population based, out-of-hospital cardiac arrest database. INTERVENTION: None. MEASUREMENT AND MAIN RESULTS: We assessed the impact of telephone dispatcher assistance on the outcomes of 1-month survival rates and favorable neurologic status among the groups. The overall rate of bystander-performed chest compression and mouth-to mouth ventilation among the witnessed pediatric out-of-hospital cardiac arrests were 39.5% and 25.6%, respectively. Telephone dispatcher assistance was offered in 28.4% of the witnessed pediatric out-of-hospital cardiac arrest cases and resulted in a significant increase in both chest compression (adjusted odds ratio 6.04; 95% confidence interval 4.72-7.72) and mouth-to-mouth ventilation (adjusted odds ratio 3.10; 95% confidence interval 2.44-3.95), and a significant improvement in 1-month survival rate (adjusted odds ratio 1.46; 95% confidence interval 1.05-2.03), but no significant effect on favorable neurologic outcomes at 1 month (adjusted odds ratio 1.15; 95% confidence interval 0.70-1.88). Potential confounding factors included age categories, sex, bystander type, cause of cardiac arrest, bystander cardiopulmonary resuscitation, and attempted defibrillation. CONCLUSIONS: Telephone dispatcher assistance could significantly increase bystander cardiopulmonary resuscitation among witnessed pediatric out-of hospital cardiac arrests. Although there was only a small, nonsignificant effect on the improvement in favorable neurologic outcome at 1 month, the improved survival associated with telephone dispatcher assistance in pediatric out-of hospital cardiac arrest is clinically important, and is of major public health importance. In cases where cardiac arrest was uncertain from the bystander's replies during the call to emergency medical services, telephone dispatcher assistance was not offered, which could affect the adjusted odds ratio of the present study. PMID- 22430246 TI - The association between body mass index, processes of care, and outcomes from mechanical ventilation: a prospective cohort study. AB - OBJECTIVE: To determine the association between excess weight and processes of care and outcomes for critically ill adults. DESIGN: Prospective cohort study. SETTING: Three medical intensive care units at two hospitals. PATIENTS: Five hundred eighty mechanically ventilated adult patients admitted between February 1, 2006 and January 31, 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After adjusting weight based on the recorded fluid balance before enrollment, 21.9% of subjects were categorized into different body mass index categories than without this adjustment. We used a competing risk analysis with events of interest considered death during hospitalization and successful liberation from mechanical ventilation. We found no statistically significant difference between body mass index categories (<25 kg/m2 vs. 25 to <30 kg/m2 vs. >=30 kg/m2) in the competing risks analyses when the results were unadjusted or adjusted for severity of illness and comorbidities. When the analyses were adjusted for the use of continuous infusions of opioids and/or sedatives and ventilator parameters (tidal volume per ideal body weight, positive end-expiratory pressure, and airway pressure), subjects with an overweight fluid-balance-adjusted body mass index had significantly lower hazard ratios for dying while hospitalized (adjusted hazard ratio 0.68 [95% confidence interval 0.47-0.99], p=.044), and those with an obese fluid-adjusted body mass index had significantly higher hazard ratios for successful extubation (adjusted hazard ratio 1.53 [95% confidence interval 1.14 2.06], p=.005). An analysis of longer-term mortality found lower adjusted hazard ratios for subjects with overweight (adjusted hazard ratio 0.74 [95% confidence interval 0.56-0.96]) and obese (adjusted hazard ratio 0.74 [95% confidence interval 0.59-0.94]) fluid-balance-adjusted body mass indices. CONCLUSIONS: Processes of provided care may affect the observed association between excess weight and outcomes for critically ill adults and should be considered when making inferences about observed results. It is unknown if disparities in processes of care are due to clinically justified reasons for variation, bias against heavier patients, or other reasons. PMID- 22430247 TI - Evaluating the use of recombinant human activated protein C in adult severe sepsis: results of the Surviving Sepsis Campaign. AB - OBJECTIVE: The Surviving Sepsis Campaign developed guidelines for the administration of recombinant human activated protein C in adult severe sepsis. However, it is not clear how these impacted clinical practice or patient outcome. DESIGN AND SETTING: The Surviving Sepsis Campaign has developed an extensive database to assess the efficacy of the overall effect of its guidelines on clinical practice and patient outcome. From data submitted to the Surviving Sepsis Campaign database from January 2005 through March 2008, we evaluated data regarding the administration of recombinant human activated protein C in adult severe sepsis. SUBJECTS: Data from 15,022 subjects at 165 sites were analyzed. MEASUREMENTS AND MAIN RESULTS: Of patients with severe sepsis in the database, 1,009 of 15,022 (8%) received recombinant human activated protein C. Recombinant human activated protein C was administered within 24 hrs of the onset of sepsis in 76% (771 of 1009) of patients. Patients in North America (7.1%) and Europe (6.8%) were more likely to receive recombinant human activated protein C than patients in South America (4.2%, p<.001). After adjusting for covariates, the group that received recombinant human activated protein C had a significantly reduced associated hospital mortality (odds ratio 0.76, 95% confidence interval 0.66-0.86, p<.001). Comparing all the patients who received recombinant human activated protein C to those who did not receive recombinant human activated protein C, the reduction in the adjusted hospital mortality was only statistically significant in patients who had multiorgan dysfunction (odds ratio 0.82, 95% confidence interval 0.69-0.98, p=.027) vs. those who only had single organ dysfunction (odds ratio 0.78, 95% confidence interval 0.59-1.02, p=.072). However, in patients who received recombinant human activated protein C before 24 hrs there was a reduction in adjusted hospital mortality in patients with only one organ dysfunction (odds ratio 0.70, 95% confidence interval 0.51-0.9, p=.03) as well as patients with multiorgan dysfunction (odds ratio 0.78, 95% confidence interval 0.64-0.94 p=.012). There was a statistically significant increase over time in the percentage compliance with the institution of a recombinant human activated protein C administration policy from the first, second, and eighth quarters (47.4%, 46.2%, and 60.7%, respectively) (p<.001). There was also a statistically significant increase in the actual administration rates of recombinant human activated protein C over the same timeline (p<.001), with administration rates of recombinant human activated protein C reaching 9.2% in the last quarter. CONCLUSIONS: Recombinant human activated protein C use was associated with a significant improvement in hospital mortality in patients who participated in the Surviving Sepsis Campaign. PMID- 22430249 TI - IL-27 induction of IL-21 from human CD8+ T cells induces granzyme B in an autocrine manner. AB - Interleukin (IL)-27 exerts an anti-inflammatory effect on human and mice CD4(+) T cells by inducing IL-10-producing T regulatory 1 cells through induction of IL 21. However, the role of IL-27 and how it regulates IL-21 from human CD8(+) T cells is unclear. Here, we show that the IL-27 receptor is expressed on human CD8(+) T cells and stimulation of human naive CD8(+) T cells in the presence of IL-27 leads to an increase in IL-21 and interferon (IFN)-gamma production. IL-21 induction in IL-27-stimulated human CD8(+) T cells correlates specifically with expression of the transcription factor T-bet. IL-27 stimulation of naive CD8(+) T cells induces a double-positive T-bet(+) IL-21(+) expressing CD8(+) T-cell population. Furthermore, IL-27 stimulation of human naive CD8(+) T cells greatly increases expression of granzyme B. Antibody-mediated neutralization of IL-21 abrogates IL-27-induced granzyme B expression. Moreover, direct addition of IL-21 greatly amplifies granzyme B expression in human naive CD8(+) T cells. Our findings identify IL-27-induced IL-21 as a key autocrine regulator of granzyme B expression in human CD8(+) T cells. PMID- 22430248 TI - Role of type I interferons in the activation of autoreactive B cells. AB - Type I interferons (IFNs) are a family of cytokines involved in the defense against viral infections that play a key role in the activation of both the innate and adaptive immune system. IFNs both directly and indirectly enhance the capacity of B lymphocytes to respond to viral challenge and produce cytotoxic and neutralizing antibodies. However, prolonged type I IFN exposure is not always beneficial to the host. If not regulated properly IFN can drive autoantibody production as well as other parameters of systemic autoimmune disease. Type I IFNs impact B-cell function through a variety of mechanisms, including effects on receptor engagement, Toll-like receptor expression, cell migration, antigen presentation, cytokine responsiveness, cytokine production, survival, differentiation and class-switch recombination. Type I IFNs are also cytotoxic for a variety of cell types and thereby contribute to the accumulation of cell debris that serves as a potential source for autoantigens. Type I IFN engagement of a variety of accessory cells further promotes B-cell survival and activation, as exemplified by the capacity of type I IFNs to increase the level of B-cell survival factors, such as B lymphocyte stimulator, produced by dendritic cells. Therefore, it is not surprising that the loss of expression of the type I IFN receptor can have dramatic effects on the production of autoantibodies and on the clinical features of systemic autoimmune diseases such as systemic lupus erythematosus. PMID- 22430250 TI - Type I interferons in regulation of mucosal immunity. AB - The mucosal system is the first line of defense against many pathogens. It is continuously exposed to dietary and microbial antigens, and thus the host must maintain a homeostatic environment between commensal microbiota and pathogenic infections. Following infections and inflammatory events, a rapid innate immune response is evoked to dampen the inflammatory processes. Type I interferons, a family of pleiotropic cytokines and major products of the innate immune response, have a key role in these early immune events at the mucosa, as reviewed here. With the emergence of new discoveries of immune cell types in mucosal tissues and their reactions to commensal and pathogenic organisms, we also review the opportunities for exciting research in this field. PMID- 22430251 TI - Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS. AB - Different viruses trigger pattern recognition receptor systems, such as Toll-like receptors or cytosolic RIG-I like helicases (RLH), and thus induce early type I interferon (IFN-I) responses. Such responses may confer protection until adaptive immunity is activated to an extent that the pathogen can be eradicated. Interestingly, the same innate immune mechanisms that are relevant for early pathogen defense have a role in ameliorating experimental autoimmune encephalomyelitis (EAE), a rodent model of human multiple sclerosis. We and others found that mice devoid of a component of the IFN-I receptor (Ifnar1(-/-)) showed significantly enhanced autoimmune disease of the central nervous system (CNS). A detailed analysis revealed that in wild-type mice IFN-I triggering of myeloid cells was instrumental in reducing brain damage. A more recent study indicated that similar to Ifnar1(-/-) mice, RLH-signaling-deficient mice showed enhanced autoimmune disease of the CNS as well. Moreover, when peripherally treated with synthetic RLH ligands wild-type animals with EAE disease showed reduced clinical scores. Under such conditions, IFN-I receptor triggering of dendritic cells had a crucial role. The therapeutic effect of treatment with RLH ligands was associated with negative regulation of Th1 and Th17 T-cell responses within the CNS. These experiments are consistent with the hypothesis that spatiotemporal conditions of, and cell types involved in, disease-ameliorating IFN-I responses differ significantly, depending on whether they were endogenously induced in the context of EAE pathogenesis within the CNS or upon therapeutic RLH triggering in the periphery. It is attractive to speculate that RLH triggering represents a new strategy to treat multiple sclerosis by stimulating endogenous immunoregulatory IFN-I responses. PMID- 22430252 TI - [Epidemiology of tuberculosis]. PMID- 22430253 TI - The C9ORF72 syndrome: implications for clinical practice. PMID- 22430254 TI - Professor Benet is considered by his peers to be one of the "founding fathers" of the modern pharmaceutical sciences. PMID- 22430256 TI - Dynamic trapping and high-throughput patterning of cells using pneumatic microstructures in an integrated microfluidic device. AB - Microfluidic trapping methods create significant opportunities to establish highly controlled cell positioning and arrangement for the microscale study of numerous cellular physiological and pathological activities. However, a simple, straightforward, dynamic, and high-throughput method for cell trapping is not yet well established. In the present paper, we report a direct active trapping method using an integrated microfluidic device with pneumatic microstructures (PMUSs) for both operationally and quantitatively dynamic localization of cells, as well as for high-throughput cell patterning. We designed and fabricated U-shape PMUS arrays to replace the conventional fixed microstructures for reversible trapping. Multidimensional dynamics and spatial consistency of the PMUSs were optically characterized and quantitatively demonstrated. Furthermore, we performed a systematic trapping investigation of the PMUSs actuated at a pressure range of 0 psi to 20 psi using three types of popularly applied mammalian cells, namely, human lung adenocarcinoma A549 cells, human hepatocellular liver carcinoma HepG2 cells, and human breast adenocarcinoma MCF-7 cells. The cells were quantitatively trapped and controlled by the U-shape PMUSs in a programmatic and parallel manner, and could be opportunely released. The trapped cells with high viability were hydrodynamically protected by the real-time actuation of specifically designed umbrella-like PMUSs. We demonstrate that PMUSs can be applied as an active microfluidic component for large-scale cell patterning and manipulation, which could be useful in many cell-based tissue organization, immunosensor, and high-throughput imaging and screening. PMID- 22430255 TI - gamma-H2AX and other histone post-translational modifications in the clinic. AB - Chromatin is a dynamic complex of DNA and proteins that regulates the flow of information from genome to end product. The efficient recognition and faithful repair of DNA damage, particularly double-strand damage, is essential for genomic stability and cellular homeostasis. Imperfect repair of DNA double-strand breaks (DSBs) can lead to oncogenesis. The efficient repair of DSBs relies in part on the rapid formation of foci of phosphorylated histone H2AX (gamma-H2AX) at each break site, and the subsequent recruitment of repair factors. These foci can be visualized with appropriate antibodies, enabling low levels of DSB damage to be measured in samples obtained from patients. Such measurements are proving useful to optimize treatments involving ionizing radiation, to assay in vivo the efficiency of various drugs to induce DNA damage, and to help diagnose patients with a variety of syndromes involving elevated levels of gamma-H2AX. We will survey the state of the art of utilizing gamma-H2AX in clinical settings. We will also discuss possibilities with other histone post-translational modifications. The ability to measure in vivo the responses of individual patients to particular drugs and/or radiation may help optimize treatments and improve patient care. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22430257 TI - Postsurgical meningitis due to multiresistant Acinetobacter baumannii successfully treated with high doses of ampicillin/sulbactam combined with rifampicin and fosfomycin. AB - We report a case of postsurgical meningitis caused by multiresistant Acinetobacter baumannii successfully treated with high doses of ampicillin/sulbactam combined with rifampicin and fosfomycin. PMID- 22430258 TI - Tumor microsomal metabolism of the food toxicant, benzo(a)pyrene, in ApcMin mouse model of colon cancer. AB - The present study was conducted to investigate whether colon tumors were capable of metabolizing benzo(a)pyrene (BaP), and fluoranthene (FLA), two toxicants that belong to the polycyclic aromatic hydrocarbon family of compounds. Microsomes were isolated from the colon tumors of Apc( Min ) mice that received subchronic doses of 50 MUg/kg BaP and incubated with either BaP or FLA (3 MUM each) alone or in combination and appropriate control groups that received nothing. Subsequent to incubation, samples were extracted with ethyl acetate and analyzed for BaP and FLA metabolites by reverse-phase HPLC equipped with fluorescence detection. Microsomes from tumor tissues were found to metabolize BaP to a greater extent than those from the non-tumor tissues. The rate of BaP metabolism (picomoles of metabolite per minute per milligram of protein) was found to be more when microsomes from BaP-pretreated mice were exposed to BaP alone and FLA in combination with BaP, compared to controls. The microsomes from BaP-preexposed mice generated greater proportion of BaP 7,8-diol and BaP 3,6- and 6,12-diones compared to other experimental groups. Additionally, microsomes from BaP pretreated mice produced greater proportion of FLA 2, 3-diol and 2, 3 D FLA when microsomes were incubated with FLA alone or a combination of BaP and FLA. Our studies revealed that the tumor microsomes were competent to metabolize BaP and FLA either singly or in combination. The biotransformation of BaP and FLA as a consequence of prior and simultaneous exposure to BaP may influence the growth of tumors. Our findings may have relevance to human long-term dietary intake of these toxicants and the consequent acceleration of the colon carcinogenesis process. PMID- 22430259 TI - HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma. AB - The purpose of the study was to evaluate the expression of the biomarkers CA125 and HE4 combined with imaging, in patients with advanced epithelial ovarian cancer (EOC). Forty-six women with EOC were included in the study all affected with peritoneal carcinomatosis. Twenty-two of 46 patients (group I) had peritoneal carcinomatosis with small implants in single or in multiple sites (score 1); 24/46 patients (group II) had macro-nodular implants and omental thickening (score 2). High levels of CA125 (350 +/- 11, mean +/- SEM) have been observed in 21/22 patients of group I, and a similar value (370 +/- 13) has been observed in all patients belonging to group II. HE4 positivity values (350 +/- 9) have been observed in all group I patients, whereas all patients belonging to group II showed a higher value of HE4 (600 +/- 12). Statistically significant differences were observed between the HE4 levels observed in group I patients in comparison with group II patients (p < 0.0001). In addition, we expressed the extension of lymph nodal disease in three scores: L1-L2-L3, and a statistically significant correlation was observed between high HE4 levels and severity of lymph nodal disease L3 (p < 0.0001). The availability of biomarkers, particularly HE4, together with sophisticated imaging techniques, strengthens the clinical relevance of this study, for the follow-up of patients with peritoneal carcinomatosis. PMID- 22430260 TI - Age-related plasticity in the synaptic ultrastructure of neurons in the mushroom body calyx of the adult honeybee Apis mellifera. AB - The mushroom bodies are high-order sensory integration centers in the insect brain. In the honeybee, their main sensory input regions are large, doubled calyces with modality-specific, distinct sensory neuropil regions. We investigated adult structural plasticity of input synapses in the microglomeruli of the olfactory lip and visual collar. Synapsin-immunolabeled whole-mount brains reveal that during the natural transition from nursing to foraging, a significant volume increase in the calycal subdivisions is accompanied by a decreased packing density of boutons from input projection neurons. To investigate the associated ultrastructural changes at pre- and postsynaptic sites of individual microglomeruli, we employed serial-section electron microscopy. In general, the membrane surface area of olfactory and visual projection neuron boutons increased significantly between 1-day-old bees and foragers. Both types of boutons formed ribbon and non-ribbon synapses. The percentage of ribbon synapses per bouton was significantly increased in the forager. At each presynaptic site the numbers of postsynaptic partners-mostly Kenyon cell dendrites-likewise increased. Ribbon as well as non-ribbon synapses formed mainly dyads in the 1-day-old bee, and triads in the forager. In the visual collar, outgrowing Kenyon cell dendrites form about 140 contacts upon a projection neuron bouton in the forager compared with only about 95 in the 1-day-old bee, resulting in an increased divergence ratio between the two stages. This difference suggests that synaptic changes in calycal microcircuits of the mushroom body during periods of altered sensory activity and experience promote behavioral plasticity underlying polyethism and social organization in honeybee colonies. PMID- 22430261 TI - Thermodynamics of chemical reactions with COSMO-RS: the extreme case of charge separation or recombination. AB - Many technically relevant chemical processes in the condensed phase involve as elementary reactive steps the formation of ions from neutral species or, as the opposite, recombination of ions. Such reactions that generate or annihilate charge defy the standard gas phase quantum chemical treatment, and also continuum solvation models are only partially able to account for the right amount of stabilization in solution. In this work, for such types of reaction, a solvation treatment involving the COSMO-RS method is assessed, which leads to improved results, i.e., errors of only around 10 kJ/mol for both protic and aprotic solvents. The examples discussed here comprise protolysis reactions and organo halide heterolysis, for both of which a comparison with reliable experimental data is possible. It is observed that for protolysis, the quality of results does not strongly depend on the quantum chemical method used for energy calculation. In contrast, in the case of heterolytic carbon-chlorine bond cleavage, clearly better results are obtained for higher correlated (coupled cluster) methods or the density functional M06-2X, which is well known for its accuracy if applied to organic chemistry. This hints at least that the right answer is obtained for the right reason and not due to a compensation of errors from gas phase thermodynamics with those from the solvation treatment. Problems encountered with certain critical solvents or upon decomposing Gibbs free energies into heats or entropies of reaction are found to relate mostly to the parameterization of the H bonding term within COSMO-RS. PMID- 22430262 TI - Recent advances in applications of capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D): an update. AB - Capillary electrophoresis with a capacitively contactless conductivity detector (CE-C4D) is becoming a significant useful technique for the analysis of analytes in various fields such as pharmaceutical, biomedical, food and environmental. This review is an update describing the recent developments in the application of CE with a C4D detector. PMID- 22430263 TI - Use of recombinant human parathyroid hormone in hypocalcemic cardiomyopathy. AB - Hypocalcemia secondary to hypoparathyroidism is a rare cause of congestive heart failure. However, its early recognition and treatment lead to significant improvement in cardiac function. We report a middle-aged woman presenting with symptoms of heart failure with a serum calcium level of 3.7 mg/dl and a serum inorganic phosphate level of 17.6 mg/dl 22 years after subtotal thyroidectomy. Besides calcium and calcitriol supplementation, she was the first patient with severe hypocalcemic cardiomyopathy to be given off-label recombinant human parathyroid hormone (PTH) because of an elevated serum calcium-phosphate product. We discuss the management and outcome of the patient and then present a brief review of similar previously reported cases. We also describe the pivotal role of calcium ion and the potential role of PTH in maintaining myocardial contractility, effective natriuresis, and possible pathogenic mechanisms contributing to heart failure secondary to hypocalcemia and hypoparathyroidism. PMID- 22430264 TI - A SDHB malignant paraganglioma with dramatic response to temozolomide capecitabine. AB - Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6 methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future. PMID- 22430265 TI - DNA repair capacity in circulating lymphocytes and influence on platinum effect in tumor cells. PMID- 22430267 TI - Financial relationships in economic analyses of targeted therapies in oncology. AB - PURPOSE: A potential financial relationship between investigators and pharmaceutical manufacturers has been associated with an increased likelihood of reporting favorable conclusions about a sponsor's proprietary agent in pharmacoeconomic studies. The purpose of this study is to investigate whether there is an association between financial relationships and outcome in economic analyses of new targeted therapies in oncology. MATERIALS AND METHODS: We searched PubMed (last update June 2011) for economic analyses of targeted therapies (including monoclonal antibodies, tyrosine-kinase inhibitors, and mammalian target of rapamycin inhibitors) in oncology. The trials were qualitatively rated regarding the cost assessment as favorable, neutral, or unfavorable on the basis of prespecified criteria. RESULTS: Overall, 81 eligible studies were identified. Economic analyses that were funded by pharmaceutical companies were more likely to report favorable qualitative cost estimates (28 [82%] of 34 v 21 [45%] of 47; P = .003). The presence of an author affiliated with manufacturer was not associated with study outcome. Furthermore, if only studies including a conflict of interest statement were included (66 of 81), studies that reported any financial relationship with manufacturers (author affiliation and/or funding and/or other financial relationship) were more likely to report favorable results of targeted therapies compared with studies without financial relationship (32 [71%] of 45 v nine [43%] of 21; P = .025). CONCLUSION: Our study reveals a potential threat for industry-related bias in economic analyses of targeted therapies in oncology in favor of analyses with financial relationships between authors and manufacturers. A more balanced funding of economic analyses from other sources may allow greater confidence in the interpretation of their results. PMID- 22430266 TI - Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. AB - PURPOSE: Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. METHODS: Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self identified Jewish status. RESULTS: Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. CONCLUSION: Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care. PMID- 22430268 TI - Effectiveness of mindfulness-based stress reduction in mood, breast- and endocrine-related quality of life, and well-being in stage 0 to III breast cancer: a randomized, controlled trial. AB - PURPOSE: To assess the effectiveness of mindfulness-based stress reduction (MBSR) for mood, breast- and endocrine-specific quality of life, and well-being after hospital treatment in women with stage 0 to III breast cancer. PATIENTS AND METHODS: A randomized, wait-listed, controlled trial was carried out in 229 women after surgery, chemotherapy, and radiotherapy for breast cancer. Patients were randomly assigned to the 8-week MBSR program or standard care. Profile of Mood States (POMS; primary outcome), Functional Assessment of Cancer Therapy-Breast (FACT-B), Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) scales and the WHO five-item well-being questionnaire (WHO-5) evaluated mood, quality of life, and well-being at weeks 0, 8, and 12. For each outcome measure, a repeated-measures analysis of variance model, which incorporated week 0 measurements as a covariate, was used to compare treatment groups at 8 and 12 weeks. RESULTS: There were statistically significant improvements in outcome in the experimental group compared with control group at both 8 and 12 weeks (except as indicated) for POMS total mood disturbance (and its subscales of anxiety, depression [8 weeks only], anger [12 weeks only], vigor, fatigue, and confusion [8 weeks only]), FACT-B, FACT-ES, (and Functional Assessment of Cancer Therapy subscales of physical, social [8 weeks only], emotional, and functional well being), and WHO-5. CONCLUSION: MSBR improved mood, breast- and endocrine-related quality of life, and well-being more effectively than standard care in women with stage 0 to III breast cancer, and these results persisted at three months. To our knowledge, this study provided novel evidence that MBSR can help alleviate long term emotional and physical adverse effects of medical treatments, including endocrine treatments. MBSR is recommended to support survivors of breast cancer. PMID- 22430269 TI - Depression and survival in metastatic non-small-cell lung cancer: effects of early palliative care. AB - PURPOSE: In a randomized trial, early palliative care (EPC) in patients with metastatic non-small-cell lung cancer (NSCLC) was observed to improve survival. In a secondary analysis, we explored the hypothesis that the survival benefit resulted from improving depression. PATIENTS AND METHODS: In total, 151 patients with newly diagnosed metastatic NSCLC participated in a randomized trial of EPC integrated with standard oncology care versus standard oncology care alone. Depression was assessed at baseline and at 12 weeks with the Patient Health Questionnaire-9 (PHQ-9) and was scored diagnostically by using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria for major depression syndrome (MDS). Depression response was considered >= 50% reduction in PHQ-9 scores at 12 weeks. Survival differences were tested with log-rank and Cox proportional hazards models. RESULTS: At baseline, 21 patients (14%) met MDS criteria. MDS significantly predicted worse survival (hazard ratio, 1.82; P = .02). Patients assigned to EPC had greater improvements in PHQ-9 scores at 12 weeks (P < .001); among patients with MDS, those receiving EPC had greater rates of depression response at 12 weeks (P = .04). However, improvement in PHQ-9 scores was not associated with improved survival, except in a sensitivity analysis in which patients who died before 12 weeks were modeled to have worse depression. The group randomly assigned to EPC remained independently associated with survival after adding improvement in PHQ-9 scores to the survival model. CONCLUSION: Depression predicted worse survival in patients with newly diagnosed metastatic NSCLC. Although EPC was associated with greater improvement in depression at 12 weeks, the data do not support the hypothesis that treatment of depression mediated the observed survival benefit from EPC. PMID- 22430270 TI - TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. AB - PURPOSE: The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2(mut)) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2(mut) in a large cohort of patients with AML in the context of other AML-associated aberrations. PATIENTS AND METHODS: Samples from 783 younger adult patients with AML were analyzed for the presence of TET2(mut) (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome. RESULTS: In total, 66 TET2(mut) were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2(mut) were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDH(mut)) that were almost mutually exclusive with TET2(mut) (P < .001). TET2(mut) were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2(mut)-associated biology. TET2(mut) did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2(mut) and/or IDH(mut) revealed shorter overall survival (P = .03), although this association was not independent from known risk factors. CONCLUSION: TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML. PMID- 22430271 TI - Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. AB - PURPOSE: Alternatives to cytotoxic agents are desirable for patients with HIV associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. PATIENTS AND METHODS: Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. RESULTS: Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T(1)), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/MUL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). CONCLUSION: Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients. PMID- 22430272 TI - Optimal colorectal cancer staging criteria in TNM classification. AB - PURPOSE: Histologic components of the TNM classification system have been repeatedly revised since the fifth edition (TNM5). TNM classification revisions provide different criteria for categorizing tumor nodules without residual lymph node structure (ND). However, there are few systematic evaluations regarding the effectiveness of these revisions. PATIENTS AND METHODS: A multicenter pathologic review for ND in colorectal cancer (CRC) was performed. Tumor staging defined by TNM5, sixth edition (TNM6), and seventh edition (TNM7) were compared on the basis of Akaike information criterion (AIC) and Harrell's concordance index (c-index). Moreover, TNM7's prognostic value was compared between the original ND and modified criteria, which considered all regional NDs as lymph node metastasis (LNM) irrespective of the original structure. RESULTS: In 1,716 treated patients with CRC (1994 to 1998), tumor stages (I/II/III) exhibited better prognoses in TNM7 (AIC, 3055.1; c-index, 0.7215) than in TNM6 (AIC, 3063.7; c-index, 0.7149), but not better than in TNM5 (AIC, 3051.6; c-index, 0.7240). Comparing the original TNM7 and modified criteria, 4.2% of patients were classified in different N stages (N0/N1/N2a/N2b); both AIC and the c-index were superior in the modified criteria (AIC, 3029.40; c-index, 0.7271) compared with the original criteria (AIC, 3040.58; c-index, 0.7230). Modified criteria were also associated with improved prognostic power of tumor stages (I/IIA/IIB/IIC/IIIA/IIIB/IIIC). These results were similar in another cohort of 2,242 treated patients with CRC (1999 to 2003). CONCLUSION: The prognostic value of TNM7 is better than that of TNM6; however, improvement over TNM5 is insignificant. By considering all regional NDs as LNM irrespective of their morphology, TNM classification can be simplified and its prognostic value improved. PMID- 22430273 TI - US Food and Drug Administration approval overview in metastatic breast cancer. PMID- 22430274 TI - Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. AB - PURPOSE: Sunitinib has shown antitumor activity with a manageable safety profile as metastatic renal cell carcinoma (RCC) treatment, when given by the standard intermittent schedule as well as a continuous daily dosing (CDD) schedule. A trial was conducted to compare the schedules. PATIENTS AND METHODS: Patients with treatment-naive, clear cell advanced RCC were randomly assigned 1:1 to receive sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2; n = 146) or 37.5 mg/d on the CDD schedule (n = 146) for up to 2 years. The primary end point was time to tumor progression. RESULTS: Median time to tumor progression was 9.9 months for schedule 4/2 and 7.1 months for the CDD schedule (hazard ratio, 0.77; 95% CI, 0.57 to 1.04; P = .090). No significant difference was observed in overall survival (23.1 v 23.5 months; P = .615), commonly reported adverse events, or patient-reported kidney cancer symptoms. Schedule 4/2 was statistically superior to CDD in time to deterioration, a composite end point of death, progression, and disease-related symptoms (P = .034). CONCLUSION; There was no benefit in efficacy or safety for continuous dosing of sunitinib compared with the approved 50 mg/d dose on schedule 4/2. Given the numerically longer time to tumor progression with the approved 50 mg/d dose on schedule 4/2, adherence to this dose and schedule remains the treatment goal for patients with advanced RCC. PMID- 22430275 TI - Effect of postdiagnosis weight change on hot flash status among early-stage breast cancer survivors. AB - PURPOSE: Hot flashes (HF) affect a large proportion of breast cancer (BC) survivors and can negatively affect their quality of life. Treatments other than estrogen replacement to alleviate HF are needed. Body weight is related to hot flashes, but little is known about the effect of weight change on HF. PATIENTS AND METHODS: We used data from 3,088 women previously treated for early-stage BC who were enrolled onto the Women's Healthy Eating and Living study to examine the association between weight change after a breast cancer diagnosis and the odds of reporting HF. RESULTS: Overall, 36.1% of participants reported moderate to severe HF at study entry. At 2 years postdiagnosis, 69.2% of women remained within 10%, 4.8% lost at least 10%, and 26.0% gained at least 10% of their prediagnosis weight. Those who gained at least 10% of their prediagnosis weight had a greater risk of reporting HF than women who remained weight stable in that same period (odds ratio [OR], 1.33; 95% CI, 1.11 to 1.60; P = .003). Weight loss of at least 10% of prediagnosis weight was associated with a nonsignificant reduced risk (OR, 0.72; 95% CI, 0.47 to 1.08; P = .118) of reporting HF. However, the trend of weight change (weight loss and weight gain) on HF was significant both when examined categorically (P = .03) and continuously (P < .001). CONCLUSION: Prevention of weight gain after a BC diagnosis-a modifiable behavior-may offer a viable intervention for relief of HF. Effects of intentional weight loss in BC survivors requires further study. PMID- 22430276 TI - Patient-reported outcomes after hepatic resection of colorectal cancer metastases. AB - PURPOSE: Hepatic resection of colorectal carcinoma (CRC) liver metastases is increasing, but evidence for the impact of surgery on patient-reported outcomes (PROs) is limited. This study aimed to describe comprehensively the impact of liver surgery for CRC hepatic metastases on PROs. PATIENTS AND METHODS: Consecutive patients selected for hepatic resection completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Quality of Life Questionnaire-Liver Metastases C21 before and 3, 6, and 12 months after surgery. For functional scales, mean scores with 95% CIs were calculated at each time point, with differences in scores of at least 10 points considered clinically significant. Responses to symptom scales and items were categorized as minimal or severe. Proportions and 95% CIs for each symptom category were calculated. RESULTS: Hepatic surgery was planned in 241 patients but abandoned in nine because of unresectable disease. There were two postoperative deaths, 58 complications (25.2%), and 32 patients (14.9%) with disease recurrence. Questionnaire compliance was excellent (> 95% at all time points). After surgery, most functional aspects of health decreased, and the proportions of patients with severe symptoms increased; role function deteriorated significantly, and 30% of patients reported severe activity/vigor problems. Functional scales recovered by 6 months and were maintained at 1 year. Postoperative symptoms returned to baseline levels at 12 months, but 32.1% of patients reported severe problems with sexual dysfunction and 11.9% with abdominal pain. CONCLUSION: These findings provide new evidence regarding outcomes of liver resection for CRC metastases. It is recommended that patients be reassured that surgery has a minimal and short-lived detrimental impact on health. PMID- 22430277 TI - Immunisation with an allogeneic peptide promotes the induction of antigen specific MHC II(pos) CD4+ rat T cells demonstrating immunostimulatory properties. AB - BACKGROUND: The phenomenon of T cell stimulation by MHC class II expressing (MHC II(pos)) CD4+ T cells has been intensively investigated for T cell clones but, so far, not for native T cells. The extensive use of T cell clones may explain the inconsistent outcomes of T cell-mediated antigen-presentation. Therefore, we used freshly isolated primed rat CD4+ T cells induced by immunisation with an allogeneic peptide P1, which is involved in allograft rejection. METHODS: MHC II(pos) and MHC II(neg) CD4+ T cells were isolated from popliteal lymph nodes of P1-immunised Lewis rats and were purified by combining depletion and positive selection steps. Purified MHC II(pos) CD4+ T cells and MHC II(neg) CD4+ T cells (105 cells per well each) were autostimulated or restimulated with P1-loaded (33 MUg/ml peptide P1) and subsequently irradiated (with 20 Gy) autologous DC. RESULTS: Seven days after immunisation, a small population of MHC II(pos) CD4+ T cells was detectable (approximately 8.0% of total lymph node cells), as well as a large population of MHC II(neg) CD4+ T cells (up to 45%). Antigen-specific proliferation was observed for both T cell populations but only P1-loaded MHC II(pos) CD4+ T cells presented antigen presenting cell (APC) function for P1 primed T cells. Their inability to activate unprimed T cells may be due to impaired surface expression of costimulatory molecules (CD80 and CD86). CONCLUSION: Immunisation with the allogeneic peptide antigen P1 induced antigen specific MHC II(pos) CD4+ rat T cells demonstrating perfect APC function for primed T cells in vitro. PMID- 22430278 TI - Current status of salvage robot-assisted laparoscopic prostatectomy for radiorecurrent prostate cancer. AB - Radiation therapy (RT) is one of the treatment options for prostate cancer (PCa). Transperineal low-dose rate brachytherapy (BT) is another safe and effective technique for low-risk PCa. Recurrence after RT for localized PCa can be defined by a PSA value of 2 ng/mL above the nadir after RT, and biochemical recurrence (BCR) rate after RT is 40-60 %. In case of radiorecurrent PCa, treatment options include salvage radical prostatectomy (RP), cryotherapy, high-intensity focused ultrasound (HIFU), and salvage BT. Only salvage RP has cancer control results for over 10-year follow-up in a substantial portion of patients (30-40 %). However, salvage RP is technically demanding, and experienced surgeons are needed; in fact, RT-induced cystitis, fibrosis, and tissue plane obliteration can lead to significant complications, such as rectal injuries, anastomotic stricture, and urinary incontinence. This review describes indications, oncologic and functional outcomes, surgical techniques, and complications of salvage robot-assisted RP. PMID- 22430279 TI - Accuracy of clinical coding from 1210 appendicectomies in a British district general hospital. PMID- 22430280 TI - Pancreas cancer treatment: a surgeon's perspective today. PMID- 22430281 TI - Prognostic significance of multidetector computed tomography in normotensive patients with pulmonary embolism: rationale, methodology and reproducibility for the PROTECT study. AB - The PROTECT study is designed to assess the prognostic significance of multidetector computed tomography (MDCT) findings in normotensive outpatients with pulmonary embolism (PE). MDCT assesses right ventricular dysfunction (RVD) by measuring the ratio of the right-to-left ventricular short axis diameters. The study uses 30-day all-cause mortality as the primary outcome. The study determined inter- and intraobserver reproducibility of CT findings of RVD. According to the local radiologists' measurements, 44 % of patients (42/96) showed RVD (defined as a ratio of the RV to the LV short axis greater than 0.9). The intraclass correlation was good (0.773, CI 95 %, 0.678-0.842). For interobserver reproducibility, the weighted kappa measurement was 0.730. Intraobserver reproducibility was very good (0.932, 95 % CI, 0.880-0.962). The PROTECT study is designed to show the prognostic significance of MDCT for PE. Inter- and intraobserver agreement of interpretation of RVD were good. PMID- 22430282 TI - Upright T wave in precordial lead V1 indicates the presence of significant coronary artery disease in patients undergoing coronary angiography with otherwise unremarkable electrocardiogram. AB - OBJECTIVE: The goal of the current work was to assess the possible relationship between upright T wave in precordial lead V1 (TV1) and the occurrence of coronary artery disease (CAD) in patients undergoing coronary angiography with an otherwise unremarkable resting electrocardiogram (ECG). METHODS: Twelve-lead resting ECGs of 2,468 patients who underwent coronary angiography were analyzed by independent reviewers blinded to the patients' clinical data. Patients with any condition known to affect cardiac repolarization were not eligible for inclusion. RESULTS: Of 126 patients included in the study, 76 (60%) had at least one significant coronary artery stenosis. Significant CAD was more frequently found in patients with upright TV1 as compared to those with negative TV1 (74 vs. 43%, p = 0.001). Left circumflex (LCx) and left anterior descending (LAD) coronary artery lesions were more frequently observed in patients with upright TV1 than in those with inverted TV1. In univariate analysis, patients with upright TV1 were approx 4 times more likely to have significant CAD than those with inverted TV1 (odds ratio (OR) 3.7, 95% confidence interval (CI) 1.744 7.897). In addition, in the multivariate logistic regression model, upright TV1 was an independent predictor of significant CAD (OR 4.249, 95% CI 1.594-11.328), along with previous myocardial infarction (OR 17.533, 95% CI 3.338-92.091), male gender (OR 3.020; 95% CI 1.214-7.510), and age (OR 1.061; 95% CI 1.003-1.122). CONCLUSION: It might be worthwhile to routinely evaluate the polarity of the T wave in lead V1 in patients with suspected CAD, since it appears to have additional risk stratification potential. PMID- 22430283 TI - Leiomyosarcoma of the inferior vena cava extending into the right atrium. A rare differential diagnosis of a right atrial tumor with fatal outcome. AB - A 54-year-old female patient presented with a progressive and deteriorating dyspnea at the slightest exertion in particular during the past few days before presentation. Transthoracic echocardiography revealed a large space-occupying lesion in the right atrium extending into the inferior vena cava (IVC). Abdominal magnetic resonance aortography showed an elongated space-occupying lesion in the IVC with a significant portion of the tumor and almost completely filling the right atrium accompanied by an infiltration of the hepatic and renal veins. A pronounced tumor infiltration of the IVC at the level of the liver was confirmed intraoperatively and immunohistochemical analysis showed a moderate to poorly differentiated leiomyosarcoma. The extended tumor was successfully removed by a complex operation of the thorax and abdomen but the procedure was accompanied by severe bleeding. A few hours following the procedure the patient died due to a further episode of irreversible intra-abdominal hemorrhage. PMID- 22430284 TI - [Cardiovascular effects of incretin-based therapies]. AB - Pharmacological modulation of the glucagon-like peptide-1 (GLP-1) system has emerged as a new therapeutic option for treatment of diabetes mellitus. In addition to the glucose lowering potential GLP-1 was found to have a variety of cardioprotective effects. GLP-1 reduced the size of myocardial infarction during acute ischemia by activation of prosurvival pathways including PI3-kinase, Akt und ERK1/2. In addition, GLP-1 prevented atherosclerotic lesion formation in experimental models and improved endothelial function while acting anti inflammatory. Furthermore GLP-1 was found to improve chronic heart failure by increasing insulin independent cellular glucose transport. Consequently GLP-1 based therapies might reduce cardiovascular events in diabetic patients which is currently evaluated in clinical endpoint studies. PMID- 22430285 TI - [Cardiac imaging in (asymptomatic) diabetic patients]. AB - Coronary artery disease (CAD) plays an important role in diabetic patients because they have a very high cardiovascular mortality risk. Therefore the question arises if all diabetic patients should be screened for CAD. In patients with (a)typical angina or anginal equivalents (e.g. shortness of breath) an extended CAD evaluation is indicated. Unselected screening in diabetic patients, however, does not seem to make sense as the only large prospective randomized study in this field did not demonstrate a survival benefit in the screened patient population. It is noteworthy that preoperative risk stratification deserves special consideration in diabetic patients. If screening is considered there is the anatomic approach (calcium score, non-invasive coronary angiography) or the functional approach (stress testing, ischemia evaluation). In diabetic patients who in general should already have all the medication with respect to coronary prevention, functional rather than anatomic testing makes sense because revascularization can be considered in patients with extensive ischemia. In contrast, anatomic testing if positive would only be confirming that a medical preventive strategy is necessary. On the other hand a normal anatomic test has a very high negative predictive value. Therefore, CAD evaluation should follow an individual patient tailored approach as long as evidence-based guidelines are lacking. PMID- 22430286 TI - Coronary revascularization in diabetic patients. A focus on the 3-year SYNTAX trial outcomes. AB - The prevalence of diabetes is growing worldwide. Diabetics are predisposed to coronary artery disease due to an increased rate of atherosclerosis. The optimal treatment for these patients remains uncertain. Randomized trials compared percutaneous coronary intervention (PCI) to coronary artery bypass surgery (CABG) to determine the most suitable revascularization strategy. Meta-analyses suggest a survival advantage in favor of surgery over angioplasty or stenting with bare metal stents (BMS). New evidence was needed since advances in medical therapy, PCI technology, and surgical techniques have emerged. The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was the first to compare a drug eluting stent to CABG and showed an increased rate of major adverse cardiac or cerebrovascular events after PCI. Results are mainly driven by the increased rates in patients with high lesion complexity; therefore, the current evidence suggests that diabetic patients with complex coronary disease have better outcomes with CABG. PMID- 22430287 TI - Induction of supramolecular chirality in di-zinc(II) bisporphyrin via tweezer formation: synthesis, structure and rationalization of chirality. AB - Two new supramolecular complexes consisting of an achiral bisporphyrin host and a chiral diamine guest are reported. One shows a remarkably high amplitude bisignate CD signal while the other one shows a very low value. X-ray structure and other spectroscopic investigations of the tweezer complexes clearly rationalize the origin of the optical activity that has so far remained an unresolved issue. PMID- 22430288 TI - A combination of evolutionary trace method, molecular surface accessibility and hydrophobicity analysis to design a high hydrophobicity laccase. AB - Laccases are industrially attractive enzymes and their applications have expanded to the field of bioremediation. The challenge of today's biotechnology in enzymatic studies is to design enzymes that not only have a higher activity but are also more stable and could fit well with the condition requirements. Laccases are known to oxidize non-natural substrates like polycyclic aromatic hydrocarbons (PAHs). We suppose by increasing the hydrophobicity of laccase, it would increase the chance of the enzyme to meet the hydrophobic substrates in a contamination site, therefore increasing the bioremediation efficacy of PAHs from environment. In this attempt, the applications of evolutionary trace (ET), molecular surface accessibility and hydrophobicity analysis on laccase sequences and laccase's crystal structure (1KYA) are described for optimal design of an enzyme with higher hydrophobicity. Our analysis revealed that Q23A, Q45I, N141A, Q237V, N262L, N301V, N331A, Q360L and Q482A could be promising exchanges to be tested in mutagenesis experiments. PMID- 22430289 TI - sRNAbase: a Web resource for small RNAs in Enterobacteriaceae. AB - Bacterial small RNAs (sRNAs) have gained considerable attention due to their multivalent roles in the survival and pathogenesis of bacteria and mostly identified through bio-computational methods. A manually curated web-resource, sRNAbase has been constructed to give comprehensive and exhaustive information on non-coding small RNAs excluding tRNAs and rRNAs in Enterobacteriaceae family. The sRNA entries curated in sRNAbase contain experimentally verified small RNAs available in the literature and their partial/non-homologs reported within the related genomes from our earlier studies. The sRNAbase aims to facilitate the scientific community by providing information on the physical genomic location of the non-coding small RNAs, its alias names, sequences, strand orientation, gene identification numbers of the conserved genes that sandwiches the particular sRNA with possible functional role and a link to the PubMed literatures. Currently, sRNAbase holding information on 1986 entries belongs to 80 sRNA families spread over 45 Enterobacteriaceae genomes. The sRNAbase is accessible on the web at http://bicmku.in:8081/srnabase/. PMID- 22430290 TI - Evolution of regulatory motifs of bacterial transcription factors. AB - Unlike evolution of genes and proteins, evolution of regulatory systems is a relatively new area of research. In particular, little systematic study has been done on evolution of DNA binding motifs in transcription factor families. We suggest an algorithm that reconstructs the most parsimonious scenario for changes in DNA binding motifs along an evolutionary tree of transcription factor binding sites. The algorithm was validated on several artificial datasets and then applied to reconstruct the evolutionary history of the NrdR, MntR, LacI, FNR, Irr, Fur and Rrf2 transcription factor families. The algorithm seems to be sufficiently robust to be applicable in realistic situations. In most transcription factor families the changes in binding motifs are limited to several branches. Changes in consensus nucleotides proceed via an intermediate stage when the respective position is not conserved. PMID- 22430291 TI - POODLE-I: disordered region prediction by integrating POODLE series and structural information predictors based on a workflow approach. AB - Under physiological conditions, many proteins that include a region lacking well defined three-dimensional structures have been identified, especially in eukaryotes. These regions often play an important biological cellular role, although they cannot form a stable structure. Therefore, they are biologically remarkable phenomena. From an industrial perspective, they can provide useful information for determining three-dimensional structures or designing drugs. For these reasons, disordered regions have attracted a great deal of attention in recent years. Their accurate prediction is therefore anticipated to provide annotations that are useful for wide range of applications. POODLE-I (where "I" stands for integration) is a web-based disordered region prediction system. POODLE-I integrates prediction results obtained from three kinds of disordered region predictors (POODLEs) developed from the viewpoint that the characteristics of disordered regions change according to their length. Furthermore, POODLE-I combines that information with predicted structural information by application of a workflow approach. When compared with server teams that showed best performance in CASP8, POODLE-I ranked among the top and exhibited the highest performance in predicting unfolded proteins. POODLE-I is an efficient tool for detecting disordered regions in proteins solely from the amino acid sequence. The application is freely available at http://mbs.cbrc.jp/poodle/poodle-i.html. PMID- 22430292 TI - A comparison of database systems for XML-type data. AB - BACKGROUND: In the field of bioinformatics interchangeable data formats based on XML are widely used. XML-type data is also at the core of most web services. With the increasing amount of data stored in XML comes the need for storing and accessing the data. In this paper we analyse the suitability of different database systems for storing and querying large datasets in general and Medline in particular. RESULTS: All reviewed database systems perform well when tested with small to medium sized datasets, however when the full Medline dataset is queried a large variation in query times is observed. CONCLUSIONS: There is not one system that is vastly superior to the others in this comparison and, depending on the database size and the query requirements, different systems are most suitable. The best all-round solution is the Oracle 11~g database system using the new binary storage option. Alias-i's Lingpipe is a more lightweight, customizable and sufficiently fast solution. It does however require more initial configuration steps. For data with a changing XML structure Sedna and BaseX as native XML database systems or MySQL with an XML-type column are suitable. PMID- 22430293 TI - Uptake of cataract surgery in Sava Region, Madagascar: role of cataract case finders in acceptance of cataract surgery. AB - The number of people coming for cataract surgery in Madagascar remains low and most ophthalmologists could do many more surgeries than currently done. Knowing why people identified with cataract do not accept surgery will help to design programs that use existing resources more effectively. The study was carried out in Sava Region of Madagascar. People with blinding (<6/60) cataract were identified by cataract case finders in the community, interviewed, and given a referral card for surgery at the hospital. We then monitored uptake of surgery at the hospital. Overall, 142 people were identified, interviewed and referred. Among the referrals, 35 (24.6%) presented at the hospital for surgery. The most important factors associated with acceptance were proximity to hospital (people from Sambava district were twice as likely to present as people from more distant districts) and perceived price of transport and food (being higher for people not accepting). The actual price of surgery was not the main barrier to acceptance of surgery; instead it appears that distance to the hospital and the willingness to pay are important predictors. Strategies to improve uptake need to be revised in order to ensure that people have access to and use cataract surgical services. PMID- 22430294 TI - Survey of perioperative prostaglandin analogue administration during cataract surgery in Greece. PMID- 22430295 TI - Updated perspectives on occipital nerve stimulator lead migration: case report and literature review. AB - OBJECTIVES: Patients with occipital neuralgia are often refractory to or intolerant of standard pharmacological and interventional management strategies. Although occipital nerve stimulation (ONS) may provide a unique alternative for such cases, a steep technical learning curve still exists. Lead migration (LM) is among the most challenging issues facing implanters performing ONS implantation. We present an unusual case of LM after ONS implantation and discuss technical aspects for successful revision. METHODS: A retrospective review of medical records and fluoroscopic images was conducted to provide a case report of ONS LM and revision. A PubMed online search for the keywords occipital, stimulation, migration, and revision was also performed for literature review. CASE REPORT: A 35-year-old man with refractory occipital neuralgia had loss of greater occipital nerve paresthesia coverage and worsened occipital headaches 11 months after ONS implantation using a midline approach. Fluoroscopic imaging confirmed lateral LM. Although most LMs occur in the lateral-to-medial trajectory, this case was unique in that LM occurred from a medial-to-lateral trajectory despite using current standard safeguards. DISCUSSION: In an era in which reducing health care expenditures is becoming increasingly important, current complication rates could curtail future acceptance and utilization of ONS. This fact and our case report underscore the importance of a continued drive toward technical advances and a reduction in complications associated with this important treatment modality. Further prospective investigation into the mechanism of action, mechanism of complications, optimization of surgical techniques, and long-term efficacy is warranted. PMID- 22430297 TI - [Antibiotic treatment of enterococcal infections in gastroenterology with daptomycin - first experiences from the EU-CORE registry study (European Cubicin(r) Outcomes Registry and Experience)]. AB - Enterococci are a frequent cause of nosocomial infections in gastroenterology. The increase of Enterococcus faecium infections with development of resistance to gentamicin and vancomycin as well as possible linezolid resistance require alternative antibiotic therapies. Study data show that daptomycin, a highly bactericidal antibiotic is effective in enterococcal infections. However, in Germany daptomycin is so far only approved for the treatment of complicated skin and soft tissue infections, bacteremia and infective endocarditis caused by Staphylococcus aureus. In the Department of Internal Medicine I, University Hospital Halle (Saale) from May 2 009 to April 2 010 all gastroenterological patients with evidence of invasive enterococcal infection received intravenous daptomycin treatment at inclusion in the European Cubicin(r) Outcomes Registry and Experience (EU-CORE). Gastroenterological diseases treated were necrotising pancreatitis, infected pancreatic pseudocysts, abscesses, obstructive cholangitis and sepsis. The clinical outcome was retrospectively detected by protocol-defined criteria. A total of 13 patients (8 male, 5 female, median age 59 years) with microbiologically assured enterococcal infections (10 * E. faecium, including 1 * VRE, 6 * E. faecalis, including double infections) were treated with intravenous daptomycin (6 mg per kg body weight). In the presence of polymicrobial infections (10 of 13 patients), an additional anti-infective therapy was initiated according to sensitivity testing. Concomitantly a direct focus approach with stenting, puncture or drainage was performed. The clinical cure rate was 92 % (12 of 13 patients). One patient died from a non-surgically uncontrollable malignancy (Klatskin tumour Bismuth IIIb). There were no adverse events. These results allow us to conclude that antibiotic therapy with daptomycin in invasive or bacteraemic enterococcal infections leads to high cure rates (up to 90 % and more) when concomitant and adequate focus relief is performed. Larger clinical studies to obtain an extended drug approval are desirable. PMID- 22430298 TI - Energy metabolism and proliferation in pancreatic carcinogenesis. AB - INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer entity with a high proliferative potential. Uncontrolled cell proliferation is mediated by a number of core signaling pathways. Recently, novel data of PDAC biology suggest that these core signal pathways affect cell proliferation and metabolism simultaneously. METHODS: Here, we reviewed the literature on core metabolic signaling pathways in pancreatic carcinogenesis. RESULTS: Results obtained from mouse genetics and in vitro experiments have demonstrated the significance of the Kras, p53, c-Myc, and Lkb1 networks in the proliferation of pancreatic epithelial and cancer cells. At the same time, these major pathways also affect energy metabolism by influencing glucose and glutamine utilization. In particular, Kras-mediated metabolic changes seem to be directly involved in carcinogenesis. However, there is a lack of solid evidence on how metabolism and proliferation are connected in pancreatic carcinogenesis. CONCLUSION: Understanding early and subtle changes in cellular metabolism of pancreatic epithelial-and specifically of acinar-cells, which accompany or directly influence malignant transformation and uncontrolled proliferation, will be paramount to define novel imaging and other modalities for earlier detection of PDAC. PMID- 22430299 TI - Complications and outcome after laparoscopic bariatric surgery: LAGB versus LRYGB. AB - BACKGROUND AND AIMS: Unsatisfactory patient compliance and unfavorable results of weight loss let centers prefer the Roux-en-Y gastric bypass (RYGB) as a combined restrictive and malabsorptive procedure. The aim of this study was to evaluate results of laparoscopic adjustable gastric banding (LAGB) versus laparoscopic RYGB. SETTING: The study was conducted at Centre Hospitalier Emil Mayrisch Clinic for specialized care (n = 618 beds) in Luxembourg (South). MATERIALS AND METHODS: Of 620 procedures, 204 patients had LAGB and 416 LRYGB. Short-term (t(1), 6 months to 2 years), middle-term (t(2), 2 to 5 years), and long-term follow-up (t(3), >5 years) were performed, including weight loss evolution, Bariatric Analysis, and Reporting Outcome System (BAROS). RESULTS: Percent EBWL mean values for LAGB vs. LRYGB were at t(1) 64.3 vs. 79.5, p = 0.01; at t(2) 49.4 vs. 91, p < 0.0001; and at t(3) 52.6 vs. 79.9, p < 0.0001. The BAROS mean values were at t(1) 3.81 vs. 4.00, p = 0.183; at t(2) 3.57 vs. 4.12, p < 0.001; and at t(3) 3.71 vs. 4.04, p = 0.02. Major complication rate (<30 days) was similar (p = 0.601). Long term (>30 days) complications were more common after LAGB (14.3 versus 3.6%, p < 0.001). Fifty patients (25%) required a second and 36 patients (18%) a third operation (LRYGB). CONCLUSION: The significant difference in %EBWL and BAROS and late adverse events with high re-operation rates in LAGB made the LRYGB more attractive. PMID- 22430300 TI - Botulinum toxin injection versus lateral internal sphincterotomy for the treatment of chronic anal fissure: randomized prospective controlled trial. AB - PURPOSE: Lateral internal sphincterotomy has been the gold standard treatment for chronic anal fissure, but it still carries the risk of permanent damage of the anal sphincter, which has led to the implementation of alternative treatment like botulinum toxin injection. The aim of this randomized prospective controlled trial was to compare the efficacy and morbidity of botulinum toxin injection and lateral internal sphincterotomy in the treatment of chronic anal fissure. METHODS: Fifty consecutive adults with chronic anal fissure were randomly treated with either lateral internal sphincterotomy or botulinum toxin (BT) injection with 50 U BT into the internal sphincter. The complications, healing and recurrence rate, and incontinence score were assessed 2, 3, 6, 12 months after the procedure. RESULTS: Inspection at the 2-month visit revealed complete healing of the fissure in 11 (44 %) of the patients in the BT group and 22 (88 %) of the patients in the lateral internal sphincterotomy (LIS) group (p = 0.001). At the 3 month visit, there was no significant difference between the two groups in healing. The overall recurrence rate after 6 months in the BT group was higher than in the LIS group (p < 0.05). In the 3-month follow-up, the LIS group had a higher rate of anal incontinence compared to the BT group (p < 0.05). The final percentage of incontinence was 4 % in the LIS group (p > 0.05). CONCLUSIONS: The treatment of chronic anal fissure must be individualized depending on the different clinical profiles of patients. Botulinum toxin injection has a higher recurrence rate than LIS, and LIS provides rapid and permanent recovery. However, LIS carries a higher risk of anal incontinence in patients. PMID- 22430301 TI - New "one-step" method for the simultaneous synthesis and anchoring of organic monolith inside COC microchip channels. AB - A new method for monolith synthesis and anchoring inside cyclic olefin copolymer (COC) microchannels in a single step is proposed. It is shown that type I photoinitiators, typically used in a polymerization mixture to generate free radicals during monolith synthesis, can simultaneously act as type II photoinitiators and react with the plastic surface through hydrogen abstraction. This mechanism is used to "photograft" poly(ethylene glycol) methacrylate (PEGMA) on COC surfaces. Contact angle measurements were used to observe the changes in surface hydrophilicity when increasing initiator concentration and irradiation duration. The ability of type I photoinitiators to synthesize and anchor a monolith inside COC microchannels in a single step was proved through SEM observations. Different concentrations of photoinitiators were tried. Finally, electrochromatographic separations of polycyclic aromatic hydrocarbons were realized to illustrate the beneficial effect of anchoring on chromatographic performances. The versatility of the method was demonstrated with two widely used photoinitiators: benzoin methyl ether (BME) and azobisisobutyronitrile (AIBN). PMID- 22430302 TI - Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity. AB - OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid beta-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis. PMID- 22430303 TI - Acute stress potentiates brain response to milkshake as a function of body weight and chronic stress. AB - OBJECTIVE: Stress is associated with an increased intake of palatable foods and with weight gain, particularly in overweight women. Stress, food and body mass index (BMI) have been separately shown to affect amygdala activity. However, it is not known whether stress influences amygdala responses to palatable foods, and whether this response is associated with chronic stress or BMI. DESIGN: A total of 14 overweight and obese women participated in a functional magnetic resonance imaging (fMRI) scan as they consumed a palatable milkshake during script-driven, autobiographical, guided imagery of stressful and neutral-relaxing scenarios. RESULTS: We report that a network including insula, somatomotor mouth area, ventral striatum and thalamus responds to milkshake receipt, but none of these areas are affected by stress. In contrast, whereas the left amygdala responds to milkshake irrespective of condition, the right amygdala responds to milkshake only under stressful conditions. Moreover, this right amygdala response is positively associated with basal cortisol levels, an objective measure of chronic stress. We also found a positive relationship between BMI and stress-related increased response to milkshake in the orbitofrontal cortex(OFC). CONCLUSION: These results demonstrate that acute stress potentiates response to food in the right amygdala and OFC as a function of chronic stress and body weight, respectively. This suggests that the influence of acute stress in potentiating amygdala and OFC responses to food is dependent upon individual factors like BMI and chronic stress. We conclude that BMI and chronic stress play a significant role in brain response to food and in stress-related eating. PMID- 22430304 TI - Time spent in sedentary behavior and changes in childhood BMI: a longitudinal study from ages 9 to 15 years. AB - OBJECTIVE: To determine if time spent in objectively measured sedentary behavior is associated with a change in body mass index (BMI) between ages 9 and 15 years, adjusting for moderate-to-vigorous physical activity (MVPA). DESIGN: Prospective observational study of children at ages 9 (2000), 11 (2002), 12 (2003) and 15 years (2006). Longitudinal quantile regression was used to model the influence of predictors on changes at the 10th, 25th, 50th, 75th and 90th BMI percentiles over time. SUBJECTS: Participants were enrolled in the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development and include both boys and girls (n=789). MEASUREMENTS: Objectively measured BMI (kg m(-2)) was the outcome variable and objectively measured sedentary behavior was the main predictor. Adjustment was also made for MVPA, gender, race, maternal education, hours of sleep and healthy eating index. RESULTS: Increases in BMI were observed at all percentiles, with the greatest increase observed at the 90th BMI percentile. Spending more time in sedentary behavior (h per day) was associated with additional increases in BMI at the 90th, 75th and 50th BMI percentiles, independent of MVPA and the other covariates (90th percentile=0.59, 95% confidence interval (95% CI): 0.19-0.98 kg m(-2); 75th percentile=0.48, 95% CI: 0.25-0.72 kg m(-2); and 50th percentile=0.19, 95% CI: 0.05-0.33 kg m(-2)). No associations were observed between sedentary behavior and changes at the 25th and 10th BMI percentiles. CONCLUSION: Sedentary behavior was associated with greater increases in BMI at the 90th, 75th and 50th BMI percentiles between ages 9 and 15 years, independent of MVPA. Preventing an increase in sedentary behavior from childhood to adolescence may contribute to reducing the number of children classified as obese. PMID- 22430305 TI - BMI-independent inverse relationship of plasma leptin levels with outcome in patients with acute pulmonary embolism. AB - OBJECTIVE: The adipocytokine leptin is an independent cardiovascular risk factor and exerts prothrombotic effects, both in arterial and venous thrombosis. We therefore investigated the relationship between leptin levels and clinical outcome in patients with acute pulmonary embolism (PE). DESIGN: We prospectively studied consecutive patients with confirmed acute PE admitted at the University Hospital of Goettingen (Germany) between 2003 and 2009. SUBJECTS: The study subjects were a total of 264 patients with PE (median age, 68 years; interquartile range, 53-75; 60% women; body mass index (BMI) 27 kg m(-2) (24.1 31.2)). Leptin levels were determined by a commercially available enzyme-linked immunosorbent assay. Patients were followed for an adverse 30-day outcome, that is, death, circulatory collapse with need for catecholamines, intubation or resuscitation, and for long-term survival. RESULTS: The median leptin level was 10.1 ng ml(-1) (3.7-25.2). Patients (n=49; 18.6%) with a complicated 30-day course had significantly lower leptin levels (5.3 ng ml(-1) (1.8-19.7) compared with patients without complications (10.4 ng ml(-1) (4.7-25.5), P=0.02). When leptin was analyzed as a continuous variable, there was a significant 36% increase in the relative risk for early complications for every decrease in the natural logarithm of leptin by one s.d. (odds ratio (OR) 1.36 (1.06-1.76), P=0.017), independently of BMI (BMI-adjusted OR, 1.52 (1.13-2.05), P=0.006). In addition, patients within the lowest leptin tertile had a 2.8- and 2.3-fold increased risk for 30-day-complications, compared with those in the middle (P=0.011) and high tertile (P=0.030), and a worse probability of long-term survival (log-rank; P=0.018). CONCLUSION: Low plasma leptin concentration is a predictor for a complicated course and high mortality in patients with acute PE. This association is independent of known factors affecting leptin levels, including gender and obesity. PMID- 22430306 TI - Evaluation of common genetic variants identified by GWAS for early onset and morbid obesity in population-based samples. AB - BACKGROUND: Meta-analysis of case-control genome-wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes. OBJECTIVE: We aimed to validate association of these variants with obesity-related traits in population-based samples. DESIGN: Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r (2)>0.8), with the odds of being overweight and obese, as well as with body mass index (BMI), percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age(2) in adults and for sex, age, age group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods. RESULTS: We had 80% power to detect odds ratios of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P>0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (beta=0.013 s.d./allele, P=0.040), but not with any of the remaining obesity-related traits (P>0.3). CONCLUSION: Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population. PMID- 22430307 TI - Ecosystem impacts of geoengineering: a review for developing a science plan. AB - Geoengineering methods are intended to reduce climate change, which is already having demonstrable effects on ecosystem structure and functioning in some regions. Two types of geoengineering activities that have been proposed are: carbon dioxide (CO(2)) removal (CDR), which removes CO(2) from the atmosphere, and solar radiation management (SRM, or sunlight reflection methods), which reflects a small percentage of sunlight back into space to offset warming from greenhouse gases (GHGs). Current research suggests that SRM or CDR might diminish the impacts of climate change on ecosystems by reducing changes in temperature and precipitation. However, sudden cessation of SRM would exacerbate the climate effects on ecosystems, and some CDR might interfere with oceanic and terrestrial ecosystem processes. The many risks and uncertainties associated with these new kinds of purposeful perturbations to the Earth system are not well understood and require cautious and comprehensive research. PMID- 22430308 TI - A multivariate Baltic Sea environmental index. AB - Since 2001/2002, the correlation between North Atlantic Oscillation index and biological variables in the North Sea and Baltic Sea fails, which might be addressed to a global climate regime shift. To understand inter-annual and inter decadal variability in environmental variables, a new multivariate index for the Baltic Sea is developed and presented here. The multivariate Baltic Sea Environmental (BSE) index is defined as the 1st principal component score of four z-transformed time series: the Arctic Oscillation index, the salinity between 120 and 200 m in the Gotland Sea, the integrated river runoff of all rivers draining into the Baltic Sea, and the relative vorticity of geostrophic wind over the Baltic Sea area. A statistical downscaling technique has been applied to project different climate indices to the sea surface temperature in the Gotland, to the Landsort gauge, and the sea ice extent. The new BSE index shows a better performance than all other climate indices and is equivalent to the Chen index for physical properties. An application of the new index to zooplankton time series from the central Baltic Sea (Latvian EEZ) shows an excellent skill in potential predictability of environmental time series. PMID- 22430309 TI - Restoring river connectivity: prioritizing passage improvements for diadromous fishes and lampreys. AB - Physical obstructions are becoming increasingly recognized as major factors influencing the migrations, population structures, spawning success and recruitment of freshwater organisms. This paper presents a simple but effective method, intended for use by environmental managers, government agencies and conservation bodies, of rapidly assessing and prioritizing barriers to the migrations of diadromous fishes and lampreys for passage improvements. A prioritization matrix was developed using information on fish stock status, the passage efficiency of fishes at individual structures, the distance from the tidal limit and the passability of downstream barriers, and the quantity and quality of habitat upstream of each structure. Importantly, the 'Likelihood of access' was incorporated into the matrix to account for passage efficiency at downstream barriers. Barriers ranked as the highest priority for passage improvements were those characterized by poor fish stocks upstream, low passage efficiency, easy passage from downstream, and a large quantity and high quality of habitat upstream. Prioritization of migration barriers should ensure that access improvements are targeted to achieve optimum benefits. PMID- 22430310 TI - Cloning and expression of tachykinins and their association with kisspeptins in the brains of zebrafish. AB - The tachykinins are a family of neuropeptides, including substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), that are encoded by the tac1 (SP and NKA) or tac2/3 (NKB) genes. Tachykinins are widely distributed in the central nervous system and have roles as neurotransmitters and/or neuromodulators. Recent studies in mammals have demonstrated the coexpression of NKB and kisspeptin and their comodulatory roles over the control of reproduction. We have recently identified two kisspeptin-encoding genes, kiss1 and kiss2, in teleosts. However, such relationship between tachykinins and kisspeptins has not been demonstrated in non-mammalian species. To determine the involvement of tachykinins in the reproduction in teleosts, we identified tac1 and two tac2 (tac2a and tac2b) sequences in the zebrafish genome using in silico data mining. Zebrafish tac1 encodes SP and NKA, whereas the tac2 sequences encode NKB and an additional peptide homologous to NKB (NKB-related peptide). Digoxigenin in situ hybridization in the brain of zebrafish showed tac1 mRNA-containing cells in the olfactory bulb, telencephalon, preoptic region, hypothalamus, mesencephalon, and rhombencephalon. The zebrafish tac2a mRNA-containing cells were observed in the preoptic region, habenula, and hypothalamus, whereas the tac2b mRNA-containing cells were predominantly observed in the dorsal telencephalic area. Furthermore, we examined the coexpression of tachykinins and two kisspeptin genes in the brain of zebrafish. Dual fluorescent in situ hybridization showed no coexpression of tachykinins mRNA with kisspeptins mRNA in hypothalamic nuclei or the habenula. These results suggest the presence of independent pathways for kisspeptins and NKB neurons in the brain of zebrafish. PMID- 22430311 TI - Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics. AB - Parasitic nematode infection of humans and livestock is a major problem globally. Attempts to control nematode populations have led to the development of several classes of anthelmintic, which target cys-loop ligand-gated ion channels. Unlike the vertebrate nervous system, the nematode nervous system possesses a large and diversified array of ligand-gated chloride channels that comprise key components of the inhibitory neurotransmission system. In particular, cys-loop GABA receptors have evolved to play many fundamental roles in nematode behaviour such as locomotion. Analysis of the genomes of several free-living and parasitic nematodes suggests that there are several groups of cys-loop GABA receptor subunits that, for the most part, are conserved among nematodes. Despite many similarities with vertebrate cys-loop GABA receptors, those in nematodes are quite distinct in sequence similarity, subunit composition and biological function. With rising anthelmintic resistance in many nematode populations worldwide, GABA receptors should become an area of increased scientific investigation in the development of the next generation of anthelmintics. PMID- 22430312 TI - Rapid determination of yunaconitine and related alkaloids in aconites and aconite containing drugs by ultra high-performance liquid chromatography-tandem mass spectrometry. AB - Yunaconitine (YAC) is a toxic aconite alkaloid that is considered to be a hidden aconite poison since it is frequently found in body fluids from aconite poisoning patients, but has not been well studied in commonly used herbal drugs. In this paper, a rapid and sensitive ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) detection combined with microwave-assisted extraction (MAE) was developed for high throughput simultaneous determination of YAC and six other toxic aconite alkaloids in 31 samples of crude, processed aconites and aconite-containing drugs. The optimized method showed excellent linearity, precision, accuracy and recovery for all target compounds with short run time. YAC was detected in some samples with contents from 0.015 to 10.41 mg/g. This is the first report on the determination of YAC in Radix Aconiti, Radix Aconiti Kusnezoffii and aconite-containing drugs. This newly developed method facilitates the rapid screening of YAC and related toxic aconite alkaloids and allows YAC to be used as a chemical marker for the quality control of aconites and aconite-containing drugs. PMID- 22430313 TI - Failure strength of human vertebrae: prediction using bone mineral density measured by DXA and bone volume by micro-CT. AB - Significant relationships exist between areal bone mineral density (BMD) derived from dual energy X-ray absorptiometry (DXA) and bone strength. However, the predictive validity of BMD for osteoporotic vertebral fractures remains suboptimal. The diagnostic sensitivity of DXA in the lumbar spine may be improved by assessing BMD from lateral-projection scans, as these might better approximate the objective of measuring the trabecular-rich bone in the vertebral body, compared to the commonly-used posterior-anterior (PA) projections. Nowadays, X ray micro-computed tomography (MUCT) allows non-destructive three-dimensional structural characterization of entire bone segments at high resolution. In this study, human lumbar cadaver spines were examined ex situ by DXA in lateral and PA projections, as well as by MUCT, with the aims (1) to investigate the ability of bone quantity measurements obtained by DXA in the lateral projection and in the PA projection, to predict variations in bone quantity measurements obtained by MUCT, and (2) to assess their respective capabilities to predict whole vertebral body strength, determined experimentally. Human cadaver spines were scanned by DXA in PA projections and lateral projections. Bone mineral content (BMC) and BMD for L2 and L3 vertebrae were determined. The L2 and L3 vertebrae were then dissected and entirely scanned by MUCT. Total bone volume (BV(tot)=cortical+trabecular), trabecular bone volume (BV), and trabecular bone volume fraction (BV/TV) were calculated over the entire vertebrae. The vertebral bodies were then mechanically tested to failure in compression, to determine ultimate load. The variables BV(tot), BV, and BV/TV measured by MUCT were better predicted by BMC and BMD measured by lateral-projection DXA, with higher R(2) values and smaller standard errors of the estimate (R(2)=0.65-0.90, SEE=11%-18%), compared to PA-projection DXA (R(2)=0.33-0.53, SEE=22%-34%). The best predictors of ultimate load were BV(tot) and BV assessed by MUCT (R(2)=0.88 and R(2)=0.81, respectively), and BMC and BMD from lateral-projection DXA (R(2)=0.82 and R(2)=0.70, respectively). Conversely, BMC and BMD from PA-projection DXA were lower predictors of ultimate load (R(2)=0.49 and R(2)=0.37, respectively). This ex vivo study highlights greater capabilities of lateral-projection DXA to predict variations in vertebral body bone quantity as measured by MUCT, and to predict vertebral strength as assessed experimentally, compared to PA-projection DXA. This provides basis for further exploring the clinical application of lateral-projection DXA analysis. PMID- 22430314 TI - Effectiveness of four-corner arthrodesis with use of a locked dorsal circular plate. AB - BACKGROUND: Compared with traditional methods of fixation in four-corner arthrodesis, reviews of results using a dorsal circular plate (DCP) have identified higher complication rates. As the use of circular plate fixation for limited wrist arthrodesis was found to be a valuable concept per se and continued innovation and technical advancement are crucial to improve future treatment, changes in plate design were encouraged. QUESTIONS/PURPOSES: To further evaluate the use of DCP fixation in four-corner arthrodesis, we report the first results using a radiolucent, nonmetallic (polyetheretherketone), locked DCP for four corner arthrodesis. METHODS: We retrospectively analyzed the clinical and radiographic results of 24 patients who underwent four-corner arthrodesis with a locked DCP at a minimum followup of 63 months (mean, 76 months; range, 63-91 months). There were nine women and 15 men, with a mean age of 53 years (range, 37 78 years) at the time of surgery. We evaluated ROM with a goniometer and grip strength with a dynamometer. Function was assessed using QuickDASH. Radiographs were evaluated for union, carpal alignment, and hardware problems. RESULTS: At latest followup, ROM averaged 66% and 77% of the uninjured side in flexion extension and radioulnar deviation, respectively. Grip strength averaged 70% of the uninjured side. The average postoperative QuickDASH score was 19.11. Union was achieved by 22 of the 24 patients. CONCLUSIONS: Our data show four-corner arthrodesis with a radiolucent, nonmetallic, locked DCP is an effective procedure that allows stable primary fixation as a basis for good functional outcome, provided surgical technique and quality of bone graft are adequate. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22430315 TI - Reliability and stability of three common classifications for Legg-Calve-Perthes disease. AB - BACKGROUND: To predict the course of Legg-Calve-Perthes disease (LCPD) and select between treatment options in the early stages, it is critical to have a reliable predictive classification. QUESTIONS/PURPOSES: We examined the reliability and stability of three common classification systems for LCPD. METHODS: We identified 69 patients with LCPD, who had hip radiographs taken more than twice after the initial presentation with at least a 3-month interval. The Herring lateral pillar, Catterall, and Salter-Thompson classifications were evaluated in terms of reliability and stability. The inter- and intrarater reliability of the classification systems was determined by three orthopaedic surgeons using intraclass correlation coefficients (ICCs). To evaluate the stability of the classification systems, the percentage agreement and ICCs among the initial rating, rating when entering fragmentation, and final rating were used. RESULTS: The interrater reliability was highest in Herring lateral pillar classification (ICC, 0.885) followed by the Catterall and Salter-Thompson classifications (ICC, 0.802 and 0.702, respectively). The percentage agreement and ICC between the initial and final rating were, respectively, 55% and 0.491 for the Herring classification and 48% and 0.378 for the Catterall classification. CONCLUSIONS: Our data show the highest reliability of the classification of Herring et al. However, more than 40% of the hip radiographs at the initial presentation, and in particular, most of Herring Group A patients, were upgraded. Therefore, for patients older than 8 years old and graded as Herring Group A initially, surgeons should keep the possibility of surgical treatment in mind. PMID- 22430316 TI - Right ventricular outflow tract systolic excursion: a novel echocardiographic parameter of right ventricular function. AB - AIMS: Right ventricular (RV) function has important prognostic and therapeutic implications. Assessment of RV function using echocardiography is challenging. The aim of this study was to evaluate a new parameter of RV function, right ventricular outflow tract systolic excursion (RVOT_SE). METHODS AND RESULTS: RVOT_SE was measured using M-Mode echocardiography from the parasternal short axis view at the level of the aortic valve, and was defined as the systolic excursion of the RVOT anterior wall. RVOT_SE was measured in 50 patients (age 64 +/- 18 years, 28 males) with normal RV function [RV fractional area change (FAC) >=35% and tricuspid annular plane systolic excursion (TAPSE) >=1.6 cm] and 40 patients (age 68 +/- 12 years, 35 males) with reduced RV function (RV FAC <35% and TAPSE <1.6 cm). R.V FAC was 46 +/- 7% in the normal RV group and 22 +/- 5% in the reduced RV group (P < 0.0001). TAPSE was 2.2 +/- 0.4 cm in the normal RV group and 1.0 +/- 0.2 cm in the reduced RV group (P < 0.0001). RVOT_SE was 9.6 +/ 1.5 mm in the normal RV group and 1.7 +/- 1.1 mm in the reduced RV group (P < 0.0001). RVOT_SE <6 mm identified patients with reduced RV function with 100% sensitivity and 100% specificity. Survival at 1 year was 63% in patients with RVOT_SE <6 mm and 84% in patients with RVOT_SE >=6 mm, P = 0.004. CONCLUSION: RVOT_SE is a novel, simple, and promising parameter for assessing RV function, and it is associated with poor survival. PMID- 22430317 TI - GABA(B) receptors involvement in the effects induced by nicotine on anxiety related behaviour in mice. AB - The aim of the present study was to evaluate the possible involvement of GABA(B) receptors in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. Animals were exposed to nicotine only once. The acute administration of low (0.05mg/kg, sc) or high (0.8mg/kg, sc) doses of nicotine produced opposite effects in the elevated plus maze test; respectively, anxiolytic- and anxiogenic like responses. The effect of pretreatment with either the GABA(B) receptor antagonist 2-OH-saclofen (0.25, 0.5 and 1mg/kg; ip) or the GABA(B) receptor agonist baclofen (0.5, 1 and 2mg/kg; ip), was evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. 2-OH-saclofen completely abolished both nicotine-induced effects (p<0.001) at the highest dose tested, suggesting an involvement of GABA(B) receptors in these behavioural responses. On the other hand, baclofen failed to modify the anxiety-related effects of nicotine. These results suggest that the GABA(B) receptors are involved in the regulation of nicotine-induced anxiety-related behavioural responses in mice, and provide new findings to support a potential pharmaco therapeutic use of GABAergic drugs in the treatment of tobacco addiction. PMID- 22430318 TI - Assessment of intermolecular interactions at three sites of the arylalkyne in phenylacetylene-containing lithium-bonded complexes: ab initio and QTAIM studies. AB - The intermolecular interactions existing at three different sites between phenylacetylene and LiX (X = OH, NH(2) , F, Cl, Br, CN, NC) have been investigated by means of second-order Moller-Plesset perturbation theory (MP2) calculations and quantum theory of "atoms in molecules" (QTAIM) studies. At each site, the lithium-bonding interactions with electron-withdrawing groups (-F, -Cl, -Br, -CN, -NC) were found to be stronger than those with electron-donating groups (-OH and -NH(2)). Molecular graphs of C(6)H(5)C=CH...LiF and piC(6)H(5)C=CH...LiF show the same connectional positions, and the electron densities at the lithium bond critical points (BCPs) of the piC(6)H(5)C=CH...LiF complexes are distinctly higher than those of the sigmaC(6)H(5)C=CH...LiF complexes, indicating that the intermolecular interactions in the C(6)H(5)C=CH...LiX complexes can be mainly attributed to the pi-type interaction. QTAIM studies have shown that these lithium-bond interactions display the characteristics of "closed-shell" noncovalent interactions, and the molecular formation density difference indicates that electron transfer plays an important role in the formation of the lithium bond. For each site, linear relationships have been found between the topological properties at the BCP (the electron density rho(b), its Laplacian ?(2)rho(b), and the eigenvalue lambda(3) of the Hessian matrix) and the lithium bond length d(Li-bond). The shorter the lithium bond length d(Li-bond), the larger rho(b), and the stronger the pi...Li bond. The shorter d(Li-bond), the larger ?(2)rho(b), and the greater the electrostatic character of the pi...Li bond. PMID- 22430320 TI - [The first e-HEART: online-only publications - more flexibility]. PMID- 22430321 TI - [Arterial hypertension in patients with coronary artery disease]. AB - Arterial hypertension is the most important risk factor for coronary artery disease (CAD). There is a high coincidence of both diseases, whereby both impair coronary microcirculatory function synergistically, which can be measured functionally by decreased coronary flow reserve. This dysfunction leads to permanent damage to the left ventricular myocardium. Lifestyle changes play a central role in the primary and secondary prevention of CAD. Additionally, there are well-established options for antihypertensive drug therapy, which should be combined with aspirin and statins. Pharmacological treatment should follow distinctive blood pressure goals in relation to the severity of CAD. Particular attention is paid in this context to the relation between diastolic blood pressure values and cardiovascular endpoints, which displays a j-shaped curve with the lowest risk at levels between 70 and 90 mmHg. PMID- 22430322 TI - New aspects in the epidemiology of craniofacial anomalies. PMID- 22430323 TI - Impending federal cuts in graduate medical education funding: an urgent threat to neurosurgery training and manpower. PMID- 22430324 TI - Acute stroke therapy: are we ready for primetime clinical trials? PMID- 22430325 TI - FoxM1 is vital in the Wnt/beta-catenin signaling pathogenesis of gliomas. PMID- 22430326 TI - Carotid plaque signal differences among four kinds of T1-weighted magnetic resonance imaging techniques: a histopathological correlation study. AB - INTRODUCTION: Several magnetic resonance (MR) imaging techniques are used to examine atherosclerotic plaque of carotid arteries; however, the best technique for visualizing intraplaque characteristics has yet to be determined. Here, we directly compared four kinds of T1-weighted (T1W) imaging techniques with pathological findings in patients with carotid stenosis. METHODS: A total of 31 patients who were candidates for carotid endarterectomy were prospectively examined using a 1.5-T MRI scanner, which produced four kinds of T1W images, including non-gated spin echo (SE), cardiac-gated black-blood (BB) fast-SE (FSE), magnetization-prepared rapid acquisition with gradient echo (MPRAGE), and source image of three-dimensional time-of-flight MR angiography (SI-MRA). The signal intensity of the carotid plaque was manually measured, and the contrast ratio (CR) against the adjacent muscle was calculated. CRs from the four imaging techniques were compared to each other and correlated with histopathological specimens. RESULTS: CRs of the carotid plaques mainly containing fibrous tissue, lipid/necrosis, and hemorrhage were significantly different with little overlaps (range: 0.92-1.15, 1.22-1.52, and 1.55-2.30, respectively) on non-gated SE. However, BB-FSE showed remarkable overlaps among the three groups (0.89-1.10, 1.07-1.23, and 1.01-1.42, respectively). MPRAGE could discriminate fibrous plaques from hemorrhagic plaques but not from lipid/necrosis-rich plaques: (0.77 1.07, 1.45-2.43, and 0.85-1.42, respectively). SI-MRA showed the same tendencies (1.01-1.39, 1.45-2.57, and 1.12-1.39, respectively). CONCLUSION: Among T1W MR imaging techniques, non-gated SE images can more accurately characterize intraplaque components in patients who underwent CEA when compared with cardiac gated BB-FSE, MPRAGE, and SI-MRA images. PMID- 22430327 TI - Self-assembling porphyrins and phthalocyanines for photoinduced charge separation and charge transport. AB - Large pi-conjugated compounds are promising building blocks for organic thin-film electronics such as organic light-emitting diodes, organic field-effect transistors, and organic photovoltaics. Utilization of porphyrins and phthalocyanines for this purpose is highly fascinating because of their excellent electric, photophysical, and electrochemical properties as well as intense self assembling abilities arising from pi-pi stacking interactions. This paper focuses on fundamental aspects of self-assembled structures that have been obtained from porphyrin and phthalocyanine building blocks and more complex composites for photoinduced charge separation and charge transport toward the potential applications to organic thin-film electronics. PMID- 22430328 TI - A temporal model for nonelite triathlon race injuries. AB - OBJECTIVE: To (1) classify types and severity of injuries, (2) establish a temporal model for both the incidence and prevalence of injuries, and (3) identify the most appropriate medical manpower needed for nonelite triathlon competition. DESIGN: Prospective observational study. SETTING: Oklahoma City Redman Triathlon. PARTICIPANTS: One hundred four triathletes seeking medical care (575 race starters). MAIN OUTCOME MEASURES: Prevalence and diagnoses of athletes seeking medical care, 15-minute injury incidence reports with severity classification, and duration of treatment. RESULTS: The prevalence of injuries sustained was 37.7% and 10.8% in the Ironman and half Ironman events, respectively. 72.2% of half Ironman injuries were sustained during hours 6 and 7, with a presentation rate of 78 per 1000 race starters during this time interval. The Ironman had a much higher rate of severe injuries at 38.2% +/- 6.0% (95% confidence interval) and a longer average duration of treatment culminating in hour 14 at 62.3 minutes. CONCLUSIONS: Triathlon medical support should be modified to fit the temporal flow of injuries sustained throughout nonelite Ironman events. Previous studies have made recommendations from data collected from elite competitions that may not be ideal for nonelite races due to the higher rate of injuries, injury severity, and longer duration competition. Therefore, we recommend increasing support by 20% during the latter stages of triathlons, starting at hour 14, to 3 physicians and 9 nurses and other medical volunteers per 100 competitors. Further research into the implementation of these strategies should be performed before these data should be applied as common practice. PMID- 22430329 TI - Musculoskeletal injuries in elite able-bodied and wheelchair foil fencers--a pilot study. AB - OBJECTIVE: To explore the incidence of musculoskeletal injuries in elite able bodied and wheelchair foil fencers. DESIGN: A 3-year prospective cohort study of sport injuries during 2006-2009. SETTING: A sample of elite able-bodied fencers (AFs) and wheelchair fencers (WFs) from the Hong Kong National Squad. PARTICIPANTS: A total of 14 wheelchair and 10 able-bodied elite fencers completed the 3-year study. METHODS: Monthly interviews with fencers to collect data related to their injuries. MAIN OUTCOME MEASURES: The incidence rate and relative risk of injury were analyzed among able-bodied and WFs with different trunk control ability. RESULTS: Wheelchair fencers had higher overall injury incidence rate (3.9/1000 hours) than AFs (2.4/1000 hours). Wheelchair fencers with poor trunk control were more vulnerable to injuries (4.9/1000 hours) than those with good trunk control (3.0/1000 hours). Upper extremity injuries were predominant in WFs (73.8%), with elbow (32.6%) and shoulder strain (15.8%) being the most common injuries. Lower extremity injuries were predominant in AFs (69.4%), with muscle strain over knee and thigh region (22.6%), ankle sprain (14.5%), and knee sprain (11.3%) being the leading injuries. CONCLUSIONS: Results of this pilot study highlighted the distinct injury incidence between the 2 different fencer groups. Larg-scale epidemiologic and biomechanical studies are warranted to improve the understanding of fencing injuries to develop specific injury prevention/rehabilitation programs. PMID- 22430330 TI - Acoustofluidics 10: scaling laws in acoustophoresis. AB - In Part 10 of the thematic tutorial series "Acoustofluidics-exploiting ultrasonic standing waves forces and acoustic streaming in microfluidic systems for cell and particle manipulation", we present and analyze a number of scaling laws relevant for microsystem acoustophoresis. Such laws are useful both in understanding, designing, and analyzing acoustofluidic devices. PMID- 22430331 TI - New problems in the scope-of-practice controversy. PMID- 22430332 TI - Osteoma of the external auditory canal. PMID- 22430333 TI - Infantile fibrosarcoma of the maxillary sinus: significant response. PMID- 22430334 TI - Oral lichen planus. PMID- 22430335 TI - Is there an ototoxicity risk from Cortisporin and comparable otic suspensions? Distortion-product otoacoustic emission findings. AB - The purpose of this investigation was to use distortion-product otoacoustic emission (DPOAE) testing to address the issue of possible ototoxicity from the use of neomycin/polymyxin B/hydrocortisone otic suspension following tympanostomy tube placement. We retrospectively reviewed our clinical records and identified 36 children (52 ears) who had met our three study criteria: (1) unilateral or bilateral placement of transtympanic ventilation tubes, (2) treatment for 3 to 5 days with neomycin/polymyxin B/hydrocortisone drops, and (3) postoperative evaluation by DPOAE testing. We identified another set of 36 children (52 ears) who had not received these drops and who had not undergone tube placement but who had been evaluated by DPOAE testing to serve as a control group. We found no significant differences in DPOAE amplitudes between the treatment and control groups. These findings are consistent with decades of clinical experience indicating that neomycin/polymyxin B/hydrocortisone otic suspension is safe when used responsibly. PMID- 22430336 TI - Otomycosis in immunocompetent and immunocompromised patients: comparative study and literature review. AB - A comparative clinical study was carried out that included 50 cases of otomycosis in immunocompetent patients and 50 cases of otomycosis in immunocompromised patients. Clinical presentation, predisposing factors, mycologic profile, and treatment outcomes were compared. Aspergillus spp were the most commonly isolated fungi in the immunocompetent group, and Candida albicans in the immunocompromised group. Bilateral involvement was more common in the immunocompromised group. All the patients were treated with topical clotrimazole ear drops. Four patients in the immunocompromised group did not respond to treatment with clotrimazole but were treated successfully with fluconazole ear drops. Three patients had a small tympanic membrane perforation due to otomycosis. PMID- 22430337 TI - Nasal eosinophilia as a marker for allergic rhinitis: a controlled study of 50 patients. AB - Eosinophils are the principal effector cells involved in the pathogenesis of allergic inflammation. We conducted a study to investigate the validity of the nasal smear examination for detecting eosinophilia in patients with allergic rhinitis. Our study group was made up of 50 patients with allergic rhinitis and 50 age- and sex-matched controls without allergic rhinitis. Smears were obtained from nasal secretions in both groups and then fixed, stained, and studied under light microscopy. Statistical analysis revealed that the odds ratio for eosinophilia positivity in nasal smears in the rhinitis group was 25.61 with a 95% confidence interval of 8 to 78. The sensitivity, specificity, positive predictive value, and negative predictive value of this test were 74, 90, 88, and 77%, respectively. We conclude that the nasal eosinophilia test is highly specific and moderately sensitive in diagnosing allergic rhinitis, and that it therefore can be used as an easy, noninvasive, and inexpensive procedure for screening patients and for conducting epidemiologic studies of this disorder. PMID- 22430338 TI - An analysis of salivary gland neoplasms: a 12-year, single-institution experience in Turkey. AB - The epidemiology of salivary gland tumors worldwide is not very well defined. Although many studies on this subject have been undertaken, the data are generally focused on specific topics such as parotid gland neoplasms or tumors of the major salivary glands. We conducted a study to establish the prevalence and distribution of benign and malignant neoplasms of both the major and minor salivary glands at a single institution. We reviewed 244,204 cases that had come through our pathology department from January 1994 through December 2005 and found 235 cases of a salivary gland neoplasm (0.09%). The female-to-male ratio was 1.04:1, and the mean age of the patients was 47 years. Of the 235 neoplasms, 159 (67.66%) were located in the parotid gland, 34 (14.47%) in the submandibular gland, and 42 (17.87%) in the minor salivary glands. A total of 146 tumors (62.13%) were benign and 89 (37.87%) were malignant. Pleomorphic adenoma was the most common neoplasm, occurring in 98 cases (41.70%). The most common malignancy was mucoepidermoid carcinoma, with 27 cases (11.49%). Our data demonstrate that the characteristics of salivary gland tumors in a Turkish population at a single institution are similar to those reported in the literature worldwide. PMID- 22430339 TI - The effects of tumor size, degree of differentiation, and depth of invasion on the risk of neck node metastasis in squamous cell carcinoma of the oral cavity. AB - Cervical lymph node metastasis is the most important prognostic factor in patients with head and neck carcinoma. We retrospectively analyzed the effects of three different variables-tumor size, degree of differentiation, and depth of invasion-on the risk of neck node metastasis in 50 adults who had been treated with surgery for primary squamous cell carcinoma of the oral cavity. Primary tumor depth and other pathologic features were determined by reviewing the pathology specimens. Preoperatively, 36 of the 50 patients were clinically N0; however, occult lymph node metastasis was found in 13 of these patients (36.1%). The prevalence of neck node metastasis in patients with T1/T2 and T3/T4 category tumors was 51.5 and 58.8%, respectively. The associations between the prevalence of neck node metastasis and both the degree of differentiation and the depth of invasion were statistically significant, but there was no significant association between neck node metastasis and tumor size. We conclude that the prevalence of neck lymph node metastasis in patients with squamous cell carcinoma of the oral cavity increases as the tumor depth increases and as the degree of tumor differentiation decreases from well to poor, as has been shown in previous studies. It is interesting that tumor size, which is the most important component of the TNM system, was not significantly associated with neck node involvement. PMID- 22430340 TI - Outcomes of intubation in difficult airways due to head and neck pathology. AB - The purpose of this study was to examine the impact of surgical pathology, anesthesiologist experience, and airway technique on surgically relevant outcomes in patients identified by preoperative laryngoscopy to have a difficult airway due to head and neck pathology. We prospectively recorded a series of 152 difficult airway cases due to head and neck pathology out of 2,145 direct laryngoscopies undertaken between November 2005 and June 2008. One of two senior anesthesiologists specializing in head and neck procedures intubated 101 (66.4%) of the 152 patients and did so 3.3 minutes faster (p = 0.51), with better oxygenation (87.3 vs. 81.8%; p = 0.02) and fewer airway plan changes (p = 0.001) than did other, nonspecialist anesthesiologists. Predictors of failure of the first intubation plan included: cancer diagnosis (p = 0.02), previous radiotherapy (p = 0.03), and supraglottic lesions (p = 0.03). Glottic/subglottic lesions required the most intubation attempts (p = 0.02). Awake fiberoptic intubation was the most common method used (44.7%) but resulted in a change in the airway plan in 6 cases (8.8%). Gas induction maintained the best oxygenation (p = 0.01). Awake tracheostomy was infrequent (1.3%) and took the longest (p = 0.006). We concluded that difficult airways due to head and neck pathology require teamwork and a backup plan. An anesthesiologist specializing in head and neck procedures may help to avoid adverse outcomes associated with cancer, especially previously irradiated supraglottic/glottic lesions, leading to a less frequent need for awake tracheostomy. PMID- 22430341 TI - Rhinoplasty and septorhinoplasty outcome evaluation. AB - Outcome measures are a crucial tool in the analysis and comparison of medical interventions. We review the subjective and objective methods of assessing outcomes of rhinoplasty and septorhinoplasty. Both form and function of the nose are considered. PMID- 22430342 TI - Is there a need for audiologic evaluation in patients with Behcet disease? AB - Behcet disease is known to be a multisystem condition. We conducted a study to determine the prevalence of hearing loss in patients with Behcet disease and to identify any associations between audiologic findings and other clinical manifestations and treatment. Our study group was made up of 41 adults with Behcet disease and 41 healthy sex- and age-matched controls. All patients and controls underwent a complete clinical otolaryngologic examination, which included pure-tone audiometry, acoustic impedance testing, and otoacoustic emissions testing. Audiology revealed that the prevalence of sensorineural hearing loss (SNHL) was significantly higher in the Behcet patients than in the controls-68.3 vs. 22.0% (p < 0.002). The duration of Behcet disease had no significant impact on whether patients did or did not experience hearing loss. Hearing loss was the fourth most common clinical finding in the Behcet group, after oral ulcers, genital ulcers, and skin lesions. We conclude that SNHL is present in a significant number of Behcet patients, and we suggest the need for an adequate investigation of hearing in the routine follow-up of these patients. PMID- 22430343 TI - Neuroendocrine carcinoma of the head and neck: a 20-year case series. AB - Neuroendocrine carcinoma (NEC) can be an aggressive disease with locoregional and distant metastasis. We present this article (1) to highlight the typical presentation of NEC in head and neck primary sites such as the parotid gland, paranasal sinuses, and supraglottis and (2) to discuss the prognosis of these tumors based on their histologic subtype and stage. We base our comments on the findings of our retrospective review of the cases of 16 adults-10 men and 6 women, aged 43 to 88 years (mean: 65.8)-who had been diagnosed with pathologically confirmed NEC of the head and neck. Analysis of subtypes revealed that 11 of these patients (68.8%) had presented with poorly differentiated NEC, 4 (25.0%) with moderately differentiated NEC, and 1 (6.3%) with well-differentiated NEC. The most common primary sites were the salivary glands (n = 5; 31.3%), paranasal sinuses (n = 4, 25.0%), and larynx (n = 4). There was no statistically significant difference in survival at 24 months between the patients with moderately differentiated NEC and those with poorly differentiated NEC (37.5 vs. 35.4%; p = 0.86); at the end of the study period, the patient with well differentiated NEC was still living, 129 months after diagnosis. Taken together, patients with stage I, II, and III disease had a combined survival of 77.8% at 12 months, which was significantly higher (p = 0.023) than the 57.1% survival at 12 months for patients with stage IV disease. PMID- 22430344 TI - A prospective study to evaluate the efficacy of isopropyl alcohol irrigations to prevent cerumen impaction. AB - We conducted a prospective crossover study to assess the safety and efficacy of 70% isopropyl alcohol delivered from a squeezable bottle with a specially designed tip as a weekly irrigant to reduce cerumen accumulation. Twenty patients were divided into 2 groups of 10 (20 ears in each group). The patients in group 1 instilled 70% isopropyl alcohol once a week for 2 months; this was followed by 2 months of no ear cleaning. The patients in group 2 performed the opposite routine. At each visit (0, 2, and 4 mo), cerumen accumulation was graded on a scale of 0 to 4, indicating 0, 25, 50, 75, and 100% occlusion, respectively. After the accumulation was graded, a cerumenectomy was performed. At the initial evaluation, the mean occlusion scores were 3.1 for group 1 and 3.3 for group 2 not a statistically significant difference. After the first 2 months of the study, there was a significant difference in occlusion scores between groups 1 and 2 (0.75 and 1.55, respectively; p < 0.0002). At 4 months, after the crossover, the occlusion scores were 1.15 and 0.95, respectively, not a significant difference (p = 0.38). At study's end, there were also significant differences within each group between occlusion scores obtained during the treatment and nontreatment periods (group 1: p < 0.02; group 2: p < 0.01). All patients tolerated the alcohol rinse well, and there were no cases of external otitis or other complications. We conclude that weekly irrigation with 70% isopropyl alcohol is safe and reduces the accumulation of cerumen in the external auditory canal. Routine use should decrease the number of office visits for cerumen removal and hearing aid cleaning. PMID- 22430345 TI - Frontal infundibular cells: pathway to the frontal sinus. AB - A frontal infundibular cell (FIC) is an uncommon anatomic variant of an anterior ethmoid pneumatization that originates from the frontal recess and typically extends into the lumen of the frontal sinus ostium. FICs may show several anatomic variants that impact the anatomy of the frontal recess. Familiarity with these variants is required for safe endoscopic sinus surgical procedures. We conducted a retrospective chart review, examining 1,040 frontal recesses in 520 adults with no frontal sinus disease, to explore the anatomy of the healthy frontal recess and to describe the prevalence of FICs in patients without a history of conditions that cause frontal pneumatization. Review of axial and coronal computed tomography data, which were reformatted for sagittal reconstruction, was performed at a computer workstation. Bent and Kuhn's classification was used to define types of FICs. We identified 167 patients (32.1%) as having unilateral or bilateral FICs. Type I infundibular cells were the most common type (found in 15.7% of the entire study population). Type II and type III FICs were found in 3.8% and 12.1%, respectively; type IV FICs were present in 0.4%. The FIC has not been emphasized as an important potential cause of frontal sinus obstruction in the radiology literature, but clinicians should specifically watch for it on all routine computed tomography of the frontal sinus. Fine-cut computed tomography scans aid in the identification of each individual cell and allow the surgeon to formulate a clear and precise surgical plan. A surgical plan with a thorough understanding of the anatomy enables confident dissection of this complex and difficult area. PMID- 22430346 TI - Two-flap palatoplasty: description of the surgical technique and reporting of results at a single center. AB - Two-flap palatoplasty is commonly used to treat cleft palate defects, but only a few reports on outcomes have been published in the literature. We conducted a retrospective analysis of 257 cases of cleft palate treated with two-flap palatoplasty at a single center in Greece over a 13-year period. Our outcomes data included surgical complication rates, the results of speech assessments, midface development, and other parameters. We found a low rate of short- and long term complications that required revision surgery, such as symptomatic fistula (5.4%) and velopharyngeal insufficiency (5.3%). Speech outcomes in relation to intelligibility, hypernasality, and nasal emissions were satisfactory in 70 to 86% of patients. Dental arch relationships, as estimated by the 5-Year-Olds Index, were judged to be either good or excellent in 62% of those evaluated. A considerable proportion of patients (45%) who had otitis media with effusion experienced a spontaneous resolution without the use of tympanostomy tubes 2 to 8 months after their operation. We conclude that two-flap palatoplasty is an effective procedure that warrants further attention. We describe the surgical technique in detail. Our technique includes a modified intravelar veloplasty that incorporates near-total muscle retropositioning. PMID- 22430347 TI - Ventricular cyst of the larynx. PMID- 22430348 TI - Endoscopic view of maxillary ostia mimicking a maxillary sinus wall. PMID- 22430349 TI - The association between Helicobacter pylori and laryngopharyngeal reflux in laryngeal pathologies. AB - We conducted a study to determine the presence or absence of Helicobacter pylori and laryngopharyngeal reflux (LPR) in 43 previously untreated patients who had presented with a laryngeal lesion. Our aim was to determine if there was any association among H pylori, LPR, and laryngeal lesions. H pylori status was determined by real-time polymerase chain reaction (PCR) assays of biopsy tissue obtained during direct laryngoscopy. The presence or absence of LPR was determined on the basis of patients' reflux symptom index (RSI) and reflux finding score (RFS), which were based on their questionnaire responses and findings on endoscopic examination of the larynx, respectively. Patients with an RSI of 14 or more and/or an RFS of 8 or more were considered to have LPR. H pylori was present in 24 patients (55.8%) and absent in 19 (44.2%)-not a statistically significant difference. The prevalence of LPR was higher than the prevalence of H pylori; it was present in 30 patients (69.8%) and absent in 13 (30.2%). The difference was statistically significant (p = 0.01). We found no association between H pylori status and LPR status. Additionally, we analyzed two subgroups based on whether their lesions were benign or malignant/premalignant and found a significant relationship between LPR positivity and the presence of malignant/premalignant laryngeal lesions (p = 0.03). We found no association between H pylori status and either of the two subgroup categories. PMID- 22430350 TI - GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia. AB - A Japanese patient presented with lymphedema, severe Varicella zoster, and Salmonella infection, recurrent respiratory infections, panniculitis, monocytopenia, B- and NK-cell lymphopenia, and myelodysplasia. The phenotype was a mixture of the monocytopenia and mycobacterial infection (MonoMAC) and Emberger syndromes. Sequencing of the GATA-2 cDNA revealed the heterozygous missense mutation 1187 G > A. This mutation resulted in the amino acid mutation Arg396Gln in the zinc fingers-2 domain, which is predicted to cause significant structural change and prevent a critical interaction with DNA. Functional analysis of the patient's GATA-2 mutation is required to understand the relationship between these distinctive syndromes. PMID- 22430351 TI - 2009 H1N1: risk factors for hospitalization in a matched case-control study. AB - In order to compare sociodemographical data and preexisting risk medical conditions in patients requiring hospital admission for 2009 pandemic influenza A (H1N1) virus infection and those managed on an outpatient basis, a prospective observational, matched case-control study in 36 hospitals of the Spanish National Health Service was conducted from July 2009 to February 2010. Cases were patients aged 6 months to 18 years hospitalized for influenza syndrome, in whom 2009 influenza A (H1N1) virus infection was confirmed using real-time reverse transcription polymerase chain reaction. Controls were patients aged 6 months to 18 years with confirmed 2009 influenza A (H1N1) infection managed on an outpatient basis. There were 195 cases and 184 controls. In a multivariate model, hospitalization was more frequent in children aged <2 years (odds ratio (OR), 13.8; 95% confidence interval (CI), 1.7-106.4), those with neurological and/or neuromuscular diseases (OR, 3.0; 95% CI, 1.1-8.2), and those whose parents had less than a secondary educational level (OR, 2.7; 95% CI, 1.4-5.2). Children aged <2 years, children with neurological diseases, and children from families with a lower educational status had a higher risk of hospitalization due to influenza A (H1N1) 2009 infection. PMID- 22430352 TI - Population-based centile curves for triceps, subscapular, and abdominal skinfold thicknesses in Polish children and adolescents--the OLAF study. AB - Skinfold thicknesses are used as valid anthropometric indicators of regional body fatness. Actual population-based values for skinfold thicknesses for Polish children are not available. The purpose of this study was to provide population based values for triceps, subscapular, and abdominal skinfold thicknesses in healthy children and adolescents. A total number of 17,416 boys and girls aged 6.5-18.5 years, randomly selected from whole Polish population of children and adolescents, were enrolled in the study. Skinfold thicknesses (triceps, subscapular, and abdominal) were measured using Harpenden skinfold caliper. All measurements were taken after the training of participating investigators. The LMS method was used to fit percentile curves across age for each skinfold. Q tests for fit were used to assess the global goodness of fit of our final models. The study shows for the first time smoothed population-based values of body fat distribution indices for Polish children and adolescents 7-18 years of age. Reported skinfold centiles are higher compared to previously established for Warsaw children and very close to the actual US data. CONCLUSION: Our study provided for the first time population-based values for skinfold thicknesses evaluation in a way allowing to calculate reliable Z scores. The early detection of abnormal fat stores, using our population-based values and respective Z scores, may be now implemented for practice. PMID- 22430353 TI - Antibiotic resistance of Helicobacter pylori in pediatric patients -- 10 years' experience. AB - The aim of this study was to assess the pattern of evolution of resistance to antibiotics in Helicobacter pylori isolated from children who underwent upper endoscopy with antral biopsy during a 10-year period (2001-2010). We retrospectively analyzed data of all children (n = 3,008) who underwent upper endoscopy during the observed period at the Children's Hospital Zagreb, a university tertiary medical center. We calculated the rate, antibiotic susceptibility and risk factors for the H. pylori infection in our cohort. Antral biopsy was performed in 2,313 (76.89%) patients. Altogether, 382 (16.51%) children had positive biopsy for H. pylori (histology and/or culture). There was no significant difference in the incidence of H. pylori during 10 years of observation (p = 0.21). Infected children compared to non-infected group were older (p = 0.005), and had more often antral nodularity (p < 0.0001), and duodenal ulcer (p = 0.002). Altogether, 22.4% of treatment-naive patients had strains resistant to tested antibiotics: majority to azithromycin (17.9%), followed by clarithromycin (11.9%), metronidazole (10.1%) and amoxicillin (0.6%). In the eradication failure group, 9/11 of children had strains resistant to tested antibiotics, mostly to metronidazole (7/11), followed by azithromycin (3/11) and clarithromycin (1/11). No correlation was found between age or gender and antibiotic resistance (p = 0.32, for both). In conclusion, our data strongly support current guidelines which recommend antibiotic susceptibility testing prior to eradication therapy. Based on our results we recommend the use of amoxicillin-metronidazole-based regimen as the first-line therapy in our study population. PMID- 22430354 TI - NMR-based metabonomics detection of differences in the metabolism of hydrolysed versus intact protein of similar amino acid profile. AB - BACKGROUND: Proton nuclear magnetic resonance (NMR)-based metabonomics has only recently been applied to nutritional research. The limitation of any analytical technique is its sensitivity in detecting the smallest variation. Alterations in nutrition often produce only subtle metabolic modulations. The objective of this study was to determine if NMR-based metabonomics could detect variations in the metabolic profile of urine from pigs digesting either native casein (NC) or the same casein that had been enzymatically hydrolysed (EHC). NMR permits simultaneous detection of a large number of metabolites, thus allowing detection of unanticipated metabolic fluctuations that may otherwise have gone undetected with the use of only targeted analysis. RESULTS: Partial least squares discriminant analysis identified significantly (P < 0.05) higher urinary excretions of leucine, valine, taurine and glycine by pigs on the EHC-based diet. CONCLUSION: NMR-based metabonomics is a sensitive method that can uncover unanticipated metabolic changes brought about by physicochemical changes to the feedstock (i.e. hydrolysis). The data show a lower efficiency of retention by the kidney of some amino acids following ingestion of a hydrolysed protein. PMID- 22430355 TI - Overlapping genes may control reprogramming of mouse somatic cells into induced pluripotent stem cells (iPSCs) and breast cancer stem cells. AB - Recent findings suggest the possibility that tumors originate from cancer cells with stem cell properties. The cancer stem cell (CSC) hypothesis provides an explanation for why existing cancer therapies often fail in eradicating highly malignant tumors and end with tumor recurrence. Although normal stem cells and CSCs both share the capacity for self-renewal and multi-lineage differentiation, suggesting that CSC may be derived from normal SCs, the cellular origin of transformation of CSCs is debatable. Research suggests that the tightly controlled balance of self-renewal and differentiation that characterizes normal stem cell function is dis-regulated in cancer. Additionally, recent evidence has linked an embryonic stem cell (ESC)-like gene signature with poorly differentiated high-grade tumors, suggesting that regulatory pathways controlling pluripotency may in part contribute to the somatic CSC phenotype. Here, we introduce expression profile bioinformatic analyses of mouse breast cells with CSC properties, mouse embryonic stem (mES) and induced pluripotent stem (iPS) cells with an emphasis on how study of pluripotent stem cells may contribute to the identification of genes and pathways that facilitate events associated with oncogenesis. Global gene expression analysis from CSCs and induced pluripotent stem cell lines represent an ideal model to study cancer initiation and progression and provide insight into the origin cancer stem cells. Additionally, insight into the genetic and epigenomic mechanisms regulating the balance between self-renewal and differentiation of somatic stem cells and cancer may help to determine whether different strategies used to generate iPSCs are potentially safe for therapeutic use. PMID- 22430356 TI - Three dimensional model for N-terminal A domain of DmpR (2-dimethylphenol) protein based on secondary structure prediction and fold recognition. AB - DmpR (dimethylphenol regulatory protein) is a member of the NtrC family of transcriptional activators and controls the transcription of the dmp operons in response to aromatic effector compounds. Secondary structure and fold recognition prediction of N-terminal A domain of this protein (210 amino acid) was performed in Genesilico Metaserver and 3DJury. The consensus result from these servers suggested MJ_1460 as a template. Three dimensional structures were generated from the sequence structure alignments of the template and target protein with MODELLER. The results suggested that the N-terminal A domain of DmpR belongs to Muramoyl pentapeptide carboxypeptidase domain family. The binding interaction sites of the known effectors were predicted using protein-ligand docking. The proposed active site of N-terminal A domain of DmpR comprises of key residues such as Phe93, Glu127, Phe132, Ser160, Phe163, Met164, Arg166 and Pro189. The findings provide some direction to the experimental studies that aim to broaden the range of phenolic derivative which can be sensed by N-DmpR in order to improve the biodegradation potential. PMID- 22430357 TI - A computational approach for identification of epitopes in dengue virus envelope protein: a step towards designing a universal dengue vaccine targeting endemic regions. AB - A major problem in designing vaccine for the dengue virus has been the high antigenic variability in the envelope protein of different virus strains. In this study, a computational approach was adopted to identify a multi-epitope vaccine candidate against dengue virus that may be suitable for large populations in the dengue-endemic regions. Different bioinformatics tools were exploited that helped the identification of a conserved immunological hot-spot in the dengue envelope protein. The tools also rendered the prediction of immunogenicity and population coverage to the proposed 'in silico' vaccine candidate against dengue. A peptide region, spanning 19 amino acids, was identified in the envelope protein which found to be conserved in all four types of dengue viruses. Ten proteasomal cleavage sites were identified within the 19-mer conserved peptide sequence and a total of 8 overlapping putative cytotoxic T cell (CTL) epitopes were identified. The immunogenicity of these epitopes was evaluated in terms of their binding affinities to and dissociation half-time from respective human leukocyte antigen (HLA) molecules. The HLA allele frequencies were studied among populations in the dengue endemic regions and compared with respect to HLA restriction patterns of the overlapping epitopes. The cumulative population coverage for these epitopes as vaccine candidates was high ranging from approximately 80% to 92%. Structural analysis suggested that a 9-mer epitope fitted well into the peptide-binding groove of HLA-A*0201. In conclusion, the 19-mer epitope cluster was shown to have the potential for use as a vaccine candidate against dengue. PMID- 22430358 TI - Models for cannabinoid-1 receptor antagonistic activity of substituted 2-(3 pyrazolyl)-1,3,4-oxadiazoles. AB - Antagonism of cannabinoid receptor-1 has emerged as a most promising therapeutic target for the development of anti-obesity drugs. In the present study, an in silico approach using decision tree, random forest and moving average analysis has been applied to a data set comprising of 76 analogues of substituted 2-(3 pyrazolyl)-1,3,4-oxadiazoles for development of models for prediction of antagonistic activity of cannabinoid receptor-1. A total of 46 2D and 3D molecular descriptors of diverse nature were employed for decision tree and random forest analysis. The values of majority of these descriptors for each analogue involved in the dataset were computed using E-Dragon software (version 1.0). Random forest correctly classified the analogues into active and inactive with an accuracy of 95%. A decision tree was also utilized for determining the importance of molecular descriptors. The decision tree learned the information from the input data with an accuracy of 99% and correctly predicted the cross validated (10 fold) data with an accuracy up to 90%. Finally, three molecular descriptors of diverse nature (including best descriptor identified by decision tree analysis) were subsequently used to build suitable models using moving average analysis. These models resulted in the prediction of cannabinoid receptor 1 antagonistic activity with an accuracy of 95-96%. High predictability of proposed models offer vast potential for providing lead structures for the development of potent cannabinoid receptor-1 antagonists for the treatment of obesity. PMID- 22430359 TI - In silico characterization of thermoactive, alkaline and detergent-stable lipase from a Staphylococcus aureus strain. AB - Bacterial true lipases having thermo and alkaline stability are highly attractive for their industrial production of pharmaceuticals, agrochemicals, cosmetics, and flavour. Staphylococcus aureus lipase (SAL3) remains active at temperatures 40-60 degrees C, with an optimum temperature of 55 degrees C and an optimum pH of 9.5 stable over a range of 5-12. Detailed understanding of the structure and insight into the activity of such lipase would aid in engineering lipases that would function in the desired extreme industrial environments. In the present study, we carried out in silico characterization and structural modeling of SAL3 which is thermoactive, alkaline and detergent-stable. Comparison of SAL3 with other staphylococcal lipases indicates that SAL3 is a true lipase having the catalytic triad (residues Ser119, Asp310 & His352) and the calcium binding site (residues Asp351, Asp354, Asp359, Asp362 and Gly286). Conservation in sequence implies that interfacial activation mechanism is possible in SAL3 with the lid formed by helix (residues 180-196) and loop (residues 197-206). Three dimensional (3D) structure model of SAL3 has been predicted for the first time and aims at understanding its function and biochemical characteristics of possessing relatively high thermal and pH stability. PMID- 22430361 TI - Brief report: concurrent validity of the Leiter-R and KBIT-2 scales of nonverbal intelligence for children with autism and language impairments. AB - The concurrent validity of the KBIT-2 Nonverbal IQ and Leiter-R Brief IQ was evaluated for two groups of children: those with high functioning autism and those with language impairments without autism. Fifty-three children between the ages of 4 and 13 years of age participated in the study. The correlation between the scales was large (r = .62) and no statistical difference was found between the means. However, large intraindividual differences were found for 11 children who received scores at least 10 points higher on the Leiter-R Brief IQ, 5 of those scored beyond 20 points higher than nonverbal scores on the KBIT-2. Conversely, 11 children scored at least 10 points higher on the KBIT-2 than on the Leiter-R with 4 of those scoring 20 points higher. These findings highlight the importance of using multiple measures when assessing individuals with autism or language disorders. PMID- 22430363 TI - Organization of the gymnotiform fish pallium in relation to learning and memory: IV. Expression of conserved transcription factors and implications for the evolution of dorsal telencephalon. AB - We have cloned the apteronotid homologs of FoxP2, Otx1, and FoxO3. There was, in the case of all three genes, good similarity between the apteronotid and human amino acid sequences: FoxP2, 78%; Otx1, 54%; FoxO3, 71%. The functional domains of these genes were conserved to a far greater extent, on average: FoxP2, 89%; Otx1, 76%; FoxO3, 82%. This led us to hypothesize that the cellular functions of these genes might also be conserved. We used in situ hybridization to examine the distribution of the mRNA transcripts of these genes in the apteronotid telencephalon. We confined our analysis to the pallial regions previously associated with learning about social signals, whose circuitry has been closely examined in the other articles of this series. We found that AptFoxP2 and AptOtx1 transcripts were expressed predominantly in the dorsocentral division of the pallium (DC); the dorsolateral division of the pallium (DL) contained only weakly labeled neurons. In both cases, the distribution of labeled neurons was very heterogeneous, and unlabeled neurons could be found adjacent to strongly labeled ones. In contrast, we found that most neurons in DL strongly expressed AptFoxO3 mRNA, although there was only weak expression in a small number of cells within DC. We briefly discuss the relevance of our results regarding the functional roles of AptFoxP2/AptOtx1-expressing neurons in DC for communication vs. foraging behavior. We extensively discuss the implications of our results for possible homologies between DL and DC and medial and dorsal pallium of tetrapods, respectively. PMID- 22430364 TI - Assessment and modulation of forsythiaside absorption with MDCKII cells and validation with in situ intestinal experiment. AB - Forsythiaside was characterized by low intestinal absorption by in situ rat experiment and Caco-2 cells. The mechanisms behind this low absorption had not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of forsythiaside as a potential mechanism for its low small-intestinal absorption following oral administration. Polarized MDCKII cell lines stably transfected with human or murine complementary DNA encoding for various efflux transporters (P-gp/MDR1, MRP2 and Bcrp1) were used to study transepithelial transport of forsythiaside and compare results with the MDCKII-Wild type cells. The transportation inhibitors GF120918, MK571 and Ko143 were used to investigate the transport mechanism. The active transport of forsythiaside was found in MDCKII-WT cells. The MDCKII-MRP2 and MDCKII-Bcrp1 cells significantly increased forsythiaside efflux ratio compared with the parental cells due to the apically directed transport by MRP2 and Bcrp1, respectively. The efflux ratios in MRP2 and Bcrp1 transfected cell lines were greatly decreased in the presence of MK-571 and Ko143, respectively, which indicated that forsythiaside efflux by MRP2 and Bcrp1 were significantly inhibited by their selective inhibitors. MDCKII-MDR1 cells did not exhibit a significant reduction in the forsythiaside efflux compared with the parental cells, indicating that it was not a good substrate for MDR1. And the results were then validated by the in situ experiment. This study presents direct evidence that forsythiaside is effluxed by both MRP2 and Bcrp1, which may contribute to its poor oral bioavailability. PMID- 22430366 TI - Morphological changes during annealing of polyethylene nanocrystals. AB - Polymer crystals are metastable and exhibit morphological changes when being annealed. To observe morphological changes on molecular scales we started from small nanometer-sized crystals of highly folded long-chain polymers. Micron-sized stripes consisting of monolayers or stacks of several layers of flat-on oriented polyethylene nanocrystals were generated via evaporative dewetting from an aqueous dispersion. We followed the morphological changes in time and at progressively higher annealing temperatures by determining the topography and viscoelastic properties of such assemblies of nanocrystals using atomic force microscopy. Due to smallness and high surface-to-volume ratio of the nanocrystals, already at 75 degrees C, i.e. about 60 degrees below the nominal melting point, the lateral size of the crystal coarsened. Intriguingly, this occurred without a noticeable reduction in the number of folds per polymer chain. Starting at around 110 degrees C, chain folds were progressively removed leading to crystal thickening. At higher temperatures, but still below the melting point, prolonged annealing allowed for surface diffusion of molten polymers on the initially bare substrate, leading eventually to the disappearance of crystals. We compared these results to the behavior of the same nanocrystals annealed in an aqueous dispersion and to bulk samples. PMID- 22430362 TI - Biological role of connexin intercellular channels and hemichannels. AB - Gap junctions (GJ) and hemichannels (HC) formed from the protein subunits called connexins are transmembrane conduits for the exchange of small molecules and ions. Connexins and another group of HC-forming proteins, pannexins comprise the two families of transmembrane proteins ubiquitously distributed in vertebrates. Most cell types express more than one connexin or pannexin. While connexin expression and channel activity may vary as a function of physiological and pathological states of the cell and tissue, only a few studies suggest the involvement of pannexin HC in acquired pathological conditions. Importantly, genetic mutations in connexin appear to interfere with GJ and HC function which results in several diseases. Thus connexins could serve as potential drug target for therapeutic intervention. Growing evidence suggests that diseases resulting from HC dysfunction might open a new direction for development of specific HC reagents. This review provides a comprehensive overview of the current studies of GJ and HC formed by connexins and pannexins in various tissue and organ systems including heart, central nervous system, kidney, mammary glands, ovary, testis, lens, retina, inner ear, bone, cartilage, lung and liver. In addition, present knowledge of the role of GJ and HC in cell cycle progression, carcinogenesis and stem cell development is also discussed. PMID- 22430367 TI - IgG gene expression and its possible significance in prostate cancers. AB - BACKGROUND: In spite of recent advances in treatment strategies, prostate cancer (PCa) remains the second leading cause of cancer death in men with its genetic and biologic behaviors still poorly understood. Recently, accumulating evidence indicates that cancer cells, as well as some normal cells can secret IgG. This study was designed to evaluate IgG gene expression and its possible significance in PCa tissue samples and cell lines. METHODS: IgG expression was assessed by immunohistochemistry, in situ hybridization, immunofluorescence, RT-PCR, and Western blot. The possible significance of IgG was evaluated on tissue array and cell lines. To assess cell viability and proliferation, MTS assay was carried out. Apoptosis was evaluated with propidium iodide and annexin-V staining. RESULTS: Expressions of IgG and its related genes were detected in cell lines. Abundant gene expressions of Iggamma and Igkappa chain were detected in PCa tissue samples, but not in normal prostate tissues. In addition, IgG expression was significantly higher in PCa tissues than in the benign prostate hyperplasia tissues (P < 0.001). Iggamma expression was positively correlated to Gleason score and histological grade (P < 0.05). Furthermore, in vitro experiments showed that anti-human monoclonal IgG antibody suppressed cell proliferation and increased apoptosis in cultured PCa cells. CONCLUSION: IgG gene expression in PCa is related to cell differentiation and clinical status. PCa cell produced IgG is involved in the biological behavior of this cancer and may serve as a useful marker for cancer cell differentiation and prognosis. Locally produced IgG could be a potential target for therapy. PMID- 22430368 TI - Andrological aspects of physical exercise and sport medicine. AB - Appropriate physical activity is one of the bases of healthy lifestyle. In fact, physical exercise and playing sport may be associated with both improvements and injury to both general and reproductive health. A biologically normal testosterone secretion appears fundamental in males to guarantee both a physiological exercise adaptation and safe sport participation. The reproductive system is highly sensitive to the effects of exercise-related stress and the reproductive hormones may both increase and decrease after different acute or chronic exercises. Exercise and sport participation may positively or negatively influence andrological health status depending on the type, intensity and duration of performed physical activity and on individual health status. In addition, prohibited substances administration (e.g. androgenic-anabolic steroids, and so forth) in competitive and non-competitive athletes represents the main cause of iatrogenic andrological diseases. Preventing and treating andrological problems in active healthy and unhealthy individuals is as important as promoting a correct lifestyle. Physicians need to be educated on the relationships between the male reproductive system and sport participation and on the great role of the pre-participation physical examination in the prevention of andrological diseases. PMID- 22430369 TI - Comparability of imazapyr-resistant Arabidopsis created by transgenesis and mutagenesis. AB - The Arabidopsis CSR1 gene codes for the enzyme acetohydroxyacid synthase (AHAS, EC 2.2.1.6), also known as acetolactate synthase, which catalyzes the first step in branched-chain amino acid biosynthesis. It is inhibited by several classes of herbicides, including the imidazolinone herbicides, such as imazapyr; however, a substitution mutation in csr1-2 (Ser-653-Asn) confers selective resistance to the imidazolinones. The transcriptome of csr1-2 seedlings grown in the presence of imazapyr has been shown in a previous study (Manabe in Plant Cell Physiol 48:1340 1358, 2007) to be identical to that of wild-type seedlings indicating that AHAS is the sole target of imazapyr and that the mutation is not associated with pleiotropic effects detectable by transcriptome analysis. In this study, a lethal null mutant, csr1-7, created by a T-DNA insertion into the CSR1 gene was complemented with a randomly-inserted 35S/CSR1-2/NOS transgene in a subsequent genetic transformation event. A comparison of the csr1-2 substitution mutant with the transgenic lines revealed that all were resistant to imazapyr; however, the transgenic lines yielded significantly higher levels of resistance and greater biomass accumulation in the presence of imazapyr. Microarray analysis revealed few differences in their transcriptomes. The most notable was a sevenfold to tenfold elevation in the CSR1-2 transcript level. The data indicate that transgenesis did not create significant unintended pleiotropic effects on gene expression and that the mutant and transgenic lines were highly similar, except for the level of herbicide resistance. PMID- 22430370 TI - Assessment of ab initio MP2 and density functionals for characterizing the potential energy profiles of the SN2 reactions at N center. AB - The potential energy profiles of five selected bimolecular nucleophilic substitution (S(N) 2) reactions at nitrogen (N) center have been reinvestigated with the CCSD(T), G3[MP2,CCSD(T)], MP2, and some density functional methods. The basis sets of 6-31+G(d,p) and 6-311+G(3d,2p) are used for the MP2 and density functional calculations. Taking the relative energies at the CCSD(T)/CBS level of theory as benchmarks, we recommend the MP2, B97-K, B2K-PLYP, BMK, omegaB97X-D, M06-2X, M05-2X, CAM-B3LYP, M08-SO, and omegaB97X methods to generally characterize the potential energy profiles for the S(N)2 reactions at N center. Furthermore, these recommended methods with the relatively small 6-31+G(d,p) basis set may also be used to perform direct classical trajectory simulations to uncover the dynamic behaviors of the S(N)2 reactions at N center. PMID- 22430371 TI - Organic base-catalyzed stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4 trifluorobutanoic acids. AB - Organic base-catalyzed reaction of (S)-N-tert-butanesulfinyl (3,3,3) trifluoroacetaldimine with dialkyl malonates was found to be effective for synthesis of both (S,S(S)) and (R,S(S)) beta-aminomalonates in high yield with good to excellent diastereoselectivity (76-98% de). The products of this Mannich reaction provide direct access to beta-trifluoromethyl-beta-alanine of either (R) or (S) absolute configuration. PMID- 22430372 TI - Testing successional hypotheses of stability, heterogeneity, and diversity in pitcher-plant inquiline communities. AB - Succession is a foundation concept in ecology that describes changes in species composition through time, yet many successional patterns have not been thoroughly investigated. We highlight three hypotheses about succession that are often not clearly stated or tested: (1) individual communities become more stable over time, (2) replicate communities become more similar over time, and (3) diversity peaks at mid-succession. Testing general patterns of succession requires estimates of variation in trajectories within and among replicate communities. We followed replicate aquatic communities found within leaves of purple pitcher plants (Sarracenia purpurea) to test these three hypotheses. We found that stability of individual communities initially decreased, but then increased in older communities. Predation was highest in younger leaves but then declined, while competition was likely strongest in older leaves, as resources declined through time. Higher levels of predation and competition corresponded with periods of higher stability. As predicted, heterogeneity among communities decreased with age, suggesting that communities became more similar over time. Changes in diversity depended on trophic level. The diversity of bacteria slightly declined over time, but the diversity of consumers of bacteria increased linearly and strongly throughout succession. We suggest that studies need to focus on the variety of environmental drivers of succession, which are likely to vary through time and across habitats. PMID- 22430373 TI - Is there sex-biased resistance and tolerance in Mediterranean wood mouse (Apodemus sylvaticus) populations facing multiple helminth infections? AB - Sex-biased parasitism is rarely investigated in relation to host tolerance and resistance, which are two defense strategies hosts can adopt when challenged by parasites. Health or fitness deteriorations in less tolerant individuals with increasing parasite burden would be faster than those in more tolerant ones. Hence, the body condition and reproductive potential of an infected individual host can be considered proxies for tolerance to parasitism. We studied Mediterranean populations of the wood mouse (Apodemus sylvaticus) and its helminth parasites. We assessed their resistance using the phytohemagglutinin test and spleen size, and their tolerance using body condition in males and females and testes mass in males. In order to avoid spurious correlations, we took into account the phylogeographic structure of the Mediterranean wood mouse populations. We used a mixed model adapted from the animal model used in quantitative genetics. While helminth infection did not differ between the two sexes, females and males differed in their measured defenses. Females seem to invest more in immune defense with increasing risk of parasite diversity, but also appear to be potentially more tolerant of parasitic diversity. These results suggest the existence of sexual differences in resistance and tolerance, and that measurements of parasitic loads alone could be insufficient to detect any underlying sexual differences in the two strategies that have evolved in response to multiple parasitic attacks. PMID- 22430374 TI - Clinical manifestations and long-term follow-up in pediatric patients living at altitude with isolated pulmonary artery of ductal origin. AB - This study's aim was to define the clinical manifestations and long-term outcome of pediatric patients living at altitude with isolated pulmonary artery (PA) of ductal origin (IPADO). This was a retrospective cohort study of 17 consecutive cases of IPADO at a single center. All patients lived at modest altitude (median 2050 m [range 1700 m to 3050 m]). Fifteen children (88%) were symptomatic at presentation. High-altitude pulmonary edema was present in 2 patients (12%) at diagnosis, and only 1 patient had episodes of hemoptysis during follow-up. Fourteen patients (82%) demonstrated evidence of pulmonary arterial hypertension (PAH). Among 14 patients with PAH, 11 patients had surgical interventions. PAH resolved in 5 of 11 patients (45%) undergoing surgical rehabilitation. One patient died during follow-up, and 7 patients are receiving oral vasodilator therapies due to residual PAH; 14 patients remained asymptomatic. Our study showed that early intervention in patients with IPADO at modest altitude can potentially rehabilitate the isolated PA and reverse PAH. Whether surgery is indicated for patients with this disorder in the absence of PAH is unknown. PMID- 22430375 TI - Cryoablation therapy for atrioventricular nodal reentrant tachycardia in children: a multicenter experience of efficacy. AB - Atrioventricular nodal reentrant tachycardia (AVNRT), a common tachycardia in children, is routinely treated by catheter ablation using radiofrequency or cryothermal energy. Acute success rates of 95-97 % are reported for cryoablation, similar to those achieved with radiofrequency ablation (RFA). However, early studies reported higher recurrence rates after cryoablation for treatment of AVNRT than those reported for RFA. This study evaluated the success and recurrence rates for cryoablation in a current cohort of pediatric patients across several institutions. Patients 21 years old or younger with AVNRT who underwent cryoablation at five participating centers between 2004 and 2009 were retrospectively reviewed. Patient demographics and procedural data were extracted from patient records and analyzed. A total of 434 patients with AVNRT who underwent cryoablation were identified. Cryoablation was used as the exclusive ablation method for 379 patients. For 97 % (368/379) of these patients, cryoablation was acutely successful. A higher acute success rate was found with the 6-mm-tip catheter (99 %) than with the 4-mm-tip catheter (91 %) (p < 0.01). Recurrence was experienced by 7.3 % of the patients. Recurrence was more likely for those treated with the 4-mm-tip catheter (6/42, 14 %) than for those who had the larger catheters (12/204, 6 %) No patient experienced permanent heart block. Success and recurrence rates for this cohort of patients were similar to those reported for RFA used to treat AVNRT in pediatric patients. The findings show a higher success rate and a lower recurrence rate after cryoablation with a 6-mm tip catheter than after use of the 4-mm-tip catheter, with an associated excellent safety profile. PMID- 22430376 TI - Reconstruction of the thumb tip using palmar neurovascular flaps. AB - OBJECTIVE: Reconstruction of the tip of the thumb using a neurovascular flap. INDICATIONS: Transverse defects of the thumb's tip or large defects of the palmar pulp (max. 2.0-2.5 cm) with exposure of bone and/or tendons. CONTRAINDICATIONS: Extensive crush injury, heavy wound contamination, circulatory disorders, acute infection, very large defects (> 2.0-2.5 cm finger length), circumferential soft tissue defects, and previous defects/operations (relative). SURGICAL TECHNIQUE: Supine position, hand supinated, tourniquet, loupe magnification. Mid-lateral incisions along both sides of the finger running from the defect to the interphalangeal joint (small defect) or proceeding further proximally. Careful elevation of the flap including both neurovascular bundles leaving dorsal branches of the bundles (long fingers only) and the flexor tendon sheath intact. Suture of the flap in either flexion position (i.e., advancement flap) (Moberg) or by creating an island-flap through an additional transverse skin incision along the flap's base (O'Brien). Finally, closure of the defect at the flap's base using a full thickness skin graft, Z plasty, or V-Y plasty. POSTOPERATIVE MANAGEMENT: Plaster cast (finger slightly flexed) for 2 weeks. RESULTS: Reliable method. Good functional results with good sensibility and only minor reduction in range of motion. PMID- 22430377 TI - Stem cells in pediatrics: state of the art and future perspectives. PMID- 22430378 TI - Induced pluripotent stem cells and severe combined immunodeficiency: merely disease modeling or potentially a novel cure? AB - For most, but not all, types of severe combined immunodeficiency (SCID) the underlying molecular defects are known, in principle allowing the cure of affected children via gene therapy. Typically such approaches have used autologous hematopoietic stem cells modified to express a therapeutic gene via gamma-retroviral vectors. Insertional mutagenesis has emerged as a significant risk for successful application of this type of gene therapy. Therefore, lentiviral vectors with a self-inactivating design have been developed. Recent advances in stem cell technology using induced pluripotent stem cells (iPSCs) allow an entire different approach to gene therapy for SCID and other genetic disorders, namely by correction of the affected gene in patient-specific iPSCs followed by hematopoietic differentiation. Here, we review these recent advances in the field from an efficacy and safety point of view. PMID- 22430379 TI - Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases. AB - Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat severe and refractory autoimmune diseases (ADs) in children and adults for more than 15 years. The aim of this treatment is to restore tolerance through an intense lymphodepleting conditioning, and many patients have achieved lasting remissions. However, HSCT is associated with significant morbidity and mortality and is therefore not yet standard of care. Pre-existing reduced organ function of patients with ADs may increase the organ toxicity of conditioning. In the early post-HSCT phase, bacterial or fungal infections occur and therapy-associated lymphopenia sets patients at risk for reactivation of endogenous viruses and other opportunistic infections. During re-emerging of lymphopoiesis after HSCT, de novo autoimmunity may develop through loss of central or peripheral control mechanisms. Late effects of autologous HSCT (e.g., on the endocrine system) and a potentially increased frequency of secondary malignancies are of concern. The steadily increasing knowledge about specific complications occurring in patients with ADs after HSCT has led to the adaption of treatment protocols and has already reduced toxicity. Further prospective long-term follow-up studies are needed to identify patients at risk for developing serious complications after HSCT. PMID- 22430380 TI - Role of mesenchymal stem cell therapy in Crohn's disease. AB - Many trials of mesenchymal stem cells (MSCs) have been published in the past 5-6 y. MSCs inhibit T-cell alloreactivity in vitro by soluble factors and direct cell to-cell contact. They are safe to infuse in humans with no acute toxicity and no ectopic tissue formation. Promising results of MSC infusion for graft-vs.-host disease and fistulizing Crohn's disease (CD) have been published. Treatment of CD requires a comprehensive treatment approach to maintain symptomatic control, improve health-related quality-of-life measures, and minimize complications from the disease. In this review, we will discuss the results of clinical trials using a novel treatment in the form of MSCs for treatment of CD and related complications. Success of these phase I, II, and III trials have set the stage for usage of this novel treatment for children with CD. PMID- 22430381 TI - Mesenchymal stem cells in osteoarticular pediatric diseases: an update. AB - Cellular therapy has gained an increasing popularity in recent years. Mesenchymal stem cells (MSCs) have the potential to differentiate into bone, cartilage, or fat tissue. In recent studies, these cells have also shown healing capability by improving angiogenesis and preventing fibrosis, which could have a role in tissue repair and tissue regeneration. Preclinical and clinical orthopedic studies conducted in the adult population support the use of MSCs for bone-healing problems, early stages of osteonecrosis, and local bone defects. Only a few published studies support the use of MSCs in pediatric osteoarticular disorders, probably due to the unknown long-term results of cellular therapy. The purpose of this review is to explain the mechanism by which MSCs could exhibit a therapeutic role in pediatric osteoarticular disorders. PMID- 22430382 TI - Umbilical cord blood mononuclear cell transplantation for neonatal hypoxic ischemic encephalopathy. AB - Despite recent advances in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE) using therapeutic hypothermia, at least 30% of the cooled infants will die or have moderate/severe neurological disability. Umbilical cord blood cells (UCBCs), which are readily available at birth, have been shown to reduce sensorimotor and/or cognitive impairments in several models of brain damage, representing a promising option for the treatment of neurological diseases. In this review, we discuss recent preclinical studies that assessed the effects of UCBC transplantation in the Rice-Vannucci animal model of HIE. We also review the possible cell types and mechanisms involved in the therapeutic effect of UCBC transplantation, including neuroprotection, immunomodulation, and stimulation of neural plasticity and regeneration. In addition, we discuss how neuroimaging methods, such as bioluminescence imaging, nuclear-medicine imaging, or magnetic resonance imaging, could be used to evaluate the biodistribution of UCBCs in both preclinical and clinical studies. PMID- 22430383 TI - Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. AB - Mesenchymal stem cell (MSC)-based therapies have been proven effective in experimental models of numerous disorders. Treatment of ischemic brain injury by transplantation of MSCs in neonatal animal models has been shown to be effective in reducing lesion volume and improving functional outcome. The beneficial effect of MSC transplantation to treat neonatal brain injury might be explained by the great plasticity of the neonatal brain. The neonatal brain is still in a developmentally active phase, leading to a better efficiency of MSC transplantation than that observed in experiments using adult models of stroke. Enhanced neurogenesis and axonal remodeling likely underlie the improved functional outcome following MSC treatment after neonatal hypoxic-ischemic (HI) brain injury. With respect to the mechanism of repair by MSCs, MSCs do not survive long term and replace damaged tissue themselves. We propose that MSCs react to the needs of the ischemic cerebral environment by secretion of several growth factors, cytokines, and other bioactive molecules to regulate damage and repair processes. Parenchymal cells react to the secretome of the MSCs and contribute to stimulate repair processes. These intrinsic adaptive properties of MSCs make them excellent candidates for a novel therapy to treat the devastating effects of HI encephalopathy in the human neonate. PMID- 22430384 TI - Transplantation of umbilical cord-derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives. AB - The prevention of perinatal neurological disabilities remains a major challenge for public health, and no neuroprotective treatment to date has proven clinically useful in reducing the lesions leading to these disabilities. Efforts are, therefore, urgently needed to test other neuroprotective strategies including cell therapies. Although stem cells have raised great hopes as an inexhaustible source of therapeutic products that could be used for neuroprotection and neuroregeneration in disorders affecting the brain and spinal cord, certain sources of stem cells are associated with potential ethical issues. The human umbilical cord (hUC) is a rich source of stem and progenitor cells including mesenchymal stem cells (MSCs) derived either from the cord or from cord blood. hUC MSCs (hUC-MSCs) have several advantages as compared to other types and sources of stem cells. In this review, we will summarize the most recent findings regarding the technical aspects and the preclinical investigation of these promising cells in neuroprotection and neuroregeneration, and their potential use in the developing human brain. However, extensive studies are needed to optimize the administration protocol, safety parameters, and potential preinjection cell manipulations before designing a controlled trial in human neonates. PMID- 22430385 TI - Stem cell therapy for cardiac disease. AB - Congenital heart disease occurs in 1% of liveborn infants, making it the most common birth defect worldwide. Many of these children develop heart failure. In addition, both genetic and acquired forms of dilated cardiomyopathy are a significant source of heart failure in the pediatric population. Heart failure occurs when the myocardium is unable to meet the body's metabolic demands. Unlike some organs, the heart has limited, if any, capacity for repair after injury. Heart transplantation remains the ultimate approach to treating heart failure, but this is costly and excludes patients who are poor candidates for transplantation given their comorbidities, or for whom a donor organ is unavailable. Stem cell therapy represents the first realistic strategy for reversing the effects of what has until now been considered terminal heart damage. We will discuss potential sources of cardiac-specific stem cells, including mesenchymal, resident cardiac, embryonic, and induced pluripotent stem cells. We will consider efforts to enhance cardiac stem cell engraftment and survival in damaged myocardium, the incorporation of cardiac stem cells into tissue patches, and techniques for creating bioartificial myocardial tissue as well as whole organs. Finally, we will review progress being made in assessing functional improvement in animals and humans after cellular transplant. PMID- 22430387 TI - Role of stemness-related molecules in neuroblastoma. AB - Neuroblastoma (NB) is the most common pediatric solid malignant tumor derived from the sympathetic nervous system. High-risk NB is still one of the most difficult tumors to cure, with only 40% long-term survival despite intensive multimodal therapy. The clinical presentation and treatment response of advanced NB, which results in relapse and a refractory state after a good response to the initial chemotherapy, suggests that cancer stem cells (CSCs) likely exist in NB tumors. Putative CSCs using primary tumor sphere formation from NB patients were reported previously, and several molecules will be elucidated from the tumor sphere to develop CSC-targeting therapies. Recently, our group reported that a CSC marker for several malignancies, CD133, and the stemness-related polycomb BMI1 have functions to repress NB cell differentiation. Depletion of CD133 or BMI1 effectively induced neurite elongation and marker molecules for differentiation in NB cells. Of note, CD133-related NB cell differentiation and RET (rearranged during transfection) repression were considerably dependent on p38MAPK and phosphoinositide 3-kinase (PI3K)/AKT pathways. Intriguingly, both CD133 and BMI1 also have a role in xenograft tumor formation and tumor sphere formation. These observations suggest that CD133 and BMI1 may be candidates for the development of CSC-targeting therapies for refractory NB patients. PMID- 22430386 TI - Targeting pediatric cancer stem cells with oncolytic virotherapy. AB - Cancer stem cells (CSCs), also termed "cancer-initiating cells" or "cancer progenitor cells," which have the ability to self-renew, proliferate, and maintain the neoplastic clone, have recently been discovered in a wide variety of pediatric tumors. These CSCs are thought to be responsible for tumorigenesis and tumor maintenance, aggressiveness, and recurrence due to inherent resistance to current treatment modalities such as chemotherapy and radiation. Oncolytic virotherapy offers a novel, targeted approach for eradicating pediatric CSCs using mechanisms of cell killing that differ from conventional therapies. Moreover, oncolytic viruses have the ability to target specific features of CSCs such as cell-surface proteins, transcription factors, and the CSC microenvironment. Through genetic engineering, a wide variety of foreign genes may be expressed by oncolytic viruses to augment the oncolytic effect. We review the current data regarding the ability of several types of oncolytic viruses (herpes simplex virus-1, adenovirus, reovirus, Seneca Valley virus, vaccinia virus, Newcastle disease virus, myxoma virus, vesicular stomatitis virus) to target and kill both CSCs and tumor cells in pediatric tumors. We highlight advantages and limitations of each virus and potential ways in which next generation engineered viruses may target resilient CSCs. PMID- 22430388 TI - Medulloblastoma stem cells: where development and cancer cross pathways. AB - Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The recent molecular classification of MB has reconceptualized the heterogeneity that exists within pathological subtypes by giving context to the role of key developmental signaling pathways in MB pathogenesis. The identification of cancer stem cell (CSC) populations, termed brain tumor-initiating cells (BTICs), in MB has provided novel cellular targets for the study of these aberrantly activated signaling pathways, namely, Sonic hedgehog (Shh) and Wingless (Wnt), along with the identification of novel BTIC self-renewal pathways. In this review, we discuss recent evidence for the presence of a MB stem cell that drives tumorigenesis in this malignant childhood tumor. We focus on evidence from cerebellar development, the recent identification of BTICs, the presence of activated developmental signaling pathways in MB, the role of epigenetic stem cell regulatory mechanisms, and how these developmental and epigenetic pathways may be targeted for novel therapeutic options. PMID- 22430389 TI - Promises and challenges of exhausting pediatric neural cancer stem cells. AB - Cancer relapse is one of the major setbacks in pediatric oncology. Cancer stem cells (CSCs) have emerged as a major driving force governing tumor recurrence. CSCs are a small subpopulation of cells capable of regenerating a tumor and are resistant to conventional anticancer therapies. No CSC therapy has been approved by the US Food and Drug Administration. Because CSCs and normal stem cells share many characteristics, CSC-directed therapies have potential detrimental effects on normal stem cells, tissue maintenance, and development. Designing treatments that specifically target neural CSCs while allowing neural tissue stem cells to normally develop the brain is a major challenge in pediatric neuro-oncology. In recent years, better identification and characterization of neural CSCs, together with identifying differences between CSCs and normal neural stem cells, have been key factors in developing tailored therapeutics for these devastating diseases. This review focuses on the promises and challenges of pediatric neural CSC directed therapies. We delineate the options currently in use to exhaust the ability of neural CSCs to self-renew. Finally, we suggest a comprehensive approach to combine anti-CSC therapies with other therapeutic approaches to prevent tumor recurrence. PMID- 22430390 TI - Improved accuracy of low affinity protein-ligand equilibrium dissociation constants directly determined by electrospray ionization mass spectrometry. AB - There is continued interest in the determination by ESI-MS of equilibrium dissociation constants (K(D)) that accurately reflect the affinity of a protein ligand complex in solution. Issues in the measurement of K(D) are compounded in the case of low affinity complexes. Here we present a K(D) measurement method and corresponding mathematical model dealing with both gas-phase dissociation (GPD) and aggregation. To this end, a rational mathematical correction of GPD (f(sat)) is combined with the development of an experimental protocol to deal with gas phase aggregation. A guide to apply the method to noncovalent protein-ligand systems according to their kinetic behavior is provided. The approach is validated by comparing the K(D) values determined by this method with in-solution K(D) literature values. The influence of the type of molecular interactions and instrumental setup on f(sat) is examined as a first step towards a fine dissection of factors affecting GPD. The method can be reliably applied to a wide array of low affinity systems without the need for a reference ligand or protein. PMID- 22430391 TI - Assisted reproduction outcomes after embryo transfers requiring a malleable stylet. AB - OBJECTIVE: This retrospective case-control study was undertaken to assess the impact of a malleable stylet application on embryo transfer (ET) outcome. METHODS: The Wallace malleable stylet was used when the soft inner catheter could not negotiate the internal os during ultrasound-guided ET. Patients having an age <=37 years, with three embryos replaced were included in the analysis. Implantation rate, clinical pregnancy rate and live birth rate were the main outcome measures. RESULTS: The Wallace malleable stylet was applied in 164 (29.6%) of the 553 ETs evaluated. Implantation rate, clinical pregnancy rate and live birth rate showed a 5.6% (19.4% vs. 13.8%), a 10.8% (41.9% vs. 31.1%) and a 9.9% (37.3% vs. 27.4%) absolute difference, respectively, in favor of ETs not requiring the stylet. These differences were statistically significant (P < 0.05). CONCLUSIONS: ETs requiring stylet are associated with lower implantation, clinical pregnancy and live birth rates. PMID- 22430392 TI - Effect of culture medium volume and embryo density on early mouse embryonic development: tracking the development of the individual embryo. AB - PURPOSE: To determine the optimal volume or density of embryos for the well-of the-well (WOW) system in order to track the development of individual embryos and to determine whether the WOW system can reverse the negative impact of culturing embryos singly. METHODS: (1) Mouse embryos (groups of nine at the 2-cell stage) were cultured in 6.25 MUl, 12.50 MUl, 25.00 MUl and 50.00 MUl of droplets of culture medium under paraffin oil; (2) Groups of three, six, nine and twelve embryos at the 2-cell stage were cultured in 50 MUl of droplet of culture medium under paraffin oil; (3) Groups of nine embryos at the 2-cell stage were cultured in 50 MUl of droplet under paraffin oil with or without nine micro-wells made on the bottom of the Petri dish into each of which were placed one of the nine embryos (WOW system). Also single 2-cell stage embryos was cultured individually in 5.5 MUl of droplet of culture medium under paraffin oil with or without a single micro-well made on the bottom of the Petri dish (WOW system for single culture). At the end of culture, the percentages of blastocyst development, hatching and hatched blastocysts were compared in each group. The blastocysts were fixed for differential staining. RESULTS: The blastocyst development was significantly higher (P < 0.05) when nine embryos were cultured in 50 MUl of droplet of culture medium compared with other volumes. The blastocyst development was significantly reduced (P < 0.05) in single embryo culture compared to group embryo culture with or without the WOW system. The blastocyst development was not improved when single embryo cultured individually in a micro-well was compared to single embryo cultured individually without micro-well. The total cell numbers of blastocysts were significantly higher in group embryo culture than single embryo culture regardless of whether the WOW system was used. In addition, the total cell numbers of blastocysts were significantly higher (P < 0.05) in single embryo culture with the WOW system than without. CONCLUSIONS: Group embryo culture is superior to single embryo culture for blastocyst development. The WOW system with 50 MUl of droplet of culture medium can be used to track the individual development of embryo cultured in groups while preserving good embryonic development. The reduced embryonic development with single embryo culture cannot be ameliorated by the WOW system. PMID- 22430393 TI - Thioester-isocyanides: versatile reagents for the synthesis of cycle-tail peptides. AB - A novel class of reagents, thioester isocyanides, have been prepared and applied in the synthesis of peptide macrocycles. The isocyanide part of the molecule is deployed in a multicomponent macrocyclization step. This step is followed by chemoselective peptide ligation at the thioester part of the macrocycle. Our method can now be used for rapid assembly and evaluation of cycle-tail peptides. PMID- 22430394 TI - The effect of cocoa, soy, oats and fish oil on metabolic syndrome in rats. AB - BACKGROUND: The effect of functional foods alone or in combination (cocoa + soy + oats + fish oil) on hepatic damage in rats affected with metabolic syndrome was investigated. RESULTS: Rats that were given cocoa showed a decrease in the levels of triglycerides (TGs) and glucose (63 and 32% respectively) as well as a decrease in blood pressure (15%). Animals fed with soy showed a reduction of 21% in total cholesterol, 15% in blood pressure and 44% in TGs, while feeding oats reduced the concentration of TGs by 53% (P < 0.5). Fish oil caused a reduction in TGs (56%) and glucose (26%). The effect on blood pressure was statistically significant for the groups supplemented with cocoa, soy, cocoa + oats and the total mix. The main finding was a reduction in liver steatosis in animals supplemented with cocoa + oats (from 30 to 4.7% steatosis). Cocoa or fish oil alone did not protect the liver from damage, while cocoa + fish oil did. CONCLUSION: The most relevant effects were that the cocoa + oats mix decreased steatosis by a very large percentage, as did the cocoa + fish oil mix and the mix of all four functional foods. PMID- 22430395 TI - Binding of hepatitis A virus to its cellular receptor 1 inhibits T-regulatory cell functions in humans. AB - BACKGROUND & AIMS: CD4+ T-regulatory (Treg) cells suppress immune responses and control self-tolerance and immunity to pathogens, cancer, and alloantigens. Most pathogens activate Treg cells to minimize immune-mediated tissue damage and prevent clearance, which promotes chronic infections. However, hepatitis A virus (HAV) temporarily inhibits Treg-cell functions. We investigated whether the interaction of HAV with its cellular receptor 1 (HAVCR1), a T-cell co-stimulatory molecule, inhibits the function of Treg cells to control HAV infection. METHODS: We studied the effects of HAV interaction with HAVCR1 on human T cells using binding, signal transduction, apoptosis, activation, suppression, cytokine production, and confocal microscopy analyses. Cytokines were analyzed in sera from 14 patients with HAV infection using bead arrays. RESULTS: Human Treg cells constitutively express HAVCR1. Binding of HAV to HAVCR1 blocked phosphorylation of Akt, prevented activation of the T-cell receptor, and inhibited function of Treg cells. At the peak viremia, patients with acute HAV infection had no Treg cell suppression function, produced low levels of transforming growth factor-beta , which limited leukocyte recruitment and survival, and produced high levels of interleukin-22, which prevented liver damage. CONCLUSIONS: Interaction between HAV and its receptor HAVCR1 inhibits Treg-cell function, resulting in an immune imbalance that allows viral expansion with limited hepatocellular damage during early stages of infection-a characteristic of HAV pathogenesis. The mechanism by which HAV is cleared in the absence of Treg-cell function could be used as a model to develop anticancer therapies, modulate autoimmune and allergic responses, and prevent transplant rejection. PMID- 22430396 TI - [ From the Editor]. PMID- 22430397 TI - Impact of infarct related artery patency after early abciximab administration on one-year mortality in patients with ST-segment elevation myocardial infarction (data from the EUROTRANSFER Registry). AB - BACKGROUND: Spontaneous early infarct related artery (IRA) recanalisation before primary percutaneous coronary intervention (pPCI) has a favourable impact on outcome. However, the role played by pharmacotherapy driven patency prior to pPCI is still a matter of debate. AIM: To assess the role of early IRA patency (TIMI flow 2 or 3) after early abciximab administration in patients with ST-segment elevation myocardial infarction (STEMI) transferred for pPCI. METHODS: Data was gathered for 1,650 consecutive STEMI patients transferred for pPCI from hospital networks in seven countries in Europe between November 2005 and January 2007. We identified 691 patients who were pretreated with abciximab before transportation to a cathlab hospital and underwent PCI. RESULTS: Angiography showed early IRA patency (TIMI flow 2 or 3) in 233 (33.7%) patients, and occluded IRA (TIMI flow 0 or 1) in 458 (66.3%) patients. In patients with patent IRA, in baseline angiography the rate of TIMI 3 flow and ECG ST-segment resolution > 50% after PCI was higher compared to patients with occluded IRA. One year mortality was significantly lower in patients with patent IRA, 1.3% vs 7% (OR 0.17; CI 0.05 0.6; p = 0.001). In multivariable Cox regression analysis, IRA patency at baseline was identified as an independent predictor of one-year mortality. CONCLUSIONS: Infarct related artery recanalisation after early pharmacological pretreatment in STEMI patients undergoing transportation for pPCI is associated with better post-procedural myocardial perfusion and lower one-year mortality. PMID- 22430398 TI - [What is best for patients with STEMI on the way to primary percutaneous coronary intervention?]. PMID- 22430399 TI - The relationship of carotid arterial stiffness to left ventricular diastolic dysfunction in untreated hypertension. AB - BACKGROUND: Interest in the role of arterial stiffness in the pathomechanism of left ventricular (LV) diastolic dysfunction has grown in recent years. AIM: To examine the relationship between local carotid arterial stiffness parameters assessed by the ultrasonic high-resolution echo-tracking (eT) method and LV diastolic function indices in patients with untreated hypertension (H). METHODS: The study group consisted of 173 subjects, 78 male and 95 female, 113 of them with untreated H, mean age 55.7 +/- 10.4 years, and 60 age-matched controls. Using 2D echo, conventional and tissue Doppler echocardiography, LV systolic and diastolic function and left ventricular hypertrophy (LVH) indices were assessed. Hypertensives were divided into two groups: those with diastolic dysfunction (HDD+: with relaxation abnormalities, n = 55 and with pseudonormalisation pattern, n = 12); and those without diastolic dysfunction (HDD-, n = 46). Using carotid arteries ultrasound, intima media thickness (IMT) and eT arterial stiffness parameters were evaluated, as also were beta - beta, Ep - epsilon, AC - arterial compliance, PWVbeta - one-point pulse wave velocity and AI - augmentation index. RESULTS: Linear regression analysis revealed significant correlations between arterial stiffness indices and diastolic function parameters in the study groups: the ratio of early to late transmitral pulse Doppler velocities - E/A - correlated to Ep,beta, AC and PWVbeta (r = -0.30, r = -0.25, r = 0.26, r = -0.30, respectively, p < 0.05); early diastolic mitral annular velocity - e' - correlated to Ep, beta and PWVbeta (r = -0.22, r = -0.26, r = 0.25, respectively, p < 0.05); the ratio of early to late diastolic mitral annular velocities - e'/a' - was correlated with beta and PWVbeta (r = -0.28, r = -0.28, respectively, p < 0.05). HDD+ did not present echocardiographic LVH. Using ROC curve analysis, we identified optimal cut-off values of different parameters in the determination of diastolic dysfunction occurrence. Univariable analysis revealed the following significant variables in determining LV diastolic dysfunction: beta > 9.2 (OR 2.65, p = 0.026), Ep > 118 kPa (OR 3.53, p = 0.040), PWVbeta > 6.2 m/s (OR 3.92, p = 0.002), AI > 7.8 (OR 2.62, p = 0.049), age > 54 (OR 4.76, p < 0.001), diabetes presence (OR 2.78, p = 0.013), IMT > 0.51 mm (OR 4.49, p < 0.001), diastolic blood pressure < 70 mm Hg (OR 3.38, p = 0.047), pulse pressure > 64 (OR 2,90, p = 0.031) and ejection fraction < 76 (OR 3.38, p = 0.019). However, at multivariate analysis, only age (OR = 2.43, p = 0.073), IMT (OR = 4.56, p = 0.002) and PWVbeta (OR = 2.18; p = 0.091) were independently associated with diastolic dysfunction occurrence. CONCLUSIONS: Carotid IMT as a marker of subclinical atherosclerosis and PWVbeta as an index of carotid arterial stiffness are, besides age, independently associated with LV early diastolic dysfunction occurrence in untreated middle-aged hypertensives. PMID- 22430400 TI - [ Evaluation of structural and functional changes in the carotid]. PMID- 22430401 TI - Comparison of on-admission ST-segment elevation tako-tsubo patients and myocardial infarction women: in-hospital course and long-term follow-up. AB - BACKGROUND: Tako-tsubo cardiomyopathy (TTC) is an uncommon transient cardiomyopathy with a clinical and electrocardiographic (ECG) presentation similar to that of ST-elevation myocardial infarction (STEMI). AIM: To compare clinical presentation, in-hospital course, and long-term outcomes in TTC female patients with on-admission ST-segment elevation and anterior STEMI female patients. METHODS: Consecutive TTC patients with on-admission ST-segment elevation were selected. Using a propensity score, a matching STEMI control group was put together. The patients were followed for a mean 1,002 +/- 552 days. Major adverse cardiac events were defined as TTC recurrence, MI recurrence, heart failure requiring hospitalisation, percutaneous coronary intervention, coronary artery bypass grafting, stroke and death. RESULTS: Forty one TTC patients were enrolled, including 29 women with on-admission ST-segment elevation. The control group consisted of 46 STEMI women with left anterior descending occlusion. The ECG at presentation showed greater ST- -segment elevation (6.0 +/- 1.6 vs 2.0 +/- 1.2 mm, p < 0.01) in the control STEMI patients than in the TTC group. Also, baseline CK-MB (16.2 +/- 20.6 vs 66.0 +/- 125.2 ng/mL, p < 0.01) and troponin-I levels (2.99 +/- 5.36 vs 42.70 +/- 64.79 ng/mL, p < 0.01) were significantly higher in the STEMI patients. Echocardiography showed higher follow-up ejection fraction in the TTC than in the STEMI group (57.0 +/- 8.0 vs 49.5 +/- 8.8%, p < 0.01). During follow-up, there was no significant difference in the major adverse cardiac events rate between the TTC and STEMI groups (-24.1% vs 41.3%, p = 0.13). CONCLUSIONS: Although there is some diversity in ECG, laboratory, and ECHO parameters, none of these patterns alone can reliably distinguish TTC from MI in female patients. TTC and STEMI females have similar in-hospital and long-term outcomes. PMID- 22430402 TI - [ Tako-tsubo a heart attack - similar or the same?]. PMID- 22430403 TI - Comparison of clinical risk assessment systems in predicting three-vessel coronary artery disease and angiographic culprit lesion in patients with non-ST segment elevated myocardial infarction/unstable angina pectoris. AB - BACKGROUND: We wanted to compare the values of clinical risk assessments and scoring systems for predicting three-vessel diseases and culprit lesions by coronary angiography in patients with unstable angina pectoris (UAP), or non-ST segment elevation myocardial infarction (NSTEMI). METHODS: A total of 154 consecutive patients, (42 [27.3%] female, and 112 [72.7%] male, mean age: 63.0 +/ 12.7 years) with UAP/NSTEMI were enrolled. Rizik and Braunwald classification, ACC/AHA risk assessment system, TIMI, GUSTO, GRACE and PURSUIT risk scores were determined, and the ROC curve was marked in accordance with the presence of three vessel disease and culprit lesion. RESULTS: In patients with NSTEMI, the rates of three-vessel disease and culprit lesion were demonstrated to be higher. With respect to the presence of three-vessel disease, only the ACC/AHA risk assessment was manifested to have a predictive value. All risk scoring systems were demonstrated to bear predictive values with different sensitivity and specificity. The TIMI and GRACE risk scores were discovered to have higher predictive values. The presence of culprit lesions could not be predicted by any of the risk assessment or scoring systems. CONCLUSIONS: Among risk assessment systems, only the ACC/AHA system can be used to predict three-vessel disease. It is possible to use all risk scoring systems for the same purpose. The predictive values of the TIMI and GRACE risk scores are higher. The culprit lesions cannot be predicted by any of the risk assessment or scoring systems. The use of cardiac enzymes seems more appropriate with very low sensitivity and specificity. PMID- 22430404 TI - [Risk stratification in patients with acute coronary syndrome without ST elevation - in search of the optimal model ]. PMID- 22430405 TI - Individuals with high-normal blood pressure have different metabolic and haemodynamic characteristics to those with optimal blood pressure. AB - BACKGROUND: The ESH classification of blood pressure includes the high-normal blood pressure (HNBP) category, which is within normal limits but associated with increased cardiovascular (CV) risk. AIM: To identify additional CV risk factors and early signs of target organ damage in healthy individuals with HNBP. METHODS: Healthy volunteers (n = 74) with optimal blood pressure or HNBP were compared with respect to metabolic and haemodynamic parameters. RESULTS: The HNBP was associated with higher serum uric acid (333.1 +/- 65.4 vs 267.7 +/- 65.4 MUmol/L, p < 0.05) and glucose (4.7 +/- 0.3 vs 4.5 +/- 0.3 mmol/L, p < 0.01) concentrations, intima-media thickness (0.39 +/- 0.06 vs 0.36 +/- 0.04 mm, p < 0.05), systemic vascular resistance index (2,678.2 +/- 955.9 vs 1,930.2 +/- 625.5 dyn x s x m(2)/cm(5), p < 0.001), lower total arterial compliance index (1.04 +/- 0.42 vs 1.44 +/- 0.48 mL/[mm Hg x m(2)], p < 0.01) and baroreflex sensitivity (14.2 +/- 3.8 vs 18.0 +/- 8.8 mm Hg(2)/Hz, p = 0.05). CONCLUSIONS: The observed differences in metabolic and haemodynamic profile in HNBP may adversely affect CV risk in these individuals. PMID- 22430406 TI - [ High normal blood pressure - a problem of growing clinical importance]. PMID- 22430407 TI - Effect of selected prothrombotic and proinflammatory factors on the incidence of venous thrombosis after pacemaker implantation. AB - BACKGROUND: Venous thrombosis (VT), a major cause of venous obstruction, is a rather rare but dangerous complication of pacemaker (PM) implantation. AIM: To assess the prognostic value of selected proinflammatory and prothrombotic markers in predicting symptomatic venous obstruction after PM implantation. METHODS: The study involved 81 patients (31 females; mean age 71 +/- 8 years) divided into 2 groups depending on the occurrence of venous obstruction. Group I included 71 patients (29 females; mean age 71 +/- 2 years) without this complication and group II included 10 patients (2 females, mean age 71.6 +/- 2) with venous obstruction. All patients were followed up for 19 months. Transthoracic echocardiography and venous ultrasonography were performed before PM implantation and at the time of incident venous obstruction. Interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP), D-dimer, fibrinogen, tissue factor (TF), factor VII and plasminogen activator inhibitor-1 (PAI-1) levels were measured at baseline and within 7 days after PM implantation. RESULTS: Patients in group II had a significantly lower left ventricular ejection fraction (LVEF), higher left ventricular end--diastolic diameter (LVEDD) and impaired left ventricular filling (Vp) compared to group I. Patients in group II developed VT on average at 13.06 (range 7-18) months following PM implantation. At baseline, IL-6, hsCRP, D-dimer, fibrinogen, TF, factor VII, and PAI-1 levels were significantly higher in group II compared to group I. In all patients, levels of prothrombotic factors were higher following PM implantation compared to baseline values, with the exception of fibrinogen level in group I. Cut-off values indicating increased thrombosis risk were determined for the examined parameters (LVEF, LVEDD, Vp, IL-6, hsCRP, D dimer, fibrinogen, factor VII, TF, PAI-1) based on the ROC curves. Major predictors of thrombotic risk included LVEF, LVEDD, and D-dimer, fibrinogen and TF levels. Highest predictive values were noted for LVEDD > 58 mm (OR = 52.8) and D-dimer level > 498 mg/L (OR = 3003). CONCLUSIONS: 1. Patients who developed VT after PM implantation had elevated baseline levels of IL-6, hsCRP, fibrinogen, D dimer, TF, factor VII, and PAI-1. 2. Levels of pro-inflammatory markers increased after the implantation procedure in all patients. 3. Parameters with the highest diagnostic value for predicting incident VT included decreased LVEF, increased LVEDD and elevated D-dimer, fibrinogen and TF levels. PMID- 22430408 TI - [Venous thrombosis after implantation of devices for electrotherapy as an increasing clinical problem]. PMID- 22430409 TI - [Acute coronary syndrome without ST segment elevation in a 78 year-old woman caused by critical proximal right coronary artery stenosis with concomitant chronic total occlusion of left main coronary artery]. AB - Total occlusion of the left main coronary artery is a rare finding at coronary angiography. When present, patients most often have extensive collateral circulation from the right coronary artery. The mainstay of treatment is surgical with coronary artery bypass grafting. We present a case of a 78 year-old woman admitted to our department with two days history of nonspecific, abdominal pain. Her coronarography revealed chronic total occlusion of left main with concomitant critical, proximal right coronary artery stenosis. PMID- 22430411 TI - Supplementation with hydrocortisone on the 3rd-5th day following dexamethasone premedicated chemotherapy eliminated severe dizziness and postural hypotension. AB - We present the case of a 60 year-old woman with a stage III fallopian tube cancer submitted to hysterectomy and bilateral salpingo-oophorectomy with partial omenectomy, followed by six courses of chemotherapy and revision surgery. After each course of chemotherapy (paclitaxel + carboplatin) preceded by premedication with dexamethasone, she suffered from side- -effects, of which the most unpleasant was severe dizziness appearing on the third, fourth and fifth day following the listed combination of drugs. It was revealed that dizziness with concomitant sweating and rapid pulse, noted in the standing position, was combined with marked postural hypotension. Considering the possibility of a temporary pituitary-adrenal axis suppression caused by premedication with a very large dose of dexamethasone, during those three days she was supplemented with small doses of hydrocortisone, which caused almost complete disappearance of the mentioned symptoms. Our conclusion is that postural hypotension causing severe dizziness initially linked with chemotherapeutic drugs can be eliminated or markedly reduced by three days supplementation with hydrocortisone applied after the expected wash out of the dexamethasone. PMID- 22430412 TI - Left main coronary artery atresia. AB - We present a report of an extremely rare case of left main coronary artery atresia in a 33 year-old male with severe symptoms of angina pectoris and dyspnoea. During coronary angiography, the left coronary artery (LCA) ostium could not be catheterised. The right coronary artery (RCA) was dilated, and the LCA was filling retrogradely via collateral vessels. The diagnosis was confirmed by multislice computed tomography. Due to severe symptoms and the high risk of sudden cardiac death, the patient was referred for coronary artery revascularisation. The left internal mammary artery was anastomosed to the left anterior descending artery. The operation and subsequent 24 months follow-up were uneventful. PMID- 22430413 TI - [Epicardial approach during ablation of ventricular tachycardia in patients with ischaemic cardiomyopathy - utility and safety of the method]. PMID- 22430414 TI - [Diagnostic problem - heart failure with preserved ejection fraction]. PMID- 22430415 TI - [Diabetes, renal dysfunction and acute coronary syndrome]. PMID- 22430416 TI - [ST-segment depression and elevation during supraventricular tachycardias]. AB - Three electrocardiograms with repolarisation abnormalities (ST-segment depression and elevation) during supraventricular tachycardias are presented. In all three cases the subjects were young and otherwise healthy. Despite this in one of these cases an acute coronary syndrome was erroneously diagnosed on the basis of pronounced ST-segment depression in several leads and troponin I elevation. Coronary angiogram and echocardiogram in this case was normal. Diagnostic value and aetiology of repolarisation abnormalities during supraventricular tachycardias are discussed. PMID- 22430418 TI - Oesophageal cancer with myocardial metastasis complicated by ventricular fibrillation: the role of echocardiography. AB - Myocardial metastasis from oesophageal cancer is very rare, and is usually detected as part of widespread metastases in the terminal stage. It is rare to detect a solitary metastasis. We present a case of solitary myocardial metastasis from distal oesophagus complicated by ventricular fibrillation. PMID- 22430419 TI - [Tako-tsubo cardiomyopathy in a patient with hypertrophic cardiomyopathy with obstruction]. AB - A 74 year-old patient was admitted to Invasive Cardiology Department. Non-ST elevation myocardial infarction was suspected. Patient has typical chest pain after strong stress. The normal coronary artery was found in coroangiography. The apical ballooning and almost closure in 1/2 of left ventricle cavity were found in ventriculography. The echocardiography shown asymmetric hypertrophy of heart walls and left ventricle outflow obstruction. The cardiac magnetic resonance was performed because of heart tumour was suspected. PMID- 22430421 TI - [A 59 year-old patient with acute anterolateral myocardial infarction, complicated by cardiogenic shock, with chest wall deformity caused by Heine-Medin disease]. AB - We report a case of a 59 year-old patient in a condition of acute myocardial infarction with ST elevation, in a cardiogenic shock, with multiple cardiac arrests in mechanism of ventricular fibrillation with a significant chest wall deformity caused by Heine-Medin disease in childhood. To our knowledge, this is the first case report of a patient in critical condition with a considerable pectus deformity after poliomyelitis who needed to undergo cardiovascular angioplasty. Although severe patient's condition and numerous difficulties during percutaneous coronary intervention, therapy was successful. PMID- 22430424 TI - [Summary of the article: Boden EW, Probstfield LJ, Anderson T et al. Niacin in patients with low LDL cholesterol levels receiving intensive statin therapy. New Engl J Med, 10.1056/NEJMoa1107579]. PMID- 22430423 TI - Breakage of extracted leads: another management option. AB - Extracted lead breakage is a well-known technical complication of lead extraction. If the remaining fragment is longer than a few cm, it should be removed. The femoral or jugular approach, with different tools, is used. We describe the utility of the extracted lead venous entry approach as the optional solution in six patients. The role of the shape of the utilised sheath and the presence of venous entry valve and favourable specific properties of basket catheters are discussed, and also the utility of a repeated Byrd dilator. PMID- 22430425 TI - [What is the future for niacin after the AIM-HIGH study?]. PMID- 22430426 TI - [New model of the optimal oral antiplatelet treatment in patients with the ST segment elevation myocardial infarction in Poland - authors' reply]. PMID- 22430427 TI - [Polish studies in hypertrophic cardiomyopathy]. PMID- 22430428 TI - [Patent foramen ovale in divers - a point of debate]. PMID- 22430430 TI - [5th Annual Congress of Working Group on Sport Cardiology of Polish Cardiac Society - summary]. PMID- 22430433 TI - A concept for ab initio prediction of cis-regulatory modules. AB - An important concern in the attempt of understanding the functional code of eukaryotic genes is to elucidate the control structures for regulating gene activation and suppression. One objective in the attempt to understand mechanisms of gene regulation is the elucidation of the regulatory network structure. A preliminary step of a detailed network analysis is identifying the transcription factor binding sites of a regulatory network. Known as cis-regulatory module (CRM), it is understood as part of the genome that comprises a set of short length binding sites. Gene regulatory systems are known to be quite stable during evolution, as compared to relatively frequent replication processes of genes and mutations of the coding sequences. This conservation property of regulatory code can advantageously be used for identifying cis-regulatory modules of potentially co-regulated genes. As the degree of similarity is expected to depend on the phylogenetic distance of homologs or orthologs, we favor an approach that is based on a comparison paradigm. The paper introduces a novel concept for measuring the similarity ofcis-regulatory modules which can then be used in an algorithm for comparing regulatory regions. The proposed algorithm searches for pairs of similar modules, and a prototype implementation is applied to human and mouse liver sequences. The results are compared to that of random sequences, and it is shown that a clear decision about co-regulation is possible at this level. PMID- 22430431 TI - The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials. AB - Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans. PMID- 22430434 TI - Evaluation of accuracy and applicability of protein models: retrospective analysis of biological and biomedical predictions. AB - In order to study protein function and activity structural data is required. Since experimental structures are available for just a small fraction of all known protein sequences, computational methods such as protein modelling can provide useful information. Over the last few decades we have predicted, with homology modelling methods, the structures for numerous proteins. In this study we assess the structural quality and validity of the biological and medical interpretations and predictions made based on the models. All the models had correct scaffolding and were ranked at least as correct or good by numerical evaluators even though the sequence identity with the template was as low as 8%. The biological explanations made based on models were well in line with experimental structures and other experimental studies. Retrospective analysis of homology models indicates the power of protein modelling when made carefully from sequence alignment to model building and refinement. Modelling can be applied to studying and predicting different kinds of biological phenomena and according to our results it can be done so with success. PMID- 22430435 TI - GEN-SNiP: an online tool to find polymorphisms in a genome. AB - An online tool named GEN-SNiP that identifies variations in a set of test DNA sequences with respect to a standard reference sequence is developed and deployed successfully. The tool generates a list of substitutions, insertions and deletions for each test sequences, determined by the reference sequence. In the key batch mode feature, the tool allows multiple sequences to be compared and contrasted even when small insertions and deletions are present, with results sent to the user via email. Other distinguishing features of the tool are grouping of continuous deletions or insertions in the test sequence into a single entity for better output handling, displaying of the alignment of test and reference sequence and the input sequence. The tool has been reported as unique in recent literature. PMID- 22430436 TI - Mutational bias and gene expression level shape codon usage in Thermobifida fusca YX. AB - In this study major factors shaping codon and amino acid usage variation in Thermobifida fusca YX are reported. It is a major degrader of plant cell walls. It produces spores that can be allergenic and has been associated with a condition called farmers lung. For comparison, two other closely related Actinobacteria, S. coelicolor and N. farcinica were considered. Correspondence analysis on RSCU (Relative Synonymous Codon Usage) showed significant correlation between the major trend of codon usage variation and gene expression level assessed by the "Codon Adaptation Index" (CAI) values. The result was further confirmed from distribution of genes along the first axis. In addition, N_{c} (effective number of codons) plot, SCUO (synonymous codon usage order) plot and correlation analyses showed that base composition and mutational bias have a dominant role in codon usage variation. Furthermore, gene expression level, hydrophobicity and aromaticity have played a significant role in the source of variations for amino acid usage. In addition, codon preference for genes at higher expression level was found to be similar among three different genera. Notably, 14 codons optimally used by Thermobifida fusca YX and its comparative study with S. coelicolor and N. farcinica might provide some useful information for their further study of molecular evolution and genetic engineering. PMID- 22430437 TI - In silico analysis of T-bet activity in peripheral blood mononuclear cells in patients with inflammatory bowel disease (IBD). AB - T-bet (TBX21) is a transcription factor that regulates T-cell differentiation, and has recently been implicated in the pathogenesis of Crohn's disease (CD). The regulatory networks through which T-bet affects immune function are unknown. An NCBI gene expression profile from patients with CD and controls was analyzed. T bet transcription factor binding sites and promoter modules were identified using promoter analysis software. Functional correlations between T-bet-containing promoters were determined using data mining and ontological analysis. T-bet expression in CD peripheral blood mononuclear cells (PBMCs) (n=59) was significantly reduced compared to control (n=42) (p<0.0001) and ulcerative colitis PBMCs (n=26), (p=0.005). The promoter regions of all genes differentially expressed in CD were probed for T-bet Transcription Factor Binding Sites (TFBSs). Twenty-three genes contained transcription-factor binding sites for T-bet; 8 were down-regulated, and 15 were up-regulated in CD-PBMCs. Three genes (S100A16, ABHD3 and EZH1) that were down-regulated in CD-PBMCs contained a complex promoter module consisting of T-bet and EGRF transcription-factor binding sites. Ontological analysis revealed that a significant number of differentially expressed genes that contain T-bet binding sites are involved in innate immunity (8 genes, Z-score 4.11) and signal transduction (5 genes, Z-score 2.65). This combination of gene expression datasets and promoter analysis has identified a network of genes that contain simple T-bet binding sites, and complex T-bet promoter modules, in their promoter regions. These results implicate a mechanism through which T-bet may influence innate immunity in CD. PMID- 22430438 TI - Interface of apoptotic protein complexes has distinct properties. AB - Apoptosis is a programmed mechanism of cell death that is a normal component of development and health of multi-cellular organisms. In this study, we ask if interface properties of apoptotic protein complexes are different from protein complexes in general. We find that although in apoptotic protein complexes the overall distribution of interface size, surface complementarity, hydrogen bonding, hydrophobicity are similar to general interface properties, apoptotic complexes tend to have more fragmented interfaces and different secondary structural preferences. The statistics on the number of interfaces where specific amino acid(s) occur with significantly enhanced frequency suggest that Arg, Met and Asp are most important functional residues. The role of Met is believed to be unique, as evidenced from the existing data on hot spot potential of residues. These findings together provide insight into the possible role of various physico chemical attributes at the protein interface in regulation of the apoptosis process. PMID- 22430439 TI - Analysis of Saccharomyces cerevisiae genome for the distributions of stress response elements potentially affecting gene expression by transcriptional interference. AB - Cellular stress responses are characterized by coordinated transcriptional induction of genes encoding a group of conserved proteins known as molecular chaperones, most of which are also known as heat shock proteins (HSPs). In S. cerevisiae, transcriptional responses to stress are mediated via two trans regulatory activators: heat shock transcription factors (HSFs) that bind to heat shock elements (HSEs), and the Msn2 and Msn4 transcription factors that bind to stress response elements (STREs). Recent studies in S. cerevisiae demonstrated that a significant portion of the non-coding region in the genome is transcribed and this intergenic transcription could regulate the transcription of adjacent genes by transcription interference. The goal of this study was to analyze the genomic distribution of HSF and Msn2/4 binding sites and to study the potential for transcription interference regulated by stress response systems. Our genome wide analysis revealed that 297 genes have STREs in their promoter region, whereas 310 genes contained HSEs. Twenty-five genes had both HSEs and STREs in their promoters. The first set of genes is potentially regulated by the Msn2/Msn4/STRE interaction. For the second set of genes, regulation by heat shock could be mediated through HSF/HSE regulatory mechanisms. The overlap between these groups suggests a co-regulation by the two pathways. Our study yielded 239 candidate genes, whose regulation could potentially be affected by heat-shock via transcription interference directed both from upstream and downstream areas relative to the native promoters. In addition we have categorized 924 genes containing HSE and/or STRE elements within the Open Reading Frames (ORFs), which may also affect normal transcription. Our study revealed a widespread possibility for the regulation of genes via transcriptional interference initiated by stress response. We provided a categorization of genes potentially affected at the transcriptional level by known stress-response systems. PMID- 22430440 TI - Challenges in the use of in silico tools for predicting peptides binding to HLA class II molecules of HCV E1, E2, and P7. AB - The application of in silico tools for the development of T-cell vaccines is crucial. Yet, due to myriad of polymorphisms of human T-lymphocytic antigen challenges, such therapeutic opportunities present unique roadblocks. There is an obvious advantage in using immunoinformatics (i.e., significantly decreasing cost related to laboratory expenses). A previous publication looked at random binding and nonbinding peptides in order to test the practicality of using such in silico tools to obtain possible immunogenic peptides. The present in silico study applied the same basic approaches to an applicable problem that was to identify promiscuous peptide vaccine candidates for hepatitis C virus (HCV) infection. The data sets used, included the proteins HCV E1, E2 and P7 as the binders (non-self antigens) and the GAD65 and ICA69, which have an association with diabetes, as non-binders (self-antigens). The in silico tools utilized were ProPred, MHC2PRED, and RANKPEP. The resulting differences were identifiable in each of the statistical parameters examined. Variations in the outcomes were evident by the dissimilarities found among the major indices of evaluation Sensitivity, Specificity, Accuracy, Positive Predictive Value (PPV), Negative Predictive Value (NPV) and Matthews's correlation coefficient (MCC) of the percentages of the predicted promiscuous peptides to HLA-DRB1*0101, *0301, and *0401. The conclusion from this study indicates that more work needs to be done in order to enhance the predictability of programs for the identification of peptide vaccine candidates for HCV. Such programs should not be solely relied upon without in vitro assay verification. PMID- 22430441 TI - Prediction of proteins putatively involved in the thiol: disulfide redox metabolism of a bacterium (Listeria): the CXXC motif as query sequence. AB - Thiol:disulfide redox metabolism (TDRM) is a central metabolic network in all living cells. However, numerous proteins with different biochemical functions and several structural domains are involved, making it not trivial to identify and annotate its constituents in sequenced genomes. We developed an uncomplicated approach to solve the problem using existing web-based tools and public databases with the gram-positive bacterium Listeria monocytogenes EGD-e as a model organism. A pattern search for the Cys-Xaa-Xaa-Cys (CXXC) motif--a hallmark of TDRM proteins--in the genome sequence of the bacterium yielded 156 proteins. After initial refinement by protein and domain analysis, 14 candidate proteins remained. Subsequent detailed analyses, supported by modeling of 3D structures and data integration yielded 6 thioredoxin-like proteins plus thioredoxin reductase, glutaredoxin, one redox-sensitive regulator, one peptide methionine reductase - all typical TDRM constituents - and three putative novel components of the TDRM. For all 14 proteins orthologues were found in other Listeria species. Homology searches and phylogenetic analyses showed that related proteins are present mainly in other Firmicutes. This fast approach required minimal resources. It is immediately applicable to any genome with appropriate modifications and should be practicable also for other conserved, functionally important amino acid motifs. PMID- 22430442 TI - Organization of the gymnotiform fish pallium in relation to learning and memory: II. Extrinsic connections. AB - This study describes the extrinsic connections of the dorsal telencephalon (pallium) of gymnotiform fish. We show that the afferents to the dorsolateral and dorsomedial pallial subdivisions of gymnotiform fish arise from the preglomerular complex. The preglomerular complex receives input from four clearly distinct regions: (1) descending input from the pallium itself (dorsomedial and dorsocentral subdivisions and nucleus taenia); (2) other diencephalic nuclei (centroposterior, glomerular, and anterior tuberal nuclei and nucleus of the posterior tuberculum); (3) mesencephalic sensory structures (optic tectum, dorsal and ventral torus semicircularis); and (4) basal forebrain, preoptic area, and hypothalamic nuclei. Previous studies have implicated the majority of the diencephalic and mesencephalic nuclei in electrosensory, visual, and acousticolateral functions. Here we discuss the implications of preglomerular/pallial electrosensory-associated afferents with respect to a major functional dichotomy of the electric sense. The results allow us to hypothesize that a functional distinction between electrocommunication vs. electrolocation is maintained within the input and output pathways of the gymnotiform pallium. Electrocommunication information is conveyed to the pallium through complex indirect pathways that originate in the nucleus electrosensorius, whereas electrolocation processing follows a conservative pathway inherent to all vertebrates, through the optic tectum. We hypothesize that cells responsive to communication signals do not converge onto the same targets in the preglomerular complex as cells responsive to moving objects. We also hypothesize that efferents from the dorsocentral (DC) telencephalon project to the dorsal torus semicircularis to regulate processing of electrocommunication signals, whereas DC efferents to the tectum modulate sensory control of movement. PMID- 22430443 TI - Occupational solvent exposure, genetic variation of DNA repair genes, and the risk of non-Hodgkin's lymphoma. AB - The main objective of this study was to test the hypothesis that genetic variations in DNA repair genes may modify the association between occupational exposure to solvents and the risk of non-Hodgkin's lymphoma (NHL). A population based case-control study was conducted on Connecticut women including 518 histologically confirmed incident NHL cases and 597 controls. Unconditional logistic regression models were used to estimate the odds ratios and effect modification from the 30 single nucleotide polymorphisms in 16 DNA repair genes of the association between solvent exposure and the risk of NHL overall and subtypes. Single nucleotide polymorphisms in MGMT (rs12917) and NBS1 (rs1805794) significantly modified the association between exposure to chlorinated solvents and the risk of NHL (Pfor interaction=0.0003 and 0.0048, respectively). After stratification by major NHL histological subtypes, MGMT (rs12917) modified the association between chlorinated solvents and the risk of diffuse large B-cell lymphoma (Pfor interaction=0.0027) and follicular lymphoma (Pfor interaction=0.0024). A significant interaction was also observed between occupational exposure to benzene and BRCA2 (rs144848) for NHL overall (Pfor interaction=0.0042). Our study results suggest that genetic variations in DNA repair genes modify the association between occupational exposure to solvents and the risk of NHL. PMID- 22430444 TI - Clinical presentation of intoxication due to synthetic cannabinoids. AB - Synthetic cannabinoids are relatively novel substances of abuse. The use of these compounds among adolescents and young adults has been increasing, making it important for pediatric providers to be familiar with the presenting signs and symptoms of intoxication. We describe three case presentations of reported synthetic cannabinoid intoxication and provide a brief discussion of these compounds. PMID- 22430445 TI - Decline in infantile hypertrophic pyloric stenosis in Germany in 2000-2008. AB - BACKGROUND AND OBJECTIVE: The incidence of infantile hypertrophic pyloric stenosis (IHPS) is highly variable over time and geographic regions. A decline in IHPS incidence was recently reported in Sweden, the United States, Denmark, and Scotland. In Sweden, the IHPS decline seemed to be concurrent with a declining incidence in sudden infant death syndrome (SIDS), which suggested a common cause; the latter was attributed to campaigns against the prone sleeping position. We investigated the time course of the IHPS incidence in all German federal states (N = 16) between 2000 and 2008. We examined correlations between the IHPS incidence and the SIDS incidence. METHODS: Data were extracted from the public report of health (Gesundheitsberichterstattung des Bundes). We collected the numbers of IHPS (International Classification of Diseases, 10th Revision [ICD 10], code 40.0), SIDS (ICD-10, R95), and live births (LB; male/female) in each federal state for 2000-2008. RESULTS: The IHPS incidence declined in Germany from 2000 (3.2086/1000 LB [range: 1.67-5.33]) to 2008 (2.0175/1000 LB [1.74-3.72]; P = .005). The recorded incidence was highly variable in different federal states and over time. The SIDS incidence also declined during the same time period (2000, median: 0.759/1000 LB [interquartile range: 0.54-1.029]; 2008, median: 0.416/1000 LB [interquartile range: 0.285-0.6485]; P = .0255). However, the SIDS regional distribution was different from that of IHPS. CONCLUSIONS: The IHPS incidence declined by ~38% nationwide. A parallel decline in SIDS displayed a different pattern in regional distribution; thus, a common cause was unlikely. The regional differences indicated that etiologic factors remained unresolved. PMID- 22430446 TI - Congruence of reproductive concerns among adolescents with cancer and parents: pilot testing an adapted instrument. AB - OBJECTIVE: To identify whether a health-related quality of life (HRQoL) instrument intended to capture reproductive concerns is sensitive and appropriate for adolescent patients with cancer. METHODS: Pilot testing was completed by administering a 10-item instrument designed to identify reproductive concerns of female adolescent patients with cancer aged 12-18. Parents were also asked to predict their daughters' responses. Fourteen patients and parents participated. The main outcome measures were language, relevance, accuracy, sensitivity, and missing content regarding the HRQoL instrument. Two pediatric hospitals and 1 local support group for patients and survivors served as the setting for this study. RESULTS: The majority of parents provided inaccurate predictions of their daughters' responses regarding their reproductive concerns. Overall, parents underestimated their daughters' concerns because the majority of adolescents reported a strong desire for future parenthood whereas parents expected their daughters to be satisfied with survivorship. CONCLUSIONS: Adolescent patients with cancer have strong reproductive concerns; however, this may not be captured on current HRQoL instruments and may be further neglected due to parents' unawareness. Discussions should be encouraged with adolescent patients before beginning treatment regarding their concerns and values about parenting in the future and cannot rely on parent-proxy reports. PMID- 22430447 TI - The outcome of ELBW infants treated with NCPAP and InSurE in a resource-limited institution. AB - BACKGROUND AND OBJECTIVE: Nasal continuous positive airway pressure (NCPAP) plus intubation, surfactant, and extubation (InSurE) with the option of back-up ventilation for those infants for whom noninvasive ventilatory support failed resulted in a significant increase in survival in extremely low birth weight (ELBW) infants. The authors sought to determine the outcome of ELBW infants treated with NCPAP and InSurE in a neonatal high care ward with limited back-up ventilation. METHODS: Three hundred eighteen inborn infants with birth weight 500 1000 g and gestational age >=25 weeks who were admitted to the neonatal high care ward were included in this observational study. InSurE was administered to infants with respiratory distress syndrome on NCPAP who had severe in-drawing and recession, apneic spells, or an Fio(2) >0.4 within 1 hour of birth. RESULTS: Two hundred twelve (68.6%) infants could be treated with NCPAP only and 97 (31.4%) required InSurE. Seventeen infants were admitted to the NICU; 90%, 87%, and 74.8% of the infants survived until day 3, 7, and discharge, respectively. Only 2 infants developed a pneumothorax and 2 had chronic lung disease. Seventy-nine percent of the infants of >=750 g or >26 weeks' gestation survived to discharge compared with 56% and 60% of the infants of <750 g or <=26 weeks' gestation, respectively. Maternal antenatal steroid administration contributed significantly to the survival of the infants (P = 0.0017, odds ratio 2.7, 95% confidence interval 1.44-5.07). CONCLUSIONS: The use of NCPAP and InSurE in a neonatal high care ward with limited resources can improve the survival of ELBW infants. Maternal antenatal steroid administration contributed significantly to survival. PMID- 22430448 TI - Role of copy number variants in structural birth defects. AB - BACKGROUND AND OBJECTIVE: Human genomes include copy number variants (CNVs), defined as regions with DNA gains or losses. Pathologic CNVs, which are larger and often occur de novo, are increasingly associated with disease. Given advances in genetic testing, namely microarray-based comparative genomic hybridization and single nucleotide polymorphism arrays, previously unidentified genotypic aberrations can now be correlated with phenotypic anomalies. The objective of this study was to conduct a nonsystematic literature review to document the role of CNVs as they relate to isolated structural anomalies of the craniofacial, respiratory, renal, and cardiac systems. METHODS: All full-length articles in the PubMed database through May 2011 that discussed CNVs and isolated structural defects of the craniofacial, respiratory, renal, and cardiac systems were considered. Search terms queried include CNV, copy number variation, array comparative genomic hybridization, birth defects, craniofacial defects, respiratory defects, renal defects, and congenital heart disease. Reports published in languages other than English and articles regarding CNVs and neurocognitive deficits were not considered. RESULTS: Evidence supports that putatively pathogenic CNVs occur at an increased frequency in patients with isolated structural birth defects and implicate specific regions of the genome. Through CNV detection, advances have been made in identifying genes and specific loci that underlie isolated birth defects. CONCLUSIONS: Although limited studies have been published, the promising evidence reviewed here warrants the continued investigation of CNVs in children with isolated structural birth defects. Patient care and genetic counseling stand to improve through a better understanding of CNVs and their effect on disease phenotype. PMID- 22430449 TI - Cerebral palsy among Asian ethnic subgroups. AB - OBJECTIVE: Asians have a reduced risk for cerebral palsy (CP) compared with whites. We examined whether individual Asian subgroups have a reduced risk of CP and whether differences in sociodemographic factors explain disparities in CP prevalence. METHODS: In a retrospective cohort of 629 542 Asian and 2 109 550 white births in California from 1991 to 2001, we identified all children who qualified for services from the California Department of Health Services on the basis of CP. Asians were categorized as East Asian (Chinese, Japanese, Koreans), Filipino, Indian, Pacific Islander (Guamanians, Hawaiians, and Pacific Islanders), Samoan, or Southeast Asian (Cambodian, Laotian, Thai, Vietnamese). RESULTS: Overall, CP prevalence was lower in Asians than whites (1.09 vs 1.36 per 1000; relative risk = 0.80, 95% confidence interval [CI] = 0.74-0.87) and ranged from 0.61/1000 in Thai children to 2.08/1000 in Samoan children. Several Asian subgroups had low risk profiles with respect to maternal age, educational attainment, and birth weight. However, after we adjusted for maternal age and education, infant gender, and birth weight, the adjusted risk of CP remained lower in East Asians (odds ratio [OR] = 0.75, 95% CI = 0.65-0.87), Filipinos (OR = 0.87, 95% CI = 0.75-0.99), Indians (OR = 0.59, 95% CI = 0.44-0.80), Pacific Islanders (OR = 0.62, 95% CI = 0.40-0.97), and Southeast Asians (OR = 0.68, 95% CI = 0.57-0.82) compared with whites. CONCLUSIONS: Most Asian national origin subgroups have a lower rate of CP than whites, and this disparity is unexplained. Additional studies that focus on the cause of ethnic disparities in CP may provide new insights into pathogenesis and prevention. PMID- 22430450 TI - Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. AB - OBJECTIVE: The optimal treatment of neonatal hyperglycemia is unclear. The aim of this trial was to determine whether tight glycemic control with insulin improves growth in hyperglycemic preterm infants, without increasing the incidence of hypoglycemia. METHODS: Randomized, controlled, nonblinded trial of 88 infants born at <30 weeks' gestation or <1500 g who developed hyperglycemia (2 consecutive blood glucose concentrations (BGC) >8.5 mmol/L, 4 hours apart) and were randomly assigned to tight glycemic control with insulin (target BGC 4-6 mmol/L, "tight" group) or standard practice (restrictive guidelines for starting insulin, target BGC 8-10 mmol/L, "control" group). The primary outcome was linear growth rate to 36 weeks' postmenstrual age. RESULTS: Eighty-eight infants were randomly assigned (tight group n = 43; control group n = 45). Infants in the tight group had a lesser lower leg growth rate (P < .05), but greater head circumference growth (P < .0005) and greater weight gain (P < .001) to 36 weeks' postmenstrual age than control infants. Tight group infants had lower daily BGC (median [interquartile range] 5.7 [4.8-6.7] vs 6.5 [5.1-8.2] mmol/L, P < .001) and greater incidence of hypoglycemia (BGC <2.6 mmol/L) (25/43 vs 12/45, P < .01) than controls. There were no significant differences in nutritional intake, or in the incidences of mortality or morbidity. CONCLUSIONS: Tight glycemic control with insulin in hyperglycemic preterm infants increases weight gain and head growth, but at the expense of reduced linear growth and increased risk of hypoglycemia. The balance of risks and benefits of insulin treatment in hyperglycemic preterm neonates remains uncertain. PMID- 22430451 TI - Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. AB - OBJECTIVES: Exposure to passive smoke is a common and avoidable risk factor for wheeze and asthma in children. Substantial growth in the prospective cohort study evidence base provides an opportunity to generate new and more detailed estimates of the magnitude of the effect. A systematic review and meta-analysis was conducted to provide estimates of the prospective effect of smoking by parents or household members on the risk of wheeze and asthma at different stages of childhood. METHODS: We systematically searched Medline, Embase, and conference abstracts to identify cohort studies of the incidence of asthma or wheeze in relation to exposure to prenatal or postnatal maternal, paternal, or household smoking in subjects aged up to 18 years old. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by using random effects model. RESULTS: We identified 79 prospective studies. Exposure to pre- or postnatal passive smoke exposure was associated with a 30% to 70% increased risk of incident wheezing (strongest effect from postnatal maternal smoking on wheeze in children aged <=2 years, OR = 1.70, 95% CI = 1.24-2.35, 4 studies) and a 21% to 85% increase in incident asthma (strongest effect from prenatal maternal smoking on asthma in children aged <=2 years, OR = 1.85, 95% CI = 1.35-2.53, 5 studies). CONCLUSIONS: Building upon previous findings, exposure to passive smoking increases the incidence of wheeze and asthma in children and young people by at least 20%. Preventing parental smoking is crucially important to the prevention of asthma. PMID- 22430452 TI - Triage nurse initiation of corticosteroids in pediatric asthma is associated with improved emergency department efficiency. AB - OBJECTIVE: To assess the effectiveness of nurse-initiated administration of oral corticosteroids before physician assessment in moderate to severe acute asthma exacerbations in the pediatric ED. METHODS: A time-series controlled trial evaluated nurse initiation of treatment with steroids before physician assessment in children with Pediatric Respiratory Assessment Measure score >=4. One-to-one periods (physician-initiated and nurse-initiated) were analyzed from September 2009 through May 2010. In both phases, triage nurses initiated bronchodilator therapy before physician assessment, per Pediatric Respiratory Assessment Measure score. We reviewed charts of 644 consecutive children aged 2 to 17 years for the following outcomes: admission rate; times to clinical improvement, steroid receipt, mild status, and discharge; and rate of return ED visit and subsequent admission. RESULTS: Nurse-initiated phase children improved earlier compared to physician-initiated phase (median difference: 24 minutes; 95% confidence interval [CI]: 1-50; P = .04). Admission was less likely if children received steroids at triage (odds ratio = 0.56; 95% CI: 0.36-0.87). Efficiency gains were made in time to steroid receipt (median difference: 44 minutes; 95% CI: 39-50; P < .001), time to mild status (median difference: 51 minutes; 95% CI: 17-84; P = .04), and time to discharge (median difference: 44 minutes; 95% CI: 17-68; P = .02). No differences were found in return visit rate or subsequent admission. CONCLUSIONS: Triage nurse initiation of oral corticosteroid before physician assessment was associated with reduced times to clinical improvement and discharge, and reduced admission rates in children presenting with moderate to severe acute asthma exacerbations. PMID- 22430453 TI - Implications of childhood autism for parental employment and earnings. AB - OBJECTIVE: To examine changes in parental labor force participation, hours of work, and annual earnings associated with childhood autism spectrum disorders (ASD). METHODS: We used the 2002-2008 Medical Expenditure Panel Survey to examine parental labor market outcomes of children with ASD relative to children with another health limitation and children without health limitations. A logit model was used to estimate parental labor force participation. A tobit model was used to estimate parental hours of work and earnings. RESULTS: On average, mothers of children with ASD earn 35% ($7189) less than the mothers of children with another health limitation and 56% ($14 755) less than the mothers of children with no health limitation. They are 6% less likely to be employed and work 7 hours less per week, on average, than mothers of children with no health limitation. There were no statistically significant differences in fathers' labor market outcomes across 3 groups. On average, children with ASD are 9% less likely to have both parents working. Family earnings of children with ASD are 21% ($10 416) less than those of children with another health limitation and 28% ($17 763) less than those of children with no health limitation. Family weekly hours of work are an average of 5 hours less than those of children with no health limitation. CONCLUSIONS: Families of children with ASD face significant economic burden. Given the substantial health care expenses associated with ASD, the economic impact of having lower income in addition to these expenses is substantial. It is essential to design universal health care and workplace policies that recognize the full impact of autism. PMID- 22430454 TI - Impact of rotavirus vaccine on diarrhea-associated disease burden among American Indian and Alaska Native children. AB - OBJECTIVE: Beginning in 2006, the Indian Health Service (IHS) began rotavirus vaccination of American Indian and Alaska Native (AI/AN) infants. To assess vaccine impact, we examined trends in IHS diarrhea-associated hospitalization and outpatient visits among AI/AN children in the pre- and postrotavirus vaccine era. METHODS: Diarrhea-associated hospitalizations and outpatient visits among AI/AN children <5 years of age during 2001 through 2010 were examined by gender, age group, and region for prevaccine years 2001-2006 and postvaccine years 2008, 2009, and 2010. To account for secular declining trends observed in prevaccine years, expected diarrhea-associated hospitalization and outpatient rates for postvaccine years were generated by using Poisson regression analysis of the 2001 2006 annual rates. RESULTS: Coverage with at least 1 dose of rotavirus vaccine among AI/AN infants aged 3 to 5 months in the first half of 2008, 2009, and 2010 ranged from 48% to 80% in various IHS regions. The prevaccine average annual diarrhea-associated hospitalization rates among AI/AN children <5 years of age was 63 per 10 000 persons (range: 57-75 per 10 000), and declined to 39, 31, and 27 per 10 000 in 2008, 2009, and 2010, respectively. Observed 2008, 2009, and 2010 rates were 24%, 37%, and 44% lower than expected rates, respectively. Decreases in diarrhea-associated hospitalizations and outpatient visits were observed in all IHS regions. CONCLUSIONS: Diarrhea-associated hospitalization and outpatient visit rates among AI/AN children have declined after implementation of rotavirus vaccination in AI/AN populations. PMID- 22430455 TI - Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age. AB - OBJECTIVE: We evaluated behavior problems in children who were prenatally exposed to methamphetamine (MA) at ages 3 and 5 years. METHODS: The Infant Development, Environment, and Lifestyle study, a prospective, longitudinal study of prenatal MA exposure and child outcome, enrolled subjects postpartum in Los Angeles, California; Honolulu, Hawaii; Des Moines, Iowa; and Tulsa, Oklahoma. Prenatal exposure was determined by maternal self-report and/or meconium results. Exposed and comparison groups were matched on race, birth weight, public health insurance, and education. Mothers in the comparison group denied use and had a negative meconium screen for amphetamines. Prenatal exposures to tobacco, alcohol, or marijuana occurred in both groups. At ages 3 and 5 years, 330 children (166 exposed and 164 comparison) were assessed for behavior problems by using the caregiver report on the Child Behavior Checklist. General linear mixed models were used to determine the effects of prenatal MA exposure, including heavy exposure (>=3 days per week), age, and the interaction of exposure and age on behavior problems with adjustment for other drugs of abuse and environmental risk factors. RESULTS: MA exposure was associated with increased emotional reactivity and anxious/depressed problems at both ages and externalizing and attention-deficit/hyperactivity disorder problems by age 5 years. Heavy exposure was related to attention problems and withdrawn behavior at both ages. There were no effects of MA on the internalizing or total behavior problems scales. CONCLUSIONS: This first report of behavior problems in patients as young as 3 years associated with MA exposure identifies an important public health problem. Continued follow-up can inform the development of preventive intervention programs. PMID- 22430456 TI - Limitations and opportunities of transcutaneous bilirubin measurements. AB - OBJECTIVE: Although transcutaneous bilirubinometers have existed for over 30 years, the clinical utility of the technique is limited to a screening method for hyperbilirubinemia, rather than a replacement for invasive blood sampling. In this study, we investigate the reason for this limited clinical value and address possibilities for improvement. METHODS: To obtain better insight into the physiology of bilirubin measurements, we evaluated a transcutaneous bilirubinometer that determines not only the cutaneous bilirubin concentration (TcB) but also the blood volume fraction (BVF) in the investigated skin volume. For 49 neonates (gestational age 30 +/- 3.1 weeks, postnatal age 6 [4-10] days) at our NICU, we performed 124 TcB and 55 BVF measurements. RESULTS: The TcB correlated well with the total serum bilirubin concentration (TSB) (r = 0.88) with an uncertainty of 55 umol/L. The BVF in the measured skin volume ranged between 0.1% and 0.75%. CONCLUSIONS: The performance of our bilirubinometer is comparable to existing transcutaneous devices. The limited clinical value of current bilirubinometers can be explained by the low BVF in the skin volume that is probed by these devices. Because the TcB depends for over 99% on the contribution of extravascular bilirubin, it is a physiologically different parameter from the TSB. Hence, the standard method of evaluation that compares the TcB to the TSB is insufficient to fully investigate the clinical value of transcutaneous bilirubinometers, ie, their predictive value for kernicterus. We suggest that the clinical value may be improved considerably by changing either the method of evaluation or the technological design of transcutaneous bilirubinometers. PMID- 22430457 TI - Shifts in BMI category and associated cardiometabolic risk: prospective results from HEALTHY study. AB - OBJECTIVES: To evaluate shifts across BMI categories and associated changes in cardiometabolic risk factors over 2.5 years in an ethnically diverse middle school sample. METHODS: As part of HEALTHY, a multisite school-based study designed to mitigate risk for type 2 diabetes, 3993 children participated in health screenings at the start of sixth and end of eighth grades. Assessments included anthropometric measures, blood pressure, and glucose, insulin, and lipids. Students were classified as underweight, healthy weight, overweight, obese, or severely obese. Mixed models controlling for school intervention status and covariates were used to evaluate shifts in BMI category over time and the relation between these shifts and changes in risk factors. RESULTS: At baseline, students averaged 11.3 (+/-0.6) years; 47.6% were boys, 59.6% were Hispanic, and 49.8% were overweight or obese. Shifts in BMI category over time were common. For example, 35.7% of youth who were overweight moved to the healthy weight range, but 13% in the healthy weight range became overweight. BMI shifts were not associated with school intervention condition, household education, or youth gender, race/ethnicity, pubertal status, or changes in height. Increases in BMI category were associated with worsening of cardiometabolic risk factors, and decreases were associated with improvements. Boys who increased BMI category were more vulnerable to negative risk factor changes than girls. CONCLUSIONS: There are substantial shifts across BMI categories during middle school that are associated with clinically meaningful changes in cardiometabolic risk factors. Programs to promote decreases in BMI and prevent increases are clearly warranted. PMID- 22430458 TI - Language functions in preterm-born children: a systematic review and meta analysis. AB - BACKGROUND AND OBJECTIVE: Preterm-born children (<37 weeks' gestation) have higher rates of language function problems compared with term-born children. It is unknown whether these problems decrease, deteriorate, or remain stable over time. The goal of this research was to determine the developmental course of language functions in preterm-born children from 3 to 12 years of age. METHODS: Computerized databases Embase, PubMed, Web of Knowledge, and PsycInfo were searched for studies published between January 1995 and March 2011 reporting language functions in preterm-born children. Outcome measures were simple language function assessed by using the Peabody Picture Vocabulary Test and complex language function assessed by using the Clinical Evaluation of Language Fundamentals. Pooled effect sizes (in terms of Cohen's d) and 95% confidence intervals (CI) for simple and complex language functions were calculated by using random-effects models. Meta-regression was conducted with mean difference of effect size as the outcome variable and assessment age as the explanatory variable. RESULTS: Preterm-born children scored significantly lower compared with term-born children on simple (d = -0.45 [95% CI: -0.59 to -0.30]; P < .001) and on complex (d = -0.62 [95% CI: -0.82 to -0.43]; P < .001) language function tests, even in the absence of major disabilities and independent of social economic status. For complex language function (but not for simple language function), group differences between preterm- and term-born children increased significantly from 3 to 12 years of age (slope = -0.05; P = .03). CONCLUSIONS: While growing up, preterm-born children have increasing difficulties with complex language function. PMID- 22430459 TI - Noninvasive measurements of bilirubin. PMID- 22430460 TI - In vivo studies on angiogenic activity of two designer self-assembling peptide scaffold hydrogels in the chicken embryo chorioallantoic membrane. AB - The rapid promotion of angiogenesis is critical for tissue engineering and regenerative medicine. The angiogenic activity of tissue-engineered scaffolds has already been the major criterion for choosing and designing ideal biological materials. We here report systematic in vivo studies on the angiogenic activity of two functionalized self-assembling peptides PRG (Ac-(RADA)(4)GPRGDSGYRGDS CONH(2)) and KLT (Ac-(RADA)(4)G(4)KLTWQELYQLKYKGI-CONH(2)) using the chicken embryo chorioallantoic membrane (CAM) assay. 3D migration/sprouting bead assays showed that the two functional motifs PRGDSGYRGDS and KLTWQELYQLKYKGI improved the bioactivities of the self-assembling peptide RADA16-I (Ac-(RADA)(4)-CONH(2)) dramatically and provided ideal synthetic microenvironments for endothelial cell migration and cordlike structure sprout formation. A CAM assay was carried out to assess the efficiency of various peptide scaffolds in inducing capillary invasion in vivo. Among these three peptide scaffolds, the functionalized peptide scaffold RAD/KLT presented a significantly better angiogenic activity inducing CAM tissue invasion and new capillary vessel formation within the scaffolds in the absence of VEGF. With the addition of VEGF, more newly formed vessel lumen could be observed in all peptide scaffolds. Our results suggested that the functionalized peptide scaffolds had satisfactory angiogenic properties, and may also have wide potential applications in tissue regeneration. PMID- 22430461 TI - Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer. AB - BACKGROUND: With the limited strategies for curative treatment of castration resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression. METHODS: Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells. RESULTS: We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor beta (ERbeta) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERbeta up regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control. CONCLUSION: These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. PMID- 22430469 TI - Bushbabies brought to light. PMID- 22430470 TI - Amending a protocol to import and breed knockout mice. Approval before import. PMID- 22430471 TI - Amending a protocol to import and breed knockout mice. PMID- 22430472 TI - Amending a protocol to import and breed knockout mice. A word from OLAW. PMID- 22430473 TI - Amending a protocol to import and breed knockout mice. New strains, strain-free. PMID- 22430474 TI - Amending a protocol to import and breed knockout mice. Significant concerns? PMID- 22430476 TI - Non-invasive genotyping of transgenic animals using fecal DNA. AB - For genotyping of transgenic animals, many IACUC guidelines recommend the use of fecal DNA when possible because this approach is non-invasive. Existing methods for extracting fecal DNA may be costly or involve the use of toxic organic solvents. Furthermore, feces contain an abundance of PCR inhibitors that may hinder DNA amplification when they are co-purified with fecal DNA. Here the authors describe a cost-effective, non-toxic method for genotyping transgenic animals by using the reagent AquaStool to extract fecal DNA and remove PCR inhibitors. Genotyping results obtained from fecal DNA samples extracted using AquaStool were reliably accurate when compared with results obtained from tail DNA samples. Because it is non-invasive, the authors believe that use of this method for genotyping transgenic animals using fecal DNA samples may improve animal welfare. PMID- 22430477 TI - Facilitating international animal research programs. PMID- 22430479 TI - A comparison between urban livestock production strategies in Burkina Faso, Mali and Nigeria in West Africa. AB - We undertook a comparative analysis of (peri-)urban livestock production strategies across three West African cities. Using a semi-structured questionnaire, livestock-keeping households (HH) were interviewed in Kano/Nigeria (84 HH), Bobo Dioulasso/Burkina Faso (63 HH) and Sikasso/Mali (63 HH). Questions covered livestock species kept, herd sizes and structure, feeds used, manure management, livestock marketing and production constraints. Sheep and goats dominated (p < 0.001) in Kano (76 and 75 % of HH) compared to Bobo Dioulasso (48 and 40 %) and Sikasso (28 and 40 %), while cattle and poultry were more frequent (p < 0.001) in Bobo Dioulasso (82 and 69 % of HH) and Sikasso (65 and 79 %) than in Kano (29 and 20 %). Across cities, ruminant feeding relied on grazing and homestead supplementation with fresh grasses, crop residues, cereal brans and cottonseed cake; cereal grains and brans were major ingredients of poultry feeds. Cattle and sheep fetched highest prices in Kano, unit prices for goats and chicken were highest in Sikasso. Across cities there was little association of gardens and livestock, whereas field cropping and livestock were integrated. There was no relation between the education of the HH head and the adoption of improved management practices (p > 0.05), but the proportion of HH heads with a long-term experience in UPA activities was higher in Kano and in Bobo Dioulasso than in Sikasso (p < 0.001). We therefore postulate that the high illiteracy rate among (peri-)urban livestock keepers in West Africa does not threaten the acceptance of improved technologies and innovations supporting the sustainability of their livestock production. PMID- 22430480 TI - KERMA ratios in pediatric CT dosimetry. AB - BACKGROUND: Patient organ doses may be estimated from CTDI values. More accurate estimates may be obtained by measuring KERMA (Kinetic Energy Released in Matter) in anthropomorphic phantoms and referencing these values to free-in-air X-ray intensity. OBJECTIVE: To measure KERMA ratios (R(K)) in pediatric phantoms at CT. MATERIALS & METHODS: CT scans produce an air KERMA K in a phantom and an air KERMA K(CT) at isocenter. KERMA ratios (R(K)) are defined as (K/K(CT)), measured using TLD chips in phantoms representing newborns to 10-year-olds. RESULTS: R(K) in the newborn is approximately constant. For the other phantoms, there is a peak R(K) value in the neck. The median R(K) values for the GE scanner at 120 kV were 0.92, 0.83, 0.77 and 0.76 for newborns, 1-year-olds, 5-year-olds and 10-year olds, respectively. Organ R(K) values were 0.91 +/- 0.04, 0.84 +/- 0.07, 0.74 +/- 0.09 and 0.72 +/- 0.10 in newborns, 1-year-olds, 5-year-olds and 10-year-olds, respectively. At 120 kV, a Siemens Sensation 16 scanner had R(K) values 5% higher than those of the GE LightSpeed Ultra. CONCLUSION: KERMA ratios may be combined with air KERMA measurements at the isocenter to estimate organ doses in pediatric CT patients. PMID- 22430481 TI - Melanotic neuroectodermal tumour of infancy: CT and MR findings. AB - BACKGROUND: Melanotic neuroectodermal tumour of infancy (MNTI) is a rare neoplasm of neural crest origin. OBJECTIVE: To describe three further cases of MNTI, with emphasis on CT and MRI findings. MATERIALS AND METHODS: Data for children with histologically confirmed MNTI following biopsy or surgery were retrieved. Three children with available imaging at the time of diagnosis were included in the study. RESULTS: All three children had primary tumour in the head and neck region: one in the maxilla, one in the occipital bone (extra-axial but with intracranial extension) and one with an unusual tumour growing exophytically from the subcutaneous tissues adjacent to the occipital bone. All tumours were iso/hypointense both on T1- and T2-weighted MRI, and showed marked contrast enhancement in their non-ossified components. CT allowed identification of bone destruction and remodelling. CONCLUSION: Our findings are consistent with previously reported cases of MNTI regarding age at presentation and location in the head and neck region. Our MR findings did not demonstrate the typical pattern of T1-shortening expected from melanin deposition. PMID- 22430482 TI - The paediatric wrist revisited--findings of bony depressions in healthy children on radiographs compared to MRI. AB - BACKGROUND: The presence of erosions is used for diagnosis and monitoring of disease activity in juvenile idiopathic arthritis (JIA). Assessment of carpal bone erosions in children is challenging due to lack of normal references. OBJECTIVE: To define normal appearances of bony depressions in the wrist on radiographs and MRI. MATERIALS AND METHODS: MRI and radiography of the wrist were performed in 88 healthy children, 5-15 years of age. We assessed the number of bony depressions within the carpals/proximal metacarpals on both modalities, separately and combined. RESULTS: A total of 75 carpal depressions were identified on radiography compared to 715 on MRI. The number of bony depressions identified radiographically showed no statistically significant difference across age-groups. Within the metacarpals, there was no significant difference between bony depressions identified by MRI or radiography, except at the bases of the second metacarpal. CONCLUSION: Bony depressions that resemble erosions are normal findings in the wrist in children. MRI identifies more depressions than radiographs in the carpus. Some bony depressions occur at typical locations and should be accounted for when assessing the wrist in JIA to avoid overstaging. PMID- 22430483 TI - Rare presentation of BK encephalitis in a child: imaging and pathological findings. AB - Clinically apparent BK virus infections mostly involve the genitourinary system of immunocompromised patients, particularly those who have undergone renal or bone marrow transplantations. Central nervous system involvement is extremely rare. In this report, we describe the pathologic and MR findings of BK encephalitis in a child. Initial involvement of the brainstem and the cervicomedullary junction was noted that later rapidly progressed to involve other regions of the supratentorial brain parenchyma including the basal ganglia and the thalami as well as the cerebellum. PMID- 22430484 TI - KERMA ratios vs. SSDE: is one better at estimating pediatric CT radiation doses? PMID- 22430485 TI - Treatments and outcomes for end-stage renal disease following Wilms tumor. AB - BACKGROUND: Little is known about treatment outcomes for children who have end stage renal disease (ESRD) after treatment for Wilms tumor (WT). METHODS: Time-to transplant, graft failure, and survival outcomes were examined for 173 children enrolled on the National Wilms Tumor Study who developed ESRD. RESULTS: Fifty five patients whose ESRD resulted from progressive bilateral WT (PBWT) experienced high early mortality from WT that limited their opportunity for transplant (47% at 5 years) and survival (44% at 10 years) in comparison to population controls. The 118 patients whose ESRD was due to other causes (termed "chronic kidney disease"), many of whom had WT-associated congenital anomalies, had transplant (77% at 5 years) and survival (73% at 10 years) outcomes no worse than those for population controls. Graft failure following transplant was comparable for the two groups. Minority children had twice the median time to transplant as non-Hispanic whites and twice the mortality rates, also reflecting population trends. CONCLUSIONS: In view of the continuing high mortality in patients with ESRD, and the dramatic improvement in outlook following kidney transplantation, re-evaluation of current guidelines for a 2-year delay in transplant following WT treatment may be warranted. PMID- 22430486 TI - Unexpectedly strong anion-pi interactions on the graphene flakes. AB - Interactions of anions with simple aromatic compounds have received growing attention due to their relevancy in various fields. Yet, the anion-pi interactions are generally very weak, for example, there is no favorable anion-pi interaction for the halide anion F(-) on the simplest benzene surface unless the H-atoms are substituted by the highly negatively charged F. In this article, we report a type of particularly strong anion-pi interactions by investigating the adsorptions of three halide anions, that is, F(-), Cl(-), and Br(-), on the hydrogenated-graphene flake using the density functional theory. The anion-pi interactions on the graphene flake are shown to be unexpectedly strong compared to those on simple aromatic compounds, for example, the F(-)-adsorption energy is as large as 17.5 kcal/mol on a graphene flake (C(84) H(24)) and 23.5 kcal/mol in the periodic boundary condition model calculations on a graphene flake C(113) (the supercell containing a F(-) ion and 113 carbon atoms). The unexpectedly large adsorption energies of the halide anions on the graphene flake are ascribed to the effective donor-acceptor interactions between the halide anions and the graphene flake. These findings on the presence of very strong anion-pi interactions between halide ions and the graphene flake, which are disclosed for the first time, are hoped to strengthen scientific understanding of the chemical and physical characteristics of the graphene in an electrolyte solution. These favorable interactions of anions with electron-deficient graphene flakes may be applicable to the design of a new family of neutral anion receptors and detectors. PMID- 22430487 TI - Visual processing for action resists similarity of relevant and irrelevant object features. AB - It has been suggested that the human brain processes visual information in different manners, depending on whether the information is used for perception or for action control. This distinction has been criticized for the lack of behavioral dissociations that unambiguously support the proposed two-visual pathways model. Here we present a new and simple dissociation between vision for perception and vision for action: Perceptual judgments are affected by the similarity of relevant and irrelevant stimulus features, while object-oriented actions are not. This dissociation overcomes the methodological problems of previously proposed differences in terms of vulnerability to visual illusions or to variability in irrelevant object features, and it can also serve as an easily applicable behavioral indicator of underlying processing modes. PMID- 22430489 TI - A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis. AB - An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress-associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1beta, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down regulation of Grp78 transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-beta-induced synoviocyte proliferation and cyclin D1 up regulation. Conversely, overexpression of the Grp78 gene prevented synoviocyte apoptosis. Moreover, Grp78 small interfering RNA inhibited VEGF(165)-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with Grp78 haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA. PMID- 22430490 TI - Characterization of resident and migratory dendritic cells in human lymph nodes. AB - Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4(+) and CD8(+) T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities. PMID- 22430491 TI - MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. AB - Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors. PMID- 22430492 TI - Notch, Id2, and RORgammat sequentially orchestrate the fetal development of lymphoid tissue inducer cells. AB - Lymphoid tissue development is initiated during embryogenesis by the migration of lymphoid tissue inducer (LTi) cells from the fetal liver to the periphery, where they induce the formation of lymph nodes and Peyer's patches. In the fetal liver, a subset of common lymphoid progenitors (CLPs) that expresses the integrin alpha4beta7 gives rise to LTi cells, a process strictly dependent on the expression of the transcriptional repressor Id2 and the nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORgammat). In this study, we show that Id2 and RORgammat are sequentially up-regulated during LTi cell development, matching two waves of differentiation with opposite requirements for Notch signaling. Both the expression of Id2 and Notch are required for the generation of alpha4beta7(+) RORgammat(-) fetal progenitors, but Notch subsequently blocks progression to the RORgammat(+) stage and final maturation of LTi cells. Notch is therefore a necessary switch to engage the LTi developmental pathway, but needs to be turned off later to avoid diversion to the T cell fate. PMID- 22430493 TI - Solid-state synthesis of luminescent silicon nitride nanocrystals. AB - Silicon nitride nanocrystals (NCs) have been prepared via in situ nitridation of magnesium followed by a metathesis reaction with sol-gel derived silica particles. Highly luminescent, freestanding beta-Si(3)N(4) NCs with complex surface chemistry dominated by Si-H and N-H moieties were isolated upon etching with hydrofluoric acid. PMID- 22430494 TI - Role of long-chain hydrocarbons in the aggregation behaviour of Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae). AB - The multicoloured Asian ladybirds, Harmonia axyridis (Pallas), form large aggregations inside dwellings to survive cold winters, causing annoyance to householders due to their abundance, allergenic properties and problems consequent on reflex bleeding. Flight to overwintering sites and macrosite choice of this species is well documented. H. axyridis shows a hypsotactic behaviour and a clear preference for contrasting visual elements. However, how the microsite is selected remains undocumented, although a better understanding of the factors implicated could lead to the development of new control methods for this pest. In this work, we hypothesised that non-volatile compounds are involved in the microsite choice and aggregation of this beetle. Long chain hydrocarbons were identified at aggregation sites, comprising saturated and unsaturated homologues. An aggregation bioassay was then conducted on overwintering individuals, highlighting the retention capacity of the identified compounds on the tested ladybirds. Additional investigations showed that H. axyridis males and females, originating from overwintering sites, deposit a similar blend of molecules while walking. A Y-shaped tube assay revealed that this blend is used by male and female congeners as cue allowing individuals to orientate towards the treated side of the olfactometer. These results suggest the use of two different blends of long chain hydrocarbons by H. axyridis during its aggregative period, the first one to lead conspecifics towards aggregation sites (microsites) and the second to ensure the cohesion of the aggregation. These findings support the potential use of these blends, in association with volatiles, in the design of traps in order to control infestations of this species in dwellings. PMID- 22430495 TI - The involvement of heat shock protein and cytochrome P450 genes in response to UV A exposure in the beetle Tribolium castaneum. AB - Sunlight is an important environmental factor that affects all living organisms on Earth. Ultraviolet A (UV-A) is one of the many frequency bands found in sunlight. Many animals use UV-A to attain visual cues, for example, in foraging and mate selection. However, UV-A can also induce damage, such as oxidative stress, DNA lesions and apoptosis. In the present study, we investigated the effects of UV-A on the survival, fecundity and expression profiles of several stress-responsive genes belonging to the heat shock protein (Hsp) and the cytochrome CYP6BQ families from the adult red flour beetle, Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). The results showed that short-term UV-A exposure (365 nm, <4h) did not influence the survival or fecundity of the beetles; however, Hsp27, Hsp68, Hsp83, CYP6BQ4 and CYP6BQ8 mRNA levels significantly increased during the first 2h of UV-A exposure. Among them, Hsp68 was the most highly up-regulated, increasing by 8.9-fold. These results indicate that these genes may participate in the defense against harmful UV-A radiation. In addition, we investigated the potential transcription factor binding motifs (TFBMs) in the promoter sequences of genes induced in similar pattern from the Hsp and P450 gene families; the results indicated that, these motifs are highly homologous to environmental stress transcription factor binding sites in mammals. Our experiments revealed that UV-A irradiation could influence the expression profile of stress-responsive genes, such as Hsps and P450s, which have universal TFBMs, and that these genes may be involved in reducing the ecological challenges posed by irradiation. PMID- 22430497 TI - Attenuation of long-range temporal correlations in the amplitude dynamics of alpha and beta neuronal oscillations in patients with schizophrenia. AB - Although schizophrenia was previously associated with affected spatial neuronal synchronization, surprisingly little is known about the temporal dynamics of neuronal oscillations in this disease. However, given that the coordination of neuronal processes in time represents an essential aspect of practically all cognitive operations, it might be strongly affected in patients with schizophrenia. In the present study we aimed at quantifying long-range temporal correlations (LRTC) in patients (18 with schizophrenia; 3 with schizoaffective disorder) and 28 healthy control subjects matched for age and gender. Ongoing neuronal oscillations were recorded with multi-channel EEG at rest condition. LRTC in the range 5-50s were analyzed with Detrended Fluctuation Analysis. The amplitude of neuronal oscillations in alpha and beta frequency ranges did not differ between patients and control subjects. However, LRTC were strongly attenuated in patients with schizophrenia in both alpha and beta frequency ranges. Moreover, the cross-frequency correlation between LRTC belonging to alpha and beta oscillations was stronger for patients than healthy controls, indicating that similar neurophysiological processes affect neuronal dynamics in both frequency ranges. We believe that the attenuation of LRTC is most likely due to the increased variability in neuronal activity, which was previously hypothesized to underlie an excessive switching between the neuronal states in patients with schizophrenia. Attenuated LRTC might allow for more random associations between neuronal activations, which in turn might relate to the occurrence of thought disorders in schizophrenia. PMID- 22430496 TI - Within-subject template estimation for unbiased longitudinal image analysis. AB - Longitudinal image analysis has become increasingly important in clinical studies of normal aging and neurodegenerative disorders. Furthermore, there is a growing appreciation of the potential utility of longitudinally acquired structural images and reliable image processing to evaluate disease modifying therapies. Challenges have been related to the variability that is inherent in the available cross-sectional processing tools, to the introduction of bias in longitudinal processing and to potential over-regularization. In this paper we introduce a novel longitudinal image processing framework, based on unbiased, robust, within subject template creation, for automatic surface reconstruction and segmentation of brain MRI of arbitrarily many time points. We demonstrate that it is essential to treat all input images exactly the same as removing only interpolation asymmetries is not sufficient to remove processing bias. We successfully reduce variability and avoid over-regularization by initializing the processing in each time point with common information from the subject template. The presented results show a significant increase in precision and discrimination power while preserving the ability to detect large anatomical deviations; as such they hold great potential in clinical applications, e.g. allowing for smaller sample sizes or shorter trials to establish disease specific biomarkers or to quantify drug effects. PMID- 22430498 TI - A novel xylanase with tolerance to ethanol, salt, protease, SDS, heat, and alkali from actinomycete Lechevalieria sp. HJ3. AB - A xylanase-coding gene (xynAHJ3, 1,104 bp) was cloned from Lechevalieria sp. HJ3 harbored in a saline soil sampled from Heijing town, aka the "town of salt", on the famous "Silk Route of the South". The gene encodes a 367-residue polypeptide (XynAHJ3) with the highest identity of 74.0 % with the endoxylanase from Streptomyces thermocarboxydus HY-15. The coding sequence of the mature protein (without the predicted signal peptide from M1 to S22) of xynAHJ3 was expressed in Escherichia coli BL21 (DE3). The activity of the purified recombinant XynAHJ3 (rXynAHJ3) was apparently optimal at 70 degrees C and pH 6.0, retained greater than 55 % xylanase activity at a concentration of 0.2-2.0 M Na(+) and 26 % at 4.0 M Na(+) (pH 7.5 20 degrees C), and showed 110.2 and 44.2 % xylanase activities in the presence of 100 mM SDS (pH 6.0 37 degrees C) and 10 % ethanol (pH 5.0 37 degrees C), respectively. rXynAHJ3 activity was stable at 50 degrees C and pH 4.0-11.0 for more than 60 min, in trypsin or proteinase K at 20 degrees C for 24 h (pH 7.5), in 10 % ethanol (v/v) (pH 5.0) at 30 or 37 degrees C for 72 h, in 80 % ethanol (v/v) for 1 h, and in 0.6 or 3 M NaCl (20 degrees C, pH 7.5) for 72 h. Compared with the majority of xylanases with tolerance to ethanol, salt, SDS, or protease (K (m) values of 1.42-15.1 mg ml(-1)), rXynAHJ3 showed a low K (m) value (0.8 mg ml(-1)) and showed only limited amino acid sequence identity with those other xylanases (less than 47 %). PMID- 22430499 TI - Fine tuning the transcription of ldhA for D-lactate production. AB - Fine tuning of the key enzymes to moderate rather than high expression levels could overproduce the desired metabolic products without inhibiting cell growth. The aims of this investigation were to regulate rates of lactate production and cell growth in recombinant Escherichia coli through promoter engineering and to evaluate the transcriptional function of the upstream region of ldhA (encoding fermentative lactate dehydrogenase in E. coli). Twelve ldhA genes with sequentially shortened chromosomal upstream regions were cloned in an ldhA deletion, E. coli CICIM B0013-080C (ack-pta pps pflB dld poxB adhE frdA ldhA). The varied ldhA upstream regions were further analyzed using program NNPP2.2 (Neural Network Promoter Prediction 2.2) to predict the possible promoter regions. Two-phase fermentations (aerobic growth and oxygen-limited production) of these strains showed that shortening the ldhA upstream sequence from 291 to 106 bp successively reduced aerobic lactate synthesis and the inhibition effect on cell growth during the first phase. Simultaneously, oxygen-limited lactate productivity was increased during the second phase. The putative promoter downstream of the -96 site of ldhA could function as a transcriptional promoter or regulator. B0013-080C/pTH-rrnB-ldhA8, with the 72-bp upstream segment of ldhA, could be grown at a high rate and achieve a high oxygen-limited lactate productivity of 1.09 g g(-1) h(-1). No transcriptional promoting region was apparent downstream of the -61 site of ldhA. We identified the latent transcription regions in the ldhA upstream sequence, which will help to understand regulation of ldhA expression. PMID- 22430500 TI - Red recombinase assisted gene replacement in Klebsiella pneumoniae. AB - The Red recombinase system, the most convenient genetic tool applied in Escherichia coli and other bacteria, was introduced for gene replacement in Klebsiella pneumoniae. The novel K. pneumoniae gene replacement system comprised the Red and FLP recombinases expression vector pDK6-red and pDK6-flp, and linear DNA fragments which encompassed a selective marker gene with target gene flanking extensions; the latter were PCR amplified using a plasmid DNA template obtained by in vivo recombination in E. coli. In this study, dhak1 gene, encoding a subunit of dihydroxyacetone kinase II, was deleted markerlessly at a transformation ratio of 260 CFU/MUg DNA, i.e., 1,000-fold higher than that achieved in the native way. Our studies provide an efficient method with detailed protocol to perform gene replacement in K. pneumoniae and has great potential to be developed as a routine genetic approach for this important industrial microorganism. PMID- 22430501 TI - A novel and efficient assay for identification and quantification of Acidithiobacillus ferrooxidans in bioleaching samples. AB - Acidithiobacillus ferrooxidans is a Gram-negative, acidophilic, and chemolithotrophic bacterium that is active in bioleaching. The leaching efficacy is directly influenced by the biomass changes of this specie in bioleaching microbial community. In order to perform a simple and sensitive assay on A. ferrooxidans from mixed strains in this process, a novel assay was developed based on sandwich hybridization assay with the aid of S1 nuclease treatment and fluorescent labeling. In the work, a designed DNA probe complementary to the conservative region of its 16S rRNA was synthesized, which showed high accuracy for distinguishing homologous species with the exclusion of even-only two base pairs difference. The specificity of this assay was verified in different systems with mixed strains, and the quantitative result was proved by comparison of microscopic cell counting. The detection sensitivity was about 8 * 10(2) cells/ml and the inter-assay coefficient of variation of three independent assays was from 3.8 to 7.7 %, respectively. In addition, the cycle of assay was about 3-4 h when the cost estimated was less than $0.5 per sample. This assay method might be applied for identifying and monitoring any kind of bacterial strain from a mixed microbial flora in bioleaching or other areas. PMID- 22430502 TI - Comparison of nutritional quality between conventional and organic dairy products: a meta-analysis. AB - As a contribution to the debate on the comparison of nutritional quality between conventional versus organic products, the present study would like to provide new results on this issue specifically on dairy products by integrating the last 3 years' studies using a meta-analysis approach with Hedges' d effect size method. The current meta-analysis shows that organic dairy products contain significantly higher protein, ALA, total omega-3 fatty acid, cis-9,trans-11 conjugated linoleic acid, trans-11 vaccenic acid, eicosapentanoic acid, and docosapentanoic acid than those of conventional types, with cumulative effect size ( +/- 95% confidence interval) of 0.56 +/- 0.24, 1.74 +/- 0.16, 0.84 +/- 0.14, 0.68 +/- 0.13, 0.51 +/- 0.16, 0.42 +/- 0.23, and 0.71 +/- 0.3, respectively. It is also observed that organic dairy products have significantly (P < 0.001) higher omega-3 to -6 ratio (0.42 vs. 0.23) and Delta9-desaturase index (0.28 vs. 0.27) than the conventional types. The current regulation on organic farming indeed drives organic farms to production of organic dairy products with different nutritional qualities from conventional ones. The differences in feeding regime between conventional and organic dairy production is suspected as the reason behind this evidence. Further identical meta-analysis may be best applicable for summarizing a comparison between conventional and organic foodstuffs for other aspects and food categories. PMID- 22430503 TI - Season and tissue type affect fungal endophyte communities of the Indian medicinal plant Tinospora cordifolia more strongly than geographic location. AB - A total of 1,151 endophytic fungal isolates representing 29 taxa were isolated from symptom-less, surface-sterilized segments of stem, leaf, petiole, and root of Tinospora cordifolia which had been collected at three locations differing in air pollution in India (Ramnagar, Banaras Hindu University, Maruadih) during three seasons (summer, monsoon, winter). Endophytes were most abundant in leaf tissues (29.38% of all isolates), followed by stem (18.16%), petiole (10.11%), and root segments (6.27%). The frequency of colonization (CF) varied more strongly among tissue type and season than location. CF was maximal during monsoon followed by winter and minimal during summer. A species each of Guignardia and Acremonium could only be isolated from leaves, whereas all other species occurred in at least two tissue types. Penicillium spp. were dominant (12.62% of all isolates), followed by Colletotrichum spp. (11.8%), Cladosporium spp. (8.9%), Chaetomium globosum (8.1%), Curvularia spp. (7.6%), and Alternaria alternata (6.8%). Species richness, evenness, and the Shannon-Wiener diversity index followed the same pattern as the CF with the tissue type and the season having the greatest effect on these indices, suggesting that tissue type and season are more influential than geography. Dissimilarity of endophyte communities in regards to species composition was highest among seasons. Colletotrichum linicola occurred almost exclusively in winter, Fusarium oxysporum only in winter and summer but never during monsoon and Curvularia lunata only in winter and during monsoon but never in summer. Emissions of NO(2), SO(2), and suspended particulate matter were negatively correlated with the CF. Ozone did not have any effect. The frequency of most species declined with increasing pollution, but some showed an opposite trend (e.g., Aspergillus flavus). Five unnamed taxa (sterile mycelia) were identified as Aspergillus tubingensis, Colletotrichum crassipes, Botryosphaeria rhodina, Aspergillus sydowii, and Pseudofusicoccum violaceum, using molecular tools. Fifteen of the 29 endophyte taxa exhibited antibacterial activity. B. rhodina (JQ031157) and C. globosum showed activity against all bacterial human pathogens tested, with the former showing higher activity than the latter. PMID- 22430504 TI - Structural shifts of fecal microbial communities in rats with acute rejection after liver transplantation. AB - Bacterial translocation and the development of sepsis after orthotopic liver transplantation (OLT) may be promoted by immunological damage to the intestinal mucosa or by quantitative and qualitative changes in intestinal microbiota. This study monitored structural shifts of gut microbiota in rats with OLT using PCR denaturing gradient gel electrophoresis (DGGE) and real-time quantitative PCR (RT qPCR). RT-qPCR targets six major microorganisms (Domain Bacteria, Bacteroides, Bifidobacteria, Enterobacteriaceae, Lactobacillus and Clostridium leptum subgroup). Isograft, Allograft and Sham model were studied. Bacterial translocation to host organs and plasma endotoxin were determined. Alteration in gut microbiota was associated with the elevation of plasma endotoxin and a higher rate of bacterial translocation (BT) to liver in rats with acute rejection. Dynamic analysis of DGGE fingerprints showed that the gut microbiota structure of animals in the three groups was similar before the operation. But significant alterations in the composition of fecal microbiota in Allograft group were observed at 1 and 2 weeks after the OLT. The acute rejection was accompanied by the shifts of gut microbiota towards members of Bacteroides and Ruminococcus. Results from RT-qPCR indicated that Bacteroides significantly increased at 2 weeks after the OLT, whereas numbers of Bifidobacterium spp. decreased at 1 week and recovered at 2 weeks after the OLT. In summary, our data showed that rats with acute rejection after OLT exhibited significant structure shifts in the gut microbiota which dominant by overgrowth of Bacteroides and Ruminococcus, and these were associated with elevation of plasma endotoxin and higher rate of BT. PMID- 22430505 TI - Local conditions structure unique archaeal communities in the anoxic sediments of meromictic Lake Kivu. AB - Meromictic Lake Kivu is renowned for its enormous quantity of methane dissolved in the hypolimnion. The methane is primarily of biological origin, and its concentration has been increasing in the past half-century. Insight into the origin of methane production in Lake Kivu has become relevant with the recent commercial extraction of methane from the hypolimnion. This study provides the first culture-independent approach to identifying the archaeal communities present in Lake Kivu sediments at the sediment-water interface. Terminal restriction fragment length polymorphism analysis suggests considerable heterogeneity in the archaeal community composition at varying sample locations. This diversity reflects changes in the geochemical conditions in the sediment and the overlying water, which are an effect of local groundwater inflows. A more in depth look at the archaeal community composition by clone library analysis revealed diverse phylogenies of Euryarchaeota and Crenarachaeota. Many of the sequences in the clone libraries belonged to globally distributed archaeal clades such as the rice cluster V and Lake Dagow sediment environmental clusters. Several of the determined clades were previously thought to be rare among freshwater sediment Archaea (e.g., sequences related to the SAGMEG-1 clade). Surprisingly, there was no observed relation of clones to known hydrogentrophic methanogens and less than 2 % of clones were related to acetoclastic methanogens. The local variability, diversity, and novelty of the archaeal community structure in Lake Kivu should be considered when making assumptions on the biogeochemical functioning of its sediments. PMID- 22430506 TI - Diversity and characterization of culturable fungi from marine sediment collected from St. Helena Bay, South Africa. AB - Marine fungi are known to originate from a wide variety of habitats within the marine environment. Marine sediment represents one environmental niche, with most fungi occurring in these sediments being facultative marine fungi with terrestrial origins. It has not been proven whether these fungi merely survive the harsh environmental conditions presented by the ocean sediment, as opposed to playing an active role in this ecological niche. During this study, marine sediment was collected from St. Helena Bay, on the west coast of the Western Cape, South Africa. Using dilution, enrichment, and repetitive culturing techniques, 59 fungal isolates were obtained from marine sediments and identified to at least genus level using morphological and molecular methods. Moreover, a series of tests were performed to characterize the physical and physicochemical attributes of the isolates. Results showed that the isolates not only survived but also had the potential to grow in the natural conditions present in this environment. Extracellular cellulase was produced by the filamentous fungal isolates indicating their probable role in detrital decay processes and therefore the carbon cycle on the ocean bed. Also, denitrification patterns were observed when isolates were grown in liquid media amended with NaNO(2), NaNO(3), and (NH(4))SO(4), implicating that these fungi have the potential to play an active role in denitrification, co-denitrification, and ammonification phases of nitrogen cycles occurring in the marine sediments. PMID- 22430507 TI - Microbial functional diversity associated with plant litter decomposition along a climatic gradient. AB - Predicted changes in climate associated with increased greenhouse gas emissions can cause increases in global mean temperature and changes in precipitation regimes. These changes may affect key soil processes, e.g., microbial CO(2) evolution and biomass, mineralization rates, primary productivity, biodiversity, and litter decomposition, which play an important role in carbon and nutrient cycling in terrestrial ecosystems. Our study examined the changes in litter microbial communities and decomposition along a climatic gradient, ranging from arid desert to humid Mediterranean regions in Israel. Wheat straw litter bags were placed in arid, semi-arid, Mediterranean, and humid Mediterranean sites. Samples were collected seasonally over a 2-year period in order to evaluate mass loss, litter moisture, C/N ratio, bacterial colony-forming units (CFUs), microbial CO(2) evolution and biomass, microbial functional diversity, and catabolic profile. Decomposition rate was the highest during the first year of the study at the Mediterranean and arid sites. Community-level physiological profile and microbial biomass were the highest in summer, while bacterial CFUs were the highest in winter. Microbial functional diversity was found to be highest at the humid Mediterranean site, whereas substrate utilization increased at the arid site. Our results support the assumption that climatic factors control litter degradation and regulate microbial activity. PMID- 22430509 TI - The chemokine receptor CXCR3 limits injury after acute toxic liver damage. AB - Although acute liver failure is a rare disease, its presence is associated with high morbidity and mortality in affected patients. While a contribution of the immune system to the outcome of toxic liver failure is anticipated, functionally relevant immune cell receptors for liver cell damage need to be better defined. We here investigate the relevance of the chemokine receptor CXCR3, which is important for hepatic immune cell infiltration, in a model of experimental acute liver failure. Liver injury was induced by a single intraperitoneal injection of carbon tetrachloride (CCl(4)) in CXCR3(-/-), CCR1(-/-), CCR5(-/-) and wild-type mice. In this model, CXCR3(-/-) mice displayed augmented liver damage compared with all other mouse strains as assessed by liver histology and serum transaminases 24 and 72 h after injury. Phenotypically, CXCR3(-/-) mice had significantly reduced intrahepatic NK and NKT cells after injury at all investigated time points (all P<0.05), but strongly elevated expression levels of IL1-beta, TNF-alpha and IFN-gamma. In line with a functional role of innate immune cells, wild-type mice depleted for NK cells with an anti-ASIALO GM1 antibody before liver injury also displayed increased liver injury after CCl(4) challenge. CXCR3(-/-) and NK cell-depleted mice show reduced apoptotic liver cells (TUNEL assay), but more necrotic hepatocytes. Functionally, the augmented liver cell necrosis in CXCR3(-/-) and NK cell-depleted mice was associated with increased expression of high mobility group 1 (HMGB1) protein and a consecutive enhanced infiltration of neutrophils into the liver. In conclusion, the results demonstrate a primarily unexpected beneficial role of CXCR3 in acute toxic liver injury. These findings should be taken into account when planning trials with CXCR3 antagonists. PMID- 22430510 TI - Editorial note on: On the feasibility of using motor imagery EEG-based brain computer interface in chronic tetraplegics for assistive robotic arm control: a clinical test and long-term post trial follow-up. PMID- 22430511 TI - The clinical characteristics of neuropathic pain in patients with spinal cord injury. AB - OBJECTIVES: The aim of the study was to evaluate the characteristics of neuropathic pain and observe intensity alterations in pain with regard to time during the day in spinal cord injury (SCI) patients. METHODS: A total of 50 SCI patients (M/F, 40/10; mean age, 35+/-12 years) with at-level and below-level neuropathic pain were included in the study. All patients were examined and classified according to the ASIA/ISCoS 2002 International Neurologic Examination and Classification Standards. The history, duration, localization and characteristics of the pain were recorded. Neuropathic pain of patients was evaluated with the McGill-Melzack Pain Questionnaire and LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) Pain Scale. Visual analog scale (VAS) was used to measure the severity of pain four times during the day. Quality of life was analyzed with Short Form 36. RESULTS: Out of 50 patients, 10 were tetraplegic and 40 were paraplegic. In all, 28 patients had motor and sensory complete injuries (AIS A), whereas 22 patients had sensory incomplete (AIS B, C and D) injuries. The most frequently used words to describe neuropathic pain were throbbing, tiring, hot and tingling. Pain intensity was significantly higher in the night than in the evening, noon and morning (P<0.05) (VAS morning: 5.16+/-2.42, VAS noon: 5.24+/-2.52, VAS evening: 5.80+/-2.46 and VAS night: 6.38+/-2.19). CONCLUSION: Neuropathic pain is a serious complaint in SCI patients and affects their quality of life. Neuropathic pain intensity was higher in the night hours than other times of day. This situation reinforces the need for a continued research and education on neuropathic pain in SCI. PMID- 22430512 TI - State of the Science in Spinal Cord Injury Rehabilitation 2011: informing a new research agenda. AB - STUDY DESIGN: This manuscript summarizes recommendations from the State of the Science Conference in Spinal Cord Injury Rehabilitation 2011. OBJECTIVES: To develop an agenda for spinal cord injury (SCI) rehabilitation research in the next decade. SETTING: Participants scheduled planning meetings and then gathered at the 2011 joint meeting of the American Spinal Injury Association and International Spinal Cord Society in Washington DC. METHODS: Recommendations were made by an international, multidisciplinary team that met in large plenary sessions and breakout groups during the meeting. RESULTS: Recommendations are organized by conference track, including neurological and functional recovery; technology issues; aging with spinal cord injury; and employment, psychosocial and quality of life issues. CONCLUSION: A number of themes emerged across the conference tracks, including the need for improved measures of process and outcome constructs, application of qualitative and quantitative research designs, and use of contemporary statistical analytic approaches. Participants emphasized the value of collaborative research that uses the latest methods, techniques and information. PMID- 22430508 TI - Culturable endophytes of medicinal plants and the genetic basis for their bioactivity. AB - The bioactive compounds of medicinal plants are products of the plant itself or of endophytes living inside the plant. Endophytes isolated from eight different anticancer plants collected in Yunnan, China, were characterized by diverse 16S and 18S rRNA gene phylogenies. A functional gene-based molecular screening strategy was used to target nonribosomal peptide synthetase (NRPS) and type I polyketide synthase (PKS) genes in endophytes. Bioinformatic analysis of these biosynthetic pathways facilitated inference of the potential bioactivity of endophyte natural products, suggesting that the isolated endophytes are capable of producing a plethora of secondary metabolites. All of the endophyte culture broth extracts demonstrated antiproliferative effects in at least one test assay, either cytotoxic, antibacterial or antifungal. From the perspective of natural product discovery, this study confirms the potential for endophytes from medicinal plants to produce anticancer, antibacterial and antifungal compounds. In addition, PKS and NRPS gene screening is a valuable method for screening isolates of biosynthetic potential. PMID- 22430513 TI - gamma-Aminobutyric acid-, glycine-, and glutamate-immunopositive boutons on mesencephalic trigeminal neurons that innervate jaw-closing muscle spindles in the rat: ultrastructure and development. AB - Unlike other primary sensory neurons, the neurons in the mesencephalic trigeminal nucleus (Vmes) receive most of their synaptic input onto their somata. Detailed description of the synaptic boutons onto Vmes neurons is crucial for understanding the synaptic input onto these neurons and their role in the motor control of masticatory muscles. For this, we investigated the distribution of gamma-aminobutyric acid (GABA)-, glycine-, and glutamate-immunopositive (+) boutons on Vmes neurons and their ultrastructural parameters that relate to transmitter release: Vmes neurons that innervate masseteric muscle spindles were identified by labeling with horseradish peroxidase injected into the muscle, and immunogold staining and quantitative ultrastructural analysis of synapses onto these neurons were performed in adult rats and during postnatal development. The bouton volume, mitochondrial volume, and active zone area of the boutons contacting labeled somata (axosomatic synapses) were similar to those of boutons forming axoaxonic synapses with Vmes neurons but smaller than those of boutons forming axodendritic or axosomatic synapses with most other neurons. GABA+ , glycine+ , and glutamate+ boutons constituted a large majority (83%) of all boutons on labeled somata. A considerable fraction of boutons (28%) was glycine(+) , and all glycine+ boutons were also GABA+ . Bouton size remained unchanged during postnatal development. These findings suggest that the excitability of Vmes neurons is determined to a great extent by GABA, glycine, and glutamate and that the relatively lower synaptic strength of axosomatic synapses may reflect the role of the Vmes neurons in modulating orofacial motor function. PMID- 22430514 TI - Supraclavicular nerve entrapment and clavicular fracture. AB - Because the supraclavicular nerve lies in close proximity to the clavicle, it is particularly vulnerable to injury in cases of clavicle fracture and in the surgical treatment of these fractures. The development of painful neuromas after iatrogenic transsection and symptomatic nerve entrapment in fracture callus after healing have previously been described. Reported here is a case of acute supraclavicular nerve entrapment and tension after fracture of the clavicle with significant pain relief after fracture fixation and nerve decompression. PMID- 22430515 TI - Invited commentary: creation of locked condylar plates for the treatment of distal femur fractures. PMID- 22430516 TI - A technical trick which reduces the need for stab incisions when using bone tenaculums for fracture reduction. AB - During the reduction of fractures using a bone tenaculum, rather than making a stab incision, a frequently successful strategy can be to place a folded operative towel placed between the patient's skin and the head of the tenaculum. Using this technique, the surgeon can decrease scarring and potential stab wound complications. When the angle is too steep for the towel to allow the tenaculum to remain stable during the reduction, the surgeon can use the towel as a safe means of trial and error to determine the necessary alignment of the tenaculum to achieve reduction and consequently the best location at which to make the stab incision for the tine of the tenaculum. PMID- 22430517 TI - Invited commentary: understanding the concept of medialization in scapula fractures. PMID- 22430518 TI - CT evaluation of extra-articular glenoid neck fractures: does the glenoid medialize or does the scapula lateralize? AB - OBJECTIVES: Medial translation of the glenoid is frequently described as the main mode of displacement after glenoid neck fracture. Indeed, plain radiographs typically show the glenoid medialized relative to the scapular body. However, whether this truly represents medialization of the glenoid relative to the axial skeleton or lateralization of the scapular body remains unclear. The goal of this investigation was to assess the relationship between the glenoid, the scapular body, and the axial skeleton in patients with glenoid neck fractures using computed tomographic data analysis with the contralateral shoulder serving as an internal control. DESIGN: Retrospective radiographic review. SETTING: Two Level I trauma centers. PARTICIPANTS: Eighteen patients (5 women and 13 men; average age, 38.7 years; range, 17-75 years) admitted between January 2000 and March 2006 with isolated extra-articular glenoid neck fractures (OTA 14C1 fractures) and chest computed tomographic scans that included both shoulders. MAIN OUTCOME MEASUREMENTS: Glenoid to midline distance and scapular width. RESULTS: The injured glenoid was lateralized an average of 9.8 mm (range, 8 mm medialized to 23 mm lateralized) (P < 0.001). Relative to the uninjured side, glenoid medialization infrequently occurred (4 of 18 patients) and when present was less than 1 cm (range, 2-8 mm). Lateralization occurred more frequently (14 of 18 patients), with an average displacement of 13.7 mm (range, 1-23 mm). The injured scapula was shortened by an average of 3.3 mm (range, 18 mm shorter to 20 mm longer) (P = 0.09). In 15 of 18 patients, the scapular width was shortened by an average of 5.9 mm (range, 1-18 mm), whereas in only 3 of 18 patients was the injured scapular width longer, an average of 9 mm (range, 1-20 mm). CONCLUSIONS: In patients with glenoid neck fractures, pure medial translation of the glenoid relative to the axial skeleton rarely occurs. Instead, there is typically a component of shortening of the scapula width combined with lateralization of the scapular body. PMID- 22430519 TI - Development and validation of the new international classification for scapula fractures. AB - OBJECTIVES: Multiple scapula classification systems exist in the literature and were developed using a consensus approach with one or several experts agreeing on a classification without stringent validation. None have gained widespread acceptance. A decision was made by the OTA classification committee and the AO Classification Advisory Group to collaborate on the development of a new validated classification system capable of addressing the limitations of the existing systems. METHODS: A feedback validation process through 4 iterations of revised classifications on radiographs and computed tomography (CT) scans was used. Statistical analyses calculated the proportion of agreement among surgeons and kappa statistics for the assessment of coding reliability. Estimates of classification accuracy were obtained using latent class modeling. RESULTS: Fractures of the scapular neck are rare injuries and were difficult to define and diagnose with kappa values ranging from 0.28 to 0.40. Although fossa fractures could be identified on plain radiographs, specific fracture patterns could only be classified with CT scans. The new classification divides the scapula into 3 segments: fossa, body, and processes. The validation has shown that the classification can be reliable using plain radiographs (kappa 0.66), increasing to kappa of 0.78 when CT scans were added. CONCLUSIONS: This basic coding system allows clinicians to describe and classify scapula fractures with a reasonable degree of reliability. This validated classification that has resulted from this process has been accepted by a disparate group of orthopaedic traumatologists as a better option for clinical communication and research documentation. PMID- 22430520 TI - The protective effect of locking screw placement on nonlocking screw extraction torque in an osteoporotic supracondylar femur fracture model. AB - OBJECTIVE: To examine the impact of number and position of locking screws in the diaphyseal portion of an osteoporotic distal femoral fracture model with hybrid fixation. METHODS: Four groups containing 5 osteoporotic bone models were used with varying combinations of diaphyseal screw fixation: 4 nonlocking screws (control); 1 locking screw adjacent to the osteotomy and 3 nonlocking screws; 1 locking screw in the most proximal screw hole of the plate and 3 nonlocking screws; and 2 locking screws at opposite ends of the diaphyseal fixation with 2 nonlocking screws in between. Fixation in the distal articular segment was identical in all constructs. Testing was performed for 50,000 cycles at 2 Hz using simultaneous axial compression (700 N) and bidirectional torque (+/-5 Nm) applied along the long axis of the bone. All screws were inserted with 4 Nm of torque. RESULTS: The extraction torque for nonlocking screws in those specimens that had a locking screw nearest the osteotomy was significantly greater than those that did not (P = 0.037). In addition, the 10 constructs with a locking screw nearest the osteotomy had no failures compared with 5 of 10 failures in those without a locking screw in this position (P = 0.033). CONCLUSIONS: The placement of a locking screw adjacent to the osteotomy was more beneficial in protecting against failure and maintaining the extraction torque of neighboring proximal nonlocking screws. No benefit in adjacent screw extraction torque was seen with a locking screw proximal in the diaphysis. Two locking screws at opposite ends of the diaphyseal fixation were not superior to a single locking screw adjacent to the osteotomy in failure rates or screw extraction torque. PMID- 22430521 TI - Biomechanical evaluation of suture-augmented locking plate fixation for proximal third fractures of the olecranon. AB - OBJECTIVES: To describe a method of suture augmentation of locking plate fixation (PF) of proximal olecranon fractures and to evaluate the biomechanical effectiveness of the suture augmentation using a human cadaveric model. METHODS: Six matched pairs of cadaveric elbows were used. Proximal one-third fractures of the olecranon were simulated via a transverse osteotomy. Identical locking PF was performed on each elbow using olecranon locking plates. One elbow of each pair was assigned to suture augmentation of the construct. The choice of left/right specimen for augmentation was performed in an alternating fashion. Augmentation was performed using a no. 2 ultra-high-molecular weight polyethylene-braided suture attaching the triceps to the plate via a modified Krackow stitch. The elbows were mounted into a custom jig and linearly loaded to failure using a hydraulic testing machine. Load to and modes of failure were recorded for each sample. The data were analyzed using the Wilcoxon signed-rank test for nonparametric distributions. RESULTS: Suture augmentation improved the single load-to-failure strength in all pairs. One pair was excluded due to failure of the triceps attachment to the test machine. A median 398 N (P = 0.04 range, 197 633 N) or a median 48% (range, 30%-130%) improvement in strength was seen. The most common mode of failure was loss of fixation of the proximal olecranon fragment. CONCLUSIONS: Suture augmentation can significantly increase the single load-to-failure strength of locking PF for proximal olecranon fractures. PMID- 22430522 TI - Preoperative skeletal versus cutaneous traction for femoral shaft fractures treated within 24 hours. AB - OBJECTIVES: To compare the advantages and disadvantages of preoperative cutaneous traction versus skeletal traction in adults with diaphyseal femur fractures amenable to fixation within 24 hours. DESIGN: Randomized prospective trial. SETTING: Level I trauma center in a major metropolitan area. PATIENTS: Sixty-five patients with 66 femur fractures were prospectively enrolled and randomized to a traction group from July 2009 to July 2010. MAIN OUTCOME MEASUREMENTS: Time of application for on call physicians/practitioners, pain relief after application of traction; time of reduction in the operating room theater, and evaluation of pain medication consumption before stabilization. RESULTS: Thirty-seven patients received cutaneous femoral traction, whereas 29 patients received skeletal traction. There was a significant reduction in time of application for the cutaneous traction (24.30 +/- 24.74 minutes) compared with skeletal traction (57.10 +/- 33.60 minutes) (P <= 0.001). There was no statistically significant difference in visual analog scale (VAS) scores when compared with pretraction application pain assessment and posttraction pain assessment between the cutaneous and skeletal traction groups with a decrease in the VAS of (0.56 +/- 3.73 and 0.54 +/- 2.76), respectively (P = 0.99). There was no difference in pain medication requirements between groups (0.12 +/- 0.17 mg/kg for cutaneous versus 0.09 +/- 0.14 mg/kg for skeletal, P = 0.39). There was no significant difference in reduction time of the fracture (skin incision or opening reamer to guide wire passage) in the operating room between cutaneous traction versus skeletal traction (P = 0.59). CONCLUSIONS: Use of cutaneous traction for diaphyseal femur fractures when compared with skeletal traction results in a statistically significant reduction in time of application to the on call practitioner with no complications or detrimental change in operative time and no difference in VAS pain scores or narcotic usage. PMID- 22430523 TI - Balloon tibioplasty: a useful tool for reduction of tibial plateau depression fractures. AB - Reduction of the articular surface in displaced tibial plateau fractures is still challenging and may result in joint incongruence, leading to posttraumatic arthrosis. Conventional techniques use bone tamps and similar instruments, which can increase the surgical trauma due to their size. "Balloon tibioplasty" is a novel minimally invasive technique for the reduction of depressed tibial plateau fractures. We successfully applied an inflatable balloon, commercially available from kyphoplasty, to elevate the depressed articular fragments. This technique allowed for reduction of the depressed tibial plateau fragment without classic fenestration of the tibia, thereby minimizing surgical trauma. Furthermore, under fluoroscopic control, optimal centering of the expanding tibioplasty balloon allows a widespread and continuously increasing reduction force to the fracture area. After fluoroscopy or arthroscopic confirmation of reduction of the articular surface, the cavity resulting from tibioplasty was filled with ceramic bone cement through small incisions and fractures were fixed with a small fragment locking T-plate (3.5 mm). Balloon tibioplasty was applied in 5 patients with displaced tibial plateau fractures (OTA type B2/3). No intra- or postoperative complications were observed. This new technique may be a useful tool to facilitate the reduction of select depressed tibial fractures in the future. PMID- 22430524 TI - Catastrophic failure after open reduction internal fixation of femoral neck fractures with a novel locking plate implant. AB - OBJECTIVES: To determine if the use of a novel proximal femoral locking plate could reduce the incidence of femoral neck shortening and improve clinical outcomes after open reduction internal fixation (ORIF) for femoral neck fractures as compared with historical controls. DESIGN: Single surgeon, retrospective case control study. SETTING: Academic level I trauma center. PATIENTS/PARTICIPANTS: Twenty-one femoral neck fractures treated with the posterolateral femoral locking plate (Synthes, Inc, Paoli, PA) were eligible for inclusion. Eighteen met inclusion/exclusion criteria with a mean follow-up of 16 months. INTERVENTION: ORIF of femoral neck fracture with the posterolateral femoral locking plate. This consists of a side plate with multiple locking screws directed into the femoral head at converging/diverging angles and a single shaft screw. Intraoperative compression was achieved with partially threaded screws before locking screw insertion. MAIN OUTCOME MEASUREMENTS: Maintenance of reduction was assessed by comparing immediate postoperative and final follow-up radiographs. Clinical outcome was assessed with Harris Hip Scores after 1 year. Complications and secondary operations were noted. RESULTS: Seven (36.8%) of 18 patients experienced catastrophic failure. Five of these patients required total hip replacement, whereas the remaining 2 died before further treatment. The remaining 11 patients (61.1%) achieved bony union; the average displacement of the center of the head did not differ when compared with historical controls (0.78 mm inferiorly, 1.62 mm medially, and 2.4 degrees of increased varus vs. 0.86 mm, 1.23 mm, and 0.6 degree). Complications in this group include 1 instance of screw fracture, 2 total hip replacements, and a peri-implant subtrochanteric femur fracture. The average patient age and proportion of displaced fractures did not differ between the historical control and experimental groups. Fracture displacement was strongly associated with catastrophic failure in the experimental group only. Average Harris Hip Scores was significantly worse compared with that of historical controls (67.9 vs. 84.7, P = 0.05). CONCLUSIONS: ORIF of femoral neck fractures using a locking plate construct yielded unacceptably poor outcomes in this patient population. We hypothesize that the stiffness of this construct prevents any fracture site micromotion, placing the mechanical burden on the implant, which can result in failure at the bone-screw interface or fatigue failure of the implant itself. PMID- 22430525 TI - The effects of hypothermia and L-arginine on skeletal muscle function in ischemia reperfusion injury. AB - OBJECTIVES: Ischemia-reperfusion (I/R) injury can have detrimental effects on skeletal muscle. We have shown that vessel permeability can be minimized in a hypothermic setting and also by administering the nitric oxide synthase (NOS) stimulator, L-arginine, at physiologic temperatures. The purpose of this study was to examine and compare skeletal muscle contractility after an I/R insult during hypothermic conditions, warm conditions, and also with the administration of L-arginine at physiologic temperatures. We hypothesized that hypothermia and L arginine administration will also demonstrate protective effects to skeletal muscle contractility. METHODS: Using Sprague-Dawley rats, the extensor digitorum longus muscle was rotated on its vascular pedicle to a thermo-controlled stage. Ischemia was established using an atraumatic femoral artery tourniquet. Reperfusion was performed under control and experimental conditions including local hypothermia and intravenous L-arginine. After harvesting experimental muscles, contractility was then quantified by using a tissue bath stimulator with force transducers. RESULTS: Warm reperfusion resulted in marked decrease in muscle contractility compared with sham animals. Local hypothermia showed statistically significant preservation of contractility compared with the sham group. This protective effect was recapitulated by the application of NOS inducers (L-arginine) at warm conditions. CONCLUSIONS: These findings demonstrate that hypothermia and L-arginine are protective of skeletal muscle contractility after an I/R injury. The results presented may have profound effects on future therapeutic recommendations and suggest possible pathways for clinical intervention to modulate I/R injury, which is commonplace in orthopaedic trauma and reconstructive surgery. PMID- 22430526 TI - CO adsorption on amorphous silica-alumina: electrostatic or Bronsted acidity probe? AB - The adsorption of CO on amorphous silica-alumina (ASA) was calculated by DFT. CO appears as a probe of the electrostatic field induced by the whole surface, at the origin of a so-called vibrational Stark effect responsible for the CO frequency shifts. Bronsted acidity of the ASA sites does not directly correlate CO frequency shifts. PMID- 22430527 TI - Accuracy of ECG-based screening for sleep-disordered breathing: a survey of all male workers in a transport company. AB - PURPOSE: Sleep-disordered breathing (SDB) is associated with increased risk for cardiovascular morbidity and mortality and for sleepiness-related accidents, but >75 % of the patients remain undiagnosed. We sought to determine the diagnostic accuracy of ECG-based detection of SDB when used for population-based screening. METHODS: All male workers, mostly truck drivers, of a transport company (n = 165; age, 43 +/- 12 years) underwent standard attended overnight polysomnography. Cyclic variation of heart rate (CVHR), a characteristic pattern of heart rate associated with SDB, was detected from single-lead ECG signals during the polysomnography by a newly developed automated algorithm of autocorrelated wave detection with adaptive threshold (ACAT). RESULTS: Among 165 subjects, the apnea hypopnea index (AHI) was >=5 in 62 (38 %), >=15 in 26 (16 %), and >=30 in 16 (10 %). The number of CVHR per hour (CVHR index) closely correlated with AHI [r = 0.868 (95 % CI, 0.825-0.901)]. The areas under the receiver operating characteristic curves for detecting subjects with AHI >=5, >=15, and >=30 were 0.796 (95 % CI, 0.727-0.855), 0.974 (0.937-0.993), and 0.997 (0.971-0.999), respectively. With a predetermined criterion of CVHR index >=15, subjects with AHI >=15 were identified with 88 % sensitivity and 97 % specificity (likelihood ratios for positive and negative test, 30.7 and 0.12). The classification performance was retained in subgroups of subjects with obesity, hypertension, diabetes mellitus, dyslipidemia, and decreased autonomic function. CONCLUSIONS: The CVHR obtained by the ACAT algorithm may provide a useful marker for screening for moderate-to-severe SDB among apparently healthy male workers. PMID- 22430528 TI - Xylocoside G reduces amyloid-beta induced neurotoxicity by inhibiting NF-kappaB signaling pathway in neuronal cells. AB - Amyloid-beta (Abeta) peptide, which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimer's disease (AD). Xylocoside G (XG) is an active compound isolated from a traditional Chinese medicinal plant, Itoa orientalis. We have previously reported that XG has neuroprotective effects, of which the mechanism is yet unknown. In this study, we investigated the possible mechanisms underlying neuroprotection of XG against Abeta-induced toxicity in SH-SY5Y cells and primary neurons. Pretreatment with XG significantly attenuated the cell viability reduction induced by Abeta exposure in a dose dependent manner which was testified by 3 [4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release assay. In addition, pretreatment with XG countered the effect of Abeta on Bax and Bcl-2 expression and repressed Abeta-induced caspase-3 activation, suggesting that the neuroprotective effect of XG is associated with apoptosis regulation. Neuroinflammation has been implicated in Abeta-induced neuronal death. XG significantly attenuated Abeta-stimulated release of inflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, and prostaglandin E2. It also downregulated the expression of cyclooxygenase-2 in SH SY5Y cells. Further molecular mechanism studies demonstrated that XG inhibited Abeta-induced NF-kappaB p65 translocation, which was probably the result of inhibition of JNK phosphorylation but not ERK or p38 MAPK pathway by XG. This is the first study to demonstrate that XG protects SH-SY5Y cells against Abeta induced inflammation and apoptosis by down-regulating NF-kappaB signaling pathways. PMID- 22430530 TI - Multiple diffusivities define white matter degeneration in amnestic mild cognitive impairment and Alzheimer's disease. AB - Different diffusivity measurements in diffusion-tensor imaging (DTI) could be helpful for detecting the distinct mechanisms of white matter degeneration in Alzheimer's disease (AD). However, few studies have explored the changes of white matter in amnestic mild cognitive impairment (aMCI) and AD by whole-brain voxel wise analyses of all diffusivity indices. The association between grey matter atrophy and white matter damage measured by distinct diffusivities is still uncertain. Structural magnetic resonance imaging and DTI with four diffusivity indices, comprising fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, were performed in 30 normal controls, 26 mild AD patients, and 40 aMCI patients with isolated memory impairment. T1 voxel-based morphometry and DTI tract-based spatial statistics were applied to compare the grey and white matter changes in the 3 groups. In contrast to the lack of significant white matter change presenting in aMCI patients, extended white matter degeneration over entire cerebral networks was exhibited in mild AD patients. Both axonal degradation and demyelination contributed to the white matter degeneration in AD; nevertheless, demyelination essentially involved the frontal portion of cerebral networks. Axonal degradation and demyelination over the temporal region were associated with the contiguous grey matter atrophy. However, only the severity of demyelination over the frontal region was correlated with the degree of atrophy over adjacent frontal grey matter. Our results suggest that different mechanisms of white matter damage demonstrate discrete regional distribution in AD. Demyelination may independently correlate with contiguous grey matter over the frontal region. PMID- 22430529 TI - Intrahippocampal administration of amyloid-beta(1-42) oligomers acutely impairs spatial working memory, insulin signaling, and hippocampal metabolism. AB - Increasing evidence suggests that abnormal brain accumulation of amyloid-beta(1 42) (Abeta(1-42)) oligomers plays a causal role in Alzheimer's disease (AD), and in particular may cause the cognitive deficits that are the hallmark of AD. In vitro, Abeta(1-42) oligomers impair insulin signaling and suppress neural functioning. We previously showed that endogenous insulin signaling is an obligatory component of normal hippocampal function, and that disrupting this signaling led to a rapid impairment of spatial working memory, while delivery of exogenous insulin to the hippocampus enhanced both memory and metabolism; diet induced insulin resistance both impaired spatial memory and prevented insulin from increasing metabolism or cognitive function. Hence, we tested the hypothesis that Abeta(1-42) oligomers could acutely impair hippocampal metabolic and cognitive processes in vivo in the rat. Our findings support this hypothesis: Abeta(1-42) oligomers impaired spontaneous alternation behavior while preventing the task-associated dip in hippocampal ECF glucose observed in control animals. In addition, Abeta(1-42) oligomers decreased plasma membrane translocation of the insulin-sensitive glucose transporter 4 (GluT4), and impaired insulin signaling as measured by phosphorylation of Akt. These data show in vivo that Abeta(1-42) oligomers can rapidly impair hippocampal cognitive and metabolic processes, and provide support for the hypothesis that elevated Abeta(1-42) leads to cognitive impairment via interference with hippocampal insulin signaling. PMID- 22430531 TI - High Blood caffeine levels in MCI linked to lack of progression to dementia. AB - Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer's disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65-88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2-4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (-51%) in mild cognitive impairment (MCI) subjects who later progressed to dementia (MCI->DEM) compared to levels in stable MCI subjects (MCI >MCI). Moreover, none of the MCI->DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI->MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (~6 MUM) in MCI subjects were associated with no conversion to dementia during the ensuing 2-4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI->DEM subjects, but not in stable MCI->MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI. PMID- 22430532 TI - Abeta25-35 injection into the temporal cortex induces chronic inflammation that contributes to neurodegeneration and spatial memory impairment in rats. AB - Amyloid-beta (Abeta)25-35 is able to cause memory impairment and neurodegenerative events. Recent evidence has shown that the injection of Abeta25 35 into the temporal cortex (TCx) of rats increases the inflammatory response; however, it is unclear how the inflammatory process could be involved in the progression of Abeta25-35 toxicity. In this study we investigated the role of inflammation in the neuronal damage and spatial memory impairment generated by Abeta25-35 in rat TCx using immunohistochemistry, ELISA, and a behavioral test in the radial maze. Our findings show that Abeta25-35 -injection into the TCx induced a reactive gliosis (GFAP and CD11b-reactivity) and an increase of pro inflammatory cytokines (IL-1beta, IL-6, IL-17, and TNF-alpha) in the TCx and the hippocampus at 5, 15, and 30 days after injection. Thirty days after Abeta25-35 injection, we observed that the inflammatory reaction probably contributed to increase the immunoreactivity of inducible nitric oxide synthase and nitrite levels, as well as to the loss of neurons in TCx and hippocampus. Behavioral performance showed that the neurodegeneration evoked by Abeta25-35 delayed acquisition of learning and impaired spatial memory, because the Abeta25-35 treated animals showed a greater number of errors during the task than the control group. Previous administration of an interleukin receptor antagonist (IL 1ra) (10 and 20 MUg/MUL, into TCx), an anti-inflammatory agent, suppressed the Abeta25-35-induced inflammatory response and neurodegeneration, as well as memory dysfunction. This study suggests that the chronic inflammatory reaction could contribute to the progression of Abeta25-35 toxicity and cause cognitive impairment. PMID- 22430533 TI - Alzheimer's disease-related loss of Pin1 function influences the intracellular localization and the processing of AbetaPP. AB - Increased amyloidogenic processing of the amyloid-beta protein precursor (AbetaPP) is a characteristic of Alzheimer's disease (AD). We previously observed that the prolyl isomerase Pin1, which is down-regulated in AD, regulates AbetaPP conformation accelerating cis/trans isomerization of the phospho-Thr668-Pro669 peptide bond, and that Pin1 knockout in mice increases the amyloidogenic processing of AbetaPP, although the underlying mechanism is still unknown. Since the intracellular localization of AbetaPP determines whether the processing will be amyloidogenic or non-amyloidogenic, here we addressed the question whether loss of Pin1 function affects the intracellular localization of AbetaPP, influencing AbetaPP processing. Using cellular models of Pin1 knockout and Pin1 knockdown, we have demonstrated that lowering Pin1 levels changed the intracellular localization and the processing of AbetaPP. Under these conditions, less AbetaPP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of AbetaPP internalization increased as well as the nuclear trafficking of AbetaPP C-terminal fragment AICD. In addition, AbetaPPThr668Ala mutant, which cannot bind to Pin1 and retains more trans conformation, rescued the levels of AbetaPP at the plasma membrane in Pin1 knockout cells. Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of AbetaPP from compartments where it is mostly non-amyloidogenic and its internalization to more amyloidogenic compartments. These data suggest that physiological levels of Pin1 are important to control the intracellular localization and metabolic fate of Thr668 phosphorylated AbetaPP, and regulation of AbetaPP conformation is especially important in pathologic conditions of AbetaPP hyperphosphorylation and/or loss of Pin1 function, associated with AD. PMID- 22430534 TI - Electrochemical amplified detection of Hg2+ based on the supersandwich DNA structure. AB - A supersandwich DNA structure was fabricated and used for the amplified detection of Hg(2+). PMID- 22430535 TI - Nanopatterning of silicon nanowires for enhancing visible photoluminescence. AB - Silicon Nanowires prepared by Metal-Assisted Chemical Etching have been nanopatterned into periodic and aperiodic array geometries displaying functionality at visible wavelengths using top-down planar processing techniques. Broadband photoluminescense enhancement up to approximately one order of magnitude is measured from golden-angle spiral arrays over a wide parameter space. PMID- 22430536 TI - Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia. AB - BACKGROUND: Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. METHODS: Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S 40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S 40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. RESULTS: S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5alpha dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. CONCLUSIONS: The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists. PMID- 22430537 TI - Abstracts of the 8th Annual Congress of the European Cardiac Arrhythmia Society, April 20-22, 2012, Munich, Germany. PMID- 22430539 TI - Lumbar spinal stenosis treatment with Aperius perclid interspinous system. AB - PURPOSE: The purpose of this study is to report clinical outcome and imaging changes of percutaneous Aperius stand-alone implant in patients with degenerative lumbar spinal stenosis and neurogenic intermittent claudication, which did not respond to conservative treatment. METHOD: Between January 2008 and July 2010, 37 patients (20 males and 17 females) with mean age of 64.3 years underwent surgery for the onset of claudicatio spinalis with Aperius PercLID interspinous device (Medtronic). In all patients, the diagnosis was: foraminal stenosis, in one case (2.7 %) it was associated to a degenerative anterior listhesis (I grade), in three cases (8.1 %) it was associated to an intraforaminal disc herniation. The mean follow-up was of 18 months (range 2-35 months). The patients were evaluated through the Oswestry disability index, Zurich Claudication Questionnaire (ZCQ), VAS scales. In all cases were obtained preoperative and in postoperative radiographs and magnetic resonance imaging. RESULTS: The VAS score decreased significantly after surgery: the patients presented a mean VAS of seven preoperatively and two postoperatively (p < 0.001). The ZCQ score significantly decreased postoperatively, with an average reduction of 21.89 % (p < 0.001). The ODI score as well showed a significant reduction postoperatively of an average 26.09 % (p < 0.001). CONCLUSION: Despite of the brief follow up, the preliminary results are encouraging, showing a significantly decrease of the disability parameters, a marked improvement of the function with the vanishing of the claudicatio spinalis and the following increase of the free interval during the walk. Aperius PercLID system seems to offer an alternative to the traditional decompression surgery. PMID- 22430540 TI - How well do observed functional limitations explain the variance in Roland Morris scores in patients with chronic non-specific low back pain undergoing physiotherapy? AB - PURPOSE: Self-rated activity limitations in patients with non-specific chronic low back pain (cLBP) do not correlate well with performance in traditional tests of impairment (e.g. back strength, ROM, etc.). Tests using more "functional activities" have therefore been recommended as alternative "objective" outcome measures. We examined the relationship between a battery of such tests and self reported activity limitations, before and in response to physiotherapy, and the influence of psychological factors on the relationship. METHODS: 37 patients with cLBP took part (45 +/- 12 years; 23 female, 14 male); 32 completed 9 weeks' physiotherapy. Before and after therapy, the patients completed the Roland Morris (RM) disability questionnaire and questionnaires to assess fear avoidance beliefs, catastrophising and psychological disturbance. They also performed eight simple functional tests (stair climb, prolonged flexion, stand to floor, lift test, sock test, roll-up test, pick-up test, fingertip-to-floor test). RESULTS: Baseline RM scores were significantly (p < 0.05) correlated with all but one of the functional test scores (ranging from r = -0.34 (half-flexion) to 0.56 (pick up test), and with a functional test index score for all tests together (r = 0.60, p < 0.0001). The correlation between the change-scores (after treatment) for RM and for the functional test index was 0.55 (p = 0.001). Psychological factors explained 7-23 % variance in RM scores (baseline, post-therapy, and change scores), beyond that which was explained by the functional tests. Effect sizes for patients with a self-rated "good global outcome" were 1.23 for RM and 0.75 for the functional test index; for those with a "poor outcome", they were 0.08 and 0.23, respectively. CONCLUSION: Moderately high correlations (for both absolute and change scores) were observed between the subjective and observed measures of activity limitation. This indicates that to some extent they are assessing the same underlying construct, but it also suggests that each is delivering a certain amount of unique information. Psychological factors explained some of the discrepancy between the two types of measure. Both were responsive to therapy, and their change scores reflected well the patients' global outcome ratings. The two methods of assessing activity limitations should serve to complement one another in the assessment of treatment outcome. PMID- 22430541 TI - Evolution of the curve patterns during brace treatment for adolescent idiopathic scoliosis. AB - The curve pattern of idiopathic scoliosis is important for making decisions concerning bracing. However, whether the curve pattern changes during brace treatment have not been fully documented. The aim of this study was to investigate the changes of curve pattern during brace treatment in skeletally immature patients with adolescent idiopathic scoliosis (AIS). METHODS: From January 2002 to January 2011, AIS patients treated with a Boston or Milwaukee brace were recruited after meeting the following inclusion criteria: older than 10 years of age at initiation of bracing; having a Cobb angle of 25 degrees -40 degrees ; with a Risser sign 0-2; being regularly followed until the weaning of brace or the necessity of surgical treatment; and without history of previous treatment. A total of 130 female and 11 male AIS patients were included. The mean age was 12.9 years at initiation of bracing, and the female patients were, on average, 2.7 months past menarche. The mean follow-up period was 2.6 years (range 1.0-5.5 years). The definitions of changes in curve patterns were divided into four categories as follows: (1) shift of the apex of the main curve; (2) change in the curve span of more than two vertebrae; (3) change in the main curve type with regard to the apex location; and (4) change of curve direction. The patients were divided into two groups. Group A was comprised of patients who had experienced one or more categories of curve pattern changes, and Group B was comprised of those who had not. RESULTS: Of these 39 patients, 14 had apex shifting, 2 underwent curve span changes, 22 experienced changes in the main curve type, and one female had both changes in the apex and curve span. At the initiation of bracing, patients in Group A demonstrated significantly lower menarchal status (P = 0.018) and lower Risser grade (P = 0.025) than those in Group B. The difference in the percentage of patients who underwent Boston bracing between the two groups was statistically significant (41.5 % for Group A vs. 24.0 % for Group B, P = 0.023). CONCLUSION: Changes in curve pattern can occur during brace treatment. Patients with less skeletal maturity and those treated with a Boston brace are more susceptible to this phenomenon. PMID- 22430542 TI - Anterior thoracic foraminotomy through mini-thoracotomy for the treatment of giant thoracic disc herniations. AB - STUDY DESIGN: A retrospective review of a case series. OBJECTIVES: Giant thoracic disc herniations remain a surgical challenge and historically have been associated with significant complications. While neurological outcomes have improved with the abandonment of decompressive laminectomy, the attempt to minimize surgical complications and associated morbidities continues through less invasive approaches. With the current study, we describe a surgical technique to treat giant thoracic disc herniations while minimizing approach-related morbidity. METHODS: Demographic and radiographic data; clinical outcome and perioperative complications were retrospectively analysed for patients with single-level giant thoracic disc herniations who underwent mini-thoracotomy and selective microsurgical anterior spinal cord decompression without instrumented fusion. RESULTS: Between 2007 and 2012, 7 consecutive patients with giant thoracic disc herniations were treated (average age of 53 years; range 45-66 years). The average canal encroachment was 73.2 % (range 40-92 %) with 5 grossly calcified discs of which 3 had transdural components. All patients had gradual myelopathic progression. The average Nurick grade was 3.5 (range 2-5). All patients were successfully treated with anterior microsurgical decompression without instrumentation. Uninstrumented fusion with rib graft was performed only in one patient with advanced degenerative changes. Average time of surgery was 337.8 min (range 220-450 min). The average length of hospital stay was 7.4 days (range 6-11 days). The average neurological status at follow-up (average 23.5 months; range 9-36 months) using the modified Nurick grading scale was 1.28. No vertebral collapse or loss of spinal alignment developed. There were no neurological complications. One patient developed an acute headache and diplopia, 10 days after surgery, following sneezing associated with a post-operative thoracic cerebrospinal fluid leakage requiring revision. Two patients suffered an approach-related complication in form of intercostal neuralgia; one was persistent. CONCLUSIONS: Anterior decompression using a mini-transthoracic approach provides sufficient exposure for microsurgical decompression of giant thoracic disc herniations without disrupting the stability of the spine. Microsurgical decompression without instrumentation does not appear to lead to vertebral collapse or spinal malalignment. PMID- 22430543 TI - Bridging the channel: the first British Isles supplement of the European Spine Journal. PMID- 22430544 TI - Introducing the Society for Back Pain Research. PMID- 22430545 TI - Editorial: Spinal education, training and research in the UK. PMID- 22430546 TI - Theoretical investigation on electronic structure and second-order nonlinear optical properties of novel hexamolybdate-organoimido-(car)borane hybrid. AB - We report a theoretical study based on density functional theory (DFT) on the geometric and electronic structure, linear optical and second-order nonlinear optical properties of a series of new inorganic-organic hybrid hexamolybdate organoimido-(car)boranes. By the incorporation of borane/carborane at the end of the phenyl ring of the organoimido segment, the studied systems show excellent nonlinear optical (NLO) response than the organoimido-substituted hexamolybdate. The computed static first hyperpolarizability beta(vec) value of [Mo(6)O(18)(NC(8)H(8))(B(12)H(11))](4-) (II) is largest, -167.2 * 10(-30) esu, and a higher beta(vec) value of [Mo(6)O(18)(NC(8)H(8))(C(2)B(10)H(11))](2-) (III 2p) is 58.6 * 10(-30) esu. Moreover, the time-dependent (TD)DFT calculation illustrates that the maximum absorption, which is helpful for the large NLO responses, is mainly assigned to the charge transfer (CT) from (car)borane and organoimido segment to the hexamolybdate cluster. The density of density (DOS) calculations further illustrate the excitation from valence orbitals of boron atoms to that of Mo and O atoms in hexamolybdate can be responsible for larger NLO responses. The linear and nonlinear optical properties of species III both vary with the position of the vertex on the carborane. Furthermore, the order of the beta(vec) values is consistent with the bathochromic shift of the maximum absorption for our studied systems, and the studied systems show a wider transparency range extending into the entire visible and infrared (IR) region. PMID- 22430547 TI - [The Anesthetist : The German journal for original articles]. PMID- 22430548 TI - [Can anesthetists improve long-term oncological results?]. PMID- 22430549 TI - [Influence of anesthesia procedure on malignant tumor outcome]. AB - Malignant tumors are the second major cause of death in Germany. The essential therapy of operable cancer is surgical removal of primary tumors combined with adjuvant therapy. However, several consequences of surgery may promote metastasis, such as shedding of tumor cells into the circulation, decrease in tumor-induced antiangiogenesis factors, excessive release of growth factors for wound healing and suppression of immunity induced by surgical stress. In the last decade it has become clear that cell-mediated immunity controls the development of metastasis. Various perioperative factors, such as surgical stress, certain anesthetic and analgesic drugs and pain can suppress the patients' immune system perioperatively. On the other hand, by modifications of the anesthesia technique (e.g. regional anesthesia) and perioperative management to minimize immunosuppression, anesthesiologists can play a considerable role for a better outcome in patients having malignant tumors. Sufficient clinical evidence is not yet available to prove or disprove the hypothesis that anesthesia practice can improve cancer prognosis. Despite difficulties in study design, several prospective randomized trials are currently running and the results are awaited to elucidate this topic. PMID- 22430550 TI - [Undergraduate teaching of anaesthesiology : a nationwide survey in Germany]. AB - BACKGROUND: In 2003 anaesthesiology was implemented as a compulsory speciality of undergraduate teaching in Germany due to the revised regulations of medical education. Besides the preexisting subject of emergency medicine an obligatory course in anaesthesiology was introduced. Thus anaesthesiology has gained considerable importance in all medical faculties. To gain insight into the current status of undergraduate medical education in the university departments of anaesthesiology a nationwide survey at all university departments in Germany was initiated. METHODS: In cooperation with the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) a standardized questionnaire was developed and sent to 36 departments of anaesthesiology of all German medical faculties. Questions concerned the structure of the respective curriculum, learning goals, teaching, assessment and evaluation methods as well as facultative courses. RESULTS: Of the 36 university departments of anaesthesiology, 35 returned the questionnaire. In 66% undergraduate education in anaesthesiology is part of the fourth or fifth year of medical training. In 91% of the faculties lectures were accompanied by teaching in small student groups. A simulator-based training is integrated either in anaesthesiology and/or in emergency medicine in 91% of the departments of anaesthesiology. In 69% of the departments contents of anaesthesia, critical care medicine, emergency medicine and pain management are an integral part of undergraduate teaching in anaesthesiology. The primary learning goals are directed towards general anaesthesia and there is less focus on topics of preoperative or postoperative care, such as preoperative risk evaluation, postoperative pain management and regional anaesthesia. Besides a multiple choice test (91%) oral (63%) and/or practical examinations (71%) are used as assessment tools. In 71% of the medical faculties the respective departments of anaesthesiology are leading and organising skills laboratories. In student evaluations anaesthesiology achieved best ranking in 66% of the medical faculties compared to other specialties. The possibility to take an elective course in anaesthesiology exists in 74% of the faculties. Half of these faculties organize this elective as a longitudinal course for one complete semester, the other half as a full time course over mostly 1 or 2 weeks. At present E-learning plays a minor role. CONCLUSIONS: This survey provides detailed information about the current status of undergraduate teaching of the university departments of anaesthesiology in Germany. The study shows a remarkable consistency of structure, contents and methods of education in anaesthesiology throughout all university departments of anaesthesiology. This information is the basis for triggering synergistic effects, for improving educational standards in anaesthesiology and for introducing a platform for developing modern learning media, e.g. through the scientific society DGAI. PMID- 22430551 TI - [Psychiatric care in emergency departments]. AB - BACKGROUND: Psychiatric emergency situations (PES) are frequent in emergency departments (EDs). There are, however, only few investigations that focus on the prevalence of these patients or on diagnostic and therapeutic standards. These PESs in EDs should be treated according to standards comparable to medically disabled patients. Thus it is necessary to learn more about the diagnostic and therapeutic possibilities in EDs, about the procedures and the decision-making process whether these patients are transferred to further outpatient or inpatient treatment. MATERIALS AND METHODS: A survey was conducted in EDs throughout Germany and 1,073 were contacted and asked to participate. The questionnaire consisted of questions concerning the size of the ED and of the hospital (e.g. number of patients and physicians), the prevalence of psychiatric disorders, the diagnostic and therapeutic possibilities, standard procedures for dealing with PES and the method of care in six typical case reports. RESULTS: A total of 74 EDs participated (76% interdisciplinary EDs) with an average of 22,827 +/- 12,303 patients per year in the ED. Psychiatry as a medical discipline was integrated into 10 EDs (14%) and psychiatric competence could be activated in 84% of EDs. Participating EDs reported prevalence rates of 15% mentally disordered patients and 9% of patients who required psychiatric diagnostic and therapeutic procedures. Of the patients 2% presented after suicide attempts and 3% were considered to be aggressive. Approximately 50% of all PESs were related to substance abuse disorders. An average of 2.5 +/- 4.2 (range 0-25) members of the medical and nursing staff were injured during a 1-year period by violent patients. Legal actions against the will of patients were initiated in 81% of EDs. Standardized diagnostic screening instruments or self-rating questionnaires were used in only four EDs. As standard procedures for the diagnostic work-up of psychiatric patients (medical clearance) physical examination, measurement of heart rate and blood pressure and conducting of some laboratory tests (glucose, blood cell count, electrolytes and renal function) were named. Diazepam (91%), lorazepam (88%) and haloperidol (87%) were considered to be indispensable psychopharmacological agents in the ED. CONCLUSIONS: In the majority of participating EDs, diagnostic standards for PES were known but were not routinely applied. It has to be assumed that many psychiatric disorders, in particular suicide attempts and suicidal ideation are not discovered. In many EDs psychiatric knowledge was available but a psychiatric consultation was only rarely requested. Physicians in the ED report a high degree of legal uncertainty with psychiatric patients. The use of screening instruments is recommended. PMID- 22430552 TI - [Dialysis for severe rhabdomyolysis 7 days after multiple trauma]. AB - A case report of severe rhabdomyolysis in a 33-year-old motorcyclist after multiple trauma is described. The injuries included severe thoracic and abdominal trauma as well as injuries to the extremities and spinal column. During the first 3 days of treatment a forced volume therapy was performed because of increased levels of creatine kinase during which the patients condition stabilized both hemodynamically and respiratorily. On day 10 the patient developed a rise in temperature to 42 degrees C with no evidence of a re-infection and the creatine kinase levels rose to 109,830 U/l. A continuous hemofiltration was started because of acute renal failure. The creatine kinase levels declined significantly and renal function also returned to normal with adequate diuresis up to day 20. After intensive questioning of the relatives a history of long-term use of anabolic steroids, clenbuterol as well as the intake of testosterone enanthate was conceded. Cocaine and amphetamines were also taken regularly by the patient. PMID- 22430553 TI - [Pompe disease : anesthesiological special features]. AB - Pompe disease is a very rare disorder of glycogen metabolism. Due to a deficiency of the enzyme glucosidase glycogen accumulates inside the lysosomes. The clinical picture varies widely as a consequence of varying participation of skeletal and heart muscle. In adults respiratory insufficiency can occur which must be taken into consideration during anesthesiology procedures for affected patients. This case report describes a 60-year-old patient scheduled for punch biopsy of the prostate. PMID- 22430554 TI - [Sexual hallucinations and dreams under anesthesia and sedation : medicolegal aspects]. AB - Dreams and hallucinations under sedation or anesthesia have been well known phenomena since the introduction of anesthesia. Sexual hallucinations may lead to allegations of sexual molestation or assault by medical doctors or professional nursing staff. Hallucinations under the influence of sedative or hypnotic drugs may be very vivid and as misinterpreted as being real and it is therefore often difficult to disprove the resulting false allegations. In this report the terms drug-induced dreams and hallucinations are defined and the probable mechanism described. By a historical review and case reports the medicolegal consequences are demonstrated and procedures recommended to avoid allegations of sexual assault. PMID- 22430555 TI - [Organ protective intensive care treatment and simulation-based training]. AB - In Germany the extent of organ donation is still inadequate and not sufficient to address patients on the waiting lists. Nevertheless, intensive care treatment of potential organ donors does not receive adequate attention. However, because of the increasing age and comorbidities of organ donors in recent years, a sufficient intensive care treatment is indispensable for the success of organ transplantations. Sufficient randomized clinical trials are lacking. This article reviews the current literature and describes approaches for improvement. Multicentre studies and education of medical staff of intensive care units, for example in intensive care simulation for organ protection, could potentially be a successful approach. The improvement and establishment of curricular training and education particularly in simulation workshops might be a promising approach to enhance the quantity and quality of organ donations. PMID- 22430556 TI - [Antimicrobial treatment in burn injury patients]. AB - Infections are a great diagnostic and therapeutic challenge in intensive care patients with burn injuries. The major problems are due to bacteria with hospital acquired multiresistance to antibiotics but fungal and viral infections may also be life-threatening. The main key points addressing pharmacotherapy with antibiotic, antifungal and antiviral agents in this special setting are exact diagnosis, early therapy with suitable drugs, adequate duration of treatment and adequate doses based on pharmacokinetic and pharmacodynamic characteristics of these compounds. The latter parameters are significantly altered in burn patients and show a wide interindividual and intraindividual variation in drug response as a result of the characteristic phases of burn injury. Drug concentration analysis may help to avoid inadequate dosing. In this review the main characteristics of burn injuries and the pharmacology of antibiotics, antifungal and antiviral agents in these patients are presented. PMID- 22430557 TI - [Cardiogenic shock]. AB - Cardiogenic shock is most commonly a complication of acute myocardial infarction. The ischemic loss of functional myocardium triggers distinct cardiovascular responses which can deteriorate to global pump failure with a mortality rate of more than 50%. Causes of cardiogenic shock beyond myocardial ischemia are very diverse. Decisive management with rapid evaluation, identification of the underlying disease and urgent initiation of supportive measures as well as definitive therapy is of prognostic value. Causal treatment of the cardiac disease is crucial but has to be weighed against the specific surgical circumstances of perioperative patients, particularly concerning anticoagulation, platelet inhibition and bleeding risks. Hemodynamic stabilization is achieved by pharmacological support of myocardial function, control of arrhythmia and volume load. Prevention and intensive care of shock-related multiorgan failure is of pivotal importance in the successful management of cardiogenic shock. PMID- 22430558 TI - Exposure to rabies virus in a population of free-ranging capuchin monkeys (Cebus apella nigritus) in a fragmented, environmentally protected area in southeastern Brazil. AB - The aim of this study is to assess the frequency of rabies antibodies in free ranging capuchin monkeys (Cebus apella nigritus) in a fragmented, environmentally protected, rural area of southeastern Brazil. Thirty-six free-ranging monkeys were tested by the rapid fluorescent focus inhibition test for detection of antibodies against rabies virus. Four individuals (11.11 %) had neutralizing antibody titers >= 0.25 IU/mL, demonstrating rabies virus exposure. PMID- 22430560 TI - An algebraic analysis of the two state Markov model on tripod trees. AB - Methods of phylogenetic inference use more and more complex models to generate trees from data. However, even simple models and their implications are not fully understood. Here, we investigate the two-state Markov model on a tripod tree, inferring conditions under which a given set of observations gives rise to such a model. This type of investigation has been undertaken before by several scientists from different fields of research. In contrast to other work we fully analyse the model, presenting conditions under which one can infer a model from the observation or at least get support for the tree-shaped interdependence of the leaves considered. We also present all conditions under which the results can be extended from tripod trees to quartet trees, a step necessary to reconstruct at least a topology. Apart from finding conditions under which such an extension works we discuss example cases for which such an extension does not work. PMID- 22430559 TI - The three human monocyte subsets: implications for health and disease. AB - Human blood monocytes are heterogeneous and conventionally subdivided into two subsets based on CD16 expression. Recently, the official nomenclature subdivides monocytes into three subsets, the additional subset arising from the segregation of the CD16+ monocytes into two based on relative expression of CD14. Recent whole genome analysis reveal that specialized functions and phenotypes can be attributed to these newly defined monocyte subsets. In this review, we discuss these recent results, and also the description and utility of this new segregation in several disease conditions. We also discuss alternative markers for segregating the monocyte subsets, for example using Tie-2 and slan, which do not necessarily follow the official method of segregating monocyte subsets based on relative CD14 and CD16 expressions. PMID- 22430561 TI - Out of Asia: natricine snakes support the Cenozoic Beringian Dispersal Hypothesis. AB - Based on a combination of six mitochondrial gene fragments (12S RNA, cyt b, ND1, ND2, ND4 and CO1) and one nuclear gene (c-mos) from 22 genera we infer phylogenetic relationships among natricine snakes and examine the date and area of origin of these snakes. Our phylogenetic results indicate: (1) the subfamily Natricinae is strongly supported as monophyletic including a majority of extant genera, and a poorly known and previously unassigned species Trachischium monticola, (2) two main clades are inferred within Natricinae, one containing solely taxa from the Old World (OW) and the other comprising taxa from a monophyletic New World (NW) group with a small number of OW relatives. Within the first clade, the genera Xenochrophis and Amphiesma are apparently not monophyletic. Divergence dating and ancestral area estimation indicate that the natricines originated in tropical Asia during the later Eocene or the Oligocene. We recover two major dispersals events out of Asia, the first to Africa in the Oligocene (28 Ma) and the second to the Western Palearctic and the New World at 27 Ma. This date is consistent with the dispersal of numerous other OW groups into the NW. PMID- 22430562 TI - Correlation between magnetic resonance imaging and clinical impairment in patients with adhesive capsulitis. AB - OBJECTIVE: To determine the relationship between clinical impairment and MRI findings in patients with adhesive capsulitis. MATERIALS AND METHODS: Contrast enhanced MRI of 97 patients with a clinical diagnosis of adhesive capsulitis (AC) were retrospectively reviewed. Specific MRI criteria, including thickness and gadolinium enhancement of the joint capsule in the axillary recess and subcoracoid fat obliteration in the rotator interval, were correlated with limited range of motion (ROM) and pain. Other variables considered in this study were rotator cuff pathology, arm dominance, diabetes mellitus, age, and gender. Statistical analysis was performed using logistic and linear regression analysis. RESULTS: Thickening of the joint capsule in the axillary recess correlated with limited external rotation (p < 0.01), gender (p < 0.01) and arm dominance (p < 0.05). Gadolinium enhancement of the joint capsule in the axillary recess correlated with pain intensity (p < 0.05). Subcoracoid fat obliteration in the rotator interval was not correlated with limited ROM or pain. CONCLUSIONS: MRI can be a useful technique to assess several clinical impairment measures in patients with adhesive capsulitis. Thickening and gadolinium enhancement of the joint capsule in the axillary recess on MRI are associated with limited ROM and pain. PMID- 22430563 TI - Shaken or swirled? Mixing gadolinium for arthrography. AB - OBJECTIVES: To better understand how variability in preparation of gadolinium solutions may affect image quality for MRI arthrography studies. METHODS: Two different mixing techniques were employed in preparation of gadolinium/saline dilutions (repeated inversion vs. swirling). Test syringes were then placed together with unmixed and control syringes in a specially prepared holder in the MRI machine and both initial and delayed T1FS sequences were performed. Qualitative assessment was performed to evaluate completeness of contrast mixing and overall signal intensity of contrast within the syringe. Quantitative measurements were performed using a circular region of interest centered on the lumen of each syringe. Three trials were performed. RESULTS: Subjective and quantitative analysis revealed that the repeatedly inverted syringe demonstrated more uniform high signal with lower standard deviation than the swirled syringe in all three trials. Subjective evaluation of the swirled syringe revealed contrast/saline levels on both initial and delayed scans. The syringe that was not mixed after addition of gadolinium demonstrated even more obvious dependant layering of contrast than did the swirled syringe on both initial and delayed scans. CONCLUSIONS: When preparing small volumes of diluted gadolinium solution for intraarticular injection, the technique of mixing may influence the composition of the injected solution. PMID- 22430564 TI - Reliability of change in lumbar MRI findings over time in patients with and without disc prosthesis--comparing two different image evaluation methods. AB - OBJECTIVES: To assess the reliability of change in lumbar magnetic resonance imaging (MRI) findings evaluated retrospectively by direct comparison of images and by non-comparison. MATERIALS AND METHODS: Pre-treatment and 2-year follow-up MRI was performed in 126 patients randomized to disc prosthesis surgery or non surgical treatment. Two experienced radiologists independently evaluated progress and regress for Modic changes, disc findings, and facet arthropathy (FA) at L3/L4, L4/L5, and L5/S1, both by non-comparison and by comparison of initial and follow-up images. FA was evaluated at all levels, and other findings at non operated levels. We calculated prevalence- and bias-adjusted kappa (PABAK) values for interobserver agreement. The impact of an adjacent prosthesis (which causes artefacts) and image evaluation method on PABAK was assessed using generalized estimating equations. RESULTS: Image comparison indicated good interobserver agreement on progress and regress (PABAK 0.63-1.00) for Modic changes, posterior high-intensity zone, disc height, and disc contour at L3-S1 and for nucleus pulposus signal and FA at L3/L4; and moderate interobserver agreement (PABAK 0.46 0.59) on decreasing nucleus signal and increasing FA at L4-S1. Image comparison indicated lower (but fair) interobserver agreement (PABAK 0.29) only for increasing FA at L5/S1 in patients with prosthesis in L4/L5 and/or L5/S1. An adjacent prosthesis had no overall impact on PABAK values (p >= 0.22). Comparison yielded higher PABAK values than non-comparison (p < 0.001). CONCLUSIONS: Regarding changes in lumbar MRI findings over time, comparison of images can provide moderate or good interobserver agreement, and better agreement than non comparison. An adjacent prosthesis may not reduce agreement on change for most findings. PMID- 22430565 TI - MRI findings of treated bacterial septic arthritis. AB - INTRODUCTION: The purpose of this study was to report the MRI findings that can be encountered in successfully treated bacterial septic arthritis. MATERIALS AND METHODS: The study included 12 patients (8 male and 4 female; mean age 38 years, range 9-85) with 13 proven cases of bacterial septic arthritis. The joints involved were hip (n = 3), knee (n = 3), shoulder (n = 2), sacroiliac (n = 2), ankle (n = 1), wrist (n = 1), and elbow (n = 1). MRI examinations following surgical debridement and at initiation of antibiotic therapy and after successful treatment were compared for changes in effusion, synovium, bone, and periarticular soft tissues. Imaging findings were correlated with microbiological and clinical findings. RESULTS: Joint effusions were present in all joints at baseline and regressed significantly at follow-up MRI (p = 0.001). Abscesses were present in 5 cases (38 %), and their sizes decreased significantly at follow-up (p = 0.001). Synovial enhancement and thickening were observed in all joints at both baseline and follow-up MRI. Myositis/cellulitis was present in 10 cases (77 %) at baseline and in 8 cases (62 %) at follow-up MRI. Bone marrow edema was present in 10 joints (77 %) at baseline and persisted in 8 joints (62 %). Bone erosions were found in 8 joints (62 %) and persisted at follow-up MRI in all cases. CONCLUSION: The sizes of joint effusions and abscesses appear to be the factors with the most potential for monitoring therapy for septic arthritis, since both decreased significantly following successful treatment. Synovial thickening and enhancement, periarticular myositis/cellulitis, and bone marrow edema can persist even after resolution of the infection. PMID- 22430567 TI - Conformational preferences of oxy-substituents in butenolide-tetrahydropyran spiroacetals and butenolide-piperidine spiro-N,O-acetals. AB - We describe the synthesis of a series of oxy-substituted butenolide spiroacetals and spiro-N,O-acetals by oxidative spirocyclisation of 2-[(4-hydroxy or 4 sulfonamido)butyl]furans. The axial-equatorial preference of each oxy-substituent is investigated (NMR) by an acid-catalysed thermodynamic relay of configuration between the spiro- and oxy-centres. The axial site is preferred for most oxy substituents at synthetically useful levels. The potential origins of this preference are discussed in terms of a stabilising gauche effect combined with the influence of solvation. These results have relevance to the synthesis of bis(acetylenic)enol ether spiroacetals including AL-1 and related compounds. PMID- 22430566 TI - Effectiveness of a psychosocial weight management program for individuals with schizophrenia. AB - The objective of this study was to examine the effectiveness of a weight loss program for individuals with schizophrenia in usual care. The study included 146 adults with schizophrenia from two mental health clinics of the Department of Veterans Affairs. The 109 individuals who were overweight or obese were offered a 16-week, psychosocial, weight management program. Weight and Body Mass Index (BMI) were assessed at baseline, 1 year later, and at each treatment session. Only 51% of those who were overweight or obese chose to enroll in the weight management program. Participants attended an average of 6.7 treatment sessions, lost an average of 2.4 pounds, and had an average BMI decrease of 0.3. There was no significant change in weight or BMI compared to the control group. Intervention strategies that both improve utilization and yield greater weight loss need to be developed. PMID- 22430568 TI - Divergent and convergent projections to the two parallel olfactory centers from two neighboring, pheromone-receptive glomeruli in the male American cockroach. AB - Many animals utilize sex pheromone for detecting conspecific mates. Sex pheromone is usually a blend of two or more components with similar chemical compositions. The pheromone receivers are equipped with localized olfactory glomeruli in the first-order olfactory center for specifically processing these pheromone components. In the American cockroach, Periplaneta americana, either periplanone A or periplanone B emitted by virgin females evokes identical sexual behaviors in males. The antennal lobes of adult male cockroaches have enlarged, neighboring A- and B-glomeruli, which preferentially process periplanones A and B, respectively. By using intracellular recording and staining of neurons in the same preparations, we provide the first detailed projection maps of output neurons (projection neurons; PNs) from the A-glomerulus and the B-glomerulus. Although both PNs project to the mushroom body calyces and the lateral horn, their proximities in the two centers largely differ: in the calyces, the axon terminals of the A-PN were located more predominantly in the periphery compared with those of the B-PN, whereas axon terminals of both PNs were highly congruent in the anteromedial region of the lateral horn. These results suggest that pheromone component signals are dispersed in the mushroom body for specific odor discrimination but are integrated in the lateral horn for generating behaviors common to the pheromone components. Stimulation of the ipsilateral antenna with various odors showed that the odor specificity of A-PN is higher than that of B PN. The different developmental lineages of A- and B-PNs suggested by these results are discussed. PMID- 22430570 TI - Fibrillisation of ring-closed amyloid peptides. AB - Ring-closing olefin metathesis reactions are used to create intra-molecularly ring closed peptides or inter-molecularly ring-closed peptide dimers based on a designed amyloid peptide sequence. The uncrosslinked peptide self-assembles into high aspect ratio nanotubes, however ring-closing leads to the formation of fibrillar and twisted/helical ribbon structures. PMID- 22430569 TI - Influence of saponins and tannins on intake and nutrient digestion of alkaloid containing foods. AB - BACKGROUND: We hypothesized that eating a food containing saponins (SAP), or tannins (TAN) prior to foods containing the alkaloids gramine (GRA) or 5-methoxy N,N-dimethyltryptamine (TRP) would provide benefits not possible when the alkaloid-containing foods were eaten alone. METHODS: In Trial 1, four groups of five lambs were first offered food with SAP for 30 min followed by food with either GRA or TRP for 3.5 h in a 2 * 2 factorial arrangement of a completely randomized design that included alkaloid (GRA or TRP) with or without SAP. In Trial 2 TAN replaced SAP. All foods were isocaloric (3.3 Mcal kg-1) and isonitrogenous (14% crude protein). Foods, fecal and urine samples were collected and analyzed for dry matter intake and apparent digestibility of dry matter, energy (in megajoules, MJ), nitrogen (N), and neutral detergent fiber. RESULTS: Supplemental SAP did not affect digestibility of the parameters tested (P > 0.10). Supplemental TAN increased digestibility of N (g kg-1, P = 0.04), N retained (g day-1, P = 0.07), N digested (g day-1, P = 0.06), and N retained/N consumed (g kg-1, P = 0.07). However, digestibilities of dry matter (g kg-1, P = 0.0026), energy (MJ 1000 MJ-1, P = 0.003), neutral detergent fiber (g kg-1, P = 0.008), and digested N retained (g kg-1, P = 0.07) were lower for lambs fed TAN than for unsupplemented animals. CONCLUSIONS: Tannin supplementation can improve retention of nitrogen in animals fed alkaloid-containing grasses such as reed canarygrass and tall fescue. Combinations of forages with complementary primary and secondary compounds enable animals to maintain intake and improve nutrient utilization. PMID- 22430571 TI - A low thymic function is associated with leukemia relapse in children given T cell-depleted HLA-haploidentical stem cell transplantation. PMID- 22430572 TI - Stannylplumbylenes: bonding between tetravalent tin and divalent lead. AB - Depending on stoichiometry, reactions of the mixed valence Sn(0)/Sn(III) compound Sn(SnAr(3))(2) (1) (Ar = C(6)H(4)(O(i)Pr)(2)-2,6) with the likewise substituted plumbylene PbAr(2) (3) afforded either the homoleptic distannylplumbylene Pb(SnAr(3))(2) (4) or the heteroleptic arylstannylplumbylene Pb(Ar)SnAr(3) (5), a valence isomer of a stannaplumbene. PMID- 22430573 TI - Outcomes of inpatient rehabilitation of patients with multiple sclerosis. AB - BACKGROUND: Several trials have demonstrated improved outcomes following inpatient rehabilitation for Multiple Sclerosis patients. Two populations were studied: patients in relapse and patients with no active medical problems recruited from the community. In every day practice, most admissions for MS inpatient rehabilitation aim to improve function following sudden deterioration. The outcomes of inpatient rehabilitation for this population were never studied. METHOD: Retrospective case note analysis of consecutive admissions of MS patients from 2005 to 2009 to a specialist neurological rehabilitation unit. RESULTS: Forty-one cases were identified. 26 were females. Age 25-71 (mean 52 +/- 12). Disease duration 0-39 years (mean 13 +/- 11). 20 patients were admitted from the community and 21 were transferred from acute hospital beds. Length of stay ranged between 11 to 152 days (mean 49 +/- 36). Mean length of stay for wheelchair dependent patients was approximately double the length of stay for ambulatory patients. Improving mobility, transfer or posture were the primary cause of admissions in 37 cases. Sixteen out of 21 ambulatory patients (76%) attained 100% mobility goals. Only 4 out of 20 wheelchair bound patients (20%) achieved 100% mobility goals (P 0.002). Neither the type of MS nor the duration of it influenced the overall outcome. CONCLUSION: Our results suggest that MS patients admitted for rehabilitation following deterioration secondary to a medical or surgical cause show the same favourable outcome that was demonstrated with MS stable patients or in relapse. Baseline mobility, but not type and duration of MS, seems to have a significant impact on the rehabilitation outcome in terms of gaol achievement. PMID- 22430574 TI - Computer-based training and cognitive improvement after adult-onset malaria: a case report. AB - Malaria infection is known to cause cognitive impairments in children and adults. To date, very little research has investigated the efficacy of computer-based cognitive rehabilitation after cerebral malaria, particularly in adults. The aim of this study was to examine whether computer-based cognitive training can be employed to rehabilitate memory and attentional deficits after cerebral malaria, particularly in adults. The current study examines the case of a 20-year-old female who acquired malaria on trip to Ghana. One year after her infection she still exhibited below-average performance on a number of neuropsychological assessments. A computer-based cognitive training program was undertaken for 14 weeks. At the end of training, performance improved on the majority of assessments and was within the normal range for all assessments. The participant also displayed greater improvements from pre-test to post-test than a normal control participant who did not complete cognitive training. The findings extend prior research on cerebral malaria and suggest possible rehabilitation methods for adults who experience cognitive impairments following malaria infection. PMID- 22430575 TI - A case of anti-NMDAR (N-methyl-D-aspartate receptor) encephalitis: a rehabilitation perspective. AB - Anti-NMDAR (N-Methyl-D-Aspartate Receptor) Encephalitis is a rare occurring autoimmune disease that is mediated by antibodies against the NR1 subunit of the NMDA receptor. While this condition has a known predilection for young females with ovarian tumors, heightened awareness has led to increasing recognition of this condition in other population groups as well. Afflicted patients typically evolve through a multi-staged course of neurological, behavioral, cognitive and physical deficits. The diverse nature of this condition often necessitates a multi-disciplinary team for management. As the recovery of patients with anti NMDAR encephalitis is often protracted, the role of the rehabilitation is important particularly beyond its acute stages. We describe a case of anti-NMDAR encephalitis in a 17-year-old girl who presented to our rehabilitation centre for management in the gradual recovery phase of her condition. This case illustrates the multiple challenges faced in the rehabilitation of such a patient. PMID- 22430576 TI - Motor recovery mechanism in a quadriplegic patient with locked-in syndrome. AB - Locked-in syndrome (LIS) is a rare neurologic condition caused by bilateral pontine lesions. Quadriplegia is one of the most serious clinical manifestations in patients with LIS. However, little is known about the motor recovery mechanism of quadriplegia in patients with LIS. In the current study, we present with a quadriplegic patient with bilateral pontine infarcts, whose motor function appeared to be reorganized into the peri-infarct areas of the infarcted pons, as demonstrated by diffusion tensor tractography (DTT). A 60-year-old was diagnosed as LIS due to bilateral pontine infarcts 6 years ago. The patient presented with complete paralysis of all four extremities at onset. After slow motor recovery, the patient was able to move all joint muscles against gravity and demonstrated some fine motor activity at the time of DTT scanning (6 years after onset). Results of DTTs for the corticospinal tract (CST) in both hemispheres showed that the CSTs originated from the primary motor cortex, descended along the known CST pathway, and passed through lateral areas of infarcts in the pons. Therefore, motor function of the four extremities of this patient appears to have been recovered by the CST, which passed through the lateral areas to the pontine infarcts. PMID- 22430577 TI - Stress, internal resources and functioning in a person with spinal cord disease. AB - INTRODUCTION: Spinal cord lesion due to injury or disease (SCD) has a severe impact on the level of functioning, results in body function impairments, causes restrictions in everyday life, and stress. This stress experience can have an additional negative impact on well-being and health of persons with SCD. Stress reduction is therefore an important aim in order to achieve and maintain health in SCD. Strengthening internal resources of a person can support this endeavor. OBJECTIVE: To describe the role of internal resources for stress reduction as rehabilitation target in the context of interdisciplinary clinical rehabilitation of SCD using ICF-based rehabilitation management tools. METHODS: Single Case Study. RESULTS: Strengthening internal resources contributed to stress reduction in the rehabilitation of a person with SCD. Active involvement in decision taking increased the patient's perceived self-determination and reduced stress. Impairments in urination function remained a major stressor and negatively affected the patient's self-esteem. ICF-based documentation tools highlighted the role of internal resources, stress and functioning in rehabilitation management. CONCLUSION: Internal resources should be strengthened when aiming at stress reduction in a patient with SCD. ICF-based documentation tools support this undertaking. PMID- 22430578 TI - Functional MRI finding by proprioceptive input in patients with thalamic hemorrhage. AB - Little is known about the recovery mechanism of somatosensory function in thalamic hemorrhage. We investigated the recovery mechanism of somatosensory function, using functional MRI (fMRI) findings by proprioceptive input in chronic patients with thalamic hemorrhage. Eleven consecutive chronic patients with thalamic hemorrhage who showed severe proprioceptive dysfunction were recruited. The subscale for kinesthetic sensation of the Nottingham Sensory Assessment (NSA) was used for determination of proprioceptive function. fMRI was performed during passive movements of the metacarpophalangeal joint. From fMRI, the laterality index (LI) was calculated for assessment of the relative activity in the ipsilateral versus the contralateral primary sensori-motor cortex (SM1). The average LI for affected and unaffected hand stimulation was 0.89 and 0.90, respectively, and there was no significant difference between LIs (p> 0.05). In addition, LI of the affected hand stimulation was positively related to NSA scores (r=0.790, p< 0.05). Our results for LI suggest that the cortical activation pattern of SM1 was similar in the affected and unaffected hemispheres. Therefore, it appears that the proprioceptive function of the affected hand likely recovered by the normally existing medial lemniscus and its thalamocortical pathway in our patients. PMID- 22430579 TI - Predictors of long-term health-related quality of life in patients with aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To determine the predictive value of physical and psychological factors assessed three months after aneurysmal subarachnoid hemorrhage (SAH) for health-related quality of life (HRQoL) one year after the SAH. DESIGN: Prospective cohort study. SUBJECTS: Patients with SAH (n=113) who visited our SAH outpatient clinic three months after SAH and who were living independently in the community one year after SAH. METHODS: HRQoL was evaluated using the Stroke Specific Quality of Life scale (SS-QoL). We used Spearman correlations, Somers'd, and linear regression analyses. Independent variables were demographic and SAH characteristics, cognitive and emotional complaints, depressive symptoms, anxiety, cognitive functioning, and passive coping style. RESULTS: In the regression analysis, female gender (beta value -0.17), cognitive complaints ( 0.31 ), cognitive functioning (0.40) and passive coping style (-0.23) were independent predictors, and together explained 45.9% of the variance of the SS QoL total score. CONCLUSION: Female gender, cognitive complaints, cognitive functioning and passive coping style assessed at 3 months after SAH are important predictors of HRQoL 1 year after SAH. Early interventions to improve cognitive and emotional functioning should be evaluated for their ability to improve long term HRQoL after SAH. PMID- 22430580 TI - Motor outcome and motor recovery mechanisms in pontine infarct: a review. AB - Characteristics of motor recovery mechanisms are known to be linked with motor outcome in stroke. Detailed knowledge of motor outcome and recovery mechanisms in stroke allow for prediction of prognosis and provide the basis for establishment of scientific rehabilitation strategies. Thirteen previous studies with regard to motor outcome (8 studies) and the motor recovery mechanisms (5 studies) in pontine infarct were reviewed. Several motor recovery mechanisms have been reported in pontine infarct: peri-lesional reorganization, and other possible recovery mechanisms (aberrant pyramidal tract, ipsilateral motor pathway, and motor recovery via spared corticospinal tract). Previous studies on motor outcome in pontine infarct have reported generally good outcome. This good motor outcome appears to be related to the characteristics of the motor recovery mechanisms recovered by the lateral corticospinal tract. We think that further studies on motor outcome and recovery mechanisms should be performed for clarification of various motor tracts including non-corticospinal tract, which can affect the motor outcome and recovery mechanisms in pontine infarct. In addition, the effect of rehabilitation on these topics should also be elucidated. PMID- 22430581 TI - Towards a mechanism-based view on post-stroke shoulder pain: theoretical considerations and clinical implications. AB - The assessment and treatment of post-stroke shoulder pain (PSSP) is largely based on the assumption that pain is due to biomechanical alterations within the shoulder joint after stroke. However, current treatment often provides limited pain relief, leading to a considerable number of patients with persistent pain. This suggests that PSSP may not be merely due to simple nociception from the shoulder joint. A better understanding of the neurophysiological mechanisms underlying the development and perpetuation of PSSP is needed. Here, a theoretical framework for presumed PSSP mechanisms and their assessment is presented based on key concepts applied in pain research. This theoretical framework assumes that although pain may be localized in one region of the body, the mechanisms causing pain may occur at any level of the somatosensory neuro axis. Detailed assessment of pain complaints and somatosensory abnormalities should, therefore, be a key element in clinical PSSP research. Studies aiming to further characterize somatosensory functions in patients with PSSP (initially) need to take a broad methodological approach including both clinical as well as more experimental pain research tools, such as quantitative sensory testing. A better understanding of pain mechanisms may explain why persistent PSSP and unsatisfactory pain relief are common despite active prevention and treatment strategies and may provide a basis for improved clinical management of PSSP. PMID- 22430582 TI - Plasma cytokine profiles at diagnosis in pediatric patients with non-hodgkin lymphoma. AB - Non-Hodgkin lymphoma (NHL) has been associated with elevated levels of inflammatory and immune-regulating cytokines, and polymorphisms in the genes encoding interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha have been associated with increased incidence of certain subtypes of NHL. The aim of the present study was to screen for a broader spectrum of growth factors and inflammatory mediators and to compare the profiles in different subtypes of NHL in pediatric patients. Serum samples were collected at diagnosis from 31 pediatric patients diagnosed with NHL admitted at Rigshospitalet, Copenhagen, between 1995 and 2008. Cytokines and growth factors were measured in serum using the Luminex platform by application of a 30-plex kit. Levels of IL-6, IL-2R, IL 10, TNF-RI, and macrophage inflammatory protein-1alpha were significantly higher in patients with anaplastic large-cell lymphoma compared with patients diagnosed with B-cell lymphomas and lymphoblastic lymphomas. High levels of IL-4, IL-13, TNF-RI, and epidermal growth factor were associated with a poorer general condition at diagnosis. The present study suggests that NHL subgrouping and the general condition of pediatric patients at diagnosis are associated with plasma levels of growth factors and inflammatory mediators at presentation. PMID- 22430583 TI - Once-daily intravenous busulfan for 47 pediatric patients undergoing autologous hematopoietic stem cell transplantation: a single center study. AB - We report our results using once-daily intravenous (IV) busulfan (Bu)-based conditioning adjusted by weight without drug monitoring as myeloablative conditioning in 47 pediatric patients undergoing first autologous hematopoietic transplantation from 2006 to 2010. Median age was 4 years (range, 1 to 22 y). There were 35 boys and 12 girls. Conditioning was Bu-based in all patients. In medulloblastoma patients (n=12), IV thiotepa at 5 mg/kg/d*2 days was associated with Bu. In solid tumors other than medulloblastoma, IV melphalan was used at 140 mg/m/d*1 day. In lymphoma patients (n=9), IV cyclophosphamide was used at 60 mg/kg/d*2 days. Median number of CD34 cells infused was 4.65*10/kg (range, 1.7 to 58.7*10/kg). Median times to neutrophil and platelet recovery (>20*10/L) were 11 days (range, 8 to 16 d) and 12 days (range, 7 to 135 d), respectively. Median hospitalization time was 14 days (range, 9 to 92 d). Sixteen patients developed grades III and IV mucositis. Only 1 patient developed mild sinusoidal obstruction syndrome. No patient developed seizures or severe neurological complications. With a median follow-up of 18 months, probability of transplantation-related mortality and disease-free survival were 0% and 70%+/-8%, respectively. In conclusion, in our experience, once-daily IV Bu-based conditioning without drug monitoring for autologous hematopoietic transplantation in pediatric patients is a safe and effective regimen with no mortality. PMID- 22430584 TI - Intact survival of refractory CMV limbic encephalitis in a patient with severe aplastic anemia after unrelated bone marrow transplantation. AB - We described a patient of refractory cytomegalovirus (CMV) limbic encephalitis who received matched unrelated bone marrow transplantation. Pyrosequencing study on serial cerebrospinal fluid samples revealed the emergence of resistant strains associated with exposure of antiviral agents. Combinations of antiviral agents had a role in partial suppression of CMV viral load but the clearance of virus mainly relied on the recovery of host's immunity and resulted in intact survival of host. Donor's CMV-seronegative status may contribute to the delay in controlling this serious infection. Prompt identification of drug-resistant mutant helps in selection of antiviral agents. PMID- 22430585 TI - Nasal eschar: a warning sign of potentially fatal invasive fungal sinusitis in immunocompromised children. AB - Most invasive fungal sinusitis occurs in immunocompromised adult patients. We present the case study of a 12-year-old boy diagnosed with acute myeloblastic leukemia undergoing chemotherapy. He developed a progressive darkening discoloration over the dorsum of the nose that turned into an eschar. Nasal endoscopy revealed extensive necrotic tissue in the nasal cavity mucosa, inferior and middle turbinates, and septal cartilage that extended to the eschar of the skin over the nasal dorsum. Histopathology showed aspergillus invasive fungal rhinosinusitis. PMID- 22430586 TI - Pseudotumor cerebri in a Turkish boy with Fanconi anemia. AB - Pseudotumor cerebri (PC) is a clinical syndrome characterized by increased intracranial pressure with a normal cerebrospinal fluid cell count and protein level in the absence of a space-occupying lesion or apparent obstruction to the cerebrospinal fluid pathway. Although PC is described in patients with various hematological diseases including iron-deficiency anemia, megaloblastic anemia, acquired aplastic anemia, hemolytic anemia, sickle cell disease, and paroxysmal nocturnal hemoglobinuria, there is no case of PC with Fanconi anemia in the English literature. Here, we report a first case of PC in an 11-year-old boy with a diagnosis of Fanconi anemia. PMID- 22430587 TI - Avoiding harmful procedures in patients with elevated alpha-fetoprotein concentrations: hereditary persistence of alpha-fetoprotein is an important and benign differential diagnosis! AB - BACKGROUND: Hereditary persistence of alpha-fetoprotein (AFP) is a rare but benign condition. OBSERVATION: A 13-year-old girl presented with dysmenorrhoic complaints and irregular cycles. Diagnostic workup revealed a cystic lesion of the ovary and elevated AFP; beta-human chorionic gonadotrophin was negative. Right-sided ovarectomy was performed. Postsurgery AFP concentration did not decline. The patient underwent further diagnostic workup with negative results. Histology revealed follicular cysts but no tumor. Finally, hereditary persistence of AFP was suspected and AFP testing was performed in the family. CONCLUSIONS: It is important to include hereditary persistence of AFP in the differential diagnosis of elevated AFP concentrations to avoid harmful procedures. PMID- 22430588 TI - Apropos "complete resolution of sickle cell chronic pain with high-dose vitamin D therapy: a case report and review of the literature". PMID- 22430589 TI - PNET spine: morbid and mortal, but ignored till late. AB - Spinal primitive neuroectodermal tumor (PNET) is rare. We present clinical, radiologic profile and treatment outcome of 15 spinal PNET patients from June 2003 to March 2010 treated with chemoradiotherapy. Median duration of backache was 6.5 months; all had features of myelopathy and/or radiculopathy; 5/15 (33.3%) patients were diagnosed initially as spinal tuberculosis. The event-free survival (EFS) was 24.73% at a median follow-up of 22 months. Complete functional recovery to treatment significantly predicted better EFS; 4 patients discontinued treatment because of poor functional recovery. It is important to recognize spinal PNET early to prevent permanent neurological damage, which in turn would improve compliance, quality of life, and perhaps EFS. PMID- 22430590 TI - Rescue by hematopoietic progenitor cells derived from engrafted cord blood unit in a child with brain tumor after transplantation for T-cell acute lymphoblastic leukemia. AB - An 8-year-old boy with T-cell acute lymphoblastic leukemia received unrelated cord blood transplantation in April 2006. His course was uneventful until February 2007, when a hyperintense lesion was noted in the pons. A subsequent bone marrow examination confirmed that he was in remission with full donor chimerism. He was therefore diagnosed with an inoperable brain tumor after cord blood transplantation. Despite radiotherapy for the brain lesion, his neurological status worsened. High-dose chemotherapy with "autologous" progenitor cell rescue was adopted, although the fact that these cells were originally derived from engrafted umbilical cord unit. He was in apparent remission of his brain tumor for 3 years. PMID- 22430591 TI - Peptides binding to prostate-specific antigen enhance its antiangiogenic activity. AB - BACKGROUND: Proteolytically active prostate-specific antigen (PSA or kallikrein related peptidase 3, KLK3) has been shown to exert antiangiogenic properties. High levels of PSA in prostatic tumors may thus slow down cancer progression by inhibiting angiogenesis. We hypothesize that factors stimulating the activity of PSA could be used to reduce prostate tumor growth. Using phage display, we have developed peptides C4 and B2 that stimulate the enzymatic activity of PSA. Our aim was to study whether these peptides enhance the antiangiogenic activity of PSA. METHODS: We used an in vitro angiogenesis assay where human umbilical vein endothelial cells (HUVECs) form tubular networks when they are grown on Matrigel. Proteolytically active PSA and peptides that stimulate the activity of PSA were added to the cells. Endothelial cell tube formation was quantified and expressed as an angiogenesis index. RESULTS: PSA reduced the angiogenesis index to ~50% of controls both in serum-containing and serum-free medium. The addition of peptide C4 or B2 together with PSA caused a significant further decrease in angiogenesis index to ~70% of that caused by PSA alone. A similar decrease in angiogenesis index was observed when PSA concentration was increased 2.4-fold of that used with peptides. CONCLUSIONS: The inhibitory effect of PSA on tube formation can be enhanced by the addition of peptides that stimulate the activity of PSA. This supports our hypothesis that stimulation of PSA activity can be used to reduce angiogenesis and thereby inhibit prostate tumor growth. PMID- 22430592 TI - Diffusion coefficients of water and leachables in methacrylate-based crosslinked polymers using absorption experiments. AB - The diffusion of water into dentin adhesive polymers and leaching of unpolymerized monomer from the adhesive are linked to their mechanical softening and hydrolytic degradation. Therefore, diffusion coefficient data are critical for the mechanical design of these polymeric adhesives. In this study, diffusion coefficients of water and leachables were obtained for sixteen methacrylate-based crosslinked polymers using absorption experiments. The experimental mass change data was interpreted using numerical solution of the two-dimensional diffusion equations. The calculated diffusion coefficients varied from 1.05 * 10(-8) cm(2)/sec (co-monomer TMTMA) to 3.15 * 10(-8) cm(2)/sec (co-monomer T4EGDMA). Correlation of the diffusion coefficients with crosslink density and hydrophilicity showed an inverse trend (R(2) = 0.41). The correlation of diffusion coefficient with crosslink density and hydrophilicity are closer for molecules differing by simple repeat units (R(2) = 0.95). These differences in the trends reveal mechanisms of interaction of the diffusing water with the polymer structure. PMID- 22430593 TI - Fabrication of PU/PEGMA crosslinked hybrid scaffolds by in situ UV photopolymerization favoring human endothelial cells growth for vascular tissue engineering. AB - Poly(ethylene glycol) methacrylate (PEGMA) was introduced into a polyurethane (PU) solution in order to prepare electrospun scaffold with improving the biocompatibility by electrospinning technology for potential application as small diameter vascular scaffolds. Crosslinked electrospun PU/PEGMA hybrid nanofibers were fabricated by a reactive electrospinning process with N,N' methylenebisacrylamide as crosslinker and benzophenone as photoinitiator. The photoinduced polymerization and crosslinking reaction took place simultaneously during the electrospinning process. The electrospinning solutions with various weight ratios of PU/PEGMA were successfully electrospun. No significant difference in the scaffold morphology was found by SEM when PEGMA content was <20 wt%. The crosslinked fibrous scaffolds of PU/PEGMA exhibited higher mechanical strength than the pure PU scaffold. The hydrophilicity of scaffolds was controlled by varying the PU/PEGMA weight ratio. The tissue compatibility of electrospun nanofibrous scaffolds were tested using human umbilical vein endothelial cells (HUVECs). Cell morphology and cell proliferation were measured by SEM, fluorescence microscopy and thiazolyl blue assay (MTT) after 1, 3, 7 days of culture. The results indicated that the cell morphology and proliferation on the crosslinked PU/PEGMA scaffolds were better than that on the pure PU scaffold. Furthermore, the appropriate hydrophilic surface with water contact angle in the range of 55-75 degrees was favorable of improvement the HUVECs adhesion and proliferation. Cells seeded on the crosslinked PU/PEGMA (80/20) scaffolds infiltrated into the scaffolds after 7 days of growth. These results indicated the crosslinked electrospun PU/PEGMA nanofibrous scaffolds were potential substitutes for artificial vascular scaffolds. PMID- 22430594 TI - Prevalence of cardiovascular risk factors amongst traders in an urban market in Lagos, Nigeria. AB - AIMS AND OBJECTIVES: A descriptive cross-sectional study was carried out to determine the prevalence of cardiovascular risk factors amongst traders in an urban market in Lagos State. SUBJECTS AND METHODS: Tejuosho market, one of the large popular markets was selected from a list of markets that met the inclusion criteria of being major markets dealing in general goods using a simple random sampling technique by balloting. Four hundred (400) traders were selected using a systematic random sampling. Each trader was interviewed with a well-structured questionnaire and had blood pressure and anthropometric measurements (height, weight and body mass index). RESULTS: Female traders made up (74.3%) 297 of the total population. The mean age was 45.48+11.88 and 42.29+10.96 years for males and females respectively. Majority 239 (59.8%) fell within the age range of 35 - 55 years. The cardiovascular risk factors identified and their prevalence rates were hypertension (34.8%), physical inactivity (92%), previously diagnosed diabetes mellitus (0.8%), risky alcohol consumption (1%), cigarette smoking (0.3%) in females and (17.5%) in males, obesity (12.3%) and overweight (39.9%). CONCLUSION: The study recommended that any health promoting, preventive or intervention programme for this population would have to be worked into their market activities if it is to make an impact. PMID- 22430595 TI - Accuracy of intra-partum prediction of birth weight using maternal anthropometric parameters. AB - AIMS AND OBJECTIVES: This study aimed at predicting foetal birth weight using various clinical methods and to determine which of the methods is the most accurate in this population. SUBJECTS AND METHODS: Parturients of all parities admitted into the labour ward of OAUTHC, Ile-Ife at term for delivery were recruited for this study. They had their symphysiofundal height, abdominal circumference at the umbilical level, height and weight measured. The body mass index was then calculated. The birth weight was calculated from these measurements using four clinical formulae. The weights of the babies were measured after delivery and compared with the individual estimated birth weights. RESULTS: There were 400 women who met the inclusion criteria during the time of this study. Three of the methods [Johnson's Rule, Ojwang's Rule and 5% maternal weight] overestimated the birth weight while 10% BMI underestimated the birth weight significantly. CONCLUSION: There is a strong correlation between the birth weights predicted by the various clinical methods and the actual birth weight. The accuracy of the methods can be improved by using the derived modified formulae. PMID- 22430596 TI - Benign prostate hyperplasia: average volume in southwestern Nigerians and correlation with anthropometrics. AB - AIMS AND OBJECTIVES: To determine the prevalent age of symptomatic benign prostate hyperplasia (BPH), the average BPH volume, and the association between BPH volumes and the age, and anthropometrics. PATIENTS, MATERIALS AND METHODS: Selected patients with lower urinary tract symptoms (LUTS) due to BPH with tissue diagnosis, and adult men of similar age group with no irritative or obstructive LUTS were prospectively studied from July 2003 to June 2009. The age, height and weight were recorded; prostate volumes determined with ultrasound, body mass index (BMI) calculated, and correlations determined between the prostate volume, the age and anthropometrics. RESULTS: One hundred and five patients aged 43 88years (mean=64.4, 8.88SD) managed for BPH were studied with 93 asymptomatic men aged 43-80years (mean=56.15, 9.89SD). The mean (SD) prostate volume, height, weight and BMI were 83.8(37.7) ml, 1.67(0.07) m, 63.6(9.32) kg and 22.8(3.03) kg/m2, and 24.5(9.2) ml, 1.69(0.06) m, 68.9(10.6) kg and 24.2(3.44) kg/m2 respectively for symptomatic and asymptomatic groups. In the symptomatic group, BPH volume showed significant positive correlation with the age (p=0.030), but no correlation with the weight (p=0.550), height (p=0.375) and BMI (p=0.840). In the asymptomatic group, prostate volume also showed significant positive correlation with the age (p=0.041), but no correlation with the weight (p=0.434), height (p= 0.394), and BMI (p=0.203). CONCLUSION: The prevalent age of symptomatic BPH in our community is 43-88years with 83.79(37.66) ml mean (SD) volume in symptomatic patients and 24.45(9.21) ml in asymptomatic men. BPH volume correlates with age but not with anthropometrics. Lack of correlation with BPH volume suggests that anthropometrics may not be risk factors for development of BPH. PMID- 22430597 TI - Frequency of distribution of oestrogen and progesterone receptors positivities in breast cancer cases in Benin-City, Nigeria. AB - AIMS AND OBJECTIVES: The aim of this study is to determine the prevalence of oestrogen and progesterone receptors positivities among histologically diagnosed breast cancer cases at the University of Benin Teaching Hospital, Benin City, Nigeria. MATERIALS AND METHODS: Cases of breast carcinomas in the records of the Department of Histopathology, University of Benin Teaching Hospital, between 2003 and 2007 constitute the materials used for this study. Immunohistochemical staining was done using representative paraffin-embedded blocks (H&E slides assessment) and stained with oestrogen and progesterone antibodies manufactured by Dako Denmark (AS Denmark). RESULTS: A total of 135 cases were studied. The female to male ratio was 44:1 with an overall mean age of 48.3+/-13 years. Invasive ductal carcinoma, NOS (not otherwise specified) was the most common histological type (81.5%). Eighty per cent of cases were categorised as grades 2 and 3 tumours. The steroid hormone receptor positivity was 17%. Oestrogen and Progesterone receptor positivity were 14.1% and 9.6% respectively. There was a statistically significant association between hormone receptor status and the grade of tumour (?2 = 6.37, df = 2, p = 0.04). CONCLUSION: This study shows a relatively low steroid hormone receptor positivity of breast cancer in Benin. This finding portends a poor prognostic effect and it is consequently recommended that steroid hormone receptor status be determined before hormonal treatment in these patients. There is the need to determine the immunohistochemical patterns of breast cancer in other centres that treat breast cancer patients. PMID- 22430598 TI - Fertility regulation among women of reproductive age in Ibadan, south-west Nigeria: contraception, abortion or both. AB - OBJECTIVES: To assess the role of contraception and abortion in fertility regulation amongst Southwestern Nigerian women. SUBJECTS AND METHODS: A survey was conducted through a self- administered questionnaire to women of reproductive age group attending gynecology clinic. Multinominal logistic regression was done to analyze the independent effects of social and demographic variables on the odds that women would adopt any fertility regulation methods instead of doing nothing. RESULTS: Only 13% of surveyed women were using modern contraception. About 42.2% of women had had induced abortion, 15% of them neither use contraception nor abortion. Fifteen per cent of women surveyed used both contraception and abortion for fertility control. Muslims women had lower odds than Christians to use any of three fertility regulation methods instead of doing nothing. Unmarried and high levels of educational attainment were associated with significant odds of adopting each of three fertility regulation methods (Odd ratios; 1.38 - 35.5). CONCLUSIONS: There is a need for better fertility regulation. High dependency on abortion especially among the young, unmarried and high level educational status should be discouraged. Government and non governmental agencies should assist in making modern contraceptives widely available with adequate rural coverage. PMID- 22430599 TI - Bacteriological agents of chronic discharging ears and their antibiotic sensitivity pattern in Ido - Ekiti, Nigeria. AB - AIMS AND OBJECTIVES: To identify bacterial agents of chronic discharging ear and determine their antibiotic sensitivities pattern in Ido - Ekiti, Nigeria. PATIENTS AND METHODS: Swab specimens of each chronically (>8 weeks) discharging ears of patients with chronic suppurative otitis media (CSOM) presenting to the Ear, Nose and Throat (ENT) clinic of the Federal Medical Centre, Ido Ekiti were bacteriologically cultured aerobically and the antibiotic sensitivity pattern of the recovered organisms determined by the modified Kirby-Bauer disc-diffusion method over a three year period starting from January 2005. RESULTS: Seventy eight patients with CSOM whose age ranged between 3 months and 85 years were seen during the study period with 73.1% of them having unilateral disease and majority were children < 15 years (71.8%). Out of 99 ear swabs that were examined, 87.9% were culture positive with 90.8% yielding a single isolate. Coliforms (34.7%) were the most frequent isolated group of organisms. Other isolates included Staphylococcus aureus (26.3%), Proteus spp (24.2%), Pseudomonas spp (9.5%) and Klebsiella spp (5.3%). Sparfloxacin and ciprofloxacin showed highest activity on all the isolates unlike cefuroxime and ceftiaxone to which all isolates were resistant. CONCLUSION: Chronic discharging ear is caused by bacteria agents most sensitive to quinolones but resistant to cefuroxime and ceftiaxone. Treatment of patients with CSOM in Ido-Ekiti with the quinolones is recommended except where contraindicated. PMID- 22430600 TI - Risk factors and seroprevalence of hepatitis C virus antibody among blood donors in Lagos. AB - AIMS AND OBJECTIVES: This study was undertaken (i) to determine the seroprevalence of antibodies to Hepatitis C virus (anti -HCV) among blood donors (ii) to document the incidence of known risk factors for HCV infection among blood donors. PATIENTS AND METHODS: This is a cross sectional prospective study among apparently normal blood donors. Subjects were recruited from three different hospitals in Lagos metropolis. All recruited donors were evaluated for HCV infection- associated risk factors by questionnaire interviews. Sera samples from recruited donors were tested for anti-HCV using third generation Murex (Murex Biotech, South Africa) and fourth generation Dialab Enzyme Linked Immunosorbent Assay (ELISA) kits (Dialab. Austria). RESULTS: A total of three hundred and thirty four blood donors were screened, of which seven (2.1 %) were positive for anti-HCV. The blood donors comprised 15 (4.5 %) females and 319 (95.5 %) males. There was an association between anti-HCV positivity and history of multiple sex partners and previous sexually transmitted infections (X2-15.9; p < 0.05) Majority of blood donors were family replacement 317 (94.9 %) with anti HCV prevalence of 2.2 % (7/317) while 5.1 % (17/334) were voluntary non remunerated with anti-HCV prevalence of 0% (p >0.05) CONCLUSION: Prevalence of anti-HCV among blood donors in Lagos (2.1%) is low as in most previous reports from Nigeria and some other parts of Africa. PMID- 22430601 TI - An overview of biological basis of pathologic scarring. AB - AIMS AND OBJECTIVES: To review the current mechanisms and biologic processes leading to the formation of pathologic scars. MATERIALS AND METHODS: A computerised literature search was carried out using MEDLINE for all published articles on ''pathologic scarring''. The medical subject headings ''scarring'' were combined with ''mechanisms''. A review of selected relevant literature was then undertaken. RESULTS: Scarless embryonal healing tends to be characterised by minimal inflammatory reaction mediated by reduced IL6,IL8 and hyaluronidase while there are elevated levels of hyaluronic acid MMP1to3, as well as IL10.The multifunctional cytokine TGF-B, its several isoforms as well as its postreceptor signalling mechanisms appears to play the key role in the scarring process . There is also evidence to show that PDGF, IGF and other cytokines regulate scarring . While conventional antiscarring agents target the fibroplasia phase, others such as tamoxifen ,calcium channel blockers, and imidazolaquinolines targets various phases of the scarring process . CONCLUSION: It appears that multiple mechanisms are involved in the phenotypical appearance of abnormal scarring. A deeper understanding of these mechanisms is pivotal to the development of better antiscarring therapies in the very near future . PMID- 22430602 TI - Widespread endometriosis mimicking ovarian malignancy: a case report. AB - A 26 year old Nigerian nulliparous woman who presented in the medical emergency unit of a teaching hospital was referred after two weeks of management to the gynecology casualty with a diagnosis of malignant left ovarian cyst, because of the ascites, massive haemorrhagic pleural effusion, a left ovarian mass and an elevated C-125 marker. However, exploratory laparotomy, cytologic and histological examination of the pleural fluid and biopsied specimens revealed endometriosis. We present a case of intra and extra-pelvic endometriosis which simulated a malignant ovarian lesion and was histologically confirmed by cytology of the haemorrhagic pleural effusion and biopsy of the ovarian mass and peritoneal deposits obtained at laparotomy. This is to draw the attention of clinicians to endometriosis as a cause of pleural effusion, ascites and groin swelling which can simulate ovarian cancer. PMID- 22430603 TI - Testicular schistosomiasis: a case report. AB - AIMS AND OBJECTIVES: To report a case of testicular Schistosomiasis with a suspicion of testicular cancer. PATIENT AND METHODS: Hospital record of a 16 year old patient with histopathology confirmation of testicular Schistosomiasis was reviewed and summarised. The patient who had painless testicular nodules and ultrasound features of heterogenous echotexture and hypoechoic focus was diagnosed as testicular cancer and treated with radical orchidectomy. Histopathology confirmed testicular Schistosomiasis and the patient had additional praziquantel therapy. RESULTS: Patient was followed up for over 26months post-operative. CONCLUSIONS: Testicular Schistosomiasis can mimick malignant testicular tumour. Hard nodular testicular mass in a patient with recent past history of schistosomiasis should arouse suspicion of testicular Schistosomiasis. Awareness and early presentation will prevent unwarranted orchidectomy. PMID- 22430604 TI - Abstracts of the American Society for Laser Medicine and Surgery. April 18-22, 2012. Kissimmee, Florida, USA. PMID- 22430605 TI - Fasting APO B48 levels are associated with microalbuminuria in patients with type 2 diabetes. AB - In view of the high incidence of macrovascular diseases in patients with type 2 diabetes mellitus and microalbuminuria, the study evaluates the association of microalbuminuria with fasting plasma Apo B48 levels, a marker of the residual presence of intestinally derived TRLs lipoproteins, thought to be highly atherogenic. We studied 50 patients with type 2 diabetes aged 35-75 years. Exclusion criteria were overt macrovascular disease, overt nephropathy (Glomerular filtration rate (GFR) <45 ml/min/1.73 m(2)), or use of hypolipidemic agents. Anthropometry, fasting plasma lipids, plasma creatinine, and HbA1c were measured. Urinary albumin excretion was measured on a morning urine sample with the ELISA and expressed as albumin/creatinine ratio. GFR was estimated using the MDRD formula. The plasma fasting Apo B48 was measured by ELISA. Age, gender distribution, fasting plasma lipids, HbA1c, smoking status, plasma creatinine, estimate GFR, and the proportion of patients treated with insulin or antihypertensive drugs were similar for patients with or without microalbuminuria. People with microalbuminuria had longer diabetes duration (borderline significance) and significantly higher Apo B48 (1.765 +/- 1.379 MUg/ml vs. 1.022 +/- 0.692 MUg/ml, p = 0.01) than those without microalbuminuria. Multivariate logistic regression analysis confirmed that fasting Apo B48 levels were significantly associated with microalbuminuria independent of major confounders measured in the study. In patients with type 2 diabetes, microalbuminuria is associated with elevated Apo B48 levels, independent of major confounders; this may partly explain the excess cardiovascular risk of these patients. PMID- 22430606 TI - Modeling and computations of the intramolecular electron transfer process in the two-heme protein cytochrome c(4). AB - The di-heme protein Pseudomonas stutzeri cytochrome c(4) (cyt c(4)) has emerged as a useful model for studying long-range protein electron transfer (ET). Recent experimental observations have shown a dramatically different pattern of intramolecular ET between the two heme groups in different local environments. Intramolecular ET in homogeneous solution is too slow (>10 s) to be detected but fast (ms-MUs) intramolecular ET in an electrochemical environment has recently been achieved by controlling the molecular orientation of the protein assembled on a gold electrode surface. In this work we have performed computational modeling of the intramolecular ET process by a combination of density functional theory (DFT) and quantum mechanical charge transfer theory to disclose reasons for this difference. We first address the electronic structures of the model heme core with histidine and methionine axial ligands in both low- and high-spin states by structure-optimized DFT. The computations enable estimating the intramolecular reorganization energy of the ET process for different combinations of low- and high-spin heme couples. Environmental reorganization free energies, work terms ("gating") and driving force were determined using dielectric continuum models. We then calculated the electronic transmission coefficient of the intramolecular ET rate using perturbation theory combined with the electronic wave functions determined by the DFT calculations for different heme group orientations and Fe-Fe separations. The reactivity of low- and high-spin heme groups was notably different. The ET rate is exceedingly low for the crystallographic equilibrium orientation but increases by several orders of magnitude for thermally accessible non-equilibrium configurations. Deprotonation of the propionate carboxyl group was also found to enhance the ET rate significantly. The results are discussed in relation to the observed surface immobilization effect and support the notion of conformationally gated ET. PMID- 22430607 TI - Optimal exploitation for a commercial fishing model. AB - A two non-linear dynamic models, first one in two state variables and one control and the second one with three state variables and one control, are presented for the purpose of finding the optimal combination of exploitation, capital investment and price variation in the commercial fishing industry. This optimal combination is determined in terms of management policies. Exploitation, capital and price variation are controlled through the utilization rate of available capital. A novel feature in this model is that the variation of the capital depends on the income. PMID- 22430608 TI - Comparison on therapeutic effects of RFT and RCTVP regimen in the treatment of patients with indolent B-cell lymphoma in China. AB - To compare the efficacy and safety of RFT (retuximab, fludarabine, pirarubicin) with RCTVP (retuximab, cyclophophamide, pirarubicin, vindesine and prednisone) in 248 indolent B-cell non-Hodgkin's lymphoma (NHL) patients. Two hundred and forty eight patients with indolent B-cell NHL were treated with combined chemotherapy, including RFT and RCTVP, from January 2002 to December 2010 in Tianjin Cancer Hospital. The rate of response, toxicity and long-term survival for the two regimens were analyzed retrospectively. For the previously untreated patients, overall response rate for RFT arm and RCTVP arm was 71.7 and 70.6%, and complete response rate was 47.5 and 54.9%, respectively (P>0.05). For the refractory and relapsed patients, overall response (OR) rate and complete response (CR) rate were significantly improved in the RFT arm versus the RCTVP arm (P<0.05). There were no statistically significant differences in overall survival (OS) between treatment groups. Comparing with RCTVP regimen, fludarabine-based treatment was associated with superior PFS both in previously untreated, refractory and relapsed patients. WHO grades 3 and 4 hematological adverse events were more common in the RFT arm. Neurotoxicity was more common in the RCTVP arm. For the previously untreated patients, there was no difference between RFT arm and RCTVP arm on OR and CR rates. For the refractory and relapsed indolent B-cell NHL patients who received RFT regimen achieved higher OR and CR rates compared with RCTVP-treated patients. No differences in OS were noted. RFT regimen was associated with superior PFS both in previously untreated, refractory and relapsed patients. RFT regimen is effective and well tolerated for patients with untreated, refractory and relapsed indolent B-cell NHL. PMID- 22430609 TI - Exponential synchronization of stochastic Cohen-Grossberg neural networks with mixed time-varying delays and reaction-diffusion via periodically intermittent control. AB - The issue of exponential synchronization for Cohen-Grossberg neural networks with mixed time-varying delays, stochastic noise disturbance and reaction-diffusion effects is investigated. An approach combining Lyapunov stability theory with stochastic analysis approaches and periodically intermittent control is taken to investigate this problem. The proposed criterion for exponential synchronization generalizes and improves those reported recently in the literature. This paper also presents an illustrative example and uses simulated results of this example to show the feasibility and effectiveness of the proposed scheme. PMID- 22430610 TI - [Food-associated anaphylaxis. Data from the anaphylaxis registry]. AB - Severe allergic reactions are reported to the anaphylaxis registry in German speaking countries. The data provides knowledge regarding the diagnosis and management of patients suffering from anaphylaxis. The ranking of the most frequent elicitors inducing anaphylaxis is age-dependent and also influenced by the group which is reporting the data. The list of food allergens inducing anaphylaxis also varies with age. In children and adolescents peanuts are common elicitors of food-dependent anaphylaxis: in adults wheat is the most frequent cause. Furthermore, the data from the anaphylaxis registry provides information about rare triggers, as well as alerting us to those causative agents which are increasing in frequency. The relevance of augmentation factors is most likely age dependent, whereas co-morbidities including atopic diseases like atopic dermatitis and allergic asthma occur frequently in children suffering from food dependent anaphylaxis. The present manuscript provides data on food allergens such as peas and cauliflower, which have been reported as rare causes of anaphylaxis. PMID- 22430611 TI - [NK/T-cell lymphoma, nasal type with cutaneous dissemination]. AB - Extranodal NK/T-cell lymphoma, nasal type, is a lymphoproliferative disorder originating from peripheral T-cells or natural killer (NK) cells. While it is a rare disease in Europe, it is more frequent in Asia and South America. It is associated with Epstein-Barr virus (EBV) infection and characterized by an extremely aggressive course and poor prognosis. We report a 46-year-old Caucasian woman who presented with multiple subcutaneous, painful nodules on the trunk first noticed a few weeks earlier. In addition to dermatological findings, the patient reported a 4-months history of necrotizing nasopharyngeal inflammation of unclear origin. Due to nonspecific histological and clinical findings mimicking a chronic inflammatory condition, a diagnosis of Wegener disease was made and immunosuppressive therapy with azathioprine was initiated. However the disease progressed under therapy. Histopathological reevaluation and immunophenotyping revealed a disseminated NK/T-cell lymphoma, nasal type. In the case of an unspecific chronic inflammatory process in the nasopharyngeal space one should always consider the possibility of this rare lymphoma, even in Europe. PMID- 22430612 TI - [Epithelioid sarcoma of the right hand]. AB - A 35-year-old man presented with swelling, indurations and nodules on the thumb, wrist and fingers of the right hand. History revealed that the findings were slowly progressive and had been present for at least eight years. Histopathologic analysis of a nodule showed a diffuse infiltrate with atypical spindle-shaped cells and expression of cytokeratin, epithelial membrane antigen (EMA) and CD34; the diagnosis of epithelioid sarcoma (ES) was made. Because of diffuse extension of the tumor, forearm amputation was performed along with axillary dissection and local radiotherapy because of axillary lymph node metastases. ES is a rare subtype of soft tissue sarcoma with a harmless appearance and indolent course over years. ES represents a diagnostic challenge, with consequent delay in diagnosis and adequate treatment. The most important measure in the treatment of ES is early surgical excision with adjuvant radiotherapy if local metastases are present. PMID- 22430613 TI - Elafin selectively regulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis. AB - OBJECTIVE: Elafin has been reported to be abundantly expressed in human epithelial ovarian carcinoma (EOC), however, its functions are poorly understood. Here, we evaluated the role of elafin in modulating the sensitivity of human EOC cells to chemotherapeutic drugs. METHODS: Elafin expression was determined by ELISA in 9 established human EOC cell lines. A lentivirus encoding elafin specific shRNA was used to down-regulate elafin expression in OVCAR3 and OV433 cells, and a plasmid encoding elafin was used to ectopically express elafin in elafin-negative SKOV3 cells. Sensitivity to cisplatin and other genotoxic agents and to paclitaxel, an inhibitor of microtubule depolymerization, was examined in OVCAR3, OV433 and SKOV3 sublines. Cell viability was determined by the MTT assay, apoptosis by annexin V/7-AAD staining and caspase activation by fluorimetric assay. RESULTS: Knockdown of the elafin gene decreases cisplatin IC50 by at least 2-folds in OVCAR3 and OVCAR433 cells (p<0.01) but does not affect paclitaxel IC50. The sensitivity to other genotoxic agents such as carboplatin, cyclophosphamide and 5-fluorouracil was also increased by silencing the expression of elafin. Apoptosis and caspase-3 activation were significantly augmented in cisplatin-treated OVCAR3 cells with silenced elafin. Overexpression of elafin in SKOV3 cells made them more resistant to cisplatin and decreased cisplatin-induced apoptosis and caspase activation (p<0.01). CONCLUSIONS: Expression of elafin decreases the sensitivity of human EOC cells to several genotoxic agents, which may have an important implication in predicting the response of patients with EOC to chemotherapy in the clinic. PMID- 22430614 TI - Reproductive outcomes of patients undergoing radical trachelectomy for early stage cervical cancer. AB - OBJECTIVE: To report the reproductive outcomes of patients undergoing fertility preserving radical trachelectomy (RT) for the treatment of early-stage cervical cancer. METHODS: We analyzed data from our institution's first 105 patients who underwent attempted fertility-sparing surgery with radical trachelectomy, pelvic lymphadenectomy, and cerclage from November 2001 to October 2010. RESULTS: Of the 105 patients who underwent attempted RT, 77 (73%) did not require a conversion to radical hysterectomy or postoperative treatment. The median age was 32 (range, 25 38 years). Most patients (75%) had stage IB1 disease. Sixty-six patients (63%) were nulliparous. Thirty-five women were actively attempting conception 6 months after surgery, and 23 (66%) women were successful in conceiving: there were 20 live births, 3 elective terminations, and 4 spontaneous miscarriages. Four patients had 2 pregnancies each; all delivered their second pregnancy between 32 and 36 weeks. Cerclage erosion through the vaginal wall occurred in 6 cases and was treated by transvaginal removal of protruding suture material. One of these patients experienced a second trimester miscarriage. CONCLUSIONS: The majority of women who attempted to conceive after radical trachelectomy were successful, and most of their pregnancies resulted in full-term births. Assisted reproduction played an important role in select women. Cerclage likely contributed to a post trachelectomy uterine ability to carry a pregnancy to the third trimester. The second post-trachelectomy pregnancy appears to be at higher risk for preterm delivery than the first pregnancy. PMID- 22430615 TI - Influence of rootstock on drought response in young 'Gale Gala' apple (Malus domestica Borkh.) trees. AB - BACKGROUND: Drought is a major environmental stress limiting plant growth, productivity, and survival worldwide. Rootstocks are widely used to enhance plants resistance to drought stresses. This study determined influence of rootstock on drought responses in 1-year-old 'Gale Gala' apple trees grafted onto Malus sieversii or M. hupehensis. RESULTS: Choice of rootstock resulted in differential response to drought stress. Specifically, M. sieversii caused less drought-induced reduction in relative growth rate, biomass accumulation, leaf area, leaf chlorophyll content, relative water content, photosynthesis rate and maximum chlorophyll fluorescence yield but greater increase in whole-plant water use efficiency compared to M. hupehensis. Secondly, compared with M. hupehensis, M. sieversii caused less drought-induced accumulation of reactive oxygen species but more increase in activities of antioxidant enzymes. In addition, xylem sap abscisic acid concentration was greater in trees grafted onto M. hupehensis than in those grafted onto M. sieversii under drought stress. CONCLUSION: 'Gale Gala' trees' response to drought stress was associated with the rootstock's genotype onto which it was grafted. Trees with M. sieversii as rootstock are more drought resistant than trees with M. hupehensis as rootstock, which suggests that M. sieversii can be widely used as rootstock in arid and semi-arid regions. PMID- 22430616 TI - Systematic review and meta-analysis of somatostatin analogues for the treatment of pancreatic fistula. AB - BACKGROUND: Somatostatin analogues are used for the treatment of pancreatic fistula, with the aim of achieving fistula closure or reduction of output. METHOD: MEDLINE, Embase and Cochrane databases were searched systematically for relevant articles followed by hand-searching of reference lists. Data on patient recruitment, intervention and outcome were extracted and meta-analysis performed where reasonable. RESULTS: Seven randomized clinical trials met the inclusion criteria and included a total of 297 patients with fistulas of the gastrointestinal tract; of these, 102 patients had fistulas of pancreatic origin. Pooling of closure rates showed no significant difference between patients treated with somatostatin analogues compared with controls: odds ratio 1.52 (95 per cent confidence interval 0.88 to 2.61). Owing to inconsistent descriptions, pooling of results was not possible for other endpoints, such as time to fistula closure. CONCLUSION: There is no solid evidence that somatostatin analogues result in a higher closure rate of pancreatic fistula compared with other treatments. PMID- 22430617 TI - Efficient automatic classifiers for the detection of A phases of the cyclic alternating pattern in sleep. AB - This study aims to develop an automatic detector of the A phases of the cyclic alternating pattern, periodic activity that generally occurs during non-REM (NREM) sleep. Eight polysomnographic recordings from healthy subjects were examined. From EEG recordings, five band descriptors, an activity descriptor and a variance descriptor were extracted and used to train different machine-learning algorithms. A visual scoring provided by an expert clinician was used as golden standard. Four alternative mathematical machine-learning techniques were implemented: (1) discriminant classifier, (2) support vector machines, (3) adaptive boosting, and (4) supervised artificial neural network. The results of the classification, compared with the visual analysis, showed average accuracies equal to 84.9 and 81.5% for the linear discriminant and the neural network, respectively, while AdaBoost had a slightly lower accuracy, equal to 79.4%. The SVM leads to accuracy of 81.9%. The performance achieved by the automatic classification is encouraging, since an efficient automatic classifier would benefit the practice in everyday clinics, preventing the physician from the time consuming activity of the visually scoring of the sleep microstructure over whole 8-h sleep recordings. Finally, the classification based on learning algorithms would provide an objective criterion, overcoming the problems of inter-scorer disagreement. PMID- 22430618 TI - Effect of membrane properties on skeletal muscle fiber excitability: a sensitivity analysis. AB - In this study, the sensitivity of skeletal muscle fiber excitability to changes in temperature and a range of geometrical, electrical and ionic membrane properties was examined using model simulation. A mathematical model of the propagating muscle fiber action potential (AP) was used to simulate muscle fiber APs while changing individual muscle fiber parameters in isolation to examine how they affect muscle fiber AP amplitude, shape and conduction velocity (CV). The behavior of the model was verified by comparison with previously reported experimental data from both in vivo studies conducted at physiological temperatures and in vitro and in silico studies conducted at lower temperatures. The simulation results presented demonstrate the sensitivity of AP amplitude, shape and CV and, therefore, muscle fiber excitability to small changes in a wide range of different muscle fiber parameters. Furthermore, they demonstrate the potential of computational modeling as a tool for investigating the underlying mechanisms of complex phenomena such as those which govern skeletal muscle excitation. PMID- 22430619 TI - Transportation safety for children with special healthcare needs. PMID- 22430620 TI - Applying basic principles of child passenger safety to improving transportation safety for children who travel while seated in wheelchairs. AB - Occupant restraint systems are designed based on knowledge of crash dynamics and the application of proven occupant-protection principles. For ambulatory children or children who use wheelchairs but can transfer out of their wheelchair when traveling in motor vehicles, there is a range of child safety seats that comply with federal safety standards and that therefore offer high levels of crash protection. For children who remain seated in wheelchairs for travel, the use of wheelchairs and wheelchair tiedown and occupant restraint systems (WTORS) that comply with voluntary industry standards significantly enhances safety. Revisions to the initial versions of these standards will further improve safety for smaller children who travel seated in wheelchairs by requiring wheelchairs for children between 13 and 22 kg (18 and 50 lb) to provide a five-point, wheelchair integrated crash-tested harness similar to that used in forward-facing child safety seats. While wheelchair and tiedown/restraint manufacturers, van modifiers, transportation personnel, clinicians, and others involved with children who use wheelchairs have clearly defined responsibilities relative to providing these children with safe transportation, parents and caregivers should be knowledgeable about best-practice in wheelchair transportation safety and should use this knowledge to advocate for the safest transportation possible. PMID- 22430621 TI - Guidelines for the use of wheelchair postural support devices during travel in motor vehicles. AB - Questions are often raised about whether the use of postural support devices while seated in a wheelchair during travel in a motor vehicle can have potential benefits or result in harm. The benefits or harm are generally unknown as current crash-test dummies are not designed to evaluate postural supports, and there are little to no injury data for these devices in the motor-vehicle environment. Despite these limitations, guidelines and best practices can be developed for use of postural support devices during travel in a motor vehicle using basic principles of occupant protection and knowledge about injury biomechanics. This document presents guidelines and recommendations for postural support devices used on wheelchairs that also serve as seats in motor vehicles. It addresses the basic principles of safe transportation for wheelchair-seated occupants and provides guidelines and recommendations for use of specific devices during transportation. PMID- 22430622 TI - School bus transportation for students seated in wheelchairs. AB - For children with Individualized Education Plans (IEPs), transportation is considered a related service and a part of their education. This paper presents an overview of the current status of wheelchair transportation for students on school buses within the United States. The review includes the school transportation environment for wheelchair-seated students, applicable regulations and voluntary standards, primary safety issues for wheelchair-seated students, and key stakeholders roles in improving wheelchair transportation safety. Future actions to improve wheelchair transportation safety in school transportation are discussed, including the need to improve data collection, mandate payment for and use of RESNA WC19-compliant wheelchairs, improve training for bus operators and attendants, and require specialty certification for school bus operators who transport wheelchair-seated students. PMID- 22430623 TI - Wheelchair transportation safety on school buses: stakeholder recommendations for priority issues and actions. AB - This paper presents results from and provides discussion of a state-of-the science workshop in which highly informed stakeholders in wheelchair transportation safety for students on school buses were participants. The Nominal Group Technique was used to create a process in which the main issues preventing safe transportation of wheelchair-seated students and key strategies to overcome these issues were identified and ranked. These results, along with a synthesis of group discussion and recommendations for action, are presented along with consideration of current policies, regulations, and political realities. Critical safety shortcomings exist in this highly specialized enterprise that varies from state to state. Recommended strategies include implementing wheelchair requirements in federal transportation safety standards, creation of a clearinghouse for wheelchair transportation best practices and education, creation of national standards for training, practices, and monitoring, and increased "buy-in" to voluntary wheelchair standards by wheelchair manufacturers. PMID- 22430624 TI - Issues and approaches to safely transporting children with special healthcare needs. AB - Transporting children with special health care needs (CSHCN) may be complex and require a multidisciplinary approach to improve a child's comfort and safety. This review (adapted from the resource manual of the National Center for the Safe Transportation of Children with Special Health Care Needs.) will discuss the basic principles of child passenger safety for CSHCN, including types of child occupant restraints, the use of child occupant restraint devices (CRD) for selected CHSCN, and how to locate or, if needed, develop programs to train child passenger safety technicians (CPST) to help with safe transportation of CSHCN. PMID- 22430625 TI - Development of an alternative five-point restraint harness to accommodate children with special healthcare needs in child safety seats. AB - Commercial automotive child restraint systems (CRSs) do not accommodate all children with special healthcare needs. This study developed an alternative harness for a commercial CRS to meet the needs of children for whom a five-point harness cannot be positioned over medically involved areas and/or children whose conditions require the harness belts to be threaded through medical devices. After initial design work and a series of frontal sled-impact tests, one of two prototype designs was chosen for fit testing on children with and without healthcare conditions. After a minor modification, additional sled-impact testing was conducted to determine compliance of the system to federal standards. The CRS with alternate harness provides good fit to children with a variety of healthcare needs and complies with all performance criteria of FMVSS 213, with the exception of peak forward head excursion using the Hybrid III 6-year-old crash-test dummy. It is expected that all performance criteria will be met using the newly-issued federal allowance to conduct CRS frontal-impact tests using an earlier version of the dummy. The new harness shows promise as a low-cost solution for achieving a safer level of transportation for children who may otherwise travel unrestrained or with a severely misused CRS harness. PMID- 22430627 TI - Quantitative imaging of mitochondrial and cytosolic free zinc levels in an in vitro model of ischemia/reperfusion. AB - The role of zinc ion in cytotoxicity following ischemic stroke, prolonged status epilepticus, and traumatic brain injury remains controversial, but likely is the result of mitochondrial dysfunction. We describe an excitation ratiometric fluorescence biosensor based on human carbonic anhydrase II variants expressed in the mitochondrial matrix, permitting free zinc levels to be quantitatively imaged therein. We observed an average mitochondrial matrix free zinc concentration of 0.2 pM in the PC12 rat pheochromacytoma cell culture line. Cytoplasmic and mitochondrial free zinc levels were imaged in a cellular oxygen glucose deprivation (OGD) model of ischemia/reperfusion. We observed a significant increase in mitochondrial zinc 1 h following 3 h OGD, at a time point when cytosolic zinc levels were depressed. Following the increase, mitochondrial zinc levels returned to physiological levels, while cytosolic zinc increased gradually over a 24 h time period in viable cells. The increase in intramitochondrial zinc observed during reoxygenation after OGD may contribute to bioenergetic dysfunction and cell death that occurs with both in vitro and in vivo models of reperfusion. PMID- 22430628 TI - CA215 and GnRH receptor as targets for cancer therapy. AB - Two monoclonal antibodies (Mabs), RP215 and GHR106, were selected for the preclinical evaluations of anti-cancer drugs targeting various human cancers including those of the ovary, cervix, lung, and liver. Both Mabs were shown to react with pan cancer markers, which are over-expressed on the surface of almost all human cancers. RP215 Mab was shown to react with the carbohydrate-associated epitope(s) of cancer cell-expressed glycoproteins, mainly consisting of immunoglobulin superfamily (IgSF) proteins and mucins, generally known as CA215. GHR106 Mab was generated against the extracellular domain of human GnRH receptor, which is also highly expressed on the cancer cell surface. Preclinical studies were performed to evaluate the efficacy of these two Mabs as anti-cancer drugs for treating human cancers. High tumor specificity of RP215 Mab was demonstrated with immunohistochemical staining studies of various cancer cell lines, as well as normal and cancerous tissue sections. These two Mabs were shown to induce apoptosis as well as complement-dependent cytotoxicity upon treatment to many cultured cancer cells. Significant dose-dependent growth inhibition of tumor cells from several different tissue origins were demonstrated by nude mouse experiments. It was further demonstrated that GHR106 Mab can function as long acting GnRH analogs in its biological actions. Efforts were made to generate human/mouse chimeric forms of the GHR106 Mab. Based on the results of these preclinical studies, we believe that these two Mabs, in chimeric or humanized forms, can be developed into suitable therapeutic agents for treatment of human cancers as anti-cancer drugs. PMID- 22430629 TI - A mechanism-based fluorescent probe for labeling O6-methylguanine-DNA methyltransferase in live cells. AB - A mechanism-based small molecular fluorescent probe has been developed to label active O(6)-methylguanine-DNA methyltransferase in live cells. PMID- 22430630 TI - Serum sarcosine increases the accuracy of prostate cancer detection in patients with total serum PSA less than 4.0 ng/ml. AB - BACKGROUND: Sarcosine is reported to be a differential metabolite that is greatly increased during prostate cancer (PCa) progression. In this study, we assessed the role of serum sarcosine as a biomarker for PCa, as well as any association between sarcosine levels and clinical-pathological parameters. METHODS: Sarcosine was measured by fluorometric assay in serum samples from 290 PCa patients and 312 patients with no evidence of malignancy (NEM), confirmed by 8-12 core prostate biopsies. Nonparametric statistical tests and receiver operating characteristics (ROC) analyses were performed to assess the diagnostic performance of sarcosine in different (prostate-specific antigen) PSA ranges. RESULTS: ROC analyses in subjects with PSA < 4 ng/ml showed a higher predictive value of sarcosine (AUC = 0.668) versus total PSA (AUC = 0.535) (P = 0.03), whereas for the other two PSA ranges (4-10 ng/ml and >10 ng/ml), percent ratio of free to total PSA (%fPSA) showed a predictive superiority over sarcosine. Moreover, in patients with a PSA < 4 ng/ml, the percentage of low/intermediate-grade cancers was positively associated with sarcosine levels (P = 0.005). The specificities for serum sarcosine, %fPSA, PSA, and the logistic regression model at 95% sensitivity were 24.4, 3.41, 2.22, and 28.4%, respectively. CONCLUSIONS: We provide evidence that serum sarcosine has a higher predictive value than tPSA and %fPSA in patients with PSA < 4 ng/ml. Moreover, sarcosine levels were significantly different in low grade versus high grade cancers in this subset of patients, suggesting that this marker may be a further tool not only for diagnosing PCa in normal PSA and abnormal DRE/TRUS patients but also for selecting candidates for non-aggressive therapies and active surveillance. PMID- 22430631 TI - Effects of L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts. PMID- 22430632 TI - Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors. AB - Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of beta-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy. PMID- 22430633 TI - Elucidation of a novel pathogenomic mechanism using genome-wide long mate-pair sequencing of a congenital t(16;21) in a series of three RUNX1-mutated FPD/AML pedigrees. PMID- 22430634 TI - Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib. AB - Hodgkin's lymphoma is frequently associated with mast cell infiltration that correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that mast cells promote the growth of Hodgkin's tumor by modifying the tumor microenvironment. A transplantation assay shows that primary murine mast cells accelerate tumor growth by established Hodgkin's cell lines, and promote marked neovascularization and fibrosis. Both mast cells and Hodgkin's cells were sensitive to bortezomib, but mast cells were more resistant to bortezomib. However, bortezomib inhibited degranulation, PGE(2) induced rapid release of CCL2, and continuous release of vascular endothelial growth factor-A from mast cells even at the concentration that did not induce cell death. Bortezomib-treated mast cells lost the ability to induce neovasculization and fibrosis, and did not promote the growth of Hodgkin tumor in vivo. These results provide further evidence supporting causal relationships between inflammation and tumor growth, and demonstrate that bortezomib can target the tumor microenvironment. PMID- 22430635 TI - Expression of CD200 on AML blasts directly suppresses memory T-cell function. PMID- 22430636 TI - Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells. PMID- 22430637 TI - Real-time PCR quantification of major Wilms' tumor gene 1 (WT1) isoforms in acute myeloid leukemia, their characteristic expression patterns and possible functional consequences. AB - Wilms' tumor gene 1 (WT1) functions including some contradictory effects may be explained by the presence and interactions of its isoforms, however, their evaluation has been so far complicated by several technical problems. We designed unique quantitative PCR systems for direct quantification of the major WT1 isoforms A[EX5-/KTS-], B[+/-], C[-/+] and D[+/+] and verified their sensitivity, specificity and reproducibility in extensive testing. With this method we evaluated WT1 total and isoform expression in 23 normal bone marrow (BM) samples, 73 childhood acute myeloid leukemia (AML), 20 childhood myelodysplastic syndrome (MDS), 9 childhood severe aplastic anemia (SAA), 30 adult AML and 29 adult MDS patients. WT1 isoform patterns showed differences among these samples and clustered them into groups representing the specific diagnoses (P<0.0001). Isoform profiles were independent of total WT1 expression and possess certain common features-overexpression of isoform D and EX5[+] variants. The KTS[+]/KTS[ ] ratio was less variable than the EX5[+]/EX5[-] ratio and differed between children and adults (P<0.001); the EX5[+]/EX5[-] ratio varied between diagnoses (AML vs MDS, P<0.001). These findings bring new insights into WT1 isoform function and suggest that the ratio of WT1 isoforms, particularly EX5 variants, is probably crucial for the process of malignant transformation. PMID- 22430638 TI - CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients. AB - Clonogenic multiple myeloma (MM) cells reportedly lacked expression of plasma cell marker CD138. It was also shown that CD19(+) clonotypic B cells can serve as MM progenitor cells in some patients. However, it is unclear whether CD138 negative clonogenic MM plasma cells are identical to clonotypic CD19(+) B cells. We found that in vitro MM colony-forming cells were enriched in CD138(-)CD19( )CD38(++) plasma cells, while CD19(+) B cells never formed MM colonies in 16 samples examined in this study. We next used the SCID-rab model, which enables engraftment of human MM in vivo. CD138(-)CD19(-)CD38(++) plasma cells engrafted in this model rapidly propagated MM in 3 out of 9 cases, while no engraftment of CD19(+) B cells was detected. In 4 out of 9 cases, CD138(+) plasma cells propagated MM, although more slowly than CD138(-) cells. Finally, we transplanted CD19(+) B cells from 13 MM patients into NOD/SCID IL2Rgammac(-/-) mice, but MM did not develop. These results suggest that at least in some MM patients CD138 negative clonogenic cells are plasma cells rather than B cells, and that MM plasma cells including CD138(-) and CD138(+) cells have the potential to propagate MM clones in vivo in the absence of CD19(+) B cells. PMID- 22430639 TI - Antimicrobial activity of saponin-rich fraction from Camellia oleifera cake and its effect on cell viability of mouse macrophage RAW 264.7. AB - BACKGROUND: As a by-product of oil production, several million tons of Camellia oleifera cake is discarded every year in China. The aim of this study was to evaluate the antimicrobial activity of a saponin-rich fraction isolated from C. oleifera cake and investigate its effect on the cell viability of RAW 264.7, a macrophage-like cell line present in almost all mouse tissues. RESULTS: The saponin-rich fraction was isolated from C. oleifera cake in several steps and had a saponin content of 95.42 +/- 0.10% (w/w). It showed significant inhibitory activity against the bacteria Staphylococcus aureus, Escherichia coli and Bacillus subtilis and the fungi Mucor racemosus, Aspergillus oryzae, Rhizopus stolonifer, Saccharomyces cerevisiae and Penicillium glaucum, with minimum inhibitory concentrations of 31.3, 31.3, 62.5, 250, 250, 250, 31.3 and 125 ug ml( 1) respectively. In addition, mouse macrophage RAW 264.7 pretreated with the saponin-rich fraction (80-200 ug mL(-1) ) exhibited a significant loss of cell viability in a dose-dependent manner. CONCLUSION: These results may be useful for the future application of saponins from C. oleifera cake. However, the potential use of the saponin-rich fraction as an antimicrobial agent should be decided according to the target micro-organisms in order to avoid causing harm in humans. PMID- 22430640 TI - Streaming weekly soap opera video episodes to smartphones in a randomized controlled trial to reduce HIV risk in young urban African American/black women. AB - Love, Sex, and Choices is a 12-episode soap opera video series created as an intervention to reduce HIV sex risk. The effect on women's HIV risk behavior was evaluated in a randomized controlled trial in 238 high risk, predominately African American young adult women in the urban Northeast. To facilitate on demand access and privacy, the episodes were streamed to study-provided smartphones. Here, we discuss the development of a mobile platform to deliver the 12-weekly video episodes or weekly HIV risk reduction written messages to smartphones, including; the technical requirements, development, and evaluation. Popularity of the smartphone and use of the Internet for multimedia offer a new channel to address health disparities in traditionally underserved populations. This is the first study to report on streaming a serialized video-based intervention to a smartphone. The approach described here may provide useful insights in assessing advantages and disadvantages of smartphones to implement a video-based intervention. PMID- 22430641 TI - "It's hard to know what is a risky or not a risky decision": gay men's beliefs about risk during sex. AB - Gay men increasingly use non condom-based risk reduction strategies to reduce the possibility of HIV transmission. Such strategies rely on men's knowledge and communication with each other, but how they employ these strategies may depend as much on their attitudes toward risk and pleasure. We explored current beliefs about safe sex, sexual desire and risk behavior in an online survey of 2306 Australian gay men. The survey included free text components to explore men's beliefs about risk and pleasure. We conducted a principal components factor analysis on the safe sex belief items in the survey, and thematic analysis of the qualitative material was used to interrogate the concepts underpinning these beliefs. We identified two measures of safe sex beliefs: risk reduction optimism (HRRO; alpha = 0.703); and viral load optimism (alpha = 0.674). In multivariate analysis, unprotected anal intercourse with casual partners (UAIC) was associated with HRRO among non HIV-positive men only (p < 0.001), but, regardless of HIV serostatus, UAIC was associated with a belief that serosorting could be an effective risk reduction strategy and with being more sexually adventurous in general. Using the qualitative data we identified four themes in how men think about HIV: 'seeking certainty', 'regretful actions', 'nothing is safe', and 'acting on beliefs'. Each theme interacted with the safe sex beliefs measures to provide a highly contextualised understanding of men's beliefs about safe in specific circumstances. Gay men think about the risk of HIV transmission in qualitatively different ways depending on specific circumstances. While measures of belief about relative risk of HIV transmission are useful indicators of men's propensity to take risk, they oversimplify men's thinking about risk, and fail to account for the role of desire, both in influencing men's thinking about risk, and in how they balance their perception of relative risk against the pursuit of pleasure. PMID- 22430642 TI - Selective laser vaporization of polypropylene mesh used in treatment of female stress urinary incontinence and pelvic organ prolapse: preliminary studies using a red diode laser. AB - BACKGROUND AND OBJECTIVES: The most common mesh-related complication experienced by patients undergoing transvaginal polypropylene synthetic slings for stress urinary incontinence (SUI) and transvaginal pelvic organ prolapse (POP) repair with mesh is vaginal mesh erosion. More than half of the patients who experience erosion from synthetic mesh require surgical excision which is technically challenging and risks damage to healthy adjacent tissue. This study explores selective laser vaporization of polypropylene suture/mesh materials commonly used in SUI and POP. MATERIALS AND METHODS: A compact, 7 Watt, 647-nm, red diode laser was operated with a radiant exposure of 81 J/cm(2) , pulse duration of 100 milliseconds, and 1.0-mm-diameter laser spot. The 647-nm wavelength was selected because its absorption by water, hemoglobin, and other tissue chromophores is low, while polypropylene absorption is high. Laser vaporization of ~200-um diameter polypropylene suture/mesh strands, in contact with fresh urinary tissue samples was performed, ex vivo. Temperature mapping of suture/mesh samples with a thermal camera was also conducted. RESULTS: Selective vaporization of polypropylene suture and mesh using a single laser pulse was achieved with peak temperatures of 180 and 232 degrees C, respectively, while direct laser irradiation of tissue alone resulted in only a 1 degrees C temperature increase. CONCLUSIONS: Selective laser vaporization of polypropylene suture/mesh materials is feasible without significant thermal elevation in the adjacent tissue. This technique may be useful for treatment of eroded mesh after SUI or POP procedures that require surgical revision. PMID- 22430643 TI - [Gastrointestinal polyposis syndromes]. AB - Hereditary gastrointestinal polyposis syndromes account for around 1% of all colorectal cancers; most of them are associated with a broad spectrum of extracolonic tumors. The initial diagnosis is based on endoscopic findings and polyp histology. Molecular genetic screening is important for the delineation of conditions with a similar phenotype such as autosomal dominant familial adenomatous polyposis (FAP) and autosomal recessive MUTYH-associated polyposis (MAP). Identification of the germline mutation in an affected person is a prerequisite for the exact evaluation of the recurrence risk in relatives and the predictive testing of asymptomatic persons at risk. Beside cases with attenuated adenomatosis or few colorectal adenomas, diagnostic difficulties are common among the hamartomatous polyposes such as the juvenile polyposis syndrome due to their broad clinical overlap and uncertainties in histological assessment. Several poorly defined nonhereditary polyposis syndromes and those with an as yet unknown etiology exist including hyperplastic polyposis syndrome. Early detection and accurate classification are essential since effective methods for surveillance and treatment are available. PMID- 22430644 TI - The hypocretin/orexin system: implications for drug reward and relapse. AB - Hypocretins (also known as orexins) are hypothalamic neuropeptides involved in the regulation of sleep/wake states and feeding behavior. Recent studies have also demonstrated an important role for the hypocretin/orexin system in the addictive properties of drugs of abuse, consistent with the reciprocal innervations between hypocretin neurons and brain areas involved in reward processing. This system participates in the primary reinforcing effects of opioids, nicotine, and alcohol. Hypocretins are also involved in the neurobiological mechanisms underlying relapse to drug-seeking behavior induced by drug-related environmental stimuli and stress, as mainly described in the case of psychostimulants. Based on these preclinical studies, the use of selective ligands targeting hypocretin receptors could represent a new therapeutical strategy for the treatment of substance abuse disorders. In this review, we discuss and update the current knowledge about the participation of the hypocretin system in drug addiction and the possible neurobiological mechanisms involved in these processes regulated by hypocretin transmission. PMID- 22430645 TI - Poly(ADP-ribose) polymerase-1 in amyloid beta toxicity and Alzheimer's disease. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme responsible for the maintenance of genome stability, transcriptional regulation, and long-term potentiation in neurons. However, the excessive activation of PARP-1 under pathological conditions may lead to an accumulation of poly(ADP-ribose) (PAR), a novel signaling molecule that induces programmed cell death, or to NAD depletion that induces energy crisis and necrotic cell death. PARP-1 is thought to be primarily a nuclear enzyme, but some data indicate that it can also be localized to the mitochondria where it is responsible for posttranslational modification of electron transport chain complexes and alteration of mitochondria function. The enhancement of PARP-1 activity and the accumulation of PAR were demonstrated in the brain of patients with Alzheimer's disease (AD), particularly in neurons of the frontal and temporal lobes and in skin fibroblasts and lymphoblasts. Moreover, it has been reported that PARP-1 gene polymorphisms are highly associated with the development of AD. The activation of PARP-1 by oxidative stress seems to be an early and important event in the pathogenesis of AD. It is now widely accepted that the overproduction and oligomerization of amyloid beta (Abeta) are responsible for the activation of a free radical cascade and oxidative stress in AD. Interestingly, the activity of PARP-1 is enhanced in AD and is also increased by Abeta peptides. The activation of PARP-1 by Abeta can lead to the PAR-mediated release of apoptosis-inducing factor from the mitochondria and its translocation to the nucleus, which leads to death of some populations of cells. A role of PARP-1 in the regulation of Abeta precursor protein metabolism processing and Abeta liberation has not been described previously. The study presented in this review indicated the relationship between PARP-1 activation, alteration of mitochondria function, and Abeta toxicity. The presented data should stimulate further studies on the role of PARP-1 in AD pathogenesis and thereby engage a new perspective regarding AD therapy. PMID- 22430647 TI - A novel JNK from Litopenaeus vannamei involved in white spot syndrome virus infection. AB - The c-Jun N-terminal kinase (JNK), a member of MAP kinases, is a serine/threonine specific protein kinase which responds to extracellular stimuli and regulate various cellular activities. It is well documented in innate immune responses and reported to be involved in various viral infections of mammals. In present study, we cloned JNK homolog in a crustacean, Litopenaeus vannamei (designated as LvJNK) and studied its role in white spot syndrome virus (WSSV) infection. Sequence analysis displayed that LvJNK shared high similarity with other members of the JNK subfamily, including the conserved TPY motif and serine/threonine protein kinase (S_TKc) domain. Western blot analysis showed that the activation of LvJNK took place in WSSV infection. LvJnk silencing mediated by specific dsRNA in shrimps could significantly inhibit the proliferation of the virus. Moreover, inhibition of shrimp JNK signaling pathway by specific inhibitor resulted in the reduction of WSSV replication and the delay of WSSV gene transcription. These results indicate for the first time that shrimp JNK is activated in response to WSSV infection and WSSV could benefit from JNK activation. It may facilitate our understanding of the molecular mechanism of virus infection and provided a potential target for preventing the WSSV infection. PMID- 22430646 TI - Increased B7-H1 expression on peripheral blood T cells in oral lichen planus correlated with disease severity. AB - BACKGROUND: Oral lichen planus (OLP) is a chronic and T cell-mediated autoimmune disease whose immunopathogenesis may involve antigen-presentation, T cells activation and migration as well as keratinocytes apoptosis. PD-1/B7-H1 pathway may have a unique function in regulating self-reactive T cells associated with inflammatory response and maintaining tolerance in peripheral tissues. In this study, we aimed to explore the contribution of PD-1/B7-H1 pathway to OLP. METHODS: We determined the expression of PD-1 and B7-H1 on peripheral blood T cells from OLP cases and analyzed their association with disease severity assessed by RAE (reticular, atrophic and erosive lesion) scoring system. In addition, interferon-gamma, interleukin (IL)-2, IL-4, IL-10 and soluble PD-1 concentrations in serum were measured using ELISA. Then, we explored the regulation of PD-1/B7-H1 pathway on T cells immune response in OLP by blockade of PD-1 or B7-H1. RESULTS: We found that PD-1 and B7-H1 were up-regulated on peripheral blood T cells from OLP patients and B7-H1 expression positively correlated with disease severity of OLP. It is suggested that Th1 dominant inflammatory situation might contribute to the high expression of PD-1 and B7-H1 in OLP. Blockade of PD-1/B7-H1 pathway significantly increased the proliferation, and IFN-gamma and IL-2 production of T cells. CONCLUSIONS: PD-1/B7-H1 pathway may play an important role in negatively modulating T cell-mediated immune response in OLP, and provide the rationale to employ B7-H1 expression on peripheral blood T cells as a marker of severity of OLP and to develop agonists targeting PD-1/B7 H1 pathway as a promising immunotherapeutic strategy for OLP. PMID- 22430648 TI - Predicting self-assembly: from empirism to determinism. AB - Self-assembly is one of the most important concepts of the 21st century. Strikingly, despite the rational design of molecules for biological and pharmaceutical applications is rather well established, only few are the attempts to formally refine predictions of self-assembly in material science. In the present tutorial review, we encompass some of the most significant efforts towards the systematic study of (thermodynamically stable) self-assembly. We discuss experimental and computer-simulated self-assembly events in hard-matter, soft-matter and higher symmetry architectures under the common framework of partition functions. In this framework, we endeavor to correlate state-of-the-art chemical design, programming and/or engineering of reversible (thermal and chemical equilibrium) self-assembly with knowledge of the underlying partition function landscape in a step towards quantitative predictions and ab initio molecular design. PMID- 22430649 TI - Saga of payment systems of ambulatory surgery centers for interventional techniques: an update. AB - The health care system in the United States has been criticized for skyrocketing expenditures and quality deficits. Simultaneously, health care providers and systems are under pressure to provide better and more proficient care. The landscape of the US health care system is shaped by federal and private payers which continue to develop initiatives designed to curtail costs. These include value-based reimbursement programs; cost-shifting expenses to the consumer and reducing reimbursement of providers and facilities. Moreover, there is an underlying thought to steer provision of health care to theoretically more efficient settings. Many of these initiatives are based on affordable health care reform. The major aspects of curtailing health care costs include hospital and other facility payments as well as physician payments and reductions in the approved services. Consequently, ambulatory surgery centers (ASCs) are not immune to these changes. Until 1970, all surgery was performed in hospitals. The development of ASCs and site of service differential payments for in-office procedures have changed the dynamics of surgical trends with outpatient surgeries outpacing inpatient surgeries by as early as 1989. By 2008, approximately 65% of procedures were performed in all outpatient settings including hospital outpatient departments. ASCs claim that improved efficiency in health care delivery allows patients to spend less time in the health care setting with quicker turn over, improving the productivity of the health care team. However, since the majority of the ASCs are owned, in part, by the physicians who staff them, the financial incentives related to ownership have been alleged to potentially alter provider behavior. The number of Medicare certified ASCs and total Medicare payments from 1999 to 2010 increased significantly, but more recent year-to-year changes are far less substantial when compared to previous years. Net percent revenue growth from 2008 to 2009 was 3.2% and from 2009 to 2010 was 6.2% with an overall increase from 1999 of 183% over a period of 11 years. Similarly, the number of Medicare certified ASCs increased from 2,786 in 1999 to 5,316 in 2010, 1.1% increased from 2009 to 2010, however, a 91% increase from 1999 over a period of 11 years. Interventional pain management is one of the fastest growing specialties with a footprint in multiple disciplines. Interventional pain management in ASC settings has come a long way since June 1998 proposed Health Care Financing Administration's ASC rule which seriously compromised interventional pain management in the ASC setting. There are many payment challenges facing interventional pain management (IPM) in 2012. Significant changes continue to occur in the payment systems with policies of paying a certain percent of hospital outpatient department payments to ASCs which declined from 63% in 2008 to 56% in 2011, with substantial reductions for add-on codes. The Centers for Medicare and Medicaid Services (CMS) evaluation of IPM codes also consists of multiple misvalued codes. In conclusion, overall the future of ASCs may appear optimistic, but in the near perspective, specifically in 2012 to 2014, there will be challenging times specifically for interventional pain management centers with the regulatory environment and rapid changes taking place with or without implementation of Affordable Care Act. PMID- 22430650 TI - A prospective evaluation of complications of 10,000 fluoroscopically directed epidural injections. AB - BACKGROUND: Among the multiple modalities of treatments available in managing chronic spinal pain, including surgery and multiple interventional techniques, epidural injections by various routes, such as interlaminar epidural injections, caudal epidural injections, transforaminal epidural injections, and percutaneous adhesiolysis are common. Even though the complications of fluoroscopically directed epidural injections are fewer than blind epidural injections, and have better effectiveness, multiple complications have been reported in scattered case reports, with only minor complications in randomized or non-randomized studies and systematic reviews. Thus, prospective studies with large patient series are essential to determine the types and incidences of complications. STUDY DESIGN: A prospective, non-randomized study of patients undergoing interventional techniques from May 2008 to December 2009. SETTING: A private interventional pain management practice, a specialty referral center in the United States. OBJECTIVES: To assess the complication rate of fluoroscopically directed epidural injections. METHODS: This study was carried out over a period of 20 months and included over 10,000 procedures: 39% caudal epidurals, 23% cervical interlaminar epidurals, 14% lumbar interlaminar epidurals, 13% lumbar transforaminal epidurals, 8% percutaneous adhesiolysis, and 3% thoracic interlaminar epidural procedures. All of the interventions were performed under fluoroscopic guidance in an ambulatory surgery center by one of 3 physicians. The complications encountered during the procedure and postoperatively were prospectively evaluated. OUTCOMES ASSESSMENT: Measurable outcomes employed were intravascular entry of the needle, profuse bleeding, local hematoma, bruising, dural puncture and headache, nerve root or spinal cord irritation with resultant injury, infectious complications, vasovagal reactions, and facial flushing. RESULTS: Intravascular entry was higher for adhesiolysis (11.6%) and lumbar transforaminal (7.9%) procedures compared to other epidurals which ranged from 0.5% for lumbar, 3.1% for caudal, 4% for thoracic, and 4.1% for cervical epidurals. Dural puncture was observed in a total of 0.5% of the procedures with 1% in the cervical region, 1.3% in the thoracic region, 0.8% with lumbar interlaminar epidurals, and 1.8% with adhesiolysis. LIMITATIONS: Limitations of this study include a single-center study even though it included a large number of patients. CONCLUSION: This study illustrates that major complications are rare and minor side effects are common. PMID- 22430651 TI - Minimally invasive interventional therapy for Tarlov cysts causing symptoms of interstitial cystitis. AB - BACKGROUND: Tarlov cysts (TC) are present in 4.6% of the population and represent a potential source of chronic pain. When present at lumbosacral levels, symptoms are classically described as perineal pain/pressure, radiculopathy, and headache. Treatment outlined to date primarily includes cyst drainage with fibrin glue sealant and surgical interventions. OBJECTIVES: We present 2 cases in which TC presented with signs and symptomatology consistent with interstitial cystitis who were treated with caudal epidural steroid injections. METHODS: Patients with urinary bladder pain and urgency received urological workups demonstrating hallmark features of interstitial cystitis including cystoscopic evidence of glomerulations. Radiographic imaging identified TC to be present on sacral nerve roots. Since pelvic pains could represent compressive radiculopathy of sacral roots, a cautious trial of minimally invasive caudal epidural steroid injections was performed. RESULTS: Both patients attained nearly 100% relief of pain for a period ranging from 6 months to 2 years following low volume, targeted caudal epidural steroid injection. They continue to be followed clinically and continue to report benefit with this treatment. LIMITATIONS: This limited case series is retrospective in nature and potential complications have been noted by others in association with TC. CONCLUSIONS: Use of caudal epidural steroid injections proved beneficial in the treatment of pelvic pain symptomatology and so may be considered as an option in patients with identified sacral TC. PMID- 22430652 TI - Cardiopulmonary arrest following cervical epidural injection. AB - Epidural steroid injection is a common treatment for the management of pain in a wide variety of patients. It is generally well tolerated and perceived to have few side effects, with a low risk of serious complications. Only a handful of reports exist that describe life-threatening complications such as subdural hematoma, respiratory depression, vasovagal response, and pneumocephalus. This is a case report of a 67-year-old woman with a relatively unremarkable past medical history, other than rheumatoid arthritis, osteoarthritis, and hypertension, who suffered from chronic neck pain treated with cervical epidural steroid injection at the C6-C7 level. She went into immediate cardiopulmonary arrest following the injection. She was brought to the emergency department by ambulance and resuscitated, and was found to have pneumocephalus. Ultimately, she made a relatively full recovery over the following weeks. Cardiopulmonary arrest is a rare but potentially deadly side effect of epidural steroid injection. To the best of our knowledge, this is the first report of such an arrest following a steroid injection in the cervical spinal region. There are several possible mechanisms for the immediate arrest, including cardioacceleratory center blockade, severe vasovagal response, iatrogenic pneumocephalus, and involvement of the phrenic nerve followed by apnea. Our conclusion in this case is that the most likely scenario was injection of the C6-C7 level led to a blockade of the cardiac accelerator fibers located just below in the T1-T4 spinal level, causing a sympathetic blockade and profound bradycardia, leading to cardiopulmonary arrest. PMID- 22430653 TI - CT-guided transforaminal epidural injections with local anesthetic, steroid, and tramadol for the treatment of persistent lumbar radicular pain. AB - BACKGROUND: A substantial number of patients with persistent lumbar radicular pain are treated with a multimodal spectrum of conservative therapies without lasting effect. The duration of pain is certainly a risk factor for chronification. There is evidence that guided periradicular infiltrations are a valid option in the treatment of radiculopathies. Usually a combination of local anesthetic and/or corticosteroid is injected. Tramadol is being used for perioperative analgesia and has been shown to provide effective, long-lasting pain relief after epidural administration. OBJECTIVE: The aim of this pilot study was to evaluate the efficacy of serial CT-guided transforaminal nerve root infiltrations with a supplement of tramadol for patients with persistent, radicular pain. STUDY DESIGN: Interventional cohort study. SETTING: Outpatient department for interdisciplinary pain medicine. METHODS: 37 patients who had radicular leg pain for over 9 weeks received up to 3 CT-guided transforaminal nerve root infiltrations at intervals of 2 weeks as long as their level of pain was over 3 on a numerical rating scale from 0 to 10. 50 mg of Tramadol were added to a combination of local anesthetic (Ropivacain, 2 mg) and corticosteroid (Triamcinolon, 40 mg). Evaluations were carried out 24 hours after the Infiltration as well as 2 weeks, 3 and 6 months after the treatment series. The intensity of their radicular pain was measured by a numerical rating scale (NRS). Pain reduction of at least 50% was defined as successful outcome. RESULTS: In total, 65 infiltrations were carried out with pain relief in more than 90% of the patients within 24 hours and an average pain reduction of 64%. Six months post injection 23 of 34 patients available for follow-up (67.6%) had a successful pain reduction of 84% on average. No adverse effects ascribable to the use of tramadol were noted. LIMITATIONS: Due to the lack of a control group we cannot make any statement if tramadol improves short-term pain reduction. CONCLUSION: Fast and lasting pain relief is the key to optimize rehabilitation for patients with radicular pain. There is a physiological rationale that the opioid receptors at the spinal level could be used to optimize the analgetic effect of guided periradicular injections. In our case series, serial CT-guided selective nerve root infiltrations with the supplement of tramadol were found to be highly effective in the treatment of persistant radiculopathies. Randomized controlled trials will be necessary to clarify the possible benefit of the supplement of an opioid. PMID- 22430654 TI - Benefits of inferential statistical methods in radiation exposure studies: another look at percutaneous spinal cord stimulation mapping [trialing] procedures. AB - BACKGROUND: Two studies, each consisting of large sample sets, were recently published on radiation exposure in percutaneous spinal cord stimulation (SCS) trialing procedures. A more rigorous use of statistical methods in the second study more accurately defined benchmark reference levels. Principally, one physician implanter-considered an advanced interventional pain physician performed all such procedures to nullify inter-physician variability. However, the literature is sparse in articles comparing exposure levels of radiation in pain procedures conducted by novice and advanced interventionally trained physicians, and inferential statistical analysis is seldom included in radiation exposure studies. OBJECTIVE: The aim of this study was to compare fluoroscopy times between novice and expert physician implanters performing SCS trialing procedures, and to the benchmarked reference level, using inferential statistical methods. As a secondary objective, the importance of statistical concepts in interpretive-imaging and image guidance studies for interventional pain procedures will be outlined. DESIGN: An observational study. SETTING: A non university outpatient Interventional Pain Management practice in the United States. METHODS: Fluoroscopy time (in seconds) was retrospectively studied in 18 SCS trialing procedures (with dual lead placement in the low thoracic spine) performed over a 3-month period. The procedures were categorized by physician experience: one novice physician implanter with n = 5 cases and one expert physician implanter with n = 13 cases. All procedures were conducted with the same fluoroscope operator and the same mobile C-arm fluoroscopy system. A two tailed t-test was used to compare mean fluoroscopy times between physician categories. Left-tailed t-tests were used to compare mean fluoroscopy times for each physician category separately to the benchmark level (MU = 71.7 seconds). Incident air kerma (KERMA) was assessed by nonsimplistic modeling. RESULTS: No statistical difference was found in mean fluoroscopy times for SCS trialing procedures between the novice- and expert-implanter, chinovice = 63.5 seconds and chiexpert = 53.9 seconds. In the case of the novice implanter, although mean fluoroscopy time was lower than the benchmark reference level, chinovice = 63.5 seconds compared to MU = 71.7 seconds, this was not significantly relevant. In the case of the expert implanter, a statistically relevant reduction in mean fluoroscopy time was observed compared to the benchmark level, chiexpert = 53.9 seconds versus MU = 71.7 seconds. KERMA ranged from 5.3 mGy to 9.1 mGy with a mean and standard deviation of 6.5 mGy and 1.5 mGy, respectively, in the novice implanter sample set. KERMA ranged from 2.6 mGy to 13.1 mGy with a mean and standard deviation of 5.8 mGy and 3.2 mGy, respectively, in the expert implanter sample set. LIMITATIONS: Given that reference levels for radiation exposure in SCS trialing procedures are established, combined with comparisons in fluoroscopy times based on physician experience, expanding the physician database will assist in data validation. CONCLUSION: Radiation exposure levels in SCS trialing procedures remain negligible. While no differences in fluoroscopy times for such procedures were detected based on physician experience, the expert implanter demonstrated the ability to use less fluoroscopy time than that of the benchmark reference level. PMID- 22430655 TI - Multivariable analysis of the relationship between pain referral patterns and the source of chronic low back pain. AB - BACKGROUND: Discogenic, facet joint, and sacroiliac joint mediated axial low back pain may be associated with overlapping pain referral patterns into the lower limb. Differences between pain referral patterns for these three structures have not been systematically investigated. OBJECTIVE: To examine the individual and combined relationship of age, hip/girdle pain, leg pain, and thigh pain and the source of internal disc disruption (IDD), facet joint pain (FJP), or sacroiliac joint pain (SIJP) in consecutive chronic low back pain (CLBP) patients. DESIGN: Retrospective chart review. SETTING: Community based interventional spine practice. PATIENTS: 378 cases from 358 consecutive patients were reviewed and 157 independent cases from 153 patients who underwent definitive diagnostic injections were analyzed. METHODS: Charts of consecutive low back pain patients who underwent definitive diagnostic spinal procedures were retrospectively reviewed. Patients underwent provocation lumbar discography, dual diagnostic medial branch blocks, or intra-articular diagnostic sacroiliac joint injections based on clinical presentation. Some subjects underwent multiple diagnostic injections until the source of their chronic low back pain (CLBP) was identified. MAIN OUTCOME MEASUREMENTS: Based on the results of diagnostic injections, subjects were classified as having IDD, FJP, SIJP, or other. The mean age/standard deviation and the count/percentage of patients reporting hip girdle pain, leg pain, or thigh pain were estimated for each diagnostic group and compared statistically among the IDD, FJP, SIJP, and other source groups. Next, the 4 predictor variables were simultaneously modeled with a single multinomial logistic regression model to explore the adjusted relationship between the predictors and the source of CLBP. RESULTS: The mean age was significantly different among the source groups. IDD cases were significantly younger than FJP, SIJP, and other source groups and FJP cases were significantly younger than other sources. The age by thigh pain interaction effect was statistically significant (P = 0.021), indicating that the effect of age on the source of CLBP depends on thigh pain, and similarly, that the effect of thigh pain on the source of CLBP depends on age. LIMITATIONS: Retrospective study design. CONCLUSIONS: The presence or absence of thigh pain possesses a significant correlation on the source of CLBP for varying ages, whereas the presence of hip/girdle pain or leg pain did not significantly discriminate among IDD, FJP, or SIJP as the etiology of CLBP. Younger age was predictive of IDD regardless of the presence or absence of thigh pain. PMID- 22430656 TI - Linguistic adaptation, validation and comparison of 3 routinely used neuropathic pain questionnaires. AB - BACKGROUND: Neuropathic pain questionnaires are efficient diagnostic tools for neuropathic pain and play an important role in neuropathic pain epidemiologic studies in China. No comparison data was available in regards to the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Neuropathic Pain Questionnaire (NPQ) and ID Pain within and among the same population. OBJECTIVE: To achieve a linguistic adaptation, validation, and comparison of Chinese versions of the 3 neuropathic pain questionnaires (LANSS, NPQ and ID Pain). STUDY DESIGN: A nonrandomized, controlled, prospective, multicenter trial. SETTING: Ten pain centers in China. METHODS: Two forward translations followed by comparison and reconciliation of the translations. Comparison of the 2 backward translations with the original version was made to establish consistency and accuracy of the translations. Pilot testing and pain specialists' evaluations were also required. A total of 140 patients were enrolled in 10 centers throughout China: 70 neuropathic pain patients and 70 nociceptive pain patients. Reliability (Cronbach's alpha coefficients and Guttman split-half coefficients) and validity (sensitivity, specificity, positive and negative predictive values, receiver operating characteristic [ROC] curves and the area under the ROC curves) of the 3 questionnaires were determined. ROC curves and the area under the ROC curves of the 3 questionnaires were also compared. RESULTS: Chinese versions of LANSS, NPQ and ID Pain had a good reliability (Cronbach's alpha coefficients and Guttman split-half coefficients were greater than 0.7). Sensitivity, specificity, positive and negative predictive values of the Chinese versions of LANSS and ID Pain were considerably high ( > 80%). The area under the ROC curves of LANSS and ID Pain was significantly higher than that of NPQ (P < 0.05). There was no statistically significant difference between the area under the ROC curves of LANSS and ID Pain (P > 0.05). LIMITATION: The study was based on patients with a high school degree or above, which limited the application of the 3 neuropathic pain questionnaires to patients with lower educational levels. CONCLUSION: The Chinese versions of LANSS and ID Pain developed and validated by this study can be used as a diagnostic tool in differentiating neuropathic pain in patients whose native language is Chinese (Mandarin). PMID- 22430657 TI - An animal model for trigeminal neuralgia by compression of the trigeminal nerve root. AB - BACKGROUND: Microvascular compression of the trigeminal nerve root is a major cause of most trigeminal neuralgia (TN) in patients; however, no reliable animal model to further study the pathogenesis of TN currently exists. OBJECTIVE: Our objective was to establish a novel and practical animal model for TN by chronic compression of the trigeminal (CCT) nerve root in rats, which would provide a better animal model to mimic the clinical feature of TN on the research of the pathogenesis of TN. STUDY DESIGN: A randomized, double blind, controlled animal trial. METHODS: Sixteen adult male Sprague-Dawley rats (200-220 g) were randomly divided into 2 groups: one group that received chronic compression of the trigeminal nerve root (the CCT group, n=8) and another group that received sham operation without compression (the sham operation group, n=8). A small plastic filament was retrogressively inserted into the intracalvarium from the inferior orbital fissure until it reached the trigeminal nerve root for compression in CCT group. Animal behaviors were observed for 4 weeks after operation. Immunohistochemistry of glial fibrillary acidic protein (GFAP), isolectin B4 (IB4), substance P (SP) and calcitonin gene-related peptide (CGRP) were performed in the trigeminal root entry zone (TREZ) and medullary dorsal horn (MDH). RESULTS: The orofacial mechanical allodynia and heat hyperalgesia in the CCT rats were obviously increased after the operation and lasted for 28 days. Increased face-grooming behavior was also observed in the CCT rats and continued for over 21 days, returning to baseline by day 28. Immunohistochemistry for GFAP in the TREZ revealed a progressive extension of astrocytic processes in the ipsilateral TREZ of rats in the CCT group. Furthermore, the IB4 positive immunoreactive nonpeptidergic C-fiber terminals in the MDH were reduced for 4 weeks after the operation. Both SP and CGRP, expressed in the peptidergic C-fiber terminals, were found to be decreased in the ipsilateral MDH of CCT animals after the trigeminal nerve root injury. LIMITATIONS: CCT animal model with a plastic filament only imitated the mechanical compression of the trigeminal root but not to display the complex vascular physiological feature as the microvascular in the TN patient. CONCLUSIONS: The chronic compression of the trigeminal nerve root in rats effectively induced persistent orofacial neuropathic pain behaviors, and it would provide a novel and practical animal model for future research on the pathogenesis of TN. PMID- 22430658 TI - Ozone therapy as a treatment for low back pain secondary to herniated disc: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Low back pain (LBP) is one of the most common and important health problems affecting the population worldwide and remains mostly unsolved. Ozone therapy has emerged as an additional treatment method. Questions persist concerning its clinical efficacy. OBJECTIVE: The purpose of our study was to evaluate the therapeutic results of percutaneous injection of ozone for low back pain secondary to disc herniation. STUDY DESIGN: A systematic review and meta analysis of randomized controlled trials. METHODS: A comprehensive literature search was conducted using all electronic databases from 1966 through September 2011. The quality of individual articles was assessed based on the modified Cochrane review criteria for randomized trials and criteria from the Agency for Healthcare Research and Quality. OUTCOME PARAMETERS: The outcome measure was short-term pain relief of at least 6 months or long-term pain relief of more than 6 months. RESULTS: Eight observational studies were included in the systematic review and 4 randomized trials in the meta-analysis. The indicated level of evidence for long-term pain relief was II-3 for ozone therapy applied intradiscally and II-1 for ozone therapy applied paravertebrally. The grading of recommendation was 1C for intradiscal ozone therapy and 1B for paravertebral ozone therapy. LIMITATIONS: The main limitations of this review are the lack of precise diagnosis and the frequent use of mixed therapeutic agents. The meta analysis included mainly active-control trials. No placebo-controlled trial was found. CONCLUSIONS: Ozone therapy appears to yield positive results and low morbidity rates when applied percutaneously for the treatment of chronic low back pain. PMID- 22430659 TI - Treatment of functional chest pain with antidepressants: a meta-analysis. AB - BACKGROUND: Recurrent Functional Chest pain (FCP) with normal coronary anatomy and no detectable gastroenterological and respiratory causes is a common problem that sometimes leads to excess use of medical care. OBJECTIVE: The purpose of this meta-analysis is to investigate the efficacy of antidepressant treatments for FCP. SETTINGS: MEDLINE, PsycINFO, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to July 2011. Randomized controlled trials (RCTs) that tested any type of antidepressants for FCP with normal coronary anatomy were analyzed. Diagnoses included non-specific chest pain, noncardiac chest pain, atypical chest pain, syndrome X, or chest pain with normal coronary anatomy. METHODS: Two authors independently extracted data. Effects were summarized using standardized mean differences (SMDs), weighed mean differences (WMD), or odds ratio (OR) by suitable effects model. RESULTS: Seven RCTs (median duration, 5 weeks; range, 3 - 16 weeks) involving 319 participants were included. There was strong evidence for an association of antidepressants with reduction in pain (SMD -1.26; 95% confidence interval [CI], -2.34 to -0.19) and psychological symptoms (SMD -0.87; 95% CI, -1.67 to - 0.08) as well as increased side effects (OR 0.34; 95% CI, 0.15 to 0.78). Current analysis did not support the association of antidepressants with improved health related quality of life (WMD 2.00; 95% CI, - 2.54 to - 6.65). LIMITATIONS: Demographics, co morbidities of study participants and the amount of co-medication were not reported, these possible sources of heterogeneity could not be examined. CONCLUSIONS: Antidepressant medications are associated with improvements in pain and psychological symptoms. The effects of factors including psychiatric co morbidity, gender, age, ethnic group, and treating period on the outcomes should be checked further. PMID- 22430660 TI - Complications of fluoroscopically directed facet joint nerve blocks: a prospective evaluation of 7,500 episodes with 43,000 nerve blocks. AB - BACKGROUND: Chronic spinal pain is common along with numerous modalities of diagnostic and therapeutic interventions utilized, creating a health care crisis. Facet joint injections and epidural injections are the 2 most commonly utilized interventions in managing chronic spinal pain. While the literature addressing the effectiveness of facet joint nerve blocks is variable and emerging, there is paucity of literature on adverse effects of facet joint nerve blocks. STUDY DESIGN: A prospective, non-randomized study of patients undergoing interventional techniques from May 2008 to December 2009. SETTING: A private interventional pain management practice, a specialty referral center in the United States. OBJECTIVES: Investigation of the incidence in characteristics of adverse effects and complications of facet joint nerve blocks. The study was carried out over a period of 20 months including almost 7,500 episodes of 43,000 facet joint nerve blocks with 3,370 episodes in the cervical region, 3,162 in the lumbar region, and 950 in the thoracic region. All facet joint nerve blocks were performed under fluoroscopic guidance in an ambulatory surgery center by 3 physicians. The complications encountered during the procedure and postoperatively were evaluated prospectively. METHODS: This study was carried out over a period of 20 months and included over 7,500 episodes or 43,000 facet joint nerve blocks. All of the interventions were performed under fluoroscopic guidance in an ambulatory surgery center by one of 3 physicians. The complications encountered during the procedure and postoperatively were prospectively evaluated. OUTCOMES ASSESSMENT: Measurable outcomes employed were intravascular entry of the needle, profuse bleeding, local hematoma, dural puncture and headache, nerve root or spinal cord irritation with resultant injury, and infectious complications. RESULTS: There were no major complications. Multiple side effects and complications observed included overall intravascular penetration in 11.4% of episodes with 20% in cervical region, 4% in lumbar region, and 6% in thoracic region; local bleeding in 76.3% of episodes with highest in thoracic region and lowest in cervical region; oozing with 19.6% encounters with highest in cervical region and lowest in lumbar region; with local hematoma seen only in 1.2% of the patients with profuse bleeding, bruising, soreness, nerve root irritation, and all other effects such as vasovagal reactions observed in 1% or less of the episodes. LIMITATIONS: Limitations of this study include lack of contrast injection, use of intermittent fluoroscopy and also an observational nature of the study. CONCLUSION: This study illustrate that major complications are extremely rare and minor side effects are common. PMID- 22430661 TI - Applaud the novel intrathecal baclofen trialing method: time to raise the bar! PMID- 22430662 TI - Necessity and implications of ICD-10: facts and fallacies. PMID- 22430663 TI - 3 things to consider before relying solely on point of care tests for determining benzodiazepine use in chronic pain. PMID- 22430665 TI - Does the diagnosis of spondylolisthesis matter? PMID- 22430667 TI - A new continuous fluorometric assay for acetylcholinesterase activity and inhibitor screening with emissive core-shell silica particles containing tetraphenylethylene fluorophore. AB - Emissive core-shell silica particles with tetraphenylethylene moieties were prepared and characterized. Fluorescence quenching was observed for the silica particles upon addition of compound 2 (Dabcyl-ACh). This was attributed to the electrostatic interaction between the silica particles and 2 and the resulting photoinduced energy transfer between them. After incubation with AChE, the fluorescence intensity started to increase. The fluorescence enhancement became more significant when the concentration of AChE was higher. The reaction kinetic parameters for AChE were successfully estimated with the silica particles and 2. These results reveal that the ensemble of the silica particles and 2 can be utilized for AChE assay. Moreover, the fluorescence spectra of the ensemble of the silica particles and 2 containing AChE were also measured after further addition of either neostigmine or tacrine which are typical inhibitors of AChE. The results manifest that the ensemble of the emissive silica particles and 2 is also useful for screening the inhibitors of AChE. PMID- 22430668 TI - Windswept deformity in a patient with Schwartz-Jampel syndrome. AB - A 13-year-old boy presented with the overall phenotypic and genotypic characterisation of Schwarz-Jampel syndrome (SJS). Windswept deformity was a major orthopaedic abnormality. Prompt diagnostic measures were applied to this patient associated with several orthopaedic procedures to move closer to acceptable appearance and function. PMID- 22430669 TI - Neutral copper-phosphido-borane complexes: synthesis, characterization, and use as precatalysts in C(sp)-P bond formation. AB - Copper-phosphido-borane complexes were synthesized and isolated for the first time. Their structures were experimentally and computationally investigated. They were shown to display catalytic activity in C(sp)-P bond formation. PMID- 22430670 TI - Level VI lymph node dissection does not decrease radioiodine uptake in patients undergoing radioiodine ablation for differentiated thyroid cancer. AB - BACKGROUND: In patients with well-differentiated thyroid cancer, the incidence of pathologic central compartment lymph node metastases is reported to be approximately 50%. Recently level VI lymph node dissection has been advocated as a means of reducing recurrence rates in these patients, even if there are no clinically apparent nodal metastases. This study investigates whether level VI lymph node dissection decreases the percent radioiodine uptake when patients undergo radioiodine ablation. METHODS: All thyroid cancer patients entered into the endocrine surgery database at a tertiary care center from 2006 to 2010 were reviewed. Those treated with radioactive iodine were analyzed with respect to performance of a central compartment lymph node dissection and the percent uptake of radioiodine ((131)I) on the preablation scan at 72 h. RESULTS: There were 277 patients with well-differentiated thyroid cancer who underwent radioiodine ablation. In all, 75% were female, and the mean age was 47.7 years. A total of 87 patients underwent total thyroidectomy and level VI lymph node dissection (TT + LVIND). The mean number of level VI nodes resected was 6 (1-27), and 60.9% of patients had nodal metastases. Altogether, 190 had a total thyroidectomy (TT) only, and the median number of nodes resected was 0 (0-10). The percent uptake of radioiodine on the preablation scan was 0.93% in patients who had undergone TT + LVIND and 1.2% in those with TT alone (p = 0.17). The median number of radioactive foci noted within the thyroid bed was two in both groups (p = 0.64). The mean preablation thyroglobulin levels, measured after thyroxine withdrawal or thyrogen stimulation, were 4.0 ng/ml in the TT + LVIND group versus 4.7 ng/ml in the TT group (p = 0.07). The average ablative dose of (131)I was 111.8 mCi in the dissection group and 98.5 mCi in the TT-only group. CONCLUSIONS: There is no evidence that uptake of (131)I is reduced by performance of a central neck dissection in patients with well-differentiated thyroid cancer. Preablation thyroglobulin levels were not altered by level VI lymph node dissection. PMID- 22430671 TI - Slit versus non-slit mesh placement in total extraperitoneal inguinal hernia repair. PMID- 22430672 TI - A simple and effective strategy for labeling cysteine sulfenic acid in proteins by utilization of beta-ketoesters as cleavable probes. AB - beta-ketoesters are robust probes for labeling sulfenic acid (-SOH) proteins allowing quantitative cleavage of the tag for improved analysis of the labeled peptides by MS. PMID- 22430673 TI - Role of MU-opioid system in the formation of memory of placebo responses. PMID- 22430674 TI - Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease. AB - Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 * 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Abeta plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Abeta42/Abeta40 ratio (best signal, P=5.4 * 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD. PMID- 22430675 TI - Comparison between CT and MR in perfusion imaging assessment of high-grade gliomas. AB - PURPOSE: The aim of our study was to compare the relative cerebral blood volume (CBV) values obtained by first-pass dynamic susceptibility-weighted contrast enhanced (DSC) T2-weighted magnetic resonance (MR) and perfusion computed tomography (P-CT) imaging in high-grade gliomas (HGG) in the same patient population. MATERIALS AND METHODS: Sixteen patients with histologically proven HGG underwent P-CT and DSC-MR brain imaging. P-CT studies were obtained using a four-row multislice CT scanner and postprocessed with a commercial software package based on a deconvolution-based technique. DSC-MR images were obtained at 1.5 T with a first-pass dynamic susceptibility contrast-enhanced T2-weighted sequence. P-CT and DSC-MR images were obtained within 4 days of each another, always before surgery. Maximum CBV ratios normalised with contralateral white matter (rCBV) were calculated. Statistical analysis was performed with the classical parametric statistic procedure. RESULTS: A linear correlation between maximum rCBV values obtained with P-CT and DSC-MR imaging was evident. The best linear model is CT=slope*MR+error and provides a highly significant estimate of the slope equal to 1.08. Thus CT results can be predicted from MR values. Therefore, it is also possible to predict MR results from CT values by estimating the linear model MR=slope*CT+error. DSC-MR imaging gave lower rCBV average values (4.92+/-1.52) compared with P-CT (5.56+/-1.55). CONCLUSIONS: In our population of patients, P-CT and DSC-MR imaging showed proportional results in rCBV assessment of HGGs, and thus both modalities may be used interchangeably in HGG of the brain. PMID- 22430676 TI - Embolisation of bone metastases from renal cancer. AB - PURPOSE: This study was done to evaluate embolisation for palliative and/or adjuvant treatment of bone metastases from renal cell carcinoma and discuss the clinical and imaging results. MATERIALS AND METHODS: We retrospectively studied 107 patients with bone metastases from renal cell carcinoma treated from December 2002 to January 2011 with 163 embolisations using N-2-butyl cyanoacrylate (NBCA). Mean tumour diameter before embolisation was 8.8 cm and mean follow-up 4 years. Clinical and imaging effects of treatment were evaluated at follow-up examinations with a pain score scale, analgesic use, hypoattenuating areas, tumour size and ossification. RESULTS: A clinical response was achieved in 157 (96%) and no response in six embolisations of sacroiliac metastases. Mean duration of clinical response was 10 (range 1-12) months. Hypoattenuating areas resembling tumour necrosis were observed in all patients. Variable ossification appeared in 41 patients. Mean maximal tumour diameter after embolisation was 4.0 cm. One patient had intraprocedural tear of the left L3 artery and iliopsoas haemorrhage and was treated with occlusion of the bleeding vessel with NBCA. All patients had variable ischaemic pain that recovered completely within 2-4 days. Postembolisation syndrome was diagnosed after 15 embolisations (9.2%). Transient paraesthesias in the lower extremities were observed after 25 embolisations (25%) of pelvis and sacrum metastatic lesions. CONCLUSIONS: Embolisation with NBCA is recommended as primary or palliative treatment of bone metastases from renal cell carcinoma. Strict adherence to the principles of transcatheter embolisation is important to avoid complications. PMID- 22430677 TI - Long-term outcome of radiofrequency thermal ablation (RFA) of liver metastases from colorectal cancer (CRC): size as the leading prognostic factor for survival. AB - PURPOSE: The aim of this study was to review some prognostic factors for survival after radiofrequency ablation (RFA) of metastases from colorectal cancer (CRC). MATERIALS AND METHODS: From 1996 to 2009, 262 patients with metastases from CRC were treated with RFA. Fourteen were lost to follow-up. The following predictors were analysed in the remaining 248: synchronous/metachronous metastases, single/multiple metastases, diameter of largest metastasis and absence/presence of extrahepatic metastases. Survival was measured from the date of metastasis diagnosis and from the date of RFA. RESULTS: Survival at 1, 2, 3 and 5 years was 93%, 78%, 62% and 35% from metastasis diagnosis, and 84%, 59%, 43% and 23% from the date of RFA. Median survival was 41 months in patients with largest metastasis <=3 cm and 21.7 months for those with metastases >3 cm (p=0.0001); survival increased to 45.2 months in patients with largest metastasis <=2.5 cm and fell to 18.5 months in those with metastasis >3.5 cm. Median survival of patients with extrahepatic metastases was significantly lower than that of patients without extrahepatic disease (23.3 vs. 32.6 months, p=0.018). CONCLUSIONS: In light of our long-term results obtained with commonly used equipment, small lesion size (diameter of largest lesion <=3 or 2.5 cm) proved to be the most favourable prognostic factor for survival in patients with CRC metastases to the liver treated with RFA. This conclusion is probably related to the possibility of obtaining radical ablation and points to the usefulness of devices allowing ablation of larger volumes. In the presence of extrahepatic metastases, RFA has less impact on survival, even though it is potentially useful in patients at a higher risk of death due to hepatic rather than extrahepatic metastases. PMID- 22430678 TI - CT-MR integrated diagnostic imaging of the oral cavity: neoplastic disease. AB - The oral cavity is a complex anatomical region consisting of different anatomical sites and subsites. Cancer undoubtedly represents the most frequent and relevant disease of this region. Clinical examination is often the first approach to oral cavity tumours. Cross-sectional computed tomography (CT) and magnetic resonance imaging (MRI) play a key role in staging locoregional disease by demonstrating submucosal spread and involvement of deep layers; evaluation of specific pathways of spread to peculiar anatomical subsites is also fundamental information that can be obtained with these techniques. The purpose of this paper is to illustrate CT and MRI findings of anatomical subsites involved by tumours of the oral cavity. PMID- 22430679 TI - Study of breast implant rupture: MRI versus surgical findings. AB - PURPOSE: This study evaluated the role of breast magnetic resonance (MR) imaging in the selective study breast implant integrity. MATERIALS AND METHODS: We retrospectively analysed the signs of breast implant rupture observed at breast MR examinations of 157 implants and determined the sensitivity and specificity of the technique in diagnosing implant rupture by comparing MR data with findings at surgical explantation. RESULTS: The linguine and the salad-oil signs were statistically the most significant signs for diagnosing intracapsular rupture; the presence of siliconomas/seromas outside the capsule and/or in the axillary lymph nodes calls for immediate explantation. CONCLUSIONS: In agreement with previous reports, we found a close correlation between imaging signs and findings at explantation. Breast MR imaging can be considered the gold standard in the study of breast implants. PMID- 22430680 TI - An empirical calibration method for an a-Si portal imaging device: applications in pretreatment verification of IMRT. AB - PURPOSE: A new calibration method for an amorphous silicon (a-Si) electronic portal imaging device (EPID) used for dose measurements in pretreatment verification (field-related) of intensity-modulated radiation therapy (IMRT) with sliding-window technique. The method is independent of data contained in the multileaf collimator (MLC) leaf-motion files and of any calculations made by the treatment planning system (TPS). MATERIALS AND METHODS: Sensitivity of the EPID is dependent on radiation energy. For fluence-modulated fields, different dose/reading calibration factors are associated with each pixel of the image acquired by calculating equivalent areas representing the exact ratio between primary and scatter components. The dose measured in the detector plane was compared with that calculated with TPS by using gamma-analysis. Each calibration factor was compared with that calculated by considering the individual contributions of primary and secondary radiation obtained using the convolution method with analytical kernel for homogeneous media. RESULTS: In 837/854 (98%) of the clinical fields analysed, the proportion of irradiated area in which the gamma-index was <1.0 exceeded 95%. The overall average gamma-index was 0.39. There was good agreement between the dose/reading calibration factors obtained with the empirical algorithm and with the convolution method. CONCLUSIONS: The proposed calibration method is suitable for routine clinical pretreatment verification in IMRT. PMID- 22430681 TI - Role of multidetector CT angiography and contrast-enhanced ultrasound in redefining follow-up protocols after endovascular abdominal aortic aneurysm repair. AB - PURPOSE: Contrast-enhanced ultrasonography (CEUS) is an appealing alternative to computed tomography angiography (CTA) for the follow-up of patients who underwent endovascular abdominal aortic aneurysm repair (EVAR). We sought to evaluate the accuracy of CEUS compared with a particularly tailored protocol of CTA performed with a 64-row multidetector CT. MATERIALS AND METHODS: The study prospectively enrolled 88 consecutive patients for CEUS and CTA imaging during follow-up after EVAR, yielding 142 paired examinations. The outcome is represented by three main goals: identification and characterisation of endoleaks, evaluation of graft patency and measurement of aneurysm diameter. Triple-phase CTA was the gold standard. RESULTS: Sensitivity and specificity of CEUS compared with CTA in endoleak and graft patency evaluation were 91.89% and 100% and 72% and 100%, respectively. A very high correlation between CTA and CEUS diameter measurements was established. CEUS did not appear superior to CTA in endoleak detection, probably because a tailored CTA protocol with a delayed phase (180 s) allows detection of low-flow endoleaks. CONCLUSIONS: Patient management was not different following CEUS and CTA results. CTA cannot yet be completely replaced, but several limitations (radiation exposure, contrast agent) encourage redefining the routine follow-up imaging modality. We suggest an algorithm of surveillance alternating CTA and CEUS. PMID- 22430682 TI - Natural history of honeycombing: follow-up of patients with idiopathic pulmonary fibrosis treated with single-lung transplantation. AB - PURPOSE: Although honeycombing is one of the key features for the diagnosis of idiopathic pulmonary fibrosis (IPF), its origin and evolution are still poorly understood. The aim of our study was to analyse the natural history of honeycombing in patients treated with single-lung transplantation. MATERIALS AND METHODS: We considered seven patients who underwent single-lung transplantation; two of them (28.6%) were excluded from our analysis because they died in the posttransplantation period, whereas the remaining five (71.4%) were evaluated with computed tomography (CT) over 67.6+/-38.56 months. Each CT scan was assessed for disease extension and cyst size (visual score and size of target cysts); CT scans acquired after 2006 were also assessed for native lung volume. RESULTS: All patients showed disease progression (with a concurrent reduction in lung volume in two, 40%) and a progression of honeycombing, with increased number and size of cysts in four (80%). We observed dimensional changes in all target cysts (enlargement or reduction); three patients (60%) also had radiological evidence of complications, such as spontaneous rupture with pneumothorax and development of mycetomas within the cysts. CONCLUSIONS: Honeycombing is a dynamic process in which the overall trend is represented by a dimensional increase in cystic pattern; however, single cysts may have a different evolution (enlargement, reduction or complications). This behaviour could be explained by the variety of the pathogenetic processes underlying honeycombing, with cysts that may present abnormal communication with the airway, including the development of a check valve mechanism. PMID- 22430683 TI - Contribution of magnetic resonance imaging to the diagnosis and monitoring of multiple sclerosis. AB - Magnetic resonance (MR) imaging is an extremely sensitive modality for detecting focal changes to the white matter (WM) in patients with multiple sclerosis (MS). For this reason, it has become an integral part of the diagnostic workup of patients with clinically isolated syndromes who are at risk of developing definite MS, and it is always recommended in patients with definite MS to confirm the diagnosis and monitor the disease course. Crucial to the use of MR imaging for diagnostic purposes is the identification of lesion features - in terms of site, shape and size - that may be considered suggestive or typical for MS, and thus help in the differential diagnosis with other neurological diseases with similar clinical presentation to MS. This need has led to the publication of several guidelines for characterising MS lesions on both dual-echo (T2 and proton density) and T1-weighted sequences after administration of contrast material. Developments in clinical research into MS have highlighted the need to formulate a diagnosis as far as possible on the basis of objective and reproducible criteria. Currently, when making a clinical diagnosis and monitoring patients with suspected MS, neurologists and neuroradiologists make use of specific diagnostic criteria that have changed over the years and will probably continue to be updated. It is therefore crucial for radiologists to become familiar with these criteria in order to improve the quality of their diagnostic assessment. In patients with a definite diagnosis of MS, on the other hand, the main problem is to define standard procedures for monitoring the course of the disease and response to pharmacological treatments. even though no guidelines currently exist, it is possible to suggest some strategies to improve the assessment in this setting. PMID- 22430684 TI - Role of first pass and delayed enhancement in assessment of segmental functional recovery after acute myocardial infarction. AB - PURPOSE: Assessing myocardial viability is crucial in decision making and prognostic restratification after acute myocardial infarction (MI). A number of noninvasive imaging modalities have been employed in viability identification, but contrast-enhanced magnetic resonance (MR) imaging has been shown to be extremely accurate because of its transmural resolution and precise definition of microvascular obstruction. Our purpose was to assess functional recovery after acute MI, with special focus on the role of infarct transmurality and microvascular obstruction. MATERIALS AND METHODS: Forty-six consecutive patients with first acute MI, reperfused by primary percutaneous transluminal coronary angioplasty (PTCA) (n=40) or fibrinolysis (n=6), underwent MR imaging within the first week to assess oedema, microvascular obstruction, function and viability and then again after 4-6 months to assess functional recovery and scar. RESULTS: At first MR examination, postcontrast images were analysed according to three patterns, based on a combination of first-pass and delayed-enhancement data: pattern 1 (normal first pass and late hyperenhancement <50% thickness) identified viable myocardium, whereas pattern 2 (late hyperenhancement >50% thickness, with or without first-pass perfusion defect) and pattern 3 (perfusion defect at first pass and late hypoenhancement) recognised nonviable myocardium, with 93% sensitivity, 75% specificity, 92% positive predictive value and 78% negative predictive value for identifying viable tissue. Furthermore, by dividing pattern 2 into two subpatterns, 2A and 2B, based on absence or presence of microvascular obstruction in >50% transmural infarcts, we were able to better identify the segments without recovery or that were nonviable with a 1.39 relative risk of failed recovery. CONCLUSIONS: After acute MI, not all infarcts with transmurality >50% can be considered nonviable; microvascular obstruction detected at first pass can help to better stratify these cases. PMID- 22430685 TI - Long-term efficacy of endovascular treatment of isolated iliac artery aneurysms. AB - PURPOSE: The aim of this study was to evaluate the efficacy of endovascular treatment of isolated iliac artery aneurysms (IIAA) and compare our data with those reported in the literature. MATERIALS AND METHODS: From May 2005 to December 2010, 32 patients (31 men and one woman; mean age 73+/-12 years) with a total of 40 IIAAs underwent endovascular treatment at our institute. We evaluated technical success, long-term patency, early and late complications and overall mortality. RESULTS: At a median follow-up of 36 months, we achieved a technical success of 100%, a primary patency of 95% and a secondary patency of 100%, with complete exclusion of the aneurysm in 84.6% of cases. In 12.8% of cases, there was a reduction in aneurysm sac volume, with an incidence of type II endoleak of 12.8%. Overall survival at 1, 2, 3, and 6 years was 96.8%, 84.2%, 66.6% and 64%, respectively. CONCLUSIONS: Our study documents the effectiveness of endovascular treatment of iliac aneurysms, which has become the first-choice treatment at our institute. This finding is consistent with the most recent literature and confirms the safety and long-term patency of stent-graft placement. PMID- 22430686 TI - Evaluation of an automated dental unit water system's contamination control protocol. AB - BACKGROUND: This study addresses the efficacy of an automated decontamination protocol using the germicide 'tetra acetyl ethylene diamine (TAED) perborate' (Farmec SpA, Italy). The germicide TAED perborate protocol is used in the Castellini Dental Units fitted with an Autosteril unit (an automated device that can cycle 0.26% TAED perborate solution and sterile water for cleaning the water system between patients and overnight). Prior to testing the Autosteril and the 0.26% TAED perborate protocol on the Logos Jr Dental Unit (Castellini SpA, Italy), TAED perborate was used on a dental unit water system simulation device. METHODS: A dental unit water system simulation device equipped with four dental unit water systems and with naturally grown and mature biofilm contamination was used in this study (three treatment units and one control). One treatment group used a simulated 5 minutes contact with TAED perborate and sterile water for irrigation; the second used a simulated 5 minutes contact with TAED perborate and 2 ppm ClO2 for irrigation; the third used a simulated 5 minutes contact with TAED perborate and municipal water for irrigation. The control group used municipal water for irrigation with no cleaning/disinfection protocols. This protocol was repeated for 30 cycles. Laser scanning confocal microscopy (LSCM) was used to study the effects on natural and mature biofilms, and R2A agar used to quantify heterotrophic plate counts in the effluent irrigant. Antimicrobial efficacy was evaluated by challenging TAED perborate with microbes and spores (M. smegmatis and B. subtilis). Deleterious effects of the germicide were evaluated on metal and nonmetal parts of dental unit water systems. Heterotrophic plate counts using R2A agar and LSCM of the lines were conducted to assess biofilm and microbial control. RESULTS: Baseline water samples showed mean contamination >5.6 log10 cfu/ml. After initial cleaning, all three groups maintained mean contamination levels of less than 1.1 (SD <0.3) log10 cfu/ml. LSCM of baseline samples was positive for live biofilm in all groups. At the end of the study, viable biofilm was only present in the control. In the microbial challenge test, all vegetative organisms were killed within 30 seconds of contact, while spores were killed within 5 minutes. Corrosion was seen in metals used in US-manufactured dental unit materials, while not observed in those used in the Castellini Logos Jr dental unit. CONCLUSION: In this study, the TAED perborate protocol was effective in biofilm control and control of dental treatment water contamination. Use of sterile water or 2 ppm ClO2 along with TAED treatment also controlled planktonic contamination effectively. CLINICAL SIGNIFICANCE: Environmental biofilms contaminate dental unit water systems over time and affect the quality of dental treatment water. Contaminants include environmental biofilms, microbes, including gram-negative rods and endotoxins in high doses that are not of acceptable quality for treating patients. There are many germicidal protocols for treating this contamination and one such is the prescribed use of TAED perborate used in conjunction with sterile water for irrigation in the autosteril device, an integral component of the Castellini dental units for between patient decontamination of dental unit water systems. This study was conducted on an automated simulation dental unit water system to test the TAED perborate protocol's efficacy on naturally grown, mature environmental biofilms, it's efficacy on microbes and spores and it's effects on materials used in dental unit water systems. This translational research addresses both microbial control and material effects of TAED perborate in studying efficacy and possible deleterious effects and simulated use in dentistry. Currently, this antimicrobial use protocol is followed worldwide in the Castellini dental units that are used in day-to-day dental patient care. PMID- 22430687 TI - Comparative evaluation of guided tissue regeneration with use of collagen-based barrier freeze-dried dura mater allograft for mandibular class 2 furcation defects (a comparative controlled clinical study). AB - AIM: The aim of periodontal surgery is complete regeneration. The present study was designed to evaluate and compare clinically soft tissue changes in form of probing pocket depth, gingival shrinkage, attachment level and hard tissue changes in form of horizontal and vertical bone level using resorbable membranes. MATERIALS AND METHODS: Twelve subjects with bilateral class 2 furcation defects were selected. After initial phase one treatment, open debridement was performed in control site while freezedried dura mater allograft was used in experimental site. Soft and hard tissue parameters were registered intrasurgically. Nine months reentry ensured better understanding and evaluation of the final outcome of the study. RESULTS: Guided tissue regeneration is a predictable treatment modality for class 2 furcation defect. There was statistically significant reduction in pocket depth as compared to control (p < 0.01). There is statistically significant increase in periodontal attachment level within control and experimental sites showed better results (p < 0.01). For hard tissue parameter, significant defect fill resulted in experimental group, while in control group, less significant defect fill was found in horizontal direction and nonsignificant defect fill was found in vertical direction. CONCLUSION: The results showed statistically significant improvement in soft and hard tissue parameters and less gingival shrinkage in experimental sites compared to control site. CLINICAL SIGNIFICANCE: The use of FDDMA in furcation defects helps us to achieve predictable results. This cross-linked collagen membrane has better handling properties and ease of procurement as well as economic viability making it a logical material to be used in regenerative surgeries. PMID- 22430688 TI - Effect of three different mouthrinses on microleakage of composite resin restorations with two adhesive systems after bleaching with 10% carbamide peroxide. AB - AIM: The aim was to evaluate the effects of Oral-B (OB), Listerine (LN) and Rembrandt Plus (RM) mouthrinses on microleakage of composite resin restorations bonded with two adhesive systems after bleaching with 10% carbamide peroxide. MATERIALS AND METHODS: A total of 60 Cl V cavities were prepared on human premolars. The occlusal and gingival margins were placed 1 mm occlusal to and apical to CEJ respectively. The teeth were randomly divided into two groups based on the adhesive system used: Excite (EX) and Clearfil SE Bond (CSE) groups. After composite resin restoration of cavities, thermocycling and bleaching with 10% carbamide peroxide for 2 hours daily for 14 days, the teeth in each adhesive group were further subdivided into three subgroups and were immersed for 12 hours in the three OB, RM and LN mouthrinses. The teeth were then placed in 2% basic fuschin for 24 hours. After dissecting the teeth, microleakage was evaluated under a stereomicroscope at 16*. Data was analyzed with multifactor ANOVA and Bonferroni test at p < 0.05. RESULTS: Microleakage with EX was significantly higher than that with CSE (p = 0.009). Microleakage at gingival margins was significantly higher than that at occlusal margins (p = 0.15). Microleakage with OB was higher than that with LN (p = 0.02). However, there were no significant differences in microleakage between LN and RM (p = 1) and between RM and OB (p = 0.15). In addition, with the EX adhesive system, microleakage with OB was higher than that with LN and RM (p = 0.02). CONCLUSION: In the present study, microleakage of composite resin restorations was influenced by the type of the adhesive system, mouthrinse type and the location of the cavity margin. CLINICAL SIGNIFICANCE: Use of some mouthrinses, such as OB after bleaching can increase postrestoration microleakage of resin composite restorations bonded with etch-and rinse adhesive systems. PMID- 22430689 TI - Effect of smear layer on the apical seal of endodontically treated teeth: an ex vivo study. AB - AIM: The purpose of this study was to evaluate the effect of smear layer on apical seal of endodontically treated teeth. MATERIALS AND METHODS: Sixty freshly extracted human maxillary central incisor teeth were selected and were randomly divided into two experimental groups. Group A of 25 teeth and group B of 25 teeth and a control group of 10 teeth. Cleaning and shaping of the root canals were performed using endodontic K-files up to no. 50 size file in step-back technique. During the process, in root canals of group A, 17% EDTA (ethylenediaminetetraacetic acid) followed by 3% NaOCl (sodium hypochlorite) was used as root canal irrigant. In group B, MTAD (mixture tetracycline citric acid and detergent) was used as a root canal irrigant. In control group, saline was used as root canal irrigant. The root surfaces were then coated with nail polish of both experimental groups and control group. The samples were then immersed in India ink dye for 1 week at 37 degrees C. RESULTS: The statistical analysis of the results showed that the apical leakage was significantly more in teeth, where smear layer was not removed. CONCLUSION: The removal of smear layer improves the longterm apical seal and success of endodontically treated teeth. CLINICAL SIGNIFICANCE: The development and maintenance of apical seal is desirable and considered to be a major prerequisite to improve the outcome of root canal treatment. PMID- 22430690 TI - In vitro comparative study of the microbial leakage of one-step, thermafil and lateral condensation techniques. AB - AIM: To compare the apical seal of lateral condensation technique, thermafil and one-step by using this model. MATERIALS AND METHODS: A two-chamber bacterial microleakage model using E. faecalis as microbial marker was used for evaluation of the leakage. Bacterial penetration was monitored over a 60-day period. Leakage was recorded when turbidity was observed in the lower chamber. RESULTS: After comparing the bacterial penetration values, total penetration was observed 45% in lateral condensation technique, 80% in thermafil and 75% in one-step. There was no significant difference between groups after 60 days; however, the microleakage in lateral condensation group was seen later than one-step and thermafil. CONCLUSION: Thermafil and one-step obturator can be advocated as effective obturation techniques for achieving predictable success in endodontic therapy. CLINICAL SIGNIFICANCE: Thermafil and one-step obturator are suitable devices for obturation. PMID- 22430691 TI - Comparison of reproducibility of natural head position using two methods. AB - Lateral cephalometric radiographs have become virtually indispensable to orthodontists in the treatment of patients. They are important in orthodontic growth analysis, diagnosis, treatment planning, monitoring of therapy and evaluation of final treatment outcome. AIM: The purpose of this study was to evaluate and compare the maximum reproducibility with minimum variation of natural head position using two methods, i.e. the mirror method and the fluid level device method. MATERIALS AND METHODS: The study included two sets of 40 lateral cephalograms taken using two methods of obtaining natural head position: (1) The mirror method and (2) fluid level device method, with a time interval of 2 months. Inclusion criteria * Subjects were randomly selected aged between 18 to 26 years Exclusion criteria * History of orthodontic treatment * Any history of respiratory tract problem or chronic mouth breathing * Any congenital deformity * History of traumatically-induced deformity * History of myofacial pain syndrome * Any previous history of head and neck surgery. RESULTS: The result showed that both the methods for obtaining natural head position-the mirror method and fluid level device method were comparable, but maximum reproducibility was more with the fluid level device as shown by the Dahlberg's coefficient and Bland-Altman plot. The minimum variance was seen with the fluid level device method as shown by Precision and Pearson correlation. CONCLUSION: The mirror method and the fluid level device method used for obtaining natural head position were comparable without any significance, and the fluid level device method was more reproducible and showed less variance when compared to mirror method for obtaining natural head position. CLINICAL SIGNIFICANCE: Fluid level device method was more reproducible and shows less variance when compared to mirror method for obtaining natural head position. PMID- 22430692 TI - Clinical evaluation of caries removal in primary teeth using conventional, chemomechanical and laser technique: an in vivo study. AB - AIM: To evaluate four different techniques of caries excavation in primary teeth in terms of efficacy, efficiency and pain experienced during the procedure. MATERIALS AND METHODS: Sample of 120 teeth from children aged 5 to 9 years were equally divided into 4 groups - Air rotor (group A), Carisolv (group B), Papacarie (group C) and Er:YAG laser (group D). Visual and tactile criteria along with DIAGNOdent pen value was used to evaluate efficacy. Time was recorded to determine efficiency and FLACC scale was used to assess the pain experienced. RESULTS: Air rotor and laser were more effective and efficient method whereas laser and CMCR methods were more comfortable methods. CONCLUSION: Laser irradiation and CMCR methods are comparable to conventional methods in terms of effectiveness and are less painful methods. CLINICAL SIGNIFICANCE: Newer techniques of CMCR and laser irradiation of dentinal caries are minimally invasive methods and are less painful and thus should be more frequently employed in pediatric dentistry. PMID- 22430693 TI - Comparative evaluation of few physical properties of epoxy resin, resin-modified gypsum and conventional type IV gypsum die materials: an in vitro study. AB - AIM: To compare and evaluate few physical properties of epoxy resin, resin modified gypsum and conventional type-IV gypsum die material. MATERIALS AND METHODS: In the present study, dimensional accuracy, surface detail reproduction and transverse strength of three die materials like epoxy resin (Diemet-E), resin modified gypsum (Synarock) and conventional type-IV gypsum (Ultrarock) are analyzed. For dimensional accuracy, master die (Bailey's die) is used and calibrations were made with digital microscope. For surface detail reproduction and transverse strength, rectangular stainless steel master die (Duke's die) was used and calibrations were made with Toolmaker's microscope and Instron universal testing machine respectively. One-way analysis of variance (ANOVA) was performed on the means and standard deviation for groups of each test. RESULTS: The results of the study showed statistically significant difference among these materials in dimensional accuracy, surface detail reproduction and transverse strength. CONCLUSION: Epoxy resin exhibited superiority in dimensional accuracy, surface detail reproduction and transverse strength and is nearest to the standards of accurate die material. PMID- 22430694 TI - Alliance of oral hygiene practices and abrasion among urban and rural residents of Central India. AB - OBJECTIVES: To attain alliance between the oral hygiene practices with prevalence of tooth abrasion among urban and rural adult population of Central India. To plan dental care services in inaccessible areas and to suggest appropriate remedial measures to prevent this avertable and self-inflicted injury of teeth in this cross-sectional study. MATERIALS AND METHODS: A sum of 1045 adult residents both from Urban (529) and rural (516) parts of Bhopal district (Central India) was selected on a random basis. The multistage sampling technique was adopted to ascertain the sample size. In urban area the study population consisted of 240 males, 289 females and 201 males and 315 females in rural area respectively. All residents above 18 years of age from the Bhopal district were included in cross sectional study. Assessment form comprises of questionnaire and general information on oral hygiene practices, dietary habits and medical history. Abrasion was assessed using diagnostic criteria recommended by Smith and Knight (modified). Chi- square test was used to test associations between categorical variables at 5% level of significance. Regression analysis attempted to define for risk factors causing abrasion. Literature on the prevalence of abrasion is very sparse, so attempt is made to correlate the etiological factors and recommend to prevent tooth wear. RESULTS: Investigation of this cross-sectional study was aggregate of 1045 residences. Result shows high prevalence of abrasion 70.2%. Higher prevalence concomitant with diffident habits related to oral hygiene maintenance was recorded more among rural (76.9%) when compared to urban dwellers (63.7%). Presence of abrasion verifies statistical significance in relation to age, rural urban difference and variations in habit of oral hygiene care. Stated in the present study, avertable and self-inflicted is tooth abrasion, recurrently resulted by the reprehensible brushing method and common use of indigenous material for the maintenance of oral hygiene. CONCLUSION: Shows significant liaisons with the presence of abrasions in relation to Urban and rural dwelling, age, material used and mode of brushing and duration of brushing. Indigenous and course material causes high amount of enamel wear and with the advancement in age abrasion tend to increase. Prevalence of abrasion does not show any gender predilection. Cultural believes, lifestyle and transition reflects in deviating presence of abrasion in populations. PMID- 22430695 TI - Reattachment of fractured anterior teeth-determining fracture strength using different techniques: an in vitro study. AB - AIM: The aim of this in vitro study was to evaluate and compare the shear bond strength of teeth reattached with sixth generation dentin bonding agent: Xeno III and microhybrid resin composite: Esthet-X, using three different techniques: (1) Simple reattachment, (2) overcontour and (3) internal dentinal groove. METHODOLOGY: A total of 70 human maxillary central incisors were selected and divided into four groups as follows. Group I: Control group comprised of 10 samples. Group II: Simple reattachment, group III: Overcontour and group IV: Internal dentinal groove. Groups II, III and IV comprised of 20 samples each. The teeth in three study groups were sectioned using a diamond disk and the fragment was reattached with Esthet-X and Xeno III using three different techniques. Specimens were stored in tap water for 24 hours and shear bond strength was determined using universal testing machine using a knife edge chisel (0.5 mm in cross-section) at a crosshead speed of 1 mm/minute. RESULTS: The results of this study showed following mean value of fracture strength in Kgf: Group I: Control 27.71; group II: Simple reattachment-9.78; group III: Overcontour-24.41; group IV: Internal dentinal groove-23.83. CONCLUSION: The overcontour technique had the highest strength recovery while the simple reattachment had the lowest. CLINICAL SIGNIFICANCE: The overcontour technique provided strength recovery almost similar to intact teeth emphasizing that tooth preparation influenced fracture resistance. PMID- 22430696 TI - Effect of three different core materials on the fracture resistance of endodontically treated deciduous mandibular second molars: an in vitro study. AB - Endodontic treatment makes the tooth brittle due to loss of bulk of tooth structure, decrease in the moisture content of dentin and dentin elasticity. The following study was carried out to evaluate the effect of endodontic treatment on the fracture resistance of the tooth and reinforcing ability of three different core materials. The following study comprised of sample size of 30 deciduous second molars divided into control group (6) and test group (24). Access opening was done in 24 and 18th teeth with access opening were restored with three different core materials namely IRM (6), silver amalgam (6), GIC (6). All the 30 were subjected to fracture test using UTM (Universal testing machine)- Instron 95. Result showed a drastic reduction in the fracture resistance of the tooth on access opening (1/3rd) and out of the three core materials glass ionomer was shown to be the best core material giving the highest fracture registrance followed by silver amalgam and IRM. PMID- 22430697 TI - Antimicrobial activity of commercially available essential oils against Streptococcus mutans. AB - INTRODUCTION: Many essential oils have been advocated for use in complementary medicine for bacterial and fungal infections. However, few of the many claims of therapeutic efficacy have been validated adequately by either in vitro testing or in vivo clinical trials. OBJECTIVE: To study the antibacterial activity of nine commercially available essential oils against Streptococcus mutans in vitro and to compare the antibacterial activity between each material. METHODOLOGY: Nine pure essential oils; wintergreen oil, lime oil, cinnamon oil, spearmint oil, peppermint oil, lemongrass oil, cedarwood oil, clove oil and eucalyptus oil were selected for the study. Streptococcus mutans was inoculated at 37oC and seeded on blood agar medium. Agar well diffusion assay was used to measure antibacterial activity. Zone of inhibition was measured around the filter paper in millimeters with vernier caliper. RESULTS: Cinnamon oil showed highest activity against Streptococcus mutans followed by lemongrass oil and cedarwood oil. Wintergreen oil, lime oil, peppermint oil and spearmint oil showed no antibacterial activity. CONCLUSION: Cinnamon oil, lemongrass oil, cedarwood oil, clove oil and eucalyptus oil exhibit antibacterial property against S. mutans. CLINICAL SIGNIFICANCE: The use of these essential oils against S. mutans can be a viable alternative to other antibacterial agents as these are an effective module used in the control of both bacteria and yeasts responsible for oral infections. PMID- 22430698 TI - Mandibular reconstruction using AO/ASIF stainless steel reconstruction plate: a retrospective study of 36 cases. AB - AIM: The study was aimed at esthetic and functional results as well as patient tolerance after reconstruction with reconstruction plate. The follow-up ranged from 1 to 4 years. MATERIALS AND METHODS: A retrospective study of 36 patients who had mandibular reconstruction with AO/ASIF stainless steel reconstruction plates after oncologic resection was evaluated. The indications and postoperative outcomes were studied. RESULTS: At the end of study, 24 of 36 patients (67%) still had the plate in place. Around three (8%) plates were fractured. Nine (25%) plates got exposed leading to surgical intervention. Surgical results were satisfying, particularly when looking at delayed healing or long-term tolerance. Esthetic (79% rated results as good or acceptable) and functional results of this reconstruction were satisfying. CONCLUSION: We conclude by saying that reconstruction plate provides a solution for safe and rapid mandibular reconstruction for patients with poor prognosis or poor condition. This method also preserves the possibility of secondary reconstruction. CLINICAL SIGNIFICANCE: The reconstruction plate may be a good clinical choice for safe and rapid mandibular reconstruction. PMID- 22430699 TI - An assessment of skeletal craniofacial asymmetry in South Indian population. AB - The present study was undertaken to assess the skeletal craniofacial asymmetry in South Indian population by a posteroanterior cephalometric radiographic method. The skeletal craniofacial structures on one side of the face were compared with that of the other, by drawing various triangles representing different craniofacial regions. The sample consisted of 60 subjects (30 males and 30 females) aged between 18 to 25 years, who were mainly dental college students from South India. Overall 52 X-rays were obtained, with four errors each in the male and the female groups. The results revealed that the total facial structures in the South Indian population were larger on the left side (statistically insignificant). The cranial base area exhibited a greater degree of asymmetry than any other component area of the face, which might be due to the inaccuracy at the condylar point. PMID- 22430700 TI - Dimensional accuracy and details of the panoramic cross-sectional tomographic images: an in vitro study. AB - INTRODUCTION: Transversal slicing system (TSS) of Planmeca PM 2002 CC is a tomographic technique which enables us to take cross-sectional views of jaws. Tomographic imaging modalities are commonly applied to acquire cross-sectional images of the jaws for preimplant assessment of bone. Among the available tomographic imaging modalities, panoramic radiography is the most accessible imaging system. MATERIALS AND METHODS: Study was conducted using 25 mandibles, out of these five were used for linear dimensional accuracy measurement and the rest 20 were utilized to study the details within the mandible. Study was aimed to evaluate dimensional stability in the images using different parameters, such as determination of direction of slice, determination of horizontal and vertical magnification, angular distortion, three dimensional distortion and determination of details. RESULTS: For the direction of slice and for determination of horizontal and vertical magnification change in + 5o to - 5o was in acceptable limit. In determination of details, it was found that there was great discrepancy in readings given by nonradiologist which offset the mean value which was attributed to lack of training for interpretation of the observers. CONCLUSION: 99% of the readings were in the clinically acceptable limits. CLINICAL SIGNIFICANCE: The easy availability, use of routine equipment, the low cost, low radiation dose for cross-sectional radiography make the TSS most preferred modality. PMID- 22430701 TI - Effect of different impression techniques on the dimensional accuracy of impressions using various elastomeric impression materials: an in vitro study. AB - Production of exemplary crowns and fixed partial dentures depends upon the usage of impression material and its technique of usage that accurately reproduces prepared teeth and their relationship to the adjacent oral structure. AIM: To evaluate the linear dimensional accuracy of the elastomeric impressions using various impression techniques using different combinations of viscosities of impression materials. MATERIALS AND METHODS: Crown preparation was done in a dentulous acrylic resin denture base model with six natural teeth embedded into it was made to represent the dentulous maxillary arch. A total of 55 impressions were obtained and poured in die stone using various impression techniques with different combinations of viscosities of impression materials. RESULTS: Among the six techniques used, the heavy body light body two-step technique using custom tray showed the least distortion which was closely followed by the putty wash two step technique with 2 mm spacer using stock tray. CONCLUSION: The study revealed that the heavy body light body two-step technique with custom tray provided the best results. CLINICAL SIGNIFICANCE: Dimensional accuracy of impressions is very much required for precisely fitting of prosthesis. This study may be helpful to select the technique and materials as per clinical requirement of accuracy of impressions. PMID- 22430702 TI - Dental education: current scenario and future trends. AB - India has more than 290 dental institutions, producing over 25,000 BDS graduates every year. There are three main characteristics that are shared by any profession: Delivering the best possible education to its students, giving priority to public service over self-interest and enforcing regulations and codes of ethics through self-government. Dentistry in India is currently being challenged to maintain the professionalism. This is partly a result of pressures applied to the educational system. This article discusses some challenges in brief and attempts to attend the challenges in positive manner. PMID- 22430703 TI - Juvenile scleredema of Buschke. AB - AIM: To recognize a line of treatment for scleredema of Buschke in an adolescent. BACKGROUND: Scleredema of Buschke is an uncommon disorder characterized by induration of the skin, which includes a non pitting hardening of the skin around the neck, shoulders, and trunk sometimes the face. Three variants are recognized. The histopathologic features of scleredema are characterized by thickened collagen bundles within the reticular dermis that are separated by mucin containing fenestrations. No consistent treatment modality is currently followed. CASE REPORT: The present case report describes scleredema of Buschke in a 10-year old female child reported with stiffness of facial skin and difficulty in opening the mouth. The patient was treated with antibiotics and vitamin supplements and there was drastic improvement with decrease in skin stiffness and increase in mouth opening. The stiffness of facial muscles decreased and mouth opening increased. CONCLUSION: Multiple treatment modalities for scleredema have been used. In the present case, high-dose antibiotic therapy was used with good prognosis. CLINICAL SIGNIFICANCE: High-dose antibiotic therapy can be used for treatment of dermatologic disorders with reasonably good prognosis. PMID- 22430704 TI - Expansive focal cemento-osseous dysplasia. AB - AIM: To present a case of expansive focal cemento-osseous dysplasia and emphasize the importance of differential diagnosis. BACKGROUND: Cemento-osseous dysplasia is categorized into three subtypes on the basis of the clinical and radiographic features: Periapical, focal and florid. The focal type exhibits a single site of involvement in any tooth-bearing or edentulous area of the jaws. These lesions are usually asymptomatic; therefore, they are frequently diagnosed incidentally during routine radiographic examinations. Lesions are usually benign, show limited growth, and do not require further surgical intervention, but periodic follow-up is recommended because occasionally, this type of dysplasia progresses into florid osseous dysplasia and simple bone cysts are formed. CASE REPORT: A 24 year-old female patient was referred to our clinic for swelling in the left edentulous mandibular premolarmolar region and felt discomfort when she wore her prosthetics. She had no pain, tenderness or paresthesia. Clinical examination showed that the swelling in the posterior mandible that was firm, nonfluctuant and covered by normal mucosa. On panoramic radiography and computed tomography, a well defined lesion of approximately 1.5 cm in diameter of mixed density was observed. The swelling increased slightly in size over 2 years making it difficult to use prosthetics and, therefore, the lesion was totally excised under local anesthesia, and surgical specimens were submitted for histopathological examination. The histopathological diagnosis was focal cemento-osseous dysplasia. CONCLUSION: In the present case, because of the increasing size of the swelling making it difficult to use prosthetics, young age of the patient and localization of the lesion, in the initial examination, cemento-ossifying fibroma was suspected, and the lesion was excised surgically; the histopathological diagnosis confirmed it as focal cemento-osseous dysplasia. CLINICAL SIGNIFICANCE: We present a case of expansive focal cemento-osseous dysplasia. Differential diagnosis is essential because ossifying fibroma is a real neoplastic entity. PMID- 22430705 TI - Management of dens invaginatus type III with large periradicular lesion. AB - AIM: This study describes a clinical case of type III dens invaginatus with an extensive periradicular lesion treated successfully. BACKGROUND: Dens invaginatus is a maldevelopment of the dental germ which occurs as a result of the invagination of the enamel organ. These cases may present difficulties with respect to its diagnosis and treatment because of canal morphology. The success of endodontic therapy requires a knowledge of dental anatomy and its anomalies. CASE REPORT: A 17-year-old female patient is reported presenting right maxillary lateral incisor (tooth no. 7) classified as type III dens invaginatus with necrotic pulp and presence of an extensive radiolucid lesion. Endodontic treatment was recommended for tooth. However, intracanal exudate was present, suggesting a resistant infection. Enucleation of the lesion was performed as a complementary approach. The root canal obturation was carried out by the gutta percha thermoplastification technique with root canal sealer, followed by restoration of the tooth. Healing of the lesion with hard tissue formation was confirmed at follow-up. CONCLUSION: A combination of endodontic and surgical treatments were fundamental to the maintenance of the tooth. The treatment was considered successful. CLINICAL SIGNIFICANCE: Root canal therapy of dens invaginatus should be based on a thorough clinical and radiographic evaluation. The knowledge of classification and anatomical variations of teeth with dens invaginatus are of great importance for correct treatment. PMID- 22430706 TI - Single visit replacement of maxillary canine using fiber-reinforced composite resin. AB - Missing a canine is of serious concern in social life of a patient in most of societies. While conventional fixed partial dentures and implant-supported restorations may often be the treatment of choice, fiber-reinforced composite (FRC) resins offer a conservative, fast and cost-effective alternative for single and multiple teeth replacement. This clinical report presents two cases where FRC technology was successfully used to restore canine edentulous area in terms of esthetic-cosmetic values and functionality. PMID- 22430707 TI - Endodontic management of maxillary supplementary premolar using cone-beam computed tomography. AB - Extra teeth in dentition is termed as 'supernumerary teeth' and is a very well known dental developmental anomaly. Supernumerary premolars are a rare anomaly in the maxillofacial complex. Its rarity and complex characteristics often makes it difficult to treat. Radiographs play an important role in assessment of both the location and the typing of supernumerary teeth. This article reports the rare case of 'nonsyndromic bilateral maxillary supernumerary premolars' in which the endodontic management of supernumerary premolar tooth is described. In this case the value of cone-beam computerized tomography is also emphasized. CLINICAL SIGNIFICANCE: Developmental anomalies can occur in any tooth and supplementary premolars are no exception. The complexity of such teeth has to be considered for planning endodontic treatment to increase the chances of success. PMID- 22430708 TI - What causes durability reduction in tooth-colored resin restorations? PMID- 22430709 TI - Supporting implementation: the role of community development teams to build infrastructure. AB - Evidence-based methods for assisting consumers, such as counties, in successfully implementing practices are lacking in the field of implementation science. To fill this gap, the Community Development Teams (CDT) approach was developed to assist counties in developing peer networks focused on problem-solving and resource sharing to enhance their possibility of successful implementation. The CDT is an interactive, solution-focused approach that shares many elements of the Interactive Systems Framework (ISF) for Dissemination and Implementation. An ongoing randomized implementation trial of Multidimensional Treatment Foster Care (MTFC) was designed to test the hypothesis that such interactive implementation methods are more successful at helping counties achieve successful and sustainable MTFC programs than standard individualized implementation methods. Using the Stages of Implementation Completion measure, developed for this study, the potential benefit of these interactive methods is examined at different stages of the implementation process ranging from initial engagement to program competency. PMID- 22430710 TI - States find creative ways to finance cancer programs: specialty license plates, sin taxes, and lotteries help states generate revenue for research, prevention, and treatment. PMID- 22430711 TI - Research links heavy alcohol consumption with lung cancer. PMID- 22430712 TI - Improved survival, treatment response associated with BRCA2 genetic mutation. PMID- 22430713 TI - Rhodium-catalysed intramolecular trans-bis-silylation of alkynes to synthesise 3 silyl-1-benzosiloles. AB - Intramolecular addition of a Si-Si bond across a C-C triple bond occurs in a trans fashion in the presence of rhodium(I) catalysts. The trans-bis-silylation reaction of (2-alkynylphenyl)disilanes affords 3-silyl-1-benzosiloles. PMID- 22430714 TI - Effect of location in the canopy on the colour development of three apple cultivars during growth. AB - BACKGROUND: Homogeneity in appearance is one of the quality aspects asked for in the supply chain. Decreasing the biological variation in batches of harvested apples (cultivars Braeburn, Fuji and Gala) becomes increasingly important. Skin colour is one of the aspects that determine both optimal harvest and stage of development. Skin colour is affected by location in the canopy. The rules of development of biological variation are now established and will be used on skin colour data. RESULTS: The Minolta colour aspects a*, b* and L* measured before commercial harvest change in a sigmoidal fashion and can be analysed including the biological variation, with a logistic model in indexed nonlinear regression, obtaining explained parts of above 90%. The mechanism of colour change is not affected by state of development or location in the canopy. The location in the canopy affects the intensity of both red and green colouring compounds. The variation in colouration is not affected by the location in the canopy. CONCLUSION: The red-coloured apple cultivar (Gala) depends more on the location in the canopy than the less-coloured cultivars (Fuji and Braeburn). The colour development in Fuji apples is considerably slower, with a much larger variation in stage of development. The location in the canopy affects all aspects of biological variation (biological shift factor and asymptotic starting level of colouration) for all three colour aspects L*, a* and b*, but only the mean value, not the standard deviation. The biological shift factors per colour aspects are linearly related. Once induced, variation remains constant during development. PMID- 22430716 TI - MR imaging of the fetal musculoskeletal system. AB - Magnetic resonance imaging (MRI) appears to be increasingly used, in addition to standard ultrasonography for the diagnosis of abnormalities in utero. Previous studies have recently drawn attention to the technical refinement of MRI to visualize the fetal bones and muscles. Beyond commonly used T2-weighted MRI, echoplanar, thick-slab T2-weighted and dynamic sequences, and three-dimensional MRI techniques, are about to provide new imaging insights into the normal and the pathological musculoskeletal system of the fetus. This review emphasizes the potential significance of MRI in the visualization of the fetal musculoskeletal system. PMID- 22430715 TI - Bacillus Calmette-Guerin (BCG) complications associated with primary immunodeficiency diseases. AB - Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guerin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases. PMID- 22430717 TI - Nuchal translucency screening in triplets: Down syndrome risk calculation taking account of between-fetus correlations. AB - OBJECTIVE: To describe a method for calculating fetus-specific Down syndrome risk in triplets, allowing for nuchal translucency (NT) correlation between fetuses. METHODS: The between-fetus correlation coefficient of log NT, in multiples of the median, was estimated from a series of 95 unaffected triplets. A trivariate log Gaussian model was used to calculate likelihood ratios for discordant and concordant Down syndrome. Applying these to the prior maternal age-specific risk yielded risks in monozygous, dizygous and trizygous triplets. The weighted average risk was then computed with weights relating to chorionicity and assisted reproduction. The method was illustrated. RESULTS: The correlation coefficient in unaffected pregnancies was 0.408 (P < 0.0001; 95% confidence interval 0.30-0.50) and estimated to be 0.205 and 0.107 in triplets pairs with one or two affected fetuses. The illustration showed that very large differences could be obtained in the risks when the extent of correlation in NT between fetuses is taken into account compared with when the measurements are treated as independent. CONCLUSION: Fetus-specific Down syndrome risks in triplets should be calculated using its own NT value and that in the other fetuses, chorionicity, and method of conception. PMID- 22430718 TI - Three-dimensional ultrasound is an accurate and reproducible technique for fetal crown-rump length measurement. AB - OBJECTIVE: The aim of the study was to evaluate the accuracy and reproducibility of fetal crown-rump length (CRL) measurement using three-dimensional ultrasound (3DUS). METHODS: We included a series of women with singleton pregnancy at 6-13 + 6 weeks. Following CRL measurement by the two-dimensional ultrasound (2DUS), a 3DUS volume was acquired. On the reconstructed midsagittal plane, CRL was measured twice by an operator and once by another. The correlation between CRL measured by 3DUS and 2DUS, as well as the intraobserver and interobserver agreement, was then calculated. Furthermore, the agreement between 2DUS and 3DUS CRL measurements together with intraobserver and interobserver agreement was calculated separately for the groups with a midsagittal acquisition plane (MSAP) and non-midsagittal acquisition plane (NMSAP). RESULTS: Overall, 137 pregnancies were included in the analysis. CRL measurements performed using 3DUS showed excellent correlation with 2DUS [intraclass correlation coefficient (ICC) = 0.992]. In addition, the 3DUS showed a high intraobserver and interobserver agreement (ICC = 0.999 and 0.993, respectively). Finally, when we divided the acquired volumes according to the plane of acquisition, excellent 2DUS-3DUS, as well as intraobserver and interobserver agreement, was maintained for both MSAP and NMSAP. CONCLUSION: 3DUS is a highly accurate and reproducible tool for fetal CRL measurement regardless of the fetal position at the time of 3D volume acquisition. PMID- 22430719 TI - Fetal Ebstein's anomaly: early and late appearance. AB - OBJECTIVE: To present sonographic findings in early and late appearance of fetal Ebstein's anomaly. METHODS: Fetal sonography was performed in 53,447 consecutive pregnant women at 14 to 16 weeks' gestation. RESULTS: Ebstein's anomaly was detected in eight fetuses, in four of them additional anomalies were observed. All eight pregnancies were terminated. In an additional fetus, a normal four chamber view without valvular regurgitation was visualized at 15 weeks' gestation. At 24 weeks, a normal four-chamber view was depicted. No Doppler examination was performed at that time. The newborn was found to have Ebstein's anomaly with pulmonary stenosis. A balloon pulmonary valvuloplasty was performed with a good outcome at three months of age. CONCLUSION: Fetal Ebstein's anomaly may be detected in early pregnancy. The incidence is higher than what is reported in newborns. Depiction of a normal fetal heart in early and midpregnancy does not exclude the possibility of subsequent development of Ebstein's anomaly. PMID- 22430720 TI - Evaluation of population parameters and mathematical strategies for the calculation of prenatal risk of Down syndrome in the first trimester of pregnancy. AB - OBJECTIVE: To evaluate the population parameters applied to the calculation of risk for Down syndrome (DS) in the first trimester screening (FTS) and the comparison of performance obtained including or excluding maternal age from the mathematical algorithm. METHODS: Three different calculation engines for prenatal risk of DS were developed on the basis of the population parameters from the Serum, Urine and Ultrasound Screening Study, the Fetal Medicine Foundation, and a combination of both of them. These calculators were evaluated in 14,645 first trimester pregnant women, including 59 DS affected fetuses, comparing their performance with that obtained by our commercial software Elipse(r) (Perkin Elmer Life and Analytical Sciences, Turku, Finland). Advanced first trimester screening (AFS) strategy was also analyzed, and a hybrid strategy (FTS + AFS) was evaluated. RESULTS: By selecting population parameters from the Serum, Urine and Ultrasound Screening Study, the detection rate increased from 76% (Elipse) to 86% with a small increase in the false positive rate (FPR), from 3.3% to 3.7%, respectively. DS screening performance significantly improved by using the hybrid strategy (AFS in pregnant women under 35 years and FTS in pregnant women over 35 years), with a 92% detection rate (FPR: 3.9%). CONCLUSIONS: In the present study, a new hybrid screening strategy has been proposed to achieve DS detection rates higher than 90%, for a convenient <4% FPR. PMID- 22430721 TI - Nasal bone assessment in fetuses with trisomy 21 at 16-24 weeks of gestation by three-dimensional ultrasound. AB - OBJECTIVE: This study aims to investigate the length and shape of the nasal bones in fetuses with trisomy 21 at 16-24 weeks' gestation. METHOD: We acquired three dimensional volumes of the fetal profile from 41 fetuses with trisomy 21. The multiplanar mode was used to measure nasal bone length in the exact midsagittal plane and in parasagittal and oblique views of the fetal face and to examine the nasal bones in the coronal plane. RESULTS: There was bilateral absence of the nasal bones in 11 (26.8%) cases and unilateral absence in one (2.4%). In 29 (70.7%) cases with present nasal bones, there was progressive over-estimation of nasal bone length when measured in parasagittal and oblique views compared to measurements taken in the exact midsagittal plane. In the coronal plane, in 18 of 29 (62.1%) fetuses with trisomy 21, the nasal bones were divergent, whereas in 131 of 135 (97.0%) euploid fetuses, the bones were entirely fused in the midline. CONCLUSION: Parasagittal and oblique scanning planes may produce over-estimation of nasal bone length in trisomy 21 fetuses because they often have divergent nasal bones. Consequently, it is essential that measurement of nasal bone length is carried out in the exact midsagittal plane of the face. PMID- 22430722 TI - Perinatal course of Ebstein's anomaly and tricuspid valve dysplasia in the fetus. AB - OBJECTIVE: We sought to better define echocardiographic predictors of perinatal mortality in fetuses with Ebstein's anomaly (EA) or tricuspid valve dysplasia (TVD). METHOD: Parameters included measured chamber size, the presence of hydrops, and Doppler recordings of the left ventricular (LV) myocardial performance index (MPI). RESULTS: Between 1 January 2000 and 31 December 2008, 21 fetuses were diagnosed with either EA (17) or TVD (4). Five fetuses were lost to follow-up, and 12 of 16 fetuses were born live (75%). Survivors were found to have smaller right atrial area index scores when compared with non-survivors (1.025 +/- 0312 vs 1.502 +/- 0.105, respectively, p = 0.013) and were less likely to present with hydrops (0% survivors vs 75% of non-survivors, p < 0.01). LV MPI sub-analysis revealed a shorter combined isovolemic contraction and relaxation time for non-survivors compared wth survivors (46.5 +/- 8.2 ms vs 82.3 +/- 21.2 ms, respectively, p = 0.004) although no difference was observed for LV ejection times or overall LV MPI between survivors and non-survivors. CONCLUSION: Physiologic analysis of left ventricular function via the LV Tei index and its component measurements demonstrates potentially novel insights into hemodynamic derangements and their association with outcomes in patients with EA/TVD. PMID- 22430723 TI - Quantitative description of the morphology and ossification center in the axial skeleton of 20-week gestation formalin-fixed human fetuses using magnetic resonance images. AB - OBJECTIVES: Human tissues are usually studied using a series of two-dimensional visualizations of in vivo or cutout specimens. However, there is no precise anatomical description of some of the processes of human fetal development. The purpose of our study is to develop a quantitative description of the normal axial skeleton by means of high-resolution three-dimensional magnetic resonance (MR) images, collected from six normal 20-week-old human fetuses fixed in formaldehyde. METHODS: Fetuses were collected after spontaneous abortion and subsequently fixed with formalin. They were imaged using a 1.5 T MR scanner with an isotropic spatial resolution of 200 um. The correct tissue discrimination between ossified and cartilaginous bones was confirmed by comparing the images achieved by MR scans and computerized axial tomographies. The vertebral column was segmented out from each image using a specially developed semi-automatic algorithm. RESULTS: Vertebral body dimensions and inter-vertebral distances were larger in the lumbar region, in agreement with the beginning of the ossification process from the thoracolumbar region toward the sacral and cephalic ends. CONCLUSION: In this article, we demonstrate the feasibility of using MR images to study the ossification process in formalin-fixed fetal tissues. A quantitative description of the ossification centers of vertebral bodies and arches is presented. PMID- 22430724 TI - Intracranial translucency at 11-13 weeks of gestation: prospective evaluation and reproducibility of measurements. AB - OBJECTIVE: This paper aimed to determine the feasibility of identification and measurement reproducibility of intracranial translucency (IT) in our population. METHODS: This is a prospective study in which five accredited operators attempted to identify and measure the IT during first-trimester sonographic screening for aneuploidy in 990 fetuses. The presence or absence of spina bifida was determined at the time of the second-trimester scan or after birth. Measurement reproducibility was assessed through intraclass correlation coefficient (ICC) on a subgroup of 150 fetuses. RESULTS: Identification and measurement of the IT were possible in 961 (97%) cases. The mean IT anteroposterior diameter was 1.8 mm (SD +/- 0.37; range 0.8-3.1), and the size increased linearly with advancing gestation (IT = 0.74 + 0.02 * crown-rump length; r(2) = 0.15, p < 0.0001). The only fetus with spina bifida in this series presented with absent IT. Intra observer and inter-observer ICCs were 0.79 and 0.75, respectively (95% confidence intervals 0.72-0.84 and 0.67-0.81, respectively; both p < 0.001). CONCLUSIONS: The IT increases linearly with increasing crown-rump length and seems to be of value in the first-trimester detection of spina bifida. It is easy to identify and measure and shows excellent intra-observer and inter-observer reproducibility measurements. PMID- 22430725 TI - Body stalk anomaly: adverse maternal outcomes in a series of 21 cases. AB - OBJECTIVE: To evaluate the demographic characteristics of cases with body stalk anomaly (BSA) and describe the obstetric outcome. METHOD: Retrospective review of a case series of BSA diagnosed from 2000 to 2010. RESULTS: Among the 21 cases, mean gestational age at diagnosis was 22 weeks (range 11-35 weeks). Ten cases elected termination of pregnancy, which was performed at a median gestational age of 24 weeks. One termination of pregnancy at 33 weeks' gestation in a woman with late diagnosis of BSA and a previous uterine scar, required cesarean section during labor because of clinical signs of uterine rupture. Of the remaining 11 cases, four were lost to follow-up, three delivered vaginally, three underwent elective cesarean sections, and one underwent cesarean section because of obstructed labor. Six of seven cases were growth restricted and six of seven were small for gestational age. There were no abnormal karyotypes among the nine cases which underwent cytogenetic studies. CONCLUSION: Continuation of pregnancy in the presence of BSA is associated with greater maternal risks, in the form of labor complications requiring cesarean section. This information should be discussed with couples at the time of diagnosis. PMID- 22430726 TI - Outcome in fetuses with isolated congenital diaphragmatic hernia with increased nuchal translucency thickness in first trimester. AB - OBJECTIVE: To examine the possible association between increased nuchal translucency (NT) thickness in the first trimester and perinatal outcome in isolated congenital diaphragmatic hernia (CDH). METHODS: We conducted a retrospective study between January 2004 and June 2010. The database was searched to identify all consecutive cases of CDH referred to the fetal medicine center of Necker Hospital in Paris. Enlarged NT was defined above the 95th centile. Only children born alive with an isolated CDH were selected for the analysis of prognostic factors. We also studied the correlation between NT thickness in the first trimester and lung-to-head ratio, observed to expected lung area-to-head ratio, lung volume estimated by magnetic resonance imaging, and other prenatal features of intrathoracic compression. RESULTS: Seventy-one cases of isolated CDH were available. The fetal NT was above the 95th centile in 9 of the 71 cases. Neonatal death occurred in 7/9 (78%) cases with enlarged NT, compared with 24/62 (38%) with normal NT (P = 0.035). Enlarged NT was significantly associated with prenatal features of intrathoracic compression. CONCLUSION: Enlarged NT thickness in CDH is associated with a poor outcome and is related to an early intrathoracic compression. PMID- 22430727 TI - Maternal smoking and fetal lung signals--an in utero MRI investigation. AB - OBJECTIVE: To investigate whether fetal lung signals and fetal lung signal progression over gestation observed on magnetic resonance imaging are different in mothers who reported smoking during pregnancy compared with nonsmoking controls. METHOD: Cross-sectional retrospective study of 100 consecutive singleton pregnancies that underwent magnetic resonance imaging. Fetal lung-liver signal intensity ratios of 18 fetuses of mothers who reported smoking during pregnancy were compared with 82 fetuses of nonsmoking controls. RESULTS: Average gestational age at magnetic resonance imaging was 26.4 +/- 5.2 weeks (Range 18.4 38.2 weeks). Cases reported smoking between 2 and 15 cigarettes per day. The mean number of cigarettes per day for cases was 9.2 +/- 3.4. Mean fetal lung-liver signal intensity ratios did not differ significantly between the two groups (p = 0.8). They showed a linear increase with gestational age (r(2) = 0.3). Multiple regression analysis of lung-liver signal intensity ratios using gestational age and smoking status as predictors revealed a significant influence of gestational age (p < 0.0001) but not maternal smoking status (p = 0.8) on fetal lung-liver signal intensity ratios. CONCLUSIONS: Fetuses of mothers who reported smoking during pregnancy show similar lung signals and lung signal progression over gestation on magnetic resonance imaging as nonsmoking controls. PMID- 22430728 TI - Isolated corpus callosum agenesis: a ten-year follow-up after prenatal diagnosis (how are the children without corpus callosum at 10 years of age?). AB - BACKGROUND: Corpus callosum agenesis (CCA) is generally diagnosed in utero. Outcome appears to be better if the malformation is isolated. The aim of this study, which is the first one with a long (10 years) and standardized follow up, was to report cognitive abilities of children with isolated CCA diagnosed prenatally. METHODS: We prospectively evaluated 17 children. Clinical examinations, neuropsychological tests were performed each year. School achievement and personal and familial data were collected. RESULTS: Twelve children completed the entire follow up. One child was finally considered to have associated CCA, because signs of fetal alcohol syndrome had become obvious. Of the 11 other children, three (27%) had borderline intelligence whereas the intelligence levels of eight (73%) were in the normal range, although half of these children experienced some difficulties in scholastic achievement. Neither epilepsy nor intellectual deficiency was noted and intellectual quotient scores correlated strongly with the mother's education level. CONCLUSION: Although prenatal diagnosis of isolated CCA is reliable, false postnatal diagnoses remain possible (10-20%) even with complete prenatal screening. Outcome is mostly favorable because intelligence is within the normal range for nearly 3/4 of the children. However, they frequently have mild learning difficulties. PMID- 22430729 TI - Identification of novel candidate maternal serum protein markers for Down syndrome by integrated proteomic and bioinformatic analysis. AB - OBJECTIVE: This study aimed to identify candidate protein biomarkers from maternal serum for Down syndrome (DS) by integrated proteomic and bioinformatics analysis. METHODS: A pregnancy DS group of 18 women and a control group with the same number were prepared, and the maternal serum proteins were analyzed by isobaric tags for relative and absolute quantitation and mass spectrometry, to identify DS differentially expressed maternal serum proteins (DS-DEMSPs). Comprehensive bioinformatics analysis was then employed to analyze DS-DEMSPs both in this paper and seven related publications. RESULTS: Down syndrome differentially expressed maternal serum proteins from different studies are significantly enriched with common Gene Ontology functions, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, transcription factor binding sites, and Pfam protein domains, However, the DS-DEMSPs are less functionally related to known DS related genes. These evidences suggest that common molecular mechanisms induced by secondary effects may be present upon DS carrying. A simple scoring scheme revealed Alpha-2-macroglobulin, Apolipoprotein A1, Apolipoprotein E, Complement C1s subcomponent, Complement component 5, Complement component 8, alpha polypeptide, Complement component 8, beta polypeptide and Fibronectin as potential DS biomarkers. CONCLUSION: The integration of proteomics and bioinformatics studies provides a novel approach to develop new prenatal screening methods for noninvasive yet accurate diagnosis of DS. PMID- 22430730 TI - Are there socio-economic inequalities in the uptake of Down syndrome screening in the UK? PMID- 22430731 TI - A novel p63 mutation in a fetus with ultrasound detection of split hand/foot malformation. PMID- 22430732 TI - Unconjugated estriol values between 14 and 22 weeks of gestation in relation to prenatal screening for Down syndrome. PMID- 22430733 TI - Expression of transcription factors controlling alpha inhibin gene expression in placental tissues from pregnancies affected by fetal Down syndrome. PMID- 22430734 TI - C5aR expression in a novel GFP reporter gene knockin mouse: implications for the mechanism of action of C5aR signaling in T cell immunity. AB - C5aR is a G protein-coupled receptor for the anaphylatoxin C5a and mediates many proinflammatory reactions. C5aR signaling also has been shown to regulate T cell immunity, but its sites and mechanism of action in this process remain uncertain. In this study, we created a GFP knockin mouse and used GFP as a surrogate marker to examine C5aR expression. GFP was knocked into the 3'-untranslated region of C5ar1 by gene targeting. We show that GFP is expressed highly on Gr-1(+)CD11b(+) cells in the blood, spleen, and bone marrow and moderately on CD11b(+)F4/80(+) circulating leukocytes and elicited peritoneal macrophages. No GFP is detected on resting or activated T lymphocytes or on splenic myeloid or plasmacytoid dendritic cells. In contrast, 5-25% cultured bone marrow-derived dendritic cells expressed GFP. Interestingly, GFP knockin prevented cell surface but not intracellular C5aR expression. We conclude that C5aR is unlikely to play an intrinsic role on murine T cells and primary dendritic cells. Instead, its effect on T cell immunity in vivo may involve CD11b(+)F4/80(+) or other C5aR-expressing leukocytes. Further, our data reveal a surprising role for the 3'-untranslated region of C5aR mRNA in regulating C5aR protein targeting to the plasma membrane. PMID- 22430735 TI - Morphine and galectin-1 modulate HIV-1 infection of human monocyte-derived macrophages. AB - Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they play a role in the development of this disease, as well as impact the overall course of disease progression. Galectin-1 is a member of a family of beta-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Because the drug abuse epidemic and the HIV-1 epidemic are closely interrelated, we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocyte derived macrophages (MDMs). In this article, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDMs. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDMs. We used a nanotechnology approach that uses gold nanorod galectin-1 small interfering RNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1, and they reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex. PMID- 22430736 TI - The FcRbeta- and gamma-ITAMs play crucial but distinct roles in the full activation of mast cells induced by IgEkappa and Protein L. AB - Previous studies suggested that Protein L (PpL), the bacterial Ig-binding protein, activates mast cells. PpL presumably performs the activation by interacting with membrane-bound IgEkappa, but the underlying mechanisms behind the process remain unclear. In the current study, we found that cell-surface FcepsilonRI expression is a critical factor participant in PpL-mediated full activation of murine mast cells, which includes cytokine production, the degranulation response, and leukotriene C(4) (LTC(4)) release, and that engagement of the FcepsilonRI with IgEkappa and PpL is enough to induce tyrosine phosphorylation of ITAM in the FcRbeta- and gamma-signaling subunits. Introduction of mutations in two canonical tyrosine residues (Y47F/Y58F) of the FcRgamma-ITAM completely abolished the above-mentioned mast cell functions, with the exception of LTC(4) release. Importantly, the FcRbeta-ITAM acts as a signal transducer that is responsible for LTC(4) release independently of the FcRgamma ITAM. Taken together, our results suggest crucial and distinct functions for the FcRbeta- and gamma-ITAMs in the FcepsilonRI-dependent full activation of mast cells induced by IgEkappa and PpL. PMID- 22430737 TI - Truncated and full-length thioredoxin-1 have opposing activating and inhibitory properties for human complement with relevance to endothelial surfaces. AB - Thioredoxin (Trx)-1 is a small, ubiquitously expressed redox-active protein with known important cytosolic functions. However, Trx1 is also upregulated in response to various stress stimuli, is found both at the cell surface and secreted into plasma, and has known anti-inflammatory and antiapoptotic properties. Previous animal studies have demonstrated that exogenous Trx1 delivery can have therapeutic effects in a number of disease models and have implicated an interaction of Trx1 with the complement system. We found that Trx1 is expressed in a redox-active form at the surface of HUVEC and acts as an inhibitor of complement deposition in a manner dependent on its Cys-Gly-Pro-Cys active site. Inhibition occurred at the point of the C5 convertase of complement, regulating production of C5a and the membrane attack complex. A truncated form of Trx1 also exists in vivo, Trx80, which has separate nonoverlapping functions compared with the full-length Trx1. We found that Trx80 activates the classical and alternative pathways of complement activation, leading to C5a production, but the inflammatory potential of this was also limited by the binding of inhibitors C4b-binding protein and factor H. This study adds a further role to the known anti-inflammatory properties of Trx1 and highlights the difference in function between the full-length and truncated forms. PMID- 22430738 TI - Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. AB - During inflammation, accumulation of immune cells in activated lymph nodes (LNs), coupled with a transient shutdown in lymphocyte exit, results in dramatic cellular expansion. Counter-regulatory measures to restrain LN expansion must exist and may include re-establishment of lymphocyte egress to steady-state levels. Indeed, we show in a murine model that egress of lymphocytes from LNs was returned to steady-state levels during prolonged inflammation following initial retention. This restoration in lymphocyte egress was supported by a preferential expansion of cortical and medullary sinuses during late inflammation. Cortical and medullary sinus remodeling during late inflammation was dependent on temporal and spatial changes in vascular endothelial growth factor-A distribution. Specifically, its expression was restricted to the subcapsular space of the LN during early inflammation, whereas its expression was concentrated in the paracortical and medullary regions of the LN at later stages. We next showed that this process was mostly driven by the synergistic cross-talk between fibroblastic reticular cells and interstitial flow. Our data shed new light on the biological significance of LN lymphangiogenesis during prolonged inflammation and further underscore the collaborative roles of stromal cells, immune cells, and interstitial flow in modulating LN plasticity and function. PMID- 22430739 TI - The role of SHIP in the development and activation of mouse mucosal and connective tissue mast cells. AB - Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP's role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-alpha production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kalpha inhibitor-2, as well as with PI3K p85alpha(-/-) BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway. PMID- 22430740 TI - CD8(+) T cells sabotage their own memory potential through IFN-gamma-dependent modification of the IL-12/IL-15 receptor alpha axis on dendritic cells. AB - CD8(+) T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4(+) T cells, leading to the tenet that CD8(+) T cells play a passive role in their own differentiation. In contrast, by using a DNA vaccination model, to separate the events of vaccination from those of CD8(+) T cell priming, we demonstrate that CD8(+) T cells, themselves, actively limit their own memory potential through CD8(+) T cell-derived IFN-gamma-dependent modification of the IL-12/IL-15Ralpha axis on DCs. Such CD8(+) T cell-driven cytokine alterations result in increased T-bet and decreased Bcl-2 expression, and thus decreased memory progenitor formation. These results identify an unrecognized role for CD8(+) T cells in the regulation of their own effector differentiation fate and a previously uncharacterized relationship between the balance of inflammation and memory formation. PMID- 22430741 TI - Fondaparinux versus enoxaprin in the management of acute coronary syndromes in Switzerland: A cost comparison analysis. AB - QUESTION UNDER STUDY: Anticoagulation therapy is routinely used in cases of non ST-segment elevation acute coronary syndromes (NSTE-ACS). The most commonly used drug in such events is enoxaparin, a low molecular weight heparin. Fondaparinux, a synthetic pentasaccharide, is as effective as enoxaparin in terms of survival or residual angina pectoris and significantly reduces bleeding complications. The purpose of this study was to assess the magnitude of cost reductions if enoxaparin were replaced by fondaparinux in Switzerland. METHODS: Costs of hospital stay for NSTE-ACS with or without bleeding complications at the Geneva University Hospitals were determined for patients admitted between July 1st, 2007 and June 30th, 2008. These costs were applied to subjects recruited in the AMIS Plus registry, which gathers information on ACS in Swiss hospitals, using three scenarios. Firstly, using the baseline incidence of bleeding episodes observed in the AMIS plus registry. Secondly, using the baseline incidence of haemorrhagic episodes observed in the Geneva University Hospitals sample and thirdly, using the incidence of haemorrhagic episodes observed in the OASIS-5 study. These results and costs were then extrapolated to the national level. RESULTS: At the Swiss national level, replacement of enoxaparin by fondaparinux would generate annual savings ranging from 854,000 Swiss Francs (scenario 1) to 3,400,000 Swiss Francs (scenario 2) and 2,845,000 Swiss Francs (scenario 3). Estimated savings accounted for 55 to 63% of total hospital costs. CONCLUSIONS: Use of fondaparinux instead of enoxaparin in patients with NSTE-ACS could yield substantial savings at the local as well as the national level in Switzerland. PMID- 22430742 TI - Distribution of granulocyte-monocyte colony-stimulating factor and its receptor alpha-subunit in the adult human brain with specific reference to Alzheimer's disease. AB - Granulocyte-monocyte colony-stimulating factor (GM-CSF) is a member of the hematopoietic growth factor family, promoting proliferation and differentiation of hematopoietic progenitor cells of the myeloid lineage. In recent years, GM-CSF has also proved to be an important neurotrophic factor in the central nervous system (CNS) via binding to the GM-CSF receptor (GM-CSF R). Furthermore, studies on rodent CNS revealed a wide distribution of both the major binding alpha subunit of the GM-CSF R (GM-CSF Ralpha) and its ligand. Since respective data on the expression pattern of these two molecules are still lacking, the present study has been designed to systematically analyze the protein expression of GM CSF and GM-CSF Ralpha in the human brain, with particular emphasis on their regulation in Alzheimer's disease (AD). One major finding is that both GM-CSF and GM-CSF Ralpha were ubiquitously but not uniformly expressed in neurons throughout the CNS. Protein expression of GM-CSF and GM-CSF Ralpha was not restricted to neurons but also detectable in astrocytes, ependymal cells and choroid plexus cells. Interestingly, distribution and intensity of immunohistochemical staining for GM-CSF did not differ among AD brains and age-matched controls. Concerning GM CSF Ralpha, a marked reduction of protein expression was predominantly detected in the hippocampus although a slight reduction was also found in various cortical regions, thalamic nuclei and some brainstem nuclei. Since the hippocampus is one of the target regions of neurodegenerative changes in AD, reduction of GM-CSF Ralpha, with consecutive downregulation of GM-CSF signaling, may contribute to in the progressive course of neurodegeneration in AD. PMID- 22430743 TI - Synthesis and investigation of the metal-metal interactions in early/late heterobimetallic complexes linking group 5 imido fragments to Co(I). AB - Phosphinoamide ligands have been utilized to link a Co(I) center to a Nb or Ta imido fragment. The resulting heterobimetallic complexes, ICo(Ph(2)PN(i)Pr)(3)M=N(t)Bu, have weakened dative metal-metal interactions as a result of the strongly donating imido ligand. These complexes can be reduced by 2 electrons to generate dinitrogen-bound complexes. PMID- 22430744 TI - Response entropy changes after noxius stimulus. AB - Small changes in the frequency of the electromyography could reflect an inadequate anesthetic or analgesic level, and it could be more specific than the hemodynamic monitors. The Datex-Ohmeda S/5 Entropy Module includes information about the electromyographic activity of the face muscles (response entropy--RE). The aim of our study is compare entropy and BIS ability to detect a nociceptive stimulus during a sevoflurane anesthesia. We designed an observational, prospective and descriptive study that included 20 patients. We performed sevoflurane anaesthesia induction, the end-tidal was kept at 3 and 4 %, during 15 min at each concentration, with no analgesic drug and no neuromuscular blocking agent, and we applied a nociceptive stimulus: tetanus 100 Hz, during 5 s. We set the standard monitorization, BIS, RE, and state entropy (SE) along the study. There was a significant difference between RE and SE post-noxious stimulus values at 3 and 4 % end-tidal sevoflurane (p < 0.05). Only RE changed significantly at the moment of the noxious stimulation at both sevoflurane concentrations studied (p < 0.05). In patients under general anesthesia only carried out with sevoflurane at concentrations that inhibit the movement to painful stimuli, the RE is a single parameter able to detect variations after the nociceptive stimulation. PMID- 22430745 TI - Using non invasive dynamic parameters of fluid responsiveness in children: there is still much to learn. PMID- 22430746 TI - [Current status of the studies on breast cancer outcomes. A review of the literature]. AB - Breast cancer is the most frequent neoplasm among women. The Outcomes Research could be a useful tool in managing this kind of tumour. A recent review of the literature evaluates the interest for this kind of research and the possible future evolution. PMID- 22430747 TI - [Cell-based strategies: novel perspectives for cancer therapy]. AB - Cellular therapies represent an emerging field in oncology. Several studies support the efficacy of cell-based immunotherapies for different solid tumors. Recent approaches, however, have been optimized in using adult stem cells, genetically modified to produce cytotoxic molecules for fighting cancer. In this review, we focused major preclinical and clinical results in this fascinating field of cell-based strategies against cancer. PMID- 22430748 TI - [Oncological quality indicators and Colorectal Cancer Program: data from 2009 2010 of University Hospital in Ferrara, Italy]. AB - The aim of this study is to analyse the oncological quality indicators on our Colorectal Cancer Program, that are reflective of the scope of care, feasible to implement and supported by evidence. We compared two different populations during the same period: patients referring to our Clinical Oncology Unit coming from Regional Colorectal Cancer Screening Program and the other population that was not in any Colorectal Cancer Program. On the basis of our experience, we concluded for high-quality care for both population. Any critical point should be carefully analysed in order to implement quality of care. PMID- 22430749 TI - [Pemetrexed monotherapy in previously treated patients with advanced non small cell lung cancer; differences by histology. Our experience]. AB - Emerging data suggest pemetrexed is active in patients with adenocarcinoma of lung compared to those with squamous cell carcinoma. We retrospectively reviewed advanced non small cell lung cancer (NSCLC) patients previously treated, analysing efficacy on histologic characteristics. From January 2007 to December 2010, 25 patients with stage IIIB or IV NSCLC (17 with adenocarcinoma and 8 with squamous cell carcinoma), who had previously failed on platinum-based chemotherapy, received pemetrexed 500 mg/mq every 3 weeks until disease progression or unacceptable toxicities. Analysing the histologic subgroups we observed 1 (5.9%) complete response, partial response in 5 patients (29.4%), stable disease in 6 (35.3%), progression disease in 5 (29.4%) in adenocarcinoma group compared to 4 (50%) stable disease and 4 (50%) progression disease in squamous cell carcinoma group. Median progression free survival was 8 months (range 3-22) for adenocarcinoma patients and 4 months (range 2-6) for squamous cell patients. According to data of the literature, also our small retrospective study conducted on unselected patients confirms the difference of pemetrexed efficacy by histology type, with better results in patients with adenocarcinoma lung cancer. PMID- 22430750 TI - [Benign multicystic peritoneal mesothelioma. A case report]. AB - Benign multicystic peritoneal mesothelioma is a rare malignancy with unknown etiology, first described in 1980, which have been reported to date about 150 cases in the literature. Although the term "benign", used mainly to distinguish it from the classic malignant mesothelioma, a more aggressive cancer, is considered "borderline" in terms of aggression: it tends to local recurrence but cases of lymph node metastases or in other locations at a distance are not described. The symptoms are often vague and nonspecific (abdominal pain, enlarged abdomen and ascites). The common diagnostic imaging techniques (CT, MRI) may appear similar to ovarian or peritoneal cancer by more aggressive mesenchymal neoplasms. Histological examination, accurately with the aid of immunohistochemical techniques, is therefore essential for diagnosis. Treatment is surgical and consists of peritonectomy. After surgery, the prognosis is generally good. In 50% of cases may have local recurrences; so rigorous follow-up is indicated. PMID- 22430751 TI - [Long-term cancer survivorship: definition and clinical implications]. AB - Defining whether long-term cancer survivorship must be considered as a disease stage with its own characteristics, or as a condition ascribable to the state of health of the general population, has significant implications for the intervention proposals and the medical psychosocial rehabilitation. This issue is noteworthy also for the dimensions of this phenomenon and its subjective impact. PMID- 22430752 TI - [From treatment to palliative care: difficult news in oncology]. AB - The transition from oncological treatment to palliative care represents one of the most difficult moments in communicating bad news to patients. Even the most experienced doctor can feel profoundly affected when facing these moments. PMID- 22430753 TI - [Abiraterone acetate: a novel therapeutic option in hormone-refractory prostate cancer]. AB - Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer. With approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the scenary for management of men with metastatic prostate cancer has dramatically changed. Abiraterone acetate was developed to specifically inhibit cytochrome P450 (CYP)17A1, which is an essential enzyme in the biosynthesis of testosterone. In the phase III, the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration-resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile, which was generally similar to that of the placebo plus prednisone group. However, adverse events resulting from elevated mineralocorticoid levels because of CYP17A1 inhibition, fluid retention and oedema, hypokalaemia, hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone. PMID- 22430754 TI - [Drug-induced liver injury]. AB - Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management. PMID- 22430755 TI - Reprogramming non-mammary and cancer cells in the developing mouse mammary gland. AB - The capacity of any portion of the murine mammary gland to produce a complete functional mammary outgrowth upon transplantation to an epithelium-divested fat pad is unaffected by the age or reproductive history of the donor. Likewise, through serial transplantations, no loss of potency is detected when compared to similar transplantations of the youngest mammary tissue tested. This demonstrates that stem cell activity is maintained intact throughout the lifetime of the animal despite aging and the repeated expansion and depletion of the mammary epithelium through multiple rounds of pregnancy, lactation and involution. These facts support the contention that mammary stem cells reside in protected tissue locales (niches), where their reproductive potency remains essentially unchanged through life. Disruption of the tissue, to produce dispersed cells results in the desecration of the protection afforded by the "niche" and leads to a reduced capacity of dispersed epithelial cells (in terms of the number transplanted) to recapitulate complete functional mammary structures. Our studies demonstrate that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary cells, including mouse and human cancer cells, may be sequestered and reprogrammed to perform mammary epithelial cell functions including those ascribed to mammary stem/progenitor cells. PMID- 22430758 TI - Integrins in mammary development. AB - Integrins are ubiquitously expressed major cell surface receptors for extracellular matrix. Integrin interaction with their extracellular ligands triggers activation of the intracellular signaling pathways that control cell shape, motility, proliferation, survival, cell-type-specific gene expression. In this review, we summarize recent studies analyzing contribution of integrins to the control of the mammary morphogenesis and differentiation, function and maintenance of mammary stem and progenitor cells and resume the data from mouse models revealing the contribution of the integrin-mediated signaling to mammary tumorigenesis. PMID- 22430757 TI - Regulation of gene expression by the ubiquitin-proteasome system. AB - Transcription is the foremost regulatory point during the process of producing a functional protein. Not only specific genes need to be turned on and off according to growth and environmental conditions, the amounts and quality of transcripts produced are fine-tuned to offer optimal responses. As a result, numerous regulatory mechanisms converge to provide temporal and spatial specificity for this process. In the past decade, the ubiquitin-proteasome system (UPS), which is best known as a pathway for intracellular proteolysis, has emerged as another pivotal player in the control of gene expression. There is increasing evidence that the UPS has both proteolytic and non-proteolytic functions in multiple aspects of the transcription process, including initiation, elongation, mRNA processing as well as chromatin dynamics. In this review, we introduce the many interfaces between the UPS and transcription with focuses on the mechanistic understanding of UPS function in each process. PMID- 22430756 TI - What is bad in cancer is good in the embryo: importance of EMT in neural crest development. AB - Although the epithelial to mesenchymal transition (EMT) is famous for its role in cancer metastasis, it also is a normal developmental event in which epithelial cells are converted into migratory mesenchymal cells. A prime example of EMT during development occurs when neural crest (NC) cells emigrate from the neural tube thus providing an excellent model to study the principles of EMT in a nonmalignant environment. NC cells start life as neuroepithelial cells intermixed with precursors of the central nervous system. After EMT, they delaminate and begin migrating, often to distant sites in the embryo. While proliferating and maintaining multipotency and cell survival the transitioning neural crest cells lose apicobasal polarity and the basement membrane is broken down. This review discusses how these events are coordinated and regulated, by series of events involving signaling factors, gene regulatory interactions, as well as epigenetic and post-transcriptional modifications. Even though the series of events involved in NC EMT are well known, the sequence in which these steps take place remains a subject of debate, raising the intriguing possibility that, rather than being a single event, neural crest EMT may involve multiple parallel mechanisms. PMID- 22430759 TI - Vibrational spectroscopic studies and DFT calculations of 4-bromo-o-xylene. AB - In the present work, we reported a combined experimental and theoretical study on molecular structure, vibrational spectra and NBO analysis of 4-bromo-o-xylene (BOX). The FT-IR (400-4000 cm(-1)) and FT-Raman spectra (50-3500 cm(-1)) of BOX were recorded. The molecular geometry, harmonic vibrational frequencies and bonding features of BOX in the ground state have been calculated by using the density functional B3LYP method with 6-311++G(d,p)/6-311+G(d,p) higher basis sets. The energy and oscillator strength are calculated by time-dependent density functional theory (TD-DFT). To determine conformational flexibility, molecular energy profile of BOX was obtained by B3LYP method with 6-311++G(d,p) basis set with respect to selected degree of torsional freedom, which gives three stable conformers. Besides, molecular electrostatic potential (MEP), non-linear properties and NMR analysis were performed at DFT level of theory. PMID- 22430760 TI - Synthesis of polysaccharide-b-PEG block copolymers by oxime click. AB - The oxime click reaction is shown to be a straightforward methodology for the synthesis of poly(ethylene glycol) (PEG)-polysaccharide diblock copolymers. The method is applicable to unmodified polysaccharides with a reductive end as demonstrated for dextran, hyaluronic acid and chitosan. Notably the oxime click reaction is applied for the first time to the end modification of polysaccharides. PMID- 22430761 TI - Measure of horizontal and vertical displacement of the acromioclavicular joint after cutting ligament using X-ray and opto-electronic system. AB - INTRODUCTION: Surgical versus orthopedic treatments of acromioclavicular disjunction are still debated. The aim of this study was to measure horizontal and vertical acromion's displacement after cutting the ligament using standard X ray and an opto-electronic system on cadaver. MATERIALS AND METHODS: Ten cadaveric shoulders were studied. A sequential ligament's section was operated by arthroscopy. The sequence of cutting was chosen to fit with Rockwood's grade. The displacement of the acromion was measured on standard X-ray and with an opto electronic system allowing measuring of the horizontal displacement. Statistical comparisons were performed using a paired Student's t test with significance set at p < 0.05. RESULTS: Cutting the coracoclavicular ligament and delto-trapezius muscles cause a statistical downer displacement of the acromion, but not after sectioning the acromioclavicular ligament. The contact surface between the acromion and the clavicle decreases statistically after sectioning the acromioclavicular ligament and the coracoclavicular ligament with no effect of sectioning the delto-trapezius muscles. Those results are superposing with those dealing with the anterior translation. DISCUSSION: The measure concerning the acromioclavicular distance and the coracoclavicular distance are superposing with those of Rockwood. However, there is a significant horizontal translation after cutting the acromioclavicular ligament. Taking into account this displacement, it may be interesting to choose either surgical or orthopedic treatment. CONCLUSION: There is a correlation between anatomical damage and importance of instability. Horizontal instability is misevaluated in clinical practice. PMID- 22430762 TI - Course anomalies of extracranial internal carotid artery and their relationship with pharyngeal wall: an evaluation with multislice CT. AB - PURPOSE: The goal of our study was to measure the prevalence of anomalies in the extracranial segment of internal carotid artery (ICA), to measure the carotid pharyngeal distance (CPD). METHODS: Computed tomography (CT) angiography images of 607 patients were retrospectively examined. The course anomaly and CPD were obtained at different image plane. The patients were divided into four groups according to their age. RESULTS: The incidence of course anomaly in ICA was shown to be 60.3 %. Prevalence of course anomaly showed an increase with age (p < 0.001). Women had more ICAs with a course anomaly than men (p < 0.001). Mean CPD among all ICAs was found to be 11.13 mm. When CPD values were compared between the groups, group 1 and group 2 did not have a significant difference, however, there was a significant difference between other groups (p < 0.05). The CPD significantly decreased with age (p < 0.001). In ICAs that showed a straight course, the mean CPD was 13.0 mm, while in ICAs that showed course anomaly, the mean CPD was determined to be 9.49, showing a significant difference (p < 0.05). CONCLUSION: In conclusion, the number of ICAs that show a course anomaly increases with age, while the CPD decreases. The CPD is decreased in groups that show anomalies. The detection of a decreased CPD before surgery may lower the chance of a perioperative hemorrhage due to artery damage during pharyngeal procedures. Hence, while reporting neck CT angiographies, it may be valuable to also report the presence of ICA anomalies and CPD. PMID- 22430763 TI - A morphometric study of suprarenal gland development in the fetal period. AB - PURPOSE: The present study's purpose was to examine the morphometric development of the suprarenal gland using anatomic dissection methods during the fetal period. METHODS: This study was performed on 172 human fetuses (76 males and 96 females) and 344 fetal suprarenal glands obtained from ages 9-40 weeks of gestation with no external pathology or anomaly. Fetuses were divided into 4 groups between gestational ages as follows: Group 1, 9-12 weeks (first trimester); Group 2, 13-25 weeks (second trimester); Group 3, 26-37 weeks (third trimester); and Group 4, 38-40 weeks (full term). Also, the fetuses were grouped into monthly cohorts: 9-12 weeks 3rd month, 13-16 weeks 4th month, 17-20 weeks 5th month, 21-24 weeks 6th month, 25-28 weeks 7th month, 29-32 weeks 8th month, 33-36 weeks 9th month, and 37-40 weeks 10th month. The suprarenal glands were dissected in the abdominal cavity. The dimensions (width, length, and thickness), volumes and weights of the suprarenal glands were evaluated. The ratio of the fetal suprarenal gland weight/fetal body weight, the ratio of the fetal suprarenal gland volume/fetal kidney volume, and the ratio of the fetal suprarenal gland dimensions/fetal kidney dimensions were evaluated. RESULTS: Mean values and standard deviations of all parameters according to gestational weeks and trimesters were calculated. It is found that all parameters increase with gestational age. There was significant correlation between gestational age and all parameters (p < 0.001). No significant differences were observed between sexes for any of the parameters (p > 0.05). There was no difference between the right and left sides of parameters except the thickness of the suprarenal glands. The left suprarenal glands were thicker than the right. The ratio of suprarenal volumes to kidney volumes was determined, and we observed that the ratio decreased during the fetal period. CONCLUSIONS: We believe that the results obtained from this study will be beneficial in understanding the development of suprarenal glands and also contribute to future studies in obstetrics, perinatology, and fetopathology. PMID- 22430764 TI - Facile, rapid and efficient biofabrication of gold nanoparticles decorated with functional proteins. AB - We report a one-pot biological approach to fabricate gold nanoparticle (AuNP)-ZZ domain conjugates using peptide-functionalized proteins that can simultaneously direct both biomineralization and surface modification of AuNPs. In addition, immuno-AuNPs are readily prepared through the specific binding of antibodies to the ZZ domain on the AuNPs. PMID- 22430765 TI - Microbiological and chemical profiles of naturally fermented table olives and brines from different Italian cultivars. AB - Six naturally fermented (Greek-style) table olives of cultivars Itrana, Peranzana, Cellina di Nardo, Nocellara del Belice and Bella di Cerignola, as well as their corresponding brines, were studied by a combined strategy consisting of chemical, microbiological and molecular analyses. In particular, organic acids, sugars, polyphenols, fatty acids, biogenic amines and cultivable microbiota were detected by standard methods. Moreover, tyramine and histamine producing bacteria were evaluated by an original approach consisting of Reverse-Transcription (RT) qPCR. At the end of the fermentation process, mesophilic lactobacilli and yeasts in brine represented the dominating biota, ranging from 6.25 to 7.84 log CFU/ml and from 6.5 to 7.56 log CFU/ml, respectively. Enterobacteriaceae and pathogens were undetectable in all the samples. In general, table olive preparations differed in chemical composition. In particular, C16:0 and C18:2c9,12 concentrations ranged from 9.9 to 18.8 % and from 5.4 to 15.4 % of total fatty acids, respectively. The main fatty acid detected was C18:1c9 while CLAc9, t11 was present only in traces. Polyphenol concentrations greatly differentiated the final product, depending on the cultivar. A low quantity of biogenic amines was found in some samples and biogenic amines producing bacteria were rapidly detectable by RT-qPCR. PMID- 22430766 TI - Roseovarius litoreus sp. nov., isolated from seawater of southern coast of Korean peninsula. AB - A gram-negative, non-flagellated and ovoid- to rod-shaped bacterial strain, designated GSW-M15(T), was isolated from seawater on the southern coast of South Korea. Strain GSW-M15(T) grew optimally at 30 degrees C, at pH 7.0-7.5 and in the presence of 2 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences revealed that strain GSW-M15(T) belonged to the genus Roseovarius. Strain GSW-M15(T) exhibited highest 16S rRNA gene sequence similarity values (98.3 and 97.5 %) to Roseovarius halotolerans HJ50(T) and Roseovarius pacificus 81-2(T) and 92.8-96.2 % sequence similarity values to the type strains of the other Roseovarius species. Strain GSW-M15(T) contained Q-10 as the predominant ubiquinone and C(18:1) omega7c and 11-methyl-C(18:1) omega7c as the major fatty acids. The major polar lipids detected in strain GSW-M15(T) were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminolipid and two unidentified lipids. The DNA G+C content of strain GSW-M15(T) was 62.9 mol% and its mean DNA-DNA relatedness values with R. halotolerans KCTC 22224(T) and R. pacificus LMG 24575(T) were 33 and 18 %, respectively. Differential phenotypic properties of strain GSW-M15(T), together with the phylogenetic and genetic distinctiveness, demonstrated that this strain is distinguishable from other Roseovarius species. On the basis of the data presented here, strain GSW-M15(T) (=KCTC 23897(T) = CCUG 62218(T)) represents a novel species of the genus Roseovarius, for which the name Roseovarius litoreus sp. nov. is proposed. PMID- 22430767 TI - Crystal-storing histiocytosis: report of a case, review of the literature (80 cases) and a proposed classification. AB - We report a case of crystal storing histiocytosis (CSH) of the upper lip and cheek in a 51-year-old woman and review the clinicopathologic features of 80 cases in the literature. These occurred in 41 men and 39 women with a respective mean age of 59 and 61 years (range 17-81 years). Forty-six patients (58%) had localized CSH, and, of these, 16 (35%) occurred in the head and neck, with the most common site being the eye/orbit. The remaining 34 patients (42%) had generalized CSH primarily involving bone marrow, liver, lymph nodes, spleen and/or kidney. Regardless of whether the CSH was localized or generalized, the vast majority of patients (90%) had an underlying lymphoproliferative or plasma cell disorder, especially multiple myeloma, lymphoplasmacytic lymphoma, or monoclonal gammopathy of undetermined significance. In 7 cases (8.8%), the CSH was associated with a variety of benign disorders, often with an inflammatory background, and no evidence of a clonal lymphoproliferative or plasma cell disorder. Treatment and prognosis varied according to the underlying disease. A classification of CSH based on etiology and/or associated disease and chemical composition of the crystal is proposed, rare non-immunoglobulin variants of CSH are discussed, and a differential diagnosis of other potentially confusing lesions is provided. PMID- 22430769 TI - Ectopic sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary gland: a clinicopathologic and immunophenotypic study of 32 cases with a comprehensive review of the english literature. AB - Ectopic sphenoid sinus pituitary adenoma (ESSPA) may arise from a remnant of Rathke's pouch. These tumors are frequently misdiagnosed as other neuroendocrine or epithelial neoplasms which may develop in this site (olfactory neuroblastoma, neuroendocrine carcinoma, sinonasal undifferentiated carcinoma, paraganglioma, melanoma). Thirty-two patients with ESSPA identified in patients with normal pituitary glands (intact sella turcica) were retrospectively retrieved from the consultation files of the authors' institutions. Clinical records were reviewed with follow-up obtained. An immunohistochemical panel was performed on available material. Sixteen males and 16 females, aged 2-84 years (mean, 57.1 years), presented with chronic sinusitis, headache, obstructive symptoms, and visual field defects, although several were asymptomatic (n = 6). By definition, the tumors were centered within the sphenoid sinus and demonstrated, by imaging studies or intraoperative examination, a normal sella turcica without a concurrent pituitary adenoma. A subset of tumors showed extension into the nasal cavity (n = 5) or nasopharynx (n = 9). Mean tumor size was 3.4 cm. The majority of tumors were beneath an intact respiratory epithelium (n = 22), arranged in many different patterns (solid, packets, organoid, pseudorosette-rosette, pseudopapillary, single file, glandular, trabecular, insular). Bone involvement was frequently seen (n = 21). Secretions were present (n = 16). Necrosis was noted in 8 tumors. The tumors showed a variable cellularity, with polygonal, plasmacytoid, granular, and oncocytic tumor cells. Severe pleomorphism was uncommon (n = 5). A delicate, salt-and-pepper chromatin distribution was seen. In addition, there were intranuclear cytoplasmic inclusions (n = 25) and multinucleated tumor cells (n = 18). Mitotic figures were infrequent, with a mean of 1 per 10 HPFs and a <1% proliferation index (Ki-67). There was a vascularized to sclerotic or calcified stroma. Immunohistochemistry highlighted the endocrine nature of the tumors, with synaptophysin (97%), CD56 (91%), NSE (76%) and chromogranin (71%); while pan-cytokeratin was positive in 79%, frequently with a dot-like Golgi accentuation (50%). Reactivity with pituitary hormones included 48% reactive for 2 or more hormones (plurihormonal), and 33% reactive for a single hormone, with prolactin seen most frequently (59%); 19% of cases were non reactive. The principle differential diagnosis includes olfactory neuroblastoma, neuroendocrine carcinoma, melanoma, and meningioma. All patients were treated with surgery. No patients died from disease, although one patient died with persistent disease (0.8 months). Surgery is curative in the majority of cases, although recurrence/persistence was seen in 4 patients (13.8%). In conclusion, ESSPAs are rare, affecting middle aged patients with non-specific symptoms, showing characteristic light microscopy and immunohistochemical features of their intrasellar counterparts. When encountering a tumor within the sphenoid sinus, ectopic pituitary adenoma must be considered, and pertinent imaging, clinical, and immunohistochemical evaluation undertaken to exclude tumors within the differential diagnosis. This will result in accurate classification, helping to prevent the potentially untoward side effects or complications of incorrect therapy. PMID- 22430770 TI - Striking pathology gold: a singular experience with daily reverberations: sinonasal hemangiopericytoma (glomangiopericytoma) and oncogenic osteomalacia. AB - Sinonasal hemangiopericytoma-like tumors(SNHPC)(glomangiopericytomas)were originally conceived as histologically similar to, but biologically distinct from, their soft tissue counterparts. Re-evaluation of "hemangiopericytiomas" has determined that SNHPC (glomangiopericytomas) represent bona-fide pericyte-derived tumors, whereas most soft tissue neoplasms previously designated as hemangiopericytomas represent cellular variants of solitary fibrous tumors or other lesions with a hemangiopericytomalike growth pattern. We present an interesting case of a woman with SNHPC (glomangiopericytomas) causing oncogenic osteomalacia, and discuss the recent advances in our understanding of phosphaturic mesenchymal tumors. This particular case is an example of "Striking Pathology Gold"-a situation where the pathologist actively guides the diagnostic process, and witnesses its repercussions. "Striking Pathology Gold" may be a rare event in one's career. However it serves to remind us of our place in the world as physicians. Working behind the scenes, we quietly change the course of countless individual destinies for the better. PMID- 22430771 TI - Infectious pseudotumors: red herrings in head and neck pathology. AB - Infectious pseudotumors are tumor-like growths caused by specific microbial organisms. Proliferating histiocytes in these lesions may show atypical cytology with nuclear pleomorphism and increased mitotic activity, erroneously suggestive of malignancies including carcinoma, sarcoma, and lymphoma. Specific and nonspecific immunohistochemical staining profiles may lead to the consideration of a wide range of benign and malignant neoplastic processes. Two such cases are reported. The first is an obstructive endotracheal mass in an AIDS patient caused by Rhodococcus equi infection. The proliferating histiocyes were cytologically atypical with deeply eosinophlic granular cytoplasm leading to the consideration of oncocytic carcinoma, Hurthle cell carcinoma, and pleomorphic rhabdomyosarcoma. The second case is a nasal mass with a microscopic and immunohistochemical profile suggestive of chordoma and paraganglioma. Special microbial stains revealed intracellular bacilli consistent with Klebsiella rhinoscleromatis. In both cases, microbial virulence factors affecting phagocytosis prolonged their intracellular survival and resulted in active histiocytic proliferation. It is of importance that the surgical pathologist be conscious that some infectious processes can clinically and microscopically mimic malignant neoplasms. Accurately identifying these lesions and the specific causative agent is of particular significance since they can be successfully treated with antibiotics. PMID- 22430772 TI - My journey into the world of salivary gland sebaceous neoplasms. AB - As part of this symposium honoring Leon Barnes, the authors were asked to present the case from which they learned the most. I chose a cystic sebaceous lymphadenoma (SL) as my case presentation. This paper presents this unusual case, as well as several additional sebaceous tumors that came across my desk the first few years I was in practice. These interesting cases led me to thoroughly review the literature on sebaceous tumors of the salivary glands, resulting in several publications, the largest series of sebaceous tumors published at this time as well as a careful review of all cases in the literature. The author will also review the current and previous literature on the five types of salivary gland sebaceous tumors: sebaceous adenoma, SL (and non-sebaceous lymphadenoma), sebaceous carcinoma, sebaceous lymphadenocarcinoma, and sebaceous differentiation in other types of salivary gland lesions. PMID- 22430773 TI - Correlation between dysplasia and ploidy status in oral leukoplakia. AB - Oral leukoplakia and other potentially malignant disorders (PMD) may progress to oral squamous cell carcinoma (OSCC). The gold standard for assessing the potential for malignant transformation remains histologic examination with the aim of grading the dysplastic changes. However, not all lesions with dysplasia will progress to OSCC. DNA ploidy has been suggested as a method to predict the clinical behaviour of PMD. This study reports on the use of high-resolution flow cytometry to determine the ploidy status of formalin-fixed, paraffin-embedded material from PMD compared to their dysplasia grade on histology. Aneuploidy was found in 13 % of mild, 31 % of moderate, and 54 % of severe dysplasia cases. This difference was statistically significant (p = 0.011). The differences in ploidy status were more significant when grouping the dysplasia into low-risk and high risk categories (p = 0.008). These findings indicate that the ploidy status of PMD as determined by high-resolution flow cytometry may be of value in predicting biological behaviour in PMD such as leukoplakia. PMID- 22430774 TI - Fates and potentials of thymus-seeding progenitors. PMID- 22430775 TI - Solving the plot: early events are the key to diabetes intervention. PMID- 22430776 TI - IgE class switching and cellular memory. PMID- 22430783 TI - An inflammatory assemblage. PMID- 22430784 TI - Inflammasomes: far beyond inflammation. AB - Nearly a decade ago, the concept of inflammasomes was introduced. Since then, the biochemical characterization of the inflammasomes has led to a richer understanding of innate immune responses in the context of infection and sterile inflammation. This has provided the rationale for successful clinical therapies for a spectrum of hereditary periodic fever syndromes and potentially for some metabolic pathologies. PMID- 22430785 TI - Sensing and reacting to microbes through the inflammasomes. AB - Inflammasomes are multiprotein complexes that activate caspase-1, which leads to maturation of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL 18 and the induction of pyroptosis. Members of the Nod-like receptor (NLR) family, including NLRP1, NLRP3 and NLRC4, and the cytosolic receptor AIM2 are critical components of inflammasomes and link microbial and endogenous danger signals to the activation of caspase-1. In response to microbial infection, activation of the inflammasomes contributes to host protection by inducing immune responses that limit microbial invasion, but deregulated activation of inflammasomes is associated with autoinflammatory syndromes and other pathologies. Thus, understanding inflammasome pathways may provide insight into the mechanisms of host defense against microbes and the development of inflammatory disorders. PMID- 22430786 TI - Regulation of inflammasome signaling. AB - Innate immune responses have the ability to both combat infectious microbes and drive pathological inflammation. Inflammasome complexes are a central component of these processes through their regulation of interleukin 1beta (IL-1beta), IL 18 and pyroptosis. Inflammasomes recognize microbial products or endogenous molecules released from damaged or dying cells both through direct binding of ligands and indirect mechanisms. The potential of the IL-1 family of cytokines to cause tissue damage and chronic inflammation emphasizes the importance of regulating inflammasomes. Many regulatory mechanisms have been identified that act as checkpoints for attenuating inflammasome signaling at multiple steps. Here we discuss the various regulatory mechanisms that have evolved to keep inflammasome signaling in check to maintain immunological balance. PMID- 22430787 TI - Inflammasomes in carcinogenesis and anticancer immune responses. AB - In the complex interplay between malignant cells and their microenvironment, caspase-1 activation complexes (inflammasomes) have contrasting roles. Inflammasomes may operate at the cell-autonomous level to eliminate malignant precursors through programmed cell death or, conversely, may stimulate the production of trophic factors for cancer cells and their stroma. In inflammatory cells, caspase-1 activation can fuel a cycle that leads to sterile inflammation and carcinogenesis, whereas in antigen-presenting cells, inflammasomes can stimulate anticancer immune responses. The inhibition of inflammasomes or neutralization of their products, mainly interleukin 1beta (IL-1beta) and IL-18, has profound effects on carcinogenesis and tumor progression. Thus, inflammasomes are promising therapeutic targets in cancer-related clinical conditions. Here we discuss present and future indications for the clinical use of inflammasome inhibitors. PMID- 22430788 TI - A role for the NLRP3 inflammasome in metabolic diseases--did Warburg miss inflammation? AB - The inflammasome is a protein complex that comprises an intracellular sensor (typically a Nod-like receptor), the precursor procaspase-1 and the adaptor ASC. Inflammasome activation leads to the maturation of caspase-1 and the processing of its substrates, interleukin 1beta (IL-1beta) and IL-18. Although initially the inflammasome was described as a complex that affects infection and inflammation, subsequent evidence has suggested that inflammasome activation influences many metabolic disorders, including atherosclerosis, type 2 diabetes, gout and obesity. Another feature of inflammation in general and the inflammasome specifically is that the activation process has a profound effect on aerobic glycolysis (the 'Warburg effect'). Here we explore how the Warburg effect might be linked to inflammation and inflammasome activation. PMID- 22430796 TI - KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia. AB - Ras-association domain family (RASSF) members are a family of genes containing an RA domain in either the C-terminus (RASSF1-RASSF6) or in the N-terminus (RASSF7 RASSF10). Members of this gene family are core members of the Salvador/Warts/Hippo (SWH) tumor suppressor network and have been shown to be involved in human tumorigenesis. Among the RASSF genes, RASSF1A is one of the most frequently methylated genes in a wide range of epithelial cancers, and we previously demonstrated that RASSF6 and RASSF10 genes are frequently epigenetically inactivated in acute leukemias, particularly in those of the B cell type. We here determined the methylation profiles of all members of the RASSF gene family as well as two recently identified (KIBRA, CRB3) upstream members of the SWH pathway in the leukemic B cells obtained from a well characterized cohort of 95 patients with chronic lymphocytic leukemia (CLL). Among the RASSF genes, RASSF10 (50%) was the most frequently methylated gene, followed by RASSF6 (16%). The remaining RASSF genes were either unmethylated or showed a frequency of methylation < 10%. The upstream SWH member KIBRA was also frequently methylated in CLL (35%) in contrast to CRB3. Interestingly, the analysis of clinical-pathological parameters showed that KIBRA methylation was associated with unfavorable biological prognostic parameters, including unmutated IGHV genes (p = 0.007) and high CD38 expression (p < 0.05). PMID- 22430797 TI - Increased DNA methyltransferase activity and DNA methylation following Epidermal Growth Factor stimulation in ovarian cancer cells. AB - Ovarian cancer progression is correlated with accumulation of aberrant CpG island methylation. In ovarian cancer, ascites fluid contains numerous Epidermal-Growth Factor-Receptor (EGFR) activators, which could result in a tumor microenvironment of constant EGFR activation. Signaling pathways downstream of EGFR, such as Ras, regulate DNA methylation. We hypothesized that chronic EGFR activation could alter DNA methylation. We found that EGFR activation increased DNA methyltransferase (DNMT) activity acutely, as well as after long-term EGF treatment or expression of a mutationally activated EGFR. Furthermore, this increase in DNMT activity was dependent on EGFR catalytic activity and resulted in increased global DNA methylation. Additionally, treatment with the DNMT inhibitor/hypomethylating agent 5-Aza-2'-deoxycytidine (AZA) inhibited the EGF induced increase of both DNMT activity and global methylation. These data support a role for EGFR in the process of accumulated DNA methylation during ovarian cancer progression and suggest that epigenetic therapy may be beneficial for the treatment of ovarian cancer. PMID- 22430798 TI - MethLAB: a graphical user interface package for the analysis of array-based DNA methylation data. AB - Recent evidence suggests that DNA methylation changes may underlie numerous complex traits and diseases. The advent of commercial, array-based methods to interrogate DNA methylation has led to a profusion of epigenetic studies in the literature. Array-based methods, such as the popular Illumina GoldenGate and Infinium platforms, estimate the proportion of DNA methylated at single-base resolution for thousands of CpG sites across the genome. These arrays generate enormous amounts of data, but few software resources exist for efficient and flexible analysis of these data. We developed a software package called MethLAB (http://genetics.emory.edu/conneely/MethLAB) using R, an open source statistical language that can be edited to suit the needs of the user. MethLAB features a graphical user interface (GUI) with a menu-driven format designed to efficiently read in and manipulate array-based methylation data in a user-friendly manner. MethLAB tests for association between methylation and relevant phenotypes by fitting a separate linear model for each CpG site. These models can incorporate both continuous and categorical phenotypes and covariates, as well as fixed or random batch or chip effects. MethLAB accounts for multiple testing by controlling the false discovery rate (FDR) at a user-specified level. Standard output includes a spreadsheet-ready text file and an array of publication-quality figures. Considering the growing interest in and availability of DNA methylation data, there is a great need for user-friendly open source analytical tools. With MethLAB, we present a timely resource that will allow users with no programming experience to implement flexible and powerful analyses of DNA methylation data. PMID- 22430799 TI - Neonatal MeCP2 is important for the organization of sex differences in vasopressin expression. AB - Several neurodevelopmental disorders are marked by atypical Methyl-CpG-binding protein 2 (MeCP2) expression or function; however, the role of MeCP2 is complex and not entirely clear. Interestingly, there are sex differences in some of these disorders, and it appears that MeCP2 has sex-specific roles during development. Specifically, recent data indicate that a transient reduction in MeCP2 within developing amygdala reduces juvenile social play behavior in males to female typical levels. These data suggest that MeCP2 within the amygdala is involved in programming lasting sex differences in social behavior. In the present study, we infused MeCP2 or control siRNA into the amygdala of male and female rats during the first three days of postnatal life in order to assess the impact of a transient reduction in MeCP2 on arginine vasopressin (AVP), a neural marker that is expressed differentially between males and females and is linked to a number of social behaviors. The expression of AVP, as well as several other genes, was measured in two-week old and adult animals. Two-week old males expressed more AVP and galanin mRNA in the amygdala than females, and a transient reduction in MeCP2 eliminated this sex difference by reducing the expression of both gene products in males. A transient reduction in MeCP2 also decreased androgen receptor (AR) mRNA in two-week old males. In adulthood, control males had more AVP immunoreactive (AVP-ir) cells than females in the centromedial amygdala (CMA), bed nucleus of the stria terminalis (BST) and in the fibers that project from these cells to the lateral septum (LS). A transient reduction in MeCP2 eliminated this sex difference. Interestingly, there were no lasting differences in galanin or AR levels in adulthood. Reducing MeCP2 levels during development did not alter estrogen receptoralpha, neurofilament or Foxg1. We conclude that a transient reduction in MeCP2 expression in the developing male amygdala has a transient impact on galanin and AR expression but a lasting impact on AVP expression, highlighting the importance of MeCP2 in organizing sex differences in the amygdala. PMID- 22430800 TI - Maternal dietary protein restriction and excess affects offspring gene expression and methylation of non-SMC subunits of condensin I in liver and skeletal muscle. AB - Recent evidence indicates that maternal nutrition during pregnancy influences gene expression in offspring through epigenetic alterations. In the present study we evaluated the effect of protein excess and deficiency during porcine pregnancy on offspring hepatic and skeletal muscular expression patterns of key genes of methionine metabolism (DNMT1, DNMT3a, DNMT3b, BHMT, MAT2B and AHCYL1), condensin I subunit genes (NCAPD2, NCAPG and NCAPH), important for chromosome condensation and segregation, global DNA methylation and gene-specific DNA methylation. German Landrace sows were randomly assigned to control (CO), high protein (HP) and low protein (LP) diet groups. Tissue samples of offspring were collected from fetal (dpc95), newborn (dpn1), weanling (dpn28) and finisher pigs (dpn188). Gene expression of DNMT1, DNMT3a and DNMT3b was influenced by both HP and LP diets, indicating an involvement of DNA methylation in fetal programming by maternal protein supply. Moreover, hepatic global methylation was significantly affected by protein restriction at dpc95 (p = 0.004) and by protein excess at dpn188 (p = 0.034). Gene expression in fetal liver was significantly different between CO and LP for NCAPD2 (p = 0.0005), NCAPG (p = 0.0009) and NCAPH (p < 0.0001). In skeletal muscle, LP fetuses had significantly altered gene expression of NCAPD2 (p = 0.020) and NCAPH (p = 0.001), compared with CO. Furthermore, NCAPG was differentially methylated among LP, HP and CO; indeed, a significant positive correlation was detected with transcript amount in fetal pigs (r = 0.47, p = 0.002). These data demonstrate that both restriction and excess dietary protein during pregnancy alters the offspring's epigenetic marks and influences gene expression. PMID- 22430801 TI - Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population. AB - Maternal diet affects offspring DNA methylation in animal models, but evidence from humans is limited. We investigated the extent to which gestational intake of methyl donor nutrients affects global DNA methylation in maternal and umbilical cord blood. Among mother-infant pairs in Project Viva, a folate-replete US population, we estimated maternal intakes of vitamin B12, betaine, choline, folate, cadmium, zinc and iron periconceptionally and during the second trimester. We examined associations of these nutrients with DNA methylation, measured as %5-methyl cytosines (%5mC) in Long Interspersed Nuclear Element-1 (LINE-1), in first trimester (n = 830) and second trimester (n = 671) maternal blood and in cord blood at delivery (n = 516). Cord blood methylation was higher for male than female infants {mean [standard deviation (SD)] 84.8 [0.6] vs. 84.4 [0.7]%}. In the multivariable-adjusted model, maternal intake of methyl donor nutrients periconceptionally and during the second trimester of pregnancy was not positively associated with first trimester, second trimester or cord blood LINE-1 methylation. Periconceptional betaine intake was inversely associated with cord blood methylation [regression coefficient = -0.08% (95% confidence interval (CI): -0.14,-0.01)] but this association was attenuated after adjustment for dietary cadmium, which itself was directly associated with first trimester methylation and inversely associated with cord blood methylation. We also found an inverse association between periconceptional choline [-0.10%, 95% CI: -0.17,-0.03 for each SD (~63 mg/day)] and cord blood methylation in males only. In this folate replete population, we did not find positive associations between intake of methyl donor nutrients during pregnancy and DNA methylation overall, but among males, higher early pregnancy intakes of choline were associated with lower cord blood methylation. PMID- 22430802 TI - Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study. AB - Lung function is a strong predictor of mortality. While inflammatory markers have been associated with lung function decrease, pathways are still poorly understood and epigenetic changes may participate in lung function decline mechanisms. We studied the cross-sectional association between DNA methylation in nine inflammatory genes and lung function in a cohort of 756 elderly men living in the metropolitan area of Boston. Participants donated a blood sample for DNA methylation analysis and underwent spirometry at each visit every 3 to 5 y from 1999-2006. We used separate multivariate mixed effects regression models to study the association between each lung function measurement and DNA methylation within each gene. Decreased CRAT, F3 and TLR2 methylation was significantly associated with lower lung function. One interquartile range (IQR) decrease in DNA methylation was associated with lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1), respectively by 2.94% (p < 10 (-4)) and 2.47% (p < 10 (-3)) for F3, and by 2.10% (p < 10 (-2)) and 2.42% (p < 10 (-3)) for TLR2. Decreased IFNgamma and IL6 methylation was significantly associated with better lung function. One IQR decrease in DNA methylation was associated with higher FEV 1 by 1.75% (p = 0.02) and 1.67% (p = 0.05) for IFNgamma and IL6, respectively. These data demonstrate that DNA methylation may be part of the biological processes underlying the lung function decline and that IFNgamma and IL6 may have ambivalent roles through activation of negative feedback. PMID- 22430803 TI - DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract. AB - Cancers of the upper aerodigestive tract (UADT) are common forms of malignancy associated with tobacco and alcohol exposures, although human papillomavirus and nutritional deficiency are also important risk factors. While somatically acquired DNA methylation changes have been associated with UADT cancers, what triggers these events and precise epigenetic targets are poorly understood. In this study, we applied quantitative profiling of DNA methylation states in a panel of cancer-associated genes to a case-control study of UADT cancers. Our analyses revealed a high frequency of aberrant hypermethylation of several genes, including MYOD1, CHRNA3 and MTHFR in UADT tumors, whereas CDKN2A was moderately hypermethylated. Among differentially methylated genes, we identified a new gene (the nicotinic acetycholine receptor gene) as target of aberrant hypermethylation in UADT cancers, suggesting that epigenetic deregulation of nicotinic acetycholine receptors in non-neuronal tissues may promote the development of UADT cancers. Importantly, we found that sex and age is strongly associated with the methylation states, whereas tobacco smoking and alcohol intake may also influence the methylation levels in specific genes. This study identifies aberrant DNA methylation patterns in UADT cancers and suggests a potential mechanism by which environmental factors may deregulate key cellular genes involved in tumor suppression and contribute to UADT cancers. PMID- 22430804 TI - Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. AB - In order to identify novel candidate tumor suppressor genes (TSGs) implicated in renal cell carcinoma (RCC), we performed genome-wide methylation profiling of RCC using the HumanMethylation27 BeadChips to assess methylation at > 14,000 genes. Two hundred and twenty hypermethylated probes representing 205 loci/genes were identified in genomic CpG islands. A subset of TSGs investigated in detail exhibited frequent tumor methylation, promoter methylation associated transcriptional silencing and reactivation after demethylation in RCC cell lines and down-regulation of expression in tumor tissue (e.g., SLC34A2 specifically methylated in 63% of RCC, OVOL1 in 40%, DLEC1 in 20%, TMPRSS2 in 26%, SST in 31% and BMP4 in 35%). As OVOL1, a putative regulator of c-Myc transcription, and SST (somatostatin) had not previously been linked to cancer and RCC, respectively, we (1) investigated their potential relevance to tumor growth by RNAi knockdown and found significantly increased anchorage-independent growth and (2) demonstrated that OVOL1 knockdown increased c-Myc mRNA levels. PMID- 22430805 TI - Peripheral blood DNA methylation profiles are indicative of head and neck squamous cell carcinoma: an epigenome-wide association study. AB - Head and neck cancer accounts for an estimated 47,560 new cases and 11,480 deaths annually in the United States, the majority of which are squamous cell carcinomas (HNSCC). The overall 5 year survival is approximately 60% and declines with increasing stage at diagnosis, indicating a need for non-invasive tests that facilitate the detection of early disease. DNA methylation is a stable epigenetic modification that is amenable to measurement and readily available in peripheral blood. We used a semi-supervised recursively partitioned mixture model (SS-RPMM) approach to identify novel blood DNA methylation markers of HNSCC using genome wide methylation array data for peripheral blood samples from 92 HNSCC cases and 92 cancer-free control subjects. To assess the performance of the resultant markers, we constructed receiver operating characteristic (ROC) curves and calculated the corresponding area under the curve (AUC). Cases and controls were best differentiated by a methylation profile of six CpG loci (associated with FGD4, SERPINF1, WDR39, IL27, HYAL2 and PLEKHA6), with an AUC of 0.73 (95% CI: 0.62-0.82). After adjustment for subject age, gender, smoking, alcohol consumption and HPV16 serostatus, the AUC increased to 0.85 (95% CI: 0.76-0.92). We have identified a novel blood-based methylation profile that is indicative of HNSCC with a high degree of accuracy. This profile demonstrates the potential of DNA methylation measured in blood for development of non-invasive applications for detection of head and neck cancer. PMID- 22430806 TI - DNA methylation pattern of the SLC25A43 gene in breast cancer. AB - Solute carrier family 25A member 43 (SLC25A43) gene is a putative tumor suppressor gene that undergoes loss of heterozygosity (LOH) in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Also, knockdown of SLC25A43 in cell lines influences cell turnover and metabolism. Absence of mutations in this gene in breast cancers prompted us to study methylation as an alternate mechanism for gene inactivation of this X encoded gene. Quantification of CpG site methylation using pyrosequencing was performed upstream of the SLC25A43 gene and at its 5' end in a cohort of breast tumor tissues (n = 80, HER2 positive or negative) with different SLC25A43 gene deletion status. Compared with control tissue, cancer tissues had lower levels of methylation at the 5' and 3' shores of the gene. Cancer tissues with no deletion in the SLC25A43 gene (Del ( )) had higher methylation in the CpG island (CGI) of the gene than cancers carrying the deletion (Del (+)). Methylation in the CGI of the SLC25A43 gene was negatively correlated with age at diagnosis. In HER2 positive breast cancer, ER negativity and lymph node positivity was associated with higher methylation in the CGI and in the adjacent shores of this gene. Our results suggest that methylation in the CGI of the SLC25A43 gene could be an alternate mechanism of gene silencing in the absence of LOH. Also, associations between site-specific methylation and clinicopathological parameters suggest that epigenetic changes in SLC25A43 gene could be of importance in breast carcinogenesis. PMID- 22430807 TI - A fruitful chromatin harvest: meeting summary of the Second European Workshop on Plant Chromatin 2011 in Versailles, France. AB - In September 2011, the Second European Workshop on Plant Chromatin took place in Versailles, France. The workshop covered a range of topics related to plant chromatin biology, including regulation of gene expression by Polycomb group proteins, chromatin dynamics, reconfiguration of epigenetic marks in response to various cues and chromatin assembly. Here, we summarize some of the highlights discussed during the meeting. PMID- 22430808 TI - Neuroplasticity may play a role in inter-individual difference among neuropsychiatric disease treatment efficacy. PMID- 22430809 TI - Association between a genome-wide association study-identified locus and the risk of lung cancer in Japanese population. AB - BACKGROUND: Genome-wide association studies have identified 15q25 and 5p15 as lung cancer risk chromosomal regions in whites. The genetic structures of these loci differ between Asians and whites, however, indicating the need for additional studies in Asian populations. To examine the impact of 15p25 and 5p15 on lung cancer risk and smoking intensity, we conducted a case-control study in Japanese population. We also examined whether these loci modify the effect of smoking behavior on lung cancer risk. METHODS: Subjects were 716 Japanese patients with lung cancer and 716 controls. Associations were examined by logistic regression models with adjustment for potential confounders. RESULTS: We found that the variants of rs12914385 and rs931794 on 15q25 modified the effect of cumulative tobacco smoking on lung cancer risk but that these two loci showed no statistically significant main effects on lung cancer risk. Compared with never smoking without the risk allele of rs931794, odds ratio for heavy smoking without the risk allele was 4.03 (95% confidence interval: 2.45-6.62) and that with the risk allele was 8.09 (5.09-12.9), and the joint effect of rs931734 and cumulative tobacco consumption was statistically significant (pinteraction < 0.001). A similar impact was observed with rs12914385 at chromosome 15q25 (pinteraction = 0.021). Associations for the TERT-CLPM1L locus on 5p15 with lung cancer risk in Japanese patients were of a similar magnitude to those in whites. CONCLUSIONS: These results support the contribution of 15q25 and 5p15 to lung cancer and indicate that the 15q25 region modifies the well-established effect of smoking on the risk of lung cancer in a Japanese population. PMID- 22430810 TI - Primary care research - trade-off between representativeness and response rate of GP teachers for undergraduates. AB - PRINCIPLES: Low response rates are common in primary care research. Our study examines the representativeness of respondents in a survey among general practitioners (GPs). One special aim was to evaluate the representativeness of the subgroup of GP teachers for undergraduates (GPTUs) and to investigate the option of a panel of GPTUs. METHODS: The representativeness of the respondents was assessed by the use of pooled public data to compare the respondents and all GPs in the German federal state of Saxony on the basis of socio-demographic and subject-specific characteristics. The representativeness of the GPTUs was examined in the same way. For the analysis, two-sided t-tests and Chi2 tests were used. RESULTS: The total response rate was low (32.87%). The respondents were not a representative sample; in particular, they were more highly qualified than the mean. However, the response rate among the special group of university-associated GP teachers for undergraduates was significantly higher than among other general practitioners. Because of this, the creation of a panel of these GPTUs for further primary care research was investigated. Unfortunately, analysis of this group showed that GPTUs were not a representative sample as they tended to be younger and more highly qualified. CONCLUSIONS: In general it is possible to create a panel of GPTUs to obtain higher response rates, but investigation of the panel's representativeness is definitely required. If the panel is not representative another option is the creation of a stratified sample according to the target population. PMID- 22430811 TI - Biologically active, magnICON(r)-expressed EPO-Fc from stably transformed Nicotiana benthamiana plants presenting tetra-antennary N-glycan structures. AB - In the past two decades plants have emerged as a valuable alternative for the production of pharmaceutical proteins. Since N-glycosylation influences functionality and stability of therapeutic proteins, the plant N-glycosylation pathway should be humanized. Here, we report the transient magnICON((r)) expression of the erythropoietin fusion protein (EPO-Fc) in Nicotiana benthamiana plants that produce multi-antennary N-glycans without the plant-specific beta1,2 xylose and alpha1,3-fucose residues in a stable manner (Nagels et al., 2011). The EPO-Fc fusion protein consists of EPO with a C-terminal-linked IgG-Fc domain and is used for pulmonary delivery of recombinant EPO to patients (Bitonti et al., 2004). Plant expressed EPO-Fc was quantified using a paramagnetic-particle chemiluminescent immunoassay and shown to be active in vitro via receptor binding experiments in HEK293T cells. Mass spectrometry-based N-glycan analysis confirmed the presence of multi-antennary N-glycans on plant-expressed EPO-Fc. The described research is the next step towards the development of a production platform for pharmaceutical proteins in plants. PMID- 22430812 TI - Dyadic coping among couples with COPD: a pilot study. AB - COPD (chronic obstructive pulmonary disease) is associated with psychological distress for patients as well as their partners. Dyadic coping can be negatively impacted by stressors. This study's objective was to compare the dyadic coping of couples in which one partner suffered from COPD with healthy couples of the same age. A total of 43 complete couples with COPD and 138 healthy couples participated in this pilot study. The surveys were sent by mail. The response rate of the COPD sample was 24.3%. In order to analyze the effect of gender and role (patient vs. partner) on dyadic coping, linear mixed models were calculated. To analyze the effect of gender and group (COPD group vs. normative comparison group) on dyadic coping, two-way analyses of variance were calculated for independent samples. COPD patients and their partners indicated that the patients received more support and were less able to provide support to their partners. This difference was also evident in comparison with the normative comparison group. In addition, couples with COPD perceived higher levels of negative coping and provided a considerably lower assessment of their positive dyadic coping. The dyadic coping of couples with COPD is unbalanced and more negative when compared to that of healthy couples. Interventions aimed at supporting COPD couples should seek to improve couples' dyadic coping in addition to individual coping strategies. PMID- 22430813 TI - The role of parental and adolescent attributions in adjustment of adolescents with chronic illness. AB - Previous literature has demonstrated the separate contributions of parental attributions and adolescent attributions to psychosocial adjustment of adolescents with chronic illness. However, it is unknown whether parental attributions affect adolescents' mental health directly or indirectly by influencing the youths' attributional style. This study evaluated the direct and indirect (through adolescent attributions) effects of parental attributions on internalizing and externalizing problems of adolescents with chronic illness. Adolescents (N = 128; M = 14.7 years) diagnosed with cystic fibrosis or diabetes and their caregivers completed measures of attributional style and adolescent adjustment. Parents' optimistic attributions were associated with fewer adolescent internalizing and externalizing problems. These effects were partly mediated by adolescent attributions. These results suggest that targeting both adolescent and parent attributions may be important for improving adolescents' adjustment to a chronic illness. PMID- 22430814 TI - Chemo-ecological studies on hexactinellid sponges from the Southern Ocean. AB - Hexactinellids (glass sponges) are an understudied class with syncytial organization and poor procariotic associations, thought to lack defensive secondary metabolites. Poriferans, though, are outstanding sources of bioactive compounds; nonetheless, a growing suspicion suggests that many of these chemicals could be symbiont-derived. In Polar latitudes, sponges are readily invaded by diatoms, which could provide natural products. Hexactinellids are typical of deep waters; but in Antarctica, they dominate the upper shelf providing shelter and food supply to many opportunistic mesograzers and macroinvertebrates, which exert strong ecological pressures on them. Aiming to examine the incidence of defensive activities of hexactinellids against consumption, feeding experiments were conducted using their lipophilic fractions. Antarctic hexactinellid and demosponge extracts were tested against the asteroid Odontaster validus and the amphipod Cheirimedon femoratus as putative sympatric, omnivorous consumers. Hexactinellids yielded greater unpalatable activities towards the amphipod, while no apparent allocation of lipophilic defenses was noted. After chemical analyses on the lipophilic fractions from these Antarctic glass sponges, quite similar profiles were revealed, and no peculiar secondary metabolites, comparable to those characterizing other poriferans, were found. Instead, the lipidic compounds 5alpha(H)-cholestan-3-one and two glycoceramides were isolated for their particular outspread presence in our samples. The isolated compounds were further assessed in asteroid feeding assays, and their occurrence was evaluated for chemotaxonomical purposes in all the Antarctic samples as well as in glass sponges from other latitudes by NMR and MS. Characteristic sphingolipids are proposed as chemical markers in Hexactinellida, with possible contributions to the classification of this unsettled class. PMID- 22430815 TI - Ovarian fluid of receptive females enhances sperm velocity. AB - The females of several internal fertilizers are able to store sperm for a long time, reducing the risk of sperm limitation. However, it also means that males can attempt to mate outside females' receptive period, potentially increasing the level of sperm competition and exacerbating sexual conflict over mating. The guppy (Poecilia reticulata), an internally fertilizing fish, is a model system of such competition and conflict. Female guppies accept courtship and mate consensually only during receptive periods of the ovarian cycle but receive approximately one (mostly forced) mating attempt per minute both during and outside their sexually receptive phase. In addition, females can store viable sperm for months. We expected that guppy females would disfavour sperm received during their unreceptive period, possibly by modulating the quality and/or quantity of the components present in the ovarian fluid (OF) over the breeding cycle. Ovarian fluid has been shown to affect sperm velocity, a determinant of sperm competition success in this and other fishes. We found that in vitro sperm velocity is slower in OF collected from unreceptive females than in OF from receptive females. Visual stimulation with a potential partner prior to collection did not significantly affect in vitro sperm velocity. These results suggest that sperm received by unreceptive females may be disfavoured as sperm velocity likely affects the migration process and the number of sperm that reach storage sites. PMID- 22430816 TI - Nanostructured lead-free ferroelectric Na0.5Bi0.5TiO3-BaTiO3 whiskers: synthesis mechanism and structure. AB - Nanostructured lead-free ferroelectric Na(0.5)Bi(0.5)TiO(3)-BaTiO(3) (NBTBT) whiskers with a high aspect ratio were synthesized topochemically using Na(2)Ti(6)O(13) (NTO) as a host structure for the first time. High energy X-ray diffraction coupled with an atomic pair distribution function (PDF) and Raman scattering analyses were used to confirm the average structure of the lead-free NBTBT whiskers, which was found to be rhombohedral, i.e. a ferroelectric enabling type. High resolution transmission electron microscopic (HRTEM) analysis revealed local monoclinic-type structural distortions, indicating a modulated structure at the nanoscale in the morphotropic phase boundary (MPB) composition of the lead free NBTBT whiskers. The structural rearrangement during the synthesis of the lead-free NBTBT whiskers was found to occur via translation of the edge shared octahedra of NTO into a corner sharing coordination. High temperature morphological changes that depict the disintegration of the isolated whiskers into their individual grains due to the higher grain boundary energy have been found to occur in close analogy with Rayleigh-type instability. PMID- 22430817 TI - The effects of moderate-intensity gradient static magnetic fields on nerve conduction. AB - Whether exposure to static magnetic fields (SMF) for medical applications poses a therapeutic benefit or a health hazard is at the focus of current debate. As a peripheral nerve model for studies of the SMF effects, we have investigated whether exposure of in vitro frog sciatic nerve fibers to moderate-intensity gradient SMF up to 0.7 T modulates membrane excitation and refractory processes. We measured the changes in the amplitudes of the electrically evoked compound action potentials for three groups: a control group without SMF exposure and two exposed groups with continuous inhomogeneous exposure to maximum flux densities (B(max)) of 0.21 and 0.7 T SMF for 6 h. The values of the nerve conduction velocity of C fibers were significantly reduced by B(max) of 0.7 T SMF during the 4- to 6-h exposure period but not by B(max) of 0.21 T SMF during the entire exposure period of 6 h, relative to the unexposed control. From these findings, we speculate that exposure to moderate-intensity gradient SMF may attenuate pain perception because the C fibers are responsible for pain transmission. Although the mechanistic reasons for this decrease have yet to be clarified, SMF could affect the behavior of some types of ion channels associated with C fibers. PMID- 22430818 TI - [Current integrated approaches for the treatment of focal atrial tachycardia]. AB - Focal atrial tachyardia constitutes more than 10% of the supraventricular tachycardias and it could be responsible for the initiation of other atrial arrhythmias, like atrial fibrillation and atrial flutter. Frequently, the focal atrial tachycardia does not respond to the medical treatment, while a definitive cure is often obtained with radiofrequency transcatheter ablations and integrated minimally-invasive approaches (atrial appendage clip). This paper describes physiopathological mechanisms underlying the focal atrial tachycardia, its anatomical localizations, the clinical patterns and the fundamentals of the diagnosis. Finally, the more recent treatment strategies will be illustrated and discussed. PMID- 22430819 TI - [Contemporary presentation of unusual adverse events during telmisartan therapy]. AB - Man, 60 years old, in two weekly haemodialysis from 2009. From 2007 in treatment with once-daily telmisartan 40 mg for hypertension. From 2008 showed recurrent pharingitys. In June 2011 bacterial cystitis showed at the same time. The telmisartan was discontinued and both problems solved. PMID- 22430820 TI - [Eluting stents implantation in patient with situs viscerum inversus]. AB - A 73 year-old man, with known situs viscerum inversus, symptomatic for effort dyspnea, was admitted to our Department for inducible myocardial ischemia. Coronary angiography showed severe narrowings of the distal right coronary artery, treated by percutaneous coronary intervention and drug eluting stents implantation. Percutaneous coronary intervention was performed using standard diagnostic and guide catheters, requiring opposite manipulation and inverted angiographic projections. PMID- 22430821 TI - [The exclusion of older patients from clinical trials regarding heart failure. Causes and consequences]. AB - Older subjects are commonly excluded from clinical trials, that are the gold standard to assess the efficacy and safety of new drugs and non pharmacological therapies. The consequence is the lack of evidence about the optimal drug therapy in this population, who makes the highest consumption of drugs, with increased risk of adverse reactions and undertreatment. A clear example is heart failure: data obtained in the context of the European Project PREDICT confirm a widespread exclusion of older individuals from ongoing clinical trials in heart failure, despite the recommendations of regulatory agencies. PMID- 22430822 TI - [Endothelial dysfunction. An integrated overview of the physiopatologic and diagnostic aspects]. AB - Endothelial dysfunction is an early alteration in the atherosclerotic process. Cardiovascular risk factors induce endothelial dysfunction, characterized by impaired endothelium-dependent vasodilatation and by new proatherogenic, proinflammatory and prothrombotic properties. It is evident as the study of the endothelium could play a key role in the cardiovascular research and can be an useful tool for risk stratification in primary prevention of cardiovascular disease. An ideal approach for the comprehensive evaluation on endothelial physiopathology would take into account and integrate informations about endothelial biology (activation, injury and regenerative capacity) and endothelial function, so to be correlated with clinical data. PMID- 22430823 TI - [Clinical decision making in left main coronary artery disease revascularization: the past, present and future]. AB - Left main coronary artery disease revascularization is one of the most debated topics in the setting of interventional cardiology. Although the gold standard therapy for left main disease is coronary artery bypass grafting, growing evidences suggest similar outcomes for percutaneous coronary intervention compared to cardiac surgery. The decision-making process aimed at selecting the best treatment option is a complex task requiring advanced expertise, Heart Team discussion, and risk stratification. The aim of this review is to provide an updated overview of treatment options for left main revascularization, highlighting current indications based on the latest international guidelines, reviewing the most important risk stratification systems with a glimpse to further clinical development in the field. PMID- 22430824 TI - A catalytic metal-free Ritter reaction to 3-substituted 3-aminooxindoles. AB - The first Ritter reaction of 3-substituted 3-hydroxyoxindoles with nitriles, catalyzed by HClO(4), is developed, which enables the synthesis of 3-substituted 3-aminooxindoles in good to excellent yield with rich diversity. PMID- 22430825 TI - Delaying blood pressure control in type 2 diabetes: illustrating principles in the practice of medicine. PMID- 22430826 TI - Prevalence and elimination of sibling neurite convergence in motor units supplying neonatal and adult mouse skeletal muscle. AB - During development, neurons form supernumerary synapses, most of which are selectively pruned leading to stereotyped patterns of innervation. During the development of skeletal muscle innervation, or its regeneration after nerve injury, each muscle fiber is transiently innervated by multiple motor axon branches but eventually by a single branch. The selective elimination of all but one branch is the result of competition between the converging arbors. It is thought that motor neurons initially innervate muscle fibers randomly, but that axon branches from the same neuron (sibling branches) do not converge to innervate the same muscle fiber. However, random innervation would result in many neonatal endplates that are co-innervated by sibling branches. To investigate whether this occurs we examined neonatal levator auris longus (LAL) and 4th deep lumbrical (4DL) muscles, as well as adult reinnervated deep lumbrical muscles (1 4) in transgenic mice expressing yellow fluorescent protein (YFP) as a reporter. We provide direct evidence of convergence of sibling neurites within single fluorescent motor units, both during development and during regeneration after nerve crush. The incidence of sibling neurite convergence was 40% lower in regeneration and at least 75% lower during development than expected by chance. Therefore, there must be a mechanism that decreases the probability of its occurrence. As sibling neurite convergence is not seen in normal adults, or at later timepoints in regeneration, synapse elimination must also remove convergent synaptic inputs derived from the same motor neuron. Mechanistic theories of synaptic competition should now accommodate this form of isoaxonal plasticity. PMID- 22430827 TI - Hypertension. Impact of having 'Prehypertension'. PMID- 22430828 TI - Prevention. Cost-effectiveness of cardiovascular disease prevention and management in the developing world. PMID- 22430829 TI - Coronary artery disease. Stents should not precede optimal medical therapy in stable CAD. PMID- 22430830 TI - Key advances in antihypertensive treatment. AB - Although various effective treatments for hypertension are available, novel therapies to reduce elevated blood pressure, improve blood-pressure control, treat resistant hypertension, and reduce the associated cardiovascular risk factors are still required. A novel angiotensin-receptor blocker (ARB) was approved in 2011, and additional compounds are in development or being tested in clinical trials. Several of these agents have innovative mechanisms of action (an aldosterone synthase inhibitor, a natriuretic peptide agonist, a soluble epoxide hydrolase inhibitor, and an angiotensin II type 2 receptor agonist) or dual activity (a combined ARB and neutral endopeptidase inhibitor, an ARB and endothelin receptor A blocker, and an endothelin-converting enzyme and neutral endopeptidase inhibitor). In addition, several novel fixed-dose combinations of existing antihypertensive agents were approved in 2010-2011, including aliskiren double and triple combinations, and an olmesartan triple combination. Upcoming fixed-dose combinations are expected to introduce calcium-channel blockers other than amlodipine and diuretics other than hydrochlorothiazide. Finally, device based approaches to the treatment of resistant hypertension, such as renal denervation and baroreceptor activation therapy, have shown promising results in clinical trials. However, technical improvements in the implantation procedure and devices used for baroreceptor activation therapy are required to address procedural safety concerns. PMID- 22430831 TI - Hypertension. Cardiac effects of renal denervation. PMID- 22430832 TI - Valvular disease. Super size me? Annular size and paravalvular leak after TAVR. AB - Paravalvular aortic regurgitation (PAR) after transcatheter aortic valve replacement is common and independently associated with increased morbidity and mortality. The determinants of PAR are uncertain, but new data extend our understanding, and a simple practice change in preprocedural imaging could help dramatically to reduce the incidence of this important complication. PMID- 22430833 TI - Probiotics are effective for the prevention and treatment of Citrobacter rodentium-induced colitis in mice. AB - BACKGROUND: Probiotics prevent disease induced by Citrobacter rodentium, a murine specific enteric pathogen. Whether probiotics can be used to interrupt the infectious process following initiation of infection was determined. METHODS: C57BL/6 adult and neonatal mice were challenged with C. rodentium, and a probiotic mixture containing Lactobacillus helveticus and Lactobacillus rhamnosus was provided 1 week before bacterial challenge, concurrently with infection, or 3 days and 6 days after infection. Mice were sacrificed 10 days after infection, and disease severity was assessed by histological analysis and in vivo intestinal permeability assay. Inflammatory pathways and the composition of the fecal microbiome were assessed in adult mice. RESULTS: Preadministration and coadministration of probiotics ameliorated C. rodentium-induced barrier dysfunction, epithelial hyperplasia, and binding of the pathogen to host colonocytes in adults, with similar findings in neonatal mice. Upregulated tumor necrosis factor alpha and interferon gamma transcripts were suppressed in the pretreated probiotic group, whereas interleukin 17 transcription was suppressed with probiotics given up to 3 days after infection. Probiotics promoted transcription of interleukin 10 and FOXP3, and increased follicular T-regulatory cells in pretreatment mice. C. rodentium infection resulted in an altered fecal microbiome, which was normalized with probiotic intervention. CONCLUSIONS: This study provides evidence that probiotics can prevent illness and treat disease in an animal model of infectious colitis. PMID- 22430835 TI - Abstracts of the 2012 Annual Meeting of the Society of Behavioral Medicine. April 11-14, 2012. New Orleans, Louisiana, USA. PMID- 22430836 TI - Type-D personality and heart disease: it might be 'one small step', but it is still moving forward: a comment on Grande et al. PMID- 22430837 TI - European attitudes on the regulation of modern biotechnology and their consequences. AB - Modern biotechnology has gradually attracted ever greater interest over the past four decades, from ever-widening communities across the world--from academic scientists, of course, and then from industrialists, journalists, medical specialists, agricultural practitioners, environmental "experts," economists, trading companies--and, so far as it concerns regulation, above all from political interests whose product is indeed legislation. As the interests widened, conflicts developed: between departments, between sectors, between countries and between international agencies. The European Community made choices, bitterly contested; the battles on conducting and regulating the field release of GMOs (genetically modified organisms) were usually won--at least in Europe--by the environment ministries, often in conflict with agriculture and/or the research and science ministries. The result has been the construction over the past 30 y of an ever heavier regulatory burden on those who seek to develop and launch products based on the use of modern biotechnology. The pretense is labeled "the precautionary principle." No lives have been saved, but many jobs have been created in bureaucracies large and small around the world. So far as academia was concerned, their experiments and field trials were repeatedly wrecked by NGOs (non-governmental organizations) claiming thus to have saved mankind and the environment. This is a story of grave political failure in Europe with globally adverse consequences. PMID- 22430838 TI - Features of small melanocytic lesions: does small mean benign? A clinical dermoscopic study. AB - The use of dermoscopy is known to increase the sensitivity and specificity in the clinical diagnosis of cutaneous pigmented melanocytic lesions compared with naked eye examinations. However, small pigmented melanocytic lesions with maximum clinical diameters of 6 mm remain the most significant diagnostic challenge to the clinician, particularly in the diagnosis of small melanoma, both in naked-eye and in dermatoscopic examinations. The aim of the present study was to analyze the clinical and dermatoscopic features of small pigmented melanocytic lesions, focusing on more frequently occurring features in small melanoma to identify them earlier. A total of 103 pigmented melanocytic lesions with diameters less than 6 mm were analyzed. On histopathological examination, 34 of these lesions were diagnosed as melanomas and the remaining lesions (n = 69) were diagnosed as benign, melanocytic lesions. Images of cases were independently and blindly administered to three dermatologist experts in dermoscopy, who were asked to examine the clinical and dermatoscopic images of melanocytic skin lesions separately and to fill out a printed questionnaire to rate the images according to the ABCD clinical criteria and according to typical dermoscopic pattern analyses. The results of the questionnaires were then analyzed and crossed in order to rate the clinical and dermoscopic features of small pigmented lesions. Our study proved that the clinical criteria for diagnosing melanoma are not as reliable in the diagnosis of pigmented lesions of less than 6 mm diameter. However, the use of dermoscopy, even if not nullifying, allows a better classification of small, melanocytic lesions through pattern analysis. PMID- 22430839 TI - Testosterone treatment in the aging male: myth or reality? AB - The definition of late onset hypogonadism in the aging male is controversially debated, and according to the latest literature consists of at least three especially sexual symptoms such as loss of morning erection, low sexual desire and erectile dysfunction as well as a total testosterone <8-11 nmol/l. Testosterone replacement therapy in the aging male has been shown to have a beneficial effect on muscle and fat mass as well as on bone mineral density, with more conflicting effects observed on muscle strength, sexual function, mood and quality of life. The prescriptions for testosterone products for the aging male increased by over 170% in the previous five years. Furthermore, there is a lot of epidemiological data showing an inverse relationship between testosterone levels and obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. However, only few small randomised placebo-controlled studies have investigated the effect of testosterone replacement therapy on insulin resistance and HbA1c levels, with controversial results. Importantly, so far the long-term safety and efficacy of testosterone replacement therapy has not been established. Although until now no clear evidence has been found that testosterone replacement therapy has a causative role in prostate cancer or indeed in changes of the biology of the prostate, in a recent meta-analysis a 4-fold increased risk of prostate-associated event rates in testosterone treated elderly men sounds a note of caution. Also the risk for cardiovascular events is still not clear and caution is warranted especially in elderly men with cardiovascular disease and limited mobility. In summary, the actual available evidence of long-term risks and outcome of testosterone replacement therapy is still very limited and carefully designed placebo-controlled trials of testosterone administration to assess the risks and benefits of such a therapy are required. Until then, testosterone treatment in elderly men should be restricted to elderly men with clearly low testosterone levels in the presence of clinical symptoms, and the advantages and disadvantages need to be accurately weighted. A careful monitoring of potential side effects is necessary. PMID- 22430840 TI - Plasma phospholipid transfer protein: a multifaceted protein with a key role in the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver. PMID- 22430841 TI - [The genetic profile of multiple sclerosis: risk genes and the "dark matter"]. AB - Multiple sclerosis (MS) is a genetically complex disease caused by the interplay of genetic and environmental factors. While it shows substantial familial accumulation, there is no evidence for typical Mendelian transmission within families. Instead, MS risk is likely governed by dozens to hundreds of genetic variants, which can also be present in the general population. The strongest genetic risk factor for MS was identified 40 years ago and lies within the HLA locus. It increases the risk of developing MS by two- to threefold. Within the last few years, genome-wide association studies (GWAS) have led to the identification of nearly 60 additional genetic risk loci. Each of these loci yields a modest to moderate risk increase (odds ratios of 1.1-1.3). Even in combination, however, the currently known risk variants merely account for a small fraction of the disease's heritability. It is likely that a major fraction of genetic MS risk that cannot be explained by GWAS, sometimes termed the "dark matter" of GWAS, is caused by other factors, such as structural variations of the genome, rare sequence variants, or inherited epigenetic modifications. PMID- 22430842 TI - Characterization of an isoflavonoid-specific prenyltransferase from Lupinus albus. AB - Prenylated flavonoids and isoflavonoids possess antimicrobial activity against fungal pathogens of plants. However, only a few plant flavonoid and isoflavonoid prenyltransferase genes have been identified to date. In this study, an isoflavonoid prenyltransferase gene, designated as LaPT1, was identified from white lupin (Lupinus albus). The deduced protein sequence of LaPT1 shared high homologies with known flavonoid and isoflavonoid prenyltransferases. The LaPT1 gene was mainly expressed in roots, a major site for constitutive accumulation of prenylated isoflavones in white lupin. LaPT1 is predicted to be a membrane-bound protein with nine transmembrane regions and conserved functional domains similar to other flavonoid and isoflavonoid prenyltransferases; it has a predicted chloroplast transit peptide and is plastid localized. A microsomal fraction containing recombinant LaPT1 prenylated the isoflavone genistein at the B-ring 3' position to produce isowighteone. The enzyme is also active with 2' hydroxygenistein but has no activity with other flavonoid substrates. The apparent K(m) of recombinant LaPT1 for the dimethylallyl diphosphate prenyl donor is in a similar range to that of other flavonoid prenyltransferases, but the apparent catalytic efficiency with genistein is considerably higher. Removal of the transit peptide increased the apparent overall activity but also increased the K(m). Medicago truncatula hairy roots expressing LaPT1 accumulated isowighteone, a compound that is not naturally produced in this species, indicating a strategy for metabolic engineering of novel antimicrobial compounds in legumes. PMID- 22430843 TI - Disruption of a rice pentatricopeptide repeat protein causes a seedling-specific albino phenotype and its utilization to enhance seed purity in hybrid rice production. AB - The pentatricopeptide repeat (PPR) gene family represents one of the largest gene families in higher plants. Accumulating data suggest that PPR proteins play a central and broad role in modulating the expression of organellar genes in plants. Here we report a rice (Oryza sativa) mutant named young seedling albino (ysa) derived from the rice thermo/photoperiod-sensitive genic male-sterile line Pei'ai64S, which is a leading male-sterile line for commercial two-line hybrid rice production. The ysa mutant develops albino leaves before the three-leaf stage, but the mutant gradually turns green and recovers to normal green at the six-leaf stage. Further investigation showed that the change in leaf color in ysa mutant is associated with changes in chlorophyll content and chloroplast development. Map-based cloning revealed that YSA encodes a PPR protein with 16 tandem PPR motifs. YSA is highly expressed in young leaves and stems, and its expression level is regulated by light. We showed that the ysa mutation has no apparent negative effects on several important agronomic traits, such as fertility, stigma extrusion rate, selfed seed-setting rate, hybrid seed-setting rate, and yield heterosis under normal growth conditions. We further demonstrated that ysa can be used as an early marker for efficient identification and elimination of false hybrids in commercial hybrid rice production, resulting in yield increases by up to approximately 537 kg ha(-1). PMID- 22430844 TI - Isolation and proteomic characterization of the Arabidopsis Golgi defines functional and novel components involved in plant cell wall biosynthesis. AB - The plant Golgi plays a pivotal role in the biosynthesis of cell wall matrix polysaccharides, protein glycosylation, and vesicle trafficking. Golgi-localized proteins have become prospective targets for reengineering cell wall biosynthetic pathways for the efficient production of biofuels from plant cell walls. However, proteomic characterization of the Golgi has so far been limited, owing to the technical challenges inherent in Golgi purification. In this study, a combination of density centrifugation and surface charge separation techniques have allowed the reproducible isolation of Golgi membranes from Arabidopsis (Arabidopsis thaliana) at sufficiently high purity levels for in-depth proteomic analysis. Quantitative proteomic analysis, immunoblotting, enzyme activity assays, and electron microscopy all confirm high purity levels. A composition analysis indicated that approximately 19% of proteins were likely derived from contaminating compartments and ribosomes. The localization of 13 newly assigned proteins to the Golgi using transient fluorescent markers further validated the proteome. A collection of 371 proteins consistently identified in all replicates has been proposed to represent the Golgi proteome, marking an appreciable advancement in numbers of Golgi-localized proteins. A significant proportion of proteins likely involved in matrix polysaccharide biosynthesis were identified. The potential within this proteome for advances in understanding Golgi processes has been demonstrated by the identification and functional characterization of the first plant Golgi-resident nucleoside diphosphatase, using a yeast complementation assay. Overall, these data show key proteins involved in primary cell wall synthesis and include a mixture of well-characterized and unknown proteins whose biological roles and importance as targets for future research can now be realized. PMID- 22430845 TI - Genotypic differences and prior defoliation affect re-growth and phytochemistry after coppicing in Populus tremuloides. AB - Although considerable research has explored how tree growth and defense can be influenced by genotype, the biotic environment, and their interaction, little is known about how genotypic differences, prior defoliation, and their interactive effects persist in trees that re-grow after damage that severs their primary stem. To address these issues, we established a common garden consisting of twelve genotypes of potted aspen (Populus tremuloides) trees, and subjected half of the trees to defoliation in two successive years. At the beginning of the third year, all trees were severed at the soil surface (coppiced) and allowed to regenerate for five months. Afterwards, we counted the number of root and stump sprouts produced and measured the basal diameter (d) and height (h) of the tallest ramet in each pot. We collected leaves one and two years after the second defoliation and assessed levels of phenolic glycosides, condensed tannins, and nitrogen. In terms of re-growth, we found that the total number of sprouts produced varied by 3.6-fold among genotypes, and that prior defoliation decreased total sprout production by 24%. The size (d(2)h) of ramets, however, did not differ significantly among genotypes or defoliation classes. In terms of phytochemistry, we observed genotypic differences in concentrations of all phytochemicals assessed both one and two years after the second defoliation. Two years after defoliation, we observed effects of prior defoliation in a genotype by-defoliation interaction for condensed tannins. Results from this study demonstrate that genotypic differences and impacts of prior defoliation persist to influence growth and defense traits in trees even after complete removal of above-ground stems, and thus likely influence productivity and plant-herbivore interactions in forests affected by natural disturbances or actively managed through coppicing. PMID- 22430846 TI - Formation of hydrogen peroxide by VUV-photolysis of water and aqueous solutions with methanol. AB - The hydrogen peroxide production upon vacuum ultraviolet (VUV) irradiation of water is reviewed, because published results from the last 10 years lead to conflicting mechanistic interpretations. This work confirms that in pure water, hydrogen peroxide is only produced in the presence of molecular oxygen. Mechanistic schemes explain these findings and confirm earlier statements that recombination of hydroxyl radicals is kinetically disfavoured. In agreement with other recent publications, this work confirms that enhanced hydrogen peroxide production takes place upon VUV irradiation of aqueous solutions of organic compounds. For these investigations, methanol was chosen as an organic model compound. During photolyses, hydrogen peroxide, dissolved molecular oxygen, pH value of the reaction system, methanol and its products of oxidative degradation were analyzed, and kinetic studies were undertaken to explain the evolution of the concentrations of these components. PMID- 22430847 TI - Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-beta. AB - Aldehyde dehydrogenase 1 (ALDH1) has been shown to serve as a marker for cancer initiating cells (CICs), but little is known about the regulation of the CIC functions of ALDH1+ cancer cells. We isolated ALDH1+ cells from human diffuse type gastric carcinoma cells and characterized these cells using an Aldefluor assay. ALDH1+ cells constituted 5-8% of the human diffuse-type gastric carcinoma cells, OCUM-2MLN and HSC-39; were more tumourigenic than ALDH1- cells; and were able to self-renew and generate heterogeneous cell populations. Using gene expression microarray analyses, we identified REG4 (regenerating islet-derived family, member 4) as one of the genes up-regulated in ALDH1+ cells, and thus as a novel marker for ALDH1+ tumour cells. Induced expression of REG4 enhanced the colony-forming ability of OCUM-2MLN cells, while knockdown of REG4 inhibited the tumourigenic potential of ALDH1+ cells. We further found that TGF-beta signalling reduces the expression of ALDH1 and REG4, and the size of the ALDH1+ cell population. In human diffuse-type gastric carcinoma tissues, the expression of ALDH1 and REG4 correlated with each other, as assessed by immunohistochemistry, and ALDH1 expression correlated inversely with Smad3 phosphorylation as a measure of TGF-beta signalling. These findings illustrate that, in diffuse-type gastric carcinoma, REG4 is up-regulated in ALDH1+ CICs, and that the increased tumourigenic ability of ALDH1+ cells depends on REG4. Moreover, TGF-beta down regulates ALDH1 and REG4 expression, which correlates with a reduction in CIC population size and tumourigenicity. Targeting REG4 in ALDH1+ CICs may provide a novel strategy in the treatment of diffuse-type gastric carcinoma. PMID- 22430848 TI - The accuracy of DFT-optimized geometries of functional transition metal compounds: a validation study of catalysts for olefin metathesis and other reactions in the homogeneous phase. AB - We have investigated the performance of eight popular density functionals, four of which are "standard" functionals not including dispersion (B3LYP, BP86, PBE, and TPSS) and four of which have been constructed to account for dispersion (B97D, wB97XD, M06, and M06L), in reproducing 18 molecular structures derived from single-crystal X-ray diffraction experiments on ruthenium-based olefin metathesis catalyst precursors. Our analysis of all the internuclear distances reveals that standard DFT predicts systematically expanded structures. In contrast, all the methods accounting for dispersion give rise to more compact structures, removing the systematic overestimation of internuclear distances. The contracting effect of dispersion is general and also affects chemical bonds, thus reducing the general overestimation of bond lengths. The best overall performance is observed for wB97XD, which offers relatively small statistical errors when considering the overall structure as well as selected distances. Only for the coordination center geometry is the accuracy of wB97XD matched by standard functionals such as PBE and TPSS, whereas M06 and M06L are associated with larger errors. At the other end of the scale, B3LYP is seen to give the largest statistical errors in general, both when considering the complete structures and the geometries of the coordination centers alone. For the organic ligands, however, B3LYP performs clearly better than the other standard functionals although not as well as the functionals accounting for dispersion. Extending the basis sets is seen to improve the structures in particular of the coordination center, thus underlining the importance of using sufficiently flexible basis sets if highly accurate geometries are to be obtained. Similar conclusions to those obtained for the ruthenium catalysts can be drawn from comparisons of the X-ray crystal structures of 10 other organometallic complexes of relevance to homogeneous catalysis, covering first (Ti, Fe, Co, Ni), second (Zr, Mo, Rh, Pd) and third (W, Ir) row transition metals, with those of DFT. The latter analyses thus offer a first indication that the picture obtained for the ruthenium alkylidene complexes may be extended to other classes of relatively large transition metal complexes. PMID- 22430849 TI - GM Crops and Food: Biotechnology in Agriculture and the Food Chain. Editorial. PMID- 22430850 TI - GM in the media. PMID- 22430851 TI - The emerging international regulatory framework for biotechnology. AB - Debate about the potential risks of genetically modified organisms (GMOs) to the environment or human health spurred attention to biosafety. Biosafety is associated with the safe use of GMOs and, more generally, with the introduction of non-indigenous species into natural or managed ecosystems. Biosafety regulation--the policies and procedures adopted to ensure the environmentally safe application of modern biotechnology--has been extensively discussed at various national and international forums. Much of the discussion has focused on developing guidelines, appropriate legal frameworks and, at the international level, a legally binding international biosafety protocol--the Cartagena Protocol on Biosafety. The Protocol is one among various international instruments and treaties that regulate specific aspects relevant to agricultural biotechnology. The present article presents the main international instruments relevant to biosafety regulation, and their key provisions. While international agreements and standards provide important guidance, they leave significant room for interpretation, and flexibility for countries implementing them. Implementation of biosafety at the national level has proven to be a major challenge, particularly in developing countries, and consequently the actual functioning of the international regulatory framework for biotechnology is still in a state of flux. PMID- 22430852 TI - Commercializing genetically modified crops under EU regulations: objectives and barriers. AB - Agriculture faces serious problems in feeding 9 billion people by 2050: production must be increased and ecosystem services maintained under conditions for growing crops that are predicted to worsen in many parts of the world. A proposed solution is sustainable intensification of agriculture, whereby yields are increased on land that is currently cultivated, so sparing land to deliver other ecosystem services. Genetically modified (GM) crops are already contributing to sustainable intensification through higher yields and lower environmental impacts, and have potential to deliver further significant improvements. Despite their widespread successful use elsewhere, the European Union (EU) has been slow to introduce GM crops: decisions on applications to import GM commodities are lengthy, and decision-making on applications to cultivate GM crops has virtually ceased. Delayed import approvals result in economic losses, particularly in the EU itself as a result of higher commodity prices. Failure to grant cultivation approvals costs EU farmers opportunities to reduce inputs, and results in loss of agricultural research and development from the EU to countries such as the United States and China. Delayed decision-making in the EU ostensibly results from scientific uncertainty about the effects of using GM crops; however, scientific uncertainty may be a means to justify a political decision to restrict cultivation of GM crops in the EU. The problems associated with delayed decision-making will not improve until there is clarity about the EU's agricultural policy objectives, and whether the use of GM crops will be permitted to contribute to achieving those objectives. PMID- 22430853 TI - Coexistence, North American style: regulation and litigation. AB - Globally, biotech crops have left a legacy of success and some notable failures due to regulatory and litigious barriers to entry, with a pipeline of potentially beneficial biotech agricultural products lined up and awaiting approval. Compared with traditional agriculture, these crops provide significant health benefits to environmental and human health benefits, including organic systems. While the rest of the world has increased acreage of biotech crops at a steady annual rate of 10%, North America-the birthplace of most biotech crops-has reached a critical turning point in its regulatory evolution. Biotech crops can play a major role in creating a more sustainable agricultural landscape, which is increasingly well documented, but future commercial use may be hampered by regulation and litigation that place organic and non-GMO agriculture on a pedestal, which could force many biotech crops into containment. If producers of biotech crops are required to prevent their crops from contaminating these other, high premium specialty crops through migration, innovation in agricultural biotechnology will suffer (as the European experience with agricultural biotechnology clearly demonstrates). PMID- 22430854 TI - Biosafety legislation and biotechnology development gains momentum in Africa. AB - Opinion in Africa over the use of genetically modified crops for food has been divided, honed by more than a decade of arguments in Europe and elsewhere. Fortunately, the perceived image of a passive Africa in this game is changing rapidly with clear positions on how to harness modern biotechnology. This article examines the status of biosafety regulation across Africa, pertinent challenges and the extent to which regulation fosters or constrains the development of agricultural biotechnology. PMID- 22430855 TI - Genetics: Personalized medicine and tumour heterogeneity. PMID- 22430856 TI - Clinical guidelines: The architectures of lung cancer. PMID- 22430858 TI - Pediatric oncology: Vinblastine in low-grade glioma. PMID- 22430857 TI - Screening for oesophageal cancer. AB - Oesophageal cancer is a global health problem with high mortality due to the advanced nature of the disease at presentation; therefore, detection at an early stage significantly improves outcome. Oesophageal squamous-cell cancer is preceded by dysplasia and oesophageal adenocarcinoma is preceded by Barrett's oesophagus, which progresses to cancer via intermediate dysplastic stages. Screening to detect these preneoplastic lesions has the potential to substantially reduce mortality and morbidity. However, the risks and benefits of such programmes to individuals and to society need to be carefully weighed. Endoscopic screening is invasive, costly and error prone owing to sampling bias and the subjective diagnosis of dysplasia. Non-endoscopic cell-sampling methods are less invasive and more cost effective than endoscopy, but the sensitivity and specificity of cytological assessment of atypia has been disappointing. The use of biomarkers to analyse samples collected using pan-oesophageal cell-collection devices may improve diagnostic accuracy; however, further work is required to confirm this. The psychological and economic implications of screening as well as the feasibility of implementing such programmes must also be considered. PMID- 22430859 TI - Highly relaxing gadolinium based MRI contrast agents responsive to Mg2+ sensing. AB - A Gd complex based on a polyphosphonated pyridyl ligand shows a very high stability in aqueous solution (log K(EuL) = 25.7), a high relaxivity (8.5 mM(-1) s(-1) at 25 degrees C and 20 MHz) and a marked and selective relaxivity enhancement (37%) in the presence of Mg(2+), opening interesting perspectives for the design of cation responsive contrast agents. PMID- 22430860 TI - Gender-specific regulation of tyrosine hydroxylase in thymocyte differentiation antigen-1 knockout mice. AB - Thymocyte differentiation antigen-1 (Thy-1) is a cell surface glycoprotein found on T cells and neurons and is involved in cell-to-cell interactions. In addition, Thy-1 knockouts (KO) are a potential mouse model of restless legs syndrome (RLS) based on clinical observations and the role of dopamine in the disease. In this study, we analyzed the activity and quantity of tyrosine hydroxylase (TH; the rate-limiting enzyme in dopamine production) and determined phosphorylation levels for the enzyme phosphoserine-40 (pSer-40). There was no significant difference in the total TH activity and pSer-40 TH levels between Thy-1 KO and control groups; however, TH specific activity was significantly lower (by 26%) in Thy-1 KO mice. This difference is due in part to increased TH protein levels in this group (increased by 29%). When analyzed by gender, Thy-1 KO female mouse striata contained less TH specific activity compared with control females (decreased by 41%) and male control or Thy-1 KO animals (decreased by 30%). TH specific activity and pSer-40 TH levels in male Thy-1 KO and control displayed no differences. However, pSer-40 TH was significantly higher in control females (38%) compared with control or Thy-1 KO males. The Thy-1 KO females exhibited significantly lower (28%) pSer-40 TH (normalized to GAPDH or TH) than control females. Indeed, the Thy-1 KO females had 50% of the pSer-40 TH found in controls. Our results suggest a gender effect on TH specific activity, TH protein levels, and serine-40 phosphorylation of TH in Thy-1 KO female mice. PMID- 22430861 TI - Arthroscopic ankle arthrodesis: a review. AB - Presently, tibiotalar fusion remains a valid treatment option in patients affected by end-stage arthritis of the ankle that is unresponsive to other treatments. Over the years, many different surgical techniques have been described to make this kind of surgery less invasive and invalidating. Consequently, the last two decades have seen arthroscopic ankle fusion gain in popularity with many studies aiming to understand its advantages compared with open surgery, indications, and contraindications. The review of literature revealed a lower rate of complication, faster recovery, and shorter time of hospitalization with arthroscopic arthrodesis, in comparison with open surgery. These characteristics, along with a reduction of costs, will probably increase the use of arthroscopic ankle arthrodesis in the near future. PMID- 22430862 TI - The role for hip surveillance in children with cerebral palsy. AB - Spastic hip displacement is the second most common deformity seen in children with cerebral palsy (CP), and the long-term effects can be debilitating. Progressive hip displacement leading to dislocation can result in severe pain as well as impaired function and quality of life. Recent population-based studies have demonstrated that a child's Gross Motor Functional Classification System (GMFCS) level is most predictive for identifying hips "at-risk" for progressive lateral displacement. As a result, in many developed countries, hip surveillance has now been adopted as an integral piece of the comprehensive care puzzle for the management of children with spastic hip displacement. This paper reviews the spectrum of treatments available for progressive hip displacement, examines the current literature on the success of hip surveillance, and illustrates an example of a current hip surveillance program stratified by the GMFCS level. PMID- 22430863 TI - Arthroscopic debridement: effective treatment for impingement after total ankle arthroplasty. AB - Total ankle arthroplasty has been gaining significant popularity for the treatment of ankle arthritis. Subsequent rates of revision surgery secondary to symptomatic bony impingement have been reported in 6-45 % of cases. Arthroscopic debridement of bony impingement following total ankle has been recently reported as an effective therapy. An arthroscopic technique has been recently published by one of the senior authors. In this paper, we expand this technique and retrospectively review our experience with arthroscopic debridement of twenty ankles in twenty patients with symptomatic bony impingement following total ankle arthroplasty. PMID- 22430864 TI - Pelvic fixation for neuromuscular scoliosis deformity correction. AB - Pelvic fixation is most frequently indicated in the pediatric population for the treatment of neuromuscular scoliosis with significant pelvic obliquity. Neuromuscular scoliosis surgery is associated with a high risk of complications, and this is further increased by extension of fusion to the sacrum. Numerous techniques have been described for pelvic fixation associated with a long spine fusion each with its own set of specific benefits and risks. This article reviews the contemporary surgical techniques of pelvic fixation used to extend a spine fusion to the sacrum and pelvis focusing on the management of neuromuscular scoliosis, including their biomechanical rationale, results, and complications. PMID- 22430865 TI - Evaluating the training of Filipino American community health advisors to disseminate colorectal cancer screening. AB - Community health advisor-led interventions are associated with improved health promotion behaviors, such as cancer screening, but the process of training community health advisors is rarely described and evaluated. We trained 91 Filipino Americans from 19 organizations to conduct small-group sessions with members of their organizations to promote colorectal cancer screening. Community health advisors completed brief pre- and post-training surveys that included knowledge of colorectal cancer screening guidelines (four items), perceived self efficacy of performing specific tasks (15-item scale, Cronbach's alpha > 0.90) and satisfaction with the training itself (five items). Community health advisors had high levels of knowledge and self-efficacy at pre-training, but levels increased significantly immediately after the 6-h training (percent of knowledge items answered correctly: 63-94 %; self-efficacy: 8.2-8.9 on a 10 point scale, both p < 0.001). Correlates of self-efficacy at pre- and post-test were high educational attainment, health care background, high level of participation in the organization, being perceived by others as a leader, and frequent participation in research activities in the past. Consistent evaluation measuring similar constructs across studies may help to standardize the quality of the training, and may improve the implementation of community health advisor-led programs. PMID- 22430866 TI - In vivo measurements of electrical conductivity of porcine organs at low frequency: new method of measurement. AB - Calculations of the induced currents created in the human body by external electromagnetic fields would be more accurate provided that more realistic experimental values of the electrical properties of the body were available. The purpose of this work is to experimentally obtain values for the conductivity of living organs in conditions close to the real situation. Two-electrode in vivo measurements of the bioimpedance of some porcine organs have been performed. From these measurements and taking into account geometrical considerations, the electrical conductivity for the kidney, liver, heart, and spinal cord has been obtained and were found to be higher than the values reported in the literature. Furthermore, a new experimental procedure is proposed where the conductivity is determined from the values of the electrical potential and currents that are induced by an external electromagnetic field created by a coil placed close to the organ under study. PMID- 22430867 TI - Incidence of disability pension and associations with socio-demographic factors in a Swedish twin cohort. AB - PURPOSE: The incidence of disability pension (DP), especially due to mental diagnoses, has increased in many countries, but knowledge of socio-demographic risk factors for DP is limited. Further, the influences of genetics and early life factors (jointly called familial factors) on these associations remain to be studied. The aims were to study incidence of DP (due to all and mental diagnoses) and associations with socio-demographic factors, and also to establish whether associations differ with DP diagnosis and sex, and are influenced by familial factors. METHODS: A prospective cohort study of all twins born in 1928-1958 (n = 52,609) in Sweden was conducted. The twins were followed from 1993 to 2008 regarding DP. Cox proportional hazard models were applied. RESULTS: The cumulative incidence of DP was 17 %. Of all the DP diagnoses 20 % were mental. Higher age (>=45 years), being a woman or unmarried, and/or living in a semi urban area were risk factors for DP. Low education, being a blue-collar worker or being self-employed predicted either higher (all diagnoses) or lower (mental diagnoses) risk of DP. Rural areas were associated with DP due to mental diagnoses. The estimates varied for men and women. After adjustment for familial factors the associations of DP with education and marital status were attenuated and no longer significant. Similar results were apparent for DP due to mental diagnoses and socioeconomic status. CONCLUSIONS: Familial factors may select individuals into some of the established risk environments for DP. Studies investigating the causes of DP need to take such confounding into account. PMID- 22430870 TI - A simple fluorescent receptor selective for Mg2+. AB - A structurally simple fluorescent receptor (receptor 1) has been synthesized and was found to show a dramatic enhancement in its fluorescence emission upon complexation with Mg(2+). This was maybe contributed to by the inhibition of the C=N isomerization in the excited state. The experimental results show that the receptor was selective and sensitive towards Mg(2+) in the presence of competing ions, with a low detection limit of 3.5 * 10(-9) mol L(-1) (3sigma). PMID- 22430869 TI - Mitochondrial adaptations to utilize hydrogen sulfide for energy and signaling. AB - Sulfur is a versatile molecule with oxidation states ranging from -2 to +6. From the beginning, sulfur has been inexorably entwined with the evolution of organisms. Reduced sulfur, prevalent in the prebiotic Earth and supplied from interstellar sources, was an integral component of early life as it could provide energy through oxidization, even in a weakly oxidizing environment, and it spontaneously reacted with iron to form iron-sulfur clusters that became the earliest biological catalysts and structural components of cells. The ability to cycle sulfur between reduced and oxidized states may have been key in the great endosymbiotic event that incorporated a sulfide-oxidizing alpha-protobacteria into a host sulfide-reducing Archea, resulting in the eukaryotic cell. As eukaryotes slowly adapted from a sulfidic and anoxic (euxinic) world to one that was highly oxidizing, numerous mechanisms developed to deal with increasing oxidants; namely, oxygen, and decreasing sulfide. Because there is rarely any reduced sulfur in the present-day environment, sulfur was historically ignored by biologists, except for an occasional report of sulfide toxicity. Twenty-five years ago, it became evident that the organisms in sulfide-rich environments could synthesize ATP from sulfide, 10 years later came the realization that animals might use sulfide as a signaling molecule, and only within the last 4 years did it become apparent that even mammals could derive energy from sulfide generated in the gastrointestinal tract. It has also become evident that, even in the present-day oxic environment, cells can exploit the redox chemistry of sulfide, most notably as a physiological transducer of oxygen availability. This review will examine how the legacy of sulfide metabolism has shaped natural selection and how some of these ancient biochemical pathways are still employed by modern-day eukaryotes. PMID- 22430871 TI - A weekly combination of carboplatin and irinotecan for previously untreated extensive disease small-cell lung cancer, results of a minimum follow-up of 3 years: a multi-center Phase II trial JMTO LC02-02. AB - OBJECTIVE: We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease small-cell lung cancer. METHODS: Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m(2)) were administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if >45 responses were observed in the 55 patients. RESULTS: Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6-87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8-18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9-7.4). CONCLUSIONS: This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial. PMID- 22430872 TI - Tissue-based proteomics reveals FXYD3, S100A11 and GSTM3 as novel markers for regional lymph node metastasis in colon cancer. AB - Regional lymph node metastasis negatively affects prognosis in colon cancer patients. The molecular processes leading to regional lymph node metastasis are only partially understood and proteomic markers for metastasis are still scarce. Therefore, a tissue-based proteomic approach was undertaken for identifying proteins associated with regional lymph node metastasis. Two complementary tissue based proteomic methods have been employed. MALDI imaging was used for identifying small proteins (<=25 kDa) in situ and label-free quantitative proteomics was used for identifying larger proteins. A tissue cohort comprising primary colon tumours without metastasis (UICC II, pN0, n = 21) and with lymph node metastasis (UICC III, pN2, n = 33) was analysed. Subsequent validation of identified proteins was done by immunohistochemical staining on an independent tissue cohort consisting of primary colon tumour specimens (n = 168). MALDI imaging yielded ten discriminating m/z species, and label-free quantitative proteomics 28 proteins. Two MALDI imaging-derived candidate proteins (FXYD3 and S100A11) and one from the label-free quantitative proteomics (GSTM3) were validated on the independent tissue cohort. All three markers correlated significantly with regional lymph node metastasis: FXYD3 (p = 0.0110), S100A11 (p = 0.0071), and GSTM3 (p = 0.0173). FXYD3 and S100A11 were more highly expressed in UICC II patient tumour tissues. GSTM3 was more highly expressed in UICC III patient tumour tissues. By our tissue-based proteomic approach, we could identify a large panel of proteins which are associated with regional lymph node metastasis and which have not been described so far. Here we show that novel markers for regional lymph metastasis can be identified by MALDI imaging or label free quantitative proteomics and subsequently validated on an independent tissue cohort. PMID- 22430873 TI - Hepatitis C virus infection enhances TNFalpha-induced cell death via suppression of NF-kappaB. AB - Hepatitis C virus (HCV) infection results in liver injury and long-term complications, such as liver cirrhosis and hepatocellular carcinoma. Liver injury in HCV infection is believed to be caused by host immune responses, not by viral cytopathic effects. Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the inflammatory processes of hepatitis C. TNF-alpha induces cell death that can be ameliorated by nuclear factor kappaB (NF-kappaB) activation. We investigated the regulation of TNF-alpha signal transduction in HCV-infected cells and identified HCV proteins responsible for sensitization to TNF-alpha induced cell death. We studied the effect of HCV infection on TNF-alpha signal transduction using an in vitro HCV infection model (JFH-1, genotype 2a) with Huh 7 and Huh-7.5 cells. We found that TNF-alpha-induced cell death significantly increased in HCV-infected cells. HCV infection diminished TNF-alpha-induced phosphorylation of IkappaB kinase (IKK) and inhibitor of NF-kappaB (IkappaB), which are upstream regulators of NF-kappaB activation. HCV infection also inhibited nuclear translocation of NF-kappaB and expression of NF-kappaB dependent anti-apoptotic proteins, such as B-cell lymphoma--extra large (Bcl-xL), X-linked inhibitor of apoptosis protein (XIAP), and the long form of cellular FLICE inhibitory protein (c-FLIP). Decreased levels of Bcl-xL, XIAP, and c-FLIP messenger RNA and protein were also observed in livers with chronic hepatitis C. Transfection with plasmids encoding each HCV protein revealed that core, nonstructural protein (NS)4B, and NS5B attenuated TNF-alpha-induced NF-kappaB activation and enhanced TNF-alpha-induced cell death. CONCLUSION: HCV infection enhances TNF-alpha-induced cell death by suppressing NF-kappaB activation through the action of core, NS4B, and NS5B. This mechanism may contribute to immune mediated liver injury in HCV infection. PMID- 22430874 TI - Vasculitis of the upper airways. AB - Systemic vasculitides are rare and potentially life-threatening diseases. Granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) and Churg Strauss syndrome (possibly to be renamed eosinophilic granulomatosis with polyangiitis; EGPA) are the 2 chief systemic vasculitides which may involve the upper respiratory tract. Chronic allergic rhinitis and nasal polyposis in EGPA, and recurrent sinusitis and/or otitis in both conditions, are not specific and can thus represent real diagnostic challenges if they are the first manifestations of the disease. Nasal septum perforation, saddle nose deformity and/or subglottic stenosis (SGS), although not totally specific, are more suggestive of GPA. Because upper airway manifestations often tend to be refractory to systemic therapy and/or to linger, local treatment represents a major aspect of management of the condition, especially for patients with SGS. PMID- 22430875 TI - Evaluation of biomedical informatics innovations and their impact on public health. AB - This issue of Methods of Information in Medicine contains four feature articles that are focused on the theme of evaluation. Evaluation approaches are increasingly essential in the assessment of determining the potential impact of contemporary informatics innovations. The featured articles offer practical perspectives to determining the impact of advancements. Internationally, there are significant advances being made across biomedical informatics and its related sub-disciplines. As with any scientific discipline, it is important for practitioners to be able to relate the potential importance of findings. To this end, it is especially important for biomedical informaticians to convey, in a quantifiable and comparable form, the significance of the informatics findings not only to peers but also to those across the biomedical research spectrum. As such, the feature articles in this issue describe the evaluation of core infrastructure and fundamental informatics innovations as well as evaluation of informatics-based resources that are a core aspect of public health initiatives. PMID- 22430876 TI - Boosting into a new terminological era. PMID- 22430877 TI - Unique [core+two] structure and optical property of a dodeca-ligated undecagold cluster: critical contribution of the exo gold atoms to the electronic structure. AB - A novel dodeca-ligated undecagold cluster having a nonagold core plus two exo attached gold atoms was synthesized. Unlike the conventional icosahedron-based "core-only" isomer, the [9+2] cluster showed an intense visible absorption band. Theoretical calculation showed the involvement of the exo gold atoms in the generation of the unique electronic structure. PMID- 22430878 TI - Recent progress in the synthesis of inorganic nanoparticles. AB - Nanoparticles probably constitute the largest class of nanomaterials. Nanoparticles of several inorganic materials have been prepared by employing a variety of synthetic strategies. Besides synthesizing nanoparticles, there has been considerable effort to selectively prepare nanoparticles of different shapes. In view of the great interest in inorganic nanoparticles evinced in the last few years, we have prepared this perspective on the present status of the synthesis of inorganic nanoparticles. This article includes a brief discussion of methods followed by reports on the synthesis of nanoparticles of various classes of inorganic materials such as metals, alloys, oxides chalcogenides and pnictides. A brief section on core-shell nanoparticles is also included. PMID- 22430879 TI - Reproductive endocrinology: Testosterone metabolite nonessential for androgen effects. PMID- 22430880 TI - Diabetes: Should we treat infection or inflammation to prevent T2DM? PMID- 22430881 TI - Fragment informatics and computational fragment-based drug design: an overview and update. AB - Fragment-based drug design (FBDD) is a promising approach for the discovery and optimization of lead compounds. Despite its successes, FBDD also faces some internal limitations and challenges. FBDD requires a high quality of target protein and good solubility of fragments. Biophysical techniques for fragment screening necessitate expensive detection equipment and the strategies for evolving fragment hits to leads remain to be improved. Regardless, FBDD is necessary for investigating larger chemical space and can be applied to challenging biological targets. In this scenario, cheminformatics and computational chemistry can be used as alternative approaches that can significantly improve the efficiency and success rate of lead discovery and optimization. Cheminformatics and computational tools assist FBDD in a very flexible manner. Computational FBDD can be used independently or in parallel with experimental FBDD for efficiently generating and optimizing leads. Computational FBDD can also be integrated into each step of experimental FBDD and help to play a synergistic role by maximizing its performance. This review will provide critical analysis of the complementarity between computational and experimental FBDD and highlight recent advances in new algorithms and successful examples of their applications. In particular, fragment-based cheminformatics tools, high throughput fragment docking, and fragment-based de novo drug design will provide the focus of this review. We will also discuss the advantages and limitations of different methods and the trends in new developments that should inspire future research. PMID- 22430882 TI - Organochlorine compounds in pine needles from Croatia. AB - Levels of seven organochlorine pesticides and 17 congeners of polychlorinated biphenyls (PCBs) were analysed in pine needles collected at eight sites along eastern Adriatic coast (Croatia). The concentration of organochlorine pesticides and PCBs ranged between 0 (below determination limit) and 7.44 ng g(-1) in 1-year old needles and between 0 (below determination limit) and 15.57 ng g(-1) dry weight in 2-year-old needles. Organochlorine levels were compared with those found in urban and mountain areas. PMID- 22430883 TI - Accumulation of polychlorinated biphenyls (PCBs) and evaluation of hematological and immunological effects of PCB exposure on turtles. AB - Concentrations of total polychlorinated biphenyls (PCBs), Aroclor 1260, and 26 congeners were measured in liver, fat, and eggs of red-eared slider turtles (Trachemys scripta elegans) collected from ponds near or on the Paducah Gaseous Diffusion Plant (PGDP), Kentucky, USA. Concentrations of total PCBs (wet mass) ranged from 0.002 to 0.480 mg/kg, 0.028 to 0.839 mg/kg, and 0.001 to 0.011 mg/kg in liver, fat, and eggs, respectively. Concentrations of Arochlor 1260 did not exceed 0.430, 0.419, and 0.007 mg/kg in liver, fat, and eggs, respectively. Exposure to PCBs in red-eared sliders collected from the PGDP is characterized by low concentrations of moderately chlorinated mono-ortho and di-ortho congeners (PCB 153, 180, and 118). Although PCB concentrations measured in the current study were low, chronic exposure to PCBs may have altered hematology and immunity of the turtles examined. Total white blood cell count and number of heterophils were negatively correlated with concentrations of total PCBs and Arochlor 1260, respectively. However, disease and other contaminants in the study area may influence the results. Because little is known regarding the influence of PCBs on hematology and immune function in turtles, additional study is needed to better evaluate results observed in the current study. PMID- 22430884 TI - Genotypic screening of the main opiate-related polymorphisms in a cohort of 139 sickle cell disease patients. AB - Because no frequency data are available for the main opiate-related polymorphisms in sickle-cell disease (SCD) populations, we decided to perform such a genotyping in a cohort of 139 individuals. For pharmacodynamics,the OPRM1 A118G and the COMT G322A single nucleotide polymorphisms (SNPs) were chosen for their negative effects on the m receptors [1,2]. For pharmacokinetics [3], important SNPs for the CYP2D6 gene (codeine to morphine conversion) and for three genes involved in morphine elimination (namely CYP3A, UGT2B7, and ABCB1) were genotyped. The allelic frequencies of the OPRM1 and COMT SNPs appeared very low (0.01 to 0.05-no double mutant homozygous),as well as the proportion of CYP2D6 poor metabolizers (1.4%)and CYP3A wild-type (17.9%) which are associated with a low morphine exposure. On the contrary, up to 35% of SCD patients may have unfavorable ABCB1 and UGT2B7 genotypes for a good morphine exposure.Obviously, pharmacokinetic studies with precise phenotype/genotype correlations are required to draw definitive conclusions. PMID- 22430885 TI - Electron microscopy in the diagnosis of viral gastroenteritis in hospitalised children in the Czech Republic. AB - Our study has been aimed at demonstrating the main role of viruses in the aetiology of acute gastroenteritis in children less than 5 years old and at pointing out the diagnostic potential of electron microscopy in the diagnosis of viral gastroenteritis. A prospective study was conducted to analyse the aetiology of diarrhoeal diseases in children less than 5 years of age admitted to the Department of Infectious Diseases between September 2006 and December 2008. All children were tested by faecal culture, latex agglutination and electron microscopy. A total of 832 children were included in the study. An aetiological agent was detected in 788 children (94.6 %). A bacterial aetiology was found in 22 (2.6 %) children and bacterial-viral co-infection was found in 146 (17.6 %) patients. The most frequent causative agents of gastroenteritis in children were viruses, which were detected in 620 (74.5 %) patients. The main causes of viral gastroenteritis were rotaviruses (detected in 410 children), followed by caliciviruses (42), coronaviruses (28), adenoviruses (19) and astroviruses (14). Dual viral infections were detected in 107 children, with rotavirus-calicivirus co-infection being the most common. Electron microscopy proved to be a more sensitive method in comparison with the latex agglutination test for the diagnosis of rotaviruses and adenoviruses. The major role of viruses in diarrhoeal diseases among children under 5 years of age in the Czech Republic has been confirmed. The diagnostic potential of electron microscopy, particularly in small outbreaks of gastroenteritis, was clearly shown. PMID- 22430886 TI - Mutations in the C-terminal tail of NS1 protein facilitate the replication of classical swine H1N1 influenza A virus in mice. AB - The NS1 protein of classical swine H1N1 influenza A virus evolved dynamically during the past 80 years, most notable changes happened in the four C-terminal sequences and the C-terminal truncation of 11 amino acids. However, the role of these changes on the virulence of classical swine H1N1 influenza A virus remains unknown. Using reverse genetics, three NS1 mutant viruses (RSEV, GSEI, and EPEV) and a wild-type virus (PEQK) were generated from A/Swine/Shanghai/1/2005 virus and the pathogenicity of the viruses was determined in mice. The results showed that RSEV and PEQK viruses could not infect the mice. By contrast, GSEI and EPEV viruses could replicate in the lungs of mice without prior adaptation. The viral titers in lungs from GSEI and EPEV virus-infected mice were 2,300 and 7 pfu/g at fourth-day post-infection, respectively. Mild-to-moderate alveolitis was observed in the histopathological test of lungs from GSEI and EPEV virus-infected mice. The results indicated that C-terminal GSEI and EPEV motifs of NS1 protein involved in viral virulence and facilitated the A/Swine/Shanghai/1/2005 virus crossing the species barrier from swine to mice. PMID- 22430887 TI - Utility of fecal and serum anti-Saccharomyces cerevisiae antibodies in the diagnosis of Crohn's disease-like condition of the pouch. AB - BACKGROUND: Fecal antibodies against bacterial products may directly reflect the interaction between luminal bacteria and mucosal immunity, and assays for these antibodies may be clinically useful in the diagnosis and differential diagnosis of Crohn's disease-like (CDL) condition of the pouch. AIMS: This study aims to evaluate stool and serum anti-Saccharomyces cerevisiae antibodies (ASCA) in normal and diseased pouches, to assess the correlation between ASCA levels and endoscopic disease activity, and to ascertain the diagnostic utility of ASCA for CDL of the pouch. METHODS: One hundred eighty-nine patients with ileal pouches were prospectively enrolled and corresponding serum and pouch aspirate samples were collected. Fecal and serum ASCA levels were measured with enzyme-linked immunosorbent assay in a blinded fashion. Statistical analysis was then conducted using the signed rank test, Spearman correlation coefficients, and analysis of variance. RESULTS: Forty-three patients (22.8 %) had irritable pouch syndrome or normal pouches, 74 (39.2 %) had pouchitis/cuffitis, 52 (27.5 %) had CDL, 9 (4.8 %) had familial adenomatous polyposis, and 11 (5.8 %) had surgical complications of the pouch. Receiver operating characteristic curves to distinguish CDL from other categories of pouch dysfunction had an area under the curve (AUC) of 0.608 for fecal ASCA and an AUC of 0.517 for serum ASCA. Neither fecal nor serum ASCA correlated with endoscopic disease activity scores. There was a significant difference in the mean values of fecal ASCA between inflammatory and fistulizing CDL (0.27 vs. 0.03 ELISA units/ml, P < 0.05). CONCLUSIONS: Fecal ASCA appears to be better than serum ASCA in differentiating CDL from other pouch disorders, although this distinction may be of limited clinical utility. PMID- 22430888 TI - Effect of neoadjuvant cetuximab, capecitabine, and radiotherapy for locally advanced rectal cancer: results of a phase II study. AB - PURPOSE: The aim of this study was to investigate the efficacy and safety of neoadjuvant cetuximab, capecitabine, and radiotherapy for patients with locally advanced rectal cancer. METHODS: Sixty-three eligible patients were selectively enrolled in this study. Neoadjuvant treatment consisted of cetuximab and capecitabine for 6 weeks and radiotherapy for 5 weeks. Surgical resection was performed 6-8 weeks after the completion of neoadjuvant treatment. KRAS mutation statuses were analyzed retrospectively after the cetuximab treatment. All the patients underwent a standardized postoperative follow-up for at least 3 years. RESULTS: A pathological complete response (pCR) was achieved in eight patients (12.7 %). Overall down-staging was found in 49 patients (77.8 %). The 3-year disease-free survival (DFS) rate and overall survival (OS) rate was 76.2 % and 81.0 %, respectively. The most common adverse events during neoadjuvant treatment were acneiform skin rash (82.5 %), radiodermatitis (46.0 %), and diarrhea (36.5 %). KRAS mutations were detected in 19 of 63 (31.2 %) tumors. The down-staging rate in patients with KRAS wild-type (WT) was significantly higher than patients with KRAS mutation (P = 0.020). There was no significant difference in the pCR rate, 3-year DFS rate or 3-year OS rate between KRAS WT patients and KRAS-mutated patients. CONCLUSION: Neoadjuvant treatment with cetuximab and capecitabine-based chemoradiotherapy is safe and well tolerated. The pCR rate, 3-year DFS rate and OS rate are not superior to the rate of neoadjuvant chemoradiotherapy using two or more cytotoxic agents. The KRAS WT is highly associated with tumor down staging to cetuximab plus capecitabine-based CRT in patients with LARC. PMID- 22430889 TI - Microscopic colitis in patients with chronic diarrhea and normal colonoscopic findings in Southern China. AB - BACKGROUND AND OBJECTIVES: Microscopic colitis includes lymphocytic colitis and collagenous colitis. The entity is considered as an important cause for unknown chronic diarrhea, but rarely reported in China before. This study aimed to determine the prevalence of microscopic colitis in patients with chronic diarrhea and normal colonoscopy findings in Southern China, and to reveal the clinical feature of microscopic colitis in these patients. METHODS: Patients with chronic diarrhea and normal colonoscopic findings were enrolled from three hospitals in Southern China from January, 2009 to June, 2010. Multiple colorectal biopsies were obtained in these patients and histological examination was underwent with hematoxyin and eosin stain, Masson's trichrome stain and immunohistochemistry for tenascin to screen lymphocytic colitis and collagenous colitis. The clinical symptom and risk factor of microscopic colitis were assessed by comparing with controls. The diagnostic overlap between microscopic colitis and irritable bowel syndrome or functional diarrhea was also analyzed. RESULTS: Randomly mucosal biopsies were performed in 613 patients with chronic diarrhea and normal or near normal colonoscopic finding. Fifty-nine cases of lymphocytic colitis and 28 cases of collagenous colitis were found by histological examination. The rates of rheumatoid arthritis in lymphocytic colitis group (15.4 %) and collagenous colitis group (14.3 %) were significant higher than in control group (2.2 %). Rheumatoid arthritis was confirmed as the risk factor of microscopic colitis by logistic regression analysis. There was no difference on the symptoms among the controls, patients with lymphocytic colitis, and patients with collagenous colitis. There were 13.8 % (12/87) of patients with microscopic colitis fulfilled Rome III criteria of irritable bowel syndrome and 42.5 % (37/87) fulfilled the criteria of functional diarrhea. CONCLUSIONS: Microscopic colitis is not an uncommon disorder in Chinese population. Rheumatoid arthritis is the risk factor of microscopic colitis. Microscopic colitis has a symptomatic overlap with irritable bowel syndrome and functional diarrhea. It is reasonable to obtain multiple biopsies in patients with chronic diarrhea when the mucosa grossly normal at colonoscopy. PMID- 22430890 TI - Bilobar spreading of colorectal liver metastases does not significantly affect survival after R0 resection in the era of interdisciplinary multimodal treatment. AB - PURPOSE: Bilobar colorectal liver metastases (CRLM) are often considered incurable or associated with poor prognosis even after R0 resection. In this single-center study, we evaluate the impact of CRLM spreading on recurrence-free survival (RFS) and cancer-specific overall survival (CSS) after R0 resection of CRLM with respect to multimodal treatment strategies including perioperative chemotherapy and multistep resections. METHODS: Between January 2001 and December 2010, R0 resection could be achieved in 70 patients with bilobar and 100 with unilobar CRLM. Extent of disease, perioperative chemotherapy, surgical procedures, adjuvant treatment, histopathological workup, RFS, and CSS were compared between both cohorts. RESULTS: Forty-six (66 %) patients with bilobar and 26 (26 %) patients with unilobar CRLM received preoperative chemotherapy (p < 0.001). For bilobar CRLM, more extended and multistep resection including portal vein occlusion were performed (29 % versus 3 %; p < 0.001). Morbidity (39 % versus 28 %, p = 0.183) and mortality (1 % versus 3 %, p = 0.644) rates were comparable in both patients' cohorts. Postoperative therapy was applied in adjuvant intent to 42 (60 %) versus 51 (51 %) patients (p = 0.275). The 5-year RFS and CSS rates were 24 % versus 31 % (p = 0.169) and 42 % versus 55 % (p = 0.131), respectively. CONCLUSIONS: To our single-center experience, there is no significant effect of CRLM spreading (bilobar versus unilobar) on RFS and CSS rates. Bilobar CRLM are more likely to require extended multimodal efforts to achieve R0 resection. PMID- 22430891 TI - Infliximab for the prevention of postoperative recurrence in patients with multiple surgeries for Crohn's disease. PMID- 22430892 TI - Postnatal development of chorda tympani axons in the rat nucleus of the solitary tract. AB - The chorda tympani nerve (CT), one of three nerves that convey gustatory information to the nucleus of the solitary tract (NTS), displays terminal field reorganization after postnatal day 15 in the rat. Aiming to gain insight into mechanisms of this phenomenon, CT axon projection field and terminal morphology in NTS subdivisions were examined using tract tracing, light microscopy, and immunoelectron microscopy at four postnatal ages: P15, P25, P35, and adult. The CT axons that innervated NTS rostrolateral subdivision both in the adult and in P15 rats were morphologically distinct from those that innervated the rostrocentral, gustatory subdivision. In both subdivisions, CT terminals reached morphological maturity before P15. Rostrolateral, but not rostrocentral axons, went through substantial axonal branch elimination after P15. Rostrocentral CT synapses, however, redistribute onto postsynaptic targets in the following weeks. CT terminal preference for GABAergic postsynaptic targets was drastically reduced after P15. Furthermore, CT synapses became a smaller component of the total synaptic input to the rostrocentral NTS after P35. The results underlined that CT axons in rostrocentral and rostrolateral subdivisions represent two distinct populations of CT input, displaying different morphological properties and structural reorganization mechanisms during postnatal development. PMID- 22430894 TI - The border community and immigration stress scale: a preliminary examination of a community responsive measure in two Southwest samples. AB - Understanding contemporary socio-cultural stressors may assist educational, clinical and policy-level health promotion efforts. This study presents descriptive findings on a new measure, the border community and immigration stress scale. The data were from two community surveys as part of community based participatory projects conducted in the Southwestern US border region. This scale includes stressful experiences reflected in extant measures, with new items reflecting heightened local migration pressures and health care barriers. Stressors representing each main domain, including novel ones, were reported with frequency and at high intensity in the predominantly Mexican-descent samples. Total stress was also significantly associated with mental and physical health indicators. The study suggests particularly high health burdens tied to the experience of stressors in the US border region. Further, many of the stressors are also likely relevant for other communities within developed nations also experiencing high levels of migration. PMID- 22430895 TI - Progress in articular surgery. PMID- 22430896 TI - Systems biology methods help develop a better understanding of hepatitis C virus induced liver injury. PMID- 22430897 TI - Metallation of N-vinylpyrroles and -indoles with Hg(OAc)2: N-vinyl vs. pyrrole nucleophilic sites. AB - N-Vinylpyrroles and -indoles bearing electron-withdrawing substituents at the pyrrole ring are mercurated, with 1 equivalent of Hg(OAc)(2) in dry MeCN (20-80 degrees C), regioselectively at the vinyl group (yields are almost quantitative), while their congeners without electron-withdrawing functions are mercurated both at the N-vinyl group and the pyrrole ring. PMID- 22430898 TI - Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression. AB - The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine-treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform-specific activation (phosphorylation) of Akt1 and Akt2 in formalin-fixed, paraffin embedded cell lines and breast cancer tumour tissues in situ. PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.14-1.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.10-1.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.34-2.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.32-2.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples. PMID- 22430899 TI - Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia. AB - PRINCIPLES: Midregional proadrenomedullin (proADM) is a novel biomarker with potential prognostic utility in patients with community-acquired pneumonia. The aim of this study was to investigate the value of proADM levels for severity assessment and outcome prediction in severe sepsis and septic shock due to CAP. METHODS: Prospective observational study including 49 patients admitted to ICU with both a clinical and radiologic diagnosis of pneumonia and fulfilling criteria for severe sepsis or septic shock. The prognostic accuracy of proADM levels was compared with those of pneumonia severity index and of procalcitonin (PCT) and C-reactive protein (CRP). RESULTS: 49 patients with severe sepsis or septic shock due to CAP were included in the study. Mortality was 24.5% for ICU and 34.7% for hospital mortality. In all cases proADM values at ICU admission were pathological (considering normal proADM levels <4 nmol/L). ProADM consistently rose as PSI class advanced from II to V (p = 0.02). Median proADM levels were higher (p <0.01) in hospital non-survivors 5.0 (1.9-10.1) nmol/L vs. survivors 1.7 (1.3-3.1) nmol/L. These differences were also significant with respect to ICU mortality. The receiver-operating characteristic curve for proADM yielded an AUC of 0.72; better than the AUC for PCT and CRP (0.40 and 0.44 respectively) and similar to PSI (0.74). CONCLUSIONS: In our study MR-proADM levels correlate with increasing severity of illness and death. High MR-proADM levels offer additional risk stratification in high-risk CAP patients. PMID- 22430900 TI - Perception and orientation in minimally invasive surgery. PMID- 22430901 TI - Is there a role for peer support in times of emotional stress?: Is it enough?: Comment on "Physicians' needs in coping with emotional stressors". PMID- 22430902 TI - Laparoscopic colectomy: should it be the standard of care?: Comment on "Reduced risk of medical morbidity and mortality in patients selected for laparoscopic colorectal resection in England". PMID- 22430903 TI - Is my patient wet or dry? Should my patient be wet or dry?: A first step in answering these queries: Comment on "Effect of the volume of fluids administered on intraoperative oliguria in laparoscopic bariatric surgery". PMID- 22430904 TI - Emergent repair of acute thoracic aortic catastrophes: a comparative analysis. AB - OBJECTIVE: To provide a contemporary institutional comparative analysis of expedient correction of acute catastrophes of the descending thoracic aorta (ACDTA) by traditional direct thoracic aortic repair (DTAR) or thoracic endovascular aortic repair (TEVAR). DESIGN: Single-center retrospective review (April 2001-January 2010). SETTING: Academic medical center. PATIENTS: One hundred patients with ACDTA treated with either TEVAR (n = 76) or DTAR (n = 24). Indications for repair included ruptured degenerative aneurysm (n = 41), traumatic transection (n = 27), complicated acute type B dissection (n = 20), penetrating ulcer (n = 4), intramural hematoma (n = 3), penetrating injury (n = 3), and embolizing lesion (n = 2). MAIN OUTCOME MEASURES: Demographics and 30-day and late outcomes were analyzed using multivariate analysis over a mean follow-up of 33.8 months. RESULTS: Among the 100 patients, mean (SD) age was 58.5 (17.3) years (range, 18-87 years). Demographics and comorbid conditions were similar between the 2 groups, except more patients in the DTAR group had prior aortic surgery (P = .02) and were older (P = .01). Overall 30-day mortality was significantly better among the TEVAR group (8% vs 29%; P = .007). Incidence of postoperative myocardial infarction, acute renal failure, stroke, and paraplegia/paresis was similar between the 2 treatment groups (TEVAR, 5%, 12%, 8%, and 8% vs DTAR, 13%, 13%, 9%, and 13%, respectively). Major respiratory complications were lower in the TEVAR group (16% vs 48%; P < .05). Mean length of hospital stay was also shorter after TEVAR (13.5 vs 16.3 days; P = .30). Independent predictors of patient mortality included age (P = .004) and DTAR (P = .001). CONCLUSION: Patients presenting with ACDTA are best treated with TEVAR whenever feasible. PMID- 22430905 TI - Thoracic aortic endovascular aneurysm repair for acute thoracic aortic catastrophes: the need for subgroup analysis: Comment on "Emergent repair of acute thoracic aortic catastrophes". PMID- 22430906 TI - Erythropoiesis-stimulating agent administration and survival after severe traumatic brain injury: a prospective study. AB - OBJECTIVE: To validate previous findings of the effects of erythropoiesis stimulating agent (ESA) administration following severe traumatic brain injury. DESIGN: Prospective observational study of all patients with severe traumatic brain injury admitted to the surgical intensive care unit (SICU) at our institution from January 1, 2009, to December 31, 2010 (head Abbreviated Injury Scale score >=3). Propensity scores were calculated to match patients who received ESA within 30 days after admission to patients who did not receive ESA. PATIENTS: A total of 566 patients with severe traumatic brain injury were admitted to the SICU. After matching in a 1:1 ratio, 75 matched pairs were analyzed. MAIN OUTCOME MEASURES: Delta Glasgow Coma Scale score (difference between admission and SICU discharge), in-hospital morbidity, and mortality. RESULTS: Patients who received ESA and control subjects who did not receive ESA had similar age, mechanisms of injury, vital signs on admission, Abbreviated Injury Scale scores, Injury Severity Scores, and specific intracranial injuries. Patients who received ESA experienced significantly longer lengths of stay in the SICU (mean [SD], 16.1 [1.3] days vs 8.6 [0.8] days; P < .001) and comparable SICU free days. There was no statistically significant difference in the incidence of major in-hospital complications including deep venous thrombosis and pulmonary embolism when comparing the 2 study cohorts. The Delta Glasgow Coma Scale mean [standard error of the mean] score was 3.0 [0.4] and 2.4 [0.5] in patients who received ESA and those who did not, respectively (P = .33). However, in-hospital mortality was significantly lower for patients who received ESA compared with those who did not (9.3% vs 25.3%; odds ratio, 0.25; 95% CI, 0.08-0.75; P = .012). CONCLUSIONS: Erythropoiesis-stimulating agent administration demonstrates a significant survival advantage without an increase in morbidity in patients with severe traumatic brain injury. PMID- 22430907 TI - Randomized clinical trial of total extraperitoneal inguinal hernioplasty vs Lichtenstein repair: a long-term follow-up study. AB - HYPOTHESIS: Mesh repair is generally preferred for surgical correction of inguinal hernia, although the merits of endoscopic techniques over open surgery are still debated. Herein, minimally invasive total extraperitoneal inguinal hernioplasty (TEP) was compared with Lichtenstein repair to determine if one is associated with less postoperative pain, hypoesthesia, and hernia recurrence. DESIGN: Prospective multicenter randomized clinical trial. SETTING: Academic research. PATIENTS: Six hundred sixty patients were randomized to TEP or Lichtenstein repair. MAIN OUTCOME MEASURES: The primary outcome was postoperative pain. Secondary end points were hernia recurrence, operative complications, operating time, length of hospital stay, time to complete recovery, quality of life, chronic pain, and operative costs. RESULTS: At 5 years after surgery, TEP was associated with less chronic pain (P = .004). Impairment of inguinal sensibility was less frequently seen after TEP vs Lichtenstein repair (1% vs 22%, P < .001). Operative complications were more frequent after TEP vs Lichtenstein repair (6% vs 2%, P < .001), while no difference was noted in length of hospital stay. After TEP, patients had faster time to return to daily activities (P < .002) and less absence from work (P = .001). Although operative costs were higher for TEP, total costs were comparable for the 2 procedures, as were overall hernia recurrences at 5 years after surgery. However, among experienced surgeons, significantly lower hernia recurrence rates were seen after TEP (P < .001). CONCLUSIONS: In the short term, TEP was associated with more operative complications, longer operating time, and higher operative costs; however, total costs were comparable for the 2 procedures. Chronic pain and impairment of inguinal sensibility were more frequent after Lichtenstein repair. Although overall hernia recurrence rates were comparable for both procedures, hernia recurrence rates among experienced surgeons were significantly lower after TEP. Patient satisfaction was also significantly higher after TEP. Therefore, TEP should be recommended in experienced hands. Trial Registration clinicaltrials.gov Identifier: NCT00788554. PMID- 22430908 TI - Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. AB - OBJECTIVE: To analyze the characteristics and outcomes following enucleation and pancreatic resections of insulinomas. DESIGN: Retrospective cohort study; prospective database. SETTINGS: Academic, tertiary, and referral centers. PATIENTS: Consecutive patients with insulinomas (symptoms of hyperinsulinism and positive fasting glucose test) who underwent surgical treatment between January 1990 and December 2009. MAIN OUTCOME MEASURES: Operative morbidity, tumor recurrence, and survival after treatment. RESULTS: A total of 198 patients (58.5% women; median age, 48 years) were identified. There were 175 (88%) neuroendocrine tumors grade G1 and 23 (12%) neuroendocrine tumors grade G2. Malignant insulinomas defined by lymph node/liver metastases were found in 7 patients (3.5%). Multiple insulinomas were found in 8% of patients, and 5.5% of patients had multiple endocrine neoplasia type 1. Surgical procedures included 106 enucleations (54%) and 92 pancreatic resections (46%). Mortality was nil. Rate of clinically significant pancreatic fistula was 18%. Enucleations had a higher reoperation rate compared with pancreatic resections (8.5% vs 1%; P = .02). Multiple endocrine neoplasia type 1 was significantly associated with younger age at onset (P < .005) and higher rates of malignancies and multiple lesions. Median follow-up was 65 months. Six patients (3%; 5 patients had neuroendocrine tumors grade G2) developed tumor recurrence. Four patients (2%) died of disease. New exocrine (1.5%) and endocrine (4%) insufficiencies were associated only with pancreatic resections. CONCLUSIONS: Outcomes following surgical resection of insulinomas are satisfactory, with no mortality and good functional results. Recurrence is uncommon (3%), and it is more likely associated with neuroendocrine tumors grade G2. Insulinomas in multiple endocrine neoplasia type 1 are at higher risk for being malignant and multifocal, requiring pancreatic resections. PMID- 22430909 TI - Incidence of iatrogenic ureteral injury after laparoscopic colectomy. AB - OBJECTIVE: To compare the incidence of iatrogenic ureteral injury between laparoscopic and open colectomies at a single institution. DESIGN: From June 1, 2005, through July 31, 2010, patients were identified from a prospectively maintained database and hospital records were retrospectively reviewed. SETTING: Mount Sinai Medical Center. PATIENTS: Fourteen patients who underwent colectomy complicated by a ureteral injury. MAIN OUTCOME MEASURES: A significant increase in ureteral injuries occurred after laparoscopic vs open procedures (0.66% vs 0.15%, P = .007). RESULTS: A total of 5729 colectomies were performed during the study period. Fourteen ureteral injuries occurred, resulting in a 0.244% incidence of iatrogenic ureteral injury. Patient demographics demonstrated that 9 injuries (64%) occurred in females and 7 patients (50%) had undergone prior abdominal operations. Operative indications were inflammatory bowel disease (n = 7), diverticulitis (n = 2), and malignant neoplasm (n = 4). Thirteen operations (87%) in this study were elective colectomies, and 7 patients (50%) underwent laparoscopic procedures, with 2 open conversions. Of the 5729 colectomies, 4669 were open and 1060 laparoscopic. Regarding ureteral injuries, no difference was observed in intraoperative identification of ureteral injury in patients who underwent preoperative ureteral stent placement (n = 4) vs those who did not (50% [2 of 4] vs 50% [5 of 10]). CONCLUSIONS: A significant increase was found in the incidence of iatrogenic ureteral injuries with laparoscopy compared with open colectomies. Preoperative stent placement did not ensure intraoperative identification of injury. Female sex and increased operative blood loss appear to predispose patients to injury. PMID- 22430910 TI - Ureteral injury during laparoscopic colectomy: the need for more information: Comment on "Incidence of iatrogenic ureteral injury after laparoscopic colectomy". PMID- 22430911 TI - Robotic vs laparoscopic posterior retroperitoneal adrenalectomy. AB - OBJECTIVE: To compare robotic vs laparoscopic posterior retroperitoneal adrenalectomy with regard to perioperative outcomes. DESIGN: Prospectively study. SETTING: Tertiary academic center. PATIENTS: Thirty-one patients who underwent robotic posterior retroperitoneal adrenalectomy and 31 consecutive patients who underwent laparoscopic posterior retroperitoneal adrenalectomy from a prospective institutional review board-approved database. MAIN OUTCOME MEASURES: Demographic and clinical parameters, operative time, presence of complications, length of hospital stay, and pain score on postoperative days 1 and 14. RESULTS: The mean (SEM) tumor sizes for the robotic and laparoscopic groups were similar (3.1 [0.2] and 3.0 [0.2] cm, respectively; P = .48). For all patients, the mean (SEM) skin to-skin operative times were similar in both groups (163.2 [10.1] and 165.7 [9.5] minutes, respectively; P = .43). When the last 21 patients who underwent robotic posterior retroperitoneal adrenalectomy were compared with the 31 patients from the laparoscopic series, it was seen that the mean (SEM) operative time was shorter for the robotic group than for the laparoscopic group (139.1 [10.9] vs 166.9 [8.2] minutes; P = .046). The mean (SEM) estimated blood losses and hospital stays were similar between groups. The mean (SEM) pain score on postoperative day 1 was lower in the robotic group than in the laparoscopic group (2.5 [0.3] vs 4.2 [0.4]; P = .008); however, the mean (SEM) pain scores for the groups were similar on postoperative day 14 (P = .53). There were no deaths or cases of morbidity in either group. CONCLUSIONS: Our study shows that, beyond the learning curve for experienced laparoscopic surgeons, robotic posterior retroperitoneal adrenalectomy shortens the skin-to-skin operative time compared with the laparoscopic approach. Our results also suggest that the immediate postoperative pain may be less severe for patients who undergo robotic posterior retroperitoneal adrenalectomy. PMID- 22430912 TI - Robotic posterior retroperitoneal adrenalectomy: for what benefit and at what cost?: Comment on "Robotic vs laparoscopic posterior retroperitoneal adrenalectomy". PMID- 22430913 TI - Management of asymptomatic inguinal hernia: a systematic review of the evidence. AB - OBJECTIVE: To establish a literature-based surgical approach to asymptomatic inguinal hernia (IH). DATA SOURCES: PubMed, the Cochrane Library database, Embase, national guidelines (including the National Library of Guidelines Specialist Library), National Institute for Health and Clinical Excellence guidelines, and the National Research Register were searched for prospective randomized trials comparing surgical treatment of patients with asymptomatic IH with conservative treatment. STUDY SELECTION: The literature search retrieved 216 article headlines, and these articles were analyzed. Of those studies, a total of 41 articles were found to be relevant and 2 large well-conducted randomized controlled studies that published their results in several articles were reviewed. DATA EXTRACTION: The pain and discomfort, general health status, complications, and life-threatening events of patients with asymptomatic IH managed by surgery or watchful waiting were determined. DATA SYNTHESIS: No significant difference in pain scores and general health status were found when comparing the patients who were followed up with the patients who had surgery. A significant crossover ratio ranging between 23% and 72% from watchful waiting to surgery was found. In patients with watchful waiting, the rates of IH strangulation were 0.27% after 2 years of follow-up and 0.55% after 4 years of follow-up. In patients who underwent elective surgery, the range of operative complications was 0% to 22.3% and the recurrence rate was 2.1%. CONCLUSION: Both treatment options for asymptomatic IH are safe, but most patients will develop symptoms (mainly pain) over time and will require operation. PMID- 22430914 TI - Disclosure of "nonharmful" medical errors and other events: duty to disclose. AB - An estimated 98 000 patients die in the United States each year because of medical errors. One million or more total medical errors are estimated to occur annually, which is far greater than the actual number of reported "harmful" mistakes. Although it is generally agreed that harmful errors must be disclosed to patients, when the error is deemed to have not resulted in a harmful event, physicians are less inclined to disclose it. Little has been written about the handling of near misses or "nonharmful" errors, and the issues related to disclosure of such events have rarely been discussed in medicine, although they are routinely addressed within the aviation industry. Herein, we elucidate the arguments for reporting nonharmful medical errors to patients and to reporting systems. A definition of what constitutes harm is explored, as well as the ethical issues underpinning disclosure of nonharmful errors. In addition, systematic institutional implications of reporting nonharmful errors are highlighted. Full disclosure of nonharmful errors is advocated, and recommendations on how to discuss errors with patients are provided. An argument that full error disclosure may improve future patient care is also outlined. PMID- 22430915 TI - Routine nasogastric decompression is unnecessary after pancreatic resections. AB - Data regarding the use of nasogastric tubes (NGTs) in patients who are undergoing pancreatic resections are limited. We analyzed outcomes after 231 consecutive pancreatectomy procedures in an academic surgical oncology practice. We routinely placed NGTs intraoperatively throughout the first part of the study interval; orogastric tubes (OGTs) were removed intraoperatively before endotracheal extubation whenever possible in the second part of the study (n = 75 [32%]). The median postoperative NGT duration was 1 day (OGT group, 0 days; NGT group, 2 days [P < .001]). Reinsertion of the NGT was necessary in 43 patients (19%) and did not differ between patients after routine NGT or OGT use (19% vs 19%). Nasogastric tubes were reinserted after 74% of major complications compared with 29% of minor complications (P < .001). Our experience demonstrates that the use of NGTs can be safely avoided in patients who are undergoing pancreatectomies. PMID- 22430916 TI - Image of the month. Portal vein gas associated with pneumatosis intestinalis. PMID- 22430917 TI - Image of the month. Internal hernia through foramen of Winslow. PMID- 22430918 TI - Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives. PMID- 22430919 TI - The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use. AB - Erythropoietin (EPO) is the main regulator of red blood cell production but there exists also a variety of nonhematopoietic properties. More recent data show that EPO is also associated with the protection of tissues suffering from ischemia and reperfusion injury as well as with improved regeneration in various organ systems, in particular the skin. This review highlights the mechanisms of EPO in the different stages of wound healing and the reparative processes in the skin emphasizing pathophysiological mechanisms and potential clinical applications. There is clear evidence that EPO effectively influences all wound-healing phases in a dose-dependent manner. This includes inflammation, tissue, and blood vessel formation as well as the remodeling of the wound. The molecular mechanism is predominantly based on an increased expression of the endothelial and inducible nitric oxide (NO) synthase with a consecutive rapid supply of NO as well as an increased content of vascular endothelial growth factor (VEGF) in the wound. The improved understanding of the functions and regulatory mechanisms of EPO in the context of wound-healing problems and ischemia/reperfusion injury, especially during flap surgery, may lead to new considerations of this growth hormone for its regular clinical application in patients. PMID- 22430920 TI - Colchicine is safe and effective for secondary prevention of recurrent pericarditis. AB - The CORP (COlchicine for Recurrent Pericarditis) trial [7]is a prospective, randomized, double-blind, placebo controlled, multicenter trial to evaluate the efficacy and safety of colchicine (1.0-2.0 mg on the first day, followed by a maintenance dose of 0.5-1.0 mg/day for 6 months) in association with conventional anti-inflammatory therapy for the secondary prevention of recurrence in patients with a first relapse of pericarditis. Patients were excluded if they were having their first episode of acute pericarditis, or their second or subsequent recurrence, or had pericarditis with tuberculous, purulent, or neoplastic causes. The primary study end point was the recurrence rate at 18 months. Secondary end points were symptom persistence after 72 h, remission rate at 1 week, number of recurrences, time to first recurrence, disease-related hospitalizations,cardiac tamponade, and constrictive pericarditis rates.120 patients (60 in the colchicine and 60 in the placebo group) were included in the analysis. The recurrence rate is 24 % in the colchicine group and 55 % in the placebo group (absolute risk reduction 0.31 [95 % CI 0.13-0.46];relative risk reduction 0.56 [0.27-0.73]; number needed to treat 3 [2-7]). Colchicine improves the persistence of symptoms at 72 h (absolute risk reduction 0.30 [95 % IC,0.13-0.45]; relative risk reduction 0.56 [0.27-0.74]). It also reduces the mean number of recurrences, increases the remission rate at 1 week and prolongs the time to subsequent recurrence. Colchicine and placebo groups have similar rates of side effects (7 %) and drug withdrawal (8 vs. 5 %, P = 0.89);no severe side effects occurred in any of the groups. Gastrointestinal intolerance was the main side effect during the study. PMID- 22430921 TI - Postpartum hemorrhage: when uterotonics and sutures fail. AB - Systemic bleeding at the time of postpartum hemorrhage (PPH) is usually the result of coagulopathy that has developed acutely as a result of massive hemorrhage after uterotonics and sutures have failed. Occasionally, the patient has a preexisting coagulopathy, but more often, coagulopathy arises acutely as the result of massive hemorrhage, which is usually related to obstetrical and less often surgical bleeding. Despite being able to identify risk factors for PPH in the antenatal and intrapartum period, the majority of women who ultimately develop PPH do not have any such factors and every pregnancy is at risk. The coagulopathy associated with massive PPH may be due to hemodilution, failure of liver synthetic function as occurs with acute liver failure of pregnancy, or disseminated intravascular coagulation (DIC). There are no data from clinical trials to help guide management of transfusion in PPH, although the management of blood component therapy in severe PPH is similar to that in other massive hemorrhage. Standard practice is to replace fibrinogen to maintain a level of >= 100 mg/dL, yet recent evidence suggests that the level of fibrinogen needed to prevent PPH is at least 400 mg/dL. Recombinant activated factor VIIa (rFVIIa) has been used in the management of severe PPH unresponsive to blood component therapy. Coagulation laboratory evaluation may be useful in guiding hemostatic management during massive PPH, but for the results to be useful, they must be rapidly available and provide information that would not be available from clinical assessment alone. The hematologist or hemostasis expert has the opportunity to make the difference between life and death for the patient experiencing massive PPH. PMID- 22430922 TI - Physicochemical performances of indomethacin in cholesteryl cetyl carbonate liquid crystal as a transdermal dosage. AB - A transdermal formulation of indomethacin (IMC) was developed by incorporation into cholesteryl cetyl carbonate (CCC). The liquid crystalline phase properties of the IMC-CCC mixture were detected by polarized light microscopy and differential scanning calorimetry. A low drug loading was obtained (1-5 %) similar to that used in conventional topical IMC in a clinical setting. A controlled release of IMC was found over 12 h. A low amount of IMC in 1 % IMC-CCC permeated the stratum corneum. Further formulation development has been carried out by the addition of lauryl alcohol into 5 % IMC-CCC mixture it was found that the permeation of IMC was significantly improved to 45 % within 24 h. PMID- 22430924 TI - Gastritis and noninvasive testing for Helicobacter pylori. PMID- 22430925 TI - Medicare reimbursement and the sustainable growth rate formula. PMID- 22430928 TI - The Patient-Centered Medical Home: transforming primary care. AB - The Patient-Centered Medical Home (PCMH) is a new care model that reorganizes primary care to improve access, coordination, quality, satisfaction, and comprehensive patient-centered care. Nurse practitioners should understand the PCMH concept, appraise the evidence, and become leaders in this transformation. PMID- 22430929 TI - Reducing STIs: screening, treatment, and counseling. AB - Screening, treatment, and counseling for sexually transmitted infections requires a thorough assessment of psychosocial, behavioral, cultural, and clinical factors. This article offers a summary of the most recent CDC data, prevention guidelines, and steps to implementing current evidence into clinical practice. PMID- 22430930 TI - The safety advantages of pentavalent vaccines. AB - The ever-growing vaccination schedule can cause patients, parents, and nurse practitioners undue concern. Combination vaccines may provide an answer. This integrative review demonstrates that pentavalent vaccines offer adequate immunity, are well tolerated, and safe when compared to vaccines administered separately. PMID- 22430932 TI - Improved population-based probability of developing cancer when direct estimates of the cancer-free population are available. AB - Age-conditional probabilities of developing a first cancer represent the transition from being cancer-free to developing a first cancer. Natural inputs into their calculation are rates of first cancer per person-years alive and cancer-free. However these rates are not readily available because they require information on the cancer-free population. Instead rates of first cancer per person-years alive, calculated using as denominator the mid-year populations, available from census data, can be easily calculated from cancer registry data. Methods have been developed to estimate age-conditional probabilities of developing cancer based on these easily available rates per person-years alive that do not directly account for the cancer-free population. In the last few years models (Merrill et al., Int J Epidemiol 29(2):197-207, 2000; Mariotto et al., SEER Cancer Statistics Review, 2002; Clegg et al., Biometrics 58(3):684-688, 2002; Gigli et al., Stat Methods Med Res 15(3):235-253, 2006, and software (ComPrev:Complete Prevalence Software, Version 1.0, 2005) have been developed that allow estimation of cancer prevalence (DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0, 2005). Estimates of population-based cancer prevalence allows for the estimation of the cancer-free population and consequently of rates per person-years alive and cancer-free. In this paper we present a method that directly estimates the age-conditional probabilities of developing a first cancer using rates per person-years alive and cancer-free obtained from prevalence estimates. We explore conditions when the previous and the new estimators give similar or different values using real data from the Surveillance, Epidemiology and End Results (SEER) program. PMID- 22430933 TI - Synthesis and computational studies of Mg complexes supported by 2,2':6,2'' terpyridine ligands. AB - The reactions of the substituted 2,2':6,2''-terpyridine ligands, 4'-mesityl 2,2':6',2''-terpyridine (mesitylterpy) (1a), 4,4',4''-tri-tert-butyl-2,2':6',2'' terpyridine (tri-(t)Buterpy) (1b) and 4'-phenyl-2,2':6',2''-terpyridine (phenylterpy) (1c) with Grignard reagents were investigated. When half an equivalent of mesitylterpy or tri-(t)Buterpy were treated with MeMgBr in diethyl ether, the only products were (R-terpy)MgBr(2) (R = mesityl (5a), or tri-(t)Bu (5b)) and Me(2)Mg and a similar reaction was observed in THF. Compounds 5a and 5b were characterized by X-ray crystallography. Changing the Grignard reagent to PhMgBr also generated 5a and 5b along with Ph(2)Mg, while the reaction between MeMgCl or PhMgCl and 1a or 1b generated (R-terpy)MgCl(2) (R = mesityl (6a), or tri-(t)Bu (6b)) and either Me(2)Mg or Ph(2)Mg, respectively. The products from reactions between phenylterpy (1c) and Grignard reagents were highly insoluble and could not be fully characterized but appeared to be the same as those from reactions with 1a and 1b. In contrast to other studies using tridentate nitrogen ligands, which formed either mixed halide alkyl species or dihalide and bis(alkyl) species depending on whether the Grignard reagent was reacted with the ligand in diethyl ether or THF, the formation of mixed halide, alkyl complexes of the type (R-terpy)MgR'X (R' = Me or Ph; X = Cl or Br) or dialkyl species such as (R-terpy)MgR'(2) (R' = Me or Ph) was not observed here, regardless of the reaction conditions. DFT studies were performed to complement the experimental studies. The experimental results could not be accurately reproduced unless pi stacking effects associated with free terpyridine were included in the model. When these effects were included, the calculations were consistent with the experimental results which indicated that the formation of the terpy Mg dihalide species and R'(2)Mg (R' = Me or Ph) is thermodynamically preferred over the formation of mixed alkyl halide Mg species. This is proposed to be due to the increased steric bulk of the terpy ligand in the coordination plane, compared with other tridentate nitrogen donors. PMID- 22430935 TI - Genotoxic effects in the Eastern mudminnow (Umbra pygmaea) after prolonged exposure to River Rhine water, as assessed by use of the in vivo SCE and Comet assays. AB - The production of drinking water from river water requires a certain minimal river water quality. The Association of River Rhine Water Works (RIWA), therefore, operates a monitoring network. In vitro mutagenicity studies have shown that the genotoxicity of the River Rhine water steadily decreased from 1981 until 2001. Compared to a study in 1978, a decrease in genotoxicity was also observed in an in vivo genotoxicity study in 2005, in which Eastern mudminnows (Umbra pygmaea) were exposed to River Rhine water, and gill cells were used for the Sister Chromatid Exchange (SCE) test and the Comet assay. In this 2005 study, the in vivo genotoxicity increased upon extending exposure of the fish from 3 to 11 days. Therefore, the objectives of this study were to investigate (i) whether new data corroborate that in vivo genotoxicity of River Rhine water is at present lower than in 1978, (ii) whether the Comet assay is a suitable alternative to the SCE assay, and (iii) whether further prolonged exposure results in a further increase in in vivo genotoxicity. The new data corroborate that in vivo genotoxicity of River Rhine water is at present lower than in 1978. The Comet assay is a useful addition but does not provide a substitute for the SCE endpoint in these in vivo genotoxicity studies. Prolonging the exposure time of Eastern mudminnows to River Rhine water from 11 to 42 days did not give a significant increase in SCEs and DNA damage (Comet assay) in gill cells. PMID- 22430936 TI - Role of retinal input on the development of striate-extrastriate patterns of connections in the rat. AB - Previous studies have shown that retinal input plays an important role in the development of interhemispheric callosal connections, but little is known about the role retinal input plays on the development of ipsilateral striate extrastriate connections and the interplay that might exist between developing ipsilateral and callosal pathways. We analyzed the effects of bilateral enucleation performed at different ages on both the distribution of extrastriate projections originating from restricted loci in medial, acallosal striate cortex, and the overall pattern of callosal connections revealed following multiple tracer injections. As in normal rats, striate-extrastriate projections in rats enucleated at birth consisted of multiple, well-defined fields that were largely confined to acallosal regions throughout extrastriate cortex. However, these projections were highly irregular and variable, and they tended to occupy correspondingly anomalous and variable acallosal regions. Moreover, area 17, but not area 18a, was smaller in enucleates compared to controls, resulting in an increase in the divergence of striate projections. Anomalies in patterns of striate-extrastriate projections were not observed in rats enucleated at postnatal day (P)6, although the size of area 17 was still reduced in these rats. These results indicate that the critical period during which the eyes influence the development of striate-extrastriate, but not the size of striate cortex, ends by P6. Finally, enucleation did not change the time course and definition of the initial invasion of axons into gray matter, suggesting that highly variable striate projections patterns do not result from anomalous pruning of exuberant distributions of 17-18a fibers in gray matter. PMID- 22430937 TI - Genetic identification and functional validation of FcgammaRIV as key molecule in autoantibody-induced tissue injury. AB - Autoantibody-mediated diseases are clinically heterogeneous and often fail conventional therapeutic strategies. Gene expression profiling has helped to identify new molecular pathways in these diseases, although their potential as treatment targets largely remains to be functionally validated. Based on weighted gene co-expression network analysis, we determined the transcriptional network in experimental epidermolysis bullosa acquisita (EBA), a paradigm of an antibody mediated organ-specific autoimmune disease characterized by autoantibodies directed against type VII collagen. We identified 33 distinct and differentially expressed modules, including Fcgamma receptor (FcgammaR) IV and components of the neutrophil-associated enzyme system in autoantibody transfer-induced EBA. Validation experiments, including functional analysis, demonstrated that FcgammaRIV expression on neutrophils crucially contributes to autoantibody induced tissue injury in the transfer model of EBA. Mice lacking the common gamma chain of activating FcgammaRs, deficient in FcgammaRIV or treated with FcgammaRIV function blocking antibody, but not mice deficient in FcgammaRI, FcgammaRIIB, FcgammaRIII or both FcgammaRI and FcgammaRIII, were effectively protected from EBA. Skin disease was restored in gamma-chain-deficient mice locally reconstituted with neutrophils from wild-type, but not from gamma-chain deficient, mice. Our findings both genetically and functionally identify a novel disease-related molecule, FcgammaRIV, in an autoantibody-mediated disorder, which may be of importance for the development of novel targeted therapies. PMID- 22430939 TI - Cardiac involvement in Churg-Strauss syndrome mimicking acute coronary syndrome. AB - Churg-Strauss syndrome (CSS) is a rare multisystemic disorder of unknown origin and cardiac involvement is one of the most serious manifestations of the disease, accounting for approximately one-half of deaths attributable to CSS. Cardiac manifestation can be acute and mimic acute coronary syndrome (ACS). In this setting checking the blood leucocyte count can reveal hypereosinophilia and lead to a diagnosis of CSS. PMID- 22430940 TI - Aldehyde dehydrogenase-2 deficiency aggravates cardiac dysfunction elicited by endoplasmic reticulum stress induction. AB - Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of ALDH2 knockout (KO) in the regulation of cardiac function after endoplasmic reticulum (ER) stress. Wild-type (WT) and ALDH2 KO mice were subjected to a tunicamycin challenge, and the echocardiographic property was examined. Protein levels of six items--78 kDa glucose-regulated protein (GRP78), phosphorylation of eukaryotic initiation factor 2 subunit alpha (p-eIF2alpha), CCAAT/enhancer-binding protein homologous protein (CHOP), phosphorylation of Akt, p47(phox) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and 4-hydroxynonenal--were determined by using Western blot analysis. Cytotoxicity and apoptosis were estimated using 3-(4, 5-dimethylthiazol 2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay and caspase-3 activity, respectively. ALDH2 deficiency exacerbated cardiac contractile dysfunction and promoted ER stress after ER stress induction, manifested by the changes of ejection fraction and fractional shortening. In vitro study revealed that tunicamycin significantly upregulated the levels of GRP78, p-eIF2alpha, CHOP, p47(phox) NADPH oxidase and 4-hydroxynonenal, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression, respectively. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation Akt. Inhibition of phosphatidylinositol 3-kinase using LY294002 did not affect ALDH2-conferred protection against ER stress, although LY294002 reversed the antiapoptotic action of ALDH2 associated with p47(phox) NADPH oxidase. These results suggest a pivotal role of ALDH2 in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against ER stress-induced cell death was probably mediated by Akt via a p47(phox) NADPH oxidase-dependent manner. These findings indicate the critical role of ALDH2 in the pathogenesis of ER stress in heart disease. PMID- 22430941 TI - Automated high-throughput fatty acid analysis of umbilical cord serum and application to an epidemiological study. AB - Large population studies show that polyunsaturated fatty acids are important for human health, but determining relationships between the health benefits and the fatty acid content has been hampered by the unavailability of labor-effective high-throughput technologies. An automated high throughput fatty acid analysis was developed from a previous procedure based on direct transesterification including the automation of chemical procedures, data acquisition and automatic data processing. The method was validated and applied to umbilical cord serum samples in an epidemiological study. The method was linear in the range of 1-600 MUg/mL serum with r2 >= 0.99. The within-run CV was <5.4% for 23 fatty acids and a range of recoveries over three concentrations were 76-119% in a low-lipid matrix with the exception of 14:0. The fatty acid concentration as measured by the robotic method for human plasma was in good agreement with the Lepage & Roy method. The fatty acid profile in umbilical cord serum from American subjects (n = 287) showed an average of 38.0, 24.9, 32.0 and 4.6% of total fatty acids for saturates, monounsaturates, n-6 and n-3 polyunsaturates, respectively. This is the first report of a complete, validated, cost-effective, automated, high throughput fatty acid measurement method along with application to a population based study. Automated fatty acid analysis coupled with automated data processing greatly facilitates the high throughput, 72 samples transesterified in 6 h, required for large population-based studies. PMID- 22430942 TI - Tetravalent dysprosium in a perovskite-type oxide. AB - The existence of tetravalent dysprosium in perovskite-type oxide barium zirconate is confirmed in this work. This discovery will stimulate many researchers in diverse fields such as catalysts, solid state ionics, sensors, and fluorescent materials. PMID- 22430943 TI - Eyeblink conditioning in healthy adults: a positron emission tomography study. AB - Eyeblink conditioning is a paradigm commonly used to investigate the neural mechanisms underlying motor learning. It involves the paired presentation of a tone-conditioning stimulus which precedes and co-terminates with an airpuff unconditioned stimulus. Following repeated paired presentations a conditioned eyeblink develops which precedes the airpuff. This type of learning has been intensively studied and the cerebellum is known to be essential in both humans and animals. The study presented here was designed to investigate the role of the cerebellum during eyeblink conditioning in humans using positron emission tomography (PET). The sample includes 20 subjects (10 male and 10 female) with an average age of 29.2 years. PET imaging was used to measure regional cerebral blood flow (rCBF) changes occurring during the first, second, and third blocks of conditioning. In addition, stimuli-specific rCBF to unpaired tones and airpuffs ("pseudoconditioning") was used as a baseline level that was subtracted from each block. Conditioning was performed using three, 15-trial blocks of classical eyeblink conditioning with the last five trials in each block imaged. As expected, subjects quickly acquired conditioned responses. A comparison between the conditioning tasks and the baseline task revealed that during learning there was activation of the cerebellum and recruitment of several higher cortical regions. Specifically, large peaks were noted in cerebellar lobules IV/V, the frontal lobes, and cingulate gyri. PMID- 22430944 TI - Evolution of approaches in conducting total diet studies. AB - One of the main routes of human exposure to contaminants is through food. To assess the health impact, it is necessary to determine the levels of contaminants in foods and evaluate the exposure estimates. Many countries regularly conduct total diet studies as a method of assessing the exposure of the population to various contaminants present in foods. It is a comprehensive approach and is based on determination of contaminants in foods. The risk assessment is done by taking into account the actual quantity consumed by specific age-sex groups of a population. The approach has developed through multiple changes since its inception. This article aims to review and summarize the changes that have occurred in different countries. Some of the attempts include the addition of analytes and the use of sophisticated instrumentation in conjunction with better extraction and types of food commodities. The present analytical methods have reduced the limits of detection for many analytes in many food matrices, making this approach much more accurate and sensitive. PMID- 22430946 TI - Posterior rectus abdominis sheath abscess after tension-free vaginal tape. AB - Tension-free vaginal tape (TVT) is commonly used to treat stress urinary incontinence (SUI). TVT is known for its simplicity of use and successful outcomes with low morbidity [1]. However, complications can occur. We report an abscess posterior to the rectus muscle following TVT. A 46-year-old woman underwent TVT for SUI. On postoperative day (POD) 13, she presented with an abscess of the left suprapubic incision, which was treated with antibiotics and drainage. She represented on POD 22 with multiple pulmonary emboli and sepsis, and computed tomography (CT) revealed a multiloculated abdominal-wall fluid collection deep to the rectus muscle. The mesh was removed via vaginal incision. The rectus sheath abscess was accessed through a subfascial but extraperitoneal midline incision. The abdominal-wall wound was connected to the suprapubic wound. Whereas major infectious complications of TVT are rare, when they do occur, debridement, drainage, and removal of the mesh are imperative to prevent morbidity. PMID- 22430945 TI - Polypropylene mesh and the host response. AB - The use of polypropylene (PP) mesh for pelvic floor repair has been increasing dramatically over the past decade; however, tissue response in humans has not been extensively studied. This review discusses PP mesh and postimplantation host tissue response. Emphasis is placed on studies investigating the relationship between individual mesh properties and specific responses. There is an immediate inflammatory response after PP mesh implantation that lays the framework for tissue ingrowth and subsequent mesh integration. This response varies based on physical properties of individual mesh, such as pore size, weight, coatings, bacterial colonization, and biofilm production. PMID- 22430947 TI - Mechanism for dynamic regulation of iNOS expression after UVB-irradiation. AB - Ultraviolet B (UVB) induces an immediate activation of cNOSs, which contributes to the early release of nitric oxide after irradiation. UVB also induces the expression of iNOS, which peaks at both the mRNA and protein level near 24 h post irradiation. The induced expression of iNOS contributes largely to the late elevation of nitric oxide after UVB irradiation. However, the regulation of iNOS expression in the early stages of UVB irradiation is not well studied. We previously reported that the UVB-induced early release of nitric oxide leads to the activation of PERK and GCN2, which phosphorylate the alpha-subunit of eIF2 and inhibit protein synthesis. In this report, we demonstrate that eIF2 phosphorylation plays a critical role in regulation of iNOS expression in the early-phase (with in 12 h) of UVB irradiation. Our data shows that with an increased phosphorylation of eIF2, the iNOS protein expression was reduced even though the iNOS mRNA expression was linearly increased in HaCaT and MEF cells after UVB irradiation. The UVB-induced dynamic up- and down-regulation of iNOS expression was almost completely lost in MEF(A/A) cells, which contain a nonphosphorylatable S51A mutation on eIF2. Our results suggest that the UVB induced eIF2 phosphorylation does not only regulate iNOS expression at the translational level, but at the transcriptional level as well. PMID- 22430948 TI - The aging patient with hemophilia. AB - The prospects for many boys born with hemophilia today include a normal life expectancy and minimal to no joint disease. However, despite the availability of safe replacement clotting factor concentrates and effective antiviral treatment, the aging patient with hemophilia today faces many challenges. These include management of their hemophilia as well as the same age-related health issues as experienced in the general population. While increasing, data on the prevalence of comorbidities and their management in the hemophilia population remain limited. This review will focus on issues related to management of hemophilia and complications of cardiovascular, musculoskeletal, hepatic, and renal disease. Available research is summarized and potential approaches to management are discussed. PMID- 22430949 TI - Modernization and cardiometabolic risk in Samoan adolescents. AB - OBJECTIVE: To describe the prevalence of cardiometabolic risk factor clustering in Samoan adolescents and to relate risk factor clustering to weight status and general modernization. METHODS: Anthropometric and biochemical data collected from adolescents aged 12-17.9 years who participated in the Samoan Family Study of Overweight and Diabetes were used to describe the prevalence of cardiometabolic risk factors (high waist circumference, high blood pressure, high triglyceride level, low-high-density lipoprotein cholesterol, and high fasting serum glucose). A total of 436 adolescents were included in this analysis; 237 (54.4%) from American Samoa (n = 123 males) and 199 (45.6%) from Samoa (n = 90 males). Risk factor clustering was indicated by the presence of >= 3 risk factors. RESULTS: Cardiometabolic risk factor clustering was greater in American Samoan adolescents (17.9% males, 21.9% females) than Samoan adolescents (1.1% males, 2.8% females). The frequency of risk factor clustering varied according to body mass index status. In males, risk factor clustering was entirely confined to obese adolescents, whereas female adolescents who were overweight or obese were at risk. CONCLUSIONS: Cardiometabolic risk factor clustering is prevalent in the young American Samoan population and is likely to become more prevalent with increasing modernization in Samoan youth. Screening and intervention should be targeted at this age group to reduce the non-communicable disease burden faced by these populations. PMID- 22430950 TI - Involvement of GPR12 in the regulation of cell proliferation and survival. AB - GPR12, a member of the orphan G-protein-coupled receptor family, constitutively activates the Gs protein and increases intracellular cyclic AMP concentrations. GPR12 can be activated by its known ligand-sphingosylphosphorylcholine, which regulates cellular physiological activities, including proliferation, neurite extension, cell clustering, and maintenance of meiotic arrest. However, signaling pathways involved in the GPR12-mediated physiological and biochemical changes are still not clearly illustrated. In the present study, heterologous GPR12 expression was demonstrated to promote proliferation and survival in human embryonic kidney 293 cells. Immunochemical analysis showed that Ki67, a prototypic cell cycle-related nuclear protein, might participate in the regulation of GPR12-mediated cell proliferation. Activation of extracellular signal-regulated protein kinase signaling and increased total Erk1/2 and B-cell lymphoma/leukemia-2 expression were also observed in HEK293 cells overexpressing human GPR12. In addition, we found that GPR12 promoted cell survival under serum deprivation, indicating that GPR12 may play a role in cell proliferation and survival. PMID- 22430951 TI - VP6-sequence-based cutoff values as a criterion for rotavirus species demarcation. AB - Indirect immunofluorescence techniques targeting the rotavirus (RV) protein VP6 are used to differentiate RV species. The ICTV recognizes RV species A to E and two tentative species, F and G. A potential new RV species, ADRV-N, has been described. Phylogenetic trees and pairwise identity frequency graphs were constructed with more than 400 available VP6 sequences and seven newly determined VP6 sequences of RVD strains. All RV species were separated into distinct phylogenetic clusters. An amino acid sequence cutoff value of 53% firmly permitted differentiation of RV species, and ADRV-N was tentatively assigned to a novel RV species H (RVH). PMID- 22430952 TI - Piperine inhibits lipopolysaccharide-induced maturation of bone-marrow-derived dendritic cells through inhibition of ERK and JNK activation. AB - Piperine, one of the main components of Piper longum Linn. and P. nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine has been shown to modulate the immune response, but the mechanism underlying this modulation remains unknown. Here, we examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses in bone-marrow-derived dendritic cells (BMDCs). Piperine significantly inhibited the expression of major histocompatibility complex class II, CD40 and CD86 in BMDCs in a dose-dependent manner. Furthermore, piperine treatment led to an increase in fluorescein isothiocyanate-dextran uptake in LPS-treated dendritic cells and inhibited the production of tumour necrosis factor alpha and interleukin (IL)-12, but not IL-6. The inhibitory effects of piperine were mediated via suppression of extracellular signal-regulated kinases and c-Jun N-terminal kinases activation, but not p38 or nuclear factor-kappaB activation. These findings provide insight into the immunopharmacological role of piperine. PMID- 22430954 TI - GPEC: a Cytoscape plug-in for random walk-based gene prioritization and biomedical evidence collection. AB - Finding genes associated with a disease is an important issue in the biomedical area and many gene prioritization methods have been proposed for this goal. Among these, network-based approaches are recently proposed and outperformed functional annotation-based ones. Here, we introduce a novel Cytoscape plug-in, GPEC, to help identify putative genes likely to be associated with specific diseases or pathways. In the plug-in, gene prioritization is performed through a random walk with restart algorithm, a state-of-the art network-based method, along with a gene/protein relationship network. The plug-in also allows users efficiently collect biomedical evidence for highly ranked candidate genes. A set of known genes, candidate genes and a gene/protein relationship network can be provided in a flexible way. PMID- 22430955 TI - Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. AB - PSI-7977, a prodrug of 2'-F-2'-C-methyluridine monophosphate, is the purified diastereoisomer of PSI-7851 and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. In this study, we profiled the activity of PSI-7977 and its ability to select for resistance using a number of different replicon cells. Results showed that PSI-7977 was active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, and 3a NS5B polymerase. Cross-resistance studies using GT 1b replicons confirmed that the S282T change conferred resistance to PSI-7977. Subsequently, we evaluated the ability of PSI-7977 to select for resistance using GT 1a, 1b, and 2a (JFH-1) replicon cells. S282T was the common mutation selected among all three genotypes, but while it conferred resistance to PSI-7977 in GT 1a and 1b, JFH-1 GT 2a S282T showed only a very modest shift in 50% effective concentration (EC(50)) for PSI-7977. Sequence analysis of the JFH-1 NS5B region indicated that additional amino acid changes were selected both prior to and after the emergence of S282T. These include T179A, M289L, I293L, M434T, and H479P. Residues 179, 289, and 293 are located within the finger and palm domains, while 434 and 479 are located on the surface of the thumb domain. Data from the JFH-1 replicon variants showed that amino acid changes within the finger and palm domains together with S282T were required to confer resistance to PSI-7977, while the mutations on the thumb domain serve to enhance the replication capacity of the S282T replicons. PMID- 22430956 TI - Integrated population pharmacokinetic analysis of voriconazole in children, adolescents, and adults. AB - To further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC(0-12)]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC(0-12)s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC(0-12) in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is >= 50 kg. Other adolescents should be dosed like adults. PMID- 22430957 TI - Activity of oxacillin versus that of vancomycin against oxacillin-susceptible mecA-positive Staphylococcus aureus clinical isolates evaluated by population analyses, time-kill assays, and a murine thigh infection model. AB - We compared the activity of dicloxacillin with that of vancomycin against 15 oxacillin-susceptible, methicillin-resistant Staphylococcus aureus (OS-MRSA) clinical isolates. By population analyses, we found that 6 OS-MRSA isolates were able to grow in the presence of up to 8 MUg/ml dicloxacillin and 9 isolates were able to grow in 12 to >32 MUg/ml dicloxacillin; all isolates grew in up to 2 MUg/ml vancomycin. Both drugs exhibited similar bactericidal activities. In experimental infections, the therapeutic efficacy of dicloxacillin was significant (P < 0.05 versus untreated controls) in 10 OS-MRSA isolates and vancomycin was effective (P < 0.05) against 12 isolates; dicloxacillin had an efficacy that was comparable to that of vancomycin (P > 0.05) in 8 isolates. The favorable response to dicloxacillin treatment might suggest that antistaphylococcal penicillins could be used against OS-MRSA infections. PMID- 22430958 TI - The combination of doripenem and colistin is bactericidal and synergistic against colistin-resistant, carbapenemase-producing Klebsiella pneumoniae. AB - We tested two-drug combinations of doripenem, colistin, gentamicin, and doxycycline against 12 carbapenemase-producing Klebsiella pneumoniae (KPC) isolates by time-kill. The combination of doripenem and colistin reduced the starting inocula by 2 logs for each isolate (range, 2.02 to 6.01 log(10)) and was bactericidal and synergistic against 75 and 50%, respectively. Among colistin- and pan-drug-resistant isolates, synergy was identified in 60 and 67%, respectively. All other combinations were inferior. We are currently evaluating the combination of doripenem and colistin as a frontline therapy for KPC infection. PMID- 22430959 TI - Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria. AB - The combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children. We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, and the children were followed up for 28 days. The primary outcome was the PCR-corrected adequate clinical and parasitological response at day 28. Secondary outcomes included day 7 and 28 uncorrected cure rates and fever (FCT) and parasite (PCT) clearance times. Fifty-two children were recruited, but only 37 patients were evaluable for the primary outcome. Day 7 cure rates were high (94.6%; 35/37), but the day 28 PCR-corrected cure rate was 45.9% (17/37). The FCT was short (median, 12 h), but the PCT was longer (median, 72 h) than in previous studies. Tolerability was good, and most common adverse events were related to the recurrence of malaria. The poor efficacy observed for the F/C combination may be a consequence of the new formulations used, differential bioavailability in younger children, naturally occurring variations in parasite sensitivity to the drugs, or an insufficient enhancement of their effects by naturally acquired immunity in young children. Additional studies should be conducted to respond to the many uncertainties arising from this trial, which should not discourage further evaluation of this promising combination. PMID- 22430960 TI - A potent plant-derived antifungal acetylenic acid mediates its activity by interfering with fatty acid homeostasis. AB - 6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid beta-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In a fluconazole-resistant clinical isolate of C. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections. PMID- 22430961 TI - Rapid, field-deployable method for genotyping and discovery of single-nucleotide polymorphisms associated with drug resistance in Plasmodium falciparum. AB - Despite efforts to reduce malaria morbidity and mortality, drug-resistant parasites continue to evade control strategies. Recently, emphasis has shifted away from control and toward regional elimination and global eradication of malaria. Such a campaign requires tools to monitor genetic changes in the parasite that could compromise the effectiveness of antimalarial drugs and undermine eradication programs. These tools must be fast, sensitive, unambiguous, and cost-effective to offer real-time reports of parasite drug susceptibility status across the globe. We have developed and validated a set of genotyping assays using high-resolution melting (HRM) analysis to detect molecular biomarkers associated with drug resistance across six genes in Plasmodium falciparum. We improved on existing technical approaches by developing refinements and extensions of HRM, including the use of blocked probes (LunaProbes) and the mutant allele amplification bias (MAAB) technique. To validate the sensitivity and accuracy of our assays, we compared our findings to sequencing results in both culture-adapted lines and clinical isolates from Senegal. We demonstrate that our assays (i) identify both known and novel polymorphisms, (ii) detect multiple genotypes indicative of mixed infections, and (iii) distinguish between variants when multiple copies of a locus are present. These rapid and inexpensive assays can track drug resistance and detect emerging mutations in targeted genetic loci in P. falciparum. They provide tools for monitoring molecular changes associated with changes in drug response across populations and for determining whether parasites present after drug treatment are the result of recrudescence or reinfection in clinical settings. PMID- 22430962 TI - In vitro activities of clindamycin, imipenem, metronidazole, and piperacillin tazobactam against susceptible and resistant isolates of Bacteroides fragilis evaluated by kill kinetics. AB - The aim of the present study was to investigate the activities of clindamycin, imipenem, metronidazole, and piperacillin-tazobactam against 12 Bacteroides fragilis isolates (resistant and susceptible strains) by kill kinetics over 24 h. In contrast to the other antimicrobial agents, clindamycin did not affect strains with MICs of >8.0 MUg/ml. For those strains with MICs of <= 8.0 MUg/ml, all employed antibiotics except clindamycin showed nearly bactericidal activity. Metronidazole proved to be the most active antimicrobial agent. PMID- 22430963 TI - Effect of milk thistle on the pharmacokinetics of darunavir-ritonavir in HIV infected patients. AB - The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir ritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavir-ritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary. PMID- 22430964 TI - Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients. AB - QDMRK was a phase III clinical trial of raltegravir given once daily (QD) (800-mg dose) versus twice daily (BID) (400 mg per dose), each in combination with once daily coformulated tenofovir-emtricitabine, in treatment-naive HIV-infected patients. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses were conducted using a 2-step approach: individual non-model-based PK parameters from observed sparse concentration data were determined, followed by statistical analysis of potential relationships between PK and efficacy response parameters after 48 weeks of treatment. Sparse PK sampling was performed for all patients (QD, n = 380; BID, n = 384); selected sites performed an intensive PK evaluation at week 4 (QD, n = 22; BID, n = 20). In the intensive PK subgroup, daily exposures (area under the concentration-time curve from 0 to 24 h [AUC(0 24)]) were similar between the two regimens, but patients on 800 mg QD experienced ~4-fold-higher maximum drug concentration in plasma (C(max)) values and ~6-fold-lower trough drug concentration (C(trough)) values than those on 400 mg BID. Geometric mean (GM) C(trough) values were similarly lower in the sparse PK analysis. With BID dosing, there was no indication of any significant PK/PD association over the range of tested PK parameters. With QD dosing, C(trough) values correlated with the likelihood of virologic response. Failure to achieve an HIV RNA level of <50 copies/ml appeared predominantly at high baseline HIV RNA levels in both treatment arms and was associated with lower values of GM C(trough) in the 800-mg-QD arm, though other possible drivers of efficacy, such as time above a threshold concentration, could not be evaluated due to the sparse sampling scheme. Together, these findings emphasize the importance of the shape of the plasma concentration-versus-time curve for long-term efficacy. PMID- 22430965 TI - Action of linezolid or vancomycin on biofilms in ventriculoperitoneal shunts in vitro. AB - Cerebrospinal fluid (CSF) shunts used to treat hydrocephalus have an overall infection rate of about 10% of operations. The commonest causative bacteria are Staphylococcus epidermidis, followed by Staphylococcus aureus and enterococci. Major difficulties are encountered with nonsurgical treatment due to biofilm development in the shunt tubing and inability to achieve sufficiently high CSF drug levels by intravenous administration. Recently, three cases of S. epidermidis CSF shunt infection have been treated by intravenous linezolid without surgical shunt removal, and we therefore investigated vancomycin and linezolid against biofilms of these bacteria in vitro. A continuous-perfusion model of shunt catheter biofilms was used to establish mature (1-week) biofilms of Staphylococcus aureus, Staphylococcus epidermidis (both methicillin resistant [MRSA and MRSE]), Enterococcus faecalis, and Enterococcus faecium. They were then "treated" with either vancomycin or linezolid in concentrations achievable in CSF for 14 days. The biofilms were then monitored for 1 week for eradication and for regrowth. Enterococcal biofilms were not eradicated by either vancomycin or linezolid. Staphylococcal biofilms were eradicated by both antibiotics after 2 days and did not regrow. No resistance was seen. Linezolid at concentrations achievable by intravenous or oral administration was able to eradicate biofilms of both S. epidermidis (MRSE) and S. aureus (MRSA). Neither vancomycin at concentrations achievable by intrathecal administration nor linezolid was able to eradicate enterococcal biofilms. It is hoped that these in vitro results will stimulate further clinical trials with linezolid, avoiding surgical shunt removal. PMID- 22430966 TI - Pharmacokinetics and pulmonary disposition of tedizolid and linezolid in a murine pneumonia model under variable conditions. AB - In vivo pharmacokinetics are often evaluated in only one variation of an infection model, and the resulting exposures are assumed to be similar in each model. We evaluated and compared the effect of lung infection and immune status on the murine pharmacokinetics and pulmonary disposition of tedizolid and linezolid. Both factors resulted in differing blood and pulmonary exposure profiles, with similar trends for tedizolid and linezolid. These data highlight the importance of pharmacokinetic confirmation in each model. PMID- 22430967 TI - In vitro antimalarial activity and drug interactions of fenofibric acid. AB - Plasmodium falciparum has developed resistance to most available treatments, underscoring the need for novel antimalarial drugs. Fibrates are lipid-modifying agents used to reduce morbidity and mortality associated with cardiovascular disease. They may have antimalarial activity through modulation of P-glycoprotein and ATP-binding cassette subfamily A member (ABC-1)-mediated nutrient transport and/or via a putative peroxisome proliferator-activated receptor alpha-like protein. We therefore examined in vitro antimalarial activities of fibrates and their interactions with chloroquine and dihydroartemisinin in chloroquine sensitive (3D7) and chloroquine-resistant (W2mef) strains of P. falciparum using the conventional isotopic assay microtechnique. A bioassay was used to assess inhibition activities of human plasma after therapeutic fenofibrate doses. Fenofibric acid, the main metabolite of fenofibrate, was the most potent of the fibrates tested, with mean 50% inhibitory concentrations of 152 nM and 1,120 nM for chloroquine-sensitive and -resistant strains, respectively. No synergistic interaction between fibrates and chloroquine or dihydroartemisinin was observed. Plasma fenofibric acid concentrations, quantified by high-performance liquid chromatography in seven healthy volunteers after treatment (mean, 15.3 mg/liter, or 48 MUM), inhibited P. falciparum. BLAST analysis revealed the likely presence of an ABC-1 transporter homolog in P. falciparum. Our findings demonstrate that fenofibric acid has activity similar to the activities of conventional antimalarial drugs at concentrations well below those achieved after therapeutic doses. It may inhibit P. falciparum growth by inhibiting intracellular lipid transport. PMID- 22430968 TI - Phase II dose-ranging trial of the early bactericidal activity of PA-824. AB - PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (+/- standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 +/- 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 +/- 0.058, 0.091 +/- 0.073, 0.078 +/- 0.074, and 0.112 +/- 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis. PMID- 22430969 TI - Carbapenem therapy for bacteremia due to extended-spectrum-beta-lactamase producing Escherichia coli or Klebsiella pneumoniae: implications of ertapenem susceptibility. AB - A retrospective study was conducted at two medical centers in Taiwan to evaluate the clinical characteristics, outcomes, and risk factors for mortality among patients treated with a carbapenem for bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing organisms. A total of 251 patients with bacteremia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates treated by a carbapenem were identified. Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs <= 0.25 MUg/ml) were 83.8% and 76.4%, respectively; those to meropenem were 100% and 99.3%, respectively; and those to imipenem were 100% and 97.9%, respectively. There were no significant differences in the critical illness rate (P = 0.1) or sepsis-related mortality rate (P = 0.2) for patients with bacteremia caused by ESBL-producing K. pneumoniae (140 isolates, 55.8%) and E. coli (111 isolates, 44.2%). Multivariate analysis of variables related to sepsis-related mortality revealed that the presence of severe sepsis (odds ratio [OR], 15.9; 95% confidence interval [CI], 5.84 to 43.34; P < 0.001), hospital-onset bacteremia (OR, 4.65; 95% CI, 1.42 to 15.24; P = 0.01), and ertapenem-nonsusceptible isolates (OR, 5.12; 95% CI, 2.04 to 12.88; P = 0.001) were independent risk factors. The patients receiving inappropriate therapy had a higher sepsis-related mortality than those with appropriate therapy (P = 0.002), irrespective of ertapenem, imipenem, or meropenem therapy. Infections due to the ertapenem-susceptible isolates (MICs <= 0.25 MUg/ml) were associated with a more favorable outcome than those due to ertapenem-nonsusceptible isolates (MICs > 0.25 MUg/ml), if treated by a carbapenem. However, the mortality for patients with bacteremic episodes due to isolates with MICs of <= 0.5 MUg/ml was similar to the mortality for those whose isolates had MICs of >0.5 MUg/ml (P = 0.8). Such a finding supports the rationale of the current CLSI 2011 criteria for carbapenems for Enterobacteriaceae. PMID- 22430970 TI - Quinolone-induced upregulation of osteopontin gene promoter activity in human lung epithelial cell line A549. AB - Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin (62%), gatifloxacin (82%), sparfloxacin, (79%), and sitafloxacin (60%). Enhancement of OPN secretion was shown to be due to the effect of quinolones on the OPN gene promoter activity. We also examined the role of quinolones on apoptosis and found that sparfloxacin decreased the late apoptosis of A549 cells, but garenoxacin did not show the antiapoptotic effect. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation. PMID- 22430971 TI - Sublimable C5A delivery provides sustained and prolonged anti-HIV microbicidal activities. AB - We have identified a short amphipathic helical peptide, called C5A, which exhibits potent microbicidal activities in vitro and which offers protection from vaginal HIV transmission in vivo in a humanized mouse model. However, there are many obstacles to overcome before C5A can be considered a true microbicidal candidate. First, it must be stabilized against enzymatic degradation in a continuously warm and moist environment. Second, it must be delivered in a controlled manner to achieve long-term and coitally independent efficacy. We demonstrate in this in vitro study that the combination of two matrices with different subliming properties ((hexamethylcyclotrisiloxane [HMCS] and cyclododecane [CDD]) containing 10% labile C5A yielded the best results in terms of controlled release and preserved anti-HIV activity of the peptide when pre exposed to cell-free medium or cell culture at body temperature for up to 2 months. PMID- 22430972 TI - Randomized trial of entecavir plus adefovir in patients with lamivudine-resistant chronic hepatitis B who show suboptimal response to lamivudine plus adefovir. AB - A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudine-resistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV+ADV, n = 45) or continuation of lamivudine plus adefovir (LAM+ADV, n = 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log(10) IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV+ADV group than in the LAM+ADV group (n = 13, 29%, versus n = 2, 4%, respectively; P = 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV+ADV group than in the LAM+ADV group (-2.2 log(10) IU/ml versus -0.6 log(10) IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV+ADV group but in 15% of patients in the LAM+ADV group (P = 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy. PMID- 22430973 TI - Association of ITPA gene polymorphisms and the risk of ribavirin-induced anemia in HIV/hepatitis C virus (HCV)-coinfected patients receiving HCV combination therapy. AB - Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = -0.7; 95% CI = -1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV coinfected patients. PMID- 22430974 TI - Effects of rilpivirine on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. AB - Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation in vitro. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT enhancer binding protein alpha (C/EBPalpha), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 MUM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 MUM) or even at lower concentrations of efavirenz (2 MUM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations. PMID- 22430975 TI - Attenuated virulence and biofilm formation in Staphylococcus aureus following sublethal exposure to triclosan. AB - Subeffective exposure of Staphylococcus aureus to the biocide triclosan can reportedly induce a small-colony variant (SCV) phenotype. S. aureus SCVs are characterized by low growth rates, reduced pigmentation, and lowered antimicrobial susceptibility. While they may exhibit enhanced intracellular survival, there are conflicting reports regarding their pathogenicity. The current study reports the characteristics of an SCV-like strain of S. aureus created by repeated passage on sublethal triclosan concentrations. S. aureus ATCC 6538 (the passage 0 [P0] strain) was serially exposed 10 times to concentration gradients of triclosan to generate strain P10. This strain was then further passaged 10 times on triclosan-free medium (designated strain *10). The MICs and minimum bactericidal concentrations of triclosan for P0, P10, and *10 were determined, and growth rates in biofilm and planktonic cultures were measured. Hemolysin, DNase, and coagulase activities were measured, and virulence was determined using a Galleria mellonella pathogenicity model. Strain P10 exhibited decreased susceptibility to triclosan and characteristics of an SCV phenotype, including a considerably reduced growth rate and the formation of pinpoint colonies. However, this strain also had delayed coagulase production, had impaired hemolysis (P < 0.01), was defective in biofilm formation and DNase activity, and displayed significantly attenuated virulence. Colony size, hemolysis, coagulase activity, and virulence were only partially restored in strain *10, whereas the planktonic growth rate was fully restored. However, *10 was at least as defective in biofilm formation and DNase production as P10. These data suggest that although repeated exposure to triclosan may result in an SCV like phenotype, this is not necessarily associated with increased virulence and adapted bacteria may exhibit other functional deficiencies. PMID- 22430976 TI - Pharmacokinetics of ferroquine, a novel 4-aminoquinoline, in asymptomatic carriers of Plasmodium falciparum infections. AB - Ferroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomatic Plasmodium falciparum infection were administered a single oral dose (n = 40) or a repeated oral dose (n = 26) given over 3 days of ferroquine in two dose escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (n = 16). The studies were carried out in Lambarene, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([C(max)] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng . h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study, C(max) and overall cumulated exposure to ferroquine (AUC(cum)) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (t(max)) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated. PMID- 22430977 TI - Characterization of UC781-tenofovir combination gel products for HIV-1 infection prevention in an ex vivo ectocervical model. AB - HIV continues to be a problem worldwide. Topical vaginal microbicides represent one option being evaluated to stop the spread of HIV. With drug candidates that have a specific action against HIV now being studied, it is important that, when appropriate and based on the mechanism of action, the drug permeates the tissue so that it can be delivered to specific targets which reside there. Novel formulations of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) and the nonnucleoside reverse transcriptase inhibitor UC781 have been developed and evaluated here. Gels with three distinct rheological properties were prepared. The three gels released both UC781 and TFV under in vitro conditions at concentrations equal to or above the reported 50% effective concentrations (EC(50)s). The drug concentrations in ectocervical tissues were well in excess of the reported EC(50)s. The gels maintain ectocervical viability and prevent infection of ectocervical explants after a HIV-1 challenge. This study successfully demonstrates the feasibility of using this novel combination of antiretroviral agents in an aqueous gel as an HIV infection preventative. PMID- 22430978 TI - Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery. AB - Antimicrobial peptides (AMPs) have therapeutic potential, particularly for localized infections such as those of the lung. Here we show that airway administration of a pegylated AMP minimizes lung tissue toxicity while nevertheless maintaining antimicrobial activity. CaLL, a potent synthetic AMP (KWKLFKKIFKRIVQRIKDFLR) comprising fragments of LL-37 and cecropin A peptides, was N-terminally pegylated (PEG-CaLL). PEG-CaLL derivatives retained significant antimicrobial activity (50% inhibitory concentrations [IC(50)s] 2- to 3-fold higher than those of CaLL) against bacterial lung pathogens even in the presence of lung lining fluid. Circular dichroism and fluorescence spectroscopy confirmed that conformational changes associated with the binding of CaLL to model microbial membranes were not disrupted by pegylation. Pegylation of CaLL reduced AMP-elicited cell toxicity as measured using in vitro lung epithelial primary cell cultures. Further, in a fully intact ex vivo isolated perfused rat lung (IPRL) model, airway-administered PEG-CaLL did not result in disruption of the pulmonary epithelial barrier, whereas CaLL caused an immediate loss of membrane integrity leading to pulmonary edema. All AMPs (CaLL, PEG-CaLL, LL-37, cecropin A) delivered to the lung by airway administration showed limited (<3%) pulmonary absorption in the IPRL with extensive AMP accumulation in lung tissue itself, a characteristic anticipated to be beneficial for the treatment of pulmonary infections. We conclude that pegylation may present a means of improving the lung biocompatibility of AMPs designed for the treatment of pulmonary infections. PMID- 22430979 TI - Four di-Cu(II)-substituted sandwich-type germanomolybdates obtained under different reaction conditions: from zero-dimensional to two-dimensional structure. AB - Four di-Cu(II)-substituted sandwich-type germanomolybdates, (H(2)en)(2)H(7){[Na(0.5)(H(2)O)(3.5)](2)[Cu(2)(beta-Y-GeMo(9)O(33))(2)]}.6H(2)O (1), (H(2)en)(2)H{[Na(2.5)(H(2)O)(12)](2)[Cu(en)(2)][Cu(2)(beta-Y GeMo(9)O(33))(2)]}.8H(2)O (2), [Na(4)(H(2)O)(12)](2)H(4)[Cu(2)(beta-Y GeMo(9)O(33))(2)]}.11H(2)O (3) and [Cu(en)(2)](2)[Cu(en)(2)(H(2)O)](2){[Cu(en)(2)](2)[Cu(2)(beta-Y GeMo(9)O(33))(2)]}.8H(2)O (4) (en = ethylenediamine), have been prepared. It is interesting that 1-3 were obtained in the same aqueous solution reaction system but exhibited different structures: 1 displays a 0D structure, 2 shows an organic inorganic 1D chain structure, while 3 displays a 2D network. 4 was synthesized under hydrothermal condition by the same reagents, which represents the first transition metal-sandwiched organic-inorganic 2D heteropolymolybdate. PMID- 22430980 TI - The effect of high doses of folic acid and iron supplementation in early-to-mid pregnancy on prematurity and fetal growth retardation: the mother-child cohort study in Crete, Greece (Rhea study). AB - PURPOSE: We examined whether high doses of folic acid and iron supplementation in early-to-mid pregnancy affect the risk of preterm birth, low birth weight, and small for gestational age neonates, in the mother-child cohort in Crete, Greece (Rhea study). METHODS: We included 1,279 women with singleton pregnancies with complete data on supplements use in early-to-mid pregnancy and birth outcomes. Anthropometric measurements at birth were obtained from medical records. Red blood cell folate concentrations in cord blood were measured in a subsample of the study population (n = 58). RESULTS: Sixty-six percent of the study participants reported high doses of supplemental folic acid use (5 mg/day), while 21 % reported excessive doses of folic acid use (>5 mg/day) in early-to-mid pregnancy. Daily intake of 5-mg supplemental folic acid was associated with a 31 % decrease in the risk of preterm birth (RR, 0.69; 95 % CI, 0.44, 0.99), 60 % decrease in the risk of delivering a low birth weight neonate (RR, 0.40; 95 % CI, 0.21, 0.76), and 66 % decrease in the risk of delivering a small for gestational age (SGA) neonate (RR, 0.34; 95 % CI, 0.16, 0.73). Daily doses of iron supplementation more than 100 mg were associated with a twofold increased risk for SGA neonates (RR, 2.14; 95 % CI, 0.99, 5.97). CONCLUSION: These findings suggest that high daily doses of supplementary folic acid in early-to-mid pregnancy may be protective for preterm birth, low birth weight, and small for gestational age neonates, while high daily doses of supplementary iron may be harmful for fetal growth. PMID- 22430981 TI - Folate deficiency is associated with the formation of complex nuclear anomalies in the cytokinesis-block micronucleus cytome assay. AB - Chromosomal instability (CIN) is an important hallmark to oncogenesis and can be diagnosed morphologically by the presence of nuclear anomalies such as micronuclei (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBuds). We have identified additional nuclear anomalies formed under folate-deficient conditions, defined as "fused" nuclei (FUS), "circular" nuclei (CIR), and "horse-shoe" nuclei (HS) and investigated their suitability for inclusion as additional CIN biomarkers in the lymphocyte cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. Although the morphological appearance of FUS, CIR, and HS suggested an origin from multiple NPB in the fusion region between the two nuclei, the very low frequency of dicentric chromosomes in metaphase spreads from these cultures did not support this model. Fluorescence in situ hybridization (FISH) analysis of cytokinesis-blocked binucleated (BN) cells with peptide nucleic acid probes for telomeres and centromeres (PNA-FISH) revealed a high proportion of fusion regions contained both centromeric and telomeric DNA. This suggests that folate deficiency may disrupt the process of sister chromatid separation and chromosome segregation during mitosis. It was concluded that the FUS, CIR, and HS morphologies represent promising biomarkers of CIN that are sensitive to folate deficiency, and further validation and investigation of the mechanisms responsible for their formation is warranted. PMID- 22430982 TI - Emotion dysregulation model of mood and anxiety disorders. AB - In this review, we present a transdiagnostic emotion dysregulation model of mood and anxiety disorders. This model posits that a triggering event, in conjunction with an existing diathesis, leads to negative or positive affect, depending on the person's affective style. Mood and anxiety disorders are the result of emotion dysregulation of negative affect, coupled with deficiencies in positive affect. The theoretical background of the model is discussed and a range of clinical applications of the model is described. PMID- 22430983 TI - Organization of the gymnotiform fish pallium in relation to learning and memory: I. Cytoarchitectonics and cellular morphology. AB - The present article examines the anatomical organization of the dorsal telencephalon of two gymnotiform fish: Gymnotus sp. and Apteronotus leptorhynchus. These electric fish use elaborate electrical displays for agonistic and sexual communication. Our study emphasizes mainly pallial divisions: dorsolateral (DL), dorsodorsal (DD), and dorsocentral (DC), previously implicated in social learning dependent on electric signals. We found that the pallial cytoarchitectonics of gymnotiformes are similar to those reported for the commonly studied goldfish, except that DC is larger and better differentiated in gymnotiformes. We identified a new telencephalic region (Dx), located between DL and DC, and describe the morphological and some biochemical properties of its neurons. Most neurons in DL, DD, and DC are glutamatergic with spiny dendrites. However, the size of these cells as well as the orientation and extent of their dendrites vary systematically across these regions. In addition, both DD and DL contained numerous small GABAergic interneurons as well as well-developed GABAergic plexuses. One important and novel observation is that the dendrites of the spiny neurons within all three regions remain confined to their respective territories. We confirm that DL and DC express very high levels of NMDA receptor subunits as well as CaMKIIalpha, a key downstream effector of this receptor. In contrast, this enzyme is nearly absent in DD, while NMDA receptors are robustly expressed, suggesting different rules for synaptic plasticity across these regions. Remarkably, GABAergic pallial neurons do not express CaMKIIalpha, in agreement with previously reported results in the cortex of rats. PMID- 22430984 TI - ARF suppresses hepatic vascular neoplasia in a carcinogen-exposed murine model. AB - Hepatic haemangiosarcoma is a deadly malignancy whose aetiology remains poorly understood. Inactivation of the CDKN2A locus, which houses the ARF and p16(INK4a) tumour suppressor genes, is a common event in haemangiosarcoma patients, but the precise role of ARF in vascular tumourigenesis is unknown. To determine the extent to which ARF suppresses vascular neoplasia, we examined the incidence of hepatic vascular lesions in Arf-deficient mice exposed to the carcinogen urethane [intraperitoneal (i.p.), 1 mg/g]. Loss of Arf resulted in elevated morbidity and increased the incidence of both haemangiomas and incipient haemangiosarcomas. Suppression of vascular lesion development by ARF was heavily dependent on both Arf gene-dosage and the genetic strain of the mouse. Trp53-deficient mice also developed hepatic vascular lesions after exposure to urethane, suggesting that ARF signals through a p53-dependent pathway to inhibit the development of hepatic haemangiosarcoma. Our findings provide strong evidence that inactivation of Arf is a causative event in vascular neoplasia and suggest that the ARF pathway may be a novel molecular target for therapeutic intervention in haemangiosarcoma patients. PMID- 22430985 TI - Controlling bulk conductivity in topological insulators: key role of anti-site defects. AB - Intrinsic topological insulators are realized by alloying Bi(2)Te(3) with Bi(2)Se(3). Angle-resolved photoemission and bulk transport measurements reveal that the Fermi level is readily tuned into the bulk bandgap. First-principles calculations of the native defect landscape highlight the key role of anti-site defects for achieving this, and predict optimal growth conditions to realize maximally resistive topological insulators. PMID- 22430986 TI - Paradoxical prosteatotic effect of hedgehog signaling pathway inhibition under conditions of steatosis. PMID- 22430987 TI - [And finally... the Revista Argentina de Microbiologia made its impact]. PMID- 22430988 TI - [Evaluation of commercial systems VITEK 2 and API 20NE for identification of Burkholderia cepacia complex bacteria from clinical samples]. AB - Species belonging to the Burkholderia cepacia complex (BCC) are capable of causing chronic respiratory tract infections in patients suffering from cystic fibrosis as well as in immunocompromised individuals. Most of these species are highly resistant to antibiotic therapy, generating the need for their rapid and accurate detection for the proper treatment and clinical management of these patients. In this work, the polymerase chain reaction (PCR) technique based on the amplification of the recA gene (PCR-recA) was applied for an accurate identification of bacteria belonging to the BCC. Sensitivity (S) and specificity (E) of two biochemically-based commercial automated systems, API 20NE and VITEK 2 (bioMerieux(r)), and of the most representative biochemical manual tests for the identification of the Burkholderia cepacia complex were herein evaluated. The commercial systems VITEK 2 and API 20NE showed the following sensitivity and specificity vaues for identification to the species level, S: 71.1 %, E: 100 %, S: 69.7 %, E: 90.2 %, respectively. More complex results were observed for phenotypic manual tests, since BCC bacteria can undergo selective pressure to survive in chronic patients causing the loss of their typical phenotypic characteristics. The PCR-recA technique was easy to implement even in medium complexity clinical diagnostic laboratories. PMID- 22430989 TI - Species distribution and susceptibility profile of yeasts isolated from blood cultures: results of a multicenter active laboratory-based surveillance study in Argentina. AB - The Mycology Department of the Instituto Nacional de Enfermedades Infecciosas "Dr. C. Malbran", conducted the Second National Multicenter Survey on Fungemia due to Yeasts in Argentina. The aim was to obtain updated data of the frequency of the causative species encountered and their in vitro susceptibility to seven antifungal agents. Yeast species were identified by micromorphological and biochemical studies. Antifungal susceptibility testing was performed by the reference microdilution method E.Def 7.1 of the European Committee on Antibiotic Susceptibility Testing (EUCAST). A total of 461 viable yeasts were identified. The most frequent species were: Candida albicans (38.4 %), Candida parapsilosis (26 %), Candida tropicalis (15.4 %) and Candida glabrata (4.3 %). Other uncommon species, such as Candida viswanathii (0.6 %), Candida haemulonii (0.4 %), Candida inconspicua (0.2 %) and Candida fermentati (0.2 %) were also isolated. Among the Candida spp., 5.4 % and 1.6 % were resistant to fluconazole and voriconazole, respectively. Itraconazole and caspofungin were the most efficient agents against all Candida spp. tested (MIC < 1 mg/l). For anidulafungin, 21.6 % of C. parapsilosis showed a MIC value of 4 mg/l. Fluconazole was less active against 53.1 % of Cryptococcus neoformans (MIC > 8 mg/l), 75 % of Trichosporon spp., and 100 % of Rhodotorula spp., Geotrichum candidum, Saccharomyces cerevisiae. The global percentage of mortality was 20 %. The presence of uncommon species reinforces the need for performing continuous laboratory surveillance in order to monitor possible changes, not only in the epidemiological distribution of species, but also in the resistance to antifungal drugs. PMID- 22430990 TI - [Spatial and temporal spread predictability of influenza A H1N1 epidemic in Argentina by the percolation method]. AB - The influenza A H1N1 epidemic has spread rapidly worldwide on account of the current conditions of high interconnectivity and transport speed both among people and countries. The spatial spread of the epidemics can be explained by the percolation theory which allows to estimate a threshold beyond which the transmission of the infection among different geographic regions occurs. The aim of this study was to test the predictive ability of the percolation model of influenza A H1N1 epidemic in Argentina according to data gathered by the National Department of Public Health. In the model, the country was considered as a set of irregular, contiguous and continuous geometric figures, which can be represented in two dimensions on a plane. We analyzed the proportion of infected provinces at the moment of percolation in relation to time in days and compared observed and expected values by curvilinear equations in a logistic model. Percolation occurred on day 45. The expected value generated by the model was 42.4 days, 95 % CI 28.5 to 56.3. The difference between observed and expected values was p = 0.997. We conclude that the model has good fit and predictive capacity. PMID- 22430991 TI - [Bacteriological diagnosis of renal tuberculosis: an experience at the regional tuberculosis laboratory in Cordoba Province, Argentina]. AB - Given the incidence of renal tuberculosis in patients suffering of pulmonary tuberculosis, we seek to study both the frequency of this association in diagnosed cases of renal tuberculosis and the Mycobacterium tuberculosis complex species that were identified (period 1997-2009), observing its incidence by sex, demonstrating the importance of serial culture of urine samples and evaluating the convenience of using solid and liquid media. The analysis of urine samples from 383 patients indicated renal tuberculosis in 24 cases; in most cases, (95.8 %) Mycobacterium tuberculosis complex species prevailed, whereas the presence of Mycobacterium bovis accounted for 4.2 % of the cases. The association of pulmonary and renal tuberculosis was found in 6 cases. The isolation of Mycobacterium bovis indicates the importance of including Stonebrink medium along with Lowenstein- Jensen medium. The liquid medium made no significant contribution to the diagnosis of renal tuberculosis, but indeed, cultivating serial samples increases sensitivity. PMID- 22430992 TI - [Crystalline keratopathy: an infrequent corneal infection produced by the Streptococcus mitis group]. AB - The objective of this report is to describe a case of crystalline keratopathy caused by the Streptococcus mitis group corresponding to a patient who attended hospital for discomfort in her right eye. The ophthalmological examination showed an interrupted stitch of 10-0 nylon suture without tension and with attached mucus secretions. The loose suture was removed under aseptic conditions. Moxifloxacin 0.5 % eye drops were topically indicated. The treated eye successfully epithelialized and evolved favorably. However, after 15 days, a white tree-shaped infiltrate developed. A corneal sample was taken in the operating room, threading the intrastromal path of the removed stitch with a 7-0 vicryl suture. Vancomycin 50 mg/ml drops were indicated. The infiltrate, which was stable for 45 days, later increased its size and tissue necrosis occurred with danger of corneal perforation. A bipedicle conjunctival flap was performed in the affected corneal area, which evolved favorably. After spontaneous conjunctival flap retraction, only corneal scarring and neovascularization outside the visual axis were observed. PMID- 22430993 TI - [VIM-2 metallo-beta-lactamase gen detection in a class 1 integron associated to bla(CTX-M-2) in a Pseudomonas aeruginosa clinical isolate in Uruguay: first communication]. AB - In order to analyze the presence of metallo-beta-lactamase in our country, we included in this study Pseudomonas aeruginosa isolates causing nosocomial infections in a hospital from Uruguay. The presence of a metallo-beta-lactamase VIM-2 in a class 1 integron and of an extended spectrum -lactamase CTX-M-2 was detected in one isolate. This is the first report of both genes, bla(CTX-M-2) and bla(VIM-2),in the same P. aeruginosa isolate. Although carbapenemases have been extensively documented in the world, this is the first report of an acquired metallo-beta-lactamase with carbapenemase activity in pathogenic bacteria in Uruguay. PMID- 22430994 TI - Xanthophyllomyces dendrorhous (Phaffia rhodozyma) on stromata of Cyttaria hariotii in northwestern Patagonian Nothofagus forests. AB - The occurrence and distribution of Xanthophyllomyces dendrorhous associated with Cyttaria hariotii parasitizing three Nothofagus species (N. dombeyi, N. antarctica and N. pumilio) in northwestern Patagonia (Argentina), as well as the factors that may affect this distribution were herein studied. Between 2000 and 2007, samples were obtained from 18 different locations. Based on physiological tests and morphological characteristics of sexual structures, 72 isolates were identified as X. dendrorhous. Representative strains were studied by MSP-PCR fingerprinting and sequence analysis of the ITS region. MSP-PCR fingerprints were similar for the newly isolated strains, and were also identical to the profiles of the strains previously found in this region. Patagonian strains appear to be a genetically uniform and distinct population, supporting the hypothesis that the association with different host species has determined genetically distinct X. dendrorhous populations worldwide. X. dendrorhous was recovered from N. dombeyi and N. antarctica. Approximately half the sampling sites and samples were positive for X. dendrorhous, but the isolation recovery rate was low. X. dendrorhous was absent in the early stages of ascostromata maturation, becoming more abundant in later stages. The present work represents a step forward in the understanding of the natural distribution and ecology of this biotechnologically relevant yeast. PMID- 22430995 TI - Antibiotic prescription in intensive care units in Latin America. AB - The intensive care units (ICUs) are often considered as the epicenters of antibiotic resistance. Therefore, the total antibiotic consumption is approximately ten fold greater in ICU wards than in general hospital wards. The aim of this study was to evaluate the current use of antibiotics in Latin American ICUs. Three cross-sectional (one-day point) prevalence studies were undertaken in 43 Latin American ICUs. Of 1644 patients admitted, 688 received antibiotic treatment on the days of the study (41.8 %) and, 392 cases (57 %) were due to nosocomial-acquired infections. Of all infections, 22 % (151/688) corresponded to septic shock; and 22 % (151/688) to nosocomial pneumonia (50/151 [33 %], ventilator-associated pneumonia). In 485 patients (70.5 %), cultures were performed before starting antibiotic treatment. The most common microorganisms isolated were extended-spectrum beta-lactamase Enterobacteriaceae, (30.5 %), and Pseudomonas aeruginosa (17 %). Carbapenems (imipenem or meropenem) were the antibiotics most frequently prescribed (151/688, 22 %), followed by vancomycin (103/688, 15 %), piperacillin-tazobactam (86/688, 12.5 %) and broad-spectrum cephalosporins (mainly cefepime) (83/688, 12 %). In summary, carbapenems were the most frequent antibiotics prescribed in Latin American ICUs. This practice seems justified for the high rates of ESBL-producing Gram-negatives found in our patients. Beyond this reason, the problem of bacterial resistance in LA requires that physicians improve the use of carbapenems. The high prevalence of carbapenem resistant A. baumannii and P. aeruginosa in the region, along with the prevalence of carbapenem-resistant Enterobacteriaceae, have increased markedly. A comprehensive evidence-based stewardship program based on local antimicrobial use and resistance problems should be implemented in our clinical settings. PMID- 22430996 TI - Phenotypic and genotypic characterization of Streptococcus uberis isolated from bovine subclinical mastitis in Argentinean dairy farms. AB - The aim of this study was to investigate the phenotypic and genotypic characteristics of Streptococcus uberis isolated from subclinical mastitis (SCM) cases, and to examine the possible association between both characteristics. A total of 32 S. uberis were isolated from 772 quarter milk samples (SCM > 250,000 cells/ml) collected from 195 cows selected randomly from 18 dairy farms located in Argentina. The S. uberis strains were characterized phenotypically by the presence of virulence factors as plasminogen activator factor (PAF), hyaluronidase (HYA), capsule (CAP) and CAMP factor, and were further characterized genotypically by pulsed-field gel electrophoresis (PFGE). S. uberis strains expressed plasminogen activator factor, hyaluronidase or capsule (65.5 %, 56.3 %, 59.4 %, respectively), but only 25 % of isolates were CAMP factor positive. Thirteen different virulence profiles were identified on the basis of the combination of virulence factors. Eighteen PFGE patterns with 90% of similarity were identified among 32 S. uberis. A great diversity of virulence profiles and PFGE patterns were present among dairy farms. S. uberis strains with the same PFGE pattern showed different virulence profiles. Bovine S. uberis strains causing SCM included in the present study showed heterogeneity in regard to their phenotypic and genotypic characteristics, and the PFGE patterns are not associated with the virulence profiles. PMID- 22430997 TI - Optimization of biomass production of a mutant of Yarrowia lipolytica with an increased lipase activity using raw glycerol. AB - The yeast Yarrowia lipolytica accumulates oils and is able to produce extracellular lipases when growing in different carbon sources including glycerol, the principal by-product of the biodiesel industry. In this study, biomass production of a novel mutant strain of Y. lipolytica was statistically optimized by Response Surface Methodology in media containing biodiesel-derived glycerol as main carbon source. This strain exhibited distinctive morphological and fatty acid profile characteristics, and showed an increased extracellular lipase activity. An organic source of nitrogen and the addition of 1.0 g/l olive oil were necessary for significant lipase production. Plackett-Burman and Central Composite Statistical Designs were employed for screening and optimization of fermentation in shaken flasks cultures, and the maximum values obtained were 16.1 g/l for biomass and 12.2 Units/ml for lipase, respectively. Optimized batch bioprocess was thereafter scaled in aerated bioreactors and the values reached for lipase specific activity after 95 % of the glycerol had been consumed, were three-fold higher than those obtained in shaken flasks cultures. A sustainable bioprocess to obtain biomass and extracellular lipase activity was attained by maximizing the use of the by-products of biodiesel industry. PMID- 22430998 TI - [Polymorphic associations of Malassezia]. PMID- 22430999 TI - An aggressive aneurysmal bone cyst of the proximal humerus and related complications in a pediatric patient. AB - Clinical behavior of aneurysmal bone cyst (ABC) in younger patients can be more aggressive than that in older children and adults. Angular deformity and shortening can occur due to growth plate destruction or tumor resection. A 11 year-old boy who had been operated twice in another center for an ABC located in the left proximal humerus presented to the author's institution with complaints of pain, deformity and shortening of the left arm. Plain radiographs revealed left proximal humerus nonunion with a large defect. Reconstruction with nonvascularized fibular autograft was applied and left upper extremity was immobilized in a velpou bandage. At the third-month follow-up, graft incorporation was observed in the distal part; however, proximal part did not show adequate healing on radiographs. Additional immobilization in a sling for 3 months was advised to the patient and his family. However, they were lost to follow-up and readmitted to the author's institution at the 12th month postoperatively. Radiographs showed failure of the fibular graft fixation and nonunion of the humerus. Autogenic bone grafts, either vascularized or nonvascularized are the best treatment method for the large defects after tumor curettage or resection. Nonvascularized grafts are technically much easier to use than vascularized grafts and provide excellent structural bone support at the recipient side. However, they may take several months to be fully incorporated. In addition, good therapeutic outcomes require patience and collaboration with the patient and parents. Most importantly, the patient should be monitored closely. PMID- 22431000 TI - miR-106a is frequently upregulated in gastric cancer and inhibits the extrinsic apoptotic pathway by targeting FAS. AB - Emerging evidence has shown the association of aberrantly expressed miR-106a with cancer development, however, little is known about its potential role in gastric carcinogenesis. In our present study, obviously overexpressed miR-106a was found in gastric cancer tissues compared with their nontumor counterparts. Suppression of miR-106a significantly inhibited gastric cancer cell proliferation and triggered apoptosis. Bioinformatic analysis combining with validation experiments identified FAS as a direct target of miR-106a. Rescue experiments and examination of caspase-8, PARP and caspase-3 further approved that miR-106a could inhibit gastric cancer cell apoptosis through interfering with FAS-mediated apoptotic pathway. Moreover, a significant inverse correlation was found between miR-106a and FAS expression not only in gastric cancer cell lines but also in gastric cancer specimens. Taken together, these findings suggest that ectopicly overexpressed miR-106a may play an oncogenic role in gastric carcinogenesis and impair extrinsic apoptotic pathway through targeting FAS. PMID- 22431001 TI - Molecular insights into the progression of crystalline silica-induced pulmonary toxicity in rats. AB - Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica. Rats were exposed to crystalline silica by inhalation (15 mg m(-3), 6 h per day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8 and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5-fold change and <0.01 false discovery rate P-value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The number of biological functions, canonical pathways and molecular networks significantly affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post-exposure time intervals, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved inflammation was the single most significant biological response to pulmonary exposure to silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a potential novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID- 22431002 TI - Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. AB - The present study reports the Spanish PETHEMA group experience in 31 heavily pretreated relapsed/refractory acute lymphoblastic leukemia (ALL) and lymphoma (LL) patients treated with clofarabine-based regimens. The complete remission (CR) rate was 31% (median CR duration of 3 months [range 2-28]) and the overall survival probability at 1 year was 10% (95%CI 4-16%). Responses were seen in B and T lineage diseases and in patients with adverse cytogenetics. Hematological and infectious grade >3 toxicities were found in 100 and 67% of the patients, respectively, with 7 (23%) treatment-related deaths. Other organ toxicities were infrequent. Clofarabine-based chemotherapy regimens might induce CRs in ALL and LL patients, but hematological toxicity and infections may limit their use in heavily pretreated patients. PMID- 22431003 TI - Topical application of fucoidan improves atopic dermatitis symptoms in NC/Nga mice. AB - Fucoidan is a sulphated polysaccharide extracted from brown seaweed and possesses a wide range of pharmacological properties including antiallergic and immunologic activities. The present study attempted to examine the effectiveness of fucoidan from Undaria pinnatifida in the treatment of atopic dermatitis (AD) in the NC/Nga mice model. Three per cent fucoidan or 0.1% dexamethasone was topically applied to the dorsal skin of AD-induced mice for 4 weeks. The dermatitis severity scores and scratch counts of fucoidan or dexamethasone-treated animals were significantly lower than the control group. Histological analysis showed that the number of mast cells infiltrating into skin lesions and the epidermis thickness were significantly decreased after the treatments. Levels of serum histamine and IgE were also decreased. There was no significant difference on improvement of AD like symptoms between fucoidan and dexamethasone. To elucidate possible mechanism of action, effects of fucoidan on regulation of AD-associated chemokines, such as thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and regulated upon activation, normal T-cell expressed and secreted (RANTES) chemokine, were investigated in human epidermal keratinocytes. Fucoidan significantly inhibited mRNA expression of these chemokines in a dose-dependent manner. This is the first animal study to demonstrate that fucoidan has significant effects on improving AD-like conditions as effective as dexamethasone, a well-recognized corticosteroid remedy for the disease. PMID- 22431004 TI - Visible-light photoredox catalysis in flow. PMID- 22431005 TI - Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. AB - Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. Many scientists think that the roles and regulation of G6PD in physiology and pathophysiology have been well established as the enzyme was first identified 80 years ago. And that G6PD has been extensively studied especially with respect to G6PD deficiency and its association with hemolysis, and with respect to the role G6PD plays in lipid metabolism. But there has been a growing understanding of the central importance of G6PD to cellular physiology as it is a major source of NADPH that is required by many essential cellular systems including the antioxidant pathways, nitric oxide synthase, NADPH oxidase, cytochrome p450 system, and others. Indeed G6PD is essential for cell survival. It has also become evident that G6PD is highly regulated by many signals that affect transcription, post-translation, intracellular location, and interactions with other protein. Pathophysiologic roles for G6PD have also been identified in such disease processes as diabetes, aldosterone-induced endothelial dysfunction, cancer, and others. It is now clear that G6PD is under complex regulatory control and of central importance to many cellular processes. In this review the biochemistry, regulatory signals, physiologic roles, and pathophysiologic roles for G6PD that have been elucidated over the past 20 years are discussed. PMID- 22431006 TI - Effect of Epimedium pubescen flavonoid on bone mineral density and biomechanical properties of femoral distal end and femoral diaphysis of passively smoking male rats. AB - BACKGROUND: Based on a rat model of human relatively high exposure to cigarette smoke, this study aimed to estimate whether Epimedium pubescen flavonoid (EPF) may prevent a smoke-induced decrease in bone mineral density (BMD) and weakening of the biomechanical properties of bone. METHODS: Fifty male Wistar rats were randomized into five groups: controls, passively smoking groups and passively smoking rats administered EPF at three dosage levels (75, 150 or 300 mg/kg/day) in drinking water for 4 months. A rat model of passive cigarette smoking was prepared by breeding male rats in a cigarette-smoking box for 4 months. Bone metabolic makers, BMD and biomechanical properties of the femoral distal end and femoral diaphysis were examined. RESULTS: Exposure to cigarette smoke decreased the BMD, affected bone turnover (inhibited bone formation and stimulated its resorption) and weakened the biomechanical properties of the femur at its distal end and diaphysis. EPF supplementation during cigarette smoke exposure prevented the decrease in BMD, accelerated bone turnover and weakened the biomechanical properties of bone. CONCLUSION: Our data suggest that EPF supplementation can prevent the adverse effects of smoke exposure on BMD and biomechanical properties by inhibiting bone turnover and preventing bone resorption, and in this way it can decrease the risk of bone fractures. PMID- 22431007 TI - Establishment of an animal model for delayed-onset muscle soreness after high intensity eccentric exercise and its application for investigating the efficacy of low-load eccentric training. AB - BACKGROUND: Delayed-onset muscle soreness (DOMS) occurs after unaccustomed exercise and is particularly associated with eccentric exercise. Previous studies have proposed the use of a single bout of eccentric exercise to prevent the muscle damage subsequent to a bout of eccentric exercise. This study aimed to establish a suitable animal model to evaluate the pain in DOMS and to assess whether low-load eccentric training confers a protective effect against a subsequent high-intensity eccentric exercise bout. METHODS: Thirty-six female Wistar rats were divided into five groups: rats that received muscular compression only (Comp); those that received high-intensity eccentric exercise only (HE); those that received muscular compression at 3, 24, 48, and 96 h after high-intensity eccentric exercise (HE + Comp/3, 24, 48, and 96 h); those that received muscular compression 48 h after a single low-load eccentric exercise (LE); and those that received a week of low-load eccentric training before high intensity eccentric exercise, which was followed by muscular compression 48 h later (LET). Immunohistochemistry was used to investigate c-fos expression in the dorsal horn of the spinal cord. RESULTS: For the HE + Comp/48 h rats, the total number of c-fos-positive neurons at the L2-3 segments was significantly greater than that in the Comp and HE rats in the same segments. A week of low-load eccentric training resulted in a decreased number of c-fos-ir neurons relative to that in the HE + Comp/48 h rats. CONCLUSIONS: Muscle tenderness after high intensity eccentric exercise was evaluated by c-fos expression in the dorsal horn of the rat spinal cord. Using this rat model, the present study clarified that the muscle tenderness following high-intensity eccentric exercise is inhibited by prior low-load eccentric training. PMID- 22431008 TI - High prevalence of acetabular retroversion in both affected and unaffected hips after Legg-Calve-Perthes disease. AB - BACKGROUND: Acetabular retroversion is observed in hips after various pediatric hip diseases. This study sought to examine the frequency of acetabular retroversion in both affected and unaffected hips after Legg-Calve-Perthes disease and its correlation with the prominence of the ischial spine. METHODS: We retrospectively investigated the version and morphological features of the acetabulum using pelvic radiographs after Legg-Calve-Perthes disease (107 affected hips treated non-operatively and 72 unaffected hips from the contralateral side). The diagnosis of acetabular retroversion was made based on the presence of a positive cross-over sign on anteroposterior pelvic radiographs. The correlation between the presence of a positive cross-over sign and modified Stulberg classes, the onset age of Legg-Calve-Perthes disease, radiographic parameters for acetabular dysplasia and the prominence of the ischial spine were examined. RESULTS: The prevalence of a positive cross-over sign was 49.5 % (45 of 91 hips) in affected hips and 45.8 % (33 of 72 hips) in unaffected hips. Hips with a positive cross-over sign were significantly coexistent bilaterally. The prevalence of prominence of the ischial spine in the positive cross-over sign group was 71.4 % in the affected side and 81.8 % in the unaffected side, indicating a significant correlation between the cross-over sign and the prominence of the ischial spine in both affected and unaffected hips. The positive cross-over sign did not have any correlation with the parameters for acetabular dysplasia and the onset age, however, had a significant correlation with the severity of the femoral head deformity. CONCLUSIONS: High prevalence of acetabular retroversion in both affected and unaffected hips after Legg-Calve Perthes disease was demonstrated. Symmetric acetabular deformity and the coexistence of prominence of the ischial spine suggested the effects of the Legg Calve-Perthes disease lesions on the skeletal development of the whole pelvis. Further follow-up is needed to clarify the pathological significance of acetabular retroversion after Legg-Calve-Perthes disease. PMID- 22431009 TI - Improvement of atelectasis after corrective fusion for lordoscoliosis with intrathoracic vertebral protrusion in arthrogryposis multiplex congenita: efficacy of positive-pressure ventilation test. PMID- 22431010 TI - Genetic toxicology and toxicogenomic analysis of three cigarette smoke condensates in vitro reveals few differences among full-flavor, blonde, and light products. AB - Cigarette smoking leads to various detrimental health outcomes. Tobacco companies produce different brands of cigarettes that are marketed as reduced harm tobacco products. Early examples included "light" cigarettes, which differ from regular cigarettes due to filter ventilation and/or differences in chemical constituents. In order to establish baseline similarities and differences among different tobacco brands available in Canada, the present study examined the cytotoxicity, mutagenicity, clastogenicity, and gene expression profiles of cigarette smoke condensate (CSC) from three tobacco products, encompassing a full-flavor, blonde, and "light" variety. Using the Salmonella mutagenicity assay, we confirmed that the three CSCs are mutagenic, and that the potency is related to the presence of aromatic amines. Using the MutaTMMouse FE1 cell line we determined that the CSCs were clastogenic and cytotoxic, but nonmutagenic, and the results showed few differences in potencies among the three brands. There were no clear brand specific changes in gene expression; each brand yielded highly similar expression profiles within a time point and concentration. The molecular pathways and biological functions affected by exposure included xenobiotic metabolism, oxidative stress, DNA damage response, cell cycle arrest and apoptosis, as well as inflammation. Thus, there was no appreciable difference in toxicity or gene expression profiles between regular brands and products marketed as "light," and hence no evidence of reduced harm. The work establishes baseline CSC cytotoxicity, mutagenicity, and expression profiles that can be used as a point of reference for comparison with data generated for products marketed as reduced harm and/or modified risk tobacco products. PMID- 22431011 TI - Metal-organic framework templated synthesis of Fe2O3/TiO2 nanocomposite for hydrogen production. AB - A new metal-organic framework (MOF)-templated method has been developed for the synthesis of a metal oxide nanocomposite with interesting photophysical properties. Fe-containing nanoscale MOFs are coated with amorphous titania, then calcined to produce crystalline Fe(2)O(3)/TiO(2) composite nanoparticles. This material enables photocatalytic hydrogen production from water using visible light, which cannot be achieved by either Fe(2)O(3) or TiO(2) alone or a mixture of the two. PMID- 22431012 TI - Incidence of fractures of the femur, including subtrochanteric, up to 8 years since initiation of oral bisphosphonate therapy: a register-based cohort study using the US MarketScan claims databases. AB - In a cohort study of users of bisphosphonates, we evaluated the incidence of fragility fractures at all sites on the femur following for up to 8 years of therapy with alendronate or risedronate. We did not find evidence for a reversal of fracture protection with long-term use of bisphosphonates. INTRODUCTION: Few studies have acquired adequate data with prolonged follow-up on bisphosphonate users in the general population to evaluate their long-term effects on the risk of hip fractures including those in the subtrochanteric region. METHODS: This cohort study utilizes a large USA database (January 1, 2000 to June 30, 2009). We compared patients with higher versus lower degrees of compliance [medication possession ratio, MPR <1/3 (the reference), 1/3-<2/3, or >= 2/3]. Radiographic adjudication of fracture site and features were not performed. Hazard ratios (HR) for fracture were estimated using time-dependent Cox models. Restricted cubic splines (RCS) were used to plot HRs for fracture against duration of therapy. RESULTS: There were 3,655 incident cases of femoral fracture (764 subtrochanteric/shaft, 2,769 hip) identified during 917,741 person-years of follow-up (median = 3 years) on 287,099 patients (267,374 were women) from the date when they initiated oral bisphosphonate therapy. The corresponding HRs (95% confidence interval, CI) for overall femoral fractures associated with each additional year of therapy were 0.93 (0.86-1.01) within 5 years, and 0.89 (0.77 1.03) beyond 5 years for risedronate and 0.86 (0.81-0.91) and 0.95 (0.84-1.07) for alendronate, respectively. The corresponding estimates for subtrochanteric/shaft fractures were 1.05 (0.87-1.26) and 0.89 (0.60-1.33) for risedronate and 0.99 (0.92-1.05) and 1.05 (0.92-1.20) for alendronate, respectively. The HRs (95% CI) for overall femoral fractures associated with each additional year of alendronate or risedronate therapy within 5 and beyond 5 years were not significantly different. CONCLUSION: Our study showed persistence of overall hip fracture protection with long-term use of alendronate or risedronate. PMID- 22431013 TI - Pneumoparotitis: a case report. AB - BACKGROUND: Pneumoparotid is a rare cause of parotid enlargement. Pneumatic enlargement of the gland is caused by retrograde insufflation via Stensen's duct. Most reported cases have been managed conservatively, thus running a short course. METHODS AND RESULTS: We report on a case of a 48-year-old man with a chronic painful right facial swelling and symptoms of repeated infection. Clinical examination found a parotid swelling with surgical emphysema and a dilated Stensen's duct. Pneumoparotitis with cystic changes and dilated intraparotid ducts was confirmed by CT. The patient proceeded to undergo excision of the gland, with subsequent resolution of symptoms. CONCLUSION: Repeated retrograde movement of air and contaminated saliva leads to chronic infection and sialectasis. Management is aimed at preventing these sequelae by identifying and addressing the insult early; however, repeated pneumoparotid leads to chronic pneumoparotitis, the management of which is excision of the gland. PMID- 22431014 TI - Back to the future: from genome to metabolome. AB - In the traditional medical genetics setting, metabolic disorders, identified either clinically or through biochemical screening, undergo subsequent single gene testing to molecularly confirm diagnosis, provide further insight on natural disease history, and inform on disease management, treatment, familial testing, and reproductive options. For decades now, this process has been responsible for saving many lives worldwide. Only recently, though, has it become possible to move in the opposite direction by starting with an individual's whole genome or exome, and, guided by this data, study more minor perturbations in the absolute values and substrate ratios of clinically important biochemical analytes. Genomic individuality can also be used to guide more detailed phenotyping aimed at uncovering milder manifestations of known metabolic diseases. Metabolomic phenotyping in the Personal Genome Project for our first 200+ participants-all of whom are scheduled to have full genome sequence at more than 40* coverage available by May 2012-is aimed at uncovering potential subclinical and preclinical disease states in carriers of known pathogenic mutations and in lesser known rare variants that are protein predicted to be pathogenic. Our initial focus targets 88 genes involved in 68 metabolic disturbances with established evidence-based nutritional and/or pharmacological therapy as part of standard medical care. PMID- 22431015 TI - Actin branching in the initiation and maintenance of lamellipodia. AB - Using correlated live-cell imaging and electron tomography we found that actin branch junctions in protruding and treadmilling lamellipodia are not concentrated at the front as previously supposed, but link actin filament subsets in which there is a continuum of distances from a junction to the filament plus ends, for up to at least 1 MUm. When branch sites were observed closely spaced on the same filament their separation was commonly a multiple of the actin helical repeat of 36 nm. Image averaging of branch junctions in the tomograms yielded a model for the in vivo branch at 2.9 nm resolution, which was comparable with that derived for the in vitro actin-Arp2/3 complex. Lamellipodium initiation was monitored in an intracellular wound-healing model and was found to involve branching from the sides of actin filaments oriented parallel to the plasmalemma. Many filament plus ends, presumably capped, terminated behind the lamellipodium tip and localized on the dorsal and ventral surfaces of the actin network. These findings reveal how branching events initiate and maintain a network of actin filaments of variable length, and provide the first structural model of the branch junction in vivo. A possible role of filament capping in generating the lamellipodium leaflet is discussed and a mathematical model of protrusion is also presented. PMID- 22431016 TI - Living with high output. PMID- 22431017 TI - Bacterial endocarditis with septic pulmonary embolism due to pacemaker lead infection. PMID- 22431018 TI - Minority HIV-1 resistant variants in recent infection and in patients who failed first-line antiretroviral therapy with no detectable resistance-associated mutations in Thailand. AB - Through the Thai National AIDS Program, approximately 200,000 patients infected with HIV are on antiretroviral (ARV) therapy. Although studies have shown low prevalence of primary HIV-1 resistance transmission in Thailand and in Southeast Asia where subtype CRF01_AE is predominant, minority HIV-1 drug resistance has not been studied. Two groups of patients, whose conventional genotyping results showed no drug resistance-associated mutations, were investigated: 104 homosexual men recently infected with HIV-1, naive to ARV treatment and 22 first-line non nucleoside reverse transcriptase inhibitor (NNRTI)-based failure patients. Pyrosequencing (PSQ) assay was developed to detect and quantify minority Y181C and M184V variants from the patients' plasma samples. The sensitivity of PSQ to detect minority Y181C and M184V variants was approximately 1%. 1/104 (0.5%) and 3/101 (3%) samples were found harboring Y181C and M184V in the group of homosexual men recently infected with HIV-1. In patients with first-line treatment failure, one had a minority M184V mutation (4.5%). The prevalence of Y181C and M184V minority variants in homosexual men recently infected and naive to treatment was low in Thailand. Systematic monitoring of primary resistance transmission in Thailand and this region is essential to guide whether genotypic resistance test is required prior to commencing the first-line highly active antiretroviral therapy (HAART). PMID- 22431019 TI - Characterization of drug resistance mutations in naive and ART-treated patients infected with HIV-1 in Yaounde, Cameroon. AB - Currently the prevalence of HIV-1 infection in Cameroon is 5.1%, CRF02_AG subtype is responsible for about 50% of infections. Since an HIV-1 drug resistance test is not yet available widely, accurate data on the prevalence of resistant viral strains are missing. The objective of this study was to determine HIV-1 genetic diversity and to characterize HIV-1 mutations conferring drug resistance among antiretroviral therapy (ART)-naive and ART-treated patients. A cohort of 239 patients infected with HIV were followed-up between January 2007 and July 2010 in Cameroon. Two hundred and sixteen plasma samples were sequenced for phylogenetic analysis and identification of drug resistance mutations in the HIV-1 pol region. A significant genetic diversity was found: Seven pure subtypes (A1, A3, D, F1, F2, G, H), nine circulating recombinant forms (CRFs: 01_AE, 02_AG, 06cpx, 09cpx, 11cpx, 13cpx, 16cpx, 18cpx, 37cpx) and one new unique recombinant form (URF) (G/F2). The rate of transmitted drug resistance (TDR) in naive patients was 8.2% (4/49). Around 80% of patients failing a first-line ART harbored a virus with at least one resistance mutation to two antiretroviral (ARV) classes, and 36% of those failing a second-line regimen carried a virus with at least one resistant mutation to three ARV classes. The high level of drug resistance observed in the cohort is alarming because this occurred as a result of only few years of treatment. Adherence to therapy, adequate education of physicians, and the appropriate use of genotypic resistance assay are critical points of intervention for the improvement of patient care. PMID- 22431020 TI - Genetic analysis of hepatitis A virus variants circulating among children presenting with acute diarrhea in Cameroon. AB - Molecular investigation was undertaken of circulating hepatitis A virus (HAV) associated with cases of acute diarrhea among children under 5 years of age in Kumba-Cameroon. Reverse transcription PCR, sequencing, and phylogenetic analysis of a 371 bp segment of the VP1/P2A junction of six isolates obtained from stool samples showed the exclusive emergence of genetically related HAV subgenotype IA. All the isolates clustered within a unique lineage exhibiting a 99.5% nucleotide identity suggesting infection from a common source. The Cameroonian HAV isolates did not intermix or cluster with those from other regions of Africa and the rest of the world. Tajima's neutralization tests using the six sequences suggested HAV/IA population expansion (D = -1.37; P = 0.016). This is the first description of indigenous HAV genotypes circulating in Cameroon revealing a community-wide spread and predominance of HAV/1A infection in the Kumba area. These findings stress the need for routine molecular tracking of HAV infection as a contributory cause of acute diarrhea in Cameroonian children. PMID- 22431021 TI - Hepatitis C virus promotes expression of the 3beta-hydroxysterol delta24 reductase through Sp1. AB - Hepatitis C virus (HCV) establishes chronic infection, which often causes hepatocellular carcinoma. Overexpression of 3beta-hydroxysterol Delta24-reductase (DHCR24) by HCV has been shown to impair the p53-mediated cellular response, resulting in tumorigenesis. In the present study, the molecular mechanism by which HCV promotes the expression of DHCR24 was investigated. A significant increase in DHCR24 mRNA transcription was observed in a cell line expressing complete HCV genome, whereas no significant difference in the expression of DHCR24 was seen in cell lines expressing individual viral proteins. The 5' flanking genomic region of DHCR24 was characterized to explore the genomic region and host factor(s) involved in the transcriptional regulation of DHCR24. As a result, the HCV response element (-167/-140) was identified, which contains AP 2alpha, MZF-1, and Sp1 binding motifs. The binding affinity of the host factor to this response element was increased in nuclear extracts from cells infected with HCV and corresponded with augmented affinity of Sp1. Both mithramycin A (Sp1 inhibitor) and small interfering RNA targeting Sp1 prevented the binding of host factors to the response element. Silencing of Sp1 also downregulated the increased expression of DHCR24. The binding affinity of Sp1 to the response element was augmented by oxidative stress, whereas upregulation of DHCR24 in cells expressing HCV was blocked significantly by a reactive oxygen species scavenger. Elevated phosphorylation of Sp1 in response to oxidative stress was mediated by the ATM kinase. Thus, activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV. PMID- 22431022 TI - The interleukin 28B rs12979860 C/T polymorphism and serum cholesterol as predictors of fibrosis progression in patients with chronic hepatitis C and persistently normal transaminases. AB - The interleukin 28B (IL-28B) rs12979860 C/T polymorphism is a predictor of spontaneous and treatment-induced hepatitis C virus (HCV) clearance. The C/C genotype is associated with higher serum cholesterol, predictor of a favorable outcome in chronic hepatitis C. Whether IL-28B polymorphism and serum cholesterol play a role in modulating the history of mild hepatitis C is unknown. To clarify this issue, 93 untreated patients infected with HCV with normal or near-normal transaminases and an initial Ishak staging score <=1 were investigated retrospectively in the longitudinal study (median histological follow-up of 10 years). An additional confirmatory cohort of 143 patients with chronic HCV infection and abnormal levels of transaminases was evaluated in the cross sectional study. In the longitudinal study, at the end of follow-up, Ishak staging scores progressed more frequently among carriers of a T/* allele who had a baseline serum cholesterol <=175 mg/dl than in remaining patients: 6/36 (change <=0), 15/45 (change 1-2), 6/12 (change >=3), improvement chi-square P < 0.02, OR 3.1, 95% C.I. 1.3-7.7. In the cross-sectional study, the frequency of patients carrying the T/T genotype or serum cholesterol values <=175 mg/dl increased starting from those with a staging score <=2 (36/76, 47.4%), to those with a staging score of 3-4 (26/41, 63.4%) and to those with a staging score of 5-6 (20/26, 76.9%, P < 0.01 for linear trend). In conclusion, the interaction between IL-28B rs12979860 T/T genotype and low serum cholesterol concentration is an independent predictor of a worse disease course among patients infected with HCV with normal or near-normal transaminases. PMID- 22431023 TI - Risk factors for hepatitis C virus infection in Inland Brazil: an analysis of pooled epidemiological sectional studies. AB - In order to assess the contribution of different parenteral routes as risk exposure to the hepatitis C virus (HCV), samples from nine surveys or cross sectional studies conducted in two Brazilian inland regions were pooled, including a total of 3,910 subjects. Heterogeneity among the study results for different risk factors was tested and the results were shown to be homogeneous. Anti-HCV antibodies were observed in 241 individuals, of which 146 (3.7%, 95% CI = 3.2-4.4) had HCV exposure confirmed by immunoblot analysis or PCR test. After adjustment for relevant variables, a correlation between confirmed HCV exposure and injection drug use, tattooing, and advance age was observed. In a second logistic model that included exposures not searched in all nine studies, a smaller sample was analyzed, revealing an independent HCV association with past history of surgery and males who have sex with other males, in addition to repeated injection drug use. Overall, these analyses corroborate the finding that injection drug use is the main risk factor for HCV exposure and spread, in addition to other parenteral routes. PMID- 22431024 TI - Increased frequency of Th17 cells in the peripheral blood of children infected with enterovirus 71. AB - Enterovirus 71 (EV71) affects the health of young children globally causing severe neurologic diseases. The relationship between EV71 infection and T helper type 17 (Th17) has not been described, although this new Th subset or interleukin 17 (IL-17) has been reported to be associated with other viral infections. The purpose of the current study was to describe the immune profile involving Th17 cells, neutrophils, and related factors and to speculate on the possible immunopathogenesis of EV71 infections. Flow cytometry and an automatic blood cell counter were used to analyze circulating Th17 cells and count neutrophils, respectively. Expression of acid-related orphan nuclear receptor gamma t (ROR gammat) was evaluated by reverse-transcriptional PCR, and enzyme linked immunosorbent assays (ELISAs) were used for detecting concentrations of IL-17, IL 23, and IFN-gamma. The results showed that the frequencies of Th17 cells (1.47 +/ 0.87%) and the number of neutrophils (7.4 +/- 4.1 * 10(9) /L) in peripheral blood samples from children infected with EV71 were significantly higher compared to controls. In addition, there was a statistically higher expression of ROR gammat in peripheral blood mononuclear cells (PBMCs) and elevated concentrations of IL-17 and IL-23 in sera, but lower IFN-gamma production during EV71 infections. The findings suggest that Th17 cells are mediators during the immunologic process. PMID- 22431025 TI - Seroreactivity against Epstein-Barr virus (EBV) among first-degree relatives of sporadic EBV-associated nasopharyngeal carcinoma in Indonesia. AB - Epstein-Barr virus (EBV) infection and family history are significant risk factors associated with undifferentiated nasopharyngeal carcinoma. The presence of aberrant immunoglobulin A (IgA) antibodies against specific EBV antigens in healthy individuals can be predictive of the disease. Very limited reports explored the EBV IgA antibody presence within families of sporadic cases of nasopharyngeal carcinoma. This study aimed to determine whether EBV IgA was observed more frequently among family members of sporadic cases of nasopharyngeal carcinoma compared to community controls and evaluated the non-viral factors as determinants of antibody level. First-degree relatives of nasopharyngeal carcinoma patients (n = 520) and case-matched community controls (n = 86) were recruited. Sera from all individuals were tested in standardized peptide-based EBV IgA ELISA. Data on demographic variables and other exogenous factors were collected using a questionnaire through face-to-face interviews. A similar frequency of EBV IgA (cut-off value/CoV 0.354) was observed in the first-degree relatives of cases and in community controls (41.2% vs. 39.5%, P = 0.770). However, with a higher antibody level (OD(450) = 1.000; about three times standard CoV), the relatives showed significantly higher frequency (36.9% vs. 14.7%, P = 0.011). When adjusted for all exogenous factors, the strongest factors associated with seropositivity are being a father (odds ratio/OR = 4.36; 95% confidence interval/CI = 1.56-12.21) or a sibling (OR = 1.89; 95% CI = 1.06-3.38) of a case of nasopharyngeal carcinoma. The higher level of EBV IgA seroreactivity in first-degree relatives of sporadic cases of nasopharyngeal carcinoma compared to the general population supports the use of EBV IgA ELISA for screening among family members. PMID- 22431026 TI - Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Los Angeles County. AB - Data on Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) in adults in the United States remain very limited. A cluster of four cases of EBV-HLH was observed in a 4-month period at a tertiary center in Los Angeles County (LA County) and the clinical and molecular characteristics identified in these cases are being described. EBV typing, immunophenotypic and molecular genetic studies were performed. Diagnostic criteria that may be used to identify EBV as a cause of HLH in adults are also being suggested. Finally, the crude incidence rate for HLH in LA County was determined and was compared to the worldwide crude incidence rate for HLH. The cases each occurred in young male adult residents of California and were associated with evidence of EBV reactivation and ferritin levels of >20,000 ug/L. A higher rate of cases of EBV HLH in 2010 was found at UCLA Medical Center than for 2007-2009 (4.9/10,000 hospital discharges vs. 0.14/10,000 hospital discharges, respectively; P = 0.0017). The cases were associated with EBV type 1, and the insertion of the codon CTC (leucine) was found in numerous of the EBNA-2 gene sequences. The annual incidence of secondary, non-familial HLH was estimated to be 0.9 cases per million persons >15 years of age in LA County. Although EBV-HLH is a rare disease, the incidence in adults in Western countries may be underestimated. PMID- 22431027 TI - In vivo and in vitro evidence for an association between the route-specific transmission of HHV-8 and the virus genotype. AB - The study was performed to determine if there is an association between the genotype and transmission of HHV-8 types A and C. These HHV-8 subtypes are prevalent in the area of North of Sardinia, which is an island off west Italy's mainland that has a high HHV-8 seroprevalence (35%). Blood and saliva samples from 30 patients with classic Kaposi's sarcoma who were lifetime residents of North Sardinia were analyzed to identify the HHV-8 genotype and quantitate the viral load. Genotype A, especially A1 subtype, was found more frequently (9/30 patients) and had a significantly higher viral load in saliva compared to blood (P = 0.029), where type C was found more frequently but with a viral load lower than 10(3) copies/ml. To determine if there is a correlation between the viral genotype and cellular tropism, type A1 and C3 HHV-8 viral particles were obtained from cell lines BCBL1 and BC3 infected chronically with HHV-8 A1 and C3 genotypes respectively and used to infect HEK293 epithelial origin cells and PBMCs in vitro. The data indicate that the A1 HHV-8 genotype is tropic and replicates at higher levels in the epithelial cell lines. PMID- 22431028 TI - Human herpesvirus 8 shedding in the mouth and blood of hemodialysis patients. AB - In Saudi Arabia, the prevalence of transplantation-associated Kaposi's sarcoma (KS) is high, and there is disparity in the prevalence rates of human herpesvirus 8 (HHV-8) infection between patients with renal disease and the general population. It was hypothesized that oral HHV-8 transmission among patients undergoing hemodialysis treatment contributes to the high prevalence of infection in renal disease patients. The detection rates of anti-HHV8-IgG in plasma and HHV 8-DNA in CD45(+)-peripheral blood cells of 72 hemodialysis patients were compared first with those of 178 blood donors and 60 pregnant women. Between the hemodialysis patients and the apparently healthy people sampled, the detection rate of anti-HHV-8-IgG was 16.7% versus 0.4% (P < 0.001) and that of HHV-8-DNA was 4.2% versus 0.4%, (P < 0.05). HHV-8 DNA was determined in oral samples and the HHV-8 viral load measured in saliva of patients undergoing hemodialysis. The amount of virus shed into saliva ranged between 8,600 and 119,562,500 (mean: 24,009,360) genome-equivalents/ml among the five patients in whom oral HHV-8 DNA was detected. Finally, HHV-8-subgenomic sequencing was conducted which showed that orally shed HHV-8 in four patients belonged to genotype C2, and in one patient to genotypes A1 and C2. HHV-8 shed in the mouth of hemodialysis patients may be extensive and diverse. Oral fluid in addition to blood is thus a likely vehicle for transmission of HHV-8, possibly contributing to the high risk of HHV 8 infection in patients undergoing hemodialysis and to KS following immunosuppression after renal transplantation. PMID- 22431029 TI - Prevalence and genotype distribution of human papillomavirus infection among female sex workers in Guangxi, China: implications for interventions. AB - Human papillomavirus (HPV) infection is a major public health concern in women, but information on HPV among female sex workers in China is limited. The aim of the study was to estimate the prevalence and genotype distribution of HPV infection among female sex workers in two cities in Guangxi, China. A total of 811 female sex workers were recruited from venues between July and September of 2009. Data on socio-demographic and behavior characteristics were collected, and cervical swabs were collected to determine HPV infection and genotype distribution. The overall prevalence of infection with any HPV type was 38.9%. HPV type 52 was the most prevalent type with prevalence of 11%, followed by HPV types 16, 58, 53, and CP8304, with prevalences of 6.5%, 5.7%, 5.6%, and 4.8%, respectively. HPV 16 or 18 accounted for 23.2% of all HPV positive cases. Age group <20 years was significantly associated with infection of the high-risk and multiple types of HPV infection. A higher prevalence of multiple HPV infection was observed among female sex workers from the outdoor venues (14.0%; 95%CI, 10.6%-17.3%). These findings have important implications for developing HPV prevention programs including HPV vaccination in female sex workers. PMID- 22431030 TI - Genetic characterization of measles viruses that circulated in Thailand from 1998 to 2008. AB - During the period between 1998 and 2008, 48 representative measles viruses (MeVs) circulating in Thailand were subjected to genetic characterization. Three genotypes, G2, D5, and D9 were detected. The results suggested that measles genotype D5, which has been circulating since at least 1998, is the endemic genotype in Thailand. Genotype G2 was detected between 1998 and 2001. In addition, almost all of the MeVs detected throughout the country in 2008 were genotype D9. This is the first report of genotype D9 in Thailand. This report provides important baseline data about measles genotypes in Thailand and this information will be needed to help verify measles elimination in Thailand. PMID- 22431031 TI - Review: antibodies to cutaneous human papillomaviruses. AB - Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the epithelia of skin or mucosa. Cutaneous HPV is ubiquitous and many children have skin warts at some stage during childhood and a high proportion of the adult population have asymptomatic skin HPV infections. While a subset of mucosal HPV types are involved in cervical cancer, the role for cutaneous HPV types in skin cancer is still under debate. There is some evidence that the skin HPV types have mechanisms to induce skin cancer, but the role of HPV infection has never been proved in larger epidemiological studies and is not well understood. Cutaneous HPV serology has been employed more commonly during the last decade to help find a link between cutaneous HPV and skin cancer. This review covers the findings from cutaneous HPV serology studies published during the last decade and discusses differences in seroprevalence and risk factors. PMID- 22431032 TI - Molecular epidemiology of human rhinovirus infections in Kilifi, coastal Kenya. AB - This study reports pediatric surveillance over 3 years for human rhinovirus (HRV) at the District Hospital of Kilifi, coastal Kenya. Nasopharyngeal samples were collected from children presenting at outpatient clinic with no signs of acute respiratory infection, or with signs of upper respiratory tract infection, and from children admitted to the hospital with lower respiratory tract infection. Samples were screened by real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and classified further to species by nucleotide sequencing of the VP4/VP2 junction. Of 441 HRV positives by real-time RT-PCR, 332 were classified to species, with 47% (155) being HRV-A, 5% (18) HRV-B, and 48% (159) HRV-C. There was no clear seasonal pattern of occurrence for any species. The species were present in similar proportions in the inpatient and outpatient sample sets, and no significant association between species distribution and the severity of lower respiratory tract infection in the inpatients could be determined. HRV sequence analysis revealed multiple but separate clusters in circulation particularly for HRV-A and HRV-C. Most HRV-C clusters were distinct from reference sequences downloaded from GenBank. In contrast, most HRV-A and HRV B sequences clustered with either known serotypes or strains from elsewhere within Africa and other regions of the world. This first molecular epidemiological study of HRV in the region defines species distribution in accord with reports from elsewhere in the world, shows considerable strain diversity and does not identify an association between any species and disease severity. PMID- 22431033 TI - Phylogenetic and computational structural analysis of VP7 gene of group a human rotavirus G1P[8] strains obtained in Sapporo, Japan from 1987 to 2000. AB - Many studies indicate that G1P[8] genotypes are the most prevalent rotavirus strains worldwide. Although two vaccines have been licensed and their value proven in many countries, continuous surveillance for genetic evolution of circulating rotavirus strains before and after the introduction of the vaccines is desirable. G and P typing were carried out on all field strains isolated during 1987-2000 in Sapporo, Japan. Phylogenetic analysis for the VP7 gene of rotavirus G1P[8] strains was performed. Amino acid substitutions were mapped on the predicted three-dimensional VP7 protein image. G1P[8] genotype predominated. One hundred thirteen strains with G1P[8] genotype were analyzed. Phylogenetic studies of the VP7 gene classified these strains into three lineages. The mean estimated substitution rate was 7.25 * 10(-4) nucleotide substitutions per site per year. One predominant lineage contained the mutant strains which had VP7 amino acid substitutions at residue 91 and 212 that is in the neutralization domains. They were estimated to locate in or near intersubunit boundary of VP7 trimer. It is suggested that the most prevalent G1P[8] lineage strains in Sapporo obtained some survival advantages by changing the neutralization domains of VP7. PMID- 22431035 TI - Patient perceptions of communications on the threshold of cancer survivorship: implications for provider responses. AB - INTRODUCTION: Although high quality professional-patient communication is recognized as fundamental to effective cancer care, less attention has been paid to developing an evidence basis for communications surrounding the stage of the cancer journey when primary cancer treatment concludes, management responsibilities shift from oncology specialist services into the generalist care domain, and the patient transitions beyond patienthood and into survivorship. METHODS: Using applied qualitative methodology, we analyzed a database of multiple interviews with 14 Canadian cancer patients from a larger study of changing communication needs and preferences across the cancer trajectory. Through constant comparative analysis, we generated a thematic summary of interpretive understandings from the patient perspective of communication patterns across the transition from active treatment to survivorship. RESULTS: The accounts illuminate the complexities of the communication environment in which the transition to survivorship occurs. Communication gaps and misinterpretations by clinicians contributed to the confusion, insecurity, vulnerability, loss, and abandonment associated with this transition when they failed to accurately and sensitively respond to individual conditions. DISCUSSION/CONCLUSIONS: Despite increasing recognition of the importance of this transition, communication gaps occur in relation to attending to cues, giving prior warning, avoiding avoidance, sensitivity to context, managing relationships, surfacing anxieties, and clarifying roles and responsibilities. These findings expand upon previous reports to explain mechanisms whereby interactions between clinicians and patients may significantly shape the transitional experience and set the stage for survivorship. IMPLICATIONS FOR CANCER SURVIVORS: From the perspective of cancer survivors, the transition beyond initial treatment warrants well-informed anticipatory and supportive healthcare communications. PMID- 22431036 TI - Distinct retinohypothalamic innervation patterns predict the developmental emergence of species-typical circadian phase preference in nocturnal Norway rats and diurnal nile grass rats. AB - How does the brain develop differently to support nocturnality in some mammals, but diurnality in others? To answer this question, one might look to the suprachiasmatic nucleus (SCN), which is entrained by light via the retinohypothalamic tract (RHT). However, because the SCN is more active during the day in all mammals studied thus far, it alone cannot determine circadian phase preference. In adult Norway rats (Rattus norvegicus), which are nocturnal, the RHT also projects to the ventral subparaventricular zone (vSPVZ), an adjacent region that expresses an in-phase pattern of SCN-vSPVZ neuronal activity. In contrast, in adult Nile grass rats (Arvicanthis niloticus), which are diurnal, an anti-phase pattern of SCN-vSPVZ neuronal activity is expressed. We hypothesized that these species differences result in part from a weak or absent RHT-to-vSPVZ projection in grass rats. Here, using a developmental comparative approach, we assessed species differences in behavior, hypothalamic activity, and RHT anatomy. We report that a robust retina-to-vSPVZ projection develops in Norway rats around the end of the second postnatal week when nocturnal wakefulness and the in-phase pattern of neuronal activity emerge. In grass rats, however, such a projection does not develop and the emergence of the anti-phase pattern during the second postnatal week is accompanied by increased diurnal wakefulness. When considered within the context of previously published reports on RHT projections in a variety of species, the current findings suggest that how and when the retina connects to the hypothalamus differentially shapes brain and behavior to produce animals that occupy opposing temporal niches. PMID- 22431037 TI - [Antitumor immune response of MHC class I chain-related gene A modified oral squamous cell carcinoma vaccine: an experimental study in mice]. AB - PURPOSE: To investigate the vaccine potency of MHC class I chain-related gene A (MICA) modified oral squamous cell carcinoma cells. METHODS: Oral squamous cell carcinoma Tb cells transfected with eukaryotic expression vector pEGFP-N1-MICA and overexpressing MICA protein were inactivated by 120Gy irradiation and vaccinated human peripheral blood leucocytes reconstituted SCID (Hu-PBL/SCID)mice via intra-peritoneal injection, and the non-transfected or blank vector transfected Tb cells were used as the controls. The inhibition effect on tumorigenicity of subcutaneously challenged Tb cells in vaccinated Hu-PBL/SCID mice was detected.The expression of NKG2D and the cytotoxicity in vitro to Tb cells of peripheral blood mononuclear cells (PBMCs) and spleen cells were measured by flow cytometry and lactate dehydrogenase (LDH) release assay. SPSS16.0 software package was used for statistical analysis. RESULTS: MICA gene modified Tb tumor vaccine resulted in remarkable loss of tumor size and tumor weight in vaccinated Hu-PBL/SCID mice. Flow cytometry and lactate dehydrogenase (LDH) release assay showed MICA gene modified Tb tumor vaccine up-regulated the expression of NKG2D on PBMC and spleen cells and enhanced the cytotoxicity to tumor cells. Significant difference was found between MICA-transfected vaccine and non-transfected and blank vector-transfected vaccine (P<0.05). CONCLUSIONS: MICA gene modified oral squamous cell carcinoma vaccine can enhance the ability of antitumor immune response,and MICA may be considered as a promising immunotherapy target of oral squamous cell carcinoma. PMID- 22431038 TI - [The influence of different alkaline pH conditions on Enterococcus faecalis in planktonic and biofilm mode]. AB - PURPOSE: To study the influence of different pH conditions on Enterococcus faecalis(E. faecalis) in planktonic and biofilm mode. METHODS: E. faecalis were prepared in planktonic and biofilm mode and cultured in TSB mediums 2 hours at pH 7,8,9,10,11 and 12. MTT assays were applied to evaluate the survival rate of bacterial cells in different pH value. SAS 6.12 software package was used for statistical analysis. RESULTS: Mild alkaline mediums (pH7-9) had no effect on cell vitality of E. faecalis and high alkaline condition (pH>10) led to significant declines of survival rate of cells. The biofilm cells of E. faecalis were more alkaline tolerant than corresponding planktonic cells. CONCLUSION: Biofilm formation is an important step in the development of alkaline tolerance of E. faecalis. PMID- 22431039 TI - [Establishment of the inferior alveolar nerve transection combined experimental periodontitis animal modal in rats]. AB - PURPOSE: To establish an animal model of the inferior alveolar nerve (IAN) transected combined experimental periodontitis in rats, in order to provide a foundation for exploring the function of nerve factor in the occurrence and development of periodontitis and periodontal tissue regeneration in vivo. METHODS: Thirty-six adult SPF Wistar rats were divided into 3 groups randomly. The IAN-transection and periodontitis group (P1): steel-wire was used to ligate to the dental cervix of the dual first lower molars, the gingiva was lacerated using a dental probe, and the surgical transection of the IAN-transection was applied to the left side of the experimental rats, the animals were provided with high-carbonhydrate diet after surgery;the IAN-transection group (P2): the surgical transection of the IAN-transection was applied to the left side of the experimental group, the animals were fed on in routine way after surgery; the sham surgical group(N): no surgery was performed, the animals were fed on in routine way after surgery.6 weeks after the operation, specimens were collected by dissecting the operation areas after internal fixation and observed by clinical examination, X-ray, and histological examination. SPSS13.0 software package were used for statistical analysis. RESULTS: The IAN-transection operation was successfully conducted in the study and there was no significant necrosis or ulceration observed in the nerve dissected rats. All experimental periodontitis models were established successfully at the time point; there was severe destruction of the periodontal tissues especially in the P1 group. There was bone losses in the specimens of IAN-transection side than that in non IAN transection side according to X-ray examination 6 weeks after operation both in the P1 and P2 group, especially in the P1 group. Periodontal tissues on both sides of the P2 group had no obvious inflammation and periodontal destruction. CONCLUSIONS: The experimental periodontitis animal model in various nerve conditions can be successfully conducted. The inferior alveolar nerve transection can result in severe destruction of the periodontal tissues, but it can not result in inflammation of normal periodontal tissue. PMID- 22431040 TI - [Effects of bovine plasma fibronectin on the proliferation, differentiation, and apoptosis of rat osteoblasts in vitro]. AB - PURPOSE: To investigate the effect of bovine plasma fibronectin (FN) on the proliferation, differentiation and apoptosis of rat osteoblasts in vitro, in order to offer an experimental basis for the clinical application. METHODS: The enzymes digesting method was used to isolate the rat osteoblasts.The activity of the osteoblasts was determined by the percents of reduced Alamar blue. Elisa method was used to measure the activity of alkaline phosphatase (ALP). Flowcytometry (FCM) was used to analyze cell cycle and apoptosis. Western blotting was used to determine the expression of Bcl-2 and Bax protein of osteoblasts affected by FN. Statistical analysis was performed using SPSS 12.0 software package. RESULTS: FN can stimulate the proliferation of rat osteoblasts, statistically significant difference was detected at dose more than 40MUg/mL (P<0.05). The alkaline phosphatase activity of rat osteoblasts also increased, significant difference was detected at dose of 10MUg/mL-50MUg/mL by dose dependent (P<0.01). FN increased the cell number of S phase,increased proliferation index (PI) and decreased the apoptosis rate(P<0.01) by dose dependent. The protein expression of Bcl-2 increased,while the protein expression of Bax decreased at dose of 30-50MUg/mL. CONCLUSIONS: Certain concentration of bovine plasma FN can stimulate the proliferation and differentiation of rat osteoblasts in vitro, increase the cell number of S phase, suppresses apoptosis of osteoblasts. PMID- 22431041 TI - [Evaluation of bond strength of three resin cements on CAD/CAM ceramic-dentin]. AB - PURPOSE: To evaluate the bond strength of 3 resin cements on ceramic-dentin. METHODS: Thirty sound human posterior tooth were selected for this study and the flat dentin surfaces were prepared. The specimens were divided into 3 groups(n=10) randomly, which were bonded to the CAD/CAM ceramics with RelyX ARC(etch-and-rinse adhesive), Clearfil DC Bond(self-etching resin cement) and RelyX Unicem(self-adhesive resin cement). The bond strengths were tested and the bond surfaces were observed under stereoscopic microscope.SPSS 11.0 software package was used for statistical analysis. RESULTS: The shear bond strength of RelyX ARC and Clearfil DC Bond was (15.90+/-6.15)MPa and (14.41+/-5.07)MPa, respectively. The shear strength of RelyX Unicem was(23.29+/-7.39)MPa, significantly higher than the others.The shear strength between the three resin cements was significantly different (P<0.05). CONCLUSION: Clearfil DC Bond and RelyX Unicem can achieve a successful bond on CAD/CAM ceramic crowns. PMID- 22431042 TI - [The study of bone formation of hUCMSCs compounded with beta-TCP biological ceramic in vitro and in vivo]. AB - PURPOSE: To observe the osteogenesis of the construct combining human umbilical cord mesenchymal stem cells (hUCMSCs) with scaffold beta-TCP biological ceramic both in vitro and in vivo. METHODS: A composite was constructed combining hUCMSCs with beta-TCP.The cellular capability of adhesion and growth on scaffold were investigated visually by scanning electron microscopy (SEM), specific immunofluorescence staining, MTT and ALP. The constructs were implanted in nude mice for osteogenic potential. The animals were divided into 3 groups: Group 1 (pure beta-TCP), Group 2 (the construct combining hUCMSCs with scaffold beta-TCP was induced to bone in vitro for 2 weeks), Group 3 (simple implantation of the hUCMSCs which was induced to bone in vitro for 2 weeks). 2 months after implantation, the specimens were harvested for gross observation, radiographic examination and histological observation. SPSS 16.0 software package was used for statistical analysis through repeated measures analysis of variances. RESULTS: Cells can be seen attached in the scaffold after 4 hours of the implantation of HUCMSCs, a large number of cells reproduce in the scaffold after 1 week. After 2 months of implantation in the nude mice, the group of hUCMSCs and beta-TCP incubation had the highest radiodensity. 2 months after implantation, the group of hUCMSCs and beta-TCP had irregular new bone and vascular formation, beta-TCP group had no obvious new bone and blood vessel formation. 2 months after implantation, hUCMSCs and beta-TCP group had a lot of collagen formation, while beta-TCP group had no obvious formation of collagen by using masson staining. 2 months after implantation, hUCMSCs and beta-TCP group had a large number of osteoid formation, while beta-TCP group had no obvious formation of osteoid by using VG staining. CONCLUSIONS: hUCMSCs and beta-TCP have good biocompatibility, the formation of new bone and blood vessels can be seen after 2 months of implantation of the construct into mice. PMID- 22431043 TI - [The stress distribution of mandibular alveolar mucosa under functional impressive complete denture studied by 3-D finite element analysis]. AB - PURPOSE: To analyze the stress distribution and displacement of the mandibular alveolar mucosa under functional impressive complete denture. METHODS: CT images were processed by Mimics and Geomagic studio, and the solid models and 3-D finite element models were established by Unigraphics NX. 3-D finite element analysis (3 D FEA) was used to study the stress distribution and displacement on the mandibular alveolar mucosa under functional impressive complete denture and anatomic impressive complete denture. RESULTS: The stress distribution on the mandibular alveolar mucosa under two types of complete denture were consistent, and arranged from large to small order as follow: alveolar process crest of molar area, alveolar process crest of anterior area, external oblique ridge and internal oblique ridge. At alveolar process crest and internal oblique ridge, the stress and Z-axis displacement of functional impressive complete denture were less than those of anatomic impressive complete denture. CONCLUSIONS: During masticatory period, the stress distribution on the mandibular alveolar mucosa under functional impressive complete denture is more even and more comprehensive than that under anatomic one. PMID- 22431044 TI - [Study of mechanical properties' secular variation of thermodynamic nickel titanium archwires]. AB - PURPOSE: To study the changes of mechanical properties of thermodynamic nickel titanium(NiTi) archwires under 37 degrees centigrade and in artificial saliva. METHODS: Using a modified partial dental arch bending device, 4 types of 0.016 inch in diameter thermodynamic NiTi archwires were tested in 37degrees centigrade artificial saliva and at different moments in 8 weeks. An Instron Universal Testing Machine delivered deflections of 3mm in the lateral incisor area. The load-deflection curves were determined from the passive position to deflections of 3mm. The following variables from unloading curves were calculated, the load value at 1.5mm of unloading deflection point(UDP),stiffness between 0.5mm UDP to 2.5mm UDP after unloading. Statistically significant differences in these variables for different brands and moment were analysed using one-way analysis of variance with SPSS11.5 software package. RESULTS: The load-deflection curves of A,B and D archwires were very similar at 0-week and 4-week, while their loading curves rised obviously at 8-week. The load-deflection curves of C archwire had significant differences at 3 moments. The load value of 1.5mm UDP of A,B and D archwires had insignificant difference at 8-week,the unloading force value of C archwire increased slightly at 8-week. There were a few fluctuations of the unloading stiffness of B and D archwires,while A and C archwires's unloading stiffness had a tendency to decrease. CONCLUSIONS: Thermodynamic NiTi archwires always exhibited superelasticity and SME in 8 weeks. Clinically, thermodynamic NiTi archwires can still deliver forces continuously when they are loaded for 2 months even longer. PMID- 22431045 TI - [Influence of platform switching on crest bone maintenance around implants: a radiographic investigation in dogs]. AB - PURPOSE: To evaluate and compare the dynamic changes in functional loading or non functional loading with platform-switching (PLS) implants and butt-joint implants,and to refine the factors leading to marginal bone loss around PLS. METHODS: Six adult dogs were selected and numbered randomly.The second,third and fourth premolars in bilateral mandible of each dog were extracted. After 3 months, the implantation operation was carried out. There were 3 kinds of implants, 36 implants in total, which were divided in to 3 groups: Group A,Group G and Group U. In particular order, A, G and U were placed on each side of every dog. Three months later, the 2nd surgery was begun. At the 4th month from the 1st surgery, for each dog, on the right side only, the abutments were installed and impression was taken. Then, after 2 weeks, the dental prostheses were put on. All dogs were executed at the end of the 12th month. X-ray film was taken at the 3rd, 6th, 9th and 12th month and the moment of the 1st surgery (baseline). Measurements were made between the implant shoulder (IS),the most coronal level of bone in contact with implant (CLB), and the level of alveolar bone crest (BC). According to the different groups of implants (A, G, U), all records were analyzed with paired and Wilcoxon's signed rank test using SPSS11.5 software package. RESULTS: The mean IS-CLB and IS-BC values of group A, G were significantly different with those of group U at the 6th, 9th and 12th month, while there was no significant difference between group A and G. No matter they were loading or not, the self-comparison of each kind of implant presented no significant difference. There was no significant difference between every kind of implant on their self-comparison during the first three months; while, the differences were significant during the next 9 months. CONCLUSIONS: The most significant changes in the absorption of marginal bone around two stage submerged implant can be observed after 3 months of implanting. The bone absorption was not related to functional loading or not. PMID- 22431046 TI - [The effect of adiponectin on human periodontal ligament fibroblasts in vitro]. AB - PURPOSE: To investigate the expression of adiponectin receptor in periodontal tissues and the effect of adiponectin with different concentrations on the proliferation of human periodontal ligament fibroblast cells. METHODS: Ten human healthy premolars extracted for orthodontic reasons were collected. The primary cells were isolated from human periodontal ligament and cultured by tissue block method,then passaged when the cells completely covered the bottom of petri dish. The expression of AdipoR1 and AdipoR2 in human periodontal ligament fibroblasts was detected by RT-PCR. Adiponectin (0,5,10,20ng/MUL) was added to petri dish in which the cells were incubated for 24 hours.The cells were then incubated with adiponectin for 7 days,and determined by MTT assay.SPSS16.0 software package was used for statistical analysis. RESULTS: By immunocytochemical method,the cells were stained positively to antibodies against vimentin,and negatively to antibodies against cytokeratin,indicating that they were external embryo mesenchymal cells ,without epithelial cell mixation. Agarose gel electrophoresis showed Adipo R2 was positively expressed in human periodontal ligament fibroblasts. MTT assay showed that proper doses of adiponectin could promote proliferation of human periodontal ligament fibroblasts (P<0.05).The number of adherent cells of group C or group D was significantly greater than that of group A after 24 hours(P<0.05); Group B, group C,and group D had significantly more adherent cells than group A after 96 hours and 168 hours (P<0.05). CONCLUSIONS: Adiponectin receptor 2 is expressed in the periodontal tissues.The proper doses of adiponectin could promote proliferation of human periodontal ligament fibroblasts. PMID- 22431047 TI - [Reliability of three dimensional resin model by rapid prototyping manufacturing and digital modeling]. AB - PURPOSE: To describe a new technique for fabricating an 3D resin model by 3D reconstruction and rapid prototyping, and to analyze the precision of this method. METHODS: An optical grating scanner was used to acquire the data of silastic cavity block , digital dental cast was reconstructed with the data through Geomagic Studio image processing software. The final 3D reconstruction was saved in the pattern of Stl. The 3D resin model was fabricated by fuse deposition modeling, and was compared with the digital model and gypsum model. The data of three groups were statistically analyzed using SPSS 16.0 software package. RESULTS: No significant difference was found in gypsum model,digital dental cast and 3D resin model (P>0.05). CONCLUSIONS: Rapid prototyping manufacturing and digital modeling would be helpful for dental information acquisition, treatment design, appliance manufacturing, and can improve the communications between patients and doctors. PMID- 22431048 TI - [Expression and clinical significance of tumor-associated macrophages and microvessel density in ameloblastomas]. AB - PURPOSE: To investigate the expression and clinical significance of tumor associated macrophages (TAMs) and microvessel density (MVD) in ameloblastomas (ABs). METHODS: The expression of TAMs (CD68) and MVD (CD34) was examined in 101 ABs and 26 oral mucosa by streptavidin-peroxidase (SP) immunohistochemical technique and then quantified. The data were analyzed by Student's t test and Pearson correlation test using SPSS 11.5 software package. RESULTS: TAMs and MVD were mainly distributed within the stroma of ABS. TAMs count and MVD count were significantly higher in ABs compared with normal oral mucosa (P<0.05). Linear correlation analysis revealed a positive correlation between TAMs count and MVD count in ABs (r=0.428, P<0.05). CONCLUSION: Increased TAMs is associated with angiogenesis and may play an important role in invasive growth of ABs. PMID- 22431049 TI - [Three dimensional changes of lower teeth with NiTi round or square rocking chair archwire]. AB - PURPOSE: To observe the three-dimensional change of lower arch when NiTi round and square rocking chair archwire was used to open overbite in patients of Angle Class I or Class II with deep overbite,in order to providing experimental basis for clinicians. METHODS: Forty patients were chosen according to the inclusion standard. The patients were divided into four groups according to different archwire and with or without use of lace back and cinch back. The patients were taken plaster model before and after the overbite opened by using typical swinging chair labial arch, Laser scan and imageware software were used to make digital model and measure the three dimensional changes of the lower teeth,All data were analyzed with SPSS 12.0 software package. RESULTS: When Rocking chair archwire was used to open overbite, it made the teeth changed in three dimensions, but the arch shape changed unconspicuously. The width between molars increased while the width between the canines and premolars had little change. The arch length had a tendency to increase and the incisors were intruded and had the tendency of labioclination, the incisor labioclination was more significant with lace back and cinch back. The canines showed the tendency of apical clination and there were obvious changes with the lace back and cinch back,the intruding-extruding change was not obvious. The second premolars were elevated, and the mesio-buccal cusp of the first molar did not move while the apo-buccal cusp was intruded.The first molars have the tendency of distal movement and lingual movement when using NiTi square wire. CONCLUSIONS: In the process of opening overbite using rocking chair labial arch, there are different three dimensional changes of the mandibular arch with NiTi round or square archwire, with or without lace back and cinch back. PMID- 22431050 TI - [Using DGGE to analyze bacteria community structure changes in subgingival plaque after periodontal initial therapy]. AB - PURPOSE: To analyze bacteria community structure changes in subgingival plaque after initial therapy, and to provide experimental evidences for clinical decision. METHODS: Six patients with chronic periodontitis were chosen. Subgingival plaque samples, as well as clinical indexes, were collected at baseline and six weeks after initial therapy. The generated two different 16S rDNA fragments of subgingival plaque samples were separated by denaturing gel, creating bands patterns representative of community structure. Subsequent cluster analysis was made. RESULTS: The clinical indexes were improved significantly. The diversity of population of clinical subgingival samples was not significantly different between baseline and 6 weeks after initial therapy. Through cluster analysis, it was confirmed that same patient got similar subgingival plaque between baseline and 6 weeks after treatment. CONCLUSIONS: Same patient tend to get similar subgingival plaque between baseline and after initial therapy. DGGE can detect the microbial composition of subgingival plaque. PMID- 22431051 TI - [Comparison of the effectiveness of two types of filter papers on gingival crevicular fluid collection]. AB - PURPOSE: To compare the effectiveness of whatman3MM chromatographic filter paper and whatman3# qualitative filter paper on gingival crevicular fluid collection and protein extraction,in order to provide the evidence of using appropriate filter paper for collection of gingival crevicular fluid in clinical researches. METHODS: Whatman3MM chromatographic filter paper was used in group A and whatman3# qualitative filter paper in group B. Both types of filter papers were clipped into 2mm+/-8mm strips, then added into 15 incremental volumes of the fuchsine solution with serum, respectively, and each volume was repeated for 4 times. The length of infiltration on each filter paper was measured. Both groups were added into 5 incremental volumes of normal human serum separately and each volume was repeated for five times. The concentration of total protein in the extraction liquid of each group was measured. Both two groups were added into 5 incremental concentrations of 1MUL normal human serum which were diluted to the corresponding multiples with 0.9% NaCl solution, and each concentration was repeated for 5 times. SPSS17.0 software package was used to conduct statistical analysis. RESULTS: The linear relation between the length of infiltration and volume of the solution were good and significant difference (P<0.05) was found between the two groups. With the exception of 0.1MUL,the lengths of infiltration in group A were all larger than that in group B. No significant difference (P>0.05) was found in two groups when considering the protein extraction yield. CONCLUSIONS: The two filter papers were both effective to measure the volume of gingival crevicular fluid which was collected according to its infiltration length on the paper. When there was a large volume of gingival crevicular fluid, Whatman3# qualitative filter paper was more applicable than whatman3MM chromatographic filter paper. However, no significant difference was found between the two filter papers in consideration of protein extraction. PMID- 22431052 TI - [Effect of health education pathway construction on outpatients with removal impacted teeth]. AB - PURPOSE: To Introduce health education pathway to patients with removal impacted teeth, with the aim of helping patients to reduce tension or anxiety and improve the level of patients' satisfaction and cognition for dental surgery. METHODS: One hundred patients with impacted teeth surgery were randomly allocated into the experimental group and the control group. Health education pathway was given to patients in the experimental group while patients in the control group received traditional health education before surgery. The Hamilton-Anxiety Scale(HAMA) was applied to evaluate the anxiety of patients before and after treatment. A self designed questionnaire survey was conducted among patients to evaluate the level of their satisfaction and cognition of dental surgery. RESULTS: Before the experiment, no significant difference in HAMA score was found between the two groups. After health education conducted, the score of the experimental group was significantly lower than that in the control group(P<0.01), meanwhile the rate of satisfaction and the level of cognition in the experimental group was significantly higher than that in the control group (P<0.01). CONCLUSIONS: Establishing and conducting the health education pathway on patients with impacted teeth removal can reduce their tension or anxiety, thus improving the quality of clinical service. PMID- 22431053 TI - [The effect of orthodontic treatment on facial profile of patients with Class II division 1 malocclusions]. AB - PURPOSE: The purpose of this study was to determine the effect of orthodontic treatment on facial esthetic changes of Class II division 1 malocclusions through visual analogue scale(VAS) scores before and after treatment. METHODS: Reference photographs were selected first. 40 males and 40 females were randomly selected from the patients treated in our hospital. A set of photographs of each patient were shown to a panel .Then each face profile was rated on a VAS. Means and standard deviations (SD) were calculated for each set of photographs. One male and one female's photographs with an average aesthetic score close to the median value and lower SD were then selected to serve as reference photographs. Forty Class II division 1 malocclusion patients were randomly selected. A set of standardized photographs together with a set of reference photographs of the same gender were placed in random order to show to the panel.Facial aesthetics of the experimental subjects were scored on a VAS. Then the VAS scores both pretreatment and posttreatment were compared and analyzed using SPSS11.0 software package by one sample t test and paired t test. RESULTS: Two sets of reference photographs of one male and one female were selected. The mean of the patients prior to treatment was 43.839, and 48.328 after treatment. When the population mean was supposed to be 50,significant difference was noted prior to treatment with one sample t Test(P<0.05),while no significant difference was found after treatment(P>0.05). Paired t test showed that post-treatment scores were significantly higher than pre-treatment(P<0.01). CONCLUSION: The facial esthetic of Class II division 1 malocclusions were worse than the average, but can be improved through orthodontic treatment to approach an level. PMID- 22431054 TI - [Analysis of the reliability and validity of the simplified Chinese version of the early childhood oral health impact scale]. AB - PURPOSE: To evaluate the reliability and validity of the Chinese version of The Early Childhood Oral Health Impact Scale. METHODS: Using translation,back translation, quality evaluation,cross-cultural adaptation and pre-assessment, a Chinese draft scale of the ECOHIS was obtained, then applied to two groups of children. One group was 200 pre-school children which were randomly selected from 2 kindergartens of Chengdu city; the other group was 100 patients aged 3-5 years old from the paediatric dentistry of West China College of Stomatology,Sichuan University. After their guardians accomplished the questionnaires, the collected data was analyzed to evaluate the reliability and validity of the scale. RESULTS: The Chinese version of the ECOHIS showed the following psychometric properties from 97.3% valid questionnaires. The Cronbach's alpha ,split-half reliability and correlation of the scale was 0.899,0.799 and 0.666,respectively. By factor analysis of construct validity,the 13 items were classified into 3 domains, the cumulative proportion was 63.87%.The scale had certain logical relation between the items in the same domain. Each item of the scale was sensitive to discriminate the Oral Health-Related Quality of Life (OHRQoL)between general population and patients(P<0.01). CONCLUSIONS: The Chinese version of ECOHIS had a good reliability and validity by rigorous psychometric properties.It can be widely used to test the OHRQoL of pre-school children. PMID- 22431055 TI - [The relationship between dietary factors and susceptibility of periodontal disease]. AB - PURPOSE: A clinical survey was made on the life style and dietary behaviors of people with non-periodontal disease and people with periodontal disease for prevention and treatment of periodontal diseases. METHODS: 72-hour diet analysis and frequency analysis of dietary intake were performed in 60 patients with moderate-to-severe periodontal disease and 60 patients with healthy periodontal tissues randomly selected in the Ninth People's Hospital for dental treatment. The data was analyzed by Student's t test and Chi-square test with SPSS13.0 software package. RESULTS: There was significant difference (P<0.05) in vitamin C, flavonoids and beta-carotene dietary intake between control group and periodontal disease group; In periodontal disease group, dietary intake of selenium and zinc intake was different from the normal control, but the difference was not statistically significant (P>0.05). CONCLUSIONS: There is a close relationship between oral health and antioxidant nutrients. Lower dietary vitamin C content, flavonoid content and beta-carotene intake lead to destruction of periodontal tissue and higher incidence of periodontal disease. PMID- 22431056 TI - [Changes of abutment alveolar height after Stern ERA attachment restoration]. AB - PURPOSE: To observe the alveolar height changes of the distal abutments in Kennedy II dentition defect restored with Stern ERA attachment. METHODS: Twenty one Kennedy II dentition defect patients restored with Stern ERA attachment were observed at the day of restoration and 1 month, 3 months and 6 months after restoration. Digital panoramic radiographs were taken to measure the vertical distances from the distal and the mesial alveolar bone crest to the apical point in the distal abutments and were used to observe and compare the alveolar height changes of the distal abutments.The data was analyzed with SPSS16.0 software package for Student's t test. RESULTS: The distal and medial alveolar height of the distal abutments was not significantly reduced (P>0.05) 1 month, 3 months and 6 months after restoration with Stern ERA attachment. CONCLUSIONS: According to the digital panoramic radiograph, the alveolar height of the distal abutments in Kennedy II dentition defect restored with Stern ERA attachment was not significantly changed in 6 months after restoration. It may benefit for the the health and stability of the distal abutments by using Stern ERA attachment in Kennedy II dentition defect. PMID- 22431057 TI - [Perforator-based chimeric anterolateral thigh flap for head and neck reconstruction after en bloc resection]. AB - PURPOSE: To discuss and report the operative techniques for harvesting perforator based chimeric flap in anterolateral thigh region and the advantages for head and neck reconstruction after en bloc resection. METHODS: A retrospective review was performed of perforator-based chimeric anterolateral thigh (ALT) flap for head and neck reconstruction since December of 2007 to March of 2011. 66 perforator based chimeric flaps were harvested including a skin paddle and a muscular flap supplied by one mother pedicle-descending branch of lateral circumflex femoral artery(d-LCFA). 32 flaps were used for the mobile tongue and floor of mouth reconstruction, 30 flaps for base of the tongue and parapharyngeal walls, two for the buccal skin, one for hemimandible and one for parotid. The muscular flap were used to eliminate the dead space of submandibular area. Flaps size ranged from 7cm+/-4cm to 16cm+/-7cm and muscular flap was 3cm+/-4cm approximately. The complications and functions of both donor and recipient sites were recorded and the operative techniques of perforator-based chimeric flap elevation were generalized. RESULTS: All 65 flaps survived completely and the total survival percentage was 98.5%. Only one flap failed and was removed 5 days postoperatively. No complications(fistula, infection, hematoma, seroma et al) were observed in recipient and donor sites. Two anteromedial thigh flaps (AMT) were used for reconstruction due to no sizable perforators in the ALT region. All cases were followed up for 0.5-3 years. The flaps didn't atrophy after six months and the contour was satisfactory. The functions of speech and swallow were recovered well. All the donor sites were closed primarily and the scar was not obvious. The leg's function recovered well. CONCLUSIONS: Using a combination of retrograde and antegrade dissection is a safe and versatile method for harvesting a perforator-based chimeric flap. A chimeric flap including multiple components can meet the requirements of three-dimensional reconstruction. Perforator-based chimeric anterolateral thigh flap is one of the best choices for complex head and neck reconstruction after en bloc resection. PMID- 22431058 TI - [Clinical analysis of routine laboratory examination for 464 dental patients]. AB - PURPOSE: To study the clinical value of routine laboratory examination for dental patients. METHODS: Routine blood and infectious disease examinations were performed in 464 dental patients. RESULTS: For the 374 patients who received routine blood test, the percentage of WBC, HGB, PLT and WBC classification abnormality were 13.6%, 8.5%, 10.4% and 20.3% respectively. For the 369 patients who received coagulation tests, the percentage of PT and APTT abnormality were 1.3% and 1.9%. For the 142 patients who received hepatitis B virus examination, the percentage of HBsAg, HBeAg, anti-HBs, anti-HBe and anti-HBc abnormality were 4.9%, 0.7%,59.8%,17.6% and 40.8%,respectively. The positive rate for hepatitis C, syphilis and HIV inspections were 2.9%(2/70), 0.6%(1/150) and 0.5%(1/199),respectively. CONCLUSION: Routine laboratory and infectious disease examinations are important in diagnosis, medical security and cross infection control in dental clinic. PMID- 22431059 TI - [Reasonable choice of dental clinical photographic equipment]. AB - The equipment of dental clinical photography is particular because of its particularity. Choosing a suitable equipment for dental clinical photography before learning is very important. A single-lens reflex camera is needed in dental photography for plate, lens and flash position. High quality is not needed for the camera. Focal distance of the micro lens is 100mm, and for surgery it could be 180mm, but in most situation 60mm is not suitable. The flash for micro lens is necessary, and the annular flash is better than double flash. PMID- 22431060 TI - [The evaluation of intercuspal occlusion of healthy people with T-Scan II system]. AB - PURPOSE: To observe the occluding movement from mandibular postural position to intercuspal position in healthy people. METHODS: The occluding movement in 30 healthy people from mandibular postural position to intercuspal position was recorded by T-Scan II system. The distribution of occlusal force, the center of force, the percentage of intercuspal position occlusal force in Max force and the occlusion time was analyzed by T-Scan II system and SAS 9.0 software package. RESULTS: The results showed that there was no significant difference between the occlusal force of the two sides under the intercuspal position mode(P=0.3242). The average percentage of intercuspal position occlusal force in Max force was 96.89%. The confidence interval (CI) was 90.88%-100%. The average occlusion time was (0.2015 +/- 0.0861)s. There was no correlation between the occlusion time and the percentage of intercuspal position occlusal force in Max force. CONCLUSIONS: We could introduce the position of the center of force, the percentage of intercuspal position occlusal force in Max force and the occlusion time to estimate the occlusal condition, and to judge the effect of occlusal therapy. ). PMID- 22431061 TI - Transcriptomic analysis of the woodchuck model of chronic hepatitis B. AB - The Eastern woodchuck (Marmota monax) is naturally infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to the human hepatitis B virus (HBV). The woodchuck is used as an animal model for studying chronic hepatitis B (CHB) and HBV-associated hepatocellular carcinoma (HCC) in humans, but the lack of sequence information has hitherto precluded functional genomics analysis. To address this major limitation of the model, we report here the sequencing, assembly, and annotation of the woodchuck transcriptome, together with the generation of custom woodchuck microarrays. Using this new platform, we characterized the transcriptional response to persistent WHV infection and WHV induced HCC. This revealed that chronic WHV infection, like HBV, is associated with (1) a limited intrahepatic type I interferon response; (2) intrahepatic induction of markers associated with T cell exhaustion; (3) elevated levels of suppressor of cytokine signaling 3 (SOCS3) in the liver; and (4) intrahepatic accumulation of neutrophils. Underscoring the translational value of the woodchuck model, this study also determined that WHV-induced HCC shares molecular characteristics with a subtype of human HCC with poor prognosis. CONCLUSION: Our data establish the translational value of the woodchuck model and provide new insight into immune pathways which may play a role either in the persistence of HBV infection or the sequelae of CHB. PMID- 22431062 TI - The pathological roles of BART miRNAs in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer prevalent in south-east Asia and southern China, where it constitutes a significant health burden. Although the close association of NPC with Epstein Barr virus (EBV) infection has been known for more than four decades, the exact role that EBV plays in the pathogenesis of this malignancy is still unclear. While NPC tumours are known to express a number of EBV-encoded proteins, they also express a large number of virus-encoded microRNAs (miRNAs), the most abundant of which are those encoded from the BamHI-A region of the viral genome: the so-called BART miRNAs. miRNAs are small non-coding mRNAs that negatively regulate the expression of various genes at the post-transcriptional level. Accumulating evidence suggests that miRNAs play important roles in tumourigenesis. Here, we review the role of EBV-encoded BART miRNAs in modulating apoptosis and host innate defence mechanisms and their contribution to NPC pathogenesis. The rationale and strategies for therapeutic targeting of BART miRNAs in EBV-infected NPC are also discussed. PMID- 22431063 TI - The dissociative subtype of posttraumatic stress disorder: rationale, clinical and neurobiological evidence, and implications. AB - BACKGROUND: Clinical and neurobiological evidence for a dissociative subtype of posttraumatic stress disorder (PTSD) has recently been documented. A dissociative subtype of PTSD is being considered for inclusion in the forthcoming Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) to address the symptoms of depersonalization and derealization found among a subset of patients with PTSD. This article reviews research related to the dissociative subtype including antecedent, concurrent, and predictive validators as well as the rationale for recommending the dissociative subtype. METHODS: The relevant literature pertaining to the dissociative subtype of PTSD was reviewed. RESULTS: Latent class analyses point toward a specific subtype of PTSD consisting of symptoms of depersonalization and derealization in both veteran and civilian samples of PTSD. Compared to individuals with PTSD, those with the dissociative subtype of PTSD also exhibit a different pattern of neurobiological response to symptom provocation as well as a differential response to current cognitive behavioral treatment designed for PTSD. CONCLUSIONS: We recommend that consideration be given to adding a dissociative subtype of PTSD in the revision of the DSM. This facilitates more accurate analysis of different phenotypes of PTSD, assist in treatment planning that is informed by considering the degree of patients' dissociativity, will improve treatment outcome, and will lead to much needed research about the prevalence, symptomatology, neurobiology, and treatment of individuals with the dissociative subtype of PTSD. PMID- 22431064 TI - Remote ischemic preconditioning in cardiac surgery: caught between clinical relevance and statistical significance? PMID- 22431065 TI - Imiquimod attenuates the growth of UVB-induced SCC in mice through Th1/Th17 cells. AB - Imiquimod (IMQ), a Toll-like receptor (TLR) 7/8 agonist, has been used to treat various skin neoplasms, including genital warts, actinic keratoses, and superficial basal cell carcinomas. Although IMQ has been recognized to activate both innate and adaptive immunity, the underlying mechanism(s) by which IMQ exerts its anti-tumor activity in vivo remains largely unknown. In this study, we took advantage of skin cancer-prone mice to characterize the effects of IMQ on ultraviolet irradiation (UV)-induced de novo carcinogenesis. Transgenic mice with keratinocytes expressing constitutively activated Stat3 (K5.Stat3C mice) developed squamous cell carcinomas (SCC in situ) as early as after 14 wk of UVB irradiation, while wild-type mice required much higher doses of UVB with more than 25 wk of UVB irradiation to produce SCC. Topical treatment of K5.Stat3C mice with IMQ attenuated UVB-induced epidermal dysplasia (SCC in situ). In addition, SCC growth due to increased total irradiation doses was significantly attenuated by IMQ treatment. Topical IMQ treatment induced T cell and plasmacytoid dendritic cell infiltrates at the tumor sites, where levels of IL-12/23p40, IL-12p35, IL 23p19, IL-17A, and IFN-gamma mRNAs were up-regulated. Immunohistochemistry revealed T cell infiltrates consisting of T1, Th17, and CD8(+) T cells. We speculate that topical IMQ treatment attenuates the de novo growth of UVB-induced SCC through activation of Th17/Th1 cells and cytotoxic T lymphocytes. PMID- 22431066 TI - Diagnosis from a blood film following dog-bite. PMID- 22431067 TI - Gene expression profiling reveals potential key pathways involved in pyrazinamide mediated hepatotoxicity in Wistar rats. AB - Pyrazinamide (PZA) is an important sterilizing prodrug that shortens the duration of tuberculosis therapy. However, hepatotoxicity has been reported during clinical trials investigating PZA. To determine the hepatotoxic effects of PZA in vivo and to further investigate the underlying cellular mechanism, we profiled the gene expression patterns of PZA-treated rat livers by microarray analysis. Wistar rats of both sexes were orally administered PZA at doses of 0.5, 1.0 and 2.0 g kg(-1) for 28 days. Body weight, absolute and relative liver weight, biochemical analysis, histopathology, oxidative stress parameters in liver homogenates and changes in global transcriptomic expression were evaluated to study the hepatotoxic effects of PZA. Our results confirm the dose-dependent and sex-related hepatotoxicity of PZA. Female rats were more sensitive to PZA-induced hepatotoxicity than males. Furthermore, changes in the activity of major antioxidant enzymes and nonenzymatic antioxidants (superoxide dismutase, total antioxidant capacity, glutathione and malondialdehyde), indicating the development of oxidative stress, were more significant in the PZA-treated group. PZA-induced gene expression changes were related to pathways involved in drug metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, oxidative stress and apoptosis. Real-time polymerase chain reaction confirmed the regulation of selected genes involved in PZA-hepatotoxicity (Ephx1, Cyp2b1, Gstm1, Gstp1, Fabp7, Acaa1, Cpt-1b, Cyp8b1, Hmox1 and Ntrk1). We observed for the first time that these genes have effects on PZA-induced hepatotoxicity. In addition, drug metabolism and PPAR signaling pathways may play an important role in PZA hepatotoxicity. Taken together, these findings will be useful for future PZA hepatotoxicity studies. PMID- 22431068 TI - Intracellular signaling MAPK pathway after cerebral ischemia-reperfusion injury. AB - The MAPK/ERK/p38 are signal transduction pathways that couple intracellular responses to the external stimuli. Contrary to ERK protein which is part of the survival route, presence of p38 could have an impact on cell injury. Tolerance induced by ischemic preconditioning (IPC) is a phenomenon of tissue adaptation, which results in increased tolerance to lethal ischemia-reperfusion injury (IRI). Paper describes changes in MAPK protein pathways after brain IPC. Ischemia was induced by 4-vessels occlusion and rats were preconditioned by sub-lethal ischemia. Western blot and immunohistochemistry identified ERK/p38 proteins in injured areas. The highest level of the pERK was detected at 24 h in IPC groups. A contrary pattern of MAPK/p38 activation was observed in this group, where the lowest level of p38 was displayed at 24 h after ischemia. This suggests that the MAPK signal transduction might have a potential role in tissues response subjected to IRI and in the phenomenon of tolerance. PMID- 22431069 TI - Radiation therapy for life-threatening huge laryngeal hemangioma involving pharynx and parapharyngeal space. AB - BACKGROUND: Adult hemangiomas are rare, slowly progressing vascular tumors. Potential complications include laryngeal involvement or massive tumor burden. METHODS: A case of recurrent, bulky laryngeal hemangioma involving the parapharyngeal space is presented herein. The clinical course and treatment are described, and a series of MRI studies are compared to demonstrate the treatment response. RESULTS: A 35-year-old woman presented with progressive hoarseness, neck fullness, and intermittent dyspnea caused by a bulky laryngeal hemangioma. Steroid therapy had a limited response. Radiation therapy with a total dose of 40 Gray (Gy) in 20 fractions successfully relieved her symptoms. Image studies after therapy revealed moderate tumor regression. The patient showed no serious complications during the next 2 years of follow-up. CONCLUSION: Radiation therapy may be effective in intractable and function-threatening laryngeal hemangiomas. PMID- 22431070 TI - Lapacho tea (Tabebuia impetiginosa) extract inhibits pancreatic lipase and delays postprandial triglyceride increase in rats. AB - Earlier work in our laboratory indicated that ethanolic extracts of Tabebuia impetiginosa, Arctium lappa L., Calendula officinalis, Helianthus annuus, Linum usitatissimum and L. propolis, inhibit pancreatic lipase in vitro. In a follow-up study we assessed their effects on plasma triglycerides in rats fed on a fatty meal. Extracts, orlistat or only ethanol were given orally to the rats together with the test meal and the rate of increase of postprandial triglycerides was assessed over 4 h. Clearing of the triglycerides from the blood compartment was abolished by inhibiting lipoprotein lipase with Triton WR-1339. Our results showed that out of all the extracts, the bark of Tabebuia impetiginosa led to a significant delay in the postprandial increase of plasma triglycerides. However, lapachol, which is contained in the bark of Tabebuia impetiginosa and soluble in ethanol, had no lipase inhibitory effect in vitro and hence this substance did not seem to mediate the pertinent effect. PMID- 22431071 TI - Asymmetric total synthesis of (+)-merobatzelladine B. PMID- 22431072 TI - Role of Ca(2+) in the rapid cooling-induced Ca(2+) release from sarcoplasmic reticulum in ferret cardiac muscles. AB - Rapid lowering of the solution temperature (rapid cooling, RC) from 24 to 3 degrees C within 3 s releases considerable amounts of Ca(2+) from the sarcoplasmic reticulum (SR) in mammalian cardiac muscles. In this study, we investigated the intracellular mechanism of RC-induced Ca(2+) release, especially the role of Ca(2+), in ferret ventricular muscle. Saponin-treated skinned trabeculae were placed in a glass capillary, and the amount of Ca(2+) released from the SR by RC and caffeine (50 mM) was measured with fluo-3. It was estimated that in the presence of ATP about 45% of the Ca(2+) content in the SR was released by RC. The amount of SR Ca(2+) released by RC was unchanged by the replacement of ATP by AMP-PCP (a non-hydrolysable ATP analogue and agonist for the ryanodine receptor but not for the Ca(2+) pump of SR), suggesting that the suppression of the Ca(2+) pump of SR at low temperature might not be a major mechanism in RC-induced Ca(2+) release. The free Ca(2+) concentration of the solution used for triggering RC-induced Ca(2+) release was estimated to be only about 20 nM with fluo-3 or aequorin. When this solution was applied to the preparation at 3 degrees C, only a small amount of Ca(2+) was released from SR presumably by the Ca(2+)-induced Ca(2+) release (CICR) mechanism. Thus, in mammalian cardiac muscles, RC releases a part of the (<50%) stored Ca(2+) contained in the SR, and the mechanism of RC-induced Ca(2+) release may differ from that of CICR, which is thought to play a role in frog skeletal muscle fibres that express ryanodine receptors of different types. PMID- 22431073 TI - Prevalence of symptoms in female Fabry disease patients: a case-control survey. AB - BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by a deficiency of alpha-galactosidase A. Several studies demonstrated that heterozygotes have symptoms such as acroparesthesia, abdominal pain and chronic fatigue. However, as these symptoms are aspecific and relatively common in the general population, it is important to compare the prevalence of these symptoms with an appropriate control group. The aim of this study was to explore the prevalence of signs and symptoms in FD females in comparison to a control group. METHODS: FD females and age-matched controls were approached to complete a questionnaire. This questionnaire was developed by the Dutch Fabry patient organisation (Fabry Support en Informatie Groep Nederland, FSIGN) with input from Fabry expert-physicians from the AMC. We compared the prevalence symptoms using Pearson's chi-square test. Bonferroni correction was used to correct for multiple comparisons. RESULTS: A total of 63 heterozygotes and 52 controls completed the questionnaire. Many symptoms were also common in controls. Yet, fatigue, palpitations, pains in hands and feet, joint pain, dizziness, loss of libido and proteinuria during pregnancy were more common in Fabry females (all p < 0.001). CONCLUSION: In addition to acroparesthesia - fatigue, palpitations, dizziness, proteinuria during pregnancy, libido loss and joint pain are more prevalent in FD females as compared to a control group. Although, these symptoms are present in a significant proportion of normal controls they deserve further attention by treating physicians to better understand their significance, treatment and relationship with FD. PMID- 22431074 TI - A new dirhodium catalyst with hemilabile tropolonato ligands for C-H bond functionalization. AB - Don't hold on too tightly! In a new dirhodium catalyst for C-H functionalization reactions, two tropolonato ligands are introduced as hemilabile chelating ligands (see scheme). Only two bridges hold the Rh-Rh core together. The tropolonato ligands can liberate a binding site in the equatorial coordination sphere of the catalyst. This opens a doorway to new mechanistic channels in C-H functionalization. PMID- 22431075 TI - Integrating novel signaling pathways involved in erythropoiesis. AB - Many extrinsic and intrinsic factors control the development of red blood cells from committed progenitors, with the Erythropoietin-receptor (Epo-R) signaling network being the primary controlling molecular hub. Although much is understood about erythroid signaling pathways, new and intriguing factors that influence different aspects of erythroid cell development are still being uncovered. New extrinsic effectors include hypoxia and polymeric IgA1 (pIgA1), and new Epo-R signaling pathway components include Lyn/Cbp and Lyn/Liar. Hypoxia directly activates committed erythroid progenitors to expand, whereas pIgA1 activates the Akt and MAP-Kinase (MAPK) pathways through transferrin receptors on more mature erythroid cells. The Lyn/Cbp pathway controls the activity and protein levels of Lyn through recruitment of Csk and SOCS1, as well as feeding into the control of other pathways mediated by recruitment of ras-GAP, PI3-kinase, PLCgamma, Fes, and EBP50. Nuclear/cytoplasmic shuttling of Lyn and other signaling molecules is influenced by Liar and results in regulation of their intersecting signaling pathways. The challenge of future research is to flesh out the details of these new signaling regulators/networks and integrate their influences during the different stages of erythropoiesis. PMID- 22431077 TI - Sensory Guillain-Barre syndrome and related disorders: an attempt at systematization. AB - The possibility that some patients diagnosed with an acute sensory neuropathy could actually have Guillain-Barre syndrome (GBS) has been repeatedly advanced in the literature, but the number of cases reported is small. The reports have shown different clinical presentations and electrophysiological findings and are variously named, thus generating terminological and nosological confusion. We operatively defined sensory GBS as an acute, monophasic, widespread neuropathy characterized clinically by exclusive sensory symptoms and signs that reach their nadir in a maximum of 6 weeks without related systemic disorders and other diseases or conditions. We reviewed the literature through searches of PubMed from 1980 to March 2011 and our own files. On the basis of the size of fibers involved and the possible site of primary damage, we propose tentatively classifying sensory GBS and related disorders into three subtypes: acute sensory demyelinating polyneuropathy; acute sensory large-fiber axonopathy ganglionopathy; and acute sensory small-fiber neuropathy-ganglionopathy. PMID- 22431078 TI - Substance abuse increases the risk of neuropathy in an HIV-infected cohort. AB - INTRODUCTION: Human immunodeficiency virus (HIV)-infected patients commonly develop distal symmetric polyneuropathy (DSP). Age, ethnicity, and toxic exposures may influence the risk. In this study we examined the association between substance use, antiretrovirals, ethnicity, and incident neuropathy in an HIV-infected cohort. METHODS: Data were obtained from the National NeuroAIDS Tissue Consortium (NNTC), an ongoing, prospective cohort started in 1998. Cox proportional hazards models were used to examine the association of substance use, demographics, neurotoxic antiretrovirals, and laboratory parameters with incident neuropathy in 636 participants who were neuropathy-free at baseline. RESULTS: The cumulative incidence of DSP was 41%. Substance use (P = 0.04), number of substances used (P = 0.04), and longer duration of HIV infection (P = 0.05) were associated with incident DSP, but demographic factors, use of neurotoxic antiretrovirals, and laboratory parameters were not. CONCLUSIONS: Substance use and longer duration of HIV infection are risk factors for DSP in HIV-infected patients. Use of multiple substances may be particularly risky. PMID- 22431079 TI - Usefulness of assessing repeater F-waves in routine studies. AB - INTRODUCTION: Repeater F-waves are sometimes seen in routine studies. METHODS: We retrospectively reviewed the clinical significance of repeater F-waves in median, ulnar, and fibular nerve recordings in 50 healthy subjects and groups of 50 patients each with diabetic polyneuropathy, amyotrophic lateral sclerosis, carpal tunnel syndrome, ulnar mononeuropathy, and L5 root lesion. The number of identical F-waves and their repetitions in samples of 20 stimuli were estimated. RESULTS: Repeater F-waves occurred significantly more frequently in all nerves and patient groups than in healthy individuals. Their persistence was negatively correlated with that of non-repeater F-waves. CONCLUSIONS: Based on the presented material and recording condition it appears that repeater F-waves differentiate between health and disease but not between different types of pathology of motor neurons or their axons. Even in routinely recorded samples of 20 traces, the index of repeater all F-waves could be used as a sign of nerve pathology. PMID- 22431080 TI - Application of futility analysis to refine jitter recordings in myasthenia gravis. AB - INTRODUCTION: The current practice of single-fiber electromyography (SFEMG) requires that 20 fiber pairs with normal jitter be collected to exclude myasthenia gravis (MG). We applied principles of futility analysis from clinical trials in an attempt to reduce that requirement. METHODS: We utilized conditional power futility analysis to assess the probability of an abnormal 20-pair SFEMG based on ongoing analysis of jitter as each pair is collected. Rules for early test termination in the presence of 0, 1, or 2 abnormal pairs were identified. These rules were then applied to previously collected SFEMG data. RESULTS: SFEMG could be stopped at just 12 pairs if all are normal and at 17 pairs if 1 is abnormal. The rules successfully determined when SFEMG could be stopped in 104 of 106 (98%) studies originally reported to be normal. CONCLUSIONS: If the first 12 SFEMG pairs have normal jitter, the study can be terminated and interpreted as normal. PMID- 22431081 TI - Clarifying distal axonal properties of the median nerve. AB - INTRODUCTION: Although length-dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified. METHODS: Axonal excitability studies were performed on median nerve at the palm and wrist in 20 healthy controls, with responses recorded over the abductor pollicis brevis. RESULTS: The strength-duration time constant was significantly shorter (palm: 0.35 +/- 0.01 ms; wrist: 0.48 +/- 0.03 ms; P < 0.001), whereas rheobase was significantly increased (palm: 2.90 +/- 1.12 mA; wrist: 2.09 +/- 1.11 mA; P < 0.05) at the palm. In addition, there was a significant increase in depolarizing threshold electrotonus at 90-100 ms (P < 0.001) and a reduction in S2 accommodation (P < 0.001) and late subexcitability (P < 0.001) at the palm. The changes in excitability were independent of factors influencing median nerve cross-sectional area. CONCLUSIONS: The present study reveals significant length dependent changes in median nerve excitability which may reflect differences in intrinsic membrane properties. PMID- 22431082 TI - The magnetic resonance imaging spectrum of facioscapulohumeral muscular dystrophy. AB - INTRODUCTION: Facioscapulohumeral muscular dystrophy (FSHD) is associated with a repeat contraction in the D4Z4 gene locus on chromosome 4q35. We used a one-step quantitative magnetic resonance imaging (MRI) method to evaluate muscle, edema, and fat in patients spanning the range of severity. METHODS: Fifteen patients with FSHD were compared with 10 healthy subjects using non-negative linear least squares fitting of 32-echo relaxation data (T2). The results were compared with a biexponential approach for characterizing muscle/fat ratio and T2 relaxation measurements from fat-suppressed inversion recovery. RESULTS: Increased T2 signal consistent with edema was common in FSHD subjects, a pattern not present in healthy controls. A varied pattern of edema and fatty replacement in muscles was shown. CONCLUSIONS: As a discrete biomarker, edema may be useful for following the clinical course of FSHD. Future work toward optimizing measurement is discussed. PMID- 22431083 TI - Decomposition-based quantitative electromyography in the evaluation of muscular dystrophy severity. AB - INTRODUCTION: Electromyography is useful in the diagnosis of myopathies, but its utility in determining disease severity requires further investigation. In this study we aimed to determine whether decomposition-based quantitative electromyography (DQEMG) could indicate the severity of involvement in a cohort of patients with muscular dystrophies (MDs). METHODS: Fifteen patients with facioscapulohumeral (FSHD), limb-girdle (LGMD), and Becker (BMD) muscular dystrophy, and 7 healthy controls, participated in this investigation. Knee extensor isometric strength differentiated the "more severe" and "less severe" MD groups. The vastus lateralis (VL), biceps brachii (BB), and tibialis anterior (TA) muscle groups were investigated using DQEMG. RESULTS: All muscles from the MD group showed changes in mean MUP (motor unit potential) AAR (area-to-amplitude ratio), and turns, compared with controls (P < 0.05). More severely affected muscles (VL and BB) also had shortened mean MUP durations compared with controls (P < 0.01). CONCLUSIONS: DQEMG was capable of indicating the severity of MD involvement, as changes in MUP morphology reflected the progressive nature of the disease. PMID- 22431084 TI - Simulation studies on the motor unit potentials with satellite components in amyotrophic lateral sclerosis and spinal muscle atrophy. AB - INTRODUCTION: We compared motor unit potentials (MUPs) with satellite components recorded in two anterior horn disorders: amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA, types II and III). METHODS: We analyzed MUPs recorded from biceps brachii muscle, including 209 associated with ALS (12 patients) and 127 with SMA (5 patients). Simulations were applied to determine the origin of satellites in these processes. RESULTS: MUP parameters differ in ALS and SMA. Simulations indicate that the satellite potential in ALS often originated from a single fiber, whereas in SMA it originated from a group of fibers of smaller diameters than the surrounding ones. CONCLUSIONS: These results suggest that, except for neurogenic factors, the variability of muscle fiber diameters also leads to the formation of MUPs with satellites. This variability seems to be responsible for the differences in the shape of the main and satellite MUP components in ALS and SMA. PMID- 22431085 TI - Intramuscular distribution of the phrenic nerve in human diaphragm as shown by Sihler staining. AB - INTRODUCTION: Intramuscular innervation of the human diaphragm has not been well described. The goal of this study was to elucidate the detailed intramuscular distribution of the phrenic nerve in the human diaphragm. METHODS: Fifteen human diaphragms were visualized using modified Sihler staining, and the detailed intramuscular phrenic nerve distribution was photographed and recorded. RESULTS: Three types of primary phrenic nerve branches were noted. Each type of primary branch innervated a confined muscular subvolume of the diaphragm, and the intramuscular branches in each subvolume anastomosed largely with one another and formed a characteristic "net" of nerve branches. A few small nerve filaments were seen entering the peripheral diaphragm. The directions and locations of nerve branches innervating the hiatal diaphragm were not symmetrical between sides. CONCLUSION: These findings may offer useful information for anatomists, physiologists, and clinicians. PMID- 22431086 TI - Intermuscular relationship of human muscle fiber type proportions: slow leg muscles predict slow neck muscles. AB - INTRODUCTION: Our aim in this study was to examine whether the muscle fiber type proportions in different muscles from the same individual are interrelated. METHODS: Samples were excised from five skeletal muscles in each of 12 human autopsy cases, and the fiber type proportions were determined by immunohistochemistry. We further examined the intermuscular relationship in fiber type proportion by reanalyzing three previously published data sets involving other muscles. RESULTS: Subjects demonstrated a predominantly high or low proportion of type 1 fibers in all examined muscles, and the overall difference between individuals was statistically significant (P < 0.001). Accordingly, the type 1 fiber proportions in most muscles were positively correlated (median r = 0.42, range -0.03-0.80). Similar results were also obtained from the three reanalyzed data sets. CONCLUSIONS: We suggest the existence of an across-muscle phenotype with respect to fiber type proportions; some individuals display generally faster muscles and some individuals slower muscles when compared with others. PMID- 22431087 TI - In vivo measurement of hindlimb neuromuscular function in mice. AB - INTRODUCTION: In vitro or in situ methods to assess neuromuscular performance in rodents are invasive and inadequate to fully assess large hindlimb muscles. METHODS: An in vivo hindlimb exertion force test (HEFT) was developed to quantify muscle function peak force (PF), peak rate of force development (PRFD), and short and long-latency reaction times (SLRT and LLRT, respectively) in C57BL/6J mice. RESULTS: PF did not change with one- and three-times-per-week repeated HEFT trials, demonstrating assessment reproducibility. However, PRFD decreased with trial, indicating that mice modified response behavior while achieving the same PF. Separately, mice were subjected to 14 days of hindlimb suspension (HS) to induce muscle atrophy. Concomitant with decreased lean carcass and individual muscle masses, HS mice showed reduced PF and LLRT. CONCLUSIONS: The results demonstrate that HEFT is an effective tool for evaluating in vivo hindlimb neuromuscular performance due to disuse muscle atrophy and potentially for other disease and injury models. PMID- 22431088 TI - Muscle function and running activity in mouse models of hereditary muscle dystrophy: impact of double knockout for dystrophin and the transcription factor MyoD. AB - INTRODUCTION: Mice that lack both the transcription factor MyoD and dystrophin display a more pronounced myopathic phenotype when compared with mdx mice. No data on skeletal muscle function and the impact of exercise training are available. METHODS: Six-month-old wild-type, mdx, myoD(-/-), mdx:myoD(+/-), and mdx:myoD(-/-) mice were randomly assigned to either 4 weeks of voluntary running or sedentary behavior. The mdx:myoD(-/-) mice were not able to exercise at all and were kept sedentary. RESULTS: The soleus muscle of sedentary 7-month-old mdx:myoD(-/-) mice showed a significantly lower force development compared with all other mice. Voluntary running beginning at the age of 6 months led to lower force development of soleus muscle in the mdx animals. CONCLUSIONS: mdx:myoD(-/-) is not a suitable model to study exercise-induced effects on dystrophic muscles. Voluntary exercise in adult mdx mice seems to have detrimental effects on the function of soleus muscle. PMID- 22431089 TI - Time-course analysis of injured skeletal muscle suggests a critical involvement of ERK1/2 signaling in the acute inflammatory response. AB - INTRODUCTION: The coupling and timing of pro- and anti-inflammatory processes in skeletal muscle injury is poorly understood. We investigated the temporal response and regulated processes of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and IkappaB kinase (IKK) alpha/beta signaling pathways after traumatic injury. METHODS: Traumatic freeze injury was delivered to the tibialis anterior (TA) muscle in C57BL/6J mice, and injured and uninjured TA muscles were analyzed 3-72 h into the recovery period. RESULTS: Significant increases in pro inflammatory cytokine transcription accompanied IKKbeta phosphorylation, robust ERK pathway activation, and reduced heat shock protein (Hsp) protein expression at 3-24 h. At 24 h, ERK activation was abolished concomitantly with a significant increase in mitogen-activated protein kinase phosphatase-1 (MKP-1). After 24 h, cytokine transcription along with ERK1/2 and IKKbeta phosphorylation remained suppressed, whereas Hsp protein expression rose to significant levels by 72 h and associated with IKKbeta. CONCLUSIONS: Results indicate a bimodal regulation of ERK1/2 in acute inflammation in which it is supportive from 3 to 24 h, and suppressive from 24 to 72 h. PMID- 22431090 TI - Effects of extracorporeal shock-wave lithotripsy directed at the parotid gland on oxidative stress parameters and some trace element levels in facial nerve of rats. AB - INTRODUCTION: This study was designed to assess the effect of extracorporeal shock-wave lithotripsy (ESWL) exposure of the parotid gland on oxidative stress and some trace element levels in the facial nerves of rats. METHODS: Twelve male Wistar albino rats were divided into two groups, each consisting of 6 animals. The rats in the first group served as controls. The left parotid glands of animals in the second group were treated with 1000 18-kV shock waves while anesthetized with ketamine. The animals in both groups were euthanized 72 h after the ESWL treatment, and the right facial nerve was harvested for determination of oxidant/antioxidant status and trace element levels. RESULTS: Lipid peroxidation product malondialdehyde (MDA) and antioxidant glutathione (GSH) levels increased, and the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), decreased in the facial nerves of ESWL-treated rats. The levels of iron, lead, manganese, and cobalt increased, and magnesium, cadmium, and copper levels decreased. CONCLUSIONS: ESWL treatment of the parotid gland may increase lipid peroxidation and decrease antioxidant enzyme activity in adjacent tissues such as the facial nerve. It also causes a decrease or increase in many mineral levels of the facial nerve, which is an undesirable condition for normal physiological function. PMID- 22431091 TI - Effect of locomotor training on muscle performance in the context of nerve-muscle communication dysfunction. AB - INTRODUCTION: The effects of locomotor training (LT) on skeletal muscle after peripheral nerve injury and acetylcholinesterase deficiency are not well documented. METHODS: We determined the effects of LT on mouse soleus muscle performance after sciatic nerve transection with excision (full and permanent denervation), nerve transection (partial functional reinnervation), nerve crush (full denervation with full functional reinnervation), and acetylcholinesterase deficiency (alteration in neuromuscular junction functioning). RESULTS: We found no significant effect of LT on the recovery of soleus muscle weight, maximal force in response to muscle stimulation, and fatigue resistance after nerve transection with or without excision. However, LT significantly increased soleus muscle fatigue resistance after nerve crush and acetylcholinesterase deficiency. Moreover, hindlimb immobilization significantly aggravated the deficit in soleus muscle maximal force production and atrophy after nerve crush. CONCLUSIONS: LT is beneficial, and reduced muscle use is detrimental for intrinsic muscle performance in the context of disturbed nerve-muscle communication. PMID- 22431092 TI - Frontal plane hip and ankle sensorimotor function, not age, predicts unipedal stance time. AB - INTRODUCTION: Changes occur in muscles and nerves with aging. In this study we explore the relationship between unipedal stance time (UST) and frontal plane hip and ankle sensorimotor function in subjects with diabetic neuropathy. METHODS: UST, quantitative measures of frontal plane ankle proprioceptive thresholds, and ankle and hip motor function were tested in 41 subjects with a spectrum of lower limb sensorimotor function ranging from healthy to moderately severe diabetic neuropathy. RESULTS: Frontal plane hip and ankle sensorimotor function demonstrated significant relationships with UST. Multivariate analysis identified only composite hip strength, ankle proprioceptive threshold, and age to be significant predictors of UST (R(2) = 0.73), explaining 46%, 24%, and 3% of the variance, respectively. CONCLUSIONS: Frontal plane hip strength was the single best predictor of UST and appeared to compensate for less precise ankle proprioceptive thresholds. This finding is clinically relevant given the possibility of strengthening the hip, even in patients with significant peripheral neuropathy. PMID- 22431093 TI - Oxidative capacity and fatigability in run-trained malignant hyperthermia susceptible mice. AB - INTRODUCTION: The purpose of this study was to test the hypothesis that malignant hyperthermia model mice (RyR1Y522S/wt) are more vulnerable to exercise-induced muscle injury and fatigability and adapt less to run training. METHODS: After 6 weeks of voluntary wheel running, we measured anterior crural muscle fatigability, muscle injury, and cytochrome oxidase (COX) and citrate synthase (CS). RESULTS: Although RyR1Y522S/wt mice ran without undergoing MH episodes, they ran 42% less distance than wild-type (WT) mice. Muscles from WT mice exhibited increased fatigue resistance and COX content after training. Muscles from RyR1Y522S/wt mice demonstrated no significant change in fatigability or COX and CS after training. However, muscles from RyR1Y522S/wt mice displayed less intrinsic fatigability and greater COX/CS content and muscle damage than WT mice. CONCLUSIONS: RyR1Y522S/wt mice can run without having rhabdomyolysis, and their inability to adapt to training appears to stem from intrinsic enhancement of mitochondrial enzymes and fatigue resistance. PMID- 22431094 TI - 7-Nitroindazole potentiates c-fos expression induced by muscle tendon vibration in the spinal cord. AB - INTRODUCTION: Expression of c-fos initiated by muscle proprioceptive signaling was studied in rats after inhibition of neuronal nitric oxide synthase (nNOS) with administration of 7-nitroindazole (7-NI). METHODS: Fos-immunoreactive (Fos ir) neurons were visualized immunohistochemically in the lumbar cord after vibration of the Achilles tendon and/or 7-NI systemic injections. RESULTS: The total number of Fos-ir interneurons and motoneurons (per slice) was significantly greater in the 7-NI-pretreated and tendon-vibrated (7-NI + Tv) group than in the isolated tendon vibration group (Tv group). The greatest increases in the number of Fos-ir neurons were found in the L4 (+100%) and L5 (+105%) segments (P < 0.05). CONCLUSIONS: Suppression of NO release after introduction of 7-NI was associated with potentiation of Fos immunoreactivity induced by muscle proprioceptive signaling within distinctive regions of the spinal cord. PMID- 22431095 TI - Supraorbital nerve conduction study in normal subjects. AB - There is currently no examination technique that allows direct measurement of supraorbital nerve conduction velocity and amplitude. Therefore, in this study we describe a novel nerve conduction technique that allows measurement of the supraorbital sensory nerve action potential (SNAP) distal to the supraorbital foramen. Supraorbital SNAPs were recorded bilaterally from 17 healthy volunteers using an antidromic technique. The SNAPs were consistently recordable over the site 6 cm lateral to the midline point that was marked 10 cm above the nasion. Measured parameters included peak latency (mean 2.3 ms, SD 0.3), amplitude (mean 14.6 MUV; SD 10.5), and velocity (mean 51.3 m/s, SD 6.8). The mean percentage of interside difference in amplitude was 25.6% (SD 17.3). Cut-off values (97th percentile) were 2.7 ms (peak latency), 3.3 MUV (amplitude), 41.9 m/s (conduction velocity), and 54.9% (interside difference in amplitude). Supraorbital SNAPs can be recorded in all normal subjects and used as a quantitative measure of the functioning large fibers in the nerve. PMID- 22431096 TI - Autosomal recessive Emery-Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the lamin A/C gene identified by exome sequencing. AB - INTRODUCTION: The aim of this study is to describe a new mutation in the LMNA gene diagnosed by whole exome sequencing. METHODS: A two-generation kindred with recessive limb-girdle muscular dystrophy was evaluated by exome sequencing of the proband's DNA. RESULTS: Exome sequencing disclosed 194,618 variants (170,196 SNPs, 8482 MNPs, 7466 insertions, 8307 deletions, and 167 mixed combinations); 71,328 were homozygotic and 123,290 were heterozygotic, with 11,753 non synonymous, stop-gain, stop-loss, or frameshift mutations occurring in the coding region or nearby intronic region. The cross-referencing of these mutations in candidate genes for muscular dystrophy showed a homozygote mutation c.G674A in exon 4 of LMNA causing a protein change R225Q in an arginine conserved from human to Xenopus tropicalis and in lamin B1. CONCLUSIONS: This technique will be preferred for studying patients with muscular dystrophy in the coming years. PMID- 22431097 TI - Periodic acid-Schiff staining on resin muscle sections: improvement in the histological diagnosis of late-onset Pompe disease. PMID- 22431098 TI - What does body mass index measure in amyotrophic lateral sclerosis and why should we care? PMID- 22431104 TI - Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ~30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA. PMID- 22431105 TI - Treatment of an iatrogenic femoral artery pseudoaneurysm with concomitant arteriovenous fistula with percutaneous implantation of an Amplatzer vascular plug. AB - Iatrogenic pseudoaneurysms can occur following percutaneous cardiac and peripheral procedures. There are multiple modalities available for the treatment of pseudoaneurysms including ultrasound guided compression repair, ultrasound guided thrombin injection, or endovascular repair with covered stent placement. If these methods are not indicated or unsuccessful, patients typically require open surgical repair. We report a case of a woman with a post-procedural pseudoaneurysm with concomitant arteriovenous fistula who was treated percutaneously with the implantation of an Amplatzer vascular plug. This novel technique was safe and effective and allowed our patient to avoid the morbidity and mortality associated with surgical repair. PMID- 22431127 TI - [Development and validation of an inventory of ego functions and self regulation (Hannover Self-Regulation Inventory, HSRI)]. AB - OBJECTIVE: The aim of this study was to construct and validate a short self rating questionnaire for the assessment of ego functions and ability of self regulation. MATERIAL AND METHODS: An item pool of 120 items covering 6 postulated dimensions was reduced by two steps in independent samples (n = 136 + 470) via factor and item analyses to the final version consisting of 35 items. RESULTS: The 5 resulting questionnaire scales "interpersonal disturbances", "frustration tolerance and impulse control", "identity disturbances", "affect differentiation and affect tolerance" and "self-esteem" were well interpretable and showed in confirmatory factor analysis the best fit to the data (CHI2/df = 3.48; RMSEA = 0.73). Total scores were found to differentiate well between diagnostic groups of patients with more or less ego pathology (FANOVA = 9.8; df = 11; p < 0.001), thus proving good concurrent validity. Reliability was shown by testing internal consistency and test-retest correlations. CONCLUSION: The "Hannover self regulation questionnaire" (HSRQ) evidently is an appropriate and reliable screening instrument in order to assess ego functions and capacities of self regulation in an economic and user-friendly means. The scale structure allows differentiated diagnostics of weak vs. stable ego functions and may be used for detailed therapy planning. PMID- 22431128 TI - [Alcohol and violence: a current review]. AB - Violent behaviour under the influence of alcohol is a long-known phenomenon and causes great suffering in affected persons and enormous costs for society. While earlier studies considered alcohol-associated violence primarily to be due to alcohol's disinhibiting effects, recent scientific studies show a complex interaction of various bio-psycho-social factors. Including recent study results, the following review presents current data on the epidemiology of alcohol associated violence, discusses possible contributing factors and causes, and possible resulting therapeutic implications. Based on these results, populations at risk such as binge drinkers, young adults and individuals with substance use disorders and comorbid psychiatric disorders can be identified, who often display a high burden of problems and therefore need a close network of medical, psychiatric and social services. PMID- 22431129 TI - Miniaturized flow cytometry-based in vitro primary human lymphocyte micronucleus assay-validation study. AB - Most in vitro mammalian genotoxicity assays show a low specificity (high rate of irrelevant positive results), and therefore, lead to an increase in follow-up in vivo genotoxicity testing. One of the sources of the high rate of in vitro irrelevant positive results that find no confirmation in in vivo studies may be the characteristics of the test system used. It has been shown that cells that are p53 deficient or carry an alteration in DNA repair genes may be more prone to produce high rate of false/irrelevant positive results. Primary human lymphocytes (HuLy) are considered to show a higher specificity in predicting the in vivo genotoxic potential of a tested compound. We recently developed a flow cytometry based primary human T-lymphocyte micronucleus test (MNT) and showed that the technology is promising and reliable in detecting genotoxic compounds. The purpose of the present work was to develop and validate a miniaturized format of the assay. For validation purposes of the flow cytometry HuLy MNT a wide selection of compounds with different mechanisms of genotoxicity was used. The evaluation covered 30 compounds: 19 commercially available genotoxicants and nongenotoxicants and 11 early pharmaceutical development compounds. Being faster and less tedious than the microscopic analysis, the miniaturized flow cytometry based methodology showed very promising results. Conveniently, cell division is verified within the same sample as the MN frequency. Moreover analysis of hypodiploid events may provide an indication for a mode of action, i.e. clastogenic versus aneugenic mechanism, for further follow-up testing. PMID- 22431130 TI - Comparison of the aneugenic properties of nocodazole, paclitaxel and griseofulvin in vitro. Centrosome defects and alterations in protein expression profiles. AB - We have comparatively investigated the aneugenic activity of two anticancer drugs, nocodazole (NOC) and paclitaxel (PTX), and the antifungal griseofulvin with promising role in cancer treatment (GF), which affect microtubule dynamics in different ways. The comparison was achieved in HFFF2 human fibroblasts, MCF-7 human breast cancer cells and C2C12 mouse myoblasts, and focused on three issues: (i) induction of chromosome delay by estimation of MN frequency using CREST analysis; (ii) disturbance of spindle organization with Aurora-A/beta-tubulin immunofluorescence; and (iii) alterations in the expression of Aurora-A, beta- and gamma-tubulin by western blotting. They induced chromosome delay, provoked metaphase arrest and promoted microtubule disorganization, reflecting their common characteristic of generating aneuploidy. In particular, NOC induced mainly monopolar metaphases, although PTX induced only multipolar metaphases. GF generated different types of abnormal metaphases, exhibiting cell specificity. Additionally, NOC decreased the expression of Aurora-A and beta-tubulin, while the opposite held true for PTX and GF. gamma-Tubulin expression was not modulated owing to NOC treatment, whereas PTX and GF increased gamma-tubulin expression. Our findings throw a light on the manifestation of the aneugenicity of the studied compounds through centrosome proliferation/separation and protein expression, reflecting their different effects on microtubule dynamics. PMID- 22431131 TI - Effect of colesevelam on liver fat quantified by magnetic resonance in nonalcoholic steatohepatitis: a randomized controlled trial. AB - Bile acid sequestrants (BAS) lower plasma low density lipoprotein levels and improve glycemic control. Colestimide, a BAS, has been claimed by computed tomography to reduce liver fat. Therefore, we examined the efficacy of colesevelam, a potent BAS, to decrease liver fat in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liver fat was measured by a novel magnetic resonance imaging (MRI) technique, the proton-density-fat-fraction (PDFF), as well as by conventional MR spectroscopy (MRS). Fifty patients with biopsy-proven NASH were randomly assigned to either colesevelam 3.75 g/day orally or placebo for 24 weeks. The primary outcome was change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Compared with placebo, colesevelam increased liver fat by MRI-PDFF in all nine segments of the liver with a mean difference of 5.6% (P = 0.002). We cross validated the MRI-PDFF-determined fat content with that assessed by colocalized MRS; the latter showed a mean difference of 4.9% (P = 0.014) in liver fat between the colesevelam and the placebo arms. MRI-PDFF correlated strongly with MRS determined hepatic fat content (r(2) = 0.96, P < 0.0001). Liver biopsy assessment of steatosis, cellular injury, and lobular inflammation did not detect any effect of treatment. CONCLUSION: Colesevelam increases liver fat in patients with NASH as assessed by MRI as well as MRS without significant changes seen on histology. Thus, MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH. Underlying mechanisms and whether the small MR-detected increase in liver fat has clinical consequences is not known. PMID- 22431132 TI - A novel amino acid substitution Ala-122-Tyr in ALS confers high-level and broad resistance across ALS-inhibiting herbicides. AB - BACKGROUND: Wild radish, a problem weed worldwide, is a severe dicotyledonous weed in crops. In Australia, sustained reliance on ALS-inhibiting herbicides to control this species has led to the evolution of many resistant populations endowed by any of several ALS mutations. The molecular basis of ALS-inhibiting herbicide resistance in a novel resistant population was studied. RESULTS: ALS gene sequencing revealed a previously unreported substitution of Tyr for Ala at amino acid position 122 in resistant individuals of a wild radish population (WARR30). A purified subpopulation individually homozygous for the Ala-122-Tyr mutation was generated and characterised in terms of its response to the different chemical classes of ALS-inhibiting herbicides. Whole-plant dose response studies showed that the purified subpopulation was highly resistant to chlorsulfuron, metosulam and imazamox, with LD50 or GR50 R/S ratio of > 1024, > 512 and > 137 respectively. The resistance to imazypyr was found to be relatively moderate (but still substantial), with LD50 and GR50 R/S ratios of > 16 and > 7.8 respectively. In vitro ALS activity assays showed that Ala-122-Tyr ALS was highly resistant to all tested ALS-inhibiting herbicides. CONCLUSION: The molecular basis of ALS-inhibiting herbicide resistance in wild radish population WARR30 was identified to be due to an Ala-122-Tyr mutation in the ALS gene. This is the first report of an amino acid substitution at Ala-122 in the plant ALS that confers high-level and broad-spectrum resistance to ALS-inhibiting herbicides, a remarkable contrast to the known mutation Ala-122-Thr endowing resistance to imidazolinone herbicide. PMID- 22431133 TI - The aging myostatin null phenotype: reduced adiposity, cardiac hypertrophy, enhanced cardiac stress response, and sexual dimorphism. AB - The natural aging process results in the physiological decline of multiple tissues and organ systems. Changes commonly occur with middle age and include decreased skeletal muscle mass, bone mineral density, cardiac output, and insulin sensitivity, and increased adiposity, all of which can contribute to the onset of sarcopenia, osteoporosis, heart failure, or type 2 diabetes. Recent studies suggest that myostatin may influence many of these systems. We therefore sought to determine whether they are affected by aging, especially in 'middle-aged' Mstn /- mice (12-20 months old (m.o.)). Although body weights were similar in wild type (WT) and Mstn-/- mice, lean fat-free mass and skeletal muscles composed of predominantly type I, II, and mixed fibers were significantly heavier in Mstn-/- mice. These differences were accompanied by lower total adiposity, especially in female mice, white and brown fat pad weights, and adipocyte size. Hearts were heavier in Mstn-/- mice across a large age range (3-24 m.o.) and exhibited signs of dilated cardiomyopathy at rest, which include lower strain measurements compared with WT myocardium. However, Mstn-/- mice responded better to isoproterenol stress tests with greater increases in fractional shortening and ejection fraction-differences that were again more apparent in females and which are consistent with physiological cardiac hypertrophy. Spleens and kidneys were also smaller, although histologically normal, in Mstn-/- mice. These data together suggest that attenuating myostatin could potentially prevent or possibly treat pathological conditions that develop with age. Additional studies are nevertheless needed to definitively assess potential risks to cardiac function. PMID- 22431134 TI - Simple localization of nanofiber scaffolds via SU-8 photoresist and their use for parallel 3D cellular assays. AB - A simple, new approach to localizing electrospun nanofiber scaffolds simply by direct writing of SU-8 photoresist followed by UV polymerization is presented. This method allows 3D cell culture arrays to be produced and it can be integrated with microfluidic devices easily to enable low-cost high-throughput cellular assays within an addressable 3D environment, which is attractive for use in drug screening, stem cell research, tissue engineering, and regenerative medicine. PMID- 22431135 TI - Negative self-appraisals and suicidal behavior among trauma victims experiencing PTSD symptoms: the mediating role of defeat and entrapment. AB - BACKGROUND: A considerable body of literature has shown a strong association between posttraumatic stress disorder (PTSD) and suicidal behavior but only a limited number of studies have investigated the putative psychological mechanisms underlying suicidal behavior in PTSD. Based on a recent theoretical model of suicide, the Schematic Appraisals Model, the current study aimed to examine whether perceptions of defeat and entrapment mediated the effects of three types of negative self-appraisals (emotion coping, problem solving, and social support) on suicidal behavior among individuals experiencing PTSD symptoms in the past month. METHODS: The sample comprised 56 individuals who had been previously exposed to a traumatic event and reported at least one PTSD symptom in the past month (confirmed through the Posttraumatic Diagnostic Scale). The mediational analyses were conducted using a nonparametric, bootstrapping method. RESULTS: The results showed that defeat and entrapment fully mediated the effect of all three types of self-appraisals on suicidal behavior. When controlling for PTSD symptom severity, defeat and entrapment continued to mediate fully the effect of two types of self-appraisals, namely the perceived ability to control negative emotions (emotion coping) and the perceived ability to cope with difficult situations/problems (problem solving) on suicidal behavior. CONCLUSIONS: The current findings provide support for the Schematic Appraisals Model of Suicide and suggest that both specific types of negative self-appraisals and general perceptions of defeat and entrapment are strongly related to suicidal behavior in those with PTSD. The findings have important clinical implications. PMID- 22431136 TI - Water chemistry matters in metal-toxicity papers. PMID- 22431138 TI - Tissue distribution of perfluorinated compounds in farmed freshwater fish and human exposure by consumption. AB - In the present study, the levels of 14 perfluorinated compounds (PFCs) were analyzed in the blood, liver, muscle, brain, and eggs of popular farmed freshwater fish from Beijing. Perfluorooctane sulfonate (PFOS) was the predominant compound in all samples, with the highest concentration at 70.7 ng/g wet weight. The highest mean levels of PFOS in all tissues were observed in bighead (1.48-22.5 ng/g wet wt) and the lowest in tilapia (0.260-1.63 ng/g wet wt). In addition, perfluoroundecanoic acid was the second dominant PFC in blood, liver, muscle, and eggs, with the highest concentration at 19.2 ng/g wet weight. However, perfluorodecanoic acid levels (less than the limit of detection [LOD] to 0.963 ng/g wet wt) were similar to or slightly higher than perfluoroundecanoic acid levels (5 degrees in any plane 1 year after surgery was 5.5 %. Proximal third fractures were at a higher risk of postoperative malalignment (17.6 %). The rate of secondary malalignment was 1.4 %. The risk of unplanned reoperation was 9.2 %. CONCLUSION: Intramedullary ETN fixation of tibia fractures results in low rates of delayed union, primary and secondary malalignment, implant-related complications, and secondary surgery. Fibula plating had a negative effect on the healing of the tibia. PMID- 22431142 TI - Klippel-Trenaunay syndrome: a rare cause of disabling pain after a femoral fracture. AB - Klippel-Trenaunay syndrome (KTS) is characterized by a cutaneous vascular nevus of the involved extremity, as well as bone and soft tissue hypertrophy of the extremity and venous malformations. We present the case of a 52-year-old man with a femoral fracture and a history of haemangiomas, limb bone hypertrophy and varicosity. The patient was finally diagnosed with KTS and treated in mini invasive surgery by endomedullary fracture nailing in general anaesthesia. Clinical management was particularly demanding, not only because of the need to monitor the risk of haemorrhage and thrombosis but also because of the onset of a rare picture of neuropathic pain with hyperalgesia and allodynia, never previously reported in patients affected by KTS, that required the administration of major opioid drugs. According to our knowledge, this is the second case of KTS managed for femoral fracture. Unlike the previous report in literature, in this case a severe disabling neuropathic pain complicated the clinical management. PMID- 22431144 TI - The effect of a tin-containing fluoride mouth rinse on the bond between resin composite and erosively demineralised dentin. AB - OBJECTIVES: To evaluate the effect of a tin-containing fluoride (Sn/F) mouth rinse on microtensile bond strength (MUTBS) between resin composite and erosively demineralised dentin. MATERIALS AND METHODS: Dentin of 120 human molars was erosively demineralised using a 10-day cyclic de- and remineralisation model. For 40 molars, the model comprised erosive demineralisation only; for another 40, the model included treatment with a NaF solution; and for yet another 40, the model included treatment with a Sn/F mouth rinse. In half of these molars (n = 20), the demineralised organic matrix was continuously removed by collagenase. Silicon carbide paper-ground, non-erosively demineralised molars served as control (n = 20). Subsequently, MUTBS of Clearfil SE/Filtek Z250 to the dentin was measured, and failure mode was determined. Additionally, surfaces were evaluated using SEM and EDX. RESULTS: Compared to the non-erosively demineralised control, erosive demineralisation resulted in significantly lower MUTBS regardless of the removal of demineralised organic matrix. Treatment with NaF increased MUTBS, but the level of MUTBS obtained by the non-erosively demineralised control was only reached when the demineralised organic matrix had been removed. The Sn/F mouth rinse together with removal of demineralised organic matrix led to significantly higher uTBS than did the non-erosively demineralised control. The Sn/F mouth rinse yielded higher MUTBS than did the NaF solution. CONCLUSIONS: Treatment of erosively demineralised dentin with a NaF solution or a Sn/F mouth rinse increased the bond strength of resin composite. CLINICAL RELEVANCE: Bond strength of resin composite to eroded dentin was not negatively influenced by treatment with a tin-containing fluoride mouth rinse. PMID- 22431145 TI - One-year results of vital pulp therapy in permanent molars with irreversible pulpitis: an ongoing multicenter, randomized, non-inferiority clinical trial. AB - OBJECTIVES: Root canal therapy (RCT) and tooth extraction have been conventional treatment options for management of human mature teeth with irreversible pulpitis. Excellent short-term treatment outcomes of vital pulp therapy with calcium-enriched mixture cement (VPT/CEM), as a new treatment option, on postoperative pain relief was demonstrated; if intermediate- and long-term treatment outcomes of the new treatment are also non-inferior compared to RCT, then VPT/CEM may become a viable treatment option for management of mature teeth with irreversible pulpitis. MATERIALS AND METHODS: In 23 healthcare centers, 407 9- to 65-year-old patients were randomly allocated into two study arms including one-visit RCT (reference treatment; n = 202) and VPT/CEM (alternative treatment; n = 205). Six- and twelve-month clinical and radiographic successes were assessed. RESULTS: Mean follow-up times at 6- and 12-month follow-ups were "6.70 +/- 0.68 and 6.72 +/- 0.71 months" and "12.96 +/- 0.67 and 12.90 +/- 0.66 months" in the available cases of RCT and VPT/CEM arms, respectively. Favorable clinical success rates in the two study arms did not show statistical difference; however, the radiographic success rate in the VPT/CEM was significantly greater than RCT arm at the two follow-ups (P < 0.001). The patients' age had no effect on the treatment outcomes (P = 0.231). CONCLUSIONS: Treatment outcomes of VPT/CEM may be superior to RCT in mature molars with irreversible pulpitis. The performance of biomaterials such CEM cement may assist in the shift towards more biologic treatments. CLINICAL RELEVANCE: VPT/CEM may be a realistic alternative treatment for human mature molar teeth with symptoms of irreversible pulpitis; the use of VPT/CEM is highly beneficial for patients as well as general dentists. PMID- 22431146 TI - Digital method for quantification of circumferential periodontal bone level using cone beam CT. AB - OBJECTIVES: The objective of this study is to develop a new approach for radiographically measuring circumferential periodontal bone level using cone beam CT (CBCT) data. Accuracy and precision were assessed using direct probe measurements on a human skull as a reference. MATERIALS AND METHODS: Digital quantification of circumferential periodontal bone levels was conducted considering bone level measurements, infrabony crater, and furcation detection. For this purpose, a human bony cadaver skull with a restoration free dentition was used, showing periodontal bony defects of teeth 15-17,25-27,35-37,45-47 (FDI classification). Image datasets were acquired using a Promax 3D CBCT device (Planmeca Oy, Helsinki, Finland) at 80 kV and 8 mA, 160 MUm voxel size. Circumferential radiographic measurements between cemento-enamel junction and the alveolar crest for the mesial, central, and distal bone levels on the oral and vestibular sides of the examined teeth were carried out based on a prototype of specifically developed software. The measurements were performed by an expert panel of three independent, calibrated, and blinded observers. Manual probe measurements of the periodontal bone loss served as reference standard. RESULTS: The adopted software allowed the quantification of periodontal bone loss at all examined teeth. Overall deviation between radiographic and manual measurements of the observers ranged between 0.36 and 0.69 mm; hereby, 83 % of all results were <0.5 mm. Comparing overall accuracy between the ten turns of radiological measurements, accuracy for all observers ranged from 0.29 to 0.46 mm. The present study design showed a 100 % detection of furcation involvement for radiographic evaluation. CONCLUSIONS: The adoption of a special measurement procedure in terms of a 3D coordinate system, which is placed through and perpendicular to the long axis of the tooth, allows consistent measurement positions of the mesial, central, and distal bone levels both for the oral and vestibular sides of the alveolar crest. In this way, reliable and reproducible quantification of circumferential periodontal bone loss using CBCT data with standardized resolution of 160 MUm can be performed in all three dimensions. CLINICAL RELEVANCE: This new approach of radiographically assessing circumferential periodontal bone level using CBCT data shows a first promising attempt of accurate detection of periodontal bony defects. Yet, possible negative impact of further clinical parameters in terms of artifact occurrence will have to be furthermore carefully investigated. PMID- 22431147 TI - Monodisperse mesocrystals of YF3 and Ce3+/Ln3+ (Ln=Tb, Eu) co-activated YF3: shape control synthesis, luminescent properties, and biocompatibility. AB - A family of monodisperse YF(3), YF(3):Ce(3+) and YF(3):Ce(3+)/Ln(3+) (Ln=Tb, Eu) mesocrystals with a morphology of a hollow spindle can be synthesized by a solvothermal process using yttrium nitrate and NH(4) F as precursors. The effects of reaction time, fluorine source, solvents, and reaction temperature on the synthesis of these mesocrystals have been studied in detail. The results demonstrate that the formation of a hollow spindle-like YF(3) can be ascribed to a nonclassical crystallization process by means of a particle-based reaction route in ethanol. It has been shown that the fluorine sources selected have a remarkable effect on the morphologies and crystalline phases of the final products. Moreover, the luminescent properties of Ln(3+)-doped and Ce(3+)/Ln(3+) co-doped spindle-like YF(3) mesocrystals were also investigated. It turns out that Ce(3+) is an efficient sensitizer for Ln(3+) in the spindle-like YF(3) mesocrystals. Remarkable fluorescence enhancement was observed in Ce(3+)/Ln(3+) co-doped YF(3) mesocrystals. The mechanism of the energy transfer and electronic transition between Ce(3+) and Ln(3+) in the host material of YF(3) mesocrystals was also explored. The cytotoxicity study revealed that these YF(3) -based nanocrystals are biocompatible for applications, such as cellular imaging. PMID- 22431148 TI - Monitoring changes in individual surgeon's workloads using anesthesia data. AB - PURPOSE: We investigated whether changes in the number of cases performed by surgeons can be used as an appropriate surrogate for anesthesia departments' billed units. METHODS: We used both number of cases performed and the American Society of Anesthesiologists' Relative Value GuideTM (ASA RVG) units to assess all operating room anesthetics of an anesthesia group for two sets of 13 four week periods. The units correspond to Canadian basic units and time units. RESULTS: Although the number of ASA RVG units is an economically important variable that quantifies perioperative workload, the number of cases is a suitable surrogate for ASA RVG units when used to monitor individual surgeons. The pooled mean Pearson correlation coefficient between the two variables was r = 0.95, with 95% confidence interval 0.94 to 0.96. In addition, there were essentially none to very weak pairwise correlations among surgeons. CONCLUSIONS: Informal hospital analyses of relative changes in a surgeon's caseload over one year using anesthesia workload data or anesthesia billing data will generally give equivalent results. The principal importance of our findings is that they can be used by anesthesiologists, specifically department heads, in their role as part of operating room committees. Such committees institute plans to revise the caseload of one or a few surgeons, and they then evaluate the results of those plans. The findings of this study are applicable to all anesthesia groups and may be especially valuable to the heads of anesthesiology departments who do not have the data to repeat our analyses. PMID- 22431149 TI - The minute brain of the copepod Tigriopus californicus supports a complex ancestral ground pattern of the tetraconate cerebral nervous systems. AB - Copepods are a diverse and ecologically crucial group of minute crustaceans that are relatively neglected in terms of studies on nervous system organization. Recently, morphological neural characters have helped clarify evolutionary relationships within Arthropoda, particularly among Tetraconata (i.e., crustaceans and hexapods), and indicate that copepods occupy an important phylogenetic position relating to both Malacostraca and Hexapoda. This taxon therefore provides the opportunity to evaluate those neural characters common to these two clades likely to be results of shared ancestry (homology) versus convergence (homoplasy). Here we present an anatomical characterization of the brain and central nervous system of the well-studied harpacticoid copepod species Tigriopus californicus. We show that this species is endowed with a complex brain possessing a central complex comprising a protocerebral bridge and central body. Deutocerebral glomeruli are supplied by the antennular nerves, and a lateral protocerebral olfactory neuropil corresponds to the malacostracan hemiellipsoid body. Glomeruli contain synaptic specializations comparable to the presynaptic "T bars" typical of dipterous insects, including Drosophila melanogaster. Serotonin like immunoreactivity pervades the brain and ventral nervous system, with distinctive deutocerebral distributions. The present observations suggest that a suite of morphological characters typifying the Tigriopus brain reflect a ground pattern organization of an ancestral Tetraconata, which possessed an elaborate and structurally differentiated nervous system. PMID- 22431150 TI - Suppressive effect of flavonoids from Korean Citrus aurantium L. on the expression of inflammatory mediators in L6 skeletal muscle cells. AB - Citrus fruits (Citrus aurantium L.) have long been used as a traditional herbal medicine. The benefits of the flavonoids found in Citrus aurantium L. include anti-inflammation, anti-cancer, anti-viral and anti-bacterial activities, and enhancement of the immune response. The study investigated the effect of the flavonoids isolated from Citrus aurantium L. native to Korea on the production of pro-inflammatory mediators by blocking signal transduction mediated by nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-induced L6 skeletal muscle cells. The flavonoids decreased the production of inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6 and tumor necrosis factor-alpha by suppressing NF-kappaB and MAPKs signal pathways in LPS-induced L6 skeletal muscle cells. These findings suggest that the flavonoids isolated from Korea Citrus aurantium L. might have anti inflammatory effects that regulate the expression of inflammatory mediators in L6 skeletal muscle cells. PMID- 22431151 TI - Development of the juxta-oral organ in rat embryo. AB - The aim of this work is to clarify the development and morphology of the juxta oral organ (JOO) in rat embryos from Day (E)14 to 19. Furthermore, in the region of the JOO, an analysis was made of the expression of the monoclonal antibody HNK 1, which recognizes cranial neural-crest cells. In this study, we report that JOO develops from an epithelial condensation at the end of the transverse groove of the primitive mouth at E14. During E15, it invaginates and is disconnected from the oral epithelium. At E16, the JOO forms an solid epithelial cord with three parts (anterior, middle, and posterior) and is related to the masseter, temporal, medial pterygoid, and tensor veli palatini muscles. During E17-19, no significant changes were detected in their position. Both the mesenchyme caudal to the anlage of the JOO at E14, as well as the mesenchyme that surrounds the bud of the JOO at E15, expressed positivity for HNK-1. Our results suggest that the mesenchyme surrounding the JOO at E15 could emit some inductive signal for the JOO to reach its position at E16. This work shows for the first time that the cranial neural crest-derived mesenchyme participates in the development of the JOO. PMID- 22431152 TI - Femoral fracture rates in people with and without disability. AB - OBJECTIVE: to estimate femoral fracture rates in community-dwelling older people without care need (CCN(-)), in community-dwelling older people with care need (CCN(+)) and in residents of nursing homes (RNH) and to determine their contribution to the overall burden of femoral fractures. METHODS: routine data of more than 1.2 million German people aged 65 years and more were used to calculate sex- and age-specific femoral fracture rates in the three groups CCN(-), CCN(+) and RNH. Those people receiving benefits of the long-term care insurance were defined as having care need. The percentile contribution of the three subpopulations to the overall burden of femoral fractures was determined. RESULTS: during 5,319,438 person-years, 44,000 femoral fractures were recorded. In each of the three subpopulations female and male fracture rates increased with increasing age. Femoral fracture rates of the total subpopulations were 6.13, 34.53 and 43.05 femoral fractures/1,000 person-years in CCN(-), CCN(+) and RNH in women and 2.66, 20.34 and 31.09 in men, respectively. The contribution of people with care need to the overall burden of femoral fractures in older people was about 50%. CONCLUSION: the incidence of femoral fractures was considerably higher in people with care need than in people without care need. This should be considered when planning medical care or targeting preventive measures. PMID- 22431153 TI - A population-based study on dementia and stroke in 97 year olds. AB - BACKGROUND: the number of nonagenarians increases dramatically worldwide. OBJECTIVES: to examine the prevalence of stroke/transient ischaemic attack (TIA) and dementia, their inter-relationship and their relation to 2-year mortality and institutionalisation in 97 year olds. METHODS: a population-based sample of 97 year olds (n=591) was examined. Information on stroke/TIA was obtained from self reports, key informants and hospital discharge registers. Dementia was diagnosed according to DSM-III-R criteria. RESULTS: the response rate was 65%. The prevalence of dementia was 32.7% in men and 59.3% in women (P<0.001). The prevalence of stroke/TIA was 21.5% (17.8% in men, 22.3% in women). Stroke/TIA was related to dementia in women (odds ratio=1.9, 95% CI: 1.2-3.0), but not in men. Dementia, but not stroke/TIA, was related to 2-year mortality and institutionalisation in logistic regression models. CONCLUSION: dementia was very common in this age group, and related to mortality and institutionalisation. Stroke/TIA in 97 year olds showed less association with dementia, mortality and institutionalisation than reported in studies of younger elderly populations. The finding that stroke was not associated with dementia in men needs to be taken cautiously due to the small number of men. The findings also emphasise that more studies are needed to scrutinise the aetiology of dementia in nonagenarians. PMID- 22431154 TI - The impact of visual impairment on Mini-Mental State Examination Scores in the Newcastle 85+ study. AB - BACKGROUND: cognitive test scores and visual acuity are strongly associated in older people. This may be due to poor vision limiting performance on cognitive tasks specifically requiring vision, or an association between visual and neurodegenerative disorders. OBJECTIVE: to explore, using data from the Newcastle 85+ cohort study, the impact of sight impairment (SI) on Mini-Mental State Examination (MMSE) scores and whether reduced scores among SI participants are limited to tasks requiring vision. RESULTS: of 839 participants aged 85 years, 44 (5.2%) were registered SI. Median (inter-quartile range) sMMSE scores were 25 (22 29) for SI and 28 (25-29) for non-SI participants (P=0.006). SI participants had lower subscale scores on tasks requiring vision (P<0.001 for each) but also for some subscale scores not obviously requiring vision: orientation (P=0.018) and repetition (P=0.030). Excluding visual items, there was no significant difference in MMSE scores between those with/without SI. CONCLUSION: SI may be an obstacle to older people completing cognitive assessments including tasks requiring vision. People with SI also scored lower on some tasks not obviously requiring vision. An association between cognitive impairment and SI may exist beyond simply being unable to see the test material in cognitive tests. PMID- 22431155 TI - Tuberculosis in ageing: high rates, complex diagnosis and poor clinical outcomes. AB - BACKGROUND: worldwide, the frequency of tuberculosis among older people almost triples that observed among young adults. OBJECTIVE: to describe clinical and epidemiological consequences of pulmonary tuberculosis among older people. METHODS: we screened persons with a cough lasting more than 2 weeks in Southern Mexico from March 1995 to February 2007. We collected clinical and mycobacteriological information (isolation, identification, drug-susceptibility testing and IS6110-based genotyping and spoligotyping) from individuals with bacteriologically confirmed pulmonary tuberculosis. Patients were treated in accordance with official norms and followed to ascertain treatment outcomes, retreatment, and vital status. RESULTS: eight hundred ninety-three tuberculosis patients were older than 15 years of age; of these, 147 (16.5%) were 65 years of age or older. Individuals >= 65 years had significantly higher rates of recently transmitted and reactivated tuberculosis. Older age was associated with treatment failure (OR=5.37; 95% CI: 1.06-27.23; P=0.042), and death due to tuberculosis (HR=3.52; 95% CI: 1.78-6.96; P<0.001) adjusting for sociodemographic and clinical variables. CONCLUSIONS: community-dwelling older individuals participate in chains of transmission indicating that tuberculosis is not solely due to the reactivation of latent disease. Untimely and difficult diagnosis and a higher risk of poor outcomes even after treatment completion emphasise the need for specific strategies for this vulnerable group. PMID- 22431156 TI - Carbon nanotubes in the liquid phase: addressing the issue of dispersion. AB - The inherent size and hollow geometry with extraordinary electronic and optical properties make carbon nanotubes (CNTs) promising building blocks for molecular or nanoscale devices. Unfortunately, their hydrophobic nature and their existence in the form of agglomerated and parallel bundles make this interesting material inadequately soluble or dispersible in most of the common solvents, which is crucial to their processing. Therefore, various ingenious techniques have been reported to disperse the CNTs in various solvents with different experimental conditions. However, by analyzing the published scientific research articles, it is evident that there is an important issue or misunderstanding between the term "dispersion" and "solubilization". As a result many researchers use the terms interchangeably, particularly when stating the interaction of CNTs with liquids, which causes confusion among the readers, students, and researchers. In this article, this fundamental issue is addressed in order to give basic insight to the researchers who are working with CNTs, as well as to the scientists who deal with nano-related research domains. PMID- 22431157 TI - Sleep disturbances and depressive symptoms in healthy postpartum women: a pilot study. AB - In this pilot study we examined the relationship between objective and subjective sleep disturbances and depressive symptoms in 22 healthy primiparous postpartum women within 3 months after delivery. We found that none of the women in our study had clinically significant depression scores on the Edinburgh Postnatal Depression Scale; nonetheless, a variable duration of night-time sleep from night to night during the 7-day monitoring period and reported awakening too early were significantly correlated with increased depressive symptoms. Results suggest that first-time mothers who complain of irregular night-time sleep duration and waking up too early should be screened and evaluated for potential postpartum depressive symptoms. PMID- 22431158 TI - The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy induced and radiotherapy-induced toxicity. AB - Protection of the patients against the side effects of chemotherapy and radiotherapy regimens has attracted increasing interest of clinicians and practitioners. Caffeic acid phenethyl ester (CAPE), which is extracted from the propolis of honeybee hives as an active component, specifically inhibits nuclear factor kappaB at micromolar concentrations and show ability to stop 5 lipoxygenase-catalysed oxygenation of linoleic acid and arachidonic acid. CAPE has antiinflammatory, antiproliferative, antioxidant, cytostatic, antiviral, antibacterial, antifungal and antineoplastic properties. The purpose of this review is to summarize in vivo and in vitro usage of CAPE to prevent the chemotherapy-induced and radiotherapy-induced damages and side effects in experimental animals and to develop a new approach for the potential usage of CAPE in clinical trial as a protective agent during chemotherapy and radiotherapy regimens. PMID- 22431159 TI - Deep intronic APC mutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis. AB - To uncover pathogenic deep intronic variants in patients with colorectal adenomatous polyposis, in whom no germline mutation in the APC or MUTYH genes can be identified by routine diagnostics, we performed a systematic APC messenger RNA analysis in 125 unrelated mutation-negative cases. Overall, we identified aberrant transcripts in 8% of the patients (familial cases 30%; early-onset manifestation 21%). In eight of them, two different out-of-frame pseudoexons were found consisting of a 167-bp insertion from intron 4 in five families with a shared founder haplotype and a 83-bp insertion from intron 10 in three patients. The pseudoexon formation was caused by three different heterozygous germline mutations, which are supposed to activate cryptic splice sites. In conclusion, a few deep intronic mutations contribute substantially to the APC mutation spectrum. Complementary DNA analysis and/or target sequencing of intronic regions should be considered as an additional mutation discovery approach in polyposis patients. PMID- 22431160 TI - IFN-gamma and IP-10 in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia. AB - BACKGROUND: Interferon-gamma (IFN-gamma) and interferon-inducible protein of 10 kDa (IP-10) are potent inflammatory mediators and contribute to acute lung injury in adults. Recently, a potential role for IFN-gamma and IP-10 in the pathogenesis of bronchopulmonary dysplasia (BPD) has been reported in animal models. OBJECTIVE: To study the association between IFN-gamma and IP-10 in tracheal aspirate (TA) and the development of BPD in premature infants. DESIGN/METHODS: TA samples collected within 48 hr after birth from 79 mechanically ventilated premature neonates [gestational age (GA) <30 weeks (w), birth weight (BW) <1,250 g (g)] were analyzed. IFN-gamma was measured in a subgroup of 38 infants by using a biochip multi-analyte immunoassay. The level of IP-10 was determined using a commercially available ELISA kit. Total protein in TA was measured by Bradford assay to correct for sampling related dilution. BPD was defined as the need of supplemental oxygen at 36 weeks postmenstrual age (PMA). RESULTS: Twenty infants (GA 26.4 +/- 1.9w, BW 860 +/- 201 g) survived without BPD at 36 weeks PMA and 59 infants (GA 25.5 +/- 1.5w, BW 751 +/- 163 g) died before 36 weeks PMA or developed BPD. The mean IFN-gamma level was higher in infants who died or developed BPD (9.7 +/- 2.8 vs. 3.1 +/- 1.1 pg/ml, P = 0.03). Similarly, the mean IP-10 level was higher in infants who died or developed BPD (63.4 +/- 17.5 pg/ml) compared to those who survived without BPD (18.5 +/- 7.5 pg/ml, P = 0.02). CONCLUSIONS: Higher IFN-gamma and IP-10 levels in TA samples are associated with the development of BPD or death in premature infants. PMID- 22431161 TI - Galectin-4, a novel neuronal regulator of myelination. AB - Myelination of axons by oligodendrocytes (OLGs) is essential for proper saltatory nerve conduction, i.e., rapid transmission of nerve impulses. Among others, extracellular matrix (ECM) molecules, neuronal signaling, and axonal adhesion regulate the biogenesis and maintenance of myelin membranes, driven by polarized transport of myelin-specific proteins and lipids. Galectin-4, a tandem-repeat type lectin with affinity to sulfatide and nonsialylated termini of N-glycans, has the ability to regulate adhesion of cells to ECM components and is also involved in polarized membrane trafficking. We, therefore, anticipated that galectin-4 might play a role in myelination. Here, we show that in developing postnatal rat brains galectin-4 expression is downregulated just before the onset of myelination. Intriguingly, when immature OLGs were treated with galectin-4, OLG maturation was retarded, while a subset of the immature OLGs reverted to a morphologically less complex progenitor stage, displaying concomitantly an increase in proliferation. Similarly, myelination was inhibited when galectin-4 or anti-galectin-4 antibodies were added to co-cultures of dorsal root ganglion neurons and OLGs. Neurons and OLGs were identified as a possible source of galectin-4, both in vitro and in vivo. In culture, neurons but not OLGs released galectin-4. Interestingly, in co-cultures, a reduced release of endogenous galectin-4 correlated with the onset of myelination. Moreover, galectin-4 reactive sites are transiently expressed on processes of premyelinating primary OLGs, but not on neurons. Taken together, these results identify neuronal galectin-4 as a candidate for a soluble regulator of OLG differentiation and, hence, myelination. (c) 2012 Wiley Periodicals, Inc. PMID- 22431163 TI - A century of miners' compensation in South Africa. AB - The year 2011 marked the centenary of compensation legislation for miners' lung disease in South Africa. This commentary aims to demonstrate that the current compensation system does not serve its intended beneficiaries, particularly the large population of former gold miners affected by high rates of silicosis and tuberculosis. The system has a complex legislative history, reflecting contending political, and economic forces, and characterized by racial discrimination. The financial basis of the system is currently in crisis owing to historical underfunding and failure to take into account the mounting burden of disease among black former miners. The real value of compensation awards fell sharply between 1973 and 1993, only partly recovering in recent years. Barriers to claiming benefits, particularly by black former miners who know little about the process, have been extensively documented. Integration of miners' compensation into general workers' compensation has been mooted since the 1980s but has stalled, owing to the high cost of closing the gap between the mostly inferior financial benefits under the mining legislation and those available under workers' compensation legislation. A recent constitutional court decision has opened the way for unprecedented civil litigation against the gold mining industry for silicosis, adding to the pressure for reform. A number of changes are called for: harmonization of financial benefits with retention of certain of the special arrangements for miner claims, a regional cross-border system of medical examination points for former miners, education of miners about the system, and some degree of privatization of claims processing. PMID- 22431164 TI - Palliative stenting of patent ductus arteriosus in older children and young adults with congenital cyanotic heart disease. AB - OBJECTIVE: To describe the indications, technique and results (early and short term follow-up) of palliative patent ductus arteriosus (PDA) stenting in selected patients (2 years and older) with congenital cyanotic heart disease with reduced pulmonary blood flow who were not candidates for definitive surgery in the immediate future. BACKGROUND: Stenting of PDA as a palliation has been advocated as safe and effective procedure in neonates, but this modality is underutilized for children and adults. METHODS: Hospital records of patients (>=2 years) undergoing PDA stenting between January 2007 and September 2009 were reviewed. The access and approach was dictated by the anatomy of the PDA. A coronary guiding catheter or a long sheath was used to access the PDA. Coronary or peripheral stents were used for stenting. RESULTS: Fifteen patients with median age 14 years (range: 2-18 years); median weight 17.5 kg (range: 7-57 Kg) were included. Indication for intervention was hypoxia (mean saturation 69% +/- 8.9%, hemoglobin 19.8 +/- 2.69 g/dl), unsuitable anatomy or economic considerations. Successful stenting was accomplished in all (mean fluoroscopy time of 24.6 +/- 16.7 min) with no complications and the saturations improved to mean of 88% +/- 2.3 %. The most recent oxygen saturations on follow-up (median: 13 months; range: 1-21 months) were 82% +/- 2.8%. One patient underwent corrective repair. CONCLUSION: PDA stenting can provide effective palliation in selected older patients with cyanotic congenital heart disease. PMID- 22431165 TI - Insights into the molecular mechanism of tolerance to carboxylic acid amide (CAA) fungicides in Pythium aphanidermatum. AB - BACKGROUND: Tolerance to the oomycete-specific carboxylic acid amide (CAA) fungicides is a poorly understood mechanism in Pythium species. The root-rot and damping-off causative agent Pythium aphanidermatum and the CAA fungicide mandipropamid (MPD) were used to investigate the molecular basis of CAA tolerance. RESULTS: Five genes putatively involved in carbohydrate synthesis were identified and characterised: one chitin synthase gene, PaChs, and four cellulose synthase genes PaCesA1 to PaCesA4, of which PaCesA3 encodes the MPD target enzyme. These genes were differentially expressed throughout the life cycle of P. aphanidermatum. Mycelium treated with MPD concentrations slightly affecting mycelial growth did not cause a change in PaCesA3 expression nor a strong upregulation of PaCesA homologues. The high tolerance level of P. aphanidermatum and the lack of PaCesA upregulation imply that MPD tolerance is the result of a specific amino acid configuration in the cellulose synthase 3 (CesA3) target enzyme. Indeed, P. aphanidermatum displays the amino acid L1109 which is also associated with MPD resistance in artificial mutants of Phytophthora species. CONCLUSION: It is concluded that MPD tolerance in P. aphanidermatum is not caused by compensatory mechanisms but most likely by an inherent target-site configuration in PaCesA3 that hinders MPD binding to the enzyme pocket. PMID- 22431166 TI - In-hospital and 1-year outcomes with drug-eluting versus bare metal stents in saphenous vein graft intervention: a report from the EVENT registry. AB - OBJECTIVES: To compare outcomes of patients receiving drug-eluting stents (DES) versus bare metal stents (BMS) during percutaneous coronary intervention (PCI) of saphenous vein bypass grafts (SVG). BACKGROUND: Long-term benefits of DES versus BMS are well established for native vessel PCI. Benefit in patients undergoing SVG intervention is less certain. We used data from a multicenter registry (evaluation of drug eluting stents and ischemic events, EVENT) to compare outcomes among patients treated with DES versus BMS 1-year following SVG interventions. METHODS: Between July 2004 and December 2007, 684 patients in EVENT underwent SVG PCI (515 DES only, 169 BMS only). The primary endpoint was a composite of death, myocardial infarction (MI), and target lesion revascularization between hospital discharge and 1-year follow-up. Propensity score stratification was used to adjust for differences between groups. RESULTS: Baseline demographic and clinical characteristics of patients treated with DES and BMS were similar. The DES group had fewer men and a higher prevalence of prior PCI. Patients receiving DES had less angiographic thrombus, less frequent use of embolic protection devices, greater total stent length, and smaller maximum stent diameters. Unadjusted outcomes between discharge and 1-year follow up did not differ between the groups. After risk adjustment, the primary outcome was less frequent among patients treated with DES (adjusted HR = 0.48, 95% CI = 0.27-0.84, P < 0.01) with similar relative benefits across the individual endpoints. CONCLUSIONS: Among patients undergoing SVG PCI in a "real world" registry analyzed using propensity score stratification, treatment with DES compared with BMS was associated with reduced MACE at 1 year following PCI. PMID- 22431167 TI - Verdicts on malpractice claims after thyroid surgery: emerging trends and future directions. AB - BACKGROUND: Few investigations have addressed malpractice litigation after thyroid surgery. The purpose of this medico-legal review was to provide a more comprehensive picture of medico-legal trends in thyroid surgery. METHODS: Reviewed were all expert opinions on claims of malpractice after thyroid surgery, commissioned between 1995 and 2010 at 1 tertiary center, and their corresponding verdicts. RESULTS: Forty-three of 75 malpractice claims involved recurrent laryngeal nerve (RLN) palsy (21 unilateral and 22 bilateral palsies), with a 45% tracheostomy rate for bilateral RLN palsy. Twenty-one claims concerned permanent hypoparathyroidism. Since 2007, intraoperative nerve monitoring (IONM) has become the subject of pleading in 4 of 7 malpractice claims involving unilateral or bilateral RLN palsy. In none of these cases did IONM follow international standards, resulting in 3 plaintiff verdicts. CONCLUSION: The growing appreciation that standardized IONM can prevent bilateral RLN palsies after signal loss on the initial side of resection may become increasingly relevant to malpractice litigation. PMID- 22431168 TI - Development of QSARs for the toxicity of chlorobenzenes to the soil dwelling springtail Folsomia candida. AB - To meet the goals of Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) as formulated by the European Commission, fast and resource effective tools are needed to predict the toxicity of compounds in the environment. We developed quantitative structure-activity relationships (QSARs) for the toxicity of nine chlorinated benzenes to the soil-dwelling collembolan Folsomia candida in natural LUFA2.2 (Landwirtschaftliche Untersuchungs und Forschungsanstalt [LUFA]) standard soil and in Organisation for Economic Co operation and Development artificial soil. Toxicity endpoints used were the effect concentrations causing 10% (EC10) and 50% (EC50) reduction in the reproduction of the test organism over 28 d, while lethal effects on survival (LC50) were used for comparisons with earlier studies. Chlorobenzene toxicity was based on concentrations in interstitial water as estimated using nominal concentrations in soil and literature soil-water partition coefficients. Additionally, for LUFA2.2 soil the estimated concentrations in interstitial water were experimentally determined by solid-phase microextraction measurements. Measured and estimated concentrations showed the same general trend, but significant differences were observed. With the exception of hexachlorobenzene, estimated EC10 and EC50 values were all negatively correlated with their logK(ow) and QSARs were developed. However, no correlation for the LC50 could be derived and 1,2,4,5-tetrachlorobenzene and hexachlorobenzene had no effect on adult survival at all. The derived QSARs may contribute to the development of better ecotoxicity-based models serving the REACH program. PMID- 22431169 TI - Synthesis and characterization of amphiphilic reduced graphene oxide with epoxidized methyl oleate. AB - Amphiphilic reduced graphene oxide is obtained by oleo-functionalization with epoxidized methyl oleate (renewable feedstock) using a green process. The excellent diverse solvent-dispersivity of the oleo-reduced amphiphilic graphene and its reduction chemistry are confirmed in this study. Oleo-reduction of amphiphilic graphene is amenable to industrially viable processes to produce future graphene-based polymer composites and systems. PMID- 22431170 TI - Chemical castration and anti-androgens induce differential gene expression in prostate cancer. AB - Endocrine therapy by castration or anti-androgens is the gold standard treatment for advanced prostate cancer. Although it has been used for decades, the molecular consequences of androgen deprivation are incompletely known and biomarkers of its resistance are lacking. In this study, we studied the molecular mechanisms of hormonal therapy by comparing the effect of bicalutamide (anti androgen), goserelin (GnRH agonist) and no therapy, followed by radical prostatectomy. For this purpose, 28 men were randomly assigned to treatment groups. Freshly frozen specimens were used for gene expression profiling for all known protein-coding genes. An in silico Bayesian modelling tool was used to assess cancer-specific gene expression from heterogeneous tissue specimens. The expression of 128 genes was > two-fold reduced by the treatments. Only 16% of the altered genes were common in both treatment groups. Of the 128 genes, only 24 were directly androgen-regulated genes, according to re-analysis of previous data on gene expression, androgen receptor-binding sites and histone modifications in prostate cancer cell line models. The tumours containing TMPRSS2-ERG fusion showed higher gene expression of genes related to proliferation compared to the fusion-negative tumours in untreated cases. Interestingly, endocrine therapy reduced the expression of one-half of these genes and thus diminished the differences between the fusion-positive and -negative samples. This study reports the significantly different effects of an anti-androgen and a GnRH agonist on gene expression in prostate cancer cells. TMPRSS2-ERG fusion seems to bring many proliferation-related genes under androgen regulation. PMID- 22431173 TI - Cytoplasmic vacuolization during exposure to drugs and other substances. AB - Cytoplasmic vacuolization upon exposure to a variety of chemicals and bioactive substances has been extensively reported. Nearly 30 years have passed since the description by Nobel Laureate Christian de Duve of the mechanism underlying the lysosomal accumulation of lipophilic weak bases referred to these substances as lysosomotropic agents. It has now been revealed, however, that vacuolization occurs upon exposure to compounds other than lipophilic weak bases. Vacuolization of organelles/vesicles other than acidic compartments has also now been reported. In this mini-review, we provide an overview of the origin, mechanism, and possible outcomes of cellular vacuolization during exposure to substances with lysosomotropic as well as other properties. PMID- 22431174 TI - Effects of clothianidin exposure on sperm quality, testicular apoptosis and fatty acid composition in developing male rats. AB - Clothianidin (CTD) is one of the latest members of the synthetic organic insecticides, the neonicotinoids. In the present study, it was aimed to investigate if daily oral administration of CTD at low doses for 90 days has any deleterious effects on reproductive functions of developing male rats. Animals were randomly divided into four groups of six rats each, assigned as control rats, or rats treated with 2 (CTD-2), 8 (CTD-8) or 32 (CTD-32) mg CTD/kg body weight by oral gavage. The significant decreases of the absolute weights of right cauda epididymis and seminal vesicles, and body weight were detected in the animals exposed to CTD administration at 32 mg/kgBW/day. Epididymal sperm concentration decreased significantly in CTD-32 group and the abnormal sperm rates increased in CTD-8 and CTD-32 groups when compared to control group. The testosterone level was significantly decreased in CTD-32 group when compared to control group. The administration of all CTD doses resulted in a significant decrease in the level of GSH. The number of TUNEL-positive cells significantly increased in the germinal epithelium of testis of rats exposed to CTD at 32 mg/kgBW/day. In groups CTD-8 and CTD-32, only docosapentaenoic, arachidonic, palmitic and palmitoleic acids were significantly elevated when compared to control. The ratios of 20:4/18:2 and 18:1n-9/18:0 were decreased when rats exposed to CTD. Sperm DNA fragmentation was observed in CTD-32 group, but not CTD 2 and CTD-8. It is concluded that low doses of CTD exposure during critical stages of sexual maturation had moderate detrimental effects on reproductive organ system and more severe effects are likely to be observed at higher dose levels. In addition, the reproductive system may be more sensitive to exposure of CTD even earlier in development (prenatal and early postnatal), and therefore it could be expected that more severe effects could also be observed at the NOAEL dose levels, if dosing had occurred in utero or early postnatal. PMID- 22431175 TI - Characterization of cell proliferation throughout the brain of the African cichlid fish Astatotilapia burtoni and its regulation by social status. AB - New cells are added in the brains of all adult vertebrates, but fishes have some of the greatest potential for neurogenesis and gliogenesis among all taxa, partly due to their indeterminate growth. Little is known, however, about how social interactions influence cell proliferation in the brain of these fishes that comprise the largest group of vertebrates. We used 5-bromo-2'-deoxyuridine (BrdU) to identify and localize proliferation zones in the telencephalon, diencephalon, mesencephalon, and rhombencephalon that were primarily associated with ventricular surfaces in the brain of the African cichlid fish Astatotilapia burtoni. Cell migration was evident in some regions by 1 day post injection, and many newborn cells coexpressed the neuronal marker HuC/D at 30 days, suggesting they had differentiated into neurons. To test the hypothesis that social status and perception of an opportunity to rise in rank influenced cell proliferation, we compared numbers of BrdU-labeled cells in multiple brain nuclei among fish of different social status. Socially suppressed subordinate males had the lowest numbers of proliferating cells in all brain regions examined, but males that were given an opportunity to rise in status had higher cell proliferation rates within 1 day, suggesting rapid upregulation of brain mitotic activity associated with this social transition. Furthermore, socially isolated dominant males had similar numbers of BrdU-labeled cells compared with dominant males that were housed in a socially rich environment, suggesting that isolation has little effect on proliferation and that reduced proliferation in subordinates is a result of the social subordination. These results suggest that A. burtoni will be a useful model to analyze the mechanisms of socially induced neurogenesis in vertebrates. PMID- 22431176 TI - Cu-catalyzed three-component synthesis of substituted benzothiazoles in water. AB - Three in one: Copper-catalyzed three-component reactions, involving 2 iodoanilines, aldehydes, and sulfur powder, afford 2-phenylbenzothiazoles in water. A variety of 2-substituted benzothiazoles can be obtained in good to excellent yields of up to 96 % (see scheme). PMID- 22431177 TI - Application of in utero electroporation and live imaging in the analyses of neuronal migration during mouse brain development. AB - Correct neuronal migration is crucial for brain architecture and function. During cerebral cortex development (corticogenesis), excitatory neurons generated in the proliferative zone of the dorsal telencephalon (mainly ventricular zone) move through the intermediate zone and migrate past the neurons previously located in the cortical plate and come to rest just beneath the marginal zone. The in utero electroporation technique is a powerful method for rapid gain- and loss-of function studies of neuronal development, especially neuronal migration. This method enabled us to introduce genes of interest into ventricular zone progenitor cells of mouse embryos and to observe resulting phenotypes such as proliferation, migration, and cell morphology at later stages. In this Award Lecture Review, we focus on the application of the in utero electroporation method to functional analyses of cytoskeleton-related protein septin. We then refer to, as an advanced technique, the in utero electroporation-based real-time imaging method for analyses of cell signaling regulating neuronal migration. The in utero electroporation method and its application would contribute to medical molecular morphology through identification and characterization of the signaling pathways disorganized in various neurological and psychiatric disorders. PMID- 22431178 TI - Expression of both hepatocellular carcinoma and cholangiocarcinoma phenotypes in hepatocellular carcinoma and cholangiocarcinoma components in combined hepatocellular and cholangiocarcinoma. AB - Expression of phenotype markers of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) in HCC and CC components of 20 combined hepatocellular and cholangiocarcinomas (CHCs) of the liver was investigated immunohistochemically. Both HCC and CC components of all CHCs expressed at least one of the CC phenotype markers [cytokeratin (CK)-7, CK-19, and carbohydrate (CA) 19-9]. HCC components in 90% of CHCs and CC components in 95% of CHCs expressed at least one of these CC phenotype markers in more than 40% of cancer cells. HCC components in all CHCs expressed at least one of the HCC phenotype markers [hepatocyte antigen (HA), alpha-fetoprotein (AFP), and canalicular carcinoembryonic antigen]. HCC components in 90% of CHCs and CC components in 75% of CHCs expressed HA, AFP, or both. HCC components in 75% of CHCs and CC components in 60% of CHCs expressed HA, AFP, or both in more than 10% of cancer cells. The present results show that both HCC and CC components of most of the CHCs expressed both HCC and CC phenotypes, supporting the hypothesis that CHC originates from a hepatic progenitor cell capable of differentiating into hepatocytes and cholangiocytes. PMID- 22431179 TI - Immunohistochemical study of metaplastic carcinoma and central acellular carcinoma of the breast: central acellular carcinoma is related to metaplastic carcinoma. AB - Metaplastic breast cancers (MBCs) [spindle cell carcinoma (SpCC), squamous cell carcinoma (SCC), and matrix-producing carcinoma (MPC)] and invasive carcinomas with central acellular zones (CACs) were analyzed with respect to biological potential by immunohistochemical analyses. Specimens from 40 patients [20 with MBCs (7 with SCC, 6 with SpCC, 5 with MPC, and 2 with mixed type)] and 20 with CACs were analyzed using antibodies to cytokeratin (CK) 8, 5/6, 14, AE1/AE3, 34alphaE12, involucrin, c-kit, vimentin (VIM), alpha-smooth muscle actin, p63, epidermal growth factor receptor, epithelial cell adhesion molecule, and estrogen receptor (ER)/progesterone receptor (PR)/HER2. Expression of CK5/6, 34betaE12, VIM, nuclear p63, and cytoplasmic p63 was significantly higher with MBCs than CACs (38%/13%, 70%/43%, 85%/33%, 68%/40%, and 48%/18%, respectively). Other markers were expressed at various levels in these tumors, but the difference between them was not significant. Eighteen MBC and 8 CAC cases were triple (ER/PR/HER2) negative; 17 MBCs and 7 CACs were basal-like tumors. Several differences were seen in MBCs and CACs, but they were heterogeneous, differentiating multipotentially into mesenchymal, myoepithelial, basal-like phenotypes with "stem cell-like" features. Thus, CACs are related to MBCs by immunohistochemical analyses as well as according to morphological findings. PMID- 22431180 TI - Cell biological characterization of a multidomain adaptor protein, ArgBP2, in epithelial NMuMG cells, and identification of a novel short isoform. AB - ArgBP2 is a member of the SoHo (sorbin-homology) family of adaptor proteins believed to play roles in cell adhesion, cytoskeletal organization, and signaling. We show here a novel splicing isoform of ArgBP2, i.e., ArgBP2TM, composed of only three SH3 (src-homology 3) domains and structurally similar to vinexinbeta. We then characterized the biochemical and cell biological properties of ArgBP2 to compare these with vinexin. Similar to vinexin, ArgBP2 was enriched at focal adhesions in REF52 fibroblast cells and induced anchorage-dependent extracellular signal-regulated kinase activation in NIH3T3 fibroblast cells. In epithelial NMuMG cells, immunofluorescence analyses revealed localization of ArgBP2 at tight junctions (TJs), whereas vinexin was distributed in cytoplasm as well as cell-cell boundaries. During TJ formation, recruitment of ZO-1 to TJs was followed by ArgBP2. Based on mutation analyses, a second SH3 domain was found to be important for ArgBP2 localization to the cell-cell contact sites. These data suggest some role of ArgBP2 in NMuMG cells at TJs that may be distinct from the function of vinexin. PMID- 22431181 TI - Significance of broad distribution of electron-dense deposits in patients with IgA nephropathy. AB - Immunoglobulin A nephropathy (IgAN) is characterized by mesangial cell proliferation and mesangial expansion with mesangial depositions of IgA. We have found that electron-dense deposits (EDD) are often observed in areas other than paramesangial areas in glomeruli. To compare electron microscopic findings with light microscopic findings and clinical data, we examined the biopsies from 178 patients with IgAN. Patients were divided into two groups: group A had only paramesangial deposits and group B had deposits not only in paramesangial areas but also in other areas. All patients examined in this study had EDD in glomerular paramesangial areas. Thirty-six patients were included in group B. Cellular crescent formation in glomeruli and urinary protein in group B were significantly higher than those in group A (P < 0.01). Serum albumin and estimated glomerular filtration rate (eGFR) in group B were significantly lower than those in group A (P < 0.05). Group B showed a significant positive correlation with histological severity, which is defined in the Japanese Clinical Guidelines on IgAN. In patients with broad distribution of EDD, urinary protein was significantly increased (P < 0.05). Detailed observation of EDD distribution has an impact on evaluation of the disease activity of IgAN. PMID- 22431182 TI - Postinflammation stage of autoimmune orchitis induced by immunization with syngeneic testicular germ cells alone in mice. AB - We previously established an immunological infertility model, experimental autoimmune orchitis (EAO), which can be induced by two subcutaneous injections of viable syngeneic testicular germ cells on days 0 and 14 in mice without using any adjuvant. In this EAO model, CD4+ T-cell-dependent lymphocytic infiltration and immune deposits were found with spermatogenic disturbance on day 120. However, the late stage of EAO (= postactive inflammation stage on day 365) has not yet been investigated. Therefore, we investigated the histopathological characteristics of the late stage. The results revealed that the lymphocytic infiltration finally resolved; however, the seminiferous epithelium persistently showed maturation arrest and the Sertoli cell-only feature. In the seminiferous tubules showing maturation arrest, both proliferation and apoptosis of germ cells had occurred simultaneously. It was also noted that there were deposits of immunoglobulin G and the third component of complement on the thickened basement membrane of seminiferous tubules in the late stage of EAO. These results indicate that histopathology after active inflammation in EAO comprises persistent damage to the seminiferous epithelium and may resemble the histopathology of "idiopathic disturbance of spermatogenesis" in man. PMID- 22431183 TI - Mucin-rich salivary duct carcinoma with signet-ring cell feature ex pleomorphic adenoma of the submandibular gland: a case report of an unusual histology with immunohistochemical analysis and review of the literature. AB - Salivary duct carcinoma (SDC) is a highly aggressive salivary gland carcinoma, and the mucin-rich variant of SDC (mSDC) is extremely rare. We report herein one case of salivary mSDC, showing predominantly signet-ring cell features. The patient was an 84-year-old Japanese woman, who noticed swelling in the left submandibular region. The tumor consisted of two components: one was of mSDC, which contained numerous signet-ring cells in large mucinous lakes, whereas the other was of preexisting pleomorphic adenoma (PA), which showed a hyalinized nodule. mSDC was markedly positive for mucin staining. Signetring cells in the mSDC component were immunopositive for androgen receptor, gross cystic disease fluid protein-15, MUC1, MUC2, MUC5AC, MUC5B, and MUC6, but negative for Her-2 and myoepithelial markers. This case was diagnosed as mSDC with the signet-ring cell feature ex PA. We discuss herein the significance of the signet-ring cell feature in mSDC and the mucin pattern of mSDC. PMID- 22431184 TI - Marked infiltration of eosinophils in necrotizing granulomas in the resected hepatic bed after cholecystectomy resulting from gallbladder cancer and metastatic liver cancer is associated with peculiar peripheral eosinophilia. AB - It is known that after transurethral resection of the prostate (TUR-P) or a bladder tumor (TUR-BT), necrotizing granuloma formation associated with massive eosinophil accumulation can be detected at the site of the scar, revealing marked eosinophilia. This condition is called post-TUR prostatitis or cystitis. In the present study, we noticed a similar phenomenon in five patients who underwent cholecystectomy, of whom four had gallbladder adenocarcinoma and one had metastatic liver cancer originating from the rectum. We detected necrotizing granulomas with massive eosinophil accumulation, associated with marked eosinophilia. To induce these phenomena, the interval between the first operation (i.e., cholecystectomy) and the second operation (i.e., resection of the hepatic bed and extrahepatic bile duct) is very important. If the interval was 1 week, no granuloma formation was detected. On the other hand, if it was more than 2 weeks, the resected hepatic bed contained necrotizing granulomas with substantial eosinophil accumulation combined with an increase in peripheral eosinophilia (up to 34% in one case). Secondary resection was necessary to induce eosinophilia after cholecystectomy. In this sense, malignancies possessed a relationship with delayed eosinophilia. In the granulomas, some foreign body-type multinucleated giant cells were positive for both anti-interleukin (IL)-5 and CD68 antibodies. In sharp contrast, no eosinophilia was detected after cholecystectomy, with or without hepatic resection consequent to severe adhesion. Clinicians as well as pathologists should keep in mind that these peculiar phenomena of eosinophil accumulation surrounding the necrotizing granulomas and peripheral eosinophilia after cholecystectomy could occur. PMID- 22431185 TI - Are the adolescent behaviors too risky? A school-based study in a district of West Bengal, India. AB - A cross-sectional study was undertaken among 2068 school-going adolescents of a subdistrict area of West Bengal, India for assessment of entire array of risk behaviors and their correlates. Aggressive, suicidal, substance use and sexual risk behaviors were measured using a self-administered, multi-item, validated questionnaire in the local vernacular. Prevalence of physical fights, weapon carrying in the last 30 days and gang fights in the last 12 months were 27.1%, 7.3% and 13.0%, respectively. Current users of tobacco, alcohol and illicit substances were 7.1%, 3.4% and 2.0%, respectively. Suicidal ideation and attempts were reported by 11.7% and 3.5% of students. Almost one-tenth of respondents had premarital sexual intercourse. Male gender, low subjective economic status, exposure to electronic media and poor academic achievements were associated with most of the studied risk behaviors, except that females showed more propensities to suicidal behavior. The magnitude and pattern of adolescent risk behaviors, though less studied in India, warrants urgent, coordinated actions. PMID- 22431186 TI - Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. AB - Hepatitis C virus (HCV) persistence in the host results from inefficiencies of innate and adaptive immune responses. Most studies addressing the role of innate immunity concentrated on peripheral blood (PB) natural killer (NK) cells, whereas only limited information is available on intrahepatic (IH) NK cells. We therefore examined phenotypic and functional features of IH and PB NK cells in paired liver biopsy and venous blood samples from 70 patients with chronic HCV infection and 26 control persons subjected to cholecystectomy for gallstones as controls. Ex vivo isolated IH NK cells from HCV-infected patients displayed unique phenotypic features, including increased expression of NKp46-activating receptor in the face of reduced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cluster of differentiation (CD) 107a expression, which resulted in impaired degranulation compared with controls. To gain insights into the effect of HCV on NK cells, we exposed peripheral blood mononuclear cells (PBMCs) from patients and healthy donors to cell-culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL, and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. Exposure of PBMCs to HCVcc significantly boosted NK degranulation, pERK1/2, and TRAIL expression in healthy donors, but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-alpha. Purified NK cells showed a minimal, though significant, increase in degranulation and TRAIL expression, both in patients and controls, after exposure to HCVcc. CONCLUSIONS: These findings indicate dysfunctional IH NK cell cytotoxicity associated with TRAIL down-regulation in chronic HCV infection, which may contribute to virus persistence. PB NK cell impairment upon exposure to HCVcc suggests the existence of an accessory cell-dependent NK cell lytic defect in chronic HCV infection predominantly involving the TRAIL pathway. PMID- 22431187 TI - Bone marrow stem cell abnormality and diabetic complications. AB - Long-lasting diabetes impairs the function of multiple organs, which consists of degeneration of various tissues with increasing apoptosis of target cells. Recently, we found that hyperglycemia induced the appearance of abnormal cells in the bone marrow and cell fusion between bone marrow-derived cells and hepatocytes, peripheral neural cells, or renal tubular cells occurred in diabetic animals. Fused cells in these organs expressed TNFalpha, and accelerated apoptosis, suggesting that these events might be a cause of diabetic complications. In this review, we propose a new concept that bone marrow stem cell abnormality causes diabetic complications, and this concept might provide new strategies for treatment of diabetes-associated tissue damage. PMID- 22431188 TI - The effects of school poverty on adolescents' sexual health knowledge. AB - Using National Longitudinal Study of Adolescent Health data, hierarchical linear modeling was conducted to estimate the association of school poverty concentration to the sexual health knowledge of 6,718 adolescents. Controlling for individual socio-economic status, school poverty had modest negative effects on sexual health knowledge. Although not directly associated with sexual health knowledge, after controlling for demographic characteristics, school poverty interactions showed that sexual health knowledge was associated with higher grade point average (GPA) and age. The combination of low GPA and high-levels of school poverty was especially detrimental for students' sexual health knowledge. There are differences in the sexual health knowledge of adolescents attending low poverty and high poverty schools that can be attributed to the school environment. PMID- 22431189 TI - Reversible hydrogenation and bandgap opening of graphene and graphite surfaces probed by scanning tunneling spectroscopy. AB - The effects of hydrogenation on the topography and electronic properties of graphene and graphite surfaces are studied by scanning tunneling microscopy and spectroscopy. The surfaces are chemically modified using an Ar/H(2) plasma. By analyzing thousands of scanning tunneling spectroscopy measurements it is determined that the hydrogen chemisorption on the surface of graphite/graphene opens on average an energy bandgap of 0.4 eV around the Fermi level. Although the plasma treatment modifies the surface topography in an irreversible way, the change in the electronic properties can be reversed by moderate thermal annealing and the samples can be hydrogenated again to yield a similar, but slightly reduced, semiconducting behavior after the second hydrogenation. PMID- 22431190 TI - Interleukin 6 protects H(2)O(2)-induced cardiomyocytes injury through upregulation of prohibitin via STAT3 phosphorylation. AB - OBJECTIVE: Hydrogen peroxide (H(2)O(2)) is a potent reactive oxygen species that causes cardiomyocytes injury. As an important cytokine, interleukin 6 (IL-6) has cardioprotective effects as it plays an essential role in the late phase of preconditioning. Our work is to investigate if IL-6 preconditioning has protective effects on neonatal rat ventricular cardiomyocytes in response to H(2)O(2) and its underlying mechanism. METHODS: Gel-based comparative proteomic approach along with small interfering RNA (siRNA) and Western blot analysis was used to analyse mechanisms of IL-6 preconditioning on H(2)O(2)-induced neonatal rat ventricular cardiomyocytes injury. RESULTS: IL-6 preconditioning protected cardiomyocytes against H(2)O(2)-induced cell death. Proteomic analysis showed that IL-6 pretreatment further increased the expression of prohibitin and improved the viability of cardiomyocytes exposed to H(2)O(2). Knocking down of prohibitin with siRNA abrogated this protection by increasing apoptosis rate. Tyrosine kinase inhibitor AG490 decreased signal transducers and activators of transcription 3 (STAT3) phosphorylation and down-regulated prohibitin expression in cardiomyocytes pretreated with IL-6 and exposed to H(2)O(2), which further dampened the protective effects of IL-6 preconditioning. CONCLUSION: Our results provide direct evidence that prohibitin is a protective factor of IL-6 preconditioning in H(2)O(2)-induced neonatal rat ventricular cardiomyocytes death. The upregulation of prohibitin by IL-6 is, at least, partially regulated through STAT3 phosphorylation. PMID- 22431191 TI - What drives breast cancer heterogeneity: oncogenic events or cell of origin? AB - Breast cancer is known to show considerable inter-tumoural heterogeneity. It is widely accepted that combinations of oncogenic events have a major role in determining tumour phenotype. However, accumulating evidence suggests that the identity of the cell that acquires the first oncogenic event, the so-called cell of origin, may define the molecular subtype of the resulting tumour. Recent work published in the Journal of Pathology by Natrajan and colleagues questions the origin of breast cancer heterogeneity. After studying BRCA1 tumours, they suggest that genomic alterations are not sufficient to determine tumour behaviour. These and other recent observations underscore the importance of defining what is causing tumour heterogeneity, so that appropriate therapy can be given. PMID- 22431192 TI - Impact of vegf on astrocytes: analysis of gap junctional intercellular communication, proliferation, and motility. AB - The purpose of the present study was to investigate the effects of vascular endothelial growth factor (VEGF) on gap junctional intercellular communication (GJIC), cell proliferation, and cell dynamics in primary astrocytes. VEGF is known as a dimeric polypeptide that potentially binds to two receptors, VEGFR-1 and VEGFR-2, however many effects are mediated by VEGFR-2, for example, actin polymerization, forced cell migration, angiogenesis, and cell proliferation. Recently it has been shown that in case of hypoxia, ischemia or injury VEGF is upregulated to stimulate angiogenesis and cell proliferation. Besides this, VEGF reveals a potent therapeutical target for averting tumor vascularization, emerging in bevacizumab, the first humanized anti-VEGF-A antibody for treating recurrent Glioblastoma multiforme. To expand our knowledge about VEGF effects in glial cells, we cultivated rat astrocytes in medium containing VEGF for 1 and 2 days. To investigate the effects of VEGF on GJIC, we microinjected neurobiotin into a single cell and monitored dye-spreading into adjacent cells. These experiments showed that VEGF significantly enhances astrocytic GJIC compared with controls. Cell proliferation measured by BrdU-labeling also revealed a significant increase of astrocytic mitose rates subsequent to 1 day of VEGF exposure, whereas longer VEGF treatment for 2 days did not have additive effects. To study cell-dynamics of astrocytes subsequent to VEGF treatment, we additionally transfected astrocytes with LifeAct-RFP. Live-cell imaging and quantitative analysis of these cells with aid of confocal laser scanning microscopy revealed higher process movement of VEGF-treated astrocytes. In conclusion, VEGF strongly affects cell proliferation, GJIC, and motility in astrocytes. PMID- 22431193 TI - Exchange rates of creatine kinase metabolites: feasibility of imaging creatine by chemical exchange saturation transfer MRI. AB - Creatine (Cr), phosphocreatine (PCr) and adenosine-5-triphosphate (ATP) are major metabolites of the enzyme creatine kinase (CK). The exchange rate of amine protons of CK metabolites at physiological conditions has been limited. In the current study, the exchange rate and logarithmic dissociation constant (pKa) of amine protons of CK metabolites were calculated. Further, the chemical exchange saturation transfer effect (CEST) of amine protons of CK metabolites with bulk water was explored. At physiological temperature and pH, the exchange rate of amine protons in Cr was found to be 7-8 times higher than PCr and ATP. A higher exchange rate in Cr was associated with lower pKa value, suggesting faster dissociation of its amine protons compared to PCr and ATP. CEST MR imaging of these metabolites in vitro in phantoms displayed predominant CEST contrast from Cr and negligible contribution from PCr and ATP with the saturation pulse parameters used in the current study. These results provide a new method to perform high-resolution proton imaging of Cr without contamination from PCr. Potential applications of these finding are discussed. PMID- 22431194 TI - Regulatory variations in the era of next-generation sequencing: implications for clinical molecular diagnostics. AB - With the successful identification of many protein-coding genes, the focus has now shifted toward deciphering functions of non-protein-coding regions that direct spatiotemporal and quantitative aspects of protein expression. Recent advances in our understanding of the regulatory architecture of the human genome coincide with growing evidence that changes in regulatory sequences are associated with human disease. Several recent reviews have highlighted disease causing potential of aberrations in transcriptional and splicing regulatory elements as well as non-protein-coding RNA. Although changes in regulatory sequences generally produce milder biological effects than their protein-coding counterparts, many act as independent risk factors for common complex disorders or as genetic modifiers for "primary" disease-causing loci. Here, we review bioinformatics and experimental approaches that are used to identify regulatory sequences and assess pathogenicity of regulatory changes. We describe the current state of knowledge on disease-causing changes in regulatory sequences, challenge protein-centric views, and discuss complexities and solutions pertaining to the interpretation of regulatory changes in the next-generation sequencing era. PMID- 22431195 TI - Liver transplantation in human immunodeficiency virus/hepatitis C virus coinfected patients: response needed! PMID- 22431196 TI - Work organization and occupational health: perspectives from Latinos employed on crop and horse breeding farms. AB - BACKGROUND: Agriculture is hazardous and increasingly dependent on Latino workers, a vulnerable population. However, little research has studied how work organization influences Latino farmworker health. METHODS: Using a work organization framework, this cross-sectional study describes and compares the work organization and occupational health characteristics of a sample of Latino crop (n = 49) and horse production (n = 54) workers in Kentucky. RESULTS: Crop workers experienced more physical demands, work-related and environmental stressors, and musculoskeletal and ill-health symptoms. Significantly more crop workers indicated work-related illness or missed work due to work-related illness/injury, though one-fourth of both groups reported work-related injury in the past year. A majority of both groups cited exposure to toxic chemicals, a minority of whom received training on their use. CONCLUSION: Further surveillance is needed to understand the rate and precursors of illness/injury in these populations, as is research on the relationship between supervisory practices, psychosocial stressors, and occupational health. PMID- 22431197 TI - Is there no end to the total syntheses of strychnine? Lessons learned in strategy and tactics in total synthesis. AB - From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this Review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis. PMID- 22431198 TI - Enhanced stent imaging improves the diagnosis of stent underexpansion and optimizes stent deployment. AB - OBJECTIVES: To investigate the clinical value and diagnostic accuracy of enhanced stent imaging (ESI) as compared with quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). BACKGROUND: ESI is an image acquisition and processing angiography-based software that improves visualization and provides measurements of deployed stents. METHODS: A total of 40 consecutive patients (42 stents) were studied. Stent deployment was evaluated sequentially and independently by angiography, ESI, and IVUS. Following each imaging modality, the operator determined the necessity of postdilation unrelated to the other modalities. Stent diameters were measured off-line by QCA, ESI, and IVUS at several sites along the deployed stent and compared. RESULTS: Following stent deployment and based solely on angiography, the operator decided to postdilate seven of the 42 stents (16.7%). This decision was not changed after reviewing the ESI images of these seven stents. Of the 35 stents not requiring postdilation based on angiography alone, ESI influenced the operator to change the decision and postdilate 10 of 35 stents (28.6%). The ESI-based measurements had better correlation with IVUS (r = 0.721, P < 0.0001) than did QCA with IVUS (r = 0.563, P < 0.0001). Bland-Altman analysis showed a trend towards better agreement between ESI and IVUS than between QCA and IVUS (mean differences = 0.038 vs. 0.121; P = 0.19, respectively). CONCLUSIONS: ESI is an easy to use modality that enhances stent visualization, helps in the decision making process whether to postdilate the stent, and provides estimation of stent expansion with better correlations than QCA when compared to IVUS. (c) 2012 Wiley Periodicals, Inc. PMID- 22431199 TI - Hearing aid processing changes tone burst onset: effect on cortical auditory evoked potentials in individuals with normal audiometric thresholds. AB - PURPOSE: The validity of using the cortical auditory evoked potential (CAEP) as an objective measure of hearing aid outcome has been questioned in the literature due to stimulus modifications caused by hearing aid processing. This study aimed to investigate the effects of hearing aid processing on the CAEP elicited with tone bursts that may have altered onsets. METHOD: CAEPs to unprocessed and hearing aid-processed tone bursts were obtained from 16 individuals with normal audiometric thresholds when the onset time, level, and signal-to-noise ratio (SNR) were matched between the 2 conditions. Tone bursts processed by the hearing aid were recorded in an anechoic box and were presented through insert receivers. Unprocessed tone bursts were superimposed with hearing aid noise floor to match the SNR of the hearing aid-processed tone bursts. RESULTS: Shortening of rise time and overshoot at the onset of the tone burst were evident in the hearing aid processed stimuli. Statistical analysis of data showed no significant effects of hearing aid processing on the latency or amplitude of CAEP peaks (p > .05). CONCLUSION: The changes in rise time occurring in the tone bursts due to hearing aid processing may not confound CAEP measures that are used to validate hearing aid fitting. PMID- 22431200 TI - Quantum dot nanoarrays: self-assembly with single-particle control and resolution. AB - The develpoment of a highly selective immobilization strategy for the self assembly of quantum dots (QDs) from solution on lithographically defined, biochemically functionalized metal nanopatterns is presented. Nanosale control is achieved for the formation of predominantly single-particle structures consisting of a QD coupled to a metal nanoparticle, and assembled into an ordered nanoarray. PMID- 22431201 TI - Patient preferences for oropharyngeal cancer treatment de-escalation. AB - BACKGROUND: The excellent prognosis of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (SCCs) against severe chemoradiotherapy (CRT) toxicities has opened discussion of deintensification trials. The purpose of this study was to describe the perspective of patients with HPV-positive and HPV-negative disease toward such studies. METHODS: Fifty-one patients with oropharyngeal SCC (post-CRT) underwent semistructured interviews contrasting toxicities of radiotherapy (RT) alone and CRT. Patients were asked what potential difference in cancer survival was acceptable to prefer RT over CRT. Initially, survival rate was the same for both treatments, then the RT rate was reduced until the preference switched. Treatment experience and preference for deintensified CRT were collected. RESULTS: Ninety-percent of patients initially selected RT, but 69% switched to CRT after 0% to 5% reduction in survival. Patients that rated their treatment experience as mild would accept lower survival versus severe treatment (p = .02). Eighty-one percent of patients (33 of 40) indicated they preferred reduced chemotherapy in CRT. CONCLUSION: Patients accept little difference in survival between treatments to avoid toxicity. PMID- 22431202 TI - Recovery of duckweed from time-varying exposure to atrazine. AB - The purpose of the present study was to evaluate the recovery of duckweed (Lemna gibba L. G3) after being removed from multiple duration exposures to the herbicide atrazine. Consequently, L. gibba were exposed under various scenarios to atrazine at nominal concentrations ranging from 5 to 160 ug/L and durations of 1, 3, 5, 7, 9, and 14 d under static-renewal test conditions. Exposures were followed by a recovery phase in untreated media for either 7 or 14 d. The 3-, 5-, 7-, 9-, and 14-d median effective concentration (EC50) values were >137, >137, 124, >77, and >75 ug/L, respectively, based on mean growth rate. No clear effect trends were apparent between exposure duration and the magnitude of effective concentrations (EC50s or EC10s). No phytocidal effects of chlorosis or necrosis were identified for any treatment scenario. Nearly all L. gibba plants transferred from treatment groups of different exposure scenarios to media without atrazine during the recovery phase had growth rates that demonstrated immediate recovery, indicating effects were phytostatic in nature and reversible. Only the 1- and 5-d exposure scenarios had growth rates indicating marginally prolonged recovery at the higher concentrations (160 ug/L; additionally, at 40 ug/L for the 5-d exposure). Time to recovery, therefore, was found to be largely independent of exposure duration except at the highest concentrations assessed. Based on growth rate by interval, all treatments demonstrated recovery by the final assessment interval (days 5-7), indicating complete recovery in all exposure scenarios by 7 d, consistent with the mode of action of atrazine. PMID- 22431203 TI - The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes. AB - MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR 1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic beta-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals. PMID- 22431204 TI - Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells. AB - The existence of multipotent cardiac stromal cells expressing stem cell antigen (Sca)-1 has been reported, and their proangiogenic properties have been demonstrated in myocardial infarction models. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac Sca-1(+) cells up regulates their secretion of proangiogenic factors. We found that Sca-1 is expressed in subsets of mouse cardiac stromal CD31(-) and endothelial CD31(+) cells. The population of Sca-1(+)CD31(+) endothelial cells was significantly reduced, whereas the population of Sca-1(+)CD31(-) stromal cells was increased 1 week after myocardial infarction, indicating their relative functional importance in this pathophysiological process. An increase in adenosine levels in adenosine deaminase-deficient mice in vivo significantly augmented vascular endothelial growth factor (VEGF) production in cardiac Sca-1(+)CD31(-) stromal cells but not in Sca-1(+)CD31(+) endothelial cells. We found that mouse cardiac Sca-1(+)CD31(-) stromal cells predominantly express mRNA encoding A(2B) adenosine receptors. Stimulation of adenosine receptors significantly increased interleukin (IL)-6, CXCL1 (a mouse ortholog of human IL-8), and VEGF release from these cells. Using conditionally immortalized Sca-1(+)CD31(-) stromal cells obtained from wild-type and A(2B) receptor knockout mouse hearts, we demonstrated that A(2B) receptors are essential for adenosine-dependent up-regulation of their paracrine functions. We found that the human heart also harbors a population of stromal cells similar to the mouse cardiac Sca-1(+)CD31(-) stromal cells that increase release of IL-6, IL-8, and VEGF in response to A(2B) receptor stimulation. Thus, our study identified A(2B) adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart. PMID- 22431205 TI - Pharmacologic properties of polyethylene glycol-modified Bacillus thiaminolyticus thiaminase I enzyme. AB - We have previously shown that the bacterial enzyme thiaminase 1 has antitumor activity. In an attempt to make thiaminase I a more effective pharmaceutical agent, we have modified it by adding polyethylene glycol (PEG) chains of various lengths. We were surprised to find that 5k-PEGylation eliminated thiaminase cytotoxic activity in all cell lines tested. Both native thiaminase and 5k PEGylated thiaminase efficiently depleted thiamine from cell culture medium, and both could use intracellular phosphorylated thiamine as substrates. However, native enzyme more effectively depleted thiamine and thiamine diphosphate in RS4 leukemia cell cytosol, and native thiaminase depressed cellular respiration, whereas PEGylated thiaminase did not. Despite the lack of in vitro cytotoxicity, PEGylation markedly increased the in vivo toxicity of the enzyme. Pharmacokinetic studies revealed that the half-life of native thiaminase was 1.5 h compared with 34.4 h for the 5k-PEGylated enzyme. Serum thiamine levels were depleted by both native and 5k-PEGylated enzyme. Despite superior pharmacokinetics, 5k-PEGylated thiaminase showed no antitumor effect against an RS4 leukemia xenograft, in contrast to native thiaminase, which showed antitumor activity. PEGylation of thiaminase I has demonstrated that depression of mitochondrial function contributes, at least in part, to its anticancer activity. PEGylation also enhances plasma retention time, which increased its vivo toxicity and decreased its activity against a leukemia xenograft, the opposite of the desired effects. These studies suggest that the mechanism of anticancer cytotoxicity of thiaminase requires acute depression of cellular respiration, whereas systemic toxicity is related to the duration of extracellular thiamine depletion. PMID- 22431206 TI - Pulmonary function and airway responsiveness in young competitive swimmers. AB - RATIONALE: Strong physical activities are often associated with large lung volumes and relatively reduced flow, which may represent a physiological variant but also an obstructive abnormality. Competitive swimmers have also spirometric values even larger than other athletes, although they are at increased risk for asthma or airway hyperresponsiveness. AIM: We aimed to investigate whether lung volumes increase with duration of swimming training and are related to an obstructive abnormality associated with airway hyperresponsiveness and asthma like symptoms. METHODS: Forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), airway responsiveness, and skin prick test were measured in 34 children/adolescents (age: 7-19 yrs old) trained for competitive swimming. Their "lifetime" exposure, i.e., the hours spent in pool was very strongly correlated with their age at the time of study. The effect of swimming activity was therefore estimated from the relationships between lung function data and age. RESULTS: FVC Z-score was positively correlated with age, indicating that absolute values increased more than expected with normal growth, but FEV(1)/FVC was negatively correlated with age. Although the majority of subjects had allergic sensitization to aeroallergens and about one half had asthma-like symptoms and/or airway hyperresponsiveness, these conditions did not alter the relationships between lung function and age. CONCLUSION: Intense swimming activity may cause a greater than normal lung growth, irrespective of the presence of allergic sensitization or airway hyperresponsiveness. The associated reduction of FEV(1) /FVC may represent a physiological variant rather than a true obstructive abnormality. PMID- 22431207 TI - Topochemical click reaction: spontaneous self-stitching of a monosaccharide to linear oligomers through lattice-controlled azide-alkyne cycloaddition. PMID- 22431208 TI - Impact of different stent alloys on human vascular response to everolimus-eluting stent: an optical coherence tomography study: the OCTEVEREST. AB - BACKGROUND: New generation drug-eluting stents (DES) incorporate thinner struts and novel alloys to improve clinical performance. Nevertheless, the impact of novel stent materials and designs on human vascular response to DES remains elusive. We sought to evaluate the in-vivo coronary artery response to platinum chromium (PtCr) versus cobalt-chromium (CoCr) stents featuring the same durable polymer and antiproliferative drug by optical coherence tomography (OCT). METHODS AND RESULTS: A total of 42 patients with de novo lesions in native coronary vessels was treated with PtCr-everolimus eluting stent (EES; n = 21) or CoCr-EES (n = 21). Angiography, intravascular ultrasound, and OCT were performed at the index procedure and 6-month follow-up. PtCr-EES and CoCr-EES had similar concentric expansion (stent eccentricity index; median 0.91 vs. 0.90, respectively, P = 0.47) and very low rate of strut malapposition (median 1.15 vs. 1.80%, P = 0.92) at post implantation. Proportion of struts embedded in tissue was lower in PtCr-EES compared to CoCr-EES (median 2.67 vs. 15.23%, P < 0.001). The primary prespecified end point, the percentage of uncovered struts per patient at 6 months follow-up, was 8.46% [interquartile range (IQR) = 3.05-17.26] in PtCr-EES and 5.88% (IQR = 1.35-13.27) in CoCr-EES (P = 0.36), whereas malapposed struts were observed in 0.00% (IQR = 0.00-0.25) versus 0.48% (IQR = 0.00-1.44), respectively, (P = 0.10). Strut-level neointimal thickness did not differ between the two platforms (median 0.09 vs. 0.08 mm, P = 0.49). CONCLUSIONS: Acute and mid-term responses to EES using PtCr or CoCr platforms were similar, with concentric stent expansion, low malapposition, similar strut coverage and limited amount of neointima. Conversely, at postprocedure, PtCr-EES had fewer embedded struts compared with CoCr-EES. PMID- 22431209 TI - A mechanics comparison between landing from a countermovement jump and landing from stepping off a box. AB - It is common practice to study jump landing mechanics by having subjects step off a box set at a certain height instead of landing from a jump. This practice assumes that the landing mechanics are similar between stepping off a box and a countermovement jump as long as the heights can be matched. The mechanics of the two methods had never been compared when landing from identical heights. Thus, the purpose of this study was to compare the mechanics of landing from a countermovement jump to landing from a step-off. Participants performed three maximal countermovement jumps. The mechanics of one countermovement jump was compared with a center of mass fall height matched step-off landing. The step-off landing showed a more rapid time to peak ground reaction force (GRF) in both genders and greater GRF peak and loading rate in males only. No difference was observed between joint angles at initial contact; however, the countermovement jump showed significantly greater joint flexion angles at peak GRF for both genders. EMG showed greater muscle activity during the countermovement jump condition in all subjects. It was concluded that countermovement jump landings are different from step-off landings; thus, results from analyses involving step off landings should be taken with caution if the aim is to relate them to landing from a jump. PMID- 22431211 TI - Walking on high heels changes muscle activity and the dynamics of human walking significantly. AB - The aim of the study was to investigate the distribution of net joint moments in the lower extremities during walking on high-heeled shoes compared with barefooted walking at identical speed. Fourteen female subjects walked at 4 km/h across three force platforms while they were filmed by five digital video cameras operating at 50 frames/second. Both barefooted walking and walking on high-heeled shoes (heel height: 9 cm) were recorded. Net joint moments were calculated by 3D inverse dynamics. EMG was recorded from eight leg muscles. The knee extensor moment peak in the first half of the stance phase was doubled when walking on high heels. The knee joint angle showed that high-heeled walking caused the subjects to flex the knee joint significantly more in the first half of the stance phase. In the frontal plane a significant increase was observed in the knee joint abductor moment and the hip joint abductor moment. Several EMG parameters increased significantly when walking on high-heels. The results indicate a large increase in bone-on-bone forces in the knee joint directly caused by the increased knee joint extensor moment during high-heeled walking, which may explain the observed higher incidence of osteoarthritis in the knee joint in women as compared with men. PMID- 22431212 TI - Leg tissue mass composition affects tibial acceleration response following impact. AB - To date, there has not been a direct examination of the effect that tissue composition (lean mass/muscle, fat mass, bone mineral content) differences between males and females has on how the tibia responds to impacts similar to those seen during running. To evaluate this, controlled heel impacts were imparted to 36 participants (6 M and 6 F in each of low, medium and high percent body fat [BF] groups) using a human pendulum. A skin-mounted accelerometer medial to the tibial tuberosity was used to determine the tibial response parameters (peak acceleration, acceleration slope and time to peak acceleration). There were no consistent effects of BF or specific tissue masses on the un-normalized tibial response parameters. However, females experienced 25% greater peak acceleration than males. When normalized to lean mass, wobbling mass, and bone mineral content, females experienced 50%, 62% and 70% greater peak acceleration, respectively, per gram of tissue than males. Higher magnitudes of lean mass and bone mass significantly contributed to decreased acceleration responses in general. PMID- 22431214 TI - Mathematical model to predict drivers' reaction speeds. AB - Mental distractions and physical impairments can increase the risk of accidents by affecting a driver's ability to control the vehicle. In this article, we developed a linear mathematical model that can be used to quantitatively predict drivers' performance over a variety of possible driving conditions. Predictions were not limited only to conditions tested, but also included linear combinations of these tests conditions. Two groups of 12 participants were evaluated using a custom drivers' reaction speed testing device to evaluate the effect of cell phone talking, texting, and a fixed knee brace on the components of drivers' reaction speed. Cognitive reaction time was found to increase by 24% for cell phone talking and 74% for texting. The fixed knee brace increased musculoskeletal reaction time by 24%. These experimental data were used to develop a mathematical model to predict reaction speed for an untested condition, talking on a cell phone with a fixed knee brace. The model was verified by comparing the predicted reaction speed to measured experimental values from an independent test. The model predicted full braking time within 3% of the measured value. Although only a few influential conditions were evaluated, we present a general approach that can be expanded to include other types of distractions, impairments, and environmental conditions. PMID- 22431216 TI - In vivo measurements of moment arm lengths of three elbow flexors at rest and during isometric contractions. AB - The purpose of this study was to determine in vivo moment arm lengths (MAs) of three elbow flexors at rest and during low- and relatively high-intensity contractions, and to examine the contraction intensity dependence of MAs at different joint positions. At 50 degrees , 80 degrees and 110 degrees of elbow flexion, MAs of the biceps brachii, brachialis and brachioradialis were measured in 10 young men using sagittal images of the right arm obtained by magnetic resonance imaging, at rest and during 20% and 60% of isometric maximal voluntary elbow flexion. In most conditions, MAs increased with isometric contractions, which is presumably due to the contraction-induced thickening of the muscles. This phenomenon was especially evident in the flexed elbow positions. The influence of the contraction intensities on the increases in MAs varied across the muscles. These results suggest that in vivo measurements of each elbow flexor MA during contractions are essential to properly examine the effects on the interrelationships between elbow flexion torque and individual muscle forces. PMID- 22431217 TI - Initial ball flight characteristics of curve and instep kicks in elite women's football. AB - Initial ball flight characteristics of curve and instep kicks were investigated. Fifteen international female footballers performed curve and instep kicks from a distance of 20 m from goal and at a 1 m2 target. Seventeen Vicon cameras tracked three-dimensional coordinates of four reflective markers adhered to the ball. Ball flight characteristics were quantified, and the coordinates of the ball relative to the target center were recorded. The lateral launch angle and the angle of the spin axis relative to the horizontal best predicted the horizontal placement of the ball relative to the target. The vertical launch angle, antero posterior velocity and amount of backspin best predicted the vertical coordinate. Regression models demonstrated how carefully controlled the flight characteristics must be with launch angles constrained within 3 degrees to hit the target. Curve kicks were characterized by significantly greater lateral and vertical launch angles, increased sidespin and spin about the antero-posterior axis, and a more vertical spin axis. This information is beneficial for coaches in training players to achieve the characteristics required to score a goal and avoid a defensive wall. For example, if players consistently kick above or below the target, these findings identify the variables that will help rectify that error. PMID- 22431218 TI - Tangential finger forces use mechanical advantage during static grasping. AB - When grasping and manipulating objects, the central controller utilizes the mechanical advantage of the normal forces of the fingers for torque production. Whether the same is valid for tangential forces is unknown. The main purpose of this study was to determine the patterns of finger tangential forces and the use of mechanical advantage as a control mechanism when dealing with objects of nonuniform finger positioning. A complementary goal was to explore the interaction of mechanical advantage (moment arm) and the role a finger has as a torque agonist/antagonist with respect to external torques (+/-0.4 N m). Five 6 df force/torque transducers measured finger forces while subjects held a prism handle (6 cm width * 9 cm height) with and without a single finger displaced 2 cm (handle width). The effect of increasing the tangential moment arm was significant (p < .01) for increasing tangential forces (in >70% of trials) and hence creating greater moments. Thus, the data provides evidence that the grasping system as a rule utilizes mechanical advantage for generating tangential forces. The increase in tangential force was independent of whether the finger was acting as a torque agonist or antagonist, revealing their effects to be additive. PMID- 22431221 TI - Kinematic variability in running: a caution regarding use of the spanning set measure. AB - The spanning set technique quantifies intertrial variability as the span between polynomial curves representing upper and lower standard deviation curves of a repeated movement. This study aimed to assess the validity of the spanning set technique in quantifying variability and specifically to determine its sensitivity to variability presented at different phases of a movement cycle. Knee angle data were recorded from a male participant completing 12 overground running trials. Variability was added to each running trial at five different phases of the running stride. Ten variability magnitudes were also used to assess the effect of variability magnitude on the spanning set measure. Variability was quantified in all trials using mean deviation and the spanning set measure. Results of a repeated-measures ANOVA showed significant differences between the spanning set score for trials using different phases of added variability. In contrast, mean deviation values showed no difference related to the phase of added variability. Therefore, the spanning set technique cannot be recommended as a valid measure of intertrial movement variability. PMID- 22431222 TI - Charge-site-dependent dissociation of hydrogen-rich radical peptide cations upon vacuum UV photoexcitation. AB - Here, 193 nm vacuum ultraviolet photodissociation (VUVPD) was used to investigate the fragmentation of hydrogen-rich radical peptide cations generated by electron transfer reactions. VUVPD offers new insight into the factors that drive radical- and photon-directed processes. The location of a basic Arg site influences photon activated C(alpha)-C(O) bond cleavages of singly charged peptide radical cations, an outcome attributed to the initial conformation of the peptide as supported by molecular dynamics simulated annealing and the population of excited states upon UV excitation. This hybrid ETD/VUVPD method was employed to identify phosphorylation sites of the kinase domain of human TRPM7/ChaK1. PMID- 22431223 TI - Isolation and characterization of cancer stem cells from cervical cancer HeLa cells. AB - Cervical cancer is one of the most common gynecologic malignancies and poses a serious health problem worldwide. Identification and characterization of cervical cancer stem cells may facilitate the development of novel strategies for the treatment of advanced and metastatic cervical cancer. Breast cancer-resistance protein (Bcrp1)-positive cells were selected from a population of parent HeLa cells using flow cytometry. The invasion capacity of Bcrp1-positive and -negative cells was analyzed with a Boyden chamber invasion test. The tumorigenicity of these cells was determined by in vivo transplantation in non-obesity diabetes/severe combined immunodeficiency (NOD/SCID) mice. The Bcrp1-positive subpopulation accounted for about 7% of the parent HeLa cell population. The proliferative capacity of the Bcrp1-positive cells was greater than that of the Bcrp1-negative cells (P < 0.05). In the invasion assay, the Bcrp1-positive cells demonstrated a greater invasive capacity through the artificial basement membrane than their Bcrp1-negative counterparts. Following transplantation of 10(4) cells, only the Bcrp1-positive cells formed tumors in NOD/SCID mice. When 10(5) or 10(6) cells were transplanted, the tumor incidence and the tumor mass were greater in the Bcrp1-positive groups than those in the Bcrp1-negative groups (P < 0.05). The Bcrp1-positive subpopulation cervical cancer stem cells. PMID- 22431224 TI - Insights from comprehensive multiple receptor docking to HDAC8. AB - A systematic investigation of the available crystal structures of HDAC8 and of the influence of different receptor structures and docking protocols is presented. The study shows that the open conformation of HDAC8 may be preferred by ligands with flexible surface binding groups, as such a conformation allows the ligands to minimize their exposure to solvent upon binding. This observation allowed us to rationalize the excellent potency of pyrazole-based inhibitors compared to that of isoxazole-based inhibitors. PMID- 22431225 TI - Density functional investigation of hydrogen gas adsorption on Fe-doped pristine and Stone-Wales defected single-walled carbon nanotubes. AB - The adsorptions of hydrogen molecule of the Fe - doped pristine and Stone - Wales defected armchair (5,5) single - walled carbon nanotubes (SWCNTs) compared with the pristine SWCNT were investigated by using the density functional theory at the B3LYP/LanL2DZ level. The doping of Fe atom into SWCNTs occurring via an exothermic process was found. The adsorptions of hydrogen molecule on the Fe - doped structures of either perfect or SW defected SWCNTs are stronger than on their corresponding undoped structures. The structural and electronic properties of the pristine and SW defected SWCNTs, their Fe - doped structures and their hydrogen molecule adsorptions are reported. PMID- 22431226 TI - Theoretical study of the decomposition mechanisms and kinetics of the ingredients RDX in composition B. AB - RDX as a component in composition B (TNT + RDX) was first studied by us on its mechanism and kinetics of decomposition reactions in this paper. We have pointed out three possible pathways and found a new low-energy process of its decomposition. The N-N bond cleavage in composition B has higher dissociation energies than the monomer, but it is also the initial step. The optimized structures and the frequencies of all the stationary points were calculated at the B3LYP/6-31G(d) level. The minimum-energy paths were obtained by using the intrinsic reaction coordinate (IRC) theory, and the reaction potential energy curve was corrected with zero-point energy. Finally, the rate constants were calculated in a wide temperature region from 200 to 2500 K using TST, TST/Eckart theories. The obtained results also indicate that the tunneling effects are remarkable at low temperature (200 K 2.5%), or (3) BAL fluid culture >10(4) colony-forming units/ml of a respiratory bacterial pathogen requiring change from usual empiric antibiotics. RESULTS: Of the 56 children undergoing FB, there were 25 occasions in 23 children where these procedures altered empiric treatment. Lower airway eosinophilia was identified in 19 (34%) children, BAL microbiology results led to antibiotic changes in 5 (9%) and an unsuspected foreign body was found in another (2%). Strongyloides serology was performed in 38 children, including 12 of the 19 with airway eosinophilia, and was positive in 5 of these 12 children (42%). CONCLUSION: Contrary to some expert recommendations that FB should only be performed when bronchiectasis is localized, our data suggest that FB with BAL should at least be included in the initial investigations of Indigenous children with non-CF bronchiectasis. PMID- 22431242 TI - Role of latency jittering correction in motion-onset VEP amplitude decay during prolonged visual stimulation. AB - Visual evoked potentials to motion-onset stimulation (M-VEPs) gradually attenuate in amplitude during examination. The observed decline in averaged responses can be caused by decreases in single response magnitudes and/or increased variability in a response delays, that is, latency jittering. To illuminate the origins of the suppression of M-VEPs during stimuli repetition, we used correlation technique to estimate an upper bound of possible latency jittering of single sweeps and we evaluated the effect of its correction on the amplitudes of three M VEP dominant peaks P1, N2 and P3. During prolonged visual motion stimulation, the variability of corrective latency shifts in the occipital region increased (r = 0.35: 0.44) and the number of single responses corresponding to the average curve declined in occipital and parietal derivations (r = -0.48: -0.62). While the P1 peak amplitude did not exhibit any time-specific behaviour, the N2 amplitude exhibited a significant decay of 29.4% that was partially reduced to 16.6% in the central occipital derivation by the latency jitter and non-correspondence corrections. The strongest attenuation (32.7%) was observed in the P3 amplitude and was less sensitive to the corrections, dropping only to 27.9%. The main part of the response suppression to repeated motion stimulation was caused by amplitude drop and represents non-stationary process that likely correspond to a fatigue model. The rise of variability in latency jitter correction and the reduction in single responses correlated with the M-VEP were significant factors associated with prolonged motion stimulation. The relation of these parameters to a hypothetical veridical response is ambiguous and can be caused by a time shift of the response or by a change of signal-to-noise ratio. Using selective averaging and latency jitter correction, the effect of response suppression was partially removed. PMID- 22431243 TI - Protein oriented ligation on nanoparticles exploiting O6-alkylguanine-DNA transferase (SNAP) genetically encoded fusion. AB - A bimodular genetic fusion comprising a delivery module (scFv) and a capture module (SNAP) is proposed as a novel strategy for the site-specific covalent conjugation of targeting peptides to nanoparticles. An scFv mutant selective for HER2 tumor antigen is chosen as the targeting ligand. SNAP-scFv is immobilized on magnetofluorescent nanoparticles and its targeting efficiency against HER2 positive cells is assessed by flow cytometry and immunofluorescence. PMID- 22431244 TI - The nature of the [TTF]+...[TTF]+ interactions in the [TTF]2(2+) dimers embedded in charged [3]catenanes: room-temperature multicenter long bonds. AB - The properties of tetrathiafulvalene dimers ([TTF](2)(2+)) and the functionalized ring-shaped bispropargyl (BPP)-functionalized TTF dimers, [BPP-TTF](2)(2+), found at room temperature in charged [3]catenanes, were evaluated by M06L calculations. The results showed that their isolated [TTF](2)(2+) and [BPP-TTF](2)(2+) dimers are energetically unstable towards dissociation. When enclosed in the 4(+) charged central cyclophane ring of charged [3]catenanes (CBPQT(4+)), [TTF](2)(2+) and [BPP-TTF](2)(2+) dimers are also energetically unstable with respect to leaving the CBPQT(4+) ring; since the barrier for the exiting process is only about 3 kcal mol(-1), that is, within the reach of thermal energies at room temperature (neutral [TTF](2)(0) dimers are stable within the CBPQT(4+) ring). However, the [BPP-TTF](2)(2+) dimers in charged [3]catenanes cannot exit, because this would imply breaking the covalent bonds of the BPP-TTF(+) macrocycle. Finally, it was shown that the [TTF](2)(2+), [BPP-TTF](2)(2+) dimers, and charged [3]catenanes are energetically stable in solution and in crystals of their salts, in the first case due to the interactions with the solvent, and in the second case mostly due to cation-anion interactions. In these environmental conditions at room temperature the TTF units of the [BPP-TTF](2)(2+) dimers make short contacts, thus allowing their SOMO orbitals to overlap: a room-temperature multicenter long bond is formed, similar to those previously found in other [TTF](2)(2+) salts and their solutions. PMID- 22431245 TI - Direct attachment of microbial organisms to material surfaces through sequence specific DNA hybridization. AB - A new technique is reported for the attachment of synthetic DNA strands to the surfaces of microbial organisms. This gives algal, bacterial, and fungal cells the ability to bind to complementary strands extending from patterned surfaces that can be produced on platforms such as microfluidic devices. The ability of this method to establish complex 2- and 3-dimensional cocultures comprising multiple organism types is also presented. PMID- 22431247 TI - Intra-abdominal Kaposiform hemangioendothelioma and the benefits of laparoscopic surveillance. AB - We report a case of a neonate presenting with the rare vascular tumor, Kaposiform hemangioendothelioma. She had a lesion arising from the left ovary with multiple intraperitoneal metastases causing small bowel obstruction. We managed this case with primary surgical resection followed by laparoscopic surveillance of the peritoneal cavity and metastectomy. The child is fit and well and free of tumor after 32 months. Neither this presentation of this tumor nor this management approach has been previously described in the literature. PMID- 22431246 TI - Bone density in post-pubertal adolescent survivors of childhood brain tumors. AB - BACKGROUND: Childhood cancer survivors are at high risk for reduced bone mineral density (BMD). Our objective was to determine whether post-pubertal adolescent survivors of brain tumors, whose tumor or treatments placed them at risk for pituitary hormone deficiencies, have low BMD near time of peak bone mass accrual, and to assess risk factors for decreased BMD. PROCEDURE: Chart review of 36 post pubertal adolescents with history of tumor or radiation therapy (RT) of the hypothalamic-pituitary area who had undergone BMD screening via dual-energy X-ray absorptiometry (DXA). RESULTS: Age at DXA was 16.9 +/- 1.9 years (mean +/- SD). Time since diagnosis was 8.5 +/- 3.6 years. Median BMD Z scores were -0.95 (range -2.7 to 1.7) at the femoral neck, -1.20 (-3.6 to 1.8) at the hip, and -0.90 (-3.7 to 1.8) at the spine. Bone mineral apparent density (BMAD) Z scores were -0.23 ( 2.7 to 1.9) at the femoral neck and -0.45 (-3.0 to 2.3) at the spine. Those with history of >=1 fracture had lower BMD Z scores of the femoral neck, total hip, and spine (P < 0.05). Those with treated GH deficiency (GHD) had a higher BMD Z score at the femoral neck, total hip, and spine (P < 0.05) than those not treated. There was no difference in BMD with respect to treatment with chemotherapy, cranial or spinal RT, or hypogonadism. Spontaneous menarche and regular periods did not correlate with BMD. CONCLUSIONS: In post-pubertal adolescent survivors of childhood brain tumors, fracture history and untreated GHD are risk factors for decreased BMD. PMID- 22431248 TI - Meeting report: development of an International Committee on Nutrition & Health for Children with Cancer, International Society of Pediatric Oncology (siop). PMID- 22431250 TI - Altered resting-state connectivity during interictal generalized spike-wave discharges in drug-naive childhood absence epilepsy. AB - PURPOSE: To investigate the intrinsic brain connections at the time of interictal generalized spike-wave discharges (GSWDs) to understand their mechanism of effect on brain function in untreated childhood absence epilepsy (CAE). METHODS: The EEG functional MRI (fMRI) was used to measure the resting state functional connectivity during interictal GSWDs in drug-naive CAE, and three different brain networks-the default mode network (DMN), cognitive control network (CCN), and affective network (AN)-were investigated. RESULTS: Cross-correlation functional connectivity analysis with priori seed revealed decreased functional connectivity within each of these three networks in the CAE patients during interictal GSWDS. It included precuneus-dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and inferior parietal lobule in the DMN; DLPFC inferior frontal junction (IFJ), and pre-supplementary motor area (pre-SMA) subregions connectivity disruption in CCN; ACC-ventrolateral prefrontal cortex (VLPFC) and DMPFC in AN; There were also some regions, primarily the parahippcampus, paracentral in AN, and the left frontal mid orb in the CCN, which showed increased connectivity. CONCLUSIONS: The current findings demonstrate significant alterations of resting-state networks in drug naive CAE subjects during interictal GSWDs and interictal GSWDs can cause dysfunction in specific networks important for psychosocial function. Impairment of these networks may cause deficits both during and between seizures. Our study may contribute to the understanding of neuro-pathophysiological mechanism of psychosocial function impairments in patients with CAE. PMID- 22431251 TI - Cluster analysis of autistic patients based on principal pathogenetic components. AB - We have recently described four principal pathogenetic components in autism: (I) circadian and sensory dysfunction, (II) immune abnormalities, (III) neurodevelopmental delay, and (IV) stereotypic behaviors. Using hierarchical and k-means clustering, the same 245 patients assessed in our principal component analysis can be partitioned into four clusters: (a) 43 (17.6%) have prominent immune abnormalities accompanied by some circadian and sensory issues; (b) 44 (18.0%) display major circadian and sensory dysfunction, with little or no immune symptoms; (c) stereotypies predominate in 75 (31.0%); and (d) 83 (33.9%) show a mixture of all four components, with greater disruptive behaviors and mental retardation. The "immune" component provides the largest contributions to phenotypic variance (P = 2.7 x 10(-45)), followed by "stereotypic behaviors." These patient clusters may likely differ in genetic and immune underpinnings, developmental trajectories, and response to treatment. PMID- 22431252 TI - Association of TNF-alpha and Fas gene promoter polymorphism with the risk of Kashin-Beck disease in Northwest Chinese population. AB - The objective of this study is to investigate the relationship between single nucleotide polymorphisms (SNPs) of the tumor necrosis factor-alpha (TNF-alpha) and Fas genes and Kashin-Beck disease (KBD) in Shaanxi province, Northwest in China. Blood samples of 388 residents were collected from 14 KBD villages in Linyou and Yongshou counties, Shaanxi, Northern of China. One hundred eighty-six cases with KBD and 202 cases of health in KBD areas were diagnosed by "Diagnosis Criterion of Kashin-Beck disease in China (WS/T207- 2010)". The TNF-alpha 308G/A, TNF-alpha -238G/A, and Fas -670A/G SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism in combination with sequence analysis in KBD and healthy control groups. The genotypes and allele frequencies distribution of these SNPs were then analyzed. TNF-alpha -308A allele frequency in KBD patients were significantly higher than that in healthy controls. Although TNF-alpha -238 genotypes and allele frequencies were not significantly different between KBD patients and the healthy controls, GA genotype and A allele frequency in KBD patients were higher than those in healthy controls. The TNF-alpha -308G/A SNPs were associated with the susceptibility of KBD. PMID- 22431253 TI - A new "tool" for transcatheter atrial defect closure: the St. Jude SL2TM sheath. AB - BACKGROUND: Orienting the left atrial disc of an atrial septal defect (ASD) closure device parallel to the septum is important, particularly in cases of ASD with deficient retroaortic rim. Standard vascular sheaths can make this challenging. We report the use of an electrophysiologic sheath, the SL2TM St. Jude Vascular sheath (St. Jude Medical, St. Paul, MN) for closure of ASD. METHODS: All patients undergoing ASD closure between July 2010 and February 2011 at The Children's Hospital at Montefiore in which the SL2 sheath was used were reviewed. RESULTS: Nine patients underwent transcatheter ASD or PFO (1/9) closure with the SL2 sheath. Mean age was 22.7 years (range, 3-58); weight was 46.5 kg (range, 14.7-78.6). The Amplatzer ASD Occluder (AGA Medical Corp., Plymouth, MN) was used in all cases. The mean measurement of the ASDs via "stop-flow" technique was 13.3 mm (range, 4-19). The mean device size was 13.9 mm (range, 5-20) or 105% the size of the defect. The retroaortic rim was deficient (<2 mm) in 3 of 9. ASD closure was achieved in 9 of 9. In all, the left atrial disk was brought toward the atrial septum parallel to the atrial septum, and repositioning or recapturing of the device was unnecessary in any case. Mean fluoroscopy time was 9.3 min (range, 2.2-18). No significant complications. CONCLUSIONS: The SL2 sheath was useful to position the ASD device parallel to the atrial septum, eliminating the need for redeployment during the procedure. This sheath was useful in those cases of deficient retroaortic rim in this study. PMID- 22431255 TI - What is the maximum coordination number in a planar structure? PMID- 22431254 TI - Kir4.1 channels mediate a depolarization of hippocampal astrocytes under hyperammonemic conditions in situ. AB - Increased ammonium (NH(4) (+) ) concentration in the brain is the prime candidate responsible for hepatic encephalopathy (HE), a serious neurological disorder caused by liver failure and characterized by disturbed glutamatergic neurotransmission and impaired glial function. We investigated the mechanisms of NH(4) (+) -induced depolarization of astrocytes in mouse hippocampal slices using whole-cell patch-clamp and potassium-selective microelectrodes. At postnatal days (P) 18-21, perfusion with 5 mM NH(4) (+) evoked a transient increase in the extracellular potassium concentration ([K(+) ](o) ) by about 1 mM. Astrocytes depolarized by on average 8 mV and then slowly repolarized to a plateau depolarization of 6 mV, which was maintained during NH(4) (+) perfusion. In voltage-clamped astrocytes, NH(4) (+) induced an inward current and a reduction in membrane resistance. Amplitudes of [K(+) ](o) transients and astrocyte depolarization/inward currents increased from P3-4 to P18-21. Perfusion with 100 MUM Ba(2+) did not alter [K(+) ](o) transients but strongly reduced both astrocyte depolarization and inward currents. NH(4) (+) -induced depolarization and inward currents were also virtually absent in slices from Kir4.1 -/- mice, while [K(+) ](o) transients were unaltered. Blocking Na(+) /K(+) -ATPase with ouabain caused an immediate and complex increase in [K(+) ](o) . Taken together, our results are in agreement with the hypothesis that reduced uptake of K(+) by the Na(+) , K(+) -ATPase in the presence of NH(4) (+) disturbs the extracellular K(+) homeostasis. Furthermore, astrocytes depolarize in response to the increase in [K(+) ](o) and by influx of NH(4) (+) through Kir4.1 channels. The depolarization reduces the astrocytes' capacity for channel-mediated flux of K(+) and for uptake of glutamate and might hereby contribute to the pathology of HE. PMID- 22431256 TI - Occupational rhinitis and asthma due to EDTA-containing detergents or disinfectants. AB - BACKGROUND: Detergents and disinfectants are an emerging cause of work-related rhinitis and asthma. These products may contain ethylenediamine tetraacetic acid (EDTA). The authors report 10 cases of EDTA-related asthma and/or rhinitis. METHODS: Review of the medical charts of patients who presented with work-related rhinitis (alone or with asthma), with a history of exposure to aerosols of EDTA containing products and who underwent a nasal provocation test (NPT) with tetrasodium EDTA (1-4%) in our occupational health unit. RESULTS: Twenty-eight patients underwent a NPT with EDTA, which was positive in 10 cases. These patients, mostly cleaners or healthcare workers, used spray formulations of cleaning products. CONCLUSIONS: This case series is the first report of EDTA related respiratory disease, documented by a specific test. An irritant mechanism is unlikely. Further studies are required to distinguish between an immunoallergic response and a pharmacological mechanism possibly resulting from calcium chelation, as suggested by animal experiments. A ban of spray preparations would be sufficient to prevent respiratory disease induced by EDTA inhalation, regardless of its mechanism. PMID- 22431257 TI - Trends in adolescent eating behaviour: a multilevel cross-sectional study of 11 15 year olds in Scotland, 2002-2010. AB - BACKGROUND: Improving the diet of the Scottish population has been a government focus in recent years. Health promotion is known to be more effective in affluent groups. Alongside trends in eating behaviour, changes in socioeconomic inequalities must be monitored. METHODS: Eating behaviour data from the 2002, 2006 and 2010 Scotland Health Behaviour in School-Aged Children survey were modelled using multilevel linear modelling. RESULTS: Fruit and vegetable consumption increased between 2002 and 2010 by 0.26 and 0.27 days per week, respectively, while consumption of sweets, chips and crisps fell by 0.73, 1.25 and 0.99 days per week, respectively. An overall healthy eating score, calculated by summing food item weekly consumption, increased significantly (at 95% level of significance) over this period. Fruit and vegetable consumption was more frequent among children with high family affluence (individual measure of socioeconomic status), while consumption of crisps and chips was less frequent. When an interaction term was added between year and family affluence, this was not significant for any outcome. Variance at the education authority and school levels remained significant for all outcomes. CONCLUSIONS: Adolescent eating behaviours in Scotland have improved over time across the family affluence scale gradient as a whole, with persistent inequalities. Alongside population programmes, initiatives directed at more deprived groups are required. PMID- 22431258 TI - Tumor angiogenesis: role in locally aggressive biological behavior of ameloblastoma and keratocystic odontogenic tumor. AB - BACKGROUND: The purpose of this study was to assess and compare angiogenesis in ameloblastoma, keratocystic odontogenic tumors, dentigerous cysts, and normal oral mucosa. METHODS: Angiogenesis was assessed in 28 ameloblastoma-36 keratocystic odontogenic tumors, 28 dentigerous cysts, and 19 normal oral mucosa by measuring the mean vascular density (MVD), total vascular area (TVA) and mean vascular area (MVA). Immunohistochemistry was carried out by using CD105. RESULTS: The nonsignificant difference of MVD was noted between ameloblastoma and keratocystic odontogenic tumors (p = .174). TVA and MVA were significantly higher in ameloblastoma than keratocystic odontogenic tumors, normal oral mucosa, and dentigerous cysts (p < .001). MVD, TVA, and MVA were significantly higher in keratocystic odontogenic tumors than normal oral mucosa and dentigerous cysts (p < .001). CONCLUSION: The results suggest that tumor angiogenesis may play an important role in locally invasive aggressive biologic behavior of ameloblastoma and keratocystic odontogenic tumor. The angiogenesis could be a potent target for developing antiangiogenic therapeutic strategies, particularly in recurrent cases of odontogenic tumors. PMID- 22431259 TI - Formation and evolution of chemical gradients and potential differences across self-assembling inorganic membranes. PMID- 22431260 TI - Effect of percutaneous coronary intervention on quality of life: a consensus statement from the Society for Cardiovascular Angiography and Interventions. AB - Percutaneous coronary intervention (PCI) decreases ischemic complications of acute coronary syndromes. The benefits of PCI in stable ischemic heart disease (SIHD) depend on its effect on quality of life (QoL), including angina, physical activity, and emotional well-being. PCI decreases angina and the need for anti anginal medications, and increases exercise capacity and QoL, compared with baseline status and compared with medical therapy without PCI. These benefits are greater when QOL is markedly impaired by severe angina before the procedure. When considering treatment options for symptomatic SIHD, physicians should consider and provide objective data regarding QoL effects for each treatment strategy. QoL outcomes should be considered in clinical trials, appropriate use criteria, practice guidelines, and reimbursement policies for PCI. PMID- 22431261 TI - Flexible bronchoscopy in managing a child with pulmonary hydatid disease. AB - Few articles have described the airway management of parenchymal lung hydatid cysts complicated by endobronchial or airway involvement, and none have described the use of flexible bronchoscopy (FB) therapeutically in children. We present a child with a ruptured pulmonary hydatid cyst who underwent repeated FB for removal of cystic material from an obstructed right upper lobe segmental bronchus. This child did not require thoracic surgery and made a full clinical recovery, demonstrating that in selected cases FB may offer curative treatment. PMID- 22431262 TI - Chronic pelvic pain syndrome/bladder pain syndrome: taking stock, looking ahead: ICI-RS 2011. AB - This review reflects the presentations and subsequent discussions at the International consultation on Incontinence Research Society's annual meeting. It updates the current definitions and diagnostic and treatment algorithms for bladder pain syndrome and chronic pelvic pain syndrome (non-bacterial prostatitis), highlights some specific basic research findings from discussion participants, looks at what we can hope to eventually learn from a large multicenter National Institutes of Health study, reviews future research pathways as articulated by the National Urologic Research Agenda of the American Urological Association and others, discusses recent therapeutic efforts, and concludes with discussion points from the ICI-RS meeting. PMID- 22431263 TI - Will we ever use stem cells for the treatment of SUI? ICI-RS 2011. AB - AIMS: To review the current state of research in the use of stem cells (SCs) for stress urinary incontinence (SUI) and assess the likelihood of this becoming a relevant treatment option. METHODS: The peer-reviewed literature consisting of relevant clinical and animal studies on the topic of SUI was surveyed and reviewed. RESULTS: Animal studies have demonstrated the potential utility of SCs in promoting functional recovery of the urethra after simulated childbirth injury. Research in animals suggests similar urethral recovery after injection of bone marrow derived mesenchymal SC secretions as after injection of the SCs themselves. Therefore, whether the improvements result from the injection of the SCs themselves or from their secretion of specific proteins is unclear. Early clinical trials have demonstrated the feasibility and short-term safety of injecting muscle-derived SCs into the urethra to treat SUI. CONCLUSIONS: Larger and longer-term clinical trials are needed. Nonetheless, efficacious SC-based therapy for the treatment of SUI is practical, achievable and should be available as a treatment modality in the near future. PMID- 22431264 TI - High-performance and stable organic transistors and circuits with patterned polypyrrole electrodes. AB - High performance p-/n-type transistors and complementary inverter circuits are demonstrated using patterned polypyrrole (PPY) as pure electrodes. Strikingly, these devices show good stability under continuous operation and long-term storage conditions. Furthermore, PPY electrodes also exhibit good applicability in solution-processed and flexible devices. All these results indicate the great potential of PPY electrodes in solution-processed, all-organic, flexible, transparent, and low-power electronics. PMID- 22431265 TI - Optical nanomanipulations of malignant cells: controlled cell damage and fusion. AB - Specifically targeting and manipulating living cells is a key challenge in biomedicine and in cancer research in particular. Several studies have shown that nanoparticles irradiated by intense lasers are capable of conveying damage to nearby cells for various therapeutic and biological applications. In this work ultrashort laser pulses and gold nanospheres are used for the generation of localized, nanometric disruptions on the membranes of specifically targeted cells. The high structural stability of the nanospheres and the resonance pulse irradiation allow effective means for controlling the induced nanometric effects. The technique is demonstrated by inducing desired death mechanisms in epidermoid carcinoma and Burkitt lymphoma cells, and initiating efficient cell fusion between various cell types. Main advantages of the presented approach include low toxicity, high specificity, and high flexibility in the regulation of cell damage and cell fusion, which would allow it to play an important role in various future clinical and scientific applications. PMID- 22431267 TI - Hyperimmunoglobulinemia in pediatric patients with Gaucher disease in Southern Brazil. PMID- 22431266 TI - Male gender bias in autism and pediatric autoimmunity. AB - Male bias in both autism and pediatric autoimmune disease is thought to involve hormonal perturbations in pregnancy or early childhood in the context of genetic control. These early molecular events, at a time of rapid development, are intimately linked to concurrent development in the brain and immune system. It is suggested here that these early regulatory events may overlap between autism and autoimmunity in determining male sex bias and may provide evidence of an etiological link among autism, immune dysregulation, and autoimmune disease. PMID- 22431268 TI - Representation and propagation of epileptic activity in absences and generalized photoparoxysmal responses. AB - Although functional imaging studies described networks associated with generalized epileptic activity, propagation patterns within these networks are not clear. In this study, electroencephalogram (EEG)-based coherent source imaging dynamic imaging of coherent sources (DICS) was applied to different types of generalized epileptiform discharges, namely absence seizures (10 patients) and photoparoxysmal responses (PPR) (eight patients) to describe the representation and propagation of these discharges in the brain. The results of electrical source imaging were compared to EEG-functional magnetic resonance imaging (fMRI) which had been obtained from the same data sets of simultaneous EEG and fMRI recordings. Similar networks were described by DICS and fMRI: (1) absence seizures were associated with thalamic involvement in all patients. Concordant results were also found for brain areas of the default mode network and the occipital cortex. (2) Both DICS and fMRI identified the occipital, parietal, and the frontal cortex in a network associated with PPR. (3) However, only when PPR preceded a generalized tonic-clonic seizure, the thalamus was involved in the generation of PPR as shown by both imaging techniques. Partial directed coherence suggested that during absences, the thalamus acts as a pacemaker while PPR could be explained by a cortical propagation from the occipital cortex via the parietal cortex to the frontal cortex. In conclusion, the electrical source imaging is not only able to describe similar neuronal networks as revealed by fMRI, including deep sources of neuronal activity such as the thalamus, but also demonstrates interactions interactions within these networks and sheds light on pathogenetic mechanisms of absence seizures and PPR. PMID- 22431269 TI - Salt-effect-based synthesis and anomalous magnetic properties of rare-earth oxide nanosheets with sub-1 nm thickness. PMID- 22431270 TI - Carrot man: a case of excessive beta-carotene ingestion. AB - In this case report, the authors describe a 48-year-old male who complained to his primary care physician of abdominal discomfort and yellow/orange skin discoloration. Physical examination was normal except for some mild mid-abdominal discomfort (no observed skin color changes). An abdominal CT scan indicated a colon that was full of stool. Laboratory studies indicated elevated liver enzymes. Upon further questioning, the patient reported ingesting 6-7 pounds of carrots per week to facilitate his dieting effort. The patient was diagnosed with constipation, hypercarotinemia, and possible vitamin A toxicity. Following the cessation of excessive carrot ingestion, his liver enzymes normalized within 1 month. PMID- 22431271 TI - Topographic anatomy of the masseter muscle focusing on the tendinous digitation. AB - The masseter muscle has superficial tendons that interdigitate like a saw (tendinous digitations), but a detailed description of these tendons is lacking in anatomic textbooks and atlases. The aim of the present study was to elucidate the topographic anatomy of the masseter muscle, focusing on its tendinous digitation. Sixty-five adult faces (113 sides) were dissected. Five parameters, including the lengths, widths, and thickness of the muscle, were measured. The number and morphology of tendinous digitations were also investigated. The length and width of the masseter muscle were longer and wider in male specimens than in female specimens. The number of masseter muscle tendinous digitations was predominantly two in males and three in females. The length of the tendinous digitations tended to be about three-quarters of that of the muscle. The second tendinous digitation was the longest in male specimens, while the first tendinous digitation was the longest in females. Based on our results, the external morphology of the masseter muscle does not match that described in anatomical atlases and textbooks. These findings may be helpful as a basic reference and in the treatment of masseter muscle hypertrophy and masseter tenomyositis. PMID- 22431272 TI - Linezolid as rescue treatment for left-sided infective endocarditis: an observational, retrospective, multicenter study. AB - The increasing number of resistant bacterial strains in infective endocarditis (IE) emphasizes the need for a constant development of antimicrobials. Linezolid is an oxazolidinone with an effect on Gram-positive cocci. Only a few casuistic reports describe its utilization in the treatment of IE. The objective of this study is to report our experience with linezolid from a large consecutive cohort of IE patients. In a retrospective cohort study, data on 550 consecutive IE patients were collected at two tertiary University Hospitals in Copenhagen, Denmark. The main endpoints were differences in the in-hospital and 12 months post-discharge mortality between IE patients receiving linezolid for a part of the treatment and IE patients receiving conventional treatment. Of the 550 patients enrolled in the study, 38 patients received linezolid treatment and 512 received conventional treatment. Reasons for adding linezolid were antibiotic intolerance (n = 13), nephrotoxicity (n = 5), pharmaceutical interactions (n = 1), inadequate clinical response (n = 14), or inadequate microbial response (n = 5). No significant differences in the cure rate (74 % vs. 71 %, p > 0.05), in hospital mortality (13 % vs. 14 %, p > 0.05), or post-discharge mortality at 12 months follow-up (26 % vs. 26 %, p > 0.05) were observed. In the current study, we found that linezolid, in general, was well tolerated and associated with the same outcome as in patients with Gram-positive IE treated with other antibiotics. PMID- 22431273 TI - A virtual histology intravascular ultrasound analysis of coronary chronic total occlusions. AB - OBJECTIVES: We used virtual histology intravascular ultrasound (VH-IVUS) to investigate plaque composition of chronic total occlusions (CTO). BACKGROUND: There are limited data on the composition of CTOs, especially in vivo. METHODS: VH-IVUS was performed in 50 CTO lesions (49 patients) after guidewire crossing or pre-dilation using a 1.5-2 mm balloon. Plaque composition in the proximal reference, distal reference, and CTO segment (subsequently divided into proximal, middle, and distal subsegments) was analyzed and reported as median and interquartile range. VH-IVUS phenotype was also assessed. The definition of a fibroatheroma was >10% confluent necrotic core (NC) in more than three consecutive frames. RESULTS: Overall, the maximum NC within the CTO [35.5% (28.7, 44.3%)] was similar to the proximal reference [35.6% (24.1, 42.1%)] and greater than the distal reference [31.5% (22.6, 35.2%), P < 0.01]. There was no difference in maximum NC observed among proximal [31.4% (25.2, 10.4%)], middle [31.0% (23.3, 38.3%)], and distal CTO subsegments [30.4% (22.0, 39.5%)]. Overall, 42/50 CTOs contained a VH-fibroathroma; and 8/50 did not. CTOs containing a VH fibroatheroma had more NC and dense calcium while CTOs not containing a fibroatheroma had more fibrotic and fibrofatty plaque. Importantly, 60.5% of VH fibroatheroma-containing CTOs had a thin-cap fibroatheroma (NC abutted to the lumen) in the proximal reference. CONCLUSIONS: Using VH-IVUS, CTO morphology can be divided into two patterns: (1) CTO with VH-fibroatheroma or (2) CTO without VH fibroatheroma. This suggests two mechanisms of CTO formation-the majority evolving from acute coronary syndrome and thrombosis and the minority from atherosclerosis progression. PMID- 22431274 TI - Fabrication of co-continuous nanostructured and porous polymer membranes: spinodal decomposition of homopolymer and random copolymer blends. PMID- 22431275 TI - Elevated gastrin-releasing peptide receptor mRNA expression in buccal mucosa: association with head and neck squamous cell carcinoma. AB - BACKGROUND: Expression of gastrin-releasing peptide receptor (GRPR) is elevated in mucosa adjacent to head and neck squamous cell carcinoma (HNSCC) compared with mucosa from cancer-free controls, suggesting elevated GRPR expression may indicate presence of HNSCC. METHODS: We measured GRPR mRNA levels in histologically normal buccal mucosa from 65 surgical patients with HNSCC and 75 cancer-free control subjects using quantitative polymerase chain reaction (PCR). We tested for association between GRPR expression and HNSCC and evaluated differences in patient progression-free survival (PFS). RESULTS: Buccal GRPR expression was higher in cases but not controls who were active smokers (p = .04). High GRPR expression was associated with HNSCC (odds ratio [OR] = 3.55; 95% confidence interval [CI] = 1.15-10.93), even after adjustment for age, sex, tobacco use, and sample storage time. PFS did not differ between patients with HNSCC with high versus low GRPR expression (p = .22). CONCLUSION: Elevated buccal GRPR expression was significantly associated with HNSCC independent of known risk factors but was not an indicator of disease prognosis. PMID- 22431276 TI - The general phase behavior of mixtures of 1-alkyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]amide ionic liquids with n-alkyl alcohols. AB - The liquid-liquid equilibrium (LLE) phase behavior of mixtures of 1-ethyl-3 methylimidazolium bis[(trifluoromethyl)sulfonyl]amide (C(2)mimNTf(2)) with the n alkyl alcohols (C(n)OH; 3<=n<=8) is described. By applying the cloud-point method, the LLEs were determined over a temperature range of 275-423 K at ambient pressure. Partial miscibility with upper critical solution temperatures (UCST) was observed. The UCST increase with increasing chain length of the alcohols. The phase diagrams were analyzed numerically by presuming Ising criticality. Concepts for the description of the asymmetry of the phase diagram by presuming the validity of the rectilinear diameter rule or a nonlinear diameter requested by the theory of complete scaling were applied. The results (UCST, critical composition, width and diameter of the phase diagrams) are compared with similar systems and discussed in terms of the corresponding state behavior; they map on a single curve. From at least 45 individual phase diagrams, general aspects of the behavior of this ionic liquid-alcohol mixture type were extracted. A simple empirical relationship was formulated to allow the description of the UCST with an accuracy of about 10 K when taking the ratio of the molar volumes of the alcohol and the 1-alkyl-3-methylimidazolium cation of the ionic liquid into account. PMID- 22431277 TI - Severe aortic valve regurgitation after percutaneous ventricular septal defect closure. AB - Percutaneous closure of ventricular septal defect is now commonly used. We report a rare case, and especially a rare image of aortic leaflet damage caused by percutaneous ventricular septal device. PMID- 22431278 TI - Abdominal aortic calcification in young adult survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort study. AB - Abdominal aortic calcification (AAC), metabolic syndrome, and low bone mineral density (BMD) are risk factors for atherosclerotic disease and cardiovascular morbidity. We evaluated AAC in 662 adult survivors of childhood ALL (median age 31 years). AAC was present in 10% of subjects, metabolic syndrome in 36%, and low BMD in 29%. The adjusted odds ratio (OR) for AAC among women with metabolic syndrome was 2.3 (95% CL = 1.0, 4.3). The adjusted OR for AAC in men with low BMD was 3.1 (95% CL = 1.3, 7.3). A substantial proportion of adult survivors of childhood ALL have AAC and/or metabolic syndrome, suggestive of early atherosclerotic disease. PMID- 22431279 TI - Transparent metals for ultrabroadband electromagnetic waves. AB - Making metals transparent, which could lead to fascinating applications, has long been pursued. Here we demonstrate that with narrow slit arrays metallic plates become transparent for extremely broad bandwidths; the high transmission efficiency is insensitive to the metal thickness. This work provides a guideline to develop novel devices, including transparent conducting panels, broadband metamaterials, and antireflective solar cells. PMID- 22431280 TI - Navigating the transition from pediatric to adult eating disorder programs: perspectives of service providers. AB - OBJECTIVE: This study aims to conduct qualitative research on the perspectives of service providers regarding the transition process from pediatric to adult specialized eating disorder tertiary care programs. METHOD: Two focus groups with a diverse group of clinicians in pediatric and adult eating disorder programs and five qualitative interviews with clinicians in the community were conducted. RESULTS: Three themes were identified as challenges during the transition process: (1) illness related factors (ambivalence and denial); (2) the interruption of normative adolescent developmental processes by the illness; and, (3) the impact of decreased parental involvement in the adult compared to pediatric eating disorder programs. DISCUSSION: These themes were compared with empirical evidence on other chronic mental or physical health concerns for the purpose of identifying ways to facilitate a more successful service transition for young adults with anorexia nervosa. Future research and clinical implications are delineated. PMID- 22431281 TI - Dynamic brain structural changes after left hemisphere subcortical stroke. AB - This study aimed to quantify dynamic structural changes in the brain after subcortical stroke and identify brain areas that contribute to motor recovery of affected limbs. High-resolution structural MRI and neurological examinations were conducted at five consecutive time points during the year following stroke in 10 patients with left hemisphere subcortical infarctions involving motor pathways. Gray matter volume (GMV) was calculated using an optimized voxel-based morphometry technique, and dynamic changes in GMV were evaluated using a mixed effects model. After stroke, GMV was decreased bilaterally in brain areas that directly or indirectly connected with lesions, which suggests the presence of regional damage in these "healthy" brain tissues in stroke patients. Moreover, the GMVs of these brain areas were not correlated with the Motricity Index (MI) scores when controlling for time intervals after stroke, which indicates that these structural changes may reflect an independent process (such as axonal degeneration) but cannot affect the improvement of motor function. In contrast, the GMV was increased in several brain areas associated with motor and cognitive functions after stroke. When controlling for time intervals after stroke, only the GMVs in the cognitive-related brain areas (hippocampus and precuneus) were positively correlated with MI scores, which suggests that the structural reorganization in cognitive-related brain areas may facilitate the recovery of motor function. However, considering the small sample size of this study, further studies are needed to clarify the exact relationships between structural changes and recovery of motor function in stroke patients. PMID- 22431282 TI - Direct gravure printing of silicon nanowires using entropic attraction forces. AB - The development of a method for large-scale printing of nanowire (NW) arrays onto a desired substrate is crucial for fabricating high-performance NW-based electronics. Here, the alignment of highly ordered and dense silicon (Si) NW arrays at anisotropically etched micro-engraved structures is demonstrated using a simple evaporation process. During evaporation, entropic attraction combined with the internal flow of the NW solution induced the alignment of NWs at the corners of pre-defined structures, and the assembly characteristics of the NWs were highly dependent on the polarity of the NW solutions. After complete evaporation, the aligned NW arrays are subsequently transferred onto a flexible substrate with 95% selectivity using a direct gravure printing technique. As a proof-of-concept, flexible back-gated NW field-effect transistors (FETs) are fabricated. The fabricated FETs have an effective hole mobility of 17.1 cm(2) .V( 1) .s(-1) and an on/off ratio of ~2.6 * 10(5) . PMID- 22431283 TI - Electron attachment to solvated dGpdG: effects of stacking on base-centered and phosphate-centered valence-bound radical anions. AB - To explore the nature of electron attachment to guanine-centered DNA single strands in the presence of a polarizable medium, a theoretical investigation of the DNA oligomer dinucleoside phosphate deoxyguanylyl-3',5'-deoxyguanosine (dGpdG) was performed by using density functional theory. Four different electron distribution patterns for the radical anions of dGpdG in aqueous solution have been located as local minima on the potential energy surface. The excess electron is found to reside on the proton of the phosphate group (dGp(H-)dG), or on the phosphate group (dGp(.-)dG), or on the nucleobase at the 5' position (dG(.-)pdG), or on the nucleobase at the 3' position (dGpdG(.-)), respectively. These four radical anions are all expected to be electronically viable species under the influence of the polarizable medium. The predicted energetics of the radical anions follows the order dGp(.-)dG>dG(.-)pdG>dGpdG(.-)>dGp(H-)dG. The base-base stacking pattern in DNA single strands seems unaffected by electron attachment. On the contrary, intrastrand H-bonding is greatly influenced by electron attachment, especially in the formation of base-centered radical anions. The intrastrand H-bonding patterns revealed in this study also suggest that intrastrand proton transfer might be possible between successive guanines due to electron attachment to DNA single strands. PMID- 22431284 TI - Electrochemical detection of the thermally induced phase transition of a thin stimuli-responsive polymer film. AB - Quick and easy: An efficient approach for a direct observation of a thermally induced phase transition of a responsive polymer film on gold surfaces is described. Voltammetric measurements show that the peak current and the peak separation for a small redox couple are particularly sensitive to the conformational change of the polymer film and allow its phase transition detection. PMID- 22431285 TI - The use of the Trellis-6 thrombectomy device in the management of acute limb ischemia due to native vessel occlusion: challenges, tips, and limitations. AB - The role of endovascular therapy is expanding in the treatment of acute limb ischemia (ALI). In addition to catheter-based thrombolysis, there are multiple devices which allow for clot disruption and aspiration. The Trellis catheter system provides mechanical agitation of thrombus coupled with chemical thrombolysis. We present two cases of native arterial occlusions in which the Trellis catheter was used for thrombolysis. Procedural tips and challenges associated with the use of this device in native vessels are discussed. PMID- 22431286 TI - Torsional injury to the ankle resulting in fibular neuropathy affects the common fibular nerve as well as its terminal branches, specifically, the articular branch. PMID- 22431287 TI - Thyroid disease associated with Cowden syndrome: A meta-analysis. AB - BACKGROUND: We investigated the pathology and surgical management of thyroid disease in patients with Cowden syndrome (CS). METHODS: A query of the PubMed database between 2001 and January 2010 was performed using the terms "cowden syndrome OR cowden's syndrome OR cowden disease OR cowden's disease." Original articles, reviews, case reports, and case series were included. Articles were excluded if they were not written in English, did not present case/cases of CS, or did not include patient information to qualify for a diagnosis of CS. Ninety five articles met the inclusion and exclusion criteria. A total of 181 cases were analyzed. RESULTS: Of the 181 patients, 99 female (54.7%) and 77 male patients (42.5%) had sex reported. The age at presentation ranged from 3 days to 78 years. Ninety-six patients (96/181, 53.0%) were reported to have thyroid disease. Surgical management of thyroid disease was performed in 80.2% (77/96) of patients with thyroid disease, with total thyroidectomy being the most common operation reported (23/77, 29.9%). Thyroid pathology reported with CS patients included goiter (39/96, 40.6%), adenoma (24/96, 25%), unknown/unspecified pathology (8/96, 8.3%), follicular carcinoma (7/96, 7.3%), thyroiditis (7/96, 7.3%), papillary carcinoma (6/96, 6.3%), cancer (unknown type) (3/96, 3.1%), medullary carcinoma (1/96, 1%), and hyperthyroidism (1/96, 1%). CONCLUSION: Careful monitoring of thyroid disease in CS patients is imperative. PMID- 22431288 TI - Insights into the mechanism of the antibiotic-synthesizing enzyme MoeO5 from crystal structures of different complexes. PMID- 22431289 TI - In vivo imaging of vessel diameter, size, and density: a comparative study between MRI and histology. AB - The aim of this study was to compare magnetic resonance imaging (MRI) and histological estimates of the mean vessel diameter (mVD), the vessel density (Density), and the vessel size index (VSI) obtained in the same tumor-bearing animals. Twenty-seven rats bearing intracranial glioma (C6 or RG2) were imaged by MRI. Changes in transverse relaxations (DeltaR 2* and R(2)) were induced by the injection of an iron-based contrast agent and were mapped using a multi gradient echo spin-echo sequence. Then, brain vascular network was studied ex vivo by histology. Three regions of interest were drawn in apparently normal tissue (neocortex and striatum) and in the tumor. In vivo mVD(MRI), Density(MRI), and VSI(MRI) were measured; ex vivo, mVD(histo), Density(histo), and VSI(histo) were quantified on the same animals. MRI and histology measurements differed by -15 to 26%. A positive correlation was found between MRI and histology for mVD, Density, and VSI counterparts (R(2) = 0.62, 0.50, 0.73, respectively; P < 0.001 in all cases). This study indicates that MRI and histology yields well correlated the estimates of mVD, Density, and VSI. VSI is the closest MRI estimate to histology. As Density and mVD or VSI provide complementary information, it is worth computing them to characterize angiogenesis beyond blood volume fraction. PMID- 22431290 TI - Difficulties with horizontal aortic root in transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) emerged to be a viable treatment option for failing bioprosthesis in the aortic position. Transfemoral approach is the most common access route for TAVI and associated with most favorable clinical outcome. However, in the presence of unfavorable aortic root anatomy, TAVI via transfemoral approach provides inadequate support for device manipulation during valve positioning, particularly performed for the indication of severe aortic regurgitation. We report our experience on TAVI utilizing CoreValve for a patient with regurgitant failing bioprosthesis with horizontal aortic root where we encountered difficulties during implantation and retrieval of valve delivery system. PMID- 22431291 TI - Characterization of deamidation of barstar using electrospray ionization quadrupole time-of-flight mass spectrometry, which stabilizes an equilibrium unfolding intermediate. AB - Deamidation of asparaginyl residues is a common posttranslational modification in proteins and has been studied extensively because of its important biological effects, such as those on enzymatic activity, protein folding, and proteolytic degradation. However, characterization of the sites of deamidation of a protein has been a difficult analytical problem. In this study, mass spectrometry has been used as an analytical tool to characterize the deamidation of barstar, an RNAse inhibitor. Upon incubation of the protein at alkaline pH for 5 h, intact mass analysis of barstar, using electrospray ionization quadrupole time-of-flight mass spectrometry (ESI QToF MS), indicated an increase in the mass of +2 Da, suggesting possible deamidation of the protein. The sites of deamidation have been identified using the conventional bottom-up approach using a capillary liquid chromatography connected on line to an ESI QToF mass spectrometer and top down approach by direct infusion of the intact protein and fragmenting inside MS. These chemical modifications are shown to lead to stabilization of an unfolding intermediate, which can be observed in equilibrium unfolding studies. PMID- 22431292 TI - Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients. AB - BACKGROUND: Cisplatin is an effective chemotherapy agent against several pediatric malignancies. One of its side effects is irreversible sensorineural hearing damage that is highly variable with a reported incidence of 22-70%. The aim of this study was to evaluate the incidence and identify clinical predictors of cisplatin-related ototoxicity. PROCEDURES: We performed a retrospective chart review of 102 pediatric patients who had completed cisplatin therapy for osteosarcoma, neuroblastoma, hepatoblastoma, or germ cell tumor. Patients were diagnosed at Riley Hospital for Children between January 1995 and June 2008, were less than 18 years old at diagnosis, and had normal hearing prior to therapy. Audiograms were scored using the Brock scale (0-4), a validated grading system for cisplatin-related hearing loss. RESULTS: Forty-two percent of the patients experienced hearing loss and 28% had moderate to severe ototoxicity (Brock score >=2). Males were at significantly greater risk for developing hearing loss than were females (P = 0.005, OR 4.812). Age at cancer diagnosis was inversely related to severity of ototoxicity. Patients who suffered Brock grade 3 ototoxicity had a mean age of 4.5 years versus 11.5 years and 7.2 years for grades 1 and 2, respectively (P = 0.02). Cumulative cisplatin dose was also identified as a risk factor for development of ototoxicity (P = 0.03). CONCLUSIONS: Gender and cumulative dose are important clinical biomarkers of cisplatin ototoxicity. Severity of ototoxicity may be inversely related to age at time of exposure, with very young patients exhibiting higher grades of hearing loss following cisplatin therapy. PMID- 22431293 TI - Spiro-linked hyperbranched architecture in electrophosphorescent conjugated polymers for tailoring triplet energy back transfer. AB - A spiro-linked hyperbranched architecture has been incorporated into electrophosphorescent conjugated polymers for the first time, aiming at simultaneously tailoring the intra- and intermolecular triplet energy back transfer from the phosphorescent guest to the conjugated polymer host. Based on a prototype with this unique structure, slower decay of triplet excitons, and 5-8 fold enhancement of device efficiencies are obtained compared with the conventional blending counterpart. PMID- 22431294 TI - Intrinsic limbic and paralimbic networks are associated with criminal psychopathy. AB - BACKGROUND: Psychopathy is a personality disorder associated with impairments in decision-making, empathy, and impulsivity. Recent brain imaging studies suggest that psychopathy is associated with abnormalities in limbic/paralimbic brain regions. To date, no studies have examined functional brain connectivity measures using independent component analyses (ICA) in adults with psychopathy. Here, we test hypotheses regarding paralimbic connectivity in adult incarcerated individuals stratified by psychopathy scores. METHODS: One hundred and two prison inmates were rated using the Hare Psychopathy Checklist-Revised (PCL-R). FMRI data were collected while subjects performed an auditory target detection "oddball" task. FMRI data were analyzed using group ICA to identify functional networks responding to the oddball task correlating with psychopathy scores. RESULTS: Components demonstrating significant correlations with psychopathy included a default mode network, a frontoparietal component, and a visual/posterior cingulate component. Modulation trends correlated strongly with factor 2 (impulsivity) and total PCL-R scores in the frontoparietal and visual/posterior cingulate networks, and with factor 1 (affective) scores within the default mode network. The posterior cingulate region factored significantly in the modulation trends observed. CONCLUSION: Consistent with the hypothesis of limbic/paralimbic abnormalities associated with psychopathy, modulation trends correlated strongly with PCL-R scores. There is strong evidence to implicate the posterior cingulate in aberrant functional connectivity associated with the manifestation of psychopathic symptoms. Future investigations comparing functional trends associated with the posterior cingulate in psychopathic subjects may provide further insight into the manifestation of this disorder. PMID- 22431295 TI - Topotaxial fabrication of vertical Aux Ag1-x nanowire arrays: plasmon-active in the blue region and corrosion resistant. AB - Topotaxial growth of Au(x) Ag(1-x) alloy nanowires (NWs) by postepitaxial deposition of Ag vapor on Au NWs and investigation of their plasmonic properties are reported. Ag vapor is supplied onto the epitaxially grown Au NWs, topotaxially turning them into Au(x) Ag(1-x) alloy NWs. The original geometries and alignments of the Au nanostructures are well preserved, while the composition of the alloy NWs is controlled by varying the Ag vapor supply time. The Au(0.5) Ag(0.5) NWs show high surface-enhanced Raman scattering (SERS) activity comparable to that of Ag NWs as well as highly increased oxidation resistance. The plasmon-active wavelength range of the Au(0.5) Ag(0.5) NW is significantly extended to the blue region compared to Au NWs. The Au(x) Ag(1-x) alloy NWs that have plasmonic activity in the blue region in addition to high corrosion resistance will make a superb material for practical plasmonic devices including SERS sensors and optical nanoantennas. PMID- 22431296 TI - Asymmetric nucleophilic monofluorobenzylation of carbonyl compounds: synthesis of enantiopure vic-fluorohydrins and alpha-fluorobenzylketones. AB - Asymmetric nucleophilic monofluoroalkylation of a broad range of aldehydes with an alpha-fluoro-gamma-sulfinylbenzyl carbanion takes place with complete control of the facial selectivity at the carbanion and good to high anti diastereoselectivity to give easily separable mixtures of two optically pure 1,2 fluorohydrin derivatives (up to 24:1 anti/syn). Separation and removal of the p tolylsulfinyl group with tBuLi provides enantiomerically pure anti-1,2 disubstituted-1,2-fluorohydrins, whereas alpha-fluorobenzylketones can be obtained by desulfinylation of the mixture followed by pyridinium chlorochromate oxidation (one-pot process). PMID- 22431297 TI - Psychosocial risk factors of loss of control eating in primary school children: a retrospective case-control study. AB - OBJECTIVE: To provide a comprehensive investigation of the retrospective correlates of loss of control (LOC) over eating in children close to the onset of their first LOC eating episodes. METHOD: A community-based, case-control design was used to compare matched groups of 60 children with and without LOC eating. Retrospective correlates were assessed using a child-adapted version of the Oxford Risk Factor Interview. RESULTS: Children with LOC eating revealed greater levels of exposure to parental problems, (e.g., underinvolvement, arguments, and depression of family members) and dieting-related risk factors than children without LOC eating. Predictors of LOC eating were risk correlates parental underinvolvement, and critical comments by the family and the critical life event change of school. DISCUSSION: Results underline the influence of parental behavior and the impact of dieting behavior on the development of non-normative eating in middle childhood. PMID- 22431298 TI - Synchronous bilateral pleomorphic adenomas of the parotid gland. AB - Bilateral pleomorphic adenomas of the parotid gland are extremely rare, accounting for less than 0.2% of all parotid gland tumors. We present a rare case of a patient with synchronous bilateral pleomorphic adenomas of the parotid gland. A 27-year-old woman presented with a 5-month history of a slowly-growing, painless swelling of the right parotid gland. After a thorough bilateral parotid examination and magnetic resonance imaging evaluation, bilateral tumors of the parotid gland were found. The patient underwent surgical excision of the bilateral tumors in one surgical setting. Histopathological examination showed that both tumors were pleomorphic adenomas. The patient has been followed for 24 months without recurrence of tumors. Careful preoperative examination and radiological evaluation of bilateral parotid glands might be necessary for the early diagnosis of synchronous bilateral tumors. We suggest that treatment be individualized depending on the sizes and locations of tumors, and the surgical and neurological risks. PMID- 22431299 TI - Molecular confinement in fluorescent magnetic mesoporous silica nanoparticles: effect of pore size on multifunctionality. PMID- 22431300 TI - Thermal hydrogen-atom transfer from methane: the role of radicals and spin states in oxo-cluster chemistry. AB - Hydrogen-atom transfer (HAT), as one of the fundamental reactions in chemistry, is investigated with state-of-the-art gas-phase experiments in conjunction with computational studies. The focus of this Minireview concerns the role that the intrinsic properties of gaseous oxo-clusters play to permit HAT reactivity from saturated hydrocarbons at ambient conditions. In addition, mechanistic implications are discussed which pertain to heterogeneous catalysis. From these combined experimental/computational studies, the crucial role of unpaired spin density at the abstracting atom becomes clear, in distinct contrast to recent conclusions derived from solution-phase experiments. PMID- 22431301 TI - An 11-channel radio frequency phased array coil for magnetic resonance guided high-intensity focused ultrasound of the breast. AB - In this study, a radio frequency phased array coil was built to image the breast in conjunction with a magnetic resonance guided high-intensity focused ultrasound (MRgHIFU) device designed specifically to treat the breast in a treatment cylinder with reduced water volume. The MRgHIFU breast coil was comprised of a 10 channel phased array coil placed around an MRgHIFU treatment cylinder where nearest-neighbor decoupling was achieved with capacitive decoupling in a shared leg. In addition a single loop coil was placed at the chest wall making a total of 11 channels. The radio frequency coil array design presented in this work was chosen based on ease of implementation, increased visualization into the treatment cylinder, image reconstruction speed, temporal resolution, and resulting signal-to-noise ratio profiles. This work presents a dedicated 11 channel coil for imaging of the breast tissue in the MRgHIFU setup without obstruction of the ultrasound beam and, specifically, compares its performance in signal-to-noise, overall imaging time, and temperature measurement accuracy to that of the standard single chest-loop coil typically used in breast MRgHIFU. PMID- 22431302 TI - Preclosure of large-sized venous access sites in adults undergoing transcatheter structural interventions. AB - BACKGROUND: Patients requiring congenital and structural heart interventions often require large-sized sheath insertion into femoral veins and arteries. Clinical outcome data on the use of suture-mediated devices for femoral venous access site closure are limited. OBJECTIVE: To assess the efficacy and safety of the PercloseTM (Abbott Vascular Devices, CA) suture-mediated device using the preclosure technique, in achieving haemostasis at femoral venous access site following large sheath insertion (>=8 Fr). DESIGN AND SETTING: Two hundred and forty-three consecutive patients underwent 310 access site closures with the PercloseTM device using the preclosure technique. There were 151 (62%) women, mean age 43 (+/-16) years. 234/243 (96%) received heparin. Mean venous access site sheath diameter was 11.5 (+/-3) Fr. RESULTS: Immediate haemostasis (<2 min) was achieved in 304/310 (98%) sites. No patients had major complications. Short term follow-up at 3 months revealed no evidence of haematoma or fistula formation or clinical evidence of vessel occlusion. On medium-term clinical follow-up (mean follow-up of 14 +/- 12 and median of 12.4 months), no complications were seen at the venous access sites. CONCLUSION: Preclosure of large-size femoral venous access sheath sites using the suture-mediated PercloseTM device is efficacious in achieving rapid haemostasis in the presence of anticoagulation in the venous site. On 1-year follow-up, there was no clinical evidence of vascular complications in the venous access sites. PMID- 22431303 TI - Perceptions of mentoring of full-time occupational therapy faculty in the United States. AB - The purpose of this study was to describe the occurrence, nature and perception of the influence of mentoring for full-time occupational therapy faculty members who are on the tenure track or eligible for re-appointment in the United States. An online survey was sent during 2010 September, the beginning of the academic year, to all 818 potential participants in the United States entry-level and doctoral programmes. Fifty six of 107 participants who met the criteria reported being in a mentoring relationship and positively rated their perception of the influence of mentoring on academic success and academic socialization. The response of all participants to open-ended questions describes preferred mentoring characteristics (providing information, support), benefits (having someone to go to, easing the stress) and challenges (not enough time, mentoring not valued). Findings inform current and potential faculty of the current state of mentoring. Administrators can use this information when designing mentoring opportunities, educating mentors and mentees about the mentoring process, arranging mentors/mentees release time for engaging in the mentoring process and finally, managing the mentor/mentee needs. The cross-sectional survey of the United States occupational therapy faculty limits generalizability yet paves the way for future studies to explore retention and recruitment of mentored faculty across countries. PMID- 22431304 TI - Associations among speech, eating, and body image concerns for surgical patients with head and neck cancer. AB - BACKGROUND: Body image can be affected by bodily experiences extending beyond physical appearance. This study evaluated associations among speech, eating, and body image concerns for surgically treated patients with oral cavity, midface, and cutaneous cancers of the head and neck. METHODS: Using a cross-sectional design, 280 participants completed the Body Image Scale, a survey evaluating disease-specific body image issues, and the Functional Assessment of Cancer Therapy Scale-General. RESULTS: Participants with speech and eating concerns reported the highest levels of body image/appearance dissatisfaction compared with those without such concerns. This group also reported greater cognitive and behavioral difficulties associated with body image concerns and significantly higher levels of interest in psychosocial interventions to address appearance related difficulties compared with all other participants. CONCLUSIONS: Findings point to the need for more comprehensive psychosocial care for patients with head and neck malignancies reporting speech and eating difficulties, which extent beyond functional rehabilitation. PMID- 22431305 TI - Long-term luminal change after drug-eluting stent implantation: serial angiographic follow-up study of the ZEST randomized trial. AB - OBJECTIVE: To evaluate long-term patterns of luminal changes after implantation of different types of drug-eluting stents (DES), we analyzed the serial angiographic outcomes of patients implanted with zotarolimus-eluting stents (ZES), sirolimus-eluting stents (SES), or paclitaxel-eluting stents (PES). BACKGROUND: Little is known regarding long-term luminal changes after DES implantation. METHODS: As a subgroup analysis of the ZEST trial, we performed complete angiographic evaluation immediately after the procedure and at 9 months and 2 years in 111 patients with 165 lesions (36 patients with ZES, 40 with SES, and 35 with PES). RESULTS: Baseline clinical, angiographic, and procedural characteristics were similar among the three groups. Quantitative angiographic analysis revealed significant decreases in minimal luminal diameter 9 months after stent implantation in the ZES (from 2.71 +/- 0.49 to 2.21 +/- 0.42 mm, P < 0.001), SES (from 2.79 +/- 0.49 to 2.58 +/- 0.57 mm, P < 0.001), and PES (from 2.66 +/- 0.45 to 2.19 +/- 0.52 mm, P < 0.001) groups. However, significant late improvements with different degree in luminal diameter were observed between 9 months and 2 years in the ZES (from 2.21 +/- 0.42 to 2.39 +/- 0.58 mm, P = 0.001), SES (from 2.58 +/- 0.57 to 2.66 +/- 0.60 mm, P = 0.039), and PES (from 2.19 +/- 0.52 to 2.43 +/- 0.52 mm, P < 0.001) groups. CONCLUSION: Serial angiographic follow-up study revealed a biphasic luminal response after DES implantation, characterized by an early progression phase for the first 9 months and a late regression phase from 9 months to 2 years. PMID- 22431306 TI - Differential roles of right temporal cortex and Broca's area in pitch processing: evidence from music and Mandarin. AB - Superior temporal and inferior frontal cortices are involved in the processing of pitch information in the domain of language and music. Here, we used fMRI to test the particular roles of these brain regions in the neural implementation of pitch in music and in tone language (Mandarin) with a group of Mandarin speaking musicians whose pertaining experiences in pitch are similar across domains. Our findings demonstrate that the neural network for pitch processing includes the pars triangularis of Broca's area and the right superior temporal gyrus (STG) across domains. Within this network, pitch sensitive activation in Broca's area is tightly linked to the behavioral performance of pitch congruity judgment, thereby reflecting controlled processes. Activation in the right STG is independent of performance and more sensitive to pitch congruity in music than in tone language, suggesting a domain-specific modulation of the perceptual processes. These observations provide a first glimpse at the cortical pitch processing network shared across domains. PMID- 22431308 TI - Unilateral absence of latissimus dorsi muscle. AB - Latissimus dorsi (LD) is the broadest muscle of the back responsible for extension and adduction of shoulder. The authors report a case of isolated unilateral absence of the latissimus dorsi muscle observed during an ablative surgical procedure and flap reconstruction. The left LD muscle was completely absent in our patient and no tendon fibers belonging to this muscle could be observable on further dissection. The surrounding muscle anatomy was normal and in place suggesting a developmental etiology for its absence. Awareness of this possible variation is of importance in considering reconstructive options. PMID- 22431309 TI - Giant moisture responsiveness of VS2 ultrathin nanosheets for novel touchless positioning interface. AB - Utilizing a thin film of VS(2) ultrathin nanosheets with giant and fast moisture responsiveness, a brand-new model of moisture-based positioning interface is put forward here, by which not only the 2D position information of finger tips can be acquired, but also the relative height can be detected as the third dimensionality, representing a promising platform for advanced man-machine interactive systems. PMID- 22431310 TI - Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms. AB - Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution. PMID- 22431311 TI - Strict perpendicular orientation of neural crest-derived neurons in vitro is dependent on an extracellular gradient of voltage. AB - We report extraordinary perpendicular orientations of neurons dependent on the presence of an external direct current (DC) voltage gradient. We chose chick dorsal root and postganglionic sympathetic neurons to evaluate. These were cultured in observation chambers in which the cells were separated from electrode products or substrate effects and maintained at 35 degrees C. Both types of neurons showed a rapid restructuring of their anatomy. Typically, neurites that were not perpendicular to the voltage gradient were quickly resorbed into the cell body within a few minutes. Over 3-6 hr, significant new neurite growth occurred and was patterned perpendicular to the DC electrical field (Ef). This preferred asymmetry was dependent on the Ef, as was the initial retrograde degeneration of fibers. At 400-500 mV/mm, over 90% of the cells in culture assumed this orientation. Removal of the DC Ef led to a loss of the preferred orientation, with further random growth within the chambers. This is the first report of such responses in dorsal root ganglion neurons. We also used sympathetic neurons as a meaningful comparison to analyze whether there were any qualitative or quantitative differences between these two cell types of neural crest origin. We discuss the means by which these orientations were achieved. PMID- 22431313 TI - Radicals in ionic liquids. AB - Stable radicals and recombination of photogenerated lophyl radicals are investigated in ionic liquids. The 2,2,6,6-tetramethylpiperidine-1-yloxyl derivatives contain various substituents at the 4-position to the nitroxyl group, including hydrogen-bond-forming or ionic substituents that undergo additional interactions with the individual ions of the ionic liquids. Some of these spin probes contain similar ions to ionic liquids to avoid counter-ion exchange with the ionic liquid. Depending on the ionic liquid anion, the Stokes-Einstein theory or the Spernol-Gierer-Wirtz theory can be applied to describe the temperature dependence of the average rotational correlation time of the spin probe in the ionic liquids. Furthermore, the spin probes give information about the micropolarity of the ionic liquids. In this context the substituent at the 4 position to the nitroxyl group plays a significant role. Covalent bonding of a spin probe to the imidazolium ion results in bulky spin probes that are strongly immobilized in the ionic liquid. Furthermore, lophyl radical recombination in the dark, which is chosen to understand the dynamics of bimolecular reactions in ionic liquids, shows a slow process at longer timescale and a rise time at a shorter timescale. Although various reactions may contribute to the slower process during lophyl radical recombination, it follows a second-order kinetics that does not clearly show solvent viscosity dependence. However, the rise time, which may be attributed to radical pair formation, increases with increasing solvent viscosity. PMID- 22431312 TI - Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease. AB - Low high-density lipoprotein (HDL)-cholesterol levels are associated with an increased risk of coronary artery disease (CAD) and myocardial infarction, which has triggered the hypothesis that HDL, in contrast to low-density lipoprotein (LDL), acts as an anti-atherogenic lipoprotein. Moreover, experimental studies have identified potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux and direct endothelial-protective effects of HDL, such as stimulation of endothelial nitric oxide production and repair, anti apoptotic, anti-inflammatory and anti-thrombotic properties. Studies in gene targeted mice, however, have also indicated that increasing HDL-cholesterol plasma levels can either limit (e.g. apolipoprotein A-I) or accelerate (e.g. Scavenger receptor class B type I) atherosclerosis. Moreover, vascular effects of HDL have been observed to be heterogenous and are altered in patients with CAD or diabetes, a condition that has been termed 'HDL dysfunction'. These alterations in biological functions of HDL may need to be taken into account for HDL-targeted therapies and considering raising of HDL-cholesterol levels alone is likely not sufficient in this respect. It will therefore be important to further determine, which biological functions of HDL are critical for its anti-atherosclerotic properties, as well as how these can be measured and targeted. PMID- 22431314 TI - Quantification of temporal, procedural, and hardware-related factors influencing radiation exposure during pediatric cardiac catheterization. AB - PURPOSE: To quantify the impact of relocation to a purpose built pediatric cardiac catheterization laboratory, on patient radiation dose and fluoroscopy time. To provide guide values for radiation exposure during common structural interventions. MATERIAL AND METHODS: DESIGN: A retrospective review of common structural cardiac interventions performed over 10-years. The era comprised two 5 year periods before and after relocation using different catheter laboratories. Multivariable analysis adjusted for the following variables: era (pre- and post move), year, operator seniority, patient age, procedure type. SETTING: A quaternary referral congenital cardiac centre. PATIENTS: All patients <18 yrs (n = 756) in whom one of 6 common structural interventions were undertaken between 2000 and 2009. MAIN OUTCOME MEASURES: Radiation dose and fluoroscopy time. RESULTS: The move to the new laboratory (latter era) was associated with a dramatic reduction in multivariable-adjusted radiation dose, ranging from 64% (aortic coarctation stenting) to 87% (patent arterial duct closure). There was also a year upon year increase in radiation dose of 5.2% [95% confidence interval (CI): 0.6-10.0%], which persisted after the relocation. However, this was associated with a 5.1% yearly decrease in fluoroscopy time (95% CI: -7.9 to 2.2%). CONCLUSION: Use of state-of-the-art catheter equipment is associated with a dramatic reduction in radiation exposure. However, the surprising finding of year upon year increase in exposure (despite the new equipment) combined with decreased fluoroscopy time suggests a temporal decrease in hardware efficiency. This has major implications for hardware replacement. PMID- 22431315 TI - Transcription expression and clinical significance of vascular endothelial growth factor mRNA and endostatin mRNA in pleural effusions of patients with lung cancer. AB - The aim of this study was to evaluate the individual and combined diagnostic utility of vascular endothelial growth factor (VEGF) mRNA and endostatin mRNA in pleural effusions of patients with lung cancer. Transcription levels of VEGF and endostatin were detected by reverse transcription polymerase chain reaction (RT PCR) in pleural effusions of patients with lung cancer (92 cases) and with lung benign disease (36 cases). Both VEGF mRNA and endostatin mRNA was significantly higher in malignant, AC, and SCC effusions than in benign effusions (P < 0.01). In the subgrouping, VEGF mRNA was obviously higher than endostatin mRNA in malignant and AC effusions (P < 0.01), whereas VEGF mRNA and endostatin mRNA did not differ between AC group and SCC group (P > 0.05). In single, VEGF mRNA had the highest sensitivity (82.6%) and accuracy (84.3%), whereas endostatin mRNA had the highest specificity (100%). When combinations of VEGF mRNA and endostatin mRNA were evaluated together, they gave a high-diagnostic performance: sensitivity of 95.7% and accuracy of 93.8%, respectively. The detection of VEGF mRNA and endostatin mRNA appears to be suitable for distinguishing carcinoma cells from reactive mesothelial cells in pleural effusions, they could be useful to diagnose the pleural micrometastasis. PMID- 22431316 TI - Incidental detection of filaria in fine-needle aspirates: a cytologic study of 14 clinically unsuspected cases at different sites. AB - Filariasis is a major health problem in tropical countries like India. Detection of microfilariae or adult worm or egg in FNAC is very unusual despite the high incidence of this parasite in endemic zone. The aim of this study was to document the value of fine-needle aspiration cytology (FNAC) in diagnosis of filaria at all possible sites presenting as mass or swelling. Fourteen patients (nine males and five females) in the age range of 14-61 years were subjected to FNAC. FNA from swellings was done using 22-gauge needles fitted with 10 or 20 ml disposable plastic syringes. The slides were stained with May-Grunwald-Giemsa stain, Haematoxylin and Eosin (H&E) stain, and Papanicolaou (Pap) stain. In total, 14 cases of filariasis were detected, which included subcutaneous swellings (six cases), epididymis/spermatic cord nodules (four cases), breast lumps (two cases), lymph nodes (one case), and thyroid swelling (one case). Larvae (microfilariae), eggs, and adult worms were detected in cytological smears. Microfilaria was present in all 14 cases whereas adult worm was found in three cases only. In four cases, eggs were seen in the smears. None of the patients was microfilariaemic and significant eosinophilia (>10%) was seen seen in two patients. Filarisis should be considered as one of the differential diagnosis of swelling in endemic area. Identification of the parasite, Wuchereria bancrofti, in FNA smears and accurate diagnosis of filaria is important to employ proper treatment. Early diagnosis and treatment prevents the more severe manifestation of the disease, lymphatic filariasis. PMID- 22431317 TI - Fine-needle aspiration cytology diagnosis of metastatic nonhaematological neoplasms of the breast: a series of seven cases. AB - Metastatic neoplasms of the breast are rare. Mammary metastases as the initial presentation are even more infrequent and can simulate a primary malignancy clinically and radiologically. Recognition of metastatic tumors in the breast is important because it would prevent unnecessary mutilating surgery and would lead to appropriate treatment of the primary tumor. There is a broad variety of cytological appearances reported about primary tumors and few reports about secondary breast malignancies, specially diagnosed by FNAC. This study was carried out to examine the clinical and cytomorphologic features of metastatic breast tumors found in 12 de Octubre University Hospital during a period of 20 years. It confirms the utility of FNAC and describes findings that can help in the differential diagnosis that sometimes can be very difficult. Seven cases of nonhematological metastatic neoplasms of the breast were identified from the files of the Department of Pathology of the 12 de Octubre University Hospital from a total of 64,000 aspirates. We included only metastatic tumors from extramammary nonhematological neoplasms. There were nine cases of hematological metastatic neoplasm that were excluded. They were diagnosed with FNAC and confirmed by histopathology, with at least three years of follow up. The breast lump was the first manifestation of malignancy in one case of synovial sarcoma. The other six cases had been previously diagnosed of cancer. These included one malignant melanoma, one alveolar rhabdomyosarcoma, one mixed mullerian tumor, one medullary carcinoma of thyroid, one colonic adenocarcinoma, and one gastric adenocarcinoma. The period of time between primary tumor and metastases ranged from one month to eight years. An accurate cytologic diagnosis was made in all the cases. Immunocytochemistry was available but diagnosis could be made with cytomorphology alone in the seven cases. Fine-needle aspiration cytology is an excellent first line diagnostic modality that is particularly informative when clinical previous data are known. If metastatic disease is suspected, the material obtained by FNAC may provide a definitive diagnosis and prevent open surgical biopsy or mastectomy. We concur with previous reports that FNAC is a reliable, rapid, secure, and cost-effective approach to the diagnosis of palpable metastatic breast tumors. PMID- 22431318 TI - Fine-needle aspiration cytology and flow cytometric immunophenotyping in diagnosis and classification of non-Hodgkin lymphoma in comparison to histopathology. AB - This prospective study aimed to compare the value of fine needle aspiration (FNA) cytology (FNAC) and flow cytometric immunophenotyping (FCI) with histopatopathology (HP) in the diagnosis and classification of non-Hodgkin lymphoma (NHL). Twenty-nine excised lymph nodes suspected of NHL were evaluated using FNAC, FCI, and HP. Specimens were divided into two equal parts; one for HP and the other for FNAC and FCI. Results were compared in terms of diagnosis (malignant, benign or reactive, and metastatic) and NHL class. With combined FNAC/FCI, 11 (37.9%) cases were diagnosed as NHL, 11 cases (37.9%) as reactive lymph node, six cases (20.6%) as Hodgkin's lymphoma, and one case (3.4%) as metastasis. HP revealed nine cases (31%) of NHL, five cases (17.2%) of reactive lymph nodes and all the diagnosed metastatic and Hodgkin's lymphoma. Considering histology as a gold standard method in diagnosis, the sensitivity, specificity, PPV and NPV of FNAC/FCI in differentiate malignant and benign lesion were 73.9%, 83.3%, 94.4%, and 45.5%, respectively and in differentiate NHL from others were 75%, 93.8%, 90%, and 83.3%, respectively. Cytology and HP in addition to FCI and HP are significantly different from determination of NHL lesions point of view (P = 0.001 and P < 0.0001, respectively). However, FCI can be considered as an adjunctive method for Cytology especially because Cytology is not competent enough to differentiate between benign lesions and Lymphoma. Additionally, FCI is shown to be an accurate method in classifying NHL. PMID- 22431319 TI - Tumor type and single-cell/mesothelial-like cell pattern of breast carcinoma metastases in pleural and peritoneal effusions. AB - Invasive ductal and lobular breast carcinomas often have different preferred metastasis sites and distinct histomorphologic characteristics. Their metastatic cytomorphologic cell features in body cavity fluids are generally readily recognized, but the single-cell/mesothelial-like pattern and its relationship to the primary tumor type have not been well studied, nor whether metastases have a propensity for certain body cavity sites on the basis of the primary tumor type. To further assess the tumor type and single-cell pattern of breast carcinoma metastases in pleural and peritoneal effusions, we retrospectively studied 853 pleural and peritoneal effusions and correlated the findings with the primary tumor type. When necessary, the single- cell/mesothelial-like pattern was documented immunohistochemically. Metastatic breast carcinomas represented 249 (50.8%) of 490 pleural and 51 (14.0%) of 363 peritoneal effusions. Most metastases in pleural and peritoneal effusions were ductal carcinomas (92.4% and 62.7%, respectively). Lobular carcinoma accounted for only 2 (0.8%) of 249 pleural and 11 (21.6%) of 51 peritoneal effusions. The single-cell/mesothelial like cell pattern was found in all lobular carcinomas but also in 11 (6.0%) of 184 reviewed ductal carcinomas (nine pleural and two peritoneal). Awareness of these findings and the use of immunohistochemical analyses are necessary for accurately diagnosing metastatic breast carcinoma, especially lobular type. PMID- 22431320 TI - IMP3 immunocytochemical staining increases sensitivity in the routine cytologic evaluation of biliary brush specimens. AB - Biliary brush cytology is an important diagnostic tool in the evaluation of biliary strictures. Here, we evaluated 64 patients with biliary strictures who underwent endoscopic retrograde cholangiopancreatography with bile duct brushings. We assessed the utility of combining routine Papanicolaou-stained cytologic evaluation with immunocytochemical expression of insulin-like growth factor mRNA-binding protein-3 (IMP3). Definitive diagnoses were obtained via tissue resection/autopsy, biopsy, fine needle aspiration, or clinical progression of disease. Thirty-nine of the 64 patients were ultimately diagnosed with malignancy. The sensitivity of routine cytology for the detection of malignancy was 33.3%, immunocytochemical-IMP3 expression was 64.1%, and the combined sensitivity was 71.8%. The specificity of each method was 100%. The sensitivity of IMP3 immunocytochemical staining in the detection of malignancy in biliary brushings was superior to routine PAP-stained cytologic evaluation. Moreover, the combined use of biliary brushing cytology and IMP3 immunohistochemistry proved superior to the use of either method alone. PMID- 22431321 TI - The prevalence of abnormal cervical cytology in women with systemic lupus erythematosus. AB - To compare the frequency of abnormal cervical cytology in women with systemic lupus erythematosus (SLE) with that of healthy women without connective tissue diseases by using ThinPrep(r) liquid based Pap Tests(TM) . A retrospective case control study over 2 years was conducted. The cases included all women with SLE who had Pap tests during their treatment period. The control group included all women without SLE or other connective tissue diseases (CTDs) that had routine Pap tests in the same period. The age and demographic features were adjusted and matched for both groups. Statistical analysis included Chi-Square test and Fischer exact test. The SLE group (n= 55) showed significantly (P < 0.05) more abnormal cervical squamous epithelial abnormalities [14 positive cases (25.4%) than the controls (n = 8,175, with 285 positive cases (3.5%)]. Women with SLE had statistically significant higher frequency and prevalence of squamous intraepithelial lesions than women without SLE of similar age and demographic background. The data suggested that women with SLE might benefit from more frequent cervical cytology screening. PMID- 22431322 TI - Squash cytology of subependymal giant cell astrocytoma: report of four cases with brief review of literature. AB - Squash cytology description of subependymal giant cell astrocytoma (SEGA) is poorly described in the literature. Objective of this study is to study the cytomorphological features of SEGA in squash smears. Introperative squash smear preparations of four patients of SEGA diagnosed from 2004 to 2010 were reviewed. One to two millimetres of the biopsy material was crushed between two glass slides to make a thin film and fixed in 95% alcohol and stained by haematoxylin and eosin (H&E). Smear cytology diagnoses were correlated with clinical, radiological data and finally with histopathological findings of the tumor specimen. We had four cases (all males; age range 11-15 years; mean age 12.5 years). All tumors were located in the lateral ventricles. The cytological smears in all four cases were cellular and display pleomorohic binucleate to multinucleate tumor cells disposed in cohesive clusters, groups or lying singly. Elongated spindle shaped and strap cells with long thick cell processes were also identified. On squash smears, SEGA can be diagnosed when cytomorphological features are correlated with clinical and radiological finding. The distinct cytomorphological features are cellular smears comprising of pleomorohic binucleate to multinucleate tumor cells with round to polygonal eccentrically placed mildly anisomorphic nuclei, prominent nucleoli, and abundant eosinophilic glassy cytoplasm. Astrocytic fibrillary background, endothelial proliferation, mitosis, and necrosis are lacking. PMID- 22431323 TI - Cholangiocarcinoma in a 17-year-old boy with primary sclerosing cholangitis and UroVysionTM fluorescent in situ hybridization. AB - Primary sclerosing cholangitis (PSC) is uncommon in the younger age range and bile duct brushing cytology can present unique challenges. We describe the case of a 17-year-old boy with a new diagnosis of PSC who presented with cholangiocarcinoma. The clinical history, endoscopic features, cytomorphologic findings, and results of UroVysionTM fluorescent in situ hybridization (FISH) on the bile duct brush are described. UroVysion FISH on bile duct brushings is an ancillary study that can improve the diagnostic sensitivity for malignancy, specially in challenging cases where the cytomorphologic or clinical characteristics of the case are not typical. The occurrence of cholangiocarcinoma in young age group with PSC is uncommon, and the utilization of UroVysion FISH has been rarely described. PMID- 22431324 TI - Air-stable, highly fluorescent primary phosphanes. AB - Light without fright: a synthetic route to fluorescent primary phosphanes (RPH(2)) that are resistant to air oxidation both in the solid state and in chloroform solution is described. These versatile precursors undergo hydrophosphination to give tripodal ligands and subsequently fluorescent transition-metal complexes. PMID- 22431325 TI - Valve prosthesis distortion after cardiac compression in a patient who underwent transcatheter aortic valve implantation (TAVI). AB - Transcatheter aortic valve implantation (TAVI) has been developed as an alternative to conventional aortic valve replacement for the treatment of symptomatic severe aortic stenosis in high-risk patients. Nevertheless, TAVI has been associated with serious complications such as stroke, vascular injury, renal failure, and arrhythmia. Herein we describe a case of distortion of the Edward Sapien prosthesis (Edwards Lifesciences, USA), which was mounted on a balloon expandable stent, after chest compression for cardiac resuscitation in a patient who underwent TAVI for severe aortic stenosis. PMID- 22431326 TI - The effects of perinatal choline supplementation on hippocampal cholinergic development in rats exposed to alcohol during the brain growth spurt. AB - Prenatal alcohol exposure leads to long-lasting cognitive and attention deficits, as well as hyperactivity. Using a rat model, we have previously shown that perinatal supplementation with the essential nutrient, choline, can reduce the severity of some fetal alcohol effects, including hyperactivity and deficits in learning and memory. In fact, choline can mitigate alcohol-related learning deficits even when administered after developmental alcohol exposure, during the postnatal period. However, it is not yet known how choline is able to mitigate alcohol-related behavioral alterations. Choline may act by altering cholinergic signaling in the hippocampus. This study examined the effects of developmental alcohol exposure and perinatal choline supplementation on hippocampal M(1) and M(2/4) muscarinic receptors. Sprague-Dawley rat pups were orally intubated with ethanol (5.25 mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human third trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. Open field activity was assessed from PD 30 through 33, and brain tissue was collected on PD 35 for autoradiographic analysis. Ethanol-exposed subjects were more active compared to controls during the first 2 days of testing, an effect attenuated with choline supplementation. Developmental alcohol exposure significantly decreased the density of muscarinic M(1) receptors in the dorsal hippocampus, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M(2/4) receptor density, an effect mitigated by choline supplementation. In fact, M(2/4) receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. These data suggest that developmental alcohol exposure can cause long-lasting changes in the hippocampal cholinergic system and that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems. PMID- 22431327 TI - Cross-modal pattern of brain activations associated with the processing of self- and significant other's name. AB - Previous neuroimaging studies have shown that the patterns of brain activity during the processing of personally relevant names (e.g., own name, friend's name, partner's name, etc.) and the names of famous people (e.g., celebrities) are different. However, it is not known how the activity in this network is influenced by the modality of the presented stimuli. In this fMRI study, we investigated the pattern of brain activations during the recognition of aurally and visually presented full names of the subject, a significant other, a famous person and unknown individuals. In both modalities, we found that the processing of self-name and the significant other's name was associated with increased activation in the medial prefrontal cortex (MPFC). Acoustic presentations of these names also activated bilateral inferior frontal gyri (IFG). This pattern of results supports the role of MPFC in the processing of personally relevant information, irrespective of their modality. PMID- 22431328 TI - Favorable outcome with conservative treatment for children with low grade brainstem tumors. PMID- 22431329 TI - Bones' adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition. AB - There is a widely held view that the relationship between mechanical loading history and adult bone mass/strength includes an adapted state or "lazy zone" where the bone mass/strength remains constant over a wide range of strain magnitudes. Evidence to support this theory is circumstantial. We investigated the possibility that the "lazy zone" is an artifact and that, across the range of normal strain experience, features of bone architecture associated with strength are linearly related in size to their strain experience. Skeletally mature female C57BL/6 mice were right sciatic neurectomized to minimize natural loading in their right tibiae. From the fifth day, these tibiae were subjected to a single period of external axial loading (40, 10-second rest interrupted cycles) on alternate days for 2 weeks, with a peak dynamic load magnitude ranging from 0 to 14 N (peak strain magnitude: 0-5000 uepsilon) and a constant loading rate of 500 N/s (maximum strain rate: 75,000 uepsilon/s). The left tibiae were used as internal controls. Multilevel regression analyses suggest no evidence of any discontinuity in the progression of the relationships between peak dynamic load and three-dimensional measures of bone mass/strength in both cortical and cancellous regions. These are essentially linear between the low-peak locomotor strains associated with disuse (~300 uepsilon) and the high-peak strains derived from artificial loading and associated with the lamellar/woven bone transition (~5000 uepsilon). The strain:response relationship and minimum effective strain are site-specific, probably related to differences in the mismatch in strain distribution between normal and artificial loading at the locations investigated. PMID- 22431330 TI - Towards a new family of photoluminescent organozinc 8-hydroxyquinolinates with a high propensity to form noncovalent porous materials. AB - We report on investigations of reactions of tBu(2)Zn with 8-hydroxyquinoline (q H) and the influence of water on the composition and structure of the final product. A new synthetic approach to photoluminescent zinc complexes with quinolinate ligands was developed that allowed the isolation of a series of structurally diverse and novel alkylzinc 8-hydroxyquinolate complexes: the trinuclear alkylzinc aggregate [tBuZn(q)](3) (1(3)), the pentanuclear oxo cluster [(tBu)(3)Zn(5)(MU(4) -O)(q)(5)] (2), and the tetranuclear hydroxo cluster [Zn(q)(2)](2)[tBuZn(OH)](2) (3). All compounds were characterized in solution by (1)H NMR, IR, UV/Vis, and photoluminescence (PL) spectroscopy, and in the solid state by X-ray diffraction, TGA, and PL studies. Density functional theory calculations were also carried out for these new Zn(II) complexes to rationalize their luminescence behavior. A detailed analysis of the supramolecular structures of 2 and 3 shows that the unique shape of the corresponding single molecules leads to the formation of extended 3D networks with 1D open channels. Varying the stoichiometry, shape, and supramolecular structure of the resulting complexes leads to changes in their spectroscopic properties. The close-packed crystal structure of 1(3) shows a redshifted emission maximum in comparison to the porous crystal structure of 2 and the THF-solvated structure of 3. PMID- 22431331 TI - Leonardo da Vinci's "A skull sectioned": skull and dental formula revisited. AB - What can be learned from historical anatomical drawings and how to incorporate these drawings into anatomical teaching? The drawing "A skull sectioned" (RL 19058v) by Leonardo da Vinci (1452-1519), hides more detailed information than reported earlier. A well-chosen section cut explores sectioned paranasal sinuses and ductus nasolacrimalis. A dissected lateral wall of the maxilla is also present. Furthermore, at the level of the foramen mentale, the drawing displays compact and spongious bony components, together with a cross-section through the foramen mentale and its connection with the canalis mandibulae. Leonardo was the first to describe a correct dental formula (6424) and made efforts to place this formula above the related dental elements. However, taking into account, the morphological features of the individual elements of the maxilla, it can be suggested that Leonardo sketched a "peculiar dental element" on the position of the right maxillary premolar in the dental sketch. The fact that the author did not make any comment on that special element is remarkable. Leonardo could have had sufficient knowledge of the precise morphology of maxillary and mandibular premolars, since the author depicted these elements in the dissected skull. The fact that the author also had access to premolars in situ corroborates our suggestion that "something went wrong" in this part of the drawing. The present study shows that historical anatomical drawings are very useful for interactive learning of detailed anatomy for students in medicine and dentistry. PMID- 22431332 TI - Red-emitting dendritic iridium(III) complexes for solution processable phosphorescent organic light-emitting diodes. AB - Functionalization of a red phosphorescent iridium(III) complex core surrounded by rigid polyphenylene dendrons with a hole-transporting triphenylamine surface allows to prevent the intermolecular aggregation-induced emission quenching, improves charge recombination, and therefore enhances photo- and electroluminescence efficiencies of dendrimer in solid state. These multifunctional shape-persistent dendrimers provide a new pathway to design highly efficient solution processable materials for phosphorescent organic light emitting diodes (PhOLEDs). PMID- 22431333 TI - Synthesis and evaluation of anticancer natural product analogues based on angelmarin: targeting the tolerance towards nutrient deprivation. AB - Inspired by nature: Angelmarin is an anticancer natural product with potent antiausterity activity, that is, selective cytotoxicity towards nutrient deprived, resistant cancer cells. Through structure-activity relationship studies, three analogues were identified as lead compounds for the develpoment of molecular probes for the investigation of the mode of action and biological targets of the antiausterity compounds. PMID- 22431334 TI - A2 noradrenergic nerve cell metabolic transducer and nutrient transporter adaptation to hypoglycemia: impact of estrogen. AB - CNS neurons exhibit sustained activation by recurring hypoglycemia in the presence of estrogen. We investigated the impact of estradiol on fuel uptake and detection of energy imbalance by hindbrain A2 metabolosensory neurons during acute vs. chronic hypoglycemia. A2 neurons were laser dissected from estradiol benzoate (EB)- and oil (O)-implanted ovariectomized rats after single or serial injection of neutral protamine Hagedorn (NPH) insulin for single-cell qPCR or high-sensitivity Western blotting. Acute NPH increased A2 GLUT3 mRNA but not protein in EB, but decreased both profiles in O rats. Single insulin dosing did not alter monocarboxylate transporter-2 (MCT2) mRNAs in EB or O, but increased MCT2 protein in EB. Preceding hypoglycemia augmented baseline transporter mRNA and protein in O, but decreased GLUT4 and increased MCT2 proteins in EB. Chronic NPH increased A2 MCT2 and GLUT3 proteins in EB, but elevated GLUT4 protein in O. A2 phospho-AMPK (pAMPK) protein was progressively diminished by acute and chronic hypoglycemia in EB, but elevated in O after serial NPH. Dopamine-beta-hydroxylase (DbetaH) transcripts were decreased in EB during acute and chronic hypoglycemia, but unaltered by serial NPH dosing in O. These results suggest that estrogen enhances A2 lactate utilization during acute hypoglycemia, thereby lessening AMPK activation relative to euglycemic controls. Cellular adaptation to chronic hypoglycemia may involve estrogen-dependent augmentation of lactate and GLUT3 mediated glucose uptake and hormone-independent increases in GLUT4 expression, coincident with diminished pAMPK-mediated signaling of energy deficiency. The data also imply that increased lactate and glucose uptake during recurring hypoglycemia may be required for sustained DbetaH transcriptional reactivity to this metabolic stress. PMID- 22431335 TI - The resonant component of human physiological hand tremor is altered by slow voluntary movements. AB - Limb resonance imparts a characteristic spectrum to hand tremor. Movement will alter the resonance. We have examined the consequences of this change. Rectified forearm extensor muscle EMG and physiological hand tremor were recorded. In postural conditions the EMG spectrum is relatively flat whereas the acceleration spectrum is sharply peaked. Consequently, the gain between EMG and acceleration is maximal at the frequency where the tremor is largest (~8 Hz). The shape of the gain curve implies mechanical resonance. Substantial alterations in posture do not significantly change the characteristics of the tremor or the shape or size of the gain curve. By contrast, slow or moderately paced voluntary wrist flexion extension movements dramatically increase the hand tremor size and lower its peak frequency. These changes in size and frequency of the tremor cannot be attributed to changes in the EMG. Instead they reflect a very large change in the size and shape of the gain curve relating EMG to acceleration. The gain becomes larger and the peak moves to a lower frequency (~6 Hz). We suggest that a movement-related (thixotropic) alteration in resonant properties of the wrist provides a simple explanation for these changes. The mechanism is illustrated by a model. Our new findings confirm that resonance plays a major role in wrist tremor. We also demonstrate that muscles operate very differently under postural and dynamic conditions. The different coupling between EMG and movement in posture and when moving must pose a considerable challenge for neural predictive control of skeletal muscles. PMID- 22431336 TI - Left ventricular mechanics in humans with high aerobic fitness: adaptation independent of structural remodelling, arterial haemodynamics and heart rate. AB - Individuals with high aerobic fitness have lower systolic left ventricular strain, rotation and twist ('left ventricular (LV) mechanics') at rest, suggesting a beneficial reduction in LV myofibre stress and more efficient systolic function. However, the mechanisms responsible for this functional adaptation are not known and the influence of aerobic fitness on LV mechanics during dynamic exercise has never been studied. We assessed LV mechanics, LV wall thickness and dimensions, central augmentation index (AIx), aortic pulse wave velocity (aPWV), blood pressure and heart rate in 28 males (age: 21+/-2 years SD) with a consistent physical activity level (no change>6 months). Individuals were examined at rest and during exercise (40% peak exercise capacity) and separated post hoc into a moderate and high aerobic fitness group (V(O2peak): 49 +/- 5 and 63 +/- 7ml kg-1 min-1, respectively, P <0.0001). At rest and during exercise, there were no significant differences in gross LVstructure, AIx, blood pressure or heart rate (P >0.05).However, for the same AIx, the high V(O2peak) group had significantly lower LV apical rotation (P =0.002) and LV twist (P =0.003) while basal rotation and strain indices did not differ between groups (P >0.05).We conclude that young males with high aerobic fitness have lower LVapical rotation at rest and during submaximal exercise that can occur without changes in gross LV structure, arterial haemodynamics or heart rate. The findings suggest a previously unknown type of physiological adaptation of the left ventricle that may have important implications for exercise training in older individuals and patient populations in which exercise training has previously failed to show clear benefits for LV function. PMID- 22431337 TI - Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors. AB - Kainate receptors (KARs) are a subfamily of ionotropic glutamate receptors (iGluRs) that mediate excitatory synaptic transmission, regulate neurotransmitter release, and show a remarkably selective distribution in the brain. Compared to other iGluRs, the precise contribution of KARs to brain function is less understood. Unlike recombinant KARs, native KARs exhibit characteristically slow channel kinetics. The underlying explanation for this dissimilar kinetics has remained elusive until recently. New research has identified Neto1 and Neto2 as KAR auxiliary subunits that determine unique properties of synaptic KARs, including their slow kinetics and high affinity for agonist. Whether these auxiliary subunits regulate KAR trafficking and targeting at the synapse is less clear. By regulating channel gating, Neto1 and Neto2 can increase the diversity of KAR functional properties. These auxiliary subunits may represent a starting point for a better understanding of the role played by neuronal KARs under normal and pathological conditions, but also, they may provide an alternative target for the development of new drugs regulating KARs and brain function. PMID- 22431338 TI - Riluzole blocks human muscle acetylcholine receptors. AB - Riluzole, the only drug available against amyotrophic lateral sclerosis (ALS), has recently been shown to block muscle ACh receptors (AChRs), raising concerns about possible negative side-effects on neuromuscular transmission in treated patients. In this work we studied riluzole's impact on the function of muscle AChRs in vitro and on neuromuscular transmission in ALS patients, using electrophysiological techniques. Human recombinant AChRs composed of alpha(1)beta(1)delta subunits plus the gamma or epsilon subunit (gamma- or epsilon-AChR) were expressed in HEK cells or Xenopus oocytes. In both preparations, riluzole at 0.5 MUm, a clinically relevant concentration, reversibly reduced the amplitude and accelerated the decay of ACh-evoked current if applied before coapplication with ACh. The action on gamma-AChRs was more potent and faster than on epsilon-AChRs. In HEK outside-out patches, riluzole induced block of macroscopic ACh-evoked current gradually developed during the initial milliseconds of ACh presence. Single channel recordings in HEK cells and in human myotubes from ALS patients showed that riluzole prolongs channel closed time, but has no effect on channel conductance and open duration. Finally, compound muscle action potentials (CMAPs) evoked by nerve stimulation in ALS patients remained unaltered after a 1 week suspension of riluzole treatment. These data indicate that riluzole, while apparently safe with regard to synaptic transmission, may affect the function of AChRs expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated. PMID- 22431339 TI - Voltage-gated potassium channels and the diversity of electrical signalling. AB - Since Hodgkin and Huxley discovered the potassium current that underlies the falling phase of action potentials in the squid giant axon, the diversity of voltage-gated potassium (Kv) channels has been manifested in multiple ways. The large and extended potassium channel family is evolutionarily conserved molecularly and functionally. Alternative splicing and RNA editing of Kv channel genes diversify the channel property and expression level. The mix-and-match of subunits in a Kv channel that contains four similar or identical pore-forming subunits and additional auxiliary subunits further diversify Kv channels. Moreover, targeting of different Kv channels to specific subcellular compartments and local translation of Kv channel mRNA in neuronal processes diversify axonal and dendritic action potentials and influence how synaptic plasticity may be modulated. As one indication of the evolutionary conservation of Kv1 channel functions, mutations of the Shaker potassium channel gene in Drosophila and the KCNA1 gene for its mammalian orthologue, Kv1.1, cause hyperexcitability near axon branch points and nerve terminals, thereby leading to uncontrolled movements and recapitulating the episodic ataxia-1 (EA1) symptoms in human patients. PMID- 22431340 TI - Effects of chemostimuli on [Ca2+]i responses of rat aortic body type I cells and endogenous local neurons: comparison with carotid body cells. AB - Mammalian aortic bodies (ABs) are putative peripheral arterial chemoreceptors whose function remains controversial, partly because information on their cellular physiology is lacking. In this study, we used ratiometric Ca2+ imaging to investigate for the first time chemosensitivity in short-term cultures of dissociated cells of juvenile rat ABs, located near the junction of the left vagus and recurrent laryngeal nerves. Among the surviving cell population were glomus or type I cell clusters, endogenous local neurons and glia-like cells. A variety of chemostimuli, including hypoxia, isohydric or acidic hypercapnia, and isocapnic acidosis, caused a rise in intracellular [Ca2+] in AB type I cells. The [Ca2+]i responses were indistinguishable from those in carotid body (CB) type I cells grown in parallel cultures from the same animals, and responses to acidic hypercapnia were prevented by the non-specific voltage-gated Ca2+ channel antagonist, 2mM Ni2+. Furthermore, we identified a subpopulation (~40%) of glia like cells in AB cultures that resembled CB type II cells based on their approximately equal sensitivity to ATP and UTP, consistent with the expression of purinergic P2Y2 receptors. Finally, we showed that some local neurons, known to be uniquely associated with these AB paraganglia in situ, generated robust [Ca2+]i responses to these chemostimuli. Thus, these AB type I cells and associated putative type II cells resemble those from the well-studied CB. Unlike the CB, however, they also associate with a special group of endogenous neurons which we propose may subserve a sensory function in local cardiovascular reflexes. PMID- 22431341 TI - Quantification of geminate and non-geminate recombination losses within a solution-processed small-molecule bulk heterojunction solar cell. AB - Direct measurements of the field-dependent efficiency with which electron-hole pairs are dissociated (1) can be combined with direct measurement of the carrier density dependent rate at which they subsequently recombine (2) to determine the proportion of carriers which may be usefully extracted (3) for a class of solution-processed organic small-molecule bulk-heterojunction solar cells. PMID- 22431342 TI - Impact of radial-to-aorta vascular anatomical variants on risk of failure in trans-radial coronary procedures. AB - OBJECTIVES: To assess the impact of an "operative" classification of vascular anatomic variants on the feasibility of trans-radial approach. BACKGROUND: Vascular anatomic variants located from the wrist to the aorta may influence the feasibility of trans-radial procedures. Recently, a new "operative" classification of these variants was proposed. METHODS: Consecutive trans-radial diagnostic or interventional catheterizations were considered. Vascular anatomic variants were classified according to 10 categories and sub-grouped according to the ABC classification (A: radial-brachial arterial axis; B: axillary-subclavian anonymous axis; C: aortic arch). Primary study end-point was failure of trans radial approach (necessity to cross-over to another approach to complete the procedure). RESULTS: Three thousand four hundred seventy-seven consecutive radial procedures were considered. Anatomic variants were diagnosed in 308 procedures (8.8%): A variants: 7.2%, B variants: 1.9%; C variants: 0.3%. Failure occurred in 2.0% of procedures. Failure rate was 0.7% in the absence of variants vs.15.2% in the presence of any variant (P < 0.0001, OR 27.7, 95%CI 16.3-46.9). Each of the 10 variants was significantly associated with increased failure rate. Each of the three level-subgroups of variants was significantly associated to the risk of failure (failure 14.7% in A level, 13.9% in B level, 33.3% in C level; P < 0.0001 vs. absence of variants). CONCLUSIONS: Failure of trans-radial procedures is associated to anatomic variants located from the wrist to the aorta. The "operative" ABC classification of anatomic variants is useful not only to categorize these anatomic variants, but also to predict the risk of failure of trans-radial approach. PMID- 22431343 TI - Direct observation of surface reconstruction and termination on a complex metal oxide catalyst by electron microscopy. PMID- 22431344 TI - CdS/CdSe quantum dot shell decorated vertical ZnO nanowire arrays by spin-coating based SILAR for photoelectrochemical cells and quantum-dot-sensitized solar cells. AB - A CdS/CdSe composite shell is assembled onto the surface of ZnO nanowire arrays with a simple spin-coating-based successive ionic layer adsorption and reaction method. The as-prepared photoelectrode exhibit a high photocurrent density in photoelectrochemical cells and also generates good power conversion efficiency in quantum-dot-sensitized solar cells. PMID- 22431345 TI - SP-SR interneurones: a novel class of neurones of the CA2 region of the hippocampus. AB - The CA2 region of the hippocampus has distinctive properties and inputs and may be linked with the pathology of specific psychiatric and neurological disorders. It is, therefore, important to understand CA2 circuitry and its involvement in the circuitry of the hippocampus. Properties of CA2 basket cells have been reported. However, other classes of CA2 interneurones with cell bodies located in stratum pyramidale remained to be described. In this study, the unusual axonal arbors of a novel subclass of dendrite-preferring CA2 interneurones whose somata are located in the pyramidal cell layer was revealed following intracellular recordings and biocytin labeling. One to four apical dendrites emerged from the soma, branched in stratum radiatum (SR) forming a tuft, but rarely penetrated stratum lacunosum-moleculare (SLM). One or two basal dendrites branched close to the soma, the branches extended through stratum oriens (SO) and often reached the alveus. Unlike CA2 bistratified cells, the axons of these cells arborized almost exclusively in SR with few, if any, branches extending to stratum pyramidale (SP), SO, or SLM. These interneurones again, unlike bistratified cells, were immunonegative for parvalbumin and cholecystokinin. Electrophysiologically, they were similar to some CA2 basket and bistratified cells in that they presented a "sag" in response to hyperpolarizing current injections and displayed spike frequency adaptation. They targeted the apical dendrites of neighboring CA2 pyramidal cells and received inputs from them. PMID- 22431346 TI - Inverse modeling in magnetic source imaging: Comparison of MUSIC, SAM(g2), and sLORETA to interictal intracranial EEG. AB - Magnetoencephalography (MEG) is used in the presurgical work-up of patients with focal epilepsy. In particular, localization of MEG interictal spikes may guide or replace invasive electroencephalography monitoring that is required in difficult cases. From literature, it is not clear which MEG source localization method performs best in this clinical setting. Therefore, we applied three source localization methods to the same data from a large patient group for which a gold standard, interictal spikes as identified in electrocorticography (ECoG), was available. The methods used were multiple signal classification (MUSIC), Synthetic Aperture Magnetometry kurtosis [SAM(g2)], and standardized low resolution electromagnetic tomography. MEG and ECoG data from 38 patients with refractory focal epilepsy were obtained. Results of the three source localization methods applied to the interictal MEG data were assigned to predefined anatomical regions. Interictal spikes as identified in ECoG were also assigned to these regions. Identified regions by each MEG method were compared to ECoG. Sensitivity and positive predictive value (PPV) of each MEG method were calculated. All three MEG methods showed a similar overall correlate with ECoG spikes, but the methods differ in which regions they detect. The choice of the inverse model thus has an unexpected influence on the results of magnetic source imaging. Combining inverse methods and seeking consensus can be used to improve specificity at the cost of some sensitivity. Combining MUSIC with SAM(g2) gives the best results (sensitivity = 38% and PPV = 82%). PMID- 22431347 TI - Endovascular stent provides more effective early relief of SVC obstruction compared to balloon angioplasty. AB - OBJECTIVE: To determine whether superior vena cava (SVC) stent implantation is superior to balloon angioplasty for relieving SVC stenosis. BACKGROUND: SVC stent and balloon dilation have been used as treatment for SVC stenosis. Although safe and effective, outcome data comparing the two methods are limited. METHODS: A Pediatric Cardiac Care Consortium review identified SVC stenosis. Patients who required SVC intervention were divided into two subgroups-balloon dilation (Group A) and stent implantation (Group B). Logistic regression and the log-rank test were used to test the need for re-intervention within 6 months after the initial procedure. RESULTS: SVC intervention was performed on 210/637 patients with SVC stenosis (33%). There were 108/210 (51%) patients with balloon dilation (Group A) and 102/210 (49%) with stent implantation (Group B). Re-intervention within 6 months of the initial intervention was more common in Group A compared to Group B [Group A = 31/40 (77.5%); Group B = 5/22 (22.7%)]. The odds-ratio for re intervention within 6 months of the initial procedure for balloon vs. stent, is 7.3 [95% CI: (2.91, 22.3), P < 0.0001]. In addition, during the first 6 months after an intervention for SVC stenosis the proportion of patients with stent implantation that remained free of re-intervention was significantly higher than after balloon angioplasty (log-rank test, P < 0.0001). Neither age nor weight was significantly associated with the need for re-intervention. CONCLUSIONS: SVC stent implantation is more effective than angioplasty in relief of SVC obstruction. Weight and age are not risk factors for early re-intervention. PMID- 22431348 TI - Is NexGen really the next generation of risk assessment? PMID- 22431349 TI - "Heavy metal"--a useful term. PMID- 22431350 TI - "Heavy metal"--cacophony, not symphony. PMID- 22431352 TI - Evolution of the toxic response: how might ecotoxicology benefit by considering evolution? PMID- 22431353 TI - Response to Huebert et al. (2011) "Canada's environmental effects monitoring program: areas for improvement". PMID- 22431355 TI - Population level risk assessments--science or fiction? PMID- 22431356 TI - Understanding interactive effects of climate change and toxicants: importance of evolutionary processes. PMID- 22431357 TI - Incorporating chemical footprint reporting into social responsibility reporting. PMID- 22431358 TI - Ruthenium(II) metallo-supramolecular polymers of click-derived tridentate ditopic ligands. AB - New ditopic 2,6-bis(1,2,3-triazol-4-yl)pyridine ligands featuring a pi-conjugated spacer and clicked-on solubilizing groups were employed in the synthesis of Ru(II) metallo-supramolecular polymers that exhibit an intense metal-to-ligand charge transfer absorption in the visible light region. The coordination polymers obtained were studied in solution by means of size exclusion chromatography and analytical ultracentrifugation, revealing a comparably high molar mass and moderate rigidity. Investigations in the solid state by atomic force and transmission electron microscopy confirmed the formation of rod-like polymers. Furthermore, film preparation by drop-casting showed good film-forming properties. Thus, the solution-processable, photoredoxactive polymers might be applicable in solar cells. PMID- 22431359 TI - [2]Catenanes built around octahedral transition-metal complexes that contain two intertwined endocyclic but non-sterically hindering tridentate ligands. AB - Sterically hindering bidentate chelates, such as 2,9-diphenyl-1,10 phenanthroline, form entwined complexes with copper(I) and other tetrahedrally coordinated transition-metal centres. To prepare octahedral complexes containing two entwined tridentate ligands and thus apply a strategy similar to that used for making catenanes with tetrahedral metal centres, the use of the classical terpy ligand (terpy=2,2':6',2''-terpyridine) appears to be attractive. In fact, 6,6''-diphenyl-2,2':6',2''-terpyridine (dp-terpy) is not appropriate due to strong "pinching" of the organic backbone by coordination to the metal and thus stable entwined complexes with this ligand cannot be obtained. Herein, we report the synthesis and coordination properties of a new family of tridentate ligands, the main features of which are their endocyclic nature and non-sterically hindering character. The coordinating fragment consists of two 8' phenylisoquinolin-3'-yl groups attached at the 2 and 6 positions of a pyridine nucleus. Octahedral complexes containing two such entangled ligands around an octahedral metal centre, such as Fe(II) , Ru(II) or Co(III) , are highly stable, with no steric congestion around the metal. By using functionalised ligands bearing terminal olefins, double ring-closing metathesis leads to [2]catenanes in good yield with Fe(II) or Co(III) as the templating metal centre. The X-ray crystallography structures of the Fe(II) precursor and the Fe(II) catenane are also reported. These show that although significant pinching of the ligand is observed in both Fe(II) complexes, the system is very open and no steric constraints can be detected. PMID- 22431360 TI - Runx1 dose-dependently regulates endochondral ossification during skeletal development and fracture healing. AB - Runx1 is expressed in skeletal elements, but its role in fracture repair has not been analyzed. We created mice with a hypomorphic Runx1 allele (Runx1(L148A) ) and generated Runx1(L148A/-) mice in which >50% of Runx1 activity was abrogated. Runx1(L148A/-) mice were viable but runted. Their growth plates had extended proliferating and hypertrophic zones, and the percentages of Sox9-, Runx2-, and Runx3-positive cells were decreased. Femoral fracture experiments revealed delayed cartilaginous callus formation, and the expression of chondrogenic markers was decreased. Conditional ablation of Runx1 in the mesenchymal progenitor cells of the limb with Prx1-Cre conferred no obvious limb phenotype; however, cartilaginous callus formation was delayed following fracture. Embryonic limb bud-derived mesenchymal cells showed delayed chondrogenesis when the Runx1 allele was deleted ex vivo with adenoviral-expressed Cre. Collectively, our data suggest that Runx1 is required for commitment and differentiation of chondroprogenitor cells into the chondrogenic lineage. PMID- 22431361 TI - Sulci of the liver found after death: Their nature and potential teaching value. AB - Accessory sulci of the liver are more commonly found after death than in life, raising questions as to their causation and possible classification. We have analyzed a group of 180 livers sampled from un-embalmed (96) and embalmed cadavers (84). In un-embalmed cadavers, no accessory sulci were found on the diaphragmatic surface in 58 cases. Diaphragmatic sulci were found in the right lobe of 38 livers. When removed from the abdominal cavity and placed flat on the examination table (the "bench position") all 58 livers without sulci appreciable in the abdominal cavity showed the appearance of two sulci. The first ran from the right side of the inferior vena cava (IVC), curving anteriorly to the inferior border of the liver, at a point midway between the right extremity of the inferior border and the gallbladder fossa, concave towards the left. The second sulcus ran from the left side of the IVC, curving anteriorly to reach the inferior border of the liver at the level of the gallbladder fossa, concave towards the right. With progressive side-to-side manual compression, the sulci on the diaphragmatic surface become more evident. Division of the hepatic parenchyma along the two sulci exposed the right and middle hepatic veins respectively in more than 90% of cases. In embalmed cadavers, 24 livers showed antero-posterior sulci in the superior surface, visible and palpable on the liver examined in situ. When the livers with sulci had been removed from the abdomen for further examination, the appearance of the superior surface did not change. In a removed liver, accessory sulci can be divided into true, "diaphragmatic," sulci and "false" sulci due to the position of the free liver on the examination table. The "false" sulci may be considered as further morphological evidence of the functional anatomical division of the liver. Their demonstration may also be useful in teaching its topographical and surgical anatomy. PMID- 22431362 TI - Heme oxygenase inhibition by alpha-(1H-imidazol-1-yl)-omega-phenylalkanes: effect of introduction of heteroatoms in the alkyl linker. AB - Several alpha-(1H-imidazol-1-yl)-omega-phenylalkanes were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds were found to be potent and selective for the stress-induced isozyme HO-1, showing mostly weak activity toward the constitutive isozyme HO-2. The introduction of an oxygen atom in the alkyl linker produced analogues with decreased potency toward HO-1, whereas the presence of a sulfur atom in the linker gave rise to analogues with greater potency toward HO-1 than the carbon-containing analogues. The most potent compounds studied contained a five-atom linker between the imidazolyl and phenyl moieties, whereas the most HO-1-selective compounds contained a four-atom linker between these groups. The compounds with a five-atom linker containing a heteroatom (O or S) were found to be the most potent inhibitors of HO-2; 1-(N benzylamino)-3-(1H-imidazol-1-yl)propane dihydrochloride, with a nitrogen atom in the linker, was found to be inactive. PMID- 22431363 TI - GM1485, a nonimmunosuppressive immunophilin ligand, promotes neurofunctional improvement and neural regeneration following stroke. AB - Stroke is the leading cause of disability in the industrialized world, and the development of pharmacologic strategies to promote poststroke recovery is of paramount importance. GM1485, a nonimmunosuppressive immunophilin ligand, promotes regeneration of multiple cell types following injury. In the present study, we evaluated the effect of GM1485 treatment on functional recovery and neurogenesis following rat stroke. Transient cerebral ischemia was induced in rats receiving daily GM1485 (5 mg/kg) beginning 24 hr postischemia and continuing for a total of 6 weeks. Neurological function was evaluated over this period using a battery of neurobehavioral tests, and immunostaining for stem-cell markers was performed following animal sacrifice. An in vitro model of oxidative stress was also employed to evaluate the ability of GM1485 to mediate stem-cell like induction and plasticity. GM1485-treated rats demonstrated improved neurological function as well as increased Sox2(+) cells in the ipsilateral SVZ and striatum relative to vehicle-treated rats. Additionally, GM1485-treated fibroblasts subjected to oxidative stress were reprogrammed to a stem-cell-like phenotype and were able to differentiate down a neuronal lineage. These data demonstrate that GM1485 administration improves neurological function and is consistent with an upregulation of endogenous neurogenesis following stroke in rats. Further experiments are necessary to characterize the molecular pathways involved in these processes. PMID- 22431364 TI - High-performance LiNi0.5Mn1.5O4 spinel controlled by Mn3+ concentration and site disorder. AB - The complex correlation between Mn(3+) ions and the disordered phase in the lattice structure of high voltage spinel, and its effect on the charge transport properties, are revealed through a combination of experimental study and computer simulations. Superior cycling stability is achieved in LiNi(0.45)Cr(0.05)Mn(1.5)O(4) with carefully controlled Mn(3+) concentration. At 250th cycle, capacity retention is 99.6% along with excellent rate capabilities. PMID- 22431365 TI - Oxidation by hydrogen in the chemistry and physics of the rare-earth metals. AB - Rare-earth metals (RE) easily react with hydrogen. For decades the bonding of hydrogen has been discussed controversially in terms of either the "proton model" or the "anion model". Detailed investigations of metal-rich compounds of the rare earth metals provide clear evidence for the incorporation of hydrogen as a hydride anion. Several categories of compounds can be distinguished regarding their behavior towards hydrogen. Low-valence compounds with metal-metal bonding frequently provide their excess electrons to form hydride ions as found with the halide hydrides REXH(n). However, there are exceptions, such as, LaI which does not react with hydrogen as a result of special electronic and electrostatic conditions. The opposite is true with La(2)C(3) although this compound does not provide excess metal valence electrons. An amorphous phase La(2)C(3)H(1.5) forms at very low temperature, around 450 K. The presence of hydrogen strongly influences the electrical and magnetic properties, for example, spin-glass formation and colossal magneto resistance arising in the presence of 4f(n) cores with the lanthanoid elements. PMID- 22431366 TI - Transcatheter closure of perimembranous ventricular septal defects: initial human experience with the Amplatzer(r) membranous VSD occluder 2. AB - Although effective, transcatheter closure of perimembranous ventricular septal defects (pmVSD) with the Amplatzer Membranous VSD Occluder (AGA Medical Corporation, MN) carries a substantial risk of complete heart block, prompting many to abandon this intervention. A newly designed Amplatzer device for pmVSD was modified, in part, to minimize this risk. After rigorous preclinical testing, we report the first human experience with the Amplatzer Membranous VSD Occluder 2 (AGA Medical Corporation) in two patients (a 5-year old with a 12-mm pmVSD and a 26-year-old male with a 8-mm defect). Both procedures were successful, with no adverse events at 7 and 4 weeks of follow-up, respectively. Herein, we discuss characteristics of the new device, potential advantages compared to the prior version, and main technical aspects related to the procedure. PMID- 22431367 TI - Ageing effects on path integration and landmark navigation. AB - Navigation abilities show marked decline in both normal ageing and dementia. Path integration may be particularly affected, as it is supported by the hippocampus and entorhinal cortex, both of which show severe degeneration with ageing. Age differences in path integration based on kinaesthetic and vestibular cues have been clearly demonstrated, but very little research has focused on visual path integration, based only on optic flow. Path integration is complemented by landmark navigation, which may also show age differences, but has not been well studied either. Here we present a study using several simple virtual navigation tasks to explore age differences in path integration both with and without landmark information. We report that, within a virtual environment that provided only optic flow information, older participants exhibited deficits in path integration in terms of distance reproduction, rotation reproduction, and triangle completion. We also report age differences in triangle completion within an environment that provided landmark information. In all tasks, we observed a more restricted range of responses in the older participants, which we discuss in terms of a leaky integrator model, as older participants showed greater leak than younger participants. Our findings begin to explain the mechanisms underlying age differences in path integration, and thus contribute to an understanding of the substantial decline in navigation abilities observed in ageing. PMID- 22431368 TI - Hyperoxia during one lung ventilation: inflammatory and oxidative responses. AB - BACKGROUND: It is common practice during one lung ventilation (OLV) to use 100% oxygen, although this may cause hyperoxia- and oxidative stress-related lung injury. We hypothesized that lower oxygen (FiO(2) ) during OLV will result in less inflammatory and oxidative lung injury and improved lung function. METHODS: Twenty pigs (8.88 +/- 0.84 kg; 38 +/- 4.6 days) were assigned to either the hyperoxia group (n = 10; FiO(2) = 100%) or the normoxia group (n = 10; FiO(2) < 50%). Both groups were subjected to 3 hr of OLV. Blood samples were tested for pro-inflammatory cytokines and lung tissue was tested for these cytokines and oxidative biomarkers. RESULTS: There were no differences between groups for partial pressure of CO(2) , tidal volume, end-tidal CO(2) , plasma cytokines, or respiratory compliance. Total respiratory resistance was greater in the hyperoxia group (P = 0.02). There were higher levels of TNF-alpha, IL-1beta, and IL-6 in the lung homogenates of the hyperoxia group than in the normoxia group (P <= 0.01, 0.001, and 0.001, respectively). Myeloperoxidase and protein carbonyls (PC) were higher (P = 0.03 and P = 0.01, respectively) and superoxide dismutase (SOD) was lower in the lung homogenates of the hyperoxia group (P <= 0.001). CONCLUSION: Higher myeloperoxidase, PC, and cytokine levels, and lower SOD availability indicate a greater degree of injury in the lungs of the hyperoxia animals, possibly from using 100% oxygen. In this translational study using a pig model, FiO(2) <= 50% during OLV reduced hyperoxic injury and improved function in the lungs. PMID- 22431369 TI - OMIP-008: measurement of Th1 and Th2 cytokine polyfunctionality of human T cells. PMID- 22431370 TI - Semiquantifying of fascicles of the C7 spinal nerve in the upper and lower subscapular nerves innervating the subscapularis and its clinical inference in Erb's palsy. AB - To elucidate anatomic basis of susceptibility for contracture of the subscapularis muscle in Erb's palsy of the brachial plexus, we semiquantitatively studied the spinal nerve origins of the subscapular nerves innervating the subscapularis, with special reference to the contribution of C7 innervation to the subscapularis. Thirty-three sides of formalin-fixed upper extremities were dissected to obtain the intact brachial plexus. After immersed in 10% acetic acid for 2 weeks, the upper and lower subscapular nerves innervating the whole subscapularis, were dissected retrogradely to verify their spinal nerve origins. The cross-sectional area by C7 innervation and that by the upper trunk innervation was calculated respectively to obtain the constituent percentage of different components in the upper and lower subscapular nerves. In the upper subscapular nerve, fascicles of C7 accounted for 0% (interquartile range, 0-1.1%) of cross-sectional area and those of the upper trunk, 100% (98.9-100%). In the lower subscapular nerve, fascicles of C7 accounted for 40.5% (23.5-47.5%) and those of the upper trunk, 59.5% (52.5-76.5%). In total, 18.6% (13.3-27.3%) of fascicles in the subscapular nerves innervating the subscapularis originated from C7, while 81.4% (72.7-86.7%) of those came from the upper trunk. It is confirmed that innervation of the subscapularis originates from more spinal cord segments than that of infraspinatus and teres minor, and this may be the main reason for which in Erb's palsy, functional recovery of the subscapularis is often faster than that of lateral rotators of the shoulder, resulting in medial rotation contracture of the shoulder. PMID- 22431371 TI - Stacking of self-assembled surface micelles in ultrathin films. AB - Nonpolar fluorophilic/lipophilic tetrablock amphiphiles are investigated on the surface of water and on solid substrates using compression isotherms, Brewster angle microscopy, and atomic force microscopy. At low pressures, the tetrablocks form monolayers of closely packed surface hemimicelles. Further compression causes a 2D/3D transition. At the end of the plateau, half of the deposited material is expelled forming a second monolayer on top of the initially formed monolayer. Both layers of the films consist of surface micelles, thus providing the first example of spontaneous or compression-driven stacking of self-assembled nano-objects. PMID- 22431372 TI - Acute coronary syndrome due to early multiple and complete fractures in sirolimus eluting stent: a case report and brief literature review. AB - Despite drug eluting stents (DES), as compared to bare metal stents, have reduced in-stent restenosis, complex and long lesions remains a challenge for interventional cardiologist. Their treatment is often associated with an unfavorable outcome, related to in-stent restenosis, stent thrombosis, and target lesion revascularization. These complications may derive from the contact between metallic structures and coronary artery endothelium, and consequent overexpression of platelet activating factors, growth factors, and inflammatory cytokines. Recently, an additional mechanism has emerged as new cause of these complications: "stent fracture." Several factors are involved in this phenomenon including material and stent platform, target vessel features, stent implantation technique, and implant duration. We reported a case of 69 years old man with rare early and complex DES fractures on right coronary that caused acute coronary syndrome 36 hr after a previous percutaneous coronary intervention. PMID- 22431373 TI - A fully substituted 3-silolene functions as promising building block for hyperbranched poly(silylenevinylene). AB - A 3-silolene derivative, 2,2,5,5-tetrakis(dimethylsilyl)-1,1-dimethyl-3,4 diphenyl-3-silolene (TDMSHS), is first synthesized and characterized by X-ray diffraction crystallography and spectroscopic methods. Hydrosilylation polymerization of TDMSHS with 1,1-dimethyl-2,5-bis(4-ethynylphenyl)-3,4 diphenylsilole in the presence of Karstedt's catalyst generates a stereoregular silole-containing hyperbranched poly(silylenevinylene) (hb-SPSV) with a high molecular weight (M(w) = 146,000, M(w)/M(n) = 1.5) in high yield (~95%). hb-SPSV exhibits excellent thermal stability and strong fluorescence, and the emission of its aggregates in aqueous mixture can be quenched efficiently by picric acid with large quenching constants K(SV) up to 414400 M(-1). PMID- 22431374 TI - A new vapor-phase hydrothermal method to concurrently grow ZnO nanotube and nanorod array films on different sides of a zinc foil substrate. PMID- 22431375 TI - Denosumab treatment for fibrous dysplasia. AB - Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, alpha subunit of the Gs stimulatory protein (G(s) alpha). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-kappaB ligand (RANKL) is a cell surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases. PMID- 22431376 TI - Activity-based probes for the study of proteases: recent advances and developments. AB - Proteases are important targets for the treatment of human disease. Several protease inhibitors have failed in clinical trials due to a lack of in vivo specificity, indicating the need for studies of protease function and inhibition in complex, disease-related models. The tight post-translational regulation of protease activity complicates protease analysis by traditional proteomics methods. Activity-based protein profiling is a powerful technique that can resolve this issue. It uses small-molecule tools-activity-based probes-to label and analyze active enzymes in lysates, cells, and whole animals. Over the last twelve years, a wide variety of protease activity-based probes have been developed. These synthetic efforts have enabled techniques ranging from real-time in vivo imaging of protease activity to high-throughput screening of uncharacterized proteases. This Review introduces the general principles of activity-based protein profiling and describes the recent advancements in probe design and analysis techniques, which have increased the knowledge of protease biology and will aid future protease drug discovery. PMID- 22431377 TI - Color-tunable photoluminescent fullerene nanoparticles. AB - Highly water-soluble and color-tunable photoluminescent fullerene nanoparticles are synthesized by using tetraethylene glycol (TEG) and lithium hydroxide as a catalyst. The maximum PL emission changes depend on the contents of the remaining pi-conjugation in oxidized C(60), which is partially covalently conjugated with TEG. The PL behavior is attributed to an electronic transition change due to the distortion of symmetrical C(60). PMID- 22431378 TI - Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models. AB - Free radical-mediated neuronal cell damage is an important pathological process in ischemic stroke. We have previously reported a novel dual-functional agent, 2 [[(1,1-dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a derivative of tetramethylpyrazine armed with anitrone moiety. In this report, we further evaluate TBN'stherapeutic parameters in a rat middle cerebral artery occlusion (MCAO) model. Its abilities to cross the blood-brain barrier, scavenge free radicals, and inhibit Ca(2+) influx were also investigated. TBN showed significant activity in both the transient MCAO (t-MCAO) and permanent MCAO (p MCAO) stroke models in the rat. The therapeutic time window is 8 hr in the t-MCAO model. TBN readily crossed the blood-brain barrier and in vitro had strong activity in neutralizing .OH, O(-)(2)., and ONOO(-) and significantly decreased intracellular Ca(2+) concentration. TBN is a promising new treatment forischemic stroke, with multiple mechanisms of action. It blocks Ca(2+) overload and neutralizes .OH, O(-)(2)., and ONOO(-). PMID- 22431379 TI - Unsynchronized translational and rotational diffusion of nanocargo on a living cell membrane. PMID- 22431380 TI - Cortical source of blink-related delta oscillations and their correlation with levels of consciousness. AB - Recently, blink-related delta oscillations (delta BROs) have been observed in healthy subjects during spontaneous blinking at rest. Delta BROs have been linked with continuous gathering of information from the surrounding environment, which is classically attributed to the precuneus. Furthermore, fMRI studies have shown that precuneal activity is reduced or missing when consciousness is low or absent. We therefore hypothesized that the source of delta BROs in healthy subjects could be located in the precuneus and that delta BROs could be absent or reduced in patients with disorders of consciousness (DOC). To test these hypotheses, electroencephalographic (EEG) activity at rest was recorded in 12 healthy controls and nine patients with DOC (four vegetative states, and five minimally conscious states). Three-second-lasting EEG epochs centred on each blink instance were analyzed in both time- (BROs) and frequency domains (event related spectral perturbation or ERSP and intertrial coherence or ITC). Cortical sources of the maximum blink-related delta power, corresponding to the positive peak of the delta BROs, were estimated by standardized Low Resolution Electromagnetic Tomography. In control subjects, as expected, the source of delta BROs was located in the precuneus, whereas in DOC patients, delta BROs were not recognizable and no precuneal localization was possible. Furthermore, we observed a direct relationship between spectral indexes and levels of cognitive functioning in all subjects participating in the study. This reinforces the hypothesis that delta BROs reflect neural processes linked with awareness of the self and of the environment. PMID- 22431381 TI - Bioresorbable vascular scaffolds: the shape of things to come? PMID- 22431382 TI - Urinary desmosine: a biomarker of structural lung injury during CF pulmonary exacerbation. AB - RATIONALE: Cystic fibrosis (CF) lung disease is characterized by structural changes and remodeling in airway architecture and lung parenchyma. Neutrophilic inflammation and infection lead to injury and breakdown of airway matrix constituents, including elastin. The non-invasive measurement of urinary desmosine (UDes), a breakdown product of elastin, may be reflective of ongoing lung injury and may serve as a biomarker of active short-term damage during pulmonary exacerbation. Our objectives were to measure desmosine in the urine of CF patients hospitalized for treatment of a pulmonary exacerbation and to explore the correlation between desmosine concentration and other markers of clinical improvement, including lung function and inflammatory mediators. METHODS: Urine and blood samples plus lung function measurements were collected at up to three points during hospitalization for treatment of a CF pulmonary exacerbation. We used a repeated measures model, adjusted for age and time between measurements, to compare log transformed urine desmosine concentrations across multiple time points and to correlate those concentrations with related clinical variables. Change in UDes concentration was investigated using a statistical model that incorporated normalization factors to account for variations in urinary concentration. RESULTS: Desmosine was measured by radioimmunoassay (RIA) in 155 spot urine samples from 53 CF patients hospitalized for 63 pulmonary exacerbations (range of results: 0-235 pmol Des/ml). Specific gravity (SG) adjusted UDes concentration decreased significantly during admission for CF pulmonary exacerbation, P < 0.01 (average length of stay = 11 days). No correlation was observed between UDes concentration and lung function or inflammatory markers. CONCLUSIONS: UDes decreased significantly following treatment for an acute pulmonary exacerbation and may be a useful biomarker of short-term injury to the CF lung. Further investigation is needed to evaluate the utility of UDes concentration in the long-term progression of CF lung disease. PMID- 22431383 TI - FCSTrans: an open source software system for FCS file conversion and data transformation. PMID- 22431385 TI - Musculotendinous architecture of pathological supraspinatus: a pilot in vivo ultrasonography study. AB - Architectural changes associated with tendon tears of the supraspinatus muscle (SP) have not been thoroughly investigated in vivo with the muscle in relaxed and contracted states. The purpose of this study was to quantify the geometric properties within the distinct regions of SP in subjects with full-thickness tendon tears using an ultrasound protocol previously developed in our laboratory, and to compare findings with age/gender matched normal controls. Twelve SP from eight participants (6 male/2 female), mean age 57 +/- 6.0 years, were investigated. Muscle geometric properties of the anterior region (middle and deep parts) and posterior region (deep part) were measured using image analysis software. Along with whole muscle thickness, fiber bundle length (FBL) and pennation angle (PA) were computed for architecturally distinct regions and/or parts. Pathologic SP was categorized according to the extent of the tear in the tendon (with or without retraction). In the anterior region, mean FBL of the pathologic SP was similar with normal controls; however, mean PA was significantly smaller in pathologic SP with retraction compared with normal controls, in the contracted state (P < 0.05). Mean FBL in the posterior region in both relaxed and contracted states was significantly shorter in the pathologic SP with retraction compared with normal controls (P < 0.05). Findings suggest FBL changes associated with tendon pathology vary between the distinct regions, and PA changes are related to whether there is retraction of the tendon. The ultrasound protocol may provide important information on architectural changes that may assist in decision making and surgical planning. PMID- 22431384 TI - Adult-born hippocampal neurons promote cognitive flexibility in mice. AB - The hippocampus is involved in segregating memories, an ability that utilizes the neural process of pattern separation and allows for cognitive flexibility. We evaluated a proposed role for adult hippocampal neurogenesis in cognitive flexibility using variants of the active place avoidance task and two independent methods of ablating adult-born neurons, focal X-irradiation of the hippocampus, and genetic ablation of glial fibrillary acidic protein positive neural progenitor cells, in mice. We found that ablation of adult neurogenesis did not impair the ability to learn the initial location of a shock zone. However, when conflict was introduced by switching the location of the shock zone to the opposite side of the room, irradiated and transgenic mice entered the new shock zone location significantly more than their respective controls. This impairment was associated with increased upregulation of the immediate early gene Arc in the dorsal dentate gyrus, suggesting a role for adult neurogenesis in modulating network excitability and/or synaptic plasticity. Additional experiments revealed that irradiated mice were also impaired in learning to avoid a rotating shock zone when it was added to an initially learned stationary shock zone, but were unimpaired in learning the identical simultaneous task variant if it was their initial experience with place avoidance. Impaired avoidance could not be attributed to a deficit in extinction or an inability to learn a new shock zone location in a different environment. Together these results demonstrate that adult neurogenesis contributes to cognitive flexibility when it requires changing a learned response to a stimulus-evoked memory. PMID- 22431386 TI - Endovascular embolization of a third jejunal artery aneurysm: isolation technique using the Amplatzer vascular plug 4. AB - Aneurysm of the jejunal artery (JA) is very uncommon with few specific symptoms, but can be a lethal entity. When at risk to rupture, it must be treated expeditiously to avoid mortality. We report a case of a 76-year-old male patient that underwent contrast-enhanced multi-detector computed tomography (MDCT) which incidentally reveals a 12 mm saccular aneurysm of the third JA at the bifurcation of the first arcade. Patient underwent successful endovascular embolization using the isolation technique with the Amplatzer Vascular Plug 4. The patient's recovery was unremarkable and he was discharged on postoperative day 5. Follow-up MDCT reveals total exclusion of the saccular aneurysm of the third jejunal artery with patency of the distal branches. PMID- 22431387 TI - Benzene oxidation at diamond electrodes: comparison of microcrystalline and nanocrystalline diamonds. AB - A comparative study of benzene oxidation at boron-doped diamond (BDD) and nitrogenated nanocrystalline diamond (NCD) anodes in 0.5 M K(2)SO(4) aqueous solution is conducted by using cyclic voltammetry and electrochemical impedance spectroscopy. It is shown by measurements of differential capacitance and anodic current that during the benzene oxidation at the BDD electrode, adsorption of a reaction intermediate occurs, which partially blocks the electrode surface and lowers the anodic current. At the NCD electrode, benzene is oxidized concurrently with oxygen evolution, a (quinoid) intermediate being adsorbed at the electrode. The adsorption and the electrode surface blocking are reflected in the impedance frequency and impedance-potential complex-plane plots. PMID- 22431389 TI - Multilevel regulation of steroid synthesis and metabolism in the bovine placenta. AB - Steroid hormones play critical roles in almost all physiological processes in male and female reproduction. In a normal pregnancy, the concentrations of steroid hormones in maternal and foetal blood vary with gestation in response to changing needs. The placenta plays a central role in producing the appropriate steroids to support the pregnancy by coordinating its own steroidogenic activity with that of the corpus luteum and responding to foetal signals. Although much is known about the steroidogenic potential of the bovine placenta, far less is known about how the placenta integrates the synthesis of steroids with their subsequent metabolism and clearance to achieve appropriate local and peripheral concentrations of steroids in maternal and foetal blood at each stage of gestation. This review focuses on the current knowledge of the temporal and spatial regulation and compartmentalization of the biochemical pathways by which potent steroid hormones are synthesized and metabolized in the bovine placenta. The aim is to increase our understanding of how the balance of synthesis and metabolism determines placental steroid output as it changes with development and differentiation, and how this is regulated in response to the variations in the foetal signals and luteal secretory activity. The review highlights knowledge gaps and suggests that mathematical modelling can help understand the effect of different levels of regulation on the steroidogenic output of an organ, such as the bovine placenta. PMID- 22431393 TI - Dual catalysis: combination of photocatalytic aerobic oxidation and metal catalyzed alkynylation reactions--C-C bond formation using visible light. PMID- 22431394 TI - Effects of pyridoxine on a high-fat diet-induced reduction of cell proliferation and neuroblast differentiation depend on cyclic adenosine monophosphate response element binding protein in the mouse dentate gyrus. AB - In this study, we challenged pyridoxine to mice fed a high-fat diet (HFD) and investigated the effects of pyridoxine on HFD-induced phenotypes such as blood glucose, reduction of cell proliferation and neuroblast differentiation in the dentate gyrus using Ki67 and doublecortin (DCX), respectively. Mice were fed a commercially available low-fat diet (LFD) as control diet or HFD (60% fat) for 8 weeks. After 5 weeks of LFD or HFD treatment, 350 mg/kg pyridoxine was administered for 3 weeks. The administration of pyridoxine significantly decreased body weight in the HFD-treated group. In addition, there were no significant differences in hepatic histology and pancreatic insulin immunoreactive (-ir) and glucagon-ir cells of the HFD-treated group after pyridoxine treatment. In the HFD-fed group, Ki67-positive nuclei and DCX-ir neuroblasts were significantly decreased in the dentate gyrus compared with those in the LFD-fed mice. However, the administration of pyridoxine significantly increased Ki67-positive nuclei and DCX-ir neuroblasts in the dentate gyrus in both LFD- and HFD-fed mice. In addition, the administration of pyridoxine significantly increased the protein levels of glutamic acid decarboxylase 67 (GAD67) and brain-derived neurotrophic factor (BDNF) and the immunoreactivity of phosphorylated cyclic AMP response element binding protein (pCREB) compared with the vehicle-treated LFD- and HFD-fed mice. In contrast, the administration of pyridoxine significantly decreased HFD-induced malondialdehyde (MDA) levels in the hippocampus. These results showed that pyridoxine supplement reduced the HFD induced reduction of cell proliferation and neuroblast differentiation in the dentate gyrus via controlling the levels of GAD67, pCREB, BDNF, and MDA. PMID- 22431395 TI - UV-cured, flexible, and transparent nanocomposite coating with remarkable oxygen barrier. AB - A polymer-layered silicate nanocomposite coating is prepared by combining a novel synthetic lithium-hectorite and an UV-curable, cationic polyurethane. Oxygen transmission measurements clearly indicate the supremacy of the lithium-hectorite as compared to a standard montmorillonite. In addition, a very high degree of optical transparency of the nanocomposite coating is achieved, rendering this material highly interesting for flexible packaging and encapsulation applications. PMID- 22431396 TI - miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1. AB - Uncontrolled oxidative stress impairs bone formation and induces age-related bone loss in humans. The FoxO family is widely accepted to play an important role in protecting diverse cells from reactive oxygen species (ROS). Activation of FoxO1, the main FoxO in bone, stimulates proliferation and differentiation as well as inhibits apoptosis of osteoblast lineage cells. Despite the important role of FoxO1, little is known about how FoxO1 expression in bone is regulated. Meanwhile, several recent studies reported that microRNAs (miRNAs) could play a role in osteoblast differentiation and bone formation by targeting various transcriptional factors. Here, we identified one additional crucial miRNA, miR 182, which regulates osteoblastogenesis by repressing FoxO1 and thereby negatively affecting osteogenesis. Overexpression of miR-182 in osteoblast lineage cells increased cell apoptosis and inhibited osteoblast differentiation, whereas in vivo overexpression of miR-182 in zebrafish impaired bone formation. From in silico analysis and validation experiments, FoxO1 was identified as the target of miR-182, and restoration of FoxO1 expression in miR-182-overexpressing osteoblasts rescued them from the inhibitory effects of miR-182. These results indicate that miR-182 functions as a FoxO1 inhibitor to antagonize osteoblast proliferation and differentiation, with a subsequent negative effect on osteogenesis. To treat bone aging, an antisense approach targeting miR-182 could be of therapeutic value. PMID- 22431397 TI - A patient with X-linked dyskeratosis congenita presenting with bronchiolitis obliterans requiring lung transplantation and immunodeficiency. AB - Dyskeratosis congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow (BM) failure, somatic abnormalities, and predisposition to malignancy, resulting from mutations in proteins involved in maintenance of telomeres. Pulmonary fibrosis resulting in respiratory failure is a serious complication affecting approximately 20% of DKC patients. Pediatric pulmonologists should consider this diagnosis in patients with lung fibrosis and concurrent immunodeficiency or BM failure. PMID- 22431398 TI - Comparative binding energy (COMBINE) analysis supports a proposal for the binding mode of epothilones to beta-tubulin. AB - The conformational preferences of epothilone A (EPA) and a 12,13-cyclopropyl C12 epimerized analogue were explored in aqueous solution using molecular dynamics simulations. The simulated conformers that provided an optimal fit in the paclitaxel binding site of mammalian beta-tubulin were then selected. The resulting modeled complexes were simulated before and after refinement of the M loop to improve the fitting and assess ligand stability within the binding pocket. The tubulin-bound conformation of EPA was found to be unlike a previously reported solution obtained through mixed crystallographic/NMR/modeling studies. However, our conformation was in agreement with an NMR-based proposal although the exact binding pose within the site was different. Molecular models were built for the complexes of 14 epothilone derivatives with beta-tubulin. A projection to latent structures regression method succeeded in providing a good prediction of the experimentally measured binding enthalpies for the whole set of ligands by assigning weights to a selection of interaction energy terms. These receptor based, quantitative structure-activity relationships support the proposed binding mode, help confirm and interpret previously acquired experimental data, shed additional light on the effect of several beta-tubulin mutations on ligand binding, and can potentially direct further experimental studies. PMID- 22431399 TI - Simple gold-catalyzed synthesis of benzofulvenes--gem-diaurated species as "instant dual-activation" precatalysts. PMID- 22431401 TI - Cognitive remediation and emotion skills training for anorexia nervosa: an observational study using neuropsychological outcomes. AB - OBJECTIVE: This study aims to evaluate a novel and brief skills-based therapy for in-patients with anorexia nervosa, which addressed 'cold' and 'hot' cognition. METHOD: Eighty one adults with anorexia nervosa were recruited from two eating disorder in-patient units. In one unit, patients received 10 sessions of cognitive remediation and emotion skills training (CREST) plus treatment as usual. In the other, patients received treatment as usual only. Primary outcomes were body mass index and neuropsychological performance scores. RESULTS: Both groups improved significantly in body mass index and cognitive flexibility. The CREST group also improved on central coherence. Neither group improved significantly on emotion-processing tasks, although the CREST group did show a larger magnitude of change. CONCLUSION: Improvement in 'cold' cognition was achieved in a short period, whereas emotion-processing difficulties might take longer and more therapeutic work to change. Given that effect sizes in the CREST group were larger for the emotion-processing tasks, improved power may benefit future studies. PMID- 22431403 TI - Late contained aortic root rupture and ventricular septal defect after transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is a highly specialized technique offering a new therapeutic option to patients at high risk for conventional surgery. However, despite continuous improvements in operators' expertise and device technology, complications associated with this catheter procedure are not uncommon. We report an unusual case of late contained rupture of the aortic annulus, combining a para-aortic false aneurysm and a ventricular septal defect, after the placement of an Edwards Sapien prosthesis. PMID- 22431402 TI - Synaptic underpinnings of altered hippocampal function in glutaminase-deficient mice during maturation. AB - Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity, mainly in CA1, and manifest behavioral and neurochemical phenotypes suggestive of schizophrenia resilience. To address the basis for the hippocampal hypoactivity, we examined synaptic plastic mechanisms and glutamate receptor expression. Although baseline synaptic strength was unaffected in Schaffer collateral inputs to CA1, we found that long-term potentiation was attenuated. In wild-type (WT) mice, GLS1 gene expression was highest in the hippocampus and cortex, where it was reduced by about 50% in GLS1 hets. In other brain regions with lower WT GLS1 gene expression, there were no genotypic reductions. In adult GLS1 hets, NMDA receptor NR1 subunit gene expression was reduced, but not AMPA receptor GluR1 subunit gene expression. In contrast, juvenile GLS1 hets showed no reductions in NR1 gene expression. In concert with this, adult GLS1 hets showed a deficit in hippocampal-dependent contextual fear conditioning, whereas juvenile GLS1 hets did not. These alterations in glutamatergic synaptic function may partly explain the hippocampal hypoactivity seen in the GLS1 hets. The maturity-onset reduction in NR1 gene expression and in contextual learning supports the premise that glutaminase inhibition in adulthood should prove therapeutic in schizophrenia. PMID- 22431404 TI - Aliskiren, ALTITUDE, and the implications for ATMOSPHERE. PMID- 22431405 TI - Microvolt T-wave alternans in an unselected heart failure population: pros and cons. PMID- 22431406 TI - Cognitive function in patients with decompensated heart failure: the Cognitive Impairment in Heart Failure (CogImpair-HF) study. AB - AIMS: The objective of this study was to examine cognitive and psychological processes systematically in patients with decompensated chronic heart failure (CHF) and to document changes in cognitive function after compensation. Executive functions, episodic memory, and attention are impaired in patients with stable CHF, influencing health behaviour and disease management. Cognitive function and psychological co-morbidities are associated with hospitalization, disability, and mortality. METHODS AND RESULTS: Cognitive performance, self-perceived quality of life, and depression were compared in 20 patients with decompensated CHF [ejection fraction (EF) 27 +/- 8%, N-terminal pro brain natriuretic peptide (NT proBNP) 10 880 pg/mL, interquartile range (4495-13 683)] before and after compensation, 20 age- and gender-matched stable CHF patients [New York Heart Association (NYHA) III-IV, EF 32 +/- 10%, NT-proBNP 1881 pg/mL (323-1502)], and 20 healthy controls (EF 70 +/- 5%). Patients with decompensated CHF showed significantly poorer performance in terms of short-term memory, working memory, executive control, and processing speed (P < 0.05) compared with stable CHF patients. Compensation improved the cognitive performance of decompensated CHF patients up to the level of patients with stable CHF. Compared with healthy controls, both patient groups were affected with respect to episodic memory (P < 0.0001) and fluid intelligence (P < 0.01). CONCLUSION: Decompensated heart failure patients are highly impaired in cognitive functioning, which improves but does not normalize after compensation. Neuropsychological diagnostics delivers important details for daily life activities and might identify individuals deserving special care. PMID- 22431407 TI - FIESTA: an MR arthrography celebration of shoulder joint anatomy, variants, and their mimics. AB - Magnetic resonance (MR) arthrography is currently the gold standard radiological investigation for shoulder joint instability. Not only does this investigation allow for identification of important disease processes, but the reduced slice thickness and increased in-plane resolution allowed by the latest imaging sequences also gives excellent demonstration of shoulder joint internal anatomy. This article describes the technique of MR arthrography of the shoulder practiced at our institution, briefly outlining features of the FIESTA (fast imaging employing steady state acquisition) MR sequence employed, including its advantages and limitations. A pictorial review of shoulder MR arthrography performed with this technique is presented, concentrating on normal shoulder joint internal anatomy and anatomical variants that may mimic pathology. PMID- 22431408 TI - Regulation of FSH receptor expression by the Wilms' tumor 1 gene product (WT1) in immature rat granulosa cells. PMID- 22431409 TI - Photocatalytic generation of syngas using combustion-synthesized silver bismuth tungstate. AB - Silver bismuth tungstate (AgBiW(2)O(8)) nanoparticles were prepared for the first time by solution combustion synthesis by using the corresponding metal nitrates as the precursor and urea as the fuel. These nanoparticles were subsequently modified with Pt catalyst islands using a photocatalytic procedure and used for the photogeneration of syngas (CO+H(2)). Formic acid was used for this purpose for the in situ generation of CO(2) and its subsequent reduction to CO. In the absence of Pt modification, H(2) was not obtained in the gas products evolved. These results were compared with those obtained with acetic acid in place of formic acid. The combustion process was simulated by thermogravimetry and the synthesized powder was characterized using transmission electron microscopy, diffuse reflectance UV/Vis spectroscopy, X-ray diffraction, surface area measurements, and X-ray photoelectron spectroscopy. Tauc plots derived from the diffuse reflectance data yielded an optical band gap of 2.74 eV. The photocatalytic activity of these nanoparticles was superior to a sample prepared by solid-state synthesis. Mechanistic aspects are finally presented, as are structural models and electronic calculations, using density functional theory (DFT). PMID- 22431410 TI - CDC reactions of N-aryl tetrahydroisoquinolines using catalytic amounts of DDQ: C H activation under aerobic conditions. PMID- 22431411 TI - PARP-1 deletion promotes subventricular zone neural stem cells toward a glial fate. AB - Identification of critical factors involved in oligodendroglial fate specification from endogenous neural stem cells is relevant to the development of therapeutic interventions that aim to promote remyelination. Here we report a novel role of the DNA repair protein poly-ADP-ribose polymerase-1 (PARP-1) in regulating the neural stem cell profile in the postnatal mouse forebrain subventricular zone (SVZ). We observed increased expression of Sox2 and Sox10 in the SVZ of postnatal day 11 (P11) PARP-1 knockout mice. This increase corresponded to increased Olig2 expression in Sox2-positive cells of the PARP-1 knockout mouse SVZ and decreased Map2abc expression compared with Sox2/Olig2 and Sox2/Map2abc expression in wild-type mice. We noted enhanced expression of proliferating oligodendrocyte progenitor cells (OPCs) at the expense of proliferating neuroblasts in the SVZ of PARP-1 knockout mice, by using Olig1/Ki67/DCX, NG2/Ki67/DCX, and PDGFR/BrdU/TuJ1 immunofluorescence labeling. In addition, the percentage of BrdU/Olig2 double-labeled cells increased in the SVZ and corpus callosum of PARP-1 knockout mice compared with wild-type mice. We also observed a decrease in DCX-positive cells without a decrease in the overall SVZ area in PARP-1 knockout mice, further indicating a switch from neuroblast to OPC fate. PARP-1 knockout mice displayed thinning of MBP expression in the corpus callosum and external capsule, suggesting that the enhanced OPC proliferation in the SVZ might compensate for deficiency in myelination. Together, our results show that PARP-1 deletion promotes SVZ neural stem cells toward a glial fate and suggest that future studies target PARP-1 as a potential therapeutic strategy for demyelinating diseases. PMID- 22431412 TI - Phosphorescent organic light-emitting diodes with outstanding external quantum efficiency using dinuclear rhenium complexes as dopants. AB - The photophysical and electroluminescence properties of two dinuclear rhenium(I) carbonyl complexes bearing 1,2-diazines are comprehensively investigated. The bromo-bridged complex is successfully used as triplet emitter for the preparation of vacuum-processed OLEDs with outstanding external quantum efficiencies, reaching a value of 10%. PMID- 22431413 TI - Time to onset of antifracture efficacy and year-by-year persistence of effect of zoledronic acid in women with osteoporosis. AB - Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 (p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years. PMID- 22431414 TI - Cyanosis when head turned to left in an infant with primary ciliary dyskinesia. AB - A 19-month-old boy with primary ciliary dyskinesia (PCD), mirror-image dextrocardia, situs inversus (SI) totalis suffered from persistent hypoxia. Cyanosis became clinically evident when the child turned the head to the left and resolved after turning the head to the right. Echocardiography demonstrated two superior caval veins; the left sided superior vena cava (SVC) entering the left sided right atrium (RA) and the right sided into the right sided left atrium (LA). Surgical redirection of the right sided caval vein into RA was performed. PMID- 22431415 TI - Pharmacodynamic effects of adjunctive cilostazol therapy in patients with coronary artery disease on dual antiplatelet therapy: impact of high on-treatment platelet reactivity and diabetes mellitus status. AB - BACKGROUND: In patients on dual antiplatelet therapy with aspirin and clopidogrel, the adjunctive use of cilostazol is associated with enhanced platelet inhibition. However, if cilostazol exerts different pharmacodynamic (PD) effects according to levels of on-treatment platelet reactivity remains unknown. This study aimed to determine the PD effects of cilostazol in patients with and without high on-clopidogrel platelet reactivity (HPR) according to diabetes mellitus (DM) status. METHODS: This is a post-hoc analysis derived from patients (n = 79) enrolled in a prospective, randomized, double-blind, double-dummy, crossover study comparing cilostazol with placebo in stable coronary artery disease patients on aspirin and clopidogrel therapy. In the present analysis, patients were divided according to the presence or absence of HPR (HPR and non HPR). HPR was defined as a P2Y12 units (PRU) > 240 as assessed by the VerifyNow P2Y12 assay. The PD effects of cilostazol were evaluated in patients with and without HPR according to DM status. RESULTS: Significant absolute changes in PRU values were observed after adjunctive cilostazol in both HPR [53.4 (95% CI 24.7 82.1), P = 0.001] and non-HPR [40.8 (95% CI 28.7-52.8), P < 0.0001] patients. This difference was statistically significant in HPR patients with DM (P = 0.001), but not without DM (P = 0.24), and in non-HPR patients with and without DM (P = 0.0001 for both). The greatest mean reduction in PRU was observed in HPR patients with DM (72.9; 95% CI 33.7-112.0). Thrombin generation was not affected by cilostazol, irrespective of HPR status. CONCLUSION: Cilostazol reduces platelet reactivity both in HPR and non-HPR patients, although these PD effects are enhanced in HPR patients with DM. Nevertheless, larger studies are needed to better evaluate possible differential effects of cilostazol on platelet reactivity by diabetes status. PMID- 22431416 TI - BCN graphene as efficient metal-free electrocatalyst for the oxygen reduction reaction. PMID- 22431417 TI - Artificial dicopper oxidase: rational reprogramming of bacterial metallo-beta lactamase into a catechol oxidase. PMID- 22431418 TI - Self-assembly of short peptides composed of only aliphatic amino acids and a combination of aromatic and aliphatic amino acids. AB - The morphology of structures formed by the self-assembly of short N-terminal t butyloxycarbonyl (Boc) and C-terminal methyl ester (OMe) protected and Boc deprotected hydrophobic peptide esters was investigated. We have observed that Boc-protected peptide esters composed of either only aliphatic hydrophobic amino acids or aliphatic hydrophobic amino acids in combination with aromatic amino acids, formed highly organized structures, when dried from methanol solutions. Transmission and scanning electron microscopic images of the peptides Boc-Ile-Ile OMe, Boc-Phe-Phe-Phe-Ile-Ile-OMe and Boc-Trp-Ile-Ile-OMe showed nanotubular structures. Removal of the Boc group resulted in disruption of the ability to form tubular structures though spherical aggregates were formed. Both Boc-Leu-Ile Ile-OMe and H-Leu-Ile-Ile-OMe formed only spherical nanostructures. Dynamic light scattering studies showed that aggregates of varying dimensions were present in solution suggesting that self-assembly into ordered structures is facilitated by aggregation in solution. Fourier transform infrared spectroscopy and circular dichroism spectroscopy data show that although all four of the protected peptides adopt well-defined tertiary structures, upon removal of the Boc group, only H-Phe Phe-Phe-Ile-Ile-OMe had the ability to adopt beta-structure. Our results indicate that hydrophobic interaction is a very important determinant for self-assembly and presence of charged and aromatic amino acids in a peptide is not necessary for self-assembly. PMID- 22431419 TI - Initiation of sulfonylureas versus metformin is associated with higher blood pressure at one year. AB - PURPOSE: To determine if incident oral antidiabetic drug (OAD) use was associated with 12-month systolic blood pressure (BP) and if this was mediated through body mass index (BMI) changes. METHODS: A retrospective cohort of veterans with hypertension who initiated metformin (n = 2057) or sulfonylurea (n = 1494) between 1 January 2000 and 31 December 2007 in the Veterans Administration Mid South Network was assembled. Patients were included if they had complete covariates, including 12-month BP and BMI, and persisted on therapy for 12 months. Linear regression was conducted to investigate the effect of OADs on 12 month systolic BP adjusting for demographics, glycated hemoglobin, creatinine, BMI, health care utilization, and comorbidities, including cardiovascular disease (CVD). A second analysis examined if these effects were mediated by BMI change. The secondary outcome was the proportion of patients who had a controlled BP (<= 140/90 mmHg) at 12 months adjusted for baseline BP and covariates. RESULTS: Patients were white (82%) males (97%) with median age of 64 years (interquartile range [IQR] 57, 72), and 27% had history of CVD. Sulfonylurea users had a 1.33 mmHg (0.16, 2.50, p = 0.03) higher 12-month systolic BP than metformin users. The median change in BMI from OAD initiation to 12 months was -0.76 (IQR -1.78, 0.07) and 0.21 (IQR -0.57, 1.03) among metformin and sulfonylurea users, respectively. In a model adjusting for BMI change, the difference in 12-month systolic BP between sulfonylurea and metformin users became insignificant (0.23 (-1.00, 1.45), p = 0.72), while one BMI unit change was associated with an increase in 12 month systolic BP of 1.07 mmHg (0.74, 1.40, p < 0.0001). At 12 months, 68.3% of metformin patients had controlled BP versus 64.2% of sulfonylurea patients (p = 0.01). CONCLUSIONS: Compared with metformin, sulfonylurea initiation was associated with increased systolic BP at 12 months, which appears to be mediated by the differential effects of these drugs on BMI. PMID- 22431420 TI - Case study interpretation--Portland: Case 1. Hairy cell leukemia with CLL-like monoclonal B lymphocytosis. PMID- 22431421 TI - Current operator volumes of invasive coronary procedures in Medicare patients: implications for future manpower needs in the catheterization laboratory. AB - OBJECTIVES: We seek to assess the per-operator volume of diagnostic catheterizations and percutaneous coronary interventions (PCI) among US cardiologists, and its implication for future manpower needs in the catheterization laboratory. BACKGROUND: The number of annual Medicare PCIs peaked in 2004 and has trended downward since, however the total number of catheterization laboratories nationwide has increased. It is unknown whether these trends have resulted in a dilution of per-operator volumes, and whether the current supply of interventional cardiologists is appropriate to meet future needs. METHODS: We analyzed the Centers for Medicare and Medicaid Services 2008 Medicare 5% sample file, and extracted the total number of Medicare fee-for service (Medicare FFS) diagnostic catheterizations and PCIs performed in 2008. We then determined per-physician procedure volumes using National Provider Identifier numbers. RESULTS: There were 1,198,610 Medicare FFS diagnostic catheterizations performed by 11,029 diagnostic cardiologists, and there were 378,372 Medicare FFS PCIs performed by 6,443 interventional cardiologists in 2008. The data reveal a marked difference in the 2008 distribution of diagnostic catheterizations and PCIs among operators. Just over 10% of diagnostic catheterizations were performed by operators performing 40 or fewer Medicare FFS diagnostic catheterizations, contrasted with almost 30% of PCIs performed by operators with 40 of fewer Medicare FFS PCIs. A significant majority of interventional cardiologists (61%) performed 40 or fewer Medicare FFS PCIs in 2008. CONCLUSIONS: There is a high percentage of low-volume operators performing PCI, raising questions regarding annual volume recommendations for procedural skill maintenance, and the future manpower requirements in the catheterization laboratory. PMID- 22431423 TI - Heinrich August Wrisberg (1736-1808): physician and anatomist. AB - The German Heinrich August Wrisberg made significant contributions to anatomical knowledge during the late 18th and early 19th centuries. However, very little is known of this early European physician and anatomist. Wrisberg was considered an excellent anatomist and wrote several textbooks in the field. Using standard computer search engines, this report reviews the known literature on this historic figure and notes his multiple contributions to the study of human morphology. PMID- 22431424 TI - Acute severe mitral regurgitation following balloon mitral valvotomy: echocardiographic features, operative findings, and outcome in 50 surgical cases. AB - OBJECTIVE: To analyze the echocardiographic and operative findings with respect to mitral valve anatomy in individuals undergoing emergency surgery for acute severe mitral regurgitation (MR) following balloon mitral valvotomy (BMV). In addition, the clinical profile and outcomes are highlighted. BACKGROUND: Acute severe MR is a major complication of BMV. There are only a few reports which have studied the echocardiographic and operative findings in this setting. In addition, optimal timing of surgery is uncertain. METHODS: Prospective study of 50 consecutive patients undergoing emergency mitral valve replacement (MVR) for acute severe MR following BMV. RESULTS: In 3855 patients who underwent BMV, acute severe MR developed in 50 cases (1.3%) and was referred for emergency MVR. Hypotension (72%), hypoxia (64%), orthopnea (14%), and pulmonary edema (12%) were the clinical manifestations. Severe MR was secondary to anterior mitral leaflet tear in 36 cases (72%), paracommisural tear with annular involvement in seven cases (14%), posterior mitral leaflet tear in five cases (10%) and chordal tear in two cases (4%). The correlation between two-dimensional transthoracic echocardiography (2D-TTE) and operative finding for mitral valve calcification was found to be strong (r = 0.862), in contrast to submitral fusion, where it was found to be moderate (r = 0.536). In-hospital mortality was 12%. Mortality was higher in patients whose time to surgery was >=24 hr when compared to those who underwent MVR within 24 hr (P < 0.001). CONCLUSIONS: Hypotension and hypoxia are the predominant manifestations of acute severe MR following BMV. Anterior mitral leaflet tear is the most common etiology for severe MR. 2D-TTE underestimated the severity of submitral disease. Early MVR (<24 hr) is recommended for optimal outcome. PMID- 22431425 TI - Synthetic (+/-)-axinellamines deficient in halogen. PMID- 22431427 TI - Enantioselective hydrosilylation with chiral frustrated Lewis pairs. PMID- 22431426 TI - Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX. AB - Denosumab has been shown to reduce the incidence of vertebral, nonvertebral, and hip fractures. The aim of the current study was to determine whether the antifracture efficacy of denosumab was dependent on baseline fracture probability assessed by FRAX. The primary data of the phase 3 FREEDOM study of the effects of denosumab in women with postmenopausal osteoporosis were used to compute country specific probabilities using the FRAX tool (version 3.2). The outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. At baseline, the median 10-year probability of a major osteoporotic fracture (with bone mineral density) was approximately 15% and for hip fracture was approximately 5% in both groups. In the simplest model adjusted for age and fracture probability, treatment with denosumab over 3 years was associated with a 32% (95% confidence interval [CI] 20% to 42%) decrease in clinical osteoporotic fractures. Denosumab reduced fracture risk to a greater extent in those at moderate to high risk. For example, at 10% probability, denosumab decreased fracture risk by 11% (p = 0.629), whereas at 30% probability (90th percentile of study population) the reduction was 50% (p = 0.001). The reduction in fracture was independent of prior fracture, parental history of hip fracture, or secondary causes of osteoporosis. A low body mass index (BMI) was associated with greater efficacy. Denosumab significantly decreased the risk of clinical osteoporotic fractures in postmenopausal women. Overall, the efficacy of denosumab was greater in those at moderate to high risk of fracture as assessed by FRAX. PMID- 22431428 TI - Selective unilateral lung ventilation in preterm infants with acquired bullous emphysema: a series of nine cases. AB - BACKGROUND AND AIMS: Immature lungs of preterm infants are particularly prone to overdistension from mechanical ventilation or continuous positive airway pressure. In these infants a localized pulmonary emphysema (PE) can develop. Conventional therapy regimens to resolve this process sometimes fail and especially in the case of bullous emphysema (BE) invasive procedures such as surgical resection of the affected lobe ultimately may be required. In the past few years we have applied selective one-sided lung ventilation, a nearly forgotten therapeutic option, in these infants with acquired BE. METHODS: Medical charts of preterm infants in two Divisions of Neonatology, born between 1993 and 2010 with acquired BE treated with selective one-sided ventilation were reviewed. Gestational age, clinical presentation, course of disease, associated treatment, duration of ventilation and outcome of one-sided lung ventilation are recorded. Therapy was deemed successful if thereafter chest X-ray showed a permanent resolution of the BE and, in case of BPD, lung appearance was comparable to a grade < III according to Weinstein [Weinstein et al. Pediatr Pulmonol 1994; 18: 284-289]. RESULTS: Overall, nine preterm infants with a gestational age between 24 and 35 weeks and a birth weight between 500 and 3,170 g underwent one-sided lung ventilation. This intervention was started between day 12 and day 35 after birth and was continued for 24 hr to 7 days. In three cases selective intubation was performed on the left side. Two patients needed a second course of one-sided ventilation and one had three courses. Therapy was successful in seven patients, who had no recurrence of BE. CONCLUSIONS: Selective one-sided intubation is technically challenging, in particular for the left bronchus, but seems to be feasible and helpful. If during selective intubation the affected lung lobe shows complete atelectasis for more than 48 hr the overdistension of airways probably will permanently resolve. PMID- 22431429 TI - Synthesis, structures, and reactivities of pincer-type ruthenium complexes bearing two proton-responsive pyrazole arms. AB - A new metal-ligand bifunctional, pincer-type ruthenium complex [RuCl(L1 H(2))(PPh(3))(2)]Cl (1; L1-H(2)=2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine) featuring two proton-delivering pyrazole arms has been synthesized. Complex 1, derived from [RuCl(2)(PPh(3))(3)] with L1-H(2), underwent reversible deprotonation with potassium carbonate to afford the pyrazolato-pyrazole complex [RuCl(L1-H)(PPh(3))(2)] (2). Further deprotonation of 1 and 2 with potassium hexamethyldisilazide in methanol resulted in the formation of the bis(pyrazolato) complex [Ru(L1)(MeOH)(PPh(3))(2)] (3). Complex 3 smoothly reacted with dioxygen and dinitrogen to give the side-on peroxo complex [Ru(L1)(O(2))(PPh(3))(2)] (4) and end-on dinitrogen complex [Ru(L1)(N(2))(PPh(3))(2)] (5), respectively. On the other hand, the reaction of [RuCl(2)(PPh(3))(3)] with less hindered 2,6-di(1H pyrazol-3-yl)pyridine (L3-H(2)) led to the formation of the dinuclear complex [{RuCl(2)(PPh(3))(2)}(2)(MU(2)-L3-H(2))(2)] (6), in which the pyrazole-based ligand adopted a tautomeric form different from L1-H(2) in 1 and the central pyridine remained uncoordinated. The detailed structures of 1-6 were determined by X-ray crystallography. PMID- 22431430 TI - Elastomer surfaces with directionally dependent adhesion strength and their use in transfer printing with continuous roll-to-roll applications. AB - In this paper we present mechanics and materials aspects of elastomeric stamps that have angled features of relief on their surfaces, designed to enable control of adhesion strength by peeling direction, in a way that can be exploited in schemes for deterministic assembly by transfer printing. Detailed mechanics models capture the essential physics of interface adhesion in this system. Experiments with cylindrical stamps that have this design demonstrate their potential for use in a continuous, roller mode of operation. PMID- 22431431 TI - Case study interpretation--Portland: Case 2. Low grade B cell lymphoma with plasmacytic differentiation. PMID- 22431432 TI - Production cost structure in US outpatient physical therapy health care. AB - This paper investigates the technology cost structure in US physical therapy care. We exploit formal economic theories and a rich national data of providers to tease out implications for operational cost efficiencies. The 2008-2009 dataset comprising over 19 000 bi-weekly, site-specific physical therapy center observations across 28 US states and Occupational Employment Statistics data (Bureau of Labor Statistics) includes measures of output, three labor types (clinical, support, and administrative), and facilities (capital). We discuss findings from the iterative seemingly unrelated regression estimation system model. The generalized translog cost estimates indicate a well-behaved underlying technology structure. We also find the following: (i) factor demands are downwardly sloped; (ii) pair-wise factor relationships largely reflect substitutions; (iii) factor demand for physical therapists is more inelastic compared with that for administrative staff; and (iv) diminishing scale economies exist at the 25%, 50%, and 75% output (patient visits) levels. Our findings advance the timely economic understanding of operations in an increasingly important segment of the medical care sector that has, up-to-now (because of data paucity), been missing from healthcare efficiency analysis. Our work further provides baseline estimates for comparing operational efficiencies in physical therapy care after implementations of the 2010 US healthcare reforms. PMID- 22431433 TI - Long-term clinical outcome of rotational atherectomy followed by drug-eluting stent implantation in complex calcified coronary lesions. AB - OBJECTIVES: To assess long-term outcome after rotational atherectomy (RA) is followed by drug-eluting stent (DES) implantation in complex calcified coronary lesions. BACKGROUND: RA can favorably modify heavily calcified coronary lesions, but long-term outcome is poor when it is used as a stand-alone therapy or combined with bare-metal stents. DES have reduced rates of restenosis in a wide range of patient and lesion subsets, but little information is available on long term clinical outcome when RA is followed by DES implantation (Rota-DES) in complex calcified lesions. METHODS AND RESULTS: Two hundred and five patients with de novo complex calcified coronary lesions treated with Rota-DES were analyzed. Mean age was 69.7 +/- 9.3 years, 63 patients (31%) had diabetes mellitus and 21 patients (10%) had chronic renal failure. Total stent length/patient was 32 mm. The majority of patients were treated with paclitaxel eluting stents (64%) or sirolimus-eluting stents (30%). Angiographic success rate was 98%. The incidence of in-hospital major adverse cardiac events (MACE), defined as death, myocardial infarction (MI), and target vessel revascularization (TVR), was 4.4%. Long-term follow-up was available for 188 patients (92%). At a median follow-up period of 15 months (range, 1-84), the cumulative incidence of MACE (Kaplan-Meier estimate) was 17.7%. Death occurred in 4.4%, MI in 3.4%, TVR in 9.9%, and target lesion revascularization (TLR) in 6.8%. One definite (0.5%) and one probable (0.5%) stent thrombosis were observed. In a multivariate analysis, low ejection fraction (<40%) was the only independent predictor of MACE, and both age and diabetes were independent predictors of TLR. CONCLUSION: This study represents the largest European data set of patients treated with RA in the DES era. RA followed by DES implantation in calcified coronary lesions appears to be feasible and effective, with a high rate of procedural success and low incidence of TLR and MACE at long term considering this complex patient and lesion subset. PMID- 22431434 TI - Native chemical ligation in dimethylformamide can be performed chemoselectively without racemization. AB - Native chemical ligation of unprotected peptides in organic solvents has been previously reported as a fast, efficient, and suitable method for coupling of hydrophobic peptides. However, it has not been determined whether the reaction can be carried out without possible side reactions or racemization. Here, we present a study on the chemoselectivity of this method by model reactions designed to test the reactivity of Arg and Lys side chains as well as that of alpha-amino groups. A possible racemization of the C-terminal amino acid of the N terminal peptide was also investigated. The results show that ligation in organic solvents can be conducted chemoselectively without side reactions with other nucleophilic groups. Furthermore, no racemization of the C-terminal amino acid was observed if both educts were added simultaneously. Thus, native chemical ligation can be performed either in aqueous buffer systems or in organic solvents paving the way for the synthesis of larger hydrophobic peptides and/or membrane proteins. PMID- 22431435 TI - The roles of endoplasmic reticulum stress and mitochondrial apoptotic signaling pathway in quercetin-mediated cell death of human prostate cancer PC-3 cells. AB - Prostate cancer has its highest incidence and is becoming a major concern. Many studies have shown that traditional Chinese medicine exhibited antitumor responses. Quercetin, a natural polyphenolic compound, has been shown to induce apoptosis in many human cancer cell lines. Although numerous evidences show multiple possible signaling pathways of quercetin in apoptosis, there is no report to address the role of endoplasmic reticulum (ER) stress in quercetin induced apoptosis in PC-3 cells. The purpose of this study was to investigate the effects of quercetin on the induction of the apoptotic pathway in human prostate cancer PC-3 cells. Cells were treated with quercetin for 24 and 48 h and at various doses (50-200 MUM), and cell morphology and viability decreased significantly in dose-dependent manners. Flow cytometric assay indicated that quercetin at 150 MUM caused G0/G1 phase arrest (31.4-49.7%) and sub-G1 phase cells (19.77%) for 36 h treatment and this effect is a time-dependent manner. Western blotting analysis indicated that quercetin induces the G0/G1 phase arrest via decreasing the levels of CDK2, cyclins E, and D proteins. Quercetin also stimulated the protein expression of ATF, GRP78, and GADD153 which is a hall marker of ER stress. Furthermore, PC-3 cells after incubation with quercetin for 48 h showed an apoptotic cell death and DNA damage which are confirmed by DAPI and Comet assays, leading to decrease the antiapoptotic Bcl-2 protein and level of DeltaPsim , and increase the proapoptotic Bax protein and the activations of caspase-3, -8, and -9. Moreover, quercetin promoted the trafficking of AIF protein released from mitochondria to nuclei. These data suggest that quercetin may induce apoptosis by direct activation of caspase cascade through mitochondrial pathway and ER stress in PC-3 cells. PMID- 22431436 TI - Francesco Parona (1842-1908) and his contributions to our understanding of surgery through anatomy. AB - Much of the life of Francesco Parona and many of his contributions to medicine are unknown outside of Europe. Parona made novel contributions to many surgical techniques and medical treatments and was an active member of society and the Italian political regime. Parona's name lives on eponymously by his "space" in the forearm. This paper will discuss the personal life and medical contributions of Francesco Parona. PMID- 22431437 TI - A role for the Warburg effect in preimplantation embryo development: metabolic modification to support rapid cell proliferation. AB - In this essay, we propose that embryos express a metabolic phenotype necessarily different from that of differentiated somatic cells and more like that of rapidly proliferating cancer cells. This metabolic adaptation, known as the Warburg effect, supports rapid cell proliferation. One of the hallmarks of the Warburg effect is that pyruvate is directed away from the tri-carboxylic acid cycle and metabolized to lactate, resulting in a buildup of glycolytic intermediates. Although this is a comparatively inefficient way to generate ATP, this adaptation allows the cell to meet other critical metabolic requirements, including biomass production and redox regulation. Thus, utilization of WE gives proliferating cells a selective growth advantage. This model represents a completely new understanding of embryo metabolism in the context of a broad, interconnected network of metabolic mechanisms that influence viability, versus the current dogma of carbohydrate metabolism via oxidative phosphorylation. A more complete understanding of embryo metabolism is critical to better support embryo viability in vitro, and to avoid forcing embryos to adapt to suboptimal culture conditions at a significant cost to future growth and development. PMID- 22431438 TI - EmbozeneTM microspheres induced nonreperfused myocardial infarction in an experimental swine model. AB - OBJECTIVES: To develop a magnetic resonance imaging (MRI) compatible, percutaneous technique for the generation of nonreperfused myocardial infarct (MI). BACKGROUND: Modeling nontreated MI has major importance in the development and preclinical testing of new therapeutic strategies for patients missing the time window suitable for revascularization following MI. METHODS: In 31 male swine, nonreperfused MI was generated by permanent occlusion of either the LAD or LCX coronary artery using 900 MUm EmbozeneTM microspheres. Animals were monitored for 90 min postocclusion. Surviving animals were followed up for 2 (n = 6), 4 (n = 6), 14 (n = 6), or 56 (n = 6) days. At the end of the planned study session, contrast enhanced MRI, triphenyl-tetrazolium-chloride staining, and microscopic histopathology were carried out. RESULTS: The mortality rate in this study was 22.6%. Intraoperative arrhythmias occurred in 14 cases: premature ventricular complexes with (5) or without (3) ventricular tachycardia, 2nd degree atrio ventricular block (1), and ventricular fibrillation (6). MRI, TTC, and histology confirmed the existence of MI in every case. Macroscopic pathology showed that the microspheres caused a practically total occlusion at the epicardial level of the coronary artery. Multiple infarcts were detected in one case, probably due to unintentional reflux of the microspheres. Microspheres retained in the coronary arteries did not cause any MRI artifact. CONCLUSIONS: The generation of nonreperfused MI is feasible by percutaneous injection of Embozene into the coronary artery system. The MI model thus obtained is suitable for the purposes of MRI experiments. PMID- 22431439 TI - Pregabalin augmentation of antidepressants in older patients with comorbid depression and generalized anxiety disorder-an open-label study. AB - OBJECTIVE: The objective of this 12-week open-label study was to evaluate the efficacy, safety, and tolerability of pregabalin as an adjunctive treatment to antidepressants in older patients suffering from depression and comorbid generalized anxiety disorder (GAD). METHODS: The initial sample of this open label study consisted of 94 older patients fulfilling criteria for depression with comorbid GAD who were treated with antidepressants. Twenty of them who had received antidepressant monotherapy for an adequate time and shown partial response to the antidepressant prescribed, in terms of either anxiety or depressive symptomatology, followed the next phase. During the 12-week study period, pregabalin was gradually added to the previously prescribed antidepressant, reaching 225 mg/day over 4 weeks. Depression and anxiety scores as well as side effects were monitored. Within groups, differences of depression and anxiety scores at baseline and during the following 12 weeks of treatment were estimated with repeated-measure analysis of variance. RESULTS: A statistical significant reduction in depression scores was observed after the 4th week of treatment (p < 0.01), which further improved between the 8th and 12th weeks (p < 0.01). Concerning overall anxiety scores, a statistically significant improvement was noted between the 2nd and 4th weeks (p < 0.01), which further continued throughout the 8th (p < 0.05) and 12th weeks (p < 0.05). CONCLUSIONS: The present study demonstrated a good therapeutic response to pregabalin in patients with depression comorbid with GAD after a 12-week treatment period. Both anxiety and depressive symptomatology significantly improved, and minimal side effects were observed. PMID- 22431440 TI - Cooperative dienamine/hydrogen-bonding catalysis: enantioselective formal [2+2] cycloaddition of enals with nitroalkenes. PMID- 22431441 TI - Antioxidant peptides from protein hydrolysate of microalgae Navicula incerta and their protective effects in HepG2/CYP2E1 cells induced by ethanol. AB - Marine microalgae have been reported as valuable new sources of pharmacologically active compounds and there are now numerous commercial applications of microalgae. Hence, in this study we evaluated the protective effects of peptides purified from marine microalgae, Navicula incerta, against alcohol-induced damage in HepG2/CYP2E1 cells. To obtain bioactive peptides from microalgae, N. incerta was hydrolysed using various enzymes (alcalase, alpha-chymotrypsin, neutrase, papain, pepsin, pronase-E and trypsin), and the hydrolysates were evaluated for cytoprotective activity. Among them, papain-derived hydrolysate exhibited higher antioxidant activities than those of other enzymes. Therefore, papain hydrolysate was purified in order to obtain potent antihepatotoxic and antioxidative peptides. The amino acid sequences of the purified peptides were analysed as; NIPP-1 (Pro-Gly-Trp-Asn-Gln-Trp-Phe-Leu) with molecular mass 1 171 Da, and NIPP-2 (Val-Glu-Val-Leu-Pro-Pro-Ala-Glu-Leu) with molecular mass 1108 Da. Furthermore, this study demonstrated that NIPP-1 and NIPP-2 peptides inhibited ethanol-induced cytotoxicity in HepG2/CYP2E1 cells. PMID- 22431442 TI - Catheter ablation of ventricular fibrillation triggers and electrical storm. AB - Ventricular fibrillation (VF) and electrical storm remain challenging conditions to manage despite the availability of various treatment modalities. Insertion of an implantable cardioverter defibrillator (ICD) remains the gold standard method for lowering the risk of sudden cardiac death in patients deemed to be at greatest risk of ventricular arrhythmias. However, ICDs do not alter the underlying substrate responsible for the arrhythmic events and a significant proportion of patients with ICDs may experience VF storm which may be life threatening and difficult to control with medication. Catheter ablation (CA) of the triggers or abnormal electrical substrate responsible for VF storm is an important treatment option in rare cases. In this article, we present an overview of the current theories underlying the mechanisms of VF and discuss how the technique of CA may be used to treat the triggers of VF and electrical storm. We review the literature on outcomes in patients who have undergone CA for VF in a variety of different settings, including those with structural heart disease and structurally normal hearts (e.g. patients with inherited arrhythmogenic diseases and idiopathic VF) and discuss the future directions in this field. PMID- 22431443 TI - Pneumothorax in cardiac pacing: a population-based cohort study of 28,860 Danish patients. AB - AIM: To identify risk factors for pneumothorax treated with a chest tube after cardiac pacing device implantation in a population-based cohort. METHODS AND RESULTS: A nationwide cohort study was performed based on data on 28 860 patients from the Danish Pacemaker Register, which included all Danish patients who received their first pacemaker (PM) or cardiac resynchronization device from 1997 to 2008. Multiple logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals for the association between risk factors and pneumothorax treated with a chest tube. The median age was 77 years (25th and 75th percentile: 69-84) and 55% were male (n = 15 785). A total of 190 patients (0.66%) were treated for pneumothorax, which was more often in women [aOR 1.9 (1.4-2.6)], and in patients with age >80 years [aOR 1.4 (1.0-1.9)], a prior history of chronic obstructive pulmonary disease [aOR 3.9 (1.6-9.5)], implantation of a dual-chamber PM [aOR 1.5 (1.0-2.2)], venous access with subclavian vein puncture [aOR 7.8 (4.9-12.5)], venous access with both subclavian vein puncture and cephalic vein cut-down [aOR 5.7 (3.0-10.8)], and implantation in a non-university centre [aOR 2.1 (1.6-2.9)]. CONCLUSION: Pneumothorax treated with a chest tube remains a clinically important problem in device therapy. The cephalic vein cut-down technique should be applied whenever possible to avoid this complication. PMID- 22431444 TI - Conductor externalization of the Riata internal cardioverter defibrillator lead: tip of the iceberg? Report of three cases and review of literature. AB - AIMS: Recently, concerns about St Jude's Riata lead family have come to light. We present three cases of patients with Riata internal cardioverter defibrillator (ICD) leads with externalized conductors. METHODS AND RESULTS: All patients had the same insulation defect, with externalized conductors, but differed in presentation and symptoms. These cases, which form 3 of 179 (1.68%) of our total Riata lead population, presented four or more years after implantation. This may be an indication that the problem with the Riata lead may well be greater than reported in the recent St Jude Medical device advisory letter. CONCLUSION: The management of the Riata lead problem is discussed as, up until now, management of patients with an implanted Riata lead has been based on detecting electric abnormalities on regular ICD interrogation only. PMID- 22431445 TI - Metal-ion permeation in congested nanochannels: the exposure effect of Ag+ ions on the phosphorescent properties of a gold(I)-pyrazolate complex that is confined in the nanoscopic channels of mesoporous silica. AB - An organometallic/silica nanocomposite of a 1D cylindrical assembly of a trinuclear gold(I)-pyrazolate complex ([Au(3)Pz(3)]) that was confined inside the nanoscopic channels of hexagonal mesoporous silica ([Au(3)Pz(3)]/silica(hex)), emitted red light with a luminescence center at 693 nm upon photoexcitation at 276 nm owing to a Au(I)-Au(I) metallophilic interaction. When a film of [Au(3)Pz(3)]/silica(hex) was dipped into a solution of Ag(+) in tetrahydrofuran (THF), the resulting nanocomposite material (Ag@[Au(3)Pz(3)]/silica(hex)) emitted green light with a new luminescence center at 486 nm, which was characteristic of a Au(I)-Ag(I) heterometallic interaction. Changes in the emission/excitation and XPS spectra of Ag@[Au(3)Pz(3)]/silica(hex) revealed that Ag(+) ions permeated into the congested nanochannels of [Au(3)Pz(3)]/silica(hex), which were filled with the cylindrical assembly of [Au(3)Pz(3)]. PMID- 22431446 TI - 6 cmH2O continuous positive airway pressure versus conventional oxygen therapy in severe viral bronchiolitis: a randomized trial. AB - OBJECTIVE: To compare the effects of nasal continuous positive airway pressure (nCPAP) and conventional oxygen therapy on the clinical signs of respiratory distress and the respiratory muscle workload in acute viral bronchiolitis. DESIGN: Prospective, randomized, monocentric study carried out in the pediatric intensive care unit (PICU) of a university hospital. PATIENTS: Infants <6 months old, admitted to the PICU with severe respiratory syncytial virus bronchiolitis. INTERVENTION: The patients were randomized into two groups for 6 hr. The nCPAP group (n = 10) received 6 cmH(2)O pressure support delivered by a jet flow generator and the control group (n = 9) received an air/oxygen mixture from a heated humidifier. Respiratory distress was assessed by the modified Wood's clinical asthma score (m-WCAS), and inspiratory muscle work was evaluated by calculating the pressure-time product per breath (PTP(insp) /breath) and per minute (PTP(insp) /min) from the esophageal pressure (Pes) recordings. MEASUREMENTS AND MAIN RESULTS: Compared with control condition, nCPAP decreased m WCAS [-2.4 (1.05) vs. -0.5 (1.3), P = 0.03], PTPes(insp)/breath [-9.7 (5.7) vs. 1.4 (8.2), P = 0.04], PTPes(insp) /min [-666 (402) vs. -116 (352), P = 0.015], and FiO(2) [-7 (10) vs. +5 (15), P = 0.05]. Significant worsening of m-WCAS was only observed in the control group (4/9 vs. 0/10, P = 0.03). CONCLUSIONS: nCPAP rapidly decreased inspiratory work in young infants with acute bronchiolitis. Improvement in the respiratory distress score at 6 hr was proportional to the initial clinical severity, suggesting the importance of rapid nCPAP initiation in the more severe forms of the disease. PMID- 22431447 TI - Case study interpretation--Portland: Case 3. Double hit lymphoma. PMID- 22431448 TI - Psychosocial aspects of post-treatment follow-up for stage I/II melanoma: a systematic review of the literature. AB - BACKGROUND: Patients treated for melanoma are advised to have lifelong full body skin examinations. Extended intervals between examinations have been proposed, but although this may be clinically effective, psychosocial aspects of follow-up are not well understood. This systematic review summarised patient and clinician preferences, experiences and adherence with recommended follow-up of stage I/II melanoma. METHODS: Medline, PsycINFO, CINAHL, Embase, Cochrane Library, ACP Journal Club and NHS Economic Evaluation Database were searched from database inception to week 3 April 2010, to identify original studies of psychosocial outcomes of follow-up after treatment of stage I/II primary cutaneous melanoma, as reported by patients or clinicians. The results were synthesised, and characteristics likely to maximise patients' well-being and adherence to follow up schedules were proposed. RESULTS: We found 15 studies that met the inclusion criteria. Anxiety with melanoma follow-up was common; patients valued reassurance, information and psychosocial support, but long-term adherence to schedules was variable. Some wanted more emotional support from their clinician than was provided. Clinicians sometimes ordered additional blood and imaging tests to reassure patients. GPs were hesitant to conduct melanoma follow-up, but a trial providing technical training and protocols reported positive outcomes. Both patients and GPs wanted prompt access to melanoma specialists when suspicious lesions were found. CONCLUSION: Psychosocial aspects of follow-up impact on patient well-being and potential adherence to schedules, and may influence clinician practice. If follow-up schedules or personnel are to be revised, psychosocial impacts on patients must be explicitly addressed, as well as guidance and specialist support for clinicians. PMID- 22431449 TI - Gray to colorless switching, crosslinked electrochromic polymers with outstanding stability and transmissivity from naphthalenediimmide-functionalized EDOT. AB - The design, synthesis, polymerization and full electrochemical and spectroelectrochemical characterization of a new naphtalendiimide-functionalized PEDOT cross-linked electrochromic material is reported. The polymer shows exceptionally high redox reversibility, almost complete colorlessness in the bleached state and a gray color in the reduced state. PMID- 22431450 TI - Infective endocarditis following transcatheter aortic valve replacement-: diagnostic and management challenges. AB - Transcatheter aortic valve replacement (TAVR) can improve the symptoms and prognosis of patients with severe aortic stenosis who, due to a high expected operative risk, would not have otherwise been treated surgically. If these patients develop prosthetic valve endocarditis, their presentations may be atypical causing a delay in the diagnosis and treatment. The management is also complicated by their comorbidities, and surgical treatment may not be feasible leading to a significant morbidity and mortality. We describe a case of an 85 year-old man with TAVI prosthetic valve endocarditis successfully treated medically, discuss the challenges in the diagnosis and management of such patients, and review available literature on the incidence and outcome of the condition. PMID- 22431451 TI - [Ca2+]i rise at in vitro maturation in bovine cumulus-oocyte complexes. AB - An intracellular calcium ([Ca(2+)]i) rise has been described in cumulus-oocyte complexes (COCs) following luteinizing hormone (LH) exposure. Together with cAMP, Ca(2+) is a candidate signal for resumption of meiosis. Here, we analyzed if the most common hormones involved in oocyte maturation can induce the same Ca(2+) signal. In addition, we characterized the source of this signal. Immature, in vitro-matured, and roscovitine-meiotically arrested COCs were loaded with Fluo-4 AM, stimulated with hormones/growth factors, and tested for [Ca(2+)](i) variations in cumulus cells. Reagents known to inhibit or stimulate [Ca(2+)](i) rises were used to characterize these [Ca(2+)](i) dynamics. Finally, expression of LH receptors (LHRs) in COCs was analyzed by immunofluorescence. In immature COCs, follicle-stimulating hormone (FSH) elicited a single [Ca(2+)](i) rise that was higher than those induced by LH and growth hormone (GH), whereas epithelial growth factor failed to induce any changes in [Ca(2+)](i). The [Ca(2+)](i) rise induced by FSH was higher in immature COCs; was reduced in roscovitine-arrested, immature COCs; and was negligible in gonadotropin-induced, in vitro-matured COCs. In the case of spontaneous- and GH-matured COCs, however, FSH stimulation caused a lower [Ca(2+)](i) rise. The hormone-induced [Ca(2+)](i) rise was due to: (i) external Ca(2+) entry; (ii) intercellular communication; and (iii) intracellular Ca(2+) stores. Immunofluorescence revealed that LHRs were expressed throughout the cumulus cells. The above results show that: (i) gonadotropins and GH cause a [Ca(2+)](i) rise in cumulus cells; (ii) this [Ca(2+)](i) rise results from extra , inter-, and intra-cellular cumulative Ca(2+) fluxes; and (iii) LHRs are distributed on either outer or inner cumulus cells. PMID- 22431452 TI - Multiple electrosprays generated from a single polycarbonate microstructured fibre. AB - Electrospray ionization (ESI) has been invaluable to the mass spectrometric detection of biomolecules, due largely to the sensitivity afforded by the ionization technique. Lower flow rates, e.g. in the nanoelectrospray regime, result in smaller initial electrosprayed droplets, leading to higher ionization efficiency and greater signal. One approach to improving sensitivity without lowering flow rate is to generate multiple electrosprays (MESs) from the same sample, essentially splitting one larger flow into smaller flows in the nanoESI regime. Presented here is a series of novel MES emitters in the form of polycarbonate fibres. Based on microstructured fibre (MSF) technology whereby a set of homogeneous parallel channels are formed in a heat-drawn fibre intended to conduct light, a custom design was fabricated in which 3, 6, 9 and 12 holes were arranged in a radial pattern to prevent inhomogeneities in the electric field. The MSFs have dimensions that are compatible with current standards in nanoESI equipment, and the tip is more compatible with standard MS orifices than other larger multielectrospray emitters. By measuring the spray current provided by the various emitters under the same solvent/voltage/total flow rate conditions, a plot was obtained clearly demonstrating the expected dependence on the square root of the number of holes, i.e. the number of independent electrosprays. With this firm proof of principle using this design/format, further effort is justified in developing similar emitters in alternative materials that better prevent surface wetting and allow greater hole density, ultimately leading to greater signal enhancement. PMID- 22431453 TI - Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC MS/MS and electrospray LC-MS/MS. AB - Melatonin (MEL) and its chemical precursor N-acetylserotonin (NAS) are believed to be potential biomarkers for sleep-related disorders. Measurement of these compounds, however, has proven to be difficult due to their low circulating levels, especially that of NAS. Few methods offer the sensitivity, specificity and dynamic range needed to monitor MEL and its precursors and metabolites in small blood samples, such as those obtained from pediatric patients. In support of our ongoing study to determine the safety, tolerability and PK dosing strategies for MEL in treating insomnia in children with autism spectrum disorder, two highly sensitive LC-MS/MS assays were developed for the quantitation of MEL and precursor NAS at pg/mL levels in small volumes of human plasma. A validated electrospray ionization (ESI) method was used to quantitate high levels of MEL in PK studies, and a validated nanospray (nESI) method was developed for quantitation of MEL and NAS at endogenous levels. In both assays, plasma samples were processed by centrifugal membrane dialysis after addition of stable isotopic internal standards, and the components were separated by either conventional LC using a Waters SymmetryShield RP18 column (2.1 * 100 mm, 3.5 um) or on a polyimide-coated, fused-silica capillary self-packed with 17 cm AquaC18 (3 um, 125 A). Quantitation was done using the SRM transitions m/z 233 -> 174 and m/z 219 -> 160 for MEL and NAS, respectively. The analytical response ratio versus concentration curves were linear for MEL (nanoflow LC: 11.7-1165 pg/mL, LC: 1165-116,500 pg/mL) and for NAS (nanoflow LC: 11.0-1095 pg/mL). PMID- 22431454 TI - Characteristics of electrical field and ion motion in surface-electrode ion traps. AB - In this article, we calculated the potential function of the surface-electrode ion trap (SEIT) by using Green's function method, optimized trap size, obtained the coefficients of the multipoles and analyzed ion trajectories in the RF potential. The optimized SEIT not only increases its trapping well depth by a factor of about 15, but also has relatively good linearity of the field (or large quadrupole component). The current design of SEIT can work well either as the ion guide for ion transmission or as the ion trap for ion confinement. Our research can be used to calculate the potential function in the SEIT with different device parameters, understand ion motions in the traps and optimize instrument performance. The method for calculating potential function can be expanded to planar and halo ion traps. PMID- 22431455 TI - In situ derivatization-liquid liquid extraction as a sample preparation strategy for the determination of urinary biomarker prolyl-4-hydroxyproline by liquid chromatography-tandem mass spectrometry. AB - Polar analytes that possess protic functional groups have often been treated with alkyl chloroformates to decrease their polarity and increase their volatility prior to gas chromatography-mass spectrometry analysis. This derivatization reaction has two distinct advantages. It proceeds smoothly in aqueous media, and the desired reaction products are efficiently separated from interfering ionic components by their extraction into a water-immiscible organic phase. In the present work, the derivatization-liquid liquid sample preparation was examined in detail for analysis of a potential urinary dipeptide biomarker L-prolyl-4-L hydroxyproline (PHP) by downstream liquid chromatography coupled to electrospray mass spectrometry. PHP was treated with a series of alkyl and fluoroalkyl chloroformates in aqueous media, and the detected reaction products were investigated. Smooth conversion of PHP into the N-isobutyloxycarbonyl isobutyl ester was accomplished by the coupled action of isobutanol, isobutyl chloroformate and the pyridine catalyst. This derivative afforded a highest detector response from all the derivatized forms examined, including the nonderivatized PHP. A simple isocratic elution on a common RP-C18 HPLC column coupled with tandem mass spectrometry, and use of the synthesized heptadeuterated analog (D7-PHP) as an internal standard, enabled validation of the method and determination of PHP in human urine in less than 5 min. The in situ derivatization-liquid liquid extraction has thus been demonstrated to be a useful sample preparation strategy for the analysis of polar metabolites by liquid chromatography-tandem mass spectrometry in the complex urine matrix. PMID- 22431456 TI - Critical evaluation of screening techniques for emerging environmental contaminants based on accurate mass measurements with time-of-flight mass spectrometry. AB - Emerging contaminants from wastewater effluent samples were analysed, using posttarget and nontarget analysis techniques. The samples were analysed with an ultra performance liquid chromatograph-time-of-flight mass spectrometer (UPLC-TOF MS), and the resulting data were processed with commercial deconvolution software. The method works well for posttarget analysis with prior information about the retention times of the compounds of interest. With positive polarity, 63 of 66 compounds and with negative polarity, 18 of 20 compounds were correctly identified in a spiked sample, while two compounds of a total of 88 fell out of the mass range. Furthermore, a four-stage process for identification was developed for the posttarget analysis lacking the retention time data. In the process, the number of candidate compounds was reduced by using the accurate mass of selected compounds in two steps (stages 1 and 2), structure-property relationships (stage 3) and isotope patterns of the analytes (stage 4). The process developed was validated by analysing wastewater samples spiked with 88 compounds. This procedure can be used to gain a preliminary indication of the presence of certain analytes in the samples. Nontarget analysis was tested by applying a theoretical mass spectra library for a wastewater sample spiked with six pharmaceuticals. The results showed a high number of false identifications. In addition, manual processing of the data was considered laborious and ineffective. Finally, the posttarget analysis was applied to a real wastewater sample. The analysis revealed the presence of six compounds that were afterwards confirmed with standard compounds as being correct. Three psycholeptics (nordiazepam, oxazepam and temazepam) could be tentatively identified, using the identification process developed. Posttarget analysis with UPLC-TOF-MS proved to be a promising method for analysing wastewater samples, while we concluded that the software for nontarget analysis will need improvement before it can be used in environmental analytical work with LC-TOF-MS systems. PMID- 22431457 TI - Mass spectrometry of rhenium complexes: a comparative study by using LDI-MS, MALDI-MS, PESI-MS and ESI-MS. AB - A group of rhenium (I) complexes including in their structure ligands such as CF(3)SO(3)-, CH(3)CO(2)-, CO, 2,2'-bipyridine, dipyridil[3,2-a:2'3'-c]phenazine, naphthalene-2-carboxylate, anthracene-9-carboxylate, pyrene-1-carboxylate and 1,10-phenanthroline have been studied for the first time by mass spectrometry. The probe electrospray ionization (PESI) is a technique based on electrospray ionization (ESI) that generates electrospray from the tip of a solid metal needle. In this work, mass spectra for organometallic complexes obtained by PESI were compared with those obtained by classical ESI and high flow rate electrospray ionization assisted by corona discharge (HF-ESI-CD), an ideal method to avoid decomposition of the complexes and to induce their oxidation to yield intact molecular cation radicals in gas state [M](+.) and to produce their reduction yielding the gas species [M](-.). It was found that both techniques showed in general the intact molecular ions of the organometallics studied and provided additional structure characteristic diagnostic fragments. As the rhenium complexes studied in the present work showed strong absorption in the UV-visible region, particularly at 355 nm, laser desorption ionization (LDI) mass spectrometry experiments could be conducted. Although intact molecular ions could be detected in a few cases, LDI mass spectra showed diagnostic fragments for characterization of the complexes structure. Furthermore, matrix-assisted laser desorption ionization (MALDI) mass spectra were obtained. Nor-harmane, a compound with basic character, was used as matrix, and the intact molecular ions were detected in two examples, in negative ion mode as the [M](-.) species. Results obtained with 2-[(2E)-3-(4-tert-buthylphenyl)-2-methylprop-2-enylidene] malononitrile (DCTB) as matrix are also described. LDI experiments provided more information about the rhenium complex structures than did the MALDI ones. PMID- 22431458 TI - Collagen-based proteinaceous binder-pigment interaction study under UV ageing conditions by MALDI-TOF-MS and principal component analysis. AB - This study focuses on acquiring information on the degradation process of proteinaceous binders due to ultra violet (UV) radiation and possible interactions owing to the presence of historical mineral pigments. With this aim, three different paint model samples were prepared according to medieval recipes, using rabbit glue as proteinaceus binders. One of these model samples contained only the binder, and the other two were prepared by mixing each of the pigments (cinnabar or azurite) with the binder (glue tempera model samples). The model samples were studied by applying Principal Component Analysis (PCA) to their mass spectra obtained with Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS). The complementary use of Fourier Transform Infrared Spectroscopy to study conformational changes of secondary structure of the proteinaceous binder is also proposed. Ageing effects on the model samples after up to 3000 h of UV irradiation were periodically analyzed by the proposed approach. PCA on MS data proved capable of identifying significant changes in the model samples, and the results suggested different aging behavior based on the pigment present. This research represents the first attempt to use this approach (PCA on MALDI-TOF-MS data) in the field of Cultural Heritage and demonstrates the potential benefits in the study of proteinaceous artistic materials for purposes of conservation and restoration. PMID- 22431459 TI - Characteristic ion clusters as determinants for the identification of pyrrolizidine alkaloid N-oxides in pyrrolizidine alkaloid-containing natural products using HPLC-MS analysis. AB - Pyrrolizidine alkaloid (PA)-containing plants are widely distributed in the world. PAs are hepatotoxic, affecting livestock and humans. PA N-oxides are often present together with PAs in plants and also exhibit hepatotoxicity but with less potency. HPLC-MS is generally used to analyze PA-containing herbs, although PA references are unavailable in most cases. However, to date, without reference standards, HPLC-MS methodology cannot distinguish PA N-oxides from PAs because they both produce the same characteristic ions in mass spectra. In the present study, the mass spectra of 10 PA N-oxides and the corresponding PAs were systemically investigated using HPLC-MS to define the characteristic mass fragment ions specific to PAs and PA N-oxides. Mass spectra of toxic retronecine type PA N-oxides exhibited two characteristic ion clusters at m/z 118-120 and 136 138. These ion clusters were produced by three unique fragmentation pathways of PA N-oxides and were not found in their corresponding PAs. Similarly, the nontoxic platynecine-type PA N-oxides also fragmented via three similar pathways to form two characteristic ion clusters at m/z 120-122 and 138-140. Further application of using these characteristic ion clusters allowed successful and rapid identification of PAs and PA N-oxides in two PA-containing herbal plants. Our results demonstrated, for the first time, that these characteristic ion clusters are unique determinants to discriminate PA N-oxides from PAs even without the availability of reference samples. Our findings provide a novel and specific method to differentiate PA N-oxides from PAs in PA-containing natural products, which is crucial for the assessment of their intoxication. PMID- 22431460 TI - Cluster TOF-SIMS imaging of human skin remains: analysis of a South-Andean mummy sample. AB - A skin sample from a South-Andean mummy dating back from the XI(th) century was analyzed using time-of-flight secondary ion mass spectrometry imaging using cluster primary ion beams (cluster-TOF-SIMS). For the first time on a mummy, skin dermis and epidermis could be chemically differentiated using mass spectrometry imaging. Differences in amino-acid composition between keratin and collagen, the two major proteins of skin tissue, could indeed be exploited. A surprising lipid composition of hypodermis was also revealed and seems to result from fatty acids damage by bacteria. Using cluster-TOF-SIMS imaging skills, traces of bio mineralization could be identified at the micrometer scale, especially formation of calcium phosphate at the skin surface. Mineral deposits at the surface were characterized using both scanning electron microscopy (SEM) in combination with energy-dispersive X-ray spectroscopy and mass spectrometry imaging. The stratigraphy of such a sample was revealed for the first time using this technique. More precise molecular maps were also recorded at higher spatial resolution, below 1 um. This was achieved using a non-bunched mode of the primary ion source, while keeping intact the mass resolution thanks to a delayed extraction of the secondary ions. Details from biological structure as can be seen on SEM images are observable on chemical maps at this sub-micrometer scale. Thus, this work illustrates the interesting possibilities of chemical imaging by cluster-TOF-SIMS concerning ancient biological tissues. PMID- 22431461 TI - Mass spectrometry of metal complexes of bis-quinolizidine alkaloids: EI and ESI mass spectral study of Co(+2), Ni(+2), Cu(+2) and Zn(+2) 2-methylsparteine complexes. PMID- 22431462 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analyses of Grubbs catalysts and ferrocene derivatives using sulfur as matrix. PMID- 22431463 TI - Future perspective of nanoparticle interaction-assisted laser desorption/ionization mass spectrometry for rapid, simple, direct and sensitive detection of microorganisms. AB - The introduction of nanoparticles into mass spectrometric research greatly influenced the applicability of this technique into various omics. Surface modified or functionalized nanoparticles (NPs) have recently extended the use of mass spectrometry into microorganism research. We survey the application of unmodified NPs, for microorganism research, on the basis of our expertise in this area within the recent years in this decade. The use of unmodified NPs in mass spectrometry, especially with respect to microorganisms, is an untreaded research area, which we have ventured to probe and have been fruitful. On the basis of our experience, we provide an insight into the principle behind the use of unmodified NPs and provide guidelines to be followed to obtain significant results. We also brief the current scenario of nanoparticle interaction-assisted laser desorption/ionization mass spectrometry (NPILDI-MS) for rapid, simple, direct and sensitive detection of microorganisms on the basis of our past and present reports, quoting examples of successful application of this technique. Finally, we address the future of the NPILDI-MS technique and the tools needed to reach those visions. PMID- 22431464 TI - Collision-induced dissociation of oligonucleotide anions fully modified at the 2' position of the ribose: 2'-F/-H and 2'-F/-H/-OMe mix-mers. AB - Gas-phase dissociation of various 2'-position modified oligonucleotide anions has been studied as a function of precursor ion charge state using ion trap and low energy beam-type collision-induced dissociation (CID). For a completely 2'-O methyl modified 6-mer, all possible dissociation channels along the phosphodiester linkage, generating complementary (a-B)/w-, b/x-, c/y-, d/z-ion series, were observed with no single dominant type of dissociation pathway. Full sequence information was generated from each charge state via ion trap CID. More sequential fragmentation was noted under beam-type CID conditions. Comparison with model DNA, in which all 2'-OH groups are converted to 2'-H, and RNA anions suggests that the 2'-OMe substitution stabilizes the phosphodiester linkage with respect to fragmentation relative to both DNA and RNA oligomers. For modified mix mer anions, comprised of DNA nucleotides and 2'-F substituted nucleotides or a mixture of DNA nucleotides and 2'-O-methyl (2'-OMe) and 2'-F substituted nucleotides, 3'-side backbone cleavage was found to be inhibited by the 2'-OMe or 2'-F modification on the nucleotides under ion trap CID conditions. Thus, the sequence information was limited to the a-Base/w-fragments from the cleavage of the 3' C-O bond of the 2'-H (DNA) nucleotides. Under beam-type CID conditions, limited additional cleavage adjacent to 2'-OMe substituted nucleotides was noted but 2'-F modified residues remained resistant to cleavage. PMID- 22431465 TI - Nebulizing conditions of pneumatic electrospray ionization significantly influence electrolyte effects on compound measurement. AB - Composition of mobile phase can greatly influence the success of electrospray ionization (ESI)-interfaced liquid chromatography-mass spectrometry analysis. To investigate the relationship between formic-acid-based modification of mobile phase and ESI nebulizing conditions, an API 4000 ESI source and a TSQ Quantum one were compared under the same chromatographic conditions. Ginkgo terpene lactones and flavonols were measured in plasma, which involved using ascorbic acid to circumvent cross-interference between the analytes. ESI responses to using formic acid included changes in signal intensity, matrix effect, and upper limit of quantification. Significant disparities in the responses were observed between the two ESI sources, suggesting that the use of electrolyte modifier in liquid chromatography mobile phase and the pneumatic nebulization for ESI should be properly balanced to accomplish optimal ESI-based analysis. The distribution of unpaired ions toward the surface of the initial droplet was assumed to be an important step in the pneumatic ESI process. When using the electrolyte in mobile phase, a too fast droplet reduction by rapid-heating-assisted pneumatic nebulization could negatively decrease the time available for the unpaired ions to migrate from droplet interior to its surface. Ascorbic acid was identified as a major interfering substance for the bioanalytical assay; the interference mechanism might be associated with hindering the unpaired analyte ions from distributing toward the droplet surface rather than outcompeting the analyte ions for the limited excess charge on droplets surface. The current work extends the knowledge base of pneumatic ESI, which has implication for optimal use of the ESI interfaced liquid chromatography-mass spectrometry technique. PMID- 22431466 TI - 'Wrong-way-round ionization' and screening for doping substances in human urine by high-performance liquid chromatography/orbitrap mass spectrometry. AB - To free analytical resources for new classes of doping substances, such as banned proteins, maximization of the number of compounds that can be determined with high sensitivity in a single run is highly urgent. This study demonstrates an application of 'wrong-way-round ionization' for the simultaneous detection of multiple classes of doping substances without the need to switch the polarity. A screening method for the detection of 137 compounds from various classes of prohibited substances (stimulants, diuretics, beta(2)-agonists, beta-blockers, antiestrogens, glucocorticosteroids and anabolic agents) has been developed. The method involves an enzymatic hydrolysis, liquid-liquid extraction and detection by liquid chromatography/orbitrap mass spectrometry with wrong-way-round ionization. Up to 64% of compounds had a 10-fold lower limit of detection (LOD) than the minimum required performance limit. To compare the efficiency of conventional ionization relative to wrong-way-round ionization of doping substances in + ESI, a fortified blank urine sample at the minimum required performance limit was analyzed using two ESI approaches. All compounds were detected with markedly better S/N in a high-pH mobile phase, with the exception of acetazolamide (minimal change in S/N, < 20%).The method was validated by spiking 10 different blank urine samples at five different concentrations. Validation parameters included the LOD, selectivity, ion suppression, extraction recovery and repeatability. PMID- 22431467 TI - Analysis of dammar resin with MALDI-FT-ICR-MS and APCI-FT-ICR-MS. AB - Comprehensive analysis of high-resolution mass spectra of aged natural dammar resin obtained with Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS) using matrix-assisted laser desorption/ionization (MALDI) and atmospheric pressure chemical ionization (APCI) is presented. Dammar resin is one of the most important components of painting varnishes. Dammar resin is a terpenoid resin (dominated by triterpenoids) with intrinsically very complex composition. This complexity further increases with aging. Ten different solvents and two-component solvent mixtures were tested for sample preparation. The most suitable solvent mixtures for the MALDI-FT-ICR-MS analysis were dichloromethane acetone and dichloromethane-ethanol. The obtained MALDI-FTMS mass spectrum contains nine clusters of peaks in the m/z range of 420-2200, and the obtained APCI-FTMS mass spectrum contains three clusters of peaks in the m/z range of 380 910. The peaks in the clusters correspond to the oxygenated derivatives of terpenoids differing by the number of C(15)H(24) units. The clusters, in turn, are composed of subclusters differing by the number of oxygen atoms in the molecules. Thorough analysis and identification of the components (or groups of components) by their accurate m/z ratios was carried out, and molecular formulas (elemental compositions) of all major peaks in the MALDI-FTMS and APCI-FTMS spectra were identified (and groups of possible isomeric compounds were proposed). In the MALDI-FTMS and APCI-FTMS mass spectrum, besides the oxidized C(30), triterpenoids also peaks corresponding to C(29) and C(31) derivatives of triterpenoids (demethylated and methylated, correspondingly) were detected. MALDI and APCI are complementary ionization sources for the analysis of natural dammar resin. In the MALDI source, preferably polar (extensively oxidized) components of the resin are ionized (mostly as Na(+) adducts), whereas in the APCI source, preferably nonpolar (hydrocarbon and slightly oxidized) compounds are ionized (by protonation). Either of the two ionization methods, when used alone, gives an incomplete picture of the dammar resin composition. PMID- 22431468 TI - Monitoring toxigenic Microcystis strains in the Missisquoi bay, Quebec, by PCR targeting multiple toxic gene loci. AB - The increasing incidence of mixed assemblages of toxic and nontoxic cyanobacterial blooms in Quebec's freshwater bodies over the last decade, coupled with inherent inadequacies of current monitoring approaches, warrants development of sensitive and reliable tools for assessing the toxigenic potential of these water blooms. In this study, we applied three independent polymerase chain reaction (PCR) assays that simultaneously target the microcystin synthetase (mcy) genes A, E, and G to rapidly and reliably detect and quantify potentially toxic Microcystis genotypes in the Missisquoi bay, Quebec, Canada. Linear regressions of quantitative PCR threshold cycles (Ct ) against the logarithm of their respective Microcystis cell number equivalents resulted in highly significant linear curves with coefficients of determination (R(2) ) greater than 0.99 (p < 0.0001, n = 6) and reaction efficiencies of 91.0, 95.8, and 92.7%, respectively, for the mcyA, mcyE, and mcyG-based quantitative real-time PCR (qPCR) assays. The three assays successfully estimated potential microcystin-producing Microcystis genotypes from all field samples. The proportions of MicrocystismcyA, mcyE, and mcyG genotypes to total Microcystis cell counts showed substantial spatial variability ranging between 1.7-21.6%, 1.9-11.2%, and 2.2-22.6%, respectively. Correlation of microscopically determined total Microcystis counts to qPCR-based MicrocystismcyA, mcyE, or mcyG cell number equivalents resulted in highly significant associations with R(2) > 0.90. Thus, PCR-based assays targeting the mcyA, mcyG, and/or mcyE genes can serve as powerful screening tools for rapid and sensitive estimation of microcystin-producing Microcystis genotypes in freshwater water bodies. PMID- 22431469 TI - Astrocyte elevated gene-1 interacts with beta-catenin and increases migration and invasion of colorectal carcinoma. AB - To investigate the astrocyte elevated gene-1 (AEG-1) expression and its relationship with the clinicopathological features of colorectal carcinoma (CRC) and beta-catenin signaling pathway. Real-time PCR, Western blot, immunohistochemistry, and immunofluorescence staining were performed to detect AEG-1 expression in CRC cell lines, 8 pairs of fresh CRC and adjacent nontumor tissues (ANT), 120 pairs of paraffin-embedded CRC specimens and ANT tissues, and 60 samples of lymph node metastatic CRC tissues. Scratch wound assay and transwell matrix penetration assay were performed to determine migration and invasion of SW480 cell lines with stable AEG-1 overexpression or SW620 cell lines with AEG-1 knockdown. AEG-1 expression was upregulated in CRC cell lines and tissues compared with ANT. Furthermore, AEG-1 expression level significantly correlated with UICC stage, and the N classification. AEG-1 overexpression significantly enhanced migration and invasion of SW480 cell lines. However, AEG-1 knockdown suppressed migration and invasion of SW620 cell lines. Meanwhile, there was a positive correlation between AEG-1 high expression and beta-catenin nuclear expression in CRC. AEG-1 overexpression increased nuclear beta-catenin accumulation in CRC cell lines. AEG-1 knockdown decreased nuclear beta-catenin accumulation in CRC cell lines. Moreover, we firstly found that AEG-1 interacted with beta-catenin in SW480 cell lines. Our results for the first time showed that AEG-1 interacted with beta-catenin in CRC cells and AEG-1 expression was closely associated with progression of CRC. AEG-1 might be a potential therapeutic target in CRC. PMID- 22431470 TI - Dendronized fullerene-porphyrin conjugates in ortho, meta, and para positions: a charge-transfer assay. AB - The physicochemical characterization, that is, ground and excited state, of a new series of dendronized porphyrin/fullerene electron donor-acceptor conjugates in nonaqueous and aqueous environments is reported. In contrast to previous work, we detail the charge-separation and charge-recombination dynamics in zinc and copper metalloporphyrins as a function of first- and second-generation dendrons as well as a function of ortho, meta, and para substitution. Both have an appreciable impact on the microenvironments of the redox-active constituents, namely the porphyrins and the fullerenes. As a matter of fact, the resulting charge-transfer dynamics were considerably impacted by the interplay between the associated forces that reach from dendron-induced shielding to dipole-charge interactions. PMID- 22431471 TI - Antibiotic treatment of children with community-acquired pneumonia: comparison of penicillin or ampicillin versus cefuroxime. AB - OBJECTIVE: Adherence to current guidelines for treatment of non-complicated community-acquired pneumonia (CAP) in children, recommending penicillin or ampicillin as first-line treatment, has been poor. Our objective was to examine whether cefuroxime confers an advantage over penicillin or ampicillin for the treatment of children hospitalized with non-complicated CAP. PATIENTS AND METHODS: All children aged 3 months to 2 years with non-complicated CAP treated with penicillin or ampicillin or cefuroxime, admitted during 2003-2008, in the Departments of Pediatrics, Hadassah University Medical Center were included. Presenting signs, symptoms, laboratory findings at presentation, clinical parameters including number of days with IV antibiotics, oxygen treatment, length of hospital stay, change of antibiotics, and clinical course 72 hr and 1 week after admission, were compared. RESULTS: Of the 319 children admitted for non complicated CAP, 66 were treated with IV penicillin or ampicillin, 253 with IV cefuroxime. Number of days of IV treatment, days of oxygen requirement, and days of hospitalization were similar (2.36 +/- 1.6 days vs. 2.59 +/- 1.6 days, 0.31 +/ 1.2 days vs. 0.64 +/- 1.3 days, and 2.67 +/- 1.4 days vs. 2.96 +/- 1.7 days, respectively). Treatment failure was not significantly different (7.6% vs. 4.7%). The number of patients who were febrile or required oxygen 72 hr after admission was similar (13.0% vs. 16.5% and 8.7% vs. 20.9%, respectively). One week after admission no difference between the two groups was seen. CONCLUSIONS: In previously healthy children, parenteral penicillin or ampicillin for treatment of non-complicated CAP in-hospital is as effective as cefuroxime, and should remain the recommended first-line therapy. PMID- 22431472 TI - A guide to fluoroscopic identification and design of bioprosthetic valves: a reference for valve-in-valve procedure. AB - Surgical aortic valve replacement remains the therapy of choice in majority of patients with aortic stenosis. Bioprosthetic heart valves are often preferred over mechanical valves as they preclude the need for anticoagulation with its associated risks of bleeding and thromboembolism. However, bioprosthetic heart valves undergo structural deterioration and eventually fail. Reoperation is the standard treatment for structural failure of the bioprosthetic valve, stenosis or regurgitation but can carry a significant risk, especially in elderly patients with multiple comorbidities. Transcatheter aortic valve implantation has recently been established as a feasible alternative to conventional valve surgery for the management of high-risk elderly patients with aortic stenosis. This treatment modality has also been shown to be of benefit in the management of degenerated aortic bioprosthesis as a valve-in-valve procedure. The success of this procedure depends on a good understanding of the failing bioprostheses. This not only includes the device design but its radiological/fluoroscopic appearance and how it correlates with the implanted valve, as transcatheter aortic valve implantation is performed under fluoroscopic guidance. Here we illustrate the fluoroscopic appearance of 11 commercially available surgical bioprostheses and two commercially available transcatheter heart valves and discuss important aspects in their design which can influence outcome of a valve-in-valve procedure. We have also collated relevant information on the aspects of the design of a bioprosthetic valve, which are relevant to the valve-in-valve procedure. PMID- 22431473 TI - Inhibitory effect of ethanol extract of Magnolia officinalis on memory impairment and amyloidogenesis in a transgenic mouse model of Alzheimer's disease via regulating beta-secretase activity. AB - Alzheimer's disease (AD) is the most common form of dementia and is characterized by deposition of amyloid beta (Abeta) in the brain. The components of the herb Magnolia officinalis are known to have antiinflammatory, antioxidative and neuroprotective activities. In this study we investigated the effects of ethanol extract of M. officinalis on memory dysfunction and amyloidogenesis in a transgenic mouse model of AD. Oral pretreatment of ethanol extract of M. officinalis (10 mg/kg in 0.05% ethanol) into drinking water for 3 months inhibited memory impairment and Abeta deposition in the brain of Tg2576 mice. Ethanol extract of M. officinalis also decreased activity of beta-secretase, cleaving Abeta from amyloid precursor protein (APP), and expression of beta-site APP cleaving enzyme 1 (BACE1), APP and its product, C99. Our results showed that ethanol extract of M. officinalis effectively prevented memory impairment via down-regulating beta-secretase activity. PMID- 22431474 TI - Case study interpretation--Portland: Case 4. Acute leukemia of ambiguous lineage, unclassifiable. PMID- 22431475 TI - Total synthesis of cyrneine A. PMID- 22431476 TI - Electrolytic hydriding of LaFe(13-x)Si(x) alloys for energy efficient magnetic cooling. AB - An effective, low-temperature and readily available electrochemical method for tuning the operation temperature of LaFe(13-x)Si(x)-type alloys is demonstrated. Electrolytically hydrided materials have the same high level magnetic properties as in high temperature gas-phase processed materials and offer an advantage of higher hydrogen absorption rate in the ferromagnetic state. PMID- 22431477 TI - Alterations in mast cell frequency and relationship to angiogenesis in the rat mammary gland during windows of physiologic tissue remodeling. AB - BACKGROUND: The mammary epithelium undergoes proliferation and regression accompanied by remodeling of the fibrocellular and vascular stroma. Mast cells are abundant in these compartments and have been implicated in remodeling during wound healing and cancer progression. The purpose of this study was to test the hypothesis that mast cell abundance correlates with physiologic mammary tissue remodeling during estrous cycling, lactogenesis (pregnancy and lactation) and involution. RESULTS: Mast cell and capillary frequency were quantified in the stroma surrounding ducts and lobules from mammary glands of rats. During estrous cycling, periductal mast cell numbers were unchanged, but lobule-associated mast cells significantly increased in the regressive phase of diestrus II. During lactogenesis, lobular stroma mast cells peaked early in pregnancy, at D2, followed by a significant decrease throughout lactation. Involution was associated with a rapid return in mast cell numbers, similar to diestrus II. Lobular vascularization peaked during the state of metestrus, when limited secretory differentiation occurs. Lobular angiogenesis peaked at D7 of pregnancy, regressed, and then returned to high levels during lactation and early involution, when secretory differentiation is high. CONCLUSIONS: These results suggest mast cells are predominantly associated with regressive lobular remodeling during cycling and involution, whereas angiogenesis is predominantly associated with secretory differentiation. PMID- 22431478 TI - Bare metal stenting for obstructed small diameter homograft conduits in the right ventricular outflow tract. AB - OBJECTIVE: Our aim was to assess acute hemodynamic changes with stent insertion, outcomes, and factors associated with increased longevity of stented small diameter homograft conduits. BACKGROUND: Right ventricle-to-pulmonary artery (RV PA) homograft conduits are commonly used to palliate RV outflow tract obstruction. Bare metal stenting (BMS) and transcatheter pulmonary valve implantation have been shown to relieve obstructed larger diameter conduits and may delay surgical conduit reintervention. Less is known about BMS of small conduits. METHODS AND RESULTS: From 1992 to 2009, BMS was performed to relieve obstruction in 106 homograft conduits that were <=12 mm at implant. The peak RV PA gradient fell from 54.3 +/- 17.4 mm Hg at baseline to 46.1 +/- 15.2 mm Hg after balloon dilation alone and to 25.1 +/- 11.4 mm Hg with stenting (all P < 0.001). Higher pre-BMS gradient and RV pressure were the only factors associated with higher post-BMS RV-PA gradient (>=30 mm Hg; both P < 0.001). There were no procedural deaths, two patients required surgical removal of embolized stents. At a median follow-up of 1.6 years, 83 conduits were replaced; freedom from conduit reoperation after BMS was 66% +/- 5% at 1 year and 28% +/- 5% at 3 years. Factors associated with shorter freedom from reoperation included implanted conduit diameter <10 mm (P = 0.009), higher post-stent RV-PA gradient (P = 0.026), and higher post-stent RV pressure (P < 0.01); only post-stent RV pressure remained significant on multivariable analysis (P < 0.001). CONCLUSION: BMS was acutely effective for the treatment of obstructed small diameter homograft conduits, with low morbidity. Prolongation of small diameter homograft conduit longevity with BMS may be useful in the lifetime management of conduit dysfunction in this patient population. PMID- 22431479 TI - Association of shorter telomere length with essential hypertension in Indian population. AB - OBJECTIVES: Essential hypertension is known to be associated with growth, development, and aging of humans. Telomeres are specialized nucleoprotein complexes consisting of tandem repeats of DNA sequences (TTAGGG)n that serve as protective caps of human chromosomes. Telomere length is considered as a biomarker of aging in somatic cells. In the present investigation, leukocyte telomere length was determined among hypertensive and normal individuals to find out the association, if any, with hypertension. MATERIALS AND METHODS: Venous blood samples were collected from normal and hypertensive individuals with written informed consent approved by ethic committee of Department of Genetics, Osmania University Hyderabad, India. Genomic DNA was isolated from blood samples of 98 normal (age range: 30-70 years, mean age: 51.01 +/- 10.12 years) and 96 hypertensive individuals (age range: 35-75 years, mean age: 49.18 +/- 6.46 years). Using a SYBR green-based real time quantitative PCR relative telomere length was determined among these individuals. RESULTS: The relative telomere length (T/S ratio) in hypertensive individuals was observed to be 0.91 +/- 0.16 which was significantly different (P < 0.001) from normal individuals where the relative telomere length was 0.99 +/- 0.13. No significant difference was observed between relative telomere length of male and female individuals, although there is negative correlation between age and telomere length was observed in both normal and hypertensive individuals. The systolic and diastolic blood pressure was negatively correlated with relative telomere length, though not significant. CONCLUSION: Shorter telomere length is associated with hypertensive individuals in Indian population. PMID- 22431480 TI - Atropisomerism in a belt-persistent nanohoop molecule: rotational restriction forced by macrocyclic ring strain. AB - Enough strain! Strain in a macrocyclic ring hinders the rotation of an arylene panel in a nanohoop molecule containing four chrysenylene units (see picture). Unlike conventional rotational restrictions in biaryl systems, the new atropisomerism does not require any steric hinderance from the substituents. The study of atropisomerism also provides the first experimental insights into the relative stability of nanohoop structures. PMID- 22431481 TI - Altered neutrophil maturation patterns that limit identification of myelodysplastic syndromes. AB - BACKGROUND: Altered neutrophil maturation patterns have been reported useful for identification of myelodysplastic syndromes (MDS). METHODS: Neutrophil maturation patterns based on CD11b, CD13, and CD16 were visually and numerically evaluated in 19 control, 23 MDS, 37 nondiagnostic for MDS (NDM) specimens, and 19 also processed 1 and 2 days subsequently. RESULTS: In contrast to maturation patterns illustrated previously by others as "normal," 84% of controls displayed diminished acquisition of CD16, imparting a contracted appearance. Such divergence from published "normal" patterns was usually mild-moderate, considered nonspecific, and associated with delayed processing: longer intervals between collection and processing (median 20.5 vs. 5.2 h), and following 1 and 2 days delay. Findings restricted to nonspecific contraction were found in 56% MDS and 78% NDM specimens. Evaluation for aberrant patterns was still performed with mild moderate contraction present, but concern for over interpretation led to use of an equivocal-aberrant category. Nine cases had aberrant or equivocal-aberrant patterns (seven MDS, two NDM) with distinct visual alterations that differed from nonspecific contraction and had numerical evidence for a left shift: myeloblasts increased (67%) and least mature neutrophils (CD11b-/low, CD16-/low) increased (78%). Although evidence for a left shift was associated with MDS, it was also seen in NDM specimens with a synchronous left shift. CONCLUSIONS: Neutrophil maturation patterns that diverge from previously illustrated "normal" patterns, not specific for MDS, may be common in some settings. Laboratories seeking to implement FC evaluation for MDS must determine which findings have sufficient specificity for MDS within their own practice and patient population. PMID- 22431482 TI - Development of reference equations for spirometry in Japanese children aged 6-18 years. AB - BACKGROUND: Spirometry is the most widely used pulmonary function test and the measured values of spirometric parameters need to be evaluated using reference values predicted for the corresponding race, sex, age, and height. However, none of the existing reference equations for Japanese children covers the entire age range of 6-18 years. The Japanese Society of Pediatric Pulmonology had organized a working group in 2006, in order to develop a new set of national standard reference equations for commonly used spirometric parameters that are applicable through the age range of 6-18 years. METHODS: Quality assured spirometric data were collected through 2006-2008, from 14 institutions in Japan. We applied multiple regression analysis, using age in years (A), square of age (A(2)), height in meters (H), square of height (H(2)), and the product of age and height (AH) as explanatory variables to predict forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), peak expiratory flow (PEF), forced expiratory flow between 25% and 75% of the FVC (FEF(25-75%)), instantaneous forced expiratory flow when 50% (FEF(50%)) or 75% (FEF(75%)) of the FVC have been expired. RESULTS: Finally, 1,296 tests (674 boys, 622 girls) formed the reference data set. Distributions of the percent predicted values did not differ by ages, confirming excellent fit of the prediction equations throughout the entire age range from 6 to 18 years. Cut-off values (around 5 percentile points) for the parameters were also determined. CONCLUSIONS: We recommend the use of this new set of prediction equations together with suggested cut-off values, for assessment of spirometry in Japanese children and adolescents. PMID- 22431483 TI - Hybrid stenting of aortic coarctation in very low birth weight premature infant. AB - A very low birth weight infant with severe aortic coarctation developed progressive left ventricular dysfunction and pulmonary overflow with hemorrhage, while receiving prostaglandins. To avoid morbidity from conventional surgery or percutaneous intervention, a two-step strategy was performed at a weight of 970 g. First vascular access was obtained through sternotomy: a 3/8 mm coronary stent was deployed through a 4 French sheath in the ascending aorta; the arterial duct was clipped. At the age of 5 months, the stent was removed and the aortic arch reconstructed with an end-to-end anastomosis through lateral thoracotomy. This strategy was not associated with morbidity typical for premature infants with congenital heart disease. PMID- 22431484 TI - The surface reactivity and implied toxicity of ash produced from sugarcane burning. AB - Sugarcane combustion generates fine-grained particulate that has the potential to be a respiratory health hazard because of its grain size and composition. In particular, conversion of amorphous silica to crystalline forms during burning may provide a source of toxic particles. In this study, we investigate and evaluate the toxicity of sugarcane ash and bagasse ash formed from commercial sugarcane burning. Experiments to determine the main physicochemical properties of the particles, known to modulate biological responses, were combined with cellular toxicity assays to gain insight into the potential reactions that could occur at the particle-lung interface following inhalation. The specific surface area of the particles ranged from ~16 to 90 m(2) g(-1) . The samples did not generate hydroxyl- or carbon-centered radicals in cell-free tests. However, all samples were able to 'scavenge' an external source of hydroxyl radicals, which may be indicative of defects on the particle surfaces that may interfere with cellular processes. The bioavailable iron on the particle surfaces was low (2-3 MUmol m(-2) ), indicating a low propensity for iron-catalyzed radical generation. The sample surfaces were all hydrophilic and slightly acidic, which may be due to the presence of oxygenated (functional) groups. The ability to cause oxidative stress and membrane rupture in red blood cells (hemolysis) was found to be low, indicating that the samples are not toxic by the mechanisms tested. Cytotoxicity of sugarcane ash was observed, by measuring lactate dehydrogenase release, after incubation of relatively high concentrations of ash with murine alveolar macrophage cells. All samples induced nitrogen oxide release (although only at very high concentrations) and reactive oxygen species generation (although the bagasse samples were less potent than the sugarcane ash). However, the samples induced significantly lower cytotoxic effects and nitrogen oxide generation when compared with the positive control. PMID- 22431486 TI - Towards artificial leaves for solar hydrogen and fuels from carbon dioxide. AB - The development of an "artificial leaf" that collects energy in the same way as a natural one is one of the great challenges for the use of renewable energy and a sustainable development. To avoid the problem of intermittency in solar energy, it is necessary to design systems that directly capture CO(2) and convert it into liquid solar fuels that can be easily stored. However, to be advantageous over natural leaves, it is necessary that artificial leaves have a higher solar energy-to-chemical fuel conversion efficiency, directly provide fuels that can be used in power-generating devices, and finally be robust and of easy construction, for example, smart, cheap and robust. This review discusses the recent progress in this field, with particular attention to the design and development of 'artificial leaf' devices and some of their critical components. This is a very active research area with different concepts and ideas under investigation, although often the validity of the considered solutions it is still not proven or the many constrains are not fully taken into account, particularly from the perspective of system engineering, which considerably limits some of the investigated solutions. It is also shown how system design should be included, at least at a conceptual level, in the definition of the artificial leaf elements to be investigated (catalysts, electrodes, membranes, sensitizers) and that the main relevant aspects of the cell engineering (mass/charge transport, fluid dynamics, sealing, etc.) should be also considered already at the initial stage because they determine the design and the choice between different options. For this reason, attention has been given to the system-design ideas under development instead of the molecular aspects of the O(2) - or H(2) -evolution catalysts. However, some of the recent advances in these catalysts, and their use in advanced electrodes, are also reported to provide a more complete picture of the field. PMID- 22431488 TI - Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan polysaccharide rat model of Crohn's disease. AB - BACKGROUND: Resveratrol has antiinflammatory and antifibrotic effects. Resveratrol decreases proliferation and collagen synthesis by intestinal smooth muscle cells. We hypothesized that resveratrol would decrease inflammation and fibrosis in an animal model of Crohn's disease. METHODS: Peptidoglycan polysaccharide (PG-PS) or human serum albumin (HSA) was injected into the bowel wall of Lewis rats at laparotomy. Resveratrol or vehicle was administered daily by gavage 1-27 days postinjection. On day 28, gross abdominal and histologic findings were scored. Cecal collagen content was measured by colorimetric analysis of digital images of trichrome-stained sections. Cecal levels of procollagen, cytokine, and growth factor mRNAs were determined. RESULTS: PG-PS injected rats (vehicle-treated) developed more fibrosis than HSA-injected rats by all measurements: gross abdominal score (P < 0.001), cecal collagen content (P = 0.04), and procollagen I and III mRNAs (P <= 0.0007). PG-PS-injected rats treated with 40 mg/kg resveratrol showed a trend toward decreased gross abdominal score, inflammatory cytokine mRNAs, and procollagen mRNAs. PG-PS-injected rats treated with 100 mg/kg resveratrol had lower inflammatory cytokine mRNAs (IL-1beta [3.50 +/- 1.08 vs. 10.79 +/- 1.88, P = 0.005], IL-6 [17.11 +/- 9.22 vs. 45.64 +/- 8.83, P = 0.03], tumor necrosis factor alpha (TNF-alpha) [0.80 +/- 0.14 vs. 1.89 +/- 0.22, P = 0.002]), transforming growth factor beta 1 (TGF-beta1) mRNA (2.24 +/- 0.37 vs. 4.06 +/- 0.58, P = 0.01), and histologic fibrosis score (6.4 +/- 1.1 vs. 9.8 +/- 1.0; P = 0.035) than those treated with vehicle. There were trends toward decreased gross abdominal score and decreased cecal collagen content. Procollagen I, procollagen III, and IGF-I mRNAs also trended downward. CONCLUSIONS: Resveratrol decreases inflammatory cytokines and TGF-beta1 in the PG-PS model of Crohn's disease and demonstrates a promising trend in decreasing tissue fibrosis. These findings may have therapeutic applications in inflammatory bowel disease. PMID- 22431489 TI - A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse. AB - The multistage model of nonmelanoma skin carcinogenesis has contributed significantly to our understanding of epithelial cancer in general. We used the Krt1-15CrePR1;R26R transgenic mouse to determine the contribution of keratin 15+ cells from the hair follicle to skin tumor development by following the labeled progeny of the keratin 15 expressing cells into papillomas. We present three novel observations. First, we found that keratin 15 expressing cells contribute to most of the papillomas by 20 weeks of promotion. Second, in contrast to the transient behavior of labeled keratin 15-derived progeny in skin wound healing, keratin 15 progeny persist in papillomas, and some malignancies for many months following transient induction of the reporter gene. Third, papillomas have surprising heterogeneity not only in their cellular composition, but also in their expression of the codon 61 signature Ha-ras mutation with approximately 30% of keratin 15-derived regions expressing the mutation. Together, these results demonstrate that keratin 15 expressing cells of the hair follicle contribute to cutaneous papillomas with long term persistence and a subset of which express the Ha-ras signature mutation characteristic of initiated cells. PMID- 22431490 TI - Fully integrated thermoplastic genosensor for the highly sensitive detection and identification of multi-drug-resistant tuberculosis. PMID- 22431491 TI - Mesoporous nitrogen-rich carbon materials as catalysts for the oxygen reduction reaction in alkaline solution. AB - ORR MNC, FTW! Mesoporous nitrogen-rich carbon (MNC) materials are synthesized by using polymer-loaded SBA-15 pyrolyzed at different temperatures. The activity and stability of the catalysts in the oxygen reduction reaction (ORR) are investigated by using cyclic voltammetry and rotating-disk electrode measurements. The MNC material pyrolyzed at 800 degrees C exhibits a high electrocatalytic activity towards the ORR in alkaline medium. PMID- 22431492 TI - Nocturnal oxygen saturation in children with stable cystic fibrosis. AB - BACKGROUND: Hypoxemia during sleep is a common finding in Cystic Fibrosis (CF) patients with more advanced lung disease. Nocturnal hypoxemia is associated with frequent awakenings and poor sleep quality. For children with CF, data of nocturnal oxygen saturation are sparse. OBJECTIVE: To assess the oxygen saturation profile during sleep in 25 clinically stable children with CF lung disease and to correlate these data with spirometry, cough frequency, sleep quality, and CT-scan scores. METHOD: During two nights cough was recorded with a digital audio recorder in 25 clinically stable CF patients. In addition oxygen saturation was measured. The day following the recording spirometry was carried out. CT scores were obtained from the most recent routine CT scan. RESULTS: Twenty-two patients were included in the study. Mean age (range) was 13 (6-18) years. Spirometry was FVC% 84 (range 52-114), FEV(1) % 77 (range 43-115), and FEF(75) % 50 (range 12-112). The mean SO(2) was 95.6% for the first and 96.2% for the second night. Mean SO(2) between the two nights correlated strongly (r(s) = 0.84, P < 0.001). Positive correlation was observed between mean SO(2) of the two nights (mean * SO(2)) and FVC, FEV(1) and FEF(75). Correlations were found between mean * SO(2) and the total CT score (r(s) = -0.45, P = 0.05) and the bronchiectasis subscore (r(s) = -0.48, P = 0.03). CONCLUSION: Nocturnal oxygen saturation in children with stable CF is lower than that in healthy children, and is correlated with lung function parameters and CT scores. Monitoring oxygen saturation during one night is sufficient to get a representative recording. PMID- 22431493 TI - Predictors of adverse clinical outcomes after successful infrapopliteal intervention. AB - OBJECTIVES: To clarify the clinical and angiographical variables related to delayed wound healing, major amputation and death after successful infrapopliteal intervention in critical limb ischemia patients with tissue loss. BACKGROUND: There is an underappreciation of adverse clinical outcomes after successful infrapopliteal intervention. METHODS: Stent-assisted infrapopliteal angioplasty was successful in 106 limbs in 85 patients. Successful intervention was defined as revascularization of at least one straight-line flow to the foot. RESULTS: At 6 months and 1, 2, and 5 years, the repeat intervention-free rates were 55.0, 49.6, 44.4, and 36.1%, respectively; the amputation-free survival rates were 85.7, 68.0, 54.5, and 39.8%, respectively; and the limb salvage rates were 96.0, 92.4, 86.3, and 86.3%, respectively. An infectious wound was an independent predictor of major amputation after successful intervention. The complete wound healing rates were 36.8, 57.5, 67.9, and 73.6% at 3, 6, 9, and 12 months, respectively. In stepwise multivariate Cox analysis, diabetes mellitus, an infectious wound, and the pedal arch classification were identified as independent predictors of wound healing. The long-term survival rates at 6 months and 1, 2, and 5 years were 89.5, 73.8, 62.0, and 43.4%, respectively. Stepwise multivariate Cox analysis indentified end-stage renal disease (ESRD) on hemodialysis to be an independent predictor of death. CONCLUSIONS: An infectious wound, comorbidities of diabetes mellitus and ESRD on hemodialysis and classification of pedal arch can be predictors of adverse clinical outcomes after successful infrapopliteal intervention. PMID- 22431494 TI - The science behind percutaneous hemodynamic support: a review and comparison of support strategies. AB - Patients in a variety of cardiovascular disease states may benefit from temporary percutaneous cardiac support, including those in acute decompensated heart failure, fulminant myocarditis, acute myocardial infarction with or without cardiogenic shock and those undergoing high-risk percutaneous coronary intervention. The ideal percutaneous cardiac support device is safe, easy to use and versatile enough to meet the needs of various clinical situations and patient cohorts. In addition, it should provide maximal hemodynamic support and protection against myocardial ischemia. With these goals in mind, the scientific principles that govern hemodynamic effectiveness and myocardial protection as they pertain to acute support devices are reviewed. PMID- 22431495 TI - HBeAg(+) and sex ratio of offspring: evidence form Taiwan's three million newborns. AB - OBJECTIVE: Mothers sero-positive for hepatitis B are slightly more likely to have a son. It is not known whether it is ever having HBV (HBsAg[+]) or currently active HBV (HBeAg[+]) which is associated with having a son. METHOD: Multivariable linear regression was used to assess the adjusted association of HBeAg(+) with offspring sex in all (90%) births (~3 million) in Taiwan from 1988 to 1999. RESULTS: Totally, 5% of mothers were HBeAg(+). HBeAg(+) mothers were slightly more likely to have a son (sex ratio 108 rather than 106) adjusted for HBsAg, birth order, mother's age, birth year, and area of residence. CONCLUSION: At a population level HBV status makes little difference to the sex ratio at birth. PMID- 22431496 TI - The impact and outcomes of establishing an integrated interdisciplinary surgical team to care for the diabetic foot. AB - OBJECTIVE: This study aimed to quantify the impact of an integrated diabetic foot surgical service on outcomes and changes in surgical volume and focus. METHODS: We abstracted registry data from 48 consecutive months at a single institution, evaluating all patients with diabetic foot complications requiring surgery or vascular intervention, and compared outcomes in the 24 months before and after integrating podiatric surgery with vascular surgical limb-salvage service. RESULTS: The service performed 2923 operations; 790 (27.0%) were related to treatment of diabetic foot complications in 374 patients. Of these, 502 were classified as non-vascular diabetic foot surgery and 288 were vascular interventions. Urgent surgery was significantly reduced after team implementation (77.7% vs 48.5%, p < 0.0001; OR = 3.7, 95% CI: 2.4-5.5). The high/low amputation ratio decreased from 0.35 to 0.27 due to an increase in low-level (midfoot) amputations (8.2% vs 26.1%, p < 0.0001; OR = 4.0, 95% CI: 2.0-83.3). A 45.7% reduction in below-knee amputations was realized with a stable above-knee/below knee amputation ratio (0.73-0.81). One-third of patients required vascular intervention. Vascular reconstructions increased 44.1% following institution of the team. Initial revascularization was endovascular in 70.6% of patients. Repeat endovascular intervention or conversion to open bypass was required in 37.1% of these patients, almost double the reintervention rate of those receiving open bypass first (18.9%). CONCLUSIONS: Interdisciplinary diabetic foot surgery teams may significantly impact surgery type, with greater focus on proactive and preventive, rather than reactive and ablative, procedures. Although endovascular limb-sparing procedures have become increasingly applicable, open bypass remains critical to success. PMID- 22431499 TI - The impact of stressful life events on relapse of generalized anxiety disorder. AB - BACKGROUND: Stressful life events (SLEs) are associated with the onset of psychiatric disorders but little is known about the effects of SLEs on individuals already diagnosed with an anxiety disorder, particularly generalized anxiety disorder (GAD) in which worry about life events is a defining characteristic. This study examined the impact of SLEs on relapse in adults already diagnosed with GAD. METHODS: Data are obtained from the Harvard/Brown Anxiety Research Project (HARP), a naturalistic longitudinal study of adults with a current or past history of anxiety disorders. One hundred and twelve adults recovered from an episode of GAD and 27 subsequently relapsed during the study. Eight categories of SLEs were assessed via interview and were examined as predictors of GAD relapse. RESULTS: An increased total number of SLEs was associated with a higher cumulative probability of relapse into episode of GAD and there was a nonsignificant statistical trend indicating specific categories of SLEs including health, death, and family/friends/household were related to an increased probability of relapse into episodes of GAD. CONCLUSIONS: SLEs impact the course of GAD and certain types of stressors may be more relevant to symptomatology than others. The change and uncertainty associated with SLEs may exacerbate existing worry tendencies even among those who have recovered from GAD. PMID- 22431501 TI - Successful percutaneous transvenous antegrade mitral valve-in-valve implantation. AB - We report a case of transcatheter valve-in-valve therapy performed on an 85-year old man with severe mitral bioprosthetic valve dysfunction. He was a high risk candidate for conventional surgery and he underwent placement of the Melody transcatheter heart valve into the mitral bioprosthesis via the right femoral vein. PMID- 22431502 TI - Interpretation of pediatric lung function: impact of ethnicity. AB - RATIONALE: To evaluate the appropriateness of spirometric and plethysmographic reference equations in healthy young children according to ethnic origin. METHODS: Spirometry data were collated in 400 healthy children (214 Black and 186 White) aged 6-12 years. Of these children, 68 Black and 115 White children also undertook plethysmography. Results were expressed as percent predicted according to commonly used equations for spirometry and plethysmography. RESULTS: Black children had lower lung function for a given height compared to White children. The magnitude and direction of these differences varied according to specific outcome. In the studied age range (6-12 years) the ethnic-specific Wang equations were adequate for spirometry (mean results approximating 100% predicted in both ethnic groups). By contrast, significant differences were found between observed and % predicted plethysmographic lung volumes according to published equations derived from White children: Among the Black children, function residual capacity (FRC) and total lung capacity (TLC) were on average, 14 and 6% lower than predicted, whereas mean residual volume (RV) and RV/TLC were 4 and 10% higher. Among White children, the Rosenthal equations gave the best fit, with the exception of FRC which was, on average, 9% lower than predicted. CONCLUSION: Spirometry equations may suffice in Black children; however, interpretation of static lung volumes in Black children is limited due to inappropriate reference equations. More appropriate plethysmographic reference equations that are applicable to all ethnic groups across the entire age range are urgently needed. PMID- 22431503 TI - Occlusion of the perimembranous ventricular septal defect using CERA(r) devices. AB - BACKGROUND: High incidence of atrioventricular (AV) block has been the major limitation of percutaneous closure of perimembranous ventricular septal defect (PMVSD). METHODS: Prospective, multicenter, nonrandomized study including 55 patients who were submitted to 56 procedures from March 2010 to November 2010. Inclusion criteria were PMVSD with diameter >= 5 mm or if <=5 mm with hemodynamic significance and age >= 1 year. Exclusion criteria were fixed pulmonary arterial hypertension and associated congenital heart disease needing surgical repair. Procedures were performed under general anesthesia and monitored by transthoracic echocardiography (TTE). The device choice was based on left ventricle (LV) angiography and on TTE images. PMVSDs were crossed by retrograde approach. RESULTS: Mean age was 9.3 +/- 7.5 years, and mean weight was 29.1 +/- 15.9 kg. Thirty-five (63.6%) patients were females. Mean pulmonary arterial mean pressure, mean LV diastolic diameter, and mean Q(p) /Q(s) were 24.0 +/- 6.5 mm Hg, 43.0 +/- 5.9 mm, and 2.2 +/- 0.8, respectively. Associated nonsurgical malformations were present in 9 (16.3%) patients, and PMVSDs were multifenestrated in 16 (46.2%) cases. Mean PMVSDs diameter was 5.8 +/- 1.8 mm by angiography and 6.8 +/- 2.3 mm by TTE. New rhythm disturbance without clinical significance was observed in 29% of the patients and was reversible in 87.5%. After procedure, trivial residual shunt was present in 5 (8.9%) patients and moderate residual shunt in other 5 (8.9%). At late FU (mean of 298.7 +/- 88.9 days), 91% of the patients had no residual shunts. Third-degree AV block and severe aortic regurgitation occurred in one patient each. CONCLUSIONS: In this experience, PMVSD closure with CERA(r) devices showed to be safe and effective with low incidence of complications at immediate and mid-term FU. PMID- 22431504 TI - Emission analysis of RE3+ (RE = Sm, Dy):B2O3-TeO2-Li2O-AlF3 glasses. AB - This article reports on the optical properties of 0.5% mol of Sm(3+), Dy(3+) ion doped B2O3-TeO2-Li2O-AlF3 (LiAlFBT) glasses. The glass samples were characterized by optical absorption and emission spectra. Judd-Ofelt theory was applied to analyze the optical absorption spectra and calculate the intensity parameters and radiative properties of the emission transitions. The emission spectra of Sm(3+) and Dy(3+):LiAlFBT glasses showed a bright reddish-orange emission at 598 nm ((4)G5/2 -> (6)H7/2) and an intense yellow emission at 574 nm ((4)F9/2 -> (6)H13/2), respectively. Full width at half maximum (FWHM), stimulated emission cross section, gain bandwidth and optical gain values were also calculated to extend the applications of the Sm(3+) and Dy(3+):LiAlFBT glasses. PMID- 22431505 TI - Severe central sleep apnea in a child with leukemia on chronic methadone therapy. AB - We describe a child with acute myeloid leukemia (AML) who developed severe central sleep apnea (CSA) on methadone therapy for chronic pain management. His chemotherapy-related cerebral atrophy and renal insufficiency with impaired methadone clearance may have also contributed to the severity of his sleep disordered breathing. Maintenance methadone treatment is not a common pediatric practice; therefore, the adverse effects of methadone therapy, including CSA, are rarely reported in children. PMID- 22431506 TI - Hermann Niemeyer Fernandez: a pioneer of Chilean science (October 26, 1918, Ovalle, Chile to June 7, 1991, Santiago, Chile). PMID- 22431507 TI - Carbon monoxide: an unusual drug. AB - The highly toxic gas carbon monoxide (CO) displays many physiological roles in several organs and tissues. Although many diseases, including cancer, hematological diseases, hypertension, heart failure, inflammation, sepsis, neurodegeneration, and sleep disorders, have been linked to abnormal endogenous CO metabolism and functions, CO administration has therapeutic potential in inflammation, sepsis, lung injury, cardiovascular diseases, transplantation, and cancer. Here, insights into the CO-based therapy, characterized by the induction or gene transfer of heme oxygenase-1 and either gas or CO-releasing molecule administration, are reviewed. PMID- 22431508 TI - Centromere-targeted de novo integrations of an LTR retrotransposon of Arabidopsis lyrata. AB - The plant genome evolves with rapid proliferation of LTR-type retrotransposons, which is associated with their clustered accumulation in gene-poor regions, such as centromeres. Despite their major role for plant genome evolution, no mobile LTR element with targeted integration into gene-poor regions has been identified in plants. Here, we report such targeted integrations de novo. We and others have previously shown that an ATCOPIA93 family retrotransposon in Arabidopsis thaliana is mobilized when the DNA methylation machinery is compromised. Although ATCOPIA93 family elements are low copy number in the wild-type A. thaliana genome, high-copy-number related elements are found in the wild-type Arabidopsis lyrata genome, and they show centromere-specific localization. To understand the mechanisms for the clustered accumulation of the A. lyrata elements directly, we introduced one of them, named Tal1 (Transposon of Arabidopsis lyrata 1), into A. thaliana by transformation. The introduced Tal1 was retrotransposed in A. thaliana, and most of the retrotransposed copies were found in centromeric repeats of A. thaliana, suggesting targeted integration. The targeted integration is especially surprising because the centromeric repeat sequences differ considerably between A. lyrata and A. thaliana. Our results revealed unexpectedly dynamic controls for evolution of the transposon-rich heterochromatic regions. PMID- 22431509 TI - A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. AB - In this study, we show the high frequency of spontaneous gammadelta T-cell leukemia (T-ALL) occurrence in mice with biallelic deletion of enhancer of zeste homolog 2 (Ezh2). Tumor cells show little residual H3K27 trimethylation marks compared with controls. EZH2 is a component of the PRC2 Polycomb group protein complex, which is associated with DNA methyltransferases. Using next-generation sequencing, we identify alteration in gene expression levels of EZH2 and acquired mutations in PRC2-associated genes (DNMT3A and JARID2) in human adult T-ALL. Together, these studies document that deregulation of EZH2 and associated genes leads to the development of mouse, and likely human, T-ALL. PMID- 22431510 TI - Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells. AB - The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell subsets, including B1 cells and marginal zone B cells. The proliferation defect of Ebf1-deficient pro-B cells and the impaired expression of multiple cell cycle regulators are overcome by transformation with v-Abl. The survival defect of transformed Ebf1(fl/fl) pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-x(L). In mature B cells, Ebf1 deficiency interferes with signaling via the B-cell-activating factor receptor (BAFF-R)- and B-cell receptor (BCR)-dependent Akt pathways. Moreover, Ebf1 is required for germinal center formation and class switch recombination. Genome wide analyses of Ebf1-mediated gene expression and chromatin binding indicate that Ebf1 regulates both common and distinct sets of genes in early and late stage B cells. By regulating important components of transcription factor and signaling networks, Ebf1 appears to be involved in the coordination of cell proliferation, survival, and differentiation at multiple stages of B lymphopoiesis. PMID- 22431511 TI - Embryonic onset of late replication requires Cdc25 down-regulation. AB - The Drosophila midblastula transition (MBT), a major event in embryogenesis, remodels and slows the cell cycle. In the pre-MBT cycles, all genomic regions replicate simultaneously in rapid S phases that alternate with mitosis, skipping gap phases. At the MBT, down-regulation of Cdc25 phosphatase and the resulting inhibitory phosphorylation of the mitotic kinase Cdk1 create a G2 pause in interphase 14. However, an earlier change in interphase 14 is the prolongation of S phase. While the signals modifying S phase are unknown, the onset of late replication-where replication of constitutively heterochromatic satellite sequences is delayed-extends S-phase 14. We injected Cdc25 mRNA to bypass the developmentally programmed down-regulation of Cdc25 at the MBT. Introduction of either Cdc25 isoform (String or Twine) or enhanced Cdk1 activity triggered premature replication of late-replicating sequences, even after their specification, and thereby shortened S phase. Reciprocally, reduction of Cdk1 activity by knockdown of mitotic cyclins extended pre-MBT S phase. These findings suggest that high Cdc25 and Cdk1 contribute to the speed of the rapid, pre-MBT S phases and that down-regulation of these activities plays a broader role in MBT associated changes than was previously suspected. PMID- 22431512 TI - RNAi keeps Atf1-bound stress response genes in check at nuclear pores. AB - RNAi pathways are prevalent throughout the eukaryotic kingdom and are well known to regulate gene expression on a post-transcriptional level in the cytoplasm. Less is known about possible functions of RNAi in the nucleus. In the fission yeast Schizosaccharomyces pombe, RNAi is crucial to establish and maintain centromeric heterochromatin and functions to repress genome activity by a chromatin silencing mechanism referred to as cotranscriptional gene silencing (CTGS). Mechanistic details and the physiological relevance of CTGS are unknown. Here we show that RNAi components interact with chromatin at nuclear pores to keep stress response genes in check. We demonstrate that RNAi-mediated CTGS represses stress-inducible genes by degrading mRNAs under noninduced conditions. Under chronic heat stress conditions, a Dicer thermoswitch deports Dicer to the cytoplasm, thereby disrupting CTGS and enabling expression of genes implicated in the acquisition of thermotolerance. Taken together, our work highlights a role for nuclear pores and the stress response transcription factor Atf1 in coordinating the interplay between the RNAi machinery and the S. pombe genome and uncovers a novel mode of RNAi regulation in response to an environmental cue. PMID- 22431513 TI - Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. AB - In mammals, leptin regulates food intake and energy balance mainly through the activation of LepRb in the hypothalamus, and estrogen has a leptin-like effect in the hypothalamic control of metabolism. However, it remains to be elucidated how estrogen signaling is intertwined with the leptin pathway. We show here that Shp2, a nonreceptor tyrosine phosphatase, acts to integrate leptin and estrogen signals. The expression of a dominant-active mutant (Shp2(D61A)) in forebrain neurons conferred female, but not male, transgenic mice resistance to high-fat diet (HFD)-induced obesity and liver steatosis, accompanied by improved insulin sensitivity and glucose homeostasis. Fed with either HFD or regular chow food, Shp2(D61A) female mice showed dramatically enhanced leptin sensitivity. Microinjection of Shp2(D61A)-expressing adeno-associated virus into mediobasal hypothalamus elicited a similar antiobese effect in female mice. Biochemical analyses showed a physical association of Shp2 with estrogen receptor alpha, which is necessary for the synergistic and persistent activation of Erk by leptin and estrogen. Together, these results elucidate a mechanism for the direct cross talk of leptin and estrogen signaling and offer one explanation for the propensity of postmenopausal women to develop obesity. PMID- 22431514 TI - A collapsin response mediator protein 2 isoform controls myosin II-mediated cell migration and matrix assembly by trapping ROCK II. AB - Collapsin response mediator protein 2 (CRMP-2) is known as a regulator of neuronal polarity and differentiation through microtubule assembly and trafficking. Here, we show that CRMP-2 is ubiquitously expressed and a splice variant (CRMP-2L), which is expressed mainly in epithelial cells among nonneuronal cells, regulates myosin II-mediated cellular functions, including cell migration. While the CRMP-2 short form (CRMP-2S) is recognized as a substrate of the Rho-GTP downstream kinase ROCK in neuronal cells, a CRMP-2 complex containing 2L not only bound the catalytic domain of ROCK II through two binding domains but also trapped and inhibited the kinase. CRMP-2L protein levels profoundly affected haptotactic migration and the actin-myosin cytoskeleton of carcinoma cells as well as nontransformed epithelial cell migration in a ROCK activity-dependent manner. Moreover, the ectopic expression of CRMP-2L but not 2S inhibited fibronectin matrix assembly in fibroblasts. Underlying these responses, CRMP-2L regulated the kinase activity of ROCK II but not ROCK I, independent of GTP-RhoA levels. This study provides a new insight into CRMP-2 as a controller of myosin II-mediated cellular functions through the inhibition of ROCK II in nonneuronal cells. PMID- 22431515 TI - Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor alpha turnover and functional activity via the SCF(Skp2) proteasomal complex. AB - The nuclear hormone receptor estrogen receptor alpha (ERalpha) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ERalpha in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ERalpha are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK)-mediated phosphorylation of ERalpha at Ser-294 that specifies its turnover by the SCF(Skp2) proteasome complex. Consistently, we observed an inverse relationship between ERalpha and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ERalpha regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ERalpha. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ERalpha protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ERalpha-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ERalpha and the responsiveness to endocrine therapy in some endocrine-insensitive ERalpha negative breast cancers. PMID- 22431516 TI - An RNA-independent linkage of noncoding transcription to long-range enhancer function. AB - The detection of noncoding transcription at multiple enhancers within the mammalian genome raises critical questions regarding whether and how this activity contributes to enhancer function. Here, using in vivo analysis of a human growth hormone (hGH) transgene locus, we report that activation of a domain of noncoding transcription adjacent to the long-range hGH-N enhancer, HSI, is established by the enhancer independent of any interactions with its target promoter. We further demonstrate that the appearance of this enhancer-linked noncoding transcription is temporally and spatially concordant with induction of hGH-N in the embryonic pituitary. Finally, we show that the level of transcriptional enhancement of hGH-N by HSI is directly related to the intensity of HSI-dependent noncoding transcription and is fully independent of the structure of the locally transcribed RNA. These data extend our understanding of the relationship of long-range enhancer activity to enhancer-dependent noncoding transcription and establish a model that may be of general relevance to additional mammalian loci. PMID- 22431517 TI - Cardiac expression of ms1/STARS, a novel gene involved in cardiac development and disease, is regulated by GATA4. AB - Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), alpha, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, alpha and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease. PMID- 22431518 TI - Vascular endothelial growth factor A competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses. AB - Certain platelet-derived growth factor (PDGF) isoforms are associated with proliferative vitreoretinopathy (PVR), a sight-threatening complication that develops in a subset of patients recovering from retinal reattachment surgery. Although these PDGF isoforms are abundant in the vitreous of patients and experimental animals with PVR, they make only a minor contribution to activating PDGF receptor alpha (PDGFRalpha) and driving experimental PVR. Rather, growth factors outside of the PDGF family are the primary (and indirect) agonists of PDGFRalpha. These observations beg the question of why vitreal PDGFs fail to activate PDGFRalpha. We report here that vitreous contains an inhibitor of PDGF dependent activation of PDGFRalpha and that a major portion of this inhibitory activity is due to vascular endothelial cell growth factor A (VEGF-A). Furthermore, recombinant VEGF-A competitively blocks PDGF-dependent binding and activation of PDGFR, signaling events, and cellular responses. These findings unveil a previously unappreciated relationship between distant members of the PDGF/VEGF family that may contribute to pathogenesis of a blinding eye disease. PMID- 22431519 TI - Scd1 plays a tumor-suppressive role in survival of leukemia stem cells and the development of chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is derived from a stem cell, and it is widely accepted that the existence of leukemia stem cells (LSCs) is one of the major reasons for the relapse of CML treated with kinase inhibitors. Key to eradicating LSCs is to identify genes that play a critical role in survival regulation of these stem cells. Using BCR-ABL-induced CML mouse model, here we show that expression of the stearoyl-CoA desaturase 1 (Scd1) gene is downregulated in LSCs and that Scd1 plays a tumor-suppressive role in LSCs with no effect on the function of normal hematopoietic stem cells. Deletion of Scd1 causes acceleration of CML development and conversely overexpression of Scd1 delays CML development. In addition, using genetic approaches, we show that Pten, p53, and Bcl2 are regulated by Scd1 in LSCs. Furthermore, we find that induction of Scd1 expression by a PPARgamma agonist suppresses LSCs and delays CML development. Our results demonstrate a critical role for Scd1 in functional regulation of LSCs, providing a new anti-LSC strategy through enhancing Scd1 activity. PMID- 22431521 TI - The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal sorting. AB - Mutations in the gene encoding CLN5 are the cause of Finnish variant late infantile Neuronal Ceroid Lipofuscinosis (NCL), and the gene encoding CLN5 is 1 of 10 genes (encoding CLN1 to CLN9 and cathepsin D) whose germ line mutations result in a group of recessive disorders of childhood. Although CLN5 localizes to the lysosomal compartment, its function remains unknown. We have uncovered an interaction between CLN5 and sortilin, the lysosomal sorting receptor. However, CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment. We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). In addition, we show that the retromer recruitment machinery is also affected by CLN5 depletion, as we found less loaded Rab7, which is required to recruit retromer. Taken together, our results support a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome. PMID- 22431520 TI - The Saccharomyces cerevisiae Nrd1-Nab3 transcription termination pathway acts in opposition to Ras signaling and mediates response to nutrient depletion. AB - The Saccharomyces cerevisiae Nrd1-Nab3 pathway directs the termination and processing of short RNA polymerase II transcripts. Despite the potential for Nrd1 Nab3 to affect the transcription of both coding and noncoding RNAs, little is known about how the Nrd1-Nab3 pathway interacts with other pathways in the cell. Here we present the results of a high-throughput synthetic lethality screen for genes that interact with NRD1 and show roles for Nrd1 in the regulation of mitochondrial abundance and cell size. We also provide genetic evidence of interactions between the Nrd1-Nab3 and Ras/protein kinase A (PKA) pathways. Whereas the Ras pathway promotes the transcription of genes involved in growth and glycolysis, the Nrd1-Nab3 pathway appears to have a novel role in the rapid suppression of some genes when cells are shifted to poor growth conditions. We report the identification of new mRNA targets of the Nrd1-Nab3 pathway that are rapidly repressed in response to glucose depletion. Glucose depletion also leads to the dephosphorylation of Nrd1 and the formation of novel nuclear speckles that contain Nrd1 and Nab3. Taken together, these results indicate a role for Nrd1 Nab3 in regulating the cellular response to nutrient availability. PMID- 22431522 TI - Tumor suppressor PDCD4 represses internal ribosome entry site-mediated translation of antiapoptotic proteins and is regulated by S6 kinase 2. AB - Apoptosis can be regulated by extracellular signals that are communicated by peptides such as fibroblast growth factor 2 (FGF-2) that have important roles in tumor cell proliferation. The prosurvival effects of FGF-2 are transduced by the activation of the ribosomal protein S6 kinase 2 (S6K2), which increases the expression of the antiapoptotic proteins X chromosome-linked Inhibitor of Apoptosis (XIAP) and Bcl-x(L). We now show that the FGF-2-S6K2 prosurvival signaling is mediated by the tumor suppressor programmed cell death 4 (PDCD4). We demonstrate that PDCD4 specifically binds to the internal ribosome entry site (IRES) elements of both the XIAP and Bcl-x(L) messenger RNAs and represses their translation by inhibiting the formation of the 48S translation initiation complex. Phosphorylation of PDCD4 by activated S6K2 leads to the degradation of PDCD4 and thus the subsequent derepression of XIAP and Bcl-x(L) translation. Our results identify PDCD4 as a specific repressor of the IRES-dependent translation of cellular mRNAs (such as XIAP and Bcl-x(L)) that mediate FGF-2-S6K2 prosurvival signaling and provide further insight into the role of PDCD4 in tumor suppression. PMID- 22431523 TI - Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. AB - Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and liver. Serum RBP4 levels correlate highly with insulin resistance, other metabolic syndrome factors, and cardiovascular disease. Elevated serum RBP4 causes insulin resistance, but the molecular mechanisms are unknown. Here we show that RBP4 induces expression of proinflammatory cytokines in mouse and human macrophages and thereby indirectly inhibits insulin signaling in cocultured adipocytes. This occurs through activation of c-Jun N-terminal protein kinase (JNK) and Toll-like receptor 4 (TLR4) pathways independent of the RBP4 receptor, STRA6. RBP4 effects are markedly attenuated in JNK1-/- JNK2-/- macrophages and TLR4-/- macrophages. Because RBP4 is a retinol-binding protein, we investigated whether these effects are retinol dependent. Unexpectedly, retinol-free RBP4 (apo-RBP4) is as potent as retinol-bound RBP4 (holo-RBP4) in inducing proinflammatory cytokines in macrophages. Apo-RBP4 is likely to be physiologically significant since RBP4/retinol ratios are increased in serum of lean and obese insulin-resistant humans compared to ratios in insulin-sensitive humans, indicating that higher apo-RBP4 is associated with insulin resistance independent of obesity. Thus, RBP4 may cause insulin resistance by contributing to the development of an inflammatory state in adipose tissue through activation of proinflammatory cytokines in macrophages. This process reveals a novel JNK- and TLR4-dependent and retinol- and STRA6-independent mechanism of action for RBP4. PMID- 22431524 TI - Glucose oxidation modulates anoikis and tumor metastasis. AB - Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis or the Warburg effect, and the cells resist matrix detachment induced apoptosis, which is called anoikis, a barrier to metastasis. It remains largely unclear whether tumor metabolism influences anoikis and metastasis. Here we show that when detached from the matrix, untransformed mammary epithelial cells undergo metabolic reprogramming by markedly upregulating pyruvate dehydrogenase (PDH) kinase 4 (PDK4) through estrogen-related receptor gamma (ERRgamma), thereby inhibiting PDH and attenuating the flux of glycolytic carbon into mitochondrial oxidation. To decipher the significance of this metabolic response, we found that depletion of PDK4 or activation of PDH increased mitochondrial respiration and oxidative stress in suspended cells, resulting in heightened anoikis. Conversely, overexpression of PDKs prolonged survival of cells in suspension. Therefore, decreased glucose oxidation following cell detachment confers anoikis resistance. Unlike untransformed cells, most cancer cells demonstrate reduced glucose oxidation even under attached conditions, and thus they inherently possess a survival advantage when suspended. Normalization of glucose metabolism by stimulating PDH in cancer cells restores their susceptibility to anoikis and impairs their metastatic potential. These results suggest that the Warburg effect, more specifically, diminished glucose oxidation, promotes anoikis resistance and metastasis and that PDKs are potential targets for antimetastasis therapy. PMID- 22431525 TI - Discriminative multimanifold analysis for face recognition from a single training sample per person. AB - Conventional appearance-based face recognition methods usually assume that there are multiple samples per person (MSPP) available for discriminative feature extraction during the training phase. In many practical face recognition applications such as law enhancement, e-passport, and ID card identification, this assumption, however, may not hold as there is only a single sample per person (SSPP) enrolled or recorded in these systems. Many popular face recognition methods fail to work well in this scenario because there are not enough samples for discriminant learning. To address this problem, we propose in this paper a novel discriminative multimanifold analysis (DMMA) method by learning discriminative features from image patches. First, we partition each enrolled face image into several nonoverlapping patches to form an image set for each sample per person. Then, we formulate the SSPP face recognition as a manifold-manifold matching problem and learn multiple DMMA feature spaces to maximize the manifold margins of different persons. Finally, we present a reconstruction-based manifold-manifold distance to identify the unlabeled subjects. Experimental results on three widely used face databases are presented to demonstrate the efficacy of the proposed approach. PMID- 22431526 TI - A novel Bayesian framework for discriminative feature extraction in Brain Computer Interfaces. AB - As there has been a paradigm shift in the learning load from a human subject to a computer, machine learning has been considered as a useful tool for Brain Computer Interfaces (BCIs). In this paper, we propose a novel Bayesian framework for discriminative feature extraction for motor imagery classification in an EEG based BCI in which the class-discriminative frequency bands and the corresponding spatial filters are optimized by means of the probabilistic and information theoretic approaches. In our framework, the problem of simultaneous spatiospectral filter optimization is formulated as the estimation of an unknown posterior probability density function (pdf) that represents the probability that a single-trial EEG of predefined mental tasks can be discriminated in a state. In order to estimate the posterior pdf, we propose a particle-based approximation method by extending a factored-sampling technique with a diffusion process. An information-theoretic observation model is also devised to measure discriminative power of features between classes. From the viewpoint of classifier design, the proposed method naturally allows us to construct a spectrally weighted label decision rule by linearly combining the outputs from multiple classifiers. We demonstrate the feasibility and effectiveness of the proposed method by analyzing the results and its success on three public databases. PMID- 22431527 TI - The evolving landscape for pathology subspecialty fellowship applications. PMID- 22431528 TI - American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. AB - An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections. PMID- 22431529 TI - Challenges and opportunities in the application process for fellowship training in pathology: an independent survey of residents and fellows demonstrates limited interest in an NRMP-style matching program. AB - A survey completed by 366 pathology residents and fellows examined preferences for 3 fellowship application systems: keeping the current system, a National Resident Matching Program (NRMP)-style match, and a unified time line. All groups showed a strong preference for a time line, accounting for 62.1% of first choices vs the current system (17.3%) or a match (20.6%). When asked for a second choice after time line was ranked first, 60.5% of respondents whose fellowship of choice was available at their residency institution and 63.5% who had accepted fellowship positions at their residency institution preferred the current system; 51.4% whose fellowship of choice was not available at their residency institution and 50.6% of those who had accepted fellowship positions elsewhere preferred a match. Location and family/personal reasons were more important than subspecialty competitiveness and program prestige when accepting fellowship positions. Pressure to choose and apply early for fellowship persists and is greatest for anatomic pathology-only and clinical pathology-only residents. PMID- 22431530 TI - Pathology consultation on the laboratory evaluation of thrombophilia: when, how, and why. AB - Venous thromboembolism (VTE) results from the interaction of the Virchow triad (venous stasis, endothelial injury, and hypercoagulability). Risk factors for increased hypercoagulability, or thrombophilia, include activated protein C resistance/factor V Leiden, the prothrombin G20210A mutation, deficiencies of the natural anticoagulants (antithrombin, proteins C and S), antiphospholipid antibodies, hyperhomocysteinemia, and increased factor VIII activity. Not all patients with VTE need to be tested for such risk factors, but patients with thrombophilia should be evaluated for all possibilities to better estimate risk. At the same time, testing should be patient-specific because assay results are affected by preanalytic variables, including thrombosis and anticoagulant therapy. PMID- 22431531 TI - Two cases of transfusion-transmitted Anaplasma phagocytophilum. AB - Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, is an obligate intracellular bacterium most commonly acquired from tick bites. High seroprevalence rates in endemic regions suggest that transfusion transmission of A phagocytophilum would be a common event; however, only 2 cases have previously been reported. The exact cause of this discrepancy is not known. Whole blood leukocyte-reduction methods used by many blood centers are thought to reduce the risk of transfusion transmission of many pathogens, including A phagocytophilum. We report 2 additional cases of transfusion-transmitted A phagocytophilum in which leukocyte reduction of all transfused units failed to prevent microbial transmission. PMID- 22431532 TI - A massive transfusion protocol incorporating a higher FFP/RBC ratio is associated with decreased use of recombinant activated factor VII in trauma patients. AB - We implemented a protocol incorporating a higher fresh frozen plasma (FFP)/RBC ratio for the management of trauma patients requiring massive transfusion in 2007. This study aims to identify issues that affected the effective deployment of the massive transfusion protocol (MTP) and compare outcome variables with a historic cohort. Data from 49 trauma patients who received at least 10 units of packed RBCs within 24 hours were analyzed and compared with a historic massively transfused cohort who had received recombinant activated factor VII (rFVIIa). Of the patients, 28 received an FFP/RBC ratio of 1:1 to 1:2; 12 received a lower ratio of 1:2 to 1:4; 3 received more than 1:1 and 6 had less than 1:4. Compared with the historic cohort, the 1:1-1:2 group received significantly fewer blood components and did not require rescue rFVIIa. An MTP incorporating a higher FFP/RBC ratio of 1:1 to 1:2 is associated with decreased use of blood components and may obviate the need for rFVII. PMID- 22431533 TI - Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. AB - New anticoagulants, like the orally available direct thrombin inhibitor (DTI) dabigatran etexilate, have recently been introduced into the market for venous thromboembolic prophylaxis and for stroke prevention in atrial fibrillation. While dabigatran has been approved for use without the need for routine therapeutic monitoring, there are clinical scenarios in which monitoring can help guide clinical management. We report herein the application of a recently described plasma-diluted thrombin time (DTI assay) used to monitor intravenous DTI as a useful and easily implemented method to monitor oral DTIs. PMID- 22431534 TI - Comparison of methods for proliferative index analysis for grading pancreatic well-differentiated neuroendocrine tumors. AB - Assessment of proliferative activity is required for grading well-differentiated pancreatic neuroendocrine tumors. However, a standardized method for obtaining the Ki-67 proliferative index is lacking. This study compared proliferative activity obtained by 3 methods: single-field hot spot (Ki-67 HS) and 10 consecutive field average (Ki-67 CFA) using the Ventana image analysis system (Ventana Medical Systems, Tucson, AZ) and mitotic index (MI). These methods resulted in discrepant grades in 30 (67%) of our 45 cases. With the current Ki-67 cutoff of more than 2% for intermediate-grade tumors, MI, CFA, and HS resulted in specificities of 91%, 94%, and 31%, respectively, for detecting metastasis, with positive predictive values (PPVs) of 25%, 67%, and 31%, respectively. At a higher Ki-67 cutoff of 7.5%, HS analysis resulted in a specificity of 94% and PPV of 71% for predicting metastasis. While single-field HS analysis may be practical and reliable at a higher cutoff, this study emphasizes the variability that can exist when different methods of assessment are used. PMID- 22431535 TI - HER2 amplification in gastroesophageal adenocarcinoma: correlation of two antibodies using gastric cancer scoring criteria, H score, and digital image analysis with fluorescence in situ hybridization. AB - We assessed 103 resected gastroesophageal adenocarcinomas for HER2 amplification by fluorescence in situ hybridization (FISH) and 2 commercial immunohistochemical assays. Of 103, 30 (29%) were FISH-amplified. Both immunohistochemical assays had greater than 95% concordance with FISH. However, as a screening test for FISH amplification, the Ventana Medical Systems (Tucson, AZ) 4B5 antibody demonstrated superior sensitivity (87%) compared with the DAKO (Carpinteria, CA) A0485 (70%). Of the cases, 28 were immunohistochemically 3+ or immunohistochemically 2+/FISH amplified with the 4B5 assay compared with only 22 cases with the A0485 assay, representing a large potential difference in patient eligibility for anti-HER2 therapy. Cases with low-level FISH amplification (HER2/CEP17, 2.2-4.0) express lower levels of HER2 protein compared with cases with high-level amplification (HER2/CEP17, >=4.0), raising the possibility of a differential response to anti HER2 therapy. The H score and digital image analysis may have a limited role in improving HER2 test performance. PMID- 22431536 TI - HER2 gene amplification in breast cancer: a rogues' gallery of challenging diagnostic cases: UKNEQAS interpretation guidelines and research recommendations. AB - International and national guidelines highlight the importance of accuracy, reproducibility, and quality control of in situ hybridization (ISH) methods for testing breast carcinomas. However, few guidelines cover the reporting of ISH cases with "unusual" signal patterns, including, eg, heterogeneity and loss of chromosome enumeration probe or gene signals. These cases are, in fact, relatively frequent, and there is a need for developing evidence- or consensus based reporting guidelines to ensure consistency of treatment. Following an audit of cases from a single center (including >1,700 cases) we show that approximately 10% of ISH results reflect unusual signal patterns. We illustrate the most common of these patterns and provide reporting guidelines for diagnosticians and recommendations for future research. Our goal is to ensure that in the future such "rogues" are reported in a consistent manner that, ultimately, will be supported by molecular and biochemical evidence. PMID- 22431537 TI - Addenda in pathology reports: trends and their implications. AB - Addenda are typically used to report results of additional studies that are delayed relative to histopathologic studies. However, the frequency and pattern of use of addenda have not been previously reported. We studied the dynamics of addenda creation within the same month at 5-year intervals during a 15-year period at our institution. The number of addenda and type and impact of information communicated in addenda were assessed in the month of July in 1993, 1998, 2003, and 2008, and the possible role of addenda in quality improvement was evaluated. Cases with addenda increased from 0.9% in 1993 to 8.6% in 2008. In 5.6% of addenda, there was information that might have been better reported in an amendment, suggesting that criteria for amendments need to be universally implemented. Charting trends and types of addenda offered opportunities for quality improvement by identifying weaknesses in the workflow organization of the laboratory. PMID- 22431538 TI - Absence of the BRAF and the GRIM-19 mutations in oncocytic (Hurthle cell) solid cell nests of the thyroid. AB - We report the first case of oncocytic solid cell nests (SCNs), found in the right lobe of the thyroid of a 70-year-old man. Conventional SCNs and 1 papillary microcarcinoma (mPTC) were also found in the left lobe. In the oncocytic SCNs, 80% of the main cells showed oncocytic cytoplasm immunoreactive for porin and proteins of the SDHB and SDHA genes. Positivity for cytokeratin 19, p63, galectin 3, and HBME-1 and negativity for thyroglobulin, thyroperoxidase, vimentin, Oct-4, and alpha-fetoprotein were found in oncocytic and conventional SCNs. An inverse correlation was found between oncocytic metaplasia and p63. Association with C cells was confirmed at protein and messenger RNA levels in both types of SCNs. No germinal mutation of GRIM-19 was detected. No somatic BRAF mutation was found in any of the SCNs nor in the mPTC. We conclude that SCNs may acquire mitochondrial alterations similar to those seen in follicular and C cells, as well as in their respective tumors. PMID- 22431539 TI - Epidemiology of Escherichia coli, Klebsiella species, and Proteus mirabilis strains producing extended-spectrum beta-lactamases from clinical samples in the Kinki Region of Japan. AB - In the present study, nonduplicate, clinical isolates of extended-spectrum beta lactamase (ESBL)-producing Escherichia coli, Klebsiella spp, and Proteus mirabilis were collected during a 10-year period from 2000 to 2009 at several hospitals in the Kinki region, Japan. The detection rate of E coli markedly increased from 0.24% to 7.25%. The detection rate of Klebsiella pneumoniae increased from 0% to 2.44% and that of P mirabilis from 6.97% to 12.85%. The most frequently detected genotypes were the CTX-M9 group for E coli, the CTX-M2 group for K pneumoniae, and the CTX-M2 group for P mirabilis. E coli clone O25:H4-ST131 producing CTX-M-15, which is spreading worldwide, was first detected in 2007. The most common replicon type of E coli was the IncF type, particularly FIB, detected in 466 strains (69.7%). Of the K pneumoniae strains, 47 (55.3%) were of the IncN type; 77 P mirabilis strains (96.3%) were of the IncT type. In the future, the surveillance of various resistant bacteria, mainly ESBL-producing Enterobacteriaceae, should be expanded to prevent their spread. PMID- 22431540 TI - Rapid detection of Klebsiella pneumoniae carbapenemase genes in enterobacteriaceae directly from blood culture bottles by real-time PCR. AB - Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are endemic in New York City hospitals and have been associated with serious infections globally. A real-time polymerase chain reaction (RT-PCR) assay was developed to detect carbapenem resistance attributable to KPC from blood culture bottles positive for gram-negative bacilli. Culture confirmation of carbapenemase production included automated imipenem and meropenem susceptibility testing and ertapenem susceptibility testing by disk-diffusion. A total of 323 Enterobacteriaceae isolates were tested, of which 8.7% (n = 28) demonstrated carbapenem-resistance by automated and manual susceptibility testing methods or by RT-PCR. The sensitivity, specificity, and positive and negative predictive values of the RT-PCR assay when compared with the automated method were 92.9%, 99.3%, 92.9%, and 99.3%, respectively, and 96.4%, 99.7%, 96.4%, and 99.7%, respectively, when compared with the ertapenem disk-diffusion method. RT-PCR is a rapid and reliable means of detecting carbapenem resistance due to KPC-plasmids in Enterobacteriaceae directly from blood culture bottles. PMID- 22431541 TI - Usefulness of flow cytometric immunophenotyping for bone marrow staging in patients with mantle cell lymphoma after therapy. AB - We evaluated the role of flow cytometric immunophenotyping (FCI) in the assessment of bone marrow (BM) specimens in 104 patients with mantle cell lymphoma (MCL) following treatment with aggressive combination chemotherapy. Of the patients, 77 had no morphologic or FCI evidence of MCL, 13 had morphologic and FCI evidence of MCL, and 14 patients were morphologically negative but FCI showed CD5+ clonal B-cells (M-/FCI+). Retrospective cyclin D1 immunostaining was positive in 3 of 12 M-/FCI+ cases. Clinical staging and follow-up showed that 4 of 12 patients had concurrent extramedullary involvement by MCL, 5 patients subsequently became M+ for MCL in BM (within 2-24 months), and 3 patients had no recurrent MCL on follow-up. We conclude that FCI is more sensitive than morphologic examination of BM at the time of restaging in patients with MCL and that positivity by only FCI in BM often correlates with concurrent disease or subsequent relapse. PMID- 22431542 TI - Monoallelic and biallelic deletions of 13q14.3 in chronic lymphocytic leukemia: FISH vs miRNA RT-qPCR detection. AB - Deletion of 13q14.3 (del(13q)) is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL) and implies a favorable prognosis. We explored the feasibility of detecting del(13q) by real-time quantitative polymerase chain reaction (PCR) for miR-15a and miR-16-1, whose loci are located in the deleted region. We analyzed 23 cases of B-CLL with monoallelic (10 cases) or biallelic del(13q) (5 cases) and used trisomy 12-positive CLL samples (n = 8) as control samples. As expected, miR-15a was expressed at significantly lower levels in monoallelic del(13qx1) samples compared with trisomy 12 control samples (P = .001). Biallelic del(13q) (del(13qx2)) samples showed further reduction of miR 15a levels compared with monoallelic del(13q) (del(13qx1)) (P = .009). In contrast, miR-16-1 expression levels were generally much lower and variable, with the highest levels detected in del(13qx1). Analyzed retrospectively, miR-15a levels differ among the del(13q) groups. However, only del(13qx2) miR-15a levels are reduced enough to determine the allelic status of an individual sample prospectively by real-time quantitative PCR. PMID- 22431543 TI - Composite chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma are biclonal lymphomas: a report of two cases. AB - Composite lymphomas (CLs) consisting of 2 indolent B-cell lymphomas are rare. We present 2 CL cases composed of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), each with unique clinicopathologic features. In the first case, the FL was negative for IGH-BCL2 and harbored a novel IGH-associated translocation; in the second case, the CL manifested in the skin. The individual components in both CLs were derived from different B-cell clones. This is the first complete characterization, including molecular analysis, of CLs composed of leukemic CLL and FL and the first report of a cutaneous CL derived from 2 low grade B cell lymphomas. Our results provide additional supporting evidence that CLs of indolent B-cell lymphomas are biclonal and suggest that they are pathogenetically different from CLs composed of a low-grade B-cell lymphoma and an aggressive B-cell lymphoma or Hodgkin lymphoma, which are usually clonally related. PMID- 22431544 TI - Expression of hemoglobin variant migration by capillary electrophoresis relative to hemoglobin A2 improves precision. AB - We report the precision of the mean migration position of hemoglobin (Hb)S, HbC, HbG (Philadelphia), and HbD (Los Angeles) in 193 samples of whole blood assayed by capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC). By expressing the migration of Hb variants by CE relative to that of HbA(2) in the same sample, there was a significant improvement in the coefficient of variation for each variant studied. The potential usefulness of expressing Hb variants relative to that of HbA(2) was evaluated by comparing the separation of 2 closely migrating Hbs. When expressed by their initial migrations on CE, 25 of the 43 cases of HbG and HbD overlapped. However, when the migrations of these variants were expressed relative to the HbA(2) in the same sample, the 24 cases of HbG separated completely from the 19 cases of HbD. These findings suggest that expressing Hb variants relative to an internal standard, such as HbA(2), may be of value for establishing a library of variant Hbs evaluated by CE. PMID- 22431545 TI - Differentiating between Burkitt lymphoma and CD10+ diffuse large B-cell lymphoma: the role of commonly used flow cytometry cell markers and the application of a multiparameter scoring system. AB - The goal of this study was to evaluate routine flow cytometric (FC) immunophenotypic markers in differentiating between Burkitt lymphoma (BL) and CD10+ diffuse large B-cell lymphoma (DLBCL). We performed retrospective analysis of FC data from 55 patients. We evaluated 9 FC parameters: forward and side scatter (FSC and SSC); mean fluorescent intensity (MFI) for CD20, CD10, CD38, CD79b, CD43, and CD71; and the percentage of neoplastic cells positive for CD71 (%CD71). The FSC; MFIs of CD10, CD43, CD79b, and CD71; and %CD71 cells were significantly different between BL and CD10+ DLBCL (P < .05; Student t test). A 5 point scoring system (FSC, %CD71, and MFIs of CD43, CD79b, and CD71) was devised, and 6 (60%) of 10 BLs scored 3 or greater and 1 (10%) of 10 CD10+ DLBCLs scored 3 (P = .04; chi(2)). Our findings indicate that routine FC parameters can aid in differentiating BL from CD10+ DLBCL. PMID- 22431548 TI - Teaching laboratory management. PMID- 22431549 TI - Association of JAK2 mutation status and cytogenetic abnormalities at diagnosis in myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms. PMID- 22431550 TI - Lighting System for Visual Perception Enhancement in Volume Rendering. AB - We introduce a lighting system that enhances the visual cues in a rendered image for the perception of 3D volumetric objects. We divide the lighting effects into global and local effects, and deploy three types of directional lights: the key light and accessory lights (fill and detail lights). The key light provides both lighting effects and carries the visual cues for the perception of local and global shapes and depth. The cues for local shapes are conveyed by gradient; those for global shapes are carried by shadows; and those for depth are provided by shadows and translucent objects. Fill lights produce global effects to increase the perceptibility. Detail lights generate local effects to improve the cues for local shapes. Our method quantifies the perception and uses an exhaustive search to set the lights. It configures accessory lights with the consideration of preserving the global impression conveyed by the key light. It ensures the feeling of smooth light movements in animations. With simplification, it achieves interactive frame rates and produces results that are visually indistinguishable from results using the nonsimplified algorithm. The major contributions of this paper are our lighting system, perception measurement and lighting design algorithm with our indistinguishable simplification. PMID- 22431551 TI - Identifying gene pathways associated with cancer characteristics via sparse statistical methods. AB - We propose a statistical method for uncovering gene pathways that characterize cancer heterogeneity. To incorporate knowledge of the pathways into the model, we define a set of activities of pathways from microarray gene expression data based on the Sparse Probabilistic Principal Component Analysis (SPPCA). A pathway activity logistic regression model is then formulated for cancer phenotype. To select pathway activities related to binary cancer phenotypes, we use the elastic net for the parameter estimation and derive a model selection criterion for selecting tuning parameters included in the model estimation. Our proposed method can also reverse-engineer gene networks based on the identified multiple pathways that enables us to discover novel gene-gene associations relating with the cancer phenotypes. We illustrate the whole process of the proposed method through the analysis of breast cancer gene expression data. PMID- 22431552 TI - Efficient genotype elimination via adaptive allele consolidation. AB - We propose the technique of Adaptive Allele Consolidation, that greatly improves the performance of the Lange-Goradia algorithm for genotype elimination in pedigrees, while still producing equivalent output. Genotype elimination consists in removing from a pedigree those genotypes that are impossible according to the Mendelian law of inheritance. This is used to find errors in genetic data and is useful as a preprocessing step in other analyses (such as linkage analysis or haplotype imputation). The problem of genotype elimination is intrinsically combinatorial, and Allele Consolidation is an existing technique where several alleles are replaced by a single "lumped" allele in order to reduce the number of combinations of genotypes that have to be considered, possibly at the expense of precision. In existing Allele Consolidation techniques, alleles are lumped once and for all before performing genotype elimination. The idea of Adaptive Allele Consolidation is to dynamically change the set of alleles that are lumped together during the execution of the Lange-Goradia algorithm, so that both high performance and precision are achieved. We have implemented the technique in a tool called Celer and evaluated it on a large set of scenarios, with good results. PMID- 22431553 TI - Fast local search for unrooted Robinson-Foulds supertrees. AB - A Robinson-Foulds (RF) supertree for a collection of input trees is a tree containing all the species in the input trees that is at minimum total RF distance to the input trees. Thus, an RF supertree is consistent with the maximum number of splits in the input trees. Constructing RF supertrees for rooted and unrooted data is NP-hard. Nevertheless, effective local search heuristics have been developed for the restricted case where the input trees and the supertree are rooted. We describe new heuristics, based on the Edge Contract and Refine (ECR) operation, that remove this restriction, thereby expanding the utility of RF supertrees. Our experimental results on simulated and empirical data sets show that our unrooted local search algorithms yield better supertrees than those obtained from MRP and rooted RF heuristics in terms of total RF distance to the input trees and, for simulated data, in terms of RF distance to the true tree. PMID- 22431554 TI - Prevalence of sarcopenia and sarcopenic obesity in the Korean population based on the Fourth Korean National Health and Nutritional Examination Surveys. AB - BACKGROUND: Sarcopenia is an important factor of functional impairment related to aging. This study is conducted to investigate the prevalence of sarcopenia and sarcopenic obesity in Korean population. METHODS: Representative Korean men (4,486) and women (5,999) aged 20 years or older were analyzed from the Fourth Korean National Health and Nutritional Examination Surveys. Sarcopenia was classified into Class I defined relative skeletal muscle mass loss within 1-2 SD of the gender-specific mean for healthy young adults and Class II below 2 SD. Relative skeletal muscle mass was represented by the appendicular skeletal muscle mass adjusted by height and body weight. Sarcopenic obesity was considered present in Class II sarcopenic participants whose waist circumference was more than or equal to 90 cm for men and more than or equal to 85 cm for women, respectively. RESULTS: The prevalence of Class II sarcopenia in the Korean elderly population was 12.4% for men and 0.1% for women by height-adjusted definition and 9.7% for men and 11.8% for women by weight-adjusted definition. The prevalence of sarcopenic obesity was 7.6% for men and 9.1% for women by weight-adjusted definition but nearly zero for men and women by height-adjusted definition. The prevalence of sarcopenia increased with age for men but for women only when applied with weight-adjusted definition. CONCLUSIONS: The prevalence of sarcopenia and sarcopenic obesity differs by gender and definition criteria. The height-adjusted definition may tend to underestimate the prevalence of sarcopenia and sarcopenic obesity, especially in women. PMID- 22431555 TI - Presence of key findings in the medical record prior to a documented high-risk diagnosis. AB - BACKGROUND: Failure or delay in diagnosis is a common preventable source of error. The authors sought to determine the frequency with which high-information clinical findings (HIFs) suggestive of a high-risk diagnosis (HRD) appear in the medical record before HRD documentation. METHODS: A knowledge base from a diagnostic decision support system was used to identify HIFs for selected HRDs: lumbar disc disease, myocardial infarction, appendicitis, and colon, breast, lung, ovarian and bladder carcinomas. Two physicians reviewed at least 20 patient records retrieved from a research patient data registry for each of these eight HRDs and for age- and gender-compatible controls. Records were searched for HIFs in visit notes that were created before the HRD was established in the electronic record and in general medical visit notes for controls. RESULTS: 25% of records reviewed (61/243) contained HIFs in notes before the HRD was established. The mean duration between HIFs first occurring in the record and time of diagnosis ranged from 19 days for breast cancer to 2 years for bladder cancer. In three of the eight HRDs, HIFs were much less likely in control patients without the HRD. CONCLUSIONS: In many records of patients with an HRD, HIFs were present before the HRD was established. Reasons for delay include non-compliance with recommended follow-up, unusual presentation of a disease, and system errors (eg, lack of laboratory follow-up). The presence of HIFs in clinical records suggests a potential role for the integration of diagnostic decision support into the clinical workflow to provide reminder alerts to improve the diagnostic focus. PMID- 22431556 TI - BRCA1/p220 loss triggers BRCA1-IRIS overexpression via mRNA stabilization in breast cancer cells. AB - BRCA1/p220-assocaited and triple negative/basal-like (TN/BL) tumors are aggressive and incurable breast cancer diseases that share among other features the no/low BRCA1/p220 expression. Here we show that BRCA1/p220 silencing in normal human mammary epithelial (HME) cells reduces expression of two RNA destabilizing proteins, namely AUF1 and pCBP2, both proteins bind and destabilize BRCA1-IRIS mRNA. BRCA1-IRIS overexpression in HME cells triggers expression of several TN/BL markers, e.g., cytokeratins 5 and 17, p-cadherin, EGFR and cyclin E as well as expression and activation of the pro-survival proteins; AKT and survivin. BRCA1-IRIS silencing in the TN/BL cell line, SUM149 or restoration of BRCA1/p220 expression in the mutant cell line, HCC1937 reduced expression of TN/BL markers, AKT and survivin and induced cell death. Collectively, we propose that BRCA1/p220 loss of expression or function triggers BRCA1-IRIS overexpression through a post-transcriptional mechanism, which in turn promotes formation of aggressive and invasive breast tumors by inducing expression of TN/BL and survival proteins. PMID- 22431557 TI - The rights and wrongs of intentional exposure research: contextualising the Guatemala STD inoculation study. AB - In its recent review of the US Public Health Service Sexually Transmitted Disease Inoculation Study, conducted in Guatemala from 1946 to 1948, the Presidential Commission for the Study of Bioethical Issues identified a number of egregious ethical violations, but failed to adequately address issues associated with the intentional exposure research design in particular. As a result, a common public misconception that the study was wrong because researchers purposefully infected their subjects has been left standing. In fact, human subjects have been exposed to disease pathogens for experimental purposes for centuries, and this study design remains an important scientific tool today. It shares key features with other types of widely accepted research on human subjects and can be conducted ethically, provided certain safeguards are implemented. That these safeguards were not implemented in Guatemala is what made that study wrong, rather than the fact of intentional exposure itself. To preserve public trust in the clinical research enterprise, this conclusion ought to be stated explicitly and emphasised. PMID- 22431558 TI - Widening the debate about conflict of interest: addressing relationships between journalists and the pharmaceutical industry. AB - The phone-hacking scandal that led to the closure of the News of the World newspaper in Britain has prompted international debate about media practices and regulation. It is timely to broaden the discussion about journalistic ethics and conduct to include consideration of the impact of media practices upon the population's health. Many commercial organisations cultivate relationships with journalists and news organisations with the aim of influencing the content of health-related news and information communicated through the media. Given the significant influence of the media on the health of individuals and populations, we should be alert to the potential impact of industry-journalist relationships on health care, health policy and public health. The approach taken by the medical profession to its interactions with the pharmaceutical industry provides a useful model for management of industry influence. PMID- 22431559 TI - Constraining the use of antibiotics: applying Scanlon's contractualism. AB - Decisions to use antibiotics require that patient interests are balanced against the public good, that is, control of antibiotic resistance. Patients carry the risks of suboptimal antibiotic treatment and many physicians are reluctant to impose even small avoidable risks on patients. At the same time, antibiotics are overused and antibiotic-resistant microbes are contributing an increasing burden of adverse patient outcomes. It is the criteria that we can use to reject the use of antibiotics that is the focus of this paper. Scanlon's contractualism explains why antibiotics should not be used to gain small benefits, even when the direct costs of antibiotics are low. We know that some individuals now (and probably more in the future will) carry a burden of irretrievable harm as a consequence of treatment- (antibiotic-) resistant infection. If we accept that the dominant justification for use of antibiotics is to prevent irretrievable harm to an individual or contact, then the use of antibiotics for self-limiting conditions, or for the treatment of individuals with conditions for which antibiotics do not substantially impact on outcomes (eg, in the latter stages of terminal illness), or for access based on preference or willingness to pay (internet or over-the counter access), or the use of antibiotics as animal growth promoters can be rejected. Scanlon's approach also suggests that, with few new antibiotics in the pipeline and an increasing burden of disease attributable to resistant microbes, control of the spread of antibiotic-resistant microbes should be given increasing priority. PMID- 22431560 TI - The burden of normality: from 'chronically ill' to 'symptom free'. New ethical challenges for deep brain stimulation postoperative treatment. AB - Although an invasive medical intervention, Deep Brain Stimulation (DBS) has been regarded as an efficient and safe treatment of Parkinson's disease for the last 20 years. In terms of clinical ethics, it is worth asking whether the use of DBS may have unanticipated negative effects similar to those associated with other types of psychosurgery. Clinical studies of epileptic patients who have undergone an anterior temporal lobectomy have identified a range of side effects and complications in a number of domains: psychological, behavioural, affective and social. In many cases, patients express difficulty adjusting from being chronically ill to their new status as 'treated' or 'seizure free'. This postoperative response adjustment has been described in the literature on epilepsy as the 'Burden of Normality' (BoN) syndrome. Most of the discussion about DBS postoperative changes to self is focused on abnormal side effects caused by the intervention (ie, hypersexuality, hypomania, etc). By contrast, relatively little attention is paid to the idea that successfully 'treated' individuals might experience difficulties in adjusting to becoming 'normal'. The purpose of this paper is (1) to articulate the postoperative DBS psychosocial adjustment process in terms of the BoN syndrome, (2) to address whether the BoN syndrome illustrates that DBS treatment poses a threat to the patient's identity, and (3) to examine whether the current framework for rehabilitation after DBS procedures should be updated and take into account the BoN syndrome as a postoperative self-change response. PMID- 22431561 TI - Derivation and validation of the Denver Human Immunodeficiency Virus (HIV) risk score for targeted HIV screening. AB - Targeted screening remains an important approach to human immunodeficiency virus (HIV) testing. The authors aimed to derive and validate an instrument to accurately identify patients at risk for HIV infection, using patient data from a metropolitan sexually transmitted disease clinic in Denver, Colorado (1996-2008). With multivariable logistic regression, they developed a risk score from 48 candidate variables using newly identified HIV infection as the outcome. Validation was performed using an independent population from an urban emergency department in Cincinnati, Ohio. The derivation sample included 92,635 patients; 504 (0.54%) were diagnosed with HIV infection. The validation sample included 22,983 patients; 168 (0.73%) were diagnosed with HIV infection. The final score included age, gender, race/ethnicity, sex with a male, vaginal intercourse, receptive anal intercourse, injection drug use, and past HIV testing, and values ranged from -14 to +81. For persons with scores of <20, 20-29, 30-39, 40-49, and >=50, HIV prevalences were 0.31% (95% confidence interval (CI): 0.20, 0.45) (n = 27/8,782), 0.41% (95% CI: 0.29, 0.57) (n = 36/8,677), 0.99% (95% CI: 0.63, 1.47) (n = 24/2,431), 1.59% (95% CI: 1.02, 2.36) (n = 24/1,505), and 3.59% (95% CI: 2.73, 4.63) (n = 57/1,588), respectively. The risk score accurately categorizes patients into groups with increasing probabilities of HIV infection. PMID- 22431562 TI - Patterns of placental development evaluated by X chromosome inactivation profiling provide a basis to evaluate the origin of epigenetic variation. AB - BACKGROUND: Inactivation of the maternally or paternally derived X chromosome (XCI) initially occurs in a random manner in early development; however as tissues form, a 'patchiness' will occur in terms of which X is inactivated if cells positioned near each other are clonally descended from a common precursor. Determining the relationship between skewed XCI in different tissues and in different samples from the same tissue provides a molecular assessment of the developmental history of a particular tissue that can then be used to understand how genetic and epigenetic variation arises in development. METHODS: XCI skewing was evaluated in and compared between amnion, chorion, trophoblast and mesenchyme using multiple sampling sites from 14 term placentae. XCI was also evaluated in chorionic villus samples obtained at multiple sites and depths from four additional term placentae. The pattern of variation was then compared with methylation variation associated with the H19/IGF2 imprinting control region (ICR); promoter regions of KISS1, PTPN6, CASP8 and APC; and LINE-1 elements. RESULTS: Mean placental level of skewing for amnion and chorion are correlated, consistent with a common developmental origin of at least a component of these membranes from inner cell mass derivatives subsequent to XCI, while trophoblast appears to be derived independently, consistent with its origin from the trophectoderm. Villus samples taken from different depths spanning the fetal to maternal side of the placenta were highly clonally related. Comparing patterns of clonal growth identified through XCI to the distribution of epigenetic variation in other genomic regions suggests that some variation arises early in development (e.g. LINE-1 methylation), whereas other variation arises predominantly after villus tree formation (e.g. methylation at H19/IGF2 ICR). CONCLUSIONS: The patterns of XCI skewing are consistent with a model whereby each biopsied site of chorionic villi represents one or a few individual villus trees, each of which is clonally derived from only one or a few precursor cells. Sampling of placentae to evaluate changes associated with clinical pathology should be done with consideration of the tree-to-tree differences. A limitation of this study is the small number of placentas used and therefore placental-specific differences in variation could not be assessed. PMID- 22431563 TI - LOV to BLUF: flavoprotein contributions to the optogenetic toolkit. AB - Optogenetics is an emerging field that combines optical and genetic approaches to non-invasively interfere with cellular events with exquisite spatiotemporal control. Although it arose originally from neuroscience, optogenetics is widely applicable to the study of many different biological systems and the range of applications arising from this technology continues to increase. Moreover, the repertoire of light-sensitive proteins used for devising new optogenetic tools is rapidly expanding. Light, Oxygen, or Voltage sensing (LOV) and Blue-Light Utilizing flavin adenine dinucleotide (FAD) (BLUF) domains represent new contributors to the optogenetic toolkit. These small (100-140-amino acids) flavoprotein modules are derived from plant and bacterial photoreceptors that respond to UV-A/blue light. In recent years, considerable progress has been made in uncovering the photoactivation mechanisms of both LOV and BLUF domains. This knowledge has been applied in the design of synthetic photoswitches and fluorescent reporters with applications in cell biology and biotechnology. In this review, we summarize the photochemical properties of LOV and BLUF photosensors and highlight some of the recent advances in how these flavoproteins are being employed to artificially regulate and image a variety of biological processes. PMID- 22431564 TI - Occupational exposure to chemical substances and time to pregnancy: a systematic review. AB - BACKGROUND: Fertility problems are an important health issue, as 10-15% of couples have difficulties conceiving. Reproductive function is thought to be compromised by lifestyle behaviours, but environmental contaminants and work related factors are also thought to play a role. The objective of this review was to systematically summarize the available evidence concerning the influence of occupational exposure to chemicals on time to pregnancy (TTP). METHODS: A structured search on occupational exposure to chemicals and TTP was carried out in PubMed and Embase. Studies were included if TTP was used as outcome measure and exposure to chemicals at the job level was described. In total, 49 studies were included in this review. RESULTS: Studies varied widely in characterization of exposure, hampering a meta-analytic approach across all studies. For lead, strong indications for adverse effects on TTP were present, supporting the mandatory provisions for pregnant women being exposed to lead in many countries. These indications were also found for pesticide exposure, and one could argue that couples working in agriculture or horticultural trades must be informed about the risks of pesticide exposure. Epidemiologic evidence on other chemicals, such as organic solvents, and other metals remains equivocal, hampering clear counselling of couples who are trying to become pregnant. CONCLUSIONS: Despite some uncertainties in the evidence base, it may still be prudent to advise against lead and pesticide exposure at the workplace for couples trying to conceive. This review also identifies several priorities for future studies in the field of occupational epidemiology. PMID- 22431565 TI - Treatment of thyroid disorders before conception and in early pregnancy: a systematic review. AB - BACKGROUND: Thyroid disorders are associated with pregnancy complications. Universal screening is currently not recommended because of a lack of evidence on the effectiveness of treatment. Women with hyperthyroidism and hypothyroidism evidently require treatment but this is less clear for women with subclinical hypothyroidism and thyroid autoimmunity. Therefore, we conducted a systematic review to provide a comprehensive overview on the available treatment interventions. METHODS: Relevant studies were identified by searching Medline, EMBASE and Cochrane Controlled Trials Register, published until December 2011. RESULTS: From a total of 7334 primary selected titles, 22 articles were included for the systematic review and 11 were appropriate for meta-analyses. Eight studies reported on hyperthyroidism. Propylthiouracil (PTU) and methimazole reduce the risk for preterm delivery [risk ratio (RR): 0.23, confidence interval (CI): 0.1-0.52], pre-eclampsia (RR: 0.23, CI: 0.06-0.89) and low birthweight (RR: 0.38, CI: 0.22-0.66). The nine studies that reported on clinical hypothyroidism showed that levothyroxine is effective in reducing the risk for miscarriage (RR: 0.19, CI: 0.08-0.39) and preterm delivery (RR: 0.41, CI: 0.24-0.68). For treatment of subclinical hypothyroidism, current evidence is insufficient. The five studies available on thyroid autoimmunity showed a not significant reduction in miscarriage (RR: 0.58, CI: 0.32-1.06), but significant reduction in preterm birth by treatment with levothyoxine (RR: 0.31, CI: 0.11-0.90). CONCLUSION: For hyperthyroidism, methimazole and PTU are effective in preventing pregnancy complications. For clinical hypothyroidism, treatment with levothyroxine is recommended. For subclinical hypothyroidism and thyroid autoimmunity, evidence is insufficient to recommend treatment with levothyroxine. The overall lack of evidence precludes a recommendation for universal screening and is only justified in a research setting. PMID- 22431566 TI - Aromatase inhibitors for PCOS: a systematic review and meta-analysis. AB - BACKGROUND: The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS. METHODS: Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs). RESULTS: The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naive women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I(2) = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates. CONCLUSIONS: In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed. PMID- 22431567 TI - Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. AB - Ligand-induced ectodomain shedding of glycoprotein VI (GPVI) is a metalloproteinase-dependent event. We examined whether shear force, in the absence of GPVI ligand, was sufficient to induce shedding of GPVI. Human-citrated platelet-rich plasma or washed platelets were subjected to increasing shear rates in a cone-plate viscometer, and levels of intact and cleaved GPVI were examined by Western blot and ELISA. Pathophysiologic shear rates (3000-10 000 seconds(-1)) induced platelet aggregation and metalloproteinase-dependent appearance of soluble GPVI ectodomain, and GPVI platelet remnant. Shedding of GPVI continued after transient exposure to shear. Blockade of alpha(IIb)beta(3), GPIbalpha, or intracellular signaling inhibited shear-induced platelet aggregation but minimally affected shear-induced shedding of GPVI. Shear-induced GPVI shedding also occurred in platelet-rich plasma or washed platelets isolated from a von Willebrand disease type 3 patient with no detectable VWF, implying that shear induced activation of platelet metalloproteinases can occur in the absence of GPVI and GPIbalpha ligands. Significantly elevated levels of sGPVI were observed in 10 patients with stable angina pectoris, with well-defined single vessel coronary artery disease and mean intracoronary shear estimates at 2935 seconds( 1) (peak shear, 19 224 seconds(-1)). Loss of GPVI in platelets exposed to shear has potential implications for the stability of a forming thrombus at arterial shear rates. PMID- 22431568 TI - Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. AB - The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11. In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11(-) MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P = .004). SOX11(-) cases had a shorter overall survival, compared with SOX11(+) cases, 1.5 and 3.2 years, respectively (P = .014). In multivariate analysis of overall survival, age > 65 (P = .001), Eastern Cooperative Oncology Group score >= 2 (P = .022), elevated LDH level (P = .001), and p53 expression (P = .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11(+) and that SOX11 cannot be used for predicting an indolent disease course. PMID- 22431569 TI - Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome. AB - The immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) leads to life threatening hematopoietic cell dysfunction. We used WAS protein (WASp)-deficient mice to analyze the in vivo efficacy of lentiviral (LV) vectors using either a viral-derived promoter, MND, or the human proximal WAS promoter (WS1.6) for human WASp expression. Transplantation of stem cells transduced with MND-huWASp LV resulted in sustained, endogenous levels of WASp in all hematopoietic lineages, progressive selection for WASp+ T, natural killer T and B cells, rescue of T-cell proliferation and cytokine production, and substantial restoration of marginal zone (MZ) B cells. In contrast, WS1.6-huWASp LV recipients exhibited subendogenous WASp expression in all cell types with only partial selection of WASp+ T cells and limited correction in MZ B-cell numbers. In parallel, WS1.6 huWASp LV recipients exhibited an altered B-cell compartment, including higher numbers of lambda-light-chain+ naive B cells, development of self-reactive CD11c+FAS+ B cells, and evidence for spontaneous germinal center (GC) responses. These observations correlated with B-cell hyperactivity and increased titers of immunoglobulin (Ig)G2c autoantibodies, suggesting that partial gene correction may predispose toward autoimmunity. Our findings identify the advantages and disadvantages associated with each vector and suggest further clinical development of the MND-huWASp LV for a future clinical trial for WAS. PMID- 22431570 TI - Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. AB - Whereas the chimeric type I anti-CD20 Ab rituximab has improved outcomes for patients with B-cell malignancies significantly, many patients with non-Hodgkin lymphoma (NHL) remain incurable. Obinutuzumab (GA101) is a glycoengineered, humanized anti-CD20 type II Ab that has demonstrated superior activity against type I Abs in vitro and in preclinical studies. In the present study, we evaluated the safety, efficacy, and pharmacokinetics of GA101 in a phase 1 study of 21 patients with heavily pretreated, relapsed, or refractory CD20(+) indolent NHL. Patients received GA101 in a dose-escalating fashion (3 per cohort, range 50/100-1200/2000 mg) for 8 * 21-day cycles. The majority of adverse events (AEs) were grades 1 and 2 (114 of 132 total AEs). Seven patients reported a total of 18 grade 3 or 4 AEs. Infusion-related reactions were the most common AE, with most occurring during the first infusion and resolving with appropriate management. Three patients experienced grade 3 or 4 drug-related infusion-related reactions. The best overall response was 43%, with 5 complete responses and 4 partial responses. Data from this study suggest that GA101 was well tolerated and demonstrated encouraging activity in patients with previously treated NHL up to doses of 2000 mg. This trial is registered at www.clinicaltrials.gov as NCT00517530. PMID- 22431571 TI - Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. AB - In inflammation, neutrophils and other leukocytes roll along the microvascular endothelium before arresting and transmigrating into inflamed tissues. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen-1 (LFA-1). Mutations of the FERMT3 gene encoding kindlin-3 underlie the human immune deficiency known as leukocyte adhesion deficiency-III. Both kindlin 3 and talin-1, another FERM domain-containing cytoskeletal protein, are required for integrin activation, but their individual roles in the induction of specific integrin conformers are unclear. Here, we induce differential LFA-1 activation in neutrophils through engagement of the selectin ligand P-selectin glycoprotein ligand-1 or the chemokine receptor CXCR2. We find that talin-1 is required for inducing LFA-1 extension, which corresponds to intermediate affinity and induces neutrophil slow rolling, whereas both talin-1 and kindlin-3 are required for induction of the high-affinity conformation of LFA-1 with an open headpiece, which results in neutrophil arrest. In vivo, both slow rolling and arrest are defective in talin-1-deficient neutrophils, whereas only arrest is defective in kindlin-3-deficient neutrophils. We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation. PMID- 22431572 TI - Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage. AB - Type 2A VWD is characterized by the absence of large VWF multimers and decreased platelet-binding function. Historically, type 2A variants are subdivided into group 1, which have impaired assembly and secretion of VWF multimers, or group 2, which have normal secretion of VWF multimers and increased ADAMTS13 proteolysis. Type 2A VWD patients recruited through the T. S. Zimmerman Program for the Molecular and Clinical Biology of VWD study were characterized phenotypically and potential mutations identified in the VWF D2, D3, A1, and A2 domains. We examined type 2A variants and their interaction with WT-VWF through expression studies. We assessed secretion/intracellular retention, multimerization, regulated storage, and ADAMTS13 proteolysis. Whereas some variants fit into the traditional group 1 or 2 categories, others did not fall clearly into either category. We determined that loss of Weibel-Palade body formation is associated with markedly reduced secretion. Mutations involving cysteines were likely to cause abnormalities in multimer structure but not necessarily secretion. When coexpressed with wild-type VWF, type 2A variants negatively affected one or more mechanisms important for normal VWF processing. Type 2A VWD appears to result from a complex intersection of mechanisms that include: (1) intracellular retention or degradation of VWF, (2) defective multimerization, (3) loss of regulated storage, and (4) increased proteolysis by ADAMTS13. PMID- 22431573 TI - Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence. AB - The extra-embryonic yolk sac (YS) is the first hematopoietic site in the mouse embryo and is thought to generate only primitive erythroid and myeloerythroid progenitor cells before definitive HSC emergence within the embryo on E10.5. Here, we have shown the existence of T cell-restricted progenitors in the E9.5 YS that directly engraft in recipient immunodeficient mice. T-cell progenitors were also produced in vitro from both YS and para-aortic splanchnopleura hemogenic endothelial cells, and these T-cell progenitors repopulated the thymus and differentiated into mature T-cell subsets in vivo on transplantation. Our data confirm that the YS produces T-lineage-restricted progenitors that are available to colonize the thymus and provide new insight into the YS as a definitive hematopoietic site in the mouse embryo. PMID- 22431574 TI - EUTOS score is not predictive for survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience. AB - To validate the recently reported European Treatment and Outcomes Study (EUTOS) score, we applied it to 465 patients with early chronic phase chronic myeloid leukemia treated with standard-dose imatinib (n=71), high-dose imatinib (n=208), or second-generation tyrosine kinase inhibitors (n=186), and assessed its ability to predict event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS). The median follow-up was 69 months. The overall complete cytogenetic response and major molecular response rates were 92% and 85%, respectively. The 3-year EFS, TFS, and OS rates were 86%, 95%, and 97%, respectively. Of the 465 patients, 427 (92%) were in low EUTOS score category. There was no difference in the major molecular response, TFS, EFS, and OS rates between patients with low and high EUTOS score, overall and within specific therapies. In conclusion, 8% of patients with chronic phase chronic myeloid leukemia treated at our institution are in the high EUTOS score; in this population, the EUTOS score was not predictive for outcome. PMID- 22431575 TI - BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management. AB - Rising BCR-ABL1 transcripts indicate potential loss of imatinib response in CML. We determined whether the BCR-ABL1 doubling time could distinguish nonadherence from resistance as the cause of lost response. Distinct groups were examined: (1) acquired clinical resistance because of blast crisis and/or BCR-ABL1 mutations; and (2) documented imatinib discontinuation/interruption. Short doubling times occurred with blast crisis (median, 9.0 days; range, 6.1-17.6 days; n = 12 patients), relapse after imatinib discontinuation in complete molecular response (median, 9.0 days; range, 6.9-26.5 days; n = 17), and imatinib interruption during an entire measurement interval (median, 9.4 days; range, 4.2-17.6 days; n = 12; P = .72). Whereas these doubling times were consistently short and indicated rapid leukemic expansion, fold rises were highly variable: 71-, 9.5-, and 10.5-fold, respectively. The fold rise depended on the measurement interval, whereas the doubling time was independent of the interval. Longer doubling times occurred for patients with mutations who maintained chronic phase (CP: median, 48 days; range, 17.3-143 days; n = 29; P < .0001). Predicted short and long doubling times were validated on an independent cohort monitored elsewhere. The doubling time revealed major differences in kinetics according to clinical context. Long doubling times observed with mutations in CP allow time for intervention. A short doubling time for a patient in CP should raise the suspicion of nonadherence. PMID- 22431576 TI - Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. AB - Diabetes mellitus has been associated with platelet hyperreactivity, which plays a central role in the hyperglycemia-related prothrombotic phenotype. The mechanisms responsible for this phenomenon are not established. In the present study, we investigated the role of CD36, a class-B scavenger receptor, in this process. Using both in vitro and in vivo mouse models, we demonstrated direct and specific interactions of platelet CD36 with advanced glycation end products (AGEs) generated under hyperglycemic conditions. AGEs bound to platelet CD36 in a specific and dose-dependent manner, and binding was inhibited by the high affinity CD36 ligand NO(2)LDL. Cd36-null platelets did not bind AGE. Using diet- and drug-induced mouse models of diabetes, we have shown that cd36-null mice had a delayed time to the formation of occlusive thrombi compared with wild-type (WT) in a FeCl(3)-induced carotid artery injury model. Cd36-null mice had a similar level of hyperglycemia and a similar level of plasma AGEs compared with WT mice under this condition, but WT mice had more AGEs incorporated into thrombi. Mechanistic studies revealed that CD36-dependent JNK2 activation is involved in this prothrombotic pathway. Therefore, the results of the present study couple vascular complications in diabetes mellitus with AGE-CD36-mediated platelet signaling and hyperreactivity. PMID- 22431577 TI - Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. AB - Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P=.05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P=.03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P<.05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT. PMID- 22431578 TI - Clinical significance of incident hypokalemia and hyperkalemia in treated hypertensive patients in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. AB - Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a large practice-based clinical trial, made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone (C) versus amlodipine or lisinopril as a first-step drug were stratified by year-1 potassium. Postyear-1 outcomes among hypokalemics (potassium, <3.5 mmol/L) and hyperkalemics (potassium, >5.4 mmol/L) were compared with normokalemics (potassium, 3.5-5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in C (12.9%) differed from amlodipine (2.1%; P<0.001) and lisinopril (1.0%; P<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than in C (1.2%; P<0.01) or amlodipine (1.9%; P<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than in normokalemics (Cox hazard ratio, 1.21 [95% CI, 1.02-1.44]) with statistically significant (interaction, P<0.01) disparity in hazard ratios for the 3 treatment arms (hazard ratios, C=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio, 1.58 [95% CI, 1.15-2.18]) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of C. Thus, for most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5-25.0 mg of C). PMID- 22431579 TI - Endothelin 1 activation of endothelin A receptor/NADPH oxidase pathway and diminished antioxidants critically contribute to endothelial progenitor cell reduction and dysfunction in salt-sensitive hypertension. AB - Circulating endothelial progenitor cells (EPCs) are reduced in hypertension, which inversely correlates with its mortality. Deoxycorticosterone acetate (DOCA) salt hypertension features elevated endothelin (ET) 1 and oxidative stress. We tested the hypothesis that ET-1 induces EPC dysfunction by elevating oxidative stress through the ET(A)/NADPH oxidase pathway in salt-sensitive hypertension. Both ET(A) and ET(B) receptors were expressed in EPCs, but only ET(A) receptors were significantly increased in EPCs of DOCA-salt rats. EPC number and function were reduced in DOCA-salt rats compared with sham controls, and both were reversed by in vivo blockade of ET(A) receptors or NADPH oxidase. The enzymatic activities of NAPDH oxidase and its subunits gp91(phox), p22(phox), and Rac1 were augmented in EPCs of DOCA-salt rats, with concomitantly decreased antioxidant enzymes manganese superoxide dismutase, copper-zinc superoxide dismutase, and glutathione peroxidase 1. Reactive oxygen species level was elevated in EPCs from DOCA-salt rats, accompanied by increased EPC telomerase inactivation, senescence, and apoptosis, which were rescued by ET(A) or NADPH oxidase blockade. Cell therapy of normal or treated DOCA EPCs, but not untreated DOCA EPCs, significantly increased capillary density and blood perfusion in ischemic hindlimbs of DOCA-salt rats. p53 and Bax/Bcl-2 ratios were increased in EPCs of DOCA-salt rats, which were reversed by ET(A) antagonist, NADPH oxidase inhibitor, or polyethylene glycol-superoxide dismutase. Finally, in ET(B)-deficient rats, plasma ET-1 was elevated, and EPC number and telomerase activity were diminished. These results demonstrate, for the first time, that both ET-1 activation of ET(A)/NADPH oxidase pathway and diminished antioxidants critically contribute to EPC reduction and dysfunction via increased oxidative stress in salt-sensitive hypertension. PMID- 22431580 TI - Orthostatic hypotension as a risk factor for incident heart failure: the atherosclerosis risk in communities study. AB - Heart failure causes significant morbidity and mortality. Distinguishing risk factors for incident heart failure can help identify at-risk individuals. Orthostatic hypotension may be a risk factor for incident heart failure; however, this association has not been fully explored, especially in nonwhite populations. The Atherosclerosis Risk in Communities Study included 12363 adults free of prevalent heart failure with baseline orthostatic measurements. Orthostatic hypotension was defined as a decrease of systolic blood pressure >=20 mmHg or diastolic blood pressure >=10 mmHg with position change from supine to standing. Incident heart failure was identified from hospitalization or death certificate disease codes. Over 17.5 years of follow-up, orthostatic hypotension was associated with incident heart failure with multivariable adjustment (hazard ratio: 1.54 [95% CI: 1.30-1.82]). This association was similar across race and sex groups. A stronger association was identified in younger individuals <=55 years old (hazard ratio: 1.90 [95% CI: 1.41-2.55]) than in older individuals >55 years old (hazard ratio: 1.37 [95% CI: 1.12-1.69]; interaction P=0.034). The association between orthostatic hypotension and incident heart failure persisted with exclusion of those with diabetes mellitus, coronary heart disease, and those on antihypertensives or psychiatric or Parkinson disease medications. However, exclusion of those with hypertension somewhat attenuated the association (hazard ratio: 1.34 [95% CI: 1.00-1.80]). We identified orthostatic hypotension as a predictor of incident heart failure among middle-aged individuals, particularly those 45 to 55 years of age. This association may be partially mediated through hypertension. Orthostatic measures may enhance risk stratification for future heart failure development. PMID- 22431581 TI - Altered vascular resistance properties and acute pressure-natriuresis mechanism in neonatal and weaning spontaneously hypertensive rats. AB - Although it has been extensively scrutinized, the factor(s) involved in the initiation and development of hypertension in spontaneously hypertensive rats (SHRs) remains unresolved. The objective of the present study was to determine whether, early in development, the causal mechanism(s) for the development of hypertension in young SHRs involves an integration of 2 processes, specifically an upregulation of structurally based vascular resistance properties and a rightward shift in the hemodynamic component of pressure-natriuresis. Mean arterial pressure was determined in conscious 4-week-old SHRs and Wistar-Kyoto rats via previously implanted aortic catheters. Structurally based hindlimb vascular resistance properties were assessed in 2- and 4-week-old SHRs and Wistar Kyoto rats. Renal interstitial hydrostatic pressure was measured after short-term manipulations of renal arterial pressure (RAP) in 4-week-old, anesthetized rats. Although mean arterial pressure in conscious SHRs (113+/-5 mm Hg) and Wistar Kyoto rats (110+/-6 mm Hg) was not significantly different at 4 weeks of age, SHRs at 2 and 4 weeks of age already had increases in structurally based vascular resistance properties of ~30% above age- and weight-matched Wistar-Kyoto rats. Furthermore, the acute RAP-renal interstitial hydrostatic pressure relationship was found to be linear in both strains, and the temporal coupling of the stimulus to response was rapid; that is, renal interstitial hydrostatic pressure responses to changes in RAP were <2 s. Although the slope of the RAP-renal interstitial hydrostatic pressure relationship was not significantly different between strains, the relationship was significantly shifted (18%) to higher RAPs in SHRs. These results suggest that alterations in both vascular structure and renal function in young SHRs occur before elevations in mean arterial pressure. PMID- 22431582 TI - Blood pressure response to controlled diesel exhaust exposure in human subjects. AB - Exposure to traffic-related air pollution is associated with risk of cardiovascular disease and mortality. We examined whether exposure to diesel exhaust increased blood pressure (BP) in human subjects. We analyzed data from 45 nonsmoking subjects, 18 to 49 years of age in double-blinded, crossover exposure studies, randomized to order. Each subject was exposed to diesel exhaust, maintained at 200 MUg/m(3) of fine particulate matter, and filtered air for 120 minutes on days separated by >=2 weeks. We measured BP pre-exposure, at 30-minute intervals during exposure, and 3, 5, 7, and 24 hours from exposure initiation and analyzed changes from pre-exposure values. Compared with filtered air, systolic BP increased at all of the points measured during and after diesel exhaust exposure; the mean effect peaked between 30 and 60 minutes after exposure initiation (3.8 mm Hg [95% CI: -0.4 to 8.0 mm Hg] and 5.1 mm Hg [95% CI: 0.7-9.5 mm Hg], respectively). Sex and metabolic syndrome did not modify this effect. Combining readings between 30 and 90 minutes, diesel exhaust exposure resulted in a 4.4-mm Hg increase in systolic BP, adjusted for participant characteristics and exposure perception (95% CI: 1.1-7.7 mm Hg; P=0.0009). There was no significant effect on heart rate or diastolic pressure. Diesel exhaust inhalation was associated with a rapid, measurable increase in systolic but not diastolic BP in young nonsmokers, independent of perception of exposure. This controlled trial in humans confirms findings from observational studies. The effect may be important on a population basis given the worldwide prevalence of exposure to traffic related air pollution. PMID- 22431583 TI - Relations between dairy food intake and arterial stiffness: pulse wave velocity and pulse pressure. AB - Modifiable risk factors, such as diet, are becomingly increasingly important in the management of cardiovascular disease, one of the greatest major causes of death and disease burden. Few studies have examined the role of diet as a possible means of reducing arterial stiffness, as measured by pulse wave velocity, an independent predictor of cardiovascular events and all-cause mortality. The aim of this study was to investigate whether dairy food intake is associated with measures of arterial stiffness, including carotid-femoral pulse wave velocity and pulse pressure. A cross-sectional analysis of a subset of the Maine-Syracuse Longitudinal Study sample was performed. A linear decrease in pulse wave velocity was observed across increasing intakes of dairy food consumption (ranging from never/rarely to daily dairy food intake). The negative linear relationship between pulse wave velocity and intake of dairy food was independent of demographic variables, other cardiovascular disease risk factors, and nutrition variables. The pattern of results was very similar for pulse pressure, whereas no association between dairy food intake and lipid levels was found. Further intervention studies are needed to ascertain whether dairy food intake may be an appropriate dietary intervention for the attenuation of age related arterial stiffening and reduction of cardiovascular disease risk. PMID- 22431584 TI - Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension. PMID- 22431585 TI - Does pseudoresistant hypertension attributed to white-coat effect define subjects with "treated normalized hypertension?". PMID- 22431586 TI - Antihypertensive therapy-associated hypokalemia and hyperkalemia: clinical implications. PMID- 22431587 TI - Whole-brain, time-locked activation with simple tasks revealed using massive averaging and model-free analysis. AB - The brain is the body's largest energy consumer, even in the absence of demanding tasks. Electrophysiologists report on-going neuronal firing during stimulation or task in regions beyond those of primary relationship to the perturbation. Although the biological origin of consciousness remains elusive, it is argued that it emerges from complex, continuous whole-brain neuronal collaboration. Despite converging evidence suggesting the whole brain is continuously working and adapting to anticipate and actuate in response to the environment, over the last 20 y, task-based functional MRI (fMRI) have emphasized a localizationist view of brain function, with fMRI showing only a handful of activated regions in response to task/stimulation. Here, we challenge that view with evidence that under optimal noise conditions, fMRI activations extend well beyond areas of primary relationship to the task; and blood-oxygen level-dependent signal changes correlated with task-timing appear in over 95% of the brain for a simple visual stimulation plus attention control task. Moreover, we show that response shape varies substantially across regions, and that whole-brain parcellations based on those differences produce distributed clusters that are anatomically and functionally meaningful, symmetrical across hemispheres, and reproducible across subjects. These findings highlight the exquisite detail lying in fMRI signals beyond what is normally examined, and emphasize both the pervasiveness of false negatives, and how the sparseness of fMRI maps is not a result of localized brain function, but a consequence of high noise and overly strict predictive response models. PMID- 22431588 TI - Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses. AB - Genome-wide studies have identified associations between polymorphisms in the IFN regulatory factor-5 (Irf5) gene and a variety of human autoimmune diseases. Its functional role in disease pathogenesis, however, remains unclear, as studies in Irf5(-/-) mice have reached disparate conclusions regarding the importance of this transcription factor in type I IFN production and antibody responses. We identified a spontaneous genomic duplication and frameshift mutation in the guanine exchange factor dedicator of cytokinesis 2 (Dock2) that has arisen in at least a subset of circulating Irf5(-/-) mice and inadvertently been bred to homozygosity. Retroviral expression of DOCK2, but not IRF-5, rescued defects in plasmacytoid dendritic cell and B-cell development, and Irf5(-/-) mice lacking the mutation in Dock2 exhibited normal plasmacytoid dendritic cell and B-cell development, largely intact type I IFN responses, and relatively normal antibody responses to viral infection. Thus, confirmation of the normal Dock2 genotype in circulating Irf5(-/-) mice is warranted, and our data may partly explain conflicting results in this field. PMID- 22431589 TI - MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme. AB - MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53 repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma. PMID- 22431590 TI - Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of beta chemokines and RNases. AB - T-cell-derived soluble factors that inhibit both X4 and R5 HIV are recognized as important in controlling HIV. Whereas three beta chemokines, regulated-on activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta, account for the suppression of R5 HIV by blockade of HIV entry, the major components responsible for the inhibition of X4 HIV strains have not been identified previously. We identify these factors primarily as a mixture of three beta chemokines [macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC), and I-309] and two RNases (angiogenin and RNase 4) of lesser potency and show that in a clade B population, some correlate with clinical status and are produced by both CD4(+) and CD8(+) T cells (chemokines, angiogenin) or only by CD8(+) T cells (RNase 4). The antiviral mechanisms of these HIV X4-suppressive factors differ from those of the previously described HIV R5-suppressive beta chemokines. PMID- 22431591 TI - Control of cell division in Streptococcus pneumoniae by the conserved Ser/Thr protein kinase StkP. AB - How the human pathogen Streptococcus pneumoniae coordinates cell-wall synthesis during growth and division to achieve its characteristic oval shape is poorly understood. The conserved eukaryotic-type Ser/Thr kinase of S. pneumoniae, StkP, previously was reported to phosphorylate the cell-division protein DivIVA. Consistent with a role in cell division, GFP-StkP and its cognate phosphatase, GFP-PhpP, both localize to the division site. StkP localization depends on its penicillin-binding protein and Ser/Thr-associated domains that likely sense uncross-linked peptidoglycan, because StkP and PhpP delocalize in the presence of antibiotics that target the latest stages of cell-wall biosynthesis and in cells that have stopped dividing. Time-lapse microscopy shows that StkP displays an intermediate timing of recruitment to midcell: StkP arrives shortly after FtsA but before DivIVA. Furthermore, StkP remains at midcell longer than FtsA, until division is complete. Cells mutated for stkP are perturbed in cell-wall synthesis and display elongated morphologies with multiple, often unconstricted, FtsA and DivIVA rings. The data show that StkP plays an important role in regulating cell wall synthesis and controls correct septum progression and closure. Overall, our results indicate that StkP signals information about the cell-wall status to key cell-division proteins and in this way acts as a regulator of cell division. PMID- 22431592 TI - Insights into the bovine rumen plasmidome. AB - Plasmids are self-replicating genetic elements capable of mobilization between different hosts. Plasmids often serve as mediators of lateral gene transfer, a process considered to be a strong and sculpting evolutionary force in microbial environments. Our aim was to characterize the overall plasmid population in the environment of the bovine rumen, which houses a complex and dense microbiota that holds enormous significance for humans. We developed a procedure for the isolation of total rumen plasmid DNA, termed rumen plasmidome, and subjected it to deep sequencing using the Illumina paired-end protocol and analysis using public and custom-made bioinformatics tools. A large number of plasmidome contigs aligned with plasmids of rumen bacteria isolated from different locations and at various time points, suggesting that not only the bacterial taxa, but also their plasmids, are defined by the ecological niche. The bacterial phylum distribution of the plasmidome was different from that of the rumen bacterial taxa. Nevertheless, both shared a dominance of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. Evidently, the rumen plasmidome is of a highly mosaic nature that can cross phyla. Interestingly, when we compared the functional profile of the rumen plasmidome to two plasmid databases and two recently published rumen metagenomes, it became apparent that the rumen plasmidome codes for functions, which are enriched in the rumen ecological niche and could confer advantages to their hosts, suggesting that the functional profiles of mobile genetic elements are associated with their environment, as has been previously implied for viruses. PMID- 22431593 TI - Residual soil phosphorus as the missing piece in the global phosphorus crisis puzzle. AB - Phosphorus (P) is a finite and dwindling resource. Debate focuses on current production and use of phosphate rock rather than on the amounts of P required in the future to feed the world. We applied a two-pool soil P model to reproduce historical continental crop P uptake as a function of P inputs from fertilizer and manure and to estimate P requirements for crop production in 2050. The key feature is the consideration of the role of residual soil P in crop production. Model simulations closely fit historical P uptake for all continents. Cumulative inputs of P fertilizer and manure for the period 1965-2007 in Europe (1,115 kg . ha(-1) of cropland) grossly exceeded the cumulative P uptake by crops (360 kg ha( 1)). Since the 1980s in much of Europe, P application rates have been reduced, and uptake continues to increase due to the supply of plant-available P from residual soil P pool. We estimate that between 2008 and 2050 a global cumulative P application of 700-790 kg . ha(-1) of cropland (in total 1,070-1,200 teragrams P) is required to achieve crop production according to the various Millennium Ecosystem Assessment scenarios [Alcamo J, Van Vuuren D, Cramer W (2006) Ecosystems and Human Well-Being: Scenarios, Vol 2, pp 279-354]. We estimate that average global P fertilizer use must change from the current 17.8 to 16.8-20.8 teragrams per year in 2050, which is up to 50% less than other estimates in the literature that ignore the role of residual soil P. PMID- 22431594 TI - Partially collapsed cristobalite structure in the non molecular phase V in CO2. AB - Non molecular CO(2) has been an important subject of study in high pressure physics and chemistry for the past decade opening up a unique area of carbon chemistry. The phase diagram of CO(2) includes several non molecular phases above 30 GPa. Among these, the first discovered was CO(2)-V which appeared silica-like. Theoretical studies suggested that the structure of CO(2)-V is related to that of beta-cristobalite with tetrahedral carbon coordination similar to silicon in SiO(2), but reported experimental structural studies have been controversial. We have investigated CO(2)-V obtained from molecular CO(2) at 40-50 GPa and T > 1500 K using synchrotron X-ray diffraction, optical spectroscopy, and computer simulations. The structure refined by the Rietveld method is a partially collapsed variant of SiO(2) beta-cristobalite, space group I42d, in which the CO(4) tetrahedra are tilted by 38.4 degrees about the c-axis. The existence of CO(4) tetrahedra (average O-C-O angle of 109.5 degrees ) is thus confirmed. The results add to the knowledge of carbon chemistry with mineral phases similar to SiO(2) and potential implications for Earth and planetary interiors. PMID- 22431595 TI - Morphology of nematic and smectic vesicles. AB - Recent experiments on vesicles formed from block copolymers with liquid crystalline side chains reveal a rich variety of vesicle morphologies. The additional internal order ("structure") developed by these self-assembled block copolymer vesicles can lead to significantly deformed vesicles as a result of the delicate interplay between two-dimensional ordering and vesicle shape. The inevitable topological defects in structured vesicles of spherical topology also play an essential role in controlling the final vesicle morphology. Here we develop a minimal theoretical model for the morphology of the membrane structure with internal nematic/smectic order. Using both analytic and numerical approaches, we show that the possible low free energy morphologies include nano size cylindrical micelles (nano-fibers), faceted tetrahedral vesicles, and ellipsoidal vesicles, as well as cylindrical vesicles. The tetrahedral vesicle is a particularly fascinating example of a faceted liquid-crystalline membrane. Faceted liquid vesicles may lead to the design of supramolecular structures with tetrahedral symmetry and new classes of nano-carriers. PMID- 22431596 TI - Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches. AB - The internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is essential for the initiation of viral protein synthesis. IRES domains adopt well-defined folds that are potential targets for antiviral translation inhibitors. We have determined the three-dimensional structure of the IRES subdomain IIa in complex with a benzimidazole translation inhibitor at 2.2 A resolution. Comparison to the structure of the unbound RNA in conjunction with studies of inhibitor binding to the target in solution demonstrate that the RNA undergoes a dramatic ligand-induced conformational adaptation to form a deep pocket that resembles the substrate binding sites in riboswitches. The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain IIa holds promise for the development of unique anti-HCV drugs with a high barrier to resistance. PMID- 22431597 TI - Redox-dependent complex formation by an ATP-dependent activator of the corrinoid/iron-sulfur protein. AB - Movement, cell division, protein biosynthesis, electron transfer against an electrochemical gradient, and many more processes depend on energy conversions coupled to the hydrolysis of ATP. The reduction of metal sites with low reduction potentials (E(0') < -500 mV) is possible by connecting an energetical uphill electron transfer with the hydrolysis of ATP. The corrinoid-iron/sulfur protein (CoFeSP) operates within the reductive acetyl-CoA pathway by transferring a methyl group from methyltetrahydrofolate bound to a methyltransferase to the [Ni Ni-Fe(4)S(4)] cluster of acetyl-CoA synthase. Methylation of CoFeSP only occurs in the low-potential Co(I) state, which can be sporadically oxidized to the inactive Co(II) state, making its reductive reactivation necessary. Here we show that an open-reading frame proximal to the structural genes of CoFeSP encodes an ATP-dependent reductive activator of CoFeSP. Our biochemical and structural analysis uncovers a unique type of reductive activator distinct from the electron transferring ATPases found to reduce the MoFe-nitrogenase and 2-hydroxyacyl-CoA dehydratases. The CoFeSP activator contains an ASKHA domain (acetate and sugar kinases, Hsp70, and actin) harboring the ATP-binding site, which is also present in the activator of 2-hydroxyacyl-CoA dehydratases and a ferredoxin-like [2Fe-2S] cluster domain acting as electron donor. Complex formation between CoFeSP and its activator depends on the oxidation state of CoFeSP, which provides evidence for a unique strategy to achieve unidirectional electron transfer between two redox proteins. PMID- 22431598 TI - Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. AB - The Ras gene is frequently mutated in cancer, and mutant Ras drives tumorigenesis. Although Ras is a central oncogene, small molecules that bind to Ras in a well-defined manner and exert inhibitory effects have not been uncovered to date. Through an NMR-based fragment screen, we identified a group of small molecules that all bind to a common site on Ras. High-resolution cocrystal structures delineated a unique ligand-binding pocket on the Ras protein that is adjacent to the switch I/II regions and can be expanded upon compound binding. Structure analysis predicts that compound-binding interferes with the Ras/SOS interactions. Indeed, selected compounds inhibit SOS-mediated nucleotide exchange and prevent Ras activation by blocking the formation of intermediates of the exchange reaction. The discovery of a small-molecule binding pocket on Ras with functional significance provides a new direction in the search of therapeutically effective inhibitors of the Ras oncoprotein. PMID- 22431599 TI - X-ray crystallographic and computational studies of the O2-tolerant [NiFe] hydrogenase 1 from Escherichia coli. AB - The crystal structure of the membrane-bound O(2)-tolerant [NiFe]-hydrogenase 1 from Escherichia coli (EcHyd-1) has been solved in three different states: as isolated, H(2)-reduced, and chemically oxidized. As very recently reported for similar enzymes from Ralstonia eutropha and Hydrogenovibrio marinus, two supernumerary Cys residues coordinate the proximal [FeS] cluster in EcHyd-1, which lacks one of the inorganic sulfide ligands. We find that the as-isolated, aerobically purified species contains a mixture of at least two conformations for one of the cluster iron ions and Glu76. In one of them, Glu76 and the iron occupy positions that are similar to those found in O(2)-sensitive [NiFe]-hydrogenases. In the other conformation, this iron binds, besides three sulfur ligands, the amide N from Cys20 and one Oepsilon of Glu76. Our calculations show that oxidation of this unique iron generates the high-potential form of the proximal cluster. The structural rearrangement caused by oxidation is confirmed by our H(2)-reduced and oxidized EcHyd-1 structures. Thus, thanks to the peculiar coordination of the unique iron, the proximal cluster can contribute two successive electrons to secure complete reduction of O(2) to H(2)O at the active site. The two observed conformations of Glu76 are consistent with this residue playing the role of a base to deprotonate the amide moiety of Cys20 upon iron binding and transfer the resulting proton away, thus allowing the second oxidation to be electroneutral. The comparison of our structures also shows the existence of a dynamic chain of water molecules, resulting from O(2) reduction, located near the active site. PMID- 22431600 TI - Structure-based ligand discovery for the protein-protein interface of chemokine receptor CXCR4. AB - G-protein-coupled receptors (GPCRs) are key signaling molecules and are intensely studied. Whereas GPCRs recognizing small-molecules have been successfully targeted for drug discovery, protein-recognizing GPCRs, such as the chemokine receptors, claim few drugs or even useful small molecule reagents. This reflects both the difficulties that attend protein-protein interface inhibitor discovery, and the lack of structures for these targets. Imminent structure determination of chemokine receptor CXCR4 motivated docking screens for new ligands against a homology model and subsequently the crystal structure. More than 3 million molecules were docked against the model and then against the crystal structure; 24 and 23 high-scoring compounds from the respective screens were tested experimentally. Docking against the model yielded only one antagonist, which resembled known ligands and lacked specificity, whereas the crystal structure docking yielded four that were dissimilar to previously known scaffolds and apparently specific. Intriguingly, several were potent and relatively small, with IC(50) values as low as 306 nM, ligand efficiencies as high as 0.36, and with efficacy in cellular chemotaxis. The potency and efficiency of these molecules has few precedents among protein-protein interface inhibitors, and supports structure-based efforts to discover leads for chemokine GPCRs. PMID- 22431601 TI - Patient sharing and population genetic structure of methicillin-resistant Staphylococcus aureus. AB - Rates of hospital-acquired infections, specifically methicillin-resistant Staphylococcus aureus (MRSA), are increasingly being used as indicators for quality of hospital hygiene. There has been much effort on understanding the transmission process at the hospital level; however, interhospital population based transmission remains poorly defined. We evaluated whether the proportion of shared patients between hospitals was correlated with genetic similarity of MRSA strains from those hospitals. Using data collected from 30 of 32 hospitals in Orange County, California, multivariate linear regression showed that for each twofold increase in the proportion of patients shared between 2 hospitals, there was a 7.7% reduction in genetic heterogeneity between the hospitals' MRSA populations (permutation P value = 0.0356). Pairs of hospitals that both served adults had more similar MRSA populations than pairs including a pediatric hospital. These findings suggest that concerted efforts among hospitals that share large numbers of patients may be synergistic to prevent MRSA transmission. PMID- 22431602 TI - High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death. AB - Human ATAD5 is a biomarker for identifying genotoxic compounds because ATAD5 protein levels increase posttranscriptionally in response to DNA damage. We screened over 4,000 compounds with a cell-based quantitative high-throughput ATAD5-luciferase assay detecting genotoxic compounds. We identified 22 antioxidants, including resveratrol, genistein, and baicalein, that are currently used or investigated for the treatment of cardiovascular disease, type 2 diabetes, osteopenia, osteoporosis, and chronic hepatitis, as well as for antiaging. Treatment of dividing cells with these compounds induced DNA damage and resulted in cell death. Despite their genotoxic effects, resveratrol, genistein, and baicalein did not cause mutagenesis, which is a major side effect of conventional anticancer drugs. Furthermore, resveratrol and genistein killed multidrug-resistant cancer cells. We therefore propose that resveratrol, genistein, and baicalein are attractive candidates for improved chemotherapeutic agents. PMID- 22431603 TI - Cells test substrate rigidity by local contractions on submicrometer pillars. AB - Cell growth and differentiation are critically dependent upon matrix rigidity, yet many aspects of the cellular rigidity-sensing mechanism are not understood. Here, we analyze matrix forces after initial cell-matrix contact, when early rigidity-sensing events occur, using a series of elastomeric pillar arrays with dimensions extending to the submicron scale (2, 1, and 0.5 MUm in diameter covering a range of stiffnesses). We observe that the cellular response is fundamentally different on micron-scale and submicron pillars. On 2-MUm diameter pillars, adhesions form at the pillar periphery, forces are directed toward the center of the cell, and a constant maximum force is applied independent of stiffness. On 0.5-MUm diameter pillars, adhesions form on the pillar tops, and local contractions between neighboring pillars are observed with a maximum displacement of ~60 nm, independent of stiffness. Because mutants in rigidity sensing show no detectable displacement on 0.5-MUm diameter pillars, there is a correlation between local contractions to 60 nm and rigidity sensing. Localization of myosin between submicron pillars demonstrates that submicron scale myosin filaments can cause these local contractions. Finally, submicron pillars can capture many details of cellular force generation that are missed on larger pillars and more closely mimic continuous surfaces. PMID- 22431604 TI - Structure of components of an intercellular channel complex in sporulating Bacillus subtilis. AB - Following asymmetric cell division during spore formation in Bacillus subtilis, a forespore expressed membrane protein SpoIIQ, interacts across an intercellular space with a mother cell-expressed membrane protein, SpoIIIAH. Their interaction can serve as a molecular "ratchet" contributing to the migration of the mother cell membrane around that of the forespore in a phagocytosis-like process termed engulfment. Upon completion of engulfment, SpoIIQ and SpoIIIAH are integral components of a recently proposed intercellular channel allowing passage from the mother cell into the forespore of factors required for late gene expression in this compartment. Here we show that the extracellular domains of SpoIIQ and SpoIIIAH form a heterodimeric complex in solution. The crystal structure of this complex reveals that SpoIIQ has a LytM-like zinc-metalloprotease fold but with an incomplete zinc coordination sphere and no metal. SpoIIIAH has an alpha-helical subdomain and a protruding beta-sheet subdomain, which mediates interactions with SpoIIQ. SpoIIIAH has sequence and structural homology to EscJ, a type III secretion system protein that forms a 24-fold symmetric ring. Superposition of the structures of SpoIIIAH and EscJ reveals that the SpoIIIAH protomer overlaps with two adjacent protomers of EscJ, allowing us to generate a dodecameric SpoIIIAH ring by using structural homology. Following this superposition, the SpoIIQ chains also form a closed dodecameric ring abutting the SpoIIIAH ring, producing an assembly surrounding a 60 A channel. The dimensions and organization of the proposed complex suggest it is a plausible model for the extracellular component of a gap junction-like intercellular channel. PMID- 22431605 TI - Distributed representation of chemical features and tunotopic organization of glomeruli in the mouse olfactory bulb. AB - In the mammalian brain, similar features of the sensory stimuli are often represented in proximity in the sensory areas. However, how chemical features are represented in the olfactory bulb has been controversial. Questions have been raised as to whether specific chemical features of the odor molecules are represented by spatially clustered olfactory glomeruli. Using a sensitive probe, we have analyzed the glomerular response to large numbers of odorants at single glomerulus resolution. Contrary to the general view, we find that the representation of chemical features is spatially distributed in the olfactory bulb with no discernible chemotopy. Moreover, odor-evoked pattern of activity does not correlate directly with odor structure in general. Despite the lack of spatial clustering or preference with respect to chemical features, some structurally related odors can be similarly represented by ensembles of spatially distributed glomeruli, providing an explanation of their perceptual similarity. Whereas there is no chemotopic organization, and the glomeruli are tuned to odors from multiple classes, we find that the glomeruli are hierarchically arranged into clusters according to their odor-tuning similarity. This tunotopic arrangement provides a framework to understand the spatial organization of the glomeruli that conforms to the organizational principle found in other sensory systems. PMID- 22431606 TI - Retraction for Lammerts van Bueren et al. The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility. PMID- 22431607 TI - Mapping patterns of long-term settlement in Northern Mesopotamia at a large scale. AB - The landscapes of the Near East show both the first settlements and the longest trajectories of settlement systems. Mounding is a characteristic property of these settlement sites, resulting from millennia of continuing settlement activity at distinguished places. So far, however, this defining feature of ancient settlements has not received much attention, or even been the subject of systematic evaluation. We propose a remote sensing approach for comprehensively mapping the pattern of human settlement at large scale and establish the largest archaeological record for a landscape in Mesopotamia, mapping about 14,000 settlement sites--spanning eight millennia--at 15-m resolution in a 23,000-km(2) area in northeastern Syria. To map both low- and high-mounded places--the latter of which are often referred to as "tells"--we develop a strategy for detecting anthrosols in time series of multispectral satellite images and measure the volume of settlement sites in a digital elevation model. Using this volume as a proxy to continued occupation, we find a dependency of the long-term attractiveness of a site on local water availability, but also a strong relation to the relevance within a basin-wide exchange network that we can infer from our record and third millennium B.C. intersite routes visible on the ground until recent times. We believe it is possible to establish a nearly comprehensive map of human settlements in the fluvial plains of northern Mesopotamia and beyond, and site volume may be a key quantity to uncover long-term trends in human settlement activity from such a record. PMID- 22431608 TI - Finessing the fracture energy barrier in ballistic seed dispersal. AB - Fracture is a highly dissipative process in which much of the stored elastic energy is consumed in the creation of new surfaces. Surprisingly, many plants use fracture to launch their seeds despite its seemingly prohibitive energy cost. Here we use Impatiens glandulifera as model case to study the impact of fracture on a plant's throwing capacity. I. glandulifera launches its seeds with speeds up to 4 m/s using cracks to trigger an explosive release of stored elastic energy. We find that the seed pod is optimally designed to minimize the cost of fracture. These characteristics may account for its success at invading Europe and North America. PMID- 22431609 TI - Phosphorus-31 MRI of hard and soft solids using quadratic echo line-narrowing. AB - Magnetic resonance imaging (MRI) of solids is rarely attempted. One of the main reasons is that the broader MR linewidths, compared to the narrow resonance of the hydrogen ((1)H) in free water, limit both the attainable spatial resolution and the signal-to-noise ratio. Basic physics research, stimulated by the quest to build a quantum computer, gave rise to a unique MR pulse sequence that offers a solution to this long-standing problem. The "quadratic echo" significantly narrows the broad MR spectrum of solids. Applying field gradients in sync with this line-narrowing sequence offers a fresh approach to carry out MRI of hard and soft solids with high spatial resolution and with a wide range of potential uses. Here we demonstrate that this method can be used to carry out three-dimensional MRI of the phosphorus ((31)P) in ex vivo bone and soft tissue samples. PMID- 22431610 TI - Fluorescence microscopy for simultaneous observation of 3D orientation and movement and its application to quantum rod-tagged myosin V. AB - Single molecule fluorescence polarization techniques have been used for three dimensional (3D) orientation measurements to observe the dynamic properties of single molecules. However, only few techniques can simultaneously measure 3D orientation and position. Furthermore, these techniques often require complex equipment and cumbersome analysis. We have developed a microscopy system and synthesized highly fluorescent, rod-like shaped quantum dots (Q rods), which have linear polarizations, to simultaneously measure the position and 3D orientation of a single fluorescent probe. The optics splits the fluorescence from the probe into four different spots depending on the polarization angle and projects them onto a CCD camera. These spots are used to determine the 2D position and 3D orientation. Q rod orientations could be determined with better than 10 degrees accuracy at 33 ms time resolution. We applied our microscopy and Q rods to simultaneously measure myosin V movement along an actin filament and rotation around its own axis, finding that myosin V rotates 90 degrees for each step. From this result, we suggest that in the two-headed bound state, myosin V necks are perpendicular to one another, while in the one-headed bound state the detached trailing myosin V head is biased forward in part by rotating its lever arm about its own axis. This microscopy system should be applicable to a wide range of dynamic biological processes that depend on single molecule orientation dynamics. PMID- 22431611 TI - Lantibiotics from Geobacillus thermodenitrificans. AB - The lantibiotic nisin has been used as an effective food preservative to combat food-borne pathogens for over 40 y. Despite this successful use, nisin's stability at pH 7 is limited. Herein, we describe a nisin analog encoded on the genome of the thermophilic bacterium Geobacillus thermodenitrificans NG80-2. This analog termed geobacillin I was obtained by heterologous expression in Escherichia coli and subsequent purification. Extensive NMR characterization demonstrated that geobacillin I contains seven thioether cross-links, two more than the five cross-links found in nisin and the most cross-links found in any lantibiotic to date. The antimicrobial spectrum of geobacillin I was generally similar to that of nisin A, with increased activity against Streptococcus dysgalactiae, one of the causative agents of bovine mastitis. Geobacillin I demonstrated increased stability compared to nisin A. In addition to geobacillin I, the genome of G. thermodenitrificans NG80-2 also contains a class II lantibiotic biosynthetic gene cluster. The corresponding compound was produced in E. coli, and has a ring topology different than that of any known lantibiotic as determined by tandem mass spectrometry. Interestingly, geobacillin II only demonstrated antimicrobial activity against Bacillus strains. Seven Geobacillus strains were screened for production of the geobacillins using whole-cell MALDI MS and five were shown to produce geobacillin I, but none produced geobacillin II. PMID- 22431612 TI - Effect of channel mutations on the uptake and release of the retinal ligand in opsin. AB - In the retinal binding pocket of rhodopsin, a Schiff base links the retinal ligand covalently to the Lys296 side chain. Light transforms the inverse agonist 11-cis-retinal into the agonist all-trans-retinal, leading to the active Meta II state. Crystal structures of Meta II and the active conformation of the opsin apoprotein revealed two openings of the 7-transmembrane (TM) bundle towards the hydrophobic core of the membrane, one between TM1/TM7 and one between TM5/TM6, respectively. Computational analysis revealed a putative ligand channel connecting the openings and traversing the binding pocket. Identified constrictions within the channel motivated this study of 35 rhodopsin mutants in which single amino acids lining the channel were replaced. 11-cis-retinal uptake and all-trans-retinal release were measured using UV/visible and fluorescence spectroscopy. Most mutations slow or accelerate both uptake and release, often with opposite effects. Mutations closer to the Lys296 active site show larger effects. The nucleophile hydroxylamine accelerates retinal release 80 times but the action profile of the mutants remains very similar. The data show that the mutations do not probe local channel permeability but rather affect global protein dynamics, with the focal point in the ligand pocket. We propose a model for retinal/receptor interaction in which the active receptor conformation sets the open state of the channel for 11-cis-retinal and all-trans-retinal, with positioning of the ligand at the active site as the kinetic bottleneck. Although other G protein-coupled receptors lack the covalent link to the protein, the access of ligands to their binding pocket may follow similar schemes. PMID- 22431613 TI - Structure of the basal components of a bacterial transporter. AB - Proteins SpoIIQ and SpoIIIAH interact through two membranes to connect the forespore and the mother cell during endospore development in the bacterium Bacillus subtilis. SpoIIIAH consists of a transmembrane segment and an extracellular domain with similarity to YscJ proteins. YscJ proteins form large multimeric rings that are the structural scaffolds for the assembly of type III secretion systems in gram-negative bacteria. The predicted ring-forming motif of SpoIIIAH and other evidence led to the model that SpoIIQ and SpoIIIAH form the core components of a channel or transporter through which the mother cell nurtures forespore development. Therefore, to understand the roles of SpoIIIAH and SpoIIQ in channel formation, it is critical to determine whether SpoIIIAH adopts a ring-forming structural motif, and whether interaction of SpoIIIAH with SpoIIQ would preclude ring formation. We report a 2.8-A resolution structure of a complex of SpoIIQ and SpoIIIAH. SpoIIIAH folds into the ring-building structural motif, and modeling shows that the structure of the SpoIIQ-SpoIIIAH complex is compatible with forming a symmetrical oligomer that is similar to those in type III systems. The inner diameters of the two most likely ring models are large enough to accommodate several copies of other integral membrane proteins. SpoIIQ contains a LytM domain, which is found in metalloendopeptidases, but lacks residues important for metalloprotease activity. Other LytM domains appear to be involved in protein-protein interactions. We found that the LytM domain of SpoIIQ contains an accessory region that interacts with SpoIIIAH. PMID- 22431614 TI - Prokineticin 2 is an endangering mediator of cerebral ischemic injury. AB - Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have been discovered, including circadian rhythms, angiogenesis, and neurogenesis. However, the role of PK2 in neuropathology is unknown. Using primary cortical cultures, we found that PK2 mRNA is up-regulated by several pathological stressors, including hypoxia, reactive oxygen species, and excitotoxic glutamate. Glutamate-induced PK2 expression is dependent on NMDA receptor activation and extracellular calcium. Enriched neuronal culture studies revealed that neurons are the principal source of glutamate-induced PK2. Using in vivo models of stroke, we found that PK2 mRNA is induced in the ischemic cortex and striatum. Central delivery of PK2 worsens infarct volume, whereas PK2 receptor antagonist decreases infarct volume and central inflammation while improving functional outcome. Direct central inhibition of PK2 using RNAi also reduces infarct volume. These findings indicate that PK2 can be activated by pathological stimuli such as hypoxia-ischemia and excitotoxic glutamate and identify PK2 as a deleterious mediator for cerebral ischemia. PMID- 22431615 TI - Coordination of the transcriptome and metabolome by the circadian clock. AB - The circadian clock governs a large array of physiological functions through the transcriptional control of a significant fraction of the genome. Disruption of the clock leads to metabolic disorders, including obesity and diabetes. As food is a potent zeitgeber (ZT) for peripheral clocks, metabolites are implicated as cellular transducers of circadian time for tissues such as the liver. From a comprehensive dataset of over 500 metabolites identified by mass spectrometry, we reveal the coordinate clock-controlled oscillation of many metabolites, including those within the amino acid and carbohydrate metabolic pathways as well as the lipid, nucleotide, and xenobiotic metabolic pathways. Using computational modeling, we present evidence of synergistic nodes between the circadian transcriptome and specific metabolic pathways. Validation of these nodes reveals that diverse metabolic pathways, including the uracil salvage pathway, oscillate in a circadian fashion and in a CLOCK-dependent manner. This integrated map illustrates the coherence within the circadian metabolome, transcriptome, and proteome and how these are connected through specific nodes that operate in concert to achieve metabolic homeostasis. PMID- 22431616 TI - Vertebrate time-tree elucidates the biogeographic pattern of a major biotic change around the K-T boundary in Madagascar. AB - The geographic and temporal origins of Madagascar's biota have long been in the center of debate. We reconstructed a time-tree including nearly all native nonflying and nonmarine vertebrate clades present on the island, from DNA sequences of two single-copy protein-coding nuclear genes (BDNF and RAG1) and a set of congruent time constraints. Reconstructions calculated with autocorrelated or independent substitution rates over clades agreed in placing the origins of the 31 included clades in Cretaceous to Cenozoic times. The two clades with sister groups in South America were the oldest, followed by those of a putative Asian ancestry that were significantly older than the prevalent clades of African ancestry. No colonizations from Asia occurred after the Eocene, suggesting that dispersal and vicariance of Asian/Indian groups were favored over a comparatively short period during, and shortly after, the separation of India and Madagascar. Species richness of clades correlates with their age but those clades that have a large proportion of species diversity in rainforests are significantly more species-rich. This finding suggests an underlying pattern of continuous speciation through time in Madagascar's vertebrates, with accelerated episodes of adaptive diversification in those clades that succeeded radiating into the rainforests. PMID- 22431617 TI - Maternal siRNAs as regulators of parental genome imbalance and gene expression in endosperm of Arabidopsis seeds. AB - Seed size is important to crop domestication and natural selection and is affected by the balance of maternal and paternal genomes in endosperm. Endosperm, like placenta in mammals, provides reserves to the developing embryo. Interploidy crosses disrupt the genome balance in endosperm and alter seed size. Specifically, paternal-excess crosses (2 * 4) delay endosperm cellularization (EC) and produce larger seeds, whereas maternal-excess crosses (4 * 2) promote precocious EC and produce smaller seeds. The mechanisms for responding to the parental genome dosage imbalance and for gene expression changes in endosperm are unknown. In plants, RNA polymerase IV (PolIV or p4) encoded by NRPD1a is required for biogenesis of a major class of 24-nt small interfering RNAs (also known as p4 siRNAs), which are predominately expressed in developing endosperm. Here we show that p4-siRNA accumulation depends on the maternal genome dosage, and maternal p4 siRNAs target transposable elements (TEs) and TE-associated genes (TAGs) in seeds. The p4-siRNAs correlate negatively with expression levels of AGAMOUS-LIKE (AGL) genes in endosperm of interploidy crosses. Moreover, disruption of maternal NRPD1a expression is associated with p4-siRNA reduction and AGL up-regulation in endosperm of reciprocal crosses. This is unique genetic evidence for maternal siRNAs in response to parental genome imbalance and in control of transposons and gene expression during endosperm development. PMID- 22431618 TI - Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. AB - Mutations in the gene encoding superoxide dismutase 1 (SOD1) account for about 20% of the cases of familial amyotrophic lateral sclerosis (fALS). It is not known how the mutant protein causes disease, or why only a subset of cell types (motor neurons) are targeted. The aggregation and misfolding of mutant SOD1 are implicated in disease pathogenesis in both animal models and humans. We used a monoclonal antibody, C4F6, which specifically reacts with mutant and/or "misfolded" SOD1, to investigate the regional distribution of mutant SOD1 protein in rodent and human tissues. C4F6 reacted only with mutant SOD1 and showed remarkable selectivity for disease-affected tissues and cells. Tissue not affected by disease but containing high levels of mutant protein (sensory neurons) did not stain with C4F6. Additionally, C4F6 intensely stained some motor neurons while leaving adjacent motor neurons unstained. Although C4F6 was generated against the G93A SOD1 mutant, it also recognized other SOD1 mutants. In human autopsy tissues from patients carrying SOD1 mutations, C4F6 identified skein-like intracellular inclusions in motor neurons, similar to those seen in rodents, and again stained only a subset of motor neurons. In spinal cords from patients with sporadic ALS, other neurodegenerative diseases, and normal controls, C4F6-immunoreactive inclusions were not detected, but the antibody did reveal diffuse immunostaining of some spinal motor neurons. The ability of C4F6 to differentiate pathologically affected tissue in mutant SOD1 ALS rodent models and humans, specifically motor neuron populations, suggests that this antibody may recognize a "toxic" form of the mutant SOD1 protein. PMID- 22431619 TI - Origin of excitation underlying locomotion in the spinal circuit of zebrafish. AB - Neural circuits in the spinal cord transform instructive signals from the brain into well-coordinated locomotor movements by virtue of rhythm-generating components. Although evidence suggests that excitatory interneurons are the essence of locomotor rhythm generation, their molecular identity and the assessment of their necessity have remained unclear. Here we show, using larval zebrafish, that V2a interneurons represent an intrinsic source of excitation necessary for the normal expression of the locomotor rhythm. Acute and selective ablation of these interneurons increases the threshold of induction of swimming activity, decreases the burst frequency, and alters the coordination of the rostro-caudal propagation of activity. Thus, our results argue that V2a interneurons represent a source of excitation that endows the spinal circuit with the capacity to generate locomotion. PMID- 22431620 TI - Persistence and uncertainty in the academic career. AB - Understanding how institutional changes within academia may affect the overall potential of science requires a better quantitative representation of how careers evolve over time. Because knowledge spillovers, cumulative advantage, competition, and collaboration are distinctive features of the academic profession, both the employment relationship and the procedures for assigning recognition and allocating funding should be designed to account for these factors. We study the annual production n(i)(t) of a given scientist i by analyzing longitudinal career data for 200 leading scientists and 100 assistant professors from the physics community. Our empirical analysis of individual productivity dynamics shows that (i) there are increasing returns for the top individuals within the competitive cohort, and that (ii) the distribution of production growth is a leptokurtic "tent-shaped" distribution that is remarkably symmetric. Our methodology is general, and we speculate that similar features appear in other disciplines where academic publication is essential and collaboration is a key feature. We introduce a model of proportional growth which reproduces these two observations, and additionally accounts for the significantly right-skewed distributions of career longevity and achievement in science. Using this theoretical model, we show that short-term contracts can amplify the effects of competition and uncertainty making careers more vulnerable to early termination, not necessarily due to lack of individual talent and persistence, but because of random negative production shocks. We show that fluctuations in scientific production are quantitatively related to a scientist's collaboration radius and team efficiency. PMID- 22431621 TI - Ultrafast large-amplitude relocation of electronic charge in ionic crystals. AB - The interplay of vibrational motion and electronic charge relocation in an ionic hydrogen-bonded crystal is mapped by X-ray powder diffraction with a 100 fs time resolution. Photoexcitation of the prototype material KH(2)PO(4) induces coherent low-frequency motions of the PO(4) tetrahedra in the electronically excited state of the crystal while the average atomic positions remain unchanged. Time dependent maps of electron density derived from the diffraction data demonstrate an oscillatory relocation of electronic charge with a spatial amplitude two orders of magnitude larger than the underlying vibrational lattice motions. Coherent longitudinal optical and tranverse optical phonon motions that dephase on a time scale of several picoseconds, drive the charge relocation, similar to a soft (transverse optical) mode driven phase transition between the ferro- and paraelectric phase of KH(2)PO(4). PMID- 22431622 TI - Molecular crowding creates traffic jams of kinesin motors on microtubules. AB - Despite the crowdedness of the interior of cells, microtubule-based motor proteins are able to deliver cargoes rapidly and reliably throughout the cytoplasm. We hypothesize that motor proteins may be adapted to operate in crowded environments by having molecular properties that prevent them from forming traffic jams. To test this hypothesis, we reconstituted high-density traffic of purified kinesin-8 motor protein, a highly processive motor with long end-residency time, along microtubules in a total internal-reflection fluorescence microscopy assay. We found that traffic jams, characterized by an abrupt increase in the density of motors with an associated abrupt decrease in motor speed, form even in the absence of other obstructing proteins. To determine the molecular properties that lead to jamming, we altered the concentration of motors, their processivity, and their rate of dissociation from microtubule ends. Traffic jams occurred when the motor density exceeded a critical value (density induced jams) or when motor dissociation from the microtubule ends was so slow that it resulted in a pileup (bottleneck-induced jams). Through comparison of our experimental results with theoretical models and stochastic simulations, we characterized in detail under which conditions density- and bottleneck-induced traffic jams form or do not form. Our results indicate that transport kinesins, such as kinesin-1, may be evolutionarily adapted to avoid the formation of traffic jams by moving only with moderate processivity and dissociating rapidly from microtubule ends. PMID- 22431623 TI - Structural basis for lack of toxicity of the diphtheria toxin mutant CRM197. AB - CRM197 is an enzymatically inactive and nontoxic form of diphtheria toxin that contains a single amino acid substitution (G52E). Being naturally nontoxic, CRM197 is an ideal carrier protein for conjugate vaccines against encapsulated bacteria and is currently used to vaccinate children globally against Haemophilus influenzae, pneumococcus, and meningococcus. To understand the molecular basis for lack of toxicity in CRM197, we determined the crystal structures of the full length nucleotide-free CRM197 and of CRM197 in complex with the NAD hydrolysis product nicotinamide (NCA), both at 2.0-A resolution. The structures show for the first time that the overall fold of CRM197 and DT are nearly identical and that the striking functional difference between the two proteins can be explained by a flexible active-site loop that covers the NAD binding pocket. We present the molecular basis for the increased flexibility of the active-site loop in CRM197 as unveiled by molecular dynamics simulations. These structural insights, combined with surface plasmon resonance, NAD hydrolysis, and differential scanning fluorimetry data, contribute to a comprehensive characterization of the vaccine carrier protein, CRM197. PMID- 22431624 TI - Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells. AB - The question of whether a single hematopoietic stem cell (HSC) gives rise to all of the B-cell subsets [B-1a, B-1b, B-2, and marginal zone (MZ) B cells] in the mouse has been discussed for many years without resolution. Studies here finally demonstrate that individual HSCs sorted from adult bone marrow and transferred to lethally irradiated recipients clearly give rise to B-2, MZ B, and B-1b, but does not detectably reconstitute B-1a cells. These findings place B-2, MZ, and B-1b in a single adult developmental lineage and place B-1a in a separate lineage derived from HSCs that are rare or missing in adults. We discuss these findings with respect to known developmental heterogeneity in other HSC-derived lymphoid, myeloid, and erythroid lineages, and how HSC developmental heterogeneity conforms to the layered model of the evolution of the immune system that we proposed some years ago. In addition, of importance to contemporary medicine, we consider the implications that HSC developmental heterogeneity may have for selecting HSC sources for human transplantation. PMID- 22431625 TI - Genome-wide analysis of histone H3.1 and H3.3 variants in Arabidopsis thaliana. AB - Nucleosomes package eukaryotic DNA and are composed of four different histone proteins, designated H3, H4, H2A, and H2B. Histone H3 has two main variants, H3.1 and H3.3, which show different genomic localization patterns in animals. We profiled H3.1 and H3.3 variants in the genome of the plant Arabidopsis thaliana and found that the localization of these variants shows broad similarity in plants and animals, along with some unique features. H3.1 was enriched in silent areas of the genome, including regions containing the repressive chromatin modifications H3 lysine 27 methylation, H3 lysine 9 methylation, and DNA methylation. In contrast, H3.3 was enriched in actively transcribed genes, especially peaking at the 3' end of genes, and correlated with histone modifications associated with gene activation, such as histone H3 lysine 4 methylation and H2B ubiquitylation, as well as RNA Pol II occupancy. Surprisingly, both H3.1 and H3.3 were enriched on defined origins of replication, as was overall nucleosome density, suggesting a novel characteristic of plant origins. Our results are broadly consistent with the hypothesis that H3.1 acts as the canonical histone that is incorporated during DNA replication, whereas H3.3 acts as the replacement histone that can be incorporated outside of S-phase during chromatin-disrupting processes like transcription. PMID- 22431626 TI - Time-lapse two-color 3D imaging of live cells with doubled resolution using structured illumination. AB - Previous implementations of structured-illumination microscopy (SIM) were slow or designed for one-color excitation, sacrificing two unique and extremely beneficial aspects of light microscopy: live-cell imaging in multiple colors. This is especially unfortunate because, among the resolution-extending techniques, SIM is an attractive choice for live-cell imaging; it requires no special fluorophores or high light intensities to achieve twice diffraction limited resolution in three dimensions. Furthermore, its wide-field nature makes it light-efficient and decouples the acquisition speed from the size of the lateral field of view, meaning that high frame rates over large volumes are possible. Here, we report a previously undescribed SIM setup that is fast enough to record 3D two-color datasets of living whole cells. Using rapidly programmable liquid crystal devices and a flexible 2D grid pattern algorithm to switch between excitation wavelengths quickly, we show volume rates as high as 4 s in one color and 8.5 s in two colors over tens of time points. To demonstrate the capabilities of our microscope, we image a variety of biological structures, including mitochondria, clathrin-coated vesicles, and the actin cytoskeleton, in either HeLa cells or cultured neurons. PMID- 22431627 TI - Globally diverse Toxoplasma gondii isolates comprise six major clades originating from a small number of distinct ancestral lineages. AB - Marked phenotypic variation characterizes isolates of Toxoplasma gondii, a ubiquitous zoonotic parasite that serves as an important experimental model for studying apicomplexan parasites. Progress in identifying the heritable basis for clinically and epidemiologically significant differences requires a robust system for describing and interpreting evolutionary subdivisions in this prevalent pathogen. To develop such a system, we have examined more than 950 isolates collected from around the world and genotyped them using three independent sets of polymorphic DNA markers, sampling 30 loci distributed across all nuclear chromosomes as well as the plastid genome. Our studies reveal a biphasic pattern consisting of regions in the Northern Hemisphere where a few, highly clonal and abundant lineages predominate; elsewhere, and especially in portions of South America are characterized by a diverse assemblage of less common genotypes that show greater evidence of recombination. Clustering methods were used to organize the marked genetic diversity of 138 unique genotypes into 15 haplogroups that collectively define six major clades. Analysis of gene flow indicates that a small number of ancestral lineages gave rise to the existing diversity through a process of limited admixture. Identification of reference strains for these major groups should facilitate future studies on comparative genomics and identification of genes that control important biological phenotypes including pathogenesis and transmission. PMID- 22431628 TI - Pantropic retroviruses as a transduction tool for sea urchin embryos. AB - Sea urchins are an important model for experiments at the intersection of development and systems biology, and technical innovations that enhance the utility of this model are of great value. This study explores pantropic retroviruses as a transduction tool for sea urchin embryos, and demonstrates that pantropic retroviruses infect sea urchin embryos with high efficiency and genomically integrate at a copy number of one per cell. We successfully used a self-inactivation strategy to both insert a sea urchin-specific enhancer and disrupt the endogenous viral enhancer. The resulting self-inactivating viruses drive global and persistent gene expression, consistent with genomic integration during the first cell cycle. Together, these data provide substantial proof of principle for transduction technology in sea urchin embryos. PMID- 22431630 TI - Poly(A) binding protein abundance regulates eukaryotic translation initiation factor 4F assembly in human cytomegalovirus-infected cells. AB - By commandeering cellular translation initiation factors, or destroying those dispensable for viral mRNA translation, viruses often suppress host protein synthesis. In contrast, cellular protein synthesis proceeds in human cytomegalovirus (HCMV)-infected cells, forcing viral and cellular mRNAs to compete for limiting translation initiation factors. Curiously, inactivating the host translational repressor 4E-BP1 in HCMV-infected cells stimulates synthesis of the cellular poly(A) binding protein (PABP), significantly increasing PABP abundance. Here, we establish that new PABP synthesis is translationally controlled by the HCMV-encoded UL38 mammalian target of rapamycin complex 1 activator. The 5' UTR within the mRNA encoding PABP contains a terminal oligopyrimidine (TOP) element found in mRNAs, the translation of which is stimulated in response to mitogenic, growth, and nutritional stimuli, and proteins encoded by TOP-containing mRNAs accumulated in HCMV-infected cells. Furthermore, UL38 expression was necessary and sufficient to regulate expression of a PABP TOP-containing reporter. Remarkably, preventing the rise in PABP abundance by RNAi impaired eIF4E binding to eIF4G, thereby reducing assembly of the multisubunit initiation factor eIF4F, viral protein production, and replication. This finding demonstrates that viruses can increase host translation initiation factor concentration to foster their replication and defines a unique mechanism whereby control of PABP abundance regulates eIF4F assembly. PMID- 22431631 TI - Comanagement of coral reef social-ecological systems. AB - In an effort to deliver better outcomes for people and the ecosystems they depend on, many governments and civil society groups are engaging natural resource users in collaborative management arrangements (frequently called comanagement). However, there are few empirical studies demonstrating the social and institutional conditions conducive to successful comanagement outcomes, especially in small-scale fisheries. Here, we evaluate 42 comanagement arrangements across five countries and show that: (i) comanagement is largely successful at meeting social and ecological goals; (ii) comanagement tends to benefit wealthier resource users; (iii) resource overexploitation is most strongly influenced by market access and users' dependence on resources; and (iv) institutional characteristics strongly influence livelihood and compliance outcomes, yet have little effect on ecological conditions. PMID- 22431632 TI - Dissecting the substrate recognition of 3-O-sulfotransferase for the biosynthesis of anticoagulant heparin. AB - Heparin is a polysaccharide-based natural product that is used clinically as an anticoagulant drug. Heparan sulfate 3-O-sulfotransferase (3-OST) is an enzyme that transfers a sulfo group to the 3-OH position of a glucosamine unit. 3-OST is present in multiple isoforms, and the polysaccharides modified by these different isoforms perform distinct biological functions. 3-OST isoform 1 (3-OST-1) is the key enzyme for the biosynthesis of anticoagulant heparin. Here, we report the crystal structure of the ternary complex of 3-OST-1, 3'-phosphoadenosine 5' phosphate, and a heptasaccharide substrate. Comparisons to previously determined structures of 3-OST-3 reveal unique binding modes used by the different isoforms of 3-OST for distinguishing the fine structures of saccharide substrates. Our data demonstrate that the saccharide substrates display distinct conformations when interacting with the different 3-OST isoforms. Site-directed mutagenesis data suggest that several key amino residues, including Lys259, Thr256, and Trp283 in 3-OST-3 and Arg268 in 3-OST-1, play important roles in substrate binding and specificity between isoforms. These results deepen our understanding of the biosynthetic mechanism of heparan sulfate and provide structural information for engineering enzymes for an enhanced biosynthetic approach to heparin production. PMID- 22431633 TI - TWIK1, a unique background channel with variable ion selectivity. AB - TWIK1 belongs to the family of background K(+) channels with two pore domains. In native and transfected cells, TWIK1 is detected mainly in recycling endosomes. In principal cells in the kidney, TWIK1 gene inactivation leads to the loss of a nonselective cationic conductance, an unexpected effect that was attributed to adaptive regulation of other channels. Here, we show that TWIK1 ion selectivity is modulated by extracellular pH. Although TWIK1 is K(+) selective at neutral pH, it becomes permeable to Na(+) at the acidic pH found in endosomes. Selectivity recovery is slow after restoration of a neutral pH. Such hysteresis makes plausible a role of TWIK1 as a background channel in which selectivity and resulting inhibitory or excitatory influences on cell excitability rely on its recycling rate between internal acidic stores and the plasma membrane. TWIK1(-/-) pancreatic beta cells are more polarized than control cells, confirming a depolarizing role of TWIK1 in kidney and pancreatic cells. PMID- 22431634 TI - Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory. AB - Growing evidence suggests serotonin's role in anxiety and depression is mediated by its effects on learned fear associations. Pharmacological and genetic manipulations of serotonin signaling in mice alter the retention of fear extinction learning, which is inversely associated with anxious temperament in mice and humans. Here, we test whether genetic variation in serotonin signaling in the form of a common human serotonin transporter polyadenylation polymorphism (STPP/rs3813034) is associated with spontaneous fear recovery after extinction. We show that the risk allele of this polymorphism is associated with impaired retention of fear extinction memory and heightened anxiety and depressive symptoms. These STPP associations in humans mirror the phenotypic effects of serotonin transporter knockout in mice, highlighting the STPP as a potential genetic locus underlying interindividual differences in serotonin transporter function in humans. Furthermore, we show that the serotonin transporter polyadenylation profile associated with the STPP risk allele is altered through the chronic administration of fluoxetine, a treatment that also facilitates retention of extinction learning. The propensity to form persistent fear associations due to poor extinction recall may be an intermediate phenotype mediating the effects of genetic variation in serotonergic function on anxiety and depression. The consistency and specificity of these data across species provide robust support for this hypothesis and suggest that the little-studied STPP may be an important risk factor for mood and anxiety disorders in humans. PMID- 22431635 TI - Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. AB - Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments. PMID- 22431636 TI - Riboswitch control of Rho-dependent transcription termination. AB - Riboswitches are RNA sensors that regulate gene expression upon binding specific metabolites or ions. Bacterial riboswitches control gene expression primarily by promoting intrinsic transcription termination or by inhibiting translation initiation. We now report a third general mechanism of riboswitch action: governing the ability of the RNA-dependent helicase Rho to terminate transcription. We establish that Rho promotes transcription termination in the Mg(2+)-sensing mgtA riboswitch from Salmonella enterica serovar Typhimurium and the flavin mononucleotide-sensing ribB riboswitch from Escherichia coli when the corresponding riboswitch ligands are present. The Rho-specific inhibitor bicyclomycin enabled transcription of the coding regions at these two loci in bacteria experiencing repressing concentrations of the riboswitch ligands in vivo. A mutation in the mgtA leader that favors the "high Mg(2+)" conformation of the riboswitch promoted Rho-dependent transcription termination in vivo and in vitro and enhanced the ability of the RNA to stimulate Rho's ATPase activity in vitro. These effects were overcome by mutations in a C-rich region of the mRNA that is alternately folded at high and low Mg(2+), suggesting a role for this region in regulating the activity of Rho. Our results reveal a potentially widespread mode of gene regulation whereby riboswitches dictate whether a protein effector can interact with the transcription machinery to prematurely terminate transcription. PMID- 22431637 TI - Carotenoid oxidation products are stress signals that mediate gene responses to singlet oxygen in plants. AB - (1)O(2) (singlet oxygen) is a reactive O(2) species produced from triplet excited chlorophylls in the chloroplasts, especially when plants are exposed to excess light energy. Similarly to other active O(2) species, (1)O(2) has a dual effect: It is toxic, causing oxidation of biomolecules, and it can act as a signal molecule that leads to cell death or to acclimation. Carotenoids are considered to be the main (1)O(2) quenchers in chloroplasts, and we show here that light stress induces the oxidation of the carotenoid beta-carotene in Arabidopsis plants, leading to the accumulation of different volatile derivatives. One such compound, beta-cyclocitral, was found to induce changes in the expression of a large set of genes that have been identified as (1)O(2) responsive genes. In contrast, beta-cyclocitral had little effect on the expression of H(2)O(2) gene markers. beta-Cyclocitral-induced reprogramming of gene expression was associated with an increased tolerance to photooxidative stress. The results indicate that beta-cyclocitral is a stress signal produced in high light that is able to induce defense mechanisms and represents a likely messenger involved in the (1)O(2) signaling pathway in plants. PMID- 22431638 TI - Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4. AB - Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ~65 degrees relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3epsilongamma and CD3epsilondelta subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T cell selection. PMID- 22431639 TI - Lifetime of carbon capture and storage as a climate-change mitigation technology. AB - In carbon capture and storage (CCS), CO(2) is captured at power plants and then injected underground into reservoirs like deep saline aquifers for long-term storage. While CCS may be critical for the continued use of fossil fuels in a carbon-constrained world, the deployment of CCS has been hindered by uncertainty in geologic storage capacities and sustainable injection rates, which has contributed to the absence of concerted government policy. Here, we clarify the potential of CCS to mitigate emissions in the United States by developing a storage-capacity supply curve that, unlike current large-scale capacity estimates, is derived from the fluid mechanics of CO(2) injection and trapping and incorporates injection-rate constraints. We show that storage supply is a dynamic quantity that grows with the duration of CCS, and we interpret the lifetime of CCS as the time for which the storage supply curve exceeds the storage demand curve from CO(2) production. We show that in the United States, if CO(2) production from power generation continues to rise at recent rates, then CCS can store enough CO(2) to stabilize emissions at current levels for at least 100 y. This result suggests that the large-scale implementation of CCS is a geologically viable climate-change mitigation option in the United States over the next century. PMID- 22431640 TI - Exploring the proton pump and exit pathway for pumped protons in cytochrome ba3 from Thermus thermophilus. AB - The heme-copper oxygen reductases are redox-driven proton pumps. In the current work, the effects of mutations in a proposed exit pathway for pumped protons are examined in the ba(3)-type oxygen reductase from Thermus thermophilus, leading from the propionates of heme a(3) to the interface between subunits I and II. Recent studies have proposed important roles for His376 and Asp372, both of which are hydrogen-bonded to propionate-A of heme a(3), and for Glu126(II) (subunit II), which is hydrogen-bonded to His376. Based on the current results, His376, Glu126(II), and Asp372 are not essential for either oxidase activity or proton pumping. In addition, Tyr133, which is hydrogen-bonded to propionate-D of heme a(3), was also shown not to be essential for function. However, two mutations of the residues hydrogen-bonded to propionate-A, Asp372Ile and His376Asn, retain high electron transfer activity and normal spectral features but, in different preparations, either do not pump protons or exhibit substantially diminished proton pumping. It is concluded that either propionate-A of heme a(3) or possibly the cluster of groups centered about the conserved water molecule that hydrogen bonds to both propionates-A and -D of heme a(3) is a good candidate to be the proton loading site. PMID- 22431641 TI - Plasmodium falciparum merozoite surface protein 1 blocks the proinflammatory protein S100P. AB - The malaria parasite, Plasmodium falciparum, and the human immune system have coevolved to ensure that the parasite is not eliminated and reinfection is not resisted. This relationship is likely mediated through a myriad of host-parasite interactions, although surprisingly few such interactions have been identified. Here we show that the 33-kDa fragment of P. falciparum merozoite surface protein 1 (MSP1(33)), an abundant protein that is shed during red blood cell invasion, binds to the proinflammatory protein, S100P. MSP1(33) blocks S100P-induced NFkappaB activation in monocytes and chemotaxis in neutrophils. Remarkably, S100P binds to both dimorphic alleles of MSP1, estimated to have diverged >27 Mya, suggesting an ancient, conserved relationship between these parasite and host proteins that may serve to attenuate potentially damaging inflammatory responses. PMID- 22431642 TI - Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder. AB - To date, electroconvulsive therapy (ECT) is the most potent treatment in severe depression. Although ECT has been successfully applied in clinical practice for over 70 years, the underlying mechanisms of action remain unclear. We used functional MRI and a unique data-driven analysis approach to examine functional connectivity in the brain before and after ECT treatment. Our results show that ECT has lasting effects on the functional architecture of the brain. A comparison of pre- and posttreatment functional connectivity data in a group of nine patients revealed a significant cluster of voxels in and around the left dorsolateral prefrontal cortical region (Brodmann areas 44, 45, and 46), where the average global functional connectivity was considerably decreased after ECT treatment (P < 0.05, family-wise error-corrected). This decrease in functional connectivity was accompanied by a significant improvement (P < 0.001) in depressive symptoms; the patients' mean scores on the Montgomery Asberg Depression Rating Scale pre- and posttreatment were 36.4 (SD = 4.9) and 10.7 (SD = 9.6), respectively. The findings reported here add weight to the emerging "hyperconnectivity hypothesis" in depression and support the proposal that increased connectivity may constitute both a biomarker for mood disorder and a potential therapeutic target. PMID- 22431643 TI - Spatial and temporal arrival patterns of Madagascar's vertebrate fauna explained by distance, ocean currents, and ancestor type. AB - How, when, and from where Madagascar's vertebrates arrived on the island is poorly known, and a comprehensive explanation for the distribution of its organisms has yet to emerge. We begin to break that impasse by analyzing vertebrate arrival patterns implied by currently existing taxa. For each of 81 clades, we compiled arrival date, source, and ancestor type (obligate freshwater, terrestrial, facultative swimmer, or volant). We analyzed changes in arrival rates, with and without adjusting for clade extinction. Probability of successful transoceanic dispersal is negatively correlated with distance traveled and influenced by ocean currents and ancestor type. Obligate rafters show a decrease in probability of successful transoceanic dispersal from the Paleocene onward, reaching the lowest levels after the mid-Miocene. This finding is consistent with a paleoceanographic model [Ali JR, Huber M (2010) Nature 463:653-656] that predicts Early Cenozoic surface currents periodically conducive to rafting or swimming from Africa, followed by a reconfiguration to present-day flow 15-20 million years ago that significantly diminished the ability for transoceanic dispersal to Madagascar from the adjacent mainland. PMID- 22431644 TI - Feline morbillivirus, a previously undescribed paramyxovirus associated with tubulointerstitial nephritis in domestic cats. AB - We describe the discovery and isolation of a paramyxovirus, feline morbillivirus (FmoPV), from domestic cat (Felis catus). FmoPV RNA was detected in 56 (12.3%) of 457 stray cats (53 urine, four rectal swabs, and one blood sample) by RT-PCR. Complete genome sequencing of three FmoPV strains showed genome sizes of 16,050 bases, the largest among morbilliviruses, because of unusually long 5' trailer sequences of 400 nt. FmoPV possesses identical gene contents (3'-N-P/V/C-M-F-H-L 5') and is phylogenetically clustered with other morbilliviruses. IgG against FmoPV N protein was positive in 49 sera (76.7%) of 56 RT-PCR-positive cats, but 78 (19.4%) of 401 RT-PCR-negative cats (P < 0.0001) by Western blot. FmoPV was isolated from CRFK feline kidney cells, causing cytopathic effects with cell rounding, detachment, lysis, and syncytia formation. FmoPV could also replicate in subsequent passages in primate Vero E6 cells. Infected cell lines exhibited finely granular and diffuse cytoplasmic fluorescence on immunostaining for FmoPV N protein. Electron microscopy showed enveloped virus with typical "herringbone" appearance of helical N in paramyxoviruses. Histological examination of necropsy tissues in two FmoPV-positive cats revealed interstitial inflammatory infiltrate and tubular degeneration/necrosis in kidneys, with decreased cauxin expression in degenerated tubular epithelial cells, compatible with tubulointerstitial nephritis (TIN). Immunohistochemical staining revealed FmoPV N protein-positive renal tubular cells and mononuclear cells in lymph nodes. A case-control study showed the presence of TIN in seven of 12 cats with FmoPV infection, but only two of 15 cats without FmoPV infection (P < 0.05), suggesting an association between FmoPV and TIN. PMID- 22431645 TI - Receptor-dependent and -independent immunomodulatory effects of phenol-soluble modulin peptides from Staphylococcus aureus on human neutrophils are abrogated through peptide inactivation by reactive oxygen species. AB - The virulence and pathogenesis mechanisms of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) strains depend on a newly described group of phenol-soluble modulin (PSM) peptides (the PSMalpha peptides) with cytolytic activity. These toxins are alpha-helical peptides with a formyl group at the N terminus, and they activate neutrophils through formyl peptide receptor 2 (FPR2), a function closely correlated to the capacity of staphylococcal species to cause invasive infections. The effects of two synthetic PSMalpha peptides were investigated, and we show that they utilize FPR2 and promote neutrophils to produce reactive oxygen species (ROS) which in turn trigger inactivation of the peptides. Independently of FPR2, the PSMalpha peptides also downregulate the neutrophil response to other stimuli and exert a cytolytic effect to which apoptotic neutrophils are more sensitive than viable cells. The novel immunomodulatory functions of the PSMalpha peptides were sensitive to ROS generated by the neutrophil myeloperoxidase (MPO)-H(2)O(2) system, suggesting a role for this enzyme system in counteracting bacterial virulence. PMID- 22431646 TI - Regulation of cytokine and chemokine expression by the ribotoxic stress response elicited by Shiga toxin type 1 in human macrophage-like THP-1 cells. AB - Shiga toxins (Stxs) are cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and Shiga toxin-producing Escherichia coli (STEC). Stxs bind to a membrane glycolipid receptor, enter cells, and undergo retrograde transport to ultimately reach the cytosol, where the toxins exert their protein synthesis-inhibitory activity by depurination of a single adenine residue from the 28S rRNA component of eukaryotic ribosomes. The depurination reaction activates the ribotoxic stress response, leading to signaling via the mitogen activated protein kinase (MAPK) pathways (Jun N-terminal protein kinase [JNK], p38, and extracellular signal-regulated kinase [ERK]) in human epithelial, endothelial, and myeloid cells. We previously showed that treatment of human macrophage-like THP-1 cells with Stxs resulted in increased cytokine and chemokine expression. In the present study, we show that individual inactivation of ERK, JNK, and p38 MAPKs using pharmacological inhibitors in the presence of Stx1 resulted in differential regulation of the cytokines tumor necrosis factor alpha and interleukin-1beta (IL-1beta) and chemokines IL-8, growth-regulated protein-beta, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta. THP-1 cells exposed to Stx1 upregulate the expression of select dual-specificity phosphatases (DUSPs), enzymes that dephosphorylate and inactivate MAPKs in mammalian cells. In this study, we confirmed DUSP1 protein production by THP-1 cells treated with Stx1. DUSP1 inhibition by triptolide showed that ERK and p38 phosphorylation is regulated by DUSP1, while JNK phosphorylation is not. Inhibition of p38 MAPK signaling blocked the ability of Stx1 to induce DUSP1 mRNA expression, suggesting that an autoregulatory signaling loop may be activated by Stxs. Thus, Stxs appear to be capable of eliciting signals which both activate and deactivate signaling for increased cytokine/chemokine production in human macrophage-like cells. PMID- 22431647 TI - Multigene families in Trypanosoma cruzi and their role in infectivity. AB - The Trypanosoma cruzi genome contains the most widely expanded content (~12,000 genes) of the trypanosomatids sequenced to date. This expansion is reflected in the high number of repetitive sequences and particularly in the large quantity of genes that make up its multigene families. Recently it was discovered that the contents of these families vary between phylogenetically unrelated strains. We review the basic characteristics of trans-sialidases and mucins as part of the mechanisms of immune evasion of T. cruzi and as ligands and factors involved in the cross talk between the host cell and the parasite. We also show recently published data describing two new multigene families, DGF-1 and MASP, that form an important part of the scenario representing the complex biology of T. cruzi. PMID- 22431648 TI - Mycobacterium tuberculosis lacking all mycolic acid cyclopropanation is viable but highly attenuated and hyperinflammatory in mice. AB - Mycolic acids, the major lipid of the Mycobacterium tuberculosis cell wall, are modified by cyclopropane rings, methyl branches, and oxygenation through the action of eight S-adenosylmethionine (SAM)-dependent mycolic acid methyltransferases (MAMTs), encoded at four genetic loci. Mycolic acid modification has been shown to be important for M. tuberculosis pathogenesis, in part through effects on the inflammatory activity of trehalose dimycolate (cord factor). Studies using the MAMT inhibitor dioctylamine have suggested that the MAMT enzyme class is essential for M. tuberculosis viability. However, it is unknown whether a cyclopropane-deficient strain of M. tuberculosis would be viable and what the effect of cyclopropane deficiency on virulence would be. We addressed these questions by creating and characterizing M. tuberculosis strains lacking all functional MAMTs. Our results show that M. tuberculosis is viable either without cyclopropanation or without cyclopropanation and any oxygenated mycolates. Characterization of these strains revealed that MAMTs are required for acid fastness and resistance to detergent stress. Complete lack of cyclopropanation confers severe attenuation during the first week after aerosol infection of the mouse, whereas complete loss of MAMTs confers attenuation in the second week of infection. Characterization of immune responses to the cyclopropane- and MAMT-deficient strains indicated that the net effect of mycolate cyclopropanation is to dampen host immunity. Taken together, our findings establish the immunomodulatory function of the mycolic acid modification pathway in pathogenesis and buttress this enzyme class as an attractive target for antimycobacterial drug development. PMID- 22431649 TI - The recall response induced by genital challenge with Chlamydia muridarum protects the oviduct from pathology but not from reinfection. AB - The significant morbidities of ectopic pregnancy and infertility observed in women after Chlamydia trachomatis genital infection result from ascension of the bacteria from the endocervix to the oviduct, where an overly aggressive inflammatory response leads to chronic scarring and Fallopian tube obstruction. A vaccine to prevent chlamydia-induced disease is urgently needed. An important question for vaccine development is whether sterilizing immunity at the level of the oviduct is essential for protection because of the possibility that a chlamydial component drives a deleterious anamnestic T cell response upon oviduct reinfection. We show that mice inoculated with attenuated plasmid-cured strains of Chlamydia muridarum are protected from oviduct pathology upon challenge with wild-type C. muridarum Nigg despite induction of a response that did not prevent reinfection of the oviduct. Interestingly, repeated abbreviated infections with Nigg also elicited recall responses that protected the oviduct from pathology despite low-level reinfection of this vulnerable tissue site. Challenged mice displayed significant decreases in tissue infiltration of inflammatory leukocytes with marked reductions in frequencies of neutrophils but significant increases in frequencies of CD4 Th1 and CD8 T cells. An anamnestic antibody response was also detected. These data indicate that exposure to a live attenuated chlamydial vaccine or repeated abbreviated genital infection with virulent chlamydiae promotes anamnestic antibody and T cell responses that protect the oviduct from pathology despite a lack of sterilizing immunity at the site. PMID- 22431650 TI - PmpG303-311, a protective vaccine epitope that elicits persistent cellular immune responses in Chlamydia muridarum-immune mice. AB - Urogenital Chlamydia serovars replicating in reproductive epithelium pose a unique challenge to host immunity and vaccine development. Previous studies have shown that CD4 T cells are necessary and sufficient to clear primary Chlamydia muridarum genital tract infections in the mouse model, making a protective CD4 T cell response a logical endpoint for vaccine development. Our previous proteomics studies identified 13 candidate Chlamydia proteins for subunit vaccines. Of those, PmpG-1 is the most promising vaccine candidate. To further that work, we derived a PmpG(303-311)-specific multifunctional Th1 T cell clone, designated PmpG1.1, from an immune C57BL/6 mouse and used it to investigate the presentation of the PmpG(303-311) epitope by infected epithelial cells. Epithelial presentation of the PmpG(303-311) epitope required bacterial replication, occurred 15 to 18 h postinfection, and was unaffected by gamma interferon (IFN gamma) pretreatment. Unlike epitopes recognized by other Chlamydia-specific CD4 T cell clones, the PmpG(303-311) epitope persisted on splenic antigen-presenting cells (APC) of mice that cleared primary genital tract infections. PmpG1.1 was activated by unmanipulated irradiated splenocytes from immune mice without addition of exogenous Chlamydia antigen, and remarkably, activation of PmpG1.1 by unmanipulated immune splenocytes was stronger 6 months postinfection than it was 3 weeks postinfection. Enhanced presentation of PmpG(303-311) epitope on splenic APC 6 months postinfection reflects some type of "consolidation" of a protective immune response. Understanding the antigen-presenting cell populations responsible for presenting PmpG(303-311) early (3 weeks) and late (6 months) postinfection will likely provide important insights into stable protective immunity against Chlamydia infections of the genital tract. PMID- 22431651 TI - Extrahepatic exoerythrocytic forms of rodent malaria parasites at the site of inoculation: clearance after immunization, susceptibility to primaquine, and contribution to blood-stage infection. AB - Plasmodium sporozoites are inoculated into the skin of the mammalian host as infected mosquitoes probe for blood. A proportion of the inoculum enters the bloodstream and goes to the liver, where the sporozoites invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic, or liver, stage. Here, we show that a small fraction of the inoculum remains in the skin and begins to develop into exoerythrocytic forms that can persist for days. Skin exoerythrocytic forms were observed for both Plasmodium berghei and Plasmodium yoelii, two different rodent malaria parasites, suggesting that development in the skin of the mammalian host may be a common property of plasmodia. Our studies demonstrate that skin exoerythrocytic stages are susceptible to destruction in immunized mice, suggesting that their aberrant location does not protect them from the host's adaptive immune response. However, in contrast to their hepatic counterparts, they are not susceptible to primaquine. We took advantage of their resistance to primaquine to test whether they could initiate a blood-stage infection directly from the inoculation site, and our data indicate that these stages are not able to initiate malaria infection. PMID- 22431652 TI - Toll-like receptor 2 ligand pretreatment attenuates retinal microglial inflammatory response but enhances phagocytic activity toward Staphylococcus aureus. AB - Staphylococcus aureus is a leading cause of severe endophthalmitis, which often results in vision loss in some patients. Previously, we showed that Toll-like receptor 2 (TLR2) ligand pretreatment prevented the development of staphylococcal endophthalmitis in mice and suggested that microglia might be involved in this protective effect (Kumar A, Singh CN, Glybina IV, Mahmoud TH, Yu FS. J. Infect. Dis. 201:255-263, 2010). The aim of the present study was to understand how microglial innate response is modulated by TLR2 ligand pretreatment. Here, we demonstrate that S. aureus infection increased the CD11b(+) CD45(+) microglial/macrophage population in the C57BL/6 mouse retina. Using cultured primary retinal microglia and a murine microglial cell line (BV-2), we found that these cells express TLR2 and that its expression is increased upon stimulation with bacteria or an exclusive TLR2 ligand, Pam3Cys. Furthermore, challenge of primary retinal microglia with S. aureus and its cell wall components peptidoglycan (PGN) and lipoteichoic acid (LTA) induced the secretion of proinflammatory mediators (tumor necrosis factor alpha [TNF-alpha] and MIP-2). This innate response was attenuated by a function-blocking anti-TLR2 antibody or by small interfering RNA (siRNA) knockdown of TLR2. In order to assess the modulation of the innate response, microglia were pretreated with a low dose (0.1 or 1 MUg/ml) of Pam3Cys and then challenged with live S. aureus. Our data showed that S. aureus-induced production of proinflammatory mediators is dramatically reduced in pretreated microglia. Importantly, microglia pretreated with the TLR2 agonist phagocytosed significantly more bacteria than unstimulated cells. Together, our data suggest that TLR2 plays an important role in retinal microglial innate response to S. aureus, and its sensitization inhibits inflammatory response while enhancing phagocytic activity. PMID- 22431653 TI - Giant superior vena caval aneurysm in a post-Glenn patient. AB - Aneurysms of mediastinal systemic veins are extremely rare, usually asymptomatic and incidentally diagnosed during chest radiography. We describe the case of a giant superior vena caval aneurysm in a 14-year old male following Glenn surgery and discuss its complications and management. PMID- 22431654 TI - Are intracostal sutures better than pericostal sutures for closing a thoracotomy? AB - A best evidence topic was written according to a structured protocol. The question addressed was to identify which thoracotomy closure method lends itself to the least postoperative pain. Altogether 109 papers were found using the reported search; of which, seven represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that the closure by intracostal sutures with intercostal nerve sparing offers a superior postoperative pain profile for thoracotomy patients when compared with conventional techniques. Up to 1-year follow-up has shown that this technique (avoiding strangulation of the intercostal nerve) leads to lower postoperative pain and analgesic use, better ambulation and a quicker return to daily activities. Three papers (including two randomized trials) found intracostal sutures with intercostal nerve sparing techniques to be superior to conventional methods such as pericostal suture closure. Rib approximation with intercostal nerve sparing was found to be superior to rib approximation without nerve sparing in one study. Two studies associated with the creation of an intercostal muscle flap prior to the insertion of a rib retractor to be associated with significantly reduced postoperative pain. One study described a novel 'edge-closure' technique, comparable to the closure with intracostal sutures without drilling, to be superior to conventional closure with pericostal sutures. Postoperative pain is a significant issue faced by thoracic surgeons both in-hospital and in the longer term where patients may complain of chronic thoracotomy pain. We would therefore recommend that some form of intercostal nerve protection be implemented during thoracotomy opening and closure. PMID- 22431655 TI - Diagnosis and management of primary hyperparathyroidism. PMID- 22431656 TI - How the low carbon economy can improve health. PMID- 22431657 TI - The health impacts of climate change. PMID- 22431658 TI - Climate change and resource security. PMID- 22431659 TI - Politics and policies: making change happen. PMID- 22431660 TI - Climate change: what needs to be done. PMID- 22431661 TI - Health risks, present and future, from global climate change. PMID- 22431662 TI - Emergency contraception. PMID- 22431663 TI - Contraction and convergence: the best possible solution to the twin problems of climate change and inequity. PMID- 22431664 TI - Members are split on how Royal College of Physicians should proceed on health bill. PMID- 22431665 TI - Additional 7000 UK women may have faulty PIP implants. PMID- 22431666 TI - Final attempts are made to stop and amend the health bill. PMID- 22431667 TI - Personal health budgets may be spent on "laptops and travel passes". PMID- 22431668 TI - Bill to reform libel law and allow more free debate is expected in next parliament. PMID- 22431671 TI - Trial is started to see whether gene therapy can improve lung function in cystic fibrosis. PMID- 22431669 TI - Mutations in the protease gene associated with virological failure to lopinavir/ritonavir-containing regimens. AB - OBJECTIVES: To assess the most frequent resistance-associated mutations (RAMs) to lopinavir/ritonavir in a cohort of patients attended in daily practice. METHODS: We retrospectively identified 195 multitreated subjects with virological failure. Patients were classified as follows: (i) 71 (36.4%) never received lopinavir/ritonavir (lopinavir/ritonavir naive); (ii) 75 (38.5%) had previously failed on lopinavir/ritonavir; and (iii) 49 (25.1%) were on lopinavir/ritonavir at failure. RAM patterns were assessed. Medians, IQRs, percentages, Kruskal Wallis, chi(2) or Fisher's exact test, and multinomial logistic regression were used whenever appropriate. RESULTS: L10I/F, K20R, L24I, L33F, M36I, M46I/L, I47V, G48V, F53L, I54V, A71V, G73S, V82A, I84V and L90M (all with P <= 0.037) were protease RAMs overexpressed in patients with lopinavir/ritonavir failure. L10I, M36I, M46I, I54V, L63P, A71V, V82A, I84V and L90M were the most common in lopinavir/ritonavir-naive patients. Other IAS-USA RAMs for lopinavir/ritonavir (L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, A71T, L76V and V82F/T/S) were not associated with previous or current failure to lopinavir/ritonavir. Lopinavir/ritonavir failure was associated with the number of protease RAMs (OR = 1.146, 95% CI = 1.287, 1.626), higher exposure to protease inhibitors, and the presence of E44D, L33F, I54V and I84V. CONCLUSIONS: In multitreated patients with previous or current lopinavir/ritonavir failure, some protease mutations are selected at significantly greater rates. L10I, M36I, I54V, L63P, A71V, V82A and L90M were found in >50% of cases. Thus, their presence should be expected when genotypic testing results are not available. The number of protease RAMs and higher prior exposures to protease inhibitors were significantly associated with lopinavir/ritonavir failure. PMID- 22431672 TI - Intervention is urgently needed to prevent humanitarian catastrophe on Sudan's border. PMID- 22431673 TI - Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. AB - BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. OBJECTIVE: To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. DESIGN: A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231) SETTING: 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. PATIENTS: 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. INTERVENTION: Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. MEASUREMENTS: The primary outcome was change in hemoglobin A(1c) from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. RESULTS: 800 patients were analyzed. After 24 weeks, mean hemoglobin A(1c) decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo (mean difference, -0.40% [95% CI, -0.54% to -0.25%] in the 2.5-mg group, 0.49% [CI, -0.65% to -0.34%] in the 5-mg group, and -0.57% [CI, -0.72% to -0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5 mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, 1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to 1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events suggesting genital infection (9.0% vs. 2.5%), and events suggesting urinary tract infection (9.7% vs. 5.1%). LIMITATION: Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. CONCLUSION: Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus. PRIMARY FUNDING SOURCE: AstraZeneca and Bristol-Myers Squibb. PMID- 22431674 TI - Peer mentoring and financial incentives to improve glucose control in African American veterans: a randomized trial. AB - BACKGROUND: Compared with white persons, African Americans have a greater incidence of diabetes, decreased control, and higher rates of microvascular complications. A peer mentorship model could be a scalable approach to improving control in this population and reducing disparities in diabetic outcomes. OBJECTIVE: To determine whether peer mentors or financial incentives are superior to usual care in helping African American veterans decrease their hemoglobin A(1c) (HbA(1c)) levels. DESIGN: A 6-month randomized, controlled trial. (ClinicalTrials.gov registration number: NCT01125956) SETTING: Philadelphia Veterans Affairs Medical Center. PATIENTS: African American veterans aged 50 to 70 years with persistently poor diabetes control. INTERVENTION: 118 patients were randomly assigned to 1 of 3 groups: usual care, a peer mentoring group, and a financial incentives group. Usual care patients were notified of their starting HbA(1c) level and recommended goals for HbA(1c). Those in the peer mentoring group were assigned a mentor who formerly had poor glycemic control but now had good control (HbA(1c) level <=7.5%). The mentor was asked to talk with the patient at least once per week. Peer mentors were matched by race, sex, and age. Patients in the financial incentive group could earn $100 by decreasing their HbA(1c) level by 1% and $200 by decreasing it by 2% or to an HbA(1c) level of 6.5%. MEASUREMENTS: Change in HbA(1c) level at 6 months. RESULTS: Mentors and mentees talked the most in the first month (mean calls, 4; range, 0 to 30), but calls decreased to a mean of 2 calls (range, 0 to 10) by the sixth month. Levels of HbA(1c) decreased from 9.9% to 9.8% in the control group, from 9.8% to 8.7% in the peer mentor group, and from 9.5% to 9.1% in the financial incentive group. Mean change in HbA(1c) level from baseline to 6 months relative to control was 1.07% (95% CI, -1.84% to -0.31%) in the peer mentor group and -0.45% (CI, -1.23% to 0.32%) in the financial incentive group. LIMITATION: The study included only veterans and lasted only 6 months. CONCLUSION: Peer mentorship improved glucose control in a cohort of African American veterans with diabetes. PRIMARY FUNDING SOURCE: National Institute on Aging Roybal Center. PMID- 22431675 TI - Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. AB - BACKGROUND: Serum 25-hydroxyvitamin D (25-[OH]D) is considered the best biomarker of clinical vitamin D status. OBJECTIVE: To determine the effect of increasing oral doses of vitamin D(3) on serum 25-(OH)D and serum parathyroid hormone (PTH) levels in postmenopausal white women with vitamin D insufficiency (defined as a 25-[OH]D level <=50 nmol/L) in the presence of adequate calcium intake. These results can be used as a guide to estimate the Recommended Dietary Allowance (RDA) (defined as meeting the needs of 97.5% of the population) for vitamin D(3). DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00472823) SETTING: Creighton University Medical Center, Omaha, Nebraska. PARTICIPANTS: 163 healthy postmenopausal white women with vitamin D insufficiency enrolled in the winter or spring of 2007 to 2008 and followed for 1 year. INTERVENTION: Participants were randomly assigned to receive placebo or vitamin D(3), 400, 800, 1600, 2400, 3200, 4000, or 4800 IU once daily. Daily calcium supplements were provided to increase the total daily calcium intake to 1200 to 1400 mg. MEASUREMENTS: The primary outcomes were 25-(OH)D and PTH levels at 6 and 12 months. RESULTS: The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D(3). The RDA of vitamin D(3) to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d. A mixed effects model predicted that 600 IU of vitamin D(3) daily could also meet this goal. Compared with participants with a normal body mass index (<25 kg/m(2)), obese women (>=30 kg/m(2)) had a 25-(OH)D level that was 17.8 nmol/L lower. Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D(3) (P = 0.012). Depending on the criteria used, hypercalcemia occurred in 2.8% to 9.0% and hypercalciuria in 12.0% to 33.0% of participants; events were unrelated to dose. LIMITATION: Findings may not be generalizable to other age groups or persons with substantial comorbid conditions. CONCLUSION: A vitamin D(3) dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5% of women; however, a model predicted the same response with a vitamin D(3) dosage of 600 IU/d. These results can be used as a guide for the RDA of vitamin D(3), but prospective trials are needed to confirm the clinical significance of these results. PRIMARY FUNDING SOURCE: National Institute on Aging. PMID- 22431676 TI - Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study. AB - BACKGROUND: Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear. OBJECTIVE: To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions. DESIGN: Prospective population-based study. SETTING: The Rotterdam Study, Rotterdam, the Netherlands. PARTICIPANTS: 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]). MEASUREMENTS: Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, carotid intima-media thickness, peripheral arterial disease, and pulse wave velocity). RESULTS: Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in predictions with other newer markers were marginal. LIMITATION: The findings may not be generalizable to younger or nonwhite populations. CONCLUSION: Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score screening as a more routine test for risk prediction requires full consideration of the financial and clinical costs of performing versus not performing the test for both persons and health systems. PRIMARY FUNDING SOURCE: Netherlands Organization for Health Research and Development (ZonMw). PMID- 22431677 TI - Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta analysis. AB - BACKGROUND: Antiplatelet agents are used to prevent cardiovascular events; however, treatment effects may differ in persons with chronic kidney disease (CKD) because atherosclerotic disease is less prevalent, whereas bleeding hazards may be increased in this population. PURPOSE: To summarize the effects of antiplatelet treatment on cardiovascular events, mortality, and bleeding in persons with CKD. DATA SOURCES: Embase and Cochrane databases through November 2011 without language restriction. STUDY SELECTION: Randomized trials that included adults with CKD and compared antiplatelet agents with standard care, placebo, or no treatment. DATA EXTRACTION: Data for populations, interventions, outcomes, and risk for bias were extracted. Quality of evidence for treatment effects on myocardial infarction, death, and bleeding was summarized by using Grading of Recommendations Assessment, Development, and Evaluation guidelines. DATA SYNTHESIS: Nine trials (all post hoc subgroup analyses for CKD) involving 9969 persons who had acute coronary syndromes or were undergoing percutaneous coronary intervention and 31 trials involving 11,701 persons with stable or no cardiovascular disease were identified. Low-quality evidence has found that in persons with acute coronary syndromes, glycoprotein IIb/IIIa inhibitors or clopidogrel plus standard care compared with standard care alone had little or no effect on all-cause or cardiovascular mortality or on myocardial infarction but increased serious bleeding. Compared with placebo or no treatment in persons with stable or no cardiovascular disease, antiplatelet agents prevented myocardial infarction but had uncertain effects on mortality and increased minor bleeding according to generally low-quality evidence. LIMITATIONS: Data for antiplatelet agents in persons with CKD are frequently derived from post hoc analyses of trials of broader populations. Definitions for bleeding outcomes and trial duration were heterogeneous. CONCLUSION: Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards. PRIMARY FUNDING SOURCE: None. PMID- 22431678 TI - Still uncertain about sodium-glucose cotransporter inhibitors despite 2 centuries of study. PMID- 22431679 TI - Framework for evaluating novel risk markers. PMID- 22431680 TI - Hard labor. PMID- 22431681 TI - A doctor's response to torture. PMID- 22431682 TI - Venous thromboembolism prophylaxis in hospitalized medical patients. PMID- 22431683 TI - Venous thromboembolism prophylaxis in hospitalized medical patients. PMID- 22431684 TI - Venous thromboembolism prophylaxis in hospitalized medical patients. PMID- 22431685 TI - Occupational syphilis following scalpel injury. PMID- 22431686 TI - Summaries for patients: Dapagliflozin treatment in patients with inadequately controlled type 2 diabetes despite the use of insulin. PMID- 22431687 TI - Summaries for patients: Peer mentoring and financial incentives to improve glucose control in African American veterans. PMID- 22431688 TI - ACP Journal Club. Earlier initiation of antiretroviral therapy after start of antituberculosis therapy reduced mortality in HIV. PMID- 22431689 TI - ACP Journal Club. Less-frequent warfarin dose assessment was noninferior for patients with stable INRs. PMID- 22431690 TI - ACP Journal Club. Meta-analysis: adjuvant tamoxifen reduces recurrence and death at 15 years in ER-positive early breast cancer. PMID- 22431691 TI - ACP Journal Club. Simvastatin reduced major vascular events at 5 years in at-risk patients; benefits were maintained at 11 years. PMID- 22431692 TI - ACP Journal Club. Review: Statins do not increase risk for intracerebral hemorrhage. PMID- 22431693 TI - ACP Journal Club. Review: Long-term use of inhaled corticosteroids increases fracture risk in COPD. PMID- 22431694 TI - ACP Journal Club. Screening with chest radiography did not reduce lung cancer mortality in older patients. PMID- 22431695 TI - ACP Journal Club. Targeting management of fever, hyperglycemia, and swallowing improved outcomes in acute stroke. PMID- 22431696 TI - ACP Journal Club. In-person or remote behavioral interventions for obesity were better than a self-directed approach. PMID- 22431697 TI - ACP Journal Club. Enhanced brief lifestyle counseling for obesity was better than usual care for weight loss at 2 years. PMID- 22431698 TI - ACP Journal Club. Ibuprofen plus acetaminophen reduced knee pain in the short term more than acetaminophen but not ibuprofen. PMID- 22431699 TI - ACP Journal Club. Review: Short-course antibiotics in hospital-acquired pneumonia do not affect mortality. PMID- 22431700 TI - A case-control study examining whether neurological deficits and PTSD in combat veterans are related to episodes of mild TBI. AB - BACKGROUND: Mild traumatic brain injury (mTBI) is a common injury among military personnel serving in Iraq or Afghanistan. The impact of repeated episodes of combat mTBI is unknown. OBJECTIVE: To evaluate relationships among mTBI, post traumatic stress disorder (PTSD) and neurological deficits (NDs) in US veterans who served in Iraq or Afghanistan. METHODS: This was a case-control study. From 2091 veterans screened for traumatic brain injury, the authors studied 126 who sustained mTBI with one or more episodes of loss of consciousness (LOC) in combat. Comparison groups: 21 combat veterans who had definite or possible episodes of mTBI without LOC and 21 veterans who sustained mTBI with LOC as civilians. RESULTS: Among combat veterans with mTBI, 52% had NDs, 66% had PTSD and 50% had PTSD and an ND. Impaired olfaction was the most common ND, found in 65 veterans. The prevalence of an ND or PTSD correlated with the number of mTBI exposures with LOC. The prevalence of an ND or PTSD was >90% for more than five episodes of LOC. Severity of PTSD and impairment of olfaction increased with number of LOC episodes. The prevalence of an ND for the 34 combat veterans with one episode of LOC (4/34=11.8%) was similar to that of the 21 veterans of similar age and educational background who sustained civilian mTBI with one episode of LOC (2/21=9.5%, p-NS). CONCLUSIONS: Impaired olfaction was the most frequently recognised ND. Repeated episodes of combat mTBI were associated with increased likelihood of PTSD and an ND. Combat setting may not increase the likelihood of an ND. Two possible connections between mTBI and PTSD are (1) that circumstances leading to combat mTBI likely involve severe psychological trauma and (2) that altered cerebral functioning following mTBI may increase the likelihood that a traumatic event results in PTSD. PMID- 22431701 TI - FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial. AB - BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer. PMID- 22431702 TI - Pegylated liposomal doxorubicin plus carboplatin in patients with metastatic breast cancer: a phase II study. AB - BACKGROUND: We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin). PATIENTS AND METHODS: Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor 2 status. TREATMENT: PLD 30 mg/m(2) followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab. RESULTS: Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3-4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; and fatigue 2%, 14%, 13%. CONCLUSIONS: PLD plus carboplatin has moderate antitumor activity and excellent tolerability. Herceptin and PLD plus carboplatin in HER2-positive patients have antitumor activity without significant cardiac toxicity. Toxicity results suggest that PLD can be combined with Herceptin with minimal cardiac toxicity. PMID- 22431703 TI - Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). AB - BACKGROUND: This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. METHODS: This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( +/- resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. RESULTS: The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2-73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1-70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42-0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7-22.1) and 9.9 months (95% CI 9.3-13.7), respectively. CONCLUSIONS: This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain. PMID- 22431704 TI - Characterization and quantification of proliferating cell patterns in endocapillary proliferation. AB - BACKGROUND: Endocapillary proliferation (EP) is a common pathological finding in proliferative glomerulonephritis (GN). Its appearance indicates the presence of active lesions of GN. In this study, we reinvestigated the pathological features of EP. METHODS: Cell markers that included CD15, CD68, CD45RO, CD31 and alpha smooth muscle actin (alpha-SMA) were used to identify the intraglomerular cells in renal biopsy tissues collected from patients with post-streptococcal acute GN (PSAGN), methicillin-resistant Staphylococcus aureus-associated GN (MRSAGN) with or without EP, membranoproliferative GN (MPGN) with or without EP, Henoch Schonlein nephritis, immunoglobulin A nephropathy, membranous nephropathy and minimal change nephrotic syndrome. Proliferating cells and apoptotic cells were investigated simultaneously. RESULTS: The glomerular infiltrating polymorphonuclear leukocytes, macrophages, T cells, mesangial cells and endothelial cells were enumerated. In PSAGN, the glomerulus was enlarged and all cell types were greatly increased. In MRSAGN EP, the glomerulus was slightly enlarged with abundant infiltrating leukocytes and monocyte/macrophages and had moderate mesangial cell proliferation with negligible endothelial cell proliferation. In MPGN, the glomerulus markedly enlarged with multiple monocyte/macrophages and remarkable mesangial proliferation. The mesangial cells in EP glomeruli were highly activated as evidenced by alpha-SMA expression, particularly in PSAGN. CONCLUSIONS: This is the first report to use monoclonal antibodies specific for cell markers to quantitatively analyze and compare the proliferating cell types in EP glomeruli in different forms of GN. The results suggest that identification of the presence of polymorphonuclear leukocytes in the capillary lumen might help in differentiating between glomerular global and segmental EP. PMID- 22431705 TI - Saquinavir in steroid-dependent and -resistant nephrotic syndrome: a pilot study. AB - BACKGROUND: Some difficult cases of idiopathic nephrotic syndrome (NS) have been treated with a HIV protease inhibitor provided with proteasome-inhibiting activity. The objective of this study was to limit nuclear factor kappaB (NF kappaB) activation which is up-regulated in these patients, aiming at decreasing proteinuria and prednisone need. METHODS: Ten cases with long-lasting (up to 15 years) history of NS with steroid dependence (six cases, of which three with secondary steroid resistance) or resistance to steroids (four cases) unsuccessfully treated with multiple immunosuppressive drugs, accepted a treatment with the protease inhibitor saquinavir. p50/p65 NF-kappaB nuclear localization and immunoproteasome/proteasome messenger RNA (mRNA) were monitored in peripheral blood mononuclear cells (PBMCs). The effects of saquinavir on NF kappaB nuclear localization in cultured PBMCs and in immortalized human podocytes were assessed. RESULTS: After a median follow-up of 14.7 months (6-68.7), 1/4 primary steroid-resistant NS (SRNS) and 5/6 steroid-dependent NS or secondary SRNS became infrequent (5) or frequent (1) relapsers, with 63% prednisone reduction (from 25.3 to 8.4 mg/kg/month, P = 0.015). Saquinavir was effective in association with low doses of calcineurin inhibitors (cyclosporine 2 mg/kg/day or tacrolimus 0.01-0.06 mg/kg/day). No side effects were observed apart from transitory mild diarrhoea. In PBMCs, NF-kappaB was down-regulated, while MECL-1 immunoproteasome/beta2 proteasome mRNA ratio was reversed to normal values. In culture, saquinavir blunted NF-kappaB activation in human podocytes and in PBMCs. CONCLUSIONS: In this pilot study, a HIV antiprotease drug reduced proteinuria and had a steroid-sparing effect in some multidrug-resistant/-dependent NS. This observation warrants further investigation. PMID- 22431706 TI - Role of vitamin D in vascular calcification: bad guy or good guy? PMID- 22431707 TI - High salt intake causes adverse fetal programming--vascular effects beyond blood pressure. AB - BACKGROUND: High salt intake causes hypertension, adverse cardiovascular outcomes and potentially also blood pressure (BP)-independent target organ damage. Excess salt intake in pregnancy is known to affect BP in the offspring. The present study was designed to assess whether high salt intake in pregnancy affects BP and vascular morphology in the offspring. METHODS: Sprague-Dawley rats were fed a standard rodent diet with low-normal (0.15%) or high (8.0%) salt content during pregnancy and lactation. After weaning at 4 weeks of age, offspring were maintained on the same diet or switched to a high- or low-salt diet, respectively. Vascular geometry was assessed in male offspring at 7 and 12 weeks postnatally. RESULTS: Up to 12 weeks of age, there was no significant difference in telemetrically measured BP between the groups of offspring. At 12 weeks of age, wall thickness of central (aorta, carotid), muscular (mesenteric) and intrapulmonary arteries was significantly higher in offspring of mothers on a high-salt diet irrespective of the post-weaning diet. This correlated with increased fibrosis of the aortic wall, more intense nitrotyrosine staining as well as elevated levels of marinobufagenin (MBG) and asymmetric dimethyl arginine (ADMA). CONCLUSIONS: High salt intake in pregnant rats has long-lasting effects on the modeling of central and muscular arteries in the offspring independent of postnatal salt intake and BP. Circulating MBG and ADMA and local oxidative stress correlate with the adverse vascular modeling. PMID- 22431708 TI - Longer dialysis session length is associated with better intermediate outcomes and survival among patients on in-center three times per week hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). AB - BACKGROUND: Longer dialysis session length (treatment time, TT) has been associated with better survival among hemodialysis (HD) patients. The impact of TT on clinical markers that may contribute to this survival advantage is not well known. METHODS: Using data from the international Dialysis Outcomes and Practice Patterns Study, we assessed the association of TT with clinical outcomes using both standard regression analyses and instrumental variable approaches. The study included 37,414 patients on in-center HD three times per week with prescribed TT from 120 to 420 min. RESULTS: Facility mean TT ranged from 214 min in the USA to 256 min in Australia-New Zealand. Accounting for country effects, mortality risk was lower for patients with longer TT {hazard ratio for every 30 min: all-cause mortality: 0.94 [95% confidence interval (CI): 0.92-0.97], cardiovascular mortality: 0.95 (95% CI: 0.91-0.98) and sudden death: 0.93 (95% CI: 0.88-0.98)}. Patients with longer TT had lower pre- and post-dialysis systolic blood pressure, greater intradialytic weight loss, higher hemoglobin (for the same erythropoietin dose), serum albumin and potassium and lower serum phosphorus and white blood cell counts. Similar associations were found using the instrumental variable approach, although the positive associations of TT with weight loss and potassium were lost. CONCLUSIONS: Favorable levels of a variety of clinical markers may contribute to the better survival of patients receiving longer TT. These findings support longer TT prescription in the setting of in-center, three times per week HD. PMID- 22431709 TI - Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension. PMID- 22431710 TI - Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival. AB - Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G(1) phase cell-cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Notably, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin-null mouse model exhibited increased levels of cyclin D1, VEGF receptor, and Akt phosphorylation, and divided significantly faster when compared with wild-type cells, with suppression of these changes following parkin reintroduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of patients with glioma. Taken together, our study provides mechanistic insight into the tumor suppressor function of parkin in brain tumors and suggests that measurement of parkin pathway activation may be used clinically as a prognostic tool in patients with brain tumor. PMID- 22431711 TI - Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death. AB - Cancer cells are long known to exhibit increased aerobic glycolysis, but glycolytic inhibition has not offered a viable chemotherapeutic strategy in part because of the systemic toxicity of antiglycolytic agents. However, recent studies suggest that a combined inhibition of glycolysis and mitochondrial function may help overcome this issue. In this study, we investigated the chemotherapeutic efficacies of mitochondria-targeted drugs (MTD) in combination with 2-deoxy-d-glucose (2-DG), a compound that inhibits glycolysis. Using the MTDs, termed Mito-CP and Mito-Q, we evaluated relative cytotoxic effects and mitochondrial bioenergetic changes in vitro. Interestingly, both Mito-CP and Mito Q synergized with 2-DG to decrease ATP levels in two cell lines. However, with time, the cellular bioenergetic function and clonogenic survival were largely restored in some cells. In a xenograft model of human breast cancer, combined treatment of Mito-CP and 2-DG led to significant tumor regression in the absence of significant morphologic changes in kidney, liver, or heart. Collectively, our findings suggest that dual targeting of mitochondrial bioenergetic metabolism with MTDs and glycolytic inhibitors such as 2-DG may offer a promising chemotherapeutic strategy. PMID- 22431712 TI - Safety of a novel microneedle device applied to facial skin: a subject- and rater blinded, sham-controlled, randomized trial. AB - OBJECTIVE: To assess the safety of a novel microneedle device on facial skin of healthy individuals of all Fitzpatrick skin types. DESIGN: Subject- and live rater-blinded, sham-controlled, randomized trial. SETTING: University-based ambulatory dermatology service providing both primary and referral care. PARTICIPANTS: Healthy adults recruited from postings. INTERVENTION: Device or sham applied with finger pressure to the right or left sides, respectively, of the participants' lateral forehead, temple, and nasolabial fold. At the 24-hour visit, a larger area (3 * 3 matrix) at the central forehead was treated with the device, and the participants applied the device to their chins. MAIN OUTCOME MEASURE: Live blinded rater determination of local skin reaction scores (SRSs). RESULTS: At the 5-minute skin assessment, the median SRS was 1 for all skin type and age groups. There was no median pain score higher than 1 for any age or skin type group. For the sham device, median SRSs were 0 at all time points for all age and skin type groups. Mean SRSs for the device and sham were significantly different only for the lateral forehead at 5 and 30 minutes (P = .04). CONCLUSIONS: The microneedle device appears to be safe and well tolerated in both sexes and various skin types and ages. Facial skin application of the device elicits mild, self-limited, and rapidly resolving erythema marginally greater than that associated with the sham control. PMID- 22431713 TI - Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. AB - BACKGROUND: The development of a novel BRAF inhibitor, vemurafenib, has been associated with impressive tumor regression in patients with BRAF-positive stage IV melanoma. In the phase 3 clinical trials, dermatologic toxic effects associated with vemurafenib were described, namely, the development of eruptive squamous cell carcinomas. Herein, 3 cases are presented that highlight the development of squamous cell carcinomas and other cutaneous sequelae that have not been previously reported and are reminiscent of those observed with administration of the multikinase inhibitor sorafenib tosylate. In addition, the current understanding of the molecular mechanisms underlying these toxic effects is reviewed. OBSERVATIONS: The development of keratosis pilaris-like eruptions; seborrheic dermatitis-like rashes; and hyperkeratotic, tender plantar papules reminiscent of those seen in sorafenib-associated hand-foot skin reaction, as well as squamous cell carcinomas, is presented in association with vemurafenib based treatment of metastatic melanoma. CONCLUSIONS: The development of sorafenib like cutaneous sequelae (squamous cell carcinomas, keratosis pilaris-like eruptions, seborrheic dermatitis-like rashes, and hand-foot skin reaction) associated with vemurafenib administration suggests that BRAF inhibition alone may be sufficient to induce these changes. PMID- 22431714 TI - Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. AB - BACKGROUND: Deficiency of interleukin 1 receptor antagonist (DIRA) is a recently described autoinflammatory syndrome of skin and bone caused by recessive mutations in the gene encoding the interleukin 1 receptor antagonist. Few studies have been published about this debilitating condition. Early identification is critical for targeted lifesaving intervention. OBSERVATIONS: A male infant, born to nonconsanguineous Puerto Rican parents, was referred for management of a pustular eruption diagnosed as pustular psoriasis. At 2 months of age, the infant developed a pustular eruption. After extensive evaluation, he was confirmed to be homozygous for a 175-kb genomic deletion on chromosome 2 that includes the IL1RN gene, commonly found in Puerto Ricans. Therapy with anakinra was initiated, with rapid clearance of skin lesions and resolution of systemic inflammation. CONCLUSIONS: Recent identification of DIRA as a disease entity, compounded by the limited number of reported cases, makes early identification difficult. It is critical to consider this entity in the differential diagnosis of infantile pustulosis. Targeted therapy with the recombinant human interleukin 1 receptor antagonist anakinra can be lifesaving if initiated early. A high carrier frequency of the 175-kb DIRA-associated genomic deletion in the Puerto Rican population strongly supports testing infants presenting with unexplained pustulosis in patients from this geographic region. PMID- 22431715 TI - Panniculitis associated with dermatomyositis and recurrent ovarian cancer. AB - BACKGROUND: Panniculitis is a rare cutaneous manifestation of dermatomyositis (DM), typically presenting as tender, erythematous subcutaneous nodules. Complications, such as pain, calcinosis, and lipoatrophy, are associated with high morbidity. While it has been suggested that panniculitis in DM may correlate with a better prognosis, our understanding of its true significance, prognostic implications, and management is limited by the paucity of reported cases. We describe the first reported case to our knowledge of DM-associated panniculitis in the setting of ovarian adenocarcinoma as well as in association with a recurrent malignancy. OBSERVATIONS: A 63-year-old woman with a history of DM and recurrent ovarian adenocarcinoma presented with multiple painful, erythematous subcutaneous nodules on the bilateral upper arms, thighs, and buttocks. Histologic examination showed lymphoplasmacytic panniculitis with associated dermal mucin deposition, consistent with lobular panniculitis in association with connective-tissue disease. Treatment with oral methotrexate resulted in sustained clinical improvement over a 10-month period. CONCLUSIONS: Although panniculitis in DM has previously been suggested to be a good prognostic indicator, our case report describes an association with ovarian adenocarcinoma and a recurrent malignancy. Methotrexate may be an effective treatment for panniculitis in DM. PMID- 22431716 TI - A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions. AB - OBJECTIVE: To determine if the complete response rates of lentigo maligna (LM) to imiquimod, 5%, cream can be improved by the addition of a topical retinoid. DESIGN: Prospective randomized study of patients treated with imiquimod alone vs imiquimod plus a topical retinoid, followed by conservative staged excisions. SETTING: Mohs surgical clinic in an academic institution. PATIENTS: Ninety patients with biopsy-confirmed LM. INTERVENTIONS: Ninety patients with 91 LMs were randomized into 2 groups. One group received imiquimod, 5%, cream 5 d/wk for 3 months, while the other group also received tazarotene, 0.1%, gel 2 d/wk for 3 months. Following topical therapy, all patients underwent staged excisions and frozen section analysis with Melan-A immunostaining to confirm negative margins. MAIN OUTCOME MEASURE: The presence or absence of residual LM at the time of staged excision. RESULTS: Forty-six patients with 47 LMs were randomized to receive monotherapy: 42 of 47 LMs reached the intended treatment duration, with 27 complete responses (64%). Forty-four patients with 44 LMs were randomized to receive combined therapy: 37 of 44 LMs reached the intended treatment duration, with 29 complete responses (78%). This difference did not reach statistical significance (P=.17). There have been no recurrences to date, with a mean follow up period of 42 months. CONCLUSIONS: Among patients who received topical imiquimod with vs without tazarotene, 22% (8 of 37) of lesions vs 36% (15 of 42) of lesions showed residual LM on staged excisions. Pretreating LM with imiquimod, 5%, cream may decrease surgical defect sizes; however, total reliance on topical imiquimod as an alternative to surgery may put the patient at increased risk of a local recurrence. PMID- 22431717 TI - Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance. AB - Myb, a cellular progenitor of v-Myb oncogenes, is amplified in prostate cancer and exhibits greater amplification frequency in hormone-refractory disease. Here, we have investigated the functional significance of Myb in prostate cancer. Our studies demonstrate Myb expression in all prostate cancer cell lines (LNCaP, C4 2, PC3 and DU145) examined, whereas it is negligibly expressed in normal/benign prostate epithelial cells (RWPE1 and RWPE2). Notably, Myb is significantly upregulated, both at transcript (>60-fold) and protein (>15-fold) levels, in castration-resistant (C4-2) cells as compared with androgen-dependent (LNCaP) prostate cancer cells of the same genotypic lineage. Using loss and gain of function approaches, we demonstrate that Myb promotes and sustains cell cycle progression and survival under androgen-supplemented and -deprived conditions, respectively, through induction of cyclins (A1, D1 and E1), Bcl-xL and Bcl2 and downregulation of p27 and Bax. Interestingly, Myb overexpression is also associated with enhanced prostate-specific antigen expression. Furthermore, our data show a role of Myb in enhanced motility and invasion and decreased homotypic interactions of prostate cancer cells. Myb overexpression is also associated with actin reorganization leading to the formation of filopodia-like cellular protrusions. Immunoblot analyses demonstrate gain of mesenchymal and loss of epithelial markers and vice versa, in Myb-overexpressing LNCaP and -silenced C4-2 cells, respectively, indicating a role of Myb in epithelial to mesenchymal transition. Altogether, our studies provide first experimental evidence for a functional role of Myb in growth and malignant behavior of prostate cancer cells and suggest a novel mechanism for castration resistance. PMID- 22431718 TI - MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma. AB - Profiling of microRNA expression in human cancers has highlighted downregulation of miR-145 as a common event in epithelial malignancies. Here, we describe recurrent underexpression of miR-145 in hepatocellular carcinoma (HCC) and the identification of a biological pathway by which miR-145 exerts its functional effects in liver tumorigenesis. In a cohort of 80 HCC patients, quantitative reverse transcription polymerase chain reaction corroborated reduced miR-145 expression in 50% of tumors, which also correlated with a shorter disease-free survival of patients. One HCC tumor analyzed with low endogenous miR-145 was propagated as cell line. This in vitro model HKCI-C2 maintained low miR-145 level and upon restoration of miR-145 expression, a consistent inhibitory effect on cell viability and proliferation was readily found. Flow cytometric analysis indicated that miR-145 re-expression could induce G(2)-M cell cycle arrest and apoptosis. Multiple in silico algorithms predicted that miR-145 could target a number of genes along the insulin-like growth factor (IGF) signaling, including insulin receptor substrate (IRS1)-1, IRS2 and insulin-like growth factor 1 receptor. We found protein expression of these putative targets was concordantly downregulated in the presence of miR-145. Luciferase reporter assay further verified direct target association of miR-145 to specific sites of the IRS1 and IRS2 3'-untranslated regions. Subsequent analysis also affirmed miR-145 modulation on the IGF signaling cascade by reducing its downstream mediator, namely the active beta-catenin level. Taken together, our study shows for the first time the pleiotropic effect of miR-145 in targeting multiple components of the oncogenic IGF signaling pathway in HCC. PMID- 22431719 TI - Total and high-molecular weight adiponectin and risk of colorectal cancer: the European Prospective Investigation into Cancer and Nutrition Study. AB - Adiponectin-an adipose tissue-derived protein-may provide a molecular link between obesity and colorectal cancer (CRC), but evidence from large prospective studies is limited. In particular, no epidemiological study explored high molecular weight (HMW) and non-HMW adiponectin fractions in relation to CRC risk, despite them being hypothesized to have differential biological activities, i.e. regulating insulin sensitivity (HMW adiponectin) versus inflammatory response (non-HMW adiponectin). In a prospective, nested case-control study, we investigated whether prediagnostic serum concentrations of total, HMW and non-HMW adiponectin are associated with risk of CRC, independent of obesity and other known CRC risk factors. A total of 1206 incident cases (755 colon and 451 rectal) were matched to 1206 controls using incidence-density sampling. In conditional logistic regression, adjusted for dietary and lifestyle factors, total adiponectin and non-HMW adiponectin concentrations were inversely associated with risk of CRC [relative risk (RR) comparing highest versus lowest quintile = 0.71, 95% confidence interval (CI) = 0.53-0.95, P(trend) = 0.03 for total adiponectin and RR = 0.45, 95% CI = 0.34-0.61, P(trend) < 0.0001 for non-HMW adiponectin]. HMW adiponectin concentrations were not associated with CRC risk (RR = 0.91, 95% CI = 0.68-1.22, P(trend) = 0.55). Non-HMW adiponectin was associated with CRC risk even after adjustment for body mass index and waist circumference (RR = 0.39, 95% CI = 0.26-0.60, P(trend) < 0.0001), whereas the association with total adiponectin was no longer significant (RR = 0.81, 95% CI = 0.60-1.09, P(trend) = 0.23). When stratified by cancer site, non-HMW adiponectin was inversely associated with both colon and rectal cancer. These findings suggest an important role of the relative proportion of non-HMW adiponectin in CRC pathogenesis. Future studies are warranted to confirm these results and to elucidate the underlying mechanisms. PMID- 22431720 TI - Maternal high-methyl diet suppresses mammary carcinogenesis in female rat offspring. AB - Maternal nutrition during pregnancy influences the development and metabolism of the fetus. Recent studies suggest that the cancer risk of offspring later in life is associated with maternal diet, but little is known about the effect of a maternal diet high in methyl nutrients on breast cancer risk. Lipotropes are methyl group-containing essential nutrients (methionine, choline, folate and vitamin B(12)) that play key roles in one-carbon metabolism. In this study, we investigated the long-term effects of maternal dietary high-dose lipotropes (five times higher than in the control diet) on the development and progression of mammary tumors in rat offspring using two separate experiments (in utero exposure with and without postnatal supplementation). In both experiments, the female offspring were injected intraperitoneally with a single dose (50 mg/kg body wt) of N-nitroso-N-methylurea during puberty to induce mammary tumors. Tumor growth and development were recorded, and at the end of the study, tissues were collected for analysis. For both experiments, the offspring from dams fed a high dose lipotropes showed significantly decreased tumor incidence, tumor multiplicity and tumor volume, while also displaying a significant increase in survival rate and tumor latency. Gene transcription analysis, as measured by quantitative real-time PCR, revealed a significant decrease of histone deacetylase 1 (Hdac1) messenger RNA in mammary tumors in both experiments. Our findings provide evidence that maternal dietary high-dose lipotropes reduce mammary carcinogenesis in offspring in association with long-term alterations in gene expression and may be useful in developing maternal dietary strategies to prevent breast cancer. PMID- 22431721 TI - miR-192, miR-194, miR-215, miR-200c and miR-141 are downregulated and their common target ACVR2B is strongly expressed in renal childhood neoplasms. AB - Micro RNAs (miRNAs) play an important role during renal development and show a tissue-specific enrichment in the kidney. Nephroblastomas, embryonal renal neoplasms of childhood, are considered to develop from nephrogenic rests (NRs) and resemble morphologically and genetically developing kidney. We therefore investigated the role of kidney-enriched miRNAs in the pathogenesis of nephroblastomas. miR-192, miR-215 and miR-194 had a significantly lower expression in nephroblastomas regardless of the subtype compared with mature kidney measured by quantitative real-time-PCR. miR-141 and miR-200c showed a significantly lower expression in blastema-type and mixed-type tumors. In comparison with NRs, a significantly lower expression of miR-192, miR-194 and miR 215 was identified in blastema-type, mixed-type and stroma-type nephroblastomas and of miR-141 and miR-200c in blastema-type tumors. Kidney parenchyma had a significantly higher expression of miR-192, miR-194, miR-215 and miR-200c compared with NRs. In this study, the activin receptor type 2B (ACVR2B), a member of the transforming growth factor (TGF)-beta pathway, was identified as single common target gene for miR-192, miR-215, miR-194, miR-141 and miR-200c in silico for the first time. The interaction between all five miRNAs and ACVR2B was also verified by an in vitro assay. Additionally, a distinct protein expression of ACVR2B was detected in 53 of 55 nephroblastomas paralleled by an upregulation of ACVR2B messenger RNA demonstrated in 25 nephroblastomas of all subtypes. A differential regulation of ACVR2B by miRNAs in NRs and nephroblastomas appears to be an important step in the pathogenesis of nephroblastomas implicating for the first time the TGF-beta pathway in this process. PMID- 22431722 TI - PARPs and the DNA damage response. AB - Adenosine diphosphate (ADP)-ribosylation is an important posttranslational modification catalyzed by a variety of enzymes, including poly (ADP ribose) polymerases (PARPs), which use nicotinamide adenine dinucleotide (NAD(+)) as a substrate to synthesize and transfer ADP-ribose units to acceptor proteins. The PARP family members possess a variety of structural domains, span a wide range of functions and localize to various cellular compartments. Among the molecular actions attributed to PARPs, their role in the DNA damage response (DDR) has been widely documented. In particular, PARPs 1-3 are involved in several cellular processes that respond to DNA lesions, which include DNA damage recognition, signaling and repair as well as local transcriptional blockage, chromatin remodeling and cell death induction. However, how these enzymes are able to participate in such numerous and diverse mechanisms in response to DNA damage is not fully understood. Herein, the DDR functions of PARPs 1-3 and the emerging roles of poly (ADP ribose) polymers in DNA damage are reviewed. The development of PARP inhibitors, their applications and mechanisms of action are also discussed in the context of the DDR. PMID- 22431723 TI - Efficient glycosylphosphatidylinositol (GPI) modification of membrane proteins requires a C-terminal anchoring signal of marginal hydrophobicity. AB - Many plasma membrane proteins are anchored to the membrane via a C-terminal glycosylphosphatidylinositol (GPI) moiety. The GPI anchor is attached to the protein in the endoplasmic reticulum by transamidation, a reaction in which a C terminal GPI-attachment signal is cleaved off concomitantly with addition of the GPI moiety. GPI-attachment signals are poorly conserved on the sequence level but are all composed of a polar segment that includes the GPI-attachment site followed by a hydrophobic segment located at the very C terminus of the protein. Here, we show that efficient GPI modification requires that the hydrophobicity of the C-terminal segment is "marginal": less hydrophobic than type II transmembrane anchors and more hydrophobic than the most hydrophobic segments found in secreted proteins. We further show that the GPI-attachment signal can be modified by the transamidase irrespective of whether it is first released into the lumen of the endoplasmic reticulum or is retained in the endoplasmic reticulum membrane. PMID- 22431724 TI - A model-structure of a periplasm-facing state of the NhaA antiporter suggests the molecular underpinnings of pH-induced conformational changes. AB - The Escherichia coli NhaA antiporter couples the transport of H(+) and Na(+) (or Li(+)) ions to maintain the proper pH range and Na(+) concentration in cells. A crystal structure of NhaA, solved at pH 4, comprises 12 transmembrane helices (TMs), arranged in two domains, with a large cytoplasm-facing funnel and a smaller periplasm-facing funnel. NhaA undergoes conformational changes, e.g. after pH elevation to alkaline ranges, and we used two computational approaches to explore them. On the basis of pseudo-symmetric features of the crystal structure, we predicted the structural architecture of an alternate, periplasm facing state. In contrast to the crystal structure, the model presents a closed cytoplasmic funnel, and a periplasmic funnel of greater volume. To examine the transporter functional direction of motion, we conducted elastic network analysis of the crystal structure and detected two main normal modes of motion. Notably, both analyses predicted similar trends of conformational changes, consisting of an overall rotational motion of the two domains around a putative symmetry axis at the funnel centers, perpendicular to the membrane plane. This motion, along with conformational changes within specific helices, resulted in closure at the cytoplasmic end and opening at the periplasmic end. Cross-linking experiments, performed between segments on opposite sides of the cytoplasmic funnel, revealed pH-dependent interactions consistent with the proposed conformational changes. We suggest that the model-structure and predicted motion represent alkaline pH induced conformational changes, mediated by a cluster of evolutionarily conserved, titratable residues, at the cytoplasmic ends of TMs II, V, and IX. PMID- 22431725 TI - Profiles of epigenetic histone post-translational modifications at type 1 diabetes susceptible genes. AB - Both genetic and environmental factors are implicated in type 1 diabetes (T1D). Because environmental factors can trigger epigenetic changes, we hypothesized that variations in histone post-translational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy nondiabetic controls, and explored their connections to T1D. We used the chromatin immunoprecipitation-linked to microarray approach to profile key histone PTMs, including H3-lysine 4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac), and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac, and H4K16Ac at the insulin-dependent diabetes mellitus 1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the insulin dependent diabetes mellitus 1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon-gamma and TNF-alpha treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response toward external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility. PMID- 22431726 TI - Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1. AB - The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system. PMID- 22431727 TI - LHCBM1 and LHCBM2/7 polypeptides, components of major LHCII complex, have distinct functional roles in photosynthetic antenna system of Chlamydomonas reinhardtii. AB - The photosystem II antenna of Chlamydomonas reinhardtii is composed of monomeric and trimeric complexes, the latter encoded by LHCBM genes. We employed artificial microRNA technology to specifically silence the LHCBM2 and LHCBM7 genes, encoding identical mature polypeptides, and the LHCBM1 gene. As a control, we studied the npq5 mutant, deficient in the LHCBM1 protein. The organization of LHCII complexes, functional antenna size, capacity for photoprotection, thermal energy dissipation and state transitions, and resistance to reactive oxygen species was studied in the various genotypes. Silencing of the LHCBM2/7 genes resulted in a decrease of an LHCII protein with an apparent molecular mass of 22 kDa, whereas silencing/lack of LHCBM1 caused the decrease/disappearance of a 23-kDa protein. A decrease in the abundance of trimeric LHCII complexes and in functional antenna size was observed in both LHCBM2/7 and LHCBM1 knockouts. In agreement with previous data, depletion of LHCBM1 decreased the capacity for excess energy dissipation but not the ability to perform state transitions. The opposite was true for LHCBM2/7, implying that this polypeptide has a different functional role from LHCBM1. The abundance of LHCBM1 and LHCBM2/7 is in both cases correlated with resistance to superoxide anion, whereas only LHCBM1 is also involved in singlet oxygen scavenging. These results suggest that different LHCBM components have well defined, non-redundant functions despite their high homology, implying that engineering of LHCBM proteins can be an effective strategy for manipulating the light harvesting system of Chlamydomonas reinhardtii. PMID- 22431728 TI - Structural rearrangements of the central region of the morbillivirus attachment protein stalk domain trigger F protein refolding for membrane fusion. AB - It is unknown how receptor binding by the paramyxovirus attachment proteins (HN, H, or G) triggers the fusion (F) protein to fuse with the plasma membrane for cell entry. H-proteins of the morbillivirus genus consist of a stalk ectodomain supporting a cuboidal head; physiological oligomers consist of non-covalent dimer of-dimers. We report here the successful engineering of intermolecular disulfide bonds within the central region (residues 91-115) of the morbillivirus H-stalk; a sub-domain that also encompasses the putative F-contacting section (residues 111 118). Remarkably, several intersubunit crosslinks abrogated membrane fusion, but bioactivity was restored under reducing conditions. This phenotype extended equally to H proteins derived from virulent and attenuated morbillivirus strains and was independent of the nature of the contacted receptor. Our data reveal that the morbillivirus H-stalk domain is composed of four tightly-packed subunits. Upon receptor binding, these subunits structurally rearrange, possibly inducing conformational changes within the central region of the stalk, which, in turn, promote fusion. Given that the fundamental architecture appears conserved among paramyxovirus attachment protein stalk domains, we predict that these motions may act as a universal paramyxovirus F-triggering mechanism. PMID- 22431729 TI - N-terminal flanking region of A1 domain in von Willebrand factor stabilizes structure of A1A2A3 complex and modulates platelet activation under shear stress. AB - von Willebrand factor (vWF) mediates platelet adhesion and thrombus formation via its interaction with the platelet receptor glycoprotein (GP)Ibalpha. We have analyzed two A1A2A3 tri-domain proteins to demonstrate that the amino acid sequence, Gln(1238)-Glu(1260), in the N-terminal flanking region of the A1 domain, together with the association between the A domains, modulates vWF GPIbalpha binding and platelet activation under shear stress. Using circular dichroism spectroscopy and differential scanning calorimetry, we have described that sequence Gln(1238)-Glu(1260) stabilizes the structural conformation of the A1A2A3 tri-domain complex. The structural stabilization imparted by this particular region inhibits the binding capacity of the tri-domain protein for GPIbalpha. Deletion of this region causes a conformational change in the A1 domain that increases binding to GPIbalpha. Only the truncated protein was capable of effectively blocking ristocetin-induced platelet agglutination. To determine the capacity of activating platelets via the interaction with GPIbalpha, whole blood was incubated with the N-terminal region truncated or intact tri-A domain protein prior to perfusion over a fibrin(ogen)-coated surface. At a high shear rate of 1,500 s(-1), platelets from blood containing the truncated protein rapidly bound, covering >90% of the fibrin(ogen) surface area, whereas the intact tri-A domain protein induced platelets to bind <10%. The results obtained in this study ascertain the relevant role of the structural association between the N-terminal flanking region of the A1 domain (amino acids Gln(1238)-Glu(1260)) and the A1A2A3 domain complex in preventing vWF to bind spontaneously to GPIbalpha in solution under high shear forces. PMID- 22431730 TI - Yeast Swd2 is essential because of antagonism between Set1 histone methyltransferase complex and APT (associated with Pta1) termination factor. AB - The Set1 complex (also known as complex associated with Set1 or COMPASS) methylates histone H3 on lysine 4, with different levels of methylation affecting transcription by recruiting various factors to distinct regions of active genes. Neither Set1 nor its associated proteins are essential for viability with the notable exception of Swd2, a WD repeat protein that is also a subunit of the essential transcription termination factor APT (associated with Pta1). Cells lacking Set1 lose COMPASS recruitment but show increased promoter cross-linking of TFIIE large subunit and the serine 5 phosphorylated form of the Rpb1 C terminal domain. Although Swd2 is normally required for bringing APT to genes, deletion of SET1 restores both viability and APT recruitment to a strain lacking Swd2. We propose a model in which Swd2 is required for APT to overcome antagonism by COMPASS. PMID- 22431731 TI - Modulation of the Pyrococcus abyssi NucS endonuclease activity by replication clamp at functional and structural levels. AB - Pyrococcus abyssi NucS is the founding member of a new family of structure specific DNA endonucleases that interact with the replication clamp proliferating cell nuclear antigen (PCNA). Using a combination of small angle x-ray scattering and surface plasmon resonance analyses, we demonstrate the formation of a stable complex in solution, in which one molecule of the PabNucS homodimer binds to the outside surface of the PabPCNA homotrimer. Using fluorescent labels, PCNA is shown to increase the binding affinity of NucS toward single-strand/double-strand junctions on 5' and 3' flaps, as well as to modulate the cleavage specificity on the branched DNA structures. Our results indicate that the presence of a single major contact between the PabNucS and PabPCNA proteins, together with the complex induced DNA bending, facilitate conformational flexibility required for specific cleavage at the single-strand/double-strand DNA junction. PMID- 22431732 TI - Arabidopsis RNA-binding protein FCA regulates microRNA172 processing in thermosensory flowering. AB - Ambient temperature fluctuates diurnally and seasonally. It profoundly influences the timing of flowering in plants. The floral integrator FLOWERING LOCUS T (FT) mediates ambient temperature signals via the thermosensory pathway in Arabidopsis flowering. microRNA172 (miR172), which promotes flowering by inducing FT, also responds to changes in ambient temperature. However, it is largely unknown how miR172 integrates ambient temperature signals into the flowering genetic network. Here, we show that Arabidopsis RNA-binding protein FCA promotes the processing of primary microRNA172 transcripts (pri-miR172) in response to changes in ambient temperature. Ambient temperature regulates miR172 biogenesis primarily at the pri miR172 processing step. miR172 abundance is elevated at 23 degrees C but not at 16 degrees C. miR172 accumulation at 23 degrees C requires functional FCA. FCA binds to the flanking sequences of the stem-loop within the pri-miR172 transcripts via the RNA recognition motif. FCA also binds to the primary transcripts of other temperature-responsive miRNAs, such as miR398 and miR399. Notably, levels of FCA mRNAs and proteins increase at 23 degrees C but remain low at 16 degrees C, supporting the role of FCA in temperature perception. Our data show that FCA regulation of miR172 processing is an early event in the thermosensory flowering pathway. We propose that the FCA-miR172 regulon provides an adaptive strategy that fine tunes the onset of flowering under fluctuating ambient temperature conditions. PMID- 22431733 TI - Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells. AB - Angiotensin II (Ang II)-mediated vascular smooth muscle cell dysfunction plays a critical role in cardiovascular diseases. However, the role of microRNAs (miRNAs) in this process is unclear. We used small RNA deep sequencing to profile Ang II regulated miRNAs in rat vascular smooth muscle cells (VSMC) and evaluated their role in VSMC dysfunction. Sequencing results revealed several Ang II-responsive miRNAs, and bioinformatics analysis showed that their predicted targets can modulate biological processes relevant to cardiovascular diseases. Further studies with the most highly induced miR-132 and miR-212 cluster (miR-132/212) showed time- and dose-dependent up-regulation of miR-132/212 by Ang II through the Ang II Type 1 receptor. We identified phosphatase and tensin homolog (PTEN) as a novel target of miR-132 and demonstrated that miR-132 induces monocyte chemoattractant protein-1 at least in part via PTEN repression in rat VSMC. Moreover, miR-132 overexpression enhanced cyclic AMP-response element-binding protein (CREB) phosphorylation via RASA1 (p120 Ras GTPase-activating protein 1) down-regulation, whereas miR-132 inhibition attenuated Ang II-induced CREB activation. Furthermore, miR-132 up-regulation by Ang II required CREB activation, demonstrating a positive feedback loop. Notably, aortas from Ang II infused mice displayed similar up-regulation of miR-132/212 and monocyte chemoattractant protein-1, supporting in vivo relevance. In addition, microarray analysis and reverse transcriptase-quantitative PCR validation revealed additional novel miR-132 targets among Ang II-down-regulated genes implicated in cell cycle, motility, and cardiovascular functions. These results suggest that miR132/212 can serve as a novel cellular node to fine-tune and amplify Ang II actions in VSMC. PMID- 22431734 TI - Deregulation of DNA damage response pathway by intercellular contact. AB - Deregulation of the DNA damage response (DDR) pathway could compromise genomic integrity in normal cells and reduce cancer cell sensitivity to anticancer treatments. We found that intercellular contact stabilizes histone H2AX and gammaH2AX (H2AX phosphorylated on Ser-139) by up-regulating N/E-cadherin and gamma-catenin. gamma-catenin and its DNA-binding partner LEF-1 indirectly increase levels of H2AX by suppressing the promoter of the RNF8 ubiquitin ligase, which decreases levels of H2AX protein under conditions of low intercellular contact. Hyperphosphorylation of DDR proteins is induced by up-regulated H2AX. Constitutive apoptosis is caused in confluent cells but is not further induced by DNA damage. This is conceivably due to insufficient p53 activation because ChIP assay shows that its DNA binding ability is not induced in those cells. Together, our results illustrate a novel mechanism of the regulation of DDR proteins by the cadherin-catenin pathway. PMID- 22431735 TI - Dopamine-derived quinones affect the structure of the redox sensor DJ-1 through modifications at Cys-106 and Cys-53. AB - The physiological role of DJ-1, a protein involved in familial Parkinson disease is still controversial. One of the hypotheses proposed indicates a sensor role for oxidative stress, through oxidation of a conserved cysteine residue (Cys 106). The association of DJ-1 mutations with Parkinson disease suggests a loss of function, specific to dopaminergic neurons. Under oxidative conditions, highly reactive dopamine quinones (DAQs) can be produced, which can modify cysteine residues. In cellular models, DJ-1 was found covalently modified by dopamine. We analyzed the structural modifications induced on human DJ-1 by DAQs in vitro. We described the structural perturbations induced by DAQ adduct formation on each of the three cysteine residues of DJ-1 using specific mutants. Cys-53 is the most reactive residue and forms a covalent dimer also in SH-SY5Y DJ-1-transfected cells, but modification of Cys-106 induces the most severe structural perturbations; Cys-46 is not reactive. The relevance of these covalent modifications to the several functions ascribed to DJ-1 is discussed in the context of the cell response to a dopamine-derived oxidative insult. PMID- 22431736 TI - Endocannabinoids stimulate human melanogenesis via type-1 cannabinoid receptor. AB - We show that a fully functional endocannabinoid system is present in primary human melanocytes (normal human epidermal melanocyte cells), including anandamide (AEA), 2-arachidonoylglycerol, the respective target receptors (CB(1), CB(2), and TRPV1), and their metabolic enzymes. We also show that at higher concentrations AEA induces normal human epidermal melanocyte apoptosis (~3-fold over controls at 5 MUM) through a TRPV1-mediated pathway that increases DNA fragmentation and p53 expression. However, at lower concentrations, AEA and other CB(1)-binding endocannabinoids dose-dependently stimulate melanin synthesis and enhance tyrosinase gene expression and activity (~3- and ~2-fold over controls at 1 MUM). This CB(1)-dependent activity was fully abolished by the selective CB(1) antagonist SR141716 or by RNA interference of the receptor. CB(1) signaling engaged p38 and p42/44 mitogen-activated protein kinases, which in turn activated the cyclic AMP response element-binding protein and the microphthalmia-associated transcription factor. Silencing of tyrosinase or microphthalmia-associated transcription factor further demonstrated the involvement of these proteins in AEA-induced melanogenesis. In addition, CB(1) activation did not engage the key regulator of skin pigmentation, cyclic AMP, showing a major difference compared with the regulation of melanogenesis by alpha-melanocyte-stimulating hormone through melanocortin 1 receptor. PMID- 22431737 TI - Transcriptional regulation of T-type calcium channel CaV3.2: bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) protein-silencing transcription factor (REST). AB - The pore-forming Ca(2+) channel subunit Ca(V)3.2 mediates a low voltage-activated (T-type) Ca(2+) current (I(CaT)) that contributes pivotally to neuronal and cardiac pacemaker activity. Despite the importance of tightly regulated Ca(V)3.2 levels, the mechanisms regulating its transcriptional dynamics are not well understood. Here, we have identified two key factors that up- and down-regulate the expression of the gene encoding Ca(V)3.2 (Cacna1h). First, we determined the promoter region and observed several stimulatory and inhibitory clusters. Furthermore, we found binding sites for the transcription factor early growth response 1 (Egr1/Zif268/Krox-24) to be highly overrepresented within the Ca(V)3.2 promoter region. mRNA expression analyses and dual-luciferase promoter assays revealed that the Ca(V)3.2 promoter was strongly activated by Egr1 overexpression in vitro and in vivo. Subsequent chromatin immunoprecipitation assays in NG108-15 cells and mouse hippocampi confirmed specific Egr1 binding to the Ca(V)3.2 promoter. Congruently, whole-cell I(CaT) values were significantly larger after Egr1 overexpression. Intriguingly, Egr1-induced activation of the Ca(V)3.2 promoter was effectively counteracted by the repressor element 1-silencing transcription factor (REST). Thus, Egr1 and REST can bi-directionally regulate Ca(V)3.2 promoter activity and mRNA expression and, hence, the size of I(CaT). This mechanism has critical implications for the regulation of neuronal and cardiac Ca(2+) homeostasis under physiological conditions and in episodic disorders such as arrhythmias and epilepsy. PMID- 22431738 TI - Spider orb webs rely on radial threads to absorb prey kinetic energy. AB - The kinetic energy of flying insect prey is a formidable challenge for orb weaving spiders. These spiders construct two-dimensional, round webs from a combination of stiff, strong radial silk and highly elastic, glue-coated capture spirals. Orb webs must first stop the flight of insect prey and then retain those insects long enough to be subdued by the spiders. Consequently, spider silks rank among the toughest known biomaterials. The large number of silk threads composing a web suggests that aerodynamic dissipation may also play an important role in stopping prey. Here, we quantify energy dissipation in orb webs spun by diverse species of spiders using data derived from high-speed videos of web deformation under prey impact. By integrating video data with material testing of silks, we compare the relative contributions of radial silk, the capture spiral and aerodynamic dissipation. Radial silk dominated energy absorption in all webs, with the potential to account for approximately 100 per cent of the work of stopping prey in larger webs. The most generous estimates for the roles of capture spirals and aerodynamic dissipation show that they rarely contribute more than 30 per cent and 10 per cent of the total work of stopping prey, respectively, and then only for smaller orb webs. The reliance of spider orb webs upon internal energy absorption by radial threads for prey capture suggests that the material properties of the capture spirals are largely unconstrained by the selective pressures of stopping prey and can instead evolve freely in response to alternative functional constraints such as adhering to prey. PMID- 22431739 TI - ADAM proteins, their ligands, and clinical implications. PMID- 22431740 TI - Ischemic stroke due to a calcified embolus from the mitral annular valve. PMID- 22431741 TI - Teaching Neuroimages: reversible splenial cytotoxic edema in acute mountain sickness. PMID- 22431742 TI - Teaching Neuroimages: TIA from an air embolism. PMID- 22431743 TI - Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. PMID- 22431744 TI - Journal Club: early stroke risk and ABCD2 score performance in tissue vs time defined TIA. PMID- 22431745 TI - Teaching neuroimages: stroke and bilateral visual loss in a young adult: more than coincidence. PMID- 22431746 TI - Sue Biggins: how kinetochores keep control of mitosis. Interview by Caitlin Sedwick. PMID- 22431747 TI - The evolution of metazoan extracellular matrix. AB - The modular domain structure of extracellular matrix (ECM) proteins and their genes has allowed extensive exon/domain shuffling during evolution to generate hundreds of ECM proteins. Many of these arose early during metazoan evolution and have been highly conserved ever since. Others have undergone duplication and divergence during evolution, and novel combinations of domains have evolved to generate new ECM proteins, particularly in the vertebrate lineage. The recent sequencing of several genomes has revealed many details of this conservation and evolution of ECM proteins to serve diverse functions in metazoa. PMID- 22431748 TI - Recognition of DNA damage by XPC coincides with disruption of the XPC-RAD23 complex. AB - The recognition of helix-distorting deoxyribonucleic acid (DNA) lesions by the global genome nucleotide excision repair subpathway is performed by the XPC-RAD23 CEN2 complex. Although it has been established that Rad23 homologs are essential to protect XPC from proteasomal degradation, it is unclear whether RAD23 proteins have a direct role in the recognition of DNA damage. In this paper, we show that the association of XPC with ultraviolet-induced lesions was impaired in the absence of RAD23 proteins. Furthermore, we show that RAD23 proteins rapidly dissociated from XPC upon binding to damaged DNA. Our data suggest that RAD23 proteins facilitate lesion recognition by XPC but do not participate in the downstream DNA repair process. PMID- 22431749 TI - MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. AB - Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a multifaceted signaling system coordinating translational control and gene transcription to promote cellular adaptation and survival. Microribonucleic acids (RNAs; miRNAs), single-stranded RNAs that typically function as posttranscriptional modulators of gene activity, have been shown to inhibit translation of certain secretory pathway proteins during the UPR. However, it remains unclear whether miRNAs regulate UPR signaling effectors directly. In this paper, we report that a star strand miRNA, miR-30c-2* (recently designated miR 30c-2-3p), is induced by the protein kinase RNA activated-like ER kinase (PERK) pathway of the UPR and governs expression of XBP1 (X-box binding protein 1), a key transcription factor that augments secretory capacity and promotes cell survival in the adaptive UPR. These data provide the first link between an miRNA and direct regulation of the ER stress response and reveal a novel molecular mechanism by which the PERK pathway, via miR-30c-2*, influences the scale of XBP1 mediated gene expression and cell fate in the UPR. PMID- 22431750 TI - The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing. AB - In myotonic dystrophy type 1 (DM1), dystrophia myotonica protein kinase messenger ribonucleic acids (RNAs; mRNAs) with expanded CUG repeats (CUG(exp)) aggregate in the nucleus and become toxic to cells by sequestering and/or misregulating RNA binding proteins, resulting in aberrant alternative splicing. In this paper, we find that the RNA-binding protein Staufen1 is markedly and specifically increased in skeletal muscle from DM1 mouse models and patients. We show that Staufen1 interacts with mutant CUG(exp) mRNAs and promotes their nuclear export and translation. This effect is critically dependent on the third double-stranded RNA binding domain of Staufen1 and shuttling of Staufen1 into the nucleus via its nuclear localization signal. Moreover, we uncover a new role of Staufen1 in splicing regulation. Overexpression of Staufen1 rescues alternative splicing of two key pre-mRNAs known to be aberrantly spliced in DM1, suggesting its increased expression represents an adaptive response to the pathology. Altogether, our results unravel a novel function for Staufen1 in splicing regulation and indicate that it may positively modulate the complex DM1 phenotype, thereby revealing its potential as a therapeutic target. PMID- 22431751 TI - A novel patch assembly domain in Num1 mediates dynein anchoring at the cortex during spindle positioning. AB - During mitosis in budding yeast, cortically anchored dynein generates pulling forces on astral microtubules to position the mitotic spindle across the mother bud neck. The attachment molecule Num1 is required for dynein anchoring at the cell membrane, but how Num1 assembles into stationary cortical patches and interacts with dynein is unknown. We show that an N-terminal Bin/Amphiphysin/Rvs (BAR)-like domain in Num1 mediates the assembly of morphologically distinct patches and its interaction with dynein for spindle translocation into the bud. We name this domain patch assembly domain (PA; residues 1-303), as it was both necessary and sufficient for the formation of functional dynein-anchoring patches when it was attached to a pleckstrin homology domain or a CAAX motif. Distinct point mutations targeting the predicted BAR-like PA domain differentially disrupted patch assembly, dynein anchoring, and mitochondrial attachment functions of Num1. We also show that the PA domain is an elongated dimer and discuss the mechanism by which it drives patch assembly. PMID- 22431753 TI - Geometry and mechanics of layered structures and materials. PMID- 22431752 TI - Hectd1 regulates intracellular localization and secretion of Hsp90 to control cellular behavior of the cranial mesenchyme. AB - Hectd1 mutant mouse embryos exhibit the neural tube defect exencephaly associated with abnormal cranial mesenchyme. Cellular rearrangements in cranial mesenchyme are essential during neurulation for elevation of the neural folds. Here we investigate the molecular basis of the abnormal behavior of Hectd1 mutant cranial mesenchyme. We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Extracellular Hsp90 enhances migration of multiple cell types. In mutant cranial mesenchyme cells, both secretion of Hsp90 and emigration of cells from cranial mesenchyme explants were enhanced. Importantly, we show that this enhanced emigration was highly dependent on the excess Hsp90 secreted from mutant cells. Together, our data set forth a model whereby increased secretion of Hsp90 in the cranial mesenchyme of Hectd1 mutants is responsible, at least in part, for the altered organization and behavior of these cells and provides a potential molecular mechanism underlying the neural tube defect. PMID- 22431754 TI - Stripe patterns and a projection-valued formulation of the eikonal equation. AB - We describe recent work on striped patterns in a system of block copolymers. A by product of the characterization of such patterns is a new formulation of the eikonal equation. In this formulation, the unknown is a field of projection matrices of the form P=e?e, where e is a unit vector field. We describe how this formulation is better adapted to the description of striped patterns than the classical eikonal equation, and illustrate this with examples. PMID- 22431755 TI - Multi-layered folding with voids. AB - In the deformation of layered materials such as geological strata, or stacks of paper, mechanical properties compete with the geometry of layering. Smooth, rounded corners lead to voids between the layers, while close packing of the layers results in geometrically induced curvature singularities. When voids are penalized by external pressure, the system is forced to trade off these competing effects, leading to sometimes striking periodic patterns. In this paper, we construct a simple model of geometrically nonlinear multi-layered structures under axial loading and pressure confinement, with non-interpenetration conditions separating the layers. Energy minimizers are characterized as solutions of a set of fourth-order nonlinear differential equations with contact force Lagrange multipliers, or equivalently of a fourth-order free-boundary problem. We numerically investigate the solutions of this free-boundary problem and compare them with the periodic solutions observed experimentally. PMID- 22431756 TI - Compressive strength of delaminated aerospace composites. AB - An efficient analytical model is described which predicts the value of compressive strain below which buckle-driven propagation of delaminations in aerospace composites will not occur. An extension of this efficient strip model which accounts for propagation transverse to the direction of applied compression is derived. In order to provide validation for the strip model a number of laminates were artificially delaminated producing a range of thin anisotropic sub laminates made up of 0 degrees , +/-45 degrees and 90 degrees plies that displayed varied buckling and delamination propagation phenomena. These laminates were subsequently subject to experimental compression testing and nonlinear finite element analysis (FEA) using cohesive elements. Comparison of strip model results with those from experiments indicates that the model can conservatively predict the strain at which propagation occurs to within 10 per cent of experimental values provided (i) the thin-film assumption made in the modelling methodology holds and (ii) full elastic coupling effects do not play a significant role in the post-buckling of the sub-laminate. With such provision, the model was more accurate and produced fewer non-conservative results than FEA. The accuracy and efficiency of the model make it well suited to application in optimum ply-stacking algorithms to maximize laminate strength. PMID- 22431757 TI - Bending strength of delaminated aerospace composites. AB - Buckling-driven delamination is considered among the most critical failure modes in composite laminates. This paper examines the propagation of delaminations in a beam under pure bending. A pre-developed analytical model to predict the critical buckling moment of a thin sub-laminate is extended to account for propagation prediction, using mixed-mode fracture analysis. Fractography analysis is performed to distinguish between mode I and mode II contributions to the final failure of specimens. Comparison between experimental results and analysis shows agreement to within 5 per cent in static propagation moment for two different materials. It is concluded that static fracture is almost entirely driven by mode II effects. This result was unexpected because it arises from a buckling mode that opens the delamination. For this reason, and because of the excellent repeatability of the experiments, the method of testing may be a promising means of establishing the critical value of mode II fracture toughness, G(IIC), of the material. Fatigue testing on similar samples showed that buckled delamination resulted in a fatigue threshold that was over 80 per cent lower than the static propagation moment. Such an outcome highlights the significance of predicting snap-buckling moment and subsequent propagation for design purposes. PMID- 22431758 TI - Folding in power-law viscous multi-layers. AB - We study high-amplitude folding in layered rocks with two-dimensional numerical simulations. We employ the finite-element method to model shortening of an incompressible multi-layer with power-law viscous rheology. The Lagrangian numerical mesh is deformed and re-meshed to accurately follow the layer interfaces. Three settings are considered: (i) pure shearing of a confined multi layer, (ii) simple shearing of a multi-layer above a detachment, and (iii) slump folding owing to gravity sliding. In our pure shear simulations, finite-amplitude folds always develop despite confinement and thin weak interlayers. The fold shapes can be significantly irregular, resulting from initial geometrical heterogeneities that are perturbations of the layer interfaces and differences in layer thickness. The bulk normal viscosity of the multi-layer decreases significantly with progressive folding. This structural softening decreases the bulk normal viscosities by a factor of 2-20. For simple shear, the multi-layer does not develop asymmetric fold shapes significantly. Fold axial planes in the multi-layer are mostly curved and not parallel. For slump folding, fold shapes can be significantly asymmetric exhibiting strongly curved fold axial planes and overturned fold limbs. The rheology of the competent layers has a major impact on the fold shapes for gravity-driven multi-layer folding. PMID- 22431759 TI - Geometric modelling of kink banding in laminated structures. AB - An analytical model founded on geometric and potential energy principles for kink band deformation in laminated composite struts is presented. It is adapted from an earlier successful study on confined layered structures that was formulated to model kink band formation in the folding of geological layers. This study's principal aim was to explore the underlying mechanisms governing the kinking response of flat, laminated components comprising unidirectional composite laminae. A pilot parametric study indicates that the key features of the mechanical response are captured well and that quantitative comparisons with experiments presented in the literature are highly encouraging. PMID- 22431760 TI - The role of delamination in failure of fibre-reinforced composites. AB - The mechanisms by which delamination contributes to the failure of fibre reinforced composites are reviewed. Through-thickness failure owing to interlaminar stresses is considered first, and the effect of delamination in impact and compression after impact. The way in which in-plane failure can occur by delamination and matrix cracks joining up to produce a fracture surface without the need to break fibres is considered next. Examples of quasi-isotropic laminates loaded at different off-axis angles, and with different numbers and thicknesses of ply blocks show large differences in unnotched tensile strength controlled by delamination from the free edge. Similar mechanisms determine the strength of notched specimens and give rise to the hole size effect, whereby tensile strength increases with decreasing hole diameter owing to increased delamination and splitting. Open hole tension and over-height compact tension tests with constant in-plane dimensions show a transition in failure mode with increasing ply block thickness from fibre-dominated fracture to complete delamination. In all these cases, the critical factor controlling strength is the relative propensity to delaminate. PMID- 22431761 TI - On longitudinal compressive failure of carbon-fibre-reinforced polymer: from unidirectional to woven, and from virgin to recycled. AB - Modelling the longitudinal compressive failure of carbon-fibre-reinforced composites has been attempted for decades. Despite many developments, no single model has surfaced to provide simultaneously a definitive explanation for the micromechanics of failure as well as validated predictions for a generic stress state. This paper explores the reasons for this, by presenting experimental data (including scanning electron microscopic observations of loaded kink bands during propagation, and brittle shear fracture at 45 degrees to the fibres) and reviewing previously proposed micromechanical analytical and numerical models. The paper focuses mainly on virgin unidirectional (UD) composites, but studies for woven and recycled composites are also presented, highlighting similarities and differences between these cases. It is found that, while kink-band formation (also referred to in the literature as microbuckling) is predominant in UD composites under longitudinal compression, another failure mode related to the failure of the fibres can be observed experimentally. It is also shown that the micromechanics of the failure process observed in UD composites is similar to that in other fibre architectures, hence encouraging the adaptation and application of models developed for the former to the latter. PMID- 22431762 TI - Effects of imperfections on localized bulging in inflated membrane tubes. AB - The problem of localized bulging in inflated membrane tubes shares the same features with a variety of other localization problems such as formation of kink bands in fibre-reinforced composites and layered structures. This type of localization is known to be very sensitive to imperfections, but the precise nature of such sensitivity has not so far been quantified. In this paper, we study effects of localized wall thinning/thickening on the onset of localized bulging in inflated membrane tubes as a prototypical example. It is shown that localized wall thinning may reduce the critical pressure or circumferential stretch by an amount of the order of the square root of maximum wall thickness reduction. As a typical example, a 10 per cent maximum wall thinning may reduce the critical circumferential stretch by 19 per cent. This square root law complements the well-known Koiter's two-thirds power law for subcritical periodic bifurcations. The relevance of our results to mathematical modelling of aneurysm formation in human arteries is also discussed. PMID- 22431763 TI - On the influence of delamination on laminated paperboard creasing and folding. AB - Laminated paperboard is used as a packaging material for a wide range of products. During production of the packaging, the fold lines are first defined in a so-called creasing (or scoring) operation in order to obtain uncracked folds. During creasing as well as folding, cracking of the board is to be avoided. A mechanical model for a single fold line has been proposed in a previous study (Beex & Peerlings 2009 Int. J. Solids Struct. 46, 4192-4207) to investigate the general mechanics of creasing and folding, as well as which precise mechanisms trigger the breaking of the top layer. In the present study, we employ this modelling to study the influence of delamination on creasing and folding. The results reveal the separate role of the cohesive zone model and the friction model in the description of delamination. They also show how the amount of delamination behaviour should be controlled to obtain the desired high folding stiffness without breaking of the top layer. PMID- 22431764 TI - Numerical optimization approach to modelling delamination and buckling of geometrically constrained structures. AB - Understanding what happens in terms of delamination during buckling of laminate materials is of importance across a range of engineering sectors. Normally concern is that the strength of the material is not significantly impaired. Carton-board is a material with a laminate structure and, in the initial creation of carton nets, the board is creased in order to weaken the structure. This means that when the carton is eventually folded into its three-dimensional form, correct folding occurs along the weakened crease lines. Understanding what happens during creasing and folding is made difficult by the nonlinear nature of the material properties. This paper considers a simplified approach which extends the idea of minimizing internal energy so that the effects of delamination can be handled. This allows a simulation which reproduces the form of buckling delamination observed in practice and the form of the torque-rotation relation. PMID- 22431765 TI - Non-smooth mode I fracture of fibre-reinforced composites: an experimental, numerical and analytical study. AB - We present a novel approach to analyse the fracture of fibre-reinforced composites. Experimental results on mode I fracture of glass fibre and carbon fibre unidirectional laminates presented here and published by others in the open literature formed the basis for the analytical and numerical results presented. When details of the external loading rate are explicitly accounted for, a new picture of fracture emerges, which encompasses the possibility for non-smooth crack growth and the necessity to relax the use of a critical strain energy release rate as a criterion for crack advancement. Results predicted by adopting the analytical model presented here are seen to capture a wide variety of fracture responses that have been observed previously. PMID- 22431766 TI - Localized and chaotic folding: the role of axial plane structures. AB - Most natural fold systems are not sinusoidal in profile. A widely held view is that such irregularity derives solely from inherited initial geometrical perturbations. Although, undoubtedly, initial perturbations can contribute to irregularity, we explore a different (but complementary) view in which the irregular geometry results from some material or system softening process. This arises because the buckling response of a layer (or layers) embedded in a weaker matrix is controlled in a sensitive manner by the nature of the reaction forces exerted by the deforming matrix on the layer. In many theoretical treatments of the folding problem, this reaction force is assumed to be a linear function of some measure of the deformation or deformation rate. This paper is concerned with the influence of nonlinear reaction forces such as arise from nonlinear elasticity or viscosity. Localized folds arising from nonlinearity form in a fundamentally different way than the Biot wavelength selection process. As a particular example of nonlinear behaviour, we examine the influence of axial plane structures made up of layers of different mineralogy formed by chemical differentiation processes accompanying the deformation; they are referred to as metamorphic layering. The alternating mineralogical composition in the metamorphic layers means that the embedding matrix exerts a reaction force on the folded layers that varies not only with the deflection or the velocity of deflection of the layer, but also in a periodic manner along the length of the folded layers. The influence of this spatially periodic reaction force on the development of localized and chaotic folding is explored numerically. PMID- 22431767 TI - Compliant shell mechanisms. AB - This paper describes a class of lightweight structures known as compliant shell mechanisms. These are novel reconfigurable solutions for advanced structures, such as morphing shells and deployable membranes. They have local, discrete corrugations, which articulate and deform to achieve dramatic changes in the overall shape of the shell. The unique kinematics are considered by highlighting examples and by performing analysis using established and novel concepts, and favourable predictions of shape compared with laboratory models are demonstrated. PMID- 22431768 TI - Intraosseous venous malformations of the facial bone: a retrospective study in 11 patients. AB - OBJECTIVES: To investigate the clinical symptoms, computed tomography (CT) features and treatments of intraosseous venous malformations (IVM) that occur in the facial bone. METHODS AND RESULTS: Eleven patients with facial IVM were treated with two surgical techniques, excision (n = 4) or curettage (n = 7). No recurrence was encountered at follow-up (45.8 +/- 16.0 months). Postoperative deformities were left in two paediatric patients who were treated with excision. CONCLUSIONS: The diagnosis of IVM can be difficult and is mainly based on clinical symptoms and CT features. IVM should be differentiated from other lesions, including ameloblastoma, odontogenic cysts, osteosarcoma, aneurysmal bone cysts and arteriovenous malformations, among others. Conventional block biopsy should be replaced by fine needle aspiration cytology for further diagnosis. Curettage is a more appropriate method for IVM compared with excessive en-bloc osteotomy, while transosseous embolo-sclerotherapy may be a promising alternative method. Finally, the terminological confusion between 'intraosseous haemangioma' and 'intraosseous venous malformation' should be avoided according to the binary classification. PMID- 22431769 TI - Absence of the right iliac vein and an unusual connection between both common femoral veins. AB - The aim of the study is to report a case of a rare congenital anomaly of the venous system and to emphasize its clinical importance. We describe a case of aplasia of the right common and external iliac veins in a healthy seven-year-old boy who was referred for Doppler ultrasound examination for further evaluation of an abnormal varicosity in the suprapubic region. Colour Doppler ultrasound revealed a dilated, arch-shaped vein. Contrast-enhanced magnetic resonance angiography showed the absence of the right common iliac vein and external iliac vein. It also clearly demonstrated the aberrant venous structure, originating from the right common femoral vein and draining to the left common femoral vein. In conclusion, in our case, the patient's life was threatened because the aberrant venous connection crossing within subcutaneous fatty tissue was not protected from external trauma and possible abdominal surgical interventions. Additional attention should be given to avoid such injuries, which can cause significant haemorrhage. PMID- 22431770 TI - Retraction of: p2y5/LPA6 attenuates LPA1-mediated VE-cadherin translocation and cell-cell dissociation through G(12/13) protein-Src-Rap1. PMID- 22431771 TI - Acitretin- and tumor necrosis factor inhibitor-resistant acrodermatitis continua of hallopeau responsive to the interleukin 1 receptor antagonist anakinra. PMID- 22431772 TI - Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: excellent response to anakinra. PMID- 22431773 TI - Practice Gaps. Improving the care of our patients who are receiving glucocorticoid therapy. PMID- 22431775 TI - Population-based estimates of the occurrence of multiple vs first primary basal cell carcinomas in 4 European regions. AB - OBJECTIVE: To estimate the population-based incidence of first and multiple basal cell carcinomas (BCCs) throughout Europe. DESIGN: The registry practices of 4 population-based cancer registries that routinely register BCC incidence were evaluated for inclusion of first and subsequent histologically confirmed BCCs. Where multiple BCCs were not routinely registered, comparisons with hospital databases were made. DATA SOURCES: Cancer registry databases from Finland, Malta, the Netherlands (Eindhoven), and Scotland were inspected for registry of first and multiple BCCs in recent years. Cross-checks with hospital and pathology databases were made to check for completeness. RESULTS: Age-standardized first BCC incidence rates varied between 77 (Malta) and 158 (Eindhoven) per 100 000 person-years. Generally, rates were higher in males than in females, and incidences increased steeply with increasing age. There were approximately 30% more patients with a BCC and 40% to 100% more BCC tumors diagnosed in a given calendar year than were routinely reported for patients with a first primary BCC. The difference between the number of first primary BCCs and the total number of BCCs in a calendar year was generally slightly higher for males than for females and increased substantially with increasing age. CONCLUSION: Currently, routinely reported first BCC incidence rates of the included countries should be multiplied by a factor of 1.3 for an estimate of total number of patients diagnosed as having a BCC in a given year. PMID- 22431777 TI - Photodynamic therapy for multiple eruptive keratoacanthomas associated with vemurafenib treatment for metastatic melanoma. AB - BACKGROUND: The development of keratoacanthomas (KAs) and well-differentiated squamous cell carcinomas (SCCs) is a known adverse effect of novel BRAF inhibitors such as vemurafenib. With multiple such neoplasms often arising after BRAF inhibitor therapy, surgical excision is often impractical. OBSERVATIONS: We describe a patient with stage IV melanoma who received the BRAF inhibitor vemurafenib (recently approved by the US Food and Drug Administration) as part of a clinical trial and developed numerous diffuse, pathology-proven KAs and SCCs. The high number of lesions across a broad area precluded surgical treatment; instead, a noninvasive field approach using photodynamic therapy (PDT) was initiated. Compared with untreated tumors, most lesions demonstrated significant clinical regression following successive cycles of PDT. CONCLUSIONS: Given vemurafenib's recent approval by the US Food and Drug Administration, we provide a timely case report on the effective use of PDT in the treatment of BRAF inhibitor-associated KAs and SCCs. Although further studies are needed to better understand the biological processes of these secondary neoplasms, our observation provides an alternative noninvasive solution for improving the quality of life for patients receiving BRAF inhibitor therapy. PMID- 22431778 TI - A randomized controlled trial of belimumab for the treatment of active systemic lupus erythematosus. PMID- 22431779 TI - DIRA, DITRA, and new insights into pathways of skin inflammation: what's in a name? PMID- 22431781 TI - Ulcers and stellate scars on bilateral ankles. PMID- 22431782 TI - A serpiginous eruption. PMID- 22431783 TI - Ulceration of abdominal striae distensae (stretch marks) in a cancer patient. PMID- 22431784 TI - A firm nodule on the glabella with recurrent facial edema. PMID- 22431785 TI - Parental response to written eczema action plans in children with eczema. PMID- 22431786 TI - Medical students' perceptions of skin cancer: confusion and disregard for warnings and the need for new preventive strategies. PMID- 22431787 TI - A comparison of Florida skin cancer screening rates with those in the rest of the United States. PMID- 22431788 TI - No association between coffee and caffeine intake and risk of psoriasis in US women. PMID- 22431789 TI - Comparison of refined and crude indigo naturalis ointment in treating psoriasis: randomized, observer-blind, controlled, intrapatient trial. PMID- 22431790 TI - Gabapentin not shown to prevent postherpetic neuralgia. PMID- 22431791 TI - Long-term use of tetracycline and Staphylococcus aureus tetracycline resistance: not only a problem of acne. PMID- 22431792 TI - Senna-containing laxative inducing blistering dermatitis in toddlers. PMID- 22431793 TI - A fatal case of mothball intoxication presenting with refractory pruritus and ichthyosis. PMID- 22431794 TI - Disseminated verrucous varicella zoster with exclusive follicular involvement. PMID- 22431796 TI - Dermoscopy and confocal microscopy of thrombosed hemangiomas. PMID- 22431797 TI - Clinical definitions of pertussis: Summary of a Global Pertussis Initiative roundtable meeting, February 2011. AB - Existing clinical case definitions of pertussis are decades old and based largely on clinical presentation in infants and children, yet an increasing burden is borne by adolescents and adults who may manifest distinct signs/symptoms. Therefore, a "one-size-fits-all" clinical case definition is no longer appropriate. Seeking to improve pertussis diagnosis, the Global Pertussis Initiative (GPI) developed an algorithm that delineates the signs/symptoms of pertussis most common to 3 age groups: 0-3 months, 4 months to 9 years, and >=10 years. These case definitions are based on clinical presentation alone, but do include recommendations on laboratory diagnostics. Until pertussis can be accurately diagnosed, its burden will remain underestimated, making the introduction of epidemiologically appropriate preventive strategies difficult. The proposed definitions are intended to be widely applicable and to encourage the expanded use of laboratory diagnostics. Determination of their utility and their sensitivity and/or specificity versus existing case definitions is required. PMID- 22431798 TI - Safety and efficacy of WC2031 versus vibramycin for the treatment of uncomplicated urogenital Chlamydia trachomatis infection: a randomized, double blind, double-dummy, active-controlled, multicenter trial. AB - BACKGROUND: Recent studies have raised concern about efficacy of azithromycin for Chlamydia trachomatis infection. Research investigating new antibiotic regimens for chlamydia has been sparse, especially regimens that may reduce adherence difficulties with the recommended twice-daily doxycycline regimen. METHODS: We conducted a randomized, double-blind, double-dummy, active-controlled, multicenter trial with the objective of evaluating the safety and efficacy of WC2031 (doxycycline hyclate delayed-release 200-mg tablet) orally once daily for 7 days versus Vibramycin (doxycycline hyclate capsule) 100 mg orally twice daily for 7 days for treatment of uncomplicated urogenital chlamydia. Men and nonpregnant women aged 19-45 years with a urogenital chlamydial diagnosis or a sexual partner with chlamydia were eligible. The primary outcome was microbial cure by nucleic acid amplification testing at day 28. Noninferiority of WC2031 was inferred if the lower limit of the 95% confidence interval (CI) of the difference in cure rates was >-10%. RESULTS: A total of 495 subjects were randomized. The modified intent-to-treat (mITT) population with evaluable efficacy consisted of 323 subjects. Baseline patient characteristics did not differ between the mITT groups. Microbial cure rates for WC2031 were 95.5% (95% CI, 92.3-98.8) versus 95.2% (95% CI, 92.0-98.4) for Vibramycin (95% CI for the difference in cure rates, -4.3% to 4.9%). Types of adverse events were comparable. Nausea and vomiting occurred less frequently with WC2031 than with Vibramycin (13% vs 21% and 8% vs 12%, respectively). CONCLUSIONS: WC2031 was noninferior to Vibramycin for uncomplicated urogenital chlamydia treatment, better tolerated, and demonstrated comparable safety. WC2031 could improve treatment adherence over twice-daily Vibramycin. CLINICAL TRIALS REGISTRATION: NCT01113931. PMID- 22431799 TI - Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. AB - BACKGROUND: Escherichia coli O157:H7 is the leading cause of hemolytic uremic syndrome (HUS). Risk factors for development of this complication warrant identification. METHODS: We enrolled children infected with E. coli O157:H7 within 1 week of the onset of diarrhea in this prospective cohort study. The study was conducted in 5 states over 9.5 years . The primary and secondary outcomes were HUS (hematocrit <30% with smear evidence of hemolysis, platelet count <150 * 10(3)/uL, and serum creatinine concentration > upper limit of normal for age) and oligoanuric HUS. Univariate and multivariable and ordinal multinomial regression analyses were used to test associations between factors apparent during the first week of illness and outcomes. RESULTS: Of the 259 children analyzed, 36 (14%) developed HUS. Univariate analysis demonstrated that children who received antibiotics during the diarrhea phase more frequently developed HUS than those who did not (36% vs 12%; P = .001). The higher rate of HUS was observed across all antibiotic classes used. In multivariable analysis, a higher leukocyte count (adjusted odds ratios [aOR] 1.10; 95% CI, 1.03-1.19), vomiting (aOR 3.05; 95% CI, 1.23-7.56), and exposure to antibiotics (aOR 3.62; 95% CI, 1.23-10.6) during the first week of onset of illness were each independently associated with development of HUS. Multinomial ordinal logistic regression confirmed that initial leukocyte count and antibiotic use were independently associated with HUS and, additionally, these variables were each associated with the development of oligoanuric HUS. CONCLUSIONS: Antibiotic use during E. coli O157:H7 infections is associated with a higher rate of subsequent HUS and should be avoided. PMID- 22431800 TI - Occult Staphylococcus aureus bacteremia in adult emergency department patients: rare but important. AB - BACKGROUND: We sought to elaborate the epidemiology and outcomes of adult patients with occult Staphylococcus aureus bacteremia who were inadvertently discharged from the emergency department (ED) before positive blood culture results were obtained. METHODS: Between 2001 and 2010, 759 true occult bacteremia cases were identified, including 65 patients with S. aureus bacteremia. Sixty-two patients were enrolled (case group) and analyzed using two 1:2 case-control strategies. Control group I patients were selected from among 997 S. aureus bacteremia patients directly admitted from the ED. Control group II patients were selected from 694 ED patients with occult bacteremia other than S. aureus. Cox regression analyses were used to assess the independent effect of occult S. aureus bacteremia on patient mortality. RESULTS: There was no significant difference between the case group and control group I with respect to organ failure, septic shock, intensive care unit (ICU) admission proportion, length of ICU stay, and 30-day mortality. However, compared with control group II, the case group had significantly higher rates of hospital admission, organ failure, septic shock, ICU admission, and 30-day mortality. Age, endocarditis, and S. aureus infection were independent predictors of mortality among adult occult bacteremia patients. CONCLUSIONS: Among patients with occult bacteremia, S. aureus infections had significantly greater adverse impacts on a variety of outcome variables than other bacterial infections. Because S. aureus bacteremia is frequently associated with endovascular or deep-seated infection, it is imperative that first-line clinicians perform prudent evaluations of cases with nonapparent infection foci before discharging febrile patients from EDs. PMID- 22431801 TI - Prevalence and factors associated with sleep disturbances among early-treated HIV infected persons. AB - BACKGROUND: Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited. METHODS: We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank. RESULTS: Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS >=10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0-142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4 5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7-.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1 fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly. CONCLUSIONS: HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life. PMID- 22431802 TI - Role of fluorine 18 fluorodeoxyglucose positron emission tomography-computed tomography in focal and generalized infectious and inflammatory disorders. AB - Several advances in imaging have become part of the work-up for localization, diagnosis, and management of infectious diseases and inflammatory disorders. Utility of multiple imaging modalities is a time-consuming step, and significant numbers of patients remain undiagnosed despite utilization of series of tests. Inflammatory cells have avidity for fluorine 18-labeled fluorodeoxyglucose ((18)F FDG), and thus positron emission tomographic-computed tomographic (PET-CT) hybrid imaging provides anatomical and metabolic information that can be used to define the extent of infectious and inflammatory diseases and assess response to treatment. PET-CT provides a "one-stop test" in which use of hybrid imaging provides anatomical and metabolic information. The extent of disease is defined quickly, and response to treatment can be assessed. This modality also helps define the metastatic and/or septic foci where there is lack of localizing symptoms. More recently, there is increasing awareness among clinicians regarding the ability of PET-CT to help in diagnosing, characterizing, and assessing inflammatory disorders. This article reviews the usefulness of this imaging modality. PMID- 22431803 TI - Potential intussusception risk versus health benefits from rotavirus vaccination in Latin America. AB - BACKGROUND: With the recent postlicensure identification of an increased risk of intussusception with rotavirus vaccine, the 14 Latin American countries currently using rotavirus vaccine must now weigh the health benefits versus risks to assess whether to continue vaccination. To inform policy considerations, we estimated excess intussusception cases and mortality potentially caused by rotavirus vaccine for each of the 14 countries and compared these estimates to hospitalizations and deaths expected to be averted through vaccination. METHODS: We used regional rotavirus disease burden and rotavirus vaccine efficacy data, global natural intussusception and regional rotavirus vaccine-related risk estimates, and country-specific diphtheria, tetanus, and pertussus vaccination coverage rates to estimate rotavirus vaccine coverage rates. We performed a probabilistic sensitivity analysis to account for uncertainty in these parameters. RESULTS: For an aggregate hypothetical birth cohort of 9.5 million infants in these 14 countries, rotavirus vaccine would annually prevent 144 746 (90% confidence interval [CI], 128 821-156 707) hospitalizations and 4124 deaths (90% CI, 3740-4239) due to rotavirus in their first 5 years of life but could cause an additional 172 hospitalizations (90% CI, 126-293) and 10 deaths (90% CI, 6-17) due to intussusception, yielding benefit-risk ratios for hospitalization and death of 841:1 (90% CI, 479:1 to 1142:1) and 395:1 (90% CI, 207:1 to 526:1), respectively. In an uncertainty analysis using 10 000 simulations of our probabilistic parameters, in comparing rotavirus disease averted to intussusception events caused, the hospitalization ratio was never below 100:1, and our death ratio fell below 100:1 only once. CONCLUSIONS: The health benefits of vaccination far outweigh the short-term risks and support continued rotavirus vaccination in Latin America. PMID- 22431804 TI - Performance of Candida real-time polymerase chain reaction, beta-D-glucan assay, and blood cultures in the diagnosis of invasive candidiasis. AB - BACKGROUND: The sensitivity of blood cultures for diagnosing invasive candidiasis (IC) is poor. METHODS: We performed a validated Candida real-time polymerase chain reaction (PCR) and the Fungitell 1,3-beta-D-glucan (BDG) assay on blood samples collected from prospectively identified patients with IC (n = 55) and hospitalized controls (n = 73). Patients with IC had candidemia (n = 17), deep seated candidiasis (n = 33), or both (n = 5). Controls had mucosal candidiasis (n = 5), Candida colonization (n = 48), or no known Candida colonization (n = 20). RESULTS: PCR using plasma or sera was more sensitive than whole blood for diagnosing IC (P = .008). Plasma or sera PCR was more sensitive than BDG in diagnosing IC (80% vs 56%; P = .03), with comparable specificity (70% vs 73%; P = .31). The tests were similar in diagnosing candidemia (59% vs 68%; P = .77), but PCR was more sensitive for deep-seated candidiasis (89% vs 53%; P = .004). PCR and BDG were more sensitive than blood cultures among patients with deep-seated candidiasis (88% and 62% vs 17%; P = .0005 and .003, respectively). PCR and culture identified the same Candida species in 82% of patients. The sensitivity of blood cultures combined with PCR or BDG among patients with IC was 98% and 79%, respectively. CONCLUSIONS: Candida PCR and, to a lesser extent, BDG testing significantly enhanced the ability of blood cultures to diagnose IC. PMID- 22431805 TI - Thinking deeper about important mass treatment trials. PMID- 22431806 TI - Both host and pathogen factors predispose to Escherichia coli urinary-source bacteremia in hospitalized patients. AB - BACKGROUND: The urinary tract is the most common source for Escherichia coli bacteremia. Mortality from E. coli urinary-source bacteremia is higher than that from urinary tract infection. Predisposing factors for urinary-source E. coli bacteremia are poorly characterized. METHODS: In order to identify urinary-source bacteremia risk factors, we conducted a 12-month prospective cohort study of adult inpatients with E. coli bacteriuria that were tested for bacteremia within +/-1 day of the bacteriuria. Patients with bacteremia were compared with those without bacteremia. Bacterial isolates from urine were screened for 16 putative virulence genes using high-throughput dot-blot hybridization. RESULTS: Twenty four of 156 subjects (15%) had E. coli bacteremia. Bacteremic patients were more likely to have benign prostatic hyperplasia (56% vs 19%; P = .04), a history of urogenital surgery (63% vs 28%; P = .001), and presentation with hesitancy/retention (21% vs 4%; P = .002), fever (63% vs 38%; P = .02), and pyelonephritis (67% vs 41%; P = .02). The genes kpsMT (group II capsule) (17 [71%] vs 62 [47%]; P = .03) and prf (P-fimbriae family) (13 [54%] vs 40 [30%]; P = .02) were more frequent in the urinary strains from bacteremic patients. Symptoms of hesitancy/retention (odds ratio [OR], 7.8; 95% confidence interval [CI], 1.6-37), history of a urogenital procedure (OR, 5.4; 95% CI, 2-14.7), and presence of kpsMT (OR, 2.9; 95% CI, 1-8.2) independently predicted bacteremia. CONCLUSIONS: Bacteremia secondary to E. coli bacteriuria was frequent (15%) in those tested for it. Urinary stasis, surgical disruption of urogenital tissues, and a bacterial capsule characteristic contribute to systemic invasion by uropathogenic E. coli. PMID- 22431807 TI - Mucormycosis in organ and stem cell transplant recipients. AB - Mucormycosis is a devastating invasive fungal disease whose incidence has increased during the past decade. Mucormycosis now represents a major threat in transplant recipients, accounting for 2% and 8% of invasive fungal infections in recent cohorts of solid-organ and allogeneic stem-cell transplant recipients, respectively. Mucormycosis most often occurs late, >3 months after transplantation, although cases occurring early have been observed, especially among liver transplant recipients and in cases of graft-transmitted infection. Recent guidelines have emphasized the direct examination of the involved fluid or tissue and culture from a sterile site as the most appropriate diagnostic strategy and the use of lipid formulations of amphotericin B and major surgery when feasible as the most appropriate first-line therapeutic strategy for mucormycosis in organ and stem cell transplant recipients. PMID- 22431808 TI - Expanding access to treatment for hepatitis C in resource-limited settings: lessons from HIV/AIDS. AB - The need to improve access to care and treatment for chronic hepatitis C virus (HCV) infection in resource-limited settings is receiving increasing attention. Key priorities for scaling up HCV treatment and care include reducing the cost of current and future treatment; simplifying the package of care; identifying opportunities to shift specific tasks to nonspecialists to overcome human resource constraints; service integration with human immunodeficiency virus (HIV) clinics, prison health services, and needle syringe and oral substitution therapy programs; improving surveillance, monitoring, and research; encouraging patient and community engagement; focusing specifically on the needs of vulnerable groups; and increasing financial and political commitment. Many of these obstacles have been addressed in rolling out treatment for human immunodeficiency virus during the last decade, and a number of lessons can be drawn to help improve access to HCV care. PMID- 22431809 TI - Effectiveness and safety of tigecycline: focus on use for approved indications. PMID- 22431810 TI - Linking Pneumocystis epidemiology, transmission, and virulence. PMID- 22431811 TI - Outbreaks of Pneumocystis pneumonia in 2 renal transplant centers linked to a single strain of Pneumocystis: implications for transmission and virulence. AB - BACKGROUND: There have been numerous reports of clustered outbreaks of Pneumocystis pneumonia (PCP) at renal transplant centers over the past 2 decades. It has been unclear whether these outbreaks were linked epidemiologically to 1 or several unique strains, which could have implications for transmission patterns or strain virulence. METHODS: Restriction fragment length polymorphism (RFLP) analysis was used to compare Pneumocystis isolates from 3 outbreaks of PCP in renal transplant patients in Germany, Switzerland, and Japan, as well as nontransplant isolates from both human immunodeficiency virus (HIV)-infected and uninfected patients. RESULTS: Based on RFLP analysis, a single Pneumocystis strain caused pneumonia in transplant patients in Switzerland (7 patients) and Germany (14 patients). This strain was different from the strain that caused an outbreak in transplant patients in Japan, as well as strains causing sporadic cases of PCP in nontransplant patients with or without HIV infection. CONCLUSIONS: Two geographically distinct clusters of PCP in Europe were due to a single strain of Pneumocystis. This suggests either enhanced virulence of this strain in transplant patients or a common, but unidentified, source of transmission. Outbreaks of PCP can be better understood by enhanced knowledge of transmission patterns and strain variation. PMID- 22431812 TI - A retrospective review of the use of autologous platelet gels for rhytidectomy. PMID- 22431813 TI - Recent advances in surgical pharyngeal modification procedures for the treatment of velopharyngeal insufficiency in patients with cleft palate. AB - Background To review recent advances in pharyngeal modification procedures for the treatment of velopharyngeal insufficiency (VPI) in patients with cleft palate after primary repair. In addition, we discuss some of the advantages and disadvantages of the various pharyngoplasty techniques, as well as their safety and efficacy. Methods A review of frequently used pharyngeal modification techniques in correction of VPI was performed, and their advantages and disadvantages are outlined. Several techniques in pharyngoplasty most recently described in the literature are compared and contrasted. Results The goal of surgical pharyngeal modification procedures is to correct the abnormal failure of velopharyngeal closure. Multiple techniques used in VPI surgery have proven to be effective. They have similar adverse effect profiles, but what distinguishes them is likely their effectiveness in cases of severe VPI. Conclusions Velopharyngeal insufficiency is a problematic issue both for the patient and the treating surgeon. The negative effect of VPI on patients' quality of life has long been known, and over the years numerous techniques have been described to correct or improve this problem. Pharyngoplasty and pharyngeal flap or combination procedures are most effective in cases of severe VPI. PMID- 22431814 TI - Simultaneous anterolateral thigh flap and temporalis tendon transfer to optimize facial form and function after radical parotidectomy. AB - Background Extirpation of aggressive parotid or cutaneous facial tumors often involves facial nerve sacrifice and the creation of a large soft-tissue defect. We describe a method for single-stage reconstruction during radical parotidectomy to restore facial form and function without additional morbidity. Methods We conducted a review of immediate reconstruction/reanimation of radical parotidectomy defects with the use of anterolateral thigh (ALT) fat and fascia flaps for facial contouring, orthodromic temporalis tendon transfer (OTTT), cable grafting of the facial nerve, and fascia lata lower lip suspension. Results Five patients (mean age, 67.4 years) underwent extirpation of malignant tumors with facial nerve sacrifice resulting in large soft-tissue deficits. All patients had ALT free tissue transfer to correct facial contour defects and OTTT to restore facial form and function. Four patients underwent cable grafting of facial nerve branches. Branches of the motor nerve to the vastus lateralis harvested from the ALT surgical site were used for cable nerve grafting in 3 patients. Fascia lata from the same ALT harvest site was used for lower lip suspension to the OTTT in 4 patients. There were no donor site complications. All patients achieved midfacial symmetry at rest, oral competence with dynamic corner-of-mouth movement, and full eye closure. Conclusions Tumor clearance, symmetric facial appearance, as well as dynamic facial rehabilitation were accomplished in a single-stage procedure using the method described herein. The ALT free flap provides versatile options for soft-tissue defects as well as access to motor nerves optimal for grafting without additional morbidity. Patients undergoing extirpation of malignant tumors requiring facial nerve sacrifice can undergo immediate free tissue contour reconstruction and facial reanimation procedures with no additional morbidity. PMID- 22431815 TI - Orbitomaxillary reconstruction using the layered fibula osteocutaneous flap. AB - OBJECTIVE: To describe a surgical technique for total palatomaxillary and orbital reconstruction using a fibula osteocutaneous free flap in a layered fashion. METHODS: Case series from a tertiary care facial plastic and reconstructive surgical practice including patients with postextirpative Brown 3a and 3b orbitopalatomaxillary defects undergoing immediate microvascular reconstruction. Application of the layered fibula free flap to composite maxillary defects permits single-stage, optimal reconstruction of contiguous orbitomaxillary defects, reconstitution of midface 3-dimensional contour, and restoration of the anterior alveolar arch with robust bone, thereby providing for potential sequential dental rehabilitation with osseointegrated implants. RESULTS: This technique demonstrates excellent long-term symmetry, support, function, and aesthetic contour. Although patients may need minor, adjunctive procedures, this technique is flexible in design and offers reliable outcomes with a minimum of morbidity. CONCLUSION: The fibula osteocutaneous free flap, because of its design flexibility and ability to provide structural support, is an excellent reconstructive option for total maxillary defects, including those that involve the orbit. PMID- 22431816 TI - Alternative 1-step nasal reconstruction technique. AB - OBJECTIVE: To describe a 1-step nasal reconstruction technique for use in lieu of a paramedian forehead flap that is usually raised at the location of the supratrochlear artery. METHODS: Using angiography in 10 fresh cadavers, we confirmed the arterial anatomy of the nasal and forehead regions to refine the paramedian forehead flap. Based on the anatomical data, we performed nasal reconstruction in 6 patients who had a full-thickness defect of the nasal ala or who needed alar base reconstruction with an island paramedian forehead flap based on the angular artery. RESULTS: From the anatomical study, we confirmed a rich network among the supratrochlear, dorsonasal, and angular arteries around the medial canthus. In the clinical cases, the subcutaneous pedicle was tunneled beneath the skin, without conspicuous bulkiness. For all patients, the operation was completed in 1 stage, and the flaps healed without evidence of necrosis. CONCLUSIONS: By moving the pedicle downward, a full-thickness nasal defect can be reconstructed in 1 stage that includes the alar lining or alar base with the paramedian forehead flap. This avoids restriction of the rotation arc, particularly when the alar lining or alar base is also needed for reconstruction. PMID- 22431817 TI - Split-thickness skin graft harvested from the scalp for the coverage of extensive temple or forehead defects in elderly patients. AB - OBJECTIVE: To review our experience of facial reconstruction with split-thickness skin grafts (STSGs) harvested from the scalp. METHODS: We included all patients undergoing STSG harvested from the scalp for the reconstruction of extensive forehead or temple defects after cancer resection. We recorded the size of resection before surgery and after healing, and we calculated the resulting contraction rate. Time of healing and occurrence of complication were also recorded. RESULTS: Forty patients were included. Their mean age was 87 years, and the mean size of resection was 26 cm(2). The duration of healing at the donor site was shorter than 12 days, and pain levels were low. The rate of contraction at the recipient site was 11% after healing. Good morphologic outcomes were reported by both patients and surgeon. CONCLUSION: Extensive forehead and temple defects can be covered in this way with a low morbidity; rapid, painless healing; and a high success rate, making this procedure particularly suitable for elderly patients. PMID- 22431818 TI - Leonardo da Vinci's Portrait of a Young Woman in Profile: studies of beauty and "ideal" proportions. PMID- 22431819 TI - The role of health links in international development: the need for greater evidence? PMID- 22431820 TI - The decision-to-delivery interval in emergency Caesarean sections and its correlation with perinatal outcome: evidence from 204 deliveries in a developing country. AB - The international standard decision-to-delivery interval (DDI) for emergency Caesarean sections (CSs) is <= 30 minutes but there is little evidence to support this recommendation. The aim of this study was to evaluate DDI for emergency CS and its relationship to perinatal outcome. We undertook a prospective observational study of consecutive cases of emergency CS. Perinatal outcomes were recorded as: Apgar score; neonates requiring admission; and perinatal deaths. The relation between DDI and perinatal outcome was analysed using chi-square and one way analysis of variance (ANOVA). Of 204 pregnancies observed, 19% of deliveries were achieved in <= 30 minutes. The mean DDI was 42.5 +/- 19.4 minutes. There was no difference between the perinatal outcome for babies with DDI of <= 30 versus 31-60 minutes. There was a significantly higher risk of poor perinatal outcome for babies with DDI > 60 minutes. The perinatal outcome between DDI of <= 30 and 31-60 minutes was statistically not different. However, the <= 30 minutes DDI should remain the gold standard. PMID- 22431821 TI - Profile of hospital admissions following acute poisoning from a major teaching hospital in North India. AB - A retrospective analysis of 584 cases of acute poisoning admitted with a medical emergency to the Department of Medicine, GTB Hospital, Delhi, over a three-year period. The patients were analysed with respect to the age, sex, mode of poisoning, type of poison consumed and mortality. Of these, 42.63% were aged 20 30 years. Poisoning was used as a suicidal agent by 63.8% of the patients. The nature of the poison could not be ascertained in 15.92% of patients. Sedatives were involved in 13.36%. Aluminium phosphide poisoning was found in 11.82%. The overall mortality was estimated to be 13.18% with 53.2% being caused by the consumption of aluminium phosphide. There has been a change in the nature of poisons consumed and the number of cases of aluminium phosphide poisoning is declining. However, aluminium phosphide poisoning still remains a major threat as it carries a high mortality rate. PMID- 22431822 TI - Treatment outcome of HIV-associated tuberculosis in a resource-poor setting. AB - Nigeria is among the countries with the world's highest tuberculosis (TB) burden, and HIV/TB co-infection is an important cause of mortality. We evaluate the treatment outcome of HIV-infected TB patients in Abakaliki, Nigeria. A retrospective cohort study of all TB patients registered at a tertiary hospital between January 2006 and December 2010 was conducted. Of 671 TB patients, 189 (28.2%) were HIV co-infected. Of these, 147 (77.8%) had pulmonary TB and 42 (22.2%) had extra-pulmonary TB. The overall treatment success rate was 52.4% (n = 99) and the defaulted in treatment rate was 30.2% (n = 57). Twenty-one (11.1%) died, and one (0.5%) had treatment failure. Younger age group (<15 years; P = 0.0024) and smear-positive status (P = 0.0056) were independent predictors of successful treatment. TB/HIV co-infection is associated with high mortality and alarming default rates during treatment. PMID- 22431823 TI - transportMYpatient: an initiative to overcome the barrier of transport costs for patients accessing treatment for obstetric fistulae and cleft lip in Tanzania. AB - Those with disabilities are often among the poorest and most vulnerable. Even when health care is provided free, transport costs may pose an insurmountable barrier to accessing treatment. This report outlines a new initiative in Tanzania which utilizes mobile phone technology to transfer funds covering transport costs for patients with obstetric fistulae or cleft lip and/or palate. The transportMYpatient initiative surpassed the set targets and saw a 65% increase in the number of fistulae repairs performed in 2010 compared with the year before and almost triple the number of cleft lip/palate repairs. Using mobile phone technology to transfer funds is an innovative way of overcoming a significant barrier to health-care access for patients in developing countries. PMID- 22431824 TI - Placental malaria and the relationship to pregnancy outcome at Gushegu District Hospital, Northern Ghana. AB - One complication of malaria infection during pregnancy is the sequestration of parasites in the placenta. The aim of this study was to determine the association between placental malaria and pregnancy outcome. This study was conducted at the Gushegu District Hospital in Ghana from June to August 2010. Sulfadoxine pyrimethamine (SP) was used as intermittent preventative treatment (IPT) during pregnancy. All mothers reporting for delivery were enrolled, except in cases of multiple pregnancies. The data was documented using a questionnaire. A placental blood sample was collected and analysed for malaria parasites. There were 56/107(52%) malaria positive samples. In women with placental malaria perinatal mortality was higher, duration of pregnancy shorter and birth weight lower. These results were statistically significant. In primigravidae the negative effects were more obvious. IPT is extensively implemented in Ghana, but this study found no evidence for an association between the number of doses and the outcome of pregnancy. PMID- 22431825 TI - Avoiding scrotal haematoma after repair of extensive scrotal hernias by postoperative scrotal compression through scrotal suspension by scrotal-abdominal skin suture. AB - Scrotal haematoma and oedema are the most frequent complications of scrotal surgery and are associated with high morbidity. Through early postoperative compression on the scrotal sac these complications can be avoided. Compression can be assured by the following simple surgical method independent of the quality of the postoperative care: extending the scrotal sac over the abdominal wall and fixing it with skin sutures under tension at the lower abdominal wall over a pile of gauzes. This method was shown to be effective after hernia repair of scrotal hernias but also seems promising for other scrotal surgery. PMID- 22431826 TI - Salvaging a diabetic foot: a new cost-effective method. AB - The method that we use has an initial cost (L 150) and uses fewer materials for dressing daily than other methods. It is easy to use at the extremities and is effective in preventing amputation in some diabetics. PMID- 22431827 TI - Is benign tertian malaria actually benign? AB - This retrospective study was conducted in order to determine the incidence of various complications of Plasmodium vivax malaria based on a review of case records in a tertiary care hospital in New Delhi, India. The case records of all confirmed cases of malaria over the period of one year were studied. Complete blood count, peripheral blood findings, liver and kidney functions were reviewed. There were 165 confirmed cases. Of these, 121 were due to P. vivax and 42 to P. falciparum. Two cases had mixed infection. The complications seen in the P. vivax cases were: thrombocytopenia; hepatic dysfunction; renal damage; and acute respiratory distress syndrome (ARDS). There were three deaths as a result of ARDS. This paper highlights the fact that P. vivax malaria, although considered to be a benign entity, can have a severe and complicated course, which is usually associated with P. falciparum malaria. PMID- 22431828 TI - Introduction of automated blood pressure devices intended for a low resource setting in rural Tanzania. AB - Regular blood pressure (BP) monitoring is a cost-effective means of early identification and management of hypertensive disease in pregnancy. In much of rural sub-Saharan Africa, the ability to take and act on accurate BP measurements is lacking as a result of poorly functioning or absent equipment and/or inadequate staff education. This study describes the feasibility of using validated automated BP devices suitable for low-resource settings (LRS) in primary health-care facilities in rural Tanzania. Following a primary survey, 19 BP devices were distributed to 11 clinics and re-assessed at one, three, six, 12 and 36 months. Devices were used frequently with high levels of user satisfaction and good durability. We conclude that the use of automated BP devices in LRS is feasible and sustainable. An assessment of their ability to reduce maternal and perinatal morbidity and mortality is vital. PMID- 22431829 TI - Changing clinico-laboratory profile of encephalitis patients in the eastern Uttar Pradesh region of India. AB - A cross-sectional study was done on 100 consecutive paediatric patients presenting with acute encephalitis syndrome. The clinico-laboratory features of all patients were recorded in a prestructured performa. Cerebrospinal fluid and serum samples were tested for: Japanese encephalitis (JE) virus; Chandipura virus; coxsackie virus; dengue virus; enterovirus 76; and West Nile virus. Twenty two (22.0%) patients were confirmed JE cases and 17% had parasitic or bacteriological aetiology. The remaining 61 cases (61.0%) in which no viral aetiological agent was found were grouped as non-JE cases. Peripheral vascular failure, splenomegaly and hypotonia were distinguishing clinical features found in the non-JE patients. A high mortality of 26.5% was seen in patients with confirmed or presumptive viral encephalitis (22/83). A fatal outcome was independently associated with peripheral vascular failure and pallor at the time of admission. Early recognition of these signs may help clinicians to manage these cases. PMID- 22431830 TI - 'Test and treat' policy in dyspepsia: time for a reappraisal. AB - The 'test and treat' policy is the recommended way to eradicate Helicobacter pylori in young patients with uninvestigated dyspepsia if the prevalence of H. pylori is high. India is considered to have a high prevalence of H. pylori. This observational study was conducted in order to discover the prevalence of H. pylori disease in uninvestigated dyspeptic patients, based on stool antigen test and immunoglobulin M (IgM) antibodies in the sera in order to ascertain the role of the 'test and treat' policy in this geographical area. Fifty patients (age <55 years) with uninvestigated dyspepsia presenting to surgery out-patient department of a tertiary teaching hospital in northern India were included in the study. Fifty healthy controls were also included. Dyspeptic patients with alarm symptoms were excluded from the study. Patients and controls were tested for IgM antibodies in their sera and H. pylori antigen in their stools. The positivity of the IgM antibody and H. pylori antigen in stools of the cases was 16% and 8%, respectively, while only 4% IgM positivity was found in the controls' samples. This study highlights the low prevalence of H. pylori in dyspeptic Indian patients. This indicates that initial proton pump therapy may be a better option than the 'test and treat' policy for young patients with uninvestigated dyspepsia. PMID- 22431831 TI - Use of fine needle aspiration cytology in the diagnosis of cutaneous leishmaniasis: a comparison with the conventional scraping method. AB - Cutaneous leishmaniasis is endemic in Iran. Scraping smears are widely used and fine needle aspiration (FNA) cytology is now attracting more attention. Both methods were performed on the clinically suspected cases in our study. Smears were stained using Giemsa. We compared the sensitivity, specificity and some other aspects of these two methods. Of our 400 patients, 346 had specimens that were positive for leishman body, and of these 328 were detected using both methods. However, 42 cases were confirmed positive by FNA cytology and 18 as a result of scraping smears. There was a significant difference between the two methods in the detection of leishman body and microgranuloma, slide background and patient comfort. The sensitivity of FNA cytology was greater even though the specificity was the same. Our study confirmed the advantages of FNA cytology as a reliable method for the diagnosis of cutaneous leishmaniasis. PMID- 22431832 TI - Animal bites in children: burden in urban Delhi. AB - Animal bites pose a significant problem throughout India. Despite the advances in and availability of modern vaccines, there remains a lack of awareness of the proper management of these bites. This study was conducted in a tertiary level referral hospital in Delhi in order to study the profile of paediatric victims of animal bites and to review the myths regarding the disease and management practices adopted by the parents of bite victims. It was found that parents are mostly unaware of the correct management practices regarding animal bites. PMID- 22431833 TI - Drain site evisceration of fallopian tube, another reason to discourage abdominal drain: report of a case and brief review of literature. AB - Placement of a drain following abdominal surgery is common despite a lack of convincing evidence in the current literature to support this practice. The use of intra-abdominal drain is associated with many potential and serious complications. We report a drain site evisceration of the right fallopian tube after the removal of an intra-abdominal drain. The drain was placed in the right iliac fossa in a patient who underwent a lower segment Caesarean section (LSCS) for meconium liquor with fetal distress. The Pfannenstiel incision made for LSCS was reopened and the protruding inflamed fimbrial end of the right fallopian tube was excised. The patient made an uneventful recovery. Routine intra-abdominal prophylactic drain following an abdominal surgery including LSCS should be discouraged. PMID- 22431834 TI - Age and rate of cognitive decline in Alzheimer disease: implications for clinical trials. AB - BACKGROUND: Factors that affect the rate of progression of Alzheimer disease (AD) need to be considered in the clinical trial designs of potential disease modifying therapies. OBJECTIVE: To determine the influence of age on AD course in a clinical trial setting. DESIGN: Pooled cohort study from 3 AD clinical trials of 18-month duration conducted by the Alzheimer Disease Cooperative Study group. SETTING: Alzheimer disease research centers from across the United States. PATIENTS: Four hundred seventy-one subjects with mild to moderate AD assigned to the placebo arm of 3 clinical trials. MAIN OUTCOME MEASURES: The relationships between baseline age and rate of change in the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-cog) 11, Mini-Mental State Examination, Clinical Dementia Rating scale Sum of Boxes score, Alzheimer Disease Cooperative Study activities of daily living scale, and Neuropsychiatric Inventory were analyzed using a mixed-effect regression model. Sample size calculation for possible future AD clinical trials lasting 18 months using the results of the change in ADAS-cog 11 by tertiles of age groups. RESULTS: Older age at baseline was associated with a slower rate of decline in the ADAS-cog 11 and the Mini-Mental State Examination scores. Almost twice as many subjects aged 80 years and older compared with those aged younger than 70 years would be required to demonstrate a 30% treatment effect on the ADAS-cog 11 in an 18-month AD trial. CONCLUSION: Subject age is an important factor to consider when defining the study population in and analyzing data from AD trials of potential disease-modifying therapies. PMID- 22431835 TI - Atypical cerebral venous thrombosis: magnetic resonance imaging and spectroscopy features. PMID- 22431836 TI - Contribution of cerebrospinal fluid thymosin beta4 levels to the clinical differentiation of Creutzfeldt-Jakob disease. AB - OBJECTIVE: To asses thymosin beta4 specificity as relevant to the diagnosis of Creutzfeldt-Jakob disease (CJD). DESIGN: A matrix-assisted laser desorption ionization time-of-flight mass spectrometry protein profiling analysis was applied to several neurological disorders that are known to lead to dementia. The relative peak area (percentage of area) of the thymosin beta4 MS signal was taken into account. SETTING: National Research Council, Cosenza, Italy. PATIENTS: Cerebrospinal fluid analysis was performed on 21 patients with neuropathologically confirmed CJD; 15 patients with frontotemporal dementia; 18 patients with probable Alzheimer disease; and 9 patients with a rapid-onset progressive dementia. A non-cognitively impaired control group consisted of 25 individuals without CJD or dementia. MAIN OUTCOME MEASURES: The thymosin beta4 test results in CJD and other dementia. RESULTS: The thymosin beta4 cerebrospinal fluid levels appeared to be markedly increased in CJD samples compared with frontotemporal cases (P = 10(-7)) and patients with Alzheimer disease (P = 10( 7)). A lower significance was observed vs the group with rapid-onset progressive dementia (P = .0004). Thus, at a cutoff value of 1.2% of the thymosin beta4 relative peak area, we estimated 100% sensitivity with 98.5% specificity. CONCLUSION: These findings indicate that cerebrospinal fluid levels of thymosin beta4 protein measured by matrix-assisted laser desorption ionization time-of flight mass spectrometry may effectively contribute to discriminate CJD from other forms of dementia. PMID- 22431838 TI - The brighter side of music in dystonia. AB - OBJECTIVE: To report a patient with genetically proven DYT1 dystonia who shows dramatic improvement in symptoms while playing the piano. DESIGN: Case study. SETTING: Sobell Department for Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, England. PATIENT: A 49-year old right-handed male civil servant. MAIN OUTCOME MEASURES: The patient was videotaped, and electromyographic activity was recorded from the splenius capitis, sternocleidomastoid, and orbicularis oculi muscles, while he was (1) at rest, (2) playing an electric piano with auditory feedback, and (3) playing an electric piano without auditory feedback (ie, when the sound of the piano is turned off). RESULTS: At baseline, the patient had generalized dystonia with prominent upper limb, neck, and facial involvement. While he was playing the piano, there was an instant and almost complete improvement in dystonia symptoms. The improvement was also noticeable when he played the piano without auditory feedback. There was a significant reduction in electromyographic activity for all recorded muscles when he played the piano, compared with his baseline electromyographic activity. CONCLUSION: This is a unique case of "paradoxical" improvement in dystonia symptoms with activity (ie, playing a piano), in contrast to the typical worsening of dystonia symptoms with activity. We discuss the possible mechanisms underlying this phenomenon. One of the most intriguing features of primary dystonia is the variability of abnormal muscle activity relative to the context in which movement is attempted (eg, the exquisite task specificity of focal hand dystonia or the phenomenon of the geste antagoniste). We present a unique case of an amateur pianist with genetically proven DYT1 dystonia who shows dramatic improvement in generalized dystonia symptoms while playing piano. PMID- 22431837 TI - Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. AB - OBJECTIVE: To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. DESIGN: Double-blind, placebo-controlled clinical trial. SETTING: Academic medical centers. PARTICIPANTS: Subjects with mild to moderate Alzheimer disease. INTERVENTION: Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (alpha-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of alpha lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. MAIN OUTCOME MEASURES: Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer's Disease Cooperative Study Activities of Daily Living Scale). RESULTS: Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Abeta42, tau, and P-tau(181) levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. CONCLUSIONS: Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2 isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00117403. PMID- 22431839 TI - Western Australia--rising to the human rights challenge? PMID- 22431840 TI - The emergence of a recovery movement for alcohol and drug dependence. PMID- 22431841 TI - A longitudinal study of mental health in refugees from Burma: the impact of therapeutic interventions. AB - OBJECTIVE: The present study seeks to examine the impact of therapeutic interventions for people from refugee backgrounds within a naturalistic setting. METHODS: Sixty-two refugees from Burma were assessed soon after arriving in Australia. All participants received standard interventions provided by a resettlement organisation which included therapeutic interventions, assessment, social assistance, and referrals where appropriate. At the completion of service provision a follow-up assessment was conducted. RESULTS: Over the course of the intervention, participants experienced a significant decrease in symptoms of post traumatic stress disorder, anxiety, depression and somatisation. Pre-intervention symptoms predicted symptoms post-intervention for post-traumatic stress, anxiety and somatisation. Post-migration living difficulties, the number of traumas experienced, and the number of contacts with the service agency were unrelated to all mental health outcomes. CONCLUSIONS: In the first Australian study of its kind, reductions in mental health symptoms post-intervention were significantly linked to pre-intervention symptomatology and the number of therapy sessions predicted post-intervention symptoms of post-traumatic stress. Future studies need to include larger samples and control groups to verify findings. PMID- 22431849 TI - Introduction: Solving the clinical problem of vancomycin resistance. PMID- 22431850 TI - Oritavancin microbiologic features and activity results from the surveillance program in the United States. AB - Oritavancin is in the final stages of clinical development for treatment of acute bacterial skin and skin structure infections. This drug has demonstrated potent activity against staphylococci (minimum inhibitory concentration [MIC] for which 90% of isolates are inhibited [MIC(90)], 0.06 MUg/mL), enterococci (MIC(90), <= 0.008 to 0.5 MUg/mL), and streptococci (MIC(90), <= 0.008 to 0.12 MUg/mL), including enhanced potency against vancomycin-resistant enterococci. During the clinical development of oritavancin, it was demonstrated that this molecule binds to plastic labware surfaces and that this feature was likely responsible for interlaboratory variability observed from in vitro investigations before 2006. Therefore, reference broth microdilution methods and MIC ranges for quality control strains were reestablished using media supplemented with a surfactant (polysorbate-80, 0.002%). These were followed by numerous experiments to reassess the in vitro characteristics of oritavancin; the results originating from those studies are summarized here. The oritavancin activity tested against a resistance surveillance collection of 12,367 Gram-positive clinical pathogens and resistant subsets from the United States (2008-2009) is also presented, with the highest MIC among staphylococci at only 0.25 MUg/mL. In vitro results for oritavancin indicate wide potential use against Gram-positive pathogens. PMID- 22431851 TI - Oritavancin: mechanism of action. AB - Oritavancin is a semisynthetic lipoglycopeptide analogue of vancomycin that contains the heptapeptide core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic N-4-(4-chlorophenyl)benzyl (also referred to as 4'-chlorobiphenylmethyl) substituent on the disaccharide sugar, the addition of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to D-alanyl-D-alanine stem termini in Gram positive bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin and contributes to oritavancin's activity versus vancomycin-resistant organisms. The presence of the hydrophobic 4'-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in depolarization, permeabilization, and concentration-dependent, rapid cell death. This mechanism is shared with telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion, oritavancin's mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin's multiple mechanisms of action confer activity against vancomycin susceptible and -resistant organisms, as well as rapid, concentration-dependent killing versus actively growing, stationary phase, and biofilm-producing Gram positive bacteria. PMID- 22431852 TI - In vivo activity of oritavancin in animal infection models and rationale for a new dosing regimen in humans. AB - Oritavancin is a novel glycopeptide antibiotic with concentration-dependent killing of Gram-positive cocci and pharmacokinetics characterized by extensive tissue distribution and a long terminal half-life. Its development was hindered by a 16- to 32-fold underestimation of activity against staphylococci and enterococci because of oritavancin's sticking to vials and tubes. Dose fractionation studies in animal models suggested the peak concentration was the major index for efficacy. Once-daily intravenous administration of oritavancin was effective in methicillin-resistant Staphylococcus aureus (MRSA) endocarditis, penicillin-susceptible and cephalosporin-resistant pneumococcal meningitis in rabbits, staphylococcal and enterococcal central venous catheter infections in rats, and 24-hour postprophylaxis of inhaled anthrax in mice. Orally administered oritavancin was more effective than vancomycin in Clostridium difficile infection in hamsters. Pharmacodynamics suggested that a single dose of oritavancin at 1200 mg would be efficacious in humans. Simulation of this dose in neutropenic mice was highly effective in methicillin-sensitive S. aureus and MRSA thigh and bacteremia infections and pneumococcal lung infections. PMID- 22431853 TI - Macrophage killing of bacterial and fungal pathogens is not inhibited by intense intracellular accumulation of the lipoglycopeptide antibiotic oritavancin. AB - Intact phagocytic effector function is fundamental to host defense against microbial pathogens. Concern has been raised regarding the potential that accumulation of certain agents, including cationic amphiphilic antibiotics, within macrophages could cause a mixed-lipid storage disorder, resulting in macrophage dysfunction in recipients. The ability of 2 macrophage cell lines (HL 60; RAW 264.7) to kill archetypal Gram-positive (Staphylococcus aureus), Gram negative (Acinetobacter baumannii), and fungal (Candida albicans) pathogens was tested following exposure of the macrophages to the lipoglycopeptide antibiotic oritavancin. Oritavancin did not affect killing of C. albicans but markedly enhanced killing of S. aureus by both macrophages. Oritavancin modestly reduced killing of A. baumannii by HL-60 cells but not by RAW 264.7 cells. Thus, macrophage killing of microbes remains intact despite substantial intracellular accumulation with a lipoglycopeptide antibiotic. PMID- 22431854 TI - Unmet needs and prospects for oritavancin in the management of vancomycin resistant enterococcal infections. AB - The treatment of infections caused by vancomycin-resistant enterococci (VRE) has become an important clinical challenge and compromises the care of critically ill patients. A striking increase in the frequency of nosocomial isolation of multidrug-resistant Enterococcus faecium has dramatically reduced the therapeutic alternatives because the majority of E. faecium isolates are resistant to ampicillin and vancomycin. Only 2 agents have US Food and Drug Administration approval for the treatment of VRE (E. faecium) infections, namely, linezolid and quinupristin/dalfopristin (Q/D). However, the use of these compounds in severe VRE infections is hampered by the lack of in vivo bactericidal activity, reports of therapeutic failures with monotherapy, a requirement for central venous access for administration (Q/D), and adverse-effect profile. The lipopeptide antimicrobial daptomycin has in vitro bactericidal activity against VRE; however, clinical use of this compound for VRE has not been well studied, and the reports of resistance emerging during therapy at the approved doses are worrisome. Tigecycline has in vitro bacteriostatic activity against VRE, but its clinical use for serious enterococcal infections is unclear due to low serum levels and static effect. Thus, current reliable therapies for VRE appear to be limited, and clinical data that use the above compounds are certainly scant. Oritavancin is an investigational semisynthetic glycopeptide with potent in vitro activity against VRE (both VanA and VanB phenotypes). Although review of the available preclinical data indicates that this compound used as a single agent is likely to have important limitations for the treatment of a severe VRE infection (ie, endocarditis), combination of oritavancin with other agents such as aminoglycosides may offer promise and deserves further investigation, as does use of oritavancin for less serious infections as monotherapy for vancomycin susceptible and multidrug-resistant enterococci. PMID- 22431855 TI - Oritavancin: a new opportunity for outpatient therapy of serious infections. AB - Oritavancin is a new antibiotic for the treatment of serious infections with Gram positive bacteria. It has been shown to be effective against methicillin susceptible and -resistant Staphylococcus aureus as well as enterococci. With a terminal half-life of 393 hours, oritavancin lends itself to a convenient and potentially cost-effective single-dose regimen. The single-dose regimen is currently being evaluated in pivotal phase 3 studies. This unique property provides an opportunity to assure consistent, effective, and safe treatment for serious infections while reducing the costs of care through the elimination of multiple infusions, reduced medical care staff, shorter hospital stays, and avoidance of hospital-acquired infections. These features seem ideal for the use of oritavancin in the outpatient management of serious infections. The impact that oritavancin will have on outpatient therapy is unclear. Current models will need to change with only a single infusion. Physician monitoring of the infection and underlying diseases may not be as frequent despite the need for close follow up and frequent evaluations. There will be less need for a team of outpatient infusion specialists. Outpatient therapy will be compensated less without multiple infusions. With the possibility of fewer physician and other medical visits, there will be more responsibility for the patient and family and a reliance on patients to care for themselves. Although oritavancin offers tremendous theoretical advantages in the outpatient treatment of serious infections, care should be taken to assure the quality of care through changes in reimbursement, patient education, and development of systems to monitor care and outcomes. PMID- 22431856 TI - Nine kindreds of familial sticky platelet syndrome phenotype. AB - INTRODUCTION: Sticky platelet syndrome (SPS) is most likely a hereditary thrombophilia characterized by platelet hyperaggregation after low concentrations of platelet inducers--adenosine diphosphate and/or epinephrine. We present 9 kindreds with SPS familial occurrence. MATERIAL AND METHODS: Familial trait of SPS was looked up in the database of the National Center of Hemostasis and Thrombosis. Families with at least 3 SPS-positive members were studied, described, and presented. RESULTS: In the group of 1093 symptomatic patients, SPS was confirmed in 240 cases. Familial occurrence with at least 3 SPS-positive relatives was found in 9 cases. CONCLUSION: The exact pathogenesis of SPS is not sufficiently explained. Our findings seem to support the idea that SPS might have an autosomal dominant hereditary fashion. PMID- 22431857 TI - Mean platelet volume in the diagnosis and prognosis of Crimean-Congo hemorrhagic fever. AB - INTRODUCTION: Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne zoonosis, which is a severe illness, causing hemorrhages in humans. Mean platelet volume (MPV) is used as a surrogate marker of platelet function and has been shown to be a sign of inflammation. The objective of the present study is to examine the association between MPV and CCHF. We also aimed to investigate the association between MPV and coagulopathy markers in the mortality rates and prognosis of patients with CCHF. PATIENTS AND METHODS: Ninety-three patients with CCHF were enrolled retrospectively into the study and 15 of them were excluded according to the exclusion criteria. Twenty-five healthy individuals were included as a control group which was age and gender matched with CCHF patients. We compared the levels of MPV between the patient and the control groups. We also compared the coagulopathy markers of fatal CCHF patients (n = 9) with nonfatal cases (n = 69). RESULTS: Platelet counts were significantly lower in the CCHF group. Levels of international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) were significantly higher in CCHF group (P < .001, <.001, <.001, respectively). A statistically significant increase in MPV was observed in patients with CCHF compared with healthy controls (8.63 +/- 1.23 fL vs 7.65 +/- 0.42 fL, P < .001). Receiver-operating characteristic curve analysis suggested that the optimum MPV level cutoff points for patients with CCHF was 8.15 fL, with a sensitivity and specificity of 65% and 88%, respectively. The MPV levels were not significantly different between group 2 (nonsurvivor) and group 1 (survivor). However, platelet count, D-dimer, INR, PT, and aPTT were also positively correlated with the mortality rates (P = .008, <.001, <.001, <.001, and <.001, respectively). Multivariable logistic regression model showed an independent correlation between MPV and mortality rate (P < .001). CONCLUSION: In conclusion, MPV may be a beneficial marker in the diagnosis of CCHF, especially in cases with thrombocytopenia, the MPV levels are high. We also conclude that MPV may independently predict the prognosis of patients with CCHF. PMID- 22431858 TI - Oral versus vaginal combined hormonal contraceptives' effect on coagulation and inflammatory biomarkers among young adult women. AB - In order to compare the effect of combined oral contraceptive (COC) and combined vaginal contraceptive (CVC) methods on the inflammation and procoagulation, we recruited female participants in 3 groups: control participants, COC users, and CVC users. We measured different blood biomarkers. The users of both COC and CVC had higher levels of C-reactive protein (P < .0001) and factor VII (P < .0001). However, CD40 ligand was only higher for COC users (P < .0001) and not the CVC users. Even though the levels of thrombin/antithrombin III were not higher for COC and CVC users, as compared to the controls, CVC users had higher levels as compared to COC users (P = .0327). As compared to the control group, we observed higher levels von Willebrand factor among CVC users but not the COC users. Longitudinal studies with larger sample size are needed to better assess the inflammatory and procoagulation response due to CVC use. PMID- 22431859 TI - Outcomes of paramedian forehead and nasolabial interpolation flaps in nasal reconstruction. AB - OBJECTIVE: To determine the factors contributing to failure of interpolation flaps in nasal reconstruction. DESIGN: Retrospective medical chart review. SETTING: Tertiary care academic center. PATIENTS: A total of 107 patients with nasal defects needing reconstruction, performed at the University of Arkansas for Medical Sciences, Little Rock. INTERVENTION: Patients underwent nasal reconstruction with 2-stage paramedian forehead or nasolabial flaps (PMFF and NLF, respectively) from 2002 to 2011. Defect thickness, location, flap type, use of cartilage grafts, and comorbidities, including diabetes mellitus, peripheral vascular or coronary artery disease, and smoking habits, were recorded. MAIN OUTCOME MEASURES: Full success, partial failure, or full failure of the respective flap. RESULTS: Eighty-two of the patients (77%) underwent 2-stage PMFF repair and 25 (23%) underwent 2-stage NLF repair. Fifty-eight defects (54%) were full thickness, in which 46 repairs used PMFF and 12 used NLF for reconstruction. The overall failure rate was 6%. Five PMFF failed (6%); 3 of these were used for full-thickness repairs. There was only 1 NLF failure (4%), which was also performed for the repair of a full-thickness defect. Use of cartilage in the reconstruction did not affect failure rates of the different soft tissue flaps. No single comorbidity was noted to have a statistically significant effect on failure rates, although 83% of failures were observed in smokers. CONCLUSIONS: The overall success rate of interpolation flaps in nasal reconstruction was 94.4%. Defect thickness, use of a cartilage graft, type of flap used, and presence of comorbidities did not affect outcome. Although the comparison was not statistically significant (P = .21), flap failures were more commonly observed in smokers. PMID- 22431860 TI - Natural history of cervical paragangliomas: outcomes of observation of 43 patients. AB - OBJECTIVE: To evaluate the outcomes, growth rate, and symptoms of nonoperated cervical paragangliomas. DESIGN: Retrospective review of clinical and radiologic records and images. SETTING: Tertiary academic medical center. PATIENTS: We studied all patients presenting with cervical paragangliomas between 1993 and 2010 who were observed rather than operated on. MAIN OUTCOME MEASURES: Growth of tumors and need for surgical removal. RESULTS: Forty-three patients with 47 tumors were identified. Mean patient age was 56 years (age range, 17-86 years). Thirty patients were asymptomatic (70%) (22 diagnosed by imaging for other reasons and 8 for workup of a neck mass), and only 5 presented with cranial nerve abnormalities (12%). No patients presented with lymphadenopathy, rapid growth, or pain. Reasons for observation were patient preference (n = 15; 35%), advanced age of patient (n = 12; 28%), and preexisting contralateral cranial nerve deficits (n = 11; 26%). Twenty-eight of the 47 tumors were suspected carotid body tumors based on imaging (60%), and 19 were suspected vagal tumors (40%). The mean greatest dimension at presentation was 2.6 cm (range, 1-7.2 cm). During a mean follow-up of 5 years (range, 1-17 years), 19 tumors remained stable in size (42%); 17 grew (38%); and 9 regressed (20%). Of the 17 tumors that grew, the mean growth was 0.2 cm/y. CONCLUSIONS: Observation of cervical paragangliomas is an option in selected patients who do not present with worrisome symptoms. The natural history of paragangliomas in these patients is typically little to no growth over time. Regular follow-up is important to ensure minimal change and stable symptoms. PMID- 22431861 TI - Complications of adenotonsillectomy in patients younger than 3 years. AB - OBJECTIVE: To evaluate the complication rate for adenotonsillectomy in children younger than 3 years, without a diagnosis of severe obstructive sleep apnea, to assess the necessity for postoperative inpatient admission. DESIGN: Retrospective medical record review (January 1, 2003, through October 31, 2009). SETTING: Tertiary care academic medical center. PATIENTS: Retrospective medical record review of 105 patients younger than 3 years who underwent adenotonsillectomy performed by a single surgeon. Nineteen patients were excluded from our review because of incomplete medical records or severe underlying disease, leaving a total of 86 patients with medical records available for inclusion in our study. Patient medical records were deidentified and reviewed for age, sex, indications for surgery, intraoperative and perioperative interventions, and postoperative complications. One child with a diagnosis of severe obstructive sleep apnea was excluded from the study. MAIN OUTCOME MEASURES: Complications, including bleeding, dehydration requiring admission, and airway intervention, during the intraoperative or perioperative period were recorded. RESULTS: The mean age of the study population was approximately 27.5 months (range, 13-35 months), with most children (76.5%) between 23 and 31 months of age. Among the patients whose records were reviewed, 80 (93.0%) did not experience any intraoperative or postoperative complications. Dehydration was the most common complication and was the cause of all documented readmissions (4.7%) in our patients who ranged in age from 14 to 30 months. Two patients had other complications, reactive airway disease (n=1) and postoperative fever (n=1), which were identified and treated in the postanesthesia care unit, resulting in same-day discharge. No airway complications were noted in our study. CONCLUSIONS: Our study reveals a low complication rate in children younger than 3 years. The recommendations for mandatory admission for children younger than 3 years should be reexamined. Criteria for inpatient admission for children younger than 3 years should be based on preoperative and postoperative clinical evaluation of the patient and an evaluation of the family resources for adequately caring for young children at home in the postoperative period. These recommendations apply only to otherwise healthy children (American Society of Anesthesiologists classifications I and II) without a diagnosis of severe obstructive sleep apnea syndrome. PMID- 22431862 TI - Long-term voice outcomes after thyroplasty for unilateral vocal fold paralysis. AB - OBJECTIVES: To investigate the long-term clinical efficacy and stability of thyroplasty type I for unilateral vocal cord palsy, and to identify the appropriate timing of posttreatment evaluations for determination of long-term voice outcome. Study DESIGN: Single-institution retrospective study. SETTING: Academic tertiary referral centers in Korea. PATIENTS: Forty patients with unilateral vocal cord palsy who underwent thyroplasty from January 1, 1996, through December 31, 2006, and were followed up for at least 5 years after the surgical procedure. INTERVENTIONS: Thyroplasty type I under local anesthesia. MAIN OUTCOME MEASURES: Acoustic and aerodynamic analyses of voice were performed on the day before the operation and at preset intervals afterward. Two blinded speech-language pathologists performed the perceptual evaluation. RESULTS: The GRBAS scale (grade of hoarseness, roughness, breathiness, asthenia, and strain) values showed significant improvement at 6 months after the operation (P < .05); these improvements continued up to 1 year and were maintained 5 years after the operation. Acoustic measurements of shimmer and jitter began to show significant improvement at 6 months after the operation, and fundamental frequency and noise harmonic ratios evidenced significant improvement at 1 year (P < .05); these improvements were maintained, to a significant extent, at 5 years after the operation. Aerodynamically, the maximum phonation time, glottal flow rate, and peak subglottic pressure improved significantly from before the operation to 6 months and 1 year after the operation, attaining near-normal values at 1 year afterward (P < . 05) CONCLUSIONS: Thyroplasty type I may provide evidence that voice outcome progressively evolves during the first years after the surgical procedure, and that subsequent vocal improvement presented long-lasting stabilization. To assess the long-term voice quality, it may be enough to perform the voice evaluation at 1 year after the procedure. PMID- 22431863 TI - Safety of multilevel surgery in obstructive sleep apnea: a review of 487 cases. AB - OBJECTIVE: To review the safety of multilevel surgery in patients with obstructive sleep apnea (OSA). DESIGN: Retrospective review. PATIENTS: A total of 487 consecutive patients with OSA and 1698 surgical procedures from January 2007 to May 2010. INTERVENTIONS: Multilevel OSA surgery comprising nasal surgery (endoscopic sinus surgery, septoplasty, and inferior turbinate reduction), palate surgery (traditional uvulopalatopharyngoplasty, expansion sphincter pharyngoplasty and anterior palatoplasty), and tongue surgery (hyoid suspension, radiofrequency tongue base, and tongue suspension suture). MAIN OUTCOME MEASURES: Surgical complications. RESULTS: The overall complication rate was 7.1%, with 1 patient having an upper airway obstruction. Complications were as follows: (1) 6 patients had postoperative oxygen desaturation within 3 hours after extubation (these patients had severe OSA [apnea-hypopnea index > 60 and lowest oxygen saturation level <80%]), (2) 15 patients had persistent hypertension (these patients had a history of hypertension), (3) 15 patients had secondary hemorrhage (7-12 days postoperatively), (4) there were 2 cases of negative pressure pulmonary edema, (5) 9 patients had tongue edema (following tongue surgery), and (6) 1 patient had upper airway obstruction requiring reintubation. Patients who had undergone tongue surgery were admitted routinely to the high-dependency unit (step-down care from the intensive care unit) overnight. CONCLUSIONS: Routine postoperative admission to the intensive care unit for all patients with OSA is unnecessary. These patients should be closely monitored in the postanesthesia care unit area after surgery, and based on the outcome of this period, they can be observed overnight in either the high-dependency unit or the general ward. PMID- 22431864 TI - Effect of rosuvastatin monotherapy and in combination with fenofibrate or omega-3 fatty acids on serum vitamin D levels. AB - BACKGROUND: Low levels of 25(OH) vitamin D [25(OH)VitD] have been recognized as a new cardiovascular disease (CVD) risk factor. Statins seem to increase 25(OH)VitD concentration. AIM: To investigate whether combined treatment with the usual dose of rosuvastatin plus fenofibrate or omega-3 fatty acids would increase 25(OH)VitD levels compared with the high-dose rosuvastatin monotherapy in participants with mixed dislipidemia. METHODS: We randomly allocated 60 patients with mixed dyslipidemia (low-density lipoprotein cholesterol: >160 mg/dL plus triglycerides: >200 mg/dL) to receive rosuvastatin 40 mg (n = 22), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 21), or rosuvastatin 10 mg plus omega-3 fatty acids 2 g (n = 17) daily for 3 months. Our primary end point was changes in the levels of serum 25(OH)VitD. RESULTS: Rosuvastatin monotherapy was associated with a 53% increase in 25(OH)VitD (from 14.6 [1.0-38.0] to 17.8 [5.3-49.6] ng/mL; P = .000). Rosuvastatin plus micronized fenofibrate and rosuvastatin plus omega-3 fatty acids were associated with increases of 64% (from 14.1 [1.0-48.0] to 18.4 [6.7 52.4] ng/mL, P = .001) and 61% (from 10.4 [6.6-38.4] to 14.0 [9.6-37.6] ng/mL, P = .04), respectively. The changes in 25(OH)VitD after treatment were comparable in the 3 groups. CONCLUSION: High-dose rosuvastatin monotherapy and the usual dose of rosuvastatin plus fenofibrate or omega-3 fatty acids are associated with significant and similar increases in the 25(OH)VitD levels. This increase may be relevant in terms of CVD risk prevention. PMID- 22431865 TI - A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). AB - BACKGROUND: Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. METHODS AND RESULTS: A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios >=4 and <=1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. CONCLUSIONS: These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1 step PG algorithm provided equivalent results and may be preferable for clinical application. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862. PMID- 22431866 TI - Warfarin pharmacogenetics: a rising tide for its clinical value. PMID- 22431867 TI - Letter by Tomaselli and Holmes regarding article, "2011 ASA/ACCF/AHA/AANN/AANS/ACR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease". PMID- 22431868 TI - Follicular variant of papillary thyroid cancer: encapsulated, nonencapsulated, and diffuse: distinct biologic and clinical entities. AB - OBJECTIVE: To examine genotypic and clinical differences between encapsulated, nonencapsulated, and diffuse follicular variant of papillary thyroid carcinoma (EFVPTC, NFVPTC, and diffuse FVPTC, respectively), to characterize the entities and identify predictors of their behavior. DESIGN: Retrospective medical chart review and molecular analysis. SETTING: Referral center of a university hospital. PATIENTS: The pathologic characteristics of 484 consecutive patients with differentiated thyroid cancer who underwent surgery by the 3 members of the New York University Endocrine Surgery Associates from January 1, 2007, to August 1, 2010, were reviewed. Forty-five patients with FVPTC and in whom at least 1 central compartment lymph node was removed were included. MAIN OUTCOME MEASURES: Patients with FVPTC were compared in terms of age, sex, tumor size, encapsulation, extrathyroid extension, vascular invasion, central nodal metastases, and the presence or absence of mutations in BRAF, H-RAS 12/13, K-RAS 12/13, N-RAS 12/13, H-RAS 61, K-RAS 61, N-RAS 61, and RET/PTC1. RESULTS: No patient with EFVPTC had central lymph node metastasis, and in this group, 1 patient (4.5%) had a BRAF V600E mutation and 2 patients (9%) had RAS mutations. Of the patients with NFVPTC, none had central lymph node metastasis (P > .99) and 2 (11%) had a BRAF V600E mutation (P = .59). Of the patients with diffuse FVPTC, all had central lymph node metastasis (P < .001), and 2 (50%) had a BRAF V600E mutation (P = .06). CONCLUSIONS: FVPTC consists of several distinct subtypes. Diffuse FVPTC seems to present and behave in a more aggressive fashion. It has a higher rate of central nodal metastasis and BRAF V600E mutation in comparison with EFVPTC and NFVPTC. Both EFVPTC and NFVPTC behave in a similar fashion. The diffuse infiltrative pattern and not just presence or absence of encapsulation seems to determine the tumor phenotype. Understanding the different subtypes of FVPTC will help guide appropriate treatment strategies. PMID- 22431869 TI - Systematic review of randomized controlled trials comparing intracapsular tonsillectomy with total tonsillectomy in a pediatric population. AB - OBJECTIVE: To perform a systematic literature review and data synthesis of level 1 evidence comparing recovery-related outcomes after intracapsular tonsillectomy (IT) (any technique) with those of total tonsillectomy (TT) (any technique) in a pediatric population. DATA SOURCES: Two independent reviewers searched the following databases: Ovid MEDLINE, including old MEDLINE and pre-MEDLINE, EBM reviews, Books@Ovid and Journals@Ovid, the Web of Science with Conference Proceedings, and references from indexed articles. STUDY SELECTION: Inclusion criteria were randomized controlled trials conducted on a pediatric population comparing IT performed by any technique of dissection with TT, also performed by any technique of dissection. Two independent reviewers determined included trials with difference of opinion resolved by a third reviewer. DATA EXTRACTION: Independent data extraction by 2 reviewers on the following outcomes: postoperative pain, analgesic use, recovery time, diet, bleeding rate, infection, and regrowth rate requiring further surgical intervention. DATA SYNTHESIS: Heterogeneity of outcome measures and lack of reporting of raw data precluded formal meta-analysis. For quantitative data that could be extracted, pooled data analysis was performed using nonparametric tests. CONCLUSION: Recovery-related outcomes for IT were superior to TT (secondary hemorrhage rate, number of days until pain free) in a pediatric population with obstructive symptoms (level-1 evidence). PMID- 22431870 TI - Adverse laryngeal effects following short-term general anesthesia: a systematic review. AB - OBJECTIVE: To conduct a systematic review to determine the occurrence and type of vocal cord injury, as well as the occurrence of hoarseness, in adults using an endotracheal tube or laryngeal mask during routine anesthetic care. DATA SOURCES: Two reviewers independently performed a literature search using PubMed, EMBASE, and Cochrane Central Register of Controlled Trials. The search was limited to articles published in English, German, French, or Dutch. In addition, reference lists of the included articles were searched manually. DATA EXTRACTION: Studies describing vocal cord injury and/or hoarseness following short-term general anesthesia (<5 hours) using an endotracheal tube or any type of laryngeal mask were included. To obtain a reliable outcome regarding the occurrence of anesthesia-related laryngeal morbidity, only studies reporting both preoperative and postoperative measurements of vocal cord function were included. DATA SYNTHESIS: A total of 4119 articles were identified; of these, 13 studies met the inclusion criteria. The studies were found to be heterogeneous and hardly comparable. Hoarseness and vocal cord injuries were common findings in most investigations. CONCLUSIONS: Hoarseness and vocal cord injuries are clinically relevant complications related to short-term general anesthesia using an endotracheal tube or laryngeal mask. However, more well-designed prospective studies are necessary to generate reliable data as well as to investigate techniques to reduce adverse laryngeal effects. For future research, a proposal to categorize the vocal cord lesions due to general anesthesia is presented. Furthermore, use of a preoperative and postoperative standardized measurement protocol using acoustic analysis and the Voice Handicap Index is advised. PMID- 22431871 TI - Alcohol-related predictors of delirium after major head and neck cancer surgery. AB - OBJECTIVE: To identify specific alcohol-related predictors of postoperative delirium. DESIGN: Inception cohort, logistic regression with step-wise selection. SETTING: Ohio State University Comprehensive Cancer Center, Columbus. PATIENTS: A total of 774 patients undergoing major resection of head and neck squamous cell carcinoma. MAIN OUTCOME MEASURES: The correlation of 19 variables with postoperative delirium. One variable was an alcohol-related blood test: mean red blood cell volume (MCV). Eight variables were patient responses to alcohol related questions. RESULTS: Eighty-nine of 774 surgical procedures (11.5%) were complicated by delirium. Six variables were significantly associated with delirium: age older than 69 years (odds ratio [OR], 2.43; P < .01), preexisting cognitive impairment (OR, 3.83; P < .01), surgery duration greater than 6 hours (OR, 2.40; P < .01), MCV greater than 95.0 femtoliters (OR, 2.23; P < .01), ever being advised to cut back on alcohol (OR, 2.25; P = .01), and not abstaining from alcohol for at least 1 continuous week in the preceding year (OR, 2.16; P = .02). The number of variables stratified delirium risk (0 variables: 198 patients, 2.5% incidence of delirium; 1 variable: 278 patients, 6% incidence of delirium; 2 variables: 206 patients, 18% incidence of delirium; and >2 variables: 92 patients, 34% incidence of delirium). CONCLUSIONS: Three clinical variables not related to alcohol drinking (age, preexisting cognitive impairment, and surgery duration), an alcohol-related laboratory test (MCV), and 2 alcohol-related questions ("At any time in your life, has anyone ever suggested that you should cut back on your drinking?" and "What is the greatest number of days in a row you have gone without an alcoholic drink in the past year?") may help in estimating a patient's risk for postoperative delirium. PMID- 22431872 TI - Comparison of chi-squared automatic interaction detection classification trees vs TNM classification for patients with head and neck squamous cell carcinoma. AB - OBJECTIVES: To compare chi-squared automatic interaction detection (CHAID) classification trees vs the seventh edition of the TNM classification for patients with head and neck squamous cell carcinoma and to assess whether CHAID classification trees might improve results obtained with the TNM classification. DESIGN: Patient disease was classified according to CHAID classification trees and the TNM classification, and the results were compared. SETTING: Academic research. PATIENTS: A total of 3373 patients with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. MAIN OUTCOME MEASURES: The 2 classification methods were evaluated objectively, measuring intrastage homogeneity (hazard consistency), interstage heterogeneity (hazard discrimination), and disease stage distribution among patients (balance). In addition, to assess agreement between CHAID classification trees and the TNM classification, we calculated the kappa statistic, weighted linearly and quadratically. RESULTS: Objective evaluation of the quality of the classification methods indicated that CHAID classification trees performed better than the TNM classification in terms of hazard consistency (2.51 for CHAID and 3.01 for TNM) and hazard discrimination (70.9% for CHAID and 52.7% for TNM) but not balance (-31.7% for CHAID and -15.5% for TNM). Analysis of concordance between the classification methods showed that the quadratic kappa statistic was 0.77 (95% CI, 0.76-0.78) and the linear kappa statistic was 0.59 (95% CI, 0.57-0.60) (P < .001 for both). CONCLUSION: CHAID classification trees performed better than the TNM classification and offer potential inclusion of new prognostic factors. PMID- 22431873 TI - Congenital cholesteatoma: predictors for residual disease and hearing outcomes. AB - OBJECTIVE: To determine predictive factors for residual disease and hearing outcomes of surgery for congenital cholesteatoma (CC). DESIGN: Retrospective record review of surgery for CC from January 1, 1998, through December 31, 2010. The initial extent of CC was staged using the system as defined by Potsic et al. SETTING: Tertiary care children's hospital. PATIENTS: Eighty-one children (82 ears) underwent a total of 230 operations for CC. The mean (SD) age was 5.3 (2.9) years, and the mean follow-up was 4.3 years. INTERVENTION: Initial and subsequent operations for CC and audiologic evaluations. MAIN OUTCOME MEASURES: Statistical analyses were performed to determine factors associated with increased residual disease for CC and poorer hearing outcomes. RESULTS: Higher initial stage of disease, erosion of ossicles, and removal of ossicles were significantly associated with increased likelihood of residual CC (46%, 50%, and 51%, respectively; P < .001). More extensive disease at initial surgery was associated with poorer final hearing outcomes (P < .05). Other significant findings included CC medial to the malleus (41.5%) or incus (54.3%), abutting the incus (51.3%) or stapes (63%), or enveloping the stapes (50%); all patients had increased residual disease (all P < .05). Excellent audiometric results (air-bone gap of <=20 decibel hearing level) were obtained in 63 (77%) of the 82 ears. CONCLUSIONS: More extensive initial disease, ossicular erosion, and the need for ossicular removal were associated with residual disease. On the basis of our data, the best chance for completely removing CC at initial surgery involves removing involved ossicles if they are eroded, if the CC is abutting or enveloping the incus or stapes, if the CC is medial to the malleus or incus, or if the matrix of the CC is violated. These results may help guide surgeons to achieve the best results for their patients. PMID- 22431874 TI - Vascular endothelial growth factor expression in nasal polyps of aspirin intolerant patients. AB - OBJECTIVE: To study differences between aspirin-tolerant patients and aspirin intolerant patients concerning vascular endothelial growth factor (VEGF) expression. Recent publications strongly suggest the involvement of VEGF and its receptors in the pathophysiologic process of nasal polyps. DESIGN: We subjected 43 polyp specimens to semiquantitative immunohistochemical analysis. We quantified VEGF and its receptors (Flk, Flt, and neuropilin) in all samples. To gain insight into potential VEGF-mediated cellular responses, we determined proliferative (Ki67) and apoptotic (caspase 3) indices. PATIENTS: Polyp samples were obtained from 22 aspirin-intolerant patients and from 21 aspirin-tolerant patients, and control specimens were obtained from 24 subjects with healthy nasal respiratory mucosa. SETTING: Laboratory; Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. MAIN OUTCOME MEASURES: Expression levels of VEGF, VEGF receptors. and proliferative and apoptotic indices. RESULTS: We found higher expressed levels of VEGF and neuropilin and stronger proliferation in nasal polyps from aspirin-tolerant and aspirin-intolerant patients compared with controls. In polyps from aspirin-intolerant patients, VEGF was expressed at considerably higher levels compared with those from aspirin-tolerant subjects. Apoptotic activity remained unchanged in all 3 groups. CONCLUSIONS: Nasal polyps from aspirin-tolerant and aspirin-intolerant patients are characterized by strong proliferation and high levels of VEGF and neuropilin expression. Nasal polyps from aspirin-intolerant patients show distinctly increased VEGF levels. The relevance of these findings for future therapeutic approaches is yet to be determined. PMID- 22431875 TI - Treatment of recalcitrant chronic rhinosinusitis with integrative East-West medicine: a pilot study. AB - OBJECTIVE: To establish the feasibility of studying the impact of integrative East-West medicine (IEWM) on sinonasal symptoms and quality of life (QOL) for patients with chronic rhinosinusitis (CRS). DESIGN: Prospective, nonrandomized trial. SETTING: Academic hospital and ambulatory clinic. PATIENTS: Patients with recalcitrant CRS offered treatment with IEWM in addition to standard medical treatment. METHODS: Prior to study enrollment, study participants were given the Sino-Nasal Outcome Test (SNOT-20) and the 36-Item Short Form (SF-36) questionnaires. INTERVENTIONS: Patients underwent 8 weeks of weekly acupuncture and counseling on dietary modification, lifestyle changes, and acupressure. MAIN OUTCOME MEASURES: Patients completed posttreatment SNOT-20 and SF-36 surveys, which were compared for changes in sinonasal symptoms and QOL measures. RESULTS: Eleven patients completed the protocol. No adverse events were observed. There were trends toward improvement in most elements of the SNOT-20, whereas "need to blow nose" (P = .002), "runny nose" (P = .04), "reduced ability to concentrate" (P = .005), and "feeling frustrated, restless, or irritable" (P = .046) were statistically significant. In the SF-36, role physical (P = .01), vitality (P = .04), and social functioning (P = .008) were significantly improved. CONCLUSIONS: Preliminary data suggest that an integrated approach of traditional Western medicine with IEWM is safe and may improve symptoms and QOL for patients with recalcitrant CRS. Future randomized controlled trials are needed to validate the effects of IEWM and clarify its role in the treatment of CRS. PMID- 22431876 TI - Visual acuity while walking and oscillopsia severity in healthy subjects and patients with unilateral and bilateral vestibular function loss. AB - OBJECTIVES: To assess visual acuity (VA) while the patient is walking and to evaluate oscillopsia severity in patients with bilateral vestibulopathy (BV) and in patients with unilateral vestibular loss (UVL). DESIGN: Prospective study with a group of patients with BV, a group of patients with UVL, and a control group of healthy subjects. SETTING: Tertiary academic center. PARTICIPANTS: Thirty seven patients with BV(age range, 29-80 years), 11 patients with UVL (age range, 48-75 years), and 57 healthy subjects (age range 20-77 years). INTERVENTION: Computation of the difference between the VA measured in static conditions and in dynamic conditions while walking on a treadmill at 2, 4, and 6 km/h. Oscillopsia severity was assessed with a questionnaire that we developed. MAIN OUTCOME MEASURES: Differences in VA at 2, 4, and 6 km/h and oscillopsia severity score. RESULTS: As a group, patients with BV showed a significant increase of the VA differences compared with healthy subjects (P < .001) and patients with UVL (P < .001) for all 3 walking velocities. Normality thresholds were defined as healthy subjects' 95% CI. Sensitivity of the test was 97% for discriminating patients with BV. Moderate to extreme oscillopsia severity was found in 81% of patients with BV and in 9% of patients with UVL. Differences in VA did not correlate with oscillopsia severity scores in patients with BV (P > .05 for all comparisons). CONCLUSIONS: We designed a highly sensitive, simple, cost-effective protocol to assess dynamic VA under physiologic conditions and a questionnaire to determine oscillopsia severity. Both tools could be used for the evaluation of new treatments for BV and patients with UVL. PMID- 22431877 TI - Anterior neck pain due to hyoid malformation. PMID- 22431878 TI - Bilateral conductive hearing impairment with hyperostosis of the temporal bone: a new finding in Robinow syndrome. PMID- 22431879 TI - Pathology quiz case 1. Liposarcoma of the hypopharynx. PMID- 22431880 TI - Pathology quiz case 2. Laryngeal sarcoidosis. PMID- 22431881 TI - Consensus statement on standard of care for congenital myopathies. AB - Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee's recommendations for symptom assessments and therapeutic interventions. It is the committee's goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome. PMID- 22431884 TI - Hypertrophic cardiomyopathy in 2012. PMID- 22431885 TI - Catheter ablation to maintain sinus rhythm. PMID- 22431886 TI - Dry gangrene after aortic dissection. PMID- 22431887 TI - Left main coronary artery acute thrombosis related to energy drink intake. PMID- 22431888 TI - Giant aorto-right ventricular fistula with single coronary artery. PMID- 22431889 TI - Improving safety of epicardial ventricular tachycardia ablation using the scar dechanneling technique and the integration of anatomy, scar components, and coronary arteries into the navigation system. PMID- 22431891 TI - Letter by Lai and Chan regarding article, "Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation". PMID- 22431892 TI - Streptococcus mutans out-competes Streptococcus gordonii in vivo. AB - Streptococcus gordonii and Streptococcus mutans avidly colonize teeth. S. gordonii glucosyltransferase (GtfG) and amylase-binding proteins (AbpA/AbpB), and S. mutans glucosyltransferase (GtfB), affect their respective oral colonization abilities. We investigated their interrelationships and caries association in a rat model of human caries, examining the sequence of colonization and non- vs. high-sucrose diets, the latter being associated with aggressive decay in humans and rats. Virulence-characterized wild-types of both species and well-defined mutants of S. gordonii with interrupted abpA and gtfG genes were studied. While both S. gordonii and S. mutans were abundant colonizers of rat's teeth in the presence of either diet, if inoculated singly, S. mutans always out-competed S. gordonii on the teeth, independent of diet, strain of S. mutans, simultaneous or sequential inoculation, or presence/absence of mutations of S. gordonii's abpA and gtfG genes known to negatively or positively affect its colonization and to interact in vitro with S. mutans GtfB. S. mutans out-competed S. gordonii in in vivo plaque biofilm. Caries induction reflected S. mutans or S. gordonii colonization abundance: the former highly cariogenic, the latter not. S. gordonii does not appear to be a good candidate for replacement therapy. These results are consistent with human data. PMID- 22431893 TI - HIV-related stigma, isolation, discrimination, and serostatus disclosure: a global survey of 2035 HIV-infected adults. AB - BACKGROUND: Little is known globally about the perspectives of people living with HIV/AIDS (PLWHA) on perceived HIV-related stigma and its consequences. METHODS: Cross-sectional study (January-March 2010) of perceived HIV-related stigma among PLWHA (N = 2035) using a standardized questionnaire. FINDINGS: Thirty-seven percent of respondents reported loneliness as a result of their HIV status. Depression was reported by 27%. While 96% reported disclosing their HIV status to at least 1 person, 17% of patients who reported being in a long-term sexual relationship had not disclosed their status to their partner. Variables associated with perceived stigma were living in Asia-Pacific versus other regions (odds ratio [OR]: 2.77; 95% confidence interval [CI] 1.96-3.92); having experienced body/face changes; reported depression (OR: 1.25; 95% CI 1.11-1.38); and nondisclosure of HIV status (OR: 1.75; 95% CI 1.28-2.41). CONCLUSION: Thirty years into the HIV pandemic, perceived HIV stigma, isolation, and discrimination persist and are associated with loneliness and depression among PLWHA. PMID- 22431894 TI - The promise of angiogenic markers for the early diagnosis and prediction of preeclampsia. AB - BACKGROUND: An imbalance in circulating factors that regulate blood vessel formation and health, referred to as angiogenic factors, plays a central role in the pathogenesis of preeclampsia. CONTENT: Several studies have demonstrated a strong association between altered circulating angiogenic factors and preeclampsia. These factors include circulating antiangiogenic proteins such as soluble fms-like tyrosine kinase 1 and soluble endoglin and proangiogenic protein such as placental growth factor. Abnormalities in these circulating angiogenic factors are not only present during clinical disease, but also antedate clinical signs and symptoms by several weeks. These alterations are particularly prominent in patients who present with preeclamptic signs and symptoms prematurely and/or in patients with severe preeclampsia. The availability of automated platforms for the rapid measurement of circulating angiogenic proteins in blood samples has now allowed researchers and clinicians to evaluate the utility of these assays in the diagnosis of the disease, in the stratification of patients in clinical trials, or in the monitoring of therapies. In this review we highlight the various studies that have been performed, with a focus on large validation studies. SUMMARY: Measurement of circulating angiogenic proteins for the diagnosis and prediction of preeclampsia is still at an early stage but is rapidly evolving. Standardization across the various automated platforms and prospective studies that demonstrate clinical utility are needed. PMID- 22431895 TI - Increased cardiac troponin I as measured by a high-sensitivity assay is associated with high odds of cardiovascular death: the Minnesota Heart Survey. AB - BACKGROUND: We examined several novel biomarkers of different pathophysiologic pathways as predictors of cardiovascular mortality in participants enrolled in the Minnesota Heart Survey (MHS), a population-based study of cardiovascular disease (CVD) risk factors. METHODS: In a nested case-control study within MHS, 7 biomarkers were assayed in serum samples from 211 patients identified after 8-15 years of follow-up who died of cardiovascular causes (cardiovascular heart disease, stroke, congestive heart failure) and 253 controls matched on age, sex, and study year. Logistic regression analysis, adjusted for age, race, sex, education, study year, smoking, abdominal obesity, diabetes, serum total cholesterol, systolic blood pressure, previous hospitalization for a CVD event, and other significant biomarkers, was used to evaluate the relations of biomarkers relative to the odds of CVD mortality. RESULTS: Cases survived a median of 7.2 years after enrollment. Increased N-terminal pro-B type natriuretic peptide (NT-proBNP) (19% vs 4.3%), increased high-sensitivity C-reactive protein (hs-CRP) (71% vs 51%), and increased high-sensitivity cardiac troponin I (hs cTnI) (8.7% vs 1.0%) were more common among cases than among controls (all P < 0.001 in unadjusted analyses). The adjusted odds of death were greater among cases compared to controls for increased NT-proBNP [odds ratio (OR) 5.67, 95% CI 2.17-15], hs-CRP (OR 1.73, 95% CI 1.03-2.89), and hs-cTnI (OR 8.53, 95% CI 1.68 43), and decreased ST2 (OR 1.92, 95% CI 1.05-3.48). CONCLUSIONS: When measured by an hs-cTnI assay, cTnI is a key biomarker associated with increased cardiovascular death in a community sample when evaluated in a multiple biomarker analysis. PMID- 22431896 TI - Rapid diagnosis of aneuploidy by high-resolution melting analysis of segmental duplications. AB - BACKGROUND: Several molecular methods, such as quantitative fluorescence PCR and multiplex ligation-dependent probe amplification, currently serve as important adjuncts to traditional karyotyping for the diagnosis of aneuploidy; however, the performance or throughput limitations of these methods hinder their use for routine prenatal diagnosis and population-based postnatal screening. We developed a novel approach, called "high-resolution melting analysis of segmental duplications," to detect common aneuploidies. METHODS: In this method, similar sequences located on different chromosomes are amplified simultaneously with a single primer set; the PCR products are then analyzed by high-resolution melting. Aneuploidy-associated dosage abnormalities produce different ratios of similar amplicons, which produce melting curves that are detectably different from those of samples from unaffected individuals. We applied this method to DNA samples isolated from individuals with trisomy 21 (n = 48), trisomy 18 (n = 10), trisomy 13 (n = 3), 45,X (n = 8), and 47,XXY (n = 14), and from unaffected controls (n = 48). RESULTS: As judged by the karyotyping results, our method attained 100% diagnostic sensitivity and 99.6% diagnostic specificity. Moreover, our method was able to detect a change in chromosome dosage as low as 1.05-fold. CONCLUSIONS: This novel method clearly differentiates samples of patients with common aneuploidies from those of unaffected controls, while markedly simplifying the assays and reducing time and costs. The assay has sufficient throughput to meet the demands of large-scale testing, such as population-based postnatal screening, and is thus suitable for routine use. PMID- 22431897 TI - Cultural considerations in planning palliative and end of life care. PMID- 22431898 TI - Social, psychological and existential well-being in patients with glioma and their caregivers: a qualitative study. AB - BACKGROUND: Cerebral glioma has a devastating impact on cognitive, physical, social, psychological and spiritual well-being. We sought to understand the multidimensional experience of patients with this form of cancer as they progressed from receiving a diagnosis to the terminal phase of the disease. METHODS: We recruited patients with a suspected brain tumour from a tertiary referral centre in the United Kingdom. We interviewed patients and their caregivers at key stages of the illness: before receiving a formal diagnosis, at the start of initial treatment, after initial treatment was completed and at six months' follow-up; caregivers were also interviewed postbereavement. We interviewed the patients' general practitioners once, after treatment had been completed. We transcribed the interviews and analyzed them thematically using the constant comparative method of a grounded theory approach. RESULTS: We conducted in-depth interviews with 26 patients, 23 of their relatives and 19 general practitioners. We saw evidence of physical, social, psychological and existential distress even before a diagnosis was confirmed. Social decline followed a similar trajectory to that of physical decline, whereas psychological and existential distress were typically acute around diagnosis and again after initial treatment. Each patient's individual course varied according to other factors including the availability of support and individual and family resources (e.g., personal resilience and emotional support). INTERPRETATION: There are practical ways that clinicians can care for patients with glioma and their caregivers, starting from before a diagnosis is confirmed. Understanding the trajectories of physical, social, psychological and existential well-being for these patients allows health care professionals to predict their patients' likely needs so they can provide appropriate support and sensitive and effective communication. PMID- 22431899 TI - Touch the screen now to see a doctor. PMID- 22431900 TI - Charcot foot. PMID- 22431901 TI - The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial. AB - BACKGROUND: Evidence from observational studies have raised the possibility that statin treatment reduces the incidence of certain bacterial infections, particularly pneumonia. We analyzed data from a randomized controlled trial of rosuvastatin to examine this hypothesis. METHODS: We analyzed data from the randomized, double-blind, placebo-controlled JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). In this trial, 17,802 healthy participants (men 50 years and older and women 60 and older) with a low-density lipoprotein (LDL) cholesterol level below 130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level of 2.0 mg/L or greater were randomly assigned to receive either rosuvastatin or placebo. We evaluated the incidence of pneumonia on an intention-to-treat basis by reviewing reports of adverse events from the study investigators, who were unaware of the treatment assignments. RESULTS: Among 17,802 trial participants followed for a median of 1.9 years, incident pneumonia was reported as an adverse event in 214 participants in the rosuvastatin group and 257 in the placebo group (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.69-1.00). In analyses restricted to events occurring before a cardiovascular event, pneumonia occurred in 203 participants given rosuvastatin and 250 given placebo (HR 0.81, 95% CI 0.67 0.97). Inclusion of recurrent pneumonia events did not modify this effect (HR 0.81, 95% CI 0.67-0.98), nor did adjustment for age, sex, smoking, metabolic syndrome, lipid levels and C-reactive protein level. INTERPRETATION: Data from this randomized controlled trial support the hypothesis that statin treatment may modestly reduce the incidence of pneumonia. (ClinicalTrials.gov trial register no. NCT0023968.). PMID- 22431902 TI - Spending eternity in liquid nitrogen. PMID- 22431903 TI - Africa's road to blood ruin. PMID- 22431905 TI - Blood testing for sensitivity, allergy or intolerance to food. PMID- 22431906 TI - CIHR doubles support for clinical research. PMID- 22431907 TI - Race and genetics in the doctor's office. PMID- 22431908 TI - See what you think: reappraisal modulates behavioral and neural responses to social stimuli. AB - The social environment requires people to quickly form contextually appropriate social evaluations. Models of social cognition suggest that this ability depends on the interaction of automatic and controlled evaluative systems. However, controlled processes, such as reappraisal of an initial response, have rarely been studied in the context of social evaluation. In the two studies reported here, participants reappraised or simply observed angry or neutral faces. In Study 1, reappraisal modulated evaluations of angry faces on explicit as well as implicit behavioral levels. In Study 2, reappraisal altered both early and late phases of evaluative electrocortical processing. These studies suggest that controlled processes, such as reappraisal, can quickly and substantially modulate early evaluative processes in the context of biologically significant social stimuli. PMID- 22431909 TI - Does power magnify the expression of dispositions? AB - Conventional wisdom holds that power holders act more in line with their dispositions than do people who lack power. Drawing on principles of construct accessibility, we propose that this is the case only when no alternative constructs are activated. In three experiments, we assessed participants' chronic dispositions and subsequently manipulated participants' degree of power. Participants then either were or were not primed with alternative (i.e., inaccessible or counterdispositional) constructs. When no alternatives were activated, the responses of power holders--perceptions of other people (Experiment 1), preferences for charitable donations (Experiment 2), and strategies in an economic game (Experiment 3)--were more in line with their chronically accessible constructs than were the responses of low-power participants. However, when alternatives had been activated, power holders' responses were no longer more congruent with their dispositions than were the responses of low-power participants. We propose a single mechanism according to which power increases reliance on accessible constructs--that is, constructs that easily come to mind-regardless of whether these constructs are chronically or temporarily accessible. PMID- 22431910 TI - Single-site surgery for simultaneous totally extraperitoneal bilateral herniorrhaphy and transperitoneal radical nephrectomy in one patient. AB - AIM: This study reports a case undergoing laparoendoscopic totally extraperitoneal herniorrhpahy and transperitoneal laparoscopic radical nephrectomy through transumbilical single-site incisions. METHOD: A 56-year-old man presented with incidental left renal tumor and bilateral inguinal hernia. Accordingly, a homemade single-port in subumbilicus was applied for totally extraperitoneal herniorrhpahy, following which the incisional wound was extended upward for transperitoneal radical nephrectomy as well. RESULTS: No extraumbilical port was required. Pathology confirmed the diagnosis of renal cell carcinoma. The peri- and postoperative course was quite smooth with rapid recovery, and the patient was discharged home on the fifth postoperative day. DISCUSSION: The laparoendoscopic single-site surgery with homemade single-port allowed extraperitoneal and transperitoneal procedures to be carried out at the same time, which was feasible and safe with negligible complications. CONCLUSIONS: Performing 2 procedures with single-site incision greatly diminished the number of port site incisions and offered obvious cosmetic advantage. PMID- 22431911 TI - Perioperative polyphenon E, a green tea extract, does not affect the wound complication rate in mice after sham laparotomy yet has an inhibitory effect on wound healing. AB - INTRODUCTION: Major surgery is associated with physiologic alterations that may promote tumor growth, and catechins in green tea may inhibit tumor growth. This study's aim was to assess the impact of a green tea extract on laparotomy wound healing in mice. METHODS: Mice were randomized to daily oral catechins solution (n = 25) or placebo (n = 20), underwent sham laparotomy after 10 days, and were sacrificed on postoperative day 7 or 21. The peak force and total energy required to rupture the abdominal wall wound, wound collagen content, and histology were assessed. RESULTS: There were no wound complications in either group, and mean peak wound rupture forces and collagen concentration were similar. Mean energy was lower and more fibroblast proliferation was found in the treatment group on postoperative day 21. CONCLUSIONS: These results suggest that catechins has only mild clinically significant adverse effect on wound healing, and its perioperative use warrants further study. PMID- 22431912 TI - How to evaluate the effectiveness of catheter-directed thrombolytic therapy in pulmonary embolism. PMID- 22431913 TI - Intervertebral disk disease with spinal cord penetration in a Yucatan pig. AB - A 9-month-old female Yucatan pig was euthanized after acute onset of paraplegia. Gross and microscopic examination revealed dorsal dissection of the nucleus of the L2-L3 intervertebral disk through the annulus fibrosus, extrusion of nucleus pulposus material through the overlying dura mater and into the spinal cord, and associated acute spinal hemorrhage and necrosis. This is, to the authors' knowledge, the first reported case of intervertebral disk disease in swine. PMID- 22431914 TI - Aprosencephaly with otocephaly in a lamb (Ovis aries). AB - Aprosencephaly is a rare condition in veterinary and human medicine characterized by the complete absence of telencephalon and diencephalon. Some cases are accompanied by a facial dysmorphism designated as otocephaly. A stillborn lamb had splanchnocranial anomalies that were classified by computed tomography, magnetic resonance imaging, and pathologic examination as aprosencephaly and otocephaly. The brain included parts of the cerebellum and brainstem but no telencephalon, diencephalon, or mesencephalon. The cerebellum had a structurally normal cortex with expression of neuronal nuclear antigen in the inner and doublecortin in the outer granular cell layers, as well as an irregularly situated nucleus dentatus. Aprosencephaly with otocephaly has been described in mice with heterozygous mutations in the Otx2 gene; however, no causative polymorphisms were detected in the Otx2 gene region of this lamb. PMID- 22431915 TI - Distinct effects of contraction-induced injury in vivo on four different murine models of dysferlinopathy. AB - Mutations in the DYSF gene, encoding dysferlin, cause muscular dystrophies in man. We compared 4 dysferlinopathic mouse strains: SJL/J and B10.SJL Dysf(im)/AwaJ (B10.SJL), and A/J and B6.A-Dysf(prmd)/GeneJ (B6.A/J). The former but not the latter two are overtly myopathic and weaker at 3 months of age. Following repetitive large-strain injury (LSI) caused by lengthening contractions, all except B6.A/J showed ~40% loss in contractile torque. Three days later, torque in SJL/J, B10.SJL and controls, but not A/J, recovered nearly completely. B6.A/J showed ~30% torque loss post-LSI and more variable recovery. Pre-injury, all dysferlinopathic strains had more centrally nucleated fibers (CNFs) and all but A/J showed more inflammation than controls. At D3, all dysferlinopathic strains showed increased necrosis and inflammation, but not more CNFs; controls were unchanged. Dystrophin-null DMD(mdx) mice showed more necrosis and inflammation than all dysferlin-nulls. Torque loss and inflammation on D3 across all strains were linearly related to necrosis. Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI. PMID- 22431916 TI - Potential stemness of frozen-thawed testicular biopsies without sperm in infertile men included into the in vitro fertilization programme. AB - We describe the potential stemness of a small amount of frozen-thawed testicular tissue without sperm obtained by biopsy from six patients undergoing assisted reproductive treatment. The patients were diagnosed with Sertoli Cell-Only Syndrome alone or combined with maturation arrest. Trying to provide the natural stem cell niche for cultured stem cells, all isolated cells from enzymatically degraded biopsies where cultured together in different culture media and the presence of putative mesenchymal and putative pluripotent ES-like stem cells was indicated using different methods. High throughput real-time quantitative PCR followed by multivariate analysis revealed the formation of distinct cell clusters reflecting high degree of similarity and some of these cell clusters expressed the genes characteristic for pluripotent stem cells. In the presence of the follicular fluid, prepared as serum, putative testicular stem cells showed a certain degree of plasticity, and spontaneously differentiated into adipose-like and neuronal-like cells. Additionally, using differentiation protocols putative testicular stem cells were differentiated into neuronal- and pancreatic-like cells. This study shows that in assisted reproduction programmes, testicular tissue with no sperm might be an important source of stem cells, although it is discarded in daily medical practice; this requires further research. PMID- 22431917 TI - Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F dependent mechanism. AB - Neurofibromatosis type 2 (NF2) is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumor suppressor gene. Patients with NF2 develop hallmark schwannomas that require surgery or radiation, both of which have significant adverse effects. Recent studies have indicated that the tumor microenvironment-in particular, tumor blood vessels-of schwannomas may be an important therapeutic target. Furthermore, although much has been done to understand how merlin, the NF2 gene product, functions as a tumor suppressor gene in schwannoma cells, the functional role of merlin in the tumor microenvironment and the mechanism(s) by which merlin regulates angiogenesis to support schwannoma growth is largely unexplored. Here we report that the expression of semaphorin 3F (SEMA3F) was specifically downregulated in schwannoma cells lacking merlin/NF2. When we reintroduced SEMA3F in schwannoma cells, we observed normalized tumor blood vessels, reduced tumor burden, and extended survival in nude mice bearing merlin-deficient brain tumors. Next, using chemical inhibitors and gene knockdown with RNA interference, we found that merlin regulated expression of SEMA3F through Rho GTPase family member Rac1. This study shows that, in addition to the tumor-suppressing activity of merlin, it also functions to maintain physiological angiogenesis in the nervous system by regulating antiangiogenic factors such as SEMA3F. Restoring the relative balance of proangiogenic and antiangiogenic factors, such as increases in SEMA3F, in schwannoma microenvironment may represent a novel strategy to alleviate the clinical symptoms of NF2-related schwannomas. PMID- 22431918 TI - Membrane-bound and exosomal metastasis-associated C4.4A promotes migration by associating with the alpha(6)beta(4) integrin and MT1-MMP. AB - Metastasis-associated C4.4A, which becomes upregulated during wound healing and, in some tumors, during tumor progression, is known to be frequently associated with hypoxia. With the function of C4.4A still unknown, we explored the impact of hypoxia on C4.4A expression and functional activity. Metastatic rat and human tumor lines upregulate C4.4A expression when cultured in the presence of CoCl(2). Although hypoxia-inducible factor 1alpha (HIF-1alpha) becomes upregulated concomitantly, HIF-1alpha did not induce C4.4A transcription. Instead, hypoxia induced C4.4A up-regulation promoted in vivo and in vitro wound healing, where increased migration on the C4.4A ligands laminin-111 and -332 was observed after a transient period of pronounced binding. Increased migration was accompanied by C4.4A associating with alpha(6)beta(4), MT1-MMP1, and TACE and by laminin fragmentation. Hypoxia also promoted the release of C4.4A in exosomes and TACE mediated C4.4A shedding. The association of C4.4A with alpha(6)beta(4) and MT1 MMP1 was maintained in exosomes and exosomal alpha(6)beta(4)- and MT1-MMP1 associated C4.4A but not shed C4.4A sufficient for laminin degradation. Hypoxia induced recruitment of alpha(6)beta(4) toward raft-located C4.4A, MT1-MMP, and TACE allows for a shift from adhesion to motility, which is supported by laminin degradation. These findings provide the first explanation for the C4.4A contribution to wound healing and metastasis. PMID- 22431919 TI - Regulation of p130(Cas)/BCAR1 expression in tamoxifen-sensitive and tamoxifen resistant breast cancer cells by EGR1 and NAB2. AB - Elevated levels of p130(Cas)/BCAR1 (Crk-associated substrate/breast cancer antiestrogen resistance 1) are found in aggressive breast tumors and are associated with tamoxifen resistance of mammary cancers. p130(Cas) promotes the integration of protein complexes involved in multiple signaling pathways frequently deregulated in breast cancer. To elucidate mechanisms leading to p130(Cas) up-regulation in mammary carcinomas and during acquired tamoxifen resistance, the regulation of p130(Cas)/BCAR1 was studied. Because multiple putative binding motifs for the inducible transcription factor EGR1 were identified in the 5' region of BCAR1, the p130(Cas)/BCAR1 regulation by EGR1 and its coregulator NAB2 was investigated. Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells. p130(Cas) depletion using siRNA showed that, in tamoxifen-sensitive MCF-7 cells, p130(Cas) regulates EGR1 and NAB2 expression, whereas in the derivative tamoxifen-resistant TAM-R cells, only NAB2 levels were influenced. BCAR1 messenger RNA and p130(Cas) protein were upregulated by phorbol esters following the kinetics of late response genes in MCF-7 but not in TAM-R cells. Thus, in MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression. Importantly, compared with MCF 7, enhanced NAB2 expression and increased EGR1 binding to the BCAR1 5' region observed in TAM-R may lead to the constitutively increased p130(Cas)/BCAR1 levels in TAM-R cells. The uncovered differences in this EGR1/NAB2/p130(Cas) network in MCF-7 versus TAM-R cells may also contribute to p130(Cas) up-regulation during acquired tamoxifen resistance. PMID- 22431920 TI - In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption. AB - We previously demonstrated the synergistic therapeutic effect of the cetuximab (anti-epidermal growth factor receptor [EGFR] monoclonal antibody, mAb) trastuzumab (anti-HER2 mAb) combination (2mAbs therapy) in HER2(low) human pancreatic carcinoma xenografts. Here, we compared the 2mAbs therapy, the erlotinib (EGFR tyrosine kinase inhibitor [TKI])-trastuzumab combination and lapatinib alone (dual HER2/EGFR TKI) and explored their possible mechanisms of action. The effects on tumor growth and animal survival of the three therapies were assessed in nude mice xenografted with the human pancreatic carcinoma cell lines Capan-1 and BxPC-3. After therapy, EGFR and HER2 expression and AKT phosphorylation in tumor cells were analyzed by Western blot analysis. EGFR/HER2 heterodimerization was quantified in BxPC-3 cells by time-resolved FRET. In K-ras mutated Capan-1 xenografts, the 2mAbs therapy gave significantly higher inhibition of tumor growth than the erlotinib/trastuzumab combination, whereas in BxPC-3 (wild-type K-ras) xenografts, the erlotinib/trastuzumab combination showed similar growth inhibition but fewer tumor-free mice. Lapatinib showed no antitumor effect in both types of xenografts. The efficacy of the 2mAbs therapy was partly Fc-independent because F(ab')(2) fragments of the two mAbs significantly inhibited BxPC-3 growth, although with a time-limited therapeutic effect. The 2mAbs therapy was associated with a reduction of EGFR and HER2 expression and AKT phosphorylation. BxPC-3 cells preincubated with the two mAbs showed 50% less EGFR/HER2 heterodimers than controls. In pancreatic carcinoma xenografts, the 2mAbs therapy is more effective than treatments involving dual EGFR/HER2 TKIs. The mechanism of action may involve decreased AKT phosphorylation and/or disruption of EGFR/HER2 heterodimerization. PMID- 22431921 TI - Efficacy of Tie2 receptor antagonism in angiosarcoma. AB - Angiosarcomas are malignant endothelial cell tumors with few effective systemic treatments. Despite a unique endothelial origin, molecular candidates for targeted therapeutic intervention have been elusive. In this study, we explored the tunica internal endothelial cell kinase 2 (Tie2) receptor as a potential therapeutic target in angiosarcoma. Human angiosarcomas from diverse sites were shown to be universally immunoreactive for Tie2. Tie2 and vascular endothelial growth factor receptor (VEGFR) antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro. In the high-grade SVR cell line, Tie2 and VEGF antagonists inhibited cell survival synergistically, whereas effects were largely additive in the low-grade MS1-VEGF cell line. Xenograft modeling using these cell lines closely recapitulated the human disease. In vivo, Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay. The combination proved more effective than either agent alone. Tie2 inhibition seemed to elicit tumor growth delay through increased tumor cell apoptosis, whereas VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation. These data identify Tie2 antagonism as a potential novel, targeted therapy for angiosarcomas and provide a foundation for further investigation of Tie2 inhibition, alone and in combinations, in the management of this disease. PMID- 22431922 TI - CLCA2 as a p53-inducible senescence mediator. AB - p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for senescent fibroblasts, we have identified chloride channel accessory 2 (CLCA2) as a p53-inducible senescence-associated gene. CLCA2 was remarkably induced by replicative senescence as well as oxidative stress in a p53 dependent manner. We also found that ectopically expressed CLCA2 induced cellular senescence, and the down-regulation of CLCA2 by small interfering RNA caused inhibition of oxidative stress-induced senescence. Interestingly, the reduced expression of CLCA2 was frequently observed in various kinds of cancers including prostate cancer, whereas its expression was not affected in precancerous prostatic intraepithelial neoplasia. Thus, our findings suggest a crucial role of p53/CLCA2-mediated senescence induction as a barrier for malignant transformation. PMID- 22431923 TI - The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells. AB - Brain tumor xenografts initiated from glioblastoma (GBM) CD133(+) tumor stem-like cells (TSCs) are composed of TSC and non-TSC subpopulations, simulating the phenotypic heterogeneity of GBMs in situ. Given that the discrepancies between the radiosensitivity of GBM cells in vitro and the treatment response of patients suggest a role for the microenvironment in GBM radioresistance, we compared the response of TSCs and non-TSCs irradiated under in vitro and orthotopic conditions. As a measure of radioresponse determined at the individual cell level, gammaH2AX and 53BP1 foci were quantified in CD133(+) cells and their differentiated (CD133(-)) progeny. Under in vitro conditions, no difference was detected between CD133(+) and CD133(-) cells in foci induction or dispersal after irradiation. However, irradiation of orthotopic xenografts initiated from TSCs resulted in the induction of fewer gammaH2AX and 53BP1 foci in CD133(+) cells compared to their CD133(-) counterparts within the same tumor. Xenograft irradiation resulted in a tumor growth delay of approximately 7 days with a corresponding increase in the percentage of CD133(+) cells at 7 days after radiation, which persisted to the onset of neurologic symptoms. These results suggest that, although the radioresponse of TSCs and non-TSCs does not differ under in vitro growth conditions, CD133(+) cells are relatively radioresistant under intracerebral growth conditions. Whereas these findings are consistent with the suspected role for TSCs as a determinant of GBM radioresistance, these data also illustrate the dependence of the cellular radioresistance on the brain microenvironment. PMID- 22431924 TI - Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice. AB - Retinoid X receptor (RXR) has been implicated in several neoplastic diseases. Previously, we have shown that RXR-alpha is downregulated in human and rodent colonic tumors, suggesting a potential target for colon cancer prevention (http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal cancer-key-statistics). Experiments were designed to assess the chemopreventive efficacy of the selective RXR agonist bexarotene for the suppression of intestinal tumorigenesis in Apc(Min/+) mice. Before the efficacy studies, we determined that the maximal tolerated dose in C57BL/6J mice was less than 400 ppm. For the efficacy study, 6-week-old male and female C57BL/6J-Apc(Min/+) mice (nine mice per group) were fed diets containing 0, 30, and 60 ppm of bexarotene or 200 ppm of bexarotene for 80 days before intestinal tumors were evaluated. Dietary administration of 30 and 60 ppm of bexarotene suppressed the intestinal polyp formation by 38% (P < .015) and 60% (P < .0001) in males, respectively, and by 8.5% and 37% (P < .007) in females, respectively. Also, significant inhibition (50%-100%) of colonic tumor formation was observed in both male and female mice with bexarotene treatment. Administration of 200 ppm of bexarotene showed significant suppression of tumor formation (66%, P < .0001); however, it had significant toxicity. Intestinal tumors of bexarotene-fed mice showed significantly reduced expression of proliferating cell nuclear antigen (60%, P < .0001), cyclin D1, and cyclooxygenase 2 and increased RXR-alpha messenger RNA and uptake of oleate (34%, P < .01). Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%-72%, P < .0001) and inflammatory cytokines. PMID- 22431925 TI - The role of Bcl-2 family proteins in therapy responses of malignant astrocytic gliomas: Bcl2L12 and beyond. AB - Glioblastoma (GBM) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ) in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs), revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12), as important regulators of therapy-induced cell death. This review will discuss the multi-faceted modi operandi of Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins. PMID- 22431926 TI - An "Uncrimped" SMart Stapes Prosthesis: A Cause of Late Hearing Deterioration in Otosclerosis. AB - Statement of Problem. Stapedotomy is the treatment of choice for otosclerosis. Numerous techniques and prosthesis are available to perform this procedure. Success rates of surgery vary from 17% to 80%, and revision surgery carries an increased risk of complications as well as poorer hearing outcomes. Method of Study. Case report. Results. We report the first case of uncrimping of a SMart stapes prosthesis with no lateral displacement as a cause of late failure despite successful crimping and improvement in audiological outcomes after initial surgery. Conclusion. The SMart stapes prosthesis is widely used and has been shown to be safe and provide good hearing outcomes. Displacement of a stapes prosthesis is the commonest cause of failure. Our case shows that deterioration of hearing thresholds can occur from uncrimping of the prosthesis with no displacement. It is important to improve our understanding of stapedotomy failure as revision procedures are associated with poorer outcomes. PMID- 22431927 TI - Case report: safety and efficacy of tocilizumab in a patient with rheumatoid arthritis and chronic hepatitis C. AB - Tocilizumab is a monoclonal humanized anti-IL-6-receptor antibody used for the treatment of rheumatoid arthritis. The safety of tocilizumab in HCV patients is an open question. We report on safety and efficacy of tocilizumab in a 71-year old female with rheumatoid arthritis and chronic hepatitis C. Monotherapy with tocilizumab (8 mg/kg every 4 weeks, i.v.) was prescribed after the discontinuation, determined by clinical inefficacy, of anti-TNF-alfa agents (adalimumab and, subsequently, etanercept). We have registered an optimal and rapid clinical response to tocilizumab with early remission (SDAI <3.3 since 4 weeks). The safety was good with no adverse events and maintenance, during a six month followup, of normal liver enzymes. These data suggest a good safety profile of tocilizumab in patients with rheumatoid arthritis and chronic hepatitis C virus pathology. PMID- 22431928 TI - A conservative bioadhesive approach to the reattachment of complicated crown fractures in permanent first molars: a case report with a 2-year followup. AB - This paper presents a clinical report demonstrating combined restorative bioadhesive treatment and prosthetic rehabilitation of uncommon type of dental injury in an eighteen-year-old female involving crown fracture of all the permanent first molars and left upper premolars due to a bicycle riding accident. To restore the coronal fracture with invasion of biologic width, flap surgery with osteotomy and osteoplasty localized on the fractured teeth was performed, and the tooth remnant was reattached to the crown with a self-etch adhesive system. Frank pulp exposure was treated by self-etch dentin adhesive after surface disinfection prior to sealing of the wound site. At 2-year recall, the teeth continue to be aesthetically and functionally stable with a favourable pulpal and periapical environment. PMID- 22431929 TI - Oral haemangioma. AB - Vascular anomalies comprise a widely heterogeneous group of tumours and malformations. Haemangioma is the most common benign tumour of vascular origin of the head and neck region. The possible sites of occurrence in oral cavity are lips, tongue, buccal mucosa, and palate. Despite its benign origin and behaviour, it is always of clinical importance to the dental profession and requires appropriate management. This case study reports a rare case of capillary haemangioma on the palatal gingiva in a 14-year-old female. PMID- 22431930 TI - Brainstem Infarction and Panuveitis due to Sarcoidosis Successfully Treated with Steroid Pulse Therapy. AB - A 36-year-old man visited our hospital because of blurred vision and redness of the conjunctiva. Slit-lamp examination showed panuveitis. Two days later, he suddenly experienced dizziness, speech disturbance, paralysis of his right extremities, and gait disturbances. Neurological examinations suggested that his symptoms were caused by a left lateral medullary lesion. He also had erythema mainly on his trunk. Magnetic resonance imaging (MRI) of his brain demonstrated a small infarct on the left side of the medulla oblongata. Clinical presentation and MRI findings were consistent with the diagnosis of a Wallenberg's syndrome. He also had bilateral hilar lymphadenopathy. A skin biopsy showed granulomatous nodular dermatitis compatible with sarcoidosis. He was treated with steroid pulse therapy and his neurological and ocular symptoms immediately improved. Only seven similar cases of intracranical sarcoidosis have been reported, but none had been treated with steroid pulse therapy. We recommend that steroid pulse therapy be considered to treat patients with sarcoidosis with signs of lesions in the central nervous system. PMID- 22431931 TI - Remitting seronegative symmetrical synovitis with pitting edema syndrome in a chronic hemodialysis patient. AB - A 75-year-old male who was undergoing chronic hemodialysis developed abrupt-onset pitting edema and pain in the dorsum of both hands and feet. Biochemical analysis disclosed increased C-reactive protein, and negative rheumatoid factor and antinuclear antibody. Radiological examination showed no bony erosion. Computed tomography and gallium scintigraphy revealed no active infection or neoplasms. The clinical diagnosis was remitting seronegative symmetrical synovitis with pitting edema (RS(3)PE) syndrome. The pitting edema and inflammatory response quickly subsided after low-dose prednisolone therapy. This case demonstrates that RS(3)PE syndrome could be a differential diagnosis in elderly patients undergoing dialysis who develop pitting edema and joint pain. PMID- 22431932 TI - The specific sagittal magnetic resonance imaging of intradural extra-arachnoid lumbar disc herniation. AB - Intradural extra-arachnoid lumbar disc herniation is a rare disease. Few MRI findings have been reported. We experienced an intradural extra-arachnoid lumbar disc herniation. We reviewed the preoperative MRI findings. Lumbar spine T2 weighted sagittal MRI showed that one line of the ventral dura was divided into two by a disc herniation. We speculated that the two lines comprised the dura and arachnoid and that a disc herniation existed between them. We believe that division of the ventral dural line on T2-weighted sagittal images is a characteristic finding of intradural extra-arachnoid lumbar disc herniation. The division of ventral dural line seemed to be a "Y," and, thus, we called it the "Y sign." The "Y sign" may be useful for diagnosing intradural extra-arachnoid lumbar disc herniation. PMID- 22431933 TI - Hemorrhagic shock as a sequela of splenic rupture in a patient with infectious mononucleosis: focus on the potential role of salicylates. AB - Despite the fact that the vast majority of splenic ruptures are traumatic, infectious mononucleosis has been incriminated as a major predisposing factor that affects the integrity of the spleen, thus causing atraumatic ruptures and life-threatening hemorrhages. Herein we present a case of a 23-year-old Caucasian male who underwent an emergency laparotomy for acute abdomen and hemorrhagic shock, caused by spontaneous splenic rupture secondary to infectious mononucleosis. The potential role of salicylates in the development of a hemorrhagic complication in a patient with infectious mononucleosis is discussed. PMID- 22431934 TI - Spermatic cord lymphoma: a case report and literature review. AB - Spermatic cord lymphoma is a rare lethal disease. It has a poor prognosis even in stage I or II disease when treated locally, therefore, multidisciplinary treatment for early stage is recommended. On the other hand, the treatment of choice for stage III or IV spermatic cord lymphoma remains to be determined. It is said that spermatic cord lymphoma is clinicopathologically similar to primary testicular lymphoma, therefore the treatment of spermatic cord lymphoma has often been determined by reference to the recommended treatment for primary testicular lymphoma. Here we report a new case of spermatic cord lymphoma, which was found in stage IV disease. We also review thirty-three cases which have been reported as spermatic cord lymphoma to date, and discuss treatment options. PMID- 22431935 TI - Sacral fracture causing neurogenic bladder: a case report. AB - A 76-year-old man presented with a Denis Zone III sacral fracture after a traffic accident. He also developed urinary retention and perineal numbness. The patient was diagnosed with neurogenic bladder dysfunction caused by the sacral fracture. A computed tomogram (CT) revealed that third sacral lamina was fractured and displaced into the spinal canal, but vertebral body did not displace. The fracture lines began at the center of lamina and extended bilateraly. The fracture pattern was unique. The sacrum was osteoporosis, and this fracture may be based on osteoporosis. We performed laminectomy to decompress sacral nerve roots. One month after surgery, the patient was able to urinate. Three months after surgery, his bladder function recovered normally. One year after surgery, he returned to a normal daily life and had no complaints regarding urination. One year postoperative CT showed the decompressed third sacrum without displacement. PMID- 22431936 TI - Iatrogenic duodenal perforation treated with endoscopic placement of metallic clips: a case report. AB - Perforation is one of the major complications encountered during endoscopic procedures. The standard of care for these complications is either surgical intervention or nonoperative medical approach with antibiotics and bowel rest with or without parenteral alimentation. Metallic clips, initially developed to secure hemostasis in bleeding, have been successfully used to close perforations in the gastrointestinal tract (GI) including the duodenum. This avoids perioperative morbidities associated with surgical intervention while limiting the leakage of intestinal contents and peritoneal contamination that is possible with medical management. We present a case of a patient with a lateral duodenal perforation during an endoscopic retrograde cholangiopancreatography (ERCP) which was successfully treated with immediate placement of metallic endoclips. PMID- 22431937 TI - A rare cause of low back pain: report of a tailgut cyst. AB - Tailgut cysts, also known as retrorectal cystic hamartomas, are rare developmental abnormalities that typically occur in the retrorectal space. They are believed to arise from remnants of the embryonic hindgut (Hjermstad and Helwig, 1988). They can present as incidental findings during routine examination but over half of patients are thought to present with symptoms. MRI has become the modality of choice to image these frequently misdiagnosed cysts. Biopsy is not recommended. Complete intact surgical excision is advised to avoid the potential complications of these cysts which include infection, fistula formation, and the possibility of malignant transformation (Hjermstad and Helwig (1988), Mathis et al. (2010)). We describe the case of a 46-year-old female who presented with a 6-month history of low back pain. CT and MRI imaging demonstrated a complex retrorectal lesion with supralevator and infralevator components. This was removed using a combined transperineal and transabdominal approach. Histology confirmed a tailgut cyst. PMID- 22431938 TI - Occult follicular thyroid carcinoma presenting as a frontal bone metastasis: a case report. AB - This is a rare case of metastatic follicular carcinoma of thyroid in a patient with no history of thyroid problem. A frontal bone mass was examined microscopically and showed the pattern of metastatic follicular carcinoma. Thyroid ultrasonography then revealed a nodule in left lobe. Total thyroidectomy was done for the patient and microscopic examination confirmed the diagnosis. PMID- 22431939 TI - Surgical treatment of persistent fetal vasculature and visual rehabilitation: one year followup. AB - We present the management and postoperative course of a persistent fetal vasculature (PFV) case. A four-year-old girl visited the Eye Department of Hippokration, General Hospital of Thessaloniki due to reduced visual acuity of her left eye. She was diagnosed with PFV and underwent surgery (lensectomy, capsulorhexis of the posterior capsule, insertion of an intraocular lens in the posterior chamber, and posterior vitrectomy) in order to dissect the PFV. Along with the postoperative medical care, she underwent intensive treatment for amblyopia. The postoperative course was uncomplicated, and the visual acuity of her left eye improved from hand movement to 20/25 with proper correction. Patients with unilateral PFV and gradually deteriorating visual acuity could be good candidates for a combined surgical procedure, as the one described above, with a good prognosis. PMID- 22431940 TI - Iliac vein compression syndrome in an active and healthy young female. AB - Iliac vein compression syndrome is a condition involving external compression of the left common iliac vein by the right iliac artery, which was first described in the 1850s. It predominates in females typically between the third and fourth decade of life and has been associated with thrombophilias. Importantly, the syndrome is amenable to endovascular treatment. Here, we describe a case of a young athletic female with an incidental finding of a left iliac vein thrombosis while taking oral contraceptives, who was identified as having iliac vein compression syndrome on follow-up MR venography with positive testing for Factor V Leiden mutation. PMID- 22431941 TI - Transient occlusion of bilateral internal iliac arteries facilitates bloodless operative field in subcapsular prostatectomy. AB - Transurethral resection of the prostate is the gold standard of surgical treatment for benign prostatic hyperplasia (BPH). Nevertheless, open subcapsular prostatectomy is still performed for large BPH. While enucleation of prostatic adenoma is being performed, unneglectable bleeding can occur and surgeons need to rush to remove adenomas, often using fingers and in a blinded fashion. The blood supply to the prostatic capsule and adenoma can be reduced to a marked extent in subcapsular prostatectomy if the bilateral internal iliac arteries are transiently occluded. Thus, a bloodless operative field is reasonably acquired during enucleation of adenoma, which would, otherwise, be a cause for concern to surgeons due to bleeding. It is not always applicable, but it could be an option if the estimated volume of BPH is more than 100 mL. In two cases, bilateral internal iliac arteries were occluded with Bulldog clamps, and then adenomas of 159 and 97 g were enucleated. PMID- 22431942 TI - Functional parathyroid cyst: a rare cause of malignant hypercalcemia with primary hyperparathyroidism-a case report and review of the literature. AB - Parathyroid cysts are rare lesions found in the neck and anterior mediastinum. They are often nonfunctional (>90%) and rarely in the functional form. This paper discusses a case of severe hypercalcemia (23 mg/dL) secondary to a rare functional parathyroid cyst. The patient was later found to have a hemorrhagic cyst with compression of the right recurrent laryngeal nerve. Preoperative diagnosis of the lesion was parathyroid carcinoma. However, reexploration of the parathyroid mass along with microscopic study confirmed the diagnosis of a parathyroid cyst. Following cystectomy, the patient restored her baseline functional status with preservation of the right recurrent laryngeal nerve. Postoperative followup three years later showed no evidence of cyst recurrence. This paper illustrates the rare presentation of parathyroid functional cysts with severe hypercalcemia and primary hyperparathyroidism. Physicians should be aware of the presence of hemorrhage, inflammation, and compressive symptoms in these cysts which mimic parathyroid carcinoma. These patients should be managed with aggressive medical and surgical intervention. PMID- 22431943 TI - Endobronchial lipomatous hamartoma: an incidental finding in a patient with atrial fibrillation-a case report. AB - Introduction. Lung hamartomas are the most common benign tumors of the lung. Typically, they are located in the peripheral lung, while an endobronchial localisation is rare. Case Presentation. We present a case with the rare diagnosis of an endobronchial hamartoma as incidental finding in a 69-year-old male, caucasian patient with atrial fibrillation. At first admission, the patient's exertional dyspnea was caused by atrial fibrillation. Relapse of exertional dyspnea in the absence of arrhythmia was due to postobstructive pneumonia caused by an endobronchial hamartoma. Conclusion. Endobronchial tumors such as endobronchial lipoma or hamartoma should be considered as potential causes of exertional dyspnea and thus as differential diagnosis of atrial fibrillation. Although endobronchial hamartomas are benign, resection is recommended to prevent postobstructive lung damage. PMID- 22431944 TI - Giant diaphragmatic angiosarcoma of adult: a case report and review of literature. AB - Angiosarcoma is a rare vascular malignant soft tissue tumor, with highly malignant, invasive, and multifocal characteristics of biology, which is prone to local recurrence and distant metastasis, so the prognosis is extremely poor. It rarely involves the diaphragm. We present the case of an adult patient who had a primary giant angiosarcoma of the left-sided diaphragm. PMID- 22431945 TI - Computed tomography and magnetic resonance imaging findings in a case with biliary microhamartomas. AB - Biliary microhamartomas, also known as bile duct hamartomas and von Meyenburg complexes, are benign neoplasms containing cystic dilated bile ducts embedded in fibrous stroma. They develop in hepatobiliary system, do not generally give clinical outcomes, and are detected incidentally. However, they can rarely show malignant transformation. Our aim was to report the contribution of computed tomography, routine magnetic resonance imaging, and magnetic resonance cholangiopancreatography in the diagnosis of biliary microhamartomas in a 61-year old woman. PMID- 22431946 TI - Atrial Remodeling in Pregnant Hypertensive Women: Comparison between Chronic and Gestational Hypertension. AB - OBJECTIVES: Left atrial (LA) enlargement is a common finding in hypertensive patients (pts), however little information is available on LA changes during pregnancy. The present study evaluated LA size and function in pregnant women with hypertension. METHODS: Patients population included 30 women with chronic hypertension and 30 patients with gestational hypertension. A control group of 16 normotensive pregnant women was selected. Serial echocardiography was performed at 12 and 24 week of gestation in chronic hypertension and at 24 week in gestational hypertension and after delivery. LA diameters and volumes were measured and compared. LA conduit volume, passive and active emptying volumes were calculated. Patients were divided in 2 groups according to max LAV Index > 32 ml/m(2) at 24 week of gestation. RESULTS: Patients with chronic hypertension showed higher LA diameters (42 +/- 2.0 vs. 36.5 +/- 1.8; p<0.001) and LA volumes (maximal volume 45.5 +/- 4.0 vs. 38.1 +/- 7.3; p<0.001) compared with patients with gestational hypertension. The median value of max LAVI was 32 + 6.2 ml/m(2) in chronic and 26 + 5 ml/m(2) in gestational hypertension (p<0.01). During follow up patients with max LAVI > 32 ml/m(2) had more clinical complications evaluated as increase of therapy, fluid retention that need diuretic and hospitalization. CONCLUSION: Patients with chronic hypertension showed a more marked increased of LA volumes compared to gestational hypertension due to a remodeling of atrial shape as effect of chronic overload. Patients with more dilated LA volumes developed a greater number of clinical complications suggesting that a dilated LA could be a parameter of hemodynamic instability. PMID- 22431947 TI - Recent advances and developments in hand surgery. PMID- 22431948 TI - An overview of the management of flexor tendon injuries. AB - Flexor tendon injuries still remain a challenging condition to manage to ensure optimal outcome for the patient. Since the first flexor tendon repair was described by Kirchmayr in 1917, several approaches to flexor tendon injury have enabled successful repairs rates of 70-90%. Primary surgical repair results in better functional outcome compared to secondary repair or tendon graft surgery. Flexor tendon injury repair has been extensively researched and the literature demonstrates successful repair requires minimal gapping at the repair site or interference with tendon vascularity, secure suture knots, smooth junction of tendon end and having sufficient strength for healing. However, the exact surgical approach to achieve success being currently used among surgeons is still controversial. Therefore, this review aims to discuss the results of studies demonstrating the current knowledge regarding the optimal approach for flexor tendon repair. Post-operative rehabilitation for flexor tendon surgery is another area, which has caused extensive debate in hand surgery. The trend to more active mobilisation protocols seems to be favoured but further study in this area is needed to find the protocol, which achieves function and gliding but avoids rupture of the tendons. Lastly despite success following surgery complications commonly still occur post surgery, including adhesion formation, tendon rupture and stiffness of the joints. Therefore, this review aims to discuss the appropriate management of these difficulties post surgery. New techniques in management of flexor tendon will also be discussed including external laser devices, addition of growth factors and cytokines. PMID- 22431949 TI - Management of extensor tendon injuries. AB - Extensor tendon injuries are very common injuries, which inappropriately treated can cause severe lasting impairment for the patient. Assessment and management of flexor tendon injuries has been widely reviewed, unlike extensor injuries. It is clear from the literature that extensor tendon repair should be undertaken immediately but the exact approach depends on the extensor zone. Zone I injuries otherwise known as mallet injuries are often closed and treated with immobilisaton and conservative management where possible. Zone II injuries are again conservatively managed with splinting. Closed Zone III or 'boutonniere' injuries are managed conservatively unless there is evidence of displaced avulsion fractures at the base of the middle phalanx, axial and lateral instability of the PIPJ associated with loss of active or passive extension of the joint or failed non-operative treatment. Open zone III injuries are often treated surgically unless splinting enable the tendons to come together. Zone V injuries, are human bites until proven otherwise requires primary tendon repair after irrigation. Zone VI injuries are close to the thin paratendon and thin subcutaneous tissue which strong core type sutures and then splinting should be placed in extension for 4-6 weeks. Complete lacerations to zone IV and VII involve surgical primary repair followed by 6 weeks of splinting in extension. Zone VIII require multiple figure of eight sutures to repair the muscle bellies and static immobilisation of the wrist in 45 degrees of extension. To date there is little literature documenting the quality of repairing extensor tendon injuries however loss of flexion due to extensor tendon shortening, loss of flexion and extension resulting from adhesions and weakened grip can occur after surgery. This review aims to provide a systematic examination method for assessing extensor injuries, presentation and management of all type of extensor tendon injuries as well as guidance on mobilisation pre and post surgery. PMID- 22431950 TI - The use of the s-quattro dynamic external fixator for the treatment of intra articular phalangeal fractures: a review of the literature. AB - Intra-articular phalangeal fractures are a common injury. If left untreated, these injuries can lead to poor functional outcome with severe dehabilitating consequences, especially in younger patients.The S-Quattro external fixator device (Surgicraft(r), UK) can be used to treat such injuries. Its use has been widely documented and has shown many advantages in comparison to other conventional treatments. Advantages include reduced operative time, rigid fixation and early range of motion.We present a review of the current literature and use of the S-Quattro serpentine system in the management of intraarticular phalangeal fractures. PMID- 22431951 TI - Advances of peripheral nerve repair techniques to improve hand function: a systematic review of literature. AB - Concepts of neuronal damage and repair date back to ancient times. The research in this topic has been growing ever since and numerous nerve repair techniques have evolved throughout the years. Due to our greater understanding of nerve injuries and repair we now distinguish between central and peripheral nervous system. In this review, we have chosen to concentrate on peripheral nerve injuries and in particular those involving the hand. There are no reviews bringing together and summarizing the latest research evidence concerning the most up-to-date techniques used to improve hand function. Therefore, by identifying and evaluating all the published literature in this field, we have summarized all the available information about the advances in peripheral nerve techniques used to improve hand function. The most important ones are the use of resorbable poly[(R)-3-hydroxybutyrate] (PHB), epineural end-to-end suturing, graft repair, nerve transfer, side to side neurorrhaphy and end to side neurorrhaphy between median, radial and ulnar nerves, nerve transplant, nerve repair, external neurolysis and epineural sutures, adjacent neurotization without nerve suturing, Agee endoscopic operation, tourniquet induced anesthesia, toe transfer and meticulous intrinsic repair, free auto nerve grafting, use of distal based neurocutaneous flaps and tubulization. At the same time we found that the patient's age, tension of repair, time of repair, level of injury and scar formation following surgery affect the prognosis. Despite the thorough findings of this systematic review we suggest that further research in this field is needed. PMID- 22431952 TI - Recent Surgical and Medical Advances in the Treatment of Dupuytren's Disease - A Systematic Review of the Literature. AB - Dupuytren's disease (DD) is a type of fibromatosis which progressively results in the shortening and thickening of the fibrous tissue of the palmar fascia. This condition which predominantly affects white-northern Europeans has been identified since 1614. DD can affect certain activities of daily living such as face washing, combing hair and putting hand in a glove. The origin of Dupuytren's contracture is still unknown, but there are a number of treatments that doctors have come across throughout the years. Historically surgery has been the mainstay treatment for DD but not the only one. The objective is to make a structured review of the most recent advances in treatment of DD including the surgical and medical interventions. We have looked at the most relevant published articles regarding the various treatment options for DD. This review has taken 55 articles into consideration which have met the inclusion criteria. The most recent treatments used are multi-needle aponeurotomy, extensive percutaneous aponeurotomy and lipografting, injecting collagenase Clostridium histolyticum, INF-gamma and shockwave therapy as well as radiotherapy. Each of these treatments has certain advantages and drawbacks and cannot be used for every patient. In order to prevent this condition, spending more time and money in the topic is required to reach better and more consistent treatments and ultimately to eradicate this disease. PMID- 22431953 TI - The Re-Emergence of Percutaneous Fasciotomy in the Management of Dupuytren's Disease. AB - Dupuytren's disease is a common condition. Its management has gradually evolved but still remains a source of much controversy. Recently there has been a resurgence in the popularity of percutaneous needle fasciotomy. It is a simple method that uses a hypodermic needle as a scalpel blade. It is usually performed in the out-patient setting under local anaesthesia without a tourniquet. It has few complications and allows almost immediate return to work with few restrictions.It can provide complete deformity correction and may offer a long term solution in selected patients. It is also useful in converting advanced contractures into milder deformities, allowing a second stage digito-palmar fasciectomy to be more successful. Recurrence is earlier than with more formal and invasive techniques but the procedure can be repeated and does not preclude the patient from further surgery.This article reviews the technique and assesses the efficacy and outcomes of published data. PMID- 22431954 TI - Recent advances and developments in neural repair and regeneration for hand surgery. AB - End-to-end suture of nerves and autologous nerve grafts are the 'gold standard' for repair and reconstruction of peripheral nerves. However, techniques such as sutureless nerve repair with tissue glues, end-to-side nerve repair and allografts exist as alternatives. Biological and synthetic nerve conduits have had some success in early clinical studies on reconstruction of nerve defects in the hand. The effectiveness of nerve regeneration could potentially be increased by using these nerve conduits as scaffolds for delivery of Schwann cells, stem cells, neurotrophic and neurotropic factors or extracellular matrix proteins. There has been extensive in vitro and in vivo research conducted on these techniques. The clinical applicability and efficacy of these techniques needs to be investigated fully. PMID- 22431955 TI - Airway compromise due to wound hematoma following anterior cervical spine surgery. AB - One of the most serious adverse events associated with anterior cervical spine surgery is wound hematoma resulting in airway compromise. The reported incidence of this postoperative complication has varied from 0.2% to 1.9%. Obstruction of the airway secondary to bleeding presents a challenging clinical scenario given the rapidity of onset, distorted anatomy of the upper respiratory tract, urgent need to act and potential for catastrophic consequences. This high-risk, life threatening clinical scenario requires specialized knowledge and a well-designed treatment protocol to achieve a positive outcome. In this review, we report a case of airway compromise secondary to wound hematoma following anterior cervical discectomy and fusion, followed by a review of relevant literature, anatomy, etiologic factors and diagnostic considerations. We also propose guidelines for the prevention and management of postoperative airway obstruction due to wound hematoma. PMID- 22431956 TI - Non-anatomic proximal realignment for recurrent patellar dislocation does not sufficiently prevent redislocation. AB - Several operative techniques have been described for recurrent patellar dislocation. Clinical results vary depending on the procedure and indication. The present study aimed to evaluate the clinical outcome of Insall's proximal realignment for recurrent patellar dislocation at mid-term follow-up. Forty-five patients were reviewed with a mean follow-up period of 49 months after having undergone Insall's procedure. Outcome measures included reports of redislocations, complications, patient-reported outcome scores (Kujala, Tegner activity scale) and subjective assessment. No statistically significant improvements (p < 0.05) in patient-reported outcome measures were noted. Sixteen patients (35%) had poor to fair results using the Kujala score. Subjective assessment revealed that 12 patients (27%) were dissatisfied with the outcome of their surgery and would not undergo the same procedure. Ten patients (22%) had suffered from redislocation at the latest follow-up. In 4 cases (9%), intra articular knee hematoma occurred which required arthroscopic intervention. The overall mid-term outcome of the present study shows low patient satisfaction. Non anatomic realignment for recurrent patellar dislocation does not adequately prevent redislocation. PMID- 22431957 TI - Case report: "spina ventosa" tuberculous dactylitis in a 2 year old boy - a very rare disease. AB - Tuberculous infection of metacarpals, metatarsals and phalanges is known as tuberculous dactylitis. There is a spindle shaped expansion of the short tubular bones due to tuberculous granuloma. Hence it is also known as spina ventosa. In our case, a two year old boy with a swelling in the metacarpal was provisionally diagnosed as enchondromata while the possibility of spina ventosa was kept in mind. He was posted for excision of the metacarpal followed by bone grafting. Histopathological examination report confirmed it as spina ventosa. PMID- 22431958 TI - Antibodies against the envelope glycoprotein promote infectivity of immature dengue virus serotype 2. AB - Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcgamma receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM containing immature and partially mature flavivirus particles. PMID- 22431959 TI - Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. AB - BACKGROUND: Liver biopsy is considered as the gold standard for assessing non alcoholic fatty liver disease (NAFLD) histologic lesions in patients with severe obesity. The aim of this study was to perform an overview of 3 studies which assessed the performance of non-invasive markers of fibrosis (FibroTest), steatosis (SteatoTest) and steato-hepatitis (NashTest, ActiTest) in these patients. METHODS: 494 patients with interpretable biopsy and biomarkers using of three prospective cohorts of patients with severe obesity (BMI >35 kg/m2) were included. Histology (NAS score) and the biochemical measurements were blinded to any other characteristics. The area under the ROC curves (AUROC), sensitivity, specificity, positive and negative predictive values were assessed. Weighted AUROC (wAUROC Obuchowski method) was used to prevent multiple testing and spectrum effect. Two meta-analyses were performed; one used the individual patient, and the other a classical meta-analysis. RESULTS: Prevalence of advanced fibrosis (bridging) was 9.9%, advanced steatosis (>33%) 54.2%, and steato hepatitis (NAS score >4) 17.2%. The mean wAUROCs were: FibroTest for advanced fibrosis (95%CI; significance) = 0.85 (0.83-0.87; P<0.0001); SteatoTest for advanced steatosis = 0.80 (0.79-0.83); and ActiTest for steato-hepatitis = 0.84 (0.82-0.86; P<0.0001). Using the classical meta-analysis (random effect model) the mean AUROCs were: FibroTest = 0.72 (0.63-0.79; P<0.0001); SteatoTest = 0.71 (0.66-0.75; P<0.0001); and ActiTest = 0.74 (0.68-0.79; P<0.0001). Despite more metabolic risk factors in one cohort, results were similar according to gender, presence of diabetes and between the 3 cohorts. CONCLUSION: In patients with severe obesity, a significant diagnostic performance of FibroTest, SteatoTest and ActiTest was observed for liver lesions. PMID- 22431960 TI - Effect of diuretic use on 30-day postdialysis mortality in critically ill patients receiving acute dialysis. AB - BACKGROUND: The impact of diuretic usage and dosage on the mortality of critically ill patients with acute kidney injury is still unclear. METHODS AND RESULTS: In this prospective, multicenter, observational study, 572 patients with postsurgical acute kidney injury receiving hemodialysis were recruited and followed daily. Thirty-day postdialysis mortality was analyzed using Cox's proportional hazards model with time-dependent covariates. The mean age of the 572 patients was 60.8+/-16.6 years. Patients with lower serum creatinine (p = 0.031) and blood lactate (p = 0.033) at ICU admission, lower predialysis urine output (p = 0.001) and PaO(2)/FiO(2) (p = 0.039), as well as diabetes (p = 0.037) and heart failure (p = 0.049) were more likely to receive diuretics. A total of 280 (49.0%) patients died within 30 days after acute dialysis initiation. The analysis of 30-day postdialysis mortality by fitting propensity score-adjusted Cox's proportional hazards models with time-dependent covariates showed that higher 3-day accumulated diuretic doses after dialysis initiation (HR = 1.449, p = 0.021) could increase the hazard rate of death. Moreover, higher time-varying 3 day accumulative diuretic doses were associated with hypotension (p<0.001) and less intense hemodialysis (p<0.001) during the acute dialysis period. BACKGROUND AND SIGNIFICANCE: Higher time-varying 3-day accumulative diuretic dose predicts mortality in postsurgical critically ill patients requiring acute dialysis. Higher diuretic doses are associated with hypotension and a lower intensity of dialysis. Caution should be employed before loop diuretics are administered to postsurgical patients during the acute dialysis period. PMID- 22431961 TI - Pain ratings, psychological functioning and quantitative EEG in a controlled study of chronic back pain patients. AB - OBJECTIVES: Several recent studies report the presence of a specific EEG pattern named Thalamocortical Dysrhythmia (TCD) in patients with severe chronic neurogenic pain. This is of major interest since so far no neuroscientific indicator of chronic pain could be identified. We investigated whether a TCD-like pattern could be found in patients with moderate chronic back pain, and we compared patients with neuropathic and non-neuropathic pain components. We furthermore assessed the presence of psychopathology and the degree of psychological functioning and examined whether the strength of the TCD-related EEG markers is correlated with psychological symptoms and pain ratings. DESIGN: Controlled clinical trial with age and sex matched healthy controls. METHODS: Spontaneous EEG was recorded in 37 back pain patients and 37 healthy controls. RESULTS: We were not able to observe a statistically significant TCD effect in the EEG data of the whole patient group, but a subsample of patients with evidence for root damage showed a trend in this direction. Pain patients showed markedly increased psychopathology. In addition, patients' ratings of pain intensity within the last 1 to 12 months showed strong correlations with EEG power, while psychopathology was correlated to the peak frequency. CONCLUSION: Out of several possible interpretations the most likely conclusion is that only patients with severe pain as well as root lesions with consecutive thalamic deafferentation develop the typical TCD pattern. Our primary method of defining 'neuropathic pain' could not reliably determine if such a deafferentation was present. Nevertheless the analysis of a specific subsample as well as correlations between pain ratings, psychopathology and EEG power and peak frequency give some support to the TCD concept. TRIAL REGISTRATION: ClinicalTrials.gov NCT00744575. PMID- 22431962 TI - A synthesis of tagging studies examining the behaviour and survival of anadromous salmonids in marine environments. AB - This paper synthesizes tagging studies to highlight the current state of knowledge concerning the behaviour and survival of anadromous salmonids in the marine environment. Scientific literature was reviewed to quantify the number and type of studies that have investigated behaviour and survival of anadromous forms of Pacific salmon (Oncorhynchus spp.), Atlantic salmon (Salmo salar), brown trout (Salmo trutta), steelhead (Oncorhynchus mykiss), and cutthroat trout (Oncorhynchus clarkii). We examined three categories of tags including electronic (e.g. acoustic, radio, archival), passive (e.g. external marks, Carlin, coded wire, passive integrated transponder [PIT]), and biological (e.g. otolith, genetic, scale, parasites). Based on 207 papers, survival rates and behaviour in marine environments were found to be extremely variable spatially and temporally, with some of the most influential factors being temperature, population, physiological state, and fish size. Salmonids at all life stages were consistently found to swim at an average speed of approximately one body length per second, which likely corresponds with the speed at which transport costs are minimal. We found that there is relatively little research conducted on open ocean migrating salmonids, and some species (e.g. masu [O. masou] and amago [O. rhodurus]) are underrepresented in the literature. The most common forms of tagging used across life stages were various forms of external tags, coded wire tags, and acoustic tags, however, the majority of studies did not measure tagging/handling effects on the fish, tag loss/failure, or tag detection probabilities when estimating survival. Through the interdisciplinary application of existing and novel technologies, future research examining the behaviour and survival of anadromous salmonids could incorporate important drivers such as oceanography, tagging/handling effects, predation, and physiology. PMID- 22431963 TI - A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. AB - BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating CFS/ME. METHODS AND FINDINGS: A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated. CONCLUSIONS/SIGNIFICANCE: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00215800. PMID- 22431964 TI - Male * female interaction for a pre-copulatory trait, but not a post-copulatory trait, among cosmopolitan populations of Drosophila melanogaster. AB - Sexual coevolution occurs when changes in the phenotype of one sex select for changes in the other sex. We can identify the "footprint" of this coevolution by mating males and females from different populations and testing for a male-female genotype interaction for a trait associated with male (or female) performance. Here we mated male Drosophila melanogaster from five different continents with females from their own and different continents to test for a male-female interaction for mating speed, a pre-copulatory trait, and female reproductive investment, a post-copulatory trait. We found a strong male-female interaction for mating speed, consistent with previous studies using different populations, suggesting that the potential for sexual coevolution for this trait is present in this species. In contrast, we did not detect a male-female interaction for female reproductive investment. Although a male-female interaction for mating speed is compatible with the hypothesis of ongoing sexual coevolution, the nature of our experimental design is unable to exclude alternate explanations. Thus, the evolutionary mechanisms promoting male-female genotype interactions for pre copulatory mating traits in D. melanogaster warrant further investigation. PMID- 22431965 TI - Insights into the ecology and evolutionary success of crocodilians revealed through bite-force and tooth-pressure experimentation. AB - BACKGROUND: Crocodilians have dominated predatory niches at the water-land interface for over 85 million years. Like their ancestors, living species show substantial variation in their jaw proportions, dental form and body size. These differences are often assumed to reflect anatomical specialization related to feeding and niche occupation, but quantified data are scant. How these factors relate to biomechanical performance during feeding and their relevance to crocodilian evolutionary success are not known. METHODOLOGY/PRINCIPAL FINDINGS: We measured adult bite forces and tooth pressures in all 23 extant crocodilian species and analyzed the results in ecological and phylogenetic contexts. We demonstrate that these reptiles generate the highest bite forces and tooth pressures known for any living animals. Bite forces strongly correlate with body size, and size changes are a major mechanism of feeding evolution in this group. Jaw shape demonstrates surprisingly little correlation to bite force and pressures. Bite forces can now be predicted in fossil crocodilians using the regression equations generated in this research. CONCLUSIONS/SIGNIFICANCE: Critical to crocodilian long-term success was the evolution of a high bite-force generating musculo-skeletal architecture. Once achieved, the relative force capacities of this system went essentially unmodified throughout subsequent diversification. Rampant changes in body size and concurrent changes in bite force served as a mechanism to allow access to differing prey types and sizes. Further access to the diversity of near-shore prey was gained primarily through changes in tooth pressure via the evolution of dental form and distributions of the teeth within the jaws. Rostral proportions changed substantially throughout crocodilian evolution, but not in correspondence with bite forces. The biomechanical and ecological ramifications of such changes need further examination. PMID- 22431966 TI - DNA methylation patterns in cord blood DNA and body size in childhood. AB - BACKGROUND: Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood. PRINCIPAL FINDINGS: A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean +/- standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m(2). This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>1.2-fold and p<10(-4)) were analysed to determine DNA methylation levels at 1-3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing (ALPL with height, p(Corrected) = 0.017). CONCLUSIONS: DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality. PMID- 22431967 TI - Effect of insecticide resistance on development, longevity and reproduction of field or laboratory selected Aedes aegypti populations. AB - Aedes aegypti dispersion is the major reason for the increase in dengue transmission in South America. In Brazil, control of this mosquito strongly relies on the use of pyrethroids and organophosphates against adults and larvae, respectively. In consequence, many Ae. aegypti field populations are resistant to these compounds. Resistance has a significant adaptive value in the presence of insecticide treatment. However some selected mechanisms can influence important biological processes, leading to a high fitness cost in the absence of insecticide pressure. We investigated the dynamics of insecticide resistance and its potential fitness cost in five field populations and in a lineage selected for deltamethrin resistance in the laboratory, for nine generations. For all populations the life-trait parameters investigated were larval development, sex ratio, adult longevity, relative amount of ingested blood, rate of ovipositing females, size of egglaying and eggs viability. In the five natural populations, the effects on the life-trait parameters were discrete but directly proportional to resistance level. In addition, several viability parameters were strongly affected in the laboratory selected population compared to its unselected control. Our results suggest that mechanisms selected for organophosphate and pyrethroid resistance caused the accumulation of alleles with negative effects on different life-traits and corroborate the hypothesis that insecticide resistance is associated with a high fitness cost. PMID- 22431968 TI - Human remains from the Pleistocene-Holocene transition of southwest China suggest a complex evolutionary history for East Asians. AB - BACKGROUND: Later Pleistocene human evolution in East Asia remains poorly understood owing to a scarcity of well described, reliably classified and accurately dated fossils. Southwest China has been identified from genetic research as a hotspot of human diversity, containing ancient mtDNA and Y-DNA lineages, and has yielded a number of human remains thought to derive from Pleistocene deposits. We have prepared, reconstructed, described and dated a new partial skull from a consolidated sediment block collected in 1979 from the site of Longlin Cave (Guangxi Province). We also undertook new excavations at Maludong (Yunnan Province) to clarify the stratigraphy and dating of a large sample of mostly undescribed human remains from the site. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a detailed comparison of cranial, including a virtual endocast for the Maludong calotte, mandibular and dental remains from these two localities. Both samples probably derive from the same population, exhibiting an unusual mixture of modern human traits, characters probably plesiomorphic for later Homo, and some unusual features. We dated charcoal with AMS radiocarbon dating and speleothem with the Uranium-series technique and the results show both samples to be from the Pleistocene-Holocene transition: ~14.3-11.5 ka. CONCLUSIONS/SIGNIFICANCE: Our analysis suggests two plausible explanations for the morphology sampled at Longlin Cave and Maludong. First, it may represent a late-surviving archaic population, perhaps paralleling the situation seen in North Africa as indicated by remains from Dar-es-Soltane and Temara, and maybe also in southern China at Zhirendong. Alternatively, East Asia may have been colonised during multiple waves during the Pleistocene, with the Longlin-Maludong morphology possibly reflecting deep population substructure in Africa prior to modern humans dispersing into Eurasia. PMID- 22431969 TI - Development and functional analysis of novel genetic promoters using DNA shuffling, hybridization and a combination thereof. AB - BACKGROUND: Development of novel synthetic promoters with enhanced regulatory activity is of great value for a diverse range of plant biotechnology applications. METHODOLOGY: Using the Figwort mosaic virus full-length transcript promoter (F) and the sub-genomic transcript promoter (FS) sequences, we generated two single shuffled promoter libraries (LssF and LssFS), two multiple shuffled promoter libraries (LmsFS-F and LmsF-FS), two hybrid promoters (FuasFScp and FSuasFcp) and two hybrid-shuffled promoter libraries (LhsFuasFScp and LhsFSuasFcp). Transient expression activities of approximately 50 shuffled promoter clones from each of these libraries were assayed in tobacco (Nicotiana tabacum cv. Xanthi) protoplasts. It was observed that most of the shuffled promoters showed reduced activity compared to the two parent promoters (F and FS) and the CaMV35S promoter. In silico studies (computer simulated analyses) revealed that the reduced promoter activities of the shuffled promoters could be due to their higher helical stability. On the contrary, the hybrid promoters FuasFScp and FSuasFcp showed enhanced activities compared to F, FS and CaMV 35S in both transient and transgenic Nicotiana tabacum and Arabidopsis plants. Northern-blot and qRT-PCR data revealed a positive correlation between transcription and enzymatic activity in transgenic tobacco plants expressing hybrid promoters. Histochemical/X-gluc staining of whole transgenic seedlings/tissue-sections and fluorescence images of ImaGene GreenTM treated roots and stems expressing the GUS reporter gene under the control of the FuasFScp and FSuasFcp promoters also support the above findings. Furthermore, protein extracts made from protoplasts expressing the human defensin (HNP-1) gene driven by hybrid promoters showed enhanced antibacterial activity compared to the CaMV35S promoter. SIGNIFICANCE/CONCLUSION: Both shuffled and hybrid promoters developed in the present study can be used as molecular tools to study the regulation of ectopic gene expression in plants. PMID- 22431970 TI - Expression of emotion in Eastern and Western music mirrors vocalization. AB - In Western music, the major mode is typically used to convey excited, happy, bright or martial emotions, whereas the minor mode typically conveys subdued, sad or dark emotions. Recent studies indicate that the differences between these modes parallel differences between the prosodic and spectral characteristics of voiced speech sounds uttered in corresponding emotional states. Here we ask whether tonality and emotion are similarly linked in an Eastern musical tradition. The results show that the tonal relationships used to express positive/excited and negative/subdued emotions in classical South Indian music are much the same as those used in Western music. Moreover, tonal variations in the prosody of English and Tamil speech uttered in different emotional states are parallel to the tonal trends in music. These results are consistent with the hypothesis that the association between musical tonality and emotion is based on universal vocal characteristics of different affective states. PMID- 22431971 TI - The effects of acute tryptophan depletion on reactive aggression in adults with attention-deficit/hyperactivity disorder (ADHD) and healthy controls. AB - BACKGROUND: The neurotransmitter serotonin (5-HT) has been linked to the underlying neurobiology of aggressive behavior, particularly with evidence from studies in animals and humans. However, the underlying neurobiology of aggression remains unclear in the context of attention-deficit/hyperactivity disorder (ADHD), a disorder known to be associated with aggression and impulsivity. We investigated the effects of acute tryptophan depletion (ATD), and the resulting diminished central nervous serotonergic neurotransmission, on reactive aggression in healthy controls and adults with ADHD. METHODOLOGY/PRINCIPAL FINDINGS: Twenty male patients with ADHD and twenty healthy male controls were subjected to ATD with an amino acid (AA) beverage that lacked tryptophan (TRP, the physiological precursor of 5-HT) and a TRP-balanced AA beverage (BAL) in a double-blind, within subject crossover-study over two study days. We assessed reactive aggression 3.25 hours after ATD/BAL intake using a point-subtraction aggression game (PSAG) in which participants played for points against a fictitious opponent. Point subtraction was taken as a measure for reactive aggression. Lowered rates of reactive aggression were found in the ADHD group under ATD after low provocation (LP), with controls showing the opposite effect. In patients with ADHD, trait impulsivity was negatively correlated with the ATD effect on reactive aggression after LP. Statistical power was limited due to large standard deviations observed in the data on point subtraction, which may limit the use of this particular paradigm in adults with ADHD. CONCLUSIONS/SIGNIFICANCE: Together with previous findings, the data provide preliminary evidence of an inverse association between trait-impulsivity and the ATD effect on reactive aggression after LP (as assessed by the PSAG) in patients with ADHD and that this relationship can be found in both adolescents and adults. Because of limited statistical power larger sample sizes are needed to find main effects of ATD/BAL administration on reactive aggression in adults with ADHD. PMID- 22431972 TI - Men and women exhibit a differential bias for processing movement versus objects. AB - Sex differences in many spatial and verbal tasks appear to reflect an inherent low-level processing bias for movement in males and objects in females. We explored this potential movement/object bias in men and women using a computer task that measured targeting performance and/or color recognition. The targeting task showed a ball moving vertically towards a horizontal line. Before reaching the line, the ball disappeared behind a masking screen, requiring the participant to imagine the movement vector and identify the intersection point. For the color recognition task, the ball briefly changed color before disappearing beneath the mask and participants were required only to identify the color shade. Results showed that targeting accuracy for slow and fast moving balls was significantly better in males compared to females. No sex difference was observed for color shade recognition. We also studied a third, dual attention task comprised of the first two, where the moving ball briefly changed color randomly just before passing beneath the masking screen. When the ball changed color, participants were required only to identify the color shade. If the ball didn't change color, participants estimated the intersection point. Participants in this dual attention condition were first tested with the targeting and color tasks alone and showed results that were similar to the previous groups tested on a single task. However, under the dual attention condition, male accuracy in targeting, as well as color shade recognition, declined significantly compared to their performance when the tasks were tested alone. No significant changes were found in female performance. Finally, reaction times for targeting and color choices in both sexes correlated highly with ball speed, but not accuracy. Overall, these results provide evidence of a sex-related bias in processing objects versus movement, which may reflect sex differences in bottom up versus top-down analytical strategies. PMID- 22431973 TI - Stochastic modeling for the expression of a gene regulated by competing transcription factors. AB - It is widely accepted that gene expression regulation is a stochastic event. The common approach for its computer simulation requires detailed information on the interactions of individual molecules, which is often not available for the analyses of biological experiments. As an alternative approach, we employed a more intuitive model to simulate the experimental result, the Markov-chain model, in which a gene is regulated by activators and repressors, which bind the same site in a mutually exclusive manner. Our stochastic simulation in the presence of both activators and repressors predicted a Hill-coefficient of the dose-response curve closer to the experimentally observed value than the calculated value based on the simple additive effects of activators alone and repressors alone. The simulation also reproduced the heterogeneity of gene expression levels among individual cells observed by Fluorescence Activated Cell Sorting analysis. Therefore, our approach may help to apply stochastic simulations to broader experimental data. PMID- 22431974 TI - Visual-gustatory interaction: orbitofrontal and insular cortices mediate the effect of high-calorie visual food cues on taste pleasantness. AB - Vision provides a primary sensory input for food perception. It raises expectations on taste and nutritional value and drives acceptance or rejection. So far, the impact of visual food cues varying in energy content on subsequent taste integration remains unexplored. Using electrical neuroimaging, we assessed whether high- and low-calorie food cues differentially influence the brain processing and perception of a subsequent neutral electric taste. When viewing high-calorie food images, participants reported the subsequent taste to be more pleasant than when low-calorie food images preceded the identical taste. Moreover, the taste-evoked neural activity was stronger in the bilateral insula and the adjacent frontal operculum (FOP) within 100 ms after taste onset when preceded by high- versus low-calorie cues. A similar pattern evolved in the anterior cingulate (ACC) and medial orbitofrontal cortex (OFC) around 180 ms, as well as, in the right insula, around 360 ms. The activation differences in the OFC correlated positively with changes in taste pleasantness, a finding that is an accord with the role of the OFC in the hedonic evaluation of taste. Later activation differences in the right insula likely indicate revaluation of interoceptive taste awareness. Our findings reveal previously unknown mechanisms of cross-modal, visual-gustatory, sensory interactions underlying food evaluation. PMID- 22431975 TI - Chronic Toxoplasma infection modifies the structure and the risk of host behavior. AB - The intracellular parasite Toxoplasma has an indirect life cycle, in which felids are the definitive host. It has been suggested that this parasite developed mechanisms for enhancing its transmission rate to felids by inducing behavioral modifications in the intermediate rodent host. For example, Toxoplasma-infected rodents display a reduction in the innate fear of predator odor. However, animals with Toxoplasma infection acquired in the wild are more often caught in traps, suggesting that there are manipulations of intermediate host behavior beyond those that increase predation by felids. We investigated the behavioral modifications of Toxoplasma-infected mice in environments with exposed versus non exposed areas, and found that chronically infected mice with brain cysts display a plethora of behavioral alterations. Using principal component analysis, we discovered that most of the behavioral differences observed in cyst-containing animals reflected changes in the microstructure of exploratory behavior and risk/unconditioned fear. We next examined whether these behavioral changes were related to the presence and distribution of parasitic cysts in the brain of chronically infected mice. We found no strong cyst tropism for any particular brain area but found that the distribution of Toxoplasma cysts in the brain of infected animals was not random, and that particular combinations of cyst localizations changed risk/unconditioned fear in the host. These results suggest that brain cysts in animals chronically infected with Toxoplasma alter the fine structure of exploratory behavior and risk/unconditioned fear, which may result in greater capture probability of infected rodents. These data also raise the possibility that selective pressures acted on Toxoplasma to broaden its transmission between intermediate predator hosts, in addition to felid definitive hosts. PMID- 22431976 TI - Interrelationships between yeast ribosomal protein assembly events and transient ribosome biogenesis factors interactions in early pre-ribosomes. AB - Early steps of eukaryotic ribosome biogenesis require a large set of ribosome biogenesis factors which transiently interact with nascent rRNA precursors (pre rRNA). Most likely, concomitant with that initial contacts between ribosomal proteins (r-proteins) and ribosome precursors (pre-ribosomes) are established which are converted into robust interactions between pre-rRNA and r-proteins during the course of ribosome maturation. Here we analysed the interrelationship between r-protein assembly events and the transient interactions of ribosome biogenesis factors with early pre-ribosomal intermediates termed 90S pre ribosomes or small ribosomal subunit (SSU) processome in yeast cells. We observed that components of the SSU processome UTP-A and UTP-B sub-modules were recruited to early pre-ribosomes independently of all tested r-proteins. On the other hand, groups of SSU processome components were identified whose association with early pre-ribosomes was affected by specific r-protein assembly events in the head platform interface of the SSU. One of these components, Noc4p, appeared to be itself required for robust incorporation of r-proteins into the SSU head domain. Altogether, the data reveal an emerging network of specific interrelationships between local r-protein assembly events and the functional interactions of SSU processome components with early pre-ribosomes. They point towards some of these components being transient primary pre-rRNA in vivo binders and towards a role for others in coordinating the assembly of major SSU domains. PMID- 22431977 TI - Rethinking 'rational imitation' in 14-month-old infants: a perceptual distraction approach. AB - In their widely noticed study, Gergely, Bekkering, and Kiraly (2002) showed that 14-month-old infants imitated an unusual action only if the model freely chose to perform this action and not if the choice of the action could be ascribed to external constraints. They attributed this kind of selective imitation to the infants' capacity of understanding the principle of rational action. In the current paper, we present evidence that a simpler approach of perceptual distraction may be more appropriate to explain their results. When we manipulated the saliency of context stimuli in the two original conditions, the results were exactly opposite to what rational imitation predicts. Based on these findings, we reject the claim that the notion of rational action plays a key role in selective imitation in 14-month-olds. PMID- 22431978 TI - Incorporation of noncanonical amino acids into Rosetta and use in computational protein-peptide interface design. AB - Noncanonical amino acids (NCAAs) can be used in a variety of protein design contexts. For example, they can be used in place of the canonical amino acids (CAAs) to improve the biophysical properties of peptides that target protein interfaces. We describe the incorporation of 114 NCAAs into the protein-modeling suite Rosetta. We describe our methods for building backbone dependent rotamer libraries and the parameterization and construction of a scoring function that can be used to score NCAA containing peptides and proteins. We validate these additions to Rosetta and our NCAA-rotamer libraries by showing that we can improve the binding of a calpastatin derived peptides to calpain-1 by substituting NCAAs for native amino acids using Rosetta. Rosetta (executables and source), auxiliary scripts and code, and documentation can be found at (http://www.rosettacommons.org/). PMID- 22431979 TI - Membrane topology and predicted RNA-binding function of the 'early responsive to dehydration (ERD4)' plant protein. AB - Functional annotation of uncharacterized genes is the main focus of computational methods in the post genomic era. These tools search for similarity between proteins on the premise that those sharing sequence or structural motifs usually perform related functions, and are thus particularly useful for membrane proteins. Early responsive to dehydration (ERD) genes are rapidly induced in response to dehydration stress in a variety of plant species. In the present work we characterized function of Brassica juncea ERD4 gene using computational approaches. The ERD4 protein of unknown function possesses ubiquitous DUF221 domain (residues 312-634) and is conserved in all plant species. We suggest that the protein is localized in chloroplast membrane with at least nine transmembrane helices. We detected a globular domain of 165 amino acid residues (183-347) in plant ERD4 proteins and expect this to be posited inside the chloroplast. The structural-functional annotation of the globular domain was arrived at using fold recognition methods, which suggested in its sequence presence of two tandem RNA recognition motif (RRM) domains each folded into betaalphabetabetaalphabeta topology. The structure based sequence alignment with the known RNA-binding proteins revealed conservation of two non-canonical ribonucleoprotein sub-motifs in both the putative RNA-recognition domains of the ERD4 protein. The function of highly conserved ERD4 protein may thus be associated with its RNA-binding ability during the stress response. This is the first functional annotation of ERD4 family of proteins that can be useful in designing experiments to unravel crucial aspects of stress tolerance mechanism. PMID- 22431980 TI - Observation of live ticks (Haemaphysalis flava) by scanning electron microscopy under high vacuum pressure. AB - Scanning electron microscopes (SEM), which image sample surfaces by scanning with an electron beam, are widely used for steric observations of resting samples in basic and applied biology. Various conventional methods exist for SEM sample preparation. However, conventional SEM is not a good tool to observe living organisms because of the associated exposure to high vacuum pressure and electron beam radiation. Here we attempted SEM observations of live ticks. During 1.5*10( 3) Pa vacuum pressure and electron beam irradiation with accelerated voltages (2 5 kV), many ticks remained alive and moved their legs. After 30-min observation, we removed the ticks from the SEM stage; they could walk actively under atmospheric pressure. When we tested 20 ticks (8 female adults and 12 nymphs), they survived for two days after SEM observation. These results indicate the resistance of ticks against SEM observation. Our second survival test showed that the electron beam, not vacuum conditions, results in tick death. Moreover, we describe the reaction of their legs to electron beam exposure. These findings open the new possibility of SEM observation of living organisms and showed the resistance of living ticks to vacuum condition in SEM. These data also indicate, for the first time, the usefulness of tick as a model system for biology under extreme condition. PMID- 22431981 TI - Short-term effect of different teaching methods on nasopharyngeal carcinoma for general practitioners in Jakarta, Indonesia. AB - In Indonesia, Nasopharyngeal Carcinoma (NPC) is the most frequent cancer of the head and neck region. At first presentation in the hospital most patients already have advanced NPC. Our previous study showed that general practitioners (GPs) working in Yogyakarta, Indonesia lack the knowledge necessary for early detection of NPC. By providing training on early symptoms of NPC we hope that the diagnosis and referral will occur at an earlier stage. Here we assess the current NPC knowledge levels of GPs in Jakarta, evaluate improvement after training, compare the effectiveness of two training formats, and estimate the loss of recall over a two week period. METHODS: Two Indonesian GPs visited 31 Primary Health Care Centres (PHCCs) and provided a lecture on NPC. The alternative format consisted of a symposium at the Universitas Indonesia, Jakarta, presented by local head and neck surgeons, with all GPs in the region being invited. To evaluate the effect of both formats a questionnaire was conducted before and after. RESULTS: The lecture in the PHCCs was attended by 130 GPs. Sixty-six GPs attended the training in the university hospital and 40 GPs attended both. Pre training the NPC knowledge level was poor with an average of 1.6 symptoms being correctly identified out of a potential maximum of 12, this was increased to 4.9 post training (p<0.0001). GPs attending the PHCC course recorded a greater increase in correct symptoms than those attending the symposium (3.8 vs. 2.8; p = 0.01). After a two week period the knowledge levels had declined slightly from 5.5 correctly identified symptoms to 4.2 (p = 0.25). CONCLUSION: These results confirm our findings regarding GPs insufficient knowledge of NPC. Lectures in the PHCC and a symposium have both been proven to be effective training tools in the education of GPs. PMID- 22431982 TI - Biodegradation of pig manure by the housefly, Musca domestica: a viable ecological strategy for pig manure management. AB - The technology for biodegradation of pig manure by using houseflies in a pilot plant capable of processing 500-700 kg of pig manure per week is described. A single adult cage loaded with 25,000 pupae produced 177.7+/-32.0 ml of eggs in a 15-day egg-collection period. With an inoculation ratio of 0.4-1.0 ml eggs/kg of manure, the amount of eggs produced by a single cage can suffice for the biodegradation of 178-444 kg of manure. Larval development varied among four different types of pig manure (centrifuged slurry, fresh manure, manure with sawdust, manure without sawdust). Larval survival ranged from 46.9+/-2.1%, in manure without sawdust, to 76.8+/-11.9% in centrifuged slurry. Larval development took 6-11 days, depending on the manure type. Processing of 1 kg of wet manure produced 43.9-74.3 g of housefly pupae and the weight of the residue after biodegradation decreased to 0.18-0.65 kg, with marked differences among manure types. Recommendations for the operation of industrial-scale biodegradation facilities are presented and discussed. PMID- 22431983 TI - Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex. AB - Nitrotyrosination of proteins, a hallmark of inflammation, may result in the production of MHC-restricted neoantigens that can be recognized by T cells and bypass the constraints of immunological self-tolerance. Here we biochemically and structurally assessed how nitrotyrosination of the lymphocytic choriomeningitis virus (LCMV)-associated immunodominant MHC class I-restricted epitopes gp33 and gp34 alters T cell recognition in the context of both H-2D(b) and H-2K(b). Comparative analysis of the crystal structures of H-2K(b)/gp34 and H-2K(b)/NY gp34 demonstrated that nitrotyrosination of p3Y in gp34 abrogates a hydrogen bond interaction formed with the H-2K(b) residue E152. As a consequence the conformation of the TCR-interacting E152 was profoundly altered in H-2K(b)/NY gp34 when compared to H-2K(b)/gp34, thereby modifying the surface of the nitrotyrosinated MHC complex. Furthermore, nitrotyrosination of gp34 resulted in structural over-packing, straining the overall conformation and considerably reducing the stability of the H-2K(b)/NY-gp34 MHC complex when compared to H 2K(b)/gp34. Our structural analysis also indicates that nitrotyrosination of the main TCR-interacting residue p4Y in gp33 abrogates recognition of H-2D(b)/gp33-NY complexes by H-2D(b)/gp33-specific T cells through sterical hindrance. In conclusion, this study provides the first structural and biochemical evidence for how MHC class I-restricted nitrotyrosinated neoantigens may enable viral escape and break immune tolerance. PMID- 22431984 TI - Epithelial proinflammatory response and curcumin-mediated protection from staphylococcal toxic shock syndrome toxin-1. AB - Staphylococcus aureus initiates infections and produces virulence factors, including superantigens (SAgs), at mucosal surfaces. The SAg, Toxic Shock Syndrome Toxin-1 (TSST-1) induces cytokine secretion from epithelial cells, antigen presenting cells (APCs) and T lymphocytes, and causes toxic shock syndrome (TSS). This study investigated the mechanism of TSST-1-induced secretion of proinflammatory cytokines from human vaginal epithelial cells (HVECs) and determined if curcumin, an anti-inflammatory agent, could reduce TSST-1-mediated pathology in a rabbit vaginal model of TSS. TSST-1 caused a significant increase in NF-kappaB-dependent transcription in HVECs that was associated with increased expression of TNF- alpha, MIP-3alpha, IL-6 and IL-8. Curcumin, an antagonist of NF-kappaB-dependent transcription, inhibited IL-8 production from ex vivo porcine vaginal explants at nontoxic doses. In a rabbit model of TSS, co-administration of curcumin with TSST-1 intravaginally reduced lethality by 60% relative to 100% lethality in rabbits receiving TSST-1 alone. In addition, TNF-alpha was undetectable from serum or vaginal tissue of curcumin treated rabbits that survived. These data suggest that the inflammatory response induced at the mucosal surface by TSST-1 is NF-kappaB dependent. In addition, the ability of curcumin to prevent TSS in vivo by co-administration with TSST-1 intravaginally suggests that the vaginal mucosal proinflammatory response to TSST-1 is important in the progression of mTSS. PMID- 22431985 TI - UniDrug-target: a computational tool to identify unique drug targets in pathogenic bacteria. AB - BACKGROUND: Targeting conserved proteins of bacteria through antibacterial medications has resulted in both the development of resistant strains and changes to human health by destroying beneficial microbes which eventually become breeding grounds for the evolution of resistances. Despite the availability of more than 800 genomes sequences, 430 pathways, 4743 enzymes, 9257 metabolic reactions and protein (three-dimensional) 3D structures in bacteria, no pathogen specific computational drug target identification tool has been developed. METHODS: A web server, UniDrug-Target, which combines bacterial biological information and computational methods to stringently identify pathogen-specific proteins as drug targets, has been designed. Besides predicting pathogen-specific proteins essentiality, chokepoint property, etc., three new algorithms were developed and implemented by using protein sequences, domains, structures, and metabolic reactions for construction of partial metabolic networks (PMNs), determination of conservation in critical residues, and variation analysis of residues forming similar cavities in proteins sequences. First, PMNs are constructed to determine the extent of disturbances in metabolite production by targeting a protein as drug target. Conservation of pathogen-specific protein's critical residues involved in cavity formation and biological function determined at domain-level with low-matching sequences. Last, variation analysis of residues forming similar cavities in proteins sequences from pathogenic versus non pathogenic bacteria and humans is performed. RESULTS: The server is capable of predicting drug targets for any sequenced pathogenic bacteria having fasta sequences and annotated information. The utility of UniDrug-Target server was demonstrated for Mycobacterium tuberculosis (H37Rv). The UniDrug-Target identified 265 mycobacteria pathogen-specific proteins, including 17 essential proteins which can be potential drug targets. CONCLUSIONS/SIGNIFICANCE: UniDrug Target is expected to accelerate pathogen-specific drug targets identification which will increase their success and durability as drugs developed against them have less chance to develop resistances and adverse impact on environment. The server is freely available at http://117.211.115.67/UDT/main.html. The standalone application (source codes) is available at http://www.bioinformatics.org/ftp/pub/bioinfojuit/UDT.rar. PMID- 22431986 TI - PhOTO zebrafish: a transgenic resource for in vivo lineage tracing during development and regeneration. AB - BACKGROUND: Elucidating the complex cell dynamics (divisions, movement, morphological changes, etc.) underlying embryonic development and adult tissue regeneration requires an efficient means to track cells with high fidelity in space and time. To satisfy this criterion, we developed a transgenic zebrafish line, called PhOTO, that allows photoconvertible optical tracking of nuclear and membrane dynamics in vivo. METHODOLOGY: PhOTO zebrafish ubiquitously express targeted blue fluorescent protein (FP) Cerulean and photoconvertible FP Dendra2 fusions, allowing for instantaneous, precise targeting and tracking of any number of cells using Dendra2 photoconversion while simultaneously monitoring global cell behavior and morphology. Expression persists through adulthood, making the PhOTO zebrafish an excellent tool for studying tissue regeneration: after tail fin amputation and photoconversion of a ~100 um stripe along the cut area, marked differences seen in how cells contribute to the new tissue give detailed insight into the dynamic process of regeneration. Photoconverted cells that contributed to the regenerate were separated into three distinct populations corresponding to the extent of cell division 7 days after amputation, and a subset of cells that divided the least were organized into an evenly spaced, linear orientation along the length of the newly regenerating fin. CONCLUSIONS/SIGNIFICANCE: PhOTO zebrafish have wide applicability for lineage tracing at the systems-level in the early embryo as well as in the adult, making them ideal candidate tools for future research in development, traumatic injury and regeneration, cancer progression, and stem cell behavior. PMID- 22431987 TI - Detection of neural activity in the brains of Japanese honeybee workers during the formation of a "hot defensive bee ball". AB - Anti-predator behaviors are essential to survival for most animals. The neural bases of such behaviors, however, remain largely unknown. Although honeybees commonly use their stingers to counterattack predators, the Japanese honeybee (Apis cerana japonica) uses a different strategy to fight against the giant hornet (Vespa mandarinia japonica). Instead of stinging the hornet, Japanese honeybees form a "hot defensive bee ball" by surrounding the hornet en masse, killing it with heat. The European honeybee (A. mellifera ligustica), on the other hand, does not exhibit this behavior, and their colonies are often destroyed by a hornet attack. In the present study, we attempted to analyze the neural basis of this behavior by mapping the active brain regions of Japanese honeybee workers during the formation of a hot defensive bee ball. First, we identified an A. cerana homolog (Acks = Apis cerana kakusei) of kakusei, an immediate early gene that we previously identified from A. mellifera, and showed that Acks has characteristics similar to kakusei and can be used to visualize active brain regions in A. cerana. Using Acks as a neural activity marker, we demonstrated that neural activity in the mushroom bodies, especially in Class II Kenyon cells, one subtype of mushroom body intrinsic neurons, and a restricted area between the dorsal lobes and the optic lobes was increased in the brains of Japanese honeybee workers involved in the formation of a hot defensive bee ball. In addition, workers exposed to 46 degrees C heat also exhibited Acks expression patterns similar to those observed in the brains of workers involved in the formation of a hot defensive bee ball, suggesting that the neural activity observed in the brains of workers involved in the hot defensive bee ball mainly reflects thermal stimuli processing. PMID- 22431988 TI - Long-term species, sexual and individual variations in foraging strategies of fur seals revealed by stable isotopes in whiskers. AB - BACKGROUND: Individual variations in the use of the species niche are an important component of diversity in trophic interactions. A challenge in testing consistency of individual foraging strategy is the repeated collection of information on the same individuals. METHODOLOGY/PRINCIPAL FINDINGS: The foraging strategies of sympatric fur seals (Arctocephalus gazella and A. tropicalis) were examined using the stable isotope signature of serially sampled whiskers. Most whiskers exhibited synchronous delta(13)C and delta(15)N oscillations that correspond to the seal annual movements over the long term (up to 8 years). delta(13)C and delta(15)N values were spread over large ranges, with differences between species, sexes and individuals. The main segregating mechanism operates at the spatial scale. Most seals favored foraging in subantarctic waters (where the Crozet Islands are located) where they fed on myctophids. However, A. gazella dispersed in the Antarctic Zone and A. tropicalis more in the subtropics. Gender differences in annual time budget shape the seal movements. Males that do not perform any parental care exhibited large isotopic oscillations reflecting broad annual migrations, while isotopic values of females confined to a limited foraging range during lactation exhibited smaller changes. Limited inter individual isotopic variations occurred in female seals and in male A. tropicalis. In contrast, male A. gazella showed large inter-individual variations, with some males migrating repeatedly to high-Antarctic waters where they fed on krill, thus meaning that individual specialization occurred over years. CONCLUSIONS/SIGNIFICANCE: Whisker isotopic signature yields unique long term information on individual behaviour that integrates the spatial, trophic and temporal dimensions of the ecological niche. The method allows depicting the entire realized niche of the species, including some of its less well-known components such as age-, sex-, individual- and migration-related changes. It highlights intrapopulation heterogeneity in foraging strategies that could have important implications for likely demographic responses to environmental variability. PMID- 22431989 TI - Controls on gut phosphatisation: the trilobites from the Weeks Formation Lagerstatte (Cambrian; Utah). AB - Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstatten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstatte (Utah). Their exquisite, three dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace. PMID- 22431990 TI - Discovery of new hydrothermal activity and chemosynthetic fauna on the Central Indian Ridge at 18 degrees -20 degrees S. AB - Indian Ocean hydrothermal vents are believed to represent a novel biogeographic province, and are host to many novel genera and families of animals, potentially indigenous to Indian Ocean hydrothermal systems. In particular, since its discovery in 2001, much attention has been paid to a so-called 'scaly-foot' gastropod because of its unique iron-sulfide-coated dermal sclerites and the chemosynthetic symbioses in its various tissues. Despite increasing interest in the faunal assemblages at Indian Ocean hydrothermal vents, only two hydrothermal vent fields have been investigated in the Indian Ocean. Here we report two newly discovered hydrothermal vent fields, the Dodo and Solitaire fields, which are located in the Central Indian Ridge (CIR) segments 16 and 15, respectively. Chemosynthetic faunal communities at the Dodo field are emaciated in size and composition. In contrast, at the Solitaire field, we observed faunal communities that potentially contained almost all genera found at CIR hydrothermal environments to date, and even identified previously unreported taxa. Moreover, a new morphotype of 'scaly-foot' gastropod has been found at the Solitaire field. The newly discovered 'scaly-foot' gastropod has similar morphological and anatomical features to the previously reported type that inhabits the Kairei field, and both types of 'scaly-foot' gastropods genetically belong to the same species according to analyses of their COI gene and nuclear SSU rRNA gene sequences. However, the new morphotype completely lacks an iron-sulfide coating on the sclerites, which had been believed to be a novel feature restricted to 'scaly-foot' gastropods. Our new findings at the two newly discovered hydrothermal vent sites provide important insights into the biodiversity and biogeography of vent-endemic ecosystems in the Indian Ocean. PMID- 22431991 TI - Identification of the first functional toxin-antitoxin system in Streptomyces. AB - Toxin-antitoxin (TA) systems are widespread among the plasmids and genomes of bacteria and archaea. This work reports the first description of a functional TA system in Streptomyces that is identical in two species routinely used in the laboratory: Streptomyces lividans and S. coelicolor. The described system belongs to the YefM/YoeB family and has a considerable similarity to Escherichia coli YefM/YoeB (about 53% identity and 73% similarity). Lethal effect of the S. lividans putative toxin (YoeBsl) was observed when expressed alone in E. coli SC36 (MG1655 DeltayefM-yoeB). However, no toxicity was obtained when co expression of the antitoxin and toxin (YefM/YoeBsl) was carried out. The toxic effect was also observed when the yoeBsl was cloned in multicopy in the wild-type S. lividans or in a single copy in a S. lividans mutant, in which this TA system had been deleted. The S. lividans YefM/YoeBsl complex, purified from E. coli, binds with high affinity to its own promoter region but not to other three random selected promoters from Streptomyces. In vivo experiments demonstrated that the expression of yoeBsl in E. coli blocks translation initiation processing mRNA at three bases downstream of the initiation codon after 2 minutes of induction. These results indicate that the mechanism of action is identical to that of YoeB from E. coli. PMID- 22431992 TI - Context modulation of facial emotion perception differed by individual difference. AB - BACKGROUND: Certain facial configurations are believed to be associated with distinct affective meanings (i.e. basic facial expressions), and such associations are common across cultures (i.e. universality of facial expressions). However, recently, many studies suggest that various types of contextual information, rather than facial configuration itself, are important factor for facial emotion perception. METHODOLOGY/PRINCIPAL FINDINGS: To examine systematically how contextual information influences individuals' facial emotion perception, the present study estimated direct observers' perceptual thresholds for detecting negative facial expressions via a forced-choice psychophysical procedure using faces embedded in various emotional contexts. We additionally measured the individual differences in affective information-processing tendency (BIS/BAS) as a possible factor that may determine the extent to which contextual information on facial emotion perception is used. It was found that contextual information influenced observers' perceptual thresholds for facial emotion. Importantly, individuals' affective-information tendencies modulated the extent to which they incorporated context information into their facial emotion perceptions. CONCLUSIONS/SIGNIFICANCE: The findings of this study suggest that facial emotion perception not only depends on facial configuration, but the context in which the face appears as well. This contextual influence appeared differently with individual's characteristics of information processing. In summary, we conclude that individual character traits, as well as facial configuration and the context in which a face appears, need to be taken into consideration regarding facial emotional perception. PMID- 22431993 TI - Training programmes can change behaviour and encourage the cultivation of over harvested plant species. AB - Cultivation of wild-harvested plant species has been proposed as a way of reducing over-exploitation of wild populations but lack of technical knowledge is thought to be a barrier preventing people from cultivating a new species. Training programmes are therefore used to increase technical knowledge to encourage people to adopt cultivation. We assessed the impact of a training programme aiming to encourage cultivation of xate (Chamaedorea ernesti-augusti), an over-harvested palm from Central America. Five years after the training programme ended, we surveyed untrained and trained individuals focusing on four potential predictors of behaviour: technical knowledge, attitudes (what individuals think about a behaviour), subjective norms (what individuals perceive others to think of a behaviour) and perceived behavioural control (self assessment of whether individuals can enact the behaviour successfully). Whilst accounting for socioeconomic variables, we investigate the influence of training upon these behavioural predictors and examine the factors that determine whether people adopt cultivation of a novel species. Those who had been trained had higher levels of technical knowledge about xate cultivation and higher belief in their ability to cultivate it while training was not associated with differences in attitudes or subjective norms. Technical knowledge and perceived behavioural control (along with socio-economic variables such as forest ownership and age) were predictors of whether individuals cultivate xate. We suggest that training programmes can have a long lasting effect on individuals and can change behaviour. However, in many situations other barriers to cultivation, such as access to seeds or appropriate markets, will need to be addressed. PMID- 22431995 TI - Delivery of a small for gestational age infant and greater maternal risk of ischemic heart disease. AB - BACKGROUND: Delivery of a small for gestational age (SGA) infant has been associated with increased maternal risk of ischemic heart disease (IHD). It is uncertain whether giving birth to SGA infant is a specific determinant of later IHD, independent of other risk factors, or a marker of general poor health. The purpose of this study was to investigate the association between delivery of a SGA infant and maternal risk for IHD in relation to traditional IHD risk factors. METHODS AND FINDINGS: Risk of maternal IHD was evaluated in a population based cross-sectional study of 6,608 women with a prior live term birth who participated in the National Health and Nutrition Examination Survey (1999-2006), a probability sample of the U.S. population. Sequence of events was determined from age at last live birth and at diagnosis of IHD. Delivery of a SGA infant is strongly associated with greater maternal risk for IHD (age adjusted OR; 95% CI: 1.8; 1.2, 2.9; p = 0.012). The association was independent of the family history of IHD, stroke, hypertension and diabetes (family history-adjusted OR; 95% CI: 1.9; 1.2, 3.0; p = 0.011) as well as other risk factors for IHD (risk factor adjusted OR; 95% CI: 1.7; 1.1, 2.7; p = 0.025). Delivery of a SGA infant was associated with earlier onset of IHD and preceded it by a median of 30 (interquartile range: 20, 36) years. CONCLUSIONS: Giving birth to a SGA infant is strongly and independently associated with IHD and a potential risk factor that precedes IHD by decades. A pregnancy that produces a SGA infant may induce long term cardiovascular changes that increase risk for IHD. PMID- 22431996 TI - Common sole larvae survive high levels of pile-driving sound in controlled exposure experiments. AB - In view of the rapid extension of offshore wind farms, there is an urgent need to improve our knowledge on possible adverse effects of underwater sound generated by pile-driving. Mortality and injuries have been observed in fish exposed to loud impulse sounds, but knowledge on the sound levels at which (sub-)lethal effects occur is limited for juvenile and adult fish, and virtually non-existent for fish eggs and larvae. A device was developed in which fish larvae can be exposed to underwater sound. It consists of a rigid-walled cylindrical chamber driven by an electro-dynamical sound projector. Samples of up to 100 larvae can be exposed simultaneously to a homogeneously distributed sound pressure and particle velocity field. Recorded pile-driving sounds could be reproduced accurately in the frequency range between 50 and 1000 Hz, at zero to peak pressure levels up to 210 dB re 1uPa(2) (zero to peak pressures up to 32 kPa) and single pulse sound exposure levels up to 186 dB re 1uPa(2)s. The device was used to examine lethal effects of sound exposure in common sole (Solea solea) larvae. Different developmental stages were exposed to various levels and durations of pile-driving sound. The highest cumulative sound exposure level applied was 206 dB re 1uPa(2)s, which corresponds to 100 strikes at a distance of 100 m from a typical North Sea pile-driving site. The results showed no statistically significant differences in mortality between exposure and control groups at sound exposure levels which were well above the US interim criteria for non-auditory tissue damage in fish. Although our findings cannot be extrapolated to fish larvae in general, as interspecific differences in vulnerability to sound exposure may occur, they do indicate that previous assumptions and criteria may need to be revised. PMID- 22431994 TI - Molecular epidemiology of Neisseria meningitidis serogroup B in Brazil. AB - BACKGROUND: Neisseria meningitidis serogroup B has been predominant in Brazil, but no broadly effective vaccine is available to prevent endemic meningococcal disease. To understand genetic diversity among serogroup B strains in Brazil, we selected a nationally representative sample of clinical disease isolates from 2004, and a temporally representative sample for the state of Sao Paulo (1988 2006) for study (n = 372). METHODS: We performed multi-locus sequence typing (MLST) and sequence analysis of five outer membrane protein (OMP) genes, including novel vaccine targets fHbp and nadA. RESULTS: In 2004, strain B:4:P1.15,19 clonal complex ST-32/ET-5 (cc32) predominated throughout Brazil; regional variation in MLST sequence type (ST), fetA, and porB was significant but diversity was limited for nadA and fHbp. Between 1988 and 1996, the Sao Paulo isolates shifted from clonal complex ST-41/44/Lineage 3 (cc41/44) to cc32. OMP variation was associated with but not predicted by cc or ST. Overall, fHbp variant 1/subfamily B was present in 80% of isolates and showed little diversity. The majority of nadA were similar to reference allele 1. CONCLUSIONS: A predominant serogroup B lineage has circulated in Brazil for over a decade with significant regional and temporal diversity in ST, fetA, and porB, but not in nadA and fHbp. PMID- 22431997 TI - Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons. AB - Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS. PMID- 22431998 TI - Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma. AB - OBJECTIVE: Major trauma is characterized by a pro-inflammatory response, followed by an immunosuppression. Recently, in trauma patients, the lack of recovery of monocyte Human Leukocyte Antigen DR (mHLA-DR, a biomarker of ICU-acquired immunosuppression) between days 1-2 and days 3-4 has been demonstrated to be independently associated with sepsis development. The main objective of this study was to determine whether early measurements of IL-6 (interleukin-6) and IL 10 plasma concentrations (as markers of initial severity) could improve, in association with mHLA-DR recovery, the prediction of sepsis occurrence in severe trauma patients. DESIGN: Prospective observational study over 24 months in a Trauma ICU at university hospital. PATIENTS: Trauma patients with an ISS over 25 and age over 18 were included. MEASUREMENTS AND MAIN RESULTS: mHLA-DR was assessed by flow cytometry, IL-6 and IL-10 concentrations by ELISA. 100 consecutive severely injured patients were monitored (mean ISS 37+/-10). 37 patients developed sepsis. IL-6 concentrations and slope of mHLA-DR expression between days 1-2 and days 3-4 were significantly different between septic and non septic patients. IL-10 was not detectable in most patients. After adjustment for usual clinical confounders, when assessed as a pair, multivariate logistic regression analysis revealed that a slope of mHLA-DR expression (days 3-4/days 1 2)<=1.1 and a IL-6 concentration >= 67.1 pg/ml remained highly associated with the development of sepsis (adjusted OR 18.4, 95% CI 4.9; 69.4, p = .00002). CONCLUSIONS: After multivariate regression logistic analysis, when assessed as a pair, a high IL-6 concentration and a persistent mHLA-DR decreased expression were found to be in relation with the development of sepsis with the best predictive value. This study underlines the usefulness of daily monitoring of immune function to identify trauma patients at a high risk of infection. PMID- 22431999 TI - Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. AB - Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs. PMID- 22432000 TI - Logging affects fledgling sex ratios and baseline corticosterone in a forest songbird. AB - Silviculture (logging) creates a disturbance to forested environments. The degree to which forests are modified depends on the logging prescription and forest stand characteristics. In this study we compared the effects of two methods of group-selection ("moderate" and "heavy") silviculture (GSS) and undisturbed reference stands on stress and offspring sex ratios of a forest interior species, the Ovenbird (Seiurus aurocapilla), in Algonquin Provincial Park, Canada. Blood samples were taken from nestlings for corticosterone and molecular sexing. We found that logging creates a disturbance that is stressful for nestling Ovenbirds, as illustrated by elevated baseline corticosterone in cut sites. Ovenbirds nesting in undisturbed reference forest produce fewer male offspring per brood (proportion male = 30%) while logging with progressively greater forest disturbance, shifted the offspring sex ratio towards males (proportion male: moderate = 50%, heavy = 70%). If Ovenbirds in undisturbed forests usually produce female-biased broods, then the production of males as a result of logging may disrupt population viability. We recommend a broad examination of nestling sex ratios in response to anthropogenic disturbance to determine the generality of our findings. PMID- 22432001 TI - Composition and localization of lipids in Penaeus merguiensis ovaries during the ovarian maturation cycle as revealed by imaging mass spectrometry. AB - Ovary maturation, oocyte differentiation, and embryonic development in shrimp are highly dependent on nutritional lipids taken up by female broodstocks. These lipids are important as energy sources as well as for cell signaling. In this study, we report on the compositions of major lipids, i.e. phosphatidylcholines (PCs), triacylglycerols (TAGs), and fatty acids (FAs), in the ovaries of the banana shrimp, Penaeus merguiensis, during ovarian maturation. Thin-layer chromatography analysis showed that the total PC and TAG signal intensities increased during ovarian maturation. Further, by using gas chromatography, we found that (1) FAs 14:0, 16:1, 18:1, 18:2, 20:1, and 22:6 proportionally increased as ovarian development progressed to more mature stages; (2) FAs 16:0, 18:0, 20:4, and 20:5 proportionally decreased; and (3) FAs 15:0, 17:0, and 20:2 remained unchanged. By using imaging mass spectrometry, we found that PC 16:0/16:1 and TAG 18:1/18:2/22:6 were detected in oocytes stages 1 and 2. PCs 16:1/20:4, 16:0/22:6, 18:3/22:6, 18:1/22:6, 20:5/22:6, and 22:6/22:6 and TAGs 16:0/16:1/18:3, 16:0/18:1/18:3, 16:0/18:1/18:1, and 16:0/18:2/22:6 were present in all stages of oocytes. In contrast, the PC- and TAG-associated FAs 20:4, 20:5, and 22:6 showed high signal intensities in stage 3 and 4 oocytes. These FAs may act as nutrition sources as well as signaling molecules for developing embryos and the hatching process. Knowledge of lipid compositions and localization could be helpful for formulating the diet for female broodstocks to promote fecundity and larval production. PMID- 22432002 TI - Integrating phosphorylation network with transcriptional network reveals novel functional relationships. AB - Phosphorylation and transcriptional regulation events are critical for cells to transmit and respond to signals. In spite of its importance, systems-level strategies that couple these two networks have yet to be presented. Here we introduce a novel approach that integrates the physical and functional aspects of phosphorylation network together with the transcription network in S.cerevisiae, and demonstrate that different network motifs are involved in these networks, which should be considered in interpreting and integrating large scale datasets. Based on this understanding, we introduce a HeRS score (hetero-regulatory similarity score) to systematically characterize the functional relevance of kinase/phosphatase involvement with transcription factor, and present an algorithm that predicts hetero-regulatory modules. When extended to signaling network, this approach confirmed the structure and cross talk of MAPK pathways, inferred a novel functional transcription factor Sok2 in high osmolarity glycerol pathway, and explained the mechanism of reduced mating efficiency upon Fus3 deletion. This strategy is applicable to other organisms as large-scale datasets become available, providing a means to identify the functional relationships between kinases/phosphatases and transcription factors. PMID- 22432003 TI - Physical stress, not biotic interactions, preclude an invasive grass from establishing in forb-dominated salt marshes. AB - BACKGROUND: Biological invasions have become the focus of considerable concern and ecological research, yet the relative importance of abiotic and biotic factors in controlling the invasibility of habitats to exotic species is not well understood. Spartina species are highly invasive plants in coastal wetlands; however, studies on the factors that control the success or failure of Spartina invasions across multiple habitat types are rare and inconclusive. METHODOLOGY AND PRINCIPAL FINDINGS: We examined the roles of physical stress and plant interactions in mediating the establishment of the smooth cordgrass, Spartina alterniflora, in a variety of coastal habitats in northern China. Field transplant experiments showed that cordgrass can invade mudflats and low estuarine marshes with low salinity and frequent flooding, but cannot survive in salt marshes and high estuarine marshes with hypersaline soils and infrequent flooding. The dominant native plant Suaeda salsa had neither competitive nor facilitative effects on cordgrass. A common garden experiment revealed that cordgrass performed significantly better when flooded every other day than when flooded weekly. These results suggest that physical stress rather than plant interactions limits cordgrass invasions in northern China. CONCLUSIONS AND SIGNIFICANCE: We conclude that Spartina invasions are likely to be constrained to tidal flats and low estuarine marshes in the Yellow River Delta. Due to harsh physical conditions, salt marshes and high estuarine marshes are unlikely to be invaded. These findings have implications for understanding Spartina invasions in northern China and on other coasts with similar biotic and abiotic environments. PMID- 22432004 TI - Identification of common biological pathways and drug targets across multiple respiratory viruses based on human host gene expression analysis. AB - BACKGROUND: Pandemic and seasonal respiratory viruses are a major global health concern. Given the genetic diversity of respiratory viruses and the emergence of drug resistant strains, the targeted disruption of human host-virus interactions is a potential therapeutic strategy for treating multi-viral infections. The availability of large-scale genomic datasets focused on host-pathogen interactions can be used to discover novel drug targets as well as potential opportunities for drug repositioning. METHODS/RESULTS: In this study, we performed a large-scale analysis of microarray datasets involving host response to infections by influenza A virus, respiratory syncytial virus, rhinovirus, SARS coronavirus, metapneumonia virus, coxsackievirus and cytomegalovirus. Common genes and pathways were found through a rigorous, iterative analysis pipeline where relevant host mRNA expression datasets were identified, analyzed for quality and gene differential expression, then mapped to pathways for enrichment analysis. Possible repurposed drugs targets were found through database and literature searches. A total of 67 common biological pathways were identified among the seven different respiratory viruses analyzed, representing fifteen laboratories, nine different cell types, and seven different array platforms. A large overlap in the general immune response was observed among the top twenty of these 67 pathways, adding validation to our analysis strategy. Of the top five pathways, we found 53 differentially expressed genes affected by at least five of the seven viruses. We suggest five new therapeutic indications for existing small molecules or biological agents targeting proteins encoded by the genes F3, IL1B, TNF, CASP1 and MMP9. Pathway enrichment analysis also identified a potential novel host response, the Parkin-Ubiquitin Proteasomal System (Parkin-UPS) pathway, which is known to be involved in the progression of neurodegenerative Parkinson's disease. CONCLUSIONS: Our study suggests that multiple and diverse respiratory viruses invoke several common host response pathways. Further analysis of these pathways suggests potential opportunities for therapeutic intervention. PMID- 22432005 TI - A cell-based small molecule screening method for identifying inhibitors of epithelial-mesenchymal transition in carcinoma. AB - Epithelial Mesenchymal Transition (EMT) is a crucial mechanism for carcinoma progression, as it provides routes for in situ carcinoma cells to dissociate and become motile, leading to localized invasion and metastatic spread. Targeting EMT therefore represents an important therapeutic strategy for cancer treatment. The discovery of oncogene addiction in sustaining tumor growth has led to the rapid development of targeted therapeutics. Whilst initially optimized as anti proliferative agents, it is likely that some of these compounds may inhibit EMT initiation or sustenance, since EMT is also modulated by similar signaling pathways that these compounds were designed to target. We have developed a novel screening assay that can lead to the identification of compounds that can inhibit EMT initiated by growth factor signaling. This assay is designed as a high content screening assay where both cell growth and cell migration can be analyzed simultaneously via time-course imaging in multi-well plates. Using this assay, we have validated several compounds as viable EMT inhibitors. In particular, we have identified compounds targeting ALK5, MEK, and SRC as potent inhibitors that can interfere with EGF, HGF, and IGF-1 induced EMT signaling. Overall, this EMT screening method provides a foundation for improving the therapeutic value of recently developed compounds in advanced stage carcinoma. PMID- 22432006 TI - Inhibition of intestinal adenoma formation in APC(Min/+) mice by Riccardin D, a natural product derived from liverwort plant Dumortiera hirsuta. AB - BACKGROUND: Mutation of tumor suppressor gene, adenomatous polyposis coli (APC), is the primary molecular event in the development of most intestinal carcinomas. Animal model with APC gene mutation is an effective tool for study of preventive approaches against intestinal carcinomas. We aimed to evaluate the effect of Riccardin D, a macrocyclic bisbibenzyl compound, as a chemopreventive agent against intestinal adenoma formation in APC(Min/+) mice. METHODS: APC(Min/+) mice were given Riccardin D by p.o. gavage for 7 weeks. Mice were sacrificed, and the number, size and histopathology of intestinal polyps were examined under a microscope. We performed immunohistochemical staining, western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in intestinal polyps to investigate the mechanism of chemopreventive effect of Riccardin D. RESULTS: Riccardin D treatment resulted in a significant inhibition of intestinal adenoma formation, showing a reduction of polyp number by 41.7%, 31.1% and 44.4%, respectively, in proximal, middle and distal portions of small intestine. The activity of Riccardin D against polyp formation was more profound in colon, wherein Riccardin D decreased polyp number by 79.3%. Size distribution analysis revealed a significant reduction in large size polyps (2-3 mm) by 40.0%, 42.5% and 33.3%, respectively, in proximal, middle and distal portions of small intestine, and 77.8% in colon. Histopathological analysis of the intestinal polyps revealed mostly hyperplastic morphology without obvious dysplasia in Riccardin D-treated mice. Molecular analyses of the polyps suggested that the inhibitory effect of Riccardin D on intestinal adenoma formation was associated with its abilities of reduction in cell proliferation, induction of apoptosis, antiangiogenesis, inhibition of the Wnt signaling pathway and suppression of inflammatory mediators in polyps. CONCLUSIONS: Our results suggested that Riccardin D exerts its chemopreventive effect against intestinal adenoma formation through multiple mechanisms including anti-proliferative, apoptotic, anti-angiogenic and anti-inflammatory activity. PMID- 22432007 TI - Disinfection of ocular cells and tissues by atmospheric-pressure cold plasma. AB - BACKGROUND: Low temperature plasmas have been proposed in medicine as agents for tissue disinfection and have received increasing attention due to the frequency of bacterial resistance to antibiotics. This study explored whether atmospheric pressure cold plasma (APCP) generated by a new portable device that ionizes a flow of helium gas can inactivate ocular pathogens without causing significant tissue damage. METHODOLOGY/PRINCIPAL FINDINGS: We tested the APCP effects on cultured Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Candida albicans, Aspergillus fumigatus and Herpes simplex virus-1, ocular cells (conjunctival fibroblasts and keratocytes) and ex-vivo corneas. Exposure to APCP for 0.5 to 5 minutes significantly reduced microbial viability (colony-forming units) but not human cell viability (MTT assay, FACS and Tunel analysis) or the number of HSV-1 plaque-forming units. Increased levels of intracellular reactive oxygen species (ROS) in exposed microorganisms and cells were found using a FACS activated 2',7'-dichlorofluorescein diacetate probe. Immunoassays demonstrated no induction of thymine dimers in cell cultures and corneal tissues. A transient increased expression of 8-OHdG, genes and proteins related to oxidative stress (OGG1, GPX, NFE2L2), was determined in ocular cells and corneas by HPLC, qRT-PCR and Western blot analysis. CONCLUSIONS: A short application of APCP appears to be an efficient and rapid ocular disinfectant for bacteria and fungi without significant damage on ocular cells and tissues, although the treatment of conjunctival fibroblasts and keratocytes caused a time-restricted generation of intracellular ROS and oxidative stress-related responses. PMID- 22432008 TI - Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. AB - Acute tubular necrosis (ATN) caused by ischemia/reperfusion (I/R) during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 alpha), using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 alpha is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 alpha promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 alpha was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 alpha induction during reperfusion with a potential critical role in renal transplant. PMID- 22432009 TI - ER stress in retinal degeneration in S334ter Rho rats. AB - The S334ter rhodopsin (Rho) rat (line 4) bears the rhodopsin gene with an early termination codon at residue 334 that is a model for several such mutations found in human patients with autosomal dominant retinitis pigmentosa (ADRP). The Unfolded Protein Response (UPR) is implicated in the pathophysiology of several retinal disorders including ADRP in P23H Rho rats. The aim of this study was to examine the onset of UPR gene expression in S334ter Rho retinas to determine if UPR is activated in ADRP animal models and to investigate how the activation of UPR molecules leads to the final demise of S334ter Rho photoreceptors. RT-PCR was performed to evaluate the gene expression profiles for the P10, P12, P15, and P21 stages of the development and progression of ADRP in S334ter Rho photoreceptors. We determined that during the P12-P15 period, ER stress-related genes are strongly upregulated in transgenic retinas, resulting in the activation of the UPR that was confirmed using western blot analysis and RT-PCR. The activation of UPR was associated with the increased expression of JNK, Bik, Bim, Bid, Noxa, and Puma genes and cleavage of caspase-12 that together with activated calpains presumably compromise the integrity of the mitochondrial MPTP, leading to the release of pro-apoptotic AIF1 into the cytosol of S334ter Rho photoreceptor cells. Therefore, two major cross-talking pathways, the UPR and mitochondrial MPTP occur in S334ter-4 Rho retina concomitantly and eventually promote the death of the photoreceptor cells. PMID- 22432011 TI - Genome features of "Dark-fly", a Drosophila line reared long-term in a dark environment. AB - Organisms are remarkably adapted to diverse environments by specialized metabolisms, morphology, or behaviors. To address the molecular mechanisms underlying environmental adaptation, we have utilized a Drosophila melanogaster line, termed "Dark-fly", which has been maintained in constant dark conditions for 57 years (1400 generations). We found that Dark-fly exhibited higher fecundity in dark than in light conditions, indicating that Dark-fly possesses some traits advantageous in darkness. Using next-generation sequencing technology, we determined the whole genome sequence of Dark-fly and identified approximately 220,000 single nucleotide polymorphisms (SNPs) and 4,700 insertions or deletions (InDels) in the Dark-fly genome compared to the genome of the Oregon R-S strain, a control strain. 1.8% of SNPs were classified as non-synonymous SNPs (nsSNPs: i.e., they alter the amino acid sequence of gene products). Among them, we detected 28 nonsense mutations (i.e., they produce a stop codon in the protein sequence) in the Dark-fly genome. These included genes encoding an olfactory receptor and a light receptor. We also searched runs of homozygosity (ROH) regions as putative regions selected during the population history, and found 21 ROH regions in the Dark-fly genome. We identified 241 genes carrying nsSNPs or InDels in the ROH regions. These include a cluster of alpha-esterase genes that are involved in detoxification processes. Furthermore, analysis of structural variants in the Dark-fly genome showed the deletion of a gene related to fatty acid metabolism. Our results revealed unique features of the Dark-fly genome and provided a list of potential candidate genes involved in environmental adaptation. PMID- 22432010 TI - Genome stability of Lyme disease spirochetes: comparative genomics of Borrelia burgdorferi plasmids. AB - Lyme disease is the most common tick-borne human illness in North America. In order to understand the molecular pathogenesis, natural diversity, population structure and epizootic spread of the North American Lyme agent, Borrelia burgdorferi sensu stricto, a much better understanding of the natural diversity of its genome will be required. Towards this end we present a comparative analysis of the nucleotide sequences of the numerous plasmids of B. burgdorferi isolates B31, N40, JD1 and 297. These strains were chosen because they include the three most commonly studied laboratory strains, and because they represent different major genetic lineages and so are informative regarding the genetic diversity and evolution of this organism. A unique feature of Borrelia genomes is that they carry a large number of linear and circular plasmids, and this work shows that strains N40, JD1, 297 and B31 carry related but non-identical sets of 16, 20, 19 and 21 plasmids, respectively, that comprise 33-40% of their genomes. We deduce that there are at least 28 plasmid compatibility types among the four strains. The B. burgdorferi ~900 Kbp linear chromosomes are evolutionarily exceptionally stable, except for a short <=20 Kbp plasmid-like section at the right end. A few of the plasmids, including the linear lp54 and circular cp26, are also very stable. We show here that the other plasmids, especially the linear ones, are considerably more variable. Nearly all of the linear plasmids have undergone one or more substantial inter-plasmid rearrangements since their last common ancestor. In spite of these rearrangements and differences in plasmid contents, the overall gene complement of the different isolates has remained relatively constant. PMID- 22432012 TI - Both TLR2 and TRIF contribute to interferon-beta production during Listeria infection. AB - Synthesis of interferon-beta (IFN-beta) is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-beta synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-beta production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, DeltapgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-beta gene, requiring TLR2 and bacterial internalization. Induction of IFN-beta was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-beta gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-beta gene expression. PMID- 22432013 TI - Composition and similarity of bovine rumen microbiota across individual animals. AB - The bovine rumen houses a complex microbiota which is responsible for cattle's remarkable ability to convert indigestible plant mass into food products. Despite this ecosystem's enormous significance for humans, the composition and similarity of bacterial communities across different animals and the possible presence of some bacterial taxa in all animals' rumens have yet to be determined. We characterized the rumen bacterial populations of 16 individual lactating cows using tag amplicon pyrosequencing. Our data showed 51% similarity in bacterial taxa across samples when abundance and occurrence were analyzed using the Bray Curtis metric. By adding taxon phylogeny to the analysis using a weighted UniFrac metric, the similarity increased to 82%. We also counted 32 genera that are shared by all samples, exhibiting high variability in abundance across samples. Taken together, our results suggest a core microbiome in the bovine rumen. Furthermore, although the bacterial taxa may vary considerably between cow rumens, they appear to be phylogenetically related. This suggests that the functional requirement imposed by the rumen ecological niche selects taxa that potentially share similar genetic features. PMID- 22432014 TI - Functional and molecular characterization of rod-like cells from retinal stem cells derived from the adult ciliary epithelium. AB - In vitro generation of photoreceptors from stem cells is of great interest for the development of regenerative medicine approaches for patients affected by retinal degeneration and for high throughput drug screens for these diseases. In this study, we show unprecedented high percentages of rod-fated cells from retinal stem cells of the adult ciliary epithelium. Molecular characterization of rod-like cells demonstrates that they lose ciliary epithelial characteristics but acquire photoreceptor features. Rod maturation was evaluated at two levels: gene expression and electrophysiological functionality. Here we present a strong correlation between phototransduction protein expression and functionality of the cells in vitro. We demonstrate that in vitro generated rod-like cells express cGMP-gated channels that are gated by endogenous cGMP. We also identified voltage gated channels necessary for rod maturation and viability. This level of analysis for the first time provides evidence that adult retinal stem cells can generate highly homogeneous rod-fated cells. PMID- 22432015 TI - Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis. AB - BACKGROUND AND AIMS: Mesenchymal stromal cells (MSCs) were shown to have immunomodulatory activity and have been applied for treating immune-mediated disorders. We compared the homing and therapeutic action of cryopreserved subcutaneous adipose tissue (AT-MSCs) and bone marrow-derived mesenchymal stromal cells (BM-MSCs) in rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS: After colonoscopic detection of inflammation AT-MSCs or BM-MSCs were injected intraperitoneally. Colonoscopic and histologic scores were obtained. Density of collagen fibres and apoptotic rates were evaluated. Cytokine levels were measured in supernatants of colon explants. For cell migration studies MSCs and skin fibroblasts were labelled with Tc-99m or CM-DiI and injected intraperitonealy or intravenously. RESULTS: Intraperitoneal injection of AT-MSCs or BM-MSCs reduced the endoscopic and histopathologic severity of colitis, the collagen deposition, and the epithelial apoptosis. Levels of TNF alpha and interleukin-1beta decreased, while VEGF and TGF-beta did not change following cell-therapy. Scintigraphy showed that MSCs migrated towards the inflamed colon and the uptake increased from 0.5 to 24 h. Tc-99m-MSCs injected intravenously distributed into various organs, but not the colon. Cm-DiI-positive MSCs were detected throughout the colon wall 72 h after inoculation, predominantly in the submucosa and muscular layer of inflamed areas. CONCLUSIONS: Intraperitoneally injected cryopreserved MSCs home to and engraft into the inflamed colon and ameliorate TNBS-colitis. PMID- 22432016 TI - In vitro aggregation behavior of a non-amyloidogenic lambda light chain dimer deriving from U266 multiple myeloma cells. AB - Excessive production of monoclonal light chains due to multiple myeloma can induce aggregation-related disorders, such as light chain amyloidosis (AL) and light chain deposition diseases (LCDD). In this work, we produce a non amyloidogenic IgE lambda light chain dimer from human mammalian cells U266, which originated from a patient suffering from multiple myeloma, and we investigate the effect of several physicochemical parameters on the in vitro stability of this protein. The dimer is stable in physiological conditions and aggregation is observed only when strong denaturating conditions are applied (acidic pH with salt at large concentration or heating at melting temperature T(m) at pH 7.4). The produced aggregates are spherical, amorphous oligomers. Despite the larger beta-sheet content of such oligomers with respect to the native state, they do not bind Congo Red or ThT. The impossibility to obtain fibrils from the light chain dimer suggests that the occurrence of amyloidosis in patients requires the presence of the light chain fragment in the monomer form, while dimer can form only amorphous oligomers or amorphous deposits. No aggregation is observed after denaturant addition at pH 7.4 or at pH 2.0 with low salt concentration, indicating that not a generic unfolding but specific conformational changes are necessary to trigger aggregation. A specific anion effect in increasing the aggregation rate at pH 2.0 is observed according to the following order: SO(4)( )?Cl(-)>H(2)PO(4)(-), confirming the peculiar role of sulfate in promoting protein aggregation. It is found that, at least for the investigated case, the mechanism of the sulfate effect is related to protein secondary structure changes induced by anion binding. PMID- 22432017 TI - Effects of particulate air pollution on cardiovascular health: a population health risk assessment. AB - Particulate matter (PM) air pollution is increasingly recognized as an important and modifiable risk factor for adverse health outcomes including cardiovascular disease (CVD). However, there are still gaps regarding large population risk assessment. Results from the nationwide Behavioral Risk Factor Surveillance System (BRFSS) were used along with air quality monitoring measurements to implement a systematic evaluation of PM-related CVD risks at the national and regional scales. CVD status and individual-level risk factors were collected from more than 500,000 BRFSS respondents across 2,231 contiguous U.S. counties for 2007 and 2009. Chronic exposures to PM pollutants were estimated with spatial modeling from measurement data. CVD outcomes attributable to PM pollutants were assessed by mixed-effects logistic regression and latent class regression (LCR), with adjustment for multicausality. There were positive associations between CVD and PM after accounting for competing risk factors: the multivariable-adjusted odds for the multiplicity of CVD outcomes increased by 1.32 (95% confidence interval: 1.23-1.43) and 1.15 (1.07-1.22) times per 10 ug/m(3) increase in PM(2.5) and PM(10) respectively in the LCR analyses. After controlling for spatial confounding, there were moderate estimated effects of PM exposure on multiple cardiovascular manifestations. These results suggest that chronic exposures to ambient particulates are important environmental risk factors for cardiovascular morbidity. PMID- 22432019 TI - Failing the future: three unsuccessful attempts to replicate Bem's 'retroactive facilitation of recall' effect. AB - Nine recently reported parapsychological experiments appear to support the existence of precognition. We describe three pre-registered independent attempts to exactly replicate one of these experiments, 'retroactive facilitation of recall', which examines whether performance on a memory test can be influenced by a post-test exercise. All three replication attempts failed to produce significant effects (combined n = 150; combined p = .83, one-tailed) and thus do not support the existence of psychic ability. PMID- 22432018 TI - Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. AB - Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset. PMID- 22432020 TI - Impact of preexisting adenovirus vector immunity on immunogenicity and protection conferred with an adenovirus-based H5N1 influenza vaccine. AB - The prevalence of preexisting immunity to adenoviruses in the majority of the human population might adversely impact the development of adaptive immune responses against adenovirus vector-based vaccines. To address this issue, we primed BALB/c mice either intranasally (i.n.) or intramuscularly (i.m.) with varying doses of wild type (WT) human adenovirus subtype 5 (HAd5). Following the development of immunity against HAd5, we immunized animals via the i.n. or i.m. route of inoculation with a HAd vector (HAd-HA-NP) expressing the hemagglutinin (HA) and nucleoprotein (NP) of A/Vietnam/1203/04 (H5N1) influenza virus. The immunogenicity and protection results suggest that low levels of vector immunity (<520 virus-neutralization titer) induced by priming mice with up to 10(7) plaque forming units (p.f.u.) of HAd-WT did not adversely impact the protective efficacy of the vaccine. Furthermore, high levels of vector immunity (approximately 1500 virus-neutralization titer) induced by priming mice with 10(8) p.f.u. of HAd-WT were overcome by either increasing the vaccine dose or using alternate routes of vaccination. A further increase in the priming dose to 10(9) p.f.u. allowed only partial protection. These results suggest possible strategies to overcome the variable levels of human immunity against adenoviruses, leading to better utilization of HAd vector-based vaccines. PMID- 22432021 TI - Species association of hepatitis B virus (HBV) in non-human apes; evidence for recombination between gorilla and chimpanzee variants. AB - Hepatitis B virus (HBV) infections are widely distributed in humans, infecting approximately one third of the world's population. HBV variants have also been detected and genetically characterised from Old World apes; Gorilla gorilla (gorilla), Pan troglodytes (chimpanzee), Pongo pygmaeus (orang-utan), Nomascus nastusus and Hylobates pileatus (gibbons) and from the New World monkey, Lagothrix lagotricha (woolly monkey). To investigate species-specificity and potential for cross species transmission of HBV between sympatric species of apes (such as gorillas and chimpanzees in Central Africa) or between humans and chimpanzees or gorillas, variants of HBV infecting captive wild-born non-human primates were genetically characterised. 9 of 62 chimpanzees (11.3%) and two from 11 gorillas (18%) were HBV-infected (15% combined frequency), while other Old world monkey species were negative. Complete genome sequences were obtained from six of the infected chimpanzee and both gorillas; those from P. t .ellioti grouped with previously characterised variants from this subspecies. However, variants recovered from P. t. troglodytes HBV variants also grouped within this clade, indicative of transmission between sub-species, forming a paraphyletic clade. The two gorilla viruses were phylogenetically distinct from chimpanzee and human variants although one showed evidence for a recombination event with a P.t.e.-derived HBV variant in the partial X and core gene region. Both of these observations provide evidence for circulation of HBV between different species and sub-species of non-human primates, a conclusion that differs from the hypothesis if of strict host specificity of HBV genotypes. PMID- 22432022 TI - Spectroscopic studies of the iron and manganese reconstituted tyrosyl radical in Bacillus cereus ribonucleotide reductase R2 protein. AB - Ribonucleotide reductase (RNR) catalyzes the rate limiting step in DNA synthesis where ribonucleotides are reduced to the corresponding deoxyribonucleotides. Class Ib RNRs consist of two homodimeric subunits: R1E, which houses the active site; and R2F, which contains a metallo cofactor and a tyrosyl radical that initiates the ribonucleotide reduction reaction. We studied the R2F subunit of B. cereus reconstituted with iron or alternatively with manganese ions, then subsequently reacted with molecular oxygen to generate two tyrosyl-radicals. The two similar X-band EPR spectra did not change significantly over 4 to 50 K. From the 285 GHz EPR spectrum of the iron form, a g(1)-value of 2.0090 for the tyrosyl radical was extracted. This g(1)-value is similar to that observed in class Ia E. coli R2 and class Ib R2Fs with iron-oxygen cluster, suggesting the absence of hydrogen bond to the phenoxyl group. This was confirmed by resonance Raman spectroscopy, where the stretching vibration associated to the radical (C-O, nu(7a) = 1500 cm(-1)) was found to be insensitive to deuterium-oxide exchange. Additionally, the (18)O-sensitive Fe-O-Fe symmetric stretching (483 cm(-1)) of the metallo-cofactor was also insensitive to deuterium-oxide exchange indicating no hydrogen bonding to the di-iron-oxygen cluster, and thus, different from mouse R2 with a hydrogen bonded cluster. The HF-EPR spectrum of the manganese reconstituted RNR R2F gave a g(1)-value of ~2.0094. The tyrosyl radical microwave power saturation behavior of the iron-oxygen cluster form was as observed in class Ia R2, with diamagnetic di-ferric cluster ground state, while the properties of the manganese reconstituted form indicated a magnetic ground state of the manganese-cluster. The recent activity measurements (Crona et al., (2011) J Biol Chem 286: 33053-33060) indicates that both the manganese and iron reconstituted RNR R2F could be functional. The manganese form might be very important, as it has 8 times higher activity. PMID- 22432023 TI - Tissue plasminogen activator and plasminogen activator inhibitor 1 contribute to sonic hedgehog-induced in vitro cerebral angiogenesis. AB - The molecular mechanisms underlying cerebral angiogenesis have not been fully investigated. Using primary mouse brain endothelial cells (MBECs) and a capillary like tube formation assay, we investigated whether the sonic hedgehog (Shh) signaling pathway is coupled with the plasminogen/plasmin system in mediating cerebral angiogenesis. We found that incubation of MBECs with recombinant human Shh (rhShh) substantially increased the tube formation in naive MBECs. This was associated with increases in tissue plasminogen activator (tPA) activation and reduction of plasminogen activator inhibitor 1 (PAI-1). Blockage of the Shh pathway with cyclopamine abolished the induction of tube formation and the effect of rhShh on tPA and PAI-1. Addition of PAI-1 reduced rhShh-augmented tube formation. Genetic ablation of tPA in MBECs impaired tube formation and downregulated of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). Addition of rhShh to tPA-/- MBECs only partially restored the tube formation and upregulated Ang1, but not VEGF, although rhShh increased VEGF and Ang1 expression on wild-type MBECs. Complete restoration of tube formation in tPA /- MBECs was observed only when both exogenous Shh and tPA were added. The present study provides evidence that tPA and PAI-1 contribute to Shh-induced in vitro cerebral angiogenesis. PMID- 22432024 TI - Visualizing the 3D architecture of multiple erythrocytes infected with Plasmodium at nanoscale by focused ion beam-scanning electron microscopy. AB - Different methods for three-dimensional visualization of biological structures have been developed and extensively applied by different research groups. In the field of electron microscopy, a new technique that has emerged is the use of a focused ion beam and scanning electron microscopy for 3D reconstruction at nanoscale resolution. The higher extent of volume that can be reconstructed with this instrument represent one of the main benefits of this technique, which can provide statistically relevant 3D morphometrical data. As the life cycle of Plasmodium species is a process that involves several structurally complex developmental stages that are responsible for a series of modifications in the erythrocyte surface and cytoplasm, a high number of features within the parasites and the host cells has to be sampled for the correct interpretation of their 3D organization. Here, we used FIB-SEM to visualize the 3D architecture of multiple erythrocytes infected with Plasmodium chabaudi and analyzed their morphometrical parameters in a 3D space. We analyzed and quantified alterations on the host cells, such as the variety of shapes and sizes of their membrane profiles and parasite internal structures such as a polymorphic organization of hemoglobin filled tubules. The results show the complex 3D organization of Plasmodium and infected erythrocyte, and demonstrate the contribution of FIB-SEM for the obtainment of statistical data for an accurate interpretation of complex biological structures. PMID- 22432025 TI - Comparison of the gene expression profiles from normal and Fgfrl1 deficient mouse kidneys reveals downstream targets of Fgfrl1 signaling. AB - Fgfrl1 (fibroblast growth factor receptor-like 1) is a transmembrane receptor that is essential for the development of the metanephric kidney. It is expressed in all nascent nephrogenic structures and in the ureteric bud. Fgfrl1 null mice fail to develop the metanephric kidneys. Mutant kidney rudiments show a dramatic reduction of ureteric branching and a lack of mesenchymal-to-epithelial transition. Here, we compared the expression profiles of wildtype and Fgfrl1 mutant kidneys to identify genes that act downstream of Fgfrl1 signaling during the early steps of nephron formation. We detected 56 differentially expressed transcripts with 2-fold or greater reduction, among them many genes involved in Fgf, Wnt, Bmp, Notch, and Six/Eya/Dach signaling. We validated the microarray data by qPCR and whole-mount in situ hybridization and showed the expression pattern of candidate genes in normal kidneys. Some of these genes might play an important role during early nephron formation. Our study should help to define the minimal set of genes that is required to form a functional nephron. PMID- 22432026 TI - Stable modality-specific activity flows as reflected by the neuroenergetic approach to the FMRI weighted maps. AB - This article uses the ideas of neuroenergetic and neural field theories to detect stimulation-driven energy flows in the brain during face and auditory word processing. In this analysis, energy flows are thought to create the stable gradients of the fMRI weighted summary images. The sources, from which activity spreads in the brain during face processing, were detected in the occipital cortex. The following direction of energy flows in the frontal cortex was described: the right inferior frontal = >the left inferior frontal = >the triangular part of the left inferior frontal cortex = >the left operculum. In the left operculum, a localized circuit was described. For auditory word processing, the sources of activity flows were detected bilaterally in the middle superior temporal regions, they were also detected in the left posterior superior temporal cortex. Thus, neuroenergetic assumptions may give a novel perspective for the analysis of neuroimaging data. PMID- 22432027 TI - Distinct regulatory functions of calpain 1 and 2 during neural stem cell self renewal and differentiation. AB - Calpains are calcium regulated cysteine proteases that have been described in a wide range of cellular processes, including apoptosis, migration and cell cycle regulation. In addition, calpains have been implicated in differentiation, but their impact on neural differentiation requires further investigation. Here, we addressed the role of calpain 1 and calpain 2 in neural stem cell (NSC) self renewal and differentiation. We found that calpain inhibition using either the chemical inhibitor calpeptin or the endogenous calpain inhibitor calpastatin favored differentiation of NSCs. This effect was associated with significant changes in cell cycle-related proteins and may be regulated by calcium. Interestingly, calpain 1 and calpain 2 were found to play distinct roles in NSC fate decision. Calpain 1 expression levels were higher in self-renewing NSC and decreased with differentiation, while calpain 2 increased throughout differentiation. In addition, calpain 1 silencing resulted in increased levels of both neuronal and glial markers, beta-III Tubulin and glial fibrillary acidic protein (GFAP). Calpain 2 silencing elicited decreased levels of GFAP. These results support a role for calpain 1 in repressing differentiation, thus maintaining a proliferative NSC pool, and suggest that calpain 2 is involved in glial differentiation. PMID- 22432028 TI - C-terminal extension of the yeast mitochondrial DNA polymerase determines the balance between synthesis and degradation. AB - Saccharomyces cerevisiae mitochondrial DNA polymerase (Mip1) contains a C terminal extension (CTE) of 279 amino acid residues. The CTE is required for mitochondrial DNA maintenance in yeast but is absent in higher eukaryotes. Here we use recombinant Mip1 C-terminal deletion mutants to investigate functional importance of the CTE. We show that partial removal of the CTE in Mip1Delta216 results in strong preference for exonucleolytic degradation rather than DNA polymerization. This disbalance in exonuclease and polymerase activities is prominent at suboptimal dNTP concentrations and in the absence of correctly pairing nucleotide. Mip1Delta216 also displays reduced ability to synthesize DNA through double-stranded regions. Full removal of the CTE in Mip1Delta279 results in complete loss of Mip1 polymerase activity, however the mutant retains its exonuclease activity. These results allow us to propose that CTE functions as a part of Mip1 polymerase domain that stabilizes the substrate primer end at the polymerase active site, and is therefore required for efficient mitochondrial DNA replication in vivo. PMID- 22432029 TI - Cap-Gly proteins at microtubule plus ends: is EB1 detyrosination involved? AB - Localization of CAP-Gly proteins such as CLIP170 at microtubule+ends results from their dual interaction with alpha-tubulin and EB1 through their C-terminal amino acids -EEY. Detyrosination (cleavage of the terminal tyrosine) of alpha-tubulin by tubulin-carboxypeptidase abolishes CLIP170 binding. Can detyrosination affect EB1 and thus regulate the presence of CLIP170 at microtubule+ends as well? We developed specific antibodies to discriminate tyrosinated vs detyrosinated forms of EB1 and detected only tyrosinated EB1 in fibroblasts, astrocytes, and total brain tissue. Over-expressed EB1 was not detyrosinated in cells and chimeric EB1 with the eight C-terminal amino acids of alpha-tubulin was only barely detyrosinated. Our results indicate that detyrosination regulates CLIPs interaction with alpha-tubulin, but not with EB1. They highlight the specificity of carboxypeptidase toward tubulin. PMID- 22432030 TI - Luteolin limits infarct size and improves cardiac function after myocardium ischemia/reperfusion injury in diabetic rats. AB - BACKGROUND: The present study was to investigate the effects and mechanism of Luteolin on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in diabetic rats with myocardial ischemia/reperfusion (I/R) injury. METHODOLOGY/PRINCIPAL FINDINGS: Diabetic rats underwent 30 minutes of ischemia followed by 3 h of reperfusion. Animals were pretreated with or without Luteolin before coronary artery ligation. The severity of myocardial I/R induced LDH release, arrhythmia, infarct size, cardiac function impairment, cardiomyocyte apoptosis were compared. Western blot analysis was performed to elucidate the target proteins of Luteolin. The inflammatory cytokine production were also examined in ischemic myocardium underwent I/R injury. Our results revealed that Luteolin administration significantly reduced LDH release, decreased the incidence of arrhythmia, attenuated myocardial infarct size, enhanced left ventricular ejection fraction and decreased myocardial apoptotic death compared with I/R group. Western blot analysis showed that Luteolin treatment up-regulated anti-apoptotic proteins FGFR2 and LIF expression, increased BAD phosphorylation while decreased the ratio of Bax to Bcl-2. Luteolin treatment also inhibited MPO expression and inflammatory cytokine production including IL-6, IL-1a and TNF-a. Moreover, co-administration of wortmannin and Luteolin abolished the beneficial effects of Luteolin. CONCLUSIONS/SIGNIFICANCE: This study indicates that Luteolin preserves cardiac function, reduces infarct size and cardiomyocyte apoptotic rate after I/R injury in diabetic rats. Luteolin exerts its action by up-regulating of anti-apoptotic proteins FGFR2 and LIF expression, activating PI3K/Akt pathway while increasing BAD phosphorylation and decreasing ratio of Bax to Bcl-2. PMID- 22432031 TI - Differentiation potential of CD14+ monocytes into myofibroblasts in patients with systemic sclerosis. AB - BACKGROUND: Circulating monocytes are a highly plastic and functionally heterogeneic cell type with an activated phenotype in patients with systemic sclerosis (SSc). CD14(+) monocytes have the potential to differentiate into extra cellular matrix (ECM) producing cells, possibly participating in fibrogenesis. AIM: To study the effect of GM-CSF, IL-4 and endothelin -1 (ET-1) alone or in combination on monocyte differentiation into myofibroblasts. METHODS: CD14(+) cells were isolated from peripheral blood from 14 SSc patients and healthy controls by positive selection and incubated with different combinations of GM CSF, IL-4 and ET-1 for 14 days. Type-1 collagen and alpha-SMA were detected by Western blot, qPCR and confocal microscopy. HLA-DR, CD11c and CD14 expression was analysed by flow cytometry. A collagen gel contraction assay was performed for functional myofibroblast assessment. RESULTS: GM-CSF both induced collagen and alpha-SMA expression after 14 days. ET-1 further increased GM-CSF-induced collagen expression in a dose dependent manner up to 30-fold. IL-4/GM-CSF combination leads to a more DC-like phenotype of monocytes associated with reduced collagen and alpha-SMA expression compared to GM-CSF alone. Collagen and alpha-SMA expression was higher in monocytes from SSc patients and monocytes were more prone to obtain a spindle form. In contrast to controls, ET-1 and IL-4 alone were sufficient to induce alpha-SMA expression in monocytes from SSc patients. Despite the induction of alpha-SMA expression, monocyte-derived myofibroblasts only had a moderate capability of contraction in functional analyses. CONCLUSION: SSc monocytes display increased maturation towards myofibroblasts demonstrated by their phenotype and alpha-SMA expression when compared to monocytes from healthy controls, however only with minor functional contraction properties. PMID- 22432032 TI - Microbial communities in long-term, water-flooded petroleum reservoirs with different in situ temperatures in the Huabei Oilfield, China. AB - The distribution of microbial communities in the Menggulin (MGL) and Ba19 blocks in the Huabei Oilfield, China, were studied based on 16S rRNA gene analysis. The dominant microbes showed obvious block-specific characteristics, and the two blocks had substantially different bacterial and archaeal communities. In the moderate-temperature MGL block, the bacteria were mainly Epsilonproteobacteria and Alphaproteobacteria, and the archaea were methanogens belonging to Methanolinea, Methanothermobacter, Methanosaeta, and Methanocella. However, in the high-temperature Ba19 block, the predominant bacteria were Gammaproteobacteria, and the predominant archaea were Methanothermobacter and Methanosaeta. In spite of shared taxa in the blocks, differences among wells in the same block were obvious, especially for bacterial communities in the MGL block. Compared to the bacterial communities, the archaeal communities were much more conserved within blocks and were not affected by the variation in the bacterial communities. PMID- 22432033 TI - Targeting bone alleviates osteoarthritis in osteopenic mice and modulates cartilage catabolism. AB - OBJECTIVE: Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism. METHODS: OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone cartilage crosstalk was tested using an OPG neutralizing antibody. RESULTS: Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0+/-0.63 vs 5.2+/-0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2 3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (73+/-8.0% and 80+/ 22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade. CONCLUSION: The inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA. PMID- 22432034 TI - Synonymous codon ordering: a subtle but prevalent strategy of bacteria to improve translational efficiency. AB - BACKGROUND: In yeast coding sequences, once a particular codon has been used, subsequent occurrence of the same amino acid tends to use codons sharing the same tRNA. Such a phenomenon of co-tRNA codons pairing bias (CTCPB) is also found in some other eukaryotes but it is not known whether it occurs in prokaryotes. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we focused on a total of 773 bacterial genomes to investigate their synonymous codon pairing preferences. After calculating the actual frequencies of synonymous codon pairs and comparing them with their expected values, we detected an obvious pairing bias towards identical codon pairs. This seems consistent with the previously reported CTCPB phenomenon, since identical codons are certainly read by the same tRNA. However, among co-tRNA but non-identical codon pairs, only 22 were often found overrepresented, suggesting that many co-tRNA codons actually do not preferentially pair together in prokaryotes. Therefore, the previously reported co-tRNA codons pairing rule needs to be more rigorously defined. The affinity differences between a tRNA anticodon and its readable codons should be taken into account. Moreover, both within-gene-shuffling tests and phylogenetic analyses support the idea that translational selection played an important role in shaping the observed synonymous codon pairing pattern in prokaryotes. CONCLUSIONS: Overall, a high level of synonymous codon pairing bias was detected in 73% investigated bacterial species, suggesting the synonymous codon ordering strategy has been prevalently adopted by prokaryotes to improve their translational efficiencies. The findings in this study also provide important clues to better understand the complex dynamics of translational process. PMID- 22432035 TI - Evaluation of a partial genome screening of two asthma susceptibility regions using bayesian network based bayesian multilevel analysis of relevance. AB - Genetic studies indicate high number of potential factors related to asthma. Based on earlier linkage analyses we selected the 11q13 and 14q22 asthma susceptibility regions, for which we designed a partial genome screening study using 145 SNPs in 1201 individuals (436 asthmatic children and 765 controls). The results were evaluated with traditional frequentist methods and we applied a new statistical method, called bayesian network based bayesian multilevel analysis of relevance (BN-BMLA). This method uses bayesian network representation to provide detailed characterization of the relevance of factors, such as joint significance, the type of dependency, and multi-target aspects. We estimated posteriors for these relations within the bayesian statistical framework, in order to estimate the posteriors whether a variable is directly relevant or its association is only mediated.With frequentist methods one SNP (rs3751464 in the FRMD6 gene) provided evidence for an association with asthma (OR = 1.43(1.2-1.8); p = 3*10(-4)). The possible role of the FRMD6 gene in asthma was also confirmed in an animal model and human asthmatics.In the BN-BMLA analysis altogether 5 SNPs in 4 genes were found relevant in connection with asthma phenotype: PRPF19 on chromosome 11, and FRMD6, PTGER2 and PTGDR on chromosome 14. In a subsequent step a partial dataset containing rhinitis and further clinical parameters was used, which allowed the analysis of relevance of SNPs for asthma and multiple targets. These analyses suggested that SNPs in the AHNAK and MS4A2 genes were indirectly associated with asthma. This paper indicates that BN-BMLA explores the relevant factors more comprehensively than traditional statistical methods and extends the scope of strong relevance based methods to include partial relevance, global characterization of relevance and multi-target relevance. PMID- 22432036 TI - Identification of serum microRNAs as novel non-invasive biomarkers for early detection of gastric cancer. AB - BACKGROUND: To investigate the potential of serum miRNAs as biomarkers for early detection of gastric cancer (GC), a population-based study was conducted in Linqu, a high-risk area of GC in China. METHODOLOGY/PRINCIPAL FINDINGS: All subjects were selected from two large cohort studies. Differential miRNAs were identified in serum pools of GC and control using TaqMan low density array, and validated in individual from 82 pairs of GC and control, and 46 pairs of dysplasia and control by real-time quantitative reverse transcription-polymerase chain reaction. The temporal trends of identified serum miRNA expression were further explored in a retrospective study on 58 GC patients who had at least one pre-GC diagnosis serum sample based on the long-term follow-up population. The miRNA profiling results demonstrated that 16 miRNAs were markedly upregulated in GC patients compared to controls. Further validation identified a panel of three serum miRNAs (miR-221, miR-744, and miR-376c) as potential biomarkers for GC detection, and receiver operating characteristic (ROC) curve-based risk assessment analysis revealed that this panel could distinguish GCs from controls with 82.4% sensitivity and 58.8% specificity. MiR-221 and miR-376c demonstrated significantly positive correlation with poor differentiation of GC, and miR-221 displayed higher level in dysplasia than in control. Furthermore, the retrospective study revealed an increasing trend of these three miRNA levels during GC development (P for trend<0.05), and this panel could classify serum samples collected up to 5 years ahead of clinical GC diagnosis with 79.3% overall accuracy. CONCLUSIONS/SIGNIFICANCE: These data suggest that serum miR-221, miR 376c and miR-744 have strong potential as novel non-invasive biomarkers for early detection of GC. PMID- 22432037 TI - Genome sequence of E. coli O104:H4 leads to rapid development of a targeted antimicrobial agent against this emerging pathogen. AB - A recent widespread outbreak of Escherichia coli O104:H4 in Germany demonstrates the dynamic nature of emerging and re-emerging food-borne pathogens, particularly STECs and related pathogenic E. coli. Rapid genome sequencing and public availability of these data from the German outbreak strain allowed us to identify an O-antigen-specific bacteriophage tail spike protein encoded in the genome. We synthesized this gene and fused it to the tail fiber gene of an R-type pyocin, a phage tail-like bacteriocin, and expressed the novel bacteriocin such that the tail fiber fusion was incorporated into the bacteriocin structure. The resulting particles have bactericidal activity specifically against E. coli strains that produce the O104 lipopolysaccharide antigen, including the outbreak strain. This O-antigen tailspike-R-type pyocin strategy provides a platform to respond rapidly to emerging pathogens upon the availability of the pathogen's genome sequence. PMID- 22432038 TI - Assessing the diversity and specificity of two freshwater viral communities through metagenomics. AB - Transitions between saline and fresh waters have been shown to be infrequent for microorganisms. Based on host-specific interactions, the presence of specific clades among hosts suggests the existence of freshwater-specific viral clades. Yet, little is known about the composition and diversity of the temperate freshwater viral communities, and even if freshwater lakes and marine waters harbor distinct clades for particular viral sub-families, this distinction remains to be demonstrated on a community scale.To help identify the characteristics and potential specificities of freshwater viral communities, such communities from two lakes differing by their ecological parameters were studied through metagenomics. Both the cluster richness and the species richness of the Lake Bourget virome were significantly higher that those of the Lake Pavin, highlighting a trend similar to the one observed for microorganisms (i.e. the specie richness observed in mesotrophic lakes is greater than the one observed in oligotrophic lakes). Using 29 previously published viromes, the cluster richness was shown to vary between different environment types and appeared significantly higher in marine ecosystems than in other biomes. Furthermore, significant genetic similarity between viral communities of related environments was highlighted as freshwater, marine and hypersaline environments were separated from each other despite the vast geographical distances between sample locations within each of these biomes. An automated phylogeny procedure was then applied to marker genes of the major families of single-stranded (Microviridae, Circoviridae, Nanoviridae) and double-stranded (Caudovirales) DNA viruses. These phylogenetic analyses all spotlighted a very broad diversity and previously unknown clades undetectable by PCR analysis, clades that gathered sequences from the two lakes. Thus, the two freshwater viromes appear closely related, despite the significant ecological differences between the two lakes. Furthermore, freshwater viral communities appear genetically distinct from other aquatic ecosystems, demonstrating the specificity of freshwater viruses at a community scale for the first time. PMID- 22432039 TI - Weak polygyny in California sea lions and the potential for alternative mating tactics. AB - Female aggregation and male territoriality are considered to be hallmarks of polygynous mating systems. The development of genetic parentage assignment has called into question the accuracy of behavioral traits in predicting true mating systems. In this study we use 14 microsatellite markers to explore the mating system of one of the most behaviorally polygynous species, the California sea lion (Zalophus californianus). We sampled a total of 158 female-pup pairs and 99 territorial males across two breeding rookeries (San Jorge and Los Islotes) in the Gulf of California, Mexico. Fathers could be identified for 30% of pups sampled at San Jorge across three breeding seasons and 15% of sampled pups at Los Islotes across two breeding seasons. Analysis of paternal relatedness between the pups for which no fathers were identified (sampled over four breeding seasons at San Jorge and two at Los Islotes) revealed that few pups were likely to share a father. Thirty-one percent of the sampled males on San Jorge and 15% of the sampled males on Los Islotes were assigned at least one paternity. With one exception, no male was identified as the father of more than two pups. Furthermore, at Los Islotes rookery there were significantly fewer pups assigned paternity than expected given the pool of sampled males (p<0.0001). Overall, we found considerably lower variation in male reproductive success than expected in a species that exhibits behavior associated with strongly polygynous mating. Low variation in male reproductive success may result from heightened mobility among receptive females in the Gulf of California, which reduces the ability of males to monopolize groups of females. Our results raise important questions regarding the adaptive role of territoriality and the potential for alternative mating tactics in this species. PMID- 22432040 TI - A genome-wide RNAi screen identifies regulators of cholesterol-modified hedgehog secretion in Drosophila. AB - Hedgehog (Hh) proteins are secreted molecules that function as organizers in animal development. In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. The absence of either modification severely disrupts the organization of numerous tissues during development. It is currently not known how lipid-modified Hh is secreted and released from producing cells. We have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI) but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway. We provide evidence that both proteolysis and cholesterol modification are necessary for the efficient trafficking of Hh through the ER and Golgi. Finally, we identified several putative regulators of protein secretion and demonstrate a role for some of these genes in Hh and Wingless (Wg) morphogen secretion in vivo. These data open new perspectives for studying how morphogen secretion is regulated, as well as provide insight into regulation of lipid-modified protein secretion. PMID- 22432041 TI - Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene. AB - Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58*10(-7), OR = 1.57; rs12711941, p = 4.26*10(-7), OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11*10( 7)). These SNPs reside in an intergenic region less than 15 kb downstream from the 3' terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r(2) = 0.92), but not (r(2)<0.80) with any other genotyped SNP +/-250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.48*10(-7), OR = 1.59) in strong LD with the two significant GWAS SNPs (r(2)>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes +/-500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ~250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s). PMID- 22432042 TI - An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda. AB - BACKGROUND: Information on causes of death in HIV-infected patients in Sub Saharan Africa is mainly derived from observational cohort and verbal autopsy studies. Autopsy is the gold standard to ascertain cause of death. We conducted an autopsy study to describe and compare the clinical and autopsy causes of death and contributory findings in hospitalized HIV-infected and HIV-uninfected patients in Uganda. METHODS: Between May and September 2009 a complete autopsy was performed on patients that died on a combined infectious diseases gastroenterology ward in Mulago Hospital in Kampala, Uganda. Autopsy cause of death and contributing findings were based on the macro- and microscopic post mortem findings combined with clinical information. Clinical diagnoses were reported by the ward doctor and classified as confirmed, highly suspected, considered or not considered, based on information derived from the medical chart. Results are reported according to HIV serostatus. RESULTS: Fifty-three complete autopsies were performed in 66% HIV-positive, 21% HIV-negative and 13% patients with an unknown HIV serological status. Infectious diseases caused death in 83% of HIV-positive patients, with disseminated TB as the main diagnosis causing 37% of deaths. The spectrum of illness and causes of death were substantially different between HIV-positive and HIV-negative patients. In HIV positive patients 12% of postmortem diagnoses were clinically confirmed, 27% highly suspected, 16% considered and 45% not considered. In HIV-negative patients 17% of postmortem diagnoses were clinically highly suspected, 42% considered and 42% not considered. CONCLUSION: Autopsy examination remains an important tool to ascertain causes of death particularly in settings with limited access to diagnostic testing during life. HIV-positive patients continue to die from treatable and clinically undiagnosed infectious diseases. Until rapid-point of care testing is available to confirm common infections, empiric treatment should be further investigated. PMID- 22432043 TI - Structural basis of Ets1 cooperative binding to widely separated sites on promoter DNA. AB - Ets1 is a member of the Ets family of transcription factors. Ets1 is expressed in autoinhibited form and its DNA binding depends on partner proteins bound to adjacent sequences or the relative positioning of a second Ets-binding site (EBS). The autoinhibition of Ets1 is mediated by structural coupling of regions flanking the DNA-binding domain. The NMR structure of Ets1 revealed that the inhibitory regions comprised of helices HI1 and HI2 and H4 are packed together on the Ets domain to form an inhibitory module. The crystal structure of Ets1 unexpectedly revealed a homodimer in which homodimerisation occurs via swapping of HI1 helices. Modeling of DNA binding indicates that the Ets1 dimer can bind to two antiparallel pieces of DNA. To verify this, we crystallized and solved the structure of the complex comprised of Ets1 dimer and two pieces of DNA. DNA binding by Ets1 dimer resulted in formation of additional intermolecular protein*DNA interactions, implying that the complex formation is cooperative. PMID- 22432044 TI - A water soluble CoQ10 formulation improves intracellular distribution and promotes mitochondrial respiration in cultured cells. AB - BACKGROUND: Mitochondria are both the cellular powerhouse and the major source of reactive oxygen species. Coenzyme Q(10) plays a key role in mitochondrial energy production and is recognized as a powerful antioxidant. For these reasons it can be argued that higher mitochondrial ubiquinone levels may enhance the energy state and protect from oxidative stress. Despite the large number of clinical studies on the effect of CoQ(10) supplementation, there are very few experimental data about the mitochondrial ubiquinone content and the cellular bioenergetic state after supplementation. Controversial clinical and in vitro results are mainly due to the high hydrophobicity of this compound, which reduces its bioavailability. PRINCIPAL FINDINGS: We measured the cellular and mitochondrial ubiquinone content in two cell lines (T67 and H9c2) after supplementation with a hydrophilic CoQ(10) formulation (Qter(r)) and native CoQ(10). Our results show that the water soluble formulation is more efficient in increasing ubiquinone levels. We have evaluated the bioenergetics effect of ubiquinone treatment, demonstrating that intracellular CoQ(10) content after Qter supplementation positively correlates with an improved mitochondrial functionality (increased oxygen consumption rate, transmembrane potential, ATP synthesis) and resistance to oxidative stress. CONCLUSIONS: The improved cellular energy metabolism related to increased CoQ(10) content represents a strong rationale for the clinical use of coenzyme Q(10) and highlights the biological effects of Qter(r), that make it the eligible CoQ(10) formulation for the ubiquinone supplementation. PMID- 22432045 TI - An insertion sequence-dependent plasmid rearrangement in Aeromonas salmonicida causes the loss of the type three secretion system. AB - Aeromonas salmonicida, a bacterial fish pathogen, possesses a functional Type Three Secretion System (TTSS), which is essential for its virulence. The genes for this system are mainly located in a single region of the large pAsa5 plasmid. Bacteria lose the TTSS region from this plasmid through rearrangements when grown in stressful growth conditions. The A. salmonicida genome is rich in insertion sequences (ISs), which are mobile DNA elements that can cause DNA rearrangements in other bacterial species. pAsa5 possesses numerous ISs. Three IS11s from the IS256 family encircle the rearranged regions. To confirm that these IS11s are involved in pAsa5 rearrangements, 26 strains derived from strain A449 and two Canadian isolates (01-B526 and 01-B516) with a pAsa5 rearrangement were tested using a PCR approach to determine whether the rearrangements were the result of an IS11-dependent process. Nine out of the 26 strains had a positive PCR result, suggesting that the rearrangement in these strains were IS-dependent. The PCR analysis showed that all the rearrangements in the A449-derived strains were IS11 dependent process while the rearrangements in 01-B526 and 01-B516 could only be partially coupled to the action of IS11. Unidentified elements that affect IS dependent rearrangements may be present in 01-B526 and 01-B516. Our results suggested that pAsa5 rearrangements involve IS11. This is the first study showing that ISs are involved in plasmid instability in A. salmonicida. PMID- 22432046 TI - The 3'-terminal hexamer sequence of classical swine fever virus RNA plays a role in negatively regulating the IRES-mediated translation. AB - The 3' untranslated region (UTR) is usually involved in the switch of the translation and replication for a positive-sense RNA virus. To understand the 3' UTR involved in an internal ribosome entry site (IRES)-mediated translation in Classical swine fever virus (CSFV), we first confirmed the predicted secondary structure (designated as SLI, SLII, SLIII, and SLIV) by enzymatic probing. Using a reporter assay in which the luciferase expression is under the control of CSFV 5' and 3' UTRs, we found that the 3' UTR harbors the positive and negative regulatory elements for translational control. Unlike other stem loops, SLI acts as a repressor for expression of the reporter gene. The negative cis-acting element in SLI is further mapped to the very 3'-end hexamer CGGCCC sequence. Further, the CSFV IRES-mediated translation can be enhanced by the heterologous 3'-ends such as the poly(A) or the 3' UTR of Hepatitis C virus (HCV). Interestingly, such an enhancement was repressed by flanking this hexamer to the end of poly(A) or HCV 3' UTR. After sequence comparison and alignment, we have found that this hexamer sequence could hypothetically base pair with the sequence in the IRES IIId1, the 40 S ribosomal subunit binding site for the translational initiation, located at the 5' UTR. In conclusion, we have found that the 3'-end terminal sequence can play a role in regulating the translation of CSFV. PMID- 22432047 TI - Placental 11-beta hydroxysteroid dehydrogenase methylation is associated with newborn growth and a measure of neurobehavioral outcome. AB - BACKGROUND: There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment. METHODOLOGY/PRINCIPAL FINDINGS: We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04). CONCLUSIONS/SIGNIFICANCE: These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health. PMID- 22432048 TI - Microbial community succession on developing lesions on human enamel. AB - BACKGROUND: Dental caries is one of the most common diseases in the world. However, our understanding of how the microbial community composition changes in vivo as caries develops is lacking. OBJECTIVE: An in vivo model was used in a longitudinal cohort study to investigate shifts in the microbial community composition associated with the development of enamel caries. DESIGN: White spot lesions were generated in vivo on human teeth predetermined to be extracted for orthodontic reasons. The bacterial microbiota on sound enamel and on developing carious lesions were identified using the Human Oral Microbe Identification Microarray (HOMIM), which permits the detection of about 300 of the approximate 600 predominant bacterial species in the oral cavity. RESULTS: After only seven weeks, 75% of targeted teeth developed white spot lesions (8 individuals, 16 teeth). The microbial community composition of the plaque over white spot lesions differed significantly as compared to sound enamel. Twenty-five bacterial taxa, including Streptococcusmutans, Atopobiumparvulum, Dialisterinvisus, and species of Prevotella and Scardovia, were significantly associated with initial enamel lesions. In contrast, 14 bacterial taxa, including species of Fusobacterium, Campylobacter, Kingella, and Capnocytophaga, were significantly associated with sound enamel. CONCLUSIONS: The bacterial community composition associated with the progression of enamel lesions is specific and much more complex than previously believed. This investigation represents one of the first longitudinally-derived studies for caries progression and supports microbial data from previous cross-sectional studies on the development of the disease. Thus, the in vivo experiments of generating lesions on teeth destined for extraction in conjunction with HOMIM analyses represent a valid model to study succession of supragingival microbial communities associated with caries development and to study efficacy of prophylactic and restorative treatments. PMID- 22432049 TI - Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide. AB - Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This review attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations. PMID- 22432050 TI - BALB/c-Fcgr2bPdcd1 mouse expressing anti-urothelial antibody is a novel model of autoimmune cystitis. AB - We report the impact of anti-urothelial autoantibody (AUAb) on urinary bladder phenotype in BALB/c mice deficient of the FcgammaRIIb and PD-1. AUAb was present in serum samples from approximately half of the double-knockout (DKO) mice, as detected by immunofluorescence and immunoblots for urothelial proteins including uroplakin IIIa. The AUAb-positive DKO mice showed degeneration of urothelial plaque and umbrella cells, along with infiltration of inflammatory cells in the suburothelial layer. TNFalpha and IL-1beta were upregulated in the bladder and the urine of AUAb-positive DKO mice. Voiding behavior of mice was analyzed by the Voided Stain on Paper method. 10-week-old and older AUAb-positive DKO mice voided significantly less urine per void than did wild type (WT) mice. Furthermore, administration of the AUAb-containing serum to WT mice significantly reduced their urine volume per void. In summary, this report presents a novel comprehensive mouse model of autoimmune cystitis. PMID- 22432051 TI - Modelling bluetongue virus transmission between farms using animal and vector movements. AB - Bluetongue is a notifiable disease of ruminants which, in 2007, occurred for the first time in England. We present the first model for bluetongue that explicitly incorporates farm to farm movements of the two main hosts, as well as vector dispersal. The model also includes a seasonal vector to host ratio and dynamic restriction zones that evolve as infection is detected. Batch movements of sheep were included by modelling degree of mixing at markets. We investigate the transmission of bluetongue virus between farms in eastern England (the focus of the outbreak). Results indicate that most parameters affecting outbreak size relate to vectors and that the infection generally cannot be maintained without between-herd vector transmission. Movement restrictions are effective at reducing outbreak size, and a targeted approach would be as effective as a total movement ban. The model framework is flexible and can be adapted to other vector-borne diseases of livestock. PMID- 22432052 TI - Factors limiting the transmission of HIV mutations conferring drug resistance: fitness costs and genetic bottlenecks. AB - Transmission of HIV strains with drug-resistance mutations (DRMs) causes public health problems in resource-rich countries. We use a stochastic model, with data from viral competition experiments, to analyze the effect of fitness costs (FCs) and genetic bottlenecks on limiting transmission of 10 clinically significant DRMs. Transmission of DRMs with low FCs (~0.2%) is similar to wild-type; transmission chains last ~8 generations causing clusters of ~60 infected individuals. Genetic bottlenecks substantially limit transmission of DRMs with moderately high FCs (~0.6%); chains last ~1-3 generations with transmission clusters of 2-7. Transmission of DRMs with extremely high FCs (>6%) only occurs from ~5% of index cases. DRMs can revert to wild-type and remain as minority strains, within treatment-naive individuals, undetectable by current resistance assays. We calculate, based on assay sensitivity, the length of time each DRM is detectable within individuals. Taken together, our results imply a hidden epidemic of transmitted resistance may exist. PMID- 22432053 TI - Fast Purcell-enhanced single photon source in 1,550-nm telecom band from a resonant quantum dot-cavity coupling. AB - High-bit-rate nanocavity-based single photon sources in the 1,550-nm telecom band are challenges facing the development of fibre-based long-haul quantum communication networks. Here we report a very fast single photon source in the 1,550-nm telecom band, which is achieved by a large Purcell enhancement that results from the coupling of a single InAs quantum dot and an InP photonic crystal nanocavity. At a resonance, the spontaneous emission rate was enhanced by a factor of 5 resulting a record fast emission lifetime of 0.2 ns at 1,550 nm. We also demonstrate that this emission exhibits an enhanced anti-bunching dip. This is the first realization of nanocavity-enhanced single photon emitters in the 1,550-nm telecom band. This coupled quantum dot cavity system in the telecom band thus provides a bright high-bit-rate non-classical single photon source that offers appealing novel opportunities for the development of a long-haul quantum telecommunication system via optical fibres. PMID- 22432054 TI - Papillary thyroid carcinoma: differential diagnosis and prognostic values of its different variants: review of the literature. AB - Papillary thyroid carcinoma is the most common thyroid malignancy, and has an excellent prognosis, even with cervical lymph node metastasis; however, histological variants are considered relevant, which may be associated with familial adenomatous polyposis and tumor aggressiveness. Histological features, such as vascular and/or lymphatic invasion, angiogenesis, multifocality, high cellular proliferation rate, neoplastic cell dissemination, and the histological varieties, are indicative of poor prognosis, together with associated clinical factors: age, sex, and tumor size. PMID- 22432055 TI - Multiple sites of highly amplified DNA sequences detected by molecular cytogenetic analysis in HS-RMS-2, a new pleomorphic rhabdomyosarcoma cell line. AB - A molecular cytogenetic analysis was performed on HS-RMS-2, a cell line established in this laboratory from a rare pleomorphic type of rhabdomyosarcoma. G-banding and multicolor-FISH analyses revealed that the cells have a complex chromosomal composition. Comparative genomic in situ hybridization (CGH) detected eight highly amplified regions at 1p36.1-p36.2, 1p31-p32, 1q21-q31, 8q12-q21, 8q24-qter, 11q12-q13, 12q13-q14 and 18q12-q22, suggesting the co-existence of multiple amplified oncogenes in these tumor cells. Reverse chromosome painting, using a probe regenerated by microdissection of a long marker chromosome, revealed the native location of three of eight possible genes to be on chromosomes 1p31-32, 12q14 and 18q21. FISH using BAC and cosmid probes revealed amplification of JUN (1p31), MYC (8q24), CCND1 (11q13), INT2 (11q13.3), MDM2 (12q14.3-q15) and MALT (18q21). These findings indicate that at least eight amplified oncogenes may contribute to the pathogenesis of a rare pleomorphic type of rhabdomyosarcoma. This new cell line should prove useful for in vitro preclinical studies of molecularly targeted therapies. PMID- 22432056 TI - Molecular genetics of testicular germ cell tumors. AB - Testicular germ cell tumors (TGCT) are the most common malignancy in young men. While most TGCT are potentially curable, approximately 5% of patients with TGCT may develop chemoresistance and die from the disease. This review article summarizes current knowledge in genetics underlying the development, progression and chemoresistance of TGCT. Most post-pubertal TGCT originate from intratubular germ cell neoplasia unclassified (IGCNU), which are transformed fetal gonocytes. Development of IGCNU may involve aberrantly activated KITLG/KIT pathway and overexpression of embryonic transcription factors such as NANOG and POU5F1, which leads to suppression of apoptosis, increased proliferation, and accumulation of mutations in gonocytes. Invasive TGCT consistently show gain of chromosome 12p, typically isochromosome 12p. Single gene mutations are uncommon in TGCT. KIT, TP53, KRAS/NRAS, and BRAF are genes most commonly mutated in TGCT and implicated in their pathogenesis. Different histologic subtypes of TGCT possess different gene expression profiles that reflect different directions of differentiation. Their distinct gene expression profiles are likely caused by epigenetic regulation, in particular DNA methylation, but not by gene copy number alterations. Resistance of TGCT to chemotherapy has been linked to karyotypic aberrations, single-gene mutations, and epigenetic regulation of gene expression in small-scale studies. The study of TGCT genetics could ultimately translate into development of new molecular diagnostic and therapeutic modalities for these tumors and improve the care of patients with these malignancies. PMID- 22432057 TI - Tumor growth is suppressed in mice expressing a truncated XRCC1 protein. AB - Tumor progression depends on the support of cells in the microenvironment, and is driven in part by the generation of reactive oxygen species (ROS). ROS can damage DNA, and the repair of damaged DNA is a well-known process involved in tumor initiation and promotion, but the role of DNA repair in tumor progression is not fully understood. In this regard the X-ray cross complementing 1 (XRCC1) protein is known to orchestrate the assembly of repair complexes at sites of DNA single strand breaks either directly or indirectly through repair of damaged bases, largely as the result of ROS-induced damage. XRCC1 polymorphisms have been shown to be associated with increased cancer. It was therefore of interest to investigate the effect of XRCC1 gene mutations on cancer progression. In an attempt to make XRCC1 point mutant mice, we generated a truncated protein (XRCC1tp) by the insertion of a neomycin cassette in intron12 of the XRCC1 gene. This unique finding allowed us to investigate cellular and tumor progression phenotypes in mice associated with expression and function of an altered XRCC1 protein on one allele. XRCC1tp cells showed increased toxicity to MMS, enhanced MMS-induced depletion of NADH suggesting increased PARP activity, and normal functional repair of MMS-induced DNA damage. Six months following treatment with the alkylating carcinogen azoxymethane (AOM) at 10 mg/kg once a week for 6 weeks, XRCC1tp mice had a decrease in average colon tumor volume of 14+/-3 mm(3) compared to 34+/-4 mm(3) in WT littermates (p <= 0.03, N= 20/genotype). XRCC1tp mice had a 72 per cent decrease in B16 melanoma tumor burden compared to wt littermates. Average tumor volume in transgenic PyMT metastatic breast cancer mice expressing XRCC1tp was 359 cubic mm in PyMT mice expressing XRCC1tp compared to 730 cubic mm in PyMT mice expressing XRCC1wt (p <= 0.001, N= 20/genotype). These data suggest that the presence of an XRCC1 truncated protein alters XRCC1 function independent of DNA repair, and is associated with anti-tumor activity. PMID- 22432058 TI - Physical state and viral load as predictive biomarkersfor persistence and progression of HPV16-positive cervical lesions: results from a population based long-term prospective cohort study. AB - Persistent infection with a high risk (hr) human papillomavirus (HPV) has been established as the main cause of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN3). Because most infections are transient, testing for hrHPV lacks specificity and has a low positive predictive value. It has been suggested that additional parameters like viral load and physical status of the viral genome could improve the effectiveness of HPV-based screening. We investigated the association between HPV16 viral load and physical state with viral persistence or risk of incident CIN3 or worse in a population-based prospective cohort study comprising 8656 women (20-29 years). All participants had two gynecological examinations two years apart and were followed through the nationwide Danish Pathology Data Bank (median follow-up: 12.9 yrs). Seventynine cervical swabs from women with a persistent HPV16 infection were available for analysis. For comparison we selected a random age-matched sample of transiently HPV16 infected women (N=91). Persistently infected women with incident CIN3 or cancer (CIN3+; N=31) were compared to women with normal cytology during follow up (non-progressors; N=39). Quantitative real-time PCR for HPV16E6, E2 and IFNb1 was done to determine the HPV16 viral load and the E2/E6 ratio was used as a surrogate marker for integration. Women with normal cytology who became persistently HPV16 infected had a significantly lower HPV16 load at baseline than women who cleared the infection (median 4.72 copies/cell versus median 20.0 copies/cell, respectively; p=0.0003). There was no difference in viral load at enrollment between women who progressed to CIN3+ and women who stayed cytologically normal (p=0.85). At the second examination viral load tended to be higher in women who progressed, but the difference was not statistically significant (p=0.39). The E2/E6 ratio was shown to be lower in the persistently infected group (p<0.0001) already at the first examination, but no difference between non-progressors and CIN3+ cases was observed at any of the two examinations (p=0.61 and 0.86). Lower viral load and integration of the viral genome are predictive for the persistence of HPV16 DNA, but not for the progression of a persistent HPV16 infection to CIN3+ in women with normal cytology. PMID- 22432059 TI - Predicting success or failure of immunotherapy for cancer: insights from a clinically applicable mathematical model. AB - The objective of this study was to create a clinically applicable mathematical model of immunotherapy for cancer and use it to explore differences between successful and unsuccessful treatment scenarios. The simplified predator-prey model includes four lumped parameters: tumor growth rate, g; immune cell killing efficiency, k; immune cell signaling factor, lambda; and immune cell half-life decay, MU. The predator-prey equations as functions of time, t, for normalized tumor cell numbers, y, (the prey) and immunocyte numbers, *, (the predators) are: dy/dt = gy - kx and dx/dt = lambdaxy - MUx. A parameter estimation procedure that capitalizes on available clinical data and the timing of clinically observable phenomena gives mid-range benchmarks for parameters representing the unstable equilibrium case in which the tumor neither grows nor shrinks. Departure from this equilibrium results in oscillations in tumor cell numbers and in many cases complete elimination of the tumor. Several paradoxical phenomena are predicted, including increasing tumor cell numbers prior to a population crash, apparent cure with late recurrence, one or more cycles of tumor growth prior to eventual tumor elimination, and improved tumor killing with initially weaker immune parameters or smaller initial populations of immune cells. The model and the parameter estimation techniques are easily adapted to various human cancers that evoke an immune response. They may help clinicians understand and predict certain strange and unexpected effects in the world of tumor immunity and lead to the design of clinical trials to test improved treatment protocols for patients. PMID- 22432060 TI - Advances in malignant pleural mesothelioma therapy: targeting EphA2 a novel approach. AB - Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with a poor prognosis. MPM grows from the mesothelial cells lining the surface of the lung and chest wall called Pleura. Exposure to asbestos is mainly linked to the development of MPM. Approximately 80% of the tumors are pleural in origin, and up to 3000 people are diagnosed with MPM in the United States annually. The incidence of MPM is expected to rise in the coming decades particularly in the developing countries. Although there is an increase in the awareness of danger associated with the use of asbestos, its use is still prevalent in Australia and Asia because of its durability and low cost. This further warns and adds to the mortality and morbidity of patients with MPM globally. The traditional treatment strategies have shown only modest improvement towards the disease. MPM is difficult to treat because of the fact that the time between the exposure to asbestos and the appearance of symptoms is extremely delayed, and also due to tumor involvement with the pleural surface and the adjoining tissues such as the chest wall, pericardium and sub-diaphragmatic organs. Despite advances in the diagnostic and treatment approaches the median survival rate for MPM is between 9 to 17 months. The standard care with double agent has shown modest improvement however, multimodality approach using novel targets may have potential to achieve the improvement in the survival rate. In this review we give an update on the conventional treatment modalities and discuss about various molecular targets including receptor EphA2, a novel target gene which may be considered as a biomarker for the diagnosis and treatment of MPM. PMID- 22432061 TI - New insights into TRAP1 pathway. AB - Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a mitochondrial heat shock protein involved in the protection from DNA damages and apoptosis induced by oxidants and several other stress conditions. Despite the well characterized role in the regulation of mitochondrial integrity, through the interaction with cyclophilin D, a mitochondrial permeability transition pore regulator, several recent studies contributed to draw a more complex "picture" of the TRAP1 pathway: most of these updated functions arise from the identification of novel specific TRAP1 "client" proteins and from the recent discovery of multiple subcellular localizations/functions for this chaperone. This review briefly highlights some general features of TRAP1, and among others its role in cytoprotection, summarizing many different functions, which contribute to its protective role upon several stress inducers. Of note, particular emphasis is given to the recent findings on the regulation of Endoplasmic Reticulum stress and protein quality control by TRAP1, as well as to its role in regulating calcium homeostasis throughout its client protein Sorcin. Starting from the above observations a preliminary "TRAP1 signature" is provided and a new intriguing and interesting field to explore is discussed. Several questions are still open given the complexity of such mechanisms. However, by translating these recent insights at the molecular and cellular levels into personalized individual anticancer treatments, designing novel strategies based on the simultaneous inhibition of multiple tumor-specific pathways, and contemplating subcellular-targeted approaches aimed at reverting drug resistance and improving antitumor activity the struggle to combat cancer become more successful and closer. PMID- 22432062 TI - Premature transcript termination, trans-splicing and DNA repair: a vicious path to cancer. AB - So far, about 800 different chromosomal translocations have been characterized in hemato-malignant and solid tumors. Chromosomal translocations mostly result in the expression of chimeric fusion proteins associated with enhanced proliferation and/or malignant transformation. Here, we demonstrate that genes frequently involved in such genetic rearrangements exhibit a unique feature: premature transcriptional termination. These early-terminated RNA molecules have an abundance of 10-20% when compared to their cognate full-length transcripts. They exhibit an unsaturated splice donor site that gives rise to trans-splicing events, leading to RNAs displaying exon repetitions or chimeric fusion RNAs. These arbitrary fusion RNAs mimic the presence of a chromosomal translocation in genetically unaffected cells. Based on our and published data, we propose the hypothesis that these artificial "chimeric fusion transcripts" may influence DNA repair processes, resulting in the generation of de novo chromosomal translocations. This idea provides a rational explanation why different individuals suffer from nearly identical genetic rearrangements. PMID- 22432063 TI - Specific chromosomal IG translocations have different prognoses in chronic lymphocytic leukemia. AB - BACKGROUND: Chromosomal translocations are usually analyzed as a single entity, and are associated with a poor outcome in chronic lymphocytic leukemia. Translocations involving immunoglobulin genes are recurrent, but uncommon (<5%), and their individual prognosis is not clear. The two most frequent partners are BCL2 (18q21) and BCL3 (19q13). DESIGNS AND METHODS: Herein, 75 cases are reported of chronic lymphocytic leukemia and t(14;18) (BCL2-CLLs). Our series benefits from morphological, immunological and cytogenetical reviews. The IGHV status analyses were performed by referring laboratories. Comparison was made with our previously published series of chronic lymphocytic leukemia patients with t(14;19) (BCL3-CLLs, n=29). RESULTS: Compared with BCL3-CLLs, lymphocytosis was lower in BCL2-CLLs (p<0.008), and splenomegaly was less frequent (p<0.0001). There were more "typical" morphologies (p<0.005) and Matutes scores >4 (p<0.001) in the BCL2-CLLs group, and less CD38 expression (p<0.04). More variant BCL2 translocations were observed (t(18;22), n=11; 2t(2;18), n=2; p<0.02), and BCL2 translocation was frequently single (p<0.002). Complex karyotypes (p<0.02), trisomy 12 (p<0.03), 6q deletion (p<0.002) and TP53 deletion (p<0.02) were less frequent in BCL2-CLLs, whereas 13q deletion was more frequent (p<0.005). The IGHV gene was frequently mutated in BCL2-CLLs (p<0.0001). Treatment-free survival was longer in BCL2-CLLs (p<0.0001). CONCLUSIONS: BCL2-CLL.S express CD5 and lack expression of CD38, and have a Matutes score >=4, frequent trisomy 12, no ATM and 6q deletions, and a mutated IGHV status. Compared to BCL3-CLLs, BCL2-CLLs are much less aggressive; indicating that identifying individual translocations and cytogenetic partners would allow improved patient stratification. PMID- 22432064 TI - Molecular mechanisms influencing NK cell development: implications for NK cell malignancies. AB - Natural Killer (NK) cells are important effector cells in both the innate and adaptive immune responses. Although they were identified almost 40 years ago, our understanding of how and where NK cells develop is rudimentary. In particular, we have only a limited understanding of the signaling pathways that need to be activated to cause NK cell commitment and maturation. Knowledge of this process is important as disruptions can lead to the development of highly aggressive NK cell malignancies. In this review, we discuss the known molecular mechanisms that trigger NK cell commitment, prompt them to mature and finally allow them to become functional killers. Known disruptions in this developmental process, and how they may contribute to malignancy, are also addressed. PMID- 22432065 TI - The ubiquitin-proteasomal system is critical for multiple myeloma: implications in drug discovery. AB - Bortezomib is a specific inhibitor of proteasomes, the most important protease complexes in protein degradation. Bortezomib can induce apoptosis of a variety of cancer cells, including leukemia, lymphoma, multiple myeloma, breast cancers, prostate cancers, lung cancers, and so on. However, extensive studies and overall evaluation suggested that multiple myeloma is the most sensitive and the best responsive disease which was later approved by Food and Drug Administration for bortezomib treatment. Because proteasomes are an essential component in the ubiquitin-proteasomal protein degradation pathway, the discovery of bortezomib implicates that the UPS is critical for myeloma pathophysiology. The UPS also contains ubiquitin, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin ligases (E3) and deubiquitinases (Dubs). In this review, we examined and analyzed the recent advancements of the UPS components in multiple myeloma and its implications in drug discovery for myeloma treatment. PMID- 22432066 TI - The evolving role of statins in hematopoietic stem and progenitor cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation is the sole curative modality for a variety of malignant and benign hematological disorders. Despite advances in supportive care and transplant conditioning regimens graft-versus-host disease (GVHD), infectious complications and end organ toxicity remain the leading causes of transplant related mortality (TRM). Development of safe and effective strategies to mitigate these significant complications associated with HSCT, are urgently needed. Statins are lipid lowering drugs, which reduce cholesterol production by inhibiting HMG-CoA reductase, with a well defined toxicity profile. Statins have pleiotropic immunomodulatory effects which are relevant in the context of treating and preventing GVHD. In addition to GVHD statins may possess several other effects that might have clinical benefit in the setting of hematopoietic cell transplantation, such as treatment of bronchiolitis obliterans and antineoplastic activity. Herein we review the emerging role of statins in improving the outcomes of patients undergoing HSCT. PMID- 22432067 TI - Mouse models as tools to understand and study BCR-ABL1 diseases. AB - Mouse models of human malignancy have greatly enhanced our understanding of disease pathophysiology and have led to novel therapeutic approaches, some with extraordinary success, one such example being inhibition of the BCR-ABL1 oncogene in chronic myeloid leukaemia (CML). Here, we review aspects of the biology of CML that have been uncovered at least in part through the generation and analysis of retroviral and transgenic mouse models of BCR-ABL1 disease. It can be expected that these models will also serve as important tools in the future, especially in the rational design of strategies to eradicate leukemic stem cells and potentially cure CML as well as other cancers. PMID- 22432069 TI - Hematopoietic stem cell transplantation in China: current status and prospects. AB - During the past four decades, a substantial progress has been made in the field of hematopoietic stem cell transplantation (HSCT). From July, 2007 to December, 2010, a transplant survey from 42 HSCT units indicates that the types of transplantation performed are related identical (43%), related mismatched/haploidentical (28%), unrelated donor matched (11%), unrelated donor mismatched (7%), umbilical cord blood (UCB, 2%) and autologous (9%). The distribution of disease entities being transplanted in allogeneic settings is acute myeloid leukemia (AML) (34%), acute lymphoblastic leukemia(ALL) (24%), chronic myeloid leukemia (CML) (20%), myelodysplastic syndrome (MDS) (8%), aplastic anemia (AA) (7%), Mediterranean anemia (MIA) (2%), non-Hodgkin's lymphoma (NHL) (3%), and other diseases (3%). Clinical data from Peking University Institute of Hematology and other transplant centers suggest that haploidentical transplantation has been a choice of the best alternative source of stem cells for individual patients without matched sibling donors. A modified donor lymphocyte infusion (DLI) approach can be safely used for prophylaxis and treatment of leukemia relapse in patients with advanced leukemia following mismatched transplant. The number of transplants from unrelated donor or related mismatched/haploidentical donor has increased significantly during recent years. Double UCBT is a promising strategy for the therapy of hematological disease. In addition, mesenchymal stem cell (MSC) transplantation may be a potential therapeutic approach for treating systemic lupus erythematosus (SLE). PMID- 22432068 TI - Bone marrow angiogenesis and progression in multiple myeloma. AB - Multiple myeloma plasma cells home and expand in the bone marrow where cause an unbalanced bone remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of patients. A clinically relevant aspect of the interactions of multiple myeloma plasma cells in the bone marrow microenvironment is neovascularization, a constant hallmark of disease progression. This process is only partially supported by factors such as vascular endothelial growth factor, fibroblast growth factor-2 and metalloproteinases, which are directly secreted by the tumor cells. In fact, the presence in the bone marrow microenvironment of cytokines, in particular interleukin-6, as a consequence of plasma cell-stromal cell interactions, induces the production and secretion of angiogenic factors by other cells present in the bone microenvironment, thus contributing to the angiogenic switch during the progression of the disease. Near angiogenesis vasculogenesis occur in the bone marrow of myeloma patients and contribute to the vascular three formation. In the bone marrow of myeloma patients haematopoietic stem cells are recruited and induced to differentiate into endothelial cells by the angiogenic cytokines present in the microenvironment. Myeloma plasma cells also induce angiogenesis indirectly via recruitment and activation of stromal inflammatory cells (i.e.: macrophages and mast cells) to secrete their own angiogenic factors. They are recruited and activated by tumor plasma cells through the secretion of fibroblast growth factor-2, interleukin-8, and other chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells are activated they secrete their angiogenic factors: fibroblast growth factor-2, vascular endothelial growth factor, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, which contribute to enhance the tumor neovascularization. Finally, myeloma macrophages when exposed to vascular endothelial growth factor and fibroblast growth factor-2 secreted by plasma cells shows vasculogenic ability and acquire endothelial cell markers and transform into cells functionally and phenotypically similar to paired bone marrow endothelial cells. So they participate to the formation of the bone marrow capillary network (vasculogenic mimicry). PMID- 22432070 TI - Infectious complications in cord blood and T-cell depleted haploidentical stem cell transplantation. AB - Infections due to post transplant immune deficiency is a major problem following allogeneic stem cell transplantation, particularly in patients receiving cord blood or T-cell depleted haploidentical transplants. We evaluated the incidence and type of infectious complications that occurred in these two types of transplant for 65 patients, 37 cord blood and 28 haploidentical, who received the same conditioning regimen: fludarabine, melphalan and thiotepa. While incidence of infections appeared similar in both types of transplant, viral infections were more frequent than bacterial or fungal infections and were the most common cause of death in both groups. Patients in the haploidentical group were 1.7 times (95% CI: 1.1 to 2.5) more likely to have a viral infection (p=0.013). Bacterial, fungal and CMV infections still quite frequent but contributed less to mortality. Pneumonia was the most common clinical syndrome and the number one cause of death in both groups. Both pneumonia and bacteremia occurred within the first 100 days in the majority of HSCT patients while CBT patients had a bimodal distribution, with more than one third of episodes after 6 months post transplant. PMID- 22432071 TI - American Journal of Blood Research: Editorial Board (2011) e-Century Publishing Corporation. PMID- 22432072 TI - Launching of american journal of blood research. PMID- 22432073 TI - Visualization of immune response kinetics in full allogeneic chimeras. AB - BACKGROUND: Donor Lymphocyte Infusion (DLI) is a well-recognized tool for augmentation of the anti-leukemia effect after mismatched bone marrow transplantation. Experimental results show, however, that DLI efficacy is strongly dependent on the number of donor hematopoietic cells persisting in recipient after transplantation. It is strong in mixed chimeras and relatively weak in full chimeras (FC) that replace host antigen-presenting cells by donor antigen-presenting cells. In this study we applied a new in vivo cytotoxicity monitoring method for evaluation of the changes in FC anti-host immunity after co transplantation of donor and host hematopoietic cells together. METHOD: Full hematopoietic chimeras and naive control mice were transplanted with a mixture of equivalent numbers of donor and recipient or donor and third party splenocytes labeled by a cell-permeable fluorescent dye CFDA-SE. The animals were sacrificed at various time points, and their splenocyte suspensions were prepared, depleted of red blood cells, stained with allophycocyanin-labeled anti-H2(b) antibodies, and analyzed using fluorescence-activated cell sorting. The immune response was assessed according to the percentage of single positive CFDA-SE(+)/ H2(b-) cells of all CFDA-SE(+) cells. RESULTS: FC grafted with splenocytes from similar FC mixed with splenocytes from naive host-type or third-party-type mice rejected host cells within 14 days, and third-party cells within 7 days. NK cell depletion in vivo had no influence on host cell rejection kinetics. Co-infusion of host type splenocytes with splenocytes obtained from naive donor-type mice resulted in significant acceleration of host cell rejection (10 days). Naive mice rejected the same amount of allogeneic lymphocytes within 3 days. CONCLUSIONS: Proposed method provides a simple and sensitive tool to evaluate in vivo post-transplant cytotoxicity in different experimental settings. The method demonstrates that FC is specifically deficient in their ability to reject host lymphocytes even when antigen-presenting host cells are provided. DLI improve anti-host immune response in FC but can not restore it to the level observed in naive donor-type mice. PMID- 22432074 TI - Galectins in hematological malignancies. AB - Carbohydrates are traditionally considered to be an important source of energy for living organisms. In the field of biology, they are defined as organic compounds composed of carbon, hydrogen, and oxygen that are organized into ring structures. The analysis of these structures and their functions has led to a new field of biology called "glycobiology." In the biomedical sciences, glycobiology is rapidly emerging to be an integral part of complex biological processes. Changes in glycan structures and the interactions of these structures with endogenous carbohydrate-binding proteins, known as lectins, are now considered to be potential biomarkers on cancer cells for monitoring tumor progression. Evidence suggesting that the interactions between lectins and their ligands have a major role in the different steps of cancer progression has accumulated at a rapid pace and has gained the attention of several oncologists. This is particularly true for galectin family members because changes in their expression levels correlate with alterations in cancer cell growth, apoptosis, and cell-cell and cell-matrix interactions. Here we provide an integrated view of the role of galectins in hematological malignancies. PMID- 22432075 TI - Progress in myeloma stem cells. AB - Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and affects about 4 in 100,000 Americans. Even though much progress has been made in MM therapy, MM remains an incurable disease for the vast majority of patients. The existence of MM stem cell is considered one of the major causes of MM drug-resistance, leading to relapse. This highlights the importance and urgency of developing approaches to target MM stem cells. However, very little is known about the molecular characteristics of the MM stem cells, which makes it difficult to target MM stem cells therapeutically. Evidence of the existence of a myeloma stem cell has been provided by Matsui et al. showing that the CD138- and CD20+ fraction, which is a minor population of the MM cells, has a greater clonogenic potential and has the phenotype of a memory B-cell (CD19+, CD27+). In this review, we report recent progress of cell surface markers in cancer stem cells, especially in myeloma and the molecular mechanisms related to drug resistance and myeloma disease progression. PMID- 22432076 TI - Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly expresses EBNA3A with conserved CD8 T-cell epitopes. AB - Post-transplantation lymphoproliferative disorders (PTLD) arise in the immunosuppressed and are frequently Epstein-Barr virus (EBV) associated. The most common PTLD histological sub-type is diffuse large B-cell lymphoma (EBV+DLBCL PTLD). Restoration of EBV-specific T-cell immunity can induce EBV+DLBCL-PTLD regression. The most frequent B-cell lymphoma in the immunocompetent is also DLBCL. 'EBV-positive DLBCL of the elderly' (EBV+DLBCL) is a rare but well recognized DLBCL entity that occurs in the overtly immunocompetent, that has an adverse outcome relative to EBV-negative DLBCL. Unlike PTLD (which is classified as viral latency III), literature suggests EBV+DLBCL is typically latency II, i.e. expression is limited to the immuno-subdominant EBNA1, LMP1 and LMP2 EBV proteins. If correct, this would be a major impediment for T-cell immunotherapeutic strategies. Unexpectedly we observed EBV+DLBCL-PTLD and EBV+DLBCL both shared features consistent with type III EBV-latency, including expression of the immuno-dominant EBNA3A protein. Extensive analysis showed frequent polymorphisms in EB-NA1 and LMP1 functionally defined CD8+ T-cell epitope encoding regions, whereas EBNA3A polymorphisms were very rare making this an attractive immunotherapy target. As with EBV+DLBCL-PTLD, the antigen presenting machinery within lymphomatous nodes was intact. EBV+DLBCL express EBNA3A suggesting it is amenable to immunotherapeutic strategies. PMID- 22432077 TI - A review of anemia as a cardiovascular risk factor in patients with myelodysplastic syndromes. AB - BACKGROUND: Anemia is an important cause of morbidity in MDS patients, principally through increased cardiovascular disease. Transfusion status has been seen to be a significant prognostic factor for disease progression and mortality, yet the relationship between anemia levels and cardiovascular disease is not well understood. OBJECTIVE: This study aimed to review the published literature on the effect of anemia on cardiovascular outcomes in patients with MDS. METHODS: A systematic literature review was undertaken to identify studies that investigated the relationship between anemia (as defined by hemoglobin levels) and cardiovascular outcomes in patients with MDS (all subtypes). RESULTS: Three studies were identified that explicitly evaluated the relationship between anemia and cardiovascular outcomes in MDS, and another study reported the relationship between hemoglobin levels and survival. The four studies consistently showed a strong relationship between lower hemoglobin levels and worse cardiovascular outcomes, including cardiac remodeling, congestive heart failure, coronary artery disease, myocardial infarction, arrhythmia, heart valve disease, and cardiovascular mortality. Anemia was seen to be an independent predictor of cardiovascular disease outcomes in patients with MDS, beyond transfusion status and IPSS. CONCLUSION: Based upon a relatively small body of evidence, there appears to be a strong and clinically significant association between anemia and cardiovascular morbidity and mortality in MDS. While further research is needed, clinicians should seek to actively manage hemoglobin levels in MDS patients before the point of transfusion dependency is reached. PMID- 22432078 TI - Use of IGK gene rearrangement analysis for clonality assessment of lymphoid malignancies: a single center experience. AB - Diagnosis of B-non Hodgkin lymphomas (NHLs) is based on clinical, morphological and immunohistochemi-cal features. However, in up to 10-15% of cases, analysis of immunoglobulin heavy (IGH) or light (IGK/IGL) chains genes is required to discriminate between malignant and reactive lymphoid proliferations. In this study, we evaluated the feasibility and efficiency of IGK analysis in the routine diagnostic of B-cell lymphoproliferative disorders (B-LD) when applied to formalin-fixed paraffin-embedded (FFPE) tissues. Clonality patterns were studied in 59 B-LD using the BIOMED-2 protocol for IGK assays, after failure of the IGH assay. PCR products were evaluated by both heterodu-plex and GeneScan analysis. IGK analysis was technically successful in all cases. Overall, it supported the histopa-thological suspicion in 52/59 cases (88%), the sensitivity and specificity being 83% and 80%, respectively. Further, positive and negative predictive values were 95% and 50%, respectively. Interestingly, among various lymphoma subtypes, marginal zone lymphoma and follicular lymphoma most frequently required IGK analysis. In conclusion, IGK study according to the BIOMED-2 protocol resulted feasible and extremely useful in supporting challenging diagnosis of B-LD even if applied on FFPE samples. Accordingly, when NHL is suspected, negative results at IGH analysis should not be considered as conclusive and further investigation of IGK is appropriate. PMID- 22432079 TI - Treatment of FLT3-ITD acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients. PMID- 22432080 TI - Novel treatment paradigm for elderly patients with multiple myeloma. AB - The treatment of multiple myeloma has undergone important changes in the last few years. The use of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, has increased the treatment options available and significantly improved the outcome of this rare disease. Several trials have shown the advantages linked to the use of novel agents both in young patients, who are considered eligible for transplantation, and elderly patients, who are considered transplant ineligible. In the non transplant setting, novel agent-containing regimens have replaced the traditional melphalan-prednisone approach. Preliminary data also support the role of consolidation and maintenance therapy to further improve outcomes. An appropriate management of side effects is fundamental for the success of the treatment, and outcome should always be balanced against the toxicity profile associated with the regimen used. This review provides an overview of the latest strategies including novel agents used to treat elderly patients with multiple myeloma. PMID- 22432081 TI - C-MOPP: the forgotten regimen plus Rituximab for untreated and relapsed follicular lymphoma. AB - C-MOPP is a chemotherapy regimen for the treatment of Non-Hodgkin lymphoma (NHL). Because rituximab improves results in B-cell NHL, we added rituximab to C-MOPP, giving it the term C-MOPP-R. We retrospectively report the results of C-MOPP-R treatment for follicular lymphoma at Saint Louis University Cancer Center from 2000-2009. Treatment response was assessed with fusion PET/CT using International Harmonization Project Criteria and toxicity using National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Thirty-seven patients with follicular lymphoma were treated at our institution with C-MOPP-R. The complete response rate was ninety-four percent and sixty-eight percent in untreated and relapsed patients, respectively. The median progression-free and overall survivals were not reached with median observation time of 34 months. Development of peripheral neuropathy required truncation of planned vincristine dosing in nearly half of patients. We believe that C-MOPP-R results in excellent response rates, progression-free, and overall survival for untreated and relapsed follicular lymphoma and capped vincristine dosing is essential to optimize safety. PMID- 22432082 TI - Vav1 in hematologic neoplasms, a mini review. AB - The Vav family of proteins are guanine nucleotide exchange factors which have been shown to be deregulated in several types of human cancer. There are three members of the Vav family that have been identified which are members of the Dbl domain superfamily and have specificity towards Rho/Rac GTPases. The Vav family plays an important role in normal hematologic system development and homeostasis, and Vav1 is largely restricted to the hematologic system. While Vav1 was originally identified as a proto-oncogene, several recent studies have shown that Vav family deletion leads to the development of T-cell malignancies in mice. In addition, Vav1 has been shown to play a role in the ATRA-mediated differentiation of promyelocytic leukemia cells. In this concise review, the gene structure and normal function of Vav1, as well as a possible role for Vav1 in the development of hematologic and other malignancies is reviewed. PMID- 22432083 TI - Role of high-dose melphalan and autologous peripheral blood stem cell transplantation in AL amyloidosis. AB - AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. The disease is often difficult to recognize because of its broad range of manifestations and, what are often, vague symptoms. Recent diagnostic and prognostic advances include the serum free light chain assay, cardiac magnetic resonance imaging, and serologic cardiac biomarkers. Treatment strategies that have evolved during the past decade are prolonging survival and preserving organ function in patients with this disease. This review outlines the role of high dose melphalan and stem cell transplantation in the treatment of AL amyloidosis. PMID- 22432084 TI - The association of hepatitis B virus infection with B-cell non-Hodgkin lymphoma - a review. AB - Epidemiological studies performed over the last decade have demonstrated a positive association between persistent, hepatitis B surface antigen (HBsAg) positive hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), with HBV-infected patients having a 2-3-fold higher risk to develop NHL than non infected patients. Moreover, there is evidence that also occult HBV infection (HBsAg-negative, HBV DNA-positive) associates with NHL. An association with HBV infection may exist also for other hematological malignancies, but available evidence is much less persuasive than for NHL. In this review article we will discuss available results on the association between HBsAg-positive HBV infection and NHL, as well as the significance of other serological markers of HBV infection in these subjects. We will also discuss the possible etiopathogenic role of HBV, and propose a multifactorial model for lymphomagenesis. Experimental evidence for multifactorial etiopathogenesis has been obtained in recent years for HBV-associated hepatocellular carcinoma (HCC), and we suggest that a similar model may apply to HBV-associated lymphoma as well. Eventually, we will also address some unresolved questions. Two of these are of particular relevance. First, do HBV-positive NHL patients show regression of their hematologic malignancy upon antiviral therapy? A positive answer would represent a direct demonstration of the necessary etiological role of the virus in the development of NHL, as has been shown previously for HCV-associated lymphomas. Second, if HBV plays a necessary role in lymphomagenesis, then expansion of HBV vaccination is expected to reduce the number of incident NHL cases, even though this effect might become evident only after a long time interval. Studies in those countries which have introduced universal HBV vaccination about two decades ago, like Italy, may soon provide results on this important point. PMID- 22432085 TI - Cancer-testis antigens: the current status on antigen regulation and potential clinical use. AB - Immunotherapy is theoretically an attractive therapeutic option for patients with hematological malignancies. Various laboratory studies suggested the importance of the choice of tumor antigen for successful immunotherapy. Cancer-testis antigens (CTAs) are potentially suitable molecules for tumor vaccines of hematological malignancies because of their high immunogenicity in vivo, even in cancer-bearing patients, and their relatively restricted normal tissue distribution. Tumor cell kill using a CTA-based immunotherapy will, therefore, be more specific and associated with less toxicities when compared to chemotherapy. Many CTAs have been identified in various hematologic malignancies. In this review, we will take the readers through the journey of hopes and the disappointments arisen from the discovery of CTAs. We will describe the features of CTAs and their expression in hematologic malignancies. We will also discuss the mechanisms regulating the expression of these CTAs, from a primary regulatory mechanism involving DNA methylation to secondary controls by cytokines. Finally, we will address the potential obstacles that will prevent the successful use of CTAs as targets for tumor immunotherapy. PMID- 22432086 TI - HMGB1 is a therapeutic target for leukemia. AB - High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein, which functions as Damage Associated Molecular Pattern molecule (DAMP) when released from cells under conditions of stress, such as injury and infection. Recent studies indicate that HMGB1 plays an important role in leukemia pathogenesis and chemotherapy resistance. Serum HMGB1 is increased in childhood acute lymphocytic leukemia as compared to healthy control and complete remission groups. Moreover, HMGB1 is a negative regulator of apoptosis in leukemia cells through regulation of Bcl-2 expression and caspase-3 activity. As a positive regulator of autophagy, intracellular HMGB1 interacts with Beclin 1 in leukemia cells leading to autophagosome formation. Additionally, exogenous HMGB1 directly induces autophagy and cell survival in leukemia cells. Experimental strategies that selectively target HMGB1 effectively reverse and prevent chemotherapy resistance in leukemia cells, suggesting that HMGB1 is a novel therapeutic target in leukemia. PMID- 22432087 TI - Platelet-derived growth factors and their receptors in normal and malignant hematopoiesis. AB - Platelet-derived growth factors (PDGF) bind to two closely related receptor tyrosine kinases, PDGF receptor alpha and beta, which are encoded by the PDGFRA and PDGFRB genes. Aberrant activation of PDGF receptors occurs in myeloid malignancies associated with hypereosinophilia, due to chromosomal alterations that produce fusion genes, such as ETV6-PDGFRB or FIP1L1-PDGFRA. Most patients are males and respond to low dose imatinib, which is particularly effective against PDGF receptor kinase activity. Recently, activating point mutations in PDGFRA were also described in hypereosinophilia. In addition, autocrine loops have been identified in large granular lymphocyte leukemia and HTLV-transformed lymphocytes, suggesting new possible indications for tyrosine kinase inhibitor therapy. Although PDGF was initially purified from platelets more than 30 years ago, its physiological role in the hematopoietic system remains unclear. Hematopoietic defects in PDGF-deficient mice have been reported but appear to be secondary to cardiovascular and placental abnormalities. Nevertheless, PDGF acts directly on several hematopoietic cell types in vitro, such as megakaryocytes, platelets, activated macrophages and, possibly, certain lymphocyte subsets and eosinophils. The relevance of these observations for normal human hematopoiesis remains to be established. PMID- 22432088 TI - The role of transcription factors in the guidance of granulopoiesis. AB - In recent years, the prospective isolation of hematopoietic stem and progenitor cells has identified the hierarchical structure of hematopoietic development and lineage-commitment. Moreover, these isolated cell populations allowed the elucitation of the molecular mechansims associated with lineage choice and revealed the indispensable functions of transcription factors as lineage determinants. This review summarizes current concepts regarding adult murine granulopoiesis and illustrates the importance of the transcription factors C/EBPalpha, PU.1 and GATA-2 for the development of neutrophil, eosinophil and basophil granulocytes. PMID- 22432089 TI - High dose methotrexate and extended hours high-flux hemodialysis for the treatment of primary central nervous system lymphoma in a patient with end stage renal disease. AB - This report discusses the case of a 52 year old female with post-transplant lymphoproliferative disorder, confined to the central nervous system, which was managed with high dose methotrexate (HDMTX) in the context of end stage renal disease. The patient received two doses of HDMTX followed by extended hours high flux hemodialysis, plasma methotrexate concentration monitoring and leucovorin rescue. The hemodialysis technique used was effective in clearing plasma methotrexate and allowed delivery of HDMTX to achieve complete remission with limited and reversible direct methotrexate-related toxicity. Dialysis-dependent renal failure does not preclude the use of HDMTX when required for curative therapy of malignancy. PMID- 22432090 TI - Chromosomal instability in in vitro cultured mouse hematopoietic cells associated with oxidative stress. AB - Hematopoietic stem cells (HSCs) that give rise to all blood cell types are important vehicles for cell-based and gene therapies. After isolation from the bone marrow, HSCs are often cultured in laboratory settings for purposes of ex vivo expansion, gene transduction, and bone marrow transplantation for the treatment of various disorders of the blood and immune systems. Here we demonstrate that during in vitro culturing outside of hypoxic bone marrow niches, HSCs may genetically alter even after short durations of time. Lineage(-) Scal 1(+) c-Kit(+) (LSK) cells that are enriched with HSCs revealed significant levels of genomic instability following culture, as evidenced by the emergence of aneuploid cells. To further determine the effects of in vitro culturing conditions, whole bone marrow cells were cultured in a hypoxic environment of 3% oxygen, mimicking conditions within the body's bone marrow, following which, cells proved to undergo less genetic alterations. Proper dosages of the antioxidant N-Acetyl-Cysteine (NAC) similarly decreased occurrences of chromosomal change. Furthermore, analysis of aged hematopoietic cells revealed enhanced in vitro normoxic culture-induced chromosomal instability compared to that of young hematopoietic cells due to noted increased oxidative stress in aged cells. These results reveal that in vitro cell culturing does indeed cause genomic instability in hematopoietic cells. Reduced oxygen to physiological levels and additions of antioxidants can be employed as possible strategies to lower oxidative stress and decrease chances of chromosomal transformation. Because hematopoietic cells are commonly processed in laboratory settings before transplantation for patient treatment, our findings also raise a concern on the therapeutic use of cultured hematopoietic cells. PMID- 22432091 TI - Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo. AB - Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim(-/-) T cells exhibited selective defects in CD69 expression and phosphorylation of PLCgamma1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation. PMID- 22432092 TI - Hydrogen-bonded Multilayers of Silk Fibroin: From Coatings to Cell-mimicking Shaped Microcontainers. AB - We present a novel type of all-aqueous non-ionic layer-by-layer films of silk fibroin with synthetic macromolecules and a natural polyphenol. We found the multilayer growth and stability to be strongly pH-dependent. Silk assembled with poly(methacrylic) and tannic acids at pH=3.5 disintegrated at pH~5; while silk/poly(N-vinylcaprolactam) interactions were stable at low and high pH values but resulting in thinner films at high pH. The results suggest that the intermolecular interactions are primary driven by hydrogen bonding with a considerable contribution of hydrophobic forces. We also demonstrated that cubical, spherical and platelet capsules with silk-containing walls can be constructed using particulate sacrificial templates. This work sets a foundation for future explorations of natural and synthetic macromolecules assemblies as biomimetic materials with tunable properties. PMID- 22432093 TI - [First multicenter epidemiological research using the Latin American Guide for Psychiatric Diagnosis (GLADP) in Argentina]. AB - Classification systems usually employed in clinical investigation as well as for epidemiological purposes present different characteristics. In latinamerican region it has been developed a Guide called Guia Latinoamericana para el Diagnostico de las Enfermedades Mentales (GLADP), originally based on the one proposed by the World Health Organization with several modifications. It has been employed in investigations performed in Mexico and Peru. In this work we inform the epidemiological results obtained by the employment of the GLADP in a sample of 374 patients consulting in public hospitals or mental health services in different regions of Argentina. Most prevalent disorders were anxiety and mood disorders (depressive disorders), psychosis and addictive disorders. Among context factors reported as having impact in mental health status, the more frequently mentioned was the family. 25% of the sample was unemployed. An original characterist of GLADP is the inclusion of qualitative data. By the qualitative interview it became clear a relationship between occupation and education status and quality of life, being more favorable for proffesionals and business men in comparison with people employed by a third party. People with tertiary or secundary studies reported also a better quality of life than people with primary studies. These preliminary data, obtained for the first time by the employment of the GLADP in Argentina should be further confirmed. PMID- 22432094 TI - [Prevalence of and screening for ADHD in Costa Rica]. AB - This research project sought to estimate the prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) and to determine if the Swanson Nolan and Pelham Rating Scale IV (SNAP-IV) Spanish version is a useful screening tool in a population of Costa Rican school children. The SNAP-IV Spanish version was given to the parents and teachers of 425 children aged 5 to 13 (mean 8.8). All subjects were also assessed with the Swanson, Kotkin, Agler, M-Flynn and Pelham Scale (SKAMP), along with diagnostic confirmation by clinical interview. The sensitivity and specificity of the SNAP-IV was assessed as a predictor of DSM-IV ADHD diagnosis. The point prevalence of Attention Deficit Hyperactivity Disorder (ADHD) in this sample was 5%. The prevalence of ADHD among girls was 7%, while that among boys was 4%. The optimal screen was the teacher-rated SNAP-IV at a 20% cutoff, which had a sensitivity of 96% and specificity of 82%. Parent sensitivities were lower than teacher sensitivities. SNAP-IV teacher ratings with a cutoff isolating the top 20% of scores correctly categorized 87% of children. PMID- 22432095 TI - [Quality of life concept evolution: the subjective dimension as a relevant factor on drug addiction]. AB - AIM: to analyze the Quality of Life Concept, is which currently used in drug addiction. We reviewed the studies published until April 2010, using two international databases: PubMed (key words: quality of life, addiction, drug dependence and dual diagnosis) and the Web of Knowledge (search by author). We identified 479 papers on quality of life and drugs abuse, of which were on: quality of life and addictions (433) and quality of life and dual pathology (37). RESULTS: the quality of life concept has evolved, from the forties decade till the present time, remains controversial and still subject to change. Most authors accept the multidimensionality of the quality of life concept, that includes the physical/biological, psychological and social dimension. Currently the patient's satisfaction concept is emerging. On the other hand, it is known that there are discrepancies in the patient's and therapist's view on the patient's quality of life, especially in dually diagnosed patients. CONCLUSIONS: The conceptual study of the quality of life is important. Quality of life components, as the perception of the disease, have been associated with treatment adherence and the disease's progress. For the previous reasons we believe. Quality of Life should be included in the regular evaluation. PMID- 22432096 TI - [Scope and limitations of placebo effect]. AB - The placebo effect is difficult to measure, since any favorable response to placebo may be related to other factors, such as spontaneous remission. There are complementary theories to explain it, such as conditioning and expectancy. In addition, the placebo effect induces neurobiological changes in the brain. However, the most important element is the interaction between doctor and patient. PMID- 22432097 TI - [Consultation-liaison activities in general hospital: strategies to improve their efficacy]. AB - This review is aimed at identifying strategies that favor compliance with the indications provided by a consultation-liaison team (C-L team). A reference is made to the development of consultation liaison as a psychiatry subspecialty to point out reasons that justify its relevance to the General Hospital (GH) setting. Attention is drawn to the few and late referrals to CLT teams despite the high prevalence of mental disorders among medical inpatients. We propose several strategies that could be useful for improving CLT team functioning: a better integration with physicians and personnel from non-psychiatric wards; use of a more comprehensible language; identification of patients whose characteristics make them more likely to be referred to a CLT team; and optimization of the CLT make-up. Lastly, we emphasize the great importance of liaison activities as the essential and paramount function of CL Teams. PMID- 22432098 TI - [History of the publicized "asylum" of Allen, Rio Negro (Argentina)]. PMID- 22432099 TI - [Plato and the physicians and their patients...]. PMID- 22432101 TI - Tattoos and sarcoidosis. PMID- 22432103 TI - Medication regimens. PMID- 22432104 TI - Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). AB - OBJECTIVE: To assess efficacy and safety of lixisenatide monotherapy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Randomized, double-blind, 12-week study of 361 patients not on glucose-lowering therapy (HbA(1c) 7-10%) allocated to one of four once-daily subcutaneous dose increase regimens: lixisenatide 2-step (10 MUg for 1 week, 15 MUg for 1 week, and then 20 MUg; n = 120), lixisenatide 1-step (10 MUg for 2 weeks and then 20 MUg; n = 119), placebo 2-step (n = 61), or placebo 1 step (n = 61) (placebo groups were combined for analyses). Primary end point was HbA(1c) change from baseline to week 12. RESULTS: Once-daily lixisenatide significantly improved HbA(1c) (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: -0.54% for 2-step, -0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA(1c) <7.0% (52.2% 2-step, 46.5% 1-step) and <= 6.5% (31.9% 2-step, 25.4% 1-step) versus placebo (26.8% and 12.5%, respectively; P < 0.01). Lixisenatide led to marked significant improvements of 2-h postprandial glucose levels and blood glucose excursions measured during a standardized breakfast test. A significant decrease in fasting plasma glucose was observed in both lixisenatide groups versus placebo. Mean decreases in body weight (~2 kg) were observed in all groups. The most common adverse events were gastrointestinal-nausea was the most frequent (lixisenatide 23% overall, placebo 4.1%). Symptomatic hypoglycemia occurred in 1.7% of lixisenatide and 1.6% of placebo patients, with no severe episodes. Safety/tolerability was similar for the two dose regimens. CONCLUSIONS: Once daily lixisenatide monotherapy significantly improved glycemic control with a pronounced postprandial effect (75% reduction in glucose excursion) and was safe and well tolerated in type 2 diabetes. PMID- 22432105 TI - Glycemic control over 5 years in 4,900 people with type 2 diabetes: real-world diabetes therapy in a clinical trial cohort. AB - OBJECTIVE: Glycemic control in type 2 diabetes generally worsens over time, requiring intensification of therapy. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial provided the opportunity to observe glycemic control in a real-world setting. We assessed the adequacy of metformin, sulfonylureas, and insulin to maintain glycemic control and their effects on weight. RESEARCH DESIGN AND METHODS: Diabetes control was measured at baseline and yearly for a median of 5 years in the 4,900 patients from the nonintervention arm of this study allocated to placebo. RESULTS: Median HbA(1c) was 6.9% at baseline and increased by an average of 0.22% over 5 years (P < 0.001). Median weight was 86.3 kg at baseline and decreased by 0.4 kg over 5 years (P = 0.002). Baseline therapy was lifestyle measures only in 27%, oral agents without insulin in 59%, and insulin in 14% (7% also taking oral agents). Over 5 years, insulin use increased to 32% (21% also taking oral agents). Use of oral agents remained similar at 56%. Only 2% of patients at baseline and 4% after 5 years were taking oral agents other than metformin or sulfonylureas. Initiation of insulin therapy in 855 patients produced a sustained reduction of HbA(1c) from a median of 8.2 to 7.7%, with a weight gain of 4.6 kg over 5 years. CONCLUSIONS: With intensification of traditional therapies, glycemic control deteriorated very little over 5 years in a large cohort of type 2 diabetes. However, the requirement for insulin therapy doubled, at the expense of significant weight gain and risk of hypoglycemia. PMID- 22432106 TI - Impact of hypoglycemia associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. AB - OBJECTIVE: Hypoglycemia is associated with failure to show cardiovascular benefit and increased mortality of intensive glycemic control in randomized clinical trials. This retrospective cohort study aimed to examine the impact of hypoglycemia on vascular events in clinical practice. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes were identified by ICD-9-CM codes (250.xx except for 250.x1 and 250.x3) between 1 January 2004 and 1 September 2010 from the Veterans Integrated Service Network 16. Index date was defined as the first date of new antihyperglycemic medications (index treatment). Patients with 1-year preindex records of hypoglycemia, cardiovascular, and microvascular diseases were excluded. The hypoglycemia group was identified by ICD-9-CM codes (250.8, 251.0, 251.1, and 251.2) within the index treatment period. A propensity score-matched group was used as control subjects. Cardiovascular events, microvascular complications, and all-cause death were compared using Kaplan-Meier analysis and Cox proportional hazards regression model. RESULTS: Among the unmatched sample (N = 44,261), the hypoglycemia incidence rate was 3.57/100 patient-years. The matched sample (hypoglycemia group: n = 761; control group: n = 761) had a median follow-up of 3.93 years, mean age of 62.6 +/- 11.0 years, and preindex HbA(1c) of 10.69 +/- 2.61%. The 1-year change in HbA(1c) was similar (hypoglycemia group 0.51 vs. control group -0.32%, P = 0.7244). The hypoglycemia group had significantly higher risks of cardiovascular events (hazard ratio 2.00 [95% CI 1.63-2.44]) and microvascular complications (1.76 [1.46-2.11]) but no statistical mortality difference. Patients with at least two hypoglycemic episodes were at higher risks of vascular events than those with one episode (1.53 [1.10-1.66]). CONCLUSIONS: Hypoglycemia is associated with higher risks of incident vascular events. Patients with hypoglycemia should be monitored closely for vascular events. PMID- 22432107 TI - Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes. AB - OBJECTIVE: To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo). RESULTS: Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001). CONCLUSIONS: Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration. PMID- 22432108 TI - Systematic assessment of etiology in adults with a clinical diagnosis of young onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. AB - OBJECTIVE: Misdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines. RESEARCH DESIGN AND METHODS: Individuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 alpha (HNF1A) and hepatocyte nuclear factor 4 alpha (HNF4A) in 20 with residual beta-cell function >= 3 years from diagnosis (random or glucagon-stimulated C-peptide >= 0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed <= 30 years and/or diabetes diagnosed <= 45 years without metabolic syndrome. We also sequenced the glucokinase (GCK) in 40 subjects with mild fasting hyperglycemia. RESULTS: In the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A, two HNF4A, and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA(1c) 8.8 vs. 7.3% at 3 months; P = 0.02). CONCLUSIONS: The systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years' duration are considered for molecular diagnostic analysis. PMID- 22432109 TI - Does diabetes care differ by type of chronic comorbidity?: An evaluation of the Piette and Kerr framework. AB - OBJECTIVE: To evaluate the relationship between diabetes care and types of comorbidity, classified by the degree to which their treatment is concordant with that for diabetes. RESEARCH DESIGN AND METHODS: Retrospective cohort study (fiscal year [FY] 2001 to FY 2004) of 42,826 veterans with new-onset diabetes in FY 2003. Veterans were classified into five chronic comorbid illness groups (CCIGs): none, concordant only, discordant only, both concordant and discordant, and dominant. Five diabetes-related care measures were assessed in FY 2004 (guideline-consistent testing and treatment goals for HbA(1c) and LDL cholesterol and diabetes-related outpatient visits). Analyses included logistic regressions adjusting for age, race, sex, marital status, priority code, and interaction between CCIGs and visit frequency. RESULTS: Only 20% of patients had no comorbidities. Mean number of visits per year ranged from 7.8 (no CCIG) to 17.5 (dominant CCIG). In unadjusted analyses, presence of any illness was associated with equivalent or better care. In the fully adjusted model, we found interaction between CCIG and visit frequency. When visits were <7 per year, the odds of meeting the goal of HbA(1c) <8% were similar in the concordant (odds ratio 0.96 [95% CI 0.83-1.11]) and lower in the discordant (0.90 [0.81-0.99]) groups compared with the no comorbidity group. Among patients with >24 visits per year, these odds were insignificant. Dominant CCIG was associated with substantially reduced care for glycemic control for all visit categories and for lipid management at all but the highest visit category. CONCLUSIONS: Our study indicates that diabetes care varies by types of comorbidity. Concordant illnesses result in similar or better care, regardless of visit frequency. Discordant illnesses are associated with diminished care: an effect that decreases as visit frequency increases. PMID- 22432110 TI - Glycated hemoglobin and risk of hypertension in the atherosclerosis risk in communities study. AB - OBJECTIVE: Diabetes and hypertension often co-occur and share risk factors. Hypertension is known to predict diabetes. However, hyperglycemia also may be independently associated with future development of hypertension. We investigated glycated hemoglobin (HbA(1c)) as a predictor of incident hypertension. RESEARCH DESIGN AND METHODS: We conducted a prospective analysis of 9,603 middle-aged participants in the Atherosclerosis Risk in Communities Study without hypertension at baseline. Using Cox proportional hazards models, we estimated the association between HbA(1c) at baseline and incident hypertension by two definitions 1) self-reported hypertension during a maximum of 18 years of follow up and 2) measured blood pressure or hypertension medication use at clinic visits for a maximum of 9 years of follow-up. RESULTS: We observed 4,800 self-reported and 1,670 visit-based hypertension cases among those without diagnosed diabetes at baseline. Among those with diagnosed diabetes at baseline, we observed 377 self-reported and 119 visit-based hypertension cases. Higher baseline HbA(1c) was associated with an increased risk of hypertension in subjects with and without diabetes. Compared with nondiabetic adults with HbA(1c) <5.7%, HbA(1c) in the prediabetic range (5.7-6.4%) was independently associated with incident self reported hypertension (hazard ratio 1.14 [95% CI 1.06-1.23]) and visit-detected hypertension (1.17 [1.03-1.33]). CONCLUSIONS: We observed that individuals with elevated HbA(1c), even without a prior diabetes diagnosis, are at increased risk of hypertension. HbA(1c) is a known predictor of incident heart disease and stroke. Our results suggest that the association of HbA(1c) with cardiovascular risk may be partially mediated by the development of hypertension. PMID- 22432111 TI - Increasing prevalence of type 2 diabetes in Chinese adults in Shanghai. AB - OBJECTIVE: Our objective was to determine the secular trend in prevalence of type 2 diabetes in Shanghai, China. RESEARCH DESIGN AND METHODS: Two consecutive population-based surveys for type 2 diabetes were conducted in randomly selected adults aged 35-74 years in Shanghai in 2002-2003 (n = 12,329) and in 2009 (n = 7,423). Diagnosed type 2 diabetes was determined based on self-report, whereas those undiagnosed were identified by measured fasting and postload glucose according to 2009 American Diabetes Association criteria. RESULTS: Age standardized prevalence of diagnosed and undiagnosed type 2 diabetes increased from 5.1 and 4.6% in 2002-2003 to 7.4 and 5.2% in 2009. The prevalence of type 2 diabetes increased with age and was higher among men and in urban residents in both surveys (P < 0.001). Between the two surveys, the increase in the prevalence was more evident in the rural population (P < 0.001) and appeared more rapid in younger birth cohorts (P < 0.05). CONCLUSIONS: Our results suggest that Shanghai has experienced an increasing burden of type 2 diabetes. PMID- 22432112 TI - Risk of Parkinson disease onset in patients with diabetes: a 9-year population based cohort study with age and sex stratifications. AB - OBJECTIVE: We retrospectively assessed the age- and sex-specific incidence and relative risk of Parkinson disease (PD) in Taiwan's diabetic population. RESEARCH DESIGN AND METHODS: Study cohort included 603,416 diabetic patients and 472,188 nondiabetic control subjects. Incidence rate and relative risk of PD (ICD-9-CM 332.0) were evaluated. RESULTS: The incidence of PD was 3.59 and 2.15 per 10,000 person-years for the diabetic and control group, respectively, representing a covariate adjusted hazard ratio (HR) of 1.61 (95% CI 1.56-1.66), which was substantially reduced to 1.37 (1.32-1.41) after adjusting for medical visits. Diabetes was associated with a significantly elevated risk of PD in all sex and age stratifications except in young women, with the highest HR noted for young men aged 21-40 years (2.10 [1.01-4.42]), followed by women aged 41-60 (2.05 [1.82 2.30]) and >60 years (1.65 [1.58-1.73]). CONCLUSIONS: Diabetes is associated with an increased risk of PD onset in a Chinese population, and the relation is stronger in women and younger patients. PMID- 22432113 TI - Maternal enterovirus infection as a risk factor for type 1 diabetes in the exposed offspring. AB - OBJECTIVE: Maternal enterovirus infections during pregnancy have been linked to an increased risk of type 1 diabetes in the offspring. The aim of this study was to evaluate this association in a unique series of pregnant mothers whose child progressed to clinical type 1 diabetes. RESEARCH DESIGN AND METHODS: Maternal and in utero enterovirus infections were studied in 171 offspring who presented with type 1 diabetes before the age of 11 years and in 316 control subjects matched for date and place of birth, sex, and HLA-DQ risk alleles for diabetes. Acute enterovirus infections were diagnosed by increases in enterovirus IgG and IgM in samples taken from the mother at the end of the first trimester of pregnancy and cord blood samples taken at delivery. RESULTS: Signs of maternal enterovirus infection were observed in altogether 19.3% of the mothers of affected children and in 12.0% of the mothers of control children (P = 0.038). This difference was seen in different HLA risk groups and in both sexes of the offspring, and it was unrelated to the age of the child at the diagnosis of diabetes or the age of the mother at delivery. CONCLUSIONS: These results suggest that an enterovirus infection during pregnancy is not a major risk factor for type 1 diabetes in childhood but may play a role in some susceptible subjects. PMID- 22432114 TI - Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. AB - OBJECTIVE: To assess the reversibility of the elevation of serum creatinine levels in patients with diabetes after 5 years of continuous on-trial fenofibrate therapy. RESEARCH DESIGN AND METHODS: An on-drug/off-drug ancillary study to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial to investigate posttrial changes in serum creatinine and cystatin C. Eligible participants were recruited into a prospective, nested, three-group study based on retrospective on-trial serum creatinine levels: fenofibrate case subjects (n = 321, >= 20% increase after 3 months of therapy); fenofibrate control subjects (n = 175, <= 2% increase); and placebo control subjects (n = 565). Serum creatinine and cystatin C were measured at trial end and 6-8 weeks after discontinuation of trial therapy. RESULTS At trial end, case subjects had the highest adjusted serum creatinine (+/- SE) mg/dL (1.11 +/- 0.02) and the lowest adjusted estimated glomerular filtration rate (eGFR) (+/- SE) mL/min/1.73 m(2) (68.4 +/- 1.0) versus control subjects (1.01 +/- 0.02; 74.8 +/- 1.3) and placebo subjects (0.98 +/- 0.01; 77.8 +/- 0.7). After 51 days off-drug, serum creatinine in case subjects was still higher (0.97 +/- 0.02) and eGFR still lower (77.8 +/- 1.0) than control subjects (0.90 +/- 0.02; 81.8 +/- 1.3) but not different from placebo subjects (0.99 +/- 0.01; 76.6 +/- 0.7). Changes in serum cystatin C recapitulated the serum creatinine changes. CONCLUSIONS: Participants with significant initial on trial increases in serum creatinine (>= 20%) returned to the same level of renal function as participants receiving placebo while participants who had <= 2% increase in serum creatinine had net preservation of renal function compared with the same unselected placebo reference group. The fenofibrate-associated on-trial increases in serum creatinine were reversible, and the reversal was complete after 51 days off-drug. The similarity of the cystatin C results suggests that the mechanism of this change is not specific for serum creatinine. PMID- 22432115 TI - Insulin requirements in type 1 diabetic pregnancy: do twin pregnant women require twice as much insulin as singleton pregnant women? AB - OBJECTIVE: To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy. RESEARCH DESIGN AND METHODS: At 8, 14, 21, 27, and 33 gestational weeks, insulin requirements and HbA(1c) were compared between 15 twin pregnant women from 2000 to 2011 and 108 singleton pregnant women from 2004 to 2006. RESULTS: In twin pregnancies, the weekly increase in daily insulin dose between 14 and 27 weeks was higher than in singleton pregnancies (median 3.0 international units [IU] [range 0.9-4.9] versus 1.5 IU [-1.5 to 5.9]; P = 0.008) and remained stable from 27 to 33 weeks. The increment in total insulin requirement from before pregnancy until 33 weeks tended to be higher in twin pregnancies (103% [36-257%] versus 71% [-20 to 276%]; P = 0.07). Throughout pregnancy, HbA(1c) was similar in twin and singleton pregnancies. CONCLUSIONS: In twin pregnancies, the weekly increase in insulin dose between 14 and 27 weeks was doubled compared with singleton pregnancies. PMID- 22432116 TI - High burden of kidney disease in youth-onset type 2 diabetes. AB - OBJECTIVE: To evaluate renal outcomes and survival in youth with type 2 diabetes (T2DM) versus type 1 diabetes (T1DM) versus nondiabetic control subjects. RESEARCH DESIGN AND METHODS: In total, 342 prevalent youth (aged 1-18 years) with T2DM, 1,011 youth with T1DM, and 1,710 control subjects identified from 1986 to 2007 were anonymously linked to health care records housed at the Manitoba Centre for Health Policy to assess long-term outcomes using ICD codes. RESULTS: Youth with T2DM were found to have a fourfold increased risk of renal failure versus youth with T1DM. Risk factors associated with renal failure were renin angiotensin aldosterone system inhibitor use and albuminuria in adolescence. Compared with control subjects (age, sex, and postal code matched), youth with T2DM had a 23-fold increased risk of renal failure and a 39-fold increased risk of dialysis. Kaplan-Meier survival at 10 years was 91.4% in the type 2 diabetic group versus 99.5% in the type 1 diabetic group (P < 0.0001). Renal survival was 100% at 10 years in both groups. It decreased to 92.0% at 15 years and 55.0% at 20 years in the type 2 diabetic group but remained stable in the type 1 diabetic group (P < 0.0001). CONCLUSIONS: Youth with T2DM are at high risk of adverse renal outcomes and death. Albuminuria and angiotensin aldosterone system inhibitor use, which may be a marker of severity of disease, are associated with poor outcomes in early adulthood. PMID- 22432117 TI - Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity. AB - OBJECTIVE: Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity. RESEARCH DESIGN AND METHODS: We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S(I)) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [(18)F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S(I) was determined by modified oral glucose tolerance test. RESULTS: Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S(I) was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand. CONCLUSIONS: Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females. PMID- 22432118 TI - Insulin resistance, cystatin C, and mortality among older adults. AB - OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes. RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age >= 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR). RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6-41) and 11% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4-43) and 4% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models. CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship. PMID- 22432119 TI - Predictors of mortality over 8 years in type 2 diabetic patients: Translating Research Into Action for Diabetes (TRIAD). AB - OBJECTIVE: To examine demographic, socioeconomic, and biological risk factors for all-cause, cardiovascular, and noncardiovascular mortality in patients with type 2 diabetes over 8 years and to construct mortality prediction equations. RESEARCH DESIGN AND METHODS: Beginning in 2000, survey and medical record information was obtained from 8,334 participants in Translating Research Into Action for Diabetes (TRIAD), a multicenter prospective observational study of diabetes care in managed care. The National Death Index was searched annually to obtain data on deaths over an 8-year follow-up period (2000-2007). Predictors examined included age, sex, race, education, income, smoking, age at diagnosis of diabetes, duration and treatment of diabetes, BMI, complications, comorbidities, and medication use. RESULTS: There were 1,616 (19%) deaths over the 8-year period. In the most parsimonious equation, the predictors of all-cause mortality included older age, male sex, white race, lower income, smoking, insulin treatment, nephropathy, history of dyslipidemia, higher LDL cholesterol, angina/myocardial infarction/other coronary disease/coronary angioplasty/bypass, congestive heart failure, aspirin, beta-blocker, and diuretic use, and higher Charlson Index. CONCLUSIONS: Risk of death can be predicted in people with type 2 diabetes using simple demographic, socioeconomic, and biological risk factors with fair reliability. Such prediction equations are essential for computer simulation models of diabetes progression and may, with further validation, be useful for patient management. PMID- 22432120 TI - Effect of longitudinal changes in visceral fat area and other anthropometric indices to the changes in metabolic risk factors in Japanese men: the Hitachi Health Study. AB - OBJECTIVE: The effects of longitudinal changes in the visceral fat area (VFA), and other anthropometric indices, on the risk factors of metabolic syndrome were not studied. We calculated the changes in metabolic risk factors in relation to changes in certain anthropometric indices in a large-scale study of Japanese men. RESEARCH DESIGN AND METHODS: The subjects were 1,106 men participating in the Hitachi Health Study who received a computed tomography examination in both 2004 and 2007. VFA, subcutaneous fat area (SFA), and waist circumference were measured using the computed tomography. We examined how longitudinal changes in each anthropometric index over a 3-year period influenced the value of each metabolic risk factor. RESULTS: Changes (Delta) over a 3-year period in body weight, SFA, and waist circumference strongly correlated, while the changes in body weight and VFA were weakly correlated. Changes in the VFA were associated with changes in metabolic risk factors, especially changes in triglyceride and HDL; we found these changes to be independent of the body weight and waist circumference. CONCLUSIONS: Change in body weight is not a precise surrogate marker of VFA, and repeated VFA measurements over time are useful. Adopting a lifestyle that does not increase the VFA is important in preventing metabolic syndrome. PMID- 22432121 TI - Environment: toxic effects. PMID- 22432122 TI - Neuropsychopharmacology of stress. PMID- 22432123 TI - The roles of carbon monoxide and nitric oxide in the control of the neuroendocrine stress response: complementary or redundant. AB - There is widespread evidence in favour of nitric oxide (NO) acting as a gaseous neurotransmitter in the central nervous system, diffusing from its cells of origin and affecting surrounding neuronal tissue in evanescent three-dimensional waves. This is also true of the hypothalamus, where amongst other activities NO inhibits stimulation of corticotrophin-releasing hormone (CRH) and vasopressin release by inflammatory stressors, effects thought to be mediated by binding with soluble guanylate cyclase (sGC). Carbon monoxide is being increasingly recognised as another gaseous neuromodulator, but with principal effects on other hemoproteins such as cyclo-oxygenase, and a distinctly different profile of localisation.NO is predominantly a pro-inflammatory agent in the periphery while CO is often anti-inflammatory. In the hypothalamus, the actions of CO are also distinct from those of NO,with marked antagonistic effects on the inflammatory release of vasopressin, both in vitro and in vivo, but with little involvement in the regulation of CRH. Thus, it would appear that these apparently similar gases exert quite distinct and separate effects, although they cause broadly similar overall changes in the secretion of neuroendocrine stress hormones. We conclude that these two gases may play significant but different roles in the control of the neuroendocrine stress response, but one common feature may be attenuation of inflammation-induced release of stress hormones. PMID- 22432124 TI - Relative importance of nitric oxide and carbon monoxide in regulating the ACTH response to immune and non-immune signals. AB - The present work investigated the effect of nitric oxide (NO) or carbon monoxide (CO) in the ACTH response to an immune signal [the intravenous injection of interleukin-1 beta (IL-1beta)] or to a neurogenic stressor (mild intermittent inescapable foot shocks). The arginine derivative N(omega)-L-arginine methylester (L-NAME), which non-specifically inhibits NO formation induced by all constitutive forms of NO synthase (NOS), significantly augmented the effect of IL 1P,but blockade of CO formation with metalloporphyrins was without effect. On the other hand, L-NAME blunted the effect of shocks on the early phase of ACTH release, while we had reported earlier that metalloporphyrins exerted a similar effect. This effect was mimicked by blockade of neuronal (n) NOS by N(omega) Propyl-L-arginine (PA), although the resulting decrease in hormone levels was less than that induced by L-NAME. These results indicate that endogenous NO, but not CO, interferes with ACTH released by a peripheral immune signal. In contrast, NO formed by nNOS enhances the ability of shocks to induce ACTH secretion. PMID- 22432125 TI - The effect of hypothalamic lesions on hypothalamo-pituitary-adrenal axis activity and inflammation in adjuvant-induced arthritis. AB - Adjuvant-induced arthritis (AA) was induced in control and in hypothalamic lesioned Piebald-Viral-Glaxo (PVG) rats. Following discrete paraventricular nucleus (PVN) lesions plasma corticosterone was increased 14 days after adjuvant injection as in controls, when hind paw inflammation was apparent. PVN lesion did not affect the severity of inflammation.In contrast, following medial basal hypothalamus (MBH) lesions adjuvant did not increase corticosterone levels and the increase in paw volume at day 14 was potentiated. Basal proopiomelanocortin(POMC) mRNA expression in the anterior lobe was unchanged by PVN lesions and decreased by MBH lesions. AA increased POMC mRNA in controls and in both PVN and MBH lesioned rats. After complete MBH lesion, surviving anterior pituitary tissue maintained morning levels of corticosterone.Thus, AA may activate the hypothalamo-pituitary-adrenal axis without the mediation of PVN neurones projecting to the median eminence. However, the loss of the corticosterone response to AA and the increase in severity of inflammation in the MBH lesioned rats suggests a central (non-PVN) component mediates effects of inflammation. Furthermore, the increase in POMC mRNA in the MBH lesioned AA rats suggests that part of this process is not mediated by releasing factors in the hypothalamo-hypophysial portal system, and that extrahypothalamic(peripheral) mediators act on the pituitary during chronic inflammation. PMID- 22432126 TI - Does IL-6 release ACTH by exerting a direct effect in the rat anterior pituitary. AB - Adult male rats were used to determine whether high circulating levels of the pro inflammatory cytokine interleukin-6 (IL-6) were capable of releasing ACTH independently of endogenous corticotropin-releasing factor (CRF). On one hand, CRF antibodies or a potent CRF antagonist significantly decreased, but did not totally abolish the ACTH response to the intravenous(i.v.) injection of recombinant rat IL-6. These results suggest that this cytokine might act either directly on the pituitary, or can release ACTH through mechanisms that do not involve CRF. On the other hand, the CRF antagonist or antibodies significantly (but not totally) blocked ACTH secretion due to the i.v. injection of endotoxin (LPS) while enhancing the ability of this immune stimulus to increase serum IL-6 concentrations. These results indicate that during endotoxemia, even very elevated circulating IL-6 concentrations were notable to release large amounts of ACTH in the absence of CRF drive. These data also illustrate the ability of a CRF antagonist or CRF antibodies to significantly augment IL-6 secretion,which indicates an inhibitory influence of the endogenous peptide in the paradigm we used.As comparable findings were obtained in adrenal-intact and adrenalectomized rats, they suggest that endogenous CRF is involved in the IL-6 response to LPS independently of circulating corticosteroids or other adrenal factors. PMID- 22432127 TI - Stress and inflammatory disease: widening roles for serotonin and substance P. AB - Serotonin has been implicated in mediating the hypothalamo-pituitary-adrenal (HPA) axis response to stress and is an important therapeutic target for a number of psychiatric disorders including depression. The neurokinin substance P has been shown to inhibit stress-induced HPA axis activity and we have demonstrated that endogenous substance P is able to reduce the duration of the HPA axis response to stress suggesting an important role in the termination of the stress response. This may be important in controlling the transition from acute to chronic stress and substance P has recently attracted attention as a potential antidepressant.In addition to these central effects, serotonin and substance P are considered to be pro-inflammatory agents. Despite being implicated in mediating inflammation there have been few studies investigating the effects of manipulations of serotonergic or substance P systems on chronic inflammatory disease. Treatment of rats with adjuvant-induced arthritis(AA), a model of chronic inflammatory stress, with a substance P antagonist specific for the NK1 receptor subtype resulted in a reduction in hind paw inflammation suggesting substance P may influence inflammation. We have noted that depletion of whole body serotonin and selective central depletion of serotonin results in a decrease in the severity of inflammation in rats with adjuvant arthritis. Furthermore, treatment with a selective serotonin reuptake inhibitor results in an earlier onset and increased severity of inflammation in adjuvant arthritis, confirming a pro-inflammatory role for serotonin. Serotonin is also present in the immune tissues and concentrations in the spleen fall following the development of inflammation in adjuvant arthritis. Concentrations of serotonin are significantly higher in normal female spleen than in males, and this may underlie the greater predisposition of females to certain autoimmune diseases.There is increasing evidence of a role for transmitters such as serotonin and substance P,both centrally and peripherally, in mediating a wide variety of inflammatory and psychiatric disorders. A better understanding of the mechanisms of action of these transmitters and the development of suitable drugs targeting specific receptor subtypes has great potential to impact on clinical practice in the near future. The purpose of this review is to consider the separate roles of serotonin and substance P in relation to HPA axis stress responses, in the context of a model of chronic inflammatory disease, highlighting novel directions of current research for each of these transmitters. PMID- 22432128 TI - The effect of stress on inflammation. AB - Stress can either enhance or suppress aspects of the immune response, depending on the nature, duration, timing and intensity of the stressor. This paper focuses on the effects on inflammation of two behavioural stress paradigms: learned helplessness (La) and the open-field test (OF), and of the immunological stressor lipopolysaccharide (LPS). We have observed that the onset and severity of inflammation in adjuvant-induced arthritis (AA) in the rat can be altered by experience of the LH paradigm, or by priming with LPS, but not by OF.In the LH test, some rats escape (LH(-)) and others do not (LH(+)). Despite the LH(-) group demonstrating a greater corticosterone response to the LH stressor compared to the LH(+)rats, they exhibited earlier onset and greater seventy of AA. In contrast, intraperitoneal injection of LPS several weeks prior to induction of AA protected against inflammation. These results provide further evidence that environmental factors influence the etiology of at least one type of inflammation. The modulation of inflammation by a defined stressor suggests that understanding of the underlying mechanisms may provide a potential for novel therapies. PMID- 22432129 TI - The activation of urocortin immunoreactive neurons in the Einger-Westphal nucleus following stress in rats. AB - Urocortin, a member of the corticotropin releasing factor (CRF) peptide family, has a 45%sequence identity to CRF. Urocortin is ten-times more potent than CRF in increasing CAMP in cells expressing the CRF, receptor, therefore it was postulated to be an endogenous ligand for this receptor. Urocortin possesses the biological activity of CRF, and by activating the CRF(2) receptors, it can directly affect autonomic functions and play an important role in modifying the efferent components of endocrine, immune and behavioral responses to stress.Although urocortin's distribution in the rat brain has been described, with the most abundant urocortin-ir perikarya present in the Edinger-Westphal nucleus (E-WN), little is known about the physiological significance of brain urocortin. Since immediate early gene expression is seen in several midbrain regions, such as in the E-WN, following acute stress, we hypothesized that acute pain stress can result in the activation of the urocortinergic neurons in the E WN.Fos immunoreactivity, the protein product of the immediate early gene c-fos, was used as a marker of cellular activity. Double-label immunohistochemical and double label immunofluorescence techniques were used in an acute pain stress model to reveal the colocalization of Fos-immunopositivity with urocortin immunoreactivity (ir) within the E-WN.Our results showed that acute pain stress resulted in the activation of urocortin-ir neurons in the E-WN, peaking at 4 h after acute pain stress, based on the colocalization of Fos-ir with urocortin-ir, and the upregulation of urocortin mRNA transcripts in the E-WN. Based on these results, we suggest that the E-WN is a brain area that shows sustained activation by a painful stressor. PMID- 22432130 TI - Cushing's disease and melancholia. AB - Striking similarities exist in the endocrinology of Cushing's disease and melancholic depression.Laboratory abnormalities, which have been found in both, include raised urinary,plasma and salivary cortisol, non-suppression of cortisol in the dexamethasone suppression test and adrenocorticotrophin (ACTH) hypersecretion. The hypercortisolism can be so severe in melancholic depression that it is difficult to distinguish from Cushing's disease and has been described as a "pseudo-Cushing's" state. Cerebrospinal fluid corticotrophin-releasing hormone (CRH) levels have been found to be lower in patients with Cushing's disease than in depressed subjects. Dynamic endocrine tests may help to distinguish between the two disorders.An exaggerated response to synacthen has been found in both but a reduced ACTH response to CRH occurs in depression, unlike those with Cushing's disease who show ACTH hyper-responsiveness. Other tests, which may help to distinguish between the two disorders,include the dexamethasone-CRH test, the naloxone test, the insulin-induced hypoglycemia test and the desmopressin stimulation test. Similarities in psychiatric symptoms have been recognised for many years. More recently, the physical complications of melancholic depression have been noted. These include osteoporosis, an increased risk of death from cardiovascular disease, hypertension, a redistribution of fat to intra abdominal sites and insulin resistance. Cushing's disease shares these physical complications and we propose that the common underlying factor is excessive plasma glucocorticoids. The increasing recognition of the physical complications and the increased morbidity and mortality in those who suffer from depression underscores the necessity for early detection and treatment of this illness and screening for undetected physical complications. PMID- 22432131 TI - The effect of variability and carryover on average bioequivalence assessment: a simulation study. AB - The purpose of this study was to evaluate the effect of residual variability and carryover on average bioequivalence (ABE) studies performed under a 22 crossover design. ABE is usually assessed by means of the confidence interval inclusion principle. Here, the interval under consideration was the standard 'shortest' interval, which is the mainstream approach in practice. The evaluation was performed by means of a simulation study under different combinations of carryover and residual variability besides of formulation effect and sample size. The evaluation was made in terms of percentage of ABE declaration, coverage and interval precision. As is well known, high levels of variability distort the ABE procedures, particularly its type II error control (i.e. high variabilities make difficult to declare bioequivalence when it holds). The effect of carryover is modulated by variability and is especially disturbing for the type I error control. In the presence of carryover, the risk of erroneously declaring bioequivalence may become high, especially for low variabilities and large sample sizes. We end up with some hints concerning the controversy about pretesting for carryover before performing ABE analysis. PMID- 22432132 TI - Depression and stress: a biopsychosocial exploration of evolved functions and mechanisms. AB - Depression is a common and debilitating disorder linked to social adversity and stress. There have been many theories suggesting possible evolved functions of depression but few have explored evolved defensive mechanisms for coping with stressful events and how these maybe compromised in human depression. This paper will review some of the current evolutionary theories of depression and explore how major depression can arise when evolved defences to cope with adversity (e.g., fight, flight, disengage, submit and help-seeking) are aroused but blocked, arrested or ineffective. Psychosocial stressors can be seen as both activating,but also as arresting, evolved stress-coping defences leading to chronic states of stress with physiological effects on mood. This paper is set in the context of an evolution informed biopsychosocial approach. PMID- 22432133 TI - Fitting E(max) models to clinical trial dose-response data. AB - We consider fitting Emax models to the primary endpoint for a parallel group dose response clinical trial. Such models can be difficult to fit using Maximum Likelihood if the data give little information about the maximum possible response. Consequently, we consider alternative models that can be derived as limiting cases, which can usually be fitted. Furthermore we propose two model selection procedures for choosing between the different models. These model selection procedures are compared with two model selection procedures which have previously been used. In a simulation study we find that the model selection procedure that performs best depends on the underlying true situation. One of the new model selection procedures gives what may be regarded as the most robust of the procedures. PMID- 22432134 TI - Pharmacological suppression of corticosterone secretion in response to a physical stressor does not prevent the delayed persistent increase in circulating basal corticosterone concentration. AB - Elevated basal plasma corticosterone concentrations have been observed for several days after the cessation of severe stress. In the present study, we examined whether or not the acute plasma corticosterone response to stress is necessary to elicit increased basal plasma corticosterone concentrations the following day. Pretreatment with metyrapone (100 m a g , intraperitoneal)1 h before inescapable stress (40 2mA tail shocks delivered over a 1-h period) (IS)blocked the acute plasma corticosterone response to IS. However, elevated basal plasma corticosterone concentrations still emerged the next day. These results suggest that the corticosterone response to stress, and its attendant feedback, are not necessary to produce persistent hypothalamic-pituitary-adrenal axis (HPAA) activation. PMID- 22432135 TI - Delta-sleep inducing peptide (DSIP) and ACTH (4-10) analogue influence fos induction in the limbic structures of the rat brain under emotional stress. AB - The effects of the ACTH (4-10) analogue, ACTH (4-7)-Pro-Gly-Pro, and delta-sleep inducing peptide (DSIP) on the induction of Fos immunoreactivity in the hypothalamic parvocellular paraventricular nucleus (pPVN) and limbic brain regions were studied in Wistar rats with high (resistant) or low (predisposed) resistance to emotional stress, predicted from differences in their open-field behaviour. Fos-immunoreactive (Fos-IR) cells were counted in brain sections automatically with a computer-based image analyser. Under basal conditions, Fos IR cell numbers were greater in the pPVN in the predisposed rats, but were lower than in the resistant rats in the basolateral amygdala and medial and lateral septum. Intraperitoneal DSIP injection (30 MUg/kg) increased basal Fos-IR cell number in the pPVN and lateral septum in resistant rats, with no effects in predisposed rats. ACTH (4-10) analogue (50 MUg/kg)increased Fos expression in the pPVN in both resistant and predisposed rats, with essentially no effects in the basolateral amygdala or medial and lateral septum. Emotional stress (60 min restraint and intermittent subcutaneous electrical shocks) increased Fos expression in the pPVN and medial and lateral septum similarly in predisposed and resistant rats, but in the basolateral amygdala in only the predisposed rats. Intraperitoneal DSIP injection reduced the increases in Fos-IR cell number after emotional stress, particularly in predisposed rats. In predisposed rats DSIP decreased the number of Fos-IR cells in the pPVN and the medial and lateral septum, with no change in the basolateral amygdala. In resistant rats, DSIP decreased Fos expression only in the lateral septum. ACTH (4-10) analogue injection inhibited stress-induced Fos expression in the pPVN and the medial septum, but only in predisposed rats. The experiments indicate that DSIP and ACTH (4-10) analogue reduce pPVN and limbic neurone responses to emotional stress in the rats predisposed to emotional stress; the effects on Fos expression may play a role in the biological activities of these peptides. PMID- 22432136 TI - Links between maternal anxiety or stress and the fetus. PMID- 22432137 TI - Effects of maternal stress on development and behaviour in rat offspring. AB - Retrospective studies suggest that gestational stress in humans can delay the attainment of developmental milestones, increase the incidence of allergic reactions and respiratory infections and cause behavioural abnormalities in the children. Our studies and others have shown that prenatal stress in rats can mimic several of these developmental and behavioural alterations. These include a suppression of immune function, but also enhanced sensitivity to allergens. Prenatally-stressed rats, like children, show a reduced propensity for social interaction and increased anxiety in intimidating or novel situations. They have physiological and behavioural alterations consistent with depressive symptoms, including a phase-shift in their circadian rhythm for corticosterone, sleep abnormalities, and greater acquisition of learned helplessness under appropriate conditions. Prenatally-stressed male rats also show demasculinisation and feminisation of their sexual behaviour. The developmental and behavioural abnormalities in prenatally-stressed offspring may be mediated by alterations in the activity of endogenous opioids or neurosteroids, since several of them can be corrected by maternal administration of an opioid antagonist or by drugs like diazepam and allopregnanolone that modulate GABA transmission. PMID- 22432138 TI - Hormonal and behavioural abnormalities induced by stress in utero: an animal model for depression. AB - Prenatal stress in rats can exert profound influence on the off spring's development, inducing abnormalities such as increased "anxiety", "emotionality" or "depression-like" behaviours.Prenatal stress has long-term effects on the development of the hypothalamo-pituitary-adrenal(HPA) axis and forebrain cholinergic systems. These long-term neuroendocrinological effects are mediated, at least in part, by stress-induced maternal corticosterone increase during pregnancy and stress-induced maternal anxiety during the postnatal period. We have shown a significant phase advance in the circadian rhythms of corticosterone secretion and locomotor activity in prenatally-stressed (PNS) rats. When subjected to an abrupt shift in the light-dark(LD) cycle, PNS rats resynchronized their activity rhythm more slowly than control rats. In view of the data suggesting abnormalities in the circadian timing system in these animals, we have investigated the effects of prenatal stress on the sleep-wake cycle in adult male rats. PNS rats exhibited various changes in sleep-wake parameters, including a dramatic increase in the amount of paradoxical sleep. Taken together, our results indicate that prenatal stress can induce increased responses to stress and abnormal circadian rhythms and sleep in adult rats.Various clinical observations in humans suggest a possible pathophysiological link between depression and disturbances in circadian rhythmicity. Circadian abnormalities in depression can be related to those found in PNS rats. Interestingly, we have recently shown that the increased immobility in the forced swimming test observed in PNS rats can be corrected by chronic treatment with the antidepressant tianeptine, or with melatonin or S23478, a melatonin agonist. Those results reinforce the idea of the usefulness of PNS rats as an appropriate animal model to study human depression and support a new antidepressant-like effect of melatonin and the melatonin agonist S23478. PMID- 22432139 TI - Prenatal stress alters early neurobehavior, stress reactivity and learning in non human primates: a brief review. AB - In this paper we review three prospective longitudinal studies from our laboratory examining the effects of prenatal stress on early neuro behavior, stress reactivity and learning performance in rhesus monkeys. Either a noise stressor or ACTH treatment was administered to pregnant monkeys during specific periods of pregnancy and offspring were examined repeatedly across development. In all three studies, the prenatally stressed monkeys showed reduced attention and impaired neuromotor functioning during the first month of life compared to controls from undisturbed pregnancies. When the monkeys were separated from their mothers or peers at 6-8 months of age, prenatally stressed monkeys exhibited more disturbance behavior and showed hypothalamic-pituitary-adrenal axis dysregulation. During adolescence, they exhibited impairments in learning, compared to controls. PMID- 22432140 TI - Maternal stress in pregnancy and its effect on the human foetus: an overview of research findings. AB - There is evidence from human studies that anxiety or stress during pregnancy can affect birth outcome, causing babies to be born earlier and possibly smaller for gestational age. There is also some suggestive evidence for longer-term behavioural problems. Animal studies indicate that antenatal stress does have a long-term effect on the behaviour of the offspring, including a hyper-responsive hypothalamo-pituitary -adrenal axis. The human foetus can mount an independent stress response from mid-gestation. Two possible mechanisms have been demonstrated by which maternal stress or anxiety may affect the human foetus, the passage of cortisol across the placenta, and an impairment of blood flow through the maternal uterine arteries. PMID- 22432141 TI - Stress and recurrent miscarriage. AB - Our current understanding into the role of stress in unexplained recurrent miscarriages comes from two different research strategies. The majority of research has examined the role of psychological support within this patient population. This support has been provided in a number of ways ranging from weekly interviews with a psychiatrist or gynaecologist and or visual re-assurance in the form of ultrasound scans. A comparison of psychological support with an absence of such intervention has found differences in successful pregnancy outcome varying from as great as 84 versus 26%, respectively. It has been assumed that psychological support reduces the miscarriage rate by reducing "stress"within this patient population. In addition it provides indirect support for a role of stress in the aetiology of unexplained recurrent miscarriage. Other studies have attempted to directly assess the effect of personality characteristics on miscarriage rate; these studies have yielded conflicting results.The mechanism by which stress may be causal in the aetiology of unexplained recurrent miscarriage has not been examined in humans. Animal studies, however, have found that psychological distress can alter immune parameters that may be intricately involved with implantation. These parameters include an elevation of the "abortive" cytokine TNF-a and a reduction in the "anti-abortive" cytokine TGF-P2. Cells that are involved in the release of TNF-a at the feto-maternal interface include T cells, macrophages and mast cells.Mechanisms through which stress may act on these cells are explored and an integrated model is postulated. PMID- 22432142 TI - Stress hormones, human pregnancy and parturition. PMID- 22432143 TI - Placental corticotrophin-releasing hormone, local effects and fetomaternal endocrinology. AB - The human placenta produces corticotrophin-releasing hormone (CRH) in exponentially increasing amounts during pregnancy with peak levels during labour. CRH in human pregnancy appears to be involved in many aspects of pregnancy including placental bloodflow, placental prostaglandin production, myornetrial function, fetal pituitary and adrenal function and the maternal stress axis. Since fetal cortisol levels are associated with pulmonary development and maturity, placental CRH may have an indirect role in fetal development.Although the precise role of placental CRH in the regulation of gestational length and timing of parturition is unclear it appears to be involved in a placental clock. While glucocorticoids inhibit hypothalamic CRH production they stimulate CRH gene expression in the placenta.This difference may allow the fetal and maternal stress axes to influence this placental clock.Maternal CRH levels are elevated in many pathological conditions of pregnancy where fetal well-being is compromised, and in these situations it may act to maintain a stable intrauterine environment. Therefore, CRH appears to link placental function, maternal well-being, fetal well-being and fetal development to the duration of gestation and the timing of parturition. PMID- 22432144 TI - Characterising the corticotropin-releasing hormone (CRH) receptors mediating CRH and urocortin actions during human pregnancy and labour. AB - The mechanism of human labour remains unresolved. One of the most important regulatory signals, however, appears to be corticotropin-releasing hormone (CRH), a hypothalamic peptide that controls the body's response to stress, which is also produced by the placenta and intrauterine tissues during pregnancy. CRH belongs to a family of peptides that includes urocortin, which shares sequence homology with CRH and is also expressed by the placenta and intrauterine tissues. During human pregnancy circulating CRH appears to have five main target tissues: the myometrium, the placenta, the fetal membranes, the fetal adrenal cortex and the vasculature. In these tissues CRH plays a role in the control of myometrial contractility,placenta vasodilation, peptide and prostaglandin production and adrenal steroidogenesis and probably many more, yet unidentified processes. The actions of CRH in these tissues are mediated via specific G-protein coupled membrane-bound receptors. These receptors have different functional characteristics, depending on where they are expressed and on the stage of pregnancy. In addition, their function depends upon other intracellular signals via communication between signalling cascades. These findings led us to propose a hypothesis for a dual role of CRH and other CRH-like peptides during pregnancy and labour. PMID- 22432145 TI - Human placental corticotropin-releasing factor (CRF) in the adaptive response to pregnancy. AB - Several findings suggest a role of placental hormones in the regulation of maternal and fetal physiology during pregnancy. The placenta and its accessory membranes, amnion and chorion, although of fetal origin, actually undertake the role of intermediary barriers and active messengers in the maternal-fetal dialogue. They synthesize, metabolize and serve as targets for numerous hormones and cytokines which control all aspects of pregnancy and parturition. Among these, corticotropin-releasing factor (CRF) has been one of the most investigated in the last decade. The secretion of placental CRF is autonomous, but increasing evidence indicates that maternal or fetal physiological and pathological conditions may influence such secretion. In the event of acute or chronic metabolic, physical or infection stress, the placenta takes part in a stress syndrome by releasing CRF, which may contribute to restore local blood flow, and to influence the timing of delivery. Placental CRF and cytokines produced in case of intrauterine infection may activate labour, thereby helping the fetus to escape from a hostile environment.On the background of maternal and/or fetal stress elicited by a number of pathological conditions, CRF appears to play a role in coordinating adaptive changes in uterine perfusion,maternal metabolism, fluid balance and possibly uterine contractility. PMID- 22432146 TI - Fetal programming of stress responses. AB - Epidemiological studies have shown that small size at birth is associated with an increased risk of coronary heart disease and its risk factors, including hypertension and Type 2 diabetes.It is suggested that these observations linking low birthweight with disease result from an imbalance between fetal nutrient demand and supply. This imbalance results in metabolic and endocrine adaptations, which benefit the fetus in the short term by reducing fetal growth and increasing fuel availability, but in the longer term they are maladaptive leading to an increased risk of coronary heart disease. Experimental data in animals and recent human observations have suggested that alterations in the set point of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system are important long term changes that occur in association with reduced fetal growth. These data suggest that the nature and amplitude of the stress response may be determined by intrauterine factors. PMID- 22432147 TI - The central nucleus of the amygdala; a conduit for modulation of HPA axis responses to an immune challenge? AB - Physical stressors such as infection, inflammation and tissue injury elicit activation of the hypothalamic-pituitary-adrenal (HPA) axis. This response has significant implications for both immune and central nervous system function. Investigations in rats into the neural substrates responsible for HPA axis activation to an immune challenge have predominantly utilized an experimental paradigm involving the acute administration of the pro-inflammatory cytokine interleukin- 1beta (IL-1beta). It is well recognized that medial parvocellular corticotrophin-releasing factor cells of the paraventricular nucleus (mPVN CRF) are critical in generating HPA axis responses to an immune challenge but little is known about how peripheral immune signals can activate and/or modulate the mPVN CRF cells. Studies that have examined the afferent control of the mPVN CRF cell response to systemic IL-1beta have centred largely on the inputs from brainstem catecholamine cells. However, other regulatory neuronal populations also merit attention and one such region is a component of the limbic system, the central nucleus of the amygdala (CeA). A large number of CeA cells are recruited following systemic IL-lbeta administration and there is a significant body of work indicating that the CeA can influence HPA axis function. However, the contribution of the CeA to HPA axis responses to an immune challenge is only just beginning to be addressed. This review examines three aspects of HPA axis control by systemic IL-1beta: (i) whether the CeA has a role in generating HPA axis responses to systemic IL-1beta, (ii) the identity of the neural connections between the CeA and mPVN CRF cells that might be important to HPA axis responses and(iii) the mechanisms by which systemic IL-Ibeta triggers the recruitment of CeA cells. PMID- 22432148 TI - Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala. AB - There is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites,including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking. PMID- 22432149 TI - Acute exposure to a novel stressor further reduces the habituated corticosterone response to restraint in rats. AB - The present study sought to identify dishabituation of the hypothalamic-pituitary adrenal(HPA) axis response to different psychological stressors. Young adult male Sprague Dawley rats were exposed to five, 1 h sessions of restraint stress on five consecutive days. On the sixth day, and 2 h before additional exposure to restraint, animals were subjected to 30 min of a small (27cm square), elevated open field stressor (pedestal), which served as the dishabituating stimulus. We predicted HPA axis response dishabituation in chronically restrained rats exposed to the novel pedestal. Rats which underwent five days of restraint stress showed significantly blunted plasma corticosterone levels to restraint (habituation) as compared to restraint-nai've rats. However, rats which underwent five sessions of restraint responded with an enhanced habituation response when confronted with restraint shortly after exposure to the novel pedestal. Instead of HPA axis response dishabituation, we observed enhanced habituation. Subsequent experiments determined that a 1.25 mgkg corticosterone injection could substitute for pedestal exposure to produce enhanced restraint habituation.Combined treatment with both the glucocorticoid receptor antagonist RU40555 (30 mgkg)and the mineralocorticoid receptor antagonist RU283 18 (50 mgkg) blocked the expression of enhanced habituation after pedestal exposure. Thus, the delayed corticosterone negative feedback produced by novel stress led to enhanced expression of corticosterone response habituation. PMID- 22432150 TI - Neuropeptides and anxiety. PMID- 22432151 TI - US drug shortages could continue for years. PMID- 22432152 TI - India faces growing breast cancer epidemic. PMID- 22432153 TI - Defending democracy and the National Health Service. PMID- 22432155 TI - Poster Abstracts of the 9th Annual BTOG Conference 2011, 26-28 January, 2011, Dublin, Ireland. PMID- 22432154 TI - Letter from the editor. PMID- 22432156 TI - Abstracts of the European Multidisciplinary Conference in Thoracic Oncology (EMCTO), 24-26 February, 2011, Lugano, Switzerland. PMID- 22432157 TI - CdSe magic-sized nuclei, magic-sized nanoclusters and regular nanocrystals: monomer effects on nucleation and growth. AB - Colloidal semiconductor quantum dots (QDs) have been well appreciated for their potential in nanophotonics with an unprecedented impact in various areas, including light emitting diodes (LEDs) and solar cells. There is an outstanding demand on the control of size and size distribution for the various applications, with rational design supported by fundamental understanding of nucleation and growth. This Research News introduces recent advances in the synthesis of colloidal CdSe magic-sized nuclei (MSN) exhibiting sharp bandgap emission, with a model proposed to illustrate the nature of monomers and their degree of supersaturation (DS) affecting the formation of various CdSe MSN, magic-sized nanoclusters (MSCs), and regular nanocrystals (RNCs). Also, this model addresses tuning the CdSe RNCs into the CdSe MSN with the presence of cadmium acetate (Cd(OAc)2) affecting the nature of the monomers. PMID- 22432161 TI - [Follow current guidelines for primary PCI]. PMID- 22432162 TI - [Abstracts of the XXVI National Congress of the Spanish Society for Parenteral and Enteral Nutrition. May 24-27, 2011. Girona, Spain]. PMID- 22432163 TI - "Accepting the group, but not the area": the South African Chinese and the Group Area Act. PMID- 22432164 TI - HIV transmission and sex in Africa: why can't we get it right? PMID- 22432166 TI - A "public health nuisance": the Victoria Street Early Morning Squatters Market, 1910-1934. PMID- 22432167 TI - Dry bones: the return of Nontetha, an Eastern Cape prophet. PMID- 22432170 TI - The voices of women in the South African War. PMID- 22432171 TI - "The military wanted to see a Zulu dance": white history and black anthropology in the Natal narrative, c. 1890-1905. PMID- 22432172 TI - Bone gain and implant stabilization after poor primary and secondary implant. Stability: a report of two cases. PMID- 22432173 TI - Is total-etch dead? Evidence suggests otherwise. AB - Both the total-etch and self-etching systems of today have the potential to provide durable adhesive interface, and despite the proclamations of some, total etch is alive and well. Indeed, evidence indicates that a viable and growing market remains for total-etch adhesive systems. This paper will discuss the origins, evolution, and idiosyncrasies of the total-etch technique as well as its place in dentistry today. New innovations, the use of antimicrobials to inhibit matrix metalloproteinases (MMPs), and sensitivity issues will also be discussed. PMID- 22432174 TI - Considerations for proper selection of dental cements. AB - Selecting the proper cement for sufficient bond strength has become progressively complicated as the number of different materials for indirect restorations has increased. The success of any restoration is highly dependent on the proper cement being chosen and used. The function of the cement is not only to seal the restoration on the tooth but also, in some cases, to support the retention of the restoration. This ability to strengthen retention varies by the cement chosen by the clinician; therefore, careful consideration must precede cement selection. PMID- 22432175 TI - Composite resin: a versatile, multi-purpose restorative material. AB - Introduced more than some 50 years ago, composite resin technology has simplified the manner in which clinicians practice restorative dentistry, offering greater predictability and improved physical properties. Decades of material science and laboratory development along with clinical trials in human subjects have culminated in composite resin being validated as a reliable, multifunctional restorative material. With a wide range of composite resins available today, clinicians can benefit from knowing the infrastructure of a given material in order to determine which type will work best in a particular clinical situation. PMID- 22432176 TI - Zirconia: a proven, durable ceramic for esthetic restorations. AB - In dental ceramics, zirconia has proven to be a durable, reliable framework material capable of inhibiting crack growth and preventing catastrophic failure. Zirconia, which is the oxidized form of zirconium, can exist in several phases, depending on temperature. Used in combination with CAD/CAM technology, zirconia enables the fabrication of esthetic all-ceramic restorations in all areas of the mouth. PMID- 22432177 TI - Chairside CAD/CAM: an overview of restorative material options. AB - A number of categories of materials are available for chairside CAD/CAM restorations that have demonstrated predictability and longevity. These materials include esthetic and high-strength ceramics, composite resins for both final and temporary restorations, and newer nanoceramics that offer ease of handling and a glossy surface finish. Each category of materials has unique features designed for specific clinical applications. This article will examine currently available materials designed for chairside CAD/CAM restorations and the various outcomes that are possible with this technologically advanced process. PMID- 22432178 TI - Provisional materials: key components of interim fixed restorations. AB - Clinicians have many choices of provisional materials from which to choose when fabricating interim fixed restorations. While traditional materials are still in use today, temporary materials are continuously being updated and improved upon. In addition to the functional necessities required of the provisional material, it must also provide esthetic value for the patient. This article provides an overview of provisional materials, including newer bis-acryls that have helped eliminate some of the challenges associated with traditional acrylic materials. Composite resin preformed crowns for single-unit provisional applications are also discussed, along with CAD/CAM-fabricated materials. Regardless of the material selected, a provisional restoration must maintain and protect the underlying tooth structure from ill effects. PMID- 22432179 TI - Current clinical strategies with lithium-disilicate restorations. AB - Ceramics have a rich history in dentistry, playing an integral role in providing high-quality, natural-appearing restorations. From the early days of porcelain jacket crowns to the leucite-reinforced glass ceramics of the 1990s, to new 3rd generation monolithic lithium-disilicate glass-ceramic material, ceramic technologies have evolved and will continue to revolutionize modern-day esthetic dentistry. In this overview article, two cases are presented that illustrate both partial- and full-coverage restorations using lithium-disilicate glass ceramics. PMID- 22432180 TI - Pre-bleaching exam vital for optimum whitening. PMID- 22432181 TI - DenMat's Cerinate One-Hour permanent veneers make porcelain smile makeovers affordable. PMID- 22432182 TI - Listening to customers drives innovation at Ultradent Products, Inc. PMID- 22432183 TI - Materials continue to expand dentistry's options. PMID- 22432184 TI - [Peculiarities of postoperative complications in laparoscopic surgery]. AB - Retrospective analysis of postoperative complications, occurred in patients, to whom laparoscopic interventions were performed in the Department of Laparoscopic Surgery and Cholelithiasis, was conducted. The rate of inflammatory and thromboembolic complications have constituted 2.2 and 0.1%, accordingly. PMID- 22432185 TI - [Vascular risk factors for occurrence of early postoperative complications in patients after pancreaticoduodenal resection]. AB - The results of pancreaticoduodenal resection (PDR), performed in 163 patients in 2006-2010 yrs, are summarized. In 51 (31.3%) patients the complications have occurred. All the patients are alive. The trustworthy connection was established between the rate of the early postoperative complications occurrence and the volume blood flow velocity in a portal vein as well as index of the common hepatic artery resistance before the operation. The indices of regional hemodynamics influence the results of PDR performance. The simultant vascular resection performance do not impact the operative risk level, when compared with such while a standard resection conduction. The risk of the early postoperative complications occurrence is not influenced by the antisecretory therapy regime choosed, using somatostatin analogues. PMID- 22432186 TI - [Impact of abdominoplasty on quality of life in patients, suffering anterior abdominal wall deformity and obesity]. AB - The modern tendencies of surgery development include not only the operative procedures improvement but guaranteeing also a maximally high level achievement in the patients quality of life in the early, as well as during remote, postoperative period. The quality of life analysis was done in 132 patients, operated on for the anterior abdominal wall defects, obesity and other surgical diseases, using special questionnaire SF-36. The patients have aged 23-65 years old, in all of them the excessive body mass or obesity of abdominal type was noted. PMID- 22432187 TI - [Classification of complications of entero- and colostomy]. AB - The authors have proposed the extended classification of enterostomy and colostomy complications, basing on the analysis of Ukrainian and the other world special literature along last 15 years (including internet data bases Medline, PubMed and Google scholar), dedicated to these problem. PMID- 22432188 TI - [Mepenam application for prophylaxis and treatment of purulent complications of an acute destructive pancreatitis]. AB - The experience of meropenem (Mepenam, manufactured by 'Arterium", Ukraine Corporation) application as a measure for conduction of empirical therapy and for prophylaxis of an acute destructive pancreatitis complications, was summarized. Efficacy of the preparation on different stages of the purulent complications treatment (while applied solely as well as in combination with various kinds of miniinvasive and open operative interventions) was estimated. The recommendations, concerning Mepenam application for various forms of an acute pancreatitis, were elaborated. PMID- 22432189 TI - [Right-sided hemihepatectomy in the closed hepatic trauma (clinical observation and review of the literature)]. AB - A case observation of a severe closed hepatic injury, treated using right-sided hemihepatectomy after primary suturing with tamponade performance and angiographic embolization of right hepatic artery, is presented. The literature review for this problem is presented with special attention to modern approaches in the treatment of the injured persons, suffering hepatic trauma. Various methods of treatment of hepatic injuries are analyzed as well as indications for their usage and efficacy. The tactics of conservative treatment in trauma of IV-V severity grade in the injured persons in conditions of a stable hemodynamics state presence was elaborated. The interventional radiology methods are more widely used in the patients, to whom conservative therapy is conducted or while their stable state is achieved, using a tamponade performance. While unstable state presence during the surgical treatment conduction a tendency is observed to use a "damage control" tactics. PMID- 22432190 TI - [An acute postoperative pancreatitis as a complication of a two-staged miniinvasive surgical treatment of nontumoral diseases of biliary system]. AB - The contrast material flowing into the pancreatic duct, electrocoagulation and mechanical lithotripsy application are the most frequent causes of an acute pancreatitis occurrence in the early postoperative period. An acute postoperative pancreatitis (APOP) constitutes frequent and unpredictable complication of the endoscopic transpapillary surgical interventions performance. Taking into account the complexity of the APOP timely diagnosis adjustment it is necessary to create the prognostic algorithm for the effective prophylaxis of this complication occurrence. PMID- 22432191 TI - [Surgical treatment of the patients, suffering alimentary--constitutional obesity]. AB - The results of surgical treatment of 105 patients, suffering alimentary constitutional obesity, using intragastric balloon placement. operative procedures of regulated gastric banding, longitudinal gastric resection, gastric and biliopancreatic shunting, were analyzed. The changes dynamics in the carbohydrate and lipid metabolism indices was estimated. Algorithm of the obesity surgical treatment, depending on the body mass index and concomitant diseases presence, was elaborated. PMID- 22432192 TI - [Analysis of lethality in the injured persons, suffering cranioabdominal trauma]. AB - The now observed enhancement of a human traumatism due to a traffic accidents occurrence demands the measures application, aimed on the improvement of results of the injured persons treatment. With this objective a retrospective analysis of the patients cases charts and of a court-medical expertise protocols was made of 161 injured persons, 69 of whom have died. Cranioabdominal trauma occupies a leading place in a tanatogenesis structure. Delivering of a timely aid to the injured persons in conditionally preventive and preventive lethal outcome constitutes the essential reserve for the treatment results improvement. PMID- 22432193 TI - [Differentiated approach for determination of the patients treatment tactics in focal affection of brain, using stereotaxic methods]. AB - There were analyzed the results of stereotaxic biopsy in 338 patients, using CRW stereotaxic system (Radionics, U.S.A.), performed with the objective for differential diagnosis and treatment conduction in the focal affection of brain (of tumoral and nontumoral etiology). In the recurrent cystic affection of brain there were determined diagnostic informativity and trustworthiness of the cysts stereotaxic aspirationance, the abscesses drainage and the Ommaya reservoir implantation. There was proved the important significance of stereotaxic methods in differential diagnosis and treatment of the brain focal affection. PMID- 22432194 TI - [Surgical treatment of a pectus excavatum deformity]. AB - The results of treatment of 114 patients, suffering pectus excavatum deformity (PED), in 42 of whom Marfan syndrome was diagnosed, were analyzed. Parasternal chondrotomy of a deformed cartilaginous parts of the ribs with subsequent fixation of their sternal ends towards sternum was used for the symmetric correction. The asymmetric PED correction on a convex side was performed similarly and on a concave one a mobilization effect was achieved, using a multiple notches putting on a cartilaginous parts of the deformed ribs. Good result in the treatment of a symmetric PED was achieved in 52 (81.2%) patients and satisfactory one--in 12 (18.7%), and in asymmetric PED--in 31 (62%) and 16 (32%) accordingly, poor result was noted in 3 (6%) patients. A sufficient efficacy of method of the deformity correction was confirmed by the analysis made on the applied surgical treatment results. PMID- 22432195 TI - [The change of some indices of coagulogram in rats in experimental pancreonecrosis under the influence of electromagnet irradiation of extremely high frequencies]. AB - The dynamics of changes of some coagulogram indices under the influence of electromagnet irradiation of extremely high frequencies was studied in rats in conditions of experimental pancreonecrosis. Irradiation of abdominal cavity in animals, using electromagnet irradiation with the 6.5 mm wave length, reduces hypercoagulation shifts essentially and raises the plasm anticoagulant and fibrinolytic activity. PMID- 22432196 TI - [The stem cells application in the complex of treatment in patients, suffering the contractile myocardial function disorder]. PMID- 22432197 TI - [Prophylaxis of a specific type diabetes mellitus development using pancreatic insuli autotranspiantation after pancreatic resection]. PMID- 22432198 TI - [A cross renal ectopy: a symptom of a compelled abdominal compression]. PMID- 22432199 TI - [Laparoscopic pancreatic distal resection for vipoma]. PMID- 22432200 TI - There should be a law. PMID- 22432201 TI - Lateral violence in the workplace: fact or fiction? PMID- 22432202 TI - Prescriptive authority, workplace violence and Campaign 2012. PMID- 22432203 TI - Bullying and the new nurse. PMID- 22432204 TI - Got help? PMID- 22432205 TI - Violence against nurses: curing an epidemic. PMID- 22432206 TI - Bullying? Be smart, don't start. PMID- 22432207 TI - What to do if you are assaulted. PMID- 22432208 TI - Angry people. No act of kindness is ever wasted. PMID- 22432209 TI - The "why" list. Tracking the things that make you go hmmmmm. PMID- 22432210 TI - Priority Calls. Cell phone technology improves emergency medical care in many ways. PMID- 22432211 TI - Assessing the pediatric patient. Observational assessment can substantially decrease the difficulty of pediatric patient assessment. AB - Pediatric patients make up less than 10% of EMS run volume, and only 10% of those require emergent interventions. For the 1 in 100 patients who require more than BLS and a safe ride to the hospital, the most valuable clues to the child's condition can be obtained from 10 feet away. Most children, even the sickest ones, can be effectively treated with BLS airway management and intraosseous infusion if emergent fluid replacement is necessary. PMID- 22432212 TI - Meet the EMS myth buster. Q&A with Bryan Bledsoe on the need for evidence to trump tradition in EMS. Interview by Jenifer Goodwin. PMID- 22432213 TI - Ending ambulance diversion. Eighteen hospitals in King County, Wash., work toward a perpetual zero-divert status. PMID- 22432214 TI - Seeking shift work solutions. Shift work can harm sleep, and sleep loss can lead to fatigue and errors--how is that impacting you and your patients? PMID- 22432215 TI - Gastrointestinal bleeding. Understanding the different causes of GI bleeding will help you perform a thorough patient assessment and provide accurate care. AB - Sarah and Michael were able to obtain their patient's blood pressure and heart rate while she was lying in bed as her blood pressure changed from 110/84 to 92/60 and her heart rate increased from 94 to 112 beats per minute. In speaking with her, they learned she was trying to break herself of long-standing alcoholism and had not had a drink in over a week. She had been taking aspirin for her "pains all over." They secured her to their cot in a position of comfort and Sarah established an IV, initiated a fluid bolus of normal saline and administered Zofran to control the patient's nausea and vomiting. In the emergency department, the patient was diagnosed with esophageal varices and was taken to the operating room for repair. PMID- 22432216 TI - Electrolyte imbalances. Part 3: Magnesium balance disorders. PMID- 22432217 TI - Transition series: topics for the EMT. Part 2: Assessment of the medical patient. PMID- 22432218 TI - House calls. Temper your brilliance with an understanding of your limitations. PMID- 22432219 TI - Gain control over payment uncertainty. PMID- 22432220 TI - Does staff have skin in the game? If they do, your practice wins. PMID- 22432221 TI - An administrator's dilemma: to cut costs or increase productivity. PMID- 22432222 TI - HHS issues administrative simplification regulations that could save billions of dollars and streamline operations. PMID- 22432223 TI - Team-oriented staff programs pay off. Highlight successes, emphasize team role in patient satisfaction. PMID- 22432224 TI - Cheerleading required: an investment in staff morale. PMID- 22432225 TI - Who says patient safety doesn't pay? PMID- 22432227 TI - Know your data. Know your patient. Registries help practices provide effective, efficient care. PMID- 22432226 TI - Could negative reviews on social media sour your appeal for buyers? PMID- 22432228 TI - New to the scene. Care coordinators play starring roles. PMID- 22432229 TI - The effect of placing sealants after fluoride treatment on bond strength (UT CAT #793). PMID- 22432230 TI - "Oh, for the good old days". PMID- 22432231 TI - Dental implants in the older adult. AB - A need for dental implant treatment in the older population is recognized considering the prevalence of partial and complete edentulism and the positive predictability of implant therapy. Even with a number of barriers to overcome for the older adult seeking implant care, dental implants provide stabilizing support for removable dental appliances and have been shown to be successful in that population. In this paper, we describe quality of life, systemic, surgical, and prosthodontic considerations of this prosthetic treatment along with maintenance challenges. PMID- 22432232 TI - Straws do not cause dry sockets when third molars are extracted. AB - PURPOSE: To provide evidence in contrast to a widely held belief that the dry socket, ie Alveolar Osteitis (AO), is primarily a biological process and not a mechanical disruption or removal of the clot due to suction from utilizing a straw in the postoperative period. PATIENTS AND METHODS: Sixty randomly selected patients had all 4 third molars extracted. One half of the patients were given straws to use with all meals for 2 days after surgery. RESULTS: Two-hundred twenty teeth were extracted. No dry socket occurred in the maxilla, 17 occurred in the mandible; 8 or 15% who had used a straw and 9 or 15% who did not. CONCLUSION: There is no evidence that there is an increased incidence of dry sockets when using a straw in the first 2 days after third molars have been extracted. PMID- 22432233 TI - Intra-oral formication induced by occupational exposure mimicking inhalation abuse. AB - Multiple cases of nail salon workers with occupational exposure to acetone, toluene, and acrylic monomers, namely methyl methacrylate and cyanoacrylates, presented separately to our clinic with similar complaints of factitious gingival stomatitis and formication--an abnormal sensation like ants crawling on or inside the skin. Recognizing oral manifestations resulting from possible toxic chemical exposure is not generally thought to be within the realm of most dental practices, yet to assure appropriate care, dentists must be vigilant and include thorough patient interviews in the diagnostic equation. PMID- 22432234 TI - Oral and maxillofacial pathology. Case of the month. Chemical mucosal burn with purpura. PMID- 22432235 TI - Gentlemen ... start your engines. PMID- 22432236 TI - Avoid the pitfalls of creating a chartless office. AB - As you move towards creating a chartless office, remember to provide enough resources such as time and money to this project. The results of a well designed and maintained digital chartless office are quite obvious. They are far more efficient than a paper office and contribute to a less stressed office environment. PMID- 22432237 TI - What healthy and happy dental teams have in common. PMID- 22432238 TI - [Why does knowledge on rare diseases allow progress in treatments?]. PMID- 22432239 TI - [New therapies for children affected by bone diseases]. AB - Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children. PMID- 22432240 TI - [Pediatric hemato-oncology: from cellular biology to individualized targeted therapies]. AB - Progresses in pediatric oncology over the last decades have been dramatic and allow current cure rates above 80%. There are mainly due to multicentre clinical trials aiming at optimizing chemotherapy protocols as well as local therapies in a stepwise approach. Most of the new anticancer drugs currently in development are based on targeted therapies, directed to specific targets present only in or on tumor cells, like growth factor receptors, mechanisms involved in proliferation, DNA repair, apoptosis, tumor invasion or angiogenesis. Concerning bone marrow transplantation also, new strategic approaches are in advanced development. They aim at reducing treatment induced toxicity and enhancing efficacy at the same time. This short paper would like to point out these new technologies, which should be known by the general practitioner. PMID- 22432241 TI - [Therapeutic trials for Duchenne muscular dystrophy: between hopes and disappointments]. AB - Duchenne muscular dystrophy is an X-linked progressive muscle disease. Since the discovery of the dystrophin gene responsible for the condition, various therapeutic strategies have been elaborated. In this paper we introduce three of them, which are well into clinical trials. The first is based on the ability to read through premature stop codons, the second is based on the technique of exon skipping. Both strategies are examples of "personalized medicines", tailored for specific mutation types. The third approach is a pharmacological one, potentially useful for all Duchenne patients, regardless of their mutation type. These first clinical trials raise many questions for researchers as well as for patients and their families, some of which are discussed. PMID- 22432242 TI - [Therapeutic advances in refractory epilepsies in children]. AB - Epilepsy concerns several thousands of children in Switzerland, and is refractory to classic antiepileptic drugs in an important proportion of cases. This percentage has remained stable, despite a constant production of new antiepileptic molecules. To alleviate this problem, several alternative approaches have been developed these last years. In this article, we present three children who suffer from different forms of pharmacoresistant epilepsy, managed with immunomodulatory or neurosurgical treatments, and we summarize the current knowledge about these therapeutic options. PMID- 22432243 TI - [New therapies in pediatric rheumatology]. AB - Biotherapies are recent treatments, which target molecules implicated in the pathogenesis of inflammatory diseases. In pediatric rheumatology, we use anti-TNF alpha and abatacept in JIA patients with polyarticular involvement, whereas anti IL-6 and anti-IL-1 blockers are efficacious in the systemic form of JIA and other auto-inflammatory conditions. These new treatments have significantly improved the control of articular and systemic inflammation and the prognosis of rheumatic diseases. Their effect and their safety on the long-term need to be assessed on large cohorts of patients. Due to the impact of these chronic illnesses on the young patient and its family, and the required specific knowledge, the care of these children should be provided by a multidisciplinary team linked to a centre of competence. PMID- 22432244 TI - [New treatments of pediatric pulmonary hypertension]. AB - Pulmonary arterial hypertension is a serious condition, with an estimated prevalence of 4 children over a million. Symptoms of this condition are not specific, leading to a potential delay in the diagnosis. Treatment of pediatric pulmonary hypertension is currently based on adult guidelines, using new targeted therapies, separated in 3 main categories: Endothelin receptor antagonists, prostacyclin and analogues, and phosphodiesterase type 5 inhibitors. These therapies improve symptoms and survival, but neither of them can cure the condition. Various new molecules are being currently tested in children or in development, offering hope to further improve the prognosis of pulmonary arterial hypertension. PMID- 22432245 TI - [I have a brown/pigmented spot on my skin]. PMID- 22432246 TI - [Infarcted hearts and their stem cells: continuation]. PMID- 22432247 TI - [Sweets: let's not give in to temptation!]. PMID- 22432248 TI - [When physicians waged war against ovaries (I)]. PMID- 22432249 TI - [Where even the wounded are tortured]. PMID- 22432250 TI - Healthy Eating Index--2005 total and component scores for adults aged 20 and over: National Health and Nutrition Examination Survey, 2003-2004. AB - OBJECTIVE: This report provides Healthy Eating Index-2005 (HEI-2005) scores for adults aged 20 and over, by sex, age groups, race and ethnicity, and level of education in the 2003-2004 National Health and Nutrition Examination Survey (NHANES 2003-2004). METHODS: The analytic sample consisted of 4,448 adults aged 20 and over from NHANES 2003-2004. The Day 1 dietary recall was used to estimate the HEI-2005 scores. Food and nutrient intakes were assessed on a density basis. The population's mean usual HEI-2005 component and total scores were calculated using a population ratio method based on programs written by the U.S. Department of Agriculture's Center for Nutrition Policy and Promotion. A two-tailed t-test was used to test significant differences between sexes, age and race, and ethnic groups and levels of education. Statistical hypotheses were tested at the p < 0.05 level of significance using a t statistic. The t-value at 0.975 with 15 degrees of freedom was 2.131. The Bonferroni method of adjustment was used to adjust the critical value for the family of pairwise comparisons for age, race and ethnicity, and education. RESULTS: Adults were below the maximum standard for all the HEI-2005 component scores except for total grains and meat and beans. Females and the oldest age group were more successful in meeting the Dietary Guidelines for Americans 2005 recommendations for the fruit and vegetable components and discretionary calories, and had a slightly higher overall diet quality score than their counterparts. Adults with more than a high school education more closely complied with the recommendations for many of the components compared with those with less education. No one racial and ethnic group stood out as having the highest HEI-2005 scores across most of the components. CONCLUSIONS: These results demonstrate that adults continue to fall short in meeting the Dietary Guidelines for Americans 2005 recommendations, and that sociodemographic characteristics influence their food choices and overall diet quality. PMID- 22432251 TI - An overview of reclaimed water reuse in China. AB - China is facing severe water problems including scarcity and pollution which are now becoming key factors restricting developments. Creating an alternative water resource and reducing effluent discharges, water reuse has been recognized as an integral part of water and wastewater management scheme in China. The government has launched nationwide efforts to optimize the benefits of utilizing reclaimed water. This article reviewed the water reuse activities in China, including: (1) application history and current status; (2) potentials of reclaimed water reuse; (3) laws, policies and regulations governing reclaimed water reuse; (4) risks associated with reclaimed water reuse; (5) issues in reclaimed water reuse. Reclaimed water in Beijing and Tianjin were given as examples. Suggestions for improving the efficiencies of reusing urban wastewater were advanced. Being the largest user of reclaimed wastewater in the world, China's experience can benefit the development of water reuse in other regions. PMID- 22432252 TI - Effectiveness of vegetation on phosphorus removal from reclaimed water by a subsurface flow wetland in a coastal area. AB - This work was conducted to evaluate the effectiveness and influence factors of vegetation on phosphorus (P) removal from reclaimed water in constructed wetlands. Comparisons were conducted between one pilot scale subsurface flow wetland (P-SSFW) and two demonstration subsurface flow wetlands, which were series-wound and named as first subsurface flow wetland (F-SSFW), and second subsurface flow wetland (S-SSFW), respectively. The three wetlands had the same vegetation and substrate, but different pH values, total dissolved solids (TDS) and P loads. Results showed that the P content in the vegetation shoots of the F SSFW was 2.16 mg/g, while 2.31 mg/g in the S-SSFW and 2.69 mg/g in the P-SSFW. These differences were likely caused by the higher pH and TDS in the reclaimed water. The P content also differed among the tissues of the plant, which were 5.94-6.44 mg/g, 2.20-2.77 mg/g, 1.31-1.46 mg/g and 1.53-1.88 mg/g in the flowers, leaves, stems, and roots, respectively. The greatest discrepancy was observed in the leaves, indicating that the environment of the wetlands had the greatest influence on the leaves. When the total phosphorus (TP) load was lower, the proportion of P removed by vegetation assimilation was 16.17% in the P-SSFW, 12.90% in the F-SSFW and 13.29% in the S-SSFW. However, the relative removal efficiency by vegetation among the three wetlands did not vary greatly from that observed in other studies. Moreover, the influence of pH, TDS and TP load was not as great as the influence of the vegetation species, type of substrate, influent style or climate. PMID- 22432253 TI - Identification of odorous compounds in reclaimed water using FPA combined with sensory GC-MS. AB - Odorous compounds in the influent of a reclaimed water treatment plant (RWTP), consisting of coagulation, sedimentation, continuous micro-filtration (CMF), and chlorination in succession, in a north China city, were identified by combining flavor profile analysis (FPA) with sensory gas chromatograph-mass spectrometry (GC-MS). The sewery/swampy/septic odor with an odor intensity of 6.4 was found to be the major odor group in the RWTP influent, and the existence of well-known odorant including dimethyl disulfide, dimethyl trisulfide, indole and skatole were confirmed using GC-MS. The result of a spiking test showed that the intensity (3.6) of the sewery/swampy/septic odor caused by these four chemicals contributed to over 50% of the odor intensity of the influent. The FPA intensity for sewery/swampy/septic odor in the RWTP effluent was 3.8, showing that the treatment process was not efficient for the removal of odorants, particularly indole and skatole. PMID- 22432254 TI - Sequential use of ultraviolet light and chlorine for reclaimed water disinfection. AB - Several disinfection processes of ultraviolet (UV), chlorine or UV followed by chlorine were investigated in municipal wastewater according to the inactivation of Escherichia coli, Shigella dysenteriae and toxicity formation. The UV inactivation of the tested pathogenic bacteria was not affected by the quality of water. It was found that the inactivated bacteria were obviously reactivated after one day in dark. Fluorescent light irradiation increased the bacteria repair. The increase of UV dosage could cause more damage to bacteria to inhibit bacteria self-repair. No photoreactivation was detected when the UV dose was up to 80 mJ/cm2 for E. coli DH5alpha, and 23 mJ/cm2 for S. dysenteriae. Nevertheless, sequential use of 8 mJ/cm2 of UV and low concentration of chlorine (1.5 mg/L) could effectively inhibit the photoreactivation and inactivate E. coli below the detection limits within seven days. Compared to chlorination alone, the sequential disinfection decreased the genotoxicity of treated wastewater, especially for the sample with high NH3-N concentration. PMID- 22432255 TI - A biological safety evaluation on reclaimed water reused as scenic water using a bioassay battery. AB - An assessment method based on three toxicity tests (algae growth inhibition, daphnia immobilization and larval fish toxicity) was used to screen the biological safety of reclaimed water which was reused as sole replenishment for scenic water system in a park (SOF Park) in northern China. A total of 24 water samples were collected from six sites of water system in the SOF Park in four different seasons. The results indicated that: (1) the reclaimed water directly discharged from a reclamation treatment plant near the SOF Park as influent of park had relatively low biological safety (all samples were ranked as C or D); (2) the biological safety of reclaimed water was improved greatly with the ecological reclamation treatment processes composing of artificial wetland system and followed oxidation pond system; (3) the biological safety of reclaimed water in the main lake of SOF Park kept at a health status during different seasons (all samples were ranked as A); (4) there was some certain correlation (R2 = 0.5737) between the sum of toxicity scores and dissolved organic carbon for the studied water samples. It was concluded that the assessment method was reliable to screen the safety of reclaimed water reused as scenic water, and the reclaimed water with further ecological purification processes such as artificial wetland and oxidation pond system can be safely reused as scenic water in park. PMID- 22432256 TI - Control of membrane fouling during hyperhaline municipal wastewater treatment using a pilot-scale anoxic/aerobic-membrane bioreactor system. AB - Membrane fouling limits the effects of long-term stable operation of membrane bioreactor (MBR). Control of membrane fouling can extend the membrane life and reduce water treatment cost effectively. A pilot scale anoxic/aerobic-membrane bioreactor (A/O-MBR, 40 L/hr) was used to treat the hyperhaline municipal sewage from a processing zone of Tianjin, China. Impact factors including mixed liquid sludge suspension (MLSS), sludge viscosity (micro), microorganisms, extracellular polymeric substances (EPS), aeration intensity and suction/suspended time on membrane fouling and pollution control were studied. The relationships among various factors associated with membrane fouling were analyzed. Results showed that there was a positive correlation among MLSS, sludge viscosity and trans membrane pressure (TMP). Considering water treatment efficiency and stable operation of the membrane module, MLSS of 5 g/L was suggested for the process. There was a same trend among EPS, sludge viscosity and TMP. Numbers and species of microorganisms affected membrane fouling. Either too high or too low aeration intensity was not conducive to membrane fouling control. Aeration intensity of 1.0 m3/hr (gas/water ratio of 25:1) is suggested for the process. A long suction time caused a rapid increase in membrane resistance. However, long suspended time cannot prevent the increase of membrane resistance effectively even though a suspended time was necessary for scale off particles from the membrane surface. The suction/suspended time of 12 min/3 min was selected for the process. The interaction of various environmental factors and operation conditions must be considered synthetically. PMID- 22432257 TI - Effect of viscosity, basicity and organic content of composite flocculant on the decolorization performance and mechanism for reactive dyeing wastewater. AB - A coagulation/flocculation process using the composite flocculant polyaluminum chloride-epichlorohydrin dimethylamine (PAC-EPI-DMA) was employed for the treatment of an anionic azo dye (Reactive Brilliant Red K-2BP dye). The effect of viscosity (eta), basicity (B = [OH]/[Al]) and organic content (W(P)) on the flocculation performance as well as the mechanism of PAC-EPI-DMA flocculant were investigated. The eta was the key factor affecting the dye removal efficiency of PAC-EPI-DMA. PAC-EPI-DMA with an intermediate eta (2400 mPa x sec) gave higher decolorization efficiency by adsorption bridging and charge neutralization due to the co-effect of PAC and EPI-DMA polymers. The W(P) of the composite flocculant was a minor important factor for the flocculation. The adsorption bridging of PAC EPI-DMA with eta of 300 or 4300 mPa x sec played an important role with the increase of W(P), whereas the charge neutralization of them was weaker with the increase of W(P). There was interaction between W(P) and B on the removal of reactive dye. The composite flocculant with intermediate viscosity and organic content was effective for the treatment of reactive dyeing wastewater, which could achieve high reactive dye removal efficiency with low organic dosage. PMID- 22432258 TI - Photoproducts of tetracycline and oxytetracycline involving self-sensitized oxidation in aqueous solutions: effects of Ca2+ and Mg2+. AB - Tetracyclines constitute one of the most important antibiotic families and represent a classic example of phototoxicity. The photoproducts of tetracyclines and their parent compounds have potentially adverse effects on natural ecosystem. In this study, the self-sensitized oxidation products of tetracycline (TC) and oxytetracycline (OTC) were determined and the effects of Ca2+ and Mg2+ on self sensitized degradation were investigated. The Ca2+ and Mg2+ in the natural water sample accounted for enhancement (pH 7.3) and inhibition (pH 9.0) of photodegradation of TC and OTC due to the formation of metal-ions complexes. The formation of Mg2+ complexes was unfavorable for the photodegradation of the tetracyclines at both pH values. In contrast, the Ca2+ complexes facilitated the attack of singlet oxygen (1O2) arising from self-sensitization at pH 7.3 and enhanced TC photodegradation. For the first time, self-sensitized oxidation products of TC and OTC were verified by quenching experiments and detected by LC/ESI-DAD-MS. The products had a nominal mass 14 Da higher than the parent drugs (designated M+14), which resulted from the 1O2 attack of the dimethylamino group on the C-4 atom of the tetracyclines. The presence of Ca2+ and Mg2+ also affected the generation of M+14 due to the formation of metal-ions complexes with TC and OTC. The findings suggest that the metal-ion complexation has significant impact on the self-sensitized oxidation processes and the photoproducts of tetracyclines. PMID- 22432260 TI - Groundwater contamination and natural attenuation capacity at a petroleum spilled facility in Korea. AB - As a remedial option, the natural attenuation capacity of a petroleum contaminated groundwater at a military facility was examined. Hydrogeological conditions, such as high water level, permeable uppermost layer and frequent heavy rainfall, were favorable to natural attenuation at this site. The changes in the concentrations of electron acceptors and donors, as well as the relevant hydrochemical conditions, indicated the occurrence of aerobic respiration, denitrification, iron reduction, manganese reduction and sulfate reduction. The calculated BTEX expressed biodegradation capacity ranged between 20.52 and 33.67 mg/L, which appeared effective for the reduction of the contaminants levels. The contribution of each electron accepting process to the total biodegradation was in the order: denitrification > iron reduction > sulfate reduction > aerobic respiration > manganese reduction. The BTEX and benzene point attenuation rates were 0.0058-0.0064 and 0.0005-0.0032 day(-1), respectively, and the remediation time was 0.7-1.2 and 2.5-30 years, respectively. The BTEX and benzene bulk attenuation rates were 8.69 x 10(-4) and 1.05 x 10(-3) day(-1), respectively, and the remediation times for BTEX and benzene were 7.2 and 17.5 years, respectively. However, most of the natural attenuation occurring in this site can be attributed to dilution and dispersion. Consequently, the biodegradation and natural attenuation capacities were good enough to lower the contaminants levels, but their rates appeared to be insufficient to reach the remediation goal within a reasonable time frame. Therefore, some active remedial measures would be required. PMID- 22432259 TI - Distribution of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in surface water and sediments from Baiyangdian Lake in North China. AB - Persistent organochlorine compounds, including hexachlorocyclohexanes (HCHs), dichlorodiphenyltrichloroethanes (DDTs) and polychlorinated biphenyls (PCBs) were analyzed in surface water and sediments from Baiyangdian Lake, North China. Total concentrations of HCHs, DDTs and PCBs in surface water were in the range of 3.13 10.60, 4.05-20.59 and 19.46-131.62 ng/L, respectively, and total concentrations of HCHs, DDTs and PCBs in sediments were 1.75-5.70, 0.91-6.48 and 5.96-29.61 ng/g dry weight, respectively. Among the groups of HCHs (sum of alpha-HCH, beta-HCH, gamma-HCH and delta-HCH) and DDTs (sum of DDT, DDD and DDE), the predominance of beta-HCH, DDE and DDD in water and sediment samples was clearly observed. This observation suggested that beta-HCH was resistant to biodegradation and the DDTs had been transformed to its metabolites, DDE and DDD. For PCBs, penta-, hexa- and hepta-chlorinated congeners were the most abundant compounds in the both phases. Furthermore, the partitioning of chlorinated compounds between sediment and water was investigated to understand their transport and fates in aquatic ecosystems. The results indicated that average logs of organic carbon-normalized sediment water partition coefficients (logK'(oc)) for OCPs varied between 3.20 and 5.53, and for PCBs, logK'(oc) values ranged from 3.19 to 5.57. The observed logK'(oc) was lower than their equilibrium logK(oc) predicted from linear model, which may be attributed to the solubility enhancement effect of colloidal matter in water phase and the disequilibrium between sediment and water. PMID- 22432261 TI - Eutrophication and algal blooms in channel type reservoirs: a novel enclosure experiment by changing light intensity. AB - To explore eutrophication and algal bloom mechanisms in channel type reservoirs, a novel enclosure experiment was conducted by changing light intensity (LI) in the Daning River of the Three Gorges Reservoir (TGR). Square enclosures (side 5.0 m) were covered on the surface with shading materials of different thickness, and with their bases open to the river. Changes and characteristics of the main eutrophication factors under the same water quality and hydrodynamic conditions but different LI were evaluated. All experimental water samples were neutral and alkalescent, with high nitrogen and phosphate concentrations, low potassium permanganate index, stable water quality, and different LI. At the same water depth, LI decreased with increasing shade material, while dissolved oxygen and water temperature were both stable. The growth peak of phytoplankton was with light of 345-4390 lux underwater or 558-7450 lux above the water surface, and water temperature of 25.6-26.5 degrees C. Algae were observed in all water samples, accounting for 6 phylum and 57 species, with algal density changing frequently. The results showed that significantly strong or weak light was unfavorable for phytoplankton growth and the function together with suitable temperature and LI and ample sunshine encouraged algal blooms under the same water quality and hydrodynamic conditions. Correlation analysis indicated that algae reduced gradually lengthwise along water depth in the same enclosure while pH became high. The power exponent relationship between chlorophyll a (Chl-a) and LI was found by curve fitting, that is Chl-a = K(LI)(n). PMID- 22432262 TI - Historical trends of heavy metal contamination and their sources in lacustrine sediment from Xijiu Lake, Taihu Lake catchment, China. AB - Concentrations of Cd, Cr, Cu, Pb, Zn and Hg in Xijiu Lake sediment from the Taihu Lake catchment, China, were analyzed. Their contamination state was investigated based on the geoaccumulation index and enrichment factors. Statistical analysis was used to differentiate the anthropogenic versus natural sources of heavy metals (HMs), and the anthropogenic accumulation fluxes were calculated to quantify anthropogenic contribution to HMs. The results indicated that the lake sediment had been heavily contaminated by Cd, enrichment of Zn and Hg was at a relatively high level, while that of Cu and Pb was in the lower-to-moderate level and Cr was in the low enrichment level. Sources of Cr in the sediment were mainly from natural inputs, while other metals, especially Cd, were predominantly derived from anthropogenic sources. In the past century, anthropogenic accumulation fluxes of Pb, Zn and Hg increased by 0.1-47.3 mg/(cm2 x yr), 2.4 398.1 mg/(cm2 x yr), and 3.7-110.3 ng/(m2 x yr), respectively, accounting for most inputs of HMs entering the sediment. The contamination state of HMs varied with industrial development of the catchment, which demonstrated that contamination started in the early 20th century, reached the maximal level between the mid-1970s and mid-1990s, and decreased a little after the implementation of constraints on high contamination industries, although the contamination of some HMs, such as Cd, Zn and Hg, is still at high levels. PMID- 22432263 TI - Macroscale and microscale analysis of Anammox in anaerobic rotating biological contactor. AB - Inoculated with conventional anaerobic activated sludge, the Anammox process was successfully developed in an anaerobic rotating biological contactor (AnRBC) fed with a low ratio of C/N synthetic wastewater. Operated in a single point feed mode, the AnRBC removed 92.1% (n = 126) of the influent N at the highest surface load of 12 g/(m2 x day). The biomass increased by 25% and 17.1 g/(m2 x day) of maximum N removal surface load was achieved by elevating flow rate with another feed point. Fluorescence in situ hybridization and polymerase chain reaction analysis indicated that the Anammox genus Candidatus Kuenenia stuttgartiensis dominated the community. Both Anammox and denitrifying activity were detected in biofilm by the application of microelectrodes. In the outer layer of the biofilm (0-2500 microm), nitrite and ammonium consumed simultaneously in a ratio of 1.12/1, revealing the occurrence of Anammox. In the inner layer (> 2500 microm), a decrease of nitrate was caused by denitrification in the absence of nitrite and ammonium. PMID- 22432264 TI - Spatial and temporal distribution of acetochlor in sediments and riparian soils of the Songhua River Basin in northeastern China. AB - The Songhua River Basin is a burgeoning agricultural area in the modern times in China. Particularly in recent years, increasing chemical fertilizers and pesticides have been applied with the development of agricultural production. However, the situation of non-point source pollution (NSP) from agricultural production in this basin is still obscure. In order to solve the problem, the occurrence and distribution of acetochlor in sediments and riparian soils of the Songhua River Basin before rain season and after rain season were investigated. In addition, total organic carbon was analyzed. The result showed that the concentration of acetochlor ranged from 0.47 to 11.76 microg/kg in sediments and 0.03 to 709.37 microg/kg in riparian soils. During the high flow period in 2009, the mean concentration was 4.79 microg/kg in sediments and 0.75 microg/kg in riparian soils, respectively. Similarly, the mean concentration was 2.53 microg/kg in sediments and 61.36 microg/kg in riparian soils, during the average flow period in 2010. There was a significant correlation between the concentration of acetochlor and total organic carbon in surface sediments. Moreover, the distribution of acetochlor in sediments of the Songhua River was significantly correlated to land use and topography of the watershed. The investigated data suggested that the concentration of acetochlor in the Songnen Plain and the Sanjiang Plain was higher than that in the other areas of the basin, and riparian buffering zones in these areas had been destroyed by human activities. The optimal agricultural measures to alleviate the contamination of pesticides should be adopted, including controlling agricultural application of acetochlor and ecological restoration of riparian buffering strips. PMID- 22432265 TI - Evaluation of the infectivity, gene and antigenicity persistence of rotaviruses by free chlorine disinfection. AB - The effects of free chlorine disinfection of tap water and wastewater effluents on the infectivity, gene integrity and surface antigens of rotaviruses were evaluated by a bench-scale chlorine disinfection experiments. Plaque assays, integrated cell culture-quantitative RT-PCR (ICC-RT-qPCR), RT-qPCR, and enzyme linked immunosorbent assays (ELISA), respectively, were used to assess the influence of the disinfectant on virus infectivity as well as genetic and antigenic integrity of simian rotavirus SA11 as a surrogate for human rotaviruses. The ICC-RT-qPCR was able to detect rotaviruses survival from chlorine disinfection at chlorine dose up to 20 mg/L (60 min contact), which suggested a required chlorine dose of 5 folds (from 1 to 5 mg/L) higher than that indicated by the plaque assay to achieve 1.8 log10 reductions in tap water with 60 min exposing. The VP7 gene was more resistant than the infectivity and existed at chlorine dose up to 20 mg/L (60 min contact), while the antigencity was undetectable with chlorine dose more than 5 mg/L (60 min contact). The water quality also impacted the inactivation efficiencies, and rotaviruses have a relatively higher resistant in secondary effluents than in the tap water under the same chlorine disinfection treatments. This study indicated that rotaviruses have a higher infectivity, gene and antigencity resistance to chlorine than that previously indicated by plaque assay only, which seemed to underestimate the resistance of rotaviruses to chlorine and the risk of rotaviruses in environments. Present results also suggested that re-evaluation of resistance of other waterborne viruses after disinfections by more sensitive infectivity detection method (such as ICC-RT-qPCR) may be necessary, to determine the adequate disinfectant doses required for the inactivation of waterborne viruses. PMID- 22432266 TI - Isolation and characterization of facultative mixotrophic ammonia-oxidizing bacteria from constructed wetlands. AB - Autotrophic ammonia-oxidizing bacteria (AOB) have been widely studied in constructed wetlands systems, while mixotrophic AOB have been less thoroughly examined. Heterotrophic bacteria were isolated from wastewater and rhizospheres of macrophytes of constructed wetlands, and then cultivated in a mixotrophic medium containing ammonium and acetic acid. A molecular characterization was accomplished using ITS-PCR amplification, and phylogenetic analysis based on 16S rRNA gene sequences. Results showed the presence of 35 bacteria, among 400 initially heterotrophic isolates, that were able to remove ammonia. These 35 isolates were classified into 10 genetically different groups based on ITS pattern. Then, a collection of 10 isolates were selected because of their relatively high ammonia removal efficiencies (ARE > or = 80%) and their phylogenetic diversity. In conditions of mixotrophy, these strains were shown to be able to grow (increase of optical density OD660 during incubation with assimilation of nitrogen into cellular biomass) and to oxidize ammonia (important ammonia oxidation efficiencies, AOE between 79% and 87%). Among these facultative mixotrophic AOB, four isolates were genetically related to Firmicutes (Bacillus and Exiguobacterium), three isolates were affiliated to Actinobacteria (Arthrobacter) and three other isolates were associated with Proteobacteria (Pseudomonas, Ochrobactrum and Bordetella). PMID- 22432267 TI - Polychlorinated dibenzo-p-dioxins and dibenzofurans in different tissues of the cormorants (Phalacrocorax carbo) from Dongting Lake, China. AB - Tissue distribution provides important information regarding the pharmacokinetic behavior of pollutants and is invaluable when analyzing the risk posed to avian species by the exposure to such kind of pollutants. In this study, concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) were determined in muscle, liver, spleen, kidney, stomach, gall bladder, skin, heart, pancreas, intestine and lung tissue extracts of cormorants collected from Dongting Lake, China. Tissue distribution results showed preferential accumulation of PCDD/Fs in both liver and skin. The total concentration of PCDD/Fs ranged from 421 to 5696 pg/g lipid weight. Octachlorinated dibenzo-p dioxin (OCDD) was the predominant congener in all tissues and contributed between 31% and 82% to all 17 PCDD/Fs in different tissues. The liver/muscle ratios progressively increased with the degree of chlorination of PCDDs, except for OCDD. The relative toxic potential of PCDDs and PCDFs in tissues were calculated using the World Health Organization (WHO) Toxic Equivalency Factors (TEFs) for birds. The concentrations of WHO-toxic equivalent in different tissues ranged between 14.8 and 2021 pg/g lipid weight. These results indicated PCDD/Fs may have been bio-accumulated in cormorant via food-web. Furthermore, when compared with studies reported in the literatures, the PCDD/Fs levels in the cormorant collected from Dongting Lake were still relatively high. PMID- 22432268 TI - Integrated assessment of biochemical responses in Mediterranean crab (Carcinus maenas) collected from Monastir Bay, Tunisia. AB - The biochemical response of Mediteranean Crab (Carcinus maenas) collected at five stations of Monastir Bay and from Kuriat station as control was studied using a set of complementary biomarkers. The catalase, glutathione S-transferase, lactate dehydrogenase, acetycholinesterase activities; and metallothionein and malonediladehyde levels in gills were evaluated. Results revealed differences among sites in relation to each specific biomarker. Hence, a suite of biomarkers can be used to discriminate sampling sites according to types of pollution, reflecting differing conditions of anthropogenic impact. Based on Integrated Biomarker Response, the highest values and critical biochemical alteration were observed at Khniss and Ksibat in response to urban and industrial discharges and the lowest IBR value was found at reference site. The current study has shown clearly that a biomarker-based index is usefulness tool in the monitoring Tunisian coast using C. maenas as sentinel specie. Further studies in progress to investigate the seasonal variations of IBR levels and its relationship to pollutants concentrations in the sediment, gills and digestive gland of Carcinus maenas from Monastir Bay. PMID- 22432269 TI - Toxicological effects involved in risk assessment of rare earth lanthanum on roots of Vicia faba L. seedlings. AB - Combined chemical analyses and biological measurements were utilized to investigate potential toxicological effects and possible mechanisms involved in risk assessment of rare earth elements (REEs) on Vicia faba L. seedlings, which were hydroponically cultivated and exposed to various concentrations of lanthanum (La) for 15 days. The results showed that La contents in both the solution and roots increased with the increase of extraneous La, contributing to hormetic dose responses of superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (GPX), ascorbate peroxidase (APX) and endoprotease (EP) isozymes activities, and HSP 70 production enhanced at low doses but suppressed at higher doses of La. These physiological responses constituted antioxidant and detoxification systems against La-induced oxidative stress. The elevated La levels also contributed to oxidatively modified proteins, which were most responsible for subsequent cell death and growth retardation of the roots. By combination of hormetic and traditional threshold dose levels, the threshold dose range was deduced to be 108 195 microg La/g dry weight in the roots, corresponding to 0.90-3.12 mg/L of soluble La in the culture solution. It suggests that persistent applications of REEs may lead to potential ecological risk in the environment. PMID- 22432270 TI - Simultaneous determination of three classes of antibiotics in the suspended solids of swine wastewater by ultrasonic extraction, solid-phase extraction and liquid chromatography-mass spectrometry. AB - This work describes a systematic approach to the development of a method for simultaneous determination of three classes of veterinary antibiotics in the suspended solids (SS) of swine wastewater, including five sulfonamides, three tetracyclines and one macrolide (tiamulin). The entire procedures for sample pretreatment, ultrasonic extraction (USE), solid-phase extraction (SPE), and liquid chromatography-mass spectrometry (LC-MS) quantification were examined and optimized. The recovery efficiencies were found to be 76%-104% for sulfonamides, 81%-112% for tetracyclines, and 51%-64% for tiamulin at three spiking levels. The intra-day and inter-day precisions, as expressed by the relative standard deviation (RSD), were below 17%. The method detection limits (MDLs) were between 0.14 and 7.14 microg/kg, depending on a specific antibiotic studied. The developed method was applied to field samples collected from three concentrated swine feeding plants located in Beijing, Shanghai and Shandong province of China. All the investigated antibiotics were detected in both SS and liquid phase of swine wastewater, with partition coefficients (logK(d)) ranging from 0.49 to 2.30. This study demonstrates that the SS can not be ignored when determining the concentrations of antibiotics in swine wastewater. PMID- 22432271 TI - Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology. AB - To more reasonably evaluate human intake of PBDEs via dust ingestion, bioaccessibility should be taken into account. Previously, we developed an in vitro method to determine the bioaccessibility of PBDEs in food. Here, this method was adapted to determine the bioaccessibility of PBDEs in dust and the digestion conditions that influenced the bioaccessibility of PBDEs were optimized. The digestion conditions included the incubation time of dust in the intestinal digestion solution (T), the bile concentration in the intestinal digestion solution (C(bile)), and the ratio of the volume of the intestinal digestion solution to dust (R). The influence of the concentrations of individual PBDE congeners (C(PBDE)) on the bioaccessibility of PBDEs was also investigated. Central composite design was used to build an experimental model and set experimental parameters, and response surface methodology was used to analyze the obtained data. The results showed that the bioaccessibility of PBDEs increased with the increases of C(bile) and R, and was independent of T and C(PBDE). Under the digestion conditions with C(bile) and R being at 4.0-7.0 g/L and 150-250, respectively, the bioaccessibility of PBDEs in the method-dust varied from 39.2% to 72.8%, which were comparable with the bioaccessibility or bioavailability of PBDEs in dust/soil in the literature. Thus, the in vitro method to measure the bioaccessibility of PBDEs in dust was established and validated. Finally, the bioaccessibility of PBDEs in four natural dust samples, which ranged from 36.1% to 43.3%, were determined using the adapted method. PMID- 22432272 TI - Biological treatment of chicken feather waste for improved biogas production. AB - A two-stage system was developed which combines the biological degradation of keratin-rich waste with the production of biogas. Chicken feather waste was treated biologically with a recombinant Bacillus megaterium strain showing keratinase activity prior to biogas production. Chopped, autoclaved chicken feathers (4%, W/V) were completely degraded, resulting in a yellowish fermentation broth with a level of 0.51 mg/mL soluble proteins after 8 days of cultivation of the recombinant strain. During the subsequent anaerobic batch digestion experiments, methane production of 0.35 Nm3/kg dry feathers (i.e., 0.4 Nm3/kg volatile solids of feathers), corresponding to 80% of the theoretical value on proteins, was achieved from the feather hydrolyzates, independently of the pre-hydrolysis time period of 1, 2 or 8 days. Cultivation with a native keratinase producing strain, Bacillus licheniformis resulted in only 0.25 mg/mL soluble proteins in the feather hydrolyzate, which then was digested achieving a maximum accumulated methane production of 0.31 Nm3/kg dry feathers. Feather hydrolyzates treated with the wild type B. megaterium produced 0.21 Nm3 CH4/kg dry feathers as maximum yield. PMID- 22432273 TI - Effect of C/N ratio, aeration rate and moisture content on ammonia and greenhouse gas emission during the composting. AB - Gaseous emission (N2O, CH4 and NH3) from composting can be an important source of anthropogenic greenhouse gas and air pollution. A laboratory scale orthogonal experiment was conducted to estimate the effects of C/N ratio, aeration rate and initial moisture content on gaseous emission during the composting of pig faeces from Chinese Ganqinfen system. The results showed that about 23.9% to 45.6% of total organic carbon (TOC) was lost in the form of CO2 and 0.8% to 7.5% of TOC emitted as CH4. Most of the nitrogen was lost in the form of NH3, which account for 9.6% to 32.4% of initial nitrogen. N2O was also an important way of nitrogen losses and 1.5% to 7.3% of initial total nitrogen was lost as it. Statistic analysis showed that the aeration rate is the most important factor which could affect the NH3 (p = 0.0189), CH4 (p = 0.0113) and N2O (p = 0.0493) emissions significantly. Higher aeration rates reduce the CH4 emission but increase the NH3 and N2O losses. C/N ratio could affect the NH3 (p = 0.0442) and CH4 (p = 0.0246) emissions significantly, but not the N2O. Lower C/N ratio caused higher NH3 and CH4 emissions. The initial moisture content can not influence the gaseous emission significantly. Most treatments were matured after 37 days, except a trial with high moisture content and a low C/N ratio. PMID- 22432274 TI - Electromagnetic irradiation exposure and its bioindication--an overview. AB - Man made electromagnetic irradiation and fields cover now the globe due to the recent extensive propagation of mobile telephony. The increased load affects animals and also plants. Especially birds have been studied. Humans are also sensitive. They are good bioindicators as epidemiological methods are available. Humans can also report symptoms which cannot be directly measured with presently available technologies. The nonionizing irradiation can as the ionizing one break the DNA, damage proteins, even increase the blood brain barrier permeability, disturb the night rest, cause fatigue and hormonal disturbances. An increase of the tumours of human head has been described in correlation with the long-term mobile phone use and on that side more exposed. The regulations covering mobile telephony are already about two decades old and need re-evaluation. The multitude of irradiation and the interaction of the different wavelength exposures, i.e., frequency sensitivity is poorly known at present. We should not forget the comparative studies of different species especially those which rely in their lives on electromagnetic orientation physiology. Some countries have issued warnings on the exposures of children. The producers of mobile technology have recently warned the users not to keep those devices in active stage in skin contact. PMID- 22432275 TI - Millennial mercury records derived from ornithogenic sediment on Dongdao Island, South China Sea. AB - Two ornithogenic sediment cores, which have a time span of 1000 years and are influenced by red-footed booby (Sula sula), were collected from Dongdao Islands, South China Sea. The determined mercury concentrations of the two cores show similar and substantial fluctuations during the past millennium, and the fluctuations are most likely caused by the changes in mercury level of the ocean environment and in anthropogenic Hg emission. For the past 500 years, the mercury concentration in the red-footed booby excrement has a striking association with global anthropogenic mercury emission. The mercury concentration increased rapidly after AD 1600 in corresponding to beginning of the unparalleled gold and silver mining in South Central America that left a large volume of anthropogenic mercury pollution. Since the Industrial Revolution, the mercury level has increased at a fast pace, very likely caused by modern coal combustion, chlor alkali and oil refining industries. The comparison of mercury profiles from different places on earth suggested that anthropogenic mercury pollution after the Industrial Revolution is more severe in Northern Hemisphere than in Antarctica. PMID- 22432276 TI - Atmospheric mercury over the marine boundary layer observed during the third China Arctic Research Expedition. AB - TGM measurements on board ships have proved to provide valuable complementary information to measurements by a ground based monitoring network. During the third China Arctic Research Expedition (from July 11 to September 24, 2008), TGM concentrations over the marine boundary layer along the cruise path were in-situ measured using an automatic mercury vapor analyzer. Here we firstly reported the results in Japan Sea, North Western Pacific Ocean and Bering Sea, where there are rare reports. The value ranged between 0.30 and 6.02 ng/m3 with an average of (1.52 +/- 0.68) ng/m3, being slightly lower than the background value of Northern Hemisphere (1.7 ng/m3). Notably TGM showed considerably spatial and temporal variation. Geographically, the average value of TGM in Bering Sea was higher than those observed in Japan Sea and North Western Pacific Ocean. In the north of Japan Sea TGM levels were found to be lower than 0.5 ng/m3 during forward cruise and displayed obviously diurnal cycle, indicating potential oxidation of gaseous mercury in the atmosphere. The pronounced episode was recorded as well. Enhanced levels of TGM were observed in the coastal regions of southern Japan Sea during backward cruise due primarily to air masses transported from the adjacent mainland reflecting the contribution from anthropogenic sources. When ship returned back and passed through Kamchatka Peninsula TGM increased by the potential contamination from volcano emissions. PMID- 22432277 TI - Ecosystem evolution of seal colony and the influencing factors in the 20th century on Fildes Peninsula, West Antarctica. AB - As the top most predator in Antarctica, the seal is a unique indicator of Antarctic environment and climate changes. In this study, we collected a sediment core from the Fildes Peninsula of West Antarctica, and used cholesterol, cholestanol, epicoprostanol, coprostanol, and seal hair numbers as the proxy indicators of seal population size and phytol as of general vegetation, and we reconstructed the 20th century history of variation of the seal population and vegetation abundance on this island. The sealing industry in the early 20th century caused the dramatic decline of seal population, and the ban of seal hunting since the 1960s led to its recovery of seal population. The seal population during the past century was primarily controlled by human activities and krill density. The reconstructed relation between seal population and vegetation abundance may offer new insights into Antarctic environment and ecology. PMID- 22432278 TI - Responses of butachlor degradation and microbial properties in a riparian soil to the cultivation of three different plants. AB - A pot experiment was conducted to investigate the biodegradation dynamics and related microbial ecophysiological responses to butachlor addition in a riparian soil planted with different plants such as Phragmites australis, Zizania aquatica, and Acorus calamus. The results showed that there were significant differences in microbial degradation dynamics of butachlor in the rhizosphere soils among the three riparian plants. A. calamus displays a significantly higher degradation efficiency of butachlor in the rhizosphere soils, as compared with Z. aquatica and P. australis. Half-life time of butachlor degradation in the rhizospheric soils of P. australis, Z. aquatica, and A. calamus were 7.5, 9.8 and 5.4 days, respectively. Residual butachlor concentration in A. calamus rhizosphere soil was 35.2% and 21.7% lower than that in Z. aquatica and P. australis rhizosphere soils, respectively, indicating that A. calamus showed a greater improvement effect on biodegradation of butachlor in rhizosphere soils than the other two riparian plant. In general, microbial biomass and biochemical activities in rhizosphere soils were depressed by butachlor addition, despite the riparian plant types. However, rhizospheric soil microbial ecophysiological responses to butachlor addition significantly (P < 0.05) differed between riparian plant species. Compared to Z. aquatica and P. australis, A. calamus showed significantly larger microbial number, higher enzyme activities and soil respiration rates in the rhizosphere soils. The results indicated that A. calamus have a better alleviative effect on inhibition of microbial growth due to butachlor addition and can be used as a suitable riparian plant for detoxifying and remediating butachlor contamination from agricultural nonpoint pollution. PMID- 22432279 TI - Distribution and characteristic of PAHs in snow of Fildes Peninsula. AB - Polycyclic aromatic hydrocarbons (PAHs) investigation in different matrices has been reported largely, whereas reports on snow samples were limited. Snow, as the main matrix in the polar region, has an important study meaning. PAHs in snow samples were analyzed to investigate the distribution and contamination status of them in the Antarctic, as well as to provide some references for global migration of PAHs. Snow samples collected in Fildes Peninsula were enriched and separated by solid-phase membrane disks and eluted by methylene dichloride, then quantified by gas chromatography/mass spectrometry. All types of PAHs were detected except for Benzo(a)pyrene. Principal component analysis method was applied to characterize them. Three factors (Naphthalene, Fluorene and Phenanthrene) accounted for 60.57%, 21.61% and 9.80%, respectively. The results showed that the major PAHs sources maybe the atmospheric transportation, and the combustion of fuel in Fildes Peninsula. The comparison of concentration and types of PAHs between accumulated snow and fresh snow showed that the main compound concentrations in accumulated snow samples were higher than those in fresh ones. The risk assessment indicated that the amount of PAHs in the snow samples would not lead to ecological risk. PMID- 22432280 TI - Anomalous Ba/Ca signals associated with low temperature stresses in Porites corals from Daya Bay, northern South China Sea. AB - Barium to calcium (Ba/Ca) ratio in corals has been considered as a useful geochemical proxy for upwelling, river flood and other oceanic processes. However, recent studies indicated that additional environmental or biological factors can influence the incorporation of Ba into coral skeletons. In this study, Ba/Ca ratios of two Porites corals collected from Daya Bay, northern South China Sea were analyzed. Ba/Ca signals in the two corals were 'anomalous' in comparison with Ba behaviors seen in other near-shore corals influenced by upwelling or riverine runoff. Our Ba/Ca profiles displayed similar and remarkable patterns characterized by low and randomly fluctuating background signals periodically interrupted by sharp and large synchronous peaks, clearly indicating an environmental forcing. Further analysis indicated that the Ba/Ca profiles were not correlated with previously claimed environmental factors such as precipitation, coastal upwelling, anthropogenic activities or phytoplankton blooms in other areas. The maxima of Ba/Ca appeared to occur in the period of Sr/Ca maxima, coinciding with the winter minimum temperatures, which suggests that the anomalous high Ba/Ca signals were related to winter-time low sea surface temperature. We speculated that the Ba/Ca peaks in corals of the Daya Bay were most likely the results of enrichment of Ba-rich particles in their skeletons when coral polyps retracted under the stresses of anomalous winter low temperatures. In this case, Ba/Ca ratio in relatively high-latitude corals can be a potential proxy for tracing the low temperature stress. PMID- 22432281 TI - Multivariate analysis of surface water quality in the Three Gorges area of China and implications for water management. AB - Multivariate statistical techniques, cluster analysis, non-parametric tests, and factor analysis were applied to analyze a water quality dataset including 13 parameters at 37 sites of the Three Gorges area, China, from 2003-2008 to investigate spatio-temporal variations and identify potential pollution sources. Using cluster analysis, the twelve months of the year were classified into three periods of low-flow (LF), normal-flow (NF), and high-flow (HF); and the 37 monitoring sites were divided into low pollution (LP), moderate pollution (MP), and high pollution (HP). Dissolved oxygen (DO), potassium permanganate index (COD(Mn)), and ammonia-nitrogen (NH4(+)-N) were identified as significant variables affecting temporal and spatial variations by non-parametric tests. Factor analysis identified that the major pollutants in the HP region were organic matters and nutrients during NF, heavy metals during LF, and petroleum during HF. In the MP region, the identified pollutants primarily included organic matter and heavy metals year-around, while in the LP region, organic pollution was significant during both NF and HF, and nutrient and heavy metal levels were high during both LF and HF. The main sources of pollution came from domestic wastewater and agricultural activities and runoff; however, they contributed differently to each region in regards to pollution levels. For the HP region, inputs from wastewater treatment plants were significant; but for MP and LP regions, water pollution was more likely from the combined effects of agriculture, domestic wastewater, and chemical industry. These results provide fundamental information for developing better water pollution control strategies for the Three Gorges area. PMID- 22432282 TI - Effect of ultrasonic pretreatment on anaerobic digestion and its sludge dewaterability. AB - To investigate the effect of ultrasonic pretreatment on anaerobic digestion and sludge dewaterability and further to probe into the influencing factors on sludge dewaterability, sludge flocs were stratified into four fractions: (1) slime; (2) loosely bound extracellular polymeric substances (LB-EPS); (3) tightly bound EPS (TB-EPS); and (4) EPS-free pellets. The results showed that ultrasonic pretreatment increased the anaerobic digestion efficiency by 7%-8%. Anaerobic digestion without ultrasonic pretreatment deteriorated the sludge dewaterability, with the capillary suction time (CST) increased from 1.42 to 47.3 (sec x L)/g TSS. The application of ultrasonic pretreatment firstly deteriorated the sludge dewaterability (normalized CST increased to 44.4 (sec x L)/g-TSS), while subsequent anaerobic digestion offset this effect and ultimately decreased the normalized CST to 23.2 (sec x L)/g-TSS. The dewaterability of unsonicated sludge correlated with protein (p = 0.003) and polysaccharide (p = 0.004) concentrations in the slime fraction, while that of sonicated sludge correlated with protein concentrations in the slime and LB-EPS fractions (p < 0.05). Fluorescent excitation-emission matrix analysis showed that the fluorescence matters in the LB-EPS fraction significantly correlated with sludge dewaterability during anarobic digestion. PMID- 22432283 TI - Role of quantum dots nanoparticles in the chemical treatment of colored wastewater: catalysts or additional pollutants. AB - The objective of the study was to investigate the presence and the activity of quantum dots nanoparticles in colored wastewaters. The special interest is devoted to the investigation of their role in the typical treatment of water or wastewater, studying their influence on the effectiveness of applied treatments methods. The standard chemical processes for water treatment and disinfection (direct UV photolysis and direct ozonation) were applied for the degradation of colored organic pollutant, reactive azo dye, in the presence/absence of CdSe/ZnS core-shells quantum dots. The obtained results indicated that investigated nanoparticles inhibit the overall efficiency of applied processes, especially in the case of direct UV photolysis, although catalytic effect might be expected in part due to the semiconductor nature of quantum dots. Such results lead to a conclusion that CdSe/ZnS nanoparticles behave as additional pollutants in the system. They should be removed from the system prior the treatment, because their presence could decrease the efficiency, i.e., prolong the time of treatment and correspondingly increase the costs of the treatment process. PMID- 22432284 TI - Reversibly enhanced aqueous solubilization of volatile organic compounds using a redox-reversible surfactant. AB - Surfactant-enhanced remediation (SER) is an effective method for the removal of volatile organic compounds (VOCs) from contaminated soils and groundwater. To reuse the surfactant the VOCs must be separated from the surfactant solutions. The water solubility of VOCs can be enhanced using reversible surfactants with a redox-acive group, (ferrocenylmethyl)dodecyldimethylammonium bromide (Fc12) and (ferrocenylmethyl)tetradecanedimethylammonium bromide (Fc14), above and below their critical micelle concentrations (CMC) under reducing (I+) and oxidative (I2+) conditions. The CMC values of Fc12 and Fc14 in I+ are 0.94 and 0.56 mmol/L and the solubilization of toluene by Fc12 and Fc14 in I+ for toluene is higher than the solubilization achieved with sodium dodecyl sulfate, cetyltrimethylammonium bromide and Trition X-114. The solubilization capacity of the ferrocenyl surfactants for each tested VOCs ranked as follows: ethylbenzene > toluene > benzene. The solubilities of VOCs by reversible surfactant in I+ were 30% higher than those in I2+ at comparable surfactant concentrations. The effects of Fc14 concentrations on VOCs removal efficiency were as follows: benzene > toluene > ethylbenzene. However, an improved removal efficiency was achieved at low ferrocenyl surfactant concentrations. Furthermore, the reversible surfactant could be recycled through chemical approaches to remove organic pollutants, which could significantly reduce the operating costs of SER technology. PMID- 22432285 TI - Pilot study on bromate reduction in ozonation of water with low carbonate alkalinities by carbon dioxide. AB - A pilot study was carried out to explore the application of carbon dioxide for pH depression in a bubble column and its ability to inhibit bromate formation for water with a low alkalinity. Results showed that in the absence of ammonia, CO2 was capable of reducing bromate 38.0%-65.4% with one-unit pH depression. CO2 caused a slightly lower bromate reduction (4.2%) than did H2SO4 when the pH was depressed to 7.4, and a more a pronounced lower reduction (8.8%) when the pH was depressed to 6.9. In the presence of 0.20 mg/L-N ammonia, bromate was largely inhibited with 73.9% reduction. When the pH was depressed to 7.4, CO2 and H2SO4 showed an 11.3% and 23.5% bromate reduction respectively, demonstrating that the joint use of CO2 and ammonia might be a plausible strategy of blocking all three bromate formation pathways. CO2 could be applied through the aeration diffuser together with ozone gas, resulting in a similar bromate reduction compared with the premixing method through Venturi mixer. PMID- 22432286 TI - Removal of heavy metal ions from aqueous solution using red loess as an adsorbent. AB - The adsorption behaviors of heavy metals onto novel low-cost adsorbent, red loess, were investigated. Red loess was characterized by X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectra. The results indicated that red loess mainly consisted of silicate, ferric and aluminum oxides. Solution pH, adsorbent dosage, initial metal concentration, contact time and temperature significantly influenced the efficiency of heavy metals removal. The adsorption reached equilibrium at 4 hr, and the experimental equilibrium data were fitted to Langmuir monolayer adsorption model. The adsorption of Cu(II) and Zn(II) onto red loess was endothermic, while the adsorption of Pb(II) was exothermic. The maximum adsorption capacities of red loess for Pb(II), Cu(II) and Zn(II) were estimated to be 113.6, 34.2 and 17.5 mg/g, respectively at 25 degrees C and pH 6. The maximum removal efficiencies were 100% for Pb(II) at pH 7, 100% for Cu(II) at pH 8, and 80% for Zn(II) at pH 8. The used adsorbents were readily regenerated using dilute HCl solution, indicating that red loess has a high reusability. All the above results demonstrated that red loess could be used as a possible alternative low-cost adsorbent for the removal of heavy metals from aqueous solution. PMID- 22432287 TI - Seasonal variation effects on the formation of trihalomethane during chlorination of water from Yangtze River and associated cancer risk assessment. AB - For the system of water samples collected from Yangtze River, the effects of seasonal variation and Fe(III) concentrations on the formation and distribution of trihalomethanes (THMs) during chlorination have been investigated. The corresponding lifetime cancer risk of the formed THMs to human beings was estimated using the parameters and procedure issued by the US EPA. The results indicated that the average concentration of THMs (100.81 microg/L) in spring was significantly higher than that in other seasons, which was related to the higher bromide ion concentration resulted from the intrusion of tidal saltwater. The total cancer risk in spring reached 8.23 x 10(-5) and 8.86 x 10(-5) for males and females, respectively, which were about two times of those in summer under the experimental conditions. Furthermore, it was found that the presence of Fe(III) resulted in the increased level of THMs and greater cancer risk from exposure to humans. Under weak basic conditions, about 10% of the increment of THMs from the water samples in spring was found in the presence of 0.5 mg/L Fe(III) compared with the situation without Fe(III). More attention should be given to the effect of the coexistence of Fe(III) and bromide ions on the risk assessment of human intake of THMs from drinking water should be paid more attention, especially in the coastland and estuaries. PMID- 22432288 TI - Comparison of polycyclic aromatic hydrocarbon pollution in Chinese and Japanese residential air. AB - Comparative studies on polycyclic aromatic hydrocarbon (PAH) pollution in residential air of Hangzhou (China) and Shizuoka (Japan) were conducted in summer (August, 2006) and winter (January, 2007). Total concentrations of 8 PAHs ranged from 7.1 to 320 ng/m3 and 0.15 to 35 ng/m3 in residential air of Hangzhou and Shizuoka, respectively. Air PAH concentrations in smoking houses were higher than that in nonsmoking houses. In nonsmoking houses, mothball emission and cooking practice were the emission sources of 2- and 3-ring PAHs in Hangzhou, respectively. The 2- and 3-ring PAHs were from use of insect repellent, kerosene heating and outdoor environment in nonsmoking houses in Shizuoka. The 5- and 6 ring PAHs in residential air were mainly from outdoor environment in both cities. Toxicity potencies of PAHs in residential air of Hangzhou were much higher than that in Shizuoka. PMID- 22432289 TI - Soil pollution by polycyclic aromatic hydrocarbons: a comparison of two Chinese cities. AB - Soil samples from Huizhou and Zhanjiang, China were analyzed for 16 priority polycyclic aromatic hydrocarbons (PAHs) with harmonized sampling, sample extraction and analysis quantification methods. The concentrations and sources of PAHs in soil samples of the two cities were compared. Almost all of the PAH components were detectable in 103 soil samples. The concentrations of sigmaPAHs ranged from 35.40 to 534.5 microg/kg in soil samples from Huizhou, and ranged from 9.50 to 6618.00 microg/kg in samples from Zhanjiang. Evident differences of concentrations, compositions and sources of PAHs in soils were observed between the two cities. The average concentrations of individual component and the sum of a group of PAHs in soil samples from Zhanjiang were significantly higher than those in Huizhou (P < 0.05). Phe, Flu, Pyr, Bbf and Baa were the dominant PAH components both in soil samples from Huizhou and Zhanjiang. Except for these five components, Bap, I1p, Daa and Bgp were also the dominant PAH components in soil samples from Zhanjiang. Coal combustion and liquid fossil fuel combustion were the same sources of PAHs in the two cities with different contributions, and petroleum played a key role in PAHs release in Zhanjiang. PMID- 22432290 TI - Adsorption and desorption of herbicide monosulfuron-ester in Chinese soils. AB - Monosulfuron-ester is a new, low rate, sulfonylurea herbicide that is being promoted for annual broadleaf and gramineal weed control; however, there is a lack of published information on its behavior in soils. The adsorption and desorption of monosulfuron-ester by seven type soils were measured using a batch equilibrium technique. The results showed that the Freundlich equation fitted its adsorption and desorption well, and the Freundlich constant values (K(f-ads)) ranged from 0.88 to 5.66. Adsorption isotherms were nonlinear with 1/n(f-ads) values < 1. Soil pH, organic matter (OM), and clay content were the main factors influencing its adsorption and desorption. Adsorption and desorption were negatively correlated with pH 4.0-8.0 while positively correlated with OM and clay content. The adsorption of monosulfuron-ester was mainly a physical process, because its free energy (deltaG) in seven soils was less than 40 kJ/mol. Monosulfuron-ester adsorption by three soils increased with increasing CaCl2 concentration using CaCl2 as a background electrolyte. Monosulfuron-ester desorption was hysteretic in all tested soils. PMID- 22432291 TI - Succession of bacterial community along with the removal of heavy crude oil pollutants by multiple biostimulation treatments in the Yellow River Delta, China. AB - Multiple biostimulation treatments were applied to enhance the removal of heavy crude oil pollutants in the saline soil of Yellow River Delta. Changes of the soil bacterial community were monitored using the terminal restriction fragment length polymorphism (T-RFLP) and clone library analyses. The 140-day microcosm experiments showed that low C:N:P ratio, high availability of surfactant and addition of bulking agent significantly enhanced the performance, leading to the highest total petroleum hydrocarbon removal. Meanwhile, the bacterial community was remarkably changed by the multiple biostimulation treatments, with the Deltaproteobacteria, Firmicutes, Actinobacteria, Acidobacteria and Planctomycetes being inhibited and the Alpha- and Beta-proteobacteria and some unknown Gammaproteobacteria bacteria being enriched. In addition, different hydrocarbon degraders came to power in the following turn. At the first stage, the Alcanivorax-related Gammaproteobacteria bacteria dominated in the biostimulated soil and contributed mainly to the biodegradation of easily degradable portion of the heavy crude oil. Then the bacteria belonging to Alphaproteobacteria, followed by bacteria belonging to Candidate division OD1, became the dominant oil degraders to degrade the remaining recalcitrant constituents of the heavy crude oil. PMID- 22432292 TI - Arsenic removal from contaminated soil via biovolatilization by genetically engineered bacteria under laboratory conditions. AB - In Rhodopseudomonas palustris, an arsM gene, encoding bacterial and archaeal homologues of the mammalian Cyt19 As(III) S-adenosylmethionine methytransferase, was regulated by arsenicals. An expression of arsM was introduced into strains for the methylation of arsenic. When arsM was expressed in Sphingomonas desiccabilis and Bacillus idriensis, it had 10 folds increase of methyled arsenic gas compared to wild type in aqueous system. In soil system, about 2.2%-4.5% of arsenic was removed by biovolatilization during 30 days. This study demonstrated that arsenic could be removed through volatilization from the contaminated soil by bacteria which have arsM gene expressed. These results showed that it is possible to use microorganisms expressing arsM as an inexpensive, efficient strategy for arsenic bioremediation from contaminated water and soil. PMID- 22432293 TI - Potential of Nassarius nitidus for monitoring organotin pollution in the lagoon of Bizerta (northern Thunisia). AB - Imposex and butyltin burden were assessed in Nassarius nitidus, Bolinus brandaris and Hexaplex trunculus collected at five stations in the Bizerta lagoon. Biological analysis showed that imposex followed type (a) in N. nitidus (distal evolution), against type (d) in the two muricids (proximal evolution). Imposex indices were higher in sites located nearby sources of tributyltin and N. nitidus was the least affected species of the five sites, followed by B. brandaris and H. trunculus. Butyltin analysis showed lower accumulation in N. nitidus followed by H. trunculus and B. brandaris. This study has allowed the gathering of data on imposex in a snail studied for the first time in Tunisia (N. nitidus). It suggests the possibility of using such snail as a complementary species for organotin monitoring programs in the Mediterranean and further confirmed that H. trunculus is the most suitable species for such investigations. PMID- 22432294 TI - Growth response and toxic effects of three antibiotics on Selenastrum capricornutum evaluated by photosynthetic rate and chlorophyll biosynthesis. AB - The effects of three types of antibiotics (erythromycin, ciprofloxacin and sulfamethoxazole) on the photosynthesis of freshwater algae, Selenastrum capricornutum Printz, were investigated by determining the growth rate, chloroplast pigments content, seven main precursors (including delta aminolevulinic acid, porphobilinogen, uroporphyrinogen III, coproporphyrinogen III, protoporphyrin IX, Mg-proporphyrin IX and protochlorophyllide), and photosynthetic rate during chlorophyll biosynthesis. The antibiotics significantly decreased the growth rate, chlorophyll content, and photosynthetic rate. Erythromycin induced a decreasing effect at a concentration of 0.06 mg/L, while ciprofloxacin and sulfamethoxazole achieved the same results at concentrations higher than 1.5 mg/L. Only erythromycin significantly inhibited chlorophyll biosynthesis, which indicated that it was considerably more toxic to S. capricornutum than ciprofloxacin and sulfamethoxazole, and may pose a high potential risk to aquatic ecosystems. PMID- 22432295 TI - Determination and assessment of total mercury levels in local, frozen and canned fish in Lebanon. AB - Fish is an important constituent of the Lebanese diet. However, very little attention in our area is given to bring awareness regarding the effect of the toxicity of mercury (Hg) mainly through fish consumption. This study aimed to report analytical data on total mercury levels in several fish species for the first time in thirty years and to also made individuals aware of the presence and danger from exposure to mercury through fish consumption. Fish samples were selected from local Lebanese markets and fisheries and included 94 samples of which were fresh, frozen, processed, and canned fish. All values were reported as microgram of mercury per gram of fish based on wet weight. The level of mercury ranged from 0.0190 to 0.5700 microg/g in fresh samples, 0.0059 to 0.0665 microg/g in frozen samples, and 0.0305 to 0.1190 microg/g in canned samples. The data clearly showed that higher levels of mercury were detected in local fresh fish as opposed to other types thus placing consumers at higher risk from mercury exposure. Moreover, the data revealed that Mallifa (yellowstripe barracuda/Sphyraena chrysotaenia), Sargous (white seabream/Diplodus sargus), Ghobbos (bogue/Boops boops), and shrimp (Penaeus sp.) were among the types containing the highest amounts of mercury. On the other hand, processed fish such as fish fillet, fish burger, small shrimp and crab are found to contain lower levels of mercury and are associated with lower exposure risks to mercury. Lebanese population should therefore, be aware to consume limited amounts of fresh local fish to minimize exposure to mercury. PMID- 22432296 TI - Antimicrobial activity of thin metallic silver flakes, waste products of a manufacturing process. AB - The aim of the research was to develop new products and processes from a manufacturing waste from an Italian metallurgic company. The company produced thin silver metallic films and the production scraps were silver flakes. The possibility to use the silver flakes in water disinfection processes was studied. The antimicrobial activity of the flakes was investigated in batch using Escherichia coli as Gram-negative microorganism model. The flakes did not show any antimicrobial activity, so they were activated with two different processes: thermal activation in reducing atmosphere and chemical activation, obtaining, respectively, reduced flakes (RF) and chemical flakes (CF). The flakes, activated with either treatment, showed antimicrobial activity against E. coli. The kill rate was dependent on the type of activated flakes. The chemical flakes were more efficient than reduced flakes. The kill rate determined for 1 g of CF, 1.0 +/- 0.2 min(-1), was greater than the kill rate determined for 1 g of RF, 0.069 +/- 0.004 min(-1). This was confirmed also by the minimum inhibitory concentration values. It was demonstrated that the antimicrobial capability was dependent on flakes amount and on the type of aqueous medium. Furthermore, the flakes maintained their properties also when used a second time. Finally, the antimicrobial activities of flakes were tested in an effluent of a wastewater treatment plant where a variety of heterotrophic bacteria were present. PMID- 22432297 TI - Silver impregnated carbon for adsorption and desorption of elemental mercury vapors. AB - The Hg(0) vapor adsorption experimental results on a novel sorbent obtained by impregnating a commercially available activated carbon (Darco G60 from BDH) with silver nitrate were reported. The study was performed by using a fundamental approach, in an apparatus at laboratory scale in which a synthetic flue gas, formed by Hg(0) vapors in a nitrogen gas stream, at a given temperature and mercury concentration, was flowed through a fixed bed of adsorbent material. Breakthrough curves and adsorption isotherms were obtained for bed temperatures of 90, 120 and 150 degrees C and for Hg(0) concentrations in the gas varying in the range of 0.8-5.0 mg/m3. The experimental gas-solid equilibrium data were used to evaluate the Langmuir parameters and the heat of adsorption. The experimental results showed that silver impregnated carbon was very effective to capture elemental mercury and the amount of mercury adsorbed by the carbon decreased as the bed temperature increased. In addition, to evaluate the possibility of adsorbent recovery, desorption was also studied. Desorption runs showed that both the adsorbing material and the mercury could be easily recovered, since at the end of desorption the residue on solid was almost negligible. The material balance on mercury and the constitutive equations of the adsorption phenomenon were integrated, leading to the evaluation of only one kinetic parameter which fits well both the experimentally determined breakthrough and desorption curves. PMID- 22432298 TI - Autotrophic denitrification for nitrate and nitrite removal using sulfur limestone. AB - Sulfur-limestone was used in the autotrophic denitrification process to remove the nitrate and nitrite in a lab scale upflow biofilter. Synthetic water with four levels of nitrate and nitrite concentrations of 10, 40, 70 and 100 mg N/L was tested. When treating the low concentration of nitrate- or nitrite contaminated water (10, 40 mg N/L), a high removal rate of about 90% was achieved at the hydraulic retention time (HRT) of 3 hr and temperature of 20-25 degrees C. At the same HRT, 50% of the nitrate or nitrite could be removed even at the low temperature of 5-10 degrees C. For the higher concentration nitrate and nitrite (70, 100 mg N/L), longer HRT was required. The batch test indicated that influent concentration, HRT and temperature are important factors affecting the denitrification efficiency. Molecular analysis implied that nitrate and nitrite were denitrified into nitrogen by the same microorganisms. The sequential two step-reactions from nitrate to nitrite and from nitrite to the next-step product might have taken place in the same cell during the autotrophic denitrification process. PMID- 22432299 TI - Bacterial community composition and abundance in leachate of semi-aerobic and anaerobic landfills. AB - The abundance and phylogenetic composition of bacterial community in leachate of semi-aerobic and anaerobic landfill were compared through real-time polymerase chain reaction and denaturing gradient gel electrophoresis. In semi-aerobic landfill scenario, the bacterial 16S rRNA copy numbers in leachate had no significant reduction from initial stage to stable period. In the scenario of anaerobic landfill, the largest bacterial 16S rRNA gene copy number was found in leachate at initial stage, but it reduced significantly at stable period. Moreover, methane-oxidizing bacteria population in stable period was lower than that in initial period in both two landfill processes. However, semi-aerobic landfill leachate had more methanotrophic bacteria populations than that in the anaerobic one. Furthermore, according to the sequences and phylogenetic analysis, obvious difference could be detected in bacterial community composition in different scenarios. Proteobacteria and bacteroidetes took up a dominantly higher proportion in semi-aerobic landfill leachate. To summarize up, different landfill methods and its landfill ages had crucial impacts on bacterial abundance and composition in leachate of semi-aerobic and anaerobic landfills. PMID- 22432300 TI - Biosorption of mercury by Macrocystis pyrifera and Undaria pinnatifida: influence of zinc, cadmium and nickel. AB - This study investigated the adsorption of Hg(II) on Macrocystis pyrifera and Undaria pinnatifida in monometallic system in the presence of Zn(II), Cd(II) and Ni(II). The two biosorbents reached the same maximum sorption capacity (q(m) = 0.8 mmol/g) for mercury. U. pinnatifida showed a greater affinity (given by the coefficient b of the Langmuir equation) for mercury compared to M. pyrifera (4.4 versus 2.7 L/mmol). Mercury uptake was significantly reduced (by more than 50%) in the presence of competitor heavy metals such as Zn(II), Cd(II) and Ni(II). Samples analysis using an environmental scanning electron microscopy equipped with an energy dispersive X-ray microanalysis showed that mercury was heterogeneously adsorbed on the surface of both biomaterials, while the other heavy metals were homogeneous distributed. The analysis of biosorbents by Fourier transform infrared spectrometry indicated that Hg(II) binding occurred on S = O (sulfonate) and N-H (amine) functional groups. PMID- 22432301 TI - Effect of anaerobic digestion on the high rate of nitritation, treating piggery wastewater. AB - The amount of piggery wastewater as domestic livestock is increasing. The volume of piggery wastewater produced is less than the volume of other wastewaters, but piggery wastewater has a heavy impact on wastewater streams due to an extremely high concentration of nitrogen and COD. In this study, laboratory reactors were operated using piggery wastewater and the effluent of anaerobic digester from piggery wastewater plants. The purpose of this study was to induce the nitritation process, which is an economically advantageous nitrogen removal method that converts ammonium nitrogen into nitrite. The results showed that the effluent of anaerobic digester from piggery wastewater was more efficient than raw piggery wastewater in terms of inducing nitritation. It can be deduced that nitritation is largely affected by an organic fraction of piggery wastewater. It can also be concluded that a small amount of biodegradable organic matter in piggery wastewater is efficient in inducing nitritation. PMID- 22432302 TI - Synthesis of polyaluminum chloride with a membrane reactor: process characteristics and membrane fouling. AB - Polyaluminum chloride was synthesized with a membrane reactor, in which NaOH was added into AlCl3 solution through the membrane's micropores to reduce the NaOH droplets size. The content of the most efficient species increased to about 80%. The process characteristics in the reaction (i.e., flow velocity, pressure drop), and membrane fouling and cleaning were investigated. The evolution of both flow velocity and pressure drop during the reaction were related to changes in species distribution and solution viscosity. The process characteristics were well interpreted in terms of the Bernoulli equation. After reaction, the membranes were recovered by cleaning with diluted hydrochloride acid. This study is crucial for process design and scale-up of membrane reactors. PMID- 22432303 TI - Involvements of chloride ion in decolorization of Acid Orange 7 by activated peroxydisulfate or peroxymonosulfate oxidation. AB - The effects of chloride anion (Cl-) (up to 1.0 mol/L) on the decolorization of a model compound, azo dye Acid Orange 7 (AO7), by sulfate radical (SO4-*) based peroxydisulfate (PS) or peroxymonosulfate (PMS) oxidation under various activated conditions (UV254 nm/PS, Thermal (70 degrees C/PS, UV254 nm/PMS, Co2+/PMS) were investigated. Methanol and NH4+ were used as quenching reagents to determine the contributions of active chlorine species (dichloride radical (Cl2-*) and hypochlorous acid (HClO)). The results indicated that the effects of Cl- on the reaction mechanism were different under various activated conditions. For UV/PS and Thermal/PS, the inhibition tendency became more clear as the Cl- concentration increased, probably due to the reaction between Cl- and SO4-* and the generation of Cl2-* or HCIO. For UV/PMS, Cl- did not exhibit inhibition when the concentration was below 0.1 mol/L. As Cl- concentration reached to 1.0 mol/L, the decolorization rate of AO7 was, however, accelerated, possibly because PMS directly reacts with Cl- to form HClO. For Co2+/PMS, Cl- exhibited a significant inhibiting effect even at low concentration (< or = 0.01 mol/L). When Cl- concentration exceeded 0.1 mol/L, the activation of PMS by Co2+ was almost completely inhibited. Under this condition, HClO maybe played a major role in decolorization of AO7. The results implicated that chloride ion is an important factor in SO4(-*) -based degradation of organic contamination in chloride containing water. PMID- 22432304 TI - Adsorptive property of Cu(2+)-loaded montmorillonite clays for Escherichia coli K88 in vitro. AB - The adsorption properties of Cu(2+)-loaded montmorillonite clays (MMT-Cu) for Escherichia coli K88 as a function of time, bacteria concentrations, pH, ionic strength and temperature were investigated. The results showed that the bacteria adsorption onto MMT-Cu surface reached equilibrium after 90 min. The percentages of E. coli K88 adsorbed onto the surfaces of MMT-Cu and montmorillonite clays (MMT) at equilibrium were 88.9% and 56.5%, respectively. Scanning electron microscopy revealed that a lot of E. coli K88 adhered to the surface of MMT-Cu. The zeta potential of MMT-Cu was relatively high as compared to that of MMT. The adsorptive ability of MMT-Cu for E. coli K88 was higher than that of MMT (P < 0.05). Moreover, pH, ionic strength and temperature produced a strong influence on the extent of E. coli K88 adsorption to surface of MMT-Cu and MMT. The mechanism of adsorption of E. coli onto MMT-Cu may involve electrostatic attraction and physiochemical properties of bacterial cell walls and minerals surfaces. PMID- 22432305 TI - Development of systems for detection, early warning, and control of pipeline leakage in drinking water distribution: a case study. AB - Water leakage in drinking water distribution systems is a serious problem for many cities and a huge challenge for water utilities. An integrated system for the detection, early warning, and control of pipeline leakage has been developed and successfully used to manage the pipeline networks in selected areas of Beijing. A method based on the geographic information system has been proposed to quickly and automatically optimize the layout of the instruments which detect leaks. Methods are also proposed to estimate the probability of each pipe segment leaking (on the basis of historic leakage data), and to assist in locating the leakage points (based on leakage signals). The district metering area (DMA) strategy is used. Guidelines and a flowchart for establishing a DMA to manage the large-scale looped networks in Beijing are proposed. These different functions have been implemented into a central software system to simplify the day-to-day use of the system. In 2007 the system detected 102 non-obvious leakages (i.e., 14.2% of the total detected in Beijing) in the selected areas, which was estimated to save a total volume of 2,385,000 m3 of water. These results indicate the feasibility, efficiency and wider applicability of this system. PMID- 22432306 TI - Biodegradation of beet molasses vinasse by a mixed culture of micro organisms: effect of aeration conditions and pH control. AB - The effect of aeration conditions and pH control on the progress and efficiency of beet molasses vinasse biodegradation was investigated during four batch processes at 38 degrees C with the mixed microbial culture composed of Bifidobacterium, Lactobacillus, Lactococcus, Streptococcus, Bacillus, Rhodopseudomonas, and Saccharomyces. The four processes were carried out in a shake flask with no pH control, an aerobic bioreactor without mixing with no pH control, and a stirred-tank reactor (STR) with aeration with and without pH control, respectively. All experiments were started with an initial pH 8.0. The highest efficiency of biodegradation was achieved through the processes conducted in the STR, where betaine (an organic pollutant occurring in beet molasses in very large quantities) was completely degraded by the microorganisms. The process with no pH control carried out in the STR produced the highest reduction in the following pollution measures: organic matter expressed as chemical oxygen demand determined by the dichromatic method + theoretical COD of betaine (COD(sum), 85.5%), total organic carbon (TOC, 78.8%) and five-day biological oxygen demand (BOD5, 98.6%). The process conditions applied in the shake flask experiments, as well as those used in the aerobic bioreactor without mixing, failed to provide complete betaine assimilation. As a consequence, reduction in COD(sum), TOC and BOD5 was approximately half that obtained with STR. PMID- 22432307 TI - Effects of different mixing ratios on emissions from passenger cars fueled with methanol/gasoline blends. AB - Regulated and unregulated emissions from four passenger cars fueled with methanol/gasoline blends at different mixing ratios (M15, M20, M30, M50, M85 and M100) were tested over the New European Driving Cycle (NEDC). Volatile organic compounds (VOCs) were sampled by Tenax TA and analyzed by thermal desorption-gas chromatograph/mass spectrometer (TD-GC/MS). Carbonyls were trapped on dinitrophenylhydrazine (DNPH) cartridges and analyzed by high performance liquid chromatography (HPLC). The results showed that total emissions of VOCs and BTEX (benzene, toluene, ethylbenzene, p, m, o-xylene) from all vehicles fueled with methanol/gasoline blends were lower than those from vehicles fueled with only gasoline. Compared to the baseline, the use of M85 decreased BTEX emissions by 97.4%, while the use of M15 decreased it by 19.7%. At low-to-middle mixing ratios (M15, M20, M30 and M50), formaldehyde emissions showed a slight increase while those of high mixing ratios (M85 and M100) were three times compared with the baseline gasoline only. When the vehicles were retrofitted with new three-way catalytic converters (TWC), emissions of carbon monoxide (CO), total hydrocarbon (THC), and nitrogen oxides (NO(x)) were decreased by 24%-50%, 10%-35%, and 24% 58% respectively, compared with the cars using the original equipment manufacture (OEM) TWC. Using the new TWC, emissions of formaldehyde and BTEX were decreased, while those of other carbonyl increased. It is necessary that vehicles fueled with methanol/gasoline blends be retrofitted with a new TWC. In addition, the specific reactivity of emissions of vehicles fueled with M15 and retrofitted with the new TWC was reduced from 4.51 to 4.08 compared to the baseline vehicle. This indicates that the use of methanol/gasoline blend at a low mixing ratio may have lower effect on environment than gasoline. PMID- 22432308 TI - Mercury removals by existing pollutants control devices of four coal-fired power plants in China. AB - The mercury removals by existing pollution control devices and the mass balances of mercury in four coal-fired power plants of China were carried out based on a measurement method with the aluminum matrix sorbent. All the plants are equipped with a cold-side electrostatic precipitator (ESP) and a wet flue gas desulfurization (FGD) in series. During the course of coal stream, the samples, such as coal, bottom ash, fly ash, gypsum and flue gas, were collected. The Hg concentrations in coals were measured by CVAAS after appropriate preparation and acid digestion. Other solid samples were measured by the RA-915+ Zeeman Mercury Spectrometer. The vapor phase Hg was collected by a sorbent trap from flue gas and then measured using CVAAS followed by acid leaching. The mercury mass balances were estimated in this study were 91.6%, 77.1%, 118% and 85.8% for the four power plants, respectively. The total Hg concentrations in the stack gas were ranged from 1.56-5.95 microg/m3. The relative distribution of Hg in bottom ash, ESP, WFGD and stack discharged were ranged between 0.110%-2.50%, 2.17% 23.4%, 2.21%-87.1%, and 21.8%-72.7%, respectively. The distribution profiles were varied with the coal type and the operation conditions. The Hg in flue gas could be removed by ESP and FGD systems with an average removal efficiency of 51.8%. The calculated average emission factor was 0.066 g/ton and much lower than the results obtained ten years ago. PMID- 22432309 TI - Frequency comparative study of coal-fired fly ash acoustic agglomeration. AB - Particulate pollution is main kind of atmospheric pollution. The fine particles are seriously harmful to human health and environment. Acoustic agglomeration is considered as a promising pretreatment technology for fine particle agglomeration. The mechanisms of acoustic agglomeration are very complex and the agglomeration efficiency is affected by many factors. The most important and controversial factor is frequency. Comparative studies between high-frequency and low-frequency sound source to agglomerate coal-fired fly ash were carried out to investigate the influence of frequency on agglomeration efficiency. Acoustic agglomeration theoretical analysis, experimental particle size distributions (PSDs) and orthogonal design were examined. The results showed that the 20 kHz high-frequency sound source was not suitable to agglomerate coal-fired fly ash. Only within the size ranging from 0.2 to 0.25 microm the particles agglomerated to adhere together, and the agglomerated particles were smaller than 2.5 microm. The application of low-frequency (1000-1800 Hz) sound source was proved as an advisable pretreatment with the highest agglomeration efficiency of 75.3%, and all the number concentrations within the measuring range decreased. Orthogonal design L16 (4)3 was introduced to determine the optimum frequency and optimize acoustic agglomeration condition. According to the results of orthogonal analysis, frequency was the dominant factor of coal-fired fly ash acoustic agglomeration and the optimum frequency was 1400 Hz. PMID- 22432310 TI - Quantifying the adsorption and uptake of CuO nanoparticles by wheat root based on chemical extractions. AB - Extensive application of metal nanoparticles is attracting more attention because of their potential environmental risks. Many studies have focused on the uptake of metal nanoparticles (NPs) by plant, but the adsorption of nanoparticles on root surface is often mistakenly regarded as their uptake. This study optimized the methods to distinguish the adsorption and uptake of CuO-NPs on the wheat root by applying different metal competing ions (Na+, Mg2+, and La3+), surfactant (i.e., sodium dodecyl benzene sulfonate, SDBS), or complexing agents like NaOAc and Na4EDTA, as well as ultrasonic technique. The results indicated that some CuO NPs is strongly adsorbed on the plant root surface, and part of them by mechanical adhesion. Competing ions could not desorb the CuO-NPs from the root surface, while NaOAc and Na4EDTA well dissolved the adsorbed CuO-NPs. In addition, the uptake and adsorption of CuO-NPs increased with increasing exposure concentrations of CuO-NPs in the range of 5-200 mg/L. The amount of CuO-NPs adsorption is always lower than that of their uptake. PMID- 22432311 TI - Archaeal community structure along a gradient of petroleum contamination in saline-alkali soil. AB - The response of archaeal communities to petroleum contamination in saline-alkali soil was characterized by analyses of three soil samples with different total petroleum hydrocarbon concentrations. Through the construction and screening of 16S rRNA gene clone libraries based on DNA extracts from these soils, nine distinct phylogenetic groups were identified. Statistical analyses showed that the distribution of archaeal community structures differ significantly along the gradient of petroleum contamination in these three saline-alkali soils. Five phylogenetic groups were dominant in the control soil, two of which were also abundant in the lightly contaminated soil. Four phylogenetic groups were dominant in heavily contaminated soil, one of which was also abundant in the lightly contaminated soil. The halophilic genus of Haloferax and the haloalkaliphilic genus of Natronomonas were more abundant in heavily contaminated soil. These results suggested that the genera of Haloferax and Natronomonas may have a role in the natural attenuation of petroleum-contaminated saline-alkali soil. PMID- 22432312 TI - Modeling the influence of ethanol on the adsorption and desorption of selected BTEX compounds on bentonite and kaolin. AB - The influence of ethanol on the adsorption capacity and desorption kinetics of benzene and toluene on bentonite and kaolin through modeling and experimental study was investigated. The results showed that the adsorption capacity of both soils for the target compounds decreased as ethanol content increased. As ethanol content increased from 0 to 50%, the adsorption capacity for benzene and toluene on bentonite decreased from 3.6 to 0.54 microg(n+1)/(L(n) x g) (by 85%) and 1.91 to 0.01 microg(n+1)/(L(n) x g) (by 99.5%), respectively. For benzene and toluene adsorption on kaolin, the adsorption capacity decreased by 86.5% (from 0.26 to 0.04 microg(n+1)/(L(n) x g) and 98.2% (from 0.13 to 0.002 microg(n+1)/(L(n) x g)), respectively, as ethanol content increased from 0 to 50%. In addition, the desorption rate of benzene and toluene from bentonite decreased by about one order of magnitude as the ethanol increased from 0 to 25% and 0 to 50%, respectively. It can be inferred that ethanol could affect the effectiveness of natural attenuation processes that rely on adsorption to soils as a containment technique for benzene and toluene by retarding the adsorption to soils and remobilizing compounds that had already been adsorbed to soils. PMID- 22432313 TI - Enhanced bioremediation of oil contaminated soil by graded modified Fenton oxidation. AB - Graded modified Fenton's (MF) oxidation is a strategy in which H2O2 is added intermittently to prevent a sharp temperature increase and undesired soil sterilization at soil circumneutral pH versus adding the same amount of H2O2 continuously. The primary objective of the present study was to investigate whether a mild MF pre-oxidation such as a stepwise addition of H2O2 can prevent sterilization and achieve a maximum degradation of tank oil in soil. Optimization experiments of graded MF oxidation were conducted using citric acid, oxalic acid and SOLV-X as iron chelators under different frequencies of H2O2 addition. The results indicated that the activity order of iron chelates decreased as: citric acid (51%) > SOLV-X (44%) > oxalic acid (9%), and citric acid was found to be an optimized iron chelating agent of graded MF oxidation. Three-time addition of H2O2 was found to be favorable and economical due to decreasing total petroleum hydrocarbon removal from three time addition (51%) to five time addition (59%). Biological experiments were conducted after graded MF oxidation of tank oil completed under optimum conditions mentioned above. After graded oxidation, substantially higher increase (31%) in microbial activity was observed with excessive H2O2 (1470 mmol/L, the mol ratio of H2O2:Fe2+ was 210:1) than that of non-oxidized soil. Removal efficiency of tank oil was up to 93% after four weeks. Especially, the oil fraction (C10-C40) became more biodagradable after graded MF oxidation than its absence. Therefore, graded MF oxidation is a mild pretreatment to achieve an effective bioremediation of oil contaminated soil. PMID- 22432314 TI - Analysis of bacterial community in bulking sludge using culture-dependent and independent approaches. AB - The bacterial community of a bulking sludge from a municipal wastewater treatment plant with anoxic-anaerobic-oxic process was investigated by combination of cultivation and 16S rRNA gene clone library analysis for understanding the causes of bulking. A total of 28 species were obtained from 63 isolates collected from six culture media. The most cultivable species belonged to gamma-Proteobacteria including Klebsiella sp., Pseudomonas sp., Aeromonas sp. and Acinetobacter sp. Further analysis of these strains by repetitive sequence based on polymerase chain reaction (rep-PCR) technology showed that rep-PCR yielded discriminatory banding patterns within the same genus using REP and BOX primer sets. While the culture-independent assessment revealed that beta-Proteobacteria was the dominant group in the bulking sample. Sequence analysis revealed that the highest proportion (14.7%) of operational taxonomic units was 98% similar to Candidatus Accumulibacter phosphatis, which is used to remove phosphorous from wastewater. Our results indicated that combining different approaches can produce complementary information, thus generate a more accurate view of microbial community in bulking sludge. PMID- 22432315 TI - Denitrification characteristics of a marine origin psychrophilic aerobic denitrifying bacterium. AB - A psychrophilic aerobic denitrifying bacterium, strain S1-1, was isolated from a biological aerated filter conducted for treatment of recirculating water in a marine aquaculture system. Strain S1-1 was preliminarily identified as Psychrobacter sp. based on the analysis of its 16S rRNA gene sequence, which showed 100% sequence similarity to that of Psychrobacter sp. TSBY-70. Strain S1-1 grew well either in high nitrate or high nitrite conditions with a removal of 100% nitrate or 63.50% nitrite, and the total nitrogen removal rates could reach to 46.48% and 31.89%, respectively. The results indicated that nitrate was mainly reduced in its logarithmic growth phase with a very low level accumulation of nitrite, suggesting that the aerobic denitrification process of strain S1-1 occurred mainly in this phase. The GC-MS results showed that N2O was formed as the major intermediate during the aerobic denitrifying process of strain S1-1. Finally, factors affecting the growth of strain S1-1 and its aerobic denitrifying ability were also investigated. Results showed that the optimum aerobic denitrification conditions for strain S1-1 were sodium succinate as carbon source, C/N ratio15, salinity 10 g/L NaCl, incubation temperature 20 degrees C and initial pH 6.5. PMID- 22432316 TI - Responses of benthic insect communities to effluent from the abandoned Ferris Haggarty copper mine in southeast Wyoming, USA. AB - Six criteria were used to evaluate 12 metrics for their sensitivity to effluent flowing from the Ferris-Haggarty copper mine into Haggarty Creek and then into Battle Creek West Fork. Through the evaluation process, we found that the Shannon Wiener index, the random runs value, and Ephemeroptera taxa richness appeared to best reflect the impacts that have occurred in both Haggarty Creek and Battle Creek West Fork. In addition, Ephemeroptera/Plecoptera/Trichoptera taxa richness, total taxa richness, and Plecoptera taxa richness, were useful in reflecting those impacts. In contrast, we found that the abundance ratios, the Hilsenhoff Biotic Index, as well as Trichoptera taxa richness, did not reflect the impacts that occurred in Haggarty Creek and Battle Creek West Fork. Finally, this study provided information about the benthic insect communities that are present in the impacted reaches of Haggarty Creek. Such information is needed to assess the potential of those reaches as habitat for the Colorado River cutthroat trout, Oncorhynchus clarki pleuriticus, which is a species of special concern to the Wyoming Department of Game and Fish. PMID- 22432317 TI - Roles of manganese oxides in degradation of phenol under UV-Vis irradiation: adsorption, oxidation, and photocatalysis. AB - Manganese oxides are known as one type of semiconductors, but their photocatalysis characteristics have not been deeply explored. In this study, photocatalytic degradation of phenol using several synthesized manganese oxides, i.e, acidic birnessite (BIR-H), alkaline birnessite (BIR-OH), cryptomelane (CRY) and todorokite (TOD), were comparatively investigated. To elucidate phenol degradation mechanisms, X-ray diffraction (XRD), ICP-AES (inductively coupled plasma-atomic emission spectroscopy), TEM (transmission electronic microscope), N2 physisorption at 77 K and UV-visible diffuse reflectance spectroscopy (UV-Vis DRS) were employed to characterize the structural, compositional, morphological, specific surface area and optical absorption properties of the manganese oxides. After 12 hr of UV-Vis irradiation, the total organic carbon (TOC) removal rate reached 62.1%, 43.1%, 25.4%, and 22.5% for cryptomelane, acidic birnessite, todorokite and alkaline birnessite, respectively. Compared to the reactions in the dark condition, UV-Vis exposure improved the TOC removal rates by 55.8%, 31.9%, 23.4% and 17.9%. This suggests a weak ability of manganese oxides to degrade phenol in the dark condition, while UV-Vis light irradiation could significantly enhance phenol degradation. The manganese minerals exhibited photocatalytic activities in the order of: CRY > BIR-H > TOD > BIR-OH. There may be three possible mechanisms for photochemical degradation: (1) direct photolysis of phenol; (2) direct oxidation of phenol by manganese oxides; (3) photocatalytic oxidation of phenol by manganese oxides. Photocatalytic oxidation of phenol appeared to be the dominant mechanism. PMID- 22432318 TI - Photocatalytic degradation kinetics and mechanism of pentachlorophenol based on superoxide radicals. AB - The micron grade multi-metal oxide bismuth silicate (Bi12SiO20, BSO) was prepared by the chemical solution decomposition technique. Photocatalytic degradation of pentachlorophenol (PCP) was investigated in the presence of BSO under xenon lamp irradiation. The reaction kinetics followed pseudo first-order and the degradation ratio achieved 99.1% after 120 min at an initial PCP concentration of 2.0 mg/L. The pH decreased from 6.2 to 4.6 and the dechlorination ratio was 68.4% after 120 min at an initial PCP concentration of 8.0 mg/L. The results of electron spin resonance showed that superoxide radical (O2*-) was largely responsible for the photocatalytic degradation of PCP. Interestingly, this result was different from that of previous photocatalytic reactions where valence band holes or hydroxyl radicals played the role of major oxidants. Some aromatic compounds and aliphatic carboxylic acids were determined by GC/MS as the reaction intermediates, which indicated that O2*- can attack the bond between the carbon and chlorine atoms to form less chlorinated aromatic compounds. The aromatic compounds were further oxidized by O2*- to generate aliphatic carboxylic acids which can be finally mineralized to CO2 and H2O. PMID- 22432319 TI - Visible light responsive N-F-codoped TiO2 photocatalysts for the degradation of 4 chlorophenol. AB - N-F-codoped TiO2 (NFTO) photocatalysts were synthesized by a simple sol-gel process with tetrabutyl titanate (Ti(OBu)4) as the precursor of TiO2 and ammonium fluoride (NH4F) as the source of N and F. The synthesized photocatalysts were investigated by Xray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis DRS) and photodegradation reaction tests of 4-chlorophenol under visible light irradiation to understand the relationship between the structure of NFTO catalyst and corresponding photocatalytic activity. The crystal phase and particle size of catalysts were found to be largely affected by the calcination temperature. In addition, N-F-codoping could inhibit phase transition of TiO2 from anatase to rutile. The presence of N and F atoms in the lattice of TiO2 is responsible for the visible light catalytic activity. In UV-Vis DRS tests, the spectrum of NFTO exhibited red shift compared with Degussa P25 and the band gap was reduced to around 2.92 eV. Under optimal calcination temperature and dopant concentration conditions, the NFTO photocatalyst exhibited the highest activity in the photodegradation reaction tests of 4-chlorophenol under visible light irradiation with a degradation rate of 75.84%. Besides, the 5-recycle test showed that NFTO photocatalyst could be reused and its activity kept stable under visible light irradiation. PMID- 22432320 TI - Sewage sludge composting simulation as carbon/nitrogen concentration change. AB - Available composting models do not describe accurately the dynamics of composting processes. Difficulty in modeling composting processes is attributed mainly to the unpredicted change in process rate caused by change in activation energy value (E). This article presented the results of an attempt made to utilize patterns of change in carbon, nitrogen and temperature profiles to model sewage sludge composting process as a multi-stage process. Results of controlled sewage sludge composting experiments were used in the study. All the experiments were carried out as batch experiments in a 300-liter Horizontal Drum Bioreactor (HDB). Analysis of the profiles of carbon, nitrogen and temperature has indicated that there were clear patterns that could be used to develop simple models of the process, the initial C/N ratio was between 7-8 and the final C/N ratio of the compost in most experiments were found to be around 15.0, indicating the compost was fully matured and could be used safely for agricultural purpose. Electrical conductivity of composting material decreased from 1.83 to 1.67 dS/m, after a period, it increased gradually from 2.01 to 2.23 dS/m and remained at around 2.33 dS/m till the end of composting. It is found that change in the concentration of total carbon can reasonably be described by three constant process rate coefficients (k1, k2, k3). It is found that the process starts with a certain process rate coefficient (k1) and continues until peak temperature is reached, then it reaches lower process (k2) in the declining phase of the thermophilic stage, and finally it proceeds with a faster process rate (k3) when maturation is reached. Change in the concentration of total nitrogen has shown to have the same patterns of change as carbon. PMID- 22432321 TI - Effects of various pretreatment methods on mixed microflora to enhance biohydrogen production from corn stover hydrolysate. AB - Five individual pretreatment methods, including three widely-used protocols (heat, acid and base) and two novel attempts (ultrasonic and ultraviolet), were conducted in batch tests to compare their effects on mixed microflora to enhance hydrogen (H2) production from corn stover hydrolysate. Experimental results indicated that heat and base pretreatments significantly increased H2 yield with the values of 5.03 and 4.45 mmol H2/g sugar utilized, respectively, followed by acid pretreatment of 3.21 mmol H2/g sugar utilized. However, compared with the control (2.70 mmol H2/g sugar utilized), ultrasonic and ultraviolet pretreatments caused indistinctive effects on H2 production with the values of 2.92 and 2.87 mmol H2/g sugar utilized, respectively. The changes of soluble metabolites composition caused by pretreatment were in accordance with H2-producing behavior. Concretely, more acetate accumulation and less ethanol production were found in pretreated processes, meaning that more reduced nicotinamide adenine dinucleotide (NADH) might be saved and flowed into H2-producing pathways. PCR-DGGE analysis indicated that the pretreatment led to the enrichment of some species, which appeared in large amounts and even dominated the microbial community. Most of the dominated species were affiliated to Enterobacter spp. and Escherichia spp. As another efficient H2 producer, Clostridium bifermentan was only found in a large quantity after heat pretreatment. This strain might be mainly responsible for better performance of H2 production in this case. PMID- 22432322 TI - Heavy metal distribution of natural and reclaimed tidal riparian wetlands in south estuary, China. AB - We evaluated the distribution and accumulation of Cd, Cr, Cu, Ni, Pb and Zn in two plant species (Scirpus tripueter Linn. and Cyperus malaccensis Lam.), in water and soils sampled from the reclaimed tidal riparian wetlands (RTRWs) and the natural riparian wetlands (NRWs) in the Pearl River Estuary (PRE). The results showed that the concentrations of studied heavy metals in soils exceeded the eco-toxic threshold recommended by US EPA. The concentrations of Cd, Cr and Zn in plants may lead to toxic effects. The heavy metal concentrations were high in water and low in soils of RTRWs compared with that in the NRWs. The accumulation of heavy metals in the roots of plants was higher in NRWs than those in RTRWs while the opposite result was found for heavy metal accumulation in shoots. Based on the bioaccumulation and translocation factors, the plants in NRWs had a higher capacity to accumulate heavy metals while higher abilities to transport heavy metals from roots to shoots were observed in RTRWs. Heavy metal contaminations in RTRWs were dominated by anthropogenic sources from both side uplands and river water, whereas in NRWs, the metal accumulations were simultaneously affected by anthropogenic and natural factors PMID- 22432323 TI - Removal of trace arsenic(V) and phosphate from water by a highly selective ligand exchange adsorbent. AB - A highly selective ligand exchange type adsorbent was developed for the removal of trace arsenic(V) (As(V)) and phosphate from water. This adsorbent was prepared by loading zirconium(IV) on monophosphonic acid resin. This adsorbent was able to remove toxic anions efficiently at wide pH ranges. However, low pH was preferable for maximum breakthrough capacity in an adsorption operation. The effect of a large amount of competing anions such as chloride, bicarbonate, and sulfate on the adsorption systems of As(V) and phosphate anions was investigated. The experimental findings revealed that the As(V) and phosphate uptakes were not affected by these competing anions despite the enhancement of the breakthrough points and total adsorption. Phosphate anion was slightly preferable than As(V) in their competitive adsorption by the adsorbent. The adsorbed As(V) and phosphate on the Zr(IV)-loaded resin were quantitatively eluted with 0.1 mol/L sodium hydroxide solution, and the adsorbent was regenerated by 0.5 mol/L sulfuric acid. During several cycles of adsorption-elution-regeneration operations, no Zr(IV) was detected in the column effluents. Therefore, the Zr(IV) loaded monophosphonic acid resin is an effective ligand exchange adsorbent for removing trace concentrations of As(V) and phosphate from water. PMID- 22432324 TI - Synthesis and adsorption performance of lead ion-imprinted micro-beads with combination of two functional monomers. AB - A novel ion-imprinted polymer, lead ion-imprinted micro-beads with combination of two functional monomers, was synthesized using the W/O/W polymerization method. Two functional monomers, 1,12-dodecanediol-O,O'-diphenyl-phosphonic acid (DDDPA) and 4-vinylpyridine, were used to form a suitable construction with micro-pores fitting the template and recognition sites. The effects of adsorbent dosage, solution pH and the competitive ions on the adsorption and separation efficiency of lead ions were investigated. The lead ion-imprinted micro-beads were efficient for lead ions removal from aqueous solution in a broad pH range (4-9), when the adsorbent dosage was above 0.1 g/L. The adsorption process obeyed the pseudo second-order kinetics model and it only took half an hour to reach the equilibrium. The adsorption isotherm of lead ion was described by the Langmuir model (R2 > 0.99) with a maximum adsorption capacity of 116.9 mg/g. In the presence of competitive ions Co2+ and Cd2+, the lead ion-imprinted micro-beads showed a high selectivity for lead ions. The selectivity coefficient of Pb2+/Cd2+ and Pb2+/Co2+ are 99.3 and 114.7, respectively. PMID- 22432325 TI - Organic pollutants removal from 2,4,6-trinitrotoluene (TNT) red water using low cost activated coke. AB - We treated 2,4,6-trinitrotoluene (TNT) red water from the Chinese explosive industry with activated coke (AC) from lignite. Since the composition of TNT red water was very complicated, chemical oxygen demand (COD) was used as the index for evaluating treatment efficiency. This study focused on sorption kinetics and equilibrium sorption isotherms of AC for the removal of COD from TNT red water, and the changes of water quality before and after adsorption were evaluated using high performance liquid chromatography, UV-Vis spectra and gas chromatography/mass spectroscopy. The results showed that the sorption kinetics of COD removal from TNT red water onto AC fitted well with the pseudo second order model. The adsorption process was an exothermic and physical process. The sorption isotherm was in good agreement with Redlich-Peterson isotherm. At the conditions of initial pH = 6.28, 20 degrees C and 3 hr of agitation, under 160 g/L AC, 64.8% of COD was removed. The removal efficiencies of 2,4-dinitrotoluene 3-sulfonate (2,4-DNT-3-SO3-) and 2,4-dinitrotoluene-5-sulfonate (2,4-DNT-5-SO3-) were 80.5% and 84.3%, respectively. After adsorption, the acute toxicity of TNT red water reduced greatly, compared with that of unprocessed TNT red water. PMID- 22432326 TI - Membrane flux dynamics in the submerged ultrafiltration hybrid treatment process during particle and natural organic matter removal. AB - Particles and natural organic matter (NOM) are two major concerns in surface water, which greatly influence the membrane filtration process. The objective of this article is to investigate the effect of particles, NOM and their interaction on the submerged ultrafiltration (UF) membrane flux under conditions of solo UF and coagulation and PAC adsorption as the pretreatment of UF. Particles, NOM and their mixture were spiked in tap water to simulate raw water. Exponential relationship, (J(P)/J(P0) = a x exp{-k[t-(n-1)T]}), was developed to quantify the normalized membrane flux dynamics during the filtration period and fitted the results well. In this equation, coefficient a was determined by the value of J(P)/J(P0) at the beginning of a filtration cycle, reflecting the flux recovery after backwashing, that is, the irreversible fouling. The coefficient k reflected the trend of flux dynamics. Integrated total permeability (SigmaJ(P)) in one filtration period could be used as a quantified indicator for comparison of different hybrid membrane processes or under different scenarios. According to the results, there was an additive effect on membrane flux by NOM and particles during solo UF process. This additive fouling could be alleviated by coagulation pretreatment since particles helped the formation of flocs with coagulant, which further delayed the decrease of membrane flux and benefited flux recovery by backwashing. The addition of PAC also increased membrane flux by adsorbing NOM and improved flux recovery through backwashing. PMID- 22432327 TI - A new method of inhibiting pollutant release from source water reservoir sediment by adding chemical stabilization agents combined with water-lifting aerator. AB - Source water reservoirs easily become thermally and dynamically stratified. Internal pollution released from reservoir sediments is the main cause of water quality problems. To mitigate the internal pollution more effectively, a new method, which combined chemical stabilization with water lifting aerator (WLA) technology, was proposed and its efficiency in inhibiting pollutant release was studied by controlled sediment-water interface experiments. The results showed that this new method can inhibit pollutant release from sediment effectively. The values of mean efficiency (E) in different reactors 2#-5# (1# with no agent, 2# 10 mg/L polymeric aluminum chloride (PAC) was added, 3# 20 mg/L PAC was added, 4# 30 mg/L PAC was added, 5# 20 mg/L PAC and 0.2 mg/L palyacrylamide (PAM) were added) for PO4(3-) were 35.0%, 43.9%, 50.4% and 63.6%, respectively. This showed that the higher the PAC concentration was, the better the inhibiting efficiency was, and PAM addition strengthened the inhibiting efficiency significantly. For Fe2+, the corresponding values of E for the reactors 2#-5# were 22.9%, 47.2%, 34.3% and 46.2%, respectively. The inhibiting effect of PAC and PAM on Mn release remained positive for a relatively short time, about 10 days, and was not so effective as for PO4(3-) and Fe2+. The average efficiencies in inhibiting the release of UV254 were 35.3%, 25.9%, 35.5%, 38.9% and 39.5% for reactors 2#-5#, respectively. The inhibiting mechanisms of the agents for different pollutants varied among the conditions and should be studied further. PMID- 22432328 TI - Removal of microcystin-LR from drinking water using a bamboo-based charcoal adsorbent modified with chitosan. AB - A new kind of low-cost syntactic adsorbent from bamboo charcoal and chitosan was developed for the removal of microcystin-LR from drinking water. Removal efficiency was higher for the syntactic adsorbent when the amount of bamboo charcoal was increased. The optimum dose ratio of bamboo charcoal to chitosan was 6:4, and the optimum amount was 15 mg/L; equilibrium time was 6 hr. The adsorption isotherm was non-linear and could be simulated by the Freundlich model (R2 = 0.9337). Adsorption efficiency was strongly affected by pH and natural organic matter (NOM). Removal efficiency was 16% higher at pH 3 than at pH 9. Efficiency rate was reduced by 15% with 25 mg/L NOM (UV254 = 0.089 cm(-1)) in drinking water. This study demonstrated that the bamboo charcoal modified with chitosan can effectively remove microcystin-LR from drinking water. PMID- 22432329 TI - Adsorptive removal of heavy metal ions from industrial effluents using activated carbon derived from waste coconut buttons. AB - Activated carbon (AC) derived from waste coconut buttons (CB) was investigated as a suitable adsorbent for the removal of heavy metal ions such as Pb(II), Hg(II) and Cu(II) from industrial effluents through batch adsorption process. The AC was characterized by elemental analysis, fourier transform infrared spectroscopy, X ray diffraction, scanning electron microscopy, thermal gravimetric and differential thermal analysis, surface area analyzer and potentiometric titrations. The effects of initial metal concentration, contact time, pH and adsorbent dose on the adsorption of metal ions were studied. The adsorbent revealed a good adsorption potential for Pb(II) and Cu(II) at pH 6.0 and for Hg(II) at pH 7.0. The experimental kinetic data were a better fit with pseudo second-order equation rather than pseudo first-order equation. The Freundlich isotherm model was found to be more suitable to represent the experimental equilibrium isotherm results for the three metals than the Langmuir model. The adsorption capacities of the AC decreased in the order: Pb(II) > Hg(II) > Cu(II). PMID- 22432330 TI - Characteristics and aluminum reuse of textile sludge incineration residues after acidification. AB - The chemical composition and aluminum speciation of sludge incineration residue (SIR) were determined. Cementation of aluminum from sulfuric acid solution using SIR was studied. The results showed that acid-soluble inorganic aluminum was the predominant component in the sludge, and the total leached aluminum increased from 62.2% to 92.9% after incineration. Sulfuric acid dosage and reaction time were found to affect aluminum recovery positively. Conversely, the increase in temperature significantly inhibited recovery reactions. The optimized leaching condition was 1.66 g sulfuric acid per gram of SIR with a reaction time of 3 hr at 20 degrees C, resulting in the highest aluminum leaching rate of 96.7%. Compared to commercial aluminum sulfate solution coagulants, the leaching solution demonstrated higher COD(Cr), turbidity and color removal efficiency for textile wastewater. PMID- 22432331 TI - Computing payment for ecosystem services in watersheds: an analysis of the Middle Route Project of South-to-North Water Diversion in China. AB - Payment for ecosystem services (PES) has attracted considerable attention as an economic incentive for promoting natural resource management recently. As emphasis has been placed on using the incentive-based mechanism by the central government, rapid progress on PES research and practice has been achieved. However PES still faces many difficulties. A key issue is the lack of a fully fledged theory and method to clearly define the design scope, accounting and feasibility of PES criteria. An improved watershed criteria model was developed in light of research on PES practices in China, investigations on the water source area for the Middle Route Project of South-to-North Water Diversion and ecosystem services outflows theory. The basic principle of assessment is the direct and opportunity cost for ecological conservation and environmental protection in the water source area deduct nationally-financed PES and internal effect. Then the scope and the criteria methods were determined, and internal effect was put forward to define benefits brought from water source area. Finally, Shiyan City, which is the main water source area for the Project of Water Diversion, was analyzed by this model and its payment was calculated. The results showed that: (1) during 2003-2050, the total direct cost and opportunity cost would reach up to 262.70 billion and 256.33 billion Chinese Yuan (CNY, 2000 constant prices), i.e., 50.61% and 49.38% of total cost, respectively; (2) Shiyan City would gain 0.23, 0.06 and 0.03 CNY/m3 in 2014-2020, 2021-2030, and 2031 2050, respectively. PMID- 22432332 TI - Effects of relative humidity on the characterization of a photochemical smog chamber. AB - Water vapor plays an important role in many atmospheric chemical reactions. A self-made indoor environmental smog chamber was used to investigate the effects of relative humidity (RH) on its characterization, which included the wall effects of reactive species such as 03 and NOx, and the determination of chamber dependent OH radicals in terms of CO-NOx irradiation experiments. Results showed that the rate constant of O3 wall losses increased with increasing RH, and that their relationship was linearly significant. Although RH affected the rate constant of NOx wall losses, their relationship was not statistically significant. Background air generated a small amount of ozone at both high and low RH. When RH varied from 5% to 79%, the apparent rate constant kNO2-->HONO for the conversion of NO2 into gas phase HONO was estimated in the range of 0.70 x 10(-3)-2.5 x 10(-3) min(-1). A linear relationship between kNO2-->HONO and RH was obtained as kNO2-->HONO (10(-3) min(-1)) = -0.0255RH + 2.64, with R2 and P value being 0.978 and < 0.01. To our knowledge, this is the first report on their relationship. The generation mechanism for HONO and OH was also discussed in this work. PMID- 22432333 TI - Ambient air quality trends and driving factor analysis in Beijing, 1983-2007. AB - The rapid development in Beijing, the capital of China, has resulted in serious air pollution problems. Meanwhile great efforts have been made to improve the air quality, especially since 1998. The variation in air quality under the interaction of pollution and control in this mega city has attracted much attention. We analyzed the changes in ambient air quality in Beijing since the 1980's using the Daniel trend test based on data from long-term monitoring stations. The results showed that different pollutants displayed three trends: a decreasing trend, an increasing trend and a flat trend. SO2, dustfall, B[a]P, NO2 and PM10 fit decreasing trend pattern, while NOx showed an increasing trend, and CO, ozone pollution, total suspended particulate (TSP), as well as Pb fit the flat trend. The cause of the general air pollution in Beijing has changed from being predominantly related to coal burning to mixed traffic exhaust and coal burning related pollution. Seasonally, the pollution level is typically higher during the heating season from November to the following March. The interaction between pollution sources change and implementation of air pollution control measures was the main driving factor that caused the variation in air quality. Changes of industrial structure and improved energy efficiency, the use of clean energy and preferred use of clean coal, reduction in pollution sources, and implementation of advanced environmental standards have all contributed to the reduction in air pollution, particularly since 1998. PMID- 22432334 TI - Preliminary report on methane emissions from the Three Gorges Reservoir in the summer drainage period. AB - Recently reported summertime methane (CH4) emissions (6.7 +/- 13.3 mg CH4/(m2 x hr)) from newly created marshes in the drawdown area of the Three Gorges Reservoir (TGR), China have triggered broad concern in academic circles and among the public. The CH4 emissions from TGR water surfaces and drawdown areas were monitored from 3rd June to 16th October 2010 with floating and static chambers and gas chromatography. The average CH4 emission flux from permanently flooded areas in Zigui, Wushan and Yunyang Counties was (0.33 +/- 0.09) mg CH4/(m2 x hr). In half of these hottest months of the year, the wilderness, cropland and deforested drawdown sites were aerobic and located above water level, and the CH4 emissions were very small, ranging from a sink at 0.12 mg CH4/(m2 x hr) to a source at 0.08 mg CH4/(m2 x hr) except for one mud-covered site after flood. Mean CH4 emission in flooded drawdown sites was 0.34 mg CH4/(m2 x hr). The emissions from the rice paddy sites in the drawdown area were averaged at (4.86 +/- 2.31) mg CH4/(m2 x hr). Excepting the rice-paddy sites, these results show much lower emission levels than previously reported. Our results indicated considerable spatial and temporal variation in CH4 emissions from the TGR. Human activities and occasional events, such as flood, may also affect emission levels. Long-term CH4 measurements and modeling in a large region are necessary to accurately estimate greenhouse gas emissions from the TGR. PMID- 22432335 TI - Effects of humic acid on phytodegradation of petroleum hydrocarbons in soil simultaneously contaminated with heavy metals. AB - The use of humic acid (HA) to enhance the efficiency of phytodegradation of petroleum hydrocarbons in soil contaminated with diesel fuel was evaluated in this study. A sample of soil was artificially contaminated with commercially available diesel fuel to an initial total petroleum hydrocarbons (TPH) concentration of 2300 mg/kg and four heavy metals with concentrations of 400 mg/kg for Pb, 200 mg/kg for Cu, 12 mg/kg for Cd, and 160 mg/kg for Ni. Three plant species, Brassica campestris, Festuca arundinacea, and Helianthus annuus, were selected for the phytodegradation experiment. Percentage degradation of TPH in the soil in a control pot supplemented with HA increased to 45% from 30% without HA. The addition of HA resulted in an increases in the removal of TPH from the soil in pots planted with B. campestris, E arundinacea, and H. annuus, enhancing percentage degradation to 86%, 64%, and 85% from 45%, 54%, and 66%, respectively. The effect of HA was also observed in the degradation of n-alkanes within 30 days. The rates of removal of n-alkanes in soil planted with B. campestris and H. annuus were high for n-alkanes in the range of C11-C28. A dynamic increase in dehydrogenase activity was observed during the last 15 days of a 30-day experimental period in all the pots amended with HA. The enhanced biodegradation performance for TPHs observed might be due to an increase in microbial activities and bioavailable TPH in soils caused by combined effects of plants and HA. The results suggested that HA could act as an enhancing agent for phytodegradation of petroleum hydrocarbons in soil contaminated with diesel fuel and heavy metals. PMID- 22432336 TI - Mercury in leaf litter in typical suburban and urban broadleaf forests in China. AB - To study the role of leaf litter in the mercury (Hg) cycle in suburban broadleaf forests and the distribution of Hg in urban forests, we collected leaf litter and soil from suburban evergreen and deciduous broadleaf forests and from urban forests in Beijing. The Hg concentrations in leaf litter from the suburban forests varied from 8.3 to 205.0 ng/g, with an average (avg) of (49.7 +/- 36.9) ng/g. The average Hg concentration in evergreen broadleaf forest leaf litter (50.8 + 39.4) ng/g was higher than that in deciduous broadleaf forest leaf litter (25.8 +/- 10.1) ng/g. The estimated Hg fluxes of leaf litter in suburban evergreen and deciduous broadleaf forests were 179.0 and 83.7 mg/(ha x yr), respectively. The Hg concentration in organic horizons (O horizons) ((263.1 +/- 237.2) ng/g) was higher than that in eluvial horizons (A horizons) ((83.9 +/- 52.0) ng/g). These results indicated that leaf litterfall plays an important role in transporting atmospheric mercury to soil in suburban forests. For urban forests in Beijing, the Hg concentrations in leaf litter ranged from 8.8-119.0 (avg 28.1 +/- 16.6) ng/g, with higher concentrations at urban sites than at suburban sites for each tree. The Hg concentrations in surface soil in Beijing were 32.0-25300.0 ng/g and increased from suburban sites to urban sites, with the highest value from Jingshan (JS) Park at the centre of Beijing. Therefore, the distribution of Hg in Beijing urban forests appeared to be strongly influenced by anthropogenic activities. PMID- 22432337 TI - Comparison of bacterial community structures in two systems of a sewage treatment plant using PCR-DGGE analysis. AB - The combination of PCR amplification of 16S rRNA genes with denaturing gradient gel electrophoresis (DGGE) analysis was used to reveal the compositions and dynamics of bacterial communities in a sewage treatment plant with two systems, i.e., an anoxic-anaerobic-aerobic system (inverted A20) and an anaerobic-anoxic aerobic one (conventional A20) over a period from February to July 2009, during which both systems experienced serious sludge bulking problems. The DGGE patterns showed that there were many common bands in both systems, suggesting the high similarity of bacterial communities of the two systems. Meanwhile, the moving window correlation analysis showed that the two systems experienced different microbial community structure changes during the period, which might be related with the different situations of the occurrence and disappearance of sludge bulking, as being reflected by sludge volume index (SVI) values. Major bands of DGGE patterns of sludge samples were further sequenced. Phylogenetic affiliation indicated that the majority of the sequences obtained were affiliated with Actinobacteria, Firmicutes, Bacteroidetes/Chlorobi group and alpha- and beta Proteobacteria. Two sequences showed high similarities to typical filamentous bacteria Microthrix parvicella and Nostocoida limicola I, indicating that these bacterial species have been involved in the sludge bulking problems. PMID- 22432338 TI - Removal of crystal violet from aqueous solution using powdered mycelial biomass of Ceriporia lacerata P2. AB - A biosorbent prepared from powdered mycelial biomass of Ceriporia lacerata (CLB), a basidiomycetous fungus, was applied for the uptake of Crystal Violet from aqueous solution. A batch adsorption experiment was used for the biosorption process, involving effect of experimental factors and biosorption kinetics and equilibrium. Biosorption process showed that the removal of Crystal Violet by CLB was effective over wide pH range, and meanwhile was independent on ionic strength. Biosorption capacities of CLB increased with the initial dye concentration increasing, due to an increase in the driving force of the concentration gradient. The adsorbed Crystal Violet amount per unit biomass weight decreased with increasing biosorbent dosage, due to the splitting effect of flux (concentration gradient) between sorbate and biosorbent. A maximum sorption capacity of 239.25 mg/g was observed. Biosorption kinetics was found to be best represented by the pseudo second-order kinetic model. The equilibrium adsorption data was well described by the Koble-Corrigan model. FT-IR (Fourier Transform Infrared Spetroscopy) spectrum showed the presence of O-H, COOH, C=O, C N, C-H, -NH2 and P-OH in the surface of CLB as functional groups. This study showed CLB can effectively remove CV from dye wastewater. PMID- 22432339 TI - Biodegradation of aniline by Candida tropicalis AN1 isolated from aerobic granular sludge. AB - Aniline-degrading microbes were cultivated and acclimated with the initial activated sludge collected from a chemical wastewater treatment plant. During the acclimation processes, aerobic granular sludge being able to effectively degrade aniline was successfully formed, from which a preponderant bacterial strain was isolated and named as AN1. Effects of factors including pH, temperature, and second carbon/nitrogen source on the biodegradation of aniline were investigated. Results showed that the optimal conditions for the biodegradation of aniline by the strain AN1 were at pH 7.0 and 28-35 degrees C. At the optimal pH and temperature, the biodegradation rate of aniline could reach as high as 17.8 mg/(L x hr) when the initial aniline concentration was 400 mg/L. Further studies revealed that the addition of 1 g/L glucose or ammonium chloride as a second carbon or nitrogen source could slightly enhance the biodegradation efficiency from 93.0% to 95.1%-98.5%. However, even more addition of glucose or ammonium could not further enhance the biodegradation process but delayed the biodegradation of aniline by the strain AN1. Based on morphological and physiological characteristics as well as the phylogenetic analysis of 26S rDNA sequences, the strain AN1 was identified as Candida tropicalis. PMID- 22432340 TI - Bioaccumulation of metals in human blood in industrially contaminated area. AB - Heavy metals were analyzed in different foods crops, milk, meat and blood samples collected from different age group subjects such as children (1-12 years), adolescent (12-18 years), adults (18-45 years) and old age (above 45 and 55 years for males and females, respectively) from polluted and relatively less polluted areas. The results revealed that the consumption of contaminated food crops, meat and milk have significantly increased the concentrations of selected metals in the human blood. Cu, Zn and Mn concentrations were significantly higher (p < 0.05) in the blood samples collected from the polluted area as compared to control area. Old people had accumulated high concentrations of metals as compared to the younger ones within the same area. Males accumulated higher concentrations of metals as compared to females. PMID- 22432341 TI - Catalytic oxidation of benzene over nanostructured porous Co3O4-CeO2 composite catalysts. AB - Mesostructured Co3O4-CeO2 composite was found to be an effective catalytic material for the complete oxidation of benzene. The Co3O4-CeO2 catalysts with different Co/Ce ratios (mol/mol) were prepared via the nanocasting method and the mesostructure was replicated from two-dimensional (2D) hexagonal SBA-15 and three dimensional (3D) cubic KIT-6 silicas, respectively. All the obtained Co3O4-CeO2 catalysts exhibited the similar symmetry with the parent silicas and well ordered mesostructures. The Co3O4-CeO2 catalysts with 2D mesostructure showed lower catalytic activities than the corresponding 3D materials. The Co3O4-CeO2 catalyst nanocasted from KIT-6 and with the Co/Ce ratio of 16/1 possessed the best catalytic benzene oxidation activity due to larger quantities of surface hydroxyl groups and surface oxygenated species. The mesostructured Co3O4-CeO2 material thus shows great potential as a promising eco-environmental catalyst for benzene effective elimination. PMID- 22432342 TI - A kinetic model of ti(IV)-catalyzed H2O2/O3 process in aqueous solution. AB - To well describe the Ti(IV)-catalyzed H2O2/O3 reaction in aqueous solution, a kinetic model was established based on its mechanism. This model was then validated by the experiments of acetic acid degradation in aqueous solution. It was found that the correlation coefficient of fittings was higher than 0.970. Three key operating factors affecting organic degradation in the Ti(IV)-catalyzed H2O2/O3 process were studied, including Ti(IV) concentration, dissolved ozone concentration and initial H2O2 concentration. Furthermore, some experiments were conducted to determine the rate constant for dissolved ozone decomposition initiated by Ti2O5(2+). The rate constant measured is almost in accord with the data analyzed by this kinetic model. The goodness of fittings demonstrated that this model could well describe the kinetics of the Ti(IV)-catalyzed H2O2/O3 reaction mathematically and chemically. Therefore, this kinetic model can provide some useful information to optimize the parameters in ozonation of water containing certain pollutants. PMID- 22432343 TI - Apathy: how to ruin a good thing. PMID- 22432344 TI - Each legislative session brings new challenges and familiar issues. PMID- 22432345 TI - Federal health reform in the Supreme Court--the lay of the land. PMID- 22432346 TI - IMS wins District Court case regarding fluoroscopy. PMID- 22432347 TI - Alignment of medical home and partnership for patients. PMID- 22432348 TI - Notes outside the medical record. PMID- 22432350 TI - Patient's page. Common mouth sores. PMID- 22432349 TI - AMA study finds that office-based physicians are vital to Iowa economy. PMID- 22432351 TI - From the 1939 January Bulletin of the Oklahoma Dental Society. January 1939. PMID- 22432352 TI - Xylitol--fast facts. PMID- 22432353 TI - Letter about Invisalign practices--important! PMID- 22432354 TI - Practical tips for managing LinkedIn and Facebook (on top of everything else). AB - Time-saving steps and strategies to help you make room for social media in your crowded day. I bet you've never thought to yourself, "I'd like more work to do". So how can you possibly accomplish everything and manage your association's LinkedIn group and Facebook page as well? PMID- 22432355 TI - Join the end of life care debate. PMID- 22432356 TI - Nurses may have technical role in assisted dying. PMID- 22432357 TI - Assisted suicide debate puts end of life care in spotlight. PMID- 22432358 TI - Media portrayal skews people's view of life in a residential home. PMID- 22432359 TI - Frail older people and emergency care. PMID- 22432360 TI - Care of patients undergoing joint replacement. AB - Hip and knee replacements are common orthopaedic procedures that can greatly improve patients' quality of life and provide relief from the pain caused by various musculoskeletal diseases. This article considers pre-operative preparation of the patient undergoing joint arthroplasty and significant post operative clinical considerations. The nurse has an important role in the preparation, care and support of the patient throughout the surgical journey. Holistic assessment and effective pre and post-operative planning facilitate patient-focused care and optimal recovery. PMID- 22432361 TI - Setting up a support group for carers of stroke survivors. AB - A stroke specialist nurse enlisted the help of women carers to develop a self supporting carers' group in Northern Ireland. Members are offered information, advice and a forum for service improvement suggestions. Two founding members discuss their experiences of attending meetings. PMID- 22432362 TI - Care home staff can detect the difference between delirium, dementia and depression. AB - Prevention of delirium is an important part of looking after care home residents, however, it can be difficult to detect, especially in those who have dementia. This article explores the perceptions and experiences of care home staff integrating delirium prevention activity in their everyday work. As part of the Stop delirium! feasibility study interviews were carried out and when they were analysed five themes were identified: triggers and knowledge; detection and observation; effect of closest contact; changes in management of care; and communication and teamwork to overcome difficulties. Together these provide insight into how carers identified a potential episode of delirium and indicated the steps that might be taken to manage residents' care. Communication and teamwork were identified as important in delirium prevention and appropriate management. PMID- 22432363 TI - How person-centred care can improve nurses' attitudes to hospitalised older patients. AB - The relationship between the attitudes and behaviours of nurses and the resulting care that they provide to older people is explored. It aims to raise nurses' awareness and encourages them to reflect on their personal values and behaviours. The person-centred framework developed by McCormack and McCance (2010) is presented as one approach to improve care. The biographical approach (Clarke et al 2003) is also described as a means to enable nurses to see patients as people first and place them at the heart of health care. PMID- 22432364 TI - Much to be celebrated. Interview by Ruth Williams. PMID- 22432365 TI - A busy year for the RACs. Learning from last year's denials and preparing for what's ahead will help providers avoid being stung in 2012. PMID- 22432366 TI - The privacy mindset. Setting better boundaries with third-party record reviewers. PMID- 22432367 TI - Staying compliant with the HIPAA privacy and security rules. PMID- 22432368 TI - ICD-10 toolkit. New toolkit provides resources to assist with the ICD-10 transition. PMID- 22432369 TI - Automation for Privacy and security compliance. PMID- 22432370 TI - Documentation trends in the health record. PMID- 22432371 TI - The facts about ICD-10-CM/PCS implementation. Implementation will improve the quality of patient care. PMID- 22432372 TI - HIM best practices for managing patient portals. PMID- 22432373 TI - Managing copy functionality and information integrity in the EHR. PMID- 22432374 TI - RAC inpatient coding denials. Key areas of improper payment in permanent program. PMID- 22432375 TI - Developing a coding quality improvement program. PMID- 22432376 TI - Both sides of apology. PMID- 22432377 TI - Apology for errors: whose responsibility? AB - When things go wrong during a medical procedure, patients' expectations are fairly straightforward: They expect an explanation of what happened, an apology if an error was made, and assurance that something will be done to prevent it from happening to another patient. Patients have a right to full disclosure; it is also therapeutic in relieving their anxiety. But if they have been harmed by our mistake, they also need an apology to maintain trust. Apology conveys respect, mutual suffering, and responsibility. Meaningful apology requires that the patient's physician and the institution both take responsibility, show remorse, and make amends. As the patient's advocate, the physician must play the lead role. However, as custodian of the systems, the hospital has primary responsibility for the mishap, for preventing that error in the future, and for compensation. The responsibility for making all this happen rests with the CEO. The hospital must have policies and practices that ensure that every injured patient is treated the way we would want to be treated ourselves--openly, honestly, with compassion, and, when indicated, with an apology and compensation. To make that happen, hospitals need to greatly expand training of physicians and others, and develop support programs for patients and caregivers. PMID- 22432378 TI - Nurturing a culture of patient safety and achieving lower malpractice risk through disclosure: lessons learned and future directions. AB - In mid-2001 and early 2002, the University of Michigan Health System systematically changed the way it responded to patient injuries and medical malpractice claims. Michigan adopted a proactive, principle-based approach, described as an "open disclosure with offer" model, built on a commitment to honesty and transparency. Implementation was followed by steady reduction in the number of claims and various other metrics, such as elapsed time for processing claims, defense costs, and average settlement amounts. Though the model continues to evolve, it has retained its core components and the culture it nurtured while spurring other initiatives such as a unique approach to peer review. In this article we review our experience, identify the essential practical components of our model, offer suggestions for tailoring the approach to other settings, and present some thoughts as to the future of this approach. PMID- 22432379 TI - Implementing disclosure: making "sorry" a reality for frontline staff. PMID- 22432380 TI - "Fix it as best you can, and learn from your mistakes": apology lessons, past and present. PMID- 22432381 TI - The medical apology: who and how? PMID- 22432382 TI - End of the year... a time to reflect. PMID- 22432383 TI - "The adoption process needs some revision, but it is not a broken system". PMID- 22432384 TI - Cold shoulder. PMID- 22432385 TI - Greater co-operation between GPs and health visitors is needed for a successful child health surveillance programme. PMID- 22432386 TI - Rise and shine. PMID- 22432387 TI - A topic in 10 questions: assessing common dietary deficiencies. PMID- 22432388 TI - Reality bites. AB - When milk teeth are replaced by adult teeth, it is crucial that a good oral health regime is maintained in order to prevent caries. Parents of infant school children should ideally supervise the twice daily cleaning regime to ensure nothing is missed. Older children and teenagers may be adversely influenced by their peers to eat sugary and other junk foods, but appealing to their vanity may work better rather than a lecture on disease prevention. PMID- 22432389 TI - Good alternatives. PMID- 22432390 TI - Risky business. AB - Unintentional injury is one of the leading causes of morbidity and mortality in children aged one to 14 and puts more children in hospital than any other cause. The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce public health guidance on the prevention of unintentional injuries among children and young people aged under 15. This paper, by a member of the NICE programme development group, aims to provide an overview of the recently published guidance. The guidance focuses on strategies, regulation, enforcement, surveillance and workforce development in relation to preventing unintentional injuries in the home, on the road and during outdoor play and leisure. A summary of the main recommendations will be given and those recommendations or considerations directly applicable to community practitioners will be outlined. PMID- 22432391 TI - Awareness of cardiovascular prevention methods among residents of post-communist Polish provinces with highest mortality rates. AB - AIM: The aim of the study was to estimate the awareness of healthy lifestyle behaviours in cardiovascular diseases (CVD) prevention and to find out possible determinants of this knowledge among adult residents of Polish provinces with the highest CVD mortality rates. MATERIAL AND METHODS: A cross-sectional analysis of randomly selected representative sample of 2,211 (51.9% women) aged 20-74 years from Lodz and Lublin voivodeships participating in the National Polish Health Survey WOBASZ. Knowledge on CVD prevention, sociodemographic and lifestyle characteristics were collected by an interviewer-administered questionnaire. Blood pressure, anthropometrics, plasma lipids and glucose were measured according to the WHO MONICA protocol. RESULTS: Approximately 68% of participants, had poor awareness of preventive methods and majority of them were not able to name any specific approach. Most often mentioned method of CVD prevention was relaxing/avoiding stress (51.2%). The least known healthy behaviour was a reduction of salt intake and adequate fruit/vegetables consumption, mentioned by 18.2% and 23%, respectively. About 16.4% of women and 23% of men with risk factors of CVD were not aware of any non-pharmacological preventive method. Poor knowledge of CVD prevention was significantly more prevalent among persons aged > or = 65 years, with elementary education level, lower income, living in the rural settings, declaring poor self-rated health. Dietary and physical activity advice given by a primary care physician was significantly related to better knowledge among men with CVD risk factors. CONCLUSIONS: There is a need to focus on increasing educational level in this regions, especially in rural settings. Due to important role of primary care physicians in health education, more attention should be paid to individuals with CVD risk factors as their preventive knowledge level is very low and comparable to the level of low-risk individuals. PMID- 22432392 TI - Measurements of the presence of pollutants among children and their mothers: European pilot study aiming at a harmonised approach for human biomonitoring. PMID- 22432393 TI - Follow-up of a cardiovascular prevention campaign. AB - The aim of this study was to evaluate the cardiovascular risk (CVR) factors and morbidity in a sample of the population that received a brief intervention on cardiovascular prevention seven years ago. All family physicians who participated in the Cardiovascular Prevention Campaign in five Belgian towns in 2002-2003 received a follow-up questionnaire for each participating patient. The questionnaire included questions about new cardiovascular diagnoses, parameters of the latest physical examination and blood tests. Analyses were based on the 318 questionnaires that included essential information such as the date of the latest contact and the new diagnosis or mortality. The proportion of patients with a low CVR decreased from 75% in 2002-2003 to 40% in 2010. Participants showed a significant increase of the abdominal circumference, triglycerides and fasting glycaemia. Only LDL-cholesterol levels decreased significantly (p = 0.002). Four percent of the patients died, more male (7 ) than female (2%) (p = 0.03). One in ten patients presented with a cardiovascular event. Most of the changes are probably attributable to age. It is clear that the long-term effect of a brief intervention only followed by usual care is not sufficient to attain optimal level of cardiovascular prevention. PMID- 22432394 TI - Health promoting behaviours and lifestyle characteristics of students at seven universities in the UK. AB - AIMS: University students' wellbeing and health promoting and damaging behaviours are important and comprise many parameters. The purpose of this study was to assess a range of health behaviours and lifestyle characteristics of 3,706 undergraduate students from seven universities in England, Wales and Northern Ireland. We compared differences in these parameters between males and females, and across the participating universities. METHODS: A self-administered questionnaire assessed socio-demographic information (e.g., gender, age), nutrition, dietary intake and food consumption patterns, as well as the importance of healthy eating, three levels of physical activity, restful sleep, tobacco smoking, use of illicit substance (recreational drugs), frequency of binge drinking and problem drinking. The data was collected in 2007-2008. RESULTS: While females generally reported lower use of tobacco, illicit substances and alcohol (binge drinking/problem drinking) and consumed more fruits and vegetables, male students had a higher level of physical activity, consumed less sweets and had more restful sleep. When lifestyle characteristics of students were compared between the different universities we observed some 'clustering' of the parameters under study, whereby favourable health practices would be exhibited at some universities; and conversely, the clustering of less favourable practices exhibited at other participating sites. CONCLUSIONS: We conclude that only a minority of students exhibited positive health practices above recommended levels and the level of binge drinking and problem drinking was high. This calls for increased awareness of university administrators, leaders and policy makers to the risky health habits of their students. The observed clustering effects also indicate the need for local (university-specific) health profiles as basis and guidance for relevant health promotion programmes at universities. PMID- 22432395 TI - Adolescents' health behaviours and its associations with psychological variables. AB - OBJECTIVE: The purpose of the study was to investigate the prevalence of health risk behaviours among a random sample of Korean adolescents and the relationship of psychological variables with health risk behaviours. METHODS: 885 students ranged from 7th to 9th grade were randomly selected from 3 junior high schools in Dobong-gu district, Seoul. Four Korean-version measures were used to assess the health risk behaviour and psychological variables of adolescents. Frequency analysis, correlation analysis, and regression analysis were performed to accomplish the purpose of the study. RESULTS: Korean adolescents showed high prevalence of physical inactivity (n = 67%), smoking (n = 54%), drinking alcohol (n = 69%), eating problem (n = 49%), mental health problem (n = 57%), and viewing pornography (n = 47%). In addition, this study revealed that the three psychological variables (multidimensional health locus of control, self-efficacy, and self-esteem) were significantly correlated with health risk behaviours, and had significant effect to account for health risk behaviours (R2 = 0.42 for physical inactivity, 0.33 for viewing pomography, 0.31 for smoking, 0.28 for mental health problems, 0.26 for illegal drug use, 0.19 for drinking alcohol, and 0.15 for eating problem). CONCLUSION: The current study provides significant information on psychological variables related to adolescents' health risk behaviour. This study has the potential to influence the development of better health education and promotion programs for adolescents. PMID- 22432396 TI - Attitude of Lithuanian residents to confidentiality of adolescent sexual and reproductive health care. AB - OBJECTIVE: To assess the attitudes of Lithuanian residents towards the protection of confidentiality in the sexual and reproductive health care of adolescents. MATERIAL AND METHODS: A public opinion survey was performed in August 2005. A random sample, taking into account age, sex, education, employment, family status, place of residence of 1,054 Lithuanian residents aged 16-74 was interviewed in their households. The topics dealt with in the 23-item questionnaire concerned attitudes towards confidentiality in adolescents' sexual and reproductive health care as well as towards sexual and reproductive health promotion for them. RESULTS: More than half (58%) of the respondents believed that confidentiality is an important issue in case of sexual and reproductive health services that address adolescents. Although only 12% of Lithuanians were ready to agree with the legalization of the right to confidentiality in health care for those younger than 16, at least one-third of the respondents stated that physicians have to protect confidential counselling for 14-15-year-old adolescents on inter alia contraception, pregnancy and sexually transmitted infections. Forty-two percent of the respondents gave top priority to the legal initiative focused on improvement of confidentiality protection. Other promising strategies selected by Lithuanian residents included the development of policies concerning confidentiality protection for minor patients, assuring the privacy of consultations and protecting the medical record keeping system. CONCLUSIONS: The Lithuanian residents surveyed had a positive attitude towards confidential sexual and reproductive health care for adolescents. They stated that guarantees of confidentiality should depend on the reason for the consultation and the age of the patient. The most promising initiatives for the improved protection of confidentiality include strengthening legislation and improving organizational procedures in health care settings. PMID- 22432397 TI - Risk factors of hepatitis C infection among Egyptian blood donors. AB - BACKGROUND: Surveillance of infectious disease markers in the blood donor population is important in recognizing trends in prevalence and incidence of transfusion related infections in asymptomatic volunteer blood donors. SUBJECTS AND METHODS: It was a cross sectional study. Samples were collected from volunteer blood donors and questionnaire was designed to collect the risk factors data. The prevalence of hepatitis C antibodies among 1,000 apparently healthy blood donors were determined. OBJECTIVE: To estimate the prevalence of virus C hepatic infection and to illustrate the various socio-economic, behavioural and medical factors related to infection with Hepatitis C (HCV) among apparently healthy individuals. It contributed to analysis of the particularities of Egyptian blood donors and helped to better understand the challenges and solutions of blood safety. RESULTS: The prevalence of HCV was 16.8%. There was an association of positive anti-HCV test with socio-demographic, medical and behavioural risk factors. CONCLUSION: This study provided comprehensive and reliable information on the possible risk factors affecting spread of Hepatitis C in the area. PMID- 22432398 TI - Evaluation of students' social hand washing knowledge, practices, and skills in a university setting. AB - BACKGROUND: Handwashing is an effective and inexpensive way to prevent diarrhea and acute respiratory infections. This study aimed to evaluate the Turkish University students' social hand washing knowledge, practices, skills and related factors. MATERIALS AND METHODS: All existing 1st year students in the Medical and Educational Faculty, plus all existing 2nd and 3rd year students in the Medical Faculty of Pamukkale University, Denizli, Turkey, from April to May, 2010, were eligible for the study. Participants filled in a questionnaire. The questionnaire tested the students' social hand washing knowledge (8 questions), practices (21 questions), and skills (10 questions) and it was prepared using previously published studies. Participants received 1 point for each correct answer provided. Final scores were calculated by summing up the points from all questions in the particular section divided by the number of questions in this section and multiplied by 100. The Family Affluence Scale was used to determine a socioeconomic status (SES). RESULTS: In all 303 students participated in this study. Participants' age (+/- SD) was 20.1 +/- 1.6 and the age range was between 18 and 32. Sixty two point seven percent of the participants were women. Forty four point nine percent of the participants were medical students. Fifty one point eight percent of the participants were in low SES. Twenty seven point four percent of the participants wash their hands less than 5 times a day. main reason for skipping hand washing was the participants' belief of 'no need' (63.7%). The mean scores (+/- SD) of participants' hand washing knowledge, practices, and skills were 71.2 +/- 20.7, 60.3 +/- 13.4 and 79.7 +/- 18.4, respectively. All scores were significantly higher in women. A multivariate analysis showed that gender was the main factor affecting all scores. CONCLUSIONS: Increasing quantity and/or quality of available campus based public health educational programs, creating hand-hygiene promotion programs to the general public and using the findings from this study are recommended. PMID- 22432399 TI - Estimated daily intake of benzoic acid through food additives in adult population of South East Serbia. AB - The aim of this study is to estimate dietary intake of benzoic acid and its salts through food additives in adult population of South East Serbia. Information on dietary intake among 620 adults (aged 18-65) was collected using a food frequency questionnaire, and 748 food samples were analyzed. The mean estimated intake of benzoic acid -0.32 mg/kg of body weight (bw) per day was below acceptable daily intake (ADI). Dietary exposure to benzoic acid (0.36 mg/kg of bw/day; 7.2% ADI) (consumer only), also did not exceed ADI. The main contributors of benzoic acid to dietary intake were non alcoholic beverages (43.1%), ketchup and tomato products (36.1%), and domestic pickled vegetables (19.4%). The results of this study indicate that dietary exposure to benzoic acid and its salts through food preservatives does not represent a public health risk for the adult population of South East Serbia. PMID- 22432400 TI - Cutaneous superficial myiasis: report of a rare nosocomial parasitic disease caused by Sarcophaga spp. (diptera, sarcophagidae). AB - Flies of the genus Sarcophaga are known to cause myiasis in necrotic wounds and in anatomical cavities where fluids have collected. We present here the first case of external cutaneous myiasis by Sarcophaga larvae in the absence of skin ulcerations or necrosis. The host in this case was a geriatric patient with limited motor and neurological capacity who lives in a nursing home. Of particular importance is that Sarcophaga is capable of causing myiasis even in the absence of cutaneous infections or significant stasis of fluids or secretions and that the larvae can cause damage in otherwise healthy tissue. PMID- 22432401 TI - Rare positive laboratory tests for the presence of influenza virus A/H1N1--2009 in May, June, July, 2011, in the districts of Kosice I-IV and surroundings of Kosice in the Slovak Republic. AB - Influenza illnesses and positive laboratory tests for the presence of influenza virus in recent years in the districts of Kosice I-IV and surroundings have only occurred during the winter season. In May to July 2010 only one positive laboratory test for the presence of influenza virus A/H1N1-2009 was reported. In 2011, during the same period, a total of 29 positive laboratory tests recorded the presence of influenza virus A/ H1N1-2009 in individuals with typical clinical symptoms of influenza. Of 29 clinical cases, 27 were diagnosed as influenza and 2 as SARI; 4 cases involved children. PMID- 22432402 TI - The Department of Physiology of the UPR-School of Medicine: history and contribution to the physiological sciences in Puerto Rico 1950-2010. AB - In 1949, the creation of the University of Puerto Rico-School of Medicine required the recruitment of a group of faculty with expertise in the physiological sciences. The assembled group established the foundation for the Department of Physiology in the fall of 1950. Since then, the Department has made important contributions to the School of Medicine, the Medical Sciences Campus, and the University of Puerto Rico. These contributions include among others, participation in the educational programs in medicine, dentistry, and the biomedical sciences, the generation of knowledge in science through research in different components of the physiological sciences, and the development of researchers and academicians, many of whom have eventually occupied key positions in the UPR system and the private sector. Through the involvement of key faculty in the development of the MBRS-SCORE and RCMI Programs, the Department has made significant contributions to the infrastructure of the Medical Sciences Campus. Recently, the Department faculty was instrumental in the formation of the Puerto Rico Physiological Society to help promote education and research in the physiological sciences in Puerto Rico. Sixty years after its creation, the Department of Physiology is stronger than ever, and looks to the future with optimism, based on our learned experiences and our capacity to adapt in response to the evolving needs of research and education. PMID- 22432403 TI - Clinical course and factors associated with remission in pemphigus vulgaris patients in Puerto Rico. AB - OBJECTIVE: To describe and identify those factors associated with remission on pemphigus vulgaris (PV) patients in Puerto Rico. METHODS: This retrospective cohort study evaluated PV patients followed at the University Puerto Rico (UPR) Bullous Diseases Clinic during the 2000-2010 period. Patients included in the study had clinical and pathologic findings consistent with PV and had a disease duration of at least 3 years. Variables including gender, date of birth, time of disease onset, and date of first partial or complete remission were collected from the medical chart for each study participant. The primary outcome was to determine the number of patients who achieved partial or complete remission. Other secondary outcomes were to identify if partial/complete remission were associated to gender, disease duration, and age at onset of disease. RESULTS: Among 35 patients included in this study, 6 (17%) achieved complete remission and 28 (80%) achieved partial remission. A statistically-significant association was found between duration of disease and remission, predicting a 52% probability of remission after ten years of disease duration. Age at onset of disease showed a trend association with remission, although it was not statistically significant. Gender was not associated with remission. CONCLUSION: These findings provide insights into the clinical course of PV and can be of value in the management and care of this patient population. PMID- 22432404 TI - Are adults diagnosed with diabetes achieving the American Diabetes Association clinical practice recommendations? AB - OBJECTIVE: This study assessed the proportion of adults with previously diagnosed diabetes mellitus (DM) who met selected preventive practices and treatment goals according to the American Diabetes Association (ADA) standards of medical care. METHODS: A secondary analysis of data collected for a previous epidemiologic study that used a probability cluster design to select 859 persons aged 21-79 years in the San Juan metropolitan area was undertaken. This study focused on 136 (15.8%) adults who self-reported DM. The Standards of Medical Care in Diabetes published by the ADA in 2011 were used to determine the proportion of adults achieving selected clinical practice recommendations. RESULTS: Less than half of adults achieved recommended treatment goals for LDL-cholesterol (47.8%), HDL cholesterol (44.1%), blood pressure (41.2%) and HbAlc (28.7%). The percentage of adults achieving recommended levels of HbAlc, blood pressure and LDL-cholesterol simultaneously was 6.6%; the percentage achieving HbA1c, blood pressure, LDL cholesterol, HDL-cholesterol, triglycerides and albumin-to-creatinine ratio target levels was only 2.2%. More than half (60.2%) reported daily self monitoring of foot ulcers and HbAlc testing at least twice over the past year (52.3%). However, less than half reported annual dilated eye examination (49.2%), annual comprehensive foot examination (43.8%), daily self-monitoring blood glucose (37.5%), moderate or vigorous physical activity (33.8%), and self management DM education (28.9%). CONCLUSION: This study showed that a substantial proportion of adults with DM did not achieve ADA recommendations on selected preventive practices and treatment goals. Strategies to improve DM medical care and surveillance of preventive-care practices and treatment goals among affected individuals are essential for planning further initiatives that contribute to reduce the burden of DM complications. PMID- 22432405 TI - Allergen sensitivity (mites, insects, and pets) in a Puerto Rican population. AB - OBJECTIVE: The people of Puerto Rico have one of the highest asthma prevalence and morbidity rates in the U.S.A. Limited information is available on the most common allergy sensitivities among island residents. The aims of the study were to determine the most common inhalant allergen sensitivities among a convenience sample in Puerto Rico and determine as well their relationship to an asthma or a rhinitis diagnosis. METHODS: In August of 2008, we evaluated a cohort of subjects visiting ambulatory clinics offering health screening; the clinics were located in two of the island's biggest cities: Guaynabo in the north and Ponce in the south. Subjects over three years of age (or their parents) visiting the clinics answered a survey on asthma and rhinitis and were skin tested for reactivity to common aeroallergens. RESULTS: The survey included 395 subjects with a mean age of 29 years. Thirty-six percent reported a history of asthma, of whom 83% (30% of the total participants) reported still having asthma, and 76% reported having rhinitis. Sixty-five percent of the subjects were sensitive to at least one antigen. Subjects sensitive to mites were 53% more likely to have suffered from asthma than were non-mite-sensitized subjects (OR = 1.53, p < 0.05) sensitivity to mosquitoes (OR = 2.25, p < 0.02), mites (OR = 2.53, p < 0.00001), feathers (OR = 2.72, p < 0.03), dogs (OR = 3.02, p < 0.01), or cats (OR = 3.42, p < 0.001) increased an individual's likelihood of suffering from rhinitis. CONCLUSION: The most common sensitivities identified were to mites and insects. Mite sensitivity was associated with rhinitis and asthma. Sensitivity to animal dander as well as to mosquitoes was associated to with rhinitis. Further studies are warranted to explore the relevance of allergen sensitivity in terms of asthma and rhinitis prevalence and morbidity among residents of Puerto Rico. PMID- 22432406 TI - Use of the Objective Grading System of the American Board of Orthodontics to evaluate treatment at the Orthodontic Graduate Program Clinic, University of Puerto Rico, 2007-2008. AB - OBJECTIVE: The Objective Grading System (OGS) was introduced in 1999 by the American Board of Orthodontics (ABO) as an instrument to reduce subjectivity when evaluating cases submitted to the ABO for examination. The objectives of this study were (1) to employ the OGS to determine the percentage of treated and completed cases from the University of Puerto Rico's (UPR) Orthodontic Graduate Program Clinic that would have earned a passing OGS score (according to the ABO standards) and (2) to assess the contribution of various patient characteristics and factors to this score. METHODS: A total of 64 cases completed during 2007 and 2008 met the inclusion criteria and were evaluated by a calibrated examiner using the OGS. Logistic regression and multiple regression analyses were performed to assess the association between the explanatory variables and the overall OGS score. RESULTS: Of the cases evaluated, 18.8% received a passing OGS score of <20, 34.4% received a borderline score of 20-30, and 46.9% received a failing score of >30. The mean OGS score was 32.17 +/- 13.03 points, similar to the mean OGS score of 34.36 +/- 10.39 reported in 2004 by a similar study. CONCLUSION: This study demonstrate that 53% of the completed cases at the university clinic obtained a potential passing score as per the ABO (OGS <30 points). Multiple and logistic regression analyses could neither explain the relationship between the explanatory variables and the OGS scores nor predict the probability of a particular case's passing when all variables were considered. PMID- 22432407 TI - Visual loss associated with influenza A: a case report and review of literature. AB - A 24-year-old female presenting with influenza A pneumonia and simultaneous visual loss was hospitalized. A complete ophthalmological examination was performed three weeks later. Best corrected visual acuity was 20/70 (right eye) and 20/30 (left eye). A dilated fundus exam revealed bilateral vitreous cells and marked bilateral optic nerve swelling with associated peripapillary hemorrhages. A submacular hemorrhage was seen in the right eye. Spinal tap opening pressure was 490 mmHg, with normal cerebrospinal fluid cell counts. Eight months after the initial clinical presentation, the patient was asymptomatic, with normal posterior poles and a best corrected visual acuity of 20/30 in the right eye and 20/25 in the left eye. Although papilledema can produce peripheral retinal hemorrhages secondary to extensive retinal venous congestion, the presence of bilateral vitritis and elevated influenza serum titers suggested that the patient might be suffering from influenza retinopathy. Vitreous polymerase chain reaction could potentially aid in the diagnosis of influenza retinopathy. PMID- 22432408 TI - An unusual cause of right lower quadrant abdominal pain. PMID- 22432409 TI - Report of the 2011 University of Puerto Rico-MD Anderson Cancer Center conference entitled "Population-Based Studies in Hispanics: Methodological Issues in Cancer Research". PMID- 22432410 TI - Venting-while-heating microwave-assisted synthesis of 3-arylthioindoles. AB - We report the first example of venting-while-heating microwave-assisted synthesis of a small library of 3-arylthioindoles. Compounds were prepared in excellent isolated yields (90-98%) within 4 min in a closed vessel by treating indoles with disulfides in the presence of sodium hydride in anhydrous N,N-dimethylformamide. The method was not affected by electron-donating and -withdrawing substituents both on 3-arylthio moiety and at 2- and 5-positions of the indole nucleus. PMID- 22432411 TI - Enhancing antioxidant capacity and reducing decay of chinese bayberries by essential oils. AB - The effects of essential oil treatment on fruit decay and antioxidant capacities in Chinese bayberries were evaluated. Chinese bayberries were treated with essential oils, including carvacrol, cinnamaldehyde, perillaldehyde, and linalool. Results from this study indicated that all essential oils significantly reduced fruit decay of Chinese bayberries, and the most effective compound was carvacrol. Treatment with carvacrol, cinnamaldehyde, perillaldehyde, and linalool significantly increased total phenolic, anthocyanin, and individual flavonoid contents. In addition, all essential oils maintained significantly higher antioxidant capacities as measured by scavenging capacity against superoxide, hydroxyl, and 1,1-diphenyl-2-picrylhydrazyl radicals and by the reducing power test compared to the control. Moreover, the activities of antioxidant enzymes were also enhanced by all essential oils. Thus, postharvest essential oil treatment has positive effects on reducing decay and enhancing antioxidant capacities in Chinese bayberries. PMID- 22432412 TI - Role of the triiodide/iodide redox couple in dye regeneration in p-type dye sensitized solar cells. AB - A series of perylene dyes with different optical and electronic properties have been used as photosensitizers in NiO-based p-type dye-sensitized solar cells. A key target is to develop dyes that absorb light in the red to near-infrared region of the solar spectrum in order to match photoanodes optically in tandem devices; however, the photocurrent produced was found to decrease dramatically as the absorption maxima of the dye used was varied from 517 to 565 nm and varied strongly with the electrolyte solvent (acetonitrile, propionitrile, or propylene carbonate). To determine the limitations of the energy properties of the dye molecules and to provide guidelines for future sensitizer design, we have determined the redox potentials of the diiodide radical intermediate involved in the charge-transfer reactions in different solvents using photomodulated voltammetry. E degrees (I(3)(-)/I(2)(*-)) (V vs Fe(Cp)(2)(+/0)) = -0.64 for propylene carbonate, -0.82 for acetonitrile, and -0.87 for propionitrile. Inefficient regeneration of the sensitizer appears to be the efficiency-limiting step in the device, and the values presented here will be used to design more efficient dyes, with more cathodic reduction potentials, for photocathodes in tandem dye-sensitized solar cells. PMID- 22432413 TI - Carbon nanotubes promote growth and spontaneous electrical activity in cultured cardiac myocytes. AB - Nanoscale manipulations of the extracellular microenvironment are increasingly attracting attention in tissue engineering. Here, combining microscopy, biological, and single-cell electrophysiological methodologies, we demonstrate that neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes interact with carbon nanotubes by forming tight contacts and show increased viability and proliferation. Furthermore, we observed changes in the electrophysiological properties of cardiomyocytes, suggesting that carbon nanotubes are able to promote cardiomyocyte maturation. PMID- 22432414 TI - Synthesis, spectral, electrochemical, and anion binding properties of 3,5 bis(dipyrromethanyl) boron-dipyrromethenes. AB - Four new boron-dipyrromethenes (BODIPYs) containing dipyrromethanyl substituents at 3,5-positions, bis(3,5-dipyrromethanyl) BODIPYs 5-8, were synthesized by treating their corresponding 3,5-diformyl BODIPYs 1-4 with excess pyrrole under mild acid catalyzed reaction conditions. The compounds 5-8 are stable and freely soluble in common organic solvents. One-dimensional, two-dimensional NMR, high resolution mass spectrometry (HRMS), absorption, fluorescence, and electrochemical techniques were used to characterize the compounds. The spectral and electrochemical studies indicated that dipyrromethanyl groups at 3,5 positions of BODIPY are less electron deficient compared to formyl groups at the same positions. The anion binding studies indicated that bis(3,5-dipyrromethanyl) BODIPY compounds containing four pyrrole NH groups showed preferential binding with F(-) ion over other anions, as confirmed by using NMR, fluorescence, and electrochemical studies. PMID- 22432415 TI - Sec24 interaction is essential for localization and virulence-associated function of the bacterial effector protein NleA. AB - Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) are food borne pathogens that cause severe diarrhoeal disease in humans. Citrobacter rodentium is a related mouse pathogen that serves as a small animal model for EPEC and EHEC infections. EPEC, EHEC and C. rodentium translocate bacterial virulence proteins directly into host cells via a type III secretion system (T3SS). Non-LEE-encoded effector A (NleA) is a T3SS effector that is common to EPEC, EHEC and C. rodentium and is required for bacterial virulence. NleA localizes to the host cell secretory pathway and inhibits vesicle trafficking by interacting with the Sec24 subunit of mammalian coatamer protein II complex (COPII). Mammalian cells express four paralogues of Sec24 (Sec24A-D), which mediate selection of cargo proteins for transport and possess distinct, but overlapping cargo specificities. Here, we show that NleA binds Sec24A-D with two distinct mechanisms. An NleA protein variant with greatly diminished interaction with all Sec24 paralogues does not properly localize, does not inhibit COPII mediated vesicle budding, and does not confer virulence in the mouse infection model. Together, this work provides strong evidence that the interaction and inhibition of COPII by NleA is an important aspect of EPEC- and EHEC-mediated disease. PMID- 22432416 TI - On graphical representation of trans-membrane proteins. AB - In the first part of this paper, we present a novel graphical representation of proteins, which starts with constructing a map of a protein that is obtained from a matrix, the elements of which record the adjacencies of pairs of amino acids in the primary structure of a protein. Starting with the novel protein map, one interprets its matrix elements as vertices of a graph, which are labelled in sequential order as in the protein sequence. The nearest vertices are connected to the nearest neighbour which has a smaller label. In the second part of this paper, we describe the construction of protein binary codes that can serve as protein descriptors. This novel graphical representation of proteins is illustrated on segments of trans-membrane proteins, which are embedded in the membrane. PMID- 22432417 TI - Biophysical modulations of functional connectivity. AB - Resting-state low frequency oscillations have been detected in many functional magnetic resonance imaging (MRI) studies and appear to be synchronized between functionally related areas. Converging evidence from MRI and other imaging modalities suggest that this activity has an intrinsic neuronal origin. Multiple consistent networks have been found in large populations, and have been shown to be stable over time. Further, these patterns of functional connectivity have been shown to be altered in healthy controls under various physiological challenges. This review will present the biophysical characterization of functional connectivity, and examine the effects of physical state manipulations (such as anesthesia, fatigue, and aging) in healthy controls. PMID- 22432418 TI - The declining infrastructure of the aging brain. AB - Great effort has been dedicated to mapping the functional architecture of the brain in health and disease. The neural centers that support cognition and behavior are the "hubs" defining the salient geographic landmarks of the cerebral topography. Similar to urban cartography, however, the functionality of these hubs is critically dependent on the infrastructure permitting the transfer of relevant information from site to site, and this infrastructure is susceptible to deterioration. The groundwork of the brain lies in the form of the complexly organized myelinated nerve fibers responsible for the inter-regional transmission of electrical impulses among distinct neural areas. Damage to the myelin sheath and reduction in the total number of nerve fibers with aging are thought to result in a degradation in the efficiency of communication among neural regions and to contribute to the decline of function in older adults. This article describes selected studies that are relevant to understanding the deterioration in structural connectivity of the aging brain with a focus on potential consequences to functional network activity. First, the neural substrates of connectivity and techniques used in the study of connectivity are described with a focus on neuroimaging methodologies. This is followed with discussion of the negative effects of age on connective integrity, and the possible mechanisms and neural and cognitive consequences of this progressive disconnection. Given the potential for natural repair of certain elements of the connective network, understanding the basis of age-associated decline in connectivity could have important implications with regard to the amelioration of neural dysfunction and the restoration of the infrastructure necessary for optimal function in older adults. PMID- 22432419 TI - The brain as a complex system: using network science as a tool for understanding the brain. AB - Although graph theory has been around since the 18th century, the field of network science is more recent and continues to gain popularity, particularly in the field of neuroimaging. The field was propelled forward when Watts and Strogatz introduced their small-world network model, which described a network that provided regional specialization with efficient global information transfer. This model is appealing to the study of brain connectivity, as the brain can be viewed as a system with various interacting regions that produce complex behaviors. In practice, graph metrics such as clustering coefficient, path length, and efficiency measures are often used to characterize system properties. Centrality metrics such as degree, betweenness, closeness, and eigenvector centrality determine critical areas within the network. Community structure is also essential for understanding network organization and topology. Network science has led to a paradigm shift in the neuroscientific community, but it should be viewed as more than a simple "tool du jour." To fully appreciate the utility of network science, a greater understanding of how network models apply to the brain is needed. An integrated appraisal of multiple network analyses should be performed to better understand network structure rather than focusing on univariate comparisons to find significant group differences; indeed, such comparisons, popular with traditional functional magnetic resonance imaging analyses, are arguably no longer relevant with graph-theory based approaches. These methods necessitate a philosophical shift toward complexity science. In this context, when correctly applied and interpreted, network scientific methods have a chance to revolutionize the understanding of brain function. PMID- 22432420 TI - MRI structural connectivity, disruption of primary sensorimotor pathways, and hand function in cerebral palsy. AB - Brain injury and subsequent plasticity of sensory and corticospinal pathways play an integral role in determining paretic hand function in congenital hemiplegia. There is limited knowledge regarding the relationship between the disruption of sensorimotor thalamic pathways projecting into the primary motor cortex and motor control. This study sought to investigate the relationship between the structural connectivity of motor networks that anatomically link the brain stem with the precentral and postcentral gyri with paretic motor sensory function by using an automated analysis strategy. Magnetic resonance imaging structural connectivity was measured by using high-angular-resolution diffusion imaging, probabilistic tractography, and the anatomic parcellation of high-resolution structural images in 16 children with congenital unilateral periventricular white-matter damage. Connectivity of the corticospinal and corticothalamic pathways was determined by using an asymmetry index based on the number of streamlines contained within these projections and compared with measures of paretic hand function and bimanual coordination. For cortical development, the volume of the ipsilesional precentral gyrus was significantly reduced. For connectivity measures, the numbers of streamlines in corticospinal tracts and corticothalamic pathways within the ipsilesional hemisphere were decreased compared with the contralesional side. The sensorimotor thalamic projections were more significantly correlated with paretic hand functions than were the corticospinal tracts. These data support the concept that preservation of sensorimotor thalamic pathways that directly project into the primary motor cortex has more influence on motor function control of the paretic hand than does preservation of corticospinal tracts. PMID- 22432421 TI - Object working memory performance depends on microstructure of the frontal occipital fasciculus. AB - Re-entrant circuits involving communication between the frontal cortex and other brain areas have been hypothesized to be necessary for maintaining the sustained patterns of neural activity that represent information in working memory, but evidence has so far been indirect. If working memory maintenance indeed depends on such temporally precise and robust long-distance communication, then performance on a delayed recognition task should be highly dependent on the microstructural integrity of white-matter tracts connecting sensory areas with prefrontal cortex. This study explored the effect of variations in white-matter microstructure on working memory performance in two separate groups of participants: patients with multiple sclerosis and age- and sex-matched healthy adults. Functional magnetic resonance imaging was performed to reveal cortical regions involved in spatial and object working memory, which, in turn, were used to define specific frontal to extrastriate white-matter tracts of interest via diffusion tensor tractography. After factoring out variance due to age and the microstructure of a control tract (the corticospinal tract), the number of errors produced in the object working memory task was specifically related to the microstructure of the inferior frontal-occipital fasciculus. This result held for both groups, independently, providing a within-study replication with two different types of white-matter structural variability: multiple sclerosis related damage and normal variation. The results demonstrate the importance of interactions between specific regions of the prefrontal cortex and sensory cortices for a nonspatial working memory task that preferentially activates those regions. PMID- 22432422 TI - MRI diffusion indices sampled along streamline trajectories: quantitative tractography mapping. AB - Abstract Several useful tractography-derived maps have recently been introduced, such as track density imaging (TDI) and the average pathlength map (APM). Here, an extension to these techniques is introduced by sampling diffusion indices along streamline trajectories (DIST). With this approach, voxels contain summary information of diffusivity measures within streamlines. The diffusion metrics can also be used as weighting factors for streamline number or length, generating DIST-weighted TDI and DIST-weighted APM, respectively. Furthermore, when higher-order models of diffusion are used to estimate the fiber orientation distribution within each voxel, it is possible to obtain directional TDI, APM, DIST, and DIST-weighted TDI and APM. The reproducibility of this approach using two b-values (1000 and 3000 s/mm(2)) and the effect of pathologic abnormalities are demonstrated. PMID- 22432423 TI - A sliding time-window ICA reveals spatial variability of the default mode network in time. AB - Recent evidence on resting-state networks in functional (connectivity) magnetic resonance imaging (fcMRI) suggests that there may be significant spatial variability of activity foci over time. This study used a sliding time window approach with the spatial domain-independent component analysis (SliTICA) to detect spatial maps of resting-state networks over time. The study hypothesis was that the spatial distribution of a functionally connected network would present marked variability over time. The spatial stability of successive sliding-window maps of the default mode network (DMN) from fcMRI data of 12 participants imaged in the resting state was analyzed. Control measures support previous findings on the stability of independent component analysis in measuring sliding-window sources accurately. The spatial similarity of successive DMN maps varied over time at low frequencies and presented a 1/f power spectral pattern. SliTICA maps show marked temporal variation within the DMN; a single voxel was detected inside a group DMN map in maximally 82% of time windows. Mapping of incidental connectivity reveals centrifugally increasing connectivity to the brain cortex outside the DMN core areas. In conclusion, SliTICA shows marked spatial variance of DMN activity in time, which may offer a more comprehensive measurement of the overall functional activity of a network. PMID- 22432424 TI - The clinical practice collaborative support model for the graduate nurse. AB - The collaborative support model for the graduate nurse is a proactive approach to supporting all aspects of nursing during the 18-week orientation. Weekly meetings include the unit manager, clinical learning educator, unit clinician, registered nurse (RN) resident, and preceptor. Weekly assessment tools containing goals are created and reviewed by the RN resident and preceptor. Learning needs are then addressed by the team. Because the support model was fully implemented, residents have been able to complete the training program successfully, demonstrating confidence, critical thinking, and a strong skill set. The most rewarding outcome has been the link with management, the clinical learning educator, clinicians, and staff. PMID- 22432425 TI - Copper catalyzed cross-coupling of iodobenzoates with bromozinc difluorophosphonate. AB - A copper-catalyzed cross-coupling of iodobenzoates with bromozinc difluorophosphonate, generated from diethyl bromodifluoromethylphosphonate and zinc in dioxane, is reported. The notable features of this reaction are its high reaction efficiency, excellent functional group compatibility, and operational simplicity. This protocol provides a useful and facile access to aryldifluorophosphonates of interest in life science. PMID- 22432426 TI - Congenital neuroblastoma: an autopsy report. AB - Neuroblastoma (NB) is the foremost malignant neoplasm of the fetus and neonate. It has a distinct biologic behavior and varied clinical manifestations. The perinatal tumors are most frequently associated with a favorable outcome. We describe an autopsy case of a 2-day-old baby with congenital NB of the left adrenal with extensive metastatic deposits in the liver. Despite the tumor having a favorable histology, it proved to be fatal with death occurring on the second day of life. PMID- 22432427 TI - Liver collagen proportionate area predicts decompensation in patients with recurrent hepatitis C virus cirrhosis after liver transplantation. AB - BACKGROUND AND AIMS: Current histological scoring systems do not subclassify cirrhosis. Computer-assisted digital image analysis (DIA) of Sirius Red-stained sections measures fibrosis morphologically producing a fibrosis ratio (collagen proportionate area [CPA]). CPA could have prognostic value within a disease stage, such as cirrhosis. The aim of the present study was to evaluate CPA in patients with recurrent hepatitis C virus (HCV) allograft cirrhosis and assess its relationship with hepatic venous pressure gradient (HVPG). METHODS: In 121 consecutively-transplanted HCV patients with HVPG, measured contemporaneously with transjugular liver biopsies, 65 had Ishak stage 5 or 6 disease (43 with HVPG measurement). Biopsies were stained with Sirius Red for DIA, and the collagen content was expressed as a CPA. In three cases, a tissue for Sirius Red staining was not obtained, and the patients were excluded. RESULTS: Sixty-two patients were analyzed. The median HVPG was 8 mmHg (interquartile range [IQR]: 5-10). Portal hypertension (HVPG >= 6 < 10 mmHg) was present in 30 (69.8%), and HVPG >= 10 mmHg in 13 (30.2%). The median CPA was 16% (IQR 10.75-23.25). Median Child Pugh score and HVPG were not significantly different between Ishak fibrosis stage 5 or 6, whereas CPA was statistically different: 13% in stage 5 (IQR 8.3-12.4) versus 23% in stage 6 (IQR 17-33.7, P < 0.001). In the multivariate analysis, CPA was the only variable significantly associated with clinically-significant portal hypertension (HVPG >= 10 mmHg, odds ratio: 1.085, confidence interval: 1.004 1.172, P = 0.040). A CPA of 14% was the best cut-off value for clinically significant portal hypertension (CSPH) and liver decompensation, which occurred in 24 patients. Event-free survival was significantly shorter in patients with CSPH or with a CPA value >= 14%, or with a combination of both. CONCLUSION: In Ishak stages 5 and 6, CPA correlated with HVPG, but had a wider range of values, suggesting a greater sensitivity for distinguishing "early" from "late" severe fibrosis/cirrhosis. CPA was a unique, independent predictor of HVPG >= 10 mmHg. CPA can be used to subclassify cirrhosis and for prognostic stratification. PMID- 22432428 TI - Diets, phytochemicals, and chemoprevention of tumorigenesis. AB - Chemoprevention of tumorigenesis is expected to be one major strategy to decrease the death and suffering from cancer. Diets and phytochemicals are the major resources of identifying chemopreventive agents against tumorigenesis. The review briefly discusses the general approach to developing promising candidates from diets and phytochemicals, exemplified by a few examples, some of which are in clinical evaluation. PMID- 22432429 TI - Creatine supplementation enhances endurance performance in trained rats. AB - Minimal evidence has shown creatine (Cr) supplementation to enhance endurance performance in either humans or rats. The purpose of this study was to examine the effects of Cr supplementation on endurance performance during high-intensity exercise in trained male rats. Endurance performance was defined as the distance run. Sixteen days of running were performed over 28 days. A cycle of 7 days consisted of 2 days of training, 1 day off, 2 days of training then 2 days off and this was repeated over a total of 28 days. Cr was administered on all 28 days. Treatment rats (n = 7) drank water containing Cr while the control rats drank water with no supplement (n = 6). The Cr group's average distance run increased significantly from baseline to exercise day 16 (baseline = 128.91 m +/- 18.23 vs. exercise day 16 = 217.11m +/- 18.11; p < 0.005), while the control groups did not (baseline = 137.24 m +/- 10.14, exercise day 16 = 101.04 m +/- 14.97; p > 0.05). Over the course of the study, the treatment group's running endurance improved by 81% compared to baseline (p < 0.001) and we conclude that Cr supplementation provided rats an increased ability to run farther demonstrating possible implications for improving endurance athletes' performances. PMID- 22432430 TI - Clove (Eugenia aromatica) and clove oil (eugenol). Natural standard monograph (www.naturalstandard.com) copyright (c) 2008. PMID- 22432431 TI - Radiomodulatory and free-radical scavenging activity of the fractionated aquo alcoholic extract of the adaptogenic nutraceutical (Rhodiola imbricata)--a comparative in vitro assessment with ascorbate. AB - OBJECTIVE: Immense interest has been generated in recent years for the development of drugs of herbal origin for the mitigation of deleterious effects of environmental pollutants like ionizing radiation, mainly to protect against radiation leakages resulting from mishaps in nuclear reactors, deliberate use of dirty bombs, etc. METHOD: The radio modifying effects of a fractionated extract of the high-altitude Himalayan plant species Rhodiola imbricata, along with its electron-donation potential, super-oxide ion scavenging (IC50 <= 0.025 mg/ml), nitric oxide (NO) scavenging potential (IC(50) = 0.5 mg/ml), and antihemolytic activity were evaluated in the present study. Reducing power, superoxide ion (O(2)(*-)), and nitric oxide scavenging ability of the fractionated extract increased in a dose-dependent manner. Rhodiola imbricata also exhibited antihemolytic potential preventing radiation-induced membrane degeneration of human erythrocytes. CONCLUSION: Thus, it can be stated that Rhodiola imbricata provides protection against gamma radiation via multifarious mechanisms that act in a synergistic manner. Rhodiola imbricata is widely used as a nutraceutical supplement in the trans-Himalayan region nations, and the current study shows that Rhodiola has immense potential for alleviation of biological damage in a radiation environment. PMID- 22432432 TI - Ma huang and alpha subtype adrenoceptors in the cat pulmonary vascular bed. AB - OBJECTIVE: To test the hypothesis that ma huang induces a pressor response in the pulmonary vascular bed of the cat and identify the alpha (1)-adrenoceptor subtype pathway(s) involved in the mediation or modulation of these effects. DESIGN: Prospective vehicle controlled study. SETTING: University research laboratory. SUBJECTS: Intact chest preparation; adult mongrel cats. INTERVENTIONS: In separate experiments, the effects of phentolamine, the alpha-adrenergic antagonist; prazosin, a selective alpha (1)-adrenoceptor antagonist; BMY 7378, a selective alpha (1) D-subtype adrenoceptor antagonist; 5-methyl-urapidil, the selective alpha (1)A-subtype adrenoceptor antagonist; and chloroethylclonidine, an alpha (1)B-subtype and (1) D-subtype adrenoceptor antagonist, were investigated on pulmonary arterial responses to ma huang and other agonist agents in the pulmonary vascular bed of the cat. MEASUREMENTS AND MAIN RESULTS: Under constant flow conditions, lobar arterial perfusion pressure and systemic pressure were continuously monitored, electronically averaged, and permanently recorded. In the feline vascular bed of the isolated left lower lobe, ma huang induced a dose-dependent vasopressor response that was not significantly attenuated following administration of 5-methyl-urapidil. However, the responses to Ma huang were significantly reduced after administration of phentolamine, prazosin, BMY 7378, and chloroethylclonidine. CONCLUSIONS: The results of the present study suggest that ma huang has potent vasopressor activity in the pulmonary vascular bed of the cat and that this response may be mediated or modulated by both alpha (1)B-subtype and (1)D-subtype adrenoceptor sensitive pathways. PMID- 22432433 TI - Quality assurance of herbal raw materials in supply chain: challenges and opportunities. AB - The herbal medicine industry is presently adopting modern scientific tools to substantiate the guarantee of efficacy that, in the past, rested only on anecdotal evidence derived from traditional knowledge systems. This is particularly true for the processes of identification of herbal raw materials adopting modern tools for phytochemical fingerprinting. The successful adaptation of available technologies and practices depends on an understanding of the phytochemical complexity and variability innate in biological material. It challenges the "mainstream medicinal mindset" that "tend(s) to reject .... therapies for which mechanisms of action do not fit within Newtonian, biochemical orientation" (Dumoff, 2003). The herbal medicinal industry is independently evolving its own rigid quality assurance and control systems using Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) guidelines, but it faces unique difficulties. These include lack of Good Agricultural and Collection Practice (GACP), lack of transparency in the raw material supply chain so as to preclude the use of unsafe practices, problems in the authentication of herbal raw materials, and a general lack of understanding of the need to reduce phytochemical variability in these materials. This paper explores these difficulties and outlines strategies to overcome them, but these strategies will require coordinated international government regulations to be fully effective. PMID- 22432434 TI - Ribose in the heart. AB - Every cell needs energy, i.e., adenosine triphosphate (ATP), to carry out its function. Decreased oxygen levels, decreased blood flow, and other stressful conditions can drastically effect the intracellular concentrations of these energy compounds. Skeletal muscle, unlike the heart, can address this drop in ATP by employing the myokinase reaction, ultimately producing ATP with a subsequent elevation in adenosine monophosphate (AMP). Ribose, a naturally occurring 5 carbon monosaccharide, is a key component of RNA, DNA (which has deoxyribose), acetyl coenzyme A, and ATP. Each cell produces its own ribose, involved in the pentose phosphate pathway (PPP), to aid in ATP production. States of ischemia and/or hypoxia can severely lower levels of cellular energy compounds in the heart, with an associated compromise in cellular processes, ultimately reflected in altered function. Ribose appears to provide a solution to the problem in replenishing the depressed ATP levels and improving functional status of patients afflicted with cardiovascular diseases. PMID- 22432435 TI - Screening and identification of insertion mutants from Bipolaris eleusines by mutagenesis based on restriction enzyme-mediated integration. AB - Ophiobolin A is sesterterpenoid-type phytotoxin and may be an important candidate for development of new crop protection and pharmaceutical products. The restriction enzyme-mediated integration (REMI) method was used to introduce the plasmid pSH75 into the ophiobolin A-producing filamentous fungus Bipolaris eleusines. A total of 323 stable transformants were obtained, all of which were capable of growing on potato-dextrose agar medium containing 200 MUg mL(-1) hygromycin B. The transformation frequency was about 4-5 transformants MUg(-1) plasmid DNA. An ophibolin A-deficient transformant (B014) was assessed and the presence of the hph gene in this transformant was confirmed by PCR. The cell-free cultural filtrates of this transformant showed significantly less inhibition on mycelial growth of the fungal pathogen Rhizoctoni solani but little effect on barnyard grass as opposed to that of the wild-type B. eleusines. There was no detectable amount of ophiobolin A in B014 samples measured with HPLC. This research suggests REMI as a potential approach for improving the production of ophiobolin A by B. eleusines via genetic engineering to upregulate certain genes responsible for desired biosynthetic pathways. PMID- 22432436 TI - Antioxidant activities and major anthocyanins of Myrobalan plum (Prunus cerasifera Ehrh.). AB - Total phenolic content, total antioxidant activity of Myrobalan plum (Prunus cerasifera Ehrh.) and anthocyanin content in peel were analyzed in this article. In addition, ultra-performance liquid chromatography with photodiode array detection and electrospray ionization tandem mass spectrometry were used to determine anthocyanin composition of this fruit. The range of total phenolic content of the tested samples was 1.34 to 6.11 g/kg fresh weight (FW), and anthocyanin content in fruit peel of Myrobalan plum was from 1.93 to 19.86 g/kg peel. Ferric reducing antioxidant power values varied from 11.20 to 44.83 MUmol Trolox equivalent/g FW. Four main kinds of anthocyanins in purple Myrobalan plum were detected while 6 kinds in red ones. PRACTICAL APPLICATION: The article showed the anthocyanin composition, phenolic content, and antioxidant activities of wild Myrobalan plum. The purple Myrobalan plum could be developed as a resource of fruit drinks because of its high antioxidant activity and the peel could be used as the resource to extract natural pigments. PMID- 22432437 TI - Development of the Persian version of the Modified Modified Ashworth Scale: translation, adaptation, and examination of interrater and intrarater reliability in patients with poststroke elbow flexor spasticity. AB - PURPOSE: Development of the Persian version of the Modified Modified Ashworth Scale (MMAS), and to investigate the interrater and intrarater reliability of the Persian MMAS when used to quantify elbow flexor spasticity in patients after stroke. METHODS: The Persian MMAS was developed by the forward and backward translation procedure, a final review by an expert committee, and testing for acceptability and the clarity of item wording so that the scale could be used by Persian-speaking examiners. Psychometric testing included interrater and intrarater reliability. Elbow flexor spasticity was examined by two raters in 30 patients after stroke twice on two occasions using the Persian MMAS. The weighted kappa was used for the statistical analysis. RESULTS: The interrater and intrarater reliability was very good for the Persian MMAS (weighted kappa: 0.81 0.91; 95% CI 0.68-0.98) with statistically significant agreement between raters and within raters (all p < 0.001). CONCLUSIONS: The Persian version of the MMAS was successfully developed. The Persian MMAS showed very good interrater and intrarater reliability in patients with elbow flexor spasticity after stroke. The results support the use of the Persian version of the MMAS both in clinical and research settings. PMID- 22432438 TI - False-positive meconium test results for fatty acid ethyl esters secondary to delayed sample collection. AB - BACKGROUND: Meconium analysis for fatty acid ethyl esters (FAEEs) is a validated method for identifying heavy prenatal ethanol (EtOH) exposure. This study investigated whether delayed sample collection can result in false-positive test results for FAEEs because of collection of samples potentially contaminated with postnatally produced stool. METHODS: Serial excretions were prospectively collected from neonates born to nondrinking mothers to capture the transition from meconium to postnatal stool. These were analyzed for FAEEs using headspace solid phase microextraction and gas chromatography-mass spectrometry. Experiments involving incubation of samples with glucose or EtOH were performed to explore a potential mechanism of FAEE elevation. RESULTS: A total of 136 samples were collected from 30 neonates during their first few days of life (median of 4 samples/baby over a mean period of 68.5 hours postpartum). Although the first collected meconium sample tested negative for FAEEs in all babies, later samples tested above the 2 nmol/g positive cutoff in 19 of 30 babies. Median time to appearance of FAEE-positive samples was 59.2 hours postpartum. In vitro experiments demonstrated that FAEE levels can be further increased in late samples (likely containing postnatal stool) after incubation with glucose, and that FAEEs are readily formed in meconium in the presence of EtOH. CONCLUSIONS: Collection of samples excreted later in the postpartum period can lead to false positive test results for FAEEs, which could be because of contamination with dietary components of postnatally produced stool and EtOH-producing microorganisms. Clinically, it is critical to collect the earliest possible excretion for determination of FAEEs to ensure that the FAEE content is representative of in utero EtOH exposure. PMID- 22432439 TI - Observer variability in a phase II trial - assessing consistency in RECIST application. AB - OBJECTIVE: To assess the consistency of Response Evaluation Criteria in Solid Tumours (RECIST) application in a phase II trial. MATERIAL AND METHODS: Patients with metastatic non-resectable colorectal cancer treated with a combination of an antibody and a chemotherapeutic drug, were included. Computed tomography (CT) scans (thorax, abdomen and pelvis) were performed at baseline and after every fourth treatment cycle. RECIST was intended for response evaluation. The scans were consecutively read by a heterogeneous group of radiologists as a part of daily work and hereafter retrospectively reviewed by a dedicated experienced radiologist. Agreement on best overall response (BOR) between readers and reviewer was quantified using kappa-coefficients and the discrepancy rate was correlated with the number of different readers per patient using a chi(2)-test. RESULTS: One hundred patients with 396 CT scans were included. Discrepancies between the readers and the reviewer were found in 47 patients. The majority of discrepancies concerned the application of RECIST. With the review, BOR changed in 17 patients, although, only in six patients the change was potentially treatment altering. Overall, the kappa-coefficient of agreement between readers and reviewer was 0.71 (good). However, in the subgroup of responding patients the kappa-coefficient was 0.21 (fair). The number of patients with discrepancies was significantly higher with three or more different readers per patient than with less (p =0.0003). CONCLUSION: RECIST was not consistently applied and the majority of the reader discrepancies were RECIST related. Post review, 17 patients changed BOR; six patients in a potentially treatment altering manner. Additionally, we found that the part of patients with discrepancies increased significantly with more than three different readers per patient. The findings support a peer-review approach where a few dedicated radiologists perform double blinded readings of all the on-going cancer trial patients' CT scans. PMID- 22432440 TI - Survival duration among patients with a noncancer diagnosis admitted to a palliative care unit: a retrospective study. AB - BACKGROUND: Palliative care unit (PCU) beds are a limited resource in Canada, so PCU admission is restricted to patients with a short prognosis. Anecdotally, PCUs further restrict admission of patients with noncancer diagnoses out of fear that they will "oversurvive" and reduce bed availability. This raises concerns that noncancer patients have unequal access to PCU resources. PURPOSE/METHODS: To clarify survival duration of patients with a noncancer diagnosis, we conducted a retrospective review of all admissions to four PCUs in Toronto, Canada, over a 1 year period. We measured associations between demographic data, prognosis, Palliative Performance Score (PPS), length of stay (LOS), and waiting time. RESULTS: We collected data for 1000 patients, of whom 21% had noncancer diagnoses. Noncancer patients were older, with shorter prognoses and lower PPS scores on admission. Noncancer patients had shorter LOS (14 versus 24, p<0.001) than cancer patients and a similar likelihood of being discharged alive to cancer patients. Noncancer patients had a trend to lower LOS across a broad range of demographic, diagnostic, prognostic, and PPS categories. Multivariable analysis showed that LOS was not associated with the diagnosis of cancer (p=0.36). DISCUSSION/CONCLUSION: Noncancer patients have a shorter LOS than cancer patients and a similar likelihood of being discharged alive from a PCU than cancer patients, and the diagnosis of cancer did not correlate with survival in our study population. Our findings demonstrate that noncancer patients are not "oversurviving," and that referring physicians and PCUs should not reject or restrict noncancer referrals out of concern that these patients are having a detrimental impact on PCU bed availability. PMID- 22432442 TI - Mitogenomic sequences better resolve stock structure of southern Greater Caribbean green turtle rookeries. AB - Analyses of mitochondrial control region polymorphisms have supported the presence of several demographically independent green turtle (Chelonia mydas) rookeries in the Greater Caribbean region. However, extensive sharing of common haplotypes based on 490-bp control region sequences confounds assessment of the scale of natal homing and population structure among regional rookeries. We screened the majority of the mitochondrial genomes of 20 green turtles carrying the common haplotype CM-A5 and representing the rookeries of Buck Island, St. Croix, United States Virgin Islands (USVI); Aves Island, Venezuela; Galibi, Suriname; and Tortuguero, Costa Rica. Five single-nucleotide polymorphisms (SNPs) were identified that subdivided CM-A5 among regions. Mitogenomic pairwise phi(ST) values of eastern Caribbean rookery comparisons were markedly lower than the respective pairwise F(ST) values. This discrepancy results from the presence of haplotypes representing two divergent lineages in each rookery, highlighting the importance of choosing the appropriate test statistic for addressing the study question. Haplotype frequency differentiation supports demographic independence of Aves Island and Suriname, emphasizing the need to recognize the smaller Aves rookery as a distinct management unit. Aves Island and Buck Island rookeries shared mitogenomic haplotypes; however, frequency divergence suggests that the Buck Island rookery is sufficiently demographically isolated to warrant management unit status for the USVI rookeries. Given that haplotype sharing among rookeries is common in marine turtles with cosmopolitan distributions, mitogenomic sequencing may enhance inferences of population structure and phylogeography, as well as improve the resolution of mixed stock analyses aimed at estimating natal origins of foraging turtles. PMID- 22432443 TI - Nitrate transport capacity of the Arabidopsis thaliana NRT2 family members and their interactions with AtNAR2.1. AB - * Interactions between the Arabidopsis NitRate Transporter (AtNRT2.1) and Nitrate Assimilation Related protein (AtNAR2.1, also known as AtNRT3.1) have been well documented, and confirmed by the demonstration that AtNRT2.1 and AtNAR2.1 form a 150-kDa plasma membrane complex, thought to constitute the high-affinity nitrate transporter of Arabidopsis thaliana roots. Here, we have investigated interactions between the remaining AtNRT2 family members (AtNRT2.2 to AtNRT2.7) and AtNAR2.1, and their capacity for nitrate transport. * Three different systems were used to examine possible interactions with AtNAR2.1: membrane yeast split ubiquitin, bimolecular fluorescence complementation in A. thaliana protoplasts and nitrate uptake in Xenopus oocytes. * All NRT2s, except for AtNRT2.7, restored growth and beta-galactosidase activity in the yeast split-ubiquitin system, and split-YFP fluorescence in A. thaliana protoplasts only when co-expressed with AtNAR2.1. Thus, except for AtNRT2.7, all other NRT2 transporters interact strongly with AtNAR2.1. * Co-injection into Xenopus oocytes of cRNA of all NRT2 genes together with cRNA of AtNAR2.1 resulted in statistically significant increases of uptake over and above that resulting from single cRNA injections. PMID- 22432444 TI - Modeling dynamics of isotropic dielectrics in a laminar heterogeneous configuration. AB - The predictive capabilities of models that satisfy the Weiner bounds and Hashin Shtrikman (HS) bounds were studied for isotropic dielectrics in a laminar heterogeneous configuration oriented perpendicular to the electric field. The dynamics were investigated isothermally using broadband dielectric relaxation spectroscopy (DRS) in the frequency range of 1 MHz to 100 mHz. The molecules chosen for study were low molecular weight glass formers, glycerol, phenyl salicylate, imidazole, and dimethyl sulfoxide, and macromolecules, polymethylhydrosiloxane, polyvinylpyrrolidone-co-vinyl acetate, poly-dl-lactic acid, and poly l-lactic acid. It was found that none of the models were able to adequately predict in entirety the resultant dynamics. Of the models studied, the most successful were the HS upper bound (HSUB), the complementary universal Weiner equation (CWE), and the Lichtenecker model for the dimensional parameter, zeta = -1/2. The least successful models were the upper Weiner bound (UWB), the Neelakantaswamy, Turkman, and Sarkar (NTS) model for zeta = 1/2, and the Lichtenecker model for zeta = 1/2. PMID- 22432445 TI - The management of hepatocellular carcinoma around the world: a comparison of guidelines from 2001 to 2011. AB - In the past 10 years, many guidelines for hepatocellular carcinoma (HCC) have been published worldwide. To promote standard care for HCC, we systematically evaluated 17 current guidelines for HCC around the world, including 5 guidelines from the USA, 7 from Asia and 5 from Europe, according to the selection criteria of credibility influence and multi-faceted. After a systematic evaluation, we found that these guidelines have both similarities and differences in terms of what organizations or bodies drafted the guidelines and the approach, applicability, content and recent updates of the guidelines as well as in terms of diagnostic and treatment algorithms. The differences could be attributed to various aetiological factors, high-risk patients, health systems, health resources, medical technology, treatment choices and income levels in different countries. Besides, although the full implementation of guidelines could benefit clinicians, patients and authorities, there is still a gap between projected goals and implementation. The factors potentially influencing implementation are what organizations or bodies are drafting guidelines, content and emphasis, modification and consistency of guidelines. Comparative analysis suggested that countries pay close attention to targeted audiences, a basis in evidence, a basis in available resources, applicable patients and systematic evaluation when establishing and implementing domestic guidelines for HCC. PMID- 22432446 TI - High quality GaAs nanowires grown on glass substrates. AB - We report for the first time the growth of GaAs nanowires directly on low-cost glass substrates using atmospheric pressure metal organic vapor phase epitaxy via a vapor-liquid-solid mechanism with gold as catalyst. Substrates used in this work were of float glass type typically seen in household window glasses. Growth of GaAs nanowires on glass were investigated for growth temperatures between 410 and 580 degrees C. Perfectly cylindrical nontapered nanowires with a growth rate of ~33 nm/s were observed at growth temperatures of 450 and 470 degrees C, whereas highly tapered pillar-like wires were observed at 580 degrees C. Nanowires grew horizontally on the glass surface at 410 degrees C with a tendency to grow in vertically from the substrate as the growth temperature was increased. X-ray diffraction and transmission electron microscopy revealed that the nanowires have a perfect zinc blende structure with no planar structural defects or stacking faults. Strong photoluminescence emission was observed both at low temperature and room temperature indicating a high optical quality of GaAs nanowires. Growth comparison on impurity free fused silica substrate suggests unintentional doping of the nanowires from the glass substrate. PMID- 22432447 TI - Molecular assembly and magnetic dynamics of two novel Dy6 and Dy8 aggregates. AB - Complexation of dysprosium(III) with the heterodonor chelating ligand o-vanillin picolinoylhydrazone (H(2)ovph) in the presence of a carbonato ligand affords two novel Dy(6) and Dy(8) clusters, namely, [Dy(6)(ovph)(4)(Hpvph)(2)Cl(4)(H(2)O)(2)(CO(3))(2)].CH(3)OH.H(2)O.CH(3)CN (2) and [Dy(8)(ovph)(8)(CO(3))(4)(H(2)O)(8)].12CH(3)CN.6H(2)O (3). Compound 2 is composed of three petals of the Dy(2) units linked by two carbonato ligands, forming a triangular prism arrangement, while compound 3 possesses an octanuclear core with an unprecedented tub conformation, in which Dy(ovph) fragments are attached to the sides of the carbonato core. The static and dynamic magnetic properties are reported and discussed. In the Dy(6) aggregate, three Dy(2) "skeletons", having been well preserved (see the scheme), contribute to the single-molecule-magnet behavior with a relatively slow tunneling rate, while the Dy(8) cluster only exhibits a rather small relaxation barrier. PMID- 22432448 TI - Hybrid one-dimensional nanostructures: one-pot preparation of nanoparticle chains via directed self-assembly of in situ synthesized discrete Au nanoparticles. AB - The fabrication of well-defined one-dimensional (1D) arrays is becoming a challenge for the development of the next generation of advanced nanodevices. Herein, a simple concept is proposed for the in situ synthesis and self-assembly of gold nanoparticles (AuNPs) into 1D arrays via a one-step process. The results demonstrated the formation of nanoparticle chains (NPC) with high aspect ratio based on discrete Au nanoparticles stabilized by short thiol ligands. A model was proposed to explain the self-assembly based on the investigation of several parameters such as pH, solvent, temperature, and nature of the ligand on the 1D assembly formation. Hydrogen bonding was identified as a key factor to direct the self-assembly of the hybrid organic-inorganic nanomaterials into the well-defined 1D nanostructures. This simple and cost-effective concept could potentially be extended to the fabrication of a variety of hybrid 1D nanostructures possessing unique physical properties leading to a wide range of applications including catalysis, bionanotechnology, nanoelectronics, and photonics. PMID- 22432449 TI - Atomistic simulations of dilute polyelectrolyte solutions. AB - The properties of short chains of poly-(styrene)-co-(styrene sulfonate) are studied using atomistic molecular dynamics simulations with explicit solvent. We study single 8-mers and 16-mers with two species of counterions, Na(+) and Mg(2+), and for various degrees of sulfonation, f. We find that single trajectories do not efficiently sample configurational space, even for fairly long 100-ns simulations, because of rotational barriers caused by nonbonded interactions. Hamiltonian replica exchange molecular dynamics (HREMD) simulations or averages over multiple trajectories are required in order to obtain equilibrium properties. A polystyrene sulfonate chain adopts collapsed conformations at low f, in which the sulfonate groups are located outside the globule and benzene rings form the inner region, and adopts extended conformations as f is increased. Interestingly, the pair correlation functions between side groups of polystyrene chains are not sensitive to f and species of counterion, i.e., the balance of electrostatic repulsion between charged groups and hydrophobic attraction between benzene rings is achieved by conformational change in a way preserving pair correlations between side groups in a polymer chain. For Na(+) counterions, no localization is observed in the simulations. For Mg(2+) counterions, there is a large free energy barrier to contact pair formation between the sulfonate groups and the Mg(2+) counterions. As a consequence we do not observe the formation or breaking of contact pairs during the course of a simulation. The simulations provide insight into the important interactions and correlations in polyelectrolyte solutions. PMID- 22432450 TI - Magnetic resonance imaging and graph theoretical analysis of complex brain networks in neuropsychiatric disorders. AB - Neurological and psychiatric disorders disturb higher cognitive functions and are accompanied by aberrant cortico-cortical axonal pathways or synchronizations of neural activity. A large proportion of neuroimaging studies have focused on examining the focal morphological abnormalities of various gray and white matter structures or the functional activities of brain areas during goal-directed tasks or the resting state, which provides vast quantities of information on both the structural and functional alterations in the patients' brain. However, these studies often ignore the interactions among multiple brain regions that constitute complex brain networks underlying higher cognitive function. Information derived from recent advances of noninvasive magnetic resonance imaging (MRI) techniques and computational methodologies such as graph theory have allowed researchers to explore the patterns of structural and functional connectivity of healthy and diseased brains in vivo. In this article, we summarize the recent advances made in the studies of both structural (gray matter morphology and white matter fibers) and functional (synchronized neural activity) brain networks based on human MRI data pertaining to neuropsychiatric disorders. These studies bring a systems-level perspective to the alterations of the topological organization of complex brain networks and the underlying pathophysiological mechanisms. Specifically, noninvasive imaging of structural and functional brain networks and follow-up graph-theoretical analyses demonstrate the potential to establish systems-level biomarkers for clinical diagnosis, progression monitoring, and treatment effects evaluation for neuropsychiatric disorders. PMID- 22432451 TI - The ubiquity of small-world networks. AB - Small-world networks, according to Watts and Strogatz, are a class of networks that are "highly clustered, like regular lattices, yet have small characteristic path lengths, like random graphs." These characteristics result in networks with unique properties of regional specialization with efficient information transfer. Social networks are intuitive examples of this organization, in which cliques or clusters of friends being interconnected but each person is really only five or six people away from anyone else. Although this qualitative definition has prevailed in network science theory, in application, the standard quantitative application is to compare path length (a surrogate measure of distributed processing) and clustering (a surrogate measure of regional specialization) to an equivalent random network. It is demonstrated here that comparing network clustering to that of a random network can result in aberrant findings and that networks once thought to exhibit small-world properties may not. We propose a new small-world metric, omega (omega), which compares network clustering to an equivalent lattice network and path length to a random network, as Watts and Strogatz originally described. Example networks are presented that would be interpreted as small-world when clustering is compared to a random network but are not small-world according to omega. These findings have important implications in network science because small-world networks have unique topological properties, and it is critical to accurately distinguish them from networks without simultaneous high clustering and short path length. PMID- 22432452 TI - Distinction in coherent neural network between resting and working brain states. AB - The resting brain is not silent; rather, it is characterized by organized resting state networks showing spontaneous and coherent neuronal activities, which can be mapped using the spatiotemporal correlation of blood oxygenation level-dependent (BOLD) signal fluctuations measured by functional magnetic resonance imaging (fMRI). However, it remains elusive whether the similar fMRI approach is able to image the coherent network in a working brain, and if yes, whether there is a distinction between the resting- and working-state coherent networks. This study aimed to address these questions in the human visual cortex with a desired activation paradigm using continuous, sustained visual stimuli. It was found that the resting-state coherent network covering the human visual cortex was spatially reorganized during the stimulation into two coherent networks with distinct temporal characteristics of BOLD fluctuations: one covering the activated visual cortical region and the other covering the remaining (nonactivated) visual cortex. The stimulus-specific reorganization of the coherent network observed in the present fMRI study in human is consistent with previous electrophysiological findings from animal studies, and may suggest an essential mechanism for brain functioning. Finally, a similar fMRI experiment was also conducted under brief, short stimulation to examine how the stimulation paradigm can affect the observations. PMID- 22432453 TI - A spectral graphical model approach for learning brain connectivity network of children's narrative comprehension. AB - Narrative comprehension is a fundamental cognitive skill that involves the coordination of different functional brain regions. We develop a spectral graphical model with model averaging to study the connectivity networks underlying these brain regions using fMRI data collected from a story comprehension task. Based on the spectral density matrices in the frequency domain, this model captures the temporal dependency of the entire fMRI time series between brain regions. A Bayesian model averaging procedure is then applied to select the best directional links that constitute the brain network. Using this model, brain networks of three distinct age groups are constructed to assess the dynamic change of network connectivity with respect to age. PMID- 22432454 TI - Empirical evaluations of slice-timing, smoothing, and normalization effects in seed-based, resting-state functional magnetic resonance imaging analyses. AB - Recently, functional connectivity analyses using spontaneous functional magnetic resonance imaging (fMRI) fluctuations have been applied in the context of neurological and psychiatry diseases. In the analyses procedure, preprocessing steps are commonly utilized in exploring functional connectivity, the same strategy as what was conducted in the fMRI process. However, the effectiveness of these preprocessing steps on resting-state fMRI (rs-fMRI) was rarely investigated, and the significance of preprocessing steps on rs-fMRI needs to be studied. Therefore, the main purpose of the current study was to evaluate the effects of multiple preprocessing procedures, including slice-timing correction, smoothing, and spatial normalization, on rs-fMRI signal. Through a seed-based correlation analysis on the motor network, we empirically estimated three indices of spontaneous fMRI fluctuations induced: correlation coefficients (CC), amplitude of low-frequency fluctuations (ALFFs), and fractional ALFF (fALFF), with different strategies of three preprocessing steps. Multiple repetition times (TRs = 2, 3, 4 sec) were also compared to address the issue of temporal mismatch. In the temporal preprocess, we found that the use of slice-timing correction and different TRs had minimal effects on CC and fALFF. However, ALFF was significantly affected using different TR but not affected by slice-timing correction as well. In the spatial preprocess, fALFF was insensitive to both smoothing and normalization. Smoothing consistently increased spatial extents and CC, but suppressed ALFF values. Performing normalization before index calculations provided better spatial sensitivity with larger variability in ALFF, whereas performing normalization after index calculations might preserve the ALFF level as in the unnormalized data. Conclusively, the effects of choosing preprocessing parameters and strategies were presented in the current study, providing practical considerations when conducting rs-fMRI analyses. PMID- 22432455 TI - Amygdala functional connectivity predicts pharmacotherapy outcome in pediatric bipolar disorder. AB - The aim of this study was to determine functional connectivity among patients with pediatric bipolar disorder (PBD) who are responders to pharmacotherapy and those who are nonresponders, and learn how they differ from healthy controls (HC) while performing a task that engages affective and cognitive neural systems. PBD participants (n = 34; 13.4 +/- 2.3 years) were defined as responders if there was >= 50% improvement in Young Mania Rating Scale (YMRS) scores (n = 22) versus nonresponders with < 50% improvement (n = 12) with one of three mood stabilizing medications (divalproex, risperidone, or lamotrigine). HC (n = 14; 14.2 +/- 3.1 years) participants also were scanned at baseline and follow-up. During functional magnetic resonance imaging, participants performed a color-matching task in which they had to match the color of positive, negative, or neutral words with colored dots. Independent component analysis was used to identify functionally connected networks across the whole brain, which were subsequently interrogated using region-of-interest analyses to test for group differences. A frontolimbic network was identified that showed impaired functional integration in PBD relative to HC when participants viewed negatively valenced words. PBD medication responders showed greater connectivity of the amygdala into the network before and after treatment compared with nonresponders, with responders showing a pattern more similar to HC than to nonresponders. Regardless of medication type, the degree of amygdala functional connectivity predicted medication response as well as the improvement in YMRS scores across responders and nonresponders. These findings suggest that increased functional integration of the amygdala within the frontolimbic network might be a biomarker of general mood stabilizer medication responsivity in bipolar disorder. PMID- 22432456 TI - Access to health care and heavy drinking in patients with diabetes or hypertension: implications for alcohol interventions. AB - Supported by a National Institute of Alcoholism and Alcohol Abuse grant, this study examined associations between health care access and heavy drinking in patients with hypertension and diabetes. Using a sample of 7,428 US adults from the 2007 National Health Interview Survey data, multivariate logistic regressions were performed. Better access to health care, as indicated by regular source of care and frequent use of primary care, was associated with reduced odds of heavy drinking. Alcohol interventions may be more effective if targeted at patients with chronic conditions adversely affected by drinking. Future research needs to investigate factors facilitating such interventions. PMID- 22432457 TI - Neuroanatomical correlates of heterotypic comorbidity in externalizing male adolescents. AB - Children and adolescents with externalizing behavior disorders including attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) often present with symptoms of comorbid internalizing psychopathology. However, few studies have examined central nervous system correlates of such comorbidity. We evaluated interactions between externalizing and internalizing symptoms in predicting mesolimbic, septo-hippocampal, and anterior cingulate volumes among 12 to 16-year-old boys with either ADHD, ADHD and CD, or no psychiatric condition (n = 35). These regions were chosen given established links to trait impulsivity, trait anxiety, and behavior regulation, respectively. Collapsed across groups, Externalizing * Internalizing symptom interactions accounted for individual differences in gray matter densities in each region. Externalizing youth with comorbid internalizing symptoms showed smaller reductions in gray matter than individuals with externalizing psychopathology alone. These results suggest that internalizing symptoms are associated with less severe structural compromises in brain regions subserving motivation and behavior regulation among externalizing boys. PMID- 22432458 TI - Infrared thermography as a high-throughput tool in catalysis research. AB - The so-called "emissivity corrected infrared thermography" (ecIRT) has been successfully developed and used to great effect in the field of combinatorial high-throughput studies in catalysis. A short introduction to the basics of ecIRT and the description of a typical setup is given. Research efforts from 1998 until present are summarized and selected publications with IRT applications in catalysis are highlighted. The last section of the article covers potential problems, which the observant may misinterpret as activity of the materials. The effects are classified and it is explained why they occur and what can be done to bypass them. PMID- 22432459 TI - Effective use of herbal medicine in urinary tract infections. AB - Urinary tract infections (UTI), acute and chronic, can be effectively treated with herbal medicine. Two strategies are essential in utilizing herbal medicine. The choice of herbs, through their herbal actions, along with appropriate therapeutic dosing strategies, will determine the effectiveness of herbal treatment and prevent the need to intervene with antibiotics. This paper will discuss urinary tract infections and botanical therapeutics through a case-study presentation. PMID- 22432460 TI - You have to ask the right questions to find the right herbal remedy. PMID- 22432461 TI - Constituents and tissue affinities in herbal medicine. AB - Western-trained researchers and clinicians can better understand herbal medicine if they master at least a basic set of essential concepts used by herbal practitioners to describe how herbs work. Constituents, such as carotenoids and flavonoids, can all be used to develop a basis for imputed herb actions. Tissue affinity is also an important concept shared by all herb traditions, which can enhance clinical results and illuminate traditional herbal use. PMID- 22432462 TI - Polyphenol extract of Greens+TM nutritional supplement stimulates bone formation in cultures of human osteoblast-like SaOS-2 cells. AB - BACKGROUND AND AIMS: Oxidative stress has been associated with osteoporosis. Greens+TM is a commercially available nutritional supplement containing antioxidative polyphenols. METHODS: To study the effects of greens+TM on differentiation and bone formation in human osteoblasts, the cells were cultured in Ham's F-12 medium in the absence or presence of varying concentrations of total free polyphenolic (TFP) in the extracts of greens+TM. RESULTS: Our results showed that the number of osteoblasts increased (p <. 05) compared to vehicle control after 2 and 4 days of treatment but were reduced (p <. 05) after 7 days of treatment with 1.2-2.0 mg greens+TM extract/ml (corresponding to 16.8-27.9 ng TFP expressed as gallic acid equivalent per milliliter). Lower concentrations of greens+TM extract stimulated alkaline phosphatase activity at early time points (days 9 and 11), while higher concentrations at the later time point of day 13 resulted in a significant (p <. 05) inhibition, in a time (p <. 0001) and dose dependent (p <. 0001) manner. Greens+TM extract stimulated (p <. 05) the mineralized bone nodule formation in a dose and time dependent manner. CONCLUSIONS: The results showed that greens+TM extract influenced the maturation of osteoprogenitors toward progression to a bone-forming stage. Our data suggest that greens+TM may have beneficial effects on bone formation in vitro due to its antioxidant polyphenolic content and we can speculate that it may be a good alternative to drugs for the prevention of osteoporosis. PMID- 22432463 TI - Effects of Agaricus blazei Murill extract on sensitivity to chemotherapeutic agents in HeLa cells and its resistant sublines. AB - Agaricus blazei Murill (ABM; Japanese name: Kawahiratake or Agarikusutake) extract is a widely used dietary supplement. However, limited information is available on the effects of the extract on the effectiveness of the chemotherapeutic agents. In this study, we examined the effects of ABM extract (Kyowa Wellness Co., Ltd.) on sensitivity to chemotherapeutic agents, paclitaxel and doxorubicin as MDR1/P-glycoprotein substrates, and cisplatin and 5 fluorouracil as non-substrates, in human cervical carcinoma HeLa cells, and paclitaxel-resistant and cisplatin-resistant derivatives (HeLa/TXL and HeLa/CDDP, respectively). The extract had no growth inhibitory effects on HeLa and the resistant cells at concentrations ranging from 7.6 * 10(-4) MU g/ml to 8.0 * 10(2)MU g/ml, indicating no remarkable cytotoxic activity in vitro. In the presence of 0.1, 0.5, and 1 MU g/ml of ABM extract, sensitivity to paclitaxel, cisplatin and 5-fluorouracil did not change in HeLa, HeLa/TXL and HeLa/CDDP cells. However, the extract reduced sensitivity to doxorubicin in HeLa/TXL and HeLa/CDDP cells in a concentration-dependent manner. In conclusion, the concomitant use of ABM extract minimally affected sensitivity to various chemotherapeutic agents in HeLa cells and resistant sublines in vitro. PMID- 22432464 TI - Influence of the plant extract complex "AdMax" on global gene expression levels in cultured human fibroblasts. AB - Ethanol/water extracts from roots of Leuzea carthamoides Iljin, Rhodiola rosea L., Eleutherococcus senticosus Maxim, and from dry berries of Schizandra chinensis Baill. are known as adaptogenic remedies, which enhance physical endurance, counteract fatigue and restore suppressed immunity. Molecular mechanisms underlying effects of the extracts are poorly understood. In this study, a combination of these four extracts called AdMaxTM (Nulab, Inc., Florida) was examined for its ability to influence gene expression levels in cultured human fibroblasts in vitro with the help of whole-genome Affymetrix oligonucleotide microarrays. We showed that AdMax treatment results in significant changes (at least 2 fold, p <. 05) in expression of 67 genes that are involved in metabolism of protein, nucleic acids, lipid and carbohydrates, in regulation of transcription, protein and ion transport, response to stimulus and stress. Enhancing expression of the PANK2 gene is of special interest in connection with AdMax ability to enhance physical endurance and counteract fatigue. PANK2 encodes a mitochondrial enzyme pantothenate kinase 2, which provides coenzyme A biosynthesis and thereby plays crucial role in energy metabolism. Partial deficiency of PANK2 gene activity leads to pantothenate kinase-associated neurodegeneration. In this connection potential therapeutic use of AdMax in patients with neurodegenerative diseases is discussed. PMID- 22432465 TI - Severe iron deficiency anemia and gastrointestinal dysfunction associated with ingestion of pan masala. AB - A severe iron deficiency state and problematic upper gastrointestinal irritation developed in an adult female who ingested pan masala that included fennel seed and betel nut. This illness illustrates the potential complexity of clinical presentation when mixtures of herbal contents are ingested. Clinical history taking should routinely consider the potential importance of traditional customs. PMID- 22432466 TI - An evidence-based systematic review of passion flower (Passiflora incarnata L.) by the Natural Standard Research Collaboration. PMID- 22432467 TI - Increased breast cancer prevalence among female orthopedic surgeons. AB - BACKGROUND: As a result of low-dose ionizing radiation exposure during clinical practice, female orthopaedic surgeons may be at increased risk for breast cancer. METHODS: The 2009 American Academy of Orthopaedic Surgeons (AAOS) membership directory was used to mail a survey to all female AAOS fellows. Survey responses were collected between June 2009 and June 2010 among 505 (69.7%) of the eligible women. We calculated standardized prevalence ratios (SPRs) and 95% confidence intervals (CIs) by dividing the observed number of cancers among female orthopaedic surgeons by the expected number, based on the gender-specific, age specific, and race-specific cancer prevalence statistics in the general U.S. population. We compared the distribution of breast cancer risk factors in our study population to that of the women in the 2007 California Health Interview Survey (CHIS, n=30,541). RESULTS: Twenty-four women reported a prior diagnosis of invasive cancer. Female orthopaedic surgeons had a prevalence of cancer that was 85% higher than that of the general U.S. female population (SPR 1.85, 95% CI 1.19 2.76). Orthopaedic surgeons in our study also had a statistically significant 2.9 fold higher prevalence of breast cancer compared to the general U.S. female population (SPR 2.9, 95% CI 1.66-4.71). Survey respondents had a higher prevalence of both protective and predisposing breast cancer factors compared to California women. CONCLUSIONS: Our findings confirm that breast cancer prevalence is elevated among female orthopaedic surgeons. Although further research is needed to determine the factors behind this population's hypothesized increased risk, taken together, our results and others suggest that the orthopaedic community consider educating current practitioners of the use of protective shielding and other modifiable breast cancer risk factors. PMID- 22432468 TI - Improvement of the nuclear transfer efficiency by using the same genetic background of recipient oocytes as the somatic donor cells in goats. AB - We have compared the effect of the genetic background of recipient oocytes on the in vitro and in vivo development of nuclear transfer reconstructed embryos in goats. Adult fibroblast cells from Boer goats were used as donor cells, and recipient oocytes were obtained from Boer goats and Boer cross-breeds (Boer?*Huanghuai?). Nuclear transfer reconstructed embryos were cultured in vitro, or transferred into recipient goats. The mitochondrial origin of 2 cloned Boer goats was investigated by analysing the D-loop region based on polymorphisms via DNA sequencing. There was no significant difference in the fusion rate and cleavage rate of reconstructed embryos (P>0.05), when using Boer and cross breeding goat oocytes as recipient cytoplast respectively. However, in vitro morula development of reconstructed embryos from Boer oocytes was significantly higher than that of cross-breeding embryos (34.1% versus 19.1%, P<0.05). There was no significant difference in the rate of pregnancy and foetus loss between the 2 breeds. However, the live-birth rate was significantly higher with Boer goat oocyte recipients than the cross-breeds (3.1% versus 0.8%, P<0.05). Mitochondrial analysis showed that the 2 cloned goats were similar to their respective oocyte donor goats, and significantly different from the nucleus donor. In conclusion, genetic background of recipient oocytes affected in vitro and in vivo development of reconstructed embryos, with the homologous background of cytoplast and nuclear donor benefiting development of reconstructed embryos. The mitochondrial origin of the 2 cloned Boer goats came from recipient oocytes, not donors. PMID- 22432469 TI - Intracellular transduction and potential of Tat PTD and its analogs: from basic drug delivery mechanism to application. AB - INTRODUCTION: It has been 20 years since the discovery of the membrane translocating property of the HIV-1 transactivator of transcription (Tat) protein. The Tat protein transduction domain (Tat PTD) is a very promising tool for non-invasive cellular import of cargos and has been successfully applied to in vitro and in vivo delivery of different therapeutic agents for the treatment of many diseases. A growing number of reports on Tat PTD-mediated delivery have extensively revealed the mechanisms involved. Yet, due to the varied conditions used, the reports on the internalization mode of Tat PTD-cargo chimera are often varied. AREAS COVERED: This article reviews the possible intracellular trafficking mechanisms of Tat PTD including its binding, cellular entry process, and the roles of participants of the cell membrane. The therapeutic applications via local administration, such as those for the treatment of skin, ocular, cardiac and cerebral diseases, are also reviewed. In addition, some novel systems built by different groups are elucidated, which are utilized to overcome the poor targeting efficiency of Tat PTD for the treatment of CNS diseases, cancer and other diseases via systemic administration. EXPERT OPINION: With the development of targeting factors, such as antibodies, some cell targeting peptides and novel polymers, Tat PTD is expected to play a more efficient and/or better tolerated therapeutic role in the drug delivery field. PMID- 22432470 TI - Plants and tortoises: mutations in the Arabidopsis jasmonate pathway increase feeding in a vertebrate herbivore. AB - Photosynthetic tissues, the major food source of many invertebrates and vertebrates, are well defended. Many defence traits in leaves are controlled via the jasmonate signalling pathway in which jasmonate acts as a hormone by binding to a receptor to activate responses that lead to increased resistance to invertebrate folivores. We predicted that mutations in jasmonate synthesis might also increase the vulnerability of leaves to vertebrate folivores and tested this hypothesis using the Eastern Hermann's tortoise (Eurotestudo boettgeri) and an Arabidopsis thaliana (Brassicaceae) allene oxide synthase (aos) mutant unable to synthesize jasmonate. Tortoises preferred the aos mutant over the wild type (WT). Based on these results, we then investigated the effect of mutating jasmonate perception using a segregating population of the recessive A. thaliana jasmonate receptor mutant coronatine insensitive1-1 (coi1-1). Genotyping of these plants after tortoise feeding revealed that the homozygous coi1-1 receptor mutant was consumed more readily than the heterozygous mutant or the WT. Therefore, the plant's ability to synthesize or perceive jasmonate reduces feeding by a vertebrate herbivore. We also tested whether or not tortoise feeding behaviour was influenced by glucosinolates, the principal defence chemicals in Arabidopsis leaves with known roles in defence against many generalist insects. However, in contrast to what has been observed with such insects, leaves in which the levels of these compounds were reduced genetically were consumed at a similar rate to those of the WT. PMID- 22432471 TI - Energetic and geometrical evidence of nonbonding character of some intramolecular halogen...oxygen and other Y...Y interactions. AB - We present high-level ab initio calculations for representative group of molecules possessing the intramolecular interaction of the X...O type (X = F, Cl, Br, and I). Few examples of molecules with intramolecular O...O and F...F interactions are also investigated. We show that, although most often investigated as bonding, all these interactions are nonbonding or repulsive, as indicated by positive values of interaction energies obtained by means of a few estimating methods, by thorough studies of geometrical changes that take place during the X...O contact formation and by the lateral contact of electron density isosurfaces of X and O atoms, which both are characterized by negative values of electrostatic potential. The presented conclusion about the repulsive nature of the intramolecular X...O and similar interactions is in opposition to the proclamation of the quantum theory of atoms in molecules of Bader that the presence of a bond path and a corresponding bond critical point is always to indicate the bonding, thus, stabilizing interaction. PMID- 22432472 TI - Therapeutic potential of mesenchymal stem cells overexpressing human forkhead box A2 gene in the regeneration of damaged liver tissues. AB - BACKGROUND AND AIM: Although a liver transplantation is considered to be the only effective long-term treatment in many cases of liver diseases, it is limited by a lack of donor organs and immune rejection. As an autologous stem cell approach, this study was conducted to assess whether forkhead box A2 (Foxa2) gene overexpression in bone marrow-derived mesenchymal stem cells (MSC) could protect the liver from hepatic diseases by stimulating tissue regeneration after cell transplantation. METHODS: Rat MSC (rMSC) were isolated, characterized, and induced to hepatocytes that expressed liver-specific markers. Four different treatments (control [phosphate-buffered saline], rMSC alone, rMSC/pIRES-enhanced green fluorescent protein (EGFP) vector, and rMSC/pIRES-EGFP/human Foxa2) were injected into the spleen of carbon tetrachloride-injured rats. Biochemical and histological analyses on days 30, 60, and 90 post-transplantation were performed to evaluate the therapeutic capacities of MSC overexpressing hFoxa2. RESULTS: rMSC transfected with hFoxa2 were induced into hepatogenic linage and expressed several liver-specific genes, such as, Foxa2, alpha-fetoprotein, cytokeratin-18, hepatocyte nuclear factor-1alpha, and hepatocyte growth factor. A group of animals treated with MSC/hFoxa2 showed significant recovery of liver-specific enzyme expressions to normal levels at the end of the study (90 days). Furthermore, when compared to the fibrotic areas of the samples treated with MSC alone or MSC/vector, the fibrotic area of the samples treated with rMSC/hFoxa2 for 90 days significantly decreased, until they were completely gone. CONCLUSIONS: Human Foxa2 efficiently promoted the incorporation of MSC into liver grafts, suggesting that hFoxa2 genes could be used for the structural or functional recovery of damaged liver cells. PMID- 22432473 TI - E.A.O. guidelines for the use of diagnostic imaging in implant dentistry 2011. A consensus workshop organized by the European Association for Osseointegration at the Medical University of Warsaw. AB - Diagnostics imaging is an essential component of patient selection and treatment planning in oral rehabilitation by means of osseointegrated implants. In 2002, the EAO produced and published guidelines on the use of diagnostic imaging in implant dentistry. Since that time, there have been significant developments in both the application of cone beam computed tomography as well as in the range of surgical and prosthetic applications that can potentially benefit from its use. However, medical exposure to ionizing radiation must always be justified and result in a net benefit to the patient. The as low a dose as is reasonably achievable principle must also be applied taking into account any alternative techniques that might achieve the same objectives. This paper reports on current EAO recommendations arising from a consensus meeting held at the Medical University of Warsaw (2011) to update these guidelines. Radiological considerations are detailed, including justification and optimization, with a special emphasis on the obligations that arise for those who prescribe or undertake such investigations. The paper pays special attention to clinical indications and radiographic diagnostic considerations as well as to future developments and trends. PMID- 22432474 TI - Linking symbiont community structures in a model arbuscular mycorrhizal system. AB - * The influence of plant communities on symbiotic arbuscular mycorrhizal fungal (AMF) communities is difficult to study in situ as both symbionts are strongly influenced by some of the same soil and environmental conditions, and thus we have a poor understanding of the potential links in community composition and structure between host and fungal communities. * AMF were characterized in colonized roots of thermal soil Mimulus guttatus in both isolated plants supporting AMF for only a few months of the growing season and plants growing in mixed plant communities composed of annual and perennial hosts. Cluster and discriminant analysis were used to compare competing models based on either communities or soil conditions. * Mimulus guttatus in adjacent contrasting plant community situations harbored distinct AMF communities with few fungal taxa occurring in both community types. Isolated plants harbored communities of fewer fungal taxa with lower diversity than plants in mixed communities. Host community type was more indicative than pH of AMF community structure. * Our results support an inherent relationship between host plant and AMF community structures, although pH-based models were also statistically supported. PMID- 22432475 TI - Ewing sarcoma with 7;22 translocation: three new cases and clinicopathological characterization. AB - Ewing sarcoma (ES) is the second most common primary bone malignancy in children and is typically characterized by a translocation involving the EWS gene on chromosome 22 and a member of the ETS family of genes: FLI1 (90%), ERG1 (5%), ETV1 (1%), ETV4 (1%), and FEV (1%). We identified three new cases of t(7;22) (p22;q12) (EWS-ETV1) ES and a literature search revealed an additional six cases. In comparison to conventional ES with t(11;22) (q24;q12) (EWS-FLI1), the t(7;22) ES variant has a higher propensity for females and children in a younger age group and it occurs more commonly in extraosseous locations. PMID- 22432477 TI - Bioactivities of chicken essence. AB - The special flavor and health effects of chicken essence are being widely accepted by people. Scientific researches are revealing its truth as a tonic food in traditional health preservation. Chicken essence has been found to possess many bioactivities including relief of stress and fatigue, amelioration of anxiety, promotion of metabolisms and post-partum lactation, improvement on hyperglycemia and hypertension, enhancement of immune, and so on. These activities of chicken essence are suggested to be related with its active components, including proteins, dipeptides (such as carnosine and anserine), polypeptides, minerals, trace elements, and multiple amino acids, and so on. Underlying mechanisms responsible for the bioactivities of chicken essence are mainly related with anti-stress, anti-oxidant, and neural regulation effects. However, the mechanisms are complicated and may be mediated via the combined actions of many active components, more than the action of 1 or 2 components alone. PMID- 22432478 TI - The future of nursing: a midwifery perspective. PMID- 22432479 TI - Immunizations for women: a midwifery responsibility. PMID- 22432480 TI - Quality patient care in labor and delivery: a call to action. PMID- 22432481 TI - The level of importance and level of confidence that midwives in the United States attach to using genetics in practice. AB - INTRODUCTION: The clinical application of genetic advances has the potential to transform preconception and pregnancy care and improve pregnancy outcomes. The study aim was to evaluate the level of importance and level of confidence that midwives in the United States attach to using genetics in practice. METHODS: The study was a descriptive, cross-sectional, online survey with a convenience sample of certified nurse-midwives who were active members of the American College of Nurse-Midwives (ACNM) and provided midwifery care in the United States. The survey contained genetic case studies and questions related to genetic activities that occur in clinical practice. Participants were asked to rate how important each genetic activity is to midwifery practice generally and their personal level of confidence in carrying out the stated activity at the present time; questions were rated on a Likert-type scale of 1 (not at all important, not at all confident) to 4 (essential, confident to teach). RESULTS: There were 612 survey responses from among the 4244 active members of ACNM (14.42%). Most midwives believed that genetics-related activities were very important or essential to their clinical practices, but they were only moderately confident in their abilities to perform these activities. The average importance survey score was 88%, and the average confidence survey score was 70%. Some midwives (17.5%) thought that taking a 3-generation family history was essential, and some midwives (20.9%) were extremely confident in their abilities to perform this activity. Almost all midwives (98.5%) indicated that they wanted to learn more about genetics and genomics. DISCUSSION: Genetics education programs need to be developed and made available to midwives to increase their confidence levels in using genetics in clinical practice. PMID- 22432482 TI - A qualitative study of women's feelings about future childbirth: dread and delight. AB - INTRODUCTION: There is extensive knowledge about expectations of and thoughts about childbirth among women who have not given birth. When it comes to women who have given birth to at least 1 child, on the other hand, knowledge about their expectations for a future birth is limited. The purpose of this study is thus to describe the emotions of this group concerning future childbirth. METHODS: Participants were 908 women in Sweden who had given birth to at least 1 child. This study is based on responses to the following request in the questionnaire sent out to women 4 to 7 years after they had given birth vaginally: "Please describe your feelings when you think about giving birth in the future." RESULTS: One-third of the women responded that they were mostly frightened of future childbirth, while the remaining two-thirds had mostly positive feelings. The qualitative analysis resulted in 3 categories and 8 subcategories and an overall theme: a mixture of dread and delight. Even with negative feelings/fears about future childbirth, many women want to give birth to more children. DISCUSSION: Despite experiences of severe pain or complications during a previous birth, many women nonetheless looked forward to future childbirth, primarily since they were motivated by having another child and encouraged by having been given good support by the midwife. PMID- 22432483 TI - The importance of mode of birth after previous cesarean: success, satisfaction, and postnatal health. AB - INTRODUCTION: The recent National Institutes of Health consensus conference on vaginal birth after cesarean (VBAC) recommended a focus on strategies that increase women's opportunities to make informed choices about VBAC. This study aimed to expand knowledge of women's experiences of planned VBAC by focusing on postnatal experiences of women who participated in an Australian birth-after cesarean study. METHODS: At 6 to 8 weeks after birth, 165 women who experienced childbirth after a previous cesarean rated satisfaction with their birth experiences using a 10-point visual analogue scale, reported on postnatal health problems, and indicated whether they would make the same birth choice again. RESULTS: Significant differences were found in satisfaction scores by mode of birth. Mean scores out of a possible score of 10 ranged from 8.86 for spontaneous vaginal birth, 7.86 for elective repeat cesarean delivery, 6.71 for emergency cesarean delivery, to 6.15 for instrumental vaginal birth (F = 5.33; P = .002). Mean satisfaction scores for spontaneous vaginal birth and elective repeat cesarean delivery were statistically higher than for instrumental vaginal birth and emergency cesarean birth. Women who experienced instrumental vaginal birth and emergency cesarean birth also reported a higher number of postnatal health related problems and were least likely to agree that they would make the same birth choice again. DISCUSSION: Mode of birth was the most important determinant of postnatal satisfaction, postnatal health, and whether women felt they would make the same birth choice again. Clinicians, researchers, and policymakers should identify effective labor management practices that enhance women's opportunities to achieve spontaneous vaginal birth during planned VBAC. PMID- 22432484 TI - Effects of LI4 acupressure on labor pain in the first stage of labor. AB - INTRODUCTION: Complementary and alternative medicines have been used to decrease labor pain for many years. Despite reports that some of these methods reduce pain, increase maternal satisfaction, and improve other obstetric outcomes, they have received limited attention in the US medical literature. The purpose of this study was to evaluate the effects of LI4 acupressure on labor pain in the first stage of labor, on labor duration, and on patient satisfaction. METHODS: A single, blind, randomized clinical trial was performed with eligible women (N = 100) who were at the beginning of the active phase of labor (3-4 cm dilatation of cervix with regular uterine contractions). The women in the acupressure group (n = 50) received LI4 acupressure at the onset of the active phase for the duration of each uterine contraction over a period of 20 minutes, and the women in the control group (n = 50) received a touch on this point without massage. Labor pain was measured using a structured questionnaire of a subjective labor pain scale (visual analogue scale) before the intervention, immediately after the intervention, 20 and 60 minutes after the intervention, and then every hour. RESULTS: There were significant differences between the groups in subjective labor pain scores immediately and 20, 60, and 120 minutes after intervention (P <= .001). Active phase duration (3-4 cm dilatation to full dilatation) and second stage duration (full dilatation to birth) were shorter in the acupressure group. The women in the acupressure group reported greater satisfaction. DISCUSSION: LI4 acupressure was effective at decreasing pain and duration of labor. The participants were satisfied, and no adverse effects were noted. PMID- 22432485 TI - A clinical audit of the number of vaginal examinations in labor: a NOVEL idea. AB - INTRODUCTION: Clinical practice audits present an opportunity for providers to examine and reflect on their practice. Vaginal examinations are an integral part of intrapartum care but can be uncomfortable for women and can increase the risk of chorioamnionitis. Thus, vaginal examinations should be performed thoughtfully and for necessary reasons. METHODS: A busy midwifery service at a large academic center underwent an audit of the number of vaginal examinations performed in labor for 205 women admitted in spontaneous labor or with spontaneous rupture of membranes. The retrospective chart audit was performed by research midwives who queried 2 electronic medical record databases, 1 for provider progress notes and 1 for nursing notes. RESULTS: On average, a woman underwent 4 vaginal examinations during labor, a rate greater than the World Health Organization recommendation of 1 examination every 4 hours during the first stage. The rate of presumed chorioamnionitis in this group of healthy, low-risk women was 6%, and women with this diagnosis averaged 7 vaginal examinations. DISCUSSION: After presentation and discussion of the audit findings, the midwives expressed appreciation for the opportunity to explore such a fundamental element of clinical practice and a heightened awareness of the importance of performing and documenting vaginal examinations. Audits of a similar nature in other midwifery practices are needed, as are studies exploring rates and possible modifiable causes of chorioamnionitis in low-risk women. PMID- 22432486 TI - How do previous mental health, social support, and stressful life events contribute to postnatal depression in a representative sample of Australian women? AB - INTRODUCTION: The purpose of this study was to examine the risk factors for postnatal depression (PND) using longitudinal data in a representative sample of Australian women. METHODS: Mailed survey data collected from the youngest cohort of the Australian Longitudinal Study on Women's Health were analyzed. Of the women in this cohort, 2451 had a child in the 4 years preceding survey 4 in 2006, and those who reported being diagnosed or treated for PND at survey 4 (n = 252) were compared to those who had no report of PND at survey 4 (n = 2324) in order to identify risk factors for PND. RESULTS: Women with a history of depression (from survey 2 in 2000 and from survey 3 in 2003) were more likely to report postnatal depression (odds ratio [OR] 2.10; 95% confidence interval [CI], 1.39 3.18 and OR 2.15; 95% CI, 1.37-3.35, respectively). Contrary to previous research, demographic factors were not significantly related to PND. Women who rated their affectionate support and positive social interaction as being available some of the time were significantly more likely to experience PND (OR 2.37; 95% CI, 1.24-4.53) than those who rated this type of support as being available all of the time. DISCUSSION: While previous mental health problems and a history of stressful life events were found to be significant risk factors for PND, the results of this study show that women with PND are also lacking some aspects of social support around the time of the birth of their children. Implications for treatment and policy are discussed. PMID- 22432487 TI - Uterine activity during the third stage of labor. AB - INTRODUCTION: The purpose of this study was to evaluate the use of intrauterine pressure catheters (IUPCs) to measure uterine activity during the third stage of labor. METHODS: The study was conducted in a tertiary-care center. All births were attended by certified nurse-midwives. Low-risk pregnant women at term gestation had intrauterine monitoring attempted during the third stage of labor. Data were analyzed using descriptive statistics and analysis of variance. RESULTS: Of the 36 women in the study, 19 had clear contractions recorded, 4 had unclear contractions, and 13 had flat tracings. The IUPC was useful for measuring uterine activity in a small number of women during the third stage of labor. When measured, uterine contractions were variable in strength and frequency. DISCUSSION: Intrauterine pressure catheters can be used as a measurement of uterine activity during the third stage of labor and should be considered for future research about third-stage physiology. Further work is needed to determine the best procedure for placement, and IUPC use before expulsion of the placenta will not be useful in all women. Effective measurement of uterine activity may guide future research on interventions to reduce the risk of postpartum hemorrhage. PMID- 22432488 TI - Decision making following a prenatal diagnosis of Down syndrome: an integrative review. AB - INTRODUCTION: Prenatal screening for Down syndrome (DS) is a routine part of prenatal care in many countries, and there is growing interest in the choices women make following a prenatal diagnosis of DS. This review describes what is known about actual and hypothetical decision making following a prenatal diagnosis of DS and adds understanding about the factors that influence women's decision making. METHODS: A search of empirical studies was conducted through electronic databases, major journals, and reference lists that were published in English between January 1999 and September 2010. Inclusion criteria were that the research explored attitudes toward continuation of pregnancy or induced abortion for DS and included at least 1 variable that explored factors influencing women's decision making following a prenatal diagnosis of DS. Studies that did not specify DS, unpublished manuscripts, review articles, and book chapters were excluded. RESULTS: A total of 11 studies were identified that met the inclusion criteria. The decision to undergo an induced abortion varied depending on whether participants were prospective parents recruited from the general population (23% 33% would terminate), pregnant women at increased risk for having a child with DS (46%-86% would terminate), or women who received a positive diagnosis of DS during the prenatal period (89%-97% terminated). Multiple factors influence women's decision making following a diagnosis of DS, including demographic factors such as religion, maternal age, gestational age, number of existing children, and history of induced abortion. Psychosocial factors including perceived parenting burden/reward, quality of life for a child with DS, attitudes toward and comfort with individuals with disabilities, and support from others also are important influences. DISCUSSION: Multiple factors influence the decisions pregnant women make following the diagnosis of fetal DS. Therefore, it is critical that health care providers who work with pregnant women are aware of these factors. PMID- 22432489 TI - The lived experiences of midwives with spirituality in childbirth: mana from heaven. AB - INTRODUCTION: The purpose of this study was to describe the lived experiences of midwives who experienced the phenomenon of spirituality when they attended births. METHODS: The research design was descriptive, using a transcendental phenomenological approach reflected in Moustakas' model. Purposive and snowball sampling were used to recruit the sample of 10 certified nurse-midwives. RESULTS: The major findings of this study consisted of 5 theme categories that revealed the essential structure of the midwives' lived experiences of spirituality during childbirth: belief in the existence of a higher power, the essence of spirituality, birth is spiritual, the essence of midwifery, and relationships. DISCUSSION: The midwives in the study experienced spirituality as an integral and essential component of childbirth. The midwives reported using elements of spirituality as instruments that helped them assist their clients through the process of pregnancy and birth. The midwives also revealed their dependence on spirituality and belief in a higher being who guided their lives and their calling to midwifery. PMID- 22432490 TI - Women's health and hygiene experiences during deployment to the Iraq and Afghanistan wars, 2003 through 2010. AB - INTRODUCTION: The purpose of this study was to describe women's health and hygiene experiences during their deployment to Iraq and Afghanistan during the war years, 2003 through 2010. METHODS: A phenomenological method described the essential structures embedded in the women's health and hygiene experiences. Colaizzi's method of data analysis was used to guide the discovery of themes. Interview data were gathered from 24 interviews with military nurses who served in the war zones. Female military nurses were specifically selected for this study because of their insight, awareness, and knowledge base. RESULTS: Seven themes emerged from the data and captured the essence of the women's experiences: 1) bathroom trips and facilities: a walk on the wild side; 2) shower challenges: lack of privacy, water problems, and location issues; 3) menstruation: to suppress or not to suppress; 4) staying clean: a monumental task; 5) various infections: annoying distractions; 6) unintended pregnancies: wartime surprises; and 7) safety issues: enemy attacks and sexual assaults. DISCUSSION: In the current military structure, more women are being deployed to combat zones and will endure the challenges and hardships described in this study. The health and hygiene experiences of deployed women are an important part of their daily lives in combat zones. Educational programs and clinical services need to be tailored to this cadre of women, with focused attention on preparation and anticipatory guidance prior to deployment. Access to health promotion and appropriate clinical services during deployment is critical. Finally, as these women return home as veterans, it is important for all providers to understand the contextual framework of their service and its impact on their lives. PMID- 22432491 TI - Reaching Latinas with Our Bodies, Ourselves and the Guia de Capacitacion para Promotoras de Salud: health education for social change. AB - As the cultural and linguistic diversity of the United States continues to grow and population shifts transform the communities where we live and work, health care providers continue to face challenges to deliver health services in demographically redefined terrains. This report describes the development of a Spanish-language training guide for community health workers (Guia de Capacitacion para Promotoras de Salud) based on the book Nuestros Cuerpos, Nuestras Vidas (NCNV), the Spanish-language translation and cultural adaptation of the classic women's health book Our Bodies, Ourselves. The guide aims to 1) provide a tool for addressing the health education needs of immigrant Latinas and 2) facilitate the use of the book NCNV as a health education tool in Latino communities. Thirty telephone interviews with individuals working in agencies and organizations serving Latinos and 2 focus groups with Latinas were conducted to select the topics included in the training guide, all of which were drawn directly from NCNV. The guide contains 11 modules organized into 6 workshops. The modules address 11 topics related to women's health, ranging from sexuality and pregnancy to domestic violence and mental health. An ecological framework is used to deliver the health information. The materials acknowledge the roles of history, environment, culture, economic conditions, migration history, and politics as key determinants of health and illness. The workshops are designed to train community health workers on the women's health topics contained in the guide and to equip them for the delivery of health education among immigrant Latinas. PMID- 22432492 TI - Pinworm in pregnancy. AB - A case of enterobiasis in pregnancy that presented as copious nocturnal vaginal discharge is reported. Enterobius vermicularis is the most common parasite infecting humans. Transmission can be fecal-oral or via fomites, and recently arrived immigrants from developing countries and individuals who live in households with young children are particularly at risk. Pinworms are most frequently found in the gastrointestinal tract but can also enter the vagina and bladder. Patients typically present with nocturnal anal itching, and diagnosis can be made by clinical history. Treatment includes an antihelminthic agent for the patient and members of the household as well as home hygiene measures to prevent transmission. PMID- 22432493 TI - Recommended adult immunization schedule--United States, 2012. PMID- 22432495 TI - Planned home birth with community midwives has outcomes as good or better than planned hospital birth. PMID- 22432496 TI - Closer surveillance in pregnancy for women with polycystic ovary syndrome may be merited. PMID- 22432497 TI - Women's health benefits of aspirin therapy. PMID- 22432499 TI - Share with women. Breastfeeding and birth control. PMID- 22432500 TI - Zygomatic Implants: The Impact of Zygoma Bone Support on Biomechanics. AB - Abstract Maxillectomy and severely resorbed maxilla are challenging to restore with provision of removable prostheses. Dental implants are essential to restore aesthetics and function and subsequently quality of life in such group of patients. Zygomatic implants reduce the complications associated with bone grafting procedures and simplify the rehabilitation of atrophic maxilla and maxillectomy. The purpose of this study was to compare, by means of three dimensional finite element analysis, the impact of different zygomatic bone support (10, 15, and 20mm) on the biomechanics of zygomatic implants. Results indicated maximum stresses within the fixture were increased by three times, when bone support decreased from 20 to 10mm, and concentrated at fixture/bone interface. However, stresses within the abutment screw and abutment itself were not significantly different regardless of the bone support level. Supporting bone at 10mm suffered double the stresses of 15 and 20mm. Fixture's deflection was decreased by two to three times when bone level support increased to 15mm and 20mm respectively. It was concluded that zygomatic bone support should not be less than 15mm and abutment screw is not at risk of fracture regardless of the zygomatic bone support. PMID- 22432501 TI - Science in brief: clinical news from the 57th convention of the American Association of Equine Practitioners, 2011. PMID- 22432502 TI - Forecasting the effect of the Amethyst initiative on college drinking. AB - BACKGROUND: A number of college presidents have endorsed the Amethyst Initiative, a call to consider lowering the minimum legal drinking age (MLDA). Our objective is to forecast the effect of the Amethyst Initiative on college drinking. METHODS: A system model of college drinking simulates MLDA changes through (i) a decrease in heavy episodic drinking (HED) because of the lower likelihood of students drinking in unsupervised settings where they model irresponsible drinking (misperception), and (ii) an increase in overall drinking among currently underage students because of increased social availability of alcohol (wetness). RESULTS: For the proportion of HEDs on campus, effects of large decreases in misperception of responsible drinking behavior were more than offset by modest increases in wetness. CONCLUSIONS: For the effect of lowering the MLDA, it appears that increases in social availability of alcohol have a stronger impact on drinking behavior than decreases in misperceptions. PMID- 22432503 TI - High-throughput screening of metal-organic frameworks for CO2 separation. AB - A parallel high-throughput sorption methodology is described for screening CO(2) and N(2) adsorption and diffusion selectivity in metal organic frameworks, before and after exposure to water vapor and acid gases. We illustrate this approach by simultaneously investigating 8 candidate Metal-Organic Framework (MOF) materials, of which the best material was found to have a CO(2)/N(2) membrane selectivity of 152 and a CO(2) permeability of 60 barrer for Co-NIC. This approach provides a significant increase in efficiency of obtaining the separation properties of MOFs. While we describe here the identification of novel materials for CO(2) capture, the methodology enables exploration of the performance and stability of novel porous materials for a wide range of applications. PMID- 22432504 TI - A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage. AB - Testicular spermatozoa are utilized to achieve pregnancy in couples with severe male factor infertility. Several studies suggest that aneuploidy rates in spermatozoa are elevated at the testicular level in infertile patients compared to ejaculates of normal controls. However, essential data regarding aneuploidy rates between ejaculated and testicular spermatozoa in the same individuals is lacking. The purpose of our study was to compare aneuploidy rates at the testicular and post-testicular level from the same patients with persistently high sperm DNA damage. Ejaculates and testicular biopsies were obtained from eight patients with persistently high DNA damage (>30%). Both ejaculated and testicular samples were analyzed for sperm DNA damage and sperm aneuploidy for chromosomes 13, 18, 21, X, and Y. In addition, semen samples from ten normozoospermic men presenting for fertility evaluation served as a control group. A strong correlation between the alteration of spermatogenesis and chromatin deterioration was observed in our study. In the same individuals, testicular samples showed a significantly lower DNA damage compared to ejaculated spermatozoa (14.9% +/- 5.0 vs. 40.6% +/- 14.8, P<0.05), but significantly higher aneuploidy rates for the five analyzed chromosomes (12.41% +/- 3.7 vs. 5.77% +/- 1.2, P<0.05). While testicular spermatozoa appear favourable for ICSI in terms of lower DNA damage, this potential advantage could be offset by the higher aneuploidy rates in testicular spermatozoa. PMID- 22432505 TI - Ion and nutrient uptake by malaria parasite-infected erythrocytes. AB - Erythrocytes infected with malaria parasites have increased permeability to diverse organic and inorganic solutes. While these permeability changes have been known for decades, the molecular basis of transport was unknown and intensively debated. CLAG3, a parasite protein previously thought to function in cytoadherence, has recently been implicated in formation of the plasmodial surface anion channel (PSAC), an unusual small conductance ion channel that mediates uptake of most solutes. Consistent with transport studies, the clag genes are conserved in all plasmodia but are absent from other genera. The encoded protein is integral to the host membrane, as also predicted by electrophysiology. An important question is whether functional channels are formed by CLAG3 alone or through interactions with other proteins. In either case, gene identification should advance our understanding of parasite biology and may lead to new therapeutics. PMID- 22432506 TI - Constructing anisotropic single-Dirac-cones in Bi(1-x)Sb(x) thin films. AB - The electronic band structures of Bi(1-x)Sb(x) thin films can be varied as a function of temperature, pressure, stoichiometry, film thickness, and growth orientation. We here show how different anisotropic single-Dirac-cones can be constructed in a Bi(1-x)Sb(x) thin film for different applications or research purposes. For predicting anisotropic single-Dirac-cones, we have developed an iterative-two-dimensional-two-band model to get a consistent inverse-effective mass-tensor and band gap, which can be used in a general two-dimensional system that has a nonparabolic dispersion relation as in the Bi(1-x)Sb(x) thin film system. PMID- 22432507 TI - Abuse, depressive symptoms, executive functioning, and overgeneral memory among a psychiatric sample of children and adolescents. AB - Prior research has established the independent associations of depressive symptoms and childhood trauma to overgeneral memory (OGM); the present study addresses the potentially interactive effects between these two risk factors on OGM. In addition, the current study comprehensively evaluates whether executive functions (EF) mediate the relation between depressive symptoms and/or abuse to OGM in a child and adolescent sample. OGM was assessed among an inpatient psychiatric sample of 49 youth (ages 7-17) with, and without, child abuse histories and depressive symptomatology. EF was assessed with standardized neuropsychological measures of verbal fluency, inhibition, and cognitive flexibility. There was a significant interaction of depressive symptoms and abuse in predicting OGM; the effect of depression on OGM was less pronounced among youth with abuse histories, who had elevated OGM at both low and high depressive symptoms relative to those with no abuse and low depressive symptoms. Among the EF measures, only category fluency was associated with OGM. An additive, rather than mediational, model was supported, whereby category fluency accounted for a significant proportion of variance in OGM above child abuse and depressive symptoms. The meaning of these findings for models of OGM and clinical practice are emphasized. PMID- 22432508 TI - Screening, diagnosing, labeling, profiling, stereotyping, and imaging "THE Substance User": where is the person? PMID- 22432509 TI - Protein-ligand binding free energies from exhaustive docking. AB - We explore the use of exhaustive docking as an alternative to Monte Carlo and molecular dynamics sampling for the direct integration of the partition function for protein-ligand binding. We enumerate feasible poses for the ligand and calculate the Boltzmann factor contribution of each pose to the partition function. From the partition function, the free energy, enthalpy, and entropy can be derived. All our calculations are done with a continuum solvation model that includes solving the Poisson equation. In contrast to Monte Carlo and molecular dynamics simulations, exhaustive docking avoids (within the limitations of a discrete sampling) the question of "Have we run long enough?" due to its deterministic complete enumeration of states. We tested the method on the T4 lysozyme L99A mutant, which has a nonpolar cavity that can accommodate a number of small molecules. We tested two electrostatic models. Model 1 used a solute dielectric of 2.25 for the complex apoprotein and free ligand and 78.5 for the solvent. Model 2 used a solute dielectric of 2.25 for the complex and apoprotein but 1.0 for the free ligand. For our test set of eight molecules, we obtain a reasonable correlation with a Pearson r(2) = 0.66 using model 1. The trend in binding affinity ranking is generally preserved with a Kendall tau = 0.64 and Spearman rho = 0.83. With model 2, the correlation is improved with a Pearson r(2) = 0.83, Kendall tau = 0.93, and Spearman rho = 0.98. This suggests that the energy function and sampling method adequately captured most of the thermodynamics of binding of the nonpolar ligands to T4 lysozyme L99A. PMID- 22432510 TI - Colloids on the frontier of ferrofluids. Rheological properties. AB - This paper is devoted to the steady-state rheological properties of two new kinds of ferrofluids. One of these was constituted by CoNi nanospheres of 24 nm in diameter, whereas the other by CoNi nanofibers of 56 nm in length and 6.6 nm in width. These ferrofluids were subjected to shear rate ramps under the presence of magnetic fields of different intensity, and the corresponding shear stress values were measured. From the obtained rheograms (shear stress vs shear rate curves) the values of both the static and the dynamic yield stresses were obtained as a function of the magnetic field. The magnetoviscous effect was also obtained as a function of both the shear rate and the magnetic field. The experimental results demonstrate that upon magnetic field application these new ferrofluids develop yield stresses and magnetoviscous effects much greater than those of conventional ferrofluids, based on nanospheres of approximately 10 nm in diameter. Besides some expected differences, such as the stronger magnetorheological effect in the case of ferrofluids based on nanofibers, some intriguing differences are found between the rheological behaviors of nanofiber ferrofluids and nanosphere ferrofluid. First, upon field application the rheograms of nanofiber ferrofluids present N-shaped dependence of the shear stress on the shear rate. The decreasing part of the rheograms takes place at low shear rate. These regions of negative differential viscosity, and therefore, unstable flow is not observed in the case of nanosphere ferrofluids. The second intriguing difference concerns the curvature of the yield stress vs magnetic field curves. This curvature is negative in the case of nanosphere ferrofluid, giving rise to saturation of the yield stress at medium field, as expected. However, in the case of nanofiber ferrofluid this curvature is positive, which means a faster increase of the yield stress with the magnetic field the higher the magnitude of the latter. These interesting differences may be due to the existence of strong interparticle solid friction in the case of nanofiber ferrofluids. Finally, theoretical models for the static yield stress of the ferrofluids were developed. These models consider that upon field application the ferrofluid nanoparticles are condensed in drops of dense phase. These drops tend to be aligned along the field direction, opposing the flow of the ferrofluids and being responsible for the static quasielastic deformation and the yield-stress phenomena. By considering the existence of interparticle dry friction only in the case of nanofiber ferrofluids, the developed models predicted quite well not only the magnitude of the static yield stress but also the differences in curvature of the yield stress vs magnetic field curves. PMID- 22432511 TI - Light-regulated supramolecular engineering of polymeric nanocapsules. AB - This article describes the light-driven supramolecular engineering of water dispersible nanocapsules (NCPs). The novelty of the method lies in the utilization of an appropriate phototrigger to stimulate spherical polymer brushes, consisting of dual-responsive 2-(dimethylamino)ethyl methacrylate (DMAEMA) and light-sensitive spiropyran (SP) moieties, for the development or disruption of the NCPs in a controlled manner. The fabrication of the nanocarriers is based on the formation of H-type pi-pi interactions between merocyanine (MC) isomers within the sterically crowded environment of the polymer brushes upon UV irradiation, which enables the SP-to-MC isomerization of the photosensitive species. After HF etching of the inorganic core, dual-responsive polymeric vesicles whose walls' robustness is provided by the MC-MC cross-link points are formed. Disruption of the vesicles can be achieved remotely by applying a harmless trigger such as visible-light irradiation. The hydrophilic nature of the DMAEMA comonomer facilitates the engineering of the vesicles in environmentally benign aqueous media and enables the controlled alteration of the NCPs size upon variation of the solution pH. The inherent ability of the NCPs to fluoresce in water opens new possibilities for the development of addressable nanoscale capsules for biomedical applications. PMID- 22432512 TI - A two-step valence tautomeric transition in a dinuclear cobalt complex. AB - A dinuclear cobalt complex with cobalt centers bridged by a bis(dioxolene) ligand exhibits a rare two-step valence tautomeric transition. PMID- 22432513 TI - Herbal medicine: an overview of the literature from three decades. AB - OBJECTIVES: To generate information about what types of articles have been published in what languages on what topics. In addition, we assessed the methodological quality of randomized clinical trials (RCTs) over time. METHODS: Searches were carried out in Medline in order to (a) identify the number of articles published in English, Chinese, German, Russian, and Japanese during the years 1977, 1987, 1997, and 2007; (b) identify the number of five types of articles, namely, systematic reviews (SRs), reviews, clinical controlled trials (CCTs), RCTs, and case reports, published in the above-mentioned 4 years; (c) identify the types of herbal medicine that were most frequently tested in CCTs and RCTs. Twenty RCTs were retrieved from each of the above-mentioned 4 years and were quality assessed using Jadad score and were statistically compared. RESULTS: (1) The number of articles on herbal medicine has increased during the last three decades. (2) Review articles and RCTs were the most numerous types of publications toward the end of our observation period; CCTs were the least. (3) Guar gum, evening primrose oil, ginseng, and Ginkgo biloba were some of the main herbal medicines that were most frequently submitted to CCTs and RCTs. (4) The average Jadad score improved continually (F = 6.27, p = .014) between 1977 and 2007. CONCLUSION: These findings are consistent with the notion that the quantity and quality of RCTs of herbal medicine have been improving during the last three decades. We suggest that the adaption of the herbal-medicine-specific Consolidated Standard of Reporting Trials guidelines might further improve the situation in future. PMID- 22432514 TI - Anti-inflammatory effects of natural product formulations on murine macrophages. AB - The popularity of herbal supplements, especially those with purported anti inflammatory effects, has drastically increased in recent years as more people have turned to natural therapeutics. As the supplement industry is loosely regulated, the safety and efficacy of these products is poorly understood. In the present study, we examined the effects of natural product formulations prepared by the Biotics Research Corporation (BRC) on cyclooxygenase (COX) enzyme activity. We also evaluated the immune responsiveness of RAW264.7 macrophages, a key cell population involved in the inflammation, to those formulations. As a result, three supplements, BRC-301, BRC-304, and BRC-306, selectively inhibited COX-2, the inducible isoform involved in inflammation. Further evaluation of these three products indicated that BRC-304 and BRC-306 produced minimal effects on the production of inflammatory mediators by lipopolysaccharide (LPS) stimulated macrophages. BRC-301 decreased the LPS-induced production of nitric oxide and IL-6, as well as CD40 expression. Collectively, these results suggest that the BRC-301 extract, comprising several polyphenolic natural products, may have a protective effect in chronic inflammatory disorders. PMID- 22432515 TI - Physicochemical characterization of creatine N-methylguanidinium salts. AB - Creatine is widely used as a dietary supplement for body builders to enhance athletic performance. As the monohydrate, its low solubility in water and high dose lead to water retention and gastrointestinal discomfort. Hence, alternative creatine derivatives with enhanced water solubility and potential therapeutic advantages have been synthesized. As a zwitterionic compound, creatine can form salts at the N-methyl guanidinium or carboxylic acid functional groups. In this study, we determined the aqueous solubilities and partition coefficients of six N methyl guanidinium salts of creatine compared to those of creatine monohydrate; two of these were new salts, namely, creatine mesylate and creatine hydrogen maleate. The aqueous solubilities of the salts were significantly more than that of creatine monohydrate with the hydrochloride and mesylate being 38 and 30 times more soluble, respectively. The partition coefficients of the creatine salts were very low indicating their relatively high polarity. Permeabilities of creatine pyruvate, citrate, and hydrochloride in Caco-2 monolayers were compared to that of creatine monohydrate. Aside from the creatine citrate salt form that had reduced permeability, there were no significant differences in permeability characteristics in Caco-2 monolayers. Typical of an amphoteric compound, creatine is least soluble in the pH region near the isoelectric point. PMID- 22432516 TI - A medicinal plant extract of Scutellaria Baicalensis and Acacia catechu reduced LPS-stimulated gene expression in immune cells: a comprehensive genomic study using QPCR, ELISA, and microarray. AB - A standardized, combined flavonoid extracts of Scutellaria baicalensis and Acacia catechu, UP446, demonstrates favorable anti-inflammatory properties. In this study, DNA microarray, quantitative polymerase chain reaction (QPCR), and enzyme linked immunosorbent assay (ELISA) were used to study the effect of UP446 on the lipopolysaccharide (LPS)-induced pro-inflammatory gene regulation of both animal and human immortalized cell lines and also primary human cells. One consistent result from microarray was that the gene expression levels stimulated or suppressed by LPS were returned to normal levels by the UP446 co-treatment. This normalization effect from UP446 was also shown for pro-inflammatory genes cyclooxygenase (COX)-2, tissue necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-6 using QPCR, and TNF-alpha using ELISA. The controlling transcriptional factor of these genes, NFkappaB, was also down-regulated by UP446 in the LPS-induced cell models. Microarray analysis for numerous genes, including cytokines, chemokines, receptors, transcriptional factors, caspase, growth factors, and phosphatases, suggests not only a genomic anti-inflammatory activity for UP446 but also signaling pathways of cell proliferation, cell death, and lipid metabolism demonstrated on different types of cells. PMID- 22432517 TI - An open label study on the supplementation of Gymnema sylvestre in type 2 diabetics. AB - Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia, and associated with long-term damage and dysfunction of various organs. Management of diabetes is therefore vital and involves maintaining euglycemia as much as possible by reducing blood glucose and by increasing insulin sensitivity and peripheral glucose uptake. Ayurveda has promoted the management of diabetes by regulating carbohydrate metabolism using several medicinal herbs, one of which is Gymnema sylvestre (GS). GS has been used in parts of India as a hypoglycemic agent and the results have been encouraging. Accordingly, we planned a quasi-experimental study to investigate the efficacy of the herb among type 2 diabetics. Patients enrolled from free-living population were purposively assigned to experimental or control groups, based on their willingness to participate in the study. The experimental group was supplemented with 500 mg of the herb per day for a period of 3 months, and the efficacy of the herb was assessed through a battery of clinical and biochemical tests. Supplementation of the diet with GS reduced polyphagia, fatigue, blood glucose (fasting and post-prandial), and glycated hemoglobin and there was a favorable shift in lipid profiles and in other clinico-biochemical tests. These findings suggest a beneficial effect of GS in the management of diabetes mellitus. PMID- 22432518 TI - An evidence-based systematic review of umckaloabo (Pelargonium sidoides) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review, including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22432519 TI - Report on the Third International Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, 26-27 September 2011 and Menton 2011 consensus. AB - One hundred and ninety-three hemato-oncologists and nuclear medicine specialists from 23 countries joined the 2-day Third International Workshop on Interim Positon Emission Tomography in Lymphoma held in September 2011. Forty scientific posters were presented or discussed in the plenary session. Final results of international validation studies of Deauville criteria and change in maximum standardized uptake value (DeltaSUV(MAX)) analysis in Hodgkin lymphoma (HL) as well as non-Hodgkin lymphoma (NHL) were reported. These studies were confirmatory of the prognostic value of interim positron emission tomography (PET) in 261 patients with advanced HL after two cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) when reported with the 5-point scale and in 120 patients with diffuse large B-cell lymphoma (DLBCL) after two cycles of a rituximab-containing immunochemotherapy regimen when using DeltaSUV analysis. A preliminary consensus on interim PET was established among experts on the assessment of marrow response, refinement of scores 4 and 5 of the 5-point scale, the need to focus on interim PET results for NHL other than DLBCL, methods to compute DeltaSUV and factors affecting DeltaSUV measurements. Recommendations were given on how to use DeltaSUV analysis in NHL taking into account the levels of initial SUV(MAX) and interim SUV(MAX). For the next meeting (October 2012), the majority of the audience strongly favored extending the topics, including in the workshop all aspects of PET in lymphoma, rather than just limiting it to interim PET. PMID- 22432520 TI - Richter transformation of chronic lymphocytic leukemia into composite diffuse large B-cell and Hodgkin lymphoma. PMID- 22432521 TI - Evaluation of a new durable insulin pen with memory function among people with diabetes and healthcare professionals. AB - OBJECTIVES: The aim of the study was to evaluate durable insulin pens among people with diabetes (PwD) and healthcare professionals (HCPs), by comparing two durable insulin pens with memory function: NovoPen(r) 5 (NP5) and HumaPen(r) MemoirTM (HPM), and two durable insulin pens without memory function: HumaPen Luxura(r) (HPL) and ClikSTAR(r) (CS). RESEARCH DESIGN AND METHODS: This cross over, multicentre usability test was conducted in China, Germany and the UK. Participants evaluated all four pens in randomised order by performing handling and usability tasks related to everyday use during a face-to-face interview. Tasks, pens and preferences were rated by completing a questionnaire comprising of rating and open-ended questions. RESULTS: NP5 was preferred by 51% of participants compared with HPM (22%, p < 0.01), HPL (12%, p < 0.01) and CS (15%, p < 0.01). Participants preferred the design of NP5 (in particular, appearance, length and robustness). Memory function for the two pens was rated equally by participants, but 54% of PwD rated NP5 as 'very easy' to learn to use versus 22% for HPM and significantly more HCPs found it 'very easy' to teach patients to use NP5 versus HPM (6-point rating scale; difference in mean score, p < 0.01). Substantially, more PwD would be confident in using NP5 (64%) compared with HPM (43%), HPL (49%) and CS (45%) (6-point rating scale; difference in mean score, p < 0.01). CONCLUSIONS: NP5 was preferred by > 50% of PwD and HCPs. NP5 was more highly rated for design, memory function and ease of learning/teaching compared with HPM. Most PwD would be confident in using NP5 for administering daily insulin injections. PMID- 22432522 TI - The effect of diabetes on bone formation following application of the GBR principle with the use of titanium domes. AB - OBJECTIVE: The aim of the study was to evaluate the effect of experimental diabetes and metabolic control on de novo bone formation following the GBR principle under titanium dome with a hydrophobic or hydrophilic surface. MATERIAL AND METHODS: Three groups of equal number of randomly allocated Wistar strain rats were created: (a) uncontrolled, streptozotocin-induced diabetes (D); (b) insulin-controlled diabetes (CD); (c) healthy (H). Each group was then further divided into two groups according to either 7 or 42 days of healing period, which received either a hydrophobic (SLA: A) or a hydrophilic (SLActive: B) dome. The undecalcified sections were evaluated by qualitative and quantitative histological analysis and the differences between means for the groups (D, CD, and H) and the type of domes (SLA and SLActive) at each of two observational periods (i.e. 7 and 42 days) were assessed by performing a two-way analysis of variance (ANOVA). RESULTS: In all experimental groups, significant de novo bone formation under the domes was observed at 42 days of healing. There was a tendency of increased new total bone (TB) formation in H and CD groups compared to D group at 42 days of healing. Also, the SLActive titanium surface showed a trend of promoting superior TB formation at the early observational period among the experimental groups, however these differences did not reach statistical significance. In regards to the bone-to-implant contact (BIC%) under the both dome treatments (SLA and SLActive), there was no statistically significant difference among the H, CD, and D groups at both 7 and 42 days. CONCLUSION: Despite of the presence of uncontrolled diabetes, substantial de novo bone formation can be achieved in titanium domes with a hydrophobic and a hydrophilic surface. The use of SLActive titanium surface may present a tendency to promote new bone formation in healthy and diabetic conditions at 7 days of healing, however the obtained data do not allow any robust conclusions. PMID- 22432523 TI - Preclinical evaluation of [99m]Tc-labeled doxorubicin as a potential scintigraphic probe for tumor imaging. AB - BACKGROUND: The currently available radiopharmaceuticals are not specific for tumor imaging. PURPOSE: The present study was conducted to radiolabel doxorubicin with Technetium-99m ([99m]Tc) as a scintigraphic marker of high DNA turnover/intercalation in malignant cells. METHODS: Labeling was done by direct method and the developed radiotracer was subjected to quality control tests. The blood kinetics, scintigraphy of tumor-bearing mice, and biodistribution were studied after intravenous injection of about 7.4 MBq of [99m]Tc-doxorubicin. The isotime (5 minutes) anterior images were acquired at different time intervals of 1.5, 3, and 4 hours. RESULTS: The labeling efficiency of [99m]Tc-doxorubicin was estimated to be more than 95%. The protein-binding efficiency was greater than 88% and in vitro stability was up to 24 hours. The biodistribution data support the clearance of the radioligand by dual (renal and hepatic) pathways. A semiquantitative data analysis of the anterior images indicated that a focal concentration of the radiotracer was seen in the tumor at 1.5 hours, which persisted in 3-hour and 4-hour images, respectively. CONCLUSIONS: This scintigraphic approach, therefore, could be a powerful tool for cancer detection at early stage. The technique, however, needs further validation through animal experimentation and clinical studies. PMID- 22432524 TI - Measurement of vapor pressures and heats of sublimation of dicarboxylic acids using atmospheric solids analysis probe mass spectrometry. AB - Vapor pressures of low volatility compounds are important parameters in several atmospheric processes, including the formation of new particles and the partitioning of compounds between the gas phase and particles. Understanding these processes is critical for elucidating the impacts of aerosols on climate, visibility, and human health. Dicarboxylic acids are an important class of compounds in the atmosphere for which reported vapor pressures often vary by more than an order of magnitude. In this study, atmospheric solids analysis probe mass spectrometry (ASAP-MS), a relatively new atmospheric pressure ionization technique, is applied for the first time to the measurement of vapor pressures and heats of sublimation of a series of dicarboxylic acids. Pyrene was also studied because its vapor pressures and heat of sublimation are relatively well known. The heats of sublimation measured using ASAP-MS were in good agreement with published values. The vapor pressures, assuming an evaporation coefficient of unity, were typically within a factor of ~3 lower than published values made at similar temperatures for most of the acids. The underestimation may be due to diffusional constraints resulting from evaporation at atmospheric pressure. However, this study establishes that ASAP-MS is a promising new technique for such measurements. PMID- 22432525 TI - Ecological and genetic factors linked to contrasting genome dynamics in seed plants. AB - The large-scale replacement of gymnosperms by angiosperms in many ecological niches over time and the huge disparity in species numbers have led scientists to explore factors (e.g. polyploidy, developmental systems, floral evolution) that may have contributed to the astonishing rise of angiosperm diversity. Here, we explore genomic and ecological factors influencing seed plant genomes. This is timely given the recent surge in genomic data. We compare and contrast the genomic structure and evolution of angiosperms and gymnosperms and find that angiosperm genomes are more dynamic and diverse, particularly amongst the herbaceous species. Gymnosperms typically have reduced frequencies of a number of processes (e.g. polyploidy) that have shaped the genomes of other vascular plants and have alternative mechanisms to suppress genome dynamism (e.g. epigenetics and activity of transposable elements). Furthermore, the presence of several characters in angiosperms (e.g. herbaceous habit, short minimum generation time) has enabled them to exploit new niches and to be viable with small population sizes, where the power of genetic drift can outweigh that of selection. Together these processes have led to increased rates of genetic divergence and faster fixation times of variation in many angiosperms compared with gymnosperms. PMID- 22432526 TI - Re: Echocardiographic and tissue Doppler imaging alterations associated with spontaneous canine systemic hypertension. PMID- 22432528 TI - Re: Radiographic heart size and its rate of increase as tests for the onset of congestive heart failure in Cavalier King Charles Spaniels with mitral valve regurgitation. PMID- 22432531 TI - High-density PhyloChip profiling of stimulated aquifer microbial communities reveals a complex response to acetate amendment. AB - There is increasing interest in harnessing the functional capacities of indigenous microbial communities to transform and remediate a wide range of environmental contaminants. Information about which community members respond to stimulation can guide the interpretation and development of remediation approaches. To comprehensively determine community membership and abundance patterns among a suite of samples associated with uranium bioremediation experiments, we employed a high-density microarray (PhyloChip). Samples were unstimulated, naturally reducing, or collected during Fe(III) (early) and sulfate reduction (late biostimulation) from an acetate re-amended/amended aquifer in Rifle, Colorado, and from laboratory experiments using field-collected materials. Deep community sampling with PhyloChip identified hundreds-to-thousands of operational taxonomic units (OTUs) present during amendment, and revealed close similarity among highly enriched taxa from drill core and groundwater well deployed column sediment. Overall, phylogenetic data suggested that stimulated community membership was most affected by a carryover effect between annual stimulation events. Nevertheless, OTUs within the Fe(III)- and sulfate-reducing lineages, Desulfuromonadales and Desulfobacterales, were repeatedly stimulated. Less consistent, co-enriched taxa represented additional lineages associated with Fe(III) and sulfate reduction (e.g. Desulfovibrionales; Syntrophobacterales; Peptococcaceae) and autotrophic sulfur oxidation (Sulfurovum; Campylobacterales). Data implies complex membership among highly stimulated taxa and, by inference, biogeochemical responses to acetate, a nonfermentable substrate. PMID- 22432532 TI - Lack of habituation to shocking words: the attentional bias to their spatial origin is context free. AB - Following a suggestion made by Aquino and Arnell (2007), we assumed that the processing of emotional words is influenced by their context of presentation. Supporting this idea, previous studies using the emotional Stroop task in its visual or auditory variant revealed different results depending on the mixed versus blocked presentation of the stimuli (Bertels, Kolinsky, Pietrons, & Morais, 2011; Richards, French, Johnson, Naparstek, & Williams, 1992). In the present study, we investigated the impact of these presentation designs on the occurrence of spatial attentional biases in a modified version of the beep-probe task (Bertels, Kolinsky, & Morais, 2010). Attentional vigilance to taboo words as well as non-spatial slowing effects of these words were observed whatever the mixed or blocked design, whereas attentional vigilance to positive words was only observed in the mixed design. Together with the results from our previous study (Bertels et al., 2010), the present data support the reliability of the effects of shocking stimuli, while vigilance to positive words would only be observed in a threatening context. PMID- 22432533 TI - Implications of nursing faculties' cultural competence. AB - Despite the need to increase diversity in the nursing profession, minority nurses continue to be underrepresented. The literature implies that nurse educators' lack of cultural competence could be contributing to minority nursing students' high attrition rate. No published studies known to this author exist on the relationship between nurse educators' cultural competence and the recruitment and graduation of minority nursing students. Using a descriptive correlational survey design, this study explored the relationship between nurse educators' cultural competence and the recruitment and graduation of minority nursing students. Nurse educators in nine accredited colleges of nursing completed the Cultural Diversity Questionnaire for Nurse Educators. A significant statistical correlation was found between mean cultural competence scores and the percentage of minority nursing students graduated from these schools. Nurse educators need to increase their cultural competence, enabling them to help students from diverse cultural backgrounds stay in school and graduate. PMID- 22432534 TI - Journal clubs: a strategy to teach civility to nursing students. AB - Incivility affects nurses and nursing students and can negatively influence patient care and the quality of nursing education. The Institute of Medicine, The Joint Commission, and the American Association of Colleges of Nursing recommended implementation of strategies to manage incivility and build social capital. The purpose of this mixed methods study was to explore the influence of a journal club as an educational intervention to build civility and academic integrity among nursing students. Seventy-nine nursing students completed the Nurses' Intervention for Civility Education Questionnaire and the Ways of Coping Questionnaire before and after the Civility Journal Club intervention. Students involved in the Civility Journal Club were more aware of civility and incivility, more likely to be helpful to their peers, and better equipped to cope with episodes of incivility. PMID- 22432535 TI - Using a clinical postconference to introduce baccalaureate nursing students to a quality framework. AB - Novice nurses are expected to contribute to an organization's quality initiatives and strategic goals. Therefore, it is imperative for nursing students to learn how a quality framework is woven within an organization. A figure was created that introduced baccalaureate nursing students to key quality concepts linking regulations, the organization, the quality department, and quality improvement (QI) methods. One important goal was to provide a visual framework that could facilitate clinical postconference discussions regarding the interrelationship of these concepts. Fifty-three undergraduate nursing students participated in a pilot over three semesters. Student response was heavily influenced based on their levels of training, which allowed for programmatic revisions each semester. Evaluation yielded improved QI knowledge and attitudes among advanced students (those in a senior transition course ready to graduate); it also served as a useful method to begin meeting the Quality and Safety Education for Nurses' QI competency. PMID- 22432536 TI - Exclusion and control: patterns aimed at limiting the influence of faculty of color. AB - This article reports on findings from a grounded theory study of the experiences of faculty of color (FOC) in predominantly Euro-American schools of nursing. Findings indicate that a dominant group sometimes referred to as the "Good Old Girls" posed a major barrier to change. To maintain the status-quo, the Good Old Girls used their influence to subject FOC to Patterns of Exclusion and Control with the goal of controlling the influence of FOC. This occurred through parallel and interrelated exclusion and control subprocesses. Exclusion and control strategies threatened FOC's success in academe while simultaneously jeopardizing their well-being. The exclusion strategies FOC experienced included Invalidation of Sense of Self, Othering, and Unequal Standards and Access to Resources. The control strategies included Insincerity and Putting You in Your Place. We describe each of these processes in detail and end with a discussion of the implications of our findings for educational practice. PMID- 22432537 TI - Use of a simulated administrative decision-making exercise in an online master's Nursing Administration course. AB - To simulate the type of ethical and informed decision making required of today's nurse executives, a unique role-playing exercise was developed in a graduate Nursing Administration course. This exercise included evidence-based information about the safety issues inherent in 12-hour nursing shifts. It then explored the decision-making process that a nurse executive would follow to weigh the conflicting concerns of safety and staff satisfaction. A blog format was used for a role-playing exercise in which students were assigned various roles, and the assignment was designed to mimic a roundtable discussion. The final step was to assume the role of the chief nurse executive and make a decision regarding the ethical dilemma of staff satisfaction versus evidence-based safety concerns. Students demonstrated an understanding of acknowledging input from others, as well as the ability to synthesize points on a difficult question. PMID- 22432538 TI - Effects of clinical practice environments on clinical teacher and nursing student outcomes. AB - The purpose of this study was to use a cross-sectional survey design, with an integrated theoretical perspective, to examine clinical teachers' (n = 64) and nursing students' (n = 352) empowerment, teachers' and students' perceptions of teachers' use of empowering teaching behaviors, students' perceptions of nurses' practice behaviors, and students' confidence for practice in acute care settings. In this study, teachers and students were moderately empowered. Teachers reported using a high level of empowering teaching behaviors, which corresponded with students' perceptions of teachers' use of such behaviors. Teachers' empowerment predicted 21% of their use of empowering teaching behaviors. Students reported nurses as using a high level of professional practice behaviors. Students felt confident for professional nursing practice. The findings have implications for practice contexts related to empowering teaching-learning environments and self efficacy. PMID- 22432539 TI - The impairing effect of acute ethanol on spreading depression is antagonized by astaxanthin in rats of 2 young-adult ages. AB - BACKGROUND: Ethanol (EtOH) abuse and insufficient ingestion of antioxidants are external factors that can alter brain electrophysiology. Our previous studies have demonstrated that the excitability-related brain electrophysiological phenomenon known as cortical spreading depression (CSD) was facilitated by chronic EtOH intake, and chronic treatment with carotenoids attenuated this effect. Here, we investigated the acute effect of a single EtOH administration on CSD in young and adult rats previously (1 hour) treated with 10 MUg/kg of astaxanthin. METHODS: Male Wistar rats (5 young- and 5 adult groups, 60 to 80 and 150 to 180 days of age, respectively) were treated by 2 gavage procedures at 1 hour interval as follows: groups 1 and 2 received astaxanthin in gavage I combined with EtOH (group 1) or water (group 2) in gavage II; groups 3 and 4 received olive oil (the vehicle in which astaxanthin was dissolved) in gavage I combined with EtOH (group 3) or water (group 4) in gavage II; group 5 received water in gavage I combined with EtOH in gavage II. CSD was recorded on the cortical surface for 4 hours. RESULTS: Compared to the respective water and oil controls (groups 2 and 4; CSD velocities: 3.73 +/- 0.09 and 3.78 +/- 0.07 mm/min in the young groups; 2.99 +/- 0.10 and 3.05 +/- 0.19 mm/min in the adult groups), a single dose of EtOH (groups 3 and 5) decreased CSD propagation velocities (3.29 +/- 0.23 and 3.16 +/- 0.10 mm/min in the young groups; 2.71 +/- 0.27 and 2.75 +/- 0.31 mm/min in the adult groups). Astaxanthin antagonized the impairing effect of acute EtOH on CSD (group 1; mean velocity: 3.70 +/- 0.19 and 3.13 +/- 0.16 mm/min for the young and adult groups, respectively). CONCLUSIONS: The results showed an antagonistic effect of acute EtOH treatment on CSD propagation that was reverted by astaxanthin. The EtOH-astaxanthin interaction was not influenced by the age, as it was found in both young and adult animals. PMID- 22432540 TI - Decreased expression of MDR1 in PEG-conjugated hemoglobin solution combined cisplatin treatment in a tumor xenograft model. AB - This study aims to examine the contribution of PEG-conjugated hemoglobin combined with cisplatin to the expression of HIF-1alpha and MDR1 in a tumor xenograft model. Cervical carcinoma models were assigned to 4 groups and treated respectively: group 1(control); group 2, cisplatin; group 3, PEG-Hb; group 4 cisplatin plus PEG-Hb. 4 weeks later, tumor volume and MVD was significantly decreased in group 4 compared with other groups. Lower expression of HIF-1alpha and MDR1 were detected in group4. Taken together, our data indicated that PEG-Hb plus cisplatin can promote tumor tissue oxygenation and enhance the chemotherapy sensitivity. HIF-1alpha regulated MDR1 pathway correlated with this process. PMID- 22432541 TI - The parent-child relationship as predictor of eating pathology and weight gain in preadolescents. AB - The present study examined the role of attachment toward mother and father as a predictor of eating pathology and weight gain among preadolescent boys and girls. Self-report questionnaires and adjusted body mass index (BMI) were administered from a community sample of 601 preadolescents (8-11 years; 48% female) at baseline and once again 1 year later. Significant baseline associations were found between attachment toward both parents and several features of eating pathology. No baseline correlations were found between the attachment variables and adjusted BMI. However, after controlling for gender and baseline levels of eating pathology and weight, an insecure attachment toward mother significantly predicted increases in dietary restraint, eating concerns, weight concerns, and shape concerns, and adjusted BMI in the children 1 year later. An insecure attachment toward father was predictive for persistence in children's subjective binge eating episodes. The present study provides preliminary evidence for the longitudinal association between attachment and eating pathology and weight gain in preadolescents. Moreover, attachment toward mother and attachment toward father appear to be differently associated with their children's disordered eating attitudes and adjusted BMI. Future research should further elucidate the mechanisms underlying this differential association. PMID- 22432542 TI - Use of a white light supercontinuum laser for confocal interference-reflection microscopy. AB - Shortly after its development, the white light supercontinuum laser was applied to confocal scanning microscopy as a more versatile substitute for the multiple monochromatic lasers normally used for the excitation of fluorescence. This light source is now available coupled to commercial confocal fluorescence microscopes. We have evaluated a supercontinuum laser as a source for a different purpose: confocal interferometric imaging of living cells and artificial models by interference reflection. We used light in the range 460-700 nm where this source provides a reasonably flat spectrum, and obtained images free from fringe artefacts caused by the longer coherence length of conventional lasers. We have also obtained images of cytoskeletal detail that is difficult to see with a monochromatic laser. PMID- 22432543 TI - Elimination half-life of intravenously administered equine cardiac troponin I in healthy ponies. AB - REASONS FOR PERFORMING STUDY: To date, no information is available on the true biological elimination half-life (T(1/2) ) of cardiac troponin I (cTnI) in the equine species. Such data are required to better evaluate the optimal time to acquire the cTnI sample following acute myocardial injury. OBJECTIVE: To determine the T(1/2) of equine cTnI. METHODS: Four healthy ponies received i.v. injections of recombinant equine cTnI. Plasma cTnI concentrations were measured with a point-of-care cTnI analyser at multiple time points after injection. Standard pharmacokinetic analysis was performed to establish the T(1/2) of cTnI. RESULTS: The average T(1/2) of cTnI was determined to be 0.47 h using a single rate elimination model. CONCLUSION: The elimination of recombinant equine cTnI following i.v. administration is very rapid. Establishing the T(1/2 ) of troponin provides critical information in understanding the clinical application of this cardiac biomarker in equine practice. PMID- 22432544 TI - Combined approach in a large placental chorioangioma case with intratumoral alcohol injection, cordocentesis, IU transfusion, and amnioreduction. AB - Large placental chorioangiomas (LPCs) are rare complications of pregnancy and these tumors are associated with increased risk of pregnancy complications. We presented a LPC case at 25th week of gestation, complicated by polyhydramnios and preterm labor in which intratumoral alcohol injection was performed succesfully. Cordocentesis, fetal intrauterine transfusion, and amnioreduction were performed at the same session, as a combined approach. The safety of the procedure was shown by the lack of alcohol in the fetal cord blood sample. Intratumoral alcohol injection is a reliable and effective treatment modality in the management of LPCs and may be combined with other invasive procedures. PMID- 22432545 TI - Diversity and a positive outlook. PMID- 22432546 TI - Twin births: cesarean section or vaginal delivery? AB - OBJECTIVE: To assess morbidity and mortality in twin pregnancy deliveries, according to chorionicity and mode of delivery. DESIGN: Population-based retrospective cohort. SETTING: Fourteen obstetric departments in Denmark. POPULATION: One thousand one hundred and seventy-five twin pregnancies with two live fetuses at 36(+0) weeks of gestation. METHODS: Pregnancy outcomes assessed according to chorionicity and mode of delivery. MAIN OUTCOME MEASURES: Poor outcome defined as five min Apgar score <= 7, umbilical artery pH < 7.10, admission to neonatal unit for more than three days or death. RESULTS: Dichorionic (DC) twins, delivered after 36 gestational weeks, with intended vaginal delivery (n= 689) compared with DC twins with planned cesarean section (n= 371) had an increased risk of poor outcome [odds ratio (OR) 1.47, p= 0.037] after adjustment for body mass index, parity and weight discordance. There was no increased risk for poor outcome in monochorionic (MC) twins with intended vaginal delivery (n= 63) compared with planned cesarean section (n= 52; OR 0.87, 95% confidence interval 0.26-2.96). Nulliparity increased the risk of poor outcome in DC (OR 1.5, p= 0.03) and in MC twins (OR 4.01, p= 0.02), as well as birthweight discordance >300 g (DC, OR 1.50, p= 0.02; and MC, OR 6.02, p= 0.002). For DC twins, we found a significantly higher risk of poor outcome of the second-born twin compared with the first (OR 1.64, p= 0.001). CONCLUSIONS: Dichorionic twins born after 36 weeks of gestation had a higher risk of poor outcome by intended vaginal delivery than by planned cesarean section. For MC twins, statistical differences in outcome by mode of delivery could not be seen. PMID- 22432547 TI - Recurring pelvic mass. PMID- 22432548 TI - Size dependence of dielectric constant in a single pencil-like ZnO nanowire. AB - Scanning conductance microscopy (SCM) is used to measure the dielectric constant of a single pencil-like zinc oxide (ZnO) nanowire with the diameters ranging from 85 to 285 nm. As the diameter decreases, the dielectric constant of ZnO nanowire is found to decrease from 6.4 to 2.7, which is much smaller than that of the bulk ZnO of 8.66. A core-shell composite nanowire model in terms of the surface dielectric weakening effect is proposed to explore the origin of the size dependence of dielectric constant, and the experimental results are well explained. PMID- 22432549 TI - Formation of different gold nanocrystal core-resin shell structures through the control of the core assembly and shell polymerization. AB - The formation of different Au nanocrystal core-resin shell structures through the control of the nanocrystal assembly and shell polymerization is investigated. 4 Mercaptophenol is employed together with formaldehyde as the resin monomers. 4 Mercaptophenol molecules bond to the surface of Au nanocrystals so that the resultant phenolic resin can intimately encapsulate Au nanocrystals. The morphologies of the obtained structures are determined by the nanocrystal assembly and the monomer polymerization behaviors, which are controlled by the solution pH as well as the monomer amounts. At pH = 8-9, Au nanorods are assembled and fused together under hydrothermal conditions in a preferential end to-end manner. The fused structures are coated with a layer of resin, with the thickness controlled by the supplied amounts of the monomers. At pH = ~10, Au nanorods are coated with resin of controllable thicknesses and separated from each other. The resin-coated Au nanorods are stable in both aqueous and nonaqueous solutions. At pH = ~12, Au nanorods are coated with a thin layer of resin and assembled together in a side-by-side manner. A similar assembly and resin coating behavior is also observed with Au nanopolyhedrons. Moreover, plasmonic-fluorescent bifunctional structures are readily produced by incorporating CdTe nanocrystals in the resin shell that is coated on Au nanocrystals, owing to the presence of a number of thiol groups in the resin shell. PMID- 22432550 TI - Dextran conjugates in drug delivery. AB - INTRODUCTION: Dextran is a family of natural polysaccharides that is widely under investigation for use as polymeric carriers in novel drug delivery systems. The optimal drug delivery (and consequently maximum therapeutic effect) will be accomplished when carrier systems are used mainly for drugs with antitumoral activity, as they increase their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. AREAS COVERED: This review summarizes the attempts that have been made in the development of dextran conjugates and their application. The manuscript describes dextran hydrogels, the use of conjugates of dextran in bioadhesive oral delivery systems, colon drug delivery, reduction of ulcerogenicity of drugs, production of micelles, solubilization, long-circulating pharmaceutical carriers as anticancer drug carriers, non-viral vectors, stabilization of enzymes, functionalization of nanomaterials, diagnosis of solid tumors and hyperthermic treatment and liver targeting. EXPERT OPINION: Dextran conjugation has aided the design of new tailor made polymers with different molecular weights, shapes, structures and with the functional groups needed for coupling at the desired positions in the chain. Dextran prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various dextran-antitumor drug conjugates enhance the effectiveness and improve the cytotoxic effects of chemotherapeutic agents. Future studies should concentrate on barriers for their clinical use and safety as a drug carrier. PMID- 22432551 TI - Low-melting salts based on a glycolated cobalt bis(dicarbollide) anion. AB - A new series of low-melting quaternary ammonium salts based on a glycolated cobalt bis(dicarbollide) anion structure have been synthesized and characterized, and their spectroscopic and physicochemical properties have been studied. The lowest melting point was obtained for 1-butyl-3-methylimidazolium (~50 degrees C) followed by 1-butyl-1-methylpiperidinium (~80 degrees C), 1-butyl-1 methylpyrrolidinium (~95 degrees C), and 1-butyl-4-methylpyridinium salts (~115 degrees C). The salts were thermally stable up to 180 degrees C [decomposition of an oligo(ethylene glycol) chain] and contained variable amounts of water. The flexible oligo(ethylene glycol) chains contributed to the waxy state of salts. The solubility of the salts was determined for 76 solvents that are commonly used in organic chemistry. Generally, the solubility increased with the dipole moment and relative polarity of the solvent. Salts exhibited good solubility in ketones and esters; moderate solubility was observed in alcohols, aromates, and chlorinated solvents, and poor solubility was obtained in ethers. The salts were practically insoluble in higher hydrocarbons and water. Salts are dissolved in the form of ion pairs or separated ions, depending on the nature of the solvent. PMID- 22432552 TI - Adherence to evidence-based guidelines for heart failure in physicians and their patients: lessons from the Heart Failure Adherence Retention Trial (HART). AB - The Heart Failure Adherence and Retention Trial (HART) provided an opportunity to determine adherence to evidence-based guidelines (EBG) in patients with heart failure (HF). Ten hospitals were the source of 692 patients with HF (EF < 40%). Physicians of patients with HF were classified as adherent to EBG if the patient chart audit showed they were on a beta-blocker, ACE-inhibitor (ACE-I), or angiotensin receptor blocker (ARB). Patients were classified as adherent to EBG if MEMS pill caps were used appropriately more than 80% of the time. Sixty-three percent of physicians prescribed evidence-based medications that were adherent to clinical practice guidelines. New York Heart Association (NYHA) III patients were less likely to be adherent (P < 0.001), as were those with renal disease (P < 0.001) and asthmatics (P < 0.001). Nonadherent physicians were less likely to treat patients with beta-blockers (39% vs 98%, P < 0.001) and ACE-I or ARBs (71% vs 98% P < 0.001). Thirty-seven percent of patients prescribed evidence-based therapy failed to use the MEMS pill cap bottles appropriately and were more likely a minority or higher NYHA class. Adherence to evidence-based therapy is less than optimal in HF patients based on a combination of both physician and patient nonadherence. PMID- 22432553 TI - Elevated red cell distribution width is associated with impaired reverse ventricular remodeling and increased mortality in patients undergoing cardiac resynchronization therapy. AB - Elevated red cell distribution width (RDW) has been associated with poor long term outcomes in patients with systolic dysfunction. The relationship between baseline RDW and reverse ventricular remodeling in advanced heart failure patients undergoing cardiac resynchronization therapy (CRT) has not been established. The authors reviewed the pre-implant and follow-up echocardiograms of 233 patients undergoing the new implantation of a CRT device at the Cleveland Clinic between December 2001 and November 2006. Patients were included in the final cohort if they had an RDW level within 7 days of CRT implantation, a left ventricular ejection fraction (LVEF) <=40%, and New York Heart Association class II to IV symptoms. Patients with a reduction in left ventricular end-systolic volume >=15% following CRT were considered "responders." Multivariate models were created to assess the relationship between baseline RDW elevation with progressive remodeling and all-cause mortality. Of 233 patients, 217 patients met inclusion criteria. Patients in the highest RDW quartile (>16.1) derived significantly less improvement in LVEF (3.5%+/-9.3% vs 10.1%+/-10.9%, P=.001) than patients in the lowest quartile (<13.6). In multivariate analysis, elevated RDW was inversely associated with response (odds ratio, 0.83; 95% confidence interval, 0.69-0.99; P=.047). The presence of elevated RDW is associated with less reverse left ventricular remodeling in patients with advanced heart failure undergoing CRT. PMID- 22432554 TI - Initial description of cerebral oximetry measurement in heart failure patients. AB - Cerebral oximetry is a noninvasive technology using near-infrared spectroscopy (NIRS) to monitor regional cerebral tissue oxygen saturation (SctO(2)). NIRS has been widely used for assessing cerebral tissue oxygenation in a variety of populations including the fields of neonatology, anesthesiology, neurology, and cardiac surgery.However, little information has been reported on cerebral oximetry in heart failure (HF) patients. In this observational study, we enrolled 30 patients (15 men) aged 23 to 82 years (mean 67 years) with stage C HF. All patients had New York Heart Association (NYHA) functional class I to III. All patients were on stable HF medical therapy. SctO(2) measurements were recorded from the left and right forehead simultaneously, using FORE-SIGHT cerebral oximeter (CAS Medical Systems Inc, Branford, CT). Feasible associations with SctO(2) risk factors, known to correlate with HF, were recorded. The mean SctO(2) value was 67.4% (range, 47.6%-76.3%), while the mean peripheral tissue saturation (SpO(2)) was 97% (range, 92%-100%). The mean difference between cerebral and peripheral tissue oxygenation (SpO(2)-SctO(2)) was 29.2% (range, 19.2%-51.4%). There was also a significant positive correlation between SctO(2) and mean arterial blood pressure (0.55, P<.01). Statistically significant lower SctO(2) values were observed in patients with diabetes (P=.026; confidence interval [CI], 0.006-0.090) and in patients with dyslipidemia (P=.007; CI, 0.018-0.103). In this initial description of SctO(2) in patients with stage C HF, we noted a wide range of SctO(2) measurements. For most patients, there was a profound SpO(2)-SctO(2) difference, despite near-normal peripheral oxygen saturations. The authors suggest that SctO(2) is a potentially important biomarker to measure in HF patients and may be a useful marker of target organ perfusion. PMID- 22432556 TI - Association of furosemide dose with clinical status, left ventricular dysfunction, natriuretic peptides, and outcome in clinically stable patients with chronic systolic heart failure. AB - In chronic heart failure (HF), high daily doses of furosemide have been associated with increased mortality. The authors sought to evaluate the relationships between orally administered furosemide doses, clinical status, left ventricular (LV) dysfunction, N-terminal proBNP (NT-proBNP), and outcome in 400 outpatients with chronic HF and LV ejection fraction (EF) <= 45%. Clinical status, NT-proBNP levels, and estimated glomerular filtration rate (eGFR) were evaluated. Median follow-up duration was 32 months. The median values of daily dose furosemide and of furosemide dose normalized to body surface area were 25 mg (12.5-62.5 mg) and 15 mg/m(2) (13-34 mg/m(2)), respectively. A total of 32% of patients had decompensated HF according to Framingham score and criteria for congestion. In clinically stable patients, a multivariable Cox model, which included clinical and echocardiographic parameters plus NT-proBNP, hemoglobin, and eGFR, showed that normalized furosemide dose (P=.017), anemia (P=.060), age (P=.080), and New York Heart Association class (P=.080) were predictors of all cause-mortality. In patients with decompensated HF, LV end-systolic volume index (P=.018), NT-proBNP (P=.060), and reduced eGFR (P=.070) were independently related to the outcome. Normalized furosemide dose was a major determinant of prognosis in patients with chronic HF but without ongoing signs and symptoms, and this suggests a possible negative interaction of this drug in clinically stable patients. PMID- 22432555 TI - Biomarker changes during acute heart failure treatment. AB - Biomarker changes may provide physicians with objective evidence of treatment efficacy in patients with acute decompensated heart failure (ADHF) and facilitate early hospital discharge. The authors hypothesize that mid-regional-pro adrenomedullin (MR-proADM), C-terminal-pro-endothelin-1 (CT-pro-ET-1), and mid regional-pro-atrial natriuretic peptide (MR-proANP) change during the first 24 hours of ADHF therapy. Eligible patients had an emergency department diagnosis of ADHF and fulfilled modified Framingham criteria. Clinical data, serum, and plasma values were collected at enrollment, 2 to 4 hours, and 12 to 24 hours after treatment. Changes in biomarker concentrations from baseline to 2 to 4 hours, baseline to 12 to 24 hours, and 2 to 4 to 12 to 24 hours were calculated. Fisher exact and Kruskal-Wallis tests were used for comparisons. Forty-eight patients were included. The median age was 62 years (range 40-88), 54% were men and 50% were white. More patients had changes in MR-pro-ANP levels in the first 2 to 4 hours after ADHF therapy compared with MR-proADM or CT-pro-ET-1 (36% vs 16% and 24%). However, 12 to 24 hours after therapy, similar proportions of patients had changes in MR-proANP, MR-proADM, and CT-proET-1 levels (47%, 41%, and 49%). In this preliminary study, patients with ADHF had measurable changes in MR-proANP, MR-proADM, and CT-pro-ET-1 24 hours after initial therapy. A study of association with clinical course and outcomes to determine the role of these markers in risk stratification is warranted. PMID- 22432557 TI - Depression and quality of life among heart failure patients in Georgia, Eastern Europe. AB - The goal of the study was to assess longitudinal changes in quality of life among patients who screened positive for depression and patients who did not enroll in an outpatient heart failure disease management program (HFDMP). Patients with an ejection fraction <=40% and clinical signs and symptoms of heart failure were enrolled over 11 months from August 2007 to July 2008. Study participants (n=314) were divided at baseline into "depressed" (9-Question Patient Health Questionnaire [PHQ-9] >=10) and "nondepressed" (PHQ-9 <10) groups. The two cohort groups had quality of life assessed by the Minnesota Living With Heart Failure Questionnaire at baseline and at 1 year while enrolled in the HFDMP. Both groups showed improved quality of life scores, with the depressed group experiencing a greater mean score decrease (14.4 vs 10.8 for nondepressed patients; P<.01). Both patients who screened positive for depression and those who did not enroll in an HFDMP improved their quality of life scores, with depressed patients experiencing a statistically significant greater mean score reduction (better quality of life). PMID- 22432558 TI - Developments in heart failure 2011. AB - Last year, the authors reviewed all studies in the field of heart failure (HF) published in the year 2010. Another year of exciting new developments has gone by and several important papers have been published. Summarized are the important studies published in the year 2011 that may be a useful review for cardiologists and other health care professionals who care for patients with HF. PMID- 22432559 TI - Organ-specific responses to circulatory disturbances in heart failure: new insights. AB - Recent studies have provided new insights into the pathophysiology of congestive heart failure. Organ-specific responses to circulatory disturbances may differ via a hypoperfusion state and a venous congestion state. The liver and the kidneys serve as a good example of a differential injury pattern based on the predominant circulatory insult. Cardiorenal syndrome appears to be a kidney specific response to predominantly right-sided backward heart failure ("congestive state"), rather than forward heart failure. Despite significant progress in our understanding of cardiorenal interactions, there is no specific therapy for the cardiorenal syndrome, which is a marker of the severity of the heart failure state. PMID- 22432560 TI - Honey collected from different floras of Chandigarh Tricity: a comparative study involving physicochemical parameters and biochemical activities. AB - BACKGROUND: Different monofloral honeys have a distinctive flavor and color because of differences in physicochemical parameters because of their principal nectar sources or floral types. METHODS: Honey samples were collected from Apis mellifera colonies forged on 10 floras to analyze the quality of honey in terms of standards laid by Honey Grading and Marking Rules (HGMR), India, 2008 and Codex Alimentarious Commission (CAC), 1969 . The honey samples were analyzed for various physicochemical parameters of honey quality control, i.e., pH, total acidity, moisture, reducing sugars, non-reducing sugars, total sugars, water insoluble solids (WIS), ash content, 5-hydroxymethylfurfural content, and diastase value. The antioxidant potential was estimated using Folin-Ciocalteu reagent. Further, honey samples were assayed for antibacterial activities against clinical isolates of Staphylococcus aureus and Escherichia coli using the hole plate diffusion method. RESULTS: The physicochemical variation in the composition of honey because of floral source shows Ziziphus honey with high pH and diastase values along with low acidity, whereas Helianthus honey contained high reducing sugar and low moisture content. Amomum, Brassica, Acacia, and Citrus contained lowest amount of non-reducing sugars, ash, WIS, and moisture, respectively. Lowest 5-hydroxymethylfurfural (HMF) value was detected in Amomum honey, while highest HMF value was observed with Eucalyptus. The maximum antibacterial and antioxidant potential was observed in Azadirachta and Citrus, respectively. CONCLUSION: The quality of honey produced by local beekeepers met HGMR and CAC standards, and the chemical composition and biological properties of honey were dependent on the floral source from which it was produced. PMID- 22432561 TI - A randomized, double-blind, crossover study on the pharmacokinetics of a novel formulation of CoQ10 with pyridoxal 5'-phosphate and phosphatidyl choline. AB - The pharmacokinetics of a single 30-mg dose of a novel enteric-coated coenzyme Q10 (CoQ(10)) formulation with pyridoxal 5'-phosphate and phosphatidyl choline (CoQ(10)-P5P-PC) was investigated against two comparators CoQ(10) (NPN 02176955) and CoQ(10) (DIN 02231736) in 21 healthy volunteers, with screening CoQ(10) levels of 0.8 +/- 0.2 mg/L. A randomized, double-blind, crossover study was designed with a washout period of 2 weeks between each formulation and blood sampled at 2, 4, 5, 6, 8, 12, 24, 48 and 72 hr postdose. Significantly, higher plasma concentrations were demonstrated for the CoQ(10) (NPN 02176955) formulation at 6 and 8 hr postdose (p = .010 and p = .042, respectively). There were no significant differences between formulations with respect to the area under the curve, AUC((0-72 hr)), or the maximum plasma concentration (C(max)). Total CoQ(10) (T(max)) reached maximum plasma concentrations at 6.4 +/- 2.5 hr after supplementation with CoQ(10) (NPN 02176955), 8.0 +/- 9.8 hr with CoQ(10) P5P-PC, and 9.5 +/- 9.3 hr with CoQ(10) (DIN 02231736). The estimated elimination half-life (t(1/2)) was 92.3 hr after a single oral dose of CoQ(10)-P5P-PC, 38.2 hr with CoQ(10) (NPN 02176955), and 80.7 hr with CoQ(10) (DIN 02231736). The results suggest that CoQ(10) is available for a longer time in subjects' administered with CoQ(10)-P5P-PC in comparison with the other two formulations studied. There were no significant differences in adverse events, by severity, causality, or organ system. The CoQ(10)-P5P-PC formulation was found to be superior in the t(1/2), and it may be suggested that fewer doses are required to maintain healthy circulatory CoQ(10) levels. PMID- 22432562 TI - Folate supplementation induces differential dose-dependent modulation of proliferative phenotypes among cancerous and noncancerous oral cell lines in vitro. AB - Sufficient folate intake confers positive health benefits, while deficiency is linked with many health problems. Although the US policy of dietary folic acid fortification has reduced the incidence of these deficiency-related health problems, recent evidence has demonstrated an association between folic acid supplementation and increased colorectal cancer incidence. Few studies have explored the possibility that folate affects other slowly developing cancers. This study sought to determine whether folic acid supplementation is sufficient to alter the growth and development of existing oral cancers. A series of in vitro growth, viability, and adhesion assays were performed using the well characterized human oral squamous cell carcinoma cell lines, CAL27 and SCC25, to determine the effects of folic acid supplementation. Folic acid administration significantly stimulated CAL27 and SCC25 proliferation in a dose-dependent manner, but it was not sufficient to increase proliferation at any concentration tested in the normal control cell line, HGF-1. Neither oral cancer cell line harbored the common C677T DNA polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, which might reduce folate bioavailability. Overexpression of p53 mRNA was observed in both cancerous cell lines, but it was differentially altered by folic acid administration in only SCC25 cells. These findings suggest folic acid administration may significantly alter growth of oral cancers in vitro via p53-dependent and p53-independent pathways. As oral cancer rates continue to rise in specific geographic areas, and among specific subsets of the US population, understanding environmental mediators, such as folic acid supplementation, becomes increasingly important for nutrition and public health scientists. PMID- 22432563 TI - The anti-inflammatory and antinociceptive properties of the chloroform fraction from Phyllanthus niruri plant is mediated via the peripheral nervous system. AB - Phyllanthus niruri (Euphorbiaceae) is used folklorically for the treatment of diabetes, malaria, fever, diarrhea, liver disease, and urolithiasis. As an initial step toward isolating compounds effective against inflammation and pain, this study is aimed at providing scientific evidence for the anti-inflammatory, antinociceptive, and antipyretic properties of the chloroform soluble fraction (PNF1) of Phyllanthus niruri methanol extract in rats and mice. Three doses of PNF1 [25, 50, 100 mg/kg body weight (bw)] were used. Screening was done using acetic-acid-induced writhing, egg-albumin-induced pedal inflammation, Randall Selitto test, hot-plate test, and yeast-induced pyresis as experimental models. Results show that PNF1 significantly (p < .01) inhibited writhing response induced by acetic acid at all doses used by 56.2%-66.7% and caused significant (p < .05, p < .01) reduction of yeast-induced pyrexia (21.6%-40.9%). Significant (p < .01) reduction of egg albumin-induced inflammation was observed only at a dose of 100 mg PNF1/kg bw, which was comparable with the effect produced by aspirin (100 mg/kg bw). At 50 and 100 mg/kg bw, PNF1 significantly (p < .05, p < .01) increased pain threshold of inflamed tissue in the Randall-Selitto test but did not increase response to thermally induced pain in the hot-plate test. It is concluded that PNF1 possesses antipyretic, anti-inflammatory, and antinociceptive effects that are peripherally mediated. This justifies its use in traditional medicine and its potential as a candidate for further development. PMID- 22432564 TI - An evidence-based systematic review of rosemary (Rosmarinus officinalis) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review of rosemary (Rosmarinus officinalis), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22432565 TI - Supplements for exercise. PMID- 22432566 TI - Testing the phonemes relevant for German verb morphology in hard-of-hearing children: the FinKon-test. AB - Many hard-of-hearing children show delays or disorders in the acquisition of morphology and syntax. There is an on-going discussion how these difficulties are connected to problems in the auditory domain. The article focuses on coronal consonants that function as suffixes in the German verbal inflectional system. Here we present a new test we developed to evaluate the ability to discriminate these consonants in syllabic offset positions. A pilot study with 22 hearing impaired (HI) children and 15 typically developing (TD) children reveals significantly lower discrimination scores in the HI group. The results highlight the necessity to measure the capacity to distinguish particular phonemes at specific syllable positions, when considering the impact of a hearing impairment on language acquisition. PMID- 22432567 TI - Selection and microevolution of coat pattern are cryptic in a wild population of sheep. AB - Understanding the maintenance of genetic variation in natural populations is a core aim of evolutionary genetics. Insight can be gained by quantifying selection at the level of the genotype, as opposed to the phenotype. Here, we show that in a natural population of Soay sheep which is polymorphic for coat pattern, recessive genetic variants at the causal gene, agouti signalling protein (ASIP) are associated with reduced lifetime fitness. This was due primarily to a reduction in juvenile survival of uniformly coloured (self-type) sheep, which are homozygous recessive, and occurs despite significantly higher reproductive success in surviving self-type adults. Consistent with their relatively low fitness, we show that the frequency of self-type individuals has declined from 1985 to 2008. Remarkably though, the frequency of the underlying self-allele has increased, because the frequency of heterozygous individuals (who harbour the majority of all self-alleles) has increased. Indeed, the ratio of observed/expected heterozygous individuals has increased during the study, such that there is now a significant excess of heterozygotyes. By employing gene dropping simulations, we show that microevolutionary trends in the frequency and excess of ASIP heterozygotes are too pronounced to be caused by genetic drift. Studying this polymorphism at the level of phenotype rather than underlying genotype would have failed to detect cryptic fitness differences. We would also have been unable to rule out genetic drift as an evolutionary force driving genetic change. This highlights the importance of resolving the underlying genetic basis of phenotypic variation in explaining evolutionary dynamics. PMID- 22432568 TI - In Operando X-ray diffraction and transmission X-ray microscopy of lithium sulfur batteries. AB - Rechargeable lithium-sulfur (Li-S) batteries hold great potential for high performance energy storage systems because they have a high theoretical specific energy, low cost, and are eco-friendly. However, the structural and morphological changes during electrochemical reactions are still not well understood. In this Article, these changes in Li-S batteries are studied in operando by X-ray diffraction and transmission X-ray microscopy. We show recrystallization of sulfur by the end of the charge cycle is dependent on the preparation technique of the sulfur cathode. On the other hand, it was found that crystalline Li(2)S does not form at the end of discharge for all sulfur cathodes studied. Furthermore, during cycling the bulk of soluble polysulfides remains trapped within the cathode matrix. Our results differ from previous ex situ results. This highlights the importance of in operando studies and suggests possible strategies to improve cycle life. PMID- 22432569 TI - Rotational spectrum and conformational composition of cyanoacetaldehyde, a compound of potential prebiotic and astrochemical interest. AB - The rotational spectrum of cyanoacetaldehyde (NCCH(2)CHO) has been investigated in the 19.5-80.5 and 150-500 GHz spectral regions. It is found that cyanoacetaldehyde is strongly preferred over its tautomer cyanovinylalcohol (NCCH?CHOH) in the gas phase. The spectra of two rotameric forms of cyanoacetaldehyde produced by rotation about the central C-C bond have been assigned. The C-C-C-O dihedral angle has an unusual value of 151(3) degrees from the synperiplanar (0 degrees ) position in one of the conformers denoted I, while this dihedral angle is exactly synperiplanar in the second rotamer called II, which therefore has C(s) symmetry. Conformer I is found to be preferred over II by 2.9(8) kJ/mol from relative intensity measurements. A double minimum potential for rotation about the central C-C bond with a small barrier maximum at the exact antiperiplanar (180 degrees ) position leads to Coriolis perturbations in the rotational spectrum of conformer I. Selected transitions of I were fitted to a Hamiltonian allowing for this sort of interaction, and the separation between the two lowest vibrational states was determined to be 58794(14) MHz [1.96112(5) cm( 1)]. Attempts to include additional transitions in the fits using this Hamiltonian failed, and it is concluded that it lacks interaction terms to account satisfactorily for all the observed transitions. The situation was different for II. More than 2000 transitions were assigned and fitted to the usual Watson Hamiltonian, which allowed very accurate values to be determined not only for the rotational constants, but for many centrifugal distortion constants as well. Two vibrationally excited states were also assigned for this form. Theoretical calculations were performed at the B3LYP, MP2, and CCSD levels of theory using large basis sets to augment the experimental work. The predictions of these calculations turned out to be in good agreement with most experimental results. PMID- 22432570 TI - Chemical engineering education: a gallimaufry of thoughts. AB - To discuss various facets of chemical engineering education, I proceed step by step through my own education and career. In this way, I touch on various points concerning the operation of the educational system that may be of interest to others. PMID- 22432571 TI - Biofuels: biomolecular engineering fundamentals and advances. AB - The biological production of fuels from renewable sources has been regarded as a feasible solution to the energy and environmental problems in the foreseeable future. Recently, the biofuel product spectrum has expanded from ethanol and fatty acid methyl esters (biodiesel) to other molecules, such as higher alcohols and alkanes, with more desirable fuel properties. In general, biosynthesis of these fuel molecules can be divided into two phases: carbon chain elongation and functional modification. In addition to natural fatty acid and isoprenoid chain elongation pathways, keto acid-based chain elongation followed by decarboxylation and reduction has been explored for higher alcohol production. Other issues such as metabolic balance, strain robustness, and industrial production process efficiency have also been addressed. These successes may provide both scientific insights into and practical applications toward the ultimate goal of sustainable fuel production. PMID- 22432572 TI - Nanocomposites: structure, phase behavior, and properties. AB - It is well recognized that nanocomposites formed by adding nanoparticles to polymers can have significantly enhanced properties relative to the native polymer. This review focuses on three aspects that are central to the outstanding problem of realizing these promised property improvements. First, we ask if there exist general strategies to control nanoparticle spatial distribution. This is an important question because it is commonly accepted that the nanoparticle dispersion state crucially affects property improvements. Because ideas on macroscale composites suggest that optimizing different properties requires different dispersion states, we next ask if we can predict a priori the particle dispersion and organization state that can optimize one (or more) properties of the resulting nanocomposite. Finally, we examine the role that particle shape plays in affecting dispersion and hence property control. This review focuses on recent advances concerning these underpinning points and how they affect measurable properties relevant to engineering applications. PMID- 22432573 TI - Structural complexities in the active layers of organic electronics. AB - The field of organic electronics has progressed rapidly in recent years. However, understanding the direct structure-function relationships between the morphology in electrically active layers and the performance of devices composed of these materials has proven difficult. The morphology of active layers in organic electronics is inherently complex, with heterogeneities existing across multiple length scales, from subnanometer to micron and millimeter range. A major challenge still facing the organic electronics community is understanding how the morphology across all of the length scales in active layers collectively determines the device performance of organic electronics. In this review we highlight experiments that have contributed to the elucidation of structure function relationships in organic electronics and also point to areas in which knowledge of such relationships is still lacking. Such knowledge will lead to the ability to select active materials on the basis of their inherent properties for the fabrication of devices with prespecified characteristics. PMID- 22432574 TI - Catalytic conversion of renewable biomass resources to fuels and chemicals. AB - Lignocellulosic biomass is renewable and cheap, and it has the potential to displace fossil fuels in the production of fuels and chemicals. Biomass-derived carboxylic acids are important compounds that can be used as platform molecules for the production of a variety of important chemicals on a large scale. Lactic acid, a prototypical biomass derivative, and levulinic acid, an important chemical feedstock produced by hydrolysis of waste cellulosic materials, can be upgraded using bifunctional catalysts (those containing metal and acid sites), which allows the integration of several transformations (e.g., oxygen removal and C-C coupling) in a single catalyst bed. This coupling between active sites is beneficial in that it reduces the complexity and cost of the biomass conversion processes. Deoxygenation of biomass derivatives is a requisite step for the production of fuels and chemicals, and strategies are proposed to minimize the consumption of hydrogen from an external source during this process. PMID- 22432575 TI - COSMO-RS: an alternative to simulation for calculating thermodynamic properties of liquid mixtures. AB - The conductor-like screening model for realistic solvation (COSMO-RS) method has been established as a novel way to predict thermophysical data for liquid systems and has become a frequently used alternative to force field-based molecular simulation methods on one side and group contribution methods on the other. Through its unique combination of a quantum chemical treatment of solutes and solvents with an efficient statistical thermodynamics procedure for the molecular surface interactions, it enables the efficient calculation of many properties that other methods can barely predict. This review presents a short delineation of the theory, the application potential and limitations of COSMO-RS, and its most important application areas. PMID- 22432576 TI - Moving beyond mass-based parameters for conductivity analysis of sulfonated polymers. AB - The proton conductivity of polymer electrolytes is critical for fuel cells and has therefore been studied in significant detail. The conductivity of sulfonated polymers has been linked to material characteristics to elucidate trends. Mass based measurements based on water uptake and ion exchange capacity are two of the most common material characteristics used to make comparisons between polymer electrolytes, but they have significant limitations when correlated to proton conductivity. These limitations arise in part because different polymers can have significantly different densities and because conduction occurs over length scales more appropriately represented by volume measurements rather than mass. Herein we establish and review volume-related parameters that can be used to compare the proton conductivity of different polymer electrolytes. Morphological effects on proton conductivity are also considered. Finally, the impact of these phenomena on designing next-generation sulfonated polymers for polymer electrolyte membrane fuel cells is discussed. PMID- 22432578 TI - Transcutaneous immunization: an overview of advantages, disease targets, vaccines, and delivery technologies. AB - Skin is an immunologically active tissue composed of specialized cells and agents that capture and process antigens to confer immune protection. Transcutaneous immunization takes advantage of the skin immune network by inducing a protective immune response against topically applied antigens. This mode of vaccination presents a novel and attractive approach for needle-free immunization that is safe, noninvasive, and overcomes many of the limitations associated with needle based administrations. In this review we will discuss the developments in the field of transcutaneous immunization in the past decade with special emphasis on disease targets and vaccine delivery technologies. We will also briefly discuss the challenges that need to be overcome to translate early laboratory successes in transcutaneous immunization into the development of effective clinical prophylactics. PMID- 22432577 TI - Polymers for drug delivery systems. AB - Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs. From early beginnings using off-the-shelf materials, the field has grown tremendously, driven in part by the innovations of chemical engineers. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. In this review, we highlight the fundamental drug delivery systems and their mathematical foundations and discuss the physiological barriers to drug delivery. We review the origins and applications of stimuli-responsive polymer systems and polymer therapeutics such as polymer-protein and polymer-drug conjugates. The latest developments in polymers capable of molecular recognition or directing intracellular delivery are surveyed to illustrate areas of research advancing the frontiers of drug delivery. PMID- 22432579 TI - Ionic liquids in chemical engineering. AB - The development of engineering applications with ionic liquids stretches back to the mid-1990s when the first examples of continuous catalytic processes using ionic liquids and the first studies of ionic liquid-based extractions were published. Ever since, the use of ionic liquids has seen tremendous progress in many fields of chemistry and engineering, and the first commercial applications have been reported. The main driver for ionic liquid engineering applications is to make practical use of their unique property profiles, which are the result of a complex interplay of coulombic, hydrogen bonding and van der Waals interactions. Remarkably, many ionic liquid properties can be tuned in a wide range by structural modifications at their cation and anion. This review highlights specific examples of ionic liquid applications in catalysis and in separation technologies. Additionally, the application of ionic liquids as working fluids in process machines is introduced. PMID- 22432580 TI - Unit operations of tissue development: epithelial folding. AB - The development of multicellular organisms relies on a small set of construction techniques-assembly, sculpting, and folding-that are spatially and temporally regulated in a combinatorial manner to produce the diversity of tissues within the body. These basic processes are well conserved across tissue types and species at the level of both genes and mechanisms. Here we review the signaling, patterning, and biomechanical transformations that occur in two well-studied model systems of epithelial folding to illustrate both the complexity and modularity of tissue development. In particular, we discuss the possibility of a spatial code specifying morphogenesis. To decipher this code, engineers and scientists need to establish quantitative experimental systems and to develop models that address mechanisms at multiple levels of organization, from gene sequence to tissue biomechanics. In turn, quantitative models of embryogenesis can inspire novel methods for creating synthetic organs and treating degenerative tissue diseases. PMID- 22432581 TI - Theoretical aspects of immunity. AB - The immune system recognizes a myriad of invading pathogens and their toxic products. It does so with a finite repertoire of antibodies and T cell receptors. We here describe theories that quantify the dynamics of the immune system. We describe how the immune system recognizes antigens by searching the large space of receptor molecules. We consider in some detail the theories that quantify the immune response to influenza and dengue fever. We review theoretical descriptions of the complementary evolution of pathogens that occurs in response to immune system pressure. Methods including bioinformatics, molecular simulation, random energy models, and quantum field theory contribute to a theoretical understanding of aspects of immunity. PMID- 22432582 TI - Controlling order in block copolymer thin films for nanopatterning applications. AB - An attractive "unconventional" lithographic technique to pattern periodic, sub 100 nm features uses self-assembled block copolymer thin films as etch masks. Unfortunately, as-cast films lack the orientational and positional order of the microphase-separated domains that are necessary for many desired applications. Reviewed herein are techniques developed to guide the self-assembly process in thin films, which permit varying degrees of control over the patterns formed by the microdomains. Techniques that can control the out-of-plane order of the microdomains are first summarized. Then, techniques that control the lateral ordering are reviewed, beginning with those that generate large defect-free grains, then those that impart orientational order to the microdomains, and finally those that can control both the orientation and position of individual microdomains. Each technique is summarized with experimental examples and discussions regarding the mechanism of the guided self-assembly process. PMID- 22432583 TI - Batteries for electric and hybrid-electric vehicles. AB - Batteries have powered vehicles for more than a century, but recent advances, especially in lithium-ion (Li-ion) batteries, are bringing a new generation of electric-powered vehicles to the market. Key barriers to progress include system cost and lifetime, and derive from the difficulty of making a high-energy, high power, and reversible electrochemical system. Indeed, although humans produce many mechanical and electrical systems, the number of reversible electrochemical systems is very limited. System costs may be brought down by using cathode materials less expensive than those presently employed (e.g., sulfur or air), but reversibility will remain a key challenge. Continued improvements in the ability to synthesize and characterize materials at desired length scales, as well as to use computations to predict new structures and their properties, are facilitating the development of a better understanding and improved systems. Battery research is a fascinating area for development as well as a key enabler for future technologies, including advanced transportation systems with minimal environmental impact. PMID- 22432584 TI - Applications of supercritical fluids. AB - This review discusses supercritical fluids in industrial and near-to-industry applications. Supercritical fluids are flexible tools for processing materials. Supercritical fluids have been applied to mass-transfer processes, phase transition processes, reactive systems, materials-related processes, and nanostructured materials. Some applications are already at industrial capacity, whereas others remain under development. In addition to extraction, application areas include impregnation and cleaning, multistage countercurrent separation, particle formation, coating, and reactive systems such as hydrogenation, biomass gasification, and supercritical water oxidation. Polymers are modified with supercritical fluids, and colloids and emulsions as well as nanostructured materials exhibit interesting phenomena when in contact with supercritical fluids that can be industrially exploited. For these applications to succeed, the properties of supercritical fluids in combination with the materials processed must be clearly determined and fundamental knowledge of the complex behavior must be made readily available. PMID- 22432585 TI - Solar energy to biofuels. AB - In a solar economy, sustainably available biomass holds the potential to be an excellent nonfossil source of high energy density transportation fuel. However, if sustainably available biomass cannot supply the liquid fuel need for the entire transport sector, alternatives must be sought. This article reviews biomass to liquid fuel conversion processes that treat biomass primarily as a carbon source and boost liquid fuel production substantially by using supplementary energy that is recovered from solar energy at much higher efficiencies than the biomass itself. The need to develop technologies for an energy-efficient future sustainable transport sector infrastructure that will use different forms of energy, such as electricity, H(2), and heat, in a synergistic interaction with each other is emphasized. An enabling template for such a future transport infrastructure is presented. An advantage of the use of such a template is that it reduces the land area needed to propel an entire transport sector. Also, some solutions for the transition period that synergistically combine biomass with fossil fuels are briefly discussed. PMID- 22432586 TI - Design rules for biomolecular adhesion: lessons from force measurements. AB - Cell adhesion to matrix, other cells, or pathogens plays a pivotal role in many processes in biomolecular engineering. Early macroscopic methods of quantifying adhesion led to the development of quantitative models of cell adhesion and migration. The more recent use of sensitive probes to quantify the forces that alter or manipulate adhesion proteins has revealed much greater functional diversity than was apparent from population average measurements of cell adhesion. This review highlights theoretical and experimental methods that identified force-dependent molecular properties that are central to the biological activity of adhesion proteins. Experimental and theoretical methods emphasized in this review include the surface force apparatus, atomic force microscopy, and vesicle-based probes. Specific examples given illustrate how these tools have revealed unique properties of adhesion proteins and their structural origins. PMID- 22432587 TI - Interactive effects of warming and invertebrate grazing on the outcomes of competitive fungal interactions. AB - Saprotrophic fungal community composition, determined by the outcomes of competitive mycelial interactions, represents a key determinant of woodland carbon and nutrient cycling. Atmospheric warming is predicted to drive changes in fungal community composition. Grazing by invertebrates can also exert selective pressures on fungal communities and alter the outcome of competitive fungal interactions; their potential to do so is determined by grazing intensity. Temperature regulates the abundance of soil collembola, but it remains unclear whether this will alter the top-down determination of fungal community composition. We use soil microcosms to explore the direct (via effects on interacting fungi) and indirect (by influencing top-down grazing pressures) effects of a 3 degrees C temperature increase on the outcomes of competitive interactions between cord-forming basidiomycete fungi. By differentially affecting the fungal growth rates, warming reversed the outcomes of specific competitive interactions. Collembola populations also increased at elevated temperature, and these larger, more active, populations exerted stronger grazing pressures. Consequently, grazing mitigated the effects of temperature on these interactions, restoring fungal communities to those recorded at ambient temperature. The interactive effects of biotic and abiotic factors are a key in determining the functional and ecological responses of microbial communities to climate change. PMID- 22432588 TI - Bladder exstrophy. AB - Bladder exstrophy is a very rare congenital malformation in which the anterior wall of the bladder is absent, and the posterior wall is exposed externally. The differential diagnosis includes omphalocele, gastroschisis, and cloacal exstrophy. Ultrasound and Doppler examinations are the main diagnostic tools. Although mortality is low, termination of pregnancy should be discussed due to serious morbidities. PMID- 22432589 TI - Impact of neoadjuvant transarterial chemoembolization on tumor recurrence and patient survival after liver transplantation for hepatocellular carcinoma: a retrospective analysis. AB - Transarterial chemoembolization (TACE) has gained wide acceptance as a bridge to liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Aim of this analysis was to compare long-term results with and without neoadjuvant TACE and to identify subgroups, which particularly benefit from TACE. Patients with HCC transplanted at our center were retrospectively analyzed. The following were excluded to increase consistency: incidental-HCC, Child-C, living-related LT, other HCC-specific-treatment. Of 336 patients, 177 were subject of this analysis, 71 received TACE and 106 no HCC therapy. Patients with and without TACE showed similar five-yr survival (73/67%) and recurrence rates (23/29%). Progression on the waiting list was associated with a higher recurrence rate in the TACE (50 vs.12%) and the non-TACE group (40 vs. 22%). HCC recurrence was reduced in patients inside Milan (0.053) and UCSF (0.037) criteria by neoadjuvant TACE but not outside UCSF (0.99). Also a trend towards an improved survival was seen within these criteria. Our large single center experience suggests that TACE lowers the HCC recurrence rate in patients inside the Milan and UCSF criteria. Moreover, the response to TACE is a good indicator of low recurrence rates. The effect of TACE might be more pronounced in patients with longer waiting time than in this cohort (mean, 4.6 months). PMID- 22432590 TI - Cellular glutathione redox homeostasis plays an important role in the brassinosteroid-induced increase in CO2 assimilation in Cucumis sativus. AB - Brassinosteroids (BRs) play a vital role in plant growth, stress tolerance and productivity. Here, the involvement of BRs in the regulation of CO(2) assimilation and cellular redox homeostasis was studied. The effects of BRs on CO(2) assimilation were studied in cucumber (Cucumis sativus) through the analysis of the accumulation of H(2)O(2) and glutathione and photosynthesis related enzyme activities using histochemical and cytochemical detection or a spectrophotometric assay, and Rubisco activase (RCA) using western blot analysis and immunogold labeling. Exogenous BR increased apoplastic H(2)O(2) accumulation, the ratio of reduced to oxidized glutathione (GSH:GSSG) and CO(2) assimilation, whereas a BR biosynthetic inhibitor had the opposite effects. BR-induced CO(2) assimilation was decreased by a H(2)O(2) scavenger or inhibition of H(2)O(2) generation, GSH biosynthesis and the NADPH-generating pentose phosphate pathway. BR-, H(2)O(2) - or GSH-induced CO(2) assimilation was associated with increased activity of enzymes in the Benson-Calvin cycle. Immunogold labeling and western blotting showed that BR increased the content of RCA and this effect was blocked by inhibitors of redox homeostasis. These results strongly suggest that BR induced photosynthesis involves an H(2)O(2) -mediated increase in the GSH:GSSG ratio, which may positively regulate the synthesis and activation of redox sensitive enzymes in carbon fixation. PMID- 22432591 TI - Treatment effects of the mandibular anterior repositioning appliance in patients with Class II skeletal malocclusions. AB - OBJECTIVE: To examine the changes produced by the mandibular anterior repositioning appliance (MARA) appliance and compare the treatment effects to an untreated Class II control group. MATERIALS AND METHODS: Thirty consecutively treated patients were matched with an untreated control group. Lateral cephalograms were taken at T1, 5 months pre-MARA (CVMS 2.7); T2, immediately after MARA removal and prior to placement of full fixed edgewise appliances (CVMS 4.2); and T3, at least 2 years after MARA removal and completion of edgewise treatment (CVMS 5.4). The mean age of the MARA patients was 11.9 years for boys and 10.8 years for girls. Repeated-measures analysis of variance (ANOVA) was used to assess if the samples were morphologically comparable at the outset and to test if there were significant differences between the groups for the various increments of change. Given a significant ANOVA, the source of the difference was explored via Tukey-Kramer tests. RESULTS: Restriction of maxillary growth and no significant mandibular growth were observed with the MARA appliance. The Class II correction was obtained mainly by slight maxillary molar distalization and intrusion, in addition to mesial migration of the lower molars and flaring of the lower incisors. No vertical effect was observed with this appliance. CONCLUSION: The MARA appliance was effective in the treatment of Class II malocclusions. Restriction of maxillary growth and dentoalveolar changes in the maxillary and mandibular arches were responsible for the correction of the Class II malocclusion. Significant mandibular growth did not contribute to this correction. PMID- 22432592 TI - Interfacial rheology and structure of tiled graphene oxide sheets. AB - The hydrophilic nature of graphene oxide sheets can be tailored by varying the carbon to oxygen ratio. Depending on this ratio, the particles can be deposited at either a water-air or a water-oil interface. Upon compression of thus-created Langmuir monolayers, the sheets cover the entire interface, assembling into a strong, compact layer of tiled graphene oxide sheets. With further compression, the particle layer forms wrinkles that are reversible upon expansion, resembling the behavior of an elastic membrane. In the present work, we investigate under which conditions the structure and properties of the interfacial layer are such that free-standing films can be obtained. The interfacial rheological properties of these films are investigated using both compressional experiments and shear rheometry. The role of surface rheology in potential applications of such tiled films is explored. The rheological properties are shown to be responsible for the efficiency of such layers in stabilizing water-oil emulsions. Moreover, because of the mechanical integrity, large-area monolayers can be deposited by, for example, Langmuir-Blodgett techniques using aqueous subphases. These films can be turned into transparent conductive films upon subsequent chemical reduction. PMID- 22432593 TI - Behavioral and neurotransmitter specific roles for the ventral tegmental area in reinforcer-seeking and intake. AB - BACKGROUND: The ventral tegmental area (VTA) is a pivotal relay site within the reinforcement circuit that has been shown to play a role in ethanol (EtOH) motivated behaviors. The primary dopamine projections within this system originate in the VTA and innervate several areas including the nucleus accumbens (NAc) and prefrontal cortex (PFC), and the PFC has afferent glutamate projections to the VTA and the NAc. The following studies utilized 2 different operant paradigms, one focusing on reinforcer-seeking and the other on reinforcer drinking (both with an EtOH and a sucrose reinforcer solution), to elucidate regulation of these behaviors by the posterior VTA, and the specific roles of dopamine and glutamate in this region. METHODS: The present experiments assessed the effects of microinjections of the glutamate (AMPA/kainate) antagonist CNQX and the dopamine D1-like antagonist SCH23390 in the posterior VTA, as well as transient chemical inactivation of this region using tetrodotoxin (TTX). In 4 separate experiments (2 dopamine, 2 glutamate, both with TTX), male Long Evans rats were trained to complete a single response requirement that resulted in access to 10% EtOH or 2% sucrose for a 20-minute drinking period. RESULTS: Prior to microinjections, EtOH-reinforced subjects were consuming approximately 0.45 to 0.65 g/kg EtOH and making approximately 50 responses during intermittent nonreinforced artificial cerebrospinal fluid sessions (Sucrose groups had similar baseline response levels). Overall, TTX inactivation of the VTA consistently decreased reinforcer-seeking but not intake in all experiments. CNQX also dose dependently decreased EtOH-seeking, with no significant effect on sucrose-seeking or reinforcer intake. SCH23390 had no significant effects on reinforcer-seeking, and very moderately decreased intake of both EtOH and sucrose. CONCLUSIONS: Inactivation of the posterior VTA implicated this region in reinforcer-seeking as opposed to reinforcer intake. Overall, the present findings provide support for the importance of posterior VTA glutamate activity specifically in EtOH-seeking behavior in animals consuming pharmacologically relevant amounts of EtOH. PMID- 22432594 TI - A novel case of Hb Phnom Penh: codons 117/118 (+ATC) as a cause of alpha+ thalassemia. AB - We report a novel case of Hb Phnom Penh [alpha117(GH5)Phe-Ile-alpha118(H1)Thr (alpha1)] detected through cord blood screening for hemoglobinopathies. Sequence analyses identified this in-frame mutation at codons 117/118 (+ATC) in exon 3 of the alpha1-globin gene. This mutation causes a silent alpha-thalassemia (alpha thal). PMID- 22432595 TI - Of mice and men: a comparative study of cancer-associated fibroblasts in mammary carcinoma. AB - INTRODUCTION: The initial clinical experience from targeted therapy for breast cancer has been mixed. While important progress has been made in the care of a subset of patients characterized by amplification of HER2 through the use of trastuzumab, other targeted therapies have failed to improve the outcome for large, unselected groups of patients. Thus, efforts to find prognostic or predictive biomarkers to enable tailored therapy are highly warranted. Genetically engineered mouse models of human cancer provide a convenient setting in which to perform explorative studies. However, there is a paucity of comparative studies between mouse and human tumours in order to validate the use of mouse models as discovery tools. MATERIALS AND METHODS: Here, we have compared the localization of markers for cancer-associated fibroblasts in the MMTV-PyMT mouse model of mammary carcinoma with that of human breast cancer. The expression of alpha-smooth muscle actin, platelet-derived growth factor receptor-alpha, and fibroblast-specific protein-1 was assessed by immunostaining of sections from tumours of MMTV-PyMT mice. Information about the distribution of the same markers in human breast cancer was derived from the publicly available database the Human Protein Atlas. RESULTS: Both mouse and human mammary carcinomas were infused by a rich fibrotic stroma. While no marker was capable of identifying all stromal fibroblasts, the expression pattern of each marker was remarkably similar in mouse and human. DISCUSSION: We conclude that the MMTV-PyMT mouse model of breast cancer will have utility as a discovery tool for biomarkers of cancer-associated fibroblasts during malignant conversion. PMID- 22432596 TI - Resistance of equine tibiae and radii to side impact loads. AB - REASONS FOR PERFORMING STUDY: There are no detailed studies describing the resistance of equine tibiae and radii to side impact loads, such as a horse kick and a better understanding of the general long bone impact behavioural model is required. OBJECTIVES: To quantify the typical impact energy required to fracture or fissure an equine long bone, as well as to determine the range and time course of the impact force under conditions similar to that of a horse kick. METHODS: Seventy-two equine tibiae and radii were investigated using a drop impact tester. The prepared bones were preloaded with an axial force of 2.5 kN and were then hit in the middle of the medial side. The impact velocity of the metal impactor, weighting 2 kg, was varied within the range of 6-11 m/s. The impact process was captured with a high-speed camera from the craniomedial side of the bone. The videos were used both for slow-motion observation of the process and for quantifying physical parameters, such as peak force via offline video tracking and subsequent numerical derivation of the 'position vs. time' function for the impactor. RESULTS: The macroscopic appearance of the resultant bone injuries was found to be similar to those produced by authentic horse kicks, indicating a successful simulation of the real load case. The impact behaviours of tibiae and radii do not differ considerably in terms of the investigated general characteristics. Peak force occurred between 0.15-0.30 ms after the start of the impact. The maximum contact force correlated with the 1.45-power of the impact velocity if no fracture occurred (F(max) ~ 0.926 . v(i) (1.45) ). Peak force scatter was considerably larger within the fractured sub-group compared with fissured bones. The peak force for fracture tended to lie below the aforementioned function, within the range of F(max) = 11-23 kN ('fracture load'). The impact energy required to fracture a bone varied from 40-90 J. CONCLUSIONS: The video-based measuring method allowed quantifying of the most relevant physical parameters, such as contact force and energy balance. POTENTIAL RELEVANCE: The results obtained should help with the development of bone implants and guards, supporting theoretical studies, and in the evaluation of bone injuries. PMID- 22432597 TI - T-cell lymphoblastic lymphoma/leukemia presenting as a pituitary mass lesion: a case report and review of the literature. AB - We present a rare case of primary T-cell lymphoblastic lymphoma of the pituitary gland. A 58-year-old woman presented with headaches, right-sided ptosis and cranial nerve III palsy. She subsequently developed polyuria, polydipsia, and hyperglycemia and was found to have hypopituitarism. MRI revealed a large, heterogeneously enhancing intrasellar/suprasellar lesion displacing the optic chiasm and extending into the right cavernous sinus. Radiologically, these findings were thought to represent an invasive pituitary adenoma. Pterional craniotomy was performed with subtotal tumor resection. Histopathological examination revealed a T-cell lymphoblastic lymphoma/leukemia (T-LBL) admixed with pituitary corticotrophic cell hyperplasia. CT scans of the chest, abdomen and pelvis showed no evidence of systemic disease. Analysis of peripheral blood and bone marrow, including flow cytometry, demonstrated no involvement by T-LBL. Follow-up MRI of the spine revealed abnormalities in the distal thoracic spinal cord and conus medullaris, raising suspicions of leptomeningeal dissemination. Only five case reports of T-cell primary pituitary lymphoma (PPL) have been previously described, four of which were associated with hypopituitarism and/or concurrent pituitary adenoma. We present the first report of a T-cell PPL associated with adenohypophyseal hyperplasia and the third documented occurrence of a primary pituitary T-LBL. PMID- 22432598 TI - Canine multifocal retinopathy in the Australian Shepherd: a case report. AB - A 1-year-old Australian Shepherd (AS) was presented for a routine hereditary eye examination. During the examination multiple raised, brown to orange lesions were noted in the fundus, which could not be attributed to a known retinal disease in this breed. As they clinically most closely resembled canine multifocal retinopathy (cmr) and no indication of an acquired condition was found, genetic tests for BEST1 gene mutations were performed. These showed the dog to be homozygous for the cmr1 (C73T/R25X) gene defect. Furthermore, ultrasound (US), electroretinography (ERG), and optical coherence tomography were performed, confirming changes typical for cmr. Subsequently, the AS pedigree members were genetically and clinically tested, demonstrating autosomal recessive inheritance with no clinical symptoms in carrier animals, as was previously described for cmr. To our knowledge, this is the first reported case of canine multifocal retinopathy in the AS breed. Further investigations are under way. PMID- 22432599 TI - Agreement between parent-adolescent ratings on psychosocial outcome and quality of-life following childhood traumatic brain injury. AB - OBJECTIVE: This study investigated parent-adolescent agreement in long-term psychosocial and quality-of-life (QoL) outcomes. The sample comprised adolescents aged 15-18 years, who sustained childhood traumatic brain injury (TBI) between birth and 5 years of age. METHODS: Thirty-three participants (17 adolescents with TBI and 16 TBI parent-proxies) were involved in the study which compared parent and adolescent ratings on the Sydney Psychosocial Reintegration Scale-Child form (SPRS-C) and the Pediatric Quality-of-Life Inventory (PedsQL). The questionnaires were administered through phone interviews. RESULTS: As hypothesized, parent adolescent agreement was acceptable for psychosocial outcome (intra-class coefficient [ICC] of 0.844, p < 0.001), whereas discrepancies were found for ratings of QoL (ICC of 0.506, p = 0.092). CONCLUSION: The finding that parents and adolescents agree on psychosocial outcome is promising for those instances when the patient is unable to report; however, discrepancies regarding QoL suggest caution needs to be taken when interpreting parent-rated QoL data. PMID- 22432601 TI - Dynamics of methionine ligand rebinding in cytochrome c. AB - Geminate recombination of the methionine ligand to the heme iron in ferrous cytochrome c protein following photodissociation displays rich kinetics. It is of particular interest to develop an understanding of fast and slow rebinding time scales, observed in experimental studies, in terms of features of the underlying complex energy landscape. The classical empirical force field in the heme pocket has been extended by incorporating ab initio potential energy surface calculations representing the ground singlet state and quintet state associated with methionine bond breaking and rebinding. An algorithm based on the Landau Zener nonadiabatic transition theory has been employed to model the electronic surface hopping between two spin states during the process of ligand dissociation and recombination. Multiple conformational substates of the dissociated methionine ligand are found to participate in the reaction dynamics. Varying time scales for interconversion between substates lead to a mechanism elucidating the fast and slow rebinding time scales. The reaction system may be understood in terms of a two-dimensional reaction coordinate distinctly separated from the coupled bath of surrounding protein and solvent degrees of freedom. Insights into the reaction dynamics provided by this study lead to suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of ligand-protein binding. PMID- 22432602 TI - Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation. AB - OBJECTIVE: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. This study was aimed to examine several brain chemical mediators, including Glx (glutamate + glutamine), using (1)H magnetic resonance spectroscopy (MRS) in medicated patients with schizophrenia, with and without psychotic exacerbation. METHOD: (1)H MRS was acquired in 24 patients with schizophrenia, with psychotic exacerbation; 22 patients without exacerbation; and 27 age- and sex-matched healthy volunteers. The levels of metabolites were measured in the left frontal and inferior parietal white matter and compared across the three groups. RESULTS: The Glx level was significantly elevated in the left inferior parietal white matter in the patients with psychotic exacerbation in comparison with that in the healthy volunteers and the patients without exacerbation (P < 0.05). We also detected that there was a significant correlation between Positive and Negative Syndrome Scale-positive scale and Glx level in the left parietal white matter (r = 0.51, P < 0.001). CONCLUSION: Higher than normal Glx levels indicate glutamatergic overactivity in the left inferior parietal white matter with schizophrenic exacerbation, a finding that is in accordance with the glutamatergic hypothesis in schizophrenia. The Glx level measured by (1)H MRS could be a biomarker for exacerbation in schizophrenia. PMID- 22432603 TI - Psychometric properties of a new tool to assess task-specific and global competency in cataract surgery. AB - BACKGROUND AND OBJECTIVE: To establish and validate an assessment tool of cataract surgery performed by residents suitable for a competency-based curriculum. PATIENTS AND METHODS: A three-component evaluation tool was created based on review of the literature and was refined using a modified Delphi technique. Faculty surgeons viewed two videos of cataract surgery, performed by a novice and an expert, and completed the evaluation tool. Results were analyzed for the psychometric properties. RESULTS: Evaluators concluded the scale had excellent face validity. Construct validity showed the scale to reliably distinguish (P < .001) between novice (30.3 +/- 6.1) and experienced (48.3 +/- 7.2) surgeons. Internal consistency of the scale was high, with Cronbach's alpha equal to 0.981. Inter-rater reliability was high with an intraclass correlation coefficient equal to 0.811 (F(df) = 53.2 (25), P < .001). CONCLUSION: The tool has excellent face validity, content validity, and reliability. Its task specific, global-index scale and quantitative data form make it a valuable tool to assess residents' surgical skills. PMID- 22432604 TI - An anatomically based approach to intralesional corticosteroid injection for eyelid capillary hemangiomas. AB - BACKGROUND AND OBJECTIVE: To describe a corticosteroid injection technique for eyelid capillary hemangiomas that minimizes the risk of a central retinal artery occlusion and is based on anatomic, physiologic, and pharmacologic rationales. PATIENTS AND METHODS: In this retrospective, non-comparative, interventional case series, the medical records of 50 eyes of 50 patients over a 10-year period were reviewed for retinal complications associated with the described injection technique. RESULTS: Ophthalmoscopy showed no retinal complications in the 50 eyes treated with this injection technique. CONCLUSION: The risk of central retinal artery occlusion from retrograde embolization can be minimized by using an anatomically based injection technique that prevents canalization of an artery and avoids injection pressures exceeding the mean systemic arterial pressure. PMID- 22432605 TI - Stereochemical consequences of oxygen atom transfer and electron transfer in imido/oxido molybdenum(IV, V, VI) complexes with two unsymmetric bidentate ligands. AB - Two equivalents of the unsymmetrical Schiff base ligand (L(tBu))(-) (4-tert-butyl phenyl(pyrrolato-2-ylmethylene)amine) and MoCl(2)(NtBu)O(dme) (dme = 1,2 dimethoxyethane) gave a single stereoisomer of a mixed imido/oxido Mo(VI) complex 2(tBu). The stereochemistry of 2(tBu) was elucidated using X-ray diffraction, NMR spectroscopy, and DFT calculations. The complex is active in an oxygen atom transfer (OAT) reaction to trimethyl phosphane. The putative intermediate five coordinate Mo(IV) imido complex coordinates a PMe(3) ligand, giving the six coordinate imido phosphane Mo(IV) complex 5(tBu). The stereochemistry of 5(tBu) is different from that of 2(tBu) as shown by NMR spectroscopy, DFT calculations, and X-ray diffraction. Single-electron oxidation of 5(tBu) with ferrocenium hexafluorophosphate gave the stable cationic imido phosphane Mo(V) complex [5(tBu)](+) as the PF(6)(-) salt. EPR spectra of [5(tBu)](PF(6)) confirmed the presence of PMe(3) in the coordination sphere. Single-crystal X-ray diffraction analysis of [5(tBu)](PF(6)) revealed that electron transfer occurred under retention of the stereochemical configuration. The rate of OAT, the outcome of the electron transfer reaction, and the stabilities of the imido complexes presented here differ dramatically from those of analogous oxido complexes. PMID- 22432606 TI - Electroglottographic contact quotient in different phonation types using different amplitude threshold levels. AB - Contact quotient (CQ), measured by electroglottogram (EGG), is a ratio which illustrates the duration of vocal fold contact during one vocal fold period. In the present study CQ(EGG) was calculated from a sustained vowel phonation in three different phonation types (breathy, normal, pressed) at three amplitude threshold levels (25%, 35%, 50%). CQ(EGG) values were compared with experts' perceptual evaluation of the firmness of phonation. The contact time of the vocal folds differed significantly between the different phonation types at all threshold levels (P < 0.01). Perceptual evaluation correlated best with CQ(EGG) at threshold levels 25% and 35%. The results of the linear regression model suggested that by using threshold level 25% the effect of F0 and SPL on CQ(EGG) were not significant. PMID- 22432607 TI - My contribution to broadening the base of chemical engineering. AB - This paper is a short account, from a personal viewpoint, of the various contributions I have made to expand the academic basis of chemical engineering from its origin in the unifying concept of unit operations, focussed on process design, to encompassing all the professional activities of industrial chemical engineers. This includes all aspects of planning and scheduling the operations as well as designing and controlling the process plant. The span of my career also happens to include the birth of the age of computing, with all the consequential implications. PMID- 22432608 TI - Catalysis in solid oxide fuel cells. AB - Solid oxide fuel cells (SOFCs) and solid oxide electrolyzers (SOEs) hold much promise as highly efficient devices for the direct interconversion of chemical and electrical energy. Commercial application of these devices, however, requires further improvements in their performance and stability. Because the performance of SOFC and SOE electrodes depends on their microstructures, electronic and ionic conductivities, and chemical reactivities, the needed improvements require the expertise of various disciplines, with catalytic science playing an important role. Highly active and thermally stable catalysts are required to limit the internal losses in the devices, increase the range of fuels they can use, and decrease the temperatures at which they operate. In this article we review some of the most important recent advances in catalysis for SOFC and SOE electrodes and highlight additional improvements that are needed. PMID- 22432609 TI - CO(2) capture from dilute gases as a component of modern global carbon management. AB - The growing atmospheric CO(2) concentration and its impact on climate have motivated widespread research and development aimed at slowing or stemming anthropogenic carbon emissions. Technologies for carbon capture and sequestration (CCS) employing mass separating agents that extract and purify CO(2) from flue gas emanating from large point sources such as fossil fuel-fired electricity generating power plants are under development. Recent advances in solvents, adsorbents, and membranes for postcombust- ion CO(2) capture are described here. Specifically, room-temperature ionic liquids, supported amine materials, mixed matrix and facilitated transport membranes, and metal-organic framework materials are highlighted. In addition, the concept of extracting CO(2) directly from ambient air (air capture) as a means of reducing the global atmospheric CO(2) concentration is reviewed. For both conventional CCS from large point sources and air capture, critical research needs are identified and discussed. PMID- 22432610 TI - Engineering antibodies for cancer therapy. AB - The advent of modern antibody engineering has led to numerous successes in the application of these proteins for cancer therapy in the 13 years since the first Food and Drug Administration approval, which has stimulated active interest in developing more and better drugs based on these molecules. A wide range of tools for discovering and engineering antibodies has been brought to bear on this challenge in the past two decades. Here, we summarize mechanisms of monoclonal antibody therapeutic activity, challenges to effective antibody-based treatment, existing technologies for antibody engineering, and current concepts for engineering new antibody formats and antibody alternatives as next generation biopharmaceuticals for cancer treatment. PMID- 22432611 TI - Silencing or stimulation? siRNA delivery and the immune system. AB - Since its inception more than a decade ago, the field of short interfering RNA (siRNA) therapeutics has demonstrated potential in the treatment of a wide variety of diseases. The power behind RNA interference (RNAi) therapy lies in its ability to specifically silence target genes of interest. As more biological data have become available, it has become evident that, in addition to mediating RNAi, siRNA molecules have the potential to potently induce the innate immune system. One of the significant challenges facing the field today is the differentiation between therapeutic effects caused by target-specific, RNAi-mediated gene silencing and those caused by nonspecific stimulation of the innate immune system. Unless appropriate experimental measures are taken to control for RNA induced immunostimulation, genetic manipulation can be confused with immune activation. This review attempts to provide an accessible background in siRNA relevant immunology and to highlight the ways in which siRNA can be engineered to avoid or provoke an innate immune response. PMID- 22432612 TI - Solubility of gases and liquids in glassy polymers. AB - This review discusses a macroscopic thermodynamic procedure to calculate the solubility of gases, vapors, and liquids in glassy polymers that is based on the general procedure provided by the nonequilibrium thermodynamics for glassy polymers (NET-GP) method. Several examples are presented using various nonequilibrium (NE) models including lattice fluid (NELF), statistical associating fluid theory (NE-SAFT), and perturbed hard sphere chain (NE-PHSC). Particular applications illustrate the calculation of infinite-dilution solubility coefficients in different glassy polymers and the prediction of solubility isotherms for different gases and vapors in pure polymers as well as in polymer blends. The determination of model parameters is discussed, and the predictive abilities of the models are illustrated. Attention is also given to the solubility of gas mixtures and solubility isotherms in nanocomposite mixed matrices. The fractional free volume determined from solubility data can be used to correlate solute diffusivities in mixed matrices. PMID- 22432613 TI - Deconstruction of lignocellulosic biomass to fuels and chemicals. AB - Plants represent a vast, renewable resource and are well suited to provide sustainably for humankind's transportation fuel needs. To produce infrastructure compatible fuels from biomass, two challenges remain: overcoming plant cell wall recalcitrance to extract sugar and phenolic intermediates, and reduction of oxygenated intermediates to fuel molecules. To compete with fossil-based fuels, two primary routes to deconstruct cell walls are under development, namely biochemical and thermochemical conversion. Here, we focus on overcoming recalcitrance with biochemical conversion, which uses low-severity thermochemical pretreatment followed by enzymatic hydrolysis to produce soluble sugars. Many challenges remain, including understanding how pretreatments affect the physicochemical nature of heterogeneous cell walls; determination of how enzymes deconstruct the cell wall effectively with the aim of designing superior catalysts; and resolution of issues associated with the co-optimization of pretreatment, enzymatic hydrolysis, and fermentation. Here, we highlight some of the scientific challenges and open questions with a particular focus on problems across multiple length scales. PMID- 22432614 TI - Hydrophobicity of proteins and interfaces: insights from density fluctuations. AB - Macroscopic characterizations of hydrophobicity (e.g., contact angle measurements) do not extend to the surfaces of proteins and nanoparticles. Molecular measures of hydrophobicity of such surfaces need to account for the behavior of hydration water. Theory and state-of-the-art simulations suggest that water density fluctuations provide such a measure; fluctuations are enhanced near hydrophobic surfaces and quenched with increasing surface hydrophilicity. Fluctuations affect conformational equilibria and dynamics of molecules at interfaces. Enhanced fluctuations are reflected in enhanced cavity formation, more favorable binding of hydrophobic solutes, increased compressibility of hydration water, and enhanced water-water correlations at hydrophobic surfaces. These density fluctuation-based measures can be used to develop practical methods to map the hydrophobicity/philicity of heterogeneous surfaces including those of proteins. They highlight that the hydrophobicity of a group is context dependent and is significantly affected by its environment (e.g., chemistry and topography) and especially by confinement. The ability to include information about hydration water in mapping hydrophobicity is expected to significantly impact our understanding of protein-protein interactions as well as improve drug design and discovery methods and bioseparation processes. PMID- 22432615 TI - Risk taking and effective R&D management. AB - Several key strategies can be used to manage the risk associated with innovation to create maximum value. These include balancing the timing of investments versus cash flows, management of fads, prioritization across the company, savvy portfolio management, and a system of metrics that measure real success. Successful R&D managers will do whatever is necessary to manage the risks associated with an R&D program and stick to their long-term strategy. PMID- 22432616 TI - Novel solvents for sustainable production of specialty chemicals. AB - We discuss novel solvents that improve the sustainability of various chemical reactions and processes. These alternative solvents include organic-aqueous tunable solvents; near-critical water; switchable piperylene sulfone, a volatile dimethylsulfoxide substitute; and reversible ionic liquids. These solvents are advantageous to a wide variety of reactions because they reduce waste and energy demand by coupling homogeneous reactions with heterogeneous separations, acting as in situ acid or base catalysts, and providing simple and efficient postreaction separations. PMID- 22432618 TI - Fundamentals and applications of gas hydrates. AB - Fundamental understanding of gas hydrate formation and decomposition processes is critical in many energy and environmental areas and has special importance in flow assurance for the oil and gas industry. These areas represent the core of gas hydrate applications, which, albeit widely studied, are still developing as growing fields of research. Discovering the molecular pathways and chemical and physical concepts underlying gas hydrate formation potentially can lead us beyond flowline blockage prevention strategies toward advancing new technological solutions for fuel storage and transportation, safely producing a new energy resource from natural deposits of gas hydrates in oceanic and arctic sediments, and potentially facilitating effective desalination of seawater. The state of the art in gas hydrate research is leading us to new understanding of formation and dissociation phenomena that focuses on measurement and modeling of time-dependent properties of gas hydrates on the basis of their well-established thermodynamic properties. PMID- 22432617 TI - Metabolic engineering for the production of natural products. AB - Natural products and their derivatives play an important role in modern healthcare as frontline treatments for many diseases and as inspiration for chemically synthesized therapeutics. With advances in sequencing and recombinant DNA technology, many of the biosynthetic pathways responsible for the production of these chemically complex yet valuable compounds have been elucidated. With an ever-expanding toolkit of biosynthetic components, metabolic engineering is an increasingly powerful method to improve natural product titers and generate novel compounds. Heterologous production platforms have enabled access to pathways from difficult to culture strains, systems biology and metabolic modeling tools have resulted in increasing predictive and analytic capabilities, advances in expression systems and regulation have enabled the fine-tuning of pathways for increased efficiency, and characterization of individual pathway components has facilitated the construction of hybrid pathways for the production of new compounds. These advances in the many aspects of metabolic engineering not only have yielded fascinating scientific discoveries but also make it an increasingly viable approach for the optimization of natural product biosynthesis. PMID- 22432619 TI - Crystal polymorphism in chemical process development. AB - Polymorphism in molecular crystals is a prevalent phenomenon and is of great interest to the pharmaceutical community. The solid-state form is a key quality attribute of a crystalline product. Inconsistencies in the solid phase produced during the manufacturing and storage of drug substances and drug products may have severe consequences. It is essential to understand the solid-state behavior of the drug and to judiciously select the optimal solid form for development. This review highlights the pervasiveness and relevance of polymorphism and describes solid form screening and selection processes. Moreover, case studies on controlling polymorphs from a chemical development perspective are provided. PMID- 22432620 TI - Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. AB - Tumors are similar to organs, with unique physiology giving rise to an unusual set of transport barriers to drug delivery. Cancer therapy is limited by nonuniform drug delivery via blood vessels, inhomogeneous drug transport into tumor interstitium from the vascular compartment, and hindered transport through tumor interstitium to the target cells. Four major abnormal physical and physiological properties contribute to these transport barriers. Accumulated solid stress compresses blood vessels to diminish the drug supply to many tumor regions. Immature vasculature with high viscous and geometric resistances and reduced pressure gradients leads to sluggish and heterogeneous blood flow in tumors to further limit drug supply. Nonfunctional lymphatics coupled with highly permeable blood vessels result in elevated hydrostatic pressure in tumors to abrogate convective drug transport from blood vessels into and throughout most of the tumor tissue. Finally, a dense structure of interstitial matrix and cells serves as a tortuous, viscous, and steric barrier to diffusion of therapeutic agents. In this review, we discuss the origins and implications of these barriers. We then highlight strategies for overcoming these barriers by modulating either drug properties or the tumor microenvironment itself to enhance the delivery and effectiveness of drugs in tumors. PMID- 22432621 TI - Surface reactions in microelectronics process technology. AB - Current integrated circuit (IC) manufacturing consists of more than 800 process steps, nearly all of which involve reactions at surfaces that significantly impact device yield and performance. From initial surface preparation through film deposition, patterning, etching, residue removal, and metallization, an understanding of surface reactions and interactions is critical to the successful continuous scaling, yield, and reliability of electronic devices. In this review, some of the most important surface reactions that drive the development of microelectronic device fabrication are described. The reactions discussed do not constitute comprehensive coverage of this topic in IC manufacture but have been selected to demonstrate the importance of surface/interface reactions and interactions in the development of new materials, processing sequences, and process integration challenges. Specifically, the review focuses on surface reactions related to surface cleaning/preparation, semiconductor film growth, dielectric film growth, metallization, and etching (dry and wet). PMID- 22432622 TI - Microfluidic chemical analysis systems. AB - The field of microfluidics has exploded in the past decade, particularly in the area of chemical and biochemical analysis systems. Borrowing technology from the solid-state electronics industry and the production of microprocessor chips, researchers working with glass, silicon, and polymer substrates have fabricated macroscale laboratory components in miniaturized formats. These devices pump nanoliter volumes of liquid through micrometer-scale channels and perform complex chemical reactions and separations. The detection of reaction products is typically done fluorescently with off-chip optical components, and the analysis time from start to finish can be significantly shorter than that of conventional techniques. In this review we describe these microfluidic analysis systems, from the original continuous flow systems relying on electroosmotic pumping for liquid motion to the large diversity of microarray chips currently in use to the newer droplet-based devices and segmented flow systems. Although not currently widespread, microfluidic systems have the potential to become ubiquitous. PMID- 22432623 TI - Microsystem technologies for medical applications. AB - Medical technologies are evolving at a very rapid pace. Portable communication devices and other handheld electronics are influencing our expectations of future medical tools. The advanced medical technologies of our future will not necessarily be large expensive systems. They are just as likely to be small and disposable. This paper reviews how microsystems are already impacting health care as commercial products or in clinical development. Example systems for point-of care testing (POCT), patient monitoring tools, systemic drug delivery, local drug delivery, and surgical tools are described. These technologies are moving care from hospitals to outpatient settings, physicians' offices, community health centers, nursing homes, and the patients' homes. Microsystems that are rapidly adopted fulfill significant medical needs and are compatible with existing clinical practice. PMID- 22432624 TI - Low-dielectric constant insulators for future integrated circuits and packages. AB - Future integrated circuits and packages will require extraordinary dielectric materials for interconnects to allow transistor advances to be translated into system-level advances. Exceedingly low-permittivity and low-loss materials are required at every level of the electronic system, from chip-level insulators to packages and printed wiring boards. In this review, the requirements and goals for future insulators are discussed followed by a summary of current state-of-the art materials and technical approaches. Much work needs to be done for insulating materials and structures to meet future needs. PMID- 22432625 TI - Tissue engineering and regenerative medicine: history, progress, and challenges. AB - The past three decades have seen the emergence of an endeavor called tissue engineering and regenerative medicine in which scientists, engineers, and physicians apply tools from a variety of fields to construct biological substitutes that can mimic tissues for diagnostic and research purposes and can replace (or help regenerate) diseased and injured tissues. A significant portion of this effort has been translated to actual therapies, especially in the areas of skin replacement and, to a lesser extent, cartilage repair. A good amount of thoughtful work has also yielded prototypes of other tissue substitutes such as nerve conduits, blood vessels, liver, and even heart. Forward movement to clinical product, however, has been slow. Another offshoot of these efforts has been the incorporation of some new exciting technologies (e.g., microfabrication, 3D printing) that may enable future breakthroughs. In this review we highlight the modest beginnings of the field and then describe three application examples that are in various stages of development, ranging from relatively mature (skin) to ongoing proof-of-concept (cartilage) to early stage (liver). We then discuss some of the major issues that limit the development of complex tissues, some of which are fundamentals-based, whereas others stem from the needs of the end users. PMID- 22432626 TI - Intensified reaction and separation systems. AB - Process intensification follows four main goals: to maximize the effectiveness of intra- and intermolecular events, to give each molecule the same processing experience, to optimize the driving forces/maximize specific interfacial areas, and to maximize the synergistic effects of partial processes. This paper shows how these goals can be reached in reaction and separation systems at all relevant time and length scales and is focused on the structuring of reactors and separation units, on the use of different energy forms to improve the reaction and separation, on combining and superimposing of different phenomena in one integrated unit or reactor, and on the application of oscillations for intensification of reaction and separation processes. PMID- 22432627 TI - Quantum mechanical modeling of catalytic processes. AB - Advances in quantum chemical methods in combination with exponential growth in the computational speed of computers have enabled researchers in the field of catalysis to apply electronic structure calculations to a wide variety of increasingly complex problems. Such calculations provide insights into why and how changes in the composition and structure of catalytically active sites affect their activity and selectivity for targeted reactions. The aim of this review is to survey the recent advances in the methods used to make quantum chemical calculations and to define transition states as well as to illustrate the application of these methods to a selected series of examples taken from the authors' recent work. PMID- 22432629 TI - Battery technologies for large-scale stationary energy storage. AB - In recent years, with the deployment of renewable energy sources, advances in electrified transportation, and development in smart grids, the markets for large scale stationary energy storage have grown rapidly. Electrochemical energy storage methods are strong candidate solutions due to their high energy density, flexibility, and scalability. This review provides an overview of mature and emerging technologies for secondary and redox flow batteries. New developments in the chemistry of secondary and flow batteries as well as regenerative fuel cells are also considered. Advantages and disadvantages of current and prospective electrochemical energy storage options are discussed. The most promising technologies in the short term are high-temperature sodium batteries with beta" alumina electrolyte, lithium-ion batteries, and flow batteries. Regenerative fuel cells and lithium metal batteries with high energy density require further research to become practical. PMID- 22432630 TI - Coal and biomass to fuels and power. AB - Systems with CO(2) capture and storage (CCS) that coproduce transportation fuels and electricity from coal plus biomass can address simultaneously challenges of climate change from fossil energy and dependence on imported oil. Under a strong carbon policy, such systems can provide competitively clean low-carbon energy from secure domestic feedstocks by exploiting the negative emissions benefit of underground storage of biomass-derived CO(2), the low cost of coal, the scale economies of coal energy conversion, the inherently low cost of CO(2) capture, the thermodynamic advantages of coproduction, and expected high oil prices. Such systems require much less biomass to make low-carbon fuels than do biofuels processes. The economics are especially attractive when these coproduction systems are deployed as alternatives to CCS for stand-alone fossil fuel power plants. If CCS proves to be viable as a major carbon mitigation option, the main obstacles to deployment of coproduction systems as power generators would be institutional. PMID- 22432628 TI - Progress and prospects for stem cell engineering. AB - Stem cells offer tremendous biomedical potential owing to their abilities to self renew and differentiate into cell types of multiple adult tissues. Researchers and engineers have increasingly developed novel discovery technologies, theoretical approaches, and cell culture systems to investigate microenvironmental cues and cellular signaling events that control stem cell fate. Many of these technologies facilitate high-throughput investigation of microenvironmental signals and the intracellular signaling networks and machinery processing those signals into cell fate decisions. As our aggregate empirical knowledge of stem cell regulation grows, theoretical modeling with systems and computational biology methods has and will continue to be important for developing our ability to analyze and extract important conceptual features of stem cell regulation from complex data. Based on this body of knowledge, stem cell engineers will continue to develop technologies that predictably control stem cell fate with the ultimate goal of being able to accurately and economically scale up these systems for clinical-grade production of stem cell therapeutics. PMID- 22432631 TI - Microbiological and mucociliary properties of the ethanol extract of Hymenocardia acida on selected respiratory clinical isolates. AB - The antimicrobial property of the ethanol leaf extract of Hymenocardia acida (H. acida) on some opportunistic respiratory pathogens was evaluated in this study. We also assessed the activity of the extract on tracheal mucociliary activity using murine tracheal mucus exudation and mucociliary motility in pigeons as experimental models. Phytochemical screening of the extract was done; and acute toxicity of the extract in mice was carried out using Lorke's method for estimation of its median lethal dose. Results show the presence of carbohydrates, saponins, tannins, flavonoids, alkaloids, resins, and balsams in the extract and the absence of anthraquinones, terpenes, and sterols. Results of the acute toxicity test showed that the extract was slightly toxic, with an estimated median lethal dose of 1,767.77 mg/kg body weight. At 50, 100, and 200 mg/kg body weight of H. acida, tracheal mucus exudation was increased by 14.29, 19.24, and 33.82%, respectively. The effect on mucociliary velocity was dose-dependent as 50, 100, and 200 mg/kg body weight of the extract led to increased ciliary activity by 7.69, 61.5, and 81.6%, respectively. The effects of the extract (200 mg/kg body weight) on mucus exudation and clearance were significant (p < .05) and higher than the effect of ammonium chloride. Although the extract did not inhibit the growth of C. albicans and K. pneumoniae, it exhibited moderate antimicrobial activity against Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and Staphylococcus aureus. These findings show the mucociliary activity and antimicrobial properties of H. acida ethanol extract, and justify its use in the treatment of airway disorders. PMID- 22432632 TI - Student and faculty perspective toward the role and value of integration of natural product information into the pharmacy curriculum. AB - BACKGROUND: Consumer use of natural products is a mainstay in our society and continues to grow in prevalence. As pharmacists are viewed as drug experts and are easily accessible to patients, it is important for them to have basic knowledge of natural products. METHODS: Students and faculty members participating in a natural product elective were surveyed upon completion of the course about their perspectives regarding incorporation of covered information into the required curriculum. RESULTS: The majority of students and faculty members agree with the necessity of natural product content in the pharmacy curriculum. Their ideas for ways of incorporating this information, however, differ. CONCLUSION: Healthcare students and faculty are beginning to recognize the need for incorporation of Natural Product information into the curriculum and healthcare programs in the country should begin to rise to the occasion. PMID- 22432633 TI - The chemical composition and the content of volatile oil: potential factors that can contribute to the oxidative stability of Nigella sativa L. crude oil. AB - The crude oil of Nigella sativa L. (Black cumin) has well-known nutraceutical and pharmaceutical properties. The oil is prone to rapid oxidative deterioration because of its high content of poly-unsaturated fatty acids. In the current investigation, different cold-pressed crude oils of N. sativa were examined for their composition of fatty acids and oxidative stability. The data obtained were correlated with the chemical composition and content of volatile oils, which correspond to each crude oil. Results indicated that different crude oils have the same fatty acid composition, and linoleic acid was the major constituent (60.0-61.7%). Though, the oxidative stability index of the crude oils was different ranging from 2.5 hr to 26.9 hr, as revealed by the Rancimate test at 100 degrees C and airflow rate of 20 ml/min. The results showed that there is a straightforward correlation between the volatile oil content and the oxidative stability of the corresponding parent crude oil. In addition, high gamma terpinene content in the constitution of volatile oil can also be another contributing factor for enhancing the oxidative stability of the crude oil. The data presented here draw attention to some important factors that may guide the nutraceutical and food supplement processors in their screening for the highest quality of Nigella crude oils with maximum health benefits. PMID- 22432634 TI - Herbs and dietary supplements in the European Union: a review of the regulations with special focus on Germany and Poland. AB - In the European Union, the manufacturing of and the trade in herbs and dietary supplements are regulated by pharmaceutical and food laws. While dietary supplements are subject to food laws, provisions dealing with herbs are primarily to be found in pharmaceutical regulations. Having a basic understanding of the complexities of this regulatory environment can help clinicians and their patients understand the unique challenges and opportunities presented by EU herbs and supplements and may help inform regulatory practices in other countries struggling to ensure quality and safety of such products. PMID- 22432635 TI - An evidence-based systematic review of saffron (Crocus sativus) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22432636 TI - Thin film polycrystalline silicon nanowire biosensors. AB - Polysilicon nanowire biosensors have been fabricated using a top-down process and were used to determine the binding constant of two inflammatory biomarkers. A very low cost nanofabrication process was developed, based on simple and mature photolithography, thin film technology, and plasma etching, enabling an easy route to mass manufacture. Antibody-functionalized nanowire sensors were used to detect the proteins interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF alpha) over a wide range of concentrations, demonstrating excellent sensitivity and selectivity, exemplified by a detection sensitivity of 10 fM in the presence of a 100,000-fold excess of a nontarget protein. Nanowire titration curves gave antibody-antigen dissociation constants in good agreement with low-salt enzyme linked immunosorbent assays (ELISAs). This fabrication process produces high quality nanowires that are suitable for low-cost mass production, providing a realistic route to the realization of disposable nanoelectronic point-of-care (PoC) devices. PMID- 22432637 TI - Experimental manipulation of sponge/bacterial symbiont community composition with antibiotics: sponge cell aggregates as a unique tool to study animal/microorganism symbiosis. AB - Marine sponges can harbor dense and diverse bacterial communities, yet we have a limited understanding of important aspects of this symbiosis. We developed an experimental methodology that permits manipulating the composition of the microbial community. Specifically, we evaluated sponge cell aggregates (SCA) from Clathria prolifera that had been treated with different classes of antibiotics to determine whether this system might offer novel experimental approaches to the study of sponge/bacterial symbioses. Microscopic analysis of the SCA demonstrated that two distinct morphological types of microbiota existed on the external surface vs. the internal regions of the SCA. Denaturing gradient gel electrophoresis and sequence analysis of 16S rRNA gene clone libraries indicated that we were unable to create entirely aposymbiotic SCA but that different classes of antibiotics produced distinctive shifts in the SCA-associated bacterial community. After exposure to antibiotics, some bacterial species were 'revealed', thus uncovering novel components of the sponge-associated community. The antibiotic treatments used here had little discernible effect on the formation of SCA or subsequent development of the adult. The experimental approach we describe offers empirical options for studying the role symbionts play in sponge growth and development and for ascertaining relationships among bacterial species in communities residing in sponges. PMID- 22432638 TI - Prognostic value and cost-effectiveness of different screening strategies for HLA antibodies prior to kidney transplantation. AB - HLA antibody screening is conducted routinely prior to kidney transplantation, but the comparative prognostic value and cost-effectiveness of different methods are unclear. Pre-transplant sera of 141 patients transplanted between 1998 and 2000 were screened by ELISA and Luminex assays, and antibody specificities of reactive sera determined using bead array techniques. ELISA screening detected donor-specific antibodies (DSA) in 19 patients, who had a higher incidence of impaired graft function (60% vs. 20%, p = 0.04) and antibody-mediated rejection (AMR) within 90 d after transplantation (AMR, 35% vs. 5%, p = 0.02). Luminex screening detected eight additional patients with DSA, among those one with AMR. Six of eight patients with Luminex-only-DSA reported no prior immunizing events. Death-censored graft survival was shorter only in patients with DSA and AMR (median, 1.7 yr instead of between 9.5 and 11.0 yr for patients without DSA or patients with DSA but no AMR, p < 0.001). Material costs per detected clinically relevant DSA were about 57% higher for Luminex screening, but this increase could be avoided by modifying the cut-off recommended by the manufacturer. Conclusively, specification of antibodies only in sera reactive in screening tests was cost-effective to prevent shortened graft survival. Preformed DSA were only harmful if AMR was diagnosed within 90 d after transplantation. PMID- 22432639 TI - Reciprocal transplants demonstrate strong adaptive differentiation of the model organism Arabidopsis thaliana in its native range. AB - To quantify adaptive differentiation in the model plant Arabidopsis thaliana, we conducted reciprocal transplant experiments for five years between two European populations, one near the northern edge of the native range (Sweden) and one near the southern edge (Italy). We planted seeds (years 1-3) and seedlings (years 4 5), and estimated fitness as the number of fruits produced per seed or seedling planted. In eight of the 10 possible site * year comparisons, the fitness of the local population was significantly higher than that of the nonlocal population (3.1-22.2 times higher at the southern site, and 1.7-3.6 times higher at the northern site); in the remaining two comparisons no significant difference was recorded. At both sites, the local genotype had higher survival than the nonlocal genotype, and at the Italian site, the local genotype also had higher fecundity. Across years, the relative survival of the Italian genotype at the northern site decreased with decreasing winter soil temperature. The results provide evidence of strong adaptive differentiation between natural populations of A. thaliana and indicate that differences in tolerance to freezing contributed to fitness variation at the northern site. In ongoing work, we explore the functional and genetic basis of this adaptive differentiation. PMID- 22432640 TI - The PAI-1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women. AB - BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial. OBJECTIVE: We aimed to assess the impact of the 4G PAI-1 polymorphism on pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. PATIENTS/METHODS: This study represents a secondary investigation of a prior prospective cohort study investigating the association between inherited thrombophilias and adverse pregnancy events in Australian women. Healthy nulliparous women were recruited to this study prior to 22 weeks gestation. Genotyping for the 4G/5G PAI-1 gene was performed using Taqman assays in an ABI prism 7700 Sequencer several years after the pregnancy was completed. Pregnancy outcome data were extracted from the medical record. The primary outcome was a composite comprising development of severe pre-eclampsia, fetal growth restriction, major placental abruption, stillbirth or neonatal death. RESULTS: Pregnancy outcome data were available in 1733 women who were successfully genotyped for this polymorphism. The primary composite outcome was experienced by 139 women (8% of the cohort). Four hundred and fifty-nine women (26.5%) were homozygous for the 4G deletion polymorphism, while 890 (51.4%) were heterozygous. Neither homozygosity nor heterozygosity for the PAI-1 4G polymorphism was associated with the primary composite outcome (homozygous OR = 1.30, 95% CI = 0.81-2.09, P = 0.28, heterozygous OR = 0.84, 95% CI = 0.53-1.31, P = 0.44) or with the individual pregnancy complications. CONCLUSION: The PAI-1 4G polymorphism is not associated with an increase in the risk of serious adverse pregnancy events in asymptomatic nulliparous women. PMID- 22432641 TI - Allylic carbon-carbon double bond directed Pd-catalyzed oxidative ortho olefination of arenes. AB - Pd-catalyzed selective ortho-olefination of arenes assisted by an allylic C-C double bond at room temperature using O(2) as a terminal oxidant is described. A possible mechanism involving the initial coordination of allylic C?C bond to Pd followed by selective o-C-H bond metalation is proposed. PMID- 22432644 TI - On early detection of myocardial dysfunction in asymptomatic severe mitral regurgitation. PMID- 22432643 TI - Nucleus accumbens mGluR5-associated signaling regulates binge alcohol drinking under drinking-in-the-dark procedures. AB - BACKGROUND: Alcohol increases the expression of Group 1 metabotropic glutamate receptors (mGluRs) and their associated scaffolding protein Homer2 and stimulates phosphatidylinositol 3-kinase (PI3K) within the nucleus accumbens (NAC). Moreover, functional studies suggest that NAC Group 1 mGluR/Homer2/PI3K signaling may be a potential target for pharmacotherapeutic intervention in alcoholism. METHODS: Immunoblotting was conducted to examine the effects of alcohol consumption under drinking-in-the-dark (DID) procedures on Group 1 mGluR associated proteins in C57BL/6J (B6) mice. Follow-up behavioral studies examined the importance of Group 1 mGluR/Homer2/PI3K signaling within the NAC shell for limited-access alcohol drinking. Finally, immunoblotting examined whether the NAC expression of Group 1 mGluR-associated proteins is a genetic correlate of high alcohol drinking using a selectively bred high DID (HDID-1) mouse line. RESULTS: Limited-access alcohol drinking under DID procedures up-regulated NAC shell Homer2 levels, concomitant with increases in mGluR5 and NR2B. Intra-NAC shell blockade of mGluR5, Homer2, or PI3K signaling, as well as transgenic disruption of the Homer binding site on mGluR5, decreased alcohol consumption in B6 mice. Moreover, transgenic disruption of the Homer binding site on mGluR5 and Homer2 deletion both prevented the attenuating effect of mGluR5 and PI3K blockade upon intake. Finally, the basal NAC shell protein expression of mGluR1 and Homer2 was increased in offspring of HDID-1 animals. CONCLUSIONS: Taken together, these data further implicate Group 1 mGluR signaling through Homer2 within the NAC in excessive alcohol consumption. PMID- 22432646 TI - Mitral valve diseases in Williams syndrome-case report and review of the literature. PMID- 22432648 TI - Assessment of right ventricular function using echocardiographic speckle tracking of the tricuspid annular motion: comparison with cardiac magnetic resonance. PMID- 22432650 TI - Live/real time three-dimensional transthoracic echocardiographic assessment of the involvement of cardiac valves and chambers in carcinoid disease. AB - We present an adult with metastatic carcinoid disease affecting the heart, in whom live/real time three-dimensional transthoracic echocardiography (3DTTE) provided incremental value over two-dimensional transthoracic echocardiography (2DTTE). Initial 2DTTE was able to demonstrate severe pulmonic and tricuspid regurgitation, but was unable to visualize the posterior leaflet of the tricuspid valve or the right (right anterior) leaflet of the pulmonic valve. Further analysis with 3DTTE demonstrated thickening, restricted mobility, and noncoaptation of all three leaflets of both the tricuspid and the pulmonary valves. En face viewing of tricuspid and pulmonary regurgitation vena contractas permitted more reliable quantification of regurgitation severity. In addition, localized, linear, echogenic areas consistent with carcinoid deposits were noted along the inner walls of the right atrium, atrial septum, and inferior vena cava. To the best of our knowledge, endocardial carcinoid deposits have never been reported by 2D or 3D echocardiography. En face viewing of these deposits by 3DTTE enabled measurement of their dimensions and areas. Subcostal examination also identified large circumscribed hepatic lesions consistent with metastatic disease. Neither the carcinoid deposits nor the metastatic lesions were detected by 2DTTE. This case demonstrates the usefulness of 3DTTE as a supplement to 2DTTE in more comprehensively assessing carcinoid involvement of the heart. PMID- 22432651 TI - Managing antimicrobial resistance requires resisting the inappropriate use of antimicrobials. PMID- 22432652 TI - Infectious diseases in Australia - the next decade. PMID- 22432653 TI - The 20th century re-emergence of epidemic infectious diseases: lessons learned and future prospects. PMID- 22432654 TI - Educating Australia's future doctors. PMID- 22432655 TI - Machine learning and data mining for epidemic surveillance. PMID- 22432656 TI - Does antibiotic use in farmed animals pose a risk to human health? - Yes. PMID- 22432657 TI - Does antibiotic use in farmed animals pose a risk to human health? - No. PMID- 22432658 TI - Improving the effectiveness of clinical medicine: the need for better science. AB - Effective clinical practice is predicated on valid and relevant clinical science a commodity in increasingly short supply. The pre-eminent place of clinical research has become tainted by methodological shortcomings, commercial influences and neglect of the needs of patients and clinicians. Researchers need to be more proactive in evaluating clinical interventions in terms of patient-important benefit, wide applicability and comparative effectiveness, and in adopting study designs and reporting standards that ensure accurate and transparent research outputs. Funders of research need to be more supportive of applied clinical research that rigorously evaluates effectiveness of new treatments and synthesis existing knowledge into clinically useful systematic reviews. Several strategies for improving the state of the science are possible but their implementation requires collective action of all those undertaking and reporting clinical research. PMID- 22432659 TI - HIV and AIDS in Africa: good news and bad news. PMID- 22432660 TI - Current challenges in appraising complementary medicine evidence. AB - Increased research in the area of complementary and alternative medicine (CAM) is urgently required, in addition to a balanced appraisal and communication of the state of evidence in the field. Current challenges for clinicians and the public in accepting purported CAM evidence concern potential selective publication of results, marked differences in product quality and standardisation, and some companies making unsubstantiated claims. To improve confidence in the industry, companies must publish all results and only make substantiated claims. In addition, providing intellectual property protection to CAM companies may encourage greater investment in research; however, more accountability of study results is critical. PMID- 22432661 TI - Concepts in epidemiology: the cohort effect. PMID- 22432662 TI - Competence and capacity at the end of life: uneasy paternalism. PMID- 22432663 TI - Should opioids be used for chronic non-cancer pain? PMID- 22432664 TI - The need for genetic studies of Indigenous Australians. PMID- 22432665 TI - Medication to prevent breast cancer - too much to swallow? PMID- 22432666 TI - A survey of injuries sustained in falls from ladders among patients at an inner city trauma centre. PMID- 22432667 TI - Inpatient subacute care in Australia: perceptions of admission and discharge barriers. PMID- 22432668 TI - We'll drink to that: the 200th anniversary of Australia's oldest hospital. PMID- 22432669 TI - Immune reconstitution inflammatory syndrome: immune restoration disease 20 years on. AB - Restoration of immune responses against opportunistic pathogens after commencing antiretroviral therapy (ART) may cause immune restoration disease (IRD) in about 10%-40% of HIV patients with low CD4(+) T-cell counts and usually presents clinically as a type of immune reconstitution inflammatory syndrome (IRIS). IRIS may be associated with many different opportunistic pathogens, but types associated with Mycobacterium tuberculosis, BCG, cryptococci, JC polyomavirus (the cause of progressive multifocal leukoencephalopathy [PML]), hepatitis C virus and hepatitis B virus infection are the most informative about disease pathogenesis and management. A CD4(+) T-cell count of < 50/MUL and a high pathogen load are the most commonly identified risk factors for IRIS. Recovery of pathogen-specific T-cell responses and perturbations of innate immune responses before and after ART appear to cause immunopathological abnormality in tissues infected by the pathogen. Prevention of IRIS may be influenced by the timing of ART: The risk of tuberculosis (TB)-associated-IRIS can be reduced by commencing ART after 8 weeks of TB treatment, but rates of AIDS or death are lower if ART is commenced during the first 4 weeks of TB treatment. Outcomes for patients with HIV and treated cryptococcal or TB meningitis may be improved by deferring ART until the opportunistic infection is fully suppressed, but data are inadequate. As ART is currently the only effective treatment for PML in patients with HIV, PML-associated IRIS cannot be prevented by manipulating the timing of ART. A greater understanding of the immunopathogenesis of IRIS may lead to targeted therapies. PMID- 22432670 TI - Murray Valley encephalitis: a review of clinical features, diagnosis and treatment. AB - Murray Valley encephalitis virus (MVEV) is a mosquito-borne virus that is found across Australia, Papua New Guinea and Irian Jaya. MVEV is endemic to northern Australia and causes occasional outbreaks across south-eastern Australia. 2011 saw a dramatic increase in MVEV activity in endemic regions and the re-emergence of MVEV in south-eastern Australia. This followed significant regional flooding and increased numbers of the main mosquito vector, Culex annulirostris, and was evident from the widespread seroconversion of sentinel chickens, fatalities among horses and several cases in humans, resulting in at least three deaths. The last major outbreak in Australia was in 1974, during which 58 cases were identified and the mortality rate was about 20%. With the potential for a further outbreak of MVEV in the 2011-2012 summer and following autumn, we highlight the importance of this disease, its clinical characteristics and radiological and laboratory features. We present a suspected but unproven case of MVEV infection to illustrate some of the challenges in clinical management. It remains difficult to establish an early diagnosis of MVEV infection, and there is a lack of proven therapeutic options. PMID- 22432671 TI - Surveillance of infection burden in residential aged care facilities. AB - OBJECTIVES: To explore the burden of illness associated with infectious syndromes and to measure the associated use of antimicrobials in residential aged care facilities (RACFs). DESIGN, SETTING AND SUBJECTS: Retrospective analysis of data for January 2006 to December 2010 from an infection surveillance system covering residents of four co-located RACFs, with a total of 150 residential care beds, in Melbourne, Victoria. MAIN OUTCOME MEASURES: Number of episodes and incidence of health care-associated infection (HCAI); rate of antimicrobial use; prescribing concordance with McGeer criteria for infection; frequency of clinical specimen collection. RESULTS: There were 1114 episodes of an infectious syndrome over 267, 684 occuppied bed-days (OBD), affording an average HCAI rate of 4.16 episodes/1000 OBD annually over 5 years (95% CI, 3.92-4.41). The mean rate of antimicrobial use was 7.07 courses/1000 OBD (range, 6.71-7.84). Around 40% of antimicrobial prescribing was for episodes that did not fulfil the McGeer criteria for clinical infection; this included about half of suspected urinary tract and upper respiratory tract infections (URTI), and about one-third of suspected lower respiratory tract and skin infections. Antimicrobials were routinely prescribed for URTI and bronchitis. Of all episodes treated with antimicrobials, 36% had documentation that a clinical specimen was obtained. CONCLUSIONS: The HCAI rate remained relatively stable over time. Routine surveillance and feedback of infection rates to the facilities did not result in a noticeable decrease of infection burden over time. It is of immediate concern that antimicrobials were being prescribed for a large proportion of suspected infections that did not meet criteria for clinical infection. Opportunities exist to further improve the use of antimicrobials in the RACF setting. PMID- 22432672 TI - Twenty-six years of enteric fever in Australia: an epidemiological analysis of antibiotic resistance. AB - OBJECTIVES: To determine incidence and trends in antibiotic resistance in Australian Salmonella enterica subspecies enterica serovars Typhi (S. Typhi) and Paratyphi (S. Paratyphi) isolates over the past 26 years. DESIGN: A retrospective analysis of consecutive microbiologically confirmed enteric fever isolates. PARTICIPANTS AND SETTING: All S. Typhi and S. Paratyphi isolates from patients diagnosed with enteric fever in Australia between 1985 and 2010. MAIN OUTCOME MEASURES: Incidence and variation in antibiotic resistance over time and according to country of origin. RESULTS: We analysed 2551 isolates, which originated from 74 countries or regions, mainly India (33%) and Indonesia (22%). The incidence among Australian residents increased from four to five before 2003 to seven cases per million person-years after 2003. Multidrug resistance (chloramphenicol, ampicillin, trimethoprim) and nalidixic acid resistance emerged rapidly from the early 1990s, with nalidixic acid resistance increasing to 70% in 2009-2010, while multidrug resistance was relatively stable at between 4% and 11%. Nalidixic acid and multidrug resistance rates are highest in isolates from the Indian subcontinent. Some countries in South-East Asia, such as Indonesia, had very low rates of resistance; however, this varied across the region. CONCLUSIONS: Nalidixic acid resistance has become widespread in enteric fever isolates from the Indian subcontinent and some parts of South-East Asia, justifying the use of ceftriaxone or azithromycin rather than ciprofloxacin as first-line treatment. However, resistance in some countries remains rare, potentially allowing treatment to be adjusted according to country of origin. PMID- 22432673 TI - Estimating the future burden of cancers preventable by better diet and physical activity in Australia. AB - OBJECTIVE: To estimate the number of cancers to be diagnosed in 2025 that could be prevented solely due to changes in diet and physical activity. DESIGN AND SETTING: We used an Australian population-based cancer database to estimate the total number of cancers to be diagnosed in 2025, by applying published age- and sex-specific population projections to current cancer incidence rates, and multiplying the projected numbers of cancers by estimates of population attributable fractions. MAIN OUTCOME MEASURES: Projected number of preventable cancers that would be diagnosed in 2025. RESULTS: Our projections suggest that there will be about 170, 000 Australians diagnosed with cancer in 2025. This represents an increase of about 60% on the 2007 incidence. Almost 43, 000 of these cancers (low estimate, 42,295; middle, 42,657; high, 43,990) could be prevented through improvements to diet and physical activity levels, including through their impact on obesity. It is likely that this is an underestimate of the true figure. The most preventable cancer types in 2025 were estimated to be bowel cancer and female breast cancer (10, 049 and 7273 preventable cases, respectively). CONCLUSIONS: About 25% of cancers, or about 43,000 cancers in 2025, can potentially be prevented through improvements in diet and physical activity. It is imperative that governments, clinicians and researchers act now if we are to reduce the significant future human and financial burden of cancer. PMID- 22432674 TI - Epidemiology, clinical features and diagnosis of Mycobacterium ulcerans in an Australian population. AB - OBJECTIVE: To describe the epidemiology, clinical features and diagnosis of Mycobacterium ulcerans infection occurring on the Bellarine Peninsula in Victoria. DESIGN, SETTING AND PATIENTS: Analysis of prospectively collected data on all patients with confirmed M. ulcerans infection reported from the Bellarine Peninsula and managed at Barwon Health between 1 January 1998 and 2 September 2011. MAIN OUTCOME MEASURES: Proportion of cases by age group and sex; duration of symptoms; number, type and site of lesions; proportions diagnosed by polymerase chain reaction (PCR) testing and mycobacterial cultures. RESULTS: We identified 180 sequential cases of M. ulcerans infection: 42 cases in 1998-2004 and 138 in 2005-2011. Median patient age was 61 years (range, 1-94 years), and 49% of patients were male. Duration of symptoms before diagnosis varied from 2 to 270 days (median, 42 days). At presentation, 95% of patients had single lesions. Lower limbs were the most common site of lesions (61%), followed by upper limbs (34%); 40% occurred over a joint. Most lesions presented as ulcers (87%). Compared with the rest of the study population, patients aged > 60 years were more likely to have multiple lesions (odds ratio [OR], 8.1; 95% CI, 1.0-176.2; P = 0.04), and patients aged < 15 years were less likely to have lesions over a joint (OR, 0.2; 95% CI, 0.0-1.0; P = 0.02). Upper limb lesions were more common (OR, 2.2; 95% CI, 1.1-4.3; P = 0.02) and lower limb lesions less common (OR, 0.5; 95% CI, 0.5-0.9; P = 0.01) in male than female patients. Lesion swabs were PCR positive in 99% of those tested, and positive on mycobacterial culture in 19%. Lesion biopsy samples were PCR-positive in 95% and mycobacterial culture-positive in 47%. CONCLUSIONS: M. ulcerans infections are increasing in the Bellarine Peninsula. They usually present as single ulcerative lesions on limbs, commonly over joints. Age and sex influence clinical presentation, and PCR of lesions has high diagnostic sensitivity. PMID- 22432675 TI - Melioidosis at Royal Darwin Hospital in the big 2009-2010 wet season: comparison with the preceding 20 years. AB - OBJECTIVE: To compare the unprecedented 91 cases of melioidosis in the Top End of the Northern Territory of Australia from 1 October 2009 to 30 September 2010 with the 540 cases in the preceding 20 years and postulate reasons for this year of very high melioidosis incidence. DESIGN, SETTING AND PARTICIPANTS: Review of prospectively collected data on all patients with culture-confirmed melioidosis at Royal Darwin Hospital, the Top End's tertiary referral centre, since 1 October 1989. MAIN OUTCOME MEASURES: Population-based annual incidence of melioidosis; differences in epidemiology, clinical presentations and outcomes for 2009-2010 compared with the preceding 20 years. RESULTS: In 2009-2010, the estimated population-based incidence of melioidosis was 50.2 cases per 100 000 in the Top End population overall, and 102.4 cases per 100 000 in the Top End Indigenous population. The proportion of patients acquiring melioidosis in the Darwin urban area increased from 49% in 1989-2009 to 65% in 2009-2010 (OR, 1.96; 95% CI, 1.20 3.19). Among the 49 Indigenous Australian patients with melioidosis in 2009-2010, 63% acquired the infection in Darwin, compared with 35% of Indigenous patients in the previous 20 years (OR, 3.17; 95% CI, 1.62-6.24). CONCLUSIONS: In 2009-2010, the Top End had the highest annual incidence of melioidosis documented from anywhere to date. The prominent increase in cases in Darwin was associated with above average rainfall in Darwin during December 2009 to February 2010. The increase in the proportion of Indigenous Australians who acquired melioidosis in Darwin may reflect movement of some Indigenous people into Darwin from remote communities. PMID- 22432676 TI - First report of human babesiosis in Australia. PMID- 22432677 TI - Challenges to Australia's national health policy from trade and investment agreements. PMID- 22432678 TI - Only the best: medical student selection in Australia. AB - Selection processes for medical schools need to be unbiased, valid, and psychometrically reliable, as well as evidence-based and transparent to all stakeholders. A range of academic and non-academic criteria are used for selection, including matriculation scores, aptitude tests and interviews. Research into selection is fraught with methodological difficulties; however, it shows positive benefits for structured selection processes. Pretest coaching and "faking good" are potential limitations of current selection procedures. Developments in medical school selection include the use of personality tests, centralised selection centres and programs to increase participation by socially disadvantaged students. PMID- 22432679 TI - Infectious diseases in the bigger picture. PMID- 22432681 TI - An overview of South African psychology. AB - This overview of psychology in South Africa presents a concise and historical account of its science and practice, from its early origins in the late nineteenth century to the present, and traces seminal influences on the discipline. It is a review of how psychology in South Africa developed over more than a century to become one of the most popular subjects in universities and an established and recognized profession, whose members play a variety of roles in the South African polity and larger society. The impact that apartheid racism had on key aspects of psychology's development is traversed, and the influences that previous ruling party politics had on professional psychological organizations are delineated. The unification of psychology under the Psychological Society of South Africa, a few months before the advent of democracy in South Africa, is explicated. The protection of the title of psychologist in law and certain other changes in the legislative environment, enabling a greater role for psychologists, are reported. The primary research sites for psychology and its funding and the main university psychology programs are described, as are the requirements for registration and licensure. The genesis and the importance of the work of internationally acclaimed South African psychologists, such as J. Wolpe and A. A. Lazarus, are contextualized. With the increased participation of progressive black psychologists in leadership and research in the past two decades, a transformed psychology has the potential to play a significant role in addressing human issues confronting South Africa. PMID- 22432682 TI - Pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors. AB - The increasing resistance to antibacterials commonly employed in the clinic and the growth of multidrug resistant strains suggest that the development of new therapeutic approaches should be of primary concern. In this context, EPIs may restore life to old drugs. In the present work, the EPI activity of the COX-2 inhibitor celecoxib was confirmed and a new class of pyrazolo[4,3 c][1,2]benzothiazine 5,5-dioxide analogues acting as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump was identified. PMID- 22432683 TI - Nephrogenic rest within a lipomyelomeningocele in a patient with unilateral renal agenesis. AB - Nephrogenic rests (NR) are foci of embryonal renal tissue that persist beyond the normal period of renal morphogenesis. They are commonly found in kidneys bearing Wilms tumor but may also rarely occur in different locations. Nephrogenic rests have been reported in the lumbosacral area in a total of nine cases, including our case. Of the nine cases, only one case prior to ours showed agenesis of one kidney in association with the NR. We report a 2-year-old female with a lipomyelomeningocele containing NRs and agenesis of the right kidney and discuss the molecular genetic basis of lumbosacral NR. PMID- 22432684 TI - Intentions to consume omega-3 fatty acids: a comparison of protection motivation theory and ordered protection motivation theory. AB - There has been limited research to date into methods for increasing people's intentions to use omega-3 polyunsaturated fatty acids (n-3 PUFA), which have been linked with decreased risk of suffering from numerous major diseases. The present study employed a cross-sectional design with 380 university students, employees, and visitors to investigate the efficacy of the protection motivation (PM) theory and the ordered protection motivation (OPM) theory, to predict behavioral intention to consume omega-3 rich foods and dietary supplements. Analysis of model fit indicated that both the PM model and the OPM model adequately represented the structural relationships between the cognitive variables and intention to consume n-3 PUFA. Further evaluation of relative fit of the two competing models suggested that the PM model might provide a better representation of decision-making following evaluation of the health threat of n 3 PUFA deficiency. Path analysis indicated that the component of coping appraisal was significantly associated with the behavioral intention to consume n-3 PUFA. Threat appraisal was found to be significantly associated with behavioral intention to consume n-3 PUFA only for the OPM model. Overall, the findings contribute to a better understanding of the roles that cognitive appraisal processes play in young and healthy individuals' protective health decision making regarding consumption of n-3 PUFA. Implications of the findings and recommendations, which include (a) encouraging the consumption of n-3 PUFA as an effective barrier against the incidence of disease, and (b) effective health messaging that focuses on beliefs about the effectiveness of n-3 PUFA in reducing health risks, are discussed. PMID- 22432685 TI - Quality of natural product clinical trials: a comparison of those published in alternative medicine versus conventional medicine journals. AB - OBJECTIVE: To compare the quality of natural product clinical trials published in alternative medicine journals versus those published in conventional medicine journals. DESIGN: Systematic search and review of the literature. Randomized controlled trials of natural products were included if they were published in English between 2003 and 2008. Articles were categorized by their journal of publication (alternative medicine versus conventional medicine). Two independent reviewers evaluated study quality using guidelines from the Cochrane Collaboration. The results with respect to the primary outcome (positive or negative) were also assessed. RESULTS: Thirty articles were evaluated, 15 published in alternative medicine journals and 15 in conventional medicine journals. Of articles published in alternative medicine journals, 33.33% (n = 5) were considered low quality, and none were considered high quality. Of articles published in conventional medicine journals, 26.67% (n = 4) were considered low quality and 6.67% (n = 1) were considered high quality. Two thirds of all trials reviewed were of unclear quality, due to inadequate reporting of information relating to the study's methodology. Similar proportions of positive and negative primary outcomes were found in alternative and conventional medicine journals, and low-quality articles were not more likely to report a positive primary outcome (Fisher's exact test, two-tailed p = .287). CONCLUSION: The quality of natural product randomized controlled trials was similar among alternative and conventional medicine journals. Efforts should be made to improve the reporting of natural product clinical trials for accurate determinations of study quality to be possible. PMID- 22432686 TI - Mitigation of DMBA-induced mammary carcinoma in experimental rats by antiangiogenic property of Kalpaamruthaa. AB - Extra cellular matrix (ECM) and basement membrane (BM) are important layers that regulate cell structure, cell migration, and cellular proliferation. Degradation of both ECM and BM mediated by proteases favors the tumor invasion and promotes angiogenesis. Female Sprague-Dawley rats weighing 180 +/- 10 g were categorized into 6 groups. Group-1 animals served as vehicle control. Group-2 to Group-4 animals were administered with 7,12-dimethylbenz(a)anthracene (25 mg/rat dissolved in olive oil, orally) on day 1 of experimental period to induce mammary carcinoma. (After 90 days, mammary carcinoma was confirmed by histopathological examination). Group-3 and Group-4 rats were subsequently treated with Semecarpus anacardium nut milk extract (SA) and Kalpaamruthaa (KA), respectively. Group-5 and Group-6 animals served as drug control for SA and KA, respectively. Pro angiogenic factors like proteases, cyclooxygenase-2, and vascular endothelial growth factor were elevated in tumor-bearing animals and decreased in SA- and KA supplemented rats. Increased levels of these angiogenic factors in tumor-bearing rats indicate the progression of mammary tumor. The decreased levels of these angiogenic in SA- and KA-treated rats may be due to the ameliorative effect of phenolic compounds such as flavonoids, tannins, and other compounds present in the drug. PMID- 22432687 TI - Cognitex supplementation in elderly adults with memory complaints: an uncontrolled open label trial. AB - BACKGROUND: The components of the nutritional supplement Cognitex have been individually shown to have beneficial effects on cognitive function. We evaluated the efficacy of the nutritional supplement in improving cognitive function in elderly with memory complaints. METHODS: Thirty participants received three capsules of the nutritional supplement per day for 12 weeks in an open label study. Efficacy and safety measures, assessed at baseline, 2 weeks, and 12 weeks of treatment, included cognitive evaluation using a computerized cognitive assessment tool, vital signs measurements, and physical examination. RESULTS: Twenty-six participants completed the 12-week study. A significant improvement in memory abilities (recall, recognition, and spatial short term) was observed following 2 weeks of Cognitex treatment (mean change from baseline: 11.15 +/- 2.90, 8.68 +/- 2.50, and 19.85 +/- 6.19, respectively). Attention (sustained and focused), visual learning, and activities of daily living (executive functions and mental flexibility) were improved as well following this short supplementation period (mean change from baseline: 9.46 +/- 3.80, 3.76 +/- 1.50, 17.31 +/- 5.33, 9.45 +/- 3.73, and 9.92 +/- 4.08, respectively). After 10 additional treatment weeks, activities of daily living demonstrated an additional statistically significant improvement while the beneficial effect observed for the rest of the tested parameters remained unchanged. CONCLUSIONS: The results indicate that the nutritional supplement may improve cognitive performance in elderly with memory complaints; however, further blinded and placebo-controlled studies are needed. TRIAL REGISTRATION: Clinicaltrials.gov, Identifier: NCT00719953. PMID- 22432688 TI - Soy protein extract (SPE) exhibits differential in vitro cell proliferation effects in oral cancer and normal cell lines. AB - Prior research has demonstrated that specific isoflavones derived from soy may exhibit antitumor effects against many cancers, including oral cancer. Most of this prior research involved isolation and testing of individual soy components, such as genistein, daidzein, and glycitein, which exhibit cytotoxicity against cancerous cells but may also have residual cytotoxic effects on normal cells. Few studies have evaluated whole soy extract, containing a combination of these isoflavones, and other bioreactive compounds, which may function synergistically and more effectively against oral cancers. This study compared the antiproliferative effects of whole soy protein extract (SPE) on CAL 27 and SCC25 oral cancer cell lines in vitro. Administration of SPE significantly inhibited oral cancer growth and exerted these effects at lower concentrations compared with another class of flavonoids (proanthocyanidins) that were previously tested on these cell lines. This SPE-induced growth inhibition correlated with down regulated mRNA expression in the oral cancer cell-cycle promoter ornithine decarboxylase (ODC), as well as upregulation of caspase-2 and caspase-8, initiators and effectors of apoptosis. These results suggest that SPE may represent a potential chemopreventive or chemotherapeutic option for oral cancer. Moreover, SPE may be more effective than other flavonoids currently used and may be effective at lower concentrations that approximate physiologic serum levels (0 2 MUmol/l). This study may help to explain why diets rich in fruits, vegetables, and soy protein are associated with protection against development and progression of oral cancers, although further study is needed to develop specific public health recommendations for oral cancer treatment and prevention. PMID- 22432689 TI - An evidence-based systematic review of senna (Cassia senna) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review, including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22432690 TI - In situ gel systems as 'smart' carriers for sustained ocular drug delivery. AB - INTRODUCTION: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol-gel conversion on receipt of biological stimulus. AREAS COVERED: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed. EXPERT OPINION: The advent of in situ gel systems has inaugurated a new transom for 'smart' ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization. PMID- 22432691 TI - Delivering bioactive molecules as instructive cues to engineered tissues. AB - INTRODUCTION: Growth factors and other bioactive molecules play a crucial role in the creation of functional engineered tissues from dissociated cells. AREAS COVERED: This review discusses the delivery of bioactive molecules - particularly growth factors - to affect cellular function in the context of tissue engineering. We discuss the primary biological themes that are addressed by delivering bioactives, the types of molecules that are to be delivered, the major materials used in producing scaffolds and/or drug delivery systems, and the principal drug delivery strategies. EXPERT OPINION: Drug delivery systems have allowed the sustained release of bioactive molecules to engineered tissues, with marked effects on tissue function. Sophisticated drug delivery techniques will allow precise recapitulation of developmental milestones by providing temporally distinct patterns of release of multiple bioactives. High-resolution patterning techniques will allow tissue constructs to be designed with precisely defined areas where bioactives can act. New biological discoveries, just as the development of small molecules with potent effects on cell differentiation, will likely have a marked impact on the field. PMID- 22432692 TI - Temporal trends of persistent organic pollutants: a comparison of different time series models. AB - We analyzed the vapor phase atmospheric concentrations of representative persistent chemicals (i.e., alpha- and gamma-hexachlorocyclohexane, phenanthrene, PCB-18 and PCB-52) in samples collected at a remote site near Eagle Harbor, Michigan, and at an urban site in Chicago, Illinois, using four time series models: a modified Clausius-Clapeyron equation, a multiple linear regression that includes both a linear and an harmonic dependence on time, digital filtration (DF), and dynamic harmonic regression (DHR). The results of these different models were evaluated in terms of goodness-of-fit, long-term trends, and halving times. The four approaches all provided highly significant descriptions of the data, with coefficients of determination (R(2)) ranging from 0.33 to 0.96. In general, the DF and DHR methods fit the data better, capturing not only the seasonal variations of the atmospheric concentrations but also smaller scale interannual variations in the long term trends. The halving times calculated using the four methods were generally similar to one another, and they ranged from about 4 years for gamma-HCH at Chicago to about 60 years for PCB-52 at Chicago. This analysis showed that each of these four statistical methods for evaluating long-term time series has advantages and disadvantages. The choice of the appropriate method should depend on the output needed, the type of audience, and the availability and usability of the necessary software. PMID- 22432693 TI - Five cases of pigmented paravenous retinochoroidal atrophy in dogs. AB - OBJECTIVE: To describe a funduscopic finding in dogs that is referred to as Pigmented Paravenous Retinochoroidal Atrophy (PPRCA). ANIMALS STUDIED: Over a period of 24 years of ophthalmological practice, five cases of a characteristic paravenous retinal atrophy were observed in dogs. PROCEDURES: A comprehensive clinical ophthalmological examination in all five dogs was complemented by abdominal sonography (cases 1, 3), clinical pathology analysis (cases 1, 3, 4), and a histological examination of both bulbi, kidneys, spleen, and liver in one dog (case 1). RESULTS: Localized hyper-reflectivity in the tapetal fundus was observed in all five dogs and demonstrated a characteristic perivascular distribution along some peripheral retinal blood vessels. In these areas, geographic copper-brown coloration that tended to become darker with time was seen. Ophthalmoscopic signs of inflammation were lacking. The funduscopic abnormalities slowly progressed in size over years. Visual impairment could not be detected. Histopathology in one dog revealed severe retinal atrophy with multifocal perivascular distribution, mainly affecting the tapetal fundus and occasionally expanding into the nontapetal fundus. CONCLUSIONS: The described retinal lesions bear similarities with PPRCA in humans. As in humans, it appears to be an incidental funduscopic finding that is not associated with obvious vision impairment. PMID- 22432694 TI - Augmentation of clozapine with another pharmacological agent: treatment for refractory schizophrenia in the 'real world'. AB - OBJECTIVE: Refractory schizophrenia (SZ) affects approximately 30% of people with SZ. Clozapine (CLZ) is the gold standard treatment; however, there are still patients who are non-responsive or partially responsive to treatment. Although a lack of evidence exists in reality, these patients are treated with a combination of agents in addition to CLZ. Therefore, this article reviews the prevalence of the augmentation of CLZ with additional agents. METHOD: This study was cross sectional; physicians in a region of Australia in May 2011 were contacted to provide details of their patients on CLZ and any additional agents. The data set consists of 84 patients. RESULTS: The majority of the patients 84.5% were taking at least one additional agent. Of those taking additional agents, they derived from the following classes' antipsychotics (72%), antidepressants (30%), mood stabilisers (17%), antimetabolic agents (13%), benzodiazepines (7%), anticholinergics (4%) and miscellaneous agents (12.5%). CONCLUSION: It is apparent that CLZ is routinely augmented with other agents despite the lack of an evidence base. However, concerning was the lack of augmentation with antimetabolic agents despite the paucity of literature reporting the detrimental impact of antipsychotic treatment upon patients metabolic indices. The findings are discussed in the context of the current recommendations and empirical literature. PMID- 22432695 TI - Incommensurate van der Waals epitaxy of nanowire arrays: a case study with ZnO on muscovite mica substrates. AB - The requirement of lattice matching between a material and its substrate for the growth of defect-free heteroepitaxial crystals can be circumvented with van der Waals epitaxy (vdWE). However, the utilization and characteristics of vdWE in nonlamellar/nonplanar nanoarchitectures are still not very well-documented. Here we establish the characteristics of vdWE in nanoarchitectures using a case study of ZnO nanowire (NW) array on muscovite mica substrate without any buffer/seed layer. With extensive characterizations involving electron microscopy, diffractometry, and the related analyses, we conclude that the NWs grown via vdWE exhibit an incommensurate epitaxy. The incommensurate vdWE allows a nearly complete lattice relaxation at the NW-substrate heterointerface without any defects, thus explaining the unnecessity of lattice matching for well crystallized epitaxial NWs on muscovite mica. We then determine the polarity of the NW via a direct visualization of Zn-O dumbbells using the annular bright field scanning transmission electron miscroscopy (ABF-STEM) in order to identify which atoms are at the base of the NWs and responsible for the van der Waals interactions. The information from the ABF-STEM is then used to construct the proper atomic arrangement at the heterointerface with a 3D atomic modeling to corroborate the characteristics of the incommensurate vdWE. Our findings suggest that the vdWE might be extended for a wider varieties of compounds and epitaxial nanoarchitectures to serve as a universal epitaxy strategy. PMID- 22432696 TI - The genetic influence on diverticular disease--a twin study. AB - BACKGROUND: The contribution of hereditary factors to the development of diverticular disease (DD) of the colon is unknown. Prevalence and location of diverticula differ in Western world compared to in Asia and several case reports describing families with DD have been published. AIM: To assess the heritability of DD in a large population-based sample of twins. METHODS: The Swedish Twin Registry was cross-linked to the Swedish Inpatient Registry. All twins, born between 1886 and 1980 and not dead before 1969, with a discharge diagnosis of DD were identified. Twins with diagnoses of colon cancer, coeliac disease or non infectious colitis were excluded to decrease bias. Co-twin odds ratio (OR), concordance rates and tetrachoric correlations were calculated for monozygotic (MZ) and same gender-dizygotic (SS-DZ) twins. Mx-analyses were used to estimate the relative contributions of genetic effects and environmental factors to susceptibility for DD. Calculations were based on both primary and secondary discharge diagnoses to provide estimates reflecting impact of severity of the disease. RESULTS: A total of 104,452 twins met the inclusion criteria. Of these, 2296 had a diagnosis of DD. The OR of developing the disease given one's co-twin was affected was 7.15 (95% CI: 4.82-10.61) for MZ and 3.20 (95% CI: 2.21-4.63) for SS-DZ twins. Similarly, concordance rates and tetrachoric correlations were higher in MZ than those in SS-DZ twins. The heritability was estimated to 40% and the non shared environmental effects to 60%. CONCLUSION: Genetic susceptibility is an important component, along with individual specific environmental factors, for the development of diverticular disease of the colon. PMID- 22432698 TI - Commentary on comparison of alcoholism subtypes as moderators of the response to sertraline treatment. PMID- 22432700 TI - Efficient singlet fission discovered in a disordered acene film. AB - Singlet exciton fission is a process that occurs in select organic semiconductors and entails the splitting of a singlet excited state into two lower triplet excitons located on adjacent chromophores. Research examining this phenomenon has recently seen a renaissance due to the potential to exploit singlet fission within the context of organic photovoltaics to prepare devices with the ability to circumvent the Shockley-Queisser limit. To date, high singlet fission yields have only been reported for crystalline or polycrystalline materials, suggesting that molecular disorder inhibits singlet fission. Here, we report the results of ultrafast transient absorption and time-resolved emission experiments performed on 5,12-diphenyl tetracene (DPT). Unlike tetracene, which tends to form polycrystalline films when vapor deposited, DPT's pendant phenyl groups frustrate crystal growth, yielding amorphous films. Despite the high level of disorder in these films, we find that DPT exhibits a surprisingly high singlet fission yield, with 1.22 triplets being created per excited singlet. This triplet production occurs over two principal time scales, with ~50% of the triplets appearing within 1 ps after photoexcitation followed by a slower phase of triplet growth over a few hundred picoseconds. To fit these kinetics, we have developed a model that assumes that due to molecular disorder, only a subset of DPT dimer pairs adopt configurations that promote fission. Singlet excitons directly excited at these sites can undergo fission rapidly, while singlet excitons created elsewhere in the film must diffuse to these sites to fission. PMID- 22432697 TI - Hydrogen sulfide in biochemistry and medicine. AB - SIGNIFICANCE: An abundance of experimental evidence suggests that hydrogen sulfide (H(2)S) plays a prominent role in physiology and pathophysiology. Many targets exist for H(2)S therapy. The molecular targets of H(2)S include proteins, enzymes, transcription factors, and membrane ion channels. RECENT ADVANCES: Novel H(2)S precursors are being synthesized and discovered that are capable of releasing H(2)S in a slow and sustained manner. This presents a novel and advantageous approach to H(2)S therapy for treatment of chronic conditions associated with a decline in endogenous H(2)S, such as diabetes and cardiovascular disease. CRITICAL ISSUES: While H(2)S is cytoprotective at physiological concentrations, it is not universally cytoprotective, as it appears to have pro-apoptotic actions in cancer cells and is well known to be toxic at supraphysiological concentrations. Many of the pleiotropic effects of H(2)S on health are associated with the inhibition of inflammation and upregulation of prosurvival pathways. The powerful anti-inflammatory, cytoprotective, immunomodulating, and trophic effects of H(2)S on the vast majority of normal cells seem to be mediated mainly by its actions as an extremely versatile direct and indirect antioxidant and free radical scavenger. While the overall effects of H(2)S on transformed (i.e., malignant) cells can be characterized as pro-oxidant and pro-apoptotic, they contrast sharply with the cytoprotective effects on most normal cells. FUTURE DIRECTIONS: H(2)S has become a molecule of great interest, and several slow-releasing H(2)S prodrugs are currently under development. We believe that additional agents regulating H(2)S bioavailability will be developed during the next 10 years. PMID- 22432701 TI - Biosynthesis of teichoic acids in Streptococcus pneumoniae and closely related species: lessons from genomes. AB - The cell wall of Streptococcus pneumoniae contains an unusually complex wall teichoic acid (WTA), which has identical repeating units as the membrane-anchored lipoteichoic acid (LTA). Both polymers share a common cytoplasmic pathway of precursor synthesis, but several TA enzymes have remained elusive. Bioinformatic analysis of the genome of various pneumococcal strains, including choline independent mutant strains, has allowed us to identify the missing TA genes. We present here the deduced complete pathways of WTA and LTA synthesis in S. pneumoniae and point to the variations occurring in different pneumococcal strains and in closely related species such as Streptococcus oralis and Streptococcus mitis. PMID- 22432702 TI - Peptidoglycan assembly machines: the biochemical evidence. AB - To make progress in understanding peptidoglycan metabolism, we will reconstitute in vitro the assembly process and the molecular machineries that carry out this formidable task. We review here the reports of isolation of complexes comprising penicillin-binding proteins (PBPs), the enzymes that synthesize the peptidoglycan from its lipid-linked precursor. PMID- 22432703 TI - The lytic transglycosylases of Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae encodes five lytic transglycosylases (LTs) in the core genome, and most gonococcal strains also carry the gonococcal genetic island that encodes one or two additional LTs. These peptidoglycan (PG)-degrading enzymes are required for a number of processes that are either involved in the normal growth of the bacteria or affect the pathogenesis and gene transfer aspects of this species that make N. gonorrhoeae highly inflammatory and highly genetically variable. Systematic mutagenesis determined that two LTs are involved in producing the 1,6-anhydro PG monomers that cause the death of ciliated cells in Fallopian tubes. Here, we review the information available on these enzymes and discuss their roles in bacterial growth, cell separation, autolysis, type IV secretion, and pathogenesis. PMID- 22432704 TI - Rga, a RofA-like regulator, is the major transcriptional activator of the PI-2a pilus in Streptococcus agalactiae. AB - Rapid adaptation to changing environments is key in determining the outcome of infections caused by the opportunistic human pathogen Streptococcus agalactiae. We previously demonstrated that the RofA-like protein (RALP) regulators RogB and Rga activate their downstream divergently transcribed genes, that is, the pilus operon PI-2a and the serine-rich repeat encoding gene srr1, respectively. Characterization of the Rga regulon by microarray revealed that the PI-2a pilus was strongly controlled by Rga, a result confirmed at the protein level. Complementation experiments showed that the expression of Rga, but not RogB, in the double DeltarogB/Deltarga mutant, or in the clinical strain 2603V/R displaying frameshift mutations in rogB and rga genes, is sufficient to restore wild-type expression levels of PI-2a pilus and Srr1. Biofilm formation was impaired in the Deltarga and Deltarga/rogB mutants and restored on complementation with rga. Paradoxically, adherence to intestinal epithelial cells was unchanged in the Deltarga mutant. Finally, the existence of several clinical isolates mutated in rga highlights the concept of strain-specific regulatory networks. PMID- 22432705 TI - Mammalian peptidoglycan recognition proteins kill bacteria by activating two component systems and modulate microbiome and inflammation. AB - Peptidoglycan recognition proteins (PGRPs) are conserved from insects to mammals and function in antibacterial immunity. We have revealed a novel mechanism of bacterial killing by innate immune system, in which mammalian PGRPs bind to bacterial cell wall or outer membrane and exploit bacterial stress defense response to kill bacteria. PGRPs enter Gram-positive cell wall at the site of daughter cell separation during cell division. In Bacillus subtilis PGRPs activate the CssR-CssS two-component system that detects and disposes of misfolded proteins exported out of bacterial cells. This activation results in membrane depolarization, production of hydroxyl radicals, and cessation of intracellular peptidoglycan, protein, RNA, and DNA synthesis, which are responsible for bacterial death. PGRPs also bind to the outer membrane in Escherichia coli and activate functionally homologous CpxA-CpxR two-component system, which also results in bacterial death. We excluded other potential bactericidal mechanisms, such as inhibition of extracellular peptidoglycan synthesis, hydrolysis of peptidoglycan, and membrane permeabilization. In vivo, mammalian PGRPs are expressed in polymorphonuclear leukocytes, skin, salivary glands, oral cavity, intestinal tract, eyes, and liver. They control acquisition and maintenance of beneficial normal gut microflora, which protects the host from enhanced inflammation, tissue damage, and colitis. PMID- 22432706 TI - Calcium-dependent complex formation between PBP2 and lytic transglycosylase SltB1 of Pseudomonas aeruginosa. AB - In Gram-negative bacteria, the bacterial cell wall biosynthetic mechanism requires the coordinated action of enzymes and structural proteins located in the cytoplasm, within the membrane, and in the periplasm of the cell. Its main component, peptidoglycan (PG), is essential for cell division and wall elongation. Penicillin-binding proteins (PBPs) catalyze the last steps of PG biosynthesis, namely the polymerization of glycan chains and the cross-linking of stem peptides, and can be either monofunctional or bifunctional. Their action is coordinated with that of other enzymes essential for cell-wall biosynthesis, such as lytic transglycosylases (LT). Here, we have studied SltB1, an LT from Pseudomonas aeruginosa, and identified that it forms a complex with PBP2, a monofunctional enzyme, which requires the presence of Ca(2+). In addition, we have solved the structure of SltB1 to a high resolution, and identified that it harbors an EF-hand like motif containing a Ca(2+) ion displaying bipyramidal coordination. These studies provide initial structural details that shed light on the interactions between the PG biosynthesis enzymes in P. aeruginosa. PMID- 22432707 TI - Novel chimerical endolysins with broad antimicrobial activity against methicillin resistant Staphylococcus aureus. AB - Due to their bacterial lytic action, bacteriophage endolysins have recently gained great attention as a potential alternative to antibiotics in the combat of Gram-positive pathogenic bacteria, particularly those displaying multidrug resistance. However, large-scale production and purification of endolysins is frequently impaired due to their low solubility. In addition, a large number of endolysins appear to exhibit reduced lytic efficacy when compared with their action during phage infection. Here, we took advantage of the high solubility of two recently characterized enterococcal endolysins to construct chimeras targeting Staphylococcus aureus. The putative cell wall binding domain of these endolysins was substituted by that of a staphylococcal endolysin that showed poor solubility. Under appropriate conditions the resulting chimeras presented the high solubility of the parental enterococcal endolysins. In addition, they proved to be broadly active against a collection of the most relevant methicillin resistant S. aureus epidemic clones and against other Gram-positive pathogens. Thus, fusion of endolysin domains of heterologous origin seems to be a suitable approach to design new potent endolysins with changed and/or extended lytic spectrum that are amenable to large-scale production. PMID- 22432708 TI - Interaction of type A lantibiotics with undecaprenol-bound cell envelope precursors. AB - Lantibiotics are a unique group within the antimicrobial peptides characterized by the presence of thioether amino acids (lanthionine and methyllanthionine). These peptides are produced by and primarily act on Gram-positive bacteria exerting multiple activities at the cytoplasmic membrane of susceptible strains. Previously, the cell wall precursor lipid II was identified as the molecular target for the prototype lantibiotic nisin. Binding and sequestration of lipid II blocks the incorporation of the central cell wall precursor into the growing peptidoglycan network, thereby inhibiting the formation of a functional cell wall. Additionally, nisin combines this activity with a unique target-mediated pore formation, using lipid II as a docking molecule. The interaction with the pyrophosphate moiety of lipid II is crucial for nisin binding. We show that, besides binding to lipid II, nisin interacts with the lipid intermediates lipid III (undecaprenol-pyrophosphate-N-acetyl-glucosamine) and lipid IV (undecaprenol pyrophosphate-N-acetyl-glucosamine-N-acetyl-mannosamine) of the wall teichoic acid (WTA) biosynthesis pathway. Binding of nisin to the precursors was observed at a stoichiometry of 2:1. The specific interaction with WTA precursors further promoted target-mediated pore formation in artificial lipid bilayers. Specific interactions with lipid III and lipid IV could also be demonstrated for related type A lantibiotics, for example, gallidermin, containing the conserved lipid-II binding motif. PMID- 22432709 TI - Characterization of colicin M and its orthologs targeting bacterial cell wall peptidoglycan biosynthesis. AB - For a long time, colicin M was known for killing susceptible Escherichia coli cells by interfering with cell wall peptidoglycan biosynthesis, but its precise mode of action was only recently elucidated: this bacterial toxin was demonstrated to be an enzyme that catalyzes the specific degradation of peptidoglycan lipid intermediate II, thereby provoking the arrest of peptidoglycan synthesis and cell lysis. The discovery of this activity renewed the interest in this colicin and opened the way for biochemical and structural analyses of this new class of enzyme (phosphoesterase). The identification of a few orthologs produced by pathogenic strains of Pseudomonas further enlarged the field of investigation. The present article aims at reviewing recently acquired knowledge on the biology of this small family of bacteriocins. PMID- 22432710 TI - The effect of bulgecin A on peptidoglycan metabolism and physiology of Helicobacter pylori. AB - Helicobacter pylori, a human-specific bacterial pathogen responsible for severe gastric diseases, constitutes a major public health issue. In the last decade, rates of H. pylori resistance to antibiotics were increasing drastically, requiring alternative therapeutic strategies to deal with eradication failures. Therefore, we evaluated the potential of bulgecin A, a glycosidic inhibitor of the lytic transglycosylase (LTG) Slt70 of Escherichia coli, as a new therapeutic approach against the H. pylori infection. In this study, we show that bulgecin A is able to specifically inactivate the H. pylori LTG Slt, but not its ortholog MltD. Moreover, bulgecin A synergized with amoxicillin, an inhibitor of penicillin binding proteins, inducing strong morphological alterations, cellular damages, and cell death. Similarly, the simultaneous inactivation of the peptidoglycan (PG) peptidase HdpA and Slt led to inhibition of H. pylori growth, highlighting the strong potential of targeting the PG biosynthetic pathway at different biochemical steps to enhance our therapeutic approaches against bacteria. Hence, we propose that bulgecin A constitutes an attractive compound for the development of new therapeutic strategies against H. pylori combined with other inhibitors of PG biosynthetic enzymes. PMID- 22432711 TI - Attachment of capsular polysaccharide to the cell wall in Streptococcus pneumoniae. AB - Streptococcus pneumoniae protects itself from components of the human immune defense system by a thick polysaccharide capsule, which in most serotypes is covalently attached to the cell wall peptidoglycan. Members of the LytR-Cps2A-Psr (LCP) protein family have recently been implicated in the attachment of anionic polymers to peptidoglycan in Gram-positive bacteria, based on genetic evidence from Bacillus subtilis mutant strains and on the crystal structure of S. pneumoniae Cps2A containing a tightly bound polyprenol (pyro)phosphate lipid. Here, we provide evidence that Cps2A and its two pneumococcal homologs, LytR and Psr, contribute to the maintenance of normal capsule levels and to the retention of the capsular polysaccharide at the cell wall in the capsular type 2 S. pneumoniae strain D39. GFP fusions of all three LCP proteins showed enhanced localization at mid-cell, indicating a role in cell wall growth. Single cps2A or psr mutants produced a reduced amount of capsule. A cps2A lytR double mutant showed greatly impaired growth and cell morphology and lost approximately half of the total capsule material into the culture supernatant. We also present the crystal structure of the B. subtilis LCP protein YwtF and provide crystallographic evidence for the phosphotransferase activity of Cps2A, supporting an enzymatic function in the attachment of capsular polysaccharides to cell wall peptidoglycan. PMID- 22432712 TI - Profound destructive effects of adolescent exposure to vincristine accompanied with some sex differences in motor and memory performance. AB - Vincristine, an anticancer drug, is known to induce neuronal cell damage. We have elucidated the alteration in performance of the hippocampus and cerebellum following chronic vincristine treatment (0.2 mg.(kg body mass)(-1).week(-1)) in male and female rats. Intraperitoneal injection of vincristine in adolescent rats caused impairment of motor and cognitive behavior. In the probe test, the length of path traveled and percent swimming time for vincristine-treated rats in the correct quadrant was significantly less than for the saline-treated (control) groups. The path length and time latency at the 2nd and 3rd blocks of trials for the male vincristine-treated group was significantly higher than that for the female saline- and the vincristine-treated rats. In the rod test, vincristine exposure impaired the motor coordination in both male and female rats. Exposure to vincristine caused a significant decrease in hanging time in male rats, compared with the saline- and the vincristine-treated female rats, while there were no differences between the female vincristine-treated rats and the saline treated rats of both sexes. The rearing frequency, total distance moved, and velocity for both male and female rats were dramatically affected by exposure to vincristine. We have observed that the hippocampal and cerebellar functions of male and female rats were profoundly affected by exposure to vincristine, especially the male rats, suggesting a sexual dimorphism in the developing central nervous system that is affected by chemicals such as anticancer drugs. PMID- 22432713 TI - Synthesis and pharmacological evaluation of dual acting antioxidant A(2A) adenosine receptor agonists. AB - A series of adenosine-5'-N-alkylcarboxamides and N(6)-(2,2 diphenylethyl)adenosine-5'-N-alkylcarboxamides bearing antioxidant moieties in the 2-position were synthesized from the versatile intermediate, O(6) (benzotriazol-1-yl)-2-fluoro-2',3'-O-isopropylideneinosine-5'-N-alkylcarboxamide (1). These compounds were evaluated as A(2A) adenosine receptor (A(2A)R) agonists in a cAMP accumulation assay, and a number of potent and selective agonists were identified. Three of these compounds were evaluated further in an ischemic injury cell survival assay and a reactive oxygen species (ROS) production assay whereby 15b and 15c were shown to reduce ROS activity and cell death due to ischemia. PMID- 22432714 TI - Biological control of bacterial wilt in Arabidopsis thaliana involves abscissic acid signalling. AB - Means to control bacterial wilt caused by the phytopathogenic root bacteria Ralstonia solanacearum are limited. Mutants in a large cluster of genes (hrp) involved in the pathogenicity of R. solanacearum were successfully used in a previous study as endophytic biocontrol agents in challenge inoculation experiments on tomato. However, the molecular mechanisms controlling this resistance remained unknown. We developed a protection assay using Arabidopsis thaliana as a model plant and analyzed the events underlying the biological control by genetic, transcriptomic and molecular approaches. High protection rates associated with a significant decrease in the multiplication of R. solanacearum were observed in plants pre-inoculated with a DeltahrpB mutant strain. Neither salicylic acid, nor jasmonic acid/ethylene played a role in the establishment of this resistance. Microarray analysis showed that 26% of the up regulated genes in protected plants are involved in the biosynthesis and signalling of abscissic acid (ABA). In addition 21% of these genes are constitutively expressed in the irregular xylem cellulose synthase mutants (irx), which present a high level of resistance to R. solanacearum. We propose that inoculation with the DeltahrpB mutant strain generates a hostile environment for subsequent plant colonization by a virulent strain of R. solanacearum. PMID- 22432715 TI - Modified donor lymphocyte infusion-associated acute graft-versus-host disease after haploidentical T-cell-replete hematopoietic stem cell transplantation: incidence and risk factors. AB - We performed a study to investigate the profile of donor lymphocyte infusion (DLI)-associated acute graft-versus-host disease (GVHD) in haploidentical T-cell replete hematopoietic stem cell transplantation (HSCT). A total of 124 patients receiving modified DLI after haploidentical T-cell-replete HSCT were enrolled. The cumulative incidence of DLI-associated acute GVHD was 53.2% for grades II-IV and 28.4% for grades III-IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI-associated grades III-IV acute GVHD (p<0.05). The cumulative incidence of grades III-IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p=0.018). Furthermore, DLI-associated grades III-IV acute GVHD was the only risk factor for overall survival (p=0.038, OR=2.869) and transplant-related mortality (p=0.018, OR=3.296) but not a risk factor for relapse after DLI (p=0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III-IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III IV acute GVHD. PMID- 22432716 TI - Neurofunctional treatment targeting participation among chronic stroke survivors: a pilot randomised controlled study. AB - Long-term disabilities are common among stroke survivors and are associated with reduced quality of life (QoL). Research on occupation-based intervention for chronic stroke survivors is sparse. The objective of this study was to examine the effectiveness of neurofunctional treatment (NFT), an occupation-based client centred treatment approach, for attaining individualised goals in chronic stroke survivors. A pilot randomised control study with a crossover design was employed. The participants were randomly allocated to treatment or control groups, with the intervention replicated for the control group after three months. Twenty three community dwelling stroke survivors, at least one year post-stroke attending a community day centre participated in this study. The 12-week intervention included NFT with individualised occupational goal setting. The treatment methods included task-specific training, environmental or task adaptation, assistive devices, motivation recruitment, and advocacy. Significant differences between the groups were found on occupational performance measures, but not on QoL. These findings were replicated after crossover for the control group. The results support the efficacy of NFT for attaining occupational goals in individuals in the chronic stage after stroke, yet further research is needed to validate these findings in additional treatment settings and over time. PMID- 22432717 TI - Spectral-domain optical coherence tomography in lightning-induced maculopathy. AB - The authors report a case of lightning-induced chorioretinal burn accompanied by mild anterior segment injuries. Spectral-domain optical coherence tomography images were used to document the progressive retinal and choroidal changes. As evidenced by this report, despite being sight-threatening, such injuries may allow for a significant functional recovery. PMID- 22432718 TI - Application of advanced in silico methods for predictive modeling and information integration. AB - INTRODUCTION: In silico predictive methods are well-known tools to the drug discovery process. In recent years, these tools have become of strategic interest to regulatory authorities to support risk-based approaches and to complement, and potentially strengthen evidence when considering product quality and safety of human pharmaceuticals. AREAS COVERED: This editorial reviews how chemically intelligent systems and computational models using structure-based assessments are important for providing predictive data on drug toxicity and safety liabilities considered at the FDA. The example of regulatory interest in application of in silico systems for mutagenicity predictions of drug impurities is discussed. EXPERT OPINION: The importance of information integration is emphasized toward the application of in silico predictive methods and enhancing data mining capabilities for safety signal detection. Modeling for cardiovascular drug safety based on human clinical trial data is one area of active testing of predictive technologies at the FDA. The FDA has taken appropriate steps in its strategies and initiatives aimed to enhance and support innovation for regulatory science and medical product development by developing and implementing the use of in silico predictive models and medical toxicity databases. This science priority area will ultimately help improve and protect public health. PMID- 22432719 TI - Low-energy states of manganese-oxo corrole and corrolazine: multiconfiguration reference ab initio calculations. AB - Manganese(V)-oxo corrole and corrolazine have been studied with ab initio multiconfiguration reference methods (CASPT2 and RASPT2) and large atomic natural orbital (ANO) basis sets. The calculations confirm the expected singlet d(delta)(2) ground states for both complexes and rule out excited states within 0.5 eV of the ground states. The lowest excited states are a pair of Mn(V) triplet states with d(delta)(1)d(pi)(1) configurations 0.5-0.75 eV above the ground state. Manganese(IV)-oxo macrocycle radical states are much higher in energy, >=1.0 eV relative to the ground state. The macrocyclic ligands in the ground states of the complexes are thus unambiguously 'innocent'. The approximate similarity of the spin state energetics of the corrole and corrolazine complexes suggests that the latter macrocycle on its own does not afford any special stabilization for the Mn(V)O center. The remarkable stability of an Mn(V)O octaarylcorrolazine thus appears to be ascribable to the steric protection afforded by the beta-aryl groups. PMID- 22432720 TI - Miscellaneous vitreous-derived IgM antibodies target numerous retinal proteins in equine recurrent uveitis. AB - OBJECTIVE: In equine recurrent uveitis (ERU), immune reactions are directed toward known antigens like S-antigen, interphotoreceptor retinoid-binding protein, and cellular retinalaldehyde-binding protein, and anti-retinal antibodies were detected in vitreous samples. The aim of this study was the investigation of intraocular immunoglobulin M (IgM) reactivities to retinal proteome. PROCEDURES: Retina was separated by one- and two-dimensional gel electrophoresis and blotted semidry on PVDF membranes. To identify intraocular IgM antibody responses to retinal tissue, blots were incubated with vitreous samples of ERU-diseased horses (n = 50) and healthy controls (n = 30), followed by an HRP-labeled secondary antibody specific for equine IgM. Noticeable 2D western blot signals were aligned on a 2D gel of retinal proteome, excised, and subsequently identified by tandem mass spectrometry. RESULTS: Interestingly, frequent and very miscellaneous IgM response patterns to the retinal proteome in 68% of ERU vitreous samples were detected. Binding of IgM antibodies was localized at 17 different molecular weights. The most frequently detected signal, in 21 of the 50 samples, was located at 49 kDa. Comparing the samples interindividually between one and up to nine different signals in one sample could be observed. All healthy vitreous samples were devoid of IgM antibodies. Analysis of targeted spots with mass spectrometry led to the clear identification of 11 different proteins (corresponding to 16 different spots). One candidate could not be discovered so far. CONCLUSION: The considerable IgM response to retinal proteins demonstrates an ongoing immune response, which might contribute to the remitting relapsing character of ERU. Novel identified target proteins point to a diverse response pattern of individual ERU cases. PMID- 22432721 TI - Foreskin analysis of circumcised boys with and without previous topical corticosteroid. AB - Problems with the foreskin are common reasons for pediatric surgery consultations. We collected the foreskin of 40 patients for 2 years and these samples were divided into groups with and without previous topical corticosteroid. We carried out histochemical hematoxylin & eosin and Picrosirius analyses of the foreskin. Collagen fibers and inflammatory infiltrate was higher in samples from patients who had complications related to phimosis. Fibrosis was higher in patients who used topical corticosteroid. A histopathologic study of the foreskin may provide an additional analysis of patients undergoing circumcision and it can also improve the accuracy of surgical indication. PMID- 22432722 TI - Complementary proteomic tools for the dissection of apoptotic proteolysis events. AB - Proteolysis is a key regulatory event that controls intracellular and extracellular signaling through irreversible changes in a protein's structure that greatly alters its function. Here we describe a platform for profiling caspase substrates which encompasses two highly complementary proteomic techniques--the first is a differential gel based approach termed Global Analyzer of SILAC-derived Substrates of Proteolysis (GASSP) and the second involves affinity enrichment of peptides containing a C-terminal aspartic acid residue. In combination, these techniques have enabled the profiling of a large cellular pool of apoptotic-mediated proteolytic events across a wide dynamic range. By applying this integrated proteomic work flow to analyze proteolytic events resulting from the induction of intrinsic apoptosis in Jurkat cells via etoposide treatment, 3346 proteins were quantified, of which 360 proteins were identified as etoposide induced proteolytic substrates, including 160 previously assigned caspase substrates. In addition to global profiling, a targeted approach using BAX HCT116 isogenic cell lines was utilized to dissect pre- and post-mitochondrial extrinsic apoptotic cleavage events. By employing apoptotic activation with a pro-apoptotic receptor agonist (PARA), a limited set of apoptotic substrates including known caspase substrates such as BH3 interacting-domain death agonist (BID) and Poly (ADP-ribose) polymerase (PARP)-1, and novel substrates such as Basic Transcription Factor 3, TRK-fused gene protein (TFG), and p62/Sequestosome were also identified. PMID- 22432723 TI - Asymmetric synthesis and absolute configuration of streptophenazine G. AB - The asymmetric synthesis of the antibacterial natural product, streptophenazine G, has been achieved by employing asymmetric alkylation and asymmetric aldol reactions using chiral oxazolidinones as the key steps. The originally proposed structure for streptophenazine G has been revised, and its absolute configuration has been determined to be 1'S,2'R,6'S. The asymmetric total synthesis of 6'-epi streptophenazine G is also described. PMID- 22432724 TI - Focus: diabetes. PMID- 22432725 TI - An open-label study on the effect of flax seed powder (Linum usitatissimum) supplementation in the management of diabetes mellitus. AB - Diabetes mellitus is characterized by hyperglycemia and associated with aberrations in the metabolism of carbohydrate, protein, and lipid that result in development of secondary complications. Extensive studies have indicated that nutritional therapy plays a pivotal role in the controlling or postponing of development of these secondary complications. Several functional foods have been shown to possess hypoglycemic and hypolipidemic properties. Flax seed (FS) is a functional food that is rich in omega 3 fatty acids and antioxidants and is low in carbohydrates. In exploratory studies, FS was incorporated in recipes, which resulted in a reduction in the glycemic index of the food items. These observations prompted us to investigate the efficacy of FS supplementation in type 2 diabetics (n = 29). Subjects were assigned to the experimental (n = 18) or the control group (n = 11) on the basis of their desire to participate in the study. The experimental group's diet was supplemented daily with 10 g of FS powder for a period of 1 month. The control group received no supplementation or placebo. During the study, diet and drug intake of the subjects remained unaltered. The efficacy of supplementation with FS was evaluated through a battery of clinico-biochemical parameters. Supplementation with FS reduced fasting blood glucose by 19.7% and glycated hemoglobin by 15.6%. A favorable reduction in total cholesterol (14.3%), triglycerides (17.5%), low-density lipoprotein cholesterol (21.8%), and apolipoprotein B and an increase in high density lipoprotein cholesterol (11.9%) were also noticed. These observations suggest the therapeutic potential of FS in the management of diabetes mellitus. PMID- 22432726 TI - Natural antidiabetic compound for the therapeutic management of diabetes mellitus and its drug delivery system. AB - A single tablet dosage form containing the freeze-dried aqueous leaf extract of Vernonia amygdalina (AD1), suitable for use in the therapeutic management of diabetes mellitus, has been developed. The compaction characteristics of the extract were studied using the Heckel equation. The mechanical properties as well as disintegration and dissolution profile of the compacts were also assessed. The results showed that AD1 exhibited very low densification due to dye filling and addition of filler-binders contributed significantly to their subsequent densification. The tablets produced had good mechanical properties. Of the three filler-binders tested, tablets containing Avicel had the shortest disintegration time of about 5 min, while tablets without any filler-binder had the longest disintegration time of 50 min. Dissolution results (T(90%)) showed that tablets containing Avicel released 100% of the extract in less than 15 min proving to be the most suitable in acute diabetes. The order of dissolution is Avicel > maize starch > lactose > extract. It is concluded that incorporation of Avicel as a filler-binder in AD1 preparation produced tablets of suitable compaction properties and ensured adequate drug release for the therapeutic management of diabetes mellitus. PMID- 22432727 TI - Hydrolyzed casein decreases postprandial glucose concentrations in T2DM patients irrespective of leucine content. AB - Lifestyle modifications, including diet, are important in the prevention and management of type 2 diabetes mellitus (T2DM). However, limited information is available on the effects of single doses of meal replacements, particularly with regard to their effect on postprandial glucose. Therefore, a study was performed comparing the effects of a single meal replacement in T2DM patients on postprandial serum glucose, insulin, and glucagon. This randomized, double-blind, partial cross-over study was performed in 36 T2DM patients who continued their oral anti-diabetic medication. Each patient received three out of four treatments separated by 7 days. The treatments were a proprietary casein hydrolysate (insuVidaTM) alone or with additional leucine, unhydrolyzed casein, or placebo. Blood sampling was done for 4 hr. Treatments were compared using repeated measures ANOVA. Results are given as an estimate of the difference (%) for the 4 hr epoch. Glucose concentrations were lowered by -4.7% by insuVida and insuVida plus added leucine compared to placebo (95% CI: -1.6 to -7.7%), while the effect of unhydrolyzed casein was -1.7% (-4.8 to 1.5%). Addition of leucine to insuVida induced the greatest increase in insulin (i.e., 51.8%; 41.1 to 63.4%). All three treatments increased glucagon concentrations by 14% (8 to 20%) compared to placebo. A single dose of insuVidaTM with or without addition of leucine significantly lowered plasma glucose compared to placebo and intact casein in T2DM patients. This is most likely due to an insulinotropic effect of insuVida. The data suggest that this type of intervention may be a viable treatment strategy in T2DM. PMID- 22432728 TI - Investigation of optimum roasting conditions to obtain possible health benefit supplement, antioxidants from coffee beans. AB - In order to investigate the role of roasting conditions in antioxidant formation, methanol and hot water extracts from Robusta coffee beans roasted for various lengths of time and at various temperatures were analyzed for total phenolic acid, chlorogenic acid, and caffeine content, as well as for their antioxidant activities using 1,1-diphenyl-2-picryhydrazyl (DPPH), thiobarbituric acid (TBA), and malonaldehyde/gas chromatography (MA/GC) assays. The amount of total phenolics in methanol extracts decreased linearly over the roasting temperature from 63.51 +/- 0.77 mg chlorogenic acid equivalent (CAE)/g coffee beans (roasted at 200 degrees C) to 42.56 +/- 0.33 mg CAE/g coffee beans (roasted at 240 degrees C). The total chlorogenic acid content decreased when the roasting time was increased from 78.33 +/- 1.41 mg/g (green coffee beans) to 4.31 +/- 0.23 mg/g (roasted for 16 min at 250 degrees C). All methanol extracts from roasted coffee beans possessed over 90% antioxidant activities in the DPPH assay. The antioxidant activity of methanol extracts ranged from 41.38 +/- 1.77% (roasted at 250 degrees C for 10 min) to 98.20 +/- 1.49% (roasted at 230 degrees C for 16 min) as tested by the TBA assay. The antioxidant activity of methanol extracts of green coffee beans and roasted coffee beans ranged from 93.01% (green coffee beans) to 98.62 +/- 1.32% (roasted at 250 degrees C for 14 min) in the MA/GC assays. All hot water extracts exhibited moderate pro-oxidant activities in TBA and MA/GC assays. The results indicated that roasting conditions of coffee beans play an important role in the formation of antioxidants in brewed coffee, which can be dietary supplements having beneficial effect to human health. PMID- 22432729 TI - An evidence-based systematic review of gymnema (Gymnema sylvestre R. Br.) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review of gymnema (Gymnema sylvestre R. Br.), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22432730 TI - Who gives a tweet: assessing patients' interest in the use of social media for health care. AB - BACKGROUND: Social media (SoMe) use is quickly accelerating in healthcare delivery. Evidence-based SoMe use may improve patient engagement and communication, leading to better outcomes. AIM: To assess patient use of and preferences regarding SoMe in their health care. METHODS: A descriptive survey was conducted using an 11-item questionnaire that was completed by 111 patients at an outpatient family practice clinic in Southern Utah, USA. Age, gender, health status, current or future SoMe use, provider use of SoMe, perceived barriers, and health mobile application use was assessed. RESULTS: Eighty three percent of respondents used some form of SoMe. Fifty six percent of the participants wanted providers to use SoMe. Gender or health status did not affect SoMe attitudes or use, however, use varied with age. Patients wanted providers to use SoMe for appointment setting and reminders, reporting diagnostic test results, prescription notifications, providing health information, and as a forum for asking general questions. Among those who did not use SoMe, 41.6% would consider using it if their healthcare provider used it. E-mail and mobile telephones were the preferred communication mode. Privacy and confidentiality concerns were the most frequently cited barriers (48%) when considering the use of SoMe. DISCUSSION AND IMPLICATIONS: This study indicates growing patient acceptance of SoMe in health care. Understanding user profiles, preferences, and barriers can help providers in prioritizing where to direct efforts when using evidence-based SoMe in their practice. PMID- 22432731 TI - Remotely activated protein-producing nanoparticles. AB - The development of responsive nanomaterials, nanoscale systems that actively respond to stimuli, is one general goal of nanotechnology. Here we develop nanoparticles that can be controllably triggered to synthesize proteins. The nanoparticles consist of lipid vesicles filled with the cellular machinery responsible for transcription and translation, including amino acids, ribosomes, and DNA caged with a photolabile protecting group. These particles served as nanofactories capable of producing proteins including green fluorescent protein (GFP) and enzymatically active luciferase. In vitro and in vivo, protein synthesis was spatially and temporally controllable, and could be initiated by irradiating micrometer-scale regions on the time scale of milliseconds. The ability to control protein synthesis inside nanomaterials may enable new strategies to facilitate the study of orthogonal proteins in a confined environment and for remotely activated drug delivery. PMID- 22432732 TI - Antibody-independent B cell effector functions in relapsing remitting multiple sclerosis: clues to increased inflammatory and reduced regulatory B cell capacity. AB - The pathogenic role for B cells in the context of relapsing remitting multiple sclerosis (MS) is incompletely defined. Although classically considered a T cell mediated disease, B cell-depleting therapies showed efficacy in treating the clinical symptoms of RRMS without decreasing plasma cells or total immunoglobulin (Ig) levels. Here, we discuss the potential implications of antibody-independent B cell effector functions that could contribute to autoimmunity with particular focus on antigen presentation, cytokine secretion, and stimulation of T cell subsets. We highlight differences between memory and naive B cells from MS patients such as our recent findings of hyper-proliferation from MS memory B cells in response to CD40 engagement. We discuss the implications of IL6 overproduction in contrast to limited IL10 production by B cells from MS patients and comment on the impact of these functions on yet unexplored aspects of B cells in autoimmune disease. Finally, we contextualize B cell effector functions with respect to current immunomodulatory therapies for MS and show that glatiramer acetate (GA) does not directly modulate B cell proliferation or cytokine secretion. PMID- 22432733 TI - Systematic review: the role of liver transplantation in the management of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage. AIM: To review systematically the role of liver transplantation in the management of HCC in current clinical practice. METHODS: An electronic literature search using PUBMED (1980-2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation. RESULTS: Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour <=50 mm in diameter or <=3 tumours <=30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important. CONCLUSIONS: Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy. PMID- 22432735 TI - Hybrid rylene arrays via combination of Stille coupling and C-H transformation as high-performance electron transport materials. AB - Hybrid rylene arrays have been prepared via a combination of Stille coupling and C-H transformation. The ability to extend the pi system along the equatorial axis of rylenes not only leads to broadened light absorption but also increases the electron affinity, which can facilitate electron injection and transport with ambient stability. PMID- 22432736 TI - Falcarindiol allosterically modulates GABAergic currents in cultured rat hippocampal neurons. AB - Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABA(A) receptor (GABA(A)R) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1 significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 MUM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1 upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1 exerts a potent modulatory action on GABA(A)Rs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co occurring GABA-inhibiting convulsant toxins. PMID- 22432737 TI - Radioprotective effect of Curcuma longa extract on gamma-irradiation-induced oxidative stress in rats. AB - This study was conducted to evaluate the modulatory effect of aqueous extract of Curcuma longa (L.) against gamma-irradiation (GR), which induces biochemical disorders in male rats. The sublethal dose of GR was determined in primary hepatocytes. Also, the effect of C. longa extract was examined for its activity against GR. In rats, C. longa extract was administered daily (200 mg/kg body mass) for 21 days before, and 7 days after GR exposure (6.5 Gy). The lipid profile and antioxidant status, as well as levels of transaminases, interleukin-6 (IL-6), and tumour necrosis factor alpha (TNFalpha) were assessed. The results showed that in hepatocytes, the aqueous extract exhibited radioprotective activity against exposure to GR. Exposure of untreated rats to GR resulted in transaminase disorders, lipid abnormalities, elevation of lipid peroxidation, trace element alterations, release of IL-6 and TNF, and decrease in glutathione and protein level of superoxide dismutase-1 (SOD-1) and peroxiredoxin-1 (PRDX-1). However, treatment of rats with this extract before and after GR exposure improved antioxidant status and minimized the radiation-induced increase in inflammatory cytokines. Changes occurred in the tissue levels of trace elements, and the protein levels of SOD-1 and PRDX-1 were also modulated by C. longa extract. Overall, C. longa exerted a beneficial radioprotective effect against radiation-induced oxidative stress in male rats by alleviating pathological disorders and modulating antioxidant enzymes. PMID- 22432738 TI - Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. AB - The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors. Furthermore, the data presented here provide rationale for further clinical development of delanzomib. PMID- 22432739 TI - Multicenter experience with transvenous lead extraction of active fixation coronary sinus leads. AB - BACKGROUND/OBJECTIVE: Active fixation coronary sinus (CS) leads limit dislodgement and represent an attractive option to the implanter. Although extraction of passive fixation CS leads is a common and frequently uncomplicated procedure, data regarding extraction of chronically implanted active fixation CS leads are limited. METHODS: We performed a retrospective cohort study of patients undergoing active fixation CS lead extraction at six centers. Patient and procedural characteristics, indications for extraction, use of extraction sheath (ES) assistance, and outcomes are reported. RESULTS: Between January 2009 and February 2011, 12 patients underwent transvenous lead extraction (TLE) of Medtronic StarFix(r) lead (Medtronic Inc., Minneapolis, MN, USA). The cohort was 83% male with mean age 71 +/- 14 years. Average implant duration was 14.2 +/- 5.7 months (2.3-23.6). All leads but one were removed for infectious indications (67% systemic infection). At the time of explant, the fixation lobes were completely retracted in only one of the 12 cases and ES assistance was required for lead removal in all cases (58% laser, 25% cutting, 25% mechanical, and 25% femoral). The majority of cases required advancement of the sheath into the CS (75.0%) and often into a branch vessel (41.7%). One lead could not be removed transvenously and required surgical lead extraction. There were no major complications. Examination of the leads after extraction frequently revealed significant tissue growth into the fixation lobes. CONCLUSIONS: Although TLE of active fixation CS leads can be a safe procedure in select patients and experienced hands, powered sheaths and aggressive techniques are frequently required for successful removal despite relatively short implant durations. This raises significant concern regarding future TLE of active fixation CS leads with longer implant durations. PMID- 22432740 TI - Kinetically competing huntingtin aggregation pathways control amyloid polymorphism and properties. AB - In polyglutamine (polyQ) containing fragments of the Huntington's disease protein huntingtin (htt), the N-terminal 17 amino acid htt(NT) segment serves as the core of alpha-helical oligomers whose reversible assembly locally concentrates the polyQ segments, thereby facilitating polyQ amyloid nucleation. A variety of aggregation inhibitors have been described that achieve their effects by neutralizing this concentrating function of the htt(NT) segment. In this paper we characterize the nature and limits of this inhibition for three means of suppressing htt(NT)-mediated aggregation. We show that the previously described action of htt(NT) peptide-based inhibitors is solely due to their ability to suppress the htt(NT)-mediated aggregation pathway. That is, under htt(NT) inhibition, nucleation of polyQ amyloid formation by a previously described alternative nucleation mechanism proceeds unabated and transiently dominates the aggregation process. Removal of the bulk of the htt(NT) segment by proteolysis or mutagenesis also blocks the htt(NT)-mediated pathway, allowing the alternative nucleation pathway to dominate. In contrast, the previously described immunoglobulin-based inhibitor, the antihtt(NT) V(L) 12.3 protein, effectively blocks both amyloid pathways, leading to stable accumulation of nonamyloid oligomers. These data show that the htt(NT)-dependent and -independent pathways of amyloid nucleation in polyQ-containing htt fragments are in direct kinetic competition. The results illustrate how amyloid polymorphism depends on assembly mechanism and kinetics and have implications for how the intracellular environment can influence aggregation pathways. PMID- 22432741 TI - Out of the Qinghai-Tibet Plateau: evidence for the origin and dispersal of Eurasian temperate plants from a phylogeographic study of Hippophae rhamnoides (Elaeagnaceae). AB - Numerous temperate plants now distributed across Eurasia are hypothesized to have originated and migrated from the Qinghai-Tibet Plateau (QTP) and adjacent regions. However, this hypothesis has never been tested through a phylogeographic analysis of a widely distributed species. Here, we use Hippophae rhamnoides as a model to test this hypothesis. We collected 635 individuals from 63 populations of the nine subspecies of H. rhamnoides. We sequenced two maternally inherited chloroplast (cp) DNA fragments and also the bi-paternally inherited nuclear ribosomal ITS. We recovered five major clades in phylogenetic trees constructed from cpDNA and internal transcribed spacer (ITS) sequence variation. Most sampled individuals of six subspecies that are distributed in northern China, central Asia and Asia Minor/Europe, respectively, comprised monophyletic clades (or subclades) nested within those found in the QTP. Two subspecies in the QTP were paraphyletic, while the placement of another subspecies from the Mongolian Plateau differed between the ITS and cpDNA phylogenetic trees. Our phylogeographic analyses supported an 'out-of-QTP' hypothesis for H. rhamnoides followed by allopatric divergence, hybridization and introgression. These findings highlight the complexity of intraspecific evolutions and the importance of the QTP as a center of origin for many temperate plants. PMID- 22432742 TI - Impact of rifaximin use for hepatic encephalopathy on the risk of early post transplant infections in liver transplant recipients. AB - BACKGROUND: Whether the use of rifaximin for hepatic encephalopathy during liver transplant candidacy has an impact on post-transplant infections is not known. METHODS: We compared the frequency and spectrum of infections within 90 d post transplant in liver transplant recipients who did and did not receive rifaximin for hepatic encephalopathy during transplant candidacy. RESULTS: Of 110 consecutive liver transplant recipients, 30 (27%) received rifaximin. Rifaximin users were more severely ill based on higher Model for End-Stage Liver Disease (MELD) score (p=0.005). When controlled for MELD (stratified by MELD<30, MELD>=30), the risk of infections was significantly lower in rifaximin vs. no rifaximin recipients (OR=0.269, 95% CI 0.078-0.0.934, p=0.026). Rifaximin use was not associated with a higher risk of multidrug resistant bacterial infections (OR=1.8, 95% CI 0.42-8.35, p=0.40). The probability of post-transplant survival at 90 d did not differ for patients with or without rifaximin use (0.90 for both groups, p=0.56). CONCLUSIONS: Rifaximin appeared to have a protective effect against early post-transplant infections in more severely ill liver transplant recipients. Rifaximin use did not select for multidrug resistant bacteria in these patients. PMID- 22432743 TI - Group intervention in pediatric rehabilitation. PMID- 22432744 TI - Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. AB - BACKGROUND AND AIM: Steatosis accentuates the severity of hepatic ischemia reperfusion injury (IRI). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") protect the heart and brain against post-ischemic injury, without necessarily lowering serum cholesterol. We tested whether 10-day or 1-day atorvastatin administration protects livers with fatty change or non-alcoholic steatohepatitis (NASH) against IRI. METHODS: Mice with dietary or genetic simple steatosis (SS) or NASH were subjected to 60 min of partial hepatic ischemia/24-h reperfusion, with/without atorvastatin administered with food (5 mg/kg body weight) for 10 days, or injected intravenously (5 mg/kg) 24 h before ischemia. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, endothelial nitric oxide synthase (eNOS), activation and thromboxane B2 production were determined. RESULTS: Atorvastatin conferred 70-90% hepatic protection against IRI in obese animals with SS or NASH, in which IRI was accentuated twofold to fivefold. IRI markedly upregulated TLR4 and activated nuclear factor-kappaB (NF kappaB); atorvastatin abrogated these effects, as well as activating eNOS. Atorvastatin dampened the post-ischemic induction of thromboxane B2, macrophage inflammatory protein-1a, monocyte chemotactic protein-1, tumor necrosis factor alpha, interleukin (IL)-12 p40, gamma-interferon, IL-6, and adhesion molecules (vascular cell adhesion molecule-1, E-selectin, vascular endothelial-cadherin), and reduced macrophage and neutrophil recruitment. There was no reduction in serum cholesterol that could explain these effects, and hepatic cholesterol was normal in these mice. A single 24-h injection of atorvastatin conferred equivalent hepatoprotection. CONCLUSION: Statins exert major hepatoprotection against IRI in lean, fatty, and NASH livers that is not due to cholesterol removal. Rather, statins downregulate TLR4 to prevent NF-kappaB activation, with resultant suppression of adhesion molecules, chemokines/cytokines, and thromboxane B2 production. Short-term statin treatment is an effective, readily available preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease. PMID- 22432746 TI - Guideline for the management of acute sore throat. AB - The European Society for Clinical Microbiology and Infectious Diseases established the Sore Throat Guideline Group to write an updated guideline to diagnose and treat patients with acute sore throat. In diagnosis, Centor clinical scoring system or rapid antigen test can be helpful in targeting antibiotic use. The Centor scoring system can help to identify those patients who have higher likelihood of group A streptococcal infection. In patients with high likelihood of streptococcal infections (e.g. 3-4 Centor criteria) physicians can consider the use of rapid antigen test (RAT). If RAT is performed, throat culture is not necessary after a negative RAT for the diagnosis of group A streptococci. To treat sore throat, either ibuprofen or paracetamol are recommended for relief of acute sore throat symptoms. Zinc gluconate is not recommended to be used in sore throat. There is inconsistent evidence of herbal treatments and acupuncture as treatments for sore throat. Antibiotics should not be used in patients with less severe presentation of sore throat, e.g. 0-2 Centor criteria to relieve symptoms. Modest benefits of antibiotics, which have been observed in patients with 3-4 Centor criteria, have to be weighed against side effects, the effect of antibiotics on microbiota, increased antibacterial resistance, medicalisation and costs. The prevention of suppurative complications is not a specific indication for antibiotic therapy in sore throat. If antibiotics are indicated, penicillin V, twice or three times daily for 10 days is recommended. At the present, there is no evidence enough that indicates shorter treatment length. PMID- 22432747 TI - Kaposiform hemangioendothelioma in the uterine cervix of a 5-year girl. AB - The occurrence of the vascular tumors in the female genital tract, particularly in the uterine cervix, is extremely rare. This kind of tumor has mainly been reported as either cavernous hemangiomas or capillary hemangiomas. To date, no Kaposiform hemangioendothelioma has been reported in this site. Here we presented a case of Kaposiform hemangioendothelioma without Kasabach-Merritt syndrome in the cervix of a 5-year-old girl. PMID- 22432748 TI - Spin delocalization over type zero copper. AB - Hard-ligand, high-potential copper sites have been characterized in double mutants of Pseudomonas aeruginosa azurin (C112D/M121X (X = L, F, I)). These sites feature a small A(zz)(Cu) splitting in the EPR spectrum together with enhanced electron transfer activity. Due to these unique properties, these constructs have been called "type zero" copper sites. In contrast, the single mutant, C112D, features a large A(zz)(Cu) value characteristic of the typical type 2 Cu(II). In general, A(zz)(Cu) comprises contributions from Fermi contact, spin dipolar, and orbital dipolar terms. In order to understand the origin of the low A(zz)(Cu) value of type zero Cu(II), we explored in detail its degree of covalency, as manifested by spin delocalization over its ligands, which affects A(zz)(Cu) through the Fermi contact and spin dipolar contributions. This was achieved by the application of several complementary EPR hyperfine spectroscopic techniques at X- and W-band (~9.5 and 95 GHz, respectively) frequencies to map the ligand hyperfine couplings. Our results show that spin delocalization over the ligands in type zero Cu(II) is different from that of type 2 Cu(II) in the single C112D mutant. The (14)N hyperfine couplings of the coordinated histidine nitrogens are smaller by about 25-40%, whereas that of the (13)C carboxylate of D112 is about 50% larger. From this comparison, we concluded that the spin delocalization of type zero copper over its ligands is not dramatically larger than in type 2 C112D. Therefore, the reduced A(zz)(Cu) value of type zero Cu(II) is largely attributable to an increased orbital dipolar contribution that is related to its larger g(zz) value, as a consequence of the distorted tetrahedral geometry. The increased spin delocalization over the D112 carboxylate in type zero mutants compared to type 2 C112D suggests that electron transfer paths involving this residue are enhanced. PMID- 22432749 TI - The global role of kidney transplantation. AB - World Kidney Day on March 8th 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end stage kidney disease include the economic limitations which, in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation and vaccination. Even in high income countries the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit. PMID- 22432750 TI - Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. AB - Solid organ transplant constitutes the definitive treatment for end-stage organ failure. Better organ preservation methods have enabled use of marginal grafts, thereby expanding the donor pool to meet the growing demand for organs. Static cold storage as a preservation method has been superseded largely by machine perfusion in kidney transplant, with work regarding its use in other organ transplants ongoing. We hope that machine perfusion will allow better graft preservation, and pretransplant assessment, and optimization. The most extensive laboratory, preclinical, and clinical research into machine perfusion organ preservation has focused on kidneys. Successful outcomes in its use in renal transplant have sparked interest for its development and application to the liver, pancreas, heart, and lungs. This article reviews the current state of machine perfusion in abdominal and thoracic organ transplant, focusing on the recent developments in assessing graft viability. PMID- 22432751 TI - Preemptive deceased-donor renal transplant in adults: single-center experience and outcome. AB - OBJECTIVES: Preemptive renal transplant has been associated with better survival of both the allograft and the recipient than has conventional renal transplant. It remains unclear, however, whether preemptive transplant is optimal for renal replacement therapy. We describe our experience with preemptive renal transplant. MATERIALS AND METHODS: We retrospectively analyzed 32 preemptive and 132 nonpreemptive deceased-donor renal transplants performed in our center between January 2006 and January 2008. RESULTS: The mean follow-up was 47.44 +/- 11.92 months in the preemptive group, compared with 47.49 +/- 14.87 months in the nonpreemptive group. The 1-, 3-, and 5-year patient survival rates were 93.8%, 90.6%, and 90.6% in the preemptive group, and 92.4%, 90.9%, and 87.6% in the nonpreemptive group; and the 1-, 3-, and 5-year graft survival rates were 93.8%, 93.8%, and 93.8% in the preemptive, and 89.4%, 85.6%, and 73.8% in the nonpreemptive group. None of these differences was statistically significant. Rates of acute rejection (P = .04) and delayed graft function (P = .03) were significantly lower in the preemptive group. The mean plasma creatinine levels at 1 day before transplant and at 1 and 12 months after transplant were 715.16 +/- 114.92 MUmol/L, 113.15 +/- 29.17 MUmol/L, and 94.59 +/- 18.56 MUmol/L in the preemptive group, and 772.62 +/- 111.38 MUmol/L, 118.46 +/- 30.94 MUmol/L, and 100.78 +/- 15.03 MUmol/L in the nonpreemptive group. None of these differences was statistically significant. CONCLUSIONS: Preemptive transplant can yield outcomes comparable to those of renal transplant after dialysis, and result in better quality of life for patients with end-stage renal disease, as well as reduced cost. Preemptive transplant is a better choice for renal replacement therapy, if possible. PMID- 22432752 TI - QT intervals in patients receiving a renal transplant. AB - OBJECTIVES: Cardiovascular disease is the most-common cause of mortality in patients with end-stage renal disease and renal transplant. Prolongation of QTc(max) and QTc dispersion are risk factors of cardiac arrhythmias and mortality. This study compares the changes of QT parameters before hemodialysis, after hemodialysis, and after renal transplant. MATERIALS AND METHODS: Patient candidates for renal transplant were selected. Mean serum electrolyte and 12-lead electrocardiogram were recorded (1) immediately, (2) before and, (3) after the last dialysis session before renal transplant, (4) and 2 weeks after a kidney transplant in 34 patients with normal graft function (plasma Cr <= 176.8 MUmol/L). Each QT interval was corrected for the patient's heart rate using Bazett's formula. The QT parameters (QTd, QTcd, QTc(max)) were compared between prehemodialysis, posthemodialysis, and 2 weeks after renal transplant using a paired t test and a general liner model repeated measure. The correlation between QT parameter changes and serum electrolyte and acidbase alternation was analyzed. RESULTS: The corrected maximal QT interval (QTc(max)) decreased significantly after successful renal transplant compared to prehemodialysis (P = .002) and posthemodialysis (P = .003) with a paired t test and a General Liner Model Repeated Measure (P < .001) between the 3 groups. Also, the mean of QTc(max) decreased significantly after renal transplant (P = .001) compared to what it was before hemodialysis and after hemodialysis. There was a significant correlation (r= -0.37) between reduction of QTc(max) and serum Ca level (P = .01) in postrenal transplant period. CONCLUSIONS: Renal transplant with normal graft function decrease QTc(max) compared to prehemodialysis and posthemodialysis that may correlate with normalization of electrolytes from the uremic state of the normal kidney function. PMID- 22432753 TI - Long-term results of conversion from calcineurin inhibitors to sirolimus in 150 maintenance kidney transplant patients. AB - OBJECTIVES: This retrospective single-center study evaluated long-term renal function after conversion from calcineurin inhibitors to sirolimus-based immunosuppression in kidney transplant recipients. MATERIALS AND METHODS: From 2001 to 2009, one hundred fifty kidney transplant recipients were converted from calcineurin inhibitors to sirolimus at least 3 months after transplant. RESULTS: After a mean follow-up of 171 weeks, 56.7% of converted patients remained on sirolimus. The 5-year survival rate of the patients (including intent-to-treat) and grafts was 85.5% and 83.6%. Patients on sirolimus showed significant improvement in renal function with a creatinine clearance of 50.9 +/- 20.7 and 52.9 +/- 20.8 mL/minute at month 0 and month 24. Independent predictive factors associated with a stable estimated glomerular filtration rate at the last follow up of sirolimus patients were (1) having a living donor, (2) absence of anti-HLA alloantibodies at month 0, and (3) cyclosporine versus tacrolimus used before conversion. Adverse effects were reported in 134 patients (89.3%). They included (1) hospitalization for infection (n=52), (2) de novo proteinuria (n=40), and (3) eight patients with biopsy-proven acute rejection. Sirolimus was stopped and replaced by calcineurin inhibitors in 37 patients after a mean of 16 months treatment. After stopping sirolimus, renal-allograft function remained stable at 2 years. CONCLUSIONS: Conversion of calcineurin inhibitors to sirolimus in kidney transplant recipients was associated with improved renal function. The reintroduction of calcineurin inhibitors was safe in patients who were withdrawn from sirolimus owing to adverse effects. PMID- 22432754 TI - Serum phosphate measured at 6 and 12 months after successful kidney transplant is independently associated with subsequent graft loss. AB - OBJECTIVES: Serum phosphate concentrations have been shown to predict graft loss in prevalent, but not incident, kidney transplant populations. The reasons for this are unknown. We investigated whether serum phosphate at 6 or 12 months posttransplant was associated with graft loss in the same cohort. MATERIALS AND METHODS: Data were collected for 325 patients transplanted and followed up at a single center (1996-2004). The association between serum phosphate at 6 and 12 months posttransplant and graft failure was analyzed. RESULTS: Univariable associations with death-censored graft failure were seen for serum phosphate at 6 and 12 months (hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.20-1.48; P < .001, and HR 1.40; CI 1.27-1.54; P < .001). On bivariable analysis (phosphate at 6 vs 12 mo), a significant association remained for both variables and increased graft failure rate (HR 1.19; CI 1.07-1.34; P = .002, and HR 1.37; CI 1.21-1.55; P < .001). These associations persisted in multivariable models (HR 1.27; CI 1.07-1.51; P = .007, and HR 1.34; CI 1.14-1.57; P < .001 for phosphate at 6 and 12 mo). CONCLUSIONS: Serum phosphate at 6 and 12 months posttransplant is an independent predictor of graft loss. Any future trial designed to investigate the benefits of phosphate lowering should consider recruiting patients as early as 6 months posttransplant. PMID- 22432755 TI - Incidence and risk factors of intraoperative adverse events during donor lobectomy for living-donor liver transplantation: a retrospective analysis. AB - OBJECTIVES: To evaluate the frequency, type, and predictors of intraoperative adverse events during donor hepatectomy for living-donor liver transplant. MATERIALS AND METHODS: Retrospective analyses of the data from 182 consecutive living-donor liver transplant donors between May 2002 and September 2008. RESULTS: Ninety-one patients (50%) had at least 1 intraoperative adverse event including hypothermia (39%), hypotension (26%), need for transfusions (17%), and hypertension (7%). Patients with an adverse event were older (P = .001), had a larger graft weight (P = .023), more frequently underwent a right hepatectomy (P = .019), and were more frequently classified as American Society of Anesthesiologists physical status class II (P = .027) than those who did not have these adverse events. Logistic regression analysis revealed that only age (95% confidence interval 1.018-1.099; P = .001) was a risk factor for intraoperative adverse events. Patients with these adverse events more frequently required admission to the intensive care unit and were hospitalized longer postoperatively. A before and after analysis showed that after introduction of in line fluid warmers and more frequent use of acute normovolemic hemodilution, the frequency of intraoperative adverse events was significantly lower (80% vs 29%; P < .001). CONCLUSIONS: Intraoperative adverse events such as hypothermia and hypotension were common in living-donor liver transplant donors, and older age was associated with an increased risk of these adverse events. However, the effect of these adverse events on postoperative recovery is not clear. PMID- 22432756 TI - Sirolimus conversion in liver transplant recipients with calcineurin inhibitor induced complications: efficacy and safety. AB - OBJECTIVES: To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications. MATERIALS AND METHODS: After receiving liver transplants, 25 patients with calcineurin inhibitor-induced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored. RESULTS: The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 +/- 21.8 MUmol/L vs 163.2 +/- 45.3 MUmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 +/- 23.4 MUmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial. CONCLUSIONS: Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes. PMID- 22432757 TI - HLA tissue typing has no effect on the outcome of patients undergoing a living donor liver transplant: a single-center experience in Egypt. AB - OBJECTIVES: To analyze the effect of human leukocyte antigen tissue typing on outcome of live-donor liver transplant. MATERIALS AND METHODS: Fifty recipients underwent live-donor liver transplant in the Dar Al-Fouad Hospital in Egypt and were retrospectively evaluated. Patients were classified into 2 groups: those with human leukocyte antigen +ve, and those with human leukocyte antigen -ve and donors. Hepatitis C virus-related end-stage liver disease was the main indication for transplant. Demographic data, preoperative laboratory data, results of human leukocyte antigen tissue typing, Child score, model for end-stage liver disease score, graft/recipient weight-ratio, ischemia times, surgical complications, postoperative laboratory data, liver biopsy, immunosuppression, and pulse steroids were collected. Graft and patient survivals were studied using Kaplan Meier curves. RESULTS: The mean model end-stage liver disease score was 18 +/- 3.61 in group 1 and 17.73 +/- 3.72 in group 2, with no significant difference. Graft/recipient weight ratio, ischemia times, and postoperative complications showed P = NS. Cyclosporine and tacrolimus were used in 5/9, 8/41, and 4/9 in group 1, and 32/41 in group 2 (P = NS). Rejection and pulse steroids were reported in 3/9 and 12/41 of group 1, and 3/12 and 11/41 of group 2 (P = NS). Hepatitis C virus-recurrence was diagnosed in 5/9 of patients (55%) and 8/41 of patients (29.5%) in groups 1 and 2 (P < .05). No statistical difference was found regarding mortality; 5-year patient and graft survival was 35/50 (70% in group 1 [human leukocyte antigen +ve]), 7/9 (77.8%), and 28/41 in group 2 (68.3%) (human leukocyte antigen -ve). CONCLUSIONS: Positive human leukocyte antigen typing before live-donor liver transplant has no effect on the incidence of postoperative complications, rejection episodes, and patient or graft survival. Recipients with positive human leukocyte antigen typing may have increased risk of hepatitis C virus-recurrence after live-donor liver transplant. PMID- 22432758 TI - Hepatitis C virus infection can affect lymphoproliferative disorders only as a cofactor for Epstein-Barr virus in liver transplant recipients: PTLD.Int survey. AB - OBJECTIVES: Hepatitis C virus infection has a 10.5% frequency in liver transplant posttransplant lymphoproliferative disorders. Studies have suggested that hepatitis C virus infection plays a role in developing posttransplant lymphoproliferative disorders. Pooling data of posttransplant lymphoproliferative disorders developing in liver recipients from the literature, we analyzed and compared characteristics, behavior, and prognoses of posttransplant lymphoproliferative disorders arising in hepatitis C virus-positive versus negative liver graft recipients. MATERIALS AND METHODS: We conducted a search for the available data though PubMed and Google Scholar for reports of posttransplant lymphoproliferative disorders and hepatitis C virus infection in liver transplant recipients. Overall, 29 studies were found and their data are included in the analyses. RESULTS: Overall, data of 212 liver transplant patients were included. Sixty-three percent were male. No difference was found between hepatitis C virus positive liver transplant patients with posttransplant lymphoproliferative disorders compared to their hepatitis C virus-negative counterparts regarding sex, time from transplant to lymphoma development, lymphoma cell type, remission, mortality rate, multiorgan involvement, disseminated posttransplant lymphoproliferative disorders, and histopathologic evaluations (P > .1 for all). Hepatitis C virus-positive liver transplant recipients representing posttransplant lymphoproliferative disorders who were concomitantly positive for Epstein-Barr virus were significantly more likely to develop lymphomas in the early posttransplant period (26 [67%] vs 16 [40%]; P = .024) and to complicate liver (19 [63%] vs 8 [30%]; P = .017) than hepatitis C virus-/Epstein-Barr virus+ patients. CONCLUSIONS: Hepatitis C virus infection alone has no significant effect on lymphoproliferative disorders after liver transplant; but when combined with Epstein-Barr virus infection, it represents some significant different presentations of the disease. However, no survival effect was found for hepatitis C virus with or without simultaneous Epstein-Barr virus infection, in the posttransplant lymphoproliferative disorders setting. Future prospective studies are needed for confirming our results. PMID- 22432759 TI - Appropriate donor size for porcine liver xenotransplant. AB - OBJECTIVES: Owing to an imbalance between demand and supply, which is more prominent in pediatric transplant, every year more patients lose their lives on waiting lists. In addition to the use of deceased-donor split and living-donor organs, xenotransplant could provide a solution if associated problems, such as immunologic and physiologic ones, are solved. This study sought to analyze the surgical aspects for liver xenotransplant in a porcine model. MATERIALS AND METHODS: Landrace pigs (n=22, 23 to 37 kg) underwent a laparotomy under general anesthesia. The hepatic hilum was prepared and the common bile ducts, common hepatic artery, portal vein, supra- and infrahepatic inferior vena cava were identified. The length and diameter of each vessel and bile duct and the weight of the liver were measured. RESULTS: Pearson tests showed a clear correlation between the increase of the pigs' weight and the livers' weight, and the length of the vessels and the bile ducts. We did not find a clear correlation between the increase of the pigs' liver weight and the diameters of the vessels and the bile duct. CONCLUSIONS: As the first reporting, this study on xenotransplants from the surgical point of view, we postulate that it could be possible to estimate the size of the liver and the proper length of its vessels and bile duct by weighing only the pigs. It was not feasible to match the diameter of mentioned structures by the livers' weight. However, the weight of pig's liver as well as vascular anatomy of pigs appeared to be suitable alternative for the human liver. PMID- 22432760 TI - Graft function after heterotopic rat heart transplant with an isolated reperfused working heart: a methodic consideration. AB - OBJECTIVES: Assessment of graft function in experimental cardiac transplant has been underused by insufficient methods (echo-cardiography, magnetic resonance imaging). The isolated reperfused working-heart model is an excellent tool for hemodynamic evaluation of rodent hearts. So far, it has never been used in a cardiac transplant setting. Our study tries to combine the in vivo technique of a rat heart transplant model with the ex vivo method of an isolated working heart. MATERIALS AND METHODS: Heterotopic heart transplants have been performed in rats with a nonsuture cuff technique. After 8 hours of cold ischemia and 24 hours of reperfusion, grafts were mounted on the working heart. To assess graft function, cardiac output was measured with increasing levels of afterload pressure. Nontransplanted hearts were mounted directly to the working heart apparatus to serve as a control group. Each heart was assessed subjectively by the Stanford score before being mounted on the working-heart apparatus. RESULTS: The working heart assessment detected significantly impaired graft function in the transplant group compared with control hearts. In contrast, functional assessment with the score-system could not detect any difference between transplanted and native hearts. CONCLUSIONS: The isolated working-heart model is an excellent tool for assessing graft function after experimental heart transplant in rodents. PMID- 22432761 TI - Introduction of modified cervical cardiac transplant model in mice. AB - OBJECTIVES: The murine cervical heterotopic heart transplant model was initially designed to test the immune response to third-party allografts, modified by cuff techniques. While cuff techniques simplify the execution of this procedure, cutting of the carotid artery and the external jugular vein alters the blood supply to central nervous system and makes it difficult to achieve long-term graft survival. In the present study, we describe modified techniques that preserve the continuity and function of blood vessels and improve transplant integrity. MATERIALS AND METHODS: The modified techniques in this study comprise the following aspects: (1) Preservation of the sternal head of the right sternocleidomastoid muscle, (2) use of the donor's intrathoracic inferior vena cava for anastomosis and (3) preservation of the function of the recipient's carotid artery and external jugular vein and thus, continuity of blood flow to the central nervous system. RESULTS: Stable, long-term, disease-free allograft survival has been achieved with syngeneic transplants (> 200 days), whereas allografts from fully major histocompatibility complex-mismatched donors were acutely rejected in a time similar to the traditional abdominal heterotopic heart transplant model (8.2 +/- 1.3 vs 8.4 +/- 1.4 days; P = .73 in the Mantel Cox test, and P = .61 in the Gehan-Breslow-Wilcoxon test). Similar alloresponses could be induced in these 2 models. CONCLUSIONS: It is possible and feasible to achieve long-term graft survival in the mouse cervical heart transplant model using the modified procedures described in the present study. PMID- 22432762 TI - Autologous noncryopreserved hematopoietic stem cell transplant with CEAM as a modified conditioning regimen in patients with Hodgkin lymphoma: a single-center experience with a new protocol. AB - OBJECTIVES: A BEAM regimen including carmustine (BiCNU: bis-chloroethyl nitrosourea), etoposide, cytarabine (cytosine arabinoside), and melphalan is a widely used conditioning regimen for autologous stem cell transplant in patients with Hodgkin lymphoma. We report the results of noncryopreserved autologous stem cell transplant of 45 patients with Hodgkin lymphoma given an alternative regimen, modified BEAM-like regimen (CEAM regimen: lomustine, etoposide, cytarabine, and melphalan), in which carmustine (BiCNU IV) was substituted by oral lomustine (CCNU: 2 chloroethyl cyclohexyl nitrosourea). PATIENTS AND METHODS: Forty-five eligible patients with relapsed/refractory Hodgkin lymphoma were consecutively enrolled and underwent conditioning regimen with BEAM-like regimen protocol as follows: Lomustine 200 mg/m(2) on day -3; etoposide 1000 mg/m(2) on day -3 and -2; cytarabine 1000 mg/m(2) on days -3, -2; and Melphalan 140 mg/m(2) on day -1. RESULTS: All 45 patients showed engraftment of infused stem cell, and there was no graft failure in the study group. The median mononuclear cell dose was 3.4 * 10(8). The median time to absolute neutrophil count > 0.5 * 10(9)/L was 11 days, and the median time to platelet count > 20 * 10(9) was 14 days. Grade 2 and grade 3 mucositis was seen in 64.5% our patients. Transplant-related mortality at 100 days occurred in 1 patient (2.2%). With a median follow-up of 27 months, median disease-free survival was 20 months, mean overall survival was 27 months, and median overall survival has not yet been reached. CONCLUSIONS: These data demonstrate the safety and feasibility of BEAM like regimen as a new and modified regimen; longer follow-up is required to evaluate fully efficacy and long-term safety of our method. PMID- 22432763 TI - Endoscopic botulinum toxin injection for the treatment of diabetic gastropathy in pancreas and islet-cell transplant patients. AB - OBJECTIVES: Gastroparesis is a well-recognized, long-term complication of diabetes. Prokinetic drugs are often not effective, prompting the development of alternative therapies. We report our experience of using one such alternative, endoscopic botulinum toxin injection, to ameliorate diabetic gastropathy in association with pancreas and islet-cell transplant patients. MATERIALS AND METHODS: Three male diabetic patients aged 42 to 55 years had been treated with botulinum toxin in our center. Two patients were both after-simultaneous pancreas kidney transplant and 1 was awaiting islet-cell transplant after pancreatectomy. Mechanical gastric outlet obstruction was first excluded by radiological and endoscopic studies. Between 100 and 200 IU of toxin were then injected in the prepyloric region using an endoscopic technique. A subjective scoring scale was used to assess symptoms before and after botulinum therapy. RESULTS: Improvement in subjective symptom severity scoring was seen in all patients, with a posttreatment improvement from 55% to 91%. Such improvement was temporary in 2 patients and long-lasting in 1 patient. CONCLUSIONS: The time for improvement of gastric autonomic function after pancreas or islet-cell transplantation remains unclear. Some patients may continue to be symptomatic, leading to increasing morbidity. However, endoscopic botulinum injections may provide short-term relief while waiting for improvement and spare patients the morbidity associated with more-invasive therapies. PMID- 22432764 TI - Co-occurrence of nonanastomotic biliary stricture and acute cellular rejection in liver transplant. AB - BACKGROUND: Nonanastomotic biliary stricture is generally considered the most troublesome biliary complication after liver transplant. Nonanastomotic biliary stricture owing to immunologic cholangiopathy (such as acute cellular rejection) has not been reported. We describe 2 patients with the co-occurrence of nonanastomotic biliary stricture and acute cellular rejection after pediatric live-donor liver transplant. CASE 1: A 13-month-old male infant with liver cirrhosis underwent an ABO-identical live-donor liver transplant using a left lateral segment graft. Eighty days after the live-donor liver transplant, ever with liver dysfunction and dilatation of the intrahepatic bile duct occurred. Percutaneous transhepatic biliary drainage and a liver biopsy were performed. The histopathologic evaluation indicated the presence of acute cellular rejection. After percutaneous transhepatic biliary drainage and steroid pulse treatment, the patient showed good clinical outcome. CASE 2: A 21-month-old female infant with biliary atresia underwent an ABO-identical live-donor liver transplant using a left lateral segment graft. Twenty-six days after the live-donor liver transplant, percutaneous transhepatic biliary drainage for B3 and a liver biopsy were performed, owing to fever, with liver dysfunction, and dilatation of the intrahepatic bile duct. Histopathologic evaluation indicated the presence of acute cellular rejection. After percutaneous transhepatic biliary drainage and steroid pulse treatment, the patient showed good clinical outcome. CONCLUSIONS: It is important for patients with nonanastomotic biliary stricture to undergo early liver biopsy because the nonanastomotic biliary stricture may be coincident with, or caused by, acute cellular rejection. PMID- 22432765 TI - Bladder rupture in immediate postrenal transplant period of uncertain cause. AB - Bladder rupture in patients undergoing renal transplant is rare. A 26-year-old man underwent a deceased-donor renal transplant. Postoperatively, he showed a good clinical course, but after removal of the urethral catheter, he complained of pain in the lower aspect of the abdomen and in the left flank. Findings of abdominal computed tomography and retrograde cystography revealed an extraperitoneal bladder rupture. We did not identify specific causes for this condition and believe that the bladder rupture was spontaneous. However, we could not rule out the possibility of traumatic rupture by the double-J ureteral stent. We decided to manage this case conservatively, with an indwelling urethral catheter and antibiotics, instead of by surgical repair. Results of repeated serial cystography during the treatment showed decreased contrast extravasation, and cystographic findings at 6 weeks showed no leakage of contrast medium. We confirmed complete healing of the ruptured bladder and removed the urethral catheter. Since then, the patient has maintained good renal function without any complications. PMID- 22432766 TI - Acute appendicitis post liver transplant: a case report and literature review. AB - Although acute appendicitis is common, reported cases after orthotopic liver transplant are rare. A 29-year-old woman presented to the emergency department with right lower-quadrant pain and mild leukocytosis 2 years after having a liver transplant. A computed tomography scan revealed an inflamed appendix. On operation, an injected appendix was noted, and she underwent an uncomplicated laparoscopic appendectomy. Histology confirmed the diagnosis and her postoperative course was unremarkable. Owing to the rarity of these cases and paucity of knowledge on management, a high index of suspicion and immediate intervention are required to prevent major complications. This case is the first successful laparoscopic appendectomy after liver transplant ever reported. PMID- 22432767 TI - ECMO after prolonged cardiopulmonary resuscitation as a successful bridge to immediate cardiac retransplant in a 6-year-old girl. AB - Heart failure, life-threatening arrhythmias, and sudden cardiac death are common complications in patients with advanced chronic cardiac allograft rejection--the major limiting factor of long-term survival after heart transplant. In patients with sustained cardiorespiratory arrest refractory to cardiopulmonary resuscitation extracorporeal membrane oxygenation therapy is a therapeutic option. We report the case of a 6-year-old girl with severe chronic allograft vasculopathy who was successfully bridged to cardiac retransplant through extracorporeal membrane oxygenation therapy after prolonged cardiopulmonary resuscitation. Our case demonstrates extracorporeal membrane oxygenation as a rescuing therapeutic option in high-risk, bridge-to-transplant patients, with cardiac arrest. Even after prolonged cardiopulmonary resuscitation, there were no neurologic events, and our patient recovered without any neurologic damage. PMID- 22432768 TI - Scedosporium apiospermum keratomycosis in a dog. AB - A 6-year-old male castrated Norfolk Terrier dog was examined following a 21-day history of an increasingly painful eye. Examination revealed marked blepharospasm and purulent ocular discharge associated with an ulcerative keratitis. There was panstromal corneal opacity with raised gray to white lesions. Corneal cytology demonstrated branching septate fungal hyphae identified by polymerase chain reaction as Scedosporium apiospermum. Treatment with topical 1% voriconazole solution was successful in resolving the keratomycosis. PMID- 22432769 TI - Enantioselective synthesis of 3,4-dihydropyran derivatives via organocatalytic Michael reaction of alpha,beta-unsaturated enones. AB - A simple chiral diamine catalyst (1a) was successfully applied in the asymmetric Michael reaction between cyclic dimedone and alpha,beta-unsaturated ketones. Both acyclic enones with aryl or alkyl beta-substituents and cyclic enones were tolerated well in the reaction. The desired adducts were obtained in high yields (up to 98%) with excellent enantioselectivities (up to 97% ee). The additives were found to increase the reactivity dramatically. The biologically active 2,4 disubstituted polyhydroquinoline scaffold was conveniently prepared through an ammoniation from the generated 3,4-dihydropyran product. PMID- 22432770 TI - Case report of perforation of an ileal neobladder after treatment of rectal cancer with bevacizumab and comment on mechanisms of intestinal perforation associated with bevacizumab. AB - WHAT IS KNOWN AND OBJECTIVE: Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) that has activity in several types of malignancies. One of the uncommon adverse effects is spontaneous bowel perforation. In patients who have undergone cystectomy, a loop of small bowel is often used to create a neobladder. We report the first case of ileal neobladder perforation associated with bevacizumab. CASE SUMMARY: We describe a 38-year-old male with metastatic rectal cancer who was receiving treatment with bevacizumab when he presented with acute abdominal pain. Radiographic evaluation revealed perforation of his ileal neobladder. WHAT IS NEW AND CONCLUSION: We describe the first report of ileal neobladder perforation in the setting of bevacizumab therapy. Although bowel perforation is a well-documented adverse effect of bevacizumab, this case suggests that displaced bowel tissue is still susceptible to these effects. We comment on what is known about bevacizumab-associated intestinal perforation. PMID- 22432771 TI - B effector cells in rheumatoid arthritis and experimental arthritis. AB - Rheumatoid arthritis is a chronic autoimmune immune disease affecting approximately 1% of the population. There has been a renewed interest in the role of B cells in rheumatoid arthritis based on the evidence that B cell depletion therapy is effective in the treatment of disease. This review summarizes the current knowledge of the mechanisms by which B cells contribute to autoimmune arthritis including roles as autoantibody producing cells, antigen-presenting cells, cytokine producing cells, and regulatory cells. PMID- 22432772 TI - Amelioration of alcohol-induced hepatotoxicity and oxidative stress in rats by Acorus calamus. AB - The protective effect of a methanolic extract (ME) of Acorus calamus against alcohol-induced hepatotoxicity and oxidative stress was studied in rats. The in vitro assays using DPPH and ABTS showed a strong antioxidant activity of the extract with the total polyphenolic content of 156 mg/g. Chronic ethanol administration causes an increase in oxidative stress and tissue injury with decreased antioxidant status. In this study, continuous administration of ethanol (7.9 g/kg body weight/day) for a period of 6 weeks resulted in a significant (p < .001) increase in the levels of serum aspartate aminotransferase, serum alanine aminotransferase, alkaline phospahatase, and bilirubin with the decreased level of total antioxidant status. Moreover, the levels of lipid peroxidation markers (malondialdehyde and hydroperoxides) as well as protein carbonyl content were also increased (p < .001), whereas the levels of non-enzymic antioxidants (glutathione, vitamin C, and vitamin E) decreased significantly in the liver tissues of ethanol-administered control rats. Pretreatment of rats with ME at doses of 300 and 600 g/kg body weight before alcohol administration significantly reduced the hepatic marker enzymes, level of lipid peroxidation, and protein oxidation, and increased the enzymatic and non-enzymatic antioxidant levels in liver. These observations were supplemented by histopathological examination of liver sections. Overall, the present study shows that the administration of ME ameliorates the antioxidant status as well as protects against the toxic effects of ethanol in rats, thereby suggesting its use as an effective botanical supplement for hepatoprotection. PMID- 22432773 TI - Yohimbine use for physical enhancement and its potential toxicity. AB - Yohimbine is a naturally sourced pharmacological agent, which produces hyperadrenergic physiological effects. In excess doses, it may typically cause agitation, anxiety, hypertension, and tachycardia. There is no conclusive evidence for this drug to be of benefit in bodybuilding, exercise tolerance, physical performance, or desirable alterations of body mass. Although tolerated generally well in low doses, the potential for dose-dependent toxicity should be recognized. PMID- 22432774 TI - Leaves of Hippophae rhamnoides prevent taste aversion in gamma-irradiated rats. AB - Hippophae rhamnoides (Sea buckthorn), a traditionally known plant for nutritional and therapeutic values, is under active investigation for radioprotective properties. This study investigated effects of aqueous leaf extract from H. rhamnoides on (60)Co-gamma-radiation induced changes in behavior, oxidative stress and serotonin levels in jejunum and plasma of rats. Conditioned taste aversion (CTA) was chosen as the assay to record behavioral changes and was assessed in terms of saccharine preference ratio (SPR). Whole body (60)Co-gamma irradiation (2 Gy) induced significant nonrecoverable CTA (25.6 +/- 3.6% SPR, t(6) = 3.499, p < .05) and loss in body weight (b.w.). One time treatment with leaf extract before irradiation, countered radiation induced CTA and loss in body weight. The 12 mg/kg b.w. concentration of leaf extract caused complete extinction of CTA [100.3 +/- 6.4% SPR, t(6) = 5.879, p < .01] after day 3 and the effect was significantly higher than positive control, Ondansetrone (70.0 +/- 8.9% SPR). Treatment with leaf extract before irradiation significantly countered radiation induced (1) decrease in antioxidant protection, (2) increase in levels of corticosterone (CS) in plasma, (3) increase in levels of serotonin in jejunum and plasma. Present investigation demonstrated that H. rhamnoides leaf extract prevented behavioral changes induced at clinical radiation doses. Hippophae leaves are nontoxic and are being consumed as tea and other beverages. CTA in rats is a considered parallel process to nausea and vomiting in human beings. These findings, put together, suggest that dietary supplements from Hippophae leaves could be developed for preventing behavioral changes in subjects exposed to radiation. PMID- 22432775 TI - Naturopathic physicians: holistic primary care and integrative medicine specialists. AB - The use of Complimentary and Alternative Medicine (CAM) is increasing in the United States; there is a need for physician level practitioners who possess extensive training in both CAM and conventional medicine. Naturopathic physicians possess training that allows integration of modern scientific knowledge and the age-old wisdom of natural healing techniques. Naturopathic philosophy provides a framework to implement CAM in concert with conventional therapies. The naturopathic physician's expertise in both conventional medicine and CAM allows a practice style that provides excellent care through employing conventional and CAM modalities while utilizing modern research and evidence-based medicine. PMID- 22432776 TI - An evidence-based systematic review of cinnamon (Cinnamomum spp.) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review of cinnamon (Cinnamomum spp.), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing, by the Natural Standard Research Collaboration is discussed in this monograph. PMID- 22432777 TI - Transmissive olefination route to putative "morinol I" lignans. AB - A series of morinol-type lignans were rapidly assembled using a Grignard-based transmissive olefination. In combination with palladium-catalyzed arylations, the strategy provides stereoselective access to (7Z,7'E), (7E,7'E), and (7E,7'Z) morinol diastereomers and the (7Z,8'E) and (7E,8'E) conjugated analogues. Critical for the E/Z stereoselectivity is a new, general method for converting alkenenitriles to alkenemethanols that circumvents the enal E/Z isomerization commonly encountered during conventional i-Bu(2)AlH reduction. PMID- 22432779 TI - High-strength, healable, supramolecular polymer nanocomposites. AB - A supramolecular polymer blend, formed via pi-pi interactions between a pi electron rich pyrenyl end-capped oligomer and a chain-folding oligomer containing pairs of pi-electron poor naphthalene-diimide (NDI) units, has been reinforced with cellulose nanocrystals (CNCs) to afford a healable nanocomposite material. Nanocomposites with varying weight percentage of CNCs (from 1.25 to 20.0 wt %) within the healable supramolecular polymeric matrix have been prepared via solvent casting followed by compression molding, and their mechanical properties and healing behavior have been evaluated. It is found that homogeneously dispersed films can be formed with CNCs at less than 10 wt %. Above 10 wt % CNC heterogeneous nanocomposites were obtained. All the nanocomposites formed could be rehealed upon exposure to elevated temperatures although, for the homogeneous films, it was found that the healing rate was reduced with increasing CNC content. The best combination of healing efficiency and mechanical properties was obtained with the 7.5 wt % CNC nanocomposite which exhibited a tensile modulus enhanced by as much as a factor of 20 over the matrix material alone and could be fully rehealed at 85 degrees C within 30 min. Thus it is demonstrated that supramolecular nanocomposites can afford greatly enhanced mechanical properties relative to the unreinforced polymer, while still allowing efficient thermal healing. PMID- 22432781 TI - NMR metabolomics of MTLn3E breast cancer cells identifies a role for CXCR4 in lipid and choline regulation. AB - The alpha chemokine receptor CXCR4 is up-regulated in certain types of breast cancer. Truncation of the C-terminus of this receptor alters cell morphology and increases invasiveness and metastatic potential. Here, to better understand the effects of CXCR4 expression and truncation in breast cancer cells, we have used high resolution magic angle spinning (HR-MAS) NMR studies of rat breast carcinoma MtLn3E cells to characterize the metabolite complement of cells heterologously expressing human CXCR4 or its C-terminal truncation mutant, Delta34-CXCR4. Notable reductions in choline levels were detected when either cells expressing wild-type CXCR4 or Delta34-CXCR4 were compared with cells containing an empty expression vector. Cells expressing CXCR4-Delta34 had reduced lipid content when compared with either the wild-type CXCR4 expressing cells or those containing the empty expression vector. Taken together, our results show that distinct effects on the metabolite complement can be linked to either CXCR4 expression or CXCR4 regulation. The metabolite markers for these two effects identified in the present study can, in turn, be used to further investigate the role of CXCR4 in metastasis. PMID- 22432783 TI - Occupational and environmental health nursing: ethics and professionalism. AB - This article provides an overview of ethical issues related to the practice of occupational and environmental health nursing and possible strategies for resolution. Also, professionalism related to professional growth and advancing the specialty is discussed. PMID- 22432784 TI - Research to practice in occupational health nursing. AB - Occupational health nursing research has gained a significant place in national and international nursing programs and has advanced occupational health nurses' understanding of the most effective ways to prevent occupational illness and injury, provide access to quality care for workers, and manage occupational injuries and return to work. This article describes the history of nursing research in general and highlights the current national shortages that must be addressed to ensure that nurses continue to impact the field. Occupational health nursing priorities are described and examples are given of nurse scientists who have established the foundation of occupational health nursing research and who illustrate varied expertise and the interdisciplinary context in which the work is conducted. PMID- 22432785 TI - Retrospective outcomes studies for orphan diseases: challenges and opportunities. AB - Retrospective outcomes studies for orphan diseases are scarce in the literature because of the significant methodological and data challenges that researchers have to overcome. Over the last two decades, many opportunities have emerged to mitigate these challenges. In this editorial we examined the common challenges in retrospective outcomes studies as well as the emerging opportunities that researchers can utilize to overcome those challenges. With the introduction of two retrospective orphan disease studies in this issue, we encourage more researchers to take advantage of the emerging opportunities to conduct and publish more retrospective outcomes studies for orphan diseases. This can provide important real-world insights into orphan diseases, including how they are being treated. PMID- 22432786 TI - Scanning the potential energy surface for synthesis of dendrimer-wrapped gold clusters: design rules for true single-molecule nanostructures. AB - The formation of true single-molecule complexes between organic ligands and nanoparticles is challenging and requires careful design of molecules with size, shape, and chemical properties tailored for the specific nanoparticle. Here we use computer simulations to describe the atomic-scale structure, dynamics, and energetics of ligand-mediated synthesis and interlinking of 1 nm gold clusters. The models help explain recent experimental results and provide insight into how multidentate thioether dendrimers can be employed for synthesis of true single ligand-nanoparticle complexes and also nanoparticle-molecule-nanoparticle "dumbbell" nanostructures. Electronic structure calculations reveal the individually weak thioether-gold bonds (325 +/- 36 meV), which act collectively through the multivalent (multisite) anchoring to stabilize the ligand nanoparticle complex (~7 eV total binding energy) and offset the conformational and solvation penalties involved in this "wrapping" process. Molecular dynamics simulations show that the dendrimer is sufficiently flexible to tolerate the strained conformations and desolvation penalties involved in fully wrapping the particle, quantifying the subtle balance between covalent anchoring and noncovalent wrapping in the assembly of ligand-nanoparticle complexes. The computed preference for binding of a single dendrimer to the cluster reveals the prohibitively high dendrimer desolvation barrier (1.5 +/- 0.5 eV) to form the alternative double-dendrimer structure. Finally, the models show formation of an additional electron transfer channel between nitrogen and gold for ligands with a central pyridine unit, which gives a stiff binding orientation and explains the recently measured larger interparticle distances for particles synthesized and interlinked using linear ligands with a central pyridine rather than a benzene moiety. The findings stress the importance of organic-inorganic interactions, the control of which is central to the rational engineering and eventual large-scale production of functional building blocks for nano(bio)electronics. PMID- 22432787 TI - Regeneration and outcome of dual grafts in living donor liver transplantation. AB - In living donor liver transplantation (LDLT), the essential aims are to provide an adequate graft volume to the recipient and to keep a sufficient remnant liver volume in the donor. In some instances, these aims cannot be met by a single donor and LDLT using dual grafts from two donors is a good solution. From 2002 to 2009, five recipients in our hospital received dual graft LDLT. Two recipients received one right lobe and one left lobe grafts; the other three received two left lobe grafts. The mean final liver regeneration rate was 91.2%. Left lobe graft atrophy in the long term was observed in recipients who received a right and a left lobe grafts. The initial bigger volume graft in all recipients was noted to have better regeneration than the smaller volume grafts. Portal flow and bilateral grafts volume size discrepancy were considered as two major factors influencing graft regeneration in this study. We also noted that the initial graft volume correlated with portal flow in the separate grafts and finally contribute to individual graft regeneration. Because of compensatory hypertrophy of the other graft, recipients who experienced atrophy of one graft did not show signs of liver dysfunction. PMID- 22432788 TI - IDH1 mutation in pediatric gliomas: has it a diagnostic and prognostic value? AB - Mutations in IDH1 gene are observed in gliomas with significant differences according to histotype, grade, prognosis, and age. We analyzed the IDH1 gene mutations frequency in 42 gliomas from 40 children (14 pilocytic astrocytomas; 3 pilomyxoid astrocytomas; 3 diffuse astrocytomas; 1 gliomatosi cerebri; 8 subependymal giant cell astrocytomas; 2 anaplastic astrocytomas; 9 glioblastomas). No IDH1 mutation was detected. Our results indicate that there is no IDH1 gene involvement in the onset and progression of pediatric astrocytomas. We argue that it is not useful in children to assess the status of IDH1 gene nor for diagnostic nor prognostic purposes. PMID- 22432789 TI - Earthworms and humans in vitro: characterizing evolutionarily conserved stress and immune responses to silver nanoparticles. AB - Little is known about the potential threats of silver nanoparticles (AgNPs) to ecosystem health, with no detailed report existing on the stress and immune responses of soil invertebrates. Here we use earthworm primary cells, cross referencing to human cell cultures with a particular emphasis on the conserved biological processes, and provide the first in vitro analysis of molecular and cellular toxicity mechanisms in the earthworm Eisenia fetida exposed to AgNPs (83 +/- 22 nm). While we observed a clear difference in cytotoxicity of dissolved silver salt on earthworm coelomocytes and human cells (THP-1 cells, differentiated THP-1 cells and peripheral blood mononuclear cells), the coelomocytes and differentiated (macrophage-like) THP-1 cells showed a similar response to AgNPs. Intracellular accumulation of AgNPs in the coelomocytes, predominantly in a phagocytic population, was evident by several methods including transmission electron microscopy. Molecular signatures of oxidative stress and selected biomarker genes probed in a time-resolved manner suggest early regulation of oxidative stress genes and subsequent alteration of immune signaling processes following the onset of AgNP exposure in the coelomocytes and THP-1 cells. Our findings provide mechanistic clues on cellular innate immunity toward AgNPs that is likely to be evolutionarily conserved across the animal kingdom. PMID- 22432790 TI - Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. AB - INTRODUCTION: Type 2 diabetes often involves derangements in lipid levels in addition to insulin resistance and diminishing insulin secretion. Colesevelam hydrochloride, a bile acid sequestrant (BAS), is approved for adjunctive therapy to diet and exercise for glycemic control in type 2 diabetes. In clinical studies in patients with type 2 diabetes, colesevelam, added to existing metformin, sulfonylurea or insulin therapy, reduced hemoglobin A(1c) (HbA(1c)) by a mean of 0.5% and low-density lipoprotein-cholesterol (LDL-C) by 13-17%. AREAS COVERED: Information pertaining to colesevelam and other BAS was collected using a PubMed literature search of journal articles dating from 1960 to present. Additional articles were identified from bibliographies and from abstracts from American Diabetes Association conferences. The authors review the pharmacology of colesevelam as well as clinical efficacy, safety and tolerability data generated from clinical trials. EXPERT OPINION: Colesevelam induces moderate but significant improvements in HbA(1c) and LDL-C. Outcomes data are needed to determine whether or not colesevelam confers long-term protection against micro- and macrovascular complications. Although colesevelam does not induce weight gain, triglyceride levels tend to increase ~ 15%, the implications of which are unknown at this time. The mechanism(s) by which colesevelam improves glycemia are not yet understood but might involve enhanced meal-induced incretin secretion and altered farnesoid X receptor signaling. PMID- 22432791 TI - Clopidogrel increases bleeding complications in patients undergoing heart rhythm device procedures. AB - BACKGROUND: Management of antiplatelet therapy at the time of device implantation remains controversial. This study aimed to assess the risk of bleeding complications in patients receiving clopidogrel at the time of cardiac device surgery. METHODS: We performed a retrospective case-control study. Between 2004 and 2010, 101 consecutive patients receiving clopidogrel underwent cardiac device surgery (pacemaker or implantable cardioverter-defibrillator implantation, and generator replacement) in our institution. Controls were 1:1 matched on age, sex, device, type of procedure, number of leads implanted, and venous approach (cephalic or subclavian). A significant bleeding complication was defined as pocket hematoma requiring surgical evacuation or prolonged hospitalization, hemothorax, pericardial effusion, or tamponade. RESULTS: Bleeding complications occurred more frequently in patients receiving clopidogrel at the time of device procedure: 11.9% versus 4.0% (P = 0.037; odds radio [OR] 3.27 [1.02-10.5]). Significant bleeding complications were noted in 12 patients (11.9%) receiving clopidogrel, including two patients with pericardial effusion and one patient with hemothorax. Four controls (4.0%) had bleeding complications (three pocket hematomas and one pericardial effusion). The single factor associated with increased bleeding complications in patients receiving clopidogrel was subclavian puncture (P = 0.008). In the entire cohort (n = 202), multivariate analysis identified two independent predictors of significant bleeding complications: clopidogrel treatment at the time of surgery (P = 0.03; OR 3.7 [1.1-12.6]) and subclavian venous puncture (P = 0.03; OR 3.44 [1.1-10.4]). CONCLUSIONS: Clopidogrel treatment at the time of heart rhythm device procedures is associated with an increased risk of significant bleeding complications. Subclavian puncture seems to strongly increase hemorrhagic complications in this setting. PMID- 22432792 TI - Impact of pretransplant antinuclear antibody and antismooth muscle antibody titers on disease recurrence and graft survival following liver transplantation in autoimmune hepatitis patients. AB - BACKGROUND AND AIMS: Disease recurrence following transplantation occurs in 20 45% of patients with autoimmune hepatitis (AIH). Factors associated with an increased risk of recurrence include human leukocyte antigen (HLA) DR3 and HLA DR4 positivity, inadequate immunosuppression, and severity of inflammation in the native liver. Titers of several autoantibodies can be elevated in patients with AIH, including antinuclear antibody (ANA) and antismooth muscle antibody (SMA); however, it is unclear whether or not the degree of elevation influences the risk of disease recurrence following transplantation. METHODS: We conducted a retrospective study to evaluate the potential impact of pretransplant titers on post-transplant outcomes for patients with AIH. Sixty-three patients with AIH who underwent 72 liver transplants between 1 January 1989 and 1 January 2009 were included, with a median follow up of 10 months. Patients were divided into group A (ANA or SMA >= 1:160) and group B (titers <= 1:160). RESULTS: There was no significant difference in the recurrence rates or death between patients in groups A and B, respectively. Only race appeared to impact outcomes, with African American patients having a higher incidence of death and recurrent disease post transplant compared to other ethnicities. CONCLUSIONS: Based on our findings, pretransplant ANA and SMA levels do not appear to impact recurrence rates or outcomes following liver transplantation for AIH. PMID- 22432793 TI - Highly efficient charge separation and collection across in situ doped axial VLS grown Si nanowire p-n junctions. AB - VLS-grown semiconductor nanowires have emerged as a viable prospect for future solar-based energy applications. In this paper, we report highly efficient charge separation and collection across in situ doped Si p-n junction nanowires with a diameter <100 nm grown in a cold wall CVD reactor. Our photoexcitation measurements indicate an internal quantum efficiency of ~50%, whereas scanning photocurrent microscopy measurements reveal effective minority carrier diffusion lengths of ~1.0 MUm for electrons and 0.66 MUm for holes for as-grown Si nanowires (d(NW) ~ 65-80 nm), which are an order of magnitude larger than those previously reported for nanowires of similar diameter. Further analysis reveals that the strong suppression of surface recombination is mainly responsible for these relatively long diffusion lengths, with surface recombination velocities (S) calculated to be 2 orders of magnitude lower than found previously for as grown nanowires, all of which used hot wall reactors. The degree of surface passivation achieved in our as-grown nanowires is comparable to or better than that achieved for nanowires in prior studies at significantly larger diameters. We suggest that the dramatically improved surface recombination velocities may result from the reduced sidewall reactions and deposition in our cold wall CVD reactor. PMID- 22432794 TI - Impact of psychosocial factors, pain, and functional limitations on throwing athletes who return to sport following elbow injuries: a case series. AB - BACKGROUND AND PURPOSE: The purpose of this case series is to explore the possibility that: (1) throwing athletes respond to fear-avoidance model (FAM) measures differently than patients in other orthopedic populations; and (2) there is an association between the FAM measures, pain and function scores. METHODS: Five competitive throwing athletes with elbow pain between the ages of 17-23 were included. Patients were given the Fear Avoidance Belief Questionnaire (FABQ), Pain Catastrophizing Scale (PCS), Tampa Scale for Kinesiophobia (TSK-11), QuickDash, and Numeric Pain Rating Scale (NPRS) at initial evaluation and at 4 weeks. OUTCOMES: Subjects all demonstrated low levels of fear on initial evaluation and all returned to sport. FABQ-PA, TSK, and PCS subscales were all highly associated with the initial total scales (r = >0.80) with the exception of the PCS helplessness subscale (r = 0.61). Subjects demonstrated an average decrease in the NPRS score of 2.3 points and average improvement of 23.6 points in their QuickDash score. There was a fair association between initial TSK fear of injury (FOI) subscale and initial QuickDash scores (r = 0.47) and a moderate association between initial TSK-11 FOI subscale and initial pain scores (r = 0.61). DISCUSSION: Subjects in this case study appeared to respond to the FAM questionnaires differently than patients in other orthopedic populations. The TSK FOI subscale may be the most beneficial to use with throwing athletes. PMID- 22432795 TI - Pharmacokinetics of tramadol in a diverse healthy Chinese population. AB - WHAT IS KNOWN AND OBJECTIVES: Drug disposition may show ethnicity and gender differences. The objective of this study is to assess whether there are gender and ethnic differences in the pharmacokinetics of tramadol. METHODS: Fifty healthy volunteers from five different ethnic Chinese groups (Han, Mongolian, Korean, Uygur and Hui) were recruited, and blood samples were obtained for up to 36 h after oral administration of a single 100 mg capsule of tramadol. The plasma concentration-time course of tramadol was measured by high-performance liquid chromatography and the pharmacokinetic estimated. RESULTS AND DISCUSSION: The mean maximum plasma concentration (C(max)) of tramadol was different between Chinese males and females. There were also statistically significant differences between Hui and the other ethnic groups in tramadol's clearance (CL/F), volume of distribution (V(d) /F), C(max) and area under the plasma concentration time curve (AUC(0-infinity)) (P < 0.05). WHAT IS NEW AND CONCLUSION: The pharmacokinetics of tramadol was different in Hui subjects compared to the other Chinese ethnic groups. Tramadol CL/F may also show gender differences. PMID- 22432796 TI - Maturity onset diabetes of the young: clinical characteristics and outcome after kidney and pancreas transplantation in MODY3 and RCAD patients: a single center experience. AB - The diabetes and renal phenotype of patients with maturity-onset diabetes of the young (MODY) on a transplantation waiting list is not known; neither is their outcome after pancreas (PT) and/or kidney transplantation (KT). Between 2002 and 2009, we screened 50 of 150 patients referred for kidney and pancreas transplantation to the Kremlin-Bicetre center for HNF1B and HNF1A mutations if one or more of the following criteria was present (i) an atypical history of diabetes (ii) diabetes with at least one affected parent or two affected relatives, (iii) an absence of auto-antibodies at diagnosis (iv) a persistent secretion of fasting C peptide (v) a personal or a family history of renal cysts or dysplasia. Their phenotype and their outcome were analyzed. Four HNF1A (MODY3) and eight HNF1B mutations [renal cysts and diabetes (RCAD)] were identified. All MODY3 patients had diabetic nephropathy, but only 50% of RCAD patients. Four patients underwent a kidney and pancreas transplantation and two a kidney transplant alone. After 4.1 +/- 1.1 years of follow-up, 83% of patients still have a functioning kidney and 75% a functioning pancreas. PT can be proposed with good results for MODY3 and RCAD patients. PMID- 22432797 TI - Presumptive electric cataracts in a Great Horned owl (Bubo virginianus). AB - This case report describes suspected electrocution in a juvenile female Great Horned owl (Bubo virginianus) with subsequent bilateral cataract formation. The bird flew into a high-voltage power line and was immediately rescued. Burn wounds of the head and ataxia with apparent blindness were noted. Initial ophthalmic examination 5 days after the incident revealed bilaterally symmetrical anterior subcapsular vacuolar cataracts with absence of intraocular inflammation and a predominantly clear view to the normal appearing fundus. The bird appeared to be nonvisual. No ophthalmic medications were prescribed at initial examination. Subsequent recheck examination at 8 weeks revealed moderate resolution of the cataracts and improved vision. To the authors' knowledge, this is the first published report of suspected electric cataracts in an avian species. PMID- 22432798 TI - The dietary supplementation of nordihydroguaiaretic acid (NDGA) delayed the loss of climbing ability in Drosophila model of Parkinson's disease. AB - Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons and the aggression of alpha Synuclein (alphaS) in the brain. Drosophila mutants and transgenes have provided a platform to understand the mechanistic insight associated with the degenerative diseases. A number of polyphenols have been reported to inhibit the alphaS aggregation resulting in the possible prevention of PD. The involvement of free radicals in mediating the neuronal death in PD has also been implicated. In the present study, the effect of Nordihydroguaiaretic acid (NDGA) was studied on the climbing ability of the PD model Drosophila expressing normal human alpha synuclein (h-alphaS) in the neurons. These flies exhibit locomotor dysfunction as the age progresses. NDGA at final concentration of 0.01, 0.1, 0.5, and 1MUl/ml was supplemented with the diet and the flies were allowed to feed for the 24 days. NDGA at 0.01 MUl/ml did not showed any significant delay in the loss of climbing ability of PD model flies. However, NDGA doses at 0.1, 0.5, and 1.0 MUl/ml showed a dose dependent significant (p < .05) delay in the loss of climbing ability of PD model flies as compared to the untreated PD flies. The results suggest that the NDGA is potent in delaying the climbing disability of PD model flies and also supports the utility of this model in studying PD symptoms. PMID- 22432799 TI - Exploration of diuretic potential and electrolyte excretion of Tephrosia purpurea (Fabaceae) in rats. AB - Tephrosia purpurea (Fabaceae) is a well-known traditional plant with diuretic effect but no scientific work published till date to support the claimed ethnomedical use. Therefore, the present study appraised the diuretic potential of methanol extract of Tephrosia purpurea (METP) in male wistar rats. The powdered plant material was extracted with methanol by hot extraction. The animals were divided into five groups for diuretic activity. The first group served as saline control (0.9%% saline solution, 25 ml/kg, body weight (b.w)), the second group received osmotic diuretic, urea (1 g/kg b.w), the third group received high-ceiling diuretic, furosemide (5 mg/kg b.w), and the other two groups were administered various concentrations of METP (200 mg/kg and 400 mg/kg b.w) orally to hydrated rats and their urine volume was measured at 5th and 24th hr after drug administration, while animals were deprived of food and water. After collection of urine, the parameters such as urine output, diuretic activity, electrolyte excretion of Na(++), K(++), Ca(2++), and Cl(-), and pH were analyzed. METP at various dose levels exhibited significant diuretic activity as evidenced by increased urine volume, electrolyte concentration, and alkaline pH in comparison to control group of animals. The present study provides a quantitative basis for explaining the folkloric use of Tephrosia purpurea as a diuretic agent in Indian traditional system of medicine. PMID- 22432800 TI - Antidiabetic and antioxidant effect of Semecarpus anacardium Linn. nut milk extract in a high-fat diet STZ-induced type 2 diabetic rat model. AB - Semecarpus anacardium commonly known as marking nut has been used in the Siddha system of medicine against various ailments. The antidiabetic and antioxidant potential of the drug was evaluated in Type 2 diabetic rats induced by feeding a high-fat diet (HFD) for 2 weeks followed by single intraperitoneal injection of streptozotocin (STZ) 35 mg/kg body weight. Three days after STZ induction, the hyperglycemic rats were treated with Semecarpus anacardium nut milk extract (SA) orally at a dosage of 200 mg/kg body weight daily for 30 days. Metformin (500 mg/kg body weight, orally) was used as a reference drug. The fasting blood glucose, insulin, Hb, HbA1c levels, and HOMA-IR and HOMA-beta were measured, and also the levels of lipid peroxidation and antioxidant enzymes were observed. SA significantly (p < .05) reduced and normalized blood glucose levels and also decreased the levels of HbA1c as compared with that of HFD STZ control group. SA treatment also significantly (p < .05) increased the levels of antioxidant enzymes while decreasing the levels of lipid peroxidation. The potential antihyperglycemic action and antioxidant role might be due to the presence of flavonoids in the drug. PMID- 22432801 TI - Effects of sodium metavanadate and germination on the sprouting of chickpeas and its content of vanadium, formononetin and biochanin A in the sprouts. AB - Chickpea sprouts (CS) may become one of the natural products of high demand due to their nutritional values. The aim of this work was to study the enrichment of vanadium (V) during the germination of chickpea seeds in order to combine the high nutritive value of sprouts with a readily bioavailable source of essential trace element-V. Chickpea seeds were germinated in sodium metavanadate solutions (NaVO(3)) with different concentrations (50, 100, 150, 200, 400, 600, 800, 1,000, 1,200, 1,400, and 1,600 mg/L as NaVO(3)) for 6 days at 28 degrees C. It was found that the addition of sodium metavanadate produced slight stress effect, and the growth of CS was inhibited. The addition of sodium metavanadate significantly increased V content in CS in a dose-dependent manner. The highest V content (1.52 mg/g) in CS was observed when germination was carried out in the NaVO(3) solution with 1,200 mg/L NaVO(3) concentration. Chickpea seeds germinated in 50 ~200 mg/L NaVO(3) solutions for 6 days at 28 degrees C showed a higher germination rate (>99%%) and a higher content of isoflavones including formononetin and biochanin A than those obtained in NaVO(3) solutions with other concentration in the same germination conditions. Therefore, a concentration of 50~200 mg/L sodium metavanadate solutions should be used for the production of V-enriched chickpea sprouts (VCS). PMID- 22432802 TI - Resveratrol: potential as anticancer agent. AB - BACKGROUND: Cancer is one of the leading causes of deaths in the world. Current chemotherapeutic agents are associated with serious side effects in patients therefore researchers are trying to find an alternative agent that is effective against cancer as well as less toxic. Resveratrol (3,5,4'-trihydroxystilbene), commonly found in red wine and grape skins, is a phytoalexin agent that was originally extracted from the roots of Polygonum cuspidatum. Resveratrol is believed to work as a chemopreventive agent by producing its effect on cell apoptosis, antiproliferation, and anti-inflammation. PURPOSE: To determine whether resveratrol is effective as an anticancer agent. METHODS: A systematic review was performed by searching various databases for primary, secondary, and tertiary references. Databases included PubMed, EBSCO, Cochrane, AccessPharmacy, and StatRef by using key terms of "resveratrol," "cancer," and "anticancer." Review search looked at both animal and human studies limited within 10 years. FINDINGS: The major mechanisms of actions through which resveratrol works include proapoptotic, antiproliferation, and anti-inflammation. Numerous in vitro and in vivo studies have supported these mechanisms thus warranting further research in human studies for resveratrol's anticancer effects. Pharmacokinetic human studies suggest good tolerability in healthy subjects, although they have low absorptive characteristics. CONCLUSION: Resveratrol appears to have anticancer effects. Additionally, these studies indicate that resveratrol's chemoprevention effect is dose and duration dependent. It has synergistic effect with anticancer drugs in vitro. Further human studies need to be done. PMID- 22432803 TI - An evidence-based systematic review of annatto (Bixa orellana L.) by the Natural Standard Research Collaboration. PMID- 22432804 TI - B cells as effectors and regulators of autoimmunity. AB - A classic understanding of the interplay between B and T cell components of the immune system that drive autoimmunity, where B cells provide an effector function, is represented by systemic lupus erythematosus (SLE), an autoimmune condition characterised by the production of auto-antibodies. In SLE, CD4+T cells provide cognate help to self-reactive B cells, which in turn produce pathogenic auto-antibodies (1). Thus, B cells act as effectors by producing auto-antibody aided by T cell help such that B and T cell interactions are unidirectional. However, this paradigm of B and T cell interactions is challenged by new clinical data demonstrating that B cell depletion is effective for T cell mediated autoimmune diseases including type I diabetes mellitus (T1D) (2), rheumatoid arthritis (3), and multiple sclerosis (4). These clinical data indicate a model whereby B cells can influence the developing autoimmune T cell response, and therefore act as effectors, in ways that extend beyond the production of autoantibody (5). In this review by largely focusing on type I diabetes we will develop a hypothesis that bi-directional B and T interactions control the course of autoimmunity. PMID- 22432805 TI - Cyclic seleninate esters as catalysts for the oxidation of sulfides to sulfoxides, epoxidation of alkenes, and conversion of enamines to alpha hydroxyketones. AB - Cyclic seleninate esters serve as catalysts for the rapid oxidation of sulfides to sulfoxides, alkenes to epoxides, and enamines to alpha-hydroxyketones. Optimal conditions were found that minimize the overoxidation of the product sulfoxides to sulfones and the hydrolysis of epoxides to diols. In some examples such as styrene derivatives, oxidative cleavage was observed instead of epoxidation. The enamine oxidations proceed via the initial formation of dimeric 2,5-diamino-1,4 dioxane species, which were hydrolyzed in situ to the final products. The structure of one such dimer was confirmed by X-ray crystallography. PMID- 22432807 TI - Design and synthesis of FRET-mediated multicolor and photoswitchable fluorescent polymer nanoparticles with tunable emission properties. AB - Novel multicolor and photoswitchcable fluorescent polymer nanoparticles were prepared by one-step miniemulsion via methyl methacrylate (MMA) copolymerization with 4-ethoxy-9-allyl-1,8-naphthalimide (EANI), allyl-(7-nitro benzo[1,2,5]oxadiazol-4-yl)-amine (NBDAA) and spiropyran-linked methacrylate (SPMA). Under visible-light conditions, SPMA moieties in polymer nanoparticles are colorless and nonfluorescent, by varying the incorporating ratio of two dyes (EANI and NBDAA), fluorescence resonance energy transfer (FRET)-mediated emission signatures can be tuned so that the nanoparticles exhibit multiple colors under a single wavelength excitation. Moreover, the fluorescence emission of EANI and NBDAA dyes in nanoparticles can be reversibly switched "on" and "off" through the FRET process by the alternating irradiation of UV and visible light. This class of novel photoswitchable multicolor fluorescent polymer nanoparticles may find potential applications in multiplexed bioanalysis. PMID- 22432809 TI - Body-identical hormone replacement. PMID- 22432810 TI - What's new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone. AB - The original conclusions of the Women's Health Initiative study have been questioned as a result of the availability of age-stratified data. Initial concerns regarding the risk of coronary heart disease (CHD) in association with the use of hormone replacement therapy (HRT) have been replaced with concerns regarding thromboembolic disease, encompassing venous thromboembolism (VTE), particularly in younger postmenopausal women, and stroke, particularly in older women. The original publication of the study results led to a dramatic decrease in the use of oral HRT; however, the use of transdermal HRT has increased over recent years. Guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and specific guidelines from the European Menopause and Andropause Society for the management of menopausal women with a personal or family history of VTE all contain positive statements regarding both transdermal estradiol and micronized progesterone. Unlike oral estrogens, transdermal estradiol has been shown not to increase the risk of VTE, or stroke (doses <= 50 MUg), and to confer a significantly lower risk for gallbladder disease. Unlike some progestogens, progesterone is also not associated with an increased risk of VTE, or with an increased risk of breast cancer. Based on these data, which are now included in the guidelines, the use of transdermal estradiol and micronized progesterone could reduce or possibly even negate the excess risk of VTE, stroke, cholecystitis, and possibly even breast cancer associated with oral HRT use. PMID- 22432806 TI - Peripheral neural targets in obesity. AB - Interest in pharmacological treatments for obesity that act in the brain to reduce appetite has increased exponentially over recent years, but failures of clinical trials and withdrawals due to adverse effects have so far precluded any success. Treatments that do not act within the brain are, in contrast, a neglected area of research and development. This is despite the fact that a vast wealth of molecular mechanisms exists within the gut epithelium and vagal afferent system that could be manipulated to increase satiety. Here we discuss mechano- and chemosensory pathways from the gut involved in appetite suppression, and distinguish between gastric and intestinal vagal afferent pathways in terms of their basic physiology and activation by enteroendocrine factors. Gastric bypass surgery makes use of this system by exposing areas of the intestine to greater nutrient loads resulting in greater satiety hormone release and reduced food intake. A non-surgical approach to this system is preferable for many reasons. This review details where the opportunities may lie for such approaches by describing nutrient-sensing mechanisms throughout the gastrointestinal tract. PMID- 22432811 TI - Postmenopausal hormone replacement therapy and cardiovascular disease: the value of transdermal estradiol and micronized progesterone. AB - Most available postmenopausal hormone replacement therapies (HRT) offer similar efficacy, but differ with respect to the cardiovascular risks associated with their use. There is a wealth of evidence to suggest that, unlike oral estrogens, transdermal estradiol does not increase the risk of venous thromboembolism, probably due to its lack of effect on the coagulation cascade, including thrombin generation and resistance to activated protein C, and does not increase the risk of stroke. It is cardioprotective, significantly reducing the incidence of myocardial infarction compared with non-users; it significantly reduces the incidence of new-onset diabetes, a risk factor for myocardial infarction. Micronized progesterone has also been shown not to increase the risk of venous thromboembolism and further reduced the incidence of new-onset diabetes when combined with transdermal estrogen. Micronized progesterone has a neutral effect on the vasculature, including a neutral or beneficial effect on blood pressure. Therefore, experimental and clinical data indicate that transdermal estradiol and micronized progesterone could represent the optimal HRT, particularly in women at risk of adverse events. PMID- 22432812 TI - Micronized progesterone and its impact on the endometrium and breast vs. progestogens. AB - It is well established that progestogens protect the endometrium against the proliferative effects of estrogens in postmenopausal women receiving hormone replacement therapy (HRT). Therefore, micronized progesterone and progestogens are recommended as part of combined HRT in women with an intact uterus. The protective effect of progestogens against hyperplasia and endometrial cancer does not appear to differ with different progestogens (micronized progesterone or progestogens), but appears to be affected by the regimen and thus the dose, with continuous combined treatment conferring better protection. However, the protective effect of progestogens seen in the endometrium is not replicated in the breast. Progestogens combined with estrogens are generally associated with a small increase in the risk of invasive breast cancer, which is believed to be due to a promoter effect. However, all progestogens are not equivalent in their effects on the breast and breast cancer risk. Micronized progesterone does not increase cell proliferation in breast tissue in postmenopausal women compared with synthetic medroxyprogesterone acetate (MPA). Experimental evidence suggests that the opposing effects of MPA and micronized progesterone on breast tissue are related to the non-specific effects of MPA, including glucocorticoid activity and differences in the regulation of gene expression. Therefore, for women with an intact uterus, micronized progesterone may be the optimal choice as part of combined HRT. PMID- 22432813 TI - Progesterone and bone: a closer link than previously realized. AB - Decreasing rates of ovulation, hormonal changes, and increasing bone loss pre date menopause by several years. Data suggest that, in addition to estradiol, progesterone may play a significant role in the interrelationship between the ovaries and the skeleton in women. Indeed, the differentiation of human osteoblasts from perimenopausal women has been shown to be dose-dependent on progesterone at physiological concentrations. Data from a pilot study in perimenopasual women also suggested that higher progesterone levels, as seen in the luteal phase of ovulatory cycles, may be associated with more bone formation and with slightly less bone resorption than anovulatory cycles in which progesterone levels are low (< 5.8 ng/ml). These data led to the initiation of a large, prospective, 2-year observational study in perimenopausal women (the PEKNO study). Interim data from the PEKNO study indicate that a decrease in ovulation correlated with an increase in the loss of bone mineral density (BMD). A meta analysis estimated a BMD increase of 0.5% per year in women with normal ovulation, and a BMD decrease of 0.7% per year in young women with ovulatory disturbances (anovulation or short luteal phase). A meta-analysis in postmenopausal women demonstrated a 1.3% increase per year in BMD when receiving hormone replacement therapy with unopposed estrogens, and a further 0.4% increase in BMD in women receiving estrogens plus progestogens. The role of progesterone in bone metabolism in perimenopausal women who are estrogen-replete requires further study. PMID- 22432814 TI - Lipid-based passivation in nanofluidics. AB - Stretching DNA in nanochannels is a useful tool for direct, visual studies of genomic DNA at the single molecule level. To facilitate the study of the interaction of linear DNA with proteins in nanochannels, we have implemented a highly effective passivation scheme based on lipid bilayers. We demonstrate virtually complete long-term passivation of nanochannel surfaces to a range of relevant reagents, including streptavidin-coated quantum dots, RecA proteins, and RecA-DNA complexes. We show that the performance of the lipid bilayer is significantly better than that of standard bovine serum albumin-based passivation. Finally, we show how the passivated devices allow us to monitor single DNA cleavage events during enzymatic degradation by DNase I. We expect that our approach will open up for detailed, systematic studies of a wide range of protein-DNA interactions with high spatial and temporal resolution. PMID- 22432815 TI - Interactions of NO2 with amine-functionalized SBA-15: effects of synthesis route. AB - SBA-15 mesoporous silica was modified using (3-aminopropyl)trimethoxysilane (APTMS) following co-condensation or grafting methods and then used as a NO(2) adsorbent at room temperature. The samples were characterized before and after exposure to NO(2) by SEM-EDX, N(2) adsorption at 77 K, potentiometric titration, thermal analysis, and FTIR spectroscopy. Even though, regardless of the synthesis route, the addition of propylamine groups leads to a significant enhancement in the amount of NO(2) adsorbed (from 21 to 124 mg(NO(2))/g), a higher retention of NO(2) and NO (released as a result of surface reactions) was measured on the grafted silica than on all of the co-condensed samples. In the case of the latter materials, improvements in both NO(2) adsorption capacity and NO retention were found for the samples treated with NaOH. This behavior is related to the higher reactivity of deprotonated propylamine groups (formed during NaOH treatment) with NO(2), the presence of silanol groups, and the residual amount of sodium present in the samples. The mechanism of NO(2) adsorption on propylamine groups involves the formation of nitramine and/or nitrosamine. Analysis of the spent materials indicates that the porosity of co-condensed materials is not affected to the same extent by adsorption of NO(2) as that of the grafted silica. PMID- 22432816 TI - Bringing Masters' level skills to the clinical setting: what is the experience like for graduates of the Master of Science in manual therapy programme? AB - INTRODUCTION: The nursing profession has been influential in conducting research to investigate the effect of continuing education programs on clinical practice. This research has indicated positive gains in competencies and behaviors, such as, becoming more research positive and dynamic as practitioners. There is, however, a dearth of studies investigating the clinical impact of Masters degrees in the physiotherapy profession. PURPOSE: The purpose of this study was to explore physiotherapists' experiences of change and/or development in their clinical practice after successfully completing a Masters in manual therapy degree. STUDY DESIGN AND METHODOLOGY: An exploratory qualitative, specifically phenomenological, approach was used. Semi-structured telephone interviews were conducted with seven Masters degree graduates, audio-taped, and transcribed. A foundational thematic analysis approach was used to analyze the data. FINDINGS: Four main themes were identified: (1) precision thinking--an ability to integrate new skills and knowledge, so that care was patient-centered and based on available research evidence. (2) Clinical outputs--development of "ingenuity" in delivering efficient clinical practice. (3) Professional outputs--assuming an enhanced professional role (role model, education resource, and lifelong learner) in the workplace and acknowledging personal development. (4) Expectations- reviewing the relevance of pre-course expectations. CONCLUSIONS: This study provided evidence for the applicability to practice of the knowledge and skills gained in Masters education and suggested that the participants experienced substantial positive change across a broad spectrum of professional and personal issues. PMID- 22432817 TI - SulA inhibits assembly of FtsZ by a simple sequestration mechanism. AB - We have investigated the inhibition by SulA of the assembly of Escherichia coli FtsZ. Using quantitative GTPase and fluorescence assays, we found that SulA inhibition resulted in an increase in the apparent critical concentration for FtsZ assembly. The increase in apparent critical concentration was always less than the total amount of SulA added, suggesting that the association of SulA and FtsZ was of modest affinity. Isothermal titration calorimetry gave a value of 0.78 MUM for the dissociation constant of the FtsZ-SulA complex, similar in magnitude to the 0.72 MUM critical concentration of FtsZ protofilament assembly at steady state. We modeled the reaction as an equilibrium competition between (a) FtsZ subunits assembling onto protofilaments or (b) binding SulA. When FtsZ was assembled in GMPCPP or in EDTA, the inhibition by SulA was reduced. The reduced inhibition could be explained by a 3- and 10-fold weaker binding of SulA to FtsZ. The mutant D212G, which has no GTPase activity and therefore minimal subunit cycling, was shown here to assemble one-stranded protofilaments, and the assembly was blocked by SulA. We also assayed the SulA and FtsZ proteins from Pseudomonas. The SulA inhibition was stronger than with the E. coli proteins, and the model indicated a 5-fold higher affinity of Pseudomonas SulA for FtsZ. PMID- 22432819 TI - Tooth discolouration: staining effects of various sealers and medicaments. AB - The aim of this investigation was to quantify the discolouration of tooth roots caused by various medicaments and sealers. The roots of extracted teeth were chemo-mechanically prepared and the smear layer removed. The roots were filled with either Multi-Cal (Pulpdent Corporation, Watertown, MA, USA), Ledermix (Lederle Laboratories, Wolfratshausen, Germany), 2% chlorhexadine acetate in polyethylene glycol (PEG), 5% clindamycin in PEG, PEG alone (as a vehicle control), sealers AH26 (De Trey Dentsply, Zurich, Switzerland), AH Plus (De Trey Dentsply), an experimental epoxy resin with zirconium dioxide (Millenium Chemicals, Rockingham, Western Australia) or Araldite (Selleys Pty Ltd, Sydney, Australia). The roots were maintained at 37 degrees C in dark humid conditions and standardised images of the coronal surfaces recorded over 12 months. Ledermix caused the most darkening of the introduced medicaments, while calcium hydroxide and the materials in PEG did not cause darkening. AH26 caused more darkening than did the other sealers. It was concluded that the use of alternatives to Ledermix and AH26 should be considered when aesthetics are important. PMID- 22432820 TI - Bacterial leakage of GuttaFlow-filled root canals compared with Resilon/Epiphany and Gutta-percha/AH26-filled root canals. AB - The purpose of this study was to assess bacterial apical leakage in root canals obturated with GuttaFlow and compare this with the leakage of root canals obturated with Resilon/Epiphany or Gutta-percha/AH26. A total of 55 single-rooted human teeth were divided randomly into three experimental (n = 15) and two control groups (n = 5). Following a standardised preparation, the teeth were obturated with either GuttaFlow, Resilon/Epiphany or Gutta-percha/AH26. A two chamber bacterial model using Enterococcus faecalis was employed to assess bacterial apical leakage for a period of 60 days. A Kruskal-Wallis test showed no significant differences between the seal of root canals obturated with GuttaFlow, Resilon/Ephiphany or Gutta-percha/AH26. PMID- 22432821 TI - Bond strength and fracture analysis between resin cements and root canal dentin. AB - The aim of this research is to evaluate bond strength between translucent fibre posts (White Post DC, FGM or FRC Postec Plus, Ivoclar/Vivadent) and intraradicular dentin at three different levels (cervical, middle and apical) using a dual-cure (AllCem, FGM) or self-curing (Multilink, Ivoclar/Vivadent) resin cement. Also, the fracture type after push-out test was analysed under SEM. Thirty-two extracted single-root teeth were selected. After undergoing endodontic therapy, they were randomly divided into four groups according to their post type and resin cement. Root canals were etched using 37% phosphoric acid, and Excite DSC adhesive (Ivoclar/Vivadent) was applied in all groups. The root was sectioned to obtain nine 1-mm-thick slices (three per third: coronal, middle, apical). All slices were subjected to push-out tests. Data were analysed using two-way anova. The mean bond strengths vary from 6.6 (4.6) MPa [apical] to 11.9 (5.9) MPa [cervical]. There were no significant differences between groups. Pearson chi(2) test revealed significant differences in fracture types for all groups (P < 0.0001). The apical third had the lowest bond strengths and it was also shown to be the most critical region for luting fibre posts. PMID- 22432822 TI - Bond strength of Resilon/Epiphany compared with Gutta-percha and sealers Sealer 26 and Endo Fill. AB - This study evaluated the bond strength of Epiphany((r))/Resilon((r)) to radicular dentine and compared this with that of Gutta-percha sealed with Sealer 26 and also Endo Fill((r)). Fifteen human single-rooted extracted teeth had their root canals enlarged to a standardised internal root diameter of 1.5 mm. The teeth were filled with: Group I--Epiphany((r))/Resilon((r)) cones, Group II--Sealer 26((r))/Gutta-percha cones and Group III--Endo Fill((r))/Gutta-percha cones. Three 2 mm-thick cross-sections were obtained from each tooth (n = 15) and subjected to a push-out test (1 mm min(-1)). The means (MPa) were compared using anova /Newman-Keuls tests. There were no statistically significant differences between Group I and Group II (P > 0.01). Both bond strengths were significantly higher than that of Group III (P < 0.01). The root canal filling system Epiphany((r))/Resilon((r)) showed bond strength similar to that of Sealer 26((r))/Gutta-percha. Both were higher than that of Endo Fill((r))/Gutta-percha. PMID- 22432823 TI - Antibacterial substantivity of a new antibiotic-based endodontic irrigation solution. AB - The aim of this study was to evaluate the residual antibacterial activity of Tetraclean, MTAD and 5.25% sodium hypochlorite (NaOCl) in bovine root dentin in vitro. One hundred and ten dentin tubes prepared from bovine incisor teeth were infected in vitro for 14 days with Enterococcus faecalis. Thereafter, the specimens were divided into five groups as follows: Tetraclean; MTAD; 5.25% NaOCl; infected dentin tubes (positive control); and sterile dentin tubes (negative control). Dentin chips were collected using round burs into tryptic soy broth and after culturing, the number of colony-forming units (CFU) was counted. The number of CFU in all experimental groups was minimum after treatment, and the results obtained were significantly different from each other at any time period (P < 0.05). The Tetraclean group showed the most effective antibacterial action at all five experimental periods (P < 0.05). MTAD group showed the least antibacterial activity after treatment. However, at days 7, 14, 21 and 28 MTAD showed more effective antibacterial action than NaOCl. In each group, the number of CFU increased significantly by time-lapse (P < 0.05). In conclusion, the residual antibacterial activity of Tetraclean was significantly greater than MTAD and 5.25% NaOCl. PMID- 22432824 TI - Prophylactic intraligamentary injection of piroxicam (feldene) for the management of post-endodontic pain in molar teeth with irreversible pulpitis. AB - The purpose of this prospective research was to evaluate the post-endodontic pain reducing effect of piroxicam (feldene), a non-selective non-steroidal anti inflammatory drug. Pain following endodontic treatment is often linked to the inflammatory process as well as additional central mechanisms. The effects of intraligamentary injection of piroxicam have not previously been studied. Sixty five patients with irreversible pulpitis were randomly divided into two groups. The active group received intraligamentary injections totalling 0.4 mL of piroxicam, while the placebo group received the same amount of lidocaine. One appointment endodontic therapy was performed by a single endodontist. Visual Analogue Scale was used to record pain before treatment and 4, 8, 12, 24 and 48 h postoperatively. The decrease in the intensity of post-treatment pain between the two groups was very significant. Intraligamentary injection of piroxicam can be considered an effective method for reducing post-endodontic pain. PMID- 22432825 TI - Endodontic management of hypo-, meso- and hypertaurodontism: case reports. AB - Taurodontism is a morpho-anatomical developmental anomaly rarely seen in teeth. It is characterised by lack of constriction at the level of cementoenamel junction with elongated pulp chambers and apical displacement of bifurcation or trifurcation of roots. This gives the tooth a rectangular or cylindrical appearance. This paper reports successful endodontic therapy of cases with hypo-, meso- and hypertaurodontism in healthy individuals with no associated syndrome or anomaly. PMID- 22432834 TI - Meconium-stained amniotic fluid and hypoglycemia among term newborn infants. AB - To evaluate whether meconium-stained amniotic fluid (MSAF) is a risk factor for neonatal hypoglycemia. Retrospective recording of medical charts of full-term infants born following observation of meconium-stained amniotic fluid to examine glucose levels in the first hours of life. Out of 803 infants of the study group, 68 (8.5%) had glucose levels lower than 47 mg/dl. Most (6.7%) had mild hypoglycemia, and 14 (1.8%) had moderate or severe hypoglycemia (1.4% and 0.4% respectively). No infant developed clinical signs clearly related to hypoglycemia. Low-risk infants born following meconium-stained amniotic fluid are not at increased risk for neonatal hypoglycemia. PMID- 22432835 TI - Carbon dioxide mediated stereoselective copper-catalyzed reductive coupling of alkynes and thiols. AB - A simple protocol for the stereoselective copper-catalyzed hydrothiolation of alkynes under a CO(2) atmosphere has been developed. The stereoselectivity is determined by the presence/absence of a CO(2) atmosphere. The reaction system is robust and utilizes inexpensive, readily available substrates. A cyclic alkene/carboxylate copper complex intermediate is proposed as the key step in determining the stereoselectivity, and an equivalent amount of water is found to play an active role as a proton donor. PMID- 22432836 TI - Assessment of inflammation and fibrosis in non-alcoholic fatty liver disease by imaging-based techniques. AB - Non-alcoholic fatty liver disease (NALFD) is a burgeoning global health problem, and the assessment of disease severity remains a clinical challenge. Conventional imaging and clinical blood tests are frequently unable to determine disease activity (the degree of inflammatory change) and fibrotic severity, while the applicability of histological examination of liver biopsy is limited. Imaging platforms provide liver-specific structural information, while newer applications of these technologies non-invasively exploit the physical and chemical characteristics of liver tissue in health and disease. In this review, conventional and newer imaging-based techniques for the assessment of inflammation and fibrosis in NAFLD are discussed in terms of diagnostic accuracy, radio-pathological correlations, and practical considerations. In particular, recent clinical studies of ultrasound (US)-based and magnetic resonance elastography techniques are evaluated, while the potential of contrast-enhanced US and magnetic resonance spectroscopy techniques is discussed. The development and application of these techniques is starting to reduce the clinical need for liver biopsy, to produce surrogate end-points for interventional and observational clinical studies, and through this, to provide new insights into the natural history of NAFLD. PMID- 22432837 TI - Determination of the hydrogen isotopic compositions of organic materials and hydrous minerals using thermal combustion laser spectroscopy. AB - Hydrogen isotopic compositions of hydrous minerals and organic materials were measured by combustion to water, followed by optical isotopic analysis of the water vapor by off-axis integrated cavity output spectroscopy. Hydrogen and oxygen isotopic compositions were calculated by numerical integration of the individual isotopologue concentrations measured by the optical spectrometer. Rapid oxygen isotope exchange occurs within the combustion reactor between water vapor and molecular oxygen so that only hydrogen isotope compositions may be determined. Over a wide range in sample sizes, precisions were +/-3-4 per mil. This is comparable but worse than continuous flow-isotope ratio mass spectroscopy (CF-IRMS) methods owing to memory effects inherent in water vapor transfer. Nevertheless, the simplicity and reduced cost of this analysis compared to classical IRMS or CF-IRMS methods make this an attractive option to determine the hydrogen isotopic composition of organic materials where the utmost precision or small sample sizes are not needed. PMID- 22432838 TI - Assessment of hemostasis in platelet transfusion clinical trials with differential follow-up. PMID- 22432839 TI - Application of monoclonal antibodies as cancer therapy in solid tumors. AB - Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab- across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development. PMID- 22432840 TI - Current status of CETP inhibitors in the treatment of hyperlipidemia: an update. AB - INTRODUCTION: The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP). AREAS COVERED: Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction. PMID- 22432841 TI - Breakthrough pain-novel analgesics. AB - Breakthrough pain (BTP) is a transitory exacerbation of pain that occurs on a background of otherwise controlled pain. It is associated in conjunction with severe chronic pain and may result in impaired physical and psychological functioning, reduced effectiveness to opioids and also, increased financial burden. It manifests commonly in malignant pain, as manifested by well managed round the clock regular opioid medication but associated with intermittent sharp pain symptoms that are not controlled by the regular medication. It is a significant clinical problem and should be independently assessed and treated. The most common approach being used is 'rescue' medication--a short acting opioid in combination with the fixed-schedule opioid regimen. The lag time between peak pain intensity during an episode of BPT and onset of analgesia of most short acting opioids is approximately 30-60 minutes. This suggests that the effectiveness of supplemental medications for BTP might be improved with analgesic agents that have a more rapid onset of action. Traditionally the rapid onset analgesia for breakthrough pain has been achieved by administering potent opioids through sublingual route bypassing the first pass metabolism. However with recent advances in drug delivery systems, transmucosal and buccal routes have gained popularity. Pharmacokinetic studies have demonstrated a high early systemic exposure to opioids well over their therapeutic dose range resulting in management of the breakthrough pain. This article proposes to review the evidence base on the effectiveness of these novel opioid delivery systems in managing the breakthrough pain. PMID- 22432842 TI - Adherence to antiretroviral therapy among Iranian HIV/AIDS patients. AB - PURPOSE: Treatment adherence of 95% or higher is recommended for appropriate therapeutic response and improving the function of immune system in HIV positive patients. To the best of our knowledge, there was report of adherence to HAART regimen from Iran. In the present study, we have reported the HAART adherence rate of Iranian HIV positive patients. METHOD: In a twelve-month period, all patients older than 18 years old who referred to HIV clinic were on HAART regimen enrolled in the study. Beside demographic and clinical characteristics of Iranian HIV positive patients, Adherence to HAART was assessed by self-report and pill count methods at during the three consecutive months of the patients' visits. RESULTS: The mean of patients' adherence to HAART regimen based on the self report method was 69.4%, 64.6% and 62.8% in the first, second and third month of follow up, respectively. The mean of adherence rates in three months followup assessed by self-report (65.5%) and pill count (60.4%) methods were correlated significantly (r=0.93 and p < 0.001). Living with family members, changing the HAART regimen and stage of disease had a significant relationship with adherence rates. CONCLUSION: Although the adherence level of Iranian HIV infected patients is acceptable compared to other countries, the available antiretroviral medications are limited in our country, therefore, encouraging patients to have higher levels of adherence is more important. PMID- 22432843 TI - Polyethylenimine as a promising vector for targeted siRNA delivery. AB - Recent discovery of RNA interference (RNAi) technology for gene therapy has triggered explosive research efforts towards development of small interfering RNA (siRNA) as therapeutic modality for gene silencing. Owing to its large molecular weight (~13 kDa), polyanionic nature (~40 negative phosphate groups) and rapid enzymatic degradation, delivery of siRNA remains an unresolved issue. Hence, there arises a need of an appropriate delivery vector to overcome the intrinsic, poor intracellular uptake and limited in vitro and in vivo stability. Amongst the various non-viral delivery vectors, the application of polymeric vectors such as polyethylenimine (PEI) or its derivatives has attracted much attention due to its high transfection efficiency and ease of manipulation. PEI has been extensively investigated for DNA delivery, only recently this polymer has been employed for siRNA delivery. This review will focus on studies done on PEI to deliver siRNA, with emphasis on the targeted, self-assembled polymeric nanoparticles with promising potential to evolve as therapeutic tool in gene therapy. PMID- 22432844 TI - Pharmacogenetics and anesthetic drugs. AB - The incidence and potential for serious adverse drug reactions (SADRs) in anesthesia are high due to the narrow therapeutic indices of anesthetic and analgesic drugs and high interindividual variability in drug responses. Genetic factors contribute to a majority of these SADRs. Pharmacogenetics (PG), the study of genetic effects on drug action, is strongly related to the field of anesthesia; historically, succinylcholine apnea and malignant hyperthermia were among the first PG disorders reported. Recent years have strengthened this affiliation with an emerging wide base of knowledge of the effects of genetic variations on the pharmacodynamics and pharmacokinetics of anesthetic drugs. Here, we review the history of anesthetic PG, the important genes influencing enzymes involved in anesthetic drug metabolism, the influence of genotypic expression and the potential ramifications of recent discoveries on the practice of clinical anesthesia. Epigenetics and functional genomics are also discussed. The article also addresses various critical deficits in our current knowledge of PG related to anesthesia that account for the minimal clinical translation of the findings in this area in the present time. The review concludes that in addition to enhanced data generation facilitated by rapidly evolving genetic techniques, robust clinical study designs in a large sample and sound statistical analyses are essential prerequisites for the successful clinical implementation of research findings to individual perioperative care for every patient. PMID- 22432845 TI - Oral beclomethasone dipropionate: a critical review of its use in the management of ulcerative colitis and Crohn's disease. AB - Crohn's disease and ulcerative colitis are inflammatory bowel diseases characterised by a chronic relapsing course. Corticosteroids represent the mainstay of medical treatment of inflammatory bowel disease for the induction of remission. Despite the high efficacy of systemic steroids, their use is limited by the high incidence of potentially serious adverse effects. The topically acting steroids are synthetic compounds characterised by high anti-inflammatory activity and low systemic effects by virtue of efficient first-pass hepatic inactivation. Budesonide and Beclomethasone Dipropionate are the two most studied topically acting steroids in inflammatory bowel disease. Oral Budesonide has been extensively studied in the treatment of mild to moderate ileo-caecal Crohn's disease but few data are available concerning oral Beclomethasone Dipropionate. This review focuses on the available evidence of efficacy and safety of oral Beclomethasone Dipropionate in the management of ulcerative colitis and Crohn's disease and a possible role of this steroid in clinical practice is suggested. PMID- 22432846 TI - GLP-1 agonists exenatide and liraglutide: a review about their safety and efficacy. AB - Recently incretin-based therapies have been developed in the clinical practice, this class includes both the dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin), and the glucagon-like peptide- 1 (GLP-1) receptor agonists [exenatide, exenatide long acting release (LAR) and liraglutide]. In particular exenatide and liraglutide have structural similarity and bind to the GLP-1 receptor, displaying a similar broad range of activities relevant to improving glycemic control, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose dependent manner. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake; it also promotes beta-cell proliferation and probably neogenesis, while reducing apoptosis in animal models. We conducted a review analyzing clinical efficacy and safety of GLP-1 receptor agonists exenatide and liraglutide, both alone and in combination with other anti diabetic drugs, including the most important studies about them in the latest ten years. We concluded that GLP-1 receptor agonists appear to be a good choice to decrease HbA1c levels and to lower postprandial blood glucose levels. They also suppress glucagon secretion and slow gastric motility. They also have positive effects on beta-cell function and they gave a significant decrease of body weight. They are not associated with hypoglycemia, but cause a relatively high frequency of gastrointestinal disturbances, with some patients experiencing one or more episodes of nausea, vomiting, or diarrhea. However, after an evaluation of the advantages and the disadvantages, we concluded that, once metformin fails to reach an adequate glycemic control, GLP-1 receptor agonists can be a valid alternative, especially in obese type 2 diabetic patients. GLP-1 receptor agonists should be considered also in patients in therapy with metformin and another agent, such as a sulfonylurea, because of the minor risk of developing hypoglycemia and the positive effect on body weight. PMID- 22432847 TI - Time course of adenosine-induced pulmonary vein reconnection after isolation: implications for mechanism of dormant conduction. AB - BACKGROUND: Adenosine (ADO) has been proposed to reconnect isolated pulmonary veins (PVs) postablation through hyperpolarization of damaged myocytes in an animal model. However, PV reconnection can occur via ADO-mediated sympathetic activation. We sought to determine the mechanism of ADO-induced PV reconnection in the clinical setting by characterizing its time course and location in patients undergoing PV isolation. METHODS: Seventy-four patients (61 male; age 61 +/- 10 years) undergoing PV isolation for atrial fibrillation (54 [73%] paroxysmal and 19 [27%] persistent) were studied. After each PV was isolated, a 12-mg intravenous bolus of ADO was administered and onset, offset, and location of ADO-induced PV reconnection and onset and offset of bradycardia were analyzed. RESULTS: In 22 (30%) patients, ADO-induced PV reconnection occurred in 34 of 270 (13%) PVs. In 24 (71%) PVs, the duration of ADO-induced reconnection exceeded that of bradycardia. The onset of ADO-induced reconnection occurred before the onset of bradycardia in 10 (30%) PVs and during bradycardia in 23 (70%) PVs. No PVs exhibited onset of reconnection after resolution of bradycardia. Common sites of PV reconnection included the carinal region (41% of right PVs and 29% of left PVs) and left PV-atrial appendageal ridge region (35% of left PVs). CONCLUSIONS: ADO-induced PV reconnection occurs during the bradycardic phase of the ADO bolus response and not during the late tachycardic phase. ADO-induced PV dormant conduction is closely associated with the negative dromotropic effects of ADO and suggests that hyperpolarization of the resting membrane is the unifying mechanism. PMID- 22432848 TI - Fluorescein angiography of the canine posterior segment using a dSLR camera adaptor. AB - PURPOSE: To describe the use of a digital single lens reflex (dSLR) camera adaptor for conducting posterior segment fluorescein angiography in canines. METHODS: Ten beagle dogs free of ocular and systemic disease were used. All dogs received maropitant citrate (1.0 mg/kg SQ), diphenhydramine (2.0 mg/kg SQ), and topical 1% tropicamide 20 min prior to sedation using butorphanol (0.2 mg/kg IV). Standard color and red-free fundus images were obtained prior to the administration of 10% sodium fluorescein (20 mg/kg IV). Image acquisition was performed using a dSLR camera (Canon 7D), dSLR camera adaptor, camera lens (Canon 60 mm macro), and a 60D indirect ophthalmic lens, in addition to an accessory flash (Canon 580EXII). Two combinations of excitation and barrier filters were assessed (absorptive vs. interference). Imaging occurred at a rate of 1/s immediately following the fluorescein bolus for a total of 30 s and then at 1, 2, 3, 4, and 5 min. RESULTS: Quality high resolution fluorescein angiographic images of the canine posterior segment were obtainable. All angiographic phases were identified and time sequences were recorded. Use of interference filters improved image contrast and transmission properties as compared to absorptive filters. No adverse events were noted. CONCLUSIONS: The described dSLR camera adaptor provides an alternative to existing posterior segment imaging systems capable of performing fluorescein angiography. High resolution image acquisition occurred at a fraction of the cost of established imaging systems. PMID- 22432849 TI - Towards an inhalative in vivo application of immunomodulating gelatin nanoparticles in horse-related preformulation studies. AB - Delivering active ingredients using biocompatible and biodegradable carriers such as gelatin nanoparticles (GNPs) to the lung constitutes a promising non-invasive route of administration. However, the pulmonary delivery of nanoparticle-based immunotherapy is still a field that requires more clarification. In this study, GNPs loaded with cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODN) loaded and plain GNPs were aerosolised either by a conventional pressured metered dose inhaler (pMDI) or by active or passive vibrating-mesh (VM) nebulisers. GNP sizes after nebulisation by active and passive VM nebulisers were 248.2 +/- 7.34 and 222.3 +/- 1.42 nm, respectively. GNP concentrations after aerosolisation were found consistent and second-stage particle deposition in an impinger was up to 65.68 +/- 11.2% of the nebulised dose. VM nebulisers produced high fine particle fractions, while pMDIs did not. Nebulised CpG-ODN-loaded GNPs remained capable to stimulate IL-10 release (225.2 +/- 56.3 pg/ml) in vitro from equine alveolar lymphocytes. Thus, a novel system for pulmonary GNP-mediated immunotherapy in vivo was established. PMID- 22432850 TI - Comparative evaluation of cyclosporine A/HPbetaCD-incorporated PLGA nanoparticles for development of effective ocular preparations. AB - To improve poor water solubility of cyclosporine A (CsA), hydroxypropyl-beta cyclodextrin (HPbetaCD) was incorporated into the nanoparticle formulation. Solid complexes of CsA with HPbetaCD in different ratios were prepared by the kneading method. CsA containing alone or in combination with HPbetaCD in poly-lactide-co glycolide (P-CsA or P-CsA-HPbetaCD) nanoparticles were prepared by the emulsification solvent evaporation method. The mean size of CsA-loaded NPs was found to be approximately 220 nm. The solubility of CsA was significantly improved and the phase solubility diagram of CsA-HPbetaCD systems showed an A(L) type phase. Nanoparticles showed high CsA encapsulation efficiency (88%) and production yield (89%). Release rate was increased by the presence of HPbetaCD and total cumulative release ranged from 75% to 96% in 24 h. In vitro cytotoxicity study assay resulted in a low toxicity for all types of nanoparticles. After 6 h incubation period, the cellular uptake was found at 33% and 32% for P-CsA and P-HPbetaCD-CsA nanoparticles, respectively. PMID- 22432851 TI - Endocrine complications in primary immunodeficiency diseases in Japan. AB - BACKGROUND: In spite of the accumulating evidence on the interaction between the immune and endocrine systems based on the recent progress in molecular genetics, there have been few epidemiological studies focused on the endocrine complications associated with primary immunodeficiency diseases (PID). OBJECTIVE: To investigate the prevalence and clinical features of endocrine complications in patients with PID in a large-scale study. DESIGN AND PARTICIPANTS: This survey was conducted on patients with PID who were alive on 1 December 2008 and those who were newly diagnosed and died between 1 December 2007 and 30 November 2008 in Japan. We investigated the prevalence and the clinical data of the endocrine complications in 923 patients with PID registered in the secondary survey. RESULTS: Among 923 PID patients, 49 (5.3%) had endocrine disorders. The prevalence of the endocrine diseases was much higher in patients with PID than in the general population in the young age group, even after excluding patients with immune dysregulation. CONCLUSIONS: Endocrine disorders are important complications of PID. Analysis of the endocrine manifestations in patients with PID in a large-scale study may provide further insights into the relationship between the immune and endocrine systems. PMID- 22432852 TI - Molecular dynamics and experimental study of conformation change of poly(N isopropylacrylamide) hydrogels in mixtures of water and methanol. AB - The conformation transition of poly(N-isopropylacrylamide) hydrogel as a function of the methanol mole fraction in water/methanol mixtures is studied both experimentally and by atomistic molecular dynamics simulation with explicit solvents. The composition range in which the conformation transition of the hydrogel occurs is determined experimentally at 268.15, 298.15, and 313.15 K. In these experiments, cononsolvency, i.e., collapse at intermediate methanol concentrations while the hydrogel is swollen in both pure solvents, is observed at 268.15 and 298.15 K. The composition range in which cononsolvency is present does not significantly depend on the amount of cross-linker. The conformation transition of the hydrogel is caused by the conformation transition of the polymer chains of its backbone. Therefore, conformation changes of single backbone polymer chains are studied by massively parallel molecular dynamics simulations. The hydrogel backbone polymer is described with the force field OPLS AA, water with the SPC/E model, and methanol with the model of the GROMOS-96 force field. During simulation, the mean radius of gyration of the polymer chains is monitored. The conformation of the polymer chains is studied at 268, 298, and 330 K as a function of the methanol mole fraction. Cononsolvency is observed at 268 and 298 K, which is in agreement with the present experiments. The structure of the solvent around the hydrogel backbone polymer is analyzed using H-bond statistics and visualization. It is found that cononsolvency is caused by the fact that the methanol molecules strongly attach to the hydrogel's backbone polymer, mainly with their hydroxyl group. This leads to the effect that the hydrophobic methyl groups of methanol are oriented toward the bulk solvent. The hydrogel+solvent shell hence appears hydrophobic and collapses in water-rich solvents. As more methanol is present in the solvent, the effect disappears again. PMID- 22432853 TI - Aggressive sinonasal natural killer/T-cell lymphoma mimicking refractory sinusitis in a 4-year-old boy. AB - Pediatric patients with nasal symptoms are common, and most of them usually have inflammatory diseases, such as sinusitis, chronic rhinitis, nasal polyp, or adenotonsillar hypertrophy. Rarely, however, these inflammatory symptoms may be associated with more sinister pathology. Recently, we experienced a case of a 4 year-old boy with sinonasal natural killer (NK)/T-cell lymphoma whose initial symptoms were of nasal obstruction and mucopurulent nasal discharge. PMID- 22432855 TI - MoO(3-x) nanowire arrays as stable and high-capacity anodes for lithium ion batteries. AB - In this study, vertical nanowire arrays of MoO(3-x) grown on metallic substrates with diameters of ~90 nm show high-capacity retention of ~630 mAhg(-1) for up to 20 cycles at 50 mAg(-1) current density. Particularly, they exhibit a capacity retention of ~500 mAhg(-1) in the voltage window of 0.7-0.1 V, much higher than the theoretical capacity of graphite. In addition, 10 nm Si-coated MoO(3-x) nanowire arrays have shown a capacity retention of ~780 mAhg(-1), indicating that hybrid materials are the next generation materials for lithium ion batteries. PMID- 22432856 TI - Stability of citrate, PVP, and PEG coated silver nanoparticles in ecotoxicology media. AB - Silver nanoparticles (AgNPs) are present in the environment and a number of ecotoxicology studies have shown that AgNPs might be highly toxic. Nevertheless, there are little data on their stability in toxicology media. This is an important issue as such dynamic changes affect exposure dose and the nature of the toxicant studied and have a direct impact on all (eco)toxicology data. In this study, monodisperse citrate, PVP, and PEG coated AgNPs with a core size of approximately 10 nm were synthesized and characterized; their behavior was examined in standard OECD media used for Daphnia sp. acute and chronic tests (in the absence of Daphnia). Surface plasmon resonance, size, aggregation, and shape were monitored over 21 days, comparable to a chronic exposure period. Charge stabilized particles (citrate) were more unstable than sterically stabilized particles. Replacement of chloride in the media (due to concerns over chloride silver interactions) with either nitrate or sulfate resulted in increased shape and dissolution changes. PVP-stabilized NPs in a 10-fold diluted OECD media (chloride present) were found to be the most stable, with only small losses in total concentration over 21 days, and no shape, aggregation, or dissolution changes observed and are recommended for exposure studies. PMID- 22432857 TI - Structure and bonding in coinage metal halide clusters M(n)X(n), M = Cu, Ag, Au; X = Br, I; n = 1-6. AB - Ab initio calculations in the framework of density functional theory (DFT) were performed to study the lowest-energy isomers of noble metal halide clusters M(n)Br(n) and M(n)I(n), for M = Cu, Ag, or Au and n = 1-6. For all species, the most stable structures were found to be cyclic arrangements. Calculated bond lengths and infrared frequencies were compared with the available experimental data. The nature of the ionocovalent bonding was characterized. The stability and fragmentation were also investigated. The present work confirms previous observations on the particular stability of the trimer. PMID- 22432858 TI - Regioselectivity switch achieved in the palladium catalyzed alpha-arylation of enones by employing the modified Kuwajima-Urabe conditions. AB - A new regioselective approach to the synthesis of alpha-aryl enones is reported. This represents an important application of the Kuwajima-Urabe protocol toward the synthesis of this simple albeit complex functional array. Several alpha-aryl enones were synthesized by the palladium catalyzed arylation of triethylsilylenol ethers of enones with high regioselectivity and broad scope, utilizing sterically encumbered electron-rich phosphine ligands to drive the reaction. PMID- 22432861 TI - Response to: a web-based referral system for neurosurgery--a solution to our problems? PMID- 22432862 TI - Insight into the molecular basis of aromatic polyketide cyclization: crystal structure and in vitro characterization of WhiE-ORFVI. AB - Aromatic polyketides are biologically active natural products. Many important pharmaceuticals are derived from aromatic polyketides. Especially important in aromatic polyketide biosynthesis is the regiospecific cyclization of a linear, preassembled polyketide chain catalyzed by aromatase/cyclase (ARO/CYC), which serves as a key control point in aromatic ring formation. How different ARO/CYCs promote different cyclization patterns is not well understood. The whiE locus of Streptomyces coelicolor A3(2) is responsible for the biosynthesis of an aromatic polyketide precursor to the gray spore pigment. The WhiE ARO/CYC catalyzes the regiospecific C9-C14 and C7-C16 cyclization and aromatization of a 24-carbon polyketide chain. WhiE ARO/CYC shares a high degree of similarity to another nonreducing PKS ARO/CYC, TcmN ARO/CYC. This paper presents the apo crystal structure of WhiE ARO/CYC, and cocrystal structures of WhiE and TcmN ARO/CYCs bound with polycyclic aromatic compounds that mimic the respective ARO/CYC products. Site-directed mutagenesis coupled with in vitro PKS reconstitution assays was used to characterize the interior pocket residues of WhiE ARO/CYC. The results confirmed that the interior pocket of ARO/CYCs is a critical determinant of polyketide cyclization specificity. A unified ARO/CYC-mediated cyclization mechanism is proposed on the basis of these structural and functional results. PMID- 22432863 TI - Current advances and perspectives in the treatment of advanced melanoma. AB - Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined. PMID- 22432864 TI - Exercise training utilizing body weight-supported treadmill walking with a young adult with cerebral palsy who was non-ambulatory. AB - PURPOSE: The purpose of this case report is to determine the effects of exercise training using body weight-supported treadmill walking (BWSTW) with an 18-year old male diagnosed with Cerebral palsy (CP) who was non-ambulatory and not receiving physical therapy. CASE DESCRIPTION: Outcome measures included the Pediatric Quality of Life Inventory (PedsQL), the Pediatric Evaluation of Disability Inventory (PEDI), heart rate (HR), rate of perceived exertion, 3 minute walk test and physiological cost index (PCI). BWSTW sessions took place twice a week for 6 weeks with a reduction of approximately 40% of the patient's weight. RESULTS: Over-ground 3-minute walk test distance and PCI were essentially unchanged. BWSTW exercise time increased by 67% with a 43% increase in speed while average working HR decreased by 8%. BWSTW PCI decreased by 26%. PedsQL parent report improved in all domains. PedsQL self-report demonstrated a mild decrease. PEDI showed improvements in self-care and mobility. DISCUSSION: Exercise utilizing BWSTW resulted in a positive training effect for this young adult with CP who was non-ambulatory. Developing effective and efficient protocols for exercise training utilizing BWSTW may aid in the use of this form of exercise and further quantify outcomes. Ensuring that young adults with CP have safe and feasible options to exercise and be physically active on a regular basis is an important role of a physical therapist. PMID- 22432866 TI - Method for the sequential online analysis of enzyme reactions based on capillary electrophoresis. AB - We have developed an easy-to-operate and effective method for performing the sequential online analysis of enzyme reactions based on capillary electrophoresis (CE). The system was constructed by passing two capillaries through a sample vial at a distance of 5 MUm between the capillary ends. Direct online sample injection and sequential CE analysis were achieved by periodically switching the high voltage power supply off and on, without any physical disturbance of the capillary inlet. The sample was injected via concentration diffusion with in column derivatization of the amino acids occurring at the interface of the capillaries. High reproducibility of the sequential injections was demonstrated with relative standard deviation values (n = 20) of 1.01%, 1.25%, and 0.80% for peak height, peak area, and migration time, respectively. Sequential online CE enzyme assay of a glutamate pyruvate transaminase catalyzed enzyme reaction was carried out by simultaneously monitoring the substrate consumption and the product formation every 30 s from the beginning to the end of the reaction. The Michaelis constants for the reaction were obtained and were found to be in good agreement with the results of traditional off-line enzyme assays. Our method has great potential for usage in sequential online CE analysis of chemical reactions with in-column chemical derivatization of the analytes for ultraviolet or laser induced fluorescence detection. PMID- 22432867 TI - Ethics in electrophysiology: who speaks for this man? AB - In this case, a patient who is incapable of participating in health-care decisions requires a pacemaker generator replacement. Because the pacemaker may no longer be necessary, the issues of surrogacy and surrogate decision-making are considered. Where there are no involved family members, each state has procedures for finding an appropriate ombudsman for the patient who can assist in healthcare choices. PMID- 22432868 TI - Metabolic syndrome is an independent risk factor for synchronous colorectal neoplasm in patients with gastric neoplasm. AB - BACKGROUND AND AIM: There are no data on how metabolic syndrome (MetS) affects the prevalence of synchronous colorectal neoplasm (CRN) in gastric neoplasm (GN) patients. The aim of this study was to investigate a model for risk stratification for colorectal screening by evaluating the clinical characteristics of synchronous CRN in GN patients classified according to the presence of MetS. METHODS: A cross-sectional, case-control study of 492 patients (368 males and 124 females) with GN, and 492 age-matched healthy controls undergoing simultaneous upper endoscopy and colonoscopy, was conducted. RESULTS: The GN group involved 446 patients without MetS, and 46 patients with MetS. In total, 177 (39.7%) and 28 (60.9%) synchronous CRN were detected in GN patients without MetS and with MetS, respectively (P=0.006). A total of 143 (34.7%) synchronous colorectal adenomas were detected in GN patients without MetS, whereas 17 (48.6%) were detected in GN patients with MetS (P=0.101), as well as more synchronous colorectal cancers (11.2% vs 37.9%, P<0.001). A multivariate logistic regression analysis revealed that the presence of GN (OR=1.54, 95% CI: 1.18-2.00, P=0.001) and the presence of MetS (odds ratio=1.82, 95% confidence interval: 1.19-2.78, P=0.006) were significant independent risk factors associated with the prevalence of CRN. The frequency of synchronous CRN in GN patients with MetS was 1.96 times greater than that in the GN group without MetS. CONCLUSION: The risk of synchronous CRN is significantly increased by the presence of GN, especially in MetS patients. Screening for synchronous CRN is highly recommended for GN patients with MetS. PMID- 22432870 TI - Design, synthesis of 4-aminoquinoline-derived thiazolidines and their antimalarial activity and heme polymerization inhibition studies. AB - The present study describes the synthesis of a series of new 4-aminoquinoline derived thiazolidines and evaluation of their antimalarial activity against a NF 54 strain of Plasmodium falciparum in vitro and N-67 strain of Plasmodium yoelii in vivo. Among the series, two compounds, 2-(4-chloro-phenyl)-thiazolidine-4 carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (14) and 2-(2,6-dichloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin 4-ylamino)-ethyl]-amide hydrochloride (22) exhibited significant suppression of parasitaemia in the in vivo assay. All the analogues were found to form strong complex with haematin and inhibited the beta-haematin formation in vitro. These results suggest that these compounds act on heme polymerization target. PMID- 22432871 TI - Temperature-dependent branching ratios of deuterated methoxy radicals (CH2DO*) reacting with O2. AB - The methoxy radical is an intermediate in the atmospheric oxidation of methane, and the branching ratio (k(1a)/k(1b)) (CH(2)DO* + O(2) -> CHDO + HO(2) (1a) and CH(2)DO* + O(2) -> CH(2)O + DO(2) (1b)) strongly influences the HD/H(2) ratio in the atmosphere, which is widely used to investigate the global cycling of molecular hydrogen. By using the FT-IR smog chamber technique, we measured the yields of CH(2)O and CHDO from the reaction at 250-333 K. Kinetic modeling was used to confirm the suppression of secondary chemistry. The resulting branching ratios are well fit by an Arrhenius expression: ln(k(1a)/k(1b)) = (416 +/- 152)/T + (0.52 +/- 0.53), which agrees with the room-temperature results reported in the only previous study. The present results will be used to test our theoretical understanding of the role of tunneling in the methoxy + O(2) reaction, which is the prototype for the entire class of alkoxy + O(2) reactions. PMID- 22432872 TI - An/micr-ophthalmia, cleft lip/palate, and short limbs: a new syndrome simulating a short rib syndrome. AB - We report on a male infant born at 38 weeks of gestation with hydrocephalus, right anophthalmia, left microphthalmia, cleft palate, midline cleft of lip, and microphallus. Autopsy showed pulmonary bronchial lymphangiectasia, hepatic periportal fibrosis, adrenal agenesis, ventricular septal defect, aortic stenosis, and undescended testes. The radiographic findings include short limbs and mild shortness of ribs. Karyotype with high-resolution banding was normal (46,XY). The combination of anomalies in this case could suggest a ciliopathy and may represent a new entity similar to that described by Cideciyan et al. [1]. PMID- 22432873 TI - Glassy behavior of denatured DNA films studied by differential scanning calorimetry. AB - We use differential scanning calorimetry (DSC) to study the properties of DNA films, made of oriented fibers, heated above the thermal denaturation temperature of the double helical form. The films show glassy properties that we investigate in two series of experiments, a slow cooling at different rates followed by a DSC scan upon heating and aging at a temperature below the glass transition. Introducing the fictive temperature to characterize the glass allows us to derive quantitative information on the relaxations of the DNA films, in particular to evaluate their enthalpy barrier. A comparison with similar aging studies on PVAc highlights some specificities of the DNA samples. PMID- 22432874 TI - Heteroepitaxial growth of GaSb nanotrees with an ultra-low reflectivity in a broad spectral range. AB - We report on the growth of GaSb nanotrees on InAs { 1 1 1}(B) substrates by chemical beam epitaxy. GaSb nanotrees form by the nucleation of Ga droplets on the surface of < 1 1 1>(B) oriented GaSb nanowires followed by the epitaxial growth of branches catalyzed by these Ga droplets. In the tip region, the trunks of the GaSb nanotrees are periodically twinned, which is attributed to a change of the effective V/III ratio at the later stage of growth as a consequence of the change in surface structure. The reflectivity of a forest of nanotrees was measured for a broad spectral range and compared to the reflectivity of a GaSb ( 1 1 1)(B) wafer and of GaSb nanowires. At wavelengths from 500 to 1700 nm, the presence of GaSb nanotrees decreased the reflection by three orders of magnitude compared to a blank GaSb substrate. PMID- 22432875 TI - Tissue-specific transcriptome analysis in nodules of Lotus japonicus. AB - Legume plants can establish symbiotic nitrogen fixation (SNF) with rhizobia mostly in root nodules, where rhizobia-infected cells are accompanied by uninfected cells in a mosaic pattern. Inside the mature nodules of the legume, carbon and nitrogen nutrients between host plant cells and their resident bacteria are actively exchanged. To elucidate the metabolite dynamics relevant for SNF in nodules, three tissues from a nodule of a model legume, Lotus japonicus, were isolated using laser microdissesction, and transcriptome analysis was done by an oligoarray of 60-mer length representing 21,495 genes. In our tissue-specific profiling, many genes were identified as being expressed in nodules in a spatial-specific manner. Among them, genes coding for metabolic enzymes were classified according to their function, and detailed data analysis showed that a secondary metabolic pathway was highly activated in the nodule cortex. In particular, a number of metabolic genes for a phenylpropanoid pathway were found as highly expressed genes accompanied by those encoding putative transporters of secondary metabolites. These data suggest the involvement of a novel physiological function of phenylpropanoids in SNF. Moreover, five representative genes were selected, and detailed tissue-specific expression was characterized by promoter-beta-glucuronidase experiments. Our results provide a new data source for investigation of both nodule differentiation and tissue specific physiological functions in nodules. PMID- 22432876 TI - An immunodominant membrane protein (Imp) of 'Candidatus Phytoplasma mali' binds to plant actin. AB - The phytopathogenic, cell-wall-less phytoplasmas exhibit a dual life cycle: they multiply in the phloem of their host plant and in the body of their insect vector. Their membrane proteins are in direct contact with both hosts and are supposed to play a crucial role in the phytoplasma spread within the plant as well as by the insect vector. Three types of nonhomologous but highly abundant and immunodominant membrane proteins (IDP) have been identified within the phytoplasmas: Amp, IdpA, and Imp. Although recent results indicate that Amp is involved in vector specificity interacting with insect proteins such as actin, little is known about the interaction of IDP with the plant. We could demonstrate that transiently expressed Imp of 'Candidatus Phytoplasma mali' as well as the Imp without transmembrane domain (Imp?Tm) bind with plant actins in vivo. Moreover, in vitro co-sediment and binding assays showed that Escherichia coli expressed recombinant Imp?Tm-His binds to both G- and F-actins isolated from rabbit muscle. Transgenic plants expressing Imp- or Imp?Tm-green fluorescent protein did not exhibit any remarkable change of phenotype compared with the wild type plant. These results indicate that Imp specifically binds to plant actin and a role of Imp-actin binding in phytoplasma motility is hypothesized. PMID- 22432877 TI - Relevance of pharmacokinetics to antibiotic dosing in critically ill patients. PMID- 22432878 TI - A new slant to the Z ring and bacterial cell branch formation. AB - Rod-shaped bacteria such as Escherichia coli accurately maintain their shape from generation to generation. The cytoskeletal proteins MreB and FtsZ, which respectively guide parallel growth of the sidewall and perpendicular growth of the division septum, are important to maintain a straight sidewall and uniformly rounded cell poles. FtsZ normally assembles into a ring at the cell midpoint, called the Z ring, which is oriented perpendicular to the cell's axis and is thus in perfect position to guide growth of a perpendicular septum. In this issue of Molecular Microbiology, Potluri et al. show that low molecular weight penicillin binding proteins, particularly PBP5, have a role in maintaining the perpendicular geometry of the Z ring and subsequent septum in E. coli. When these factors are absent or perturbed, division septa are readily deformed, which results in abnormal cell poles that often bifurcate over time to generate branches. The data suggest that cellular branching in E. coli is specifically induced by aberrant septation events caused by mis-oriented Z rings and not by deformation of a growing cell pole or emergence of new tips from the sidewall, which are likely mechanisms of branching in other bacterial families. PMID- 22432880 TI - The challenge of relaying the right public health messages in allergy. PMID- 22432881 TI - Allergy in children: practical recommendations of the Finnish Allergy Programme 2008-2018 for prevention, diagnosis, and treatment. AB - The Finnish Allergy Programme 2008-2018 is a comprehensive plan intended to reduce the burden of allergies. One basic goal is to increase immunologic tolerance and change attitudes to encourage health instead of medicalizing common and mild allergy symptoms. The main goals can be listed as to: (i) prevent the development of allergic symptoms; (ii) increase tolerance to allergens; (iii) improve diagnostics; (iv) reduce work-related allergies; (v) allocate resources to manage and prevent exacerbations of severe allergies, and (vi) reduce costs caused by allergic diseases. So far, the Allergy Programme has organized 135 educational meetings for healthcare professionals around Finland. These meetings are multidisciplinary meetings gathering together all healthcare professionals working with allergic diseases. Since the start of the program in spring 2008, more than 7000 participants have taken part. Educational material for patient care has been provided on special Web sites/therapeutic portals, which can be accessed by all physicians caring for allergic patients. Local Allergy Working Groups have been created in different parts of Finland. As a part of the Programme, a set of guidelines for child welfare clinics was prepared. Child welfare clinics have a key role in the screening of illnesses and providing advice to families with a symptomatic child. The guidelines aimed to facilitate pattern recognition and clinical decision making for public health nurses and doctors are described in this paper. PMID- 22432882 TI - Allergy to goat's and sheep's milk in a population of cow's milk-allergic children treated with oral immunotherapy. AB - BACKGROUND: Cow's milk oral immunotherapy (CMOIT) is a recognized treatment for persistent cow's milk (CM) allergy. However, further data are necessary on tolerance to milk from other mammals. OBJECTIVE: To describe the clinical and immunologic features of goat's and sheep's milk (GSM) allergy in patients who tolerated CM after CMOIT. METHODS: Fifty-eight CM-allergic patients who successfully underwent CMOIT in our department were evaluated using skin prick test (SPT), specific immunoglobulin (Ig) E determination, enzyme-linked immunoassay (ELISA), and controlled oral challenge to assess allergy to GSM. Statistical analysis was carried out to identify markers of allergy to GSM. RESULTS: Fifteen of 58 (25.9%) patients were allergic to either goat's or sheep's milk or to both, as confirmed by a controlled positive oral challenge. Forty-seven percent of all positive oral challenges were classified as anaphylactic reactions. Specific IgE to CM casein, goat's whole milk, and sheep's whole milk was 13.2, 18.0, and 21.4 kU(A)/l in the group of GSM-allergic patients and 6.6, 6.5, and 6.5 kU(A) /l in the GSM-non-allergic patients (p < 0.05). Decision-making cut-off points based on sIgE for diagnosing symptomatic GSM allergy could not be determined. ELISA inhibition assays showed limited cross reactivity (up to 77.2%) between CM casein and GSM casein in the group of GSM allergic patients in contrast with almost 100% in GSM-not-allergic patients. CONCLUSION: We found a high prevalence (26%) of allergy to GSM in our population of CM-allergic children treated with oral immunotherapy. Therefore, tolerance to GSM should be assessed in order to provide accurate nutritional advice and minimize life-threatening accidental intake. Specific IgE to CM casein, goat's and sheep's whole milk is a good marker of this allergy. Although CM oral immunotherapy is a specific treatment for CM allergy, it may not be effective against allergy to the milk of other mammals. PMID- 22432883 TI - Risk of asthma and allergic outcomes in the offspring in relation to maternal food consumption during pregnancy: a Finnish birth cohort study. AB - BACKGROUND: Epidemiological and immunological studies suggest that maternal diet during pregnancy might affect the development of allergic diseases in the offspring. The authors set out to study the effect of maternal food consumption during pregnancy on the emergence of the International Study of Asthma and Allergies in Childhood (ISAAC)-based allergic outcomes: asthma, allergic rhinitis, and wheeze by the 5 yr of age. METHODS: Data from 2441 children at 5 yr of age were analyzed within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study, a population-based birth cohort study. Maternal diet was assessed with a validated food frequency questionnaire. RESULTS: In multiple regression models adjusted for known confounders, low maternal consumption of leafy vegetables (adjusted odds ratio [aOR]: 1.55; 95% CI: 1.21, 1.98), malaceous fruits (aOR: 1.45; 95% CI: 1.15, 1.84), and chocolate (aOR: 1.36; 95% CI: 1.09, 1.70) were positively associated with the risk of wheeze in children. High maternal consumption of fruit and berry juices was positively associated with the risk of allergic rhinitis (aOR: 1.40; 95% CI: 1.03, 1.90) in children. No associations were observed between maternal food consumption and asthma. CONCLUSIONS: Development of allergic diseases in preschool children may be influenced by intrauterine exposure to maternal diet. PMID- 22432884 TI - Abnormal IL-7 signaling may lead to the loss of bone mineral density in common variable immunodeficiency. PMID- 22432887 TI - Tree nut introduction in peanut allergic children is not without risk. PMID- 22432888 TI - Perspective on dabigatran etexilate dosing: why not follow standard pharmacological principles? PMID- 22432889 TI - Electrophysiological studies in American Quarter horses with neuroaxonal dystrophy. AB - OBJECTIVE: Neuroaxonal dystrophy (NAD) is a disease characterized by the sudden onset of neurologic signs in horses ranging from 4 to 36 months of age. Equine degenerative myeloencephalopathy (EDM), a disease that has been associated with low vitamin E concentrations, is considered a more advanced form of NAD. The objective of this report is to describe the electrophysiological features of NAD/EDM in American Quarter horses (QHs). HORSES: Six NAD/EDM-affected QHs and six unaffected QHs were evaluated by ophthalmic examination and electroretinography. Five of the NAD/EDM-affected QH and five unaffected QHs were also evaluated by electroencephalography (EEG). RESULTS: Ophthalmic examination, ERGs, and EEGs were unremarkable in NAD/EDM cases. CONCLUSIONS: Neuroaxonal dystrophy/EDM does not appear to cause clinical signs of ocular disease or functional ERG/EEG deficits in QHs. PMID- 22432890 TI - Phasic GABAA -receptor activation is required to suppress epileptiform activity in the CA3 region of the immature rat hippocampus. AB - PURPOSE: Despite the consistent observation that gamma-aminobutyric acid A (GABA(A) ) receptors mediate excitatory responses at perinatal stages, the role of the GABAergic system in the generation of neonatal epileptiform activity remains controversial. Therefore, we analyzed whether tonic and phasic GABAergic transmission had differential effects on neuronal excitability during early development. METHODS: We performed whole cell patch-clamp and field potential recordings in the CA3 region of hippocampal slices from immature (postnatal day 4 7) rats to analyze the effect of specific antagonists and modulators of tonic and phasic GABAergic components on neuronal excitability. KEY FINDINGS: The GABAergic antagonists gabazine (3 MUm) and picrotoxin (100 MUm) induced epileptiform discharges, whereas activation of GABA(A) receptors attenuated epileptiform discharges. Under low-Mg(2+) conditions, 100 nm gabazine and 1 MUm picrotoxin were sufficient to provoke epileptiform activity in 63.2% (n = 19) and 53.8% (n = 26) of the slices, respectively. Whole-cell patch-clamp experiments revealed that these concentrations significantly reduced the amplitude of phasic GABAergic postsynaptic currents but had no effect on tonic currents. In contrast, 1-MUm 4,5,6,7-tetrahydroisoxaz-olo[5,4-c]-pyridin-3-ol (THIP) induced a tonic current of -12 +/- 2.5 pA (n = 6) and provoked epileptiform discharges in 57% (n = 21) of the slices. SIGNIFICANCE: We conclude from these results that in the early postnatal rat hippocampus a constant phasic synaptic activity is required to control excitability and prevent epileptiform activity, whereas tonic GABAergic currents can mediate excitatory responses. Pharmacologic intervention at comparable human developmental stages should consider these ambivalent GABAergic actions. PMID- 22432892 TI - Introducing axial chirality into mesoionic 4,4'-bis(1,2,3-triazole) dicarbenes. AB - Mesoionic 4,4'-bis(1,2,3-triazole-5,5'-diylidene) Rh(I) complexes having a C2 chiral 4,4'-axis were accessed from 3-alkyltriazolium salts in virtually complete de. Their structure and configurational integrity were assessed by NMR spectroscopy, X-ray crystallography, and chiral HPLC. Computational analysis of the MICs involved in the reaction suggested the formation of a highly stable and unprecedented cation-carbene intermediate species, which could be evidenced experimentally by cyclic voltammetry analysis. PMID- 22432893 TI - Interleukin-28B single nucleotide polymorphism of donors and recipients can predict viral response to pegylated interferon/ribavirin therapy in patients with recurrent hepatitis C after living donor liver transplantation. AB - BACKGROUND AND AIM: Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long-term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living-donor liver transplantation (LDLT). METHODS: Thirty-five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy. RESULTS: The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG+GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG+GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT:TT (donors':recipients'), TT:TG+GG, TG+GG:any group were 81%, 50%, and 20%, respectively. The VR rate of TT:TT, TT:TG+GG and TG+GG:any group at 12 weeks were 28%, 0%, and 0%; those at 48weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors:recipients (TT:TT) as the only independent determinant of SVR (odds ratio 15.0, P=0.035). CONCLUSION: Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients. PMID- 22432894 TI - The potentials of selected therapeutic targets for inflammation: a snapshot. AB - Inflammation is a complex integrated host response to infection and injury. Inflammatory cells respond to foreign substances and inflammatory stimulus by producing various chemical bioactive mediators such as prostanoids, cytokines and chemokines. These mediators have complex, pleiotropic effects and interact with many cell types and cellular pathways to amplify the inflammatory response. Dysregulation of these processes can lead to acute and chronic inflammatory diseases necessitating pharmacological intervention to attenuate cellular inflammation pathways. This review focuses on new targets and alternative approaches to the development of novel therapeutics based on the endogenous chemicals mediators and the regulation of the associated cellular pathways that modulate inflammation leading its resolution and patents relevant to these targets. PMID- 22432896 TI - Bromide ion effect on N-nitrosodimethylamine formation by monochloramine. AB - N-Nitrosodimethylamine (NDMA) formation experiments conducted in phosphate buffer demonstrated that in waters containing monochloramine, the presence of bromide ion enhanced NDMA formation at the relatively high pH values of 8 and 9 after 24 h of reaction time, which was consistent with literature results. However, at relatively low to neutral pH (6 to 7), the presence of bromide resulted in lower NDMA formation as compared to results obtained in the absence of bromide. The hypothesis that bromamines were the species directly responsible for enhanced NDMA formation at high pH was tested and was shown not to be valid. Additional active bromine species were also tested, including hypobromous acid, hypobromite ion, and tribromide ion, with no species showing an ability to directly enhance NDMA formation. Analysis of the UV spectral data corresponding to the NDMA experiments suggest that the mechanism by which bromide enhances NDMA formation lies in the formation of a haloamine compound, possibly the mixed dihaloamine bromochloramine. PMID- 22432895 TI - Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular beta glucosidase 2, and other glycosidases. AB - Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve ring-closing metathesis and Sharpless asymmetric dihydroxylation and for the four-membered analogues Sharpless epoxidation, epoxide ring-opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6) was moderately active against rat-derived ceramide-specific glucosyltransferase, and four of the other eight-membered analogues were weakly active against rat-derived beta-glucosidase 2. Among the four-membered analogues, ((2R,3S,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25) displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat derived enzyme. ((2S,4S)-3-Hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of beta-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived beta-glucosidase, and the 1-nonylazetidine 25 inhibited alpha glucosidase (Saccharomyces cerevisiae) with an IC(50) of 600 nM and beta glucosidase (almond) with an IC(50) of 20 MUM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied. PMID- 22432897 TI - The use of advance directives among patients with implantable cardioverter defibrillators. AB - BACKGROUND: We aimed to determine the prevalence of advance directives (ADs) among patients with implantable cardioverter defibrillators (ICDs) and of ADs that addressed ICD management at the end of life. METHODS: The medical records of all patients who underwent ICD implantation during 2007 at a single institution were reviewed retrospectively to determine the number of patients with an AD and the number of ADs mentioning the ICD specifically (i.e. ICD management at end of life). RESULTS: During 2007, 420 patients (males, 71%) underwent ICD implantation at our institution (mean age [range] at implantation, 63 [1-90] years). Primary prevention was the most common indication for device therapy (254 patients [61%]). Overall, 127 patients (30%) had an AD, with 83 ADs (65%) completed more than 12 months before ICD implantation and 10 (8%) completed after it. Several life-sustaining treatments were mentioned in the ADs: tube feeding, 46 (37%); cardiopulmonary resuscitation, 25 (20%); mechanical ventilation, 22 (17%); and hemodialysis, nine (7%). Pain control was mentioned in 58 ADs (46%) and comfort measures in 38 (30%). However, only two ADs (2%) mentioned the ICD or its deactivation at end of life. CONCLUSIONS: About one-third of patients with ICDs had an AD, but only a couple ADs mentioned the ICD. These results suggest that clinicians should not only encourage patients with ICDs to complete an AD, but also encourage them to address ICD management specifically. Not addressing ICD management in an AD may result in ethical dilemmas during end-of-life care. PMID- 22432898 TI - Water barrier properties in biaxially drawn poly(lactic acid) films. AB - Crystallization is among the easiest ways to improve polymer barrier properties because of the tortuosity increase within the material and the strong coupling between amorphous and crystalline phases. In this work, poly(lactic acid) (PLA) films have undergone alpha' thermal crystallization or different drawing processes. Although no effect of alpha' thermal crystallization on water permeability is observed, the drawing processes lead to an enhancement of the PLA barrier properties. This work clearly shows that, in the case of PLA, the crystallinity degree is not the main parameter governing the barrier properties contrary to the crystalline and amorphous phase organizations which play a key role. X-ray analyses confirm that the macromolecular chain orientation in the amorphous phase is the main cause of the improvement of the drawn PLA water barrier property. This improvement is due to the orthotropic structure formation for sufficient draw ratios, particularly when using the Simultaneous Biaxial drawing mode. Moreover, independently of the draw conditions, the drawing process tends to reduce the plasticization coefficient. Consequently, the drawn material barrier properties are not much affected by the water passage. PMID- 22432899 TI - Prevalence of chronic obstructive pulmonary disease in Cyprus: a population-based study. AB - BACKGROUND: The prevalence of Chronic Obstructive Pulmonary Disease (COPD) in Cyprus is largely unknown. The aim of the study was to estimate the prevalence of COPD in Cyprus through a spirometry population- based program and to identify certain disease characteristics in the Cypriot population. METHODS: The study was performed in 1,233 randomly selected individuals covering representative urban and rural areas. Inclusion criteria were: age >= 35 years old and lifetime smoking history of at least 100 cigarettes. Participants answered a detailed questionnaire and underwent spirometry before and after the inhalation of 200 MUg of salbutamol. COPD diagnosis and severity were based on criteria developed by the Global Initiative for Chronic Obstructive Lung Diseases. RESULTS: The overall prevalence of spirometry diagnosed COPD subjects was 4.9% (5.1% in men vs 3.5% in women). Mild COPD was found in 33.3% of COPD individuals, moderate in 45%, severe and very severe COPD was found in 20% and 1.7%, respectively. Physician diagnosis was reported in 48.3% of spirometry diagnosed COPD subjects, whereas 55.9% were asymptomatic. Age (p = 0.000), increased tobacco consumption (p = 0.001) and cough with phlegm (p = 0.048) were found to have a synergistic effect on the diagnosis of COPD. CONCLUSIONS: Results suggest that COPD is an important health problem in Cyprus. Programs that raise public awareness focusing on prevention, early detection and treatment are needed. Under-diagnosis of COPD raises the need for spirometry screening programs in high risk individuals and guideline implementation for the management of the disease. PMID- 22432900 TI - Development of a fetal rabbit model to study amniotic band syndrome. AB - Amniotic band syndrome (ABS) is a group of fetal malformations caused by fibrous adherences. Species such as sheep, rats, and mice have been used to study this syndrome. We developed a fetal rabbit model using 24 fetuses from punctured uteri. We found one case of syndactyly, one case of amniotic banding, two cases of extremity deformities, one case of a tail deformity, one case of head compression, and one case of open eyelids. Other malformations have been described in an amnion rupture sequence model (exencephaly and cleft palate). The rabbit fetus is an adequate model in which to develop this syndrome. PMID- 22432901 TI - A case series of skin necrosis following use of non invasive ventilation pressure masks. AB - Two cases of nasal skin necrosis secondary to pressure from the use of continuous positive airway pressure (CPAP) face masks are presented. Both developed skin necrosis as a result of wearing these masks over the nasal bridge. These cases highlight the need for clinical vigilance in application of CPAP masks, the need for monitoring the skin of the nose during CPAP use and the possible need for modifications in design to help prevent this serious complication. PMID- 22432903 TI - Cross-frequency power correlations reveal the right superior temporal gyrus as a hub region during working memory maintenance. AB - In the present study, we characterized within- and cross-frequency power correlations from magnetoencephalography (MEG) data in order to understand how different brain regions cooperate as a network to maintain working memory representations with several features. The working memory items were composed of spatially arranged dots supposedly requiring both the dorsal and the ventral stream to be engaged during maintenance. Using a beamforming technique, we localized memory-dependent sources in the alpha, beta, and gamma bands. After the single-trial power values were extracted from these frequency bands with respect to each source, we calculated the correlations within- and cross-frequency bands. The following general picture emerged: gamma power in right superior temporal gyrus (STG) during working memory maintenance was correlated with numerous other sources in the alpha band in prefrontal, parietal, and posterior regions. In addition, the power correlations within the alpha band showed correlations across posterior-parietal-frontal regions. From these findings, we suggest that the STG dominated by gamma activity serves as a hub region for the network nodes responsible for the retention of the stimulus used in this study, which is likely to depend on both the "where-" and the "what-" visual system simultaneously. The present study demonstrates how oscillatory dynamics reflecting the interaction between cortical areas can be investigated by means of cross-frequency power correlations in source space. This methodological framework could be of general utility when studying functional network properties of the working brain. PMID- 22432902 TI - Characterization of cerebral white matter properties using quantitative magnetic resonance imaging stains. AB - The image contrast in magnetic resonance imaging (MRI) is highly sensitive to several mechanisms that are modulated by the properties of the tissue environment. The degree and type of contrast weighting may be viewed as image filters that accentuate specific tissue properties. Maps of quantitative measures of these mechanisms, akin to microstructural/environmental-specific tissue stains, may be generated to characterize the MRI and physiological properties of biological tissues. In this article, three quantitative MRI (qMRI) methods for characterizing white matter (WM) microstructural properties are reviewed. All of these measures measure complementary aspects of how water interacts with the tissue environment. Diffusion MRI, including diffusion tensor imaging, characterizes the diffusion of water in the tissues and is sensitive to the microstructural density, spacing, and orientational organization of tissue membranes, including myelin. Magnetization transfer imaging characterizes the amount and degree of magnetization exchange between free water and macromolecules like proteins found in the myelin bilayers. Relaxometry measures the MRI relaxation constants T1 and T2, which in WM have a component associated with the water trapped in the myelin bilayers. The conduction of signals between distant brain regions occurs primarily through myelinated WM tracts; thus, these methods are potential indicators of pathology and structural connectivity in the brain. This article provides an overview of the qMRI stain mechanisms, acquisition and analysis strategies, and applications for these qMRI stains. PMID- 22432904 TI - Structural network topology revealed by white matter tractography in cannabis users: a graph theoretical analysis. AB - Endocannabinoid receptors modulate synaptic plasticity in the brain and may therefore impact cortical connectivity not only during development but also in response to substance abuse in later life. Such alterations may not be evident in volumetric measures utilized in brain imaging, but could affect the local and global organization of brain networks. To test this hypothesis, we used a novel computational approach to estimate network measures of structural brain connectivity derived from diffusion tensor imaging (DTI) and white matter tractography. Twelve adult cannabis (CB) users and 13 healthy subjects were evaluated using a graph theoretic analysis of both global and local brain network properties. Structural brain networks in both CB subjects and controls exhibited robust small-world network attributes in both groups. However, CB subjects showed significantly decreased global network efficiency and significantly increased clustering coefficients (degree to which nodes tend to cluster around individual nodes). CB subjects also exhibited altered patterns of local network organization in the cingulate region. Among all subjects, schizotypal and impulsive personality characteristics correlated with global efficiency but not with the clustering coefficient. Our data indicate that structural brain networks in CB subjects are less efficiently integrated and exhibit altered regional connectivity. These differences in network properties may reflect physiological processes secondary to substance abuse-induced synaptic plasticity, or differences in brain organization that increase vulnerability to substance use. PMID- 22432905 TI - Functional cliques in the amygdala and related brain networks driven by fear assessment acquired during movie viewing. AB - One of the greatest challenges involved in studying the brain mechanisms of fear is capturing the individual's unique instantaneous experience. Brain imaging studies to date commonly sacrifice valuable information regarding the individual real-time conscious experience, especially when focusing on elucidating the amygdala's activity. Here, we assumed that by using a minimally intrusive cue along with applying a robust clustering approach to probe the amygdala, it would be possible to rate fear in real time and to derive the related network of activation. During functional magnetic resonance imaging scanning, healthy volunteers viewed two excerpts from horror movies and were periodically auditory cued to rate their instantaneous experience of "I'm scared." Using graph theory and community mathematical concepts, data-driven clustering of the fear-related functional cliques in the amygdala was performed guided by the individually marked periods of heightened fear. Individually tailored functions derived from these amygdala activation cliques were subsequently applied as general linear model predictors to a whole-brain analysis to reveal the correlated networks. Our results suggest that by using a localized robust clustering approach, it is possible to probe activation in the right dorsal amygdala that is directly related to individual real-time emotional experience. Moreover, this fear-evoked amygdala revealed two opposing networks of co-activation and co-deactivation, which correspond to vigilance and rest-related circuits, respectively. PMID- 22432906 TI - Impact of comorbidity on complications after nephrectomy: use of the Clavien Classification of Surgical Complications. AB - What's known on the subject? and What does the study add? Tumour characteristics, physical status and comorbidities are considered important for surgical outcome and prognosis. The present study objectively evaluates the association between comorbidity and postoperative complications after nephrectomy for RCC, by using the modified Clavien Classification of Surgical Complications to grade complications after nephrectomy. OBJECTIVE: To present a single-centre experience of open nephrectomy for lesions suspected for renal cell carcinoma (RCC), evaluating the association between comorbidity and postoperative complications using a standardized classification system for postoperative complications. PATIENTS AND METHODS: Clinicopathological data of 198 patients undergoing open radical or partial nephrectomy for lesions suspected of RCC were retrospectively analysed. Comorbidity scored by the Charlson comorbidity index (CCI), body mass index, age, gender, surgical procedure and surgical history were examined as predictive factors for postoperative complications, which were scored using the modified Clavien Classification of Surgical Complications (CCSC). RESULTS: The overall complication rate was 34%: 7% grade I, 15% grade II, 5% grade III, 3% grade IV and 4% grade V. Preoperative comorbidities were present in 51% of all patients. There were significantly more major complications (CCSC >2) in patients with major comorbidities (CCI >2), at 16% vs 7% (P = 0.018). Patients with high stage RCC had significantly more severe complications than low-stage RCC (P = 0.018). In multivariable analysis, comorbidity (odds ratio [OR] 7.55, P = 0.004) and tumour stage 3-4 (OR 6.23, P = 0.007) were independent predictive factors for major complications. CONCLUSIONS: Major complications occur significantly more often when major comorbidities are present. Comorbidity scores can be used in risk stratification for complications and should be considered during decision making and counselling of patients before nephrectomy. PMID- 22432907 TI - Constitutively active glutaminase variants provide insights into the activation mechanism of anthranilate synthase. AB - The glutamine amidotransferase (GATase) family comprises enzyme complexes which consist of glutaminase and synthase subunits that catalyze in a concerted reaction the incorporation of nitrogen within various metabolic pathways. An important feature of GATases is the strong stimulation of glutaminase activity by the associated synthase. To understand the mechanism of this tight activity regulation, we probed by site-directed mutagenesis four residues of the glutaminase subunit TrpG from anthranilate synthase that are located between the catalytic Cys-His-Glu triad and the synthase subunit TrpE. In order to minimize structural perturbations induced by the introduced exchanges, the amino acids from TrpG were substituted with the corresponding residues of the closely related glutaminase HisH from imidazole glycerol phosphate synthase. Steady-state kinetic characterization showed that, in contrast to wild-type TrpG, two TrpG variants with single exchanges constitutively hydrolyzed glutamine in the absence of TrpE. A reaction assay performed with hydroxylamine as a stronger nucleophile replacing water and a filter assay with radiolabeled glutamine indicated that the formation of the thioester intermediate is the rate-limiting step of constitutive glutamine hydrolysis. Molecular dynamics simulations with wild-type TrpG and constitutively active TrpG variants suggest that the introduced amino acid exchanges result in a distance reduction between the active site Cys-His pair, which facilitates the deprotonation of the sulfhydryl group of the catalytic cysteine and thus enables its nucleophilic attack onto the carboxamide group of the glutamine side chain. We propose that native TrpG in the anthranilate synthase complex is activated by a similar mechanism. PMID- 22432908 TI - The Ala-9Val (Mn-SOD) and Arg213Gly (EC-SOD) polymorphisms in the pathogenesis of preeclampsia in Romanian women: association with the severity and outcome of preeclampsia. AB - OBJECTIVE: To check whether individual or combined mutated genotypes for Ala-9Val (Mn-SOD) and Arg213Gly (EC-SOD) are associated with preeclampsia; to check the influence of the mutated genotypes on the degree of severity and perinatal outcome of preeclampsia. METHODS: We genotyped 97 pregnant women (47 with preeclampsia and 50 normal pregnant women) using PCR-RFLP analysis. RESULTS: The Val/Val (Mn-SOD) genotype (OR 5.99, p = 0.004) but not the Gly/Gly (EC-SOD) genotype (OR 4.23, p = 0.027) was significantly associated with preeclampsia. Higher frequency of both polymorphisms in women with preeclampsia (42.55%) compared to normal pregnant women (8%). Higher frequency of women diagnosed with PIH (27.27%, OR 4.31), mild (50%, OR 11.5) and severe preeclampsia (37.5%, OR 6.9) positive for both polymorphism compared to control women (8%). There was a statistically significant difference in gestational age at delivery according to Mn-SOD (Ala/Ala vs. Val/Val, 39 +/- 1.41 weeks vs. 32.77 +/- 3.7 weeks) and EC SOD genotypes (Arg/Arg vs. Gly/Gly, 37.05 +/- 3.18 weeks vs. 31.5 +/- 3.84 weeks). There also was a statistically significant difference in birth weight according to Mn-SOD (grams, Ala/Ala vs. Val/Val, 3080 +/- 481.66 vs. 2376.92 +/- 916.88) and EC-SOD genotypes (grams, Arg/Arg vs. Gly/Gly, 2934.09 +/- 662.14 vs. 2080 +/- 721.19). CONCLUSIONS: Our study demonstrates a relationship between these two mutated genes, the clinical severity and the perinatal outcome of preeclampsia. PMID- 22432909 TI - Alpha and Beta traits and egoistic and moralistic self-enhancement: a point of convergence between two research traditions. AB - OBJECTIVE: The current study investigated the relationship of egoistic and moralistic self-enhancement with Alpha and Beta, the two higher-order factors of personality encompassing the Big Five. METHOD: Four hundred sixteen Italian adults (59% females, mean age = 41.13) completed self-report measures of the Big Five and of egoistic and moralistic self-enhancement. They were also rated by acquaintances on the two self-enhancement measures. A cross-observer design within the framework of structural equation modeling was used to disentangle the variance shared by the constructs that is due to (a) substantive personality characteristics (i.e., the variance of egoistic and moralistic self-enhancement common to different informants), (b) response bias (i.e., the tendency to exaggerate agentic and communal qualities), and (c) halo effect (i.e., the common factor underlying all self-report measures). RESULTS: Findings revealed significant correlations between Alpha and Beta and the substantive parts of egoistic and moralistic dimensions. Beta was primarily related to egoistic self enhancement, whereas alpha was mostly related to moralistic self-enhancement. Nevertheless, a substantial portion of variance in Alpha and Beta was explained by response bias and halo effect. CONCLUSIONS: Substance, bias, and method variance all represent important sources of covariation among the Big Five. PMID- 22432910 TI - Robust and multifunctional nanosheath for chemical and biological nanodevices. AB - The contribution of advanced nanoscale chemical and biological devices to life science has been limited to a small number of nanomaterials, due to the absence of effective surface modification routes. Herein, we demonstrate a polymer-like nanosheath synthesized by nonthermal plasma technology (NPT) that can protect the core nanomaterial from the solution environment and provide a multifunctional platform for chemical and biological nanosensors. For ZnO nanowires (NWs) which are unstable in solution, we demonstrate that this nanosheath makes it possible for ZnO NW field-effect transistors to act as a pH sensor for 24 h and a biosensor for the real-time, label-free detection of liver cancer markers. PMID- 22432911 TI - Postictal generalized EEG suppression is linked to seizure-associated respiratory dysfunction but not postictal apnea. AB - PURPOSE: The relationship of postictal generalized electroencephalography (EEG) suppression (PGES) with sudden unexpected death in epilepsy (SUDEP) is controversial. It has been suggested that PGES is associated with respiratory inhibition leading to SUDEP, but the relationship between PGES and respiratory depression is unknown. Respiratory rate and amplitude of airflow increase following seizures but there is persistent hypercapnia and hypoxemia. To determine whether seizures with PGES result in respiratory dysfunction, we analyzed respiratory parameters recorded during video-EEG telemetry in patients with localization-related epilepsy. METHODS: Secondarily generalized convulsive seizures (GC) with PGES on scalp EEG or bilateral postictal attenuation (BA) on intracranial recordings were compared to GC without PGES/BA. Oxygen desaturation nadir and duration, end-tidal CO(2) (ETCO(2) ), apnea duration, and duration of the seizure and of the convulsive component were compared in GC with or without PGES/BA. KEY FINDINGS: There was no significant difference between GC with (n = 30) or without PGES/BA (n = 72) for total seizure duration or duration of the convulsion. GC with PGES/BA had a mean oxygen desaturation nadir of 68.8 +/- 11.8% (71.5, 43-88) (mean +/- standard deviation [median, range]) that was lower (p = 0.002) than seizures without PGES/BA (76.31 +/- 10.17% [79, 42-93]). The duration of desaturation was significantly longer and peak ETCO(2) higher in GC with PGES/BA. There was no difference in apnea duration. Apnea did not start during PGES/BA and did not typically extend into the postictal period in GC with or without PGES/BA. SIGNIFICANCE: PGES is not associated with postictal central apnea but is more likely related to the severity of seizure-associated intrinsic pulmonary dysfunction. PMID- 22432912 TI - Enantioselective total synthesis of (+)-amabiline. AB - The first total synthesis of (+)-amabiline, an unsaturated pyrrolizidine alkaloid from Cynoglossum amabile, is reported. This convergent, enantioselective synthesis proceeds in 15 steps (10-step longest linear sequence) in 6.2% overall yield and features novel methodology to construct the unsaturated pyrrolizidine or (-)-supinidine core. PMID- 22432913 TI - High basophil allergen sensitivity (CD-sens) is associated with severe allergic asthma in children. AB - Children with problematic severe asthma (PA) have persistent symptoms and/or severe exacerbations despite treatment with several drugs. Classification of asthma severity is currently based on level of treatment and assessment of asthma control, but objective biomarkers of asthma severity are needed. To investigate the clinical relevance of basophil allergen threshold sensitivity (CD-sens) as a measure of allergen sensitivity in a well-characterized cohort of children with different manifestations of persistent allergic asthma. Cat-allergic children (6 18 yr) with problematic severe asthma (n = 11) according to GINA were compared with eleven age-matched children with controlled, but persistent asthma (CA). The protocol included standardized questionnaires, asthma control test (ACT), spirometry, methacholine challenges, measurement of FE(NO,) IgE, cat IgE and IgG antibodies, and analysis of CD-sens (CD63-expression) by flow cytometry. The 11 cat-allergic children with PA had a significantly lower ACT score (p < 0.001), reduced FEV(1) (p = 0.04), and increased numbers of blood eosinophils (p = 0.03) compared with the 11 children with CA. The former exhibited a higher CD-sens to cat (p = 0.02). No significant differences were detected with respect to FE(NO) (p = 0.17), IgE (p = 0.84), cat IgE (p = 0.12), and the major cat-allergen rFel d 1 (p = 0.30). CD-sens significantly correlated with ACT (p = 0.002, r = -0.63) and FE(NO) (p = 0.01, r = 0.55). No significant differences between PA and CA were found regarding IgG antibodies to rFel d 1. Cat-allergic children with problematic severe asthma have higher sensitivity to cat allergen, as measured by CD-sens, compared with children with controlled asthma. This suggests that CD sens could be used as an additional marker for identifying children with the most severe allergic asthma. PMID- 22432915 TI - Pneumatosis intestinalis in pediatric hematopoietic stem cell transplantation patients: an uncommon complication. AB - Hematopoietic stem cell transplantation (HSCT) causes many complications including the development of graft-versus-host disease (GVHD). Pneumatosis intestinalis (PI), a rare side affect in patients with post-HSCT GVHD, is uncommonly seen in non-neonatal patients. In neonates, surgical intervention is common, yet in non-neonatal patients, medical management is advisable. We present four pediatric patients who post-HSCT developed GVHD and subsequently PI. Surgery was performed on one patient while the other three were successfully managed conservatively. Although PI is rare in this group of patients, clinicians should be aware of this post-HSCT complication to ensure early diagnosis and proper management. PMID- 22432916 TI - Overexpression of galectin-1 is associated with poor prognosis in human hepatocellular carcinoma following resection. AB - BACKGROUND AND AIM: The high expression of the galectin-1 predicts poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. METHODS: Galectin-1 and tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients (n = 386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. RESULTS: We found that galectin-1, which was prevalently upregulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number, and large tumor size). Patients with high galectin-1 expression had a significantly poorer tumor recurrence (P = 0.025) and overall survival (P = 0.021) than those with low galectin-1 expression. Even in early-stage disease, high galectin-1 expression was also independently associated with shortened survival (P < 0.001) and increased tumor recurrence (P = 0.005). Multivariate Cox proportional hazards analysis showed that galectin-1 was an independent marker for predicting the poor prognosis of HCC. The galectin-1 level was positively related to the number of tumor-infiltrating FoxP3(+) Tregs (r = 0.416, P < 0.001), and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin-1(high) and FoxP3(high) were significantly poorer than the other groups (both P < 0.001). CONCLUSIONS: Galectin-1 might be a new prognostic factor for HCC after resection and could potentially be a high-priority therapeutic target. PMID- 22432917 TI - From weight management goals to action planning: identification of a logical sequence from goals to actions and underlying determinants. AB - BACKGROUND: Weight gain prevention (WGP) among adults who are overweight is an important target in the prevention of obesity. However, little is known about the process from WGP as a goal to successful weight-management. The present study aimed to: (i) gain more insight into this process; (ii) identify cognitive predictors of intention for WGP; and (iii) examine WGP as a potential predictor for the intention to change weight-related behaviours [dietary intake (DI) and physical activity (PA)] and specific action planning. METHODS: In this cross sectional study, overweight adults [n = 510; body mass index 25-30 kg m(-2); mean (SD) age 48 (9.5) years; 30.8% male] completed an online questionnaire, assessing goal intention for WGP, behavioural intention for DI and PA, planning for change in DI and PA and socio-cognitive correlates. Ordinal regression analyses were used to analyse the data. RESULTS: In 89% of the sample, (parts of) the proposed sequence from goal intention (for WGP), behavioural intention (for DI/PA) and planning (for DI/PA) was observed. Attitude, social norm and perceived control towards WGP, and perceived weight status and risk perception, were associated with intention for WGP. Behaviour-specific perceived control and preferences were more strongly associated with intention to change DI or PA and planning for change than intention for WGP was. CONCLUSIONS: Intention for WGP is important in the process toward weight-management because, for most people, intention for WGP precedes behavioural intention, which precedes planning. Intention for WGP is associated with behavioural intention but behaviour-specific factors are the strongest correlates of behavioural intention and planning. PMID- 22432918 TI - Development and validation of a PCR-based assay for the selection of patients more likely to benefit from therapeutic treatment with alkylating drugs. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Previous studies have indicated that the levels of DNA damage induced in peripheral blood mononuclear cells by the alkylating drugs melphalan, cisplatin and carboplatin can serve as useful biomarkers predictive of the therapeutic response of cancer patients to these drugs. WHAT THIS STUDY ADDS: In the present study we developed a quantitative PCR based assay, for the measurement of DNA damage. The advantages of this methodology are based on: its far greater sensitivity (about 250 times) than the traditional Southern blot-based method (the detection limit is ~10-20 lesions/10(6) nucleotides from the equivalent DNA of ~8000 cells); its simplicity and speed (results obtained within ~8h); its excellent reproducibility, with a coefficient of variance of 10-15% for different DNA preparations from similarly treated cells; its requirement for only minute amounts of material, and; the avoidance of radioisotope labeling. Moreover, emphasis was given to translate basic research findings into clinical practice through the validation of this assay for prediction of clinical outcome in multiple myeloma patients. AIM: In order to develop and validate a simple, sensitive and rapid method for the quantitation of alkylating drug-induced DNA damage. METHODS: HepG2 cells and blood samples were treated with alkylating drugs (melphalan, cisplatin, carboplatin). Gene-specific damage was examined using Southern blot and a multiplex long quantitative PCR (QPCR) carried out in a 7 kb fragment (part of the p53 gene) and a 0.5 kb fragment (part of the IFN-beta1 sequence; internal standard). RESULTS: The extent of PCR amplification of a p53 fragment was inversely proportional to the treatment concentrations of all anticancer drugs examined, indicating a dose-related inhibition by the DNA adducts formed. Parallel analysis of the same samples using both Southern blot and QPCR showed that the DNA adducts measured by QPCR corresponded to the interstrand cross-links in the case of melphalan, and to total drug-induced lesions in the case of the platinum drugs. The detection limit was ~10-20 lesions/10(6) nucleotides using DNA from ~8000 cells. The method is about 250 times more sensitive than the Southern blot-based method and the reproducibility is excellent, with an intraday coefficient of variance (CV) of 5-9% and an interday CV of 4-12%. Application of the QPCR assay to ex vivo melphalan-treated peripheral blood mononuclear cells from multiple myeloma patients, showed that the positive predictive value of this assay for clinical response to melphalan therapy was 92.9%. CONCLUSION: The PCR based assay developed in this study can be used for the selection of cancer patients more likely to benefit from therapeutic treatment with alkylating drugs. PMID- 22432919 TI - In situ TCE degradation mediated by complex dehalorespiring communities during biostimulation processes. AB - The bioremediation of chloroethene contaminants in groundwater polluted systems is still a serious environmental challenge. Many previous studies have shown that cooperation of several dechlorinators is crucial for complete dechlorination of trichloroethene to ethene. In the present study, we used an explorative functional DNA microarray (DechloArray) to examine the composition of specific functional genes in groundwater samples in which chloroethene bioremediation was enhanced by delivery of hydrogen-releasing compounds. Our results demonstrate for the first time that complete biodegradation occurs through spatial and temporal variations of a wide diversity of dehalorespiring populations involving both Sulfurospirillum, Dehalobacter, Desulfitobacterium, Geobacter and Dehalococcoides genera. Sulfurospirillum appears to be the most active in the highly contaminated source zone, while Geobacter was only detected in the slightly contaminated downstream zone. The concomitant detection of both bvcA and vcrA genes suggests that at least two different Dehalococcoides species are probably responsible for the dechlorination of dichloroethenes and vinyl chloride to ethene. These species were not detected on sites where cis-dichloroethene accumulation was observed. These results support the notion that monitoring dechlorinators by the presence of specific functional biomarkers using a powerful tool such as DechloArray will be useful for surveying the efficiency of bioremediation strategies. PMID- 22432920 TI - Evolution of the potential energy landscape with static pulling force for two model proteins. AB - The energy landscape is analyzed for off-lattice bead models of protein L and protein G as a function of a static pulling force. Two different pairs of attachment points (pulling directions) are compared in each case, namely, residues 1/56 and 10/32. For the terminal residue pulling direction 1/56, the distinct global minimum structures are all extended, aside from the compact geometry that correlates with zero force. The helical turns finally disappear at the highest pulling forces considered. For the 10/32 pulling direction, the changes are more complicated, with a variety of competing arrangements for beads outside the region where the force is directly applied. These alternatives produce frustrated energy landscapes, with low-lying minima separated by high barriers. The calculated folding pathways in the absence of force are in good agreement with previous work. The N-terminal hairpin folds first for protein L and the C-terminal hairpin for protein G, which exhibits an intermediate. However, for a relatively low static force, where the global minimum retains its structure, the folding mechanisms change, sometimes dramatically, depending on the protein and the attachment points. The scaling relations predicted by catastrophe theory are found to hold in the limit of short path lengths. PMID- 22432921 TI - Correlations between computation and experimental thermodynamics of halogen bonding. AB - Correlations between experimental, solution-phase thermodynamic data and calculated gas-phase energies of interaction are investigated for noncovalent halogen bonding interactions between electron-deficient iodo compounds and Lewis bases. The experimental data consist of free energies of interaction spanning roughly 7 kcal/mol; they encompass halogen bonds involving both organic (iodoperfluoroarene or iodoperfluoroalkane) and inorganic (I(2), IBr, ICN) donors with nitrogen- and oxygen-based acceptors and are divided into two sets according to the identity of the solvent in which they were determined (alkanes or CCl(4)). Adiabatic energies of halogen bonding were calculated using a variety of methods, including 22 DFT exchange-correlation functionals, using geometries optimized at the MP2/6-31+G(d,p) level of theory. Certain DFT functionals, particularly the B97-1, B97-2, and B98 family, provide outstanding linear correlations with the experimental thermodynamic data, as assessed by a variety of statistical methods. PMID- 22432922 TI - Quasi-linear viscoelastic properties of costal cartilage using atomic force microscopy. AB - Costal cartilage (CC) is one of the load-bearing tissues of the rib cage. Literature on material characterisation of the CC is limited. Atomic force microscopy (AFM) has been extremely successful in characterising the elastic properties of soft biomaterials such as articular cartilage and hydrogels, which are often the material of choice for cartilage models. But AFM data on CC are absent in the literature. In this study, AFM indentations using spherical beaded tips were performed on human CC to isolate the mechanical properties. A novel method was developed for modelling the relaxation indentation experiments based on Fung's quasi-linear viscoelasticity and a continuous relaxation spectrum. This particular model has been popular for uniaxial compression test data analysis. Using the model, the mean Young's modulus of CC was found to be about 2.17, 4.11 and 5.49 MPa for three specimens. A large variation of modulus was observed over the tissue. Also, the modulus values decreased with distance from the costochondral junction. PMID- 22432923 TI - Initial clinical experiences with a new, portable, single-use negative pressure wound therapy device. AB - Since the introduction of negative pressure wound therapy in combination with reticulated open cell foam (NPWT/ROCF) in 1997, the clinical and economic benefits of this therapy have been showed in several randomised-controlled studies. This article describes the clinical application of a new portable NPWT unit. The V.A.C.ViaTM Therapy System (KCI USA, Inc., San Antonio, TX) offers continuous negative pressure and dynamic pressure control for wound treatment of low exudating (<80 ml/day), small-to-medium size wounds, grafts and flaps in all care settings, including homecare. We describe four cases in which this new device was successfully used. PMID- 22432924 TI - Ecophylogenetics: advances and perspectives. AB - Ecophylogenetics can be viewed as an emerging fusion of ecology, biogeography and macroevolution. This new and fast-growing field is promoting the incorporation of evolution and historical contingencies into the ecological research agenda through the widespread use of phylogenetic data. Including phylogeny into ecological thinking represents an opportunity for biologists from different fields to collaborate and has provided promising avenues of research in both theoretical and empirical ecology, towards a better understanding of the assembly of communities, the functioning of ecosystems and their responses to environmental changes. The time is ripe to assess critically the extent to which the integration of phylogeny into these different fields of ecology has delivered on its promise. Here we review how phylogenetic information has been used to identify better the key components of species interactions with their biotic and abiotic environments, to determine the relationships between diversity and ecosystem functioning and ultimately to establish good management practices to protect overall biodiversity in the face of global change. We evaluate the relevance of information provided by phylogenies to ecologists, highlighting current potential weaknesses and needs for future developments. We suggest that despite the strong progress that has been made, a consistent unified framework is still missing to link local ecological dynamics to macroevolution. This is a necessary step in order to interpret observed phylogenetic patterns in a wider ecological context. Beyond the fundamental question of how evolutionary history contributes to shape communities, ecophylogenetics will help ecology to become a better integrative and predictive science. PMID- 22432925 TI - Flexible NO(x) abatement from power plants in the eastern United States. AB - Emission controls that provide incentives for maximizing reductions in emissions of ozone precursors on days when ozone concentrations are highest have the potential to be cost-effective ozone management strategies. Conventional prescriptive emissions controls or cap-and-trade programs consider all emissions similarly regardless of when they occur, despite the fact that contributions to ozone formation may vary. In contrast, a time-differentiated approach targets emissions reductions on forecasted high ozone days without imposition of additional costs on lower ozone days. This work examines simulations of such dynamic air quality management strategies for NO(x) emissions from electric generating units. Results from a model of day-specific NO(x) pricing applied to the Pennsylvania-New Jersey-Maryland (PJM) portion of the northeastern U.S. electrical grid demonstrate (i) that sufficient flexibility in electricity generation is available to allow power production to be switched from high to low NO(x) emitting facilities, (ii) that the emission price required to induce EGUs to change their strategies for power generation are competitive with other control costs, (iii) that dispatching strategies, which can change the spatial and temporal distribution of emissions, lead to ozone concentration reductions comparable to other control technologies, and (iv) that air quality forecasting is sufficiently accurate to allow EGUs to adapt their power generation strategies. PMID- 22432926 TI - Oxygen activation in flavoprotein oxidases: the importance of being positive. AB - The oxidation of flavin hydroquinones by O(2) in solution is slow, with second order rate constants of ~250 M(-1) s(-1). This is due to the obligatory, single electron transfer that initiates the reaction being thermodynamically unfavored and poorly catalyzed. Notwithstanding considerations of O(2) accessibility to the reaction site, its desolvation and geometry and other factors that can also contribute to further rate acceleration, flavoprotein oxidases must activate O(2) for reaction with flavin hydroquinones to be able to achieve the 100-1000-fold rate enhancements typically observed. Protein positive charges have been identified in glucose oxidase, monomeric sarcosine oxidase, N-methyltryptophan oxidase and fructosamine oxidase that electrostatically stabilize the transition state for the initial single electron transfer that generates the O(2)(-*)/flavin semiquinone radical pair. In choline oxidase despite the presence of three histidines in the active site, the trimethylammonium group of the reaction product provides such an electrostatic stabilization. A nonpolar site proximal to the flavin C(4a) atom in choline oxidase has also been identified, which contributes to the geometry and desolvation of the O(2) reaction site. The relevance of O(2) activation by product charges to other flavoprotein oxidases, such as for example those catalyzing amine oxidations, is discussed in this review. A nonpolar site close to the flavin C(4a) atom and a positive charge is identified through structural analysis in several flavoprotein oxidases. Mutagenesis has disclosed nonpolar sites in O(2)-reducing enzymes that utilize copper/TPQ or iron. It is predicted that classes of O(2)-reducing enzymes utilizing other cofactors also contain a similar catalytic motif. PMID- 22432927 TI - Trouble at rest: how correlation patterns and group differences become distorted after global signal regression. AB - Resting-state functional magnetic resonance imaging (RS-FMRI) holds the promise of revealing brain functional connectivity without requiring specific tasks targeting particular brain systems. RS-FMRI is being used to find differences between populations even when a specific candidate target for traditional inferences is lacking. However, the problem with RS-FMRI is a lacking definition of what constitutes noise and signal. RS-FMRI is easy to acquire but is not easy to analyze or draw inferences from. In this commentary we discuss a problem that is still treated lightly despite its significant impact on RS-FMRI inferences; global signal regression (GSReg), the practice of projecting out signal averaged over the entire brain, can change resting-state correlations in ways that dramatically alter correlation patterns and hence conclusions about brain functional connectedness. Although Murphy et al. in 2009 demonstrated that GSReg negatively biases correlations, the approach remains in wide use. We revisit this issue to argue the problem that GSReg is more than negative bias or the interpretability of negative correlations. Its usage can fundamentally alter interregional correlations within a group, or their differences between groups. We used an illustrative model to clearly convey our objections and derived equations formalizing our conclusions. We hope this creates a clear context in which counterarguments can be made. We conclude that GSReg should not be used when studying RS-FMRI because GSReg biases correlations differently in different regions depending on the underlying true interregional correlation structure. GSReg can alter local and long-range correlations, potentially spreading underlying group differences to regions that may never have had any. Conclusions also apply to substitutions of GSReg for denoising with decompositions of signals aggregated over the network's regions to the extent they cannot separate signals of interest from noise. We touch on the need for careful accounting of nuisance parameters when making group comparisons of correlation maps. PMID- 22432928 TI - Early repolarization and its modification by preexcitation in two patients with intermittent Wolff-Parkinson-White syndrome. AB - We report two cases of intermittent Wolff-Parkinson-White (WPW) syndrome. In one patient, early repolarization (ER) was masked during preexcitation whereas in the other, J wave-like notches were observed in the right precordial leads only during preexcitation. The clinical significance of ER is not apparent in WPW syndrome but some possible mechanisms are discussed. PMID- 22432929 TI - Traceless cross-linker for photocleavable bioconjugation. AB - Photoresponsive bioconjugation empowers the development of novel methods for drug discovery, disease diagnosis, and high-throughput screening, among others. In this paper, we report on the characteristics of a traceless photocleavable cross linker, di-6-(3-succinimidyl carbonyloxymethyl-4-nitro-phenoxy)-hexanoic acid disulfide diethanol ester (SCNE). The traceless feature and the biocompatibility of this photocleavable cross-linking reagent were corroborated. Consequently, we demonstrated its application in reversible phage particle immobilization that could provide a platform for direct single-phage screening. We also applied it in protein-photoprinting, where SCNE acts as a "photo-eraser" to remove the cross linked protein molecules at a desired region in a simple, clean, and light controllable fashion. We further demonstrated the two-tier atomic force microscopic (AFM) method that uses SCNE to carry out two subsequent AFM tasks in situ. The approach allows guided protein delivery and subsequent high-resolution imaging at the same local area, thus opening up the possibility of monitoring protein functions in live cells. The results imply that SCNE is a versatile cross linker that can be used for a wide range of applications where photocleavage ensures clean and remote-controllable release of biological molecules from a substrate. PMID- 22432930 TI - Ultrafast relaxation dynamics via acoustic phonons in carbon nanotubes. AB - Carbon nanotubes as one-dimensional nanostructures are ideal model systems to study relaxation channels of excited charged carriers. The understanding of the ultrafast scattering processes is the key for exploiting the huge application potential that nanotubes offer, e.g., for light-emitting and detecting nanoscale electronic devices. In a joint study of two-color pump-probe experiments and microscopic calculations based on the density matrix formalism, we extract, both experimentally and theoretically, a picosecond carrier relaxation dynamics, and ascribe it to the intraband scattering of excited carriers with acoustic phonons. The calculated picosecond relaxation times show a decrease for smaller tube diameters. The best agreement between experiment and theory is obtained for the (8,7) nanotubes with the largest investigated diameter and chiral angle for which the applied zone-folded tight-binding wave functions are a good approximation. PMID- 22432931 TI - Genetic influences on psychological well-being: a nationally representative twin study. AB - OBJECTIVE: Psychological well-being, or eudaimonia, features strongly in theories of human development and thriving. However, the factors of eudaimonia are debated, and their genetic architecture has not been studied in detail. METHOD: A classical twin design was used to decompose behavioral variance into genetic and environmental components implemented in a multigroup, multivariate structural equation modeling framework. Subjects were 837 pairs of adult U.S. twins from the nationally representative MIDUS II sample. Psychological well-being was measured using the 42-item Ryff Psychological Well-Being Scale, which assesses autonomy, environmental mastery, personal growth, positive relations with others, purpose in life, and self-acceptance. RESULTS: Substantial genetic influences were observed on all components of well-being. Attempts to model these six factors as reflecting a single common psychological mechanism gave a poor fit to the data. The best-fitting model supported the existence of five distinct genetic effects. Effects of shared environment were weak and nonsignificant. Unique environmental effects for all measures were mostly trait specific. CONCLUSIONS: These results indicate that psychological well-being is underpinned by a general genetic factor influencing self-control, and four underlying biological mechanisms enabling the psychological capabilities of purpose, agency, growth, and positive social relations. PMID- 22432932 TI - Efficacy of tiotropium in COPD patients with FEV1 >= 60% participating in the UPLIFT(r) trial. AB - GOLD stage II COPD encompasses patients with FEV1 50-80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV1 <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT(r) trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 >=60% predicted from UPLIFT(r). Outcomes included pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. Of the 5,992 UPLIFT(r) cohort, 1,210 (632 tiotropium, 578 control) had baseline post bronchodilator FEV1 >=60% predicted (range 60-78%), mean age was 64 years, 70% were men, and mean SGRQ total score was 39.9 units. Mean annual rate of post bronchodilator FEV1 decline was 41 (tiotropium) and 49 (control) mL/year (P = 0.07); corresponding pre-bronchodilator values were 32 and 37 mL/year (P = 0.24). Morning pre-drug FEV1 and FVC improvements for tiotropium versus control were 87 127 mL and 139-186 ml, respectively (P < 0.001, all time-points). SGRQ total score improvements (tiotropium-control) were 2.0-3.4 units (P < 0.05 for all); a higher percentage of patients had an improvement of >=4 units with tiotropium (P <0.05). Tiotropium reduced risk for an exacerbation (HR [95% CI] = 0.83 [0.71, 0.96]) and mortality for the 4-year protocol-defined treatment period (HR [95% CI] = 0.66 [0.45, 0.96]). Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV1 >=60% predicted, supporting current GOLD guidelines for COPD treatment. (ClinicalTrials.gov number NCT00144339). PMID- 22432933 TI - Holoprosencephaly-polydactyly (pseudotrisomy 13) syndrome: case report and diagnostic criteria. AB - We report a new case of a fetus with holoprosencephaly-polydactyly syndrome, also known as pseudo-trisomy 13 syndrome, and no other apparent abnormalities except for septal agenesis of the left lung. The fetal karyotype was normal. Mutational analysis of five genes (SHH, SIX3, TGIF, ZIC2, and GLI3), which are major genes associated with holoprosencephaly, did not disclose any mutational findings. We therefore propose that the abnormalities of our fetus support the demarcation of this syndrome as an autonomous phenotype. Specific diagnostic criteria for holoprosencephaly-polydactyly syndrome need to be complemented by the absence of mutations in the major holoprosencephaly genes. PMID- 22432934 TI - Double- and triple-cobalt catalysis in multicomponent reactions. AB - The combination of different types of cobalt-catalyzed transformations in one-pot procedures is described. One of the key building blocks, a boron-functionalized isoprene derivative (boroprene), led to the realization of four-component reaction sequences comprising the cobalt-catalyzed Diels-Alder and a 1,4 hydrovinylation reaction. Eventually, a reaction sequence including a cobalt catalyzed Diels-Alder reaction, a cobalt-catalyzed 1,4-hydrovinylation, an allylboration, and a cobalt-catalyzed Alder-ene reaction led to a five-component one-pot reaction sequence in which five carbon-carbon bonds were formed in excellent regio- and diastereoselectivity to generate complex products in good overall yields. PMID- 22432935 TI - Convulsive seizure detection using a wrist-worn electrodermal activity and accelerometry biosensor. AB - The special requirements for a seizure detector suitable for everyday use in terms of cost, comfort, and social acceptance call for alternatives to electroencephalography (EEG)-based methods. Therefore, we developed an algorithm for automatic detection of generalized tonic-clonic (GTC) seizures based on sympathetically mediated electrodermal activity (EDA) and accelerometry measured using a novel wrist-worn biosensor. The problem of GTC seizure detection was posed as a supervised learning task in which the goal was to classify 10-s epochs as a seizure or nonseizure event based on 19 extracted features from EDA and accelerometry recordings using a Support Vector Machine. Performance was evaluated using a double cross-validation method. The new seizure detection algorithm was tested on >4,213 h of recordings from 80 patients and detected 15 (94%) of 16 of the GTC seizures from seven patients with 130 false alarms (0.74 per 24 h). This algorithm can potentially provide a convulsive seizure alarm system for caregivers and objective quantification of seizure frequency. PMID- 22432937 TI - The efficacy of ProTaper Universal rotary retreatment instrumentation to remove single gutta-percha cones cemented with several endodontic sealers. AB - AIM: To evaluate residual root filling material following removal of three newly developed root canal sealers used with a matched-taper single-cone root filling technique and to compare the efficacy of ProTaper Universal rotary retreatment instruments with that of a conventional manual technique. METHODOLOGY: The canals of 120 palatal roots in maxillary molar teeth were instrumented with EndoWave nickel-titanium rotary instruments and filled using Hybrid Root SEAL, EndoSequence BC Sealer, Activ GP system or AH Plus with matched-taper single gutta-percha cones. The root fillings were then removed with ProTaper Universal retreatment rotary instruments or a manual technique. Buccolingual and proximal digital radiographs of the roots were exposed to determine the area of remaining filling material in the coronal, middle and apical thirds. The area percentages of remaining filling material in each third and total canal area were calculated. Data were analysed statistically with Kruskal-Wallis and Mann-Whitney U-tests. The level of significance was set at P<0.05. RESULTS: Irrespective of the sealer type and retreatment technique, filling material could not be removed completely from the root canals. Significantly, more remaining filling material was observed in the apical third (P<0.05). When comparing the sealers, the only significant difference was detected between AH Plus/manual and Activ GP/manual groups with respect to residual material in the total canal area (P<0.05). There were no significant differences between manual and ProTaper groups. CONCLUSIONS: When using gross radiographic criteria, the Activ GP was more effectively removed from root canals than AH Plus with hand instrumentation. Hybrid Root SEAL, EndoSequence BC Sealer and AH Plus were removed to a similar extent. ProTaper Universal retreatment instruments were as safe and effective as hand instruments in reaching the working length. PMID- 22432938 TI - Non-genetic risk factors and predicting efficacy for docetaxel--drug-induced liver injury among metastatic breast cancer patients. AB - BACKGROUND AND AIM: Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel-drug induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear. METHODS: We conducted a retrospective cohort study to identify non-genetic risk factors for docetaxel-DILI among 647 metastasis breast cancer patients treated with docetaxel-containing regimens. RESULTS: Sixty-seven (10.36%) patients were diagnosed as docetaxel-DILI. By logistic regression analysis, premenopausal status (odds ratio [OR][95% confidence interval {CI}] = 2.24 [1.30-3.87]), past hepatitis B virus (HBV) infections (OR [95% CI] = 4.23 [1.57-11.42]), liver metastasis (OR [95% CI] = 3.70 [2.16-6.34]). The predominant occurrence of DILI was seen in groups with docetaxel combination regimens. (OR [95% CI] = 2.66 [1.59-4.55]). The potential increasing occurrence of docetaxel-DILI was associated with multiple risk factors in an exposure-response manner (P < 0.001), and patients with more than three risk factors would be exposed to a 36.61-fold risk of DILI (95% CI = 10.18 131.62). Further analysis by the risk score and area under the receiver-operator characteristic curve (AUC) showed that those four factors contributed to an AUC of 0.7536 (95% CI = 0.70-0.81), with a predictive sensitivity of 74.63% and specificity of 65.17%. CONCLUSIONS: Docetaxel-DILI with a relatively higher incidence should be addressed among metastatic breast cancer patients. Four predominant risk factors, including premenopausal status, past HBV infection, liver metastasis, and docetaxel combination regimens, were potential predicators for DILI. PMID- 22432939 TI - The association between DRESS and the diminished numbers of peripheral B lymphocytes and natural killer cells. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) is a drug-induced, severe multiorgan system reaction whose exact pathogenesis remains unknown. This study aimed at evaluating specific changes in peripheral blood lymphocyte subtypes associated with DRESS during antibiotic treatment. We analyzed six patients with DRESS. A complete blood count and peripheral blood lymphocytes immunophenotyping were carried out at symptom onset and at follow-up visits. Acute-phase reactants and liver enzymes were measured in all patients. Other tests - viral serology, serum immunoglobulin levels, and skin tests were performed when possible. B-cell counts were low in all patients at the onset of DRESS, and natural killer (NK) cells were low in all cases except one. During recovery, B-cell numbers were within a normal range in five patients. In one, there was even a 10-fold increase in B-cell counts, although the level was mildly low after 3 months. NK-cell numbers were within a normal range in three patients. The mean numbers of B cells and NK cells were significantly higher in the second samples compared to the values on admission. Serum IgA and IgM levels were low in one patient. The drug provocation test was positive with cefotaxime in one patient. Viral serology, performed on five patients, was negative. A decrease in B-cell and NK-cell counts was the most consistent finding associated with the onset of antibiotic-induced DRESS in our patients. This immunologic alteration might be a useful predictor of DRESS development. PMID- 22432940 TI - Ontogenesis of the reticulum with special reference to neuroendocrine and glial cells: a comparative analysis of the Merino sheep and Iberian red deer. AB - The present study was designed to compare the differences in the ontogenesis of the reticulum in sheep (domestic ruminant) and deer (wild ruminant). A total of 50 embryos and foetuses Merino sheep and 50 Iberian deer were used, from the first pre-natal life until birth. The appearance of the reticulum from the primitive gastric tube was earlier in the sheep (22% gestation, 33 days) than in the deer (25% gestation, 66 days). In both cases, it displayed a primitive epithelium of a stratified, cylindrical, non-ciliary type. At around 48% gestation in the sheep (72 days) and 36% (97 days) in the deer, the reticulum was configured of four clearly differentiated layers: mucosa (with epithelial layer and lamina propria), submucosa, tunica muscularis and serosa. The stratification of the epithelial layer was accompanied by modifications in its structure with the appearance of the primitive reticular ribs. The primary ribs began to be formed first in the deer, at 117 days of pre-natal life (40% gestation) and later in the sheep (79 days, 53% gestation). The differentiation of the corneum papillae in the primary ribs coincided with the appearance of secondary reticular ribs. These structures began to be formed first in the deer, at 142 days of pre natal life (51% gestation) and later in the sheep (83 days, 55% gestation). The presence of neuroendocrine cells (non-neuronal enolase-positive cells) in the reticular mucosa was not detected until 97 days (36% gestation) in deer and 81 days (54% gestation) in sheep. The presence of glial cells (GFAP-positive cells) occurred at around 142 days (51% gestation) in deer and at 112 days (75% gestation) in sheep. In conclusion, the presence of neuroendocrine and glial cells was detected in deer at earlier stages than sheep. PMID- 22432941 TI - Conductive hybrid nanofibers self-assembled with three different amphiphilic salts. AB - Upon supramolecular self-assembly, novel conductive hybrid nanofibers were successfully fabricated using three amphiphilic salts, azopyridinium, aniline hydrochloride, and alkylbenzenesulfate-based anionic surfactants. The interactions like pi-pi stacking and ionic bonding among the different compounds played important roles in preparation of these multicomponent hybrid nanofibers. These were demonstrated by measurements of XRD, UV-vis absorption, and FTIR spectra. Interesting conductivity in an order of magnitude of 1 * 10(-7) to 1 * 10(-5) S/cm was observed in films of the fabricated hybrid nanofibers, which was attributed to the existence of freely movable ions, showing their possible applications as bionanomaterials and nanoelectronic devices. The fabrication processes of the conductive nanofibers might provide references for simulation of nerve fibers in nature. PMID- 22432942 TI - Detection of medullary thyroid microcarcinoma using ultrasound-guided fine needle aspiration cytology. AB - OBJECTIVE: Compared with incidental papillary thyroid microcarcinoma (microPTC), incidental medullary thyroid microcarcinoma (microMTC) is clinically more significant. The objective of the present study was to summarize our experience in detecting microMTCs. METHODS: From 1995 to 2011, there were 10825 thyroid fine needle aspirates (FNAs) guided using high-resolution ultrasound with on-site preparation and evaluation by a cytopathologist. Of the 140 microcarcinomas detected, 132 were microPTCs and eight were microMTCs, which are the subject of the present study. RESULTS: All eight cases were incidentalomas and none of the five women and three men, age 37-70 years, had a family history of MTC. One patient had two FNAs at an interval of 10 months, two had a single lymph node metastasis and one had a 0.1-cm tumour nodule near the main tumour. Four of five plasmacytoid cell microMCTs had irregular borders; two round cell and one rectangular cell tumours had smooth borders. In contrast, 17 larger MTCs diagnosed in the same period included seven plasmacytoid, four giant cell and six spindle cell types. All five plasmacytoid microMTCs were correctly diagnosed on FNA, but the round cell and rectangular cell tumours were undercalled as follicular lesions. Sampling of colloid from adjacent follicles was noted in microMTCs. Two were diagnosed on histology following recommended surgery and one was diagnosed on recommended repeat FNA. CONCLUSIONS: US-guided FNA of thyroid lesions is a powerful tool in the detection of microMTCs, provided that cytopathologists are alerted to the pitfalls described in the present study. PMID- 22432943 TI - The future of biological warfare. PMID- 22432944 TI - Cloning and characterization of trypsin- and chymotrypsin-like genes in the striped rice stem borer, Chilo suppressalis. AB - Serine proteinases including trypsins and chymotrypsins play various important roles in insects, including food digestion, immune defense, and zymogen activation. Studies on insect serine proteinases could reveal their feeding preference (polyphagous and monophagous) and facilitate identification of protease inhibitors, which can be engineered for pest management. In this paper, 11 transcripts encoding trypsin- and chymotrypsin-like proteins were cloned from the striped rice stem borer, Chilo suppressalis (Walker). All the predicted proteins share high sequence similarity with known trypsin- and chymotrypsin-like proteins from either lepidopterans or dipterans, and most of the proteins have conserved motifs that are characteristics of serine proteinases. Among the 11 cloned genes, six were expressed predominantly and one exclusively in the midgut of the insect, three were expressed relatively evenly in examined tissues, and one was not expressed in either the gut or hemolymph based on RT-PCR results. The seven genes that were predominantly or exclusively expressed in the gut were also affected by feeding on different host plants. The genes that were expressed in the gut and were affected by host plants are likely to encode digestive proteinases. The identification of trypsin- and chymotrypsin-like genes in this insect species is the first step towards further comparative studies and for identification of insect-specific proteinase inhibitors, which might be engineered to protect rice plants against the striped rice stem borer, which is one of the destructive pests of rice. PMID- 22432945 TI - Enzyme-based logic analysis of biomarkers at physiological concentrations: and gate with double-sigmoid "filter" response. AB - We report the first realization of a biomolecular AND gate function with double sigmoid response (sigmoid in both inputs). Two enzyme biomarker inputs activate the gate output signal, which can then be used as indicating liver injury, but only when both of these inputs have elevated pathophysiological concentrations, effectively corresponding to logic-1 of the binary gate functioning. At lower, normal physiological concentrations, defined as logic-0 inputs, the liver-injury output levels are not obtained. High-quality gate functioning in handling of various sources of noise, on time scales of relevance to potential applications, is enabled by utilizing "filtering" effected by a simple added biocatalytic process. The resulting gate response is sigmoid in both inputs when proper system parameters are chosen, and the gate properties are theoretically analyzed within a model devised to evaluate its noise-handling properties. PMID- 22432946 TI - Safety evaluation of intracameral and subconjunctival injection of a novel mucoadhesive polysaccharide isolated from Bletilla striata in rabbit eye. AB - PURPOSE: To evaluate the safety of intracameral and subconjunctival injection of a novel mucoadhesive polysaccharide isolated from Bletilla striata in rabbit eye. METHODS: One hundred microliters (100 MUL) of Bletilla striata polysaccharide (BsP) at concentrations of 10, 40, and 80 mg/mL was intracamerally or subconjunctivally injected into rabbit eyes. Phosphate-buffered saline and 10 mg/mL hyaluronic acid solution were also injected as controls. BsP safety was evaluated via clinical follow-up and histological analysis. The dead corneal endothelial cells were observed by vital staining with alizarin red and trypan blue at 14 days after intracameral injection. Finally, in the intracameral injection study, scanning electron microscopy was performed for evaluation of the structure of the corneal endothelium and anterior lens capsules. RESULTS: Subconjunctival injection of 10 mg/mL BsP does not cause pathological changes or an inflammatory response. Concentration greater than 10 mg/mL of BsP (40 or 80 mg/mL) leaded to a slight inflammatory response, but the rabbits recovered well in 3 days. The pathological observation further confirmed the safety of subconjunctival injection of BsP, and subconjunctival injection of 80 mg/mL BsP caused no lesion of the ocular tissues. Intracameral injection of 80 mg/mL of BsP did not cause a significant inflammatory reaction, and an even lower inflammatory response was observed in rabbits intracamerally injected with 40 or 10 mg/mL BsP. All rabbits intracamerally injected with BsP recovered within 7-14 days. BsP had little effect on the blood-aqueous barrier's integrity when the concentration was 10 mg/mL; at 40 or 80 mg/mL, a mild effect was observed, and the rabbits recovered in 1-3 days. Intracameral BsP injected at a concentration of 80 mg/mL had a negative impact on the corneal endothelium and lens, but concentrations of 40 or 10 mg/mL could be injected safely. CONCLUSIONS: BsP injection into the subconjunctival space and anterior chamber in rabbits at low concentrations (such as 10 mg/mL) did not have adverse effects. PMID- 22432947 TI - Evaluation of the performance of a new compression system in patients with lymphoedema. AB - In the acute phase of lymphoedema, patients require comprehensive decongestive therapy (CDT), which includes skin care, an exercise regimen, manual lymphatic drainage (MLD) and regular bandaging. This study was established to determine the effectiveness of a new system of bandage therapy, the 3MTM CobanTM 2 compression system. In total, 24 patients were entered into the study (12 from UK and 12 from Canada) with a variety of clinical presentations. The mean age of the groups was 57.4 years, which varied from 26 to 79 years. Body mass index (BMI) averaged 38.9 kg/m(2), with a range from 22.7 to 67.5 kg/m(2). Of the total, eight were women with arm lymphoedema, the remainder being men and women with lymphoedema of the lower limb. All were considered to be in need of CDT. After 19 days, the reduction of limb volume was measured, which indicated a mean limb volume reduction of 1210 ml (95% confidence interval, CI, 780-1641, P < 0.001). Leg affected patients experienced greater reduction than arm affected patients (1596 ml versus 438 ml), although both groups experienced significant reduction in limb volumes (both P < 0.001). Mean percentage changes in limb volume were 14.9% and 16.1% for legs and arms, respectively. The Measure Your Medical Outcome Profile questionnaire indicated significant improvement in symptoms considered important by the patient (P < 0.0001), which also led to improvements in skin quality by reducing skin thickness and firmness. The Coban 2 compression system provides good oedema reduction in both arms and legs to reduce limb volume and improvements in symptoms associated with lymphoedema. PMID- 22432948 TI - Evaluating the effectiveness of a web-based intervention to promote mental wellbeing in women and partners following miscarriage, using a modified patient preference trial design: an external pilot. AB - This article describes an external pilot study of a modified 'partially randomised patient preference' trial comparing a web-based intervention (designed to promote mental wellbeing) with standard care post-miscarriage. Assessment comprised an online administration of baseline measures with follow-up at 3 months following registration. Baseline data were obtained from 60 women (and seven partners) post-discharge from one of two Early Pregnancy Assessment Units. 'Intention to treat' versus a 'per protocol' sensitivity analysis showed the effects of introducing a 'preference' option post-randomisation, and highlights the benefits compared with a randomised controlled trial design to enable a robust evaluation of the website in promoting mental wellbeing after miscarriage. PMID- 22432949 TI - Antidepressants and the relief of osteoarthritic pain - findings from a study examining adjunctive duloxetine. PMID- 22432950 TI - Brain connectivity: a new journal emerges. PMID- 22432951 TI - The restless brain. AB - The pressing need to better understand human brain organization is appreciated by all who have labored to explain the uniqueness of human behavior in health and disease. Early work on the cytoarchitectonics of the human brain by Brodmann and others accompanied by several centuries of lesion behavior work, although valuable, has left us far short of what we need. Fortunately, modern brain imaging techniques have, over the past 40 years, substantially changed the situation by permitting the safe appraisal of both anatomical and functional relationships within the living human brain. An unexpected feature of this work is the critical importance of ongoing, intrinsic activity, which accounts for the majority of brain's energy consumption and exhibits a surprising level of organization that emerges with dimensions of both space and time. In this essay, some of the unique features of intrinsic activity are reviewed, as it relates to our understanding of brain organization. PMID- 22432952 TI - Functional and effective connectivity: a review. AB - Over the past 20 years, neuroimaging has become a predominant technique in systems neuroscience. One might envisage that over the next 20 years the neuroimaging of distributed processing and connectivity will play a major role in disclosing the brain's functional architecture and operational principles. The inception of this journal has been foreshadowed by an ever-increasing number of publications on functional connectivity, causal modeling, connectomics, and multivariate analyses of distributed patterns of brain responses. I accepted the invitation to write this review with great pleasure and hope to celebrate and critique the achievements to date, while addressing the challenges ahead. PMID- 22432954 TI - A signal-processing pipeline for magnetoencephalography resting-state networks. AB - To study functional connectivity using magnetoencephalographic (MEG) data, the high-quality source-level reconstruction of brain activity constitutes a critical element. MEG resting-state networks (RSNs) have been documented by means of a dedicated processing pipeline: MEG recordings are decomposed by independent component analysis (ICA) into artifact and brain components (ICs); next, the channel maps associated with the latter ones are projected into the source space and the resulting voxel-wise weights are used to linearly combine the IC time courses. An extensive description of the proposed pipeline is provided here, along with an assessment of its performances with respect to alternative approaches. The following investigations were carried out: (1) ICA decomposition algorithm. Synthetic data are used to assess the sensitivity of the ICA results to the decomposition algorithm, by testing FastICA, INFOMAX, and SOBI. FastICA with deflation approach, a standard solution, provides the best decomposition. (2) Recombination of brain ICs versus subtraction of artifactual ICs (at the channel level). Both the recombination of the brain ICs in the sensor space and the classical procedure of subtracting the artifactual ICs from the recordings provide a suitable reconstruction, with a lower distortion using the latter approach. (3) Recombination of brain ICs after localization versus localization of artifact-corrected recordings. The brain IC recombination after source localization, as implemented in the proposed pipeline, provides a lower source level signal distortion. (4) Detection of RSNs. The accuracy in source-level reconstruction by the proposed pipeline is confirmed by an improved specificity in the retrieval of RSNs from experimental data. PMID- 22432953 TI - Superficially located white matter structures commonly seen in the human and the macaque brain with diffusion tensor imaging. AB - The white matter of the brain consists of fiber tracts that connect different regions of the brain. Among these tracts, the intrahemispheric cortico-cortical connections are called association fibers. The U-fibers are short association fibers that connect adjacent gyri. These fibers were thought to work as part of the cortico-cortical networks to execute associative brain functions. However, their anatomy and functions have not been documented in detail for the human brain. In past studies, U-fibers have been characterized in the human brain with diffusion tensor imaging (DTI). However, the validity of such findings remains unclear. In this study, DTI of the macaque brain was performed, and the anatomy of U-fibers was compared with that of the human brain reported in a previous study. The macaque brain was chosen because it is the most commonly used animal model for exploring cognitive functions and the U-fibers of the macaque brain have been already identified by axonal tracing studies, which makes it an ideal system for confirming the DTI findings. Ten U-fibers found in the macaque brain were also identified in the human brain, with a similar organization and topology. The delineation of these species-conserved white matter structures may provide new options for understanding brain anatomy and function. PMID- 22432956 TI - Synchrony of two brain regions predicts the blood oxygen level dependent activity of a third. AB - Spontaneously emerging coherent fluctuations have been long observed in electrophysiological and functional magnetic resonance imaging studies. These dynamics have been identified in multiple brain areas in the 1-100 and < 0.1 Hz frequency ranges spanning neurophysiological oscillations and blood oxygen level dependent (BOLD) signals, respectively. In this article, we demonstrate that transient neural synchronization between two sites may lead to the emergence of ultra-slow frequency fluctuations in the BOLD signal at another (third) site. Starting with a network model comprised of three neural oscillators, we illustrate the critical role of time delay and coupling strength in generating these slow coherent fluctuations as a function of intermittently occurring neural coherence. When extending the network toward biologically realistic primate connectivity, we find that the BOLD activation patterns arise from neurophysiological coherence, especially among medial cortical areas. This finding demonstrates a network-level mechanism whereby the BOLD activity at a given region is critically influenced by the neuroelectric synchronization patterns of other regions in the network. PMID- 22432955 TI - Amygdala functional connectivity in young women with borderline personality disorder. AB - Borderline personality disorder (BPD) is a complex psychiatric disorder that involves the core feature of affect dysregulation. Prior neuroimaging studies have indicated that BPD patients have (1) excessive amygdala activation to negative emotion and (2) diminished frontal regulation. This study examined amygdala functional connectivity in 12 women with BPD and 12 matched healthy comparison volunteers. We explored how connectivity patterns would change in the context of processing neutral, overt fear, or masked fear face expressions. Each participant underwent three 5-min fMRI scans in which they primarily viewed: (1) neutral, (2) overt fear, and (3) masked fear faces. In comparison to their healthy counterparts, young women with BPD showed (1) lower connectivity between bilateral amygdala and mid-cingulate cortex during the neutral scan; (2) higher connectivity between bilateral amygdala and rostral anterior cingulate cortex during the overt fear scan; and (3) higher right amygdala connectivity with bilateral thalamus and right caudate during the masked fear scan. Exploratory analyses revealed interesting correlations between amygdala connectivity in these conditions with multiple clinical measures. Results from the neutral scan add to the few prior connectivity studies in BPD that have been suggestive of lower fronto-limbic connectivity in BPD. However, the connectivity findings during fear processing are novel, and map onto basic research models for amygdala connectivity, that is, connections to frontal areas for overt fear processing versus connections to thalamus for automatic fear processing. Further, results suggest that BPD subjects tap into both pathways more strongly than healthy comparisons. PMID- 22432957 TI - Two-axis acceleration of functional connectivity magnetic resonance imaging by parallel excitation of phase-tagged slices and half k-space acceleration. AB - Whole brain functional connectivity magnetic resonance imaging requires acquisition of a time course of gradient-recalled (GR) volumetric images. A method is developed to accelerate this acquisition using GR echo-planar imaging and radio frequency (RF) slice phase tagging. For N-fold acceleration, a tailored RF pulse excites N slices using a uniform-field transmit coil. This pulse is the Fourier transform of the profile for the N slices with a predetermined RF phase tag on each slice. A multichannel RF receive coil is used for detection. For n slices, there are n/N groups of slices. Signal-averaged reference images are created for each slice within each slice group for each member of the coil array and used to separate overlapping images that are simultaneously received. The time-overhead for collection of reference images is small relative to the acquisition time of a complete volumetric time course. A least-squares singular value decomposition method allows image separation on a pixel-by-pixel basis. Twofold slice acceleration is demonstrated using an eight-channel RF receive coil, with application to resting-state functional magnetic resonance imaging in the human brain. Data from six subjects at 3 T are reported. The method has been extended to half k-space acquisition, which not only provides additional acceleration, but also facilitates slice separation because of increased signal intensity of the central lines of k-space coupled with reduced susceptibility effects. PMID- 22432958 TI - Biofeedback of real-time functional magnetic resonance imaging data from the supplementary motor area reduces functional connectivity to subcortical regions. AB - Recent studies have reported that biofeedback of real-time functional magnetic resonance imaging data can enable people to gain control of activity in specific parts of their brain and can alter functional connectivity between brain areas. Here we describe a study using biofeedback of real-time functional magnetic resonance imaging data to train healthy subjects to control activity in their supplementary motor area (SMA), a region of interest in Tourette syndrome (TS). Although a significant increase in control over the SMA during biofeedback was not found, subjects were able to exert significant control over the SMA in later biofeedback sessions despite not having control in the first biofeedback session. Further, changes were found in their resting state functional connectivity. Specifically, when comparing functional connectivity to the SMA before and after biofeedback, the strength of functional connectivity with subcortical regions was reduced after the biofeedback. This suggests that biofeedback may allow subjects to develop greater conscious control over activity in their SMA by reducing the influence of corticostriatothalamocortical loops on the region. This possibility is promising for TS, where aberrant dynamics in corticostriatothalamocortical loops have long been suspected to give rise to tic symptoms. Further studies in TS patients are needed. PMID- 22432959 TI - Compression of nanowires using a flat indenter: diametrical elasticity measurement. AB - A new experimental approach for the characterization of the diametrical elastic modulus of individual nanowires is proposed by implementing a micro/nanoscale diametrical compression test geometry, using a flat punch indenter. A 250 nm diameter single crystal silicon nanowire is compressed inside of a scanning electron microscope. Since silicon is highly anisotropic, the wire crystal orientation in the compression axis is determined by electron backscatter diffraction. In order to analyze the load-displacement compression data, a two dimensional analytical closed-form solution based on a classical contact model is proposed. The results of the analytical model are compared with those of finite element simulations and to the experimental diametrical compression results and show good agreement. PMID- 22432960 TI - Uncovering and overcoming ambivalence: the role of chronic and contextually activated attachment in two-person social dilemmas. AB - OBJECTIVE: Humans face an enduring conflict between desires to affiliate with others but to protect the self; effective social functioning often requires reconciling the resulting ambivalence between these motives. Attachment anxiety is characterized by chronically heightened concerns about affiliation and self protection; we investigated how anxious individuals' chronic relational ambivalence affects interpersonal behavior. METHOD: We used the Prisoner's Dilemma and the Assurance Game to examine how the ambivalence associated with attachment anxiety affects pro-social behavior, comparing chronic attachment anxiety with both chronic (Study 1; N = 94) and contextually activated (Study 2; N = 56) security. RESULTS: Chronic attachment anxiety was associated with ambivalent behavior in the social dilemma games. Specifically, the chronically anxious were mistrustfully inconsistent in their strategic choices and took more time to make these choices. However, priming the chronically anxious with attachment security decreased ambivalence by promoting more fluent cooperative behavior. CONCLUSIONS: To our knowledge, these are the first studies to examine the effect of the anxiously attached's chronic relational ambivalence on pro social behavior. These findings illustrate that the simultaneous activation of affiliation and self-protection can have interpersonal consequences, increasing mistrust and hesitance. Importantly, however, we were able to attenuate these effects by priming felt security. PMID- 22432961 TI - Persistent source influences on the trailing edge of a groundwater plume, and natural attenuation timeframes: the F-Area Savannah River Site. AB - At the Savannah River Site's F-Area, wastewaters containing radionuclides were disposed into seepage basins for decades. After closure and capping in 1991, the U.S. Department of Energy (DOE) has being monitoring and remediating the groundwater plume. Despite numerous studies of the plume, its persistence for over 20 years has not been well understood. To better understand the plume dynamics, a limited number of deep boreholes were drilled to determine the current plume characteristics. A mixing model was developed to predict plume tritium and nitrate concentrations. We found that the plume trailing edges have emerged for some contaminants, and that contaminant recharge from the basin's vadose zone is still important. The model's estimated time-dependent basin drainage rates combined with dilution from natural recharge successfully predicted plume tritium and nitrate concentrations. This new understanding of source zone influences can help guide science-based remediation, and improve predictions of the natural attenuation timeframes. PMID- 22432962 TI - Cardiac resynchronization therapy: double cannulation approach to coronary venous lead placement via a prominent thebesian valve. AB - We report identification of a prominent Thebesian valve by cardiovascular computed tomography (CT) angiography impeding cannulation of the coronary sinus, with subsequent successful coronary venous lead placement with cannulation of the coronary sinus ostium via a transvenous femoral vein approach and subsequent cannulation of the ostium with the coronary venous lead with a left subclavian approach. A 57-year-old man with nonischemic dilated cardiomyopathy, New York Heart Association Class III heart failure, left bundle branch block, and an ejection fraction of 15%, underwent an attempted cardiac resynchronization therapy implantable cardiac defibrillator (ICD). As the coronary sinus ostium could not be cannulated, a dual chamber ICD was placed. The patient subsequently underwent cardiovascular CT angiography, which identified a prominent Thebesian valve at the coronary sinus ostium as the anatomic obstacle to cannulation. Reattempted transvenous cardiac resynchronization therapy was accomplished successfully with a double cannulation approach: cannulation of the coronary sinus ostium with a catheter via a transvenous femoral vein approach and subsequent cannulation with the coronary venous lead via a left subclavian approach. When a prominent Thebesian valve is identified as an obstacle to transvenous left ventricular lead placement, cannulation of the coronary sinus by an alternate venous approach may allow for a coronary venous route rather than necessitate an epicardial approach. PMID- 22432963 TI - Flavor compounds and quality parameters of chevon as influenced by sericea lespedeza hay. AB - This research assessed the utilization of sericea lespedeza (SL, Lespedeza cuneata ) hay, a highly condensed tannin (CT) forage (87-181 g CT/kg), as a dietary regimen of meat goats, and thereby the effects on physicochemical properties of goat meat (chevon) and flavor compounds in cooked chevon chops were evaluated. Although it is commonly believed that higher amounts of CT can have deleterious effects on animal performance due to low digestibility and low voluntary intakes in ruminants, feeding meat goats with SL hay increased the body weight compared to goats fed bermudagrass hay without altering the chemical composition and meat quality of chevon. Feeding SL hay to meat goats also did not significantly influence the flavor volatiles in cooked chevon chops. The findings indicate that SL hay can be used as a low-input forage to replace expensive forages. PMID- 22432964 TI - BODE-index, modified BODE-index and ADO-score in chronic obstructive pulmonary disease: relationship with COPD phenotypes and CT lung density changes. AB - COPD is a heterogeneous disorder whose assessment is going to be increasingly multidimensional. Grading systems such as BODE (Body-Mass Index, Obstruction, Dyspnea, Exercise), mBODE (BODE modified in grading of walked distance), ADO (Age, Dyspnea, Obstruction) are proposed to assess COPD severity and outcome. Computed tomography (CT) is deemed to reflect COPD lung pathologic changes. We studied the relationship of multidimensional grading systems (MGS) with clinically determined COPD phenotypes and CT lung density. Seventy-two patients underwent clinical and chest x-ray evaluation, pulmonary function tests (PFT), 6 minute walking test (6MWT) to derive: predominant COPD clinical phenotype, BODE, mBODE, ADO. Inspiratory and expiratory CT was performed to calculate mean lung attenuation (MLA), relative area with density below-950 HU at inspiration (RAI( 950)), and below -910 HU at expiration (RAE(-910)). MGS, PFT, and CT data were compared between bronchial versus emphysematous COPD phenotype. MGS were correlated with CT data. The prediction of CT density by means of MGS was investigated by direct and stepwise multivariate regression. MGS did not differ in clinically determined COPD phenotypes. BODE was more closely related and better predicted CT findings than mBODE and ADO; the better predictive model was obtained for CT expiratory data; stepwise regression models of CT data did not include 6MWT distance; the dyspnea score MRC was included only to predict RA-950 and RA-910 which quantify emphysema extent. BODE reflect COPD severity better than other MGS, but not its clinical heterogeneity. 6MWT does not significantly increase BODE predictivity of CT lung density changes. PMID- 22432965 TI - Extension of the Contingency Naming Test to adult assessment: psychometric analysis in a college student sample. AB - The Contingency Naming Test (CNT; Taylor, Albo, Phebus, Sachs, & Bierl, 1987) was initially designed to assess aspects of executive functioning, such as processing speed and response inhibition, in children. The measure has shown initial utility in identifying differences in executive function among child clinical groups; however, there is an absence of adequate psychometric data for use with adults. The current study expanded psychometric data upward for use with a college student sample and explored the measure's test-retest reliability and factor structure. Performance in the adult sample showed continued improvement above child norms, consistent with theories of executive function development. Exploratory factor analysis showed that the CNT is most closely related to measures of processing speed, as well as elements of response inhibition within the latter trials. Overall, results from the current study provide added support for the utility of the CNT as a measure of executive functioning in young adults. However, more research is needed to determine patterns of performance among adult clinical groups, as well as to better understand how performance patterns may change in a broader age range, including middle and older adulthood. PMID- 22432966 TI - Types of maternal hypertensive disease and their association with pathologic lesions and clinical factors. AB - Hypertensive disease (HD) during pregnancy includes chronic hypertension (HTN), gestational hypertension (GH), and preeclampsia/eclampsia (PEC). Differences between types of HD have not been well studied. Clinicopathologic features were compared between the HD groups and controls. HD was associated with lower Apgar scores, intrauterine growth restriction, IUGR, and delivery at an earlier gestational age (GA). IUGR was less common in the GH group, gestational age was lowest in the PEC. As expected, HD is associated with placental lesions of malperfusion, younger GA, and increased incidence of IUGR and controls showed less chronic and more "acute" lesions (ACA, MEC). Finally, comparisons of the HD groups showed differences only in GA and IUGR in the GH group as compared to the HTN and PEC groups. This suggests that GH may be associated with less severe clinical disease while showing similar pathologic features. PMID- 22432967 TI - Mapping the availability, price, and affordability of antiepileptic drugs in 46 countries. AB - PURPOSE: In low- and middle-income countries (LMICs), a large proportion of people with epilepsy do not receive treatment. An analysis of the availability, price, and affordability of antiepileptic drugs (AEDs) was conducted to evaluate whether these factors contribute to the treatment gap. METHODS: Data for five AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, and diazepam) were obtained from facility-based surveys conducted in 46 countries using the World Health Organization/Health Action International (WHO/HAI) methodology. Outcome measures were percentage availability, ratios of local prices to international reference prices, and number of days' wages needed by the lowest-paid unskilled government worker to purchase treatment. Prices were adjusted for inflation/deflation and purchasing power parity. KEY FINDINGS: The average availability of generic AEDs in the public sector was <50% for all medicines except diazepam injection. Private sector availability of generic oral AEDs ranged from 42.2% for phenytoin to 69.6% for phenobarbital. Public sector patient prices for generic carbamazepine and phenytoin were 4.95 and 17.50 times higher than international reference prices, respectively, whereas private sector patient prices were 11.27 and 24.77 times higher, respectively. For both medicines, originator brand prices were about 30 times higher. The highest prices were observed in the lowest income countries. The lowest-paid government worker would need wages from 1-2.6 days' to purchase a month's supply of phenytoin, whereas carbamazepine would cost 2.7-16.2 days' wages. Despite its widespread use in LMICs, WHO/HAI survey data for phenobarbital was only available from a small number of countries. SIGNIFICANCE: In LMICs, availability and affordability of AEDs are poor and may be acting as a barrier to accessing treatment for epilepsy. Ensuring a consistent supply of AEDs at an affordable price should be a priority. PMID- 22432968 TI - Vinyl sulfone functionalization: a feasible approach for the study of the lectin carbohydrate interactions. AB - Carbohydrate-mediated molecular recognition is involved in many biological aspects such as cellular adhesion, immune response, blood coagulation, inflammation, and infection. Considering the crucial importance of such biological events in which proteins are normally involved, synthetic saccharide based systems have emerged as powerful tools for the understanding of protein carbohydrate interactions. As a new approach to create saccharide-based systems, a set of representative monosaccharides (D-mannose, D-glucose, N-acetyl-D glucosamine, and L-fucose) and disaccharides (lactose, maltose, and melibiose) were derivatized at their anomeric carbon with a vinyl sulfone group spanned by an ethylthio linker. This vinyl sulfone functionalization is demonstrated to be a general strategy for the covalent linkage of a saccharide in mild conditions via Michael-type additions with the amine and thiol groups from functionalized supports and those naturally present in biomolecules. The introduction of the ethylthio linker between the biorecognizable element (i.e., saccharide) and the reactive group (i.e., vinyl sulfone) was found to preserve the functionality of the former. The capability of the vinyl sulfone saccharides for the study of lectin-carbohydrate interactions was demonstrated by (i) immobilizing them on both amine-functionalized supports (glass slides and microwell plates) and polylysine-coated glass slides to create sugar arrays that selectively bind lectins (ii) coupling to model proteins to yield neoglycoproteins that are recognized by lectins and (iii) using vinyl sulfone saccharides as tags to allow the detection of the labeled biomolecule by HRP-lectins. The above results were further put tothe test with a real case: detection of carbohydrate binding proteins present in rice ( Oryza sativa ). PMID- 22432969 TI - Transient elastography and simple blood markers in the diagnosis of esophageal varices for compensated patients with hepatitis B virus-related cirrhosis. AB - BACKGROUND AND AIM: Transient elastography (TE) has been useful in esophageal varices (EV) diagnosis for chronic hepatitis C patients. In the present study, we evaluate the usefulness of TE and simple blood markers in the EV diagnosis of patients with hepatitis B virus (HBV)-related cirrhosis, prospectively. METHODS: Consecutive patients with compensated cirrhosis and positive HBV surface antigen were enrolled, prospectively. At enrollment, the aspartate aminotransferase (AST) to alanine aminotransferase ratio (AAR) and the AST to platelet ratio index (APRI) were recorded, and TE was performed. Two experienced endoscopists assessed EV independently. High-risk EV was defined as small size with a red color sign, and medium or large in size. The diagnostic performances, optimal cut-offs, and the validities of TE, APRI, platelet count (PLT), and AAR in EV diagnosis were assessed. RESULTS: A total of 126 patients (male/female: 93/33; mean age: 54.5 years) with reliable TE results were analyzed. There was good agreement between two endoscopists in assessing the presence of EV and high-risk EV (kappa value: 0.82 and 0.96). Forty-eight (38.1%) patients had EV (small: 35; high risk: 13). There was correlation between TE result and EV size (r = 0.515, P < 0.001). TE, APRI, and PLT were similar; however, superior to AAR in the diagnostic accuracies for EV and high-risk EV. In high-risk EV prediction, the negative predictive value (NPV) was 97%, 98%, and 98%, with cut-offs of 21 kPa, 1.24, and 110 (* 10(9) /L) for TE, APRI, and PLT, respectively. CONCLUSIONS: For compensated patients with HBV-related cirrhosis, TE, APRI, and PLT are useful in excluding high-risk EV with high NPV. PMID- 22432970 TI - Anatomy and anaesthesia of the equine external ear canal. AB - Anaesthesia of the external ear canal (external acoustic meatus) is usually performed by blocking both the great and internal auricular nerves by regional infiltration. However, exact landmarks for blocking the internal auricular nerve to accomplish effective anaesthesia have not been described yet. In this study, detailed anatomical dissection of the equine external ear canal and its nerve supply was carried out on fifteen cadaver heads. Tissue samples of the dissected nerves were taken from two cadaver heads processed and were evaluated microscopically. Prior to the dissection, the region of interest was evaluated ultrasonographically, and injection of a local anaesthetic was simulated with an injection of methylene blue on ten cadaver heads. The tympanic membranes of three cadaver heads were obtained by microdissection and processed for microscopic evaluation. The entrance point of the internal auricular nerve, which is a branch of the facial nerve, into the ear canal is formed by the styloid process of the auricular cartilage. Using ultrasound, the styloid process presented as a thin hyperechoic line 2.17-2.97 cm deep, based on the skin surface. Landmarks for performing a complete and reliable anaesthesia of the external ear canal were established, and the simulated anaesthesia with methylene blue injection was evaluated as successful in all ten cases. Additionally, the histological composition of the equine tympanic membrane is described and illustrated. PMID- 22432971 TI - A biometric study of C-shaped root canal systems in mandibular second molars using cone-beam computed tomography. AB - AIM: To investigate the configuration of C-shaped canals in mandibular second molars, canal wall thickness and the orientation of the thinnest area at 1-mm intervals from the canal orifice to the apex by using cone-beam computed tomographic (CBCT) images. METHODOLOGY: Three-dimensional CBCT images of 92 Korean mandibular second molars having C-shaped root canals were analysed to determine their configuration using a modification of Melton's classification, as well as the thinnest walls and their location. Associations between configuration type and distance from the canal orifice to the apex, as well as associations between the directional orientation of the thinnest root wall and distance from the canal orifice to the apex, were assessed by Fisher's exact test. Because serial measurements of minimum wall thicknesses were correlated with individual teeth, a mixed-effects analysis was applied. RESULTS: The most common configuration types were Melton's type I in the coronal region and Melton's type III in the apical region. Mean thicknesses of the thinnest root canal walls were 1.39 +/- 0.38, 0.85 +/- 0.25 and 0.77 +/- 0.20 mm in the coronal, middle and apical regions, respectively. The thicker the root canal walls at the orifice region, the greater the decrease in thickness towards the apical region (P < 0.05), with the linguo-central root area being the thinnest. The pattern of decreasing thickness from the orifice to the apex formed a nonlinear cubic curve. CONCLUSIONS: The most prevalent configuration types were Melton's type I (coronal region) and type III (apical region). The linguo-central root area was the thinnest in C-shaped root canals of Korean mandibular second molars. These anatomical variations should be considered during surgical or nonsurgical endodontic procedures. PMID- 22432972 TI - Total synthesis of the terpenoid buddledone A: 11-membered ring-closing metathesis. AB - The first total synthesis of buddledone A was accomplished in seven steps from methyl ethyl ketone (MEK). The key step in the sequence featured an 11-membered ring formation by ring-closing metathesis. PMID- 22432973 TI - Covalent cum noncovalent functionalizations of carbon nanotubes for effective reinforcement of a solution cast composite film. AB - Although carbon nanotubes have impressive tensile properties, exploiting these properties in composites, especially those made by the common solution casting technique, seems to be elusive thus far. The reasons could be partly due to the poor nanotube dispersion and the weak nanotube/matrix interface. To solve this dual pronged problem, we combine noncovalent and covalent functionalizations of nanotubes in a single system by the design and application of a novel dispersant, hydroxyl polyimide-graft-bisphenol A diglyceryl acrylate (PI(OH)-BDA), and use them with epoxidized single-walled carbon nanotubes (O-SWNTs). Our novel PI(OH) BDA dispersant functionalizes the nanotubes noncovalently to achieve good dispersion of the nanotubes because of the strong pi-pi interaction due to main chain and steric hindrance of the BDA side chain. PI(OH)-BDA also functionalizes O-SWNTs covalently because it reacts with epoxide groups on the nanotubes, as well as the cyanate ester (CE) matrix used. The resulting solution-cast CE composites show 57%, 71%, and 124% increases in Young's modulus, tensile strength, and toughness over neat CE. These values are higher than those of composites reinforced with pristine SWNTs, epoxidized SWNTs, and pristine SWNTs dispersed with PI(OH)-BDA. The modulus and strength increase per unit nanotube weight fraction, i.e., dE/dW(NT) and dsigma/dW(NT), are 175 GPa and 7220 MPa, respectively, which are significantly higher than those of other nanotube/thermosetting composites (22-70 GPa and 140-3540 MPa, respectively). Our study indicates that covalent cum noncovalent functionalization of nanotubes is an effective tool for improving both the nanotube dispersion and nanotube/matrix interfacial interaction, resulting in significantly improved mechanical reinforcement of the solution-cast composites. PMID- 22432974 TI - Environmental tobacco smoke and male sex modify the influence of IL-13 genetic variants on cord blood IgE levels. AB - Elevated cord blood IgE (cIgE) levels enhance the risk of childhood atopic diseases. However, genetic determinants of cIgE elevation and their potential modifiers remain inconclusive. We aimed to investigate the associations of single nucleotide polymorphisms (SNPs) in the IL-13 gene (IL-13) with cIgE elevation and their interactions with prenatal environmental tobacco smoke (ETS) and neonatal sex. A structured questionnaire regarding prenatal environmental exposures was completed during pregnancy. Birth information was extracted from the medical records. Cord blood from 794 term neonates was genotyped for three SNPs (rs1800925, rs20541, and rs848) of IL-13 and measured for cIgE levels. SNP rs20541 and a 3-SNP haplotype containing rs1800925, rs20541, and rs848 (denoted as h011) were significantly associated with cIgE elevation (p = 0.04 and 0.003, respectively). Two-way interaction analysis revealed that the associations of IL 13 rs20541 and h011 with cIgE elevation were synergistically enhanced by prenatal ETS (p for interaction = 0.03 and 0.03, respectively), but not by male sex. If the association analyses were stratified by prenatal ETS and neonatal sex simultaneously, IL-13 rs20541 and h011 had the highest risks for cIgE elevation in male babies prenatally exposed to ETS, with adjusted odds ratios (95% confidence interval) being 3.03 (1.56-5.88) and 2.81 (1.54-5.15), respectively. When three-way interactions were examined, both IL-13 rs20541 and h011 exhibited significant interactions with male sex and ETS (p for interaction = 0.03 and 0.007, respectively). In conclusion, the influence of IL-13 genetic variants on cIgE elevation was modified by male sex and prenatal ETS. PMID- 22432975 TI - Radical cations of branched alkanes in solutions: time-resolved magnetic field effect and quantum chemical studies. AB - Radical cations of heptane and octane isomers, as well as several longer branched alkanes, were detected in irradiated n-hexane solutions at room temperature by the method of time-resolved magnetic field effect (TR MFE). To identify radical cations, the hyperfine coupling constants as determined by simulation of the TR MFE curves were compared to the constants calculated using the density functional theory (DFT) approach. The g-values of the observed radical cations were close to that of the 2,2,3,3-tetramethylbutane radical cation studied earlier by optically detected electron spin resonance (ESR) and TR MFE techniques. No evidence of the decay of the radical cations of branched alkanes to produce olefin radical cations was found, which was further supported by the observation of positive charge transfer from the observed radical cations to cycloalkane molecules. The lifetimes of the radical cations of the branched alkanes were found to be longer than tens of nanoseconds. PMID- 22432976 TI - Efficacy of Ficus spp. on renal injury induced by hypercholesterolaemia. AB - The ethanol and hexane extracts of Ficus microcarpa, Ficus religiosa and Ficus mysorensis leaves were evaluated against renal injury induced by hypercholesterolaemia. Phytochemical screening of the investigated plants was undertaken. For the in vivo study, all rats were orally given cholesterol (30 mg kg-1 body weight, BW) and leaves extract (500 mg kg-1 BW) five times per week for 9 weeks. Hypercholesterolaemic rats showed significant increases in urea nitrogen and creatinine while serum protein and albumin levels, nitric oxide (NO), Na+-K+ ATPase and phospholipids in kidney tissue were all decreased. Treatment with leaves extract improved kidney function indices (urea nitrogen, creatinine, serum protein and albumin), kidney disorder biochemical parameters (NO, Na+-K+-ATPase and phospholipids), haematological profile (haemoglobin, RBCs and WBCs) and kidney histopathology. In conclusion, Ficus spp. succeeded in improving renal injury induced by hypercholesterolaemia, with the most potent effects seen while using Ficus microcarpa hexane extract. PMID- 22432977 TI - What do we mean by "Hyperhaemolysis" and what is the cause? PMID- 22432978 TI - Symptoms and treatment of bipolar patients in Sweden. AB - OBJECTIVE: The objective of the study was to investigate affective symptoms and pharmacological treatment in bipolar I disorder patients, and to test whether self-rated symptoms could predict hospital admissions during a 12-month follow-up period. METHODS: A total of 231 outpatients with clinical bipolar I disorder were recruited. The clinical diagnoses were reassessed by a semi-structured interview. Twenty-four patients (10%) was reclassified as bipolar disorder type II or schizoaffective disorder (bipolar type). Medication status was recorded and symptoms were assessed with the self-rating scale AS-18. Patients were prospectively followed for 12 months and hospitalizations during that time were recorded. RESULTS: More than half (60%) rated themselves as normothymic. Mixed affective symptoms were more common than either depressive or manic/hypomanic symptoms. The admission rate during 1 year of follow-up was 13% (95% C.I. 8-17%). Patients which at baseline rated themselves high in either mania or in depression had a significantly increased risk for hospitalization (OR = 3.15; 95% C.I. 1.38 7.19). CONCLUSIONS: The findings should encourage clinicians to use patient self ratings in order to identify patients with a high risk for hospitalization for targeted interventions. PMID- 22432980 TI - Acceptability of misoprostol-only medical termination of pregnancy compared with vacuum aspiration: an international, multicentre trial. AB - OBJECTIVE: To compare women's acceptance of misoprostol-only medical termination of pregnancy (TOP) with surgical TOP. DESIGN: Prospective cohort study. SETTING: Termination of pregnancy clinics in New Delhi, Mumbai, Hanoi, Tbilisi, Trivandrum and Yerevan. POPULATION: Women requesting TOP, at 63 days of gestation or less, at study sites where both medical and surgical methods were available. METHODS: Serial surveys eliciting measures of women's satisfaction and acceptance of TOP method were administered. Data were analysed using cross-tabulation and logistic regression to determine if TOP method was predictive of acceptability. MAIN OUTCOME MEASURES: Patient acceptance. RESULTS: High acceptability of both surgical and misoprostol-only TOP. CONCLUSIONS: Where medical TOP with mifepristone is not available, misoprostol-only medical TOP is acceptable to women who have the choice between medical or surgical techniques. PMID- 22432981 TI - Interaction of premicellar states of a PEO-PPO-PEO triblock copolymer with partially hydrophobic substances: NMR study. AB - According to (1)H and (13)C NMR spectra, relaxations, and PFG NMR self-diffusion measurements, partially hydrophobic additives methyl-ethyl ketone (MEK), methyl isopropyl ketone (MIPK), and methyl-t-butyl ketone (MTBK) facilitate the conformation change and subsequent self-association of the copolymer Pluronic L64. The correlation time (4-9 ms) and activation energy (43-52 kJ/mol) of transition between its conformation states decrease with the increasing hydrophobicity and bulkiness of the additive. The temperature of the first PPO self-association decreases in the same order (by 4 K for MTBK). The interaction of the additives was indirectly proved by the decrease of their rotational and translational mobility in the presence of L64. The rotational correlation time tau(c) is between 3 and 6 * 10(-11) s, whereas that of the same molecules in the absence of L64 is lower than 6 * 10(-12) s. The normalized self-diffusion coefficient decreases to about 0.7 of its original value in the presence of L64. The interaction of the additive with the PPO block is transient but effective enough to facilitate its conformational change and self-association. Its mediation by a water molecule bound to PPO as a possible mechanism is suggested. PMID- 22432982 TI - As clear as MUD. PMID- 22432983 TI - Management of opioid substitution therapy during medical intervention. AB - Opioid substitution therapy (OST) for opioid dependence is common, and injection drug users have significant medical and psychiatric comorbidity. Many physicians will encounter OST patients in their usual practice. This article provides guidance on management of common clinical problems in this population, including OST management in hepatic failure, respiratory disease, pain management and potential drug interactions. PMID- 22432984 TI - No evidence or no alternative? Taking responsibility for off-label prescribing. AB - Recombinant activated factor VII (rFVIIa) is registered for patients with rare haematological disorders, but is used 'off-label' in many other situations, including intracranial haemorrhage, cardiac surgery, trauma, transplantation and prostatectomy. Lack of systematic evidence to support these off-label uses has not slowed the growth of off-label prescribing of rFVIIa. We use the case of rFVIIa to illustrate the issues raised by off-label prescribing, and the kind of impasse that can arise when views about evidence, expertise and clinical necessity are in conflict. We argue that clinicians, hospital drug committees and regulators all need to acknowledge the complexity of prescribing decisions, and ensure that decisions to prescribe off-label are sufficiently justified. PMID- 22432985 TI - Pneumatosis cystoides intestinalis in scleroderma-related conditions. AB - AIMS: Pneumatosis cystoides intestinalis (PCI) is a rare life-threatening gastrointestinal complication in the course of connective tissue disease (CTD). PCI is characterised by the appearance of intramural clusters of gas in the small and large bowel wall on X-ray or computed tomography and often is accompanied by free air in the peritoneal cavity. METHODS: We present three cases of PCI in patients with scleroderma-related conditions. A review of the English language literature published on MEDLINE from 1973 to 2008 was conducted using the terms: 'systemic sclerosis', 'connective tissue disease' and 'pneumatosis cystoides intestinalis'. This review focused on clinical features, diagnostic and treatment strategies of PCI in the context of CTD. RESULTS: Symptoms of PCI are non specific: abdominal pain, vomiting, constipation, bloating and weight loss. Coexistence of PCI with other manifestations of CTD, such as intestinal pseudo obstruction and/or bacterial overgrowth, complicates the clinical diagnosis. Treatment approach to PCI is mostly conservative: intestinal 'rest', parenteral nutrition, antibiotics, fluids and electrolyte supplementation, and inhaled oxygen. Surgical intervention should be performed only in cases of bowel perforation, ischaemia or necrosis. Patients with PCI have high mortality rates due to PCI itself but also to the severity and variety of basic CTD complications. CONCLUSION: Recognition of PCI, particularly in the context of underlying CTD, is necessary for proper therapeutic application. In patients with underlying CTD and symptoms of abdominal emergency, recruitment of multidisciplinary teams, including rheumatologist, gastroenterologist, imaging specialist and surgeons familiar with intestinal complications of CTD-related conditions, is warranted. PMID- 22432986 TI - Diffuse large cell non-Hodgkin lymphoma with pituitary and bilateral adrenal involvement. AB - We describe an elderly male patient who presented with fever of unknown origin and refractory hyponatraemia. Following (18) fluorine-fluorodeoxyglucose positron emission tomography/computed tomography scan and core adrenal biopsy, the diagnosis of diffuse large B-cell non-Hodgkin lymphoma with pituitary and bilateral adrenal involvement was confirmed. After chemotherapy, his symptoms resolved, and all the lesions shrank significantly. PMID- 22432987 TI - From blood transfusion to patient blood management: a new paradigm for patient care and cost assessment of blood transfusion practice. AB - The ageing population in developed countries, including Australia, is putting increasing demands on blood transfusion services. With a falling donor pool there is likely to be a shortage of blood and blood products in the next 20 to 30 years unless there are significant changes in medical practice. The National Health and Medical Research Council/Australasian Society of Blood Transfusion Clinical Practice Guidelines on the Use of Blood Components from 2001 are being redeveloped by the National Health and Medical Research Council/Australian and New Zealand Society of Blood Transfusion as evidence-based patient-focused Patient Blood Management guidelines with the aim of improving patient outcomes by reducing inappropriate blood and blood product use and targeting therapies for improving the management of anaemia and coagulopathies. PMID- 22432988 TI - Purtscher's retinopathy associated with acute pancreatitis. PMID- 22432989 TI - Bead-like coronary spasm. PMID- 22432990 TI - Extracorporeal membrane oxygenation with plasma exchange in a patient with alveolar haemorrhage secondary to Wegener's granulomatosis. PMID- 22432991 TI - Carcinoid crisis induced by repeated abdominal examination. PMID- 22432992 TI - A 67-year-old man with persistent fever and high titers of serum anticardiolipin antibody. PMID- 22432993 TI - Hair-pulling and borderline personality symptomatology among internal medicine outpatients. PMID- 22432994 TI - Mortality risk stratification in severely anaemic Jehovah's Witness patients. AB - The aim of this retrospective cohort study was to identify early risk factors of mortality and develop a mortality risk stratification instrument for severely anaemic Jehovah's Witness patients. It has been shown that Jehovah's Witness patients with the Auckland Anaemia Mortality Risk Score (Auckland AMRS) of 0 to 3 had 4% mortality, Auckland AMRS 4 to 5 32%, Auckland AMRS 6 to 7 50% and Auckland AMRS 8 and above 83%. It is concluded that the Auckland AMRS predicts mortality of severely anaemic Jehovah's Witness patients. PMID- 22432995 TI - Rituximab-induced interstitial lung disease in a patient with immune thrombocytopenia purpura. AB - We report the case of an 84-year-old man with refractory immune thrombocytopenia purpura (ITP) who was treated with rituximab and subsequently developed severe interstitial lung disease. There has been increasing use of rituximab in the treatment of ITP with success rates of up to 62% in adult patients with recurrent ITP. Interstitial lung disease is a rare but recognised complication of rituximab but has been rarely reported in the setting of ITP. PMID- 22432996 TI - Role for the left atrial appendage occlusion device in managing thromboembolic risk in atrial fibrillation. AB - Only 50% of patients who would benefit from warfarin therapy for atrial fibrillation (AF) receive treatment because of clinical concerns regarding chronic anti-coagulation. Percutaneous strategies to treat AF, including pulmonary vein isolation with a curative intent or atrioventricular nodal ablation and implantation of a permanent pacemaker for palliative rate control, have not eliminated the need to manage thromboembolic risk. With the development of a percutaneous left atrial appendage (LAA) occlusion device (the WATCHMAN percutaneous left atrial appendage occluder - Atritech Inc., Plymouth, MN, USA) for thromboembolic protection in non-valvular AF a significant therapeutic option for select patients may be available. We present the first case performed in Australia (24 November 2009) and explore this new methodology. PMID- 22432997 TI - Prevalence of error-prone abbreviations used in medication prescribing for hospitalised patients: multi-hospital evaluation. AB - The use of error-prone abbreviations in prescribing is a potential cause of misinterpretation that may lead to medication error. This study determined frequency and type of error-prone abbreviations in inpatient medication prescribing across three Australian hospitals. Three hundred and sixty-nine (76.9%) patients had one or more error-prone abbreviations used in prescribing, with 8.4% of orders containing at least one error-prone abbreviation and 29.6% of these considered to be high risk for causing significant harm. PMID- 22432998 TI - Efficacy of rituximab in refractory antisynthetase syndrome. AB - We report the successful use of repeated administration of rituximab in a patient with antisynthetase syndrome refractory to conventional immunosuppressive medications. A literature review revealed that previous experience with rituximab in this condition has been sparse. The rationale for the use of B-cell depleting therapies in antisynthetase syndrome has been explored in light of the current understanding of the pathogenesis of this condition. PMID- 22432999 TI - Case of anti-glomerular basement membrane antibody-induced glomerulonephritis with cytomegalovirus-induced thrombotic microangiopathy. AB - Although the involvement of cytomegalovirus (CMV) infections in the development of thrombotic microangiopathy (TMA) in HIV patients and transplant recipients has been reported, it is still controversial whether CMV itself can cause TMA. We report herein a rare case with rapid improvement of TMA by ganciclovir treatment in a patient who is neither HIV-positive nor a transplant recipient, suggesting a pathogenic role for CMV in TMA. PMID- 22433000 TI - Efficient fabrication of carbon nanotube micro tip arrays by tailoring cross stacked carbon nanotube sheets. AB - Carbon nanotube (CNT) micro tip arrays with hairpin structures on patterned silicon wafers were efficiently fabricated by tailoring the cross-stacked CNT sheet with laser. A blade-like structure was formed at the laser-cut edges of the CNT sheet. CNT field emitters, pulled out from the end of the hairpin by an adhesive tape, can provide 150 MUA intrinsic emission currents with low beam noise. The nice field emission is ascribed to the Joule-heating-induced desorption of the emitter surface by the hairpin structure, the high temperature annealing effect, and the surface morphology. The CNT emitters with hairpin structures will greatly promote the applications of CNTs in vacuum electronic devices and hold the promises to be used as the hot tips for thermochemical nanolithography. More CNT-based structures and devices can be fabricated on a large scale by this versatile method. PMID- 22433001 TI - Exercise-related QT interval shortening with a peaked T wave in a healthy boy with a family history of sudden cardiac death. AB - An asymptomatic 15-year-old boy, who had a family history of sudden cardiac death, was referred for screening for cardiac disease. The 12-lead electrocardiogram at rest showed a short QT/QTc(Bazett)/QTc(Fredericia) interval of 320/388/364 ms, but the intervals were further shortened to 200/339/284 ms after the treadmill test concomitant with appearance of a peaked T wave. Other conventional cardiac examinations were normal, but effective refractory period was less than 180 ms in both ventricles, and double ventricular extrastimulation reproducibly induced nonsustained polymorphic ventricular tachycardia. Intravenous administration of epinephrine also induced a short QT interval and a peaked T wave, and a hump was manifested on the T wave of the first postpacing beat with a longer preceding R-R interval. Furthermore, a couple of premature ventricular complexes originated from a similar timing as the hump. Genetic analysis did not show the mutation in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, SCN5A genes but revealed single nucleotide polymorphism (C5457T) in SCN5A gene. PMID- 22433002 TI - Dyadic parent-child interaction during early childhood: contributions of parental and child personality traits. AB - Individual differences in personality play a major role for functioning in a multitude of important life domains, including one's interpersonal relationships. The present study examined the effects of parental personality and child temperament traits on dyadic parent-child interaction during early childhood. Participants were a community sample of 145 mothers, 145 fathers, and their 3- to 6-year-old children. Child traits were assessed using standardized laboratory paradigms, parents reported on their own traits, and parent-child interaction was assessed observationally. Parental positive emotionality, negative emotionality, and constraint subtraits were related to parental responsiveness; the number and type of parental bids and the quality of parental responsiveness were also a function of child positive emotionality and effortful control subtraits and, for mothers, child negative emotionality subtraits. Child traits were related to their own interaction behaviors; children higher on positive emotionality subtraits made more social bids, and children higher on effortful control subtraits made more influence attempts and fewer negative bids; child positive emotionality and effortful control subtraits were associated with higher quality child responsiveness. Findings speak to coherence in personality constructs across the life span, with comparable traits measured in adults and early childhood-aged children demonstrating remarkably consistent effects on dyadic interaction behavior. PMID- 22433003 TI - Licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in human mesangial cells. AB - Licofelone, a novel dual anti-inflammatory drug that inhibits 5-lipoxygenase (5 LOX) and cyclooxygenase (COX), has recently been defined to have therapeutic effects in osteoarthritis. Both 5-LOX and COX play functional roles in the pathogenesis of glomerulonephritis in children as well. Interleukin-18 is a pro inflammatory cytokine. It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells (HMC) exposed to interleukin-18. In this study, HMC were cultured and exposed to interleukin-18 with or without pre-treatment of licofelone. COX-2 and 5-LOX enzyme activities in mesangial cells were determined with chromometry or high-performance liquid chromatography. Prostaglandin E2, cysteinyl leukotriene, monocyte chemotactic protein-1 and interferon-gamma concentrations in culture medium were measured using an enzyme linked immunosorbent assay. Western blotting was employed to detect phosphorylated mitogen-activated protein kinases ERK1/2, p38 and JNK1/2 in HMC. It was found that licofelone attenuated interleukin-18-induced COX-2 enzyme activity in HMC and prostaglandin E2 release in a dose-dependent manner. Similarly, licofelone inhibited interleukin-18-induced 5-LOX enzyme activity and leukotriene release. Licofelone reduced interleukin-18-induced phosphorylation of p38 mitogen-activated protein kinase and suppressed monocyte chemotactic protein 1 and interferon-gamma synthesis. Moreover, licofelone inhibited IL-18-induced proliferation of mesangial cells. We conclude that licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in HMC, which may represent a really interesting therapeutic approach for glomerulonephritis in children. PMID- 22433004 TI - Effects of well spacing on geological storage site distribution costs and surface footprint. AB - Geological storage studies thus far have not evaluated the scale and cost of the network of distribution pipelines that will be needed to move CO(2) from a central receiving point at a storage site to injection wells distributed about the site. Using possible injection rates for deep-saline sandstone aquifers, we estimate that the footprint of a sequestration site could range from <100 km(2) to >100,000 km(2), and that distribution costs could be <$0.10/tonne to >$10/tonne. Our findings are based on two models for determining well spacing: one which minimizes spacing in order to maximize use of the volumetric capacity of the reservoir, and a second that determines spacing to minimize subsurface pressure interference between injection wells. The interference model, which we believe more accurately reflects reservoir dynamics, produces wider well spacings and a counterintuitive relationship whereby total injection site footprint and thus distribution cost declines with decreasing permeability for a given reservoir thickness. This implies that volumetric capacity estimates should be reexamined to include well spacing constraints, since wells will need to be spaced further apart than void space calculations might suggest. We conclude that site-selection criteria should include thick, low-permeability reservoirs to minimize distribution costs and site footprint. PMID- 22433005 TI - Intrinsic functional-connectivity networks for diagnosis: just beautiful pictures? AB - Resting-state functional connectivity has become a topic of enormous interest in the Neuroscience community in the last decade. Because resting-state data (1) harbor important information that often is diagnostically relevant and (2) are easy to acquire, there has been a rapid increase in the development of a variety of network analytic techniques for diagnostic applications, stimulating methodological research in general. While we are among those who welcome the increased interest in the resting state and multivariate analytic tools, we would like to draw attention to some entrenched practices that undermine the scientific quality of diagnostic functional-connectivity research, but whose correction is relatively easy to accomplish. With the current commentary we also hope to benefit the field at large and contribute to a healthy debate about research goals and best practices. PMID- 22433006 TI - On network derivation, classification, and visualization: a response to Habeck and Moeller. AB - In the decade and a half since Biswal's fortuitous discovery of spontaneous correlations in functional imaging data, the field of functional connectivity (FC) has seen exponential growth resulting in the identification of widely replicated intrinsic networks and the innovation of novel analytic methods with the promise of diagnostic application. As such a young field undergoing rapid change, we have yet to converge upon a desired and needed set of standards. In this issue, Habeck and Moeller begin a dialog for developing best practices by providing four criticisms with respect to FC estimation methods, interpretation of FC networks, assessment of FC network features in classifying subpopulations, and network visualization. Here, we respond to Habeck and Moeller and provide our own perspective on the concerns raised in the hope that the neuroimaging field will benefit from this discussion. PMID- 22433007 TI - Anatomical connectivity between subcortical structures. AB - Understanding anatomical connectivity is crucial for improving outcomes of deep brain stimulation surgery. Tractography is a promising method for noninvasively investigating anatomical connectivity, but connections between subcortical regions have not been closely examined by this method. As many connections to subcortical regions converge at the internal capsule (IC), we investigate the connectivity through the IC to three subcortical nuclei (caudate, lentiform nucleus, and thalamus) in six macaques. We show that a statistical correction for a known distance-related artifact in tractography results in large changes in connectivity patterns. Our results suggest that care should be taken in using tractography to assess anatomical connectivity between subcortical structures. PMID- 22433008 TI - Broadband local field potentials correlate with spontaneous fluctuations in functional magnetic resonance imaging signals in the rat somatosensory cortex under isoflurane anesthesia. AB - Resting-state functional magnetic resonance imaging (fMRI) is widely used for exploring spontaneous brain activity and large-scale networks; however, the neural processes underlying the observed resting-state fMRI signals are not fully understood. To investigate the neural correlates of spontaneous low-frequency fMRI fluctuations and functional connectivity, we developed a rat model of simultaneous fMRI and multiple-site intracortical neural recordings. This allowed a direct comparison to be made between the spontaneous signals and interhemispheric connectivity measured with the two modalities. Results show that low-frequency blood oxygen level-dependent (BOLD) fluctuations (<0.1 Hz) correlate significantly with slow power modulations (<0.1 Hz) of local field potentials (LFPs) in a broad frequency range (1-100 Hz) under isoflurane anesthesia (1%-1.8%). Peak correlation occurred between neural and hemodynamic activity when the BOLD signal was delayed by ~4 sec relative to the LFP signal. The spatial location and extent of correlation was highly reproducible across studies, with the maximum correlation localized to a small area surrounding the site of microelectrode recording and to the homologous area in the contralateral hemisphere for most rats. Interhemispheric connectivity was calculated using BOLD correlation and band-limited LFP (1-4, 4-8, 8-14, 14-25, 25-40, and 40-100 Hz) coherence. Significant coherence was observed for the slow power changes of all LFP frequency bands as well as in the low-frequency BOLD data. A preliminary investigation of the effect of anesthesia on interhemispheric connectivity indicates that coherence in the high-frequency LFP bands declines with increasing doses of isoflurane, whereas coherence in the low-frequency LFP bands and the BOLD signal increases. These findings suggest that resting-state fMRI signals might be a reflection of broadband LFP power modulation, at least in isoflurane anesthetized rats. PMID- 22433009 TI - A resting-state connectivity metric independent of temporal signal-to-noise ratio and signal amplitude. AB - Temporal signal-to-noise ratio (tSNR) and the amplitude of low-frequency resting state fluctuations (signal amplitude [SA]) can vary between magnetic resonance imaging sessions, thereby decreasing the reliability and reproducibility of measurements of resting-state connectivity between regions of interest (ROIs) in the human brain. In this study, a new metric for quantifying the strength of resting-state connections is introduced, which possesses low sensitivity to tSNR and SA but maintains high sensitivity to expected changes in connectivity magnitude or region volume caused by the presence of neurological disease, for example. This new metric is one that essentially divides the temporal cross correlation of two ROIs by the temporal cross-correlation of one the ROIs with itself (i.e., a relative connectivity [RelCon]). The robustness of the new metric is demonstrated and compared with several existing metrics, using simulated datasets of varying tSNR and SA, as well as in data collected over multiple sessions from healthy subjects. For both simulated and real datasets, relative connectivity exhibited lower sensitivity to tSNR and SA compared with existing (i.e., absolute) connectivity metrics. Further, simulation suggests that for RelCon, it is better to calculate the correlation between all possible pairs of ROI voxel signals and then appropriately average the correlation coefficients, whereas for absolute connectivity it is better to average signals within the ROIs and then determine the correlation between the averaged signals. RelCon permits the comparison of connectivity across datasets acquired with different scanners or imaging parameters that potentially generate data with differing tSNR and SA. PMID- 22433010 TI - Effect of composite resin contamination with powdered and unpowdered latex gloves on its shear bond strength to bovine dentin. AB - The aim of the present study was to evaluate the effect of composite resin contamination with powdered and unpowdered latex gloves on the shear bond strength of etch-and-rinse and two-step self-etch adhesive systems. Standard flat dentin surfaces were prepared on the facial aspect of 120 bovine incisors and randomly assigned into two (n=60) groups: group 1: Single Bond (SB), group 2: Clearfil SE Bond (CSE). Furthermore, each group was randomly subdivided into three (n=20) based on the type of composite contamination (without contamination, contamination with powdered latex gloves, and contamination with unpowdered latex gloves). The adhesives were applied and resin composite bonded to the dentin. After thermocycling, the specimens were subjected to a shear bond strength test. Two-way analysis of variance (ANOVA) and a post hoc Bonferroni test were used for statistical analysis. One-way ANOVA was used to compare shear bond strength values in each group. Statistical significance was set at p < 0.02. Two-way ANOVA showed that the shear bond strength was significantly influenced by the type of composite surface contamination (p=0.001). In the SB group there were no significant differences between different surface treatments (p=0.08). In the CSE group a significant difference was observed between the subgroup without contamination and the subgroup with powdered latex glove contamination (p=0.01); however, no significant differences were observed between the other subgroups. PMID- 22433011 TI - Canadian Cohort Obstructive Lung Disease (CanCOLD): Fulfilling the need for longitudinal observational studies in COPD. AB - Awareness, diagnosis and treatment of COPD, compared to other major causes of death, remains far too low. This article describes the protocol objectives, design and the approaches taken in the Canadian Chronic Obstructive Lung Disease (CanCOLD) study, an epidemiological and integrated research. The CanCOLD study aims at better understanding heterogeneity of COPD presentation and disease progression. We hypothesize that individuals with unfavourable COPD "phenotypes" and subjects at-risk (ever smokers) with unhealthy lifestyle habits, environmental/work exposure, or co-morbidities will have increased risk of lung function decline independent of their cumulative exposure to cigarette smoke. The study is a prospective multi-center cohort study (9 sites in 6 provinces) built on the Canadian COPD prevalence study "COLD." The study plan is to include 1800 subjects at least 40 years old who were sampled from the general population and who were found to fall within 4 groups: 1) COPD moderate-severe (GOLD 2-4); 2) COPD mild (GOLD 1); 3) subjects at-risk (ever smoker); and, 4) subjects never smoker free of airflow obstruction. Data collection is based on using strictly standardized methods involving questionnaires, pulmonary function and cardiorespiratory exercise tests, CT scans, and blood sampling. CanCOLD is a unique study that will address challenging and important research questions on COPD disease evolution and disease management and will help to define the natural history of COPD disease evolution in individuals at-risk for COPD and in those with COPD who have mild disease. PMID- 22433012 TI - A classic twin study of isolated gastroschisis. AB - The etiology of gastroschisis remains elusive. A classic twin study was used to assess the relative contribution of environmental and genetic factors in its development. Screening of 4872 twin pregnancies identified three unreported twin pairs comprising two monozygous and one dizygous discordant pair of twins. Review of the literature identified an additional 21 twin pairs. We observed lower pair- and proband-wise concordance rates for monozygotic compared to dizygotic twin pairs, pair- and proband-wise concordance ratios below 1.0. Our results suggest environmental to play a greater role than genetic factors in the development of gastroschisis. PMID- 22433013 TI - Cellular uptake of gold nanoparticles bearing HIV gp120 oligomannosides. AB - Dendritic cells are the most potent of the professional antigen-presenting cells which display a pivotal role in the generation and regulation of adaptive immune responses against HIV-1. The migratory nature of dendritic cells is subverted by HIV-1 to gain access to lymph nodes where viral replication occurs. Dendritic cells express several calcium-dependent C-type lectin receptors including dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), which constitute a major receptor for HIV-1. DC-SIGN recognizes N-linked high-mannose glycan clusters on HIV gp120 through multivalent and Ca(2+)-dependent protein carbohydrate interactions. Therefore, mimicking the cluster presentation of oligomannosides from the virus surface is a strategic approach for carbohydrate based microbicides. We have shown that gold nanoparticles (mannoGNPs) displaying multiple copies of structural motifs (di-, tri-, tetra-, penta-, or heptaoligomanosides) of the N-linked high-mannose glycan of viral gp120 are efficient inhibitors of DC-SIGN-mediated trans-infection of human T cells. We have now prepared the corresponding fluorescent-labeled glyconanoparticles (FITC mannoGNPs) and studied their uptake by DC-SIGN expressing Burkitt lymphoma cells (Raji DC-SIGN cell line) and monocyte-derived immature dendritic cells (iDCs) by flow cytometry and confocal laser scanning microscopy. We demonstrate that the 1.8 nm oligomannoside coated nanoparticles are endocytosed following both DC-SIGN dependent and -independent pathways and part of them colocalize with DC-SIGN in early endosomes. The blocking and sequestration of DC-SIGN receptors by mannoGNPs could explain their ability to inhibit HIV-1 trans-infection of human T cells in vitro. PMID- 22433014 TI - Anti-inflammatory effects of spermidine in lipopolysaccharide-stimulated BV2 microglial cells. AB - BACKGROUND: Spermidine, a naturally occurring polyamine, displays a wide variety of internal biological activities including cell growth and proliferation. However, the molecular mechanisms responsible for its anti-inflammatory activity have not yet been elucidated. METHODS: The anti-inflammatory properties of spermidine were studied using lipopolysaccharide (LPS)-stimulated murine BV2 microglia model. As inflammatory parameters, the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were evaluated. We also examined the spermidine's effect on the activity of nuclear factor-kappaB (NF-kappaB), and the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) pathways. RESULTS: Pretreatment with spermidine prior to LPS treatment significantly inhibited excessive production of NO and PGE2 in a dose-dependent manner, and was associated with down-regulation of expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Spermidine treatment also attenuated the production of pro-inflammatory cytokines, including IL-6 and TNF-alpha, by suppressing their mRNA expressions. The mechanism underlying spermidine-mediated attenuation of inflammation in BV2 cells appeared to involve the suppression of translocation of NF-kappaB p65 subunit into the nucleus, and the phosphorylation of Akt and MAPKs. CONCLUSIONS: The results indicate that spermidine appears to inhibit inflammation stimulated by LPS by blocking the NF-kappaB, PI3K/Akt and MAPKs signaling pathways in microglia. PMID- 22433015 TI - Effects of antioxidants on rapeseed oil oxidation in an artificial digestion model analyzed by UHPLC-ESI-MS. AB - A normal diet contains large quantities of oxidized fatty acids, glycerolipids, cholesterol, and their cytotoxic degradation products because many foods in the diet are fried, heated, or otherwise processed and consumed often after long periods of storage. There is also evidence that the acid medium of the stomach promotes lipid peroxidation and that the gastrointestinal tract is a major site of antioxidant action, as demonstrated by various colorimetric methods. The identity and yields of specific products of lipid transformation have seldom been determined. The present study describes the molecular species profiles of all major gastrointestinal lipids formed during digestion of autoxidized rapeseed oil in an artificial digestion model in the presence of L-ascorbic acid, 6-palmitoyl O-L-ascorbic acid, 3,5-di-tert-butyl-4-hydroxytoluene (BHT), DL-alpha-tocopherol, and DL-alpha-tocopheryl acetate. Differences in oxidized lipid profiles were detected in the samples digested in the presence of different antioxidants, but none of them could prevent the formation of oxidized lipids or promote their degradation in a gastric digestion model. The lack of effect is attributed to the inappropriate nature of the gastrointestinal medium for the antioxidant activity of these vitamins and BHT. A fast ultrahigh performance liquid chromatographic electrospray ionization-mass spectrometric method was developed for the analysis of lipolysis products, including epoxy, hydroperoxy, and hydroxy fatty acids, and acylglycerols, utilizing lithium as ionization enhancer. PMID- 22433016 TI - Clinical utility of single-operator cholangiopancreatoscopy using a SpyGlass probe through an endoscopic retrograde cholangiopancreatography catheter. AB - BACKGROUND AND AIM: A single-operator cholangiopancreatoscopy was developed to overcome a problem in conventional peroral cholangiopancreatoscopy. The aim of this pilot study was to clarify the clinical utility of single-operator cholangiopancreatoscopy using a SpyGlass probe through an endoscopic retrograde cholangiopancreatography (ERCP) catheter. METHODS: Patients undergoing ERCP with a SpyGlass probe passed through a catheter were included in this study. The SpyGlass probe was inserted into the catheter following successful cannulation, and cholangiopancreatoscopy was performed by a single operator. We retrospectively analyzed the successful visualization rate of this technique. RESULTS: Fifteen patients were included in this study. SpyGlass cholangiopancreatoscopy was technically successful in all patients. Successful visualization was obtained in nine patients (60%). The median SpyGlass procedure time was 10 min. Cholangiopancreatoscopic diagnoses were as follows: bile duct carcinoma in three patients; intraductal papillary mucinous adenoma in two; and intraductal pancreatic stone, benign biliary stricture, gallbladder cholesterolosis, and gallbladder carcinoma in one each. There were no cases of post-ERCP pancreatitis. CONCLUSIONS: While the low rate of successful visualization must be improved, single-operator cholangiopancreatoscopy using a SpyGlass probe through an ERCP catheter is a safe and effective procedure. PMID- 22433017 TI - How do psychosocial challenges associated with living with congenital heart disease translate into treatment interests and preferences? A qualitative approach. AB - OBJECTIVES: There is an increasing amount of research being conducted regarding the psychosocial challenges associated with living with congenital heart disease (CHD), however little is known about how these challenges influence the type of psychosocial services patients want. This study investigated (1) the type of services patients want; (2) how they want to access these services; and (3) why they want these services. METHODS: Three focus groups with adults with CHD (total of 14 participants aged 19-67) were conducted and thematic analysis was used to identify emerging themes. RESULTS: Participants described wanting to access specific psychosocial services in three broad categories (counselling, connecting with other adults with CHD and psycho-education) and in three main formats (individual/group therapy, mentorship programmes and patient conferences). Reasons for wanting these services were grouped under two overarching themes, namely intrapersonal factors and interpersonal challenges. CONCLUSIONS: Psychosocial challenges are part of the everyday lives of adults with CHD, yet they are rarely addressed as part of routine medical care. Patients themselves have clear opinions regarding the psychological services most appropriate to target their experiences of living with CHD. PMID- 22433018 TI - Demographic response to perturbations: the role of compensatory density dependence in a North American duck under variable harvest regulations and changing habitat. AB - 1. Most wild animal populations are subjected to many perturbations, including environmental forcing and anthropogenic mortality. How population size varies in response to these perturbations largely depends on life-history strategy and density regulation. 2. Using the mid-continent population of redhead Aythya americana (a North American diving duck), we investigated the population response to two major perturbations, changes in breeding habitat availability (number of ponds in the study landscape) and changes in harvest regulations directed at managing mortality patterns (bag limit). We used three types of data collected at the continental scale (capture-recovery, population surveys and age- and sex ratios in the harvest) and combined them into integrated population models to assess the interaction between density dependence and the effect of perturbations. 3. We observed a two-way interaction between the effects on fecundity of pond number and population density. Hatch-year female survival was also density dependent. Matrix modelling showed that population booms could occur after especially wet years. However, the effect of moderate variation in pond number was generally offset by density dependence the following year. 4. Mortality patterns were insensitive to changes in harvest regulations and, in males at least, insensitive to density dependence as well. We discuss potential mechanisms for compensation of hunting mortality as well as possible confounding factors. 5. Our results illustrate the interplay of density dependence and environmental variation both shaping population dynamics in a harvested species, which could be generalized to help guide the dual management of habitat and harvest regulations. PMID- 22433019 TI - Intradermal and serological testing for mites in healthy beagle dogs. AB - BACKGROUND: Intradermal testing (IDT) is widely used in veterinary medicine to select allergens for immunotherapy. The recommended concentration for mites is 250 protein nitrogen units (PNU)/mL. It is not known whether healthy dogs responding to this concentration have asymptomatic sensitization or irritation. Furthermore, interbatch and intersupplier variability of allergens has not been fully addressed. HYPOTHESIS/OBJECTIVES: The incidence of positive IDTs in healthy beagles was recorded and the value of combining these results with serology to differentiate between asymptomatic sensitization and irritancy evaluated. Additionally, the interbatch and intersupplier variability of allergens was assessed. ANIMALS: Seventeen healthy laboratory beagles with no history or clinical signs of canine atopic dermatitis were used. METHODS: Intradermal tests were performed with four mite allergens from two suppliers (varying batches). An initial IDT at 250 PNU/mL was used to determine whether decreasing or increasing test concentrations were used in the subsequent titration IDTs. Additionally, two IgE ELISA tests from different manufacturers were performed. RESULTS: Seven of 17 dogs showed IDT reactions at 250 PNU/mL. There were highly significant allergen interbatch and significant intersupplier correlations and agreement. The associations between the IDT reactions and the IgE serologies statistically identified two groups of dogs: one with positive serology and IDT reactions at 250 PNU/mL; and another with negative serology and IDT reactions. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that dogs that have IDT reactions and positive serology are asymptomatically sensitized, while dogs that react at higher allergen concentrations, but have negative serology, do so as a result of irritant reactions. PMID- 22433020 TI - Effect of clarithromycin on acute asthma exacerbations in children: an open randomized study. AB - BACKGROUND: Asthma exacerbations are major contributors to asthma morbidity and rather difficult to treat. There is inconclusive evidence that macrolide antibiotics may have an effect on asthma exacerbations through their antibacterial and/or anti-inflammatory properties. The aim of the study was to evaluate the efficacy of clarithromycin on medium-term asthma activity when given as an add-on therapy in children with acute asthma. METHODS: This pilot, open labeled, randomized, prospective study included 40 school-aged children, with intermittent or mild persistent asthma, presenting with an acute exacerbation. Children were randomized to receive 15 mg/kg of clarithromycin for 3 wk, in addition to their regular (GINA-guided) exacerbation treatment. The microbial trigger of exacerbations was assessed by serology and PCR. Children were followed up with diary cards for 12 wk; lung function was assessed at entry, 3, and 12 wk after the exacerbation. RESULTS: Children in the clarithromycin group had significantly more symptom-free days (78 +/- 2 vs. 69 +/- 6 days, p < 0.00001) and less total number of periods with loss of control (9 vs. 19, respectively, p = 0.013) during the follow-up period, compared to controls. Moreover, treated children presented reduced duration of the index episode (5.0 +/- 1 vs. 7.5 +/- 1 days, p < 0.00001). Lung function did not differ between groups. CONCLUSIONS: When added to regular treatment, a 3-wk course of clarithromycin was associated with an increase in the number of symptom-free days, reductions in the number and severity of days with loss of control following index episode, and a decrease in the duration of the initial asthma exacerbation. PMID- 22433021 TI - Intensive communication skills teaching for specialist training in palliative medicine: development and evaluation of an experiential workshop. AB - BACKGROUND: The Australasian Chapter of the Palliative Medicine (AChPM) Curriculum Development Group identified communication as a core skill that trainees in palliative medicine need to acquire, and proposed the development of a communication skills workshop that should become a compulsory part of training to achieve accreditation as a palliative medicine specialist in Australia and New Zealand. This paper describes the development and subsequent evaluation of this module. METHODS: A three-day communication workshop was developed in collaboration with expert communication skills facilitators from the United States and Australia. The teaching consists of: (1) brief plenary presentations providing an evidence-based framework for communication and a demonstration of suggested strategies; (2) small group experiential learning providing opportunities to practice communication skills with clinically relevant simulated patients, self-appraisal, constructive feedback, and reflective exercises; and (3) accompanying course-specific written material. Participants completed de identified questionnaires before, after, and three months following completion of the workshop. RESULTS: Forty-one participants completed the training in two workshops held in 2008 and 2009. Participants said in their questionnaire responses that the training was useful, would be helpful for their communication with patients, and that they would recommend the training to others. Qualitative feedback was highly positive. Self-assessed confidence in communication skills significantly increased following the workshop (p<.001) and was sustained at three months (p<.001). CONCLUSION: The training is highly valued by participants and increases confidence in communication skills. Facilitator training and capacity planning will be critical for the ongoing success of the communication workshop. PMID- 22433022 TI - A mouse model for adolescent alcohol abuse: stunted growth and effects in brain. AB - BACKGROUND: Adolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month. METHODS: Using the high ethanol-consuming C57BL/6J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri-adolescence (postnatal day [P]25 to 70) or adulthood (P180 to 225) of both males and females. RESULTS: In control peri-adolescent animals, body weight gain was greater in males compared with females. In the peri-adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri-adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri-adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points. CONCLUSIONS: Ethanol treatment significantly reduced the mass of the cerebral cortex in peri-adolescent (-3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (-5.4%), but not peri-adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri-adolescent brain. PMID- 22433023 TI - Synthesis of 1,3-diaminated stereotriads via rearrangement of 1,4 diazaspiro[2.2]pentanes. AB - The synthesis of 1,3-diaminated stereotriads via the bis-aziridination of allenes is reported. The reactive 1,4-diazaspiro[2.2]pentane intermediates undergo a mild Bronsted acid-promoted rearrangement to yield 1,3-diaminated ketones in good yields with excellent stereocontrol. Directed reduction of the ketone can be achieved to yield a C-N/C-O/C-N stereotriad in high dr. The ability to transfer the axial chirality of the substrates to the products allows for the facile preparation of enantioenriched stereotriads from allenes in two simple steps. PMID- 22433024 TI - Telephone follow-up to a mail survey: when to offer an interview compared to a reminder call. AB - BACKGROUND: Using a different mode of contact on the final follow-up to survey non-respondents is an identified strategy to increase response rates. This study was designed to determine if a reminder phone call or a phone interview as a final mode of contact to a mailed survey works better to increase response rates and which strategy is more cost effective. METHODS: A randomized study was embedded within a survey study of individuals treated with ulcerative colitis conducted in March 2009 in Olmsted County, Minnesota. After two mail contacts, non-respondents were randomly assigned to either a reminder telephone call or a telephone interview. Average cost per completed interview and response rates were compared between the two experimental conditions. RESULTS: The response rate in the reminder group and the interview did not differ where we considered both a completed survey and a signed form a complete (24% vs. 29%, p = 0.08). However, if such a signed form was not required, there was a substantial advantage to completing the interview over the phone (24% vs. 43%, p < 0.0001). The reminder group on average cost $27.00 per completed survey, while the interview group on average cost $53.00 per completed survey when a signed form was required and $36.00 per complete when a signed form was not required. CONCLUSIONS: The additional cost of completing an interview is worth it when an additional signed form is not required of the respondent. However, when such a signed form is required, offering an interview instead of a reminder phone call as a follow up to non-respondents does not increase response rates enough to outweigh the additional costs. PMID- 22433025 TI - A systematic review of the use of aromatherapy in treatment of behavioral problems in dementia. AB - We aimed to fill the literature gap by identifying the clinical benefits of aromatherapy in older adults with dementia, and its efficacy in reducing behavioral and psychological symptoms of dementia (BPSD) based on available randomized controlled trials (RCT). A systematic review of 11 clinical trials shortlisted from electronic databases from 1995 to 2011 was carried out. The RCT showed that aromatherapy had positive effects on reduction of BPSD, improvement in cognitive functions, increasing quality of life, enhancing independence of activities of daily living and so on. However, adverse effects were noted in some studies. Limitations on methodology are discussed and suggestions on directions of further studies are made. It is recommended that aromatherapy shows the potential to be applied as a therapeutic and safe complementary and alternative therapy for the management of BPSD on more evidence collected from better designed RCT. PMID- 22433026 TI - Ultrafast pump-probe study of the excited-state charge-transfer dynamics in blue copper rusticyanin. AB - We have used femtosecond pump-probe spectroscopy to investigate the excited-state dynamics of the anticancer blue copper protein rusticyanin, by exciting its ligand to metal charge-transfer band with 25 fs pump pulses centered at 585 nm. The charge-transfer excited state decays exponentially to the ground state with a time constant of about 230 fs, and its recovery is modulated by coherent oscillations. The Fourier transform of the oscillatory component of the signal provides most of the vibrational modes obtained by means of conventional resonance Raman studies, in addition to the low frequency modes below 80 cm(-1) believed to reflect collective motions of biological relevance. PMID- 22433027 TI - Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. AB - BACKGROUND: Biomarkers have been proposed for identification of women at increased risk of developing pre-eclampsia. OBJECTIVES: To investigate the capacity of circulating placental growth factor (PlGF), vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG) to predict pre-eclampsia. SEARCH STRATEGY: Medline and Embase through October 2010 and reference lists of reviews, without constraints. SELECTION CRITERIA: We included original publications on testing of PlGF, VEGF, sFLT1 and sENG in serum or plasma of pregnant women at <30 weeks of gestation and before clinical onset of pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two reviewers independently identified eligible studies, extracted descriptive and test accuracy data and assessed methodological quality. Summary estimates of discriminatory performance were obtained. MAIN RESULTS: We included 34 studies. Concentrations of PlGF (27 studies) and VEGF (three studies) were lower in women who developed pre-eclampsia: standardised mean differences (SMD) -0.56 (95% CI 0.77 to -0.35) and -1.25 (95% CI -2.73 to 0.23). Concentrations of sFLT1 (19 studies) and sENG (ten studies) were higher: SMD 0.48 (95% CI 0.21-0.75) and SMD 0.54 (95% CI 0.24-0.84). The summary diagnostic odds ratios were: PlGF 9.0 (95% CI 5.6-14.5), sFLT1 6.6 (95% CI 3.1-13.7), sENG 4.2 (95% CI 2.4-7.2), which correspond to sensitivities of 32%, 26% and 18%, respectively, for a 5% false positive rate. AUTHOR'S CONCLUSIONS: PlGF, sFLT1 and sENG showed modest but significantly different concentrations before 30 weeks of gestation in women who developed pre-eclampsia. Test accuracies of all four markers, however, are too poor for accurate prediction of pre-eclampsia in clinical practice. PMID- 22433028 TI - Hydration and dehydration periods of crown fragments prior to reattachment. AB - INTRODUCTION: Tooth fragment bonding is an excellent treatment option in dealing with traumatic injuries of the anterior teeth. Rewetting the tooth fragment has been shown to increase restoration durability. The present study examined the effect various dry and wet storage periods had on the reattached fragment's bond to the tooth. MATERIALS AND METHODS: One hundred and eight human mandibular incisors were fractured and assigned to undergo a dehydration period of 30 minutes, six hours, 24 hours, or three days before the rewetting procedure. After fracturing the teeth and drying the fragments, each of the specimens was assigned to one of the three main groups (A, B, or C) intended to evaluate the effect of different rehydration periods. Groups A and B underwent a 30-minute and a 24-hour rewetting period, respectively. Group C served as a control (without a rewetting stage). Tooth fragments were then reattached and prepared for the strength test. Force was applied on the lingual side of the tooth at a 1 mm/min rate until failure. RESULTS: The mean loads (N) required to fracture the restored teeth were as follows: 204.43 +/- 33.48 N, 322.59 +/- 34.62 N, and 253.25 +/- 29.05 N for groups A, B, and C, respectively. Two-way analysis of variance (p<0.05) showed that rehydration and dehydration periods as well as their interaction caused significant differences in the strength of the final restoration. Multiple comparison tests showed that, in general, significant differences were not seen among different dehydration times prior to the rewetting stage (p>0.05), except in the case of the 30-minute dehydrated specimens (p<0.05). CONCLUSION: Compared to a 30-minute period, a 24-hour rehydration of the tooth fragment before treatment seems to salvage enough moisture to result in an increase in reattachment strength. PMID- 22433029 TI - Effect of hydrogen peroxide at 35% on the morphology of enamel and interference in the de-remineralization process: an in situ study. AB - This study evaluated the microhardness and histomorphology of bovine enamel when 35% hydrogen peroxide is used. A total of 44 specimens were adapted to removable devices used by 11 individuals subjected to dental caries challenge. A decrease in microhardness was observed for all groups after the cariogenic challenge. Microscopic analysis revealed that fragments subjected to cariogenic challenge associated with bleaching had more intense superficial histologic changes, but the depth of the lesions remained unchanged. It was concluded that 35% hydrogen peroxide enhanced the reduction in hardness and histomorphologic changes in the enamel surface exposed to cariogenic challenge. PMID- 22433030 TI - Multidisciplinary approach in the rehabilitation of missing lateral incisors: a new trend in daily practice. AB - This article reports the case of a patient with bilateral hypodontia of the maxillary lateral incisors who was dissatisfied with the outcome of initial orthodontic treatment, highlighting the importance of a multidisciplinary interaction among Restorative Dentistry, Orthodontics, and Implantology to achieve satisfactory esthetics and functional results. PMID- 22433031 TI - Effect of chemical and mechanical degradation on surface roughness of three glass ionomers and a nanofilled resin composite. AB - Nanofillers have been incorporated into glass ionomer (GI) restorative materials to improve their mechanical and surface properties. The aim of this present laboratory study was to compare the superficial roughness (Ra) of nanofilled GI (Ketac N100) with that of conventional GI (Fuji IX GP), resin-modified GI (Vitremer), and a nanofilled resin composite (Filtek Supreme) after pH cycling and toothbrush abrasion. Ten specimens of each material were made using Teflon molds, which were polished using aluminum-oxide abrasive disks. Three measurements of Ra were made of each specimen to serve as baseline values. The specimens were submitted to pH cycling for 10 days in a demineralization solution for six hours (pH 4.3) and were then stored in remineralization solution for 18 hours (pH 7.0). Ra measurements were recorded after the pH cycling. Specimens were then submitted to toothbrush abrasion in a brushing machine with a 200g load for 30,000 cycles at 250 cycles/min. The Ra values were then recorded. The surface morphology of specimens from each group was analyzed using a scanning electron microscope. Data were analyzed by analysis of variance, Tukey, and t tests. After toothbrushing, only Fuji IX GP (1.10 +/- 0.80) showed Ra values that were statistically different from those of the other materials evaluated. Ketac N100 (0.68 +/- 0.16) showed intermediate Ra values, but it did not differ statistically from the results associated with Vitremer (1.04 +/- 0.46) and Filtek (0.30 +/- 0.15). Ketac N100 showed intermediate values of superficial roughness among the conventional glass ionomer cement, resin-modified glass ionomer cements, and the nanofilled resin after chemical and mechanical degradation. PMID- 22433032 TI - Influence of hydrogen peroxide bleaching gels on color, opacity, and fluorescence of composite resins. AB - The aim of the present study was to evaluate the effect of 20% and 35% hydrogen peroxide bleaching gels on the color, opacity, and fluorescence of composite resins. Seven composite resin brands were tested and 30 specimens, 3-mm in diameter and 2-mm thick, of each material were fabricated, for a total of 210 specimens. The specimens of each tested material were divided into three subgroups (n=10) according to the bleaching therapy tested: 20% hydrogen peroxide gel, 35% hydroxide peroxide gel, and the control group. The baseline color, opacity, and fluorescence were assessed by spectrophotometry. Four 30-minute bleaching gel applications, two hours in total, were performed. The control group did not receive bleaching treatment and was stored in deionized water. Final assessments were performed, and data were analyzed by two-way analysis of variance and Tukey tests (p<0.05). Color changes were significant for different tested bleaching therapies (p<0.0001), with the greatest color change observed for 35% hydrogen peroxide gel. No difference in opacity was detected for all analyzed parameters. Fluorescence changes were influenced by composite resin brand (p<0.0001) and bleaching therapy (p=0.0016) used. No significant differences in fluorescence between different bleaching gel concentrations were detected by Tukey test. The greatest fluorescence alteration was detected on the brand Z350. It was concluded that 35% hydrogen peroxide bleaching gel generated the greatest color change among all evaluated materials. No statistical opacity changes were detected for all tested variables, and significant fluorescence changes were dependent on the material and bleaching therapy, regardless of the gel concentration. PMID- 22433034 TI - Evaluation of chemical treatment on zirconia surface with two primer agents and an alkaline solution on bond strength. AB - OBJECTIVES: This study evaluated the effect of an alkaline solution and two 10 methacryloyloxydecyl dihydrogen phosphate (MDP)-based primer agents on bond strength to zirconia (yttria-stabilized tetragonal zirconium polycrystal [Y-TZP]) through the shear bond strength (SBS) test. MATERIALS AND METHODS: Sixty square shaped Y-TZP samples were embedded in an acrylic resin mold, polished, and randomly assigned to one of six groups (n=10) according to treatment surface: group CR, no treatment (control); group NaOH, 0.5 M NaOH; group AP, Alloy Primer; group ZP, Z-Primer Plus; group NaOH-AP, 0.5 M NaOH + Alloy Primer; and group NaOH ZP, 0.5 M NaOH + Z-Primer Plus. The resin cement (Rely X U100) was applied inside a matrix directly onto the Y-TZP surface, and it was light-cured for 40 seconds. The samples were stored in distilled water at 37 degrees C for 24 hours prior to the test, which was performed in a universal machine at a crosshead-speed of 0.5 mm/min. The data were analyzed by one-way analysis of variance and Tukey tests (p<0.05). Light stereomicroscopy and scanning electron microscopy were used to assess the surface topography and failure mode. RESULTS: The SBS was significantly affected by the chemical treatment (p<0.0001). The AP group displayed the best results, and the use of NaOH did not improve SBS results relative to either AP or ZP. The samples treated with Alloy Primer displayed mainly mixed failures, whereas those conditioned with Z-Primer Plus or with 0.5 M NaOH presented a balanced distribution of adhesive and mixed failure modes. CONCLUSIONS: The use of a NaOH solution may have modified the reactivity of the Y TZP surface, whereas the employment of a MDP/6-4-vinylbenzyl-n-propyl amino-1,3,5 triazine-2,4-dithione-based primer enhanced the Y-TZP bond strength. PMID- 22433035 TI - Comparison of two at-home whitening products of similar peroxide concentration and different delivery methods. AB - PURPOSE: This study compared the whitening efficacy, side effects, and patients' preferences/perceptions of two whitening systems of similar peroxide concentration but different formulation and delivery methods. METHODS: The tooth color change of 24 participants was measured using a shade guide (BSG) and a spectrophotometer (ES). Color difference was calculated: DeltaE* = [(DeltaL*)(2) + (Deltaa*)(2) + (Deltab*)(2)](1/2). One whitening treatment was randomly applied to the right or left maxillary anterior teeth and the other was applied to the contralateral teeth, at-home with 35% carbamide peroxide in a tray (TW) or with 14% hydrogen peroxide in strips (WS). The tooth color was evaluated at baseline, 15 and 30 days (15 days postwhitening). Participants rated their tooth and soft tissue sensitivity (1-10 scale) and completed a questionnaire on their preferences. Results were analyzed by repeated measurement regression analysis/Tukey and Mann-Whitney (p<0.05). RESULTS: At 15 days, the teeth treated with TW and WS presented DeltaE* = 7 and 6, respectively (DeltaBSG=3 for both), and at 30 days, they presented DeltaE* = 7.5 and 6.5, respectively (DeltaBSG=3 for both). There was no significant difference in tooth and soft tissue sensitivity between treatments. No participant reported tooth and gingival sensitivity at the postwhitening appointment. Of the participants, 83% preferred the TW over WS. CONCLUSION: Both DeltaE* and DeltaBSG showed no significant difference in tooth color change between TW and SW at either time point. By the end of the study no participants reported tooth and gingival sensitivity. Participants preferred TW over SW. PMID- 22433036 TI - A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. AB - BACKGROUND: Antipsychotic medications often have a variety of side effects, however, it is not well understood how the presence of specific side effects correlate with adherence in a real-world setting. The aim of the current study was to examine the relationship between these variables among community-dwelling patients with schizophrenia. METHODS: Data were analyzed from a 2007-2008 nationwide survey of adults who self-reported a diagnosis of schizophrenia and were currently using an antipsychotic medication (N = 876). The presence of side effects was defined as those in which the patient reported they were at least "somewhat bothered". Adherence was defined as a score of zero on the Morisky Medication Adherence Scale. To assess the relationship between side effects and adherence, individual logistic regression models were fitted for each side effect controlling for patient characteristics. A single logistic regression model assessed the relationship between side effect clusters and adherence. The relationships between adherence and health resource use were also examined. RESULTS: A majority of patients reported experiencing at least one side effect due to their medication (86.19%). Only 42.5% reported complete adherence. Most side effects were associated with a significantly reduced likelihood of adherence. When grouped as side effect clusters in a single model, extra pyramidal symptoms (EPS)/agitation (odds ratio (OR) = 0.57, p = 0.0007), sedation/cognition (OR = 0.70, p = 0.033), prolactin/endocrine (OR = 0.69, p = 0.0342), and metabolic side effects (OR = 0.64, p = 0.0079) were all significantly related with lower rates of adherence. Those who reported complete adherence to their medication were significantly less likely to report a hospitalization for a mental health reason (OR = 0.51, p = 0.0006), a hospitalization for a non-mental health reason (OR = 0.43, p = 0.0002), and an emergency room (ER) visit for a mental health reason (OR = 0.60, p = 0.008). CONCLUSIONS: Among patients with schizophrenia, medication side effects are highly prevalent and significantly associated with medication nonadherence. Nonadherence is significantly associated with increased healthcare resource use. Prevention, identification, and effective management of medication-induced side effects are important to maximize adherence and reduce health resource use in schizophrenia. PMID- 22433037 TI - Site-specific fluorescent labeling and oriented immobilization of a triple mutant of CYP3A4 via C64. AB - The generation of site-specific bioconjugates of proteins is highly desired for a number of biophysical and nanotechnological applications. To this end, many strategies have been developed that allow the specific modification of certain canonical amino acids and, more recently, noncanonical functional groups. P450 enzymes are heme-dependent monooxygenases involved in xenobiotic metabolism and in the biosynthesis of a variety of secondary metabolites. We became interested in the site-specific modification of these enzymes, CYP3A4 in particular, through our studies of their in vitro biocatalytic properties and our desire to exploit their remarkable ability to oxidize unactivated C-H bonds in a regio- and stereospecific manner. Obtained via a partial cysteine-depletion approach, a functional triple mutant of CYP3A4 (C98S/C239S/C468G) is reported here which is singly modified at C64 by maleimide-containing groups. While cysteine-labeling of the wild-type enzyme abolished >90% of its enzymatic activity, this mutant retained >=75% of the activity of the unmodified wild-type enzyme with 9 of the 18 maleimides that were tested. These included both fluorescent and solid supported maleimides. The loss of activity observed after labeling with some maleimides is attributed to direct enzyme inhibition rather than to steric effects. We also demonstrate the functional immobilization of this mutant on maleimide-functionalized agarose resin and silica microspheres. PMID- 22433038 TI - Sleep syncope: treatment with a permanent pacemaker. AB - Vasovagal syncope usually occurs during upright posture, but Jardine et al. have described a variant that occurs at night. During "sleep syncope" patients are awakened from sleep with nausea, abdominal cramping, or a sense of impending diarrhea; get up; and faint in the bathroom. We report on a patient with recurrent sleep syncope (with physical injury) in whom an asystolic pause was documented during one of her "sleep syncope" spells. Implantation of a dual chamber pacemaker (5-year follow-up) "cured" her of further syncope. This is a report of pacemaker use for this unusual form of reflex syncope. PMID- 22433039 TI - Speech and language therapy interventions for children with cleft palate: a systematic review. AB - Objective : (1) To examine the evidence for the effectiveness of differences in timing and type of speech and language therapy for children with cleft palate with or without a cleft lip and (2) to identify types of interventions assessed. Design : Nine databases, including MEDLINE and EMBASE, were searched between inception and March 2011 to identify published articles relating to speech and language therapy for children with cleft palate with or without cleft lip. Studies that included at least 10 participants and reported outcome measures for speech and/or language measures were included. Studies where the experimental group had less than 90% of children with cleft palate with or without cleft lip were excluded. Two reviewers independently completed inclusion assessment, data extraction, and risk of bias assessment for all studies identified. Results : A total of 17 papers were evaluated: six randomized control trials and 11 observational studies. Studies varied widely on risk of bias, intervention used, and outcome measures reported. None of the studies had a low risk of bias. In terms of intervention approaches, seven studies evaluated linguistic approaches and 10 evaluated motor approaches. Outcomes measures did not support either approach over the other, and based on data reported it was difficult to ascertain which approach is more effective for children with cleft palate with or without cleft lip. Conclusions : The review found little evidence to support any specific intervention. Key uncertainties need to be identified and adequately powered, methodologically rigorous studies conducted to provide a secure evidence base for speech-language therapy practice in children with cleft palate with or without cleft lip. PMID- 22433040 TI - The status-signaling property of self-esteem: the role of self-reported self esteem and perceived self-esteem in personality judgments. AB - OBJECTIVE: The provision of information appears to be an important feature of self-esteem. The present studies examined whether self-esteem possesses a status signaling property such that an individual's level of self-esteem is associated with how the individual is perceived by others. METHOD: In Study 1, trained judges watched brief videos of 157 participants and rated targets as having higher levels of self-esteem when the targets were believed to possess more positive personality characteristics. Study 2 found that participants (357 targets) were rated as having higher levels of self-esteem when they were given more positive personality evaluations by their friends and family members (1,615 perceivers). RESULTS: Consistent with the proposed status-signaling model, high levels of self-esteem were generally associated with the perception of positive personality characteristics. CONCLUSIONS: These findings are discussed in the context of an extended informational model of self-esteem consisting of both the status-tracking and status-signaling properties of self-esteem. PMID- 22433041 TI - Effect of Asparagus falcatus on acetaminophen toxicity in mice: a comparison of antioxidative effect with N-acetyl cysteine. AB - OBJECTIVE: In this study, the effect of Asparagus falcatus extract on acetaminophen-induced liver injury was investigated in vivo. METHOD: Six arms of study. ICR mice (n = 20) were treated with acetaminophen at a single dose of 300 mg/kg (in saline, after a 16-hr fast) to induce hepatotoxicity. Drug control group and pre- and posttreated groups were administered 0.9 g/kg of Asparagus falcatus orally. Serum ALT, AST, ALP, liver GSH, antioxidant enzymes, GPx (glutathione peroxidase), GR (glutathione reductase), GST (glutathione-S transferase), and liver/serum malondialdehyde (MDA) concentrations were estimated. Liver damage was also assessed histopathologically. The effect of the plant extract was compared with N-acetyl cysteine. RESULTS: Acetaminophen produced liver damage, as manifested by a significant rise (P <. 001, one-way ANOVA) in serum ALT, AST, and ALP, and a reduction (P <. 001) in the liver reduced glutathione (GSH) as compared to respective controls. All enzyme activities and liver GSH were significantly improved in Asparagus-treated mice, with pretreatment providing better results than posttreatment (P <. 05). Histopathologically, mice pretreated with Asparagus showed no liver necrosis. A significant improvement was observed in antioxidant enzyme activities of GPx, GR, and GST in the Asparagus pretreated group (P <. 05). Mice posttreated with Asparagus showed a significant reduction in MDA formation (P <. 05). CONCLUSION: These results suggest that the feeding regimen with Asparagus extract inhibited the progression of hepatic injury induced by acetaminophen. PMID- 22433042 TI - Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis. AB - There has been interest in the use of exogenous creatine (Cr) as an adjunct treatment for neurological disorders. Creatine enhances bouts of activity through augmenting phosphocreatine for increased synthesis of ATP; however, multiple sclerosis (MS) individuals suffering from muscle weakness have not been shown to improve muscle work after 5 days of Cr supplementation. This study's purpose was to determine whether the extended duration would increase muscle capacity. In a double-blind, crossover trial, with a 3-week washout period, eleven MS subjects were randomly assigned to either Cr (5 g 4/day, day 1-7: 2.5 g 2/day, day 8-14) or placebo groups for two 14-day periods. Biodex Dynamometer recorded total work and power over three bouts of 30 maximal knee extensions and flexions. Total work was nonsignificant with Cr for knee extension (pretest 1277.7 +/- 214.9 J vs. posttest = 1313.14 +/- 200.5 J; p = 0.81) and flexion (pretest = 1220.7 +/- 200.5 J vs. posttest = 1302.10 J +/- 189.64 J; p = 0.93). Creatine did not enhance muscle power in knee extension (p = 0.31; pretest = 82.1 +/- 12.7 W vs. posttest = 87.7 +/- 12.6 W) or flexion (p = 0.29; pretest = 75.3 +/- 12.1 W vs. posttest = 81.2 +/- 11.1 W). Therefore, 14 days of Cr supplementation did not improve muscle capacity or habitual fatigue in MS individuals. PMID- 22433043 TI - Effect of sea buckthorn leaves based herbal formulation on hexachlorocyclohexane induced oxidative stress in rats. AB - Medicinal preparations based on sea buckthorn (SBT), a medicinal plant, have been clinically used to treat different diseases. We have developed a dietary additive based on SBT, the effect of which was evaluated against hexachlorocyclohexane (HCH), which was used to induce oxidative stress and toxicity in rats. Six groups of six male rats each were maintained for 12 weeks as (a) Control, (b) HCH, (c) 1% SBT based herbal formulation (SHF) incorporated diet, (d) 1% SHF incorporated diet + HCH, (e) 2% SHF incorporated diet, and (f) 2% SHF incorporated diet + HCH. Results revealed that HCH induction resulted in a significant hepatic lipid peroxidation with reduction in antioxidants and activities of antioxidant enzymes. The prefeeding of SHF resulted in decreased hepatic levels of lipid peroxides and increased the multicomponent antioxidant system namely glutathione (GSH), GSH-peroxidase, GSH-reductase, superoxide dismutase, catalase, and GSH S transferase activities. The study suggests that HCH induction resulted in free radicals, which could be reduced by the incorporation of the herbal formulation in diet. PMID- 22433044 TI - Impact of ingestion of rice bran and shitake mushroom extract on lymphocyte function and cytokine production in healthy rats. AB - This article provides a controlled evaluation of the ability of dietary supplementation with a commercially available rice bran extract modified with shitake mushroom extract (MGN-3) to support the immune function by assessing the ability of immunocytes to proliferate and produce cytokines in response to a mitogenic challenge. Twenty-four male Lewis rats were fed a control diet (Maypo sweetened oatmeal) or Maypo containing the recommended daily dose of MGN-3 for 2 weeks. This treatment modestly enhanced mitogen enhanced proliferation of splenocytes and interferon-gamma (IFN-g) production, and significantly increased proliferation of splenocytes to the superantigen toxic shock syndrome toxin-1 (TSST-1) as well as natural killer (NK) cell activity and production of interleukin-2 (IL-2) by stimulated lymphocytes. These data support the contention that ingestion of MGN-3 can support immune cell function. These data add to a growing body of data showing that ingestion of MGN-3 improves the ability of immune cells to proliferate the lyse tumor cells, suggesting that it may have utility as a dietary aid to support the immune system. PMID- 22433045 TI - Boron. AB - OBJECTIVE: To evaluate the scientific evidence on boron including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. This review serves as a clinical support tool. METHODS: Electronic searches were conducted in nine databases, 20 additional journals (not indexed in common databases), and bibliographies from 50 selected secondary references. No restrictions were placed on language or quality of publications. All literature collected pertained to efficacy in humans, dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory assays, and mechanisms of action. Standardized inclusion/exclusion criteria are utilized for selection. Grades were assigned using an evidence-based grading rationale. RESULTS: There was a lack of systematic study on the safety and effectiveness of boron in humans. However, based on popular use and supportive scientific data, nine indications are discussed in this review: hormone regulation, improving cognitive function, osteoarthritis, osteoporosis, vaginitis (topical), bodybuilding aid (increasing testosterone), menopausal symptoms, prevention of blood clotting (coagulation effects), and psoriasis (topical). CONCLUSION: Although studies assessing the use of boron for osteoarthritis and osteoporosis are in preliminary stages, reports are promising. There is conflicting evidence to support the use of boron in hormonal regulation and cognitive function. Future randomized controlled trials are warranted. There is fair negative evidence regarding the use of boron as an anticoagulant, a bodybuilding aid, for menopausal symptoms, or for psoriasis. Excessive use may be harmful, and caution is advised. PMID- 22433046 TI - Tractography: where do we go from here? AB - Diffusion tractography offers enormous potential for the study of human brain anatomy. However, as a method to study brain connectivity, tractography suffers from limitations, as it is indirect, inaccurate, and difficult to quantify. Despite these limitations, appropriate use of tractography can be a powerful means to address certain questions. In addition, while some of tractography's limitations are fundamental, others could be alleviated by methodological and technological advances. This article provides an overview of diffusion magnetic resonance tractography methods with a focus on how future advances might address challenges in measuring brain connectivity. Parts of this review are somewhat provocative, in the hope that they may trigger discussions possibly lacking in a field where the apparent simplicity of the methods (compared to their functional magnetic resonance imaging counterparts) can hide some fundamental issues that ultimately hinder the interpretation of findings, and cast doubt as to what tractography can really teach us about human brain anatomy. PMID- 22433047 TI - Role of ongoing, intrinsic activity of neuronal populations for quantitative neuroimaging of functional magnetic resonance imaging-based networks. AB - A primary objective in neuroscience is to determine how neuronal populations process information within networks. In humans and animal models, functional magnetic resonance imaging (fMRI) is gaining increasing popularity for network mapping. Although neuroimaging with fMRI-conducted with or without tasks-is actively discovering new brain networks, current fMRI data analysis schemes disregard the importance of the total neuronal activity in a region. In task fMRI experiments, the baseline is differenced away to disclose areas of small evoked changes in the blood oxygenation level-dependent (BOLD) signal. In resting-state fMRI experiments, the spotlight is on regions revealed by correlations of tiny fluctuations in the baseline (or spontaneous) BOLD signal. Interpretation of fMRI based networks is obscured further, because the BOLD signal indirectly reflects neuronal activity, and difference/correlation maps are thresholded. Since the small changes of BOLD signal typically observed in cognitive fMRI experiments represent a minimal fraction of the total energy/activity in a given area, the relevance of fMRI-based networks is uncertain, because the majority of neuronal energy/activity is ignored. Thus, another alternative for quantitative neuroimaging of fMRI-based networks is a perspective in which the activity of a neuronal population is accounted for by the demanded oxidative energy (CMR(O2)). In this article, we argue that network mapping can be improved by including neuronal energy/activity of both the information about baseline and small differences/fluctuations of BOLD signal. Thus, total energy/activity information can be obtained through use of calibrated fMRI to quantify differences of DeltaCMR(O2) and through resting-state positron emission tomography/magnetic resonance spectroscopy measurements for average CMR(O2). PMID- 22433048 TI - Negative functional connectivity and its dependence on the shortest path length of positive network in the resting-state human brain. AB - It is suggested that structurally segregated and functionally specialized brain regions are mediated by synchrony over large-scale networks in order to provide the formation of dynamic links and integration functions. The existence of negative synchrony, or negative functional connectivity (NFC), however, has been a subject of debate in terms of its origin, interpretation, relationship with structural connectivity, and possible neurophysiological function. The present study, which incorporated 20 cognitively healthy elderly human subjects, focused on testing the hypothesis that NFC significantly correlates with the shortest path length (SPL) in the human brain network. Our theoretical calculation, simulated data, and human study results support this hypothesis. In the human study, we find that (1) the percentage of NFC connections among all connections between brain regions significantly correlates with spatial Euclidian distance; (2) the strength of the NFC between the right amygdala and the left dorsolateral prefrontal cortex is significantly correlated with the SPL across the 20 human subjects; (3) such a significant relationship between the NFC and SPL exists in all the NFC connections in the whole brain; and (4) the correlations between the NFC and SPL also are frequency bandwidth dependent. These results suggest that an accumulated phased delay gives rise to the NFC, along the shortest path in the large-scale brain functional network. It is suggested that our study can be extended to examine a variety of neurological diseases and psychiatric disorders by measuring the changes of SPL and functional reorganization in the brain. PMID- 22433049 TI - Abnormalities in resting-state functional connectivity in early human immunodeficiency virus infection. AB - Limited information is available concerning changes that occur in the brain early in human immunodeficiency virus (HIV) infection. This investigation evaluated resting-state functional connectivity, which is based on correlations of spontaneous blood oxygen level-dependent functional magnetic resonance imaging (fMRI) oscillations between brain regions, in 15 subjects within the first year of HIV infection and in 15 age-matched controls. Resting-state fMRI data for each session were concatenated in time across subjects to create a single 4D dataset and decomposed into 36 independent component analysis (ICA) using Multivariate Exploratory Linear Optimized Decomposition into Independent Components. ICA components were back-reconstructed for each subject's 4D data to estimate subject specific spatial maps using the dual-regression technique. Comparison of spatial maps between HIV and controls revealed significant differences in the lateral occipital cortex (LOC) network. Reduced coactivation in left inferior parietal cortex within the LOC network was identified in the HIV subjects. Connectivity strength within this region correlated with performance on tasks involving visual motor coordination (Grooved Pegboard and Rey Figure Copy) in the HIV group. The findings indicate prominent changes in resting-state functional connectivity of visual networks early in HIV infection. This network may sustain injury in association with the intense viremia and brain viral invasion before immune defenses can contain viral replication. Resting-state functional connectivity may have utility as a noninvasive neuroimaging biomarker for central nervous system impairment in early HIV infection. PMID- 22433050 TI - The influence of handedness on hemispheric interaction during word production: insights from effective connectivity analysis. AB - Overt picture naming causes activation in both left and right hemispheres as demonstrated by functional magnetic resonance imaging (fMRI) studies. Unexpectedly, a previous experiment revealed that there was no difference in brain lateralization related to handedness. To understand the mechanisms behind this phenomenon and to investigate the influence that each hemisphere exerts over the other in more detail, we analyzed the effective connectivity in the naming network. More specifically, we examined the impact of handedness on hemispheric interactions. Four brain regions activated for correct naming in the previous fMRI experiment served as volumes of interest: Bilateral fusiform gyrus (FG) related to visual-semantic processing and bilateral Brodmann's area (BA) 44 related to phonological processing. We defined three dynamic causal models (DCMs) representing different symmetrical connectivity patterns, compared them using Bayesian model selection, and considered differential connection strengths. For the majority of 31 participants, the same model featuring early integration of visual-semantic processing and independent phonological processing was optimal. This also held true if right-handers, left-handers, and ambidexters were considered as independent groups. For left-handers, the connection of right FG and right BA 44 was significantly stronger compared with the other two groups, and it was significantly stronger than its left-hemisphere equivalent. In right handers, the according left-hemisphere connection was significant, but connectivities were rather symmetrical. These findings reveal significant and unique right-hemisphere contributions to word production. PMID- 22433051 TI - Hearing without listening: functional connectivity reveals the engagement of multiple nonauditory networks during basic sound processing. AB - The present functional magnetic resonance imaging (fMRI) study presents data challenging the traditional view that sound is processed almost exclusively in the classical auditory pathway unless imbued with behavioral significance. In a first experiment, subjects were presented with broadband noise in on/off fashion as they performed an unrelated visual task. A conventional analysis assuming predictable sound-evoked responses demonstrated a typical activation pattern that was confined to classical auditory centers. In contrast, spatial independent component analysis (sICA) disclosed multiple networks of acoustically responsive brain centers. One network comprised classical auditory centers, but four others included nominally "nonauditory" areas: cingulo-insular cortex, mediotemporal limbic lobe, basal ganglia, and posterior orbitofrontal cortex, respectively. Functional connectivity analyses confirmed the sICA results by demonstrating coordinated activity between the involved brain structures. In a second experiment, fMRI data obtained from unstimulated (i.e., resting) subjects revealed largely similar networks. Together, these two experiments suggest the existence of a coordinated system of multiple acoustically responsive intrinsic brain networks, comprising classical auditory centers but also other brain areas. Our results suggest that nonauditory centers play a role in sound processing at a very basic level, even when the sound is not intertwined with behaviors requiring the well-known functionality of these regions. PMID- 22433052 TI - Anxiety modulates insula recruitment in resting-state functional magnetic resonance imaging in youth and adults. AB - Research on resting-state functional connectivity reveals intrinsically connected networks in the brain that are largely consistent across the general population. However, there are individual differences in these networks that have not been elucidated. Here, we measured the influence of naturally occurring mood on functional connectivity. In particular, we examined the association between self reported levels of anxiety and connectivity in the default mode network (DMN). Healthy youth (n=43; ages 10-18) and adult participants (n=24, ages 19-59) completed a 6-min resting-state functional magnetic resonance imaging scan, then immediately completed questionnaires assessing their mood and thoughts during the scan. Regression analyses conducted separately for the youth and adult samples revealed brain regions in which increases in connectivity differentially corresponded to higher anxiety in each group. In one area, the left insular cortex, both groups showed similar increased connectivity to the DMN (youth: -30, 26, 14; adults: -33, 12, 14) with increased anxiety. State anxiety assessed during scanning was not correlated with trait anxiety, so our results likely reflect state levels of anxiety. To our knowledge, this is the first study to relate naturally occurring mood to resting state connectivity. PMID- 22433053 TI - Electrical tongue stimulation normalizes activity within the motion-sensitive brain network in balance-impaired subjects as revealed by group independent component analysis. AB - Multivariate analysis of functional magnetic resonance imaging (fMRI) data allows investigations into network behavior beyond simple activations of individual regions. We apply group independent component analysis to fMRI data collected in a previous study looking at the sustained neuromodulatory effects of electrical tongue stimulation in balance-impaired individuals. Twelve subjects with balance disorders viewed optic flow in an fMRI scanner before and after 5 days of electrical tongue stimulation. Nine healthy controls also viewed the visual stimuli but did not receive any stimulation. Multiple regression of the 47 estimated components found two that were modulated by the visual stimuli. Component 7, comprised primarily of the primary visual cortex (V1), responded to all visual stimuli and showed no difference in task-related activity between the healthy controls and the balance-impaired subjects before or after stimulation. Component 11 responded only to motion in the visual field and contained multiple cortical and subcortical regions involved in processing information pertinent to balance. Two-sample t-tests of the calculated signal change revealed that the task-related activity of this network is greater in balance-impaired subjects compared with controls before stimulation (p=0.02), but that this network hypersensitivity decreases after electrical tongue stimulation (p=0.001). PMID- 22433054 TI - Altering the communication networks of multispecies microbial systems using a diverse toolbox of AI-2 analogues. AB - There have been intensive efforts to find small molecule antagonists for bacterial quorum sensing (QS) mediated by the "universal" QS autoinducer, AI-2. Previous work has shown that linear and branched acyl analogues of AI-2 can selectively modulate AI-2 signaling in bacteria. Additionally, LsrK-dependent phosphorylated analogues have been implicated as the active inhibitory form against AI-2 signaling. We used these observations to synthesize an expanded and diverse array of AI-2 analogues, which included aromatic as well as cyclic C-1 alkyl analogues. Species-specific analogues that disrupted AI-2 signaling in Escherichia coli and Salmonella typhimurium were identified. Similarly, analogues that disrupted QS behaviors in Pseudomonas aeruginosa were found. Moreover, we observed a strong correlation between LsrK-dependent phosphorylation of these acyl analogues and their ability to suppress QS. Significantly, we demonstrate that these analogues can selectively antagonize QS in single bacterial strains in a physiologically relevant polymicrobial culture. PMID- 22433055 TI - New filtration systems for extra-virgin olive oil: effect on antioxidant compounds, oxidative stability, and physicochemical and sensory properties. AB - The purpose of this work was to evaluate some new filtration systems in relation to the quality of extra-virgin olive oil (EVOO). Filtration processes were undertaken using a polypropylene filter bag and two different inert gas flows as filter aids (argon and nitrogen). Qualitative and quantitative variations of the glyceride composition, antioxidant and pro-oxidant compounds, and water content were correlated with the oxidative stability to establish the effect on EVOO shelf life. The influence on physicochemical and sensorial properties was also evaluated. After filtration, the oxidative stability was reduced. The behavior of the polyphenols and water content on the filtration process could explain the lowest oxidative stability of filtered EVOO. Moreover, the results of the sensorial analysis confirmed that filtration using inert gases did not decrease the intensity of the main positive sensory attributes. The results could help olive-oil producers to improve EVOO quality and establish optimal storage conditions. PMID- 22433056 TI - Limitation of repeated radiofrequency ablation in hepatocellular carcinoma: proposal of a three (times) * 3 (years) index. AB - BACKGROUND AND AIM: Percutaneous radiofrequency ablation (RFA) has been shown to be a highly effective treatment for hepatocellular carcinoma (HCC). We investigated the controllability of HCC and explored the algorithm of therapeutic strategy for HCC in patients who met the RFA criteria. METHODS: We enrolled 472 patients with HCC who met the RFA criteria (<= 3 nodules, <= 3 cm) and underwent RFA for initial therapy. Patients who underwent repeated RFA were evaluated retrospectively when HCC exceeded the RFA criteria, or the functional hepatic reserve progressed to Child-Pugh grade C. RESULTS: Overall survival rates were: 1 year, 96%; 3 years, 79%; and 5 years, 56%. In 5 years, 14% of patients progressed to Child-Pugh grade C. Meanwhile, 47% of patients exceeded the RFA criteria. Annually, 8% of patients deviated from the RFA criteria. The percentage of patients who were able to receive RFA significantly decreased at the fourth session compared with up to the third session. The survival rates decreased at the rate of 7% annually until the third year after the initial RFA. Afterwards, it shifted to a decrease at the rate of 12% annually. In a multivariate analysis, the presence of hepatitis C virus infection and the existence of a single tumor were identified as significant independent factors contributing to probabilities exceeding the RFA criteria. CONCLUSIONS: HCC was controlled by RFA up to three RFA treatments and 3 years from the initial therapy. On this basis, we propose a "three (times) * 3 (years) index" for considering a shift from RFA to other treatment modalities. PMID- 22433057 TI - Combined effect of Hsp90 inhibitor geldanamycin and parthenolide via reactive oxygen species-mediated apoptotic process on epithelial ovarian cancer cells. AB - Hsp90 inhibitor geldanamycin and parthenolide have been shown to induce apoptosis in cancer cells. However, the combined effect of geldanamycin and parthenolide on epithelial ovarian cancer cells has not been studied. In respect of cell death process, we investigated the promoting effect of parthenolide on geldanamycin induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Geldanamycin induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels; an increase in Bax and tumour suppressor p53 levels; loss of the mitochondrial transmembrane potential; cytochrome c release; activation of caspases (-8, -9 and -3); cleavage of PARP-1; and increase in the reactive oxygen species formation. Parthenolide enhanced geldanamycin-induced changes in the apoptosis-related protein levels, reactive oxygen species formation, nuclear damage and cell death. The combined effect was inhibited by the addition of oxidant scavengers. The results suggest that parthenolide may potentiate the apoptotic effect of geldanamycin on ovarian carcinoma cell lines by the activation of the caspase-8- and Bid-dependent pathway and the mitochondria mediated apoptotic pathway. The apoptosis-promoting effect seems to be mediated by the stimulatory effect on the formation of reactive oxygen species. PMID- 22433059 TI - Phase range of the type-I clathrate Sr8Al(x)Si(46-x) and crystal structure of Sr8Al10Si36. AB - Samples of the type-I clathrate Sr(8)Al(x)Si(46-x) have been prepared by direct reaction of the elements. The type-I clathrate structure (cubic space group Pm3n) which has an Al-Si framework with Sr(2+) guest atoms forms with a narrow composition range of 9.54(6) <= x <= 10.30(8). Single crystals with composition A(8)Al(10)Si(36) (A = Sr, Ba) have been synthesized. Differential scanning calorimetry (DSC) measurements provide evidence for a peritectic reaction and melting point at ~1268 and ~1421 K for Sr(8)Al(10)Si(36) and Ba(8)Al(10)Si(36), respectively. Comparison of the structures reveals a strong correlation between the 24k-24k framework sites distances and the size of the guest cation. Electronic structure calculation and bonding analysis were carried out for the ordered models with the compositions A(8)Al(6)Si(40) (6c site occupied completely by Al) and A(8)Al(16)Si(30) (16i site occupied completely with Al). Analysis of the distribution of the electron localizability indicator (ELI) confirms that the Si-Si bonds are covalent, the Al-Si bonds are polar covalent, and the guest and the framework bonds are ionic in nature. The Sr(8)Al(6)Si(40) phase has a very small band gap that is closed upon additional Al, as observed in Sr(8)Al(16)Si(30). An explanation for the absence of a semiconducting "Sr(8)Al(16)Si(30)" phase is suggested in light of these findings. PMID- 22433058 TI - The metabolic response of P. putida KT2442 producing high levels of polyhydroxyalkanoate under single- and multiple-nutrient-limited growth: highlights from a multi-level omics approach. AB - BACKGROUND: Pseudomonas putida KT2442 is a natural producer of polyhydroxyalkanoates (PHAs), which can substitute petroleum-based non-renewable plastics and form the basis for the production of tailor-made biopolymers. However, despite the substantial body of work on PHA production by P. putida strains, it is not yet clear how the bacterium re-arranges its whole metabolism when it senses the limitation of nitrogen and the excess of fatty acids as carbon source, to result in a large accumulation of PHAs within the cell. In the present study we investigated the metabolic response of KT2442 using a systems biology approach to highlight the differences between single- and multiple-nutrient limited growth in chemostat cultures. RESULTS: We found that 26, 62, and 81% of the cell dry weight consist of PHA under conditions of carbon, dual, and nitrogen limitation, respectively. Under nitrogen limitation a specific PHA production rate of 0.43 (g.(g.h)-1) was obtained. The residual biomass was not constant for dual- and strict nitrogen-limiting growth, showing a different feature in comparison to other P. putida strains. Dual limitation resulted in patterns of gene expression, protein level, and metabolite concentrations that substantially differ from those observed under exclusive carbon or nitrogen limitation. The most pronounced differences were found in the energy metabolism, fatty acid metabolism, as well as stress proteins and enzymes belonging to the transport system. CONCLUSION: This is the first study where the interrelationship between nutrient limitations and PHA synthesis has been investigated under well controlled conditions using a system level approach. The knowledge generated will be of great assistance for the development of bioprocesses and further metabolic engineering work in this versatile organism to both enhance and diversify the industrial production of PHAs. PMID- 22433060 TI - Protein analysis meets visual word recognition: a case for string kernels in the brain. AB - It has been recently argued that some machine learning techniques known as Kernel methods could be relevant for capturing cognitive and neural mechanisms (Jakel, Scholkopf, & Wichmann, 2009). We point out that ''String kernels,'' initially designed for protein function prediction and spam detection, are virtually identical to one contending proposal for how the brain encodes orthographic information during reading. We suggest some reasons for this connection and we derive new ideas for visual word recognition that are successfully put to the test. We argue that the versatility and performance of String kernels makes a compelling case for their implementation in the brain. PMID- 22433061 TI - Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis. AB - OBJECTIVE: X-linked lymphoproliferative syndrome (XLP) type 1 is a rare immunodeficiency, which is caused by mutations in SH2D1A gene. The prognosis of XLP is very poor, and hematopoietic stem cell transplantation (HSCT) is the only curative therapy. We characterized the clinical features and outcome of Japanese patients with XLP-1. METHODS: We used a combination of flow cytometric analysis and genetic analysis to identify XLP-1 and reviewed the patient characteristics and survival with HSCT. RESULTS: We identified 33 patients from 21 families with XLP-1 in Japan. Twenty-one of the patients (65%) who did not undergo a transplant died of the disease and complications. Twelve patients underwent HSCT, and 11 of these (92%) survived. CONCLUSION: We described the clinical characteristics and outcomes of Japanese patients with XLP-1, and HSCT was the only curative therapy for XLP-1. The rapid and accurate diagnosis of XLP with the combination of flow cytometric assay and genetic analysis is important. PMID- 22433062 TI - RNA interference mortality points to noncircadian functions for the clock gene in the desert locust Schistocerca gregaria. AB - One of the core genes in the circadian regulation network is clock (clk). By forming a heterodimer with CYCLE (CYC) that binds on an E-box in the promoter region, it induces the transcription of other elements in the circadian transcriptional feedback loops and different clock output genes. In contrast to other insects, a clk double-stranded RNA (dsRNA) treatment is lethal in adults and fifth instar nymphs of the desert locust, Schistocerca gregaria, in a dose dependent manner. Clk knock down fifth instar nymphs are able to undergo their imaginal moult but, depending on the amount of dsRNA, it takes them longer than the controls to reach adulthood. As adults, clk knock down animals do not develop their fat body and ovaries like the control animals. Therefore, we tested the expression of different genes involved in energy metabolism and reproduction to see the effect of the clk RNA interference knock down. Surprisingly, the expression of the vitellogenin gene was up-regulated in the clk knock down females who did not appear to invest their energy in egg development. Taken together, our results point out that the clk gene in the desert locust has an additional function in development besides its established role in maintaining the circadian rhythms in the brain. PMID- 22433063 TI - A technique for pediatric total skin electron irradiation. AB - BACKGROUND: Total skin electron irradiation (TSEI) is a special radiotherapy technique which has generally been used for treating adult patients with mycosis fungoides. Recently, two infants presented with leukemia cutis isolated to the skin requiring TSEI. This work discusses the commissioning and quality assurance (QA) methods for implementing a modified Stanford technique using a rotating harness system to position sedated pediatric patients treated with electrons to the total skin. METHODS AND RESULTS: Commissioning of pediatric TSEI consisted of absolute calibration, measurement of dosimetric parameters, and subsequent verification in a pediatric patient sized cylindrical phantom using radiographic film and optically stimulated luminance (OSL) dosimeters. The depth of dose penetration under TSEI treatment condition was evaluated using radiographic film sandwiched in the phantom and demonstrated a 2 cm penetration depth with the maximum dose located at the phantom surface. Dosimetry measurements on the cylindrical phantom and in-vivo measurements from the patients suggested that, the factor relating the skin and calibration point doses (i.e., the B-factor) was larger for the pediatric TSEI treatments as compared to adult TSEI treatments. Custom made equipment, including a rotating plate and harness, was fabricated and added to a standard total body irradiation stand and tested to facilitate patient setup under sedated condition. A pediatric TSEI QA program, consisting of daily output, energy, flatness, and symmetry measurements as well as in-vivo dosimetry verification for the first cycle was developed. With a long interval between pediatric TSEI cases, absolute dosimetry was also repeated as part of the QA program. In-vivo dosimetry for the first two infants showed that a dose of +/- 10% of the prescription dose can be achieved over the entire patient body. CONCLUSION: Though pediatric leukemia cutis and the subsequent need for TSEI are rare, the ability to commission the technique on a modified TBI stand is appealing for clinical implementation and has been successfully used for the treatment of two pediatric patients at our institution. PMID- 22433064 TI - Thermal sensitivity does not determine acclimation capacity for a tropical reef fish. AB - 1. Short-term measures of metabolic responses to warmer environments are expected to indicate the sensitivity of species to regional warming. However, given time, species may be able to acclimate to increasing temperature. Thus, it is useful to determine if short-term responses provide a good predictor for long-term acclimation ability. 2. The tropical reef fish Acanthochromis polyacanthus was used to test whether the ability for developmental thermal acclimation of two populations was indicated by their short-term metabolic response to temperature. 3. While both populations exhibited similar short-term responses of resting metabolic rate (RMR) to temperature, fish from the higher-latitude population were able to fully acclimate RMR, while the lower-latitude population could only partially compensate RMR at the warmest temperature. These differences in acclimation ability are most likely due to genetic differences between the populations rather than differences in thermal regimes. 4. This research indicates that acclimation ability may vary greatly between populations and that understanding such variation will be critical for predicting the impacts of warming environmental temperatures. Moreover, the thermal metabolic reaction norm does not appear to be a good predictor of long-term acclimation ability. PMID- 22433065 TI - Decreased sensitivity of NMDA receptors on dopaminergic neurons from the posterior ventral tegmental area following chronic nondependent alcohol consumption. AB - BACKGROUND: The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally applied N-methyl-d aspartic acid (NMDA; glutamate receptor subtype agonist) were evaluated. METHODS: P rats were assigned to alcohol naive (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from naive rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically applied NMDA. Current-response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between group comparisons were made for EC(50) (effective current producing a half maximal excitatory response), E(max) (maximal excitatory effect), and C(DB) (the current at which depolarization block-marked decrease in neuronal activity occurred). RESULTS: Drinking P rats steadily consumed alcohol over the 8-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher C(DB) values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC(50) values), consistent with decreased receptor affinity. Maximal excitatory responses (E(max) ) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation. CONCLUSIONS: NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence. PMID- 22433066 TI - Photochromic thienylpyridine-bis(alkynyl)borane complexes: toward readily tunable fluorescence dyes and photoswitchable materials. AB - A series of diarylethene-containing N^C chelated thienylpyridine bis(alkynyl)borane complexes has been designed and synthesized. Their photophysical and photochromic properties have been investigated and presented. The characteristic low-energy absorption band of their closed forms could be readily tuned from the visible range to the near-infrared region. PMID- 22433067 TI - Development of a real-time PCR method for the detection of fossil 16S rDNA fragments of phototrophic sulfur bacteria in the sediments of Lake Cadagno. AB - Lake Cadagno is a crenogenic meromictic lake situated in the southern range of the Swiss Alps characterized by a compact chemocline that has been the object of many ecological studies. The population dynamics of phototrophic sulfur bacteria in the chemocline has been monitored since 1994 with molecular methods such as 16S rRNA gene clone library analysis. To reconstruct paleo-microbial community dynamics, we developed a quantitative real-time PCR methodology for specific detection of 16S rRNA gene sequences of purple and green sulfur bacteria populations from sediment samples. We detected fossil 16S rDNA of nine populations of phototrophic sulfur bacteria down to 9-m sediment depth, corresponding to about 9500 years of the lake's biogeological history. These results provide the first evidence for the presence of 16S rDNA of anoxygenic phototrophic bacteria in Holocene sediments of an alpine meromictic lake and indicate that the water column stratification and the bacterial plume were already present in Lake Cadagno thousands of years ago. The finding of Chlorobium clathratiforme remains in all the samples analyzed shows that this population, identified in the water column only in 2001, was already a part of the lake's biota in the past. PMID- 22433068 TI - Climate change impacts on tree ranges: model intercomparison facilitates understanding and quantification of uncertainty. AB - Model-based projections of shifts in tree species range due to climate change are becoming an important decision support tool for forest management. However, poorly evaluated sources of uncertainty require more scrutiny before relying heavily on models for decision-making. We evaluated uncertainty arising from differences in model formulations of tree response to climate change based on a rigorous intercomparison of projections of tree distributions in France. We compared eight models ranging from niche-based to process-based models. On average, models project large range contractions of temperate tree species in lowlands due to climate change. There was substantial disagreement between models for temperate broadleaf deciduous tree species, but differences in the capacity of models to account for rising CO(2) impacts explained much of the disagreement. There was good quantitative agreement among models concerning the range contractions for Scots pine. For the dominant Mediterranean tree species, Holm oak, all models foresee substantial range expansion. PMID- 22433069 TI - Effect of architecture on the formation of surface multilayer structures at the air-solution interface from mixtures of surfactant with small poly(ethyleneimine)s. AB - The impact of ethyleneimine architecture on the adsorption behavior of mixtures of small poly(ethyleneimines) and oligoethyleneimines (OEIs) with the anionic surfactant sodium dodecylsulfate (SDS) at the air-solution interface has been studied by surface tension (ST) and neutron reflectivity (NR). The strong surface interaction between OEI and SDS gives rise to complex surface tension behavior that has a pronounced pH dependence. The NR data provide more direct access to the surface structure and show that the patterns of ST behavior are correlated with substantial OEI/SDS adsorption and the spontaneous formation of surface multilayer structures. The regions of surface multilayer formation depend upon SDS and OEI concentrations, on the solution pH, and on the OEI architecture, linear or branched. For the linear OEIs (octaethyleneimine, linear poly(ethyleneimine) or LPEI(8), and decaethyleneimine, LPEI(10)) with SDS, surface multilayer formation occurs over a range of OEI and SDS concentrations at pH 7 and to a much lesser extent at pH 10, whereas at pH 3 only monolayer adsorption occurs. In contrast, for branched OEIs BPEI(8) and BPEI(10) surface multilayer formation occurs over a wide range of OEI and SDS concentrations at pH 3 and 7, and at pH 10, the adsorption is mainly in the form of a monolayer. The results provide important insight into how the OEI architecture and pH can be used to control and manipulate the nature of the OEI/surfactant adsorption. PMID- 22433070 TI - The South-to-North Water Diversion Project: effect of the water diversion pattern on transmission of Oncomelania hupensis, the intermediate host of Schistosoma japonicum in China. AB - BACKGROUND: The South-to-North Water Diversion Project (SNWDP) is the largest national water conservancy project in China. However, the Eastern Route Project (ERP) of SNWDP will refer to the habitats of Oncomelania hupensis, the intermediate host of Schistosoma japonicum. The present study was aimed at investigating the effects of some factors relating to the water diversion pattern on the spread north of O. hupensis and transmission of S. japonicum. METHODS: Marked snails were attached to the floating debris, and then placed on the water surface, the passage of snails through water pumps was observed. Some marked living adult snails were placed under water in the 5 spots, 15, 30, 60, 90 and 120 days later, their survival and transfer under water were investigated. 2, 4, 8, 16, 32, 64 and 128 juvenile snails, with a male: female ratio of about 1, were caged, 1 year later, their reproductions were calculated. RESULTS: The snails attached on the floating debris at 100-, 50- and 20-cm-distance from the inlet pipe of the big pump (with a diameter of 80 cm), could be absorbed into the pumps, with passing rates of 2.45%, 3.93% and 43.46%, respectively, compared with 72.07% and 91.00% for the snails at 20 cm and 10 cm-distance from the inlet pipe of the small pump (with a diameter of 20 cm). A total of 36,600 marked living snails were put into 5 ponds and ditches, with the water depths of 1-1.6 m, 15 120 days later, no marked ones were found along the ponds and ditches or in the straw packages. The juvenile snails did not reproduce until their density reached up to 8 snails (ratio of male: female of 1)/0.16 m2. CONCLUSIONS: During the construction of ERP of SNWDP, the risk of northward spread of schistosomiasis japonica will be decreased or eliminated as long as long-term reliable interventions for snail control are implemented. PMID- 22433071 TI - Mechanical ventilation with high tidal volumes attenuates myocardial dysfunction by decreasing cardiac edema in a rat model of LPS-induced peritonitis. AB - BACKGROUND: Injurious mechanical ventilation (MV) may augment organ injury remote from the lungs. During sepsis, myocardial dysfunction is common and increased endothelial activation and permeability can cause myocardial edema, which may, among other factors, hamper myocardial function. We investigated the effects of MV with injuriously high tidal volumes on the myocardium in an animal model of sepsis. METHODS: Normal rats and intraperitoneal (i.p.) lipopolysaccharide (LPS) treated rats were ventilated with low (6 ml/kg) and high (19 ml/kg) tidal volumes (Vt) under general anesthesia. Non-ventilated animals served as controls. Mean arterial pressure (MAP), central venous pressure (CVP), cardiac output (CO) and pulmonary plateau pressure (Pplat) were measured. Ex vivo myocardial function was measured in isolated Langendorff-perfused hearts. Cardiac expression of endothelial vascular cell adhesion molecule (VCAM)-1 and edema were measured to evaluate endothelial inflammation and leakage. RESULTS: MAP decreased after LPS treatment and Vt-dependently, both independent of each other and with interaction. MV Vt-dependently increased CVP and Pplat and decreased CO. LPS induced peritonitis decreased myocardial function ex vivo but MV attenuated systolic dysfunction Vt-dependently. Cardiac endothelial VCAM-1 expression was increased by LPS treatment independent of MV. Cardiac edema was lowered Vt dependently by MV, particularly after LPS, and correlated inversely with systolic myocardial function parameters ex vivo. CONCLUSION: MV attenuated LPS-induced systolic myocardial dysfunction in a Vt-dependent manner. This was associated with a reduction in cardiac edema following a lower transmural coronary venous outflow pressure during LPS-induced coronary inflammation. PMID- 22433072 TI - Incongruous consultation behaviour: results from a UK-wide population survey. AB - BACKGROUND: Symptom characteristics are strong drivers of care seeking. Despite this, incongruous consultation behaviour occurs and has implications for both individuals and health-care services. The aim of this study was to determine how frequently incongruous consultation behaviour occurs, to examine whether it is more common for certain types of symptoms and to identify the factors associated with being an incongruous consulter. METHODS: An age and sex stratified random sample of 8,000 adults was drawn from twenty UK general practices. A postal questionnaire was used to collect detailed information on the presence and characteristics of 25 physical and psychological symptoms, actions taken to manage the symptoms, general health, attitudes to symptom management and demographic/socio-economic details. Two types of incongruous consultation behaviour were examined: i) consultation with a GP for symptoms self-rated as low impact and ii) no consultation with a GP for symptoms self-rated as high impact. RESULTS: A fifth of all symptoms experienced resulted in consultation behaviour which was incongruous based on respondents' own rating of the symptoms' impact. Low impact consultations were not common, although symptoms indicative of a potentially serious condition resulted in a higher proportion of low impact consultations. High impact non-consultations were more common, although there was no clear pattern in the type of associated symptoms. Just under half of those experiencing symptoms in the previous two weeks were categorised as an incongruous consulter (low impact consulter: 8.3%, high impact non-consulter: 37.1%). Employment status, having a chronic condition, poor health, and feeling that reassurance or advice from a health professional is important were associated with being a low impact consulter. Younger age, employment status, being an ex-smoker, poor health and feeling that not wasting the GPs time is important were associated with being a high impact non-consulter. CONCLUSIONS: This is one of the first studies to examine incongruous consultation behaviour for a range of symptoms. High impact non-consultations were common and may have important health implications, particularly for symptoms indicative of serious disease. More research is now needed to examine incongruous consultation behaviour and its impact on both the public's health and health service use. PMID- 22433073 TI - Metabolomics in agriculture. AB - Metabolome refers to the complete set of metabolites synthesized through a series of multiple enzymatic steps from various biochemical pathways processing the information encrypted in the plant genome. Knowledge about synthesis and regulation of various plant metabolic substances has improved substantially with availability of Omics data originating from sequencing of plant genomes. Metabolic profiling of crops is increasingly becoming popular in assessing plant phenotypes and genetic diversity. Metabolic compositional changes vividly reflect the changes occurring during plant growth, development, and in response to stress. Hence, study of plant metabolic pathways, the interconnections between them in context of systems biology is increasingly becoming popular in identification of candidate genes. The present article reviews recent developments in analysis of plant metabolomics, available bioinformatics techniques and databases employed for comparative pathway analysis, metabolic QTLs, and their application in plants. PMID- 22433074 TI - Semirna: searching for plant miRNAs using target sequences. AB - Many plant genomes are already known, and new ones are being sequenced every year. The next step for researchers is to identify all of the functional elements in these genomes, including the important class of functional elements known as microRNAs (miRNAs), which are involved in posttranscriptional regulatory pathways. However, computational tools for predicting new plant miRNAs are limited, and there is a particular need for tools that can be used easily by laboratory researchers. We present semirna, a new tool for predicting miRNAs in plant genomes, available as a Web server. This tool takes a putative target sequence such as a messenger RNA (mRNA) as input, and allows users to search for miRNAs that target this sequence. It can also be used to determine whether small RNA sequences from massive sequencing analysis represent true miRNAs and to search for miRNAs in new genomes using homology. Semirna has shown a high level of accuracy using various test sets, and gives users the ability to search for miRNAs with several different adjustable parameters. Semirna, a user-friendly and intuitive Web server for predicting miRNA sequences, can be reached at http://www.bioinfocabd.upo.es/semirna/ . It is useful for researchers searching for miRNAs involved in particular pathways, as well as those searching for miRNAs in newly sequenced genomes. PMID- 22433075 TI - A cascade of recently discovered molecular mechanisms involved in abiotic stress tolerance of plants. AB - Today, agriculture is facing a tremendous threat from the climate change menace. As human survival is dependent on a constant supply of food from plants as the primary producers, we must aware of the underlying molecular mechanisms that plants have acquired as a result of molecular evolution to cope this rapidly changing environment. This understanding will help us in designing programs aimed at developing crop plant cultivars best suited to our needs of a sustainable agriculture. The field of systems biology is rapidly progressing, and new insight is coming out about the molecular mechanisms involved in abiotic stress tolerance. There is a cascade of changes in transcriptome, proteome, and metabolome of plants during these stress responses. We have tried to cover most pronounced recent developments in the field of "omics" related to abiotic stress tolerance of plants. These changes are very coordinated, and often there is crosstalk between different components of stress tolerance. The functions of various molecular entities are becoming more clear and being associated with more precise biological phenomenon. PMID- 22433076 TI - Identification of SNP mutations in DREB1, HKT1, and WRKY1 genes involved in drought and salt stress tolerance in durum wheat (Triticum turgidum L. var durum). AB - Tolerance mechanisms to salinity and drought stress are quite complex. Plants have developed a complex and elaborate signaling network that ensures their adaptation to this stress. For example, salinity tolerance is thought to be due to three main factors: Na(+) exclusion, tolerance to Na(+) in the tissues and osmotic tolerance. Recently, many transcription factors for tolerance to salt and drought stresses have been identified. In this study, multialignments of conserved domains in DREB1, WRKY1 transcription factors (TFs), and HKT-1 have been utilized to design specific primers in order to identify functional single nucleotide polymorphisms (SNPs). These primers have been used to probe on several genotypes of durum wheat that are differentially tolerant to salt and drought stress; they were grown in increasing concentrations of NaCl. The selected portions have been analyzed using high-resolution melting curve (HRM) technology that currently represents one of the most recent and powerful tools for detecting SNP and INDEL mutations. Analyzing the amplification profiles, observed in the resulting melting curves, samples corresponding to different treatment conditions were selected, sequenced, and aligned with the homolog sequences present in gene databases to identify and characterize potential SNP and INDEL mutations. The PCR amplicons, containing single and double SNPs, produced distinctive HRM profiles. By sequencing the polymerase chain reaction (PCR) products, several SNPs have been identified and validated. All the discovered mutations were able to generate changes in amino acid sequences of the corresponding proteins. Most of the identified SNPs were found in salt and drought tolerant durum wheat genotypes. These varieties are of great value for durum wheat breeding works. PMID- 22433077 TI - Why we should stop inferring simple correlations between antioxidants and plant stress resistance: towards the antioxidomic era. AB - A large number of studies have investigated the relationship between different forms of abiotic stress and antioxidants. However, misconceptions and technical flaws often affect studies on this important topic. Reactive oxygen species (ROS) generated under stress conditions should not be considered just as potential threats, because they are essential components of the signaling mechanism inducing plant defenses. Similarly, the complexity of the antioxidant system should be considered, to avoid misleading oversimplifications. Recent literature is discussed, highlighting the importance of accurate experimental setups for obtaining reliable results in this delicate field of research. A tentative "troubleshooting guide" is provided to help researchers interested in improving the quality of their work on the role of antioxidants in plant stress resistance. Significant advancements in the field could be reached with the development of antioxidomics, defined here as a new branch of research at the crossroads of other disciplines including metabolomics and proteomics, studying the complex relationship among antioxidants and their functions. PMID- 22433078 TI - Determination of 15 isoflavone isomers in soy foods and supplements by high performance liquid chromatography. AB - Soy isoflavone is the generic name for the isoflavones found in soy. We determined the concentrations of 15 soy isoflavone species, including 3 succinyl glucosides, in 22 soy foods and isoflavone supplements by high-performance liquid chromatography (HPLC). The total isoflavone contents in 14 soy foods and 8 supplements ranged from 45 to 735 MUg/g and from 1,304 to 90,224 MUg/g, respectively. Higher amounts of succinyl glucosides were detected in natto, a typical fermented soy product in Japan; these ranged from 30 to 80 MUg/g and comprised 4.1-10.9% of the total isoflavone content. In soy powder, 59 MUg/g of succinyl glucosides were detected, equivalent to 4.6% of the total isoflavone content. These data suggest that the total isoflavone contents may be underestimated in the previous studies that have not included succinyl glucosides, especially for Bacillus subtilis -fermented soy food products. PMID- 22433079 TI - Renal cortical and medullary blood flow during modest saline loading in humans. AB - AIM: Renal medullary blood flow (RMBF) is considered an important element of sodium homeostasis, but the experimental evidence is incongruent. Studies in anaesthetized animals generally support the concept in contrast to measurements in conscious animals. We hypothesized that saline-induced natriuresis is associated with changes in RMBF in humans. METHODS: After 4 days of low-sodium diet, healthy men were subjected to slow intravenous saline loading (12 MUmol kg( 1) min(-1)) for 4 h. Renal medullary and cortical blood flow was determined by positron emission tomography with H(2)(15)O before and after saline infusion using two independent imaging processing methods. One based on a previously published algorithm (voxel peeling) and a novel method based on contrast-enhanced computed tomography (CT). Blood pressure was measured oscillometrically every 10 min. Cardiac output, heart rate and total peripheral resistance were recorded continuously. RESULTS: Saline loading increased the urinary sodium excretion by 3.6-fold (21-76 MUmol min(-1) , P < 0.01). The RMBF was 2.6 +/- 0.2 mL g(-1) tissue min(-1) before and 2.7 +/- 0.1 mL g(-1) tissue min(-1) after saline (n.s.). Cortical blood flow was 3.6 +/- 0.1 before and 3.4 +/- 0.2 after saline (n.s.). Mean arterial blood pressure did not change measurably (90 vs. 90 mmHg). Bland-Altman analysis suggested agreement between results obtained with voxel peeling (2.6 +/- 0.2 mL g(-1) tissue min(-1)) and contrast-enhanced CT (2.0 +/- 0.1 mL g(-1) tissue min(-1)). CONCLUSION: In normal humans, changes in RMBF are not necessarily involved in the natriuretic response to modest saline loading. This result is in line with data from conscious rodents. PMID- 22433080 TI - Impact of short-term dietary modification on postprandial oxidative stress. AB - BACKGROUND: We have recently reported that short-term (21-day) dietary modification in accordance with a stringent vegan diet (i.e., a Daniel Fast) lowers blood lipids as well as biomarkers of oxidative stress. However, this work only involved measurements obtained in a fasted state. In the present study, we determined the postprandial response to a high-fat milkshake with regards to blood triglycerides (TAG), biomarkers of oxidative stress, and hemodynamic variables before and following a 21-day Daniel Fast. METHODS: Twenty-two subjects (10 men and 12 women; aged 35 +/- 3 years) completed a 21-day Daniel Fast. To induce oxidative stress, a milkshake (fat = 0.8 g.kg-1; carbohydrate = 1.0 g.kg 1; protein = 0.25 g.kg-1) was consumed by subjects on day one and day 22 in a rested and 12-hour fasted state. Before and at 2 and 4 h after consumption of the milkshake, heart rate (HR) and blood pressure were measured. Blood samples were also collected at these times and analyzed for TAG, malondialdehyde (MDA), hydrogen peroxide (H2O2), advanced oxidation protein products (AOPP), nitrate/nitrite (NOx), and Trolox Equivalent Antioxidant Capacity (TEAC). RESULTS: A time effect was noted for HR (p = 0.006), with values higher at 2 hr post intake of the milkshake as compared to pre intake (p < 0.05). Diastolic blood pressure was lower post fast as compared to pre fast (p = 0.02), and a trend for lower systolic blood pressure was noted (p = 0.07). Time effects were noted for TAG (p = 0.001), MDA (p < 0.0001), H2O2 (p < 0.0001), AOPP (p < 0.0001), and TEAC (p < 0.0001); all concentrations were higher at 2 h and 4 h post intake compared to pre intake, except for TEAC, which was lower at these times (p < 0.05). A condition effect was noted for NOx (p = 0.02), which was higher post fast as compared to pre fast. No pre/post fast * time interactions were noted (p > 0.05), with the area under the curve from pre to post fast reduced only slightly for TAG (11%), MDA (11%), H2O2 (8%), and AOPP (12%), with a 37% increase noted for NOx. CONCLUSION: Partaking in a 21-day Daniel Fast does not result in a statistically significant reduction in postprandial oxidative stress. It is possible that a longer time course of adherence to the Daniel Fast eating plan may be needed to observe significant findings. PMID- 22433081 TI - Pharmacogenomics and personalized medicine: wicked problems, ragged edges and ethical precipices. AB - In the age of genomic medicine we can often now do the genetic testing that will permit more accurate personal tailoring of medications to obtain the best therapeutic results. This is certainly a medically and morally desirable result. However, in other areas of medicine pharmacogenomics is generating consequences that are much less ethically benign and much less amenable to a satisfactory ethical resolution. More specifically, we will often find ourselves left with 'wicked problems,' 'ragged edges,' and well-disguised ethical precipices. This will be especially true with regard to these extraordinarily expensive cancer drugs that generally yield only extra weeks or extra months of life. Our key ethical question is this: Does every individual faced with cancer have a just claim to receive treatment with one of more of these targeted cancer therapies at social expense? If any of these drugs literally made the difference between an unlimited life expectancy (a cure) and a premature death, that would be a powerful moral consideration in favor of saying that such individuals had a strong just claim to that drug. However, what we are beginning to discover is that different individuals with different genotypes respond more or less positively to these targeted drugs with some in a cohort gaining a couple extra years of life while others gain only extra weeks or months. Should only the strongest responders have a just claim to these drugs at social expense when there is no bright line that separates strong responders from modest responders from marginal responders? This is the key ethical issue we address. We argue that no ethical theory yields a satisfactory answer to this question, that we need instead fair and respectful processes of rational democratic deliberation. PMID- 22433083 TI - Solid-phase N-terminus PEGylation of recombinant human fibroblast growth factor 2 on heparin-sepharose column. AB - Recombinant fibroblast growth factor-2 (FGF-2) has been extensively studied and used in several clinical applications including wound healing, bone regeneration, and neuroprotection. Poly(ethylene glycol) (PEG) modification of recombinant human FGF-2 (rhFGF-2) in solution phase has been studied to increase the in vivo biostabilities and therapeutic potency. However, the solution-phase strategy is not site-controlled and the products are often not homogeneous due to the generation of multi-PEGylated proteins. In order to increase mono-PEGylated rhFGF 2 level, a novel solid-phase strategy for rhFGF-2 PEGylation is developed. RhFGF 2 proteins were loaded onto a heparin-sepharose column and the PEGylaton reaction was carried out at the N-terminus by PEG20 kDa butyraldehyde through reductive alkylation. The PEGylated rhFGF-2 was purified to near homogeneity by SP sepharose anion-exchange chromatography and the purity was more than 95% with a yield of mono-PEGylated rhFGF-2 of 58.3%, as confirmed by N-terminal sequencing and MALDI-TOF mass spectrometry. In vitro biophysical and biochemical measurements demonstrated that PEGylated rhFGF-2 has an unchanged secondary structure, receptor binding activity, cell proliferation, and MAP kinase stimulating activity, and an improved bio- and thermal stability. Animal assay showed that PEGylated rhFGF-2 has an increased half-life and reduced immunogenicity. Compared to conventional solution-phase PEGylation, the solid phase PEGylation is advantageous in reaction time, production of mono-PEGylated protein, and improvement of biochemical and biological activity. PMID- 22433082 TI - Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain. AB - Genome-wide association studies have nominated many genetic variants for common human traits, including diseases, but in many cases the underlying biological reason for a trait association is unknown. Subsets of genetic polymorphisms show a statistical association with transcript expression levels, and have therefore been nominated as expression quantitative trait loci (eQTL). However, many tissue and cell types have specific gene expression patterns and so it is not clear how frequently eQTLs found in one tissue type will be replicated in others. In the present study we used two appropriately powered sample series to examine the genetic control of gene expression in blood and brain. We find that while many eQTLs associated with human traits are shared between these two tissues, there are also examples where blood and brain differ, either by restricted gene expression patterns in one tissue or because of differences in how genetic variants are associated with transcript levels. These observations suggest that design of eQTL mapping experiments should consider tissue of interest for the disease or other traits studied. PMID- 22433085 TI - Investing in success versus paying for failure: Maryland oral health case history. PMID- 22433086 TI - Commentary on "breaking the cycle in Maryland: oral health policy change in the face of tragedy". PMID- 22433087 TI - Commentary on "breaking the cycle in Maryland: oral health policy change in the face of tragedy". PMID- 22433088 TI - Oral health trends in Maryland. AB - OBJECTIVES: This paper describes the trends in oral health in Maryland over the past decade. METHODS: Data were compiled from several surveillance systems and then summarized to assess the trends in oral health in Maryland over the past ten years. RESULTS: The percentage of Maryland children with dental sealants increased from 33.8 to 42.8 percent; the percentage of children that have had a dental visit increased from 18.9 to 47.5 percent; and the percentage of children that received "dental treatment" increased from 8.4 to 22.4 percent. CONCLUSIONS: Maryland has made considerable progress in improving the oral health care for children covered by Medicaid. The availability of affordable oral health care for new mothers, adults, and elderly persons is a problem that goes beyond the Maryland boundaries. Following national trends, edentulism and deaths due to oral cancer have declined. PMID- 22433089 TI - Reaction to "oral epidemiological trends in Maryland". PMID- 22433090 TI - Good oral health and a system that supports it have never been more important. PMID- 22433091 TI - Oral health literacy: a pathway to reducing oral health disparities in Maryland. AB - Oral health literacy is a relatively new but critical concept in our efforts to decrease disparities and increase oral health for all Marylanders. Oral health literacy is important because low health literacy contributes to disease which results in increased costs for all of us. Those with low health literacy are usually at highest risk for oral diseases and problems. These individuals include the poor, those with low levels of education, minorities, and the elderly. Prompted by the untimely demise of Deamonte Driver, Maryland has taken the lead in developing a statewide approach to improving oral health literacy with the ultimate objective of reducing disparities. PMID- 22433093 TI - Oral health literacy: correcting the mismatch. PMID- 22433094 TI - Commentary on "oral health literacy: a pathway to reducing oral health disparities in Maryland". PMID- 22433095 TI - Outcomes of oral cancer early detection and prevention statewide model in Maryland. AB - A high oral cancer mortality rate and a moderately high oral cancer incidence rate prompted Maryland to develop a statewide approach to oral cancer early detection and prevention. This approach can serve as a model for other states. Key lessons learned include the need to: develop a comprehensive plan that focuses on actions to increase awareness, education and training for the public, dental and non-dental providers and policy makers; include oral cancer in the state's comprehensive cancer control plan to keep attention focused on this disease; and maintain high vigilance among stakeholders to keep oral cancer prevention and early detection a high priority within the state. Future efforts will focus on: requiring all dental and dental hygiene students to perform a set number of supervised oral cancer examinations for licensure to ensure a dental workforce that is competent and predisposed to providing routine oral cancer examinations; training health care providers such as doctors, nurse practitioners, and physician assistants to perform oral cancer examinations as part of a comprehensive cancer screening exam to expand the number of individuals that receive oral cancer examinations; and continuing to educate the public about oral cancer risk factors, its symptoms, and ways to prevent it. PMID- 22433096 TI - Steps to further reduce oral cancer burden for Marylanders. PMID- 22433097 TI - Commentary on "outcomes of oral cancer early detection and prevention statewide model in Maryland". PMID- 22433098 TI - State oral health infrastructure and capacity: lessons learned from other states. AB - This paper discusses some preliminary findings from the Infrastructure Enhancement Project conducted by the Association of State and Territorial Dental Directors (ASTDD), which focuses on state oral health programs and their roles in addressing core public health functions and essential public health services. Findings from analysis of state data since 2000, surveys, reports, and key informant interviews substantiate the value of the following: a) state oral health surveillance; b) oral health improvement plans; c) collaborations and coalitions; d) evidence-based practices and evaluation; e) diversified funding; f) placement and authority of the programs and directors; and g) competencies versus staffing formulas. No single program model fits all the unique populations and political and economic variations among states. Each state is encouraged to use the many tools, resources, and best practices/lessons learned available through ASTDD, federal agencies, and national organizations to design effective and sustainable programs. PMID- 22433099 TI - The three-legged stool of success for states. PMID- 22433100 TI - Doing more with less: the challenge facing state oral health efforts. PMID- 22433101 TI - Potential to improve oral health care through evidence, protocols, and payment models. AB - Evidence-based health care aims to utilize the best available evidence from scientific methods and apply this evidence to clinical and public health practice. Evidence of the benefits and risks of treatment is derived from randomized controlled clinical trials, systematic reviews, and expert panels. Evidence-based clinical parameters and guidelines should foster the best health outcomes for individuals or populations at reduced costs. By incorporating evidence-based guidelines into payment models, the payers - private or public - have the capacity to improve oral health care and ultimately oral health outcomes. This paper uses examples from pediatric dentistry to show how adoption of caries risk factors, clinical management protocols, and a reimbursement system based on evidence-based guidelines may allow for better quality of care to more individuals and at a lower cost. PMID- 22433102 TI - Fulfilling the legacy of a 12-year-old boy. PMID- 22433103 TI - Commentary on "potential to improve oral health care through evidence, protocols, and payment models". PMID- 22433104 TI - Commentary on "potential to improve oral health care through evidence, protocols, and payment models". PMID- 22433105 TI - Federal supports for state oral health plans. AB - The past decade has witnessed both a proliferation of state oral health plans that include very specific proposals for action and an emergence of federal laws that include support for oral health. This paper provides an overview of state oral health priorities for action as reflected in 40 oral health plans that were developed independently by states. It examines four federal laws - the 2002 Safety Net Improvement Act, the 2009 CHIP Reauthorization Act, the 2009 economic stimulus law, and the 2010 health reform law - to identify opportunities for alignment with action steps proposed in state plans. This analysis identifies 23 categories of activity proposed by states in their action plans and determines that all but six of these activities are now supported by one or more of these four federal laws. State activities undertaken through grants provided under the 2002 Safety Net Improvement Act are analyzed as an example of how states can leverage federal legislation to advance their oral health plans. The paper concludes with consideration of the steps needed for states to promote their oral health plans by leveraging the full capacity of federal legislation. PMID- 22433106 TI - Oral health advocacy - state-based and federal priorities. PMID- 22433107 TI - Federal support for oral health care: the long view. PMID- 22433108 TI - The Maryland oral health summit: pathways to common ground and action. PMID- 22433109 TI - Enlightened self-interest and public/private partnerships. PMID- 22433110 TI - Breaking the cycle in Maryland: oral health policy change in the face of tragedy. AB - In response to the death of a young child, efforts by many partners have enabled Maryland to institute oral health reforms that ensure that low-income children remain visible and have continued access to dental services. This paper shows how proponents of oral health in Maryland used issues that were already on the oral health policy agenda to break the cycle of nonaction and become a role model for other states. Deriving from the knowledge and advice of an advisory committee, Maryland administrators and state and federal legislators, with the support of many community partners, took appropriate action to elevate the oral health agenda. Maryland continues to address oral health issues, ensuring that the policy agenda is inclusive of all its citizens. PMID- 22433111 TI - Psychometric analysis of the new ADHD DSM-V derived symptoms. AB - BACKGROUND: Following the agreements on the reformulating and revising of ADHD diagnostic criteria, recently, the proposed revision for ADHD added 4 new symptoms to the hyperactivity and Impulsivity aspect in DSM-V. This study investigates the psychometric properties of the proposed ADHD diagnostic criteria. METHOD: ADHD diagnosis was made according to DSM-IV. The parents completed the screening test of ADHD checklist of Child Symptom Inventory-4 and the 4 items describing the new proposed symptoms in DSM-V. RESULTS: The confirmatory factor analysis of the ADHD DSM-V derived items supports the loading of two factors including inattentiveness and hyperactivity/impulsivity. There is a sufficient reliability for the items. However, confirmatory factor analysis showed that the three-factor model is better fitted than the two-factor one. Moreover, the results of the exploratory analysis raised some concerns about the factor loading of the four new items. CONCLUSIONS: The current results support the two-factor model of the DSM-V ADHD diagnostic criteria including inattentiveness and hyperactivity/impulsivity. However, the four new items can be considered as a third factor. PMID- 22433112 TI - Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation. AB - PURPOSE: Angiotensin (1-7) [A(1-7)] is a component of the renin angiotensin system (RAS) that stimulates hematopoietic recovery after myelosuppression. In a Phase I/IIa clinical trial, thrombocytopenia after chemotherapy was reduced by A(1-7). In this study, the ability of A(1-7) to improve recovery after total body irradiation (TBI) is shown with specific attention to radiation-induced hematopoietic injury. MATERIALS AND METHODS: Mice were exposed to TBI (doses of 2 7 Gray [Gy]) of cesium 137 gamma rays, followed by treatment with A(1-7), typical doses were 100-1000 MUg/kg given once or once daily for a specified number of days depending on the study. Animals are injected subcutaneously via the nape of the neck with 0.1 ml drug in saline. The recovery of blood and bone marrow cells was determined. Effects of TBI and A(1-7) on survival and bleeding time was also evaluated. RESULTS: Daily administration of A(1-7) after radiation exposure improved survival (from 60% to 92-97%) and reduced bleeding time at day 30 after TBI. Further, A(1-7) increased early mixed progenitors (3- to 5-fold), megakaryocyte (2- to 3-fold), myeloid (3- to 6-fold) and erythroid (2- to 5-fold) progenitors in the bone marrow and reduced radiation-induced thrombocytopenia (RIT) (up to 2-fold). Reduction in the number of treatments to 3 per week also improved bone marrow recovery and reduced RIT. As emergency responder and healthcare systems in case of nuclear accident or/and terrorist attack may be overwhelmed, the consequence of delayed initiation of treatment was ascertained. Treatment with A(1-7) can be delayed up to 5 days and still be effective in the reduction of RIT or acceleration of bone marrow recovery. CONCLUSIONS: The data presented in this paper indicate that A(1-7) reduces the consequences of critical radiation exposure and can be initiated well after initial exposure with maximal effects on early responding hematopoietic progenitors when treatment is initiated 2 days after exposure and 5 days after exposure for the later responding progenitors and reduced thrombocytopenia. There was some effect of A(1-7) even when given days after radiation exposure. PMID- 22433113 TI - Extracorporeal shockwave therapy in musculoskeletal disorders. AB - The sources of shockwave generation include electrohydraulic, electromagnetic and piezoelectric principles. Electrohydraulic shockwaves are high-energy acoustic waves generated under water explosion with high voltage electrode. Shockwave in urology (lithotripsy) is primarily used to disintegrate urolithiasis, whereas shockwave in orthopedics (orthotripsy) is not used to disintegrate tissues, rather to induce tissue repair and regeneration. The application of extracorporeal shockwave therapy (ESWT) in musculoskeletal disorders has been around for more than a decade and is primarily used in the treatment of sports related over-use tendinopathies such as proximal plantar fasciitis of the heel, lateral epicondylitis of the elbow, calcific or non-calcific tendonitis of the shoulder and patellar tendinopathy etc. The success rate ranged from 65% to 91%, and the complications were low and negligible. ESWT is also utilized in the treatment of non-union of long bone fracture, avascular necrosis of femoral head, chronic diabetic and non-diabetic ulcers and ischemic heart disease. The vast majority of the published papers showed positive and beneficial effects. FDA (USA) first approved ESWT for the treatment of proximal plantar fasciitis in 2000 and lateral epicondylitis in 2002. ESWT is a novel non-invasive therapeutic modality without surgery or surgical risks, and the clinical application of ESWT steadily increases over the years. This article reviews the current status of ESWT in musculoskeletal disorders. PMID- 22433114 TI - Long term impact of large scale community-directed delivery of doxycycline for the treatment of onchocerciasis. AB - BACKGROUND: Anti-Wolbachia treatment with doxycycline is effective in sterilising and killing adult Onchocerca volvulus nematodes, proving superior to ivermectin and of great potential as an alternative approach for the treatment and control of onchocerciasis, particularly in areas of Loa loa co-endemicity. Nevertheless, the length of the required treatment poses potential logistical problems and risk of poor compliance, raising a barrier to the use of doxycycline in Mass Drug Administration (MDA) strategies. In 2007 and 2008 a feasibility trial of community-directed treatment with doxycycline was carried out in two health districts in Cameroon, co-endemic for O. volvulus and L. loa. With 17,519 eligible subjects, the therapeutic coverage was 73.8% with 97.5% compliance, encouraging the feasibility of using doxycycline community-directed delivery in restricted populations of this size. The current study evaluated the effectiveness of this community-directed delivery of doxycycline four years after delivery. FINDINGS: Infection with O. volvulus was evaluated by skin biopsy and nodule palpation. Of the 507 subjects recruited, 375 had completed the treatment with doxycycline followed by one or two rounds of annual ivermectin MDA and 132 received one or two rounds of annual ivermectin MDA alone. Statistically significant lower microfilarial prevalence (17.0% [doxycycline plus ivermectin group], 27.0% [ivermectin only group], p = 0.014) and load (p = 0.012) were found in people that had received doxycycline followed by ivermectin compared to those who received ivermectin only. CONCLUSIONS: This study demonstrates the long-term effectiveness of doxycycline treatment delivered with a community-directed strategy even when evaluated four years after delivery in an area of ongoing transmission. This finding shows that a multi-week course of treatment is not a barrier to community-delivery of MDA in restricted populations of this size and supports its implementation to compliment existing control strategies for onchocerciasis, where needed. PMID- 22433115 TI - Chikungunya virus impacts the diversity of symbiotic bacteria in mosquito vector. AB - Mosquitoes transmit numerous arboviruses including dengue and chikungunya virus (CHIKV). In recent years, mosquito species Aedes albopictus has expanded in the Indian Ocean region and was the principal vector of chikungunya outbreaks in La Reunion and neighbouring islands in 2005 and 2006. Vector-associated bacteria have recently been found to interact with transmitted pathogens. For instance, Wolbachia modulates the replication of viruses or parasites. However, there has been no systematic evaluation of the diversity of the entire bacterial populations within mosquito individuals particularly in relation to virus invasion. Here, we investigated the effect of CHIKV infection on the whole bacterial community of Ae. albopictus. Taxonomic microarrays and quantitative PCR showed that members of Alpha- and Gammaproteobacteria phyla, as well as Bacteroidetes, responded to CHIKV infection. The abundance of bacteria from the Enterobacteriaceae family increased with CHIKV infection, whereas the abundance of known insect endosymbionts like Wolbachia and Blattabacterium decreased. Our results clearly link the pathogen propagation with changes in the dynamics of the bacterial community, suggesting that cooperation or competition occurs within the host, which may in turn affect the mosquito traits like vector competence. PMID- 22433117 TI - Liquid exfoliation of defect-free graphene. AB - Due to its unprecedented physical properties, graphene has generated huge interest over the last 7 years. Graphene is generally fabricated in one of two ways: as very high quality sheets produced in limited quantities by micromechanical cleavage or vapor growth or as a rather defective, graphene-like material, graphene oxide, produced in large quantities. However, a growing number of applications would profit from the availability of a method to produce high quality graphene in large quantities. This Account describes recent work to develop such a processing route inspired by previous theoretical and experimental studies on the solvent dispersion of carbon nanotubes. That work had shown that nanotubes could be effectively dispersed in solvents whose surface energy matched that of the nanotubes. We describe the application of the same approach to the exfoliation of graphite to give graphene in a range of solvents. When graphite powder is exposed to ultrasonication in the presence of a suitable solvent, the powder fragments into nanosheets, which are stabilized against aggregation by the solvent. The enthalpy of mixing is minimized for solvents with surface energies close to that of graphene (~68 mJ/m(2)). The exfoliated nanosheets are free of defects and oxides and can be produced in large quantities. Once solvent exfoliation is possible, the process can be optimized and the nanosheets can be separated by size. The use of surfactants can also stabilize exfoliated graphene in water, where the zeta potential of the surfactant-coated graphene nanosheets controls the dispersed concentration. Liquid exfoliated graphene can be used for a range of applications: graphene dispersions as optical limiters, films of graphene flakes as transparent conductors or sensors, and exfoliated graphene as a mechanical reinforcement for polymer-based composites. Finally, we have extended this process to exfoliate other layered compounds such as BN and MoS(2). Such materials will be important in a range of applications from thermoelectrics to battery electrodes. This liquid exfoliation technique can be applied to a wide range of materials and has the potential to be scaled up into an industrial process. We believe the coming decade will see an explosion in the applications involving liquid exfoliated two-dimensional materials. PMID- 22433118 TI - Standing orders for influenza and pneumococcal polysaccharide vaccination: correlates identified in a national survey of U.S. Primary care physicians. AB - BACKGROUND: Standing orders programs (SOPs) allow non-physician medical staff to assess eligibility and administer vaccines without a specific physician's order. SOPs increase vaccination rates but are underutilized. METHOD: In 2009, correlates of SOPs use for influenza vaccine and pneumococcal polysaccharide vaccination (PPV) were assessed in a nationally representative, stratified random sample of U.S. physicians (n = 880) in family and internal medicine who provided office immunization. The response rate was 67%. Physicians reporting no SOPs, only influenza SOPs, and joint influenza and PPV SOPs were compared using multinomial and logistic regression models to examine individual and practice level correlates. RESULTS: 23% reported using SOPs consistently for both influenza vaccine and PPV, and 20% for influenza vaccination only, with the remainder not using SOPs. Practice-level factors that distinguished practices with joint influenza-PPV SOPs included perceived practice openness to change, strong practice teamwork, access to an electronic medical record, presence of an immunization champion in the practice, and access to nurse/physician assistant staff as opposed to medical assistants alone. DISCUSSION: Physicians in practices with SOPs for both vaccines reported greater awareness of ACIP recommendations and/or Medicare regulations and were more likely to agree that SOPs are an effective way to boost vaccination coverage. However, implementation of both influenza and PPV SOPs was also associated with a variety of practice-level factors, including teamwork, the presence of an immunization champion, and greater availability of clinical assistants with advanced training. CONCLUSIONS: Practice-level factors are critical for the adoption of more complex SOPs, such as joint SOPs for influenza and PPV. PMID- 22433119 TI - Occupation and three-year incidence of respiratory symptoms and lung function decline: the ARIC Study. AB - BACKGROUND: Specific occupations are associated with adverse respiratory health. Inhalation exposures encountered in these jobs may place workers at risk of new onset respiratory disease. METHODS: We analyzed data from 8,967 participants from the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal cohort study. Participants included in this analysis were free of chronic cough and phlegm, wheezing, asthma, chronic bronchitis, emphysema, and other chronic lung conditions at the baseline examination, when they were aged 45-64 years. Using data collected in the baseline and first follow-up examination, we evaluated associations between occupation and the three-year incidence of cough, phlegm, wheezing, and airway obstruction and changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured by spirometry. All associations were adjusted for age, cigarettes per day, race, smoking status, and study center. RESULTS: During the approximately three-year follow-up, the percentage of participants developing chronic cough was 3%; chronic phlegm, 3%; wheezing, 3%; and airway obstruction, defined as FEV1 < lower limit of normal (LLN) and FEV1/FVC < LLN, 2%. The average annual declines in FEV1 and FVC were 56 mL and 66 mL, respectively, among men and 40 mL and 52 mL, respectively, among women. Relative to a referent category of managerial and administrative support occupations, elevated risks of new-onset chronic cough and chronic phlegm were observed for mechanics and repairers (chronic cough: RR: 1.81, 95% CI: 1.02, 3.21; chronic phlegm: RR: 2.10, 95% CI: 1.23, 3.57) and cleaning and building service workers (chronic cough: RR: 1.85, 95% CI: 1.01, 3.37; chronic phlegm: RR: 2.28, 95% CI: 1.27, 4.08). Despite the elevated risk of new-onset symptoms, employment in cleaning and building services was associated with attenuated lung function decline, particularly among men, who averaged annual declines in FEV1 and FVC of 14 mL and 23 mL, respectively, less than the declines observed in the referent population. CONCLUSIONS: Employment in mechanic and repair jobs and cleaning and building service occupations are associated with increased incidence of respiratory symptoms. Specific occupations affect the respiratory health of adults without pre-existing respiratory health symptoms and conditions, though long-term health consequences of inhalation exposures in these jobs remain largely unexplored. PMID- 22433120 TI - Forecasting phenology: from species variability to community patterns. AB - Shifts in species' phenology in response to climate change have wide-ranging consequences for ecological systems. However, significant variability in species' responses, together with limited data, frustrates efforts to forecast the consequences of ongoing phenological changes. Herein, we use a case study of three North American plant communities to explore the implications of variability across levels of organisation (within and among species, and among communities) for forecasting responses to climate change. We show how despite significant variation among species in sensitivities to climate, comparable patterns emerge at the community level once regional climate drivers are accounted for. However, communities differ with respect to projected patterns of divergence and overlap among their species' phenological distributions in response to climate change. These analyses and a review of hypotheses suggest how explicit consideration of spatial scale and levels of biological organisation may help to understand and forecast phenological responses to climate change. PMID- 22433121 TI - Characterization of inhalation exposure to jet fuel among U.S. Air Force personnel. AB - BACKGROUND: Jet propulsion fuel-8 (JP-8) is the primary jet fuel used by the US military, collectively consuming ~2.5 billion gallons annually. Previous reports suggest that JP-8 is potentially toxic to the immune, respiratory, and nervous systems. The objectives of this study were to evaluate inhalation exposure to JP 8 constituents among active duty United States Air Force (USAF) personnel while performing job-related tasks, identify significant predictors of inhalation exposure to JP-8, and evaluate the extent to which surrogate exposure classifications were predictive of measured JP-8 exposures. METHODS: Seventy three full-time USAF personnel from three different air force bases were monitored during four consecutive workdays where personal air samples were collected and analyzed for benzene, ethylbenzene, toluene, xylenes, total hydrocarbons (THC), and naphthalene. The participants were categorized a priori into high- and low-exposure groups, based on their exposure to JP-8 during their typical workday. Additional JP-8 exposure categories included job title groups and self-reported exposure to JP-8. Linear mixed-effects models were used to evaluate predictors of personal air concentrations. RESULTS: The concentrations of THC in air were significantly different between a priori exposure groups (2.6 mg m(-3) in high group versus 0.5 mg m(-3) in low, P < 0.0001), with similar differences observed for other analytes in air. Naphthalene was strongly correlated with THC (r = 0.82, P < 0.0001) and both were positively correlated with the relative humidity of the work environment. Exposures to THC and naphthalene varied significantly by job categories based on USAF specialty codes and were highest among personnel working in fuel distribution/maintenance, though self-reported exposure to JP-8 was an even stronger predictor of measured exposure in models that explained 72% (THC) and 67% (naphthalene) of between worker variability. In fact, both self-report JP-8 exposure and a priori exposure groups explained more between-worker variability than job categories. CONCLUSIONS: Personal exposure to JP-8 varied by job and was positively associated with the relative humidity. However, self-reported exposure to JP-8 was an even stronger predictor of measured exposure than job title categories, suggesting that self-reported JP-8 exposure is a valid surrogate metric of exposure when personal air measurements are not available. PMID- 22433124 TI - High prevalence of major neurological disorders in two Albanian communities: results of a door-to-door survey. AB - BACKGROUND: There are few epidemiological studies on neurological disorders in Albania. METHODS: A door-to-door survey was undertaken in two geographical areas (Tirana and Saranda) with different socioeconomic backgrounds. Two random samples of the local population underwent a structured interview to ascertain headache, epilepsy, dementia, parkinsonism, multiple sclerosis, polyneuropathy, stroke and cerebral palsy. Each diagnosis was made using standard criteria for epidemiological studies and was confirmed by history, neurological examination and, where available, the review of personal medical records. Lifetime prevalence ratios with 95% confidence intervals were calculated. RESULTS: Of the 9,869 individuals screened (Tirana 4,953; Saranda 4,916), 4,867 were males aged 1-91 years (median 39 years) and 5,002 were females aged 1-96 years (median 37 years). Crude prevalence ratios (per 1,000) were: headache 241.9 (233.5-250.3), polyneuropathy 32.5 (29.0-36.0), epilepsy 14.2 (11.7-16.3), stroke 12.4 (10.2 14.6), dementia 9.6 (7.7-11.5), parkinsonism 8.0 (6.2-9.8), cerebral palsy 4.8 (3.4-6.2), and multiple sclerosis 0.3 (0.0-0.6). Prevalence varied with age and gender, with differences across diseases. Except for polyneuropathy (Tirana 39.8; Saranda 25.2), ratios were not different in the two study areas. CONCLUSIONS: The prevalence of selected neurological disorders in Albania is higher than in other countries. Differences may be explained by study design, population structure and/or genetic and environmental factors. PMID- 22433125 TI - Sagittal plane articulation of the contralateral knee of subjects with posterior cruciate ligament deficiency: an observational study. AB - BACKGROUND: The aim of the present study was to compare the in vivo articulation of the healthy knee to the contralateral knee of subjects with acute and chronic PCL injuries. METHODS: Magnetic resonance was used to generate sagittal images of 10 healthy knees and 10 knees with isolated PCL injuries (5 acute and 5 chronic). The subjects performed a supine leg press against a 150 N load. Images were generated at 15 degree intervals as the knee flexed from 0 to 90 degrees. The tibiofemoral contact (TFC), and the centre of the femoral condyle (as defined by the flexion facet centre (FFC)), were measured from the posterior tibial cortex. RESULTS: There was no significant difference in the TFC and FFC between the healthy knee and contralateral knee of subjects with acute and chronic PCL injuries in the medial and lateral compartments of the knee. CONCLUSIONS: The findings of this study suggest there is no predisposing articulation abnormality to PCL injury, in the setting of chronic injury the contralateral knee does not modify its articulation profile and the contralateral knee can be used as a valid control when evaluating the articulation of the PCL deficient knee. PMID- 22433123 TI - Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation. AB - Steroid hormones are synthesized from cholesterol primarily in the adrenal gland and the gonads and play vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligand-activated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNA response element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, having more or less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action. PMID- 22433126 TI - Large-scale spatial population databases in infectious disease research. AB - Modelling studies on the spatial distribution and spread of infectious diseases are becoming increasingly detailed and sophisticated, with global risk mapping and epidemic modelling studies now popular. Yet, in deriving populations at risk of disease estimates, these spatial models must rely on existing global and regional datasets on population distribution, which are often based on outdated and coarse resolution data. Moreover, a variety of different methods have been used to model population distribution at large spatial scales. In this review we describe the main global gridded population datasets that are freely available for health researchers and compare their construction methods, and highlight the uncertainties inherent in these population datasets. We review their application in past studies on disease risk and dynamics, and discuss how the choice of dataset can affect results. Moreover, we highlight how the lack of contemporary, detailed and reliable data on human population distribution in low income countries is proving a barrier to obtaining accurate large-scale estimates of population at risk and constructing reliable models of disease spread, and suggest research directions required to further reduce these barriers. PMID- 22433127 TI - Effect of combination therapy with the angiotensin receptor blocker losartan plus hydrochlorothiazide on brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease: a SPECT study. AB - BACKGROUND: While the combination of an angiotensin receptor blocker with thiazide diuretics produces a clinically beneficial reduction in blood pressure in patients who otherwise only partially respond to monotherapy with an angiotensin receptor blocker, blood pressure-lowering therapy with combination antihypertensive drug regimens in patients with cerebral hemodynamic impairment may adversely affect cerebral hemodynamics. The purpose of the present exploratory study was to determine whether blood pressure-lowering therapy with the combination of the angiotensin receptor blocker losartan plus hydrochlorothiazide (LPH) worsens brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease. METHODS: Patients with losartan resistant hypertension and reduced cerebrovascular reactivity (CVR) to acetazolamide due to symptomatic chronic internal carotid artery (ICA) or middle cerebral artery (MCA) steno-occlusive disease were prospectively entered into the present study and received 50 mg/day of losartan plus 12.5 mg/day of hydrochlorothiazideat 14 weeks after the last ischemic event. Cerebral blood flow (CBF) and CVR were measured before and 12 weeks after initiating LPH using N isopropyl-p-[(123)I]-iodoamphetamine single-photon emission computed tomography (SPECT). A region of interest (ROI) was automatically placed in the MCA territory on each SPECT image using a three-dimensional stereotactic ROI template. RESULTS: None of the 18 patients who participated in the study experienced any new neurological symptoms or adverse effects related to antihypertensive drugs. Systolic (p < 0.001) and diastolic (p < 0.001) blood pressures were significantly reduced after the administration of LPH, with average reductions of 11 mm Hg in systolic blood pressure and 10 mm Hg in diastolic blood pressure. While in the affected hemisphere CBF did not differ between measurements taken before and after the administration of LPH, CVR was significantly higher after the administration of LPH than before (p = 0.007) and was significantly improved in 5 of 18 patients. In the contralateral hemisphere, CBF and CVR did not differ between measurements taken before and after the administration of LPH. There were no patients who experienced a significant deterioration in CBF or CVR in the affected or contralateral hemisphere after the administration of LPH. CONCLUSIONS: Although the present study was exploratory and its results were preliminary due to the small sample size, the current data suggest that blood pressure-lowering therapy with LPH apparently does not result in worsening of cerebral hemodynamics in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic ICA or MCA steno-occlusive disease. PMID- 22433128 TI - Spatial repellency of transfluthrin-treated hessian strips against laboratory reared Anopheles arabiensis mosquitoes in a semi-field tunnel cage. AB - BACKGROUND: Vapour phase spatial repellents deter mosquitoes from attacking one or more humans in a protected space. Simulation models indicate that high coverage of spatial repellents can enhance the impact of long - lasting insecticide nets (LLINs) and indoor residual spraying (IRS) where mosquito vectors commonly bite humans outdoors. Here we report a preliminary evaluation of an effective, user-friendly prototype product for delivering spatial repellents to protect against malaria vector mosquitoes. FINDINGS: Protective efficacy of a 4.0 * 0.3 m strip of hessian sacking treated with 10 ml of transfluthrin was evaluated in a 60 m * 2 m * 2.5 m netting tunnel with malaria-free insectary reared Anopheles arabiensis Patton mosquitoes. Personal protection, in terms of proportional reduction of exposure to bites, was measured by comparing human landing catches of volunteers with treated and untreated strips. A freshly treated hessian strip reduced mosquito attack rate on human volunteers by > 99% and consistently conferred > 90% protective efficacy for a period of 6 months. Over the entire study period, only 22 out of 1400 released mosquitoes bit volunteers using the treated sacking strip while 894 out of 1400 mosquitoes released into cages containing volunteers using an untreated strip fed upon them. CONCLUSION: Locally available natural fibers may be promising absorbent substrates for delivering spatial repellents, such as transfluthrin, to protect against mosquitoes in tropical settings. However, these observations relate to a single prototype specimen of this particular device, therefore, much more detailed, well replicated studies are essential to establish long-term efficacy, effectiveness, practicability and affordability. PMID- 22433129 TI - Embolic protection devices during TAVI - the "proof of the pudding". PMID- 22433134 TI - Extra-oesophageal reflux: state of the knowledge base. PMID- 22433122 TI - Hormone replacement therapy and physical function in healthy older men. Time to talk hormones? AB - Improving physical function and mobility in a continuously expanding elderly population emerges as a high priority of medicine today. Muscle mass, strength/power, and maximal exercise capacity are major determinants of physical function, and all decline with aging. This contributes to the incidence of frailty and disability observed in older men. Furthermore, it facilitates the accumulation of body fat and development of insulin resistance. Muscle adaptation to exercise is strongly influenced by anabolic endocrine hormones and local load sensitive autocrine/paracrine growth factors. GH, IGF-I, and testosterone (T) are directly involved in muscle adaptation to exercise because they promote muscle protein synthesis, whereas T and locally expressed IGF-I have been reported to activate muscle stem cells. Although exercise programs improve physical function, in the long-term most older men fail to comply. The GH/IGF-I axis and T levels decline markedly with aging, whereas accumulating evidence supports their indispensable role in maintaining physical function integrity. Several studies have reported that the administration of T improves lean body mass and maximal voluntary strength in healthy older men. On the other hand, most studies have shown that administration of GH alone failed to improve muscle strength despite amelioration of the detrimental somatic changes of aging. Both GH and T are anabolic agents that promote muscle protein synthesis and hypertrophy but work through separate mechanisms, and the combined administration of GH and T, albeit in only a few studies, has resulted in greater efficacy than either hormone alone. Although it is clear that this combined approach is effective, this review concludes that further studies are needed to assess the long-term efficacy and safety of combined hormone replacement therapy in older men before the medical rationale of prescribing hormone replacement therapy for combating the sarcopenia of aging can be established. PMID- 22433135 TI - Validation study of the "Sniffin' Sticks" olfactory test in a British population: a preliminary communication. AB - OBJECTIVE: The 'Sniffin' Sticks' olfactory test contains pen-like odour dispensing devices which are used to assess olfactory threshold, discrimination and identification. Odour identification is strongly dependent on familiarity with the odours and has an important cultural component which has limited the usefulness of other validated tests. The 'Sniffin' Sticks' test was developed in Germany and is validated in other countries but not in the UK. This study aims to validate the applicability of 'Sniffin' Sticks' in a local population. DESIGN: Prospective controlled study. SETTING: Rhinology or olfactory disorder clinic. PARTICIPANTS: About 82 subjects, 33 healthy volunteers with a reported normal sense of smell, and 49 patients with an impaired sense of smell presenting either at a rhinology or an olfactory disorder clinic. Each subject's olfactory function was assessed using the 'Sniffin' Sticks' test with a maximum score of 48. MAIN OUTCOME MEASURES: Threshold, discrimination and identification scores along with the combined olfactory score. RESULTS: The mean age of the subjects tested was 46.7 years; 46 female and 36 male. In the patient group 36 were hyposmic and 13 anosmic. In the healthy volunteers group all subjects were normosmic. In the control group the mean combined olfactory score was 34.5 (+/-2.5). The mean combined score in the patients group was 20.8 (+/-7.4). Odour threshold scores were 3.7(+/-2.8) for patients (hyposmics and anomics) and 8.3(+/-1.8) for controls. In the identification test the controls mean score was 13.6 (+/-1.2) for while the patients' mean score was 8.6 (+/-3.5). CONCLUSIONS: In our sample of the local population the combined olfactory and odour identification scores for healthy volunteers and patients with olfactory disorders are comparable with the normative data published on large samples of European populations. However, modification of a few of the distracters is recommended for British patients based on our findings. PMID- 22433136 TI - What other journals tell us. Laryngeal transplantation: working party final report, June 2011. PMID- 22433137 TI - 'Voicing' considerations in laryngeal transplantation: a commentary of the Royal College of Surgeons working party final report. PMID- 22433138 TI - The influence of medical school and residency training program upon choice of an academic career and academic productivity among otolaryngology faculty in the United States of America: our experience of 1433 academic otolaryngologists. PMID- 22433139 TI - Neuroendocrine carcinoma of the larynx - an extraordinary malignancy with high recurrence rates and long survival: our experience in 11 patients. PMID- 22433140 TI - A new method for the treatment of severe drooling: the four duct diversion: our experience in 8 children. PMID- 22433141 TI - Against the clock: estimating theatre time in ENT: our experience in 1266 patients. PMID- 22433142 TI - Re: The troublesome aural foreign body - a useful technique. PMID- 22433144 TI - Re: Bone-anchored hearing aids for people with bilateral hearing impairment: a systematic review. PMID- 22433145 TI - Re: The importance of an extended preoperative trial of BAHA in unilateral sensorineural hearing loss: a prospective cohort. PMID- 22433148 TI - Re: the diagnosis of infectious mononucleosis. PMID- 22433150 TI - A useful tool - systematic checklist for evaluating sinus scans. PMID- 22433151 TI - Time taken for digital dictation-examining the impact of a new hospital system. PMID- 22433152 TI - Current ENT training within the UK. PMID- 22433153 TI - The modified Merocel((r)) pope ear wick in severe acute otitis externa management. PMID- 22433154 TI - Resource implications of SNOT22 data submission. PMID- 22433155 TI - Recurrence of peritonsillar abscess: a 2-year follow-up. PMID- 22433156 TI - Use of balloon dilatation as an adjunctive treatment for complete nasopharyngeal stenosis: a technical innovation. PMID- 22433157 TI - Sentinel node biopsy using 3D lymphatic mapping by freehand SPECT in early stage oral cancer: a new technique. PMID- 22433158 TI - Trends in advertised NHS otolaryngology consultant posts 2007-2011. PMID- 22433160 TI - Intracerebral hemorrhage in southern Norway--a hospital-based incidence study. AB - BACKGROUND/AIMS: Newer Scandinavian data on intracerebral hemorrhage (ICH) are scarce. We aimed at providing updated community-based data on the incidence, characteristics and outcome of ICH leading to hospitalization in the southernmost region in Norway. METHODS: We analyzed data from all consecutive patients hospitalized with a first-ever ICH in the five-year period 2005-2009 in a well defined area served by one single hospital. Cases were found by computerized search in a register covering all in- and outpatients. RESULTS: Adjusted to the standard European population the annual incidence rate per 100,000 was 16.9 for men, 8.8 for women (p < 0.001) and 12.5 for both sexes. The incidence rates rose continuously with increasing age through all age groups in both sexes. The proportion with warfarin-associated ICH was 26.9%. The overall 30-day case fatality rate was 36.6%. The hematoma location was lobar in 36.6%, deep cerebral in 45.5%, cerebellar in 9.7%, and brain stem in 8.2%. CONCLUSIONS: The incidence of ICH in the southernmost region in Norway is in the midrange in Europe and lower than in previous Scandinavian studies. Men are at higher risk than women. The proportion with warfarin-associated ICH is higher than previously reported from Scandinavia. PMID- 22433161 TI - Analyses from a centre of short- and long-term growth in Turner's syndrome on standard growth hormone doses confirm growth prediction algorithms and show normal IGF-I levels. AB - AIMS AND METHODS: Prediction algorithms suggest factors determining short- and long-term growth response to growth hormone (GH) in Turner's syndrome (TS). A total of 133 patients (group A; 53% with karyotype 45,X) completed 1 year of treatment and 77 patients (group B) reached adult height (AH) after >4 years on GH treatment. The patients were analysed for factors determining the outcomes, and in addition, the validity of published algorithms was tested. RESULTS: In group A [values are given as medians (10th-90th percentiles)], starting age was 9.4 (4.8-14) years, height was -3.2 (-4.4 to -1.9) SDS (Prader references), and GH dose was 38 (23-48) MUg/kg/day. Observed height velocity was 7.7 (5.2-9.8) cm/years and was equal to the predicted height velocity. In group B, projected adult height (PAH) was 147.4 (139.5-154.8) cm. Total gain in height over PAH of 6.1 (2.0-12.6) cm was negatively correlated with height at start, but positively correlated with GH duration, first year Deltaheight SDS, or index of responsiveness. Observed AH was 153.5 (146.6-160.1) cm and predicted AH was 155.0 (147.4-161.0) cm, which is statistically not different. On GH <5% IGF-I levels were >2 SDS. CONCLUSIONS: The published prediction algorithms were found to be valid. If normal AH is to be reached at the lowest costs and risks, probably only TS children with a good growth potential and a high responsiveness to GH can be treated successfully with GH doses of <50 MUg/kg/day. PMID- 22433162 TI - Giant enhancement of upconversion in ultra-small Er3+/Yb3+:NaYF4 nanoparticles via laser annealing. AB - Most of the synthesis routes of lanthanide-doped phosphors involve thermal processing which results in nanocrystallite growth, stabilization of the crystal structure and augmentation of luminescence intensity. It is of great interest to be able to transform the sample in a spatially localized manner, which may lead to many applications like 2D and 3D data storage, anti-counterfeiting protection, novel design bio-sensors and, potentially, to fabrication of metamaterials, 3D photonic crystals or plasmonic devices. Here we demonstrate irreversible spatially confined infrared-laser-induced annealing (LIA) achieved in a thin layer of dried colloidal solution of ultra-small ~8 nm NaYF4 nanocrystals (NCs) co-doped with 2% Er3+ and 20% Yb3+ ions under a localized tightly focused beam from a continuous wave 976 nm medium power laser diode excitation. The LIA results from self-heating due to non-radiative relaxation accompanying the NIR laser energy upconversion in lanthanide ions. We notice that localized LIA appears at optical power densities as low as 15.5 kW cm-2 (~354 +/- 29 mW) threshold in spots of 54 +/- 3 um diameter obtained with a 10 * microscope objective. In the course of detailed studies, a complete recrystallization to different phases and giant 2-3 order enhancement in luminescence yield is found. Our results are highly encouraging and let us conclude that the upconverting ultra-small lanthanide-doped nanophosphors are particularly promising for direct laser writing applications. PMID- 22433163 TI - Fournier's gangrene: etiology and outcome analysis of 41 patients. AB - INTRODUCTION: Fournier's gangrene (FG) is the necrotizing fasciitis of the perineum and genital area with high mortality. MATERIALS AND METHODS: A retrospective review included 41 patients diagnosed with FG in our hospitals from 1995 to 2010, divided into survivors and nonsurvivors. We analyzed anamnestic, clinical and laboratory data. RESULTS: The mortality rate was 36.6% (15/41 patients). Elevated heart and respiratory rates, high serum creatinine, low serum bicarbonate, pre-existing kidney disease, and higher median extent of affected body surface were associated with higher mortality. Severe sepsis on admission and hypotension below 90 mm Hg were also predictive for higher mortality. The median FG severity index (FGSI) score was higher in nonsurvivors (11 compared to 6, p < 0.0001). No cases of testicular necrosis were noted. CONCLUSION: Besides standard clinical and laboratory parameters included in the FGSI calculation, higher extent of affected body surface area and presence of hypotension on admission were also positively associated with mortality. PMID- 22433164 TI - Non-steroidal anti-inflammatory drugs for the treatment of pain and immobility associated osteoarthritis: consensus guidance for primary care. AB - BACKGROUND: Osteoarthritis is a common presentation in primary care, and non selective non-steroidal anti-inflammatory drugs (sometimes also referred to as traditional NSAIDs or tNSAIDs) and selective cyclo-oxygenase 2 inhibitors (COX-2 inhibitors) are commonly used to treat it. The UK's National Institute for Health and Clinical Excellence (NICE) recommends taking patient risk factors into account when selecting a tNSAID or a COX-2 inhibitor, but GPs have lacked practical guidance on assessing patient risk. METHODS: A multi-disciplinary group that included primary care professionals (PCPs) developed an evidence-based consensus statement with an accompanying flowchart that aimed at providing concise and specific guidance on NSAID use in osteoarthritis treatment. An open invitation to meet and discuss the issue was made to relevant healthcare professionals in South Yorkshire. A round table meeting was held that used a modified nominal group technique, aimed at generating opinions and ideas from all stakeholders in the consensus process. A draft developed from this meeting went through successive revisions until a consensus was achieved. RESULTS: Four statements on the use of tNSAIDs and COX-2 inhibitors (and an attached category of evidence) were agreed: 1) tNSAIDs are effective drugs in relieving pain and immobility associated with osteoarthritis. COX-2 inhibitors are equally effective; 2) tNSAIDs and COX-2 inhibitors vary in their potential gastrointestinal, liver, and cardio-renal toxicity. This risk varies between individual treatments within both groups and is increased with dose and duration of treatment; 3) COX-2 inhibitors are associated with a significantly lower gastrointestinal toxicity compared to tNSAIDs. Co-prescribing of aspirin reduces this advantage; 4) PPIs should always be considered with a tNSAID and with a COX 2 inhibitor in higher GI risk patients. An accompanying flowchart to guide management was also agreed. CONCLUSIONS: Individual patient risk is an important factor in choice of treatment for patients with osteoarthritis and the consensus statement developed offers practical guidance for GPs and others in primary care. Where there are clinical uncertainties, guidance developed and agreed by local clinicians has a role to play in improving patient management. PMID- 22433165 TI - Donor lung derived myeloid and plasmacytoid dendritic cells differentially regulate T cell proliferation and cytokine production. AB - BACKGROUND: Direct allorecognition, i.e., donor lung-derived dendritic cells (DCs) stimulating recipient-derived T lymphocytes, is believed to be the key mechanism of lung allograft rejection. Myeloid (cDCs) and plasmacytoid (pDCs) are believed to have differential effects on T cell activation. However, the roles of each DC type on T cell activation and rejection pathology post lung transplantation are unknown. METHODS: Using transgenic mice and antibody depletion techniques, either or both cell types were depleted in lungs of donor BALB/c mice (H-2(d)) prior to transplanting into C57BL/6 mice (H-2(b)), followed by an assessment of rejection pathology, and pDC or cDC-induced proliferation and cytokine production in C57BL/6-derived mediastinal lymph node T cells (CD3+). RESULTS: Depleting either DC type had modest effect on rejection pathology and T cell proliferation. In contrast, T cells from mice that received grafts depleted of both DCs did not proliferate and this was associated with significantly reduced acute rejection scores compared to all other groups. cDCs were potent inducers of IFNgamma, whereas both cDCs and pDCs induced IL-10. Both cell types had variable effects on IL-17A production. CONCLUSION: Collectively, the data show that direct allorecognition by donor lung pDCs and cDCs have differential effects on T cell proliferation and cytokine production. Depletion of both donor lung cDC and pDC could prevent the severity of acute rejection episodes. PMID- 22433166 TI - Cardiovascular inflammation in healthy women: multilevel associations with state level prosperity, productivity and income inequality. AB - BACKGROUND: Cardiovascular inflammation is a key contributor to the development of atherosclerosis and the prediction of cardiovascular events among healthy women. An emerging literature suggests biomarkers of inflammation vary by geography of residence at the state-level, and are associated with individual level socioeconomic status. Associations between cardiovascular inflammation and state-level socioeconomic conditions have not been evaluated. The study objective is to estimate whether there are independent associations between state-level socioeconomic conditions and individual-level biomarkers of inflammation, in excess of individual-level income and clinical covariates among healthy women. METHODS: The authors examined cross-sectional multilevel associations among state level socioeconomic conditions, individual-level income, and biomarkers of inflammation among women (n = 26,029) in the Women's Health Study, a nation-wide cohort of healthy women free of cardiovascular diseases at enrollment. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen were measured between 1993 and 1996. Biomarker levels were examined among women within quartiles of state-level socioeconomic conditions and within categories of individual-level income. RESULTS: The authors found that favorable state-level socioeconomic conditions were correlated with lower hsCRP, in excess of individual-level income (e.g. state-level real per capital gross domestic product fixed effect standardized Betaeta coefficient [Std B] -0.03, 95% CI -0.05, -0.004). Individual-level income was more closely associated with sICAM-1 (Std B -0.04, 95% CI -0.06, -0.03) and fibrinogen (Std B 0.05, 95% CI -0.06, -0.03) than state-level conditions. CONCLUSIONS: We found associations between state-level socioeconomic conditions and hsCRP among healthy women. Personal household income was more closely associated with sICAM-1 and fibrinogen than state-level socioeconomic conditions. Additional research should examine these associations in other cohorts, and investigate what more-advantaged states do differently than less-advantaged states that may influence levels of cardiovascular inflammation among healthy women. PMID- 22433167 TI - New generation "nanohybrid supercapacitor". AB - To meet growing demands for electric automotive and regenerative energy storage applications, researchers all over the world have sought to increase the energy density of electrochemical capacitors. Hybridizing battery-capacitor electrodes can overcome the energy density limitation of the conventional electrochemical capacitors because they employ both the system of a battery-like (redox) and a capacitor-like (double-layer) electrode, producing a larger working voltage and capacitance. However, to balance such asymmetric systems, the rates for the redox portion must be substantially increased to the levels of double-layer process, which presents a significant challenge. An in situ material processing technology called "ultracentrifuging (UC) treatment" has been used to prepare a novel ultrafast Li4Ti5O12 (LTO) nanocrystal electrode for capacitive energy storage. This Account describes an extremely high-performance supercapacitor that utilizes highly optimized "nano-nano-LTO/carbon composites" prepared via the UC treatment. The UC-treated LTO nanocrystals are grown as either nanosheets or nanoparticles, and both have hyperlinks to two types of nanocarbons: carbon nanofibers and supergrowth (single-walled) carbon nanotubes. The spinel structured LTO has been prepared with two types of hyperdispersed carbons. The UC treatment at 75 000G stoichiometrically accelerates the in situ sol-gel reaction (hydrolysis followed by polycondensation) and further forms, anchors, and grafts the nanoscale LTO precursors onto the carbon matrices. The mechanochemical sol-gel reaction is followed by a short heat-treatment process in vacuo. This immediate treatment with heat is very important for achieving optimal crystallization, inhibiting oxidative decomposition of carbon matrices, and suppressing agglomeration. Such nanocrystal composites can store and deliver energy at the highest rate attained to this date. The charge-discharge profiles indicate a very high sustained capacity of 80 mAh g(-1) at an extremely high rate of 1200 C. Using this ultrafast material, we assembled a hybrid device called a "nanohybrid capacitor" that consists of a Faradaic Li-intercalating LTO electrode and a non-Faradaic AC electrode employing an anion (typically BF4(-)) adsorption-desorption process. The "nanohybrid capacitor" cell has demonstrated remarkable energy, power, and cycleability performance as an electrochemical capacitor electrode. It also exhibits the same ion adsorption-desorption process rates as those of standard activated carbon electrodes in electrochemical capacitors. The new-generation "nanohybrid capacitor" technology produced more than triple the energy density of a conventional electrochemical capacitor. Moreover, the synthetic simplicity of the high-performance nanostructures makes it possible to scale them up for large volume material production and further applications in many other electrochemical energy storage devices. PMID- 22433169 TI - Kirsch et al.'s (2008) calculations are correct: reconsidering Fountoulakis & Moller's re-analysis of the Kirsch data. PMID- 22433170 TI - Post-antibiotic effect of orbifloxacin against Escherichia coli and Pseudomonas aeruginosa isolates from dogs. AB - Orbifloxacin is a fluoroquinolone drug used widely in companion animal medicine. In this study, we firstly determined post-antibiotic effects (PAEs) and post antibiotic sub-minimum inhibitory concentrations (MIC) effects (PA-SMEs) of orbifloxacin for two strains each of Escherichia coli and Pseudomonas aeruginosa from dogs, and these parameters were compared with those of enrofloxacin. At twice the MIC, the PAEs of orbifloxacin ranged from -0.28-0.93 h (mean, 0.29 h) for E. coli and -0.18-1.18 h (mean, 0.37 h) for P. aeruginosa. These parameters were not significantly different for E. coli and shorter for P. aeruginosa, compared to enrofloxacin (P < 0.05). Continued exposure to 0.1, 0.2, and 0.3 the MIC of orbifloxacin resulted in average PA-SMEs of 0.55, 1.11, and 2.03 h, respectively, for E. coli, and 1.04, 1.40, and 2.47 h, respectively, for P. aeruginosa. These PA-SMEs, which had no significant differences with those of enrofloxacin, were significantly longer than the corresponding PAEs (P < 0.05). These results suggest that the PA-SME of orbifloxacin for E. coli and P. aeruginosa can be meaningfully prolonged by increase of sub-MICs. PMID- 22433171 TI - Influence of vitamin D supplementation on plasma lipid profiles: a meta-analysis of randomized controlled trials. AB - Observational studies have shown that low serum levels of vitamin D have been associated with an atherogenic lipid profile. However, the intervention studies gave divergent results. We conducted a meta-analysis of randomized controlled trials that evaluated the effects of vitamin D supplementation on blood lipids. A systematic literature search was conducted via MEDLINE, Cochrane library, and EMBASE for randomized controlled clinical trials assessing the effects of vitamin D supplementation on lipids. The mean change in total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) from baseline was treated as a continuous variable. In all, 12 clinical trials consisting of 1346 participants were included in the analysis. The pooled estimate of effect for vitamin D supplementation on LDL-C was 3.23 mg/dl (95% confidence interval, 0.55 to 5.90 mg/dl). No statistically significant effects for vitamin D supplementation were observed for TC, HDL-C and TG (differences in means were 1.52 mg/dl (-1.42 to 4.46 mg/dl), -0.14 mg/dl (-0.99 to 0.71 mg/dl) and -1.92 mg/dl (-7.72 to 3.88 mg/dl) respectively). The lipid modulating effects of vitamin D supplementation should be further investigated though large-scale, randomized trials with adequate doses which can effectively elevated the active form of vitamin D in plasma and with proper population which has hyperlipemia as an inclusion criterion. PMID- 22433172 TI - Vector-borne diseases--constant challenge for practicing veterinarians: recommendations from the CVBD World Forum. AB - The human-animal bond has been a fundamental feature of mankind's history for millennia. The first, and strongest of these, man's relationship with the dog, is believed to pre-date even agriculture, going back as far as 30,000 years. It remains at least as powerful today. Fed by the changing nature of the interactions between people and their dogs worldwide and the increasing tendency towards close domesticity, the health of dogs has never played a more important role in family life. Thanks to developments in scientific understanding and diagnostic techniques, as well as changing priorities of pet owners, veterinarians are now able, and indeed expected, to play a fundamental role in the prevention and treatment of canine disease, including canine vector-borne diseases (CVBDs).The CVBDs represent a varied and complex group of diseases, including anaplasmosis, babesiosis, bartonellosis, borreliosis, dirofilariosis, ehrlichiosis, leishmaniosis, rickettsiosis and thelaziosis, with new syndromes being uncovered every year. Many of these diseases can cause serious, even life threatening clinical conditions in dogs, with a number having zoonotic potential, affecting the human population.Today, CVBDs pose a growing global threat as they continue their spread far from their traditional geographical and temporal restraints as a result of changes in both climatic conditions and pet dog travel patterns, exposing new populations to previously unknown infectious agents and posing unprecedented challenges to veterinarians.In response to this growing threat, the CVBD World Forum, a multidisciplinary group of experts in CVBDs from around the world which meets on an annual basis, gathered in Nice (France) in 2011 to share the latest research on CVBDs and discuss the best approaches to managing these diseases around the world.As a result of these discussions, we, the members of the CVBD Forum have developed the following recommendations to veterinarians for the management of CVBDs. PMID- 22433173 TI - Co-inherited beta-thalassemia trait and HbH disease: clinical characteristics and interference in diagnosis of thalassemia by high-performance liquid chromatography. AB - INTRODUCTION: To identify the clinical and hematological characteristics in a large group of patients with combined HbH disease and beta-thalassemia trait. METHODS: Hemoglobinopathy analysis and full genotyping identified a cohort of patients with HbH disease, beta-thalassemia trait, or combined HbH disease and beta-thalassemia trait. RESULTS: Co-inheritance of beta-thalassemia trait and HbH disease significantly decreased the mean corpuscular volume (MCV) in 27 patients when compared to 287 patients with HbH disease alone. The combined condition also alleviated anemia in nondeletional HbH disease but not in the deletional cases. Beta-thalassemia trait also significantly decreased the expression of HbH, Hb Constant Spring when present, and HbA(2) , with levels as low as 3.6% on high performance liquid chromatography (HPLC). CONCLUSION: These cases, although relatively common in the South Chinese population, may be difficult do diagnose correctly when only examined on HPLC. Therefore, molecular analysis of the alpha and beta globin genes should be done in all cases with hemolytic anemia and low MCV without clear HbH disease or beta-thalassemia parameters. PMID- 22433174 TI - Alternative splicing produces structural and functional changes in CUGBP2. AB - BACKGROUND: CELF/Bruno-like proteins play multiple roles, including the regulation of alternative splicing and translation. These RNA-binding proteins contain two RNA recognition motif (RRM) domains at the N-terminus and another RRM at the C-terminus. CUGBP2 is a member of this family of proteins that possesses several alternatively spliced exons. RESULTS: The present study investigated the expression of exon 14, which is an alternatively spliced exon and encodes the first half of the third RRM of CUGBP2. The ratio of exon 14 skipping product (R3delta) to its inclusion was reduced in neuronal cells induced from P19 cells and in the brain. Although full length CUGBP2 and the CUGBP2 R3delta isoforms showed a similar effect on the inclusion of the smooth muscle (SM) exon of the ACTN1 gene, these isoforms showed an opposite effect on the skipping of exon 11 in the insulin receptor gene. In addition, examination of structural changes in these isoforms by molecular dynamics simulation and NMR spectrometry suggested that the third RRM of R3delta isoform was flexible and did not form an RRM structure. CONCLUSION: Our results suggest that CUGBP2 regulates the splicing of ACTN1 and insulin receptor by different mechanisms. Alternative splicing of CUGBP2 exon 14 contributes to the regulation of the splicing of the insulin receptor. The present findings specifically show how alternative splicing events that result in three-dimensional structural changes in CUGBP2 can lead to changes in its biological activity. PMID- 22433175 TI - 'Online' geriatric assessment procedure for older adults referred for geriatric assessment during an acute care episode for consideration of reliability of triage decisions. AB - BACKGROUND: Comprehensive geriatric assessment has been shown to improve patient outcomes, but the geriatricians who deliver it are in short-supply. A web-based method of comprehensive geriatric assessment has been developed with the potential to improve access to specialist geriatric expertise. The current study aims to test the reliability and safety of comprehensive geriatric assessment performed "online" in making geriatric triage decisions. It will also explore the accuracy of the procedure in identifying common geriatric syndromes, and its cost relative to conventional "live" consultations. METHODS/DESIGN: The study population will consist of 270 acutely hospitalized patients referred for geriatric consultation at three sites. Paired assessments (live and online) will be conducted by independent, blinded geriatricians and the level of agreement examined. This will be compared with the level of agreement between two independent, blinded geriatricians each consulting with the patient in person (i.e. "live"). Agreement between the triage decision from live-live assessments and between the triage decision from live-online assessments will be calculated using kappa statistics. Agreement between the online and live detection of common geriatric syndromes will also be assessed using kappa statistics. Resource use data will be collected for online and live-live assessments to allow comparison between the two procedures. DISCUSSION: If the online approach is found to be less precise than live assessment, further analysis will seek to identify patient subgroups where disagreement is more likely. This may enable a protocol to be developed that avoids unsafe clinical decisions at a distance. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: ACTRN12611000936921. PMID- 22433176 TI - Evaluation of a Dutch school-based depression prevention program for youths in highrisk neighborhoods: study protocol of a two-armed randomized controlled trial. AB - BACKGROUND: Research has indicated that depression prevention programs attenuate the development of symptoms of depression in adolescents. To implement these programs on a large scale, implementation in a school setting with teachers providing the programs is needed. In the present study, the effectiveness of the Dutch depression prevention program Op Volle Kracht (OVK) provided by school teachers during school hours with adolescents from high risk neighborhoods will be tested. The mediating effects of cognitive distortions and alexithymia will be evaluated as well. We hypothesize that the OVK program will prevent or decrease reported depressive symptoms, and that this association will be mediated by cognitive distortions and alexithymia. METHODS/DESIGN: Schools with at least 30% of their pupils living in low income areas in the Netherlands are invited to participate in the study. Classes from vocational training up to pre-university level are eligible and 1324 adolescents (11-14 years) will be participating in the study. Randomisation will be done at class level, randomly assigning participants to an intervention group (OVK) and a control group (care as usual), stratifying by school level (high versus low). Trained school teachers will be delivering the program, which covers cognitive-behavioral and social problem solving skills. Longitudinal data will be collected with self-report measurements administered in the school setting at baseline, post intervention and at two follow ups (at 6 and 12 months). Primary outcome is the level of depressive symptoms, and secondary outcomes include: cognitive errors, response style, attributional style, alexithymia, stressful life events, substance use, happiness, and school grades. DISCUSSION: If the OVK program proves to be effective when it is provided by school teachers, a structural implementation of the program in the school curriculum will enhance the quality of the lives of adolescents and their families and will reduce costs in health care. In addition, the results of the study advances current knowledge on the underlying mechanisms of the development of depression and may aid the improvement of depression prevention programs in general. TRIAL REGISTRATION: Dutch Trial Register NTR3110. PMID- 22433177 TI - Impact of statin use and lipid profile on symptomatic intracerebral haemorrhage, outcome and mortality after intravenous thrombolysis in acute stroke. AB - BACKGROUND: It is unclear if a certain lipid profile and/or statin use contribute to symptomatic intracerebral haemorrhage (sICH), poor outcome or mortality after intravenous thrombolysis for ischaemic stroke. The aim of the current study was to assess the impact of statin use and lipid profile on sICH, outcome and mortality following thrombolysis in acute stroke. METHODS: From 2001 to 2010, all patients admitted to our hospital and undergoing intravenous thrombolysis for acute ischaemic stroke were included into an open, prospective database. Initial stroke severity was assessed using the National Institute of Health Stroke Scale. Demographics, vascular risk factors, admission blood pressure, glucose levels, previous medication including statin use, lipid profiles including low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were recorded. Outcome measures included sICH according to the European Cooperative Acute Stroke Study II criteria, modified Rankin scale and mortality at 3 months. RESULTS: 1,066 patients were included in the analysis; 5.3% (57 patients) had sICH. Mortality at 3 months was 17.6% (188 patients). A favourable outcome (modified Rankin scale 0-1) at 3 months was attained by 35.6% (379 patients). Prior statin use was not associated with increased odds for sICH (OR 1.05, 95% CI 0.55-2.04, p = 0.864), mortality (OR 1.32, 95% CI 0.90-1.93, p = 0.152) or favourable outcome (OR 0.89, 95% CI 0.65-1.24, p = 0.507). Similar results were found for the different lipid variables: high LDL (OR 0.96, 95% CI 0.36-2.60, p = 0.942), high triglyceride (OR 1.74, 95% CI 0.84-3.56, p = 0.132) and low HDL (OR 1.78, 95% CI 0.68-4.65, p = 0.279) were not associated with increased odds for sICH. Likewise, neither mortality nor functional outcome at 3 months was significantly associated with any of the lipid variables in the univariable analysis following Bonferroni adjustment for multiple comparisons. The same results were found in the multivariable analysis adjusting for imbalances in baseline characteristics. CONCLUSIONS: In contrast to previous studies, we found that in stroke patients receiving thrombolysis therapy, neither the lipid profile nor prior statin use were associated with increased odds for sICH, functional outcome or mortality at 3 months. PMID- 22433178 TI - Protein dynamics studied with ultrafast two-dimensional infrared vibrational echo spectroscopy. AB - Proteins, enzymes, and other biological molecules undergo structural dynamics as an intrinsic part of their biological functions. While many biological processes occur on the millisecond, second, and even longer time scales, the fundamental structural dynamics that eventually give rise to such processes occur on much faster time scales. Many decades ago, chemical kineticists focused on the inverse of the reaction rate constant as the important time scale for a chemical reaction. However, through transition state theory and a vast amount of experimental evidence, we now know that the key events in a chemical reaction can involve structural fluctuations that take a system of reactants to its transition state, the crossing of a barrier, and the eventual relaxation to product states. Such dynamics occur on very fast time scales. Today researchers would like to investigate the fast structural fluctuations of biological molecules to gain an understanding of how biological processes proceed from simple structural changes in biomolecules to the final, complex biological function. The study of the fast structural dynamics of biological molecules requires experiments that operate on the appropriate time scales, and in this Account, we discuss the application of ultrafast two-dimensional infrared (2D IR) vibrational echo spectroscopy to the study of protein dynamics. The 2D IR vibrational echo experiment is akin to 2D NMR, but it operates on time scales many orders of magnitude faster. In the experiments, a particular vibrational oscillator serves as a vibrational dynamics probe. As the structure of the protein evolves in time, the structural changes are manifested as time-dependent changes in the frequency of the vibrational dynamics probe. The 2D IR vibrational echo experiments can track the vibrational frequency evolution, which we then relate to the time evolution of the protein structure. In particular, we measured protein substate interconversion for mutants of myoglobin using 2D IR chemical exchange spectroscopy and observed well defined substate interconversion on a sub-100 ps time scale. In another study, we investigated the influence of binding five different substrates to the enzyme cytochrome P450(cam). The various substrates affect the enzyme dynamics differently, and the observed dynamics are correlated with the enzyme's selectivity of hydroxylation of the substrates and with the substrate binding affinity. PMID- 22433179 TI - Modulation of recombinant GABA(A) receptors by neurosteroid dehydroepiandrosterone sulfate. AB - AIM: To investigate whether long-term exposure to the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces adaptive changes of GABA(A) receptors related to the development of tolerance and dependence. METHODS: We compared the parameters of [(3)H]DHEAS binding and the effects of DHEAS on [(3)H]flunitrazepam binding in the membranes of HEK 293 cells, nontransfected or stably transfected with recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors. In HEK 293 cells expressing alpha(1)beta(2)gamma(2S) GABA(A) receptors, we investigated the effects of long-term DHEAS treatment on the [(3)H]flunitrazepam and [(3)H]t-butylbicycloorthobenzoate ([(3)H]TBOB) binding and on their modulation with GABA. RESULTS: DHEAS behaves as an allosteric antagonist of the recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors expressed in HEK 293 cells. Exposure of cells to 100 MUmol/l DHEAS for 48 h did not change the number or affinity of benzodiazepine and convulsive binding sites. Long-term DHEAS treatment failed to affect functional allosteric interactions between GABA(A) receptor binding sites, as evidenced by an unchanged ability of GABA to stimulate or to inhibit [(3)H]flunitrazepam and [(3)H]TBOB binding, respectively. CONCLUSION: The findings that prolonged DHEAS treatment does not produce changes in GABA(A) receptor expression and functional coupling, assumed to underlie the development of tolerance and dependence, might have importance in the long-term therapy necessary for the observed beneficial effects of DHEAS. PMID- 22433181 TI - Ureteral stent exchange under fluoroscopic guidance using the crochet hook technique in women. AB - PURPOSE: We developed a method for ureteral stent exchange in female patients under fluoroscopic guidance using a crochet hook technique (CHEX). PATIENTS AND METHODS: A total of 45 female patients (51 stents) underwent exchange of ureteral stents. In these patients, 21 ureteral stents were exchanged using CHEX. All procedures were carried out with the patients under conscious sedation. At the time of the procedures, we extracted the ureteral stent from the external urethral orifice using CHEX under fluoroscopic guidance and inserted the new stent under fluoroscopic guidance without cystoscopy. RESULTS: 20 of the 21 stents (95.2%) were successfully exchanged. Ureteral stent exchange using CHEX was unsuccessful in 1 patient, including migration to the ureter. CONCLUSIONS: Ureteral stent exchange using a crochet hook is easy, safe and cost-effective. This technique was also easy to learn. PMID- 22433180 TI - Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. AB - BACKGROUND: The study was performed to investigate the expression of chemokine receptors (CR) on circulating tumor cells (CTC), which may be of importance for organ-specific metastases and cancer treatment since CR are potential drug targets. METHODS: Blood samples from patients with metastatic carcinoma (MC) or melanoma (MM) were enriched for CTC and expression of CR (CXCR4, CCR6, CCR7 and CCR9) was evaluated by flow cytometry. RESULTS: CTC were detected in 49 of 68 patients (72%) [28 MC; 21 MM] with a median number of 3 CTC (range: 1-94)/10 mL of blood. CXCR4 was expressed on CTC in 82% (40/49) of patients [median number 1 CTC/10 mL blood; range 1-14] and CCR6 in 29 patients (59%; median 1, range: 1 14). In MM patients, CCR7 was expressed on CTC in 6 (29%) samples and CCR9 in 12 (57%). A positive correlation between surface expression of CR and organ-specific metastatic pattern was not observed. CONCLUSIONS: CR were expressed on CTC of patients with solid tumors. Along with our findings, the observation that CR could be involved in CTC proliferation and migration of tumor cells appoints CTC as potential CR-antagonist therapeutic target. PMID- 22433182 TI - Ballistic and non-ballistic gas flow through ultrathin nanopores. AB - We show that ultrathin porous nanocrystalline silicon membranes exhibit gas permeance that is several orders of magnitude higher than other membranes. Using these membranes, gas flow obeying Knudsen diffusion has been studied in pores with lengths and diameters in the tens of nanometers regime. The components of the flow due to ballistic transport and transport after reflection from the pore walls were separated and quantified as a function of pore diameter. These results were obtained in pores made in silicon. We demonstrate that changing the pore interior to carbon leads to flow enhancement resulting from a change in the nature of molecule-pore wall interactions. This result confirms previously published flow enhancement results obtained in carbon nanotubes. PMID- 22433184 TI - Psychosomatic problems and countermeasures in Japanese children and adolescents. AB - In Japan there are a number of children and adolescents with emotion-related disorders including psychosomatic diseases (orthostatic dysregulation, anorexia nervosa, recurrent pains), behavior problems and school absenteeism. According to our previous report, the Japanese children had significantly higher score of physical symptoms and psychiatric complaints than did the Swedish children, and these were more strongly influenced by school-related stress than by home-related stress. To enforce countermeasures for psychosomatic problems in children, the Japanese Society of Psychosomatic Pediatrics (established in 1982) have started several new projects including multi-center psychosomatic researches and society based activities. In this article, we present an outline of our study on mental health in Japanese children in comparison with Swedish children. Countermeasures including clinical guidelines for child psychosomatic diseases are reviewed and discussed. PMID- 22433183 TI - Regulation of macrophage and dendritic cell responses by their lineage precursors. AB - Tissue macrophages (Mo) and dendritic cells (DC) are thought to derive from hematopoietic stem cells, which exist in the bone marrow and generate intermediate precursor populations with increasingly restricted lineage potentials. There exists several precursors committed to the Mo and DC lineages; these cells exhibit distinct tropism and function and respond differentially in pathophysiologic conditions. In this review, we consider experimental contexts in which Mo and DC responses in tissue are not only dictated by the local environment, but also by the quantity and quality of newly recruited lineage precursor cells. Consequently, we discuss whether therapeutic control of Mo and DC responses in tissue may be achieved through manipulation of their lineage precursors. PMID- 22433185 TI - Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder. AB - Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1-6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) -1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = -2.7, 95% CI 5.0 to -0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5-6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder. PMID- 22433187 TI - Reflections on questions in valve and structural heart. PMID- 22433186 TI - Biogeography of the two major arbovirus mosquito vectors, Aedes aegypti and Aedes albopictus (Diptera, Culicidae), in Madagascar. AB - BACKGROUND: In the past ten years, the Indian Ocean region has been the theatre of severe epidemics of chikungunya and dengue. These outbreaks coincided with a high increase in populations of Aedes albopictus that outcompete its sister taxon Aedes aegypti in most islands sampled. The objective of this work was to update the entomological survey of the two Aedes species in the island of Madagascar which has to face these arboviroses. METHODS: The sampling of Aedes mosquitoes was conducted during two years, from October 2007 to October 2009, in fifteen localities from eight regions of contrasting climates. Captured adults were identified immediately whereas immature stages were bred until adult stage for determination. Phylogenetic analysis was performed using two mtDNA genes, COI and ND5 and trees were constructed by the maximum likelihood (ML) method with the gene time reversible (GTR) model. Experimental infections with the chikungunya virus strain 06.21 at a titer of 107.5 pfu/mL were performed to evaluate the vector competence of field-collected mosquitoes. Disseminated infection rates were measured fourteen days after infection by immunofluorescence assay performed on head squashes. RESULTS: The species Aedes aegypti was detected in only six sites in native forests and natural reserves. In contrast, the species Aedes albopictus was found in 13 out of the 15 sites sampled. Breeding sites were mostly found in man-made environments such as discarded containers, used tires, abandoned buckets, coconuts, and bamboo cuts. Linear regression models showed that the abundance of Ae. albopictus was significantly influenced by the sampling region (F = 62.00, p < 2.2 * 10(-16)) and period (F = 36.22, p = 2.548 * 10( 13)), that are associated with ecological and climate variations. Phylogenetic analysis of the invasive Ae. albopictus distinguished haplotypes from South Asia and South America from those of Madagascar, but the markers used were not discriminant enough to discern Malagasy populations. The experimental oral infection method showed that six Ae. albopictus populations exhibited high dissemination infection rates for chikungunya virus ranging from 98 to 100%. CONCLUSION: In Madagascar, Ae. albopictus has extended its geographical distribution whereas, Ae. aegypti has become rare, contrasting with what was previously observed. Changes are predominantly driven by human activities and the rainfall regime that provide suitable breeding sites for the highly anthropophilic mosquito Ae. albopictus. Moreover, these populations were found to be highly susceptible to chikungunya virus. In the light of this study, Ae. albopictus may have been involved in the recent outbreaks of chikungunya and dengue epidemics in Madagascar, and consequently, control measures should be promoted to limit its current expansion. PMID- 22433188 TI - Why the provisional single-stent approach is not always the right strategy; arguments for the development of dedicated bifurcation devices. PMID- 22433189 TI - EAPCI and TAVI: acronyms that bring us together. PMID- 22433190 TI - An interdisciplinary debate initiated by the European Society of Cardiology Working Group on Valvular Heart Disease. PMID- 22433191 TI - Transcatheter aortic bioprosthesis dislocation: technical aspects and midterm follow-up. AB - AIMS: Prosthesis dislocation during transcatheter aortic valve implantation (TAVI) is a rare but important complication. There is scarce data on the performance of prosthesis in the aorta that have become dislocated from their intended anatomical position in the aortic annulus. We investigated the causes of dislocation during TAVI of the self-expanding CoreValve ReValvingTM System (CRS) (Medtronic Inc., Minneapolis, MN, USA). This included midterm follow-up of patients experiencing this acute complication. METHODS AND RESULTS: Among 176 consecutive patients undergoing TAVI with the CRS prosthesis, seven (3.9%) experienced acute valve dislocation. A comprehensive analysis of the mechanism of dislocation and clinical outcomes of patients experiencing this complication was performed. Based on the underlying mechanism, all cases of prosthesis displacement were classified into the following three groups: 1) accidental dislocation immediately after valve implantation (n=1; 14.3%); 2) dislocation during the snaring manoeuvre to reposition a low deployment of the CRS prosthesis (lower edge >10 mm) below the aortic annulus accompanied with haemodynamically significant regurgitation (n=4; 57.1%); 3) intentional dislocation performed with the snaring manoeuvre as a bailout in cases of coronary ostia impairment or severe prosthetic leak due to higher deployment for a suboptimal sealing of the device with valve calcifications (n=2; 28.6%). The majority of cases occurred during early experiences with the new AccutrakTM (Medtronic Inc., Minneapolis, MN, USA) delivery system. In six patients a second CRS was implanted in the appropriate position. The dislodged CRS functioned normally, without any evidence of structural deterioration, thrombosis or further distal migration and showed complete apposition against the aortic wall. No thromboembolic events were reported in any patient. CONCLUSIONS: Dislocation of a CRS device can be managed effectively with the implantation of a second device in a standard fashion leaving the dislocated device safely in the aorta. Intentional repositioning of a CRS device in the aorta can be accomplished by experienced operators without any serious neurologic or vascular events in the post-procedure period or at midterm follow-up. PMID- 22433192 TI - A prospective multicentre registry, evaluating real-world usage of the Tryton side branch stent: results of the E-Tryton 150/Benelux registry. AB - AIMS: The percutaneous treatment of coronary bifurcation lesions remains hampered by suboptimal results, mainly in the side branch (SB), even with the use of drug eluting stents. Dedicated bifurcation stents could provide an attractive alternative to improve early outcomes and reduce SB restenosis. We aimed to assess in a prospective single-arm multicentre registry, safety and effectiveness at 6-month clinical follow-up of the Tryton dedicated side branch (SB) stent. METHODS AND RESULTS: In this prospective international registry, patients with coronary bifurcation lesions underwent treatment with a dedicated stenting technique using the Tryton stent, in conjunction with a "workhorse" main branch (MB) stent (drug-eluting or bare metal). The Tryton stent is specifically designed for bifurcations, with minimal strut/vessel ratio in the proximal MB, providing full strut coverage at the SB ostium, with short stent length in the SB and with the ability to adapt to the wide spectrum of bifurcation angles and sizes. The primary endpoint was 6-month major adverse cardiac events (MACE: cardiac death, myocardial infarction and target lesion revascularisation). Secondary endpoints were technical and procedural success (respectively defined as successful implantation of Tryton at the intended lesion and successful performance of the whole procedure with Tryton without in-hospital MACE). A total of 302 patients were enrolled. Of these, 296 had 6-month data available for evaluation. Technical and procedural success occurred in 98.0% (95% confidence interval: 95.7%-99.1%) and 94.4% (91.2%-96.5%) patients, respectively. The cumulative 6-month MACE rate was 6.4% (4.2%-9.7%), including 4.7% (2.9%-7.7%) myocardial infarctions (3.7% periprocedural), and 3.4% (2.0%-6.1%) target lesion revascularisations (2.4% in the MB, 0.7% in the SB, and 0.3% in both MB and SB). One stent thrombosis (0.3% [0%-1.6%]) occurred. CONCLUSIONS: The treatment of bifurcation lesions with a dedicated Tryton stent is safe and feasible, with good technical and procedural success, very low revascularisation, MACE and stent thrombosis rates at 6-month clinical follow-up. PMID- 22433193 TI - Procedural and early clinical outcomes of patients with de novo coronary bifurcation lesions treated with the novel Nile PAX dedicated bifurcation polymer free paclitaxel coated stents: results from the prospective, multicentre, non randomised BIPAX clinical trial. AB - AIMS: To demonstrate the acute and early outcomes of the novel Nile PAX dedicated polymer-free paclitaxel-coated stents (Minvasys SAS, Gennevilliers, France) in the treatment of de novo coronary bifurcation lesions. METHODS AND RESULTS: The Nile PAX device incorporates a cobalt-chromium alloy with a side aperture in the mid-stent designed to optimise scaffold at the bifurcation carina and side branch (SB) ostium, while maintaining SB access during procedure. From December 2008 to February 2010, 101 patients were prospectively enrolled in a non-randomised, multicentre study. Lesion criteria were: vessel size 2.5-3.5 mm in the parent vessel (PV) and 2.0-3.0 mm in the SB, and lesion length <14 mm in the PV, and <5 mm in the SB. Mean age was 63 years, 29% had diabetes, LAD/Dg was involved in 80.4%, and 61.7% had significant involvement of both branches. The study stent was successfully attempted and implanted in 98%. SB received additional stent in 26% final kissing-balloon inflation was performed in 93% and lesion (angiographic) success was achieved in 98%. There was only one non-Q myocardial infarction during hospitalisation, and no additional events up to 30 days. CONCLUSIONS: Preliminary results of the prospective, non-randomised, multicentre BIPAX clinical trial demonstrated encouraging results with the novel Nile PAX bifurcation DES in the treatment of coronary bifurcation lesions, including high device and procedural success. Overall, there was only one major adverse cardiac event during hospitalisation, with no additional events up to 30 days follow-up. Long-term follow-up is warranted. PMID- 22433194 TI - Optimal diameter of diseased bifurcation segment: a practical rule for percutaneous coronary intervention. AB - AIMS: The percutaneous repair of a diseased segment should consider the dimensions of other segments of a bifurcation in order to ensure the optimality of flow through the bifurcation. The question is, if the diameters of two segments of a bifurcation are known, can an optimal diameter of the third diseased segment be determined such that the bifurcation has an optimal geometry for flow transport? Various models (i.e., Murray, Finet, area-preservation and HK models) that express a diameter relationship of the three segments of a bifurcation have been proposed to answer the question. METHODS AND RESULTS: In this study the four models were compared with experimental measurements on epicardial coronary bifurcations of patients and swine. The HK model is found to be in agreement with morphometric measurements of all bifurcation types and is based on the minimum energy hypothesis while Murray and area-preservation models are in agreement with experimental measurements for bifurcations with daughter diameter ratio (i.e., small daughter diameter/large daughter diameter) <=0.25 and Finet model is in agreement for bifurcations with daughter diameter ratio >=0.75. CONCLUSIONS: The HK model provides a comprehensive rule for the percutaneous reconstruction of the diameters of diseased vessels and has a physical basis. PMID- 22433195 TI - Interventional catheterisation of stenotic or occluded systemic veins in children with or without congenital heart diseases: early results and intermediate follow up. AB - AIMS: Limited data exists on midterm results concerning paediatric interventions on stenotic or occluded systemic veins following indwelling lines, cardiac surgery, or catheterisations. The purpose of this study was to report our acute and intermediate results concerning patients with (Group A) and without (Group B) congenital heart diseases (CHD) over a 10-year period. METHODS AND RESULTS: From January 2000 to December 2010, 32 patients (23 in Group A and nine in Group B, respectively) underwent 39 interventional catheterisations aimed to dilate or recanalise occluded iliofemoral veins, inferior or superior venae cavae. Initial and follow-up catheterisation data were reviewed retrospectively. Midterm results were evaluated by means of echography, angiography, and CT scan in all 15 and 17 patients, respectively. Median age and weight of all patients at catheterisation were five years (range 0.1-18) and 15 kg (range 2-60), respectively. Fifty-two stents were implanted in 29 patients (32 vessels). In 25 patients 28 vessels were occluded and required recanalisation. There were no major complications. In all but three patients it was possible to treat the lesion. There were two procedural complications (5.1%): one acute stent occlusion and one local dissection. At a median follow-up of 2.5 years (range 1-10) we observed six complications of stenting (11.5%): two fractures, two occlusions and two restenoses. CONCLUSIONS: Interventional catheterisation of stenotic or occluded systemic veins grants good immediate results at a low rate of complication. Stent dilatation or recanalisation may open the vessel for use during future procedures. However, long-term results are yet to be established. PMID- 22433196 TI - Advances in two-dimensional quantitative coronary angiographic assessment of bifurcation lesions: improved small lumen diameter detection and automatic reference vessel diameter derivation. AB - AIMS: To validate a new two dimensional (2-D) bifurcation quantitative coronary angiography (QCA) software. METHODS AND RESULTS: In the latest edition of the Cardiovascular Angiography Analysis System (CAAS 5.9; Pie Medical Imaging, Maastricht, The Netherlands) video-densitometric information is dynamically integrated into the edge-detection algorithm of 11- and 6-segment models to reduce overestimation of small diameters. Furthermore, automatic reference obstruction analysis was optimised. Values of the minimal lumen diameter (MLD), reference vessel diameter (RVD), percent diameter stenosis (DS) and bifurcation angle (BA) for the different bifurcation segment models were validated against precision manufactured plexiglass phantoms. In anteroposterior views, accuracy and precision (mean difference+/-SD) of 11- and 6-segment models for MLD were 0.013+/-0.082 mm vs. 0.003+/-0.100 mm, for RVD -0.030+/-0.047 mm vs. -0.029+/ 0.045 mm and for DS -0.48+/-3.66% vs. -0.11+/-3.97%. In smaller vessel segments (true MLD <0.7 mm), MLD overestimation was reduced. Inter-observer variability for MLD, RVD and DS for either model was <=0.052 mm, <=0.043 mm and <=2.24%, respectively. Agreement between models for MLD, RVD and DS was +/-0.076 mm, +/ 0.021 mm and +/-2.53%, respectively. Accuracy and precision for BA were -2.6+/ 3.5 degrees , and variability was <=1.2 degrees . Accuracy and precision for diameter-derived parameters were slightly decreased in projections with 30 degrees rotation; BA precision dropped to 6.2 degrees . CONCLUSIONS: MLD quantification is improved for true MLD <0.7 mm, resulting in highly accurate and precise diameter measurements over the entire range of phantom diameters. Automatic reference obstruction analysis provides highly accurate, precise and reproducible RVD and DS measurements. PMID- 22433197 TI - Tools & Techniques: Intravascular ultrasound and optical coherence tomography. PMID- 22433198 TI - How should I treat a mural perforation due to acute stent fracture in a calcified proximal LAD? PMID- 22433199 TI - Percutaneous closure of left atrial appendage after transcatheter aortic valve implantation - an interventional approach to avoid anticoagulation therapy in elderly patients: TAVI and closure of LAA to avoid warfarin therapy. PMID- 22433200 TI - Mechanical circulatory support after paediatric heart transplantation. AB - OBJECTIVES: Mechanical circulatory support (MCS) may be required after orthotopic heart transplantation (OHTx) in children for the treatment of failure or rejection. We review the incidence and outcomes of post-transplant MCS in our institution. METHODS: MCS was classified as early (<1 month since transplant) or late (>1 month since transplant) and the support offered was either veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) or a ventricular assist device (VAD). From 2003 to the present, 100 children (<16 years) underwent OHTx. Fifteen (15%) had 17 episodes of MCS. MCS was instituted early in 10 and late in seven episodes. Two children required two episodes of support. VA-ECMO was used in 12 episodes (71%). Two children required VAD support alone (12%). In three (17%) episodes ECMO was subsequently converted from VAD. RESULTS: Among 10 children with early failure, eight were successfully weaned from support with recovery of graft function. In the late failure group, three of six patients died. All but four patients underwent re-transplantation with no perioperative deaths. Overall survival to discharge was 66%. The early failure group shows a better survival rate to hospital discharge compared with the late failure group (78 vs 50%; P < 0.0001). CONCLUSIONS: The incidence of post-transplant MCS for graft failure in our patients was 15%. Early graft failure has a better outcome than late failure. Re-transplantation has good mid-term outcomes in children. A stepwise approach with a multimodality MCS strategy improves survival in this group of patients. PMID- 22433201 TI - Anchoring depth electrodes for bedside removal: a "break-away" suturing technique for intracranial monitoring. AB - BACKGROUND: Intracranial depth electrodes for epilepsy are easily dislodged during long-term monitoring unless adequately anchored, but a technique is not available that is both secure and allows easy explantation without reopening the incision. OBJECTIVE: To describe a convenient and inexpensive method for anchoring depth electrodes that prevents migration and incidental pullout while allowing electrode removal at the bedside. METHODS: An easily breakable suture (eg, MONOCRYL) is tied around both the depth electrode and a heavy nylon suture and anchored to a hole at the edge of the burr hole; the tails of both are tunneled together percutaneously. The "break-away" MONOCRYL suture effectively anchors the electrode for as long as needed. At the completion of the intracranial electroencephalography session, the 2 tails of the nylon suture are pulled to break their encompassing MONOCRYL anchor suture, thus freeing the depth electrode for easy removal. RESULTS: The break-away depth electrode anchoring technique was used for 438 electrodes in 68 patients, followed by explantation of these and associated strip electrodes without reopening the incision. Only 1 electrode (0.2%) migrated spontaneously, and 3 depth electrodes (0.7%) fractured in 2 patients (2.9%) on explantation, necessitating open surgery to remove them in 1 of the patients (1.5%). CONCLUSION: An easy and inexpensive anchoring configuration for depth electrodes is described that provides an effective and safe means of securing the electrodes while allowing easy explantation at the bedside. PMID- 22433205 TI - MU-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. AB - BACKGROUND: Preclinical studies suggest that opioids may promote tumor growth. Genetic polymorphisms have been shown to affect opioid receptor function and to modify the clinical effects of morphine. In this study we assessed the association between six common polymorphisms in the MU-opioid receptor gene, including the well known A118G polymorphism, and breast cancer survival. METHODS: A total of 2,039 women ages 23-74 yr (38% African-American, 62% European American, 55% postmenopausal) diagnosed with breast cancer between 1993-2001 were followed through 2006. Genotyping was performed using the TaqMan platform (Applied Biosystems Inc., Foster City, CA). Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models were used to examine the association between each genotype and survival. RESULTS: After Bonferroni correction for multiple testing, patient genotype at A118G was associated with breast cancer-specific mortality at 10 yr. Women with one or more copies of the G allele had decreased breast cancer-specific mortality (P < 0.001). This association was limited to invasive cases only; effect size appeared to increase with clinical stage. Cox regression model adjusted for age and ethnicity also showed decreased mortality in A/G and G/G genotypes compared with A/A genotype (hazard ratio = 0.57 [0.38, 0.85] and 0.32 [0.22, 0.49], respectively; P = 0.006). CONCLUSIONS: These results suggest that opioid pathways may be involved in tumor growth. Further studies examining the association between genetic variants influencing opioid system function and cancer survival are warranted. PMID- 22433207 TI - Lung protective ventilation in the intraoperative period. PMID- 22433210 TI - Utilization of intraoperative transthoracic ultrasound for diagnosis of pneumothorax. PMID- 22433211 TI - Transthoracic ultrasound for diagnosing pneumothorax. PMID- 22433213 TI - Endotracheal intubation is not always easy. PMID- 22433215 TI - Thromboelastography versus thromboelastometry: time for a fair appraisal. PMID- 22433220 TI - Molecular organization and chromosomal localization of 5S rDNA in Amazonian Engystomops (Anura, Leiuperidae). AB - BACKGROUND: For anurans, knowledge of 5S rDNA is scarce. For Engystomops species, chromosomal homeologies are difficult to recognize due to the high level of inter and intraspecific cytogenetic variation. In an attempt to better compare the karyotypes of the Amazonian species Engystomops freibergi and Engystomops petersi, and to extend the knowledge of 5S rDNA organization in anurans, the 5S rDNA sequences of Amazonian Engystomops species were isolated, characterized, and mapped. RESULTS: Two types of 5S rDNA, which were readily differentiated by their NTS (non-transcribed spacer) sizes and compositions, were isolated from specimens of E. freibergi from Brazil and E. petersi from two Ecuadorian localities (Puyo and Yasuni). In the E. freibergi karyotypes, the entire type I 5S rDNA repeating unit hybridized to the pericentromeric region of 3p, whereas the entire type II 5S rDNA repeating unit mapped to the distal region of 6q, suggesting a differential localization of these sequences. The type I NTS probe clearly detected the 3p pericentromeric region in the karyotypes of E. freibergi and E. petersi from Puyo and the 5p pericentromeric region in the karyotype of E. petersi from Yasuni, but no distal or interstitial signals were observed. Interestingly, this probe also detected many centromeric regions in the three karyotypes, suggesting the presence of a satellite DNA family derived from 5S rDNA. The type II NTS probe detected only distal 6q regions in the three karyotypes, corroborating the differential distribution of the two types of 5S rDNA. CONCLUSIONS: Because the 5S rDNA types found in Engystomops are related to those of Physalaemus with respect to their nucleotide sequences and chromosomal locations, their origin likely preceded the evolutionary divergence of these genera. In addition, our data indicated homeology between Chromosome 5 in E. petersi from Yasuni and Chromosomes 3 in E. freibergi and E. petersi from Puyo. In addition, the chromosomal location of the type II 5S rDNA corroborates the hypothesis that the Chromosomes 6 of E. petersi and E. freibergi are homeologous despite the great differences observed between the karyotypes of the Yasuni specimens and the others. PMID- 22433221 TI - Subjective and objective assessment of edema during adjuvant chemotherapy for breast cancer using taxane-containing regimens in a randomized controlled trial: The National Surgical Adjuvant Study of Breast Cancer 02. AB - OBJECTIVE: To elucidate the time course of taxane-induced edema which may affect the patients' quality of life (QOL). PATIENTS AND METHODS: Our study included the first 300 Japanese patients assigned to 1 of 4 regimens using docetaxel (DTX) or paclitaxel (PTX) by 1:1:1:1 in a randomized controlled trial to evaluate the efficacy of adjuvant therapies for node-positive breast cancer. Patients' QOL was prospectively assessed by the functional assessment of cancer therapy (FACT) breast and -taxane (FACT-T) subscale. The scores of FACT items regarding edema and body weight were used as indicators of edema. RESULTS: The scores for 'anasarca', 'edema of the hands' and 'edema of the legs and feet' of the FACT-T subscale worsened up to 1-2 months after chemotherapy, and body weights increased remarkably until cycle 8 in patients treated with DTX alone (75 mg/m(2), 8 cycles, every 3 weeks). Edema-related symptoms and body weight were relatively stable in the other treatment groups. There were statistically significant differences in the scores of those items and in the changes of body weight both between the DTX-alone group and the other three groups combined, and between the groups using DTX and those using PTX. CONCLUSION: Many patients receiving DTX for >4 cycles suffered significantly from edema. PMID- 22433222 TI - NF-kappaB as potential target in the treatment of melanoma. AB - The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas. Very recently, selective and potent BRAF inhibitors have been developed. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Among these, NFkappaB is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. Inhibition of NF kappaB activation appears to be a very promising option for anti-cancer therapies. PMID- 22433224 TI - Identification of internal carotid artery dissection by transoral carotid ultrasonography. AB - BACKGROUND AND PURPOSE: Conventional transsurface carotid ultrasonography (TSCU) via the cervical surface often fails to detect dissection of the extracranial internal carotid artery (ICA). The role of transoral carotid ultrasonography (TOCU) in the detection of ICA dissection was examined. METHOD: Patients with unilateral extracranial ICA dissection identified by digital subtraction angiography (DSA) from our database of patients with ischemic stroke or transient ischemic attack (TIA) were reviewed. Findings of dissection were compared between TSCU and TOCU. RESULTS: Eight patients (7 men, 37-69 years old), including 7 with ischemic stroke and 1 with TIA, had ICA dissection. By DSA, dissection was identified between the first and third vertebrae in 4 patients and from the third cervical vertebra to the intracranial level in the remaining 4. TOCU images revealed an intimal flap as definite evidence of dissection in all patients. In 7 patients, color flow signals were not seen in false lumens, indicating thrombosed lumens. Four patients showed morphological changes of dissection on follow-up TOCU, including a patient with recovery of color flow signals in false lumens. The diameter of the dissected ICA was 7.3 +/- 0.7 mm and that of the contralateral ICA was 4.9 +/- 0.6 mm (p = 0.008). In contrast, TSCU did not enable any conclusive findings of ICA dissection to be made in any patient. Six patients had intramural hematoma on T(1)-weighted MRI, and 2 had an intimal flap with a double lumen on magnetic resonance angiography. CONCLUSION: TOCU has advantages over TSCU in achieving an accurate diagnosis and follow-up evaluation of ICA dissection. PMID- 22433225 TI - A polished and reinforced thinned-skull window for long-term imaging of the mouse brain. AB - In vivo imaging of cortical function requires optical access to the brain without disruption of the intracranial environment. We present a method to form a polished and reinforced thinned skull (PoRTS) window in the mouse skull that spans several millimeters in diameter and is stable for months. The skull is thinned to 10 to 15 MUm in thickness with a hand held drill to achieve optical clarity, and is then overlaid with cyanoacrylate glue and a cover glass to: 1) provide rigidity, 2) inhibit bone regrowth and 3) reduce light scattering from irregularities on the bone surface. Since the skull is not breached, any inflammation that could affect the process being studied is greatly reduced. Imaging depths of up to 250 MUm below the cortical surface can be achieved using two-photon laser scanning microscopy. This window is well suited to study cerebral blood flow and cellular function in both anesthetized and awake preparations. It further offers the opportunity to manipulate cell activity using optogenetics or to disrupt blood flow in targeted vessels by irradiation of circulating photosensitizers. PMID- 22433226 TI - The "justice gap" for sexual assault cases: future directions for research and reform. AB - Media coverage often reports "good" news about the criminal justice system's ability to effectively respond to sexual assault, concluding that the past two decades have seen an increase in rape reporting, prosecution, and conviction. The objective of this article is to examine the validity of such conclusions by critically reviewing the strengths and weaknesses of various data sources and comparing the statistics they produce. These statistics include estimates for sexual assault reporting rates and case outcomes in the criminal justice system. We conclude that such pronouncements are not currently supported by statistical evidence, and we outline some directions for future research and reform efforts to make the "good news" a reality in the United States. PMID- 22433227 TI - The criminal justice system's response to sexual violence. AB - The legal reforms of the 1960s and 1970s notwithstanding, sexual assault is a crime characterized by underreporting and case attrition. In this article, the authors synthesize research examining the criminal justice system's response to sexual assault. The authors begin by examining research on the victim's decision to report the crime to the police. This is followed by a discussion of the findings of sexual assault case processing research, with a focus on the criminal justice system's response to aggravated and simple rape and to intimate partner sexual violence. The authors end the article with a discussion of questions that research has yet to adequately answer. PMID- 22433228 TI - Use of forensic science in investigating crimes of sexual violence: contrasting its theoretical potential with empirical realities. AB - This article contrasts the theoretical potential of modern forensic science techniques in the investigation of sexual violence cases with empirical research that has assessed the role played by scientific evidence in the criminal justice processing of sexual assault cases. First, the potential of forensic scientific procedures (including DNA testing) are outlined and the sexual assault literature that examines the importance of physical and forensic evidence in resolving such cases is reviewed. Then, empirical data from a recent National Institute of Justice (NIJ) study of 602 rapes are presented that describe the forensic evidence collected and examined in such cases and its impact on decisions to arrest, prosecute, adjudicate, and sentence defendants. The article closes with a discussion of research and policy recommendations to enhance the role played by forensic science evidence in sexual assault investigations. PMID- 22433229 TI - Prosecution of adult sexual assault cases: a longitudinal analysis of the impact of a sexual assault nurse examiner program. AB - Most sexual assaults are never reported to law enforcement, and even among reported cases, most will never be successfully prosecuted. This reality has been a long-standing source of frustration for survivors, victim advocates, as well as members of the criminal justice system. To address this problem, communities throughout the United States have implemented multidisciplinary response interventions to improve post-assault care for victims and increase reporting and prosecution rates. One such model is the Sexual Assault Nurse Examiner (SANE) program, whereby specially trained nurses (rather than hospital emergency department [ED] physicians) provide comprehensive psychological, medical, and forensic services for sexual assault victims. The purpose of this study was to examine whether adult sexual assault cases were more likely to be investigated and prosecuted after the implementation of a SANE program within a large Midwestern county. A quasi-experimental design was used to compare criminal justice system case progression pre-SANE to post-SANE. Results from longitudinal multilevel ordinal regression modeling revealed that case progression through the criminal justice system significantly increased pre- to post-SANE: more cases reached the "final" stages of prosecution (i.e., conviction at trial and/or guilty plea bargains) post-SANE. These findings are robust after accounting for changes in operation at the focal county prosecutors' office and seasonal variation in rape reporting. Implications for policy and practice are discussed. PMID- 22433230 TI - Alcohol drinking patterns among high school students in Ethiopia: a cross sectional study. AB - BACKGROUND: Alcohol use is an important risk factor for morbidity, mortality and social harm among adolescents. There is paucity of data on alcohol use among high school students in Ethiopia. This study aimed to determine the prevalence and factors associated with alcohol use among high school students in Ethiopia METHODS: A cross-sectional study was conducted to assess the prevalence of alcohol use and its predictors among high school students in eastern Ethiopia in April 2010. A sample of students was taken from all schools based on their enrollment size. Prevalence estimates and their 95% confidence intervals were calculated. Logistic regression was performed to adjust and examine associations. RESULTS: A total of 1721 students participated in the study. The mean age of the study population was 16.4 (SD 1.6) years. A total of 372 (22.2%; 95% CI 20.2 - 24.2%) students drink alcohol. Of these, 118 (31.7%) were females and 254 (68.3) males. Multivariate analysis indicated that males (OR 2.09; 95% CI 1.45-3.00), older age (OR 1.16; 95% CI 1.01-1.34), having friends who used alcohol (OR 10.09; 95% CI 6.84-14.89) and living with people who use alcohol (OR 2.77; 95% CI 1.89 4.07) increased the odds of drinking among students. CONCLUSION: There is a high level of alcohol use among high school students in the study area. Involvement of parents, health workers and school authorities are necessary to avert the problem. Specifically, their involvement in awareness campaigns and peer education training are important to encourage students to avoid alcohol use. PMID- 22433223 TI - Influence of social support on cognitive change and mortality in old age: results from the prospective multicentre cohort study AgeCoDe. AB - BACKGROUND: Social support has been suggested to positively influence cognition and mortality in old age. However, this suggestion has been questioned due to inconsistent operationalisations of social support among studies and the small number of longitudinal studies available. This study aims to investigate the influence of perceived social support, understood as the emotional component of social support, on cognition and mortality in old age as part of a prospective longitudinal multicentre study in Germany. METHODS: A national subsample of 2,367 primary care patients was assessed twice over an observation period of 18 months regarding the influence of social support on cognitive function and mortality. Perceived social support was assessed using the 14-item version of the FSozU, which is a standardised and validated questionnaire of social support. Cognition was tested by the neuropsychological test battery of the Structured Interview for the Diagnosis of Dementia (SIDAM). The influence of perceived support on cognitive change was analysed by multivariate ANCOVA; mortality was analysed by multivariate logistic and cox regression. RESULTS: Sample cognitive change (N = 1,869): Mean age was 82.4 years (SD 3.3) at the beginning of the observation period, 65.9% were female, mean cognition was 49 (SD 4.4) in the SIDAM. Over the observation period cognitive function declined in 47.2% by a mean of 3.4 points. Sample mortality (N = 2,367): Mean age was 82.5 years (SD 3.4), 65.7% were female and 185 patients died during the observation period. Perceived social support showed no longitudinal association with cognitive change (F = 2.235; p = 0.135) and mortality (p = 0.332; CI 0.829-1.743). CONCLUSIONS: Perceived social support did not influence cognition and mortality over an 18 months observation period. However, previous studies using different operationalisations of social support and longer observation periods indicate that such an influence may exist. This influence is rather small and the result of complex interaction mechanisms between different components of social support; the emotional component seems to have no or only a limited effect. Further research is needed to describe the complex interactions between components of social support. Longer observation periods are necessary and standardised operationalisations of social support should be applied. PMID- 22433231 TI - Agreement of dermatopathologists in the evaluation of clinically difficult melanocytic lesions: how golden is the 'gold standard'? AB - BACKGROUND: The 'gold standard' for the diagnosis of melanocytic lesions is dermatopathology. Although most of the diagnostic criteria are clearly defined, the interpretation of histopathology slides may be subject to interobserver variability. OBJECTIVES: The aim of this study was to determine the variability among dermatopathologists in the interpretation of clinically difficult melanocytic lesions. METHODS: This study used the database of MelaFind(r), a computer-vision system for the diagnosis of melanoma. All lesions were surgically removed and sent for independent evaluation by four dermatopathologists. Agreement was calculated using kappa statistics. RESULTS: A total of 1,249 pigmented melanocytic lesions were included. There was a substantial agreement among expert dermatopathologists: two-category kappa was 0.80 (melanoma vs. non melanoma) and three-category kappa was 0.62 (malignant vs. borderline vs. benign melanocytic lesions). The agreement was significantly greater for patients >=40 years (three-category kappa = 0.67) than for younger patients (kappa = 0.49). In addition, the agreement was significantly lower for patients with atypical mole syndrome (AMS) (kappa = 0.31) than for patients without AMS (kappa = 0.76). LIMITATIONS: The data were limited by the inclusion/exclusion criteria of the MelaFind(r) study. This might represent a selection bias. The agreement was evaluated using kappa statistics. This is a standard method for evaluating agreement among pathologists, but might be considered controversial by some statisticians. CONCLUSIONS: Expert dermatopathologists have a high level of agreement when diagnosing clinically difficult melanocytic lesions. However, even among expert dermatopathologists, the current 'gold standard' is not perfect. Our results indicate that lesions from younger patients and patients with AMS may be more problematic for the dermatopathologists, suggesting that improved diagnostic criteria are needed for such patients. PMID- 22433232 TI - Synthesis, electron tomography and single-particle optical response of twisted gold nano-bipyramids. AB - A great number of works focus their interest on the study of gold nanoparticle plasmonic properties. Among those, sharp nanostructures appear to exhibit the more interesting features for further developments. In this paper, a complete study on bipyramidal-like gold nanostructures is presented. The nano-objects are prepared in high yield using an original method. This chemical process enables a precise control of the shape and the size of the particles. The specific photophysical properties of gold bipyramids in suspension are ripened by recording the plasmonic response of single and isolated objects. Resulting extinction spectra are precisely correlated to their geometrical structure by mean of electron tomography at the single-particle level. The interplay between the geometrical structure and the optical properties of twisted gold bipyramids is further discussed on the basis of numerical calculations. The influence of several parameters is explored such as the structural aspect ratio or the tip truncation. In the case of an incident excitation polarized along the particle long axis, this study shows how the plasmon resonance position can be sensitive to these parameters and how it can then be efficiently tuned on a large wavelength range. PMID- 22433233 TI - Development and application of biological age prediction models with physical fitness and physiological components in Korean adults. AB - BACKGROUND: Several biological age (BA) prediction models have been suggested with a variety of biomarkers. Valid models should be able to measure BA in a relatively short time period and predict subsequent physiological capability. Physiological and physical fitness variables have been shown to be distinctive markers for predicting BA and morbidity. The practical and noninvasive nature of such variables makes them useful as clinical assessment tools in estimating BA for in-depth diagnosis and corresponding intervention. OBJECTIVE: To identify, develop and evaluate biomarkers and BA prediction models and validate their clinical usefulness for the practical diagnosis of functional aging. METHODS: Fourteen variables were measured in 3,112 male and 1,233 female participants aged 30 and older between the years 2004 and 2007. Through a series of parsimonious stepwise elimination processes, two sets of 8 gender-specific variables were selected as candidate biomarkers for 1,604 men and 760 women. Principal component analysis, linear regression analysis and adjustment methods were further applied to obtain two sets of true BA (TBA) prediction models. The TBA models were examined for validity by comparing TBA to the corresponding chronological age (CA) with clinical risk factors. RESULTS: TBA prediction models with r(2) values of 0.638 and 0.672 were developed, each unique to men and women, respectively. The overall mean TBA and CA of the participants were 53.9 and 51.8 years, respectively, with a marginal difference of -2.1 and -1.3 years. The regression slopes or rates of TBA as a function of CA were 1.00 and 1.28 for men and women with r values of 0.799 and 0.820 (p < 0.001), respectively. In comparing TBA to CA rates between healthy and clinical risk groups, both sarcopenic and obese groups showed significant increases in TBA. CONCLUSIONS: The selected biomarkers encompass various complex physiopathological factors related to intrinsic and extrinsic physiological and functional aging. The BA prediction models based on the selected biomarkers could be practical in assessing BA for Korean adults. PMID- 22433234 TI - Clinical patterns and pathophysiology of hypermotor seizures: an ictal SPECT study. AB - Hypermotor seizures (HMS) can include different forms of hypermotor behaviour due to various mechanisms associated with generation of ictal automatisms. Despite the varied location of seizure onset, similar semiologic features during seizures may exist. Ictal single-photon emission tomography (SPECT) apparently reflects not only the origin of epileptic discharge but also the spread to adjacent cortical areas. Taking this benefit of SPECT studies into account, preoperative SPECT results from 13 patients with HMS who underwent epilepsy surgery were analysed. The radioisotope 99mTc-ECD was injected in all patients within five seconds after seizure onset. Group analysis was performed with statistical parametric mapping (SPM) of paired ictal-interictal SPECTs in order to identify regions of significant ictal hyperperfusion. Hyperperfused regions with a corrected cluster-level significance p-value of < 0.002 were considered significant. Seizure onset at implanted subdural electrodes was defined as the epileptic focus in 12 of 13 patients. Two patterns were recognized: HMS-1 with marked agitation and HMS-2 with mild agitation. Ictal hyperperfusion images revealed significant hyperperfusion in the anterior cingulate cortex, orbito frontal gyrus, lentiform nucleus, midbrain and pons. These hyperperfused areas represent the symptomatogenic zone which was different from the epileptogenic zone, as confirmed by the favourable outcomes after surgical resection. The present findings suggest that a network, including frontal and possibly extrafrontal brainstem and limbic structures, is involved in the genesis of the complex epileptic manifestations of HMS. Moreover, ictal SPECT analysed by SPM is a useful method for studying the neural networks of different types of seizures. PMID- 22433235 TI - Functional near-infrared spectroscopy studies in children. AB - Psychosomatic and developmental behavioral medicine in pediatrics has been the subject of significant recent attention, with infants, school-age children, and adolescents frequently presenting with psychosomatic, behavioral, and psychiatric symptoms. These may be a consequence of insecurity of attachment, reduced self confidence, and peer -relationship conflicts during their developmental stages. Developmental cognitive neuroscience has revealed significant associations between specific brain lesions and particular cognitive dysfunctions. Thus, identifying the biological deficits underlying such cognitive dysfunction may provide new insights into therapeutic prospects for the management of those symptoms in children. Recent advances in noninvasive neuroimaging techniques, and especially functional near-infrared spectroscopy (NIRS), have contributed significant findings to the field of developmental cognitive neuroscience in pediatrics. We present here a comprehensive review of functional NIRS studies of children who have developed normally and of children with psychosomatic and behavioral disorders. PMID- 22433236 TI - Notes on the blood-feeding behavior of Aedes albopictus (Diptera: Culicidae) in Cameroon. AB - BACKGROUND: The invasive mosquito Aedes albopictus is often considered a poor vector of human pathogens, owing to its catholic feeding behavior. However, it was recently incriminated as a major vector in several Chikungunya epidemics, outside of its native range. Here we assessed two key elements of feeding behavior by Ae. albopictus females in Yaounde, Cameroon, Central Africa. Host preference was explored and the human-biting activity of females was monitored over 24 h to determine periods of maximum bite exposure. FINDINGS: Analysis of ingested blood in outdoor-resting females showed that Ae. albopictus preferentially fed on humans rather than on available domestic animals (95% of the blood meals contained human blood). Our results further showed that Ae. albopictus is a day-biting species in Yaounde, with a main peak of activity in the late afternoon. CONCLUSION: This is the first report on the feeding behavior of Ae. albopictus in Central Africa. The species is highly aggressive to humans and might therefore be involved in human-human virus transmission in this setting. PMID- 22433237 TI - Are male nurses emotionally intelligent? PMID- 22433238 TI - The differential impact of social defeat on mice living in isolation or groups in an enriched environment: plasma corticosterone and monoamine variations. AB - Social defeat in mice is a potent stressor that promotes the development of depressive- and anxiety-like behaviours, as well as variations of neuroendocrine and brain neurotransmitter activity. Although environmental enrichment may protect against some of the adverse behavioural and biological effects of social defeat, it seems that, among male group-housed mice maintained in an enriched environment (EE), aggressive behaviours may be more readily instigated, thus promoting distress and exacerbating psychopathological features. Thus, although an EE can potentially have numerous beneficial effects, these may depend on the general conditions in which mice were raised. It was observed in the current investigations that EE group-housed BALB/cByJ mice displayed increased anxiety like behaviours compared to their counterparts maintained in a standard environment (SE). Furthermore, in response to social defeat, EE group-housed male mice exhibited decreased weight gain, exaggerated corticosterone elevations and altered hippocampal norepinephrine utilization compared to their SE counterparts. These effects were not apparent in the individually housed EE mice and, in fact, enrichment among these mice appeared to buffer against serotonin changes induced by social defeat. It is possible that some potentially beneficial effects of enrichment were precluded among group-housed mice, possibly owing to social disturbances that might occur in these conditions. In fact, even if social interaction is an essential feature of enrichment, it seems that some of the positive effects of this housing condition might be optimal when mice are housed individually, particularly with regard to buffering the effects of social defeat. PMID- 22433239 TI - Pupillometry to guide postoperative analgesia. PMID- 22433240 TI - Tidal volumes during general anesthesia: size does matter! PMID- 22433241 TI - Exposure to suicide and suicidality in Korea: differential effects across men and women? AB - BACKGROUND: Little is known about whether exposure to suicide within close social networks is associated with the suicidality in exposed individuals, and potential gender differences regarding this association. AIMS: This study examines the effect of exposure to suicide on the suicidality in exposed individuals. METHODS: The data were drawn from the 2009 Korean General Social Survey, a nationally representative interview survey. Suicidality was measured by the suicidality module in the Mini International Neuropsychiatric Interview (MINI), with exposure to suicide being determined by asking about the experience of a failed or completed suicide attempt by a closely related person. RESULTS: Exposure to the suicide of someone close was significantly associated with higher suicidality in exposed individuals. While the effect of a failed attempt became non-significant after controlling for psychological factors, that of exposure to a completed act of suicide remained significant. A subsample analysis by gender indicated a significant gender difference: with control for demographic and psychological factors, exposure to a completed suicide had a significant effect on the suicidality of females only. The effect of exposure to a failed attempt became non-significant both in males and females after controlling for other factors. CONCLUSIONS: Findings suggest the necessity of screening for prior exposure to suicide in suicide risk assessment and the need for gender-tailored suicide prevention strategies. PMID- 22433242 TI - The treatment outcome of psychotic disorders by traditional healers in central Sudan. AB - BACKGROUND: Alternative and traditional healing methods are common and popular in Sudan, particularly for treating people with mental disorders, but little information is available about the outcome of theses traditional healing approaches. OBJECTIVES: To study the outcome of treating patients with psychotic disorders by traditional healers, and to understand the type of services, interventions procedures and treatments methods used by traditional healers to manage patients with psychotic disorders. METHOD: A prospective follow-up quantitative study of a cohort of inpatients with psychotic disorders was carried out from admission until discharge. Subjects were people with psychotic disorders undergoing treatment in traditional healer centres in central Sudan. The Mini International Neuropsychiatric Interview (MINI) was used to diagnose the psychotic disorders and the Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychotic symptoms on admission and discharge from the traditional healer centre. RESULTS: We interviewed 129 inpatients with psychotic disorders on admission and discharge from the traditional healers centres. There was a significant reduction in the PANSS score (p = .0001) after a mean period of stay of 4.5 months. The mean for the overall PANSS score was 118.36 on admission and 69.36 on discharge. CONCLUSION: Although traditional-healing approaches produce a significant improvement in the signs and symptoms of psychotic disorders measured on the PANSS, they need to be further investigated, assessed and studied. PMID- 22433243 TI - The Schedule for Evaluating Persistent Symptoms (SEPS): a new method of recording medically unexplained symptoms. AB - BACKGROUND: Medically unexplained symptoms are difficult to measure and in most cases the diagnosis is made either from independent data such as consultants' opinions or medical outcomes, or by proxy measures such as numbers of symptoms or consultations. A valid self-rated measure would be of value in assessing this highly prevalent condition. AIMS: To describe a new scale of nine items, the Schedule for Evaluation of Persistent Symptoms (SEPS), its properties, its internal consistency, its distribution in a sample of 470 medical patients, its relationship to social functioning and health anxiety (hypochondriasis), and its construct validity by comparing its results with an independent diagnostic examination of each patient's notes two years subsequent to assessment. METHOD: A prevalence study was carried out in 405 consenting medical patients in primary care, cardiology, respiratory medicine, gastroenterology and endocrine clinics, in which the SEPS scale, the Health Anxiety Inventory (HAI) and the Social Functioning Questionnaire (SFQ) were each completed. RESULTS: The mean score on the SEPS scale in 470 patients was 13.4. Exploratory factor analysis revealed two main factors, one concerned focus on symptoms and the other on their attribution. Examination of all data showed a cut-off point of 14 as indicating the presence of pathological medically unexplained symptoms (MUS). Agreement between the consultants' diagnosis and pathological MUS scores was fairly good with a score of 14 or more on the SEPS showing sensitivity of 0.65 and negative predictive accuracy of 0.90. CONCLUSION: It is concluded that the SEPS scale has potential value in screening patients with suspected medically unexplained symptoms. PMID- 22433244 TI - Carer psychoeducation in first-episode psychosis: evaluation outcomes from a structured group programme. AB - BACKGROUND: Carers play an important role in supporting client adjustment and relapse prevention following a first psychotic episode. The caring experience however is a stressful and demanding one, and carers require support to develop coping strategies and sustain themselves in their role. AIMS: To evaluate a psychoeducation programme provided within a public adult mental health service, designed for the families of clients experiencing first-episode psychosis. METHODS: A pre- and post-test questionnaire was administered to quantitatively measure the participants' changes in perceptions of their knowledge and understanding regarding mental illness and its treatment through attending the group. Qualitative items were included to ascertain other knowledge gained or benefits perceived and any critical feedback. RESULTS: The programme significantly improved carers' perceptions of their understanding of psychosis, recovery and relapse prevention. Additional feedback replicated previous findings that participants value support and feel less isolated through group attendance, gaining a sense of collective experience and the opportunity to share experiences and feel heard by peers. CONCLUSIONS: The evaluation demonstrates the efficacy of such a group and the importance of public mental health services in providing family interventions in first-episode psychosis care. PMID- 22433245 TI - Living with a depressed person in Denmark: a qualitative study. AB - BACKGROUND: Strategies for coping with the burdens of living with a depressed person affect a family's psychosocial environment. AIM: The aim of this qualitative study was to explore how relatives make personal sense of living with a depressed family member. METHODS: Thirteen cohabitant relatives were interviewed either individually or in a focus group. The transcribed interviews were interpreted thematically. RESULTS: Relatives went through a psychosocial transformation process driven by the twin challenges of their attitudes towards the depressed family member and of stigma. CONCLUSIONS: More could be done to resolve families' need for information and for emotional and practical support promoting recovery. PMID- 22433246 TI - Influence of dependent personality status on the outcome and health service costs of health anxiety. AB - OBJECTIVE: To assess the effect of dependent personality disturbance as an influence on the cost and clinical outcome of health anxiety. METHOD: In the course of a randomized trial of treatments for patients with high health anxiety over 12 months, we also recorded dependent personality status by two methods: the Personality Assessment Schedule (an observer-rated instrument) and the self-rated Dependent Personality Questionnaire (DPQ), the latter being administered at baseline, six months and 12 months. The two main hypotheses tested were that patients with dependent personality features would have a worse outcome and attract greater health service costs. RESULTS: Forty-nine patients took part in the trial; all had baseline dependent personality data, 44 provided health service costs, and 38 had observer-rated personality assessments. At baseline patients with any personality disorder had higher clinical ratings for health anxiety, and dependent personality disturbance, mainly in the form of personality difficulty, was associated with a worse outcome than those without dependent personalities after correction for baseline differences. The DPQ at a score of 15 successfully identified all patients with dependent personality disorder in both ICD and DSM classifications and showed a significant but relatively modest reduction in scores of 1.5 (13%) during the course of the 12-month trial. Costs in those separated by personality status showed those with dependent personality incurred 45% more health service costs than those without these personality characteristics (p = .10). No patient with dependent personality disorder dropped out of treatment compared with 6 out of 38 (16%) of those with no dependence. CONCLUSIONS: The DPQ is probably a reliable instrument for assessing dependent personality characteristics without the need for interview and its scores, unlike many ratings of personality, are stable over time. The findings may have been influenced by different responses to those treated in the trial with cognitive behaviour therapy compared with control treatment. PMID- 22433247 TI - A simple strategy for jumping straight up. AB - Jumping from a stationary standing position into the air is a transition from a constrained motion in contact with the ground to an unconstrained system not in contact with the ground. A simple case of the jump, as it applies to humans, robots and humanoids, is studied in this paper. The dynamics of the constrained rigid body are expanded to define a larger system that accommodates the jump. The formulation is applied to a four-link, three-dimensional system in order to articulate the ballistic motion involved. The activity of the muscular system and the role of the major sagittal muscle groups are demonstrated. The control strategy, involving state feedback and central feed forward signals, is formulated and computer simulations are presented to assess the feasibility of the formulations, the strategy and the jump. PMID- 22433248 TI - Development of simple and rapid elution methods for proteins from various affinity beads for their direct MALDI-TOF downstream application. AB - Commercially available desalting techniques, necessary for downstream MALDI-TOF analysis of proteins, are often costly or time consuming for large-scale analysis. Here, we present techniques to elute proteins from various affinity resins, free from salt and ready for MALDI mass spectrometry. We showed that 0.1% TFA in 50% acetonitrile or 40% ethanol can be used as salt-free eluents for His tagged proteins from variety of polyhistidine-affinity resins, while washing of resin beads twice with double-distilled water prior to the elution effectively desalted and recovered wide-range-molecular size proteins than commercially available desalting devices. Modified desalting and elution techniques were also applied for Flag- and Myc-tag affinity resins. The technique was further applied in co-precipitation assay, where the maximum recovery of wide-range molecular size proteins is crucial. Further, results showed that simple washing of the beads with double distilled water followed by elution with acetonitrile effectively desalted and recovered 150 kDa factor H protein of the sheep and its binding partner ~30 kDa BbCRASP-1 in co-precipitation assay. In summary, simple modifications in the desalting and elution strategy save time, labor and cost of the protein preparation for MALDI mass spectrometry; and large-scale protein purifications or co-precipitations can be performed with ease. PMID- 22433249 TI - Genetic polymorphisms located in TGFB1, AGTR1, and VEGFA genes are associated to chronic renal allograft dysfunction. AB - BACKGROUND: Persistent inflammation and fibrosis have been related to active progression of renal deterioration and reduced survival of kidney transplant. The aim of this study was to determine the impact of single-nucleotide polymorphisms (SNPs) located in regions related to inflammatory and immune processes on the development of chronic renal allograft dysfunction (CRAD). METHODS: A retrospective study was carried out on 276 patients who received kidney transplant (KT). SNPs were genotyped via the SNPlex platform. Statistical analysis was performed with SNPstat and regression logistic analyses were adjusted by age and gender of recipients and donors, cold ischemia time and the number of human leukocyte antigen (HLA) mismatches. RESULTS: From 276 patients with KT, 118 were non-CRAD and 158 were CRAD. Three SNPs showed significant associations with CRAD development: rs1800471 in transforming growth factor beta 1 (TGFB1), rs5186 in angiotensin II receptor type 1 (AGTR1), and rs699947 in vascular endothelial growth factor A (VEGFA). GC genotype of rs1800471 was associated with increased odds of CRAD compared to GG genotype (OR=2.65 (95% confidence interval (CI)=1.09; 6.47), p=0.025), as well as AC and AA genotype of rs699947 assuming a dominant model (OR=1.80 (95% CI=1.02; 3.20), p=0.044). Besides, AC and CC genotypes of rs5186 were associated with reduced odds of CRAD assuming a dominant model (OR=0.56 (95% CI=0.33; 0.96), p=0.033). CONCLUSION: Our findings suggest that three genes related to immunity and inflammation (rs1800471, rs5186 and rs699947) are associated to susceptibility or protection to CRAD, and might have diagnostic utility in predicting the likelihood of developing CRAD. PMID- 22433250 TI - Imaging of HIV-1 envelope-induced virological synapse and signaling on synthetic lipid bilayers. AB - Human immunodeficiency virus type 1 (HIV-1) infection occurs most efficiently via cell to cell transmission(2,10,11). This cell to cell transfer between CD4(+) T cells involves the formation of a virological synapse (VS), which is an F-actin dependent cell-cell junction formed upon the engagement of HIV-1 envelope gp120 on the infected cell with CD4 and the chemokine receptor (CKR) CCR5 or CXCR4 on the target cell (8). In addition to gp120 and its receptors, other membrane proteins, particularly the adhesion molecule LFA-1 and its ligands, the ICAM family, play a major role in VS formation and virus transmission as they are present on the surface of virus-infected donor cells and target cells, as well as on the envelope of HIV-1 virions(1,4,5,6,7,13). VS formation is also accompanied by intracellular signaling events that are transduced as a result of gp120 engagement of its receptors. Indeed, we have recently showed that CD4(+) T cell interaction with gp120 induces recruitment and phosphorylation of signaling molecules associated with the TCR signalosome including Lck, CD3zeta, ZAP70, LAT, SLP-76, Itk, and PLCgamma(15). In this article, we present a method to visualize supramolecular arrangement and membrane-proximal signaling events taking place during VS formation. We take advantage of the glass-supported planar bi-layer system as a reductionist model to represent the surface of HIV-infected cells bearing the viral envelope gp120 and the cellular adhesion molecule ICAM-1. The protocol describes general procedures for monitoring HIV-1 gp120-induced VS assembly and signal activation events that include i) bi-layer preparation and assembly in a flow cell, ii) injection of cells and immunofluorescence staining to detect intracellular signaling molecules on cells interacting with HIV-1 gp120 and ICAM-1 on bi-layers, iii) image acquisition by TIRF microscopy, and iv) data analysis. This system generates high-resolution images of VS interface beyond that achieved with the conventional cell-cell system as it allows detection of distinct clusters of individual molecular components of VS along with specific signaling molecules recruited to these sub-domains. PMID- 22433251 TI - Performance indicators for public mental healthcare: a systematic international inventory. AB - BACKGROUND: The development and use of performance indicators (PI) in the field of public mental health care (PMHC) has increased rapidly in the last decade. To gain insight in the current state of PI for PMHC in nations and regions around the world, we conducted a structured review of publications in scientific peer reviewed journals supplemented by a systematic inventory of PI published in policy documents by (non-) governmental organizations. METHODS: Publications on PI for PMHC were identified through database- and internet searches. Final selection was based on review of the full content of the publications. Publications were ordered by nation or region and chronologically. Individual PI were classified by development method, assessment level, care domain, performance dimension, diagnostic focus, and data source. Finally, the evidence on feasibility, data reliability, and content-, criterion-, and construct validity of the PI was evaluated. RESULTS: A total of 106 publications were included in the sample. The majority of the publications (n = 65) were peer-reviewed journal articles and 66 publications specifically dealt with performance of PMHC in the United States. The objectives of performance measurement vary widely from internal quality improvement to increasing transparency and accountability. The characteristics of 1480 unique PI were assessed. The majority of PI is based on stakeholder opinion, assesses care processes, is not specific to any diagnostic group, and utilizes administrative data sources. The targeted quality dimensions varied widely across and within nations depending on local professional or political definitions and interests. For all PI some evidence for the content validity and feasibility has been established. Data reliability, criterion- and construct validity have rarely been assessed. Only 18 publications on criterion validity were included. These show significant associations in the expected direction on the majority of PI, but mixed results on a noteworthy number of others. CONCLUSIONS: PI have been developed for a broad range of care levels, domains, and quality dimensions of PMHC. To ensure their usefulness for the measurement of PMHC performance and advancement of transparency, accountability and quality improvement in PMHC, future research should focus on assessment of the psychometric properties of PI. PMID- 22433252 TI - Sequential local injection of low-dose interferon-beta for maintenance therapy in stage II and III melanoma: a single-institution matched case-control study. AB - OBJECTIVE: To determine the beneficial effect of maintenance therapy in stage II and III melanoma by sequential local injection of low-dose interferon-beta. METHODS: We reviewed 46 patients with stage II and III primary melanoma at our institution from 2004 through 2009. Twenty-one patients were treated with interferon-beta maintenance therapy consisting of subcutaneous injection of natural interferon-beta at a dose of 3 * 10(6) IU/day for 10 consecutive days, and 25 patients underwent observation alone. RESULTS: Compared with all patients, overall survival and relapse-free survival were significantly worse in the observation group than in the interferon-beta group (p = 0.024 and 0.029, respectively). In stage II, a significant difference in overall survival, but not in relapse-free survival, was seen between the two groups (p = 0.041). When the interferon-beta group was stratified by subgroup, there was a statistical difference only between dosage and duration (p = 0.027 and p < 0.001, respectively). CONCLUSIONS: This study demonstrates that maintenance therapy by interferon-beta is beneficial in the outcome of the disease without substantial toxic effects, especially in patients with stage II melanoma. Extension of the duration of treatment beyond 2 years could further improve the therapeutic efficacy of interferon-beta. PMID- 22433253 TI - Ambulatory non-convulsive status epilepticus evolving into a malignant form. AB - We retrospectively analysed the clinical characteristics, electroencephalogram (EEG) records, brain magnetic resonance imaging (MRI) scans, antiepileptic therapy and prognosis of a case series with ambulatory non-convulsive status epilepticus (NCSE) which evolved into a malignant form (mNCSE). mNCSE was defined as NCSE that continues or recurs five days or more after the onset of general anaesthesia, including those cases where NCSE recurs upon reduction or withdrawal of anaesthetic therapy. Four women and two men were studied. The mean age was 42.8 years (range: 19-63 years). Two of six patients had a previous diagnosis of epilepsy. Four patients died. Two patients had a good outcome with return to consciousness and activities of daily life, and one of these subjects developed temporal lobe epilepsy. In four patients, the cause of mNCSE was encephalitis. Clinical presentation was complex partial status epilepticus (CPSE) in three patients and generalised NCSE (GNCSE) in the other three. Two of the latter had encephalitis and one was diagnosed with progressive myoclonus epilepsy (PME) of Lafora type. The mean duration of the NCSE episode was 47.5 days (range: 9-139 days; SD: 53.1). In three patients, continuous or rhythmic focal epileptiform discharges were the EEG pattern at onset. In the other three, continuous rhythmic generalised spike-wave, polyspike-wave or sharp slow-wave complexes were observed. Antiepileptic treatment was heterogeneous and patients were treated with an average of 6.0 AEDs (range: 3-10; SD: 3.0). In summary, mNCSE is a severe epileptic condition that occurs often in the context of encephalitis or pre existing epilepsy. Both CPSE and GNCSE may occur. Although high mortality is associated with mNCSE, some patients may survive with normal or good recovery. PMID- 22433254 TI - Lovastatin regulates brain spontaneous low-frequency brain activity in neurofibromatosis type 1. AB - In the neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a Phase 1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9 +/- 2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-min 3-T echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a flanker task. After regressing-out task associated variance, we used the residual time series as "continuous resting state data" for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model. PMID- 22433255 TI - The reliability of plantar pressure assessment during barefoot level walking in children aged 7-11 years. AB - BACKGROUND: Plantar pressure assessment can provide information pertaining to the dynamic loading of the foot, as well as information specific to each region in contact with the ground. There have been few studies which have considered the reliability of plantar pressure data and therefore the purpose of this study was to investigate the reliability of assessing plantar pressure variables in a group of typically developing children, during barefoot level walking. METHODS: Forty five participants, aged 7 to 11 years, were recruited from local primary and secondary schools in East London. Data from three walking trials were collected at both an initial and re-test session, taken one week apart, to determine both the within- and between-session reliability of selected plantar pressure variables. The variables of peak pressure, peak force, pressure-time and force time integrals were extracted for analysis in the following seven regions of the foot; lateral heel, medial heel, midfoot, 1st metatarsophalangeal joint, 2nd-5th metatarsophalangeal joint, hallux and the lesser toes. Reliability of the data were explored using Intra Class Correlation Coefficients (ICC 3,1 and 3,2) and variability with Coefficients of Variation (CoV's). RESULTS: The measurements demonstrated moderate to good levels of within-session reliability across all segments of the foot (0.69-0.93), except the lesser toes, which demonstrated poor reliability (0.17-0.50). CoV's across the three repeated trials ranged from 10.12 19.84% for each of the measured variables across all regions of the foot, except the lesser toes which demonstrated the greatest variability within trials (27.15 56.08%). The between-session results demonstrated good levels of reliability across all foot segments (0.79-0.99) except the lesser toes; with moderate levels of reliability reported at this region of the foot (0.58-0.68). The CoV's between sessions demonstrated that the midfoot (16.41-36.23%) and lesser toe region (29.64-56.61) demonstrated the greatest levels of variability across all the measured variables. CONCLUSIONS: These findings indicate that using the reported protocols, reliable plantar pressure data can be collected in children, aged 7 to 11 years in all regions of the foot except the lesser toes which consistently reported poor-to-moderate levels of reliability and increased variability. PMID- 22433256 TI - Weight status associations with physical activity intensity and physical self perceptions in 10- to 11-year-old children. AB - The study examined associations between children's weight status, physical activity intensity, and physical self-perceptions. Data were obtained from 409 children (224 girls) aged 10-11 years categorized as normal-weight or overweight/obese. Physical activity was assessed using accelerometry, and children completed the Physical Self-Perception Profile. After controlling for the effects of age, maturation, and socioeconomic status vigorous physical activity was significantly associated with normal-weight status among boys (OR = 1.13, p = .01) and girls (OR = 1.13, p = .03). Normal-weight status was significantly associated with perceived Physical Condition (Boys: OR = 5.05, p = .008; Girls: OR = 2.50, p = .08), and Body Attractiveness (Boys: OR = 4.44, p = .007; Girls: OR = 2.56, p = .02). Weight status of 10-11 year old children was significantly associated with time spent in vigorous physical activity and self perceptions of Body Attractiveness and Physical Condition. PMID- 22433257 TI - Variation in sport participation, fitness and motor coordination with socioeconomic status among Flemish children. AB - Socioeconomic status (SES) is often indicated as a factor that influences physical activity and associated health outcomes. This study examined the relationship between SES and sport participation, morphology, fitness and motor coordination in a sample of 1955 Flemish children 6-11 years of age. Gender, age and SES-specific values for morphologic dimensions, amount and type of sport participation and fitness and motor coordination tests were compared. SES was positively and significantly associated with sport participation and sports club membership in both sexes. Although differences were not consistently significant, morphologic dimensions and tests of fitness and motor coordination showed a trend in favor of children from higher SES. The results suggest that public and local authorities should consider providing equal opportunities for children in all social strata and especially those in the lower SES to experience the beneficial effects of sport participation through which they can enhance levels of physical fitness and motor coordination. PMID- 22433258 TI - Validity of the oxygen uptake efficiency slope in children with cystic fibrosis and mild-to-moderate airflow obstruction. AB - PURPOSE: The oxygen uptake efficiency slope (OUES) has been proposed as an 'effort-independent' measure of cardiopulmonary exercise capacity, which could be used as an alternative measurement for peak oxygen uptake (VO(2peak)) in populations unable or unwilling to perform maximal exercise. The aim of the current study was to investigate the validity of the OUES in children with cystic fibrosis (CF). METHODS: Exercise data of 22 children with CF and mild to moderate airflow obstruction were analyzed and compared with exercise data of 22 healthy children. The OUES was calculated using data up to three different relative exercise intensities, namely 50%, 75%, and 100% of the total exercise duration, and normalized for body surface area (BSA). RESULTS: Only the OUES/BSA using the first 50% of the total exercise duration was significantly different between the groups. OUES/BSA values determined at different exercise intensities differed significantly within patients with CF and correlated only moderately with VO(2peak) and the ventilatory threshold. CONCLUSION: The OUES is not a valid submaximal measure of cardiopulmonary exercise capacity in children with mild to moderate CF, due to its limited distinguishing properties, its nonlinearity throughout progressive exercise, and its moderate correlation with VO(2peak) and the ventilatory threshold. PMID- 22433259 TI - Sensory integration and standing balance in adolescent taekwondo practitioners. AB - Taekwondo (TKD) is a popular sport among adolescents. This study aims to (a) compare the balance performance between adolescent TKD practitioners at different levels of expertise with nonpractitioners and (b) determine the sensory system(s) that contributed to the balance function in adolescents with and without TKD training. Subjects with >5 years of TKD training (n = 11), <4 years of training (n = 10), and no training (n = 10) participated in this study. The sway velocity, somatosensory, vestibular and visual ratios were recorded during standing on a balance testing system. Both short- and long-term TKD practitioners swayed slower than control subjects when standing on one leg (p = .016 and 0.012, respectively). However, only short-term practitioners have better visual ratio (p = .018) and vestibular ratio (p = .029) than control subjects. There was no significant difference in the somatosensory ratio among the 3 groups. We conclude that adolescents undertaking TKD training may have better balance performance than untrained subjects. PMID- 22433261 TI - Commentary on child-adult differences in muscle activation--a review. PMID- 22433260 TI - Child-adult differences in muscle activation--a review. AB - Children differ from adults in many muscular performance attributes such as size normalized strength and power, endurance, fatigability and the recovery from exhaustive exercise, to name just a few. Metabolic attributes, such as glycolytic capacity, substrate utilization, and VO2 kinetics also differ markedly between children and adults. Various factors, such as dimensionality, intramuscular synchronization, agonist-antagonist coactivation, level of volitional activation, or muscle composition, can explain some, but not all of the observed differences. It is hypothesized that, compared with adults, children are substantially less capable of recruiting or fully employing their higher-threshold, type-II motor units. The review presents and evaluates the wealth of information and possible alternative factors in explaining the observations. Although conclusive evidence is still lacking, only this hypothesis of differential motor-unit activation in children and adults, appears capable of accounting for all observed child-adult differences, whether on its own or in conjunction with other factors. PMID- 22433262 TI - Analyses of gait and jump tasks in female obese adolescents. AB - In spite of the advances in knowledge on the multi-factorial nature of obesity, many questions related to the consequences of the disease continue to be unanswered. Several studies have reported biomechanic and kinematic adaptation and alterations in walking and in tasks of every day life, motivated by the additional load of fat mass in children and adults. The main objective of this study was to understand the effect of obesity in the electromyographic activity of four lower extremity muscles during three speeds of walking and during a countermovement jump (CMJ) in twenty two (9 obese and 13 normal weight) female adolescents aged 13. Although electromyographic differences were not observed between groups for normal, slow and fast speeds, data suggests that the preferred pace of the obese is less efficient than that of the normal weight group. In CMJ task, differences in the after-fall jump phase were observed. More studies are needed to explain if the few differences observed between groups are caused by the bigger amount of fat mass. PMID- 22433263 TI - The relationship between motor proficiency and pedometer-determined physical activity in young children. AB - The aim of this study was to examine the relationship between motor proficiency and pedometer-determined physical activity in 5-6 year-old children. Participants (n = 232) were randomly recruited and assessed from 30 kindergartens in Northern Greece. Two trained researchers administered the measurements for the assessment of children's motor proficiency by using the BOTMP-SF. Physical activity was assessed by OMRON pedometers. Significant relationships between BOTMP-SF standard score and steps (S), aerobic walking time (AWT) and aerobic steps (AS), (p < .05) were found. When motor proficiency was divided into quartiles to assess the distribution of the relationship between motor proficiency and pedometer-derived variables, significant associations were found for AWT, S and AS (p < .001). Young children with high levels of motor proficiency were more active in contrast to their peers with lower motor proficiency. The findings add to the growing body of literature that considers motor skills/abilities as important elements of physical activity participation. ( ABBREVIATIONS: S-steps per day; AS-aerobic steps per day; AWT-aerobic walking time (minutes.day(-1)); BOTMP-SF-Bruininks Oseretsky Test of Motor Proficiency-Short Form (standard score)). PMID- 22433264 TI - Schools with fitter children achieve better literacy and numeracy results: evidence of a school cultural effect. AB - Relationships of academic achievement (government tests) with physical fitness (multistage run), physical activity (pedometers) and percent body fat (dual emission X-ray absorptiometry) were examined at both the aggregate school level and the individual child level using data collected from 757 children in 29 elementary schools. Statistical adjustments included gender, grade and socioeconomic status. Between-school relationships of the academic scores with fitness and physical activity were strong and positive, with some evidence of (negative) relationships with percent body fat. The between-child relationships were weaker, and nonexistent with percent body fat. Stronger between-school than between-child relationships favor the argument that variation in school cultures, characterized by concurrent attention to fitness and academic achievement, might play a more dominant role in explaining these relationships than any direct effect of fitness on academic achievement. PMID- 22433265 TI - A longitudinal evaluation of physical activity in Brazilian adolescents: tracking, change and predictors. AB - This study aimed to: 1) describe the change in leisure-time physical activity (LTPA) during early-to-mid adolescence; 2) analyze the tracking of LTPA; 3) identify the predictors of LTPA change. 4,120 adolescents were from 11 to 15 years old. Outcome was self-reported LTPA (min/wk). Boys increased their LTPA level over the four years (mean: 75 min/wk; 95%CI: 49,100), whereas a decrease was observed among girls (mean: -42 min/wk; 95%CI: -57,-28). Likelihood to be active at 15 years of age was 50% higher (95%CI: 39-62) among those who were active at 11 years. The main predictor of LTPA change was the number of physical activities performed at baseline. Regular physical activity early in life can predict this behavior afterward. PMID- 22433266 TI - The influence of relative age effects on the cardiorespiratory fitness levels of children age 9 to 10 and 11 to 12 years of age. AB - The aims of this study were firstly to examine whether there was an observed relative age effect in the cardiorespiratory fitness scores of 9-10 and 11-12 year old children, and secondly whether any observed effect was maintained after controlling for somatic maturity. Cardiorespiratory fitness data from 11,404 children aged 9-10 years and 3,911 children aged 11-12 years were obtained from a large cross-sectional field-based fitness testing program. A one-way ANOVA revealed a statistically significant relative age effect (p < .01) existed in the 20mSRT scores across all the age groups. Furthermore, ANCOVA analyses identified a statistically significant relative age effect was maintained after controlling for somatic maturation (p < .05). From a public health perspective these results confirm the existence of relative age effects for the first time and consequently may hold implications for relatively younger children in the accurate assessment of their cardiorespiratory fitness scores. PMID- 22433267 TI - The effect of training at a specific time-of-day on the diurnal variations of short-term exercise performances in 10- to 11-year-old boys. AB - The aim of this study was to assess the effect of time-of-day-specific training on the diurnal variations of short-term performances in boys. Twenty-four boys were randomized into a morning-training-group (07:00-08:00h; MTG), an evening training-group (17:00-18:00h; ETG) and a control-group (CG). They performed four tests of strength and power (unilateral isometric maximal voluntary contraction of the knee extensor muscles, Squat-Jump, Counter-Movement-Jump and Wingate tests) at 07:00 and 17:00h just before (T0) and after 6 weeks of resistance training (T1). In T0, the results revealed that short-term performances improved and oral temperature increased significantly from morning to afternoon (amplitudes between 2.36 and 17.5% for both oral temperature and performances) for all subjects. In T1, the diurnal variations of performances were blunted in the MTG and persisted in the ETG and CG. Moreover, the training program increase muscle strength and power especially after training in the morning hours and the magnitude of gains was greater at the time-of-day-specific training than at other times. In conclusion, these results suggest that time-of-day-specific training increases the child's anaerobic performances specifically at this time-of-day. Moreover, the improvement of these performances was greater after morning than evening training. PMID- 22433268 TI - Measuring and improving patient experience in primary care. PMID- 22433269 TI - Utilisation of strategic communication to create willingness to change work practices among primary care staff: a long-term follow-up study. AB - AIM: To evaluate the long-term utilisation of strategic communication as a factor of importance when changing work practices among primary care staff. BACKGROUND: In many health care organisations, there is a gap between theory and practice. This gap hinders the provision of optimal evidence-based practice and, in the long term, is unfavourable for patient care. One way of overcoming this barrier is systematically structured communication between the scientific theoretical platform and clinical practice. METHODS: This longitudinal evaluative study was conducted among a primary care staff cohort. Strategic communication was considered to be the intervention platform and included a network of ambassadors who acted as a component of the implementation. Measurements occurred 7 and 12 years after formation of the cohort. A questionnaire was used to obtain information from participants. In total, 846 employees (70%) agreed to take part in the study. After 12 years, the 352 individuals (60%) who had remained in the organisation were identified and followed up. Descriptive statistics and multivariate analysis were used to analyse the data. FINDINGS: Continuous information contributed to significant improvements over time with respect to new ideas and the intention to change work practices. There was a statistically significant synergistic effect on the new way of thinking, that is, willingness to change work practices. During the final two years, the network of ambassadors had created a distinctive image for itself in the sense that primary care staff members were aware of it and its activities. This awareness was associated with a positive change with regard to new ways of thinking. More years of practice was inversely associated with willingness to change work practices. Strategic communication may lead to a scientific platform that promotes high-quality patient care by means of new methods and research findings. PMID- 22433270 TI - Nurse-led case management in the National Health Service: bridging clinical and social worlds. AB - AIM: To understand the effects of Nurse Case Managers (NCMs) working in primary care in the English National Health Service (NHS) from multiple perspectives and how this new role impacts on social workers, this paper reports and discusses findings from a multi-level study of the role of NCMs working in primary care in the English NHS. BACKGROUND: Case management as understood by the NHS is equivalent to key-worker type care management as understood by social workers. However, English health and social services are separately organised with different organisational principles; health services are free at the time of need, whereas social services are means-tested and access is restricted. METHODS: The study included reviews of evaluations and policy, a national survey of nurse case management in Primary Care Trusts (PCTs) and case studies in three purposively selected PCTs. The views and experiences of patients were collected through face-to-face and telephone interviews with 51 older people and their carers, and these experiences are illustrated. In this paper, we further draw on data reporting the views of NCMs and stakeholders from other disciplines and services. FINDINGS: The opinions of older people receiving nurse case management reveal the value of high intensity support to individuals with major health and social needs. The NCMs' clinical expertise, the improved continuity of care they provided and the psychosocial support they offered, were all emphasised by older people or their carers. NCMs substituted for social workers in some cases, when the older person would not have been eligible for publicly funded social care or had declined it. In other cases, they supplemented social services by identifying unmet needs. In a third category of cases, they may have curtailed social services' involvement by preventing hospital admission and social services' involvement as a consequence. The implications of this from the viewpoint of other study participants are discussed. PMID- 22433271 TI - What are the patient-held illness beliefs after a transient ischaemic attack, and do they determine secondary prevention activities: an exploratory study in a North London General Practice. AB - BACKGROUND: A transient ischaemic attack (TIA) is a strong predictor of future stroke. Stroke is the most common cause of mortality in the United Kingdom. Management of risk factors can reduce the possibility of future strokes; however, these are often difficult to achieve optimally. Current evidence suggests that beliefs about causal attributions, severity and perceived risk of stroke may influence uptake of secondary prevention activities amongst this patient group. AIM: To explore the illness beliefs of patients about TIAs and future risk of stroke, and to determine whether these beliefs determine secondary stroke prevention activities. METHOD: A qualitative study comprising face-to-face, semi structured interviews conducted in the homes of participants. Sampling was purposive and drawn from a single North London General Practice. A thematic framework analysis method was followed. FINDINGS: Eleven participants took part in the study (aged 46-86 years, three female participants and eight male participants). Time since diagnosis ranged from 2 to 25 years. There was a commonly held belief that TIAs are 'short-lived events' associated with full recovery, whereas strokes always lead to permanent 'disability'. Only those who believed their TIAs to be 'serious' undertook activities to prevent further recurrence. Concordance with medication was the most popular prevention activity. CONCLUSION: The traditional medical definition of TIA and stroke do not reflect the views of patients who have had TIAs. One's perception of the severity of the initial TIA event and the risk of future stroke episodes may influence the uptake of secondary stroke prevention activities. Post TIA stroke prevention interventions should include tailored discussions focussing on the importance of the acute event and its implications for long-term health and future stroke risk. PMID- 22433272 TI - SAPC Hot Topic: the importance of 'health literacy' in primary care. PMID- 22433273 TI - Genome-wide microarray analysis of tomato roots showed defined responses to iron deficiency. AB - BACKGROUND: Plants react to iron deficiency stress adopting different kind of adaptive responses. Tomato, a Strategy I plant, improves iron uptake through acidification of rhizosphere, reduction of Fe3+ to Fe2+ and transport of Fe2+ into the cells. Large-scale transcriptional analyses of roots under iron deficiency are only available for a very limited number of plant species with particular emphasis for Arabidopsis thaliana. Regarding tomato, an interesting model species for Strategy I plants and an economically important crop, physiological responses to Fe-deficiency have been thoroughly described and molecular analyses have provided evidence for genes involved in iron uptake mechanisms and their regulation. However, no detailed transcriptome analysis has been described so far. RESULTS: A genome-wide transcriptional analysis, performed with a chip that allows to monitor the expression of more than 25,000 tomato transcripts, identified 97 differentially expressed transcripts by comparing roots of Fe-deficient and Fe-sufficient tomato plants. These transcripts are related to the physiological responses of tomato roots to the nutrient stress resulting in an improved iron uptake, including regulatory aspects, translocation, root morphological modification and adaptation in primary metabolic pathways, such as glycolysis and TCA cycle. Other genes play a role in flavonoid biosynthesis and hormonal metabolism. CONCLUSIONS: The transcriptional characterization confirmed the presence of the previously described mechanisms to adapt to iron starvation in tomato, but also allowed to identify other genes potentially playing a role in this process, thus opening new research perspectives to improve the knowledge on the tomato root response to the nutrient deficiency. PMID- 22433274 TI - Off-target cannabinoid effects mediated by GPR55. AB - Given the vast therapeutic potential of the endocannabinoid system, the revelation of a novel cannabinoid-sensitive target was treated with great excitement. The orphan G-protein coupled receptor 55 (GPR55) was initially touted as a novel cannabinoid target in early industrial patent literature. Consequently, numerous studies have revealed GPR55 expression in a diverse array of cells and tissues, regulating various physiological and pathological processes. Although a confusing cannabinoid profile has prevented its classification as a cannabinoid receptor, the therapeutic potential of the receptor cannot be denied, with roles in cancer progression, bone resorption and analgesia. This commentary aims to summarize GPR55 expression data and speculate on potential therapeutic exploitation of this enigmatic orphan receptor. PMID- 22433275 TI - Influence of an alkalizing supplement on markers of endurance performance using a double-blind placebo-controlled design. AB - BACKGROUND: Previous research has shown that ingestion of substances that enhance the body's hydrogen ion buffering capacity during high intensity exercise can improve exercise performance. The present study aimed to determine whether the chronic ingestion of an alkalizing supplement, which purports to enhance both intracellular and extracellular buffering capacity, could impact cardiorespiratory and performance markers in trained Nordic skiers. METHODS: Twenty-four skiers (12 men, 12 women), matched for upper body power (UBP), were split into treatment and placebo groups. The treatment group ingested Alka Myte(r)-based alkalizing tablets (1 tablet/22.7 kg body mass/day) over seven successive days while the placebo group consumed placebo tablets (i.e., no Alka Myte(r)) at the same dosage. Prior to tablet ingestion (i.e., pre-testing), both groups completed a constant power UBP test, three successive 10-sec UBP tests, and then a 60-sec UBP test. Next, skiers completed the 7-day ingestion of their assigned tablets followed immediately by a repeat of the same UBP tests (i.e., post-testing). Neither the skiers nor the researchers were aware of which tablets were being consumed by either group until after all testing was complete. Dependent measures for analysis included heart rate (HR), oxygen consumption (VO2), minute ventilation (VE), blood lactate (LA), as well as 10-sec (W10, W) and 60-sec (W60, W) UBP. All data were evaluated using a two-factor multivariate repeated measures ANOVA with planned contrasts for post-hoc testing (alpha = 0.05). RESULTS: Post-testing cardiorespiratory (HR, VO2, VE) and LA measures for the treatment group tended to be significantly lower when measured for both constant power and UBP60 tests, while measures of both 10-sec (W10: 229 to 243 W) and 60-sec UBP (W60: 190 to 198 W) were significantly higher (P < 0.05). In contrast, there were no significant changes for the placebo group (P > 0.05). CONCLUSIONS: Following the 7-day loading phase of Alka-Myte(r)-based alkalizing tablets, trained Nordic skiers experienced significantly lower cardiorespiratory stress, lower blood lactate responses, and higher UBP measures. Thus, the use of this supplement appeared to impart an ergogenic benefit to the skiers that may be similar to the effects expected from consuming well-studied extracellular buffering agents such as sodium bicarbonate. PMID- 22433276 TI - Protecting the retinal neurons from glaucoma: lowering ocular pressure is not enough. AB - The retina is theater of a number of biochemical reactions allowing, within its layers, the conversion of light impulses into electrical signals. The axons of the last neuronal elements, the ganglion cells, form the optic nerve and transfer the signals to the brain. Therefore, an appropriate cellular communication, not only within the different retinal cells, but also between the retina itself and the other brain structures, is fundamental. One of the most diffuse pathologies affecting retinal function and communication, which thus reverberates in the whole visual system, is glaucoma. This insidious disease is characterized by a progressive optic nerve degeneration and sight loss which may finally lead to irreversible blindness. Nevertheless, the progressive nature of this pathology offers an opportunity for therapeutic intervention. To better understand the cellular processes implicated in the development of glaucoma useful to envision a targeted pharmacological strategy, this manuscript first examines the complex cellular and functional organization of the retina and subsequently identifies the targets sensitive to neurodegeneration. Within this context, high ocular pressure represents a key risk factor. However, recent literature findings highlight the concept that lowering ocular pressure is not enough to prevent/slow down glaucomatous damage, suggesting the importance of combining the hypotensive treatment with other pharmacological approaches, such as the use of neuroprotectants. Therefore, this important and more novel aspect is extensively considered in this review, also emphasizing the idea that the neuroprotective strategy should be extended to the entire visual system and not restricted to the retina. PMID- 22433277 TI - Prevalence, genetic diversity and antiretroviral drugs resistance-associated mutations among untreated HIV-1-infected pregnant women in Gabon, central Africa. AB - BACKGROUND: In Africa, the wide genetic diversity of HIV has resulted in emergence of new strains, rapid spread of this virus in sub-Saharan populations and therefore spread of the HIV epidemic throughout the continent. METHODS: To determine the prevalence of antibodies to HIV among a high-risk population in Gabon, 1098 and 2916 samples were collected from pregnant women in 2005 and 2008, respectively. HIV genotypes were evaluated in 107 HIV-1-positive samples to determine the circulating subtypes of strains and their resistance to antiretroviral drugs (ARVs). RESULTS: The seroprevalences were 6.3% in 2005 and 6.0% in 2008. The main subtype was recombinant CRF02_AG (46.7%), followed by the subtypes A (19.6%), G (10.3%), F (4.7%), H (1.9%) and D (0.9%) and the complex recombinants CRF06_cpx (1.9%) and CRF11_cpx (1.9%); 12.1% of subtypes could not be characterized. Analysis of ARVs resistance to the protease and reverse transcriptase coding regions showed mutations associated with extensive subtype polymorphism. In the present study, the HIV strains showed reduced susceptibility to ARVs (2.8%), particularly to protease inhibitors (1.9%) and nucleoside reverse transcriptase inhibitors (0.9%). CONCLUSIONS: The evolving genetic diversity of HIV calls for continuous monitoring of its molecular epidemiology in Gabon and in other central African countries. PMID- 22433278 TI - Aciclovir for dual infection with HIV and HSV. PMID- 22433279 TI - Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial. AB - BACKGROUND: Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV 1 disease progression in Rakai, Uganda. METHODS: We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per MUL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per MUL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to treat analysis used Cox proportional hazards models, adjusting for baseline log(10) viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. FINDINGS: 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0.75, 95% CI 0.58-0.99; p=0.040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50,000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0.62, 0.43-0.96; p=0.03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50,000 copies per mL (0.90, 0.54-1.5; p=0.688). No safety issues related to aciclovir treatment were identified. INTERPRETATION: Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50,000 copies per mL or more before initiation of antiretroviral treatment. FUNDING: National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA). PMID- 22433280 TI - Gastric autoimmunity in children and adolescents with type 1 diabetes: a prospective study. AB - BACKGROUND/AIMS: Type 1 diabetes (T1DM) is associated with gastric autoimmunity, which is characterized by the presence of parietal cell antibodies (APCA). We investigated gastric autoimmunity prevalence in T1DM children, its manifestations, determinants and association with thyroid gland (anti-Tg, anti TPO) and pancreatic beta-cell autoimmunity (anti-GAD) at baseline and 4 years later. METHODS: The initial cohort (D1) included 97 children with T1DM. At follow up after 4 years (D2), 84.5% of participants were evaluated. We assessed APCA, anti-Tg, anti-TPO, and anti-GAD presence, as well as symptoms of gastritis. APCA positive patients were evaluated with gastrin, B12, ferritin levels and were submitted to gastroscopy. RESULTS: Thyroid antibody positivity was increased among the APCA-positive patients. Four years later, among initially APCA-positive patients, 2/6 became APCA negative, while 4/6 developed high titers of APCA. On gastroscopy, 2 patients had chronic hypertrophic gastritis and one Helicobacter pylori gastritis. CONCLUSIONS: Gastric autoimmunity was associated with thyroid autoimmunity and anti-GAD persistence. After 4 years, the majority of APCA positive patients developed high titers of APCA and mild symptoms of gastritis. Thus, patients with T1DM, and in particular those with thyroid and/or pancreatic autoimmunity, should have periodic autoantibody screening for the early diagnosis and follow-up of gastric autoimmunity. PMID- 22433281 TI - JETTA: junction and exon toolkits for transcriptome analysis. AB - SUMMARY: High-throughput genome-wide studies of alternatively spliced mRNA transcripts have become increasingly important in clinical research. Consequently, easy-to-use software tools are required to process data from these studies, for example, using exon and junction arrays. Here, we introduce JETTA, an integrated software package for the calculation of gene expression indices as well as the identification and visualization of alternative splicing events. We demonstrate the software using data of human liver and muscle samples hybridized on an exon-junction array. AVAILABILITY: JETTA and its demonstrations are freely available at http://igenomed.stanford.edu/~junhee/JETTA/index.html PMID- 22433282 TI - Aortic or carotid intima-media thickness to evaluate children born small for gestational age? PMID- 22433283 TI - The transition of adult patients with childhood-onset chronic diseases from pediatric to adult healthcare systems: a survey of the perceptions of Japanese pediatricians and child health nurses. AB - BACKGROUND: Advances in medical science have enabled many children with chronic diseases to survive to adulthood. The transition of adult patients with childhood onset chronic diseases from pediatric to adult healthcare systems has received attention in Europe and the United States. We conducted a questionnaire survey among 41 pediatricians at pediatric hospitals and 24 nurses specializing in adolescent care to compare the perception of transition of care from pediatric to adult healthcare services for such patients. FINDINGS: Three-fourths of the pediatricians and all of the nurses reported that transition programs were necessary. A higher proportion of the nurses realized the necessity of transition and had already developed such programs. Both pediatricians and nurses reported that a network covering the transition from pediatric to adult healthcare services has not been established to date. CONCLUSIONS: It has been suggested that spreading the importance of a transition program among pediatricians and developing a pediatric-adult healthcare network would contribute to the biopsychosocial well-being of adult patients with childhood-onset chronic disease. PMID- 22433284 TI - Discovery of novel A3 adenosine receptor ligands based on chromone scaffold. AB - A project focused on the discovery of new chemical entities (NCEs) as AR ligands that incorporate a benzo-gamma-pyrone [(4H)-1-benzopyran-4-one] substructure has been developed. Accordingly, two series of novel chromone carboxamides placed at positions C2 (compounds 2-13) and C3 (compounds 15-26) of the gamma-pyrone ring were synthesized using chromone carboxylic acids (compounds 1 or 14) as starting materials. From this study and on the basis of the obtained structure-activity relationships it was concluded that the chromone carboxamide scaffold represent a novel class of AR ligands. The most remarkable chromones were compounds 21 and 26 that present a better affinity for A3AR (Ki = 3680 nM and Ki = 3750 nM, respectively). Receptor-driven molecular modeling studies provide information on the binding/selectivity data of the chromone. The data so far acquired are instrumental for future optimization of chromone carboxamide as a selective A3AR antagonist. PMID- 22433285 TI - Lack of association of white matter lesions with ipsilateral carotid artery stenosis. AB - BACKGROUND: White matter lesions (WML) are commonly seen on brain MRI and are generally considered a marker of tissue damage from cerebral small vessel disease. WML are associated with increasing age and vascular risk factors, but their precise cause is unknown. A role for carotid artery atherothromboemboli has been suggested. If this is the case, more WML would be expected ipsilateral to increasing degrees of carotid stenosis. METHODS: We recruited patients with ischaemic stroke from two large, separate prospective stroke studies, assessed with brain MRI and carotid Doppler ultrasound. We scored hemispheric WML visually in periventricular and deep locations. We assessed the association between carotid stenosis asymmetry and WML asymmetry, and vice versa. Further, we assessed the association between carotid stenosis and ipsilateral WML, before and after adjusting for vascular risk factors, and tested associations between ipsilateral and contralateral stenoses and WML. RESULTS: We recruited 247 (Study 1) and 253 (Study 2) patients. In Study 1 and Study 2, 36 (15%) and 29 (11%) patients had >=50% carotid stenosis, and 27 (11%) and 15 (6%) had >=70% stenosis, respectively. Carotid stenosis was asymmetric in 28 (11%) and 26 (10%) patients and WML were asymmetric in 22 (9%) and 11 (4%) patients in Study 1 and Study 2, respectively. We found no association between carotid stenosis and ipsilateral WML score, before or after adjusting for vascular risk factors or sidedness, but WML were strongly associated with increasing age (p < 0.001). CONCLUSION: In two large cohorts of ischaemic stroke patients, we found no association between carotid stenosis and ipsi- or contralateral WML. There is now substantial evidence that atherothromboemboli are unlikely to cause most WML or other forms of cerebral small vessel lesions. Future studies should focus on determining what causes the intrinsic small vessel pathological changes that appear to underlie most WML. PMID- 22433286 TI - Hepatic steatosis, GH deficiency and the effects of GH replacement: a Liverpool magnetic resonance spectroscopy study. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is reported to be more common in patients with GH deficiency (GHD) than in the general population. we aimed to determine: i) liver fat in patients with GHD compared with age and body mass index (BMI)-matched controls; and ii) effect of 6 months of GH replacement (GHR) on liver fat. PARTICIPANTS AND METHODS: The study included 28 GHD patients and 24 controls. 12 patients were studied before and after 6 months of GHR. Anthropometry, liver enzymes and lipid profiles were measured, and body composition and intrahepatocellular lipid (IHCL) were determined by magnetic resonance imaging and spectroscopy. RESULTS: Age and BMI (median (inter-quartile range)) of patients and controls were 52.6 (14) vs 52.6 (12) years (P=0.9) and 27.8 (24.7, 34.7) vs 27.9 (25.1, 32.1) kg/m(2) (P=0.9). IGF1 was lower in the patients (11.5 vs 16.0 nmol/l, P=0.002). There was no difference in liver transaminases, lipids or IHCL between patients and controls (2.8 (1.3, 8.6) vs 5.0 (1.5, 12.7), P=0.72), despite significantly higher visceral fat in GHD patients. Thirty-two percent of patients and 50% of controls had NAFLD (defined as IHCL >5.6%), and the relationship between IHCL and BMI was the same in each group. GHR significantly reduced abdominal subcutaneous and visceral fat in all patients; however, GHR did not reduce liver fat. CONCLUSIONS: NAFLD is equally common in patients with GHD and matched controls. GHR is associated with a hierarchical reduction in fat deposition (fat loss: visceral > subcutaneous > liver). Further studies involving GHD patients with NAFLD are required to conclude the role of GHR in treating NAFLD. PMID- 22433287 TI - Two networks involved in producing and realizing plans. AB - Planning is essential for normal daily activities. Although the dorsolateral prefrontal cortex (DLPFC) is thought to be crucially involved in planning, it remains to be understood whether this contribution is attributable to working memory requirements of the tasks and when it occurs, whether during initial planning or during subsequent plan execution. Here, we compared patterns of activation observed when participants planned and executed their plans to solve Tower of Hanoi problems to when they had to memorize and reproduce externally presented sequences of moves. The DLPFC was preferentially active during initial planning relative to both plan execution and initial memorization of sequences of moves. By contrast, plan execution relied on posterior temporal areas, inferior frontal regions and the dorsolateral premotor cortex. We attribute activation in DLPFC to generation and evaluation of abstract sequences of responses, and activation in the regions underlying plan execution to rehearsal of planned sequences of moves. PMID- 22433288 TI - Ventromedial frontal lobe damage disrupts the accuracy, but not the speed, of value-based preference judgments. AB - The ventromedial frontal lobe (VMF) plays a role in decision making, but its precise function remains unclear. Several lines of evidence suggest that VMF is involved in representing the economic value of options. A prior study from our lab has shown that patients with lesions to the VMF are less consistent than controls in making simple preference judgments between stimuli presented in pairs. Here, we followed up that observation in a larger sample, using more sensitive tasks, and examining the category-specificity of this effect. Patients with damage to VMF (N=15) were compared to patients with frontal damage sparing that region (N=8) and to demographically matched healthy control participants (N=23). Five separate preference tasks were administered, requiring subjects to indicate their preference for 12 stimuli presented two at a time, in all possible combinations. Categories included fruits, vegetables, colors, landscapes, and puppies. Choices were analyzed for internal consistency, and decision times were measured. Three control tasks with the same format, but requiring perceptual judgments, were also administered. VMF patients were significantly more erratic than both non-VMF and healthy control participants in their preference judgments across all stimulus categories. However, decision times, and the relationship between decision time and relative value, were similar to that seen in control participants. The groups did not differ in perceptual judgment performance. These findings add further weight to the claim that VMF plays a critical role in simple value-based decision-making under conditions of certainty. This region appears to be necessary for consistent choices across a variety of stimulus categories, supporting the view that human VMF represents the (relative) value of decision options rather generally. That such damage impairs decision 'accuracy' without affecting reaction time has implications for theories of the role of VMF in decision-making, arguing that this region may be critical for linking a particular value to a particular option. PMID- 22433289 TI - Spatio-temporal manipulation of small GTPase activity at subcellular level and on timescale of seconds in living cells. AB - Dynamic regulation of the Rho family of small guanosine triphosphatases (GTPases) with great spatiotemporal precision is essential for various cellular functions and events(1, 2). Their spatiotemporally dynamic nature has been revealed by visualization of their activity and localization in real time(3). In order to gain deeper understanding of their roles in diverse cellular functions at the molecular level, the next step should be perturbation of protein activities at a precise subcellular location and timing. To achieve this goal, we have developed a method for light-induced, spatio-temporally controlled activation of small GTPases by combining two techniques: (1) rapamycin-induced FKBP-FRB heterodimerization and (2) a photo-caging method of rapamycin. With the use of rapamycin-mediated FKBP-FRB heterodimerization, we have developed a method for rapidly inducible activation or inactivation of small GTPases including Rac(4), Cdc42(4), RhoA(4) and Ras(5), in which rapamycin induces translocation of FKBP fused GTPases, or their activators, to the plasma membrane where FRB is anchored. For coupling with this heterodimerization system, we have also developed a photo caging system of rapamycin analogs. A photo-caged compound is a small molecule whose activity is suppressed with a photocleavable protecting group known as a caging group. To suppress heterodimerization activity completely, we designed a caged rapamycin that is tethered to a macromolecule such that the resulting large complex cannot cross the plasma membrane, leading to virtually no background activity as a chemical dimerizer inside cells(6). Figure 1 illustrates a scheme of our system. With the combination of these two systems, we locally recruited a Rac activator to the plasma membrane on a timescale of seconds and achieved light induced Rac activation at the subcellular level(6). PMID- 22433290 TI - Plasma diamine oxidase activity is a useful biomarker for evaluating gastrointestinal tract toxicities during chemotherapy with oral fluorouracil anti cancer drugs in patients with gastric cancer. AB - OBJECTIVES: Diamine oxidase (DAO) is an enzyme that catalyzes oxidation and is highly active in the mature upper villus cells of the intestinal mucosa. This study sought to evaluate plasma DAO activities during adjuvant chemotherapy in patients with gastric cancer. METHODS: We investigated 20 patients with gastric cancer who were treated with oral fluorouracil anti-cancer drugs as adjuvant chemotherapy. Plasma DAO activity was measured in all patients before chemotherapy and at 2, 4 and 6 weeks after the start of chemotherapy, and quality of life was evaluated simultaneously. RESULTS: The median DAO activity after 4 weeks of chemotherapy was significantly decreased compared to the pre chemotherapy levels (6.6 vs. 7.5 U/l; p = 0.038). The changes in the rate of DAO activity at 2 and 6 weeks following the start of chemotherapy in patients with gastrointestinal tract toxicity were significantly lower than in those without toxicity (p =0.021 and 0.047, respectively). The patient cohort showed a slightly positive correlation between DAO activity and global health status and a negative correlation between DAO activity and appetite loss. CONCLUSIONS: Plasma DAO activities may be useful for monitoring and evaluating gastrointestinal tract toxicities induced by adjuvant chemotherapy with oral fluorouracil in patients with gastric cancer. PMID- 22433291 TI - Alcohol and cannabis use among adolescents in Flemish secondary school in Brussels: effects of type of education. AB - BACKGROUND: Research regarding socio-economic differences in alcohol and drug use in adolescence yields mixed results. This study hypothesizes that (1) when using education type as a proxy of one's social status, clear differences will exist between students from different types of education, regardless of students' familial socio-economic background; (2) and that the effects of education type differ according to their cultural background. METHODS: Data from the Brussels youth monitor were used, a school survey administered among 1,488 adolescents from the 3rd to 6th year of Flemish secondary education. Data were analyzed using multilevel logistic regression models. RESULTS: Controlling for their familial background, the results show that native students in lower educational tracks use alcohol and cannabis more often than students in upper educational tracks. Such a relationship was not found for students from another ethnic background. CONCLUSION: Results from this study indicate that research into health risks should take into account both adolescents' familial background and individual social position as different components of youngsters' socio-economic background. PMID- 22433292 TI - Positron emission tomography detection of human endothelial cell and fibroblast monolayers: effect of pretreament and cell density on 18FDG uptake. AB - BACKGROUND: The non-destructive assessment and characterization of tridimensional (3D) cell and tissue constructs in bioreactors represents a challenge in tissue engineering. Medical imaging modalities, which can provide information on the structure and function of internal organs and tissues in living organisms, have the potential of allowing repetitive monitoring of these 3D cultures in vitro. Positron emission tomography (PET) is the most sensitive non-invasive imaging modality, capable of measuring picomolar amounts of radiolabeled molecules. However, since PET imaging protocols have been designed almost exclusively for in vivo investigations, suitable methods must be devised to enable imaging of cells or tissue substitutes. As a prior step to imaging 3D cultures, cell radiotracer uptake conditions must first be optimized. METHODS: In this study, human umbilical vein endothelial cells (HUVEC) and human fibroblasts were cultured at different densities and PET was used to non-destructively monitor their glycolytic activity by measuring 18F-fluorodeoxyglucose (18FDG) uptake. Various cell preconditioning protocols were investigated by adjusting the following parameters to optimize 18FDG uptake: glucose starvation, insulin stimulation, glucose concentration, 18FDG incubation time, cell density and radiotracer efflux prevention. RESULTS: The conditions yielding optimal 18FDG uptake, and hence best detection sensitivity by PET, were as follows: 2-hour cell preconditioning by glucose deprivation with 1-hour insulin stimulation, followed by 1-hour 18FDG incubation and 15-minute stabilization in standard culture medium, prior to rinsing and PET scanning. CONCLUSIONS: A step-wise dependence of 18FDG uptake on glucose concentration was found, but a linear correlation between PET signal and cell density was observed. Detection thresholds of 36 +/- 7 and 21 +/- 4 cells were estimated for endothelial cells and fibroblasts, respectively. PMID- 22433293 TI - In vitro screening for cestocidal activity of three species of Cassia plants against the tapeworm Raillietina tetragona. AB - Different species of Cassia plant are widely available in India and are commonly used either for their laxative, antimicrobial or antibacterial activity. In the present study the effectiveness in vitro of the crude alcoholic extracts of three species, namely Cassia alata, C. occidentalis and C. angustifolia, in the early paralysis and mortality of the fowl tapeworm Raillietina tetragona at concentrations ranging from 5 to 80 mg/ml was investigated. Time of paralysis and death were monitored frequently. Immediately after paralysis the tapeworms were processed for electron microscopic studies. While the untreated or control parasites survived for 81.93 +/- 5.85 h, the parasites treated with C. alata took less time (1.68 +/- 0.27 h) to be paralysed, followed by those treated with C. angustifolia (2.95 +/- 0.29 h). Although C. occidentalis took more time (4.13 +/- 0.31 h) to paralyse, in combination with either C. alata or C. angustifolia the time taken to paralyse became shorter. All the plant-treated parasites showed irrevocable changes in the scolex and proglottids as compared with the control, and these observations are comparable with those obtained with praziquantel. These results indicate that the three plants tested can be claimed to have anthelmintic activity in addition to their known properties, both when used individually and in combination. Further investigations will be required to evaluate their mechanism of action. PMID- 22433294 TI - Differential effects of cocaine access and withdrawal on glutamate type 1 transporter expression in rat nucleus accumbens core and shell. AB - Cocaine addiction is characterized by compulsive drug seeking, including relapse after a period of withdrawal. The relapse response requires increased glutamate transmission in the nucleus accumbens (NAc). Consistent with this view, glutamate type 1 transporter (GLT1), the transporter responsible for >90% of glutamate uptake, is downregulated in NAc after several days of withdrawal in rats previously trained to self-administer cocaine under limited access conditions (1 2 h/d). Human addiction, however, appears to be better modeled by extending daily drug access (6-8 h/d) and introducing long periods of withdrawal. Here, we determined the combined effects of manipulating cocaine access and withdrawal on GLT1 expression in NAc core and shell. Rats were trained to self-administer cocaine (0.25 mg per intravenous infusion) in daily limited or extended access sessions for 11 days followed by a period of short (1 day) or long (40-45 days) withdrawal. We found that although cocaine withdrawal decreases GLT1 expression in both core and shell, only in core is GLT1 downregulation sensitive to both access and withdrawal. In fact, after long withdrawal, GLT1 in core is downregulated more than in shell in either the limited or extended access condition. Thus, glutamate regulation in core appears to be a critical factor in the drug-seeking behavior that follows relatively long periods of cocaine withdrawal. PMID- 22433295 TI - Structural hemispheric asymmetries in the human precentral gyrus hand representation. AB - The superior region of the precentral gyrus (preCG) is known to be actively involved with hand function and has been proposed as a possible neural correlate of handedness. To test this hypothesis, we used a combined voxel-based morphometric (VBM) asymmetry analysis of structural MRI, along with diffusion MRI (dMRI) tractography to investigate laterality indices of corticomotor white matter (WM) pathways, based on measures of fractional anisotropy (FA). The relationship between measures of motor performance and FA laterality indices was also investigated. In a cohort of 14 right-handed healthy participants, the VBM asymmetry analysis revealed an area within the preCG associated with hand representation. The tractography analysis revealed that this region possessed a number of major WM intrahemispheric connections to the brain stem, thalamus, cerebellum, postcentral, caudal middle and superior frontal, and superior and inferior parietal corticomotor regions. Within the corticospinal tracts, we found FA was significantly higher in the left hemisphere compared with the right. Furthermore, significant correlations were found between FA asymmetry measures projecting from this region, namely corticospinal tracts and those connecting the postcentral gyri, with grip strength and finger-tapping performance, respectively. A number of the motor pathways projecting from this region also exhibited leftward asymmetry of FA distributions. The findings from this study highlight the role of the left motor cortex in skilled motor performance and provide a framework for the study of the relationship between handedness and preCG hand representation in larger normative populations. PMID- 22433296 TI - Social status alters defeat-induced neural activation in Syrian hamsters. AB - Although exposure to social stress leads to increased depression-like and anxiety like behavior, some individuals are more vulnerable than others to these stress induced changes in behavior. Prior social experience is one factor that can modulate how individuals respond to stressful events. In this study, we investigated whether experience-dependent resistance to the behavioral consequences of social defeat was associated with a specific pattern of neural activation. We paired weight-matched male Syrian hamsters in daily aggressive encounters for 2 weeks, during which they formed a stable dominance relationship. We also included control animals that were exposed to an empty cage each day for 2 weeks. Twenty-four hours after the final pairing or empty cage exposure, half of the subjects were socially defeated in 3, 5-min encounters, whereas the others were not socially defeated. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non aggressive intruder. We collected brains after social defeat and processed the tissue for c-Fos immunoreactivity. We found that dominants were more likely than subordinates to counter-attack the resident aggressor during social defeat, and they showed less submissive and defensive behavior at conditioned defeat testing compared with subordinates. Also, social status was associated with distinct patterns of defeat-induced neural activation in select brain regions, including the amygdala, prefrontal cortex, hypothalamus, and lateral septum. Our results indicate that social status is an important form of prior experience that predicts both initial coping style and the degree of resistance to social defeat. Further, the differences in defeat-induced neural activation suggest possible brain regions that may control resistance to conditioned defeat in dominant individuals. PMID- 22433297 TI - Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization. AB - Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3 methoxypropionamide ((R)-lacosamide [LCM]), which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM-binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ~8-fold. LCM also reduced CRMP2 mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization, which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison with injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM's mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting. PMID- 22433298 TI - The hemisegmental locomotor network revisited. AB - The organization of the minimal neuronal substrate capable of generating locomotor rhythmicity in vertebrates is investigated in several species, with an emphasis on identifying evolutionary-conserved features. In lamprey, an eel-like lower vertebrate that swims by undulatory movements of the body, the network has been identified as a recurrent network of excitatory interneurons localized in each spinal hemisegment. This conclusion rested upon the observation that each side of the spinal cord is able to express rhythmic locomotor-related bursting after being surgically separated along the midline, even in the absence of inhibition. An important caveat, however, is that this rhythmicity must be an intrinsic capability of the hemisegmental networks and not a newly acquired property as a result of a plastic remodeling of the network occurring after the lesion. Here we examine this issue by recording the motor output expressed by the electrically activated hemicord in the first minutes after hemisection. We observed clear rhythmic bursting in the frequency range previously linked to the operation of the central pattern generator for swimming. Moreover, we recorded the output of the unilateral networks in the intact spinal cord (i.e. no midline section performed) by activating them with asymmetrical stimulation. We thus conclude that the lamprey hemicord does possess the intrinsic capability of generating the basic rhythmic drive of locomotion. The wider significance of these data stems from the lamprey being a model of axial locomotion, and from the many lesion studies previously performed in other animals. PMID- 22433299 TI - Orexin signaling in the paraventricular thalamic nucleus modulates mesolimbic dopamine and hedonic feeding in the rat. AB - Data from our laboratory indicate that the orexin system is involved in the regulation of both conditioned and unconditioned responding for palatable foods. Anticipation of food rewards activates orexin receptor containing neurons within the paraventricular nucleus of the thalamus (PVT). The PVT regulates mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens and modulates the processing of cognitive-emotional information, suggesting that the PVT may represent a unique brain region with the capacity to mediate orexinergic effects on brain dopamine and behavior. Here, we tested the hypothesis that PVT orexin signaling mediates mesolimbic dopamine and reward-based feeding. To do this we used a behavioral pharmacological approach in tandem with central genetic manipulation of the orexin-1 receptor in the PVT. Data from these studies indicate that orexin-A action in the PVT increases dopamine levels in the nucleus accumbens. In addition, endogenous orexin signaling in the PVT mediates locomotor activity and hedonic feeding responses. Together these data highlight the PVT as a critical site capable of mediating orexin action on brain dopamine and reward based feeding. PMID- 22433300 TI - A randomised, two-period, cross-over, open-label study to evaluate the pharmacokinetic profiles of single doses of two different flurbiprofen 8.75-mg lozenges in healthy volunteers. AB - AIMS: To compare the bioavailability of a new oromucosal formulation of flurbiprofen 8.75-mg lozenges, developed by Alfa Wassermann S.p.A. (test drug) to that of marketed flurbiprofen 8.75-mg lozenges (Benactiv Gola(r), reference drug). METHODS: This was an open, randomised, two-period, crossover, pharmacokinetic (PK) study in which flurbiprofen plasma levels were compared in 12 healthy volunteers after the administration of single doses (8.75 mg * 2) of two different oromucosal lozenges to be sucked and slowly dissolved in the mouth. A wash-out period of at least 7 days separated the two study periods. Blood samples were collected prior to dosing and at predefined intervals for 24 h after dose. Flurbiprofen plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. PK parameters maximum plasma concentration (C(max)), time to maximum plasma concentration (T(max)), area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-t)), area under the plasma concentration-time curve from time zero to infinity (AUC(0 )infinity) and half-life were calculated and compared by analysis of variance using treatment, period and sequence as sources of variation. Bioequivalence between the two formulations was based on 90% confidence intervals of the ratio of the geometric means of C(max) and AUC falling within the 0.80-1.25 range as defined in bioequivalence guidelines by regulators. Tolerability of the two formulations was assessed by adverse event monitoring, routine laboratory tests, physical examination, electrocardiographic tracing and vital sign measurements. RESULTS: All enrolled subjects completed the study. Bioequivalence without significant treatment effect was demonstrated between the test drug/reference drug ratios of mean C(max) and AUCs. Moreover, mean T(max) was superimposable. No safety parameter presented a clinically relevant variation after administration of either formulation that were therefore well tolerated. CONCLUSION: The new formulation of flurbiprofen 8.75-mg compressed lozenges developed by Alfa Wassermann S.p.A. is bioequivalent to the reference product flurbiprofen 8.75-mg lozenges (Benactiv Gola) in healthy volunteers. PMID- 22433301 TI - [Quantitative analyses of intrahepatic HBV cccDNA and serum HBsAg in 54 patients with chronic hepatitis B]. AB - OBJECTIVE: To quantitatively detect intrahepatic HBV covalently closed circular DNA (cccDNA) and serum HBsAg; and to analyze the relationship between the two parameters and with serum HBV DNA level. METHODS: Intrahepatic cccDNA (copies/cell) was quantitated by plasmid-safe ATP-dependent Danes (PSAD) digestion in combination with rolling circle amplification and gap-spanning selective real-time PCR assay using formalin fixed paraffin-embedded liver biopsy samples. HBsAg was measured by chemiluminescence's reagent manufactured by Abbott Company using sera sampled at time-point of liver biopsy. RESULTS: Intrahepatic cccDNA level was positively correlated with serum HBsAg level (r = 0.459, P < 0.001), but not correlated with serum HBV DNA level. Serum HBsAg level was positively correlated with serum HBV DNA level (r = 0.328, P = 0.015), and reversely correlated with HBV replicative efficiency defined as the ratio of serum HBV DNA to cccDNA (r = -0.373, P = 0.005). CONCLUSION: In patients with chronic hepatitis B, intrahepatic cccDNA level is correlated with serum HBsAg level. The two parameters combined with serum HBV DNA may comprehensively reflect HBV replication activity and help evaluation of antiviral therapeutic efficacy. PMID- 22433302 TI - [Abstract efficacy of combined vaccine for the prevention of HBV transmission in highly viremic HBeAg+ mothers and the HBV markers' dynamic change of babies in follow-up]. AB - OBJECTIVE: To evaluate the efficacy of combined vaccination with 200IU dose of HBIG and 20 MUg of anti-HBV vaccine for the prevention of HBV vertical transmission in babies delivered by HBeAg + and highly viremic mothers and the HBV markers' dynamic changes in babies during follow-up. METHODS: HBeAg + mothers with HBV DNA >= to 1.0 * 6 log(10) copies/ml were enrolled and their babies were followed up until 12 months old. The infants received HBIG 200 IU IM in 24 hrs and on day 15, and 20 MUg recombinant anti-HBV vaccine at 0, 1 and 6 months. The HBV markers and HBV DNA were tested at birth day, and 1, 7, 12 months after birth respectively. The vertical transmission rate at birth and intrauterine infection rate, the HBsAb positive rate and the HBV markers' dynamic changes during follow up were evaluated. RESULTS: (1) 29 out of 127 infants with HBsAg (+) at birth, 11 of which were HBV DNA (+), HBV perinatal transmission rate was 22.83%. 2 infants' HBsAg were positive at month 1 and became negative at month 7 and 10 infants were still HBsAg (+) and HBV DNA (+). HBV intrauterine infection rate was 7.87%. (2) The positive rate of HBeAg and HBcAb in uninfected infants were 96.58% and 98.29% respectively, which declined gradually to undetectable level after immunization. No infants were HBeAb (+). (3) Infants uninfected produced effective HBsAb after vaccination. The level of HBsAb elevated gradually, and the level of HBeAg decreased quickly even to undetectable. CONCLUSION: The combination vaccination of 200 IU HBIG with 20 MUg recombinant anti-HBV vaccine in the Infants delivered by HBeAg (+) and highly viremic mothers reduced obviously the rate of perinatal transmission of HBV, enhanced largely the production of antibody against HBV surface antigen and dropped the maternal HBeAg and HBcAb in infants or even to negative. PMID- 22433303 TI - [A five-year follow-up of one hundred and thirty-six patients of hepatitis C]. AB - OBJECTIVE: To investigate the clinical outcome and effect of interferon treatment on patients with chronic hepatitis C. METHODS: 136 cases of patients with chronic hepatitis C were followed up by methods of retrospective survey combined with prospective study. SPSS16. 0 was used to perform chi-square test and multiple logistic regression. RESULTS: 136 cases of patients were infected with HCV virus mainly through blood and blood products transfusion. They were diagnosed mainly between 2000 and 2005. 98 cases of them had anti-viral treatment with interferon and ribavirin, while the rest did not; 12 new cases developed HCV-related cirrhosis or liver carcinoma in five years, which accounted for 8.8% of the total. Among 76 cases once treated with interferon, 46 cases (60.5%) relapsed in five years. For patients with age < 40, the rates of cirrhosis and liver cancer were 0, and patients with age >= 40 but < 60 years, the rates of cirrhosis and liver cancer were 12.5% (7/56 cases), while for those >= 60 years old the rates were 35.7% (10/28 cases). The difference was significant ( B = 0.111, Wald = 4.324, P = 0.038) as analysed by logistic regression. The rates of cirrhosis and liver cancer were zero for those with normal or within twice the upper normal AST limit in five years, 43.5% (10/23 cases) for those with AST ranging from 2 to 4 fold the upper normal limit, and 58.3% (7/12 cases) for those with AST higher than four times the upper normal limit. The difference was also significant ( B = 2.184, Wald = 5.443, P = 0.02) by logistic regression analysis. The rate of relapse was 29.7% (11/37 cases) for those using pegylated interferon and 89.7% (35/39 cases) for those using interferon. The difference was significant ( Result of logistic regression showed-B = -2.077, Wald = 4.352, P = 0.037). The rate of relapse was 100% (15/15 cases) for those with treatment less than 24 weeks, 76.2% (16/21 cases) for those with treatment more than 24 weeks but less than 48 weeks, and 37.5% (14/40 cases) for those with treatment more than 48 weeks. The difference was significant (Result of logistic regression showed-B = -1.632, Wald = 6.651, P = 0.01). 42 cases of the relapsed (91.3%) were administrated with interferon once again with ideal effect. CONCLUSION: Hepatitis C virus infection increases the risk of liver cirrhosis and liver cancer. Interferon combined with ribavirin therapy could effectively control the virus and improve outcomes. We can reduce the incidence of relapse by choosing the treatment of pegylated interferon instead of interferon and by completing the full treatment. PMID- 22433304 TI - [Entecavir 1.0mg monotherapy or entecavir plus adefovir dipivoxil for patients with lamivudine-resistant chronic hepatitis B had suboptimal response to lamivudine plus adefovir dipivoxil]. AB - OBJECTIVE: To evaluate the efficacy of entecavir (ETV) 1.0 mg/d or ETV plus adefovir dipivoxil (ADV) in adults with chronic hepatitis B virus (HBV) infection who had previously resisted lamivudine (LAM) and failed with rescue treatment of LAM + ADV. METHODS: 40 patients were enrolled. 14 patients were treated with ETV 1.0 mg/d monotherapy while 26 patients were treated with ETV 1.0 mg/d + ADV 10 mg/d. The HBV DNA level, liver function, HBV serology and renal function were observed. RESULTS: There was no statistically significant difference with baseline situation between group ETV 1.0 mg and group ETV + ADV. HBV DNA level in group ETV 1.0 mg was (5.768 +/- 0.709) log10 copies/ml on baseline, and it declined to (4.712 +/- 0.846) log10 copies/ml, (3.914 +/- 0.996) log10 copies/ml, (3.702 +/- 0.934) log10 copies/ml, (3.879 +/- 0.913) log10 copies/ml and (3.855 +/- 1.070) log10 copies/ml at 4, 8, 12, 24 and 48 weeks. HBV DNA level in group ETV + ADV was (5.703 +/- 0.845) log10 copies/ml on baseline, and it declined to (4.476 +/- 0.905) log10 copies/ml, (3.590 +/- 0.884) log10 copies/ml, (2.987 +/- 0.673) log10 copies/ml and (2.933 +/- 0.535) log10 copies/ml at 4, 8, 12 and 24 weeks. At 24 weeks, there were 28.6% patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but there were 80.8% patients in group ETV + ADV achieved this level. Statistically significant difference existed between (x(2) = 8.469, P = 0.004 ). At 48 weeks, there were still 4 patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but patients in group ETV + ADV all achieved it. At 24 weeks, ALT levels of 42.9% patients in group ETV 1.0 mg were back to normal, but there were 92.3% patients' ALT levels back to normal in group ETV + ADV. There was statistically significant difference (x(2) = 9.337, P = 0.002). At 48 weeks, ALT levels of 57.1% patients in group ETV 1.0 mg were back to normal, but all patients' ALT levels were back to normal in group ETV + ADV. At 48 weeks, there was 1 patient with HBeAg seroconversion in group ETV 1.0 mg while there were 4 patients in group ETV + ADV. CONCLUSION: As rescue treatment for patients with chronic hepatitis B who had previously resisted LAM and failed with treatment of LAM + ADV, ETV + ADV was more efficient than ETV 1.0 mg monotherapy, and it can achieve better virological and biochemical response. PMID- 22433305 TI - [KCTD9, a novel potassium channel related gene, was highly expressed in hepatic NK cells and T cells of fulminant hepatitis mice induced by MHV-3]. AB - OBJECTIVE: To explore the mechanisms of a novel potassium channel gene named KCTD9 (potassium channel tetramerization domain containing 9) in model of fulminant viral hepatitis induced by murine hepatitis virus 3 (MHV-3). METHODS: 78 BALB/cJ mice(6 male) were randomly and equally assigned to two groups, model group of fulminant viral hepatitis induced by MHV3 and its control. 75 C3H/HeJ female mice were done into two groups, 39 for model group of chronic hepatitis induced by MHV3, 36 for control. Various samples including spleen, liver and lymphocytes from mice of two model groups and the controls were examined for KCTD9 expression by real time quantitative PCR and Immunohistochemistry. Independent-samples T test or one-way ANOVA were carried out in different groups. RESULTS: Increased expressions of KCTD9 mRNA was observed in livers of both model mice of fulminant viral hepatitis and chronic hepatitis. Compared with the control mice, the expressions of KCTD9 mRNA were up-regulated by 577.1-, 8.8-, 59.4- and 10.8-fold in hepatic NK cells, CD4+ T cells, CD8+ T cells and splenic NK cells respectively in model mice of fulminant viral hepatitis 48 hr post MHV-3 infection, whereas down-regulation by 43% and 69% in splenic CD4 + T cells and CD8+ T cells were found respectively. In contrast, in model mice of chronic viral hepatitis the expressions of KCTD9 mRNA were down-regulated by 71% and 51% in hepatic CD4+ T cells and NK cells, respectively. The expression of KCTD9 protein was mainly evidenced in infiltrative mononuclear cells of liver as shown by immunohistochemistry. Basal expression was also investigated and showed constitutive expression of KCTD9 in brain, thymus and other organs in BALB/cJ mice. CONCLUSION: A novel potassium channel gene KCTD9 was highly expressed in hepatic NK cells and T cells of fulminant hepatitis mice induced by MHV-3. PMID- 22433306 TI - [Toll-like receptor dependent innate immune responses by primary mouse hepatocytes and its control of HBV replication]. AB - OBJECTIVE: This report aims to investigate the Toll-like receptor (TLR) signaling pathways and induced antiviral activity in hepatocytes. METHODS: We isolated primary hepatocytes from wild-type C57BL/6 mice and examined the expression of TLR by realtime RT-PCR. Hepatocytes were stimulated with TLR 1-9 agonists and the supernatants were harvested. The secretion of cytokines were tested by ELISA. The antiviral effectors in supernatants were assayed via virus protection assay (in EMCV system) and the control of HBV replication were assessed via Southern blotting (in HBV system). RESULTS: We demonstrated that hepatocytes expressed TLR1-9. In accordance with these TLR expression profiles, hepatocytes responded to all TLR ligands by producing inflammatory cytokines (TNF-alpha or IL-6), to TLR -1,-3,-7 and -9 ligands by producing type I IFN (IFN-alpha or IFN-beta). Only TLR 3 and TLR 7 agonists could stimulate the production of high amounts of antiviral mediators by hepatocytes in virus protection assay. By contrast, supernatants from TLR1, -3 and -4 directly stimulated hepatocytes and TLR 3, -7 and -9 transfected hepatocytes were able to potently suppress HBV replication. CONCLUSION: Primary hepatocytes display a unique TLR signaling pathway and can control HBV replication after stimulation by TLR agonists in mice. It may be helpful for the development of TLR-based therapeutic approaches against hepatotropic virus. PMID- 22433307 TI - [Effects of exogenous TGF-beta3 on the expression of endogenous TGF-beta3 in hepatic stellate cell-T6 (HSC-T6)]. AB - OBJECTIVE: To investigate the effects of exogenous TGF-beta3 on the expression of endogenous TGF-b3 in hepatic stellate cell (HSC). METHODS: HSCs were cultured and divided into two groups: TGF-beta3 group and blank control group, the cells of TGF-beta3 group were exposed to TGF-b3 (10 ng/ml), whereas the blank control group was not treated. The cells were incubated in the presence of exogenous TGF beta3 and then (1) were harvested at 0h, 1h, 2h, 4h, 12h, 24h, and real time PCR was performed to detect the mRNA expression of endogenous TGF-beta3. (2) The cells were collected at 0h, 1h, 6h, 12h, and western-blot was used to detect the protein synthesis of endogenous TGF-beta3 in HSC; (3) The cell culture supernatant was harvested at 0h, 1h, 2h, 4h, 8h, 14h, 24h, and ELISA was performed to measure the total protein of extracellular TGF-beta3; HSCs were treated with TGF-beta3 (10 ng/ml) for 2h. The cells were then incubated in serum free medium and the cell culture supernatant was harvested at 2.25h, 2.5h, 3h, 4h, 6h, 10h and 14h. ELISA was used to detect the extracellular secret ion of endogenous TGF-beta3 by HSCs. RESULTS: (1) Exogenous TGF-beta3 treatment induced a marked increase in TGF-beta3 mRNA expression. By 2h of exogenous TGF-beta3 treatment, maximal TGF-beta3 mRNA expression levels (2.796 +/- 0.518) of 2.74 fold above control values (1.022 +/- 0.038) was reached (P < 0.05). Thereafter, TGF-beta3 mRNA expression level declined, and the expression level was maintained at level of 1.45-fold for at least 10h and was 1.18-fold above control values by 24h TGF-beta3 treatment (P < 0.05); (2) No significant difference about the intracellular protein expression level of endogenous TGF-beta3 was found between two groups. (P > 0.05); (3) The total expression level of TGF-beta3 reached a peak [(18.931 +/- 2.904) ng/ml] at 4h after TGF-beta3 treatment (1.89-fold higher than basic TGF-beta3 (10 ng/ml). After that, it slowly declined. The expression peak [(0.835 +/- 0.027) ng/ml] induction of extracellular secreted TGF-beta3 was at 3h (32.12-fold higher than control [(0.026 +/- 0.022) ng/ml], (P < 0.05). Thereafter, TGF-beta3 slowly decreased after the peak time, and their expressions were still statistically significant as compared to the control (P < 0.05). CONCLUSION: Exogenous TGF-beta3 could increase the expression of endogenous TGF beta3 mRNA and extracellular secreted TGF-beta3 protein obviously. PMID- 22433308 TI - [Dynamic expression of tropomyosin 1 in rat model of hepatic fibrosis and hepatic stellate cells]. AB - OBJECTIVE: To investigate the dynamic expression of TPM1 in rat model of hepatic fibrosis and hepatic stellate cells induced by TGFbeta1. METHOD: Thirty male SD rats were divided into control group (n = 6) and model group (n = 24). The rat model of hepatic fibrosis was established by intraperitoneal injection of dimethylnitrosamine(DMN). The sera were collected from portal vein and liver tissues were taken from animals 2, 4, 6, 8 weeks HSC-T6 cells were cultured and induced 48 hours by 5 ng/ml TGF-beta1. The pathological changes of liver were observed by Hematoxylin-Eosin and Masson Staining. Reverse Transcription polymerase chain reaction (RT-PCR), immunohistochemistry and Western-blotting were used to determine the mRNA and protein expressions of TPM1, TGFbeta1 and alpha-SMA in rat models and HSC-T6 cells and the localization of TPM1 in rat models. RESULTS: Rat models of hepatic fibrosis were successfully established. TPM1 was lowly stained in the wall of blood vessels in portal areas in normal livers, in fibrotic livers TPM1 was mainly stained along the fibrotic septum. The mRNA and protein expressions of TPM1 and alpha-SMA in rat models of hepatic fibrosis increased at the week 2 and peaked at week 6, which was statistical significance compared to control group, P < 0.05; TGF-beta1 increased at week 2 and it was higher than the levels in other groups at week 4, which was statistical significance compared to control group P < 0.05; Correlation analysis showed that TPM1 positively correlated with alpha-SMA and TGF-beta1, rs = 0.688, rs = 0.692, P < 0.01. In HSC-T6, the mRNA expressions of TPM1 and alpha-SMA increased after being induced by TGF -beta1. compare with control group, the differences were significant, P less than 0.05. CONCLUSION: TPM1 may be playing an important role in the occurrence and development of liver fibrosis. Maybe it could become a potential therapeutic target for hepatic fibrosis. PMID- 22433309 TI - [Effect of let-7c on the proliferation of human hepatocellular carcinoma cell HCCLM3]. AB - OBJECTIVE: To investigate let-7c's effect on the proliferation of human hepatocellular carcinoma cell HCCLM3 by transient transfection and the mechanism inside. METHODS: Lipofectamine 2000 was used to transfect miRNAs into HCCLM3 cells. The cells were divided into three groups, let-7c group: let-7c was transfected, negative control group: negative control miRNA was transfected, blank control group: nothing was transfected. The proliferation of HCCLM3 cells was evaluated using Cell Counting Kit-8 (CCK-8). The cell cycles of each group were assayed by flow cytometry. Western blot and Real time PCR were used to analyze the protein and mRNA expressions of cyclin D1. Statistical analysis was performed with SPSS 17.0. RESULTS: The absorbances of let-7c group were 0.70 +/- 0.05, 0.77 +/- 0.09 at 48 h and 72 h after transfection, lower than that of blank control group (0.97 +/- 0.10, 1.21 +/- 0.12) and negative control group (0.91 +/- 0.07, 1.12 +/- 0.09), 48 h: F = 14.431, P < 0.05, 72 h: F = 21.146, P < 0.05. The flow cytometry at 72 h after transfection revealed that let-7c increased the percentage of cells in G1 phase. The percentage of blank control group was 43.53% +/- 0.86%, the negative control group was 44.82% +/- 0.77%, and the let-7c group was 54.52% +/- 0.13%, F = 240.739, P < 0.05. let-7c suppressed expressions of cyclin D1 at both protein and mRNA levels. The protein levels of cyclin D1 were 0.48 +/- 0.09, 0.47 +/- 0.06 and 0.23 +/- 0.06 (F = 11.316, P < 0.05) in blank control group, negative control group and let-7c group, respectively. The mRNA levels were 1.03% +/- 0.29%, 1.01% +/- 0.11% and 0.63% +/- 0.14% (F=6.315, P < 0.05) in the above three groups, respectively. CONCLUSION: Let-7c can inhibit proliferation of HCCLM3 cells and increase the proportion of cells in G1 phase. The mechanism may be that let-7c represses the expressions of cyclin D1 at both protein and mRNA levels. PMID- 22433310 TI - [HBx gene down-regulates miR-192 expression and inhibits apoptosis of human hepatoma cell line HepG2]. AB - OBJECTIVE: To explore the mechanism by which HBV X gene(HBx) inhibits apoptosis of human hepatoma cell line HepG2 in terms of miRNA. METHODS: Three cell lines were prepared: HepG2 cells stably transfected with HBx (HepG2/HBx), HepG2 cells stably transfected with pcDNA3.1 (HepG2/pcDNA3.1) and HepG2 cells. Flow cytometry was adopted to measure the apoptosis of these three cells and Taqman fluorescence quantitative PCR was used to examine miR-192 expression. After HepG2 cells was transfected with miR-192, the apoptosis was analyzed by flow cytometry and the expressions of p53 and PUMA at mRNA and protein levels were evaluated by SYBR Green quantitative PCR and Western blot, respectively. RESULTS: Compared with HepG2/pcDNA3.1 cells (11.46% +/- 0.69%) and HepG2 cells (12.5% +/- 0.66%), the apoptosis rate of HepG2/HBx cells (2.37% +/- 0.35%) was significantly reduced (F = 171.722, P < 0.01). The level of miR-192 was 49.1% +/- 5.9% in HepG2 cells, which was dramatically down-regulated (F = 14.319, P = 0.019) as compared to the other two groups (HepG2/pcDNA3.1: 98.0% +/- 8.9%; HepG2: 100%). Compared with HepG2 cells transfected with miR-NC (10.74% +/- 1.15%), transfection of miR-192 into HepG2 cells led to increased apoptosis (15.74% +/- 1.17%) (F = 18.415, P = 0.013) and higher p53 and PUMA expressions at mRNA (p53: 1.68 +/- 0.12 vs 0.90 +/ 0.09, F = 43.115, P = 0.003, PUMA: 1.66 +/- 0.10 vs 0.98 +/- 0.06, F = 22.541, P = 0.009) and protein (p53: 3.07 vs 1, PUMA: 2.13 vs 1) levels. CONCLUSION: HBx could inhibit apoptosis of HepG2 cells through down-regulation of miR-192 which induces apoptosis of HepG2 cells. PMID- 22433311 TI - Genome-wide dynamic transcriptional profiling in Clostridium beijerinckii NCIMB 8052 using single-nucleotide resolution RNA-Seq. AB - BACKGROUND: Clostridium beijerinckii is a prominent solvent-producing microbe that has great potential for biofuel and chemical industries. Although transcriptional analysis is essential to understand gene functions and regulation and thus elucidate proper strategies for further strain improvement, limited information is available on the genome-wide transcriptional analysis for C. beijerinckii. RESULTS: The genome-wide transcriptional dynamics of C. beijerinckii NCIMB 8052 over a batch fermentation process was investigated using high-throughput RNA-Seq technology. The gene expression profiles indicated that the glycolysis genes were highly expressed throughout the fermentation, with comparatively more active expression during acidogenesis phase. The expression of acid formation genes was down-regulated at the onset of solvent formation, in accordance with the metabolic pathway shift from acidogenesis to solventogenesis. The acetone formation gene (adc), as a part of the sol operon, exhibited highly coordinated expression with the other sol genes. Out of the > 20 genes encoding alcohol dehydrogenase in C. beijerinckii, Cbei_1722 and Cbei_2181 were highly up regulated at the onset of solventogenesis, corresponding to their key roles in primary alcohol production. Most sporulation genes in C. beijerinckii 8052 demonstrated similar temporal expression patterns to those observed in B. subtilis and C. acetobutylicum, while sporulation sigma factor genes sigE and sigG exhibited accelerated and stronger expression in C. beijerinckii 8052, which is consistent with the more rapid forespore and endspore development in this strain. Global expression patterns for specific gene functional classes were examined using self-organizing map analysis. The genes associated with specific functional classes demonstrated global expression profiles corresponding to the cell physiological variation and metabolic pathway switch. CONCLUSIONS: The results from this work provided insights for further C. beijerinckii strain improvement employing system biology-based strategies and metabolic engineering approaches. PMID- 22433312 TI - On the importance of mathematical methods for analysis of MALDI-imaging mass spectrometry data. AB - In the last decade, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), also called as MALDI-imaging, has proven its potential in proteomics and was successfully applied to various types of biomedical problems, in particular to histopathological label-free analysis of tissue sections. In histopathology, MALDI-imaging is used as a general analytic tool revealing the functional proteomic structure of tissue sections, and as a discovery tool for detecting new biomarkers discriminating a region annotated by an experienced histologist, in particular, for cancer studies. A typical MALDI imaging data set contains 108 to 109 intensity values occupying more than 1 GB. Analysis and interpretation of such huge amount of data is a mathematically, statistically and computationally challenging problem. In this paper we overview some computational methods for analysis of MALDI-imaging data sets. We discuss the importance of data preprocessing, which typically includes normalization, baseline removal and peak picking, and hightlight the importance of image denoising when visualizing IMS data. PMID- 22433314 TI - Quantum-mechanical predictions of DNA and RNA ionization by energetic proton beams. AB - Among the numerous constituents of eukaryotic cells, the DNA macromolecule is considered as the most important critical target for radiation-induced damages. However, up to now ion-induced collisions on DNA components remain scarcely approached and theoretical support is still lacking for describing the main ionizing processes. In this context, we here report a theoretical description of the proton-induced ionization of the DNA and RNA bases as well as the sugar phosphate backbone. Two different quantum-mechanical models are proposed: the first one based on a continuum distorted wave-eikonal initial state treatment and the second perturbative one developed within the first Born approximation with correct boundary conditions (CB1). Besides, the molecular structure information of the biological targets studied here was determined by ab initio calculations with the Gaussian 09 software at the restricted Hartree-Fock level of theory with geometry optimization. Doubly, singly differential and total ionization cross sections also provided by the two models were compared for a large range of incident and ejection energies and a very good agreement was observed for all the configurations investigated. Finally, in comparison with the rare experiment, we have noted a large underestimation of the total ionization cross sections of uracil impacted by 80 keV protons,whereas a very good agreement was shown with the recently reported ionization cross sections for protons on adenine, at both the differential and the total scale. PMID- 22433313 TI - HIV incidence estimate combining HIV/AIDS surveillance, testing history information and HIV test to identify recent infections in Lazio, Italy. AB - BACKGROUND: The application of serological methods in HIV/AIDS routine surveillance systems to identify persons with recently acquired HIV infection has been proposed as a tool which may provide an accurate description of the current transmission patterns of HIV. Using the information about recent infection it is possible to estimate HIV incidence, according to the model proposed by Karon et al. in 2008, that accounts for the effect of testing practices on the number of persons detected as recently infected. METHODS: We used data from HIV/AIDS surveillance in the period 2004-2008 to identify newly diagnosed persons. These were classified with recent/non-recent infection on the basis of an avidity index result, or laboratory evidence of recently acquired infection (i.e., previous documented negative HIV test within 6 months; or presence of HIV RNA or p24 antigen with simultaneous negative/indeterminate HIV antibody test). Multiple imputation was used to impute missing information. The incidence estimate was obtained as the number of persons detected as recently infected divided by the estimated probability of detection. Estimates were stratified by calendar year, transmission category, gender and nationality. RESULTS: During the period considered 3,633 new HIV diagnoses were reported to the regional surveillance system. Applying the model, we estimated that in 2004-2008 there were 5,465 new infections (95%CI: 4,538-6,461); stratifying by transmission category, the estimated number of infections was 2,599 among heterosexual contacts, 2,208 among men-who-have-sex-with-men, and 763 among injecting-drug-users. In 2008 there were 952 (625-1,229) new HIV infections (incidence of 19.9 per 100,000 person-years). In 2008, for men-who-have-sex-with-men (691 per 100,000 person-years) and injecting drug users (577 per 100,000 person-years) the incidence remained comparatively high with respect to the general population, although a decreasing pattern during 2004-2008 was observed for injecting-drug-users. CONCLUSIONS: These estimates suggest that the transmission of HIV infection in Lazio remains frequent and men-who-have-sex-with men and injecting-drug-users are still greatly affected although the majority of new infections occurs among heterosexual individuals. PMID- 22433315 TI - Cardiovascular effects of antidiabetic agents: focus on blood pressure effects of incretin-based therapies. AB - Hyperglycemia is associated with increased risk of cardiovascular disease. Nevertheless, results of large clinical trials suggest that tight glucose control does not reduce the risk of macrovascular cardiovascular events in type 2 diabetes mellitus and may cause harm. This may reflect the adverse consequences of increased hypoglycemia or the adverse effects of many antidiabetic agents on weight gain. The consequences of intensive therapy may also depend on the mechanism of the antidiabetic agent(s) used to achieve tight control. Metformin, an antidiabetic agent that reduces weight and activates AMP-activated protein kinase, reduces risk of cardiovascular events in overweight diabetics. In contrast, the thiazolidinedione rosiglitazone increases cardiovascular risk. Sulfonylureas may increase the risk of cardiovascular events through effects on the SUR1 of the cardiac K(ATP) channel. Stable analogues of glucagon-like peptide 1 reduce body weight and blood pressure, and have favorable effects on ischemia following reperfusion in animal models. The dipeptidyl peptidase IV inhibitors prevent the breakdown of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, but also decrease the degradation of several vasoactive peptides. Dipeptidyl peptidase IV inhibitors have favorable effects in animal models of ischemia/reperfusion. They have been reported both to decrease and to increase blood pressure. Clinical trials will address the effect of the incretin-based agents on macrovascular cardiovascular events. PMID- 22433317 TI - Patients with generalised epilepsy have a higher white blood cell count than patients with focal epilepsy. AB - BACKGROUND: Immunological alterations have been noted following seizures in the acute period, however little is known about the effect of type and severity of epilepsy on leukocyte count in the absence of seizures. METHODS: We performed a retrospective chart review of adult epilepsy patients presenting for evaluation over a four-month period. Demographics, epilepsy type and characteristics, number and type of antiepileptic drugs, as well as medical co-morbidities were noted. RESULTS: A total of 241 patients fulfilled study criteria. Variables correlating with leukocyte count were identified using univariate analysis. Based on multivariate analysis, only the correlation with type of epilepsy and use of more than two antiepileptic drugs remained statistically significant. Patients with generalised epilepsy had a higher leukocyte count (7.21 k/MUL) compared to those with focal epilepsy (6.53 k/MUL); the main difference was due to the number of monocytes. CONCLUSION: These findings raise the possibility that there are different neuro-immune profiles between patients with generalised and focal epilepsy. PMID- 22433316 TI - The cerebrospinal fluid proteome in HIV infection: change associated with disease severity. AB - BACKGROUND: Central nervous system (CNS) infection is a nearly universal feature of untreated systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. RESULTS: After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral therapy and correlated abundances of identified proteins a) within and between subjects, b) with all other proteins across the entire sample set, and c) with "external" CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/ 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) <= -0.3 and >=0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. CONCLUSIONS: Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases. PMID- 22433318 TI - Overview of smart phone video essentials. PMID- 22433319 TI - Leading from the future: the nursing informatics executive. PMID- 22433322 TI - A study of the face recognition ability of orthodontists and lay persons of different age groups. AB - OBJECTIVE: To determine the face recognition ability of orthodontists and lay persons of different age groups. DESIGN: Cross-sectional study design, in which participants completed a 'Face Recognition Test'. SETTING: Participants were recruited from the Royal London Hospital, Ashford Hospital, Southend University Hospital and the British Orthodontic Society Conference, 2006. SUBJECTS AND METHOD: Colour photographs and 3D laser scans of eight volunteers were displayed and participants were asked to match the photographs of each face with the corresponding laser scan within 90 seconds. Participants consisted of 85 orthodontists under 50 years of age, 83 adolescents aged 15-18 years, 85 younger lay adults aged 19-49 years and 83 older lay adults aged 50-70 years. RESULTS: Female orthodontists were more successful in the face recognition test than female lay persons (P<=0.001) and were four times more successful than the male orthodontists (P = 0.003). There were no differences in face recognition ability between males and females in the lay persons groups (P = 0.970) or between male orthodontists and male lay persons (P = 0.240). When comparing age groups, no significant difference in successfully completing the face recognition test was detected between the adolescent, adult and older adult age groups (P = 0.070). CONCLUSIONS: Overall, our understanding of facial recognition is limited and the mechanisms by which lay people perceive and recognise other faces are important for the orthodontist to consider. PMID- 22433323 TI - A randomized clinical trial of two alternative designs of Twin-block appliance. AB - OBJECTIVE: To test if placing a Southend clasp on the upper and lower incisors during Twin-block appliance treatment will control their angulation and enhance skeletal correction. DESIGN: Prospective, randomized, controlled clinical trial (ISRTCTN 45965219). SETTING: Orthodontic Department, Royal Preston District General Hospital, Preston, UK. PARTICIPANTS: Fifty-two consecutive patients aged 9-30 years undergoing treatment for Class II division 1 malocclusion (ANB>5 degrees , OJ>6 mm). METHODS: Two alternative designs of Twin-block appliance were allocated randomly. One with a Southend clasp on the upper and lower central incisors and one without. The appliances were identical in all other aspects. OUTCOMES: Skeletal and dental changes measured on before and after treatment lateral cephalometric radiographs. RESULTS: There was a statistically significant change in ANB angle between the Southend group (-3.5 degrees ) and the Non Southend group (-2.6 degrees ) (P = 0.004). The change in upper incisor angulation was -6.1 degrees for the Southend group and -12.0 degrees for the Non-Southend group, which was statistically significant (P = 0.005). The change in lower incisor angulation was 3.0 degrees for the Southend group and 6.9 degrees for the Non-Southend group, which was statistically significant (P = 0.005). CONCLUSIONS: The presence of a Southend clasp on the upper and lower incisors during Twin-block treatment limited their tipping which enhanced the skeletal correction. PMID- 22433324 TI - Deformation and warping of the bracket slot in select self-ligating orthodontic brackets due to an applied third order torque. AB - OBJECTIVE: To measure the plastic deformation of three different self-ligated brackets as a result of third order torque by analysing slot dimensions and determine its impact on torque play. METHODS: Three different self-ligating orthodontic brackets (0.022-inch slot) were investigated: Damon Q(r), In-Ovation R(r), and Speed(r) (30 per group). A digital SLR camera coupled to a microscope was used to capture images of the slot profile of each bracket before and after torquing. Each bracket was torqued to 63 degrees in the same manner using a 0.019*0.025-inch SS wire. RESULTS: The mean change in slot height as measured at the top of the slot was 0.013 mm (SD 0.020), 0.007 mm (SD 0.010) and 0.070 mm (SD 0.03) for Damon Q(r), In-Ovation R(r) and Speed(r), respectively. Slot taper increased 0.75 degrees (SD 0.96), 0.41 degrees (SD 1.05) and 9.30 degrees (SD 4.24), respectively. Increase in torque play was calculated to be 0.9, 0.6 and 7.7 degrees respectively, as calculated using the novel formula presented in this study. CONCLUSIONS: Damon Q(r) and In-Ovation R(r) maintain high levels of linearity in the shape of the slot walls and experience small, but significant amounts of plastic deformation that are physically insignificant. Speed(r) demonstrates the most plastic deformation with visually identifiable warping in the bracket slot. PMID- 22433325 TI - Accuracy of positioning three types of self-ligating brackets compared with a conventionally ligating bracket. AB - OBJECTIVES: The aim of this study was to determine whether the morphology of three different self-ligating brackets affects the accuracy of their positioning when compared with a conventionally ligating bracket. DESIGN: An ex vivo prospective comparison of the accuracy of positioning self-ligating brackets with conventionally ligating brackets. SETTING: Orthodontic Department, Eastman Dental Institute, London, UK. SUBJECTS AND METHODS: Twenty-five clinicians with 2 or more years experience of bracket placement bonded four identical typodont malocclusions with Damon MX(TM), In-Ovation System R(TM) and SmartClip(TM) self ligating brackets and also Victory Series(TM) conventionally ligating brackets. Four hundred brackets of each type were positioned. Vertical, horizontal and angular bracket position errors were assessed by reference to the FA point and FACC respectively, using digital images and image analysis software. RESULTS: Method error analysis showed no evidence of bias and minimal random error. The Victory Series brackets were the most accurately positioned. Although the amount of positioning error for all the self-ligating brackets was small, a greater number were positioned outside vertical and horizontal tolerance limits compared to the conventionally ligated brackets (P<0.001). The Damon MX bracket type was nearly 10 times more likely to be inaccurately placed relative to the FA point compared with the Victory Series bracket. The differences relating to angular positioning error were not statistically significant (P>0.05). CONCLUSION: The findings indicate that the positioning of three types of self-ligating brackets was less accurate than the conventional pre-adjusted edgewise bracket, when using a direct bonding technique. This may have implications for their clinical application. PMID- 22433326 TI - Versatility and benefits of mini-implants for vertical and sagittal anchorage in a growing open bite class II patient. AB - This case report presents the details of a growing patient with a class II malocclusion, anterior open bite, and posterior crossbite, where the side effects of treatment mechanics were significantly reduced by the use of mini-implants for anchorage. PMID- 22433330 TI - Committee opinion no. 522: incidentally detected short cervical length. PMID- 22433327 TI - Where do we go from here? Northcroft Memorial Lecture 2010. AB - The article aims to identify some of the challenges for future training of orthodontics and subsequently the delivery of orthodontic care. Clearly, in any aspect of future prediction, the precision is simply that of an art. However, it is hoped that some of the reported bibliography will allow those that wish to, the opportunity to look further. The global economy is undergoing a significant period of rationalization and luxury items such as Orthodontics may become less publicly funded. In order to maintain the specialty as one in which clinicians are appropriately trained, there needs to be a reconsideration of the way in which education is delivered and assessment assured. This presentation will identify possible challenges and identify a strategy to consider, construct and deliver a rational way forward in a positive way that ensures that the strengths of how the profession has developed are maintained. PMID- 22433331 TI - Experience counts. PMID- 22433332 TI - The evolution of cervical screening and the specialty of obstetrics and gynecology. AB - The American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society of Clinical Pathologists have released revised consensus recommendations for cervical cancer screening. These new recommendations integrate molecular testing and include significant changes in screening, particularly in women from 30 to 65 years of age without complications who now may be screened every 5 years by co-testing with cervical cytology and high-risk human papillomavirus testing and women 21-29 years who may be screened with cervical cytology alone every 3 years. The revised recommendations include clarification on when to start and stop screening and management of women who have undergone hysterectomy. They also clarify the management of results of co testing. The new recommendations achieve the same degree of protection against cervical cancer as previous recommendations. They require less screening and will be much more convenient for our patients. They are a further step away from the days of annual Pap tests, and the decreased requirements for cervical cancer screening pose an exciting opportunity for focusing on many other important health issues during the well woman visit. PMID- 22433333 TI - Effect of surgical volume on outcomes for laparoscopic hysterectomy for benign indications. AB - OBJECTIVE: To estimate the influence of surgical volume on outcome and resource utilization for laparoscopic hysterectomy for benign indications. METHODS: Patients who underwent laparoscopic hysterectomy from 2000 to 2010 and recorded in a commercial database were analyzed. Patients were stratified into tertiles according to the number of procedures performed by their surgeons and at their hospital. The influence of surgeon and hospital volume on perioperative morbidity and resource utilization was examined using multivariable regression models. RESULTS: A total of 124,615 patients were identified. The overall complication rate decreased from 6.2% for low-volume surgeons to 4.2% for high-volume surgeons (P<.001). Patients operated on by high-volume surgeons were 25% (risk ratios [RRs] 0.75, 95% confidence interval [CI] 0.68-0.82) less likely to experience a complication. In multivariable models intraoperative complications, surgical-site complications, medical complications, prolonged hospitalization, and transfusion rates were lower for high-volume surgeons. Overall morbidity was 5.8% for women treated at low-volume hospitals compared with 4.7% at high-volume centers (P<.001). Women treated at high-volume centers were 18% (RR 0.82, 95% CI 0.75 0.90) less likely to experience a complication. Procedure costs for high-volume surgeons were $867 lower than for low-volume surgeons, and treatment at a high volume center reduced costs by $966 per procedure. CONCLUSION: Performance of laparoscopic hysterectomy by high-volume surgeons and at high-volume hospitals is associated with modest reductions in morbidity and lower costs. LEVEL OF EVIDENCE: II. PMID- 22433334 TI - Outcomes and cost comparisons after introducing a robotics program for endometrial cancer surgery. AB - OBJECTIVE: To evaluate the effect of introducing a robotic program on cost and patient outcome. METHODS: This was a prospective evaluation of clinical outcome and cost after introducing a robotics program for the treatment of endometrial cancer and a retrospective comparison to the entire historical cohort. RESULTS: Consecutive patients with endometrial cancer who underwent robotic surgery (n=143) were compared with all consecutive patients who underwent surgery (n=160) before robotics. The rate of minimally invasive surgery increased from 17% performed by laparoscopy to 98% performed by robotics in 2 years. The patient characteristics were comparable in both eras, except for a higher body mass index in the robotics era (median 29.8 compared with 27.6; P<.005). Patients undergoing robotics had longer operating times (233 compared with 206 minutes), but fewer adverse events (13% compared with 42%; P<.001), lower estimated median blood loss (50 compared with 200 mL; P<.001), and shorter median hospital stay (1 compared with 5 days; P<.001). The overall hospital costs were significantly lower for robotics compared with the historical group (Can$7,644 compared with Can$10,368 [Canadian dollars]; P<.001) even when acquisition and maintenance cost were included (Can$8,370 compared with Can$10,368; P=.001). Within 2 years after surgery, the short-term recurrence rate appeared lower in the robotics group compared with the historic cohort (11 recurrences compared with 19 recurrences; P<.001). CONCLUSION: Introduction of robotics for endometrial cancer surgery increased the proportion of patients benefitting from minimally invasive surgery, improved short-term outcomes, and resulted in lower hospital costs. LEVEL OF EVIDENCE: II. PMID- 22433335 TI - Uterine rupture with attempted vaginal birth after cesarean delivery: decision-to delivery time and neonatal outcome. AB - OBJECTIVE: To estimate the time from the diagnosis of uterine rupture to delivery that would prevent adverse neonatal sequelae. METHODS: Cases of uterine rupture from January 1, 2000, to December 31, 2009, were identified in nine hospitals in the Intermountain Health Care system and at the University of Utah. Maternal demographics, labor characteristics, and neonatal outcomes were obtained. Primary adverse outcome was abnormal umbilical artery pH level less than 7.0 or 5-minute Apgar score less than 7. Adverse secondary outcome included fetal or neonatal death and neonatal neurologic injury attributed to uterine rupture. RESULTS: Thirty-six cases of uterine rupture occurred during 11,195 trials of labor after cesarean delivery. Signs of uterine rupture were fetal (n=24), maternal (n=8), or a combination of maternal and fetal (n=3). In one case, uterine rupture was not suspected. Mean time to delivery from the onset of symptoms or signs for the primary adverse outcome group (n=13) was 23.3 (+/-10.8) minutes compared with 16.0 (+/-7.7) minutes for those without an adverse outcome (P=.02). No neonate delivered in fewer than 18 minutes had an umbilical pH level below 7.0. Three neonates delivered at more than 30 minutes met criteria for an adverse secondary outcome. CONCLUSION: The frequency of uterine rupture was 0.32% in patients attempting a trial of labor after cesarean delivery. Neonates delivered within 18 minutes after a suspected uterine rupture had normal umbilical pH levels or 5 minute Apgar scores greater than 7. Poor long-term outcome occurred in three neonates with a decision-to-delivery time longer than 30 minutes. LEVEL OF EVIDENCE: II. PMID- 22433336 TI - Normal first stage of labor in women undergoing trial of labor after cesarean delivery. AB - OBJECTIVE: To compare first-stage labor patterns in women undergoing trial of labor after cesarean delivery (TOLAC) and those without a previous cesarean to explore whether a uterine scar alters this stage of labor. METHODS: A retrospective cohort study was conducted of consecutive term vertex singletons who reached the second stage of labor. Cervical examinations and obstetric outcomes were collected from medical records. Labor curves of those laboring spontaneously, stratified by TOLAC status, were constructed using a repeated measures analysis. Interval-censored regression was used to estimate duration of labor, centimeter by centimeter, stratified by TOLAC status and adjusted for race, obesity, macrosomia, and previous vaginal delivery. RESULTS: Of 5,388 consecutive term births, 2,021 labored spontaneously and were included. The 1,881 laboring women with no previous cesarean delivery were compared with 140 women undergoing TOLAC. There was no significant difference in rates of cervical dilation between the groups. The median time for dilation from 4 to 10 cm was 3.0 hours for TOLAC and 2.8 hours for non-TOLAC (P=.52). A post hoc sample size calculation (alpha=0.05) shows 90% power to detect a median difference of 0.4 hours with the fixed sample size available. CONCLUSION: There was no significant difference in first-stage labor curves or cervical dilation rate between women undergoing TOLAC and those without a previous cesarean. Diagnoses of labor disorders should be made with similar standards between those with and without a uterine scar. LEVEL OF EVIDENCE: II. PMID- 22433337 TI - Trends and characteristics of home vaginal birth after cesarean delivery in the United States and selected States. AB - OBJECTIVE: To examine trends and characteristics of home vaginal birth after cesarean delivery (VBAC) in the United States and selected states from 1990-2008. METHODS: Birth certificate data were used to track trends in home and hospital VBACs from 1990-2008. Data on planned home VBAC were analyzed by sociodemographic and medical characteristics for the 25 states reporting this information in 2008 and compared with hospital VBAC data. RESULTS: In 2008, there were approximately 42,000 hospital VBACs and approximately 1,000 home VBACs in the United States, up from 664 in 2003 and 656 in 1990. The percentage of home births that were VBACs increased from less than 1% in 1996 to 4% in 2008, whereas the percentage of hospital births that were VBACs decreased from 3% in 1996 to 1% in 2008. Planned home VBACs had a lower risk profile than hospital VBACs with fewer births to teenagers, unmarried women, or smokers; fewer preterm or low-birth-weight deliveries; and higher maternal education levels. CONCLUSION: Recent increases in the proportion of U.S. women with a prior cesarean delivery mean that an increasing number of women are faced with the choice and associated risks of either VBAC or repeat cesarean delivery. Recent restrictions in hospital VBAC availability have coincided with increases in home VBACs; however, home VBAC remains rare, with approximately 1,000 occurrences in 2008. LEVEL OF EVIDENCE: II. PMID- 22433338 TI - Effect of maternal obesity on the risk of fetal loss after amniocentesis and chorionic villus sampling. AB - OBJECTIVE: To estimate the risk of fetal loss in obese women undergoing amniocentesis and chorionic villus sampling (CVS). METHODS: This was a retrospective cohort study of all women undergoing amniocentesis or CVS. The primary outcome was any fetal loss before 24 weeks of gestation. A secondary analysis was performed examining pregnancy loss within 14 days of the procedure, excluding termination of pregnancy. Obese (body mass index [BMI] 30.0 or higher) and nonobese (BMI lower than 30.0) patients were compared, and the postprocedure loss rate was also estimated by BMI strata. Obese and nonobese patients were compared with univariable and bivariate statistics; multivariable logistic regression models were developed to estimate the effect of maternal obesity. RESULTS: Between obese (n=2,742) and nonobese (n=8,037) women undergoing amniocentesis, no difference existed in the risk of fetal loss before 24 weeks of gestation (4.7% [combined background and procedure loss] compared with 4.2%, adjusted odds ratio [OR] 1.1, 95% confidence interval [CI] 0.8-1.5). For women undergoing CVS, no difference in the risk of pregnancy loss was seen between obese (n=855) and nonobese (n=4,125) women (6.4% compared with 6.3%, adjusted OR 1.0, 95% CI 0.7-1.3). Compared with women not undergoing a procedure, the attributable risk for obese women was 0.3% (95% CI -0.2 to 0.9) amniocentesis and 0.1% (95% CI -0.1 to 0.2) CVS. The difference in fetal loss between the BMI 40.0 or higher and BMI lower than 25.0 groups after amniocentesis was significant after adjusting for maternal age (adjusted OR 2.2, 95% CI 1.2-3.9). This study had greater than 90% power to detect a 50% increase in the risk of pregnancy loss after amniocentesis and CVS (with an alpha error of 0.05). CONCLUSION: A BMI of 30.0-40.0 does not increase the risk for fetal loss after invasive prenatal diagnostic procedures. A higher loss rates with class III obesity (BMI 40.0 or higher) was observed for amniocentesis procedures. LEVEL OF EVIDENCE: II. PMID- 22433340 TI - Health care provider attitudes and practices related to intrauterine devices for nulliparous women. AB - OBJECTIVE: To examine predictors of health care providers perceiving intrauterine devices (IUDs) as unsafe for nulliparous women and of infrequent provision of IUDs to nulliparous women. METHODS: We analyzed questionnaire data obtained during December 2009 to March 2010 from 635 office-based providers (physicians) and 1,323 Title X clinic providers (physicians, physician assistants, certified nurse midwives, nurse practitioners, and nurses). Using multivariable logistic regression, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between patient, health care provider, and clinic and practice variables and provider misconceptions about the safety of IUDs for nulliparous women and with infrequent IUD provision. RESULTS: Approximately 30% of respondents had misconceptions about the safety of IUDs for nulliparous women. Factors associated with increased odds of misconceptions about the copper IUD and levonorgestrel-releasing IUD included: being an office-based family medicine physician (copper IUD adjusted OR 3.20, 95% CI 1.73-5.89; levonorgestrel releasing IUD adjusted OR 2.03, 95% CI 1.10-3.76); not being trained in IUD insertion (copper IUD adjusted OR 4.72, 95% CI 2.32-9.61; levonorgestrel releasing IUD adjusted OR 2.64, 95% CI 1.34-5.22); and nonavailability of IUDs on site at their practice or clinic (copper IUD adjusted OR 2.18, 95% CI 1.20-3.95; levonorgestrel-releasing IUD adjusted OR 3.45, 95% CI 1.95-6.08). More than 60% of providers infrequently provided IUDs to nulliparous women. Nonavailability of IUDs on-site (copper IUD adjusted OR 1.78, 95% CI 1.01-3.14; levonorgestrel releasing IUD adjusted OR 2.10, 95% CI 1.22-3.62) and provider misconceptions about safety (copper IUD adjusted OR 6.04, 95% CI 2.00-18.31; levonorgestrel releasing IUD adjusted OR 6.91, 95% CI 3.01-15.85) were associated with infrequent IUD provision. CONCLUSION: Health care provider misconceptions about the safety of IUDs for nulliparous women are prevalent and are associated with infrequent provision. Improved health care provider education and IUD availability are needed to increase IUD use among nulliparous women. LEVEL OF EVIDENCE: III. PMID- 22433339 TI - Vasomotor symptoms and lipid profiles in women transitioning through menopause. AB - OBJECTIVE: To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol, and follicle stimulating hormone. METHODS: Study of Women's Health Across the Nation participants (N=3,201), aged 42-52 years at entry, completed interviews on frequency of hot flushes and night sweats (none, 1-5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoprotein A 1, apolipoprotein B, lipoprotein[a], triglycerides, serum estradiol, follicle stimulating hormone) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones. RESULTS: Compared with no flushes, experiencing hot flushes was associated with significantly higher LDL (1-5 days: beta [standard error]=1.48 [0.47], P<.01; 6 days or more: beta [standard error]=2.13 [0.62], P<.001), HDL (1-5 days: beta [standard error]=0.30 [0.18]; 6 days or more: beta [standard error]=0.77 [0.24], P<.01), apolipoprotein A-1 (1-5 days: beta [standard error]=0.92 [0.47], P<.10; 6 days or more: beta [standard error]=1.97 [0.62], P<.01), apolipoprotein B (1-5 days: beta [standard error]=1.41 [0.41], P<.001; 6 days or more: beta [standard error]=2.51 [0.54], P<.001), and triglycerides (1-5 days: percent change [95% confidence interval]=2.91 [1.41 4.43], P<.001; 6 days or more: percent change [95% confidence interval[=5.90 [3.86-7.97], P<.001) in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences in lipid levels between hot flushes 6 days or more compared with no days ranged from less than 1 (for HDL) to 10 mg/dL (for triglycerides). Night sweats were similar. Associations were strongest for lean women. CONCLUSION: Vasomotor symptoms were associated with higher LDL, HDL, apolipoprotein A-1, apolipoprotein B, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk. LEVEL OF EVIDENCE: II. PMID- 22433341 TI - Recovery at home after major gynecologic surgery: how do our patients fare? AB - OBJECTIVES: To describe women's recovery and pain control during the first 6 weeks after hospital discharge after gynecologic surgery and estimate the prevalence of inadequate pain control during the first 2 weeks of home recovery after abdominal compared with vaginal gynecologic surgery. METHODS: Participants, women without chronic pelvic pain undergoing benign nonlaparoscopic gynecologic surgery, completed daily evaluation of pain and pain medication use during the first 2 weeks after discharge and a validated recovery instrument 1, 2, and 6 weeks after discharge. Inadequate pain control was defined as a score of 4 or more (out of 10) on the four-item Surgical Pain Scale. RESULTS: Of 140 eligible participants, 13 were lost to follow-up. Of remaining 127 women, 80 underwent vaginal and 47 abdominal surgery. Inadequate pain control was reported by 45% and 51% of women after vaginal and abdominal surgery, respectively, on recovery day 3 (P=.5); 23% and 30%, respectively, on day 7 (P=.4); and 5% and 23%, respectively, on day 14 (P<.005). Two weeks after discharge, 10% and 32% of women after vaginal and abdominal surgery, respectively, required narcotic pain medications (P<.01). By 6 weeks, approximately half of the women in either group reported they felt recovered and two-thirds felt "back to normal." CONCLUSION: Pain control after hospital discharge is suboptimal for many women after both vaginal and abdominal surgery. The time to full recovery is longer than 6 weeks for half of women. Given increasingly rapid hospital discharge, optimizing the patient's experience at home is a priority. LEVEL OF EVIDENCE: II. PMID- 22433342 TI - Practitioner-specific medians for nuchal translucency to improve first-trimester screening performance. AB - OBJECTIVE: Nuchal translucency medians are used to convert nuchal translucency measurements to multiple of the median values for use in risk assessment. There has been much debate about the use of practitioner-specific medians instead of population-based medians to correct for practitioner bias. This study examined data from the California Prenatal Screening Program to evaluate the effect of individual medians on screening performance. METHODS: For this retrospective study, we identified first-trimester specimens in the California Prenatal Screening Program database for which screening results were calculated using a practitioner-specific median (n=55,286) and recalculated risk assessment using a population-based median. We looked at positive rates for Down syndrome and Trisomy 18 as well as overall screening results. We also looked at the recalculated risks for cases in which there has been a positive diagnosis of a chromosomal abnormality to determine if cases would have been missed if practitioner-specific medians had not been used. RESULTS: Nuchal translucency multiples of the median would be lower for the majority of nuchal translucency practitioners if a population-based median were used instead of practitioner specific medians. Outcomes data from the California Prenatal Screening Program's database indicate that 14 positively diagnosed cases would have been missed by the screening program if population-based medians had been used. CONCLUSION: The use of practitioner-specific medians corrects for practitioner bias in measuring nuchal translucency. Practitioner-specific medians improve screening performance and help meet detection rate goals. LEVEL OF EVIDENCE: II. PMID- 22433343 TI - Improving survival of extremely preterm infants born between 22 and 25 weeks of gestation. AB - OBJECTIVE: To estimate observed compared with predicted survival rates of extremely premature infants born during 2000-2009, to identify contemporary predictors of survival, and to determine if improved survival rates occurred during the decade. METHODS: We conducted a retrospective cohort analysis of 237 inborn neonates without major congenital anomalies born from 2000 to 2009 after 22 to 25 completed weeks of gestation. Observed survival rates at each gestational age were compared with predicted survival rates based on gestational age, birth weight, sex, singleton or multiple gestation, and antenatal corticosteroid administration estimated by a Web-based calculator that was derived from 1998 to 2003 outcomes of a large national cohort. Multivariable logistic regression analysis was used to identify significant predictors of survival of the study cohort, including year of birth. RESULTS: Survival rates for the decade by gestational age (compared with predicted rates) were: 22 weeks, 33% (compared with 19%); 23 weeks, 58% (compared with 38%); 24 weeks, 87% (compared with 58%); and 25 weeks, 85% (compared with 70%). Antenatal corticosteroids were administered in 96% of pregnancies. Variables that significantly predicted survival and their odds ratios (OR) with 95% confidence intervals (CI) are: antenatal corticosteroid administration (OR 5.27, CI 1.26 22.08); female sex (OR 3.21, CI 1.42-7.26); gestational age (OR 1.89, CI 1.27 2.81); 1-minute Apgar score (OR 1.39, CI 1.15-1.69); and birth year (OR 1.17, CI 1.02-1.34). The number needed to treat with any antenatal corticosteroid therapy to prevent one death was 2.4. CONCLUSION: In this single-institution cohort treated aggressively (antenatal corticosteroid administration [even if less than 24 weeks], tocolysis until steroid course complete, cesarean for fetal distress) by perinatologists and neonatologists, survival rates at 22-25 weeks of gestation age for inborn infants during the 2000s exceeded predicted rates, with increasing odds of survival during the decade. Antenatal corticosteroid administration had a significant effect on survival. LEVEL OF EVIDENCE: II. PMID- 22433344 TI - Epidemiology of retained placenta: oxytocin as an independent risk factor. AB - OBJECTIVE: To identify factors related to retained placenta in the context of contemporary obstetric practice. METHODS: This was a case-control study comparing 408 cases of retained placenta and an equivalent number of control individuals. Epidemiological and delivery-related variables were registered in computerized prenatal and in-hospital medical records. Univariable and multivariable logistic regressions were used for estimation of risk ratios and statistical significance. RESULTS: Independent risk factors for retained placenta were: previous retained placenta (odds ratio [OR] 12.61, 95% confidence interval [CI] 3.61-44.08); preterm delivery (OR 3.28, 95% CI 1.60-6.70); oxytocin use for 195-415 minutes (OR 2.00, 95% CI 1.20-3.34); oxytocin use more than 415 minutes (OR 6.55, 95% CI 3.42-12.54, number needed to harm 2.3); preeclampsia (OR 2.85, 95% CI 1.20-6.78); two or more previous miscarriages (OR 2.62, 95% CI 1.31-5.20); and one or more previous abortion (OR 1.58, 95% CI 1.09-2.28). Parity of two or more had a seemingly protective effect (OR 0.40, 95% CI 0.24-0.70), as did smoking at the start of pregnancy (OR 0.28, 95% CI 0.09-0.88). Retained placenta was significantly associated with an increased risk of postpartum hemorrhage. The OR related to blood loss exceeding 500 mL, 1,000 mL, and 2,000 mL and the need for blood transfusion was 33.07 (95% CI 20.57-53.16), 43.44 (95% CI 26.57-71.02), 111.24 (95% CI 27.26-454.00), and 37.48 (95% CI 13.63-103.03), respectively. Diabetes was numerically overrepresented in the case group, but the power of the study to detect a significant difference in risk outcome was insufficient. CONCLUSION: Identifying risk factors for retained placenta is important in the assessment of women after delivery. The increased risk associated with duration of oxytocin use is of interest, considering its widespread use. LEVEL OF EVIDENCE: II. PMID- 22433345 TI - Uterine synechiae and pregnancy complications. AB - OBJECTIVE: Uterine synechiae have generally been considered benign findings in pregnancy. We used a large perinatal database to test the hypothesis that uterine synechiae are associated with pregnancy complications. METHODS: We performed a retrospective cohort study of women with singleton pregnancies presenting for routine ultrasonographic examinations at 17-22 weeks from 1990-2009. Pregnancies with multiple fetuses, amniotic bands, and congenital uterine anomalies were excluded. We compared pregnancy outcomes between women with and without uterine synechiae. Multivariable logistic regression was used to adjust for confounders. RESULTS: Of 65,518 pregnancies meeting inclusion criteria, 296 (0.45%) were diagnosed with uterine synechiae. Women with uterine synechiae were significantly more likely to have placental abruption (2.1% compared with 0.6%, adjusted odds ratio [OR] 3.25, 95% confidence interval [CI] 1.43-7.36), preterm premature rupture of membranes (PROM) (5.5% compared with 2.3%, adjusted OR 2.51, 95% CI 1.51-4.18), and cesarean delivery for malpresentation (5.1% compared with 3.0%, adjusted OR 1.75, 95% CI 1.04-2.95). The risks of placenta previa, fetal growth restriction, stillbirth, and preterm delivery were not significantly different. CONCLUSION: Uterine synechiae are associated with significant increase in the risk of preterm PROM, placental abruption, and cesarean delivery for malpresentation. The notion of uterine synechiae as benign findings in pregnancy should be re-evaluated. LEVEL OF EVIDENCE: II. PMID- 22433346 TI - Cost and effectiveness of intrapartum group B streptococcus polymerase chain reaction screening for term deliveries. AB - OBJECTIVE: To estimate the cost and consequences of intrapartum polymerase chain reaction (PCR) screening on early-onset group B streptococcal (GBS) disease compared with the antenatal lower vagina culture screening recommended in France. METHODS: This was a single-institution study comparing the intrapartum PCR screening strategy implemented in 2010 with antenatal culture strategy in place in 2009. Early-onset GBS disease in newborns was monitored exhaustively. We estimated direct costs, including screening test costs and hospital costs, for deliveries of healthy newborns compared with those infected with GBS. Costs in 2009 and 2010 were compared on an intention-to-treat basis. RESULTS: Term deliveries were 2,761 and 2,814 in 2009 and 2010, respectively. Among the screened mothers, the vaginal GBS colonization rate was 11.7% based on antenatal GBS culture screening in 2009 compared with 16.7% in 2010 using the intrapartum PCR testing. The overall probabilities of neonatal GBS disease were 0.9% compared with 0.5%, and the average total cost per delivery was $1,759+/-1,209 in 2009 compared with $1,754+/-842 in 2010 (P=.9) in antenatal and intrapartum screening strategies, respectively. The number and severity of cases of early-onset GBS disease and the resulting hospital costs were higher in 2009. CONCLUSION: Polymerase chain reaction intrapartum screening strategy was cost-neutral when compared with the 2009 antenatal lower vagina culture screening, with a significant decrease in early-onset GBS disease. PMID- 22433347 TI - A survey of central association members about the definition, management, and complications of shoulder dystocia. AB - OBJECTIVES: To determine practice patterns for shoulder dystocia and concepts dealing with brachial plexus palsy. METHODS: An Internet-based 25-question survey was electronically disseminated to all current members of the Central Association of Obstetricians and Gynecologists. For those individuals who did not respond, an additional opportunity to complete the assessment was provided during the 2009 annual meeting. RESULTS: Of 429 Central Association of Obstetricians and Gynecologists members, 268 (62%) responded, with 192 (78%) filling out the survey online. Nearly 90% of those queried believed that shoulder dystocia was unpredictable and unpreventable. Thirty-seven percent felt that an elective cesarean delivery should be offered for an estimated fetal weight of 4,500 g among nondiabetics. Just 40% would have allowed a trial of labor with a documented history of shoulder dystocia. Slightly more than half answered that they never used either lateral or excessive traction and obstetrician gynecologists were more likely than maternal-fetal medicine specialists to conclude that traction applied by the clinician doing the delivery was the cause of shoulder dystocia-related brachial plexus palsy (36% compared with 12%, P=.005). Maternal-fetal medicine specialists were more likely to believe that 40 50% of brachial plexus palsies occur without concomitant shoulder dystocia (21% compared with 9%, P=.015). CONCLUSION: Differences in practice patterns exist among with regard to management recommendations of the American College of Obstetricians and Gynecologists' Practice Bulletin on shoulder dystocia. LEVEL OF EVIDENCE: III. PMID- 22433348 TI - U.S. obstetrician-gynecologists' estimates of their patients' breastfeeding rates. AB - OBJECTIVES: To estimate obstetrician-gynecologists' promotion and support of breastfeeding and their perception of patient breastfeeding practices to examine whether variation in physician practice contributes to low breastfeeding rates. METHODS: We conducted a survey study of 290 members of the Collaborative Ambulatory Research Network, a sample of college fellows (response rate 48.3%). We compared the results with the Centers for Disease Control and Prevention state by-state Breastfeeding Report Card data: 75% or more initiating breastfeeding termed high, 65-74% termed medium, and 64% or lower termed low. The survey consisted of questions regarding physician and patient demographics, physician satisfaction regarding breastfeeding practices, opinions and knowledge of breastfeeding, opinions of breastfeeding duration, and physicians' effort toward encouraging breastfeeding. An "effort" score was created from these questions. RESULTS: Physicians' perceptions of breastfeeding initiation rates were consistent with Centers for Disease Control and Prevention data for high (77.3%+/ 1.5%), medium (70.9%+/-2.7%), and low states (59.4%+/-3.4%). Physicians with a high proportion of African American or Medicaid-eligible patients reported lower rates of initiating breastfeeding; a high proportion of Medicaid-eligible patients was associated with lower breastfeeding at 3, 6, and 12 months. More physicians were satisfied in high breastfeeding states (72.7%) than in medium (60%) or low states (34.3%). We found no association between the effort score and physician age or patient demographics; however, women (10.2+/-0.2) scored higher than men (8.6+/-0.3, P=.001). Effort score did not differ among high, medium, or low breastfeeding states. CONCLUSION: Physician satisfaction reflected perceived patient behavior. Physician effort scores were similar across patient breastfeeding behavior. Patient demographics rather than physician practice predicted low breastfeeding rates. LEVEL OF EVIDENCE: III. PMID- 22433349 TI - Trends in the surgical management of stress urinary incontinence. AB - OBJECTIVES: To estimate the rates of stress urinary incontinence (SUI) surgery from 2000 to 2009 by type of procedure, year, age, and region of the country. METHODS: We used data between 2000 and 2009 from a database containing health care claims data from employer-based plans in the United States. We analyzed data for all women age 18-64 years, identifying all SUI procedures in this population. Rates per 100,000 person-years and 95% confidence intervals (CI) were calculated each year by procedure type, age, and region. RESULTS: The study population included 32.9 million women age 18-64 years observed for 74,007,937 person-years between 2000 and 2009. During that time, there were 182,110 SUI procedures for a rate of 246.1 per 100,000 person-years (95% CI 239.7-252.6). The most common SUI surgery was sling (198.3 per 100,000 person-years, 95% CI 192.8-203.9) followed by Burch (25.9 per 100,000 person-years, 95% CI 24.8-27.2). There was a dramatic increase in slings, with a corresponding decrease in Burch procedures from 2000 to 2009. Other SUI surgeries had lower rates. Although this trend was evident across all regions, the Northeast had the lowest rate of SUI surgery, whereas rates in the West, Midwest, and South were 1.44-times, 1.76-times, and 2.09-times higher, respectively. CONCLUSION: In a dramatic shift over the past decade, slings have become the dominant procedure for SUI among women age 18-64 years. Although this trend was seen across the United States, considerable variability exists in the SUI surgery rates by region. LEVEL OF EVIDENCE: III. PMID- 22433350 TI - Nonsurgical management of pelvic organ prolapse. AB - Although surgical management of symptomatic pelvic organ prolapse (POP) is common and often necessary, conservative treatments such as pessaries, pelvic floor muscle training, or both can usually result in symptomatic improvement. When treating patients with POP, health care practitioners should focus primarily on identification and alleviation of POP-related symptoms. It is appropriate to offer nonsurgical management to most people with POP. This article reviews the objective and subjective evaluation and nonsurgical management of POP, emphasizing a simple, practical approach to pessary fitting and management. PMID- 22433351 TI - What is new in primary care? Best articles from the past year. PMID- 22433352 TI - Management of obstructive sleep apnea in pregnant women. PMID- 22433353 TI - Oral misoprostol for labor augmentation: a randomized controlled trial. PMID- 22433355 TI - Malpositioned intrauterine contraceptive devices: risk factors, outcomes, and future pregnancies. PMID- 22433357 TI - Neonatal outcomes after implementation of guidelines limiting elective delivery before 39 weeks of gestation. PMID- 22433359 TI - Lethal fetal anomalies: why the big void? PMID- 22433364 TI - Allergy in evolution. AB - The 'foreignness' of proteins that we encounter in our homes and outdoors is in large part dependent on their evolutionary distance from man. This is relevant to understanding the differences between mammalian allergens, e.g. cats, and arthropod allergens, e.g. mites and cockroaches, as well as to understanding responses to a wide range of food allergens. On the other hand, allergic disease has gone through a major evolution of its own from a prehygiene state where there is minimal production of allergen-specific IgE, to the production of high-titer IgE, and then to the dramatic increase in asthma. The challenge is to understand how changes in both hygiene and lifestyle have contributed to the changes in allergic disease. PMID- 22433365 TI - Climate change, environment and allergy. AB - Climate change with global warming is a physicometeorological fact that, among other aspects, will also affect human health. Apart from cardiovascular and infectious diseases, allergies seem to be at the forefront of the sequelae of climate change. By increasing temperature and concomitant increased CO(2) concentration, plant growth is affected in various ways leading to prolonged pollination periods in the northern hemisphere, as well as to the appearance of neophytes with allergenic properties, e.g. Ambrosia artemisiifolia (ragweed), in Central Europe. Because of the effects of environmental pollutants, which do not only act as irritants to skin and mucous membranes, allergen carriers such as pollen can be altered in the atmosphere and release allergens leading to allergen containing aerosols in the ambient air. Pollen has been shown not only to be an allergen carrier, but also to release highly active lipid mediators (pollen associated lipid mediators), which have proinflammatory and immunomodulating effects enhancing the initiation of allergy. Through the effects of climate change in the future, plant growth may be influenced in a way that more, new and altered pollens are produced, which may affect humans. PMID- 22433366 TI - The hygiene hypothesis does not apply to atopic eczema in childhood. AB - There is evidence that environmental factors are important for the development of eczema. Different mechanisms have been discussed in the literature, the best known of which is the hygiene hypothesis. However, epidemiological data give reason for questioning this hypothesis with regard to childhood eczema. We present results from two German birth cohort studies (LISAplus and GINIplus) concerning regional prevalence patterns of eczema and the association of eczema with day care center attendance and older siblings. Our findings are not in line with the hygiene hypothesis and question its validity with regard to eczema. It seems reasonable to assume that the effect of environmental factors is somehow disease-specific. PMID- 22433367 TI - Molecular genetics of atopic eczema. AB - In both clinical experience and molecular genetic studies, atopic diseases (asthma, rhinoconjunctivitis and eczema) have been found to be strongly genetically influenced. The epidermal protein filaggrin seems to play a crucial role and is encoded within the so-called epidermal differentiation complex on chromosome 1. Filaggrin mutations predispose significantly to an increased risk to develop atopic eczema. Apart from filaggrin, other proteins involved in skin barrier functions such as lipid synthesis and metabolism, protease or protease inhibitor functions also seem to play a role. Besides skin barrier function, immune deviation versus a Th2 dominance and increased IgE production is also genetically determined. Polymorphisms have been found in genes encoding IL-4, IL 13 and STAT-6, and recently a polymorphism on the high-affinity IgE receptor gene has been found. Using genome-wide association studies, new genes with yet unknown functions have been determined to be associated with atopy and atopic eczema. PMID- 22433368 TI - Mechanisms of immune tolerance to allergens. AB - In allergic diseases, immune responses are induced by normally well-tolerated allergens, which result in chronic inflammation characterized by antibody secretion and T cell activation. For almost 100 years, allergen-specific immunotherapy (allergen-SIT) has been the potentially curative and antigen specific method for the treatment of allergic diseases. Allergen-SIT alters the course of allergic diseases and can reduce allergic symptoms and medication use. The key mechanism behind allergen-SIT is the induction of peripheral T cell tolerance by altering the balance between Th cells and regulatory T cells. Both naturally occurring thymus-derived FOXP3(+)CD4(+)CD25(+) regulatory T cells and inducible type 1 regulatory T cells suppress the development of allergic diseases via several mechanisms including suppression of dendritic cells, Th cells, mast cells, eosinophils and basophils; suppression of inflammatory cell migration to tissues; and decrease of the ratio between allergen-specific IgE and IgG4 antibodies. These effects are mainly mediated by the suppressive cytokines IL-10 and TGF-beta. Knowledge of this molecular basis is crucial to understanding the regulation of the immune response and their possible therapeutic applications for allergic diseases. PMID- 22433369 TI - Th17 and Th22 in skin allergy. AB - Development of eczematous skin reactions depends on disease-specific and time dependent recruitment of a variety of leukocytes affecting resident skin cells through cytotoxic mechanisms and release of cytokines. Th17 and Th22, defined as RORC+IL-17+ and IL-17-IFN-gamma-IL-22+ cells, respectively, belong to a newly identified class of lymphocytes specifically involved in dialogue with non-immune cells. In line with this function, both Th17 and Th22 cells are enriched in many immune-mediated skin diseases, such as a topic dermatitis, allergic contact dermatitis and psoriasis. Both IL-17 and IL-22 activate keratinocyte innate immune defenses, thus protecting the skin from pathogen invasion. However, Th17 and Th22 differ in their proinflammatory functions, being prominent in the first T cell subset and occasional/opportunistic in the second T cell subset. Most of the proinflammatory functions of Th17 depend on the synergic activity of IFN gamma and IL-17 on target cells. Together with IFN-gamma, IL-17 strongly enhances adhesion molecules on keratinocytes, thus promoting T cell-keratinocyte adhesion and T cell-mediated cytotoxicity, resulting in keratinocyte apoptosis. In contrast, Th22 cells guarantee skin integrity by inducing keratinocyte proliferation and migration. However, in inflamed skin, Th22 could contribute to the amplification of immune responses by enhancing the TNF-alpha-induced cytokines and chemokines released by keratinocytes. PMID- 22433370 TI - IL-25 induces both inflammation and skin barrier dysfunction in atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic relapsing skin disease characterized by having both an epidermal and a dermal component, shown as a barrier deficiency and inflammation. The mechanisms resulting in skewing the immune response in a Th2 direction in AD are still not fully elucidated. We suggest that IL-25 could be a major target in AD. IL-25 is produced by cells within the dermis of AD patients, and we suggest these to be dendritic cells (DCs). Furthermore, we show that IL-25 can inhibit filaggrin synthesis in keratinocytes. These results point towards a central role of IL-25 producing DCs that can induce both a Th2 response and inhibit filaggrin synthesis. We believe this strongly supports a role for IL 25 in AD, bridging the gap between inflammation and impaired skin barrier function. PMID- 22433371 TI - Angiogenesis, lymphangiogenesis and atopic dermatitis. AB - Angiogenesis and morphological and functional alterations of microvessels are hallmark features of chronic inflammatory disorders, including certain skin diseases. Vascular endothelial growth factors (VEGFs) are key regulators of blood vessel growth. The VEGF family includes VEGF-A, -B, -C, -D and placental growth factor. VEGF-A and -B are the most important proangiogenic factors, while VEGF-C and -D primarily regulate lymphangiogenesis. Angiopoietins are promoters of neovascularization by interacting with Tie-1 and Tie-2 receptors present on endothelial cells. High levels of VEGF-A have been detected in skin tissue of atopic dermatitis (AD) patients and correlate with disease activity. The vascular changes in the skin of AD patients appear to be linked to the inflammatory process. Effector cells of skin inflammation (human mast cells, basophils, eosinophils, macrophages, lymphocytes, etc.) are major sources of a vast array of angiogenic and lymphangiogenic factors. The role of lymphangiogenesis in AD is largely unknown. PMID- 22433372 TI - What can dogs bring to atopic dermatitis research? AB - Besides humans, dogs are the only animals that naturally develop skin lesions of atopic dermatitis (AD). In the last two decades, numerous studies have helped establish the close similarity between human and canine AD at the pathogenesis, clinical, epidemiological and therapeutic levels. The study of dogs with AD could potentially be very useful to human AD research because of the species' historical inbred selection that would permit breed-specific genetic, epidemiological or mechanistic studies. Clinical trials enrolling privately owned dogs are helpful for testing the validity of novel preventive or therapeutic interventions before these are used in human patients. Finally, skin lesions of AD can be provoked via environmental, systemic or epicutaneous allergen challenges in dogs that are spontaneously or experimentally sensitized to common dietary or environmental allergens. These experimental canine AD models have proven their utility to test the efficacy of novel treatment modalities in a preclinical setting. In conclusion, natural or experimental canine AD can provide researchers with a unique model to investigate genetic, epidemiological, mechanistic or treatment facets of the human disease. Due to the unique similarity of the disease in both species, the obtained information would very likely be translatable to human patients. PMID- 22433373 TI - Can microbial superantigens influence atopic dermatitis flares? AB - Although atopic dermatitis is accepted as a chronic and recurrent dermatitis, it is clear that several acute flares are due to superficial but not clearly infectious colonization of the skin by bacteria or mold. This short article provides a brief overview of (nearly all) the evidence concerning the possible mechanism of action of this phenomenon. PMID- 22433374 TI - Inflammation-induced alterations in the skin barrier function: implications in atopic dermatitis. AB - The pathogenesis of atopic dermatitis (AD) is very complex, but best characterized by an inflammatory reaction in the skin and a disrupted skin barrier. Until recently, these two factors have been studied as separate entities; however, it has been shown that inflammatory cytokines can regulate filaggrin, a very important component of the skin barrier, as well as proteins involved in the processing and maturation of filaggrin. Therefore, inflammation itself may be able to induce a functional skin barrier dysfunction and thereby aggravate the eczematous reaction in AD. PMID- 22433375 TI - Itch and eczema. AB - Eczema/dermatitis belongs to the most pruritic of skin diseases. Pruritogenic mediators in the skin are still mostly unknown. Recent studies, however, have shown that the histamine 4 receptor plays an important role in itch pathophysiology; tryptase and IL-31 are also involved in atopic eczema itch. Differences in itch perception and itch kinetics between healthy volunteers and eczema patients point towards ongoing central nervous inhibitory activity in patients. Questionnaire studies reported comparatively higher loads in affective items chosen by patients with atopic eczema. In the concept of eczema patient management, the therapy of clinical pruritus has to consider pathophysiology and perception by combining topical and systemic treatment. PMID- 22433376 TI - Eczema herpeticum. AB - Atopic dermatitis (AD) patients tend to develop viral infections such as herpes simplex, molluscum contagiosum or verrucae vulgares more frequently than nonatopic patients. In addition, disseminated viral infections occur in the skin lesions of AD. Though these diseases are relatively rare and little is known about their specific pathogenesis, some of them are among the true medical emergencies in dermatology. This contribution covers eczema herpeticum, the disseminated viral infection of an eczematous skin disease with the herpes simplex virus, as it is the clinically most important viral complication of AD. PMID- 22433377 TI - Bone mineral density in patients with atopic dermatitis. AB - In a recent investigation of bone mineral density (BMD) in patients with moderate to-severe AD, we found that one third of the patients had a low BMD, predominately males. This could be due to the use of topical corticosteroids or due to chronic inflammation. However, neither could be held responsible for the above finding. Low BMD at baseline does not seem to progress quickly, as assessed in a 2-year follow-up study. Treatment of low BMD is questionable as the effect of vitamin D and/or calcium supplementation on low BMD is controversial. We recommend performing long-term follow-up studies to assess the course of BMD over time from onset of AD. PMID- 22433378 TI - Immunosuppressive effect of prolactin-induced protein. AB - Prolactin-induced protein (PIP) has been shown to bind to CD4 and is speculated to block CD4-HLA-DR interaction. However, the immunomodulatory effect of PIP on chronic allergic contact dermatitis (ACD) remains to be elucidated. The aim of this work was to define the role of PIP during the immunoresponse. Using an oxazolone-induced mouse chronic ACD model, expression of PIP was immunohistologically examined. Furthermore, effects of continued exposure of a peptide mimicking the major binding site of PIP (amino acids 106-132) for CD4 was examined in a mouse chronic ACD model. We clarified that keratinocytes and dermal infiltrating cells are positively stained with anti-PIP antibody. The PIP peptide significantly downregulated oxazolone-induced mouse ACD compared to the controls. We also found that inflammation of PIP-non-applied control ear was also suppressed in a synchronized manner in the late phase of the PIP peptide applied mouse. These findings suggest that PIP might have an immunosuppressive effect in mouse chronic ACD. PMID- 22433379 TI - Is food allergy testing reliable in pediatric atopic dermatitis? A population based study. AB - We sought to assess the value and reliability of serologic testing for predicting clinical food allergy in a population-based cohort of infants with atopic dermatitis (AD). Infants 3-18 months of age, recruited from the general population, were followed quarterly for 3 years and carefully evaluated for evidence of immediate reactions to foods. Specific serum IgE levels for six foods were assayed at 3-5 years. Parents were interviewed at each visit regarding past/current immediate food-specific reactions involving skin, gut or respiratory systems. Data were entered into Excel for calculations of performance characteristics. Nine of the 40 patients (23%) who completed 3 years of follow-up had reactions to one or more foods. Reactions occurred in 5, 11 and 18% to milk, peanut and egg ingestion, respectively. In contrast, 30% of food-specific serum IgE tests were above normal. Predictive reliability of tests was generally low unless values were in the high range for peanut and milk. Conversely, egg allergy could be seen across a nearly full-spectrum of IgE values, making prediction highly unreliable. We conclude that physician and patient misinterpretation of the relevance and reliability of allergy testing may misdirect proper prevention and therapy of AD. PMID- 22433380 TI - New strategies for dealing with Staphylococcus aureus colonization and the emerging methicillin-resistant Staphylococcus aureus epidemic in atopic dermatitis. AB - Atopic dermatitis is a common inflammatory skin disease and a global health problem. Patients are often colonized or infected by Staphylococcus aureus, usually by toxin-producing strains. Methicillin-resistant S. aureus (MRSA) has emerged as an important pathogen. Community-acquired MRSA, a frequent cause of skin and soft tissue infections has become epidemic. Basic skin care measures emphasizing repair and protection of the skin barrier reduce microbial colonization and decrease the need for specific antimicrobial therapy even in patients colonized by MRSA. Novel approaches directed at S. aureus colonization and prevention of infection include compounds mimicking antimicrobial peptides, vaccines targeting unique antigens and toxin-neutralizing agents. PMID- 22433381 TI - Anti-IL-4 as a new strategy in allergy. AB - Allergic diseases are characterized by an overreaction characterized by Th2-type cell response, and as a consequence, an IgE-switched B cell immunity. Obviously, type-2 cytokines (IL-4, IL-5, IL-9, IL-13) and particularly IL-4 have been identified as potential targets for allergy treatment. While initial experiences using anti-IL-4 principles in asthma were rather ambiguous, more recent studies using an IL-4 mute in blocking the IL-4 and IL-13 receptor have shown promising results. Furthermore, our understanding of IL-4 biology is more specific and may promote more targeted interventions. A key function of IL-4 is the induction of 'master switch' transcription factor GATA3 that drives Th2 differentiation and also effectively inhibits the induction of regulatory T cells. Consequences for treatment of allergic diseases are also discussed. PMID- 22433382 TI - New drug targets in atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by eczematous skin lesions, pruritus and typical histopathological features. T cells are thought to play a key role, but B cells might also participate in the pathogenesis of AD. In two investigator-initiated pilot studies, we studied the effects of B cell depletion by monoclonal anti-CD20 antibody therapy or a reduction of activated T cells by LFA3-IgG fusion protein on moderate-to-severe AD. All patients treated with either rituximab or alefacept showed an improvement of their skin symptoms with a sustained effect after treatment. In both studies, histological alterations, such as spongiosis, acanthosis and dermal infiltrate, including T and B cell numbers, dramatically improved and the expression of IL-5 and IL-13 was reduced after therapy. Upon rituximab therapy, allergen-specific IgE levels were not altered and total serum IgE levels only slightly decreased. According to recent studies, neutralizing B and T cells products such as IgE or IL-5 might be effective in subgroups of patients with AD. PMID- 22433383 TI - Latest approaches to treating atopic dermatitis. AB - Recent investigations have shown atopic dermatitis (AD) results from the interplay of epidermal barrier defects, immune dysfunction and environmental triggers. These discoveries teach the importance of addressing all of these factors in treating patients. The barrier issues remind us of the need for moisturizers, especially after bathing, to replenish lipids and decrease water loss. Addition of dilute sodium hypochlorite (bleach) to bathwater often improves the dermatitis of children with moderate-to-severe dermatitis, especially with a history of staphylococcal infection. Oral vitamin D(3) has been suggested to increase the deficient antimicrobial peptide that results from cutaneous inflammation, although studies to date are inconclusive. Topical corticosteroids and calcineurin inhibitors continue to predominate as therapy and, to date, their safety record seems good, despite the Black Box warning issued in the United States. Poor compliance may explain the failure to respond to therapy, and contact dermatitis from topical application of emollients and medications may mimic AD, erroneously suggesting recalcitrance. For patients with severe AD, administration of systemic immunosuppressants may be required; ongoing studies of newer agents, including biologics, may revolutionize therapy for individuals with severe dermatitis, providing more targeted therapy in the future. PMID- 22433384 TI - Methods to assay Drosophila behavior. AB - Drosophila melanogaster, the fruit fly, has been used to study molecular mechanisms of a wide range of human diseases such as cancer, cardiovascular disease and various neurological diseases(1). We have optimized simple and robust behavioral assays for determining larval locomotion, adult climbing ability (RING assay), and courtship behaviors of Drosophila. These behavioral assays are widely applicable for studying the role of genetic and environmental factors on fly behavior. Larval crawling ability can be reliably used for determining early stage changes in the crawling abilities of Drosophila larvae and also for examining effect of drugs or human disease genes (in transgenic flies) on their locomotion. The larval crawling assay becomes more applicable if expression or abolition of a gene causes lethality in pupal or adult stages, as these flies do not survive to adulthood where they otherwise could be assessed. This basic assay can also be used in conjunction with bright light or stress to examine additional behavioral responses in Drosophila larvae. Courtship behavior has been widely used to investigate genetic basis of sexual behavior, and can also be used to examine activity and coordination, as well as learning and memory. Drosophila courtship behavior involves the exchange of various sensory stimuli including visual, auditory, and chemosensory signals between males and females that lead to a complex series of well characterized motor behaviors culminating in successful copulation. Traditional adult climbing assays (negative geotaxis) are tedious, labor intensive, and time consuming, with significant variation between different trials(2-4). The rapid iterative negative geotaxis (RING) assay(5) has many advantages over more widely employed protocols, providing a reproducible, sensitive, and high throughput approach to quantify adult locomotor and negative geotaxis behaviors. In the RING assay, several genotypes or drug treatments can be tested simultaneously using large number of animals, with the high-throughput approach making it more amenable for screening experiments. PMID- 22433385 TI - Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition. AB - OBJECTIVE: The main aim of this work is to investigate the expression of factors related to senescence and cell death pathways in non-small cell lung cancers (NSCLCs) and colorectal cancers (CRCs) in relation to telomere status. METHODS: We analyzed 158 tissue samples, 36 NSCLCs, 43 CRCs, and their corresponding control tissues obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. Expression of factors related to senescence, cell death pathways, transformation and tumorigenesis was investigated using arrays. Results were validated by real-time quantitative PCR. RESULTS: Considering tumors with telomere shortening, expression for BNIP3, DAPK1, NDRG1, EGFR, and CDKN2A was significantly higher in NSCLC than in CRC, whereas TP53 was overexpressed in CRC with respect to NSCLC. Moreover, compared to nontumor samples, DAPK1, GADD45A, SHC1, and TP53 were downregulated in the group of NSCLCs with telomere shortening, and no significant differences were found in CRC. CONCLUSIONS: In NSCLC, the failure of pathways which involve factors such as DAPK1, GADD45A, SHC1, and TP53, in response to short telomeres, could promote tumor progression. In CRC, the viability of these pathways in response to short telomeres could contribute to limiting tumorigenesis. PMID- 22433386 TI - H-ras mutation detection in bladder cancer by COLD-PCR analysis and direct sequencing. AB - OBJECTIVE: A sensitive mutation detection method called co-amplification at lower denaturation temperature-polymerase chain reaction (COLD-PCR) was applied to improve the detection frequencies of expressive mutations in the H-ras gene, including exons 1 and 2, in a group of Chinese patients diagnosed with bladder cancer. MATERIALS AND METHODS: The expressive mutations in the H-ras gene in 86 fresh tissues of human bladder cancer were identified by COLD-PCR or conventional PCR, followed by direct sequencing. RESULTS: A high frequency of silent mutations of 29.1% (25 of 86) in exon 1 (c.81T>C, H27H) and activating mutations of 8.1% (7 of 86) were detected by COLD-PCR, yielding a 36% improvement in mutation detection compared with conventional PCR. No significant association was shown between activating mutations and clinicopathologic parameters, but the frequencies of silent mutations in recurrent tumors were higher than those in primary tumors (p = 0.034). CONCLUSIONS: COLD-PCR is a highly sensitive, reliable, and convenient clinical assay for mutation detection. The adoption of the method is straightforward and requires no additional reagents or instruments. Silent mutations might be important genomic alterations in bladder cancer, and play a role in bladder cancer recurrence. PMID- 22433387 TI - Importance and usefulness of evaluating self-esteem in children. AB - Self-esteem is the "feeling of self-appreciation" and is an indispensable emotion for people to adapt to society and live their lives. For children, in particular, the environment in which they are raised contributes profoundly to the development of their self-esteem, which in turn helps them to adapt better to society. Various psychologists have provided definitions of self-esteem, and examined methods of objectively evaluating self-esteem. Questionnaire-style assessment methods for adult include Rosenberg Self-Esteem Scale and Janis-Field Feeling of Inadequacy Scale, and these for children include Coopersmith Self Esteem Inventory, Pope's 5-Scale Test of Self-Esteem for children, and Kid- KINDL(r). Other methods include Ziller Social Self-Esteem Scale and Implicit Association Test. The development of children's self-esteem is heavily influenced by their environment, that is, their homes, neighborhoods, and schools. Children with damaged self-esteem are at risk of developing psychological and social problems, which hinders recovery from low self-esteem. Thus, to recover low self esteem, it is important for children to accumulate a series of successful experiences to create a positive concept of self. Evaluating children's self esteem can be an effective method for understanding their past and present circumstances, and useful to treat for children with psychosomatic disorders. PMID- 22433388 TI - Geographical, clinical, clinicopathological and radiographic features of canine angiostrongylosis in Irish dogs: a retrospective study. AB - BACKGROUND: Angiostrongylus vasorum infection is associated with high morbidity and mortality in dogs. Although recognised in Ireland, there are no large series of cases reported. The aim of this retrospective study was to identify pertinent clinical and geographical features in Irish dogs. RESULTS: The case records of dogs presenting to the University College Dublin Veterinary Hospital (1999-2010) were reviewed. A contemporaneous review of external faecal parasitology and post mortem submissions was also performed. A positive diagnosis of angiostrogylosis was identified in 49 dogs including 24 clinical, 10 post mortem and 15 external faecal sample cases. The majority (n = 44 (90%)) resided on the East Coast.In the clinical cases, the median age was 20 months, 29% of cases were older than 2 years. Clinical features included cardiorespiratory (63%), coagulopathic (71%) and other (63%) signs. Cough (n = 10), dyspnoea (n = 5) and tachypnoea (n = 3) were the most common cardiorespiratory abnormalities. Of animals with evidence of coagulopathy, excessive haemorrhage from a wound (n = 5), airway haemorrhage (n = 9), epistaxis (n = 3), haematoma (n = 4), suspected haemarthrosis (n = 3), neurological signs (n = 2) and haematuria (n = 1) were found. Ten dogs were anaemic, of which two were severe (haematocrit <= 0.20 L/L). Ten animals had thrombocytopenia, with four severely affected (<=50 * 109/L). PT and APTT values were prolonged in 4 (24%) of 17 and a BMBT was prolonged in 5 (63%) of 8 cases. Vague signs of exercise intolerance (n = 6), lethargy (n = 6) and weakness (n = 2) were identified, with two (8%) animals having only these signs. In one animal the diagnosis appeared to be incidental. Thoracic radiographs (n = 19) identified abnormalities in 100% of cases. Four (17%) animals died before or within 24 hours of treatment and post mortem examinations confirmed angiostrongylosis. Fenbendazole was administered in 19 cases, 18 (95%) recovered. Two animals were euthanised, one which failed to respond to therapy and another in which an ante mortem diagnosis had not been made. CONCLUSIONS: Angiostrongylosis is not uncommon in Ireland, is not confined to young dogs or the East Coast and can present with a wide variety of signs, particularly coagulopathic, respiratory or neurological signs. PMID- 22433389 TI - Rubbings deposited by cats elicit defensive behavior in rats. AB - Laboratory rats display pronounced defensive behaviors when confronted with a range of cat-derived stimuli, including collars worn by a cat, cloths rubbed on a cat, and cat fur. One possible explanation of this phenomenon (the "kairomone hypothesis") is that rats derive a survival advantage by eavesdropping on signals used by cats to communicate with each other. Cats are known to rub their bodies on objects at strategic environmental locations to signal their identity and mating potential to other cats. The current study assessed the sensitivity of laboratory rats to these body rubbings. In Experiment 1, food deprived Sprague Dawley rats were trained to consume food pellets in one arm of a Y maze. On test day a damp cloth was placed near the food pellets that had been rubbed on a location (wall) where a cat had recently engaged in body rubbing. A control cloth and a collar worn by the cat were also tested. The presence of both the body rubbing residue and the cat collar increased latency to eat and decreased amount of food eaten. The disruption of consummatory behavior in the test environment was still evident 24h later in the absence of odor stimuli. Experiment 2 tested the reaction of naive Wistar rats to body rubbings using a paradigm in which rats were given the opportunity to hide. Relative to a control condition, rats exposed to a cotton pad wiped on a cat body rubbing location showed increased hiding behavior, decreased exploration and reduced stimulus approach and investigation. These defensive responses persisted for up to 4days following a single stimulus exposure. These results suggest that rats eavesdrop readily on body rubbings cats use for identification purposes, providing further support for a kairomone hypothesis of predator odor avoidance. PMID- 22433390 TI - Choline dietary supplementation improves LiCl-induced context aversion retention in adult rats. AB - Previous studies have demonstrated that choline is an essential nutrient during prenatal and early postnatal developmental periods. Thus, the availability of choline during these periods produces some beneficial effects on hippocampal dependent learning and memory in rats. However, research on the effect of adult choline supplementation on learning and memory abilities is scarce. In the present study, 3-4 month-old male Wistar rats receiving a 7-week choline supplemented diet (4.5 fold that of a standard diet) and control rats receiving a standard diet were trained in a LiCl-induced contextual aversion task. Short and long-term context aversion retention was assessed by recording the consumption of a flavoured solution in the aversive and safe contexts over two subsequent tests. Statistical analysis showed that the supplemented group exhibited greater intake suppression in the aversive context than in the safe context when two retention tests were applied 3 and 15 days after conditioning. These results suggest that increasing dietary choline availability during adulthood may favour the retention of a context aversion. PMID- 22433391 TI - Familial translocation t(6;20)(p21;p13) resulting in partial trisomy 6p and partial monosomy 20p: report of a new case and review of the literature. AB - Carriers of completely balanced chromosomal translocations have all necessary genetic information. Nevertheless, because of the possibility of maldistribution during gametogenesis, they are at increased risk for infertility, miscarriage, stillbirth or having a child with congenital anomalies including mental retardation. As postnatal clinical reports are infrequent, prediction of clinical course for specific unbalanced karyotypes diagnosed during pregnancy remains difficult. Here, we report the 6th case of partial trisomy 6p and partial monosomy 20p due to an unbalanced adjacent-1 segregation of the rare familial translocation t(6;20)(p21;p13). We give a thorough clinical description of the present case, demonstrating broad phenotypic overlap with the 5 previously published cases reviewed here, providing important data on postnatal outcome. PMID- 22433392 TI - Circulating microRNA in digestive tract cancers. PMID- 22433394 TI - The scientific status of childhood dissociative identity disorder: a review of published research. PMID- 22433395 TI - 3D cultures of human neural progenitor cells: dopaminergic differentiation and genetic modification. [corrected]. AB - Central nervous system (CNS) disorders remain a formidable challenge for the development of efficient therapies. Cell and gene therapy approaches are promising alternatives that can have a tremendous impact by treating the causes of the disease rather than the symptoms, providing specific targeting and prolonged duration of action. Hampering translation of gene-based therapeutic treatments of neurodegenerative diseases from experimental to clinical gene therapy is the lack of valid and reliable pre-clinical models that can contribute to evaluate feasibility and safety. Herein we describe a robust and reproducible methodology for the generation of 3D in vitro models of the human CNS following a systematic technological approach based on stirred culture systems. We took advantage of human midbrain-derived neural progenitor cells (hmNPCs) capability to differentiate into the various neural phenotypes and of their commitment to the dopaminergic lineage to generate differentiated neurospheres enriched in dopaminergic neurons. Furthermore, we describe a protocol for efficient gene transfer into differentiated neurospheres using CAV-2 viral vectors and stable expression of the transgene for at least 10 days. CAV-2 vectors, derived from canine adenovirus type 2, are promising tools to understand and treat neurodegenerative diseases, in particular Parkinson's disease. CAV-2 vectors preferentially transduce neurons and have an impressive level of axonal retrograde transport in vivo. Our model provides a practical and versatile in vitro approach to study the CNS in a 3D cellular context. With the successful differentiation and subsequent genetic modification of neurospheres we are increasing the collection of tools available for neuroscience research and contributing for the implementation and widespread utilization of 3D cellular CNS models. These can be applied to study neurodegenerative diseases such as Parkinson's disease; to study the interaction of viral vectors of therapeutic potential within human neural cell populations, thus enabling the introduction of specific therapeutic genes for treatment of CNS pathologies; to study the fate and effect of delivered therapeutic genes; to study toxicological effects. Furthermore these methodologies may be extended to other sources of human neural stem cells, such as human pluripotent stem cells, including patient-derived induced pluripotent stem cells. PMID- 22433396 TI - Two new cytotoxic triterpenoid saponins from the roots of Clematis argentilucida. AB - Bioassay-guided fractionation of the n-BuOH extract of the roots of Clematis argentilucida led to the isolation of two new triterpenoid saponins along with a known one, cussonside B (3). By extensive spectral analysis and chemical evidences, the structures of the two new saponins were determined to be 3beta-O [beta-D-ribopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1->2)-alpha-L arabinopyranosyl] hederagenin-11,13-dien-28-oic acid (1) and 3beta-O-{beta-D ribopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1->2)-[beta-D-glucopyranosyl-(1 >4)]-beta-D-xylopyranosyl} oleanolic acid (2), respectively. Saponin 1 is the first example of triterpenoid saponins with two double bonds located at C-11 and C-13 in the aglycone from the genus Clematis. The two new saponins exhibited significant cytotoxicity against human leukemia HL-60 cell lines, human hepatocellular carcinoma Hep-G2 cell lines and human glioblastoma U251MG cell lines with a range of IC(50) values from 2.74 to 25.40MUM, while 3 showed inactivity against all of the three cancer cell lines. PMID- 22433397 TI - Anti-inflammatory and cytotoxic 2-arylbenzofurans from Morus wittiorum. AB - Three new 2-arylbenzofurans named wittifuran H, wittifuran I and wittifuran U (1 3) were obtained during our ongoing investigation of an ethanol extract from the stem bark of Morus wittiorum. Their structures were elucidated on the basis of spectroscopic data. Compound 2 displayed potent anti-inflammatory activity and selective cytotoxicity against human gastric cancer cell line BGC-823 with an IC(50) value of 1.45MUM. PMID- 22433398 TI - [Acute encephalopathy due to late-onset maple syrup urine disease in a school boy]. AB - Maple syrup urine disease is a common amino acids metabolic disease. In most patients, onset occurs in the neonatal period and infancy. In this study, the case of a school boy with acute encephalopathy due to late-onset maple syrup urine disease is summarized. The boy (8.5 years) was admitted because of acute encephalopathy after suffering from infection for two days at the age of eight and a half years. Metabolic acidosis, hyperuricemia and decreased protein level in cerebrospinal fluid were found by general laboratory tests. Magnetic resonance imaging of the brain revealed signal intensity abnormalities in the bilateral cerebellum dentate nucleus, brainstem, thalamus, putamen, caudate nucleus and cortex of the cerebral hemispheres. On T1WI and T2WI scanning, hyperintensive signal was found. Blood leucine and valine were significantly elevated. Urinary 2 hydroxy isovaleric acid, 3-hydroxybutyric acid, 2-keto isovaleric acid, and 2 keto acid also increased. Both the blood amino acid and urine organic acid profiles led to the diagnosis of maple syrup urine disease. In the acute period, the patient was treated with a large dose of vitamin B1, glucose, L-carnitine and a protein-restrict diet. The patient's condition improved significantly after five days of treatment, and he recovered completely two days later. Afterwards, treatment with vitamin B1, L-carnitine and a protein-restrict diet (1 g/kg/day) was continued. One and a half months later, blood amino acids and urine organic acids returned to normal. Magnetic resonance imaging of the brain also indicated a great improvement. It was concluded that inborn metabolic disease should be considered in the patients with an onset similar to acute encephalopathy. Early diagnosis and proper treatment can prevent brain damage and improve prognosis. PMID- 22433399 TI - [Fecal calprotectin levels in preterm infants during the early neonatal period]. AB - OBJECTIVE: To explore whether fecal calprotectin (f-calprotectin, FC) may be an early marker for the identification of gastrointestinal injury in preterm infants by measuring FC concentration and changes of FC concentration in infants with different perinatal factors. METHODS: FC concentration was measured using ELISA in 76 samples (50-100 mg) obtained from 38 preterm infants (gestation 29 to 33 weeks), at birth and on the third day after birth (the 1st and the 2nd FC levels). The infants were classified into three groups according to the reason for preterm birth: premature rupture of membranes (PROM; n=13), spontaneous preterm birth (SPB; n=5) and indicated preterm birth (IPB; n=20). RESULTS: There were no significant differences between the 1st and 2nd FC levels in the 38 infants. The 1st FC level in the PROM group was significantly higher than that in the IPB group (P<0.05). The 1st FC level in infants whose mothers received antenatal antibiotics treatment was significantly lower. Infants born by cesarean section had a significantly lower 1st FC level than those born by vaginal delivery (P<0.05). Both the 1st and 2nd FC levels in infants with feeding intolerance were significantly higher than in infants with feeding tolerance (P<0.05). The 2nd FC level was negatively correlated with 1 min Apgar score (r= 0.3, P<0.05). CONCLUSIONS: Premature rupture of membranes and perinatal asphyxia may lead to an increase in the excretion of FC in preterm infants. FC may be used as a marker for early evaluation of gastrointestinal conditions in preterm infants. PMID- 22433400 TI - [Application of non-nutritive sucking in preterm infants requiring mechanical ventilation]. AB - OBJECTIVE: To study the role of non-nutritive sucking in preterm infants requiring mechanical ventilation therapy. METHODS: In a study of 68 preterm infants requiring mechanical ventilation, a randomly selected observation group of 35 infants was provided with non-nutritive sucking and a control group of 33 infants was not. The time to reach full enteral feeding, birth weight recovery time, body weight growth rate, hospitalization time, feeding tolerance and mechanical ventilation-related complications were compared between the two groups. RESULTS: The time to reach full enteral feeding and hospitalization time were shorter (P<0.01), the incidence of feeding intolerance was lower (P<0.05), and the body weight growth rate was higher (P<0.05) in the observation group than in the control group. There were no significant differences in the birth weight recovery time and the incidence of mechanical ventilation-related complications between the two groups. CONCLUSIONS: The use of non-nutritive sucking can increase growth rate, shorten hospitalization time and improve feeding tolerance in preterm infants requiring mechanical ventilation therapy. Moreover, it does not result in an increase in mechanical ventilation-related complications. PMID- 22433401 TI - [Treatment of myocardial damage with creatine phosphate following neonatal asphyxia: a meta-analysis]. AB - OBJECTIVE: To evaluate the effects of creatine phosphate (CP) in the treatment of myocardial damage following neonatal asphyxia. METHODS: Medical databases were searched for a systematic literature review and meta-analysis of randomized and quasi-randomized trials on the treatment of myocardial damage with CP following neonatal asphyxia. The data was analyzed using Review Manager 5.1. RESULTS: Six trials involving 400 patients (CP treatment/control: 202/198) were included in the survey. The meta-analysis indicated that CP treatment for 7 days decreased serum myocardial enzyme levels (CK, CK-MB, LDH, HBDH and cTnI levels). Both the total effective rate (RR: 1.29; 95% CI: 1.12, 1.48) and the significantly effective rate (RR: 1.78; 95% CI: 1.32, 2.41) in the CP treatment group were significantly higher than in the control group. CP treatment reduced the hospitalization period by 4.07 days compared with the control group (95% CI: 5.25, -2.89). CONCLUSIONS: CP treatment appears to be more effective than routine treatment alone for myocardial damage following neonatal asphyxia. It appears to be safe and it can both decrease serum myocardial enzyme levels and shorten the period of hospitalization. However, as the evidence obtained in this study is not robust due to the poor quality of current studies, further studies of high quality, large-scale trails are needed. PMID- 22433402 TI - [Urinary tract infections in the neonatal intensive care unit: clinical analysis of 229 cases]. AB - OBJECTIVE: To study the clinical features, distribution of pathogens, drug susceptibility, and treatment effectiveness in neonates with urinary tract infection (UTI) and admitted to the neonatal intensive care unit (NICU). METHODS: The clinical data of 229 neonates who developed UTI during their stay in the NICU were retrospectively studied. RESULTS: The main clinical manifestations of these children included fever/irregular body temperature, refusing to milk feeding, jaundice, vomiting, diarrhea, poor weight gain, and lethargy. The top three pathogens were Escherichia coli, Enterococcus feces, and Klebsiella pneumoniae. Escherichia coli and Klebsiella pneumoniae were highly resistant to ampicillin and most cephalosporins (>= 85%), and were highly sensitive to imipenem (100%), meropenem (100%), cefoperazone/sulbactam and piperacillin/tazobactam (>90%). Enterococcus feces were highly resistant to penicillin (100%), rifampicin (84%) and gentamicin (79%), but were sensitive to vancomycin. CONCLUSIONS: The clinical manifestations of neonatal UTI are often atypical and manifested as systemic symptoms. The main pathogenic bacterium is Escherichia coli, and the isolation rate of enterococci can also be high. Most pathogenic bacteria are resistant to penicillin and cephalosporins, and therefore decision-making on drug administration must be based on the results of drug sensitivity tests. PMID- 22433403 TI - [Causes of neonatal death in the Xiaogan region of Hubei Province between 2007 and 2010]. AB - OBJECTIVE: To study the causes of neonatal death in the Xiaogan region of Hubei Province between 2007 and 2010. METHODS: The causes of 664 cases of neonatal death between 2007 and 2010, from 7 counties (cities) of the Xiaogan region of Hubei Province, were investigated. RESULTS: Neonatal mortality in the Xiaogan region between 2007 and 2010 accounted for 51.12% of under-five mortality. The top three causes of neonatal death in this region were preterm birth/low birth weight, birth asphyxia and congenital diseases. CONCLUSIONS: It is important to reduce neonatal mortality through the prevention of preterm birth, low birth weight, birth asphyxia and congenital defects. PMID- 22433404 TI - [Effect of bacillus Callmette-Guerin on cytotxicity of cytotoxic T lymphocyte from children with acute lymphoblastic leukemia for killing HL-60 cells in vitro]. AB - OBJECTIVE: To study the effect of bacillus Callmette-Guerin (BCG) on cytotxicity of cytotoxic T lymphocyte (CTL) from human peripheral blood of children with acute lymphoblastic leukemia (ALL) for killing HL-60 cells in vitro. METHODS: The mononuclear cells were isolated from peripheral blood of ALL children and healthy children, and were cultured with RPMI1640, interleukin-2 (IL-2), phytohemagglutinin (PHA) and BCG.The growth of CTLs was observed by light microscopy. The proportions of CD3, CD3+CD4+ and CD3+CD8+ were determined by flow cytometry 10 days after culture. MTT method was performed to detect the cytotoxicity of CTLs for killing HL-60 cells. RESULTS: Neither the cell number nor the volume of CTLs changed significantly within 2 days of culture, but both began increasing on the 3rd day of culture and reached a peak on the 6-10th days. On the 10th day of culture, the cell number of CTLs in the BCG treatment group was much higher than in the group without BCG treatment. The CD3+CD8+ proportion in the leukemia group was much higher than in the control group. With the effect of BCG, the CD3+CD8+ proportion of the two groups became much higher. The cytotoxicity of CTLs for killing HL-60 cells in the leukemia group was weaker than in the control group. CONCLUSIONS: BCG along with IL-2 and PHA promotes the proliferation of CTLs and enhances the ability of CTLs in killing HL-60 cells. PMID- 22433405 TI - [Immunophenotyping and its clinical significance in childhood acute lymphoblastic leukemia]. AB - OBJECTIVE: To study the immunophenotype and its relationship with clinical characteristics in children with acute lymphoblastic leukemia (ALL). METHODS: Bone marrow or blood samples (2-3 mL) with heparin anticoagulation from 139 children with ALL were obtained, and immunophenotypes were identified by flow cytometry. RESULTS: In 139 ALL children, there were 103 cases (74.1%) of B-ALL, 24 cases (17.3%) of T-ALL, 12 cases of T/B biphenotypic (8.6% of T/BALL). In the 103 children with B-ALL, CD19 (90.3%), CD10 (83.5%) and CD20 (27.2%) were expressed as major antigens. In the 24 children with T-ALL, the major antigens were CD3 (79.2%), CD7 (66.7%) and CD5 (33.3%). In the 12 children with B/T-ALL, T lymphoid antigens included CD7 (50.0%) and CD5 (41.7%), while the B-lymphoid antigens included CD19 (50.0%) and CD10 (33.3%). Of the 139 children with ALL, 32 cases (23.0%) showed myeloid antigen expression (My+ ALL) and the main expression antigens were CD13, CD33, CD14 and MPO. CD34 was expressed in 31 cases. CD34 positive expression (15.6%) in My+ ALL children was significantly lower than in My-ALL children (24.3%). HLA-DR was expressed in 82 of the 139 ALL children. The expression of CD10, CD34 and HLA-DR in the standard-risk, medium risk, high-risk ALL children was significantly different. There were significant differences in gender and incidence of bleeding between the My+ ALL and My-ALL groups (P<0.05). CONCLUSIONS: Immunetyping can differentiate the sources of leukemic cells. The expression of CD10, CD34 and HLA-DR antigen is related to the clinical classification of ALL. PMID- 22433406 TI - [Prevalent characteristics in children with hand-foot-mouth disease in the Kunming area in 2010]. AB - OBJECTIVE: To study the prevalent characteristics in children with hand-foot mouth disease (HFMD) in the Kunming area in 2010. METHODS: The clinical data of 13286 outpatient and inpatient children with HFMD in Kunming Children's Hospital between January and December, 2010, including 8 death cases, 715 serious cases and 12563 non-serious cases, were retrospectively studied. RESULTS: Human enterovirus was detected in 8200 children (61.72%). Children infected with EV71 and CoxA16 accounted for 29.49% (2418/8200) and 53.21% (4363/8200), respectively. Seventy-five children (0.91%) were found to have a mixed infection of the two viruses. Other types of human enterovirus were detected in 1344 children (16.39%). There were significant differences in the total positive rate of human enterovirus in the four quarters of the year (P<0.01). The total positive rate in the second quarter represented the highest proportion (71.56%), and the number of patients was also highest, accounting for 52.94% of the total number of patients in the whole year. EV71 infection was common in the serious case group while CoxA16 was found to be the main pathogen in the non-serious case group. Serious cases were common in children under three years old. In the positive EV71 cases, the viral load of EV71 was not statistically different between the death cases, serious and non-serious cases. CONCLUSIONS: In 2010, children with HFMD in the Kunming area were mainly infected with CoxA16. Serious cases of HFMD were more common in those who were infected with EV71, and the majority of serious infections were suffered by children who were less than three years old. The viral load was not associated with disease severity. The highest morbidity rate was in the second quarter of the year. PMID- 22433407 TI - [Epidemiologic characteristics of hand-foot-mouth disease in Guiyang between 2008 and 2010]. AB - OBJECTIVE: To study the epidemiologic characteristics of hand-foot-mouth disease (HFMD) in Guiyang between 2008 and 2010. METHODS: The epidemiologic characteristics of HFMD were analyzed by descriptive statistical methods based on the data from the China Information System for Disease Control and Prevention. RESULTS: A total of 27383 cases of HFMD were recorded in Guiyang between 2008 and 2010. The incidence of HFMD increased from 66.4439/100000 in 2008 to 163.9276/100000 in 2009 and 471.5515/100000 in 2010 (P<0.01). The mortality rate was 0.1026/100000 in 2010, which was significantly lower than in 2009 (0.2821/100000) (P<0.05). HFMD occurrence showed seasonality and reached a peak between April and June. HFMD cases were commonly noted in children under 5 years old, and especially in children under 3 years old. The main detected pathogen was human enterovirus 71 (EV17) in 2009. Whereas in 2010 the disease was mainly caused by CoxA16 and other intestinal viruses. CONCLUSIONS: The incidence of HFMD in Guiyang increased year by year from 2008 to 2010, but the mortality rate decreased year by year. HFMD occurrence showed an obvious seasonality. HFMD was common in children under the age of five. The main pathogens of this disease included EV17, CoxA16 and other intestinal viruses. PMID- 22433408 TI - [Value of antiviral therapy for infectious monocytosis in children]. AB - OBJECTIVE: To study the value of antiviral therapy for infectious monocytosis (IM) in children by comparing the near-term therapeutic efficacies and long-term follow-up results in children with this disorder between receiving antiviral therapy or not. METHODS: The medical data of IM children between 1999 and 2009 were retrospectively reviewed. A total of 172 cases with a follow-up visit period of 1 year and more were eligible. The children were classified into three groups according to the treatment protocol: ganciclovir treatment (n=49), acyclovir treatment (n=72) and symptomatic treatment (control; n=51). The children in the ganciclovir group received an intravenous drip of 10 mg/kg per day of ganciclovir, administered in twice-daily doses; Seven days later the drip volume was changed to 5 mg/kg, administered once each day; the total course lasting 10 14 days. The children in the acyclovir group received acyclovir orally at 20 mg/kg per day, administered in three times daily doses; the total course lasting 10-14 days. The children in the control group received symptomatic treatment only. In the three groups, indicators including fever course, improvement of isthmitis symptoms, lymph node retraction, hepatic and splenic lymph node retraction time, atypical lymphocyte fallback time and alteration of granulocyte amount after drug use were observed. The long-term follow-up visits covered such indicators as blood routine reexamination, hepatic function, liver and spleen B ultrasonography, recovery rate, recurrence rate and mortality rate. RESULTS: In the acute phase, there were no differences in terms of fever course, isthmitis improvement, hepatic and splenic lymph node retraction time and the time of atypical lymphocyte falling back to below 10% among the three groups (P>0.05). During the period of follow-up visits between 1 year and 8 years and 10 months, no significant differences were observed in the recovery rate, the recurrence rate and the mortality rate among the three groups (P>0.05). CONCLUSIONS: The efficacies of antiviral therapy for IM children appear to be similar to non antiviral therapy, suggesting that antiviral therapy fails to be beneficial for IM children. PMID- 22433409 TI - [Value of oral mucosa cast-off cells as samples in fluorescent in situ hybridization for the diagnosis of Down's syndrome]. AB - OBJECTIVE: At present, blood and skin biopsy tissues are used in the fluorescent in situ hybridization (FISH) test for the diagnosis of Down's syndrome, however, the samples are usually obtained invasively. This study explores the value of oral mucosa cast-off cells in the FISH test, as samples obtained non-invasively, for the diagnosis of this disorder. METHODS: Peripheral blood and oral mucosa cast-off cells were sampled for the FISH test in 16 children with suspected Down's syndrome between March 2010 and March 2011. Chromosomal karyotype analysis of peripheral blood lymphocytes ("gold standard" for the diagnosis of Down's syndrome) was also conducted. RESULTS: The FISH test, in which both peripheral blood and oral mucosa cast-off cells were examined, showed that 14 children had 21-trosomy syndrome and the other 2 children had normal numbers of cromosome 21. The results of the FISH test were the same as the results of the chromosomal karyotype analysis. CONCLUSIONS: Use of the FISH method to test samples of oral musoca cast-off cells is non-invasive and reliable for the diagnosis of Down's syndrome in children, and is hence worthy of recommendation. PMID- 22433410 TI - [Effect of methylation inhibitor on EphB4 gene expression, proliferation and apoptosis in CEM cells]. AB - OBJECTIVE: To study the regulation of methylation inhibitor 5-aza-2' deoxycytidine on transcription of EphB4 gene and effects on the proliferation and apoptosis of human acute lymphocyte leukemia cell line CEM. METHODS: Bisulfite sequencing PCR was used to detect CpG island methylation density in EphB4 promoter. The expression of EphB4 mRNA and protein was determined by Q-PCR and Western blot. MTS assay and flow cytometry were used to detect the apoptosis of CEM cells after treatment with different concentrations of 5-aza-2'-deoxycytidine (1.0, 2.5 and 5 MUmol/L). RESULTS: Methylation of EphB4 gene promoter was detected in CEM cells (31.4%). The methylation level of EphB4 gene was down regulated after treatment with various concentrations of 5-aza-2'-deoxycytidine. The EphB4 mRNA and protein expression in CEM cells increased after 5-aza-2' deoxycytidine treatment. 5-Aza-2'-deoxycytidine significantly inhibited the cell growth in dose and time dependent manners. Early apoptosis rates of CEM cells increased from 4.1% to 24.8% 96 hrs after 5-aza-2'-deoxycytidine treatment. CEM cells in G1 phase decreased from 62.4% to 46.8%, cells in G2 phase increased from 2.1% to 16.2%, and CEM cells were arrested in G2 phase after treatment with 5 MUmol/L 5-aza-2'-deoxycytidine for 96 hrs. CONCLUSIONS: 5-Aza-2'-deoxycytidine, an inhibitor of specific methylation transferase, can induce expression of the silent EphB4 gene in CEM cells, inhibit the proliferation of leukemia cells and induce cell apoptosis. PMID- 22433411 TI - [Pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension]. AB - OBJECTIVE: To study the changes of pulmonary vascular remodeling in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) in neonatal rats. METHODS: Ninety-six newborn Wistar rats were randomly divided into an HPH group (hypoxia exposure) and a control group (room air exposure). The mean pulmonary arteria pressure (mPAP), right ventricle hypertrophy index (RVHI), and vascular remodeling indexes MT% and MA% were measured 3, 5, 7, 10, 14 and 21 days after exposure (n=8 each time point). The ultrastructure of pulmonary vascular was observed under a transmission electron microscope. RESULTS: mPAP in the HPH group 3, 5, 7, 10, 14 and 21 days after hypoxia exposure increased compared with the control group (P<0.05). With the prolonged hypoxia time, mPAP in the HPH group increased more significantly. MT%, MA% and RVHI increased significantly in the HPH group after 7 days of hypoxia exposure in a time-dependent manner compared with the control group (P<0.05). The transmission electron microscopy demonstrated that small pulmonary arterials became thickened, endothelial cell hyperplasia and degeneration, and organelles increased in the HPH group after 7 days of hypoxia exposure. Besides, collagen deposition in the extracellular matrix and the changes of pulmonary vascular remodeling were observed. CONCLUSIONS: mPAP increases between 3 and 5 days of hypoxia exposure, resulting from pulmonary vascular spasm caused by hypoxia. After hypoxia of 7 days, the mPAP increases more significantly, pulmonary vascular remodeling occurs, and right ventricle becomes irreversibly hypertrophic. These changes may be intensified as the prolonged hypoxia time. PMID- 22433412 TI - [miR-124-1 promotes neural differentiation of rat bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To study the effects of miR-124-1 on neuronal differentiation of rat bone marrow mesenchymal stem cells (MSCs). METHODS: MSCs cells were assigned into three groups: control (uninfected and untransfected), miR-124-1+ (infected with miR-124-1), and miR-124-1- (transfected with Anti-rno-miR-124* Inhibitor). MSCs were induced by beta-mercaptoethanol (beta-ME) to differentiate into neurons. The fluorescence expressed by infected MSCs was observed under an inverted fluorescence microscope. MTT method was used to measure cell survival rate after transfection or infection. Immunocytochemistry, RT-PCR and Western blot methods were used to detect the expression of beta3 tubulin, MAP-2 and GFAP 6 days after beta-ME induction. RESULTS: The expression of miR-124-1 in the miR-124-1+ group was significantly higher 2 days after infection of lentivirus vector compared with the control group (P<0.01). In the miR-124-1- group, the cell survival rate and the miR-124-1 expression level decreased significantly 24 hrs after transfection of anti-rno-miR-124* inhibitor (P<0.01). After 6 days of beta-ME induction, the protein and mRNA expression levels of beta3 tubulin and MAP-2 in the miR-124-1+ group were much higher than the other two groups (P<0.01); while the expression levels of beta3 tubulin and MAP-2 in the miR-124-1-group were lower than the control group (P<0.01). The expression of GFAP in the three groups was weak (<1%). CONCLUSIONS: miR-124 might promote neuronal differentiation of rat MSCs. PMID- 22433413 TI - [Cloning and sequence analysis of SLC25A13 transcripts in human amniocytes]. AB - OBJECTIVE: This research intends to amplify the entire coding region sequences of SLC25A13 mRNA which encodes citrin, and to investigate sequence features of the transcripts for this gene in cultured human amniocytes. This study will provide laboratory evidence for prenatal diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) at mRNA level. METHODS: One amniocyte sample was collected from a pregnant woman who underwent prenatal diagnosis of citrin deficiency and whose fetus has proven a carrier of 851del4 mutation by genomic DNA analysis. Another amniocyte sample, as a control, was from a fetus without family history of citrin deficiency. Total RNA was extracted from cultured amniocytes, cDNA was synthesized, and then nested-PCR was performed to amplify the entire coding region sequences of SLC25A13. The PCR products were cloned and analyzed by sequencing. RESULTS: The entire coding region of SLC25A13 gene was successful amplified from two cultured human amniocytes. The splice variant of SLC25A13, SLCA (normal mRNA), was identified in the two samples. SLCB (CAG insertion between exon 9-10) was identified in the control. SLCC (exon 5-11 skipping), but not transcriptional product from the allele with 851del4 mutation, was identified in the 851del4 mutation carrier. CONCLUSIONS: This study demonstrated that the entire coding region of SLC25A13 cDNA can be successfully amplified from two cultured human amniocytes, and revealed exon 5-11 skipping as a novel SLC25A13 transcript. Normal mRNA predominated in the transcripts in normal control and 851del4 mutation carrier, suggesting that the two fetuses were not at risk for NICCD. These SLC25A13 transcription features provided laboratory evidence for prenatal diagnosis of NICCD. PMID- 22433414 TI - [Partial splenic embolization for the treatment of chronic idiopathic thrombocytopenic purpura in children]. PMID- 22433415 TI - [Drug resistance of Acinetobacter baumanii isolated from children in the pediatric intensive care unit]. PMID- 22433416 TI - [Osteogenesis imperfecta complicated by bilateral pallidal calcification in two sibships]. PMID- 22433417 TI - [Skin lesions induced by malnutrition in an infant with methylmalonic aciduria and homocysteic acidemia]. PMID- 22433418 TI - [Hand foot and mouth disease complicated by peripheral facial paralysis: a case report]. PMID- 22433419 TI - [Progress in pharmacotherapy of pulmonary arterial hypertension in children]. AB - This paper provides an overview of the current state of pharmacotherapy in children with pulmonary arterial hypertension (PAH) and a brief introduction to the potentially novel pharmacologic targets for PAH. Currently, 3 classes of drugs including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase-5 inhibitors are approved for the treatment of PAH in children, which has led to improved hemodynamics, increased exercise capacity and prolonged survival. Despite these improvements, there is still a need to carry out well designed, randomized, controlled studies with larger samples. In addition, novel drugs targeting other molecular pathways should be developed. PMID- 22433420 TI - Gender differences in alcohol-related non-consensual sex; cross-sectional analysis of a student population. AB - BACKGROUND: Sexual offences are a global public health concern. Recent changes in the law in England and Wales have dramatically altered the legal landscape of sexual offences, but sexual assaults where the victim is voluntarily intoxicated by alcohol continue to have low conviction rates. Worldwide, students are high consumers of alcohol. This research aimed to compare male and female students in relation to their knowledge and attitudes about alcohol and sexual activity and to identify factors associated with being the victim of alcohol-related non consensual sex. METHODS: 1,110 students completed an online questionnaire. Drinking levels were measured using the Alcohol Use Disorder Identification Test. Non-consensual sexual experiences were measured using the Sexual Experience Survey. Univariate and multivariate analyses were undertaken using chi square and backwards stepwise logistic regression respectively. RESULTS: A third of respondents had experienced alcohol-related non-consensual sex. Male and female students differed in the importance they gave to cues in deciding if a person wished to have sex with them and their understanding of the law of consent. 82.2% of women who had experienced alcohol-related non-consensual sex were hazardous drinkers compared to 62.9% who drank at lower levels (P < 0.001). Differences existed between men and women, and between those who had and had not experienced alcohol-related non-consensual sex, in relation to assessments of culpability in scenarios depicting alcohol-related intercourse. A third of respondents believed that a significant proportion of rapes were false allegations; significantly more men than women responded in this way. CONCLUSIONS: Alcohol-related coerced sexual activity is a significant occurrence among students; attitudinal and knowledge differences between males and females may explain this. Educational messages that focus upon what is deemed acceptable sexual behaviour, the law and rape myths are needed but are set against a backdrop where drunkenness is commonplace. PMID- 22433421 TI - Childhood trajectories of anxiousness and disruptiveness explain the association between early-life adversity and attempted suicide. AB - BACKGROUND: Suicidal behavior is frequently associated with a history of childhood abuse yet it remains unclear precisely how early life adversity may increase suicide risk later in life. As such, our aim was to examine whether lifetime trajectories of disruptiveness and anxiousness trait dysregulation explain the association between childhood adversity and suicidal behavior; and moreover, to test the potential modifying effects of mental disorders on these associations. METHOD: A sample of 1776 individuals from a prospective school based cohort followed longitudinally for over 22 years was investigated. We tested the influence of disruptiveness and anxiousness trajectories from age 6 to 12 years on the association between childhood adversity (i.e. sexual and physical abuse) and history of suicide attempts (SA) using logistic regression models. Both adolescent externalizing and internalizing Axis I disorders and gender were tested as potential modifiers of these associations. RESULTS: Four distinct longitudinal trajectories were identified for both disruptiveness and anxiousness. The high disruptiveness trajectory accounted for the association between childhood adversity and SA, but only for females. The high anxiousness trajectory also explained the association between adversity and SA; however, in this case it was not sex but mental disorders that influenced the potency of the mediating effect. More specifically, anxiousness fully explained the effect of adversity on SA in the presence of externalizing disorders, whereas in the absence of these disorders, this effect was significantly attenuated. CONCLUSIONS: This study provides evidence that both disruptiveness and anxiousness play an important role in explaining the relationship between childhood adversity and SA. PMID- 22433422 TI - Synthetic Hounsfield units from spectral CT data. AB - Beam-hardening-free synthetic images with absolute CT numbers that radiologists are used to can be constructed from spectral CT data by forming 'dichromatic" images after basis decomposition. The CT numbers are accurate for all tissues and the method does not require additional reconstruction. This method prevents radiologists from having to relearn new rules-of-thumb regarding absolute CT numbers for various organs and conditions as conventional CT is replaced by spectral CT. Displaying the synthetic Hounsfield unit images side-by-side with images reconstructed for optimal detectability for a certain task can ease the transition from conventional to spectral CT. PMID- 22433423 TI - Ancestral synteny shared between distantly-related plant species from the asterid (Coffea canephora and Solanum Sp.) and rosid (Vitis vinifera) clades. AB - BACKGROUND: Coffee trees (Rubiaceae) and tomato (Solanaceae) belong to the Asterid clade, while grapevine (Vitaceae) belongs to the Rosid clade. Coffee and tomato separated from grapevine 125 million years ago, while coffee and tomato diverged 83-89 million years ago. These long periods of divergent evolution should have permitted the genomes to reorganize significantly. So far, very few comparative mappings have been performed between very distantly related species belonging to different clades. We report the first multiple comparison between species from Asterid and Rosid clades, to examine both macro-and microsynteny relationships. RESULTS: Thanks to a set of 867 COSII markers, macrosynteny was detected between coffee, tomato and grapevine. While coffee and tomato genomes share 318 orthologous markers and 27 conserved syntenic segments (CSSs), coffee and grapevine also share a similar number of syntenic markers and CSSs: 299 and 29 respectively. Despite large genome macrostructure reorganization, several large chromosome segments showed outstanding macrosynteny shedding new insights into chromosome evolution between Asterids and Rosids. We also analyzed a sequence of 174 kb containing the ovate gene, conserved in a syntenic block between coffee, tomato and grapevine that showed a high-level of microstructure conservation. A higher level of conservation was observed between coffee and grapevine, both woody and long life-cycle plants, than between coffee and tomato. Out of 16 coffee genes of this syntenic segment, 7 and 14 showed complete synteny between coffee and tomato or grapevine, respectively. CONCLUSIONS: These results show that significant conservation is found between distantly related species from the Asterid (Coffea canephora and Solanum sp.) and Rosid (Vitis vinifera) clades, at the genome macrostructure and microstructure levels. At the ovate locus, conservation did not decline in relation to increasing phylogenetic distance, suggesting that the time factor alone does not explain divergences. Our results are considerably useful for syntenic studies between supposedly remote species for the isolation of important genes for agronomy. PMID- 22433424 TI - A severe valproate overdose with complete recovery in a newborn. AB - Valproate overdose, extensively described in adults and older children, has been reported in only 1 newborn: a 26-day-old female who developed a severe cerebral edema leading to a fatal outcome. Therefore, the consequences of valproate overdose are largely unknown in the neonatal period. Here, we present the clinical evolution of a 6-day-old newborn who developed hyperammonemic encephalopathy after the accidental administration of 310 mg/kg of oral valproate in a single dose. Despite the very high valproate and blood ammonia levels, he did not develop life-threatening complications and he completely recovered without sequels. His brain magnetic resonance imaging showed symmetric focal T1 prolonged signals in both globi pallidi that completely resolved over time, a neuroimaging pattern that was not previously described in valproate overdose. Our case report suggests that valproate overdose in newborns can be completely reversible even when the valproate and ammonium blood levels are very high. PMID- 22433425 TI - Botulinum toxin type A for the treatment of equinus deformity in patients with mucopolysaccharidosis type II. AB - Mucopolysaccharidoses are lysosomal storage disorders that are caused by a deficiency in the enzymes that degrade glycosaminoglycans. The accumulation of glycosaminoglycans affects multiple systems, resulting in coarse facial features, short stature, organomegaly, and variable neurological changes from normal intelligence to severe mental retardation and spasticity. Effects on the musculoskeletal system include dysostosis multiplex, joint stiffness, and muscle shortening. This article reports 2 patients with mucopolysaccharidosis type II (Hunter syndrome) who showed progressive equinus deformity of the feet. Both patients were treated with intramuscular botulinum toxin type A injections in the gastrocnemius and the soleus muscles, followed by serial casting. In both patients, passive range of motion, muscle tone, and gait performance were significantly improved. Botulinum toxin type A injections followed by serial casting are a therapeutic option for contractures in patients with mucopolysaccharidosis. However, the long-term effects and the effect of application in other muscles remain unknown. PMID- 22433426 TI - Vibration perception thresholds in children with idiopathic toe walking gait. AB - This study investigated the vibration perception differences between children with an idiopathic toe walking gait and their non-toe walking peers. Sixty children, between the ages of four and eight years, were grouped into an idiopathic toe walking group and non-toe walking group. Vibration perception threshold was assessed at the right hallux. A highly significant difference in the vibration perception threshold between the groups was determined. The idiopathic toe walking group demonstrated a lower vibration perception threshold (P = .001), indicating this group was highly sensitive to vibration input. This change in vibration perception could be symptomatic of physiological changes in the localized receptors within the skin or at a neural perception level. Heightened sensitivity to touch has not yet been explored with children who have an idiopathic toe walking gait. This finding could assist in understanding this gait pattern and allow further research into improved treatment options. PMID- 22433427 TI - Spontaneous spinal epidural hematoma in an infant. AB - Spontaneous spinal epidural hematoma is a rare entity, especially in infants. The cervicothoracic region is the most commonly affected site in children. The clinical features are often nonspecific, leading to a delay in diagnosis. Early management is probably associated with better functional outcomes. Here the authors report a 12-month-old girl who presented with excessive irritability and weakness of limbs. Magnetic resonance imaging of spine revealed epidural hematoma on the dorsal aspect of the spinal cord in the C2-C5 region. There were no predisposing factors. She started showing neurological recovery even prior to presentation. She was managed conservatively. This case report aims to raise awareness about this otherwise morbid neurological emergency, in which early intervention is pivotal. PMID- 22433428 TI - Mycotic aneurysm and subarachnoid hemorrhage following tubercular meningitis in an infant with congenital tuberculosis and cytomegalovirus disease. AB - We describe autopsy findings in a 5-month-old infant with disseminated tuberculosis and congenital cytomegalovirus disease. The infant manifested with tubercular meningitis complicating as ruptured mycotic right middle cerebral artery aneurysm. Infiltrative, proliferative, and necrotizing vascular pathologies have been described; however, the occurrence of these is dependent on the duration of illness. The vessel pathology appears to be a payback of its immersion in the local inflammatory cell-rich exudates. Strokes early in the course of the disease are believed to be a consequence of vasospasm, and those occurring later during the disease course are due to proliferative intimal disease. Intracranial mycotic aneurysm following tubercular meningitis developing at such a young age has not been reported in the literature. The lung lesions in a congenitally transmitted tuberculosis and cytomegalovirus disease have also been elaborated. PMID- 22433429 TI - The ITS2 Database. AB - The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution(1) and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation(2-8). The ITS2 Database(9) presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank(11) accurately reannotated(10). Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold(12) (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling(13). In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold. The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST(14) search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE(15,16) and ProfDistS(17) for multiple sequence-structure alignment calculation and Neighbor Joining(18) tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure. In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large scale analyses. PMID- 22433430 TI - Administration of vincristine in a patient with Machado-Joseph disease. AB - Chemotherapy-induced peripheral neurotoxicity is a major problem because it represents the dose-limiting side effect of a significant number of antineoplastic drugs, such as vinca alkaloids. Hereditary neuropathies usually predispose to severe vincristine neurotoxicity. Here, we report the case of a 56 year-old man with Machado-Joseph disease, also known as spinocerebellar ataxia type 3, treated with a vinca alkaloid without exacerbation of neurological symptoms. PMID- 22433431 TI - The evaluation of a web-based incident reporting system. AB - A Web-based reporting system is essential to report incident events anonymously and confidentially. The purpose of this study was to evaluate a Web-based reporting system in Taiwan. User satisfaction and impact of system use were evaluated through a survey answered by 249 nurses. Incident events reported in paper and electronic systems were collected for comparison purposes. Study variables included system user satisfaction, willingness to report, number of reports, severity of the events, and efficiency of the reporting process. Results revealed that senior nurses were less willing to report events, nurses on internal medicine units had higher satisfaction than others, and lowest satisfaction was related to the time it took to file a report. In addition, the Web-based reporting system was used more often than the paper system. The percentages of events reported were significantly higher in the Web-based system in laboratory, environment/device, and incidents occurring in other units, whereas the proportions of reports involving bedsores and dislocation of endotracheal tubes were decreased. Finally, moderate injury event reporting decreased, whereas minor or minimal injury event reporting increased. The study recommends that the data entry process be simplified and the network system be improved to increase user satisfaction and reporting rates. PMID- 22433432 TI - Timing and source of subtype-C HIV-1 superinfection in the newly infected partner of Zambian couples with disparate viruses. AB - BACKGROUND: HIV-1 superinfection occurs at varying frequencies in different at risk populations. Though seroincidence is decreased, in the negative partner of HIV-discordant couples after joint testing and counseling in the Zambia Emory HIV Research Project (ZEHRP) cohort, the annual infection rate remains relatively high at 7-8%. Based on sequencing within the gp41 region of each partner's virus, 24% of new infections between 2004 and 2008 were the result of transmission from a non-spousal partner. Since these seroconvertors and their spouses have disparate epidemiologically-unlinked viruses, there is a risk of superinfection within the marriage. We have, therefore, investigated the incidence and viral origin of superinfection in these couples. RESULTS: Superinfection was detected by heteroduplex mobility assay (HMA), degenerate base counting of the gp41 sequence, or by phylogenetic analysis of the longitudinal sequences. It was confirmed by full-length env single genome amplification and phylogenetic analysis. In 22 couples (44 individuals), followed for up to five years, three of the newly infected (initially HIV uninfected) partners became superinfected. In each case superinfection occurred during the first 12 months following initial infection of the negative partner, and in each case the superinfecting virus was derived from a non-spousal partner. In addition, one probable case of intra couple HIV-1 superinfection was observed in a chronically infected partner at the time of his seroconverting spouse's initial viremia. Extensive recombination within the env gene was observed following superinfection. CONCLUSIONS: In this subtype-C discordant couple cohort, superinfection, during the first year after HIV-1 infection of the previously negative partner, occurred at a rate similar to primary infection (13.6% [95% CI 5.2-34.8] vs 7.8% [7.1-8.6]). While limited intra-couple superinfection may in part reflect continued condom usage within couples, this and our lack of detecting newly superinfected individuals after one year of primary infection raise the possibility that immunological resistance to intra-subtype superinfection may develop over time in subtype C infected individuals. PMID- 22433433 TI - Functional characterization of the 19q12 amplicon in grade III breast cancers. AB - INTRODUCTION: The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification. METHODS: We investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification. RESULTS: 19q12 amplification was identified in 7.8% of ER negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival. CONCLUSIONS: The 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers. PMID- 22433434 TI - Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells. AB - BACKGROUND: Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion--a property previously demonstrated to mediate cell detachment and invasion. The studies reported here propose a novel role for alpha5beta1 integrin--the principle mediator of fibronectin matrix assembly (FNMA)--as an invasion suppressor of prostate cancer cells. METHODS: Using a combination of biophysical and cell biological methods, and well-characterized prostate cancer cell lines of varying invasiveness, we explore the relationship between cohesion, invasiveness, and FNMA. RESULTS: We show that cohesion is inversely proportional to invasive capacity. We also show that more invasive cells express lower levels of alpha5beta1 integrin and lack the capacity for FNMA. Cells were generated to over-express either wild-type alpha5 integrin or an integrin in which the cytoplasmic domain of alpha5 was replaced with that of alpha2. The alpha2 construct does not promote FNMA. We show that only wild-type alpha5 integrin promotes aggregate compaction, increases cohesion, and reduces invasion of the more aggressive cells, and that these effects can be blocked by the 70-kDa fibronectin fragment. CONCLUSIONS: We propose that restoring capacity for FNMA in deficient cells can increase tumor intercellular cohesion to a point that significantly reduces cell detachment and subsequent invasion. In prostate cancer, this could be of therapeutic benefit by blocking an early key step in the metastatic cascade. PMID- 22433435 TI - Yap1: a DNA damage responder in Saccharomyces cerevisiae. AB - Activation of signaling pathways in response to genotoxic stress is crucial for cells to properly repair DNA damage. In response to DNA damage, intracellular levels of reactive oxygen species increase. One important function of such a response could be to initiate signal transduction processes. We have employed the model eukaryote Saccharomyces cerevisiae to delineate DNA damage sensing mechanisms. We report a novel, unanticipated role for the transcription factor Yap1 as a DNA damage responder, providing direct evidence that reactive oxygen species are an important component of the DNA damage signaling process. Our findings reveal an epistatic link between Yap1 and the DNA base excision repair pathway. Corruption of the Yap1-mediated DNA damage response influences cell survival and genomic stability in response to exposure to genotoxic agents. PMID- 22433436 TI - Topoisomerase IIbeta regulates base excision repair capacity of neurons. AB - Topoisomerase IIbeta (TopoIIbeta), an enzyme involved in DNA rearrangements, is predominantly present in brain and its levels are shown to decrease with age. This study characterizes the function of TopoIIbeta in regulating BER (base excision repair) activity. TopoIIbeta deficient granule neurons (CGNT-) show greater sensitivity to N-ethyl N-nitroso urea (ENU)-mediated DNA damage. The cell free extracts of TopoIIbeta knockdown cells (ECGNT-) show a significant decrease in G-U BER activity during ENU-treatment as well as during recovery, suggesting that TopoIIbeta promotes G-U BER activity. Since G-U BER activity is not affected in the presence of ICRF-193, catalytic inhibitor of TopoIIbeta, the activity of enzyme per se may not be participating in BER activity. Further characterization of the activities of BER enzymes present in ECGNT- shows that uracil DNA glycosylase (UDG) and ligase (LIG) activities decrease significantly in both ENU treatment and recovery. Supplementation of TopoIIbeta to ECGNT- does not restore ligation activity and ICRF-193 does not influence the LIG activity. These results suggest a role, at least an indirect one, of TopoIIbeta in the repair of ENU mediated strand breaks via BER pathway including the activities of UDG and LIG. PMID- 22433437 TI - Predicting new molecular targets for rhein using network pharmacology. AB - BACKGROUND: Drugs can influence the whole biological system by targeting interaction reactions. The existence of interactions between drugs and network reactions suggests a potential way to discover targets. The in silico prediction of potential interactions between drugs and target proteins is of core importance for the identification of new drugs or novel targets for existing drugs. However, only a tiny portion of drug-targets in current datasets are validated interactions. This motivates the need for developing computational methods that predict true interaction pairs with high accuracy. Currently, network pharmacology has used in identifying potential drug targets to predicting the spread of drug activity and greatly contributed toward the analysis of biological systems on a much larger scale than ever before. METHODS: In this article, we present a computational method to predict targets for rhein by exploring drug reaction interactions. We have implemented a computational platform that integrates pathway, protein-protein interaction, differentially expressed genome and literature mining data to result in comprehensive networks for drug-target interaction. We used Cytoscape software for prediction rhein-target interactions, to facilitate the drug discovery pipeline. RESULTS: Results showed that 3 differentially expressed genes confirmed by Cytoscape as the central nodes of the complicated interaction network (99 nodes, 153 edges). Of note, we further observed that the identified targets were found to encompass a variety of biological processes related to immunity, cellular apoptosis, transport, signal transduction, cell growth and proliferation and metabolism. CONCLUSIONS: Our findings demonstrate that network pharmacology can not only speed the wide identification of drug targets but also find new applications for the existing drugs. It also implies the significant contribution of network pharmacology to predict drug targets. PMID- 22433438 TI - A study of magnesium deficiency in human and experimental pulmonary hypertension. AB - Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure above 25 mmHg. Pulmonary vasoconstriction, cellular proliferation, inflammation, and oxidative stress are involved in the pathophysiology of PH. Since hypomagnesemia was reported to promote endothelial cell dysfunction leading to inflammation and oxidative stress, we investigated the potential involvement of magnesium (Mg) deficiency in experimental and human PH. Our results indicate that Mg deficiency has no impact on hypoxia-induced PH development or severity, and that no reduction in Mg plasma concentration was observed in patients with severe pulmonary arterial hypertension. Thus, hypomagnesemia does not appear to play a role in the pathophysiology of experimental and human pulmonary hypertension. PMID- 22433439 TI - PI3 kinase delta is a key regulator of synoviocyte function in rheumatoid arthritis. AB - Class I phosphoinositide 3 kinase (PI3K) delta is a promising therapeutic target for rheumatoid arthritis (RA) because of its contribution to leukocyte biology. However, its contribution in fibroblasts has not been studied as a mechanism that contributes to efficacy. We investigated the expression and function of PI3Kdelta in synovium and cultured fibroblast-like synoviocytes (FLS). Immunohistochemistry demonstrated that PI3Kdelta is highly expressed in RA synovium, especially in the synovial lining. Using quantitative PCR and Western blot analysis, we found that PI3Kdelta mRNA and protein expression is higher in RA than in osteoarthritis (OA) synovium. PI3Kdelta was also expressed in cultured FLS, along with PI3Kalpha and PI3Kbeta, whereas PI3Kgamma was not detectable. PI3Kdelta mRNA expression was selectively induced by inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) but not by growth factors platelet-derived growth factor (PDGF) and transforming growth factor beta (TGFbeta). The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3Kdelta inhibitor INK007, showed that PI3Kdelta is required for PDGF- and TNF-induced Akt activation. PI3Kdelta inhibition also diminished PDGF-mediated synoviocyte growth and sensitized cells to H(2)O(2)-induced apoptosis. These data are the first documentation of increased PI3Kdelta expression in both RA synovium and cultured synoviocytes. Furthermore, these are the first data demonstrating that PI3Kdelta is a major regulator of PDGF-mediated fibroblast growth and survival via Akt. Thus, targeting PI3Kdelta in RA could modulate synoviocyte function via anti inflammatory and disease-altering mechanisms. PMID- 22433440 TI - Long-term recurrence rate of large and difficult to treat cutaneous squamous cell carcinomas after superficial radiotherapy. AB - BACKGROUND: Surgical excision is the gold standard for cutaneous squamous cell carcinoma (cSCC), however its application is limited in specific cases. Superficial radiotherapy (RTx) is an alternative treatment option, but long-term follow-up data are limited. OBJECTIVE: To determine the outcome of superficial RTx of cSCC in correlation to histological differentiation grade and tumor localization. METHODS: The outcome of 180 large cSCCs after superficial RTx between 1960 and 2004 was retrospectively reviewed. RESULTS: Mean tumor size was 3.5 cm(2) (SD 7.5) and mean follow-up period was 4.9 years (SD 4.7). Relapse-free survival was 95.8 and 80.4% after 1 and 10 years. Two-year relapse-free survival was 94.8% for good, 88.9% for moderate and 85.7% for poor differentiated tumors. Five-year relapse-free survival was highest in cSCCs located around the eyes (100%) and cheeks (90.9%). CONCLUSION: Superficial RTx is an effective alternative for cSCC if surgery is difficult due to localization or concomitant disease. PMID- 22433441 TI - Cyanidin-3-O-beta-D-glucopyranoside concentrated materials from mulberry fruit have a potency to protect erectile function by minimizing oxidative stress in a rat model of diabetic erectile dysfunction. AB - OBJECTIVE: The aim of this study was to evaluate the effect of cyanidin-3-O-beta D-glucopyranoside (C3G) concentrated materials from mulberry fruit on improvement and protection of erectile function. MATERIALS AND METHODS: Sprague-Dawley rats (12 weeks old) were divided into three groups (n = 12 in each): normal control, diabetes mellitus (DM), and DM with C3G concentrated material treatment (DM + C3G). DM and DM + C3G group rats received a single injection of streptozotocin (50 mg/kg), and 4 weeks after induction of diabetes, the DM + C3G group rats were treated with daily concentrated material treatment (10 mg/kg) dissolved in water for 8 weeks. After 12 weeks of streptozotocin injections, the rats in each group underwent intracavernosal pressure measurement and then the corporal tissues were sampled. RESULTS: The DM group rats showed markedly lower erectile parameters than those in the control group, whereas rats in the DM + C3G group showed improved erectile function by minimizing corporal apoptosis and increasing the expression of endothelial nitric oxide synthase (NOS) and neuronal NOS protein. A significant increase in 8-hydroxy-2-deoxyguanosine (8-OHdG) was shown in the DM group compared with the normal group. However, in the DM + C3G group, 8-OHdG was statistically significantly reduced compared with the DM group. CONCLUSIONS: The current study is the first to suggest that C3G concentrated materials may have a potency to improve and protect erectile function under conditions of diabetes induced oxidative stress. PMID- 22433442 TI - Methamphetamine mimics the neurochemical profile of aging in rats and impairs recognition memory. AB - Brain neurochemistry and cognition performance are thought to decline with age. Accumulating data indicate that similar events occur after prolonged methamphetamine (MA) exposure. Using the rat as a model, the present study was designed to uncover common alteration patterns in brain neurochemistry and memory performance between aging and prolonged MA exposure. To this end, animals were treated with a chronic binge MA administration paradigm (20mg/kg/day from postnatal day 91 to 100). Three-age control groups received isovolumetric saline treatment and were tested at the MA age-matched period, and at 12 and 20 months. We observed that both MA and aged animals presented a long, but not short, time impairment in novelty preference and an increased anxiety-like behavior. Neurochemical analysis indicated similar MA- and age-related impairments in dopamine, serotonin and metabolites in the striatum, prefrontal cortex and hippocampus. Thus, the present data illustrate that MA may be used to mimic age related effects on neurotransmitter systems and advocate MA treatment as a feasible animal model to study neuronal processes associated with aging. PMID- 22433443 TI - Is concern about young people's anti-social behaviour associated with poor health? Cross-sectional evidence from residents of deprived urban neighbourhoods. AB - BACKGROUND: Young people in disadvantaged neighbourhoods are often the focus of concerns about anti-social behaviour (ASB). There is inconsistent evidence to support the hypothesis that perceptions of ASB (PASB) are associated with poor health. We ask whether perceptions of young people's ASB are associated with poor health; and whether health, demographic and (psycho)social characteristics can help explain why PASB varies within disadvantaged neighbourhoods (Glasgow, UK). METHODS: Regression analysis of survey data exploring associations between perceiving teenagers hanging around to be a serious neighbourhood problem and SF 12v2 mental and physical health scores (higher = better), including adjustment for demographic characteristics. Further analysis explored associations with self reported measures of health service use, psychosocial characteristics of homes and neighbourhoods and social contacts. RESULTS: 6008 adults participated (50% response) and 22% (n = 1,332) said teenagers were a serious neighbourhood problem (the most frequently reported local problem). Demographic characteristics associated with perceiving serious teenager problems included regular health service use, age (inverse relationship), financial problems and living with children. Lower SF-12v2 physical health scores were associated with perceiving teenager problems after adjustment for demographic variables (OR 0.98; 95%CI 0.97,0.99; p = < 0.001), whilst adjusted findings for mental health scores were less conclusive (OR 0.99; 95%CI 0.98,1.00; p = 0.103). Further analysis suggested that perceiving teenager problems was more strongly associated with a number of self-reported psychosocial factors: e.g. lacking social support, < weekly family contacts, poor neighbourhood safety, low trust in neighbours, neighbourhood perceived to be a barrier to self-esteem, and neighbourhood decline. CONCLUSIONS: Given the evidence we found of weak and small associations between PASB and health, we caution against assuming that tackling concern about teenagers' ASB will lead to substantial public health gains in disadvantaged areas. Although the findings do not present a compelling case for making PASB a public health priority, it is still important to address concerns about young people's ASB. Reasons for doing so may include improving social cohesion, reducing fear and isolation, and improving the general quality of people's lives - particularly in neighbourhoods burdened by multiple disadvantages. Future research should evaluate interventions that attempt to reduce PASB in disadvantaged areas. Findings from this study could help inform the targeting of such interventions. PMID- 22433444 TI - Chitinase 3-like 1 gene-329G/A polymorphism, plasma concentration and risk of coronary heart disease in a Chinese population. AB - BACKGROUND: The chitinase-like 1 protein, YKL-40, is involved in inflammation and tissue remodeling. Patients with coronary heart disease (CHD) and acute myocardial infarction have elevated levels of serum YKL-40. The goal of the present study was to investigate whether the chitinase-like 1 gene-329G/A variant (rs10399931) confers susceptibility to CHD, and whether it is associated with the clinical phenotype and severity of disease. METHODS: We performed a case-control study of 410 unrelated CHD patients (coronary stenosis >=50% or documented myocardial infarction) and 442 controls from China. A ligase detection reaction was used to determine a single-nucleotide polymorphism in rs10399931. The genotypic and allelic associations of this single-nucleotide polymorphism with CHD, phenotypes and severity were also evaluated. Plasma levels of YKL-40 were measured using ELISA assays. RESULTS: Three genotypes, CC, CT, and TT, existed in rs10399931 and there were no significant differences found in either the genotypic or allelic frequencies between the CHD cases and controls. Patients with CHD had higher YKL-40 levels compared to controls and those with acute myocardial infarction had the highest levels of YKL-40 compared to patients with either stable or unstable angina pectoris (all p<0.01). Rs10399931 affected neither the main anthropometric or metabolic characteristics, nor did there exists any association between rs10399931 and the severity of coronary lesions assessed by Gensini scores (all p>0.05). CONCLUSIONS: Our results do not support that rs10399931 is associated with clinical phenotypes of CHD and the extent of coronary lesions; however, YKL-40 levels are higher in CHD patients and associated with its clinical phenotypes. PMID- 22433445 TI - Complexity of a complex trait locus: HP, HPR, haemoglobin and cholesterol. AB - HP and HPR are related and contiguous genes in strong linkage disequilibrium (LD), encoding haptoglobin and haptoglobin-related protein. These bind and chaperone free Hb for recycling, protecting against oxidation. A copy number variation (CNV) within HP (Hp1/Hp2) results in different possible haptoglobin complexes which have differing properties. HPR rs2000999 (G/A), identified in meta-GWAS, influences total cholesterol (TC) and LDL-cholesterol (LDL-C). We examined the relationship between HP CNV, HPR rs2000999, Hb, red cell count (RCC), LDL-C and TC in the British Women's Heart and Health Study (n=2779 for samples having CNV, rs2000999, and phenotypes). Analysing single markers by linear regression, rs2000999 was associated with LDL-C (beta=0.040 mmol/L, p=0.023), TC (beta=-0.040 mmol/L, p=0.019), Hb (beta=-0.044 g/dL, p=0.028) and borderline with RCC (beta=-0.032 * 10(12)/L, p=0.066). Analysis of CNV by linear regression revealed an association with Hb (Hp1 vs Hp2, beta=0.057 g/dL, p=0.004), RCC (beta=0.045 * 10(12)/L, p=0.014), and showed a trend with LDL-C and TC. There were 3 principal haplotypes (Hp1-G 36%; Hp2-G 45%; Hp2-A 18%). Haplotype comparisons showed that LDL-C and TC associations were from rs2000999; Hb and RCC associations derived largely from the CNV. Distinct genotype-phenotype effects are evident at the genetic epidemiological level once LD has been analysed, perhaps reflecting HP-HPR functional biology and evolutionary history. The derived Hp2 allele of the HP gene has apparently been subject to malaria driven positive selection. Haptoglobin-related protein binds Hb and apolipoprotein-L, i.e. linking HPR to the cholesterol system; and the HPR/apo-L complex is specifically trypanolytic. Our analysis illustrates the complex interplay between functions and haplotypes of adjacent genes, environmental context and natural selection, and offers insights into potential use of haptoglobin or haptoglobin-related protein as therapeutic agents. PMID- 22433447 TI - Efficient expression and purification of recombinant glutaminase from Bacillus licheniformis (GlsA) in Escherichia coli. AB - Glutaminase or L-glutamine aminohydrolase (EC 3.5.1.2) is an enzyme that catalyzes the formation of glutamic acid and ammonium ion from glutamine. This enzyme functions in cellular metabolism of every organism by supplying nitrogen required for the biosynthesis of a variety of metabolic intermediates, while glutamic acid plays a role in both sensory and nutritional properties of food. So far there have been only a few reports on cloning, expression and characterization of purified glutaminases. Microbial glutaminases are enzymes with emerging potential in both the food and the pharmaceutical industries. In this research a recombinant glutaminase from Bacillus licheniformis (GlsA) was expressed in Escherichia coli, under the control of a ptac promoter. The recombinant enzyme was tagged with decahistidine tag at its C-terminus and could be conveniently purified by one-step immobilized metal affinity chromatography (IMAC) to apparent homogeneity. The enzyme could be induced for efficient expression with IPTG, yielding approximately 26,000 units from 1-l shake flask cultures. The enzyme was stable at 30 degrees C and pH 7.5 for up to 6h, and could be used efficiently to increase glutamic acid content when protein hydrolysates from soy and anchovy were used as substrates. The study demonstrates an efficient expression system for the production and purification of bacterial glutaminase. In addition, its potential application for bioconversion of glutamine to flavor-enhancing glutamic acid has been demonstrated. PMID- 22433448 TI - Overcoming antibody expression and screening limitations by smart design: applications to PSA immunoassay development. AB - Improving the functional and structural properties of target proteins can often be a challenge for researchers. This paper highlights the importance of antibody construct on screening performance, and ultimately, the clone that is selected. We report the reformatting of phage-selected single chain antibody variable region fragments (scFvs) into single chain antibody fragments (scAbs) for improved screening and binding studies. The generation of a scAb, which had a fused human kappa light chain constant domain (C(k)), was shown to significantly improve expression levels in Escherichia coli. Antibody expression levels were compared between the two antibody constructs (scFv and scAb) by ELISA and a 100 fold improvement was observed. The C(k) domain in the expressed scAb also facilitated high throughput analysis by a Biacore capture assay approach. Individual functional scAbs were ranked on the basis of their remaining binding percentage after 5 min dissociation. Selected antibodies were further characterised by kinetic analysis and a sandwich-based immunoassay developed. The scAb construct enhanced expression levels significantly, facilitating antibody screening and immunoassay development for prostate-specific antigen (PSA), a marker for prostate cancer. PMID- 22433449 TI - Decreased cognitive control in response to negative information in patients with remitted depression: an event-related potential study. AB - BACKGROUND: Major depressive disorder (MDD) is associated with difficulty disengaging attention from emotionally negative information. Few studies have investigated whether euthymic individuals with a history of depression (remitted MDD [rMDD]) show similar deficits, and little is known about concomitant neurophysiological features of such deficits. To fill these gaps, we investigated cognitive control over emotional stimuli in participants with rMDD and controls without history of depression or psychopathology. METHODS: We collected 128- channel event-related potentials (ERPs) while participants performed a cued emotional conflict task. During the task, a cue instructed the participant to respond to the actual or opposite valence of an upcoming happy or sad face. RESULTS: We enrolled 15 individuals with rMDD and 18 controls in our study. Event related potentials showed no group differences in response to the cues, highlighting preserved preparatory processes when anticipating an emotional conflict. However, relative to the control group, the rMDD group responded more slowly and showed reduced N450 amplitudes on trials that required disengaging from negative faces (pressing "happy" in response to a sad face). LIMITATIONS: The sample size was small, and the null finding in the cue-locked N2 analyses may be owing to low power. CONCLUSION: Our results suggest a selective deficit in cognitive control over sad stimuli in individuals with rMDD. Additional studies will be required to pinpoint whether the current findings stem from impairments in response conflict, conflict monitoring and/or attentional disengagement in response to sad stimuli. Moreover, future studies are warranted to evaluate whether decreased cognitive control in response to negative information might increase the risk for future depressive episodes. PMID- 22433450 TI - Association between the NMDA glutamate receptor GRIN2B gene and obsessive compulsive disorder. AB - BACKGROUND: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. METHODS: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3' UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. RESULTS: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. LIMITATIONS: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3' UTR and exon 13 of GRIN2B. CONCLUSION: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder. PMID- 22433451 TI - Lensfree computational microscopy tools for cell and tissue imaging at the point of-care and in low-resource settings. AB - The recent revolution in digital technologies and information processing methods present important opportunities to transform the way optical imaging is performed, particularly toward improving the throughput of microscopes while at the same time reducing their relative cost and complexity. Lensfree computational microscopy is rapidly emerging toward this end, and by discarding lenses and other bulky optical components of conventional imaging systems, and relying on digital computation instead, it can achieve both reflection and transmission mode microscopy over a large field-of-view within compact, cost-effective and mechanically robust architectures. Such high throughput and miniaturized imaging devices can provide a complementary toolset for telemedicine applications and point-of-care diagnostics by facilitating complex and critical tasks such as cytometry and microscopic analysis of e.g., blood smears, Pap tests and tissue samples. In this article, the basics of these lensfree microscopy modalities will be reviewed, and their clinically relevant applications will be discussed. PMID- 22433452 TI - Biophotonics techniques for structural and functional imaging, in vivo. AB - In vivo optical imaging is being conducted in a variety of medical applications, including optical breast cancer imaging, functional brain imaging, endoscopy, exercise medicine, and monitoring the photodynamic therapy and progress of neoadjuvant chemotherapy. In the past three decades, in vivo diffuse optical breast cancer imaging has shown promising results in cancer detection, and monitoring the progress of neoadjuvant chemotherapy. The use of near infrared spectroscopy for functional brain imaging has been growing rapidly. In fluorescence imaging, the difference between autofluorescence of cancer lesions compared to normal tissues were used in endoscopy to distinguish malignant lesions from normal tissue or inflammation and in determining the boarders of cancer lesions in surgery. Recent advances in drugs targeting specific tumor receptors, such as AntiBodies (MAB), has created a new demand for developing non invasive in vivo imaging techniques for detection of cancer biomarkers, and for monitoring their down regulations during therapy. Targeted treatments, combined with new imaging techniques, are expected to potentially result in new imaging and treatment paradigms in cancer therapy. Similar approaches can potentially be applied for the characterization of other disease-related biomarkers. In this chapter, we provide a review of diffuse optical and fluorescence imaging techniques with their application in functional brain imaging and cancer diagnosis. PMID- 22433453 TI - Transcriptome sequencing of field pea and faba bean for discovery and validation of SSR genetic markers. AB - BACKGROUND: Field pea (Pisum sativum L.) and faba bean (Vicia faba L.) are cool season grain legume species that provide rich sources of food for humans and fodder for livestock. To date, both species have been relative 'genomic orphans' due to limited availability of genetic and genomic information. A significant enrichment of genomic resources is consequently required in order to understand the genetic architecture of important agronomic traits, and to support germplasm enhancement, genetic diversity, population structure and demographic studies. RESULTS: cDNA samples obtained from various tissue types of specific field pea and faba bean genotypes were sequenced using 454 Roche GS FLX Titanium technology. A total of 720,324 and 304,680 reads for field pea and faba bean, respectively, were de novo assembled to generate sets of 70,682 and 60,440 unigenes. Consensus sequences were compared against the genome of the model legume species Medicago truncatula Gaertn., as well as that of the more distantly related, but better-characterised genome of Arabidopsis thaliana L.. In comparison to M. truncatula coding sequences, 11,737 and 10,179 unique hits were obtained from field pea and faba bean. Totals of 22,057 field pea and 18,052 faba bean unigenes were subsequently annotated from GenBank. Comparison to the genome of soybean (Glycine max L.) resulted in 19,451 unique hits for field pea and 16,497 unique hits for faba bean, corresponding to c. 35% and 30% of the known gene space, respectively. Simple sequence repeat (SSR)-containing expressed sequence tags (ESTs) were identified from consensus sequences, and totals of 2,397 and 802 primer pairs were designed for field pea and faba bean. Subsets of 96 EST-SSR markers were screened for validation across modest panels of field pea and faba bean cultivars, as well as related non-domesticated species. For field pea, 86 primer pairs successfully obtained amplification products from one or more template genotypes, of which 59% revealed polymorphism between 6 genotypes. In the case of faba bean, 81 primer pairs displayed successful amplification, of which 48% detected polymorphism. CONCLUSIONS: The generation of EST datasets for field pea and faba bean has permitted effective unigene identification and functional sequence annotation. EST-SSR loci were detected at incidences of 14 17%, permitting design of comprehensive sets of primer pairs. The subsets from these primer pairs proved highly useful for polymorphism detection within Pisum and Vicia germplasm. PMID- 22433454 TI - Immunohistochemical detection of breast cancer stem cells in hormone receptor positive breast cancer and their role in response to endocrine therapy and clinical outcome. AB - BACKGROUND: Breast cancer stem cells are rich in triple negative or human epidermal growth factor receptor-2-positive breast cancers. The role of these stem cells in hormone receptor-positive breast cancers is unknown. Therefore, we launched this retrospective biomarker analysis to clarify the role of stem cells in relation with endocrine therapy in hormone receptor-positive breast cancer. METHODS: Formalin-fixed paraffin-embedded tissue samples from primary stage IV, hormone receptor-positive breast cancers prior to endocrine therapy were obtained from 4 cancer centers in Japan between 1999 and 2008. We examined the expression of ALDH1 and CD44/CD24 in breast tissue and correlated the results with response to endocrine therapy and patient prognosis. RESULTS: ALDH1-positive and CD44+ CD24- cancer cells were found in 16% of 92 samples and 27% of 77 samples, respectively. Response to endocrine therapy was similar in the ALDH1-positive and ALDH1-negative tumor groups, and between CD44+ CD24- and other tumor groups. After a median follow-up period of 793 days, neither ALDH1 positivity nor CD44+ CD24- status of tumor cells was related to progression-free survival (ALDH1 positive vs. negative, 378 vs. 292 days, p = 0.53; CD44+ CD24- vs. others, 224 vs. 269 days, p = 0.52) or overall survival (ALDH1 positive vs. negative, 1,348 vs. 1,479 days, p = 0.17; CD44+ CD24- vs. others, 1,071 vs. 1,462 days, p = 0.54). CONCLUSIONS: There is no correlation between biomarker expression and outcome in hormone receptor-positive breast cancer. PMID- 22433455 TI - Pulmonary arterial dilatation in pulmonary hypertension: prevalence and prognostic relevance. AB - OBJECTIVES: Pulmonary arterial dilatation is considered a consequence of chronic pulmonary hypertension (PH), but despite its relatively common detection, its prevalence and prognostic impact have not yet been systematically investigated. The aim of the study was to investigate these factors in a relatively large cohort of severe PH patients. METHODS: One hundred and forty-one consecutive patients diagnosed with PH were monitored for a mean of 957 days. Data including functional class, exercise capacity, invasive hemodynamics and pulmonary artery (PA) echo/CT scan measurement were performed and outcomes prospectively collected. RESULTS: PA dilatation is a common feature, present in the 76.6% of cases in this cohort of severe PH patients. Survival at 1, 2 and 3 years was 83, 71 and 58%, respectively. On univariate analysis, the baseline variables associated with a poor outcome were related to pulmonary arterial hypertension associated with connective tissue disease (CDT-PAH), New York Heart Association (NYHA) functional class, 6-min walk test and right atrial pressure. On multivariate analysis only CDT-PAH and NYHA functional class remained independently associated with poor survival. CONCLUSIONS: PA dilatation is commonly detected in severe PH patients and is not associated with an increased risk of death. PMID- 22433456 TI - Reproductive aging-associated common genetic variants and the risk of breast cancer. AB - INTRODUCTION: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown. METHODS: In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait. RESULTS: After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile. CONCLUSIONS: Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer. PMID- 22433457 TI - Sonographic evidence in dengue. PMID- 22433459 TI - The interaction and integration of auxin signaling components. AB - IAA, a naturally occurring auxin, is a simple signaling molecule that regulates many diverse steps of plant development. Auxin essentially coordinates plant development through transcriptional regulation. Auxin binds to TIR1/AFB nuclear receptors, which are F-box subunits of the SCF ubiquitin ligase complex. The auxin signal is then modulated by the quantitative and qualitative responses of the Aux/IAA repressors and the auxin response factor (ARF) transcription factors. The specificity of the auxin-regulated gene expression profile is defined by several factors, such as the expression of these regulatory proteins, their post transcriptional regulation, their stability and the affinity between these regulatory proteins. Auxin-binding protein 1 (ABP1) is a candidate protein for an auxin receptor that is implicated in non-transcriptional auxin signaling. ABP1 also affects TIR1/AFB-mediated auxin-responsive gene expression, implying that both the ABP1 and TIR1/AFB signaling machineries coordinately control auxin mediated physiological events. Systematic approaches using the comprehensive mapping of the expression and interaction of signaling modules and computational modeling would be valuable for integrating our knowledge of auxin signals and responses. PMID- 22433458 TI - Twisted blood vessels: symptoms, etiology and biomechanical mechanisms. AB - Tortuous arteries and veins are commonly observed in humans and animals. While mild tortuosity is asymptomatic, severe tortuosity can lead to ischemic attack in distal organs. Clinical observations have linked tortuous arteries and veins with aging, atherosclerosis, hypertension, genetic defects and diabetes mellitus. However, the mechanisms of their formation and development are poorly understood. This review summarizes the current clinical and biomechanical studies on the initiation, development and treatment of tortuous blood vessels. We submit a new hypothesis that mechanical instability and remodeling could be mechanisms for the initiation and development of these tortuous vessels. PMID- 22433460 TI - Arginase induction represses gall development during clubroot infection in Arabidopsis. AB - Arginase induction can play a defensive role through the reduction of arginine availability for phytophageous insects. Arginase activity is also induced during gall growth caused by Plasmodiophora brassicae infection in roots of Arabidopsis thaliana; however, its possible role in this context has been unclear. We report here that the mutation of the arginase-encoding gene ARGAH2 abrogates clubroot induced arginase activity and results in enhanced gall size in infected roots, suggesting that arginase plays a defensive role. Induction of arginase activity in infected roots was impaired in the jar1 mutant, highlighting a link between the arginase response to clubroot and jasmonate signaling. Clubroot-induced accumulation of the principal amino acids in galls was not affected by the argah2 mutation. Because ARGAH2 was previously reported to control auxin response, we investigated the role of ARGAH2 in callus induction. ARGAH2 was found to be highly induced in auxin/cytokinin-triggered aseptic plant calli, and callus development was enhanced in argah2 in the absence of the pathogen. We hypothesized that arginase contributes to a negative control over clubroot symptoms, by reducing hormone-triggered cellular proliferation. PMID- 22433461 TI - Chloroplast downsizing under nitrate nutrition restrained mesophyll conductance and photosynthesis in rice (Oryza sativa L.) under drought conditions. AB - The phenomenon whereby ammonium enhances the tolerance of rice seedlings (Oryza sativa L., cv. 'Shanyou 63' hybrid indica China) to water stress has been reported in previous studies. To study the intrinsic mechanism of biomass synthesis related to photosynthesis, hydroponic experiments supplying different nitrogen (N) forms were conducted; water stress was simulated by the addition of polyethylene glycol. Water stress decreased leaf water potential (Psi(leaf)) under nitrate nutrition, while it had no negative effect under ammonium nutrition. The decreased Psi(leaf) under nitrate nutrition resulted in chloroplast downsizing and subsequently decreased mesophyll conductance to CO(2) (g(m)). The decreased g(m) and stomatal conductance (g(s)) under nitrate nutrition with water stress restrained the CO(2) supply to the chloroplast and Rubisco. The relatively higher distribution of leaf N to Rubisco under ammonium nutrition might also be of benefit for photosynthesis under water stress. In conclusion, chloroplast downsizing induced a decline in g(m), a relatively higher decrease in g(s) under nitrate nutrition with water stress, restrained the CO(2) supply to Rubisco and finally decreased the photosynthetic rate. PMID- 22433462 TI - Properties of resistant cells generated from lung cancer cell lines treated with EGFR inhibitors. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) signaling plays an important role in non-small cell lung cancer (NSCLC) and therapeutics targeted against EGFR have been effective in treating a subset of patients bearing somatic EFGR mutations. However, the cancer eventually progresses during treatment with EGFR inhibitors, even in the patients who respond to these drugs initially. Recent studies have identified that the acquisition of resistance in approximately 50% of cases is due to generation of a secondary mutation (T790M) in the EGFR kinase domain. In about 20% of the cases, resistance is associated with the amplification of MET kinase. In the remaining 30-40% of the cases, the mechanism underpinning the therapeutic resistance is unknown. METHODS: An erlotinib resistant subline (H1650-ER1) was generated upon continuous exposure of NSCLC cell line NCI-H1650 to erlotinib. Cancer stem cell like traits including expression of stem cell markers, enhanced ability to self-renew and differentiate, and increased tumorigenicity in vitro were assessed in erlotinib resistant H1650-ER1 cells. RESULTS: The erlotinib resistant subline contained a population of cells with properties similar to cancer stem cells. These cells were found to be less sensitive towards erlotinib treatment as measured by cell proliferation and generation of tumor spheres in the presence of erlotinib. CONCLUSIONS: Our findings suggest that in cases of NSCLC accompanied by mutant EGFR, treatment targeting inhibition of EGFR kinase activity in differentiated cancer cells may generate a population of cancer cells with stem cell properties. PMID- 22433463 TI - Comment on "Quality of life and emotional distress in early stage and locally advanced cervical cancer patients: a prospective, longitudinal study" by Ferrandina et al. (GYNECOL ONCOL 2012; 124:389-394). PMID- 22433464 TI - Impact of smoking on perioperative pulmonary and upper respiratory complications after laparoscopic gynecologic surgery. AB - OBJECTIVE: To determine the impact of smoking on the rate of pulmonary and upper respiratory complications following laparoscopic gynecologic surgery. METHODS: We retrospectively identified all patients who underwent laparoscopic gynecologic surgery at one institution between January 2000 and January 2009. Pulmonary and upper respiratory complications were defined as atelectasis, pneumonia, upper respiratory infection, acute respiratory failure, hypoxemia, pneumothorax, or pneumomediastinum occurring within 30 days after surgery RESULTS: Nine hundred three patients underwent attempt at laparoscopic surgery. Fifty-four were excluded because of conversion to laparotomy and 31 because of insufficient data. Of the 818 patients included, 356 (43%) had cancer. A total of 576 (70%) patients were never smokers, 156 (19%) were past smokers, and 86 (10%) were current smokers (smoked within 6 weeks before surgery). These three groups were similar with regard to median body mass index, operative time, and length of hospital stay. Compared to never and past smokers, current smokers were more likely to undergo high-complexity laparoscopic procedures (10.4%, 15.4%, and 19.8%, respectively; p=0.015) and had younger median age 49 years, 51 years, and 46 years, respectively; p=0.035. Nineteen (2.3%) patients experienced pulmonary complications - symptomatic atelectasis (n=9), pneumonia (n=5), acute respiratory failure (n=2), hypoxemia (n=1), pneumomediastinum (n=1), and pneumothorax (n=2). The rate of pulmonary complications was 2.1% (12 of 564 patients) in never smokers, 4.5% (7 of 156 patients) in past smokers, and zero in current smokers. CONCLUSION: In this cohort, smoking history did not appear to impact postoperative pulmonary and upper respiratory complications. In smokers scheduled for operative procedures, laparoscopy should be considered when feasible. PMID- 22433465 TI - Expression and purification of the cystic fibrosis transmembrane conductance regulator protein in Saccharomyces cerevisiae. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel, that when mutated, can give rise to cystic fibrosis in humans.There is therefore considerable interest in this protein, but efforts to study its structure and activity have been hampered by the difficulty of expressing and purifying sufficient amounts of the protein(1-3). Like many 'difficult' eukaryotic membrane proteins, expression in a fast-growing organism is desirable, but challenging, and in the yeast S. cerevisiae, so far low amounts were obtained and rapid degradation of the recombinant protein was observed (4-9). Proteins involved in the processing of recombinant CFTR in yeast have been described(6-9) .In this report we describe a methodology for expression of CFTR in yeast and its purification in significant amounts. The protocol describes how the earlier proteolysis problems can be overcome and how expression levels of CFTR can be greatly improved by modifying the cell growth conditions and by controlling the induction conditions, in particular the time period prior to cell harvesting. The reagants associated with this protocol (murine CFTR expressing yeast cells or yeast plasmids) will be distributed via the US Cystic Fibrosis Foundation, which has sponsored the research. An article describing the design and synthesis of the CFTR construct employed in this report will be published separately (Urbatsch, I.; Thibodeau, P. et al., unpublished). In this article we will explain our method beginning with the transformation of the yeast cells with the CFTR construct - containing yeast plasmid (Fig. 1). The construct has a green fluorescent protein (GFP) sequence fused to CFTR at its C terminus and follows the system developed by Drew et al. (2008)(10). The GFP allows the expression and purification of CFTR to be followed relatively easily. The JoVE visualized protocol finishes after the preparation of microsomes from the yeast cells, although we include some suggestions for purification of the protein from the microsomes. Readers may wish to add their own modifications to the microsome purification procedure, dependent on the final experiments to be carried out with the protein and the local equipment available to them. The yeast-expressed CFTR protein can be partially purified using metal ion affinity chromatography, using an intrinsic polyhistidine purification tag. Subsequent size-exclusion chromatography yields a protein that appears to be >90% pure, as judged by SDS-PAGE and Coomassie-staining of the gel. PMID- 22433466 TI - A designer hyper interleukin 11 (H11) is a biologically active cytokine. AB - BACKGROUND: Interleukin 11 (IL-11) is a pleiotropic cytokine with anti-apoptotic, anti-inflammatory and hematopoietic potential. The IL-11 activity is determined by the expression of the IL-11R receptor alpha (IL-11Ralpha) and the signal transducing subunit beta (gp130) on the cell membrane. A recombinant soluble form of the IL-11Ralpha (sIL-11Ralpha) in combination with IL-11 acts as an agonist on cells expressing the gp130 molecule. We constructed a designer cytokine Hyper IL 11 (H11), which is exclusively composed of naturally existing components. It contains the full length sIL-11Ralpha connected with the mature IL-11 protein using their natural sequences only. Such a construct has two major advantages: (i) its components are as close as possible to the natural forms of both proteins and (ii) it lacks an artificial linker what should avoid induction of antibody production. RESULTS: The H11 construct was generated, the protein was produced in a baculovirus expression system and was then purified by using ion exchange chromatography. The H11 protein displayed activity in three independent bioassays, (i) it induced acute phase proteins production in HepG2 cells expressing IL-11, IL-11Ralpha and gp130, (ii) it stimulated the proliferation of B9 cells (cells expressing IL-11Ralpha and gp130) and (iii) proliferation of Baf/3-gp130 cells (cells not expressing IL-11 and IL-11Ralpha but gp130). Moreover, the preliminary data indicated that H11 was functionally distinct from Hyper-IL-6, a molecule which utilizes the same homodimer of signal transducing receptor (gp130). CONCLUSIONS: The biologically active H11 may be potentially useful for treatment of thrombocytopenia, infertility, multiple sclerosis, cardiovascular diseases or inflammatory disorders. PMID- 22433467 TI - Power is nothing without control. PMID- 22433468 TI - Home birth and barriers to referring women with obstetric complications to hospitals: a mixed-methods study in Zahedan, southeastern Iran. AB - BACKGROUND: One factor that contributes to high maternal mortality in developing countries is the delayed use of Emergency Obstetric-Care (EmOC) facilities. The objective of this study was to determine the factors that hinder midwives and parturient women from using hospitals when complications occur during home birth in Sistan and Baluchestan province, Iran, where 23% of all deliveries take place in non- hospital settings. METHODS: In the study and data management, a mixed methods approach was used. In the quantitative phase, we compared the existing health-sector data with World Health Organization (WHO) standards for the availability and use of EmOC services. The qualitative phase included collection and analysis of interviews with midwives and traditional birth attendants and twenty-one in-depth interviews with mothers. The data collected in this phase were managed according to the principles of qualitative data analysis. RESULTS: The findings demonstrate that three distinct factors lead to indecisiveness and delay in the use of EmOC by the midwives and mothers studied. Socio-cultural and familial reasons compel some women to choose to give birth at home and to hesitate seeking professional emergency care for delivery complications. Apprehension about being insulted by physicians, the necessity of protecting their professional integrity in front of patients and an inability to persuade their patients lead to an over-insistence by midwives on completing deliveries at the mothers' homes and a reluctance to refer their patients to hospitals. The low quality and expense of EmOC and the mothers' lack of health insurance also contribute to delays in referral. CONCLUSIONS: Women who choose to give birth at home accept the risk that complications may arise. Training midwives and persuading mothers and significant others who make decisions about the value of referring women to hospitals at the onset of life-threatening complications are central factors to increasing the use of available hospitals. The hospitals must be safe, comfortable and attractive environments for parturition and should give appropriate consideration to the ethical and cultural concerns of the women. Appropriate management of financial and insurance-related issues can help midwives and mothers make a rational decision when complications arise. PMID- 22433469 TI - Acute compartment syndrome of the forearm as a rare complication of toxic epidermal necrolysis: a case report. AB - INTRODUCTION: Toxic epidermal necrolysis lies within the spectrum of severe cutaneous adverse reactions induced by drugs, affecting skin and mucous membranes. Toxic epidermal necrolysis is considered a medical emergency as it is considered to be potentially fatal and carries a high mortality rate. To the best of our knowledge the association of toxic epidermal necrolysis and compartment syndrome has been rarely mentioned in the literature. In this case we treated the compartment syndrome promptly despite the poor general condition and skin status of our patient. Despite the poor skin condition, wound healing was uneventful with no complications. CASE PRESENTATION: A 62-year-old Caucasian man with a generalized macular-vesicular rash involving 90% of his body surface area and mucous membranes, as well as impaired renal and hepatic functions following ingestion of allopurinol for treatment of gout, was admitted to our hospital. Skin biopsies were taken and he was started on a steroid infusion. Within hours of admission, he developed acute compartment syndrome of the dominant forearm and hand. CONCLUSIONS: Despite its rare incidence, toxic epidermal necrolysis is a condition with a high incidence of complications and mortality. Patients with severe conditions affecting a large degree of the skin surface area should be treated as promptly and effectively as patients with burns, with close monitoring and the anticipation that rare musculoskeletal complications might arise. The association of compartment syndrome and toxic epidermal necrolysis might lead to a rapid deterioration and fatal systemic involvement and multiple organ failures. PMID- 22433470 TI - Standard versus tubeless percutaneous nephrolithotomy: a systematic review. AB - OBJECTIVE: This article systematically analyses comparative studies to evaluate the efficacy and safety of tubeless percutaneous nephrolithotomy (PCNL) versus standard PCNL. METHODS: The Medline, EMBASE, PsycINFO, Cochrane and DARE databases were searched from 1997 to February 2011. Comparative studies evaluating outcomes from standard versus tubeless PCNL were included. Primary outcome measures were post-operative pain scoring, analgesic requirements, duration of hospitalisation/convalescence, operation time, major/minor complications and stone-free rates. RESULTS: Twenty-four studies were included (11 randomised control trials and 13 retrospective or prospective studies). Levels of pain recorded, analgesic requirements, duration of inpatient stay and convalescence time were all significantly reduced in the tubeless PCNL group. Cost was reduced in two studies. Morbidity was not significantly different between the groups. There was no significant difference between groups regarding stone-free status. DISCUSSION: This systematic review has demonstrated that tubeless PCNL is a viable alternative to tubed PCNL in uncomplicated cases. Benefits are as described above. There is no evidence suggesting that patient safety is compromised by the absence of post-operative nephrostomy. The tubeless method has been reported in challenging cases such as stag-horn stones, horseshoe or ectopic kidneys. Promising outcomes have been demonstrated in elderly patients and when clinical needs demand a supracostal approach. Multi-centre randomised controlled trials are needed to fully establish the effectiveness of the tubeless method. PMID- 22433471 TI - Polymorphic form of piroxicam influences the performance of amorphous material prepared by ball-milling. AB - The objective of this study was to investigate the influence of the starting solid state form of piroxicam (anhydrate form I: PRXAH I vs form II: PRXAH II) on the properties of the resulting amorphous material. The second objective was to obtain further insight into the impact of critical factors like thermal stress, dissolution medium and storage conditions on the thermal behavior, solid state transformations and physical stability of amorphous materials. For analysis differential scanning calorimetry (DSC), Raman spectroscopy and X-ray powder diffractometry (XRPD) were used. Pair-wise distribution function (PDF) analysis of the XRPD data was performed. PDF analysis indicated that the recrystallization behavior of amorphous samples was influenced by the amount of residual order in the samples. The recrystallization behavior of amorphous samples prepared from PRXAH I showed similarity to the starting material, whereas the recrystallization behavior of amorphous samples prepared from PRXAH II resembled to that of the PRX form III (PRXAH III). Multivariate data analysis (MVDA) helped to identify that the influence of storage time and temperature was more pronounced in the case of amorphous PRX prepared from PRXAH I. Furthermore, the wet slurry experiments with amorphous materials revealed the recrystallization of amorphous material as PRXMH in the biorelevant medium. PMID- 22433472 TI - Effect of process variables on morphology and aerodynamic properties of voriconazole formulations produced by thin film freezing. AB - The particle engineering process, thin film freezing (TFF), was used to produce particulate voriconazole (VRC) formulations with enhanced properties. The effect of various processing parameters on the solid state properties and aerodynamic performance of the TFF-processed powders was investigated in order to evaluate the suitability of these formulations for dry powder inhalation and to optimize the aerodynamic properties. Thin film freezing of VRC solution without stabilizing excipients resulted in microstructured, crystalline low density aggregate particles with specific surface areas of approximately 10m(2)/g. Thin film freezing of VRC-PVP solutions produced nanostructured, amorphous low density aggregate particles with specific surface areas ranging from 15 to 180m(2)/g, depending on the solvent system composition, polymer grade, and drug to polymer ratio utilized. VRC formulations manufactured with 1,4-dioxane, with and without PVP K12, resulted in the lowest specific surface areas but displayed the best aerodynamic properties. Using a Handihaler((r)) dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K12 (1:2) displayed total emitted fractions of 80.6% and 96.5%, fine particle fractions of 43.1% and 42.4%, and mass median aerodynamic diameters of 3.5 and 4.5MUm, respectively. PMID- 22433473 TI - Comparison of magnesium status using X-ray dispersion analysis following magnesium oxide and magnesium citrate treatment of healthy subjects. AB - The magnesium content in food consumed in the Western world is steadily decreasing. Hypomagnesemia is associated with increased incidence of diabetes mellitus, metabolic syndrome, all-cause and coronary artery disease mortality. We investigated the impact of supplemental oral magnesium citrate versus magnesium oxide on intracellular magnesium levels ([Mg2+]i) and platelet function in healthy subjects with no apparent heart disease. In a randomized, prospective, double-blind, crossover study, 41 (20 women) healthy volunteers [mean age 53+/-8 (range 31-75) years] received either magnesium oxide monohydrate tablets (520 mg/day of elemental magnesium) or magnesium citrate tablets (295.8 mg/day of elemental magnesium) for one month (phase 1), followed by a four-week wash-out period, and then crossover treatment for one month (phase 2). [Mg2+]i was assessed from sublingual cells through x-ray dispersion (normal values 37.9+/-4.0 mEq/L), serum magnesium levels, platelet aggregation, and quality-of-life questionnaires were assessed before and after each phase. Oral magnesium oxide, rather than magnesium citrate, significantly increased [Mg2+]i (34.4+/-3 versus 36.3+/-2 mEq/L, p<0.001 and 34.7+/-2 versus 35.4+/-2 mEq/L, p=0.097; respectively), reduced total cholesterol (201+/-37 versus 186+/-27 mg/dL, p=0.016 and 187+/-28 versus 187+/-25 mg/dL, p=0.978; respectively) and low-density lipoprotein (LDL) cholesterol (128+/-22 versus 120+/-25 mg/dL, p=0.042 and 120+/ 23 versus 121+/-22 mg/dL, p=0.622; respectively). Noteworthy is that both treatments significantly reduced epinephrine-induced platelet aggregation (78.9+/ 16% versus 71.7+/-23%, p=0.013 and 81.3+/-15% versus 73.3+/-23%, p=0.036; respectively). Thus, oral magnesium oxide treatment significantly improved [Mg2+]i, total and LDL cholesterol compared with magnesium citrate, while both treatments similarly inhibited platelet aggregation in healthy subjects with no apparent heart disease. PMID- 22433474 TI - The impact of visual complexity on visual short-term memory in children with specific language impairment. AB - Many studies have assessed visual short-term memory (VSTM) abilities in children with specific language impairment (SLI), with contrasting results: some studies observed preserved VSTM capacities, while others reported impaired VSTM. The present study explores the hypothesis that the complexity of the visual information to be encoded and stored might underlie these discrepancies. Four VSTM conditions were administered to a group of 15 children with SLI, as well as to two groups of typically developing children, matched for chronological age and for VSTM capacity for visually simple stimuli, respectively. The stimuli to be remembered varied in their visual similarity and in the number of their visual features. Across the four VSTM conditions, children with SLI showed significantly reduced performance relative to an age-matched control group, and they were more strongly affected by visual similarity and number of features when compared to a control group matched for VSTM capacity for visually simple stimuli. The present results support the hypothesis that stimulus complexity is a determining factor of the poor VSTM performances in children with SLI. PMID- 22433475 TI - HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib. AB - PURPOSE: Biliary cancers (BCs) respond poorly to chemotherapy. Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and HER2/neu, both implicated in cholangiocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in BC. METHODS: A Fleming phase II design with a single stage of 25 patients was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/neu and EGFR. RESULTS: Nine patients with BC enrolled in this study. The study was terminated early because of futility. The most common toxicities were nausea and fatigue (78%) and diarrhea (67%). No responses were observed. Of 8 evaluable patients, 4 (50%) had stable disease. Median progression free survival was 2.6 months (95% CI 1.6-4.4) and median overall survival was 5.1 months (95% CI 2.0-16.5). No somatic mutations in EGFR (exons 18-21) or HER2/neu were found. We did not find evidence of HER2 overexpression. CONCLUSIONS: Lapatinib is well tolerated but failed to show activity as a single agent in treating patients with BC. Despite the small patient population, our study is consistent with previous findings, suggesting that targeting HER2/neu does not appear to be an effective therapy for BC. PMID- 22433476 TI - Hypolipidemic effect of diet supplementation with bacterial levan in cholesterol fed rats. AB - Levan polysaccharide, a type of fructan, has been shown to have industrial applications as a new industrial gum in the fields of cosmetics, foods like dietary fiber and pharmaceutical goods. The objective of this current study was to investigate the possible hypolipidemic and antioxidative effects of levan in rats fed with a high-cholesterol diet. Animals were allocated into four groups of six rats each: a normal diet group (Control), normal rats received levan (L), a high-cholesterol diet group (Chol) and a high-cholesterol diet with a daily dose of levan equivalent to 5%. Treated hypercholesterolemic rats were administrated with levan in drinking water through oral gavage for 60 days. After the treatment period, the plasma antioxidant enzymes and lipid profiles were determined. Our results show that treatment with levan polysaccharide positively changed plasma antioxidant enzyme activities and lipid profiles (total cholesterol, HDL cholesterol, LDL-cholesterol and triglycerides) in cholesterol-rats, and thus may have potential hypolipidemic and antioxidant effects. Levan could protect against oxidative stress linked atherosclerosis and decrease the atherogenic index. PMID- 22433477 TI - The role of nurses in meeting the health care needs of older people with intellectual disabilities: a review of the published literature. AB - People with intellectual disabilities are now living longer and as a consequence are likely to have greater physical and mental health needs compared to the general population. Nurses may have a crucial role to play in meeting such needs, although it is unclear whether nurses are prepared for this role. This review of the available literature found little evidence of nurses undertaking effective interventions in meeting the health needs of older people with intellectual disabilities in the UK and Ireland. Nurses have been alerted to the increase in numbers of older people with intellectual disabilities and offered some direction on their future role in this area. Most of the available literature is based mainly on informed opinion rather than research findings. PMID- 22433478 TI - Non-verbal communication between Registered Nurses Intellectual Disability and people with an intellectual disability: an exploratory study of the nurse's experiences. Part 2. AB - This is the second of two articles presenting the findings of a qualitative study which explored the experiences of Registered Nurses Intellectual Disability (RNIDs) of communicating with people with an intellectual disability who communicate non-verbally. While Part 1 outlined the study background, context and methodology along with the overarching, multi-dimensional category of 'familiarity/knowing the person', the current article critically discusses the themes and subthemes encapsulated in this category. Each theme is considered in the light of current policies, strategies and philosophies shaping the provision of services to people with an intellectual disability in Ireland. The results suggest that the RNID is ideally located and key to supporting the implementation of these policies and strategies due to their highly developed and proficient skill set as well as experience of communicating with people with an intellectual disability who communicate non-verbally. PMID- 22433479 TI - Automated external defibrillation. PMID- 22433480 TI - When should rescue breathing be removed from the ABCs of CPR? PMID- 22433481 TI - Mechanical devices for cardiopulmonary resuscitation. PMID- 22433482 TI - The use of vasopressor agents during cardiopulmonary resuscitation. PMID- 22433483 TI - Optimizing the timing of defibrillation: the role of ventricular fibrillation waveform analysis during cardiopulmonary resuscitation. PMID- 22433484 TI - Emergency cardiopulmonary bypass: a promising rescue strategy for refractory cardiac arrest. PMID- 22433485 TI - Therapeutic hypothermia after cardiac arrest in adults: mechanism of neuroprotection, phases of hypothermia, and methods of cooling. PMID- 22433487 TI - Advances in brain resuscitation: beyond hypothermia. PMID- 22433486 TI - Protecting mitochondrial bioenergetic function during resuscitation from cardiac arrest. PMID- 22433488 TI - The role of emergency coronary intervention during and following cardiopulmonary resuscitation. PMID- 22433489 TI - Risk stratification for acute pulmonary embolism. PMID- 22433490 TI - Preface. PMID- 22433491 TI - Results of penetrating keratoplasty triple procedure with 25-gauge core vitrectomy. AB - PURPOSE: To report and compare the outcomes of penetrating keratoplasty (PKP) triple procedures [combined PKP, cataract extraction, and intraocular lens (IOL) implantation] with a 25-gauge (G) system, 20-G system, and without core vitrectomy. SUBJECTS AND METHODS: Subjects comprised the following 3 groups: the 25-G group including 12 eyes of 12 patients (4 men and 8 women) that underwent PKP with 25-G core vitrectomy, the 20-G group including 9 eyes of 9 patients (3 men and 6 women) that underwent PKP with 20-G core vitrectomy, and the non-core vitrectomy group including 9 eyes of 9 patients (1 man and 8 women) that underwent PKP without core vitrectomy. RESULTS: In the 25-G, 20-G, and non-core vitrectomy groups, the success rates of IOL implantation were 91.7% (11 of 12 eyes), 88.9% (8 of 9 eyes), and 66.7% (6 of 9 eyes), respectively; the average operation times were 69 minutes, 82 minutes, and 90 minutes, respectively. The 25 G group showed significantly shorter operation time than the other 2 groups. Although not statistically significant, a higher rate of capsular rupture was seen in the non-core vitrectomy group. CONCLUSIONS: A PKP triple procedure with the 25-G system can be a safe treatment that offers a better success rate of IOL implantation and a significantly shorter operation time. PMID- 22433492 TI - Multilocus microsatellite analysis of 'Candidatus Liberibacter asiaticus' associated with citrus Huanglongbing worldwide. AB - BACKGROUND: Huanglongbing (HLB) is one of the most destructive citrus diseases in the world. The disease is associated with the presence of a fastidious, phloem limited alpha- proteobacterium, 'Candidatus Liberibacter asiaticus', 'Ca. Liberibacter africanus' or 'Ca. Liberibacter americanus'. HLB-associated Liberibacters have spread to North America and South America in recent years. While the causal agents of HLB have been putatively identified, information regarding the worldwide population structure and epidemiological relationships for 'Ca. L. asiaticus' is limited. The availability of the 'Ca. L. asiaticus' genome sequence has facilitated development of molecular markers from this bacterium. The objectives of this study were to develop microsatellite markers and conduct genetic analyses of 'Ca. L. asiaticus' from a worldwide collection. Two hundred eighty seven isolates from USA (Florida), Brazil, China, India, Cambodia, Vietnam, Taiwan, Thailand, and Japan were analyzed. RESULTS: A panel of seven polymorphic microsatellite markers was developed for 'Ca. L. asiaticus'. Microsatellite analyses across the samples showed that the genetic diversity of 'Ca. L. asiaticus' is higher in Asia than Americas. UPGMA and STRUCTURE analyses identified three major genetic groups worldwide. Isolates from India were genetically distinct. East-southeast Asian and Brazilian isolates were generally included in the same group; a few members of this group were found in Florida, but the majority of the isolates from Florida were clustered separately. eBURST analysis predicted three founder haplotypes, which may have given rise to three groups worldwide. CONCLUSIONS: Our results identified three major genetic groups of 'Ca. L. asiaticus' worldwide. Isolates from Brazil showed similar genetic makeup with east-southeast Asian dominant group, suggesting the possibility of a common origin. However, most of the isolates recovered from Florida were clustered in a separate group. While the sources of the dominant 'Ca. L. asiaticus' in Florida were not clearly understood, the less-pervasive groups may have been introduced directly from Asia or via Brazil. Notably, the recent outbreak of HLB in Florida probably occurred through multiple introductions. Microsatellite markers developed in this study provide adequate discriminatory power for the identification and differentiation of closely-related isolates, as well as for genetic studies of 'Ca. L. asiaticus'. PMID- 22433493 TI - Automated tracing of filaments in 3D electron tomography reconstructions using Sculptor and Situs. AB - The molecular graphics program Sculptor and the command-line suite Situs are software packages for the integration of biophysical data across spatial resolution scales. Herein, we provide an overview of recently developed tools relevant to cryo-electron tomography (cryo-ET), with an emphasis on functionality supported by Situs 2.7.1 and Sculptor 2.1.1. We describe a work flow for automatically segmenting filaments in cryo-ET maps including denoising, local normalization, feature detection, and tracing. Tomograms of cellular actin networks exhibit both cross-linked and bundled filament densities. Such filamentous regions in cryo-ET data sets can then be segmented using a stochastic template-based search, VolTrac. The approach combines a genetic algorithm and a bidirectional expansion with a tabu search strategy to localize and characterize filamentous regions. The automated filament segmentation by VolTrac compares well to a manual one performed by expert users, and it allows an efficient and reproducible analysis of large data sets. The software is free, open source, and can be used on Linux, Macintosh or Windows computers. PMID- 22433494 TI - Characterization of colon cancer cells: a functional approach characterizing CD133 as a potential stem cell marker. AB - BACKGROUND: Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures. METHODS: We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo. RESULTS: All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on >= 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.In vivo growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones. CONCLUSIONS: Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target. PMID- 22433495 TI - Expression of a disintegrin and metalloprotease in human abdominal aortic aneurysms. AB - OBJECTIVES: The a disintegrin and metalloprotease (ADAM) family of metalloproteases possesses a proteolytic function and activates various inflammatory factors. Their expression pattern in an abdominal aortic aneurysm (AAA) is as yet unknown. The aim of this study was to make a detailed analysis of the expression of ADAMs 8, 9, 10, 12, 15 and 17, and their tissue inhibitors of metalloprotease (TIMP)-1 and TIMP-3 in patients with AAA. DESIGN: The aortic vessel walls of AAA patients (n=20) and non-aneurysmal aortic specimens (n=10) were obtained by conventional surgical repair and autopsy. SYBR green-based real time PCR, histology and immunohistochemistry were performed on all samples. MAIN OUTCOME MEASURES: Quantitative expression analysis and the localisation of various ADAMs in AAA. RESULTS: ADAMs tested in our study were expressed in both AAA and control aorta without any significant differences between the groups. In contrast, expression of TIMP-1 was significantly reduced in AAA compared to control vessels. Smooth muscle cells (SMCs), neovessels and macrophages were positive for all ADAMs and TIMPs tested. Infiltrates were negative for TIMP-3, and luminal endothelial cells were positive for ADAMs 15 and 17. A significant positive correlation was observed between ADAMs 10, 12, 15, 17, TIMP-3 and SMCs. CONCLUSION: ADAMs are constitutively expressed in normal aortic vessel walls and AAA, particularly in SMCs. PMID- 22433496 TI - A survey of current controversies in scoliosis surgery in the United Kingdom. AB - STUDY DESIGN: A 10-point questionnaire was constructed to identify the philosophy of surgeons on various aspects of scoliosis surgery, such as choice of implant, bone graft, autologous blood transfusion, cord monitoring, and computer-assisted surgery. Comparisons were then made with recommendations published in the spinal literature. OBJECTIVE: To determine certain aspects of the current practice of scoliosis surgery in the United Kingdom. SUMMARY OF BACKGROUND DATA: Guidelines for good clinical practice in spinal deformity surgery are available in the United Kingdom but do not cover a number of controversial issues. METHODS: Consultants and fellows attended the 2009 British Scoliosis Society meeting. Fifty questionnaires were completed by 45 consultants and 5 fellows. RESULTS: All pedicle screw constructs favored by 25 of 50, hybrid 24 of 50 (1 undecided). Posterior construct of fewer than 10 levels, 20 of 50 would not cross-link, 11 of 50 used 1, and 19 of 20 used 2 or more. More than 10 levels 17 of 50 considered cross-links unnecessary, 4 of 50 used 1 and 29 of 50 used 2 or more. Eighty-eight percent preferred titanium alloy implants, whereas others used a mixture of stainless steel and cobalt chrome. When using bone graft, respondents used bone substitutes (24), iliac crest graft (14), allograft (12) and demineralized bone matrix (9) in addition to local bone. Ten of 50 would use recombinant bone morphogenetic protein (3 for revision cases only). Thirty-nine of 50 routinely used intraoperative cell salvage and 4 of 50 never used autologous blood. All used cord monitoring: sensory (19 of 50), motor (2 of 50), and combined (29 of 50). None used computer-aided surgery. Twenty-six operated alone, 12 operated in pairs, and 12 varied depending on type of case. CONCLUSION: This survey shows interesting variations in scoliosis surgery in the United Kingdom. It may reflect the conflicting evidence in the literature. PMID- 22433497 TI - Where the United States spends its spine dollars: expenditures on different ambulatory services for the management of back and neck conditions. AB - STUDY DESIGN: Serial, cross-sectional, nationally representative surveys of noninstitutionalized US adults. OBJECTIVE: To examine expenditures on common ambulatory health services for the management of back and neck conditions. SUMMARY OF BACKGROUND DATA: Although it is well recognized that national costs associated with back and neck conditions have grown considerably in recent years, little is known about the costs of care for specific ambulatory health services that are used to manage this population. METHODS: We used the Medical Expenditure Panel Survey to examine adult (aged 18 yr or older) respondents from 1999 to 2008 who sought ambulatory health services for the management of back and neck conditions. We used complex survey design methods to make national estimates of mean inflation-adjusted annual expenditures on medical care, chiropractic care, and physical therapy per user for back and neck conditions. RESULTS: Approximately 6% of US adults reported an ambulatory visit for a primary diagnosis of a back or neck condition (13.6 million in 2008). Between 1999 and 2008, the mean inflation-adjusted annual expenditures on medical care for these patients increased by 95% (from $487 to $950); most of the increase was accounted for by increased costs for medical specialists, as opposed to primary care physicians. During the study period, the mean inflation-adjusted annual expenditures on chiropractic care were relatively stable; although physical therapy was the most costly service overall, in recent years those costs have contracted. CONCLUSION: Although this study did not explore the relative effectiveness of different ambulatory services, recent increasing costs associated with providing medical care for back and neck conditions (particularly subspecialty care) are contributing to the growing economic burden of managing these conditions. PMID- 22433498 TI - Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system. AB - STUDY DESIGN: Homing of human bone marrow-derived mesenchymal stem cells (BMSCs) was studied using ex vivo cultured bovine caudal intervertebral discs (IVDs). OBJECTIVE: To investigate in a whole organ culture whether metabolic and mechanical challenges can induce BMSC recruitment into the IVD. SUMMARY OF BACKGROUND DATA: Cells from injured tissues release cytokines and mediators that enable the recruitment of progenitor cells. BMSCs have the ability to survive within the IVD. METHODS: Bovine IVDs with or without endplates were cultured for 1 week under simulated physiological or degenerative conditions; disc cells were analyzed for cell viability and gene expression, whereas media was analyzed for nitric oxide production and chemotaxis. Homing of BMSCs was investigated by supplying PKH-labeled human BMSCs onto cultured IVDs (1 * 10(6) cells/disc on d 8, 10, and 12 of culture); on day 14, the number of homed BMSCs was microscopically assessed. Moreover, a comparative study was performed between transduced BMSCs (transduced with an adenovirus encoding for insulin-like growth factor 1 [IGF-1]) and nontransduced BMSCs. Disc proteoglycan synthesis rate was quantified via (35)S incorporation. The secretion of IGF-1 was evaluated by enzyme-linked immunosorbent assay on both simulated physiological and degenerative discs. RESULTS: Discs cultured under degenerative conditions showed reduced cell viability, upregulation of matrix degrading enzymes, and increased nitric oxide production compared with simulated physiological discs. Greater homing occurred under degenerative compared with physiological conditions with or without endplate. Media of degenerative discs demonstrated a chemoattractive activity toward BMSCs. Finally, discs homed with IGF-1-transduced BMSCs showed increased IGF-1 secretion and significantly higher proteoglycan synthesis rate than discs supplied with nontransduced BMSCs. CONCLUSION: We have demonstrated for the first time that degenerative conditions induce the release of factors promoting BMSC recruitment in an ex vivo organ culture. Moreover, IGF-1 transduction of BMSCs strongly increases the rate of proteoglycan synthesis within degenerative discs. This finding offers a new delivery system for BMSCs and treatment strategy for IVD regeneration. PMID- 22433499 TI - A pragmatic multicentered randomized controlled trial of yoga for chronic low back pain: economic evaluation. AB - STUDY DESIGN: Multicentered randomized controlled trial with quality of life and resource use data collected. OBJECTIVE: The objective of this study was to evaluate the cost-effectiveness of yoga intervention plus usual care compared with usual care alone for chronic or recurrent low back pain. SUMMARY OF BACKGROUND DATA: Yoga has been shown as an effective intervention for treating chronic or recurrent low back pain. However, there is little evidence on its cost effectiveness. The data are extracted from a pragmatic, multicentered, randomized controlled trial that has been conducted to evaluate the effectiveness and cost effectiveness of a 12-week progressive program of yoga plus usual care in patients with chronic or recurrent low back pain. METHODS: With this trial data, a cost-effectiveness analysis during the time period of 12 months from both perspectives of the UK National Health Service and the societal is presented. Main outcome measure is an incremental cost per quality-adjusted life-year (QALY). RESULTS: From the perspective of the U.K. National Health Service, yoga intervention yields an incremental cost-effectiveness ratio of L13,606 per QALY. Given a willingness to pay for an additional QALY of L20,000, the probability of yoga intervention being cost-effective is 72%. From the perspective of the society, yoga intervention is a dominant treatment compared with usual care alone. This result is surrounded by fewer uncertainties-the probability of yoga being cost-effective reaches 95% at a willingness to pay for an additional QALY of L20,000. Sensitive analyses suggest the same results that yoga intervention is likely to be cost-effective in both perspectives. CONCLUSION: On the basis of this trial, 12 weekly group classes of specialized yoga are likely to be a cost effective intervention for treating patients with chronic or recurrent low back pain. PMID- 22433500 TI - Optimal intravertebral cement volume in percutaneous vertebroplasty for painful osteoporotic vertebral compression fractures. AB - STUDY DESIGN: A prospective follow-up study. OBJECTIVE: Assessment of the relation between accomplishment of pain relief through percutaneous vertebroplasty (PVP) in painful osteoporotic vertebral compression fractures (OVCFs) and the cemented fraction of the vertebral body and subsequent determination of the optimal intravertebral cement volume. SUMMARY OF BACKGROUND DATA: The mechanism of pain relief of PVP as a treatment modality for painful OVCFs remains unclear. Generally, benefit of PVP is thought to result from stabilization of micromovements and collapse of the fractured vertebral body. However, studies indicating a relation between intravertebral cement volume and pain relief are lacking and an optimal value of the intravertebral cement volume is unknown. METHODS: One hunderd six patients who received PVP for 196 painful OVCFs were prospectively followed on back pain (score 0-10) and occurrence of new OVCFs during the first postoperative year. Patients were classified as responders (average postoperative back pain <= 6) and nonresponders (average postoperative back pain >6). The cemented fraction of the vertebral body was determined using volumetric analysis of the postoperative CT scan of the treated levels. Analysis was performed using receiver-operating characteristic (ROC) analysis and multivariable regression techniques. RESULTS: Twenty-nine patients (27.3%) were found to be nonresponders. Mean intravertebral cement volume in all 196 treated OVCFs was 3.94 mL (SD = 1.89, range 0.13-10.8). The mean cemented vertebral body fraction was significantly lower in nonresponders (0.15 vs. 0.21, P = 0.002). The ROC area-under-curve of the cemented fraction as a predictor of accomplishment of pain relief was 0.67 (95% CI: 0.57-0.78, P = 0.006). In subgroups without specific influential factors (new OVCFs, intravertebral clefts), significantly stronger associations were found. A vertebral body fraction of 24% was identified as the optimal fraction to be cemented. This fraction corresponded to a 93% to 100% specificity for accomplishment of pain relief (i.e., few to no cases without pain relief in the presence of adequate cementing) without being significantly associated with a higher risk of occurrence of cement leakage or new OVCFs. Corresponding values for the recommended (optimal) intravertebral cement volume were provided based on its governing characteristics (fracture level, fracture severity, and patient's sex). CONCLUSION: An optimal intravertebral cement volume was identified for accomplishment of pain relief through PVP in painful OVCFs. Appropriate thresholds were provided to guide the operator. PMID- 22433501 TI - In vivo topographic analysis of lumbar facet joint space width distribution in healthy and symptomatic subjects. AB - STUDY DESIGN: In vivo 3-dimensional facet joint space width measurement. OBJECTIVE: To determine lumbar facet joint space width within clinically relevant topographical zones in vivo and its correlations with age, level, and presence of lower back pain symptoms. SUMMARY OF BACKGROUND DATA: Facet joint gap narrowing, articular cartilage thinning, and subarticular cortical bone hypertrophy are frequently observed age-related changes. Facet joint space width is a well defined parameter to evaluate osteoarthritis. To the best of our knowledge, there is no other study that quantifies 3-dimensional facet joint space width distribution in vivo. METHODS: Three-dimensional measurement to quantify facet joint space width distribution based on 5 clinically relevant topographic zones in a cohort of healthy and symptomatic volunteers with low back pain, using subject-based 3-dimensional computed tomographic models with respect to spinal level, subject age, sex, and presence/absence of lower back pain. RESULTS: Facet joint space width (mean +/- SD) was 1.93 +/- 0.51 mm for the central zone, 1.75 +/- 0.48 mm for the superior zone, 1.63 +/- 0.49 mm for the inferior zone, 1.48 +/- 0.44 mm for the medial zone, and 1.65 +/- 0.48 mm for the lateral zone, respectively. There were no significant differences between right and left facet joints. Male patients showed larger space width than female patients. Overall, space width of symptomatic subjects was significantly narrower than that of the asymptomatic group. Facet joints in the peripheral zones were narrower than in the central zone. Age-group comparisons showed that local narrowing occurring as early as in the third decade at the inferior zone of L5-S1, with all the remaining zones implicated after the fourth decade. CONCLUSION: This in vivo study shows variations in facet joint space width narrowing with spinal level and region within the facet joint and in vivo evidence of localized, age-influenced facet cartilage thinning. Techniques developed in this study may be applied in the detection of early osteoarthritis-related changes in the facet joints. PMID- 22433502 TI - Outcome of pedicle subtraction osteotomies for fixed sagittal imbalance of multiple etiologies: a retrospective review of 140 patients. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate the efficacy and safety of the pedicle subtraction osteotomy (PSO) as a technique for correction of fixed sagittal imbalance with multiple etiologies. SUMMARY OF BACKGROUND DATA: This report represents the largest and longest series of patients with fixed sagittal imbalance other than ankylosing spondylitis who were managed with PSO. METHODS: A total of 140 consecutive patients who had undergone PSO for the management of sagittal imbalance with any etiology were reviewed. Etiologic diagnoses were ankylosing spondylitis in 86 patients, flatback syndrome in 20, post-traumatic kyphosis in 17, congenital kyphoscoliosis in 9, and post tuberculotic kyphosis in 8 patients. The average duration of the follow-up period was 8 years (range, 5-12.5 yr). Radiological and clinical outcome analyses were performed. RESULTS: All patients showed a solid union upon follow-up radiographs and no pseudarthrosis was noted. Correction with PSO averaged 36.2 degrees . Blood loss averaged 1515.6 mL. The Oswestry Disability Index improved from 40.5 to 18.8 at the last follow-up, and 90.7% of the patients were very or somewhat satisfied. There were 15 cases (10.7%) of reversible complications including transient radiculopathy and 3 cases (2.1%) of irreversible complications. CONCLUSION: Based on the results of this study, PSO is considered a reliable and relatively safe procedure for the correction of fixed sagittal imbalance with multiple etiologies. PMID- 22433503 TI - The effect of pedicle screw insertion at a young age on pedicle and canal development. AB - STUDY DESIGN: A longitudinal case study. OBJECTIVE: To determine whether pedicle screws placed in an immature spine exert effect on the continued growth of the vertebral body. SUMMARY OF BACKGROUND DATA: Pedicle screws have revolutionized surgical treatment of spinal deformities by allowing a mode of secure fixation that provides consistently better correction rates in adults and adolescents. In the young child, however, the trajectory of pedicle screws takes them through an open physis: the neurocentral cartilage. There exists little information regarding the possible effect of pedicle screws inserted at a young age on further development of the spine and the spinal canal. METHODS: Patients undergoing pedicle screw instrumentation of at least 2 levels before the age of 5 years (60 mo) for the first time for any diagnosis and who had been followed for at least 24 months were included. Measurements were performed in instrumented and adjacent noninstrumented levels without visible deformity in pre- and postoperative cross-sectional images and compared using statistical methods. RESULTS: Ninety segments in 15 patients met the inclusion criteria (average age at instrumentation 46.3 mo [range, 29-60 mo]). Forty segments had no screws and 50 had at least 1 screw. Pedicle length and vertebral body diameter had significantly increased in both groups, whereas spinal canal parameters did not change significantly. No significant difference was observed between the growth rates in levels with or without screws in pedicle length, vertebral body diameter, or spinal canal parameters (anterior-posterior and interpedicular diameters, and area). CONCLUSION: Pedicle screw instrumentation performed before the age of 5 years does not cause a negative effect on the growth of pedicles, the transverse plane of the vertebral body, or the spinal canal. It can be safely performed in the treatment of deformity in this age group. PMID- 22433504 TI - Gross morphological changes of the spinal cord immediately after surgical decompression in a large animal model of traumatic spinal cord injury. AB - STUDY DESIGN: Quantitative in vivo ultrasound imaging study of spinal cord and dura morphology after acute experimental spinal cord injury (SCI) and decompression in a pig model. OBJECTIVE: To study the morphological changes of the spinal cord and dura immediately after surgical decompression for acute SCI. SUMMARY OF BACKGROUND DATA: Surgical decompression for traumatic SCI is currently a topic of debate. After decompression, relief of bony impingement on the thecal sac and spinal cord can be confirmed intraoperatively. However, postoperative imaging often reveals that the cord has swollen to fill the subarachnoid space. Little is known about the extent and timing of this morphological response. METHODS: Yucatan miniature pigs received sham surgery (N = 1) or a moderate (N = 6, 20 g, 2.3 m/s) or high (N = 6, 20 g, 4.7 m/s) severity weight-drop SCI followed by 8 hours of sustained compression (100 g) and 6 hours of postdecompression monitoring. Sagittal-plane ultrasound images were used to quantify spinal cord, dura, and subarachnoid space dimensions preinjury and once per hour after decompression. RESULTS: Animals with a moderate SCI exhibited a residual cord deformation of up to 0.64 mm within 10 minutes of decompression, which tended to resolve during 6 hours because of tissue relaxation and swelling. For animals with high-severity SCIs, cord swelling was immediate and resulted in occlusion of the subarachnoid space within 10 minutes to 5 hours, whereas this occurred for only half of the moderate injury group. CONCLUSION: Decompression of an acute SCI may result in residual cord deformation followed by gradual swelling or immediate swelling leading to subarachnoid occlusion. The response is dependent on initial injury severity. These observations may partly explain the lack of benefit of decompression in some patients and suggest a need to reduce cord swelling to optimize the clinical outcome after acute SCI. PMID- 22433505 TI - Platelet-rich plasma combined with hydroxyapatite for lumbar interbody fusion promoted bone formation and decreased an inflammatory pain neuropeptide in rats. AB - STUDY DESIGN: A prospective interventional trial, using a rat model of lumbar interbody fusion. OBJECTIVE: To examine the potential efficacy of platelet-rich plasma (PRP) for lumbar interbody fusion, using hydroxyapatite (HA). SUMMARY OF BACKGROUND DATA: PRP is an autologous product containing a high concentration of platelets in a small volume of plasma and has osteoinductive effects. HA has osteoconductive ability and has been used in combination with autogenous bone for spine fusion. However, reports using PRP with HA for spine fusion are very few. The purpose of this study was to examine the efficacy of PRP with HA for spinal interbody fusion and at the same time to estimate the change in immunoreactivity of the inflammatory neuropeptide, calcitonin gene-related peptide (CGRP), in dorsal root ganglion (DRG) neurons innervating spinal discs. METHODS: A total of 35 Sprague-Dawley rats were used in this study. Twenty-one rats were used for conducting interbody fusion experiments, 7 rats were used as immunostaining controls, and 7 other rats were used as blood donors for making PRP. L5-L6 interbody fusion was performed on 21 rats using HA + PRP (n = 7), HA + platelet poor plasma (n = 7), or HA + saline (n = 7). Simultaneously, Fluoro-Gold neurotracer was applied to the intervertebral space to detect DRG neurons innervating the discs. L5-L6 lumbar radiographs were obtained and lumbar DRGs were immunostained for CGRP. The rate of bone union and the change in CGRP immunoreactive DRG neurons innervating the discs were evaluated and compared among groups. RESULTS: All L5-L6 lumbar discs were fused in the PRP + HA group (fused 7/total 7), whereas only 1 case was fused in the platelet-poor plasma group (1 of 7) and no cases in the HA-only group (0 of 7), which was a significant difference. Upon immunohistochemical analysis, CGRP-positive neurons innervated L5-L6 intervertebral discs in nonunion cases, and these were significantly increased compared with those in union cases. CONCLUSION: Our study suggests that using PRP with HA was beneficial for spine fusion. This combination may promote bone union and also decrease inflammatory neuropeptide in sensory neurons innervating the discs. PMID- 22433506 TI - Comparison of 3 fusion techniques in the treatment of the degenerative cervical spine disease. Is stand-alone autograft really the "gold standard?": prospective study with 2-year follow-up. AB - STUDY DESIGN: A prospective study. OBJECTIVE: The aim of this study was to compare the 3 different methods of interbody fusion of the cervical spine autograft in stand-alone technique, autograft with anterior plate, and polyetheretherketone cage supported by anterior plate. The clinical and radiological data obtained were analyzed and discussed. SUMMARY OF BACKGROUND DATA: Although degenerative cervical spine disease has been treated by an anterior approach for more than 50 years, there is not one generally accepted operative approach. There is a very low-quality evidence of little or no difference in pain relief between each of the techniques. Iliac crest autograft still seems to be the "gold standard" for interbody fusion. METHODS: Prospective study collecting clinical and radiological data of 81 patients undergoing anterior cervical interbody fusion, in which the interbody fusion of 1 or 2 motion segments from C3 to C7 was done by any of the 3 techniques--stand-alone insertion of autograft (group 1: 28 patients), autograft and anterior plate (group 2: 18 patients), and polyetheretherketone cage filled with beta-tricalcium phosphate and plate (group 3: 29 patients). Patients were followed for 2 years after surgery. RESULTS: Significant interaction of relative height in the segment and time was found (P < 0.001). The values of the relative height of stand-alone autograft dropped below 95% of initial height and the values of the other 2 groups remained above 105%. Significant interaction of time and group was found for Cobb S angles (P < 0.001). Values of group 1 decreased substantially and remained significantly lower than values of other 2 groups. Fusion rate was 100% in all groups. Neck Disability Index group and time interaction was found (P = 0.023). During postoperative follow-up, group 1 scored in all controls higher than the other 2 groups, but differences were not significant. Visual analogue scale showed effect of time (P < 0.001). This was due to a smaller improvement of patients in group 1 during the whole follow-up in comparison with the other 2 groups. Highest proportion of unsatisfied patients was in group 1 compared with the other 2 groups after 2 years (P = 0.034). CONCLUSION: Significantly worse radiological and clinical results after 2 years of follow-up were achieved using stand-alone autograft technique in comparison with autograft supported by anterior plating similarly as in comparison with cage implant and anterior plating. Using artificial fusion substrate together with plate and cage can offer the same clinical and radiological results such as iliac autograft and plating. Anterior plating seems to be an important factor influencing the postoperative cervical spine alignment and also the clinical outcome. PMID- 22433507 TI - Pullout analysis of a lumbar plate with varying screw orientations: experimental and computational analyses. AB - STUDY DESIGN: Experimental and finite element analysis of anterior lumbar interbody fixation (ALIF) plate pullout. OBJECTIVE: The objective of this study was to determine the effect of screw angle and orientation on ALIF plate pullout strength. SUMMARY OF BACKGROUND DATA: It has been thought that angling the screws in an ALIF plate leads to better fixation strength; however, a few studies are published on this question, which produced conflicting results. METHODS: Using custom guides, screws were configured in 9 different orientations to affix ALIF plates to polyurethane foam blocks. Pullout tests were performed at a rate of 1 mm/min. In addition, finite element analyses were performed on a 2-dimensional screw-block model to gain insight into the internal stress during pullout. RESULTS: The pullout load was the greatest, with screws positioned 12 degrees outward sagittaly and 6 degrees inward coronally (936 +/- 72 N). This orientation was statistically greater than the orientation with the lowest pullout load (812 +/- 45 N, P < 0.05); however, no group was statistically different than placing the screws straight in (868 +/- 86 N, P > 0.05). Finite elements analysis showed some gain in pullout strength at 12 degrees followed by some loss at greater angles. As the screw insertion angle increased, stress levels elevated within the block even in the regions away from the screw. CONCLUSION: Significant difference was found between certain screw-angle configurations; however, when compared with simply placing the screws straight in, the difference was never more than 8%. This implies that there is greater freedom in the angle and placement of screws than previously thought. Our results show that there is little change in fixation strength when placing the screw in a different direction. PMID- 22433508 TI - Short-term outcome after cystectomy: comparison of two different perioperative protocols. AB - AIM: To compare the outcome of two perioperative protocols with respect to postoperative management of cystectomy patients. PATIENTS AND METHODS: Between June 2007 and November 2008, 85 consecutive patients with bladder cancer were treated with cystectomy and urinary diversion. Patients were operated in two hospitals by four urologic surgeons. In protocol A, patients were enterally fed via a postpyloric tube while the nasogastric tube (NGT) was removed directly after cystectomy and selective decontamination of the digestive tract was given until normal oral intake. In protocol B, postcystectomy management consisted of total parenteral nutrition by a central venous line and NGT removal after 24 h. Hospital stay and complications were compared between the two hospitals. RESULTS: More than half of all patients (52%) developed one or more complications within 30 days after surgery, 37% in protocol A and 71% in protocol B (p = 0.002). Higher ASA score and protocol type were the only factors significantly associated with early complications in both uni- and multivariate analyses. Length of stay was significantly shorter with protocol A as compared to protocol B, 13 days versus 19 days (p = 0.006). CONCLUSIONS: Cystectomy and urinary diversion is a procedure with considerable risk of complications. Enteral nutrition might be advantageous as compared to parenteral nutrition, showing fewer complications and shorter hospital stay. A high ASA score is associated with more early complications. Selective bowel decontamination may have an additional role in preventing infectious complications after cystectomy. PMID- 22433509 TI - A structural model of the E. coli PhoB dimer in the transcription initiation complex. AB - BACKGROUND: There exist > 78,000 proteins and/or nucleic acids structures that were determined experimentally. Only a small portion of these structures corresponds to those of protein complexes. While homology modeling is able to exploit knowledge-based potentials of side-chain rotomers and backbone motifs to infer structures for new proteins, no such general method exists to extend our understanding of protein interaction motifs to novel protein complexes. RESULTS: We use a Motif Binding Geometries (MBG) approach, to infer the structure of a protein complex from the database of complexes of homologous proteins taken from other contexts (such as the helix-turn-helix motif binding double stranded DNA), and demonstrate its utility on one of the more important regulatory complexes in biology, that of the RNA polymerase initiating transcription under conditions of phosphate starvation. The modeled PhoB/RNAP/sigma-factor/DNA complex is stereo chemically reasonable, has sufficient interfacial Solvent Excluded Surface Areas (SESAs) to provide adequate binding strength, is physically meaningful for transcription regulation, and is consistent with a variety of known experimental constraints. CONCLUSIONS: Based on a straightforward and easy to comprehend concept, "proteins and protein domains that fold similarly could interact similarly", a structural model of the PhoB dimer in the transcription initiation complex has been developed. This approach could be extended to enable structural modeling and prediction of other bio-molecular complexes. Just as models of individual proteins provide insight into molecular recognition, catalytic mechanism, and substrate specificity, models of protein complexes will provide understanding into the combinatorial rules of cellular regulation and signaling. PMID- 22433510 TI - Carbon nanotube synthesis: from large-scale production to atom-by-atom growth. AB - The extraordinary electronic, thermal and mechanical properties of carbon nanotubes (CNTs) closely relate to their structure. They can be seen as rolled-up graphene sheets with their electronic properties depending on how this rolling up is achieved. However, this is not the way they actually grow. Various methods are used to produce carbon nanotubes. They all have in common three ingredients: (i) a carbon source, (ii) catalyst nanoparticles and (iii) an energy input. In the case where the carbon source is provided in solid form, one speaks about 'high temperature methods' because they involve the sublimation of graphite which does not occur below 3200 degrees C. The first CNTs were synthesized by these techniques. For liquid or gaseous phases, the generic term of 'medium or low temperature methods' is used. CNTs are now commonly produced by these latter techniques at temperatures ranging between 350 and 1000 degrees C, using metal nanoparticles that catalyze the decomposition of the gaseous carbon precursor and make the growth of nanotubes possible. The aim of this review article is to give a general overview of all these methods and an understanding of the CNT growth process. PMID- 22433511 TI - Impact of age and body site on adult female skin surface pH. AB - BACKGROUND: pH is known as an important parameter in epidermal barrier function and homeostasis. AIM: The impact of age and body site on skin surface pH (pH(SS)) of women was evaluated in vivo. METHODS: Time domain dual lifetime referencing with luminescent sensor foils was used for pH(SS) measurements. pH(SS) was measured on the forehead, the temple, and the volar forearm of adult females (n = 97, 52.87 +/- 18.58 years, 20-97 years). Every single measurement contained 2,500 pH values due to the luminescence imaging technique used. RESULTS: pH(SS) slightly increases with age on all three investigated body sites. There are no significant differences in pH(SS) between the three investigated body sites. CONCLUSION: Adult pH(SS) on the forehead, the temple and the volar forearm increases slightly with age. This knowledge is crucial for adapting medical skin care products. PMID- 22433512 TI - Post-extraction stabilization of HIV viral RNA for quantitative molecular tests. AB - Two approaches to stabilize viral nucleic acid in processed clinical specimens were evaluated. HIV-1 RNA extracted from clinical specimens was stabilized in a dry matrix in a commercial product (RNAstable, Biomatrica, San Diego, CA, USA) and in a reverse-transcription reaction mixture in liquid form as cDNA. As few as 145 HIV-1 genome copies of viral RNA are reliably stabilized by RNAstable at 45 degrees C for 92 days and in the cDNA format at 45 degrees C for 7 days as determined by real-time PCR. With RNAstable the R(2) at days 1, 7, and 92 were 0.888, 0.871, and 0.943 when compared to baseline viral load values. The cDNA generated from the same clinical specimens was highly stable with an R(2) value of 0.762 when comparing viral load determinations at day 7 to baseline values. In conclusion viral RNA stabilized in a dry RNAstable matrix is highly stable for long periods of time at high temperatures across a substantial dynamic range. Viral RNA signal can also be stabilized in liquid in the form of cDNA for limited periods of time. Methods that reduce reliance on the cold chain and preserve specimen integrity are critical for extending the reach of molecular testing to low-resource settings. Products based on anhydrobiosis, such as the RNAstable should be evaluated further to support viral pathogen diagnosis. PMID- 22433513 TI - Development and optimization of a PCR assay for detection of Dobrava and Puumala hantaviruses in Bosnia and Herzegovina. AB - Hantavirus-specific serology tests are the main diagnostic technique for detection of hantavirus infection in Bosnia and Herzegovina. In order to enhance hantavirus infections monitoring a sensitive PCR based assay was developed to detect Dobrava (DOBV) and Puumala (PUUV) hantaviruses. Nested primer sets were designed within three different regions of the viral RNA (S and M segment of DOBV and M segment of PUUV) based on highly similar regions from a number of different European hantavirus strains. Assay conditions were optimized using cell cultures infected with DOBV Slovenia, PUUV Sotkamo and PUUV CG 18-20. This sensitive and specific assay has proven to be useful for detection of both Puumala and Dobrava hantaviruses. PMID- 22433514 TI - Comparison of neutralizing and hemagglutination-inhibiting antibody responses for evaluating the seasonal influenza vaccine. AB - Evaluation of the efficacy of influenza vaccines is essential for vaccine development. This study evaluated the neutralizing and hemagglutination inhibition antibody response in subjects receiving the 2006-07 and 2007-08 seasonal influenza vaccines. ELISA-based microneutralization demonstrated a greater mean-fold increase and seroconversion rate than the hemagglutination inhibition assay. The increase in the antibody titers against influenza H1 were higher than those against influenza H3 and influenza B, indicating that the H1 vaccine strain in the 2006-07 and 2007-08 seasons was more immunogenic. These data suggest that the neutralizing antibody response is a better measurement of influenza vaccine efficacy. PMID- 22433515 TI - Increased sensitivity to perceptual interference in adults with attention deficit hyperactivity disorder. AB - Difficulty with selective attention is a frequent complaint of adult patients with ADHD, but selective attention tasks have not provided robust evidence of attentional dysfunction in this group. Two experiments examine this puzzle by distinguishing between failures of spatial selection and problems due to sensitivity to perceptual interference. In Experiment 1, we measured the level of perceptual interference generated by targets in crowded displays with nearby distractors by comparing luminance thresholds in both distractor-present (noise) and distractor-absent (clean) displays. ADHD and control participants had comparable thresholds for clean displays, but ADHD individuals had elevated thresholds to crowded displays. These effects could be explained in two distinct ways. Deficits may have arisen from amplified visual interference in the noise condition, or from abnormalities in top-down attentional processes that reduce visual interference. Experiment 2 adjusted for individual perceptual differences with clean and noise displays, before measuring visual interference resolution at attended versus unattended locations. ADHD and control groups had comparable interference resolution at attended locations. These results suggest that perceptual interference rather than spatial attention deficits may account for some deficits in ADHD. This putative deficit in sensory function highlights a potential early-stage perceptual processing deficit in ADHD distinct from selective attention. PMID- 22433516 TI - [Tracheoplasty after circular trachea resection]. AB - One of the crucial features of the reconstructive surgery of the trachea is the choice of suturing method and materials. The authors' experience of tracheal stenoses treatment counts 759 patients, aged from 9 to 77 years. The number of administered patients, who had been operated earlier in other hospitals, has drastically increased recently. The amount of patients with long tracheal stenoses has also increased. The novel operative techniques of tracheal suture, suggested by the authors, permit better results of rehabilitation. PMID- 22433517 TI - [Thoracic ultrasound in penetrating chest trauma: the tactics management]. AB - The thoracic ultrasound for the detection of hemothorax and hemopericardium was performed in 655 patients with penetrating thoracic trauma. Ultrasound findings were compared with the results of surgical exploration. Sensitivity and specificity of ultrasound in detection of hemothorax was 72.1 and 90.1%; in detection of hemopericardium - 70.6 and 73.7%, respectively. The results of the US diagnostics depended on patients' position (supine or when seated) and on time interval between the examination and surgery. The isolated US investigation in supine position leads to the increase of false negative results. We consider that in hemodynamically stable patients the doutbtfull US data in detection of hemopericardium is the indication to videothoracoscopy. The lower-chest injuries with the US signs of hemothorax are considered to be the indication for VATS except for the obvious left-side thoracoabdominal injuries. PMID- 22433518 TI - [Diagnostics and treatment of pulmonary embolism in patients with floating thrombus of the infrainguinal area]. AB - The results of management of 25 patients with floating thrombus of the deep infrainguinal veins were analyzed in the article. The US scanning proved to be enough for the reliable diagnostics of the disease. The surgical management of the category of patients was considered to be the mainstay of the pulmonary embolism prophylaxis. PMID- 22433519 TI - [Lower limb omental implantation in patients with obliterative thrombangiitis]. AB - The experience of 34 operations of omental implantation to the patients with the critical lower limb ischemia due to the obliterative thrombangiitis was analyzed. 5 patients had the procedure on the both limbs simultaneously. The operative technique had been thoroughly described in the article. The procedure, being accomplished according to the certain standards, proved to be extremely effective. PMID- 22433520 TI - [The optimal treatment algorithm of radial nerve injuries]. AB - The results of rehabilitation of 52 patients with radial nerve injuries were comparatively analyzed: the traditional rehabilitation complex (massage, training, etc.) was compared with the method of functional biomanagement. The technical characteristics of the designed functional cast were thoroughly described. The study demonstrated that reinnervation and functional recovery of the denervated muscles without segmental influence were significantly slower. PMID- 22433521 TI - [The primary mammoplasty in patients with breast cancer]. AB - The novel technique of the primary mammoplasty for patients with the breast cancer T1 - 2N0-1M0 was worked out. The submammar skin flap preservation provides the more natural breast form and make the breast modeling technically easier for the surgeon. The method can be applied solitary or in combination with breast prostheses. Of the 23 patients, operated on, 4 had postoperative complications. The long-term follow up revealed no tumor recurrence in these patients. PMID- 22433522 TI - [The prophylaxis and treatment of renal dysfunction by pancreatogenic endotoxicosis]. AB - The treatment of 386 patients with the acute pancreatitis of various etiology was analyzed. Renal dysfunction was revealed in 243 (63%) of them. The prognostic factors of renal dysfunction were carried out. The timely application of the treatment scheme, including early extracorporal detoxification, permit the significant improvement of the treatment results of the acute pancreatitis. PMID- 22433523 TI - [Endoscopic transmural and transpapillar procedures for the treatment of chronic pancreatitis]. AB - 93 patients with chronic pancreatitis were treated endoscopically: 44 had transpapillar procedures and 49 patients had transmural operations. The transmural procedures were applied in case of pancreatic pseudicysts, whereas transpapillar endoscopic operations were applied in cases of the obstructive jaundice, pseudocyst, connected of the main pancreatic duct, virsungolithyasis or ductal pancreatitis with pain syndrome. The endoscopic procedures by chronic pancreatitis proved to be the reliable alternative to the traditional surgery. PMID- 22433524 TI - [Videoendoscopic surgery of cholelythiasis in elderly patients]. AB - 43 patients aged 60-84 years were operated on calculous cholecystitis. Patients were divided according to the operative technique: laparoscopic and traditional. The laparoscopic cholecystectomy demonstrated good early results. The goal of the study was to define criteria of the elderly patients selection for the laparoscopic operation. PMID- 22433525 TI - [Diagnostics and surgical treatment of the posttraumatic septic mediastinitis]. AB - Treatment results of 38 cases of septic mediastinitis for the last 17 years were analyzed. The frequency of mediastinitis as a complication of the penetrating wound was 0.28%, and of the closed thoracic trauma - 0.1%. Reasons and risk factors of the mediastinitis development have been revealed. The enlargement of the mediastinum on the X-ray allowed the primary diagnostics of suspicion on the mediastinitis in 39.5% of cases. The spiral computed tomography provided information for the further treatment options. The mediastinum drainage was an effective method of treatment, providing the improvement in 69.6% patients after penetrating wound and in 73.3% after the closed thoracic trauma. PMID- 22433526 TI - [The surgical treatment of the incarcerated hernia]. AB - The treatment results of 1540 patients with the incarcerated hernias of various localization were analyzed. It was revealed, that treatment results depend not only of the patient's age and concomitant diseases and operating time but the choice of surgical access and the type of intestinal anastomosis. The main postoperative negative factor proved to be the increase of the intraabdominal pressure, which severely impairs the lung ventilation. The factor can be excluded by using the prosthetic methods of hernioplasty, though. PMID- 22433527 TI - [The influence of draining on the quality of the intestinal suture]. AB - The Billroth II gastric resection with mechanical suture of the gastro jejunoanastomosis was performed in 8 dogs. The amount of E.coli and neutrophiles in tissue edges were registered morphometrically within 30 days. The important defencive role of the mucosa was proved. The inverted and everted mechanical intestinal suture were accessed from the positions of draining possibility. PMID- 22433528 TI - [Free radical processes in patients with the gastro-intestinal bleedings]. AB - The role of the free radical processes (FRP) is shown and objectified in the development of the ulcer gastro-intestinal bleedings (UGIB). It is revealed on the first day of hospitalization already. The greatest imbalance of the FRP is registered in heavy patients with acute UGIB. It appeared like decrease of the oxygen and activation of the lipid FRP disregulation. Unheavy patients have FRP changes refer to the oxygen part of the oxidation process only. Intensification FRP in process of increase of weight disease consists in decrease activity oxygen and increase a lipid disbalance. FRP disbalance has long time proceeds, last till the patient's discharge. Results of the research prove as much as possible early inclusion in a complex of medical actions antoixidant therapy. The high efficiency of the energetic corrector reamberin in a dose of 400-800 ml was shown in patients with UGIB. PMID- 22433529 TI - [The cystobiliary fistula complicated by liver abscess after echinococcectomy]. PMID- 22433530 TI - [Hemopericardium - a rare late complication after surgical treatment of funnel chest syndrome]. PMID- 22433531 TI - Addition of an external electron donor to in vitro assays of cysteine dioxygenase precludes the need for exogenous iron. AB - Cysteine dioxygenase (CDO) utilizes a 3-His facial triad for coordination of its metal center. Recombinant CDO present in cellular lysate exists primarily in the ferrous form and exhibits significant catalytic activity. Removal of CDO from the reducing cellular environment during purification results in the loss of bound iron and oxidation of greater than 99% of the remaining metal centers. The as isolated recombinant enzyme has comparable activity as the background level of L cysteine oxidation confirming that CDO is inactive under the aerobic conditions required for catalysis. Including exogenous ferrous iron in assays resulted in non-enzymatic product formation; however, addition of an external reductant in assays of the purified protein resulted in the recovery of CDO activity. EPR spectroscopy of CDO in the presence of a reductant confirms that the recovered activity is consistent with reduction of iron to the ferrous form. The as isolated enzyme in the presence of L-cysteine was nearly unreactive with the dioxygen analog, but had increased affinity when pre-incubated with an external reductant. These studies shed light on the discrepancies among reported kinetic parameters for CDO and also juxtapose the stability of the 3-His and 2-His/1 carboxylate ferrous enzymes in the presence of dioxygen. PMID- 22433532 TI - The American Psychiatric Association's guideline for major depressive disorder: a commentary. PMID- 22433533 TI - Antimalarial activities of medicinal plants traditionally used in the villages of Dharmapuri regions of South India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: An ethnopharmacological investigation of medicinal plants traditionally used to treat diseases associated with fevers in Dharmapuri region of South India was undertaken. Twenty four plants were identified and evaluated for their in vitro activity against Plasmodium falciparum and assessed for cytotoxicity against HeLa cell line. AIM OF THE STUDY: This antimalarial in vitro study was planned to correlate and validate the traditional usage of medicinal plants against malaria. MATERIALS AND METHODS: An ethnobotanical survey was made in Dharmapuri region, Tamil Nadu, India to identify plants used in traditional medicine against fevers. Selected plants were extracted with ethyl acetate and methanol and evaluated for antimalarial activity against erythrocytic stages of chloroquine (CQ)-sensitive 3D7 and CQ-resistant INDO strains of Plasmodium falciparum in culture using the fluorescence-based SYBR Green I assay. Cytotoxicity was determined against HeLa cells using MTT assay. RESULTS: Promising antiplasmodial activity was found in Aegle marmelos [leaf methanol extract (ME) (IC(50)=7 MUg/mL] and good activities were found in Lantana camara [leaf ethyl acetate extract (EAE) IC(50)=19 MUg/mL], Leucas aspera (flower EAE IC(50)=12.5 MUg/mL), Momordica charantia (leaf EAE IC(50)=17.5 MUg/mL), Phyllanthus amarus (leaf ME IC(50)=15 MUg/mL) and Piper nigrum (seed EAE IC(50)=12.5 MUg/mL). The leaf ME of Aegle marmelos which showed the highest activity against Plasmodium falciparum elicited low cytotoxicity (therapeutic index>13). CONCLUSION: These results provide validation for the traditional usage of some medicinal plants against malaria in Dharmapuri region, Tamil Nadu, India. PMID- 22433534 TI - Screening for in vivo (anti)estrogenic and (anti)androgenic activities of Tropaeolum majus L. and its effect on uterine contractility. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tropaeolum majus L. (Tropaeolaceae) is a medicinal herb popularly used in Brazil for treatment of inflammatory and cardiovascular diseases. Despite some published data on its efficacy, there are still few toxicological data describing the safety of this plant. The aim of this study was to evaluate the (anti)estrogenic and (anti)androgenic activity of the hydroethanolic extract obtained from Tropaeolum majus L. (HETM), as well as its possible effects on uterine contractility. MATERIALS AND METHODS: Three experimental protocols were performed, (a) uterotrophic assay, (b) Hershberger assay and (c) an ex vivo test to investigate the effects of maternal administration of HETM on uterine contractility at the end of pregnancy. In all protocols three doses of the HETM were administered to Wistar rats: 3, 30 and 300mg/kg. RESULTS: In vivo tests for detection of (anti)androgenic and (anti)estrogenic activities did not show any significant alterations. Similarly, no alterations were observed on uterine contractility induced by oxytocin and arachidonic acid. CONCLUSIONS: HETM was unable to produce (anti)estrogenic or (anti)androgenic activities in the short-term in vivo screening assays performed. In addition, there was no evidence that HETM can affect uterine contractility following gestational exposure of rats. PMID- 22433535 TI - Anti-inflammatory and cytoprotective effects of selected Pakistani medicinal plants in Helicobacter pylori-infected gastric epithelial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Helicobacter pylori infection is associated with gastritis, peptic ulcer, and gastric cancer. Due to its high global prevalence and uprising resistance to available antibiotics, efforts are now directed to identify alternative source to treat and prevent associated disorders. In the present study, effect of selected indigenous medicinal plants of Pakistan was evaluated on the secretion of interleukin-8 (IL-8) and generation of reactive oxygen species (ROS) in a bid to rationalize their medicinal use and to examine the anti-inflammatory and cytoprotective effects in gastric epithelial cells. MATERIALS AND METHODS: AGS cells and clinically isolated Helicobacter pylori strain (193C) were employed for co-culture experiments. Anti-Helicobacter pylori activity and cytotoxic effects of the selected plants were determined by serial dilution method and DNA fragmentation assay respectively. ELISA and flow cytometry were performed to evaluate the effect on IL-8 secretion and ROS generation in Helicobacter pylori-infected cells. RESULTS: At 100MUg/ml, extracts of Alpinia galangal, Cinnamomum cassia, Cinnamomum tamala, Mentha arvensis, Myrtus communis, Oligochaeta ramose, Polygonum bistorta, Rosa damascena, Ruta graveolens, Syzygium aromaticum, Tamarix dioica, and Terminalia chebula exhibited strong inhibitory activity against IL-8 secretion. Of these, four extracts of Cinnamomum cassia, Myrtus communis, Syzygium aromaticum, and Terminalia chebula markedly inhibited IL-8 secretion at both 50 and 100MUg/ml. Cinnamomum cassia was further assessed at different concentrations against Helicobacter pylori and TNF alpha stimulated IL-8 secretion, which displayed significant suppression of IL-8 in a concentration-dependent-manner. Among the plants examined against ROS generation, Achillea millefolium, Berberis aristata, Coriandrum sativum, Foeniculum vulgare, Matricaria chamomilla and Prunus domestica demonstrated significant suppression of ROS from Helicobacter pylori-infected cells (p<0.01). CONCLUSION: Results of the study revealed anti-inflammatory and cytoprotective effects of selected medicinal plants which could partially validate the traditional use of these plants in GI disorders particularly associated with Helicobacter pylori. Furthermore, results obtained may lead to possible future candidates of chemoprevention against peptic ulcer or gastric cancer. PMID- 22433536 TI - Herbal medicines used in the treatment of diabetes mellitus in Arunachal Himalaya, northeast, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants have played an important role in treating and preventing a variety of diseases throughout the world. Khampti tribal people living in the far-flung Lohit district of the Eastern Arunachal Himalaya, India still depend on medicinal plants and most of them have a general knowledge of medicinal plants which are used for treating a variety of ailments. This survey was undertaken in Lohit district in order to inventory the medicinal plants used in folk medicine to treat diabetes mellitus. MATERIALS AND METHODS: Field investigations were conducted in seventeen remote villages of Lohit district starting from April 2002 to May 2004 through interviews among 251 key informants who were selected randomly during our household survey. To elucidate community domains and determine differences in indigenous traditional knowledge of medicinal plants with anti-diabetic efficacy, we repeated our field survey starting from April 2008 to May 2010 with one hundred traditional healers locally called as "Chau ya" in Khampti of Lohit district. "Chau ya" traditional healers who know and use medicinal plants for treating diabetes mellitus were interviewed using a semi-structured questionnaire. RESULTS: This study reports an ethnobotanical survey of medicinal plants in Lohit district of Arunachal Pradesh reputed for the treatment of diabetes mellitus. Forty-six plant species were identified in the study area to treat diabetes mellitus by the Khamptis "Chau ya" traditional healers. Comparative published literature survey analysis of this study with other ethnobotanical surveys of plants used traditionally in treating diabetes mellitus suggests that eleven plant species make claims of new reports on antidiabetic efficacy. These plant species are Begonia roxburghii, Calamus tenuis, Callicarpa arborea, Cuscuta reflexa, Dillenia indica, Diplazium esculentum, Lectuca gracilis, Millingtonia hortensis, Oxalis griffithii, Saccharum spontaneum, and Solanum viarum. Some of the plants reported in this study have an antidiabetic effect on rodent models but none have sufficient clinical evidence of effectiveness. CONCLUSIONS: The wide variety of medicinal plants that are used to treat diabetes mellitus in this area supports the importance of plants in the primary healthcare system of the rural people of Lohit district of Arunachal Pradesh. The finding of new plant uses in the current study reveals the importance of the documentation of such ethnobotanical knowledge. PMID- 22433537 TI - [Now we are introducing the theme series as status articles]. PMID- 22433538 TI - [Denosumab--treatment of osteoporosis and cancer]. PMID- 22433539 TI - [Nutritional suggestion in heart insufficiency]. PMID- 22433540 TI - [Developments in sports medicine]. PMID- 22433541 TI - [Chemoembolization of liver metastasis]. PMID- 22433542 TI - [Treatment failure after anterior cruciate ligament reconstruction]. PMID- 22433543 TI - [Reprogramming of adult cells to neurons]. PMID- 22433544 TI - [PET/MR scanning]. PMID- 22433545 TI - [New Delhi-metallo-beta-lactamase 1--an unwanted souvenir]. PMID- 22433546 TI - [Renal denervation in patients with treatment-resistant hypertension]. PMID- 22433548 TI - [New-onset diabetes mellitus after kidney transplantation]. PMID- 22433549 TI - [Military psychiatry in Denmark]. PMID- 22433550 TI - [History of hemoglobin A 1c]. PMID- 22433551 TI - [JOPCAB and hybrid coronary intervention]. PMID- 22433552 TI - [New times for the treatment of chronic hepatitis C]. PMID- 22433553 TI - [Virologic safety of donor blood after NAT testing]. PMID- 22433554 TI - [Elbow hemiarthroplasty in fracture treatment]. PMID- 22433555 TI - [Clinical pathways for rehabilitation of adults with acquired brain injury]. PMID- 22433556 TI - [Ultrasound-guided peripheral venous access with focus on dynamic needle tip positioning]. PMID- 22433557 TI - [Municipal health services web-based tools]. PMID- 22433558 TI - [News from the Danish Society of Internal Medicine--the new DSIM ]. PMID- 22433559 TI - [Increased knowledge and use of pressure chamber therapy]. PMID- 22433560 TI - [Acupuncture and research]. PMID- 22433561 TI - [Rheumatology--a glimpse of a rapidly developing discipline]. PMID- 22433562 TI - Extravascular migration of a guide wire with perforation of the heart eight months after percutaneous coronary intervention: consequence of a conservative approach. AB - Impingement of a guide wire is not unusual during complex percutaneous coronary intervention procedures. It is mostly retrieved by endovascular procedures. If not possible, conservative therapy is frequently the next option, leaving the guide wire in place. This case describes the consequence of such an approach 9 months after initial percutaneous coronary intervention. The guide wire migrated through the abdominal cavity and finally perforated the heart. We therefore defend a more aggressive approach if a guide wire is locked in or lost. Surgical retrieval seems to be the best choice. Fixation of the guide wire with a stent is an acceptable alternative in high-risk patients. PMID- 22433563 TI - Kinetic study of batch and fed-batch enzymatic saccharification of pretreated substrate and subsequent fermentation to ethanol. AB - BACKGROUND: Enzymatic hydrolysis, the rate limiting step in the process development for biofuel, is always hampered by its low sugar concentration. High solid enzymatic saccharification could solve this problem but has several other drawbacks such as low rate of reaction. In the present study we have attempted to enhance the concentration of sugars in enzymatic hydrolysate of delignified Prosopis juliflora, using a fed-batch enzymatic hydrolysis approach. RESULTS: The enzymatic hydrolysis was carried out at elevated solid loading up to 20% (w/v) and a comparison kinetics of batch and fed-batch enzymatic hydrolysis was carried out using kinetic regimes. Under batch mode, the actual sugar concentration values at 20% initial substrate consistency were found deviated from the predicted values and the maximum sugar concentration obtained was 80.78 g/L. Fed batch strategy was implemented to enhance the final sugar concentration to 127 g/L. The batch and fed-batch enzymatic hydrolysates were fermented with Saccharomyces cerevisiae and ethanol production of 34.78 g/L and 52.83 g/L, respectively, were achieved. Furthermore, model simulations showed that higher insoluble solids in the feed resulted in both smaller reactor volume and shorter residence time. CONCLUSION: Fed-batch enzymatic hydrolysis is an efficient procedure for enhancing the sugar concentration in the hydrolysate. Restricting the process to suitable kinetic regimes could result in higher conversion rates. PMID- 22433564 TI - Implications of different CA 15-3 levels according to breast cancer subtype at initial diagnosis of recurrent or metastatic breast cancer. AB - BACKGROUND: CA 15-3 is derived from proteolytic shedding of the extracellular domain of mucin 1 (MUC1) glycoprotein. Luminal subtype breast cancer shows a higher expression in MUC1 genes, and a positive relationship between MUC1 expression and estrogen receptor (ER) expression has been reported. In this study, we attempted to determine the difference of CA 15-3 level according to the subtype of breast cancer. METHODS: From January 2000 to December 2009, a total of 707 patients who were diagnosed with metastatic or recurrent breast cancer at Samsung Medical Center were included in this study. Among these, 536 patients with available clinical data including pretreatment CA 15-3 and immunohistochemistry for ER, progesterone receptor (PgR) and hormone receptor 2 (HER2) were analyzed in this study. Patients were classified into 3 groups according to their receptor status: ER-positive (ER+) and/or PgR+ irrespective of HER2 (HR+), ER-/PgR-/HER2+ (HER2-enriched) and ER-/PgR-/HER2- (triple negative, TN). RESULTS: The supranormal values of CA 15-3 were frequently observed in HR+ breast cancer compared to other types (45.6% for HR+, 24.4% for HER2-enriched and 28.8% for TN; p < 0.001). The increase of marker levels differed significantly among the 3 groups (24 U/ml for HR+, 13 U/ml for HER2-enriched and 18 U/ml for TN; p < 0.001). CONCLUSIONS: The increase of both marker levels and the frequency of supranormal values of CA 15-3 were more frequently observed in HR+ breast cancer, which is positively associated with MUC1 expression. These results could potentially serve as a basis for expanding the clinical implications of CA 15-3 in the field of clinical trials for novel targeted therapies in breast cancer. PMID- 22433565 TI - PRAF3 induces apoptosis and inhibits migration and invasion in human esophageal squamous cell carcinoma. AB - BACKGROUND: Prenylated Rab acceptor 1 domain family member 3 (PRAF3) is involved in the regulation of many cellular processes including apoptosis, migration and invasion. This study was conducted to investigate the effect of PRAF3 on apoptosis, migration and invasion in human esophageal squamous cell carcinoma (ESCC). METHODS: The expression of PRAF3 mRNA and protein in primary ESCC and the matched normal tissues (57cases) was determined by quantitative RT-PCR and Western blot. Immunohistochemical analysis of PRAF3 expression was carried out in paraffin-embedded sections of ESCC and correlated with clinical features. The role of PRAF3 in apoptosis, migration and invasion was studied in ESCC cell lines of Eca109 and TE-1 through the adenovirus mediated PRAF3 gene transfer. The effect of PRAF3 on apoptosis was analyzed by annexin V-FITC assay. The regulation of PRAF3 on migration was determined by transwell and wounding healing assay, while the cellular invasion was analyzed by matrigel-coated transwell assay. RESULTS: We found that the expression of PRAF3 was significantly down-regulated in ESCC tissue compared with the matched normal tissue and was correlated with the clinical features of pathological grade, tumor stage and lymph node metastasis. Moreover, overexpression of PRAF3 induced cell apoptosis through both caspase-8 and caspase-9 dependent pathways, and inhibited cell migration and invasion by suppressing the activity of both MMP-2 and MMP-9 in human ESCC cell lines. CONCLUSIONS: Our data suggest that PRAF3 plays an important role in the regulation of tumor progression and metastasis and serves as a tumor suppressor in human ESCC. We propose that PRAF3 might be used as a potential therapeutic agent for human ESCC. PMID- 22433566 TI - EGF activates TTP expression by activation of ELK-1 and EGR-1 transcription factors. AB - BACKGROUND: Tristetraprolin (TTP) is a key mediator of processes such as inflammation resolution, the inhibition of autoimmunity and in cancer. It carries out this role by the binding and degradation of mRNA transcripts, thereby decreasing their half-life. Transcripts modulated by TTP encode proteins such as cytokines, pro-inflammatory agents and immediate-early response proteins. TTP can also modulate neoplastic phenotypes in many cancers. TTP is induced and functionally regulated by a spectrum of both pro- and anti-inflammatory cytokines, mitogens and drugs in a MAPK-dependent manner. So far the contribution of p38 MAPK to the regulation of TTP expression and function has been best described. RESULTS: Our results demonstrate the induction of the gene coding TTP (ZFP36) by EGF through the ERK1/2-dependent pathway and implicates the transcription factor ELK-1 in this process. We show that ELK-1 regulates ZFP36 expression by two mechanisms: by binding the ZFP36 promoter directly through ETS binding site (+ 883 to +905 bp) and by inducing expression of EGR-1, which in turn increases ZFP36 expression through sequences located between -111 and -103 bp. CONCLUSIONS: EGF activates TTP expression via ELK-1 and EGR-1 transcription factors. PMID- 22433567 TI - Continuous cyclic compressive loading modulates biological and mechanical properties of collagen hydrogels seeded with human chondrocytes. AB - PURPOSE: This study investigated the potential of cyclic compressive loading in the generation of in vitro engineered cartilaginous tissue with the aim of contributing to a better understanding of mechanical preconditioning and its possible role in further optimizing existing matrix-associated cartilage replacement procedures. METHODS: Human chondrocytes were harvested from 12 osteoarthritic knee joints and seeded into a type I collagen (col-I) hydrogel at low density (2 * 10(5) cells/ml gel). The cell-seeded hydrogel was condensed and cultivated under continuous cyclic compressive loading (frequency: 0.3 Hz; strain: 10%) for 14 days under standardized conditions. After retrieval, specimens were subject to staining, histomorphometric evaluation, gene expression analysis and biomechanical testing. RESULTS: Cellular morphology was altered by both stimulation and control conditions as was staining for collagen II (col-II). Gene expression measurements revealed a significant increase for col-II under either cultivation condition. No significant differences in col-I, aggrecan and MMP-13 gene expression profiles were found. The col-II/col-I mRNA ratio significantly increased under stimulation, whereas the biomechanical properties deteriorated under either cultivation method. CONCLUSIONS: Although the effects observed are small, mechanical preconditioning has demonstrated its potential to modulate biological properties of collagen hydrogels seeded with human chondrocytes. PMID- 22433568 TI - A new viscosupplement based on partially hydrophobic hyaluronic acid: a comparative study. AB - A novel partially hydrophobized derivative of hyaluronic acid (HYADD(r) 4), containing a low number of C16 side-chains per polysaccharide backbone, provides injectable hydrogels stabilized by side-chain hydrophobic interactions. The rheological properties of Hymovis(r), a physical hydrogel based on the hyaluronic acid derivative HYADD(r) 4, were evaluated using as reference a solution of the parent natural polysaccharide, hyaluronic acid. The rheological measurements were performed both in flow and oscillation regimes at the physiological frequency values of the knee, typically spanning the range from 0.5 Hz (walking frequency) to 3 Hz (running frequency). Moreover, the viscoelastic features of Hymovis(r) were compared with the market-available viscosupplementation products in view of its use in joint diseases.The different behavior of the investigated materials in crossover frequency measurements and in structure recovery experiments can be explained on the basis of the structural and dynamic properties of the polymeric systems. PMID- 22433569 TI - Plasma expander viscosity effects on red cell-free layer thickness after moderate hemodilution. AB - The objective of the study was to investigate the effects of plasma viscosity after hemodilution on the thickness of the erythrocyte cell free layer (CFL) and on the interface between the flowing column of erythrocytes and the vascular endothelium. The erythrocyte CFL thickness was measured in the rat cremaster muscle preparation. Plasma viscosity was modified in an isovolemic hemodilution, in which the systemic hematocrit (Hctsys) was lowered to 30%. The plasma expanders (PE) of similar nature and different viscosities were generated by glutaraldehyde polymerization of human serum albumin (HSA) at various molar ratios glutaraldehyde to HSA: (i) unpolymerized HSA; (ii) PolyHSA24:1, molar ratio = 24 and (iii) PolyHSA60:1, molar ratio = 60. The HSA viscosities determined at 200 s(-1) were 1.1, 4.2 and 6.0 dyn x cm(-2), respectively. CFL thickness, vessel diameter and blood flow velocity were measured, while volumetric flow, shear rate and stress were calculated. Hemodilution with PolyHSA60:1 increased plasma viscosity and the blood showed marked shear thinning behavior. CFL thickness decreased as plasma viscosity increased after hemodilution; thus the CFL thickness with HSA and PolyHSA24:1 increased compared to baseline. Conversely, the CFL thickness of PolyHSA60:1 was not different from baseline. Blood flow increased with both PolyHSA's compared to baseline. Wall shear rate and shear stress increased for PolyHSA60:1 compared to HSA and PolyHSA24:1, respectively. In conclusion, PE viscosity determined plasma viscosity after hemodilution and affected erythrocyte column hydrodynamics, changing the velocity profile, CFL thickness, and wall shear stress. This study relates the perfusion caused by PolyHSA60:1 to hemodynamic changes induced by the rheological properties of blood diluted with PolyHSA60:1. PMID- 22433570 TI - Assessment of oxidant susceptibility of red blood cells in various species based on cell deformability. AB - The present study was designed to investigate the oxidant susceptibility of red blood cells (RBC) from four species (echidna, human, koala, Tasmanian devil) based on changes in cellular deformability. These species were specifically chosen based on differences in lifestyle and/or biology associated with varied levels of oxidative stress. The major focus was the influence of superoxide radicals generated within the cell (phenazine methosulfate, PMS, 50 MUM) or in the extracellular medium (xanthine oxidase-hypoxanthine, XO-HX, 0.1 U/ml XO) on RBC deformability at various shear stresses (SS). RBC deformability was assessed by laser-diffraction analysis using a "slit-flow ektacytometer". Both superoxide generating treatments resulted in significant increases of methemoglobin for all species (p < 0.01), with Tasmanian devil RBC demonstrating the most sensitivity to either treatment. PMS caused impaired RBC deformability for all species, but vast interspecies variations were observed: human and koala cells exhibited a similar sigmoid-like response to SS, short-beaked echidna values were markedly lower and only increased slightly with SS, while Tasmanian devil RBC were extremely rigid. The effect of XO-HX on RBC deformability was less when compared with PMS (i.e., smaller increase in rigidity) with the exception of Tasmanian devil RBC which exhibited essentially no deformation even at the highest SS; Tasmanian devil RBC response to XO-HX was thus comparable to that observed with PMS. Our findings indicate that ektacytometry can be used to determine the oxidant susceptibility of RBC from different species which varies significantly among mammals representing diverse lifestyles and evolutionary histories. These differences in susceptibility are consistent with species-specific discrepancies between observed and allometrically-predicted life spans and are compatible with the oxidant theory of aging. PMID- 22433571 TI - Analysis of early embryonic great-vessel microcirculation in zebrafish using high speed confocal MUPIV. AB - In the developing cardiovascular system, hemodynamic vascular loading is critical for angiogenesis and cardiovascular adaptation. Normal zebrafish embryos with transgenically-labeled endothelial and red blood cells provide an excellent in vivo model for studying the fluid-flow induced vascular loading. To characterize the developmental hemodynamics of early embryonic great-vessel microcirculation in the zebrafish embryo, two complementary studies (experimental and numerical) are presented. Quantitative comparison of the wall shear stress (WSS) at the first aortic arch (AA1) of wild-type zebrafish embryos during two consecutive developmental stages is presented, using time-resolved confocal micro-particle image velocimetry (MUPIV). Analysis showed that there was significant WSS difference between 32 and 48 h post-fertilization (hpf) wild-type embryos, which correlates with normal arch morphogenesis. The vascular distensibility of the arch wall at systole and the acceleration/deceleration rates of time-lapse phase averaged streamwise blood flow curves were also analyzed. To estimate the influence of a novel intermittent red-blood cell (RBC) loading on the endothelium, a numerical two-phase, volume of fluid (VOF) flow model was further developed with realistic in vivo conditions. These studies showed that near-wall effects and cell clustering increased WSS augmentation at a minimum of 15% when the distance of RBC from arch vessel wall was less than 3 MUm or when RBC cell-to cell distance was less than 3 MUm. When compared to a smooth wall, the WSS augmentation increased by a factor of ~1.4 due to the roughness of the wall created by the endothelial cell profile. These results quantitatively highlight the contribution of individual RBC flow patterns on endothelial WSS in great vessel microcirculation and will benefit the quantitative understanding of mechanotransduction in embryonic great vessel biology, including arteriovenous malformations (AVM). PMID- 22433573 TI - Description of an Atlantic salmon (Salmo salar L.) type II interleukin-1 receptor cDNA and analysis of interleukin-1 receptor expression in amoebic gill disease affected fish. AB - Previously, we showed that IL-1beta transcription is induced in the gills of amoebic gill disease (AGD)-affected fish in an AGD lesion-restricted fashion. However, in this environment, there is very little evidence of inflammation on histopathological or transcriptional levels and we hypothesised that aberrant signalling may occur. As a first step in investigating this issue, we cloned and sequenced the Atlantic salmon IL-1 receptor type II (IL-1RII) mRNA, and then examined the expression of both the IL-1RI (IL-1 receptor-like protein) and II during Neoparamoeba perurans infection. In gill lesions from AGD-affected fish, a step-wise temporal increase in the relative expression of IL-1beta coincided with a significant reduction in IL-1RI, whereas the IL-1RII mRNA remained unchanged. Down-regulation of IL-1RI could explain the paucity of inflammation in affected tissue, although simultaneous up-regulation of IL-1beta-inducible transcripts indicated that this is not due to a complete blockage of the IL-1RI pathway. Rather, it appears that IL-1RI transcription is reduced and this rate limits the effects of chronic IL-1beta over-expression. PMID- 22433574 TI - A sigma-class glutathione S-transferase from Solen grandis that responded to microorganism glycan and organic contaminants. AB - Glutathione S-transferases (GSTs) are a superfamily of antioxidant enzymes, which play crucial roles in detoxification and protection of tissues from oxidative damage caused by reactive oxygen species (ROS). In this study, a sigma-class GST was identified from razor clam Solen grandis (designated as SgGST-S1), and its expression patterns, both in tissues and toward microorganism glycan as well as organic contaminants stimulation, were then characterized. The full-length cDNA of SgGST-S1 was of 1291 bp, containing a 5' untranslated region (UTR) of 27 bp, and a 3' UTR of 619 bp with a poly (A) tail. The open reading frame (ORF) was of 645 bp, encoding a polypeptide of 214 amino acids with the predicted molecular weight of 24.8 kDa, which shared 47% identity with GST from Ruditapes philippinarum. The analysis of conserved domain and phylogenetic relationship strongly suggested that SgGST-S1 was a member of sigma-class GST. The mRNA of SgGST-S1 was constitutively expressed in all tested tissues of healthy razor clam, including mantle, gill, gonad, hemocytes, muscle, and hepatopancreas, and it was highly expressed in hepatopancreas. The mRNA expression of SgGST-S1 in hemocytes was significantly up-regulated (P < 0.01) after razor clam was stimulated by peptidoglycan (PGN) or beta-1, 3-glucan, but not LPS. In addition, the SgGST-S1 transcript level was also significantly (P < 0.01) induced by exposure of benzo[a]pyrene (B[a]P) or Polybrominated Diphenyl Ethers (PBDE). All the results indicated that SgGST-S1 might serve as an antioxidant enzyme involving in the detoxification cause by both microorganism glycan and organic contaminants. PMID- 22433575 TI - Differentiation of multipotent adult germline stem cells derived from mouse testis into functional endothelial cells. AB - Pluripotent stem cells hold great promise for the treatment of cardiovascular disease. We previously described multipotent adult germline stem cells (maGSCs) from mouse testis with differentiation potential similar to embryonic stem cells. The aim of this work was to differentiate maGSCs into functional endothelial cells and to study their potential for vasculogenesis. MaGSCs were cocultivated with OP9 stromal cells to induce differentiation into cardiovascular progenitors, i.e. fetal liver kinase 1-positive (Flk-1+) cells. Five days later, Flk-1+ cells were separated using fluorescence-activated cell sorting, followed by cultivation on collagen type IV under endothelial differentiation conditions. At different time points, maGSC-derived endothelial-like cells were characterized using RT PCR, flow cytometry, immunofluorescence and functional assays. Cultivation of Flk 1+ cells resulted in the progressive upregulation of endothelial cell markers, including VE-cadherin, von Willebrand factor and endothelial nitric oxide synthase. Moreover, Flk-1+ maGSC-derived endothelial-like cells were able to branch and form networks in vitro and promoted functional blood vessel formation in vivo. Importantly, Flk-1+ cells retained their potential to proliferate and could be continuously expanded, while the ability of contact inhibition was preserved. Thus, maGSCs may provide a useful source of endothelial-like cells to study the basic mechanisms of vasculogenesis or endothelial differentiation. PMID- 22433576 TI - Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. AB - The Canadian Cardiovascular Society (CCS) published the complete set of 2010 Atrial Fibrillation (AF) Guidelines in the January, 2011 issue of the Canadian Journal of Cardiology. During its deliberations, the CCS Guidelines Committee engaged to a timely review of future evidence, with periodic composition of focused updates to address clinically important advances. In 2011, results were published from 3 pivotal AF trials: the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS), comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease risk-factor burden. Each of these large randomized trials provided clear results with major implications for AF management. Other important evidence that has emerged since the 2010 Guidelines includes findings about prediction instruments for AF-associated stroke and bleeding risk, stroke risk in paroxysmal-AF patients, risk-benefit considerations related to oral anticoagulation in patients with chronic kidney disease, and risk/benefit considerations in the use of antiplatelet agents, alone and in combination with each other or with oral anticoagulants, in AF patients. The Guidelines Committee judged that this extensive and important new evidence required focused updating of the 2010 Guidelines with respect to stroke prevention and rate/rhythm control. This report presents the details of the new recommendations, along with the background and rationale. PMID- 22433577 TI - Canadian Cardiovascular Society/Canadian Anesthesiologists' Society/Canadian Heart Rhythm Society joint position statement on the perioperative management of patients with implanted pacemakers, defibrillators, and neurostimulating devices. AB - There are more than 200,000 Canadians living with permanent pacemakers or implantable defibrillators, many of whom will require surgery or invasive procedures each year. They face potential hazards when undergoing surgery; however, with appropriate planning and education of operating room personnel, adverse device-related outcomes should be rare. This joint position statement from the Canadian Cardiovascular Society (CCS) and the Canadian Anesthesiologists' Society (CAS) has been developed as an accessible reference for physicians and surgeons, providing an overview of the key issues for the preoperative, intraoperative, and postoperative care of these patients. The document summarizes the limited published literature in this field, but for most issues, relies heavily on the experience of the cardiologists and anesthesiologists who contributed to this work. This position statement outlines how to obtain information about an individual's type of pacemaker or implantable defibrillator and its programming. It also stresses the importance of determining if a patient is highly pacemaker-dependent and proposes a simple approach for nonelective evaluation of dependency. Although the document provides a comprehensive list of the intraoperative issues facing these patients, there is a focus on electromagnetic interference resulting from electrocautery and practical guidance is given regarding the characteristics of surgery, electrocautery, pacemakers, and defibrillators which are most likely to lead to interference. The document stresses the importance of preoperative consultation and planning to minimize complications. It reviews the relative merits of intraoperative magnet use vs reprogramming of devices and gives examples of situations where one or the other approach is preferable. PMID- 22433578 TI - Fabrication and resistive switching characteristics of high compact Ga-doped ZnO nanorod thin film devices. AB - This study investigates the resistive switching behavior of Ga-doped ZnO (GZO) nanorod thin films with various Ga/Zn molar ratios. Vertically well-aligned and uniform GZO nanorod thin films were successfully grown on Au/Ti/SiO(2)/p-Si substrates using an aqueous solution method. X-ray diffraction (XRD) results indicate that GZO nanorods have [0001] highly preferred orientation. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations show the formation of highly ordered and dense nanorod thin films. These compact GZO nanorod thin films can be used to make resistive switching memory devices. Such memory devices can be reversibly switched between ON and OFF states, with a stable resistance ratio of ten times, narrow dispersion of ON and OFF voltages, and good endurance performance of over 100 cycles. The resistive switching mechanism in these devices is related to the formation and rupture of conducting filaments consisting of oxygen vacancies, occurring at interfaces between GZO nanorods (grain boundaries). Results show that the resulting compact GZO nanorod thin films have a high potential for resistive memory applications. PMID- 22433579 TI - Acute toxicity evaluation, antibacterial, antioxidant and immunomodulatory effects of Melastoma malabathricum. AB - Melastoma malabathricum (MM) is a well-known plant in Malaysian traditional medicine, locally known as senduduk. Its ethanol and aqueous extracts have been used in the present investigation to study the immunomodulatory role on human peripheral blood mononuclear cell (PBMC), and the DPPH, ABTS and FRAP free radical scavenging activities were also measured. Total flavonoids and total phenolic contents were assayed and the antibacterial effect was tested against four species of bacteria; two Gram-positive (Staphylococcus aureus and Streptococcus agalactiae) and two Gram-negative (Escherichia coli and Klebsilla pneumonia). The tests were carried out using the disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods. Moreover, the acute toxicity was evaluated in vivo on the ethanol extract of MM to establish its safety when administered orally. In our results, both extracts of MM showed abilities to scavenge DPPH and ABTS free radicals, IC(50) values: (11.599 +/- 0.84, 10.573 +/- 0.58 umol/L) and (62.657 +/- 0.78, 63.939 +/- 0.48 umol/L) for ethanol and aqueous extracts respectively. Indeed the ethanol extract evidenced high phenolic content (384.33 +/- 0.005 mg/g), flavonoids contents (85.8 +/- 0.009 mg/g) and ferric reducing antioxidant power (33,590 +/- 0.038 mmol/g), with high activity against S. aureus and S. agalactiae (11 +/- 0.3 and 12 +/- 0.6 mm inhibition zones). Likewise, the percentage of peripheral blood mononuclear cells (PBMC) viability was increased in response to MM, IC(50) values (1.781 +/- 1.2 and 6.545 +/- 0.93 ug/mL) for ethanol and aqueous extracts, respectively. In addition, our results showed that the MM extract is safe even at a high dose of 5,000 mg/kg and has no oral toxicity. These findings suggest the excellent medicinal bioactivity of MM and explain the popularity of this plant in the folk medicine as a remedy for different illnesses. PMID- 22433580 TI - Ultrastructure of book gill development in embryos and first instars of the horseshoe crab Limulus polyphemus L. (Chelicerata, Xiphosura). AB - BACKGROUND: The transmission electron microscope (TEM) is used for the first time to study the development of book gills in the horseshoe crab. Near the end of the nineteenth century the hypothesis was presented for homology and a common ancestry for horseshoe crab book gills and arachnid book lungs. The present developmental study and the author's recent ones of book gills (SEM) and scorpion book lungs (TEM) are intended to clarify early histological work and provide new ultrastructural details for further research and for hypotheses about evolutionary history and relationships. RESULTS: The observations herein are in agreement with earlier reports that the book gill lamellae are formed by proliferation and evagination of epithelial cells posterior to opisthosomal branchial appendages. A cartilage-like endoskeleton is produced in the base of the opisthosomal appendages. The lamellar precursor cells in the appendage base proliferate, migrate outward and secrete the lamellar cuticle from their apical surface. A series of external, posteriorly-directed lamellae is formed, with each lamella having a central channel for hemolymph and pillar-type space holders formed from cells of the opposed walls. This repeated, page-like pattern results also in water channels (without space holders) between the sac-like hemolymph lamellae. CONCLUSIONS: The developmental observations herein and in an earlier study (TEM) of scorpion book lungs show that the lamellae in book gills and book lungs result from some similar activities and features of the precursor epithelial cells: proliferation, migration, alignment and apical/basal polarity with secretion of cuticle from the apical surface and the basal surface in contact with hemolymph. These cellular similarities and the resulting book-like structure suggest a common ancestry, but there are also substantial developmental differences in producing these organs for gas exchange in the different environments, aqueous and terrestrial. For scorpion book lungs, the invaginated precursor cells align in rows and secrete rows of cell fragments that are the basis for the internal, anterior-directed air sacs. The hemolymph sacs of book gills are formed by epithelial evagination or outfolding from the posterior surface of the branchial appendages. PMID- 22433581 TI - Non-inferiority of short-term urethral catheterization following fistula repair surgery: study protocol for a randomized controlled trial. AB - BACKGROUND: A vaginal fistula is a devastating condition, affecting an estimated 2 million girls and women across Africa and Asia. There are numerous challenges associated with providing fistula repair services in developing countries, including limited availability of operating rooms, equipment, surgeons with specialized skills, and funding from local or international donors to support surgeries and subsequent post-operative care. Finding ways of providing services in a more efficient and cost-effective manner, without compromising surgical outcomes and the overall health of the patient, is paramount. Shortening the duration of urethral catheterization following fistula repair surgery would increase treatment capacity, lower costs of services, and potentially lower risk of healthcare-associated infections among fistula patients. There is a lack of empirical evidence supporting any particular length of time for urethral catheterization following fistula repair surgery. This study will examine whether short-term (7 day) urethral catheterization is not worse by more than a minimal relevant difference to longer-term (14 day) urethral catheterization in terms of incidence of fistula repair breakdown among women with simple fistula presenting at study sites for fistula repair service. METHODS/DESIGN: This study is a facility-based, multicenter, non-inferiority randomized controlled trial (RCT) comparing the new proposed short-term (7 day) urethral catheterization to longer term (14 day) urethral catheterization in terms of predicting fistula repair breakdown. The primary outcome is fistula repair breakdown up to three months following fistula repair surgery as assessed by a urinary dye test. Secondary outcomes will include repair breakdown one week following catheter removal, intermittent catheterization due to urinary retention and the occurrence of septic or febrile episodes, prolonged hospitalization for medical reasons, catheter blockage, and self-reported residual incontinence. This trial will be conducted among 512 women with simple fistula presenting at 8 study sites for fistula repair surgery over the course of 24 months at each site. DISCUSSION: If no major safety issues are identified, the data from this trial may facilitate adoption of short-term urethral catheterization following repair of simple fistula in sub-Saharan Africa and Asia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01428830. PMID- 22433582 TI - Inhibition of Epstein-Barr virus infection by lactoferrin. AB - Lactoferrin (LF) is a multifunctional glycoprotein that plays an important role in native immune defense against infections, including human herpetic viruses, such as cytomegalovirus and herpes simplex virus types 1 and 2. However, its anti Epstein-Barr virus (EBV, a gamma-herpesvirus) function has not been reported in the literature. EBV is widespread in all human populations and is believed to be linked to tumorigenesis, such as lymphomas and nasopharyngeal carcinoma (NPC). We previously reported that LF expressed a significantly lower level in NPC tissues and was a likely tumor suppressor. Since EBV infection is a major carcinogen of NPC development, we investigated the effect of LF on EBV infection and found that LF could protect human primary B lymphocytes and nasopharyngeal epithelial cells from EBV infection, but had no effect on EBV genome DNA replication. LF prevented EBV infection of primary B cells mediated by its direct binding to the EBV receptor (CD21) on the B-cell surface. Tissue array immunohistochemistry revealed that LF expression was significantly downregulated in NPC specimens, in which high EBV viral capsid antigen-IgA levels were observed. These data suggest that LF may inhibit EBV infection and that its downregulation could contribute to NPC development. PMID- 22433583 TI - Controversy on virus designation: Alkhumra sive Alkhurma hemorrhagic fever flavivirus. PMID- 22433584 TI - Antioxidant administration prevents memory impairment in an animal model of maple syrup urine disease. AB - Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder resulting from deficiency of branched-chain alpha-keto acid dehydrogenase complex leading to branched chain amino acids (BCAA) leucine, isoleucine, and valine accumulation as well as their corresponding transaminated branched-chain alpha keto acids. MSUD patients present neurological dysfunction and cognitive impairment. Here, we investigated whether acute and chronic administration of a BCAA pool causes impairment of acquisition and retention of avoidance memory in young rats. We have used two administration protocols. Acute administration consisted of three subcutaneous administrations of the BCAA pool (15.8 MUL/g body weight at 1-h intervals) containing 190 mmol/L leucine, 59 mmol/L isoleucine, and 69 mmol/L valine or saline solution (0.85% NaCl; control group) in 30 days old Wistar rats. Chronic administration consisted of two subcutaneous administrations of BCAA pool for 21 days in 7 days old Wistar rats. N-acetylcysteine (NAC; 20 mg/kg) and deferoxamine (DFX; 20 mg/kg) co administration influence on behavioral parameters after chronic BCAA administration was also investigated. BCAA administration induced long-term memory impairment in the inhibitory avoidance and CMIA (continuous multiple-trials step-down inhibitory avoidance) tasks whereas with no alterations in CMIA retention memory. Inhibitory avoidance alterations were prevented by NAC and DFX. BCAA administration did not impair the neuropsychiatric state, muscle tone and strength, and autonomous function evaluated with the SHIRPA (SmithKline/Harwell/ImperialCollege/RoyalHospital/Phenotype Assessment) protocol. Taken together, our results indicate that alterations of motor activity or emotionality probably did not contribute to memory impairment after BCAA administration and NAC and DFX effects suggest that cognition impairment after BCAA administration may be caused by oxidative brain damage. PMID- 22433585 TI - Impaired auditory discrimination learning following perinatal nicotine exposure or beta2 nicotinic acetylcholine receptor subunit deletion. AB - Maternal smoking during pregnancy can impair performance of the exposed offspring in tasks that require auditory stimulus processing and perception; however, the tobacco component(s) responsible for these effects and the underlying neurobiological mechanisms remain uncertain. In this study, we show that administration of nicotine during mouse perinatal development can impair performance in an auditory discrimination paradigm when the exposed animals are mature. This suggests that nicotine disrupts auditory pathways via nicotinic acetylcholine receptors (nAChRs) that are expressed at an early stage of development. We have also determined that mice which lack nAChRs containing the beta2 subunit (beta2* nAChRs) exhibit similarly compromised performance in this task, suggesting that beta2* nAChRs are necessary for normal auditory discrimination or that beta2* nAChRs play a critical role in development of the circuitry required for task performance. In contrast, no effect of perinatal nicotine exposure or beta2 subunit knockout was found on the acquisition and performance of a differential reinforcement of low rate task. This suggests that the auditory discrimination impairments are not a consequence of a general deficit in learning and memory, but may be the result of compromised auditory stimulus processing in the nicotine-exposed and knockout animals. PMID- 22433586 TI - Evaluation of clinically significant adverse events in patients discharged from a tertiary-care emergency department in Taiwan. AB - OBJECTIVE: To investigate the reasons for the occurrence of clinically significant adverse events (CSAEs) in emergency department-discharged patients through emergency physicians' (EPs) subjective reasoning and senior EPs' objective evaluation. DESIGN: This was a combined prospective follow-up and retrospective review of cases of consecutive adult non-traumatic patients who presented to a tertiary-care emergency department in Taiwan between 1 September 2005 and 31 July 2006. Data were extracted from 'on-duty EPs' subjective reasoning for discharging patients with CSAEs (study group) and without CSAEs (control group)' and 'objective evaluation of CSAEs by senior EPs, using clinical evidences such as recording history, physical examinations, laboratory/radiological examinations and observation of inadequacies in the basic management process (such as recording history, physical examinations, laboratory/radiological examinations and observation) as the guide'. Subjective reasons for discharging patients' improvement of symptoms, and the certainty of safety of the discharge were compared in the two groups using chi(2) statistics or t test. RESULTS: Of the 20,512 discharged cases, there were 1370 return visits (6.7%, 95% CI 6.3% to 7%) and 165 CSAEs due to physicians' factors (0.82%, 95% CI 0.75% to 0.95%). In comparisons between the study group and the control group, only some components of discharge reasoning showed a significant difference (p<0.001). Inadequacies in the basic management process were the main cause of CSAEs (164/165). CONCLUSION: The authors recommended that EP follow-up of the basic management processes (including history record, physical examination, laboratory and radiological examinations, clinical symptoms/signs and treatment) using clinical evidence as a guideline should be made mandatory. PMID- 22433587 TI - Learning and retention of emergency first aid skills in a violent, developing South African township. AB - Community members in developing areas can effectively learn first responder training, and skill decay afterwards is not continuous. It is critical that training be done in the trainees' primary language, even if they speak other languages fluently. Making first responder training obligatory for employees and students may be an effective way to generate first responders. PMID- 22433588 TI - National standards in prehospital resuscitation training are required. PMID- 22433589 TI - Management of distal radius fractures in emergency departments in England and Wales. AB - AIMS: To examine variations and consistencies in the emergency management of distal radial fractures across England and Wales. METHODS: A survey was conducted of emergency departments (ED) in England and Wales regarding the acute management of patients with distal radius fractures. The study investigated the use of anaesthesia, the person performing both the anaesthetic and the manipulation, the use of resuscitation facilities and monitoring, the cast applied, the follow-up and the management of complex injuries or those in younger patients. RESULTS: Surveys were conducted in 105 units, giving a response rate of 91% of ED in England and Wales. The most frequent anaesthetic types were haematoma block (50%), intravenous benzodiazepines (20%), Bier's block (17%) and a small minority using other techniques such as brachial plexus blocks (2%). Basic cardiorespiratory monitoring was variable, and 10% of trusts did not routinely monitor patients undergoing Bier's blocks or manipulation with sedatives. Only 50% of ED would manipulate comminuted fractures or fractures in young adult patients. CONCLUSION: There are significant regional variations. The use of monitoring is highly variable and there are no consistent standards when administering potentially potent anaesthetic medications. The low percentage of units attempting reduction of complex fractures or fractures in young patients will disadvantage training in ED as well as patients. Guidelines are required to improve care, which is highly inconsistent at present. PMID- 22433590 TI - Decision-making by ambulance clinicians in London when managing patients with epilepsy: a qualitative study. AB - BACKGROUND: In the UK, epilepsy is the neurological condition with the highest rate of accident and emergency department re-attendance, with most arriving by ambulance. Ambulance clinicians triage patients and assess their need for attendance. This study examined the decision-making process of ambulance clinicians in these situations. METHODS: In-depth interviews with 15 ambulance clinicians working in South London. RESULTS: Interviewees identified that epileptic seizures that self-resolve present a triage challenge. They reported insufficient training and guidance available for these situations and substantial reliance on experience to direct their practice. Fears of litigation in the event of complications, pressures of public expectation and limited on-scene access to relevant patient information or appropriate alternative care pathways were reported to be significant factors influencing decisions for care for epilepsy seizures. DISCUSSION: Ambulance clinicians reported negotiating a balance between patient safety and patient choice, when deciding whether to transport a patient with epilepsy to hospital or not. Clinician fears and the pressures and limitations of practice may result in hospital conveyance being used as a safety precaution in some instances. CONCLUSIONS: Decisions regarding conveyance of patients with epilepsy in this study were substantially guided by ambulance clinician experience rather than by robust training and guidelines. This study supports the need for improved guidance that addresses this common area of practice and the development of alternative care pathways that may be used by ambulance clinicians for patients with epilepsy. PMID- 22433591 TI - Fever and neck pain in a paraplegic patient. PMID- 22433592 TI - Preparedness to care for victims of violence and their families in emergency departments. AB - OBJECTIVE: To describe the preparedness to provide care for victims of violence and their families in emergency departments (EDs) in Sweden. METHODS: A web-based questionnaire was sent to all hospital EDs in Sweden (N=66). RESULTS: A total of 46 out of 66 (70%) heads of EDs completed the questionnaire. The results show that most of the EDs are prepared to care for women and children who are victims of violence. However, there seems to be a lack of preparedness to care for other groups of patients, such as victimised men. Very few EDs have routines to identify victims of violence among patients. Results also indicate that nurses play a key role in the care for victims of violence; however, family members are rarely included in care. CONCLUSIONS: A lack of general preparedness in EDs to care for all victims of violence, regardless of gender and age, can lead to many patients not receiving appropriate care and treatment. To correct this there is a need to implement guidelines and routines about the care for victims of violence. Further research can shed more light on which measures are needed to improve quality of care for these patients and their families. PMID- 22433593 TI - Human African trypanosomiasis in travellers to Kenya. PMID- 22433594 TI - Trypanosoma brucei rhodesiense infection in a German traveller returning from the Masai Mara area, Kenya, January 2012. AB - In January 2012, a case of Human African Trypanosomiasis (HAT) has been identified in Germany in a traveller returning from the Masai Mara area in Kenya. The 62-year-old man had travelled to the Masai Mara game park from 18 to 19 January 2012 and developed fever on 28 January. The infection with Trypanosoma brucei rhodesiense was confirmed by laboratory testing three days hereafter. PMID- 22433595 TI - Human African trypanosomiasis in a Belgian traveller returning from the Masai Mara area, Kenya, February 2012. AB - A Belgian traveller was diagnosed with human African trypanosomiasis (HAT) due to Trypanosoma brucei rhodesiense nine days after visiting the Masai Mara area in Kenya. He presented with an inoculation chancre and was treated with suramin within four days of fever onset. Two weeks earlier, HAT was also reported in a German traveller who had visited the Masai Mara area. Because no cases have occurred in the area for over 12 years, this may indicate a focal cluster of HAT. PMID- 22433596 TI - Rabid puppy-dog imported into the Netherlands from Morocco via Spain, February 2012. AB - In February 2012 a rabid puppy dog was imported into Amsterdam, the Netherlands from Morocco via Spain. In a joint action between the Netherlands' Food and Consumer Product Safety Authority, the Public Health Service of Amsterdam and the Centre for Infectious Disease Control all exposed human and animal contacts were traced and, when necessary, provided with post-exposure prophylaxis. During the importation, the international legislations with respect to vaccination requirements were not fully obeyed by veterinarians and custom services. PMID- 22433597 TI - Increased reports of Mycoplasma pneumoniae from laboratories in Scotland in 2010 and 2011 - impact of the epidemic in infants. AB - In common with reports from other European countries, we describe a substantial increase in the number of laboratory reports of Mycoplasma pneumoniae in Scotland in 2010 and 2011. The highest number of reports came from those aged one year and younger. However, reports from young children were more likely to come from PCR testing than serological testing. PMID- 22433598 TI - Letter to the editor: commitment needed for the prevention of congenital rubella syndrome in Europe. PMID- 22433599 TI - The European Union summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in 2010. PMID- 22433602 TI - Breast-feeding in infancy and major depression in adulthood: a retrospective analysis. PMID- 22433603 TI - The optimal dose of omega-3 supplementation for non-alcoholic fatty liver disease. PMID- 22433604 TI - Rare statin hepatotoxicity: convincing evidence based on breakthrough case study. PMID- 22433606 TI - miR-127-5p targets the 3'UTR of human beta-F1-ATPase mRNA and inhibits its translation. AB - The mitochondrial H(+)-ATP synthase is a bottleneck component in the provision of metabolic energy by oxidative phosphorylation. The expression of its catalytic subunit (beta-F1-ATPase) is stringently controlled at post-transcriptional levels during oncogenesis, the cell cycle and in development. Here we show that miR-127 5p targets the 3'UTR of beta-F1-ATPase mRNA (beta-mRNA) significantly reducing its translational efficiency without affecting beta-mRNA abundance. Despite the reduced expression of beta-F1-ATPase in most human carcinomas, we observed no expression of miR-127-5p in different human cancer cell lines, minimizing the potential role of miR-127-5p as a regulator of the bioenergetic activity of mitochondria in cancer. In contrast, miR-127-5p is highly over-expressed in the human fetal liver. Consistent with previous findings in the rat, the expression of beta-F1-ATPase in the human liver also seems to be controlled at post transcriptional levels during development, what might suggest a role for miR-127 5p in controlling beta-mRNA translation and thus in defining the bioenergetic activity of human liver mitochondria. Moreover, immunolocalization techniques and subcellular fractionation experiments using different antibodies against beta-F1 ATPase reveal that the ectopic expression of beta-F1-ATPase at the cell surface of the hepatocytes and HepG2 cells is negligible or stands for scrutiny. PMID- 22433607 TI - Compensatory upregulation of respiratory chain complexes III and IV in isolated deficiency of ATP synthase due to TMEM70 mutation. AB - Early onset mitochondrial encephalo-cardiomyopathy due to isolated deficiency of ATP synthase is frequently caused by mutations in TMEM70 gene encoding enzyme specific ancillary factor. Diminished ATP synthase results in low ATP production, elevated mitochondrial membrane potential and increased ROS production. To test whether the patient cells may react to metabolic disbalance by changes in oxidative phosphorylation system, we performed a quantitative analysis of respiratory chain complexes and intramitochondrial proteases involved in their turnover. SDS- and BN-PAGE Western blot analysis of fibroblasts from 10 patients with TMEM70 317-2A>G homozygous mutation showed a significant 82-89% decrease of ATP synthase and 50-162% increase of respiratory chain complex IV and 22-53% increase of complex III. The content of Lon protease, paraplegin and prohibitins 1 and 2 was not significantly changed. Whole genome expression profiling revealed a generalized upregulation of transcriptional activity, but did not show any consistent changes in mRNA levels of structural subunits, specific assembly factors of respiratory chain complexes, or in regulatory genes of mitochondrial biogenesis which would parallel the protein data. The mtDNA content in patient cells was also not changed. The results indicate involvement of posttranscriptional events in the adaptive regulation of mitochondrial biogenesis that allows for the compensatory increase of respiratory chain complexes III and IV in response to deficiency of ATP synthase. PMID- 22433608 TI - Cytotoxicity of a mitochondriotropic quercetin derivative: mechanisms. AB - The mitochondriotropic compound 7-O-(4-triphenylphosphoniumbutyl)quercetin iodide (Q-7BTPI) in the MUM concentration range caused necrotic death of cultured cells by acting as a prooxidant, with generation of superoxide anion in the mitochondria. Externally added membrane-permeating superoxide dismutase or catalase largely prevented death. Rescue by permeant catalase indicates that the toxicant is H(2)O(2), or reactive species derived from it. Rescue by permeant dismutase suggests the possibility of a chain mechanism of H(2)O(2) production, in which dismutation of superoxide constitutes a termination step. Oxidative stress was due to the presence of free phenolic hydroxyls and to accumulation in mitochondria, since the analogous mitochondriotropic per-O-methylated compound 3,3',4',5-tetra-O-methyl,7-O-(4-triphenylphosphoniumbutyl) quercetin iodide (QTM 7BTPI)-or Quercetin itself induced no or little superoxide production and cell death. Q-7BTPI did not cause a significant perturbation of the mitochondrial transmembrane potential or of respiration in cells. On the other hand its presence led to inhibition of glutathione peroxidase, an effect expected to accentuate oxidative stress by interfering with the elimination of H(2)O(2). An exogenous permeable glutathione precursor determined a strong increase of cellular glutathione levels but did not rescue the cells. Death induction was selective for fast-growing C-26 tumoral cells and mouse embryonic fibroblasts (MEFs) while sparing slow-growing MEFs. This suggests a possible use of Q-7BTPI as a chemotherapeutic agent. PMID- 22433609 TI - Compensatory brain activity during encoding among older adults with better recognition memory for face-name pairs: an integrative functional, structural, and perfusion imaging study. AB - Many neuroimaging studies interpret the commonly reported findings of age-related increases in frontal response and/or increased bilateral activation as suggestive of compensatory neural recruitment. However, it is often unclear whether differences are due to compensation or reflective of other cognitive or physiological processes. This study aimed to determine whether there are compensatory age-related changes in brain systems supporting successful associative encoding while taking into account potentially confounding factors including age-related differences in task performance, atrophy, and resting perfusion. Brain response during encoding of face-name pairs was measured using functional magnetic resonance imaging in 10 older and nine young adults and was correlated with memory performance. During successful encoding, older adults demonstrated increased frontal and decreased occipital activity as well as greater bilateral involvement relative to the young. Findings remained significant after controlling for age-related cortical atrophy and hypoperfusion. Among the older adults, greater response was associated with better memory performance. Cognitive aging may involve recruitment of compensatory mechanisms to improve performance or prevent impairment. Results extend previous findings by suggesting that age-related alterations in activation cannot be attributed to the commonly observed findings of poorer task performance, reduced resting perfusion, or cortical atrophy among older adults. PMID- 22433610 TI - Roflumilast: a novel treatment for chronic obstructive pulmonary disease. AB - OBJECTIVE: To evaluate the efficacy and safety of roflumilast, approved by the Food and Drug Administration in February 2011 as a treatment to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DATA SOURCES: Literature was retrieved through MEDLINE (1977-December 2011), using the terms roflumilast and COPD. In addition, US government Web sites, including clinicaltrials.gov and fda.gov, were reviewed for pertinent information. Lastly, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated. For the evaluation of clinical efficacy and safety, only Phase 3 studies were included. DATA SYNTHESIS: Limited treatment options are available for patients with moderate-to-severe COPD and repeated exacerbations. In 6 published Phase 3 trials to date, roflumilast 500 MUg daily exhibited modest improvements in lung function, measured by pre- and postbronchodilator forced expiratory volume in 1 second, and reduced rates of moderate and severe exacerbations. Roflumilast was generally well tolerated, with diarrhea, nausea, and headache the most common adverse events seen in clinical trials, although it has also been associated with an increased risk of neuropsychiatric abnormalities and dose-limiting weight loss. The greatest benefit seen with roflumilast was among patients with moderate-to-severe COPD associated with chronic bronchitis along with a recent history of exacerbations. The benefits were demonstrated with monotherapy and in combination with long acting beta(2)-agonists or anticholinergic agents. CONCLUSIONS: Despite its only modest benefits in improving lung function and reducing exacerbation rates, roflumilast serves as a safe and effective option in the treatment of COPD. PMID- 22433611 TI - Dapagliflozin for the treatment of type 2 diabetes. AB - OBJECTIVE: To review the literature and describe the pharmacologic, pharmacokinetic, and pharmacodynamic properties; clinical safety; and efficacy of dapagliflozin, a new drug currently under review by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes. DATA SOURCES: A MEDLINE (1995-November 2011) and ClinicalTrials.gov search was conducted using the terms dapagliflozin, sodium-glucose cotransporter 2 inhibitor, and SGLT2 inhibitor. Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language studies, including abstracts, evaluating dapagliflozin use in humans were included in this review. DATA SYNTHESIS: Dapagliflozin is the first-in-class oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that represents a new potential therapeutic option for the treatment of type 2 diabetes mellitus. Its mechanism of action is insulin- and insulin-sensitivity independent. Preliminary data suggest that dapagliflozin decreases hemoglobin A(1c), fasting plasma glucose, and postprandial plasma glucose, while also promoting weight loss. In Phase 1, 2, and 3 clinical trials, dapagliflozin has exhibited a safety and tolerability profile similar to that of placebo. CONCLUSIONS: Dapagliflozin is a novel oral antihyperglycemic agent that has demonstrated promise as monotherapy and as synergistic combination therapy with currently available agents in Phase 3 clinical trials. On January 19, 2012, the FDA issued a complete response letter to AstraZeneca and Bristol-Myers Squibb regarding the new drug application for dapagliflozin. The FDA is requesting additional clinical data-from ongoing studies and potentially new clinical trials-to better describe the risk-benefit profile of the drug. Both manufacturers remain committed to the development of dapagliflozin, and there are currently 8 Phase 3 trials ongoing. Dapagliflozin has the potential to be the next new oral agent in the diabetes drug armamentarium. PMID- 22433612 TI - Overweight prevention implemented by primary school teachers: a randomised controlled trial. AB - OBJECTIVE: To describe the effects of URMEL-ICE, a German school-based intervention for overweight prevention, on children's BMI and other measures of fat mass. METHODS: A cluster-randomised controlled design was used. The intervention which focused on physical activity, TV time and soft drink consumption was integrated into a second-grade curriculum and was implemented by classroom teachers themselves. It comprised 29 teaching lessons, 2 short exercise blocks per day and 6 family homework lessons. BMI was assessed as primary outcome measure, waist circumference and skinfold thickness as secondary outcomes. Data of 945 children were analysed. RESULTS: Multivariate analyses adjusted for baseline values showed no statistically significant effect of the intervention on BMI, but on waist circumference (-0.85; 95% confidence interval (95% CI) -1.59 to -0.12) and subscapular skinfold thickness (-0.64; 95% CI -1.25 to -0.02). After additional adjustment for individual time lag between baseline and follow-up, these effects were reduced to -0.60 (95% CI -1.25 to 0.05) and -0.61 (95% CI 1.26 to 0.04) and lost their statistical significance. CONCLUSION: This study contributes to the field of randomised school-based studies on overweight prevention and shows that within a 1-year, integrated intervention no effect on BMI, but a tendency towards effects on fat mass can be achieved. PMID- 22433613 TI - Hypocaloric diet and regular moderate aerobic exercise is an effective strategy to reduce anthropometric parameters and oxidative stress in obese patients. AB - BACKGROUND: Studies show that diet and exercise are important in the treatment of obesity. The aim of this study was to determine whether additional regular moderate aerobic exercise during a treatment with hypocaloric diet has a beneficial effect on oxidative stress and molecular damage in the obese patient. METHODS: Oxidative stress of 16 normal-weight (NW) and 32 obese 1 (O1) subjects (BMI 30-34.9 kg/m(2)) were established by biomarkers of oxidative stress in plasma. Recombinant human insulin was incubated with blood from NW or O1 subjects, and the molecular damage to the hormone was analyzed. Two groups of treatment, hypocaloric diet (HD) and hypocaloric diet plus regular moderate aerobic exercise (HDMAE), were formed, and their effects in obese subjects were analyzed. RESULTS: The data showed the presence of oxidative stress in O1 subjects. Molecular damage and polymerization of insulin was observed more frequently in the blood from O1 subjects. The treatment of O1 subjects with HD decreased the anthropometric parameters as well as oxidative stress and molecular damage, which was more effectively prevented by the treatment with HDMAE. CONCLUSION: HD and HDMAE treatments decreased anthropometric parameters, oxidative stress, and molecular damage in O1 subjects. PMID- 22433614 TI - Differences in aerobic fitness and lifestyle characteristics in preschoolers according to their weight status and sports club participation. AB - OBJECTIVE: This study assesses differences in adiposity, aerobic fitness, and lifestyle characteristics in preschoolers according to their weight status and sports club (SC) participation. METHOD: As part of the Ballabeina study, 600 randomly selected preschoolers (mean age 5.1 +/- 0.6 years; 50.2% girls) were analyzed. Body composition was measured by bioelectrical impedance, aerobic fitness by the 20-meter shuttle run test, and physical activity by accelerometers. Eating habits, media use, and SC participation were assessed by questionnaires. RESULTS: Overweight children (Swiss national percentiles) and children not participating in SC had both lower aerobic fitness and higher % body fat compared to their respective counterparts (all p <= 0.028). In addition, children not participating in SC were less physically active, had more media use, and ate less healthy compared to children participating in SC (all p <= 0.023). Controlling for parental sociocultural determinants attenuated differences in % body fat, in physical activity, and in eating habits. CONCLUSION: Aerobic fitness differs both according to weight status and SC participation in preschoolers. Furthermore, in view of the many differences in lifestyle behaviors, SC participation at this age could represent a more discriminatory indicator of healthy lifestyle characteristics than weight status. PMID- 22433615 TI - Importance of age for 3-year continuous behavioral obesity treatment success and dropout rate. AB - OBJECTIVE: To assess whether first year weight loss, age, and socioeconomic background correlate with the success rate of continuous long-term behavioral obesity treatment. METHODS: In a 3-year longitudinal study, obese children (n = 684) were divided into three groups based on age at the start of treatment, age 6 9 years, 10-13 years, and 14-16 years. RESULTS: The mean BMI standard deviation score (BMI-SDS) decline was age-dependent (p = 0.001), independently of adjustment for missing data: -1.8 BMI-SDS units in the youngest, -1.3 in the middle age group, and -0.5 in the oldest age group. SES and parental BMI status did not affect the results. 30% of the adolescents remained in treatment at year 3. There was only a weak correlation between BMI-SDS change after 1 and 3 years: r = 0.51 (p < 0.001). Among children with no BMI-SDS reduction during year 1 (n = 46), 40% had a clinically significantly reduced BMI-SDS after year 3. CONCLUSION: Behavioral treatment should be initiated at an early age to increase the chance for good results. Childhood obesity treatment should be continued for at least 3 years, regardless of the initial change in BMI-SDS. PMID- 22433616 TI - Identification of the translation start site of the human melanocortin 3 receptor. AB - BACKGROUND: The melanocortin-3-receptor (MC3R) is a G-protein coupled receptor participating in hypothalamic energy metabolism. So far, it was assumed that the translation of the human MC3R starts at the non-conserved first ATG, however, a second evolutionary conserved ATG is located 37 amino acids downstream. One frequent polymorphism, T6K, is located between these two ATGs. METHODS: For characterization of the two potential start ATGs, COS-7 cells were transfected with plasmids encoding the longer and the shorter form of the human MC3R. For signal transduction properties, cAMP was measured. Cell surface expression was determined by using an ELISA method. The translational start point of the MC3R was investigated by a GFP-based method. RESULTS: Signal transduction was comparable for the long and the short receptor form. Cell surface expression via aminoterminal hemagglutinin tag could only be detected in the shorter form, but not in the longer one. In our study we show that the translation of the human MC3R protein starts at the evolutionary conserved ATG codon which results in a shorter protein than previously assumed. CONCLUSION: The polymorphism T6K is not located in the coding region of the human MC3R and has no influence on translation initiation which makes an impact on body weight unlikely. PMID- 22433617 TI - Olive oil consumption, BMI, and risk of obesity in Spanish adults. AB - BACKGROUND: Olive oil is an energy-dense food frequently consumed in south European countries with increasingly high obesity prevalence. Evidence of the impact of olive oil consumption on BMI and the risk of obesity is limited. We analyzed this association taking into consideration the problem of energy underreporting. METHODS: Cross-sectional data on 6,352 Spanish adults were analyzed. Dietary intake was assessed using a validated food frequency questionnaire. Height and weight were measured. RESULTS: Higher olive oil consumption was not associated with energy compensation in the overall diet. Olive oil consumption was positively associated (p < 0.004) with BMI in non energy-adjusted multivariate linear regression models. Statistical significance of this association disappeared after controlling for energy intake in plausible energy intake reporters. The obesity risk increased for olive oil consumption of more than 2 tablespoons/day in both plausible energy intake reporters (odds ratio 1.30 (95% CI 1.01-1.70)) and energy intake underreporters (odds ratio 3.06 (95% CI 2.15-4.35)). This association was not significant after additional adjustment for energy intake (odds ratio 1.19 (95% CI 0.91-1.56)) in plausible energy intake reporters. CONCLUSION: Olive oil intake did not affect BMI and the risk of obesity after adjustment for total energy intake in plausible energy intake reporters. The lack of energy intake compensation for olive oil consumption might explain the positive associations in models not adjusted for energy. PMID- 22433618 TI - Obesity-independent inverse association between regular alcohol consumption and hemoglobin A(1C). AB - OBJECTIVE: The aim of this study was to determine whether obesity influences relationships between habitual alcohol drinking and hemoglobin A(1C) (HbA(1C)) level. METHODS: Japanese men (35-70 years old, n = 24858) were divided into non-, light (<22 g ethanol/day), moderate (>=22 and <44 g ethanol/day), and heavy (>=44 g ethanol/day) drinkers. Relationships of alcohol with HbA(1C) were investigated in overall subjects and subjects of quartile groups for degree of obesity. RESULTS: HbA(1C) tended to be higher as quartiles of BMI and waist-to-height ratio increased. HbA(1C) was significantly lower in light, moderate and heavy drinkers than in nondrinkers. These associations in overall subjects were also found in all of the quartiles of BMI and waist-to-height ratio, except for light drinkers in the 3rd and 4th quartiles of BMI and the 4th quartile of waist-to height ratio. Odds ratios versus nondrinkers for high HbA(1C) were significantly lower than a reference level of 1.0 in all drinker groups, and these associations were not altered after adjustment for age, history of smoking, and BMI or waist to-height ratio. CONCLUSION: The results suggest that alcohol consumption is associated with lower HbA(1C) level independent of degree of obesity. PMID- 22433619 TI - Insulin sensitivity deteriorates after short-term lifestyle intervention in the insulin sensitive phenotype of obesity. AB - OBJECTIVE: To investigate the effects of a 3-month lifestyle intervention on insulin sensitivity and its related cardiometabolic factors in obese patients. METHODS: Anthropometry, body composition, oral glucose tolerance test, lipids, alanine aminotransferase, insulin sensitivity (insulinogenic index (ISI), homeostasis model assessment, beta-cell performance (disposition index)) were evaluated in 263 obese women and 93 obese men before and after 3 months of hypocaloric low fat/high protein diet associated with physical activity 30 min/day. RESULTS: Patients were divided into 3 groups according to the intervention-induced ISI changes: group 1 (decrease), group 2 (stability) and group 3 (increase). Insulin sensitivity and the disposition index were significantly higher before the intervention in group 1 than in group 3. BMI, waist circumference, and fat mass significantly decreased in groups 1 and 3 in both sexes. beta-cell performance decreased in group 1 and increased in group 3. Metabolic variables improved in group 3, whereas glucose levels increased in women of group 1. The post-intervention insulin sensitivity was lower in group 1 than in group 3. CONCLUSION: Lifestyle intervention induces changes in insulin sensitivity and metabolic factors that depend on the pre-intervention degree of insulin sensitivity. Weight loss leads to metabolic benefits in insulin resistant, obese patients, whereas it may paradoxically worsen the metabolic conditions in the insulin-sensitive phenotype of obesity. PMID- 22433620 TI - Body fat percentiles for German children and adolescents. AB - OBJECTIVE: The aim of this study was to define body fat percentiles for German children and adolescents aged 3-16 years using the largest German database. METHODS: The study population included 11,632 girls and 11,604 boys. Data were pooled from: i) Kiel Obesity Prevention Study (KOPS), acquisition period: 1996 2008, n = 12,237; ii) 'Better diet. More exercise. KINDERLEICHT-REGIONS', acquisition period: 2007, n = 9,405; and iii) examination of Jena schoolchildren, acquisition period: 2005, n = 1,594. Body fat mass was measured by bioelectrical impedance analysis using a population-specific algorithm. Data were weighted to achieve a representative sample for Germany. Percentile curves were constructed by the LMS method and proved by Worm plots and Q-statistic. RESULTS: In both genders, the higher body fat percentile curves sloped downwards to age 7 years, whereas the lower percentiles declined up to 8.5 years. Thereafter fat mass remained nearly constant with age in boys and increased in girls. The 10th percentile achieved a minimum of 10-11% body fat in both genders, whereas the 90th percentile curve fluctuated between 29 and 44% in boys or 30-43% in girls. The association between fat mass and blood pressure was too weak to define disease-related cut-offs. CONCLUSION: These body fat percentiles are suitable reference values for German children and adolescents. PMID- 22433621 TI - Physical fitness is independently related to blood leptin concentration and insulin sensitivity index in male subjects with central adiposity. AB - AIM: To compare the maximal power output (MPO) of subjects presenting a central adiposity to those of controls and to study the links between plasma leptin or indices of insulin sensitivity (QUICKI) and physical fitness (PF). METHODS: MPO was determined for 169 middle-aged men divided into two groups according to waist circumference (WC- < 94 cm, WC+ >= 94 cm) each subdivided in two subgroups with low and high PF (WC-L, WC-H, WC+L, WC+H) determined from the median MPO relative to fat free mass (3.06 W/kg(FFM)). RESULTS: MPO (W/kg(FFM)) was lower in WC+ than in WC-. Expressed relative to fat mass, leptin was lower and QUICKI higher in WC- than in WC+. In WC+H, leptin and QUICKI were significantly less disturbed than in WC+L and were independently correlated to MPO (r = -0.36 and r = 0.32 respectively; p < 0.001). In WC+, when visceral perimeter was added to the analysis, the relationships MPO/leptin remained significant but not MPO/QUICKI. CONCLUSION: The low PF in subjects with abdominal obesity is independently linked to plasma leptin and insulin sensitivity even if leptin and insulin may share common pathways in their peripheral effects. Visceral adiposity participates to the link between MPO and QUICKI, but not between MPO and leptin. PMID- 22433622 TI - The expression of omental 11beta-HSD1 is not increased in severely obese women with metabolic syndrome. AB - OBJECTIVE: Plasma cortisol in obese subjects does not differ from that in normoweight subjects. Extra-adrenal cortisol production by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) can result in local hypercortisolemia. The aim of the present study was to examine the role of visceral hypercortisolemia in the development of metabolic syndrome in severe obesity. METHODS: Eight lean women during hysterectomy (controls) and 19 severely obese women during bariatric surgery were studied, 8 without metabolic syndrome (OM- group) and 11 with it (OM+ group). Biopsies of omental and subcutaneous fat were performed in the severely obese women during surgery, but only omental biopsies in the controls. Expression of 11beta-HSD1, glucocorticoid receptor alpha (GRalpha) and glucocorticoid receptor beta (GRbeta) was evaluated using real-time PCR. RESULTS: Omental 11beta-HSD1 expression was different between groups (one-way ANOVA, p < 0.01). Post-hoc analysis revealed that mean omental 11beta-HSD1 mRNA levels were higher in the OM- group compared to controls, whereas they were similar when comparing the OM+ group with lean controls. Expression of 11beta-HSD1 in subcutaneous fat was not different between OM+ and OM- groups. GRalpha expression in omental fat did not differ among groups or between omental and subcutaneous fat in severely obese patients. An expression of GRbeta was not detected. CONCLUSION: Contrary to our original hypothesis, omental 11beta-HSD1 expression is not increased in the OM+ group. PMID- 22433623 TI - BMI trends, socioeconomic status, and the choice of dataset. AB - OBJECTIVE: This study is a descriptive investigation of trends in BMI in the USA over time, across race/ethnicity, gender, and socioeconomic status (SES) groups, and across different datasets. METHODS: The study analyzes micro-level data from three widely used cross-sectional US health datasets: the National Health and Nutrition Examination Survey (NHANES), the National Health Interview Survey (NHIS), and the Behavioral Risk Factor Surveillance System (BRFSS), from the 1970s to 2008. Consistent race/ethnicity and SES groups are constructed for all datasets. SES is measured by education and income. Focusing on adults aged 20-74 years, the study estimates BMI time trends, distributional shifts, and incremental associations (gradients) with SES. RESULTS: SES-BMI gradients are consistently larger for women than for men, differ across race/ethnicity groups, and are similar across datasets. Trends in mean BMI are comparable across White, Black and Hispanic males, while Hispanic females range between White and Black females. Self-reported BMI in the NHANES differs markedly from self-reports in the NHIS and BRFSS. CONCLUSION: The NHANES, NHIS, and BRFSS provide similar evidence regarding BMI trends over time and across race/ethnicity, gender, and SES groups. Racial disparities in BMI remain after adjusting for SES and should be studied further. PMID- 22433624 TI - Prevalence of the metabolic syndrome and its components among obese men and women in Italy. AB - OBJECTIVE: Assessment of the prevalence of the metabolic syndrome (MetS) and its components in Italian obese individuals. METHODS: Cross-sectional estimate of MetS prevalence using the IDF definition in 635 obese (BMI >= 35 kg/m(2)) individuals (286 men, 349 women) aged 19-78 years hospitalised for mass excess treatment. RESULTS: MetS prevalence was significantly (p < 0.001) higher in males (75.9%) than in females (61.9%), due to the increased prevalence of 4/5 involved abnormalities. A multivariate binary logistic regression analysis disclosed a contributory independent effect of ageing (p < 0.01-0.001), but not of BMI, whereas large waist circumference (p < 0.01) and high waist-to-hip ratio (p < 0.01) contributed to MetS prevalence only in women. Affected individuals were significantly older (males p = 0.022; females p < 0.001), affected men being younger than affected women (p < 0.01). The prevailing clinical picture included all abnormalities (21.2% in men, 22.2% in women); in minimal trait MetS (3/5 abnormalities), the prevailing combination was, beside central obesity, hypertension-hyperglycaemia in men (12.4%), and hypertension-dyslipidemia in women (19.4%). CONCLUSIONS: MetS is a highly prevalent condition among Italian obese individuals. Prevalence and combinations of involved abnormalities differ considerably between genders and suggest a different pathophysiology of the MetS in men and women, with possible relevance for prevention and treatment of the condition. PMID- 22433625 TI - Leptin in early life: a key factor for the development of the adult metabolic profile. AB - Leptin levels during the perinatal period are important for the development of metabolic systems involved in energy homeostasis. In rodents, there is a postnatal leptin surge, with circulating leptin levels increasing around postnatal day (PND) 5 and peaking between PND 9 and PND 10. At this time circulating leptin acts as an important trophic factor for the development of hypothalamic circuits that control energy homeostasis and food seeking and reward behaviors. Blunting the postnatal leptin surge results in long-term leptin insensitivity and increased susceptibility to diet-induced obesity during adulthood. Pharmacologically increased leptin levels in the postnatal period also have long-term effects on metabolism. Nevertheless, this effect is controversial as postnatal hyperleptinemia is reported to both increase and decrease the predisposition to obesity in adulthood. The different effects reported in the literature could be explained by the different moments at which this hormone was administered, suggesting that modifications of the neonatal leptin surge at specific time points could selectively affect the development of central and peripheral systems that are undergoing modifications at this moment resulting in different metabolic and behavioral outcomes. In addition, maternal nutrition and the hormonal environment during pregnancy and lactation may also modulate the offspring's response to postnatal modifications in leptin levels. This review highlights the importance of leptin levels during the perinatal period in the development of metabolic systems that control energy homeostasis and how modifications of these levels may induce long-lasting and potentially irreversible effects on metabolism. PMID- 22433626 TI - OBESITY FACTS--a success story. PMID- 22433627 TI - Expression of the central growth regulator BIG BROTHER is regulated by multiple cis-elements. AB - BACKGROUND: Much of the organismal variation we observe in nature is due to differences in organ size. The observation that even closely related species can show large, stably inherited differences in organ size indicates a strong genetic component to the control of organ size. Despite recent progress in identifying factors controlling organ growth in plants, our overall understanding of this process remains limited, partly because the individual factors have not yet been connected into larger regulatory pathways or networks. To begin addressing this aim, we have studied the upstream regulation of expression of BIG BROTHER (BB), a central growth-control gene in Arabidopsis thaliana that prevents overgrowth of organs. Final organ size and BB expression levels are tightly correlated, implying the need for precise control of its expression. BB expression mirrors proliferative activity, yet the gene functions to limit proliferation, suggesting that it acts in an incoherent feedforward loop downstream of growth activators to prevent over-proliferation. RESULTS: To investigate the upstream regulation of BB we combined a promoter deletion analysis with a phylogenetic footprinting approach. We were able to narrow down important, highly conserved, cis-regulatory elements within the BB promoter. Promoter sequences of other Brassicaceae species were able to partially complement the A. thaliana bb-1 mutant, suggesting that at least within the Brassicaceae family the regulatory pathways are conserved. CONCLUSIONS: This work underlines the complexity involved in precise quantitative control of gene expression and lays the foundation for identifying important upstream regulators that determine BB expression levels and thus final organ size. PMID- 22433628 TI - Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients. AB - Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia. A quantitative Western blot method was devised to detect CAF in sera of humans. A first trial on consenting blood donors (n=169; age 19-74 years) detected CAF in the limited range of 2.76 +/- 0.95 ng/ml. In sarcopenia patients (diagnosed according to clinical and instrumental standards) mean CAF levels were significantly elevated (p=9.8E10-9; n=73; age 65-87 years) compared to aged matched controls. Of all sarcopenia patients, 40% had elevated, non-overlapping CAF levels compared to controls. Evidence is presented for a pathogenic role of the agrin/neurotrypsin system in a substantial subset of sarcopenia patients. These patients are characterized by elevated CAF blood levels compared to aged matched healthy volunteers suggesting the identification of an agrin-dependent form of sarcopenia. Elevated CAF levels in a large subpopulation of sarcopenic patients suggest the existence of a specific form of sarcopenia for which CAF could become a biomarker and a new target for therapeutic interventions. The feasibility of this approach was demonstrated by the development of a small molecule capable of inhibiting neurotrypsin in vitro and in vivo. PMID- 22433629 TI - High hepatitis B virus infection in B-cell lymphoma tissue and its potential clinical relevance. AB - Our previous studies found that patients with B-cell non-Hodgkin lymphoma (NHL) had a higher incidence of hepatitis B virus (HBV) infection in serum than patients with T-cell NHL or other cancers. We sought to identify a possible role of HBV infection in B-cell NHL tumorigenesis and to understand its underlying clinical relevance. Fresh and paraffin-embedded primary tumor tissue from patients with NHL as well as from those with other lymphatic system diseases were investigated by PCR and immunohistochemistry. Many more patients with B-cell lymphoma whose serum was positive for hepatitis B surface antigen (HBsAg) were also positive for HBV-DNA than were those with T-cell NHL or other lymphatic system diseases whose serum was positive for HBsAg, in both fresh (55 vs. 15.4%) and paraffin-embedded (38.3 vs. 11.8%) tissue. Positive expression of the HBV associated proteins HBsAg and hepatitis B core antigen was found in B-cell NHL lymphocytes and endothelial cells. Only 8.3% of patients with B-cell NHL who were negative for HBsAg but positive for other HBV markers were positive for HBV-DNA in tumor tissue. These results suggest that chronic HBV infection in lymph nodes could be associated with B-cell lymphoma. PMID- 22433630 TI - The relationship between smoking and severe dysplastic disease in patients with Barrett's columnar-lined oesophagus. AB - The aim of this study was to examine the relationship between smoking and oesophageal high-grade dysplasia (HGD) or adenocarcinoma (AC) in a large cohort of patients with Barrett's columnar-lined oesophagus (CLO). A total of 1280 patients diagnosed with CLO and registered with the UK National Barrett's Oesophagus Registry were included. Data, including smoking habits, were collected from the patient's notes and development of HGD or AC noted. Analysis was performed with SPSS using logistic regression for calculation of odds ratios (ORs) for development of HGD/AC. Data on smoking habits were available in 956 (74.6%) patients. There was no significant difference between smokers and nonsmokers in mean age (P=0.877) or length of follow-up (P=0.359). There was a significant risk of HGD/AC in patients with any history of smoking compared with those who had never smoked (P<0.001, OR 2.81). Ex-smokers of 10 years or more remained at a significantly higher risk of HGD/AC compared with those who had never smoked (P=0.001, OR 3.37). Current smokers were not at a significantly higher risk of HGD/AC compared with ex-smokers (P=0.857) nor were those who smoked at least 20 a day compared with those who smoked fewer than 20 a day (P=0.632). In patients with CLO, smoking appears to be a significant risk factor for the development of severe dysplastic disease; however, we did not observe a dose-dependent effect of smoking on progression of disease. PMID- 22433631 TI - Quality of urological cancer diagnoses in the Danish National Registry of Patients. AB - Valid and up-to-date data on cancer diagnoses are needed for clinical quality monitoring and epidemiological research. The Danish National Registry of Patients (DNRP) is continuously updated, recording all Danish hospital contacts including cancer diagnoses. The Danish Cancer Registry (DCR) is updated once a year and includes quality control of diagnoses. We compared the quality of urological cancer diagnoses in the DNRP with the DCR to assess whether data in an administrative hospital registry are valid compared with data from a well established cancer registry. We identified 60 434 incident urological cancer cases in the DNRP and/or the DCR from 2001 to 2009. Completeness and the positive predictive value (PPV) of urological cancer registration in the DNRP were estimated using the DCR as the reference standard. To examine the impact of potential misclassification, we computed mortality estimates for urological cancer patients in each registry. Because DCR registration procedures changed in 2004, the periods 2001-2003 and 2004-2009 were analyzed separately. In 2004-2009, the overall completeness and PPV of urological cancer registration in the DNRP were 94.9% (95% confidence interval: 94.7-95.2%) and 86.6% (95% confidence interval: 86.3-86.9%), respectively, compared with diagnoses recorded in the DCR. Completeness and PPV of cancer registration in the DNRP varied between cancer subgroups. In 2001-2003, both completeness and PPV in the DNRP were slightly lower compared with 2004-2009. Mortality estimates in patients registered in the DNRP and the DCR varied slightly. The DNRP could be a valuable source of data for clinical quality monitoring and epidemiological research for some urological cancers, especially when current data are essential. PMID- 22433632 TI - Use of wireless phones and the risk of salivary gland tumours: a case-control study. AB - The last decades of increasing use of wireless phones, including mobile as well as cordless desktop phones, have led to concerns about the potential carcinogenic effects of radiofrequency electromagnetic fields. Among the most exposed areas of the body when the phone is used for talking are the salivary glands, mainly the parotid gland, located in front of the ear. The objective of this case-control study was to assess whether the use of wireless phones is associated with an increased risk of tumour at this site. Sixty-nine patients with salivary gland tumours (63 with a parotid gland tumour) and 262 randomly recruited controls were included. Unconditional logistic regression - adjusted for age at diagnosis, sex, year of diagnosis and socioeconomic index - was used to produce odds ratios and 95% confidence intervals. The use of wireless phones was not associated with an overall increased risk of salivary gland tumours, odds ratio 0.8, 95% confidence interval 0.4-1.5. Neither was there an increased risk for the different phone types when calculated separately nor was there an increased risk for different latencies or when cumulative use was divided into three groups (1-1000, 1001-2000 and >2000 h). The overall results were similar for the risk of parotid gland tumours. In conclusion, our data add to the evidence against there being an increased risk for parotid gland tumours associated with light-to-moderate use of wireless phones and for less than 10 years of use but offers little information on risk related to more prolonged and/or heavy use. PMID- 22433633 TI - Risk of subsequent primary cancer among prostate cancer patients in Bavaria, Germany. AB - As the prevalence of prostate cancer in Germany is increasing, the issue of subsequent primary cancer (SPC) becomes more relevant. The aim of this study was to estimate the risk and its changes over time of developing SPC among prostate cancer patients compared with the general male population in Bavaria, southern Germany. Utilizing data from the Population-Based Cancer Registry Bavaria, the risk of SPC was evaluated in 59 259 men with prostate cancer diagnosed between 2002 and 2008 who contributed 159 892 person-years. The relative and absolute risk of developing SPC were calculated using the standardized incidence ratio (SIR) and the excess absolute risk. Changes in the risk were examined by plotting the SIR and its 95% confidence interval against time after the diagnosis of prostate cancer. The overall risk of SPC was significantly increased by 14% compared with the general male population. With regard to specific cancer types, a significantly increased risk of SPC was found for the urinary bladder, kidney, pancreas, melanoma of skin, leukemia, myeloma, brain/nervous system, renal pelvis/ureter, thyroid, and the small intestine. The absolute risk of SPC for most cancer types, however, was below 10 cases per 10 000 person-years. A significantly decreased risk of SPC was found in the lung/bronchus and the liver. Although detection bias cannot be excluded as a contributing factor for our results, we recommend continuing follow-up care of prostate cancer patients particularly with respect to SPC of the urinary system as a precaution. PMID- 22433634 TI - [Loading, volumes, kinds and structure of work of doctors-dental-surgeons working in system of obligatory medical insurance]. AB - The message concerns problems of calculation of loading of doctors-dental surgeons, their structures of work. "The Korolevskaya dental polyclinic" is offered to carry out on example STPE the analysis of loading, volumes, kinds and structure of work of the doctors-dental-surgeons working in system OMI. PMID- 22433635 TI - [Some aspects of immune reaction in chronic generalized parodontal disease in elderly patients]. AB - Chronic parodontit inflammation in elderly patients was found to be accompanied by inbalance of complement system; IgA (sIgA), IgA, IgG, IgM hyperproduction; the increase of IL-8, IL-1alpha concentration and decrease of IL-4 level; increase Hsp-70 antibodies. PMID- 22433636 TI - [Effectiveness of chronic periodontal disease treatment by infrared laser light]. AB - Thirty-six patients with light and moderate chronic periodontal disease (CPD) were included in the study. The patients were divided in two groups according to treatment options: first group (18 patients) received conventional periodontal treatment, second (18 patients) - in addition to conventional treatment were treated by phototherapy (infrared laser light). Control group included 10 persons with no signs of periodontal disease. Treatment effectiveness was assessed by local cytokine profile (IL-1beta, IL-1ra, IL-6, IL-10, TNF-alpha, OPG and RANKL). Increased level of inflammatory cytokines TNF-alpha, IL-1beta, IL-6 confirmed pronounced inflammation in periodontal tissues in CPD patients. OPG level was lower than in control group while RANKL level increased significantly. After treatment in both CRD groups TNF-alpha and IL-6 decrease was observed, IL-1beta (had not changed. In the second group RANKL level also decreased dramatically - 6.7-fold compared to its values before treatment. PMID- 22433637 TI - [Some aspects of correction of nasal tip congenital deformities]. AB - The paper reviews both short- and lon-termed results of conventional methods for the correction of nasal tip congenital deformities: Converse for broad tip correction, Armstrong for long tip and Burian for protruding tip. The revealed disadvantages of the abovementioned methods are summarized. Treatment efficiency proved to be higher when classifying nasal tip deformities in monodeformities and combined ones. This allows more precise analyzing of deformity compounds and provides better short- and long-termed results. PMID- 22433638 TI - [The improvement of safe sedation and dental treatment in patients with metabolic syndrome]. AB - The paper concerns the anesthetic aspects of safe conscious sedation and dental treatment of patients with metabolic syndrome. BIS monitoring in combination with routine pulse oximetry and blood pressure measurement is getting dental sedation safer. Independently of the bolus or continuous intravenous midazolam infusion the investigators approved high efficacy of bispectral index in benzodiazepine dose titration. Successful dental treatment under conscious sedation and no evident associated with analgesia complications show the importance of BIS monitoring in the improvement of safe sedation and dental treatment in patients with metabolic syndrome. PMID- 22433639 TI - [General anaesthesia with sevoflurane in dental surgery with use of LMA-Flexible and LMA-ProSeal]. AB - To compare the laryngeal mask airways (LMA), LMA - Flexible (LMA-F) and LMA ProSeal (PLMA) with respect to airway management in dental surgery. 35 patients, with the pathology of stomatological area (cysts of the lower jaw; diseases maxillary sinus) were investigated during the operation. Anesthesia was induced with propofol, fentanyl and atracurium besylate. Anesthesia was maintained with sevoflurane and neuromuscular blockade with mechanical ventilation. The operation lasted 30-40 min. For airway management was used LMA-F in 20 patients, in 15 patients was made PLMA. There were no statistically significant differences between LMA-F/PLMA groups for SpO(2), ET CO(2) or airway pressure during anesthesia. As for the gas exchange no difference was noticed in both groups (p<0.05). Undesirable laryngo-phryngeal reflexes were not noticed in total myoplegia. The reaction of cardiovascular system while installating LMA-F and PLMA was absent. As for the gas exchange no difference was noticed in both groups (p<0.05). A correctly placed LMA-F or PLMA during general anaesthesia with sevoflurane is effective for airway management in surgery. PMID- 22433640 TI - [Rational (injection) of calcitonin for stimulation of the mandibular reparative regeneration]. AB - This investigation permit to detect, that first resorption stage of the mandible reparative regeneration terminats after fracture 5 days later. Calcitonine injection during 5 days after fracture i.e. in paratiroid hormone dependent stage distorts normal reparative process. Rats with traumatic osteomielitis become 1.5 times more and rats with normal regeneration become 3 times less. Injection calcitonine in KT-dependent stage, i.e. in 6-11 days after fracture increases quantity of rats with normal regeneration in 7 times and decreases quantity animals with traumatic osteomielitis on 50%. There's recommendation to inject KT from 6 days after trauma. PMID- 22433641 TI - [Efficiency rating of various types of implants when placing into the socket of an extracted tooth]. AB - The method of the immediate implantation was used in 138 patients after a tooth (teeth) extraction, with one-phase and two-phase spiral constructions placed in 45 (32.6%) sick people of the control group and with cylindrical and laminar implants with shape-memory effect placed in 93 (67.4%) cases adapted for placement into the socket and through the socket of an extracted tooth of the frontal and masticatory group. Application of one-phase spiral implants, the self locking cylindrical and laminar ones allows to reduce time of the prosthetics from 1 to 30 days, to bring down the atrophy of an alveolar process in the range of an extracted tooth. The good long-term functional result of the prosthetics remains in 97.8% of patients of the main group and in 86.6% of cases of the control group. PMID- 22433642 TI - [Laser photocoagulation in treatment of plexiform neurofibromas in maxilla-facial area]. AB - The incidence of plexiform neurofibromas (PN) is 1:2500-3000, the disease affects maxilla-facial area in 31% of cases. The current paper describes results of treatment of 23 patients as well as preliminary data on using laser coagulation as treatment option for PN, namely on preoperative stage of treatment. PMID- 22433643 TI - [Malocclusion class III treatment by the Postnikov appliance]. AB - In examined patients (45 persons aged 12-15) malocclusion Class III was caused by mesial position of mandible and it has dentoalveolar form. Significant increase of mandible body length indicated more intensive mandible growth because of reverse overbite. The use of Postnikov appliance caused changes in interposition of front teeth of maxilla and mandible due to upper dental arch extension thus normalizing occlusion. PMID- 22433644 TI - [Effectiveness of adjustment of bar constructions on implants by hydrogen and laser welding, metal soldering and electroerosive processing]. AB - Marginal fit of bar constructions on dental implants was revealed. It's investigated success of correction with soldering, laser welding, "cast to" method and spark erosion. PMID- 22433645 TI - [Microcirculation in supporting tissues in patients with unilateral terminal defect of dental arch]. AB - By the method laser Doppler fluometry microcirculation in a mucosa of an alveolar process at orthopedic treatment of patients with unilateral trailer defect of a dentition with application of the prosthetic design leaning on dental implants with the help unklammer of bracing. Taped dynamics of change of indicators testified to compensatory changes in regulation of a fabric blood flow in reply to a rendered load. Studying of microhemodynamic processes in tissues of a prosthetic bed, according to LDF, has shown stimulating influence of rational orthopedic treatment on a microcirculation condition. PMID- 22433646 TI - [Provisional implants for immediate overdenture fixation after multiple tooth extraction]. AB - The aim of the study was to assess the effectiveness of immediate overdenture supported by provisional mini-implants after multiple tooth extraction. The study included 39 patients aged 55+/-17, followed up for 12 months. The first group included 14 patients with 65 mini-implants and 17 soft-lined immediate overdentures. In the second group (10 patients, 45 mini-implants) 12 immediate overdentures had hard liner. In the third group (15 patients) immediate overdentures with hard liner were used without implant support. 12-month implant survival was 98.5% in the I and 91.1% in the II group (1 and 4 implants failed correspondently). The number of denture basis corrections was minimal in the second group (2.9+/-0.46) and largest in the third group (4.32+/-0.67). Mini implants provided better fixation of complete denture, facilitated mucosal adaptation to denture compared with immediate dentures without implant support. PMID- 22433647 TI - [Microabrasive tooth preparation for early caries prevention and treatment]. AB - Based on the 4-year experience with the method of air-abrasion treatment on the stages of treatment and prevention of dental caries in the article provides data on the indications for its use, benefits and complications. PMID- 22433648 TI - [Dependence of caries protective effect of fluoride varnishes applications on first permanent molars in schoolchildren on the intensity of caries of temporary teeth]. AB - There are four-year clinical research results of the efficacy of the varnishes with different fluoride compounds on first permanent molars in young schoolchildren depending on the lesion of caries of temporary molars. It was determined that for children, whose molars were healthy during the basic examination, the highest caries protective effect was achieved with the help of varnish, containing CaF(2) (the reduction of increase of the intensity of caries of permanent molars formed 59.7%), and for children with initial high lesion of caries of permanent molars the best caries preventive effect was achieved with the varnish "Bifluorid 12(r)" (the reduction of increase of the intensity of caries of permanent molars formed 52.5%). PMID- 22433649 TI - [Long-term results of prevention of dental caries among children using fluoridated milk in city Maikop]. AB - The prevalence of dental caries among preschool and school-age children in Maikop is a consistently high level. The purpose of this study was to examine the state of teeth in children aged 6, 9 and 12 years who drink fluorinated milk during three years they visit kindergartens. The results showed that the irregular production of fluoridated milk due to the economic crisis in the past three years made no possible to achieve adequate antidecay effect in preschool children. Remote prophylactic effect as a result of regular consumption of fluoridated milk registered among children aged 9 and 12 years. It show reducing the decay intensity by 30.9 and 33.2% respectively. PMID- 22433650 TI - Growth factor therapy and autologous lymph node transfer in lymphedema. AB - Lymphedema after cancer treatment is a common clinical challenge, but curative treatment options are rarely available. Lymph node transfer is a novel technique in lymphedema surgery. Lymphatic tissue can be transferred as a vascularized free flap, but in this technique the lymphatic vascular network is expected to regrow spontaneously. Recently, we have learned how to regulate the growth of lymphatic vessels in experimental models. We envision that lymph node transfer should be combined with lymphatic growth factor therapy in the treatment of lymphedema patients. PMID- 22433651 TI - MicroRNA regulation of angiogenesis and arteriogenesis. AB - MicroRNAs are short, nonprotein-coding RNA molecules that play a crucial role in the post-transcriptional regulation of gene expression. By binding to specific target sequences, mostly located in the 3'-untranslated region of their target mRNA, they can induce mRNA decay or translational inhibition. Unlike siRNA, microRNAs show imperfect matching to their target mRNAs and can therefore modulate the expression of several mRNA genes at once. Although microRNAs have already been extensively studied in invertebrates, their function in mammalian organisms and in human disease is largely unknown. Several studies have shown an important regulatory function of microRNAs in embryonic and postnatal blood vessel development. Here, we provide an overview on these recent findings and summarize these so-called "angiomiRs" and their mode of action. PMID- 22433652 TI - Challenges in allogeneic mesenchymal stem cell-mediated cardiac repair. AB - Autologous mesenchymal stem cells (MSCs) have been proven safe in phase I and II clinical trials in patients who have suffered a myocardial infarction. However, their potential for proliferation and differentiation decreases with age, which limits their efficacy in elderly patients. Allogeneic MSCs offer several key advantages over autologous MSCs, including a high regenerative potential and availability for clinical use without the delay required for expansion. It was believed that allogeneic MSCs were immune privileged and thus able to escape the recipient's immune system. In several preclinical studies, allogeneic MSCs were successful in regenerating the myocardium, and the transplanted MSCs improved heart function early after implantation. However, the long-term ability of allogeneic MSCs to preserve heart function is limited because of a transition from an immune privileged to an immunogenic phenotype after the cells differentiate. The initial phase I/II clinical study using allogeneic MSCs in patients with acute myocardial infarction was safe, and no side effects were observed. However, the long-term safety and efficacy of allogeneic MSCs remain to be established. In this review, we discuss the challenges of using allogeneic MSCs for cardiac repair and present strategies to prevent the immune rejection of allogeneic MSCs to increase their potential for use in cardiac patients. PMID- 22433653 TI - Autonomic denervation using magnetic nanoparticles. AB - Nanoparticles with their unique physical and biochemical properties, such as modifiable surface functionalization and versatility for carrying various therapeutic payloads, are excellent vehicles for targeted drug delivery. The diffuse nature of cardiovascular diseases presents a great challenge to nanotechnology-based drug delivery therapy. Cardiac arrhythmias, frequently caused by heterogeneity of conduction, repolarization, and cell-cell communication, are particularly sensitive to any therapy that targets the presumed arrhythmogenic myocardium but inadvertently introduces further heterogeneity into the heart. In this review, we focus on an alternative approach that is to target the ganglionated plexi of the cardiac autonomic nervous system responsible for many arrhythmias. These ganglionated plexi, serving as the "integration centers" of the cardiac autonomic nervous system, are located in discrete sites on the epicardial surface and potentially can be targeted by magnetic nanoparticles navigated by externally applied magnetic field. PMID- 22433654 TI - Leukocyte and cardiac phosphoinositide 3-kinase gamma activity in pressure overload-induced cardiac failure. AB - Class IB phosphoinositide 3-kinase p110gamma is a master regulator of both leukocyte and cardiomyocyte function. Whereas in the immune system p110gamma is principally involved in the control of leukocyte chemotaxis and inflammatory reactions, in cardiomyocytes p110gamma affects multiple aspects of beta adrenergic receptor signaling and cardiac function. Because inflammatory cell recruitment/activation and cardiac dysfunction are strictly connected, p110gamma has recently been revealed as a promising target for drug design in the treatment of heart failure. This review discusses recent works that dissect the relative contribution of leukocyte p110gamma and its cardiac counterpart in the onset and progression of pressure overload-induced cardiac remodeling and the ensuing therapeutic implications. PMID- 22433655 TI - Myeloperoxidase may help to differentiate coronary plaque erosion from plaque rupture in patients with acute coronary syndromes. AB - Coronary thrombosis is the most frequent final event leading to an acute coronary syndrome. In approximately two-thirds of cases, the thrombus overlies a ruptured plaque, whereas in one-third of cases it overlies an intact plaque with superficial endothelial erosion, a finding showed initially by histopathological postmortem studies and more recently confirmed by in vivo optical coherence tomography imaging. Interestingly, recent observations suggest that mechanisms leading to plaque rupture or erosion are different. In fact, in a recent study, we showed that myeloperoxidase levels in peripheral blood and expression within thrombi overlying the culprit plaque are much higher in patients with plaque erosion than in those with plaque rupture. These observations suggest that innate immunity activation is likely to play a key role, in particular, in plaque erosion and might become a therapeutic target in this subset of patients. PMID- 22433656 TI - Young Native American men and their intention to use family planning services. AB - This study examines the extent to which age, fatherhood, relationship status, self-control of birth control method, and the use of birth control influence young Native American men's intention to use family planning services. Data were collected for this study during in-depth interviews with 112 Native American men between the ages of 18 and 24 years. The mean age reported was 21. Thirty-eight percent of the young men reported having children. Almost 70% of the young men reported being in a steady relationship. Eighty-eight percent reported that it was very important that they have self-control of the type of birth control that they use. In addition, 88% of the young men reported that they would use some type of birth control within the next year to prevent a pregnancy with their partner. Logistic regression analysis indicated that as age increased, young men were less likely to seek family planning services for birth control. The young men who reported being fathers were more likely than the young men who did not report being fathers to seek family planning services for birth control. Findings from this study suggest that public health efforts to educate Native American men about family planning services are most effective in their adolescence, before they transition into young adulthood. Fatherhood may also be considered a protective factor that may increase the likelihood that young Native American men will seek family planning services for birth control. Public health efforts that address reproductive health among young Native American men may be effective with Native American men in adolescence, prior to their transition to young adulthood. Family planning services that provide outreach education and care to Native American fathers may also be effective. PMID- 22433657 TI - Male breast cellular myofibroblastoma with a rich reticulinic network: case report. AB - Myofibroblastoma is a rare mesenchymal tumor located not only in breast but also in extramammary sites. This is the 79th case of breast myofibroblastoma reported in the literature. This tumor presents a great variety of morphological features, which increase the difficulty of differential diagnosis. The authors report a breast myofibroblastoma diagnosed in a 73-year-old male. The article discusses a bilateral gynecomastia and a palpable right breast well-defined tumor, without calcifications on mammography, which was surgically removed. Macroscopically, a well-circumscribed uncapsulated nodule was seen with lobular arrangement on cut section, and microscopically, a nodule with pushing borders and a connective pseudocapsule was seen. The spindle cells were arranged in fascicular clusters, with focally collagen bundles and a rich reticulinic network stained black with Gomori impregnation. Immunohistochemically, the tumor cells were marked by vimentin, CD34, desmin, and smooth muscle antigen and did not express cytokeratin, S-100 protein, CD99, CD10, and factor VIII-related antigen. More than 90% of the cells expressed estrogen receptor. No recurrences were reported 2 years after surgical excision. This case is a variant of cellular myofibroblastoma, with a rich reticulinic network and scanty collagen bands. PMID- 22433658 TI - A multi-modal investigation of behavioral adjustment: post-error slowing is associated with white matter characteristics. AB - When people make mistakes in speeded cognitive tasks, their response time on the next trial will typically be slower. This is referred to as post-error slowing (PES), and is important for optimization of performance, but its exact function remains to be decided. However, although PES is relatively stable over time, we have almost no knowledge about how PES is affected by structural brain characteristics. The aim of this study was to test to what extent white matter (WM) macro- and microstructure can account for individual differences in PES. PES was calculated for 255 healthy participants who performed a modified version of the Eriksen flanker task and underwent structural magnetic resonance imaging and diffusion tensor imaging (DTI). PES was positively related to WM volume in the caudal and rostral middle and superior frontal, medial orbitofrontal gyri and pars orbitalis. DTI analyses with tract-based spatial statistics (TBSS) showed that mean diffusivity in the superior longitudinal fasciculus, inferior fronto occipital fasciculus and anterior thalamic radiation, as well as axial diffusivity in the corpus callosum, was negatively related to PES. Path analysis demonstrated that WM micro- and macrostructure were complementary in accounting for PES. It is concluded that individual differences in WM characteristics can partly explain why some people are better at adjusting their behavior in response to poor performance than others. PMID- 22433659 TI - fMRI at 20: has it changed the world? AB - The prevalence of fMRI in cognitive neuroscience research is clear, but the overall impact of the associated research in the broader scope of our scientific community, and of society, is less obvious. The first reports of fMRI garnered huge interest in many areas, giving rise to a wide range of applications and technical developments over the past 20 years. Using five primary areas, i.e. scientific impact, clinical practice, cognitive neuroscience, mental illness, and society-this essay examines the question: Has fMRI changed the world? PMID- 22433661 TI - Effect of oral supplementation of the probiotic capsule UB-01BV in the treatment of patients with bacterial vaginosis. AB - Bacterial vaginosis (BV) is a common condition affecting millions of women annually and is characterised by a reduction in native lactobacilli. Antimicrobial therapy used to cure the disease is often found to be ineffective. We postulate that the potential probiotic capsule UB-01BV might be efficient in the treatment of BV. In the present study, 30 Indian women diagnosed with BV presenting symptoms such as white discharge, pH greater than 4.7, increased discharge, odour, colour of discharge and pruritus were included. All subjects were assigned to receive two potential probiotic capsules UB-01BV a day for 7 days. At the end of the treatment all subjects showed significant (P<0.001) positive response as revealed by a reduction in vaginosis symptoms. Therefore, the results of the present study provide the first preliminary evidence that the potential probiotic capsule UB-01BV can exert a significant reduction in vaginal infection. PMID- 22433660 TI - Disconnectivity of the cortical ocular motor control network in autism spectrum disorders. AB - Response inhibition, or the suppression of prepotent but contextually inappropriate behaviors, is essential to adaptive, flexible responding. Individuals with autism spectrum disorders (ASD) consistently show deficient response inhibition during antisaccades. In our prior functional MRI study, impaired antisaccade performance was accompanied by reduced functional connectivity between the frontal eye field (FEF) and dorsal anterior cingulate cortex (dACC), regions critical to volitional ocular motor control. Here we employed magnetoencephalography (MEG) to examine the spectral characteristics of this reduced connectivity. We focused on coherence between FEF and dACC during the preparatory period of antisaccade and prosaccade trials, which occurs after the presentation of the task cue and before the imperative stimulus. We found significant group differences in alpha band mediated coherence. Specifically, neurotypical participants showed significant alpha band coherence between the right inferior FEF and right dACC and between the left superior FEF and bilateral dACC across antisaccade, prosaccade, and fixation conditions. Relative to the neurotypical group, ASD participants showed reduced coherence between these regions in all three conditions. Moreover, while neurotypical participants showed increased coherence between the right inferior FEF and the right dACC in preparation for an antisaccade compared to a prosaccade or fixation, ASD participants failed to show a similar increase in preparation for the more demanding antisaccade. These findings demonstrate reduced long-range functional connectivity in ASD, specifically in the alpha band. The failure in the ASD group to increase alpha band coherence with increasing task demand may reflect deficient top-down recruitment of additional neural resources in preparation to perform a difficult task. PMID- 22433662 TI - Evaluation of Bacillus subtilis strains as probiotics and their potential as a food ingredient. AB - Spores of Bacillus subtilis including one strain used commercially were evaluated for their potential value as a probiotic and as potential food additives. Two isolates of B. subtilis examined here were HU58, a human isolate and PXN21, a strain used in an existing commercial product. Compared to a domesticated laboratory strain of B. subtilis both isolates carried traits that could prove advantageous in the human gastro-intestinal tract. This included full resistance to gastric fluids, rapid sporulation and the formation of robust biofilms. We also showed that PXN21 spores when administered weekly to mice conferred non specific cellular immune responses, indicative signs of the stimulation of innate immunity. Spores mixed in wholemeal biscuits were found to survive baking at 235 degrees C for 8 minutes with only a 1-log reduction in viability. That spores can survive the baking process offers the possibility of using spores as probiotic supplements in a range of novel food products. PMID- 22433663 TI - Effects of fatty acid activation on photosynthetic production of fatty acid-based biofuels in Synechocystis sp. PCC6803. AB - BACKGROUND: Direct conversion of solar energy and carbon dioxide to drop in fuel molecules in a single biological system can be achieved from fatty acid-based biofuels such as fatty alcohols and alkanes. These molecules have similar properties to fossil fuels but can be produced by photosynthetic cyanobacteria. RESULTS: Synechocystis sp. PCC6803 mutant strains containing either overexpression or deletion of the slr1609 gene, which encodes an acyl-ACP synthetase (AAS), have been constructed. The complete segregation and deletion in all mutant strains was confirmed by PCR analysis. Blocking fatty acid activation by deleting slr1609 gene in wild-type Synechocystis sp. PCC6803 led to a doubling of the amount of free fatty acids and a decrease of alkane production by up to 90 percent. Overexpression of slr1609 gene in the wild-type Synechocystis sp. PCC6803 had no effect on the production of either free fatty acids or alkanes. Overexpression or deletion of slr1609 gene in the Synechocystis sp. PCC6803 mutant strain with the capability of making fatty alcohols by genetically introducing fatty acyl-CoA reductase respectively enhanced or reduced fatty alcohol production by 60 percent. CONCLUSIONS: Fatty acid activation functionalized by the slr1609 gene is metabolically crucial for biosynthesis of fatty acid derivatives in Synechocystis sp. PCC6803. It is necessary but not sufficient for efficient production of alkanes. Fatty alcohol production can be significantly improved by the overexpression of slr1609 gene. PMID- 22433664 TI - Synthesis and electroplating of high resolution insulated carbon nanotube scanning probes for imaging in liquid solutions. AB - High resolution and isolated scanning probe microscopy (SPM) is in demand for continued development of energy storage and conversion systems involving chemical reactions at the nanoscale as well as an improved understanding of biological systems. Carbon nanotubes (CNTs) have large aspect ratios and, if leveraged properly, can be used to develop high resolution SPM probes. Isolation of SPM probes can be achieved by depositing a dielectric film and selectively etching at the apex of the probe. In this paper the fabrication of a high resolution and isolated SPM tip is demonstrated using electron beam induced etching of a dielectric film deposited onto an SPM tip with an attached CNT at the apex. PMID- 22433665 TI - Dementia diagnosis differs in men and women and depends on age and dementia severity: data from SveDem, the Swedish Dementia Quality Registry. AB - AIMS: We examine the dementia assessment with focus on age and gender differences. METHODS: Data from the national quality database, Swedish Dementia Registry (SveDem), including 6,937 dementia patients diagnosed during 2007-2009 at memory clinics were used. We have studied the use of investigations for dementia diagnostics such as cognitive tests, blood and cerebrospinal fluid analyses, electroencephalography, radiological examinations and assessments of functions. Severity of cognitive impairment was assessed with the Mini Mental State Examination (MMSE). RESULTS: There was a significant decrease in the number of total tests used in the elderly group (>75 years) when compared with the middle-aged group (65-75 years) and younger patients (<65 years). The oldest group was examined with 4 of 11 possible tests, the middle-aged group had 5/11 tests performed and the youngest age group 6/11 tests. There was also a significant gender difference in the diagnostic workup, however, mostly attributable to age. The number of tests positively correlated with the level of cognition assessed by the MMSE. CONCLUSION: We show here for the first time the impact of age, gender and MMSE score on the dementia diagnostic workup in a large memory clinic patient population in one country. PMID- 22433666 TI - Restoring nitric oxide cytosolic calcium regulation by cyclic guanosine monophosphate protein kinase I alpha transfection in coronary endothelial cells of spontaneously hypertensive rats. AB - In microcoronary endothelial cells (RCEs) from spontaneously hypertensive rats (SHR), the nitric oxide (NO)/cyclic guanosine monophosphate (GMP)-dependent proteinkinase I (cGKI) pathway cannot regulate the cytosolic calcium ([Ca2+]i) dynamic as in RCEs from Wistar Kyoto rats (WKY). We investigated the altered downstream NO target in SHR cells and, since cGKI expression was low, whether the re-expression of cGKIalpha in SHR RCEs could restore NO calcium responsiveness. We measured [Ca2+]i dynamic by fura-2 imaging analysis and the cGKI level by RT PCR and Western blot in SHR and WKY RCEs. Plasmids encoding for enhanced green fluorescence protein or cGKIalpha-enhanced green fluorescence protein were transiently transfected in SHR RCEs, and [Ca2+]i was evaluated. Angiotensin-II (AT-II) increased [Ca2+]i in a concentration-dependent way in both strains. Whereas in WKY, endogenously produced NO and cyclic GMP analog decreased the AT II-induced [Ca2+]i transient, they were ineffective in SHR RCEs. The cGKI level was low in SHR cells. However, after cGKIalpha re-expression, endogenous NO decreased the AT-II-induced [Ca2+]i transient, while endothelial NO synthase and cGKI inhibition prevented it. The low expression of cGKI in SHR accounts for the absent regulation of the agonist-induced [Ca2+]i transient by the NO/cyclic GMP pathway. Studies on cGKI in humans could contribute to a better understanding of cardiovascular pathologies. PMID- 22433667 TI - Sinus arrest following right coronary artery stent implantation. AB - Sinus arrest rarely occurs during acute myocardial infarction involving the right coronary artery (RCA) and sinus node (SN) artery. We report a rare case of sinus arrest caused by SN artery occlusion following RCA stenting. A 56-year-old woman with a significant history of RCA stenosis with prior bare metal stenting, presented to the emergency department with anginal chest pain. Initial work up showed significant elevation of cardiac troponin T with T-wave inversion in the inferior leads on electrocardiogram (ECG). Coronary angiography revealed a 90% stenosis of midportion of the RCA, mild occlusion in the left anterior descending coronary and left circumflex coronary arteries. Stenting was performed on the RCA lesion. Immediately after undergoing those interventions, thrombosis developed and occluded SN artery. Electrocardiogram showed junctional escape rhythm without P waves at a heart rate of 30 beats per minute, suggesting sinus arrest. The clot in the SN artery was identified and thrombectomy was performed. Neither symptoms nor hypotension were identified during this arrhythmia. Six days later, normal sinus rhythm began to appear on EKG with improving heart rate, and patient still remained completely hemodynamically stable. Pre-discharge exercise stress test had shown 50% predicted heart rate without ST segment change. Sinus node dysfunction is commonly related to degenerative processes, and rarely caused by thrombosis in the SN artery. In our case, we emphasize the potential complication of sinus arrest after RCA stent implantation. PMID- 22433669 TI - Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-beta peptide accumulation. AB - In brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH chol) and eliminated into the circulation across the blood-brain barrier. 24S-OH chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes embedded in the basal lamina of this barrier (close to the brain compartment) have not been previously studied. We used primary cultures of brain pericytes to demonstrate that the latter express LXR nuclear receptors and their target gene ATP-binding cassette, sub-family A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid homeostasis. Treatment with 24S-OH-chol caused an increase in ABCA1 expression that correlated with a reverse cholesterol transfer to apolipoprotein E, apolipoprotein A-I, and high density lipoprotein particles. Inhibition of ABCA1 decreased this efflux. As pericytes are able to internalize the amyloid-beta peptides which accumulate in brain of Alzheimer's disease patients, we then investigated the effects of 24S-OH chol on this process. We found that the cellular accumulation process was not modified by 24S-OH-chol treatment. Overall, our results highlight the importance of the LXR/ABCA1 system in brain pericytes and suggest a new role for these cells in brain cholesterol homeostasis. PMID- 22433668 TI - Type 2 diabetes and cognitive impairment: linking mechanisms. AB - This manuscript provides a brief review of current concepts in the mechanisms potentially linking type-2-diabetes (T2D) with cognitive impairment. Existing epidemiologic studies, imaging studies, autopsy studies, and clinical trials provide insights into the mechanisms linking T2D and cognitive impairment. There seems to be little dispute that T2D can cause cerebrovascular disease and thus cause vascular cognitive impairment (VCI). Whether T2D can cause late onset Alzheimer's disease (LOAD) remains to be elucidated. Many epidemiologic studies show an association between T2D and cognitive impairment, but the association with VCI seems to be stronger compared to LOAD, suggesting that cerebrovascular disease may be the main mechanism linking T2D and cognitive impairment. Imaging studies show an association between T2D and imaging markers of LOAD, but these observations could still be explained by cerebrovascular mechanisms. Autopsy studies are few and conflicting, with some suggesting a predominantly cerebrovascular mechanism, and others providing support for a neurodegenerative mechanism. Thus far, the evidence from clinical trials is mixed in supporting a causal association between T2D and cognitive impairment, and most clinical trials that can answer this question are yet to be reported or finished. Given the epidemic of T2D in the world, it is important to elucidate whether the association between T2D and cognitive impairment, particularly LOAD, is causal, and if so, what the mechanisms are. PMID- 22433670 TI - An e-learning reproductive health module to support improved student learning and interaction: a prospective interventional study at a medical school in Egypt. AB - BACKGROUND: The Public Health (PH) course at the medical college of Cairo University is based on traditional lectures. Large enrollment limits students' discussions and interactions with instructors. AIM: Evaluate students' learning outcomes as measured by improved knowledge acquisition and opinions of redesigning the Reproductive Health (RH) section of the PH course into e-learning and assessing e-course utilization. METHODS: This prospective interventional study started with development of an e-learning course covering the RH section, with visual and interactive emphasis, to satisfy students' diverse learning styles. Two student groups participated in this study. The first group received traditional lecturing, while the second volunteered to enroll in the e-learning course, taking online course quizzes. Both groups answered knowledge and course evaluation questionnaires and were invited to group discussions. Additionally, the first group answered another questionnaire about reasons for non participation. RESULTS: Students participating in the e-learning course showed significantly better results, than those receiving traditional tutoring. Students who originally shunned the e-course expressed eagerness to access the course before the end of the academic year. Overall, students using the redesigned e course reported better learning experiences. CONCLUSIONS: An online course with interactivities and interaction, can overcome many educational drawbacks of large enrolment classes, enhance student's learning and complement pit-falls of large enrollment traditional tutoring. PMID- 22433671 TI - Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta analysis of clinical evidence. AB - BACKGROUND: The characteristics of cervical lymphatic metastasis in nasopharyngeal carcinoma (NPC) are not completely understood. As such, radiotherapy to the entire lymphatic of the neck bilaterally has been empirically practiced even in early stage disease, although not supported by clinical evidence. We studied the pattern and probability of nodal metastasis through a meta-analysis of published evidences, with an aim to establish an evidence-based guideline for selecting and delineation of clinical target volume of neck lymphatics for conformation radiation for NPC. METHODS: A literature search yielded an initial 411 original articles, and 13 studies with 2920 NPC cases staged via MRI were included in this analysis. The occurrence of nodal metastasis was calculated and analyzed according to the respective regional nodal levels. RESULTS: 85% of NPC cases presented with lymphadenopathy. The most commonly involved regions include retropharyngeal (69%) and level II lymph nodes (70%). The overall probability of levels III, IV, and V nodal involvement are 45%, 11%, and 27%, respectively. Low-risk node groups included the supraclavicular, levels IA/IB and VI nodes, and parotid nodes with involvement rates at 3%, 0%, 3%, 0%, and 1%, respectively. Nodal metastases followed an orderly pattern and the probability of "skip" metastasis between levels varied between 0.5-7.9%. CONCLUSIONS: Lymph node metastasis in NPC follows a predictable and orderly pattern. The rarity of metastasis in certain nodal groups and "skip" metastasis suggest that reduced treatment volume is feasible in conformal radiotherapy for NPC. PMID- 22433672 TI - HRM confirmation of Neisseria gonorrhoeae in clinical specimens by G->A (position 857) mutation detection in the 16S rRNA gene before sequencing and after porA confirmation. AB - A total of 2273 specimens submitted to the Austin Hospital Pathology Service for Neisseria gonorrhoeae screening between September 1, 2009 and May 11, 2011 were used in this study. Specimens were simultaneously screened and confirmed with a previously published real time PCR assay for the opa gene (extra primers were included to increase sensitivity) and the porA gene respectively. The opa gene screen and initial porA gene confirmation yielded an N. gonorrhoeae positivity rate of 0.88% (20/2273) and 0.49% (11/2191) for specimens and patients respectively. A 16S rDNA High Resolution Melt confirmatory PCR was developed subsequently; this reduced the N. gonorrhoeae positivity rate to 0.35% (8/2273) and 0.27% (6/2191) for specimens and patients respectively (not altered by 16S sequencing). The higher rate of secondary confirmation (16S HRM) in patients compared with samples was due to the detection of species other than N. gonorrhoeae detected by the initial screening and confirmation test. This underlines the importance of performing the secondary confirmatory test that has been developed in this study. PMID- 22433673 TI - Streptococcal M1 protein-provoked CXC chemokine formation, neutrophil recruitment and lung damage are regulated by Rho-kinase signaling. AB - Streptococcal toxic shock syndrome is frequently caused by Streptococcus pyogenes of the M1 serotype. The aim of this study was to determine the role of Ras homologous (Rho)-kinase signaling in M1 protein-provoked lung damage. Male C57BL/6 mice received the Rho-kinase-specific inhibitor Y-27632 before administration of M1 protein. Edema, neutrophil accumulation and CXC chemokines were quantified in the lung 4 h after M1 protein challenge. Flow cytometry was used to determine Mac-1 expression. Quantitative RT-PCR was used to determine gene expression of CXC chemokine mRNA in alveolar macrophages. M1 protein increased neutrophil accumulation, edema and CXC chemokine formation in the lung as well as enhanced Mac-1 expression on neutrophils. Inhibition of Rho-kinase signaling significantly reduced M1 protein-provoked neutrophil accumulation and edema formation in the lung. M1 protein-triggered pulmonary production of CXC chemokine and gene expression of CXC chemokines in alveolar macrophages was decreased by Y-27632. Moreover, Rho-kinase inhibition attenuated M1 protein induced Mac-1 expression on neutrophils. We conclude that Rho-kinase-dependent neutrophil infiltration controls pulmonary tissue damage in response to streptococcal M1 protein and that Rho-kinase signaling regulates M1 protein induced lung recruitment of neutrophils via the formation of CXC chemokines and Mac-1 expression. PMID- 22433674 TI - Fungal pretreatment of lignocellulosic biomass. AB - Pretreatment is a crucial step in the conversion of lignocellulosic biomass to fermentable sugars and biofuels. Compared to thermal/chemical pretreatment, fungal pretreatment reduces the recalcitrance of lignocellulosic biomass by lignin-degrading microorganisms and thus potentially provides an environmentally friendly and energy-efficient pretreatment technology for biofuel production. This paper provides an overview of the current state of fungal pretreatment by white rot fungi for biofuel production. The specific topics discussed are: 1) enzymes involved in biodegradation during the fungal pretreatment; 2) operating parameters governing performance of the fungal pretreatment; 3) the effect of fungal pretreatment on enzymatic hydrolysis and ethanol production; 4) efforts for improving enzymatic hydrolysis and ethanol production through combinations of fungal pretreatment and physical/chemical pretreatment; 5) the treatment of lignocellulosic biomass with lignin-degrading enzymes isolated from fungal pretreatment, with a comparison to fungal pretreatment; 6) modeling, reactor design, and scale-up of solid state fungal pretreatment; and 7) the limitations and future perspective of this technology. PMID- 22433675 TI - Binding of cationic pentapeptides with modified side chain lengths to negatively charged lipid membranes: Complex interplay of electrostatic and hydrophobic interactions. AB - Basic amino acids play a key role in the binding of membrane associated proteins to negatively charged membranes. However, side chains of basic amino acids like lysine do not only provide a positive charge, but also a flexible hydrocarbon spacer that enables hydrophobic interactions. We studied the influence of hydrophobic contributions to the binding by varying the side chain length of pentapeptides with ammonium groups starting with lysine to lysine analogs with shorter side chains, namely omithine (Orn), alpha, gamma-diaminobutyric acid (Dab) and alpha, beta-diaminopropionic acid (Dap). The binding to negatively charged phosphatidylglycerol (PG) membranes was investigated by calorimetry, FT infrared spectroscopy (FT-IR) and monolayer techniques. The binding was influenced by counteracting and sometimes compensating contributions. The influence of the bound peptides on the lipid phase behavior depends on the length of the peptide side chains. Isothermal titration calorimetry (ITC) experiments showed exothermic and endothermic effects compensating to a different extent as a function of side chain length. The increase in lipid phase transition temperature was more significant for peptides with shorter side chains. FTIR-spectroscopy revealed changes in hydration of the lipid bilayer interface after peptide binding. Using monolayer techniques, the contributions of electrostatic and hydrophobic effects could clearly be observed. Peptides with short side chains induced a pronounced decrease in surface pressure of PG monolayers whereas peptides with additional hydrophobic interactions decreased the surface pressure much less or even lead to an increase, indicating insertion of the hydrophobic part of the side chain into the lipid monolayer. PMID- 22433676 TI - Alkhumra, not Alkhurma, is the correct name of the new hemorrhagic fever flavivirus identified in Saudi Arabia. PMID- 22433678 TI - [Diagnostic endoscopy of the nasal cavity and nasopharynx in premature newborn infants]. AB - Disturbed nasal breathing in the children always was a topical socio-medical problem and has remained such up to now. The objective of the present investigation was to estimate the potential of modern endoscopic techniques for diagnostics of disturbed nasal breathing in the premature infants and to develop therapeutic measures aimed at the prevention of destructive changes in the nose during therapy with the use of continuous positive airway pressure (CPAP). The study included 43 children ranging in the age from 1 month to 2 years (24 boys and 19 girls). All the newborn babies were transferred to the department of resuscitation and intensive therapy for the urgent treatment including respiratory support with the use of the CPAP technique. The endoscopic surveillance made it possible to exactly determine the causes responsible for the disturbances of nasal breathing in the children who survived the critical conditions, to estimate the anatomical and functional conditions of the nasopharyngeal structures, and to develop therapeutic and preventive measures to protect the nose from further destructive changes. PMID- 22433677 TI - Influence of aldosterone and salt or ouabain in a10 rat aorta smooth muscle cells. AB - BACKGROUND/AIMS: It is currently under debate whether aldosterone is able to induce fibrosis or whether it acts only as a cofactor under pathological conditions, e.g. as an elevated salt (NaCl) load. METHODS: We tested the interaction of 10 nM aldosterone, 15 mM NaCl and 1 MUM ouabain using rat aorta smooth muscle cells (A10) with respect to the following parameters: necrosis, apoptosis, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase activity, glutathione (GSH) content, collagen and fibronectin homeostasis and intracellular calcium distribution. RESULTS: Necrosis rates were increased after 48 h of incubation with aldosterone, salt or ouabain and in the combination of aldosterone and salt or ouabain. Apoptosis rates were decreased. A reduced defense capacity against oxidative stress was mirrored in the decreased G6PD activity and GSH content. Collagen III or fibronectin synthesis rates were unchanged, but gelatinase activity was increased resulting in a decreased media collagen III and fibronectin content. Calcium stores were increased by aldosterone in combination with ouabain. CONCLUSION: Aldosterone and salt per se can lead to cell injury that is aggravated in combination or with cardiotonic steroids. In cooperation with other vascular cells, this can generate a permissive milieu enabling aldosterone or salt to promote more extensive vascular injury. PMID- 22433679 TI - [Current potential of otorhinolaryngology for diagnostics of hearing impairment in breastfeeding and young children presenting with otitis media]. AB - Acute otitis media (AOM) is one on the most common diseases in the young children. From 21 to 62% of the infants experience AOM within the first year of life; the number of such patients amounts to 71-74% by the age of 3 years. Modern approaches to diagnostics of the loss of hearing in breastfeeding and young children as a result of acute otitis media. The authors emphasize the importance of early diagnostics of acoustical disturbances resulting from otitis media and discuss the methods for their therapy and rehabilitative treatment aimed at reducing the adverse effects of hearing impairment on the speech development and intellectual abilities of the children. PMID- 22433680 TI - [The hearing function in prematurely born children during the first year of life depending on the duration of gestation estimated by the otoacoustic technique]. AB - A total of 239 premature infants of different gestational age remained under the observation throughout the first year of their life for the elucidation of dynamics of the parameters of DP-gram. It was shown that the absence of the distortion-product otoacoustic emission (DPOAE) response during the first months of life of the premature infants was due to immaturity of their cochlear receptor apparatus. The predominant peak was recorded at a frequency of 2 kHz, regardless of the gestational age. The amplitude of DP-gram values in premature infants lay in the low-frequency region (f2=1 kHz) and never reached the high level. The most intensive maturation of the cochlear receptor apparatus is observed during the first 6 months in premature infants of the gestational age below 28 weeks. After the sixth month, the "high-level" response must develop, regardless of the gestational age. By this time, the intensity of maturation of the cochlear receptor apparatus in all age groups of premature infants is virtually identical (p>0.05). PMID- 22433681 TI - [Endoscopic surgery for the treatment of rhinosinusogenic orbital complications in children]. AB - To-day, the problem of rhinosinusogenic orbital complications in children remains as topical as it used to be in the past. More than 70% of children with these conditions fail to receive adequate pathogenetic therapy during the first days after the onset of the disease because of poor diagnostics which leads to the development of severe purulent complications in both the paranasal sinuses and the orbit necessitating the surgical treatment. The use of endoscopic endonasal surgery in children with these problems provides a number of advantages, such as safety, efficacy, and physiological treatment. They promote a significant reduction in the duration of the treatment, permit to avoid unnecessary radical interventions, and prevent the development of relapses of the disease. PMID- 22433682 TI - [The rationale for the efficacious puncture therapy of acute suppurative sinusitis in the children]. AB - The objective of the present study was to estimate the clinical efficacy of local antibacterial therapy in the children presenting with sinusitis. The study included a total of 104 patients allocated to 2 groups. In one of them, the patients underwent therapeutic and diagnostic punctures of the maxillary sinuses to obtain the material for subsequent microbiological analysis and to administer antibiotics into the sinuses. The results of the study give evidence that local application of antibacterial agents in combination with mucolytic drugs is at least as efficient for the treatment of acute maxillary sinusitis as the traditional methods for the management of the same conditions with the use of systemic antibiotics. The study confirmed the expediency of using the puncture technique for the treatment of patients with acute inflammatory process in maxillary sinuses. PMID- 22433683 TI - [The state of the larynx in children following repeated and recurrent croup]. AB - The obstructive forms of laryngitis and/or laryngotracheitis are the emergency conditions in the pediatric practice that frequently necessitate hospitalization of the affected patients. According to R.J. Rosychuk and co-workers, such patients make up to 6% of the total number of children admitted to stationary clinics. The authors discuss the problem of recurrent catarrhal croup in the children and its differential diagnosis from other diseases. The results of endoscopic and virological examination of the children with repeated or recurring croup are discussed. The children of this group most frequently present with infections by respiratory syncytial and parainfluenza viruses. The endoscopic examination has revealed various forms of chronic laryngitis in 21 (42%) children, subacute (including reactive) laryngitis in 8 (16%), and the developing nodules in the vocal cords of 15 (30%) patients. Six (12%) patients experienced a change of the quality of voice in the absence of structural alterations in the larynx (functional dysphonia). It is concluded that the results of endoscopic and virological examination do not correlate with one another. PMID- 22433684 TI - [The influence of application of the assisted reproductive technologies on the state of ENT organs in children]. AB - The objective of the present study was to estimate the state of ENT organs in the children born after assisted reproductive technologies (ART). A group of 208 children at the age from 1 to 3 years enrolled in the study included 97 ones born following application of the assisted reproductive technologies. It is concluded that the use of the assisted reproductive technologies has no appreciable effect on the extent and the structure of ENT organ morbidity in the children. PMID- 22433685 TI - [The results of audiologic examination by the method of evoked otoacoustic emission in children born from multiple pregnancies]. AB - The objectives of the present work were to study and evaluate the state of the peripheral portion of the acoustic analyzer in premature infants born after multiple pregnancies. The measurements were made by the so-called evoked otoacoustic emission technique. A total of 62 premature infants born after multiple pregnancies were available for the examination. Diagnostics of the hearing function by the method of evoked otoacoustic emission was performed using an ECLIPSE device (Interacoustics, Denmark). Analysis of the results of audiological examination indicates that up to 90.3% and 3.2% of the premature infants aged 6 months showed otoacoustic emission from both ears and from one ear respectively. 6.5% of the children failed otoacoustic emission screening. PMID- 22433686 TI - [Endoscopic surgical correction of congenital choanal atresia in children]. AB - The authors present a review of the literature and their original data concerning etiology, clinical manifestations, diagnostics, and methods of surgical intervention for the management of children presenting with congenital choanal atresia. The method of endoscopic choanotomy employed by the authors is described. PMID- 22433687 TI - [The state of the middle ear and the audiological profile in the children operated after the first three years of life for correction of congenital labial and palatal clefts]. AB - The methods of otoscopy, acoustic tympanometry, and tonal threshold audimetry was used to examine 22 children above the age of 3 years who had been operated for the correction of congenital labial and palatal clefts. Tympanograms of types B and C were obtained in 19 (86%) and 3 (13%) patients respectively, regardless of the cleft type. The impairment of hearing due to compromised sound conduction was documented in 14 (74%) children presenting with type B tympanograms; the mixed hearing loss with an air-bone interval up to 20-25 dB and the upper sound conduction threshold of 40 dB was recorded in 3 (14%) patients. Two (9%) children suffered grade 1 sensorineural loss of hearing with the bone conduction threshold elevated up to 30 dB at all frequencies. The conservative treatment resulted in the complete normalization of the otoscopic picture and audiological profile in 2 (9%) children while 7 (32%) ones experienced retraction of the tympanic membranes during otoscopy in conjunction with the incomplete light reflex, whity-pink colour, type B or C tympanograms, and conductive hearing impairment. The auditory threshold was as high as 10-20 dB in 13 (59%) children presenting with various types of hearing loss and impairment of sound conduction to 40 dB. The conservative treatment had no appreciable positive effect on these patients. PMID- 22433688 TI - [Endoscopic diagnostics of voice disorders in breastfed and young children]. AB - The objective of the present work was to study the prevalence, etiology, and semiotics of lesions in the acoustic apparatus. The secondary objectives were to estimate the informative and diagnostic value of various methods for the assessment of the state of the vocal apparatus (rigid endoscopy, fibroscopy, stroboscopy, and acoustic analysis of the voice) and to evaluate the prospects for their use in clinical practice. Moreover, the study was aimed at the development of an optimal therapeutic and diagnostic algorithm for the breastfeeding and young children suffering voice disturbances. The study included a total of 188 children aged from 4 days to 3 years presenting with the altered quality of voice who were examined using the clinical and instrumental methods for the estimation of the state of the larynx (rigid endoscopy, fibroscopy, and acoustic analysis of the voice) in combination with the modern computer-assisted technologies for the recording and processing of video images. It was found that disturbances of vocalization formation in the overwhelming majority of breastfeeding and young children (95.7%) can be attributed to dysphonia. Laryngeal pathology is most frequently diagnosed during the first year of life (28.2%). The leading cause of laryngeal lesions is inflammatory diseases (56.4%) followed by congenital malformations (25%). PMID- 22433689 TI - [Verification of the computed tomography data on the topography of the facial nerve canal in young children with the use of dissection technique]. AB - The authors describe decompression of the facial nerve in the preparations of the temporal bone from young children. The results of dissection were compared with computed tomographic images that reflect the X-ray topography of the facial nerve. It is concluded that the data thus obtained should be taken into consideration when planning and performing surgical interventions on the middle ear in the young children. PMID- 22433690 TI - [Congenital malformations of the ear--state-of-the-art review]. AB - The rehabilitative treatment of the children presenting with congenital malformations of the external and middle ear requires the use of up-to-date technologies for diagnostics, surgical interventions, and prosthetic treatment in combination with genetic counseling. Many problems related to these issues remain unresolved despite recent progress in this field. PMID- 22433691 TI - [First experience with the application of the implantable prostheses of osseous conduction BAHA]. AB - The first experience with the application of the implantable prostheses of osseous conduction (BAHA) is described. The results of the present study suggest high efficacy of the method in question for the rehabilitative treatment of children with bilateral chronic otitis and/or congenital malformations of the ear. PMID- 22433692 TI - [Histiocytosis of the temporal bone with the destruction of the walls of the superior and posterior semicircular canals]. AB - A case report of histiocytosis of the temporal bone in a child with the destruction of the walls of the superior and posterior semicircular canals is presented. The treatment given to the patient resulted in positive dynamics of his clinical condition. Computed tomography revealed the signs of reparation of osseous pyramidal defects. PMID- 22433693 TI - [Changes of immunological status in children presenting with recurrent nasal furuncles]. AB - The authors present the original observations of the occurrence of nasal furuncles in the children residing in Moscow. They investigated the lymphocyte subpopulation composition and the content of the main classes of immunoglobulins in the peripheral blood of the children with clinical manifestations of recurrent nasal furuncles. It was shown that functional disturbances of the immune system in the children suffering recurring nasal furuncles affect both its cellular and humoral components, i.e. T-helpers and B-lymphocytes/immunoglobulin synthesis respectively. PMID- 22433694 TI - [Anatomical and morphological peculiarities of endonasal structures in children with allergic rhinitis]. AB - The paper considers the current concepts of diagnostics and treatment aspects of allergic rhinitis in children. Both conservative and surgical methods of treatment are presented. Personal data is presented. Practical issues discussed in the paper concern pediatric allergists as well as pediatric ENT-specialists. A joint tactic to management of these patients is outlined. PMID- 22433695 TI - [Diagnostics of acute otitis media in newborn and breastfed babies]. AB - A method for the examination of the middle ear in newborn and breastfeeding infants with the use of a digital video otoscope is discussed. This non-invasive otoscopic technique is currently believed to be the most informative, convenient, and time-saving tool for the examination of the entire tympanic membrane in children of the above age groups. Its application allows for timely diagnostics and treatment of acute otitis media. PMID- 22433696 TI - [Recurrent and severe paratonsillitis in children]. AB - The authors report their original observations of the peculiarities of recurrent and severe paratonsillitis in the children surveyed in Moscow. Special attention is given to the age-structure of the affected patients, causes underlying the development of paratonsillitis, and risk factors of its recurrent clinical course. Analysis of characteristics of local immunity of the palatal tonsils (such as the defensive level in tonsillar mucosa) involved the children with clinical manifestations of recurrent paratonsillitis and its episodic flares. It was shown that paratonsillitis is associated not only with inflammation of the paratonsillar cellular tissue but also with the immunodeficiency disorders at the local level. PMID- 22433697 TI - [The role of congenital immunity components in the protection of the intranasal mucous membrane under normal conditions and in the case of hypertrophy of adenoid vegetation]. AB - The objective of the present work was to evaluate expression of the genes recognizing receptors of congenital immunity (Toll-like receptors) and human antimicrobial peptide HBD-2 in the cells of nasal cavity mucosa of the children aged from 2 to 8 years and suffering hypertrophy of adenoid vegetations. A total of 49 patients at the age from 2 to 8 years were included in the study. The control group was comprised of 12 age-matched healthy children. The level of gene expression in epithelial cells was measured in the samples obtained from nasal cavity mucosa using the real-time polymerase chain reaction technique. It is concluded that the proposed approach makes it possible to estimate the state of the congenital immunity system at the level of nasal cavity mucosa in the patients with a variety of ENT organ diseases and to choose the most adequate strategy for their treatment. PMID- 22433698 TI - [Experience with the treatment of juvenile respiratory papillomatosis in childhood]. AB - A total of 384 children at the age ranging from 8 months to 17 years were admitted to the Russian Children's Clinical Hospital during the period between 1995 and 2009 for the treatment of juvenile respiratory papillomatosis. The overwhelming majority of the patients (n=242 or 63%) presented with the extensive lesions involving more than two segments of the larynx. 115 (30%) children had lesions in both the larynx and the trachea (including 4 (1.1%) ones with the affected bronchi and lungs). The laryngeal and tracheal neoplasms were removed with the help of microinstruments, such as tracheal forceps, under microscopic or endoscopic control. The combined treatment included therapy with roferon-A and ribavirin supplemented by interferon-alpha 2v. The duration of the treatment was 6 months in the least. It resulted in the almost two-fold lengthening of the periods between the relapses and the reduction of the extent of the pathological process. The outcome of the treatment was considered as positive (duration of remission 1 year or more) according to the currently accepted classification in 282 (73.4%) children. PMID- 22433699 TI - [Surgical treatment of children presenting with juvenile angiofibroma of the skull base]. AB - A total of 475 children have been operated at the Russian Children's Clinical Hospital during the last 20 years for the removal of benign and tumour-like neoplasms localized mostly in the nasal cavity, paranasal sinuses, and nasopharynx. As many as 361 (76%) of these patents were found to have juvenile angiofibroma of the base of the skull. In most of them, the tumour was diagnosed at the late stages of development. Accordingly, the scarcity and non-specific character of early clinical manifestations of the disease taken together with complicated topographic anatomy of angiofibromas and the difficulty of detailed visualization of the affected zone in young children account for their late hospitalization. The angiomatous lesions prevailed in the spheno-ethmoidal and basiliar regions. The children were operated through the nasomaxillary approach as described by Denker (in V.S. Pogosov's modification) without ligation of external carotid arteries. Since 1996, surgery has been performed after endovascular occlusion of the vessels feeding the tumour, with the maximally possible sparing of bone structures and taking into account the continuing active growth and formation of the facial skeleton. Relapses were documented in 43 (12%) patients. Postoperative radiotherapy had to be applied in the children showing recurrent growth of the tumour or its intracranial extension and in the cases when radical removal of the tumour proved impracticable because of its localization in the vitally important anatomical regions. PMID- 22433700 TI - [Experience with the treatment of cicatrical laryngotracheal obstruction in children]. AB - A total of 152 children presenting with various forms of laryngotracheal obstruction were admitted to the Russian Children's Clinical Hospital during the period between 1995 and 2009. Cicatrical stenosis predominated in the structure of chronic laryngeal obstruction accounting for 33% of the cases. In the overwhelming majority of these patients, the main cause underlying the process of formation of rough cicatrical tissue in the larynx was a long-standing intubation injury (3-4 days during the inflammatory reaction and 7-8-day laryngeal intubation period). The patients with pronounced cicatrical obliteration of the larynx underwent laryngotracheal reconstruction of the laryngeal lumen with the formation of an external passage, removal the cicatrical conglomerate with the obligatory enlargement of the laryngeal cross section area in the stenosed region, and subsequent long-term prosthetic treatment with plastic closure of tracheostoma. Endoscopic microsurgery in the cicatrical stenosis region during direct laringoscopy under video control was used to treat the patients with superficial forms of cicatrical stenosis, such as membrane stenosis, synechiae, and circular stenosis, characterized by moderate narrowing of the laryngeal lumen. PMID- 22433701 TI - [Surgical treatment of chronic rhinosinusitis in childhood]. AB - The objective of the present study was to evaluate the long-term results of surgical treatment of chronic rhinosinusitis in 320 children depending on the from of the disease. The main cause of relapses of the exudative forms was obliteration of natural and artificial (formed in the course of surgical intervention) intersinus anastomoses as a result of the adhesion process. One step combined surgery for the treatment of chronic rhinosinusitis (sinusotomy with simultaneous septoplasty, adenotomy, and turbinate reduction) is rarely performed in the children because of the high risk of the adhesive process. The highest frequency of relapses was documented after the surgical treatment of polypous forms of chronic rhinosinusitis. It is recommended that the treatment of polyposis in the young children should be restricted to polypotomy in the nasal cavity in combination with corticosteroid therapy whereas that in the elder patients should be extended to sinusotomy since it is known to result in fewer relapses. The best results were obtained with the management of cystic forms of chronic rhinosinusitis. PMID- 22433702 TI - [First experience with the use of tympanostomy for the management of acute otitis media in children]. AB - The present study included 140 children presenting with acute suppurative otitis media (AOM) who received the standard treatment in combination with paracentesis. In 14% of the patients (28 ears), paracentesis had to be repeated, sometimes in triplicate or even oftener. Seven children with AOM were treated with the use of tympanostomy. This method makes it possible to avoid repetition of paracentesis, ensures faster evacuation of the contents of the tympanic cavity, and reduces the duration of hospitalization; moreover, it prevents the development of exudative otitis media and accelerates the recovery of the hearing function. PMID- 22433703 TI - [Prevention of respiratory infection in patients following surgical intervention]. AB - The objective of the present study was to estimate the efficacy of therapy with hexetedine for the prevention of the respiratory infection in the patients undergoing surgical intervention. The study included 64 patients (28 adults and 36 children) ranging in the age from 3 to 55 years who were examined before and after surgery (radiosurgical tonsillectomy and radiosurgical uvulopalatoplasty). Complete clinical examination was supplemented by a microbiological study of cultivated mucosal swab samples obtained from the pharynx before and after the treatment. 41 patients of the study group received hexetedine (hexoral) for the 4 days preceding the operation and during 3 days of the postoperative period. It was shown that the patients treated with hexetedine both in the pre- and postoperative periods experienced a substantial decrease in microbial infestation of pharyngeal mucosa and accelerated elimination of the inflammatory process. Moreover, the general therapeutic effect on day 5 after surgery was more pronounced in the hexetedine-treated patients compared with controls. PMID- 22433704 TI - [Efficacy of Ingavirin in the combined treatment of ARVI complicated by tonsillitis]. AB - This paper was designed to report the results of an open randomized comparative study of therapeutic efficacy of Ingavirin used for the treatment of adult patients with acute respiratory viral infections (ARVI) complicated by lacunar tonsillitis. The study has demonstrated that the combined application of an antibacterial agent and Ingavirin showing antiviral and anti-inflammatory properties produces a significantly more pronounced therapeutic effect compared with the standard treatment of the disease in question. This finding gives reason to recommend Ingavirin for the wide clinical application as an agent for combined therapy of acute respiratory viral infections. PMID- 22433705 TI - [Estimation of efficacy of Hexalyse used for the treatment of acute pharyngitis]. AB - The objective of the present study was to elucidate the relationship between the activity of the interferon system at the local level and the frequency of the development of relapses of acute inflammation of pharyngeal mucosa. The secondary objective was to estimate the possibility, necessity, and efficacy of the correction of the abnormal local immune response with the use of immunomodulatory agents. A total of 45 patients presenting with acute pharyngitis were available for the examination. They were allocated to two groups comprised of 25 and 20 patients respectively. Those in group 1 were given Hexalyse, a composite preparation for the local application. The patients of group 2 were treated with Strepsils. The study included general and specialized otorhinological examination as well as the evaluation of interferon production at the local level by measuring (using immunoenzyme assay) the concentration of interferon-alpha in the saliva before and on days 3 and 5 after the initiation of therapy. It was shown that the adaptive mechanisms of pharyngeal mucosa in acute pharyngitis are realized through activation of the interferon system. Elimination of the inflammatory process was accompanied by normalization of interferon-alpha level in the saliva regardless of the therapeutic modality used. One third of the patients presenting with acute pharyngitis suffered insufficiency of interferon production. It is concluded that the inclusion of an immunomodulatory agent, such as Hexalyse, in the combined treatment of such patients activates biosynthesis of interferon-alpha and leads to the reduction in the frequency of relapses of the disease. The results of the study of the relationship between the concentration of interferon-alpha in the saliva, the duration of acute pharyngitis, and the frequency of its post-treatment relapses were used to develop the practical recommendations for the prescription of Hexalyse for the treatment of patients with this pathology. PMID- 22433706 TI - [Use of original herbal medicinal product Sinupret for treating patients in the postoperative period following surgical intervention on internasal septum and inferior turbinated bones]. AB - The present study was designed to estimate the efficacy of the herbal medicinal preparation sinupret applied for the treatment of the patients who underwent the surgical intervention on the internasal septum and inferior turbinated bones. A total of 78 such patients were examined in the postoperative period following the operative correction of the deformed internasal septum. The study has shown that the restoration of functional activity of intranasal mucosa occurred faster in the patients treated with Sinupret than in those receiving standard therapy. PMID- 22433707 TI - [The estimation of clinical efficacy of eurespal in the postoperative period following surgical intervention on paranasal sinuses]. AB - The objective of the present study was to estimate the influence of Eurespal (Fenspiride) on the changes of fibrous coating in the nasal cavities, transport function of ciliated epithelium, and dynamics of electrochemical properties of the nasal secretion by means of direct joulemetry following surgical intervention on paranasal sinuses (PNS). The study included 30 patients aged from 18 to 65 years presenting with chronic purulent sinusitis in the phase of exacerbation, polypous rhinosinusitis, and acute pyogenic process in PNS. The results of the study indicate that the use of Eurespal significantly accelerates the recovery of the transport function of intranasal mucociliated epithelium which results in a faster regression of the fibrous coat on intranasal mucosa and mucosal oedema. These changes lead to the improvement of drainage and aeration of the paranasal sinuses. PMID- 22433708 TI - [Off-season manifestations of pollen hypersensitization]. PMID- 22433709 TI - [The modern algorithm for treatment and diagnostics of otomycosis]. AB - The author presents the results of analysis of the current scientific literature concerning the prevalence of otomycosis in conjunction with the original data obtained during observation of 1762 patients who applied for the medical aid to the Counseling Department of this Centre and the study of out-patient medical records. It was shown that ENT fungal infections make up an appreciable proportion in the structure of inflammatory ear pathology. Specifically, the prevalence of fungal otitis amounts to 25.23% of the total ENT morbidity. In addition, the major factors responsible for the development of otomycosis and its most characteristic clinical symptoms were revealed. The analysis of the spectrum of pathogenic agents contributing to the evolvement of fungal otitis was performed. It has demonstrated the ever increasing involvement of Candida non albicans strains in the development of chronic ENT inflammation. Various medicamental preparations for the treatment of fungal otitis are characterized with special reference to the composite agent sandibiotic designed for the treatment of this pathology. PMID- 22433710 TI - [External otitis in children: etiology and principles of therapy]. AB - External otitis accounts for 21 to 25% of all inflammatory ear diseases. This paper presents the original data providing a deeper insight into etiology of this disease taking into consideration the great variety of its pathogenic agents, the possibility of development of mixed forms, and changes of whether conditions at the peak of morbidity. In addition, the results of assessment of the efficacy of Pimafucort designed for both mono- and combined therapy of the disease of interest are reported. PMID- 22433711 TI - Synergistic antitumor efficacy of sequentially combined paclitaxel with sorafenib in vitro and in vivo NSCLC models harboring KRAS or BRAF mutations. AB - Studies on non-small cell lung cancer (NSCLC) patients with KRAS or BRAF mutations are urgently needed to improve clinical outcomes. We evaluated the cytotoxicities of paclitaxel and sorafenib alone and in combination in NSCLC cell lines with KRAS or BRAF mutations and investigated the mechanism of the interaction between the drugs. We found synergistic antitumor efficacy with paclitaxel followed by sorafenib in in vitro and in vivo models of NSCLC. And, we determined that downregulation of the phosphorylated ERK and Rb, and Mcl-1 plays a critical role in the synergistic activity of the drugs. Further clinical trials are needed to verify the antitumor efficacy of this combination. PMID- 22433712 TI - Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation. AB - Identification of tumor-suppressor genes (TSGs) silenced by aberrant methylation of promoter CpG islands (CGIs) is important, but hampered by a large number of genes methylated as passengers of carcinogenesis. To overcome this issue, we here took advantage of the fact that the vast majority of genes methylated in cancers lack, in normal cells, RNA polymerase II (Pol II) and have trimethylation of histone H3 lysine 27 (H3K27me3) in their promoter CGIs. First, we demonstrated that three of six known TSGs in breast cancer and two of three in colon cancer had Pol II and lacked H3K27me3 in normal cells, being outliers to the general rule. BRCA1, HOXA5, MLH1, and RASSF1A had high Pol II, but were expressed only at low levels in normal cells, and were unlikely to be identified as outliers by their expression statuses in normal cells. Then, using epigenome statuses (Pol II binding and H3K27me3) in normal cells, we made a genome-wide search for outliers in breast cancers, and identified 14 outlier promoter CGIs. Among these, DZIP1, FBN2, HOXA5, and HOXC9 were confirmed to be methylated in primary breast cancer samples. Knockdown of DZIP1 in breast cancer cell lines led to increases of their growth, suggesting it to be a novel TSG. The outliers based on their epigenome statuses contained unique TSGs, including DZIP1, compared with those identified by the expression microarray data. These results showed that the epigenome-based outlier approach is capable of identifying a different set of TSGs, compared to the expression-based outlier approach. PMID- 22433713 TI - Crosstalk between NFkB and glucocorticoid signaling: a potential target of breast cancer therapy. AB - Breast cancer (BC) is an aggressive and high mortality cancer that can be classified into five molecular subtypes, based on gene expression profiling. The extreme heterogeneity poses difficulties for understanding and treating BC. Among many risk factors, inflammation plays a causal role in BC progression and recurrence, wherein NFkB and glucocorticoid receptor (GR) are critical transcription factors in regulating inflammation. NFkB is generally pro inflammatory, and GR is anti-inflammatory, constituting a Yin-Yang mode in regulation. Thus, the crosstalk between these two transcription factors exerts even more important functions in determining the survival or apoptosis of BC cells. NFkB is widely involved in the initiation and progression of BC; its inhibitors are emerging as a potent primary or adjuvant therapy. On the other hand, glucocorticoids (GCs) are already used as neo-adjuvant and adjuvant therapies to treat various cancers with remarkable effects to induce apoptosis in leukemia and lymphoma. However, GCs unexpectedly promote cancer cell survival and induce chemo-resistance in BC. To understand this unique transcriptional interplay in BC, in this review we discuss the functions of NFkB and GR in BC development and progression by emphasizing their cross talk at cell signaling and protein interaction levels; and the future perspectives are proposed for the development of new therapeutic approaches for BC based on these signaling pathways. PMID- 22433714 TI - An easy and versatile 2-step protocol for targeted modification and subcloning of DNA from bacterial artificial chromosomes using non-commercial plasmids. AB - BACKGROUND: Promoter-specific expression of foreign DNA in transgenic organisms often relies on bacterial artificial chromosomes (BACs). This approach requires modification and subcloning of BAC-DNA by recombineering technologies in Escherichia coli. Most current protocols rely on commercial kits or isolation of BACs, their transfer between different host strains, and their restriction. FINDINGS: In this report we present a 2-step protocol for efficient modification and subcloning of DNA from bacterial artificial chromosomes using the non commercial plasmids pKM208 and pTP223, distributed from addgene.com. A targeting cassette was successfully integrated into a BAC and 42 kb of this construct were subcloned. Both a plasmid-derived substrate with longer homology arms and a PCR generated substrate with short homology arms (50 bp) were used for recombination. pKM208 and pTP223 contain all required genes for recombineering, but differ in their antibiotic resistance genes. This makes the system independent of the selection markers on the DNA molecules targeted for recombination. CONCLUSIONS: The time and cost saving protocol presented here compares favorably to currently used systems. Using non-commercial plasmids, it allows targeted modification and cloning of large DNA (> 40 kb) fragments in vivo without restriction and ligation. Furthermore, both steps are performed in the same host eliminating the need to isolate BAC DNA and to use different bacterial strains. PMID- 22433715 TI - Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. AB - There is genetic evidence that schizophrenia is a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) of schizophrenia have had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood of schizophrenia patients and controls. We examined the 6192 single-nucleotide polymorphisms (SNPs) with significance threshold at P<0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n=437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set of schizophrenia cases and controls (n=202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5, TRIM26 and HLA-DRB3) coincided with the direction expected from meta analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region in schizophrenia susceptibility. PMID- 22433716 TI - Graphene resist interlacing process for versatile fabrication of free-standing graphene. AB - We present a graphene resist interlacing process (GRIP) to sandwich graphene between polymer lines in a cloth-like fashion, making it more accessible for experiments and applications. We demonstrate the handling of large-area graphene in this way. Here, GRIP is used to fabricate supports for transmission electron microscopy. These supports improve the imaging quality of nanoparticles, as we show by comparison to imaging on standard lacey carbon supports. PMID- 22433718 TI - Evidence-based management of carotid stenosis: recommendations from international guidelines. AB - A 50-99% stenosis of the extracranial internal carotid artery can be in detected in 1-3% of all adults. Embolising plaques or acute carotid occlusions cause cerebral ischemia in 1-5% of all patients with an asymptomatic 50-99% stenosis of the internal carotid artery. The prevention of carotid-related strokes by best medical treatment, carotid endarterectomy, or carotid stenting has been evaluated by several prospective randomized multi-center trials. Under the auspices of the German Vascular Society an interdisciplinary evidence- and consensus-based guideline for the management of patients with an extracranial carotid stenosis was initiated and will be published in 2012. Therefore all recent national and international guidelines for stroke management, stroke prevention and carotid artery disease published between 2008 and 2011 were reviewed. This paper gives an overview about these guidelines and their most important recommendations with respect to carotid artery stenosis. PMID- 22433719 TI - Local anesthesia and exposure for carotid endarterectomy: background and technical realization. AB - While carotid endarterectomy is an established method for the treatment of symptomatic as well as high-grade asymptomatic carotid artery stenoses, there is a considerable variation concerning the kind of anesthesia used as well as technical details of the operation. In the present article differing arguments on local versus general anesthesia as well as a transverse versus a longitudinal skin incision will be discussed. Furthermore, possible access routes to the carotid bifurcation, the retrojugular compared to the ventrojugular approach, will be presented in detail. PMID- 22433720 TI - Strategies for reducing microemboli during carotid artery stenting. AB - Carotid stenting in standard risk patients has recently received supportive recommendations from the American Heart Association, in a guideline document endorsed by 14 societies with diverse but vested interest in carotid intervention. The procedural hazard i.e. the composite endpoint: all stroke/death/myocardial infarction (MI) for carotid stenting and endarterectomy are equivalent, as is survival free of ipsilateral stroke for the two interventional strategies. However, the microembolic burden generated by endarterectomy and stenting is discrepant and although the fate and clinical relevance of diffusion-weighted magnetic resonance imaging new white lesions and of microembolic signals on transcranial Doppler remain disputed, empathic reasoning would suggest that technical and/or procedural modifications should be explored and employed during carotid stenting in order to try addressing microemboli. This article seeks to define those procedural steps likely to be associated with microemboli during carotid stenting and thus provide avoidance manoeuvres and/or possible solutions. PMID- 22433721 TI - Biology and treatment of recurrent carotid stenosis. AB - The benefit of carotid revascularization in long term stroke prevention is hampered by the occurrence of restenosis at the site of surgery, which is associated with a modestly increased risk of stroke. Preventing restenosis is an important part in the overall treatment and prevention of stroke in patients with carotid artery disease. The site of recurrent stenosis is primarily situated at the ends of, or within the confines of the original endarterectomy site and the suture lines. Several etiological factors but also surgical technique play a key role in the development of carotid recurrent stenosis. However, the exact pathophysiology of recurrent disease is not fully understood. The morphogenesis of recurrent lesions is a process of ongoing thrombogenesis beginning immediately after blood flow is restored across the endarterectomized surface. The early lesion is subsequently formed as the thrombus organizes and smooth muscle cell ingrow occurs, creating a supposed morphologic distinction between early (within 2 years of CEA) and late (over 2 years) recurrent carotid disease. Further, plaque composition at primary CEA is an independent predictor of restenosis after CEA and dissection of a lipid-rich and macrophage infiltrated plaque is associated with a reduced risk of stenosis. CEA of stable atherosclerotic plaques has been associated with an increased risk for restenosis. In addition, stable atherosclerotic plaque characteristics with low macrophage content and small lipid core size are associated with an increased incidence of restenosis compared with unstable inflammatory lesions. The implication of these findings is that macrophage infiltration and lipid core size are the plaque characteristics that should be targeted with noninvasive plaque imaging to assess the risk of patients with recurrent carotid stenosis to become symptomatic. Furthermore, the longer the delay from stroke until revascularization, the more the lesion stabilizes and the higher the risk for restenosis. Thus, operating on symptomatic patients within a few weeks after the index event could potentially reduce the risk of restenosis. The optimal treatment strategy for restenosis has yet to be defined. Optimally, one would strive to a "tailor-made" treatment comprising of best medical therapy, surgery or CAS including regular follow-up. With the ongoing developments and insights in histological plaque characterization this tailor made treatment might be available in the near future, thereby reducing the risk of, or maybe even avoiding the development of restenosis. PMID- 22433722 TI - Endovascular strategies for the management of aortic connective tissue disorders. AB - During the last several decades, the endovascular management of patients with aortic connective tissue disorders (CTD) has greatly evolved. While open surgery remains the gold standard, endovascular strategies can play an important role in the overall management of arterial lesions. CTD result from mutations in specific genes responsible for maintaining and regulating tissue integrity. While each CTD has a unique phenotype, all patients are at an increased risk for the early onset of aortic aneurysms and dissections, leading to premature death if left untreated. In such patients, the interface between the device and arterial wall remains the primary concern, guiding the selection of appropriate landing zones and the means to ensure a circumferential seal excluding the aneurysm. In patients with aortic dissections, the goal of the endovascular treatment should achieve true lumen perfusion, favorable remodeling of the false lumen, and prevent aortic growth and rupture. While patients with proximal dissections should be treated with open surgery, distal dissections can be managed with a pure endovascular approach by placing the stent- graft proximal and distal to the entry sites of false lumen. Albeit less common than aortic lesions, aneurysms of the subclavian, vertebral, visceral, iliac, and internal iliac arteries may be present, underscoring the need to screen the entire vascular bed. Endovascular strategies may be implemented in each of these anatomical locations but may require a hybrid approach, involving both open and surgical techniques. Last, it must be stressed that both endovascular and open surgical repair represent treatments, not cures for these diseases. Therefore, every intervention must be strategized with the need for future reoperations. PMID- 22433723 TI - Endovascular treatment of acute aortic dissection: indications, techniques and results. AB - Acute aortic dissection is the commonest life-threatening event involving the aorta. Endovascular solutions have revolutionised the treatment of this pathology. This article describes the optimal management of acute dissection, through primary medical management, planning endovascular solutions, technique of stent-graft deployment, adjuncts to endovascular therapy and future developments. It reports the current evidence for improved outcomes with endovascular management and explores the challenges that increasing application of this technology will face. PMID- 22433724 TI - Technical challenges and anatomic anomalies encountered during aortic surgery. AB - Since the introduction of endovascular techniques for the treatment of aortic pathologies, clinical application of these lesser invasive procedures has increased exponentially during the last two decades and changed daily vascular practice completely. Starting in the infra-renal aorta, the indications for endovascular repair have gradually extended to the suprarenal aorta, aortic arch, descending and thoracoabdominal aorta. In addition, other pathologies than aneurysms have been treated by endovascular means, including dissection, traumatic injuries, penetrating aortic ulcer, intramural hematoma and aorto bronchial fistula. With increased application, short-term and longer-term technical failures have developed, in the majority of cases managed by repeat endovascular techniques. However, these complications cannot always be solved by endotechniques, requiring conversion to open surgery. At present there are additional reasons why open surgical repair remains a mainstay in the treatment of complex aortic diseases. Younger patients might choose for traditional surgery because of the unknown durability of complex endovascular reconstructions. Patients with connective tissue disease suffer from vulnerable aortic tissue in which endografts might behave different as compared to degenerative aneurysms. Therefore, the modern vascular surgeon should not only be trained in endovascular procedures but also master the wide spectrum of open surgical techniques. Besides anatomical knowledge and standard vascular handling, the surgeon must be familiar with unusual variations and unexpected situations. PMID- 22433725 TI - EVAR for aortoiliac aneurysms, including iliac branched grafts. AB - For aortoiliac aneurysms involving the common iliac arteries several treatment options have been developed. In the early stages of the endovascular era the internal iliac artery was usually overstented with or without embolization. Thereafter relocation or bypass techniques were used in an attempt to preserve the internal iliac artery. Then endovascular techniques were used that involved the need for a femoro-femoral cross-over bypass. The development of iliac branched devices made it possible to preserve the internal iliac artery by endovascular means only. A first version of the iliac bifurcated graft needed to be pulled into the internal iliac artery but this technique proved too difficult. Newer versions including straight side-branches or helical side-branches for the internal iliac artery require a cross-over catheterization and introduction of a stent-graft to bridge the gap between the internal iliac artery and the iliac branch. Anatomical criteria including sufficient length of the common iliac artery and a normal calibre internal iliac artery should be taken into account, but also the health status of the patient, before one decides to use an iliac branched device for a patient with an aortoiliac aneurysm. Additional costs and technical challenges need to be balanced with the potential benefits for active patients who would be at risk for buttock claudication. PMID- 22433726 TI - Fenestrated and branched technology: what's new? AB - This review article presents the latest published clinical series evaluating fenestrated and branched endografts for the treatment of complex aortic aneurysms incorporating the visceral branches, iliac arteries and supra-aortic trunks. In addition, an overview of the recent developments in devices and imaging modalities is also proposed. PMID- 22433727 TI - Penetrating aortic ulcer, intramural hematoma, acute aortic syndrome: when to do what. AB - Acute aortic syndrome (AAS) is a modern term to describe interrelated emergency aortic conditions with similar clinical characteristics and challenges. These conditions include aortic dissection, intramural hematoma (IMH), and penetrating aortic ulcer (PAU). Population-based studies suggest that the incidence of aortic dissection ranges from 2.6-3.5 cases per 100,000 person/year; hypertension and a variety of genetic disorders with altered connective tissue are the most prevalent risk conditions. One in eight patients diagnosed with acute aortic dissection has either an IMH or a PAU. Pain is the most commonly presenting symptom of acute aortic syndrome and should prompt immediate attention including diagnostic imaging modalities (such as multislice computed tomography, transesophageal ultrasound, or magnetic resonance imaging). IMH and PAU need a specific therapeutic approach, because without treatment they have a very poor evolution, are unpredictable and can be worse than acute aortic dissection. All patients must receive the best medical treatment available at admission. High risk but asymptomatic patients with IMH and PAU can probably be followed-up without intervention. All symptomatic patients will need treatment. In many of these patients, a direct surgical approach is often prohibitive, due to age and multiple comorbidities. Endovascular treatment offers superior results and is becoming a recognized indication for patients. Irrespective of treatment modality, a close follow-up is mandatory in order to detect disease progression. PMID- 22433728 TI - Treatment of endoleaks: techniques and outcome. AB - Endoleaks are one of the most common reasons for reinterventions and failure after endovascular aneurysm repair (EVAR). Current classifications divide endoleaks into type I-V but a more pragmatic definition is of direct and indirect endoleaks. Direct endoleaks (type I and III) transmit direct systemic pressure to the aneurysm sac and carry a high risk of aneurysm growth and rupture if left untreated. Immediate intervention is generally warranted. Indirect endoleaks (type II, IV, V) may have a more benign course and should be treated only under the presence of aneurysm growth. Appropriate procedural planning and device selection is critical to avoid endoleaks and most direct endoleaks can be identified and treated periprocedurally by use of high quality intraoperative imaging techniques. Late endoleaks can be treated predominately by endovascular means and the need for conversion to open surgery is rare. PMID- 22433729 TI - Decision making in AAA repair in 2012: open or endo? AB - With data from four randomized trials on elective endovascular abdominal aortic aneurysm repair and many more additional post-hoc publications, the evidence can be somewhat overwhelming for the surgeon, let alone the patient. This chapter aims to present the most recent and relevant data for decision making in abdominal aortic aneurysm (AAA) repair in a comparative and concise format. After a comparison of the short- and long-term survival data of the randomized trials, the following post-hoc analyses of the four randomized trials will be presented: causes of death, reinterventions, renal function, prediction of complications, and quality of life. When both open and endovascular repair are a reasonable option for an individual patient, we need to objectively inform our patient about the available evidence from the trials. The three-fold reduction of operative mortality with endovascular repair as compared to open repair should be presented. Next, the convergence of the overall survival curves should be discussed as a key factor in the decision process. The counterintuitive observation may be considered that if endovascular repair is better for any specific subgroup it is for younger patients with low surgical risks. Finally, the patient needs to understand that the risks of reintervention and complications are higher after endovascular than after open repair and that this is even more relevant in older patients with larger aneurysms. The information that the quality of life advantage of endovascular repair is only short lived and for several domains surpassed by open repair is most likely not suitable for direct discussion with the individual patient, but it may put the procedures in the right perspective for the physician and health care managers. PMID- 22433730 TI - Technical aspects of EVAR for infrarenal AAA. AB - Technical aspects are crucial for planning and performing successful endovascular repair of abdominal aortic aneurysms (AAA). Planning should be based on high quality computed tomography angiography scans with a slice thickness of <= 1 mm. However, even without a workstation for image postprocessing, important angle estimations can be easily performed. Several devices are available today to treat abdominal aneurysms. In most elective cases all currently available 3rd generation devices perform comparably if minimal requirements are kept in mind. A safe and technically precise implantation requires cooperation with the involved anesthesiologist in order to manage anticoagulation, blood pressure regulation in general and in currently evolving regional anesthesia. Modern endograft implantation involves highly technical resources, for example guide wires or catheters. Beside patient selection, an optimal procedure planning, graft model choice and endovascular skills are mandatory aspects. In the near future, further improvements in device design and deployment mechanism will allow better device alignment, paving the way for an even broader application of endovascular aneurysm repair (EVAR). PMID- 22433731 TI - Open repair for infrarenal AAA: technical aspects. AB - The aim of this study was to describe the technique and report our single center experience of abdominal aortic aneurysm (AAA) open surgical repair over the last 17 years. From 1993 to 2010, a total of 4347 open surgical procedures for repair of AAA were performed in our center. The details of 3857 (88.7%) patients undergoing infrarenal AAA open repair were analyzed; mean age at the time of surgery was 71.8 years ranging from 58 to 89 years. Among all repairs, 23.7% (914) were performed in women and 24.3% (937) in octogenarians; 3587 (93.0%) procedures were performed for degenerative aneurysms, 146 (3.8%) for inflammatory aneurysms, 100 (2.6%) for dissecting aneurysms, and 19 (0.5%) for other pattern of disease. In 162 cases (4.2%) surgery was performed for ruptured aneurysm. In most cases (N.=2596; 67.3%) infrarenal AAA open repair was performed by means of aorto-aortic bypass using a tube graft. A total of 1261 patients were treated using a bifurcated graft: 417 (33.1%) aorto-iliac bypasses, 530 (42.0%) aorto femoral bypasses and 314 (24.9%) aorto-iliac-femoral bypasses were performed. In elective aorto-aortic bypass, mean aortic clamping time was 21.3+6.7 minutes. The average duration of the procedure was 126+84 minutes (range, 42-410 minutes). Mean intraoperative bleeding was 803.4+422.7 mL (range 250-3,100). Overall intraoperative mortality was 0.2%. Intraoperative mesenteric ischemia was observed in 3% of cases, all treated with inferior mesenteric artery reimplantation. The rate of intraoperative lower limbs ischemia was 2.2%. One intraoperative acute type A aortic dissection occurred. The overall 30-day mortality was 0.6%. Permanent renal function impairment occurred in 4.3% of cases. The rate of pulmonary complications was 9.8%. Other complications were myocardial infarction, congestive heart failure, late ischemic colitis, late leg ischemia, wound infection, urinary tract infection, and sepsis. Although endovascular techniques have emerged as a less invasive alternative to open repair, short- and long-term outcomes associated to the surgery of infrarenal AAAs remain satisfactory for a large range of patients. PMID- 22433732 TI - Hybrid procedures for acute limb ischemia. AB - The most efficient treatment for acute arterial embolism is operative embolectomy using Fogarty's balloon catheter, especially if a single large artery is involved. Unfortunately, although the early surgical success of arterial thromboembolectomy often seems acceptable, the early clinical outcome still remains unsatisfactory. This may be related to the incomplete restoration of perfusion (i.e. residual thrombus in distal vessels not reached by the balloon catheter thromboembolectomy), propagation of residual thrombi or presence of underlying steno-occlusive lesions. In such a situation a meticulous intraoperative assessment of the adequacy of clot removal is decisive. Residual thrombus, chronic atherosclerotic disease and even vessel injuries secondary to balloon catheter passage can be corrected by endovascular techniques (hybrid procedures). The combination of surgical and endovascular options may overcome the limitations that characterize the traditional approach, and it is likely that in the future many treatments will be a mix of techniques that can be performed by vascular surgeons in the operating room or in a dedicated endovascular suite. This review article summarizes the hybrid treatment options for acute arterial occlusion caused by either embolism or local thrombosis. PMID- 22433733 TI - Intraoperative quality control in vascular surgery. AB - Since graft patency is the predominant predictor of long-term survival after vascular surgery, intraoperative graft patency control is of major importance for improving quality assurance. Intraoperative quality control is of major importance to obtain good short- and longterm results and to eliminate the need for reoperation. Currently there is no standardized approach and intraoperative quality control is not performed routinely by most surgeons. The most commonly used intraoperative assessment techniques include arteriography, duplex ultrasonography, angioscopy and transit-time flow measurement (TTFM). Fluorescent angiography (FA) using the dye indocyanine green (ICG) is a novel noninvasive technology for intraoperative visualization and documentation of vessels, bypass grafts, and perfusion with an infrared sensitive imaging device, so far validated for quality control in coronary bypass surgery. FA and TTFM are methods for quantitative assessment of blood flow measurement, which are currently exclusively used as intraoperative quality control in cardiac bypass surgery. Up to now, there are no experiences published for peripheral vascular reconstructions. However, transposition and implementation of these techniques seem to be valuable and useful. Therefore further studies for intraoperative quality control in vascular surgery are necessary. PMID- 22433734 TI - New surgical and hybrid techniques for crural and pedal anastomoses. AB - Although there is currently a trend using endovascular methods to treat long and/or complex distal lesions, there are some interesting new approaches, technical modifications and simplifications in open surgery. Some of these are new, and some are older, but their effectiveness is now starting to be recognized. 1) Anatomical concepts: the lower leg/foot consists of 6 angiosomes, which are supplied by the 3 main arteries. It has been shown that the revascularization of the correct angiosome could lead to a higher rate of success when compared to the connection of an indirect artery. Other anatomical concepts describe the use of a flow-thru flap, and the advances in the use of homografts in peripheral bypass surgery. 2) New materials for implantation: while biological graft materials (tissue engineering) are still under development, no fundamental changes in clinical use have taken place. If autologous vein is missing, alloplastic materials made from polyester or polytetrafluorethylene (PTFE) are the available alternatives. On the basis of studies published so far, heparin coating does appear to offer advantages. 3) New aids for operative treatment: in contrast to rather slow (clinical) advancement with regard to bypass materials, there have been some interesting developments with regard to ancillary products. There are clips for stapled anastomoses, small shunts or thermosensitive polymers to avoid clamping. Furthermore some techniques perform anastomoses without sewing, like intraluminal protein tubes or ring anastomoses. The Viabahn Padova Sutureless (ViPS) technique anastomoses a stent-graft to the artery by placing it openly into the vessel and then releasing a stent by a simple pulling mechanism. In summary, peripheral bypass surgery remains a very standardized operation. Although not spectacular, there are some interesting new approaches, technical modifications and simplifications. PMID- 22433735 TI - Treatment strategies for extensive chronic SFA occlusions: indications and results. AB - Treatment modalities for extensive chronic occlusive disease of the superficial femoral artery (SFA) have changed during the last decades. In this chapter we provide an overview of current treatment modalities for extensive chronic occlusive disease of the SFA. Although the autologous venous conduit is still considered the gold standard for treatment of long occlusive SFA lesions, endoluminal therapy is gaining territory. Its' minimal invasive character has great advantages in the frail vascular patient population. Percutaneous transluminal angioplasty is first choice in short SFA lesions, but patency rates decrease with longer lesions. When percutaneous transluminal angioplasty is combined with nitinol stent placement patency rates significantly improve. Patency rates of percutaneous transluminal angioplasty combined with covered stents are within reach of patency rates of prosthetic surgical bypasses. Drug bonding in surgical PTFE bypasses increased patency rates significantly. In the near future drug-eluting and drug-bonded devices might further increase results of endovascular treatment. PMID- 22433736 TI - Stent evolution for peripheral arterial disease. AB - Endovascular treatment and stent implantation for peripheral arterial disease have been proposed for over 20 years. However, the first experiments with stainless stents were relatively disappointing. The first improvement consisted in the introduction of nitinol self-expanding stents. This technology allowed an initial improvement of clinical performances, but the first generation of nitinol stents demonstrated a relatively high rate of fractures. Better knowledge of arterial biomechanics and advances in technology allowed to propose a second generation of nitinol stents with improved flexibility, which decreased the rates of fracture. In-stent restenosis related to neointimal hyperplasia has also led to the development of new concepts to improve patency rates after stenting: drug eluting stents (coated-stents), biodegradable stents, and covered stents. These technologies will help to treat more complex lesions in the future, but we are still waiting for results of ongoing studies. PMID- 22433737 TI - Results of the "endovascular treatment first" policy for infrapopliteal disease. AB - Even though differences between first-bypass vs. first-endovascular approach in below the knee (BTK) lesions have never been adequately compared, endovascular strategy first approach can be currently successfully used to treat BTK lesions in patients with critical limb ischemia (CLI). Success however is strongly associated with risk groups, severity of disease and degree of clinical presentation beside the method of revascularization. From available data, the best results of endovascular first approach for BTK lesions can be achieved with multivessel and tibial (more than peroneal alone) recanalization and Rutherford 4 or 5 ischemia changes, especially if the correct angiosome can be revascularized (direct flow to the feeding artery of the foot) and there is no renal failure. For patients in Rutherford class 6 and extensive gangrene/tissue loss, BTK endovascular strategy alone does not seem to provide ideal results. Outcomes of interventional therapy for BTK lesions are consistently better when applied in experienced centers with the use of more advanced technology and use of eluting materials. According to limited but randomized evidence, drug-eluting stent (DES) placement might be recommended in BTK lesions under 40 mm long since yields significantly better results than angioplasty alone or implantation of bare metal stents in this lesion subset. Nevertheless, this policy raises doubts on the efficacy of treatment due to limitations in generalizability of outcomes in common hospital settings and related costs. Furthermore, there are still no consistent numbers to provide the efficacy of this approach and long-term data are lacking. Waiting for the long-term results of ongoing trials and new researches, a more comprehensive analysis of outcomes with BTK endovascular first strategy can be provided in the next future. PMID- 22433738 TI - Development and evaluation of a high-fidelity canine patient simulator for veterinary clinical training. AB - High-fidelity human patient simulators have been used for decades in medical education to provide opportunities for students to practice technical skills, diagnostic and therapeutic planning, and communication skills in a safe environment. A high-fidelity canine patient simulator (CPS) was developed using components from a human patient simulator and a low-fidelity foam core canine mannequin. Ninety-six veterinary students participated in cardiopulmonary arrest scenarios in groups of three to five students. Afterwards, participants were asked to complete an anonymous online survey describing their experiences. A total of 70 students (73%) completed the survey. All of the students (100%) felt that the simulator session expanded their cardiopulmonary resuscitation (CPR) knowledge base, and 97% responded that their skills and abilities had improved. Students also expressed positive opinions about the CPS, with 89% agreeing or strongly agreeing that the CPS was realistic and 73% agreeing or strongly agreeing that the scenarios generated emotions similar to real clinical situations. Most participants (98.5%) agreed or strongly agreed that the simulator was an engaging learning experience. Students commonly commented that the simulations allowed them to practice communication and teamwork skills and were more effective than paper-based, problem-oriented learning opportunities and lecture. Students also commented that they wanted more opportunities to participate in simulation exercises. These results suggest that high-fidelity veterinary simulation is an engaging educational methodology that addresses some limitations of other forms of problem-based learning. More studies are needed to quantitatively determine the effectiveness of this novel veterinary educational technology in comparison with more traditional approaches. PMID- 22433739 TI - The use of digital games and simulators in veterinary education: an overview with examples. AB - In view of current technological possibilities and the popularity of games, the interest in games for educational purposes is remarkably on the rise. This article outlines the (future) use of (digital) games and simulators in several disciplines, especially in the veterinary curriculum. The different types of game based learning (GBL)-varying from simple interactive computer board games to more complex virtual simulation strategies-will be discussed as well as the benefits, possibilities, and limitations of the educational use of games. The real breakthrough seems to be a few years away. Technological developments in the future might diminish the limitations and stumbling blocks that currently exist. Consequently, educational games will play a new and increasingly important role in the future veterinary curriculum, providing an attractive and useful way of learning. PMID- 22433740 TI - Evaluation of an internal research funding program in a school of veterinary medicine. AB - The present article describes a paradigm for evaluating the internal research funding program of a college or school of veterinary medicine, using as an example a similar exercise recently conducted at the Louisiana State University School of Veterinary Medicine (LSU SVM). The purpose of the exercise was to quantify and evaluate the effectiveness of the LSU SVM internal research funding mechanism known as the Competitive Organized Research Program (CORP). The evaluation resulted in several important observations that will allow us to further improve the effectiveness of our internal research funding program investment. Among the most important of these was the greater return on investment for CORP projects funded with smaller awards (approximately $10,000 US) compared to projects funded with larger awards (approximately $52,000 US). Other colleges and schools of veterinary medicine may find such an exercise similarly informative and beneficial. PMID- 22433741 TI - Predictors of employer satisfaction: technical and non-technical skills. AB - Employers of 2007-2009 graduates from Iowa State University College of Veterinary Medicine were asked to respond to a survey regarding their overall satisfaction with their new employees as well as their new employees' preparation in several technical and non-technical skill areas. Seventy-five responses contained complete data and were used in the analysis. Four technical skill areas (data collection, data interpretation, planning, and taking action) and five non technical skill areas (interpersonal skills, ability to deal with legal issues, business skills, making referrals, and problem solving) were identified. All of the skill area subscales listed above had appropriate reliability (Cronbach's alpha>0.70) and were positively and significantly correlated with overall employer satisfaction. Results of two simultaneous regression analyses indicated that of the four technical skill areas, taking action is the most salient predictor of employer satisfaction. Of the five non-technical skill areas, interpersonal skills, business skills, making referrals, and problem solving were the most important skills in predicting employer satisfaction. Hierarchical regression analysis revealed that all technical skills explained 25% of the variation in employer satisfaction; non-technical skills explained an additional 42% of the variation in employer satisfaction. PMID- 22433742 TI - A review of student evaluation of teaching: applications to veterinary medical education. AB - Student evaluation of teaching is ubiquitous to teaching in colleges and universities around the world. Since the implementation of student evaluations in the 1970s in the US, considerable research has been devoted to their appropriate use as a means of judging the effectiveness of teaching. The present article aims to (1) examine the evidence for the reliability, validity, and utility of student ratings; (2) provide seven guidelines for ways to identify effective instruction, given that the purpose of student evaluation is to assess effective teaching; and (3) conclude with recommendations for the integration of student ratings into the continuous evaluation of veterinary medical education. PMID- 22433743 TI - Failure to acknowledge high suicide risk among veterinarians. AB - A high suicide risk has been reported among veterinarians in comparison to the general population. Postulated causes have included depression, substance abuse, work-related stress, reluctance to admit psychiatric problems, and access to lethal drugs and/or familiarity with euthanasia. Members of the Student Chapter of the American Veterinary Medical Association (AVMA), all veterinarians licensed in Alabama, and all US veterinary-association executive directors were surveyed regarding their attitudes concerning mental health issues, including veterinarian suicide. Only 10% of veterinary student respondents (N=58) believed that suicide risk is higher among veterinarians than in the general population. Of the 22 state associations' executive directors who participated in the survey, 37% believed that suicide is a significant concern for veterinarians and only 44% indicated that a veterinary wellness program was available in their respective states. Of the 1,455 licensed veterinarians in Alabama, 701 responded to the survey; 11% of respondents believed that suicide among veterinarians was a problem. In addition, 66% of respondents indicated that they had been "clinically depressed," but 32% of those with depression had not sought treatment. More females (27%) than males (20%) admitted that they had "seriously considered suicide" (p<.01). Female veterinarians were more likely than male veterinarians (15% versus 7%) to indicate that they were "not sure they'd made the right career choice" (p<.001), and 4% of all respondents indicated "definitely not being happy with their career." It is of concern that veterinarians not only have a higher risk of suicide but that they also have fewer support structures. The wide discrepancies between the published risk of suicide for veterinarians and their own views of their risk suggests an inadequate awareness of their own mental health vulnerability which could put them at higher risk. PMID- 22433744 TI - Psychological services for US and international veterinary students. AB - Given the importance of psychological services for veterinary students, a survey was administered to all US veterinary schools and many international ones, asking them to report on the amount and type of psychological support services they offer to students, faculty, and staff. This article reports on the results of this survey and presents suggestions for increasing the accessibility of counseling services. One objective of the current study was to initiate an avenue for ongoing communication between individuals involved in student counseling within each school. A list of individuals currently working in the field and their contact information is provided in Appendix 2. PMID- 22433745 TI - Is it time to define veterinary professionalism? AB - The medical profession has spent much time and many resources engaging in a discourse of medical professionalism and debating the appropriate attitudes and behavior of physicians, but little has been published concerning the concept of veterinary professionalism. Physicians are commonly examined by social scientists and educationalists to establish definitions of medical professionalism in order to teach and assess these values within curricula. This challenging process has not been without criticism, however, with some calling the numerous definitions unhelpful, especially when these behaviors are not demonstrated in practice or the wider sociological implications of medical professionalism are ignored. Veterinary curricula often include professional skills, and there has been some discussion about their inclusion as well as the scope of veterinary surgeons and their role in society. Despite this, no true definition of veterinary professionalism exists, and the teaching of the values and behaviors expected of veterinary professionals may not be explicit. Regardless of the difficulties of engaging in such a discourse, perhaps it is time that this occurred and a realistic and usable definition of veterinary professionalism is established. This is a period of change for the veterinary profession, and a teachable and assessable definition can provide some clarity and assist educators within ever evolving veterinary curricula. PMID- 22433746 TI - Fibrin membrane pupillary-block glaucoma after uneventful cataract surgery treated with intracameral tissue plasminogen activator: a case report. AB - BACKGROUND: Fibrin pupillary-block glaucoma is a rare complication after cataract surgery. The treatment for this condition is still controversial, since Nd:YAG laser fibrin membranotomy tends to reocclude and laser peripheral iridotomy entails the risk of damaging the corneal endothelium in the presence of corneal edema associated with elevated intraocular pressure. CASE PRESENTATION: A 62-year old man with diabetes mellitus developed acute elevation of intraocular pressure with a shallow anterior chamber five days after uneventful cataract surgery. Initially, slit lamp examination provided only limited information due to severe corneal edema. After resolution of corneal edema with systemic glaucoma therapy, a complete fibrin membrane was observed across the pupil by slit lamp examination. Anterior segment optic coherence tomography clearly revealed a thin fibrin membrane covering the entire pupillary space, a shallow anterior chamber, and a deep posterior chamber. The intraocular lens was not observed by anterior segment optic coherence tomography. In contrast, ultrasound biomicroscopy, which has superior penetration depth, was able to visualize the intraocular lens deep in the posterior chamber. Injection of tissue plasminogen activator into the anterior chamber resulted in complete fibrinolysis and released the pupillary block. CONCLUSION: This case suggests that ocular anterior segment imaging modalities, especially ultrasound biomicroscopy, serve as powerful diagnostic tools to identify mechanisms of acute angle closure glaucoma, which is often accompanied by poor intraocular visibility. This is the first reported case of fibrin pupillary-block glaucoma after cataract surgery successfully treated with intracameral tissue plasminogen activator. PMID- 22433747 TI - Dairy consumption and cardiometabolic health: outcomes of a 12-month crossover trial. AB - BACKGROUND: A growing body of research suggests that regular consumption of dairy foods may counteract obesity and other components of the metabolic syndrome. However, human intervention trials are lacking. We aimed to determine the cardiometabolic health effects of increasing the consumption of reduced fat dairy foods in adults with habitually low dairy intakes in the absence of energy restriction. METHODS: An intervention trial was undertaken in 61 overweight or obese adults who were randomly assigned to a high dairy diet (HD, 4 serves of reduced fat dairy/day) or a low dairy control diet (LD, <=1 serve/day) for 6 months then crossed over to the alternate diet for a further 6 months. A range of anthropometric and cardiometabolic parameters including body composition, metabolic rate, blood lipids, blood pressure and arterial compliance were assessed at the end of each diet phase. RESULTS: Total energy intake was 1120 kJ/day higher during the HD phase, resulting in slight weight gain during this period. However, there were no significant differences between HD and LD in absolute measures of waist circumference, body weight, fat mass or any other cardiometabolic parameter. CONCLUSION: Recommended intakes of reduced fat dairy products may be incorporated into the diet of overweight adults without adversely affecting markers of cardiometabolic health. TRIAL REGISTRATION: The trial was registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12608000538347) on 24th October, 2008. PMID- 22433748 TI - Impact of life events on survival of patients with localized melanoma. PMID- 22433749 TI - Apolipoprotein E gene polymorphism in a Chinese population with vascular dementia: a meta-analysis. AB - BACKGROUND: Apolipoprotein E (ApoE) gene has been reported to be associated with the development of vascular dementia (VD); however, results from observational studies are conflicting. METHODS: We surveyed all case-control studies on ApoE gene and VD patients with comprehensive search and review of the references. A meta-analysis was performed to demonstrate the association of ApoE gene with VD by random effects models. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). RESULTS: A total of 18 studies including 935 patients and 1,686 controls were eligible and abstracted. ApoE epsilon3/4 and epsilon4/4 genotype, as well as epsilon4 allele (OR = 1.95, 95% CI: 1.52-2.49; OR = 3.47, 95% CI: 1.85-6.51 and OR = 2.12, 95% CI: 1.64-2.74, respectively) were associated with an increased risk of VD, while ApoE epsilon3/3 genotype and epsilon3 allele (OR = 0.65, 95% CI: 0.53-0.79 and OR = 0.65, 95% CI: 0.53-0.80, respectively) trended to protect against VD. There was no significant difference in ApoE epsilon2 allele frequency, epsilon2/2, epsilon2/3 or epsilon2/4 genotype between VD and controls (OR = 0.85, 95% CI: 0.61-1.17; OR = 0.89, 95% CI: 0.39 2.01; OR = 0.82, 95% CI: 0.61-1.09 and OR = 1.03, 95% CI: 0.57-1.84, respectively). CONCLUSIONS: Our results support a genetic association between ApoE polymorphism and VD in the Chinese population. PMID- 22433750 TI - Does an activity based remuneration system attract young doctors to general practice? AB - BACKGROUND: The use of increasingly complex payment schemes in primary care may represent a barrier to recruiting general practitioners (GP). The existing Norwegian remuneration system is fully activity based - 2/3 fee-for-service and 1/3 capitation. Given that the system has been designed and revised in close collaborations with the medical association, it is likely to correspond - at least to some degree - with the preferences of current GPs (men in majority). The objective of this paper was to study which preferences that young doctors (women in majority), who are the potential entrants to general practice have for activity based vs. salary based payment systems. METHODS: In November-December 2010 all last year medical students and all interns in Norway (n = 1.562) were invited to participate in an online survey. The respondents were asked their opinion on systems of remuneration for GPs; inclination to work as a GP; risk attitude; income preferences; work pace tolerance. The data was analysed using one-way ANOVA and multinomial logistic regression analysis. RESULTS: A total of 831 (53%) responded. Nearly half the sample (47%) did not consider the remuneration system to be important for their inclination to work as GP; 36% considered the current system to make general practice more attractive, while 17% considered it to make general practice less attractive. Those who are attracted by the existing system were men and those who think high income is important, while those who are deterred by the system are risk averse and less happy with a high work pace. On the question of preferred remuneration system, half the sample preferred a mix of salary and activity based remuneration (the median respondent would prefer a 50/50 mix). Only 20% preferred a fully activity based system like the existing one. A salary system was preferred by women, and those less concerned with high income, while a fully activity based system was preferred by men, and those happy with a high work pace. CONCLUSIONS: Given a concern about low recruitment to general practice in Norway, and the fact that an increasing share of medical students is women, we were interested in the extent to which the current Norwegian remuneration system correspond with the preferences of potential GPs. This study suggests that an existing remuneration mechanism has a selection effect on who would like to become a GP. Those most attracted are income motivated men. Those deterred are risk averse, and less happy with a high work pace. More research is needed on the extent to which experienced GPs differ along the questions we asked potential GPs, as well as studying the relative importance of other attributes than payment schemes. PMID- 22433751 TI - Can observational studies approximate RCTs? PMID- 22433752 TI - Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. AB - OBJECTIVE: In both the United States and Europe there has been an increased interest in using comparative effectiveness research of interventions to inform health policy decisions. Prospective observational studies will undoubtedly be conducted with increased frequency to assess the comparative effectiveness of different treatments, including as a tool for "coverage with evidence development," "risk-sharing contracting," or key element in a "learning health care system." The principle alternatives for comparative effectiveness research include retrospective observational studies, prospective observational studies, randomized clinical trials, and naturalistic ("pragmatic") randomized clinical trials. METHODS: This report details the recommendations of a Good Research Practice Task Force on Prospective Observational Studies for comparative effectiveness research. Key issues discussed include how to decide when to do a prospective observational study in light of its advantages and disadvantages with respect to alternatives, and the report summarizes the challenges and approaches to the appropriate design, analysis, and execution of prospective observational studies to make them most valuable and relevant to health-care decision makers. RECOMMENDATIONS: The task force emphasizes the need for precision and clarity in specifying the key policy questions to be addressed and that studies should be designed with a goal of drawing causal inferences whenever possible. If a study is being performed to support a policy decision, then it should be designed as hypothesis testing-this requires drafting a protocol as if subjects were to be randomized and that investigators clearly state the purpose or main hypotheses, define the treatment groups and outcomes, identify all measured and unmeasured confounders, and specify the primary analyses and required sample size. Separate from analytic and statistical approaches, study design choices may strengthen the ability to address potential biases and confounding in prospective observational studies. The use of inception cohorts, new user designs, multiple comparator groups, matching designs, and assessment of outcomes thought not to be impacted by the therapies being compared are several strategies that should be given strong consideration recognizing that there may be feasibility constraints. The reasoning behind all study design and analytic choices should be transparent and explained in study protocol. Execution of prospective observational studies is as important as their design and analysis in ensuring that results are valuable and relevant, especially capturing the target population of interest, having reasonably complete and nondifferential follow-up. Similar to the concept of the importance of declaring a prespecified hypothesis, we believe that the credibility of many prospective observational studies would be enhanced by their registration on appropriate publicly accessible sites (e.g., clinicaltrials.gov and encepp.eu) in advance of their execution. PMID- 22433753 TI - Cost-effectiveness evaluation in Sweden of escitalopram compared with venlafaxine extended-release as first-line treatment in major depressive disorder. AB - OBJECTIVES: Major depressive disorder (MDD) is a major public health concern associated with a high burden to society, the health-care system, and patients and an estimated cost of ?3.5 billion in Sweden. The objective of this study was to assess the cost-effectiveness of escitalopram versus generic venlafaxine extended-release (XR) in MDD, accounting for the full clinical profile of each, adopting the Swedish societal perspective, and identifying major cost drivers. METHODS: Cost-effectiveness of escitalopram versus venlafaxine XR was analyzed over a 6-month time frame, on the basis of a decision tree, for patients with MDD seeking primary care treatment in Sweden. Effectiveness outcomes for the model were quality-adjusted life-years and probability of sustained remission after acute treatment (first 8 weeks) and sustained for 6 months. Cost outcomes included direct treatment costs and indirect costs associated with sick leave. RESULTS: Compared with generic venlafaxine XR, escitalopram was less costly and more effective in terms of quality-adjusted life-years (expected gain 0.00865) and expected 6-month sustained remission probability (incremental gain 0.0374). The better tolerability profile of escitalopram contributed to higher expected quality-adjusted life-years and lower health-care resource utilization in terms of pharmacological treatment of adverse events (though only a minor component of treatment costs). Expected per-patient saving was ?169.15 for escitalopram versus venlafaxine. Cost from sick leave constituted about 85% of total costs. CONCLUSIONS: Escitalopram was estimated as more effective and cost saving than generic venlafaxine XR in first-line MDD treatment in Sweden, driven by the effectiveness and tolerability advantages of escitalopram. The study findings are robust and in line with similar pharmacoeconomic analyses. PMID- 22433754 TI - A review of the cost of atrial fibrillation. AB - OBJECTIVES: To systematically review and synthesize the literature on the costs of atrial fibrillation (AF) with attention to study design and costing methods, geography, and intervention approaches. METHODS: A systematic search for previously published studies reporting the costs for AF patients was conducted. Data were analyzed in three steps: first by evaluating overall system costs; second by evaluating the relative contribution of specific cost components; and third by examining variations across study designs, across primary treatment approach, and by geography. Finally, a specific review of the treatment costs associated with anticoagulation treatment was examined given the clinical importance and attention given to these costs in the literature. RESULTS: The literature search resulted in 115 articles. On review of the abstracts or full text of these articles, 21 articles met all study criteria and reported on health system AF-related direct costs. A further six articles focused exclusively on anticoagulation costs for patients with AF. The overall average annual system cost across 27 estimates obtained from the literature was $5450 (SD = $3624) in 2010 Canadian dollars and ranged from a low of $1,632 to a high of $21,099. About one-third of these costs could be attributed to anticoagulation management. The largest cost component was acute care, followed by outpatient and physician and then medication-related costs. CONCLUSION: AF-related medical costs are high, reflecting resource-intensive and long-term treatments including anticoagulation treatment. These costs, accompanied with increasing prevalence, justify increased attention to the management of patients with AF. Future studies of AF cost should ensure a broad assessment of the incremental direct medical and societal cost associated with this diagnosis. PMID- 22433755 TI - Cost-effectiveness analysis of collaborative care management of major depression among low-income, predominantly Hispanics with diabetes. AB - OBJECTIVE: To evaluate the cost-effectiveness of a socioculturally adapted collaborative depression care program among low-income Hispanics with diabetes. RESEARCH DESIGN AND METHODS: A randomized controlled trial of 387 patients with diabetes (96.5% Hispanic) with clinically significant depression followed over 18 months evaluated the cost-effectiveness of the Multifaceted Diabetes and Depression Program aimed at increasing patient exposure to evidence-based depression psychotherapy and/or pharmacotherapy in two public safety net clinics. Patient medical care costs and utilization were captured from Los Angeles County Department of Health Services claims records. Patient-reported outcomes included Short-Form Health Survey-12 and Patient Health Questionnaire-9-calculated depression-free days. RESULTS: Intervention patients had significantly greater Short-Form Health Survey-12 utility improvement from baseline compared with controls over the 18-month evaluation period (4.8%; P < 0.001) and a corresponding significant improvement in depression-free days (43.0; P < 0.001). Medical cost differences were not statistically significant in ordinary least squares and log-transformed cost regressions. The average costs of the Multifaceted Diabetes and Depression Program study intervention were $515 per patient. The program's cost-effectiveness averaged $4053 per quality-adjusted life-year per MDDP recipient and was more than 90% likely to fall below $12,000 per quality-adjusted life-year. CONCLUSIONS: Socioculturally adapted collaborative depression care improved utility and quality of life in predominantly low-income Hispanic patients with diabetes and was highly cost effective. PMID- 22433756 TI - Cost-effectiveness of adjuvant FOLFOX therapy for stage III colon cancer in Japan based on the MOSAIC trial. AB - OBJECTIVE: To evaluate the cost-effectiveness of adjuvant FOLFOX therapy versus 5 fluorouracil/leucovorin (FU/LV) for patients with stage III colorectal cancer. METHODS: We performed the cost-effectiveness of FOLFOX compared with standard FU/LV treatment by the retrospective analysis of patient-level data from the randomized controlled Multicenter International Study of Oxaliplatin, 5 Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial. Predicted mean time spent in each disease state was calculated by our statistical model, which takes into account the cure rate and treats death from causes other than colon cancer as a competing risk. We performed this analysis from the perspective of the health-care payer. Using a time horizon of 30 years, both cost and effectiveness were discounted by 3% per year. RESULTS: Estimated cure rates for colon cancer were 0.715 (FOLFOX) and 0.622 (FU/LV). Estimated medical costs of FOLFOX were JPY 3.1 million (USD 34,000) compared with JPY 1.9 million (USD 22,000) of FU/LV. The mean estimated quality-adjusted life-year was 9.83 with FOLFOX and 9.07 with that of FU/LV. The incremental cost-effectiveness ratio of FOLFOX was JPY 1.5 million (USD 17,000) per quality-adjusted life-year compared with FU/LV, which was supported by sensitivity analysis. Even if we assume that Japanese outcomes were better than those reported by the MOSAIC trial, which would reduce the difference between cure rates for each treatment to 5%, the incremental cost-effectiveness ratio remained below 5.0 million (USD 56,000) per quality-adjusted life-year. CONCLUSIONS: Adjuvant FOLFOX is a cost effective treatment for stage III colon cancer in Japan compared with FU/LV therapy. Even when parameters were changed to reflect smaller improvements with FOLFOX, the conclusion is the same. PMID- 22433757 TI - Lifetime cost-effectiveness of skin cancer prevention through promotion of daily sunscreen use. AB - OBJECTIVES: Health-care costs for the treatment of skin cancers are disproportionately high in many white populations, yet they can be reduced through the promotion of sun-protective behaviors. We investigated the lifetime health costs and benefits of sunscreen promotion in the primary prevention of skin cancers, including melanoma. METHODS: A decision-analytic model with Markov chains was used to integrate data from a central community-based randomized controlled trial conducted in Australia and other epidemiological and published sources. Incremental cost per quality-adjusted life-year was the primary outcome. Extensive one-way and probabilistic sensitivity analyses were performed to test the uncertainty in the base findings with plausible variation to the model parameters. RESULTS: Using a combined household and government perspective, the discounted incremental cost per quality-adjusted life-year gained from the sunscreen intervention was AU$40,890. Over the projected lifetime of the intervention cohort, this would prevent 33 melanomas, 168 cutaneous squamous-cell carcinomas, and 4 melanoma-deaths at a cost of approximately AU$808,000. The likelihood that the sunscreen intervention was cost-effective was 64% at a willingness-to-pay threshold of AU$50,000 per quality-adjusted life-year gained. CONCLUSIONS: Subject to the best-available evidence depicted in our model, the active promotion of routine sunscreen use to white populations residing in sunny settings is likely to be a cost-effective investment for governments and consumers over the long term. PMID- 22433758 TI - Comparative health-care cost advantage of ipratropium over tiotropium in COPD patients. AB - OBJECTIVE: To compare the total direct health-care costs of patients treated with tiotropium and ipratropium. METHODS: We conducted a cohort study of health-care costs in British Columbia, Canada, by comparing new patients on tiotropium with new patients on ipratropium. Direct health-care costs for study patients were measured in the first 2 years after initiating inhaled anticholinergic treatment. Differences in direct health-care costs between tiotropium and ipratropium patients were estimated by using quantile regression. We analyzed cost differences in the 10th percentile, median, and 90th percentile of patients by cost. High-dimensional propensity score analysis was used as a method of adjustment for potential confounding factors. RESULTS: The study population had 3,140 tiotropium patients and 26,182 ipratropium patients. Higher health system costs in patients who started on tiotropium instead of ipratropium were observed in patients in the median and 10th percentile. The magnitude of these increases was comparable to the price difference between the two drugs. Health system costs in the 90th percentile were not significantly different between tiotropium and ipratropium patients. CONCLUSIONS: The results of this study did not support the preferential use of tiotropium over ipratropium as a basis for savings in direct health-care costs. PMID- 22433759 TI - Resource use, costs, and utility estimates for patients with cystic fibrosis with mild impairment in lung function: analysis of data collected alongside a 48-week multicenter clinical trial. AB - OBJECTIVES: Transport of ions to generate epithelial rehydration (TIGER)-1 was a randomized trial conducted to evaluate the safety and efficacy of denufosol versus placebo in patients with cystic fibrosis with mild impairment in lung function. The trial met its primary end point at 24 weeks, but a subsequent trial did not show a sustained effect of denufosol at 48 weeks. By using the 48-week data, we characterized resource use, direct medical costs, indirect costs, and utility estimates. METHODS: Data on medications, outpatient and emergency visits, hospital admissions, tests, procedures, and home nursing were captured on study case report forms. Sources for unit costs included the Medicare Physician Fee Schedule, the Nationwide Inpatient Sample, and the Red Book. Health utilities were derived from the Health Utilities Index Mark 2/3. We used multivariable regression to evaluate the impact of baseline covariates on costs. RESULTS: Characteristics of the 352 participants at enrollment included mean age of 14.6 years, history of Pseudomonas aeruginosa colonization in 45.2%, use of dornase alfa in 77.0%, and long-term use of inhaled antibiotics in 37.2%. Over 48 weeks, 22.4% of participants were hospitalized and, on average, participants missed 7.4 days of school or work. Mean total costs (excluding denufosol) were $39,673 (SD $26,842), of which 85% were attributable to medications. Female sex and P. aeruginosa colonization were independently associated with higher costs. CONCLUSIONS: Prospective economic data collection alongside a clinical trial allows for robust estimates of cost of illness. The mean annual cost of care for patients with cystic fibrosis with mild impairment in lung function exceeds $43,000 and is driven by medication costs. PMID- 22433760 TI - Cost-effectiveness of different strategies for selecting and treating individuals at increased risk of osteoporosis or osteopenia: a systematic review. AB - OBJECTIVES: To compare cost-effectiveness modeling analyses of strategies to prevent osteoporotic and osteopenic fractures either based on fixed thresholds using bone mineral density or based on variable thresholds including bone mineral density and clinical risk factors. METHODS: A systematic review was performed by using the MEDLINE database and reference lists from previous reviews. On the basis of predefined inclusion/exclusion criteria, we identified relevant studies published since January 2006. Articles included for the review were assessed for their methodological quality and results. RESULTS: The literature search resulted in 24 analyses, 14 of them using a fixed-threshold approach and 10 using a variable-threshold approach. On average, 70% of the criteria for methodological quality were fulfilled, but almost half of the analyses did not include medication adherence in the base case. The results of variable-threshold strategies were more homogeneous and showed more favorable incremental cost effectiveness ratios compared with those based on a fixed threshold with bone mineral density. For analyses with fixed thresholds, incremental cost effectiveness ratios varied from ?80,000 per quality-adjusted life-year in women aged 55 years to cost saving in women aged 80 years. For analyses with variable thresholds, the range was ?47,000 to cost savings. CONCLUSIONS: Risk assessment using variable thresholds appears to be more cost-effective than selecting high risk individuals by fixed thresholds. Although the overall quality of the studies was fairly good, future economic analyses should further improve their methods, particularly in terms of including more fracture types, incorporating medication adherence, and including or discussing unrelated costs during added life-years. PMID- 22433761 TI - Incorporating indirect costs into a cost-benefit analysis of laparoscopic adjustable gastric banding. AB - OBJECTIVES: The objective of this study was to estimate the time to breakeven and 5-year net costs of laparoscopic adjustable gastric banding (LAGB) taking both direct and indirect costs and cost savings into account. METHODS: Estimates of direct cost savings from LAGB were available from the literature. Although longitudinal data on indirect cost savings were not available, these estimates were generated by quantifying the relationship between medical expenditures and absenteeism and between medical expenditures and presenteeism (reduced on-the-job productivity) and combining these elasticity estimates with estimates of the direct cost savings to generate total savings. These savings were then combined with the direct and indirect costs of the procedure to quantify net savings. RESULTS: By including indirect costs, the time to breakeven was reduced by half a year, from 16 to 14 quarters. After 5 years, net savings in medical expenditures from a gastric banding procedure were estimated to be $4970 (+/-$3090). Including absenteeism increased savings to $6180 (+/-$3550). Savings were further increased to $10,960 (+/-$5864) when both absenteeism and presenteeism estimates were included. CONCLUSIONS: This study presented a novel approach for including absenteeism and presenteeism estimates in cost-benefit analyses. Application of the approach to gastric banding among surgery-eligible obese employees revealed that the inclusion of indirect costs and cost savings improves the business case for the procedure. This approach can easily be extended to other populations and treatments. PMID- 22433762 TI - Comparison of FACT- and EQ-5D-based utility scores in cancer. AB - OBJECTIVE: Although utility-based algorithms have been developed for the Functional Assessment of Cancer Therapy (FACT), their properties are not well known compared with those of generic utility measures such as the EQ-5D. Our objective was to compare EQ-5D and FACT preference-based scores in cancer patients. METHODS: A retrospective analysis was conducted on cross-sectional data collected from 472 cancer patients who completed both FACT-General and the EQ-5D. Preference-based scores were calculated by using published scoring functions for the EQ-5D (Dolan P. Modeling valuations for EuroQol health states. Med Care 1997;35:1095-108; Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing of the D1 valuation model. Med Care 2005;43:203 20) and FACT (Dobrez D, Cella D, Pickard AS, et al. Estimation of patient preference-based utility weights from the Functional Assessment of Cancer Therapy General. Value Health 2007;10:266-72; Kind P, Macran S. Eliciting social preference weights for Functional Assessment of Cancer Therapy-Lung health states. Pharmacoeconomics 2005;23:1143-53; Cheung YB, Thumboo J, Gao F, et al. Mapping the English and Chinese versions of the Functional Assessment of Cancer Therapy-General to the EQ-5D utility index. Value Health 2009;12:371-6). Scores were compared on the basis of clinical severity by using Eastern Cooperative Oncology Group performance status ratings by physicians and patients. Relative efficiency of each scoring function was examined by using ratios of F statistics. RESULTS: Mean scores for the overall cohort were lowest when using Kind and Macran's FACT UK societal algorithm (0.55, SD 0.09) and highest when using Dobrez et al.'s FACT US patient algorithm (0.83, SD 0.08). Mean difference scores associated with clinical severity, when extrapolated to quality-adjusted life years (QALYs), had a range of 0.18 QALYs gained using FACT (Kind and Macran) to 0.45 QALYs gained using the EQ-5D (Dolan). However, relative efficiencies suggested that FACT (Kind and Macran) scores may provide greater statistical power to detect significant differences based on clinical severity. CONCLUSIONS: We found important differences in utilities scores estimated by each algorithm, with FACT-based algorithms tending to underestimate the QALY benefit compared with algorithms based on the EQ-5D. These differences highlight some of the challenges in using disease-specific preference-based measures for decision making despite potentially more relevant disease-specific content. PMID- 22433763 TI - Health-related quality of life measurement in children and adolescents in Ibero American countries, 2000 to 2010. AB - OBJECTIVES: To analyze the characteristics of instruments designed to assess the health-related quality of life (HRQOL) in children, developed or adapted from 2000 to 2010 in Argentina, Chile, Mexico, Spain, and Uruguay. METHODS: The protocol-led literature review included database searching (e.g., Medline, ISI Science Citation Index) and manual searching to retrieve studies focused on measures of HRQOL, health status, or well-being addressed to children and adolescents. Country-specific filters were applied to identify studies carried out in the participating countries. The characteristics of the instruments and type of studies were analyzed. Descriptive characteristics and psychometric properties were analyzed following the guidelines of the Scientific Advisory Committee of the Medical Outcomes Trust. RESULTS: Ninety-nine documents were included. Thirty-one questionnaires were identified, 24 instruments were adapted, and the psychometric properties of 20 HRQOL instruments were reported in the study period. There was substantial variability in the number and characteristics of the dimensions included. Reliability was generally acceptable, and the majority of instruments provided data on internal consistency (n = 18) and, to a lesser extent, on test-retest reliability (n = 12). Nearly all studies reported construct validity, but only four analyzed sensitivity to change. CONCLUSIONS: There is a scarcity of instruments to measure HRQOL of children and adolescents in the countries analyzed. Certain psychometric characteristics have been reasonably well tested, but others, most notably sensitivity to change, have not been tested in most instruments. Extension of this study to other Latin American countries would help to further identify gaps in this area and promote the use of HRQOL measurement in children and adolescents in Spanish-speaking cultures. PMID- 22433764 TI - Improving the measurement of QALYs in dementia: developing patient- and carer reported health state classification systems using Rasch analysis. AB - OBJECTIVES: Cost-utility analysis is increasingly used to inform resource allocation. This requires a means of valuing health states before and after intervention. Although generic measures are typically used to generate values, these do not perform well with people with dementia. We report the development of a health state classification system amenable to valuation for use in studies of dementia, derived from the DEMQOL system, measure of health-related quality of life in dementia by patient self-report (DEMQOL) and carer proxy-report (DEMQOL Proxy). METHODS: Factor analysis was used to determine the dimensional structure of DEMQOL and DEMQOL-Proxy. Rasch analysis was subsequently used to investigate item performance across factors in terms of item-level ordering, functioning across subgroups, model fit, and severity-range coverage. This enabled the selection of one item from each factor for the classification system. A sample of people with a diagnosis of mild/moderate dementia (n = 644) and a sample of carers of those with mild/moderate dementia (n = 683) were used. RESULTS: Factor analysis found different five-factor solutions for DEMQOL and DEMQOL-Proxy. Following item reduction and selection by using Rasch analysis, a five-dimension classification for DEMQOL and a four-dimension classification for DEMQOL-Proxy were developed. Each item contained four health state levels. CONCLUSION: Combining Rasch and classical psychometric analysis is a valid method of selecting items for dementia health state classifications from both the patient and carer perspectives. The next stage is to obtain preference weights so that the measure can be used in the economic evaluation of treatment, care, and support arrangements for dementia. PMID- 22433765 TI - Quality-adjusted life expectancies in patients with rheumatoid arthritis- comparison of index scores from EQ-5D, 15D, and SF-6D. AB - BACKGROUND: The aim of this study was to compare quality-adjusted life expectancy (QALE) for patients with rheumatoid arthritis generated from three generic health related quality-of-life instruments. METHODS: Patients from 11 Danish rheumatology outpatient clinics were asked to report current health status using the EuroQol five-dimensional questionnaire (EQ-5D), 15D, and six-dimensional health state short form (derived from SF-12) (SF-6D) instruments. Clinical staff provided data on current disease status (C-reactive protein and Disease Activity Score that involves clinical assessment of 28 joints). National mortality data were retrieved from Statistics Denmark. For each of the three instruments, mean index scores were estimated by gender and 5-year age groups. Partial QALE was estimated for the age interval 30 to 79 years for different subsamples. RESULTS: Although the three quality-of-life index scores were highly correlated, there were statistically significant differences between the average index scores from the three instruments. The 15D provided the highest index score and SF-6D the lowest score. For a 30-year-old patient, the partial QALE ranged from 37.9 quality-adjusted life-years using the SF-6D to 45.6 quality-adjusted life-years using the 15D. The QALE for men and women differed by 6.2%, 4.0%, and 5.3% when the calculation was based on EQ-5D, SF-6D, and 15D index scores, respectively. The largest differences were observed when patients were grouped by functional status (Health Assessment Questionnaire score), where the EQ-5D showed a 50% difference in index score between the best and worst functional group while the SF-6D and 15D showed smaller differences (32% and 14%, respectively). DISCUSSION: This analysis has shown the difference in QALE estimates related to different instruments. The study emphasizes that unless outcome studies use the same instruments and scoring algorithms, the results will not be directly comparable. PMID- 22433766 TI - Learning effects in time trade-off based valuation of EQ-5D health states. AB - OBJECTIVES: In EuroQol five-dimensional questionnaire valuation studies, each participant typically assesses more than 10 hypothetical health states by using the time trade-off (TTO) method. We wanted to explore potential learning effects when using the TTO method, that is, whether the valuations were affected by the number of previously rated health states (the sequence number). METHODS: We included 3773 respondents from the US EQ-5D valuation study, each of whom valued 12 health states (plus unconscious) in random order. With linear regression, we used sequence number to predict mean and standard deviations across all health states. We repeated the analysis separately for TTO responses indicating a state better than death and a state worse than death. Each TTO value requires a specific number of choice iterations. To test whether respondents used fewer iterations with experience, we used linear regression with sequence number as the independent variable and number of iterations as the dependent variable. RESULTS: Mean TTO values were fairly stable across the sequence number, but analyzing state better than death and state worse than death values separately revealed a tendency toward more extreme values: state better than death values increased by 0.02, while state worse than death values decreased by 0.21 (P < 0.0001) over the full sequence. The standard deviations increased slightly, while the number of choice iterations was the same over the sequence number. The findings were stable across the levels of health state severity, age, and sex. CONCLUSIONS: TTO values become more extreme with increasing experience. Because of the randomized valuation order, these effects do not bias specific health states; however, they reduce the overall validity and reliability of TTO values. PMID- 22433767 TI - Estimating preference-based single index measures for dementia using DEMQOL and DEMQOL-Proxy. AB - OBJECTIVE: Although condition-specific measures are commonly used in dementia, they cannot be used in analyses of cost per quality-adjusted life-year because they do not incorporate preferences. We addressed this gap by estimating two preference-based single index measures: the DEMQOL-U from the self-report DEMQOL (mild-to-moderate dementia severity) and the DEMQOL-Proxy-U from the carer-report DEMQOL-Proxy (all levels of dementia severity). METHODS: We conducted valuation studies on 593 members of the general population (306 for the DEMQOL-U, 287 for the DEMQOL-Proxy-U) using the time trade-off elicitation technique. We then fitted a range of mean and individual-level multivariate regression models to the valuation data to derive preference weights for each measure. We applied the estimated weights to a large, clinically representative sample. RESULTS: Mean observed time trade-off values ranged from 0.18 to 0.95 for DEMQOL-U and from 0.33 to 0.96 for DEMQOL-Proxy-U. The best performing models for each measure were main effects models estimated using individual-level data. DEMQOL-Proxy-U had inconsistent but insignificant coefficient estimates for one dimension. Models were estimated to remove these inconsistencies. CONCLUSION: Preference-based single index measures from DEMQOL and DEMQOL-Proxy for use in economic evaluation will enable economic evaluation using quality-adjusted life-years to be undertaken for people across the full range of dementia severity. Future research will examine how the utilities from each measure can be used and combined to populate cost-effectiveness models. PMID- 22433768 TI - Informing shared decisions about advance directives for patients with severe chronic obstructive pulmonary disease: a modeling approach. AB - OBJECTIVE: To estimate the survival and quality-adjusted life-years (QALYs) of Full Code versus Do Not Intubate (DNI) advance directives in patients with severe chronic obstructive pulmonary disease and to evaluate how patient preferences and place of residence influence these outcomes. METHODS: A Markov decision model using published data for COPD exacerbation outcomes. The advance directives that were modeled were as follows: DNI, allowing only noninvasive mechanical ventilation, or Full Code, allowing all forms of mechanical ventilation including invasive mechanical ventilation with endotracheal tube (ETT) insertion. RESULTS: In community-dwellers, Full Code resulted in a greater likelihood of survival and higher QALYs (4-year survival: 23% Full Code, 18% DNI; QALYs: 1.34 Full Code, 1.24 DNI). When considering patient preferences regarding complications, however, if patients were willing to give up >3 months of life expectancy to avoid ETT complications, or >1 month of life expectancy to avoid long-term institutionalization, DNI resulted in higher QALYs. For patients in long-term institutions, DNI resulted in a greater likelihood of survival and higher QALYs (4-year survival: 2% DNI, 1% Full Code; QALYs: 0.29 DNI, 0.24 Full Code). In sensitivity analyses, the model was sensitive to the probabilities of ETT complication and noninvasive mechanical ventilation failure and to patient preferences about ETT complications and long-term institutionalization. CONCLUSION: Our model demonstrates that patient preferences regarding ETT complications and long-term institutionalization, as well as baseline place of residence, affect the advance directive recommendation when considered in terms of both survival and QALYs. Decision modeling can demonstrate the potential trade off between survival and quality of life, using patient preferences and disease specific data, to inform the shared advance directive decision. PMID- 22433769 TI - Comparative effectiveness, cost, and utilization of radical prostatectomy among young men within managed care insurance plans. AB - BACKGROUND: Costs and benefits of emerging prostate cancer treatments for young men (age < 65 years) in the United States are not well understood. We compared utilization, clinical outcomes, and costs between two types of radical prostatectomy (RP)--minimally invasive prostatectomy (MIRP) and retropubic prostatectomy (RRP)--among young patients. METHODS: We extracted from LifeLink Health Plan Claims Database, a commercial claims database, information on 10,669 patients receiving either MIRP or RRP between 2003 and 2007. In unadjusted analyses, we used chi-square tests to compare clinical outcomes and nonparametric bootstrapping method to compare costs between the MIRP and RRP groups. We applied logistic, Cox proportional hazard, and extended estimation equation methods to examine the association between surgical modality and perioperative complications, anastomotic stricture, and costs while controlling for age, comorbidity, and health plan characteristics. RESULTS: The percentage of prostatectomies performed as MIRP increased from 5.7% in 2003 to 50.3% in 2007. Patients with more comorbidity were more likely to undergo RRP than MIRP. Compared with the RRP group, the MIRP group had a significantly lower rate of perioperative complications (23.0% vs. 30.4%; P < 0.001) and a lesser tendency for anastomotic strictures (hazard ratio 0.42; 95% CI 0.35-0.50) within the first postoperative year but had higher hospitalization costs ($19,998 vs. $18,424; P < 0.001) despite shorter hospitalizations (1.7 days vs. 3.1 days; P < 0.001). Similar findings were reported in the subgroup analysis of patients with comorbidity score 0. CONCLUSION: MIRP among nonelderly patients increased substantially over time. MIRP was found to have fewer complications. Lower costs of complications appeared to have offset higher hospitalization costs of MIRP. PMID- 22433770 TI - Innovation and the burden of disease: retrospective observational study of new and emerging health technologies reported by the EuroScan Network from 2000 to 2009. AB - OBJECTIVES: Medical innovation in developed countries has been linked to burden of disease, with more innovation in areas representing greater investment return. This study used horizon scanning or early awareness and alert activity as a novel measure of innovation to determine whether new and emerging health technologies reported by international horizon scanning agencies reflected diseases constituting the greatest burden. METHODS: This was a retrospective observational study of the 20 member agencies of EuroScan (the International Information Network on New and Emerging Health Technologies), representing 17 developed countries. Burden of disease was defined as disability-adjusted life-years, taken from the 2004 World Health Organization Global Burden of Disease estimates. This analysis focused on 102 specific diseases within 21 broader groups. Horizon scanning output was measured as the number of technologies reported by EuroScan member agencies between 2000 and 2009. RESULTS: At best there was a weak association between innovation and burden of disease. An apparent high-level association was dependent on just three high-prevalence disease groups: malignant neoplasms, neuropsychiatric conditions, and cardiovascular disease. Disaggregating broader groups into specific diseases further weakened the association. Innovation is disproportionately strong in cancer and nonischemic heart disease and disproportionately weak in mental health. CONCLUSIONS: Innovations reported by early awareness and alert systems do not always reflect conditions accounting for the highest morbidity and mortality. The results do not support previous reports of a positive relationship between burden of disease and innovation, but accord with evidence of notable discrepancies among key groups. Factors other than disease burden drive innovation. PMID- 22433771 TI - Antihypertensive drugs: a perspective on pharmaceutical price erosion and its impact on cost-effectiveness. AB - OBJECTIVE: When comparators' prices decrease due to market competition and loss of exclusivity, the incremental clinical effectiveness required for a new technology to be cost-effective is expected to increase; and/or the minimum price at which it will be funded will tend to decrease. This may be, however, either unattainable physiologically or financially unviable for drug development. The objective of this study is to provide an empirical basis for this discussion by estimating the potential for price decreases to impact on the cost-effectiveness of new therapies in hypertension. METHODS: Cost-effectiveness at launch was estimated for all antihypertensive drugs launched between 1998 and 2008 in the United Kingdom using hypothetical degrees of incremental clinical effectiveness within the methodologic framework applied by the UK National Institute for Health and Clinical Excellence. Incremental cost-effectiveness ratios were computed and compared with funding thresholds. In addition, the levels of incremental clinical effectiveness required to achieve specific cost-effectiveness thresholds at given prices were estimated. RESULTS: Significant price decreases were observed for existing drugs. This was shown to markedly affect cost-effectiveness of technologies entering the market. The required incremental clinical effectiveness was in many cases greater than physiologically possible so, as a consequence, a number of products might not be available today if current methods of economic appraisal had been applied. CONCLUSIONS: We conclude that the definition of cost effectiveness thresholds is fundamental in promoting efficient innovation. Our findings demonstrate that comparator price attrition has the potential to put pressure in the pharmaceutical research model and presents a challenge to new therapies being accepted for funding. PMID- 22433772 TI - Pharmaceutical cost-containment policies and sustainability: recent Irish experience. AB - OBJECTIVE: Our objective is to review and assess the main pharmaceutical cost containment policies used in Ireland in recent years, and to highlight how a policy that improved fiscal sustainability but worsened economic sustainability could have improved both if an option-based approach was implemented. METHOD: The main public pharmaceutical cost-containment policy measures including reducing the ex-factory price of drugs, pharmacy dispensing fees and community drug scheme coverage, and increasing patient copayments are outlined along with the resulting savings. We quantify the cost implications of a new policy that restricts the entitlement to free prescription drugs of persons older than 70 years and propose an alternative option-based policy that reduces the total cost to both the state and the patient. RESULTS: This set of policy measures reduced public spending on community drugs by an estimated ?380m in 2011. The policy restricting free prescription drugs for persons older than 70 years, though effective in reducing public cost, increased the total cost of the drugs supplied. The policy-induced cost increase stems from a fees anomaly between the two main community drugs schemes which is circumvented by our alternative option-based policy. CONCLUSIONS: Our findings highlight the need for policymakers, even when absorbed with reducing cost, to design cost-containment policies that are both fiscally and economically sustainable. PMID- 22433773 TI - Conducting comparative effectiveness research on medications: the views of a practicing epidemiologist from the other Washington. PMID- 22433774 TI - Patient access to new cancer drugs in the United States and Australia. PMID- 22433776 TI - Potential roles of peroxisomes in Alzheimer's disease and in dementia of the Alzheimer's type. AB - In Alzheimer's disease (AD) and dementia of the Alzheimer's type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the beta-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the alpha-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in neural cells and are essential components of myelin. Several studies conducted in animal models and in humans provided evidence for a role of DHA in preventing brain degeneration. Significantly lower levels of PLGN were observed in patients with severe dementia. Moreover, a decreased activity of carnitine acetyltransferase, an enzyme present in peroxisome (but also detected in mitochondria, endoplasmic reticulum, and nucleus), was reported in AD patients. We give an overview of the potential role of peroxisomes, especially in the part played by DHA, PLGN, carnitine, and carnitine-dependent peroxisomal enzymes, on the development of AD and DAT. The potential of developing novel therapies targeted on peroxisomal metabolism to prevent cognitive decline and other age-related neurological disorders is discussed. PMID- 22433778 TI - An analysis of timing and frequency of malaria infection during pregnancy in relation to the risk of low birth weight, anaemia and perinatal mortality in Burkina Faso. AB - BACKGROUND: A prospective study aiming at assessing the effect of adding a third dose sulphadoxine-pyrimethamine (SP) to the standard two-dose intermittent preventive treatment for pregnant women was carried out in Hounde, Burkina Faso, between March 2006 and July 2008. Pregnant women were identified as earlier as possible during pregnancy through a network of home visitors, referred to the health facilities for inclusion and followed up until delivery. METHODS: Study participants were enrolled at antenatal care (ANC) visits and randomized to receive either two or three doses of SP at the appropriate time. Women were visited daily and a blood slide was collected when there was fever (body temperature > 37.5 degrees C) or history of fever. Women were encouraged to attend ANC and deliver in the health centre, where the new-born was examined and weighed. The timing and frequency of malaria infection was analysed in relation to the risk of low birth weight, maternal anaemia and perinatal mortality. RESULTS: Data on birth weight and haemoglobin were available for 1,034 women. The incidence of malaria infections was significantly lower in women having received three instead of two doses of SP. Occurrence of first malaria infection during the first or second trimester was associated with a higher risk of low birth weight: incidence rate ratios of 3.56 (p < 0.001) and 1.72 (p = 0.034), respectively. After adjusting for possible confounding factors, the risk remained significantly higher for the infection in the first trimester of pregnancy (adjusted incidence rate ratio = 2.07, p = 0.002). The risk of maternal anaemia and perinatal mortality was not associated with the timing of first malaria infection. CONCLUSION: Malaria infection during first trimester of pregnancy is associated to a higher risk of low birth weight. Women should be encouraged to use long-lasting insecticidal nets before and throughout their pregnancy. PMID- 22433779 TI - Time-based prospective memory in severe traumatic brain injury patients: the involvement of executive functions and time perception. AB - Prospective memory (PM) is the ability to remember to perform a future action at a specified later time, which is investigated through the use of event-based and time-based tasks. Prior investigations have found that PM is impaired following traumatic brain injury (TBI). However, there is limited information regarding the cognitive functions that mediate TBI and PM performance. Thus, this study investigated time-based PM in TBI patients, and the relationship among time-based PM, time perception, and executive functions. To accomplish this objective, 18 severe TBI patients and 18 healthy matched controls performed a time-based PM task, a time reproduction task, and two executive functions (Stroop and n-back) tasks. While both groups increased their monitoring frequency close to the target time, TBI patients monitored more and were less accurate than healthy controls at the target time confirming the time-based PM dysfunction in these patients. Importantly, executive functions, particularly inhibition and updating abilities, were strongly related to time-based PM performance; both time perception and executive functions are involved in time-based prospective memory in controls, whereas, only executive functions appear to be involved in TBI time-based prospective memory performance. PMID- 22433780 TI - The paradox of cortisol awakening response in children: a critical perspective. PMID- 22433781 TI - Bone repair cells for craniofacial regeneration. AB - Reconstruction of complex craniofacial deformities is a clinical challenge in situations of injury, congenital defects or disease. The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response for craniofacial wound healing. Both somatic and stem cells have been adopted in the treatment of complex osseous defects and advances have been made in finding the most adequate scaffold for the delivery of cell therapies in human regenerative medicine. As an example of such approaches for clinical application for craniofacial regeneration, Ixmyelocel-T or bone repair cells are a source of bone marrow derived stem and progenitor cells. They are produced through the use of single pass perfusion bioreactors for CD90+ mesenchymal stem cells and CD14+ monocyte/macrophage progenitor cells. The application of ixmyelocel-T has shown potential in the regeneration of muscular, vascular, nervous and osseous tissue. The purpose of this manuscript is to highlight cell therapies used to repair bony and soft tissue defects in the oral and craniofacial complex. The field at this point remains at an early stage, however this review will provide insights into the progress being made using cell therapies for eventual development into clinical practice. PMID- 22433782 TI - Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues. AB - Non-invasive treatment of injuries and disorders affecting bone and connective tissue remains a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several important roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair. PMID- 22433783 TI - Growth factor delivery: how surface interactions modulate release in vitro and in vivo. AB - Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases. PMID- 22433784 TI - Development of macromolecular prodrug for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL 6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases. PMID- 22433785 TI - Application of a homogenous membrane potential assay to assess mitochondrial function. AB - Decreases in mitochondrial membrane potential (MMP) have been associated with mitochondrial dysfunction that could lead to cell death. The MMP is generated by an electrochemical gradient via the mitochondrial electron transport chain coupled to a series of redox reactions. Measuring the MMP in living cells is commonly used to assess the effect of chemicals on mitochondrial function; decreases in MMP can be detected using lipophilic cationic fluorescent dyes. To identify an optimal dye for use in a high-throughput screening (HTS) format, we compared the ability of mitochondrial membrane potential sensor (Mito-MPS), 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolylcarbocyanine iodide, rhodamine 123, and tetramethylrhodamine to quantify a decrease in MMP in chemically exposed HepG2 cells cultured in 1,536-well plates. Under the conditions used, the optimal dye for this purpose is Mito-MPS. Next, we developed and optimized a homogenous cell-based Mito-MPS assay for use in 1,536-well plate format and demonstrated the utility of this assay by screening 1,280 compounds in the library of pharmacologically active compounds in HepG2 cells using a quantitative high-throughput screening platform. From the screening, we identified 14 compounds that disrupted the MMP, with half-maximal potencies ranging from 0.15 to 18 MUM; among these, compound clusters that contained tyrphostin and 3'-substituted indolone analogs exhibited a structure-activity relationship. Our results demonstrate that this homogenous cell-based Mito-MPS assay can be used to evaluate the ability of large numbers of chemicals to decrease mitochondrial function. PMID- 22433786 TI - Combined medical and surgical therapy improves olfaction in patients with nasal polyposis. AB - OBJECTIVE: The aim of the present study was to evaluate the outcomes of combined oral steroid, nasal steroid and surgical therapy in patients with impaired olfaction due to nasal polyposis. PATIENTS AND METHODS: This prospective observational study was undertaken in the otolaryngology department of a university hospital. During the study, 19 nasal polyposis patients were evaluated three times, i.e. before oral steroid therapy, before surgery (after steroid therapy) and after surgery, with smell identification tests, acoustic rhinometry, subjective smell score, endoscopic grading and a visual analog scale for nasal obstruction. RESULTS: All subjective and objective measures were significantly improved after medical and surgical therapy (p < 0.01). The median smell identification score improved from 2 (interquartile range 0-4) to 5 (interquartile range 4-7) after combined therapy. Smell identification scores were found to be modestly correlated with all other examination findings. CONCLUSION: Combined therapy seems efficient in improving smell identification scores of nasal polyposis patients. PMID- 22433787 TI - The characteristics of remnant lipoproteins in the fasting and postprandial plasma. AB - BACKGROUND: Remnant-like lipoprotein particles (RLP) have been measured by cholesterol as RLP-C for CHD risk assessment in the fasting plasma. However, RLP triglyceride (TG) is a better marker of the characteristics of remnant lipoproteins in the postprandial plasma, especially in plasma with TG concentrations <150 mg/dl. METHOD: The RLP-TG and RLP-C concentrations in subjects undergoing a health check-up and in volunteers receiving an oral fat load were determined in the fasting and postprandial plasma. TC, TG, HDL-C, LDL C, apoB 100, apoB48, RLP apoB-100 and RLP apoB48 were also determined. RESULTS: When fasting TG concentrations were <150 mg/dl, the 95th percentile of RLP-TG was 20mg/dl and the RLP-C 7.5 mg/dl in healthy subjects. The prevalence of RLP-TG and RLP-C above the cut-off values with a TG concentration <150 mg/dl was significantly higher in the metabolic syndrome cases than in the controls. RLP-TG increased significantly in plasma to >20mg/dl after an oral fat load in cases with TG concentrations >80 mg/dl. Further, RLP apoB100, but not RLP apoB48 was highly correlated with the increase of TG in the postprandial plasma. CONCLUSION: RLP-TG and RLP-C were increased significantly above the cut-off values in the postprandial plasma in healthy volunteers from a TG concentration >80 mg/dl. RLP apoB100, but not RLP apoB48, increased significantly when the plasma TG increased after an oral fat load despite the increase of plasma apoB48. The results show that the major lipoproteins which were increased in postprandial plasma were VLDL remnants, not CM remnants. PMID- 22433789 TI - Increased expression of Nox1 in neointimal smooth muscle cells promotes activation of matrix metalloproteinase-9. AB - OBJECTIVE: Vascular injury causes neointimal hypertrophy, which is characterized by redox-mediated matrix degradation and smooth muscle cell (SMC) migration and proliferation. We hypothesized that, as compared to the adjacent medial SMCs, neointimal SMCs produce increased superoxide via NADPH oxidase, which induces redox-sensitive intracellular signaling to activate matrix metalloproteinase-9 (MMP-9). METHODS AND RESULTS: Two weeks after balloon injury, rat aorta developed a prominent neointima, containing increased expression of NADPH oxidase and reactive oxygen species (ROS) as compared to the medial layer. Next, SMCs were isolated from either the neointima or the media and studied in culture. Neointimal-derived SMCs exhibited increased Nox1 expression and ROS levels as compared to medial SMCs. Neointimal SMCs had higher cell growth rates than medial SMCs. ROS-dependent ERK1/2 phosphorylation was greater in neointimal SMCs. MMP-9 activity, as detected by gel zymography, was greater in neointimal SMCs under resting and stimulated conditions and was prevented by expression of an antisense to Nox1 or treatment with an ERK1/2 inhibitor. CONCLUSIONS: Following vascular injury, the increased expression of Nox1 in SMCs within the neointima initiates redox-dependent phosphorylation of ERK1/2 and subsequent MMP-9 activation. PMID- 22433790 TI - Usefulness of endoscopic submucosal dissection for the treatment of rectal carcinoid tumors. AB - BACKGROUND AND AIM: Various techniques of endoscopy have been developed to treat rectal carcinoids. This retrospective study aimed to evaluate the feasibility and efficacy of endoscopic submucosal dissection for the treatment of rectal carcinoids smaller than 10 mm in diameter. PATIENTS AND METHODS: A total of 18 consecutive patients were enrolled with 20 carcinoid tumors that had the following characteristics: the diagnosis of a rectal carcinoid smaller than 10 mm, no endoscopic evidence of muscularis propria invasion, and no evidence of lymph node or distant metastasis (11 men and seven women; median age, 69 years; median tumor size, 4 mm). Tumors were resected by endoscopic submucosal dissection with a needle knife and a hook knife. After marking, a one-third to one-half circumferential mucosal incision was made, and subsequently, the submucosa under the lesion was exfoliated. After the submucosa under the tumor was exfoliated, the residual mucosa was incised and the tumor was removed. Complete resection, complication rates, and operation time were evaluated. RESULTS: Complete resection was achieved in all cases (100%) without complications. The mean operation time was 34.2 min, which was acceptable in clinical practice. CONCLUSION: Endoscopic submucosal dissection with the strategy described above is feasible and efficacious for selected patients with a rectal carcinoid smaller than 10 mm. PMID- 22433791 TI - Diagnostic and therapeutic utility of single-operator peroral cholangioscopy for indeterminate biliary lesions and bile duct stones. AB - BACKGROUND AND AIM: We aimed to evaluate the diagnostic utility of single operator peroral cholangioscopy (SOC) for indeterminate biliary lesions and its usefulness in electrohydraulic lithotripsy (EHL) of biliary stones not amenable to conventional endoscopic therapy. PATIENTS AND METHODS: All patients undergoing SpyGlass SOC in four UK tertiary centres between 2008 and 2010 were retrospectively enrolled. Patients were followed up until death or the last clinic visit until May 2011. The operating characteristics of SOC for detecting malignant lesions and the stone clearance rate after SOC-guided EHL were calculated. RESULTS: A total of 165 patients underwent 179 SOC procedures. Sixty six percent were referred for indeterminate biliary strictures, 13% for filling defects and 21% for SOC-guided EHL. Cannulation with the SOC system was successful in 95% but visualization was inadequate in 13%. Primary sclerosing cholangitis was a risk factor for failed cannulation and conscious sedation (vs. general anaesthesia) for inadequate visualization (P<0.05). The accuracy of SOC for diagnosing malignant lesions was 87%. SOC-guided biopsies were adequate in 72%. Obtaining at least four versus less than four biopsy specimens resulted more often in adequate samples (90 vs. 64%, P=0.037). Complete stone clearance could be achieved in 73% of patients. The adverse event rate was 9.6%. Cholangitis was the most common event (56%, one fatal). CONCLUSION: SOC is useful for the differential diagnosis of indeterminate biliary lesions and the treatment of 'difficult' biliary stones. The adequacy of SOC-guided biopsies is related to the number of specimens obtained. Primary sclerosing cholangitis is related to failed cannulation with the SOC system, whereas general anaesthesia is related to adequate visualization. PMID- 22433792 TI - Functional chest pain responds to biofeedback treatment but functional heartburn does not: what is the difference? AB - BACKGROUND: Patients with functional esophageal disorders represent a challenging treatment group. The purpose of this study was to evaluate the role of biofeedback in the treatment of patients with functional esophageal disorders. METHODS: In this prospective study, patients with typical/atypical symptoms of gastroesophageal reflux disease underwent upper endoscopy and 24-h pH monitoring. All patients filled out gastroesophageal Reflux Disease Symptom, Hospital Anxiety and Depression, and Symptom Stress Rating questionnaires. Patients with functional heartburn and those with functional chest pain were offered biofeedback treatment. A global assessment questionnaire was filled out at the end of treatment and then 2.8 (range 1-4) years later. RESULTS: From January 2006 to December 2009, 22 patients with functional esophageal diseases were included in the study. Thirteen had functional heartburn and nine had functional chest pain. Six patients from each group received biofeedback treatment. After treatment for 1-4 years, patients with functional chest pain showed significant improvements in symptoms compared with those who were not treated. Patients with functional heartburn showed no improvement. Patients with functional chest pain had a longer time of esophageal acid exposure than those with functional heartburn. CONCLUSION: Patients with functional chest pain have different central and intraesophageal factors associated with symptom generation in comparison with patients with functional heartburn. Biofeedback is a useful tool in the treatment of patients with functional chest pain, but not for those with functional heartburn. PMID- 22433793 TI - The diagnostic value of multimodal evoked potentials in the determination of subclinical neurological involvement of Wilson's disease. AB - AIMS: Wilson's disease (WD) is a progressive degeneration of hepatolenticular tissue caused by excessive tissue-damaging copper accumulation and in which liver involvement most frequently presents in childhood. Neurological signs also accompany liver disease with time. However, subclinical neurological involvement may occur earlier and diagnostic methods that reveal this subclinical involvement are not well established. The aim of the current study is to assess the subclinical neurological involvement by using multimodality evoked potential (EP) measurements and to explore the relationship between neurological disease and the severity of liver damage. METHODS: The patient group included 28 children (mean age 11.8 +/- 2.9 years, range 5.5-17) diagnosed with WD and a control group included 24 age-matched healthy children. Multimodality EP tests (Nihon Kohden Neuropack 8 4200K) of both groups were performed at the Department of Neurology Electrophysiology Laboratory of Ege University. RESULTS: At least one abnormal EP value was observed in 53.5% of the children in the patient group. At least on one side, there were abnormal values for visual evoked potential (VEP) P100, brainstem auditory evoked potential (BAEP) and somatosensory evoked potential (SEP), where the ratios were 25, 28.5, and 11%, respectively. Absolute latency values of patients with right-side VEP P100 and left-side BAEP I, and the interpeak latency values of right-side BAEP I-III were significantly high. The difference in right-side BAEP I-III interpeak latency between cirrhotic and noncirrhotic groups was found to be statistically significant (P<0.05). CONCLUSION: The EP examinations can be an indicator of subclinical brain damage in non-neurological WD; however, cirrhosis because of WD does not cause an increase in the EP values. Detection of changes in the EP values periodically, especially at the time of diagnosis and during the treatment follow-up, may be valuable for revealing subclinical impairment. PMID- 22433794 TI - Prospective observational study on antibiotic-associated bloody diarrhea: report of 21 cases with a long-term follow-up from Turkey. AB - OBJECTIVE: Antibiotic-associated hemorrhagic colitis is a distinct form of antibiotic-associated bloody diarrhea (AABD) in which Clostridium difficile is absent. Although the cause is not exactly known, reports have suggested the role of Klebsiella oxytoca and/or C. difficile. MATERIALS AND METHODS: Between 2001 and 2006, stool samples of 21 consecutive patients with AABD were cultured for common enteric pathogens and K. oxytoca, and were tested for the presence of parasites and C. difficile toxin A+B within the first 24 h of their initial admission and a colonoscopy was performed when available. The patients were followed up prospectively by telephone interviews. RESULTS: The occurrence of symptoms ranged between 6 h and 14 days following the first dose of the antibiotic responsible and the duration of the AABD ranged between 6 h and 21 days. The antibiotic responsible was oral ampicillin/sulbactam in 18 (85%) cases. C. difficile toxin A+B production by enzyme-linked immunosorbent assay and K. oxytoca growth in stool cultures were detected in six (29%) and 11 (51%) of 21 patients, respectively. Endoscopic morphology and histology in a limited number of patients revealed no more than a nonspecific inflammation and acute colitis, respectively. CONCLUSION: This study confirms that antibiotic-associated hemorrhagic colitis, as a distinct entity in relation to K. oxytoca, is seen in half of the patients with AABD. Most of the cases are seen within a week following the antibiotic use. Almost all of the patients did not develop any flares during the long-term antibiotic-free follow-up. In some of the patients with AABD, there was coexistence of K. oxytoca with C. difficile toxin A+B. PMID- 22433795 TI - Eosinophilic gastroenteritis associated with multiple gastric cancer. AB - Eosinophilic gastroenteritis (EG) is an inflammation of the digestive tract that is characterized by eosinophilic infiltration. There are no specific symptoms, and are related to the layer in which eosinophilic infiltration is observed. A 69 year-old Japanese man presented to our hospital with a history of general malaise, diarrhea, and dysgeusia. Esophagogastroduodenoscopy showed reddish elevated lesions that were edematous all over the gastric mucosa. In addition, three tumors were also observed. The biopsies of the reddish elevated mucosa revealed eosinophilic infiltration and tubular adenocarcinoma from the tumors. Colonoscopy showed abnormal reddish elevated mucosa. The biopsies from the reddish elevated mucosa showed eosinophilic infiltration. From the abdominal contrast computed tomography scan, tumor stain was seen in the anterior wall of the gastric body. No ascites, intestinal wall thickening, or lymph node swelling were found. A slight elevation in the serum immunoglobulin E (IgE), 480 IU/ml, was found from the laboratory test results; other laboratory results were within normal limits including the number of peripheral eosinophils. No specific allergen was found from the multiple antigen simultaneous test and from the skin patch test. The parasitic immunodiagnosis was negative. He was diagnosed with EG associated with gastric cancer and underwent total gastrectomy, regional lymph node dissection with reconstruction by a Roux-en-Y method. He was prescribed prednisolone after the operation and showed a good clinical response. There are many case reports on EG, but none of them were associated with cancer. We encountered a case of EG associated with multiple gastric cancer; the patient underwent total gastrectomy. PMID- 22433796 TI - Ranking predictors of a sustained viral response for patients with chronic hepatitis C treated with pegylated interferon and ribavirin in Scotland. AB - OBJECTIVES: From the literature on the hepatitis C virus, the existence of a gap between a sustained virologic response (SVR) attainable in randomized clinical trials (RCTs) versus routine practice is not clear. Further, in terms of the pretreatment prediction of SVR, to date, studies have focused only on reporting the magnitude of association (MOA) between each predictor and an SVR. They fail to acknowledge that a predictor with a large MOA is of little value to clinicians if it has low variability in the treatment population. METHODS: Hepatitis C virus clinical databases were used to derive a large, representative cohort of Scottish pegylated interferon and ribavirin initiates. RESULTS: Overall, 39% [123/315, 95% confidence interval (CI) 34-45%] of genotype 1 and 70% (414/594, 95% CI 66-73%) of genotype 2/3 patients achieved an SVR; this compares with the pooled estimates of 47% for genotype 1 (95% CI 41-52%) and 80% for genotype 2/3 (95% CI 75-85%) RCT participants. Significant predictors of SVR identified from logistic regression were ranked on the basis of the akaike information criteria (reflecting an approach that will account for each predictor's MOA and variability) as follows: (i) genotype, % increase in akaike information criteria of the final model when variables are excluded, 58.49%; (ii) gamma-glutamyl transferase, 18.64%; (iii) platelet count, 6.48%; (iv) alanine aminotransferase quotient, 4.63%; (v) ever infected with hepatitis B virus, 4.31% and (vi) sex, 3.10%. CONCLUSION: (i) The proportion of patients attaining an SVR in Scottish routine practice is marginally lower than in RCTs and (ii) other than genotype, gamma-glutamyl transferase emerges as a valuable predictor of an SVR in routine practice. Further, we demonstrate an approach to more clearly discern the predictive value of response predictors. PMID- 22433797 TI - A simple method for construction of pir+ Enterobacterial hosts for maintenance of R6K replicon plasmids. AB - BACKGROUND: The R6K replicon is one of the best studied bacterial plasmid replicons. Replication of the R6K plasmid and derivatives harboring its gamma origin of replication (ori(R6Kgamma)) is dependent on the pir gene-encoded pi protein. Originally encoded by R6K, this protein is usually provided in trans in hosts engineered to support replication of plasmids harboring ori(R6Kgamma). In Escherichia coli this is commonly achieved by chromosomal integration of pir either via lysogenization with a lambdapir phage or homologous recombination at a pre-determined locus. FINDINGS: Current methods for construction of host strains for ori(R6Kgamma)-containing plasmids involve procedures that do not allow selection for presence of the pir gene and require cumbersome and time-consuming screening steps. In this study, we established a mini-Tn7-based method for rapid and reliable construction of pir+ host strains. Using a curable mini-Tn7 delivery plasmid, pir expressing derivatives of several commonly used E. coli cloning and mobilizer strains were isolated using both the wild-type pir+ gene as well as the copy-up pir-116 allele. In addition, we isolated pir+ and pir-116 expressing derivatives of a clinical isolate of Salmonella enterica serovar Typhimurium. In both E. coli and S. enterica serovar Typhimurium, the presence of the pir+ wild type or pir-116 alleles allowed the replication of ori(R6Kgamma)-containing plasmids. CONCLUSIONS: A mini-Tn7 system was employed for rapid and reliable engineering of E. coli and S. enterica serovar Typhimurium host strains for plasmids containing ori(R6Kgamma). Since mini-Tn7 elements transpose in most, if not all, Gram negative bacteria, we anticipate that with relatively minor modifications this newly established method will for the first time allow engineering of other bacterial species to enable replication of plasmids with ori(R6Kgamma). PMID- 22433798 TI - Preparation and characterization of controlled release matrices based on novel seaweed interpolyelectrolyte complexes. AB - Novel interpolyelectrolyte complexes (IPECs) between naturally sulfated polysaccharides of the seaweed Polysiphonia nigrescens (PN) and cationized agaroses (CAG) and Eudragit E (EE) were prepared using an organic solvent free process, characterized, and explored for controlled drug release. Tablets containing model drug ibuprofen and IPECs were prepared by direct compression. Drug release in acid medium was low owing to the low solubility of ibuprofen in that condition and to the matrix action. Zero order drug release was determined in the buffer stage (pH=6.8), with Fickian diffusion predominating over relaxation during the initial phases. Relaxation appears to increase along the release process and even overcomes diffusion for some systems. Drug release profiles could be controlled by varying the content of IPECs in the tablets. Also, the change in molecular weight and the degree of substitution of the components allowed altering the release profiles. PMID- 22433800 TI - Cognitive behaviour therapy for psychosis: the impact of therapist training and supervision. PMID- 22433799 TI - Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study. AB - BACKGROUND: While a possible link between assisted reproductive technology (ART) and rare imprinting disorders has been found, it is not clear if this is indicative of subtler disruptions of epigenetic mechanisms. Results from previous studies have been mixed, but some methylation differences have been observed. METHODS: Children conceived through ART and children conceived spontaneously were recruited for this cross-sectional study. Information about reproductive history, demographic factors, birth characteristics, and infertility treatment was obtained from maternal interview and medical records. Peripheral blood lymphocytes and buccal cell samples were collected from participating children. Methylation analysis was performed on five loci using pyrosequencing. Statistical analysis of methylation differences was performed using linear regression with generalized estimating equations. Results are reported as differences with 95% confidence intervals (CI). RESULTS: A total of 67 ART children and 31 spontaneously conceived (SC) children participated. No significant difference in methylation in lymphocyte samples was observed between groups for any loci. Possible differences were found in buccal cell samples for IGF2 DMR0 (Difference: 2.07; 95% confidence interval (CI): -0.28, 4.42; p = 0.08) and IGF2R (Difference: -2.79; 95% CI: -5.74, 0.16; p = 0.06). Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility. CONCLUSIONS: Observed differences in methylation between the ART and SC groups were small for all loci in the two sample types examined and no statistical differences were observed. It is still unclear whether or not small differences observed in several studies represent a real difference between groups and if this difference is biologically meaningful. Larger studies with long term follow up are needed to fully answer these questions. PMID- 22433801 TI - [The marker of discogenic diseases of the nervous system in the cerebrospinal fluid]. AB - Using a novel diagnostic technology that allows to investigate the structure of a biological fluid formed during its phase transition into a dried film, we revealed a cause of mistaken results of protein concentrations in the cerebrospinal fluid of patients with discogenic radiculitis. The traditional laboratory study does not reveal the elevated content of protein in patients with discogenic radiculitis and hernia of invertebral discs due to its more active binding with salts with the following sedimentation during centrifugation. It can be explained by the involvement of salt crystals in the formation of the inert organic-mineral aggregate with protein molecules which structure was changed by dystrophy, ischemia, hypoxia, mechanic damage, tumor process. The aggregate is characterized by abnormally tight links. This phenomenon is known as biomineralization, the universal mechanism preventing the organism from toxic effects of products of degraded tissues. PMID- 22433802 TI - [Manifest depressive-delusional episodes of juvenile endogenous psychosis]. AB - The structure of the first psychotic episode of juvenile endogenous intermittent psychosis with the dominance of depressive and delusional disorders was studied in a sample of 50 male patients aged 16-25 years. Three types of first episodes were singled out: episodes with homonomous structure - 11 (22%) patients, heteronomous episodes with the dominance of delusional disorders - 20 (40%) patients and heteronomous episodes with the dominance of depressive disorders - 19 (38%) patients. The differences between these types were determined by characteristics of the structure, the ratio of affective to delusional symptomatology, dynamic changes in the status, objective measures of the PANSS and CDSS. The main characteristics of these states due to the pathoplastic effect of the age factor were revealed. The authors suggest that the typological subdivision is significant for the diagnosis and prognosis of an endogenous psychosis with manifest depressive-delusional episodes. This suggestion should be verified in the follow-up study. PMID- 22433803 TI - [Ceraxon (citicoline) in the treatment of the mild cognitive impairment syndrome]. AB - The objective was to study efficacy and safety of ceraxon (citicoline) used perorally in dose 1000 mg daily in the treatment of cognitive disturbances in patients with amnesic type of mild cognitive impairment (MCI). Twenty patients, aged from 50 to 90 years, received ceraxon in dose 1000 mg twice a day during 90 days. The state of patients was assessed with a battery of scales and tests with the following statistical data analysis. The significant results on the clinical effect of the drug on cognitive disturbances and good tolerability of ceraxon have been obtained. The authors recommend ceraxon for long-term preventive treatment in high risk populations for Alzheimer's disease. PMID- 22433804 TI - [Dysport in the treatment of essential tremor]. AB - Head tremor develops in one-third of patients with essential tremor. It is resistant to peroral antitremor medications. The efficacy of dysport, a botulinum toxin type A preparation, injected in the neck muscles, was examined in 12 patients with head tremor. After the injection of 500 U of the drug (150 U in each splenius muscle of the head and 100 U in each sternal-clavicular-mammiform muscle), the intensity of head tremor assessed by the rating tremor scale was decreased by more than 50%. The clinically significant effect was registrated in more than 2/3 of patients. Five patients who received repeated injections of dysport 2 times a year were followed-up for 3 years that allowed to find a trend towards the slow cumulative effect. The use of botulinum toxin type A preparations is recommended as a method of choice in patients with essential tremor and significant head tremor interfering with life activities. PMID- 22433805 TI - [A search for new markers of oxidative stress in brain ischemia for the optimization of treatment approaches]. AB - Data of literature on the role of inflammation factors in the pathogenesis of stroke are presented. The study of myeloperoxidase level in the early acute phase of ischemic stroke and dynamics of this parameter after the antioxidant treatment with the alpha-lipoic acid preparation berlition was carried out. It has been shown that the activation of systemic inflammation and related oxidative stress recorded in the early acute phase of brain infarction needs pharmacological treatment. Neuroprotective action of alpha-lipoic acid related to the prevention of damaging effect of free radicals on cell membranes and reduction of oxidative stress intensity is a pathogenetic explanation for using its preparations in ischemic brain lesions. The decrease in plasma myeloperoxidase content after the treatment with berlition may consider as a criterion of its efficacy. PMID- 22433806 TI - [Reduction of the severity of affective disorders in patients with the first episode of schizophrenia using the method of bioacoustics correction]. AB - Authors examined 17 adolescents, aged 15-17 years, during the manifestation of slow-progressive schizophrenia. The possibility of the correction of affective disorders, on the basis of involuntary self-regulation using bioacoustics correction (BAC), was studied. BAC method is based on on computed EEG transformation into acoustic signals. The use of BAC method led to the stable reduction of depression and anxiety and their corresponding clinical presentations. The positive changes in the patient's state were accompanied by the EEG reorganization. The decrease in the intensity of beta- and delta-index, the increase of the power of the alpha-rhythm and the decrease of the interhemispheric asymmetry were noted. It has been concluded, that the bioacoustics correction procedures promote the formation of new skills and behaviors by means of restructuring of conditioned reflexes and reshaping (redesigning) of time constraints in the central nervous system. BAC is recommended as an effective and physiologically adequate way of therapy in adolescent schizophrenic patients with anxiety-depressive syndromes. PMID- 22433807 TI - [Efficacy of the combination of cycloferon and reamberin in treatment of resistant patients with paranoid schizophrenia]. AB - The 160 patients with paranoid schizophrenia (PSH) with neuroleptic therapeutic resistance (TR) was investigated. The 90 (basic group) patients got of modern detoxic and metabolically active preparation reamberin and immunotropic facilities cycloferon combination additionally to psychotropic preparations and 70 patients (comparison group) - only the generally accepted therapy. Positive influence of reamberin and cycloferon combination was set on clinical states at the patients of PSH such as disease remission, and endogenous toxicosis syndrome liquidation. Positive influence of this preparations combination was rationed on immunological indexes, characterizing composition and functional activity of cellular immunity. PMID- 22433808 TI - [Repetitive botulinum toxine injections in children with cerebral palsy: causes of parents' decline and the ways to resolve]. AB - The refuse of the parents of the child with spastic cerebral palsy to use botulinum toxine as a part of multidisciplinary prolonged treatment can be destructive for the achievement of the goals of the rehabilitation. 65 parents of children with CP were assessed to clarify the substituted causes for rejection. Answers, caused by real adverse effects of the medication were rarest. Most of the parents were afraid of the reactions, which are the part of pharmaceutical effect. Psychological background and the opinion of the other persons are the most difficult causes to be resolved. PMID- 22433809 TI - [The video motion analysis as a method of the diagnosis of the basal ganglion lesion in Parkinson's disease]. AB - Movement disturbances in patients with Parkinson's disease (PD) are one of the most important clinical symptoms. Locomotion analysis systems are one of perspective directions of instrumental diagnosis of movement disturbances. We studied 113 patients, including 53 patients with PD (18 with the tremor type, 25 with rigid type), and 60 healthy volunteers. Indices of purposeful and no purposeful movements and useful movements' coefficient were specified in the motion analysis software V&A. The index of no-purposeful movements can be used as a reliable marker of side-dependent clinical symptoms in the rigid PD type. PMID- 22433810 TI - [Clinical-genetic correlations in the hereditary motor-sensor neuropathy caused by mutations in the MPZ (P0) gene]. AB - Hereditary motor-sensor neuropathy (HMSN) caused by mutations in the MPZ (P0) gene is a rare variant of hereditary demyelinating polyneuropathies that makes up 5-10% of all cases in different populations. Based on the complex examination of patients of the Russian Federation with different MPZ (P0) mutations, we obtained clinical-genetic, electromyographic and molecular-genetic characteristics of HMSN caused by mutations in the MPZ (P0) gene. Peculiarities of clinical presentations in patients with HMSN, types 1B and 2I, are presented. Diagnostic criteria of these genetic variants have been formed. The new allelic variants of HMSN caused by mutations in the MPZ (P0) gene are described. The distribution of mutations by protein domains has been analyzed. PMID- 22433811 TI - [Clinical features of LRRK2-associated Parkinson's disease]. AB - Mutations in the Leucine Reach Repeat Kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Previously, we have sequenced the coding region of the LRRK2 gene in 85 PD patients and showed the prevalence of G2019S-associated PD (G2019S-PD) among all cases of LRRK2-associated PD in Russia. Screening of the most frequent LRRK2 mutations (G2019S, R1441C, R1441G) in the extended sample of PD patients (100 familial cases, 14 relatives and 230 sporadic cases) revealed two novel families with G2019S-PD in the addition to LRRK2-associated PD cases identified earlier. In summary, the frequency of LRRK2 associated PD among familial PD cases was estimated as 8%. The G2019S mutation was the most frequent (7% - in familial and 0.5% - in sporadic PD). Comparative analyses of the age-at-onset and main neurological symptoms in 13 patients with LRRK2-associated PD (8 with G2019S, 2 - V1613A and 1 - R1441C) and 80 PD patients without mutations in the LRRK2 gene did not reveal any differences. However, the G2019S LRRK2 mutation carriers had the increased rate of drug induced side effects in comparison with genetically undefined patients (OR=6.4, p<0.02). The data obtained could improve our understanding of the pathogenesis of LRRK2 associated PD and be useful in clinical practice during disease therapy. PMID- 22433812 TI - [The state of the immune system in endogenous mental diseases with pronounced affective disorders]. AB - Parameters of innate and adaptive immunity were studied in the blood serum of 180 patients, aged 15-25 years, with different endogenous mental diseases with depressive and mania disorders in the clinical picture (affective psychoses (29 patients), schizoaffective psychoses (106 patients) , slow-progressive schizophrenia (23 patients) and intermittent-progressive schizophrenia (22 patients)). The activation of innate immunity (the increase in the degranulation activity of leukocyte elastase (LE) and functional activity of alpha-1-proteinase inhibitor (alpha1-PI) were found in all the diseases. The increase in disease severity (from affective disorders to intermittent-progressive schizophrenia) was correlated with the significant elevation of LE activity. The LE activity did not depend on the polarity and severity of affective pathology in each diagnostic group. The mean levels of autoantibodies to the nerve growth factor and the myelin basic protein did not differ from the control values in all the groups of patients. PMID- 22433813 TI - [Evaluation of antiepileptic effects of cortexin in a model of convulsions]. AB - We studied antiepileptic effects of cortexin administered in doses 0,015, 0,15 and 1,0 mg/kg intraperitoneally in solution or intranasally in the complex with nanoparticles in a model of acute and chronic convulsions in rats induced by pentylenetetrazole. In the model of epileptic status, the long-term preliminary administration of cortexin had no effect on convulsions while in the model of chronic convulsions (temporal epilepsy), cortexin had a marked dose-dependent antiepileptic effect. The influence of cortexin on neuroplasticity and its clinical potential are discussed. PMID- 22433814 TI - [Clinical and epidemiological aspects of Parkinson's disease]. PMID- 22433815 TI - [Neurosyphilis in the psychiatric practice]. PMID- 22433816 TI - [Betamax (sulpirid): potential for clinical application]. PMID- 22433817 TI - [Fatal cases of neurosyphilis]. PMID- 22433818 TI - Serum 25-hydroxyvitamin D3, parathyroid hormone and blood pressure in an elderly cohort from Germany: a cross-sectional study. AB - BACKGROUND: Although several studies indicate a link between vitamin D status and blood pressure (BP), the results are inconsistent. The purpose of this study is to investigate whether in predominantly non-obese elderly people without vitamin D deficiency or very high intact parathyroid hormone (iPTH) levels serum 25 hydroxyvitamin D3 [25(OH)D3] and iPTH are independently associated with BP. METHODS: Cross-sectional data of 132 non-institutionalised subjects (90 women and 42 men, aged 66- 96 years) from Giessen, Germany, were analysed. Serum 25(OH)D3 and iPTH were measured by an electrochemiluminescence immunoassay and BP was determined with a sphygmomanometer. We performed univariate and multiple regression analyses to examine the influence of 25(OH)D3 and iPTH on BP with adjustments for age, body composition and lifestyle factors. RESULTS: While iPTH had no impact on BP, 25(OH)D3 was negatively associated with systolic BP in men, but not in women. After splitting the cohort into antihypertensive medication users and non-users, 25(OH)D3 was a significant predictor for systolic and diastolic BP only in men not receiving antihypertensive medicine, even after multiple adjustment. Adjustment for 25(OH)D3 resulted in an inverse association of iPTH with diastolic BP also only in men without intake of antihypertensive medicine. CONCLUSIONS: In elderly men without vitamin D deficiency and not taking antihypertensive medicine, 25(OH)D3 may be a negative determinant of BP, independent of iPTH, body composition and lifestyle factors. Furthermore, iPTH may be an independent negative determinant of diastolic BP in men not taking antihypertensive medicine. PMID- 22433819 TI - A stamped PEDOT:PSS-silicon nanowire hybrid solar cell. AB - A novel stamped hybrid solar cell was proposed using the stamping transfer technique by stamping an active PEDOT:PSS thin layer onto the top of silicon nanowires (SiNWs). Compared to a bulk-type counterpart that fully embeds SiNWs inside PEDOT:PSS, an increase in the photovoltaic efficiency was observed by a factor of ~4.6, along with improvements in both electrical and optical responses for the stamped hybrid cell. Such improvements for hybrid cells was due to the formation of well-connected and linearly aligned active PEDOT:PSS channels at the top ends of the nanowires after the stamping process. These stamped channels facilitated not only to improve the charge transport, light absorption, but also to decrease the free carriers as well as exciton recombination losses for stamped hybrid solar cells. PMID- 22433820 TI - Evaluation of primary care midwifery in The Netherlands: design and rationale of a dynamic cohort study (DELIVER). AB - BACKGROUND: In the Netherlands, midwives are autonomous medical practitioners and 78% of pregnant women start their maternity care with a primary care midwife. Scientific research to support evidence-based practice in primary care midwifery in the Netherlands has been sparse. This paper describes the research design and methodology of the multicenter multidisciplinary prospective DELIVER study which is the first large-scale study evaluating the quality and provision of primary midwifery care. METHODS/DESIGN: Between September 2009 and April 2011, data were collected from clients and their partners, midwives and other healthcare professionals across the Netherlands. Clients from twenty midwifery practices received up to three questionnaires to assess the expectations and experiences of clients (e.g. quality of care, prenatal screening, emotions, health, and lifestyle). These client data were linked to data from the Netherlands Perinatal Register and electronic client records kept by midwives. Midwives and practice assistants from the twenty participating practices recorded work-related activities in a diary for one week, to assess workload. Besides, the midwives were asked to complete a questionnaire, to gain insight into collaboration of midwives with other care providers, their tasks and attitude towards their job, and the quality of the care they provide. Another questionnaire was sent to all Dutch midwifery practices which reveals information regarding the organisation of midwifery practices, provision of preconception care, collaboration with other care providers, and provision of care to ethnic minorities. Data at client, midwife and practice level can be linked. Additionally, partners of pregnant women and other care providers were asked about their expectations and experiences regarding the care delivered by midwives and in six practices client consults were videotaped to objectively assess daily practice. DISCUSSION: In total, 7685 clients completed at least one questionnaire, 136 midwives and assistants completed a diary with work-related activities (response 100%), 99 midwives completed a questionnaire (92%), and 319 practices across the country completed a questionnaire (61%), 30 partners of clients participated in focus groups, 21 other care providers were interviewed and 305 consults at six midwifery practices were videotaped.The multicenter DELIVER study provides an extensive database with national representative data on the quality of primary care midwifery in the Netherlands. This study will support evidence-based practice in primary care midwifery in the Netherlands and contribute to a better understanding of the maternity care system. PMID- 22433821 TI - Conventional MRI evaluation of gliomas. AB - MRI using T(1) weighted, T(2) weighted and gadolinium-enhanced sequences plays a central clinical role in diagnosis, characterisation, surveillance and therapeutic monitoring of gliomas. Such conventional MRI protocols provide high resolution multiplanar structural information, and substantially improved tissue characterisation compared with CT. However, the MRI signal lacks biological specificity, e.g. T(2) weighted dependent signal abnormality is dominated by tissue water content, and contrast enhancement reflects a non-specific increase in blood-brain barrier permeability. This limits non-invasive glioma diagnosis, characterisation and therapeutic planning and assessment of active tumour load may be confounded by treatment-related effects. The complex features of glioma morphology and often subtle changes between MRI examinations are also frequently difficult to detect reliably by visual inspection of the images, even by an experienced radiologist. Moreover, the most widely used response criteria in clinical practice and therapeutic trials rely on linear measurements of enhancing tumour and are further challenged by the irregular shape and heterogeneous composition of gliomas. This contributes to the poor correlation of these criteria with hard clinical endpoints. While conventional MRI is widely available and provides essential anatomical information, the lack of pathology-specific biomarkers available from standard MRI sequences and methods of image analysis used limit overall diagnostic and prognostic efficacy of the examination. PMID- 22433822 TI - Dynamic contrast-enhanced imaging techniques: CT and MRI. AB - Over the last few decades there has been considerable research into quantifying the cerebral microvasculature with imaging, for use in studies of the human brain and various pathologies including cerebral tumours. This review highlights key issues in dynamic contrast-enhanced CT, dynamic contrast-enhanced MRI and arterial spin labelling, the various applications of which are considered elsewhere in this special issue of the British Journal of Radiology. PMID- 22433823 TI - Methodology of diffusion-weighted, diffusion tensor and magnetisation transfer imaging. AB - MRI offers a number of opportunities to examine characteristics of tissue well below the spatial resolution of the imaging technique. The best known of these is diffusion imaging, which allows the production of images whose contrast reflects the ability of water molecules to move through the extravascular extracellular space. Less well-known, but increasingly important, is magnetisation transfer imaging, which produces contrast based on the ability of protons to move between the free water pool and local macromolecules. Both of these techniques offer unique information about the microscopic and molecular structure of tumour tissue. This article will briefly review the underlying theory and technical aspects associated with these imaging techniques. PMID- 22433824 TI - Imaging biomarkers of angiogenesis and the microvascular environment in cerebral tumours. AB - Conventional contrast-enhanced CT and MRI are now in routine clinical use for the diagnosis, treatment and monitoring of diseases in the brain. The presence of contrast enhancement is a proxy for the pathological changes that occur in the normally highly regulated brain vasculature and blood-brain barrier. With recognition of the limitations of these techniques, and a greater appreciation for the nuanced mechanisms of microvascular change in a variety of pathological processes, novel techniques are under investigation for their utility in further interrogating the microvasculature of the brain. This is particularly important in tumours, where the reliance on angiogenesis (new vessel formation) is crucial for tumour growth, and the resulting microvascular configuration and derangement has profound implications for diagnosis, treatment and monitoring. In addition, novel therapeutic approaches that seek to directly modify the microvasculature require more sensitive and specific biological markers of baseline tumour behaviour and response. The currently used imaging biomarkers of angiogenesis and brain tumour microvascular environment are reviewed. PMID- 22433825 TI - Imaging hypoxia in gliomas. AB - Hypoxia plays a central role in tumour development, angiogenesis, growth and resistance to treatment. Owing to constant developments in medical imaging technology, significant advances have been made towards in vitro and in vivo imaging of hypoxia in a variety of tumours, including gliomas of the central nervous system. The aim of this article is to review the literature on imaging approaches currently available for measuring hypoxia in human gliomas and provide an insight into recent advances and future directions in this field. After a brief overview of hypoxia and its importance in gliomas, several methods of measuring hypoxia will be presented. These range from invasive monitoring by Eppendorf polarographic O(2) microelectrodes, positron electron tomography (PET) tracers based on 2-nitroimidazole compounds [(18)F-labelled fluoro-misonidazole ((18)F-MISO) or 1-(2-[((18))F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2 nitroimidazole (FRP-170)], (64)Cu-ATSM Cu-diacetyl-bis(N4 methylthiosemicarbazone) (Cu-ATSM) or (99m)Tc- and (68)Ga-labelled metronidazole (MN) agents to advanced MRI methods, such as blood oxygenation level dependent (BOLD) MRI, oxygen-enhanced MRI, diffusion-weighted MRI (DWI-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and (1)H-magnetic resonance spectroscopy. PMID- 22433826 TI - Imaging biomarkers of brain tumour margin and tumour invasion. AB - Invasion of tumour cells into the normal brain is one of the major reasons of treatment failure for gliomas. Although there is a good understanding of the molecular and cellular processes that occur during this invasion, it is not possible to detect the extent of the tumour with conventional imaging. However, there is an understanding that the degree of invasion differs with individual tumours, and yet they are all treated the same. Newer imaging techniques that probe the pathological changes within tumours may be suitable biomarkers for invasion. Imaging methods are now available that can detect subtle changes in white matter organisation (diffusion tensor imaging), tumour metabolism and cellular proliferation (using MR spectroscopy and positron emission tomography) occurring in regions of tumour that cannot be detected by conventional imaging. The role of such biomarkers of invasion should allow better delineation of tumour margins, which should improve treatment planning (especially surgery and radiotherapy) and provide information on the invasiveness of an individual tumour to help select the most appropriate therapy and help stratify patients for clinical trials. PMID- 22433827 TI - Specific biomarkers of receptors, pathways of inhibition and targeted therapies: pre-clinical developments. AB - A deeper understanding of the role of specific genes, proteins, pathways and networks in health and disease, coupled with the development of technologies to assay these molecules and pathways in patients, promises to revolutionise the practice of clinical medicine. Especially the discovery and development of novel drugs targeted to disease-specific alterations could benefit significantly from non-invasive imaging techniques assessing the dynamics of specific disease related parameters. Here we review the application of imaging biomarkers in the management of patients with brain tumours, especially malignant glioma. In our other review we focused on imaging biomarkers of general biochemical and physiological processes related with tumour growth such as energy, protein, DNA and membrane metabolism, vascular function, hypoxia and cell death. In this part of the review, we will discuss the use of imaging biomarkers of specific disease related molecular genetic alterations such as apoptosis, angiogenesis, cell membrane receptors and signalling pathways and their application in targeted therapies. PMID- 22433828 TI - Specific biomarkers of receptors, pathways of inhibition and targeted therapies: clinical applications. AB - A deeper understanding of the role of specific genes, proteins, pathways and networks in health and disease, coupled with the development of technologies to assay these molecules and pathways in patients, promises to revolutionise the practice of clinical medicine. In particular, the discovery and development of novel drugs targeted to disease-specific alterations could benefit significantly from non-invasive imaging techniques assessing the dynamics of specific disease related parameters. Here we review the application of imaging biomarkers in the management of patients with brain tumours, especially malignant glioma. This first part of the review focuses on imaging biomarkers of general biochemical and physiological processes related to tumour growth such as energy, protein, DNA and membrane metabolism, vascular function, hypoxia and cell death. These imaging biomarkers are an integral part of current clinical practice in the management of primary brain tumours. The second article of the review discusses the use of imaging biomarkers of specific disease-related molecular genetic alterations such as apoptosis, angiogenesis, cell membrane receptors and signalling pathways. Current applications of these biomarkers are mostly confined to experimental small animal research to develop and validate these novel imaging strategies with future extrapolation in the clinical setting as the primary objective. PMID- 22433829 TI - Clinical applications of imaging biomarkers. Part 2. The neurosurgeon's perspective. AB - Advances in imaging, including multivoxel spectroscopy, tractography, functional MRI and positron emission spectroscopy, are being used by neurosurgeons to target aggressive areas in gliomas, and to help identify tumour boundaries, functional areas and tracts. Neuro-oncological surgeons need to understand these techniques to help maximise tumour resection, while minimising morbidity in an attempt to improve the quality of patient outcome. This article reviews the evidence for the practical use of multimodal imaging in modern glioma surgery. PMID- 22433830 TI - Clinical applications of imaging biomarkers. Part 3. The neuro-oncologist's perspective. AB - Radiation therapy is an important treatment modality in the management of brain tumours. Imaging biomarkers continue to be a focus of active investigation and there is increasing evidence of the utility of biomarkers in refining the overall management plan. This article briefly reviews the literature and outlines the possible clinical applications of imaging biomarkers in neuro-oncology. PMID- 22433831 TI - Multicentre imaging measurements for oncology and in the brain. AB - Multicentre imaging studies of brain tumours (and other tumour and brain studies) can enable a large group of patients to be studied, yet they present challenging technical problems. Differences between centres can be characterised, understood and minimised by use of phantoms (test objects) and normal control subjects. Normal white matter forms an excellent standard for some MRI parameters (e.g. diffusion or magnetisation transfer) because the normal biological range is low (<2-3%) and the measurements will reflect this, provided the acquisition sequence is controlled. MR phantoms have benefits and they are necessary for some parameters (e.g. tumour volume). Techniques for temperature monitoring and control are given. In a multicentre study or treatment trial, between-centre variation should be minimised. In a cross-sectional study, all groups should be represented at each centre and the effect of centre added as a covariate in the statistical analysis. In a serial study of disease progression or treatment effect, individual patients should receive all of their scans at the same centre; the power is then limited by the within-subject reproducibility. Sources of variation that are generic to any imaging method and analysis parameters include MR sequence mismatch, B(1) errors, CT effective tube potential, region of interest generation and segmentation procedure. Specific tissue parameters are analysed in detail to identify the major sources of variation and the most appropriate phantoms or normal studies. These include dynamic contrast-enhanced and dynamic susceptibility contrast gadolinium imaging, T(1), diffusion, magnetisation transfer, spectroscopy, tumour volume, arterial spin labelling and CT perfusion. PMID- 22433832 TI - Diagnosis and treatment in neuro-oncology: an oncological perspective. AB - Although brain tumours are rare compared with other malignancies, they are responsible, in many cases, for severe physical and cognitive disability and have a high case fatality rate (13% overall survival at 5 years). Gliomas account for over 60% of primary brain tumours and usually present with one or more symptoms of raised intracranial pressure, progressive neurological deficit, seizures, focal or global cognitive decline. The diagnosis is made by a combination of imaging and histological examination of tumour specimen. Contrast-enhanced MRI is the gold standard imaging modality and provides highly sensitive anatomical information about the tumour. Advanced imaging modalities provide complementary information about brain tumour metabolism, blood flow and ultrastructure and are being increasingly incorporated into routine clinical sequences. Imaging is essential for guiding surgery and radiotherapy treatments and for monitoring response to, and progression of, therapy. However, changes in imaging over time may be misinterpreted and lead to incorrect assumptions about the effectiveness of treatments. Thus, the disappearance of contrast enhancement and resolution of oedema after anti-angiogenesis treatments is seen early while conventional T(2) weighted/FLAIR sequences demonstrate continual tumour growth (pseudoregression). Conversely imaging may suggest lack of efficacy of treatment e.g. increasing tumour size and contrast enhancement following chemoradiation for malignant gliomas (pseudoprogression), which then stabilise or resolve after a few months of continued treatment and that paradoxically may be associated with a better outcome. These factors have led to a re-evaluation of the role of standard sequences in the assessment of treatment response spurning interest in the development of quantitative biomarkers. PMID- 22433834 TI - Association between KLK3 rs2735839 G/A polymorphism and serum PSA levels in Japanese men. AB - OBJECTIVES: To clarify the association of kallikrein-related peptidase 3 (KLK3) rs2735839 G/A polymorphism with serum prostate-specific antigen (PSA) levels in Japanese men. METHODS: Subjects were participants of the Japan Multi Institutional Collaborative Cohort (J-MICC) Study who visited the Seirei Preventive Health Care Center in Shizuoka, Japan. Among the 5,040 individuals aged 35-69 years who were enrolled in 2006-2007, serum PSA data were available for 2,323 male subjects without a past history of prostate cancer. The diagnostic criteria for PSA positivity was PSA >= 4.0 ng/ml. Genotyping of the KLK3 polymorphism was conducted by the polymerase chain reaction with the confronting two-pair primers (PCR-CTPP) method. RESULTS: The mean +/- SD of PSA levels (mg/dl) were 1.54 +/- 1.73 for those with KLK3 rs2735839 G/G genotype, 1.34 +/- 1.33 for G/A, and 1.20 +/- 1.23 for A/A, which was significantly different (p < 0.0001). The age-adjusted odds ratios of PSA test positivity were 0.62 (95% confidence interval 0.41-0.94) for those with G/A + A/A relative to those with G/G. CONCLUSIONS: The present study revealed that the KLK3 rs2735839 G allele was significantly associated with higher serum PSA levels also in Japanese. PMID- 22433833 TI - Biology, genetics and imaging of glial cell tumours. AB - Despite advances in therapy, gliomas remain associated with poor prognosis. Clinical advances will be achieved through molecularly targeted biological therapies, for which knowledge of molecular genetic and gene expression characteristics in relation to histopathology and in vivo imaging are essential. Recent research supports the molecular classification of gliomas based on genetic alterations or gene expression profiles, and imaging data supports the concept that molecular subtypes of glioma may be distinguished through non-invasive anatomical, physiological and metabolic imaging techniques, suggesting differences in the baseline biology of genetic subtypes of infiltrating glioma. Furthermore, MRI signatures are now being associated with complex gene expression profiles and cellular signalling pathways through genome-wide microarray studies using samples obtained by image guidance which may be co-registered with clinical imaging. In this review we describe the pathobiology, molecular pathogenesis, stem cells and imaging characteristics of gliomas with emphasis on astrocytomas and oligodendroglial neoplasms. PMID- 22433835 TI - Impact of orange juice consumption on macronutrient and energy intakes and body composition in the US population. AB - OBJECTIVE: The present study evaluated the contribution of 100 % orange juice (OJ) consumption to the intakes of macronutrients and energy and its impact on body composition. DESIGN: A cross-sectional study was conducted. The main exposure was OJ consumption based on two non-consecutive 24 h diet recalls. Macronutrient and energy intakes and body composition parameters were outcome measures. All statistical analyses were carried out using SAS and SUDAAN statistical software packages to allow for multistage sample designs. SETTING: The US population and its subgroups. SUBJECTS: The US population aged >=4 years (n 13 971) from the National Health and Nutrition Examination Survey 2003-2006, conducted by the National Center for Health Statistics. RESULTS: In this US population, OJ consumers had lower BMI and healthier lifestyle behaviours (including lower alcohol consumption and smoking as well as higher exercise level) than non-consumers (P < 0.05). After adjusting for covariates, OJ consumers had higher daily intakes of carbohydrate, total sugar, total fat and energy than non-consumers (P < 0.01). However, these linear trends still remained even after OJ was removed from the food list of items consumed. Adult OJ consumers had lower BMI, waist circumference and percentage body fat than non consumers (P < 0.01), as well as lower odds ratio for overweight and obesity (P < 0.01). These effects were not seen in children and adolescents, where there was no significant difference in BMI, waist circumference and percentage body fat in OJ consumers compared with non-consumers. CONCLUSIONS: OJ consumption was associated with healthier body composition in adults; while there were no significant associations between OJ consumption and body composition in children and adolescents. PMID- 22433836 TI - Related transcriptional enhancer factor 1 increases endothelial-dependent microvascular relaxation and proliferation. AB - OBJECTIVE: Related transcriptional enhancer factor 1 (RTEF-1) is a key transcriptional regulator in endothelial function. In this study, we investigated a possible role for RTEF-1 in the regulation of microvascular relaxation and the underlying mechanism involved. Activation of fibroblast growth factor receptor 1 (FGFR1) by FGFs increases vasodilation, although transcriptional control of the molecular mechanisms underlying FGFR1 is still unclear. MATERIALS AND METHODS: We demonstrated that RTEF-1 stimulated FGFR1 expression at the transcriptional level, specifically an area including Sp1 elements, as evidenced by promoter assays. Additionally, RTEF-1 increased FGFR1 mRNA and protein expression in vitro and in VE-cadherin-promoted RTEF-1 (VE-Cad/RTEF-1) transgenic mice, whereas RTEF 1 siRNA blocked the upregulation of FGFR1 expression. Furthermore, increased endothelial-dependent microvessel relaxation was observed in the coronary arteries of VE-Cad/RTEF-1 mice, and increased proliferation was observed in RTEF 1-overexpressing cells, both of which correlated to increased FGF/FGFR1 signaling and endothelial nitric oxide synthase (eNOS) upregulation. Our results indicate that RTEF-1 acts as a transcriptional stimulator of FGFR1 and is involved in FGF pathways by increasing microvessel dilatation via eNOS. CONCLUSIONS: These findings suggest that RTEF-1 plays an important role in FGFR1- stimulated vasodilatation. Understanding the effect of RTEF-1 in microvessel relaxation may provide beneficial knowledge in improving treatments in regards to ischemic vascular disorders. PMID- 22433837 TI - Blockade of pro-cognitive effects of angiotensin IV and physostigmine in mice by oxytocin antagonism. AB - Low doses of oxytocin enhance learning and memory in animal models. Angiotensin IV inhibits cysteine aminopeptidase, also known as insulin-regulated aminopeptidase and oxytocinase, and enhances memory in animals. The mechanism of this effect of angiotensin IV is unknown. This study explored the role of oxytocin in the cognitive effects of angiotensin IV with physostigmine as a control and used isolated smooth muscle to assess the pharmacological selectivity of the observed antagonism. Using novel object recognition in male mice, the effects of angiotensin IV (4.7 MUg/kg), oxytocin (0.1 ng/kg) or physostigmine (200 MUg/kg) administered subcutaneously immediately after the second training trial, were assessed in the presence and absence of 10 MUg/kg beta-mercapto-beta beta-cyclopenta-methylenepropionyl; O-Me-Tyr2, Orn8-oxytocin, an oxytocin antagonist; n=8 in all cases. The effects of the antagonist on angiotensin IV, oxytocin and acetylcholine-induced contractions of rat isolated uterus were also determined. Oxytocin, angiotensin IV and physostigmine significantly enhanced consolidation of learning (P=0.04, 0.004 and 0.008 respectively), and there were no significant effects on locomotor activity. The oxytocin antagonist similarly not only significantly improved novel object recognition (P=0.03) but also significantly increased locomotor activity (P=0.04). In the learning paradigm the oxytocin antagonist prevented the effects of oxytocin, angiotensin IV and physostigmine but in the uterus, contractions induced by angiotensin IV and acetylcholine were unaffected whilst effects of oxytocin were significantly reduced. These results suggest that the pro-cognitive effects of angiotensin IV may be mediated by accumulation of endogenous oxytocin although the mechanisms underlying the observed interaction between the oxytocin antagonist and physostigmine are unclear. PMID- 22433838 TI - Lrig1: a new master regulator of epithelial stem cells. PMID- 22433839 TI - Mechanisms regulating epidermal stem cells. AB - The skin epidermis contains different appendages such as the hair follicle and the sebaceous glands. Recent studies demonstrated that several types of stem cells (SCs) exist in different niches within the epidermis and maintain discrete epidermal compartments, but the exact contribution of each SC populations under physiological conditions is still unclear. In addition, the precise mechanisms controlling the balance between proliferation and differentiation of epidermal SC still remain elusive. Recent studies provide new insights into these important questions by showing the contribution of hair follicle SC to the sebaceous lineage and the importance of chromatin modifications and micro-RNAs (miRs) in regulating epidermal SCs renewal and differentiation. In this review, we will discuss the importance of these papers to our understanding of the mechanisms that control epidermal SC functions. PMID- 22433840 TI - Mcm10 plays an essential role in origin DNA unwinding after loading of the CMG components. AB - The CMG complex composed of Mcm2-7, Cdc45 and GINS is postulated to be the eukaryotic replicative DNA helicase, whose activation requires sequential recruitment of replication proteins onto Mcm2-7. Current models suggest that Mcm10 is involved in assembly of the CMG complex, and in tethering of DNA polymerase alpha at replication forks. Here, we report that Mcm10 is required for origin DNA unwinding after association of the CMG components with replication origins in fission yeast. A combination of promoter shut-off and the auxin inducible protein degradation (off-aid) system efficiently depleted cellular Mcm10 to <0.5% of the wild-type level. Depletion of Mcm10 did not affect origin loading of Mcm2-7, Cdc45 or GINS, but impaired recruitment of RPA and DNA polymerases. Mutations in a conserved zinc finger of Mcm10 abolished RPA loading after recruitment of Mcm10. These results show that Mcm10, together with the CMG components, plays a novel essential role in origin DNA unwinding through its zinc finger function. PMID- 22433841 TI - Mcm10 associates with the loaded DNA helicase at replication origins and defines a novel step in its activation. AB - Mcm10 is essential for chromosome replication in eukaryotic cells and was previously thought to link the Mcm2-7 DNA helicase at replication forks to DNA polymerase alpha. Here, we show that yeast Mcm10 interacts preferentially with the fraction of the Mcm2-7 helicase that is loaded in an inactive form at origins of DNA replication, suggesting a role for Mcm10 during the initiation of chromosome replication, but Mcm10 is not a stable component of the replisome subsequently. Studies with budding yeast and human cells indicated that Mcm10 chaperones the catalytic subunit of polymerase alpha and preserves its stability. We used a novel degron allele to inactivate Mcm10 efficiently and this blocked the initiation of chromosome replication without causing degradation of DNA polymerase alpha. Strikingly, the other essential helicase subunits Cdc45 and GINS were still recruited to Mcm2-7 when cells entered S-phase without Mcm10, but origin unwinding was blocked. These findings indicate that Mcm10 is required for a novel step during activation of the Cdc45-MCM-GINS helicase at DNA replication origins. PMID- 22433842 TI - Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. AB - Mitochondria are dynamic subcellular organelles that convert nutrient intermediates into readily available energy equivalents. Optimal mitochondrial function is ensured by a highly evolved quality control system, coordinated by protein machinery that regulates a process of continual fusion and fission. In this work, we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin related GTPase OPA1 (optic atrophy 1). We also show that OMA1 deficiency causes a profound perturbation of the mitochondrial fusion-fission equilibrium that has important implications for metabolic homeostasis. Thus, ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters. Additionally, Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis. These alterations are especially significant under metabolic stress conditions, indicating that an intact OMA1-OPA1 system is essential for developing the appropriate adaptive response to different metabolic stressors such as a high-fat diet or cold-shock. This study provides the first description of an unexpected role in energy metabolism for the metalloprotease OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function. PMID- 22433843 TI - Diagnosis and management of pediatric urethral injuries. AB - OBJECTIVE: The incidence of urethral injuries in children is rare due to the fact that the urethra is short, mobile and protected by the pubic bone. The management of urethral trauma in childhood remains controversial because of the limited expertise of most urologists. MATERIAL AND METHODS: We performed a literature review by searching the Medline database for articles published between 1975 and 2010 based on clinical relevance. Electronic searches were limited to the keywords 'pediatric', 'urethral injury', 'trauma' and 'reconstruction'. RESULTS: Retrograde urethrography is considered the gold standard for diagnosis of urethral injuries. The initial management should ensure drainage of the bladder either by suprapubic cystostomy or urethral realignment if possible: in complete anterior urethral disruption as well as in children with life-threatening pelvic and intra-abdominal injuries after posterior urethral injuries, a deferred repair after 3 months is necessary. Immediate primary suturing of disrupted and dislocated urethral ends should be avoided because of high complication rates. Primary repair, however, of the defect is possible in girls avoiding a 2-stage approach. CONCLUSION: The aim of therapy is minimizing remote damages such as urethrocutaneous fistulae, periurethral diverticulae, strictures, incontinence and impotence with different therapeutic management depending on classification of the injury and the presence of life-threatening injuries. PMID- 22433844 TI - Antimicrobial and antioxidant activity of kaempferol rhamnoside derivatives from Bryophyllum pinnatum. AB - BACKGROUND: Bryophyllum pinnatum (Lank.) Oken (Crassulaceae) is a perennial succulent herb widely used in traditional medicine to treat many ailments. Its wide range of uses in folk medicine justifies its being called "life plant" or "resurrection plant", prompting researchers' interest. We describe here the isolation and structure elucidation of antimicrobial and/or antioxidant components from the EtOAc extract of B. pinnatum. RESULTS: The methanol extract displayed both antimicrobial activities with minimum inhibitory concentration (MIC) values ranging from 32 to 512 MUg/ml and antioxidant property with an IC50 value of 52.48 MUg/ml. Its partition enhanced the antimicrobial activity in EtOAc extract (MIC = 16-128 MUg/ml) and reduced it in hexane extract (MIC = 256-1024 MUg/ml). In addition, this process reduced the antioxidant activity in EtOAc and hexane extracts with IC50 values of 78.11 and 90.04 MUg/ml respectively. Fractionation of EtOAc extract gave seven kaempferol rhamnosides, including; kaempferitrin (1), kaempferol 3-O-alpha-L-(2-acetyl)rhamnopyranoside-7-O-alpha-L rhamnopyranoside (2), kaempferol 3-O-alpha-L-(3-acetyl)rhamnopyranoside-7-O-alpha L-rhamnopyranoside (3), kaempferol 3-O-alpha-L-(4-acetyl)rhamnopyranoside-7-O alpha-L-rhamnopyranoside (4), kaempferol 3-O-alpha-D- glucopyranoside-7-O-alpha-L rhamnopyranoside (5), afzelin (6) and alpha-rhamnoisorobin (7). All these compounds, except 6 were isolated from this plant for the first time. Compound 7 was the most active, with MIC values ranging from 1 to 2 MUg/ml and its antioxidant activity (IC50 = 0.71 MUg/ml) was higher than that of the reference drug (IC50 = 0.96 MUg/ml). CONCLUSION: These findings demonstrate that Bryophyllum pinnatum and some of its isolated compounds have interesting antimicrobial and antioxidant properties, and therefore confirming the traditional use of B. pinnatum in the treatment of infectious and free radical damages. PMID- 22433845 TI - Prevention with people with HIV in the United States: the nexus of HIV prevention and treatment. PMID- 22433846 TI - Rates and predictors of failure of first-line antiretroviral therapy and switch to second-line ART in South Africa. AB - OBJECTIVES: To measure rates and predictors of virologic failure and switch to second-line antiretroviral therapy (ART) in South Africa. DESIGN: : Observational cohort study. METHODS: We included ART-naive adult patients initiated on public sector ART (January 2000 to July 2008) at 5 sites in South Africa who completed >=6 months of follow-up. We estimated cumulative risk of virologic failure (viral load >=400 copies/mL with confirmation above varying thresholds) and switching to second-line ART. RESULTS: Nineteen thousand six hundred forty-five patients (29,935 person-years) had a median of 1.3 years of study follow-up (1.8 years on ART) and a median CD4 count of 93 (IQR: 39-155) cells per microliter at ART initiation. About 9.9% (4.5 per 100 person-years) failed ART in median 16 (IQR: 12-23) months since ART initiation, with median 2.7 months (IQR: 1.6-4.7) months between first elevated and confirmatory viral loads. By survival analysis, using a confirmatory threshold of 400 copies per milliliter, 16.9% [95% confidence interval (CI): 15.4% to 18.6%] failed by 5 years on ART, but only 7.8% (95% CI: 6.6% to 9.3%) using a threshold of 10,000. CD4 <25 versus 100-199 (adjusted HR: 1.60; 95% CI: 1.37 to 1.87), ART initiation viral load >=1,000,000 versus <10,000, (1.32; 0.91 to 1.93), and 2+ gaps in care versus 0 (95% CI: 7.25; 4.95 to 10.6) were predictive of failure. Overall, 10.1% (95% CI: 9.0% to 11.4%) switched to second-line by 5 years on ART. Lower CD4 at failure and higher rate of CD4 decline were predictive of switch (decline 100% to 51% versus 25% to -25%, adjusted HR: 1.96; 95% CI: 1.35 to 2.85). CONCLUSIONS: In resource-limited settings with viral load monitoring, virologic failure rates are highly sensitive to thresholds for confirmation. Despite clear guidelines there is considerable variability in switching failing patients, partially in response to immunologic status and postfailure evolution. PMID- 22433847 TI - M-phase phosphoprotein 11 is a highly immunogenic tumor antigen in patients with acute myeloid leukemia. PMID- 22433848 TI - ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). AB - Important cellular processes are regulated by poly(ADP-ribosyl)ation. This protein modification is catalyzed mainly by nuclear poly(ADP-ribose) polymerase (PARP) 1 in response to DNA damage. Cytosolic PARP isoforms have been described, whereas the presence of poly(ADP-ribose) (PAR) metabolism in mitochondria is controversial. PAR is degraded by poly(ADP-ribose) glycohydrolase (PARG). Recently, ADP-ribosylhydrolase 3 (ARH3) was also shown to catalyze PAR degradation in vitro. PARG is encoded by a single, essential gene. One nuclear and three cytosolic isoforms result from alternative splicing. The presence and origin of a mitochondrial PARG is still unresolved. We establish here the genetic background of a human mitochondrial PARG isoform and investigate the molecular basis for mitochondrial poly(ADP-ribose) degradation. In common with a cytosolic 60-kDa human PARG isoform, the mitochondrial protein did not catalyze PAR degradation because of the absence of exon 5-encoded residues. In mice, we identified a transcript encoding an inactive cytosolic 52-kDa PARG lacking the mitochondrial targeting sequence and a substantial portion of exon 5. Thus, mammalian PARG genes encode isoforms that do not catalyze PAR degradation. On the other hand, embryonic fibroblasts from ARH3(-/-) mice lack most of the mitochondrial PAR degrading activity detected in wild-type cells, demonstrating a potential involvement of ARH3 in PAR metabolism. PMID- 22433849 TI - OspC is potent plasminogen receptor on surface of Borrelia burgdorferi. AB - Host-derived proteases are crucial for the successful infection of vertebrates by several pathogens, including the Lyme disease spirochete bacterium, Borrelia burgdorferi. B. burgdorferi must traverse tissue barriers in the tick vector during transmission to the host and during dissemination within the host, and it must disrupt immune challenges to successfully complete its infectious cycle. It has been proposed that B. burgdorferi can accomplish these tasks without an endogenous extra-cytoplasmic protease by commandeering plasminogen, the highly abundant precursor of the vertebrate protease plasmin. However, the molecular mechanism by which B. burgdorferi immobilizes plasminogen to its surface remains obscure. The data presented here demonstrate that the outer surface protein C (OspC) of B. burgdorferi is a potent plasminogen receptor on the outer membrane of the bacterium. OspC-expressing spirochetes readily bind plasminogen, whereas only background levels of plasminogen are detectable on OspC-deficient strains. Furthermore, plasminogen binding by OspC-expressing spirochetes can be significantly reduced using anti-OspC antibodies. Co-immunofluorescence staining assays demonstrate that wild-type bacteria immobilize plasminogen only if they are actively expressing OspC regardless of the expression of other surface proteins. The co-localization of plasminogen and OspC on OspC-expressing spirochetes further implicates OspC as a biologically relevant plasminogen receptor on the surface of live B. burgdorferi. PMID- 22433850 TI - Cardiolipin and mitochondrial phosphatidylethanolamine have overlapping functions in mitochondrial fusion in Saccharomyces cerevisiae. AB - The two non-bilayer forming mitochondrial phospholipids cardiolipin (CL) and phosphatidylethanolamine (PE) play crucial roles in maintaining mitochondrial morphology. We have shown previously that CL and PE have overlapping functions, and the loss of both is synthetically lethal. Because the lack of CL does not lead to defects in the mitochondrial network in Saccharomyces cerevisiae, we hypothesized that PE may compensate for CL in the maintenance of mitochondrial tubular morphology and fusion. To test this hypothesis, we constructed a conditional mutant crd1Deltapsd1Delta containing null alleles of CRD1 (CL synthase) and PSD1 (mitochondrial phosphatidylserine decarboxylase), in which the wild type CRD1 gene is expressed on a plasmid under control of the TET(OFF) promoter. In the presence of tetracycline, the mutant exhibited highly fragmented mitochondria, loss of mitochondrial DNA, and reduced membrane potential, characteristic of fusion mutants. Deletion of DNM1, required for mitochondrial fission, restored the tubular mitochondrial morphology. Loss of CL and mitochondrial PE led to reduced levels of small and large isoforms of the fusion protein Mgm1p, possibly accounting for the fusion defect. Taken together, these data demonstrate for the first time in vivo that CL and mitochondrial PE are required to maintain tubular mitochondrial morphology and have overlapping functions in mitochondrial fusion. PMID- 22433851 TI - Ectopically expressed human tumor biomarker MutS homologue 2 is a novel endogenous ligand that is recognized by human gammadelta T cells to induce innate anti-tumor/virus immunity. AB - Human (h) MutS homologue 2, a nuclear protein, is a critical element of the DNA mismatch repair system. Our previous studies suggest that hMSH2 might be a protein ligand for TCRgammadelta. Here, we show that hMSH2 is ectopically expressed on a large panel of epithelial tumor cells. We found that hMSH2 interacts with both TCRgammadelta and NKG2D and contributes to Vdelta2 T cell mediated cytolysis of tumor cells. Moreover, recombinant human MSH2 protein stimulates the proliferation and IFN-gamma secretion of Vdelta2 T cells in vitro. Finally, hMSH2 expression is induced on the cell surface of Epstein-Barr virus transformed lymphoblastoid cell lines, and the induction increases the sensitivity of these lymphoblastoid cell lines to gammadelta T cell-mediated cytolysis. Our data suggest that hMSH2 functions as a tumor-associated or virus infection-related antigen recognized by both Vdelta2 TCR and NKG2D, and it plays a role in eliciting the immune responses of gammadelta T cells against tumor- and virus-infected cells. The recognition of ectopic surface-expressing endogenous antigen by TCRgammadelta and NKG2D may be an important mechanism of innate immune response to carcinogenesis and viral infection. PMID- 22433852 TI - NMR studies of hexaacylated endotoxin bound to wild-type and F126A mutant MD-2 and MD-2.TLR4 ectodomain complexes. AB - Host response to invasion by many gram-negative bacteria depends upon activation of Toll-like receptor 4 (TLR4) by endotoxin presented as a monomer bound to myeloid differentiation factor 2 (MD-2). Metabolic labeling of hexaacylated endotoxin (LOS) from Neisseria meningitidis with [(13)C]acetate allowed the use of NMR to examine structural properties of the fatty acyl chains of LOS present in TLR4-agonistic and -antagonistic binary and ternary complexes with, respectively, wild-type or mutant (F126A) MD-2 +/- TLR4 ectodomain. Chemical shift perturbation indicates that Phe(126) affects the environment and/or position of each of the bound fatty acyl chains both in the binary LOS.MD-2 complex and in the ternary LOS.MD-2.TLR4 ectodomain complex. In both wild-type and mutant LOS.MD-2 complexes, one of the six fatty acyl chains of LOS is more susceptible to paramagnetic attenuation, suggesting protrusion of that fatty acyl chain from the hydrophobic pocket of MD-2, independent of association with TLR4. These findings indicate that re-orientation of the aromatic side chain of Phe(126) is induced by binding of hexaacylated E, preceding interaction with TLR4. This re-arrangement of Phe(126) may act as a "hydrophobic switch," driving agonist-dependent contacts needed for TLR4 dimerization and activation. PMID- 22433853 TI - Bacterial acyl-CoA mutase specifically catalyzes coenzyme B12-dependent isomerization of 2-hydroxyisobutyryl-CoA and (S)-3-hydroxybutyryl-CoA. AB - Coenzyme B(12)-dependent acyl-CoA mutases are radical enzymes catalyzing reversible carbon skeleton rearrangements in carboxylic acids. Here, we describe 2-hydroxyisobutyryl-CoA mutase (HCM) found in the bacterium Aquincola tertiaricarbonis as a novel member of the mutase family. HCM specifically catalyzes the interconversion of 2-hydroxyisobutyryl- and (S)-3-hydroxybutyryl CoA. Like isobutyryl-CoA mutase, HCM consists of a large substrate- and a small B(12)-binding subunit, HcmA and HcmB, respectively. However, it is thus far the only acyl-CoA mutase showing substrate specificity for hydroxylated carboxylic acids. Complete loss of 2-hydroxyisobutyric acid degradation capacity in hcmA and hcmB knock-out mutants established the central role of HCM in A. tertiaricarbonis for degrading substrates bearing a tert-butyl moiety, such as the fuel oxygenate methyl tert-butyl ether (MTBE) and its metabolites. Sequence analysis revealed several HCM-like enzymes in other bacterial strains not related to MTBE degradation, indicating that HCM may also be involved in other pathways. In all strains, hcmA and hcmB are associated with genes encoding for a putative acyl-CoA synthetase and a MeaB-like chaperone. Activity and substrate specificity of wild type enzyme and active site mutants HcmA I90V, I90F, and I90Y clearly demonstrated that HCM belongs to a new subfamily of B(12)-dependent acyl-CoA mutases. PMID- 22433854 TI - Sensitivity of heterozygous alpha1,6-fucosyltransferase knock-out mice to cigarette smoke-induced emphysema: implication of aberrant transforming growth factor-beta signaling and matrix metalloproteinase gene expression. AB - We previously demonstrated that a deficiency in core fucosylation caused by the genetic disruption of alpha1,6-fucosyltransferase (Fut8) leads to lethal abnormalities and the development of emphysematous lesions in the lung by attenuation of TGF-beta1 receptor signaling. Herein, we investigated the physiological relevance of core fucosylation in the pathogenesis of emphysema using viable heterozygous knock-out mice (Fut8(+/-)) that were exposed to cigarette smoke (CS). The Fut8(+/-) mice exhibited a marked decrease in FUT8 activity, and matrix metalloproteinase (MMP)-9 activities were elevated in the lung at an early stage of exposure. Emphysema developed after a 3-month CS exposure, accompanied by the recruitment of large numbers of macrophages to the lung. CS exposure substantially and persistently elevated the expression level of Smad7, resulting in a significant reduction of Smad2 phosphorylation (which controls MMP-9 expression) in Fut8(+/-) mice and Fut8-deficient embryonic fibroblast cells. These in vivo and in vitro studies show that impaired core fucosylation enhances the susceptibility to CS and constitutes at least part of the disease process of emphysema, in which TGF-beta-Smad signaling is impaired and the MMP-mediated destruction of lung parenchyma is up-regulated. PMID- 22433855 TI - Activation of moesin, a protein that links actin cytoskeleton to the plasma membrane, occurs by phosphatidylinositol 4,5-bisphosphate (PIP2) binding sequentially to two sites and releasing an autoinhibitory linker. AB - Many cellular processes depend on ERM (ezrin, moesin, and radixin) proteins mediating regulated linkage between plasma membrane and actin cytoskeleton. Although conformational activation of the ERM protein is mediated by the membrane PIP2, the known properties of the two described PIP2-binding sites do not explain activation. To elucidate the structural basis of possible mechanisms, we generated informative moesin mutations and tested three attributes: membrane localization of the expressed moesin, moesin binding to PIP2, and PIP2-induced release of moesin autoinhibition. The results demonstrate for the first time that the POCKET containing inositol 1,4,5-trisphosphate on crystal structure (the "POCKET" Lys-63, Lys-278 residues) mediates all three functions. Furthermore the second described PIP2-binding site (the "PATCH," Lys-253/Lys-254, Lys-262/Lys 263) is also essential for all three functions. In native autoinhibited ERM proteins, the POCKET is a cavity masked by an acidic linker, which we designate the "FLAP." Analysis of three mutant moesin constructs predicted to influence FLAP function demonstrated that the FLAP is a functional autoinhibitory region. Moreover, analysis of the cooperativity and stoichiometry demonstrate that the PATCH and POCKET do not bind PIP2 simultaneously. Based on our data and supporting published data, we propose a model of progressive activation of autoinhibited moesin by a single PIP2 molecule in the membrane. Initial transient binding of PIP2 to the PATCH initiates release of the FLAP, which enables transition of the same PIP2 molecule into the newly exposed POCKET where it binds stably and completes the conformational activation. PMID- 22433856 TI - Ubc13 and COOH terminus of Hsp70-interacting protein (CHIP) are required for growth hormone receptor endocytosis. AB - Growth hormone receptor (GHR) endocytosis is a highly regulated process that depends on the binding and activity of the multimeric ubiquitin ligase, SCF(betaTrCP) (Skp Cullin F-box). Despite a specific interaction between beta transducin repeat-containing protein (betaTrCP) and the GHR, and a strict requirement for ubiquitination activity, the receptor is not an obligatory target for SCF(betaTrCP)-directed Lys(48) polyubiquitination. We now show that also Lys(63)-linked ubiquitin chain formation is required for GHR endocytosis. We identified both the ubiquitin-conjugating enzyme Ubc13 and the ubiquitin ligase COOH terminus of Hsp70 interacting protein (CHIP) as being connected to this process. Ubc13 activity and its interaction with CHIP precede endocytosis of GHR. In addition to betaTrCP, CHIP interacts specifically with the cytosolic tails of the dimeric GHR, identifying both Ubc13 and CHIP as novel factors in the regulation of cell surface availability of GHR. PMID- 22433857 TI - A Rab8 guanine nucleotide exchange factor-effector interaction network regulates primary ciliogenesis. AB - Primary cilia are microtubule-based solitary membrane projections on the cell surface that play important roles in signaling and development. Recent studies have demonstrated that polarized vesicular trafficking involving the small GTPase Rab8 and its guanine nucleotide exchange factor Rabin8 is essential for primary ciliogenesis. In this study, we show that a highly conserved region of Rabin8 is pivotal for its activation as a guanine nucleotide exchange factor for Rab8. In addition, in its activated conformation, Rabin8 interacts with Sec15, a subunit of the exocyst and downstream effector of Rab8. Expression of constitutively activated Rab8 promotes the association of Sec15 with Rabin8. Using immunofluorescence microscopy, we found that Sec15 co-localized with Rab8 along the primary cilium. Inhibition of Sec15 function in cells led to defects in primary ciliogenesis. The Rabin8-Rab8-Sec15 interaction may couple the activation of Rab8 to the recruitment of the Rab8 effector and is involved in the regulation of vesicular trafficking for primary cilium formation. PMID- 22433858 TI - Nonsteroidal anti-inflammatory drugs alter the spatiotemporal organization of Ras proteins on the plasma membrane. AB - Ras proteins on the inner leaflet of the plasma membrane signal from transient nanoscale proteolipid assemblies called nanoclusters. Interactions between the Ras lipid anchors and plasma membrane phospholipids, cholesterol, and actin cytoskeleton contribute to the formation, stability, and dynamics of Ras nanoclusters. Many small biological molecules are amphiphilic and capable of intercalating into membranes and altering lipid immiscibility. In this study we systematically examined whether amphiphiles such as indomethacin influence Ras protein nanoclustering in intact plasma membrane. We found that indomethacin, a nonsteroidal anti-inflammatory drug, induced profound and complex effects on Ras spatial organization, all likely related to liquid-ordered domain stabilization. Indomethacin enhanced the clustering of H-Ras.GDP and N-Ras.GTP in cholesterol dependent nanoclusters. Indomethacin also abrogated efficient GTP-dependent lateral segregation of H- and N-Ras between cholesterol-dependent and cholesterol independent clusters, resulting in mixed heterotypic clusters of Ras proteins that normally are separated spatially. These heterotypic Ras nanoclusters showed impaired Raf recruitment and kinase activation resulting in significantly compromised MAPK signaling. All of the amphiphilic anti-inflammatory agents we tested had similar effects on Ras nanoclustering and signaling. The potency of these effects correlated with the membrane partition coefficients of the individual agents and was independent of COX inhibition. This study shows that biological amphiphiles have wide-ranging effects on plasma membrane heterogeneity and protein nanoclustering, revealing a novel mechanism of drug action that has important consequences for cell signaling. PMID- 22433859 TI - Identification of function for CD44 intracytoplasmic domain (CD44-ICD): modulation of matrix metalloproteinase 9 (MMP-9) transcription via novel promoter response element. AB - CD44 is a multifunctional cell receptor that conveys a cancer phenotype, regulates macrophage inflammatory gene expression and vascular gene activation in proatherogenic environments, and is also a marker of many cancer stem cells. CD44 undergoes sequential proteolytic cleavages that produce an intracytoplasmic domain called CD44-ICD. However, the role of CD44-ICD in cell function is unknown. We take a major step toward the elucidation of the CD44-ICD function by using a CD44-ICD-specific antibody, a modification of a ChIP assay to detect small molecules, and extensive computational analysis. We show that CD44-ICD translocates into the nucleus, where it then binds to a novel DNA consensus sequence in the promoter region of the MMP-9 gene to regulate its expression. We also show that the expression of many other genes that contain this novel response element in their promoters is up- or down-regulated by CD44-ICD. Furthermore, hypoxia-inducible factor-1alpha (Hif1alpha)-responsive genes also have the CD44-ICD consensus sequence and respond to CD44-ICD induction under normoxic conditions and therefore independent of Hif1alpha expression. Additionally, CD44-ICD early responsive genes encode for critical enzymes in the glycolytic pathway, revealing how CD44 could be a gatekeeper of the Warburg effect (aerobic glycolysis) in cancer cells and possibly cancer stem cells. The link of CD44 to metabolism is novel and opens a new area of research not previously considered, particularly in the study of obesity and cancer. In summary, our results finally give a function to the CD44-ICD and will accelerate the study of the regulation of many CD44-dependent genes. PMID- 22433860 TI - Protein kinase A (PKA) phosphorylation of Na+/K+-ATPase opens intracellular C terminal water pathway leading to third Na+-binding site in molecular dynamics simulations. AB - Phosphorylation is one of the major mechanisms for posttranscriptional modification of proteins. The addition of a compact, negatively charged moiety to a protein can significantly change its function and localization by affecting its structure and interaction network. We have used all-atom Molecular Dynamics simulations to investigate the structural consequences of phosphorylating the Na(+)/K(+)-ATPase (NKA) residue Ser(936), which is the best characterized phosphorylation site in NKA, targeted in vivo by protein kinase A (PKA). The Molecular Dynamics simulations suggest that Ser(936) phosphorylation opens a C terminal hydrated pathway leading to Asp(926), a transmembrane residue proposed to form part of the third sodium ion-binding site. Simulations of a S936E mutant form, for which only subtle effects are observed when expressed in Xenopus oocytes and studied with electrophysiology, does not mimic the effects of Ser(936) phosphorylation. The results establish a structural association of Ser(936) with the C terminus of NKA and indicate that phosphorylation of Ser(936) can modulate pumping activity by changing the accessibility to the ion-binding site. PMID- 22433861 TI - Apoptotic cells can deliver chemotherapeutics to engulfing macrophages and suppress inflammatory cytokine production. AB - Immunosuppression via cell-cell contact with apoptotic cells is a well studied immunological phenomenon. Although the original studies of immune repression used primary cells, which undergo spontaneous cell death or apoptosis in response to irradiation, more recent studies have relied on chemotherapeutic agents to induce apoptosis in cell lines. In this work, we demonstrate that Jurkat cells induced to die with actinomycin D suppressed inflammatory cytokine production by macrophages, whereas cells treated with etoposide did not. This immune repression mediated by actinomycin D-treated cells did not require phagocytosis or cell-cell contact and thus occurs through a different mechanism from that seen with primary apoptotic neutrophils. Moreover, cells induced to die with etoposide and then treated for a short time with actinomycin D also suppressed macrophage responses, indicating that suppression was mediated by actinomycin D independent of the mechanism of cell death. Finally, phagocytosis of actinomycin D-treated cells caused apoptosis in macrophages, and suppression could be blocked by inhibition of caspase activity in the target macrophage. Together, these data indicate that apoptotic cells act as "Trojan horses," delivering actinomycin D to engulfing macrophages. Suppression of cytokine production by macrophages is therefore due to exposure to actinomycin D from apoptotic cells and is not the result of cell receptor interactions. These data suggest that drug-induced death may not be an appropriate surrogate for the immunosuppressive activity of apoptotic cells. Furthermore, these effects of cytotoxic drugs on infiltrating immune phagocytes may have clinical ramifications for their use as antitumor therapies. PMID- 22433862 TI - Small efficient cell-penetrating peptides derived from scorpion toxin maurocalcine. AB - Maurocalcine is the first demonstrated example of an animal toxin peptide with efficient cell penetration properties. Although it is a highly competitive cell penetrating peptide (CPP), its relatively large size of 33 amino acids and the presence of three internal disulfide bridges may hamper its development for in vitro and in vivo applications. Here, we demonstrate that several efficient CPPs can be derived from maurocalcine by replacing Cys residues by isosteric 2 aminobutyric acid residues and sequence truncation down to peptides of up to 9 residues in length. A surprising finding is that all of the truncated maurocalcine analogues possessed cell penetration properties, indicating that the maurocalcine is a highly specialized CPP. Careful examination of the cell penetration properties of the truncated analogues indicates that several maurocalcine-derived peptides should be of great interest for cell delivery applications where peptide size matters. PMID- 22433863 TI - Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics simulations, and biochemical assays. AB - The apoptotic effector caspase-6 (CASP6) has been clearly identified as a drug target due to its strong association with neurodegeneration and axonal pruning events as well as its crucial roles in Huntington disease and Alzheimer disease. CASP6 activity is suppressed by ARK5-mediated phosphorylation at Ser(257) with an unclear mechanism. In this work, we solved crystal structures of DeltaproCASP6S257E and p20/p10S257E, which mimicked the phosphorylated CASP6 zymogen and activated CASP6, respectively. The structural investigation combined with extensive biochemical assay and molecular dynamics simulation studies revealed that phosphorylation on Ser(257) inhibited self-activation of CASP6 zymogen by "locking" the enzyme in the TEVD(193)-bound "inhibited state." The structural and biochemical results also showed that phosphorylation on Ser(257) inhibited the CASP6 activity by steric hindrance. These results disclosed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design. PMID- 22433864 TI - Selective recruitment of an E2~ubiquitin complex by an E3 ubiquitin ligase. AB - RING E3 ligases are proteins that must selectively recruit an E2-conjugating enzyme and facilitate ubiquitin transfer to a substrate. It is not clear how a RING E3 ligase differentiates a naked E2 enzyme from the E2~ubiquitin-conjugated form or how this is altered upon ubiquitin transfer. RING-box protein 1 (Rbx1/ROC1) is a key protein found in the Skp1/Cullin-1/F-box (SCF) E3 ubiquitin ligase complex that functions with the E2 ubiquitin conjugating enzyme CDC34. The solution structure of Rbx1/ROC1 revealed a globular RING domain (residues 40-108) stabilized by three structural zinc ions (root mean square deviation 0.30 +/- 0.04 A) along with a disordered N terminus (residues 12-39). Titration data showed that Rbx1/ROC1 preferentially recruits CDC34 in its ubiquitin-conjugated form and favors this interaction by 50-fold compared with unconjugated CDC34. Furthermore, NMR and biochemical assays identified residues in helix alpha2 of Rbx1/ROC1 that are essential for binding and activating CDC34~ubiquitin for ubiquitylation. Taken together, this work provides the first direct structural and biochemical evidence showing that polyubiquitylation by the RING E3 ligase Rbx1/ROC1 requires the preferential recruitment of an E2~ubiquitin complex and subsequent release of the unconjugated E2 protein upon ubiquitin transfer to a substrate or ubiquitin chain. PMID- 22433865 TI - Toll-like receptor activation of human cells by synthetic triacylated lipid A like molecules. AB - Recognition of microbial molecules by mammalian host receptors is essential to mount an immune response. Hexaacylated LPS is the prototypic example of a bacterial molecule recognized by the receptor complex TLR4/MD-2 with its lipid A moiety, whereas bacterial lipopeptides are recognized by TLR2. Here we show that a series of synthetic triacylated lipid A-like molecules are weak Toll-like receptor (TLR) agonists (mainly TLR2 agonists) but very potent TLR4/MD-2 antagonists (submicromolar range). Not only do they block human cell responses to LPS but also to whole gram-negative bacteria, and they inhibit the phagocytosis of gram-negative bacteria. These compounds may represent promising immunomodulatory agents. PMID- 22433866 TI - Slit2 regulates the dispersal of oligodendrocyte precursor cells via Fyn/RhoA signaling. AB - Oligodendrocyte precursor cells (OPCs) are a unique type of glia that are responsible for the myelination of the central nervous system. OPC migration is important for myelin formation during central nervous system development and repair. However, the precise extracellular and intracellular mechanisms that regulate OPC migration remain elusive. Slits were reported to regulate neurodevelopmental processes such as migration, adhesion, axon guidance, and elongation through binding to roundabout receptors (Robos). However, the potential roles of Slits/Robos in oligodendrocytes remain unknown. In this study, Slit2 was found to be involved in regulating the dispersal of OPCs through the association between Robo1 and Fyn. Initially, we examined the expression of Robos in OPCs both in vitro and in vivo. Subsequently, the Boyden chamber assay showed that Slit2 could inhibit OPC migration. RoboN, a specific inhibitor of Robos, could significantly attenuate this effect. The effects were confirmed through the explant migration assay. Furthermore, treating OPCs with Slit2 protein deactivated Fyn and increased the level of activated RhoA-GTP. Finally, Fyn was found to form complexes with Robo1, but this association was decreased after Slit2 stimulation. Thus, we demonstrate for the first time that Slit2 regulates the dispersal of oligodendrocyte precursor cells through Fyn and RhoA signaling. PMID- 22433867 TI - Identification of novel potentially toxic oligomers formed in vitro from mammalian-derived expanded huntingtin exon-1 protein. AB - Huntington disease is a genetic neurodegenerative disorder that arises from an expanded polyglutamine region in the N terminus of the HD gene product, huntingtin. Protein inclusions comprised of N-terminal fragments of mutant huntingtin are a characteristic feature of disease, though are likely to play a protective role rather than a causative one in neurodegeneration. Soluble oligomeric assemblies of huntingtin formed early in the aggregation process are candidate toxic species in HD. In the present study, we established an in vitro system to generate recombinant huntingtin in mammalian cells. Using both denaturing and native gel analysis, we have identified novel oligomeric forms of mammalian-derived expanded huntingtin exon-1 N-terminal fragment. These species are transient and were not previously detected using bacterially expressed exon-1 protein. Importantly, these species are recognized by 3B5H10, an antibody that recognizes a two-stranded hairpin conformation of expanded polyglutamine believed to be associated with a toxic form of huntingtin. Interestingly, comparable oligomeric species were not observed for expanded huntingtin shortstop, a 117 amino acid fragment of huntingtin shown previously in mammalian cell lines and transgenic mice, and here in primary cortical neurons, to be non-toxic. Further, we demonstrate that expanded huntingtin shortstop has a reduced ability to form amyloid-like fibrils characteristic of the aggregation pathway for toxic expanded polyglutamine proteins. Taken together, these data provide a possible candidate toxic species in HD. In addition, these studies demonstrate the fundamental differences in early aggregation events between mutant huntingtin exon-1 and shortstop proteins that may underlie the differences in toxicity. PMID- 22433868 TI - 4-O-carboxymethyl ascochlorin causes ER stress and induced autophagy in human hepatocellular carcinoma cells. AB - The synthetic derivative of ascochlorin, 4-O-carboxymethyl ascochlorin (AS-6) is an agonist of the nuclear hormone receptor PPARgamma and has been shown to induce differentiation in mouse pre-adipocytes and to ameliorate type II diabetes in a murine model. AS-6 was cytotoxic when added at micromolar concentrations to cultures of three different human cancer cell lines. We used gel electrophoresis and mass spectrometry to identify proteins with altered expression in human hepatocarcinoma cells (HepG2) cells after 12 h in the presence of AS-6 and found 58 proteins that were differentially expressed. Many of the proteins showing increased expression in cells treated with AS-6 are involved in protein quality control, including glucose-regulated protein 78 (GRP78/BiP), a regulator of ER stress responses, and the transcriptional regulator CHOP, which mediates ER stress-induced apoptosis. Cells treated with AS-6 undergo an autophagic response accompanied by increased expression of beclin1, ATG5, and LC3-II and autophagosome formation marked by the appearance of large vesicles containing LC3 II. Grp78 induction was inhibited when the PPARgamma antagonist, GW9662, was added together with AS-6, and autophagy and cell death were partially blocked. 3 methyl-adenine (3-MA), an inhibitor of phosphatidyl inositol 3-kinase (PI3 kinase) prevented induction of ATG5 and activation of LC3-II and blocked autophagosome formation. 3-MA also blocked induction of GRP78 and CHOP, suggesting that PI3-kinase, which is known to mediate ER stress-induced autophagy, also plays a role in initiating apoptosis in response to ER stress. Together these data establish that the cytotoxicity of AS-6 operates by a mechanism dependent on ER stress-induced autophagy and apoptosis. PMID- 22433869 TI - Both LRP5 and LRP6 receptors are required to respond to physiological Wnt ligands in mammary epithelial cells and fibroblasts. AB - A canonical Wnt signal maintains adult mammary ductal stem cell activity, and this signal requires the Wnt signaling reception, LRP5. However, previous data from our laboratory have shown that LRP5 and LRP6 are co-expressed in mammary basal cells and that LRP6 is active, leading us to question why LRP6 is insufficient to mediate canonical signaling in the absence of LRP5. Here, we show that at endogenous levels of LRP5 and LRP6 both receptors are required to signal in response to some Wnt ligands both in vitro (in mouse embryonic fibroblasts and mammary epithelial cells) and in vivo (in mammary outgrowths). This subgroup of canonical ligands includes Wnt1, Wnt9b, and Wnt10b; the latter two are expressed in mammary gland. In contrast, the ligand commonly used experimentally, Wnt3a, prefers LRP6 and requires just one receptor regardless of cellular context. When either LRP5 or LRP6 is overexpressed, signaling remains ligand-dependent, but the requirement for both receptors is abrogated (regardless of ligand type). We have documented an LRP5-6 heteromer using immiscible filtration assisted by surface tension (IFAST) immunoprecipitation. Together, our data imply that under physiological conditions some Wnt ligands require both receptors to be present to generate a canonical signal. We have designed a model to explain our results based on the resistance of LRP5-6 heteromers to a selective inhibitor of E1/2 binding Wnt-LRP6 interaction. These data have implications for stem cell biology and for the analysis of the oncogenicity of LRP receptors that are often overexpressed in breast tumors. PMID- 22433870 TI - Tyrosine-phosphorylated caveolin-1 (Tyr-14) increases sensitivity to paclitaxel by inhibiting BCL2 and BCLxL proteins via c-Jun N-terminal kinase (JNK). AB - Paclitaxel, an anti-microtubule agent, is an effective chemotherapeutic drug in breast cancer. Nonetheless, resistance to paclitaxel remains a major clinical challenge. The need to better understand the resistant phenotype and to find biomarkers that could predict tumor response to paclitaxel is evident. In estrogen receptor alpha-positive (ER(+)) breast cancer cells, phosphorylation of caveolin-1 (CAV1) on Tyr-14 facilitates mitochondrial apoptosis by increasing BCL2 phosphorylation in response to low dose paclitaxel (10 nM). However, two variants of CAV1 exist: the full-length form, CAV1alpha (wild-type CAV1 or wtCAV1), and a truncated form, CAV1beta. Only wtCAV1 has the Tyr-14 region at the N terminus. The precise cellular functions of CAV1 variants are unknown. We now show that CAV1 variants play distinct roles in paclitaxel-mediated cell death/survival. CAV1beta expression is increased in paclitaxel-resistant cells when compared with sensitive cells. Expression of CAV1beta in sensitive cells significantly reduces their responsiveness to paclitaxel. These activities reflect an essential role for Tyr-14 phosphorylation because wtCAV1 expression, but not a phosphorylation-deficient mutant (Y14F), inactivates BCL2 and BCLxL through activation of c-Jun N-terminal kinase (JNK). MCF-7 cells that express Y14F are resistant to paclitaxel and are resensitized by co-treatment with ABT 737, a BH3-mimetic small molecule inhibitor. Using structural homology modeling, we propose that phosphorylation on Tyr-14 enables a favorable conformation for proteins to bind to the CAV1 scaffolding domain. Thus, we highlight novel roles for CAV1 variants in cell death; wtCAV1 promotes cell death, whereas CAV1beta promotes cell survival by preventing inactivation of BCL2 and BCLxL via JNK in paclitaxel-mediated apoptosis. PMID- 22433871 TI - Oxidatively truncated phospholipids are required agents of tumor necrosis factor alpha (TNFalpha)-induced apoptosis. AB - TNFalpha generates reactive oxygen species (ROS) at the cell surface that induce cell death, but how ROS communicate to mitochondria and their specific apoptotic action(s) are both undefined. ROS oxidize phospholipids to hydroperoxides that are friable and fragment adjacent to the (hydro)peroxide function, forming truncated phospholipids, such as azelaoyl phosphatidylcholine (Az-PC). Az-PC is relatively soluble, and exogenous Az-PC rapidly enters cells to damage mitochondrial integrity and initiate intrinsic apoptosis. We determined whether this toxic phospholipid is formed within cells during TNFalpha stimulation in sufficient quantities to induce apoptosis and if they are essential in TNFalpha induced cytotoxicity. We found that TNFalpha induced ROS formation and phospholipid peroxidation in Jurkat cells, and either chemical interference with NADPH oxidase activity or siRNA suppression of the NADPH oxidase-4 subunit blocked ROS accumulation and phospholipid peroxidation. Mass spectrometry showed that phospholipid peroxides and then Az-PC increased after TNFalpha exposure, whereas ROS inhibition abolished Az-PC accumulation and TNFalpha-induced cell death. Glutathione peroxidase-4 (GPx4), which specifically metabolizes lipid hydroperoxides, fell in TNFalpha-stimulated cells prior to death. Ectopic GPx4 overcame this, reduced peroxidized phospholipid accumulation, blocked Az-PC accumulation, and prevented death. Conversely, GPx4 siRNA knockdown enhanced phospholipid peroxidation, increasing TNFalpha-stimulated Az-PC formation and apoptosis. Truncated phospholipids were essential elements of TNFalpha-induced apoptosis because overexpression of PAFAH2 (a phospholipase A(2) that selectively hydrolyzes truncated phospholipids) blocked TNFalpha-induced Az-PC accumulation without affecting phospholipid peroxidation. PAFAH2 also abolished apoptosis. Thus, phospholipid oxidation and truncation to apoptotic phospholipids comprise an essential element connecting TNFalpha receptor signaling to mitochondrial damage and apoptotic death. PMID- 22433872 TI - Interactions of nucleolin and ribosomal protein L26 (RPL26) in translational control of human p53 mRNA. AB - Ribosomal protein RPL26 enhances p53 translation after DNA damage, and this regulation depends upon interactions between the 5'- and 3'-UTRs of human p53 mRNA (Takagi, M., Absalon, M. J., McLure, K. G., and Kastan, M. B. (2005) Cell 123, 49-63; Chen, J., and Kastan, M. B. (2010) Genes Dev. 24, 2146-2156). In contrast, nucleolin (NCL) suppresses the translation of p53 mRNA and its induction after DNA damage. We confirmed reports that RPL26 and NCL interact with each other and then explored the potential role of this interaction in the translational control of p53 after stress. NCL repression of p53 translation utilizes both the 5'- and 3'-UTRs of p53 mRNA, and NCL binds to the same 5'-3' UTR interaction region that is critical for the recruitment of RPL26 to p53 mRNA after DNA damage. We also found that NCL is able to oligomerize, consistent with a model in which NCL stabilizes this double-stranded RNA structure. We found that the RNA-binding domain of NCL participates in binding to p53 mRNA, is required for both NCL dimerization and NCL-mediated translational repression, and is the domain of NCL that interacts with RPL26. Excessive RPL26 disrupts NCL dimerization, and point mutations in the NCL-interacting region of RPL26 reduce NCL-RPL26 interactions and attenuate both RPL26 binding to human p53 mRNA and p53 induction by RPL26. These observations suggest a model in which the base pairings in the p53 UTR interaction regions are critical for both translational repression and stress induction of p53 by NCL and RPL26, respectively, and that disruption of a NCL-NCL homodimer by RPL26 may be the switch between translational repression and activation after stress. PMID- 22433873 TI - The evaluation of an evidence-based clinical answer format for pediatricians. AB - BACKGROUND: Clinicians are increasingly using electronic sources of evidence to support clinical decision-making; however, there are multiple demands on clinician time, and summarised and synthesised evidence is needed. Clinical Answers (CA) have been developed to address this need; the CA is a synthesised evidence-based summary that supports point-of-care clinical decision-making. The aim of this paper is to report on a survey used to test and improve the CA format. METHODS: An online survey was sent to pediatricians via e-mail and posted on a child health clinical standards website. Quantitative data analysis consisted primarily of descriptive statistics; qualitative data analysis consisted of content analysis. RESULTS: Eighty-three pediatricians responded to the survey. Most respondents found the CA useful or very useful (93%) and agreed or strongly agreed that the layout was effective and allowed them to quickly locate critical information (82%). Quantitative and qualitative data suggested that respondents thought there should be less detail in the linked figures and tables (p = 0.0002), but overall respondents seemed to think there was an appropriate level of detail in most sections of the CA. CONCLUSIONS: Based on the quantitative and qualitative survey responses, major and minor modifications to the CA format were implemented, such as removing forest plots, adding links in each addendum to bring the user back to the front page, and adding an 'Implications for practice' section to the CA. Findings suggest that CAs will be a useful tool for pediatricians; thus, the research team has now begun creating CAs to assist busy clinicians in their day-to-day clinical practice by providing high-quality information for decision-making at the point-of-care. PMID- 22433874 TI - Targeting calcium homeostasis as the therapy of Chagas' disease and leishmaniasis - a review. AB - Ca(2+) has been largely recognized as an essential messenger in all eukaryotes, from mammals to parasites. The disruption of Ca(2+) homeostasis in any cell usually drives to lethal effects resulting in cell death by apoptosis or necrosis. This appears also to be the case in human trypanosomatids, such as Trypanosoma cruzi, the causative agent of Chagas' disease, Trypanosoma brucei, which produces "sleeping sickness" and Leishmania sp, responsible for leishmaniasis. The aim of this review is to describe the intracellular Ca(2+) regulation and the cytotoxic effect of new drugs regarding the disruption of Ca(2+) homeostasis in these parasites. With regard to intracellular Ca(2+) regulation, all these trypanosomatids possess a single mitochondrion that occupies 12% of the total volume of the parasite which is able to accumulate large amounts of Ca(2+). The endoplasmic reticulum is also involved in Ca(2+) regulation. These parasites also possess acidocalcisomes, an unusual organelle involved in the bioenergetics of these cells in accumulating large amounts of polyphosphates together with Ca(2+) ions. Trypanosomatids possess relatively large amounts of calmodulin. While this well conserved protein is identical among all vertebrates, there is 89% amino acid sequence identity between T. cruzi and vertebrate calmodulin. Recently, this protein has been cloned and expressed from T. cruzi, allowing a further characterization corroborating significant differences between calmodulin from T. cruzi and mammals. It has also been reported that a commonly used antiarrhytmic, amiodarone, which is used in chronic Chagas' patients with heart problems, is able to produce a large trypanocidal effect. The intracellular compartments responsible for the increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) upon the addition of amiodarone are the single large mitochondrion and the acidocalcisomes. Amiodarone is also capable to inhibit the oxidosqualene cyclase, a key enzyme in the synthesis of ergosterol. The effect of amiodarone was highly synergistic with posaconazole, a known potent inhibitor of the synthesis of ergosterol. Interestingly, posaconazole by itself is able to produce an increase in the [Ca(2+)](i). Concerning putative treatments in humans, amiodarone was reported to induce the cure of a patient with Chagas' disease, when used in combination with itraconazole. Seemingly, a recent case indicated the cure of a patient with Chagas' disease by the administration of posaconazole. Miltefosine, an orally active alkyl-lysophospholipid with potent anti-Leishmania activity, represents a major advance in the treatment of leishmaniasis. Recently it was reported that miltefosine also disrupts the parasite's intracellular Ca(2+) homeostasis, by inducing a large increase in [Ca(2+)](i), through the activation of a plasma membrane Ca(2+) channel. It has been found that the combination of miltefosine and amiodarone have synergistic effects on the proliferation of amastigotes growing inside macrophages and this led to 90% of parasitological cure in a murine model of leishmaniasis, as revealed by a PCR assay. More recently, posaconazole has been used successfully in a case of a human Old World cutaneous leishmaniasis. All these findings strongly suggest that the alteration of the intracellular Ca(2+) homeostasis of these parasites is a promising strategy as a target of new as well as repurposed old-known drugs. PMID- 22433875 TI - Effects of solvents and surfactants against Haemaphysalis bispinosa. AB - As per the report published by FAO (2004), the tick population in India has developed resistance against all the available acaricides. Hence, newer methods of control including potential herbal agents are required to reduce the problems caused by the ticks. Most of the herbal extracts or their fractions are dissolved in polar or non-polar solvents or detergents before tested for acaricidal activity and these diluents should be of little acaricidal activity. In the present study, adult immersion test (AIT) was carried out on adult engorged female Haemaphysalis bispinosa ticks to detect the acaricidal activity of different solvents viz., nbutanol, glycerol, acetone, ethanol, methanol and surfactants (at 1 per cent dilution) like dimethyl sulphoxide (DMSO), tween 20 and triton X- 100. The study revealed that methanol was the least toxic solvent while tween 20 (1 per cent) was the least toxic detergent against H. bispinosa. PMID- 22433876 TI - Molecular characterization of Giardia parasite isolated from stool samples collected from different hospitals in Taif City (Saudi Arabia). AB - Giardia parasite is prevalent endemically in Taif city. Infection is more prevalent in children under 5 years old and elderly people. The sickness is more intense in immunecompromised people. The disease is usually diagnosed by stool examination by the microscope, for the identification of the both trophozoite and cyst stages. Usually the disease is overlooked during stool analyses due to the minute size of the parasite and due to the scarcity of infection sometimes. Hence molecular characterization or diagnosis is used as an alternative method for the diagnosis of infection. Molecular characterization is based on polymerase chain reaction (PCR). This technique is regarded as a highly sensitive and accurate method of diagnosis. The prevalence of Giardia duodenalis was 15% in stool samples collected from different hospital in Taif. By means of RAPD technique, most G. duodenalis isolates were genetically similar, forming two main groups, with about 60% of similarity one another. PMID- 22433877 TI - Rapid detection of pathogenic leptospires by lyophilized reagent-based polymerase chain reaction. AB - A simple and reliable tool for the early diagnosis of leptospirosis is urgently needed. We report the development of a lyophilized reagent-based polymerase chain reaction (PCR) assay targeting lipL32 gene, which is present only in pathogenic leptospires. To determine the effectiveness of the newly developed assay in the early diagnosis of leptospirosis, the sensitivity and specificity was evaluated. In simulated clinical samples, the assay was able to detect 102 and 103 leptospires/ml in spiked urine and blood samples, respectively. In experimentally infected animals, leptospiral DNA could be detected in blood and lung samples as early as Day 1 post infection. This assay was also shown to be stable and remained sensitive for up to five months at ambient temperature. Hence, this lyophilized reagent-based PCR assay with high specificity, sensitivity and stability would provide a simple, rapid and reliable method in diagnosing acute leptospirosis, especially in the field of veterinary medicine. PMID- 22433878 TI - Optimization of the expression of surface antigen SAG1/2 of Toxoplasma gondii in the yeast Pichia pastoris. AB - Surface antigens are the most abundant proteins found on the surface of the parasite Toxoplasma gondii. Surface antigen 1 (SAG1) and Surface antigen 2 (SAG2) remain the most important and extensively studied surface proteins. These antigens have been identified to play a role in host cell invasion, immune modulation, virulence attenuation. Recombinant SAG1/2 was cloned and expressed in yeast Pichia pastoris. We describe here optimization of critical parameters involved in high yield expression of the recombinant SAG1/2. Our results suggest that recombinant SAG1/2 were best expressed at 30oC, pH 6 and 1% methanol as the carbon source by X33 Pichia cells. Additional optimizations included the downstream process such as ammonium sulphate precipitation and dialysis. The fusion protein was purified using Ni-NTA purification system with 80% recovery. The purified protein was 100% specific and sensitive in detection of toxoplasmosis. PMID- 22433879 TI - Seroprevalence of Neospora spp. in horses in South of Iran. AB - Neospora caninum, an apicomplexan protozoan parasite, is recognized as a major cause of abortion in cattle. However, limited information is presently available on the seroprevalence of Neospora antibodies in horses worldwide. The aim of the present study is to determine serological prevalence of Neospora infection in horses in Iran. Blood samples were obtained from 200 horses and tested for serum antibodies against Neospora spp. by the Neospora modified direct agglutination test (N-MAT). Antibodies were found in 64 (32%) horses being tested with titers of 1:80. This is the first serological survey for Neospora antibodies performed on horses in Iran. PMID- 22433880 TI - A novel management method for disseminated intravascular coagulation like syndrome after a sting of Hemiscorpius lepturus: a case series. AB - In this case series report we aim to report a Disseminated Intravascular Coagulation (DIC)-like syndrome associated with Hemiscorpius lepturus sting in 4 individuals and a novel management protocol for this life-threatening condition that comprised partial exchange transfusion in severe scorpionism. PMID- 22433881 TI - Life table of Synthesiomyia nudiseta (Van der Wulp) (Diptera: Muscidae) under uncontrolled laboratory environments - a preliminary study. AB - The life history of the male and female of the indoor forensic fly, Synthesiomyia nudiseta was studied under fluctuating temperature of indoor environments and analysed based on the age-stage and two sex life table. The life cycle of S. nudiseta was 14.0+/-1.0 days from the egg stage to adult emergence. The population parameters calculated were; net reproduction rate (R(o)= 108.6), mean generation time (T(o)= 12.2), intrinsic rate of increase (r(m)= 0.38), and finite rate of increase (lambda= 1.46). The pre-oviposition period (APOP) was 6.0+/- 0.1 days. All population parameters suggested that S. nudiseta exhibits the r-strategist characteristics. PMID- 22433882 TI - The use of multiplex real-time PCR improves the detection of the bacterial etiology of community acquired pneumonia. AB - Community-acquired pneumonia (CAP) is still a major cause of morbidity and mortality especially to children and compromised hosts, such as the old and those with underlying chronic diseases. Knowledge of pathogens causing CAP constitutes the basis for selection of antimicrobial treatment. Previous data have shown that etiological agents can be identified in only up to 50% of patients, but this figure can be improved by using polymerase chain reaction (PCR). This study was designed to evaluate multiplex real-time PCR as a method for rapid differential detection of five bacterial causes of CAP (Streptococcus pneumoniae, Burkholderia pseudomallei and atypical bacterial pathogens namely Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila) in CAP patients attending Hospital Tengku Ampuan Afzan (HTAA)/ Kuantan, Pahang, Malaysia. Two previously developed multiplex real-time PCR assays, duplex for the differential detection of S. pneumoniae and B. pseudomallei and triplex for the atypical bacterial pathogens, were used to detect a bacterial cause of CAP in blood and respiratory samples. Thus, 46 blood and 45 respiratory samples collected from 46 adult CAP patients admitted to HTAA were analysed by multiplex real-time PCR assays and conventional methods. The microbial etiology of CAP could be established for 39.1% (18/46) of CAP patients by conventional methods and this was increased to 65.2% (30/46) with the additional use of real time PCR. The most frequently detected pathogens were S. pneumoniae (21.7% - all by PCR alone), Klebsiella pneumoniae (17.3%), B. pseudomallei (13% - 83% of them positive by PCR alone and 17% by both culture and PCR), Pseudomonas aeruginosa (6.5%), M. pneumoniae (6.5% - all by serology), C. pneumoniae (4.3% all positive by both PCR and serology), L. pneumophila (2.1% - all by PCR alone), Escherichia coli (4.3%). Haemophilus infuenzae, Acinetobacter lwoffii and Acinetobacter baumannii were detected by conventional methods (2.1% for each). PMID- 22433883 TI - Development of multiplex real-time PCR for the rapid detection of five bacterial causes of community acquired pneumonia. AB - Establishing a microbial diagnosis for patients with community-acquired pneumonia (CAP) is still challenging and is often achieved in only 30-50% of cases. Polymerase chain reaction (PCR) has been shown to be more sensitive than conventional microbiological methods and it could help to increase the microbial yield for CAP patients. This study was designed to develop, optimize and evaluate multiplex real-time PCR as a method for rapid differential detection of five bacterial causes of CAP namely Streptococcus pneumoniae, Burkholderia pseudomallei and atypical bacterial pathogens, Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila. Duplex and triplex real-time PCR assays were developed using five sets of primers and probes that were designed based on an appropriate specific gene for each of the above CAP pathogens. The performance of primers for each organism was tested using SYBR Green melt curve analysis following monoplex realtime PCR amplification. Monoplex real-time PCR assays were also used to optimize each primers-probe set before combining them in multiplex assays. Two multiplex real time PCR assays were then optimized; duplex assay for the differential detection of S. pneumoniae and B. pseudomallei, and triplex assay for the atypical bacterial pathogens. Both duplex and triplex real-time PCR assays were tested for specificity by using DNA extracted from 26 related microorganisms and sensitivity by running serial dilutions of positive control DNAs. The developed multiplex real-time PCR assays shall be used later for directly identifying CAP causative agents in clinical samples. PMID- 22433884 TI - Intestinal parasitic infections in hosted Saharawi children. AB - Literatures on intestinal parasitic infections in Saharawi children were scarce and distributed in non parasitological journals. This was the first article that specifically highlighted on the prevalence of these infections in 270 Saharawi children aged from 6 to 12 years hosted in Spain. Six different intestinal parasites were identified in this study and 78, 46, 40, 24, 13 and 5 were positive for Giardia lamblia (29%), Entamoeba coli (17%), Blastocystis hominis (15%), Endolimax nana (9%), Hymenolepis nana (5%) and Enterobius vermicularis (2%), respectively. Mixed intestinal parasitic infections were seen in 12 (4.4%) studied children. Six (2.2%) double infections for G. lamblia and B. hominis were seen in these children while in four (1.5%) had G. lamblia and H. nana. Triple intestinal parasitic infections of G. lamblia, B. hominis and H. nana were observed in two (0.7%) of the children studied. In the other hand, about 14.8% of the studied children had a mild anaemia and 15.5 and 16.6% had iron deficiency and eosinophilia, respectively. PMID- 22433885 TI - Application of amplified ribosomal DNA restriction analysis in identification of Acinetobacter baumannii from a tertiary teaching hospital, Malaysia. AB - Acinetobacter baumannii, genomic species 3 and 13TU are being increasingly reported as the most important Acinetobacter species that cause infections in hospitalized patients. These Acinetobacter species are grouped in the Acinetobacter calcoaceticus- Acinetobacter baumannii (Acb) complex. Differentiation of the species in the Acb-complex is limited by phenotypic methods. Therefore, in this study, amplified ribosomal DNA restriction analysis (ARDRA) was applied to confirm the identity A. baumannii strains as well as to differentiate between the subspecies. One hundred and eighty-five strains from Intensive Care Unit, Universiti Malaya Medical Center (UMMC) were successfully identified as A. baumannii by ARDRA. Acinetobacter genomic species 13TU and 15TU were identified in 3 and 1 strains, respectively. ARDRA provides an accurate, rapid and definitive approach towards the identification of the species level in the genus Acinetobacter. This paper reports the first application ARDRA in genospecies identification of Acinetobacter in Malaysia. PMID- 22433886 TI - Wolbachia endobacteria in a natural population of Culex quinquefasciatus from filariasis endemic villages of south India and its phylogenetic implication. AB - Understanding Wolbachia mosquito interactions have been recognized as an important concept to develop novel vector control strategies. The prevalence of Wolbachia endobacteria in a natural population of the filariasis vector Culex quinquefasciatus was determined by the polymerase chain reaction method. Earlier workers had estimated the infection rates of Wolbachia with only one or very few individuals per species. In our study large number of specimens were assayed, and a total of 750 adult Culex quinquefasciatus mosquitoes were collected from three south Indian villages of Tirukoilur and Mugaiyur blocks, monthly for a period of five months (December 2006 to April 2007) and screened for the presence of Wolbachia. The percentage prevalence in adult males ranged from 88% to 96%; while in females from 84% to 100%. An overall prevalence of 91.2% was observed. There was no significant difference observed in the proportion of mosquitoes positive for Wolbachia between males and females, and also between different months of the survey; except during the month of February '07. The wsp gene sequence of the Wolbachia strain of Cx. quinquefasciatus detected was BLAST analysed and showed 99% sequence similarity with Wolbachia sp. of Culex pipiens isolated from different geographical regions. Phylogenetic analysis based on wsp gene fragments showed that the present Wolbachia isolate was closely related with Wolbachia from Culex pipens pipiens, Niphotettix virescens (Order: Hemiptera) and Cnaphalocrosis medinalis (Order: Lepidoptera). PMID- 22433887 TI - Simulium (Gomphostilbia) taitungense, a new species of black fly (Diptera: Simuliidae) from Taiwan, with description of the male of Simulium (Gomphostilbia) tuenense Takaoka. AB - Simulium (Gomphostilbia) taitungense sp. nov. is described on the basis of reared adult, pupal and mature larval specimens collected from Taitung, Taiwan. This new species is placed in the ceylonicum species-group within the subgenus Gomphostilbia and is distinguished from related known species by the characteristic colour markings on the ventral surface of the head capsule and on the dorsal surface of the abdomen in the larva. The male of Simulium (Gomphostilbia) tuenense Takaoka, which was originally described from a pharate pupa and a larva, is described for the first time; the association of the adult stage with the larval stage was confirmed by the comparison of the sequences of the mitochondrial 16S rRNA gene; this species is also placed in the ceylonicum species-group. PMID- 22433888 TI - Expression analysis of SIR2 and SAPs1-4 gene expression in Candida albicans treated with allicin compared to fluconazole. AB - One of the main factors for virulence of fungus such as Candida albicans is the ability to change its morphology from yeast to hyphae. Allicin, one of the volatile sulfur-oil compounds from freshly crushed garlic, has a variety of antifungal activities. In this study, the effect of allicin on growth and hyphae production in C. albicans as compared to fluconazole, an antifungal drug was investigated using survival time in vitro and microscopic image at different time intervals. Additionally, the expression of selected genes involved in hyphae formation and development such as SIR2 and SAP1-4 was evaluated by semi-quantitative RT-PCR and relative real time RT-PCR. Allicin was shown to down-regulate the expression of SIR2 (5.54 fold), similar to fluconazole (3.48 fold) at 2x MIC concentrations. Interestingly, allicin had no effect on SAPs1-4 expression, whereas fluconazole was able to suppress SAP4 expression. Our findings showed that allicin was effective in suppressing hyphae development of C. albicans to an extent that is sometimes equal or more than fluconazole. Moreover, allicin and fluconazole seemed to share a common anti-Candida mechanism through inhibition of SIR2 gene, while fluconazole appeared to also exert its fungistatic effect through another pathway that involved SAP4 suppression. PMID- 22433889 TI - An eight-year review of blood culture and susceptibility among sepsis cases in an emergency department in Northeastern Malaysia. AB - An understanding of common pathogens and their antibiotic sensitivity patterns is critical for proper management of sepsis in Emergency Department (ED). The goal of the study was to identify common organisms isolated from blood cultures of patients attended to ED and their antimicrobial susceptibility. Beginning from 2002, all cases of positive blood culture collected by the ED, Hospital Universiti Sains Malaysia (HUSM) were recorded and analysed. Over the period of eight years, we documented 995 cases of positive blood cultures. Of these samples, 549 (55.2%) were Gram-negative bacteria; 419 (42.1%) were Gram-positive bacteria; 10 (1.0%) were anaerobic organisms; 10 (1.0%) were fungus; and 7 (0.7%) cases were mixed organisms. Gram-negative bacteria were observed to develop more resistance to antimicrobial agents, especially those commonly used in an outpatient setting with less than 80% sensitivity to ampicillin, cotrimoxazole and ciprofloxacin. By contrast, there has been no marked change in the sensitivity trends of Gram-positive bacteria over the same period. In conclusion, ED physicians are more equipped to initiate empirical antimicrobial therapy especially when dealing with possibility of Gram-negative sepsis. PMID- 22433890 TI - A Toxoplasma gondii 10 kDa in vitro excretory secretory antigen reactive with human IgM and IgA antibodies. AB - Toxoplasmosis can cause serious disease in immunocompromised patients and to congenitally infected foetuses. Appropriate laboratory investigations in potential cases of acute Toxoplasma infection are important. Excretory secretory antigen (ESA) is immunogenic during both human and experimental infections, therefore is considered as a good candidate for investigation into new infection markers. In this study, ESA was prepared from in vitro cultures of Toxoplasma gondii to identify T. gondii ESA antigenic component(s) that is/are most reactive with serum samples from probable acute cases of toxoplasmosis. Serum samples were obtained from several categories of individuals with the following Toxoplasma serology: Group I: IgM+ IgG+ (low IgG avidity) or IgM+ IgG from sera of patients who had clinical query of toxoplasmosis (n=35). Group II: IgM- IgG+ (high IgG avidity) from chronically infected individuals (n=30). Group III: normal/healthy individuals with anti-Toxoplasma IgMIgG- (n=20). Group IV: individuals with other infections who had anti-Toxoplasma IgM- IgG- (n=10). The ESA was subjected to SDS-PAGE, followed by Western blot analysis using the above sera and probed with peroxidase conjugated anti-human IgM and IgA antibodies. The blots were then developed using chemiluminescence substrate. The selected antigenic band was excised from the gel after two dimensional electrophoresis and sent for mass spectrometry analysis using MALDI TOF-TOF. The most promising antigenic band was a 10 kDa protein which showed sensitivity of 80% in both IgM and IgA blots, and specificity of 96.7% with sera from other infections and healthy controls. The two best identifications for the 10 kDa band were ubiquitin (ribosomal protein CEP52 fusion protein) and polyubiquitin. PMID- 22433891 TI - Case of fatal congenital toxoplasmosis associated with I/III recombinant genotype. AB - We report a case of fatal congenital toxoplasmosis case in Tunis (North of Tunisia) associated with I/III recombinant genotype. The Toxoplasma gondii strain was isolated from placenta and characterized molecularly by a multilocus typing (3'SAG2, 5'SAG2, SAG3, AK69, APICO, and UPRT1) and a sulfadiazine resistance mutation analysis. The isolate was shown to be a wild drug sensitive I/III recombinant strain. PMID- 22433892 TI - Optimal protein extraction methods from diverse sample types for protein profiling by using Two-Dimensional Electrophoresis (2DE). AB - There is a great diversity of protein samples types and origins, therefore the optimal procedure for each sample type must be determined empirically. In order to obtain a reproducible and complete sample presentation which view as many proteins as possible on the desired 2DE gel, it is critical to perform additional sample preparation steps to improve the quality of the final results, yet without selectively losing the proteins. To address this, we developed a general method that is suitable for diverse sample types based on phenolchloroform extraction method (represented by TRI reagent). This method was found to yield good results when used to analyze human breast cancer cell line (MCF-7), Vibrio cholerae, Cryptocaryon irritans cyst and liver abscess fat tissue. These types represent cell line, bacteria, parasite cyst and pus respectively. For each type of samples, several attempts were made to methodically compare protein isolation methods using TRI-reagent Kit, EasyBlue Kit, PRO-PREPTM Protein Extraction Solution and lysis buffer. The most useful protocol allows the extraction and separation of a wide diversity of protein samples that is reproducible among repeated experiments. Our results demonstrated that the modified TRI-reagent Kit had the highest protein yield as well as the greatest number of total proteins spots count for all type of samples. Distinctive differences in spot patterns were also observed in the 2DE gel of different extraction methods used for each type of sample. PMID- 22433893 TI - Effect of host portal and peripheral sera fractions on cell proliferation of Schistosoma mansoni schistosomules. AB - Schistosomules of Schistosoma mansoni were incubated in medium containing hamster (highly susceptible host) portal or peripheral venous serum, or rat (poorly susceptible host) portal or peripheral venous serum or their fractions in the presence of bromodeoxyuridine (BrdU) in order to determine effects of host sera on cell proliferation. BrdU labeling indices (BLIs) were significantly increased in the presence of portal (33.05+/-0.70, p<0.05), but not in peripheral serum (19.1+/-0.85, p>0.05) of hamsters, compared to schistosomules cultured in presence of control medium (18.96+/-0.66). This stimulatory effect was substantially reproduced by fraction 4 (31.03+/-0.69, p>0.05) separated from hamster portal serum. In contrast, no significant differences were observed in the BLIs in rat portal or peripheral sera as well as their fractions when compared to control medium. Taken together, it was concluded that portal serum of hamster and its fraction which includes a low molecular weight protein (20 kDa) enhanced cell proliferation of S. mansoni schistosomules. This could explain the localization and preference of S. mansoni schistosomules and worms to portal-mesenteric venous system. PMID- 22433894 TI - Malaria in seasonal migrant population in Southern Gujarat, India. AB - Malaria in migrant workers is always a major problem to control due to their temporary stay in shelters, and other operational constraints. Hence, a study was undertaken in brick kilns in Bharuch district, Gujarat state, India to study the problem of malaria in the work force. Mass blood surveys were carried out in 15 brick kilns. Blood slides were collected from both febrile and afebrile cases. Positive cases were treated as per the national drug policy and were followed up. Mosquito collections were carried out by pyrethrum spray collection in early morning hours. Human blood index and sporozoite rates were determined as per standard procedures. All age groups were found affected with malaria at brick kilns. Prevalence of malaria was significantly higher in <= 14 years of age-group as compared to adults. Post treatment follow up examination of patients revealed high malaria infection due to non-compliance of chloroquine. The appearance of parasitaemia among Plasmodium falciparum treated cases indicate the possibility of chloroquine resistance. The proportion of P. falciparum was >50% in migrant population. In stable population in villages, overall decline in malaria cases was observed in 2008-2010. The sporozoite rate of 4.2% in Anopheles culicifacies indicates active malaria transmission at brick kilns. The investigation demonstrated that suitable microclimatic conditions for malaria transmission exist in these areas during hottest period. The district health department should consider these factors in planning malaria surveillance and control. As current magnitude and diversity of population movements in rural as well as in urban areas are unprecedented, this issue is worthy of attention. PMID- 22433895 TI - Reduced susceptibility of Malaysian clinical isolates of Burkholderia pseudomallei to ciprofloxacin. AB - Ciprofloxacin, a quinolone with good intracellular penetration may possibly be used for treatment of melioidosis caused by Burkholderia pseudomallei, but problems with resistance may be encountered. Amino acid substitutions in gyrA/gyrB have given rise to fluoroquinolone resistance in various microorganisms. Using published primers for gyrA and gyrB, PCR was performed on 11 isolates of B. pseudomallei with varying degrees of sensitivity to ciprofloxacin, followed by DNA sequencing to detect possible mutations. Results showed an absence of any point mutation in either gene. Local isolates have yet to develop full resistance to ciprofloxacin and probably other mechanisms of resistance may have been involved in the decreased sensitivity to ciprofloxacin. PMID- 22433896 TI - Characterization and antimicrobial activities of two Streptomyces isolates from soil in the periphery of Universiti Putra Malaysia. AB - This study was to assess the identification and antimicrobial activities of two actinomycete isolates. The two isolates designated as B8 and C2, were isolated from a patch of soil in the peripheral area of Universiti Putra Malaysia by streaking on starch casein agar after standard serial dilution procedures. Their antimicrobial activities were first evaluated against eight clinical laboratory strains namely Bacillus sp., Enterococcus sp., Escherichia coli, Klebsiella sp., Pseudomonas sp., Salmonella sp., Staphylococcus aureus, and Staphylococcus epidermidis by perpendicular streak method on Mueller Hinton and Tryptic Soy agar. In both media, a broad-spectrum antibacterial activity was observed for both isolates, with B8 against all the test bacteria and C2 against five of them (Bacillus sp., E. coli, Pseudomonas sp., S. aureus and S. epidermidis). Re-assessment against E. coli ATCC 25922 and S. aureus ATCC 25923 strains by similar method showed antibacterial activities by isolate B8 against both ATTC strains while C2 only against S. aureus ATCC 25923. Streptomyces griseus ATCC 10137 was included in the later experiment and showed antibacterial activity against both ATCC strains. Subsequently, the two isolates were identified by PCR/sequencing techniques and phylogenetic analysis to be Streptomyces species (>93% homology based on 16S rRNA and rpoB genes). Characterization on cultural characteristic and viable count at different temperatures (37oC and 28oC), on different microbiological media (AIA, ISP-2, MHA, NA, PDA and TSA), were performed. More morphological features were observed on ISP-2 for both isolates. A higher growth yield was also observed at 28oC in all media but in comparing that between the two isolates, isolate B8 outnumbered C2 at all experimental conditions. The observed variation in cultural traits and growth yield indicate unique properties between the two antibiotic-producing isolates. PMID- 22433897 TI - Cross-reactivity of Malaysian rat cytomegalovirus strains with its human counterpart. AB - This study probes into the prospect of cross-reactivity of HCMV with RCMV which has not been acknowledged to date. We describe the uncovering of a protein with an estimated size of between 61-68 kDa from local RCMV strains which reacted with HCMV positive sera. Our findings are a first disclosure of a plausible immunological cross-reactivity between RCMV with its human counterpart which grounds substantial interest implying existence of conserved determinants between rat and human CMV polypeptides. The cross-reactive protein most likely represents an enveloped glycoprotein, though the precise identification and its degree of similarity needs to be evidently defined and further elucidated in forthcoming experiments. PMID- 22433898 TI - The integron prevalence of extended-spectrum beta-lactamase producing enterobacterial isolates in a Malaysian teaching hospital. AB - The increased frequency of antibiotic resistance is known to be associated with the dissemination of integrons in the Enterobacteriaceae. This study determined the prevalence and type of integrons amongst 160 extended-spectrum beta lactamase producing enterobacterial isolates kept in our culture collection. Integrons were detected in 98(61.3%) isolates, including 28(62.2%) Escherichia coli, 34(64.2%) Klebsiella spp., 27(61.4%), Enterobacter spp. and 9(50.0%) Citrobacter spp. investigated in this study. Restriction analysis of the integron gene fragments revealed that class I integron was the principal integron detected in 92(57.5%) of our isolates. Class II integron was detected in 6(3.8%) of our isolates, while no class III integron was detected in this study. The high rates of integron prevalence particularly of the class I integron in the E. coli and Klebsiella spp. concur with previous studies in other geographical regions. The higher (>=50%) integron prevalence of Citrobacter and Enterobacter isolates comparing to previous studies suggests the potential of these isolates as sources for dissemination of resistance determinants. The finding in this study serves as a basis for further study on the antibiotic resistance mechanisms of enterobacterial species in this teaching hospital. PMID- 22433899 TI - Influence of chronic moderate sleep restriction and exercise on inflammation and carcinogenesis in mice. AB - The effects of chronic moderate sleep restriction and exercise training on carcinogenesis were examined in adenomatous polyposis coli multiple intestinal neoplasma (APC Min(+/-)) mice, a genetic strain which is predisposed to developing adenomatous polyposis. The mice were randomized to one of four 11 week treatments in a 2*2 design involving sleep restriction (by 4 h/day) vs. normal sleep and exercise training (1h/day) vs. sedentary control. Wild-type control mice underwent identical experimental treatments. Compared with the wild-type mice, APC Min(+/-) mice had disrupted hematology and enhanced pro-inflammatory cytokine production from peritoneal exudate cells. Among the APC Min(+/-) mice, consistent interactions of sleep loss and exercise were found for measures of polyp formation, inflammation, and hematology. Sleep loss had little effect on these variables under sedentary conditions, but sleep loss had clear detrimental effects under exercise conditions. Exercise training resulted in improvements in these measures under normal sleep conditions, but exercise tended to elicit no effect or to exacerbate the effects of sleep restriction. Significant correlations of inflammation with polyp burden were observed. Among wild-type mice, similar, but less consistent interactions of sleep restriction and exercise were found. These data suggest that the benefits of exercise on carcinogenesis and immune function were impaired by chronic moderate sleep restriction, and that harmful effects of sleep restriction were generally realized only in the presence of exercise. PMID- 22433900 TI - Standardized mitochondrial analysis gives new insights into mitochondrial dynamics and OPA1 function. AB - Mitochondria form dynamic tubular networks through processes of fission and fusion. Defect in mitochondrial dynamics lead to various pathologies, including several common and some rare neurodegenerative disorders. OPA1 and MFN2 are two key players in mitochondrial fusion associated with Autosomal Dominant Optic Atrophy and Charcot Marie Tooth neuropathy type 2A respectively. We used micropatterned coverslips to standardize the visualization of mitochondrial distribution in skin fibroblasts. In fibroblasts from affected patients, mutations in the OPA1 and MFN2 genes were found to affect the volume and cellular distribution of mitochondria. In G1/S cell cycle phase, mitochondria emerging from the microtubule organizing centre may be crucial to mitochondrial biogenesis since it appeared to be protected against mitochondrial fragmentation induced by OPA1 mutations. The standardized quantitative analysis of the mitochondrial network and the description of mitochondrial subcellular distribution should lead to better diagnostic criteria for mitochondrial diseases and yield new insights into mitochondrial dysfunction in disease and aging. PMID- 22433901 TI - Transforming growth factor-beta1 promotes nasal mucosal mast cell chemotaxis in murine experimental allergic rhinitis. AB - BACKGROUND: Recent studies have shown that transforming growth factor-beta(1) (TGF-beta(1)) plays an important role in the progression of allergic diseases. METHODS: Mouse models of allergic rhinitis were established by ovalbumin sensitization and challenge. Immunostaining was used to analyze the expression of TGF-beta(1) in the mouse nasal mucosa. A chemotaxis assay was conducted to analyze the impact of TGF-beta(1) stimulation on migration of mast cells differentiated from mouse bone marrow cells. Chemotaxis and Western blot analysis were further applied to investigate the pathways involved in mast cell migration induced by TGF-beta(1) stimulation. RESULTS: TGF-beta(1) expression was induced in allergic rhinitis and phosphorylated Smad2 was expressed in mast cells present in the nasal mucosa. TGF-beta(1) could induce migration of mast cells, but HTS466284, a TGF-beta receptor 1 kinase inhibitor, inhibited this chemotactic activity. After TGF-beta(1) stimulation, mast cell RhoA expression was significantly increased. TGF-beta(1)-induced mast cell chemotaxis could be inhibited by the RhoA inhibitor Tat-C3 and myosin light chain kinase inhibitor ML 7. CONCLUSION: TGF-beta(1) plays a major role in inducing the accumulation of mast cells in allergic rhinitis. PMID- 22433902 TI - Elevated serum adipocyte fatty acid-binding protein concentrations are independently associated with renal dysfunction in patients with stable angina pectoris. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with cardiovascular events. Adipocyte fatty acid-binding protein (A-FABP) plays an important role in atherosclerosis. We investigated whether plasma A-FABP is involved in renal function in patients with stable angina pectoris. METHODS: A total of 221 patients with significant coronary artery stenosis were enrolled after coronary angiography. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The severity of coronary stenosis was assessed using a modified Gensini score and coronary angiography. Serum A-FABP levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum A-FABP levels were significantly correlated with both eGFR (r = -0.41, p < 0.01) and the severity of coronary artery stenosis (r = 0.16, p = 0.02), and these relationships remained significant after adjusting for confounding factors. The prevalence of CKD and multi-vessel disease was significantly higher among patients with serum A-FABP levels above the median value of 20.3 ng/ml than among patients with serum A-FABP levels below the median value (57% vs. 27%, p < 0.01 and 64% vs. 48%, p = 0.02, respectively). Multivariate analysis revealed that the presence of three-vessel disease in comparison with single-vessel disease was independently associated with the higher A-FABP (per doubling) (odds ratio; 2.26, 95% confidential interval; 1.28-3.98, p < 0.01) and tended to be associated with the lower eGFR (p = 0.06). CONCLUSION: Serum A-FABP may have a significant role in the interplay between renal dysfunction and coronary atherosclerosis. PMID- 22433903 TI - Red meat consumption and mood and anxiety disorders. PMID- 22433904 TI - Brain tumors in children. Foreword. PMID- 22433905 TI - Brain tumors in children. PMID- 22433906 TI - Acetylcholinesterase inhibition ameliorates deficits in motivational drive. AB - BACKGROUND: Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. METHODS: We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. RESULTS: CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. CONCLUSIONS: Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive. PMID- 22433907 TI - A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor mediated synaptic transmission in the hippocampus. AB - Perampanel is a non-competitive AMPA receptor antagonist that is under development as an anti-epileptic therapy. Although it is known to reduce calcium flux mediated by AMPA receptors in cultured cortical neurons, there are no studies of its selectivity in synaptic transmission in more intact systems. In the present study using hippocampal slices, perampanel (0.01-10 MUM) has been tested on pharmacologically isolated synaptic responses mediated by AMPA, NMDA or kainate receptors. Perampanel reduced AMPA receptor-mediated excitatory postsynaptic field potentials (f-EPSPs) with an IC(50) of 0.23 MUM and a full block at 3 MUM. This compares with an IC(50) of 7.8 MUM for GYKI52466 on these responses. By contrast, perampanel at 10 MUM had no effect on responses mediated by NMDA or kainate receptors, which were completely blocked by 30 MUM D-AP5 and 10 MUM NBQX respectively. The concentrations of perampanel required to reduce AMPA receptor-mediated responses are not dissimilar to those in plasma following anti-convulsant doses and are consistent with AMPA receptor antagonism being its primary mode of action. PMID- 22433908 TI - Immunomodulation of memory-impairing protein tau in Alzheimer's disease. AB - BACKGROUND: Neurodegeneration induced by misfolded tau protein and neuroinflammation represent the major hallmarks of human tauopathies including Alzheimer's disease (AD). While tau driven neurodegeneration significantly correlates with disease progression, inflammation is considered to be an important factor regulating the resistance or susceptibility to AD. The emerging evidence suggests that the genes related to immunity can influence neurodegeneration. OBJECTIVE: In order to determine the role of MHC class II in the tau neurofibrillary cascade, we generated and used transgenic lines expressing human truncated tau protein in either spontaneously hypertensive rat (SHR) or Wistar-Kyoto rat (WKY) genetic background. METHODS: Brains of WKY and SHR transgenic rats and their age-matched nontransgenic littermates were examined by immunohistochemistry and RT-PCR. RESULTS: Our results clearly showed that genetic background determined the inflammatory pattern (MHC class II) induced by tau neurodegenerative cascade in the transgenic rats expressing human misfolded truncated tau. CONCLUSION: Using two transgenic rat lines with different immunogenetic backgrounds, expressing the same transgene, we conclude that genetic background is a potent modifier of the type of the immune response induced by tau neurodegeneration. PMID- 22433909 TI - Particle size and magnetic properties dependence on growth temperature for rapid mixed co-precipitated magnetite nanoparticles. AB - Magnetite nanoparticles have been prepared by co-precipitation using a custom designed jet mixer to achieve rapid mixing (RM) of reactants in a timescale of milliseconds. The quick and stable nucleation obtained allows control of the particle size and size distribution via a more defined growth process. Nanoparticles of different sizes were prepared by controlling the processing temperature in the first few seconds post-mixing. The average size of the nanoparticles investigated using a Tecnai transmission electron microscope is found to increase with the temperature from 3.8 nm at 1 +/- 1 degrees C to 10.9 nm for particles grown at 95 +/- 1 degrees C. The temperature dependence of the size distribution follows the same trend and is explained in terms of Ostwald ripening of the magnetite nanoparticles during the co-precipitation of Fe(2+) and Fe(3+). The magnetic properties were studied by monitoring the blocking temperature via both DC and AC techniques. Strikingly, the obtained RM particles maintain the high magnetization (as high as ~88 A m(2) kg(-1) at 500 kA m(-1)) while the coercivity is as low as ~12 A m(-1) with the expected temperature dependence. Besides, by adding a drop of tetramethylammonium hydroxide, aqueous ferrofluids with long term stability are obtained, suggesting their suitability for applications in ferrofluid technology and biomedicine. PMID- 22433910 TI - Aggregation induced emission for the recognition of latent fingerprints. AB - The aggregation-induced emission of tetraphenylethene was explored for enhancing the visualization of latent fingerprints on wet non-porous surfaces. PMID- 22433911 TI - Chronic constriction of the sciatic nerve and pain hypersensitivity testing in rats. AB - Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of the population(1,2). Symptoms include spontaneous (tingling, burning, electric-shock like) pain, dysaesthesia, paraesthesia, allodynia (pain resulting from normally non-painful stimuli) and hyperalgesia (an increased response to painful stimuli). The sensory symptoms are co-morbid with behavioural disabilities, such as insomnia and depression. To study chronic neuropathic pain several animal models mimicking peripheral nerve injury have been developed, one of the most widely used is Bennett and Xie's (1988) unilateral sciatic nerve chronic constriction injury (CCI)(3) (Figure 1). Here we present a method for performing CCI and testing pain hypersensitivity. CCI is performed under anaesthesia, with the sciatic nerve on one side exposed by making a skin incision, and cutting through the connective tissue between the gluteus superficialis and biceps femoris muscles. Four chromic gut ligatures are tied loosely around the sciatic nerve at 1 mm intervals, to just occlude but not arrest epineural blood flow. The wound is closed with sutures in the muscle and staples in the skin. The animal is then allowed to recover from surgery for 24 hrs before pain hypersensitivity testing begins. For behavioural testing, rats are placed into the testing apparatus and are allowed to habituate to the testing procedure. The area tested is the mid plantar surface of the hindpaw (Figure 2), which falls within the sciatic nerve distribution. Mechanical withdrawal threshold is assessed by mechanically stimulating both injured and uninjured hindpaws using an electronic dynamic plantar von Frey aesthesiometer or manual von Frey hairs(4). The mechanical withdrawal threshold is the maximum pressure exerted (in grams) that triggers paw withdrawal. For measurement of thermal withdrawal latency, first described by Hargreaves et al (1988), the hindpaw is exposed to a beam of radiant heat through a transparent glass surface using a plantar analgesia meter(5,6). The withdrawal latency to the heat stimulus is recorded as the time for paw withdrawal in both injured and uninjured hindpaws. Following CCI, mechanical withdrawal threshold, as well as thermal withdrawal latency in the injured paw are both significantly reduced, compared to baseline measurements and the uninjured paw (Figure 3). The CCI model of peripheral nerve injury combined with pain hypersensitivity testing provides a model system to investigate the effectiveness of potential therapeutic agents to modify chronic neuropathic pain. In our laboratory, we utilise CCI alongside thermal and mechanical sensitivity of the hindpaws to investigate the role of neuro-immune interactions in the pathogenesis and treatment of neuropathic pain. PMID- 22433912 TI - Comparing the availability, price, variety and quality of fruits and vegetables across retail outlets and by area-level socio-economic position. AB - OBJECTIVE: To explore whether area-level socio-economic position or the form of retail stream (conventional v. farmers' market) is associated with differences in the price, availability, variety and quality of a range of fresh fruit and vegetables. DESIGN: A multi-site cross-sectional pilot study of farmers' markets, supermarkets and independent fruit and vegetable retailers. Each was surveyed to assess the price, availability, variety and quality of fifteen fruit and eighteen vegetable items. SETTING: Retail outlets were located in south-east Queensland. SUBJECTS: Fifteen retail outlets were surveyed (five of each retail stream). RESULTS: Average basket prices were not significantly different across the socio economic spectrum, but prices in low socio-economic areas were cheapest. Availability, variety and quality did not differ significantly across levels of socio-economic position; however, the areas with the most socio-economic disadvantage scored poorest for quality and variety. Supermarkets had significantly better fruit and vegetable availability than farmers' markets, although price, variety and quality scores were not different across retail streams. Results demonstrate a trend to fruit and vegetable prices being more expensive at farmers' markets, with the price of the fruit basket being significantly greater at the organic farmers' market compared with the non organic farmers' markets. CONCLUSIONS: Neither area-level socio-economic position nor the form of retail stream was significantly associated with differences in the availability, price, variety and quality of fruit and vegetables, except for availability which was higher in supermarkets than farmers' markets. Further research is needed to determine what role farmers' markets can play in affecting fruit and vegetable intake. PMID- 22433913 TI - Identification of novel Babesia and Theileria genotypes in the endangered marsupials, the woylie (Bettongia penicillata ogilbyi) and boodie (Bettongia lesueur). AB - Piroplasms, which include the genera Theileria and Babesia, are blood-borne parasites transmitted mainly by tick vectors. Relatively little is known about their prevalence and clinical impact in Australian marsupials. In the present study the occurrence and molecular phylogeny of these parasites were studied in both wild and captive marsupials from Western Australia (WA) and Queensland (QLD). Blood samples were screened by microscopy and molecular methods, using PCR and DNA sequencing of the 18S ribosomal RNA gene (18S rDNA). Overall, 7.1% of the blood samples (8/113) were positive for piroplasm 18S rDNA. Theileria and Babesia rDNA was detected in 0.9% (1/113) and 6.2% (7/113) of the animals, respectively. The single Theileria positive was identified in one of three boodies (Bettongia lesueur) screened from a wildlife rehabilitation centre in WA, while all seven Babesia positives were detected in WA in wild captured woylies (Bettongia penicillata ogilbyi). Small intraerythrocytic inclusions were observed in blood films made from six of these individuals. This is the first report of a Babesia sp. in woylies, and Theileria sp. in boodies. Phylogenetic analysis indicated that the woylie-derived Babesia was genetically distinct and most closely related to Babesia occultans, the causative agent of a benign form of cattle babesiosis (genetic similarity 98.4%). The Theileria identified was most closely related to the marsupial-derived species Theileria penicillata from the woylie, Theileria brachyuri from the quokka (Setonix brachyurus), and Theileria sp. from the long nosed potoroo (Potorous tridactylus). PMID- 22433914 TI - Association of PHRF1-IRF7 region polymorphism with clinical manifestations of systemic lupus erythematosus in a Japanese population. AB - Interferon regulatory factor 7 (IRF7) has an essential role in the production of type I interferon. Although recent studies detected association of a single nucleotide polymorphism (SNP) rs4963128 in PHD and ring finger domains 1 (PHRF1)/KIAA1542, located closely to IRF7, and IRF7 rs1131665 (glutamine (Gln) 412 arginine (Arg)) with systemic lupus erythematosus (SLE), causal variants have not been established. In this study, we resequenced exons and introns of IRF7 to screen for all common polymorphisms, and examined whether they were associated with SLE in 416 Japanese patients with SLE and 505 healthy controls. We also tested whether the association of PHRF1 rs4963128 with SLE was replicated in a Japanese population. None of the IRF7 polymorphisms was associated with SLE. PHRF1 rs4963128T was not significantly associated with occurrence of SLE either; however, this allele was significantly increased in SLE with anti-Sm antibodies (6.8%) as compared with healthy controls (3.1%, P = 0.014, odds ratio [OR] 2.31) and SLE without anti-Sm antibodies (3.3%, P =0.041, OR 2.12). This allele was also increased in SLE with renal disorder (5.1%) as compared with those without renal disorder (2.4%, P = 0.047, OR 2.17). These results confirmed recently reported association of PHRF1 rs4963128T with anti-Sm antibody positive SLE in African-American populations, and supported the role of PHRF1-IRF7 region in the genetics of SLE. PMID- 22433915 TI - Evidence that abnormally large seasonal declines in vitamin D status may trigger SLE flare in non-African Americans. AB - Cross-sectional studies have shown that low vitamin D (25-hydroxyvitamin D (25(OH)D)) is associated with increased systemic lupus erythematosus (SLE) activity. This study is the first to assess the temporal relationship between 25(OH)D levels and onset of SLE flare. This assessment was made possible because of the specimen bank and database of the Ohio SLE Study (OSS), a longitudinal study of frequently relapsing SLE that involved regular bimonthly patient follow up. We identified for this study 82 flares from 46 patients that were separated by at least 8 months from previous flares. Serum 25(OH)D levels were measured at 4 and 2 months before flare, and at the time of flare (a flare interval). We found that for flares occurring during low daylight months (LDM, Oct-Mar), 25(OH)D levels were decreased at the time of flare, but only in non-African American (non-AA) patients (32% decrease at flare, compared to 4 months prior, p < 0.001). To control for seasonal effects, we also measured 25(OH)D levels in the LDM "no-flare" intervals, which were intervals that matched to the same calendar months of the patients' LDM flare intervals, but that didn't end in flare (n = 24). For these matches, a significant decrease occurred in 25(OH)D levels during the flare intervals (18.1% decrease, p < 0.001), but not during the matching no flare intervals (6.2% decrease, p = 0.411). For flares occurring during high daylight months (HDM), 25(OH)D levels changed only in non-AA patients, increasing slightly (5.6%, p = 0.010). Analysis of flare rates for the entire OSS cohort (n = 201 flares) revealed a tendency for higher flare rates during LDM compared to HDM, but again only in non-AA patients (p = 0.060). Flare rates were lower during HDM for non-AA patients compared to AA patients (p = 0.028). In conclusion, in non-AA SLE patients, unusually large declines in 25(OH)D during LDM may be mechanistically related to SLE flare, whereas relatively high 25(OH)D levels during HDM may protect against flare. PMID- 22433916 TI - Neuropsychological assessment in mixed connective tissue disease: comparison with systemic lupus erythematosus. AB - OBJECTIVE: The aims of the study were to assess cognitive functions (CF) in patients with mixed connective tissue disease (MCTD) and to compare MCTD patients with systemic lupus erythematosus patients with and without neuropsychiatric manifestations (NP-SLE and non-NP-SLE, respectively) in terms of CF. METHODS: Neuropsychological examination was performed in 141 patients: 30 with MCTD (24 women, 6 men), mean age: 48.07 years, 37 with non-NP-SLE (36 women, 1 man), mean age: 40.76 years and 74 with NP-SLE (68 women, 6 men), mean age: 41.97 years. Neuropsychological tests and structured interview were used. Emotional state was assessed by Hospital Anxiety and Depression Scale and clinical review. RESULTS: We observed cognitive impairment in six MCTD patients (20%); in one (3%) the impairment was severe. MCTD patients achieved significantly higher results in seven out of 11 tests compared with patients with NP-SLE. MCTD and non-NP-SLE patients did not differ significantly. The differences were irrespective of premorbid IQ, education, disease duration and steroid treatment. CONCLUSIONS: In the majority of MCTD patients, CF were not impaired and severe impairment was unusual. Cognitive functioning was most disturbed in NP-SLE. The cognitive deficits observed in connective tissue diseases can be connected with nervous system involvement. PMID- 22433917 TI - Development of a conceptual model of health-related quality of life for systemic lupus erythematosus from the patient's perspective. AB - AIMS: The aim of this study was to evaluate the impact of systemic lupus erythematosus (SLE) on the lives of patients in order to inform the development of a conceptual model. METHODS: Twenty-two participants with SLE (defined as meeting four of the 11 ACR criteria) were recruited for this study. Semi structured, in-person interviews were conducted with each participant, exploring the symptoms experienced and the impact on the patient's life. Thematic analysis of interview transcripts was conducted in ATLAS.ti software to identify areas of impact and explore the interrelationships between concepts to inform the development of a conceptual model. RESULTS: Almost all participants were female (95%); the sample was diverse in terms of age (mean age of 45.5 years; age range of 20-60 years), ethnicity (59% black/African American) and disease duration. Commonly reported symptoms were pain, fatigue/tiredness and skin problems. Qualitative analysis revealed seven themes relating to the impact of SLE symptoms on patient's Health Related Quality of Life (HRQL): emotions, social, family and leisure activities, daily activities, cognition, appearance, employment activities and independence. The interrelationships between symptoms, impacts and symptom triggers are illustrated in a conceptual model. CONCLUSIONS: The conceptual model illustrates the wide-reaching impact of SLE symptoms on a patient's HRQL, and the potential broad impact of a treatment that improves SLE symptoms. PMID- 22433918 TI - Successful treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in systemic lupus erythematosus (SLE) with oral cyclophosphamide. AB - Peripheral neuropathy is a known manifestation of systemic lupus erythematosus. However, the association of primary autoimmune inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) with SLE is uncommon. We report a 26-year-old man who simultaneously presented with severe CIDP and photosensitive rash, but was unresponsive to intravenous immunoglobulin infusion and continued to progress. He was found to have underlying SLE and improved with combined corticosteroid and immunosuppressive therapy with oral cyclophosphamide. CIDP with underlying SLE may be more resistant to conventional therapy with IVIG, requiring the addition of other immunosuppressive agents. PMID- 22433919 TI - Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus. AB - We report a 37-year-old female of intractable rheumatoid arthritis (RA) complicated by systemic lupus erythematosus (SLE), who was successfully treated with a combination of tocilizumab (TCZ) and tacrolimus. She was diagnosed with RA when she was 21 years old, and was administered oral prednisolone, injectable gold and salazosulfapyridine, but deformity of her hands gradually developed. She developed high fever and thrombocytopenia when she was 35 years old. Renal involvement, pericarditis, positive antinuclear antibody and high level of anti double-stranded DNA antibody were found and the patient was diagnosed with SLE. Polyarthritis and immunological abnormalities developed despite aggressive immunosuppressive therapy including high-dose corticosteroids and intravenously administered cyclophosphamide. Tacrolimus (TAC) therapy gave only partial improvement of joint symptoms. After the initiation of combination therapy with TCZ, not only was a complete remission of RA obtained, but also the serum levels of SLE markers dramatically decreased. Our report suggests the possibility that this combination therapy is effective in treating SLE as well as RA. PMID- 22433920 TI - Long-term consequences of iron-fortified flour consumption in nonanemic men. AB - BACKGROUND/AIMS: Despite the advantages of fortifying flour with iron, there are still special concerns regarding the possible adverse effects of the extra iron consumed by nonanemic individuals. This study aimed to investigate the oxidative stress and iron status following 8 and 16 months of consumption of iron-fortified flour in nonanemic men. METHODS: In a before-and-after intervention study, 78 nonanemic apparently healthy 40- to 65-year-old men were randomly selected from Semnan, in the northeast of Iran. Data were collected at three time points. Evaluation of oxidative stress biomarkers as well as the assessment of iron status was performed in all three stages. After baseline data collection, the flour fortification program was started with 30 mg/kg iron as ferrous sulfate. RESULTS: After 16 months, serum iron levels had significantly increased from 102.9 +/- 31.5 MUg/dl (baseline) to 117.2 +/- 29.8 MUg/dl (p < 0.001). The mean total antioxidant capacity (1.71 +/- 0.10 MUM) was significantly lower than that at baseline (1.83 +/- 0.17 MUM; p < 0.01). Among other oxidative stress biomarkers, only superoxide dismutase and glutathione peroxidase activity increased significantly compared to the beginning of the study (p < 0.001 and p < 0.001, respectively). The results of this study did not show any symptoms of iron overload after 8 and 16 months. CONCLUSIONS: Our data did not support the safety of flour fortification with 30 mg/kg iron as ferrous sulfate as a community-based approach to control iron deficiency in nonanemic healthy men. PMID- 22433922 TI - Feasibility and accuracy of confocal endomicroscopy in comparison with narrow band imaging and chromoendoscopy for the differentiation of colorectal lesions. AB - OBJECTIVES: Several advanced imaging techniques have been developed to improve differentiation of colorectal lesions. These techniques need to be assessed for both feasibility and accuracy in order to prove their value in daily clinical practice. The current study assessed the feasibility of probe-based confocal laser endomicroscopy (pCLE) in acquiring videos of sufficient quality. Furthermore, the accuracy of pCLE for the differentiation of colorectal lesions was assessed and compared with narrow-band imaging (NBI) and chromoendoscopy (CE). METHODS: Consecutive patients scheduled for surveillance colonoscopy at our centre were included. All procedures were performed by two expert colonoscopists, who previously participated in studies evaluating pCLE, NBI, and CE. All detected lesions during colonoscopy were differentiated real-time with NBI and CE for Kudo pit pattern. Lesions were also assessed real-time for vascular pattern intensity (VPI) during NBI. Subsequently, pCLE videos of each lesion were acquired and biopsies were taken for histopathology. All pCLE videos were assessed post-hoc for the percentage of time demonstrating sufficient image quality (i.e., depicting at least one crypt or vessel). Finally, pCLE videos were assessed post hoc for diagnostic accuracy by two experts. RESULTS: A total of 154 lesions detected in 64 patients were included. Accuracy of Kudo pit pattern with NBI for predicting neoplasia (88.7%) was significantly better than accuracy of VPI (77.5%, P = 0.05) but not significantly different from CE (89.3%, P = 0.125). During pCLE, no histology was shown at all on the video in 19 lesions (12%). The mean time to acquire a pCLE video of the remaining 135 lesions was 50 seconds (s.d. 47) per lesion. The median percentage demonstrating sufficient quality per video was 40.5% (interquartile range 21.2-67.0). Accuracy of pCLE for both observers (66.7 and 71.9%) was significantly lower than accuracy of CE (P < 0.001) and NBI (P < 0.001). CONCLUSIONS: Video acquisition with pCLE could not be achieved in a small number of lesions. The majority of pCLE videos demonstrated insufficient quality in more than half of the time recorded. Moreover, post-hoc accuracy of pCLE was significantly lower in comparison with real-time accuracy of CE and NBI. Future research should assess whether further increase in experience could improve pCLE video acquisition and determine the real-time accuracy of pCLE for differentiating colorectal lesions. PMID- 22433921 TI - Efficacy of twice-daily rabeprazole for reflux esophagitis patients refractory to standard once-daily administration of PPI: the Japan-based TWICE study. AB - OBJECTIVES: Approximately 10% of patients with reflux esophagitis (RE) are not cured with the standard 8-week q.d. regimen with a proton pump inhibitor (PPI). Thus, b.i.d. dosing is often used in refractory RE (rRE) patients, although there has been no report of endoscopically confirmed healing with b.i.d. dosing of PPIs. This study aimed to assess the efficacy and safety of 8-week therapy with rabeprazole (RPZ) sodium at 20 mg b.i.d. or 10 mg b.i.d. as compared with RPZ at 20 mg q.d. in patients with RE refractory to the standard PPI regimen in Japan. METHODS: Endoscopically confirmed rRE patients (Los Angeles grade A-D) who had received a standard PPI regimen for at least 8 weeks were randomized in a double blind manner into groups receiving RPZ at 20 and 10 mg b.i.d. or 20 mg q.d. (control) daily for up to 8 weeks. The primary efficacy endpoint was the rate of endoscopically confirmed healing after week 8. RESULTS: A total of 337 rRE patients treated at 71 sites were randomized. The rate of endoscopically confirmed healing after 8 weeks was significantly higher in those who received RPZ at 20 mg b.i.d. (77.0%, P = 0.003) and 10 mg b.i.d. (78.4%, P = 0.001) as compared with 20 mg q.d. (58.8%), and the rates of resolution of heartburn after week 8 were 80.0%, 74.0%, and 56.4%, respectively. All treatment regimens were well tolerated. CONCLUSIONS: Regimens of RPZ at 20 and 10 mg b.i.d. for 8 weeks were more effective than 20 mg q.d. with regard to endoscopically confirmed healing and symptom resolution of RE refractory to a standard PPI regimen. PMID- 22433923 TI - Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus. AB - BACKGROUND & AIMS: Increased waist circumference and visceral fat are associated with increased risk of Barrett's esophagus (BE) and esophageal adenocarcinoma. This association might be mediated by mechanical and endocrine mechanisms. We investigated the distribution of fat in subjects with BE and its association with esophageal inflammation and dysplasia. METHODS: We collected data from 50 BE cases and 50 controls (matched for age and sex, identified from a radiology trauma database) seen at the Mayo Clinic in 2009. Abdominal (subcutaneous and visceral) and gastroesophageal junction (GEJ) fat area was measured using computed tomography with standard techniques. Esophageal inflammation (based on a histologic score) and dysplasia grade were assessed from esophageal biopsies of BE cases by a gastrointestinal pathologist. Conditional logistic regression was used to assess the association of body fat depot area with BE status, esophageal inflammation, and dysplasia. RESULTS: All BE subjects had controlled reflux symptoms without esophagitis, based on endoscopy. The GEJ fat area (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.3-27.7; P = .02), visceral fat area (OR, 4.9; 95% CI, 1.0-22.8; P = .04), and abdominal circumference (OR, 9.1; 95% CI, 1.4-57.2; P = 0.02) were associated with BE, independent of body mass index (BMI). The subcutaneous fat area was not associated with BE. Visceral and GEJ fat were significantly greater in BE subjects with esophageal inflammation (compared with those without, P = .02) and high-grade dysplasia (compared with those without, P = .01), independent of BMI. CONCLUSIONS: GEJ and visceral fat are associated with BE, and with increased esophageal inflammation and high-grade dysplasia in BE subjects, independent of BMI. Visceral fat therefore might promote esophageal metaplasia and dysplasia. PMID- 22433924 TI - Detection, treatment, and prevention of Clostridium difficile infection. AB - Clostridium difficile is a gram-positive anaerobic bacillus responsible for approximately 1 of 5 cases of antibiotic-associated diarrhea. C difficile infection (CDI) is defined by at least 3 unformed stools in a 24-hour period and stool, endoscopic, or histopathologic test results that indicate the presence of this bacteria. The history of CDI research can be divided into early (before 2000) and modern eras (after 2000). C difficile was first described in 1935, and the characteristics and causes of CDI as well as therapies were identified during the early era of research. During the modern era, CDI has become a more common, aggressive nosocomial infection. Our understanding of the epidemiology, diagnosis, treatment, and prevention of CDI has increased at a rapid pace. We review features of CDI diagnosis, treatment, and prevention. PMID- 22433928 TI - The effect of parity conservation on the spin-orbit conserving and spin-orbit changing differential cross sections for the inelastic scattering of NO(X) by Ar. AB - The fully Lambda-doublet resolved state-to-state differential cross sections (DCSs) for the collisions of NO(X, (2)Pi, v = 0, j = 0.5) with Ar have been shown to depend sensitively on the conservation of the total parity of the NO molecular wavefunction. Parity changing collisions exhibit a single maximum only in the DCS, while parity conserving transitions exhibit multiple rainbow peaks. This behaviour is shown to arise directly from the constructive or destructive interference of collisions impacting on the two pointed ends and on the flatter middle of the NO molecule. A simple hard shell, four path model has been employed to determine the relative phase shifts of the paths contributing to the scattering amplitude. The model calculations using the V(sum) potential, together with the results of a quasi-quantum treatment, provide good qualitative agreement with the experimental spin-orbit conserving (DeltaOmega = 0) DCSs, suggesting that the dynamics for all but the lowest Deltaj transitions are determined largely by the repulsive part of the potential. The collisions leading to spin orbit changing transitions (DeltaOmega = 1) have been also found to be dominated by repulsive forces, even for the lowest Deltaj values. However, they are less well reproduced by hard shell calculations, because of the crucial participation of the V(diff) potential in determining the outcome of these collisions. PMID- 22433929 TI - How to optimally manage growth hormone therapy: survey of Chilean pediatric endocrinologists. AB - Early referral is the key to the optimal management of growth failure. Evidence shows that there is no universal consensus for endocrinologists on the handling, tracking and monitoring of growth hormone (GH) treatment. The monitoring of therapy varies due to national prescription guidelines. The aim of this work was to assess the clinical management of short-stature patients who use GH prescribed by pediatric endocrinologists (n = 30) who belong to the Chilean Endocrinology Society (SOCHED). We conducted a questionnaire through an anonymous survey. We observed a large variability of responses to all of the questions. Once the clinician suggests GH treatment, patients usually begin treatment with a strong motivation, and maintenance of this motivation will improve the treatment outcomes. We propose 3-4 months of medical follow-up during which strict physician-patient communication and education is critical. PMID- 22433930 TI - Stroke in South Asia: a systematic review of epidemiologic literature from 1980 to 2010. AB - BACKGROUND: Globally 15 million people have an acute stroke every year and one third of them die secondary to stroke events. Most research on stroke prevention and treatment is done in developed countries, yet more than 85% of strokes occur in developing countries. In particular, stroke remains an underrecognized cause of death and disability in South Asia. METHODS: We conducted a systematic review to identify reliable and comparable epidemiological evidence on stroke in South Asia from 1980 to 2010. Publications were screened for eligibility to identify only population-based stroke studies. RESULTS: Of the 71 studies retrieved, only 6 studies from South Asia gave us acceptable estimates of the burden of stroke. Population-based studies from South Asia have stroke prevalence in the range of 45-471 per 100,000. The age-adjusted incidence rate varied from approximately 145 per 100,000 to 262 per 100,000. Rural parts of South Asia have a lower stroke prevalence compared with urban areas. CONCLUSIONS: Our review highlights the paucity of research data in South Asia. This must be addressed in order to accurately determine the burden of stroke in South Asia, so that specific policy recommendations can be formulated to combat the stroke epidemic in this region. PMID- 22433931 TI - Predictors of HIV and iron-deficiency anaemia: a comment. PMID- 22433932 TI - Probiotics: Can they fight against the allergic disease? PMID- 22433933 TI - Metal-organic framework supported ionic liquid membranes for CO2 capture: anion effects. AB - IRMOF-1 supported ionic liquid (IL) membranes are investigated for CO(2) capture by atomistic simulation. The ILs consist of identical cation 1-n-butyl-3 methylimidazolium [BMIM](+), but four different anions, namely hexafluorophosphate [PF(6)](-), tetrafluoroborate [BF(4)](-), bis(trifluoromethylsulfonyl)imide [Tf(2)N](-), and thiocyanate [SCN](-). As compared with the cation, the anion has a stronger interaction with IRMOF-1 and a more ordered structure in IRMOF-1. The small anions [PF(6)](-), [BF(4)](-), and [SCN](-) prefer to locate near to the metal-cluster, particularly the quasi spherical [PF(6)](-) and [BF(4)](-). In contrast, the bulky and chain-like [BMIM](+) and [Tf(2)N](-) reside near the phenyl ring. Among the four anions, [Tf(2)N](-) has the weakest interaction with IRMOF-1 and thus the strongest interaction with [BMIM](+). With increasing the weight ratio of IL to IRMOF-1 (W(IL/IRMOF-1)), the selectivity of CO(2)/N(2) at infinite dilution is enhanced. At a given W(IL/IRMOF-1), the selectivity increases as [Tf(2)N](-) < [PF(6)](-) < [BF(4)](-) < [SCN](-). This hierarchy is predicted by the COSMO-RS method, and largely follows the order of binding energy between CO(2) and anion estimated by ab initio calculation. In the [BMIM][SCN]/IRMOF-1 membrane with W(IL/IRMOF-1) = 1, [SCN](-) is identified to be the most favorable site for CO(2) adsorption. [BMIM][SCN]/IRMOF-1 outperforms polymer membranes and polymer-supported ILs in CO(2) permeability, and its performance surpasses Robeson's upper bound. This simulation study reveals that the anion has strong effects on the microscopic properties of ILs and suggests that MOF-supported ILs are potentially intriguing for CO(2) capture. PMID- 22433934 TI - Laparoscopic sleeve gastrectomy in obese adolescents: results in 51 patients. AB - BACKGROUND: Adolescent obesity has become an important health problem. Bariatric surgery in this population continues to be a matter of debate. The aim of our study was to present our experience and results with laparoscopic sleeve gastrectomy (LSG) in obese adolescents at the digestive surgery department of the Hospital Clinico Pontificia Universidad Catolica de Chile. METHODS: Obese adolescent patients <19 years old underwent LSG from January 2006 to October 2009. The percentage of excess weight loss and quality of life were analyzed. RESULTS: A total of 51 patients aged <19 years underwent LSG. Of these, 80.4% were girls and aged 15-19 years (mean age 18 +/- 1.45). The mean preoperative weight and body mass index was 98 +/- 13.3 kg and 38.5 +/- 3.7 kg/m(2), respectively. Of these patients, 76% had preoperative co-morbidities, including insulin resistance in 59.2%, dyslipidemia in 23.5%, hepatic steatosis in 16%, and type 2 diabetes mellitus in 3.9%. The operative time was 69 +/- 24 minutes, with a 2.8 +/- 20.6-day postoperative hospital stay. No conversion to open surgery was necessary. One patient had a suture line leak that required both endoscopic and laparoscopic treatment. The percentage of excess weight loss at 6 months and 1 and 2 years was 94.6%, 96.2%, and 92.9%, respectively. Of the 76% of patients with preoperative co-morbidities, all resolved or improved their condition. In the quality of life survey (Moorehead-Ardelt Quality of Life Questionnaire) conducted, all reported very good or good quality of life after surgery (40% and 60%, respectively). CONCLUSION: In our experience, LSG as a treatment of obese adolescent patients is safe, with good short-term weight loss and resolution of co-morbidities. PMID- 22433935 TI - Combining mixed titania morphologies into a complex assembly thin film by iterative block-copolymer-based sol-gel templating. AB - Sol-gel templating combined with iterative spin-coating steps are used to custom tailor hierarchically structured titania thin films. Using poly(styrene-block ethylene oxide) P(S-b-PEO) as the structure directing agent, a foam-like structure is combined with nanogranules. Both structural elements are merged into a complex assembly in thin film geometry. The resulting morphology is pictured by SEM and probed with GISAXS. The installed mesoporous titania sandwich structure exhibits holes with a size of 45 nm which makes it promising for applications in photovoltaics or photocatalysis. An optical characterization completes the structural investigation. PMID- 22433936 TI - Non-covalent versus covalent donor-acceptor systems based on near-infrared absorbing azulenocyanines and C60 fullerene derivatives. AB - A novel supramolecular electron donor-acceptor hybrid (2.1) and an electron donor acceptor conjugate (3), both exhibiting a remarkably shifted Q band in the NIR region of the solar spectrum, were prepared. Irradiation of the supramolecular ensemble 2.1 within the visible range leads to a nanosecond lived radical-ion pair state Zn-azulenocyanine(+)-C(60)(-). PMID- 22433937 TI - MRI-guided disruption of the blood-brain barrier using transcranial focused ultrasound in a rat model. AB - Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB(1-5). The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size(6). FUS induced BBB disruption (BBBD) is temporary and reversible(4) and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB(2,5,7), there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment. PMID- 22433938 TI - Single dose testosterone increases total cholesterol levels and induces the expression of HMG CoA reductase. AB - BACKGROUND: Cholesterol is mainly synthesised in liver and the rate-limiting step is the reduction of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) to mevalonate, a reaction catalysed by HMG-CoA reductase (HMGCR). There is a comprehensive body of evidence documenting that anabolic-androgenic steroids are associated with deleterious alterations of lipid profile. In this study we investigated whether a single dose of testosterone enanthate affects the cholesterol biosynthesis and the expression of HMGCR. METHODS: 39 healthy male volunteers were given 500 mg testosterone enanthate as single intramuscular dose of Testoviron(r)--Depot. The total cholesterol levels prior to and two days after testosterone administration were analysed. Protein expression of HMGCR in whole blood was investigated by Western blotting. In order to study whether testosterone regulates the mRNA expression of HMGCR, in vitro studies were performed in a human liver cell-line (HepG2). RESULTS: The total cholesterol level was significantly increased 15% two days after the testosterone injection (p = 0.007). This is the first time a perturbation in the lipoprotein profile is observed after only a single dose of testosterone. Moreover, the HMGCR mRNA and protein expression was induced by testosterone in vitro and in vivo, respectively. CONCLUSION: Here we provide a molecular explanation how anabolic androgenic steroids may impact on the cholesterol homeostasis, i.e. via an increase of the HMGCR expression. Increasing knowledge and understanding of AAS induced side-effects is important in order to find measures for treatment and care of these abusers. PMID- 22433939 TI - Comparison of low-dose oxytocin and dinoprostone for labor induction in postterm pregnancies: a randomized controlled prospective study. AB - AIMS: The aim of this study was to compare the efficacy of oxytocin and dinoprostone in achieving successful labor induction and vaginal delivery in postterm women with an unfavorable cervix. METHODS: Postterm women with an uncomplicated pregnancy and a Bishop score of <=6 were randomized to receive either dinoprostone vaginal pessary (Propess(r)) or low-dose oxytocin. The primary outcomes were the length of the induction-to-delivery period and the incidence of vaginal delivery. RESULTS: A total of 144 women were available for the analysis. The overall vaginal delivery rates were 75% (54/72) for the dinoprostone group and 80.6% (58/72; p = 0.35) for the oxytocin group; the mean induction-to-vaginal delivery interval was 13.3 and 10.3 h in the dinoprostone and the oxytocin group, respectively (p = 0.003). Uterine hyperstimulation was 7.4% compared with 6.8% (p = 0.8), and abnormal fetal heart rate was 26.4% compared with 18% (p = 0.2), respectively. CONCLUSION: Both oxytocin and dinoprostone seem to have similar obstetric outcomes in postterm pregnancies with an unfavorable cervix, except for a significant superiority of oxytocin for delivery in a shorter period. PMID- 22433940 TI - Growth and endocrine effects of recombinant bovine growth hormone treatment in non-transgenic and growth hormone transgenic coho salmon. AB - To examine the relative growth, endocrine, and gene expression effects of growth hormone (GH) transgenesis vs. GH protein treatment, wild-type non-transgenic and GH transgenic coho salmon were treated with a sustained-release formulation of recombinant bovine GH (bGH; Posilac). Fish size, specific growth rate (SGR), and condition factor (CF) were monitored for 14 weeks, after which endocrine parameters were measured. Transgenic fish had much higher growth, SGR and CF than non-transgenic fish, and bGH injection significantly increased weight and SGR in non-transgenic but not transgenic fish. Plasma salmon GH concentrations decreased with bGH treatment in non-transgenic but not in transgenic fish where levels were similar to controls. Higher GH mRNA levels were detected in transgenic muscle and liver but no differences were observed in GH receptor (GHR) mRNA levels. In non transgenic pituitary, GH and GHR mRNA levels per mg pituitary decreased with bGH dose to levels seen in transgenic salmon. Plasma IGF-I was elevated with bGH dose only in non-transgenic fish, while transgenic fish maintained an elevated level of IGF-I with or without bGH treatment. A similar trend was seen for liver IGF-I mRNA levels. Thus, bGH treatment increased fish growth and influenced feedback on endocrine parameters in non-transgenic but not in transgenic fish. A lack of further growth stimulation of GH transgenic fish suggests that these fish are experiencing maximal growth stimulation via GH pathways. PMID- 22433941 TI - Characterization of the true ortholog of the urotensin II-related peptide (URP) gene in teleosts. AB - It has been recently established that the urotensin II (UII) family consists of four distinct paralogs in bony vertebrates, namely UII, and the three UII-related peptides (URPs) called URP, URP1 and URP2. These four peptides are encoded by genes which arose from the two rounds of tetraploidization (2R) which took place early during vertebrate evolution. Up to now, three of them, UII, URP1 and URP2, have been identified in teleosts, while only two, UII and URP, have been reported in tetrapods. The fact that fish URP has not been found in previous studies led to the suggestion that the corresponding gene had been lost in the teleost lineage. In the present study, we show that this view is not correct. A search of the most recent release of the Ensembl genome database led us to identify a novel UII/URP-like gene in teleosts. Using synteny analysis, we demonstrate that this gene corresponds to the true ortholog of the tetrapod URP gene. Molecular cloning of the corresponding cDNA in medaka revealed that URP gene encodes a putative peptide, with the primary structure GEPCFWKYCV. In stickleback, tilapia and takifugu, URP exhibited the same sequence while, in tetraodon, it differed by only one amino acid substitution Gly <-> Ser. In zebrafish, URP appeared totally divergent at its N-terminus with the structure DDTCFWKYCV. In conclusion, the occurrence of a true URP in teleosts shows that the quartet of UII-related genes which arose from 2R has been integrally preserved in this lineage. PMID- 22433942 TI - The endocrine changes, the timing of ovulation and the efficacy of the Doublesynch protocol in the Murrah buffalo (Bubalus bubalis). AB - Experiments were conducted to investigate (a) the timing of ovulation and the associated endocrine changes (progesterone, estrogen and LH) during estrous cycle and (b) the efficacy, with respect to the pregnancy rate, in cycling and anestrus in Murrah buffaloes subjected to the Doublesynch protocol during the low breeding season. In experiment 1, 10 cycling buffaloes were administered PGF(2alpha) on day 0 (without regard to the estrous cycle stage), GnRH on day 2, a second PGF(2alpha) injection on day 9, and a second GnRH injection on day 11. Transrectal palpation was performed at 2-h intervals after the first and second GnRH treatments until ovulation was detected or for upto 96 h. The plasma progesterone and total estrogen concentrations were determined in blood samples collected at daily intervals starting 2 days before the onset of the protocol and continued until the day of the second detected ovulation. The plasma LH and total estrogen concentrations were measured in blood samples collected at 30-min intervals for 8h following the first and second GnRH injections and thereafter at 2-h intervals until 2h after the detection of ovulation. Ovulation occurred in 9/10 buffaloes (90%) at 22.2 +/- 1.2 h (mean +/- S.E.M.; range 18.0-26.0 h) and 10/10 buffaloes (100%) at 23.2 +/- 1.0 h (mean +/- S.E.M.; range 20.0-28.0 h) after the first and second GnRH treatments, respectively. The peak LH concentrations of 99.8 +/- 28.5 ng/ml (range 37.8-320.0 ng/ml) and 62.3 +/- 11.9 ng/ml (range 20.9-143.9 ng/ml) occurred 2.1 +/- 0.3 h (range 1.0-3.5 h) and 2.3 +/- 0.3 h (range 0.5-3.0 h) after the first and second GnRH treatments, respectively. The total estrogen concentration gradually increased from the day of both the first and second PGF(2alpha) administrations until the LH peak (with great variability) and then gradually declined to the basal level, which was reached at the time ovulation was detected. In experiment 2, 10 cycling and 11 non-lactating anestrus buffaloes were subjected to the Doublesynch protocol with timed artificial insemination (TAI) 16 and 24 h after the second GnRH treatment, and 55 cycling buffaloes were inseminated after spontaneous estrus was detected (control group). The pregnancy rates were 60% using TAI on cycling buffaloes (experiments 1 and 2), 55% for anestrus buffaloes (experiment 2), and 27.3% for cycling buffaloes inseminated following spontaneous estrus. The overall pregnancy success rates after the Doublesynch protocol in both cycling and anestrus buffaloes increased by 30.8% compared to spontaneous estrus (58.1% vs. 27.3%). In conclusion, the Doublesynch protocol effectively synchronized ovulation twice (after the first and second GnRH treatments) irrespective of the stage of estrous cycle in Murrah buffaloes. The study also demonstrated that the Doublesynch protocol followed by TAI significantly (P<0.005) enhanced the pregnancy rate in cycling and anestrus buffaloes in comparison to untreated controls during the low breeding season. PMID- 22433943 TI - Mechanisms of red blood cells agglutination in antibody-treated paper. AB - Recent reports on using bio-active paper and bio-active thread to determine human blood type have shown a tremendous potential of using these low-cost materials to build bio-sensors for blood diagnosis. In this work we focus on understanding the mechanisms of red blood cell agglutination in the antibody-loaded paper. We semi quantitatively evaluate the percentage of antibody molecules that are adsorbed on cellulose fibres and can potentially immobilize red blood cells on the fibre surface, and the percentage of the molecules that can desorb from the cellulose fibre surface into the blood sample and cause haemagglutination reaction in the bulk of a blood sample. Our results show that 34 to 42% of antibody molecules in the papers treated with commercial blood grouping antibodies can desorb from the fibre surface. When specific antibody molecules are released into the blood sample via desorption, haemagglutination reaction occurs in the blood sample. The reaction bridges the red cells in the blood sample bulk to the layer of red cells immobilized on the fibre surface by the adsorbed antibody molecules. The desorbed antibody also causes agglutinated lumps of red blood cells to form. These lumps cannot pass through the pores of the filter paper. The immobilization and filtration of agglutinated red cells give reproducible identification of positive haemagglutination reaction. Results from this study provide information for designing new bio-active paper-based devices for human blood typing with improved sensitivity and specificity. PMID- 22433944 TI - Neural connectivity of the pedunculopontine nucleus in relation to walking ability in chronic patients with intracerebral hemorrhage. AB - OBJECTIVES: As the mesencephalic locomotor center, the pedunculopontine nucleus (PPN) is known to be involved in control of locomotor function. We investigated neural connectivity of the PPN in relation to walking ability in chronic patients with spontaneous intracerebral hemorrhage. METHODS: Forty-three consecutive chronic patients with subcortical hemorrhage and 20 healthy control subjects were recruited. A seed region of interest was manually drawn on the PPN and connectivity of the PPN was measured. RESULTS: In the affected hemisphere, connectivity with the ipsilesional cerebellar locomotor center and connectivity with the contralesional pontine locomotor center were decreased in patients who could not walk, compared with patients who could walk and normal controls (p < 0.05). CONCLUSIONS: Connectivity between the PPN and ipsi-lesional cerebellum locomotor center and contralesional pontine locomotor center in the affected hemisphere appears to be related to walking ability. PMID- 22433945 TI - Amiodarone and the thyroid: a 2012 update. AB - Amiodarone-induced thyroid dysfunction occurs in 15-20% of amiodarone-treated patients. Amiodarone-induced hypothyroidism (AIH) does not pose relevant problems, is easily controlled by L-thyroxine replacement, and does not require amiodarone withdrawal. Most frequently AIH develops in patients with chronic autoimmune thyroiditis. Amiodarone- induced thyrotoxicosis (AIT) is most frequently due to destructive thyroiditis (type 2 AIT) causing discharge of thyroid hormones from the damaged, but otherwise substantially normal gland. Less frequently AIT is a form of hyperthyroidism (type 1 AIT) caused by the iodine load in a diseased gland (nodular goiter, Graves' disease). A clearcut differentiation between the two main forms is not always possible, despite recent diagnostic advances. As a matter of fact, mixed or indefinite forms do exist, contributed to by both thyroid damage and increased thyroid hormone synthesis. Treatment of type 1 (and mixed forms) AIT is based on the use of thionamides, a short course of potassium perchlorate and, if treatment is not rapidly effective, oral glucocorticoids. Glucocorticoids are the first-line treatment for type 2 AIT. Amiodarone should be discontinued, if feasible from a cardiac standpoint. Continuation of amiodarone has recently been associated with a delayed restoration of euthyroidism and a higher chance of recurrence after glucocorticoid withdrawal. Whether amiodarone treatment can be safely reinstituted after restoration of euthyroidism is still unknown. In rare cases of AIT resistance to standard treatments, or when a rapid restoration of euthyroidism is advisable, total thyroidectomy represents a valid alternative. Radioiodine treatment is usually not feasible due to the low thyroidal iodine uptake. PMID- 22433946 TI - Long term impact of prenatal exposure to SSRIs on growth and body weight in childhood: evidence from animal and human studies. AB - Prenatal exposure to SSRIs has the potential to alter fetal 5-HT signalling during critical periods of development: the long-term consequences of which have not been well studied. Of particular interest are the potential long-term effects of prenatal SSRI exposure on growth and body weight in later life, given the role of the serotonergic system in regulating food intake and body weight. Animal studies demonstrate that changes in 5-HT homeostasis during critical periods of fetal development can lead to sex-specific molecular and functional alterations in the serotonergic and HPA systems, leading to an increased risk of overweight in male, but not female, offspring in later life. This review highlights the evidence and the need for studies in humans to determine whether prenatal SSRI exposure is associated with alterations in child growth and body weight and the importance of delineating these effects from those of the underlying maternal illness. PMID- 22433947 TI - Diabetes insipidus--diagnosis and management. AB - Central diabetes insipidus (CDI) is the end result of a number of conditions that affect the hypothalamic-neurohypophyseal system. The known causes include germinoma/craniopharyngioma, Langerhans cell histiocytosis (LCH), local inflammatory, autoimmune or vascular diseases, trauma resulting from surgery or an accident, sarcoidosis, metastases and midline cerebral and cranial malformations. In rare cases, the underlying cause can be genetic defects in vasopressin synthesis that are inherited as autosomal dominant, autosomal recessive or X-linked recessive traits. The diagnosis of the underlying condition is challenging and raises several concerns for patients and parents as it requires long-term follow-up. Proper etiological diagnosis can be achieved via a series of steps that start with clinical observations and then progress to more sophisticated tools. Specifically, MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered a clear marker of neurohypophyseal functional integrity, together with the careful analysis of pituitary stalk shape and size, have provided the most striking findings contributing to the diagnosis and understanding of some forms of 'idiopathic' CDI. MRI STIR (short-inversion-time inversion recovery sequencing) is a promising technology for the early identification of LCH-dependent CDI. PMID- 22433948 TI - CO2 hydrogenation on a metal hydride surface. AB - The catalytic hydrogenation of CO(2) at the surface of a metal hydride and the corresponding surface segregation were investigated. The surface processes on Mg(2)NiH(4) were analyzed by in situ X-ray photoelectron spectroscopy (XPS) combined with thermal desorption spectroscopy (TDS) and mass spectrometry (MS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). CO(2) hydrogenation on the hydride surface during hydrogen desorption was analyzed by catalytic activity measurement with a flow reactor, a gas chromatograph (GC) and MS. We conclude that for the CO(2) methanation reaction, the dissociation of H(2) molecules at the surface is not the rate controlling step but the dissociative adsorption of CO(2) molecules on the hydride surface. PMID- 22433949 TI - Polo-like kinase-activating kinases: Aurora A, Aurora B and what else? AB - The events of cell division are regulated by a complex interplay between kinases and phosphatases. Cyclin-dependent kinases (Cdks), polo-like kinases (Plks) and Aurora kinases play central roles in this process. Polo kinase (Plk1 in humans) regulates a wide range of events in mitosis and cytokinesis. To ensure the accuracy of these processes, polo activity itself is subject to complex regulation. Phosphorylation of polo in its T loop (or activation loop) increases its kinase activity several-fold. It has been shown that Aurora A kinase, with its co-factor Bora, activates Plk1 in G(2), and that this is essential for recovery from cell cycle arrest induced by DNA damage. In a recent article published in PLoS Biology, we report that Drosophila polo is activated by Aurora B kinase at centromeres, and that this is crucial for polo function in regulating chromosome dynamics in prometaphase. Our results suggest that this regulatory pathway is conserved in humans. Here, we propose a model for the collaboration between Aurora B and polo in the regulation of kinetochore attachment to microtubules in early mitosis. Moreover, we suggest that Aurora B could also function to activate Polo/Plk1 in cytokinesis. Finally, we discuss recent findings and open questions regarding the activation of polo and polo-like kinases by different kinases in mitosis, cytokinesis and other processes. PMID- 22433950 TI - Ectopic transgenic expression of NKX2.2 induces differentiation of adult pancreatic progenitors and mediates islet regeneration. AB - To pursue islet regeneration in situ in adult pancreas with a diabetic animal model, we used ultrasound targeted microbubble destruction (UTMD) to deliver islet transcription factor genes to the pancreas of STZ-treated rats, specifically using a piggyBac transposon gene delivery system for long-term transgene expression of Nkx2.2 in STZ rat pancreas. Our results show that Nkx2.2 gene induced robust proliferation and differentiation of adult pancreatic progenitors. Our high-resolution confocal images precisely displayed how one single pancreatic progenitor cell differentiated into islets-like clusters and, further, into mature islets with normal morphology in situ in postnatal pancreas. Nkx2.2 targeted to the pancreas by UTMD induces pancreatic progenitor cell proliferation and differentiation with subsequent islet regeneration and cure of STZ-induced diabetes for three months. PMID- 22433951 TI - Death-associated proliferation kinetic in normal and transformed cells. AB - Pyruvate kinase M2 (PKM2) may occur in both a tetrameric and a dimeric form. When the majority of PKM2 molecules are in the highly active tetrameric conformation, glucose is primarily degraded to pyruvate and lactate with the regeneration of energy. A tumor suppressor protein, death-associated protein kinase (DAPK), interacts with PKM2 protein and stabilizes PKM2 in its active tetrameric form in normal proliferating cells. However, DAPK is widely inactivated in cancer cells, leading to the loss of the active conformation of PKM2. This may render PKM2 sensitive to cellular oxidants, switching the enzyme into its inactive dimeric form. Consequently, inhibition of PKM2 after oxidative stress contributes optimal tumor growth and allows cancer cells to withstand oxidative stress. PMID- 22433952 TI - Posttranslational control of telomere maintenance and the telomere damage response. AB - Telomeres help maintain genome integrity by protecting natural chromosome ends from being recognized as damaged DNA. When telomeres become dysfunctional, they limit replicative lifespan and prevent outgrowth of potentially cancerous cells by activating a DNA damage response that forces cells into senescence or apoptosis. On the other hand, chromosome ends devoid of proper telomere protection are subject to DNA repair activities that cause end-to-end fusions and, when cells divide, extensive genomic instability that can promote cancer. While telomeres represent unique chromatin structures with important roles in cancer and aging, we have limited understanding of the way telomeres and the response to their malfunction are controlled at the level of chromatin. Accumulating evidence indicates that different types of posttranslational modifications act in both telomere maintenance and the response to telomere uncapping. Here, we discuss the latest insights on posttranslational control of telomeric chromatin, with emphasis on ubiquitylation and SUMOylation events. PMID- 22433953 TI - Scale matters: the spatial correlation of yeast meiotic DNA breaks with histone H3 trimethylation is driven largely by independent colocalization at promoters. AB - During meiosis in many organisms, homologous chromosomes engage in numerous recombination events initiated by DNA double-strand breaks (DSBs) formed by the Spo11 protein. DSBs are distributed nonrandomly, which governs how recombination influences inheritance and genome evolution. The chromosomal features that shape DSB distribution are not well understood. In the budding yeast Saccharomyces cerevisiae, trimethylation of lysine 4 of histone H3 (H3K4me3) has been suggested to play a causal role in targeting Spo11 activity to small regions of preferred DSB formation called hotspots. The link between H3K4me3 and DSBs is supported in part by a genome-wide spatial correlation between the two. However, this correlation has only been evaluated using relatively low-resolution maps of DSBs, H3K4me3 or both. These maps illuminate chromosomal features that influence DSB distributions on a large scale (several kb and greater) but do not adequately resolve features, such as chromatin structure, that act on finer scales (kb and shorter). Using recent nucleotide-resolution maps of DSBs and meiotic chromatin structure, we find that the previously described spatial correlation between H3K4me3 and DSB hotspots is principally attributable to coincident localization of both to gene promoters. Once proximity to the nucleosome-depleted regions in promoters is accounted for, H3K4me3 status has only modest predictive power for determining DSB frequency or location. This analysis provides a cautionary tale about the importance of scale in genome-wide analyses of DSB and recombination patterns. PMID- 22433954 TI - Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cancer cells. AB - Many cancer cells are unable to maintain a numerically stable chromosome complement. It is well established that aberrant cell division can generate progeny with increased ploidy, but the genetic factors required for maintenance of diploidy are not well understood. Using an isogenic model system derived by gene targeting, we examined the role of Chk1 in p53-proficient and -deficient cancer cells. Targeted inactivation of a single CHK1 allele in stably diploid cells caused an elevated frequency of mitotic bypass if p53 was naturally mutated or experimentally disrupted by homologous recombination. CHK1-haploinsufficient, p53-deficient cells frequently underwent sequential rounds of DNA synthesis without an intervening mitosis. These aberrant cell cycles resulted in whole genome endoreduplication and tetraploidization. The unscheduled bypass of mitosis could be suppressed by targeted reversion of a p53 mutation or by exogenous expression of Cdk1. In contrast, the number of tetraploid cells was not increased in isogenic cell populations that harbor hypomorphic ATR mutations, suggesting that suppression of unscheduled mitotic bypass is a distinct function of Chk1. These results are consistent with a recently described role for Chk1 in promoting the expression of genes that promote cell cycle transitions and demonstrate how Chk1 might prevent tetraploidization during the cancer cell cycle. PMID- 22433955 TI - The struggle for energy in podocytes leads to nephrotic syndrome. AB - Podocytes are terminally differentiated post-mitotic cells similar to neurons, and their damage leads to nephrotic syndrome, which is characterized by massive proteinuria associated with generalized edema. A recent functional genetic approach has identified the pathological relevance of several mutated proteins in glomerular podocytes to the mechanism of proteinuria in hereditary nephrotic syndrome. In contrast, the pathophysiology of acquired primary nephrotic syndrome, including minimal change disease, is still largely unknown. We recently demonstrated the possible linkage of an energy-consuming process in glomerular podocytes to the mechanism of proteinuria. Puromycin aminonucleoside nephrosis, a rat model of minimal change disease, revealed the activation of the unfolded protein response (UPR) in glomerular podocytes to be a cause of proteinuria. The pretreatment of puromycin aminonucleoside rat podocytes and cultured podocytes with the mammalian target of rapamycin (mTOR) inhibitor everolimus further revealed that mTOR complex 1 consumed energy, which was followed by UPR activation. In this paper, we will review nutritional transporters to summarize the energy uptake process in podocytes and review the involvement of the UPR in the pathogenesis of glomerular diseases. We will also present additional data that reveal how mTOR complex 1 acts upstream of the UPR. Finally, we will discuss the potential significance of targeting the energy metabolism of podocytes to develop new therapeutic interventions for acquired nephrotic syndrome. PMID- 22433956 TI - Successful management of atrophic nonunion of a severely osteoporotic femoral shaft in a child. AB - We present a case illustrating the successful use of a conventional intramedullary rod and vascularized iliac crest graft in atrophic nonunion combined with severe osteoporosis of the femoral shaft in a child, in whom classical osteosynthesis failed after two operations. The conventional intramedullary rod offered excellent purchase in the severely porotic, partially destroyed bone. Combined with a vascularized iliac crest grafted laterally, mechanical support and an osteoinductive stimulus were provided. The atrophic nonunion healed completely after this revision surgery. PMID- 22433957 TI - Hip pathology in Hutchinson-Gilford progeria syndrome: a report of two children. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder. The estimated incidence is one in 4 million births. Orthopaedic manifestations include abnormality of the hips occurring early in the disease process. Severe coxa valga can be apparent by the age of 2 years. We report two cases of HGPS, one in a 7-year-old girl with avascular necrosis of the left hip and the second in a 13-year-old girl with recurrent traumatic hip dislocations. We demonstrate the pathoanatomical changes in the hip with HGPS using a combination of imaging modalities including radiographic, computed tomographic and MRI scans. These include coxa magna, coxa valga and acetabular dysplasia. We also comment on how these would affect the surgical management of this high-risk group of patients. PMID- 22433958 TI - Hip joint pigmented villonodular synovitis in a young girl: a case report. AB - Pigmented villonodular synovitis is a rare condition in children. We report a case of a 7-year-old girl with pigmented villonodular synovitis in her left hip. The diagnosis was confirmed with an arthroscopic hip biopsy. We completed a synovectomy twice for hip pain and were able to control her pain with these surgeries. There was, however, joint space narrowing in the affected hip. In addition, there was early closure of the proximal femoral epiphysis in the affected limb, leading to a discrepancy in leg length. This case report suggests that pigmented villonodular synovitis should be considered in children with a painful hip. PMID- 22433959 TI - Reply to: economic evaluation of second generation pneumococcal conjugate vaccines in Norway. PMID- 22433960 TI - Repeated dose intramuscular injection of the CIMAvax-EGF vaccine in Sprague Dawley rats induces local and systemic toxicity. AB - CIMAvax-EGF consists of a human recombinant epidermal growth factor (EGF), coupled to P64k, a recombinant carrier protein from N. meningitis, and Montanide ISA 51 as adjuvant. The vaccine immunization induces a specific antibody production, inhibiting the EGF/EGF-R interaction through EGF deprivation. The objective of this study was to assess the CIMAvax-EGF toxicity in Sprague Dawley rats after intramuscular administration of repeated doses (6 months) and at the same time to determine if rat is a relevant species for studying CIMAvax-EGF vaccine. Rats were randomly distributed into four groups: control, Montanide ISA 51, treated with 1* and 15* of human total dose of the antigen. Animals were immunized weekly during 9 weeks, plus 9 immunizations every 14 days. Rats were inspected daily for clinical signs. Body weight, food consumption, and rectal temperature were measured during the administration of doses. Blood samples were collected for hematological, serum biochemical determinations and EGF titles at the beginning, three months and at the end of experimentation. Gross necropsy and histological examination of tissues were performed on animals at the end of the assay. Vaccine provoked the apparition of antibodies against EGF in the rats, demonstrating rat species relevance in these studies. Body weight gain, food and water consumption were not affected. CIMAvax-EGF and Montanide ISA 51 produced local damage at the administration site, showing multiple cysts and granulomas. Both vaccine-treated groups showed neutrophil elevation, besides an AST increase probably related to the damage at the administration site. Rectal temperature was found to be significantly higher in 15* treated group after immunizations, probably induced by the inflammatory process at the injection site. In summary, the clinical pathology findings together with the body temperature results, appear to be caused by the inflammatory reaction at the administration site of the vaccine, mainly mediated by the oil-based adjuvant Montanide ISA 51, probably enhanced by the immunological properties of the antigen. This study showed evidences that intramuscular administration during 26 weeks of CIMAvax-EGF at doses up to 15* human total dose is well tolerated in rats and it has a clinical importance since this long lasting study in relevant species allows to treat cancer patients with tumors during long periods with relative weight safety margin. PMID- 22433961 TI - Safety and immunogenicity of a vaccine targeting human papillomavirus types 6, 11, 16 and 18: a randomized, double-blind, placebo-controlled trial in Chinese males and females. AB - In this randomized, double-blind, placebo-controlled trial, 9-15 year old Chinese males (n=100) and 9-45 year old Chinese females (n=500) from Wuzhou, Guangxi, China were randomized (1:1) to receive either quadrivalent HPV vaccine or adjuvant-containing placebo. Blood samples were obtained at day 1 and one month post-dose 3 to determine the level of vaccine-induced antibodies. Among vaccine recipients, high antibody levels were observed for each of the four HPV types and seroconversion was >96%. The vaccine was generally well tolerated, with no vaccine-related serious adverse events. This study demonstrated that the quadrivalent HPV vaccine is highly immunogenic and generally well tolerated among Chinese males and females. PMID- 22433962 TI - Quantitative evaluation of the effect of the hepatitis B vaccine based on the HBsAg- and anti-HBs-positive rates in the Chinese population over the last 33 years. AB - OBJECTIVE: The purpose of the study was to quantitatively evaluate the effect of the hepatitis B vaccine based on 33 years of data published on the HBsAg- and anti-HBs-positive rates. METHODS: All data were obtained from studies in published Chinese scientific journals from 1977 to 2009. The HBsAg- or anti-HBs positive rate over a certain observation period was presented. RESULTS: When the anti-HBs-positive rate was low, the ability of anti-HBs to control the HBsAg positive rate is not apparent. When the anti-HBs level is high, the ability of anti-HBs to control the HBsAg-positive rate increases gradually, and a linear relationship was observed between the HBsAg-positive rate and the anti-HBs positive rate. However, the rate of decrease of HBsAg positivity was markedly higher than the theoretical rate. CONCLUSION: The effect of other known or unknown factors, in addition to the vaccination campaign, could have contributed to the decrease in the prevalence of HBV infection. PMID- 22433965 TI - A novel, externally validated inflammation-based prognostic algorithm in hepatocellular carcinoma: the prognostic nutritional index (PNI). AB - BACKGROUND: There is increasing evidence that the presence of an ongoing systemic inflammatory response is a stage-independent predictor of poor outcome in patients with cancer. The aim of this study was to investigate whether an inflammation-based prognostic score, the prognostic nutritional index (PNI), is associated with overall survival (OS) in patients with hepatocellular carcinoma (HCC). METHODS: All patients with a new diagnosis of HCC presenting to the Medical Oncology Department, Hammersmith Hospital between 1993 and 2011 (n=112) were included. Demographic and clinical data were collected. Patients in whom the combined albumin (g l(-1)) * total lymphocyte count * 10(9) l(-1) was >=45, at presentation, were allocated a PNI score of 0. Patients in whom this total score was <45 were allocated a score of 1. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with OS. Independent predictors of survival identified on multivariate analysis were validated in an independent, stage-matched cohort of 68 patients. RESULTS: Univariate analyses showed that PNI (P=0.003), intrahepatic spread (P<0.001), the presence of extrahepatic disease (P=0.006), portal vein thrombosis (P=0.02), tumour multifocality (P=0.003), alfa-fetoprotein >400 ng ml(-1) (P<0.001) and Barcelona Clinic Liver Cancer score (P<0.01) were all predictors of OS in the training set. Multivariate analysis revealed the PNI (P=0.05), presence of extrahepatic disease (P<0.001) and degree of intrahepatic spread (P<0.001) as independent predictors of worse OS in this population. The PNI retained independent prognostic value in the validation set (P<0.001). CONCLUSION: The presence of a systemic inflammatory response, as measured by the PNI, is an independent and externally validated predictor of poor OS in patients with HCC. PMID- 22433966 TI - Loss of partner and breast cancer prognosis - a population-based study, Denmark, 1994-2010. AB - BACKGROUND: The extent to which experiencing a stressful life event influences breast cancer prognosis remains unknown, as the findings of the few previous epidemiological studies are inconsistent. This large population-based study examines the association between a common major life event, loss of a partner and breast cancer recurrence and all-cause mortality. METHODS: N=21,213 women diagnosed with a first primary breast cancer 1994-2006, who had a cohabiting partner in the 4 years before their breast cancer diagnosis, were followed for death and recurrence in population-based registers and clinical databases. Information on education, disposable income, comorbidity and prognostic risk factors were included in Cox regression analyses. RESULTS: Women who had lost a partner either before diagnosis or in subsequent years were not at significantly higher risk of recurrence or dying than women who had not lost a partner. CONCLUSION: Our results do not support the concern that experiencing a stressful life event, the loss of a partner, negatively affects prognosis of breast cancer. PMID- 22433967 TI - High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancer. AB - BACKGROUND: Lin28 is a negative regulator of the tumour suppressor microRNA, let 7, suggesting its role in tumourigenesis. However, the clinical significance of Lin28 expression in oesophageal cancer has not been elucidated. METHODS: Lin28 and Lin28B expression was examined by immunohistochemistry in 161 tissues from patients with oesophageal cancer who had undergone curative surgery. The relationship between the expressions of Lin28 and Lin28B and various clinicopathological factors was examined. In vitro assays were conducted to determine the role of Lin28 in aggressiveness of oesophageal cancers using oesophageal cancer cell line. RESULTS: Lin28 and Lin28B were overexpressed in oesophageal cancer cells compared with non-cancerous epithelial cells, especially in the invasive front. High expression of Lin28 and Lin28B correlated significantly with lymph node metastasis and poor prognosis. High expression of Lin28B expression correlated significantly with low expression of let-7. Multivariate analysis also identified Lin28B expression as an independent prognostic factor. In vitro assays showed that the proliferative and invasive activities were significantly reduced in Lin28B-knockdown cells, compared with control cells. CONCLUSION: High expression of Lin28 is associated with poor prognosis and high tumour aggressiveness in oesophageal cancer and these effects are mediated through increased proliferation and invasiveness of oesophageal cancer cells. PMID- 22433968 TI - Serum matrix metalloproteinase 9 and colorectal neoplasia: a community-based evaluation of a potential diagnostic test. AB - BACKGROUND: A blood test may be a more acceptable routine colorectal cancer (CRC) screening test than faecal occult blood test, flexible sigmoidoscopy or colonoscopy, and could be safer and cheaper. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test for CRC in a non-presenting symptomatic population. METHODS: A cohort, aged 50-69 with lower gastrointestinal symptoms, was identified by community-based survey. Accuracy of serum MMP9 was assessed by comparison with colonoscopy. Logistic regression identified predictors of neoplasia and receiver operating characteristic curve analyses determined the cutoff to maximise the sensitivity. RESULTS: Data were available for 748 patients. Overall, 46 cases of neoplasia were identified. Univariate analysis demonstrated that demographic characteristics, behavioural factors, clinical symptoms and raised serum MMP9 concentration were all significantly associated with the presence of neoplasia. Our final logistic regression model had a sensitivity of 79% and specificity of 70%. CONCLUSION: We demonstrated a significant association between serum MMP9 concentration and the presence of neoplasia. Serum MMP9 levels are raised in those with cancer and high-risk adenomas, although MMP9 estimation is likely to have the greatest predictive utility when used as part of a panel of biomarkers. Further work is required to identify biomarkers that are sufficiently accurate for implementing into routine practice. PMID- 22433969 TI - Application of MassSQUIRM for quantitative measurements of lysine demethylase activity. AB - Recently, epigenetic regulators have been discovered as key players in many different diseases (1-3). As a result, these enzymes are prime targets for small molecule studies and drug development( 4). Many epigenetic regulators have only recently been discovered and are still in the process of being classified. Among these enzymes are lysine demethylases which remove methyl groups from lysines on histones and other proteins. Due to the novel nature of this class of enzymes, few assays have been developed to study their activity. This has been a road block to both the classification and high throughput study of histone demethylases. Currently, very few demethylase assays exist. Those that do exist tend to be qualitative in nature and cannot simultaneously discern between the different lysine methylation states (un-, mono-, di- and tri-). Mass spectrometry is commonly used to determine demethylase activity but current mass spectrometric assays do not address whether differentially methylated peptides ionize differently. Differential ionization of methylated peptides makes comparing methylation states difficult and certainly not quantitative (Figure 1A). Thus available assays are not optimized for the comprehensive analysis of demethylase activity. Here we describe a method called MassSQUIRM (mass spectrometric quantitation using isotopic reductive methylation) that is based on reductive methylation of amine groups with deuterated formaldehyde to force all lysines to be di-methylated, thus making them essentially the same chemical species and therefore ionize the same (Figure 1B). The only chemical difference following the reductive methylation is hydrogen and deuterium, which does not affect MALDI ionization efficiencies. The MassSQUIRM assay is specific for demethylase reaction products with un-, mono- or di-methylated lysines. The assay is also applicable to lysine methyltransferases giving the same reaction products. Here, we use a combination of reductive methylation chemistry and MALDI mass spectrometry to measure the activity of LSD1, a lysine demethylase capable of removing di- and mono-methyl groups, on a synthetic peptide substrate (5). This assay is simple and easily amenable to any lab with access to a MALDI mass spectrometer in lab or through a proteomics facility. The assay has ~8-fold dynamic range and is readily scalable to plate format (5). PMID- 22433970 TI - VEGF-induced growth cone enhancement is diminished by inhibiting tyrosine-residue 1214 of VEGFR-2. AB - Axonal outgrowth is of paramount significance for establishing the intricate neuronal network both during embryogenesis and nerve regeneration. Vascular endothelial growth factor (VEGF), which is known for its essential role in vascular sprouting and its involvement in cancer, has recently been found to exert a trophic activity on neurons leading to an increased axonal outgrowth. Although two receptors, VEGFR-2 and neuropilin-1, were identified on neurons, the signaling pathways associated with them are not well understood. The aim of this study was to analyze the influence of VEGF on the growth cone morphology and motility of dorsal root ganglia (DRG) neurons. Moreover, we aimed for a deeper understanding of VEGFR-2 on growth cones that potentially mediates the stimulating and attractive effects. We cultivated chicken DRG in medium containing mouse VEGF and analyzed growth cone size. The data presented here show a positive effect of VEGF on growth cone size. Furthermore, we interrupted the activity of VEGFR-2 by either blocking the tyrosine residue 1214 (tyr1214) or by inhibiting the receptor phosphorylation with axitinib, a novel small molecule, which has recently entered phase III trials for cancer treatment. Disruption of the VEGFR-2 leads to a significantly diminished growth cone size. Based on these findings, we propose a positive effect of VEGF on peripheral nervous system growth cone size and show for the first time quantitative data to underline this hypothesis. Additionally, we propose that VEGFR-2 and especially the tyr1214 dependent pathway of VEGFR-2 are of importance in VEGF signaling in the growth cone of DRG neurons. PMID- 22433971 TI - Prevalence of dementia in Al Kharga District, New Valley Governorate, Egypt. AB - BACKGROUND: With aging, there is a parallel increase in the prevalence of dementia worldwide. The aim of this work is to determine the prevalence of dementia among the population of Al Kharga District, New Valley, Egypt. METHODS: Screening of all subjects aged >=50 years (n = 8,173 out of 62,583 inhabitants) was done through a door-to-door survey by 3 neurologists, using a short standardized Arabic screening test and a modified Mini-Mental State Examination. Suspected cases were subjected to full clinical examination, psychometric assessment using the Cognitive Abilities Screening Instrument, Instrumental Activities of Daily Living Scale, Geriatric Depression Scale, Hachinski Ischemic Score, DSM-IV-TR diagnostic criteria, neuroimaging, and laboratory investigations, when indicated. RESULTS: The prevalence rate of dementia was 2.26% for the population aged >=50 years. It increased steeply with age to a maximum of 18.48% for those aged >=80 years. Alzheimer's disease (51.2%) was the most common subtype, followed by vascular dementia (28.7%), dementia due to general medical conditions (12.8%), and lastly dementia due to multiple etiologies (7.3%). Mild dementia was the commonest (53.7%). CONCLUSION: Dementia is prevalent in Egypt as elsewhere. Detection through a door-to-door survey is the best method in developing countries for early detection of mild cases. PMID- 22433972 TI - Microchip electrophoresis of oligosaccharides using lectin-immobilized preconcentrator gels fabricated by in situ photopolymerization. AB - A lectin-impregnated gel was fabricated at the channel crossing point in a microfluidic chip made from polymethyl methacrylate (PMMA). The acrylamide containing lectin was photopolymerized to form a round gel (radius 60 MUm) by irradiation with an argon laser, which was also used for fluorometric detection. This gel was applied to specific concentration, elution, and electrophoretic separation of fluorescent-labeled oligosaccharides. Because the lectin in the polyacrylamide gel was mechanically immobilized, it maintained its activity. The lectin was used to trap up to a few tens of femtomoles of specific oligosaccharides labeled with 8-aminopyrene-1,3,6-trisulfonic acid with 2 min by a factor >800, and the amount trapped corresponded to ca. 70% of lectin in the gel. The trapped oligosaccharides were released from the gel by lowering the pH with an acidic background electrolyte. The oligosaccharides that eluted as a broad band were concentrated by transient isotachophoresis stacking using concentrated sodium borate buffer (pH 11.0). The stacked sample components were then separated and fluorometrically detected at the end of the separation channel. Under the optimized conditions, resolution of the saccharides was good, and was similar to that obtained by pinched injection. The method was applied to preconcentration and analysis of oligosaccharides derived from some glycoproteins. PMID- 22433973 TI - Clinicopathological features of serrated adenocarcinoma defined by Makinen in dukes' B colorectal carcinoma. AB - OBJECTIVE: Serrated adenocarcinoma (SAC), proposed as a new pathologic type, arises predominantly in the right side of the colon and has a poorer prognosis than conventional colorectal carcinoma. The prognosis of colorectal carcinoma is variable in Dukes' B, so the aim of this study was to determine whether or not SAC has a poor prognosis in Dukes' B. METHODS: The study group comprised 64 patients who underwent surgery for colorectal carcinoma. We undertook a statistical analysis of the association of SAC and non-SAC with sex, age, histologic type, depth of tumor, location of tumor, venous invasion and lymphatic invasion. RESULTS: SACs were encountered in 17.5% of cases (n = 11). SAC had a less favorable 5-year survival than non-SAC (p = 0.0396 log-rank, Kaplan-Meier). The factors that achieved statistical significance in the univariate analysis were subsequently included in a multivariate analysis and we found that SAC was an independent factor (p = 0.027). CONCLUSIONS: SAC has a poor prognosis and is not affected by other factors confirming that SAC is an independently less favorable prognostic factor. PMID- 22433974 TI - Small molecule solar cells based on a series of water-soluble zinc phthalocyanine donors. AB - Organic solar cells based on a series of water-soluble zinc phthalocyanines (wsZnPc) with varying numbers of sulfonate peripheral substituents and a C60 donor have been fabricated and characterised. We find that the number of substituents affects both the V(oc) and J(sc) of the devices, with the disulfonated wsZnPc devices performing best. PMID- 22433975 TI - The difference in blood pressure readings between arms and survival: primary care cohort study. AB - OBJECTIVE: To determine whether a difference in systolic blood pressure readings between arms can predict a reduced event free survival after 10 years. DESIGN: Cohort study. SETTING: Rural general practice in Devon, United Kingdom. PARTICIPANTS: 230 people receiving treatment for hypertension in primary care. INTERVENTION: Bilateral blood pressure measurements recorded at three successive surgery attendances. MAIN OUTCOME MEASURES: Cardiovascular events and deaths from all causes during a median follow-up of 9.8 years. RESULTS: At recruitment 24% (55/230) of participants had a mean interarm difference in systolic blood pressure of 10 mm Hg or more and 9% (21/230) of 15 mm Hg or more; these differences were associated with an increased risk of all cause mortality (adjusted hazard ratio 3.6, 95% confidence interval 2.0 to 6.5 and 3.1, 1.6 to 6.0, respectively). The risk of death was also increased in 183 participants without pre-existing cardiovascular disease with an interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more (2.6, 1.4 to 4.8 and 2.7, 1.3 to 5.4). An interarm difference in diastolic blood pressure of 10 mm Hg or more was weakly associated with an increased risk of cardiovascular events or death. CONCLUSIONS: Differences in systolic blood pressure between arms can predict an increased risk of cardiovascular events and all cause mortality over 10 years in people with hypertension. This difference could be a valuable indicator of increased cardiovascular risk. Bilateral blood pressure measurements should become a routine part of cardiovascular assessment in primary care. PMID- 22433976 TI - Differences in blood pressure between arms. PMID- 22433977 TI - Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: This analysis was conducted to determine the efficacy of extracted or synthesized soybean isoflavones in the alleviation of hot flashes in perimenopausal and postmenopausal women. METHODS: PubMed and The Cochrane Controlled Clinical Trials Register Database were searched for relevant articles reporting double-blinded randomized controlled trials through December 14, 2010. References within identified articles, as well as peer-reviewed articles that had come to the attention of the authors through other means, were also examined for suitability. This systematic review and meta-analysis, which evaluated the effects of isoflavones on the frequency, severity, or composite score (frequency * severity) of hot flashes compared with placebo was conducted according to Cochrane Handbook guidelines. RESULTS: From 277 potentially relevant publications, 19 trials (reported in 20 articles) were included in the systematic review (13 included hot flash frequency; 10, severity; and 3, composite scores), and 17 trials were selected for meta-analyses to clarify the effect of soybean isoflavones on hot flash frequency (13 trials) and severity (9 trials). Meta analysis revealed that ingestion of soy isoflavones (median, 54 mg; aglycone equivalents) for 6 weeks to 12 months significantly reduced the frequency (combined fixed-effect and random effects model) of hot flashes by 20.6% (95% CI, -28.38 to -12.86; P < 0.00001) compared with placebo (heterogeneity P = 0.0003, I = 67%; random effects model). Meta-analysis also revealed that isoflavones significantly reduced hot flash severity by 26.2% (95% CI: -42.23 to -10.15, P = 0.001) compared with placebo (heterogeneity, P < 0.00001, I = 86%; random effects model). Isoflavone supplements providing more than 18.8 mg of genistein (the median for all studies) were more than twice as potent at reducing hot flash frequency than lower genistein supplements. CONCLUSIONS: Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash frequency, and treatment duration. PMID- 22433978 TI - Effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes: a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to determine the effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes. METHODS: A randomized, blinded, multicenter, placebo-controlled parallel-group 8-week trial with 205 women (95 African American, 102 white, 8 other) was conducted between July 2009 and June 2010. The participants received escitalopram (10-20 mg/d) or placebo. Insomnia symptoms (Insomnia Severity Index [ISI]) and subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at weeks 4 and 8 were the prespecified secondary outcomes. A total of 199 women (97%) provided ISI data, and 194 (95%) women provided PSQI data at follow-up. RESULTS: At baseline, mean hot flash frequency was 9.78 per day (SD, 5.60), mean ISI was 11.4 (SD, 6.3), and mean PSQI was 8.0 (SD, 3.7). Treatment with escitalopram reduced ISI at week 8 (mean difference, 2.00; 95% CI, -3.43 to -0.57; P < 0.001 overall treatment effect), with mean differences of -4.73 (95% CI, -5.72 to -3.75) in the escitalopram group and -2.73 (95% CI, -3.78 to -1.69) in the placebo group. The reduction in PSQI was greater in the escitalopram than in the placebo group at week 8 (mean difference, -1.31; 95% CI, -2.14 to -0.49; P < 0.001 overall treatment effect). Clinical improvement in insomnia symptoms and subjective sleep quality (>=50% decreases in ISI and PSQI from baseline) was observed more frequently in the escitalopram group than in the placebo group (ISI, 50.0% vs 35.4%, P = 0.04; PSQI, 29.6% vs 19.2%, P = 0.09). CONCLUSIONS: Among healthy perimenopausal and postmenopausal women with hot flashes, escitalopram at 10 to 20 mg/day compared with placebo reduced insomnia symptoms and improved subjective sleep quality at 8 weeks of follow-up. PMID- 22433979 TI - Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands. AB - Sigma1 receptors (Sigma1R) are intracellular chaperone proteins that bind psychotropic drugs and also clinically used drugs such as ketamine and haloperidol. Co-expression of the Sigma1R has been reported to enhance the sensitivity of several voltage-gated ion channels to Sigma1R ligands. Kv1.3 is the predominant voltage-gated potassium channel expressed in T lymphocytes with a documented role in immune activation. To gain a better understanding of Sigma1R modulation of Kv ion channels, we investigated the effects of Sigma1R co expression on Kv1.3 physiology and pharmacology in ion channels expressed in Xenopus oocytes. We also explored the protein domains of Kv1.3 necessary for protein:protein interaction between Kv1.3 and Sigma1R through co immunoprecipitation studies. Slowly inactivating outward-going currents consistent with Kv1.3 expression were elicited on step depolarizations. The current characterized by E(rev), V(1/2), and slope factor remained unchanged when co-expressed with Sigma1R. Analysis of inactivation time constant revealed a faster Kv1.3 current decay when co-expressed with Sigma1R. However the sensitivity to Sigma1R ligands remained unaltered when co-expressed with the Sigma1R in contrast to the previously reported modulation of ligand sensitivity in closely related Kv1.4 and Kv1.5 voltage gated potassium channels. Co immunoprecipitation assays of various Kv1.3 truncation constructs indicated that the transmembrane domain of the Kv1.3 protein was responsible for the protein:protein interaction with the Sigma1R. Sigma1R likely interacts with different domains of Kv ion channel family proteins resulting in distinct modulation of different channels. PMID- 22433980 TI - The use of tacit and explicit knowledge in public health: a qualitative study. AB - BACKGROUND: Planning a public health initiative is both a science and an art. Public health practitioners work in a complex, often time-constrained environment, where formal research literature can be unavailable or uncertain. Consequently, public health practitioners often draw upon other forms of knowledge. METHODS: Through use of one-on-one interviews and focus groups, we aimed to gain a better understanding of how tacit knowledge is used to inform program initiatives in public health. This study was designed as a narrative inquiry, which is based on the assumption that we make sense of the world by telling stories. Four public health units were purposively selected for maximum variation, based on geography and academic affiliation. RESULTS: Analysis revealed different ways in which tacit knowledge was used to plan the public health program or initiative, including discovering the opportunity, bringing a team together, and working out program details (such as partnering, funding). CONCLUSIONS: The findings of this study demonstrate that tacit knowledge is drawn upon, and embedded within, various stages of the process of program planning in public health. The results will be useful in guiding the development of future knowledge translation strategies for public health organizations and decision makers. PMID- 22433981 TI - A simplified PCR-based method for detection of gray coat color allele in horse. AB - Coat color of gray horses is associated with a 4.6-kb duplication, which can be determined using PCR amplification of about 5-kb DNA fragment. In practice, this means that amplification might fail frequently. Therefore, a novel genetic screening method based on amplification of the 246 bp DNA fragment has been developed. PMID- 22433982 TI - A case of canine chimerism diagnosed using coat color tests. AB - Through the use of PCR based coat color tests, we were able to diagnose a dog that exhibits an unusual coat color phenotype as an XX/XX chimera. Coat color alleles vary widely among dog breeds, presenting a novel method for detecting chimerism using diagnostic tests for known coat color alleles. PMID- 22433983 TI - Fragrance material review on ethyl phenyl carbinyl acetate. AB - A toxicologic and dermatologic review of ethyl phenyl carbinyl acetate when used as a fragrance ingredient is presented. Ethyl phenyl carbinyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for ethyl phenyl carbinyl acetate were evaluated, then summarized, and includes: physical properties; acute toxicity; skin irritation; and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances. PMID- 22433984 TI - Toxicological effects of red wine, orange juice, and other dietary SULT1A inhibitors via excess catecholamines. AB - SULT1A enzymes protect humans from catecholamines, but natural substances in many foods have been found to inhibit these enzymes in vitro. Given the hormonal roles of catecholamines, any in vivo SULT1A inhibition could have serious consequences. This paper uses a re-analysis of published data to confirm that SULT1A inhibitors have effect in vivo in at least some patients. Nineteen studies are cited that show ingestion of SULT1A inhibitors leading to catecholamine increases, blood pressure changes, migraine headaches, or atrial fibrillation. SULT1A inhibition does not create the catecholamines, but prevents normal catecholamine deactivation. Susceptible patients probably have lower-activity SULT1A alleles. The paper discusses new hypotheses that SULT1A inhibition can cause "holiday heart" arrhythmias and type 2 diabetes in susceptible patients. Subgroup analysis based on SULT1A alleles, and addition of a catecholamine source, should improve the consistency of results from tests of SULT1A inhibitors. SULT1A inhibition may be a key contributor to cheese-induced migraines (via annatto), false positives in metanephrine testing, and the cardiovascular impacts of recreational alcohols. PMID- 22433985 TI - Use of advanced techniques for the extraction of phenolic compounds from Tunisian olive leaves: phenolic composition and cytotoxicity against human breast cancer cells. AB - A comparison among different advanced extraction techniques such as microwave assisted extraction (MAE), supercritical fluid extraction (SFE) and pressurized liquid extraction (PLE), together with traditional solid-liquid extraction, was performed to test their efficiency towards the extraction of phenolic compounds from leaves of six Tunisian olive varieties. Extractions were carried out at the best selected conditions for each technique; the obtained extracts were chemically characterized using high-performance liquid chromatography (HPLC) coupled to electrospray time-of-flight mass spectrometry (ESI-TOF-MS) and electrospray ion trap tandem mass spectrometry (ESI-IT-MS(2)). As expected, higher extraction yields were obtained for PLE while phenolic profiles were mainly influenced by the solvent used as optimum in the different extraction methods. A larger number of phenolic compounds, mostly of a polar character, were found in the extracts obtained by using MAE. Best extraction yields do not correlate with highest cytotoxic activity against breast cancer cells, indicating that cytotoxicity is highly dependent on the presence of certain compounds in the extracts, although not exclusively on a single compound. Therefore, a multifactorial behavior is proposed for the anticancer activity of olive leaf compounds. PMID- 22433986 TI - Nanocavities and germanium nanocrystals produced by Ge ion implantation in fused silica. AB - High-resolution SEM images of germanium nanocrystals (Ge-nc) synthesized by ion implantation in fused silica samples annealed at temperatures below and above the melting point of Ge show a strong size-selective depth-distribution of nanostructures, as evidenced by the correlation between the dimension of the observed objects and the local concentration of implanted Ge measured by Rutherford backscattering spectroscopy (RBS). Whereas the Ge-nc nucleation seems to obey the Ostwald ripening process in samples annealed below 900 degrees C, Ge desorption effects, non-uniform in depth, in conjunction with the formation of large and spherical nanocavities, become dominant for annealing performed above the solid-liquid phase transition of Ge. Measurements for different annealing times at 1050 degrees C show two distinct processes in the Ge desorption dynamics: the first is related to direct Ge outgassing effects during the nucleation of Ge-nc, which occurs within the first minutes of the thermal annealing, while the second is due to the release of Ge from Ge-nc, associated with the formation of nanocavities. The formation rate of these nanocavities is more efficient at greater depth than in the vicinity of the sample surface. It appears to be strongly dependent on the local concentration of defects, responsible for the reduction of the Ge diffusion, and to be related to the breaking of Ge-O and Si-Ge bonds at the Ge-nc/SiO(2) interface. PMID- 22433987 TI - Likert pain score modeling: a Markov integer model and an autoregressive continuous model. AB - Pain intensity is principally assessed using rating scales such as the 11-point Likert scale. In general, frequent pain assessments are serially correlated and underdispersed. The aim of this investigation was to develop population models adapted to fit the 11-point pain scale. Daily Likert scores were recorded over 18 weeks by 231 patients with neuropathic pain from a clinical trial placebo group. An integer model consisting of a truncated generalized Poisson (GP) distribution with Markovian transition probability inflation was implemented in NONMEM 7.1.0. It was compared to a logit-transformed autoregressive continuous model with correlated residual errors. In both models, the score baseline was estimated to be 6.2 and the placebo effect to be 19%. Developed models similarly retrieved consistent underlying features of the data and therefore correspond to platform models for drug effect detection. The integer model was complex but flexible, whereas the continuous model can more easily be developed, although requires longer runtimes. PMID- 22433988 TI - Secretion of the housekeeping protein glyceraldehyde-3-phosphate dehydrogenase by the LEE-encoded type III secretion system in enteropathogenic Escherichia coli. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional housekeeping protein secreted by pathogens and involved in adhesion and/or virulence. Previously we reported that enterohemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli secrete GAPDH into the culture medium. This bacterial protein binds human plasminogen and fibrinogen and remains associated with Caco-2 cells upon infection. In these pathogens, GAPDH secretion is not linked to outer membrane vesicles and depends on growth conditions, although the secretion mechanism is still unknown. EPEC is an attaching and effacing pathogen able to secrete and translocate multiple effector proteins into infected cells through a type III secretion system (T3SS). The secretion process is often dependent on a bacterial chaperone. The chaperone CesT displays broad substrate specificity and plays a central role in the recruitment of multiple type III effectors to the T3SS apparatus. Here we provide genetic evidences on GAPDH secretion through T3SS by EPEC grown in DMEM. Secretion of GAPDH is increased in DeltasepD mutants and abolished in mutants defective in the type III ATPase EscN. Complementation with escN gene restores GAPDH secretion. In addition, we prove by means of pull down experiments, overlay immunoblotting and biolayer interferometry a novel interaction between GAPDH and the chaperone CesT. This interaction, which is strong and slow dissociating, may stabilize a population of GAPDH molecules in a secretion competent-state and target them to the type III secretion apparatus. This is the first description of CesT interaction with a housekeeping protein and its export through T3SS. PMID- 22433989 TI - LewisX: a neural stem cell specific glycan? AB - LewisX (LeX) detecting antibodies are routinely used for cell sorting of neural stem- and progenitor cells (NSPCs). Applications include the enrichment of NSPCs after neural differentiation of human induced pluripotent- or embryonic stem cells, as well as their direct isolation from mouse neural tissue. Nevertheless, only little is known about the role of LeX in the central nervous system. Here we review the current knowledge on LeX-containing glycans expressed by neural stem cells and their progeny. New LeX-carrier proteins and ligands have recently been identified which reveal further insights into the potential function(s) of LeX glycans. Moreover, evidence accumulates that individual LeX detecting antibody clones vary in their suitability as neural stem cell specific biomarker. Each antibody clone detects a unique LeX-containing glycan epitope. This allows a versatile utilization of anti-LeX antibodies that goes beyond neural stem cell sorting applications. PMID- 22433990 TI - Wnt signaling from membrane to nucleus: beta-catenin caught in a loop. AB - beta-catenin is the central nuclear effector of the Wnt signaling pathway, and regulates other cellular processes including cell adhesion. Wnt stimulation of cells culminates in the nuclear translocation of beta-catenin and transcriptional activation of target genes that function during both normal and malignant development. Constitutive activation of the Wnt pathway leads to inappropriate nuclear accumulation of beta-catenin and gene transactivation, an important step in cancer progression. This has generated interest in the mechanisms regulating beta-catenin nuclear accumulation and retention. Here we discuss recent advances in understanding feedback loops that trap beta-catenin in the nucleus and provide potential insights into Wnt signaling and the development of anti-cancer drugs. PMID- 22433991 TI - Alginate microcapsule as a 3D platform for propagation and differentiation of human embryonic stem cells (hESC) to different lineages. AB - Human embryonic stem cells (hESC) are emerging as an attractive alternative source for cell replacement therapy since they can be expanded in culture indefinitely and differentiated to any cell types in the body. Various types of biomaterials have also been used in stem cell cultures to provide a microenvironment mimicking the stem cell niche(1-3). The latter is important for promoting cell-to-cell interaction, cell proliferation, and differentiation into specific lineages as well as tissue organization by providing a three-dimensional (3D) environment(4) such as encapsulation. The principle of cell encapsulation involves entrapment of living cells within the confines of semi-permeable membranes in 3D cultures(2). These membranes allow for the exchange of nutrients, oxygen and stimuli across the membranes, whereas antibodies and immune cells from the host that are larger than the capsule pore size are excluded(5). Here, we present an approach to culture and differentiate hESC DA neurons in a 3D microenvironment using alginate microcapsules. We have modified the culture conditions(2) to enhance the viability of encapsulated hESC. We have previously shown that the addition of p160-Rho-associated coiled-coil kinase (ROCK) inhibitor, Y-27632 and human fetal fibroblast-conditioned serum replacement medium (hFF-CM) to the 3D platform significantly enhanced the viability of encapsulated hESC in which the cells expressed definitive endoderm marker genes(1). We have now used this 3D platform for the propagation of hESC and efficient differentiation to DA neurons. Protein and gene expression analyses after the final stage of DA neuronal differentiation showed an increased expression of tyrosine hydroxylase (TH), a marker for DA neurons, >100 folds after 2 weeks. We hypothesized that our 3D platform using alginate microcapsules may be useful to study the proliferation and directed differentiation of hESC to various lineages. This 3D system also allows the separation of feeder cells from hESC during the process of differentiation and also has potential for immune isolation during transplantation in the future. PMID- 22433993 TI - Renal autotransplantation as savior in hybrid surgery for aortic aneurysm repair. AB - Renal autotransplantation is a safe and effective procedure to reconstruct the urinary tract. The current indications for autotransplantation include renal vascular disease, severe ureteral damage, tumours of the kidney and ureter, complex nephrolithiasis and retroperitoneal fibrosis. We report a rare case where we had to perform renal autotransplantation along with hybrid surgery for aortic aneurysm repair. To our knowledge, this is the first case report of its kind for this specific condition. PMID- 22433994 TI - Objective measures of physical functional capacity warrant exploration to complement or replace the subjective physician estimated performance status. AB - Performance status, a measure of physical functioning, can be influenced by several undefined physician and patient-related factors, and is inherently subjective. Although disappointing results in phase 3 trials may reflect a lack of improved outcomes due to biological mechanisms, a confounding effect of imbalances of physical functioning cannot be excluded in the context of modest increments in antitumor activity. Therefore, performance status estimation may complicate drug development, and an objective measure of physical reserve is desirable and may complement or outperform performance status. We explore and discuss attractive candidates for objective measures of physical functioning. PMID- 22433995 TI - ACR Appropriateness Criteria(r) local-regional recurrence (LR) and salvage surgery: breast cancer. AB - Despite the success of both breast conserving surgery and mastectomy, some women will experience a local-regional recurrence (LRR) of their breast cancer. Predictors for LRR after breast-conserving therapy or mastectomy have been identified, including patient, tumor, and treatment-related factors. The role of surgery, radiation, and chemotherapy as treatment has evolved over time and many patients now have the potential for salvage after LRR. This review of LRR of breast cancer and management recommendations, including the use of common clinical scenarios, represents a compilation of evidence-based data and expert opinion of the American College of Radiology Appropriateness Criteria Expert Panel on local-regional recurrence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 22433996 TI - Trastuzumab-induced cardiotoxicity: is it time for troponin for all patients? PMID- 22433997 TI - The role of crustacean fisheries and aquaculture in global food security: past, present and future. AB - The 1996 World Food Summit defined food security as "Food security exists when all people, at all times, have physical and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life". This paper looks at the status of production from both shrimp capture fisheries and shrimp aquaculture, as well as trade, in order to understand the contribution of the crustacean sector to overall fish production and thus to global food security. This paper also examines some sustainability issues that will potentially affect the contribution of the crustacean sector (particularly shrimp) to food security. These include sustainable shrimp capture fisheries, sustainable shrimp trade and sustainable shrimp aquaculture. The paper concludes that crustaceans are an important source of aquatic food protein. Production (as food and ornamental) and trade are extremely important for developing countries. It provides both economic development and empowerment in terms of contribution to GDP, consumption, employment, catch value and exports. The crustacean sector generates high value export products which enables producers to buy lower value products in the world market - thus a positive contribution to food security in both producing and exporting countries. PMID- 22433998 TI - Advances in our understanding of the global diversity and distribution of Hematodinium spp. - significant pathogens of commercially exploited crustaceans. AB - Hematodinium species are parasitic dinoflagellates known to infect a growing number of marine crustacean genera from around the world, many of which support important commercial fisheries. Affected hosts undergo dramatic pathological alterations to their organs, tissues and hemolymph. There are no known control measures for this disease. Economically important wild fished hosts known to be susceptible to Hematodinium spp. include Tanner crabs Chionoecetes bairdi and snow crabs Chionoecetes opilio in the Northeast Pacific and Atlantic Oceans, blue crabs Callinectes sapidus from the Atlantic and Gulf coasts of the United States, and Norway lobsters Nephrops norvegicus and Edible crabs Cancer pagurus from European waters. In recent years, several farmed aquatic crustaceans in China have also been negatively impacted by Hematodinium-associated diseases, likely representing an emerging issue for that expanding industry. Molecular sequence data indicates that there are two species, Hematodinium perezi, and a second species, currently unnamed, infecting hosts from the Northern Hemisphere. Three subtly different H. perezi genotypes have been identified infecting hosts from different geographical locations: the English Channel, the eastern seaboard of the United States and Gulf of Mexico, and eastern China. Genotypic variability between isolates of the Hematodinium sp. infecting hosts from the North Atlantic and North Pacific has also been reported, though it is unclear whether there is any correlation with host or location. Identification of Hematodinium species (and genotypes of H. perezi) is largely dependent upon geographical location, rather than host species. However this is not exclusive, as both Hematodinium species can be found infecting multiple species from same location, as is the case in the English Channel. PMID- 22433999 TI - Ensuring crustacean product quality in the post-harvest phase. AB - Recent studies of the fisheries for the Norway lobster, Nephrops norvegicus (L.), have illustrated the negative effects of pathogens and of the physiological stresses of capture processes on the exploitation of live animals and their products, and have identified mitigating measures. Firstly, having established that trawl capture of N. norvegicus is highly stressful, but that these animals have powerful physiological mechanisms of recovery, procedures for on-board recovery of animals destined for vivier transport to distant European markets have been implemented commercially, with significant improvements in survival rates. Such procedures also mitigate against the initiation of a stress-induced muscle necrosis. Secondly, measurements of post-mortem autolytic and spoilage processes have identified the existence of a post-capture 'handling window' of several hours which allows the whole or tailed products to be preserved, by icing or freezing, without detriment to quality. Commercial consortia of Scottish fishermen are exploiting this opportunity to extend product shelf-life by freezing at sea within this handling window. Thirdly, the well-documented infections of Scottish N. norvegicus populations by the dinoflagellate Hematodinium sp. not only provide examples of pathogen-induced mortality, but also have effects on post-harvest products including vivier transport losses and changes in post-mortem degradation leading to earlier organoleptic rejection. Under commercial conditions these effects can be mitigated by post-capture visual screening, but only during the periods of peak patent infection when parasitised animals are visually identifiable. Wider implementation of such mitigating procedures during the harvesting of wild-caught crustaceans will contribute to a more sustainable exploitation of these valuable marine resources. PMID- 22434000 TI - Historic emergence, impact and current status of shrimp pathogens in the Americas. AB - Shrimp farming in the Americas began to develop in the late 1970s into a significant industry. In its first decade of development, the technology used was simple and postlarvae (PLs) produced from wild adults and wild caught PLs were used for stocking farms. Prior to 1990, there were no World Animal Health Organization (OIE) listed diseases, but that changed rapidly commensurate with the phenomenal growth of the global shrimp farming industry. There was relatively little international trade of live or frozen commodity shrimp between Asia and the Americas in those early years, and with a few exceptions, most of the diseases known before 1980 were due to disease agents that were opportunistic or part of the shrimps' local environment. Tetrahedral baculovirosis, caused by Baculovirus penaei (BP), and necrotizing hepatopancreatitis (NHP) and its bacterial agent Hepatobacterium penaei, were among the "American" diseases that eventually became OIE listed and have not become established outside of the Americas. As the industry grew after 1980, a number of new diseases that soon became OIE listed, emerged in the Americas or were introduced from Asia. Spherical baculovirus, caused by MBV, although discovered in the Americas in imported live Penaeus monodon, was subsequently found to be common in wild and farmed Asian, Australian and African penaeids. Infectious hypodermal and hematopoietic necrosis virus (IHHNV) was introduced from the Philippines in the mid 1970s with live P. monodon and was eventually found throughout the Americas and subsequently in much of the shrimp farming industry in the eastern hemisphere. Taura syndrome emerged in Penaeus vannamei farms in 1991-1992 in Ecuador and was transferred to SE Asia with live shrimp by 1999 where it also caused severe losses. White Spot Disease (WSD) caused by White spot syndrome virus (WSSV) emerged in East Asia in ~1992, and spread throughout most of the Asian shrimp farming industry by 1994. By 1995, WSSV reached the eastern USA via frozen commodity products and it reached the main shrimp farming countries of the Americas located on the Pacific side of the continents by the same mechanism in 1999. As is the case in Asia, WSD is the dominant disease problem of farmed shrimp in the Americas. The most recent disease to emerge in the Americas was infectious myonecrosis caused by IMN virus. As had happened before, within 3years of its discovery, the disease had been transferred to SE Asia with live P. vannamei, and because of its impact on the industry and potential for further spread in was listed by the OIE in 2005. Despite the huge negative impact of disease on the shrimp farming industry in the Americas, the industry has continued to grow and mature into a more sustainable industry. In marked contrast to 15-20years ago when PLs produced from wild adults and wild PLs were used to stock farms in the Americas, the industry now relies on domesticated lines of broodstock that have undergone selection for desirable characteristics including disease resistance. PMID- 22434001 TI - The impact of pathogens on exploited populations of decapod crustaceans. AB - Several crustacean fisheries have experienced significant outbreaks of disease that have damaged their industries. Not only do fisheries suffer from direct losses to pathogens, such as disease-induced mortalities or reduced product value, but they can also incur indirect losses such as stunting, castration, and increased risk of predation. In some cases, the indirect losses can be substantial, yet they are often overlooked by the fishing industry as their primary focus is on recruits to the fishery, and not on the affected juvenile pre recruits. Low levels of pathogens are to be expected in natural populations of commercial species, but baseline data on the prevalence and intensity of even the most common agents is often lacking. It is important to establish baselines for two reasons. First, it is important to know what pathogens exist in heavily exploited populations so as to gauge their potential to damage the industry; and second, during outbreaks, it is important to know whether an outbreak is a newly emergent event or whether it is a component of a cyclical phenomenon. Pathogens frequently act in concert with environmental stressors, and a variety of stressors have contributed to outbreaks of emerging agents in crustacean fisheries. Pollution, poor water quality, hypoxia, temperature extremes, and overexploitation have all been implicated as stressors in various outbreaks. This review focuses on epidemic diseases of commercially fished crustaceans. Outbreaks in cultured stocks are not covered. Disease epizootics have occurred in fished populations of crayfish and shrimp but they are less well known than the issues arising from extensive aquaculture of these species. PMID- 22434002 TI - Disease will limit future food supply from the global crustacean fishery and aquaculture sectors. AB - Seafood is a highly traded food commodity. Farmed and captured crustaceans contribute a significant proportion with annual production exceeding 10 M metric tonnes with first sale value of $40bn. The sector is dominated by farmed tropical marine shrimp, the fastest growing sector of the global aquaculture industry. It is significant in supporting rural livelihoods and alleviating poverty in producing nations within Asia and Latin America while forming an increasing contribution to aquatic food supply in more developed countries. Nations with marine borders often also support important marine fisheries for crustaceans that are regionally traded as live animals and commodity products. A general separation of net producing and net consuming nations for crustacean seafood has created a truly globalised food industry. Projections for increasing global demand for seafood in the face of level or declining fisheries requires continued expansion and intensification of aquaculture while ensuring best utilisation of captured stocks. Furthermore, continued pressure from consuming nations to ensure safe products for human consumption are being augmented by additional legislative requirements for animals (and their products) to be of low disease status. As a consequence, increasing emphasis is being placed on enforcement of regulations and better governance of the sector; currently this is a challenge in light of a fragmented industry and less stringent regulations associated with animal disease within producer nations. Current estimates predict that up to 40% of tropical shrimp production (>$3bn) is lost annually, mainly due to viral pathogens for which standard preventative measures (e.g. such as vaccination) are not feasible. In light of this problem, new approaches are urgently required to enhance yield by improving broodstock and larval sourcing, promoting best management practices by farmer outreach and supporting cutting-edge research that aims to harness the natural abilities of invertebrates to mitigate assault from pathogens (e.g. the use of RNA interference therapeutics). In terms of fisheries losses associated with disease, key issues are centred on mortality and quality degradation in the post-capture phase, largely due to poor grading and handling by fishers and the industry chain. Occurrence of disease in wild crustaceans is also widely reported, with some indications that climatic changes may be increasing susceptibility to important pathogens (e.g. the parasite Hematodinium). However, despite improvements in field and laboratory diagnostics, defining population level effects of disease in these fisheries remains elusive. Coordination of disease specialists with fisheries scientists will be required to understand current and future impacts of existing and emergent diseases on wild stocks. Overall, the increasing demand for crustacean seafood in light of these issues signals a clear warning for the future sustainability of this global industry. The linking together of global experts in the culture, capture and trading of crustaceans with pathologists, epidemiologists, ecologists, therapeutics specialists and policy makers in the field of food security will allow these issues to be better identified and addressed. PMID- 22434003 TI - Global transboundry disease politics: the OIE perspective. AB - Reviewed in this paper are the steps for listing or de-listing of an aquatic animal disease, the current list of OIE listed aquatic animal diseases, and the reporting requirements for listed diseases by member countries. The current OIE listed aquatic animal diseases includes two diseases of amphibians, nine of fish, seven of mollusks, and eight of crustaceans. Of interest is the difference in importance of the listed diseases in each of the four groups of aquatic animals. In mollusks, parasitic diseases dominate the list, while in fish and crustaceans virus diseases are dominant. Whether a listed disease is due to a virus, fungus, bacterium or a parasite, the occurrence of the disease may adversely affect international trade among trading partners that have, or do not have, the listed disease. By its very nature, the international trade in terrestrial animals and aquatic animals, and their products, is influenced by national and international politics. When the occurrence of an OIE listed or emerging disease becomes an issue between trading partners, trade restrictions may be put in place and disputes are often a consequence. The World Trade Organization named the OIE as the reference body for animal health as it relates to international trade. This action recognized the 88 year history of the work by the OIE in disease control, listing of diseases, the development of the terrestrial and aquatic codes and the diagnostic manuals, and the prompt notification of members by the OIE of the occurrence of listed diseases. The intent of the WTO with this action was likely to minimize disease related trade disputes brought before the WTO. PMID- 22434004 TI - Transboundary movement of shrimp viruses in crustaceans and their products: a special risk? AB - Shrimp and shrimp products form the most valuable internationally traded fisheries commodity, and the volumes are huge, estimated to be about 3.6 million tonnes. However, despite the existence under the General Agreement on Tariffs and Trade, of the Sanitary and Phytosanitary Measures (SPS Agreement) and the activities of the World Organisation for Animal Health (OIE), viral shrimp epizootics have spread and continue to spread, affecting world production. Though most attention has focussed on the movement of live shrimp product, the spread of new and emerging diseases through other crustaceans and their nonviable products is of increasing concern. The risks associated with the unrestricted movement of nonviable product will be outlined and measures that can be taken to mitigate the risk are discussed. Ultimately, for crustacean diseases, the paradigm under which the OIE has operated for the past 80 years needs to change. PMID- 22434005 TI - The role of selective breeding and biosecurity in the prevention of disease in penaeid shrimp aquaculture. AB - About 3.5 million metric tons of farmed shrimp were produced globally in 2009 with an estimated value greater than USD$14.6 billion. Despite the economic importance of farmed shrimp, the global shrimp farming industry continues to be plagued by disease. There are a number of strategies a shrimp farmer can employ to mitigate crop loss from disease, including the use of Specific Pathogen Free (SPF), selectively bred shrimp and the adoption of on-farm biosecurity practices. Selective breeding for disease resistance began in the mid 1990s in response to outbreaks of Taura syndrome, caused by Taura syndrome virus (TSV), which devastated populations of farmed shrimp (Litopenaeus vannamei) throughout the Americas. Breeding programs designed to enhance TSV survival have generated valuable information about the quantitative genetics of disease resistance in shrimp and have produced shrimp families which exhibit high survival after TSV exposure. The commercial availability of these selected shrimp has benefitted the shrimp farming industry and TSV is no longer considered a major threat in many shrimp farming regions. Although selective breeding has been valuable in combating TSV, this approach has not been effective for other viral pathogens and selective breeding may not be the most effective strategy for the long-term viability of the industry. Cost-effective, on-farm biosecurity protocols can be more practical and less expensive than breeding programs designed to enhance disease resistance. Of particular importance is the use of SPF shrimp stocked in biosecure environments where physical barriers are in place to mitigate the introduction and spread of virulent pathogens. PMID- 22434006 TI - Costs and benefits of freedom from shrimp diseases in the European Union. AB - The growth in penaeid shrimp aquaculture has been mirrored by the emergence of a number of serious diseases, some of which (e.g. white spot syndrome virus - WSSV) spread rapidly across the globe through movement of infected stock. The World Organisation for Animal Health (OIE) lists six penaeid shrimp pathogens of which three are notifiable in the EU: WSSV (listed as non-exotic to the EU), Taura syndrome virus (TSV) and yellow head disease (YHD) (both listed as exotic). EU Member States (MS) must determine a status for non-exotic diseases (e.g. disease free, unknown, infected). In developing a policy for WSSV, import risk analysis (IRA) can be used to systematically assess the risks of introduction and justify risk mitigation to maintain freedom. OIE guidelines recommend that countries assess the risk of disease introduction via commodities, not listed by the OIE as safe, and apply sanitary measures if necessary. The sanitary measures necessary to maintain freedom from WSSV may not be compatible with current EU animal health legislation. The recent revision by OIE of products listed as safe for international trade strengthens the case for the risks of TSV and YHD introduction into the EU to be assessed. Freedom from WSSV is an important criterion for the development of shrimp aquaculture in the EU. However, in developing disease control policy, governments need to balance the potentially competing interests of all stakeholders, including consumers. Thus economic modelling of the impact of possible sanitary measures on consumer prices of imported products is needed to support decision making. The creation of disease free compartments and post-import risk mitigation for commodities may create the conditions conducive to the development of shrimp aquaculture whilst minimising the costs of maintaining disease freedom. PMID- 22434007 TI - Utility of ultrasound-based measurement of carotid intima-media thickness in children as a sensitive marker of atherosclerosis risk. PMID- 22434008 TI - Chemistry of the heavy group 15 elements with the pyridyl tethered 1,2 bis(imino)acenaphthene "clamshell" ligand. AB - Cobaltocene has been used as a one-electron reductant in a facile route to generate pnictogen(I) (P, As) synthons. These subsequently undergo a formal 4 + 2 cycloaddition with a pyridyl tethered 1,2-bis(imino)acenaphthene "clamshell" ligand to yield N-heterocyclic chlorophosphines and -arsines, which are precursors to the corresponding N-heterocyclic pnictenium cations. In the absence of a reductant the "clamshell" ligand can be used in forming hypervalent donor acceptor complexes with heavy main group elements (Sn, Sb and Bi). PMID- 22434010 TI - Proton sponge-functionalized silica as high performance adsorbents for solid phase extraction of trace perfluoroalkyl sulfonates in the environmental water samples and their direct analysis by MALDI-TOF-MS. AB - 1,8-Bis(dimethylamino)naphthalene (DMAN), a classical 'proton sponge', was functionalized on silica particles as a novel solid-phase extraction (SPE) adsorbent (DMAN@silica) for extracting perfluoroalkyl sulfonates (PFSs). High reproducibility and excellent extraction capability for PFSs were obtained in a wide pH range (3.0~8.5). The adsorbed PFSs on DMAN@silica sorbents could be efficiently eluted by 1,8-bis(tetramethylguanidino)naphthalene (TMGN) solution which is a proton sponge with higher proton affinity than DMAN. The elution could be directly analyzed by MALDI-TOF-MS using TMGN as matrix. Clear mass spectra for the PFSs were obtained due to no matrix ions interference observed. Furthermore, a novel strategy based on the DMAN@silica-SPE enrichment, followed by MALDI-TOF MS analysis, was proposed and applied for PFSs quantification in environmental water samples. The calibration curves of each of the target analytes showed a wide linear dynamic range of response (0.1-10 ng L(-1) for perfluorooctane sulfonate (PFOS), perfluorohexyl sulfonate (PFHxS) and perfluorobutylsulfonate (PFBS)), which were over 2 orders of magnitude. The detection limits for PFOS, PFHxS, and PFBS were 0.021, 0.016, and 0.013 ng L(-1), respectively (S/N = 3). Recoveries of PFOS, PFHxS, and PFBS are in the ranges of 92-104%, 95-102%, and 98 109% for spiked river water samples. These results indicated that the prepared DMAN@silica adsorbents could efficiently enrich PFSs and that the proposed method is reliable. PMID- 22434011 TI - Accelerating the initial rate of hydrolysis of methyl parathion with laser excitation using monolayer protected 10 nm Au nanoparticles capped with a Cu(bpy) catalyst. AB - Using a low power green laser, we have demonstrated a rate acceleration of ~2 fold for the hydrolysis of methyl parathion by irradiating the plasmon absorption band of Au nanoparticles capped with a Cu(bpy) catalyst. PMID- 22434013 TI - On the comparison of population-level estimates of haplotype and nucleotide diversity: a case study using the gene cox1 in animals. AB - Estimates of genetic diversity represent a valuable resource for biodiversity assessments and are increasingly used to guide conservation and management programs. The most commonly reported estimates of DNA sequence diversity in animal populations are haplotype diversity (h) and nucleotide diversity (pi) for the mitochondrial gene cytochrome c oxidase subunit I (cox1). However, several issues relevant to the comparison of h and pi within and between studies remain to be assessed. We used population-level cox1 data from peer-reviewed publications to quantify the extent to which data sets can be re-assembled, to provide a standardized summary of h and pi estimates, to explore the relationship between these metrics and to assess their sensitivity to under-sampling. Only 19 out of 42 selected publications had archived data that could be unambiguously re assembled; this comprised 127 population-level data sets (n >= 15) from 23 animal species. Estimates of h and pi were calculated using a 456-base region of cox1 that was common to all the data sets (median h=0.70130, median pi=0.00356). Non linear regression methods and Bayesian information criterion analysis revealed that the most parsimonious model describing the relationship between the estimates of h and pi was pi=0.0081 h(2). Deviations from this model can be used to detect outliers due to biological processes or methodological issues. Subsampling analyses indicated that samples of n>5 were sufficient to discriminate extremes of high from low population-level cox1 diversity, but samples of n >= 25 are recommended for greater accuracy. PMID- 22434014 TI - High and low throughput screens with root-knot nematodes Meloidogyne spp. AB - Root-knot nematodes (genus Meloidogyne) are obligate plant parasites. They are extremely polyphagous and considered one of the most economically important plant parasitic nematodes. The microscopic second-stage juvenile (J2), molted once in the egg, is the infective stage. The J2s hatch from the eggs, move freely in the soil within a film of water, and locate root tips of suitable plant species. After penetrating the plant root, they migrate towards the vascular cylinder where they establish a feeding site and initiate feeding using their stylets. The multicellular feeding site is comprised of several enlarged multinuclear cells called 'giant cells' which are formed from cells that underwent karyokinesis (repeated mitosis) without cytokinesis. Neighboring pericycle cells divide and enlarge in size giving rise to a typical gall or root knot, the characteristic symptom of root-knot nematode infection. Once feeding is initiated, J2s become sedentary and undergo three additional molts to become adults. The adult female lays 150-250 eggs in a gelatinous matrix on or below the surface of the root. From the eggs new infective J2s hatch and start a new cycle. The root-knot nematode life cycle is completed in 4-6 weeks at 26-28 degrees C. Here we present the traditional protocol to infect plants, grown in pots, with root-knot nematodes and two methods for high-throughput assays. The first high-throughput method is used for plants with small seeds such as tomato while the second is for plants with large seeds such as cowpea and common bean. Large seeds support extended seedling growth with minimal nutrient supplement. The first high throughput assay utilizes seedlings grown in sand in trays while in the second assay plants are grown in pouches in the absence of soil. The seedling growth pouch is made of a 15.5 x 12.5cm paper wick, folded at the top to form a 2-cm deep trough in which the seed or seedling is placed. The paper wick is contained inside a transparent plastic pouch. These growth pouches allow direct observation of nematode infection symptoms, galling of roots and egg mass production, under the surface of a transparent pouch. Both methods allow the use of the screened plants, after phenotyping, for crossing or seed production. An additional advantage of the use of growth pouches is the small space requirement because pouches are stored in plastic hanging folders arranged in racks. PMID- 22434015 TI - Chemiresistive response of silicon nanowires to trace vapor of nitro explosives. AB - Silicon nanowires are observed to behave as chemically modulated resistors and exhibit sensitive and fast electrical responses to vapors of common nitro explosives and their degradation by-products. The nanowires were prepared with a top-down nano-fabrication process on a silicon-on-insulator wafer. The surface of the silicon nanowires was modified by plasma treatments. Both hydrogen and oxygen plasma treatments can significantly improve the responses, and oxygen plasma changes the majority carrier from p- to n-type on the surface of silicon nanowire thin films. The sensitivity is found to increase when the cross-section of the nanowires decreases. PMID- 22434012 TI - Population divergence and gene flow in an endangered and highly mobile seabird. AB - Seabirds are highly vagile and can disperse up to thousands of kilometers, making it difficult to identify the factors that promote isolation between populations. The endemic Hawaiian petrel (Pterodroma sandwichensis) is one such species. Today it is endangered, and known to breed only on the islands of Hawaii, Maui, Lanai and Kauai. Historical records indicate that a large population formerly bred on Molokai as well, but this population has recently been extirpated. Given the great dispersal potential of these petrels, it remains unclear if populations are genetically distinct and which factors may contribute to isolation between them. We sampled petrels from across their range, including individuals from the presumably extirpated Molokai population. We sequenced 524 bp of mitochondrial DNA, 741 bp from three nuclear introns, and genotyped 18 microsatellite loci in order to examine the patterns of divergence in this species and to investigate the potential underlying mechanisms. Both mitochondrial and nuclear data sets indicated significant genetic differentiation among all modern populations, but no differentiation was found between historic samples from Molokai and modern birds from Lanai. Population-specific nonbreeding distribution and strong natal philopatry may reduce gene flow between populations. However, the lack of population structure between extirpated Molokai birds and modern birds on Lanai indicates that there was substantial gene flow between these populations and that petrels may be able to overcome barriers to dispersal prior to complete extirpation. Hawaiian petrel populations could be considered distinct management units, however, the dwindling population on Hawaii may require translocation to prevent extirpation in the near future. PMID- 22434016 TI - The IP6 micelle-stabilized small Ag cluster for synthesizing Ag-Au alloy nanoparticles and the tunable surface plasmon resonance effect. AB - The stable small Ag seeds (size in diameter < 10 nm) were obtained in the presence of inositol hexakisphosphoric (IP6) micelles. Then Ag-Au bimetallic nanoparticles were synthesized through a replacement reaction with the rapid interdiffusion process between such small Ag seeds in nanoclusters and HAuCl4. Adjusting the dosage of HAuCl4 resulted in different products, which possessed unique surface plasmon resonances (SPR). The morphologies of the as-made nanoparticles were observed using transmission electron microscopy and field emission scanning electron microscopy and their compositions were determined by energy-dispersive x-ray spectroscopy. Among them, the Ag-Au alloy nanoparticles with the cauliflower-like structure had a suitable SPR for highly sensitive Raman detection application as a surface-enhanced Raman scattering (SERS) substrate with a long-term stability of six months. PMID- 22434017 TI - Depression and its correlates among older adults accessing aging services. AB - OBJECTIVES: : To define the prevalence and correlates of depression among older adults receiving assessments by nonmedical community-based care managers at the point of entry to care and thus prior to provision of aging services. Our long term goal is to inform development of collaborative care models for late life depression that incorporate Aging Services Providers. METHODS: : Aging Services Provider Network (ASPN) clients receiving in-home assessments were administered the Structured Clinical Interview for DSM-IV-TR (SCID) module for affective disorders and measures of depression symptom severity, alcohol use, physical health, functional status, social support, stressful life events, and religiosity. Engagement in mental healthcare was documented. RESULTS: : Subjects (N = 378) were primarily white (84%) and women (69%) with household incomes under $1,750/month (62%). Half lived alone (48%). Their mean age was 77 years. Thirty one percent had clinically significant depressive symptoms and 27% met criteria for a current major depressive episode, of which 61% were being treated with medication and 25% by a mental health provider. Nearly half (47%) had experienced one or more episodes of major depression during their lives. Disability, number of medical conditions, number and severity of recent stressful life events, low social support, and low religiosity were independently associated with current major depression. CONCLUSION: : Depressive illness was common among this sample of ASPN clients. Because ASPN care managers have expertise in managing many of the problems correlated with depression, they may play a significant role in identifying, preventing, and collaborating in the treatment of depressive illnesses among community-dwelling older adults. PMID- 22434018 TI - The effect of hearing augmentation on cognitive assessment scales at admission to hospital. AB - OBJECTIVES: : The aim was to assess how the use of a commercially available hearing augmentation device affected performance on cognitive assessment scales on admission to hospital. DESIGN: : This was a randomized controlled trial. SETTING: : The study was conducted on all of the acute assessment wards in a department of medicine for the elderly. PARTICIPANTS: : All patients admitted to the department from December 1, 2007, until February 28, 2008, were considered for admission to the study. Patients with delirium were excluded. INTERVENTION: : A commercially available device provided hearing augmentation in the intervention group on the second day. MEASUREMENTS: : All participants had cognitive assessments using the Mini-Mental State Examination (MMSE) and the Abbreviated Mental Test (AMT) on two consecutive days. RESULTS: : A total of 192 patients (60.4% women, mean [+/-SD] age 82.4 [+/-7.0] years) were recruited and randomized into control (N = 58) or intervention groups (N = 134). Paired and unpaired t tests were used to compare mean improvements in scores within and between groups, respectively. The mean improvement in MMSE scores was 2.00 (p <0.001) in the intervention group and 0.49 in the control group (p = 0.46), and the mean improvement in AMT scores was 0.48 (p <0.001) for the intervention group and 0.24 (p = 0.04) for the control group. In comparing mean improvements between groups, unpaired t-test results were significant for MMSE (p <0.001) but not for AMT (p = 0.23). These results were confirmed on repeated-measures ANOVA (group by time interaction). CONCLUSIONS: : Hearing augmentation significantly improves performance on MMSE scores. The use of hearing augmentation devices in routine screening for cognitive impairment merits further study. PMID- 22434020 TI - Kumral et al. reported 6 cases of acute respiratory failure due to unilateral dorsolateral bulbar infarction. PMID- 22434021 TI - Transcriptomics analysis of primary mouse thymocytes exposed to bis(tri-n butyltin)dioxide (TBTO). AB - The biocide bis(tri-n-butyltin)oxide (TBTO) causes thymus atrophy in rodents and is toxic to many cell types of which thymocytes are the most sensitive. To obtain insight in the mechanisms of action of TBTO, we exposed primary mouse thymocytes in vitro for 3, 6 and 11 h to 0.1, 0.5, 1 and 2 MUM TBTO. Subsequently, the cells were subjected to whole-genome gene expression profiling. Biological interpretation of the gene expression data revealed that TBTO affects a wide range of processes. Cell proliferation related genes were downregulated by all treatments except for 3 and 6 h 0.5 MUM TBTO which upregulated these genes. Treatment with TBTO resulted in upregulation of genes involved in endoplasmatic reticulum (ER) stress, NFkB and TNFalpha pathways, and genes involved in DNA damage, p53 signaling and apoptosis. Remarkably, TBTO also increased the expression of genes that are known to be upregulated during T cell activation or during negative selection of thymocytes. The effect of TBTO on expression of genes involved in ER stress and apoptosis was confirmed by qPCR. Induction of the T cell activation response was corroborated by demonstrating that TBTO exposure resulted in translocation of NFAT to the nucleus, which is an essential event for T cell activation. PMID- 22434022 TI - Anticipatory planning of functional reach-to-grasp: a pilot study. AB - BACKGROUND: Intensive task-oriented training such as constraint-induced movement therapy (CIMT) is thought to engage motor learning and decision-making processes, including anticipatory action planning. OBJECTIVE: To identify the effects of CIMT on anticipatory hand posture selection and movement time for task-specific reach-to-grasp performance. METHODS: Subacute and chronic poststroke participants were recruited into CIMT (n = 10) or non-CIMT (n = 10) groups. Arm and hand functions were assessed before and after 2 weeks with the Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and a unique skilled reach-to-grasp task designed to test anticipatory hand posture selection. The reach-to-grasp tasks included power and precision grasping in 2 conditions achieved optimally with either a pronated (low difficulty) or supinated (high difficulty) hand posture. Outcome measures included success rate, frequency of optimal strategy selection, and movement time. RESULTS: Between-group comparisons revealed a significant treatment effect for WMFT and MAL scores. The CIMT group showed larger gains in success rate, optimal posture selection (precision grasp only), and faster movement times for the supinated conditions. CONCLUSION: Together, a faster movement time and greater frequency of optimal hand posture selection in the more difficult task condition highlights a set of novel findings. These results provide evidence for training-induced improvements in upper-extremity function that support neurobehavioral recovery more than compensation. Although these findings are preliminary in view of the small sample size, the authors suggest that they may be useful to design and power larger-scale studies to further the understanding of the fundamental mechanisms induced by task-oriented training interventions in neurorehabilitation. PMID- 22434023 TI - System engineering approach to documentation: an evaluation of the documentation process in a gastroenterology laboratory. AB - Documentation processes are an indispensible part of patient care. Timely access to complete and accurate documentation is crucial to patient safety. However, there is no sufficient tool to help health care professionals effectively manage documentation processes. In this study, we developed an evaluation methodology, including a documentation matrix, a documentation process flow diagram, and a document value tool, to analyze the necessity and redundancy of the documentation processes. We applied this methodology in a gastrointestinal lab and improved the transparency of the documentation processes among providers. PMID- 22434024 TI - Insights from impedance spectroscopy into the mechanism of thermal decomposition of M(NH2BH3), M = H, Li, Na, Li(0.5)Na(0.5), hydrogen stores. AB - We report the first solid-state impedance study of hydrogen-rich ammonia borane, AB, and its three alkali metal amidoborane derivatives. Temperature-dependent impedance spectra of solid M(NH(2)BH(3)) salts are predominated by ionic conductivity, which at room temperature ranges from 5.5 MUS cm(-1) (M = Li) to 2.2-3.0 mS cm(-1) (Na, Na(0.5)Li(0.5)), while the activation energy for conductivity is rather high (140-158 kJ mol(-1)). Variation of conductivity with time can be used to extract information about the evolution of the system during thermal decomposition. By using a combination of impedance spectroscopy, thermogravimetric analysis, scanning calorimetry, evolved gas analysis, infrared absorption spectroscopy as well as (11)B and (1)H MAS NMR, we were able to reconfirm the complex pathway of thermal decomposition of amidoboranes postulated by two of us earlier (J. Mater. Chem. 2009, 19, 2043). PMID- 22434026 TI - Optimizing therapeutics: the next front in the war on rheumatoid arthritis. PMID- 22434029 TI - Therapeutic blockade of interleukin-6 in chronic inflammatory disease. PMID- 22434030 TI - Autoimmunity and Graves' disease. AB - Current treatment options for Graves' hyperthyroidism and the related ophthalmopathy (GO) are not uniformly effective and carry with them potentially serious side effects. As a result, efforts have been focused on the development of novel therapies. Progress has been made, particularly in the production of thyroid-stimulating hormone receptor (TSHR) antagonists, as either monoclonal blocking antibodies or small-molecule ligands. In addition, rituximab (RTX) is the first targeted biological therapy to be studied as treatment for these conditions. PMID- 22434032 TI - Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle. AB - BACKGROUND: Remodeling of ion channel expression is well established in heart failure (HF). We determined the extent to which I(to) is reduced in tachypacing induced HF and assessed the ability of an I(to) activator (NS5806) to recover this current. METHOD AND RESULTS: Whole-cell patch clamp was used to record I(to) in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular wedge preparations. Right ventricular tachypacing-induced heart failure reduced I(to) density in Epi myocytes (Control=22.1+/-1.9pA/pF vs 16.1+/-1.4 after 2weeks and 10.7+/-1.4pA/pF after 5 weeks, +50mV). Current decay as well as recovery of I(to) from inactivation progressively slowed with the development of heart failure. Reduction of I(to) density was paralleled by a reduction in phase 1 magnitude, epicardial action potential notch and J wave amplitude recorded from coronary-perfused left ventricular wedge preparations. NS5806 increased I(to) (at +50mV) from 16.1+/-1.4 to 23.9+/-2.1pA/pF (p<0.05) at 2weeks and from 10.7+/-1.4 to 14.4+/-1.9pA/pF (p<0.05) in 5 weeks tachypaced dogs. NS5806 increased both fast and slow phases of I(to) recovery in 2 and 5-week HF cells and restored the action potential notch and J wave in wedge preparations from HF dogs. CONCLUSIONS: The I(to) agonist NS5806 increases the rate of recovery and density of I(to), thus reversing the HF-induced reduction in these parameters. In wedge preparations from HF dogs, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed. PMID- 22434034 TI - Energetics of cation mixing in urania-ceria solid solutions with stoichiometric oxygen concentrations. AB - Cation mixing energetics in urania-ceria solid solutions with stoichiometric oxygen concentrations (U(1-y)Ce(y)O(2)) have been measured by high-temperature oxide-melt drop-solution calorimetry. Measurements have been performed on eight samples with compositions spanning y = 0.119 to y = 0.815. The measured mixing enthalpies (DeltaH(mix)) range from -0.6 +/- 3.3 to 3.9 +/- 3.0 kJ mol(-1). These values are discussed in the context of results from atomistic modeling which take into consideration the possibility of charge transfer between uranium and cerium cations to form solid solutions with mixed charge states. A comparison between measured and calculated results for DeltaH(mix) suggests that such charge transfer takes place to a limited extent in the most concentrated mixtures studied. PMID- 22434036 TI - Use of interferon-gamma enzyme-linked immunospot assay to characterize novel T cell epitopes of human papillomavirus. AB - A protocol has been developed to overcome the difficulties of isolating and characterizing rare T cells specific for pathogens, such as human papillomavirus (HPV), that cause localized infections. The steps involved are identifying region(s) of HPV proteins that contain T-cell epitope(s) from a subject, selecting for the peptide-specific T cells based on interferon-gamma (IFN-gamma) secretion, and growing and characterizing the T-cell clones (Fig. 1). Subject 1 was a patient who was recently diagnosed with a high-grade squamous intraepithelial lesion by biopsy and underwent loop electrical excision procedure for treatment on the day the T cells were collected(1). A region within the human papillomavirus type 16 (HPV 16) E6 and E7 proteins which contained a T-cell epitope was identified using an IFN- g enzyme-linked immunospot (ELISPOT) assay performed with overlapping synthetic peptides (Fig. 2). The data from this assay were used not only to identify a region containing a T-cell epitope, but also to estimate the number of epitope specific T cells and to isolate them on the basis of IFN- gamma secretion using commercially available magnetic beads (CD8 T-cell isolation kit, Miltenyi Biotec, Auburn CA). The selected IFN-gamma secreting T cells were diluted and grown singly in the presence of an irradiated feeder cell mixture in order to support the growth of a single T-cell per well. These T-cell clones were screened using an IFN- gamma ELISPOT assay in the presence of peptides covering the identified region and autologous Epstein-Barr virus transformed B-lymphoblastoid cells (LCLs, obtained how described by Walls and Crawford)(2) in order to minimize the number of T-cell clone cells needed. Instead of using 1 x 10(5) cells per well typically used in ELISPOT assays(1,3), 1,000 T-cell clone cells in the presence of 1 x 10(5) autologous LCLs were used, dramatically reducing the number of T-cell clone cells needed. The autologous LCLs served not only to present peptide antigens to the T-cell clone cells, but also to keep a high cell density in the wells allowing the epitope-specific T cell clone cells to secrete IFN-gamma. This assures successful performance of IFN gamma ELISPOT assay. Similarly, IFN- gamma ELISPOT assays were utilized to characterize the minimal and optimal amino acid sequence of the CD8 T-cell epitope (HPV 16 E6 52-61 FAFRDLCIVY) and its HLA class I restriction element (B58). The IFN- gamma ELISPOT assay was also performed using autologous LCLs infected with vaccinia virus expressing HPV 16 E6 or E7 protein. The result demonstrated that the E6 T-cell epitope was endogenously processed. The cross recognition of homologous T-cell epitope of other high-risk HPV types was shown. This method can also be used to describe CD4 T-cell epitopes(4). PMID- 22434037 TI - Direct measurement of extracellular electrical signals from mammalian olfactory sensory neurons in planar triode devices. AB - An artificial nose was developed to mimic aspects of sensory transduction of the peripheral mammalian olfactory system. We directly cultured and differentiated rat olfactory sensory neurons (OSNs) on indium-tin oxide electrodes of planar triode substrates without a coupling agent. Direct voltage (~50 MUV) and current (~250 nA) signals were measured simultaneously when OSNs on the planar triode substrates were exposed to odorant mixtures. The response signals were sensitive to the concentration of the odorant mixture, with a typical lifetime, shape, and adaptation profile as seen in responses upon repeated stimulation in vivo. We found that the rising time to the peak current was ~161 ms, while the signal back to baseline was in 1.8 s, which are in agreement with the natural intracellular electrophysiological responses. These results provide the first evidence that mature OSNs grown in a planar triode device are able to detect direct electrophysiological responses to odorants. PMID- 22434038 TI - Computational insight into the reductive oligomerisation of CO at uranium(III) mixed-sandwich complexes. AB - Calculations reveal a multistep pathway towards formation of linear [U](2)-(MU eta(1):eta(1)-C(2)O(2)); [U] = U(eta-C(8)H(6){SiH(3)-1,4}(2))(eta-Cp). However formation of deltate-bridged [U](2)-(MU-eta(1):eta(2)-C(3)O(3)) requires an alternative mechanism, involving a side-on [U](2)-(MU-eta(2):eta(2)-CO) complex and whereby the bridging units of [U](2)-(MU-eta(2):eta(2)-C(n)O(n)) intermediates (n = 1, 2) react directly with free CO. PMID- 22434039 TI - Serine/threonine/tyrosine protein kinase phosphorylates oleosin, a regulator of lipid metabolic functions. AB - Plant oils are stored in oleosomes or oil bodies, which are surrounded by a monolayer of phospholipids embedded with oleosin proteins that stabilize the structure. Recently, a structural protein, Oleosin3 (OLE3), was shown to exhibit both monoacylglycerol acyltransferase and phospholipase A(2) activities. The regulation of these distinct dual activities in a single protein is unclear. Here, we report that a serine/threonine/tyrosine protein kinase phosphorylates oleosin. Using bimolecular fluorescence complementation analysis, we demonstrate that this kinase interacts with OLE3 and that the fluorescence was associated with chloroplasts. Oleosin-green fluorescent protein fusion protein was exclusively associated with the chloroplasts. Phosphorylated OLE3 exhibited reduced monoacylglycerol acyltransferase and increased phospholipase A(2) activities. Moreover, phosphatidylcholine and diacylglycerol activated oleosin phosphorylation, whereas lysophosphatidylcholine, oleic acid, and Ca(2+) inhibited phosphorylation. In addition, recombinant peanut (Arachis hypogaea) kinase was determined to predominantly phosphorylate serine residues, specifically serine-18 in OLE3. Phosphorylation levels of OLE3 during seed germination were determined to be higher than in developing peanut seeds. These findings provide direct evidence for the in vivo substrate selectivity of the dual-specificity kinase and demonstrate that the bifunctional activities of oleosin are regulated by phosphorylation. PMID- 22434040 TI - The small GTPase ROP6 interacts with NFR5 and is involved in nodule formation in Lotus japonicus. AB - Nod Factor Receptor5 (NFR5) is an atypical receptor-like kinase, having no activation loop in the protein kinase domain. It forms a heterodimer with NFR1 and is required for the early plant responses to Rhizobium infection. A Rho-like small GTPase from Lotus japonicus was identified as an NFR5-interacting protein. The amino acid sequence of this Rho-like GTPase is closest to the Arabidopsis (Arabidopsis thaliana) ROP6 and Medicago truncatula ROP6 and was designated as LjROP6. The interaction between Rop6 and NFR5 occurred both in vitro and in planta. No interaction between Rop6 and NFR1 was observed. Green fluorescent protein-tagged ROP6 was localized at the plasma membrane and cytoplasm. The interaction between ROP6 and NFR5 appeared to take place at the plasma membrane. The expression of the ROP6 gene could be detected in vascular tissues of Lotus roots. After inoculation with Mesorhizobium loti, elevated levels of ROP6 expression were found in the root hairs, root tips, vascular bundles of roots, nodule primordia, and young nodules. In transgenic hairy roots expressing ROP6 RNA interference constructs, Rhizobium entry into the root hairs did not appear to be affected, but infection thread growth through the root cortex were severely inhibited, resulting in the development of fewer nodules per plant. These data demonstrate a role of ROP6 as a positive regulator of infection thread formation and nodulation in L. japonicus. PMID- 22434041 TI - Genetic manipulation of a "vacuolar" H(+)-PPase: from salt tolerance to yield enhancement under phosphorus-deficient soils. PMID- 22434042 TI - Overexpression of PIP2;5 aquaporin alleviates effects of low root temperature on cell hydraulic conductivity and growth in Arabidopsis. AB - The effects of low root temperature on growth and root cell water transport were compared between wild-type Arabidopsis (Arabidopsis thaliana) and plants overexpressing plasma membrane intrinsic protein 1;4 (PIP1;4) and PIP2;5. Descending root temperature from 25 degrees C to 10 degrees C quickly reduced cell hydraulic conductivity (L(p)) in wild-type plants but did not affect L(p) in plants overexpressing PIP1;4 and PIP2;5. Similarly, when the roots of wild-type plants were exposed to 10 degrees C for 1 d, L(p) was lower compared with 25 degrees C. However, there was no effect of low root temperature on L(p) in PIP1;4 and PIP2;5-overexpressing plants after 1 d of treatment. When the roots were exposed to 10 degrees C for 5 d, L(p) was reduced in wild-type plants and in plants overexpressing PIP1;4, whereas there was still no effect in PIP2;5 overexpressing plants. These results suggest that the gating mechanism in PIP1;4 may be more sensitive to prolonged low temperature compared with PIP2;5. The reduction of L(p) at 10 degrees C in roots of wild-type plants was partly restored to the preexposure level by 5 mm Ca(NO(3))(2) and protein phosphatase inhibitors (75 nm okadaic acid or 1 MUm Na(3)VO(4)), suggesting that aquaporin phosphorylation/dephosphorylation processes were involved in this response. The temperature sensitivity of cell water transport in roots was reflected by a reduction in shoot and root growth rates in the wild-type and PIP1;4 overexpressing plants exposed to 10 degrees C root temperature for 5 d. However, low root temperature had no effect on growth in plants overexpressing PIP2;5. These results provide strong evidence for a link between growth at low root temperature and aquaporin-mediated root water transport in Arabidopsis. PMID- 22434043 TI - Orthographic transparency modulates the functional asymmetry in the fusiform cortex: an artificial language training study. AB - The laterality difference in the occipitotemporal region between Chinese (bilaterality) and alphabetic languages (left laterality) has been attributed to their difference in visual appearance. However, these languages also differ in orthographic transparency. To disentangle the effect of orthographic transparency from visual appearance, we trained subjects to read the same artificial script either as an alphabetic (i.e., transparent orthography) or a logographic (i.e., nontransparent orthography) language. Consistent with our previous results, both types of phonological training enhanced activations in the left fusiform gyrus. More interestingly, the laterality in the fusiform gyrus (especially the posterior region) was modulated by the orthographic transparency of the artificial script (more left-lateralized activation after alphabetic training than after logographic training). These results provide an alternative account (i.e., orthographic transparency) for the laterality difference between Chinese and alphabetic languages, and may have important implications for the role of the fusiform in reading. PMID- 22434044 TI - Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice. AB - Acute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity. Here we tested if regulation of Akt and GSK3 was similarly affected by longer-term administration of amphetamine, as well as of methylphenidate, since each of these is administered chronically in patients with attention deficit hyperactivity disorder (ADHD). Akt is activated by post-translational phosphorylation on Thr308, and modulated by Ser473 phosphorylation, whereas phosphorylation on Ser21/9 inhibits the two GSK3 isoforms, GSK3alpha and GSK3beta. After eight days of amphetamine or methylphenidate treatment, striatal Akt and GSK3 were dephosphorylated similar to reported changes after acute amphetamine treatment. Oppositely, in the cerebral cortex and hippocampus Akt and GSK3 phosphorylation increased after eight days of amphetamine or methylphenidate treatment. These opposite brain region changes in Akt and GSK3 phosphorylation matched opposite changes in the association of Akt with beta-arrestin and GSK3, which after eight days of amphetamine treatment were increased in the striatum and decreased in the cerebral cortex. Thus, whereas the acute dephosphorylating effect of stimulants on Akt and GSK3 in the striatum was maintained, the response switched in the cerebral cortex after eight days of amphetamine or methylphenidate treatment to cause increased phosphorylation of Akt and GSK3. These results demonstrate that prolonged administration of stimulants causes brain region-selective differences in the regulation of Akt and GSK3. PMID- 22434045 TI - Down-regulation of Fer induces ROS levels accompanied by ATM and p53 activation in colon carcinoma cells. AB - Fer is an intracellular tyrosine kinase which resides in both the cytoplasm and nucleus of mammalian cells. This kinase was also found in all malignant cell lines analyzed and was shown to support cell-cycle progression in cancer cells. Herein we show that knock-down of Fer, both, impairs cell-cycle progression and imposes programmed cell death in colon carcinoma (CC) cells. The cell-cycle arrest and apoptotic death invoked by the depletion of Fer were found to depend on the activity of p53. Accordingly, down regulation of Fer led to the activation of the Ataxia Telangiectasia Mutated protein (ATM) and its down-stream effector p53. Knock-down of Fer also increased the level of Reactive-Oxygen Species (ROS) in CC cells, and subjection of Fer depleted cells to ROS neutralizing scavengers significantly decreased the induced phosphorylation and activation of ATM and p53. Notably, over-expression of Fer opposed the Doxorubicin driven activation of ATM and p53, which can be mediated by ROS. Collectively, our findings imply that Fer sustains low ROS levels in CC cells, thereby restraining the activation of ATM and p53 in these cells. PMID- 22434046 TI - Quantum conductance and switching kinetics of AgI-based microcrossbar cells. AB - Microcrossbar structured electrochemical metallization (ECM) cells based on silver iodide (AgI) solid electrolyte were fabricated and analyzed in terms of the resistive switching effect. The switching behavior implies the existence of quantized conductance higher than 78 uS which can be identified as a multiple of the single atomic point contact conductivity. The nonlinearity of the switching kinetics has been analyzed in detail. Fast switching in at least 50 ns was observed for short pulse measurements. PMID- 22434047 TI - Comparing the effects on work performance of mental and physical disorders. AB - OBJECTIVE: To estimate work loss days due to absenteeism and presenteeism associated with commonly occurring mental and physical disorders. METHODS: In a nationally representative face-to-face survey (Netherlands Mental Health Survey and Incidence Study-2) including 4,715 workers, the presence of 13 mental and 10 chronic physical disorders was assessed using the Composite International Diagnostic Interview 3.0 and a physical disorder checklist. Questions about absent days due to illness and days of reduced quantitative and qualitative functioning while at work were based on the WHO Disability Assessment Schedule. Total work loss days were defined as the sum of the days of these three types of loss, where days of reduced functioning were counted as half. Both individual and population-level effects of disorders on work loss were studied, taking comorbidity into account. RESULTS: Any mental disorder was associated with 10.5 additional absent days, 8.0 days of reduced-qualitative functioning and 12.0 total work loss days. For any physical disorder, the number of days was 10.7, 3.5 and 11.3, respectively. Adjusted for comorbidity, drug abuse, bipolar disorder, major depression, digestive disorders and panic disorder were associated with the highest number of additional total work loss days. At population-level, major depression, chronic back pain, respiratory disorders, drug abuse and digestive disorders contributed the most. Annual total work loss costs per million workers were estimated at 360 million for any mental disorder; and 706 million for any physical disorder. CONCLUSIONS: Policies designed to lessen the impact of commonly occurring disorders on workers will contribute to a reduction in absenteeism and presenteeism. As the indirect costs of (mental) disorders are much higher than their medical costs, prevention and treatment of these conditions may be cost-effective. PMID- 22434048 TI - Splicing aberration in naevoid basal cell carcinoma syndrome. PMID- 22434049 TI - Functional imaging techniques in hepatocellular carcinoma. AB - Novel biological therapies, including tyrosine kinase inhibitors such as sorafenib, improve the survival of patients with unresectable hepatocellular carcinoma. However, assessment of therapeutic efficacy remains challenging with conventional imaging techniques such as ultrasonography, CT or MRI that predominantly rely on size change to detect a treatment response. A beneficial tumour effect may go unrecognized in some patients who do not show tumour shrinkage and conversely, some patients may be maintained on treatment that is not active. This paper explores the use of functional imaging methods that are showing promise in the assessment of hepatocellular carcinoma. PMID- 22434050 TI - Impact of a second FDG PET scan before adjuvant therapy for the early detection of residual/relapsing tumours in high-risk patients with oral cavity cancer and pathological extracapsular spread. AB - PURPOSE: Extracapsular spread (ECS) to the cervical lymph nodes is a major adverse prognostic factor in oral cavity squamous cell carcinoma (OSCC). We prospectively examined the value of FDG PET immediately before postoperative radiotherapy/concurrent chemoradiotherapy (pre-RT/CCRT PET) to detect residual/relapsing disease in the early postsurgical follow-up period in high risk OSCC patients with ECS. METHODS: We examined 183 high-risk OSCC patients with ECS who underwent preoperative FDG PET/CT for staging purposes. Of these patients, 29 underwent a second pre-RT/CCRT FDG PET/CT scan. The clinical utility of the second FDG PET/CT was examined using Kaplan-Meier curve analysis. RESULTS: Patients who underwent the second FDG PET/CT scan had baseline clinicopathological characteristics similar to those who did not undergo a second scan. Of the patients who underwent the second scan, seven (24 %) had unexpected, newly discovered lesions. Five eventually died of the disease, and two had no evidence of recurrence after a change in RT field and dose. In an event-based analysis at 2 months, rates of neck control (6/29 vs. 6/154, p = 0.001), distant metastases (3/29 vs. 4/154, p = 0.046), and disease-free survival (7/29 vs. 10/154, p = 0.003) were significantly higher in patients who received a second PET scan than in those who did not. The second pre-RT/CCRT PET scan was of particular benefit for detecting new lesions in OSCC patients with both ECS and lymph node standardized uptake value (SUV) of >= 5.2 in the first PET scan. CONCLUSION: The present findings support the clinical value of pre-RT/CCRT FDG PET for defining treatment strategy in OSCC patients with both ECS and high nodal SUV, even when FDG PET had already been performed during the initial staging work up. PMID- 22434051 TI - Postprandial platelet aggregation: effects of different meals and glycemic index. AB - BACKGROUND/OBJECTIVES: Hyperglycaemia is associated with increased platelet aggregation that increases the risk of thrombosis in people with type-2 diabetes and cardiovascular disease. Low glycemic index (GI) meals high in carbohydrate or moderately high in protein have been shown to acutely reduce postprandial excursions of plasma glucose and insulin compared with high carbohydrate high GI meals. However, it is not known whether these differences in glucose and insulin profile also impact on postprandial platelet aggregation. This study aimed to investigate the acute effects of three iso-energetic meals, on measures of postprandial platelet aggregation, in healthy individuals. SUBJECTS/METHODS: A randomised cross-over study compared the acute effects of a high GI high carbohydrate (HGI-HC), a low GI high carbohydrate (LGI-HC) and a low GI moderately high in protein and fat (LGI-MPF) meal on postprandial platelet aggregation, glucose, insulin and triglyceride concentrations. Comparisons were made at fasting, 60 and 120 min postprandially. RESULTS: A total of 32 volunteers (mean +/- s.d.; age 59.9 +/- 11.7 years, BMI 27.1 +/- 3.7 kg/m(2)) participated in the study. Results showed significant reductions in maximum platelet aggregation postprandially with nonsignificant differences (all P > 0.29) between the three meals. Glucose and insulin were significantly (both P < 0.001) higher at 60 min postprandially on the HGI-HC meal compared with both LGI-HC and LGI-MPF meals. Triglycerides were not significantly different (all P > 0.25) between the three test meals. CONCLUSION: In healthy individuals platelet aggregation is reduced postprandially but this decrease is similar between meals of different GI that induce different glucose and insulin responses. PMID- 22434052 TI - Association between dairy product intake and abdominal obesity in Azorean adolescents. AB - BACKGROUND: Some studies have reported an inverse association between dairy product (DP) consumption and weight or fat mass loss. OBJECTIVES: The objective of our study was to assess the association between DP intake and abdominal obesity (AO) among Azorean adolescents. SUBJECTS/METHODS: This study was a cross sectional analysis. A total of 903 adolescents (370 boys) aged 15-16 years was evaluated. Anthropometric measurements were collected (weight, height and waist circumference (WC)) and McCarthy's cut-points were used to categorize WC. AO was defined when WC was >=90th percentile. Adolescent food intake was assessed using a self-administered semiquantitative food frequency questionnaire and DP intake was categorized in <2 and >=2 servings/day. Data were analyzed separately for girls and boys, and logistical regression was used to estimate the association between DPs and AO adjusting for potential confounders. RESULTS: The prevalence of AO was 54.9% (boys: 32.1% and girls: 70.7%, P<0.001). For boys and girls, DP consumption was 2.3+/-1.9 and 2.1+/-1.6 servings/day (P=0.185), respectively. In both genders, the proportion of adolescents with WC <90th percentile was higher among individuals who reported a dairy intake of <2 servings/day compared with those with an intake <2 servings/day (boys: 71% vs 65% and girls: 36% vs 24%, P<0.05). After adjustments for confounders, two or more DP servings per day were a negative predictor of AO (odds ratio, 0.217; 95% confidence interval, 0.075 0.633) only in boys. CONCLUSION: We found a protective association between DP intake and AO only in boys. PMID- 22434053 TI - Skin carotenoid status measured by resonance Raman spectroscopy as a biomarker of fruit and vegetable intake in preschool children. AB - BACKGROUND/OBJECTIVE: Dietary assessment in children is difficult, suggesting a need to develop more objective biomarkers of intake. Resonance Raman spectroscopy (RRS) is a non-invasive, validated method of measuring carotenoid status in skin as a biomarker of fruit/vegetable intake. The purpose of this study was to examine the feasibility of using RRS in preschool children, to describe inter individual variability in skin carotenoid status and to identify factors associated with the biomarker in this population. SUBJECTS/METHODS: We conducted a cross-sectional study of 381 economically disadvantaged preschoolers in urban centers in Connecticut (USA). In all, 85.5% were black non-Hispanic or Hispanic/Latino, and 14.1% were obese and 16.9% were overweight by age- and sex specific body mass index (BMI) percentiles. Children had their skin carotenoid status assessed by RRS in the palm of the hand. Fruit/vegetable consumption was assessed by a brief parent/guardian-completed food frequency screener and a liking survey. RESULTS: We observed inter-individual variation in RRS values that was nearly normally distributed. In multiple regression analysis, higher carotenoid status, measured by RRS, was positively associated with fruit/vegetable consumption (P=0.02) and fruit/vegetable preference (P<0.01). Lower carotenoid status was observed among younger children, those participating in the US Supplemental Nutrition Assistance Program, and those with greater adiposity (P<0.05 for all). CONCLUSIONS: We observed wide variability in skin carotenoid status in a population of young children, as assessed by RRS. Parent reported fruit/vegetable intake and several demographic factors were significantly associated with RRS-measured skin carotenoid status. We recommend further development of this biomarker in children, including evaluating response to controlled interventions. PMID- 22434054 TI - Fabrication of nanoelectrode ensembles by electrodepositon of Au nanoparticles on single-layer graphene oxide sheets. AB - Nanoelectrode ensembles (NEEs) have been fabricated by the electrodeposition of Au nanoparticles (AuNPs) on single-layer graphene oxide (GO) sheets coated on a glassy carbon electrode (GCE). The fabricated NEEs show a typical sigmoidal shaped voltammetric profile, arising from the low coverage density of AuNPs on GCE and large distance among them, which can be easily controlled by varying the electrodeposition time. As a proof of concept, after the probe HS-DNA is immobilized on the NEEs through the Au-S bonding, the target DNA is detected with the methylene blue intercalator. Our results show that the target DNA can be detected as low as 100 fM, i.e. 0.5 amol DNA in 5 MUL solution. PMID- 22434056 TI - Prenatal screening characteristics in Emanuel syndrome: a case series and review of the literature. AB - PURPOSE: Emanuel syndrome is a rare chromosomal disorder characterized by severe mental retardation and multiple anomalies. The syndrome is caused by chromosomal imbalance due to a supernumerary derivative chromosome 22. Little is known regarding the characteristics of prenatal biochemical screening, or ultrasonographic markers in this syndrome. We aimed to identify a prenatal screening pattern characteristic of Emanuel Syndrome. METHODS: We report the prenatal characteristics of five fetuses with Emanuel syndrome, four of which were diagnosed prenatally. RESULTS: We found no consistent pattern of prenatal biochemical markers or other prenatal characteristics. Nevertheless, increased NT, low PAPP-A and ultrasound features such as intra uterine growth restriction, posterior fossa, cardiac and bowel abnormalities may be helpful in raising the suspicion for this rare genetic syndrome. CONCLUSION: Review of the biochemical screening results, ultrasound findings, and demographic characteristics of this Emanuel syndrome case series, as well as of the relevant literature fail to suggest a characteristic prenatal pattern. PMID- 22434057 TI - Induction of delivery by mifepristone and misoprostol in termination of pregnancy and intrauterine fetal death: 2nd and 3rd trimester induction of labour. PMID- 22434058 TI - Foley catheter versus intra-vaginal misoprostol for induction of labor in post term gestations. AB - OBJECTIVE: To investigate whether a fluid filled intra-uterine extra-amniotic Foley catheter is an effective alternative to vaginal misoprostol in inducing labor in primigravid women with post-term gestations. PATIENTS AND METHODS: A prospective quasi-randomized controlled trial was designed and 100 primigravid women with post-term gestations were enrolled and equally allocated into two groups. A fluid filled intra-uterine extra-amniotic Foley catheter was inserted in women of group I. Women in group II received 25 microgram misoprostol vaginally every 4 h. Artificial rupture of membranes was performed for all women when their cervices reached 3-4 cm dilatation followed by oxytocin infusion if needed. The main primary outcome parameter was the induction to delivery interval. Results were tabulated and statistically analyzed. RESULTS: No significant difference was noted in any of the demographic data between both groups. The induction to delivery interval was shorter in the Foley group (897.36 +/- 116.0 vs. 960.98 +/- 94.18 min; P = 0.003). There were 34 cases which needed oxytocin augmentation in group I compared to 11 cases in group II (P < 0.01). Abnormal uterine activity occurred in three cases in the misoprostol group, but none in the Foley group. Ominous fetal heart rate was noted in one case in group I but three in group II. CONCLUSION: Fluid filled Foley catheter seems to be superior to 25 MUg vaginal misoprostol regimen, when used to induce labor in primigravidae with post-term gestations with the advantage of having a shorter induction delivery interval, but more need for oxytocin augmentation. PMID- 22434059 TI - Suppression of the Jahn-Teller distortion in a six-coordinate copper(II) complex by doping it into a host lattice. AB - The electronic structures of [Cu(terpy)(2)](2+) and [Cu(bpp)(2)](2+) (bpp = 2,6 di[pyrazol-1-yl]pyridine) are different, when doped into [M(bpp)(2)][BF(4)](2) (M(2+) = Fe(2+) or Zn(2+)). The [Cu(terpy)(2)](2+) dopant is a typical pseudo Jahn-Teller elongated copper(II) center. However, the [Cu(bpp)(2)](2+) sites show EPR spectra consistent with a tetragonally compressed {d(z(2))}(1) configuration. PMID- 22434060 TI - Push-through direct injection NMR: an optimized automation method applied to metabolomics. AB - There is a pressing need to increase the throughput of NMR analysis in fields such as metabolomics and drug discovery. Direct injection (DI) NMR automation is recognized to have the potential to meet this need due to its suitability for integration with the 96-well plate format. However, DI NMR has not been widely used as a result of some insurmountable technical problems; namely: carryover contamination, sample diffusion (causing reduction of spectral sensitivity), and line broadening caused by entrapped air bubbles. Several variants of DI NMR, such as flow injection analysis (FIA) and microflow NMR, have been proposed to address one or more of these issues, but not all of them. The push-through direct injection technique reported here overcomes all of these problems. The method recovers samples after NMR analysis, uses a "brush-wash" routine to eliminate carryover, includes a procedure to push wash solvent out of the flow cell via the outlet to prevent sample diffusion, and employs an injection valve to avoid air bubbles. Herein, we demonstrate the robustness, efficiency, and lack of carryover characteristics of this new method, which is ideally suited for relatively high throughput analysis of the complex biological tissue extracts used in metabolomics, as well as many other sample types. While simple in concept and setup, this new method provides a substantial improvement over current approaches. PMID- 22434061 TI - Splitting water with rust: hematite photoelectrochemistry. AB - This article focuses on the promise, problems and progress of utilizing hematite for photocatalyzed water oxidation. Issues which require further research are also presented. PMID- 22434062 TI - Carbon coated nano-LiTi2(PO4)3 electrodes for non-aqueous hybrid supercapacitors. AB - The Pechini type polymerizable complex decomposition method is employed to prepare LiTi(2)(PO(4))(3) at 1000 degrees C in air. High energy ball milling followed by carbon coating by the glucose-method yielded C-coated nano LiTi(2)(PO(4))(3) (LTP) with a crystallite size of 80(+/-5) nm. The phase is characterized by X-ray diffraction, Rietveld refinement, thermogravimetry, SEM, HR-TEM and Raman spectra. Lithium cycling properties of LTP show that 1.75 moles of Li (~121 mA h g(-1) at 15 mA g(-1) current) per formula unit can be reversibly cycled between 2 and 3.4 V vs. Li with 83% capacity retention after 70 cycles. Cyclic voltammograms (CV) reveal the two-phase reaction mechanism during Li insertion/extraction. A hybrid electrochemical supercapacitor (HEC) with LTP as negative electrode and activated carbon (AC) as positive electrode in non-aqueous electrolyte is studied by CV at various scan rates and by galvanostatic cycling at various current rates up to 1000 cycles in the range 0-3 V. Results show that the HEC delivers a maximum energy density of 14 W h kg(-1) and a power density of 180 W kg(-1). PMID- 22434063 TI - Resistin is associated with the inflammation process in patients with systemic autoimmune diseases undergoing glucocorticoid therapy: comparison with leptin and adiponectin. AB - OBJECTIVES: We investigated the role of adipokines in patients with systemic autoimmune diseases who received glucocorticoid therapy. METHODS: Fifty-two patients with systemic autoimmune diseases who had started glucocorticoid therapy were prospectively enrolled. One hundred forty healthy persons were also studied as controls. Serum levels of 3 adipokines [resistin, leptin, and high molecular weight (HMW)-adiponectin] were measured with enzyme-linked immunosorbent assay kits before and at weekly intervals for 4 weeks during glucocorticoid therapy. The effects of lipopolysaccharide and dexamethasone on adipokine expression in human peripheral blood mononuclear cells (PBMCs) were also examined. RESULTS: The serum resistin level was significantly higher in patients than in controls before glucocorticoid therapy, and it decreased after glucocorticoid therapy. Consistent with these results, dexamethasone inhibited lipopolysaccharide-induced upregulation of resistin expression in PBMCs in vitro. Serum leptin and HMW adiponectin levels were lower in the patients than in the controls at baseline, and both adipokine levels were increased after glucocorticoid therapy. There was a significant correlation between serum resistin and high-sensitivity C-reactive protein. However, there was no association between serum adipokines and intima media thickness. CONCLUSION: Resistin may be associated with the inflammatory process but not atherosclerosis in patients with systemic autoimmune diseases. PMID- 22434064 TI - Overexpression of insulin like growth factor binding protein 5 reduces liver fibrosis in chronic cholangiopathy. AB - The ATP-binding cassette, sub-family B member 4 knock-out mouse (Abcb4(-/-)) is a relevant model for chronic cholangiopathy in man. Due to the lack of this P glycoprotein in the canalicular membrane of hepatocytes, the secretion of phospholipids into bile is absent, resulting in increased bile toxicity. Expression of insulin like growth factor binding protein 5 (Igfbp5) increases in time in the livers of these mice. It is unclear whether this induction is a consequence of or plays a role in the progression of liver pathology. The aim of this study was therefore to investigate the effect of IGFBP5 induction on the progression of liver fibrosis caused by chronic cholangiopathy. IGFBP5 and, as a control, green fluorescent protein were overexpressed in the hepatocytes of Abcb4(-/-) mice, using an adeno-associated viral vector (AAV). Progression of liver fibrosis was studied 3, 6, and 12 weeks after vector injection by analyzing serum parameters, collagen deposition, expression of pro-fibrotic genes, inflammation and oxidative stress. A single administration of the AAV vectors provided prolonged expression of IGFBP5 and GFP in the livers of Abcb4(-/-) mice. Compared to GFP control, fractional liver weight, extracellular matrix deposition and amount of activated hepatic stellate cells significantly decreased in IGFBP5 overexpressing mice even 12 weeks after treatment. This effect was not due to a change in bile composition, but driven by reduced inflammation, oxidative stress, and proliferation. Overexpression of IGFBP5 seems to have a protective effect on liver pathology in this model for chronic cholangiopathy. PMID- 22434065 TI - Subsurface atomic force microscopy: towards a quantitative understanding. AB - Recent experiments in the field of subsurface atomic force microscopy have demonstrated that it is possible to nondestructively image micro- and even nanoparticles that are embedded significantly deep within the bulk of a sample. In order to get insights into the contrast formation mechanism, we performed a finite element analysis and an analytical study, in which we calculated the amplitude and phase variation on the surface of an ultrasound wave that has traveled through the sample. Our calculations were performed as closely as possible to the situation in the experiments to enable a (future) comparison based on our predictions. We show that Rayleigh scattering of acoustic waves accounts for the measured contrast and we verify the characteristic Rayleigh dependences. The numerical results show that the contrast is independent of the depth at which a particle is buried, whereas the analytical study reveals a 1/depth dependence. In addition, we find a large deviation in the width of the particle in the contrast at the surface when applying the numerical or the analytical calculation respectively. These results indicate the importance of both the reflections of sound waves at the sample interfaces and bulk damping, as both are treated differently in our two models. PMID- 22434066 TI - Ischemic neuroprotection by TRPV1 receptor-induced hypothermia. AB - Although treatment of stroke patients with mild hypothermia is a promising therapeutic approach, chemicals inducing prompt and safe reduction of body temperature are an unmet need. We measured the effects of the transient receptor potential vanilloid-1 (TRPV1) agonist rinvanil on thermoregulation and ischemic brain injury in mice. Intraperitoneal or intracerebroventricular injection of rinvanil induces mild hypothermia that is prevented by the receptor antagonist capsazepine. Both intraischemic and postischemic treatments provide permanent neuroprotection in animals subjected to transient middle cerebral artery occlusion (MCAo), an effect lost in mice artificially kept normothermic. Data indicate that TRPV1 receptor agonists are promising candidates for hypothermic treatment of stroke. PMID- 22434067 TI - The development, past achievements, and future directions of brain PET. AB - The early developments of brain positron emission tomography (PET), including the methodological advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clinical applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodology and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochemistry technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments. PMID- 22434068 TI - Molecular brain imaging in the multimodality era. AB - Multimodality molecular brain imaging encompasses in vivo visualization, evaluation, and measurement of cellular/molecular processes. Instrumentation and software developments over the past 30 years have fueled advancements in multimodality imaging platforms that enable acquisition of multiple complementary imaging outcomes by either combined sequential or simultaneous acquisition. This article provides a general overview of multimodality neuroimaging in the context of positron emission tomography as a molecular imaging tool and magnetic resonance imaging as a structural and functional imaging tool. Several image examples are provided and general challenges are discussed to exemplify complementary features of the modalities, as well as important strengths and weaknesses of combined assessments. Alzheimer's disease is highlighted, as this clinical area has been strongly impacted by multimodality neuroimaging findings that have improved understanding of the natural history of disease progression, early disease detection, and informed therapy evaluation. PMID- 22434069 TI - Updated energy budgets for neural computation in the neocortex and cerebellum. AB - The brain's energy supply determines its information processing power, and generates functional imaging signals. The energy use on the different subcellular processes underlying neural information processing has been estimated previously for the grey matter of the cerebral and cerebellar cortex. However, these estimates need reevaluating following recent work demonstrating that action potentials in mammalian neurons are much more energy efficient than was previously thought. Using this new knowledge, this paper provides revised estimates for the energy expenditure on neural computation in a simple model for the cerebral cortex and a detailed model of the cerebellar cortex. In cerebral cortex, most signaling energy (50%) is used on postsynaptic glutamate receptors, 21% is used on action potentials, 20% on resting potentials, 5% on presynaptic transmitter release, and 4% on transmitter recycling. In the cerebellar cortex, excitatory neurons use 75% and inhibitory neurons 25% of the signaling energy, and most energy is used on information processing by non-principal neurons: Purkinje cells use only 15% of the signaling energy. The majority of cerebellar signaling energy use is on the maintenance of resting potentials (54%) and postsynaptic receptors (22%), while action potentials account for only 17% of the signaling energy use. PMID- 22434070 TI - Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) has been used to demonstrate metabolic changes in the visual cortex on visual stimulation. Small (2% to 11%) but significant stimulation induced increases in lactate, glutamate, and glutathione were observed along with decreases in aspartate, glutamine, and glycine, using (1)H-MRS at 7 T during single and repeated visual stimulation. In addition, decreases in glucose and increases in gamma-aminobutyric acid (GABA) were seen but did not reach significance. Changes in glutamate and aspartate are indicative of increased activity of the malate-aspartate shuttle, which taken together with the opposite changes in glucose and lactate, reflect the expected increase in brain energy metabolism. These results are in agreement with those of Mangia et al. In addition, increases in glutamate and GABA coupled with the decrease in glutamine can be interpreted in terms of increased activity of the neurotransmitter cycles. An entirely new observation is the increase of glutathione during prolonged visual stimuli. The similarity of its time course to that of glutamate suggests that it may be a response to the increased release of glutamate or to the increased production of reactive oxygen species. Together, these observations constitute the most detailed analysis to date of functional changes in human brain metabolites. PMID- 22434071 TI - Changes in callosal motor fiber integrity after subcortical stroke of the pyramidal tract. AB - In the healthy brain, there are close correlations between task-related activation of the primary motor cortex (M1), the magnitude of interhemispheric inhibition, and microstructural properties of transcallosal fiber tracts. After subcortical stroke affecting the pyramidal tract (PT), an abnormal pattern of bilateral activity develops in M1. With this prospective longitudinal study, we aimed to determine whether a morphological correlate of poststroke disinhibition could be measured within 20 days and 6 months of PT stroke. Using diffusion tensor imaging with tractography, we delineated transcallosal motor fibers (CMF) in nine PT stroke patients, six patients with subcortical infarct not affecting the PT (NonPT) and six transient ischemic attack patients. We compared changes in CMF fractional anisotropy ratios (rFA) with rFA in a distinct bundle of callosal occipital fibers (COF). At the initial time point, there were no significant differences in rFA between groups and fiber bundles. At follow-up, PT-group rFA(CMF) was significantly lower than PT-group rFA(COF) and NonPT-group rFA(CMF). PT-group rFA(CMF) decreased over time and correlated with rFA of the PT (rFA(PT)) retrograde to the infarct at 6 months. Our data suggest a progressive degenerative transsynaptic effect of PT stroke on CMF, which could be a morphological correlate of transcallosal disinhibition. PMID- 22434072 TI - Prolonged therapeutic hypothermia does not adversely impact neuroplasticity after global ischemia in rats. AB - Hypothermia improves clinical outcome after cardiac arrest in adults. Animal data show that a day or more of cooling optimally reduces edema and tissue injury after cerebral ischemia, especially after longer intervention delays. Lengthy treatments, however, may inhibit repair processes (e.g., synaptogenesis). Thus, we evaluated whether unilateral brain hypothermia (~33 degrees C) affects neuroplasticity in the rat 2-vessel occlusion model. In the first experiment, we cooled starting 1 hour after ischemia for 2, 4, or 7 days. Another group was cooled for 2 days starting 48 hours after ischemia. One group remained normothermic throughout. All hypothermia treatments started 1 hour after ischemia equally reduced hippocampal CA1 injury in the cooled hemisphere compared with the normothermic side and the normothermic group. Cooling only on days 3 and 4 was not beneficial. Importantly, no treatment influenced neurogenesis (Ki67/Doublecortin (DCX) staining), synapse formation (synaptophysin), or brain derived neurotropic factor (BDNF) immunohistochemistry. A second experiment confirmed that BDNF levels (ELISA) were equivalent in normothermic and 7-day cooled rats. Last, we measured zinc (Zn), which is important in plasticity, with X-ray fluorescence imaging in normothermic and 7-day cooled rats. Hypothermia did not alter the postischemic distribution of Zn within the hippocampus. In summary, cooling significantly mitigates injury without compromising neuroplasticity. PMID- 22434073 TI - Sequencing-based molecular typing of treponema pallidum strains in the Czech Republic: all identified genotypes are related to the sequence of the SS14 strain. AB - A set of 415 clinical samples isolated from 294 patients suspected of having syphilis collected in the Czech Republic between 2004 and 2010 was tested for the presence of treponemal DNA. Standard serological tests showed that 197 patients were syphilis-seropositive and 97 patients were syphilis-seronegative. In each sample, PCR tests for polA (TP0105), tmpC (TP0319), TP0136, TP0548 and 23S rRNA genes were performed. Samples taken from 91 patients were PCR-positive. Molecular typing of treponemal DNA was based on the sequencing of TP0136, TP0548 and 23S rRNA genes. Treponemal DNA was typeable in samples taken from 64 PCR-positive patients and 9 different genotypes were found. The proportion of treponemal strains resistant to macrolide antibiotics was 37.3%. In the DNA samples taken from 39 patients, a parallel treponemal typing approved by Centers for Disease Control and Prevention was performed. The variants of arp and tpr genes appear to combine independently with sequence variants of TP0136, TP0548 and 23S rRNA genes. PMID- 22434075 TI - Loss of GATA-6 and GATA-4 in granulosa cells blocks folliculogenesis, ovulation, and follicle stimulating hormone receptor expression leading to female infertility. AB - Single GATA-6 (G6(gcko)), GATA-4 (G4(gcko)), and double GATA-4/6 (G4/6(gcko)) granulosa cell-specific knockout mice were generated to further investigate the role of GATA transcription factors in ovarian function in vivo. No reproductive defects were found in G6(gcko) animals. G4(gcko) animals were subfertile as indicated by the reduced number of pups per litter and the release of significantly fewer oocytes at ovulation. In marked contrast, G4/6(gcko) females fail to ovulate and are infertile. Furthermore, G4/6(gcko) females had irregular estrous cycles, which correlate with the abnormal ovarian histology found in unstimulated adult G4/6(gcko) females showing lack of follicular development and increased follicular atresia. Moreover, treatment with exogenous gonadotropins did not rescue folliculogenesis or ovulation in double-knockout G4/6(gcko) mice. In addition, ovary weight and estradiol levels were significantly reduced in G4(gcko) and G4/6(gcko) animals when compared with control and G6(gcko) mice. Aromatase, P450scc, and LH receptor expression was significantly lower in G4(gcko) and G4/6(gcko) mice when compared with control animals. Most prominently, FSH receptor (FSHR) protein was undetectable in granulosa cells of G4(gcko) and G4/6(gcko). Accordingly, gel shift and reporter assays revealed that GATA-4 binds and stimulates the activity of the FSHR promoter. These results demonstrate that GATA-4 and GATA-6 are needed for normal ovarian function. Our data are consistent with a role for GATA-4 in the regulation of the FSHR gene and provide a possible molecular mechanism to explain the fertility defects observed in animals with deficient GATA expression in the ovary. PMID- 22434076 TI - AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol. AB - AMP-activated protein kinase (AMPK) enhances glucose transporter GLUT4 regulation. AMPK also suppresses energy-consuming pathways such as cholesterol synthesis. Interestingly, recent in vitro and in vivo data suggest that excess membrane cholesterol impairs GLUT4 regulation. Therefore, this study tested whether a beneficial, GLUT4-regulatory aspect of AMPK stimulation involved cholesterol lowering. Using L6 myotubes stably expressing an exofacial myc epitope-tagged-GLUT4, AMPK stimulation by 5-aminoimidazole-4-carboxamide-1-beta-d ribonucleoside (AICAR; 45 min, 1 mm) or 2,4-dinitrophenol (DNP; 30 min, 200 MUm) increased cell surface GLUT4myc labeling by approximately ~ 25% (P < 0.05). Insulin (20 min, 100 nm) also increased GLUT4myc labeling by about 50% (P < 0.05), which was further enhanced (~ 25%, P < 0.05) by AICAR or DNP. Consistent with AMPK-mediated suppression of cholesterol synthesis, AICAR and DNP decreased membrane cholesterol by 20-25% (P < 0.05). Whereas AMPK knockdown prevented the enhanced basal and insulin-stimulated GLUT4myc labeling by AICAR and DNP, cholesterol replenishment only blocked the AMPK-associated enhancement in insulin action. Cells cultured in a hyperinsulinemic milieu, resembling conditions in vivo that promote the progression/worsening of insulin resistance, displayed an increase in membrane cholesterol. This occurred concomitantly with a loss of cortical filamentous actin (F-actin) and defects in GLUT4 regulation by insulin. These derangements were prevented by AMPK stimulation. Examination of skeletal muscle from insulin-resistant Zucker rats revealed a similar elevation in membrane cholesterol and loss of F-actin. Lowering cholesterol to control levels restored F-actin structure and insulin sensitivity. In conclusion, these data suggest a novel aspect of GLUT4 regulation by AMPK involves membrane cholesterol lowering. Moreover, this AMPK-mediated process protected against hyperinsulinemia induced insulin resistance. PMID- 22434077 TI - Differential entrainment of peripheral clocks in the rat by glucocorticoid and feeding. AB - The suprachiasmatic nucleus is the master circadian clock and resets the peripheral clocks via various pathways. Glucocorticoids and daily feeding are major time cues for entraining most peripheral clocks. However, recent studies have suggested that the dominant timing factor differs among organs and tissues. In our current study, we reveal differences in the entrainment properties of the peripheral clocks in the liver, kidney, and lung through restricted feeding (RF) and antiphasic corticosterone (CORT) injections in adrenalectomized rats. The peripheral clocks in the kidney and lung were found to be entrained by a daily stimulus from CORT administration, irrespective of the meal time. In contrast, the liver clock was observed to be entrained by an RF regimen, even if daily CORT injections were given at antiphase. These results indicate that glucocorticoids are a strong zeitgeber that overcomes other entrainment factors regulating the peripheral oscillators in the kidney and lung and that RF is a dominant mediator of the entrainment ability of the circadian clock in the liver. PMID- 22434078 TI - Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. AB - The links between obesity in parents and their offspring and the role of genes and a shared environment are not completely understood. Adipocytokines such as leptin and adiponectin play important roles in glucose and lipid metabolism. Therefore, we examined whether the offspring from dams exposed to a high-fat diet during pregnancy (OH mice) exhibited hypertension, insulin resistance, and hyperlipidemia along with epigenetic changes in the expression of adipocytokine genes. OH mice were significantly heavier than the offspring of dams exposed to a control diet during pregnancy (OC mice) from 14 wk of age after an increased caloric intake from 8 wk. OH mice exhibited higher blood pressure and worse glucose tolerance than the OC mice at 24 wk. Total triglyceride and leptin levels were significantly higher and the adiponectin level was significantly lower in OH compared with OC mice at 12 wk of age. This was associated with changes in leptin and adiponectin expression in white adipose tissue. There were lower acetylation and higher methylation levels of histone H3 at lysine 9 of the promoter of adiponectin in adipose tissues of OH mice at 2 wk of age as well as at 12 and 24 wk of age compared with OC mice. In contrast, methylation of histone 4 at lysine 20 in the leptin promoter was significantly higher in OH compared with OC mice. Thus, exposure to a high-fat diet in utero might cause a metabolic syndrome-like phenomenon through epigenetic modifications of adipocytokine, adiponectin, and leptin gene expression. PMID- 22434079 TI - Immune cells have sex and so should journal articles. AB - Males and females have the same immunological cells, proteins, and pathways in place to protect against the development of disease. The kinetics, magnitude, and skewing of the responses mounted against pathogens, allergens, toxins, or self antigens, however, can differ dramatically between the sexes. Generally, females mount higher innate and adaptive immune responses than males, which can result in faster clearance of pathogens but also contributes to increased susceptibility to inflammatory and autoimmune diseases in females compared with males. Hormonal and genetic factors contribute significantly to sex differences in immune function and disease pathogenesis. In particular, the expression of X-linked genes and microRNA as well as sex steroid hormones signaling through hormone receptors in immune cells can affect responses to immunological stimuli differently in males and females. Despite data illustrating profound differences between the sexes in immune function, sex differences in the pathogenesis of disease are often overlooked in biomedical research. Establishing journal policies that require authors to report the sex of their cells, animals, and subjects will improve our understanding of the pathogenesis of diseases, with the long-term goal of personalizing treatments for immune-mediated diseases differently for males and females in an effort to protect us equally. PMID- 22434080 TI - Placental restriction reduces insulin sensitivity and expression of insulin signaling and glucose transporter genes in skeletal muscle, but not liver, in young sheep. AB - Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (-43%, P < 0.001) and skeletal muscle expression of INSR (-36%), IRS1 (-28%), AKT2 ( 44%), GLUT4 (-88%), GSK3alpha (-35%), and GYS1 (-31%) overall (each P < 0.05) and decreased AMPKgamma3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKgamma2, and AMPKgamma3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver. PMID- 22434082 TI - Identification of iopanoic acid as substrate of type 1 deiodinase by a novel nonradioactive iodide-release assay. AB - Enzymatic 5'- and 5-deiodination are key reactions for local and systemic activation and inactivation of iodothyronines and thyronamines. Expression of the three deiodinase (DIO) isoenzymes is regulated by a number of parameters, including thyroid status, genotype, micronutrient availability, and disease related signaling. In addition, DIO are potential targets of pharmacological as well as environmentally derived substances, which might affect their enzymatic activity (endocrine disruptors). With the classical DIO activity assay, testing depends on the availability of radioactively labeled substrates (e.g. (125)I rT(3)) to monitor the release of radioactive iodide. Recently, liquid chromatography-tandem mass spectrometry was described as an alternative method apparently resolving this limitation. However, it has a high demand in technical equipment and analytical routine and is limited in sample number by considerable measuring time. We therefore combined the classical deiodination assay with an easily accessible photometric method taking advantage of the Sandell-Kolthoff reaction for measuring iodide release. In brief, iodine works as a catalyst within this redox reaction between Ce(4+) and As(3+) leading to an acceleration of destaining. Furthermore, the protocol was adapted to minimize handling effort and time consumption. Because this method is not dependent on radioactivity, it expands the substrate spectrum of the classical method. Suitability of this assay was tested with tissue samples from animal experiments (hepatic Dio1 activity in hypo- and hyperthyroid mice) and established DIO inhibitors. As a new but not unexpected finding, the alleged inhibitor iopanoic acid turned out to be a DIO substrate. This finding was confirmed by liquid chromatography-tandem mass spectrometry, and its potential clinical impact requires further studies. PMID- 22434081 TI - Expression of P450c17 in the human fetal nervous system. AB - P450c17 catalyzes steroid 17alpha-hydroxylase and 17,20 lyase activities. P450c17 is expressed in human fetal and postnatal adrenals and gonads and in the developing mouse nervous system, but little is known about its expression in the human nervous system. We obtained portions of 9-, 10-, and 11-wk gestation human fetuses and delineated the pattern of expression of P450c17 in their peripheral nervous systems by immunocytochemistry using the P450c17 antiserum previously used to characterize P450c17 in the mouse brain. P450c17 was readily detected in the dorsal root ganglia (DRG) and spinal cord. Neural structures were identified with antisera to the cytoskeletal protein neural cell adhesion molecule; DRG were identified with antisera to the neuronal transcription factor BRN3A and neurotrophin receptor tropomyosin-receptor-kinase B. The identification of P450c17 was confirmed using commercial antisera directed against different domains of P450c17 and by using antisera immunodepleted with authentic human P450c17. We also found expression of the P450 cholesterol side-chain cleavage enzyme (P450scc) in the spinal cord and DRG. Expression of P450scc is limited to cell bodies; unlike P450c17, we never detected P450scc in fiber tracts. Catalysis by P450c17 requires electron donation from P450 oxidoreductase (POR). Dual-label immunohistochemistry detected P450c17 and POR colocalized in DRG bundles, but some fibers containing P450c17 lacked POR. These data suggest that neurosteroids synthesized via these two enzymes may act in the developing human nervous system. The expression of P450c17 in structures lacking POR means that P450c17 may not be steroidogenic in those locations, suggesting that P450c17 may have additional functions that do not require POR. PMID- 22434083 TI - One dose of ghrelin prevents the acute and sustained increase in cardiac sympathetic tone after myocardial infarction. AB - Acute myocardial infarction (MI) increases sympathetic nerve activity (SNA) to the heart, which exacerbates chronic cardiac deterioration. The hormone ghrelin, if administered soon after an MI, prevents the increase in cardiac SNA and improves early survival prognosis. Whether these early beneficial effects of ghrelin also impact on cardiac function in chronic heart failure has not yet been addressed and thus was the aim of this study. MI was induced in Sprague Dawley rats by ligating the left coronary artery. One bolus of saline (n = 7) or ghrelin (150 MUg/kg, sc, n = 9) was administered within 30 min of MI. Two weeks after the infarct (or sham; n = 7), rats were anesthetized and cardiac function was evaluated using a Millar pressure-volume conductance catheter. Cardiac SNA was measured using whole-nerve electrophysiological techniques. Untreated-MI rats had a high mortality rate (50%), evidence of severe cardiac dysfunction (ejection fraction 28%; P < 0.001), and SNA was significantly elevated (102% increase; P = 0.03). In comparison, rats that received a single dose of ghrelin after the MI tended to have a lower mortality rate (25%; P = NS) and no increase in SNA, and cardiac dysfunction was attenuated (ejection fraction of 43%; P = 0.014). This study implicates ghrelin as a potential clinical treatment for acute MI but also highlights the importance of therapeutic intervention in the early stages after acute MI. Moreover, these results uncover an intricate causal relationship between early and chronic changes in the neural control of cardiac function in heart failure. PMID- 22434084 TI - Understanding the sexome: measuring and reporting sex differences in gene systems. AB - The current male bias in biomedical research should be eliminated. The large sex differences in incidence and progression of diseases mean that sex-biased factors are an untapped source of factors that protect from disease. Greater understanding will come from intensified study of the "sexome," which is the sum of sex-biased effects on gene networks and cell systems. The global search for sites and mechanisms of sex-specific regulation in diverse tissues will provide unanticipated insights into physiological regulation and targets for novel therapies. PMID- 22434085 TI - Angiotensin-(1-7) administration reduces oxidative stress in diabetic bone marrow. AB - Diabetics have an increased risk of developing cardiovascular disease, in part due to oxidative stress, resulting in endothelial nitric oxide synthase (eNOS) dysfunction. Studies have demonstrated that angiotensin-(1-7) [Ang-(1-7)] can activate eNOS activity. Because the bone marrow is a primary source of a number of progenitors important in physiological homeostasis and healing, the goal of this study was to evaluate the in vivo effects of Ang-(1-7) treatment on oxidative stress and the ensuing nitrative stress in diabetic bone marrow and its potential pathways. BKS.Cg-Dock7(m) +/+ Lepr(db)/J mice and their heterozygous controls were administered Ang-(1-7) alone or combined with A-779, losartan, PD123,319, nitro-l-arginine methyl ester, or icatibant sc for 14 d. The bone marrow was then collected to measure nitric oxide levels, eNOS phosphorylation, and expression of nitric oxide synthase, superoxide dismutase, and p22-phox. Nitric oxide levels in the bone marrow were significantly decreased in diabetic mice, and Ang-(1-7) treatment was able to significantly increase these measures (P < 0.01). This effect was blocked by the coadministration of PD123,319, A-779, nitro-l-arginine methyl ester, and icatibant. In addition, Ang-(1-7) treatment reversed the paradoxical increase in eNOS and neuronal nitric oxide synthase expression and decreased the phosphorylation of eNOS at Thr495 seen in diabetic mice. Ang-(1-7) also reversed diabetes-induced production of reactive oxygen species by decreasing p22-phox expression and increasing superoxide dismutase 3 expression, leading to a significant reduction in 3-nitrotyrosine formation in diabetic bone marrow (P < 0.05). Our findings demonstrate that Ang-(1-7) administration decreases diabetes-induced oxidative stress in the bone marrow and modifies pathways involved in eNOS dysfunction. PMID- 22434086 TI - The ERbeta ligand 5alpha-androstane, 3beta,17beta-diol (3beta-diol) regulates hypothalamic oxytocin (Oxt) gene expression. AB - The endocrine component of the stress response is regulated by glucocorticoids and sex steroids. Testosterone down-regulates hypothalamic-pituitary-adrenal (HPA) axis activity; however, the mechanisms by which it does so are poorly understood. A candidate testosterone target is the oxytocin gene (Oxt), given that it too inhibits HPA activity. Within the paraventricular nucleus of the hypothalamus, oxytocinergic neurons involved in regulating the stress response do not express androgen receptors but do express estrogen receptor-beta (ERbeta), which binds the dihydrotestosterone metabolite 3beta,17beta-diol (3beta-diol). Testosterone regulation of the HPA axis thus appears to involve the conversion to the ERbeta-selective ligand 5alpha-androstane, 3beta-diol. To study mechanisms by which 3beta-diol could regulate Oxt expression, we used a hypothalamic neuronal cell line derived from embryonic mice that expresses Oxt constitutively and compared 3beta-diol with estradiol (E2) effects. E2 and 3beta-diol elicited a phasic response in Oxt mRNA levels. In the presence of either ligand, Oxt mRNA levels were increased for at least 60 min and returned to baseline by 2 h. ERbeta occupancy preceded an increase in Oxt mRNA levels in the presence of 3beta-diol but not E2. In tandem with ERbeta occupancy, 3beta-diol increased occupancy of the Oxt promoter by cAMP response element-binding protein and steroid receptor coactivator-1 at 30 min. At the same time, 3beta-diol led to the increased acetylation of histone H4 but not H3. Taken together, the data suggest that in the presence of 3beta-diol, ERbeta associates with cAMP response element-binding protein and steroid receptor coactivator-1 to form a functional complex that drives Oxt gene expression. PMID- 22434087 TI - Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. AB - Puberty onset in female sheep is marked by a decrease in estradiol-negative feedback, allowing for the increase in GnRH and LH pulses that heralds the first ovulation. Based on recent genetic studies in humans, two possible neuropeptides that could promote puberty onset are kisspeptin and neurokinin B (NKB). Our first experiment determined whether the NKB agonist, senktide, could stimulate LH secretion in prepubertal ewes. A second study used prepubertal and postpubertal ewes that were intact or ovariectomized (OVX) to test the hypothesis that expression of kisspeptin and NKB in the arcuate nucleus increased postpubertally. For comparison, kisspeptin and NKB expression in age-matched intact, and castrated males were also examined. In experiment 1, the percentage of ewes showing an LH pulse immediately after injection of senktide (100 MUg, 60%; 500 MUg, 100%) was greater than that for water-injected controls (experiment 1a, 25%; experiment 1b, 20%). In experiment 2, kisspeptin-positive cell numbers in the arcuate nucleus increased after puberty in intact females and were increased by OVX in prepubertal but not postpubertal ewes. Changes in kisspeptin cell numbers were paralleled by changes in kisspeptin-close contacts onto GnRH neurons in the medial preoptic area. NKB cell numbers did not differ significantly between intact prepubertal and postpubertal ewes but increased with OVX in both age groups. NKB fiber immunoreactivity was greater in postpubertal than in prepubertal intact ewes. In age-matched males, kisspeptin and NKB cell numbers increased with castration, but decreased with age. These results support the hypothesis that kisspeptin is a gatekeeper to female ovine puberty and raise the possibility that NKB may also play a role, albeit through different means. PMID- 22434088 TI - Time to harmonise common laboratory test profiles. PMID- 22434089 TI - Patient safety, satisfaction, and quality of hospital care: cross sectional surveys of nurses and patients in 12 countries in Europe and the United States. AB - OBJECTIVE: To determine whether hospitals with a good organisation of care (such as improved nurse staffing and work environments) can affect patient care and nurse workforce stability in European countries. DESIGN: Cross sectional surveys of patients and nurses. SETTING: Nurses were surveyed in general acute care hospitals (488 in 12 European countries; 617 in the United States); patients were surveyed in 210 European hospitals and 430 US hospitals. PARTICIPANTS: 33 659 nurses and 11 318 patients in Europe; 27 509 nurses and more than 120 000 patients in the US. MAIN OUTCOME MEASURES: Nurse outcomes (hospital staffing, work environments, burnout, dissatisfaction, intention to leave job in the next year, patient safety, quality of care), patient outcomes (satisfaction overall and with nursing care, willingness to recommend hospitals). RESULTS: The percentage of nurses reporting poor or fair quality of patient care varied substantially by country (from 11% (Ireland) to 47% (Greece)), as did rates for nurses who gave their hospital a poor or failing safety grade (4% (Switzerland) to 18% (Poland)). We found high rates of nurse burnout (10% (Netherlands) to 78% (Greece)), job dissatisfaction (11% (Netherlands) to 56% (Greece)), and intention to leave (14% (US) to 49% (Finland, Greece)). Patients' high ratings of their hospitals also varied considerably (35% (Spain) to 61% (Finland, Ireland)), as did rates of patients willing to recommend their hospital (53% (Greece) to 78% (Switzerland)). Improved work environments and reduced ratios of patients to nurses were associated with increased care quality and patient satisfaction. In European hospitals, after adjusting for hospital and nurse characteristics, nurses with better work environments were half as likely to report poor or fair care quality (adjusted odds ratio 0.56, 95% confidence interval 0.51 to 0.61) and give their hospitals poor or failing grades on patient safety (0.50, 0.44 to 0.56). Each additional patient per nurse increased the odds of nurses reporting poor or fair quality care (1.11, 1.07 to 1.15) and poor or failing safety grades (1.10, 1.05 to 1.16). Patients in hospitals with better work environments were more likely to rate their hospital highly (1.16, 1.03 to 1.32) and recommend their hospitals (1.20, 1.05 to 1.37), whereas those with higher ratios of patients to nurses were less likely to rate them highly (0.94, 0.91 to 0.97) or recommend them (0.95, 0.91 to 0.98). Results were similar in the US. Nurses and patients agreed on which hospitals provided good care and could be recommended. CONCLUSIONS: Deficits in hospital care quality were common in all countries. Improvement of hospital work environments might be a relatively low cost strategy to improve safety and quality in hospital care and to increase patient satisfaction. PMID- 22434090 TI - What will the Health and Social Care Bill mean for the NHS in England? PMID- 22434091 TI - Girl who had surgery to correct bronchial atresia in utero is healthy. PMID- 22434092 TI - European research is launched into hypothermia stroke treatment. PMID- 22434093 TI - An organocatalytic Michael-aldol cascade: formal [3+2] annulation to construct enantioenriched spirocyclic oxindole derivatives. AB - An efficient organocatalytic Michael-aldol cascade reaction for the asymmetric synthesis of spirocyclic oxindole derivatives fused with tetrahydrothiophenes has been developed through a formal [3+2] annulation strategy. PMID- 22434094 TI - Enhancing the SERS properties of nanoworms by matrix formation. AB - A highly SERS-active substrate was fabricated by trapping gold "nanoworms" on commercially available filter membranes providing significant enhancement of the Raman signal as a result of the remarkable electromagnetic couplings induced by the dense packing. The resultant substrate provides a simple and cost-effective porous SERS surface for use and quantitative analytical procedures. PMID- 22434095 TI - Lactobacillus plantarum 299v does not reduce enteric bacteria or bacterial translocation in patients undergoing colon resection. AB - BACKGROUND: Probiotics may exert beneficial effects in the gastrointestinal tract. This randomized trial investigated the effect of the probiotic Lactobacillus plantarum 299v on the intestinal load of potentially pathogenic bacteria, bacterial translocation, and cell proliferation in elective colon surgery. METHODS: Seventy-five patients were randomized to pre- and postoperative oral intake of Lactobacillus plantarum 299v or placebo. Rectal swabs and mucosal biopsies were taken before the start of intake, after 1 week, at surgery, and after 6 days, weeks, and months. Viable counts were quantified for clostridia, Enterobacteriaceae, Gram-negative anaerobes, and lactobacilli. Bacterial translocation was determined by the analysis of bacterial DNA genes in mesenteric lymph nodes. Ki-67 was used as a marker of cell proliferation in normal mucosa and tumor. RESULTS: Lactobacillus plantarum 299v was given without adverse effects. Lactobacillus plantarum 299v as well as Enterobacteriaceae and Gram negative anaerobes increased in the colon 1 week after the administration of Lactobacillus plantarum 299v. There were no significant differences between patients receiving Lactobacillus plantarum 299v and placebo in the incidence of bacterial translocation (27 vs. 13%) and postoperative complications (16 vs. 31%). CONCLUSIONS: Lactobacillus plantarum 299v was established in the intestine, but no inhibitory effect on enteric bacteria, bacterial translocation, or postoperative complications was found. The mechanism behind the protective effects of probiotics found in animal and some human studies remain elusive and require further explorations. No adverse effects were recorded after the administration of high doses of Lactobacillus plantarum 299v. PMID- 22434096 TI - Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. PMID- 22434098 TI - Energetics and dynamics of a new type of extended line defects in graphene. AB - We revealed a novel extended line defect (ELD) containing tetragonal rings embedded in graphene, formed as a growth fault, with its energetic and dynamic behavior studied via first-principles calculations. In our finding based upon the molecular dynamics simulation, transformation between locally stable ELDs in graphene at high temperatures simultaneously with contrastive electronic properties can be applied to predetermine the formation process and reconstruction of ELDs. PMID- 22434099 TI - Comparative analysis of tumor-infiltrating lymphocytes in a syngeneic mouse model of oral cancer. AB - OBJECTIVE: To perform a comparative analysis of infiltrating immune cells in a newly developed C57BL/6 background syngeneic transplantable mouse oral cancer (MOC) model. STUDY DESIGN/SETTING: Scientific study in an academic medical center. METHODS: Use of carcinogen-induced tumorigenesis, tissue culture, cell line transplantation, and flow cytometric analysis techniques. RESULTS: Previously, the authors established a series of cell line models that displayed dichotomous growth phenotypes when transplanted into immunocompetent mice. They now show that the indolent growth pattern of the MOC1-generated tumors is associated with increased baseline and inducible major histocompatibility complex class I expression and increased CD8(+) T-cell infiltration into the tumor microenvironment. Conversely, the aggressive and metastatic pattern of MOC2 generated tumors has decreased basal and inducible class I expression and is associated with FOXP3(+)CD4(+) regulatory T-cell infiltration. Delayed primary tumor growth after targeted monoclonal antibody therapy of these FOXP3(+) regulatory cells further suggests that these immune cells contribute to the aggressive phenotype of MOC2. CONCLUSION: These data validate that key infiltrating immune cells identified here parallel findings in human head and neck cancer, making this newly developed syngeneic model a critical platform for the continued dissection of tumor-host interactions in head and neck cancer. PMID- 22434100 TI - A case of anthracofibrosis presenting with paratracheal mass compressing trachea. PMID- 22434101 TI - Cricopharyngeal muscle electromyography findings in patients with gastroesophageal reflux disease. AB - OBJECTIVE: To analyze the grade of reflux and the behavior of the cricopharyngeal muscle (CPM) in patients with gastroesophageal reflux (GER) by means of electromyographic (EMG) analysis of CPM. STUDY DESIGN: Prospective clinical study. SETTING: Istanbul Training and Research Hospital. SUBJECT AND METHODS: Motor unit potential (MUP) recordings and kinesiological recordings of CPM were performed using a concentric needle electrode during dry material swallowing and 3-, 5-, and 10-mL water swallowing. Twenty-four patients with GER were compared with 21 healthy volunteers. RESULTS: GER was mild in 15 patients and moderate-to severe in 9 patients. MUP recordings were normal in both groups during the preswallowing/postswallowing periods. Kinesiological investigations revealed that the number of patients who did not show a preswallow EMG burst had a positive correlation with the severity of reflux and the amount of liquid swallowed. Rebound bursts were observed in the patient and the control groups. Duration of preswallow and rebound bursts was similar in all groups. Duration of swallowing was shorter in mild GER patients compared with healthy volunteers and moderate-to severe GER patients. Piecemeal deglutition during 10-mL liquid swallowing was higher in moderate-to-severe GER patients. We also found a positive correlation between the number of swallows and the severity of reflux. CONCLUSION: Needle EMG of the upper esophageal sphincter was normal in GER patients. Kinesiological evaluations showed increased piecemeal deglutition and number of swallows that correlated positively with the severity of GER. PMID- 22434102 TI - Association between HLA-DQB1 gene and patients with acute lymphoblastic leukemia (ALL). AB - Acute lymphoblastic leukemia (ALL) affects both children and adults. Survival in ALL has improved in recent decades due to recognition of its biological heterogeneity. Although children have higher remission and cure rates than adults, both populations have benefited from these improvements. Our aim in this study is to determine the association between HLA-DQB1 genes with childhood and adult ALL patients. To define this association, we compared HLA-DQB1 allele frequencies and allele carrier frequencies in a cohort of 135 adults and children with ALL with 150 controls, using polymerase chain reaction with sequence specific primers. Allele carrier frequencies in childhood ALL show a deficiency in DQ2 (*0201) (P 0.049 and RR 0.75), but an increase in DQ5 (*0501-*0504) and DQ7 (*0301, *0304) compared to the control group (P 0.001 RR 1.89, P 0.003 RR 1.48, respectively). Allele carrier frequencies in adult ALL indicated an increase in DQ5 (*0501-*0504) (P0.045 RR 2.28). Allelic frequencies in childhood ALL revealed the same increase in DQ5 and DQ7, and a decrease in DQ2. In adult ALL it shows a decrease in DQ7. Therefore, our results in adult ALL were similar to childhood ALL addressing DQ5 allele carriers, which showed an increase in both age groups. We suggest that DQ5 could be more strongly considered as an ALL susceptibility allele, and that this allele may underlie a pathogenic phenotype with a major role in the immunologic process involved in both adults and children with ALL. PMID- 22434103 TI - Introduction to RAMPs. AB - Receptor activity modifying proteins (RAMPs) are single transmembrane proteins discovered for their role in the regulation of translocation of certain G-protein coupled receptors (GPCRs) to the plasma membrane. Since its discovery in 1998, several pivotal advances have been made in understanding the function of this family of proteins. This chapter provides a basic introduction to RAMPs as well as details on the various chapters in this book. PMID- 22434104 TI - RAMPs and CGRP receptors. AB - Receptor activity modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor (CLR) to produce the receptor for calcitonin gene-related peptide (CGRP). RAMP1 has two main roles. It facilitates the cell-surface expression of CLR. It is also essential for the binding of CGRP to the receptor. It seems likely that Y66, F93, H97 and F101, amongst other residues, form a binding site for CLR. These cluster together on the same face of the extracellular portion of RAMP1, probably close to where it enters the plasma membrane. Residues at the other end of RAMP1 are most likely to be involved in CGRP recognition, although it is currently unclear how they do this. Within this area, W74 is important for the binding of the nonpeptide antagonist, BIBN4096BS, although it does not seem to be involved in the binding of CGRP itself. It has been shown that there is an epitope within residues 23-60 of CLR that are essential for RAMP recognition. Under some circumstances, changes in the expression of RAMP1 can alter the sensitivity of cells to CGRP, demonstrating that regulation of its levels may be of physiological or pathophysiological importance. PMID- 22434105 TI - Regulation of GPCR trafficking by RAMPs. AB - AM and CGRP receptors undergo differential intracellular receptor trafficking upon ligand stimulation. Intracellular trafficking of CLR/RAMP receptor complexes is regulated by posttranslational modifications and protein-protein interactions that differ for each cell type. Recent evidence is accumulating to suggest that the RAMP isoform in complex with CLR may play a role in determining the intracellular trafficking and fate of ligand-stimulated receptor complexes. In this chapter, we will review the current literature on mechanisms of regulating receptor trafficking and roles that have been demonstrated for RAMPs in this regulation. PMID- 22434106 TI - Regulation of calcium sensing receptor trafficking by RAMPs. AB - As mentioned earlier in this book, RAMPs were identified as proteins escorting the Calcitonin Receptor-Like Receptor (CRLR) to the plasma membrane (PM) to generate either CGRP (when associated with RAMP1), or adrenomedullin receptors (when associated with RAMP2 or RAMP3). Some years after this initial discovery, it was established that RAMPs can accompany four additional class B G Protein Coupled Receptors-GPCRs- (PTH1, PTH2, glucagon receptor and VPAC1) to the PM.(1) By demonstrating that the sorting traffic of the Calcium Sensing Receptor (CaSR), a class C GPCR, is positively modulated by RAMP1 and RAMP3,(2) our data extended the concept of RAMPs as escorting molecules to another class of GPCRs. PMID- 22434107 TI - Understanding RAMPs through genetically engineered mouse models. AB - The family of Receptor Activity Modifying Proteins (RAMPs) consists of three members, RAMP1, 2 and 3, which are each encoded by a separate gene and have diverse spatiotemporal expression patterns. Biochemical and pharmacological studies in cultured cells have shown that RAMPs can modulate several aspects of G receptor (GPCR) signaling, including receptor trafficking, ligand binding affinity, second messenger signaling and receptor desensitization. Moreover, these studies have shown that RAMPs can interact with several GPCRs other than the canonical calcitonin receptor-like receptor (CLR), with which they were first identified. Given these expanding roles for RAMPs, it becomes interesting to question how these biochemical and pharmacological properties bear significance in normal or disease physiology. To this end, several gene targeted knockout and transgenic models have been generated and characterized in recent years. Fortunately, they have each supported important roles for RAMPs during embryonic development and adulthood. This chapter provides a comprehensive overview of the most recent findings from gene targeted knockout mouse models and transgenic over expression models, and gives special consideration to how comparative phenotyping approaches and conditional deletion strategies can be highly beneficial. In the future, these genetically engineered mouse models will provide both insights and tools for the exploitation of RAMP-based therapies for the treatment of human diseases. PMID- 22434108 TI - RAMPs as drug targets. AB - The receptor activity-modifying protein (RAMP) family of membrane proteins regulates G protein-coupled receptor (GPCR) function in several ways. RAMPs can alter their pharmacology and signalling as well as the trafficking of these receptors to and from the cell surface. Accordingly, RAMPs may be exploited as drug targets, offering new opportunities for regulating the function of therapeutically relevant RAMP-interacting GPCRs. For example, several small molecule antagonists of RAMP1/ calcitonin receptor-like receptor complexes, which block the actions of the neuropeptide calcitonin gene-related peptide are in development for the treatment of migraine headache. PMID- 22434109 TI - RAMP like proteins : RTP and REEP family of proteins. AB - Mammalian odorant receptors (ORs) are typically retained in the endoplasmic reticulum (ER) when expressed in heterologous cells. The RTP (Receptor Transporting Protein) and REEP (Receptor Expression Enhancing Protein) family of proteins were first identified as partners for ORs, promoting cell-surface expression and leading to functional responses in heterologous cell systems. Like RAMPs, the RTP and REEP proteins appear to partner with GPCRs to promote cell surface expression. Unlike RAMPs, they do not appear to alter the pharmacology of the partner receptor. PMID- 22434110 TI - Regulation of RAMP expression in diseases. AB - Receptor-activity modifying proteins (RAMPs) belong to a single family of transmembrane proteins. RAMPs determine ligand specificity of G-protein coupled receptors; calcitonin receptor and the calcitonin-receptor like receptor (CLR). To date, three members of RAMP family (RAMP-1, -2, -3) have been identified. The co-expression of RAMP-1 with CLR constitutes the calcitonin gene related peptide receptor whereas the association of the RAMP-2 or RAMP-3 with CLR forms the adrenomedullin (AM) receptor. Alterations in signaling and subcellular distribution of G-protein coupled receptors can be responsible for the regulation of many disease conditions. These changes may be mediated by the different isoforms of RAMPs associated with such receptors. In this chapter, we describe the differential responses associated with upregulation of RAMPs in disease conditions. For instance, the upregulation of all three RAMP isoforms contributes to the cardioprotective effects of the CLR/RAMP ligands. On the other hand, strong evidence exists for the involvement of AM in various cancers and that its action is mediated by the upregulation of RAMP isoforms, RAMP-2 and -3. Though limited, a few studies have been reported on the differential response associated with the upregulation of RAMP in other disease conditions such as sepsis, liver cirrhosis, glomerulonephritis, Type 1 diabetes and Parkinson's disease. Thus, the regulation of RAMP expression is involved in the pathophysiology associated with various diseases. PMID- 22434111 TI - Perspectives on some recent studies on RAMPs. AB - This book on RAMPs covers a number of aspects on the biology of RAMPs. However, due to the uniqueness of some recent studies, they were not covered under a general title. Therefore, in this chapter, we describe three recent studies wherein RAMPs were found to be important players in cancer, hypertension and asthma. PMID- 22434112 TI - Cutaneous and mucocutaneous leishmaniasis resembling borderline-tuberculoid leprosy: a new clinical presentation? AB - Both cutaneous and mucocutaneous leishmaniasis are endemic in Northern Ethiopia. The different clinical presentations depend on the responsible organism and the host's immune response. Localized cutaneous leishmaniasis is the type most frequently seen. Diffuse cutaneous leishmaniasis is relatively rare and usually associated with mucous membrane involvement. Diffuse cutaneous leishmaniasis presents with multiple lesions, can be difficult to diagnose and responds less favourably to treatment. We report here 2 patients with unusual presentations of diffuse cutaneous leishmaniasis presenting with large hypopigmented skin lesions mimicking borderline-tuberculoid leprosy. To our knowledge this presentation has not been described before and may present difficulties in making a definite diagnosis in regions where both leprosy and cutaneous leishmaniasis are endemic. Lepromatous leprosy and diffuse cutaneous leishmaniasis are regularly confused, particularly when no skin smears for acid-fast bacillus or Leishman-Donovan bodies are performed. PMID- 22434113 TI - Cancer incidence and soil arsenic exposure in a historical gold mining area in Victoria, Australia: a geospatial analysis. AB - Soil and mine waste around historical gold mining sites may have elevated arsenic concentrations. Recent evidence suggests some systemic arsenic absorption by residents in the goldfields region of Victoria, Australia. Victorian Cancer Registry and geochemical data were accessed for an ecological geographical correlation study, 1984-2003. Spatial empirical Bayes smoothing was applied when estimating standardised incidence ratios (SIRs) for cancers in 61 statistical local areas. The derived soil arsenic exposure metric ranged from 1.4 to 1857 mg/kg. Spatial autoregressive modelling detected increases in smoothed SIRs for all cancers of 0.05 (95% confidence interval (CI), 0.02-0.08) and 0.04 (0.01 0.07) per 2.7-fold increase in the natural log-transformed exposure metric for males and females, respectively, in more socioeconomically disadvantaged areas; for melanoma in males (0.05 (0.01-0.08) adjusted for disadvantage) and females (0.05 (0.02-0.09) in disadvantaged areas). Excess risks were estimated for all cancers (relative risk 1.21 (95% CI, 1.15-1.27) and 1.08 (1.03-1.14)), and melanoma (1.52 (1.25-1.85) and 1.29 (1.08-1.55)), for males and females, respectively, in disadvantaged areas in the highest quintile of the exposure metric relative to the lowest. Our findings suggest small but significant increases in past cancer risk associated with increasing soil arsenic in socioeconomically disadvantaged areas and demonstrate the robustness of this geospatial approach. PMID- 22434114 TI - Quantifying children's aggregate (dietary and residential) exposure and dose to permethrin: application and evaluation of EPA's probabilistic SHEDS-Multimedia model. AB - Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticide's widespread use and potential health effects. SHEDS-Multimedia was applied to estimate US population permethrin exposures for 3- to 5-year-old children from residential, dietary, and combined exposure routes, using available dietary consumption data, food residue data, residential concentrations, and exposure factors. Sensitivity and uncertainty analyses were conducted to identify key factors, pathways, and research needs. Model evaluation was conducted using duplicate diet data and biomonitoring data from multiple field studies, and comparison to other models. Key exposure variables were consumption of spinach, lettuce, and cabbage; surface to-skin transfer efficiency; hand mouthing frequency; fraction of hand mouthed; saliva removal efficiency; fraction of house treated; and usage frequency. For children in households using residential permethrin, the non-dietary exposure route was most important, and when all households were included, dietary exposure dominated. SHEDS-Multimedia model estimates compared well to real-world measurements data; this exposure assessment tool can enhance human health risk assessments and inform children's health research. The case study provides insights into children's aggregate exposures to permethrin and lays the foundation for a future cumulative pyrethroid pesticides risk assessment. PMID- 22434115 TI - Highly ordered staging structural interface between LiFePO4 and FePO4. AB - A highly ordered interface between LiFePO(4) phase and FePO(4) phase with staging structure along the a axis and perpendicular to the b axis direction has been observed for the first time, in a partially chemically delithiated Li(0.90)Nb(0.02)FePO(4) by advanced aberration-corrected annular-bright-field (ABF) scanning transmission electron microscopy (STEM). PMID- 22434116 TI - Competitive inhibition of a metal-free porphyrin oxygen-reduction catalyst by water. AB - A stopped-flow method is used to study the effects of water and reactant acid anion TB(-) = tetrakis(pentafluorophenyl)borate on the homogeneous oxygen reduction catalyzed by the protonated tetraphenylporphyrin. Observed competitive inhibition of the catalyst is linked to the DFT free energy of extraction of O(2), water, and TB(-) from the porphyrin complex. PMID- 22434117 TI - Gene expression profiling of a cold-shocked earthworm Eisenia andrei. AB - To identify genes that are modulated under cold-stress conditions in the earthworm Eisenia andrei, we performed a genome-wide analysis of gene expression in cold-shocked earthworms by using Serial Analysis of Gene Expression (SAGE). We identified 5,977 and 5,407 unique SAGE tags under normal and cold-stressed conditions, respectively. The majority of the SAGE tags did not match to any known expressed sequences, due to a paucity of expression data in earthworms. We converted the statistically significant SAGE tags for the cold-stressed condition into expressed sequence tags (ESTs), and the results showed that particular genes associated with energy homeostasis, cellular defense mechanisms, and ion balance were up-regulated or down-regulated. We constructed a regulatory network of some of these genes and identified rps-6 as a core gene in the cold-response regulatory-gene network. Our data provide a baseline for gene expression studies of cold shock in the Lumbricidae. PMID- 22434118 TI - V-cryo-plate procedure as an effective protocol for cryobanks: case study of mint cryopreservation. AB - A vitrification procedure using aluminium cryo-plates (V-Cryo-plate procedure) was successfully developed and adjusted for in vitro-grown mint (Mentha spp.) shoot tips. Shoots were cultured at 25 degrees C on MS medium containing 0.088 M sucrose for 7 to 14 days after the last subculture. Shoot tips with a basal part (1-1.5 mm * 1 mm) were dissected from the shoots and precultured at 25 degrees C for 1 day on the same medium. Precultured shoot tips were placed on aluminium cryo-plates with 10 wells and embedded in alginate gel. Osmoprotection was performed by immersing the cryo-plates for 30 min at 25 degree C in 25 ml pipetting reservoirs filled with loading solution (2 M glycerol + 0.8 M sucrose). For dehydration, the cryo-plates were transferred and immersed in 25 ml pipetting reservoirs filled with PVS2 for 20 min at 25 degree C. Then the cryo-plates were transferred in uncapped 2 ml cryotubes and directly plunged into liquid nitrogen. For rewarming, shoot tips attached to the cryo-plates were immersed in cryotubes containing 2 ml 1 M sucrose solution at room temperature. Using this procedure, regrowth of cryopreserved shoot tips of line 'Fukuyamajisei' reached over 90 percent. This protocol was successfully applied to 16 additional Mentha lines, with regrowth ranging from 73 percent to 100 percent. This V-Cryo-plate method will facilitate the cryostorage of mint germplasm in our genebank. PMID- 22434119 TI - Effect of cytochalasin B pre-treatment of in vitro matured porcine oocytes before vitrification. AB - The study tested the efficacy of pre-treating mature porcine oocytes with cytochalasin B before vitrification by the open pulled straw method (OPS) in a low toxicity solution containing ice blockers. The effects of pre-treating the oocytes with 7.5 micrograms per ml cytochalasin B before vitrification on membrane integrity, chromosome organisation and cortical granule distribution were evaluated. When oocytes pre-treated with cytochalasin B before vitrification were compared with control oocytes, similar membrane integrity was observed. In contrast, when both vitrified oocytes groups (treated and untreated with cytochalasin B) were compared with fresh oocytes, significantly lower proportions of oocytes with normal chromosomes aligned regularly on the metaphase plate and peripheral cortical granule distribution were observed. The percentages of oocytes with normal chromosomes aligned regularly on the metaphase plate were similar between those treated or untreated with cytochalasin B before vitrification. Similar results were found for normal cortical granules distribution. Irrespective of previous cytochalasin B exposure, vitrification gave rise to higher abnormal cortical granule distribution percentages. Cytochalasin B pretreatment of oocytes before vitrification does not help to reduce the damage induced by the cryopreservation process of porcine oocytes. PMID- 22434120 TI - Assessment of external heat transfer coefficient during oocyte vitrification in liquid and slush nitrogen using numerical simulations to determine cooling rates. AB - In oocyte vitrification, plunging directly into liquid nitrogen favor film boiling and strong nitrogen vaporization. A survey of literature values of heat transfer coefficients (h) for film boiling of small metal objects with different geometries plunged in liquid nitrogen revealed values between 125 to 1000 W per per square m per K. These h values were used in a numerical simulation of cooling rates of two oocyte vitrification devices (open-pulled straw and Cryotop), plunged in liquid and slush nitrogen conditions. Heat conduction equation with convective boundary condition was considered a linear mathematical problem and was solved using the finite element method applying the variational formulation. COMSOL Multiphysics was used to simulate the cooling process of the systems. Predicted cooling rates for OPS and Cryotop when cooled at -196 degree C (liquid nitrogen) or -207 degree C (average for slush nitrogen) for heat transfer coefficients estimated to be representative of film boiling, indicated lowering the cooling temperature produces only a maximum 10 percent increase in cooling rates; confirming the main benefit of plunging in slush over liquid nitrogen does not arise from their temperature difference. Numerical simulations also demonstrated that a hypothetical four-fold increase in the cooling rate of vitrification devices when plunging in slush nitrogen would be explained by an increase in heat transfer coefficient. This improvement in heat transfer (i.e., high cooling rates) in slush nitrogen is attributed to less or null film boiling when a sample is placed in slush (mixture of liquid and solid nitrogen) because it first melts the solid nitrogen before causing the liquid to boil and form a film. PMID- 22434121 TI - Effect of "ice blockers" in solutions for vitrification of in vitro matured ovine oocytes. AB - Polymers have been used as a substitute for serum in vitrification solutions for embryos and oocytes. This study was designed to replace serum with defined commercial macromolecules in vitrification solution for in vitro matured ovine oocytes. Oocytes were cryopreserved in two vitrification solutions (16.5 percent ethylene glycol + 16.5 percent dimethyl sulphoxide) supplemented with 1 percent of SuperCool X-1000 and 1 percent SuperCool Z-1000 (Ice Blockers) or 20 percent foetal calf serum (FCS). After warming, oocytes viability and developmental potential after processing for in vitro embryo production were assessed. The number of viable oocytes (87.4 percent and 85.9 percent), cleaveage rates (21.4 percent and 19.6 percent) and blastocyst development rates (4.8 percent and 4.5 percent) were similar for Ice Blockers and FCS, respectively. On the basis of these findings, it may be concluded that combined use of Ice Blockers (SuperCool X-1000 and SuperCool Z-1000) as supplementation in vitrification solution offers similar results to serum for vitrification of in vitro matured ovine oocytes. PMID- 22434122 TI - Cryobanking of Korean allium germplasm collections: results from a 10 year experience. AB - This paper reviews a 10-year experience in establishing a cryopreserved Allium germplasm collection at the genebank of the National Agrobiodiversity Center, Republic of Korea. A systematic approach to Allium cryopreservation included: 1. revealing the most critical factors that affected regeneration after cryostorage; 2. understanding the mechanisms of cryoprotection by analyzing the thermal behavior of explants and cryoprotectant solutions using DSC and influx/efflux of cryoprotectants using HPLC; 3. assessing genetic stability of regenerants; and 4. revealing the efficiency of cryotherapy. Bulbil primordia, i.e. asexual bulbs formed on unripe inflorescences, proved to be the most suitable material for conservation of bolting varieties due to high post-cryopreservation regrowth and lower microbial infection level, followed by apical shoot apices from single bulbs and cloves. A total of 1,158 accessions of garlic as well as some Allium species have been cryopreserved during 2005-2010 using the droplet-vitrification technique with a mean regeneration percentage of 65.9 percent after cryostorage. These results open the door for large-scale implementation of cryostorage and for simplifying international exchange for clonal Allium germplasm. PMID- 22434123 TI - Vitrification-based cryopreservation of shoot-tips of Pinus kesiya Royle ex. Gord. AB - The present investigation was aimed at developing a protocol for long-term preservation of germplasm of Pinus kesiya Royle ex. Gord. through vitrification. Some of the critical components affecting explant tolerance to cryopreservation, such as effects of preculture, vitrification solutions, exposure time to vitrification solutions, volume of vitrification solution and its toxicity, washing of vitrified tissues after thawing, were analysed. The results showed that shoot regrowth of P. kesiya shoot-tips was considerably affected when exposed to cryoprotectants for longer periods of time (longer than 10 min). Among different vitrification solutions studied, maximum survival (76 percent) of shoot tips was achieved with mVSL (using 0.6 ml of the solution) in MS basal medium containing 4.0 mg l-1 N6-benzyladenine (BA). PMID- 22434124 TI - Cryopreservation of in vitro grown shoot tips of Diospyros kaki thunb. using different methods. AB - The objective of this study was to compare the potential of different cryopreservation strategies for in vitro shoot tips of Diospyros kaki Thunb. The treatments consisted of three different cryopreservation methods: vitrification, droplet-vitrification and modified droplet-vitrification. The following variables were assessed: cold acclimation, sucrose concentration in the preculture medium and PVS2 treatment time. A higher average survival level was obtained using the modified droplet-vitrification method compared to the other two methods. PMID- 22434125 TI - Expression and distribution of aquaporin 8 in rat hepatocytes cold stored 72 hours in modified University of Wisconsin and bes-gluconate-sucrose solutions. Study of their correlation with water content. AB - Since few data are availble on the genetic responses to low temperatures, we investigated if cold storage of hepatocytes (0 degree C, mUW or BGS solutions, 72 h) can affect gene expression and/or cellular localization of AQP8 and their correlation with water movements. Cold preserved hepatocytes showed a significant decrease in water content (P less than 0.05) but were able to regulate their volume when they returned to physiological conditions. These changes were not related to modulation in the expression and the pattern of distribution of AQP8 suggesting that other mechanisms are involved. The study of the quantitative changes in the expression of genes coding for liver specific proteins in cold preserved hepatic cells is of interest in order to develop new preservation methods or solutions that could contribute to maintain the utility of these cells when destined to be applied in clinical models. PMID- 22434126 TI - Electrochemical impedance spectroscopic measurements of FCCP-induced change in membrane permeability of MDCK cells. AB - This study demonstrates a new electrochemical impedance spectroscopic (EIS) method for measurements of the changes in membrane permeability during the process of cell anoxia. Madin-Darby canine kidney (MDCK) cells were employed as the model cells and were cultured onto gelatin-modified glassy carbon (GC) electrodes. EIS measurements were conducted at the MDCK/gelatin-modified GC electrodes with Fe(CN)(6)(3-/4-) as the redox probe. The anoxia of the cells grown onto electrode surface was induced by the addition of carbonycyanide p (trifluoromethoxy) phenylhydrazone (FCCP) into the cell culture, in which the MDCK/gelatin-modified GC electrodes were immersed for different times. The EIS results show that the presence of FCCP in the cell culture clearly decreases the charge-transfer resistance of the Fe(CN)(6)(3-/4-) redox probe at the MDCK/gelatin-modified GC electrodes, and the charge-transfer resistance decreases with increasing time employed for immersing the MDCK/gelatin-modified GC electrodes into the cell culture containing FCCP. These results demonstrate that the EIS method could be used to monitor the changes in the cell membrane permeability during the FCCP-induced cell anoxia. To simulate the EIS system, a rational equivalent circuit was proposed and the values of ohmic resistance of the electrolyte, charge-transfer resistance and constant phase elements for both the gelatin and the cell layers are given with the fitting error in an acceptable value. This study actually offers a new and simple approach to measuring the dynamic process of cell death induced by anoxia through monitoring the changes in the cell membrane permeability. PMID- 22434127 TI - The role of orbiting resonances in the vibrational relaxation of I(2)(B,v' = 21) by collisions with He at very low energies: a theoretical and experimental study. AB - The low-energy collisions of I(2)(B,v' = 21) with He involving collision-induced vibrational relaxation of I(2) are investigated both experimentally and by means of wave packet simulations. The theoretical cross sections exhibit a structure of peaks originated by orbiting resonances of the I(2)(B,v' = 21) - He van der Waals complex formed in the I(2) + He collisions. Such a structure has similar characteristics as the structure of peaks found in the experimental cross sections. In fact, four of the five peaks of the measured cross sections appear at positions nearly coincident with those of four of the peaks found in the theoretical cross sections. Thus this result confirms the experimental finding that enhancement of I(2) vibrational relaxation is caused by the population of I(2)(B,v' = 21) - He orbiting resonances populated upon the low-energy collisions. The possibility of using this mechanism in the vibrational cooling of diatomic molecules is discussed. PMID- 22434129 TI - Trial tests new combination of drugs to treat tuberculosis. PMID- 22434130 TI - Royal Brompton is accused of putting "a spanner in the works" of reorganising children's heart services by premature legal action. PMID- 22434131 TI - A flexible UV nanosensor based on reduced graphene oxide decorated ZnO nanostructures. AB - A low-cost, compatible with flexible electronics, high performance UV sensor has been achieved from a reduced graphene oxide (RGO) decorated hydrangea-like ZnO film on a PDMS substrate. The hydrangea-like ZnO UV sensor has the best UV sensing performance among devices made of three kinds of ZnO nanostructures synthesized by a hydrothermal method, and demonstrated a dramatic enhancement in on/off ratio and photoresponse current by introducing an appropriate weight ratio of RGO. The on/off ratio of the 0.05% RGO/ZnO sensor increases almost one order of magnitude compared to that of a pristine hydrangea-like ZnO UV sensor. While for the 5% RGO decorated ZnO sensor, the photoresponse current reaches as high as ~1 MUA and exceeds 700 times that of a ZnO UV sensor. These results indicate that RGO is an appropriate material to enhance the performance of ZnO nanostructure UV sensors based on its unique features, especially the high optical transparency and excellent electronic conductivity. Our findings will make RGO/ZnO nanohybrids extraordinarily promising in optoelectronics, flexible electronics and sensor applications. PMID- 22434132 TI - Intra- and extra-articular planes of reference for use in total hip arthroplasty: a preliminary study. AB - PURPOSE: Acetabular component malalignment in total hip arthroplasty can lead to potential complications such as dislocation, component impingement and excessive wear. Computer-assisted orthopaedic surgery systems generally use the anterior pelvic plane (APP). Our aim was to investigate the reliability of anatomical landmarks accessible during surgery and to define new potential planes of reference. METHODS: Three types of palpations were performed: virtual, on dry bones and on two cadaveric specimens. Four landmarks were selected, the reproducibility of their positioning ranging from 0.9 to 2.3 mm. We then defined five planes and tested them during palpations on two cadaveric specimens. RESULTS: Two planes produced a mean orientation error of 5.0 degrees [standard deviation (SD 3.3 degrees )] and 5.6 degrees (SD 2.7 degrees ). CONCLUSIONS: Even if further studies are needed to test the reliability of such planes on a larger scale in vivo during surgery, these results demonstrated the feasibility of defining a new plane of reference as an alternative to the APP. PMID- 22434133 TI - Loss of miR-29 in myoblasts contributes to dystrophic muscle pathogenesis. AB - microRNAs (miRNAs) are noncoding RNAs that regulate gene expression in post transcriptional fashion, and emerging studies support their importance in a multitude of physiological and pathological processes. Here, we describe the regulation and function of miR-29 in Duchenne muscular dystrophy (DMD) and its potential use as therapeutic target. Our results demonstrate that miR-29 expression is downregulated in dystrophic muscles of mdx mice, a model of DMD. Restoration of its expression by intramuscular and intravenous injection improved dystrophy pathology by both promoting regeneration and inhibiting fibrogenesis. Mechanistic studies revealed that loss of miR-29 in muscle precursor cells (myoblasts) promotes their transdifferentiation into myofibroblasts through targeting extracellular molecules including collagens and microfibrillar associated protein 5 (Mfap5). We further demonstrated that miR-29 is under negative regulation by transforming growth factor-beta (TGF-beta) signaling. Together, these results not only identify TGF-beta-miR-29 as a novel regulatory axis during myoblasts conversion into myofibroblasts which constitutes a novel contributing route to muscle fibrogenesis of DMD but also implicate miR-29 replacement therapy as a promising treatment approach for DMD. PMID- 22434134 TI - CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes. AB - The interleukin-17 (IL-17) cytokine family is crucial to the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). It has been shown in a neuroectoderm-specific knockout study that astrocyte-restricted ablation of Act1, a key and common transcription factor for signals mediated by IL-17 family members (IL-17A, IL-17F, and IL-17C), ameliorates EAE. However, the effect of Act1 deficiency in astrocytes on ongoing disease, which is of clinical relevance for MS therapy, has not been investigated. Here we report that intracerebroventricular (i.c.v.) injection of a novel lentiviral vector (shAct1) to knockdown Act1 expression in astrocytes effectively inhibited disease progression at EAE induction, clinical onset, and peak of disease (ongoing phases), with significantly reduced numbers of infiltrating inflammatory cells and percentage of Th17 cells in the central nervous system (CNS). This was mainly due to the suppressed expression of Th17 related chemokines in astrocytes, while neurotrophic factors in the CNS and immune responses in the periphery were not affected. These results demonstrate that blocking the IL-17 pathways in astrocytes is a promising therapeutic approach for MS in a CNS-specific manner, which does not interfere with systemic immune responses, a major concern in conventional MS therapy. PMID- 22434135 TI - Isolation and optimization of murine IL-10 receptor blocking oligonucleotide aptamers using high-throughput sequencing. AB - Interleukin-10 (IL-10) is a key suppressor of inflammation in chronic infections and in cancer. In mice, the inability of the immune system to clear viral infections or inhibit tumor growth can be reversed by antibody-mediated blockade of IL-10 action. We used a modified selection protocol to isolate RNA-based, nuclease-resistant, aptamers that bind to the murine IL-10 receptor. After 5 rounds of selection high-throughput sequencing (HTS) was used to analyze the library. Using distribution statistics on about 11 million sequences, aptamers were identified which bound to IL-10 receptor in solution with low K(d). After 12 rounds of selection the predominant IL-10 receptor-binding aptamer identified in the earlier rounds remained, whereas other high-affinity aptamers were not detected. Prevalence of certain nucleotide (nt) substitutions in the sequence of a high-affinity aptamer present in round 5 was used to deduce its secondary structure and guide the truncation of the aptamer resulting in a shortened 48-nt long aptamer with increased affinity. The aptamer also bound to IL-10 receptor on the cell surface and blocked IL-10 function in vitro. Systemic administration of the truncated aptamer was capable of inhibiting tumor growth in mice to an extent comparable to that of an anti- IL-10 receptor antibody. PMID- 22434136 TI - UU/UA dinucleotide frequency reduction in coding regions results in increased mRNA stability and protein expression. AB - UU and UA dinucleotides are rare in mammalian genes and may offer natural selection against endoribonuclease-mediated mRNA decay. This study hypothesized that reducing UU and UA (UW) dinucleotides in the mRNA-coding sequence, including the codons and the dicodon boundaries, may promote resistance to mRNA decay, thereby increasing protein production. Indeed, protein expression from UW-reduced coding regions of enhanced green fluorescent protein (EGFP), luciferase, interferon-alpha, and hepatitis B surface antigen (HBsAg) was higher when compared to the wild-type protein expression. The steady-state level of UW reduced EGFP mRNA was higher and the mRNA half-life was also longer. Ectopic expression of the endoribonuclease, RNase L, did not reduce the wild type or UW reduced mRNA. A mutant form of the mRNA decay-promoting protein, tristetraprolin (TTP/ZFP36), which has a point mutation in the zinc-finger domain (C124R), was used. The wild-type EGFP mRNA but not the UW-reduced mRNA responded to the dominant negative action of the C124R ZFP36/TTP mutant. The results indicate the efficacy of the described rational approach to formulate a general scheme for boosting recombinant protein production in mammalian cells. PMID- 22434137 TI - Extensive methylation of promoter sequences silences lentiviral transgene expression during stem cell differentiation in vivo. AB - Lentiviral vectors (LV) are widely used to stably transfer genes into target cells investigating or treating gene functions. In addition, gene transfer into early murine embryos may be improved to efficiently generate transgenic mice. We applied lentiviral gene transfer to generate a mouse model transgenic for SET binding protein-1 (Setbp1) and enhanced green fluorescent protein (eGFP). Neither transgenic founders nor their vector-positive offspring transcribed or expressed the transgenes. Bisulfite sequencing of the internal spleen focus-forming virus (SFFV) promoter demonstrated extensive methylation of all analyzed CpGs in the transgenic mice. To analyze the impact of Setbp1 on epigenetic silencing, embryonic stem cells (ESC) were differentiated into cardiomyocytes (CM) in vitro. In contrast to human promoters in LV, virally derived promoter sequences were strongly methylated during differentiation, independent of the transgene. Moreover, the commonly used SFFV promoter (SFFVp) was highly methylated with remarkable strength and frequency during hematopoietic differentiation in vivo in LV but less in gamma-retroviral (gamma-RV) backbones. In summary, we conclude that LV using an internal SFFVp are not suitable to generate transgenic mice or perform constitutive expression studies in differentiating cells. Choosing the appropriate promoter is also crucial to allow stable transgene expression in clinical gene therapy. PMID- 22434138 TI - Off-the-shelf adenoviral-mediated immunotherapy via bicistronic expression of tumor antigen and iMyD88/CD40 adjuvant. AB - Recent modest successes in ex vivo dendritic cell (DC) immunotherapy have motivated continued innovation in the area of DC manipulation and activation. Although ex vivo vaccine approaches continue to be proving grounds for new DC manipulation techniques, the intrinsic limits of ex vivo therapy, including high cost, minimal standardization, cumbersome delivery, and poor accessibility, incentivizes the development of vaccines compatible with in vivo DC targeting. We describe here a method to co-deliver both tumor-specific antigen (TSA) and an iMyD88/CD40 adjuvant (iMC), to DCs that combines toll-like receptor (TLR) and CD40 signaling. In this study, we demonstrate that simple TSA delivery via adenoviral vectors results in strong antitumor immunity. Addition of iMC delivered in a separate vector is insufficient to enhance this effect. However, when delivered simultaneously with TSA in a single bicistronic vector (BV), iMC is able to significantly enhance antigen-specific cytotoxic T-cell (CTL) responses and inhibit established tumor growth. This study demonstrates the spatial-temporal importance of concurrent DC activation and TSA presentation. Further, it demonstrates the feasibility of in vivo molecular enhancement of DCs necessary for effective antitumor immune responses. PMID- 22434139 TI - Cell Membrane-associated heparan sulfate is a receptor for prototype foamy virus in human, monkey, and rodent cells. AB - Foamy viruses (FVs) (spumaretroviruses) are good alternative to retroviruses as gene therapy vector. Despite four decades since the discovery of FV, its receptor molecule is still unknown. FV vector transduction of human CD34(+) cells was inhibited by culture with fibronectin. Because fibronectin contains heparin binding domain, the interactions of fibronectin with heparan sulfate (HS) on cells might be inhibitory to FV transduction. These observations led us to investigate whether HS is a receptor for FV. Two mutant CHO cell lines (but not parental wild type) lacking cell surface HS but not chondroitin sulfate (CS) were largely resistant to FV attachment and transduction. Inhibition of HS expression using enzymes or chemicals greatly reduced FV transduction in human, monkey, and rodent cells. Raji cells, which lack HS and were largely resistant to FV, were rendered more permissive through ectopic expression of syndecan-1, which contains HS. In contrast, mutant syndecan-1-expressing cells were largely resistant to FV. Our findings indicate that cellular HS is a receptor for FV. Identifying FV receptor will enable better understanding of its entry process and optimal use as gene therapy vector to treat inherited and pathogenic diseases. PMID- 22434140 TI - Interferon-beta sensitivity of tumor cells correlates with poor response to VA7 virotherapy in mouse glioma models. AB - In our recent study, replicative alphaviral vector VA7 was found to be effective against orthotopic human U87-glioma xenografts in an athymic mouse model eradicating the tumors with single intravenous (i.v.) injection. Here, we tested the efficacy of VA7 in immunocompetent orthotopic GL261 and CT-2A glioma models of C57BL/6 mouse in vivo. The cell lines were susceptible to VA7 infection in vitro, but GL261 infection was highly restricted in confluent cell cultures, and mouse interferon-beta (IFNbeta) pretreatment prevented the replication of VA7 in both cell lines. When mice bearing orthotopic GL261 or CT-2A tumors were administered neurotropic VA7, either i.v. or intracranially (i.c.), the vector was unable to infect the tumor and no survival benefit was achieved. Pretreatments with immunosuppressive cyclophosphamide (CPA) and rapamycin markedly lowered serum-neutralizing antibodies (NAbs) but had no effect on tumor infection or survival. Intracranial GL261 tumors were refractory also in athymic C57BL/6 mice, which have serious defects in their adaptive immunity. Implanted VA7-infected GL261 cells formed tumors with only slightly delayed kinetics and without improving survival thus excluding the participation of physical barriers and indicating robust host IFN action. Mouse and human IFNbeta do not seem be species cross-reactive, which might limit the translational relevance of xenograft models in oncolytic virotherapy. PMID- 22434141 TI - The beta-globin locus control region in combination with the EF1alpha short promoter allows enhanced lentiviral vector-mediated erythroid gene expression with conserved multilineage activity. AB - Some gene therapy strategies are compromised by the levels of gene expression required for therapeutic benefit, and also by the breadth of cell types that require correction. We designed a lentiviral vector system in which a transgene is under the transcriptional control of the short form of constitutively acting elongation factor 1alpha promoter (EFS) combined with essential elements of the locus control region of the beta-globin gene (beta-LCR). We show that the beta LCR can upregulate EFS activity specifically in erythroid cells but does not alter EFS activity in myeloid or lymphoid cells. Experiments using the green fluorescent protein (GFP) reporter or the human adenosine deaminase (ADA) gene demonstrate 3-7 times upregulation in vitro but >20 times erythroid-specific upregulation in vivo, the effects of which were sustained for 1 year. The addition of the beta-LCR did not alter the mutagenic potential of the vector in in vitro mutagenesis (IM) assays although microarray analysis showed that the beta-LCR upregulates ~9% of neighboring genes. This vector design therefore combines the benefits of multilineage gene expression with high-level erythroid expression, and has considerable potential for correction of multisystem diseases including certain lysosomal storage diseases through a hematopoietic stem cell (HSC) gene therapy approach. PMID- 22434142 TI - Glucose regulated protein 78 diminishes alpha-synuclein neurotoxicity in a rat model of Parkinson disease. AB - Accumulation of human wild-type (wt) alpha-synuclein (alpha-syn) induces neurodegeneration in humans and in experimental rodent models of Parkinson disease (PD). It also leads to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). We overexpressed glucose regulated protein 78, also known as BiP (GRP78/BiP), to test the hypothesis that this ER chaperone modulates the UPR, blocks apoptosis, and promotes the survival of nigral dopamine (DA) neurons in a rat model of PD induced by elevated level of human alpha-syn. We determined that alpha-syn activates ER stress mediators associated with pancreatic ER kinase-like ER kinase (PERK) and activating transcription factor-6 (ATF6) signaling pathways as well as proaoptotic CCAAT/ enhancer-binding protein homologous protein (CHOP) in nigral DA neurons. At the same time, overexpression of GRP78/BiP diminished alpha-syn neurotoxicity by down regulating ER stress mediators and the level of apoptosis, promoted survival of nigral tyrosine hydroxylase (TH) positive cells and resulted in higher levels of striatal DA, while eliminating amphetamine induced behavioral asymmetry. We also detected a complex between GRP78/BiP and alpha-syn that may contribute to prevention of the neurotoxicity caused by alpha-syn. Our data suggest that the molecular chaperone GRP78/BiP plays a neuroprotective role in alpha-syn-induced Parkinson-like neurodegeneration. PMID- 22434144 TI - Time-course of the change in titre of antibodies against type VII collagen in a patient with epidermolysis bullosa acquisita. PMID- 22434145 TI - Nano-graphite functionalized mesocellular carbon foam with enhanced intra penetrating electrical percolation networks for high performance electrochemical energy storage electrode materials. AB - Mesocellular carbon foam (MSU-F-C) is functionalized with hollow nanographite by a simple solution-phase method to enhance the intrapenetrating electrical percolation network. The electrical conductivity of the resulting material, denoted as MSU-F-C-G, is increased by a factor of 20.5 compared with the pristine MSU-F-C. Hollow graphite nanoparticles are well-dispersed in mesocellular carbon foam, as confirmed by transmission electron microscopy (TEM), and the d spacing of the (002) planes is 0.343 nm, which is only slightly larger than that of pure graphite (0.335 nm), suggesting a random combination of graphitic and turbostratic stacking. After nanographitic functionalization, the BET surface area and total pore volume decreased from 928 m(2) g(-1) and 1.5 cm(3) g(-1) to 394 m(2) g(-1) and 0.7 cm(3) g(-1), respectively. Thermogravimetric analysis in air shows that the thermal stability of MSU-F-C-G is improved relative to that of MSU-F-C, and the one-step weight loss indicates that the nanographite is homogeneously functionalized on the MSU-F-C particles. When the resulting mesocellular carbon materials are used as electrode materials for an electric double layer capacitor (EDLC), the specific capacitances (C(sp)) of the MSU-F-C and MSU-F-C-G electrodes at 4 mV s(-1) are 109 F g(-1) and 93 F g(-1), respectively. The MSU-F-C-G electrode exhibited a very high area capacitance (C(area), 23.5 MUF cm(-2)) compared with that of the MSU-F-C electrode (11.7 MUF cm(-2)), which is attributed to the enhanced intraparticle conductivity by the nanographitic functionalization. MSU-F-C-G exhibited high capacity retention (52%) at a very high scan rate of 512 mV s(-1), while only a 23% capacity retention at 512 mV s(-1) was observed in the case of the MSU-F-C electrode. When applied as an anode in a lithium ion battery, a significant increase in the initial efficiency (44%), high reversible discharge capacity (580 mA h g(-1)) in the lower voltage region, and a higher rate capability were observed. The high rate capability of the MSU-F-C-G electrode as charge storage was due to the low resistance derived from the nanographitic functionalization. PMID- 22434146 TI - Molecular cloning of heat shock protein 60 (PtHSP60) from Portunus trituberculatus and its expression response to salinity stress. AB - Heat shock protein 60 (HSP60) is a highly conserved and multi-functional molecular chaperone that plays an essential role in both cellular metabolism and stress response. Portunus trituberculatus is an important marine fishery and aquaculture species, and water salinity condition influenced its artificial propagations significantly. In order to investigate the function of P. trituberculatus HSP60 against osmotic stress, P. trituberculatus HSP60 gene was firstly cloned. The full-length cDNA of PtHSP60 contains 1,743 nucleotides encoding 577 amino acids with a calculated molecular weight of 61.25 kDa. Multiple alignments indicated that the deduced amino acid sequences of PtHSP60 shared a high level of identity with invertebrate and vertebrate HSP60 sequence including shrimp, fruit fly, zebrafish, and human. The expression profiles of PtHSP60 at mRNA and protein levels under salinity treatment were investigated by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. It was found that the mRNA transcripts of PtHSP60 gene varied among different tissues under normal salinity conditions, and the antennal gland showed the highest expression level among the tissues tested. As for low salinity challenge, the mRNA expression of PtHSP60 gene was higher in the gill and appendicular muscle compared with other tissues, and gill and hypodermis represented the higher gene expressions during the hyperosmotic stress, which indicated that those tissues were salinity-sensitive tissues. In addition, salinity challenges significantly altered the expression of PtHSP60 at mRNA and protein level in a salinity- and time-dependent manner in P. trituberculatus gill tissue. The results indicate that PtHSP60 played important roles in mediating the salinity stress in P. trituberculatus. PMID- 22434148 TI - A study that shows nothing. PMID- 22434147 TI - Retinoic acid as target for local pharmacokinetic interaction with modafinil in neural cells. AB - While the biological importance of the cytochrome P450 system in the liver is well established, much less is known about its role in the brain and drug interactions at the level of brain cells have hardly been investigated. Here, we show that modafinil, a well-known inducer of hepatic CYP enzymes, also increases CYP3A4 expression in human-derived neuron-like SH-SY5Y cells. Upregulation of CYP3A4 by modafinil was associated with increased retinoic acid (RA) degradation, which could be blocked by specific CYP3A4 inhibitor erythromycin. In turn, reduced RA levels in culture medium during modafinil treatment resulted in decreased neuronal differentiation of SH-SY5Y cells as assessed by intracellular neurotransmitter concentrations and proliferative activity. Again, this differentiation-impeding effect of modafinil on SH-SY5Y cells was antagonized by erythromycin. Similarly, modafinil treatment of the murine GL261 glioma cell line resulted in increased proliferative activity. This was associated with upregulation of RA-degrading CYP26A1 in GL261 cells. Taken together, our results indicate that psychopharmacological agents such as modafinil may directly act on CYP enzymes in neural tissue. These kinds of drug effects may become highly relevant especially in the context of biomolecules such as RA whose local metabolism in brain is under tight spatial and temporal control. PMID- 22434149 TI - Distinguishing between polymorphic forms of linezolid by solid-phase electronic and vibrational circular dichroism. AB - For the first time two crystalline forms of the same compound (linezolid polymorphs) were investigated by means of the solid-phase ECD and VCD spectra. The ECD spectra show distinct differences and the band at 221 nm serves as a diagnostic one because it is present in form II but absent in form III. The VCD spectra strongly differ in the diagnostic carbonyl absorption range exhibiting two relatively strong bands of opposite signs. PMID- 22434150 TI - Structural and technical details of the Kirkwood-Buff integrals from the optimization of ionic force fields: focus on fluorides. AB - Results on the structural details of Kirkwood-Buff integrals obtained from the optimization of ionic force fields are presented. We have proposed and make use of an optimization scheme for ionic force fields, which is based on the modification of the cation-anion mixing rules, the calculation of the thermodynamics properties of various monovalent salt solutions according to the Kirkwood-Buff theory of solutions and the comparison to relevant experimental findings. Here, we complete and extend our calculations and analysis as we focus on the technical details of this optimization procedure and the case of fluorides, which have been proven difficult to handle. Important insight is given on the dependence of the radial distribution functions, the short-ranged potentials of mean force, and the Kirkwood-Buff integrals of the salt solutions on the different scaling factors in the mixing rules. Specifically, the way the structural details and inherent characteristics of the above properties are affected by the quantitative and qualitative differences in the mixing rules for a variety of common biologically relevant monovalent salts is mainly addressed. We conclude on the efficiency of this scheme, again with a focus on the fluorides. In the end, we provide a variation of the ion-pair mixing rules scaling factors with salt concentration to identify regimes for which different mixing rules prefactors lead to well-optimized force fields. All results are obtained through Molecular Dynamics simulations using previously optimized force fields for the monovalent ions. PMID- 22434151 TI - Flow-through PCR on a 3D qiandu-shaped polydimethylsiloxane (PDMS) microdevice employing a single heater: toward microscale multiplex PCR. AB - Consistent temperature control in an on-chip flow-through polymerase chain reaction (PCR) employing two or more heaters is one of the main obstacles for device miniaturization and integration when realizing micro total analysis systems (MUTAS), and also leads to operational complexity. In this study, we propose a qiandu (right triangular prism)-shaped polydimethylsiloxane (PDMS) microdevice with serpentine microchannels fabricated on its slanted plane, and apply the device for an on-chip flow-through PCR employing a single heater. The inclined nature of the qiandu-shaped microdevice enables the formation of a surface temperature gradient along the slanted plane of the microdevice in a height-dependent manner by the use of a single heater, and enables liquid to traverse over wide ranges of temperatures, including the three temperature zones- denaturation, annealing, and extension temperatures--required in a typical PCR. The feasibility of the qiandu-shaped PDMS microdevice as a versatile platform for performing a flow-through PCR was examined by employing multiple templates and varying the inclination angle of the device. In addition, the potential of performing a multiplex PCR using a single qiandu-shaped PDMS microdevice was explored. A 409 bp long gene fragment effective as a marker for diagnosing lung cancer and a 230 bp long gene fragment from a plasmid vector were simultaneously amplified in less than 25 min on a single microdevice, paving the way for a microscale, multiplex PCR on a single device employing a single heater. PMID- 22434152 TI - Acute and chronic effects of atrazine and sodium dodecyl sulfate on the tropical freshwater cladoceran Pseudosida ramosa. AB - Toxicities of atrazine and sodium dodecyl sulfate (SDS) to the tropical freshwater cladoceran Pseudosida ramosa were studied in the laboratory. Acute tests showed that the 48-h LC50 of atrazine was 20.9 mg l-1, while that of SDS was 11.1 mg l-1. P. ramosa showed to be slightly more sensitive than the other species of temperate cladocerans, in the assay conditions specified for each one. Long-term exposure of P. ramosa individuals to atrazine decreased the 21-day fecundity, the 21-day fertility and r(m), at concentrations ranging from 0.8 to 3.2 mg l-1. Furthermore, fecundity and fertility at each brood decreased from the first to the fifth, at concentrations ranging from 0.8 to 3.2 mg l-1 and for the first three broods at the concentration of 0.4 mg l-1. Long-term exposure of female P. ramosa to SDS decreased the 21-day fecundity, the 21-day fertility and r(m), at concentrations of 2 and 4 mg l-1. Fecundity and fertility of each brood were reduced from the first to the fifth, at concentrations of 2-4 mg l-1, and for the first three at concentrations of 0.5 and 1 mg l-1. The survival and moulting of the adult females were not affected by either chemical at the concentrations tested. Many water quality criteria in tropical regions are based on ecotoxicological tests with non-native species and this may lead to errors in setting the maximum permissible levels of chemicals in water bodies. Therefore, we reiterate here the idea of using native species in ecotoxicological assessments. PMID- 22434153 TI - Salt and genotype impact on antioxidative enzymes and lipid peroxidation in two rice cultivars during de-etiolation. AB - Crop yield is severely affected by soil salinity, as salt levels that are harmful to plant growth occur in large terrestrial areas of the world. The present investigation describes the studies of enzymatic activities, in-gel assays, gene expression of some of the major antioxidative enzymes, tocopherol accumulation, lipid peroxidation, ascorbate and dehydroascorbate contents in a salt-sensitive rice genotype PB1, and a relatively salt-tolerant cultivar CSR10 in response to 200 mM NaCl. Salt solution was added to the roots of hydroponically grown 5-day old etiolated rice seedlings, 12 h prior to transfer to cool white fluorescent + incandescent light (100 MUmol photons m(-2) s(-1)). Total tocopherol and ascorbate contents declined in salt-stressed rice seedlings. Among antioxidative enzymes, an increase in the activities of superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), ascorbate peroxidase (EC 1.11.1.11), glutathione reductase (EC 1.6.4.2), and their gene expression was observed in both cultivars in response to salt stress. The salt-tolerant cultivar CSR10 resisted stress due to its early preparedness to combat oxidative stress via upregulation of gene expression and enzymatic activities of antioxidative enzymes and a higher redox status of the antioxidant ascorbate even in a non-stressed environment. PMID- 22434154 TI - Mad, bad or heroic? Gender, identity and accountability in lay portrayals of suicide in late twentieth-century England. AB - Suicide research has relied heavily on the psychological autopsy method, which uses interviews with the bereaved to ascertain the mental health status of the deceased prior to death. The resulting data are typically interpreted within a clinical diagnostic framework, which reinforces psychiatric assumptions concerning the ubiquity of mental illness amongst those who take their own lives. The ways in which informants reconstruct the past and the meanings they attach to events preceding the suicide are rarely examined. This paper uses qualitative methods to analyse the narratives given by bereaved people in an English psychological autopsy study, in order to understand how they made sense of a family member's suicide. Some clear differences between the portrayal of male and female suicides emerged. The paper discusses the gendering of agency and accountability in relation to the differential medicalisation of male and female distress in the UK, and suggests that a preoccupation with mental illness in suicide research may have obscured other culturally normative understandings of self-accomplished death. PMID- 22434155 TI - [Building the future together]. PMID- 22434156 TI - Conjugate addition of isocyanides to chromone 3-carboxylic acid: an efficient one pot synthesis of chroman-4-one 2-carboxamides. AB - We report a novel Lewis acid catalysed tandem reaction of isocyanides, chromone 3 carboxylic acid and nucleophiles. An experimentally very simple procedure, involving the use of microwave irradiation in the presence of a Lewis acid catalyst, affords a representative collection of chromone-2-carboxamides and chromone-2-carboxamido-3-esters in high yields, in just a few minutes. Such an unprecedented strategy is formally equivalent to a conjugate addition of isocyanides to Michael acceptors. PMID- 22434157 TI - Contour restoration of the forehead by lipofilling: our experience. AB - BACKGROUND: A slightly convex forehead without wrinkles adds attractiveness to a woman's face and to the general perceived image. It is also important for the balance and harmony of the face, especially in the lateral and oblique views. We used a new fat injection technique for correction of the contours of the forehead. METHODS: In this study fat injection was applied in nine female patients for restoring the contour and reducing forehead wrinkles, along with a primary rhinoplasty operation. After dissecting all forehead skin from the underlying muscle with a sharp curved-tip epidural needle, fat grafts were injected into the newly created pocket until the forehead area looked moderately ballooned and gentle digital pressure was used for feathering. The patients wore hair bandages continuously for 2 weeks after the operation. RESULTS: The minimal follow-up time was 12 months (range=12-48 months) and all the patients were pleased with the results. When we compared the photos before and after the operation, it was observed that the fat grafts were stable and retained the volume replacement. Patients declared that they had glossy and better quality skin after the operation and also had new regenerated contours. We did not observe any complications. We performed only one additional lipofilling in one patient to obtain an optimal forehead contour. CONCLUSIONS: This technique is easy to perform and effective in reducing forehead wrinkles and correcting the contour. It was also observed that better perceived nasal results could be obtained with concomitant forehead lipofilling in rhinoplasty operations. PMID- 22434158 TI - Natural course in tennis elbow--lateral epicondylitis after all? AB - Tennis elbow is a common and difficult-to-treat condition largely because of lack of evidence. The natural history is unknown, but the condition is described as self-limiting. The objective of this case report is to describe the natural course of two control participants (pain free), who later developed tennis elbow, patient history, clinical findings, and ultrasound and colour Doppler examination before, during and after a period of tennis elbow. PMID- 22434159 TI - Analgesic effectiveness of nerve block in shoulder arthroscopy: comparison between interscalene, suprascapular and axillary nerve blocks. AB - PURPOSE: Postoperative pain in arthroscopic shoulder surgery cannot be easily controlled with analgesics and nerve blocks. This study shows the analgesic effect of interscalene block (ISB) and suprascapular nerve block and axillary nerve block (SSNB + ANB) in patients under patient controlled analgesia (PCA). METHODS: Sixty-one patients (26 men and 35 women) who underwent arthroscopic rotator cuff repair were selected and allocated non-randomly to one of three groups: PCA only-group, PCA with ISB-group and PCA with SSNB + ANB-group. Visual analogue scale (VAS) score, degree of satisfaction, PCA usage and incidence of nausea and vomiting were evaluated at the recovery room, 8, 16 and 24 postoperative hours. RESULTS: The VAS score of the PCA only-group was highest at the recovery room. The VAS score of the PCA with ISB-group was the lowest, however, with large fluctuations over time. Although the VAS score of the PCA with SSNB + ANB-group was higher than that of the PCA with ISB-group, it was steadily lower than the PCA-only group, without any fluctuations. The degree of satisfaction of the PCA with ISB-group was highest at the recovery room. The number of times the PCA was used at the 8-h postoperative evaluation was largest in the PCA only-group. CONCLUSIONS: The initial 24 h after surgery plays a key role in controlling pain after arthroscopic shoulder surgery. PCA with SSNB + ANB is a better anaesthetic choice than PCA with ISB or PCA only during the initial 24 h of the postoperative period. LEVEL OF EVIDENCE: Clinical study, Level II. PMID- 22434160 TI - Enhancement of bone formation with a synthetic matrix containing bone morphogenetic protein-2 by the addition of calcium citrate. AB - PURPOSE: The aim of the study was to test whether calcium citrate combined with rhBMP-2 was able to enhance bone regeneration compared with a matrix containing only rhBMP-2. METHODS: In each of experimental mice, one cylinder of calcium citrate-rhBMP-2 or rhBMP-2 alone was implanted into the thigh muscle pouches of the mouse. The following two treatment modalities were randomly allocated: (1) empty control with rhBMP-2 alone in a gelatin matrix and (2) a gelatin matrix including both calcium citrate and BMP-2. After several weeks, bone granules were obtained by histological analysis. RESULTS: Histomorphometric analysis showed the greatest amount of newly formed bone was observed in the group that contained 10.0 mg calcium citrate with 2.0 mg rhBMP-2 (p < 0.05). Quantitative histomorphometry revealed in the calcium citrate-rhBMP-2 group an obvious increase in the fractional area and the average new bone mineral density of newly formed bone at 2, 4 and 6 weeks than in the rhBMP-2 group (p < 0.05). At 2 weeks time-point, the mature cancellous bone had formed in the calcium citrate-rhBMP-2 group. CONCLUSIONS: From this study, it can be concluded that calcium citrate combined with rhBMP-2 significantly enhances bone regeneration in muscle. This synthetic gelatin matrix containing calcium citrate/gelatin granules fulfils a number of criteria required for an ideal carrier system for rhBMP-2. The calcium ions that calcium citrate releases into the surrounding environment can activate bone formation when used as part of a combination of calcium citrate and BMP-2. PMID- 22434161 TI - Interference screws should be shorter than the hamstring tendon graft in the bone tunnel for best fixation. AB - PURPOSE: Interference screw fixation of hamstring tendon grafts in bone has to overcome the challenges that tendons have a slippery surface and viscoelastically adapt under pressure. As the typical failure mode of the graft is to slip past the interference screw, it was hypothesized that the position and configuration of the graft end may be of influence on the fixation strength. METHODS: Different configurations of the graft ending and its effect to primary fixation with interference screws after viscoelastic adaptation were tested in six groups: I: graft and the screw inserted at the same depth, II/III: the graft overlaps the tip of the screw (interference screw of 28 and 19 mm in length, respectively), IV: strengthening of the graft ending with additional suture knots, V: Endopearl, respectively, and VI: effect of partial retraction of the screw after excessive insertion. In vitro tests were performed with fresh calf tendon grafts and interference screws in bone tunnels (fresh porcine distal femur) all of 8 mm in diameter. RESULTS: The relative position of the graft ending to the tip of the interference screw thereby was recognized as a significant factor on pullout forces. Further strengthening at the graft endings with additional suture knots or an Endopearl device could improve primary hold as well. CONCLUSIONS: Better fixation strength is achieved if the tip of interference screw does not extend past the end of a tendon graft. Enforcement of the tendon end with sutures or an implant can further improve fixation. PMID- 22434162 TI - Prevalence and phenomenology of eye tics in Gilles de la Tourette syndrome. AB - Eye tics seem to be common in Gilles de la Tourette syndrome (GTS). We analyzed the frequency and clinical characteristics of eye tics in 212 GTS patients. Of the 212 patients, 201 (94.8 %) reported eye tics in their life-time; 166 (78.3 %) reported eye movement tics (rolling eyes up/down, eyes looking sideways, staring), and 194 (91.5 %) eyelid/eyebrow movement tics (frowning, raising eyebrows, blinking or winking). Patients with eye movement tics were younger at age of GTS onset (7.1 +/- 4 years) than those without (8.9 +/- 6.8; p = 0.024). Tic severity positively correlated to lifetime history of eye and/or eyelid/eyebrow movement tics. Our data confirm that eye and eyelid/eyebrow movement tics are very common in GTS, and most patients have several types of eye tics over time. Eye tic phenomenology was similar in patients with or without co morbidity. Eye tics are therefore likely to be a core feature of GTS and should be routinely evaluated in order to strengthen the clinician's confidence in diagnosing GTS. PMID- 22434163 TI - Intracerebral mass lesion diagnosed as cryptococcoma in a patient with sarcoidosis, a rare opportunistic manifestation induced by immunosuppression with corticosteroids. AB - Cryptococcal infection of the central nervous system (CNS) typically affects patients with HIV infection. In addition, opportunistic infections can also occur during immunosuppressive therapies. Some patients develop cryptococcal meningitis. Cryptococcomas, however, are rarely observed. A 42-year-old patient with sarcoidosis known for 21/2 years presented with a cerebral mass lesion primarily thought to be CNS sarcoidosis. Stereotactic biopsy and extensive micro- and macrobiological investigations revealed a cryptococcoma which had emerged from cryptococcal meningitis despite 3 months of treatment. Differential diagnosis of cerebral cryptococcoma is difficult due to the unspecific findings in the CSF analysis if C. neoformans fails to be detected using Indian ink staining or PCR studies. In this case, stereotactic biopsy and pathohistological examination revealed C. neoformans causing intracerebral mass lesion. Intensive treatment with antifungal drugs was followed by remission of all symptoms. In conclusion, cryptococcoma of the CNS represents a very important indication of mass lesions in patients suffering from sarcoidosis and treated with corticosteroids. PMID- 22434164 TI - Silks: properties and uses of natural and designed variants. PMID- 22434166 TI - [Promotion of young academics - also a purpose of evidence- and science-based education]. PMID- 22434167 TI - [Recent advances in Raynaud's syndrome]. PMID- 22434168 TI - [Endocrine hypertension: new aspects and developments]. PMID- 22434169 TI - [Protein requirements in the elderly]. PMID- 22434170 TI - [Current perspectives in the treatment of multiple myeloma - news and views]. PMID- 22434171 TI - [Paradigmatic change in treatment of viral hepatitides]. PMID- 22434172 TI - [Weaning from mechanical ventilation - new aspects]. PMID- 22434173 TI - [Aortic valve stenosis: Matching the approach to the patient]. PMID- 22434174 TI - [Acute kidney injury: new insights from diagnostics and treatment]. PMID- 22434175 TI - [Recent developments in home mechanical ventilation]. PMID- 22434176 TI - [Connective tissue diseases]. PMID- 22434177 TI - [Anorectal diseases: an update]. PMID- 22434178 TI - [72-year-old patient with arterial heart disease and valvular aortic stenosis]. PMID- 22434179 TI - [Acute coronary syndrome as a first manifestation of Churg-Strauss syndrome]. AB - HISTORY AND ADMISSION FINDINGS: A 53-year-old woman was admitted to our chest pain unit because of an acute coronary syndrome (non ST-elevation myocardial infarction). She complained of asthma, chronic sinusitis and involuntary weight loss, occasional fever and night sweats over the past six months. INVESTIGATIONS: Coronary angiography did not show any signs of macroscopic coronary artery disease, while echocardiography demonstrated a hemodynamically not significant pericardial effusion. Magnetic resonance imaging of the heart revealed a subendocardial scar, extension and localization pointing to a vascular genesis. Thoracic computed tomography revealed pulmonary opacities and blood tests showed an eosinophilia, leading to the clinical diagnosis of Churg-Strauss syndome. TREATMENT AND COURSE: The patient responded quickly to oral steroids, and blood parameters returned to normal. CONCLUSION: Acute coronary syndrome in youngish patients without classical cardiovascular risk factors is suggestive for myocarditis but also for vasculitis. Churg-Strauss syndrome usually responds quickly to immunosuppressive therapy, associated with a rather good prognosis without high mortality. PMID- 22434180 TI - [Immunoglobulins in PID, SID and neurological autoimmune disease]. AB - Human immunoglobulins (IG, mostly IgG) are used as replacement therapy in patients with inherited primary immunodeficiencies, and in patients with secondary immuno-deficiencies often observed in multiple myeloma or chronic lymphocytic leukemia. Ig are also approved as immunomodulatory therapy in neurological autoimmune diseases (NAID) such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). 16 different Ig preparations for intravenous and subcutaneous use are at the moment available in Germany. The SIGNS study (Assessment of immunoglobulins in a long-term non-interventional study) investigates the clinical use of these drugs under clinical practice conditions. In this non-interventional prospective open-label cohort study, 550 patients with new or maintenance Ig therapy are observed with respect to drug utilization, effectiveness, (i. e. number of infections in PID and SID, functionality in NAID), tolerability, quality of life and costs in approximately 50 sites throughout Germany (neurologists, pediatricians, oncologists, other) for at least two years. This largest study of its kind is expected to contribute to optimization of Ig therapy in the postmarketing setting. PMID- 22434181 TI - High confidence and sensitivity four-dimensional fractionation for human plasma proteome analysis. AB - Reducing the complexity of plasma proteome through complex multidimensional fractionation protocols is critical for the detection of low abundance proteins that have the potential to be the most specific disease biomarkers. Therefore, we examined a four dimension profiling method, which includes low abundance protein enrichment, tryptic digestion and peptide fractionation by IEF, SCX and RP-LC. The application of peptide pI filtering as an additional criterion for the validation of the identifications allows to minimize the false discovery rate and to optimize the best settings of the protein identification database search engine. This sequential approach allows for the identification of low abundance proteins, such as angiogenin (10(-9) g/L), pigment epithelium growth factor (10( 8) g/L), hepatocyte growth factor activator (10(-7) g/L) and thrombospondin-1 (10(-6) g/L), having concentrations similar to those of many other growth factors and cytokines involved in disease pathophysiology. PMID- 22434182 TI - Effect of beta-alanine supplementation on repeated sprint performance during the Loughborough Intermittent Shuttle Test. AB - The aim of this study was to examine the effect of beta-alanine supplementation on repeated sprint performance during an intermittent exercise protocol designed to replicate games play. Sixteen elite and twenty non-elite game players performed the Loughborough Intermittent Shuttle Test (LIST) on two separate occasions. Trials were separated by 4 weeks of supplementation with either beta alanine (BA) or maltodextrin (MD). There was no deterioration in sprint times from Set 1 to Set 6 of the LIST in either group prior to supplementation (elite: P=0.92; non-elite: P=0.12). Neither BA nor MD supplementation affected sprint times. Blood lactate concentrations were elevated during exercise in both groups, with no effect of supplementation. beta-Alanine supplementation did not significantly improve sprint performance during the LIST. Neither group showed a performance decrement prior to supplementation, which might have masked any benefit from increased muscle buffering capacity due to beta-alanine supplementation. PMID- 22434184 TI - Multi-scale mechanics of traumatic brain injury: predicting axonal strains from head loads. AB - The length scales involved in the development of diffuse axonal injury typically range from the head level (i.e., mechanical loading) to the cellular level. The parts of the brain that are vulnerable to this type of injury are mainly the brainstem and the corpus callosum, which are regions with highly anisotropically oriented axons. Within these parts, discrete axonal injuries occur mainly where the axons have to deviate from their main course due to the presence of an inclusion. The aim of this study is to predict axonal strains as a result of a mechanical load at the macroscopic head level. For this, a multi-scale finite element approach is adopted, in which a macro-level head model and a micro-level critical volume element are coupled. The results show that the axonal strains cannot be trivially correlated to the tissue strain without taking into account the axonal orientations, which indicates that the heterogeneities at the cellular level play an important role in brain injury and reliable predictions thereof. In addition to the multi-scale approach, it is shown that a novel anisotropic equivalent strain measure can be used to assess these micro-scale effects from head-level simulations only. PMID- 22434185 TI - Enamel defects in carriers of a novel LAMA3 mutation underlying epidermolysis bullosa. PMID- 22434186 TI - Celiac disease is overrepresented in patients with constipation. AB - OBJECTIVE: It is suggested that patients with constipation should be screened for celiac disease. Similarly, it is recommended to investigate these patients for hypothyroidism and hypercalcemia. However, no evidence for these recommendations is available so far. We therefore set out to determine the prevalence of celiac disease, hypothyroidism, and hypercalcemia in children with constipation. METHODS: Prospective cohort study of 370 consecutive patients who met the Rome III criteria for constipation. These patients were referred by a general practitioner to a pediatrician because of failure of laxative treatment. RESULTS: Seven of these patients had biopsy-proven celiac disease. This is significantly higher (p < 0.001) than the 1:198 prevalence of celiac disease in the Netherlands. Two patients had auto-immune thyroiditis. No patient had hypercalcemia. CONCLUSIONS: We conclude that celiac disease is significantly overrepresented in patients with constipation who are referred by a general practitioner to a pediatrician because of failure of laxative treatment. All such patients should, therefore, be screened for celiac disease. PMID- 22434187 TI - Giant spin-dependent thermoelectric effect in magnetic tunnel junctions. AB - Thermoelectric effects in magnetic nanostructures and the so-called spin caloritronics are attracting much interest. Indeed it provides a new way to control and manipulate spin currents, which are key elements of spin-based electronics. Here we report on a giant magnetothermoelectric effect in a magnetic tunnel junction. The thermovoltage in this geometry can reach 1 mV. Moreover a magnetothermovoltage effect could be measured with ratio similar to the tunnel magnetoresistance ratio. The Seebeck coefficient can then be tuned by changing the relative magnetization orientation of the two magnetic layers in the tunnel junction. Therefore, our experiments extend the range of spintronic devices application to thermoelectricity and provide a crucial piece of information for understanding the physics of thermal spin transport. PMID- 22434188 TI - Recovering three-dimensional shape around a corner using ultrafast time-of-flight imaging. AB - The recovery of objects obscured by scattering is an important goal in imaging and has been approached by exploiting, for example, coherence properties, ballistic photons or penetrating wavelengths. Common methods use scattered light transmitted through an occluding material, although these fail if the occluder is opaque. Light is scattered not only by transmission through objects, but also by multiple reflection from diffuse surfaces in a scene. This reflected light contains information about the scene that becomes mixed by the diffuse reflections before reaching the image sensor. This mixing is difficult to decode using traditional cameras. Here we report the combination of a time-of-flight technique and computational reconstruction algorithms to untangle image information mixed by diffuse reflection. We demonstrate a three-dimensional range camera able to look around a corner using diffusely reflected light that achieves sub-millimetre depth precision and centimetre lateral precision over 40 cm*40 cm*40 cm of hidden space. PMID- 22434189 TI - Transient activation of specific neurons in mice by selective expression of the capsaicin receptor. AB - The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches. PMID- 22434190 TI - Observation of an evolving magnetic flux rope before and during a solar eruption. AB - Explosive energy release is a common phenomenon occurring in magnetized plasma systems ranging from laboratories, Earth's magnetosphere, the solar corona and astrophysical environments. Its physical explanation is usually attributed to magnetic reconnection in a thin current sheet. Here we report the important role of magnetic flux rope structure, a volumetric current channel, in producing explosive events. The flux rope is observed as a hot channel before and during a solar eruption from the Atmospheric Imaging Assembly telescope on board the Solar Dynamic Observatory. It initially appears as a twisted and writhed sigmoidal structure with a temperature as high as 10 MK, and then transforms toward a semi circular shape during a slow-rise phase, which is followed by fast acceleration and onset of a flare. The observations suggest that the instability of the magnetic flux rope triggers the eruption, thus making a major addition to the traditional magnetic-reconnection paradigm. PMID- 22434191 TI - Enhanced electromechanical response of ferroelectrics due to charged domain walls. AB - While commonly used piezoelectric materials contain lead, non-hazardous, high performance piezoelectrics are yet to be discovered. Charged domain walls in ferroelectrics are considered inactive with regards to the piezoelectric response and, therefore, are largely ignored in this search. Here we demonstrate a mechanism that leads to a strong enhancement of the dielectric and piezoelectric properties in ferroelectrics with increasing density of charged domain walls. We show that an incomplete compensation of bound polarization charge at these walls creates a stable built-in depolarizing field across each domain leading to increased electromechanical response. Our model clarifies a long-standing unexplained effect of domain wall density on macroscopic properties of domain engineered ferroelectrics. We show that non-toxic ferroelectrics like BaTiO(3) with dense patterns of charged domain walls are expected to have strongly enhanced piezoelectric properties, thus suggesting a new route to high performance, lead-free ferroelectrics. PMID- 22434192 TI - FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome mediated proteolysis. AB - FAT10 is the only ubiquitin-like modifier that can target proteins for degradation by the proteasome in a ubiquitin-independent manner. The degradation of FAT10-linked proteins by the proteasome is strongly accelerated by the ubiquitin-like-ubiquitin-associated protein NEDD8 ultimate buster-1 long (NUB1L). Here we show how FAT10 and NUB1L dock with the 26S proteasome to initiate proteolysis. We identify the 26S proteasome subunit hRpn10/S5a as the receptor for FAT10, whereas NUB1L can bind to both Rpn10 and Rpn1/S2. Unexpectedly, FAT10 and NUB1L both interact with hRpn10 via the VWA domain. FAT10 degradation in yeast shows that human Rpn10 can functionally reconstitute Rpn10-deficient yeast and that the VWA domain of hRpn10 suffices to enable FAT10 degradation. Depletion of hRpn10 causes an accumulation of FAT10-conjugates also in human cells. In conclusion, we identify the VWA domain of hRpn10 as a receptor for ubiquitin-like proteins within the 26S proteasome and elucidate how FAT10 mediates efficient proteolysis by the proteasome. PMID- 22434193 TI - Degradation of MONOCULM 1 by APC/C(TAD1) regulates rice tillering. AB - A rice tiller is a specialized grain-bearing branch that contributes greatly to grain yield. The MONOCULM 1 (MOC1) gene is the first identified key regulator controlling rice tiller number; however, the underlying mechanism remains to be elucidated. Here we report a novel rice gene, Tillering and Dwarf 1 (TAD1), which encodes a co-activator of the anaphase-promoting complex (APC/C), a multi-subunit E3 ligase. Although the elucidation of co-activators and individual subunits of plant APC/C involved in regulating plant development have emerged recently, the understanding of whether and how this large cell-cycle machinery controls plant development is still very limited. Our study demonstrates that TAD1 interacts with MOC1, forms a complex with OsAPC10 and functions as a co-activator of APC/C to target MOC1 for degradation in a cell-cycle-dependent manner. Our findings uncovered a new mechanism underlying shoot branching and shed light on the understanding of how the cell-cycle machinery regulates plant architecture. PMID- 22434194 TI - Structure-guided evolution of cyan fluorescent proteins towards a quantum yield of 93%. AB - Cyan variants of green fluorescent protein are widely used as donors in Forster resonance energy transfer experiments. The popular, but modestly bright, Enhanced Cyan Fluorescent Protein (ECFP) was sequentially improved into the brighter variants Super Cyan Fluorescent Protein 3A (SCFP3A) and mTurquoise, the latter exhibiting a high-fluorescence quantum yield and a long mono-exponential fluorescence lifetime. Here we combine X-ray crystallography and excited-state calculations to rationalize these stepwise improvements. The enhancement originates from stabilization of the seventh beta-strand and the strengthening of the sole chromophore-stabilizing hydrogen bond. The structural analysis highlighted one suboptimal internal residue, which was subjected to saturation mutagenesis combined with fluorescence lifetime-based screening. This resulted in mTurquoise2, a brighter variant with faster maturation, high photostability, longer mono-exponential lifetime and the highest quantum yield measured for a monomeric fluorescent protein. Together, these properties make mTurquoise2 the preferable cyan variant of green fluorescent protein for long-term imaging and as donor for Forster resonance energy transfer to a yellow fluorescent protein. PMID- 22434195 TI - Rice APC/C(TE) controls tillering by mediating the degradation of MONOCULM 1. AB - Rice MONOCULM 1 (MOC1) and its orthologues LS/LAS (lateral suppressor in tomato and Arabidopsis) are key promoting factors of shoot branching and tillering in higher plants. However, the molecular mechanisms regulating MOC1/LS/LAS have remained elusive. Here we show that the rice tiller enhancer (te) mutant displays a drastically increased tiller number. We demonstrate that TE encodes a rice homologue of Cdh1, and that TE acts as an activator of the anaphase promoting complex/cyclosome (APC/C) complex. We show that TE coexpresses with MOC1 in the axil of leaves, where the APC/C(TE) complex mediates the degradation of MOC1 by the ubiquitin-26S proteasome pathway, and consequently downregulates the expression of the meristem identity gene Oryza sativa homeobox 1, thus repressing axillary meristem initiation and formation. We conclude that besides having a conserved role in regulating cell cycle, APC/C(TE) has a unique function in regulating the plant-specific postembryonic shoot branching and tillering, which are major determinants of plant architecture and grain yield. PMID- 22434196 TI - Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis. AB - The emergence of multi- and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) has intensified the critical public health implications of this global disease. The fitness of Mycobacterium tuberculosis (M.tb.) strains exhibiting MDR and XDR phenotypes is of fundamental importance in predicting whether the MDR-/XDR-TB epidemic will be sustained across the human population. Here we describe a potential mechanism of M.tb. resistance to the TB drug isoniazid (INH) conferred by loss of a sigma factor, SigI. We demonstrate that the gain of INH resistance in the M.tb. DeltasigI mutant might not diminish the organism's fitness for causing disease. These findings have significant implications when considering the ability of drug-resistant M.tb. strains to initiate untreatable TB epidemics, as it is possible that loss or alteration of SigI function could have a role in the generation of MDR and XDR M.tb. strains of suitable fitness to spread in a community setting. PMID- 22434197 TI - Bariatric surgery evolution from the malabsorptive to the hormonal era. AB - While bariatric procedures continued to evolve and develop since the 1950s, their classification has not matched this evolution. The procedures are commonly classified into restrictive, malabsorptive, or combined. In this day and age, we recognize different mechanisms of action of the bariatric procedures. This article aims to review and update the old classifications based on our current understanding of the hormonal aspects of the various bariatric procedures and the role of gut hormones in weight loss and treatment of the associated metabolic comorbidities. The article suggests the need for a new classification of the bariatric procedures, based on the mechanism of action, involving the hormonal aspects of the procedure. PMID- 22434198 TI - Quantifying the effects of conservation practices on soil, water, and nutrients in the Loess Mesa Ravine Region of the Loess Plateau, China. AB - A large number of soil and water conservation programs have been implemented on the Loess Plateau of China since the 1950s. To comprehensively assess the merits and demerits of the conservation practices is of great importance in further supervising the conservation strategy for the Loess Plateau. This study calculates the impact factors of conservation practices on soil, water, and nutrients during the period 1954-2004 in the Nanxiaohegou Catchment, a representative catchment in the Loess Mesa Ravine Region of the Loess Plateau, China. Brief conclusions could be drawn as follows: (1) Soil erosion and nutrient loss had been greatly mitigated through various conservation practices. About half of the total transported water and 94.8 % of the total transported soil and nutrients, had been locally retained in the selected catchment. The soil retained from small watersheds do not only form large-scale fertile farmland but also safeguard the Yellow River against overflow. (2) Check dam was the most appropriate conservation practice on the Loess Plateau. In the selected catchment, more than 90 % of the retained soil and water were accomplished by the dam farmland, although the dam farmland occupied only 2.3 % of the total area of all conservation measures. Retention abilities of the characteristic conservation practices were in the following order: dam farmland > terrace farmland > forest land and grassland. (3) The conservation practices were more powerful in retaining sediment than in reducing runoff from the Loess Plateau, and the negative effects of the conservation practices on reducing water to the Yellow River were relatively slight. PMID- 22434199 TI - Detection of SERS active labelled DNA based on surface affinity to silver nanoparticles. AB - Developments in specific DNA detection assays have been shown to be increasingly beneficial for molecular diagnostics and biological research. Many approaches use optical spectroscopy as an assay detection method and, owing to the sensitivity and molecular specificity offered, surface enhanced Raman scattering (SERS) spectroscopy has become a competitively exploited technique. This study utilises SERS to demonstrate differences in affinity of dye labelled DNA through differences in electrostatic interactions with silver nanoparticles. Results show clear differences in the SERS intensity obtained from single stranded DNA, double stranded DNA and a free dye label and demonstrate surface attraction is driven through electrostatic charges on the nucleotides and not the SERS dye. It has been further demonstrated that, through optimisation of experimental conditions and careful consideration of sequence composition, a DNA detection method with increased sample discrimination at lower DNA concentrations can be achieved. PMID- 22434200 TI - Clinical guidelines: what's the difference? PMID- 22434201 TI - Rapid enrichment of cell phospholipids in long-chain polyunsaturated omega-3 fatty acids after a bolus intravenous injection of a medium-chain triacylglycerol: fish oil emulsion in humans. AB - The present review aims at highlighting the use of a recently developed medium chain triacylglycerol:fish oil (MCT:FO) emulsion for the rapid and sustained enrichment of long-chain polyunsaturated omega-3 fatty acids in cell phospholipids. Preclinical in vitro, in vivo, and ex vivo experiments are briefly considered with emphasis on the changes in the fatty acid pattern of cell phospholipids in several organs, the partial correction of liver steatosis, and the cardiovascular modification of cationic and functional variables observed in omega-3-depleted rats examined 60-120 minutes after a bolus intravenous (IV) injection (1.0 mL) of the MCT:FO emulsion. The clinical findings collected in healthy male volunteers before or after the bolus IV injection (50.0 mL) of either the MCT:FO emulsion or a control medium-chain triacylglycerol:long-chain triacylglycerol emulsion are also reviewed, with emphasis on the rapid (within 60 minutes) and sustained (up to 2-3 days) enrichment of platelet and white blood cell phospholipids in long-chain polyunsaturated omega-3 fatty acids and hemostatic safety of the present procedure proposed as a tool for the rapid prevention or correction of metabolic and functional disturbances in humans with a relative deficiency in such omega-3 fatty acids. PMID- 22434204 TI - Physical performance, bone and joint diseases, and incidence of falls in Japanese men and women: a longitudinal cohort study. AB - SUMMARY: This study examined whether physical performance and bone and joint diseases were risk factors for falls in 745 men and 1,470 women from the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study (mean, 69.7 years). Slower walking speed was a risk factor for falls in men and women. Knee pain was a risk factor for falls in women. INTRODUCTION: The objective of the present study was to clarify the incidence of falls by sex and age and to determine whether physical performance and bone and joint diseases are risk factors for falls in men and women using a large-scale population-based cohort of the ROAD. METHODS: A total of 745 men and 1,470 women were analyzed in the present study (mean age, 68.5 years). A questionnaire assessed the number of falls during 3 years of follow-up. Grip strength and walking speed were measured at baseline. Knee and lumbar spine radiographs were read by Kellgren-Lawrence (KL) grade; radiographic knee osteoarthritis and lumbar spondylosis were defined as KL = 3 or 4. Knee and lower back pain were estimated by an interview. RESULTS: During a mean follow-up of 3 years, 141 (18.9 %) men and 362 (24.6 %) women reported at least one fall. Slower walking speed was a risk factor for falls in men (0.1 m/s decrease; odds ratio [OR], 1.15; 95 % confidence interval [CI], 1.09 1.23) and women (0.1 m/s decrease; OR, 1.05; 95 % CI, 1.01-1.10). Knee pain was also a risk factor for falls (OR, 1.38; 95 % CI, 1.03-1.84) in women, but lower back pain was not. CONCLUSION: We examined the incidence and risk factors for falls in men and women. Slower walking speed was a risk factor for falls in men and women. Knee pain was a risk factor for falls in women. PMID- 22434203 TI - A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. AB - This paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18 years and over in whom oral glucocorticoid therapy is considered for 3 months or longer. INTRODUCTION: The need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010. METHODS AND RESULTS: The epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review. CONCLUSIONS: Guidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country. PMID- 22434205 TI - Impact of educational level on health-related quality of life (HRQL): results from Germany based on the EuroQol 5D (EQ-5D). AB - BACKGROUND: To date, there is hardly any study focussing on the question how the concept of HRQL could deepen our understanding of health inequalities. The study aims at describing this potential by analysing data for adults from Germany. METHODS: The analyses are based on three national, representative surveys conducted from 2006 to 2008. HRQL was assessed by the EuroQol-5D (EQ-5D), the descriptive part (problems in five dimensions) and the valuation of health by visual analogue scale (VAS) rendering a value between '0' (worst) and '100' (best imaginable). The major independent variable is educational level (high vs. low). Four other variables were included (i.e. age, sex, per capita income and chronic disease). Multivariate analyses were performed by logistic and linear regression. RESULTS: Data were available for 5676 persons aged >= 20 years (response rate 73%). The prevalence of 'moderate or severe problems' is especially high in the dimension 'pain/discomfort' (low resp. high educational level: 46.3% resp. 25.0%). The mean VAS-value is 79.8 (low resp. high educational level: 75.3 resp. 83.6). Bivariate and multivariate analyses show that similar differences in VAS values can be seen even after restricting the analyses to participants with a chronic disease. CONCLUSION: Empirical analyses concerning HRQL could further our understanding of health inequalities. They indicate that low status groups are faced with a double burden, first by increased levels of health impairments, and second by lower levels of HRQL once health is impaired. Thus, the extent of health inequalities could be underestimated if measures of HRQL are not taken into account. PMID- 22434206 TI - Making an impact instead of 'publish or perish'. PMID- 22434207 TI - The relationship between personal debt and specific common mental disorders. AB - BACKGROUND: Personal debt is now recognized as one of the many factors associated with common mental disorders (CMD). We aim to estimate the prevalence of 'specific' mental disorders based on ICD-10 research diagnostic criteria by type of debt and quantify the additional influence of addictive behaviours. METHOD: A random probability sample comprising 7461 respondents were interviewed for the third national survey of psychiatric morbidity of adults in England carried out in 2007. The prevalence of CMD was estimated from the administration of the CIS R. Respondents were asked about sources of debt and their borrowing choices. RESULTS: In 2007, 8.5% of adults were in arrears. Adults in debt were three times more likely than those not in debt to have CMD. The increased likelihood of CMD among those in arrears was found for all CMD and was irrespective of source of debt--housing, utilities and purchases on credit. The situation was exacerbated among those with addictive behaviours--alcohol or drug dependence or problem gambling. Those with multiple sources of debt and who had to obtain money from pawnbrokers and moneylenders had the highest rate of CMD, ~ 50%. CONCLUSIONS: Debt is one of the major risk factors for CMD. This has practical implications for both health services and financial services, which both need to be alert to the association and adapt and train their respective services accordingly so that people in debt can access help for mental disorders and people with mental disorders can access help for debt. PMID- 22434208 TI - Data display format and hospital ward reports: effects of different presentations on data interpretation. AB - BACKGROUND: Graphs are often used in medical communication, both in clinical practice and health management. They can help the processing of quantitative information but may also contribute to drawing wrong conclusions. The aim of the survey is to study the graphical perception of the data at the management level and its possible effects, showing how some criteria of appraisal of a phenomenon are influenced by the graphical format. METHODS: One hundred and five medical doctors and health direction professionals of hospitals in Naples, Rome, Siena and Turin were interviewed. Four different graphs or table related to the same hypothetical data on average hospital stay in the period January 2000 to September 2003 were shown to participants, and their impressions were recorded. RESULTS: Less than one-fourth of the participants understood that the data set was the same for the different diagrams. The process of understanding is mostly correlated with being a director, having a degree in medicine and working in central-northern cities. The table seems easier for interpretation (98.1%), more suitable (84.8%), more used (92.4%) and more pleasant than other data presentation. On the other hand radar format had worse results in all questions. CONCLUSIONS: The choice of a graphical format may influence the understanding of data. Further research is needed in order to sustain the improvement of medical and health professionals' knowledge in the display data format. PMID- 22434209 TI - Ketosulfonyl indoles in the regiodefined synthesis of tryptophols and related indole derivatives. AB - Reduction of ketosulfonyl indoles with sodium borohydride provides a ready entry to tryptophols in a regiocomplementary fashion with respect to the traditional oxirane ring-opening by indoles under Friedel-Crafts conditions. Compared to traditional beta-ketosulfones, ketosulfonyl indoles show a peculiar behavior since they undergo a Lewis acid promoted elimination of the arylsulfonyl group allowing the preparation of indolyl-substituted 1,4-dicarbonyl derivatives. PMID- 22434210 TI - Sustained elevation of intraocular pressure after intravitreal injections of bevacizumab in eyes with neovascular age-related macular degeneration. AB - BACKGROUND: The use of intravitreal anti-VEGF agents in general, and of bevacizumab (Avastin) in particular, has become the common first-line treatment of neovascular age-related macular degeneration (AMD). Several reports addressed the possible elevation of intraocular pressure (IOP) following intravitreal injection of anti-VEGF. The aim of this study was to determine the prevalence of sustained IOP elevation following intravitreal bevacizumab injections for neovascular AMD and identify possible risk factors for the development of increased IOP. METHODS: This retrospective cohort study included 174 consecutive patients (201 eyes) receiving intravitreal bevacizumab (1.25 mg/0.05 ml) as treatment for neovascular AMD. The records of the study patients were reviewed for age, gender, history of glaucoma, phakic status, IOP levels, length of follow up, total number of injections, intervals between injections, and IOP management in eyes that exhibited IOP elevation. Sustained IOP elevation was defined as IOP >=22 mmHg and a change from baseline of >=6 mmHg recorded on at least two consecutive visits and lasting >=30 days. Risk factors for an IOP increase were identified from the association between the studied variables and IOP elevations. RESULTS: Sustained IOP elevation was found in 22 of 201 eyes (11%). The increased IOP was controlled with topical medications in all eyes. Among the variables studied, only male gender [OR = 3.1, 95% CI (1.1, 8.5) p = 0.029] and length of interval between injections <8 weeks [OR = 3.0, 95%CI (1.1, 7.9), p = 0.028] emerged as risk factors for IOP elevation in a multivariable model. The prevalence of IOP elevation was significantly higher when the interval between injections was <8 weeks than >=8 weeks (17.6 and 6%, respectively, p = 0.009). Pre-existing glaucoma was not associated with IOP elevation (p = 0.9). CONCLUSIONS: Sustained IOP elevations can occur in normotensive eyes undergoing intravitreal bevacizumab treatment for neovascular AMD. This phenomenon was related to shorter intervals between injections, with 8 weeks being taken as the cut-off point. AMD eyes that receive intravitreal bevacizumab injections need to be monitored for IOP changes, especially those in which the intervals between injections are <8 weeks. PMID- 22434211 TI - Diagnostic yield of vitreous biopsy in presumed sarcoidosis-related posterior segment inflammation. AB - PURPOSE: Diagnostic vitrectomy is frequently used to help establish a diagnosis in challenging uveitis cases. The usefulness of this procedure in patients with suspected sarcoidosis with posterior segment involvement, in whom a diagnosis cannot be determined by conventional methods, has not been well-described. We hypothesized that diagnostic vitrectomy would help establish a diagnosis of presumed sarcoidosis-related posterior segment inflammation in these challenging cases, and evaluated the diagnostic yield of vitreous biopsy in these eyes. DESIGN: Retrospective interventional case series. METHODS: Diagnostic vitrectomy was performed on eyes with intermediate, posterior, or panuveitis in which an etiology could not be characterized by history, clinical examination, ancillary testing, and/or laboratory testing. Retrospective chart review was conducted on consecutive eyes that underwent diagnostic, or diagnostic and therapeutic vitrectomy by a single surgeon between January 1989 and June 2006. RESULTS: Diagnostic and therapeutic vitrectomy was performed on 150 eyes. The final diagnosis was established by positive vitreous fluid analysis in 63 eyes (42 %). Eight of these vitreous specimens (5.3 %) yielded cytopathology consistent with presumed sarcoidosis-related posterior segment inflammation. CONCLUSIONS: Sarcoidosis can cause characteristic inflammatory changes in the vitreous. In the appropriate clinical setting, cytopathologic assessment of these inflammatory changes observed in vitreous specimens can support the diagnosis of presumed sarcoidosis-related posterior segment inflammation, and help direct clinical management. PMID- 22434212 TI - Inferior rectus muscle recession as a treatment for vertical diplopia following cataract extraction. AB - BACKGROUND: Persistent vertical diplopia may occur after cataract surgery as a rare complication of retro- or parabulbar anesthesia. This is probably caused by structural changes in the muscles, altering muscular elasticity and function and thus complicating setting of the dosage for corrective strabismus surgery. The aim of our study was to investigate the effect of strabismus surgery in this specific motility disorder. METHODS: The findings from 15 consecutive patients (six women, nine men, median age 76 years), who had undergone initial strabismus surgery in our eye clinic between 2007 and 2010 due to vertical diplopia following cataract surgery, were investigated retrospectively. In all cases, cataract surgery had been performed under retro- or parabulbar anesthesia. RESULTS: Preoperatively, all affected eyes (five right eyes, ten left eyes) showed hypotropia with elevation deficiency and overaction of the inferior rectus muscle and/or superior oblique muscle on down-gaze. The median vertical deviation in primary position was 9.1 deg (min. 4.6, max. 24.7), measured with the alternate prism cover test, and 8 deg (min. 3.5, max.18) at the tangent screen of Harms. In all cases, the inferior rectus muscle was recessed 3 to 6 mm (median 3.5 mm). On the first day after surgery, the median angle of squint in primary position was 2.3 deg (min. 0, max. 10.2), when measured with the alternate prism cover test, with a mean dose-effect relationship of 1.8 +/- 0.7 deg angle reduction per millimetre recession (median 1.9 deg/mm). In the postoperative period, eight patients examined after 2 to 20 months (median 3.5 months) showed a median vertical deviation of 5.7 deg (min. 1.7, max. 11.3), with a mean dose effect relationship of 1.7 +/- 1.3 deg/mm (median 1.8 deg/mm), but the values ranged widely. Four patients were not examined but interviewed by telephone. There was no feed-back from three patients. Six of 12 follow-up patients had no complaints, three had prisms to correct a persisting angle, and three patients needed further squint surgery. CONCLUSIONS: The efficacy of inferior rectus muscle recession for correction of hypotropia following cataract surgery with local anesthesia ranged widely. In this condition, operating on one muscle is a good option for correction of squint angles of less than 12 deg. Squint angle enlargement can occur in the postoperative course, and may necessitate further surgery. PMID- 22434213 TI - Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome. AB - Gilles de la Tourette syndrome is a clinically heterogeneous disorder with poor known pathophysiology. Recent neuropathological and structural neuroimaging data pointed to the dysfunction of cortico-basal ganglia networks. Nonetheless, it is not clear how these structural changes alter the functional activity of the brain and lead to heterogeneous clinical expressions of the syndrome. The objective of this study was to evaluate global integrative state and organization of functional connections of sensori-motor, associative and limbic cortico-basal ganglia networks, which are likely involved in tics and behavioural expressions of Gilles de la Tourette syndrome. We also tested the hypothesis that specific regions and networks contribute to different symptoms. Data were acquired on 59 adult patients and 27 gender- and age-matched controls using a 3T magnetic resonance imaging scanner. Cortico-basal ganglia networks were constructed from 91 regions of interest. Functional connectivity was quantified using global integration and graph theory measures. We found a stronger functional integration (more interactions among anatomical regions) and a global functional disorganization of cortico-basal ganglia networks in patients with Gilles de la Tourette syndrome compared with controls. All networks were characterized by a shorter path length, a higher number of and stronger functional connections among the regions and by a loss of pivotal regions of information transfer (hubs). The functional abnormalities correlated to tic severity in all cortico-basal ganglia networks, namely in premotor, sensori-motor, parietal and cingulate cortices and medial thalamus. Tic complexity was correlated to functional abnormalities in sensori-motor and associative networks, namely in insula and putamen. Severity of obsessive-compulsive disorder was correlated with functional abnormalities in associative and limbic networks, namely in orbito-frontal and prefrontal dorsolateral cortices. The results suggest that the pattern of functional changes in cortico-basal ganglia networks in patients could reflect a defect in brain maturation. They also support the hypothesis that distinct regions of cortico basal ganglia networks contribute to the clinical heterogeneity of this syndrome. PMID- 22434214 TI - Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling. AB - Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X C motif chemokine 1 and C-C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients. Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis. PMID- 22434215 TI - Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele. AB - Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia-cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons ('mirror neurons') in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia-cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger activity in the right ventrolateral premotor cortex during execution and perception of affective facial gestures than healthy controls. Furthermore, Parkin mutation carriers showed a slightly reduced ability to recognize facial emotions that was least severe in individuals who showed the strongest increase of ventrolateral premotor activity. In addition, Parkin mutation carriers showed a significantly weaker than normal increase of activity in the left lateral orbitofrontal cortex (inferior frontal gyrus pars orbitalis, Brodmann area 47), which was unrelated to facial emotion recognition ability. These findings are consistent with the hypothesis that compensatory activity in the ventrolateral premotor cortex during processing of affective facial gestures can reduce impairments in facial emotion recognition in subclinical Parkin mutation carriers. A breakdown of this compensatory mechanism might lead to the impairment of facial expressivity and facial emotion recognition observed in manifest Parkinson's disease. PMID- 22434216 TI - How home-smoking habits affect children: a cross-sectional study using urinary cotinine measurement in Italy. AB - OBJECTIVES: To assess the impact of different home-smoking rules and smoking habits of cohabitant on environmental tobacco smoke (ETS) exposure of children. METHODS: Information about 396 Italian children (5-11 years old) and cohabitants' smoking habits was collected by a questionnaire. Exposure assessment was performed by determination of urinary cotinine (u-cotinine). RESULTS: Median u cotinine concentrations in children significantly increased in a similar fashion as theoretical ETS exposure increase: cohabitants do not smoke (1.79 MUg/g creatinine), cohabitant(s) smoker(s) never smoke at home (2.84), smoke at home only when children are out (3.90), and smoke at home even if children are in (6.02). Median u-cotinine levels of exposed children were associated to the strength of cohabitant's smoking behaviours when smoker(s) consume daily a high number of cigarettes (>= 20) respect to light consumption (1-9) (4.52 and 3.24 MUg/g creatinine). CONCLUSIONS: The magnitude of ETS exposure in children is correlated with smoking habits and home-smoking precautions adopted by their cohabitants. Educational interventions on parents are essential to increase their awareness about ETS exposure and to teach correct behaviours to protect health of kids, especially in household environment. PMID- 22434219 TI - Assessment and management of aortic valve disease in patients with left ventricular dysfunction. AB - The onset of symptoms or left ventricular systolic dysfunction heralds a poor prognosis for patients with either aortic stenosis or aortic regurgitation. Echocardiography is the primary imaging modality for assessment of aortic valvular lesions. Cardiac catheterization is indicated to determine the severity of the aortic valve lesion when there is a discrepancy between the clinical findings and the results of echocardiography in patients with either symptoms or left ventricular dysfunction. For patients with low-gradient, low-output aortic stenosis, dobutamine provocation should be used to differentiate truly severe aortic stenosis from patients with a primary cardiomyopathy and low aortic valve area due to low forward flow. Aortic valve surgery improves myocardial performance by relief of ventricular afterload in both patients with severe stenosis and those with severe regurgitation. Surgery should be pursued in both patients with severe aortic stenosis and those with severe regurgitation regardless of the degree of left ventricular dysfunction. PMID- 22434220 TI - Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice. AB - The endocannabinoid system (ECS) tightly controls emotional responses to acute aversive stimuli. Repeated stress alters ECS activity but the role played by the ECS in the emotional consequences of repeated stress has not been investigated in detail. This study used social defeat stress, together with pharmacology and genetics to examine the role of cannabinoid type-1 (CB(1)) receptors on repeated stress-induced emotional alterations. Seven daily social defeat sessions increased water (but not food) intake, sucrose preference, anxiety, cued fear expression, and adrenal weight in C57BL/6N mice. The first and the last social stress sessions triggered immediate brain region-dependent changes in the concentrations of the principal endocannabinoids anandamide and 2 arachidonoylglycerol. Pretreatment before each of the seven stress sessions with the CB(1) receptor antagonist rimonabant prolonged freezing responses of stressed mice during cued fear recall tests. Repeated social stress abolished the increased fear expression displayed by constitutive CB(1) receptor-deficient mice. The use of mutant mice lacking CB(1) receptors from cortical glutamatergic neurons or from GABAergic neurons indicated that it is the absence of the former CB(1) receptor population that is responsible for the fear responses in socially stressed CB(1) mutant mice. In addition, stress-induced hypolocomotor reactivity was amplified by the absence of CB(1) receptors from GABAergic neurons. Mutant mice lacking CB(1) receptors from serotonergic neurons displayed a higher anxiety but decreased cued fear expression than their wild-type controls. These mutant mice failed to show social stress-elicited increased sucrose preference. This study shows that (i) release of endocannabinoids during stress exposure impedes stress-elicited amplification of cued fear behavior, (ii) social stress opposes the increased fear expression and delayed between-session extinction because of the absence of CB(1) receptors from cortical glutamatergic neurons, and (iii) CB(1) receptors on central serotonergic neurons are involved in the sweet consumption response to repeated stress. PMID- 22434221 TI - Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic, endocannabinoid and GABAergic pathways. AB - Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9 tetrahydrocannabinol (THC) during adolescence (postnatal day 32-52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype * THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia. PMID- 22434222 TI - Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume. AB - The common genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been related to depressive symptoms, in particular after stressful life events. Although it has been investigated in the past, results suggesting that the 5-HTTLPR genotype also affects hippocampal volume are often inconsistent and it remains unclear to what extent reduced hippocampal volume is influenced by the effect of stressful life events and 5-HTTLPR genotype. Moreover, sex, which is known to affect the prevalence of depression substantially, has not been taken into account when trying to disentangle the interactive effect of common genetic variation and environmental stressors on the hippocampus. We investigated this potentially relevant three-way interaction using an automatic magnetic resonance imaging (MRI)-based segmentation of the hippocampus in 357 healthy individuals. We determined the 5-HTTLPR genotype as a biallelic locus and childhood adversity (CA) using a standard questionnaire. An interaction for hippocampal volume was found between the factors sex, genotype, and severe CA (p=0.010) as well as an interaction between genotype and severe CA (p=0.007) in men only. Post hoc tests revealed that only male S'-allele carriers with severe CA had smaller hippocampi (p=0.002). Interestingly, there was no main effect of genotype in men, while female S'-allele carriers had smaller hippocampi than L'L' carriers (p=0.023). Our results indicate that sex modulates the interactive effect of the 5-HTTLPR genotype and CA on hippocampal volume. While the S'-allele is associated with hippocampal volume independent of CA in women, men only have smaller hippocampi if they carry the risk allele and experienced severe CA. PMID- 22434223 TI - Neurobiological changes mediating the effects of chronic fluoxetine on cocaine use. AB - Acute SSRI (selective serotonin reuptake inhibitor) treatment has been shown to attenuate the abuse-related effects of cocaine; however, SSRIs have had limited success in clinical trials for cocaine abuse, possibly due to neurobiological changes that occur during chronic administration. In order to better understand the role of serotonin (5HT) in cocaine abuse and treatment, we examined the effects of chronic treatment with the SSRI fluoxetine at clinically relevant serum concentrations on cocaine-related neurobiology and behavior. Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans. Self administration and reinstatement were monitored throughout the treatment and washout period. In vivo microdiaylsis was used to assess changes in dopaminergic and serotonergic neurochemistry. Positron emission tomography was used to assess changes in the 5HT transporter and 2A receptor binding potential (BP). Functional output of the 5HT system was assessed using prolactin levels. Cocaine-primed reinstatement and cocaine-elicited dopamine overflow were significantly suppressed following chronic fluoxetine treatment. 5HT2A receptor BP was increased in the frontal cortex following treatment while prolactin release was blunted, suggesting desensitization of the 5HT2A receptor. These effects persisted after a 6-week washout period. Measures of pre-synaptic serotonergic function and cocaine self-administration were unaffected. These data demonstrate that acute and chronic fluoxetine treatments exert different effects on cocaine related behavior. Furthermore, chronic fluoxetine treatment causes alterations in 5HT2A receptors in the frontal cortex that may selectively disrupt cocaine-primed reinstatement. Fluoxetine may not be useful for treatment of ongoing cocaine abuse but may be useful in relapse prevention. PMID- 22434224 TI - Ankle reconstruction in type II fibular hemimelia. AB - Ankle reconstruction prior to limb lengthening for was performed in 13 patients with fibular hemimelia with complete radiological absence of the fibula (type II). There were different degrees of absence of metatarsal rays. The hindfoot deformity was a heel valgus in 12 patients and equinovarus in 1 patient. The patients' ages ranged from 9 to 26 months. Excision of the fibular anlage was performed with lateral subtalar and ankle soft tissue releases to restore the ankle and subtalar joint relationships. In all cases, the fibular anlage ended distally in a cartilaginous lateral malleolar remnant that was fused to the talus in two patients. This fibular remnant was advanced distally and fixed to the tibia with 2 Kirschner wires to recreate an ankle mortise. The period of follow up ranged from 12 to 38 months. All patients had a stable ankle without tendency to valgus deformity or subluxation. The ankle range of movement was a mean of 27.3 degrees plantarflexion (25-30) and 18 degrees dorsiflexion (15-20). Reconstruction of the ankle in type II fibular hemimelia using advancement of the cartilaginous lateral malleolar remnant has produced encouraging results in the short-term but longer follow-up is needed. PMID- 22434225 TI - Proximal tibial osteotomies for the medial compartment arthrosis of the knee: a historical journey. AB - Several proximal tibial osteotomy techniques for the medial compartment arthrosis of the knee are described and traced in their development. These techniques are of the closed wedge, dome and open wedge types. We detail the differences in planning and surgery as well the need for different fixation devices. This historical and technical description will benefit those surgeons wishing to undertake the procedure as an alternative to joint replacement strategies. PMID- 22434227 TI - Advanced necrotizing enterocolitis part 1: mortality. AB - AIM OF THE STUDY: The aim of this study was to investigate the factors associated with mortality in infants referred for the surgical treatment of advanced necrotizing enterocolitis (NEC). METHODS: Retrospective review of all infants with confirmed (Bell stage II or III) NEC treated in our unit during the past 8 years (January 2002 to December 2010). Data for survivors and nonsurvivors were compared using Mann-Whitney test and Fisher's exact test and are reported as median (range). RESULTS: Of the 205 infants with NEC, 35 (17%) were medically managed; 170 (83%) had surgery; 66 (32%) infants died; all had received surgery. Survivors and nonsurvivors were comparable for gestational age, birth weight, and gender distribution. Overall mortality was 32%, the highest mortality was in infants with pan-intestinal disease (86%) but remained significant in those with less severe disease (multifocal 39%; focal disease 21%). The commonest cause of mortality was multiple organ dysfunction syndrome and nearly half of the nonsurvivors had care withdrawn. CONCLUSION: Despite improvement in neonatal care, overall mortality (32%) for advanced NEC has not changed in 10 years. Mortality is significant even with minimal bowel involvement. PMID- 22434228 TI - Advanced necrotizing enterocolitis part 2: recurrence of necrotizing enterocolitis. AB - AIM OF THE STUDY: The aim of this study was to report incidence and clinical outcomes of recurrent necrotizing enterocolitis (NEC). METHODS: Review of infants treated for recurrent episode(s) of NEC at a tertiary Neonatal Surgical Intensive Care Unit over 8 years (January 2002 to February 2011). Demographic, clinical, radiological, and operative data were analyzed and compared using Mann-Whitney or Fisher's exact tests. Data are reported as median (range). RESULTS: A total of 212 consecutive infants were referred for surgical evaluation and treatment of NEC (Bell stage II or III). Of these patients, 22 (10%) had suspected recurrent NEC: in 11 of these the primary episode was Bell stage I successfully treated before coming to our institution (suspected recurrent NEC); in the remaining 11, the primary episode was confirmed (Bell stage II or III) NEC successfully treated in our hospital. Birth weight, gestational age at birth, corrected gestational age, weight on admission, gender, need for surgery, stricture, and mortality rates were similar between infants with recurrent NEC and those with a single episode. Long-term parenteral nutrition (PN) dependency (>28 days) was significantly more common following recurrent NEC compared with a single episode. Among the infants with recurrent NEC, medical therapy alone was not successful in the majority (82%) of cases during the first episode and all required surgery during the recurrent episode. CONCLUSION: Infants (10%) referred for surgical treatment of NEC develop recurrence of the disease. Surprisingly, these infants have similar mortality and stricture rates to those with a single episode. However, the incidence of long-term PN dependency was significantly increased in those with recurrent episodes of NEC. PMID- 22434229 TI - Elevated serum IL-18 and interferon-gamma in medium-term survivors of biliary atresia. AB - INTRODUCTION: Biliary atresia (BA) is a fatal disease in children. Its main pathological feature is progressive immune-mediated cholangiopathy. Interleukin (IL)-12, IL-18, and interferon-gamma (IFN-gamma) play important roles in various immunological diseases. THE OBJECTIVE: was to investigate whether these serum markers were associated with clinical outcome in BA. METHODS: Serum levels of IL 12, IL-18, and IFN-gamma were determined using enzyme-linked immunosorbent assay from 46 BA patients (median age of 9 years) and 19 normal controls. The BA patients were then categorized into three groups according to their outcome: jaundice-free (29 cases), mild to moderate jaundice (10 cases), and marked jaundice (7 cases). The comparisons of serum IL-12, IL-18, and IFN-gamma levels among groups of the patients were performed using one-way analysis of variance with post-hoc tests. Data are expressed as mean + standard deviation. RESULTS: Serum IL-18 and IFN-gamma in BA patients were higher than the normal controls (IL 18: 113.3 + 82.6 vs. 80.5 + 9.9 pg/mL, p = 0.011 and IFN-gamma: 41.7 + 5.1 vs. 38.0 + 1.9 pg/mL, p < 0.001). There was no difference in serum IL-12 between BA and controls. Further analysis demonstrated that, in BA patients, only serum IL 18 levels significantly increased with the degree of jaundice (test for trend, p = 0.004). CONCLUSIONS: Serum IL-18 and IFN-gamma levels were increased in medium term survivors of BA. The elevated serum IL-18 in BA patients was associated with worse clinical outcome. These results suggest that IL-18 and IFN-gamma play roles in the pathophysiology of BA. Additionally, IL-18 is likely to be involved in the disease progression. PMID- 22434230 TI - Alignment of training curriculum and surgical practice: implications for competency, manpower, and practice modeling. AB - OBJECTIVE: The attractiveness of pediatric surgery (PS) as a specialty includes its primary role in the care of multisystemic disease. We were interested in identifying changes in operative case quality and quantity when comparing PS residents to PS practitioners. METHODS: The 2006 Accreditation Council for Graduate Medical Education PS resident current procedural terminology (CPT) code database (26,077 resident cases) was merged with the 2006 Kids' Inpatient Database of International Classification of Diseases (ICD)-9 procedure codes (230,504 practitioner cases) and categorized by case type and volumes according to a resident CPT reference file. Cases were categorized into 84 procedure types. A recent estimate of 691 practicing pediatric surgeons was used as denominator to calculate case volume per surgeon. Our analysis focused on the PS index cases and we compared PS residents to subspecialty board certified general pediatric surgeons in practice. We excluded cases that may be performed by general surgeons without PS training. RESULTS: Our data indicate that, on average, 501 cases are performed annually by each PS resident. We identified significant differences in case volume per surgeon between training and practice for most PS index cases.CONCLUSIONS The PS index case quantity declined significantly from training to practice. If a volume to outcome relationship applies to these complex and infrequent PS cases, then to sustain and improve clinical quality post-training will require a new paradigm of continued learning. Additionally, a relook at the optimal manpower and more focused regionalization is warranted. PMID- 22434231 TI - Fundoplication in ventilator-dependent infants with gastro-oesophageal reflux. AB - AIM: In ventilator-dependent infants with complex comorbidities, severe gastro oesophageal reflux (GOR) may contribute to prolonging the period of ventilation. It is often difficult to predict whether antireflux surgery will improve the respiratory status of an infant and assist with weaning off the ventilator. The aim of this study was to review the outcomes in a cohort of ventilator-dependent infants who underwent fundoplication to help wean them off ventilation. METHODS: Between January 2006 and December 2010, out of 596 infants who underwent fundoplication for symptoms of GOR, 26 were ventilator dependent before surgery; 13 patients had an emergency fundoplication following an acute life-threatening event (n = 5, 19%) or an acute deterioration of respiratory status (n = 8, 31%). Fundoplication was planned in the rest of the group (n = 13, 50%) with the aim of improving respiratory status and weaning from ventilation. The median age at surgery was 5.8 months (range: 0.8 to 19.4 months). The median weight at surgery was 6.3 kg (range: 4 to 15.1 kg). Data were collected for each infant on comorbidities, pre- and postoperative ventilation status, pre- and postoperative GOR symptoms, and survival. RESULTS: All infants underwent a Nissen fundoplication with no intraoperative morbidity or mortality. Of these, 12 infants had a laparoscopic fundoplication; 14 infants had an open fundoplication. Postoperatively, all infants received invasive positive pressure ventilation in the intensive care unit (ICU). All infants were successfully weaned from ventilation. The median time to extubation was 4 days (range: 2 to 18 days). The median postoperative ICU stay was 9 days (range: 3 to 52 days). Of the patients, 9 (34%) had a recurrence of symptoms following fundoplication; 5 (19%) subsequently underwent revision of fundoplication and 1 (3.8%) underwent oesophago-gastric dissociation; and 10 (38%) died within the study period. CONCLUSION: In infants with severe GOR, ventilator dependence, and complex comorbidities, fundoplication may be a useful procedure to assist weaning off ventilator dependence. Rates of symptom recurrence, of revision of fundoplication, and of mortality within this cohort were higher than expected. These data reflect the challenges of patient selection in high-risk groups. PMID- 22434232 TI - Effects of oxidative stress on intestinal type I insulin-like growth factor receptor expression. AB - INTRODUCTION: Oxidative stress activates multiple signaling transduction pathways, including the phosphatidylinositol 3-kinase (PI3-K), in an injured intestine as occurs in necrotizing enterocolitis (NEC). We have previously shown that hydrogen peroxide (H2O2)-induced PI3-K activation is significantly enhanced with exogenous insulin-like growth factor (IGF)-1 in intestinal epithelial cells. However, the effects of oxidative stress on IGF receptor type I (IGF-IR) activation and expression in the neonatal intestine during NEC are unknown. MATERIAL AND METHODS: Intestinal sections from neonates undergoing bowel resections (control = 3, NEC = 20) were analyzed for IGF-IR expression. NEC was induced in newborn mouse pups using hypoxia and hyperosmolar feeds, and distal small bowel segments were analyzed for IGF-IR expression (control = 3, NEC = 7). H2O2 was used to induce oxidative stress in rat (RIE-1) and fetal human (FHs74 Int) intestinal epithelial cells. Phosphorylation of IGF-IR, Akt, a downstream effector of PI3-K, and IGF-IR levels were determined by Western blotting. Flow cytometry, immunofluorescence, immunohistochemistry, IGF-IR tyrosine phosphorylation array, cell death enzyme-linked immunosorbent assay, and Western blotting were used to determine the IGF-IR expression. RESULTS: An increased IGF IR expression was noted in intestinal sections from NEC as well as murine model of NEC. H2O2 treatment rapidly activated IGF-IR and increased the expression in RIE-1 and FHs74 Int cells. Inhibition of IGF-IR resulted in significant RIE-1 cell apoptosis during oxidative stress. IGF-IR tyrosine phosphorylation array showed the recruitment of several key SH2 domain-containing proteins and oncogenes to the IGF-IR tyrosine kinase domain in H2O2-treated RIE-1 cells. CONCLUSION: IGF-IR-mediated activation of intracellular signaling may play a critical role during oxidative stress-induced apoptosis in NEC. PMID- 22434233 TI - Efficient gene transfer into neonatal mouse brain using electroporation. AB - In vivo electroporation works as an effective method to transfer exogenous genes into postnatal rodent forebrain. Nevertheless, two deficiencies were found in the reported methods. First, surgical operation brings unnecessary trauma to newborn pups. Second, the procedure was complicated and the transfection efficiency was relatively low. Here we improved the previous electroporation method and make it more simple and efficient. The pulse voltage was decreased to 90 v. DNA injection into one pup's forebrain could be completed within 30 s without any surgical operation. More than 94% of injected neonates survived. Almost 100% of the survivors expressed the introduced gene and the expression persists as long as 20 days after injection. Thus, this method offers a powerful new way for gene function study in postnatal neurogenesis and neural development. PMID- 22434234 TI - Correct indication for surgery can prevent postoperative ascites in cirrhotic patients affected by hepatocellular carcinoma. PMID- 22434235 TI - Admissions due to pneumonia and biomass burning: a spatial approach. AB - OBJECTIVE: To identify spatial patterns in rates of admission for pneumonia among children and relate them to the number of fires reported in the state of Mato Grosso, Brazil. METHODS: We conducted an ecological and exploratory study of data from the state of Mato Grosso for 2008 and 2009 on hospital admissions of children aged 0 to 4 years due to pneumonia and on fires in the same period. Admission rates were calculated and choropleth maps were plotted for rates and for fire outbreaks, Moran's I was calculated and the kernel estimator used to identify "hotspots." Data were analyzed using TerraView 3.3.1. RESULTS: Fifteen thousand six hundred eighty-nine children were hospitalized (range zero to 2,315), and there were 161,785 fires (range 7 to 6,454). The average rate of admissions per 1,000 inhabitants was 2.89 (standard deviation [SD] = 5.18) and the number of fires per 1,000 inhabitants was 152.81 (SD = 199.91). Moran's I for the overall number of admissions was I = 0.02 (p = 0.26), the index for rate of admission was I = 0.02 (p = 0.21) and the index for the number of fires was I = 0.31 (p < 0.01). It proved possible to identify four municipalities with elevated rates of admissions for pneumonia. It was also possible to identify two regions with high admission densities. A clustering of fires was evident along what is known as the "arc of deforestation." CONCLUSIONS: This study identified municipalities in the state of Mato Grosso that require interventions to reduce rates of admission due to pneumonia and the number fires. PMID- 22434236 TI - Prognostic occupational factors for persistent low back pain in primary care. AB - PURPOSE: To reduce the socio-economic burden of persistent low back pain (LBP), factors influencing the progression of acute/subacute LBP to the persistent state must be identified at an early stage. METHODS: Prospective inception cohort study of patients attending a health practitioner for their first episode of acute/subacute or recurrent LBP. Patients were assessed at baseline addressing occupational, psychological, biomedical and demographic/lifestyle factors and followed up over 6 months. Multivariate logistic regression analysis was performed separately for the variables groups of the four different domains, controlling for age, gender and body mass index. The overall predictive value was calculated for the full regression models of the different domains. Finally, all significant variables from the different domains were combined into a final predictor model. RESULTS: The final four-predictor model predicted 51 % of variance of persistent LBP and included 'resigned attitude towards the job' (OR 1.73; 95 % CI 1.16-2.59), 'social support at work' (OR 0.54; 95 % CI 0.32-0.90), 'functional limitation' (OR 1.05; 95 % CI 1.01-1.10) and 'duration of LBP' (OR 1.04; 95 % CI 1.02-1.06). The accuracy of the model was 83 %, with 92 % of non persistent and 67 % of persistent LBP patients correctly identified. CONCLUSIONS: In this study of patients with acute/subacute LBP, 'resigned attitude towards the job' increased the likelihood of persistent LBP at 6 month. Addressing this factor with workplace interventions has the potential to modify the outcome. In patients experiencing 'social support at work', the development of persistent LBP was less likely and might therefore be considered as potential resource for prevention of persistent LBP. PMID- 22434237 TI - Gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium. AB - An efficient gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium under mild reaction conditions has been developed. PMID- 22434239 TI - The neurodevelopmental basis of math anxiety. AB - Math anxiety is a negative emotional reaction to situations involving mathematical problem solving. Math anxiety has a detrimental impact on an individual's long-term professional success, but its neurodevelopmental origins are unknown. In a functional MRI study on 7- to 9-year-old children, we showed that math anxiety was associated with hyperactivity in right amygdala regions that are important for processing negative emotions. In addition, we found that math anxiety was associated with reduced activity in posterior parietal and dorsolateral prefrontal cortex regions involved in mathematical reasoning. Multivariate classification analysis revealed distinct multivoxel activity patterns, which were independent of overall activation levels in the right amygdala. Furthermore, effective connectivity between the amygdala and ventromedial prefrontal cortex regions that regulate negative emotions was elevated in children with math anxiety. These effects were specific to math anxiety and unrelated to general anxiety, intelligence, working memory, or reading ability. Our study identified the neural correlates of math anxiety for the first time, and our findings have significant implications for its early identification and treatment. PMID- 22434240 TI - Lewis acid-mediated radical cyclization: stereocontrol in cascade radical addition-cyclization-trapping reactions. AB - An efficient approach for achieving radical cyclizations by using hydroxamate ester as a coordination tether with Lewis acid was studied. The chiral Lewis acid mediated cascade radical addition-cyclization-trapping reaction proceeded smoothly with good enantio- and diastereoselectivities, providing various chiral gamma-lactams. PMID- 22434241 TI - Protective effect of Okuzgozu (Vitis vinifera L. cv.) grape juice against carbon tetrachloride induced oxidative stress in rats. AB - The consumption of fruits plays an important role as a health protecting factor. Grapes (Vitis vinifera L.) are believed to have health benefits due to their antioxidant activity. Okuzgozu is the largest among the grape varieties grown in Turkey. Carbon tetrachloride (CCl4) causes free radical generation in many tissues such as the liver, kidney, heart, lung, testis, brain and blood. Ursodeoxycholic acid (UDCA) is the only drug to treat primary biliary cirrhosis, but the effects remain controversial. The aim of the present study is to investigate the protective effect of Okuzgozu grape juice or UDCA against tissue damage induced by CCl4 in rats. The amount of total phenolics and flavonoids were found to be 1208.00 +/- 43.00 MUg ml-1 as the gallic acid equivalent and 5.2 +/- 0.19 MUg ml-1 as the quercitin equivalent in Okuzgozu grape juice, respectively. In vivo administration of CCl4 caused a significant increase of various biochemical parameters such as alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin (TB) and a decrease in albumin (ALB) levels in serum or an increase in malondialdehyde (MDA) levels in the tissues when compared to a control. Administration of CCl4 along with Okuzgozu grape juice or ursodeoxycolic acid (UDCA) significantly reduces these changes. Histopathalogical studies also support the protective effect of the extract. This study demonstrates the protective activity of Okuzgozu grape juice and thus scientifically supports the usage of this fruit in various traditional medicines for the treatment of tissue disorders. The effect of Okuzgozu grape juice was comparable with that of UDCA. PMID- 22434242 TI - Race and the prognostic influence of p53 in women with breast cancer. AB - BACKGROUND: Prior study suggests that p53 status behaves as an independent marker of prognosis in African American (AA) women with breast cancer. We investigate whether the influence of p53 is unique to AAs or is present in other race/ethnic groups, and how this compares with known prognostic factors. METHODS: Cox regression models [hazard ratios (HRs), 95% confidence intervals (CIs)] were used to select and evaluate factors prognostic for all-cause mortality in 331 AA and 203 non-AA consecutively treated women. RESULTS: Statistically significant baseline prognostic factors were as follows. For AAs: stage [(III/I) HR 5.57; 95% CI 3.08-10.09], grade [(higher/low) HR 1.55; 95% CI 1.14-2.11], estrogen receptor (ER)/progesterone receptor (PR) status [(-/+) HR 2.01; 95% CI 1.38-2.93], triple negative (ER-, PR-, HER2-) subtype [(+/-) HR 1.95; 95% CI 1.33-2.85], and p53 status [(+/-) HR 1.69; 95% CI 1.10-2.58]. For non-AAs: stage [HR 11.93; 95% CI 2.80-50.84], grade [HR 1.61; 95% CI 0.96-2.71], and ER/PR status [HR 2.13; 95% CI 1.19-3.81]. There was a differential effect of race within p53 groups (P=0.05) and in multivariate modeling p53-positive status remained an adverse prognostic factor in AAs only [HR 1.82; 95% CI 1.04-3.17]. Compared to non-AAs, 5-year unadjusted survival was worse for AAs overall (73.4% vs. 63.6%; P=0.032), and also for AAs with p53-positive status (80.3% vs. 54.2%; P=0.016), but not for AAs with p53-negative disease (68.4% vs. 67.9%; P=0.81). CONCLUSIONS: Among women with breast cancer of different race/ethnicity, an adverse prognostic effect as a result of p53 positivity was only observed in AA women. PMID- 22434243 TI - Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis. AB - BACKGROUND: Complete pathologic response (CPR) after neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer seems associated with improved survival compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single institution design. METHODS: A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR and NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Study end points included rates of CPR, local recurrence (LR), distant recurrence (DR), 5-year overall survival (OS), and disease-free survival (DFS). RESULTS: Twelve studies (1,913 patients) with rectal cancer treated with CMT were included. CPR was observed in 300 patients (15.6%). CPR and NPR patient groups were similar with respect to age, sex, tumor size, distance of tumor from the anus, and stage of disease before treatment. Median follow-up ranged from 23 to 46 months. CPR patients had lower rates of LR [0.7% vs. 2.6%; odds ratio (OR) 0.45, 95% confidence interval (CI) 0.22-0.90, P = 0.03], DR (5.3% vs. 24.1%; OR 0.15, 95% CI 0.07-0.31, P = 0.0001), and simultaneous LR + DR (0.7% vs. 4.8%; OR 0.32, 95% CI 0.13-0.79, P = 0.01). OS was 92.9% for CPR versus 73.4% for NPR (OR 3.6, 95% CI 1.84-7.22, P = 0.002), and DFS was 86.9% versus 63.9% (OR 3.53, 95% CI 1.62-7.72, P = 0.002). CONCLUSIONS: CPR after CMT for rectal cancer is associated with improved local and distal control as well as better OS and DFS. PMID- 22434244 TI - Hereditary breast cancer: practical pursuit for clinical translation. AB - The benefits of a skillful medical history and histologic confirmation of relevant pathology are potentially lifesaving. Appropriately directed DNA testing based on these initial steps provides an opportunity for clinical translation into a cancer prevention program targeted to family members. Unfortunately, cancer prevention strategies that are based on genetics are frequently overlooked or underestimated in the overall practical management of patients at high risk for breast cancer as well as integral cancers that constitute a hereditary breast cancer syndrome. DNA testing, particularly for BRCA1 and BRCA2 in hereditary breast-ovarian cancer syndrome and p53 in the Li-Fraumeni syndrome, and many other syndromes is commercially available for inclusion in a cancer control program and merits attention in this major public health problem. It is clear that the time and effort expended for a hereditary cancer syndrome diagnosis may significantly reduce both morbidity and mortality in breast cancer. We have found that genetic counselors can partner with the clinical physicians and make significant contributions to this labor-intensive effort. PMID- 22434245 TI - A comparative study of voiding and sexual function after total mesorectal excision with autonomic nerve preservation for rectal cancer: laparoscopic versus robotic surgery. AB - PURPOSE: To evaluate the protection of the urogenital function after robot assisted total mesorectal excision (R-TME) for rectal cancer compared to those of laparoscopic TME (L-TME). METHODS: 69 patients who underwent L-TME (n = 39) or R TME (n = 30) were prospectively enrolled. Their urogenital function was evaluated by uroflowmetry, a standard questionnaire of the international prostate symptom score (IPSS) and the international index of erectile function (IIEF) before surgery and 1, 3, 6, and 12 months after surgery. The pre- and postoperative IPSS and IIEF scores were compared to detect functional deterioration by paired t test for each group. How postoperative IPSS and IIEF scores and uroflowmetry data deviated from the preoperative values (Delta) were statistically compared between the two groups. RESULTS: The IPSS score significantly increased 1 month after surgery; the recovery from decreased urinary function took 6 months for patients in the L-TME group (8.2 +/- 6.3; P = 0.908) but 3 months in the R-TME group (8.36 +/- 5.5; P = 0.075). The DeltaIPSS scores were significantly different between the two groups at 3 months (P = 0.036). In male patients (L-TME 20, R-TME 18), the total IIEF score in R-TME and L-TME significantly decreased 1 month after surgery, L-TME gradually recovered over 12 months (46.00 +/- 16.9; P = 0.269), but R-TME recovered within 6 months (44.61 +/- 13.76; P = 0.067). The DeltaIIEF score value was not significantly different at any time between the two groups, but in an itemized analysis of the change in erectile function and sexual desire, there were significant differences at 3 months between the two groups. CONCLUSIONS: R-TME for rectal cancer is associated with earlier recovery of normal voiding and sexual function compared to patients who underwent L-TME, although this result needs to be verified by larger prospective comparative studies. PMID- 22434246 TI - Increased risk for CRC in diabetic patients with the nonrisk allele of SNPs at 8q24. AB - BACKGROUND: Colorectal cancer (CRC) oncogenesis was considered to be determined by interactions between genetic and environmental factors. Specific interacting factors that influence CRC morbidity have yet to be fully investigated. METHODS: A multi-institutional collaborative study with 1511 CRC patients and 2098 control subjects was used to compare the odds ratios for the occurrence of polymorphisms at 11 known single nucleotide polymorphisms (SNPs). TaqMan PCR and questionnaires were used to evaluate the effects of environmental exposures. RESULTS: Variants of rs6983267 on 8q24 were the most significant markers of risk for CRC (odds ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.0015). Non-insulin-dependent diabetes mellitus (DM), a higher body mass index at age 20, and meat consumption were environmental risk factors, whereas a tuna-rich diet and vitamin intake were protective factors. The cohort of rs6983267 SNP major (T) allele at 8q24 and DM had a 1.66-fold higher risk ratio than the cohort of major allele patients without DM. CONCLUSIONS: We confirmed that interactions between the genetic background and environmental factors are associated with increased risk for CRC. There is a robust risk of the minor G allele at the 8q24 rs6983267 SNP; however, a major T allele SNP could more clearly reveal a correlation with CRC specifically when DM is present. PMID- 22434247 TI - Classification of parathyroid cancer. AB - PURPOSE: Parathyroid cancer is rare and often has a poor outcome. There is no classification system that permits prediction of outcome in patients with parathyroid cancer. This study was designed to validate two prognostic classification systems developed by Talat and Schulte in 2010 ("Clinical Presentation, Staging and Long-term Evolution of Parathyroid Cancer," Ann Surg Oncol 2010;17:2156-74) derived from a retrospective literature review of 330 patients. METHODS: This study contains 82 formerly unreported patients with parathyroid cancer. Death due to disease was the primary end point, and recurrence and disease-free survival were the secondary end points. Data acquisition used a questionnaire of predefined criteria. Low risk was defined by capsular and soft tissue invasion alone; high risk was defined by vascular or organ invasion, and/or lymph node or distant metastasis. A differentiated classification system further classified high-risk cancer into vascular invasion alone (class II), lymph node metastasis or organ invasion (class III), and distant metastasis (class IV). Statistical analyses included risk analysis, Kaplan-Meier analysis, and receiver-operating characteristic (ROC) analysis. RESULTS: Follow-up ranged 2-347 months (mean 76 months). Mortality was exclusive to the high- risk group, which also predicted a significant risk of recurrence (risk ratio 9.6; 95% confidence interval 2.4-38.4; P < 0.0001), with significantly lower 5-year disease-free survival (chi(2) = 8.7; P < 0.005 for n = 45). The differentiated classification also provided a good prognostic model with an area under the ROC curve of 0.83 in ROC analysis, with significant impairment of survival between classes (98.6%, 79.2%, 71.4%, 40.0%, P < 0.05 between each class). CONCLUSIONS: This study confirms the validity of both classification systems for disease outcome in patients with parathyroid cancer. PMID- 22434248 TI - N-O bond cleavage mechanism(s) in nitrous oxide reductase. AB - Quantum chemical calculations of active-site models of nitrous oxide reductase (N(2)OR) have been undertaken to elucidate the mechanism of N-O bond cleavage mediated by the supported tetranuclear Cu(4)S core (Cu(Z)) found in the enzymatic active site. Using either a minimal model previously employed by Gorelsky et al. (J. Am. Chem. Soc. 128:278-290, 2006) or a more extended model including key residue side chains in the active-site second shell, we found two distinct mechanisms. In the first model, N(2)O binds to the fully reduced Cu(Z) in a bent MU-(1,3)-O,N bridging fashion between the Cu(I) and Cu(IV) centers and subsequently extrudes N(2) while generating the corresponding bridged MU-oxo species. In the second model, substrate N(2)O binds loosely to one of the coppers of Cu(Z) in a terminal fashion, i.e., using only the oxygen atom; loss of N(2) generates the same MU-oxo copper core. The free energies of activation predicted for these two alternative pathways are sufficiently close to one another that theory does not provide decisive support for one over the other, posing an interesting problem with respect to experiments that might be designed to distinguish between the two. Effects of nearby residues and active-site water molecules are also explored. PMID- 22434249 TI - [From a method for family planning to a differentiating lifestyle drug: images of the pill and its consumer in gynaecological advertising since the 1960s in West Germany and France]. AB - Based upon flyers and advertisements for the contraceptive pill from 1961 until 2005, this paper discusses the ways in which the drug and its female users were represented in the marketing of two West European countries, France and the German Federal Republic. As my analysis suggests, national differences are only discernible in the marketing until the end of the 1970s. In West Germany, the pill was depicted from early on as a contraceptive, whereas, due to the restrictive legal situation, in France the pill was marketed as a multi-purpose drug. Nevertheless, the sources in both countries emphasized the safety of the drug. Likewise the representations of women changed from the notion of the married mother to a more diverse image, including young, modern and active women. From the early 1980s on, French and German materials conformed to one another. Now more classification systems were developed, emphasizing the differences between types of pills and types of women. Lifestyle, leisure and fun became increasingly central topics. Correspondingly, the female user was often portrayed in a sexualized way and represented as an active consumer with individual needs and wishes. PMID- 22434250 TI - Experimental arthritis: Targeted anti-C5 drug neutralizes complement in the joint. PMID- 22434251 TI - Bone: Vitamin E: friend or foe to bone? PMID- 22434252 TI - Hydration profile and influence of beverage contents on fluid intake by women during outdoor recreational walking. AB - This study examined hydration status, sweat losses, and the effects of flavoring and electrolytes on fluid intake for women (n = 27, age = 24 +/- 4 years) walking at a self-selected pace for ~1 h on a 1 km outdoor path during summer mornings or evenings. Over five consecutive days, participants consumed ad libitum one non caloric beverage containing: (1) water (W), (2) acidified water (AW), (3) acidified water with electrolytes (AWE), (4) acidified water with flavor (AWF), and (5) acidified water with flavor and electrolytes (AWFE) in a counter-balanced order during walks and a 1-h recovery period. Walk Wet bulb globe temperature (26.2 +/- 1.8 degrees C) and pace (6.0 +/- 0.5 km/h) did not differ among beverages (P > 0.05). Thirty-four percent of pre-walk urine specific gravity samples exceeded 1.020. Flavoring (AWF 700 +/- 393 mL; AWFE 719 +/- 405 mL) did not result in greater consumption (P > 0.05) over W (560 +/- 315 mL), with all three beverages exceeding grand mean sweat losses (528 +/- 208 mL). Addition of electrolytes did not influence (P > 0.05) the intake between AW versus AWE or AWF versus AWFE. The results of this study indicate that the majority of women will consume fluids in excess of their sweat losses within 1 h post-walk. Over half of consumption took place during walks, highlighting the importance of fluid availability during exercise. Great among-subjects variability in sweat losses and fluid intake support the need for promoting individualized hydration strategies based on the changes in body mass for athletic populations. PMID- 22434253 TI - The senescent rat diaphragm does not exhibit age-related changes in caspase activities, DNA fragmentation, or myonuclear domain. AB - The diaphragm muscle is essential for normal ventilation and it is chronically active throughout the lifespan. In most skeletal muscles, aging is associated with increased oxidative stress and myofiber atrophy. Since the diaphragm maintains a unique chronic contractile activity, we hypothesized that these alterations would not occur in senescent diaphragms compared to young diaphragms. In addition, we investigated whether senescence leads to altered diaphragmatic caspase activity and myonuclear domain. We harvested diaphragm muscles from 6 and 24-26 month old male Fisher 344 rats (n = 10 per group). Measurements of protein carbonyls, caspase 2, 3, 9, and 12 activities, DNA fragmentation, myofiber cross sectional area, and myonuclear domain of diaphragm muscles were performed. No age related changes (p > 0.05) in diaphragmatic protein oxidation or activities of caspase 2, 3, 9, and 12 were observed between groups. In addition, DNA fragmentation, as detected by the ligation-mediated polymerase chain reaction ladder assay, was not different (p > 0.05) between young and senescent diaphragms. Importantly, the cross-sectional area and myonuclear domain of diaphragm myofibers from senescent animals were also not different (p > 0.05) from young diaphragms. In conclusion, our data show that the senescent diaphragm does not atrophy or exhibit changes in select markers of the apoptotic pathway and this may be a result of the diaphragm's unique continuous contractile activity. PMID- 22434254 TI - Decline in voluntary activation contributes to reduced maximal performance of fatigued human lower limb muscles. AB - In upper limb muscles, altered corticospinal excitability and reduction in neural drive are observed in parallel with peripheral fatigue during prolonged and/or repeated contractions. However, the fatigue-induced adaptations of central and peripheral elements and their relative contribution to lower limb muscle performance are yet to be fully explored. In the present study, corticospinal excitability and peripheral contractility of ankle flexor muscles were quantified before, during and after repeated brief unilateral maximal dorsiflexions to fatigue in eleven healthy volunteers. Transcranial magnetic stimulation of the motor cortex area related to lower limb muscles was performed, and the evoked twitch and EMG responses in tibialis anterior (TA) and soleus (SOL) were measured. The motor evoked potentials (MEPs) in fatigued TA during post-exercise maximal dorsiflexions were smaller (-20 +/- 6 %, p = 0.026) and remained depressed for at least 5 min. Post-exercise MEPs in fatigued SOL and silent periods in TA and SOL were not different compared to pre-exercise. These changes were accompanied by lower voluntary torque (-8 +/- 3 %, p = 0.013), estimated resting twitch (-36 +/- 5 %, p = 0.003) and voluntary activation (-17 +/- 9 %, p = 0.021) versus pre-exercise. During last versus first maximal contraction in the fatiguing protocol lower voluntary torque (-40 +/- 4 %, p = 0.003), higher MEP amplitudes (>+49 %, p < 0.021) and longer silent periods (>+24 %, p < 0.004) were recorded in both muscles. Decreased corticospinal excitability contributes significantly to the reduced maximal performance of fatigued lower limb muscles. During prolonged intermittent maximal dorsiflexions the performance of ankle muscles declines despite enhanced corticospinal excitability presumably due to deficient descending drive and/or spinal motoneuron responsiveness to the cortical drive. PMID- 22434255 TI - Hypothalamic pituitary complications in Kabuki syndrome. AB - Kabuki syndrome is characterized by distinctive facial features, multiple anomalies and mental retardation. In this syndrome, structural CNS abnormalities are commonly observed, but congenital abnormalities in the pituitary gland or hypothalamus have rarely been reported. We searched the published medical literature on the complications in hypothalamic pituitary axis in this syndrome. As a result, only nine patients with Kabuki syndrome had been reported to have complications in hypothalamic pituitary axis in previous papers. Among the nine reported patients and one presented case in this report, GH deficiency was the most frequent complication and found in six patients. Precocious puberty and central diabetes insipidus (DI) was identified in two cases, respectively, and ACTH deficiency was found in one. One case had combination of GH deficiency and central DI. Three of the 10 patients demonstrated abnormal pituitary findings in MRI study. Two of the six patients with GH deficiency were accompanied with premature thelarche. This review highlights that patients with Kabuki syndrome could present various clinical manifestations due to abnormalities in hypothalamic pituitary axis. PMID- 22434256 TI - CT volumetry of normal pancreas: correlation with the pancreatic diameters measurable by the cross-sectional imaging, and relationship with the gender, age, and body constitution. AB - PURPOSE: The purpose of this study was to estimate the volume of normal pancreas in adults using the CT volumetry (summation of the areas technique), analyze the correlation between the volume and the diameters of pancreas, which are measurable by the cross-sectional imaging, and assess the relationship with the gender, age, and body constitution. METHODS: 220 CT examinations were analyzed retrospectively (102 females, 118 males; age 16-82, average 56). Following diameters were measured: cranial-caudal-CC(pancreas), CC(body&tail), CC(body), CC(head); anterior-posterior--AP(tail), AP(body), AP(head); lengths--LL(head), L(body&tail); and maximal transversal diameter of the L1 vertebral body (LL(L1)) and thickness of the abdominal subcutaneous fat (AP(ASF)), as markers of body constitution. RESULTS: The average volume of the pancreas was 79.2 +/- 24.1 cm3 (ranging from 37.4 to 168.2 cm3). Pancreatic volume strongly correlated with all measured diameters of the pancreas (P < 0.0001). Pancreatic volume significantly correlated with gender (M:F = 86.1:72.8 cm3, P = 0.002) and the LL(L1) (r = 0.185, P = 0.008), and did not correlate with the age (r = -0.110, P = 0.151) and the AP(ASF) (r = -0.115, P = 0.104). Correlation of vertebral body-pancreas volume ratio of each subject and the age was strongly negative (r = -0.202, P = 0.006). CONCLUSIONS: Marked individual variations in normal pancreas volume were observed. Pancreatic volume could be computed using the diameters measurable by the cross-sectional imaging employing the formula: V = (AP(tail) + AP(body))/2 * L(body&tail) * CC(body) + (AP(head)/2)2 * 3.14 * CC(head). PMID- 22434257 TI - Visualization of the ophthalmic artery by phase-contrast magnetic resonance angiography: a pilot study. AB - OBJECTIVE: This study aimed at investigating whether phase-contrast (PC) magnetic resonance (MR) angiography is useful for visualizing the ophthalmic artery (OA). METHODS: This prospective study enrolled 196 consecutive outpatients who underwent three-dimensional PC MR angiography. The basal image parallel to the anteroposterior dimension of the OA was extracted for analysis from the imaging data. RESULTS: The 99 male and 97 female subjects were aged from 10 years to 80 years (mean 47.9 years). The OAs were supplied only by the external carotid system or in combination with the internal carotid artery (ICA) in 18 subjects (9.2%). The bilateral OAs were symmetrical in 12%, asymmetrical in 87%, and unidentified in 1%. The contour of the proximal segment of the OAs could be classified into straight, curved, and tortuous types. The ICA-OA angle defined by the angle between the approximate line of the proximal OA and the vertical line was also variable. The first bend of the OA corresponded to the anastomosis site with the external carotid system. The proximal medial bend was the origin of the posterior ethmoidal artery, and the distal medial bend was the origin of the anterior ethmoidal artery. CONCLUSIONS: According to the results the OA not only possesses three characteristic bends, but also shows prominent individual variability and commonly shows bilateral asymmetry. The contour of the OA may be regulated by the anchor effect at the bend sites. PC MR Angiography is useful for visualizing the main trunk of the OA. PMID- 22434258 TI - Stability of amorphous pharmaceutical solids: crystal growth mechanisms and effect of polymer additives. AB - We review recent progress toward understanding and enhancing the stability of amorphous pharmaceutical solids against crystallization. As organic liquids are cooled to become glasses, fast modes of crystal growth can emerge. One such growth mode, the glass-to-crystal or GC mode, occurs in the bulk, and another exists at the free surface, both leading to crystal growth much faster than predicted by theories that assume diffusion defines the kinetic barrier of crystallization. These phenomena have received different explanations, and we propose that GC growth is a solid-state transformation enabled by local mobility in glasses and that fast surface crystal growth is facilitated by surface molecular mobility. In the second part, we review recent findings concerning the effect of polymer additives on crystallization in organic glasses. Low concentration polymer additives can strongly inhibit crystal growth in the bulk of organic glasses, while having weaker effect on surface crystal growth. Ultra thin polymer coatings can inhibit surface crystallization. Recent work has shown the importance of molecular weight for crystallization inhibitors of organic glasses, besides "direct intermolecular interactions" such as hydrogen bonding. Relative to polyvinylpyrrolidone, the VP dimer is far less effective in inhibiting crystal growth in amorphous nifedipine. Further work is suggested for better understanding of crystallization of amorphous organic solids and the prediction of their stability. PMID- 22434259 TI - Synthesis of a new family of acyclic nucleoside phosphonates, analogues of TPases transition states. AB - A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2 hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase. PMID- 22434260 TI - DNA methylation regulates lineage-specifying genes in primary lymphatic and blood endothelial cells. AB - During embryonic development, the lymphatic system emerges by transdifferentiation from the cardinal vein. Although lymphatic and blood vasculature share a close molecular and developmental relationship, they display distinct features and functions. However, even after terminal differentiation, transitions between blood endothelial cells (BEC) and lymphatic endothelial cells (LEC) have been reported. Since phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we hypothesized that DNA methylation might play a role in regulating cell type specific expression in endothelial cells. By analyzing global gene expression and methylation patterns of primary human dermal LEC and BEC, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in LEC revealed involvement in developmental and transdifferentiation processes. We further identified a set of novel genes, which might be implicated in regulating BEC-LEC plasticity and could serve as therapeutic targets and/or biomarkers in vascular diseases associated with alterations in the endothelial phenotype. PMID- 22434261 TI - Portal vein complications after pediatric liver transplantation. AB - Relatively few pediatric donors are available in relation to the number of children waiting for a liver transplant. This limited number of pediatric donor livers leads to the use of adult livers, usually requiring more complex portal vein (PV) anastomoses. These anastomoses are complicated by differences in PV caliber between donors and recipients, as well as by limitations of PV length, which may be inadequate to reach the recipient spleno-mesenteric junction. Three types of post-transplant complications result from these complexities: 1) anomalies of the portal flow; 2) stenosis of the PV anastomosis; and 3) PV thrombosis. Abnormal portal flow may rarely need a specific intervention, but persistent stenosis or appearance of signs of portal hypertension need to be corrected. Balloon dilatation and placement of a stent are usually successful to repair stenosis. Portal vein thromboses are in general diagnosed in the immediate post-operative period and frequently lead to re-transplantation; however, thrombolytic therapy should be attempted in children without major signs of liver necrosis. When intra-hepatic portal vein(s) are permeable, despite extrahepatic PV thrombosis, a Meso-Rex shunt may be the indicated therapy. PMID- 22434262 TI - A theoretic insight into the catalytic activity promotion of CeO2 surfaces by Mn doping. AB - In this paper, we investigated the primary reduction and oxygen replenishing processes over Mn substitutionally doped CeO(2)(111) surfaces by density functional theory with the on-site Coulomb correction (DFT + U). The results indicated that Mn doping could make the surface much more reducible and the adsorbed O(2) could be effectively activated to form superoxo (O(2)(-)) and/or peroxo species (O(2)(2-)). The Mn doping induced the Mn 3d-O 2p gap state instead of Ce 4f acting as an electrons acceptor and donor during the first oxygen vacancy formation and O(2) replenishing, which helped to lower the formation energy of the first and second oxygen vacancies to -0.46 eV and 1.40 eV, respectively. In contrast, the formation energy of a single oxygen vacancy in the pure ceria surface was 2.08 eV and only peroxo species were identified as the O(2) molecule adsorbed. Our work provides a theoretical and electronic insight into the catalytic redox processes of Mn doped ceria surfaces, which may help to understand the enhanced catalytic performances of MnO(x)-CeO(2) oxides, as reported in previous experimental works. PMID- 22434263 TI - High-rate lithium-sulfur batteries promoted by reduced graphene oxide coating. AB - Lithium-sulfur batteries have a poor rate performance and low cycle stability due to the shuttling loss of intermediate lithium polysulfides. To address this issue, a carbon-sulfur nanocomposite coated with reduced graphene oxide was designed to confine the polysulfides. PMID- 22434264 TI - Suppressive effects of N-acetyl-D-glucosamine on rheumatoid arthritis mouse models. AB - We examined effects of N-acetyl-D: -glucosamine (GlcNAc) on rheumatoid arthritis (RA) mouse models and effects of GlcNAc and glucosamine hydrochloride (GlcN) on several serum cytokine productions in RA mouse models. SKG/jcl mice were divided into control, GlcNAc, and GlcN groups. For 56 days, the control group received normal food, the GlcNAc group received 0.5 % GlcNAc-containing food, and the GlcN group received 0.5 % GlcN-containing food. GlcNAc and GlcN equally suppressed arthritis scores and histopathological scores compared to the control group. In the GlcN group, serum tumor necrosis factor-alpha and interleukin (IL)-6 concentrations were significantly decreased compared to the control group. In the GlcNAc group, serum IL-10, transforming growth factor beta-1, and IL-2 concentrations were significantly increased compared to the control group. Our results indicated that GlcNAc also has suppressive effects on experimental RA in mouse models. The results of serum cytokine concentrations suggested that compared to GlcN, GlcNAc has a different suppressive mechanism in experimental RA models. PMID- 22434265 TI - Bibliometric assessment of publication output of child and adolescent psychiatric/psychological affiliations between 2005 and 2010 based on the databases PubMed and Scopus. AB - We aimed to determine the quantitative scientific publication output of child and adolescent psychiatric/psychological affiliations during 2005-2010 by country based on both, "PubMed" and "Scopus" and performed a bibliometric qualitative evaluation for 2009 using "PubMed". We performed our search by affiliation related to child and adolescent psychiatric/psychological institutions using "PubMed". For the quantitative analysis for 2005-2010, we counted the number of abstracts. For the qualitative analysis for 2009 we derived the impact factor of each abstract's journal from "Journal Citation Reports". We related total impact factor scores to the gross domestic product (GDP) and population size of each country. Additionally, we used "Scopus" to determine the number of abstracts for each country that was identified via "PubMed" for 2009 and compared the ranking of countries between the two databases. 61 % of the publications between 2005 and 2010 originated from European countries and 26 % from the USA. After adjustment for GDP and population size, the ranking positions changed in favor of smaller European countries with a population size of less than 20 million inhabitants. The ranking of countries for the count of articles in 2009 as derived from "Scopus" was similar to that identified via the "PubMed" search. The performed search revealed only minor differences between "Scopus" and "PubMed" related to the ranking of countries. Our data indicate a sharp difference between countries with a high versus low GDP with regard to scientific publication output in child and adolescent psychiatry/psychology. PMID- 22434266 TI - Effect of pre-exposure to sevoflurane on the bispectral index in women undergoing Caesarean delivery under general anaesthesia. AB - BACKGROUND: Patients undergoing Caesarean delivery under inhalation anaesthesia are at a high risk of awareness, especially in the period before delivery. We assessed the effects of pre-exposure to sevoflurane on the bispectral index (BIS) in the interval before delivery. METHODS: Sixty-four patients undergoing elective Caesarean delivery were randomly assigned to receive 1.0-1.1 vol% (control 1) or 1.2-1.3 vol% (control 2) end-tidal sevoflurane, or the same concentrations of end tidal sevoflurane combined with pre-exposure to 1 vol% sevoflurane for the last 1 min of the preoxygenation period (the preSevo 1 and preSevo 2 groups, respectively). We assessed BIS values, arterial pressure, and heart rate at the time of induction; before intubation; and upon skin incision, uterine incision, and delivery. We also determined the maternal incidence of intraoperative awareness and the neonatal Apgar scores, and conducted umbilical blood gas analysis. RESULTS: At skin incision, BIS values were significantly lower in the preSevo 1 group than in the control 1 group [50 (13) vs 72 (8), P<0.001] and in the preSevo 2 group than in the control 2 group [44 (11) vs 67 (10), P<0.001]. The mean BIS values in the preSevo 1 and 2 groups were maintained below 60 in the period before delivery. No other parameter differed among groups, and no patient exhibited intraoperative awareness. CONCLUSIONS: Pre-exposure to low concentrations of sevoflurane reduced BIS values in the interval before delivery, suggesting that this approach may reduce the risk of maternal awareness. Clinical Research Information Service (code KCT0000069, http://cris.cdc.go.kr). PMID- 22434267 TI - Theoretical calculations of physico-chemical and spectroscopic properties of bioinorganic systems: current limits and perspectives. AB - In the last decade, we have witnessed substantial progress in the development of quantum chemical methodologies. Simultaneously, robust solvation models and various combined quantum and molecular mechanical (QM/MM) approaches have become an integral part of quantum chemical programs. Along with the steady growth of computer power and, more importantly, the dramatic increase of the computer performance to price ratio, this has led to a situation where computational chemistry, when exercised with the proper amount of diligence and expertise, reproduces, predicts, and complements the experimental data. In this perspective, we review some of the latest achievements in the field of theoretical (quantum) bioinorganic chemistry, concentrating mostly on accurate calculations of the spectroscopic and physico-chemical properties of open-shell bioinorganic systems by wave-function (ab initio) and DFT methods. In our opinion, the one-to-one mapping between the calculated properties and individual molecular structures represents a major advantage of quantum chemical modelling since this type of information is very difficult to obtain experimentally. Once (and only once) the physico-chemical, thermodynamic and spectroscopic properties of complex bioinorganic systems are quantitatively reproduced by theoretical calculations may we consider the outcome of theoretical modelling, such as reaction profiles and the various decompositions of the calculated parameters into individual spatial or physical contributions, to be reliable. In an ideal situation, agreement between theory and experiment may imply that the practical problem at hand, such as the reaction mechanism of the studied metalloprotein, can be considered as essentially solved. PMID- 22434268 TI - Single-cell level co-culture platform for intercellular communication. AB - A cell in vivo is part of a large, networked community. An individual cell's fate is strongly influenced by its interactions with neighbouring cells. While this interaction has been recognized as critical in determining cell behaviour, its complexity and heterogeneity has thus far defied characterization by currently available techniques. Herein, we present a single-cell level co-culture platform for studies of dynamic cellular interactions, which is capable of maintaining and tracking single-cell pair interactions to simplify the complexity of intercellular communication. In this platform, heterotypic pairing on a single cell level is achieved through sequential cell trapping and dynamic variation of fluidic resistance. Individual culture chambers provide trapped cells enough space to migrate and proliferate through multiple generations. Furthermore, the semi-isolated chambers, combined with continuously refreshed medium supplement, allow a stable communication environment around the cells. To demonstrate the platform capability, we cultured and tracked stem cell-fibroblast pairs for several generations. The subsequent effects of cell-cell interactions were then easily observed, due to the addressability of each isolated chamber, and quantitatively characterized. Specifically, we found that paired cells' migration patterns were dependent on their initial distance from each other, and that heterotypic pairing led to distinct proliferation patterns from homotypic, single cell culture. This study demonstrates the platform utility in providing a detailed and quantitative understanding of the complexity of cellular communication and its effects on cell behaviour in a variety of biological systems. PMID- 22434271 TI - Direct analysis of biological samples using extractive electrospray ionization mass spectrometry (EESI-MS). AB - Mass spectrometry (MS) is one of the most widely used techniques for the analysis of biological samples. In the past decade, a novel improvement in MS was the invention of ambient ionization which stands out owing to its unique capability of direct analysis of complex samples with no or minimal pretreatment. In this review, extractive electrospray ionization (EESI), a representative ambient ionization technique, is introduced focusing on its mechanism, instrumentation, and applications in biological analysis. EESI uses a traditional ESI channel to produce primary ions which subsequently ionize neutral chemicals from the sample introduction channel through an online extraction process. When analyzing biological samples, EESI has advantages of rapid analysis, high matrix tolerance, and the ability to perform in vivo analysis. According to previous studies, EESI is able to directly analyze various chemicals in complex biological specimens in liquid, gas, and solid states. EESI can provide a sensitive and selective measurement of biological samples for both qualitative and quantitative purposes. Therefore, it is anticipated that EESI will have promising applications, especially in fields which require the fast and/or in vivo analysis of biological samples with complicated matrixes. PMID- 22434272 TI - Rapid determination of anilines in water samples by dispersive liquid-liquid microextraction based on solidification of floating organic drop prior to gas chromatography-mass spectrometry. AB - A rapid, sensitive and environmentally friendly method for the analysis of 14 anilines in water samples by dispersive liquid-liquid microextraction based on solidification of floating organic drop (DLLME-SFO) prior to gas chromatography mass spectrometry (GC-MS) was developed and optimized. In the proposed method, cyclohexane was used as the extraction solvent as its toxicity was much lower than that of the solvent usually used in dispersive liquid-liquid microextraction (DLLME). In the optimized conditions, the method exhibited good analytical performance. Based on a signal-to-noise ratio of 3, limits of detection for anilines were in the range of 0.07 to 0.29 MUg L(-1), and the linear range was 0.5-200 MUg L(-1) with regression coefficients (r(2)) higher than 0.9977. It was efficient for qualitative and quantitative analysis of anilines in water samples. The relative standard deviations varied from 2.9 to 8.6% depending on different compounds indicating good precision. Tap water and river water were selected for evaluating the application to real water samples. The relative recoveries of anilines for the two real samples spiked with 10 MUg L(-1) anilines were in the scope of 78.2-114.6% and 77.3-115.6%, respectively. PMID- 22434273 TI - Fingerprinting of red wine by headspace solid-phase dynamic extraction of volatile constituents. AB - Headspace solid-phase dynamic extraction (HS-SPDE) was investigated for its applicability in quality control analysis of wine volatiles using gas chromatography-mass spectrometry. In total, 196 German red wines were analysed and 22 flavour-relevant alcohols and esters were quantified. The method detection limits were between 0.1 and 9.3 MUg L(-1), allowing the dilution of the samples to decrease matrix and competition effects. Quantification resulted in a concentration range from about 1 MUg L(-1) linalool up to 380 mg L(-1) 2-methyl-1 propanol. The measurement uncertainty budget was determined for all compounds in a "top-down" approach and was between 2.5 and 7.9%, with an average of 5.5%. A surveillance of the extraction performance of the HS-SPDE devices showed constant results for up to 400 extractions using one extraction needle tip. A chromatogram library for quality and authenticity control of wine samples was created using commercially available chromatogram comparison software. PMID- 22434274 TI - Determination of the in vivo redox potential by one-wavelength spectro-microscopy of roGFP. AB - For the quantitative analysis of molecular processes in living (plant) cells, such as the perception and processing of environmental and endogenous signals, new combinatorial approaches in optical and spectroscopic technologies are required and partly already became established in many fields of the life sciences. One hallmark of the in vivo analysis of cell biological processes is the use of visible fluorescent proteins to create fluorescent fusion proteins. Recent progress has been made in generating a redox-sensitive mutant of green fluorescent proteins (roGFP), which exhibits alterations in its spectral properties in response to changes in the redox state of the surrounding medium. An established method to probe the local redox potential using roGFP is based on a ratiometric protocol. This readout modality requires two excitation wavelengths, which makes the technique less suited for in vivo studies of e.g. dynamic samples. We clarify the origin of the redox sensitivity of roGFP by ab initio calculations, which reveal a changed protonation equilibrium of the chromophore in dependence on the redox potential. Based on this finding, we test and compare different spectroscopic readout modalities with single wavelength excitation to determine the local redox potential and apply these techniques to live cell analytics. PMID- 22434275 TI - Determination of 5-nitroimidazoles and metabolites in environmental samples by micellar electrokinetic chromatography. AB - A method based on micellar electrokinetic chromatography (MEKC) with UV detection has been developed for the determination of nine 5-nitroimidazoles (5-NDZs), including metabolites in river water samples. Due to the relative insensitivity of UV detection in MEKC, a solid-phase extraction (SPE) method has been proposed that preconcentrates water samples fiftyfold and cleans them up off-line. An on line preconcentration approach based on sweeping and the use of an extended light path fused-silica capillary (64.5 cm * 50 MUm i.d., 56 cm effective length) was also found to improve the sensitivity of the method. Separation was carried out in <21 min using 20 mM phosphate buffer (pH 6.5) and 150 mM SDS as the background electrolyte (BGE). The temperature of the capillary was kept constant at 20 degrees C, a voltage of 25 kV was applied (normal mode), and a detected wavelength of 320 nm was utilized. Hydrodynamic injection (50 mbar for 15 s) of the samples, which were dissolved in 20 mM phosphate (pH 6.5), was employed. The limits of detection were lower than 1.1 MUg L(-1). Recoveries of >80% from spiked river water samples were obtained for most of the analytes at three different concentration levels with acceptable precision. This method could provide an efficient and economical alternative to the use of chromatographic methods to monitor nitroimidazole residues, thus supplementing the relatively few methods available for the analysis of these compounds in environmental samples. PMID- 22434276 TI - A combination of metabolomics and metallomics studies of urine and serum from hypercholesterolaemic rats after berberine injection. AB - Berberine, long used as a remedy in China and India for intestinal infections, has been discovered in recent years in western countries and is now being used to treat ailments ranging from urinary tract infections to diabetes and obesity. In order to study the effect of berberine more deeply, a combined metabolomic and metallomic approach was developed in this study using the hypercholesterolaemic rat model, which involved the use of proton nuclear magnetic resonance for the analysis of rat urine to achieve metabolic fingerprinting and inductively coupled plasma mass spectrometry for the analysis of rat blood serum to achieve metallomic fingerprinting. The results obtained indicated that major metabolic processes like Krebs cycle, cholesterol metabolism and osmoregulation in hypercholesterolaemic rats are perturbed upon berberine injection. In addition, the changes of some elements, such as V, Mn, Na and K, revealed in the metallomic study may contribute to the search of new biomarkers for hypercholesterolaemic disease. We concluded that both the metabolomic and metallomic profiles of berberine-treated hypercholesterolaemic rats were different from those of the control group and that the selected metabolites and elements could probably be applied as potential biomarkers for the understanding of the effect of berberine on biochemical process in the animal model. Such a multi-analytical approach will potentially provide an information-rich platform for the elucidation of effects of xenobiotics and drug efficacy studies. PMID- 22434277 TI - The development of paper microzone-based green analytical chemistry methods for determining the quality of wines. AB - The colorimetric determination of the concentration of polyphenols, flavonoids, and anthocyanins in wine samples, using a mobile phone camera for sample spot capture on a paper microzone and a remote computer with dedicated software for quantification, is presented as an illustrative application of green analytical chemistry. A comparison of the results with conventional spectrophotometry demonstrates that both methods yield similar results. Developing the assay took approximately 2 months, and the use of chemicals, compared with spectrophotometry, was reduced by about two orders of magnitude: the paper assay consumed 0.4 mL of reagent for 100 samples, whereas the spectrophotometric assay required 100 mL. The relative testing times for 100 samples were 7 h by spectrophotometry and 2 h for paper-a savings on the order of 3.5. No analytical instrumentation was used for the colorimetry on paper microzones. Instead, the assay took advantage of the existing communication technology and free software. The assay was found to be effective, with a nonlinear response at the concentration range of 0.2-5 g/L. The detection limit of the proposed method is in sub-grams per liter. PMID- 22434279 TI - Protein C and free protein S in children with sickle cell anemia. PMID- 22434278 TI - A qualitative investigation of visual tasks with which to assess distance specific visual function. AB - BACKGROUND: The ability to perform many daily tasks relies on good visual acuity at various distances. A review of existing measures of visual function revealed gaps in task content, particularly tasks that rely on intermediate vision. PURPOSE: This research sought to extend the content base and visual range coverage of tasks used to assess visual function. METHODS: Ophthalmology patients (n = 72) with myopia, hyperopia, presbyopia, astigmatism, cataracts, and/or glaucoma were involved in various qualitative sub-studies, including life event journaling, telephone interviews, and both on-line and face-to-face focus groups. The resulting journal entries and transcripts were thematically analyzed to identify visual tasks that rely on visual acuity in the near, intermediate, and distant visual ranges. RESULTS: A wide variety of distance-specific visual tasks were identified. Certain types of tasks relied on distance vision, such as; ambulation, driving, leisure and sports, and social functions. Other task groupings such as technology use and activities of daily living relied primarily on near and intermediate vision. Two new content areas were identified, technology use and safe task performance. CONCLUSIONS: This thematic analysis provides a rich body of information about tasks that affect daily life and are made more difficult by poor visual acuity at various distance ranges. PMID- 22434280 TI - Support for a link between the local processing bias and social deficits in autism: an investigation of embedded figures test performance in non-clinical individuals. AB - The aim of this investigation was to explore the degree to which specific subsets of autistic-like traits relate to performance on the Embedded Figures Test (Witkin et al. in A manual for the embedded figures test. Consulting Psychologists Press, Palo Alto, CA, 1971). In the first group-based investigation with this focus, students were selected for their extreme scores (either high or low) on each of the 'Social Skills' and 'Details/Patterns' factors of the Autism Spectrum Quotient (Baron-Cohen et al. in J Austim Dev Disord 31:5-17, 2001). The resulting 2 * 2 factorial design permitted examination of the degree to which the social and non-social autistic-like traits separately relate to EFT performance. Surprisingly, in two studies, superior EFT performance was found to relate only to greater social difficulty, suggesting that the local processing bias in autism may be linked specifically to the social deficits. PMID- 22434281 TI - Cognitive control of intentions for voluntary actions in individuals with a high level of autistic traits. AB - Impairments in cognitive control generating deviant adaptive cognition have been proposed to account for the strong preference for repetitive behavior in autism. We examined if this preference reflects intentional deficits rather than problems in task execution in the broader autism phenotype using the Autism-Spectrum Quotient (AQ). Participants chose between two tasks differing in their relative strength by indicating first their voluntary task choice and then responding to the subsequently presented stimulus. We observed a stronger repetition bias for the harder task in high AQ participants, with no other differences between the two groups. These findings indicate that the interference between competing tasks significantly contributes to repetitive behavior in autism by modulating the formation of task intentions when choosing tasks voluntarily. PMID- 22434282 TI - Stress and coping in women living with HIV: a meta-analytic review. AB - To examine effects between stressors and coping mechanisms on behavioral health outcomes a meta-analysis was conducted using forty empirical articles which sampled 7,602 adult women living with HIV/AIDS in the U.S. (M = 36.3 years). Three independent reviewers conducted searches in abstract databases from 1997 to present day. Articles reporting effect sizes amongst psychosocial stressors and coping mechanisms with indices of behavioral/mental health were selected. The meta-analyses revealed that in a time frame characterized by the widespread availability of anti-retroviral medication, poor mental health outcomes were predicted, in a similar manner, by psychosocial stress and HIV/AIDS symptomology. Significant effects were also observed with functional impairment, though to a lesser degree. Coping by avoidance and social isolation predicted more severe mental health outcomes. Spirituality and positive reappraisal predicted greater psychological adaptation than did social support seeking. Despite advancements in anti-retroviral treatment for women, HIV/AIDS symptoms and acute and/or chronic psychosocial stress pose the same threat to behavioral and mental health. In the face of these stressors, positive reframing appears to promote psychological adaptation in a way which may lead to positive health outcomes in women living with HIV/AIDS. PMID- 22434283 TI - Cost-utility analysis of a female condom promotion program in Washington, DC. AB - A retrospective economic evaluation of a female condom distribution and education program in Washington, DC. was conducted. Standard methods of cost, threshold and cost-utility analysis were utilized as recommended by the U.S. Panel on cost effectiveness in health and medicine. The overall cost of the program that distributed 200,000 female condoms and provided educational services was $414,186 (at a total gross cost per condom used during sex of $3.19, including educational services). The number of HIV infections that would have to be averted in order for the program to be cost-saving was 1.13 in the societal perspective and 1.50 in the public sector payor perspective. The cost-effectiveness threshold of HIV infections to be averted was 0.46. Overall, mathematical modeling analyses estimated that the intervention averted approximately 23 HIV infections (even with the uncertainty inherent in this estimate, this value appears to well exceed the necessary thresholds), and the intervention resulted in a substantial net cost savings. PMID- 22434284 TI - A unified access to diverse heteroaromatic scaffolds using the radical chemistry of xanthates. AB - The degenerate transfer of xanthates allows generally difficult radical transformations, such as intermolecular additions to unactivated alkenes and cyclisations onto aromatic and heteroaromatic rings, to be accomplished under very practical experimental conditions. This translates into numerous approaches for the construction or modification of heteroaromatic structures. The present report aims to provide a brief overview of the various synthetic possibilities, with particular emphasis on medicinally interesting families of compounds. PMID- 22434285 TI - Abnormal ECGs secondary to electrolyte abnormalities. PMID- 22434286 TI - The Mayo brothers (William James Mayo 1861-1939, Charles Horace Mayo 1865-1939): pioneers of group surgical practice. PMID- 22434287 TI - Thyroid malignancy among goitrous thyroid lesions: a review of hospital-based studies in Malaysia and Myanmar. AB - Endemic goitre is a major concern in many parts of the world, including Southeast Asia. Goitrous thyroid lesion is postulated as a precursor lesion to thyroid cancer (TC). This paper reviews the prevalence rates and characteristics of TC among cases of goitrous thyroid-swelling in different parts of Malaysia and Myanmar. Recorded data from hospital-based retrospective studies of thyroid cases, whose study periods ranged from three to 11 years, were analysed. These included research findings from the author's publications as well as other published review articles of retrospective analyses. The incidence of TC varies among gender, age, race/ethnicity and histological type. There appears to be a higher rate of occurrence among females aged 21-60 years. Papillary thyroid carcinoma is the more common histological type compared to follicular cancer. This review also presents a descriptive analysis and discussion on studies conducted in other countries. Further exploration is warranted in order to uncover the possible risk factors for the rising incidence of TC. PMID- 22434288 TI - Risk scoring system for prediction of contrast-induced nephropathy in patients with pre-existing renal impairment undergoing percutaneous coronary intervention. AB - INTRODUCTION: Baseline renal impairment is the most recognised risk factor for development of contrast-induced nephropathy (CIN) post percutaneous coronary intervention (PCI). We examined the additional risk factors in this high-risk group and aimed to develop a risk model for prediction of CIN. METHODS: A cohort of 770 consecutive patients with existing impaired renal function (estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2), who received routine prophylactic saline hydration and oral N-acetylcysteine treatment while undergoing PCI between May 2005 to October 2008 in our centre, were enrolled. The study endpoint, CIN, was defined as > 25% increase from baseline creatinine within 48 hours post PCI. RESULTS: Despite routine prophylaxis, CIN occurred in 11.4% of the patients. Important clinical predictors for CIN were age (odds ratio [OR] 1.59, 95% confidence level [CI] 1.0-2.52, p = 0.049), anaemia with haemoglobin < 11 mg/dL (OR 2.26, 95% CI 1.41-3.61, p = 0.001), post-procedure creatinine kinase rise (OR 1.12, 95% CI 1.07-1.16 for every 500 u/L increase, p < 0.001), systolic hypotension with blood pressure < 100 mmHg (OR 2.53, 95% CI 1.16 5.52, p = 0.016) and higher contrast volume. The incidence of CIN was significantly higher in patients with more severe renal failure (6.3%, 17.4% and 40.8% when eGFR was 40-60, 20-40 and < 20 ml/min/1.73 m2 respectively, p < 0.001). A prediction model was developed based on these findings. The incidence of CIN could vary from 2% to > 50% depending on these additional risk profiles. CONCLUSION: Patients with impaired renal function undergoing PCI are at high risk of developing CIN despite traditional prophylaxis. A model of risk prediction could be used to predict its occurrence. PMID- 22434289 TI - Outcomes of permanent inferior vena cava filters: experiences in Thai patients. AB - INTRODUCTION: We aimed to study the outcomes of permanent inferior vena cava (IVC) filter implantation in Thai patients. METHODS: This was a retrospective study of 28 patients with deep vein thrombosis (DVT) who underwent prophylactic implantation of IVC filters for fatal pulmonary embolism (PE) between January 2005 and June 2008. The patients' operative records, protocol and follow-up data were analysed. 11 (39%) patients had PE at the initial diagnosis. The mean age of the patients was 62.1 (range 33-83) years. Indications for IVC filter implantation included contraindications to and complications of anticoagulant therapy and floating thrombi in the iliofemoral veins. RESULTS: No significant technical complication was noted, except for malposition in one patient (3.5%) and failure of the permanent IVC filter to open fully in another. During the follow-up period (mean 17.5 +/- 10.9 months), no patients had any episode of PE and nine (32%) died of unrelated causes. Two patients were lost to follow-up. Among the 17 survivors, six (35.2%) had non-recanalised thrombosis vein, four (23.5%) had clinical evidence of chronic venous insufficiency, two (11.7%) had recurrent DVT in the contralateral limb and one (5.8%) developed IVC thrombosis. There was no evidence of migration of the caval filters. No statistical significance was observed in the effects of post-filter anticoagulation drug on current DVT and in the relation between PE at initial diagnosis and death during follow-up. CONCLUSION: Permanent IVC filter implantation may be effective for preventing symptomatic PE in Thai patients, with no significant sequelae in the lower extremities. PMID- 22434290 TI - Suboptimal consideration and management of potential familial hypercholesterolaemia in patients with suspected premature coronary artery disease. AB - INTRODUCTION: Familial hypercholesterolaemia (FH) is caused by an autosomal dominant mutation of the low density lipoprotein (LDL) receptor gene, resulting in high levels of LDL cholesterol and premature coronary artery disease (P-CAD). Studies have shown low detection rates of FH in patients admitted with P-CAD and suboptimal therapy at discharge. METHODS: Males aged <= 55 years and females aged <= 60 years who were admitted with P-CAD to the Gold Coast Hospital during a 12 month period were included in the study. The demographics, cardiovascular risk factors, examination findings, admission and discharge cardiac medications and provisional diagnoses were recorded. Diagnosis of FH was made according to internationally accepted criteria. RESULTS: 210 patients were included in the study; 60% were male and 40% female (mean age 48 and 50 years, respectively). Only 96 (46%) patients' fasting lipid levels were documented (LDL-C 2.75 +/- 1.0 mmol/L), and FH was considered in three (1%) cases. According to the Dutch Lipid Network criteria, three (1%) patients had probable FH, 50 (24%) had possible FH and 60 (29%) had unlikely FH. Of the 53 patients with probable or possible FH, 12 (23%) were discharged without statin therapy and 13 (25%) on the maximum recommended statin dose. CONCLUSION: Our study has found inadequate documentation and screening for FH and suboptimal therapy in patients admitted with P-CAD. We propose a simple screening tool that can be applied to all patients admitted with suspected P-CAD in order to improve the detection rate of FH and its management. PMID- 22434291 TI - Short-term results of physiotherapy in patients with newly diagnosed degenerative cervical spine disease. AB - INTRODUCTION: Degenerative cervical spine diseases are common, and physiotherapy is widely used as an initial form of treatment. We aimed to analyse the effects of the initial sessions of physiotherapy for patients who were newly diagnosed with degenerative cervical spine disorders. METHODS: A prospective series of 30 patients with newly diagnosed degenerative cervical spine disease were referred to our department and followed up for the initial two sessions of physiotherapy. The patients were assessed after each session. Outcome parameters studied included pain using a visual analogue scale (VAS), neck range of movements and activities of daily living (ADL). RESULTS: Our study subjects comprised mainly females (60%) in their fifties (46.7%) who worked as clerks or secretaries (53.3%). There was an improvement in the patients' pain score (VAS) from a median of 8 to 4 after two visits to the physiotherapists. Slight improvement in the neck range of movements was also observed. Marked improvement was seen in ADL, especially in the ability to carry heavy objects. CONCLUSION: Physiotherapy is an effective initial option for patients with newly presented degenerative cervical spine disease. The results of this study can be used to advise patients on the short-term benefits of physiotherapy. PMID- 22434292 TI - Comparison of clinical and radiological results of posterolateral fusion, posterior lumbar interbody fusion and transforaminal lumbar interbody fusion techniques in the treatment of degenerative lumbar spine. AB - INTRODUCTION: Lower back pain due to degenerative disc disease is a common problem that requires surgical treatment, such as posterolateral fusion and posterior instrumentation (PLF), posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF). This retrospective study aimed to compare the clinical and radiological outcomes of these techniques. METHODS: 81 patients were treated between 2003 and 2006. The patients were divided into three groups: Group I (PLF n = 17 [43 levels]); Group II (PLIF n = 27 [52 levels]); and Group III (TLIF n = 37 [70 levels]). All patients underwent the same pre- and postoperative clinical and radiological evaluations (using Oswestry Disability Index [ODI], Stanford score and local criteria). Follow-ups were performed at three months and yearly for three years. RESULTS: There was no significant difference in the rates of intra-operative complications (Group I: 17.6%; Group II: 11.1%; Group III: 18.9%; p = 0.688) and postoperative complications (Group I: 11.8%; Group II: 25.9%; Group III: 13.5%; p = 0.343) among the groups. There was a significant decrease in the ODI scores over time (p < 0.005) but no significant difference among the groups at different follow-up times. Radiographic fusion rates for Groups I, II and III were 88%, 88.9% and 91.9%, respectively. CONCLUSION: Surgical techniques such as PLF, PLIF and TLIF are equally suitable for treating degenerative disc disease, with no differences observed in complications and clinical outcomes. However, in our study, the best radiological outcome was found in patients treated with TLIF. PMID- 22434293 TI - Arthroscopic debridement of intercarpal ligament and triangular fibrocartilage complex tears. AB - INTRODUCTION: Wrist arthroscopy has evolved since its inception to become an essential diagnostic and therapeutic tool for the management of various wrist disorders. Our study aimed to examine the outcomes of arthroscopic debridement in the treatment of scapholunate (SL), lunotriquetral (LT) and triangular fibrocartilage complex (TFCC) tears. METHODS: We conducted a retrospective review of 68 consecutive wrist arthroscopies performed at our institution between January 2000 and July 2005. All the patients complained of wrist pain, which often interfered with their daily activities, work or sports. A standard arthroscopic technique was employed in all. Any intercarpal ligament or TFCC tears found were debrided. RESULTS: There were 42 patients with TFCC tears, 58 with SL tears and 49 with LT tears. At a mean follow-up time of 16.6 months, 85.3% of the patients reported an improvement in symptoms and 27.9% had improved range of motion. Grip strength improved by 11.8%. All except two patients returned to their original activities. Outcome following arthroscopic debridement was determined using the Mayo Modified Wrist Score. Based on the postoperative wrist scores of 47 patients, 24 were rated excellent, 17 good, four fair and two poor. By comparing the pre- and postoperative wrist scores of 31 patients, we were able to demonstrate significant improvement in patients who underwent wrist arthroscopies. CONCLUSION: Our study demonstrated that there is a definite role for arthroscopic debridement in the management of SL, LT and TFCC tears. PMID- 22434294 TI - Do children die? A retrospective review of deaths in a children's hospital. AB - INTRODUCTION: We present a profile of deaths over two years in the medical departments of a children's hospital. The findings would help us better understand the individual dying experience of these patients. Service gaps and ways to optimise provision of supportive care were identified in the process. METHODS: The inpatient notes of all children who died in the medical wards, including intensive care unit, were traced and reviewed by the investigators. Demographic data, diagnoses, length of stay and the care received were recorded. RESULTS: A total of 68 children died in the two years. They were representative of all deaths nationally in terms of diagnoses. Two-thirds of the children died in the intensive care unit after having stayed there for an average of five days. All but one patient had invasive ventilation till they died. Eight out of every ten cases were assessed to be actively dying while being cared for. Most had 'Do Not-Resuscitate' status in place, but few had been offered the option to choose the place of care or death when it became clear that they would not survive. CONCLUSION: More efforts could be made to improve the care of dying children and their families. The Paediatric Palliative Service could assist in advance care planning at the end of life. PMID- 22434295 TI - Views of Malaysian interns and their supervisors on the adequacy of undergraduate clinical skills training. AB - INTRODUCTION: This study aimed to determine the views of Malaysian interns and their supervisors on whether undergraduate clinical skills training adequately equipped them for internship and their suggestions for improvement. METHODS: Pre tested questionnaires covering demographic characteristics, the participants' views on clinical skills training (communication, history taking, physical examination, diagnosis, patient management and procedures) and their suggestions for improvement were sent to all interns and their supervisors through the hospital directors. Data compiled was analysed to determine any significant association. RESULTS: Out of the 32 hospitals with interns, 22 participated in the study. 521 completed questionnaires (350 interns, 171 supervisors) were analysed. The majority of interns felt that their undergraduate clinical skills training was adequate in all the aspects studied. The majority of supervisors, however, felt that it was grossly inadequate to poor in the areas of communication: breaking bad news (77% supervisors versus 13% interns), dealing with angry patients (75% versus 20%), giving information (59% versus 3%), communicating with patients' families (53% versus 7%); adult resuscitation: intubation (72% versus 23%), defibrillation (77% versus 31%), use of drugs (62% versus 19%); and all aspects of child resuscitation. This was statistically significant (p < 0.05). Suggestions for improvement included more clinical exposure, communication skills workshop and monitoring of logbooks. CONCLUSION: This study suggests that there are deficiencies, particularly in communication and resuscitation skills training, in undergraduate clinical skills training. In depth studies are required to identify ways to improve training. PMID- 22434296 TI - Clinico-epidemiological features of viper bite envenomation: a study from Manipal, South India. AB - INTRODUCTION: Snakebite is an important and preventable health hazard. Viper bites are more common than other poisonous snakebites in human beings. The present study aimed to collate the victim profile of viper bite cases in the region and to determine the pattern, manifestations, complications and the associated risk factors of these bites. METHODS: This was a prospective study of viper bite cases admitted to Kasturba Hospital, Manipal, India between August 2003 and November 2005. The demographic and clinical details of each case were obtained from the patients, their relatives and the patients' hospital records, and analysed. RESULTS: A total of 31 viper bite cases were reported during the study period. The victims were predominantly male and aged 25-55 years. The highest number of cases occurred during daytime in the months of September and October, which coincided with the harvesting season, and involved the lower limbs. 94% of the snakebite victims were farmers, suggesting that this was an occupational hazard. Envenomation was observed in patients with scratch marks, suggesting the importance of keeping the victim under observation in all alleged snakebite cases, even in the absence of clear fang marks. The mortality rate in our study was 6.5%. CONCLUSION: Immobilising and transporting snakebite victims to the hospital and prompt administration of anti-snake venom remain the best way to reduce morbidity and mortality. It is also important to practise correct first aid measures, as otherwise they may cause more harm than good. PMID- 22434297 TI - A morphological study of variations in the branching pattern and termination of the radial artery. AB - INTRODUCTION: Coronary artery bypass grafting is an established means of treating advanced coronary artery disease. In recent years, there has been an increased interest in the radial artery as an entry route during coronary angiography. Accurate knowledge of the branching pattern of this artery and its relation to surrounding structures is of great importance in the care of surgical patients. METHODS: This study was conducted on 75 formalin-fixed upper limbs in order to note the variations in the branching pattern and termination of the radial artery. RESULTS: The radial artery divided into three branches in 2.7% of cases and into two branches in 52.0% of cases. The radial recurrent artery originated from the brachial artery instead of the radial artery in 12.0% of cases. The radial recurrent artery, palmar carpal artery, first dorsal metacarpal artery and superficial palmar artery were absent in 1.3%, 26.7%, 9.3% and 5.3% of cases, respectively. 6.7% of cases had a high origin of the superficial palmar artery. CONCLUSION: The rich photographic documentation of the variation of branching pattern and termination of radial artery is not only of academic interest but also useful to surgeons and radiologists working in the same area. PMID- 22434298 TI - Clinics in diagnostic imaging (138). Emphysematous pyelitis. AB - We present the case of a 49-year-old woman with poorly controlled diabetes mellitus of ten years' duration. She presented to the emergency department with nonspecific left lower abdominal pain. Ultrasonography showed mild left renal hydronephrosis, but the cause was not demonstrated. Computed tomography (CT) showed a swollen left kidney with a mildly dilated collecting system containing gas and dense fluid, confirming the diagnosis of emphysematous pyelitis. Management consisted of emergency antegrade nephrostomy drainage and parenteral antibiotics. Subsequently, the patient made a good recovery and was well when discharged home after two weeks. Gas-forming infections of the genitourinary tract carry high mortality and morbidity, and usually occur in patients with poorly controlled diabetes mellitus. Escherichia coli is the most common microorganism. This case emphasises the importance of CT in making an early diagnosis of emphysematous pyelitis, which allows prompt treatment and improves prognosis. PMID- 22434299 TI - Dose of intravenous gammaglobulin in toxic epidermal necrolysis. PMID- 22434303 TI - Anaesthetic management of a child posted for excision of lymphangioma of the tongue. AB - Lymphangioma is a congenital malformation of the lymphatic system, often involving areas of the head and neck. Patients may require surgical excision. Anaesthetic concerns include bleeding, difficulty visualising the airway, extrinsic and intrinsic pressure on the airway causing distortion, and enlarged upper respiratory structures, including the lips, tongue and epiglottis, which make airway management challenging. We report lymphangioma of the tongue in a six year-old patient. There is limited information on the optimal anaesthetic management for this age group. The challenges with airway management, including bleeding, laryngospasm and difficult intubation, are outlined. Awareness of potential airway involvement and possible complications is necessary in order to provide safe anaesthesia to patients with lymphangioma. PMID- 22434304 TI - Follicular thyroid carcinoma with insular component: a retrospective case study, immunohistochemical analysis and literature review. AB - This is a retrospective case study of a 61-year-old woman diagnosed with follicular thyroid carcinoma. The patient underwent thyroidectomy for the treatment of goitre after being admitted for shortness of breath. Microscopic and immunohistochemical studies were performed, which confirmed follicular carcinoma of the thyroid with an insular component. We also conducted a review of the literature on this uncommon entity. PMID- 22434305 TI - Atypical femoral shaft fracture in a patient with non-metastatic prostate cancer on zoledronic acid therapy: effect of therapy or coincidence? AB - There have been recent concerns of atypical non-spinal fractures in patients with osteoporosis who are on long-term bisphosphonate therapy. These fractures are less commonly reported in cancer patients on zoledronic acid therapy, where it is used in higher doses as compared to patients with osteoporosis. We report the case of a 70-year-old man with non-metastatic prostate cancer who was on androgen deprivation therapy following bilateral orchiectomy. He was on bone protection with intravenous zoledronic acid 4 mg monthly for a period of two years. He presented with spontaneous acute right mid-thigh pain. Radiograph of the right femur showed an atypical femoral shaft fracture, which was treated with intramedullary nailing and teriparatide. This case report raises concerns of atypical fractures in cancer patients who receive high doses of zoledronic acid. Patients receiving bisphosphonates who present with thigh or groin pain must undergo radiographic examination of the femur to rule out atypical femoral fractures. PMID- 22434306 TI - Antiphospholipid antibody-related Bell's palsy in young women. AB - The present report describes three young women aged 25, 20 and 15 years who presented with Bell's palsy. Two of the patients had a past history of the disease, which responded to steroid treatment. All three patients were positive for antiphospholipid antibody (APLA). In addition, one of the patients tested positive for antinuclear antibodies; however, there was no clinical evidence of systemic lupus erythematosus. All three patients responded well to steroid therapy. We conclude that Bell's palsy may be one of the manifestations of APLA syndrome, and thus, APLA testing should be done in such cases. PMID- 22434307 TI - Indigo carmine-induced hypotension in patients undergoing general anaesthesia. AB - Indigo carmine is a blue dye that is widely applied to localise ureteral orifices. It is generally believed to be a safe, biologically inert substance, and hypotensive reactions are extremely rare. However, we experienced three cases of indigo carmine-induced hypotension within a period of two weeks. PMID- 22434308 TI - Recurrent nasopharyngeal carcinoma masquerading as acoustic neuroma. AB - This is the first report of recurrent nasopharyngeal carcinoma (NPC) presenting as a cerebellopontine angle mass. The clinical presentation, investigation and management of this case, as well as the confusion and dilemma caused, are discussed. We hope to increase awareness on the multifaceted ways in which recurrent NPC could present and to share the lessons learnt from our management of this unusual and unfortunate case. PMID- 22434309 TI - Paratesticular fibrous hamartoma in an infant. AB - Fibrous hamartoma of infancy is a rare benign tumour with local infiltration. The lesion is usually found in the upper torso and rarely occurs in the genital region. Diagnosis before surgery is rare, and complete excision is essential to prevent recurrence. We present a case in which fibrous hamartoma of infancy involving the spermatic cord was found. A pre-operative clinical diagnosis could not be made. On inguinal exploration, the tumour could not be dissected away from the testicular vessels, which necessitated an orchidectomy for complete removal. The case is presented due to its rarity and successful management. PMID- 22434310 TI - Chemical reactivity analysis of deoxyribonucleosides and deoxyribonucleoside analogues (NRTIs): a first-principles density functional approach. AB - The structures, energetics, as well as several important chemical parameters, of antiretroviral drugs - nucleoside reverse transcriptase inhibitors (NRTIs) - and natural deoxyribonucleosides in both neutral, and positively and negatively charged states, are investigated. These studies are carried out within the frame work of first-principles density-functional theory (DFT), using the Becke-Lee Yang-Parr (BLYP) generalized gradient corrections to the local spin density approximation exchange and correlation energy, norm-conserving pseudopotentials and a plane-wave expansion of Kohn-Sham orbitals. Conceptual DFT is used to determine global and local chemical reactivity parameters. Our results are in good agreement with the best available experiments to date. The variation in the bond lengths and bond angles on cation formation indicates that the electron is lost from the base part of these molecules. Further, the presence of the deoxyribose sugar moiety lowers their ionization potential and increases their electron affinity, in comparison to the isolated DNA base. The effectiveness of the drug action in terminating the viral DNA chain, is explained using the global reactivity parameters, by comparing the reactivities of the drug molecules with those of the competing deoxyribonucleosides. The widely followed clinical practice, of avoiding the simultaneous administration of certain drugs, is also explained from the hardness and softness parameters. For most of the drug molecules, our study validates the generally accepted wisdom, that monophosphorylation is the crucial reaction step in the phosphorylation reaction in DNA nucleotide synthesis. PMID- 22434311 TI - In silico development, validation and comparison of predictive QSAR models for lipid peroxidation inhibitory activity of cinnamic acid and caffeic acid derivatives using multiple chemometric and cheminformatics tools. AB - The design and development of antioxidant molecules have lately gained a great deal of focus which is attributed to their immense biomedicinal importance in combating the free radical associated health hazards. In a situation to replenish the endogenous antioxidant loss, synthetic molecules with potent antioxidant activity is demanded. The present work thus aims at in silico modeling of antioxidant molecules that may facilitate in searching and designing of new chemical entities with enhanced activity profile. A series of cinnamic acid and caffeic acid derivatives having the ability to inhibit lipid peroxidation have been modeled in the present work. Three different types of models were developed using different chemometric and cheminformatics tools to identify the essential structural attributes: (a) descriptor based QSAR models, (b) 3D pharmacophore models and (c) HQSAR (hologram QSAR) models. For the conventional QSAR modeling, descriptors belonging to different categories [quantum chemical descriptors (Mulliken charges of the common atoms of the molecules), thermodynamic descriptors, electronic descriptors, structural descriptors and spatial descriptors] were calculated for the development of statistically significant as well as well interpretable quantitative structure-activity relationship (QSAR) models. Two different chemometric tools [genetic function approximation (GFA) and genetic partial least squares (G/PLS)] were employed for the development of the QSAR models. The 3D pharmacophore model focused on the essential pharmacophoric features while the HQSAR model implicated the prime structural fragments that were necessitated for the optimal anti-lipid peroxidative activity of the molecules. All the models were validated based on internal, external and overall validation statistics. Randomization was performed in order to ensure the absence of chance correlation in the developed models. Among all models, the descriptor based model developed using the GFA-spline technique yielded the most satisfactory results. The results obtained from all the models corroborate well with each other and chiefly signify the importance of the ketonic oxygen of the amide/ acid fragment and the ethereal oxygen substituted on the parent phenyl ring of the molecules under study. Thus the models can efficiently be utilized for extensive screening of large datasets and their subsequent activity prediction. PMID- 22434312 TI - Circulating biomarkers in advanced renal cell carcinoma: clinical applications. AB - Advances in understanding the biology of renal cell carcinoma (RCC) have resulted in treatment strategies based on molecularly targeted agents that have substantially improved the outcomes of patients with metastatic RCC. Agents targeting the vascular endothelial growth factor pathway and the mammalian target of rapamycin have shown efficacy in randomized clinical trials and received international approval for treating RCC. Multiple candidate biomarkers of the biologic activity of such targeted therapies as well as markers of treatment response and patients' prognosis are being evaluated to improve drug development and to identify patients who may obtain the greatest benefit from the various treatment options. This review summarizes recent developments in identifying circulating biomarkers of targeted therapies for metastatic RCC, including soluble proteins and circulating cells. PMID- 22434313 TI - Pancreatic neuroendocrine and carcinoid tumors: what's new, what's old, and what's different? AB - Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (panNETs). Recently, two therapies have been FDA approved for progressive well-differentiated pancreatic NETs but have not been submitted for use in carcinoid tumors (Yao, Shah, Ito, et al. N Engl J Med 364:514-23, 2011**; Raymond, Dahan, Raoul, et al. N Engl J Med 364:501-13, 2011**). The first is sunitinib (Sutent((r)), Pfizer, Inc.), an orally administered, multitargeted receptor kinase inhibitor. The second targeted agent is everolimus (Afinitor((r)), Novartis Pharmaceuticals), a mammalian target of rapamycin (mTOR) inhibitor (Yao, Shah, Ito, et al. N Engl J Med 364:514-23, 2011**). Both agents demonstrated improved progression-free survival but can also result in non trivial toxicities and therefore, should only be considered in patients with progressing or symptomatic pancreatic NET. This review will discuss "new" NET therapies and provides an overview of liver directed and "older" cytotoxic treatment options. We also briefly outline "what's different" by describing a recent genetics report identifying genetic mutations in panNETs. Such a discovery could potentially be used to stratify treatment and such studies are currently being investigated. PMID- 22434314 TI - Management of hepatocellular carcinoma: beyond sorafenib. AB - The positive results of sorafenib have unveiled a new direction of research in the management of hepatocellular carcinoma (HCC). Since then intensive efforts have been focused on development of novel management strategy to further improve the outcome for patients with HCC. Emerging data have suggested that tumor progression of HCC is driven by a number of deregulated signaling pathways and/or epigenetic mechanism. Thus much effort is dedicated to identification of novel agents targeting these dysregulated pathways. Combinations of targeted therapeutics and transarterial chemoembolization (TACE), or different systemic therapeutics also hold the promise to improve treatment outcome beyond sorafenib. This review aims to summarize the current status of clinical development of treatment in HCC. Perspectives on future direction of research will also be discussed. PMID- 22434315 TI - Modification of esterified cell wall phenolics increases vulnerability of tall fescue to herbivory by the fall armyworm. AB - Feruloylation of arabinoxylan in grass cell walls leads to cross-linked xylans. Such cross-linking appears to play a role in plant resistance to pathogens and insect herbivores. In this study, we investigated the effect of ferulate cross linking on resistance to herbivory by fall armyworm (Spodoptera frugiperda) making use of genetically modified tall fescue [Schedonorus arundinaceus (Festuca arundinacea)] expressing a ferulic acid esterase gene. Mature leaves of these plants have significant reduced levels of cell wall ferulates and diferulates but no change in acid detergent lignin. These reduced levels of esterified cell wall ferulates in transgenic plants had a positive effect on all measures of armyworm larval performance examined. More larvae survived (89 vs. 57 %) and grew faster (pupated 2.1 days sooner) when fed transgenic leaves with reduced levels of cell wall ferulates, than when fed control tall fescue leaves where levels of cell wall ferulates were not altered. Overall, mortality, growth and food utilization were negatively associated with level of esterified cell wall ferulates and diferulates in leaves they were fed. This study is the first to use transgenic plants with modified level of cell wall esterified ferulates to test the role of feruloylation in plant resistance to insects. It is concluded that the accumulation of ferulates and the cross-linking of arabinoxylans via diferulate esters in the leaves of tall fescue underlies the physical barrier to insect herbivory. Reducing ferulate cross-linking in grass cell walls could increase susceptibility of these plants to insect folivores. PMID- 22434316 TI - Tumor associated glycoprotein-72 is a novel marker for poor survival in hepatocellular carcinoma. AB - To investigate the relationship of tumor associated glycoprotein-72 (TAG-72) expression with clinicopathological features in hepatocellular carcinoma (HCC) patients. Sixty pairs of HCC and paracarcinomatous (PCLT) tissues, and 10 normal liver (NL) tissues were collected for Western blot analysis, and 244 pairs of HCC and PCLT tissues were collected for immunohistochemistry analysis. TAG-72 protein expression was elevated significantly in HCC tissues compared with PCLT and NL tissues. Its increased expression was correlated with TNM stage, Edmondson Steiner grade, vein invasion and multiple tumor nodes. It is noteworthy that the HCC patients with high TAG-72 expression had shorter overall survival and disease free survival than the patients with low expression. Multivariate Cox regression analysis revealed that TAG-72 expression was an independent prognostic factor for HCC patients. The current study demonstrated for the first time that the increased expression of TAG-72 was correlated with poor survival in patients with HCC, indicating that TAG-72 is a novel prognostic marker for HCC. PMID- 22434317 TI - Desmoplastic small round cell tumor-clinicopathological spectrum, including unusual features and immunohistochemical analysis of 45 tumors diagnosed at a tertiary cancer referral centre, with molecular results t(11; 22) (p13; q12) (EWS WT1) in select cases. PMID- 22434318 TI - Quantum effects in biological electron transfer. AB - Over recent decades, quantum effects such as coherent electronic energy transfers, electron and hydrogen tunneling have been uncovered in biological processes. In this Perspective, we highlight some of the main conceptual and methodological tools employed in the field to investigate electron tunneling in proteins, with a particular emphasis on the methodologies we are currently developing. In particular, we describe our recent contributions to the development of a mixed quantum-classical framework aimed at describing physical systems lying at the border between the quantum and semi-classical worlds. We present original results obtained by combining our approach with constrained Density Functional Theory calculations. Moving to coarser levels of description, we summarize our latest findings on electron transfer between two redox proteins, thereby showing the stabilization of inter-protein, water-mediated, electron transfer pathways. PMID- 22434319 TI - A miniature gas analyzer made by integrating a chemoresistor with a microchannel. AB - A microfluidic channel is integrated with a tin oxide-based generic gas sensor on a PMMA (polymethyl methacrylate) substrate to fabricate a miniature gas analyzer. The analyte gas diffuses along the air-filled channel to affect the sensor installed in a microcavity positioned at the end of the channel. Analyte diffusion rates, experimentally estimated based on the temporal responses received from the sensor, are connected to the analyte's interactions with the channel walls as well as its diffusivity in air. The analyte-related information is extracted from the recorded responses and used for analyte recognition. A single PMMA channel of 80 MUm * 3 mm * 50 mm dimensions facilitates the correct classification of single component contaminants each introduced in a wide concentration range in air. The device is also shown to identify 15 ppm of 2 butanol in air contaminated with 1500 ppm of 1-butanol. The gas analyzer fabricated based on this concept is durable, inexpensive, handheld and suitable for a variety of applications. PMID- 22434321 TI - A structural and surface approach to size and shape control of sulfur-modified undoped and Fe-doped TiO2 anatase nano-materials. AB - In situ synchrotron X-ray diffraction and diffuse reflectance infrared spectroscopy (DRIFTS) are combined to study the influence of sulfur on the crystallization of pure and Fe-doped titania nano-materials. Using these two tools we have investigated the effect of sulfur on the nucleation and growth processes of the anatase polymorph from amorphous powders and show how the addition of sulfur controls the primary particle size and shape of the materials. As well known, sulfur leads to the stabilization of the oxide particle size against sintering during thermal treatments and here we interpret the physico chemical basis of such behaviour as an exclusive effect on grain growth kinetics, in turn linked to the dehydration of the surface layers of the materials. In addition this work shows that the presence of sulfur also affects the shape of the anatase particles, favouring the existence of (101)-type surfaces and elongated (along the c crystallographic axis) particles. This combined analysis of how sulfur influences morphological aspects of the anatase phase as it grows provides a basis for understanding of surface and chemical properties of anatase nano-powders that are highly dependent upon particle morphology. PMID- 22434322 TI - Unsuccessful attempt at gene-editing by homologous recombination in the zebrafish germ line using the approach of "Rong and Golic". AB - We have investigated the practicality of implementing a strategy for site specific editing by homologous recombination in zebrafish analogous to that developed by Rong and Golic (Rong and Golic in Genetics 157:1307-1312, 2001) in Drosophila melanogaster. We analysed approximately 7,300 offspring from 22 crosses and demonstrated successful excision of the gene editing construct but failed to detect either gene editing or the random integration of the intact editing construct subsequent to excision. The clustering of events in our data set demonstrates that the excision events are not occurring independently and emphasise that a promoter driving high level, tissue-specific transcription in meiotic cells is likely to be necessary if this general approach to site-specific editing by homologous recombination is to fulfil its potential. PMID- 22434323 TI - Phase transfer catalyst supported, room-temperature biphasic synthesis: a facile approach to the synthesis of coordination polymers. AB - A facile approach, named phase transfer catalyst supported, room temperature biphasic synthesis, has been developed to synthesize a new type of coordination polymers. Compared to the traditional biphasic solvothermal synthesis that was run at high temperature (100-200 degrees C), the new approach introduced here can be operated under a mild condition (room temperature) with the support of phase transfer catalyst. With the application of this new approach, two copper coordination complexes with 1D metal-organic nanotube and 1D coordination polymer containing large water clusters have been successfully synthesized and characterized. Furthermore, the synthetic approach presented here can be extended to synthesize other coordination polymers, including porous lanthanide-organic frameworks. PMID- 22434324 TI - Transcranial direct current stimulation of the left prefrontal cortex improves attention in patients with traumatic brain injury: a pilot study. AB - OBJECTIVE: To determine whether a single session of anodal transcranial direct current stimulation to the left dorsolateral prefrontal cortex improves attention in patients with traumatic brain injury. DESIGN: Double-blinded, cross-over design. PATIENTS: Nine patients with attention deficit after traumatic brain injury. METHODS: Patients underwent a computerized contrast reaction time task before and after the administration of real transcranial direct current stimulation (2 mA for 20 min) or sham transcranial direct current stimulation (2 mA for 1 min) to the left dorsolateral prefrontal cortex in a double-blind, crossover manner. RESULTS: Immediately post-stimulation, the transcranial direct current stimulation group showed a tendency of shortened reaction time relative to baseline (87.3 +/- 7.8%), whereas the sham stimulation group (122.4 +/- 715.5%) did not (p = 0.056). However, this difference was not significant 3 or 24 h after stimulation (p > 0.05). The numbers of correct responses were not changed at any time after stimulation. CONCLUSION: Anodal transcranial direct current stimulation applied to the left dorsolateral prefrontal cortex improves attention compared with sham stimulation in patients with traumatic brain injury, which suggests a potential role for this intervention in improving attention during cognitive training after traumatic brain injury. A further prospective randomized trial is required to confirm the benefits conferred by transcranial direct current stimulation in this patient population. PMID- 22434326 TI - High capacity vertical aligned carbon nanotube/sulfur composite cathodes for lithium-sulfur batteries. AB - Binder free vertical aligned (VA) CNT/sulfur composite electrodes with high sulfur loadings up to 70 wt% were synthesized delivering discharge capacities higher than 800 mAh g(-1) of the total composite electrode mass. PMID- 22434327 TI - Using the interactive systems framework in understanding the relation between general program capacity and implementation in afterschool settings. AB - The present study uses the Interactive Systems Framework (ISF) to understand how general capacity influences the implementation of prevention programs in afterschool settings. Eight afterschool sites received the Good Behavior Game (GBG) intervention, a program designed to foster supportive behavioral management and positive youth behavior. In line with the Prevention Support System component of ISF, the intervention afterschool staff were trained and received weekly on site support from coaches in implementing the GBG. It was found that GBG implementation scores were greatest in afterschool programs that rated high on both organizational- and community-levels of general capacity; high scores on only one level of general capacity resulted in lower implementation scores. Thus, afterschool sites that were more organized, maintained adequate facilities, and developed strong linkages to individuals or organizations in the community scored highest in implementation fidelity and quality. This study highlights the importance of considering interactions among multiple levels of general capacity in efforts to promote evidence-based practices in afterschool settings. Caution should be taken in generalizing findings due to the small sample in this study. PMID- 22434325 TI - Glycosylation of IgA1 and pathogenesis of IgA nephropathy. AB - IgA nephropathy, described in 1968 as IgA-IgG immune-complex disease, is an autoimmune disease. Galactose-deficient IgA1 is recognized by unique autoantibodies, resulting in the formation of pathogenic immune complexes that ultimately induce glomerular injury. Thus, formation of the galactose-deficient IgA1-containing immune complexes is a critical factor in the pathogenesis of IgA nephropathy. Studies of molecular defects of IgA1 can define new biomarkers specific for IgA nephropathy that can be developed into clinical assays to aid in the diagnosis, assessment of prognosis, and monitoring of disease progression. PMID- 22434328 TI - Exploring the use of the interactive systems framework to guide school mental health services in post-disaster contexts: building community capacity for trauma focused interventions. AB - Over the past two decades schools have been identified as the de facto mental health system for youth. Therefore, improving and expanding school mental health (SMH) has become a pressing agenda item for researchers, practitioners, policy makers, and funders. Advancing this agenda includes not only translating intervention research into practice within schools, but building capacities for these interventions to occur. The interactive systems framework (ISF) of Wandersman and colleagues, and the focus of this special issue, provides guidance in bridging the gap between research and practice through multisystem capacity building. There is some evidence that application of the ISF has helped to build capacity for SMH in states, but this evidence is preliminary. In addition, application of the ISF has not occurred in SMH at the community level or in relation to the specific stresses a community undergoes in relation to a disaster. The purpose of this article was to conduct a preliminary attempt to connect these three areas-the ISF, SMH and strengthening SMH through the ISF to better address impacts of a community level disaster; in this case, we explore the impacts of Hurricane Katrina on New Orleans schools, their students and families, and SMH programming within them. PMID- 22434329 TI - Blending theory with practice: implementing kindergarten transition using the interactive systems framework. AB - The Interactive Systems Framework (ISF; Wandersman et al. in Am J Commu Psychol 41(3-4):171-181, 2008) was used to implement a kindergarten transition demonstration project collaboratively developed by elementary and early education providers, community-based family and housing services, parents, and a University intermediary and technical assistance group. First person accounts from stakeholders at all levels provide a complementary and broad perspective on the project's implementation. The practice model blended existing research on kindergarten transition and parent involvement with feedback from stakeholders to create a community-specific program designed to help all children make a smooth entry into kindergarten. During implementation, evidence-based approaches needed to be adjusted to fit the specific needs of each community. Using the ISF as a guide, next steps and lessons learned include increasing leadership through a district-wide plan that is still flexible within each school community, increasing information and supports to individual schools, and improving data collection for continuous program improvement. PMID- 22434330 TI - Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. AB - BACKGROUND: Total pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated. METHODS: MEDLINE (1950 to present), Embase (1980 to present) and the Cochrane Library were searched to identify studies of outcomes in patients undergoing TP/IAT. Cohort studies that reported the outcomes following the procedure were included. The MOOSE guidelines were used as a basis for this review. RESULTS: Five studies met the inclusion criteria. The techniques reported for pancreatectomy and islet cell isolation varied between studies. TP/IAT was successful in reducing pain in patients with chronic pancreatitis. Comparing morphine requirements before and after the procedure, two studies recorded significant reductions. Concurrent IAT reduced the insulin requirement after TP; the rate of insulin independence ranged from 46 per cent of patients at 5 years' mean follow-up to 10 per cent at 8 years. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis. CONCLUSION: This systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation. PMID- 22434331 TI - An appraisal of the Food and Drug Administration warning on urogynecologic surgical mesh. AB - Currently, there is no consensus on the use of mesh in transvaginal surgical repairs for the treatment of pelvic organ prolapse. This review recapitulates and assesses the recent U. S. Food and Drug Administration (FDA) warnings about the use of surgical mesh in transvaginal pelvic organ prolapse repair and summarizes the responses of the national organizations that represent the health care providers most invested in treating patients with transvaginal surgical mesh. Mesh exposure or extrusion through the vaginal wall, true mesh erosion into viscera, and infection are the major complications that are currently used to define the safety of synthetic mesh use. Other potential adverse postsurgical outcomes that can affect quality of life, sexual function, and patient satisfaction include dyspareunia, "hispareunia" (ie, complaints of a sexual partner), prosthetic contraction or prominence, vaginal shortening, pelvic pain, urinary dysfunction, and failure of the repair. These outcomes are frequently attributed to mesh use, and can result in expense, frustration, and the need for further medical and surgical interventions for patients undergoing treatment for pelvic floor disorders. Information regarding the FDA's reports on the use of surgical mesh in pelvic organ prolapse repair should be made available to patients at the time of surgical planning and should be used as an adjunct in the process of obtaining informed consent. PMID- 22434332 TI - Clinicopathological analysis of nine consecutive central nervous system primitive neuroectodermal tumors in a single institute. AB - The objective of this study was to determine the outcome of central nervous system primitive neuroectodermal tumors (CNS PNETs) and to clarify the histopathological findings as prognostic factors. We performed a retrospective analysis of nine consecutive patients with CNS PNETs who underwent treatment at our institute between 1993 and 2011. All patients were treated by surgical resection followed by chemoradiotherapy. Additional treatment, including surgical resection, was performed at relapse. Expression of immunohistochemical markers was examined for neuronal, astrocytic, mesenchymal, and epithelial differentiation, and also for TP53, O(6)-methylguanine-DNA methyltransferase, and Ki-67. Five-year progression-free survival was 18.2 % and the overall survival was 52.5 %. Five the 9 patients had recurrence and 4 patients died during the median follow-up period of 41.1 months. All 4 patients died of dissemination not local recurrence. After relapses, the extent of differentiation was different in each case and TP53 changed to positive or negative, but the Ki-67 labeling index did not reveal any differences between primary and recurrent tumors. A treatment procedure to prevent and treat dissemination of CNS PNETs should be established. Because the pathological change after relapse was different in each case, definitive histopathological prognostic factors for CNS PNETs are still difficult to propose. PMID- 22434333 TI - Characterization of hydroxycinnamic acid derivatives binding to bovine serum albumin. AB - Hydroxycinnamic acid derivatives (HCAs) are a group of naturally occurring polyphenolic compounds which possess various pharmacological activities. In this work, the interactions of bovine serum albumin (BSA) with six HCA derivatives, including chlorogenic acid (CHA), caffeic acid (CFA), m-coumaric acid (m-CA), p coumaric acid (p-CA), ferulic acid (FA) and sinapic acid (SA) have been investigated by NMR spectroscopic techniques in combination with fluorescence and molecular modeling methods. Competitive STD NMR experiments using warfarin sodium and L-tryptophan as site-selective probes indicated that HCAs bind to site I in the subdomain IIA of BSA. From the analysis of the STD NMR-derived binding epitopes and molecular docking models, it was deduced that CHA, CFA, m-CA and p CA show similar binding modes and orientation, in which the phenyl ring is in close contact with protein surface, whereas carboxyl group points out of the protein. However, FA and SA showed slightly different binding modes, due to the steric hindrance of methoxy-substituents on the phenyl ring. Relaxation experiments provided detailed information about the relationship between the affinity and structure of HCAs. The binding affinity was the strongest for CHA and ranked in the order CHA > CFA > m-CA >= p-CA > FA > SA, which agreed well with the results from fluorescence experiments. Based on our experimental results, we also conclude that HCAs bind to BSA mainly by hydrophobic interaction and hydrogen bonding. This study therefore provides valuable information for elucidating the mechanisms of BSA-HCAs interaction. PMID- 22434334 TI - Ganglionated plexi ablation in right atrium to treat cardioinhibitory neurocardiogenic syncope. PMID- 22434335 TI - Detection of inadvertent catheter movement into the coronary sinus ostium or middle cardiac vein by real-time impedance monitoring prior to radiofrequency ablation in the right atrial posteroseptal region. AB - OBJECTIVE: The objective of this study was to evaluate the use of continuous catheter impedance monitoring prior to ablation to facilitate differentiation of the coronary sinus ostium (CSO) and the middle cardiac vein (MCV) from the right atrial posteroseptal region (RPS). BACKGROUND: Empiric observations have suggested that continuous catheter impedance monitoring could differentiate the CSO and MCV from the RPS region. Radiofrequency ablation in the MCV or coronary sinus has been associated with coronary artery injury. Differentiation of these areas may be difficult with either fluoroscopy or electrogram characteristics. METHODS AND RESULTS: Continuous impedance measurements using a 4-mm Navistar (Biosense Webster) ablation catheter were conducted in 17 consecutive patients undergoing ablation for supraventricular tachycardia. The average impedance value was recorded at the right atrial septum (RS) posterior to the bundle of His, the RPS region, within 1 cm inside the CSO and in the MCV. These areas were confirmed and demarcated with 3-D mapping and biplane fluoroscopy. A significant increase in impedance was observed between the CSO (X = 146.6 +/- 24.8) and RPS [Formula: see text] regions (p < 0.001). Furthermore, a significant rise in impedance was seen between the MCV [Formula: see text] and RPS and CSO, respectively (p < 0.001). No significant change in impedance was found between the RS [Formula: see text] and RPS regions. CONCLUSIONS: Continuous impedance measurements during mapping can facilitate differentiation of catheter locations inside the CSO and MCV from extracoronary sinus regions. This may reduce the risk of inadvertent coronary artery damage during the ablation procedure. PMID- 22434336 TI - Improved motor sequence retention by motionless listening. AB - This study examined the effect of listening to a newly learned musical piece on subsequent motor retention of the piece. Thirty-six non-musicians were trained to play an unfamiliar melody on a piano keyboard. Next, they were randomly assigned to participate in three follow-up listening sessions over 1 week. Subjects who, during their listening sessions, listened to the same initial piece showed significant improvements in motor memory and retention of the piece despite the absence of physical practice. These improvements included increased pitch accuracy, time accuracy, and dynamic intensity of key pressing. Similar improvements, though to a lesser degree, were observed in subjects who, during their listening sessions, were distracted by another task. Control subjects, who after learning the piece had listened to nonmusical sounds, showed impaired motoric retention of the piece at 1 week from the initial acquisition day. These results imply that motor sequences can be established in motor memory without direct access to motor-related information. In addition, the study revealed that the listening-induced improvements did not generalize to the learning of a new musical piece composed of the same notes as the initial piece learned, limiting the effects to musical motor sequences that are already part of the individual's motor repertoire. PMID- 22434337 TI - [Antimicrobial treatment of patients with severe acute exacerbation of COPD]. AB - Chronic obstructive lung disease (COPD) is a leading cause of death worldwide. In patients with acute exacerbations admitted to an intensive care unit (ICU), potentially pathogenic microorganisms can be found in approximately 50%, with Haemophilus influenzae and Streptococcus pneumoniae as the leading strains, followed by enterobacteria and Pseudomonas aeruginosa. Viruses can also be detected in a large proportion of patients. The indication for antimicrobial treatment of acutely exacerbated COPD is still controversial but recommended by guidelines for all patients admitted to an ICU. Appropriate agents for an empiric initial treatment are penicillins + betalactamase inhibitor, 2(nd) and 3(rd) generation cephalosporins, carbapenems, and quinolones. Antimicrobial treatment should be adjusted according to the results of microbial investigation of sputum or endotracheal aspirate. PMID- 22434338 TI - Micro-patterned porous substrates for cell-based assays. AB - In the search for new therapeutic chemicals, lab-on-a-chip systems have recently emerged as innovative and efficient tools for cell-based assays and high throughput screening. Here, we describe a novel, versatile and simple device for cell-based assays at the bench-top. We created spatial variations of porosity on the surface of a membrane filter by microcontact printing with a biocompatible polymer (PDMS). We called such systems Micro-Printed Membranes (MUPM). Active compounds dispensed on the porous areas, where the membrane pores are not clogged by the polymer, can cross the membrane and reach cells growing on the opposite side. Only cells immediately below those porous areas could be stimulated by chemicals. We performed proof-of-principle experiments using Hoechst nuclear staining, calcein-AM cell viability assay and destabilization of the cytoskeleton organisation by cytochalasin B. Resulting fluorescent staining properly matched the drops positioning and no cross-contaminations were observed between adjacent tests. This well-less cell-based screening system is highly flexible by design and it enables multiple compounds to be tested on the same cell tissue. Only low sample volumes in the microlitre range are required. Moreover, chemicals can be delivered sequentially and removed at any time while cells can be monitored in real time. This allows the design of complex, sequential and combinatorial drug assays. MUPMs appear as ideal systems for cell-based assays. We anticipate that this lab-on-chip device will be adapted for both manual and automated high content screening experiments. PMID- 22434339 TI - A peroxide-bridged imidazole dimer formed from a photochromic naphthalene-bridged imidazole dimer. AB - 2,4,5-Triphenylimidazole (lophine) is known as the first chemiluminescence substrate, and its oxidized derivative, the 2,4,5-triphenylimidazolyl radical, corresponds to the coloured species in the photochromic reaction of hexaarylbiimidazole (HABI). We report the first direct observation of the O(2) adduct of the imidazolyl radical that forms the end-on peroxide-bridged imidazole dimer. The ring-opening reaction of the peroxide-bridged imidazole dimer leading to the formation of an N-benzoylbenzamidine derivative supports the presence of the 4,5-epidioxide of lophine as a reaction intermediate of its chemiluminescence. PMID- 22434340 TI - Cephalosporins periprostatic injection: are really effective on infections following prostate biopsy? AB - PURPOSE: To compare the antibiotic prophylaxis based on quinolone administered orally with a combination of cephalosporin administered periprostatically and a fluoroquinolone orally, in terms of post-prostate bioptic infectious complication rates in those men undergoing transrectal ultrasound-guided prostate biopsy (TRUS gpb). METHODS: In a prospective, randomized, double-blind study, 150 consecutive patients were randomized to receive 10 ml lidocaine 1 % in Group A and ceftriaxone 1 g diluted in a solution of 10 ml of lidocaine 1 % in Group B, before TRUS gpb. All signed the informed consent. The men were asked to grade the pain using a ten points visual analogue scale close after TRUS gpb. In a telephone interview at 3 and 6 days, they were asked about early and late complications, assessing rectal bleeding, urinary retection, fewer, haematuria, urethral bleeding and hematospermia. RESULTS: Of the 150 men enrolled, 135, 70 in Groups A and 65 in Group B, completed the study. Four men (5.7 %) in Group A developed sepsis after TRUS gpb requiring hospital admission and intravenous antibiotic treatment, while none in Group B. Escherichia coli was the only organism isolated. The mean pain score was 2.76 +/- 1.69 and 1.73 +/- 1.26 for Group A and B, respectively (p = 0.08). Complications, evaluated at 3 and 6 days after the procedure through a telephone interview, were similar in both Groups. CONCLUSIONS: The antibiotic prophylaxis based on the combination of ceftriaxone administered periprostatically and ciprofloxacin orally is able to offer a best control on infections caused by fluoroquinolone-resistant E. coli. PMID- 22434341 TI - Comparing movement patterns associated with Huntington's chorea and Parkinson's dyskinesia. AB - Involuntary movements such as levodopa-induced dyskinesia in Parkinson's disease (PD) and chorea in Huntington's disease (HD) are the consequence of two distinct basal ganglia dysfunctions. Yet, their clinical manifestations seem to resemble each other. We seek to determine how to detect PD dyskinesia and HD chorea during quiet stance using healthy control subjects' postural sway as a base measure and identify means to distinguish mathematically HD chorea from PD dyskinesia. Movements were recorded using a magnetic tracker system with fifteen sensors placed strategically to capture whole-body displacement. Choreic and dyskinetic patients as well as healthy controls were asked to stand with arms stretched horizontally in front of them for 60 s. We examined amplitude, frequency dispersion, proportional energy, sample entropy, kurtosis, skewness, amplitude fluctuation, maximum coherency between 44 pairs of body segments. The choreic and dyskinetic movements revealed similar patterns of sample entropy, amplitude fluctuation, and coherencies between body segments. However, skewness and kurtosis for velocity of movements were found to be higher in HD chorea than in PD dyskinesia, reflecting rapid movements in HD patients. There was also a tendency for the frequency composition of PD dyskinesia to be more concentrated in the 1.0-1.5 Hz range. Our results show that despite their similarities in apparent randomness and lack of coordination, dyskinesia associated with treatment of PD and chorea in HD each have their own distinctive characteristics which may be related to their specific pathophysiology. PMID- 22434342 TI - Neural correlates of oddball detection in self-motion heading: a high-density event-related potential study of vestibular integration. AB - The perception of self-motion is a product of the integration of information from both visual and non-visual cues, to which the vestibular system is a central contributor. It is well documented that vestibular dysfunction leads to impaired movement and balance, dizziness and falls, and yet our knowledge of the neuronal processing of vestibular signals remains relatively sparse. In this study, high density electroencephalographic recordings were deployed to investigate the neural processes associated with vestibular detection of changes in heading. To this end, a self-motion oddball paradigm was designed. Participants were translated linearly 7.8 cm on a motion platform using a one second motion profile, at a 45 degrees angle leftward or rightward of straight ahead. These headings were presented with a stimulus probability of 80-20 %. Participants responded when they detected the infrequent direction change via button-press. Event-related potentials (ERPs) were calculated in response to the standard (80 %) and target (20 %) movement directions. Statistical parametric mapping showed that ERPs to standard and target movements differed significantly from 490 to 950 ms post-stimulus. Topographic analysis showed that this difference had a typical P3 topography. Individual participant bootstrap analysis revealed that 93.3 % of participants exhibited a clear P3 component. These results indicate that a perceived change in vestibular heading can readily elicit a P3 response, wholly similar to that evoked by oddball stimuli presented in other sensory modalities. This vestibular-evoked P3 response may provide a readily and robustly detectable objective measure for the evaluation of vestibular integrity in various disease models. PMID- 22434343 TI - Olfactory and trigeminal interaction of menthol and nicotine in humans. AB - The purpose of the study was to investigate the interactions between two stimuli menthol and nicotine-both of which activate the olfactory and the trigeminal system. More specifically, we wanted to know whether menthol at different concentrations modulates the perception of burning and stinging pain induced by nicotine stimuli in the human nose. The study followed an eightfold randomized, double-blind, cross-over design including 20 participants. Thirty phasic nicotine stimuli at one of the two concentrations (99 and 134 ng/mL) were applied during the entire experiment every 1.5 min for 1 s; tonic menthol stimulation at one of the three concentrations (0.8, 1.5 and 3.4 MUg/mL) or no-menthol (placebo control conditions) was introduced after the 15th nicotine stimulus. The perceived intensities of nicotine's burning and stinging pain sensations, as well as perceived intensities of menthol's odor, cooling and pain sensations, were estimated using visual analog scales. Recorded estimates of stinging and burning sensations induced by nicotine initially decreased (first half of the experiment) probably due to adaptation/habituation. Tonic menthol stimulation did not change steady-state nicotine pain intensity estimates, neither for burning nor for stinging pain. Menthol-induced odor and cooling sensations were concentration dependent when combined with low-intensity nicotine stimuli. Surprisingly, this dose dependency was eliminated when combining menthol stimuli with high-intensity nicotine stimuli. There was no such nicotine effect on menthol's pain sensation. In summary, we detected interactions caused by nicotine on menthol perception for odor and cooling but no effect was elicited by menthol on nicotine pain sensation. PMID- 22434344 TI - The psychological profiles of internet, contact, and mixed internet/contact sex offenders. AB - A sample of 526 contact offenders, 459 internet offenders, and 143 mixed contact/internet offenders was compared on a range of self-report psychological measures assessing offense-supportive beliefs, socioaffective functioning, emotional management, and socially desirable responding. A multivariate general linear model found a mixed offender profile that was similar to internet offenders rather than contact offenders. The contact group demonstrated lower victim empathy, a greater level of pro-offending attitudes, an externalized locus of control, more assertiveness, a diminished ability to relate to fictional characters, and greater impulsivity than the internet and mixed offender groups. The mixed offender group demonstrated a higher level of empathic concern than the other two groups. The mixed offender group could also be distinguished from the internet group by increased personal distress and perspective-taking ability. A discriminant function analysis highlighted the key linear factor distinguishing between the groups to be one relating to offense-supportive attitudes and identification with fictional characters. A second factor was related to higher levels of empathic concern and poor self-management. These findings are discussed in the context of the potential pathways between internet and contact sexual offenses. PMID- 22434345 TI - New Zealand youth that sexually offend: improving outcomes for Maori rangatahi and their whanau. AB - Maori youth are overrepresented in criminal justice statistics and youth forensic services. Maori youth that engage in sexual offending behaviors have a higher risk of dropping out of treatment than Pakeha(1) youth. Research into Maori mental health is important to inform ongoing service development and is essential to strive for equity in mental health outcomes and offending rates among Maori. In this study, the researchers investigated the coexisting emotional and behavioral problems and victimization histories of an age-matched sample of Maori (n = 75) and Pakeha (n = 75) youth who were referred to a community treatment program for sexual offending in Auckland between 1996 and 2008. The Child Behavior Checklist was used to investigate ethnic differences. After controlling for socioeconomic deprivation, Maori youth scored significantly higher than Pakeha youth on the Delinquent Behaviors syndrome scale. Maori youth were also more likely than Pakeha youth to have a background of physical abuse. Implications of these findings are discussed, with regard to the unique needs of Maori youth and appropriate interventions. PMID- 22434346 TI - South African serial rapists: the offenders, their victims, and their offenses. AB - Serial rapists have the propensity to cause harm to a significant number of victims, meaning that they are of concern to the police as well as to treatment providers. Despite the serious nature of their offending, there are surprisingly few studies that provide information regarding their characteristics, the types of victim they target, or the nature of the sexual offenses they commit, and those studies that do exist are varied in their findings. This study provides a descriptive analysis of serial rape in South Africa. One hundred and nineteen sexual offenses committed by 22 serial rapists were sampled. Information regarding the victims, the offenders, and the crimes they had committed were extracted from police files. The characteristics of victims and offenders are reported as well as the frequencies for 114 different crime scene behaviors. When compared with samples of serial sex offenders from other countries, differences emerged in victim characteristics and crime scene behaviors, including how the victims were targeted, the sexual behaviors engaged in, and the incidence of physical violence. The implications of these observed differences for practice are discussed. PMID- 22434347 TI - Green and controlled synthesis of Cu2O-graphene hierarchical nanohybrids as high performance anode materials for lithium-ion batteries via an ultrasound assisted approach. AB - A low-cost, fast, facile, green method, namely an ultrasound assisted approach, has been developed for the controlled synthesis of Cu(2)O-graphene hybrid nanomaterials. By the protection of graphene nanosheets, the as-obtained anode material exhibited enhanced lithium ion battery performance. PMID- 22434348 TI - Amycolatopsis bartoniae sp. nov. and Amycolatopsis bullii sp. nov., mesophilic actinomycetes isolated from arid Australian soils. AB - The status of two mesophilic filamentous actinomycetes isolated from an arid Australian soil sample was determined using a polyphasic taxonomic approach. The isolates had chemical and morphological properties consistent with their classification in the genus Amycolatopsis, assignments that were supported by analysis of 16S rRNA gene sequence data. Isolate SF26(T) formed a distinct phyletic line and hence was sharply separated from its nearest phylogenetic neighbour, Amycolatopsis sacchari DSM 44468(T). In contrast, isolate SF27(T) formed a subclade in the Amycolatopsis tree with Amycolatopsis vancoresmycina DSM 44592(T) but was separated readily from the latter by DNA:DNA pairing data. The two isolates were distinguished from one another and from their respective nearest phylogenetic neighbours using a range of phenotypic properties. These data indicate that the two isolates should be recognized as new species in the genus Amycolatopsis. The names proposed for these new taxa are Amycolatopsis bartoniae sp. nov. and Amycolatopsis bullii sp. nov. with isolates SF26(T) (=NCIMB 14706(T) = NRRL B-2846(T)) and SF27(T) (=NCIMB 14707(T) = NRRL B 24847(T)) as the respective type strains. PMID- 22434349 TI - Decomposition of insoluble and hard-to-degrade animal proteins by enzyme E77 and its potential applications. AB - Insoluble and hard-to-degrade animal proteins are group of troublesome proteins, such as collagen, elastin, keratin, and prion proteins that are largely generated by the meat industry and ultimately converted to industrial wastes. We analyzed the ability of the abnormal prion protein-degrading enzyme E77 to degrade insoluble and hard-to-degrade animal proteins including keratin, collagen, and elastin. The results indicate that E77 has a much higher keratinolytic activity than proteinase K and subtilisin. Maximal E77 keratinolytic activity was observed at pH 12.0 and 65 degrees C. E77 was also adsorbed by keratin in a pH independent manner. E77 showed lower collagenolytic and elastinolytic specificities than proteinase K and subtilisin. Moreover, E77 treatment did not damage collagens in ovine small intestines but did almost completely remove the muscles. We consider that E77 has the potential ability for application in the processing of animal feedstuffs and sausages. PMID- 22434350 TI - Synthesis of pure meso-2,3-butanediol from crude glycerol using an engineered metabolic pathway in Escherichia coli. AB - meso-2,3-Butanediol (meso-2,3-BDO) is essential for the synthesis of various economically valuable biosynthetic products; however, the production of meso-2,3 BDO from expensive carbon sources is an obstacle for industrial applications. In this study, genes involved in the synthesis of 2,3-BDO in Klebsiella pneumoniae were identified and used to genetically modify Escherichia coli for meso-2,3-BDO production. Two 2,3-BDO biosynthesis genes-budA, encoding acetolactate, and meso budC, encoding meso-SADH-from K. pneumoniae were cloned into the pUC18 plasmid and introduced into E. coli. In 2 l batch culture, the SGSB03 E. coli strain yielded meso-2,3-BDO at 0.31 g/g(glucose) (with a maximum of 15.7 g/l(culture) after 48 h) and 0.21 g/g(crude glycerol) (with a maximum of 6.9 g/l(culture) after 48 h). Batch cultures were grown under optimized conditions (aerobic, 6% carbon source, 37 degrees C, and initial pH 7). To find the optimal culture conditions for meso-2,3-BDO production, we evaluated the enzyme activity of meso SADH and the whole cell conversion yield (meso-2,3-BDO/acetoin) of the E. coli SGSB02, which contains pSB02. meso-SADH showed high enzyme activity at 30-37 degrees C and pH 7 (30.5-41.5 U/mg of protein), and the conversion yield of SGSB02 E. coli was highest at 37-42 degrees C and a pH of 7 (0.25-0.28 g( meso 2,3-BDO)/g(acetoin)). PMID- 22434351 TI - Agrobacterium-mediated genetic transformation of Pogostemon cablin (Blanco) Benth. Using leaf explants: bactericidal effect of leaf extracts and counteracting strategies. AB - An optimized protocol for Agrobacterium tumefaciens-mediated transformation of patchouli using leaf disk explants is reported. In vitro antibacterial activity of leaf extracts of the plants revealed Agrobacterium sensitivity to the extracts. Fluorometric assay of bacterial cell viability indicated dose-dependent cytotoxic activity of callus extract against Agrobacterium cells. Addition of 0.1% Tween 20 and 2 g/l L-glutamine to Agrobacterium infection medium counteracted the bactericidal effect and significantly increased the T-DNA delivery to explants. A short preculture of explants for 2 days followed by infection with Agrobacterium in medium containing 150 MUM of acetosyringone were found essential for efficient T-DNA delivery. Cocultivation for 3 days at 22 degrees C in conjunction with other optimized factors resulted in maximum T-DNA delivery. The Agrobacterium-mediated transformation of leaf disk explants were found significantly related to physiological age of the explants, age and origin of the of the donor plant. Leaf explants from second node of the 3-month-old in vivo plants showed highest transformation efficiency (94.3%) revealed by transient GUS expression assay. Plants selected on medium containing 20 mg/l kanamycin showed stable GUS expression in leaves and stem. The elongated shoots readily developed roots on kanamycin-free rooting medium and on transfer to soil, plants were successfully established. Polymerase chain reaction (PCR) and reverse transcriptase PCR analysis in putative plants confirmed their transgenic nature. The established transformation method should provide new opportunities for the genetic improvement of patchouli for desirable trait. PMID- 22434352 TI - Sugar ester synthesis by thermostable lipase from Streptomyces thermocarboxydus ME168. AB - The extracellular lipase from Streptomyces thermocarboxydus ME168 was purified to 9.5-fold with 20% yield, following concentration by acetone precipitation, ion exchange chromatography (Resource Q) and gel filtration chromatography (Superdex 200), respectively. The purified enzyme had an apparent molecular mass of 21 kDa by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The N terminal sequence of the lipase was ASDFDDQILG and was different from most other reported lipase. The enzyme showed maximum activity at 50 degrees C with the half-life of 180 min at 65 degrees C. It showed high stability at a broad pH range of 5.5-9.5 and was thermostable at the temperature range of 25-60 degrees C. The K(m) and V(max) were 0.28 mM and 1,428 U/mg, respectively, using p nitrophenyl palmitate as substrate. It was active toward p-nitrophenyl ester with medium to long acyl chain (C(8)-C(16)). Lipase activity was inhibited by Zn(2+), dithiothreitol (DTT), EDTA and some organic solvents, e.g., ethanol, acetone, dioxane, acetronitrile, tert-butanol and pyridine. Immobilized crude lipase of S. thermocarboxydus ME168 on celite could be used to synthesize sugar esters from glucose and vinyl acetate, vinyl butyrate or vinyl caproate in tert butanol:pyridine (55:45 v/v) at 45 degrees C with conversion yields of 93, 67 and 55%, respectively. PMID- 22434353 TI - Induced biofilm cultivation enhances riboflavin production by an intertidally derived Candida famata. AB - The aim of the investigation was to ascertain if surface attachment of Candida famata and aeration enhanced riboflavin production. A newly designed polymethylmethacrylate (PMMA) conico-cylindrical flask (CCF) holding eight equidistantly spaced rectangular strips mounted radially on a circular disk allowed comparison of riboflavin production between CCFs with hydrophobic surface (PMMA-CCF), hydrophilic glass surface (GS-CCF), and 500-ml Erlenmeyer flask (EF). Riboflavin production (mg/l) increased from 12.79 to 289.96, from 54.44 to 238.14, and from 36.98 to 158.71 in the GS-CCF, EF, and PMMA-CCF, respectively, when C. famata was grown as biofilm-induced cultures in contrast to traditional planktonic culture. Production was correlated with biofilm formation and planktonic growth was suppressed in cultivations that allowed higher biofilm formation. Enhanced aeration increased riboflavin production in hydrophilic vessels. Temporal pattern of biofilm progression based on two-channel fluorescence detection of extracellular polymeric substances and whole cells in a confocal laser scanning microscope followed by application of PHLIP and ImageJ volume viewer software demonstrated early maturity of a well-developed, stable biofilm on glass in contrast to PMMA surface. A strong correlation between hydrophilic reactor surface, aeration, biofilm formation, and riboflavin production was established in C. famata. Biofilm culture is a new-found means to improve riboflavin production by C. famata. PMID- 22434354 TI - Effects of selenium and light wavelengths on liquid culture of Cordyceps militaris Link. AB - To investigate the effects of selenium and light wavelengths on the growth of liquid-cultured Cordyceps militaris and the main active components' accumulation, culture conditions as selenium selenite concentrations and light of different wavelengths were studied. The results are: adenosine accumulation proved to be significantly selenium dependent (R(2) = 0.9403) and cordycepin contents were determined to be not significantly selenium dependent (R(2) = 0.3845) but significantly enhanced by selenium except for 20 ppm; there were significant differences in cordycepin contents, adenosine contents, and mycelium growth caused by light wavelengths: cordycepin, blue light > pink light > daylight, darkness, red light; adenosine, red light > pink light, darkness, daylight, blue light; and mycelium growth, red light > pink light, darkness, daylight > blue light. In conclusion, light wavelength had a significant influence on production of mycelia, adenosine, and cordycepin, so lightening wavelength should be changed according to target products in the liquid culture of C. militaris. PMID- 22434355 TI - Production of coconut protein powder from coconut wet processing waste and its characterization. AB - Virgin coconut oil (VCO) has been gaining popularity in recent times. During its production, byproducts such as coconut skim milk and insoluble protein are obtained which are underutilized or thrown away to the environment at present. This study deals with utilization of these byproducts to obtain a value-added product, namely, coconut protein powder. When coconut milk was subjected to centrifugation, three phases, namely, fat phase (coconut cream), aqueous phase (coconut skim milk), and solid phase (insoluble protein) were obtained. The coconut skim milk and insoluble protein were mixed and homogenized before spray drying to obtain a dehydrated protein powder. The proximate analysis of the powder showed high protein content (33 % w/w) and low fat content (3 % w/w). Protein solubility was studied as a function of pH and ionic content of solvent. Functional properties such as water hydration capacity, fat absorption capacity, emulsifying properties, wettability, and dispersibility of coconut protein powder were evaluated along with morphological characterization, polyphenol content, and color analysis. Coconut protein powder has shown to have good emulsifying properties and hence has potential to find applications in emulsified foods. Sensory analysis showed high overall quality of the product, indicating that coconut protein powder could be a useful food ingredient. PMID- 22434356 TI - The bioflavonoid galangin suppresses the growth of ehrlich ascites carcinoma in Swiss Albino mice: a molecular insight. AB - Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancer caused by various stress conditions. Galangin (4H-1-Benzopyran-4-one, 3, 5, 7-trihydroxy-2-phenyl-), a flavonoid, is a polyphenolic compound found primarily in medicinal herb, Alpinia galanga. This study aims to demonstrate the galangin as a pharmacological lead compound using in vitro, in vivo, and in silico model targeting specific cancer condition and proteins. The proliferation of MCF-7 and Ehrlich ascites carcinoma (EAC) cells was significantly inhibited with an IC50 of 34.11 and 22.29 MUg/ml, respectively. In an animal model system, galangin has inhibited the tumor growth by 73.51% +/- 4.742 in EAC-induced Swiss Albino mice with no evidences of mortality as compared to standard drug, 5-fluorouracil. The effectiveness of galangin is proven in an animal system suggesting its pharmacokinetics behavior in an animal model which is also complemented by outcome of in silico analysis with more than 88 % of human intestinal absorption and significant Caco-2 cell, MDCK cell, and skin permeability as predicted by in silico methods. Galangin was docked against 19 different proteins involved in tumorogenesis and apoptosis; the energetic analysis indicates that it exhibits higher predicted binding free energy of -12.7 kcal/mol with Bcl-xL protein. PMID- 22434357 TI - A reverse vaccinology approach for the identification of potential vaccine candidates from Leishmania spp. AB - Leishmaniasis is a group of diseases with a spectrum of clinical manifestations ranging from cutaneous ulcers to visceral leishmaniasis, which results from the bite of an infected sandfly to human. Attempts to develop an effective vaccine have been shown to be feasible but no vaccine is in active clinical use. This study adopts a Reverse Vaccinology approach to identify common vaccine candidates from both highly pathogenic species Leishmania major and Leishmania infantum. Total proteome of both species were compared to identify common proteins, which are further taken for sub-cellular localization and transmembrane helices prediction. Plasma membrane proteins having only one transmembrane helix were first identified and analyzed which are non-homologous in human and mouse in order to avoid molecular mimicry with other proteins. Selected proteins were analyzed for their binding efficiency to both major histocompatibility complex (MHC) class I and class II alleles. As a result, 19 potential epitopes are screened in this study using different approaches, which can be further verified through in vivo experiments in MHC compatible animal models. This study demonstrates that Reverse Vaccinology approach has potential in discovering various immunogenic antigens from in silico analysis of pathogen's genome or proteome instead of culturing the whole organism by conventional methods. PMID- 22434358 TI - Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. AB - Mutations of the SMARCB1 gene have been implicated in several human tumour predisposing syndromes. They have recently been identified as an underlying cause of the tumour suppressor syndrome schwannomatosis. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have carried out extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for schwannomatosis. In our current cohort, we identified novel mutations within the SMARCB1 gene and detected several mutations that have been previously identified in other schwannomatosis cohorts. Of the schwannomatosis screens reported to date, including our current dataset, SMARCB1 mutations have been found in 45 % of familial probands and 7 % of sporadic patients. The exon 1 mutation, c.41C >A, and the 3' untranslated region mutation, c.*82C >T, are the most common changes reported in schwannomatosis disease so far, indicating mutation hotspots at both 5' and 3' portions of the gene. SMARCB1 mutations are found in a significant proportion of schwannomatosis patients, but there remains the possibility that further causative genes remain to be found. PMID- 22434359 TI - Paradoxical scintigraphic pattern in regions with myocardial necrosis on myocardial perfusion gated SPECT with 99mTc-tetrofosmin. AB - OBJECTIVES: To assess the significance of a paradoxical pattern (PP) (greater tracer uptake during stress than at rest) on gated myocardial perfusion SPECT in myocardial regions with myocardial necrosis. METHODS: A review of 1,764 consecutive stress-rest myocardial perfusion SPECT studies in patients with prior myocardial infarction (MI) was conducted. Of these, 117 patients (6.6%) with a PP corresponding to a region with myocardial necrosis were identified. An assessment of perfusion, contractility, wall thickening, scintigraphic criteria for viability, and the characteristics of the culprit artery in regions with a PP was performed. RESULTS: Of the 160 regions with necrosis, 125 (75%) had a PP: 67 in the anterior region and 58 in the inferior-lateral region. In the PP group, the average tracer activity of defects during stress was significantly higher than at rest (P < .0001). Ninety-three (86.6%) out of 110 PP segments without scintigraphic criteria of viability at rest met viability criteria on stress imaging. The artery supplying regions with a PP was patent in 88% of cases. In the remaining patients it was occluded, although collateral circulation was always present. CONCLUSIONS: In scintigraphic segments corresponding to regions with infarction and PP, a mixture of viable and well perfused myocardium was observed. In most cases, the vessel that supplied the region with PP was either patent, or when the artery was occluded, there was evident collateral circulation. PMID- 22434360 TI - Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study. AB - BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m(2) ) plus cisplatin (75 mg/m(2) ; n = 398) or placebo plus cisplatin (75 mg/m(2) ; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebo-cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P = .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n = 347) led to longer OS and PFS than placebo-cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n = 86) resulted in longer OS and PFS than placebo-cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intent-to-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. PMID- 22434361 TI - The effect of continuous positive airway pressure on total cerebral blood flow in healthy awake volunteers. AB - PURPOSE: Continuous positive airway pressure (CPAP) is the gold standard treatment for obstructive sleep apnea. However, the physiologic impact of CPAP on cerebral blood flow (CBF) is not well established. Ultrasound can be used to estimate CBF, but there is no widespread accepted protocol. We studied the physiologic influence of CPAP on CBF using a method integrating arterial diameter and flow velocity (FV) measurements obtained for each vessel supplying blood to the brain. METHODS: FV and lumen diameter of the left and right internal carotid, vertebral, and middle cerebral arteries were measured using duplex Doppler ultrasound with and without CPAP at 15 cm H(2)O, applied in a random order. Transcutaneous carbon dioxide (PtcCO(2)), heart rate (HR), blood pressure (BP), and oxygen saturation were monitored. Results were compared with a theoretical prediction of CBF change based on the effect of partial pressure of carbon dioxide on CBF. RESULTS: Data were obtained from 23 healthy volunteers (mean +/- SD; 12 male, age 25.1 +/- 2.6 years, body mass index 21.8 +/- 2.0 kg/m(2)). The mean experimental and theoretical CBF decrease under CPAP was 12.5 % (p < 0.001) and 11.9 % (p < 0.001), respectively. The difference between experimental and theoretical CBF reduction was not statistically significant (3.84 +/- 79 ml/min, p = 0.40). There was a significant reduction in PtcCO(2) with CPAP (p = <0.001) and a significant increase in mean BP (p = 0.0017). No significant change was observed in SaO(2) (p = 0.21) and HR (p = 0.62). CONCLUSION: Duplex Doppler ultrasound measurements of arterial diameter and FV allow for a noninvasive bedside estimation of CBF. CPAP at 15 cm H(2)O significantly decreased CBF in healthy awake volunteers. This effect appeared to be mediated predominately through the hypocapnic vasoconstriction coinciding with PCO(2) level reduction. The results suggest that CPAP should be used cautiously in patients with unstable cerebral hemodynamics. PMID- 22434362 TI - Studies of iron(II) and iron(III) complexes with fac-N2O, cis-N2O2 and N2O3 donor ligands: models for the 2-His 1-carboxylate motif of non-heme iron monooxygenases. AB - Enzymes in the oxygen-activating class of mononuclear non-heme iron oxygenases (MNOs) contain a highly conserved iron center facially ligated by two histidine nitrogen atoms and one carboxylate oxygen atom that leave one face of the metal center (three binding sites) open for coordination to cofactor, substrate, and/or dioxygen. A comparative family of [Fe(II/III)(N(2)O(n))(L)(4-n))](+/-x), n = 1-3, L = solvent or Cl(-), model complexes, based on a ligand series that supports a facially ligated N,N,O core that is then modified to contain either one or two additional carboxylate chelate arms, has been structurally and spectroscopically characterized. EPR studies demonstrate that the high-spin d(5) Fe(III)g = 4.3 signal becomes more symmetrical as the number of carboxylate ligands decreases across the series Fe(N(2)O(3)), Fe(N(2)O(2)), and Fe(N(2)O(1)), reflecting an increase in the E/D strain of these complexes as the number of exchangeable/solvent coordination sites increases, paralleling the enhanced distribution of electronic structures that contribute to the spectral line shape. The observed systematic variations in the Fe(II)-Fe(III) oxidation-reduction potentials illustrate the fundamental influence of differential carboxylate ligation. The trend towards lower reduction potential for the iron center across the [Fe(III)(N(2)O(1))Cl(3)](-), [Fe(III)(N(2)O(2))Cl(2)](-) and [Fe(III)(N(2)O(3))Cl](-) series is consistent with replacement of the chloride anions with the more strongly donating anionic O-donor carboxylate ligands that are expected to stabilize the oxidized ferric state. This electrochemical trend parallels the observed dioxygen sensitivity of the three ferrous complexes (Fe(II)(N(2)O(1)) < Fe(II)(N(2)O(2)) < Fe(II)(N(2)O(3))), which form MU-oxo bridged ferric species upon exposure to air or oxygen atom donor (OAD) molecules. The observed oxygen sensitivity is particularly interesting and discussed in the context of alpha-ketoglutarate-dependent MNO enzyme mechanisms. PMID- 22434363 TI - Stray dogs of northern Jordan as reservoirs of ticks and tick-borne hemopathogens. AB - Dogs are competent reservoir hosts of several hemopathogens including zoonotic agents and can serve as readily available source of nutrition for many blood feeding arthropods. Three hemopathogens had been detected for the first time in Jordan. The PCR prevalence of Anaplasma phagocytophilum, Hepatozoon canis, and piroplasmid DNA were 39.5%, 28.9%, and 7.9% (n=38) respectively. Sequencing of amplicons of PCR with universal primers targeting the 18S rRNA gene of piroplasmids shows the highest similarity to equine piroplasmids species Theileria equi from two dogs and Babesia caballi from a single dog. Ticks of two genera Rhipicephalus and Haemaphysalis, were detected in this study (n=268). The brown dog tick, Rhipicephalus sanguineus was the most abundant species (95.1%, n=255), followed by Haemaphysalis erinacei (3%, n=8) and Haemaphysalis parva (1.9%, n=5). The two Haemaphysalis species were detected for the first time from dogs in Jordan. Regarding its high prevalence, we expect R. sanguineus being a possible vector of detected pathogens. PMID- 22434364 TI - [The contradictory contexts of interdisciplinarity]. AB - The benefits of interdisciplinary approaches in patient care, research and education are quite obvious and set the trend for more interdisciplinary structures. In order to achieve sustained success, however, there are numerous risks of interdisciplinary collaboration that have to be considered. Interdisciplinarity leads to an increasing degree of specialization and consequently to a greater experience of specialists in highly specific procedures. Nevertheless, this is accompanied by a loss of experience of those who do not perform these procedures anymore. Not least, due to the high specialization, the surgeon's profession is changing from generalist to specialist. Hence, the education of young physicians, students and researchers has to be adapted to this reality. It remains unanswered if these changes contribute to the decline in the number of applicants in surgery. In conclusion, the risks of the contradictory contexts of interdisciplinarity can be counteracted with simple principles of fair and cooperative partnership. PMID- 22434365 TI - [Spleen injuries during colorectal carcinoma surgery. Effect on the early postoperative result]. AB - INTRODUCTION: Unlike gastric carcinomas, the consequences of spleen damage during operative treatment of colorectal carcinoma have barely been investigated, as splenectomy is not performed on these tumor patients to extend the radicality. In this context, the only interest is in the iatrogenic intraoperative spleen lesions, which make a splenectomy necessary or require reconstructive spleen preservation. METHODOLOGY: During the study period from January 2000 to the end of December 2004 the perioperative data of a prospective multicenter observational study of 46,682 Patients whose tumor had been removed with a curative or palliative intent were analyzed with respect to the early postoperative consequences of an iatrogenic spleen lesion. RESULTS: Of these 46,682 Patients, 640 (1.4%) suffered an iatrogenic spleen injury during the operative therapy. The spleens of 127 Patients (0.3%) were removed and the spleens of 513 Patients (1.1%) could be left in situ following repair. In more than 80% of the cases with an iatrogenic spleen injury, the tumor was localized in the left colon and in the rectum. Logistic regression analysis showed that the decisive risk factor for this organ lesion was the mobilization of the left colonic flexure with tumor localization in the left colon and rectum. Following spleen lesion a significantly higher morbidity rate was registered (47.2% following splenectomy, 48.5% following spleen repair) compared to patients without spleen injury (36.5%). Anastomotic leaks requiring surgery were most frequently observed following splenectomy (7.9%) but this was significantly lower following spleen preservation (3.3%, p = 0.003). The total hospital mortality was 3.1%. In patients with splenectomy the hospital mortality was 11.8% and subsequent repair with organ preservation was 4.7% (p < 0.0001). CONCLUSIONS: Iatrogenic spleen lesions during colorectal carcinoma surgery represent a significant risk factor for a poor early postoperative result. In particular, this concerns the high rate of anastomotic leaks and infectious septic complications. This also leads to a higher rate of total morbidity and hospital mortality. By comparison significantly worse postoperative results were found in the group of splenectomised patients compared to the group with organ preservation through repair of the injured spleen. PMID- 22434366 TI - (-)-Epigallocathechin-3-gallate, an AMPK activator, decreases ovariectomy-induced bone loss by suppression of bone resorption. AB - Previously, we showed that AMP-activated protein kinase (AMPK) negatively regulates receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation in vitro. The present study investigated the effect of (-) epigallocathechin-3-gallate (EGCG), an AMPK activator, on ovariectomy (OVX) induced bone loss in mice. Female mice subjected to OVX were administered EGCG for 8 weeks. We measured total-body bone mineral density (BMD) before and after the operation at an interval of 4 weeks. We performed micro-computed tomography (micro-CT) of the tibia and bone histomorphometric examination of the femur. Western blot analysis was additionally performed, to detect levels of the phosphorylated and total forms of AMPK-alpha in calvarial extracts. EGCG prevented OVX-induced body weight gain. The OVX control did not show a significant increase in BMD values at baseline and after treatment, unlike the sham control. EGCG attenuated OVX-induced bone loss. Micro-CT experiments revealed that EGCG induced a significant increase in trabecular bone volume and trabecular number and a decrease in trabecular spacing compared to the OVX control. Histomorphometric analyses further showed that EGCG suppressed osteoclast surface and number. Phosphorylated AMPK expression was significantly elevated in bone following EGCG treatment. Our findings collectively indicate that EGCG decreases OVX-induced bone loss via inhibition of osteoclasts. PMID- 22434367 TI - Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. AB - Development of an in vitro living cell-based model of the intestine that mimics the mechanical, structural, absorptive, transport and pathophysiological properties of the human gut along with its crucial microbial symbionts could accelerate pharmaceutical development, and potentially replace animal testing. Here, we describe a biomimetic 'human gut-on-a-chip' microdevice composed of two microfluidic channels separated by a porous flexible membrane coated with extracellular matrix (ECM) and lined by human intestinal epithelial (Caco-2) cells that mimics the complex structure and physiology of living intestine. The gut microenvironment is recreated by flowing fluid at a low rate (30 MUL h(-1)) producing low shear stress (0.02 dyne cm(-2)) over the microchannels, and by exerting cyclic strain (10%; 0.15 Hz) that mimics physiological peristaltic motions. Under these conditions, a columnar epithelium develops that polarizes rapidly, spontaneously grows into folds that recapitulate the structure of intestinal villi, and forms a high integrity barrier to small molecules that better mimics whole intestine than cells in cultured in static Transwell models. In addition, a normal intestinal microbe (Lactobacillus rhamnosus GG) can be successfully co-cultured for extended periods (>1 week) on the luminal surface of the cultured epithelium without compromising epithelial cell viability, and this actually improves barrier function as previously observed in humans. Thus, this gut-on-a-chip recapitulates multiple dynamic physical and functional features of human intestine that are critical for its function within a controlled microfluidic environment that is amenable for transport, absorption, and toxicity studies, and hence it should have great value for drug testing as well as development of novel intestinal disease models. PMID- 22434368 TI - Clinical pilot study for the automatic segmentation and recognition of abdominal adipose tissue compartments from MRI data. AB - PURPOSE: In the diagnosis and risk assessment of obesity, both the amount and distribution of adipose tissue compartments are critical factors. We present a hybrid method for the quantitative measurement of human body fat compartments. MATERIALS AND METHODS: MRI imaging was performed on a 1.5 T scanner. In a pre processing step, the images were corrected for bias field inhomogeneity. For segmentation and recognition a hybrid algorithm was developed to automatically differentiate between different adipose tissue compartments. The presented algorithm is designed with a combination of shape and intensity-based techniques. To incorporate the presented algorithm into the clinical routine, we developed a graphical user interface. Results from our methods were compared with the known volume of an adipose tissue phantom. To evaluate our method, we analyzed 40 clinical MRI scans of the abdominal region. RESULTS: Relatively low segmentation errors were found for subcutaneous adipose tissue (3.56 %) and visceral adipose tissue (0.29 %) in phantom studies. The clinical results indicated high correlations between the distribution of adipose tissue compartments and obesity. CONCLUSION: We present an approach that rapidly identifies and quantifies adipose tissue depots of interest. With this method examination and analysis can be performed in a clinically feasible timeframe. PMID- 22434369 TI - [Pain management in pathologic sacrum fracture with CT guided balloon sacral vertebroplasty]. PMID- 22434370 TI - [Adult type rhabdomyoma of the nasopharynx]. PMID- 22434371 TI - [S3 guideline - diagnosis and treatment of gastric carcinoma: relevance for radiologic imaging]. AB - The new German S3 guideline regarding stomach cancer includes a variety of innovations with respect to the diagnosis and treatment of adenocarcinoma of the stomach and the esophagogastric junction. The guideline has been strongly supported by the "oncology" guidelines program consisting of the "Deutsche Krebshilfe" and the German Cancer Society and the AWMF (Dr. M. Follmann). This guideline contains evidence-based treatment recommendations and quality indicators for guideline implementation and evaluation in order to improve broad medical care and to facilitate development and subsequent adjustment. The purpose of this article is to introduce the innovations with regard to radiological diagnosis and to discuss the latest literature on the subject. PMID- 22434372 TI - [Phantom studies using a high-resolution CT for ex-vivo imaging of degradable magnesium implants and simulated peri-implant bone formation in rabbit tibiae]. AB - PURPOSE: Evaluation of the suitability of the high-resolution CT XtremeCT for ex vivo imaging of degradable magnesium implants with simulated peri-implant bone formation in rabbit tibiae and development of a method for calibrating the mass concentration of a magnesium alloy in an implant volume. MATERIALS AND METHODS: Using specially designed phantoms, degradable magnesium implants of the alloys LAE442, ZEK100, AX30 and MgCa 0.8 %, without coating and with peri-implant bone formation simulated by a coating, as well as rabbit tibiae were scanned. CT numbers and the contrast-to-noise-ratio (CNR) of the studied materials were determined. The visual distinction between implant and coating was evaluated. To calibrate the implant density, exemplary LAE442 pins with different mass concentrations were scanned using a specially constructed phantom. Subsequently, CT numbers corresponding to the appropriate mass concentration were determined. RESULTS: The implants, coating and substantia corticalis showed a similar density. Visual distinction between coating and implant was strongly dependent on the respective magnesium alloy and chosen scan parameter. A CNR of at least 0.2 was required for a distinction between implant and coating. For the mass concentration, a high CT number linearity (R2=0.99) throughout the measuring range (1811-1273 mg/cm3 LAE442) was found. CONCLUSION: As expected, the XtremeCT is primarily suitable for the imaging of bone tissue and implants. Good visual distinction of peri-implant bone formation on magnesium implants in an ex vivo phantom model ranges from possible to difficult depending on the bone density and alloy composition. PMID- 22434373 TI - Stereoselective synthesis and hormonal activity of novel dafachronic acids and naturally occurring steroids isolated from corals. AB - A stereoselective synthesis of (25S)-Delta(1)-, (25S)-Delta(1,4)-, (25S) Delta(1,7)-, (25S)-Delta(8(14))-, (25S)-Delta(4,6,8(14))-dafachronic acid, methyl (25S)-Delta(1,4)-dafachronate and (25S)-5alpha-hydroxy-3,6-dioxocholest-7-en-26 oic acid is described. (25S)-Delta(1,4)-Dafachronic acid and its methyl ester are natural products isolated from corals and have been obtained by synthesis for the first time. (25S)-5alpha-Hydroxy-3,6-dioxocholest-7-en-26-oic acid represents a promising synthetic precursor for cytotoxic marine steroids. PMID- 22434374 TI - A benzoboroxole-functionalized monolithic column for the selective enrichment and separation of cis-diol containing biomolecules. AB - A benzoboroxole-functionalized monolithic column was synthesized, which exhibited the best specificity and affinity towards cis-diol containing biomolecules as compared with the boronate affinity monolithic columns reported as well as significant secondary separation capability under acidic conditions. PMID- 22434375 TI - Amplification activation loop between caspase-8 and -9 dominates artemisinin induced apoptosis of ASTC-a-1 cells. AB - Although caspases have been demonstrated to be involved in artemisinin (ARTE) induced apoptosis, their exact functions are not well understood. The aim of this report is to explore the roles of caspase-8, -9 and -3 during ARTE-induced apoptosis in human lung adenocarcinoma (ASTC-a-1) cells. ARTE treatment induces a rapid generation of reactive oxygen species (ROS), and ROS-dependent apoptosis as well as the activation of caspase-8, -9 and -3 via time- and dose-dependent fashion. Of upmost importance, inhibition of caspase-8 or -9, but not caspase-3, almost completely blocks the ARTE-induced not only activation of the caspase-8, 9 and -3 but also apoptosis. In addition, the apoptotic process triggered by ARTE does not involve the Bid cleavage, tBid translocation, significant loss of mitochondrial membrane potential and cytochrome c release from mitochondria. Moreover, silencing Bax/Bak does not prevent the ATRE-induced cell death as well as the activation of caspase-8, -9 and -3. Collectively, our data firstly demonstrate that ARTE triggers a ROS-mediated positive feedback amplification activation loop between caspase-8 and -9 independent of mitochondria, which dominantly mediated the ARTE-induced apoptosis via a caspase-3-independent apoptotic pathway in ASTC-a-1 cells. Our findings imply a potential to develop new derivatives from artemisinin to effectively initiate the amplification activation loop of caspases. PMID- 22434376 TI - miR-1228 prevents cellular apoptosis through targeting of MOAP1 protein. AB - Apoptosis is a critical cellular process that balances the effects of cell proliferation and cell death. MicroRNAs play important roles in cell growth, differentiation, and apoptosis. In this study, we observed a reduction of miR 1228 expression in apoptotic cells. Enforced miR-1228 expression can reduce MOAP1 expression and delay the progression of stress-induced cell apoptosis. Rescue experiment demonstrated that miR-1228 inhibition of cellular apoptosis is significantly attenuated by repressing MOAP1 expression, suggesting the direct interaction between miR-1228 and MOAP1 protein. Taken together, this study provides evidences that miR-1228 plays an inhibitory role in stress-induced cellular apoptosis. miR-1228 may become a critical therapeutic target for apoptosis relevant diseases in the future. PMID- 22434377 TI - Five really easy steps to build a homemade low-cost simulator. AB - AIM: The aim of this study was to evaluate how simple it is to build a homemade low-cost simulator using a simple 5-step scheme. METHODS: A scheme explaining how to build an endoscopic surgery simulator in 5 easy steps was presented to 26 surgeons. The simulator required a pair of scissors and easy-to-find materials. Its total cost was less than ?35. The participants assessed the simulator using common endoscopic training toys or ex vivo tissue and completed an anonymous query comparing it with other commercial simulators that they had experienced before. RESULTS: In all, 84.6% found the simulator really easy to build. Every participant felt that he or she could do the same simulator themselves. Comparing with other commercial available box simulators, the majority of participants found the homemade simulator easier to (a) mount and dismount, (b) transport, (c) clean, and (d) use when practicing alone. CONCLUSIONS: Anyone can build its own simulator for a small amount of money. PMID- 22434378 TI - Association between clinical and work-related interventions and return-to-work for patients with musculoskeletal or mental disorders. AB - OBJECTIVE: The aim of this study was to explore what characterizes patients receiving clinical interventions vs combined clinical and work-related interventions in a cohort of sick-listed subjects with musculoskeletal or mental disorders. Factors associated with return-to-work were also analysed. DESIGN: A prospective cohort study. METHODS: A total of 699 newly sick-listed patients responded to a questionnaire on sociodemographics, measures of health, functioning, work ability, self-efficacy, social support, work conditions, and expectations. The 3-month follow-up questionnaire included patients' self reported measures of return-to-work, work ability and type of interventions. The most frequent International Classification of Diseases-10 diagnoses for patients' musculoskeletal disorders were dorsopathies (M50-54) and soft tissue disorders (M70-79), and for patients with mental disorders, depression (F32-39) and stress reactions (F43). RESULTS: Patients with mental disorders who received combined interventions returned to work to a higher degree than those who received only clinical intervention. The prevalence of work-related interventions was higher for those who were younger and more highly educated. For patients with musculoskeletal disorders better health, work ability and positive expectations of return-to-work were associated with return-to-work. However, combined interventions did not affect return-to-work in this group. CONCLUSION: Receiving combined interventions increased the probability of return-to-work for patients with mental disorders, but not for patients with musculoskeletal disorders. Better health, positive expectations of return-to-work and better work ability were associated with return-to-work for patients with musculoskeletal disorders. PMID- 22434379 TI - Germ cell tumour compressing the right atrium. PMID- 22434380 TI - Zinc inhibits H(2)O(2)-induced MC3T3-E1 cells apoptosis via MAPK and PI3K/AKT pathways. AB - Zinc has been shown to increase bone mass and promote bone cell proliferation and differentiation. We, therefore, hypothesized that zinc might be cytoprotective for bone cells during oxidative stress. The cells were divided into H(2)O(2), zinc and zinc+H(2)O(2) groups. In the present study, zinc was found to inhibit H(2)O(2)-induced apoptosis in MC3T3-E1 cells, as shown by analysis of Annexin V/PI double staining. Western blot data showed that in zinc+H(2)O(2)-treated cells, zinc decreased the levels of AIF, Bax and active caspase-9 and -3, which are pro-apoptotic factors. And zinc inhibited release of cytochrome c from mitochondria to cytosol in zinc+H(2)O(2)-treated cells. Further investigation shows that protection is via activation of PI3K/Akt/mTor and MAPK /ERK pathways and inhibition of MAPK/P38 and MAPK/JNK pathways. Protecting osteoblast cells from oxidative damage presents a potential application in the treatment of osteoporosis. PMID- 22434381 TI - Chromium picolinate modulates serotonergic properties and carbohydrate metabolism in a rat model of diabetes. AB - Chromium picolinate (CrPic) has shown both antidepressant and antidiabetic properties. In this study, the effects of CrPic on serotonergic properties and carbohydrate metabolism in diabetic rats were evaluated. Sixty male Sprague Dawley rats were divided into four groups. (1) The control group received only standard diet (8 % fat). (2) The CrPic group was fed standard diet and CrPic (80 MUg CrPic per kilogram body mass (b.m.)/day), for 10 weeks (microgram/kilogram b.m./day). (3) The HFD/STZ group fed a high-fat diet (HFD, 40 % fat) for 2 weeks and then received streptozotocin (STZ, 40 mg/kg, i.p.) (i.v.) HFD-STZ-CrPic group treated as the previous group and then were administered CrPic. CrPic administration to HFD/STZ-treated rats increased brain chromium levels and improved all measurements of carbohydrate metabolism and serotonergic properties (P<0.001). CrPic also significantly increased levels of insulin, tryptophan, and serotonin (P<0.001) in the serum and brain, and decreased cortisol levels in the serum (P<0.01). Except chromium levels, no significant effect of CrPic supplementation was detected on the overall measured parameters in the control group. CrPic administration was well tolerated without any adverse events. The results support the use of CrPic supplementation which improves serotonergic properties of brain in diabetes. PMID- 22434382 TI - Arsenic accumulation and speciation in the submerged macrophyte Ceratophyllum demersum L. AB - INTRODUCTION: Ceratophyllum demersum L. is a widespread submerged macrophyte in aquatic environments. METHODS: Simulation experiments were conducted in the laboratory to investigate arsenic (As) accumulation, speciation, and efflux of C. demersum exposed to arsenate and arsenite solutions. RESULTS: Plant shoots showed a significant accumulation of As with a maximum of 862 and 963 MUg As g(-1) dry weight after 4 days of exposure to 10 MUM arsenate and arsenite, respectively. Regardless of whether arsenate or arsenite was supplied to the plants, arsenite was the predominant species in plant shoots. Furthermore, a dramatically higher influx rate of arsenate compared with arsenite was observed in C. demersum exposed to As solutions without the addition of phosphate (P). Arsenate uptake was considerably inhibited by P in this study, suggesting that arsenate is taken up by C. demersum via the phosphate transporters. However, arsenite uptake was unaffected by P and markedly reduced in the presence of glycerol and antimonite (Sb), indicating arsenite shares the aquaporin transport pathway. In addition, C. demersum rapidly reduces arsenate to arsenite in the shoot of the plant and extrudes most of them (>60 %) to the external solutions. The efflux of arsenite was much higher than that of arsenate; the former is supposed to be both active and passive processes, and the latter through passive leakage. CONCLUSION: C. demersum is a strong As accumulator and an interesting model plant to study As uptake and metabolism due to the lack of a root-to-shoot translocation barrier. PMID- 22434383 TI - Identification of EBP50 as a specific biomarker for carcinogens via the analysis of mouse lymphoma cellular proteome. AB - To identify specific biomarkers generated upon exposure of L5178Y mouse lymphoma cells to carcinogens, 2-DE and MALDI-TOF MS analysis were conducted using the cellular proteome of L5178Y cells that had been treated with the known carcinogens, 1,2-dibromoethane and O-nitrotoluene and the noncarcinogens, emodin and D-mannitol. Eight protein spots that showed a greater than 1.5-fold increase or decrease in intensity following carcinogen treatment compared with treatment with noncarcinogens were selected. Of the identified proteins, we focused on the candidate biomarker ERM-binding phosphoprotein 50 (EBP50), the expression of which was specifically increased in response to treatment with the carcinogens. The expression level of EBP50 was determined by western analysis using polyclonal rabbit anti-EBP50 antibody. Further, the expression level of EBP50 was increased in cells treated with seven additional carcinogens, verifying that EBP50 could serve as a specific biomarker for carcinogens. PMID- 22434384 TI - Enhancing life after cancer in diverse communities. AB - BACKGROUND: Although large numbers of cancer survivors exist in every community, including minority communities, there is a significant gap in knowledge about best practices for these patients. METHODS: The Community Networks Program, funded by the National Cancer Institute Center to Reduce Cancer Health Disparities, has developed and tested unique services for these communities. These programs have used community-based participatory research techniques under a framework of diffusion of innovation and communications theory. RESULTS: This article describes some specifically tailored interventions that may be useful to a wide range of providers working with the underserved. CONCLUSIONS: Enhancing life after cancer can be achieved in underserved communities by supplementing local resources. PMID- 22434385 TI - Identification and synthesis of a male-produced pheromone for the neotropical root weevil Diaprepes abbreviatus. AB - An unsaturated hydroxy-ester pheromone was isolated from the headspace and feces of male Diaprepes abbreviatus, identified, and synthesized. The pheromone, methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate, was discovered by gas chromatography-coupled electroantennogram detection (GC-EAD), and identified by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). The synthesis yielded an 86:14 mixture of methyl (E)-3-(2 hydroxyethyl)-4-methyl-2-pentenoate (active) and methyl (Z)-3-(2-hydroxyethyl)-4 methyl-2-pentenoate (inactive), along with a lactone breakdown product. The activity of the synthetic E-isomer was confirmed by GC-EAD, GC-MS, NMR, and bioassays. No antennal response was observed to the Z-isomer or the lactone. In a two-choice olfactometer bioassay, female D. abbreviatus moved upwind towards the synthetic pheromone or natural pheromone more often compared with clean air. Males showed no clear preference for the synthetic pheromone. This pheromone, alone or in combination with plant volatiles, may play a role in the location of males by female D. abbreviatus. PMID- 22434386 TI - Fully Lambda-doublet resolved state-to-state differential cross-sections for the inelastic scattering of NO(X) with Ar. AB - Fully Lambda-doublet resolved state-to-state differential cross-sections (DCSs) for the collisions of the open-shell NO(X, (2)Pi(1/2), nu = 0, j = 0.5) molecule with Ar at a collision energy of 530 cm(-1) are presented. Initial state selection of NO(X, (2)Pi(1/2), j = 0.5, f) was performed using a hexapole so that the (low field seeking) parity of epsilon = -1, corresponding to the f component of the Lambda-doublet, could be selected uniquely. Although the Lambda-doublet levels lie very close in energy to one another and differ only in their relative parities, they exhibit strikingly different DCSs. Both spin-orbit conserving and spin-orbit changing collisions have been studied, and the previously unobserved structures in the fully quantum state-to-state resolved DCSs are shown to depend sensitively on the change in parity of the wavefunction of the NO molecule on collision. In all cases, the experimental data are shown to be in excellent agreement with rigorous quantum mechanical scattering calculations. PMID- 22434387 TI - Parahydrogen induced polarization in face of keto-enol tautomerism: proof of concept with hyperpolarized ethanol. AB - Hyperpolarization (HP) techniques are increasingly important in magnetic resonance imaging (MRI) and spectroscopy (MRS). HP methods have the potential to overcome the fundamentally low sensitivity of magnetic resonance (MR). A breakthrough of HP-MR in life sciences and medical applications is still limited by the small number of accessible, physiologically relevant substrates. Our study presents a new approach to extend PHIP to substrates that primarily cannot be hyperpolarized due to a steady intramolecular re-arrangement, the so-called keto enol tautomerism. To overcome this obstacle we exploited the fact that instead of the instable enol form the corresponding stable ester can be used as a precursor molecule. This strategy now enables the hydrogenation which is required to apply the standard PHIP procedure. As the final step a hydrolysis is necessary to release the hyperpolarized target molecule. Using this new approach ethanol was successfully hyperpolarized for the first time. It may therefore be assumed that the outlined multi-step procedure can be used for other keto-enol tautomerized substances thereby opening the application of PHIP to a multitude of molecules relevant to analyzing metabolic pathways. PMID- 22434388 TI - Regulation of TGF-beta storage and activation in the human idiopathic pulmonary fibrosis lung. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause. The pathogenesis of the disease is characterized by fibroblast accumulation and excessive transforming growth factor-beta (TGF-beta) activation. Although TGF beta activation is a complex process involving various protein interactions, little is known of the specific routes of TGF-beta storage and activation in human lung. Here, we have systematically analyzed the expression of specific proteins involved in extracellular matrix targeting and activation of TGF-beta. Latent TGF-beta-binding protein (LTBP)-1 was found to be significantly upregulated in IPF patient lungs. LTBP-1 expression was especially high in the fibroblastic foci, in which P-Smad2 immunoreactivity, indicative of TGF-beta signaling activity, was less prominent. In cultured primary lung fibroblasts and epithelial cells, short-interfering-RNA-mediated downregulation of LTBP-1 resulted in either increased or decreased TGF-beta signaling activity, respectively, suggesting that LTBP-1-mediated TGF-beta activation is dependent on the cellular context in the lung. Furthermore, LTBP-1 was shown to colocalize with fibronectin, fibrillin-1 and fibrillin-2 proteins in the IPF lung. Fibrillin 2, a developmental gene expressed only in blood vessels in normal adult lung, was found specifically upregulated in IPF fibroblastic foci. The TGF-beta-activating integrin beta8 subunit was expressed at low levels in both control and IPF lungs. Alterations in extracellular matrix composition, such as high levels of the TGF beta storage protein LTBP-1 and the re-appearance of fibrillin-2, probably modulate TGF-beta availability and activation in different pulmonary compartments in the fibrotic lung. PMID- 22434389 TI - The use of medication against attention deficit hyperactivity disorder in Denmark: a drug use study from a national perspective. AB - PURPOSE: The purpose of the study was to characterize the utilization of medication against attention deficit hyperactivity disorder (ADHD) in Denmark between 1995 and 2011 from a national perspective, by using population-based prescription data. METHODS: National data on drug use in Denmark between 1 January 1995 and 30 September 2011 were extracted from the Registry of Medicinal Product Statistics (RMPS). Drug utilization was characterized using descriptive statistics. RESULTS: A total of 1,085,090 prescriptions issued to 54,020 persons were identified. The incidence rate was stable in the last 3 years of the study period, and a slightly decreasing incidence rate and a stabilizing prevalence were observed towards the end of this period. The therapeutic intensity was 6.7 defined daily dose/person/day, with large regional differences that ranged from 64 to 145 % of the national average. Methylphenidate accounted for 92.6 % of DDDs used. The general practitioner (GP) rarely initiated treatment, although treatment initiation based on the GP's advice increased with older age of the patient. Maintenance treatment was found to be distributed roughly equally between prescriber types. For methylphenidate, 1 % of users accounted for 6.1 % of the drug volume and 50 % of users accounted for 84.4 %. The data therefore do not suggest a high proportion of heavy users. CONCLUSION: The findings of this analysis are mostly reassuring, with the data indicating a seemingly stagnant incidence and prevalence rate and lacking evidence of heavy users. However, the prescriber profile for incident users and the large regional variances raise concerns. It is therefore vital that the use of ADHD drugs is closely monitored. PMID- 22434390 TI - Hydrogen-bonding modulation of excited-state properties of flavins in a model of aqueous confined environment. AB - The singlet and triplet excited states properties of lumiflavin (LF), riboflavin (RF), flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) in reversed micelles (RM) of sodium docusate (AOT) in n-hexane solutions were evaluated as a function of the water to surfactant molar ratio, w(0) = [H(2)O]/[AOT], by both steady-state and time-resolved absorption and fluorescence spectroscopy. The results indicated that hydrogen-bonding interactions between the isoalloxazine ring of the flavins with the water molecules of the micellar interior play a crucial role on the modulation of the excited state properties of the flavins. Fluorescence dynamic experiments in the RM, allowed the calculation of similar values for both the internal rotational time of the flavins (theta(i)) and the hydrogen-bonding relaxation time (tau(HB)), e.g.~ 7 and 1.5 ns at w(0) = 1 and 20, respectively. In turn, the triplet state lifetimes of the flavins were also enlarged in RM solutions at low w(0), without modifications of their quantum yields. A hydrogen bonding relaxation model is proposed to explain the singlet excited state properties of the flavins, while the changes of the triplet state decays of the flavins were related with the global composition and strength of the hydrogen bonding network inside of the RM. PMID- 22434391 TI - Effectiveness of multidisciplinary early rehabilitation in reducing behaviour related risk factors. AB - OBJECTIVE: To evaluate the effect of a 4-week primary prevention programme on health-risk behaviours amongst employees at increased risk of work incapacity. METHODS: Based on survey data and health records from 53,416 public sector employees in Finland, we identified 872 employees who participated in early rehabilitation after the baseline survey. We selected 2,440 propensity-score matched controls for these rehabilitants. Changes in the prevalence of physical inactivity, obesity, heavy drinking, and smoking, as well as in the intensity of leisure-time physical activity, weight, and alcohol consumption after the intervention were examined between the baseline and two subsequent surveys representing short-term (mean follow-up 1.7 years) and long-term (mean 5.8 years) follow-ups. RESULTS: There were no statistically significant differences between the rehabilitants and controls in terms of changes in weight, alcohol consumption, intensity of leisure-time physical activity, or prevalence of obesity, heavy drinking and physical inactivity during short-term or long-term follow-ups. During short-term follow-up, a higher rate of smoking cessation was observed for rehabilitants than controls (31.7% vs. 20.2%, p = 0.037). CONCLUSION: Vocationally oriented multidisciplinary early rehabilitation had little effect on health risk behaviours. PMID- 22434394 TI - Mathematical modelling and numerical simulations of actin dynamics in the eukaryotic cell. AB - The aim of this article is to study cell deformation and cell movement by considering both the mechanical and biochemical properties of the cortical network of actin filaments and its concentration. Actin is a polymer that can exist either in filamentous form (F-actin) or in monometric form (G-actin) (Chen et al. in Trends Biochem Sci 25:19-23, 2000) and the filamentous form is arranged in a paired helix of two protofilaments (Ananthakrishnan et al. in Recent Res Devel Biophys 5:39-69, 2006). By assuming that cell deformations are a result of the cortical actin dynamics in the cell cytoskeleton, we consider a continuum mathematical model that couples the mechanics of the network of actin filaments with its bio-chemical dynamics. Numerical treatment of the model is carried out using the moving grid finite element method (Madzvamuse et al. in J Comput Phys 190:478-500, 2003). Furthermore, by assuming slow deformations of the cell, we use linear stability theory to validate the numerical simulation results close to bifurcation points. Far from bifurcation points, we show that the mathematical model is able to describe the complex cell deformations typically observed in experimental results. Our numerical results illustrate cell expansion, cell contraction, cell translation and cell relocation as well as cell protrusions. In all these results, the contractile tonicity formed by the association of actin filaments to the myosin II motor proteins is identified as a key bifurcation parameter. PMID- 22434395 TI - What is anticipation and what is not? Comment on Nauts, Metzmacher, Verwijmeren, Rommeswinkel, and Karremans (2011). PMID- 22434396 TI - Client retention and health among sex workers in Nairobi, Kenya. AB - It is still a small body of research that directly addresses female sex workers' relationships with their regular commercial male partners. I used ethnographic data from Nairobi, Kenya to interrogate motivations and strategies for recruiting and retaining regular male clients among female sex workers (FSWs). Regular commercial male partners, popularly called customer care, wera or wesh by Nairobi's FSWs, played diverse roles in their lives. Client retention enabled sex workers to manage the risk of reduced marriage prospects, guaranteed them steady work, livelihoods, and incomes, and prevented their victimization and harassment. To retain clients, sex workers obliged them a great deal, pretended they had quit prostitution, and sometimes resorted to magical practices. However, these strategies were also accompanied by risks that reinforced the vulnerability of sex workers. Lack of critical attention to sex workers' practices for managing perceived risks in their particular type of work may hamper current programmatic efforts to make their job safer. PMID- 22434397 TI - Sex differences in the use of delayed semantic context when listening to disrupted speech. AB - Female as opposed to male listeners were better able to use a delayed informative cue at the end of a long sentence to report an earlier word which was disrupted by noise. Informative (semantically related) or uninformative (semantically unrelated) word cues were presented 2, 6, or 10 words after a target word whose initial phoneme had been replaced with noise. A total of 84 young adults (45 males) listened to each sentence and then repeated it after its offset. The semantic benefit effect (SBE) was the difference in the accuracy of report of the disrupted target word during informative vs. uninformative sentences. Women had significantly higher SBEs than men even though there were no significant sex differences in terms of number of non-target words reported, the effect of distance between the disrupted target word and the informative cue, or kinds of errors generated. We suggest that the superior ability of women to use delayed semantic information to decode an earlier ambiguous speech signal may be linked to women's tendency to engage the hemispheres more bilaterally than men during word processing. Since the maintenance of semantic context under ambiguous conditions demands more right than left hemispheric resources, this may give women an advantage. PMID- 22434398 TI - Effects of cations and anions of ionic liquids on the production of 5 hydroxymethylfurfural from fructose. AB - Ionic liquids (ILs) with different cations and anions were used to study the effects on 5-hydroxymethylfurfural (HMF) preparation. It was found that both aggregations of cations and hydrogen bonds of anions with fructose played important roles. Molecular dynamics simulations were also performed to explain the experimental results. PMID- 22434399 TI - Respiratory failure, lung infiltrates, and hemoptysis in a woman with chronic isopropyl alcohol inhalation. PMID- 22434400 TI - Prospective analysis of association between use of statins and melanoma risk in the Women's Health Initiative. AB - BACKGROUND: Melanoma is the most lethal form of skin cancer, with an estimated 68,130 new cases and 8700 deaths in the United States in 2010. The increasing incidence and high death rate associated with metastatic disease support the need to focus on prevention. The authors used data from the Women's Health Initiative (WHI) to assess whether 3-hydroxy-3 methylglutaryl coenzyme A inhibitors (statins) are associated with a decreased risk of melanoma. METHODS: The study population consisted of 119,726 postmenopausal white women, in which 1099 cases of malignant melanoma were identified over an average (+/- standard deviation) of 11.6 +/- 3.2 years. All diagnoses were confirmed by medical record review and pathology reports. Information on statin use was collected at baseline and during follow-up. Self-administered and interview-administered questionnaires were used to collect information on other risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses investigated the association of any statin use, type, potency, lipophilic status, and duration of use with melanoma. RESULTS: Statins were used by 8824 women (7.4%) at baseline. The annualized rate of melanoma was 0.09% among statin users and 0.09% among nonusers The multivariable adjusted HR for statin users compared with nonusers was 1.14 (95% CI, 0.91-1.43). There were no significant differences in risk based on statin type, potency, category, duration, or in time-dependent models. CONCLUSIONS: There was no significant association between statin use and melanoma risk among postmenopausal women in the WHI. PMID- 22434401 TI - Retrospective analysis of perioperative ketorolac and postoperative bleeding in reduction mammoplasty. AB - PURPOSE: We conducted a retrospective review following concerns involving a suspected increase in the requirement for surgical re-exploration for hematoma evacuation when ketorolac was administered perioperatively in patients undergoing reduction mammoplasty. METHODS: Following ethics approval, a retrospective chart review was conducted of all patients who underwent reduction mammoplasty at our two institutions from the time ketorolac became available in 2004 until surgeons requested its use discontinued in 2007. The data we collected included patient demographics, ketorolac administration, requirement for surgical re-exploration, documented hematoma formation not requiring surgical re-exploration, and excessive bleeding in the perioperative period. Three hundred and seventy-nine patient records were reviewed; 127 of the patients received a single intravenous dose of ketorolac (15 or 30 mg), and 252 of the patients did not receive ketorolac. RESULTS: Patients who received ketorolac were at an increased risk of requiring surgical re-exploration for hematoma evacuation (relative risk [RR] = 3.6; 95% confidence interval [CI], 1.4 to 9.6) and hematoma formation not requiring re-exploration (RR = 2.2; 95% CI, 1.3 to 3.6). CONCLUSIONS: A single perioperative intravenous dose of ketorolac was associated with a greater than three-fold increase in the likelihood of requirement for surgical hematoma evacuation. Our data suggest that it may be prudent to consider carefully whether the potential risks associated with the use of ketorolac outweigh the potential benefits of using ketorolac in patients undergoing reduction mammoplasty. PMID- 22434402 TI - Visual discrimination and object categorization in the cichlid Pseudotropheus sp. AB - Object categorization is an important function of the visual system, quickly providing an animal with relevant information about its surrounding and current situation, as for example during predator detection. While the ability to categorize objects has already been observed in several vertebrate and even invertebrate species, no attempt has previously been made to evaluate this function in fish, the most species-rich vertebrate group. This study assessed form discrimination abilities and object categorization skills in the African cichlid Pseudotropheus sp. Fish could discriminate between a variety of two dimensional geometrical shapes, forms and sizes and learned to distinguish between two categories, "fish" versus "snail". Performance remained undisturbed by extensive modifications to the stimuli, as long as key features were maintained. Results indicate that fish not only memorized the features of the positive stimulus (categorized the positive stimulus), but also categorized the negative stimulus. During transfer trials involving a previously unknown object, fish were able to discriminate between both the negative and the positive stimulus and the unknown stimulus and responded accordingly. PMID- 22434403 TI - Delaying gratification for food and tokens in capuchin monkeys (Cebus apella) and chimpanzees (Pan troglodytes): when quantity is salient, symbolic stimuli do not improve performance. AB - Capuchin monkeys have been tested for the capacity to delay gratification for accumulating rewards in recent studies and have exhibited variable results. Meanwhile, chimpanzees have consistently excelled at this task. However, neither species have ever been tested at accumulating symbolic tokens instead of food items, even though previous reports indicate that tokens sometimes facilitate performance in other self-control tasks. Thus, in the present study, we tested capuchin monkeys and chimpanzees for their capacity to delay gratification in a delay maintenance task, in which an experimenter presented items, one at a time, to within reach of an animal for as long as the animal refrained from taking them. In Experiment 1, we assessed how long capuchin monkeys could accumulate items in the delay maintenance task when items were food rewards or tokens exchangeable for food rewards. Monkeys accumulated more food rewards than they did tokens. In Experiment 2, we tested capuchin monkeys and chimpanzees in a similar accumulation test. Whereas capuchins again accumulated more food than tokens, all chimpanzees but one showed no difference in performance in the two conditions. These findings provide additional evidence that chimpanzees exhibit greater self-control capacity in this task than do capuchin monkeys and indicate that symbolic stimuli fail to facilitate delay maintenance when they do not abstract away from the quantitative dimension of the task. This is consistent with previous findings on the effects of symbols on self-control and illuminates what makes accumulation a particularly challenging task. PMID- 22434404 TI - Photosensitization of imidazole derivative by ZnO nanoparticle. AB - A sensitive imidazole based fluorescent sensor like 4, 5-diphenyl-2(E)-styryl-1H imidazole, for ZnO has been designed and synthesized via simple steps. The absorption, fluorescence, SEM, EDX and IR studies indicate that imidazole derivative is bound on the surface of ZnO semiconductor. Based on photo-induced electron transfer (PET) mechanism, fluorescent enhancement has been explained and apparent binding constant has been calculated. Ligand adsorption on ZnO nanoparticle lowers of the HOMO and LUMO energy levels of imidazole derivative and the chemical affinity between the nitrogen atom of the imidazole and zinc ion on the surface of the nano oxide may be a reason for strong adsorption of the ligand on nanoparticle. The electron injection from photo excited imidazole derivative to the ZnO conduction band (S(*)->S(+) + e (CB) (-) ) accounts for the enhanced fluorescence. PMID- 22434405 TI - Fluorescent function-spacer-lipid construct labelling allows for real-time in vivo imaging of cell migration and behaviour in zebrafish (Danio rerio). AB - Real-time in vivo imaging of cell migration and behavior has advanced our understanding of physiological processes in situ, especially in the field of immunology. We carried out the transplantation of a mixed population of blood cells from adult zebrafish (Danio rerio) to 2 day old embryos. The blood cells were treated ex vivo with Function-Spacer-Lipid constructs (FSL) incorporating either fluorescein or Atto488 fluorophores (FSL-FLRO4-I or -II). Excellent labeling efficiency was demonstrated by epifluorescence microscopy and FACScan analysis. Real-time video imaging of the recipient fish showed that the functionality of these cells was retained and not affected by the labeling. The usefulness of FSL-FLRO4-I as a contrast agent in microangiography was explored. Overall, we found both FSL-FLRO4-I and-II promising labeling dyes for real-time in vivo imaging in zebrafish. PMID- 22434406 TI - Genetically based differentiation in growth of multiple non-native plant species along a steep environmental gradient. AB - A non-native plant species spreading along an environmental gradient may need to adjust its growth to the prevailing conditions that it encounters by a combination of phenotypic plasticity and genetic adaptation. There have been several studies of how non-native species respond to changing environmental conditions along latitudinal gradients, but much less is known about elevational gradients. We conducted a climate chamber experiment to investigate plastic and genetically based growth responses of 13 herbaceous non-native plants along an elevational gradient from 100 to 2,000 m a.s.l. in Tenerife. Conditions in the field ranged from high anthropogenic disturbance but generally favourable temperatures for plant growth in the lower half of the gradient, to low disturbance but much cooler conditions in the upper half. We collected seed from low, mid and high elevations and grew them in climate chambers under the characteristic temperatures at these three elevations. Growth of all species was reduced under lower temperatures along both halves of the gradient. We found consistent genetically based differences in growth over the upper elevational gradient, with plants from high-elevation sites growing more slowly than those from mid-elevation ones, while the pattern in the lower part of the gradient was more mixed. Our data suggest that many non-native plants might respond to climate along elevational gradients by genetically based changes in key traits, especially at higher elevations where low temperatures probably impose a stronger selection pressure. At lower elevations, where anthropogenic influences are greater, higher gene flow and frequent disturbance might favour genotypes with broad ecological amplitudes. Thus the importance of evolutionary processes for invasion success is likely to be context-dependent. PMID- 22434407 TI - Intraclutch variation in avian eggshell pigmentation: the anaemia hypothesis. AB - Many passerine species lay eggs that are speckled with dark protoporphyrin pigmentation. Because protoporphyrin is mainly derived from the blood, we here formulate and test a new hypothesis that links an increase in anaemia along the laying sequence to within-clutch variation in egg pigmentation. More intense pigmentation is expected if pigments accumulate during enhanced red blood cell production in response to anaemia. Reduced pigmentation is expected if pigments are derived from the degradation of red blood cells that circulate in smaller numbers due to blood loss. To test this hypothesis, we manipulated anaemia in great tit (Parus major) females by infesting the nests with hen fleas (Ceratophyllus gallinae) prior to egg laying. Polychromatophil (i.e., immature red blood cells) percentage, as a measure of blood cell production, was positively correlated with parasite load confirming that female great tits experienced stronger anaemia when infested with haematophagous parasites during egg laying. We found a positive relationship between spot darkness and laying order that weakened under high parasite load. This result suggests that anaemia in females due to blood-sucking parasites led to diminished protoporphyrin from disintegrated red blood cells and hence a decreased deposition of protoporphyrin. However, the overall increase in pigment darkness along the laying sequence suggests that pigments also accumulate by enhanced red blood cell production caused by anaemia due to egg production itself. PMID- 22434408 TI - A computed tomography (CT) wish list, from a medical physicist's perspective. PMID- 22434409 TI - Poor letter "H". PMID- 22434410 TI - Attenuating effect of Fufang Xueshuantong Capsule on kidney function in diabetic nephropathy model. AB - Fufang Xueshuantong Capsule (FXST) can reduce urinary albumin and whole blood viscosity in early diabetic nephropathy (DN) patients. This research aimed to investigate the effect of FXST on kidney function in DN rats and to identify the underlying molecular mechanisms. We performed Illumina RatRef-12 Expression BeadChip gene array analysis, and found that 3-month treatment with FXST significantly decreased 24-h urinary albumin, serum creatinine and blood urea nitrogen, and increased urinary creatinine in DN model rats. Kidney hypertrophy and glomerular mesangial matrix expansion were also ameliorated. Kidneys from the high-dose FXST group had 67 genes with significantly changed expression (34 increased, 33 decreased). DAVID analysis showed that the fold enrichment score of "collagen type 1" was the highest in all GO functional categories. DAVID function annotation cluster analysis indicated that the top annotation cluster included three GO function categories: "response to nutrient", "response to nutrient levels" and "response to extracellular stimulus". Based on KEGG pathway analysis, we found that the most two significant pathways were "metabolism of xenobiotics by cytochrome P450" and "drug metabolism". Real-time PCR showed that relative levels of Col1a1 (collagen type 1 alpha 1), Ctgf (connective tissue growth factor) and Tgfb1 (transforming growth factor beta 1) were significantly decreased in the FXST group, while Cyp2c23 (cytochrome P-450 family 2 subfamily C polypeptide 23) and Nphs1 (nephrin) were increased. The increased expressions of TGFbeta and collagen (type 1, alpha2) in the kidneys of DN rats were attenuated by FXST. Our data suggest that FXST can moderate kidney function in DN rats. The mechanism may involve the BMP2-TGFbeta-CTGF pathway, CYP2C23 and podocyte proteins. PMID- 22434411 TI - Consistence and discrepancy of neuropathic pain screening tools DN4 and ID-Pain. AB - Pain is a subjective condition that cannot be objectively measured; for this reason, self patient-perspective is crucial. Recently, several screening tools to discriminate between nociceptive and neuropathic pain have been developed. We aimed at assessing the consistence and discrepancy of two widely used screening tools, The Douleur Neuropathique 4 (DN4) and the 6-item questionnaire (ID-Pain), by comparing their ability in discriminating neuropathic from nociceptive pain. DN4 and ID-Pain were administered to 392 Italian patients attending 16 outpatient services for peripheral nerve diseases. Based on medical history, clinical findings and diagnostic tools, patients were divided into two groups (neuropathic and nociceptive). Globally, ID-Pain identified neuropathic pain in 60 % of patients (38 % probable, 22 % likely). Interestingly also DN4 diagnosed neuropathic pain in 60 % of cases. A discrepancy was observed in 16 % of cases. DN4 and ID-Pain resulted to be highly interrelated in the identification of neuropathic pain. Sensitivity of DN4 was 82 % and specificity was 81 %, while ID Pain (considering both probable and likely groups) showed sensitivity 78 % and specificity 74 %. Reliable screening tools for neuropathic pain are well related between them; hence, they are available for researchers and clinicians who may choose the most appropriate for their activity. Since the gold standard for the diagnosis and treatment of neuropathic pain cannot do without a neurological evaluation, perhaps DN4, that includes physician objective measures, may help reducing the percentage of dubious cases. Conversely, when needing a more agile tool (not needing a physician) ID-Pain may be adopted. PMID- 22434412 TI - Obesidomics: contribution of adipose tissue secretome analysis to obesity research. AB - Obesity is presently reaching pandemic proportions and it is becoming a major health concern in developed and developing countries due to its comorbidities like type II diabetes, cardiovascular pathologies, and some cancers. The discovery of the adipose tissue role as an endocrine gland able to secrete adipokines that affects whole-body energy homeostasis has become a key break through toward a better molecular understanding of obesity. Among the known adipokines involved in the regulation of energy metabolism very few have been clearly seen as central regulators of insulin sensitivity, metabolism, and energy homeostasis. Thus, the discovery and characterization of new adipocyte-derived factors is still in progress. Proteomics technology has emerged as a useful tool to analyze adipose tissue secretion (secretome) dynamics giving a wider picture into the molecular events that control body weight. Besides the identification of new secreted proteins, the advantage of using this approach is the possibility to detect post-translational modifications and protein interactions that generally cannot be predicted by genome studies. In this review, we summarize the recent efforts to identify new bioactive adipokines by proteomics especially in pathological situations such as obesity. PMID- 22434414 TI - [New criteria for assessment of response to treatment of gliomas]. PMID- 22434413 TI - Clinical implications of growth hormone-secreting tumor subtypes. AB - Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence. Differing clinical behavior between the two GH tumor subtypes, sparsely granulated (SG) versus densely granulated (DG), has been reported, but has not been used routinely in clinical management. SG tumors are more common in younger patients (<50 years), and are usually larger tumors. SG tumors have been reported to be less responsive to somatostatin analogs (SSA) than DG tumors. The mechanisms underlying these potential differences in tumor behavior, however, are poorly defined. Subsets (up to 50 %) of DG adenomas harbor a gsp mutation that can activate cAMP that provides a theoretical intracellular target for somatostatin therapy. In contrast, some SG tumors have reduced somatostatin receptor expression and mutations in the extracellular domain of the GH receptor that may contribute to SSA resistance. While DG versus SG growth hormone adenomas are readily distinguished by immunohistochemistry, other less common GH adenoma variants still require electron microscopy (EM) for confident subclassification. Whether these less common variants possess unique clinical features is unknown. Research is needed to identify clinically relevant biomarkers of GH pituitary tumors that predict risk of recurrence and response to medical therapy. PMID- 22434415 TI - The efficacy of color duplex sonography in preoperative assessment of anterolateral thigh flap. AB - The anterolateral thigh (ALT) flap has become a workhorse in reconstructive surgery of the head and neck region and the extremities. However, its inconsistent vascular anatomy and frequent intramuscular course of perforators often cause difficulties during the dissection of this versatile flap. Hence, reliable preoperative perforator mapping and identification of vascular anomalies may render the raising of the flap easier and safer. The aim of this study was to evaluate the use of Color Duplex sonography and whether it allows the distinction between septocutaneous and musculocutaneous perforators. For this purpose, the thighs of 13 patients undergoing reconstruction with ALT flaps were examined preoperatively, and results were compared to intraoperative findings. A total of 30 perforators could be detected preoperatively, of which 29 were confirmed during flap dissection. Preoperative Color Duplex sonography correctly predicted the course of all perforators as either running through the vastus lateralis muscle or the intermuscular septum. In our investigations, Color Doppler sonography had a 96.7% positive predictive value and a 96.7% true positive rate in detecting perforators. Color Duplex sonography is a highly reliable tool in the preoperative assessment of ALT flaps. Localization and course of perforators can be determined accurately and vascular anomalies can be identified. PMID- 22434416 TI - BaGa2MQ6 (M = Si, Ge; Q = S, Se): a new series of promising IR nonlinear optical materials. AB - The four compounds BaGa(2)MQ(6) (M = Si, Ge; Q = S, Se) have been identified as a new series of IR nonlinear optical (NLO) materials and are promising for practical applications. They are isostructural and crystallize in the noncentrosymmetric polar space group R3 of the trigonal system. Their three dimensional framework is composed of corner-sharing (Ga/M)Q(4) (M = Si, Ge; Q = S, Se) tetrahedra with Ba(2+) cations in the cavities. The polar alignment of one (Ga/M)-Q2 bond for each (Ga/M)Q(4) tetrahedra along the c direction is conducive to generating a large NLO response, which was confirmed by powder second-harmonic generation (SHG) using a 2090 nm laser as fundamental wavelength. The SHG signal intensities of the two sulfides were close to that of AgGaS(2) and those for the two selenides were similar as that of AgGaSe(2). The large band gaps of 3.75(2) eV, 3.23(2) eV, 2.88(2) eV, and 2.22 (2) eV for BaGa(2)SiS(6), BaGa(2)GeS(6), BaGa(2)SiSe(6), and BaGa(2)GeSe(6), respectively, will be very helpful to increase the laser damage threshold. Moreover, all the four BaGa(2)MQ(6) (M = Si, Ge; Q = S, Se) compounds exhibit congruent-melting behavior, which indicates that bulk crystals needed for practical applications can be obtained by the Bridgman Stockbarger method. The calculated birefringence indicates that these materials may be phase-matchable in the IR region and the calculated SHG coefficients agree with the experimental observations. According to our preliminary study, the BaGa(2)MQ(6) compounds represent a new series of promising IR nonlinear optical (NLO) materials which do not belong to the traditional chalcopyrite-type materials such as AgGaQ2 (Q = S, Se) and ZnGeP(2). PMID- 22434417 TI - Facetted patchy particles through entropy-driven patterning of mixed ligand SAMS. AB - We present a microscopic theory that describes the ordering of two distinct ligands on the surface of a facetted nanoparticle. The theory predicts that when one type of ligand is significantly bulkier than all others, the larger ligands preferentially align themselves along the edges and vertices of the nanoparticle. Monte Carlo simulations confirm these predictions. We show that the intrinsic conformational entropy of the ligands stabilizes this novel edge-aligned phase. PMID- 22434418 TI - Eicosanoids and their drugs in cardiovascular diseases: focus on atherosclerosis and stroke. AB - Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2), are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2)) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists. PMID- 22434419 TI - Mechanistic analysis of iron accumulation by endothelial cells of the BBB. AB - The mechanism(s) by which iron in blood is transported across the blood-brain barrier (BBB) remains controversial. Here we have examined the first step of this trans-cellular pathway, namely the mechanism(s) of iron uptake into human brain microvascular endothelial cells (hBMVEC). We show that hBMVEC actively reduce non transferrin bound Fe(III) (NTBI) and transferrin-bound Fe(III) (TBI); this activity is associated with one or more ferrireductases. Efficient, exo cytoplasmic ferri-reduction from TBI is dependent upon transferrin receptor (TfR), also. Blocking holo-Tf binding with an anti-TfR antibody significantly decreases the reduction of iron from transferrin by hBMVEC, suggesting that holo Tf needs to bind to TfR in order for efficient reduction to occur. Ferri reduction from TBI significantly decreases when hBMVEC are pre-treated with Pt(II), an inhibitor of cell surface reductase activity. Uptake of (59)Fe from (59)Fe-Tf by endothelial cells is inhibited by 50 % when ferrozine is added to solution; in contrast, no inhibition occurs when cells are alkalinized with NH(4)Cl. This indicates that the iron reduced from holo-transferrin at the plasma membrane accounts for at least 50 % of the iron uptake observed. hBMVEC-dependent reduction and uptake of NTBI utilizes a Pt(II)-insensitive reductase. Reductase independent uptake of Fe(II) by hBMVEC is inhibited up to 50 % by Zn(II) and/or Mn(II) by a saturable process suggesting that redundant Fe(II) transporters exist in the hBMVEC plasma membrane. These results are the first to demonstrate multiple mechanism(s) of TBI and NTBI reduction and uptake by endothelial cells (EC) of the BBB. PMID- 22434420 TI - Quantification of diffusion tensor imaging in normal white matter maturation of early childhood using an automated processing pipeline. AB - OBJECTIVES: The degree and status of white matter myelination can be sensitively monitored using diffusion tensor imaging (DTI). This study looks at the measurement of fractional anistropy (FA) and mean diffusivity (MD) using an automated ROI with an existing DTI atlas. METHODS: Anatomical MRI and structural DTI were performed cross-sectionally on 26 normal children (newborn to 48 months old), using 1.5-T MRI. The automated processing pipeline was implemented to convert diffusion-weighted images into the NIfTI format. DTI-TK software was used to register the processed images to the ICBM DTI-81 atlas, while AFNI software was used for automated atlas-based volumes of interest (VOIs) and statistical value extraction. RESULTS: DTI exhibited consistent grey-white matter contrast. Triphasic temporal variation of the FA and MD values was noted, with FA increasing and MD decreasing rapidly early in the first 12 months. The second phase lasted 12-24 months during which the rate of FA and MD changes was reduced. After 24 months, the FA and MD values plateaued. CONCLUSION: DTI is a superior technique to conventional MR imaging in depicting WM maturation. The use of the automated processing pipeline provides a reliable environment for quantitative analysis of high-throughput DTI data. KEY POINTS: Diffusion tensor imaging outperforms conventional MRI in depicting white matter maturation. * DTI will become an important clinical tool for diagnosing paediatric neurological diseases. * DTI appears especially helpful for developmental abnormalities, tumours and white matter disease. * An automated processing pipeline assists quantitative analysis of high throughput DTI data. PMID- 22434421 TI - Prediction of the histopathological grade of hepatocellular carcinoma using qualitative diffusion-weighted, dynamic, and hepatobiliary phase MRI. AB - OBJECTIVES: To investigate the effectiveness of qualitative diffusion-weighted imaging (DWI), subtraction of unenhanced from arterial phase images, and hepatobiliary phase (HBP) images in estimating the histopathological grade of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed gadoxetic acid-enhanced magnetic resonance images of 175 patients with 201 surgically resected HCCs. The signal intensity and its relationship with histopathological grade were assessed for each sequence and a combination of sequences. RESULTS: There was a tendency towards higher grades in tumours showing restricted diffusion on DWI (P < 0.001) or arterial enhancement on subtraction imaging (P < 0.001), but not hepatocyte-defect on HBP images (P = 0.33). When lesions were divided into three groups based on combined findings on DWI and subtraction imaging, a linear trend was observed between group and grade (P < 0.001). The positive predictive value (PPV) of the combination of no restricted diffusion and no arterial enhancement in predicting well-differentiated HCC was 100%, higher than the PPV of individual findings on DWI (74%) or subtraction imaging (81%). CONCLUSIONS: DWI and subtraction imaging are helpful for predicting the histopathological grade of HCC, especially when the two sequences are considered together. KEY POINTS: * Predicting the histopathological grade of hepatocellular carcinoma (HCC) preoperatively is important. * Diffusion-weighted imaging (DWI) and subtraction imaging are recently developed MR techniques. * Retrospective study showed DWI and subtraction imaging helps predict HCC grades. * Management of patients with HCC becomes more appropriate. PMID- 22434422 TI - Delayed recovery of gait function in a patient with intracerebral haemorrhage. AB - OBJECTIVE: We report here on a patient with intracerebral haemorrhage (ICH), who showed unusually delayed motor recovery of the leg, which started at 6 months after ICH onset. CASE REPORT: A 53-year-old man underwent craniotomy and drainage for a right putaminal ICH. The patient presented with complete paralysis of the left extremities at ICH onset. Despite having undergone rehabilitation starting at 7 weeks after onset, the patient did not show significant motor recovery of the left extremities until 6 months after onset, when the affected left leg began to show motor recovery to the point that he was able to extend his hip and knee without gravity 7 months after onset. As a result, he was able to walk independently on an even floor 9 months after onset. RESULTS: On 6-month diffusion tensor tractography, the right corticospinal tract showed disruption with Wallerian degeneration to the pontomedullary junction. CONCLUSION: This case study highlights the extensive potential for the human brain to aid in the recovery of walking after injury. In conclusion, clinicians should attempt to determine the causes of difficulty walking when examining patients with ICH and then perform intensive rehabilitation for the recovery of walking. PMID- 22434423 TI - Gay, lesbian, and bisexual patients' recommendations for genetic counselors: a qualitative investigation. AB - Gay, lesbian, and bisexual (GLB) individuals comprise a growing patient population in genetic counseling. However, only one article from a genetic counseling journal provides empirical data on GLB patients' genetic counseling experiences and genetic counselor attitudes and practices regarding GLB patients. The present study, an extension of the aforementioned article, gathered further information about patients' genetic counseling experiences through semi structured telephone interviews. Twelve of the previous study's 29 patient respondents (n = 10 lesbian women, n = 1 gay man, n = 1 bisexual woman) participated. Interview questions concerned the use of medically inclusive forms, factors influencing patient disclosure, counselors' ability to relate to them, and their expectations of genetic counselors. Inductive analysis of the interviews yielded seven themes: 1) Medically inclusive forms with gender neutral terms are important; 2) Genetic counselor ability to relate to a GLB person depends more on the relationship established during the session and less on external symbols; 3) The presence of GLB-friendly symbols increases comfort when disclosing one's orientation; 4) Inclusion of the patient's partner is important and best done by encouraging their active participation in sessions; 5) When GLB patients disclose their orientation, they expect to be treated like any other patient; 6) Providers should ask about orientation if medically pertinent and the remaining discussion should take orientation into consideration; and 7) When a provider inquires about orientation it should be done in a safe and appropriate way. Illustrative quotations, genetic counseling practice implications, and research recommendations are presented. PMID- 22434424 TI - Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents. AB - BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy. PMID- 22434425 TI - Single-cell sequencing provides clues about the host interactions of segmented filamentous bacteria (SFB). AB - Segmented filamentous bacteria (SFB) are host-specific intestinal symbionts that comprise a distinct clade within the Clostridiaceae, designated Candidatus Arthromitus. SFB display a unique life cycle within the host, involving differentiation into multiple cell types. The latter include filaments that attach intimately to intestinal epithelial cells, and from which "holdfasts" and spores develop. SFB induce a multifaceted immune response, leading to host protection from intestinal pathogens. Cultivation resistance has hindered characterization of these enigmatic bacteria. In the present study, we isolated five SFB filaments from a mouse using a microfluidic device equipped with laser tweezers, generated genome sequences from each, and compared these sequences with each other, as well as to recently published SFB genome sequences. Based on the resulting analyses, SFB appear to be dependent on the host for a variety of essential nutrients. SFB have a relatively high abundance of predicted proteins devoted to cell cycle control and to envelope biogenesis, and have a group of SFB specific autolysins and a dynamin-like protein. Among the five filament genomes, an average of 8.6% of predicted proteins were novel, including a family of secreted SFB-specific proteins. Four ADP-ribosyltransferase (ADPRT) sequence types, and a myosin-cross-reactive antigen (MCRA) protein were discovered; we hypothesize that they are involved in modulation of host responses. The presence of polymorphisms among mouse SFB genomes suggests the evolution of distinct SFB lineages. Overall, our results reveal several aspects of SFB adaptation to the mammalian intestinal tract. PMID- 22434426 TI - Unusual combinatorial involvement of poly-A/T tracts in organizing genes and chromatin in Dictyostelium. AB - Dictyostelium discoideum is an amoebozoa that exists in both a free-living unicellular and a multicellular form. It is situated in a deep branch in the evolutionary tree and is particularly noteworthy in having a very A/T-rich genome. Dictyostelium provides an ideal system to examine the extreme to which nucleotide bias may be employed in organizing promoters, genes, and nucleosomes across a genome. We find that Dictyostelium genes are demarcated precisely at their 5' ends by poly-T tracts and precisely at their 3' ends by poly-A tracts. These tracts are also associated with nucleosome-free regions and are embedded with precisely positioned TATA boxes. Homo- and heteropolymeric tracts of A and T demarcate nucleosome border regions. Together, these findings reveal the presence of a variety of functionally distinct polymeric A/T elements. Strikingly, Dictyostelium chromatin may be organized in di-nucleosome units but is otherwise organized as in animals. This includes a +1 nucleosome in a position that predicts the presence of a paused RNA polymerase II. Indeed, we find a strong phylogenetic relationship between the presence of the NELF pausing factor and positioning of the +1 nucleosome. Pausing and +1 nucleosome positioning may have coevolved in animals. PMID- 22434427 TI - Targeted gene addition to a predetermined site in the human genome using a ZFN based nicking enzyme. AB - Zinc-finger nucleases (ZFNs) drive highly efficient genome editing by generating a site-specific DNA double-strand break (DSB) at a predetermined site in the genome. Subsequent repair of this break via the nonhomologous end-joining (NHEJ) or homology-directed repair (HDR) pathways results in targeted gene disruption or gene addition, respectively. Here, we report that ZFNs can be engineered to induce a site-specific DNA single-strand break (SSB) or nick. Using the CCR5 specific ZFNs as a model system, we show that introduction of a nick at this target site stimulates gene addition using a homologous donor template but fails to induce significant levels of the small insertions and deletions (indels) characteristic of repair via NHEJ. Gene addition by these CCR5-targeted zinc finger nickases (ZFNickases) occurs in both transformed and primary human cells at efficiencies of up to ~1%-8%. Interestingly, ZFNickases targeting the AAVS1 "safe harbor" locus revealed similar in vitro nicking activity, a marked reduction of indels characteristic of NHEJ, but stimulated far lower levels of gene addition-suggesting that other, yet to be identified mediators of nick induced gene targeting exist. Introduction of site-specific nicks at distinct endogenous loci provide an important tool for the study of DNA repair. Moreover, the potential for a SSB to direct repair pathway choice (i.e., HDR but not NHEJ) may prove advantageous for certain therapeutic applications such as the targeted correction of human disease-causing mutations. PMID- 22434428 TI - Racial differences in presentation and management of follicular non-Hodgkin lymphoma in the United States: report from the National LymphoCare Study. AB - BACKGROUND: Racial differences in follicular lymphoma (FL) in the United States have not been investigated. METHODS: The National LymphoCare Study is a multicenter, longitudinal, observational cohort study collecting data on treatment patterns and outcomes for patients with newly diagnosed FL in the United States between 2004 and 2007 without any predefined, study-specific intervention. The authors investigated differences between white (W) patients, African American (AA) patients, and Hispanic (H) patients. RESULTS: Among 2744 enrolled patients, there were 95 (3%) AA patients, 125 (5%) H patients, and 2476 (90%) W patients. Compared with W patients, more AA and H patients were diagnosed at age <45 years (P < .0001). H patients more commonly were diagnosed with grade 3 FL compared with AA and W patients (29%, 13%, and 18%, respectively; P = .019) and more commonly received rituximab plus chemotherapy as initial therapy compared with W patients (66% vs 50%; P = .036), while AA patients less commonly received anthracyclines (49% vs 64% in W patients; P = .027). H and AA patients who received rituximab plus chemotherapy were less likely than W patients to receive maintenance rituximab (27% vs 31% vs 40%, respectively; P = .031). At a median follow-up of 52 months, progression-free survival was similar between AA and W patients but was longer in H patients, and there was no difference in overall survival. CONCLUSIONS: In the largest prospective cohort to date of AA and H patients with FL in the United States, AA and H patients were younger at presentation. Although racial differences in treatment patterns for FL were noted, additional follow-up is needed to determine the impact of these differences on survival. PMID- 22434430 TI - AMPKalpha modulation in cancer progression: multilayer integrative analysis of the whole transcriptome in Asian gastric cancer. AB - Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and miRNAs). A multilayer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations, and key differentially expressed miRNAs. Through this approach, we identified the central metabolic regulator AMP-activated protein kinase (AMPK)alpha as a potential functional target in Asian gastric cancer. Furthermore, we experimentally showed the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets. PMID- 22434431 TI - Real-time Raman spectroscopy for in vivo skin cancer diagnosis. AB - Raman spectroscopy is a noninvasive optical technique capable of measuring vibrational modes of biomolecules within viable tissues. In this study, we evaluated the application of an integrated real-time system of Raman spectroscopy for in vivo skin cancer diagnosis. Benign and malignant skin lesions (n = 518) from 453 patients were measured within 1 second each, including melanomas, basal cell carcinomas, squamous cell carcinomas, actinic keratoses, atypical nevi, melanocytic nevi, blue nevi, and seborrheic keratoses. Lesion classification was made using a principal component with general discriminant analysis and partial least-squares in three distinct discrimination tasks: skin cancers and precancers from benign skin lesions [receiver operating characteristic (ROC) = 0.879]; melanomas from nonmelanoma pigmented lesions (ROC = 0.823); and melanomas from seborrheic keratoses (ROC = 0.898). For sensitivities between 95% and 99%, the specificities ranged between 15% and 54%. Our findings establish that real-time Raman spectroscopy can be used to distinguish malignant from benign skin lesions with good diagnostic accuracy comparable with clinical examination and other optical-based methods. PMID- 22434433 TI - Solar energy. Preface. PMID- 22434434 TI - Overview: capturing the sun for energy production. AB - Solar energy has potential to provide a major part of our energy for our future, as heat, electricity, and fuels. Most solar technologies are still at the research and development stage, however. There is therefore a need for bold and enduring efforts in research, development and commercialization, including strategic legislative measures and infrastructure investments. This overview article serves as an introduction to the present Special Report, briefly outlining the potential, principles and possibilities as well as some of the challenges of solar energy conversion. PMID- 22434435 TI - Conversion of concentrated solar thermal energy into chemical energy. AB - When a concentrated solar beam is irradiated to the ceramics such as Ni-ferrite, the high-energy flux in the range of 1500-2500 kW/m(2) is absorbed by an excess Frenkel defect formation. This non-equilibrium state defect is generated not by heating at a low heating-rate (30 K/min), but by irradiating high flux energy of concentrated solar beam rapidly at a high heating rate (200 K/min). The defect can be spontaneously converted to chemical energy of a cation-excess spinel structure (reduced-oxide form) at the temperature around 1773 K. Thus, the O(2) releasing reaction (alpha-O(2) releasing reaction) proceeds in two-steps; (1) high flux energy of concentrated solar beam absorption by formation of the non equilibrium Frenkel defect and (2) the O(2) gas formation from the O(2-) in the Frenkel defect even in air atmosphere. The 2nd step proceeds without the solar radiation. We may say that the 1st step is light reaction, and 2nd step, dark reaction, just like in photosynthesis process. PMID- 22434436 TI - Thin film solar cells: research in an industrial perspective. AB - Electricity generation by photovoltaic conversion of sunlight is a technology in strong growth. The thin film technology is taking market share from the dominant silicon wafer technology. In this article, the market for photovoltaics is reviewed, the concept of photovoltaic solar energy conversion is discussed and more details are given about the present technological limitations of thin film solar cell technology. Special emphasis is given for solar cells which employ Cu(In,Ga)Se(2) and Cu(2)ZnSn(S,Se)(4) as the sunlight-absorbing layer. PMID- 22434437 TI - Position-controlled III-V compound semiconductor nanowire solar cells by selective-area metal-organic vapor phase epitaxy. AB - We demonstrate position-controlled III-V semiconductor nanowires (NWs) by using selective-area metal-organic vapor phase epitaxy and their application to solar cells. Efficiency of 4.23% is achieved for InP core-shell NW solar cells. We form a 'flexible NW array' without a substrate, which has the advantage of saving natural resources over conventional thin film photovoltaic devices. Four junction NW solar cells with over 50% efficiency are proposed and discussed. PMID- 22434438 TI - Ultra-high efficiency photovoltaic cells for large scale solar power generation. AB - The primary targets of our project are to drastically improve the photovoltaic conversion efficiency and to develop new energy storage and delivery technologies. Our approach to obtain an efficiency over 40% starts from the improvement of III-V multi-junction solar cells by introducing a novel material for each cell realizing an ideal combination of bandgaps and lattice-matching. Further improvement incorporates quantum structures such as stacked quantum wells and quantum dots, which allow higher degree of freedom in the design of the bandgap and the lattice strain. Highly controlled arrangement of either quantum dots or quantum wells permits the coupling of the wavefunctions, and thus forms intermediate bands in the bandgap of a host material, which allows multiple photon absorption theoretically leading to a conversion efficiency exceeding 50%. In addition to such improvements, microfabrication technology for the integrated high-efficiency cells and the development of novel material systems that realizes high efficiency and low cost at the same time are investigated. PMID- 22434439 TI - Spectroscopic analysis of NIR-dye sensitization in bulk heterojunction polymer solar cells. AB - The photovoltaic conversion efficiency for near-infrared (NIR) sunlight is improved successfully by dye sensitization of bulk heterojunction polymer solar cells, in which the active layer was prepared by a ternary blend of poly(3 hexylthiophene), a fullerene derivative (1-(3-methoxycarbonyl)propyl-1-phenyl [6,6]-methanofullerene), and an NIR dye, silicon phthalocyanine bis(trihexylsilyl oxide). The mechanism of the NIR-dye sensitization is studied by femtosecond transient absorption spectroscopy. PMID- 22434440 TI - Current mode atomic force microscopy (C-AFM) study for local electrical characterization of conjugated polymer blends. AB - A blend of regioregular poly(3-hexylthiophene) (P3HT) and poly{[N,N'-bis(2 octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2' bithiophene)} (P(NDI2OD-T2), which has the potential for polymer solar cells application, was prepared for current mode atomic force microscopy (C-AFM) measurements in this study. Phase-separated domains and the local electrical characteristics of P3HT/P(NDI2OD-T2) blends were investigated by the C-AFM. PMID- 22434441 TI - Alternating copolymers and alternative device geometries for organic photovoltaics. AB - The efficiency of conversion of light to electrical energy with the help of conjugated polymers and molecules is rapidly improving. The optical absorption properties of these materials can be designed, and implemented via molecular engineering. Full coverage of the solar spectrum is thus feasible. Narrow absorption spectra allow construction of tandem solar cells. The poor transport properties of these materials require thin devices, which limits optical absorption. Alternative device geometries for these flexible materials compensate for the optical absorption by light trapping, and allow tandem cells. PMID- 22434442 TI - Quantitative evaluation of electron injection efficiency in dye-sensitized TiO(2) films. AB - The efficiency of electron injection (Phi(inj)) in dye-sensitized nanocrystalline films was studied through transient absorption (TA) and time-resolved microwave conductivity (TRMC) measurements. Here, I show the absolute value of Phi(inj) for several dye-sensitized nanocrystalline films and discuss the relationship between Phi(inj) and the free energy change (-DeltaG (inj)) for the injection process. Some systems exhibited lower Phi(inj) values even when -DeltaG (inj) was sufficiently large to promote electron injection. Recent experimental findings are used to propose possible explanations for this phenomenon. Quantitative evaluation of Phi(inj) using TA and TRMC will give us new insights for developing high-performance solar cell devices. PMID- 22434443 TI - Characterization of photovoltaic performance of the dye-sensitized solar cell with a novel ruthenium complex having a bisdemethoxycurcumin as a ligand. AB - The first example of a ruthenium sensitizer (TUS-22) having a natural dye, bisdemethoxycurcumin, as a ligand has been synthesized. The dye-sensitized solar cell based on this novel dye showed 5.8% conversion efficiency under AM 1.5 (100 mW/cm(2)) irradiation. PMID- 22434444 TI - Brief overview of dye-sensitized solar cells. AB - Dye-sensitized solar cells (DSC) are based on molecular and nanometer-scale components. Record cell efficiencies of 12%, promising stability data and means of energy-efficient production methods have been accomplished. As selling points for the DSC technology the prospect of low-cost investments and fabrication are key features. DSCs offer the possibilities to design solar cells with a large flexibility in shape, color, and transparency. The basic principles of the operation of DSC, the state-of-the-art as well as the potentials for future development are described. PMID- 22434445 TI - Solar fuels: vision and concepts. AB - The world needs new, environmentally friendly and renewable fuels to allow an exchange from fossil fuels. The fuel must be made from cheap and 'endless' resources that are available everywhere. The new research area on solar fuels, which are made from solar energy and water, aims to meet this demand. The paper discusses why we need a solar fuel and why electricity is not enough; it proposes solar energy as the major renewable energy source to feed from. The present research strategies, involving direct, semi-direct and indirect approaches to produce solar fuels, are overviewed. PMID- 22434446 TI - Design, engineering, and construction of photosynthetic microbial cell factories for renewable solar fuel production. AB - There is an urgent need to develop sustainable solutions to convert solar energy into energy carriers used in the society. In addition to solar cells generating electricity, there are several options to generate solar fuels. This paper outlines and discusses the design and engineering of photosynthetic microbial systems for the generation of renewable solar fuels, with a focus on cyanobacteria. Cyanobacteria are prokaryotic microorganisms with the same type of photosynthesis as higher plants. Native and engineered cyanobacteria have been used by us and others as model systems to examine, demonstrate, and develop photobiological H(2) production. More recently, the production of carbon containing solar fuels like ethanol, butanol, and isoprene have been demonstrated. We are using a synthetic biology approach to develop efficient photosynthetic microbial cell factories for direct generation of biofuels from solar energy. Present progress and advances in the design, engineering, and construction of such cyanobacterial cells for the generation of a portfolio of solar fuels, e.g., hydrogen, alcohols, and isoprene, are presented and discussed. Possibilities and challenges when introducing and using synthetic biology are highlighted. PMID- 22434447 TI - Genetic engineering of cyanobacteria to enhance biohydrogen production from sunlight and water. AB - To mitigate global warming caused by burning fossil fuels, a renewable energy source available in large quantity is urgently required. We are proposing large scale photobiological H(2) production by mariculture-raised cyanobacteria where the microbes capture part of the huge amount of solar energy received on earth's surface and use water as the source of electrons to reduce protons. The H(2) production system is based on photosynthetic and nitrogenase activities of cyanobacteria, using uptake hydrogenase mutants that can accumulate H(2) for extended periods even in the presence of evolved O(2). This review summarizes our efforts to improve the rate of photobiological H(2) production through genetic engineering. The challenges yet to be overcome to further increase the conversion efficiency of solar energy to H(2) also are discussed. PMID- 22434448 TI - Game dynamic model for yeast development. AB - Game theoretic models, along with replicator equations, have been applied successfully to the study of evolution of populations of competing species, including the growth of a population, the reaching of the population to an equilibrium state, and the evolutionary stability of the state. In this paper, we analyze a game model proposed by Gore et al. (Nature 456:253-256, 2009) in their recent study on the co-development of two mixed yeast strains. We examine the mathematical properties of this model with varying experimental parameters. We simulate the growths of the yeast strains and compare them with the experimental results. We also compute and analyze the equilibrium state of the system and prove that it is asymptotically and evolutionarily stable. PMID- 22434449 TI - The relationship between bone mineral density and arterial stiffness in women. AB - PURPOSE: The aim of this study was to investigate the correlation between bone mineral density (BMD) and arterial stiffness as a preclinical atherosclerosis criterion. MATERIALS AND METHODS: Carotid and femoral artery Doppler ultrasonography and arterial stiffness measurements were performed on 113 female patients referred for BMD measurements. RESULTS: The cross-sectional compliance and cross-sectional distensibility of the carotid artery were positively correlated with the BMD of the Ward's triangle, the femoral neck, and the lower femoral neck; and the Ward's triangle, respectively. A negative correlation was found between the intima-media thickness of the femoral artery and the femoral elastic modulus with the BMD of L1, L12, L13, and L23; and the BMD of L1, L3, L13, L24, L34, the femoral neck, the lower femoral neck, and Ward's triangle, respectively. The cross-sectional compliance and cross-sectional distensibility of the femoral artery were positively correlated with the BMD of the femoral neck, upper femoral neck, lower femoral neck, Ward's triangle; and the BMD of the total femur and Ward's triangle, respectively. CONCLUSION: The arterial stiffness measurements in women are correlated with BMD, regardless of age and other demographic factors. PMID- 22434450 TI - MRI of the lung: state of the art. AB - Magnetic resonance imaging (MRI) of the lung is technically challenging due to the low proton density and fast signal decay of the lung parenchyma itself. Additional challenges consist of tissue loss, hyperinflation, and hypoxic hypoperfusion, e.g., in emphysema, a so-called "minus-pathology". However, pathological changes resulting in an increase of tissue ("plus-pathology"), such as atelectases, nodules, infiltrates, mucus, or pleural effusion, are easily depicted with high diagnostic accuracy. Although MRI is inferior or at best equal to multi-detector computed tomography (MDCT) for the detection of subtle morphological features, MRI now offers an increasing spectrum of functional imaging techniques such as perfusion assessment and measurement of ventilation and respiratory mechanics that are superior to what is possible with MDCT. Without putting patients at risk with ionizing radiation, repeated examinations allow for the evaluation of the course of lung disease and monitoring of the therapeutic response through quantitative imaging, providing a level of functional detail that cannot be obtained by any other single imaging modality. As such, MRI will likely be used for clinical applications beyond morphological imaging for many lung diseases. In this article, we review the technical aspects and protocol suggestions for chest MRI and discuss the role of MRI in the evaluation of nodules and masses, airway disease, respiratory mechanics, ventilation, perfusion and hemodynamics, and pulmonary vasculature. PMID- 22434451 TI - The nomenclature of venous flow-through flaps: updated classification and review of the literature. AB - Venous flow-through flaps (venous flaps) are useful reconstructive options, particularly in the repair of defects with segmental vessel loss. They are relatively easy to harvest and confer several benefits at the donor site. However, given that they are based on a single central vein, their survival is notoriously unreliable and they are susceptible to ischemia and venous congestion. Various designs have been suggested to improve the circulatory physiology, and hence survival, of venous flap. More recent designs involve adaptations to the arrangement and number of efferent veins draining arterialized venous flaps. The most commonly used classification system for venous flaps, proposed by Chen, Tang, and Noordhoff, does not afford adequate description of these alternate designs. This article offers a classification system that can incorporate all reported modifications to venous flaps. This simple adaptation to the classification system proposed by Chen et al. restores its usefulness in describing modern variations to venous flap design. PMID- 22434452 TI - The effects of dietary silver on larval growth in the echinoderm Lytechinus variegatus. AB - Previous studies have demonstrated that the euryhaline copepod Acartia tonsa is extremely sensitive to dietborne silver (Ag) exposure, with a 20 % inhibition (EC(20)) of survival occurring when copepods are fed algae with 1.6 MUg g(-1) dry weight (dw) Ag, corresponding to a waterborne Ag concentration of 0.46 MUg l(-1) Ag. In contrast, 43 MUg l(-1) Ag is required to elicit similar effects in copepods exposed to Ag by way of water. In the current study, we investigated whether another planktonic marine organism might also be sensitive to dietary Ag. Specifically, we tested larvae of the echinoderm, Lytechinus variegatus in an 18 day study in which larvae were continuously exposed to Ag-laden algae (Isochrysis galbana). After 7 days of exposure, no significant effects were observed on larval growth up to the highest concentration tested (10.68 MUg g(-1) dw Ag in algae after exposure to 3.88 MUg l(-1) waterborne Ag). After 18 days, significant effects were observed in all Ag treatments resulting in a lowest-observable effect concentration of 0.68 MUg g(-1) dw Ag in algae and corresponding waterborne Ag concentration of 0.05-0.07 MUg l(-1) Ag (depending on background Ag [see Results]). However, the dose-response relationship was quite flat with a similar level of growth inhibition (approximately 15 %) in all Ag treatments, resulting in an EC(20) of >10.68 MUg g(-1) dw Ag in algae (>3.88 MUg l(-1) Ag in water). This flat dose-response relationship is characteristic of dietary metal (silver, copper, cadmium, nickel, and zinc) toxicity to copepods as well, although the effect is slightly more robust (approximately 20-30 % inhibition of survival or reproduction). We conclude that echinoderm larvae may be similar to copepods in their sensitivity to dietary Ag, although a better understanding of the mechanisms underlying the apparent flat dose-response relationships is clearly needed. PMID- 22434453 TI - Transport of a solvent mixture across two glove materials when applied in a paint matrix. AB - The transport of mixed paint solvents through natural rubber latex (4 mil) and nitrile rubber (5 mil) gloves was evaluated after spray application of the paint formulation directly on the glove surface. Glove materials and thicknesses were those selected by the majority of spray painters in the local automobile repair industry. A flat panel containing glove specimens mounted in multiple permeation cells permitted evaporation of solvents from the applied paint and incorporated a solid sorbent receiving medium for measuring glove membrane transport. The panel was sprayed in a paint booth to simulate use conditions. Charcoal cloth under the glove adsorbed transported solvents, which were quantified by gas chromatography. For each solvent component, results were expressed as mass transported through the glove relative to the mass applied, per unit area, during 30 min after spray application. The paint formulation contained ketones, acetates, and aromatics. Natural rubber latex allowed 6-10 times the transport of solvents relative to nitrile rubber for all eight solvent components: methyl ethyl ketone, toluene, styrene, ethyl benzene, xylene isomers, and 2-heptanone. m-Xylene showed the largest difference in transport between the two glove materials. This solvent also had the highest transport for each material. The results indicate that nitrile rubber gloves offer somewhat greater chemical resistance to all eight solvents studied compared with natural rubber latex gloves, regardless of the chemical properties of the individual solvent components. However, it must be emphasized that neither of the glove materials, in the thicknesses used in this study, provide adequate protection when exposed by direct spray painting. Simulation of realistic spray conditions may offer a source of useful information on the performance of chemical protective gloves because it accounts for solvent evaporation and the effect of paint polymerization after application on glove transport. PMID- 22434454 TI - Quantitative PCR and in vivo efficacy of antibiotics in the treatment of Vibrio vulnificus infection in a mouse model. AB - The Centers for Disease Control and Prevention (CDC) recommend oral or intravenous doxycycline plus a third-generation cephalosporin or fluoroquinolone alone for the treatment of Vibrio vulnificus infections. Until now, no study has compared oral with parenteral administered doxycycline with respect to their in vivo efficacy. In the present work, ICR mice infected with a high dose of V. vulnificus were administered ciprofloxacin, ceftriaxone, and doxycycline. The bacterial DNA copy number in surviving and non-surviving mice was determined using quantitative polymerase chain reaction (qPCR). In this setting, ciprofloxacin was the most effective monotherapeutic drug, but a higher survival rate (50%) was achieved using the combination therapy of intraperitoneal doxycycline plus ceftriaxone. The blood of non-surviving mice at 12 h post infection contained at least 10(4) DNA copies/MUL, in contrast to 10(2) to 10(3) DNA copies/MUL in surviving mice. Thus, in the treatment of V. vulnificus infections in humans, when the intravenous form of doxycycline is unavailable, ciprofloxacin might be a better option than oral doxycycline to lower mortality. In addition, our results demonstrate that qPCR can be a useful tool for identifying the V. vulnificus load in infected patients, with the DNA copy number providing a marker of either disease severity or mortality. PMID- 22434455 TI - Obesity and symptomatic osteoarthritis of the knee. AB - Given the growing prevalence of obesity around the world and its association with osteoarthritis of the knee, orthopaedic surgeons need to be familiar with the management of the obese patient with degenerative knee pain. The precise mechanism by which obesity leads to osteoarthritis remains unknown, but is likely to be due to a combination of mechanical, humoral and genetic factors. Weight loss has clear medical benefits for the obese patient and seems to be a logical way of relieving joint pain associated with degenerative arthritis. There are a variety of ways in which this may be done including diet and exercise, and treatment with drugs and bariatric surgery. Whether substantial weight loss can delay or even reverse the symptoms associated with osteoarthritis remains to be seen. Surgery for osteoarthritis in the obese patient can be technically more challenging and carries a risk of additional complications. Substantial weight loss before undertaking total knee replacement is advisable. More prospective studies that evaluate the effect of significant weight loss on the evolution of symptomatic osteoarthritis of the knee are needed so that orthopaedic surgeons can treat this patient group appropriately. PMID- 22434456 TI - The World Health Organization '5 moments of hand hygiene': the scientific foundation. AB - The World Health Organization (WHO) launched the first Global Patient Safety Challenge in 2005 and introduced the '5 moments of hand hygiene' in 2009 in an attempt to reduce the burden of health care associated infections. Many NHS trusts in England adopted this model of hand hygiene, which prompts health care workers to clean their hands at five distinct stages of caring for the patient. Our review analyses the scientific foundation for the five moments of hand hygiene and explores the evidence, as referenced by WHO, to support these recommendations. We found no strong scientific support for this regime of hand hygiene as a means of reducing health care associated infections. Consensus-based guidelines based on weak scientific foundations should be assessed carefully to prevent shifting the clinical focus from more important issues and to direct limited resources more effectively. We recommend caution in the universal adoption of the WHO '5 moments of hand hygiene' by orthopaedic surgeons and other health care workers and emphasise the need for evidence-based principles when adopting hospital guidelines aimed at promoting excellence in clinical practice. PMID- 22434457 TI - The early management of patients with multiple injuries: an evidence-based, practical guide for the orthopaedic surgeon. AB - There have been many advances in the resuscitation and early management of patients with severe injuries during the last decade. These have come about as a result of the reorganisation of civilian trauma services in countries such as Germany, Australia and the United States, where the development of trauma systems has allowed a concentration of expertise and research. The continuing conflicts in the Middle East have also generated a significant increase in expertise in the management of severe injuries, and soldiers now survive injuries that would have been fatal in previous wars. This military experience is being translated into civilian practice. The aim of this paper is to give orthopaedic surgeons a practical, evidence-based guide to the current management of patients with severe, multiple injuries. It must be emphasised that this depends upon the expertise, experience and facilities available within the local health-care system, and that the proposed guidelines will inevitably have to be adapted to suit the local resources. PMID- 22434458 TI - An information revolution in orthopaedics. AB - With the established success of the National Joint Registry and the emergence of a range of new national initiatives for the capture of electronic data in the National Health Service, orthopaedic surgery in the United Kingdom has found itself thrust to the forefront of an information revolution. In this review we consider the benefits and threats that this revolution poses, and how orthopaedic surgeons should marshal their resources to ensure that this is a force for good. PMID- 22434459 TI - A prospective randomised controlled trial comparing three alternative bearing surfaces in primary total hip replacement. AB - The ideal bearing surface for young patients undergoing total hip replacement (THR) remains controversial. We report the five-year results of a randomised controlled trial comparing the clinical and radiological outcomes of 102 THRs in 91 patients who were < 65 years of age. These patients were randomised to receive a cobalt-chrome on ultra-high-molecular-weight polyethylene, cobalt-chrome on highly cross-linked polyethylene, or a ceramic-on-ceramic bearing. In all, 97 hip replacements in 87 patients were available for review at five years. Two hips had been revised, one for infection and one for peri-prosthetic fracture. At the final follow-up there were no significant differences between the groups for the mean Western Ontario and McMaster Universities osteoarthritis index (pain, p = 0.543; function, p = 0.10; stiffness, p = 0.99), Short Form-12 (physical component, p = 0.878; mental component, p = 0.818) or Harris hip scores (p = 0.22). Radiological outcomes revealed no significant wear in the ceramic group. Comparison of standard and highly cross-linked polyethylene, however, revealed an almost threefold difference in the mean annual linear wear rates (0.151 mm/year versus 0.059 mm/year, respectively) (p < 0.001). PMID- 22434460 TI - Impact of arthroscopy of the hip for femoroacetabular impingement on quality of life at a mean follow-up of 3.2 years. AB - The benefit of arthroscopy of the hip in the treatment of femoroacetabular impingement (FAI) in terms of quality of life (QoL) has not been reported. We prospectively collected data on 612 patients (257 women (42%) and 355 men (58%)) with a mean age at the time of surgery of 36.7 years (14 to 75) who underwent arthroscopy of the hip for FAI under the care of a single surgeon. The minimum follow-up was one year (mean 3.2 years (1 to 7)). The responses to the modified Harris hip score were translated using the Rosser Index Matrix in order to provide a QoL score. The mean QoL score increased from 0.946 (-1.486 to 0.995) to 0.974 (0.7 to 1) at one year after surgery (p < 0.001). The mean QoL score in men was significantly higher than in women, both before and one year after surgery (both p < 0.001). However, the mean change in the QoL score was not statistically different between men and women (0.02 (-0.21 to 0.27) and 0.04 (-0.16 to 0.87), respectively; p = 0.12). Linear regression analysis revealed that the significant predictors of a change in QoL score were pre-operative QoL score (p < 0.001) and gender (p = 0.04). The lower the pre-operative score, the higher the gain in QoL post-operatively (rho = -0.66; p < 0.001). One year after surgery the QoL scores in the 612 patients had improved in 469 (76.6%), remained unchanged in 88 (14.4%) and had deteriorated in 55 (9.0%). PMID- 22434461 TI - Ten-year clinical, radiological and metal ion analysis of the Birmingham Hip Resurfacing: from a single, non-designer surgeon. AB - We present the clinical results and survivorship of consecutive 100 Birmingham Hip Resurfacings in 90 patients at a minimum follow-up of ten years. All procedures were carried out by an independent surgeon who commenced a prospective study in 1998. Patients were assessed clinically using the Western Ontario and McMaster Universities osteoarthritis index, Short-Form 36, Harris hip score and University of California, Los Angeles activity score. Radiological analysis was performed by an independent observer and blood metal ion levels concentrations were measured at ten years post-operatively in 62 patients. The median acetabular component inclination was 46.2 degrees (34 degrees to 59 degrees ) and anteversion 11.0 degrees (0 degrees to 30 degrees ). The median chromium concentration in the unilateral group was 1.74 (0.41 to 15.23) and for the bilateral group was 2.98 (1.57 to 18.01). The equivalent values for cobalt were 1.67 (0.54 to 20.4) and 1.88 (1.38 to 19.32). In total there were eight failures giving an overall survival at ten years of 92% (95% confidence interval (CI) 86.7 to 97.3). BHR in male patients had an improved survivorship of 94.6% (95% CI 89.4 to 100) compared with females at 84.6% (95% CI 70.7 to 98.5), but this did not reach statistical significance (p = 0.119). Four of the nine BHRs with a bearing diameter of 42 mm failed. The overall results were consistent with data produced from other centres in that the clinical outcome of large male patients was extremely encouraging, whereas the survival of the smaller joints was less satisfactory. PMID- 22434462 TI - Femoral offset is underestimated on anteroposterior radiographs of the pelvis but accurately assessed on anteroposterior radiographs of the hip. AB - The aim of this retrospective cohort study was to identify any difference in femoral offset as measured on pre-operative anteroposterior (AP) radiographs of the pelvis, AP radiographs of the hip and corresponding CT scans in a consecutive series of 100 patients with primary end-stage osteoarthritis of the hip (43 men and 57 women with a mean age of 61 years (45 to 74) and a mean body mass index of 28 kg/m(2) (20 to 45)). Patients were positioned according to a standardised protocol to achieve reproducible projection and all images were calibrated. Inter and intra-observer reliability was evaluated and agreement between methods was assessed using Bland-Altman plots. In the entire cohort, the mean femoral offset was 39.0 mm (95% confidence interval (CI) 37.4 to 40.6) on radiographs of the pelvis, 44.0 mm (95% CI 42.4 to 45.6) on radiographs of the hip and 44.7 mm (95% CI 43.5 to 45.9) on CT scans. AP radiographs of the pelvis underestimated femoral offset by 13% when compared with CT (p < 0.001). No difference in mean femoral offset was seen between AP radiographs of the hip and CT (p = 0.191). Our results suggest that femoral offset is significantly underestimated on AP radiographs of the pelvis but can be reliably and accurately assessed on AP radiographs of the hip in patients with primary end-stage hip osteoarthritis. We, therefore, recommend that additional AP radiographs of the hip are obtained routinely for the pre-operative assessment of femoral offset when templating before total hip replacement. PMID- 22434463 TI - Hip resurfacing with femoral osteotomy for painful subluxed or dislocated hips in patients with cerebral palsy. AB - The painful subluxed or dislocated hip in adults with cerebral palsy presents a challenging problem. Prosthetic dislocation and heterotopic ossification are particular concerns. We present the first reported series of 19 such patients (20 hips) treated with hip resurfacing and proximal femoral osteotomy. The pre operative Gross Motor Function Classification System (GMFCS) was level V in 13 (68%) patients, level IV in three (16%), level III in one (5%) and level II in two (11%). The mean age at operation was 37 years (13 to 57). The mean follow-up was 8.0 years (2.7 to 11.6), and 16 of the 18 (89%) contactable patients or their carers felt that the surgery had been worthwhile. Pain was relieved in 16 of the 18 surviving hips (89%) at the last follow-up, and the GMFCS level had improved in seven (37%) patients. There were two (10%) early dislocations; three hips (15%) required revision of femoral fixation, and two hips (10%) required revision, for late traumatic fracture of the femoral neck and extra-articular impingement, respectively. Hence there were significant surgical complications in a total of seven hips (35%). No hips required revision for instability, and there were no cases of heterotopic ossification. We recommend hip resurfacing with proximal femoral osteotomy for the treatment of the painful subluxed or dislocated hip in patients with cerebral palsy. PMID- 22434464 TI - Autologous chondrocyte implantation for osteochondral lesions in the knee using a bilayer collagen membrane and bone graft: a two- to eight-year follow-up study. AB - Matrix-induced autologous chondrocyte implantation (MACI) is an established technique used to treat osteochondral lesions in the knee. For larger osteochondral lesions (> 5 cm(2)) deeper than approximately 8 mm we have combined the use of two MACI membranes with impaction grafting of the subchondral bone. We report our results of 14 patients who underwent the 'bilayer collagen membrane' technique (BCMT) with a mean follow-up of 5.2 years (2 to 8). There were 12 men and two women with a mean age of 23.6 years (16 to 40). The mean size of the defect was 7.2 cm(2) (5.2 to 12 cm(2)) and were located on the medial (ten) or lateral (four) femoral condyles. The mean modified Cincinnati knee score improved from 45.1 (22 to 70) pre-operatively to 82.8 (34 to 98) at the most recent review (p < 0.05). The visual analogue pain score improved from 7.3 (4 to 10) to 1.7 (0 to 6) (p < 0.05). Twelve patients were considered to have a good or excellent clinical outcome. One graft failed at six years. The BCMT resulted in excellent functional results and durable repair of large and deep osteochondral lesions without a high incidence of graft-related complications. PMID- 22434465 TI - Loss to follow-up after arthroplasty: a new use for registry data. AB - We assessed the outcome of patients who were lost to follow-up after arthroplasty by a single surgeon. The aim was to validate the surgeon's data set with the Australian Orthopaedic Association National Joint Replacement Registry and determine the outcome of those patients lost to follow-up. Prospective data on patient demographics, operative details and outcomes of the surgeon's 1192 primary unicompartmental knee arthroplasty (UKA) procedures were analysed. There were 69 knees in patients who were lost to follow-up, among whom the Registry identified 31 deaths and eight revisions. The cumulative percentage revision (CPR) at seven years using the additional Registry data was 8.8% (95% confidence interval (CI) 7 to 11). Using the surgeon's data, the CPR at seven years was 8% (95% CI 6.3 to 10.1) for the best-case scenario where loss to follow-up was excluded, and 16% (95% CI 13.8 to 19.4) for the worst-case scenario, where all patients lost to follow-up were deemed to have been revised. There was a significantly higher mortality rate in those patients lost to follow-up. This study demonstrates that a national joint registry can be used by individual surgeons to establish more accurate revision rates in their arthroplasty patients. This is expected to facilitate a more rigorous audit of surgical outcomes by surgeons and lead to more accurate and uniform reporting of the results of arthroplasty in general. PMID- 22434466 TI - A prospective clinical and radiological study comparing hydroxyapatite-coated with cemented tibial components in total knee replacement. AB - This prospective study compares the outcome of 157 hydroxyapatite (HA)-coated tibial components with 164 cemented components in the ROCC Rotating Platform total knee replacement in 291 patients. The mean follow-up was 7.6 years (5.2 to 11). There were two revisions for loosening: one for an HA-coated and one for a cemented tibial component. Radiological evaluation demonstrated no radiolucent lines with the HA-coated femoral components. A total of three HA-coated tibial components exhibited radiolucent lines at three months post-operatively and these disappeared after three further months of protected weight-bearing. With HA coated components the operating time was shorter (p < 0.006) and the radiological assessment of the tibial interface was more stable (p < 0.01). Using revision for aseptic loosening of the tibial component as the end point, the survival rates at nine years was identical for both groups at 99.1%. Our results suggest that HA coated components perform at least as well as the same design with cemented components and compare favourably with those of series describing cemented or porous-coated knee replacements, suggesting that fixation of both components with hydroxyapatite is a reliable option in primary total knee replacement. PMID- 22434467 TI - Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee. AB - Autologous chondrocyte implantation (ACI) and mosaicplasty are methods of treating symptomatic articular cartilage defects in the knee. This study represents the first long-term randomised comparison of the two techniques in 100 patients at a minimum follow-up of ten years. The mean age of the patients at the time of surgery was 31.3 years (16 to 49); the mean duration of symptoms pre operatively was 7.2 years (9 months to 20 years). The lesions were large with the mean size for the ACI group being 440.9 mm(2) (100 to 1050) and the mosaicplasty group being 399.6 mm(2) (100 to 2000). Patients had a mean of 1.5 previous operations (0 to 4) to the articular cartilage defect. Patients were assessed using the modified Cincinnati knee score and the Stanmore-Bentley Functional Rating system. The number of patients whose repair had failed at ten years was ten of 58 (17%) in the ACI group and 23 of 42 (55%) in the mosaicplasty group (p < 0.001). The functional outcome of those patients with a surviving graft was significantly better in patients who underwent ACI compared with mosaicplasty (p = 0.02). PMID- 22434468 TI - Review of Kinemax total knee replacements performed at the NHS treatment centre, Weston-Super-Mare: five-year results. AB - As part of the national initiative to reduce waiting times for joint replacement surgery in Wales, the Cardiff and Vale NHS Trust referred 224 patients to the NHS Treatment Centre in Weston-Super-Mare for total knee replacement (TKR). A total of 258 Kinemax TKRs were performed between November 2004 and August 2006. Of these, a total of 199 patients (232 TKRs, 90%) have been followed up for five years. This cohort was compared with 258 consecutive TKRs in 250 patients, performed at Cardiff and Vale Orthopaedic Centre (CAVOC) over a similar time period. The five year cumulative survival rate was 80.6% (95% confidence interval (CI) 74.0 to 86.0) in the Weston-Super-Mare cohort and 95.0% (95% CI 90.2 to 98.2) in the CAVOC cohort with revision for any reason as the endpoint. The relative risk for revision at Weston-Super-Mare compared with CAVOC was 3.88 (p < 0.001). For implants surviving five years, the mean Oxford knee scores (OKS) and mean EuroQol (EQ-5D) scores were similar (OKS: Weston-Super-Mare 29 (2 to 47) vs CAVOC 29.8 (3 to 48), p = 0.61; EQ-5D: Weston-Super-Mare 0.53 (-0.38 to 1.00) vs CAVOC 0.55 (-0.32 to 1.00), p = 0.79). Patients with revised TKRs had significantly lower Oxford knee and EQ-5D scores (p < 0.001). The results show a higher revision rate for patients operated at Weston-Super-Mare Treatment Centre, with a reduction in functional outcome and quality of life after revision. This further confirms that patients moved from one area to another for joint replacement surgery fare poorly. PMID- 22434469 TI - Zona conoidea of the elbow: another articulation between the radial head and lateral trochlear of the elbow. AB - The zona conoidea comprises the area of the lateral trochlear ridge of the humerus. The purpose of this study is to reintroduce this term 'zona conoidea' to the discussion of the human elbow and to investigate its significance in the development of osteoarthritis of the elbow. The upper extremities of 12 cadavers were prepared. With the forearm in neutral, pronation and supination, the distance between the bevel of the radial head and zona conoidea was inspected. A total of 12 healthy volunteers had a CT scan. The distance between the zona conoidea and the bevelled rim of the radial head was measured in these positions. In the anatomical specimens, early osteo-arthritic changes were identified in the posteromedial bevelled rim of the radial head, and the corresponding zona conoidea in supination. Measurement in the CT study showed that in full supination, the distance between the bevel of the radial head and the zona conoidea was at a minimum. This study suggests that the significant contact between the bevel of the radial head and the zona conoidea in supination is associated with the initiation of osteoarthritis of the elbow in this area. PMID- 22434470 TI - Nerve injuries sustained during warfare: part I--Epidemiology. AB - We describe 261 peripheral nerve injuries sustained in war by 100 consecutive service men and women injured in Iraq and Afghanistan. Their mean age was 26.5 years (18.1 to 42.6), the median interval between injury and first review was 4.2 months (mean 8.4 months (0.36 to 48.49)) and median follow-up was 28.4 months (mean 20.5 months (1.3 to 64.2)). The nerve lesions were predominantly focal prolonged conduction block/neurapraxia in 116 (45%), axonotmesis in 92 (35%) and neurotmesis in 53 (20%) and were evenly distributed between the upper and the lower limbs. Explosions accounted for 164 (63%): 213 (82%) nerve injuries were associated with open wounds. Two or more main nerves were injured in 70 patients. The ulnar, common peroneal and tibial nerves were most commonly injured. In 69 patients there was a vascular injury, fracture, or both at the level of the nerve lesion. Major tissue loss was present in 50 patients: amputation of at least one limb was needed in 18. A total of 36 patients continued in severe neuropathic pain. This paper outlines the methods used in the assessment of these injuries and provides information about the depth and distribution of the nerve lesions, their associated injuries and neuropathic pain syndromes. PMID- 22434471 TI - Nerve injuries sustained during warfare: part II: Outcomes. AB - The outcomes of 261 nerve injuries in 100 patients were graded good in 173 cases (66%), fair in 70 (26.8%) and poor in 18 (6.9%) at the final review (median 28.4 months (1.3 to 64.2)). The initial grades for the 42 sutures and graft were 11 good, 14 fair and 17 poor. After subsequent revision repairs in seven, neurolyses in 11 and free vascularised fasciocutaneous flaps in 11, the final grades were 15 good, 18 fair and nine poor. Pain was relieved in 30 of 36 patients by nerve repair, revision of repair or neurolysis, and flaps when indicated. The difference in outcome between penetrating missile wounds and those caused by explosions was not statistically significant; in the latter group the onset of recovery from focal conduction block was delayed (mean 4.7 months (2.5 to 10.2) vs 3.8 months (0.6 to 6); p = 0.0001). A total of 42 patients (47 lower limbs) presented with an insensate foot. By final review (mean 27.4 months (20 to 36)) plantar sensation was good in 26 limbs (55%), fair in 16 (34%) and poor in five (11%). Nine patients returned to full military duties, 18 to restricted duties, 30 to sedentary work, and 43 were discharged from military service. Effective rehabilitation must be early, integrated and vigorous. The responsible surgeons must be firmly embedded in the process, at times exerting leadership. PMID- 22434472 TI - Modern military surgery: lessons from Iraq and Afghanistan. AB - The types of explosive devices used in warfare and the pattern of war wounds have changed in recent years. There has, for instance, been a considerable increase in high amputation of the lower limb and unsalvageable leg injuries combined with pelvic trauma. The conflicts in Iraq and Afghanistan prompted the Department of Military Surgery and Trauma in the United Kingdom to establish working groups to promote the development of best practice and act as a focus for research. In this review, we present lessons learnt in the initial care of military personnel sustaining major orthopaedic trauma in the Middle East. PMID- 22434473 TI - Validation of a standardised gait score to predict the healing of tibial fractures. AB - There is no absolute method of evaluating healing of a fracture of the tibial shaft. In this study we sought to validate a new clinical method based on the systematic observation of gait, first by assessing the degree of agreement between three independent observers regarding the gait score for a given patient, and secondly by determining how such a score might predict healing of a fracture. We used a method of evaluating gait to assess 33 patients (29 men and four women, with a mean age of 29 years (15 to 62)) who had sustained an isolated fracture of the tibial shaft and had been treated with a locked intramedullary nail. There were 15 closed and 18 open fractures (three Gustilo and Anderson grade I, seven grade II, seven grade IIIA and one grade IIIB). Assessment was carried out three and six months post-operatively using videos taken with a digital camera. Gait was graded on a scale ranging from 1 (extreme difficulty) to 4 (normal gait). Bivariate analysis included analysis of variance to determine whether the gait score statistically correlated with previously validated and standardised scores of clinical status and radiological evidence of union. An association was found between the pattern of gait and all the other variables. Improvement in gait was associated with the absence of pain on weight-bearing, reduced tenderness over the fracture, a higher Radiographic Union Scale in Tibial Fractures score, and improved functional status, measured using the Brazilian version of the Short Musculoskeletal Function Assessment questionnaire (all p < 0.001). Although further study is needed, the analysis of gait in this way may prove to be a useful clinical tool. PMID- 22434474 TI - Reporting and interpretation of the functional outcomes after the surgical treatment of disruptions of the pelvic ring: a systematic review. AB - We performed a systematic review of the literature to evaluate the use and interpretation of generic and disease-specific functional outcome instruments in the reporting of outcome after the surgical treatment of disruptions of the pelvic ring. A total of 28 papers met our inclusion criteria, with eight reporting only generic outcome instruments, 13 reporting only pelvis-specific outcome instruments, and six reporting both. The Short-Form 36 (SF-36) was by far the most commonly used generic outcome instrument, used in 12 papers, with widely variable reporting of scores. The pelvis-specific outcome instruments were used in 19 studies; the Majeed score in ten, Iowa pelvic score in six, Hannover pelvic score in two and the Orlando pelvic score in one. Four sets of authors, all testing construct validity based on correlation with the SF-36, performed psychometric testing of three pelvis-specific instruments (Majeed, IPS and Orlando scores). No testing of responsiveness, content validity, criterion validity, internal consistency or reproducibility was performed. The existing literature in this area is inadequate to inform surgeons or patients in a meaningful way about the functional outcomes of these fractures after fixation. PMID- 22434475 TI - Growth disturbance after lengthening of the lower limb and quantitative assessment of physeal closure in skeletally immature patients with achondroplasia. AB - This study evaluated the effect of limb lengthening on longitudinal growth in patients with achondroplasia. Growth of the lower extremity was assessed retrospectively by serial radiographs in 35 skeletally immature patients with achondroplasia who underwent bilateral limb lengthening (Group 1), and in 12 skeletally immature patients with achondroplasia who did not (Group 2). In Group 1, 23 patients underwent only tibial lengthening (Group 1a) and 12 patients underwent tibial and femoral lengthening sequentially (Group 1b). The mean lengthening in the tibia was 9.2 cm (59.5%) in Group 1a, and 9.0 cm (58.2%) in the tibia and 10.2 cm (54.3%) in the femur in Group 1b. The mean follow-up was 9.3 years (8.6 to 10.3). The final mean total length of lower extremity in Group 1a was 526.6 mm (501.3 to 552.9) at the time of skeletal maturity and 610.1 mm (577.6 to 638.6) in Group 1b, compared with 457.0 mm (411.7 to 502.3) in Group 2. However, the mean actual length, representing the length solely grown from the physis without the length of distraction, showed that there was a significant disturbance of growth after limb lengthening. In Group 1a, a mean decrease of 22.4 mm (21.3 to 23.1) (4.9%) was observed in the actual limb length when compared with Group 2, and a greater mean decrease of 38.9 mm (37.2 to 40.8) (8.5%) was observed in Group 1b when compared with Group 2 at skeletal maturity. In Group 1, the mean actual limb length was 16.5 mm (15.8 to 17.2) (3.6%) shorter in Group 1b when compared with Group 1a at the time of skeletal maturity. Premature physeal closure was seen mostly in the proximal tibia and the distal femur with relative preservation of proximal femur and distal tibia. We suggest that significant disturbance of growth can occur after extensive limb lengthening in patients with achondroplasia, and therefore, this should be included in pre operative counselling of these patients and their parents. PMID- 22434476 TI - The development of fibronectin-functionalised hydroxyapatite coatings to improve dermal fibroblast attachment in vitro. AB - The success of long-term transcutaneous implants depends on dermal attachment to prevent downgrowth of the epithelium and infection. Hydroxyapatite (HA) coatings and fibronectin (Fn) have independently been shown to regulate fibroblast activity and improve attachment. In an attempt to enhance this phenomenon we adsorbed Fn onto HA-coated substrates. Our study was designed to test the hypothesis that adsorption of Fn onto HA produces a surface that will increase the attachment of dermal fibroblasts better than HA alone or titanium alloy controls. Iodinated Fn was used to investigate the durability of the protein coating and a bioassay using human dermal fibroblasts was performed to assess the effects of the coating on cell attachment. Cell attachment data were compared with those for HA alone and titanium alloy controls at one, four and 24 hours. Protein attachment peaked within one hour of incubation and the maximum binding efficiency was achieved with an initial droplet of 1000 ng. We showed that after 24 hours one-fifth of the initial Fn coating remained on the substrates, and this resulted in a significant, three-, four-, and sevenfold increase in dermal fibroblast attachment strength compared to uncoated controls at one, four and 24 hours, respectively. PMID- 22434477 TI - Fracture of a ceramic component in total hip replacement. AB - Fracture of a ceramic component in total hip replacement is a rare but potentially catastrophic complication. The incidence is likely to increase as the use of ceramics becomes more widespread. We describe such a case, which illustrates how inadequate initial management will lead to further morbidity and require additional surgery. We present the case as a warning that fracture of a ceramic component should be revised to another ceramic-on-ceramic articulation in order to minimise the risk of further catastrophic wear. PMID- 22434479 TI - Density-cluster NMA: A new protein decomposition technique for coarse-grained normal mode analysis. AB - Normal mode analysis has emerged as a useful technique for investigating protein motions on long time scales. This is largely due to the advent of coarse-graining techniques, particularly Hooke's Law-based potentials and the rotational translational blocking (RTB) method for reducing the size of the force-constant matrix, the Hessian. Here we present a new method for domain decomposition for use in RTB that is based on hierarchical clustering of atomic density gradients, which we call Density-Cluster RTB (DCRTB). The method reduces the number of degrees of freedom by 85-90% compared with the standard blocking approaches. We compared the normal modes from DCRTB against standard RTB using 1-4 residues in sequence in a single block, with good agreement between the two methods. We also show that Density-Cluster RTB and standard RTB perform well in capturing the experimentally determined direction of conformational change. Significantly, we report superior correlation of DCRTB with B-factors compared with 1-4 residue per block RTB. Finally, we show significant reduction in computational cost for Density-Cluster RTB that is nearly 100-fold for many examples. PMID- 22434480 TI - Correspondence of Ru(III) Ru(II) and Ru(IV) Ru(III) mixed valent states in a small dinuclear complex. AB - The diruthenium(III) compound [(MU-oxa){Ru(acac)(2)}(2)] [1, oxa(2-) =oxamidato(2 ), acac(-) =2,4-pentanedionato] exhibits an S=1 ground state with antiferromagnetic spin-spin coupling (J=-40 cm(-1)). The molecular structure in the crystal of 1?2 C(7)H(8) revealed an intramolecular metal-metal distance of 5.433 A and a notable asymmetry within the bridging ligand. Cyclic voltammetry and spectroelectrochemistry (EPR, UV/Vis/NIR) of the two-step reduction and of the two-step oxidation (irreversible second step) produced monocation and monoanion intermediates (K(c) =10(5.9)) with broad NIR absorption bands (epsilon ca. 2000 M(-1)cm(-1)) and maxima at 1800 (1(-)) and 1500 nm (1(+)). TD-DFT calculations support a Ru(III)Ru(II) formulation for 1(-) with a doublet ground state. The 1(+) ion (Ru(IV)Ru(III)) was calculated with an S=3/2 ground state and the doublet state higher in energy (DeltaE=694.6 cm(-1)). The Mulliken spin density calculations showed little participation of the ligand bridge in the spin accommodation for all paramagnetic species [(MU-oxa){Ru(acac)(2)}(2)](n), n=+1, 0, -1, and, accordingly, the NIR absorptions were identified as metal-to-metal (intervalence) charge transfers. Whereas only one such NIR band was observed for the Ru(III)Ru(II) (4d(5)/4d(6)) system 1(-), the Ru(IV)Ru(III) (4d(4)/4d(5)) form 1(+) exhibited extended absorbance over the UV/Vis/NIR range. PMID- 22434481 TI - Different clonal origin of bilateral papillary thyroid carcinoma, with a review of the literature. AB - Papillary thyroid carcinoma (PTC) often presents with two or more anatomically separate foci. A long-standing argument is whether this multifocality is the result of multiple independent tumors ("multicentricity") or of intrathyroidal spread originating from a single tumor mass, presumably through permeation of intrathyroidal lymph vessels. We reexamined this issue with a clonality assay and compared our results with those in the literature. A total of 27 nodules from 11 female patients with bilateral PTC treated with total thyroidectomy were investigated for clonality using the HUMARA assay. Eight of 11 cases were informative (72.7 %). All but one of tumor foci showed a monoclonal population. The outlier sample gave a value indicative of balanced X-inactivation in one nodule. The monoclonality was concordant in three patients, discordant in three, and mixed in two (with both concordant and discordant results). Interestingly, in both of the latter cases (composed of over two samples per case), the contralateral nodules were discordant. Moreover, all four ipsilateral nodules were concordant. The results of our study suggest that some cases of multifocal PTC are the result of true multicentricity, whereas others are the consequence of intrathyroid spread by an originally single tumor mass. These conclusions support those made in the past years on the basis of morphologic considerations. Specifically, the incidental finding of two or more microscopic foci of PTC widely separate from each other was felt to favor multicentricity, whereas the finding of multiple ipsilateral foci of PTC within vascular spaces, often accompanied by multiple lymph node metastases, suggested intrathyroid spread; the most striking manifestation of this phenomenon being seen in the diffuse sclerosing variant of PTC. PMID- 22434482 TI - [Laser now also to be used in organ-preserving kidney surgery?]. AB - Kidney surgery is subject to continuous change. Partial nephrectomy is the prevailing method for small and medium-sized tumours and proven to be superior to radical nephrectomy. The conventional technique usually includes clamping the renal vessels. The duration of the ischaemia caused determines the outcome of the remaining renal function. The shorter the ischaemic time the more likely the renal function will be preserved. Thus, new techniques are needed to abandon renal vessel clamping. Essential is a combination of good cutting abilities and assured haemostasis. To date, the commonly used techniques for cutting in partial nephrectomy only partially fulfil these requirements. Establishment of laser in urology offers a new surgical technique that combines both. In spite of the still limited data on laser use in kidney surgery, this method can be assessed favourably. Laser offers a possibility of both open and laparoscopic partial nephrectomy avoiding renal vessel clamping without additional risks or complications. PMID- 22434483 TI - [Imperative cystectomy in patients at risk. Ileal conduit or ureterocutaneostomy?]. AB - Due to the demographic trends, the incidence of bladder cancer will rise. Based on progress in perioperative management, radical cystectomy has become feasible also in elderly patients with muscle-invasive bladder cancer. Also caused by the increase of age-related comorbidities, the question arises as to the optimal urinary diversion in patients at risk. The ileal conduit is the accepted standard due to its safe, well-proven, and low-risk performance. Nevertheless, it was shown to have relevant complication rates in patients at risk, mostly because of the bowel involvement. The ureterocutaneostomy is a safer and easier alternative, which was initially shown to have a high rate of stomal stenosis. However, new data suggest that the stent-free rate is comparable to the ileal conduit. In addition, quality of life analyses show comparable results. Therefore, ureterocutaneostomy should be considered as an option for urinary diversion in patients at risk. PMID- 22434484 TI - A numerical model of birch pollen emission and dispersion in the atmosphere. Model evaluation and sensitivity analysis. AB - An evaluation of performance of the System for Integrated modeLling of Atmospheric coMposition (SILAM) in application to birch pollen dispersion is presented. The system is described in a companion paper whereas the current study evaluates the model sensitivity to details of the pollen emission module parameterisation and to the meteorological input data. The most important parameters are highlighted. The reference year considered for the analysis is 2006. It is shown that the model is capable of predicting about two-thirds of allergenic alerts, with the odds ratio exceeding 12 for the best setup. Several other statistics corroborate with these estimations. Low-pollen concentration days are also predicted correctly in more than two-thirds of cases. The model experiences certain difficulties only with intermediate pollen concentrations. It is demonstrated that the most important input parameter is the near-surface temperature, the bias of which can easily jeopardise the results. The model sensitivity to random fluctuations of temperature is much lower. Other parameters important at various stages of pollen development, release, and dispersion are precipitation and ambient humidity, as well as wind direction. PMID- 22434486 TI - Manufacturing of inorganic nanomaterials: concepts and perspectives. AB - The present paper aims at extracting key physical and chemical concepts for the development of inorganic nanomaterials with controlled size, shape, and topology. In particular, efforts are made to identify general guiding principles for the rational design of 0D, 1D, 2D and 3D architectures, focusing on selected model systems as representative case studies. To this aim, different strategies and approaches are discussed, in an attempt to unify concepts and ideas common to solid-, liquid- and gas-phase synthetic routes. Furthermore, the importance of tailoring the nanomaterial composition, structure and morphology is also highlighted in relation to their eventual technological applications. PMID- 22434485 TI - Effect of polyphenols extracted from tamarind (Tamarindus indica L.) seed coat on pathophysiological changes and red blood cell glutathione peroxidase activity in heat-stressed broilers. AB - The purpose of this study was to determine the effect of polyphenols extracted from the tamarind seed coat (PETSC) on glutathione peroxidase (GPx) activity, red blood cell parameters and bilirubin in heat-stressed broilers. One hundred forty seven broilers, 18-days old were divided into two groups. In group 1, broilers were maintained at an environmental temperature of 26 +/- 2 degrees C throughout the experimental period. In group 2, the broilers were maintained at 38 +/- 2 degrees C (cyclic temperature: 26 +/- 2 degrees C; -38 +/- 2 degrees C; and -26 +/- 2 degrees C, and broilers were maintained at 38 +/- 2 degrees C for 6 h/ day) and received PETSC at a concentration of 0, 100, 200, 300, 400 or 500 mg/kg in their diet ad libitum. Parameters were investigated on days 1, 7, 14 and 21 of the experimental period. Results showed that GPx activity of heat-stressed broilers that received 100 mg/kg of PETSC in their diet was lower (P < 0.05) than that in broilers fed the other concentrations. The mean total red blood cell count and hemoglobin concentration of heat-stressed broilers that received 100 mg/kg PETSC was higher (P < 0.05) than those in broilers in group 1 and those fed the other concentrations. The mean bilirubin level in the excreta of heat stressed broilers that received 100 mg/kg of PETSC was lower (P < 0.05) than that in broilers that received 0, 300, 400 and 500 mg/kg of PETSC. This showed that PETSC could reduce GPx activity and bilirubin in feces, and increase red blood cell parameters in heat-stressed broilers. PMID- 22434487 TI - Suicide by home made "guillotine" to the chest: a case report. AB - Cases of suicide by use of elaborate and complex devices are rare in the literature and popular media, despite the media attention such cases attract. These suicide cases have employed guillotines, contraptions involving guns and self-made firearms, and devices capable of delivering asphyxiating gases such as carbon monoxide. All previously reported cases of suicide by guillotine have been by decapitation. While suicidal sharp force injuries are rare, suicidal injuries to the chest are rarer still. This case is unusual because the lethal sharp force injury to the chest was inflicted by a home-made "guillotine". Investigators initially suspected a homicide because the body was found face down in the woods, far from human habitation. Thorough death scene and background investigation were essential in classifying it as an elaborate suicide. PMID- 22434488 TI - Electrochemically active cross-linking reaction for fluorescent labeling of aliphatic alkenes. AB - Although cross-linking reactions serve as a valuable tool for the integration of two or more functionalities or properties, the application of electrochemical synthesis to cross-linking reactions is restricted due to the difficulty of mass transfer. Thus, the primary purpose of this research is to explore electrochemical cross-linking systems to construct a fluorescent probe, triggered by the formation of a covalent linkage. The second purpose is to apply the probe to insoluble targets. Towards these goals, a combination of electrochemically active phenol derivatives and aliphatic alkenes were employed to form polycyclic compounds. Several of the dihydrobenzofuran derivatives formed through [3+2] cyclization reactions exhibited fluorescence. Furthermore, this approach allowed the effective modification of alkene-modified silica gel with electrochemically active species, which enables the construction of fluorescent probes that are triggered by C-C bond formation. PMID- 22434489 TI - Impact of disease progression date determination on progression-free survival estimates in advanced lung cancer. AB - BACKGROUND: In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression-free survival (PFS)-based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates. METHODS: Individual patient data from 21 trials (14 North Central Cancer Treatment Group trials and 7 Southwest Oncology Group trials) were used. The reported PD (RPD) was defined as either the radiographic scan date or the clinical deterioration date. PD was determined using Method 1 (M1), the RPD; M2, 1 day after the last progression free scan; M3, midpoint between the last progression-free scan and the RPD; and M4, an interval-censoring approach. PFS was estimated using Kaplan-Meier (M1-M3), and maximum-likelihood (M4) methods. Simulation studies were performed to understand the impact of the length of time elapsed between the last progression free scan and the PD on time-to-progression estimates. RESULTS: PFS estimates using the RPD were the highest, and M2 was the most conservative. M3 and M4 were similar because the majority of progressions occurred during treatment (ie, frequent disease assessments). M3 was influenced less by the length of the assessment schedules (percentage difference from the true time-to-progression, <1.5%) compared with M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials. CONCLUSIONS: The magnitude of difference in the PFS estimates was large enough to alter trial conclusions in patients with advanced lung cancer. The results indicate that standards for PD determination, the use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS-based endpoints. PMID- 22434492 TI - Can regenerated nerve fibers return to normal size? A long-term post-traumatic study of the rat median nerve crush injury model. AB - Whether post-traumatic regeneration can eventually result in rat peripheral nerve fibers regaining their pretrauma size is still an open question. While it has been shown that, after a sufficient duration in post-traumatic time, the number of regenerated rat peripheral nerve fibers can return to pretrauma numbers and the animal can regain normal prelesion function, no information regarding long term changes in the size parameters of the regenerated nerve fibers is available. To fill this gap, we have investigated the post-traumatic changes in myelinated axon and nerve fiber diameter, myelin thickness, and g-ratio (the ratio of the inner axonal diameter to the fiber diameter) at three different time points following nerve injury: week-6, week-8, and week-24. A standardized nerve crush injury of the rat median nerve obtained using a nonserrated clamp was used for this study. The results showed that, consistent with previous studies, fiber number returned to normal values at week-24, but both axon and fiber diameter and myelin thickness were still significantly lower at week-24 than prelesion, and the g-ratio, which remained unchanged during the regeneration process, was significantly reduced at week-24 in comparison to the prelesion value. On the basis of these results, the hypothesis that regenerated rat peripheral nerve fibers are able to return spontaneously to their normal pretrauma state, provided there is a sufficiently long recovery time postaxonotmesis, is not supported. PMID- 22434493 TI - Doctor-patient communication in radiology: a great opportunity for future radiology. AB - This text discusses several aspects of doctor-patient communication in radiology, including the origins, advantages, and ethical and legal aspects. Over the last 10 years, radiologists have assumed increasing responsibilities towards patients and society. Patients, who are becoming better informed and more aware about medical issues, have a right to be given a timely diagnosis and want to receive as much information as possible from the radiologist. This has implications for several levels of everyday radiological practice, including the organisation of work, legal and ethical aspects and radiologist training. Better interaction with the patient helps to build a closer, more trusting, relationship with the result that the radiologist will be more motivated in his or her work. Until now, radiologists were not adequately trained to communicate the diagnosis directly and verbally to patients, especially when the diagnosis was unfavourable. It is important to emphasise the need for more specific and practical training in this respect, which is indispensable for future developments of the discipline. PMID- 22434494 TI - MR imaging of rectal cancer before and after chemoradiation therapy. AB - PURPOSE: This study was done to determine the diagnostic accuracy of magnetic resonance (MR) imaging in patients with rectal carcinoma by comparing post chemoradiation MR imaging with pathological specimens. MATERIALS AND METHODS: We enrolled 39 patients with locally advanced rectal cancer. All patients received chemoradiation therapy before surgery and neoadjuvant chemoradiation therapy followed by MR imaging. MR images were analysed by a team of two expert radiologists unaware of the clinical and histopathological findings. RESULTS: Following neoadjuvant chemoradiation therapy, the analysis of MR images showed 23 (59%) patients with a rectal disease staged <=T2 and 16 (41%) with a disease staged >T2. Post-treatment histological staging (TNM) revealed 13 patients with a disease >T2 and 26 patients with a disease <=T2. Cohen's kappa to measure concordance between post-chemoradiation MR staging and histological response showed 83.6% concordance for disease confined to the serosa (<=T3): concordance was 97.22% for disease <=N1 and 33.33% for disease >N1. CONCLUSIONS: MR imaging is critical for discovering T3 disease; moreover, morphological MR imaging does not always provide the opportunity to discern small residual cancer cells hidden in fibrotic tissue that could cause involvement of circumferential resection margin (CRM) on histology. PMID- 22434495 TI - Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery. AB - The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood-brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug-targeting approaches and targeted nanotechnology-based systems, two promising strategies for BBB targeting and delivery of drugs to the brain. PMID- 22434496 TI - Compensation allows recovery of functional independence in people with severe motor impairments following spinal cord injury. PMID- 22434497 TI - Oral health is an important issue in end-of-life cancer care. AB - PURPOSE: This study aims to assess the prevalence of oral morbidity in patients receiving palliative care for cancers outside the head and neck region and to investigate if information concerning oral problems was given. METHODS: Patients were recruited from two Norwegian palliative care inpatient units. All patients went through a face-to-face interview, completed the Edmonton Symptom Assessment System (ESAS) covering 10 frequent cancer-related symptoms, and went through an oral examination including a mouth swab to test for Candida carriage. RESULTS: Ninety-nine of 126 patients (79 %) agreed to participate. The examined patients had a mean age of 64 years (range, 36-90 years) and 47 % were male. Median Karnofsky score was 40 (range, 20-80) and 87 % had metastatic disease. Estimated life expectancy was <3 months in 73 %. Dry mouth was reported by 78 %. The highest mean scores on the modified 0-10 ESAS scale were 4.9 (fatigue), 4.7 (dry mouth), and 4.4 (poor appetite). Clinical oral candidiasis was seen in 34 % (86 % positive cultures). Mouth pain was reported by 67 % and problems with food intake were reported by 56 %. Moderate or rich amounts of dental plaque were seen in 24 %, and mean number of teeth with visible carious lesions was 1.9. One patient was diagnosed with bisphosphonate-related osteonecrosis of the jaw. Overall, 78 % said they had received no information about oral adverse effects of cancer treatment. CONCLUSION: Patients in palliative care units need better mouth care. Increased awareness among staff about the presence and severity of oral problems is necessary. Systematic information about oral problems is important in all stages of cancer treatment. PMID- 22434498 TI - Ru(II) complexes with N-heterocyclic carbene ligands or terpyridine analogues: synthesis, characterization, and electrochemical and proton-dependent spectrometric properties. AB - Four ruthenium(II) complexes, BPT, BPN, BPPT, and BPPN, have been prepared and characterized by (1)H NMR, (13)C NMR, high resolution mass spectrometry (HRMS), elemental analysis, and X-ray crystallography. All the complexes incorporate a pyridyl unit on the terpyridine-type or N-heterocyclic carbene (NHC) ligand and the pyridyl unit can be protonated upon addition of 1.0 M HCl in diethyl ether. The proton-dependent absorption and luminescence spectrum were measured in CH(3)CN. In the case of BPT, the lambda(max)(abs) was moved by 10 nm from 490 nm to 500 nm after the addition of 12 equiv. of HCl and the intensity of the emission spectrum increased. In contrast, in the case of BPN, the lambda(max)(abs) was red-shifted by 43 nm from 424 nm to 467 nm and the emission was dramatically quenched upon the addition of the equiv. of HCl. However, there were no noticeable changes in the lambda(max)(abs) values of BPPT and BPPN even after the addition of the HCl to a solution of those complexes. Moreover, BPN has a selective sensing property for a proton among many cations. PMID- 22434499 TI - Performance of a new fluorescence camera for detection of occlusal caries in vitro. AB - The aim of this study was firstly to assess inter- and intra- examiner reproducibility and accuracy in the detection of occlusal caries in extracted human teeth using the newly developed fluorescence-based camera VistaCam iX and secondly to compare the performance to the established fluorescence device VistaProof. The occlusal surfaces of 101 teeth were assessed. The distribution of the lesions were characterized first visually using ICDAS-II (consensus score). The investigation sites were assessed by two examiners with different levels of experience in cariology (one experienced dentist, one final-year dental student) by both fluorescence-based cameras VistaCam iX (FC1) and VistaProof (FC2). The teeth were hemisectioned and assessed for lesion depth. Intra-class-correlation coefficients for inter- and intra-examiner reproducibility were 0.88-0.97 (FC1) and 0.82-0.98 (FC2), respectively. There was significant positive correlation (r (s), p < 0.01) between all methods (ICDAS-II, fluorescence, and histological examinations: 0.63-0.89) and between FC1 and FC2 (r (s) 0.85-0.90), respectively. Areas under the ROC curves (AUC) were 0.87-0.92 (D(1) and D(3) diagnostic threshold, FC1) and 0.91-0.96 (FC2). There were no significant differences between the AUC of both fluorescence cameras (p values > 0.05). Both fluorescence cameras demonstrated high reproducibility and good performance for the detection of occlusal caries at various stages of the disease process. The novice and the experienced examiner were able to apply both systems for detection of lesions. The in vitro performance of both devices was comparable to each other, although there was a tendency of a better performance for the FC2. Thus, within the limitations of an in vitro study, measurements with the FC2 can be continued by the new fluorescence camera (FC1) and data formerly assessed can be compared without significant loss of information. PMID- 22434500 TI - Effects of point mutations on protein structure are nonexponentially distributed. AB - Inspection of structure changes in proteins borne by altering their sequences brings understanding of physics, functioning and evolution of existing proteins, and helps engineer modified ones. On single amino acid substitutions, the most frequent mutation type, shifts in backbone conformation are typically small, raising doubts if and how such minor modifications could drive evolutionary divergence. Here, we report that the distribution of magnitudes of structure change on such substitutions is heavy-tailed--whereas protein structures are robust to most substitutions, changes much larger than average occur with raised odds compared to what would be expected for exponential distribution with the same mean. This nonexponential behavior allows for reconciling the apparent contradiction between the observed conservation of protein structures and the substantial evolutionary plasticity implied in their diversity. The presence of the heavy tail in the distribution promotes structure divergence, facilitating exploration of new functionality, and conformations within folds, as well as exploration of structure space for new folds. PMID- 22434502 TI - Partial resistance to powdery mildew in German spring wheat 'Naxos' is based on multiple genes with stable effects in diverse environments. AB - Powdery mildew is one of the most important wheat diseases in temperate regions of the world. Resistance breeding is considered to be an economical and environmentally benign way to control this disease. The German spring wheat cv. 'Naxos' exhibits high levels of partial and race non-specific resistance to powdery mildew in the field and is a valuable source in resistance breeding. The main objective of the present study was to map the genetic factors behind the resistance in Naxos, based on a population of recombinant inbred lines (RIL) from a cross with the susceptible CIMMYT breeding line SHA3/CBRD. Powdery mildew severity was evaluated in six field trials in Norway and four field trials in China. The major quantitative trait locus (QTL) with resistance from Naxos was detected close to the Pm3 locus on 1AS in all environments, and explained up to 35% of the phenotypic variation. Naxos was shown to carry another major QTL on 2DL and minor ones on 2BL and 7DS. QTL with resistance from SHA3/CBRD were detected on 1RS, 2DLc, 6BL and 7AL. The QTL on the 1B/1R translocation showed highly variable effects across environments corresponding to known virulence differences against Pm8. SHA3/CBRD was shown to possess the Pm3 haplotype on 1AS, but none of the known Pm3a-g alleles. The RIL population did not provide any evidence to suggest that the Pm3 allele of SHA3/CBRD acted as a suppressor of Pm8. PMID- 22434503 TI - Construction of a high-resolution linkage map of Rfd1, a restorer-of-fertility locus for cytoplasmic male sterility conferred by DCGMS cytoplasm in radish (Raphanus sativus L.) using synteny between radish and Arabidopsis genomes. AB - Cytoplasmic male sterility caused by Dongbu cytoplasmic and genic male-sterility (DCGMS) cytoplasm and its nuclear restorer-of-fertility locus (Rfd1) with a linked molecular marker (A137) have been reported in radish (Raphanus sativus L.). To construct a linkage map of the Rfd1 locus, linked amplified fragment length polymorphism (AFLP) markers were screened using bulked segregant analysis. A 220-bp linked AFLP fragment sequence from radish showed homology with an Arabidopsis coding sequence. Using this Arabidopsis gene sequence, a simple PCR marker (A220) was developed. The A137 and A220 markers flanked the Rfd1 locus. Two homologous Arabidopsis genes with both marker sequences were positioned on Arabidopsis chromosome-3 with an interval of 2.4 Mb. To integrate the Rfd1 locus into a previously reported expressed sequence tag (EST)-simple sequence repeat (SSR) linkage map, the radish EST sequences located in three syntenic blocks within the 2.4-Mb interval were used to develop single nucleotide polymorphism (SNP) markers for tagging each block. The SNP marker in linkage group-2 co segregated with male fertility in an F(2) population. Using radish ESTs positioned in linkage group-2, five intron length polymorphism (ILP) markers and one cleaved amplified polymorphic sequence (CAPS) marker were developed and used to construct a linkage map of the Rfd1 locus. Two closely linked markers delimited the Rfd1 locus within a 985-kb interval of Arabidopsis chromosome-3. Synteny between the radish and Arabidopsis genomes in the 985-kb interval were used to develop three ILP and three CAPS markers. Two ILP markers further delimited the Rfd1 locus to a 220-kb interval of Arabidopsis chromosome-3. PMID- 22434504 TI - The protein gp74 from the bacteriophage HK97 functions as a HNH endonuclease. AB - The last gene in the genome of the bacteriophage HK97 encodes the protein gp74. We present data in this article that demonstrates, for the first time, that gp74 possesses HNH endonuclease activity. HNH endonucleases are small DNA binding and digestion proteins characterized by two His residues and an Asn residue. We demonstrate that gp74 cleaves lambda phage DNA at multiple sites and that gp74 requires divalent metals for its endonuclease activity. We also present intrinsic tryptophan fluorescence data that show direct binding of Ni(2+) to gp74. The activity of gp74 in the presence of Ni(2+) is significantly decreased below neutral pH, suggesting the presence of one or more His residues in metal binding and/or DNA digestion. Surprisingly, this pH-dependence of activity is not seen with Zn(2+) , suggesting a different mode of binding of Zn(2+) and Ni(2+) . This difference in activity may result from binding of a second Zn(2+) ion by a putative zinc finger in gp74 in addition to binding of a Zn(2+) ion by the HNH motif. These studies define the biochemical function of gp74 as an HNH endonuclease and provide a platform for determining the role of gp74 in life cycle of the bacteriophage HK97. PMID- 22434505 TI - Representation of the brain's superior protocerebrum of the flesh fly, Neobellieria bullata, in the central body. AB - The central complex of the insect brain is a system of midline neuropils involved in transforming sensory information into behavioral outputs. Genetic studies focusing on nerve cells supplying the central complex from the protocerebrum propose that such neurons play key roles in circuits involved in learning the distinction of visual cues during operant conditioning. To better identify the possible sites of such circuits we used Bodian and anti-synapsin staining to resolve divisions of the superior protocerebrum into discrete neuropils. Here we show that in the fly Neobellieria bullata, the superior protocerebrum is composed of at least five clearly defined regions that correspond to those identified in Drosophila melanogaster. Intracellular dye fills and Golgi impregnations resolve "tangential neurons" that have intricate systems of branches in two of these regions. The branches are elaborate, decorated with specializations indicative of pre- and postsynaptic sites. The tangentially arranged terminals of these neurons extend across characteristic levels of the central complex's fan-shaped body. In this and another blowfly species, we identify an asymmetric pair of neuropils situated deep in the fan-shaped body, called the asymmetric bodies because of their likely homology with similar elements in Drosophila. One of the pair of bodies receives collaterals from symmetric arrangements of tangential neuron terminals. Cobalt injections reveal that the superior protocerebrum is richly supplied with local interneurons that are likely participants in microcircuitry associated with the distal processes of tangential neurons. Understanding the morphologies and arrangements of these and other neurons is essential for correctly interpreting functional attributes of the central complex. PMID- 22434506 TI - Large-scale objective phenotyping of 3D facial morphology. AB - Abnormal phenotypes have played significant roles in the discovery of gene function, but organized collection of phenotype data has been overshadowed by developments in sequencing technology. In order to study phenotypes systematically, large-scale projects with standardized objective assessment across populations are considered necessary. The report of the 2006 Human Variome Project meeting (Cotton et al, 2007) recommended documentation of phenotypes through electronic means by collaborative groups of computational scientists and clinicians using standard, structured descriptions of disease-specific phenotypes. In this report, we describe progress over the past decade in three dimensional (3D) digital imaging and shape analysis of the face, and future prospects for large-scale facial phenotyping. Illustrative examples are given throughout using a collection of 1,107 3D face images of healthy controls and individuals with a range of genetic conditions involving facial dysmorphism. PMID- 22434507 TI - Highly enantioselective proline-catalysed direct aldol reaction of chloroacetone and aromatic aldehydes. PMID- 22434508 TI - Correlation of heart rate and cardiac dysfunction in Duchenne muscular dystrophy. AB - Sinus tachycardia is common in cases of Duchenne muscular dystrophy (DMD). The authors hypothesized that an elevated heart rate would herald cardiomyopathy onset. A retrospective case-control study was performed with 55 DMD boys and 150 age-matched control boys. The variables were age, heart rate, shortening fraction, and left ventricular end-diastolic dimension. Cardiomyopathy was defined as a shortening fraction less than 28%. The DMD boys had a higher initial heart rate with no baseline echocardiographic evidence of cardiomyopathy. The control subjects showed a statistically significant age-related decline in heart rate (p = 0.001) but not the DMD boys. Cardiomyopathy developed in 17 of the 55 DMD boys over a period of 4.6 +/- 1.6 years. The DMD upper and lower heart rate groups were similar in age, follow-up time, and initial shortening fraction, yet cardiomyopathy developed in 14 (42%) of 33 upper quartile boys but only 3 (14%) of 22 lower quartile DMD boys (odds ratio, 6.5 (95% confidence interval, 1.15 18.92; p < 0.05). Compared with the control subjects, the DMD boys had a higher resting heart rate and a lack of age-related heart rate decline. The DMD boys in the upper heart rate quartile were more likely to progress to cardiomyopathy than those in the lower quartiles. This study establishes heart rate elevation as a statistically significant risk factor for cardiomyopathy. Further studies may define heart rate cutoffs for early pharmacologic intervention for incipient cardiomyopathy. PMID- 22434509 TI - Children with protein-losing enteropathy after the Fontan operation are at risk for abnormal bone mineral density. AB - Protein-losing enteropathy (PLE) is a rare but potentially devastating complication of single-ventricle physiology after the Fontan operation. Although abnormal bone mineral density (BMD) is a known complication of chronic disease and congenital heart disease, no reports have described BMD in patients with PLE. This study investigated a cross-sectional sample of children and young adults with a confirmed diagnosis of PLE. Serum levels of 25(OH)D, calcium, total protein, and albumin were recorded from the first outpatient encounter with each subject. Corrected calcium (cCa) was calculated from the serum calcium and albumin levels. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD, and z-scores were generated using appropriate software. DXA results were available for 12 patients (eight males and four females). The age at DXA ranged from 7.2 to 25.2 years. The mean z-score was -1.73 standard deviation (SD) for the entire cohort, with 42 % z-scores below -2 SDs. Serum 25(OH)D levels were abnormal in 58 % of the patients. There was a positive correlation between cCa and DXA z-score and a negative correlation between total protein and DXA z-score. Patients receiving corticosteroid therapy had a significantly lower DXA z-score than those not receiving corticosteroids (-3.15 vs. -0.31; p = 0.02). Children with PLE are at risk for abnormal BMD compared with age- and sex-matched control subjects. In the study cohort, corticosteroid exposure, a marker of disease severity, appeared to be associated with decreased BMD. Routine bone health screening is warranted for children with PLE, particularly those receiving corticosteroid therapy. PMID- 22434510 TI - Cutaneous cryptococcosis mimicking basal cell carcinoma in a patient with Sezary syndrome. PMID- 22434511 TI - Surgery after intracranial investigation with subdural electrodes in patients with drug-resistant focal epilepsy: outcome and complications. AB - Video-EEG monitoring with intracranial subdural electrodes is a useful assessment tool for the localization of the epileptogenic zone in patients with drug resistant focal epilepsy. We aimed at assessing the morbidity related to electrode implantation and the surgical outcome in patients who underwent epilepsy surgery after intracranial EEG monitoring. All patients (N = 58) admitted to our Epilepsy Surgery Centre for drug-resistant focal epilepsy who underwent resective surgery after intracranial monitoring with subdural electrodes and were followed up for at least 2 years were included in the study. Their mean age was 30.4 years (range 8-60 years), 25 (43 %) were female, and 44 (76 %) had a preoperatively detected structural lesion. The mean duration of invasive recording was 2.3 days (range 1-14 days). Extraoperative ECoG allowed the identification of the epileptogenic focus in all cases. The temporal lobe was involved in 21 (36 %) patients, whereas extratemporal foci were identified in 24 (41 %) patients. Thirteen patients (23 %) had multilobar involvement. Functional brain mapping was performed in 15 (26 %) patients. Transient complications related to electrode implantation occurred in three patients. Among patients with evidence of lesion on preoperative MRI, lesionectomy alone was performed in 12 cases (27 %), while it was combined with tailored cortical resection in the remaining cases. Tailored cortical resection was also performed in patients without evidence of lesion on MRI. After resective surgery, transient neurological deficits occurred in five cases, while another patient experienced permanent lateral homonymous hemianopia. At the last follow-up observation, 34 (57 %) patients were seizure-free (Engel class I). This study suggests that invasive EEG recording with subdural electrodes may be useful and fairly safe for many candidates for epilepsy surgery. PMID- 22434512 TI - Comment on: "On the accuracy of DFT methods in reproducing ligand substitution energies for transition metal complexes in solution: the role of dispersive interactions" by H. Jacobsen and L. Cavallo. PMID- 22434513 TI - Human poly- and cross-reactive anti-viral antibodies and their impact on protection and pathology. AB - Anti-viral immune responses have been studied extensively in order to inform rational vaccine design. Following viral infection, the balance of pathologic and protective antibody responses in the host can critically influence clinical outcomes. Comparisons of the different classes of antibodies produced after acute or chronic viral infections have uncovered common features of anti-viral responses, but these analyses have also revealed temporal differences in neutralizing antibody production, variable neutralization potency and differential induction of cross-reactive antibodies. Cross-reactive antibodies are known to play crucial protective roles in host responses to chronic viral infections; recent studies in human immunodeficiency virus long-term controllers have identified a novel class of broadly neutralizing antibodies generated from highly mutated and selected memory B cells. Here, we summarize the various roles played by cross- and poly-reactive antibodies in acute and persistent viral infections, with a focus on the potential contribution of these antibodies to dengue virus (DENV) immunopathology and host protection. Since host antibodies profoundly alter the course of viral infections, effective DENV vaccine design will require a better understanding of the origin, affinity maturation and protective potential of the poly-reactive and cross-reactive antibodies induced by different interventions. PMID- 22434515 TI - Single-cell force spectroscopy: mechanical insights into the functional impacts of interactions between antigen-presenting cells and T cells. AB - Antigen recognition and discrimination by T lymphocyte are essential in initiating appropriate immune responses. The mechanisms underlying exquisite sensitivity and specificity of antigen discrimination are not fully elucidated but involved physical intercellular interactions between T cell and antigen presenting cell (APC). The specificity of T-cell activation is tightly regulated by T-cell receptor (TCR) recognition of antigenic peptides in complex with major histocompatibility complex (pMHC) glycoproteins on the cell surface of APC. Antigen recognition via TCR/pMHC interactions, together with other co-receptors and co-stimulatory molecules, are spatially organized into the two-dimensional contact zone between T cells and APC, resulting in the formation of an immune synapse (IS). Here, we will review current implementations and applications of a cutting-edge biophysical technique, namely single-cell force spectroscopy (SCFS) that allows us to quantify mechanical forces of IS at APC/T cell-cell contact. The functional impacts of the mechanical strength in regulating T-cell functional activity will be discussed. We will also describe limitations of SCFS techniques, and outline recent investigations focusing on the functional roles of IS as mechanotransducer in regulating T-cell activities. PMID- 22434514 TI - TLR7 and TLR9 in SLE: when sensing self goes wrong. AB - Autoreactive B and T cells are present in healthy, autoimmunity-free individuals, but they are kept in check by various regulatory mechanisms. In systemic lupus erythematosus (SLE) patients, however, autoreactive cells are expanded, activated, and produce large quantities of autoantibodies, directed especially against nuclear antigens. These antibodies form immune complexes with self nucleic acids present in SLE serum. Since self-DNA and self-RNA in the form of protein complexes can act as TLR9 and TLR7 ligands, respectively, TLR stimulation is suggested as an additional signal contributing to activation and/or modulation of the aberrant adaptive immune response. Data from mouse models suggest a pathogenic role for TLR7 and a protective role for TLR9 in the pathogenesis of SLE. Future investigations are needed to elucidate the underlying modulatory mechanisms and the role of TLR7 and TLR9 in the complex pathogenesis of human SLE. PMID- 22434516 TI - Structural and functional distinctiveness of HLA-A2 allelic variants. AB - Human leukocyte antigen (HLA) class I molecules are involved in the presentation of antigenic peptides to CD8(+) cytotoxic T lymphocytes (CTLs), which is important for the development of cellular immunity during viral infections and in cancers. HLA-A2 is one of the most frequent HLA class I specificities and thus is extensively studied structurally and functionally. Since its discovery, more than 300 allelic variants of this HLA specificity have been recorded. Among the HLA-A2 allelic variants, HLA-A*02:01 is the most prevalent, hence commonly used as a model to study HLA-A2-restricted CTL responses. However, HLA-A2 alleles are unevenly distributed globally such that HLA-A2 allelic variants besides A*02:01 are expressed at considerably high frequencies in Asian and African populations. Furthermore, increasing evidence of variations in the peptide-binding repertoire and CTL responses among HLA-A2 allelic variants suggests the need to understand these differences among various frequently expressed HLA-A2 molecules. In this review, the structural and functional distinctiveness of HLA-A2 allelic variants will be discussed. PMID- 22434517 TI - Treatments for food allergy: how close are we? AB - Food allergy continues to be a challenging health problem, with prevalence continuing to increase and anaphylaxis still an unpredictable possibility. While improvements in diagnosis are more accurately identifying affected individuals, treatment options remain limited. The cornerstone of treatment relies on strict avoidance of the offending allergens and education regarding management of allergic reactions. Despite vigilance in avoidance, accidental ingestions and reactions continue to occur. With recent advances in the understanding of humoral and cellular immune responses in food allergy and mechanisms of tolerance, several therapeutic strategies for food allergies are currently being investigated with the hopes of providing a cure or long-term remission from food allergy. PMID- 22434518 TI - Delineating the autoimmune mechanisms in Graves' disease. AB - The immunologic processes involved in autoimmune thyroid disease (AITD), particularly Graves' disease (GD), are similar to other autoimmune diseases with the emphasis on the antibodies as the most unique aspect. These characteristics include a lymphocytic infiltrate at the target organs, the presence of antigen reactive T and B cells and antibodies, and the establishment of animal models of GD by antibody transfer or immunization with antigen. Similar to other autoimmune diseases, risk factors for GD include the presence of multiple susceptibility genes, including certain HLA alleles, and the TSHR gene itself. In addition, a variety of known risk factors and precipitators have been characterized including the influence of sex and sex hormones, pregnancy, stress, infection, iodine and other potential environmental factors. The pathogenesis of GD is likely the result of a breakdown in the tolerance mechanisms, both at central and peripheral levels. Different subsets of T and B cells together with their regulatory populations play important roles in the propagation and maintenance of the disease process. Understanding different mechanistic in the complex system biology interplay will help to identify unique factors contributing to the AITD pathogenesis. PMID- 22434519 TI - Outcomes of anterolateral thigh-free flaps and conversion from external to internal fixation with bone grafting in gustilo type IIIB open tibial fractures. AB - The purpose of this study was to analyze the utility and the clinical outcomes of anterolateral thigh (ALT)-free flaps and conversion from external to internal fixation with plating and bone grafting in Gustilo type IIIB open tibial fractures. A total of 21 patients were analyzed retrospectively. The mean follow up period was 18 months and the mean age was 46.7 years. There were 18 men and three women. The mean time from injury to flap coverage was 11.6 days. The mean size of flaps used was 15.3 * 8.2 cm. The mean size of bone defects was 2.26 cm. Segmental bone defects were observed in 5 five cases, for which bone transport or vascularized fibular graft were performed. When flaps were successful and the fracture sites did not have any evidence of infection, internal fixation with plates and bone grafting were performed. Flaps survived in 20 cases. In the 20 cases with successful flaps, two cases developed osteomyelitis, but the 20 cases achieved solid bone union at a mean of 8.6 months after the injury, salvaging the lower extremity in 100% of the cases. At the last follow-up, 9 nine cases were measured excellent or good; 6, fair; and 6, poor in the functional assessment based on the method developed by Puno et al. ALT- free flaps to cover soft tissue defects in Gustilo type IIIB open tibial fractures are considered as useful option for the treatment of composite defects. In addition, conversion to internal fixation and bone grafting can be an alternative method in order to reduce the risk of complications and inconvenience of external fixators. PMID- 22434520 TI - Role of sonographic elastography in the differential diagnosis of papillary lesions in breast. AB - PURPOSE: The purpose of this study was to compare the diagnostic performance of elastography, conventional ultrasonography (US) and combined conventional US and elastography for differentiation of papillary breast lesions. MATERIALS AND METHODS: A total of 95 papillary lesions (69 benign, 20 atypical and 6 malignant) in 87 patients were examined with conventional US and elastography. We evaluated conventional US images according to the Breast Imaging Reporting and Data System and internal composition (solid vs. cystic) and elastographic images according to elasticity scores. We compared diagnostic performances of elastography, conventional US and the combined method. RESULTS: Areas under the receiver operating curve were 0.794 for elastography, 0.875 for conventional US and 0.787 for the combined method. When the elasticity score cutoff was between 2 and 3, the sensitivity, specificity, positive predictive value and negative predictive value were 100, 55.1, 13 and 100 %, respectively. The combined method showed similar sensitivity (100 vs. 100 %) to and higher specificity (57.3 vs. 5.6 %) than conventional US alone. No significant difference was found in the elasticity scores of cystic papillary lesions according to pathology. CONCLUSION: Elastography improved the specificity of conventional US in differentiating between benign or atypical and malignant papillary breast lesions when it was combined with conventional US. PMID- 22434521 TI - Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin. AB - Large genomic rearrangements (LGRs) at the BRCA2 locus explain a non-negligible proportion of hereditary breast and ovarian cancer (HBOC) syndromes. The multiplex ligation and probe amplification (MLPA) assay has permitted in recent years to identify several families carrying LGRs at this locus, but very few such alterations have been fully characterized at the molecular level. Yet, molecular characterization is essential to identify recurrent alterations, to analyze the genetic mechanisms underlying such alterations, or to investigate potential genotype/phenotype relationships. We have used MLPA to identify BRCA2 LGRs in 7 out of 813 Spanish HBOC families previously tested negative for BRCA1 and BRCA2 small genomic alterations (substitutions and indels) and BRCA1 LGRs. We used a combination of long-range PCR, restriction mapping, and cDNA analysis to characterize the alterations at the molecular level. We found that Del Exon1 Exon2, Del Exon12-Exon16 and Del Exon22-Exon24 explain one family each, while Del Exon2 appears to be a Spanish founder mutation explaining four independent families. Finally, we have combined our data with a comprehensive review of the literature to reevaluate the genetic mechanisms underlying LGRs at the BRCA2 locus. Our study substantially increases the spectrum of BRCA2 LGRs fully characterized at the molecular level. Further on, we provide data to suggest that non-allelic homologous recombination has been overestimated as a mechanism underlying these alterations, while the opposite might be true for microhomology mediated events. PMID- 22434522 TI - Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway. AB - The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (beta-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 MUM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor > normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal > tumor, N > T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of beta-APN (300 MUM) and magnolol (25 MUM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of beta-APN. PMID- 22434523 TI - Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study. AB - Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AI therapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D(3) (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was <30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15-2.20 %] bone loss at LS (0.017 g/cm(2) [0.012-0.024], P < 0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to -0.3 %], adjusted P = 0.0001), and those who reached levels >=40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4-3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (<30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health. PMID- 22434524 TI - Benign thyroid disease is associated with breast cancer: a meta-analysis. AB - The controversial relationship between benign thyroid diseases and breast cancer (BC) has been investigated for over 50 years. Despite extensive population studies, the results as a whole have been inconsistent. The purpose of this study was to collate and analyse available data, calculating a pooled odds ratio (OR) of the risk of BC in patients diagnosed with benign thyroid diseases. Studies were obtained from a database search of MEDLINE, EMBASE, PubMed, Current Contents Connect and Google Scholar with additional cross checking of reference lists. Inclusion criteria required a confirmed diagnosis of a benign thyroid disease, reporting of an OR or data to calculate an OR (and 95% confidence interval, CI) and the use of an internal control group as the comparator. Collated data was assessed for heterogeneity and a pooled OR calculated. 28 studies were included in the meta-analysis. There was significant evidence of an increased risk of BC in patients with autoimmune thyroiditis, evident in a pooled OR 2.92 (95% CI 2.13 4.01). In addition, the results supported an increased risk associated with the presence of anti-thyroid antibodies (OR 2.02, 95% CI 1.63-2.50) and goitre (OR 2.26, 95% CI 1.39-3.69). Subgroup analysis of antibody presence revealed increased risk associated with both anti-TPO (OR 2.64, 95% CI 1.82-3.83) and anti TG (2.71, 95% CI 1.58-4.69). Quantitative analysis of hypothyroidism and hyperthyroidism was not significant. While these results indicate an association between thyroid auto-immunity and BC, further prospective studies are required to definitively prove causality. PMID- 22434525 TI - Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study. AB - In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations. Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8%. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77% of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple negative breast cancer patients (16%). Median age of onset for mutation carriers was 39 years. Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36%) had a BRCA1 mutation, while 27% of women with triple negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48% (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer. It is noteworthy, however, that of the 65 carriers, 15 (23%) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98%). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer. PMID- 22434526 TI - Germline copy number variants are not associated with globally acquired copy number changes in familial breast tumours. AB - A characteristic of sporadic and familial breast tumours is genomic instability, resulting from either inherited mutations in genes that control genome integrity or mutations that are acquired in somatic cells during development. It is well established that abnormal chromosome number and structural changes to chromosomes play an important role in the cause and progression of breast cancer. Familial BRCA1 breast tumours are characterised by basal-like phenotype and high histological grade which are typically associated with increased genomic instability. Consistent with previous studies, the genomes with the greatest number of base pairs covered by copy number change were typically found in basal like and/or high-histological grade breast tumours within our cohort. Moreover, we show that luminal A tumours that are high grade had significantly less copy number variant (CNV) coverage than the more clinically aggressive high-grade luminal B tumours, suggesting that chromosomal instability rather than cellular differentiation contributes to the aggressive nature of luminal B tumours. It has previously been proposed that germline CNVs may contribute to somatically acquired chromosome changes in the tumour, but this is the first study to address this idea in breast cancer. By comparing germline CNVs and tumour-specific CNVs in matched breast tumour and normal tissue using data from the Illumina Human CNV370 duo beadarray, we provide evidence that germline CNVs do not tend to act as a foundation on which larger chromosome copy number aberrations develop in tumour cells. Further studies are required with increased sequence resolution that will detect smaller CNVs and define CNV breakpoints to comprehensively assess the relationship between inherited genomic variation and genome evolution in breast cancer. PMID- 22434527 TI - An abnormal screening mammogram causes more anxiety than a palpable lump in benign breast disease. AB - Being recalled for further diagnostic procedures after an abnormal screening mammogram (ASM) can evoke a high state anxiety with lowered quality of life (QoL). We examined whether these adverse psychological consequences are found in all women with benign breast disease (BBD) or are particular to women referred after ASM. In addition, the influence of the anxiety as a personality characteristic (trait anxiety) was studied. Between September 2002 and February 2010 we performed a prospective longitudinal study in six Dutch hospitals. Women referred after ASM or with a palpable lump in the breast (PL), who were subsequently diagnosed with BBD, were included. Before diagnosis (at referral) and during follow-up, questionnaires were completed examining trait anxiety (at referral), state anxiety, depressive symptoms (at referral, one, three and 6 months after diagnosis), and QoL (at referral and 12 months). Women referred after ASM (N=363) were compared with women with PL (N=401). A similar state anxiety score was found in both groups, but a lower psychological QoL score at 12 months was seen in the ASM group. In women with not-high trait anxiety those in the ASM group were more anxious with more depressive symptoms at referral, and reported impaired psychological QoL at referral and at 12 months compared with the PL group. No differences were found between ASM and PL in women with high trait anxiety, but this group scored unfavorably on anxiety, depressive symptoms and QoL compared with women with not-high trait anxiety. ASM evokes more anxiety and depressive symptoms and lowered QoL compared with women referred with PL, especially in women who are not prone to anxiety. Women should be fully informed properly about the risks and benefits of breast cancer screening programs. We recommend identifying women at risk of reduced QoL using a psychometric test. PMID- 22434528 TI - An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis. AB - BACKGROUND AND AIMS: Hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis. METHODS: Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot. RESULTS: Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients' survival. CONCLUSIONS: Our results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human. PMID- 22434529 TI - Trends in colorectal cancer screening with home-based fecal occult blood tests in adults ages 50 to 64 years, 2000-2008. AB - BACKGROUND: National surveys have reported declines in rates of home-based fecal occult blood test (FOBT) screening for colorectal cancer (CRC) in the last decade. However, socioeconomic status (SES) and racial/ethnic differences in FOBT trends and their changes relative to endoscopic CRC screening have not been evaluated. METHODS: Data on adults ages 50 to 64 years from the 2000, 2005, and 2008 National Health Interview Surveys were used. Weighted analyses and multivariate logistic regression were used to study trends in the use of FOBT and endoscopic CRC screening during this period. RESULTS: Between 2000 and 2008, significant declines in FOBT prevalence occurred in higher SES groups, but not in lower SES groups (uninsured and publicly insured, those without a usual source of care, lower educated, lower income, and immigrants to the United States) or Hispanics. Endoscopic CRC screening during the period studied consistently increased in all higher SES subgroups. In contrast, few lower SES subgroups (publicly insured, lower educated, near poor individuals, long-term immigrants) and Hispanics experienced increases in CRC endoscopic screening, and these increases were smaller than those observed in higher SES subgroups. CONCLUSIONS: Socially and economically disadvantaged groups experienced little or no change in FOBT prevalence, and few of these groups experienced contemporaneous increases in CRC endoscopic screening. These trends suggest the continued availability and acceptance of FOBT in these groups. If national CRC screening goals are to be achieved in populations with lower access to colonoscopy, then annual high sensitivity FOBT should be promoted as an immediately accessible and viable alternative. PMID- 22434530 TI - Effectiveness of a bone substitute (CERAMENTTM) as an alternative to PMMA in percutaneous vertebroplasty: 1-year follow-up on clinical outcome. AB - PURPOSE: The aim of the study was to evaluate the efficacy of an injectable and partly absorbable calcium bone cement (CERAMENTTM, Bone Support, Sweden) in the treatment of osteoporotic or traumatic vertebral fractures by percutaneous vertebroplasty. METHODS: From March 2009 to October 2010 an open, prospective study in two centres was performed. 33 patients with symptomatic vertebral fractures were enrolled. Patients were included based on evaluation by X-ray, CT, and MRI. Clinical evaluation by Visual Analogue Scale (VAS, 0-10) and Oswestry Disability index test (ODI, 0-100 %) was performed before the operation as well as 1, 6 and 12 months after the procedure. Radiology assessment post-procedure was carried out by X-ray, CT, and MRI at 1, 6 and 12 months post-op. Intake of analgesic medications pre- and post-procedure was monitored. RESULTS: 66 vertebral bodies underwent percutaneous vertebroplasty. VAS score demonstrated a significant decrease from 8.61 (SD 19.8) pre-operatively to 2.48 (SD 2.36) at 1 month. The score was 2.76 (SD 2.68) at 6 months and 1.36 (SD 1.33) at the latest follow up. ODI score dropped significantly from 58.86 pre-op to 26.94 at 6 months and further down to 7.61 at 12 months. No re-fractures or adjacent level fractures were reported. CONCLUSION: Data show that CERAMENT can be a substitute of PMMA in the treatment of osteoporotic and traumatic vertebral fractures, especially in young patients. PMID- 22434531 TI - Bisphosphonate therapy in multiple myeloma in preventing vertebral collapses: preliminary report. AB - PURPOSE: The aim of the study was to report and discuss the preliminary data obtained in a homogeneous series of 50 patients affected by multiple myeloma treated with bisphosphonates. METHODS: Patients were followed for a minimum of 1 year. Main orthopaedic data were recorded. Visual Analogue Score and QLQ-C30 and MY 20 were used to assess the quality of life. RESULTS: Statistical analysis showed less lytic lesions in the group with zoledronate therapy and stable primary disease compared with a greater number of lesions in the non-treated group. Results regarding VAS score and QLQ-C30 and MY were statistically better in the first group than in the second. CONCLUSIONS: Our results confirm the efficacy of zoledronate in ensuring an acceptable quality of life restraining the aggressiveness of the myeloma on bone tissue, especially in spine although further prospective studies have to be conducted to determine its correct use in myeloma patients. PMID- 22434532 TI - A slip above a slip: retrolisthesis of the motion segment above a spondylolytic spondylolisthesis. AB - OBJECTIVE: The purpose of this study is to assess the degenerative changes in the motion segments above a L5S1 spondylolytic spondylolisthesis and to view these in light of the retrolisthesis in the segment immediately above the slip. A spondylolytic spondylolisthesis causes an abnormal motion and predisposes to degenerative changes at the L5S1 disc. Degenerative changes in the adjacent segments would influence the symptomatology and natural history of the disease and the treatment options. The extent of degenerative changes in the levels immediately above a L5S1 spondylolytic spondylolisthesis is not well documented in the literature. We have noted retrolisthesis at this level, but this has not been previously reported or assessed. MATERIALS AND METHODS: Thirty-eight patients with a symptomatic L5S1 spondylolytic spondylolisthesis with a mean age of 52.8 years (95% CI 47.2-58.4); 55.3% (n = 21) females and 44.7% (n = 17) males. We assessed the lumbar lordosis, slip angle, sacral slope, grade of the slip, facet angles at L34 and L45 on both sides, facet degenerative score (cartilage and sclerosis values), disc degenerative score (Pfirrmann) at L34, L45 and L5S1 and the presence of retrolisthesis at L45. RESULTS: We noted that 29% (11) had a retrolisthesis at L45. The degenerative scores reduced significantly from L5S1 through L45 and L34. Slip angle and L45 disc degenerative score were the only factors that occurred consistently in patients with a retrolisthesis. CONCLUSIONS: There is a cascade of degenerative changes that involve both the disc and the facet joints at the levels above a spondylolytic spondylolisthesis. The degenerative changes at the L45 disc and a higher slip angle are consistent findings in patients with a retrolisthesis at the level above the slip. PMID- 22434533 TI - Sann: solvent accessibility prediction of proteins by nearest neighbor method. AB - We present a method to predict the solvent accessibility of proteins which is based on a nearest neighbor method applied to the sequence profiles. Using the method, continuous real-value prediction as well as two-state and three-state discrete predictions can be obtained. The method utilizes the z-score value of the distance measure in the feature vector space to estimate the relative contribution among the k-nearest neighbors for prediction of the discrete and continuous solvent accessibility. The Solvent accessibility database is constructed from 5717 proteins extracted from PISCES culling server with the cutoff of 25% sequence identities. Using optimal parameters, the prediction accuracies (for discrete predictions) of 78.38% (two-state prediction with the threshold of 25%), 65.1% (three-state prediction with the thresholds of 9 and 36%), and the Pearson correlation coefficient (between the predicted and true RSA's for continuous prediction) of 0.676 are achieved An independent benchmark test was performed with the CASP8 targets where we find that the proposed method outperforms existing methods. The prediction accuracies are 80.89% (for two state prediction with the threshold of 25%), 67.58% (three-state prediction), and the Pearson correlation coefficient of 0.727 (for continuous prediction) with mean absolute error of 0.148. We have also investigated the effect of increasing database sizes on the prediction accuracy, where additional improvement in the accuracy is observed as the database size increases. The SANN web server is available at http://lee.kias.re.kr/~newton/sann/. PMID- 22434534 TI - Process-oriented integration and coordination of healthcare services across organizational boundaries. AB - The paper presents a methodology that follows a top-down approach based on a Model-Driven Architecture for integrating and coordinating healthcare services through cross-organizational processes to enable organizations providing high quality healthcare services and continuous process improvements. The methodology provides a modeling language that enables organizations conceptualizing an integration agreement, and identifying and designing cross-organizational process models. These models are used for the automatic generation of: the private view of processes each organization should perform to fulfill its role in cross organizational processes, and Colored Petri Net specifications to implement these processes. A multi-agent system platform provides agents able to interpret Colored Petri-Nets to enable the communication between the Healthcare Information Systems for executing the cross-organizational processes. Clinical documents are defined using the HL7 Clinical Document Architecture. This methodology guarantees that important requirements for healthcare services integration and coordination are fulfilled: interoperability between heterogeneous Healthcare Information Systems; ability to cope with changes in cross-organizational processes; guarantee of alignment between the integrated healthcare service solution defined at the organizational level and the solution defined at technological level; and the distributed execution of cross-organizational processes keeping the organizations autonomy. PMID- 22434535 TI - Socioeconomic position and stage of cervical cancer in Danish women diagnosed 2005 to 2009. AB - BACKGROUND: To reduce social disparities in cervical cancer survival, it is important to understand the mechanisms by which social position influence cancer prognosis. We investigated the relations between socioeconomic factors, comorbidity, time since last Papanicolau smear, and stage at diagnosis in Danish women with cervical cancer. METHODS: We identified 1,651 cervical cancer cases diagnosed 2005 to 2009 from the Danish Gynaecological Cancer Database. Date of diagnosis, clinical cancer stage, tumor histology, and treating hospital were retrieved; Pap smear registrations were obtained from the Danish Pathology Register; data on comorbid conditions from the Danish National Patients Register; and data on education, income, and cohabitation from Statistics Denmark. Logistic regression models were used to analyze the relations between socioeconomic factors and cancer stage in a four-step model, with stepwise inclusion of mediators. RESULTS: The risk for advanced (stage II-IV) compared with early-stage cancer (stage I) was increased for women with short and medium education (OR = 2.40; 1.67-3.45 and 1.76; 1.44-2.16), women living without a partner (OR = 1.31; 1.10-1.55), and older women (OR = 1.07; 1.06-1.08 increase per year). The relations between socioeconomic factors and cancer stage were partly mediated by time since last Pap smear test and to a lesser extent by comorbidity. CONCLUSIONS: Shorter education, living alone, and older age were related to advanced stage cervical cancer, due partly to Pap smear testing and less to comorbidity. IMPACT: It is relevant to further investigate how to decrease delay in cervical cancer diagnosis among disadvantaged groups. PMID- 22434536 TI - Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase producing cells promotes islet regeneration. AB - AIMS/HYPOTHESIS: We sought to investigate the stimulation of islet regeneration by transplanted human umbilical cord blood (UCB) cells purified according to high aldehyde dehydrogenase (ALDH) activity (ALDH(hi)), a conserved characteristic of multiple progenitor lineages. We hypothesised that direct intrapancreatic (iPan) delivery of ALDH(hi) progenitors would augment islet regeneration via timely and localised exposure to islet-regenerative stimuli. METHODS: Cells were purified from UCB based on flow cytometry for low ALDH activity (ALDH(lo)) vs ALDH(hi). UCB ALDH(lo) or ALDH(hi) cells were compared for surface marker expression, as well as haematopoietic, endothelial and multipotent stromal progenitor content in vitro. UCB ALDH(lo) or ALDH(hi) cells were i.v. or iPan injected into streptozotocin-treated non-obese diabetic/severe combined immune-deficient mice temporally monitored for blood glucose, serum insulin and glucose tolerance. Human cell recruitment and survival in the pancreas, insulin content, islet associated cell proliferation and islet vascularisation were documented in situ. RESULTS: UCB-derived ALDH(hi) cells were highly enriched for haematopoietic and endothelial progenitor frequency, and showed increased expression of progenitor and myeloid cell surface markers. Although i.v. transplantation of ALDH(hi) cells demonstrated low pancreas engraftment and only transient blood glucose lowering capacity, iPan injected ALDH(hi) cells reversed established hyperglycaemia, increased serum insulin and improved the response to a glucose challenge. iPan injected ALDH(hi) cells surrounded damaged islets at early time points and increased islet-associated cell proliferation, resulting in the recovery of beta cell mass. CONCLUSIONS/INTERPRETATION: iPan delivery of UCB ALDH(hi) cells potentiated islet-associated cell proliferation, insulin production and islet revascularisation, resulting in the recovery of host islet function. Elucidation of the progenitor-specific pathways stimulated during islet regeneration may provide new approaches to promote islet expansion during diabetes. PMID- 22434537 TI - Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. AB - AIMS/HYPOTHESIS: Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. METHODS: Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. RESULTS: Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. CONCLUSIONS/INTERPRETATION: Central insulin action in specific brain areas, including the hypothalamus, may time dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism. PMID- 22434538 TI - Localization of serotonin in the nervous system of Biomphalaria glabrata, an intermediate host for schistosomiasis. AB - The digenetic trematode Schistosoma mansoni that causes the form of schistosomiasis found in the Western Hemisphere requires the freshwater snail Biomphalaria glabrata as its primary intermediate host. It has been proposed that the transition from the free-living S. mansoni miracidium to parasitic mother sporocyst depends on uptake of biogenic amines, e.g. serotonin, from the snail host. However, little is known about potential sources of serotonin in B. glabrata tissues. This investigation examined the localization of serotonin-like immunoreactivity (5HTli) in the central nervous system (CNS) and peripheral tissues of B. glabrata. Emphasis was placed on the cephalic and anterior pedal regions that are commonly the sites of S. mansoni miracidium penetration. The anterior foot and body wall were densely innervated by 5HTli fibers but no peripheral immunoreactive neuronal somata were detected. Within the CNS, clusters of 5HTli neurons were observed in the cerebral, pedal, left parietal, and visceral ganglia, suggesting that the peripheral serotonergic fibers originate from the CNS. Double-labeling experiments (biocytin backfill * serotonin immunoreactivity) of the tentacular nerve and the three major pedal nerves (Pd n. 10, Pd n. 11, and Pd n. 12) disclosed central neurons that project to the cephalopedal periphery. Overall, the central distribution of 5HTli neurons suggests that, as in other gastropods, serotonin regulates the locomotion, reproductive, and feeding systems of Biomphalaria. The projections to the foot and body wall indicate that serotonin may also participate in defensive, nociceptive, or inflammation responses. These observations identify potential sources of host-derived serotonin in this parasite-host system. Inc. PMID- 22434539 TI - FMS Kinase Inhibitors: Current Status and Future Prospects. AB - FMS, first discovered as the oncogene responsible for Feline McDonough Sarcoma, is a type III receptor tyrosine kinase that binds to the macrophage or monocyte colony-stimulating factor (M-CSF or CSF-1). Signal transduction through that binding results in survival, proliferation, and differentiation of monocyte/macrophage lineage. Overexpression of CSF-1 and/or FMS has been implicated in a number of disease states such as the growth of metastasis of certain types of cancer, in promoting osteoclast proliferation in bone osteolysis, and many inflammatory disorders. Inhibition of CSF-1 and/or FMS may help treat these pathological conditions. This article reviews FMS gene, FMS kinase, CSF-1, IL-34, and their roles in bone osteolysis, cancer biology, and inflammation. Monoclonal antibodies, FMS crystal structure, and small molecule FMS kinase inhibitors of different chemical scaffolds are also reviewed. PMID- 22434540 TI - Optimal antigen retrieval for ethanol-fixed cytologic smears. AB - BACKGROUND: Antigen retrieval, a crucial technique for immunostaining, is often carried out on formalin-fixed, paraffin-embedded (FFPE) tissue sections. The role of antigen retrieval in immunostaining of ethanol-fixed smears remains unclear. The authors evaluated the effects of 2 common antigen retrieval procedures, heat induced antigen retrieval and protease-induced antigen retrieval, for immunostaining using a broad panel of antibodies. METHODS: Papanicolaou-stained ethanol-fixed smears from 36 surgical specimens were immunostained with 43 antibodies. Three widely used heat-induced antigen retrieval solutions, namely, citrate buffer (pH 6.0 and pH 7.0) and ethylenediaminetetraacetic acid solution (pH 8.0) for heat-induced antigen retrieval, and pronase were used. The staining results were compared between the ethanol-fixed smears and the corresponding FFPE tissue sections. RESULTS: Heat-induced antigen retrieval was essential for all the 9 antibodies examined against nuclear antigens, and for 7 of 26 antibodies against cytoplasmic and cell membrane antigens. Superior results were obtained using lower-pH heat-induced antigen retrieval solutions for ethanol-fixed smears than was the case for FFPE tissue sections; use of citrate buffer (pH 6.0) was optimal for most antibodies. For 17 antibodies against cytoplasmic/cell membrane antigens, satisfactory results were obtained even without antigen retrieval on the ethanol-fixed smears, whereas antigen retrieval was necessary for detection on the FFPE tissue sections. Protease-induced antigen retrieval frequently exerted deleterious effects on ethanol-fixed smears. Despite antigen retrieval, detection of 2 lymphocytic markers failed on ethanol-fixed smears. This limitation was overcome by heat-induced antigen retrieval on formalin vapor-fixed smears. CONCLUSIONS: In ethanol-fixed smears, most of the antibodies can be immunostained successfully without antigen retrieval treatment or mild heat induced antigen retrieval using citrate buffer (pH 6.0). The optimal antigen retrieval condition for each antibody must be individually determined. PMID- 22434541 TI - Gold(I)-catalyzed unprecedented rearrangement reaction between 2 aminobenzaldehydes with propargyl amines: an expedient route to 3 aminoquinolines. AB - Access to aminoquinolines: a gold(I)-catalyzed unprecedented rearrangement reaction between 2-aminobenzaldehydes with propargyl amine was studied. The study provided, for the first time, direct access to 3-aminoquinolines in one step starting from readily available starting materials. Elegantly designed experiments were employed to unravel the mechanism of this unprecedented rearrangement, which are corroborated by DFT calculations. PMID- 22434542 TI - Fully-branched hyperbranched polymers with a diselenide core as glutathione peroxidase mimics. AB - A novel glutathione peroxidase (GPx) mimic has been prepared by incorporation of a selenium-based catalytic unit into the focal point of a fully-branched hyperbranched polymer. First, an AB(2) monomer consisting of isatin and an electron rich aromatic moiety was polycondensed in the presence of 5-nitroisatin as a core reagent, resulting in a polymer with 100% degree of branching. The latter was coupled to the catalytically active moiety, Br(CH(2))(5) SeSe(CH(2))(5) Br, by nucleophilic substitution of the bromides by the residual amide groups of the incorporated nitroisatin core. The obtained polymer has demonstrated prominent GPx activity as desired, which could be attributed to the hydrophobic, densely branched and core-shell structure of the polymer surrounding the catalytic center. PMID- 22434543 TI - Laparoscopy for sigmoid colon and rectal cancers in septuagenarians: a retrospective, comparative study. AB - BACKGROUND: The aim of the study is to analyze the results of laparoscopy in septuagenarians with sigmoid colon or rectal cancer. METHODS: Patients who underwent laparoscopic or hand-assisted laparoscopic sigmoid or rectal resections for cancer were retrospectively selected from the database of our institution. The study group (Lap > 70 group), contained the cancer patients over 70 years old who were treated with laparoscopy. Patients less than 70 years old who underwent a laparoscopic procedure (Lap < 70 group), and those over than 70 years old who underwent conventional surgery (Open > 70 group), were assigned to control groups. Demographics, information regarding tumors, perioperative data, pathological results, and survival in the three groups were compared. RESULTS: There were 56, 166, and 34 patients in the Lap > 70, Lap < 70, and Open > 70 groups, respectively. Patients in the Lap > 70 group were significantly older than other groups. The American Society of Anesthesiologists scores were higher, and the presence of the studied risk factors was more common in the Lap > 70 group than the Lap < 70 group. Intraoperative bleeding and the amount and number of perioperative transfusions required were less in the Lap > 70 group than in the Open > 70 group. The number of harvested lymph nodes was less in the Lap > 70 group than both study groups. Five-year survival in the Lap > 70 group was similar to that in the Lap < 70 group and significantly better than in the Open > 70 group. CONCLUSIONS: Laparoscopy for sigmoid colon and rectal cancer in patients over 70 may be feasible and safe as it is in younger patients. The present study has revealed that laparoscopy in the elderly may be superior to conventional techniques as regards some intraoperative findings and survival. PMID- 22434544 TI - Evidence for a genetic overlap between body dysmorphic concerns and obsessive compulsive symptoms in an adult female community twin sample. AB - Body dysmorphic disorder (BDD) is thought to be etiologically related to obsessive-compulsive disorder (OCD) but the available evidence is incomplete. The current study examined the genetic and environmental sources of covariance between body dysmorphic and obsessive-compulsive symptoms in a community sample of adult twins. A total of 2,148 female twins (1,074 pairs) completed valid and reliable measures of body dysmorphic concerns and obsessive-compulsive symptoms. The data were analyzed using bivariate twin modeling methods and the statistical programme Mx. In the best-fitting model, the covariation between body dysmorphic and obsessive-compulsive traits was largely accounted for by genetic influences common to both phenotypes (64%; 95% CI: 0.50-0.80). This genetic overlap was even higher when specific obsessive-compulsive symptom dimensions were considered, with up to 82% of the phenotypic correlation between the obsessing and symmetry/ordering symptom dimensions and dysmorphic concerns being attributable to common genetic factors. Unique environmental factors, although influencing these traits individually, did not substantially contribute to their covariation. The results remained unchanged when excluding individuals reporting an objective medical condition/injury accounting for their concern in physical appearance. The association between body dysmorphic concerns and obsessive-compulsive symptoms is largely explained by shared genetic factors. Environmental risk factors were largely unique to each phenotype. These results support current recommendations to group BDD together with OCD in the same DSM-5 chapter, although comparison with other phenotypes such as somatoform disorders and social phobia is needed. PMID- 22434545 TI - Novel oral anticoagulants after acute coronary syndromes. AB - PURPOSE: A number of novel oral anticoagulants, including direct thrombin inhibitors and direct factor Xa inhibitors, have been developed. This review discusses these agents and their respective clinical trials in patients with acute coronary syndromes. METHODS: This review discusses the results of phase 2 and 3 clinical trials with novel oral anticoagulants. RESULTS: Phase 2 clinical trials demonstrated that novel oral anticoagulants increase the risk of bleeding in a dose-related fashion, particularly when used in addition to dual antiplatelet therapy. What was less clear is their impact on recurrent ischemic events. In phase 3 trials, rivaroxaban was found to have a benefit on ischemic events and perhaps a greater benefit at the lower dose. The phase 3 trial with apixaban was stopped early due to increased bleeding without a meaningful reduction in ischemic events. CONCLUSIONS: Novel oral anticoagulants represent a promising, potentially beneficial treatment for patients with a recent acute coronary syndrome but come with a risk of bleeding. The benefits and risks of these agents will need to be carefully weighed and may depend on both patient risk and concomitant therapy. Additional research is needed to determine how to best integrate these medications into the care of patients with acute coronary syndromes. PMID- 22434546 TI - Process improvement methods increase the efficiency, accuracy, and utility of a neurocritical care research repository. AB - BACKGROUND: Reliable and efficient data repositories are essential for the advancement of research in Neurocritical care. Various factors, such as the large volume of patients treated within the neuro ICU, their differing length and complexity of hospital stay, and the substantial amount of desired information can complicate the process of data collection. METHODS: We adapted the tools of process improvement to the data collection and database design of a research repository for a Neuroscience intensive care unit. By the Shewhart-Deming method, we implemented an iterative approach to improve the process of data collection for each element. After an initial design phase, we re-evaluated all data fields that were challenging or time-consuming to collect. We then applied root-cause analysis to optimize the accuracy and ease of collection, and to determine the most efficient manner of collecting the maximal amount of data. RESULTS: During a 6-month period, we iteratively analyzed the process of data collection for various data elements. For example, the pre-admission medications were found to contain numerous inaccuracies after comparison with a gold standard (sensitivity 71% and specificity 94%). Also, our first method of tracking patient admissions and discharges contained higher than expected errors (sensitivity 94% and specificity 93%). In addition to increasing accuracy, we focused on improving efficiency. Through repeated incremental improvements, we reduced the number of subject records that required daily monitoring from 40 to 6 per day, and decreased daily effort from 4.5 to 1.5 h/day. CONCLUSIONS: By applying process improvement methods to the design of a Neuroscience ICU data repository, we achieved a threefold improvement in efficiency and increased accuracy. Although individual barriers to data collection will vary from institution to institution, a focus on process improvement is critical to overcoming these barriers. PMID- 22434547 TI - Volume status and fluid responsiveness. Advanced hemodynamic monitoring: neurocrit care. PMID- 22434548 TI - Effect of interferon-beta on neuroinflammation, brain injury and neurological outcome after experimental subarachnoid hemorrhage. AB - INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) has a poor outcome, particularly attributed to progressive injury after the initial incident. Several studies suggest a critical role for inflammation in lesion progression after SAH. Our goal was to test whether treatment with anti-inflammatory interferon-beta, which has shown promise as a therapeutic agent in experimental ischaemic stroke, can protect the brain after SAH. METHODS: SAH was induced in adult male Wistar rats by puncturing the intracranial bifurcation of the right internal carotid artery. Treatment effects of daily interferon-beta (n = 16) or vehicle (n = 14) injections were serially evaluated with multiparametric MRI and behavioral tests from day 0 to 7, in compliance with recent recommendations for pre-clinical drug testing. Outcome measures included neurological status, brain lesion volume, blood-brain barrier (BBB) leakage, and levels of inflammatory markers. RESULTS: In animals that survived up to 7 days post-SAH, we found no significant differences between vehicle- and interferon-beta-treated animals with respect to final neurological score (14.3 +/- 1.0 vs. 13.0 +/- 2.2), brain lesion size on T(2)-weighted MR images (59 +/- 83 vs. 124 +/- 99 mm(3)), BBB leakage (0.26 +/- 0.05 vs. 0.22 +/- 0.08 contrast-induced relative MR signal change), upregulation of brain RNA for cytokines, chemokines and cell adhesion molecules, and increased neutrophil activation. CONCLUSIONS: In contrast to previously published findings in experimental ischemic stroke models, interferon-beta has no clear efficacy to protect the brain after SAH. In line with recent highlighting of the significance of negative findings, our data currently do not recommend clinical testing of interferon-beta to prevent neurological damage in SAH patients. PMID- 22434549 TI - DF3 epitope expression on MUC1 mucin is associated with tumor aggressiveness, subsequent lymph node metastasis, and poor prognosis in patients with oral squamous cell carcinoma. AB - BACKGROUND: DF3/MUC1 mucin is expressed in various cancer tissues, and many in vitro studies have suggested that it may play a role in the aggressive behavior of malignant tumors. However, to the best of the authors' knowledge, the relation between DF3/MUC1 expression and outcome has not yet been investigated in patients with oral squamous cell carcinoma (OSCC). The objective of the current study was to evaluate the prognostic significance of DF3/MUC1 expression in patients with OSCC. METHODS: The expression profile of DF3/MUC1 in OSCC tissues from 206 patients was examined using immunohistochemistry. Its prognostic significance in OSCC was statistically analyzed on the basis of detailed clinicopathologic factors. RESULTS: DF3/MUC1 expression was found to be significantly correlated with tumor aggressiveness, such as pathologic lymph node metastasis (P = .002), advanced tumor stage (P = .02), diffuse invasion of cancer cells (P = .03), and vascular invasion (P = .01). Respectively, the overall survival (OS)and disease free survival (DFS) rates were significantly worse for patients with DF3/MUC1 expression compared with those without DF3/MUC1 expression (P = .001 and P = .0003, respectively). Multivariate analysis demonstrated that DF3/MUC1 expression was an independent prognostic factor for both OS and DFS (P = .04 for both). In addition, DF3/MUC1 expression was found to be an independent risk factor for subsequent regional lymph node metastasis (P = .03). CONCLUSIONS: Aberrant expression of DF3/MUC1 is an independent prognostic factor indicating poor prognosis in patients with OSCC. DF3/MUC1 expression is a risk factor for subsequent lymph node metastasis in patients with OSCC and therefore may represent an indication for elective neck dissection. Patients with OSCC demonstrating positive expression of DF3/MUC1 should be followed carefully. PMID- 22434550 TI - Angiogenesis of buffalo choroid plexuses: structural and immunocytochemical study. AB - Mammalian choroid plexuses (CPs) are vascularized structures involved in numerous exchange processes that supply nutrients and hormones to the brain, and that remove deleterious compounds and metabolites from the brain. Studies in the adult Mediterranean buffalo have investigated the morphology of CPs using histochemical and immunohistochemical techniques. To date, however, there have been no studies conducted on ruminants regarding this removal process which serves to repair functional vascular damage in the CPs. Each of these vascular repair processes is a very complex and none of these has not yet been completely understood. Then, the aim of the present study is to investigate the morphological processes during angiogenesis in the CPs of healthy adult buffaloes, utilizing transmission electron microscopy (TEM), scanning electron microscopy (SEM), and immunogold labeling SEM analysis (biomarkers: angiopoietin-2 [Ang-2], vascular endothelial growth factor receptor-3 [VEGFR-3], and CD133). At TEM, the inner surface of the blood capillaries sometimes showed pillar-like cells, which in contact with endothelial cells formed prominences, which in turn formed neo-blood capillaries. With immunogold-labeling SEM analysis, the CP blood capillaries showed Ang-2 and VEGF-3, respectively, in positive particles and spheroid formations. In addition, the external surface of the blood capillaries showed spheroid formations that originated from the neo-vascular capillaries whose terminals formed a capillary network, positive to CD133. On the basis of these results, the following hypothesis can be made, namely, that these CPs are vascular structures which play a fundamental role in maintaining brain homeostasis and self-repairing of functional vascular damage, independently of the presence of rete mirabile in this species. PMID- 22434551 TI - Fibulo-scapho-lunate arthrodesis after resection of the distal radius for giant cell tumor of the bone. AB - BACKGROUND: Giant-cell tumors of the distal radius are rare. They have a high risk of local recurrence and a risk of pulmonary metastasis. Curettage alone or combined with adjunctive agents is often associated with local recurrence. METHODS: Three patients with giant-cell tumor of the distal radius are presented. All patients showed Campanacci grade 3 lesions. All patients underwent complete distal radius resection and reconstruction with a vascularized fibular graft distally fused with the scaphoid and the lunate, allowing midcarpal motion. RESULTS: The follow-up period ranged from 6 to 60 months. For all three patients, emotional acceptance was excellent. The postoperative motion of the wrist was good, with a range of motion of 30-0-30 degrees , 40-0-0 degrees , and 30-0-10 degrees (extension-flexion). There was neither tumor recurrence nor pulmonary metastasis. CONCLUSION: Fibulo-scapho-lunate fusion is an elegant method of distal radius reconstruction with good functional outcome and low risk of pulmonary metastasis. PMID- 22434552 TI - Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings. AB - Neuroimaging identified abnormalities associated with traumatic brain injury (TBI) are but gross indicators that reflect underlying trauma-induced neuropathology at the cellular level. This review examines how cellular pathology relates to neuroimaging findings with the objective of more closely relating how neuroimaging findings reveal underlying neuropathology. Throughout this review an attempt will be made to relate what is directly known from post-mortem microscopic and gross anatomical studies of TBI of all severity levels to the types of lesions and abnormalities observed in contemporary neuroimaging of TBI, with an emphasis on mild traumatic brain injury (mTBI). However, it is impossible to discuss the neuropathology of mTBI without discussing what occurs with more severe injury and viewing pathological changes on some continuum from the mildest to the most severe. Historical milestones in understanding the neuropathology of mTBI are reviewed along with implications for future directions in the examination of neuroimaging and neuropathological correlates of TBI. PMID- 22434553 TI - Association of initial CT findings with quality-of-life outcomes for traumatic brain injury in children. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of acquired disability in children and adolescents. OBJECTIVE: To demonstrate the association between specific findings on initial noncontrast head CT and long-term outcomes in children who have suffered TBI. MATERIALS AND METHODS: This was an IRB approved prospective study of children ages 2-17 years treated in emergency departments for TBI and who underwent a head CT as part of the initial work-up (n = 347). The change in quality of life at 12 months after injury was measured by the PedsQL scale. RESULTS: Children with TBI who had intracranial injuries identified on the initial head CT had a significantly lower quality-of-life scores compared to children with TBI whose initial head CTs were normal. In multivariate analysis, children whose initial head CT scans demonstrated intraventricular hemorrhage, parenchymal injury, midline shift >= 5 mm, hemorrhagic shear injury, abnormal cisterns or subdural hematomas >= 3 mm had lower quality of life scores 1 year after injury than children whose initial CTs did not have these same injuries. CONCLUSION: Associations exist between findings from the initial noncontrast head CT and quality of life score 12 months after injury in children with TBI. PMID- 22434554 TI - Visualization of the normal appendix with MR enterography in children. AB - BACKGROUND: Magnetic resonance (MR) imaging may provide a radiation-sparing alternative to CT in diagnosing appendicitis in children in whom US is equivocal. However, comparability with CT in the detection of the appendix remains to be established. OBJECTIVE: To determine the detection rate of the normal appendix in children on oral and IV contrast-enhanced MRI. METHODS: MR imaging of 58 patients who had previously undergone MR enterography was retrospectively reviewed. Detection rate, body mass index, age and gender were recorded. RESULTS: The normal appendix was detected in 28 cases (48%), with greatest detection rate on the axial fast imaging employing steady-state acquisition (FIESTA) sequence. Children in whom the appendix was detected had significantly higher BMI compared to children in whom the appendix was not seen. Neither age nor gender demonstrated a significant association with detection rate. CONCLUSION: The detection rate of the normal appendix in children on oral and IV contrast enhanced MRI was 48%, which is comparable to detection rates on CT, as well as to previously reported detection rates on MR imaging with neither oral nor IV contrast agents. These findings may serve to guide the development of MRI protocols for pediatric appendicitis. PMID- 22434555 TI - Persistent genomic instability in peripheral blood lymphocytes from Hodgkin lymphoma survivors. AB - Advances in cancer treatment have led to an increase in patient survival. However, exposure to genotoxic chemotherapeutic agents and ionizing radiation may induce persistent genetic damage in cancer survivors. In this study, we detected genomic instability in chromosomes of peripheral blood lymphocytes from Hodgkin lymphoma patients, 2-17 years after MOPP (nitrogen mustard, Oncovin, procarbazine, and prednisone) chemotherapy with or without radiotherapy. Samples were obtained from 11 healthy individuals, 5 pretreatment patients, and 20 posttreatment patients. Cytogenetic analysis with GTG banding was performed on 1,000 lymphocyte metaphases per donor to identify genomic instability, including numerical and structural chromosomal aberrations, at a resolution of 10 Mb across the entire genome. Our results showed that anticancer treatment did not induce significant differences in the frequency of aneuploidy among the three study groups. However, 1 of the 11 healthy individuals, and 13 of the 20 posttreatment patients had a high frequency of chromosomal breaks and gross chromosomal rearrangements. The types of aberrations observed were random and complex, consistent with persistent genomic instability that was induced by cancer treatment. Clonal expansion of cells with chromosomal lesions was observed in one posttreatment patient only. These findings show that anticancer treatments induce persistent genomic instability, but not aneuploidy. Chemotherapy may affect genes with a role in DNA damage surveillance or repair, which in turn allows the accumulation of nontargeted structural chromosomal damage in future generations of cells. This genomic instability may facilitate the development of second malignancies in Hodgkin lymphoma survivors. PMID- 22434556 TI - Acute malignant intestinal obstruction accompanied by synchronous multifocal intestinal cancer in Peutz-Jeghers syndrome: report of a case. AB - Acute mechanical intestinal obstruction is one of the most common modes of presentation in patients with Peutz-Jeghers syndrome (PJS). This report presents a case of PJS with malignant acute jejunal obstruction accompanied by synchronous foci of duodenal, jejunal, and ileal cancer originated from hamartomatous polyps. The follow-up endoscopic findings of the patient also revealed severe polyposis of the entire gastrointestinal tract, including the stomach and colon, in addition to the small intestine. Very few cases of multifocal synchronous small intestinal cancer in PJS patients have been reported in the previous literature. PMID- 22434557 TI - Prevention of major infectious complications by pre-emptive enterostomy in patients awaiting allogeneic stem cell transplantation. PMID- 22434558 TI - The changing role of gesture in linguistic development: a developmental trajectory and a cross-cultural comparison between British and Finnish children. AB - We studied how gesture use changes with culture, age and increased spoken language competence. A picture-naming task was presented to British (N = 80) and Finnish (N = 41) typically developing children aged 2-5 years. British children were found to gesture more than Finnish children and, in both cultures, gesture production decreased after the age of two. Two-year-olds used more deictic than iconic gestures than older children, and gestured more before the onset of speech, rather than simultaneously or after speech. The British 3- and 5-year olds gestured significantly more when naming praxic (manipulable) items than non praxic items. Our results support the view that gesture serves a communicative and intrapersonal function, and the relative function may change with age. Speech and language therapists and psychologists observe the development of children's gestures and make predictions on the basis of their frequency and type. To prevent drawing erroneous conclusions about children's linguistic development, it is important to understand developmental and cultural variations in gesture use. PMID- 22434559 TI - Abstract rule learning in 11- and 14-month-old infants. AB - This study tests the hypothesis that distributional information can guide infants in the generalization of word order movement rules at the initial stage of language acquisition. Participants were 11- and 14-month-old infants. Stimuli were sentences in Russian, a language that was unknown to our infants. During training the word order of each sentence was transformed following a consistent pattern (e.g., ABC-BAC). During the test phase infants heard novel sentences that respected the trained rule and ones that violated the trained rule (i.e., a different transformation such as ABC-ACB). Stimuli words had highly variable phonological and morphological shapes. The cue available was the positional information of words and their non-adjacent relations across sentences. We found that 14-month-olds, but not 11-month-olds, showed evidence of abstract rule generalization to novel instances. The implications of this finding to early syntactic acquisition are discussed. PMID- 22434560 TI - Escape from the island: grammaticality and (reduced) acceptability of wh-island violations in Danish. AB - In the syntax literature, it is commonly assumed that a constraint on linguistic competence blocks extraction of wh-expressions (e.g. what or which book) from embedded questions, referred to as wh-islands. Furthermore, it is assumed that there is an argument/adjunct asymmetry in extraction from wh-islands. We report results from two acceptability judgment experiments on long and short wh-movement and wh-extraction from wh-islands in Danish. The results revealed four main findings: (1) No adjunct/argument asymmetry in extraction from wh-islands. (2) Long adjunct wh-movement is less acceptable than long argument wh-movement, and this difference is attributable to matrix verb compatibility and factivity, not D linking. (3) Long movement reduces acceptability, but is more acceptable than island violations. (4) Training effects reveal that island violations, though degraded, are grammatical in Danish. Since the standard assumptions cannot account for the range of results, we argue in favor of a processing account referring to locality (processing domains) and working memory. PMID- 22434561 TI - Synergistic interactions between PBDEs and PCBs in human neuroblastoma cells. AB - Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants. Exposure to these chemicals has been associated with developmental neurotoxicity, endocrine dysfunction, and reproductive disorders. Humans and wildlife are generally exposed to a mixture of these environmental pollutants, highlighting the need to evaluate the potential effects of combined exposures. In this study, we investigated the cytotoxic effects of the combined exposure to two PBDEs and two PCBs in a human neuronal cell line. 2,2',4,4'-Tetrabromodiphenyl ether, 2,2',4,4',5-pentabromodiphenyl ether, PCB-126 (3,3',4,4',5-pentachlorobiphenyl; a dioxin-like PCB), and PCB-153 (2,2',4,4',5,5'-hexachlorobiphenyl; a non-dioxin-like PCB) were chosen, because their concentrations are among the highest in human tissues and the environment. The results suggest that the nature of interactions is related to the PCB structure. Mixtures of PCB-153 and both PBDEs had a prevalently synergistic effect. In contrast, mixtures of each PBDE congener with PCB-126 showed additive effects at threshold concentrations, and synergistic effects at higher concentrations. These results emphasize the concept that the toxicity of xenobiotics may be affected by possible interactions, which may be of significance given the common coexposures to multiple contaminants. PMID- 22434562 TI - Study of ballistic gold conductor using ultra-high-vacuum transmission electron microscopy. AB - Metal contacts are regarded as key elements of nanometer-scale electronics. Since gold contacts show quantized conductance even at room temperature, much effort has been devoted to understand their conductance behavior on the nanoscale. However, gold contacts do not always show quantized conductance steps during their thinning process, the reason for which has been an open question. Thus, it is necessary to investigate the relationship between the atomic structure and conductance of gold contacts. We developed a custom-made scanning tunneling microscope combined with an ultra-high vacuum transmission electron microscope to clarify the structural dependence of conductance quantization in gold contacts. We found that [111] and [001] gold contacts with a bottleneck shape showed a gradual decrease in conductance with elastic elongation and successive conductance jumps with periodic plastic deformation. In contrast, [110] gold contacts had a hexagonal prism shape (termed gold [110] nanowires). In the conductance histogram, peaks appeared nearly in steps of the quantum unit. We found that the prominent peaks corresponded to stable gold nanowires with a regular hexagonal cross-section. Following first-principles calculations, we confirmed that very thin gold [110] nanowires were ballistic conductors. The conductance behavior differed depending on the contact shape. PMID- 22434566 TI - Tailoring nanostructures using copolymer nanoimprint lithography. AB - The generation of defect-free polymer nanostructures by nanoimprinting methods is described. Long-range nanorheology and shorter-range surface energy effects can be efficiently combined to provide alignment of copolymer lamellae over several micrometers. As an example, a perpendicular organization with respect to circular tracks is shown, demonstrating the possibility of writing ordered radial nanostructures over large distances. PMID- 22434567 TI - Small differences between anatomical and mechanical sagittal femur axes: a radiological and navigated study of 50 patients. AB - BACKGROUND AND PURPOSE: The purposes of the study were to define the orientation of the anatomical and mechanical axes of the femur on the lateral plane on long leg X-rays including the femoral head, and to compare these results to the intra operative measurement of the mechanical axis by a nonimage-based navigation system. METHODS: Fifty cases of patients operated on for total knee replacement were included. All patients had digital pre- and post-operative long leg lateral X-rays including the femoral head. All prostheses were implanted with a nonimage based navigation system. Five sagittal femur axes were measured on pre- and post operative X-rays. The sagittal orientation of the distal femoral resection was measured by the navigation system and on the post-operative X-rays. RESULTS: Significant, but small differences were observed in the orientation of the different axes on the pre- and post-operative X-rays. The correlation and the agreement between all axes were good. There was no significant modification on the post-operative X-rays. There were significant, but small differences between the navigated and radiological orientation of the distal femur resection, but the correlation and the agreement were good. INTERPRETATION: The differences observed are small and have probably little clinical relevance. The distal cortical axis may be the best compromise. The navigation system allows measuring accurately the orientation of the distal femoral resection in the sagittal plane. PMID- 22434568 TI - Adherence to surveillance care guidelines after breast and colorectal cancer treatment with curative intent. AB - BACKGROUND: Evidence-based guidelines recommend routine surveillance, including office visits and testing, to detect new and recurrent disease among survivors of breast and colorectal cancer. The extent to which surveillance practice is consistent with guideline recommendations or may vary by age is not known. METHODS: Cohorts of adult patients diagnosed with breast (n = 6205) and colorectal (n = 2297) cancer between 2000 and 2008 and treated with curative intent in 4 geographically diverse managed care environments were identified via tumor registries. Kaplan-Meier estimates were used to describe time to initial and subsequent receipt of surveillance services. Cox proportional hazards models evaluated the relation between patient characteristics and receipt of metastatic screening. RESULTS: Within 18 months of treatment, 87.2% of breast cancer survivors received recommended mammograms, with significantly higher rates noted for patients aged 50 years to 65 years. Among survivors of colorectal cancer, only 55.0% received recommended colon examinations, with significantly lower rates for those aged >= 75 years. The majority of breast (64.7%) and colorectal (73.3%) cancer survivors received nonrecommended metastatic disease testing. In patients with breast cancer, factors associated with metastatic disease testing include white race (hazards ratio [HR], 1.13), comorbidities (HR, 1.17), and younger age (HR, 1.13; 1.15; 1.13 for age groups: <50, 50-64, and 65-74 respectively). In those with colorectal cancer, these factors included younger age (HR, 1.31; 1.25 for age groups: <50 and 50-64 respectively) and comorbidities (HR, 1.10). CONCLUSIONS: Among an insured population, wide variation regarding the use of surveillance care was found by age and relative to guideline recommendations. Breast cancer survivors were found to have high rates of both guideline-recommended recurrence testing and non-guideline-recommended metastatic testing. Only approximately 50% of colorectal cancer survivors received recommended tests but greater than 67% received metastatic testing. PMID- 22434569 TI - Function and limits of biofilters for the removal of methane in exhaust gases from the pig industry. AB - The agricultural sector is responsible for an important part of Canadian greenhouse gas (GHG) emissions, 8 % of the 747 Mt eq. CO(2) emitted each year. The pork industry, a key sector of the agrifood industry, has had a rapid growth in Canada since the middle 1980s. For this industry, slurry storage accounts for the major part of methane (CH(4)) emissions, a GHG 25 times higher than carbon dioxide (CO(2)) on a 100-year time horizon. Intending to reduce these emissions, biofiltration, a process effective to treat CH(4) from landfills and coal mines, could be effective to treat CH(4) from the pig industry. Biofiltration is a complex process that requires the understanding of the biological process of CH(4) oxidation and a control of the engineering parameters (filter bed, temperature, etc.). Some biofiltration studies show that this technology could be used to treat CH(4) at a relatively low cost and with a relatively high purification performance. PMID- 22434570 TI - Denitrification in soil amended with thermophile-fermented compost suppresses nitrate accumulation in plants. AB - NO (3) (-) is a major nitrogen source for plant nutrition, and plant cells store NO (3) (-) in their vacuoles. Here, we report that a unique compost made from marine animal resources by thermophiles represses NO (3) (-) accumulation in plants. A decrease in the leaf NO (3) (-) content occurred in parallel with a decrease in the soil NO (3) (-) level, and the degree of the soil NO (3) (-) decrease was proportional to the compost concentration in the soil. The compost induced reduction of the soil NO (3) (-) level was blocked by incubation with chloramphenicol, indicating that the soil NO (3) (-) was reduced by chloramphenicol-sensitive microbes. The compost-induced denitrification activity was assessed by the acetylene block method. To eliminate denitrification by the soil bacterial habitants, soil was sterilized with gamma irradiation and then compost was amended. After the 24-h incubation, the N(2)O level in the compost soil with presence of acetylene was approximately fourfold higher than that in the compost soil with absence of acetylene. These results indicate that the low NO (3) (-) levels that are often found in the leaves of organic vegetables can be explained by compost-mediated denitrification in the soil. PMID- 22434571 TI - High-temperature sorbose fermentation with thermotolerant Gluconobacter frateurii CHM43 and its mutant strain adapted to higher temperature. AB - We succeeded in obtaining a strain adapted to higher temperature from a thermotolerant strain, Gluconobacter frateurii CHM43, for sorbose fermentation. The adapted strain showed higher growth and L-sorbose production than original CHM43 strain at higher temperature around 38.5-40 degrees C. It was also shown to be useful even with the fermentation without temperature control. To understand the sorbose fermentation ability of the adapted strain at higher temperature, D-sorbitol-oxidizing respiratory chain was compared with the CHM43 strain and the adapted strain. We found that the activity of pyrroloquinoline quinone (PQQ)-dependent glycerol dehydrogenase (GLDH), which is a primary dehydrogenase of the respiratory chain and responsible for L-sorbose production, was decreased when the temperature increased, but the decreased activity of GLDH was recovered by the addition of PQQ. Since the adapted strain was found to produce more PQQ than the CHM43 strain, it was suggested that the adapted strain keeps GLDH as holoenzyme with the increased PQQ production, and thus produces more L-sorbose and grows better under higher temperature. PMID- 22434572 TI - Axillary nerve neurotization with the anterior deltopectoral approach in brachial plexus injuries. AB - Combined neurotization of both axillary and suprascapular nerves in shoulder reanimation has been widely accepted in brachial plexus injuries, and the functional outcome is much superior to single nerve transfer. This study describes the surgical anatomy for axillary nerve relative to the available donor nerves and emphasize the salient technical aspects of anterior deltopectoral approach in brachial plexus injuries. Fifteen patients with brachial plexus injury who had axillary nerve neurotizations were evaluated. Five patients had complete avulsion, 9 patients had C5, six patients had brachial plexus injury pattern, and one patient had combined axillary and suprascapular nerve injury. The long head of triceps branch was the donor in C5,6 injuries; nerve to brachialis in combined nerve injury and intercostals for C5-T1 avulsion injuries. All these donors were identified through the anterior approach, and the nerve transfer was done. The recovery of deltoid was found excellent (M5) in C5,6 brachial plexus injuries with an average of 134.4 degrees abduction at follow up of average 34.6 months. The shoulder recovery was good with 130 degrees abduction in a case of combined axillary and suprascapular nerve injury. The deltoid recovery was good (M3) in C5-T1 avulsion injuries patients with an average of 64 degrees shoulder abduction at follow up of 35 months. We believe that anterior approach is simple and easy for all axillary nerve transfers in brachial plexus injuries. PMID- 22434573 TI - Simple bipolar molecules constructed from biphenyl moieties as host materials for deep-blue phosphorescent organic light-emitting diodes. AB - Simple is good! Based on biphenyl molecules, two bipolar host materials with high triplet energies have been rationally designed, synthesized, and fully characterized. Deep blue phosphorescent organic light-emitting diodes, which employ the new hosts and an iridium(III) complex as triplet emitter, show a maximum current efficiency of 40 cd A(-1), a maximum power efficiency of 36 lm W( 1), and a maximum external quantum efficiency of 19.5 %. PMID- 22434574 TI - Effects of 4-nonylphenol on balance of steroid and thyroid hormones in sexually immature male yellowfin seabream (Acanthopagrus latus). AB - Nonylphenol (NP) is an endocrine disrupting chemical which has been shown to be able to modulate the endocrine system of various organisms by different mechanisms. The objective of this study was to investigate the potential effects of 4-NP on steroid and thyroid hormone levels in sexually immature male yellowfin seabream (Acanthopagrus latus), a protandrous hermaphrodite species. For this, the fish were injected with ascending doses (10, 50, 100, and 200 MUg g(-1) body weight) of 4-nonylphenol (4-NP) or vehicle during 2 weeks. After 7 and 14 days the fish were anesthetized, blood sample were collected and plasma steroid and thyroid hormone concentrations were quantified by radioimmunoassay. The result showed that 4-NP induced a significant increase in 17beta-etradiol levels at dose 10 MUg g(-1) , while the levels of this hormone in the higher doses decreased compared with the control group. However, 4-NP treatment did not have any significant effect on plasma levels of testosterone. In addition, it was observed that 4-NP affect the level of thyroid hormones in fish. Plasma thyroxine levels increased in a dose-dependent manner after 7 and 14 days of the exposure. In contrast, a significant decrease in triiodothyronine levels was observed during the experiment period. Moreover, no significant change was detected for thyroid stimulating hormone levels in 4-NP-treated fish. These results indicated that 4 NP could lead to disturb the balance of steroid and thyroid hormones with potential consequences for sexually immature male yellowfin seabream. PMID- 22434575 TI - Biciliated ependymal cell proliferation contributes to spinal cord growth. AB - Two neurogenic regions have been described in the adult brain, the lateral ventricle subventricular zone and the dentate gyrus subgranular zone. It has been suggested that neural stem cells also line the central canal of the adult spinal cord. Using transmission and scanning electron microscopy and immunostaining, we describe here the organization and cell types of the central canal epithelium in adult mice. The identity of dividing cells was determined by 3D ultrastructural reconstructions of [(3) H]thymidine-labeled cells and confocal analysis of bromodeoxyuridine labeling. The most common cell type lining the central canal had two long motile (9+2) cilia and was vimentin+, CD24+, FoxJ1+, Sox2+, and CD133+, but nestin- and glial fibrillary acidic protein (GFAP)-. These biciliated ependymal cells of the central canal (Ecc) resembled E2 cells of the lateral ventricles, but their basal bodies were different from those of E2 or E1 cells. Interestingly, we frequently found Ecc cells with two nuclei and four cilia, suggesting they are formed by incomplete cytokinesis or cell fusion. GFAP+ astrocytes with a single cilium and an orthogonally oriented centriole were also observed. The majority of dividing cells corresponded to biciliated Ecc cells. Central canal proliferation was most common during the active period of spinal cord growth. Pairs of labeled Ecc cells were observed within the central canal in adult mice 2.5 weeks post labeling. Our work suggests that the vast majority of postnatal dividing cells in the central canal are Ecc cells and their proliferation is associated with the growth of the spinal cord. PMID- 22434576 TI - The perspective of psychosomatic medicine on the effect of religion on the mind body relationship in Japan. AB - Shintoism, Buddhism, and Qi, which advocate the unity of mind and body, have contributed to the Japanese philosophy of life. The practice of psychosomatic medicine emphasizes the connection between mind and body and combines the psychotherapies (directed at the mind) and relaxation techniques (directed at the body), to achieve stress management. Participation in religious activities such as preaching, praying, meditating, and practicing Zen can also elicit relaxation responses. Thus, it is time for traditional religions to play an active role in helping those seeking psychological stability after the Great East Japan Earthquake and the ongoing crisis related to the nuclear accident in Fukushima, Japan, to maintain a healthy mind-body relationship. PMID- 22434577 TI - Gerotrancscendence through Jewish eyes. AB - The Swedish sociologist Tornstam perceives old age as the peak of human maturation whose favorable culmination is gerotranscendence. The latter is characterized by breaking out of one's finite existence and uniting with a greater world with respect to past, present, and future. Tornstam relates to gerotranscendent roots in Eastern cultures; this study will examine how gerotranscendence finds expression in Jewish sources. Varied Jewish texts speak to how the wisdom that accrues from life experience enables one to rise above physical decline and enrich relationships via self, fellow man, and cosmos. Three major biblical exemplars of gerotranscendors are depicted: Abraham, focusing on limitless giving to fellow man; Isaac, overcoming psychological barriers of past paternal disappointments; and Jacob uniting with his children and grandchildren through the blessing that becomes a legacy for perpetuating the future of the nation. Practical applications of the study for more meaningful aging are discussed. PMID- 22434578 TI - MRT letter: extended depth from focus reconstruction method for stretch zone measurement in 15-5PH steel. AB - The stretch zone width (SZW) data for 15-5PH steel CTOD specimens fractured at 150 degrees C to + 23 degrees C temperature were measured based on focused images and 3D maps obtained by extended depth-of-field reconstruction from light microscopy (LM) image stacks. This LM-based method, with a larger lateral resolution, seems to be as effective for quantitative analysis of SZW as scanning electron microscopy (SEM) or confocal scanning laser microscopy (CSLM), permitting to clearly identify stretch zone boundaries. Despite the worst sharpness of focused images, a robust linear correlation was established to fracture toughness (K(C) ) and SZW data for the 15-5PH steel tested specimens, measured at their center region. The method is an alternative to evaluate the boundaries of stretched zones, at a lower cost of implementation and training, since topographic data from elevation maps can be associated with reconstructed image, which summarizes the original contrast and brightness information. Finally, the extended depth-of-field method is presented here as a valuable tool for failure analysis, as a cheaper alternative to investigate rough surfaces or fracture, compared to scanning electron or confocal light microscopes. PMID- 22434579 TI - The cytopathology of malignant peripheral nerve sheath tumor: a report of 55 fine needle aspiration cases. AB - BACKGROUND: Among sarcomas, a diagnosis of malignant peripheral nerve sheath tumor (MPNST) is often one of exclusion due to the absence of unequivocally characteristic histopathology, a conclusive immunohistochemical profile, or even a unique chromosomal anomaly. Because of this, the fine-needle aspiration (FNA) cytopathology of MPNST is extremely challenging. In the current study, the authors review their FNA experience with this neoplasm. METHODS: The authors searched their combined departmental cytology files for all lesions signed out as MPNST or suspicious for MPNST, as well as their own surgical pathology files for any cases of MPNST that had corresponding cytology. FNA was performed using standard techniques. RESULTS: A total of 55 cases of MPNST, all with tissue confirmation, and 1 misdiagnosed example of melanoma were retrieved from 52 patients (M:F ratio of 1.5:1; average age, 46 years), 26 of whom had a history of neurofibromatosis type 1 (NF-1). Aspirates were from primary (27 cases), locally recurrent (14 cases), or metastatic (10 cases) MPNST; 4 primary tumor aspirates were of ex vivo specimens. Sites included the extremities (22 cases), trunk/pelvis (22 cases), head and neck (6 cases), and deep-seated masses (6 cases). FNA diagnoses were MPNST (24 patients); consistent with MPNST (5 patients); sarcoma, not otherwise specified (10 patients); atypical (3 patients); spindle cell neoplasm (6 patients); malignant neoplasm (1 patient); and nondiagnostic (3 patients). A definitive diagnosis of either MPNST or consistent with MPNST was issued in 30%, 93%, and 70%, respectively, of primary, locally recurrent, and metastatic lesions. CONCLUSIONS: FNA cytopathology is limited as a diagnostic instrument for the initial diagnosis of MPNST, but is exceedingly accurate and valuable in the recognition of metastatic and locally recurrent MPNST. PMID- 22434580 TI - Vinyl-type polynorbornenes with pendant PCBM: a novel acceptor for organic solar cells. AB - Vinyl addition homo- and copolymerization of norbornene monomer (M1) functionalized with a PCBM moiety using a Pd(II) catalyst in combination with a 1 octene chain transfer agent efficiently produces polynorbornenes with side-chain PCBM groups. Characterization by NMR spectroscopy and elemental analysis reveals that the copolymers constitute a well-defined polymer structure with controlled incorporation of M1. Although the homopolymer is insoluble in organic solvents, the copolymers containing 62 mol% (P2) and 50 mol% (P3) of the PCBM moiety are soluble in chlorinated solvents such as o-dichlorobenzene. The bulk heterojunction organic photovoltaic devices fabricated based on the P3HT:P3 blends show that P3 can adequately function as an electron acceptor, leading to a cell with a power conversion efficiency of 1.5%, which is outstanding among the polymeric rivals. PMID- 22434581 TI - Peroxisome proliferator-activated receptor gamma (PPAR-gamma) and neurodegenerative disorders. AB - As the growth of the aging population continues to accelerate globally, increased prevalence of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, has generated substantial public concern. Unfortunately, despite of discoveries of common factors underlying these diseases, few drugs are available to effectively treat these diseases. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. PPAR-gamma has been shown to influence the expression or activity of a large number of genes in a variety of signaling networks, including regulation of insulin sensitivity, glucose homeostasis, fatty acid oxidation, immune responses, redox balance, cardiovascular integrity, and cell fates. Recent epidemiological, preclinical animal, and clinical studies also show that PPAR-gamma agonists can lower the incidence of a number of neurological disorders, despite of multiple etiological factors involved in the development of these disorders. In this manuscript, we review current knowledge on mechanisms underlying the beneficial effect of PPAR-gamma in different neurodegenerative diseases, in particular, AD, PD, and stroke, and attempt to analyze common and overlapping features among these diseases. Our investigation unveiled information suggesting the ability for PPAR-gamma to inhibit NF-kappaB-mediated inflammatory signaling at multiple sites, and conclude that PPAR-gamma agonists represent a novel class of drugs for treating neuroinflammatory diseases. PMID- 22434582 TI - Neither P-gp SNP variants, P-gp expression nor functional P-gp activity predicts MDR in a preliminary study of plasma cell myeloma. AB - INTRODUCTION: Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) can compromise the successful treatment of many malignancies including plasma cell myeloma (PCM). However, methods do not yet exist that can accurately determine P gp activity in PCM patient samples. METHODS: In this study, we have utilized new advances in flow cytometric methods to determine the activity of P-gp in PCM tumor cells. Furthermore, we have used several PCR-based approaches to perform a pilot study determining the functional impact of ABCB1 SNPs in patients with PCM. RESULTS: No associations were seen between P-gp activity or expression and subgroups of PCM. Similarly, no association was seen between P-gp expression and SNPs within ABCB1 although a nonsignificant reduction in activity was demonstrated for rs1045642 (P = 0.121). CONCLUSIONS: We have described a new method for the determination of P-gp and MRP activity suitable for use in clinical studies and have optimized this method to include a gating strategy, allowing routine use on PCM bone marrow aspirate samples. This is the first patient study to consider the full impact of SNPs within ABCB1 all the way from the genome to the proteome in PCM. The methods described here could also be utilized for future studies of "stem cell like" side populations in PCM that are considered to be drug resistant. Furthermore, minor amendments to these methods will facilitate studies of P-gp, MRP, and BCRP activity in other haematological malignancies. PMID- 22434583 TI - Elastin-derived peptides increase invasive capacities of lung cancer cells by post-transcriptional regulation of MMP-2 and uPA. AB - Elastin-rich lung extracellular matrix is largely remodeled during tumor invasion. Elastin degradation produces peptides displaying a wide range of biological activities. These elastin derived peptides (EP) interact with the elastin receptor complex (ERC) but also bind to alpha(V)beta(3) integrin and galectin-3. In this study, we explored the role of EP and their receptors in tumor progression of lung carcinomas. Non-invasive and invasive lung tumor cell lines were incubated in presence of kappa-elastin (kappaE) or with synthetic peptides displaying receptor-specific sequences (VGVAPG, GRKRK, AGVPGLGVG and AGVPGFGAG). Modified Boyden chamber assays revealed an increased invasive capacity of invasive cells induced by kappaE. EP treatment had no effect on cell proliferation but zymography analysis revealed an increase of pro-MMP-2 and uPA levels in the conditioned media of treated cells. Moreover, the active form of MMP-2 was increased in invasive cells. Interestingly, this regulation was not observed at the mRNA level and actinomycin D was unable to inhibit kappaE effects. We also observed that the regulation of proteases protein level following kappaE treatment was an early process detectable after 1 h. All these effects could not be inhibited by lactose and V14, two ERC antagonists, or by blocking antibodies against alpha(V)beta(3) integrin and galectin-3. Finally, VGVAPG and GRKRK failed to reproduce kappaE effects whereas nonapeptides partially mimicked them. These results demonstrate that treatment with EP up regulates invasiveness of lung tumor cells via the release of proteolytic enzymes. This modulation involves post-transcriptional mechanisms and a nonapeptide-receptor different from the ERC, alpha(V)beta(3) integrin and galectin-3. PMID- 22434584 TI - Cationic peptidopolysaccharides show excellent broad-spectrum antimicrobial activities and high selectivity. PMID- 22434585 TI - The long-term functional recovery of repair of sciatic nerve transection with biogenic conduits. AB - INTRODUCTION: The aim of this study was to evaluate long-term regenerative capacity over a 15-mm nerve gap of an autologous nerve conduit, the biogenic conduit (BC), 16 weeks after sciatic nerve transection in the rat. METHODS: A 19 mm long polyvinyl chloride (PVC) tube was implanted parallely to the sciatic nerve. After implantation, a connective tissue cover developed around the PVC tube, the so-called BC. After removal of the PVC-tube the BCs filled with fibrin (n = 8) were compared to autologous nerve grafts (n = 8). Sciatic functional index (SFI) was evaluated every 4 weeks, histological evaluation was performed at 16 weeks postimplantation. Regenerating axons were visualized by retrograde labelling. RESULTS: SFI revealed no significant differences. Nerve area and axon number in the BC group were significantly lower than in the autologous nerve group (P < 0.05; P < 0.01). Analysis of myelin formation showed no significant difference in both groups. Analysis of N-ratio revealed lower values in the BC group (P < 0.001). CONCLUSION: This study reveals the suitability of BC for nerve gap bridging over a period of 16 weeks with functional recovery to comparable extent as the autologous nerve graft despite impaired histomorphometric parameters. PMID- 22434586 TI - Differentiation capacity of native pituitary folliculostellate cells and brain astrocytes. AB - Pituitary folliculostellate (FS) cells are characterized by producing S100B protein, as do brain astrocytes. FS cells have some functions in the pituitary gland, i.e. scavenger functions, sustentacular cell activity through cytokines, and intercellular communication through gap junctions. However, the biological significances of FS cells, especially their differentiation capacities in the anterior pituitary gland, are still under discussion. To understand FS cells with new approaches, we generated a transgenic rat expressing GFP under S100b gene promoter, which regulates tissue-specific expression of S100b gene. Using the transgenic rat, we succeeded in inducing skeletal muscle cells from FS cells by culturing it in serum-free medium containing B-27 supplement, thyroid hormone (tri-iodothyronine), epidermal growth factor, and basic fibroblast growth factor. In this study, we also succeeded in inducing skeletal muscle cells from primary cultured astrocytes and astrocyte cell line, C6 cells. Hence, we concluded that pituitary FS cells have wide differentiation potential and have similar characteristics to astrocytes, which not only support cell activity but also support differentiation capacity. PMID- 22434587 TI - Dependence of paranodal junctional gap width on transverse bands. AB - Mouse mutants with paranodal junctional (PNJ) defects display variable degrees of neurological impairment. In this study we compare control paranodes with those from three mouse mutants that differ with respect to a conspicuous PNJ component, the transverse bands (TBs). We hypothesize that TBs link the apposed junctional membranes together at a fixed distance and thereby determine the width of the junctional gap, which may in turn determine the extent to which nodal action currents can be short-circuited underneath the myelin sheath. Electron micrographs of aldehyde-fixed control PNJs, in which TBs are abundant, show a consistent junctional gap of ~3.5 nm. In Caspr-null PNJs, which lack TBs entirely, the gap is wider (~6-7 nm) and more variable. In CST-null PNJs, which have only occasional TBs, the mean PNJ gap width is comparable to that in Caspr null mice. In the shaking mutant, in contrast, which has approximately 60% of the normal complement of TBs, mean PNJ gap width is not significantly different from that in controls. Correspondingly, shaking mice are much less impaired neurologically than either Caspr-null or CST-null mice. We conclude that in the absence or gross diminution of TBs, mean PNJ gap width increases significantly and suggest that this difference could underlie some of the neurological impairment seen in those mutants. Surprisingly, even in the absence of TBs, paranodes are to some extent maintained in their usual form, implying that in addition to TBs, other factors govern the formation and maintenance of overall paranodal structure. PMID- 22434588 TI - Ethanol-glycerin fixation with thymol conservation: a potential alternative to formaldehyde and phenol embalming. AB - Anatomical fixation and conservation are required to prevent specimens from undergoing autolysis and decomposition. While fixation is the primary arrest of the structures responsible for autolysis and decomposition, conservation preserves the state of fixation. Although commonly used, formaldehyde has been classified as carcinogenic to humans. For this reason, an adequate substitute was developed. Ethanol-glycerin fixation and thymol conservation are described and compared with formaldehyde and phenol in this technical report. The setup, tissue qualities, financial aspects, and health concerns of this method are discussed. Ethanol-glycerin fixation and thymol conservation provide outstanding haptic and optic tissue qualities. Typical formaldehyde and phenol effects, such as skin, airway, and eye irritation, as well as carcinogenic effects, can be circumvented by using ethanol-glycerin and thymol instead. Ethanol-glycerin fixation is more expensive than formaldehyde and requires an explosion-proof facility. However, the absence of health effects and its convincing tissue qualities balance these higher costs. Therefore, ethanol-glycerin fixation and thymol conservation provide a potential alternative and complement established fixation techniques. The use of carcinogenic formaldehyde and toxic phenol can be effectively restricted through the use of the described method. PMID- 22434589 TI - Impaired letter-string processing in developmental dyslexia: what visual-to phonology code mapping disorder? AB - Poor parallel letter-string processing in developmental dyslexia was taken as evidence of poor visual attention (VA) span, that is, a limitation of visual attentional resources that affects multi-character processing. However, the use of letter stimuli in oral report tasks was challenged on its capacity to highlight a VA span disorder. In particular, report of poor letter/digit-string processing but preserved symbol-string processing was viewed as evidence of poor visual-to-phonology code mapping, in line with the phonological theory of developmental dyslexia. We assessed here the visual-to-phonological-code mapping disorder hypothesis. In Experiment 1, letter-string, digit-string and colour string processing was assessed to disentangle a phonological versus visual familiarity account of the letter/digit versus symbol dissociation. Against a visual-to-phonological-code mapping disorder but in support of a familiarity account, results showed poor letter/digit-string processing but preserved colour string processing in dyslexic children. In Experiment 2, two tasks of letter string report were used, one of which was performed simultaneously to a high taxing phonological task. Results show that dyslexic children are similarly impaired in letter-string report whether a concurrent phonological task is simultaneously performed or not. Taken together, these results provide strong evidence against a phonological account of poor letter-string processing in developmental dyslexia. PMID- 22434590 TI - Paralabral cysts in the hip joint: findings at MR arthrography. AB - PURPOSE: The purpose of this research was to retrospectively characterize paralabral cysts of the hip as seen at MR arthrography. MATERIALS AND METHODS: After Institutional Review Board approval, 704 patients who had MR arthrography were identified over a 3-year period and 40 patients were identified as having a cyst or fluid collection at the hip by MR report. MR images from these 40 patients were retrospectively reviewed by three radiologists where 18 were found to have a paralabral cyst, which were characterized as follows: location, configuration, contrast filling, size of the cyst, extent, direction, and whether associated osseous changes were present. In addition, the acetabular labrum was assessed for tears and, if present, the location and pattern were characterized. RESULTS: Paralabral cysts were located anterosuperiorly in 56%, anteriorly in 22%, posterosuperiorly in 17%, and anteroinferiorly in 6% of cases. The vast majority (94%) were multilocular and filled with intra-articular contrast medium. The average dimensions were 8 * 7 * 11 mm. The paralabral cyst demonstrated extracapsular extension in 72% of cases, with 39% located between the ilium and gluteus minimus, and 22% between the ilium and iliopsoas. Remodeling of the ilium adjacent to the cyst was observed in 50% of these cases. A labral tear was at the base of the labrum adjacent to the cyst in 78% of cases, while the tear was isolated to the body of the labrum in 22%. Tears were most commonly anterosuperior (55%) or anterior (28%) in location. CONCLUSION: Our results show that paralabral cysts of the hip are most commonly located anterosuperiorly, are multilocular, fill with intra-articular contrast medium, have average dimensions up to 11 mm, and often extend extracapsularly between muscle and bone where they may remodel the adjacent ilium. PMID- 22434591 TI - Enhancing the efficiency of directed evolution in focused enzyme libraries by the adaptive substituent reordering algorithm. AB - Directed evolution is a broadly successful strategy for protein engineering in the quest to enhance the stereoselectivity, activity, and thermostability of enzymes. To increase the efficiency of directed evolution based on iterative saturation mutagenesis, the adaptive substituent reordering algorithm (ASRA) is introduced here as an alternative to traditional quantitative structure-activity relationship (QSAR) methods for identifying potential protein mutants with desired properties from minimal sampling of focused libraries. The operation of ASRA depends on identifying the underlying regularity of the protein property landscape, allowing it to make predictions without explicit knowledge of the structure-property relationships. In a proof-of-principle study, ASRA identified all or most of the best enantioselective mutants among the synthesized epoxide hydrolase from Aspergillus niger, in the absence of peptide seeds with high E values. ASRA even revealed a laboratory error from irregularities of the reordered E-value landscape alone. PMID- 22434594 TI - Manipulating nature: Might there be a cardiovascular price to pay for the miracle of assisted conception? PMID- 22434595 TI - Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. AB - BACKGROUND: Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual's susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. METHODS AND RESULTS: We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7 +/- 1.6% versus 8.6 +/- 1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. CONCLUSIONS: Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00837642. PMID- 22434596 TI - Computing theoretical rates of part C eligibility based on developmental delays. AB - Part C early intervention is a nationwide program that serves infants and toddlers who have developmental delays. This article presents a methodology for computing a theoretical estimate of the proportion of children who are likely to be eligible for Part C services based on delays in any of the 5 developmental domains (cognitive, motor, communication, social-emotional and adaptive) that are assessed to determine eligibility. Rates of developmental delays were estimated from a multivariate normal cumulative distribution function. This approach calculates theoretical rates of occurrence for conditions that are defined in terms of standard deviations from the mean on several variables that are approximately normally distributed. Evidence is presented to suggest that the procedures described produce accurate estimates of rates of child developmental delays. The methodology used in this study provides a useful tool for computing theoretical rates of occurrence of developmental delays that make children candidates for early intervention. PMID- 22434597 TI - Preparation of micron-sized monodisperse poly(ionic liquid) particles. AB - Micron-sized monodisperse poly(ionic liquid) (PIL) particles, poly([2 (methacryloyloxy)ethyl]trimethylammonium bis(trifluoromethanesulfonyl)amide), were prepared by dispersion polymerization at 70 degrees C in methanol with poly(vinylpyrrolidone) as a stabilizer. The obtained particle size could be controlled by addition of ethanol to the methanol medium while maintaining narrow monodispersity. The PIL particles exhibit unique properties; they can be observed by scanning electron microscopy without platinum coating, which is generally used to avoid an electron charge. Moreover, the solubility of the PIL particles can be easily changed by changing the counter anion, similar to the process for ionic liquids. PMID- 22434598 TI - Clinical expert consensus statement on best practices in the cardiac catheterization laboratory: Society for Cardiovascular Angiography and Interventions. PMID- 22434599 TI - Variety and overeating: comments on long-term habituation to food. PMID- 22434600 TI - Joint association of glycemic load and alcohol intake with type 2 diabetes incidence in women. PMID- 22434601 TI - trans Fatty acids and fetal growth. PMID- 22434602 TI - Effects of 16-carbon and 18-carbon trans isomeric fatty acids in the perinatal period. PMID- 22434603 TI - Energy balance and its components: implications for body weight regulation. PMID- 22434605 TI - Expression of coagulation factor XIII subunit A in acute promyelocytic leukemia. AB - Leukemic cells often express markers, which are not characteristic of their particular cell lineage. In this study, we identified the "A" subunit of coagulation factor XIII (FXIII-A) in leukemic promyelocytes in de novo AML M3 cases. The cytoplasmic presence of factor XIII-A has previously been shown only in platelets/megakaryocytes and monocytes/macrophages. Furthermore, more recently we described the presence of FXIII-A in leukemic lymphoblasts. We studied 14 patients with this rare type of acute leukemia in a period of 4 years and investigated their bone marrow samples by 3-color flow cytometry upon diagnosis, mainly focusing on FXIII-A expression of leukemic cells. We detected FXIII-A also by ELISA, Western-blot, and confocal laser scanning microscopy. This was a homogenous group of AML M3 patients with translocation t(15;17)(q22;q21) detected by fluorescence in situ hybridization (FISH). In 10 out of 14 samples, FXIII-A was detectable by flow cytometry and was coexpressed with markers characteristic for leukemic promyleocytes (CD45dim/CD13+/CD33+/CD117+/cyMPO+ and HLA-DR-/CD34 /CD14-/CD15-). Staining for the markers GPIIb and GPIX were negative, and FXIII-A was identified in the cytoplasm of the cells by confocal microscopy in a relatively high quantity, as measured by ELISA. By Western blot analysis we could identify FXIII-A in the native 82 kDa form and in cleaved forms corresponding to cleavage products observed when purified FXIII-A was treated by human neutrophil elastase. This novel expression site of FXIII-A in AML M3 can be considered as a leukemia associated immunophenotype and may have pathophysiological significance. PMID- 22434606 TI - Fabrication of graphene nanomesh by using an anodic aluminum oxide membrane as a template. PMID- 22434607 TI - Distinct regional and subcellular localization of the actin-binding protein filamin A in the mature rat brain. AB - Filamin A (FLNa) is an actin-binding protein that regulates cell motility, adhesion, and elasticity by cross-linking filamentous actin. Additional roles of FLNa include regulation of protein trafficking and surface expression. Although the functions of FLNa during brain development are well studied, little is known on its expression, distribution, and function in the adult brain. Here we characterize in detail the neuroanatomical distribution and subcellular localization of FLNa in the mature rat brain, by using two antisera directed against epitopes at either the N' or the C' terminus of the protein, further validated by mRNA expression. FLNa was widely and selectively expressed throughout the brain, and the intensity of immunoreactivity was region dependent. The most intensely FLNa-labeled neurons were found in discrete neuronal systems, including basal forebrain structures, anterior nuclear group of thalamus, and hypothalamic parvocellular neurons. Pyramidal neurons in neocortex and hippocampus and magnocellular cells in basolateral amygdaloid nucleus were also intensely FLNa immunoreactive, and strong FLNa labeling was evident in the pontine and medullary raphe nuclei and in sensory and spinal trigeminal nuclei. The subcellular localization of FLNa was evaluated in situ as well as in primary hippocampal neurons. Punctate expression was found in somata and along the dendritic shaft, but FLNa was not detected in dendritic spines. These subcellular distribution patterns were recapitulated in hippocampal and neocortical pyramidal neurons in vivo. The characterization of the expression and subcellular localization of FLNa may provide new clues to the functional roles of this cytoskeletal protein in the adult brain. PMID- 22434608 TI - Repeated capture of a cytoplasmic linear plasmid by the host nucleus in Debaryomyces hansenii. AB - Debaryomyces hansenii is a halotolerant yeast species that has been shown to carry various nuclear genes of plasmid or viral origin (NUPAVs). However, a recent ancestor of such NUPAVs has not been identified. Here we determined for the first time the molecular structure of an entire cytoplasmic linear plasmid, pDH1A, indigenous to this species. The element is related to non-autonomous killer plasmids from Kluyveromyces lactis and Pichia acaciae and carries a B-type DNA polymerase as well as remnants of a killer toxin system, a secreted chitin binding protein. Other essential toxin subunits or an immunity function, however, appear to be lost, while two additional small open reading frames are present. Transcripts for all four genes located on pDH1A could be verified by RT-PCR. Interestingly, all genes from pDH1A could be identified as ancestors of NUPAVs located at different chromosomes within the nucleus of D. hansenii, suggesting repeated nuclear capture of fragments originating from pDH1A. PMID- 22434609 TI - Borylene complexes (BH)L2 and nitrogen cation complexes (N+)L2: isoelectronic homologues of carbones CL2. AB - Quantum chemical calculations using DFT (BP86, M05-2X) and ab initio methods (CCSD(T), SCS-MP2) have been carried out on the borylene complexes (BH)L(2) and nitrogen cation complexes (N(+))L(2) with the ligands L=CO, N(2), PPh(3), NHC(Me), CAAC, and CAAC(model). The results are compared with those obtained for the isoelectronic carbones CL(2). The geometries and bond dissociation energies of the ligands, the proton affinities, and adducts with the Lewis acids BH(3) and AuCl were calculated. The nature of the bonding has been analyzed with charge and energy partitioning methods. The calculated borylene complexes (BH)L(2) have trigonal planar coordinated boron atoms which possess rather short B-L bonds. The calculated bond dissociation energies (BDEs) of the ligands for complexes where L is a carbene (NHC or CAAC) are very large (D(e) =141.6-177.3 kcal mol(-1)) which suggest that such species might become isolated in a condensed phase. The borylene complexes (BH)(PPh(3))(2) and (BH)(CO)(2) have intermediate bond strengths (D(e) =90.1 and 92.6 kcal mol(-1)). Substituted homologues with bulky groups at boron which protect the boron atom from electrophilic attack might also be stable enough to become isolated. The BDE of (BH)(N(2))(2) is much smaller (D(e) =31.9 kcal mol(-1)), but could become observable in a low-temperature matrix. The proton affinities of the borylene complexes are very large, particularly for the bulky adducts with L=PPh(3), NHC(Me), CAAC(model) and CAAC and thus, they are superbases. All (BH)L(2) molecules bind strongly AuCl either eta(1) (L=N(2), PPh(3), NHC(Me), CAAC) or eta(2) (L=CO, CAAC(model)). The BDEs of H(3)B-(BH)L(2) adducts which possess a hitherto unknown boron->boron donor acceptor bond are smaller than for the AuCl complexes. The strongest bonded BH(3) adduct that might be isolable is (BH)(PPh(3))(2)-BH(3) (D(e) =36.2 kcal mol(-1)). The analysis of the bonding situation reveals that (BH)-L(2) bonding comes mainly from the orbital interactions which has three major contributions, that is, the donation from the symmetric (sigma) and antisymmetric (pi(||)) combination of the ligand lone-pair orbitals into the vacant MOs of BH L->(BH)<-L and the L<-(BH)->L pi backdonation from the boron lone-pair orbital. The nitrogen cation complexes (N(+))L(2) have strongly bent L-N-L geometries, in which the calculated bending angle varies between 113.9 degrees (L=N(2)) and 146.9 degrees (L=CAAC). The BDEs for (N(+))L(2) are much larger than those of the borylene complexes. The carbene ligands NHC and CAAC but also the phosphane ligands PPh(3) bind very strongly between D(e) =358.4 kcal mol(-1) (L=PPh(3)) and D(e) =412.5 kcal mol(-1) (L=CAAC(model)). The proton affinities (PA) of (N(+))L(2) are much smaller and they bind AuCl and BH(3) less strongly compared with (BH)L(2). However, the PAs (N(+))L(2) for complexes with bulky ligands L are still between 139.9 kcal mol( 1) (L=CAAC(model)) and 168.5 kcal mol(-1) (L=CAAC). The analysis of the (N(+)) L(2) bonding situation reveals that the binding interactions come mainly from the L->(N(+))<-L donation while L<-(N(+) )->L pi backdonation is rather weak. PMID- 22434610 TI - Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) affects people during their prime reproductive years. The thiopurines (6-mercaptopurine and azathioprine), commonly used for induction and maintenance of remission, are U.S. Food and Drug Administration (FDA) pregnancy category D, raising concern for fetal risk. We performed a systematic review and meta-analysis to evaluate the effects of thiopurine exposure during pregnancy or at the time of conception on three measures of fetal risk in women and men with IBD. METHODS: A systematic search of PubMed and Web of Science using a combination of Mesh and text terms was performed to identify studies reporting birth outcomes from IBD women and men exposed to thiopurines within 3 months of conception and/or during pregnancy. A meta-analysis was performed using the random effects model to pool estimates and report odds ratio (OR) for three outcomes in women: low birth weight (LBW), preterm birth, and congenital abnormalities and one in men: congenital abnormalities. RESULTS: In women with IBD exposed to thiopurines, the pooled ORs for LBW, preterm birth, and congenital abnormalities were 1.01 (95% confidence interval [CI] 0.96, 1.06), 1.67 (95% CI 1.26, 2.20), and 1.45 (95% CI 0.99, 2.13), respectively. In men, the pooled OR for congenital abnormality was 1.87 (95% CI 0.67, 5.25). CONCLUSIONS: Thiopurine exposure in women with IBD was not associated with LBW or congenital abnormalities, but was associated with preterm birth. Exposure in men at the time of conception was not associated with congenital abnormalities. PMID- 22434612 TI - Transforming nursing's future. PMID- 22434611 TI - Who is stressed? Comparing cortisol levels between individuals. AB - Cortisol is the most commonly used biomarker to compare physiological stress between individuals. Its use, however, is frequently inappropriate. Basal cortisol production varies markedly between individuals. Yet, in naturalistic studies that variation is often ignored, potentially leading to important biases. OBJECTIVES: Identify appropriate analytical tools to compare cortisol across individuals and outline simple simulation procedures for determining the number of measurements required to apply those methods. METHODS: We evaluate and compare three alternative methods (raw values, Z-scores, and sample percentiles) to rank individuals according to their cortisol levels. We apply each of these methods to first morning urinary cortisol data collected thrice weekly from 14 cycling Mayan Kaqchiquel women. We also outline a simple simulation to estimate appropriate sample sizes. RESULTS: Cortisol values varied substantially across women (ranges: means: 1.9-2.7; medians: 1.9-2.8; SD: 0.26-0.49) as did their individual distributions. Cortisol values within women were uncorrelated. The accuracy of the rankings obtained using the Z-scores and sample percentiles was similar, and both were superior to those obtained using the cross-sectional cortisol values. Given the interindividual variation observed in our population, 10-15 cortisol measurements per participant provide an acceptable degree of accuracy for across women comparisons. CONCLUSIONS: The use of single raw cortisol values is inadequate to compare physiological stress levels across individuals. If the distributions of individuals' cortisol values are approximately normal, then the standardized ranking method is most appropriate; otherwise, the sample percentile method is advised. These methods may be applied to compare stress levels across individuals in other populations and species. PMID- 22434613 TI - How do we promote independent ostomy management for people with disability? AB - PURPOSE: To describe how people with ostomies became independent with their ostomy management. METHOD: Two clinical ostomy consultations which incorporated traditional ostomy management along with state-of-the-art ostomy technology aimed at the needs of the disabled person. RESULTS: The newer technologies eliminated several of the traditional steps and made a one-handed approach possible. DISCUSSION: This article describes two clinical consultations which incorporated traditional ostomy management along with state-of-the-art ostomy technology aimed at the needs of the disabled person. Peristomal skin preparation and protection, barrier wafer preparation, proper pouch emptying, and newer technology are discussed. CONCLUSION: The consultations resulted in ostomy care autonomy and an improved quality of life in both patients. PMID- 22434614 TI - Falls on an inpatient rehabilitation unit: risk assessment and prevention. AB - PURPOSE: To determine the relationship between admission diagnosis and admission score on Functional Independence Measure (FIM) to the likelihood that a patient will fall. To measure the effectiveness of a multifactorial program to reduce falls. METHOD: The Quality Improvement Team put in place a multifactorial program to reduce the incidence of falls on an inpatient rehabilitation unit. The authors reviewed the records of all patients admitted to the rehabilitation unit between January 2006 and December 2009 to determine if the program resulted in a reduced rate of falls. The authors also reviewed the data to evaluate if admission score on the FIM and the diagnosis or impairment group of the patient are related to the risk of fall. RESULTS: FIM score is inversely related to the rate of falls. Patients with admission diagnosis of stroke, brain injury, amputation, neurologic disorders (Parkinson's disease, multiple sclerosis, Guillain-Barre, myopathy, peripheral neuropathy), and spinal cord injury are at higher risk for fall than patients whose admission diagnosis related to orthopedic, cardiac, pulmonary disorders, prolonged stay on medical or surgical units, or trauma without spinal cord injury or head injury. There was a significant reduction in the rate of falls from 14.9% to 7.3% of patients admitted to the IRF. DISCUSSION: Patients with low FIM scores, disorders of the central and peripheral nervous system, and amputations are at high risk of fall. Compliance with recommended guidelines can reduce the rate of fall and improve patient safety. CONCLUSION: The rate of falls on an IRF will be determined in part by the case mix and functional levels of the patients on the unit. Strict adherence to appropriate nursing protocols can reduce the rate of falls. PMID- 22434615 TI - Bags and blogs: creating an ostomy experience for nursing students. AB - BACKGROUND: There are well over three-quarters of a million people living in the United States with an ostomy. These individuals experience many physical and emotional challenges which nurses should address during the in-patient hospitalization experience. PURPOSE: The purpose of this educational activity was to provide undergraduate nursing students with a simulated laboratory experience which allowed the student to discuss and experience some of the challenges of living with an ostomy. METHOD: Small group work, an experiential learning activity, and blogging were used to foster the cognitive, psychomotor, and affective development of the nursing students. RESULTS: All 134 students participated in the small group work and blogging experience and over 100 students participated in the experiential learning activity of wearing an ostomy bag overnight with the bag containing a small amount of simulated fecal material. DISCUSSION: The impact of the simulated experience is evident in the depth of awareness and emotion expressed in the blogs. The students collectively acknowledged the value of the activity and the impact the gained awareness had on their careers as nurses. CONCLUSION: The use of social technology and the provision of learning activities, not available on the clinical unit, can have a significant impact on the cognitive, psychomotor, and affective development of nursing students. PMID- 22434616 TI - Impact of cardiac rehabilitation on metabolic syndrome in Iranian patients with coronary heart disease: the role of obesity. AB - BACKGROUND: Due to high prevalence of metabolic syndrome (MetS) and coronary heart disease (CHD) in Iran, and their mutual relationship, we evaluated how comprehensive cardiac rehabilitation (CR) can affect MetS in patients with CHD. METHOD: In this study (1998-2003), we evaluated 547 patients with CHD undergoing comprehensive CR. RESULTS: Cases with MetS decreased from 42.8% to 33.3% after CR program (p < .001). Decrease in high fasting plasma glucose, triglyceridemia, systolic and diastolic blood pressures, and increase in HDL cholesterol, functional capacity, and left ventricular ejection fraction was more prominent in the "MetS but not obese" group. However, total cholesterol, low-density lipoprotein, weight, body mass index, and waist circumference showed a greater decrease in groups with obesity. CONCLUSION: Cardiac rehabilitation is an effective treatment of MetS, particularly in the absence of obesity. This represents an additional argument for the prevention of obesity and the linked insulin resistance. PMID- 22434617 TI - Breast cancer screening barriers and disability. AB - There is evidence that early detection from breast cancer screening is an effective means to reduce overall mortality from breast cancer. Findings from multiple research studies suggest that women with chronic disabling conditions are less likely to participate in breast cancer screening due to the multiple barriers they face. Barriers include those related to finances, environment, physical limitations, health carers' attitudes and lack of knowledge, and psychosocial issues. The purpose of this article is to provide an overview of the existing evidence of the barriers to breast cancer screening experienced by women with physical disabilities. Rehabilitation nurses that work with women who have chronic disabling conditions can be instrumental in eliminating these barriers to breast cancer screening through their efforts to promote health which is consistent with the philosophy of maximizing the health potential and quality of life of these women whose needs are often overlooked. PMID- 22434618 TI - Warfarin use post hospitalization: pilot comparative effectiveness of telephone follow-up. AB - PURPOSE: This study's aims were to evaluate patient knowledge of safe warfarin practices early in treatment, and to pilot a nursing telephone follow-up enhancement to a pharmacy-facilitated discharge. METHOD: Forty-two randomized patients in either "enhanced follow-up" or "treatment as usual" groups completed the study. RESULTS: Enhanced treatment resulted in significant improvement in warfarin knowledge (86% versus 71%). In critical safety related knowledge questions even larger improvements were present (~96% compared to ~77%). DISCUSSION: The hypothesis that non-adherence generating rehospitalization is a function of poorer knowledge was not supported as there were no warfarin-related readmissions during the study. CONCLUSION: The study supports the use of enhanced follow up and the need for larger studies to delineate what patient knowledge prevents rehospitalization and cost effective educational efforts. PMID- 22434619 TI - Factors influencing physical activity in institutionalized elderly patients with leprosy. AB - PURPOSE: The nursing literature has devoted little attention to the long-term influence of infectious diseases and the subsequent rehabilitation needs of the affected patients. This study was conducted to identify the factors associated with physical activity (PA) in older institutionalized adults with leprosy. METHOD: A cross-sectional research design was used. RESULTS: Data from 248 subjects (75.28 +/- 8.64 years old) were analyzed. We found that fewer subjects in PA compared to older adults in general. Amputation, fear of falling (FF), the ability to perform activities of daily living, and instrumental activities of daily living (IADL) were the influencing factors of PA. Doing laundry, preparing a meal, taking medicines, and making telephone calls accounted for 23.4% of the PA variance. CONCLUSION: We suggest incorporating FF in the psychosocial indicators of the mobility assessment. The importance of promoting or maintaining four specific IADL abilities and participating in PA for leprosy patients living in a sanatorium is emphasized. PMID- 22434620 TI - Mutual inhibition and capacity sharing during parallel preparation of serial eye movements. AB - Many common activities, like reading, scanning scenes, or searching for an inconspicuous item in a cluttered environment, entail serial movements of the eyes that shift the gaze from one object to another. Previous studies have shown that the primate brain is capable of programming sequential saccadic eye movements in parallel. Given that the onset of saccades directed to a target are unpredictable in individual trials, what prevents a saccade during parallel programming from being executed in the direction of the second target before execution of another saccade in the direction of the first target remains unclear. Using a computational model, here we demonstrate that sequential saccades inhibit each other and share the brain's limited processing resources (capacity) so that the planning of a saccade in the direction of the first target always finishes first. In this framework, the latency of a saccade increases linearly with the fraction of capacity allocated to the other saccade in the sequence, and exponentially with the duration of capacity sharing. Our study establishes a link between the dual-task paradigm and the ramp-to-threshold model of response time to identify a physiologically viable mechanism that preserves the serial order of saccades without compromising the speed of performance. PMID- 22434621 TI - Relative and absolute configuration of vatiparol (1 mg): a novel anti inflammatory polyphenol. AB - Bioactive natural products offer multiple opportunities for the discovery of novel chemical entities with potential pharmaceutical, nutraceutical and agrochemical applications. Many new organic compounds with novel scaffolds are isolated in small quantities and established methods often fail to determine the structure and bioactivity of such novel natural products. To meet this challenge, we present here a new methodology combining RDC (residual dipolar coupling)-based NMR spectroscopy in microtubes, with a motif-inspired biological assessment strategy. Using only one milligram (ca. 1.5 MUmol) of sample, the new protocol established the bioactivity as well as the relative and absolute configuration of vatiparol obtained from Vatica parvifolia. Vatiparol is unique in its unprecedented carbon skeleton and selective inhibitory effect on the expression of monocyte chemo-attractant protein-1 (MCP-1, also known as CCL2). The plausible biosynthetic pathway of vatiparol is briefly discussed. The approach introduced here promises to be widely applicable to the determination of the structure and bioactivity of structurally unknown organic samples available in very limited amounts. PMID- 22434622 TI - Double stereodifferentiation in the catalytic asymmetric aziridination of imines prepared from alpha-chiral amines. AB - The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for alpha-methylbenzyl amine for cis aziridines from alpha-diazo esters and for trans-aziridines from alpha-diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis-aziridines involved the (R)-amine with the (S)-ligand, but curiously, for trans-aziridines the matched case involved the (R)-amine with the (R)-ligand for imines derived from benzaldehyde and n-butanal, and the (R)-amine with the (S)-ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde. PMID- 22434624 TI - Intracellular SPIO labeling of microglia: high field considerations and limitations for MR microscopy. AB - The purpose of this study is to investigate MRI contrast as a function of magnetic field strength for microglia labeled with superparamagnetic iron oxide (SPIO) nanoparticles. A rat microglia cell line, Bv2, was incubated with SPIOs for 6 h. In two separate experiments conducted at 11.75 and 21.1 T, the impact of SPIO loading and cell count on T(1) , T(2) and T(2) * contrast were evaluated: (a) cells were incubated with 1, 2 or 5 ul of Feridex; and (b) cells incubated with 5 ul of Feridex were used to form layers of 25 000, 50 000, 100 000 or 200 000 cells. Intracellular iron was analyzed with ICP-MS and histological staining while cell viability was evaluated by Trypan blue dye exclusion. Bv2 cells displayed increases in intracellular iron concentration with SPIO exposure, with the highest labeling yielding 0.83 pg of Fe per cell. Although no differences were identified for T(1) mechanisms, both fields displayed trends toward increasing T(2) and T(2) * contrast with increasing SPIO loading or cell count, with few differences evident between fields. Bv2 cells can be labeled readily with commercially available SPIOs, with the potential of increasing the intracellular iron content over short incubation times without impacting viability. This phagocytotic cell line not only provides direct SPIO uptake but also plays a critical role in inflammation after brain injury, providing a possible neurodegeneration biomarker. With few differences between field strengths and limited ability to quantify intracellular iron content and cell count, this study demonstrates only a slight benefit of SPIO-based contrast agent at high fields based on susceptibility-based contrast and detection, necessitating unique agents for such applications. PMID- 22434625 TI - Efficacy of positive contrast imaging techniques for molecular MRI of tumor angiogenesis. AB - Superparamagnetic iron oxide particles (SPIOs) are promising contrast agents for molecular MRI. To improve the in vivo detection of iron-based contrast media, positive contrast imaging techniques have been developed. Here, the efficacy of two positive contrast techniques, white marker and susceptibility gradient mapping (SGM), were evaluated for molecular MRI of tumor angiogenesis and compared with conventional negative contrast gradient echo (GE) imaging. In vitro, cylindrical phantoms containing varying iron oxide concentrations were used to measure the response of positive contrast techniques. In vivo, tumor bearing mice were used as a model for tumor angiogenesis. Mice were injected with unlabeled SPIOs (n = 5) or SPIOs labeled with cyclic NGR peptide (cNGR) (n = 5), which homes specifically to angiogenic microvessels. Pre- and post-contrast GE and white marker images were acquired. Subsequently, SGM images and R(2)(*) maps were calculated. For image analysis, the contrast-to-noise ratio (CNR) and the percentage of enhanced voxels (EVs) in the tumor rim and core were calculated. In vitro, the linear increases in MRI signal response for increasing iron oxide concentration were much stronger for SGM than white marker. In vivo, the CNR of GE, white marker and SGM imaging was 5.7, 1.2 and 6.2, respectively, with equal acquisition times. Significant differences in the percentage of EVs between the tumor rim and core were found using R(2)(*) mapping, GE and SGM (p < 0.05). The two contrast agents had significantly different percentages of EVs by R(2)(*) mapping and SGM in the rim (p < 0.001). The in vivo efficacy of white marker and SGM was evaluated for molecular MRI relative to GE imaging and R(2)(*) mapping. Only SGM, and not white marker, can be used to transfer the negative contrast from targeted SPIOs in a positive contrast signal without loss of CNR. PMID- 22434626 TI - Limitations and caveats of magnetic cell labeling using transfection agent complexed iron oxide nanoparticles. AB - Cell labeling with various types of nanomaterial, such as FDA-approved iron oxide nanoparticles (IONPs) has become common practice in biomedical research. The low uptake of IONPs stimulates the use of transfection agents (TA), but the effect on stability of the IONPs and their cellular interactions has received minimal attention. In the present study, we evaluated the use of Lipofectamine as a commonly used TA and tested different ratios of TA and IONPs. While the TA-IONP complexes are stable in saline, at a high ratio of TA over IONP, substantial aggregation occurred in serum-containing media. Even for the highest ratio, TA was unable to completely cover the IONPs, resulting in a net negative charge of all complexes. At high TA-IONP ratios, more complexes remained surface-associated without internalization, resulting in cell death, while at lower TA-IONP ratios, complexes were more avidly taken up through fluid-phase pinocytosis and clathrin mediated endocytosis. At later time points, the endocytosed complexes accumulated within the lysosomes and affected the appearance of lysosomal structures. The data indicate that TAs should be used with care as, depending on the ratio of TA and IONP, the complexes may aggregate, inducing cell death and preventing internalization. PMID- 22434627 TI - Functionalized single-walled carbon nanotubes containing traces of iron as new negative MRI contrast agents for in vivo imaging. AB - Single-walled carbon nanotubes (SWCNTs) containing traces of iron oxide were functionalized by noncovalent lipid-PEG or covalent carboxylic acid function to supply new efficient MRI contrast agents for in vitro and in vivo applications. Longitudinal (r(1)) and transversal (r(2)) water proton relaxivities were measured at 300 MHz, showing a stronger T(2) feature as an MRI contrast agent (r(2)/r(1) = 190 for CO(2) H functionalisation). The r(2) relaxivity was demonstrated to be correlated to the presence of iron oxide in the SWNT carboxylic function COOH, in comparison to iron-free ones. Biodistribution studies on mice after a systemic injection showed a negative MRI contrast in liver, suggesting the presence of the nanotubes in this organ until 48 h after i.v. injection. The presence of carbon nanotubes in liver was confirmed after ex vivo carbon extraction. Finally, cytotoxicity studies showed no apparent effect owing to the presence of the carbon nanotubes. The functionalized carbon nanotubes were well tolerated by the animals at the dose of 10 ug g(-1) body weight. PMID- 22434628 TI - Radiolabelled GLP-1 analogues for in vivo targeting of insulinomas. AB - Internalizing agonists are usually selected for peptide receptor targeting. There is increasing evidence that non-internalizing receptor antagonists can be used for this purpose. We investigated whether the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin(9-39) can be used for in vivo targeting of GLP-1R expressing tumours and compared the in vitro and in vivo characteristics with the GLP-1R agonists exendin-3 and exendin-4. The binding and internalization kinetics of labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) were determined in vitro using INS-1 cells. The in vivo targeting properties of [Lys(40) ((111) In-DTPA)]exendin-3, [Lys(40) ((111) In DTPA)]exendin-4 and [Lys(40) ((111) In-DTPA)]exendin(9-39) were examined in BALB/c nude mice with subcutaneous INS-1 tumours. (nat) In-labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) exhibited similar IC(50) values (13.5, 14.4 and 13.4 n m, respectively) and bound to 26 * 10(3) , 41 * 10(3) and 37 * 10(3) receptors per cell, respectively. [Lys(40) ((111) In-DTPA)]exendin-3 and [Lys(40) ((111) In-DTPA)]exendin-4 showed rapid in vitro binding and internalization kinetics, whereas [Lys(40) ((111) In DTPA)]exendin(9-39) showed lower binding and minimal internalization in vitro. In mice, high specific uptake of [Lys(40) ((111) In-DTPA)]exendin-3 [25.0 +/- 6.0% injected dose (ID) g(-1) ] in the tumour was observed at 0.5 h post-injection (p.i.) with similar uptake up to 4 h p.i. [Lys(40) ((111) In-DTPA)]exendin-4 showed higher tumour uptake at 1 and 4 h p.i. (40.8 +/- 7.0 and 41.9 +/- 7.2% ID g(-1), respectively). Remarkably, [Lys(40) ((111) In-DTPA)]exendin(9-39) showed only low specific uptake in the tumour at 0.5 h p.i. (3.2 +/- 0.7% ID g(-1)), rapidly decreasing over time. In conclusion, the GLP-1R agonists [Lys(40) (DTPA)]exendin-3 and [Lys(40) (DTPA)]exendin-4 labelled with (111) In could be useful for in vivo GLP-1R targeting, whereas [Lys(40) (DTPA)]exendin(9-39) is not suited for in vivo targeting of the GLP-1R. PMID- 22434629 TI - Improved quantification in pinhole gated myocardial perfusion SPECT using micro CT and ultrasound information. AB - Absolute quantification using single photon emission computed tomography (SPECT) was demonstrated in vitro and in large immobile organs in vivo. To determine the feasibility of in vivo quantification of myocardial perfusion in pinhole gated SPECT, we added an ultrasound derived partial volume correction factor to attenuation and scatter corrections, in combination with gated acquisitions. In nine male Wistar rats, cardiac ultrasound was performed prior to SPECT/CT scans to determine the myocardial wall thickness. SPECT/CT scans were then performed 30 min after injection of (99m) Tc Tetrofosmin. Animals were killed and six midventricular segments of the left ventricle were excised and counted in a gamma well counter. Using AMIDE, regional myocardial activity was measured after combined scatter correction (SC) and attenuation correction (AC). These image derived activities were compared with the ex vivo counted activity. To correct for the partial volume effect, a recovery coefficient was determined from a phantom study, to determine the thickness specific partial volume effect. Combined AC and SC led to a significant underestimation of activity compared with ex vivo data (root mean squared error = 0.145 mCi g(-1)). The recovery coefficient calculated from the phantom study showed a linear relationship with object size from 1 to 6 mm, positioned in the vicinity of the center of the field of view (R(2) = 0.98). Correction of nongated SPECT images with a recovery coefficient derived from the diastolic phase results in a global overestimation with root mean squared error = 0.04 mCi g(-1). Nongated SPECT images corrected with a recovery coefficient with a weighted average ratio diastolic and systolic phase led to an improved root mean squared error of 0.03 mCi g(-1). Combining attenuation correction with scatter correction and a gated partial volume correction yields the best correlation with ex vivo counting (root mean squared error = 0.021 mCi g(-1) (systolic) and 0.025 mCi g(-1) (diastolic). This study demonstrates a method for improved segmental myocardial perfusion quantification in pinhole gated SPECT, using combined attenuation-, scatter- and ultrasound derived partial volume effect corrections. PMID- 22434630 TI - Novel Gd(III)-based probes for MR molecular imaging of matrix metalloproteinases. AB - Two novel Gd-based contrast agents (CAs) for the molecular imaging of matrix metalloproteinases (MMPs) were synthetized and characterized in vitro and in vivo. These probes were based on the PLG*LWAR peptide sequence, known to be hydrolyzed between Gly and Leu by a broad panel of MMPs. A Gd-DOTA chelate was conjugated to the N-terminal position through an amide bond, either directly to proline (compd Gd-K11) or through a hydrophilic spacer (compd Gd-K11N). Both CA were made strongly amphiphilic by conjugating an alkyl chain at the C-terminus of the peptide sequence. Gd-K11 and Gd-K11N have a good affinity for beta cyclodextrins (K(D) 310 and 670 u m respectively) and for serum albumin (K(D) 350 and 90 u m respectively), and can be efficiently cleaved in vitro at the expected site by MMP-2 and MMP-12. Upon MMP-dependent cleavage, the CAs lose the C terminal tetrapeptide and the alkyl chain, thus undergoing to an amphiphilic-to hydrophilic transformation that is expected to alter tissue pharmacokinetics. To prove this, Gd-K11 was systemically administered to mice bearing a subcutaneous B16.F10 melanoma, either pre-treated or not with the broad spectrum MMP inhibitor GM6001 (Ilomastat). The washout of the Gd-contrast enhancement in MR images was significantly faster for untreated subjects (displaying MMP activity) with respect to treated ones (MMP activity inhibited). The washout kinetics of Gd contrast enhancement from the tumor microenvironment could be then interpreted in terms of the local activity of MMPs. PMID- 22434631 TI - Polyglycerol-grafted superparamagnetic iron oxide nanoparticles: highly efficient MRI contrast agent for liver and kidney imaging and potential scaffold for cellular and molecular imaging. AB - Polyglycerol as a water-soluble and biocompatible hyperbranched polymer was covalently grafted on the surface of superparamagnetic iron oxide nanoparticles. With this aim, superparamagnetic magnetite nanoparticles were prepared by coprecipitation in aqueous media, then the surface of nanoparticles was modified to introduce the reactive groups on the surface of nanoparticles. After that, polyglycerol was grafted on the surface of nanoparticles by ring-opening anionic polymerization of glycidol using n-bulyllithium as initiator. The magnetometry, relaxometry and phantom MRI experiments of this highly stable ferrofluid showed its high potential as a negative MRI contrast agent. Calculated r(1) and r(2) relaxivities at different magnetic fields were higher than the values reported for commercially available iron oxide contrast agents. The in vivo MRI studies showed that, after intravenous injection into mice, the particles produced a strong negative contrast in liver and kidneys, which persisted for 80 min (in liver) to 110 min (in kidneys). The negative contrast of the liver and kidneys weakened over the time, suggesting that polyglycerol coating renders the nanoparticles stealth and possibly optimal for renal excretion. PMID- 22434632 TI - Cell quantification: evolution of compartmentalization and distribution of iron oxide particles and labeled cells. AB - The purpose of the study was to show the feasibility of quantification in the case of cell death, cell migration and cell division by parametric MRI. We identify limitations for quantitative cell tracking owing to mixed parallel processes. Various intravoxel SPIO-labeled cell, super paramagnetic iron oxide particles (SPIO) and micron-sized paramagnetic iron oxide (MPIO) particle distributions were prepared by methods mimicking biologically relevant processes (compartmentalization, migration, division and cell death). R(2)* and R(2) relaxometry measurements were performed at 3.0 T; iron concentration was measured by optical emission spectrometry. The effects of spatial distribution and compartmentalization of paramagnetic iron-oxide particles on relaxivity were analyzed. Assessment of R(2)' (R(2)*-R(2)) allowed differentiation between intracellular and extracellular SPIO only if no high-iron-content extracellular particles were present. Relaxivity was sensitive to variations in cell labeling. Samples of the same cell types embedded in the same suspension media at the same cell density produced different relaxivity values, depending on the preparation of the labeled cells. In the case of cell division, a unique relationship between relaxation rate and iron concentration was found, where the relaxivity proved to be independent of initial cell labeling. In case of cell mixing, the cell density could be derived from relaxation values, even if iron concentration was undetermined. We demonstrated that relaxometry does not allow labeled cell quantification when multiple physiological processes such as cell division and cell migration coexist. The measured transversal relaxation rates were sensitive to the labeling technique. However, under special circumstances, despite the numerous limiting factors, quantification of the number of labeled cells by relaxometry was feasible. PMID- 22434633 TI - An approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber. AB - The development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key players in plaque rupture could provide improved triage of patients. However, so far the efficiency of contrast agents targeting human pathologies can only be examined in animal experiments, which do not necessarily reflect human in vivo conditions. We therefore describe application of a contrast agent targeting activated human platelets in an MRI tissue flow chamber, allowing detection and characterization of contrast agent binding. Microparticles of iron oxide (MPIO) were conjugated to an antibody targeting ligand-induced binding sites (LIBS) on the activated platelet glycoprotein IIb/IIIa-receptor or to control antibody, resulting in LIBS-MPIO or control-MPIO contrast agent. Human endarterectomy specimens from patients with acute stroke or transient ischemic attack were imaged ex vivo before and after contrast agent perfusion using a 9.4 T MRI system. Specimens were measured under static (n = 18) or flow conditions (n = 18) in a specially designed flow chamber setup, simulating physiological conditions in a stenosed vessel. A significant MPIO-induced negative contrast was achieved in MRI by LIBS-MPIO in specimens under static and flow conditions (LIBS-MPIO vs control-MPIO: p < 0.01), and the location of LIBS-MPIO binding corresponded well between histology and MRI (p < 0.05). The number of MPIOs per platelet area on endarterectomy specimens in histology was significantly higher with LIBS-MPIO (p < 0.001). Furthermore, the intensity of contrast agent binding and signal change showed the potential to reflect the severity of clinical symptoms. LIBS-MPIO allows the detection of activated platelets on the surface of symptomatic atherosclerotic human plaques using molecular MRI. Furthermore, the MRI tissue flow chamber setup described could help to evaluate binding properties of contrast agents, and might therefore be an interesting tool for contrast agent development from animal experiments towards clinical application. PMID- 22434634 TI - Dual-isotope 111In/177Lu SPECT imaging as a tool in molecular imaging tracer design. AB - The synthesis, design and subsequent pre-clinical testing of new molecular imaging tracers are topic of extensive research in healthcare. Quantitative dual isotope SPECT imaging is proposed here as a tool in the design and validation of such tracers, as it can be used to quantify and compare the biodistribution of a specific ligand and its nonspecific control ligand, labeled with two different radionuclides, in the same animal. Since the biodistribution results are not blurred by experimental or physiological inter-animal variations, this approach allows determination of the ligand's net targeting effect. However, dual-isotope quantification is complicated by crosstalk between the two radionuclides used and the radionuclides should not influence the biodistribution of the tracer. Here, we developed a quantitative dual-isotope SPECT protocol using combined (111)Indium and (177)Lutetium and tested this tool for a well-known angiogenesis specific ligand (cRGD peptide) in comparison to a potential nonspecific control (cRAD peptide). Dual-isotope SPECT imaging of the peptides showed a similar organ and tumor uptake to single-isotope studies (cRGDfK-DOTA, 1.5 +/- 0.8%ID cm(-3); cRADfK-DOTA, 0.2 +/- 0.1%ID cm(-3)), but with higher statistical relevance (p value 0.007, n = 8). This demonstrated that, for the same relevance, seven animals were required in case of a single-isotope test design as compared with only three animals when a dual-isotope test was used. Interchanging radionuclides did not influence the biodistribution of the peptides. Dual-isotope SPECT after simultaneous injection of (111)In and (177)Lu-labeled cRGD and cRAD was shown to be a valuable method for paired testing of the in vivo target specificity of ligands in molecular imaging tracer design. PMID- 22434635 TI - A radiolabeled nonapeptide probe targeting PC-3 cells and bone metastases of prostate cancer in mice. AB - Previous investigations showed that interleukin-11 (IL-11) and the IL-11 receptor (IL-11R) are correlated with regulation of tumor progression and may play significant roles in bone metastases. The nonapeptide structure c(CGRRAGGSC) is a phage-display-selected IL-11 mimic that binds to IL-11R. The aim of this study was to synthesize radiolabeled c(CGRRAGGSC) and to investigate the possible interaction between this radioactive probe and an IL-11R-positive bone metastasis model of PC-3 prostate cancer. The molecular probe (99m)Tc-DTPA-c(CGRRAGGSC) was radiolabeled with (99m)Tc using the diethylenetriaminepentaacetic acid (DTPA) chelate. Counterstaining was performed with LSS670, a near-infrared dye. The binding sites of the molecular probe in PC-3 cells were observed under a fluorescence microscope. The binding characteristics of the labeled probe were analyzed using radioreceptor analysis. Single photon emission tomography imaging and biodistribution of the probe were investigated using xenografts of PC-3 cells into tibias of nude mice. The labeled product, (99m) Tc-DTPA-c(CGRRAGGSC), was obtained with high labeling efficiency, high radiochemical purity and good stability. The molecular probe was combined with the PC-3 cell membrane and cytoplasm through fluorescence tracing. In the saturation and competitive inhibition experiments performed in vitro, the K(d) value was 0.32 +/- 0.02 n m and the B(max) value was 754 +/- 34 fmol mg(-1) pro. The probe exhibited a high tumor uptake in vivo. The radioactive molecular probe (99m) Tc-DTPA-c(CGRRAGGSC) may be used as a specific molecular imaging agent for detecting IL-11R overexpression in tumors and bone metastasis, such as prostate cancers. PMID- 22434636 TI - Optimized synthesis of 100 nm diameter magnetoliposomes with high content of maghemite particles and high MRI effect. AB - Magnetoliposomes are liposomes surrounding an iron oxide core, which are used as contrast enhancing agents in magnetic resonance imaging (MRI). One method for producing magnetoliposomes consists of hydration of a lipid film with citrate coated iron oxide particles followed by extrusion. Two parameters are of major importance for in vivo applications of magnetoliposomes, namely their size, which must be small, optimally around 100 nm diameter, in order to ensure their prolonged circulation in the bloodstream, and their iron content, which must be maximal for generating high MRI effect. We studied the formation of magnetoliposomes by passive encapsulation of maghemite (gamma-Fe(2)O(3)) particle suspensions of varying concentrations, with the objective of producing magnetoliposomes of small size and high iron content. The iron to lipid ratio was used to determine the iron content of the magnetoliposomes after the successive purification steps and cryo-TEM was used to characterize their size, their homogeneity and the efficiency of purification. The size of citrate-coated maghemite clusters was found to be of critical importance for obtaining magnetoliposomes smaller than 200 nm. We were able to reproducibly synthesize magnetoliposomes of 100 nm diameter with high iron content -up to 77 particles per liposome (5.6 moles iron per mole lipid) - and high r(2) MRI relaxivity - up to 320 m m(-1) . s(-1) . The magnetoliposomes present improved characteristics compared with previous reports. Future research will focus on using these magnetoliposomes as drug delivery systems for in vivo diagnostics or therapeutics applications. PMID- 22434637 TI - Evaluation of eXIA 160 cardiac-related enhancement in C57BL/6 and BALB/c mice using micro-CT. AB - Evaluation of cardiovascular function in mice using micro-CT requires that a contrast agent be administered to differentiate the blood from the myocardium. eXIA 160, an aqueous colloidal poly-disperse contrast agent with a high iodine concentration (160 mg I ml(-1)), creates strong contrast between blood and tissue with a low injection volume. In this study, the blood-pool enhancement time course of eXIA 160 is monitored over a 48 h period to determine its optimal use during cardiac function studies in C57BL/6 and BALB/c mice. Eight-second scans were performed (80 kV(p), 110 mA) using the GE Locus Ultra micro-CT scanner. Six C57BL/6 and six BALB/c male mice (22-24 g) were injected via tail vein with 5 ul g(-1) body weight eXIA 160. A precontrast scan was performed; following injection, mice were scanned at 5, 15, 30, 45 and 60 min, and 2, 4, 8, 12, 24 and 48 h. Images were reconstructed, and enhancement-time curves were generated for each of the following tissues: left ventricle (LV), myocardium, liver, spleen, renal cortex, bladder and brown adipose tissue. The highest contrast in the LV occurred at 5 min in both strains (~670 HU above precontrast value). Uptake of the contrast agent by the myocardium was also observed: myocardial tissue showed increasing enhancement over a 4 h period in both strains, remaining even once the contrast was eliminated from the vasculature. In both C57BL/6 and BALB/c strains, eXIA 160 provided high contrast between blood and myocardial tissue for a period of 30 min following injection. Notably, this contrast agent was also taken up by the myocardium and provided continued enhancement when it was eliminated from the blood, making LV wall motion studies possible. In conclusion, eXIA 160, with its high iodine concentration and targeted tissue uptake characteristics, is an ideal agent to use when evaluating cardiovascular function in mice. PMID- 22434638 TI - MR and optical imaging of early micrometastases in lymph nodes: triple labeling with nano-sized agents yielding distinct signals. AB - Few imaging methods are available for depicting in vivo cancer cell migration within the lymphatic system. Detection of such early micrometastases requires extremely high target to background. In this study, we dual-labeled human breast cancer cells (MDA-MB468) with a small particle of iron oxide (SPIO) and a quantum dot (QD), and tracked these cells in the lymphatic system in mice using in vivo MRI and optical imaging. A generation-6 gadolinium-dendrimer-based MRI contrast agent (Gd-G6) was employed for visualizing regional lymphatic channels and nodes. Since Gd-G6 shortened T(1) leading to high signal, whereas SPIO-labeled cancer cells greatly lowered signal, a small number of cells were simultaneously visualized within the draining lymphatic basins. One million dual-labeled cancer cells were subcutaneously injected into the paws of mice 24 h prior to imaging. Then whole body images were acquired pre- and post-intracutaneous injection of Gd G6 with 3D-T(1) w-FFE and balanced-FFE sequences for cancer cell tracking and MR lymphangiography. In vivo MRI clearly visualized labeled cancer cells migrating from the paw to the axillary lymph nodes using draining lymphatics. In vivo optical imaging using a fluorescence surgical microscope demonstrated tiny cancer cell clusters in the axillary lymph node with high spatial resolution. Thus, using a combination of MRI and optical imaging, it is possible to depict macro- and early micrometastases within the lymphatic system. This platform offers a versatile research tool for investigating and treating lymphatic metastases in animal models. PMID- 22434639 TI - Development of 177Lu-nanobodies for radioimmunotherapy of HER2-positive breast cancer: evaluation of different bifunctional chelators. AB - Nanobodies show favourable pharmacokinetic characteristics for tumor targeting, including high tumor-to-background-ratios. Labelled with a therapeutic radionuclide, nanobodies could be used as an adjuvant treatment option for HER2 overexpressing minimal residual disease. The therapeutic radionuclide Lutetium 177 is linked to the nanobody using a bifunctional chelator. The choice of the bifunctional chelator could affect the in vivo behaviour of the radiolabeled nanobody. Consequently, we compared four different bifunctional chelators - p-SCN Bn-DOTA, DOTA-NHS-ester, CHX-A"-DTPA or 1B4M-DTPA - in order to select the optimal chemical link between Lutetium-177 and a HER2 targeting nanobody. MS results revealed different degrees of chelator-conjugation. High stability in time was observed, together with nanomolar affinities on HER2-expressing tumor cells. Ex vivo biodistributions as well as SPECT/micro-CT analyses showed high activities in tumors expressing medium HER2 levels with low background activity except for the kidneys. The 1B4M-DTPA-coupled conjugate was further evaluated in a high HER2-expressing tumor model. Here, tumor uptake values of 5.99 +/- 0.63, 5.12 +/- 0.17, 2.83 +/- 0.36 and 2.47 +/- 0.38 %IA/g were obtained at 1, 3, 24 and 48h p.i., which coincided with exceptionally low background values, except for the kidneys, and unprecedented tumor-to-background ratios. No specific binding was observed in a HER2-negative model. In conclusion, the in-house developed anti-HER2 nanobody 2Rs15dHIS can be successfully labeled with (177) Lu using different bifunctional chelators. Both macrocyclic and acyclic chelators show high stability in time. High specific tumor uptake combined with the lowest background uptake was measured using the 1B4M-DTPA-based conjugate. PMID- 22434640 TI - Mn-alginate gels as a novel system for controlled release of Mn2+ in manganese enhanced MRI. AB - The aim of the present study was to test alginate gels of different compositions as a system for controlled release of manganese ions (Mn(2+)) for application in manganese-enhanced MRI (MEMRI), in order to circumvent the challenge of achieving optimal MRI resolution without resorting to high, potentially cytotoxic doses of Mn(2+). Elemental analysis and stability studies of Mn-alginate revealed marked differences in ion binding capacity, rendering Mn/Ba-alginate gels with high guluronic acid content most stable. The findings were corroborated by corresponding differences in the release rate of Mn(2+) from alginate beads in vitro using T(1)-weighted MRI. Furthermore, intravitreal (ivit) injection of Mn alginate beads yielded significant enhancement of the rat retina and retinal ganglion cell (RGC) axons 24 h post-injection. Subsequent compartmental modelling and simulation of ivit Mn(2+) transport and concentration revealed that application of slow release contrast agents can achieve a significant reduction of ivit Mn(2+) concentration compared with bolus injection. This is followed by a concomitant increase in the availability of ivit Mn(2+) for uptake by RGC, corresponding to significantly increased time constants. Our results provide proof-of-concept for the applicability of Mn-alginate gels as a system for controlled release of Mn(2+) for optimized MEMRI application. PMID- 22434641 TI - 1H chemical shift magnetic resonance imaging probes with high sensitivity for multiplex imaging. AB - Proton-based chemical shift imaging probes were encapsulated inside nano-carriers to increase the sensivitity of the reporters. Co-encapsulation with a relaxation agent results in improved sensitivity and suppresses background signals. Simultaneous imaging of different chemical shift reporters allows multiplexed detection. PMID- 22434643 TI - Decreased mucosal sulfide detoxification is related to an impaired butyrate oxidation in ulcerative colitis. AB - BACKGROUND: Defective detoxification of sulfides leads to damage to the mucosa and may play a role in the etiology of ulcerative colitis (UC). The colonic mucosal thiosulfate sulfurtransferase (TST) enzyme removes H(2) S by conversion to the less toxic thiocyanate. In this study we measured colonic mucosal TST enzyme activity and gene expression in UC and controls. In addition, the influence of sulfides on butyrate oxidation was evaluated. METHODS: Colonic mucosal biopsies were collected from 92 UC patients and 24 controls. TST activity was measured spectrophotometrically. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (RT-PCR). In 20 UC patients, gene expression was reassessed after their first treatment with infliximab. To evaluate the effect of sulfides on butyrate oxidation, biopsies were incubated with 1.5 mM NaHS. RESULTS: TST enzyme activity and gene expression were significantly decreased in UC patients vs. controls (P < 0.001). UC patients, classified into disease activity subgroups, showed a significantly decreased TST activity and gene expression in the subgroups as compared to healthy subjects (P < 0.05 for all). In 20 patients, gene expression was reassessed after their first infliximab therapy. In responders to infliximab, a significant increase in TST gene expression was observed. However, TST mRNA levels did not return to control values after therapy in the responders. In controls, but not in UC, sulfide significantly decreased butyrate oxidation. CONCLUSIONS: We found an impaired detoxification mechanism of sulfide at TST protein and RNA level in UC. Inflammation was clearly associated with the observed TST deficiency. PMID- 22434644 TI - The irradiation of bone: old idea, new insight. PMID- 22434645 TI - Misclassification does not explain increased cardiovascular risks of calcium supplements. PMID- 22434647 TI - Organization of the gymnotiform fish pallium in relation to learning and memory: III. Intrinsic connections. AB - The present article reports on the telencephalic connections of regions of the dorsal telencephalon of the weakly electric fish Apteronotus leptorhynchus and Gymnotus sp. that are involved in learning and memory: the lateral (DL), central (DC), and dorsal (DD) regions of the pallium and the intermediate region between DL and DC (Dx). We find that the main route of transmission consists of diencephalic (preglomerular complex; PG) glutamatergic input to DL; glutamatergic projections from DL to DC and Dx; and glutamatergic output from DC/Dx to di-, mes , and rhombencephalic nuclei. Although PG efferents to DL are spatially organized, the projection from DL to DC appears to be diffuse. The connections of DD are entirely intrinsic to the pallium: DL projects to DD (glutamatergic) and DD feeds back to DL (glutamatergic); DD also projects to DC and has strong contralateral connections. In addition, DL and DD receive input from subpallial regions; we suggest that these are associated with the previously identified gamma-aminobutyric acid (GABA)-ergic, dopaminergic, and somatostatin-positive input to these regions. The DL/DD connections are very complex, because DL projects to and receives input from different subdivisions of DD. These subdivisions are linked by circuitry intrinsic to DD itself. DL and DD both contain recurrent putatively excitatory (glutamatergic) connections as well as local putatively inhibitory (GABAergic) interneurons. In contrast, recurrent excitatory connections appears to be absent in DC, and local inhibition is also barely present. Finally, we speculate on the implications of this pattern of connectivity for theories of short-term memory and long-term associative memory. PMID- 22434648 TI - Treatment with ginseng total saponins reduces the secondary brain injury in rat after cortical impact. AB - The present study was designed to investigate the neuroprotective effect of ginseng total saponins (GTSs) and its underlying mechanisms in a rat model of traumatic brain injury (TBI). Rats were injected with GTSs (20 mg/kg, i.p.) or vehicle for 14 days after TBI. Neurological functions were determined using beam balance and prehensile traction tests at 1-14 days after trauma. Brain samples were extracted at 1 day after trauma for determination of water content, Nissl staining, enzyme-linked immunosorbent assay, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling, and measurement of oxidative stress variables and inflammatory cytokines. Moreover, the dose response of the neuroprotective effect and time window of the efficacy of GTSs were also determined. We found that treatment of GTSs 1) improved the neurological function with an effective dosage of 5-80 mg/kg and an efficacy time window of 3-6 hr after TBI; 2) reduced brain water content and neuronal loss in the hippocampal CA3 area; 3) increased the activity of superoxide dismutase and decreased the activity of nitric oxide synthase and the amount of malondialdehyde and nitric oxide; 4) down-regulated interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha and upregulated interleukin-10 in the cortical area surrounding the injured core; and 5) inhibited the apoptotic cell death and expression of caspase-3 and bax and raised the expression of bcl-2. These findings suggest that administration of GTSs after TBI could reduce the secondary injury through inhibiting oxidative and nitrative stress, attenuating inflammatory response, and reducing apoptotic cell death. PMID- 22434649 TI - Learning surgically oriented anatomy in a student-run extracurricular club: an education through recreation initiative. AB - Didactic and laboratory anatomical education have seen significant reductions in the medical school curriculum due, in part, to the current shift from basic science to more clinically based teaching in North American medical schools. In order to increase medical student exposure to anatomy, with clinical applicability, a student-run initiative called surgically oriented anatomy prosectors (SOAP) club was created within the extracurricular program at the Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada. SOAP invites surgeons and residents from various surgical specialties to demonstrate, on a cadaver, a surgical procedure of their choosing. During the demonstration, the anatomy, as it relates to the surgical procedure, is discussed. The students then break into smaller groups to examine the relevant anatomy on the cadavers, during which time the discussion is broadened. The group continues the conversation in a social environment with refreshments. SOAP is one of the most popular extracurricular clubs with 65% of first and second year medical students registered as members. The high demand for SOAP, along with the positive participant feedback, may be due to its utilization of the principle of education through recreation, which seeks to provide opportunities for learning seamlessly throughout all facets of life. It also demonstrates the desire, amongst certain medical students, to learn applied anatomy, particularly within a surgical context. PMID- 22434650 TI - Distribution of three SNPs related to low bone mineral density in Amerindian groups and Mestizos from Mexico. AB - OBJECTIVES: Some Single nucleotide polymorphisms (SNPs) of several candidate genes have been associated with low bone mineral density (BMD) and fracture risk. As the genetic variability of such SNPs in Hispanic and Native American populations is scarce, we analyzed the three SNPs that have been related with bone mass disorders (Sp1, A163G, and BsmI) located in the genes of Type I Collagen (COL1A1), Osteoprotegerin (OPG), and Vitamin D receptor (VDR) in Mexican Mestizos (people resulting from post-Columbian admixture) and five Amerindian populations. METHODS: We genotyped these three SNPs by Polymerase chain reaction (PCR) and Restriction fragment length polymorphisms (RFLPs) in 523 individuals from five Mexican Amerindian groups (Nahua, Maya, Purepecha, Tarahumara, and Huichol) and 227 western Mestizos (Jalisco state). RESULTS: The modal allele was the same in all the six populations for Sp1-COL1A1 (S > 77%), A163G-OPG (A > 80%), and BsmI-VDR (b > 62%). Genotype distribution was in Hardy-Weinberg equilibrium in all SNPs/populations, excepting Sp1-COL1A1 in the Purepecha group and BsmI-VDR in Mestizo. In terms of the presumably Sp1-COL1A1 risk allele to low BMD (allele "s"), the Purepecha group showed the highest allele (23%) and homozygous (14.5%) frequencies. If the role of this allele as a genetic predisposing factor to low BMD were confirmed, this would mean increased susceptibility of Purepechas with regard to Europeans (14.5 vs. 6.8%). CONCLUSIONS: This finding presumably could influence the genetic susceptibility to low BMD in Purepechas. For the SNPs, BsmI-VDR and A163G-OPG, relative homogeneity was observed among the Mexican populations analyzed here. PMID- 22434651 TI - Heparin-modified small-diameter nanofibrous vascular grafts. AB - Due to high incidence of vascular bypass procedures, an unmet need for suitable vessel replacements exists, especially for small-diameter vascular grafts. Here we produced 1-mm diameter vascular grafts with nanofibrous structure via electrospinning, and successfully modified the nanofibers by the conjugation of heparin using di-amino-poly(ethylene glycol) (PEG) as a linker. Antithrombogenic activity of these heparin-modified scaffolds was confirmed in vitro. After 1 month implantation using a rat common carotid artery bypass model, heparin modified grafts exhibited 85.7% patency, versus 57.1% patency of PEGylated grafts and 42.9% patency of untreated grafts. Post-explant analysis of patent grafts showed complete endothelialization of the lumen and neovascularization around the graft. Smooth muscle cells were found in the surrounding neo-tissue. In addition, greater cell infiltration was observed in heparin-modified grafts. These findings suggest heparin modification may play multiple roles in the function and remodeling of nanofibrous vascular grafts, by preventing thrombosis and maintaining patency, and by promoting cell infiltration into the three dimensional nanofibrous structure for remodeling. PMID- 22434653 TI - Time course of tinnitus development following noise exposure in mice. AB - Gap-induced prepulse inhibition of acoustic startle (GPIAS) has been used in rats and mice to study the problem of tinnitus. The current study demonstrates that similar methods can be used to study the temporal development of tinnitus over time in middle-aged mice. Six-month-old mice on a mixed C57Bl6 * 129 background were anesthetized with isoflurane and exposed to unilateral noise (n = 15), or sham exposure for controls (n = 8), for 1 hr (16-kHz octave band signal, 116-dB SPL). Tinnitus was tested in eight different sound frequency bands before and at postexposure time points of 1, 3-4, 7, 14, 21, and 30 days and monthly thereafter until 7 months postexposure. Noise-exposed mice displayed a number of changes in GPIAS consistent with the presence of hyperacusis and tinnitus. Noise exposure was associated with acute tinnitus measured 1 day later at several frequencies at and above the exposure frequency center. Consistent, chronic tinnitus then emerged in the 24-kHz range. Several time points following noise exposure suggested evidence of hyperacusis, often followed temporally by the development of deficits in GPIAS (reflecting tinnitus). Temporal development of these changes following noise exposure are discussed in the context of the interactions among aging, noise exposure, and the associated neurochemical changes that occur at early stages of auditory processing. PMID- 22434654 TI - Varicella zoster virus infection in inflammatory bowel disease. AB - BACKGROUND: The risk of viral infection is increased in immunosuppressed inflammatory bowel disease (IBD) patients. Varicella zoster virus (VZV) is of particular interest in IBD because of a number of reports of severe, disseminated, and occasionally fatal varicella infection in immunosuppressed IBD patients. METHODS: We reviewed publications describing VZV infection in IBD patients and combined these data with a review of the current literature relating to both primary and secondary varicella in IBD. RESULTS: Twenty cases of primary varicella infection and 32 cases of herpes zoster infection have been reported in IBD. Additional cases are reported in clinical trials. The risk of VZV infection is increased with all immunosuppressants used in IBD, but corticosteroids and combination immunosuppression appear to be a particular risk. CONCLUSIONS: Healthcare providers need to be aware of the various manifestations of primary and secondary VZV infection in immunosuppressed IBD patients. Patients should be screened for VZV immunity and vaccinated prior to commencing immunosuppression. PMID- 22434656 TI - Serum response factor regulates bone formation via IGF-1 and Runx2 signals. AB - Serum response factor (SRF) plays vital roles in numerous cellular processes; however, the physiological function of SRF in skeletal tissue remains unknown. In several organ systems, SRF regulates the expression of insulin-like growth factor 1 (IGF-1), which is crucial for normal development of mineralized skeleton and bone remodeling throughout life. Here, we show that conditional deletion of SRF in osteoblasts by osteocalcin-Cre generated viable mice with normal body size and body weight. Compared with normal siblings, osteoblast-specific SRF-deficient adult mice exhibited a marked decrease in bone mineral density and bone formation rate. Deletion of SRF in primary mouse calvarial osteoblasts reduced cell differentiation and mineralization in vitro. This was accompanied by a decrease in IGF-1 expression and secretion. Addition of IGF-1 in the culture media enhanced osteoblast differentiation in control cells and partially restored the mineralization defect of SRF-deficient cells, supporting an important role of SRF in regulating IGF-1 and IGF-1-mediated osteoblast differentiation. IGF-1-induced Akt activation was inhibited in SRF-deficient calvarial cells and enhanced in the SRF overexpressed cells. In addition, SRF deficiency decreased the transcriptional activity of Runx2, the key transcription factor for osteogenesis. Overexpression of SRF induced Runx2 transactivity in control cells and restored Runx2 transactivity in the SRF-deficient cells. Taken together, we conclude that SRF is important for IGF-1-induced osteoblast differentiation and mineralization via regulating IGF-1 expression and Runx2 transactivity. PMID- 22434657 TI - Formation of lipid sheaths around nanoparticle-supported lipid bilayers. AB - High-surface-area nanoparticles often cluster, with unknown effects on their cellular uptake and environmental impact. In the presence of vesicles or cell membranes, lipid adsorption can occur on the nanoparticles, resulting in the formation of supported lipid bilayers (SLBs), which tend to resist cellular uptake. When the amount of lipid available is in excess compared with that required to form a single-SLB, large aggregates of SLBs enclosed by a close fitting lipid bilayer sheath are shown to form. The proposed mechanism for this process is one where small unilamellar vesicles (SUVs) adsorb to aggregates of SLBs just above the gel-to-liquid phase transition temperature, T(m) , of the lipids (as observed by dynamic light scattering), and then fuse with each other (rather than to the underlying SLBs) upon cooling below T(m) . The sacks of SLB nanoparticles that are formed are encapsulated by the contiguous close-fitting lipid sheath, and precipitate below T(m) , due to reduced hydration repulsion and the absence of undulation/protrusion forces for the lipids attached to the solid support. The single-SLBs can be released above T(m) , where these forces are restored by the free lipid vesicles. This mechanism may be useful for encapsulation/release of drugs/DNA, and has implications for the toxic effects of nanoparticles, which may be mitigated by lipid sequestration. PMID- 22434658 TI - Mechanism of the transition-metal-catalyzed hydroarylation of bromo-alkynes revisited: hydrogen versus bromine migration. AB - A comprehensive mechanistic study of the InCl(3)-, AuCl-, and PtCl(2)-catalyzed cycloisomerization of the 2-(haloethynyl)biphenyl derivatives of Furstner et al. was carried out by DFT/M06 calculations to uncover the catalyst-dependent selectivity of the reactions. The results revealed that the 6-endo-dig cyclization is the most favorable pathway in both InCl(3)- and AuCl-catalyzed reactions. When AuCl is used, the 9-bromophenanthrene product could be formed by consecutive 1,2-H/1,2-Br migrations from the Wheland-type intermediate of the 6 endo-dig cyclization. However, in the InCl(3)-catalyzed reactions, the chloride assisted intermolecular H-migrations between two Wheland-type intermediates are more favorable. These Cl-assisted H-migrations would eventually lead to 10 bromophenanthrene through proto-demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl(2) catalyst in the experiments by the Furstner group was predicted. It was found that both the PtCl(2)-catalyzed alkyne-vinylidene rearrangement and the 5-exo-dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9- and 10-bromophenanthrene products, as a result of the Cl-assisted H-migrations after the cyclization of the Pt-vinylidene intermediate. Alternatively, the intermediate from the 5-exo-dig cyclization would be transformed into a relatively stable Pt-carbene intermediate irreversibly, which could give rise to the 9-alkylidene fluorene product through a 1,2-H shift with a 28.1 kcal mol(-1) activation barrier. These findings shed new light on the complex product mixtures of the PtCl(2)-catalyzed reaction. PMID- 22434659 TI - Asymmetric Michael addition of N-boc-protected oxindoles to nitroalkenes catalyzed by a chiral secondary amine. AB - New mission for prolinol ethers: A secondary-amine-catalyzed Michael addition of N-Boc-protected oxindoles to nitroalkenes through a Bronsted base activation mode has been developed, furnishing the products in excellent yields (88-98 %), diastereoselectivities (d.r.=98:2->99:1) and high to excellent enantioselectivities (82->99 % ee; see scheme). PMID- 22434660 TI - Raster image correlation spectroscopy as a novel tool for the quantitative assessment of protein diffusional behaviour in solution. AB - The application of raster image correlation spectroscopy (RICS) as a tool for the characterisation of protein diffusion was assessed using a model protein, bovine serum albumin (BSA), as a function of formulation and denaturing conditions. RICS results were also validated against dynamic light scattering and fluorescence correlation spectroscopy. Results from this study demonstrate correlation between outputs obtained from the three experimental techniques. Ionic strength independency was observed at pH 7, and a reduction in the corresponding diffusion coefficients was noted at pH 4.5 for 1 uM BSA-Alexa Fluor 488. Conversely, at pH 5.2, higher-concentration samples exhibited ionic strength dependency. Buffer composition, sample pretreatment, thermal denaturation and freeze-thaw cycling were also found to influence RICS output, with a reduction in the diffusion coefficient and the number of particles observed for both pH values. In conclusion, RICS analysis of images acquired using a commercial confocal microscope offers a potential scope for application to both quantitative and qualitative characterisation of macromolecular behaviour in solution. PMID- 22434661 TI - The effects of passive and active learning on student preference and performance in an undergraduate basic science course. AB - Active learning is based on self-directed and autonomous teaching methods, whereas passive learning is grounded in instructor taught lectures. An animal physiology course was studied over a two-year period (Year 1, n = 42 students; Year 2, n = 30 students) to determine the effects of student-led seminar (andragogical) and lecture (pedagogical) teaching methods on students' retention of information and performance. For each year of the study, the course was divided into two time periods. The first half was dedicated to instructor-led lectures, followed by a control survey in which the students rated the efficiency of pedagogical learning on a five-point Likert scale from one (strongly disagree) to five (strongly agree). During the second period, students engaged in andragogical learning via peer-led seminars. An experimental survey was then administered to students using the same scale as above to determine students' preferred teaching method. Raw examination scores and survey results from both halves of the course were statistically analyzed by ANOVA with Newman-Keuls multiple comparison test. By the end of the study, student preference for peer led seminars increased [mean +/- SD: (2.47 +/- 0.94)/(4.03 +/- 1.36), P < 0.04], and examination scores significantly increased [mean +/- SD: (73.91% +/- 13.18)/(85.77 +/- 5.22), P < 0.001]. A majority of students (68.8%) preferred a method that contained peer-led seminars and instructor-led lectures. These results may indicate that integration of active and passive learning into undergraduate courses may have greater benefit in terms of student preference and performance than either method alone. PMID- 22434662 TI - Predictors of breast milk macronutrient composition in Filipino mothers. AB - OBJECTIVES: There is increasing evidence that breastfeeding has long-term effects on offspring biology and health, which has heightened interest in understanding the extent of variation in breast milk composition and its underlying determinants. Here, we report variation in milk macronutrient composition in a well-characterized cohort of young Filipino mothers and test underlying maternal predictors of this variation. METHODS: Morning breast milk samples, anthropometrics, dietary recalls, and other interview data were collected in 102 Filipino young breastfeeding mothers (age range 24.6-25.4 years) living in Cebu City, Philippines. Milk samples were analyzed for protein, fat, sugar, and milk energy density. Regression models were used to test associations between milk macronutrient composition and maternal diet, body composition, breastfeeding duration, and feeding frequency. RESULTS: Consistent with past studies, milk fat and energy increased with duration of breastfeeding; there were no associations between maternal diet or percent body fat and milk composition with the exception of a modest, inverse association between maternal adiposity and milk sugar content. CONCLUSIONS: The relative lack of associations between maternal diet or body composition and milk composition at Cebu is consistent with past studies and suggests that milk composition may be buffered against fluctuations in maternal dietary intake or nutritional status. We speculate that the tendency for milk composition to vary between populations faced with different nutritional ecologies, but to show minimal responsiveness to intake during lactation, may enhance the reliability of milk composition as a stable intergenerational cue of typical local environmental quality. PMID- 22434663 TI - Alcohol hangover symptoms and their contribution to the overall hangover severity. AB - AIMS: Scientific literature suggests a large number of symptoms that may be present the day after excessive alcohol consumption. The purpose of this study was to explore the presence and severity of hangover symptoms, and determine their interrelationship. METHODS: A survey was conducted among n = 1410 Dutch students examining their drinking behavior and latest alcohol hangover. The severity of 47 presumed hangover symptoms were scored on a 10-point scale ranging from 0 (absent) to 10 (maximal). Factor analysis was conducted to summarize the data into groups of associated symptoms that contribute significantly to the alcohol hangover and symptoms that do not. RESULTS: About half of the participants (56.1%, n = 791) reported having had a hangover during the past month. Most commonly reported and most severe hangover symptoms were fatigue (95.5%) and thirst (89.1%). Factor analysis revealed 11 factors that together account for 62% of variance. The most prominent factor 'drowsiness' (explained variance 28.8%) included symptoms such as drowsiness, fatigue, sleepiness and weakness. The second factor 'cognitive problems' (explained variance 5.9%) included symptoms such as reduced alertness, memory and concentration problems. Other factors, including the factor 'disturbed water balance' comprising frequently reported symptoms such as 'dry mouth' and 'thirst', contributed much less to the overall hangover (explained variance <5%). CONCLUSION: Drowsiness and impaired cognitive functioning are the two dominant features of alcohol hangover. PMID- 22434664 TI - Abstinence and 'low-risk' consumption 1 year after the initiation of high-dose baclofen: a retrospective study among 'high-risk' drinkers. AB - AIMS: The aim of the study was to assess the proportions of 'high-risk' drinkers' abstinent or with 'low-risk' consumption levels 1 year after the initiation of high-dose baclofen. METHODS: This is a retrospective 'open' study; the outcome of this study was to assess the level of alcohol consumption in the 12th month of treatment. RESULTS: Of the 181 patients included, a follow-up evaluation was possible in 132 patients. The initial alcohol consumption of the 132 patients analysed averaged 182 +/- 92 g/day. After 1 year, 80% of the 132 (i.e. 58% of 181) were either abstinent (n = 78) or drinking at low-risk levels (n = 28) in their 12th month of treatment. The mean baclofen dose at 1 year was 129 +/- 71 mg/day. CONCLUSION: High-dose baclofen should be tested in randomized placebo controlled trials among high-risk drinkers. PMID- 22434666 TI - L-BLP25 vaccine plus letrozole induces a TH1 immune response and has additive antitumor activity in MUC1-expressing mammary tumors in mice. AB - PURPOSE: In this study, we examine the immunomodulatory effects and antitumor activity of tamoxifen and letrozole when combined with the human epithelial mucin (hMUC1)-specific vaccine, L-BLP25, in the hMUC1-expressing mammary tumor (MMT) mouse model. EXPERIMENTAL DESIGN: Dose-finding studies were conducted for both tamoxifen and letrozole. Letrozole and L-BLP25 combination studies used 69 MMT female mice assigned to five groups: untreated, cyclophosphamide + placebo, cyclophosphamide + L-BLP25, letrozole 0.8 mg/kg, and cyclophosphamide + L-BLP25 + letrozole. Tamoxifen and L-BLP25 combination studies used 48 MMT female mice assigned to five treatment groups: untreated, cyclophosphamide + placebo, cyclophosphamide + L-BLP25, tamoxifen 50 mg/kg, and cyclophosphamide + L-BLP25 + tamoxifen 50 mg/kg group. Mice were injected subcutaneously with L-BLP25 (10 MUg) weekly for 8 weeks. Serum cytokines were serially measured using a Luminex assay, whereas splenocytes at termination were analyzed by ELISpot to determine T-helper (T(H))1/T(H)2 polarization of immune response. RESULTS: Daily oral doses of 50 and 0.8 mg/kg of tamoxifen and letrozole, respectively, resulted in a significant survival advantage over controls (P < 0.05). A predominant T(H)1-polarized immune response in vaccinated mice was seen with or without tamoxifen or letrozole treatments. In the L-BLP25 plus letrozole treatment group, statistically significant (P < 0.05) additive antitumor activity was observed, whereas tamoxifen plus L-BLP25 was not significantly different (P > 0.05). CONCLUSION: The results of this study show that hormonal therapy does not interfere with L BLP25-induced predominant T(H)1 response, and the combination of L-BLP25 with letrozole has additive antitumor activity in the MMT mouse model. PMID- 22434667 TI - Defective tumor necrosis factor release from Crohn's disease macrophages in response to Toll-like receptor activation: relationship to phenotype and genome wide association susceptibility loci. AB - BACKGROUND: Recent work provides evidence of a failure of acute inflammation in Crohn's disease (CD), and suggests that the primary defect operates at the level of the macrophage and cytokine release. Here we extend the characterization of the innate immune defect in CD by investigating the macrophage response to Toll like receptor (TLR) agonists and assess potential links between genome-wide association study (GWAS) susceptibility loci, disease phenotype, and therapeutic regimens on tumor necrosis factor alpha (TNF) release. METHODS: Peripheral blood derived macrophages were cultured from control subjects and patients with CD, stimulated with TLR ligands, and the release of TNF measured. Genomic DNA was purified from blood and genotyped for 34 single nucleotide polymorphisms (SNPs) identified as being associated with CD by GWAS. RESULTS: All stimuli resulted in a reduction (32%-48%) in TNF release from macrophages derived from CD patients (n = 28-101) compared to those from healthy control (HC) subjects. All phenotypes demonstrated impaired TNF release, with the greatest defect in patients with colonic disease. There was no detectable relationship between the level of TNF released and the presence of GWAS susceptibility loci in CD patients. Reduced TNF levels were not influenced by age, gender, or use of aminosalicylate (5-ASA) medication. CONCLUSIONS: This study supports the hypothesis of defective proinflammatory cytokine secretion and an innate immunodeficiency in CD. Abnormal TNF secretion is evident downstream of multiple TLRs, affects all disease phenotypes, and is unrelated to 34 polymorphisms associated with CD by GWAS. PMID- 22434665 TI - An apoptosis methylation prognostic signature for early lung cancer in the IFCT 0002 trial. AB - PURPOSE: To evaluate prognostic and predictive molecular biomarkers in early stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes. RESULTS: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25-2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26-3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79-6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97-3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23-0.97, P(interaction) = 0.042). CONCLUSIONS: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC. PMID- 22434668 TI - The importance of dehydration in determining ion transport in narrow pores. AB - The transport of hydrated ions through narrow pores is important for a number of processes such as the desalination and filtration of water and the conductance of ions through biological channels. Here, molecular dynamics simulations are used to systematically examine the transport of anionic drinking water contaminants (fluoride, chloride, nitrate, and nitrite) through pores ranging in effective radius from 2.8 to 6.5 A to elucidate the role of hydration in excluding these species during nanofiltration. Bulk hydration properties (hydrated size and coordination number) are determined for comparison with the situations inside the pores. Free energy profiles for ion transport through the pores show energy barriers depend on pore size, ion type, and membrane surface charge and that the selectivity sequence can change depending on the pore size. Ion coordination numbers along the trajectory showed that partial dehydration of the transported ion is the main contribution to the energy barriers. Ion transport is greatly hindered when the effective pore radius is smaller than the hydrated radius, as the ion has to lose some associated water molecules to enter the pore. Small energy barriers are still observed when pore sizes are larger than the hydrated radius due to re-orientation of the hydration shell or the loss of more distant water. These results demonstrate the importance of ion dehydration in transport through narrow pores, which increases the current level of mechanistic understanding of membrane-based desalination and transport in biological channels. PMID- 22434669 TI - Effects of embryonic hypoxia on lip formation. AB - The upper lip is formed by the fusion of facial processes, a process in which many genetic and environmental factors are involved. Embryonic hypoxia is induced by uterine anemia and the administration of vasoconstrictors during pregnancy. To define the relationship between hypoxia and upper lip formation, hypoxic conditions were created in a whole embryo culture system. Hypoxic embryos showed a high frequency of impaired fusion, reflecting failure in the growth of the lateral nasal process (LNP). In hypoxic embryos, cell proliferation activity in the LNP mesenchyme was decreased following downregulation of genes that are involved in lip formation. We also observed upregulation of vascular endothelial growth factor expression along with the induction of apoptosis in the LNP. These results suggest that embryonic hypoxia during lip formation induces apoptosis in physiologically hypoxic regions, hypoxia-induced gene expression and downregulation of the genes involved in maxillofacial morphogenesis as immediate responses, followed by reduction of mesenchymal cell proliferation activity, resulting in insufficient growth of the facial processes. PMID- 22434670 TI - Ellipsoidal TiO2 hierarchitectures with enhanced photovoltaic performance. AB - Hierarchical TiO(2) ellipsoids 250-500 nm in size have been synthesized on a large scale by a template-free hydrothermal route. The submicrometer-sized hierarchitectures are assembled from highly crystallized anatase nanorods about 17 nm in diameter with macroporous cavities on the outer shells. Based on the time-dependent morphological evolution under hydrothermal conditions, an oriented attachment process is proposed to explain formation of the hierarchical structures. Such hierarchical TiO(2) not only adsorbs large amounts of dye molecules due to high surface area, but also shows good light scattering caused by the submicrometer size. The TiO(2) hierarchitectures were deposited on top of a transparent TiO(2) nanocrystalline main layer to construct a double-layered photoanode for dye-sensitized solar cell (DSC) application, exhibiting enhanced light harvesting and power-conversion efficiency compared to a commercial TiO(2) based electrode. PMID- 22434671 TI - Chiral transcription and retentive helical memory: probing peptide auxiliaries appended with naphthalenediimides for their one-dimensional molecular organization. AB - Right or left paradox: Homochiral, heterochiral and achiral peptide auxiliaries appended with naphthalenediimide (NDI, see figure) were employed to demonstrate chiral transcription. We report an interesting phenomenon coined as retentive helical memory. Remarkably, NDI-peptide conjugates were tuned into hierarchical 1D molecular assemblies of opposite helicity in case of homochiral peptide auxiliaries. PMID- 22434672 TI - Experimental evidence for improved neuroimaging interpretation using three dimensional graphic models. AB - Three-dimensional (3D) or volumetric visualization is a useful resource for learning about the anatomy of the human brain. However, the effectiveness of 3D spatial visualization has not yet been assessed systematically. This report analyzes whether 3D volumetric visualization helps learners to identify and locate subcortical structures more precisely than classical cross-sectional images based on a two dimensional (2D) approach. Eighty participants were assigned to each experimental condition: 2D cross-sectional visualization vs. 3D volumetric visualization. Both groups were matched for age, gender, visual spatial ability, and previous knowledge of neuroanatomy. Accuracy in identifying brain structures, execution time, and level of confidence in the response were taken as outcome measures. Moreover, interactive effects between the experimental conditions (2D vs. 3D) and factors such as level of competence (novice vs. expert), image modality (morphological and functional), and difficulty of the structures were analyzed. The percentage of correct answers (hit rate) and level of confidence in responses were significantly higher in the 3D visualization condition than in the 2D. In addition, the response time was significantly lower for the 3D visualization condition in comparison with the 2D. The interaction between the experimental condition (2D vs. 3D) and difficulty was significant, and the 3D condition facilitated the location of difficult images more than the 2D condition. 3D volumetric visualization helps to identify brain structures such as the hippocampus and amygdala, more accurately and rapidly than conventional 2D visualization. This paper discusses the implications of these results with regards to the learning process involved in neuroimaging interpretation. PMID- 22434673 TI - Helper effects on breeder allocations to direct care. AB - INTRODUCTION: Mothers receive childcare and productive assistance from allomaternal helpers in many societies. Although much effort has been aimed toward showing helper effects on maternal reproductive success, less has been directed toward highlighting the full range of potential effects on breeder behavior. I present a model of optimal maternal care with helpers, and tests of derived hypotheses with data collected among the Karo Batak-a group of Indonesian agriculturalists. METHODS: To test the model's predictions I compared the effect of women receiving help from patrilateral versus matrilateral kin because those kin may provide help with different maternal responsibilities. The model predicts a decrease in maternal allocation to care that is substitutable with the helper contribution and the helper assists with that type of care; it predicts an increase in care that is nonsubstitutable with the helper contribution or substitutable care when the helper assists with other responsibilities. With the exception of one other, most models have failed to account for an increase. RESULTS/CONCLUSIONS: Analyses of time spent carrying children supported the model. With matrilateral helpers, women increased carrying; with patrilateral helpers, they decreased it. Time spent farmworking showed the opposite pattern, suggesting that matrilateral helpers effectively decrease costs, nudging optimal maternal care upward. Patterns of breastfeeding provided little support for the model. The results do, however, suggest potential proximate mechanisms by which helpers influence maternal reproductive success in cooperative breeding societies. PMID- 22434674 TI - 3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. AB - Niacin raises high-density lipoprotein and lowers low-density lipoprotein through the activation of the beta-hydroxybutyrate receptor hydroxycarboxylic acid 2 (HCA2) (aka GPR109a) but with an unwanted side effect of cutaneous flushing caused by vascular dilation because of the stimulation of HCA2 receptors in Langerhans cells in skin. HCA1 (aka GPR81), predominantly expressed in adipocytes, was recently identified as a receptor for lactate. Activation of HCA1 in adipocytes by lactate results in the inhibition of lipolysis, suggesting that agonists for HCA1 may be useful for the treatment of dyslipidemia. Lactate is a metabolite of glucose, suggesting that HCA1 may also be involved in the regulation of glucose metabolism. The low potency of lactate to activate HCA1, coupled with its fast turnover rate in vivo, render it an inadequate tool for studying the biological role of lactate/HCA1 in vivo. In this article, we demonstrate the identification of 3-hydroxybenzoic acid (3-HBA) as an agonist for both HCA2 and HCA1, whereas 3,5-dihydroxybenzoic acid (3,5-DHBA) is a specific agonist for only HCA1 (EC(50) ~150 MUM). 3,5-DHBA inhibits lipolysis in wild-type mouse adipocytes but not in HCA1-deficient adipocytes. Therefore, 3,5-DHBA is a useful tool for the in vivo study of HCA1 function and offers a base for further HCA1 agonist design. Because 3-HBA and 3,5-DHBA are polyphenolic acids found in many natural products, such as fruits, berries, and coffee, it is intriguing to speculate that other heretofore undiscovered natural substances may have therapeutic benefits. PMID- 22434675 TI - A mouse kindling model of perimenstrual catamenial epilepsy. AB - Catamenial epilepsy is caused by fluctuations in progesterone-derived GABA(A) receptor-modulating anticonvulsant neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (midluteal phase) and increases during their withdrawal (perimenstrual periods) in close association with GABA(A) receptor plasticity. A chronic seizure condition was created by using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully kindled mice. Fully kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the alpha4 and delta subunits of GABA(A) receptors in the hippocampus. These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly caused by specific changes in GABA(A) receptor-subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for the investigation of disease mechanisms and new therapeutic approaches. PMID- 22434676 TI - Effects of ethanol on GABA(A) receptors in GABAergic and glutamatergic presynaptic nerve terminals. AB - Ethanol (EtOH) has a number of behavioral effects, including intoxication, amnesia, and/or sedation, that are thought to relate to the activation of GABA(A) receptors. However, GABA(A) receptors at different cellular locations have different sensitivities to EtOH. The present study used the "synaptic bouton" preparation where we could stimulate nerve endings on mechanically dissociated single rat hippocampal CA1 and CA3 pyramidal neurons and investigate the effects of EtOH on presynaptic and postsynaptic GABA(A) receptors. Low concentrations of EtOH (10 mM) had no effect on postsynaptic GABA(A) and glutamate receptors or voltage-dependent Na(+) and Ca(2+) channels. Higher concentrations (>=100 mM) could significantly inhibit these current responses. EtOH at 10 mM had no direct effect on inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) evoked by focal stimulation of single boutons [evoked IPSCs (eIPSCs) and evoked EPSCs (eEPSCs)]. However, coapplication of 10 mM EtOH with muscimol decreased the amplitude of eIPSCs and eEPSCs and increased their paired pulse ratio. The effects on eEPSCs were reversed by bicuculline. Coapplication of muscimol and EtOH significantly increased the frequency of spontaneous IPSCs and EPSCs. The EtOH effects on the postsynaptic responses and eEPSCs were similar in neurons from neonatal and mature rats. These results revealed that low concentrations of EtOH can potentiate the activation of presynaptic GABA(A) receptors to inhibit evoked GABA and glutamate release. These results indicate a high sensitivity of presynaptic GABA(A) receptor to EtOH, which needs to be accounted for when considering the cellular mechanisms of EtOH's physiological responses. PMID- 22434678 TI - Direct cauterization of the nasal septal artery for epistaxis. AB - Emergency management of epistaxis may include the use of local pressure and vasoconstrictors, chemical or electric cautery, hemostatic agents, nasal packing, embolization, and surgical arterial ligation. There is no definitive protocol for the management of epistaxis, although various protocols have been proposed in the literature. As approaches to surgical ligation of the arterial supply of the nasal cavity have evolved from external carotid ligation to minimally invasive approaches, surgical management of epistaxis has become more effective than embolization and may be less risky. In the surgical management of epistaxis, arterial ligation immediately proximal to the bleeding site is preferred. We propose a simple variation of the endoscopic sphenopalatine artery ligation that may be used to manage epistaxis arising from the nasal septum and floor. PMID- 22434677 TI - Behavioral effects and central nervous system levels of the broadly available kappa-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo. AB - Active blood-brain barrier mechanisms, such as the major efflux transporter P glycoprotein (mdr1), modulate the in vivo/central nervous system (CNS) effects of many pharmacological agents, whether they are used for nonmedical reasons or in pharmacotherapy. The powerful, widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy, selective kappa-opioid agonist and displays fast-onset behavioral effects (e.g., within 1 min of administration) and relatively short duration of action. In vitro studies suggest that salvinorin A may be a P-glycoprotein substrate; thus, the functional status of P glycoprotein may influence the behavioral effects of salvinorin A or its residence in CNS after parenteral administration. We therefore studied whether a competing P-glycoprotein substrate (the clinically available agent loperamide; 0.032-0.32 mg/kg) or a selective P-glycoprotein blocker, tariquidar (0.32-3.2 mg/kg) could enhance unconditioned behavioral effects (ptosis and facial relaxation, known to be caused by kappa-agonists in nonhuman primates) of salvinorin A, as well as its entry and residence in the CNS, as measured by cerebrospinal fluid sampling. Pretreatment with either loperamide or tariquidar dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation. In a control study, loperamide and tariquidar were inactive when given as a pretreatment to ((+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1 oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593), a kappa-agonist known to be a very poor P-glycoprotein substrate. Furthermore, pretreatment with tariquidar (3.2 mg/kg) also enhanced peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier. PMID- 22434679 TI - Petrous apex cholesterol granulomas: endonasal versus infracochlear approach. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate and compare the surgical anatomy of two different routes to access and drain petrous apex (PA) cholesterol granulomas: the expanded endonasal approach (EEA) and the transcanal infracochlear approach (TICA). STUDY DESIGN: Anatomic and radiologic study. METHODS: The EEA and TICA to the PA were performed in 11 anatomic specimens with the assistance of imaging guidance. The PA was categorized into three zones: superior PA, anterior-inferior PA, and posterior-inferior PA. The maximum drainage window achieved by each approach was calculated using the imaging studies of each anatomic specimen. RESULTS: The EEA was able to reach superior PA and anterior-inferior PA in all specimens and posterior-inferior PA in 90%. The TICA did not provide access to superior PA in any case. The TICA was suitable to reach anterior-inferior PA in 80% of specimens and posterior-inferior PA in 60%. Based on the radiologic study, the EEA provided a drainage window three times larger than the TICA. CONCLUSIONS: The transnasal approach provides reliable access to the PA when combined with internal carotid artery exposure and allows for large drainage window. The transcanal approach is less versatile and more limited than the transnasal approach but provides access to the most posterior and inferior portion of the PA without Eustachian tube transection. Here we propose a new surgical classification that may help to decide the most suitable approach to the PA according to the location and extension of the lesion. PMID- 22434680 TI - The head-mounted microscope. AB - Microsurgical equipment has greatly advanced since the inception of the microscope into the operating room. These advancements have allowed for superior surgical precision and better post-operative results. This study focuses on the use of the Leica HM500 head-mounted microscope for the operating phonosurgeon. The head-mounted microscope has an optical zoom from 2* to 9* and provides a working distance from 300 mm to 700 mm. The headpiece, with its articulated eyepieces, adjusts easily to head shape and circumference, and offers a focus function, which is either automatic or manually controlled. We performed five microlaryngoscopic operations utilizing the head-mounted microscope with successful results. By creating a more ergonomically favorable operating posture, a surgeon may be able to obtain greater precision and success in phonomicrosurgery. Phonomicrosurgery requires the precise manipulation of long handled cantilevered instruments through the narrow bore of a laryngoscope. The head-mounted microscope shortens the working distance compared with a stand microscope, thereby increasing arm stability, which may improve surgical precision. Also, the head-mounted design permits flexibility in head position, enabling operator comfort, and delaying musculoskeletal fatigue. A head-mounted microscope decreases the working distance and provides better ergonomics in laryngoscopic microsurgery. These advances provide the potential to promote precision in phonomicrosurgery. PMID- 22434681 TI - Paradoxical vocal cord motion: classification and treatment. AB - Paradoxical vocal cord motion (PVCM), or vocal cord dysfunction, is a descriptive term for inappropriate adduction of the vocal folds during respiration. The laryngeal mistiming leads to breathing difficulty and is often misdiagnosed as refractory asthma. The etiology of PVCM has been unclear but has long been hypothesized to be psychological. The present thesis is a prospective study of 170 patients older than 18 years being evaluated for PVCM, with 117 of the 170 (68.8%) identified as having PVCM by video laryngoscopy. Laryngeal edema (P = .021) and reflux (P = .026) were increased in patients with PVCM. A flat inspiratory arm of the flow volume loop during spirometry testing was a predictor of PVCM (P = .034). A subgroup of 47 newly diagnosed patients with PVCM underwent psychological analysis. The psychological profiles were elucidated using the Minnesota Multiphasic Personality Inventory and the Life Experiences Survey to evaluate stress. Compared to established normative data, PVCM demonstrated a conversion disorder pattern (P < .01) but not an anxiety disorder or a correlation with stress. A subgroup, 11 of the 47 (23.4%), had normal psychological outcomes, and two of the 47 (4.3%) were identified as malingering. Previous studies have suggested that PVCM is strictly a psychological disorder. It is proposed that PVCM is a descriptive term that is multifactorial and the etiology should direct treatment. A classification scheme divides PVCM into primary, or psychological, and secondary. The secondary form consists of medical disorders divided into irritable larynx syndrome and neurologic disorders. PMID- 22434682 TI - New perspectives of an old cytokine. PMID- 22434683 TI - Nanostructured, molecularly imprinted, and template-patterned polythiophenes for chiral sensing and differentiation. AB - An innovation to thin-film molecular imprinting is presented for the sensitive detection and effective discrimination of chiral compounds using a portable quartz crystal microbalance transduction technique. The facile approach involves i) colloidal sphere layering of latex particles onto the surface via a Langmuir Blodgett-like technique followed by ii) template molecular imprinting using electrodeposition of a single functional and cross-linking monomer. PMID- 22434684 TI - Metamagnetism and single-chain magnetic behavior in a homospin one-dimensional iron(II) coordination polymer. AB - Reaction of FeCl(2).4H(2)O with KNCSe and pyridine in ethanol leads to the formation of the discrete complex [Fe(NCSe)(2)(pyridine)(4)] (1) in which the Fe(II) cations are coordinated by two N-terminal-bonded selenocyanato anions and four pyridine co-ligands. Thermal treatment of compound 1 enforces the removal of half of the co-ligands leading to the formation of a ligand-deficient (lacking on neutral co-ligands) intermediate of composition [Fe(NCSe)(2)(pyridine)(2)](n) (2) to which we have found no access in the liquid phase. Compound 2 is obtained only as a microcrystalline powder, but it is isotypic to [Cd(NCSe)(2)(pyridine)(2)](n) and therefore, its structure was determined by Rietveld refinement. In its crystal structure the metal cations are coordinated by two pyridine ligands and four selenocyanato anions and are linked into chains by MU-1,3 bridging anionic ligands. Magnetic measurements on compound 1 show only paramagnetic behavior, whereas for compound 2 an unexpected magnetic behavior is found, which to the best of our knowledge was never observed before for a iron(II) homospin compound. In this compound metamagnetism and single-chain magnetic behavior coexist. The metamagnetic transition between the antiferromagnetically ordered phase and a field-induced ferromagnetic phase of the high-spin iron(II) spin carriers is observed at a transition field H(C) of 1300 Oe and the single-chain magnetic behavior is characterized by a blocking temperature T(B), estimated to be about 5 K. PMID- 22434685 TI - Interference with kinesin-based anterograde neurofilament axonal transport increases neurofilament-neurofilament bundling. AB - Neurofilaments (NFs) associate with each other and with other cytoskeletal elements to form a lattice that supports the mature axon. Phosphorylation contributes to formation of this stationary population of NFs by fostering cation dependent interactions among NF sidearms. Association of NFs with the stationary phase indirectly competes with NF axonal transport by withdrawing NFs from kinesin-dependent motility along microtubules. We therefore hypothesized that inhibition of anterograde NF transport may increase incorporation into the stationary phase. To test this hypothesis, we treated differentiated NB2a/d1 cells expressing GFP-tagged NF subunits with monastrol, a specific inhibitor of kinesin-5. Monastrol significantly inhibited anterograde axonal transport of NF-H but not NF-M, and increased the incorporation of newly-transported NF subunits into axonal NF bundles. These findings support the notion that NF transport and bundling exert opposing forces on axonal NF dynamics, and that inhibition of anterograde transport of NFs can increase their incorporation into the stationary phase. PMID- 22434686 TI - Teratogen update: methotrexate. AB - Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure. PMID- 22434687 TI - Daily patterns of clock and cognition-related factors are modified in the hippocampus of vitamin A-deficient rats. AB - The circadian expression of clock and clock-controlled cognition-related genes in the hippocampus would be essential to achieve an optimal daily cognitive performance. There is some evidence that retinoid nuclear receptors (RARs and RXRs) can regulate circadian gene expression in different tissues. In this study, Holtzman male rats from control and vitamin A-deficient groups were sacrificed throughout a 24-h period and hippocampus samples were isolated every 4 or 5 h. RARalpha and RXRbeta expression level was quantified and daily expression patterns of clock BMAL1, PER1, RORalpha, and REVERB genes, RORalpha and REVERB proteins, as well as temporal expression of cognition-related RC3 and BDNF genes were determined in the hippocampus of the two groups of rats. Our results show significant daily variations of BMAL1, PER1, RORalpha, and REVERB genes, RORalpha and REVERB proteins and, consequently, daily oscillating expression of RC3 and BDNF genes in the rat hippocampus. Vitamin A deficiency reduced RXRbeta mRNA level as well as the amplitude of PER1, REVERB gene, and REVERB protein rhythms, and phase-shifted the daily peaks of BMAL1 and RORalpha mRNA, RORalpha protein, and RC3 and BDNF mRNA levels. Thus, nutritional factors, such as vitamin A and its derivatives the retinoids, might modulate daily patterns of BDNF and RC3 expression in the hippocampus, and they could be essential to maintain an optimal daily performance at molecular level in this learning-and-memory-related brain area. PMID- 22434688 TI - Absence of sclerostin adversely affects B-cell survival. AB - Increased osteoblast activity in sclerostin-knockout (Sost(-/-)) mice results in generalized hyperostosis and bones with small bone marrow cavities resulting from hyperactive mineralizing osteoblast populations. Hematopoietic cell fate decisions are dependent on their local microenvironment, which contains osteoblast and stromal cell populations that support both hematopoietic stem cell quiescence and facilitate B-cell development. In this study, we investigated whether high bone mass environments affect B-cell development via the utilization of Sost(-/-) mice, a model of sclerosteosis. We found the bone marrow of Sost(-/ ) mice to be specifically depleted of B cells because of elevated apoptosis at all B-cell developmental stages. In contrast, B-cell function in the spleen was normal. Sost expression analysis confirmed that Sost is primarily expressed in osteocytes and is not expressed in any hematopoietic lineage, which indicated that the B-cell defects in Sost(-/-) mice are non-cell autonomous, and this was confirmed by transplantation of wild-type (WT) bone marrow into lethally irradiated Sost(-/-) recipients. WT->Sost(-/-) chimeras displayed a reduction in B cells, whereas reciprocal Sost(-/-) ->WT chimeras did not, supporting the idea that the Sost(-/-) bone environment cannot fully support normal B-cell development. Expression of the pre-B-cell growth stimulating factor, Cxcl12, was significantly lower in bone marrow stromal cells of Sost(-/-) mice, whereas the Wnt target genes Lef-1 and Ccnd1 remained unchanged in B cells. Taken together, these results demonstrate a novel role for Sost in the regulation of bone marrow environments that support B cells. PMID- 22434689 TI - Gender role affects experimental pain responses: a systematic review with meta analysis. AB - Gender role refers to the culturally and socially constructed meanings that describe how women and men should behave in certain situations according to feminine and masculine roles learned throughout life. The aim of this meta analysis was to evaluate the relationship between gender role and experimental pain responses in healthy human participants. We searched computerized databases for studies published between January 1950 and May 2011 that had measured gender role in healthy human adults and pain response to noxious stimuli. Studies were entered into a meta-analysis if they calculated a correlation coefficient (r) for gender role and experimental pain. Searches yielded 4465 'hits' and 13 studies were eligible for review. Sample sizes were 67-235 participants and the proportion of female participants was 45-67%. Eight types of gender role instrument were used. Meta-analysis of six studies (406 men and 539 women) found a significant positive correlation between masculine and feminine personality traits and pain threshold and tolerance, with a small effect size (r = 0.17, p = 0.01). Meta-analysis of four studies (263 men and 297 women) found a significant negative correlation between gender stereotypes specific to pain and pain threshold and tolerance, with a moderate effect size (r = -0.41, p < 0.001). In conclusion, individuals who considered themselves more masculine and less sensitive to pain than the typical man showed higher pain thresholds and tolerances. Gender stereotypes specific to pain scales showed stronger associations with sex differences in pain sensitivity response than masculine and feminine personality trait scales. PMID- 22434690 TI - Adjunctive ultrasonography during carotid artery stenting to minimize iodine contrast use. AB - Carotid artery stenting (CAS) in patients with chronic kidney disease carries a significant risk of contrast-induced nephropathy. We report a case of CAS with adjunctive sonography to reduce the amount of contrast medium during angiography. A 71-year-old man presented with a symptomatic right carotid stenosis. He was selected for CAS due to significant medical comorbidity, which included severe renal impairment. A preoperative noncontrast CT was performed to assess anatomical suitability and to plan arch vessel cannulation. We undertook CAS with the use of intraoperative ultrasound. Sonography was used to monitor the manipulation of wires, catheters, and stents. Four milliliters of contrast was required to complete the procedure successfully with no deterioration in postoperative renal function. Adjunctive ultrasound is feasible to reduce contrast use in patients with severe renal impairment undergoing CAS. PMID- 22434691 TI - A moisture- and air-stable cationic ruthenium complex as catalyst for highly atom economical stereo- and regioselective vinylation of azoles. PMID- 22434692 TI - Genotoxic effects of catmint (Nepeta meyeri Benth.) essential oils on some weed and crop plants. AB - This study investigates the genotoxicity of the essential oils extracted from the aerial parts of catmint (Nepeta meyeri Benth.) against two weeds (Bromus danthoniae and Lactuca serriola) and two crop plants (Brassica napus and Zea mays). The essential oils of N. meyeri analyzed by gas chromatography-mass spectrometry contained 14 compounds, with 4aalpha, 7alpha, 7abeta-nepetalactone (83.4%), 4aalpha, 7alpha, and 7aalpha-nepetalactone (8.83%) as the major components. The oils were diluted (25, 50, 100, and 150 ppm) and the solutions were applied to seeds or leaves of these plants. The study compared the germination percentage and random amplified polymorphic DNA (RAPD) results with the control group. The results showed that the oils had a strong inhibitory activity and caused a change in RAPD profiles in terms of variation in band intensity, loss of bands, and appearance of new bands compared with the control group. The results suggested that RAPD analysis could be applied as a suitable biomarker assay for the detection of genotoxic effects of plant allelochemicals. This study indicates the genotoxical potential of N. meyeri essential oils on weed and crop plants. PMID- 22434693 TI - Enhancing surface interactions with colon cancer cells on a transferrin conjugated 3D nanostructured substrate. AB - A transferrin-conjugated PEG-Fe(3) O(4) nanostructured matrix is developed to explore cellular responses in terms of enhanced cell adhesion, specific interactions between ligands in the matrix and molecular receptors on the cell membrane, comparison of cell shapes on 2D and 3D surfaces, and effect of polymer architecture on cell adhesion. Integration of such advanced synthetic nanomaterials into a functionalized 3D matrix to control cell behavior on surfaces will have implications in nanomedicine. PMID- 22434694 TI - Haploidentical bone marrow transplantation in Mexico. AB - Haploidentical hematopoietic cell transplantation using CD34(+) cells depleted of T lymphocytes by the CliniMACS is a treatment for hematological malignancy. We report on four Mexican children, three with acute lymphocytic leukemia and one with chronic myelocytic leukemia, who was transplanted with 12 * 10(6) CD34(+) stem cells/kg body weight (98% of purity) with a follow-up of 91/2 years. The engraftment was successful in three of the four children. All showed cytomegalovirus reactivation, and one died because of graft rejection and infectious complication. The risk of infections was a major problem. PMID- 22434695 TI - Inhibition of the sodium-calcium exchanger via SEA0400 altered manganese-induced T1 changes in isolated perfused rat hearts. AB - Manganese (Mn(2+) )-enhanced MRI (MEMRI) provides the potential for the in vivo evaluation of calcium (Ca(2+) ) uptake in the heart. Recent studies have also suggested the role of the sodium-calcium (Na(+) -Ca(2+) ) exchanger (NCX) in Mn(2+) retention, which may have an impact on MEMRI signals. In this study, we investigated whether MEMRI with fast T(1) mapping allowed the sensitive detection of changes in NCX activity. We quantified the dynamics of the Mn(2+) -induced T(1) changes in isolated perfused rat hearts in response to SEA0400, an NCX inhibitor. The experimental protocol comprised 30 min of Mn(2+) perfusion (wash in), followed by a 30-min wash-out period. There were three experimental groups: 1, NCX inhibition by 1 u m SEA0400 during Mn(2+) wash-in only (SEAin, n=6); 2, NCX inhibition by 1 u m SEA0400 during Mn(2+) wash-out only (SEAout, n=6); 3, no NCX inhibition during both wash-in and wash-out to serve as the control group (CNTL, n=5). Rapid T(1) mapping at a temporal resolution of 3 min was performed throughout the perfusion protocol using a triggered saturation-recovery Look Locker sequence. Our results showed that NCX inhibition during Mn(2+) wash-in caused a significant increase in relaxation rate (R(1) ) at the end of Mn(2+) perfusion. During the wash-out period, NCX inhibition led to less reduction in R(1) . Further analysis of Mn(2+) content in myocardium with flame atomic absorption spectroscopy was consistent with the MRI findings. These results suggest that Mn(2+) accumulation and retention in rat hearts are, in part, dependent on NCX activity. Hence, MEMRI may provide an imaging method that is also sensitive to changes in NCX activity. PMID- 22434696 TI - Relationship between microstructure and degree of mineralization in subchondral bone of osteoarthritis: a synchrotron radiation uCT study. AB - We analyzed the microstructure and degree of mineralization of the subchondral trabecular bone in hip osteoarthritis (OA) using synchrotron radiation computed tomography (SRCT) to identify the relationship between bone structure and bone turnover. Subchondral bone samples were extracted from femoral heads of 10 terminal-staged hip OA patients. The SRCT scan was performed at 30 keV energy and 5.9 um voxel size. Trabecular bone structure, bone cyst volume, and the degree of trabecular bone mineralization were measured, and correlations between bone structure and the degree of mineralization were analyzed. In addition, the trabecular bone was divided into the area immediately surrounding the bone cyst and the remaining area, and they were compared. The average cyst volume fraction in the whole region was 31.8%, and the bone volume fraction in the bone region was 55.6%. Cyst volume was the only structural parameter that had a significant correlation with the degree of mineralization. The degree of mineralization was diminished when the bone cyst was larger (r = -0.81, p = 0.004). The trabecular bone immediately surrounding the bone cyst had a lower degree of mineralization when compared with the remaining trabecular bone (p = 0.008). In the bone sclerosis of OA subchondral bone, there are many large and small bone cysts, which are expected to play a significant part in the high bone turnover of OA. PMID- 22434697 TI - Tumor response assessments with diffusion and perfusion MRI. AB - There is an increasing awareness that the evaluation of tumor response to oncologic treatments based solely on anatomic imaging assessments face many limitations, particularly in this era of novel biologic targeted therapies. Functional imaging techniques such as diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) have the ability to depict important tumor biologic features and are able to predict therapy response based on assessments of cellularity and tumor vascularity, which often precede morphologic alterations. In this article we focus on DW-MRI and DCE-MRI as response parameters addressing the technologies involved, quantification methods, and validation for each technique and their current role in imaging response to conventional and novel therapies. We also discuss the challenges that lie ahead in the deployment of these imaging methods into the clinical environment. PMID- 22434698 TI - Magnetic resonance imaging of triangular fibrocartilage. AB - Due to their small size and complex structure, diagnosing injury of the proximal wrist ligamentous structures can be challenging. The triangular fibrocartilage complex (TFCC) is an example of one such structure, for which lesions may be missed unless high-resolution magnetic resonance imaging (MRI) obtained via a standard matrix with a small field of view or high-resolution imaging matrix (small spatial scale matrix elements/large matrix size) is utilized. While there have been recent advances in increasing MRI spatial resolution, attempts at improved visualization by isolated increase in the spatial resolution will be ineffective if the signal-to-noise ratio (SNR) of the images obtained is low. Additionally, high contrast resolution is important to facilitate a more precise visualization of these structures and their pathology. Thus, a balance of the three important imaging factor qualifications of high spatial resolution, high SNR, and high contrast resolution must be struck for optimized TFCC and wrist imaging. The goal of this article, then, is to elucidate the theory and techniques of effective high-resolution imaging of the proximal ligamentous structures of the wrist, balancing SNR and high contrast resolution constraints, and focusing on imaging of the TFCC as a prototypical example. PMID- 22434700 TI - Factors affecting time required to reach maintenance dose during subcutaneous immunotherapy. AB - BACKGROUND: Subcutaneous immunotherapy (SCIT) demands a significant time commitment on the part of the patient, especially during the escalation period when weekly visits are required. Many patients refuse or discontinue treatment in spite of the demonstrated clinical efficacy of SCIT. Understanding the factors that affect the length of the escalation phase would allow for counseling of patients, which may improve patient compliance. The aims of this study were to determine the mean time required to reach maintenance dose during conventional protocol SCIT and to identify factors that significantly affect the time required to reach maintenance dose. METHODS: We conducted a retrospective chart review of 55 patients (total of 79 treatment vials) who began SCIT between January 2007 and December 2010 and reached maintenance dose. The effect of demographic data, medical and social history, and SCIT allergen data on the time required to reach maintenance dose were examined using bivariate and multivariate analyses. RESULTS: The mean time to maintenance dose for the 79 treatment vials was 240.2 days (range, 76-720 days). Males (mean 294.7 days) took significantly longer than females (mean 205.1 days) to reach maintenance dose (p = 0.007). Asthmatics (mean 285.5 days) took significantly longer than nonasthmatics (mean 218.0 days) to reach maintenance dose (p = 0.008). Age also significantly affected the length of the escalation phase; each additional year of age was associated with an increase in 3.9 days needed to reach maintenance dose (p = 0.002). CONCLUSION: Gender, asthma, and age significantly impact the time required to reach maintenance dose during SCIT. PMID- 22434701 TI - Production of nitric oxide by human salivary peroxidase and by bovine lactoperoxidase. AB - Peroxidases catalyze the oxidation of nitrite to nitrate in the presence of hydrogen peroxide. Two pathways may occur: one entailing the intermediate formation of NO(2) and the other implying the generation of peroxynitrite. The products of nitrite (NO(2) (-) ) oxidation by salivary peroxidase (SPO) and commercial bovine lactoperoxidase (LPO) are studied by utilizing an electrochemical assay that allows the direct, continuous monitoring of NO and/or NO(2) and by HPLC to assess nitrates at the end of the reaction. Dialyzed saliva and LPO, in the presence of H(2) O(2) , convert nitrite into nitrate and form some NO, with a molar ratio of 10(3) . In our experimental conditions, no NO(2) was detectable among the products of nitrite oxidation. SCN(-) inhibits NO formation and so does I(-) , although at higher concentrations. No effects are observed with Cl(-) or Br(-) . We conclude that SPO and LPO transform NO(2) (-) into nitrate-forming small amounts of NO in the presence of H(2) O(2) as an intermediate or a by-product, synthesized through the peroxynitrite pathway. PMID- 22434702 TI - Metabolic adaptations to arsenic-induced oxidative stress in male wistar rats. AB - The present study was planned to investigate the effect of arsenic in rats on several biochemical indices of oxidative stress. Rats were exposed to arsenite in drinking water for upto 12 weeks. Chronic exposure to arsenic for a period of 12 weeks significantly (p < 0.05) increased arsenic burden in blood, liver, and kidney. Several intrinsic antioxidant defenses were activated after a 4-week exposure to arsenic. Some remained elevated, but others became depressed over a longer exposure period. Alterations in most of the biochemical variables reached statistical significant (p < 0.05). Arsenic significantly (p < 0.01) reduced mRNA expression of the superoxide dismutase 2 (SOD2) gene with respect to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. These observations indicated that prolong exposure to arsenic causes induction of oxidative stress and biochemical alterations. PMID- 22434703 TI - Breast hemangiomas: correlation between imaging and pathologic findings. AB - Hemangiomas are benign vascular tumors that are rare in the breast. A high percentage of hemangiomas are diagnosed incidentally during imaging examinations. They have mammographic, sonographic, and pathologic characteristics that allow radiologists and pathologists to diagnose them. We present four different cases of breast hemangiomas showing their mammographic and sonographic features. Two were diagnosed with an 18-gauge core needle biopsy and they underwent surgical excision. The other two cases were diagnosed with a 14-gauge core needle biopsy and their radiologic and pathologic appearances were concordant with breast hemangiomas, so they did not need surgical excision and are being followed. PMID- 22434704 TI - Bistable cucurbituril rotaxanes without stoppers. AB - Bistable rotaxanes are important design elements of molecular devices for a broad range of applications, such as controlled drug release, molecular rotary motors, and chemical sensors. The host-guest complexes of cucurbit[6]uril and 1,4 bis(alkylaminomethyl)benzene were found to exhibit two stable binding modes with an unexpectedly high barrier between them. Their structural and dynamic properties, kinetic and thermodynamic parameters, as well as different chemical reactivity towards the azide-alkyne [3+2] cycloaddition reaction (click chemistry), were discovered by NMR spectroscopy, X-ray crystallography, and isothermal titration microcalorimetry. The highly stable 2:1 complex, which is formed at room temperature, was found to be a kinetic product, which may be converted to the thermodynamic 1:1 complex upon prolonged heating to 100 degrees C. The latter is a very stable rotaxane despite the fact that it lacks bulky end groups. PMID- 22434705 TI - Transcript characteristic of myostatin in sheep fibroblasts. AB - Myostatin, a secreted growth factor highly expressed in skeletal muscle, negatively regulates skeletal muscle growth and differentiation. Recently, myostatin is emerged as a potential target for anti-atrophy and anti-fibrotic therapies. Therefore, to investigate the regulation of myostatin in sheep adult fibroblasts, we used the RNA interference mediated by lentiviral vector to gene silence myostatin. Simultaneously, we also had constructed the sheep myostatin overexpression vector to further explore the function of myostatin in fibroblasts. The results here demonstrated that the lentiviral vector could significantly reduce myostatin gene both at mRNA and protein level by 71% and 67%, respectively (P < 0.01). Inhibition of myostatin also resulted in a remarkable increase of activin receptor 2B (ACV2B), p21, PPARgamma, leptin, C/EBPbeta, and MEF2A expression, and a decrease of Akt1, CDK2, MEF2C, and Myf5 expression. Ectopic myostatin mRNA and protein were also present in the fibroblasts transfection. Furthermore, we observed that overexpression of myostatin contributed to an increase of Akt1, CDK2, Myf5 and PPARgamma, and a decrease of p21, C/EBPalpha and leptin at the transcript level. These results suggested that myostatin positively regulated Akt1, CDK2, Myf5, leptin, and C/EBPalpha, but negatively regulated p21 mRNA expression in adult fibroblasts, and it also expanded our understanding of the regulation mechanism of myostatin. Moreover, the lentiviral system inactivated myostatin gene in fibroblasts would be used to generate transgenic sheep and to ameliorate muscle fibrosis and atrophy by gene therapy in the future. PMID- 22434707 TI - An exploratory epidemiological study of Langerhans cell histiocytosis. AB - We explored potential risk factors associated with Langerhans cell histiocytosis (LCH) in a predominantly Hispanic population in Los Angeles. Sixty children with LCH (cases) and, 150 randomly selected patients (controls) were interviewed. There was no statistically significant difference between cases and controls in the following: Family history of thyroid disease, smokers in the family, maternal problems during pregnancy, and pesticide exposure. Cases were more likely to report a family history of cancer (OR 2.5), infection during infancy (OR 2.76), and parental occupational exposure to metal, granites, or wood dust (OR 2.48). PMID- 22434706 TI - Psychogenic palatal tremor may be underrecognized: reappraisal of a large series of cases. AB - BACKGROUND: Palatal tremor is characterized by rhythmic movements of the soft palate and can be essential or symptomatic. Some patients can have palatal movements as a special skill or due to palatal tics. Psychogenic palatal tremor is recognized but rarely reported in the literature. METHODS: We retrospectively evaluated all patients with palatal tremor seen in our center over a period of 10 years. RESULTS: Of 17 patients with palatal tremor, we identified 10 patients with isolated palatal tremor. In 70% of those the diagnosis of psychogenic palatal tremor could be made. Of the remainder, 2 had palatal tics and 1 essential palatal tremor. CONCLUSIONS: We suggest that psychogenic palatal tremor may be underrecognized and propose that targeted clinical examination of positive signs for psychogenic movement disorders in these patients is essential. The correct identification of such patients has important clinical and scientific implications. PMID- 22434708 TI - Excessive sodium ions delivered into cells by nanodiamonds: implications for tumor therapy. AB - Nanodiamonds (NDs) possess many excellent physical and chemical properties that make them attractive materials for applications in biomedicine. In this paper, the adsorption and delivery of a large amount of sodium ions into the cell interior by NDs in serum-free medium is demonstrated. The excess sodium ions inside the cells induce osmotic stresses followed by cell swelling and an increase in the intracellular levels of calcium and reactive oxygen species (ROS), which leads to severe cellular damage. In complete culture medium, however, serum proteins wrapped around the NDs effectively prevent the sodium ions from adsorbing onto the NDs, and thus the NDs show no cytotoxicity. This work is the first to elaborate on the correlation between the sodium ions adsorbed on the nanomaterials and their bio-effects. Excessive ions delivered into cells by NDs might have potential applications in tumor therapy. PMID- 22434709 TI - Anti-integrase abzymes from the sera of HIV-infected patients specifically hydrolyze integrase but nonspecifically cleave short oligopeptides. AB - In contrast to canonical proteases, total immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies (Abs) from HIV-infected patients hydrolyze effectively only HIV integrase (IN), reverse transcriptase (RT), human casein, and serum albumin. Anti-IN IgG and IgM isolated by chromatography on IN-Sepharose hydrolyze specifically only IN but not many other tested proteins. Total Abs from HIV-infected patients hydrolyze not only globular proteins but also different specific and nonspecific tri-, tetra-, and 20- to 25-mer oligopeptides (OPs) with a higher rate than anti-IN Abs isolated using IN-Sepharose. A similar situation was observed for IgG from patients with multiple sclerosis and HIV-infected patients, which after purification on myelin basic protein (MBP)-Sepharose and RT Sepharose specifically hydrolyze only MBP and RT, respectively. The active sites of all anti-protein abzymes are localized on their light chains, whereas the heavy chain is responsible for the affinity of protein substrates. Interactions of intact globular proteins with both light and heavy chains of abzymes provide the specificity of protein hydrolysis. The affinity of anti-IN and anti-MBP abzymes for intact IN and MBP is approximately 10(2)- to 10(5)-fold higher than for short and long specific and nonspecific OPs. The data suggest that all OPs interact mainly with the light chain of different Abs, which possesses a lower affinity for substrates, and therefore, depending on the OP sequences, their hydrolysis may be less specific or completely nonspecific. The data indicate that the relative activity of Abs not fractionated on specific protein sorbents in the hydrolysis of specific and nonspecific OPs can correspond to an average proteolytic activity of light chains of polyclonal Abs directed against many different proteins. PMID- 22434710 TI - Increasing throughput of surface plasmon resonance-based biosensors by multiple analyte injections. AB - Surface plasmon resonance-based biosensors are now acknowledged as robust and reliable instruments to determine the kinetic parameters related to the interactions between biomolecules. These kinetic parameters are used in screening campaigns: there is a considerable interest in reducing the experimental time, thus improving the throughput of the surface plasmon resonance assays. Kinetic parameters are typically obtained by analyzing data from several injections of a given analyte at different concentrations over a surface where its binding partner has been immobilized. It has been already proven that an iterative optimization approach aiming at determining optimal analyte injections to be performed online can significantly reduce the experimentation time devoted to kinetic parameter determination, without any detrimental effect on their standard errors. In this study, we explore the potential of this iterative optimization approach to further reduce experiment duration by combining it with the simultaneous injection of two analytes. PMID- 22434711 TI - Classifying compound mechanism of action for linking whole cell phenotypes to molecular targets. AB - Drug development programs have proven successful when performed at a whole cell level, thus incorporating solubility and permeability into the primary screen. However, linking those results to the target within the cell has been a major setback. The Phenotype Microarray system, marketed and sold by Biolog, seeks to address this need by assessing the phenotype in combination with a variety of chemicals with known mechanism of action (MOA). We have evaluated this system for usefulness in deducing the MOA for three test compounds. To achieve this, we constructed a database with 21 known antimicrobials, which served as a comparison for grouping our unknown MOA compounds. Pearson correlation and Ward linkage calculations were used to generate a dendrogram that produced clustering largely by known MOA, although there were exceptions. Of the three unknown compounds, one was definitively placed as an antifolate. The second and third compounds' MOA were not clearly identified, likely because the unique MOA was not represented within the database. The availability of the database generated in this report for Staphylococcus aureus ATCC 29213 will increase the accessibility of this technique to other investigators. From our analysis, the Phenotype Microarray system can group compounds with clear MOA, but the distinction of unique or broadly acting MOA at this time is less clear. PMID- 22434712 TI - Effect of the multifunctional proteins RPA, YB-1, and XPC repair factor on AP site cleavage by DNA glycosylase NEIL1. AB - DNA glycosylases are key enzymes in the first step of base excision DNA repair, recognizing DNA damage and catalyzing the release of damaged nucleobases. Bifunctional DNA glycosylases also possess associated apurinic/apyrimidinic (AP) lyase activity that nick the damaged DNA strand at an abasic (or AP) site, formed either spontaneously or at the first step of repair. NEIL1 is a bifunctional DNA glycosylase capable of processing lesions, including AP sites, not only in double stranded but also in single-stranded DNA. Here, we show that proteins participating in DNA damage response, YB-1 and RPA, affect AP site cleavage by NEIL1. Stimulation of the AP lyase activity of NEIL1 was observed when an AP site was located in a 60 nt-long double-stranded DNA. Both RPA and YB-1 inhibited AP site cleavage by NEIL1 when the AP site was located in single-stranded DNA. Taking into account a direct interaction of YB-1 with the AP site, located in single-stranded DNA, and the high affinity of both YB-1 and RPA for single stranded DNA, this behavior is presumably a consequence of a competition with NEIL1 for the DNA substrate. Xeroderma pigmentosum complementation group C protein (XPC), a key protein of another DNA repair pathway, was shown to interact directly with AP sites but had no effect on AP site cleavage by NEIL1. PMID- 22434713 TI - The absence of tertiary interactions in a self-assembled DNA crystal structure. AB - DNA is a highly effective molecule for controlling nanometer-scale structure. The convenience of using DNA lies in the programmability of Watson-Crick base-paired secondary interactions, useful both to design branched molecular motifs and to connect them through sticky-ended cohesion. Recently, the tensegrity triangle motif has been used to self-assemble three-dimensional crystals whose structures have been determined; sticky ends were reported to be the only intermolecular cohesive elements in those crystals. A recent communication in this journal suggested that tertiary interactions between phosphates and cytosine N(4) groups are responsible for intermolecular cohesion in these crystals, in addition to the secondary and covalent interactions programmed into the motif. To resolve this issue, we report experiments challenging this contention. Gel electrophoresis demonstrates that the tensegrity triangle exists in conditions where cytosine PO(4) tertiary interactions seem ineffective. Furthermore, we have crystallized a tensegrity triangle using a junction lacking the cytosine suggested for involvement in tertiary interactions. The unit cell is isomorphous with that of a tensegrity triangle crystal reported earlier. This structure has been solved by molecular replacement and refined. The data presented here leave no doubt that the tensegrity triangle crystal structures reported earlier depend only on base pairing and covalent interactions for their formation. PMID- 22434715 TI - Distinct work-related, clinical and psychological factors predict return to work following treatment in four different cancer types. AB - OBJECTIVE: Many factors influence return to work (RTW) following cancer treatment. However specific factors affecting RTW across different cancer types are unclear. This study examined the role of clinical, sociodemographic, work and psychological factors in RTW following treatment for breast, gynaecological, head and neck, and urological cancer. METHODS: A 12-month prospective questionnaire study was conducted with 290 patients. Cox regression analyses were conducted to calculate hazard ratios (HR) for time to RTW. RESULTS: Between 89-94% of cancer survivors returned to work. Breast cancer survivors took the longest to return (median 30 weeks), and urology cancer survivors returned the soonest (median 5 weeks). Earlier return among breast cancer survivors was predicted by a greater sense of control over their cancer at work (HR 1.2; 95% CI: 1.09-1.37) and by full-time work (HR 2.1; CI: 1.24-3.4). Predictive of a longer return among gynaecological cancer survivors was a belief that cancer treatment may impair ability to work (HR 0.75; CI: 0.62-0.91). Among urological cancer survivors constipation was predictive of longer RTW (HR 0.99; CI: 0.97-1.00), whereas undertaking flexible working was predictive of returning sooner (HR 1.70; CI: 1.07-2.7). Head and neck cancer survivors who perceived greater negative consequences of their cancer took longer to return (HR 0.27; CI: 0.11-0.68). Those reporting better physical functioning returned sooner (HR1.04; CI: 1.01 1.08). CONCLUSION: A different profile of predictive factors emerged for the four cancer types. In addition to optimal symptom management and workplace adaptations, the findings suggest that eliciting and challenging specific cancer and treatment-related perceptions may facilitate RTW. PMID- 22434716 TI - A comparison of attrition rates in patients undergoing sublingual immunotherapy vs subcutaneous immunotherapy. AB - BACKGROUND: Effective allergy immunotherapy (IT) requires patient compliance. Numerous studies have shown high noncompliance rates in patients undergoing IT. For patients enrolled in subcutaneous IT (SCIT), noncompliance rates were noted to range from 11% to 50%, whereas sublingual IT (SLIT) patients had noncompliance rates ranging from 3% to 25%. Comparing noncompliance rates is difficult because noncompliance in SCIT is defined as withdrawal from therapy, whereas in SLIT it is considered poor adherence to daily administration. The aim of this study was to compare attrition rates in patients enrolled in SCIT vs SLIT, as well as major factors leading to termination of IT. METHODS: We retrospectively compared attrition rates, IT duration, and reasons for termination between patients enrolled in SCIT (n = 139) and SLIT (n = 78), over a 4-year period. RESULTS: Attrition rates for SCIT and SLIT were 45% and 41%, respectively (p = 0.669). No significant difference in duration of IT was observed between the groups (<=1 month, p = 0.079; 1-2 months, p = 0.486; 2-3 months, p = 0.165; 3-6 months, p = 0.575; 6-12 months, p = 0.361; 12-24 months, p = 1.000; and >=24 months, p = 0.258). Among reasons cited for discontinuing IT, SCIT patients reported inconvenience (p = 0.001), whereas SLIT patients indicated efficacy concerns (p = 0.022) as the major basis for withdrawal. CONCLUSION: No significant difference was observed in attrition rates between SCIT and SLIT. While there was no significant difference in duration of IT prior to withdrawal, there was a trend toward earlier withdrawal in SCIT patients. The reasons for withdrawal, however, were considerably different between the 2 groups. PMID- 22434717 TI - A combined solid-state NMR and X-ray crystallography study of the bromide ion environments in triphenylphosphonium bromides. AB - Multinuclear ((31)P and (79/81)Br), multifield (9.4, 11.75, and 21.1 T) solid state nuclear magnetic resonance experiments are performed for seven phosphonium bromides bearing the triphenylphosphonium cation, a molecular scaffold found in many applications in chemistry. This is undertaken to fully characterise their bromine electric field gradient (EFG) tensors, as well as the chemical shift (CS) tensors of both the halogen and the phosphorus nuclei, providing a rare and novel insight into the local electronic environments surrounding them. New crystal structures, obtained from single-crystal X-ray diffraction, are reported for six compounds to aid in the interpretation of the NMR data. Among them is a new structure of BrPPh(4), because the previously reported one was inconsistent with our magnetic resonance data, thereby demonstrating how NMR data of non-standard nuclei can correct or improve X-ray diffraction data. Our results indicate that, despite sizable quadrupolar interactions, (79/81)Br magnetic resonance spectroscopy is a powerful characterisation tool that allows for the differentiation between chemically similar bromine sites, as shown through the range in the characteristic NMR parameters. (35/37)Cl solid-state NMR data, obtained for an analogous phosphonium chloride sample, provide insight into the relationship between unit cell volume, nuclear quadrupolar coupling constants, and Sternheimer antishielding factors. The experimental findings are complemented by gauge-including projector-augmented wave (GIPAW) DFT calculations, which substantiate our experimentally determined strong dependence of the largest component of the bromine CS tensor, delta(11), on the shortest Br-P distance in the crystal structure, a finding that has possible application in the field of NMR crystallography. This trend is explained in terms of Ramsey's theory on paramagnetic shielding. Overall, this work demonstrates how careful NMR studies of underexploited exotic nuclides, such as (79/81)Br, can afford insights into structure and bonding environments in the solid state. PMID- 22434718 TI - Conversion of phenolic constituents in aqueous Hamamelis virginiana leaf extracts during fermentation. AB - INTRODUCTION: Hamamelis virginiana, known for its high level of tannins and other phenolics is widely used for treatment of dermatological disorders. Although reports on hydroalcoholic and aqueous extracts from Hamamelis leaf and bark exist, knowledge on fermented leaf preparations and the underlying conversion processes are still scant. OBJECTIVE: Aqueous Hamamelis leaf extracts were monitored during fermentation and maturation in order to obtain an insight into the bioconversion of tannins and other phenolics. METHODOLOGY: Aliquots taken during the production period were investigated by HPLC-DAD-MS/MS as well as GC-MS after derivatisation into the corresponding trimethylsilyl compounds. RESULTS: In Hamamelis leaf extracts, the main constituents exhibited changes during the observational period of 6 months. By successive depside bond cleavage, the gallotannins were completely transformed into gallic acid after 1 month. Although not completely, kaempferol and quercetin glycosides were also converted during 6 months to yield their corresponding aglycones. Following C-ring fission, phloroglucinol was formed from the A-ring of both flavonols. The B-ring afforded 3-hydroxybenzoic acid from quercetin and 3,4-dihydroxybenzoic acid as well as 2 (4-hydroxyphenyl)-ethanol from kaempferol. Interestingly, hydroxycinnamic acids remained almost stable in the same time range. CONCLUSION: The present study broadens the knowledge on conversion processes in aqueous fermented extracts containing tannins, flavonol glycosides and hydroxycinnamic acids. In particular, the analogy between the microbial metabolism of phenolics from fermented Hamamelis extracts, fermented sourdough by heterofermentative lactic acid bacteria or conversion of phenolics by the human microbial flora is indicated. PMID- 22434719 TI - Epidemiology of rhabdoid tumors of early childhood. AB - BACKGROUND: Rhabdoid tumors are a rare and aggressive cancer subtype which is usually diagnosed in early childhood. Little is known about their etiology. The purpose of this study was to describe the epidemiology of rhabdoid tumors and examine their relation to perinatal characteristics. METHODS: We identified 44 atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS) and 61 rhabdoid sarcomas (renal and extra-renal non-CNS tumors) from California Cancer Registry records of diagnoses 1988-2007 among children <6 years of age. We randomly selected 208,178 controls from California birthrolls. Multivariable logistic regression was used to examine associations between rhabdoid tumors and perinatal characteristics. RESULTS: After adjustment for demographic characteristics, low birthweight (<2,500 g) strongly increased risk for developing both rhabdoid sarcomas (OR = 2.43, 95% CI 1.09, 5.41) and AT/RT (OR = 2.99, 95% CI 1.31, 6.84). Both preterm delivery (<37 weeks gestation, OR = 2.63, 95% CI 1.34, 5.17) and late term delivery (>42 weeks, OR = 3.66, 95% CI 1.54, 8.71) also increased risk of rhabdoid sarcomas. Rhabdoid sarcoma cases (OR = 3.08, 95% CI 1.11, 8.55) and AT/RT cases (OR = 3.16, 95% CI 1.23, 8.13) also were more likely to be multiple births. CONCLUSION: The excess of twin pregnancies may suggest an association with infertility treatments. This is the first population based epidemiologic study to examine these rare tumors. PMID- 22434720 TI - A functional network of the tumor suppressors APC, hDlg, and PTEN, that relies on recognition of specific PDZ-domains. AB - APC and PTEN are tumor suppressor proteins that bind through their C-termini to the PDZ domain containing-hDlg scaffolding protein. We have found that co expression of PTEN and hDlg enhanced the negative regulation of the PI3K/Akt pathway by PTEN, indicating the physiologic importance of these interactions. APC and PTEN share other PDZ domain containing-interacting partners, including the MAGI scaffolding proteins and the MAST family of protein kinases. Mutational analysis revealed that the C-terminal PDZ-binding motifs from APC and PTEN were differentially recognized by distinct PDZ domains. APC bound to the three PDZ domains from hDlg, whereas PTEN mainly bound to PDZ-2/hDlg. This indicates the existence of overlapping, but distinct PDZ-domain recognition patterns by APC and PTEN. Furthermore, a ternary complex formed by APC, PTEN, and hDlg was detected, suggesting that hDlg may serve as a platform to bring in proximity APC and PTEN tumor suppressor activities. In line with this, tumor-related mutations targeting the PDZ-2/hDlg domain diminished its interaction with APC and PTEN. Our results expand the PDZ-domain counterparts for the tumor suppressor APC, show that APC and PTEN share PDZ-domain partners but have individual molecular determinants for specific recognition of PDZ domains, and suggest the participation of the tumor suppressors APC, PTEN, and hDlg in PDZ-domain interaction networks which may be relevant in oncogenesis. PMID- 22434721 TI - Lack of lipid phosphate phosphatase-3 in embryonic stem cells compromises neuronal differentiation and neurite outgrowth. AB - BACKGROUND: Bioactive lipids such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) have been recently described as important regulators of pluripotency and differentiation of embryonic stem (ES) cells and neural progenitors. Due to the early lethality of LPP3, an enzyme that regulates the levels and biological activities of the aforementioned lipids, it has been difficult to assess its participation in early neural differentiation and neuritogenesis. RESULTS: We find that Ppap2b(-/-) (Lpp3(-/-) ) ES cells differentiated in vitro into spinal neurons show a considerable reduction in the amount of neural precursors and young neurons formed. In addition, differentiated Lpp3(-/-) neurons exhibit impaired neurite outgrowth. Surprisingly, when Lpp3(-/ ) ES cells were differentiated, an unexpected appearance of smooth muscle actin positive cells was observed, an event that was partially dependent upon phosphorylated sphingosines. CONCLUSIONS: Our data show that LPP3 plays a fundamental role during spinal neuron differentiation from ES and that it also participates in regulating neurite and axon outgrowth. PMID- 22434722 TI - High-performance photoconductive channels based on (carbon nanotube)-(CdS nanowire) hybrid nanostructures. AB - A photoconductive channel based on hybrid nanostructures comprising carbon nanotubes (CNTs) and CdS nanowires is fabricated by a directed assembly strategy and catalyst-assisted chemical vapor deposition (CVD). The photoconductive channels simultaneously exhibit large photocurrent and fast response speed. Furthermore, it can be easily applied to surfaces that are not flat, such as a glass tube. This is a simple but efficient strategy for various optoelectronic applications. PMID- 22434723 TI - Crystal structure of the TLDc domain of oxidation resistance protein 2 from zebrafish. AB - The oxidation resistance proteins (OXR) help to protect eukaryotes from reactive oxygen species. The sole C-terminal domain of the OXR, named TLDc is sufficient to perform this function. However, the mechanism by which oxidation resistance occurs is poorly understood. We present here the crystal structure of the TLDc domain of the oxidation resistance protein 2 from zebrafish. The structure was determined by X-ray crystallography to atomic resolution (0.97A) and adopts an overall globular shape. Two antiparallel beta-sheets form a central beta sandwich, surrounded by two helices and two one-turn helices. The fold shares low structural similarity to known structures. PMID- 22434724 TI - Efficacy of NVC-422 against Staphylococcus aureus biofilms in a sheep biofilm model of sinusitis. AB - BACKGROUND: Bacterial biofilms are a major obstacle in management of recalcitrant chronic rhinosinusitis. NVC-422 is a potent, fast-acting, broad-spectrum, nonantibiotic, antimicrobial with a new mechanism of action effective against biofilm bacteria in in vitro conditions. The aim of this study was to investigate the safety and efficacy of NVC-422 as local antibiofilm treatment in a sheep model of rhinosinusitis. METHODS: After accessing and occluding frontal sinus ostia in 24 merino sheep via staged endoscopic procedures, S. aureus clinical isolate was instilled in frontal sinuses. Following biofilm formation, ostial obstruction was removed and sinuses irrigated with 0.1% and 0.5% NVC-422 in 5 mM acetate isotonic saline at pH 4.0. Sheep were monitored for adverse effects and euthanized 24 hours after treatment. Frontal sinuses were assessed for infection and changes in mucosa after the treatment. S. aureus biofilms were identified with Baclight-confocal scanning microscopy protocol and the biofilm biomass assayed by applying the COMSTAT2 program to recorded image stacks. RESULTS: After 2 irrigations with 0.1% NVC-422, S. aureus biofilm biomass was reduced when compared to control sinuses (p = 0.0001), though this effect was variable in samples. NVC-422 0.5% solution irrigations reduced biofilm even more significantly and consistently over all samples (p < 0.0001). NVC-422 0.5% was also more effective than 0.1% NVC-422, vehicle control, and normal saline sinus irrigations in reducing biofilm biomass (p < 0.05 for all subgroups). No adverse events were observed in sheep after sinus irrigations with 0.1% and 0.5% NVC-422 solutions. CONCLUSION: NVC-422 is an effective topical agent against S. aureus biofilms, with dose-dependent efficacy in this animal model of biofilm-associated sinusitis. PMID- 22434728 TI - Interatrial mechanical dyssynchrony shown by tissue doppler imaging during atrial flutter. AB - Although regular supraventricular tachycardia is traditionally classified on the basis of P-wave morphology, diagnostic accuracy is limited to information obtained from surface electrocardiography. Intracardiac electrophysiology is a conclusive although invasive diagnostic method. We report a case of regular supraventricular tachycardia with a heart rate of 162 bpm. M-mode echocardiography of the interatrial septum clarified both the atrial rate and the ventricular response ratio. Tissue Doppler M-mode imaging demonstrated the delay between the posterior wall motion of the left and right atrium. Although it deserves further study, transthoracic echocardiography may provide useful information in addition to electrocardiography. PMID- 22434729 TI - Label-free detection of nanomolar unmodified single- and double-stranded DNA by using surface-enhanced Raman spectroscopy on Ag and Au colloids. AB - Unlabelled single- and double-stranded DNA (ssDNA and dsDNA, respectively) has been detected at concentrations >=10(-9) M by surface-enhanced Raman spectroscopy. Under appropriate conditions the sequences spontaneously adsorbed to the surface of both Ag and Au colloids through their nucleobases; this allowed highly reproducible spectra with good signal-to-noise ratios to be recorded on completely unmodified samples. This eliminated the need to promote absorption by introducing external linkers, such as thiols. The spectra of model ssDNA sequences contained bands of all the bases present and showed systematic changes when the overall base composition was altered. Initial tests also showed that small but reproducible changes could be detected between oligonucleotides with the same bases arranged in a different order. The spectra of five ssDNA sequences that correspond to different strains of the Escherichia coli bacterium were found to be sufficiently composition-dependent so that they could be differentiated without the need for any advanced multivariate data analysis techniques. PMID- 22434730 TI - Caspases cleave and inhibit the microRNA processing protein DiGeorge Critical Region 8. AB - DGCR8 (DiGeorge Critical Region 8) is an essential microRNA (miRNA) processing protein that recognizes primary transcripts of miRNAs (pri-miRNAs) and triggers their cleavage by the Drosha nuclease. We previously found that Fe(III) heme binds and activates DGCR8. Here we report that in HeLa cells, DGCR8 undergoes two proteolytic events that produce two C-terminal fragments called DGCR8(C1) and DGCR8(C2) , respectively. DGCR8(C2) accumulates during apoptosis and is generated through cleavage by a caspase. The caspase cleavage site is located in the central loop of the heme-binding domain. Cleavage of DGCR8 by caspase-3 in vitro results in loss of the otherwise tightly bound Fe(III) heme cofactor, dissociation of the N- and C-terminal proteolytic fragments, and inhibition of the pri-miRNA processing activity. These results reveal an intrinsic mechanism in the DGCR8 protein that seems to have evolved for regulating miRNA processing via association with Fe(III) heme and proteolytic cleavage by caspases. Decreased expression of miRNAs has been observed in apoptotic cells, and this change was attributed to caspase-mediated cleavage of a down-stream miRNA processing nuclease Dicer. We suggest that both the Drosha and Dicer cleavage steps of the miRNA maturation pathway may be inhibited in apoptosis and other biological processes where caspases are activated. PMID- 22434731 TI - A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low-grade glioma (LGG). AB - BACKGROUND: To determine the toxicity and efficacy of rapamycin and erlotinib for the treatment of recurrent pediatric low-grade gliomas (LGGs). METHODS: Patients <21 years of age with recurrent LGGs who had failed conventional treatment were eligible, including those with NF1. The treatment consisted of two phases, a feasibility portion which assessed the toxicity of erlotinib at 65 mg/m(2) /day once daily and rapamycin at 0.8 mg/m(2) /dose twice daily for 28 consecutive days. RESULTS: Nineteen (19) patients, median age of 8 years, with recurrent LGGs received the two-drug regimen. Eight (8) of the patients had NF1. The combination of erlotinib and rapamycin was well tolerated and no patient was removed from study due to toxicity. All 19 patients were evaluable for response and one child, with NF1, had a partial response to treatment. Six (6) patients received the planned 12 courses of treatment. The reasons for stoppage of therapy before 1 year of treatment were poor compliance (1), parental desire for withdrawal (1), persistent vomiting which pre-dated initiation of therapy (1), and radiographic progression (10). In those patients with stabilization of disease for 12 months or greater, 3 stayed on therapy and ultimately developed progressive disease, and one patient stopped therapy at 12 months and progressed. Two (2) patients, both with NF1, have had >1 year disease control. CONCLUSIONS: The combination of rapamycin and erlotinib is well tolerated in children with LGGs. Objective responses were infrequent, although there was prolonged disease stabilization in some patients with LGGs, especially in two children with NF1. PMID- 22434732 TI - Myogenic waves and myogenic programs during Xenopus embryonic myogenesis. AB - Although Xenopus is a key model organism in developmental biology, little is known about the myotome formation in this species. Here, we assessed the expression of myogenic regulatory factors of the Myod family (MRFs) during embryonic development and revealed distinct MRF programs. RESULTS: The expression pattern of each MRF during embryonic development highlights three successive myogenic waves. We showed that a first median and lateral myogenesis initiates before dermomyotome formation: the median cell population expresses Myf5, Myod, and Mrf4, whereas the lateral one expresses Myod, moderate levels of Myogenin and Mrf4. The second wave of myoblasts arising from the dermomyotome is characterized by the full MRF program expression, with high levels of Myogenin. The third wave is revealed by Myf5 expression in the myotome and could contribute to the formation of plurinucleated fibers at larval stages. Furthermore, Myf5- or Myod expressing anlagen are identified in craniofacial myogenesis. CONCLUSIONS: The first median and lateral myogenesis and their associated MRF programs have probably disappeared in mammals. However, some aspects of Xenopus myogenesis have been conserved such as the development of somitic muscles by successive myogenic waves and the existence of Myf5-dependent and -independent lineages. PMID- 22434733 TI - Interferon regulatory factor-1 as a positive regulator for high glucose-induced proliferation of vascular smooth muscle cells. AB - High glucose-induced proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development of diabetic vascular diseases. However, molecular mediators responding for the proliferation of VSMCs remain to be determined. In this study, VSMCs were isolated from the rat thoracic aorta, and two cell models with Irf-1 knockdown and overexpression were established by transfecting cells with pGCsi-FU-Irf-1 and pGC-FU-Irf-1, respectively. Subsequently, high glucose was added to cells to induce proliferation. Proliferation assays were performed to see whether Irf-1 was involved in high glucose-induced proliferation of VSMCs. In addition, the expression of Irf-1 was detected in VSMCs stimulated with high glucose and the thoracic aorta of diabetic rats to confirm the relationship between Irf-1 expression and the proliferation of hyperglycemia-dependent VSMCs. The results showed that Irf-1 expression was significantly higher in the thoracic aorta of diabetic rats and VSMCs stimulated with high glucose than that in nondiabetic rats and untreated cells. Overexpression of Irf-1 accelerated the proliferation of VSMCs, and down regulation of Irf-1 expression significantly depressed the proliferative ability of VSMCs under high-glucose conditions, indicating that Irf-1 was a positive regulator for high glucose-induced proliferation of VSMCs. It could be presumed that Irf-1 is associated with the accelerated proliferation of VSMCs in diabetic vascular diseases and may prove to be a potential target gene for disease treatment. PMID- 22434735 TI - Study design and baseline description of the BMI2 trial: reducing paediatric obesity in primary care practices. AB - OBJECTIVES: This study will test the efficacy of motivational interviewing (MI) conducted by primary care providers and dieticians among children ages 2-8 years old with a body mass index (BMI) >= 85th and <= 97th percentile. METHODS: Forty two practices from the American Academy of Pediatrics, Pediatric Research in Office Settings Network were assigned to one of three groups. Group 1 (usual care) measures BMI percentile at baseline, and at 1- and 2-year follow-ups and receives standard health education materials. Group 2 providers deliver three proactive MI counselling sessions with a parent of the index child in Year 1 and one additional 'booster' visit in Year 2. Group 3 adds six MI counselling sessions from a trained dietician. The primary outcome is the child's BMI percentile at 2-year follow-up. Secondary outcomes include parent report of the child's screen time, physical activity, intake of fruits and vegetables, and sugar-sweetened beverages. RESULTS: We enrolled 633 eligible children whose mean BMI percentile was 92.0 and mean age of 5.1. The cohort was 57% female. Almost 70% of parents reported a household income of >= $40,000 per year, and 39% had at least a college education. The cohort was 63% white, 23% Hispanic, 7% black and 7% Asian. Parent self-reported confidence that their child will achieve a healthy weight was on average an 8 (out of 10). CONCLUSION: To date, several aspects of the study can inform similar efforts including our ability to use volunteer clinicians to recruit participants and their willingness to dedicate their time, without pay, to receive training in MI. PMID- 22434736 TI - Effects of a randomized maintenance intervention on adiposity and metabolic risk factors in overweight minority adolescents. AB - OBJECTIVE: The objective of this study was to assess the effects of a maintenance programme (monthly newsletters vs. monthly group classes and telephone behavioural sessions) on obesity and metabolic disease risk at 1 year in overweight minority adolescents. METHODS: After a 4-month nutrition and strength training intervention, 53 overweight Latino and African-American adolescents (15.4 +/- 1.1 years) were randomized into one of two maintenance groups for 8 months: monthly newsletters (n = 23) or group classes (n = 30; monthly classes + individualized behavioural telephone sessions). The following outcomes were measured at months 4 (immediately following the intense intervention) and 12: height, weight, blood pressure, body composition via BodPodTM (Life Measurement Instruments, Concord, CA, USA), lipids and glucose/insulin indices via frequently sampled intravenous glucose tolerance test. RESULTS: There were no significant group by time interactions for any of the health outcomes. There were significant time effects in several outcomes for both groups from months 4 to 12: bench press and leg press decreased by 5% and 14%, respectively (P = 0.004 & P = 0.01), fasting insulin and acute insulin response decreased by 26% and 16%, respectively (P < 0.001 & P = 0.046); while high-density lipoprotein cholesterol and insulin sensitivity improved by 5% and 14% (P = 0.042 & P = 0.039). CONCLUSIONS: Newsletters as opposed to group classes may suffice as follow-up maintenance programmes to decrease type 2 diabetes and cardiovascular risk in overweight minority adolescents. PMID- 22434737 TI - Efficacy of U.S. paediatric obesity primary care guidelines: two randomized trials. AB - OBJECTIVE: The objective of this study was to examine the efficacy of U.S. primary care paediatric obesity treatment recommendations, within two randomized trials. METHODS: Between November 2005 to September 2007, 182 families (children aged 4-9 years, body mass index [BMI] >=85th percentile) were recruited for two separate trials and randomized within trial to a 6-month intervention. Each trial had one intervention that increased child growth-monitoring frequency and feedback to families (GROWTH MONITORING). Each trial also had two interventions, combining GROWTH MONITORING with an eight-session, behavioural, parent-only intervention targeting two energy-balance behaviours (Trial 1: reducing snack foods and sugar-sweetened beverages [DECREASE], and increasing fruits, vegetables and low-fat dairy [INCREASE]; Trial 2: decreasing sugar-sweetened beverages and increasing physical activity [TRADITIONAL] and increasing low-fat milk consumption and reducing television watching [SUBSTITUTES]). Child standardized BMI (ZBMI) and energy intake were assessed at 0, 6 and 12 months. RESULTS: In both trials, main effects of time were found for ZBMI, which decreased at 6 and 12 months (P < 0.01). In Trial 1, ZBMI reduced from 0 to 6 months, which was maintained from 6 to 12 months (DeltaZBMI 0 to 12 months = -0.12 +/- 0.22). In Trial 2, ZBMI reduced from 0 to 6 and from 6 to 12 months (DeltaZBMI 0-12 months = -0.16 +/- 0.31). For energy intake, main effects of time were found in both trials and intake reduced from 0 to 6 months (P < 0.05), with Trial 1 reducing intake from 0 to 12 months (P < 0.05). CONCLUSIONS: All interventions improved weight status. Future research should examine effectiveness and translatability of these approaches into primary care settings. PMID- 22434738 TI - Circulating follistatin in the human foetus at term birth. AB - BACKGROUND: Prenatal weight partitioning is gender specific, and infants born small for gestational age (SGA) have a lower fat mass and a lower fat-free mass than infants born appropriate for gestational age (AGA). Follistatin is an adipokine with adipogenic properties. OBJECTIVES: We examined whether follistatin circulates in the human foetus at term birth and, if so, whether cord blood follistatin relates to birthweight and neonatal body composition. METHODS: The study population was comprised of 248 term newborns (128 girls, 120 boys; 133 AGA, 115 SGA). The main outcome measures used for the study were birthweight, follistatin and insulin in umbilical cord serum, and neonatal body composition by absorptiometry. RESULTS: Follistatin was detectable in all cord serum samples. Cord follistatin concentrations were similar in girls and boys, being about 25% higher (P < 0.001) in SGA than AGA infants. In SGA infants, higher follistatin concentrations related to lower fat mass. CONCLUSION: [corrected] Follistatin is detectable in the circulation of the human foetus at term birth. The circulating levels of follistatin, an adipogenic adipokine, are higher in SGA than AGA infants, particularly so in SGA infants with a lower fat mass. PMID- 22434739 TI - Relation between sleep duration and BMI varies by age and sex in youth age 8-19. AB - OBJECTIVES: The objectives of this study were to (i) compare the strength of associations between sleep duration and body mass index (BMI) in middle childhood, and early and late adolescence; (ii) determine whether sleep duration in middle childhood predicts BMI in early or late adolescence; and (iii) examine the consistency of these associations by sex. METHODS: Subjects included 313 children/adolescents aged 8-19 participating in a longitudinal cohort study on sleep and health. Participants were assessed at three time points approximately 4 years apart: ages 8-11, 12-15 and 16-19. BMI z-score (BMIz) was calculated using age and sex normative data from the Centers for Disease Control. Sleep duration was reported by the parent (ages 8-15) or the adolescent (ages 16-19). RESULTS: [corrected] Half of the participants were male and 79% were Caucasian. Sleep duration had a negative linear association with BMIz for boys but not girls, and the magnitude of this association decreased with age. Sleep duration at age 8-11 predicted BMIz in early and late adolescence for boys but not girls, and associations were largely attenuated after adjusting for BMIz at age 8-11. The strongest predictor of adolescent BMIz was BMIz at age 8-11 for both boys and girls. CONCLUSION: We conclude that the association between sleep duration and BMIz varies by sex and age, with stronger associations in boys and in middle childhood compared with adolescence. PMID- 22434740 TI - Breakfast consumption and meal frequency interaction with childhood obesity. AB - OBJECTIVES: Increased meal frequency and daily breakfast consumption have been inversely associated with childhood obesity. The purpose of the study was to examine the possible interaction effect between meal frequency and breakfast consumption on childhood obesity. METHODS: Seven hundred children (323 boys) aged 10-12 years were enrolled in this cross-sectional study. Several lifestyle, dietary and physical activity characteristics were recorded with food frequency and physical activity questionnaires. Body height and weight were measured and body mass index was calculated in order to classify children as overweight or obese (International Obesity Task Force classification). Multiple logistic regression analysis was used in order to evaluate the interaction between daily breakfast intake and more than three meals per day consumption with overweight or obesity. RESULTS: Of the children, 27.6% and 9.0% were overweight and obese, respectively. Moreover, 60.2% consumed three or more meals per day and 62.7% consumed breakfast in a regular daily basis. Children who consumed more than three meals per day and also consumed breakfast daily, were two times less likely to be overweight or obese (adjusted odds ratio: 0.49, 95% confidence interval: 0.27-0.88). CONCLUSION: A combined higher meal frequency and daily breakfast consumption dietary pattern may prevent overweight and obesity in children. PMID- 22434741 TI - Physical activity fluctuations and body fat during adolescence. AB - OBJECTIVE: The objective of the study was to test the hypothesis that greater fluctuations in physical activity lead to greater increases in body fat during adolescence. METHODS: Seven hundred fifty-six adolescents in Montreal, Canada, aged 12-13 years at baseline, completed a 7-d physical activity recall questionnaire every 3 months over 5 years. Body mass index (BMI), waist circumference, and triceps and subscapular skinfold thickness were measured at baseline and at the end of follow-up. Subject-specific linear regressions, expressing physical activity as a function of time, were fitted and physical activity fluctuation scores were obtained by averaging the absolute values of regression residuals. The association between body fat after 5 years and the physical activity fluctuation score was assessed in linear regressions adjusting for baseline body fat, average number of physical activity sessions per week, diet and sociodemographic variables. RESULTS: Among boys, there were statistically significant positive associations between physical activity fluctuation and BMI (beta, 95% confidence interval: 0.12, 0.02-0.21) and triceps skinfold (0.40, 0.17-0.63). The associations with waist circumference or subscapular skinfold were not statistically significant (0.22, -0.04-0.49; 0.13, 0.05-0.32, respectively). In girls, there were statistically significant negative associations between physical activity fluctuation and BMI (-0.12, -0.20 to 0.03), waist circumference (-0.54, -0.91 to -0.17), subscapular skinfold (-0.41, 0.56 to -0.26) and triceps skinfold (-0.22, -0.38 to -0.05). CONCLUSION: Physical activity fluctuations appear to affect body fat during adolescence. Sex-specific interventions may be needed given that greater physical activity fluctuations seem unfavourable for boys and beneficial for girls. PMID- 22434742 TI - A recess intervention to promote moderate-to-vigorous physical activity. AB - BACKGROUND: Schools provide a prime environment for interventions that attempt to increase physical activity and prevent obesity. OBJECTIVE: This study examined the effect of a 30-min, structured recess using 22 games of known energy expenditure on moderate-to-vigorous physical activity when compared to free play implemented with third graders from two elementary schools over 9 weeks. METHODS: Moderate-to-vigorous physical activity and other cardiovascular risk factors were assessed pre- and post-intervention in 27 children. RESULTS: Moderate-to-vigorous physical activity during recess increased significantly in intervention school children from 6.9 +/- 0.8 to 14.9 +/- 0.9 min pre- and post-intervention, respectively (adjusted mean change 8.0 +/- 1.1; P < 0.0001), with no differences by gender or body mass index (BMI). In-school, moderate-to-vigorous physical activity also increased significantly more for intervention compared to control children (adjusted mean change 14 +/- 4 min vs. 3 +/- 3 min; P = 0.014, respectively). CONCLUSION: There was no significant difference in BMI and cardiovascular risk factors. A structured recess is feasible to implement and can significantly increase moderate-to-vigorous physical activity. PMID- 22434743 TI - Synthesis of sulfondiimines by N-chlorosuccinimide-mediated oxidative imination of sulfiliminium salts. PMID- 22434744 TI - Psychometric properties of the Spanish version of the Health-Promoting Lifestyle Profile II. AB - The Health-Promoting Lifestyle Profile II (HPLPII) has been psychometrically validated across several linguistic and cultural groups; however the Spanish version has not been psychometrically tested for the Spanish population. The purpose of this research was to evaluate the reliability and factor structure of the Spanish version of the HPLPII for Spanish people. Principal component analysis (PCA) revealed that a six-component model for 44 items accounted for 40% of the variance, and the scale had an internal consistency of .87. Confirmatory factor analysis demonstrated that a better fit of the six-component structure emerged from the PCA than from the model proposed in the original version of the HPLPII, suggesting that the health-promoting lifestyle might be sensitive to context and culture. PMID- 22434745 TI - Simulations of substrate transport in the multidrug transporter EmrD. AB - EmrD is a multidrug resistance (MDR) transporter from Escherichia coli, which is involved in the efflux of amphipathic compounds from the cytoplasm, and the first MDR member of the major facilitator superfamily to be crystallized. Molecular dynamics simulation of EmrD in a phospholipid bilayer was used to characterize the conformational dynamics of the protein. Motions that support a previously proposed lateral diffusion pathway for substrate from the cytoplasmic membrane leaflet into the EmrD central cavity were observed. In addition, the translocation pathway of meta-chloro carbonylcyanide phenylhydrazone (CCCP) was probed using both standard and steered molecular dynamics simulation. In particular, interactions of a few specific residues with CCCP have been identified. Finally, a large motion of two residues, Val 45 and Leu 233, was observed with the passage of CCCP into the periplasmic space, placing a lower bound on the extent of opening required at this end of the protein for substrate transport. Overall, our simulations probe details of the transport pathway, motions of EmrD at an atomic level of detail, and offer new insights into the functioning of MDR transporters. PMID- 22434746 TI - Prospectively examining physical activity in young adult survivors of childhood cancer and healthy controls. AB - BACKGROUND: This study compares young adult survivors of childhood cancer (YASCC) and young adults without a history of serious illness/injury on physical activity levels and examines psychological predictors of physical activity in survivors over a 2-month period. PROCEDURE: YASCC participants (n = 117) and healthy controls (n = 148), ages 18-30, recruited during cancer survivorship clinic or primary care clinics completed self-report measures of physical activity, health problems, psychological distress, and health beliefs (Health Perceptions, Satisfaction with Healthcare, Cognitive Competence, and Autonomy). Survivorship providers completed ratings of health problems and treatment intensity for survivors. RESULTS: Survivors had significantly lower levels of physical activity than controls. Family income, survivor-reported health problems and less positive health beliefs were associated with lower rates of physical activity. Provider reported survivor health problems and ratings of cancer treatment intensity were not related to survivor physical activity. Less positive survivor beliefs about their cognitive competence predicted survivor physical activity 2 months later after accounting for other pertinent demographic, medical and psychological variables. CONCLUSIONS: YASCC were significantly less active than healthy controls. YASCC with more self-identified health problems and negative beliefs about their cognitive competence were less physically active. Beliefs about their health and cognitive competencies may be viable areas for assessment and intervention in order to promote increased engagement in physical activity. PMID- 22434747 TI - Sensitive non-invasive circulating markers in paediatric non-alcoholic fatty liver disease. PMID- 22434748 TI - Shifting curves? Trends in thinness and obesity among Australian youth, 1985 to 2010. AB - OBJECTIVE: To describe 25-year trends in the prevalence of <=Grade 2 thinness and obesity among Australian children by sex, age and socioeconomic (SES) background. METHODS: Cross-sectional surveys of New South Wales school-aged children aged 6.0 16.9 years conducted in 1985-1997-2004-2010 (n = 19 434). Height/weight were measured, and thinness and obesity were defined by international standards. SES was derived from children's residential postcode using the Australian Bureau of Statistics' Index of Relative Socioeconomic Disadvantage, most proximal to the survey year. RESULTS: Since 1985, the prevalence of thinness has not varied by survey year. Age was not associated with thinness; however, thinness was lower among middle SES boys, compared with high SES (OR: 0.45, 95%CI: 0.21, 0.97). The prevalence of obesity trebled between 1985 and 1997 (1.7% vs. 5.1% P = 0.000); however, since 1997, obesity prevalence has not significantly changed. Since 1997, obesity was higher among younger compared with older girls (OR: 2.11, 95%CI: 1.48, 3.00) and SES was inversely associated with obesity in boys (OR: 2.05, 95%CI: 1.44, 2.92) and girls (OR: 1.86, 95%CI: 1.27, 2.74). CONCLUSIONS: The apparent plateau in child obesity is a welcome finding; however, the SES gradients are of concern. If the obesity stabilization is associated with the impact of multiple lifestyle behavioural interventions, the findings suggest obesity programmes have done 'no harm', but potentially the dose/delivery of interventions has not been sufficient or appropriate to reduce child obesity levels. PMID- 22434749 TI - Birth weight, early weight gain and pubertal maturation: a longitudinal study. AB - OBJECTIVE: To investigate the effect of birth weight and early weight gain on the timing of various measures of puberty in both girls and boys. METHODS: A total of 856 newborns enrolled in the North Carolina Infant Feeding Study were followed to age 5 years, with 600 children followed up at adolescence. Birth weight was obtained from medical records and children were weighed at study visits until age 5 years; gains in standardized weights were calculated over four early age intervals: 0-6 months, 6-12 months, 1-2 years and 2-5 years. Age at menarche in girls and age at advanced Tanner stages in both girls and boys were reported by adolescents and their parents. Survival models were used to analyse the effects of birth weight and early weight gain on these outcomes. RESULTS: Girls with higher birth weight and greater weight gains during the four early age intervals were younger when they reached menarche and advanced Tanner stages; boys with greater early weight gains also were younger when they reached advanced Tanner stages, but few of these effects were statistically significant. CONCLUSIONS: Higher birth weights and greater weight gains during infancy and early childhood can lead to earlier sexual maturation in girls. PMID- 22434750 TI - Self-reported waist circumference: a screening tool for classifying children with overweight/obesity and cardiometabolic risk factor clustering. AB - OBJECTIVES: The objectives of this study were twofold - (i) to assess the agreement between self-reported waist circumference (SRWC) and assessor measured waist circumference (MWC) and (ii) to evaluate the diagnostic ability of SRWC for classifying (i) a clustering of cardiometabolic risk factors (CMRFs) and (ii) overweight/obese status in Hong Kong Chinese children aged 6-18 years. METHODS: A cross-sectional study with cluster random sampling was conducted. A self administrated questionnaire, which included demographic data, body weight, body height and waist circumference, was given to children to bring home for completion. Children were asked to return the questionnaire and fast themselves for at least 8 h on the day of the survey. Anthropometric measurements and blood pressure were taken by trained research staff and fasting blood samples were collected for measurements of fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. RESULTS: A total of 515 boys and 711 girls were included in the data analysis. Agreement between SRWC and MWC was assessed by intra-class correlation coefficient and it ranged from 0.77 to 0.87. The ability of sex-specific SRWC values to classify children with a clustering of CMRFs and overweight/obesity exhibited moderately high to high sensitivity and specificity, and the area under the receiver operating characteristics ranged from acceptable to excellent (from 0.76 to 0.84). CONCLUSIONS: SRWC has good agreement with MWC and could be used as a screening tool to classify children with a clustering of CMRFs and overweight/obesity status in Hong Kong Chinese children. PMID- 22434751 TI - What would Batman eat?: priming children to make healthier fast food choices. AB - BACKGROUND: Fast food patronage is a frequent reality for many children and their parents. Although there are increasingly healthier alternatives for popular menu items (apple slices instead of French fries), they are infrequently selected. OBJECTIVES: We investigated whether either of two priming tactics - the priming of a role model's food choices or the priming of healthy foods - could influence children to make healthier fast food choices. METHODS: In the priming model condition, 22 children (ranging in age from 6 to 12 years) were presented with 12 photos of 6 admirable and 6 less admirable models and asked, 'Would this person order apple fries or French fries?' In the health prime condition, the same children were shown 12 photos of 6 healthy foods and 6 less healthy foods and asked to indicate if each food was healthy or unhealthy. RESULTS: When children were asked what various admirable people - such as Batman or Spiderman - would eat, 45% chose apple slices over French fries, which was higher than the health prime (P < 0.001) or the control condition (P < 0.001). CONCLUSIONS: Advising a parent to ask their child 'What would Batman (or another admired character or person) eat?' might be an easy step to take in what could be a healthier fast food world. PMID- 22434752 TI - Maternal depression and child BMI: longitudinal findings from a US sample. AB - OBJECTIVE: To examine the association between maternal depression and child body mass index (BMI) from Kindergarten (K) to fifth grade. METHODS: Analysis of four waves of data from the Early Childhood Longitudinal Study - Kindergarten spanning K to fifth grade. Maternal depressive symptoms (MDSs) were measured by a brief version of the Center for Epidemiological Studies Depression scale. Data were analyzed using multiple regression analyses, adjusting for key covariates and potential confounders. The analytic sample was restricted to children of normal birth weight. RESULTS: The relationship between MDS and child BMI varies by child gender and age. Among girls, severe MDS at K was related to lower BMI at third grade (but not later at fifth grade) and to an increase in BMI from K to third and K to fifth grades. Among boys, severe MDS at K was related to higher boys' BMI at fifth grade. When severe MDS occurred at third grade, it was related to higher BMI at fifth grade among girls whereas no statistically significant relationship was found for boys. Low levels of physical activity in comparison to peers at fifth grade and more screen time on weekends at third grade are likely mediators of the relationship between MDS and child BMI among girls, while among boys the relationship appears to be mediated by unhealthy eating habits. CONCLUSIONS: Our findings, indicating developmental and gender differences in the relationship between maternal depression and child BMI, if confirmed, suggest that interventions addressing maternal depression may have concomitant impact on childhood obesity. PMID- 22434753 TI - Gestational weight gain and predicted changes in offspring anthropometrics between early infancy and 3 years. AB - OBJECTIVE: To determine how gestational weight gain (GWG), categorized using the 2009 Institute of Medicine recommendations, relates to changes in offspring weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length z-scores (WLZ) between early infancy and 3 years. METHODS: Women with singleton infants were recruited from the third cohort of the Pregnancy, Infection, and Nutrition Study (2001-2005). Term infants with at least one weight or length measurement during the study period were included (n = 476). Multivariable linear mixed effects regression models estimated longitudinal changes in WAZ, LAZ and WLZ associated with GWG. RESULTS: In early infancy, compared with infants of women with adequate weight gain, those of women with excessive weight gains had higher WAZ, LAZ and WLZ. Excessive GWG >= 200% of the recommended amount was associated with faster rates of change in WAZ and LAZ and noticeably higher predicted mean WAZ and WLZ that persisted across the study period. CONCLUSIONS: GWG is associated with significant differences in offspring anthropometrics in early infancy that persisted to 3 years of age. More longitudinal studies that utilize maternal and paediatric body composition measures are necessary to understand the nature of this association. PMID- 22434754 TI - The contribution of parental BMI to the metabolic health of their offspring: a longitudinal cohort study (EarlyBird 55). AB - OBJECTIVE: The objective of this study was to establish the extent to which parental factors influence the metabolic health of their offspring. DESIGN: The study was designed as a prospective longitudinal cohort study SUBJECTS: The study's subjects were 226 healthy trios from a 1995 to 1996 birth cohort randomly recruited in the city of Plymouth, UK MEASUREMENTS: Body mass index (BMI) and metabolic z-score (derived from natural log HOMA-IR, triglycerides, total/high density lipoprotein cholesterol ratio), measured at nine annual time points, from 5 to 13 years. RESULTS: As expected, the metabolic z score was closely related to BMI in both genders and at all ages (r = 0.40-0.57, P < 0.001). Accordingly, there were large and significant differences in the metabolic z-score between children categorized as normal weight or overweight/obese. At 13 years, for example, the metabolic z score of the overweight/obese girls was 14-fold greater than that of the normal-weight girls (P < 0.001). However, parental BMI and metabolic status had little effect on these differences. Indeed, mixed effects modelling showed that, as the child's BMI increased, so the influence of parental factors became less relevant. Time-lag analyses confirmed that weight gain preceded metabolic disturbances in the children. CONCLUSION: The impact of obesity on the metabolic health of contemporary children is a function of their own weight gain, rather than that of their parents, and is therefore potentially preventable. PMID- 22434755 TI - The association between childhood overweight and obesity and otitis media. AB - OBJECTIVE: The objective of this study was to examine the association between otitis media and childhood obesity in a population-based sample of elementary school children in the Canadian province of Nova Scotia. METHODS: The study design is a prospective cohort study, linking data from a population-based survey of Grade 5 students (aged 10-11 years) in the Canadian province of Nova Scotia in 2003 with Nova Scotia administrative health data. Measured body mass index was used to define weight status based on the age- and gender-specific cut-off points of the International Obesity Task Force. Health administration data for each child was linked via Health Card numbers. The primary outcome was healthcare utilization (physician visits and costs) for suppurative otitis media (International Classification of Diseases [ICD]9: 382; ICD10: H65-66) with no previous diagnosis of otitis in the last 30 days. RESULTS: Relative to normal weight children, obese children had more healthcare provider contacts for otitis media (adjusted incidence rate ratio 2.03, 95% confidence interval [CI] 1.66 2.49), incurred more costs per otitis media-related visit ($47 vs. $24, P = 0.0001) and had higher odds to have repeated otitis media (adjusted odds ratio 2.27, 95% CI 1.54-3.35). Socioeconomic factors, a history of breastfeeding, presence of an allergic disorder or chronic adenoid/tonsil disorder did not change the association between obesity and otitis media. CONCLUSION: There is a clear association between childhood obesity and otitis media that cannot be explained by confounding by socioeconomic factors or clinically associated disorders. PMID- 22434756 TI - Influence of elevated liver fat on circulating adipocytokines and insulin resistance in obese Hispanic adolescents. AB - OBJECTIVE: We performed this study to examine the metabolic differences arising from higher liver fat accumulation in obese Hispanic adolescents, with a particular focus on circulating levels of adipocytokines and insulin resistance. METHODS: Forty-one obese Hispanic adolescents (15.3 +/- 1.0 years, body mass index percentile: 97.0 +/- 3.9) were assessed for: visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and hepatic fat fraction (HFF) by magnetic resonance imaging; fasting measures of serum glucose, insulin and adipocytokines; homeostasis model assessment of insulin resistance (HOMA-IR); and insulin sensitivity (SI) and the acute insulin response to glucose (AIR) by intravenous glucose tolerance test. Subjects with normal levels of HFF (below 5%; n = 25) were compared to those with HFF > 5% (n = 16). RESULTS: The two groups differing in HFF were similar for total body fat, VAT and SAT. The group with HFF > 5% had significantly (P < 0.05) higher interleukin-8 (IL-8) (6.1 +/- 1.6 vs. 3.2 +/- 0.4 pg mL(-1) ), NGF (30.2 +/- 9.9 vs. 13.9 +/- 1.6 pg mL(-1) ), HOMA-IR (8.8 +/- 1.1 vs. 5.5 +/- 0.5), AIR (1869 +/- 206 vs. 1092 +/- 165) and a tendency for lower SI (1.2 +/- 0.4 vs. 2.1 +/- 0.3; P = 0.06), with no significant differences in any of other factors measured. CONCLUSIONS: These data suggest that elevated liver fat is most closely associated with elevated serum IL-8 and NGF levels as well as increased AIR and HOMA-IR. These elevated factors may play significant roles in the metabolic abnormalities associated with elevated liver fat in obese Hispanics. PMID- 22434757 TI - Serum protein N-glycosylation in paediatric non-alcoholic fatty liver disease. AB - OBJECTIVE: We have previously shown the potential of glycomics to distinguish patients with steatosis from patients with non-alcoholic steatohepatitis (NASH) in an adult population. The pattern of disease in paediatric patients is distinct from adults. The objective of this study was to characterize the N -glycomic profile of children with varying degrees of non-alcoholic fatty liver disease (NAFLD) and identify potential biomarker profiles of disease. METHODS: Serum protein N-glycosylation patterns of 51 paediatric NAFLD patients were assessed with deoxyribonucleic acid sequencer-assisted fluorophore-assisted capillary electrophoresis and compared with histology. RESULTS: Peak 1 (NGA2F) is the most significantly elevated N-glycan in paediatric NASH patients with peak 5 (NA2) demonstrating the largest decrease. The logarithmically transformed ratio of peak 1 to peak 5 was -0.85 (standard deviation [SD] 0.22) in patients with steatosis and borderline NASH and -0.73 (SD 0.12) in NASH (P = 0.02). The biomarker correlated well with the amount of lobular inflammation with a consistent increase of marker score in ascending stage of lobular inflammation. There was also a trend in differentiating patients with significant fibrosis >=F2; -0.74 (SD 0.13) from patients with no/minimal fibrosis 4 h d(-1) TV during week days (OR: 1.30, 95% CI, 1.02-1.67) (in boys) and eating every day with TV (OR: 1.18, 95% CI, 1.07-1.30) and >2 h d( 1) TV during weekend days (OR: 1.68, 95% CI, 1.25-2.26) (in girls) were significantly associated with total obesity. Likewise, in both sexes, having a TV set at bedroom was significantly associated with abdominal obesity. CONCLUSIONS: Adolescents spending excessive TV time are prone to obesity independently of their PA levels. Families should put TV sets out of adolescents' bedroom and keep TV sets off during meal times. PMID- 22434780 TI - Cyclin D1 inactivation extends proliferation and alters histogenesis in the postnatal mouse retina. AB - BACKGROUND: The cell-cycle regulator Cyclin D1 is expressed in embryonic retinal progenitor cells (RPCs) and regulates their cell-cycle rate and neurogenic output. We report here that Cyclin D1 also has important functions in postnatal retinal histogenesis. RESULTS: The initial production of Muller glia and bipolar cells was enhanced in Cyclin D1 knockout (Ccnd1(-/-) ) retinas. Despite a steeper than normal rate of depletion of the RPC population at embryonic ages, postnatal Ccnd1(-/-) retinas exhibited an extended window of proliferation, neurogenesis, and gliogenesis. Cyclin D3, normally confined to Muller glia, was prematurely expressed in Ccnd1(-/-) RPCs. However, Cyclin D3 did not compensate for Cyclin D1 in regulating cell-cycle kinetics or neurogenic output. CONCLUSIONS: The data presented in this study along with our previous finding that Cyclin D2 was unable to completely compensate for the absence of Cyclin D1 indicate that Cyclin D1 regulates retinal histogenesis in ways not shared by the other D-cyclins. PMID- 22434781 TI - A universal expression tag for structural and functional studies of proteins. AB - Modified ubiquitin sequences, each completed with a His tag and a TEV cleavage site, were designed to enhance the expression of protein/peptide targets. With this new system we have been able to characterize several peptide-protein interactions by ITC and by NMR and CD spectroscopic methods, including the interactions of LIR domains with autophagy modifiers. PMID- 22434782 TI - Gold catalysis: one-pot alkylideneoxazoline synthesis/Alder-ene reaction. AB - Based on the gold-catalyzed synthesis of methyleneoxazolines, a one-pot combination with an Alder-ene reaction was developed. For azodicarboxylates, good to very good yields (51-99%) of the oxazolemethylhydrazinedicarboxylates were achieved with 3 mol% of the Gagosz catalyst, [Ph(3)PAuNTf(3)]. In a less selective reaction, 4-phenyl-3H-1,2,4-triazol-3,5(4H)-dione gave lower yields (41 49%) of the corresponding oxazolemethylphenyltriazolidinediones. Overall, five new bonds were formed. Tetracyanoethylene afforded a cyclobutane derivative through a [2+2] cycloaddition reaction at -40 degrees C, but only 45% of the spiro compound was obtained. The less-readily available KITPHOS ligands on gold gave even higher yields at lower catalyst loadings (2 mol%), but longer reaction times were required. PMID- 22434783 TI - Twice-weekly, in-school jumping improves lean mass, particularly in adolescent boys. AB - OBJECTIVE: To determine the effect of a twice-weekly, school-based, 10-min jumping regime on muscle and fat tissue in healthy adolescent boys and girls. METHODS: We replaced regular warm-up activities with jumping in physical education (PE) classes of early high school students for 8 months to observe the effect on muscle and fat tissue. A total of 99 adolescents (46 boys, 53 girls; 13.8 +/- 0.4 years) volunteered to participate. Intervention group subjects performed 10 min of varied jumping activity, while control subjects performed a regular PE warm-up. Biometrics, Tanner staging, age of peak height velocity (PHV), vertical jump, whole body lean tissue and fat mass (dual-energy X-ray absorptiometry-derived) were measured at baseline and follow-up. Physical activity was determined by questionnaire. RESULTS: There were no differences in any measured variable between control and intervention groups at baseline. Boys had a significantly older age of PHV than girls (p = 0.02). No group differences were detected for 8-month change in height, weight or maturity measures for the combined sample; however, at 8 months, jumpers had accrued greater lean tissue mass than controls (p = 0.002). Sex-specific analysis revealed that intervention group boys had gained more lean tissue mass than controls (p = 0.016) and experienced significant fat loss (p = 0.010) than controls, an effect that was not observed in the girls. CONCLUSION: Regular, short-duration, jumping activity during adolescence increased lean tissue mass and boys additionally lost fat mass. Sex-specific and/or maturation-specific factors may explain the disparity in effect. PMID- 22434784 TI - Facile synthesis of nanoporous Pt-Ru alloy spheres with various compositions toward highly active electrocatalysts. PMID- 22434785 TI - Surgical management of complications of multimodal therapy. AB - Multimodality therapies that include surgery, chemotherapy, radiotherapy, and various newer forms of targeted therapies have been commonly applied in childhood cancers. Such modalities are associated with complications that may adversely affect the outcome of cancer treatment. Acute complications that require surgical management form the focus of our discussion. These patients are often compromised by immunosuppression, thrombocytopenia, and malnutrition. The complications discussed include typhlitis, invasive aspergillosis (IA), pancreatitis, hemorrhagic cystitis, gastrointestinal hemorrhage, necrotizing skin and soft tissue infections, and perianal infection. Familiarity with the spectrum of complications and their appropriate management approaches will minimize the patients' morbidity. PMID- 22434786 TI - Glycine in 1-butyl-3-methylimidazolium acetate and trifluoroacetate ionic liquids: effect of fluorination and hydrogen bonding. AB - The solvation of glycine in two ionic liquids (ILs), namely, 1-butyl-3 methylimidazolium acetate, [C(1)C(4)Im][OAc], and 1-butyl-3-methylimidazolium trifluoroacetate, [C(1)C(4)Im][TFA], was studied by a combination of experimental and theoretical methods. The solubility of glycine in both ILs was determined at 333.15 K to be (8.1+/-0.5) and (1.0+/-0.5) wt % in [C(1)C(4)Im][OAc] and [C(1)C(4)Im][TFA], respectively. By IR spectroscopy it was found that, when dissolved in the ILs, glycine was mainly present in its zwitterionic form. Structural and energetic aspects of the solvation of glycine in the ILs and in mixtures of ILs and water were investigated by ab initio calculations and molecular dynamic simulations. It was observed that the firstly solvation shell around glycine consisted predominantly of acetate or trifluoroacetate anions, which formed hydrogen bonds either with the carboxylic group of neutral glycine or with the protonated ammonium group of the zwitterionic form. When water is present in the solutions, hydrogen bonds between water and the anion prevail. The overall energy of the system was decomposed into its components between pairs of species. It was established that the dominant contribution to the interaction energy between glycine and the IL was due to hydrogen bonds with the anions and the statistics of hydrogen bonds were analysed. PMID- 22434787 TI - The consequences of hospital autonomization in Colombia: a transaction cost economics analysis. AB - Granting autonomy to public hospitals in developing countries has been common over recent decades, and implies a shift from hierarchical to contract-based relationships with health authorities. Theory on transactions costs in contractual relationships suggests they stem from relationship-specific investments and contract incompleteness. Transaction cost economics argues that the parties involved in exchanges seek to reduce transaction costs. The objective of this research was to analyse the relationships observed between purchasers and the 22 public hospitals of the city of Bogota, Colombia, in order to understand the role of relationship-specific investments and contract incompleteness as sources of transaction costs, through a largely qualitative study. We found that contract-based relationships showed relevant transaction costs associated mainly with contract incompleteness, not with relationship-specific investments. Regarding relationships between insurers and local hospitals for primary care services, compulsory contracting regulations locked-in the parties to the contracts. For high-complexity services (e.g. inpatient care), no restrictions applied and relationships suggested transaction-cost minimizing behaviour. Contract incompleteness was found to be a source of transaction costs on its own. We conclude that transaction costs seemed to play a key role in contract-based relationships, and contract incompleteness by itself appeared to be a source of transaction costs. The same findings are likely in other contexts because of difficulties in defining, observing and verifying the contracted products and the underlying information asymmetries. The role of compulsory contracting might be context-specific, although it is likely to emerge in other settings due to the safety-net role of public hospitals. PMID- 22434788 TI - Branded food references in children's magazines: 'advertisements' are the tip of the iceberg. AB - OBJECTIVE: While children's magazines 'blur the lines' between editorial content and advertising, this medium has escaped the calls for government restrictions that are currently associated with food advertisements aired during children's television programming. The aim of this study was to address significant gaps in the evidence base in relation to commercial food messages in children's magazines by systematically investigating the nature and extent of food advertising and promotions over a 12-month period. METHOD: All issues of Australian children's magazines published in the calendar year 2009 were examined for references to foods or beverages. RESULTS: Approximately 16% of the 1678 food references identified were portrayals of branded food products (or food brands). However, only 83 of these 269 were clearly identified as advertisements. Of these 269 branded food references, 86% were for non-core (broadly, less healthy) foods, including all but seven of the advertisements. CONCLUSIONS: It appears that recent reductions in televised promotions for non-core foods, and industry initiatives to reduce the targeting of children, have not carried through to magazine advertising. This study adds to the evidence base that the marketing of unhealthy food to children is widespread, and often covert, and supports public health calls for the strengthening of advertising regulation. PMID- 22434789 TI - Features associated with locoregional spread of papillary carcinoma correlate with diagnostic category in the Bethesda System for reporting thyroid cytopathology. AB - BACKGROUND: Most malignancies identified by thyroid fine-needle aspiration (FNA) are papillary thyroid carcinoma (PTC). This study sought to determine if clinically adverse features of PTC correlate with the preceding cytologic diagnosis. METHODS: Thyroid FNA diagnoses were correlated with subsequent histopathologic findings. RESULTS: From 6175 thyroid FNAs, histologic follow-up confirmed PTC in 52 of 184 (28%) FNAs with atypia of undetermined significance (AUS), 52 of 190 (27%) FNAs suspicious for follicular neoplasm, 182 of 229 (79%) FNAs that were suspicious for malignancy, and 188 of 198 (95%) FNAs that were malignant (M). Sex, age, and disease multifocality did not differ among FNA diagnosis groups. However, PTCs following an M FNA were more likely to have a higher American Joint Committee on Cancer T and N stage, and have lymphovascular invasion and/or extrathyroidal extension. Two patients had distant metastasis at initial surgery, whereas 16 developed subsequent recurrence and/or metastasis; all had a preceding M FNA. High-risk histologic subtypes of PTC also stratify to the M category, accounting at least partly for the association of cytologic diagnosis with adverse pathological parameters. Conversely, follicular variants of PTC predominate in non-M categories. CONCLUSIONS: The Bethesda System for Reporting Thyroid Cytopathology conveys malignancy risk, but also predicts the presence of pathological risk factors and disease progression when the malignancy is PTC. M diagnoses identify higher risk PTCs, whereas AUS diagnoses identify low risk PTCs, mostly follicular variants. These findings support the concept of conservative clinical management for some patients with AUS, while suggesting that a central neck dissection may be routinely justified in some patients with a M FNA. PMID- 22434790 TI - Making schools healthy among Burmese migrants in Thailand. AB - In Thailand, a health-promoting school (HPS) program is in place nationwide. However, this policy has not covered Burmese migrant schools. Therefore, to ensure the feasibility of the implementation of a HPS program, we conducted evaluations and an intervention on school health in migrant schools in Thailand. We included 44 primary-level schools in the Tak province in 2008. We were able to evaluate the results of the intervention in 43 of 44 schools in the subsequent year. For measurement, we used a comprehensive school-health checklist with five components: 'personal health and life skills', 'healthy school environment', 'health and nutrition services', 'common disease control and prevention', 'school and community partnership'. The checklist contained 59 items; item scores ranged from 0 to 3. We compared the results of the two surveys (performed before and after the intervention) by calculating the mean score of each item. A 1.3-fold increase was seen in the mean of all items measured in the evaluation (from 1.7 to 2.2, n= 43). Out of the five components, the greatest difference was detected in 'school and community partnership', which increased from 1.0 to 2.4. Notably, the mean score of item 4 of component 5, 'clear definition of the roles and responsibilities with the Burmese community', increased from 0.4 to 2.7. Although further study is necessary to investigate the association between our intervention and the improvements among schools, our school health evaluation and intervention were successfully implemented in Burmese migrant schools. PMID- 22434791 TI - Arginase-1 is a more sensitive marker of hepatic differentiation than HepPar-1 and glypican-3 in fine-needle aspiration biopsies. AB - BACKGROUND: Distinguishing hepatocellular carcinoma (HCC) from adenocarcinoma in fine-needle aspiration biopsies (FNAB) is often diagnostically challenging. Arginase-1 was recently described as a marker of hepatic differentiation in surgical resection specimens. We compared the expression of arginase-1, HepPar-1, and glypican-3 in FNAB of HCC and adenocarcinoma involving the liver. METHODS: Ninety-eight FNABs including 37 primary or metastatic HCCs (30 well or moderately differentiated and 7 poorly differentiated) and 61 adenocarcinomas involving the liver were evaluated for immunohistochemical expression of arginase-1, HepPar-1, and glypican-3 using formalin-fixed paraffin-embedded cell block material. RESULTS: Arginase-1 was more sensitive (81%) than HepPar-1 (70%) or glypican-3 (54%) for HCC. Arginase-1 more often demonstrated diffuse staining, defined as reactivity in >50% of the tumor, in HCC (21 of 37; 57%) compared with HepPar-1 (15 of 37; 41%) and glypican-3 (12 of 37; 32%). Of the 7 poorly differentiated HCCs, 3 (43%) were immunoreactive for both arginase-1 and glypican-3, whereas only 1 (14%) demonstrated HepPar-1 staining. Arginase-1 expression was identified in adenocarcinomas of pancreatic, colorectal, and breast origin, and reactivity was diffuse in 2 pancreatic adenocarcinomas (2 of 15; 13%). CONCLUSIONS: Arginase 1 is a more sensitive marker of hepatic differentiation than either HepPar-1 or glypican-3 in FNAB. In addition, arginase-1 exhibits more diffuse staining in HCC than either HepPar-1 or glypican-3, making interpretation easier in limited FNAB samples. Arginase-1 is not entirely specific for hepatic differentiation, as immunoreactivity can be identified in adenocarcinomas, particularly of pancreatic origin. PMID- 22434792 TI - Morphology-based automatic seizure detector for intracerebral EEG recordings. AB - In this paper, a new seizure detection system aimed at assisting in a rapid review of prolonged intracerebral EEG recordings is described. It is based on quantifying the sharpness of the waveform, one of the most important electrographic EEG features utilized by experts for an accurate and reliable identification of a seizure. The waveform morphology is characterized by a measure of sharpness as defined by the slope of the half-waves. A train of abnormally sharp waves resulting from subsequent filtering are used to identify seizures. The method was optimized using 145 h of single-channel depth EEG from seven patients, and tested on another 158 h of single-channel depth EEG from another seven patients. Additionally, 725 h of depth EEG from 21 patients was utilized to assess the system performance in a multichannel configuration. Single channel test data resulted in a sensitivity of 87% and a specificity of 71%. The multichannel test data reported a sensitivity of 81% and a specificity of 58.9%. The new system detected a wide range of seizure patterns that included rhythmic and nonrhythmic seizures of varying length, including those missed by the experts. We also compare the proposed system with a popular commercial system. PMID- 22434793 TI - Realtime recognition of complex human daily activities using human motion and location data. AB - Daily activity recognition is very useful in robot-assisted living systems. In this paper, we proposed a method to recognize complex human daily activities which consist of simultaneous body activities and hand gestures in an indoor environment. A wireless power-aware motion sensor node is developed which consists of a commercial orientation sensor, a wireless communication module, and a power management unit. To recognize complex daily activities, three motion sensor nodes are attached to the right thigh, the waist, and the right hand of a human subject, while an optical motion capture system is used to obtain his/her location information. A three-level dynamic Bayesian network (DBN) is implemented to model the intratemporal and intertemporal constraints among the location, body activity, and hand gesture. The body activity and hand gesture are estimated using a Bayesian filter and a short-time Viterbi algorithm, which reduces the computational complexity and memory usage. We conducted experiments in a mock apartment environment and the obtained results showed the effectiveness and accuracy of our method. PMID- 22434794 TI - Classification of periodic activities using the Wasserstein distance. AB - In this paper, we introduce a novel nonparametric classification technique based on the use of the Wasserstein distance. The proposed scheme is applied in a biomedical context for the analysis of recorded accelerometer data: the aim is to retrieve three types of periodic activities (walking, biking, and running) from a time-frequency representation of the data. The main interest of the use of the Wasserstein distance lies in the fact that it is less sensitive to the location of the frequency peaks than to the global structure of the frequency pattern, allowing us to detect activities almost independently of their speed or incline. Our system is tested on a 24-subject corpus: results show that the use of Wasserstein distance combined with some supervised learning techniques allows us to compare with some more complex classification systems. PMID- 22434795 TI - Automatic detection and quantification of tree-in-bud (TIB) opacities from CT scans. AB - This study presents a novel computer-assisted detection (CAD) system for automatically detecting and precisely quantifying abnormal nodular branching opacities in chest computed tomography (CT), termed tree-in-bud (TIB) opacities by radiology literature. The developed CAD system in this study is based on 1) fast localization of candidate imaging patterns using local scale information of the images, and 2) Mobius invariant feature extraction method based on learned local shape and texture properties of TIB patterns. For fast localization of candidate imaging patterns, we use ball-scale filtering and, based on the observation of the pattern of interest, a suitable scale selection is used to retain only small size patterns. Once candidate abnormality patterns are identified, we extract proposed shape features from regions where at least one candidate pattern occupies. The comparative evaluation of the proposed method with commonly used CAD methods is presented with a dataset of 60 chest CTs (laboratory confirmed 39 viral bronchiolitis human parainfluenza CTs and 21 normal chest CTs). The quantitative results are presented as the area under the receiver operator characteristics curves and a computer score (volume affected by TIB) provided as an output of the CAD system. In addition, a visual grading scheme is applied to the patient data by three well-trained radiologists. Interobserver and observer-computer agreements are obtained by the relevant statistical methods over different lung zones. Experimental results demonstrate that the proposed CAD system can achieve high detection rates with an overall accuracy of 90.96%. Moreover, correlations of observer-observer (R(2)=0.8848, and observer-CAD agreements (R(2)=0.824, validate the feasibility of the use of the proposed CAD system in detecting and quantifying TIB patterns. PMID- 22434796 TI - Reconstruction of irregularly-sampled volumetric data in efficient box spline spaces. AB - We present a variational framework for the reconstruction of irregularly-sampled volumetric data in, nontensor-product, spline spaces. Motivated by the sampling theoretic advantages of body centered cubic (BCC) lattice, this paper examines the BCC lattice and its associated box spline spaces in a variational setting. We introduce a regularization scheme for box splines that allows us to utilize the BCC lattice in a variational reconstruction framework. We demonstrate that by choosing the BCC lattice over the commonly-used Cartesian lattice, as the shift invariant representation, one can increase the quality of signal reconstruction. Moreover, the computational cost of the reconstruction process is reduced in the BCC framework due to the smaller bandwidth of the system matrix in the box spline space compared to the corresponding tensor-product B-spline space. The improvements in accuracy are quantified numerically and visualized in our experiments with synthetic as well as real biomedical datasets. PMID- 22434797 TI - Segmentation of skin lesions in 2-D and 3-D ultrasound images using a spatially coherent generalized Rayleigh mixture model. AB - This paper addresses the problem of jointly estimating the statistical distribution and segmenting lesions in multiple-tissue high-frequency skin ultrasound images. The distribution of multiple-tissue images is modeled as a spatially coherent finite mixture of heavy-tailed Rayleigh distributions. Spatial coherence inherent to biological tissues is modeled by enforcing local dependence between the mixture components. An original Bayesian algorithm combined with a Markov chain Monte Carlo method is then proposed to jointly estimate the mixture parameters and a label-vector associating each voxel to a tissue. More precisely, a hybrid Metropolis-within-Gibbs sampler is used to draw samples that are asymptotically distributed according to the posterior distribution of the Bayesian model. The Bayesian estimators of the model parameters are then computed from the generated samples. Simulation results are conducted on synthetic data to illustrate the performance of the proposed estimation strategy. The method is then successfully applied to the segmentation of in vivo skin tumors in high frequency 2-D and 3-D ultrasound images. PMID- 22434798 TI - Fast higher-order MR image reconstruction using singular-vector separation. AB - Medical resonance imaging (MRI) conventionally relies on spatially linear gradient fields for image encoding. However, in practice various sources of nonlinear fields can perturb the encoding process and give rise to artifacts unless they are suitably addressed at the reconstruction level. Accounting for field perturbations that are neither linear in space nor constant over time, i.e., dynamic higher-order fields, is particularly challenging. It was previously shown to be feasible with conjugate-gradient iteration. However, so far this approach has been relatively slow due to the need to carry out explicit matrix vector multiplications in each cycle. In this work, it is proposed to accelerate higher-order reconstruction by expanding the encoding matrix such that fast Fourier transform can be employed for more efficient matrix-vector computation. The underlying principle is to represent the perturbing terms as sums of separable functions of space and time. Compact representations with this property are found by singular-vector analysis of the perturbing matrix. Guidelines for balancing the accuracy and speed of the resulting algorithm are derived by error propagation analysis. The proposed technique is demonstrated for the case of higher-order field perturbations due to eddy currents caused by diffusion weighting. In this example, image reconstruction was accelerated by two orders of magnitude. PMID- 22434799 TI - Game-theoretic pricing for video streaming in mobile networks. AB - Mobile phones are among the most popular consumer devices, and the recent developments of 3G networks and smart phones enable users to watch video programs by subscribing data plans from service providers. Due to the ubiquity of mobile phones and phone-to-phone communication technologies, data-plan subscribers can redistribute the video content to nonsubscribers. Such a redistribution mechanism is a potential competitor for the mobile service provider and is very difficult to trace given users' high mobility. The service provider has to set a reasonable price for the data plan to prevent such unauthorized redistribution behavior to protect or maximize his/her own profit. In this paper, we analyze the optimal price setting for the service provider by investigating the equilibrium between the subscribers and the secondary buyers in the content-redistribution network. We model the behavior between the subscribers and the secondary buyers as a noncooperative game and find the optimal price and quantity for both groups of users. Based on the behavior of users in the redistribution network, we investigate the evolutionarily stable ratio of mobile users who decide to subscribe to the data plan. Such an analysis can help the service provider preserve his/her profit under the threat of the redistribution networks and can improve the quality of service for end users. PMID- 22434800 TI - Image deblurring using derivative compressed sensing for optical imaging application. AB - The problem of reconstruction of digital images from their blurred and noisy measurements is unarguably one of the central problems in imaging sciences. Despite its ill-posed nature, this problem can often be solved in a unique and stable manner, provided appropriate assumptions on the nature of the images to be recovered. In this paper, however, a more challenging setting is considered, in which accurate knowledge of the blurring operator is lacking, thereby transforming the reconstruction problem at hand into a problem of blind deconvolution. As a specific application, the current presentation focuses on reconstruction of short-exposure optical images measured through atmospheric turbulence. The latter is known to give rise to random aberrations in the optical wavefront, which are in turn translated into random variations of the point spread function of the optical system in use. A standard way to track such variations involves using adaptive optics. Thus, for example, the Shack-Hartmann interferometer provides measurements of the optical wavefront through sensing its partial derivatives. In such a case, the accuracy of wavefront reconstruction is proportional to the number of lenslets used by the interferometer and, hence, to its complexity. Accordingly, in this paper, we show how to minimize the above complexity through reducing the number of the lenslets while compensating for undersampling artifacts by means of derivative compressed sensing. Additionally, we provide empirical proof that the above simplification and its associated solution scheme result in image reconstructions, whose quality is comparable to the reconstructions obtained using conventional (dense) measurements of the optical wavefront. PMID- 22434801 TI - Generalized block-lifting factorization of M-channel biorthogonal filter banks for lossy-to-lossless image coding. AB - Generalized block-lifting factorization of M-channel (M > 2) biorthogonal filter banks (BOFBs) for lossy-to-lossless image coding is presented in this paper. Since the proposed block-lifting structure is more general than the conventional lifting factorizations and does NOT require many restrictions such as paraunitary, number of channels, and McMillan degree in each building block unlike the conventional lifting factorizations, its coding gain is higher than that of the previous methods. Several proposed BOFBs are designed and applied to image coding. Comparing the results with conventional lossy-to-lossless image coding structures, including the 5/3- and 9/7-tap discrete wavelet transforms in JPEG 2000 and a 4 * 8 hierarchical lapped biorthogonal transform in JPEG XR, the proposed BOFBs achieve better result in both objective measure and perceptual visual quality for the images with a lot of high-frequency components. PMID- 22434802 TI - Shape-from-focus by tensor voting. AB - In this correspondence, we address the task of recovering shape-from-focus (SFF) as a perceptual organization problem in 3-D. Using tensor voting, depth hypotheses from different focus operators are validated based on their likelihood to be part of a coherent 3-D surface, thereby exploiting scene geometry and focus information to generate reliable depth estimates. The proposed method is fast and yields significantly better results compared with existing SFF methods. PMID- 22434803 TI - Making the unbearable bearable. PMID- 22434804 TI - Schwartz Rounds: reviving compassion in modern healthcare. PMID- 22434805 TI - Data re-entry overload: time for a paradigm shift in maternity information technology? PMID- 22434806 TI - John Marshall's first description of surgical electrocautery. PMID- 22434808 TI - The neuroscience of prevention. PMID- 22434809 TI - Why we cannot afford not to engage junior doctors in NHS leadership. PMID- 22434810 TI - Development of the social brain in adolescence. AB - The brain has evolved to understand and interact with other people. We are increasingly learning more about the neurophysiological basis of social cognition and what is known as the social brain, that is the network of brain regions involved in understanding others. This paper focuses on how the social brain develops during adolescence. Adolescence is a time characterized by change - hormonally, physically, psychologically and socially. Yet until recently this period of life was neglected by cognitive neuroscience. In the past decade, research has shown that the brain develops both structurally and functionally during adolescence. Large-scale structural MRI studies have demonstrated development during adolescence in white matter and grey matter volumes in regions within the social brain. Activity in some of these regions, as measured using fMRI, also shows changes between adolescence and adulthood during social cognition tasks. I will also present evidence that theory of mind usage is still developing late in adolescence. Finally, I will speculate on potential implications of this research for society. PMID- 22434811 TI - Supporting hospital staff to provide compassionate care: do Schwartz Center Rounds work in English hospitals? AB - OBJECTIVE: To assess (1) whether the Schwartz Center Rounds ("Rounds"), a multidisciplinary forum which brings together hospital staff to discuss the nonclinical, social and emotional aspects of caring for patients, could transfer from the US to a UK setting; and (2) whether UK Rounds would achieve a similar positive impact on individuals and teams, and hospital culture. DESIGN: The results reported are based on 41 qualitative interviews with context provided by additional quantitative research. SETTING: We introduced Rounds at two pilot sites, both NHS hospitals providing acute care. PARTICIPANTS: Over the one-year, ten-Rounds pilot period, Rounds were attended by 1250 staff across the two sites. We conducted qualitative research into the experiences of staff involved in implementing Rounds at the outset and the end of the pilot. MAIN OUTCOME MEASURES: Interviewees' assessment of the effects of Rounds on participants, their relationships with colleagues, and the wider hospital. RESULTS: The findings show that in the two pilot trusts, Rounds are perceived by participants as a source of support and that their benefit may translate into benefits for patients and team working; and that Rounds have the potential to effect change in the hospital culture. CONCLUSION: Rounds appear to transfer successfully from the US to the UK, and there is some evidence that they are having a similarly positive impact, but more research is needed. PMID- 22434812 TI - Changing patterns of infant death over the last 100 years: autopsy experience from a specialist children's hospital. AB - OBJECTIVES: Infant mortality has undergone a dramatic reduction in the UK over the past century because of improvements in public health policy and medical advances. Postmortem examinations have been performed at Great Ormond Street Hospital for over 100 years, and analysis of cases across this period has been performed to assess changing patterns of infant deaths undergoing autopsy. DESIGN: Autopsy reports from 1909 and 2009 were examined. Age, major pathology and cause of death was reviewed from these cases and entered into an anonymized database. A subsequent comparative analysis was performed. SETTING: All postmortems performed and reported at Great Ormond Street Hospital in 1909 and 2009. PARTICIPANTS: Infant deaths, aged 0-365 days, were identified and subsequently analysed for the two years. MAIN OUTCOME MEASURES: Comparative proportional analysis of postmortem findings from the two time periods. RESULTS: Three-hundred and fifty-seven and 347 autopsy reports were identified from 1909 and 2009 including 178 and 128 infant deaths, respectively. The commonest cause of death in 1909 was infection (74%) compared to 20% of deaths in 2009. The most frequent final 'diagnosis' in 2009 was 'unexplained sudden unexpected infant death (SUDI)', despite a full postmortem including ancillary investigations. In contrast, there were no such cases recorded in 1909, but there were frequent deaths due to gastroenteritis and malnutrition together accounting for 16% of cases, compared to one case of gastroenteritis in 2009. Fifteen percent of 1909 cases had infections which are almost never fatal with appropriate treatment in 2009, including tuberculosis, diphtheria and syphilis. Congenital anomalies were detected with similar frequencies at both time points, (21% and 19% in 1909 and 2009, respectively). CONCLUSION: In the UK, significant changes in patterns of pathology have occurred in paediatric autopsy cases performed at a single specialist centre. Fatal infections and malnutrition (both poverty-related) have reduced yet the incidence of congenital anomalies has remained similar. PMID- 22434813 TI - Thomas John MacLagan (1838-1903). PMID- 22434816 TI - T-S-Fuzzy-Model-Based Approximation and Controller Design for General Nonlinear Systems. AB - This paper presents a novel approach to control general nonlinear systems based on Takagi-Sugeno (T-S) fuzzy dynamic models. It is first shown that a general nonlinear system can be approximated by a generalized T-S fuzzy model to any degree of accuracy on any compact set. It is then shown that the stabilization problem of the general nonlinear system can be solved as a robust stabilization problem of the developed T-S fuzzy system with the approximation errors as the uncertainty term. Based on a piecewise quadratic Lyapunov function, the robust semiglobal stabilization and Hinfinity control of the general nonlinear system are formulated in the form of linear matrix inequalities. Simulation results are provided to illustrate the effectiveness of the proposed approaches. PMID- 22434817 TI - Ultrasound beamforming using compressed data. AB - The rapid advancements in electronics technologies have made software-based beamformers for ultrasound array imaging feasible, thus facilitating the rapid development of high-performance and potentially low-cost systems. However, one challenge to realizing a fully software-based system is transferring data from the analog front end to the software back end at rates of up to a few gigabits per second. This study investigated the use of data compression to reduce the data transfer requirements and optimize the associated trade-off with beamforming quality. JPEG and JPEG2000 compression techniques were adopted. The acoustic data of a line phantom were acquired with a 128-channel array transducer at a center frequency of 3.5 MHz, and the acoustic data of a cyst phantom were acquired with a 64-channel array transducer at a center frequency of 3.33 MHz. The receive channel data associated with each transmit event are separated into 8 * 8 blocks and several tiles before JPEG and JPEG2000 data compression is applied, respectively. In one scheme, the compression was applied to raw RF data, while in another only the amplitude of baseband data was compressed. The maximum compression ratio of RF data compression to produce an average error of lower than 5 dB was 15 with JPEG compression and 20 with JPEG2000 compression. The image quality is higher with baseband amplitude data compression than with RF data compression; although the maximum overall compression ratio (compared with the original RF data size), which was limited by the data size of uncompressed phase data, was lower than 12, the average error in this case was lower than 1 dB when the compression ratio was lower than 8. PMID- 22434818 TI - An integrated healthcare system for personalized chronic disease care in home hospital environments. AB - Facing the increasing demands and challenges in the area of chronic disease care, various studies on the healthcare system which can, whenever and wherever, extract and process patient data have been conducted. Chronic diseases are the long-term diseases and require the processes of the real-time monitoring, multidimensional quantitative analysis, and the classification of patients' diagnostic information. A healthcare system for chronic diseases is characterized as an at-hospital and at-home service according to a targeted environment. Both services basically aim to provide patients with accurate diagnoses of disease by monitoring a variety of physical states with a number of monitoring methods, but there are differences between home and hospital environments, and the different characteristics should be considered in order to provide more accurate diagnoses for patients, especially, patients having chronic diseases. In this paper, we propose a patient status classification method for effectively identifying and classifying chronic diseases and show the validity of the proposed method. Furthermore, we present a new healthcare system architecture that integrates the at-home and at-hospital environment and discuss the applicability of the architecture using practical target services. PMID- 22434819 TI - Health informatics design for assisted diagnosis of subclinical atherosclerosis, structural, and functional arterial age calculus and patient-specific cardiovascular risk evaluation. AB - Traditional methods used to assess cardiovascular risk (i.e., the Framingham Risk Score) exhibit clear limitations. To aid in patient-specific risk stratification and diagnosis it has been proposed to evaluate noninvasively structural and functional arterial parameters. A National Public University Center (CUiiDARTE) was created in Uruguay with the aim of developing and applying strategies to improve cardiovascular risk stratification and subclinical vascular disease detection. To this end a health informatics approach and tool was designed, developed, and implemented in CUiiDARTE. Its goals were to: 1) promote screening for subclinical atherosclerosis, 2) develop a centralized database to store information obtained noninvasively from anywhere in our country, 3) develop a biomathematical model integrating values for arterial structure and function into traditional cardiovascular risk assessment, 4) generate a detailed and comprehensive report for the specialist comparing patient data with reference data from the healthy population, 5) generate a similar report (using a structural and functional arterial age calculator) for the patients assessing the state of their arteries. In this paper, we present the main characteristics of the CUiiDARTE health informatics development. PMID- 22434820 TI - Molecular communication using Brownian motion with drift. AB - Inspired by biological communication systems, molecular communication has been proposed as a viable scheme to communicate between nano-sized devices separated by a very short distance. Here, molecules are released by the transmitter into the medium, which are then sensed by the receiver. This paper develops a preliminary version of such a communication system focusing on the release of either one or two molecules into a fluid medium with drift. We analyze the mutual information between transmitter and the receiver when information is encoded in the time of release of the molecule. Simplifying assumptions are required in order to calculate the mutual information, and theoretical results are provided to show that these calculations are upper bounds on the true mutual information. Furthermore, optimized degree distributions are provided, which suggest transmission strategies for a variety of drift velocities. PMID- 22434821 TI - Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation. AB - ATP-binding cassette transporter A3 (ABCA3) is a lipid transporter active in lung alveolar epithelial type II cells (ATII) and is essential for their function as surfactant-producing cells. ABCA3 mutational defects cause respiratory distress in newborns and interstitial lung disease (ILD) in children. The molecular pathomechanisms are largely unknown; however, viral infections may initiate or aggravate ILDs. Here, we investigated the impact of the clinically relevant ABCA3 mutations, p.Q215K and p.E292V, by stable transfection of A549 lung epithelial cells. ABCA3 mutations strongly impaired expression of the ATII differentiation marker SP-C and the key epithelial cell adhesion proteins E-cadherin and zonula occludens-1. Concurrently, cells expressing ABCA3 mutation acquired mesenchymal features as observed by increased expression of SNAI1, MMP-2 and TGF-beta1, and elevated phosphorylation of Src. Infection with respiratory syncytial virus (RSV), the most common viral respiratory pathogen in small children, potentiated the observed mutational effects on loss of epithelial and acquisition of mesenchymal characteristics. In addition, RSV infection of cells harboring ABCA3 mutations resulted in a morphologic shift to a mesenchymal phenotype. We conclude that ABCA3 mutations, potentiated by RSV infection, induce loss of epithelial cell differentiation in ATII. Loss of key epithelial features may disturb the integrity of the alveolar epithelium, thereby comprising its functionality. We suggest the impairment of epithelial function as a mechanism by which ABCA3 mutations cause ILD. PMID- 22434822 TI - Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Abeta production. AB - Understanding the mechanisms that control processing of the amyloid precursor protein (APP) to produce amyloid-beta (Abeta) peptide represents a key area of Alzheimer's disease research. Here, we show that siRNA-mediated loss of calsyntenin-1 in cultured neurons alters APP processing to increase production of Abeta. We also show that calsyntenin-1 is reduced in Alzheimer's disease brains and that the extent of this reduction correlates with increased Abeta levels. Calsyntenin-1 is a ligand for kinesin-1 light chains and APP is transported through axons on kinesin-1 molecular motors. Defects in axonal transport are an early pathological feature in Alzheimer's disease and defective APP transport is known to increase Abeta production. We show that calsyntenin-1 and APP are co transported through axons and that siRNA-induced loss of calsyntenin-1 markedly disrupts axonal transport of APP. Thus, perturbation to axonal transport of APP on calsyntenin-1 containing carriers induces alterations to APP processing that increase production of Abeta. Together, our findings suggest that disruption of calsyntenin-1-associated axonal transport of APP is a pathogenic mechanism in Alzheimer's disease. PMID- 22434823 TI - The DISC1 promoter: characterization and regulation by FOXP2. AB - Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia. Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap. PMID- 22434824 TI - Ontogeny of classical and operant learning behaviors in zebrafish. AB - The performance of developing zebrafish in both classical and operant conditioning assays was tested with a particular focus on the emergence of these learning behaviors during development. Strategically positioned visual cues paired with electroshocks were used in two fully automated assays to investigate both learning paradigms. These allow the evaluation of the behavioral performance of zebrafish continuously throughout development, from larva to adult. We found that learning improves throughout development, starts reliably around week 3, and reaches adult performance levels at week 6. Adult fish quickly learned to perform perfectly, and the expression of the learned behavior is manifestly controlled by vision. The memory is behaviorally expressed in adults for at least 6 h and retrievable for at least 12 h. PMID- 22434825 TI - Computer-based and paper-based reading comprehension in adolescents with typical language development and language-learning disabilities. AB - PURPOSE: With the global expansion of technology, our reading platform has shifted from traditional text to hypertext, yet little consideration has been given to how this shift might help or hinder students' reading comprehension. The purpose of this study was to compare reading comprehension of computer-based and paper-based texts in adolescents with and without language-learning disabilities (LLD). METHOD: Fourteen adolescents with LLD and 25 adolescents with typical language development (TLD) read literary texts in computer-based and paper-based formats and then answered reading comprehension questions. RESULTS: The LLD group scored significantly lower than the TLD group on the reading comprehension measure, but there were no significant between-group differences for reading or answering time. In addition, there were no significant within-group differences for the computer-based or paper-based conditions. Predictors for reading comprehension varied by group and condition. CONCLUSION: Neither group appeared to be affected by the additional cognitive load imposed by hypertext in the computer-based condition; however, the load between conditions may not have been sufficient to differentially impact reading comprehension. Based on the regression analyses, it appears that working memory, oral language, and decoding differed in their contribution to reading comprehension for each group and condition. PMID- 22434826 TI - Considerations for creating and annotating the budding yeast Genome Map at SGD: a progress report. AB - The Saccharomyces Genome Database (SGD) is compiling and annotating a comprehensive catalogue of functional sequence elements identified in the budding yeast genome. Recent advances in deep sequencing technologies have enabled for example, global analyses of transcription profiling and assembly of maps of transcription factor occupancy and higher order chromatin organization, at nucleotide level resolution. With this growing influx of published genome-scale data, come new challenges for their storage, display, analysis and integration. Here, we describe SGD's progress in the creation of a consolidated resource for genome sequence elements in the budding yeast, the considerations taken in its design and the lessons learned thus far. The data within this collection can be accessed at http://browse.yeastgenome.org and downloaded from http://downloads.yeastgenome.org. DATABASE URL: http://www.yeastgenome.org. PMID- 22434827 TI - Annotation of functional sites with the Conserved Domain Database. AB - The overwhelming fraction of proteins whose sequences have been collected in comprehensive databases may never be assessed for function experimentally. Commonly, putative function is assigned based on similarity to experimentally characterized homologs, either on the level of the entire protein or for single evolutionarily conserved domains. The annotation of individual sites provides more detailed insights regarding the correspondence between sequence and function, as well as context for the interpretation of sequence variation and the outcomes of experiments. In general, site annotation has to be extracted from the published literature, and can often be transferred to closely related sequence neighbors. The National Center for Biotechnology Information's Conserved Domain Database (CDD) provides a system for curators to record functional (such as active sites or binding sites for cofactors) or characteristic sites (such as signature motifs), which are conserved across domain families, and for the transfer of that annotation to protein database sequences via high-confidence domain matches. Recently, CDD curators have begun to sort-site annotations into seven categories (active, polypeptide binding, nucleic acid binding, ion binding, chemical binding, post-translational modification and other) and here we present a first comparative analysis of sites obtained via domain model matches, juxtaposed with existing site annotation encountered in high-quality data sets. Site annotation derived from domain annotation has the potential to cover large fractions of protein sequences, and we observe that CDD-based site annotation complements existing site annotation in many cases, which may, in part, originate from CDD's curation practice of collecting sites conserved across diverse taxa and supported by evidence from multiple 3D structures. PMID- 22434828 TI - Biocurators and biocuration: surveying the 21st century challenges. AB - Curated databases are an integral part of the tool set that researchers use on a daily basis for their work. For most users, however, how databases are maintained, and by whom, is rather obscure. The International Society for Biocuration (ISB) represents biocurators, software engineers, developers and researchers with an interest in biocuration. Its goals include fostering communication between biocurators, promoting and describing their work, and highlighting the added value of biocuration to the world. The ISB recently conducted a survey of biocurators to better understand their educational and scientific backgrounds, their motivations for choosing a curatorial job and their career goals. The results are reported here. From the responses received, it is evident that biocuration is performed by highly trained scientists and perceived to be a stimulating career, offering both intellectual challenges and the satisfaction of performing work essential to the modern scientific community. It is also apparent that the ISB has at least a dual role to play to facilitate biocurators' work: (i) to promote biocuration as a career within the greater scientific community; (ii) to aid the development of resources for biomedical research through promotion of nomenclature and data-sharing standards that will allow interconnection of biological databases and better exploit the pivotal contributions that biocurators are making. DATABASE URL: http://biocurator.org. PMID- 22434829 TI - Building a biomedical semantic network in Wikipedia with Semantic Wiki Links. AB - Wikipedia is increasingly used as a platform for collaborative data curation, but its current technical implementation has significant limitations that hinder its use in biocuration applications. Specifically, while editors can easily link between two articles in Wikipedia to indicate a relationship, there is no way to indicate the nature of that relationship in a way that is computationally accessible to the system or to external developers. For example, in addition to noting a relationship between a gene and a disease, it would be useful to differentiate the cases where genetic mutation or altered expression causes the disease. Here, we introduce a straightforward method that allows Wikipedia editors to embed computable semantic relations directly in the context of current Wikipedia articles. In addition, we demonstrate two novel applications enabled by the presence of these new relationships. The first is a dynamically generated information box that can be rendered on all semantically enhanced Wikipedia articles. The second is a prototype gene annotation system that draws its content from the gene-centric articles on Wikipedia and exposes the new semantic relationships to enable previously impossible, user-defined queries. DATABASE URL: http://en.wikipedia.org/wiki/Portal:Gene_Wiki. PMID- 22434830 TI - YeastMine--an integrated data warehouse for Saccharomyces cerevisiae data as a multipurpose tool-kit. AB - The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org/) provides high-quality curated genomic, genetic, and molecular information on the genes and their products of the budding yeast Saccharomyces cerevisiae. To accommodate the increasingly complex, diverse needs of researchers for searching and comparing data, SGD has implemented InterMine (http://www.InterMine.org), an open source data warehouse system with a sophisticated querying interface, to create YeastMine (http://yeastmine.yeastgenome.org). YeastMine is a multifaceted search and retrieval environment that provides access to diverse data types. Searches can be initiated with a list of genes, a list of Gene Ontology terms, or lists of many other data types. The results from queries can be combined for further analysis and saved or downloaded in customizable file formats. Queries themselves can be customized by modifying predefined templates or by creating a new template to access a combination of specific data types. YeastMine offers multiple scenarios in which it can be used such as a powerful search interface, a discovery tool, a curation aid and also a complex database presentation format. DATABASE URL: http://yeastmine.yeastgenome.org. PMID- 22434831 TI - Disease model curation improvements at Mouse Genome Informatics. AB - Optimal curation of human diseases requires an ontology or structured vocabulary that contains terms familiar to end users, is robust enough to support multiple levels of annotation granularity, is limited to disease terms and is stable enough to avoid extensive reannotation following updates. At Mouse Genome Informatics (MGI), we currently use disease terms from Online Mendelian Inheritance in Man (OMIM) to curate mouse models of human disease. While OMIM provides highly detailed disease records that are familiar to many in the medical community, it lacks structure to support multilevel annotation. To improve disease annotation at MGI, we evaluated the merged Medical Subject Headings (MeSH) and OMIM disease vocabulary created by the Comparative Toxicogenomics Database (CTD) project. Overlaying MeSH onto OMIM provides hierarchical access to broad disease terms, a feature missing from the OMIM. We created an extended version of the vocabulary to meet the genetic disease-specific curation needs at MGI. Here we describe our evaluation of the CTD application, the extensions made by MGI and discuss the strengths and weaknesses of this approach. DATABASE URL: http://www.informatics.jax.org/ PMID- 22434832 TI - Community annotation and bioinformatics workforce development in concert--Little Skate Genome Annotation Workshops and Jamborees. AB - Recent advances in high-throughput DNA sequencing technologies have equipped biologists with a powerful new set of tools for advancing research goals. The resulting flood of sequence data has made it critically important to train the next generation of scientists to handle the inherent bioinformatic challenges. The North East Bioinformatics Collaborative (NEBC) is undertaking the genome sequencing and annotation of the little skate (Leucoraja erinacea) to promote advancement of bioinformatics infrastructure in our region, with an emphasis on practical education to create a critical mass of informatically savvy life scientists. In support of the Little Skate Genome Project, the NEBC members have developed several annotation workshops and jamborees to provide training in genome sequencing, annotation and analysis. Acting as a nexus for both curation activities and dissemination of project data, a project web portal, SkateBase (http://skatebase.org) has been developed. As a case study to illustrate effective coupling of community annotation with workforce development, we report the results of the Mitochondrial Genome Annotation Jamborees organized to annotate the first completely assembled element of the Little Skate Genome Project, as a culminating experience for participants from our three prior annotation workshops. We are applying the physical/virtual infrastructure and lessons learned from these activities to enhance and streamline the genome annotation workflow, as we look toward our continuing efforts for larger-scale functional and structural community annotation of the L. erinacea genome. PMID- 22434833 TI - MEDIC: a practical disease vocabulary used at the Comparative Toxicogenomics Database. AB - The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators manually curate a triad of chemical-gene, chemical-disease and gene disease relationships from the scientific literature. The CTD curation paradigm uses controlled vocabularies for chemicals, genes and diseases. To curate disease information, CTD first had to identify a source of controlled terms. Two resources seemed to be good candidates: the Online Mendelian Inheritance in Man (OMIM) and the 'Diseases' branch of the National Library of Medicine's Medical Subject Headers (MeSH). To maximize the advantages of both, CTD biocurators undertook a novel initiative to map the flat list of OMIM disease terms into the hierarchical nature of the MeSH vocabulary. The result is CTD's 'merged disease vocabulary' (MEDIC), a unique resource that integrates OMIM terms, synonyms and identifiers with MeSH terms, synonyms, definitions, identifiers and hierarchical relationships. MEDIC is both a deep and broad vocabulary, composed of 9700 unique diseases described by more than 67 000 terms (including synonyms). It is freely available to download in various formats from CTD. While neither a true ontology nor a perfect solution, this vocabulary has nonetheless proved to be extremely successful and practical for our biocurators in generating over 2.5 million disease-associated toxicogenomic relationships in CTD. Other external databases have also begun to adopt MEDIC for their disease vocabulary. Here, we describe the construction, implementation, maintenance and use of MEDIC to raise awareness of this resource and to offer it as a putative scaffold in the formal construction of an official disease ontology. DATABASE URL: http://ctd.mdibl.org/voc.go?type=disease. PMID- 22434834 TI - The mouse-human anatomy ontology mapping project. AB - The overall objective of the Mouse-Human Anatomy Project (MHAP) was to facilitate the mapping and harmonization of anatomical terms used for mouse and human models by Mouse Genome Informatics (MGI) and the National Cancer Institute (NCI). The anatomy resources designated for this study were the Adult Mouse Anatomy (MA) ontology and the set of anatomy concepts contained in the NCI Thesaurus (NCIt). Several methods and software tools were identified and evaluated, then used to conduct an in-depth comparative analysis of the anatomy ontologies. Matches between mouse and human anatomy terms were determined and validated, resulting in a highly curated set of mappings between the two ontologies that has been used by other resources. These mappings will enable linking of data from mouse and human. As the anatomy ontologies have been expanded and refined, the mappings have been updated accordingly. Insights are presented into the overall process of comparing and mapping between ontologies, which may prove useful for further comparative analyses and ontology mapping efforts, especially those involving anatomy ontologies. Finally, issues concerning further development of the ontologies, updates to the mapping files, and possible additional applications and significance were considered. DATABASE URL: http://obofoundry.org/cgi bin/detail.cgi?id=ma2ncit. PMID- 22434835 TI - Research resources: curating the new eagle-i discovery system. AB - Development of biocuration processes and guidelines for new data types or projects is a challenging task. Each project finds its way toward defining annotation standards and ensuring data consistency with varying degrees of planning and different tools to support and/or report on consistency. Further, this process may be data type specific even within the context of a single project. This article describes our experiences with eagle-i, a 2-year pilot project to develop a federated network of data repositories in which unpublished, unshared or otherwise 'invisible' scientific resources could be inventoried and made accessible to the scientific community. During the course of eagle-i development, the main challenges we experienced related to the difficulty of collecting and curating data while the system and the data model were simultaneously built, and a deficiency and diversity of data management strategies in the laboratories from which the source data was obtained. We discuss our approach to biocuration and the importance of improving information management strategies to the research process, specifically with regard to the inventorying and usage of research resources. Finally, we highlight the commonalities and differences between eagle-i and similar efforts with the hope that our lessons learned will assist other biocuration endeavors. DATABASE URL: www.eagle-i.net. PMID- 22434836 TI - CvManGO, a method for leveraging computational predictions to improve literature based Gene Ontology annotations. AB - The set of annotations at the Saccharomyces Genome Database (SGD) that classifies the cellular function of S. cerevisiae gene products using Gene Ontology (GO) terms has become an important resource for facilitating experimental analysis. In addition to capturing and summarizing experimental results, the structured nature of GO annotations allows for functional comparison across organisms as well as propagation of functional predictions between related gene products. Due to their relevance to many areas of research, ensuring the accuracy and quality of these annotations is a priority at SGD. GO annotations are assigned either manually, by biocurators extracting experimental evidence from the scientific literature, or through automated methods that leverage computational algorithms to predict functional information. Here, we discuss the relationship between literature based and computationally predicted GO annotations in SGD and extend a strategy whereby comparison of these two types of annotation identifies genes whose annotations need review. Our method, CvManGO (Computational versus Manual GO annotations), pairs literature-based GO annotations with computational GO predictions and evaluates the relationship of the two terms within GO, looking for instances of discrepancy. We found that this method will identify genes that require annotation updates, taking an important step towards finding ways to prioritize literature review. Additionally, we explored factors that may influence the effectiveness of CvManGO in identifying relevant gene targets to find in particular those genes that are missing literature-supported annotations, but our survey found that there are no immediately identifiable criteria by which one could enrich for these under-annotated genes. Finally, we discuss possible ways to improve this strategy, and the applicability of this method to other projects that use the GO for curation. DATABASE URL: http://www.yeastgenome.org. PMID- 22434837 TI - AntiFam: a tool to help identify spurious ORFs in protein annotation. AB - As the deluge of genomic DNA sequence grows the fraction of protein sequences that have been manually curated falls. In turn, as the number of laboratories with the ability to sequence genomes in a high-throughput manner grows, the informatics capability of those labs to accurately identify and annotate all genes within a genome may often be lacking. These issues have led to fears about transitive annotation errors making sequence databases less reliable. During the lifetime of the Pfam protein families database a number of protein families have been built, which were later identified as composed solely of spurious open reading frames (ORFs) either on the opposite strand or in a different, overlapping reading frame with respect to the true protein-coding or non-coding RNA gene. These families were deleted and are no longer available in Pfam. However, we realized that these may perform a useful function to identify new spurious ORFs. We have collected these families together in AntiFam along with additional custom-made families of spurious ORFs. This resource currently contains 23 families that identified 1310 spurious proteins in UniProtKB and a further 4119 spurious proteins in a collection of metagenomic sequences. UniProt has adopted AntiFam as a part of the UniProtKB quality control process and will investigate these spurious proteins for exclusion. PMID- 22434838 TI - PRIDE: quality control in a proteomics data repository. AB - The PRoteomics IDEntifications (PRIDE) database is a large public proteomics data repository, containing over 270 million mass spectra (by November 2011). PRIDE is an archival database, providing the proteomics data supporting specific scientific publications in a computationally accessible manner. While PRIDE faces rapid increases in data deposition size as well as number of depositions, the major challenge is to ensure a high quality of data depositions in the context of highly diverse proteomics work flows and data representations. Here, we describe the PRIDE curation pipeline and its practical application in quality control of complex data depositions. DATABASE URL: http://www.ebi.ac.uk/pride/. PMID- 22434839 TI - A hybrid human and machine resource curation pipeline for the Neuroscience Information Framework. AB - The breadth of information resources available to researchers on the Internet continues to expand, particularly in light of recently implemented data-sharing policies required by funding agencies. However, the nature of dense, multifaceted neuroscience data and the design of contemporary search engine systems makes efficient, reliable and relevant discovery of such information a significant challenge. This challenge is specifically pertinent for online databases, whose dynamic content is 'hidden' from search engines. The Neuroscience Information Framework (NIF; http://www.neuinfo.org) was funded by the NIH Blueprint for Neuroscience Research to address the problem of finding and utilizing neuroscience-relevant resources such as software tools, data sets, experimental animals and antibodies across the Internet. From the outset, NIF sought to provide an accounting of available resources, whereas developing technical solutions to finding, accessing and utilizing them. The curators therefore, are tasked with identifying and registering resources, examining data, writing configuration files to index and display data and keeping the contents current. In the initial phases of the project, all aspects of the registration and curation processes were manual. However, as the number of resources grew, manual curation became impractical. This report describes our experiences and successes with developing automated resource discovery and semiautomated type characterization with text-mining scripts that facilitate curation team efforts to discover, integrate and display new content. We also describe the DISCO framework, a suite of automated web services that significantly reduce manual curation efforts to periodically check for resource updates. Lastly, we discuss DOMEO, a semi-automated annotation tool that improves the discovery and curation of resources that are not necessarily website-based (i.e. reagents, software tools). Although the ultimate goal of automation was to reduce the workload of the curators, it has resulted in valuable analytic by-products that address accessibility, use and citation of resources that can now be shared with resource owners and the larger scientific community. DATABASE URL: http://neuinfo.org. PMID- 22434840 TI - Aptamer Base: a collaborative knowledge base to describe aptamers and SELEX experiments. AB - Over the past several decades, rapid developments in both molecular and information technology have collectively increased our ability to understand molecular recognition. One emerging area of interest in molecular recognition research includes the isolation of aptamers. Aptamers are single-stranded nucleic acid or amino acid polymers that recognize and bind to targets with high affinity and selectivity. While research has focused on collecting aptamers and their interactions, most of the information regarding experimental methods remains in the unstructured and textual format of peer reviewed publications. To address this, we present the Aptamer Base, a database that provides detailed, structured information about the experimental conditions under which aptamers were selected and their binding affinity quantified. The open collaborative nature of the Aptamer Base provides the community with a unique resource that can be updated and curated in a decentralized manner, thereby accommodating the ever evolving field of aptamer research. DATABASE URL: http://aptamer.freebase.com. PMID- 22434841 TI - Tetrahymena Genome Database Wiki: a community-maintained model organism database. AB - When funding for Tetrahymena Genome Database (TGD) ended in 2006, no further updates were made to this important community resource and the main database was taken offline in 2008. We have restored and updated this important resource for use by the Tetrahymena research community. We have also retooled the TGD website (now TGD Wiki) to allow members of the community to directly update the information presented for each gene, including gene names, descriptions and Gene Ontology annotations, from a web browser. Maintenance of genome annotations by the authors generating and publishing primary data, rather than dedicated scientific curators, is a viable alternative for the upkeep of genomes, particularly for organisms with smaller research communities. By combining simple, intuitive displays with the powerful search functions made possible by its underlying relational database, TGD Wiki has been designed to maximize participation by bench scientists in the development of their community bioinformatics resource. DATABASE URL: http://ciliate.org. PMID- 22434842 TI - Tracking and coordinating an international curation effort for the CCDS Project. AB - The Consensus Coding Sequence (CCDS) collaboration involves curators at multiple centers with a goal of producing a conservative set of high quality, protein coding region annotations for the human and mouse reference genome assemblies. The CCDS data set reflects a 'gold standard' definition of best supported protein annotations, and corresponding genes, which pass a standard series of quality assurance checks and are supported by manual curation. This data set supports use of genome annotation information by human and mouse researchers for effective experimental design, analysis and interpretation. The CCDS project consists of analysis of automated whole-genome annotation builds to identify identical CDS annotations, quality assurance testing and manual curation support. Identical CDS annotations are tracked with a CCDS identifier (ID) and any future change to the annotated CDS structure must be agreed upon by the collaborating members. CCDS curation guidelines were developed to address some aspects of curation in order to improve initial annotation consistency and to reduce time spent in discussing proposed annotation updates. Here, we present the current status of the CCDS database and details on our procedures to track and coordinate our efforts. We also present the relevant background and reasoning behind the curation standards that we have developed for CCDS database treatment of transcripts that are nonsense-mediated decay (NMD) candidates, for transcripts containing upstream open reading frames, for identifying the most likely translation start codons and for the annotation of readthrough transcripts. Examples are provided to illustrate the application of these guidelines. DATABASE URL: http://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi. PMID- 22434843 TI - Community gene annotation in practice. AB - Manual annotation of genomic data is extremely valuable to produce an accurate reference gene set but is expensive compared with automatic methods and so has been limited to model organisms. Annotation tools that have been developed at the Wellcome Trust Sanger Institute (WTSI, http://www.sanger.ac.uk/.) are being used to fill that gap, as they can be used remotely and so open up viable community annotation collaborations. We introduce the 'Blessed' annotator and 'Gatekeeper' approach to Community Annotation using the Otterlace/ZMap genome annotation tool. We also describe the strategies adopted for annotation consistency, quality control and viewing of the annotation. DATABASE URL: http://vega.sanger.ac.uk/index.html. PMID- 22434844 TI - Argo: an integrative, interactive, text mining-based workbench supporting curation. AB - Curation of biomedical literature is often supported by the automatic analysis of textual content that generally involves a sequence of individual processing components. Text mining (TM) has been used to enhance the process of manual biocuration, but has been focused on specific databases and tasks rather than an environment integrating TM tools into the curation pipeline, catering for a variety of tasks, types of information and applications. Processing components usually come from different sources and often lack interoperability. The well established Unstructured Information Management Architecture is a framework that addresses interoperability by defining common data structures and interfaces. However, most of the efforts are targeted towards software developers and are not suitable for curators, or are otherwise inconvenient to use on a higher level of abstraction. To overcome these issues we introduce Argo, an interoperable, integrative, interactive and collaborative system for text analysis with a convenient graphic user interface to ease the development of processing workflows and boost productivity in labour-intensive manual curation. Robust, scalable text analytics follow a modular approach, adopting component modules for distinct levels of text analysis. The user interface is available entirely through a web browser that saves the user from going through often complicated and platform dependent installation procedures. Argo comes with a predefined set of processing components commonly used in text analysis, while giving the users the ability to deposit their own components. The system accommodates various areas and levels of user expertise, from TM and computational linguistics to ontology-based curation. One of the key functionalities of Argo is its ability to seamlessly incorporate user-interactive components, such as manual annotation editors, into otherwise completely automatic pipelines. As a use case, we demonstrate the functionality of an in-built manual annotation editor that is well suited for in-text corpus annotation tasks. DATABASE URL: http://www.nactem.ac.uk/Argo. PMID- 22434845 TI - Biocuration Virtual Issue 2012. PMID- 22434846 TI - The importance of identifying alternative splicing in vertebrate genome annotation. AB - While alternative splicing (AS) can potentially expand the functional repertoire of vertebrate genomes, relatively few AS transcripts have been experimentally characterized. We describe our detailed manual annotation of vertebrate genomes, which is generating a publicly available geneset rich in AS. In order to achieve this we have adopted a highly sensitive approach to annotating gene models supported by correctly mapped, canonically spliced transcriptional evidence combined with a highly cautious approach to adding unsupported extensions to models and making decisions on their functional potential. We use information about the predicted functional potential and structural properties of every AS transcript annotated at a protein-coding or non-coding locus to place them into one of eleven subclasses. We describe the incorporation of new sequencing and proteomics technologies into our annotation pipelines, which are used to identify and validate AS. Combining all data sources has led to the production of a rich geneset containing an average of 6.3 AS transcripts for every human multi-exon protein-coding gene. The datasets produced have proved very useful in providing context to studies investigating the functional potential of genes and the effect of variation may have on gene structure and function. DATABASE URL: http://www.ensembl.org/index.html, http://vega.sanger.ac.uk/index.html. PMID- 22434847 TI - Ontology searching and browsing at the Rat Genome Database. AB - The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40 000 rat gene records, as well as human and mouse orthologs, 1857 rat and 1912 human quantitative trait loci (QTLs) and 2347 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. RGD uses more than a dozen different ontologies to standardize annotation information for genes, QTLs and strains. That means a lot of time can be spent searching and browsing ontologies for the appropriate terms needed both for curating and mining the data. RGD has upgraded its ontology term search to make it more versatile and more robust. A term search result is connected to a term browser so the user can fine-tune the search by viewing parent and children terms. Most publicly available term browsers display a hierarchical organization of terms in an expandable tree format. RGD has replaced its old tree browser format with a 'driller' type of browser that allows quicker drilling up and down through the term branches, which has been confirmed by testing. The RGD ontology report pages have also been upgraded. Expanded functionality allows more choice in how annotations are displayed and what subsets of annotations are displayed. The new ontology search, browser and report features have been designed to enhance both manual data curation and manual data extraction. DATABASE URL: http://rgd.mcw.edu/rgdweb/ontology/search.html. PMID- 22434848 TI - Genotype-phenotype associations in a nonmodel prokaryote. AB - To help define the biological functions of nonessential genes of Francisella novicida, we measured the growth of arrayed members of a comprehensive transposon mutant library under a variety of nutrition and stress conditions. Mutant phenotypes were identified for 37% of the genes, corresponding to ten carbon source utilization pathways, nine amino acid- and nucleotide-biosynthetic pathways, ten intrinsic antibiotic resistance traits, and six other stress resistance traits. The greatest surprise of the analysis was the large number of genotype-phenotype relationships that were not predictable from studies of Escherichia coli and other model species. The study identified candidate genes for a missing glycolysis function (phosphofructokinase), an unusual proline biosynthetic pathway, parallel outer membrane lipid asymmetry maintenance systems, and novel antibiotic resistance functions. The analysis provides an evaluation of annotation predictions, identifies cases in which fundamental processes differ from those in model species, and helps create an empirical foundation for understanding virulence and other complex processes. IMPORTANCE: The value of genome sequences as foundations for analyzing complex traits in nonmodel organisms is limited by the need to rely almost exclusively on sequence similarities to predict gene functions in annotations. Many genes cannot be assigned functions, and some predictions are incorrect or incomplete. Due to these limitations, genome-scale experimental approaches that test and extend bioinformatics-based predictions are sorely needed. In this study, we describe such an approach based on phenotypic analysis of a comprehensive, sequence defined transposon mutant library. PMID- 22434849 TI - Regulatory tasks of the phosphoenolpyruvate-phosphotransferase system of Pseudomonas putida in central carbon metabolism. AB - Two branches of the phosphoenolpyruvate-phosphotransferase system (PTS) operate in the soil bacterium Pseudomonas putida KT2440. One branch encompasses a complete set of enzymes for fructose intake (PTS(Fru)), while the other (N related PTS, or PTS(Ntr)) controls various cellular functions unrelated to the transport of carbohydrates. The potential of these two systems for regulating central carbon catabolism has been investigated by measuring the metabolic fluxes of isogenic strains bearing nonpolar mutations in PTS(Fru) or PTS(Ntr) genes and grown on either fructose (a PTS substrate) or glucose, the transport of which is not governed by the PTS in this bacterium. The flow of carbon from each sugar was distinctly split between the Entner-Doudoroff, pentose phosphate, and Embden Meyerhof-Parnas pathways in a ratio that was maintained in each of the PTS mutants examined. However, strains lacking PtsN (EIIA(Ntr)) displayed significantly higher fluxes in the reactions of the pyruvate shunt, which bypasses malate dehydrogenase in the TCA cycle. This was consistent with the increased activity of the malic enzyme and the pyruvate carboxylase found in the corresponding PTS mutants. Genetic evidence suggested that such a metabolic effect of PtsN required the transfer of high-energy phosphate through the system. The EIIA(Ntr) protein of the PTS(Ntr) thus helps adjust central metabolic fluxes to satisfy the anabolic and energetic demands of the overall cell physiology. IMPORTANCE: This study demonstrates that EIIA(Ntr) influences the biochemical reactions that deliver carbon between the upper and lower central metabolic domains for the consumption of sugars by P. putida. These findings indicate that the EIIA(Ntr) protein is a key player for orchestrating the fate of carbon in various physiological destinations in this bacterium. Additionally, these results highlight the importance of the posttranslational regulation of extant enzymatic complexes for increasing the robustness of the corresponding metabolic networks. PMID- 22434850 TI - Transforming the untransformable: application of direct transformation to manipulate genetically Staphylococcus aureus and Staphylococcus epidermidis. AB - The strong restriction barrier present in Staphylococcus aureus and Staphylococcus epidermidis has limited functional genomic analysis to a small subset of strains that are amenable to genetic manipulation. Recently, a conserved type IV restriction system termed SauUSI (which specifically recognizes cytosine methylated DNA) was identified as the major barrier to transformation with foreign DNA. Here we have independently corroborated these findings in a widely used laboratory strain of S. aureus. Additionally, we have constructed a DNA cytosine methyltransferase mutant in the high-efficiency Escherichia coli cloning strain DH10B (called DC10B). Plasmids isolated from DC10B can be directly transformed into clinical isolates of S. aureus and S. epidermidis. We also show that the loss of restriction (both type I and IV) in an S. aureus USA300 strain does not have an impact on virulence. Circumventing the SauUSI restriction barrier, combined with an improved deletion and transformation protocol, has allowed the genetic manipulation of previously untransformable strains of these important opportunistic pathogens. IMPORTANCE: Staphylococcal infections place a huge burden on the health care sector due both to their severity and also to the economic impact of treating the infections because of prolonged hospitalization. To improve the understanding of Staphylococcus aureus and Staphylococcus epidermidis infections, we have developed a series of improved techniques that allow the genetic manipulation of strains that were previously refractory to transformation. These developments will speed up the process of mutant construction and increase our understanding of these species as a whole, rather than just a small subset of strains that could previously be manipulated. PMID- 22434851 TI - Emotional and relational aspects of egg-sharing: egg-share donors' and recipients' feelings about each other, each others' treatment outcome and any resulting children. AB - BACKGROUND: This paper presents finding from a study of the emotional and relational aspects of egg-sharing, exploring egg-share donors' and recipients' thoughts and feelings about each other, about each other's treatment outcome and any resulting children, as well as their attitudes towards disclosure of donor origins and contact between donors and donor offspring in the future. It is the first study of this population since the removal of donor anonymity in 2005. METHODS: A paper or online questionnaire was completed anonymously by 48 donors and 38 recipients who took part in egg-sharing between 2007 and 2009. Data were obtained on a range of measures-including demographics, family circumstances, motivations and anxieties, feelings about egg-sharing, retrospective assessments and views on regulation-and analysed to facilitate cross-group and within-group comparisons of donors and recipients. RESULTS: This study found very few differences between donors and recipients, as well as between successful and unsuccessful egg-share participants. Donors and recipients expressed sentiments of goodwill towards one another, and displayed attitudes of openness regarding disclosure decisions and future contact among donors and donor-conceived offspring. While some donors and recipients wanted to know the outcome of their donor's/recipient's treatment, others preferred not to. CONCLUSIONS: Most significantly, concerns voiced regarding the potential psychological harm to donors, particularly those whose own treatment ends unsuccessfully, were not borne out by the data. PMID- 22434852 TI - Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. AB - BACKGROUND: Animal models of endocrine dysfunction have associated male genital defects with reduced anogenital distance (AGD). Human studies have correlated shorter AGD with exposure to putative endocrine disruptors in the environment but have not examined AGD in hypospadiac boys. We measured AGD in boys with hypospadias and those with normal genitals. METHODS: Data were collected prospectively on boys undergoing urologic procedures at the University of California San Francisco and the Children's Hospital of Oakland, CA, USA. Data included age, race, height, weight, BMI, urologic diagnoses and AGD. To minimize any potential effects of race on observed AGD, we examined only Caucasian boys. Differences between boys with hypospadias and those with normal genitals were examined through two-tailed Student's t-tests. RESULTS: One hundred and nineteen Caucasian boys ranging in age from 4 to 86 months underwent AGD measurement, of which 42 and 77 were boys with normal genitals and hypospadias, respectively. The mean (+/-SD) AGD of boys with hypospadias was 67 +/- 1.2 versus 73 +/- 1 mm for boys with normal genitals (P = 0.002). In these age-unmatched patient groups, there were also differences in age, height and weight (P = 0.0001, 0.0002 and 0.0004, respectively). After age matching (all <2 years of age), boys with hypospadias (n= 26) still featured a shorter AGD than boys with normal genitals (n= 26; 62 +/- 2 versus 68 +/- 2 mm respectively, P = 0.033) but the differences in age, height and weight were no longer significant. CONCLUSIONS: In humans, hypospadias may indeed be associated with reduced AGD. Additional studies are needed to corroborate these preliminary findings and to determine their etiology. PMID- 22434853 TI - Localization and hormonal regulation of endometrial matrix metalloproteinase-26 in the rhesus macaque. AB - BACKGROUND: The current understanding of hormonal regulation of matrix metalloproteinase-26 (MMP-26) in the primate endometrium is incomplete. The goal of this work was to clarify estrogen and progesterone regulation of MMP-26 in the endometrium of ovariectomized, hormone-treated rhesus macaques. METHODS: Ovariectomized rhesus macaques (n= 66) were treated with estradiol (E(2)), E(2) plus progesterone, E(2) followed by progesterone alone or no hormone. Endometrium was collected from the hormone-treated animals during the early, mid- and late proliferative and secretory phases of the artificial menstrual cycle. MMP-26 expression was quantified by real-time PCR, and MMP-26 transcript and protein were localized by in situ hybridization and immunohistochemistry and correlated with estrogen receptor 1 and progesterone receptor (PGR). RESULTS: MMP-26 was localized to glandular epithelium and was undetectable in the endometrial stroma and vasculature. MMP-26 transcript levels were minimal in the hormone-deprived macaques and treatment with E(2) alone did not affect MMP-26 levels. Treatment with progesterone both in the presence and absence of E(2) stimulated MMP-26 expression in the early and mid-secretory phases (P < 0.001). MMP-26 expression preceded decidualization of endometrial stroma. MMP-26 levels then declined to baseline in the late secretory phase (P < 0.01) despite continued E(2) plus progesterone treatment. Loss of detectable MMP-26 expression in the late secretory phase was correlated with late secretory phase loss of glandular epithelial PGR. CONCLUSIONS: Endometrial MMP-26 expression is dependent on the presence of progesterone in the early secretory phase and then gradually becomes refractory to progesterone stimulation in the late secretory phase. In the macaque, MMP-26 is a marker of the pre-decidual, secretory endometrium. During the second half of the late secretory phase, and during decidualization, MMP-26 loses its response to progesterone concurrent with the loss of epithelial PGR. The decline in MMP-26 levels between the mid- and late secretory phases may play a role in the receptive window for embryo implantation. PMID- 22434854 TI - A uterovaginal septum and imperforate hymen with a double pyocolpos. AB - The presence of both a uterovaginal septum and imperforate hymen is described in a young patient presenting with ongoing chronic pelvic pain and a double pyocolpos. Ultrasound and magnetic resonance imaging scans were performed. The patient underwent laparoscopic adesiolysis, hymenotomy with drainage of 200 mL of pus, and excision of a complete longitudinal vaginal septum. Over the past 5 years of regular follow-up examinations, the patient has always reported regular menstrual cycles and an absence of pelvic pain. PMID- 22434855 TI - Possible involvement of the E-cadherin gene in genetic susceptibility to endometriosis. AB - BACKGROUND: Endometriotic cells display invasive characteristics, despite their benign histological appearance. Recently, the epithelial-mesenchymal transition, in which epithelial cells acquire mesenchymal and migratory properties, has attracted attention as a mechanism of tumor invasion. We aimed to investigate the association between endometriosis and polymorphisms of the E-cadherin gene, a central player in the epithelial-mesenchymal transition, in Japanese women. METHODS: Twelve single-nucleotide polymorphisms (SNPs) in the E-cadherin gene were identified by real-time polymerase chain reaction using a TaqMan assay in 511 women with endometriosis (the majority in Stages III and IV) and 498 healthy controls. RESULTS: Allele frequency analysis indicated that there was a marginally higher frequency of the rs4783689 C allele in women with endometriosis compared with controls (corrected P = 0.007; odds ratio = 1.37; 95% confidence interval, 1.14-1.64). No significant associations with endometriosis were found for the other 11 SNPs. CONCLUSIONS: Although this study was limited by sample size, the E-cadherin gene polymorphism rs4783689 was marginally associated with endometriosis in the Japanese population, suggesting that E-cadherin might be involved in genetic susceptibility to endometriosis. PMID- 22434856 TI - Retraction: Role of ribosomal protein RPS2 in controlling let-7a expression in human prostate cancer. PMID- 22434857 TI - Re-exploration for bleeding or tamponade after cardiac operation. AB - The aim of this study was to determine the outcome of patients who had a chest resternotomy and to identify risk factors for higher in-hospital mortality after re-exploration for bleeding and/or tamponade after cardiac operations. We present our experience of an acceptably low re-exploration rate after cardiac surgery, and the outcomes of those re-explored. This was a retrospective analysis of medical records of all patients who had a chest re-exploration for the control of bleeding and cardiac tamponade over a 7-year period (2000-06), at the Cardiothoracic Centre of the Hospital Ceske Budejovice, Czech Republic. Between 2000 and 2006, 152 patients (3.4% of the total heart operations) underwent re exploration after heart surgery. One hundred and seven (70.4%) were re-explored for bleeding, 36 (23.7%) for possible tamponade and nine (5.9%) for both. An identifiable source of bleeding was found in 72.4% patients. Risk factors associated with higher in-hospital mortality after re-exploration for bleeding and tamponade include delayed resternotomy, higher levels of lactate and lower levels of haematocrit before revision and other well-known risk factors such as older age, more complex cardiac procedures, redo operations, longer cardiopulmonary bypass, renal failure and diabetes mellitus. Patients who need re exploration are at a higher risk of complications, morbidity and mortality if the time until re-exploration is prolonged. PMID- 22434858 TI - Thermodynamics and docking of agonists to the beta(2)-adrenoceptor determined using [(3)H](R,R')-4-methoxyfenoterol as the marker ligand. AB - G protein-coupled receptors (GPCRs) are integral membrane proteins that change conformation after ligand binding so that they can transduce signals from an extracellular ligand to a variety of intracellular components. The detailed interaction of a molecule with a G protein-coupled receptor is a complicated process that is influenced by the receptor conformation, thermodynamics, and ligand conformation and stereoisomeric configuration. To better understand the molecular interactions of fenoterol analogs with the beta(2)-adrenergic receptor, we developed a new agonist radioligand for binding assays. [(3)H](R,R') methoxyfenoterol was used to probe the binding affinity for a series of fenoterol stereoisomers and derivatives. The results suggest that the radioligand binds with high affinity to an agonist conformation of the receptor, which represents approximately 25% of the total beta(2)-adrenoceptor (AR) population as determined with the antagonist [(3)H]CGP-12177. The beta(2)-AR agonists tested in this study have considerably higher affinity for the agonist conformation of the receptor, and K(i) values determined for fenoterol analogs model much better the cAMP activity of the beta(2)-AR elicited by these ligands. The thermodynamics of binding are also different when interacting with an agonist conformation, being purely entropy-driven for each fenoterol isomer, rather than a mixture of entropy and enthalpy when the fenoterol isomers binding was determined using [(3)H]CGP 12177. Finally, computational modeling identified the molecular interactions involved in agonist binding and allow for the prediction of additional novel beta(2)-AR agonists. The study underlines the possibility of using defined radioligand structure to probe a specific conformation of such shape-shifting system as the beta(2)-adrenoceptor. PMID- 22434859 TI - Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitors. AB - In efforts to identify novel small molecules with anti-inflammatory properties, we discovered a unique series of tetracyclic indenoquinoxaline derivatives that inhibited lipopolysaccharide (LPS)-induced nuclear factor-kappaB/activating protein 1 activation. Compound IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) was found to be a potent, noncytotoxic inhibitor of pro-inflammatory cytokine [interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, tumor necrosis factor (TNF) alpha, interferon-gamma, and granulocyte-macrophage colony-stimulating factor] and nitric oxide production by human and murine monocyte/macrophages. Three additional potent inhibitors of cytokine production were identified through further screening of IQ-1 analogs. The sodium salt of IQ-1 inhibited LPS-induced TNF-alpha and IL-6 production in MonoMac-6 cells with IC(50) values of 0.25 and 0.61 MUM, respectively. Screening of 131 protein kinases revealed that derivative IQ-3 [11H-indeno[1,2-b]quinoxalin-11-one-O-(2-furoyl)oxime]was a specific inhibitor of the c-Jun N-terminal kinase (JNK) family, with preference for JNK3. This compound, as well as IQ-1 and three additional oxime indenoquinoxalines, were found to be high-affinity JNK inhibitors with nanomolar binding affinity and ability to inhibit c-Jun phosphorylation. Furthermore, docking studies showed that hydrogen bonding interactions of the active indenoquinoxalines with Asn152, Gln155, and Met149 of JNK3 played an important role in enzyme binding activity. Finally, we showed that the sodium salt of IQ-1 had favorable pharmacokinetics and inhibited the ovalbumin-induced CD4(+) T-cell immune response in a murine delayed-type hypersensitivity model in vivo. We conclude that compounds with an indenoquinoxaline nucleus can serve as specific small-molecule modulators for mechanistic studies of JNKs as well as a potential leads for the development of anti-inflammatory drugs. PMID- 22434860 TI - Cohort profile: the Themba Lethu Clinical Cohort, Johannesburg, South Africa. AB - The Themba Lethu Clinical Cohort was established in 2004 to allow large patient level analyses from a single HIV treatment site to evaluate National Treatment Guidelines, answer questions of national and international policy relevance and to combine an economic and epidemiologic focus on HIV research. The current objectives of the Themba Lethu Clinical Cohort analyses are to: (i) provide cohort-level information on the outcomes of HIV treatment; (ii) evaluate aspects of HIV care and treatment that have policy relevance; (iii) evaluate the cost and cost-effectiveness of different approaches to HIV care and treatment; and (iv) provide a platform for studies on improving HIV care and treatment. Since 2004, Themba Lethu Clinic has enrolled approximately 30,000 HIV-positive patients into its HIV care and treatment programme, over 21,000 of whom have received anti retroviral therapy since being enrolled. Patients on treatment are typically seen at least every 3 months with laboratory monitoring every 6 months to 1 year. The data collected include demographics, clinical visit data, laboratory data, medication history and clinical diagnoses. Requests for collaborations on analyses can be submitted to our data centre. PMID- 22434861 TI - Cohort Profile: the international childhood cardiovascular cohort (i3C) consortium. AB - This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence. PMID- 22434862 TI - Cohort profile: the Amsterdam Growth and Health Longitudinal Study. AB - The Amsterdam Growth and Health Longitudinal Study (AGHLS) is a unique, multidisciplinary cohort study that was initially set up to examine growth and health among teenagers. Throughout the years, the AGHLS has aimed to answer research questions dealing with the relationships between the (natural) development of anthropometry, lifestyle and health from adolescence into adulthood. The AGHLS specifically focuses on anthropometrics, physical activity and fitness, cardiovascular disease risk, lifestyle, musculoskeletal health, psychological health and well-being. Besides this, many methodological issues related to the analysis of longitudinal data were also explored within the framework of the AGHLS. In 1976, students from two secondary schools from the greater Amsterdam area were included in the study. Between 1976 and 2006, 10 rounds of measurement were performed covering an age range between 13 and 43 years. The huge database collected so far has been primarily used to answer relevant research questions regarding the longitudinal relationship between lifestyle and health. Further information about the study can be obtained from the principal investigator Jos Twisk (jwr.twisk@vumc.nl), and up-to-date information on AGHLS can be found by visiting the website www.aggo.nl. PMID- 22434863 TI - Cochrane column. PMID- 22434864 TI - The use of ethnically specific norms for ventilatory function in African-American and white populations. AB - BACKGROUND: In the USA, different standards are usually set for spirometric values in African-American and white populations. It is unclear to what extent the lower lung function found in African-Americans is 'normal' in the sense of having no adverse consequences. METHODS: African-American and white participants in the Atherosclerosis Risk in Communities (ARIC) limited access data set, from four communities in the USA had spirometric testing at baseline beginning in 1986 and were followed up to assess survival to the end of 2002. RESULTS: Forced Expiratory Volume in 1 s (FEV(1)) and Forced Vital Capacity (FVC) were lower in the African-American than the white sample both for men and women and adjustment for potential confounders had little effect on the estimated difference {difference in FVC after adjustment: men, -0.68 l [95% confidence interval (95% CI) -0.75 to -0.61]; women, -0.41 l (95%CI -0.45 to -0.36)}. The FEV(1)/FVC ratio was slightly greater among African-American than white participants [difference: men, 1.5% (95%CI 0.7-2.1); women, 1.7% (95%CI 1.1-2.2)]. After adjustment for age and height, survival was similar in each ethnic group for any given level of FVC before and after adjustment for potential confounders. The hazard ratio for African-American compared with white participants was 1.24 for men (95% CI 0.91 1.69) and 0.96 for women (95% CI 0.66-1.38). CONCLUSIONS: A given FVC has the same prognostic significance for 'normal' African-American and white participants. It is inappropriate to use ethnic norms when assessing prognosis. PMID- 22434865 TI - An interview with Jose Xavier Neto. Interviewed by Eva Amsen. AB - The Latin American Society for Developmental Biology (LASDB) is getting ready for their Sixth International Meeting, which will be held in Montevideo, Uruguay, from April 26th to 29th, 2012. To find out more about the society, and about developmental biology in Latin America, we talked to LASDB president Jose Xavier Neto, who studies heart morphogenesis at the Laboratorio Nacional de Biociencias in Sao Paulo, Brazil. PMID- 22434866 TI - Diverse roles for VEGF-A in the nervous system. AB - Vascular endothelial growth factor A (VEGF-A) is best known for its essential roles in blood vessel growth. However, evidence has emerged that VEGF-A also promotes a wide range of neuronal functions, both in vitro and in vivo, including neurogenesis, neuronal migration, neuronal survival and axon guidance. Recent studies have employed mouse models to distinguish the direct effects of VEGF on neurons from its indirect, vessel-mediated effects. Ultimately, refining our knowledge of VEGF signalling pathways in neurons should help us to understand how the current use of therapeutics targeting the VEGF pathway in cancer and eye disease might be expanded to promote neuronal health and nerve repair. PMID- 22434867 TI - Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin. AB - MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205. PMID- 22434868 TI - The transcriptional co-repressor Grg3/Tle3 promotes pancreatic endocrine progenitor delamination and beta-cell differentiation. AB - Pancreatic beta-cells arise from Ngn3(+) endocrine progenitors within the trunk epithelium of the embryonic pancreas. The emergence of endocrine cells requires E cadherin downregulation, but the crucial steps that elicit such are not clear, yet probably important for ultimately being able to efficiently generate beta cells de novo from stem cells. Grg3 (groucho-related gene 3, also known as Tle3), encodes a member of the Groucho/TLE family of co-repressors and its function in various cell contexts is mediated by recruitment to target genes by different transcription factors. Grg proteins broadly regulate the progression of progenitor cells to differentiated cell types, but specific developmental mechanisms have not been clear. We find that Grg3 is expressed in most beta-cells and a subset of other endocrine cell types in the pancreas. Grg3 is highly expressed in Ngn3(+) endocrine progenitor descendants just after transient Ngn3 expression. Grg3-null embryos die at E14.5, which is associated with placental defects, so we explanted E12.5 pancreata to allow endocrine differentiation to occur in culture. Grg3 knockout explants displayed a drastic decrease in the differentiation of all endocrine cell types owing to defects in the delamination of early endocrine progenitors from the trunk epithelium. We find that Grg3 normally suppresses E-cadherin gene expression, thereby allowing delamination of endocrine cells from the trunk epithelium and revealing how this transcriptional co-repressor modulates this crucial step of beta-cell development. PMID- 22434870 TI - The utility of immunohistochemistry for the identification of hematopoietic and lymphoid cells in normal tissues and interpretation of proliferative and inflammatory lesions of mice and rats. AB - Expression of antigens in cells and tissues can be readily studied immunohistochemically with the use of antibodies. A panel of antibodies to cell specific markers can be used to diagnose lesions, including tumors, in the hematopoietic and lymphoid systems. This review discusses the use of readily available antibodies and procedures to identify antigens expressed in normal tissues and in proliferative and inflammatory lesions in formalin-fixed, paraffin embedded (FFPE) murine specimens. PMID- 22434869 TI - Dermal beta-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. AB - Dermal fibroblasts are required for structural integrity of the skin and for hair follicle development. Uniform Wnt signaling activity is present in dermal fibroblast precursors preceding hair follicle initiation, but the functional requirement of dermal Wnt signaling at early stages of skin differentiation and patterning remains largely uncharacterized. We show in mice that epidermal Wnt ligands are required for uniform dermal Wnt signaling/beta-catenin activity and regulate fibroblast cell proliferation and initiation of hair follicle placodes. In the absence of dermal Wnt signaling/beta-catenin activity, patterned upregulation of epidermal beta-catenin activity and Edar expression are absent. Conversely, forced activation of beta-catenin signaling leads to the formation of thickened dermis, enlarged epidermal placodes and dermal condensates that result in prematurely differentiated enlarged hair follicles. These data reveal functional roles for dermal Wnt signaling/beta-catenin in fibroblast proliferation and in the epidermal hair follicle initiation program. PMID- 22434871 TI - New information from large tissue volumes to the smallest structures of the cell: what new methods and electron microscopy can do for your research. AB - This article presents an overview of microscopy and its ability to assist in understanding what happens in cells and tissues. From the 1960s to 1980s, electron microscopy was the best way to understand cell processes, but the advent in the mid-1980s of light microscopy and the ability to do fluorescence imaging displaced electron microscopy in this area. However, the 21st century has seen several improvements in electron microscopy that, along with the need for more detailed ultrastructural information, make it again very attractive in the study of cells, tissues, and organs, and electron microscopy has resumed its place as the preeminent method in understanding cell processes. PMID- 22434873 TI - RNA sequencing reveals dynamic changes of mRNA abundance of cytochromes P450 and their alternative transcripts during mouse liver development. AB - Cytochromes P450 (P450s) are a superfamily of enzymes that have critical functions in liver to catalyze the biotransformation of numerous drugs. However, the functions of most P450s are not mature at birth, which can markedly affect the metabolism of drugs in newborns. Therefore, characterization of the developmental profiles and regulatory mechanisms of P450 expression is needed for more rational drug therapy of pediatric patients. An animal model is indispensable for studying the mechanisms of postnatal development of the P450s. Hence we used RNA sequencing (RNA-Seq) to provide a "true quantification" of mRNA expression of all P450s in mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used. Total mRNAs of the 103 mouse P450s displayed two rapid increasing stages after birth, reflecting critical functional transition of liver during development. Four ontogenic expression patterns were identified among the 71 significantly expressed P450s, which categorized genes into neonatal-, adolescent-, adolescent/adult-, and adult-enriched groups. The 10 most highly expressed subfamilies of mouse P450s in livers of adult mice were CYP2E, -2C, -2D, -3A, 4A, -2F, -2A, -1A, -4F, and -2B, which showed diverse expression profiles during development. The expression patterns of multiple members within a P450 subfamily were often classified to different groups. RNA-Seq also enabled the quantification of known transcript variants of CYP2C44, CYP2C50, CYP2D22, CYP3A25, and CYP26B1 and identification of novel transcripts for CYP2B10, CYP2D26, and CYP3A13. In conclusion, this study reveals the mRNA abundance of all the P450s in mouse liver during development and provides a foundation for mechanistic studies in the future. PMID- 22434874 TI - Sulfation of 4-hydroxy toremifene: individual variability, isoform specificity, and contribution to toremifene pharmacogenomics. AB - Toremifene (TOR) is a selective estrogen receptor modulator used in adjuvant therapy for breast cancer and in clinical trials for prostate cancer prevention. The chemical structure of TOR differs from that of tamoxifen (TAM) by the presence of a chlorine atom in the ethyl side chain, resulting in a more favorable toxicity spectrum with TOR. In addition, some patients who fail on TAM therapy benefit from high-dose TOR therapy. Several studies have indicated that functional genetic variants in the TAM metabolic pathway influence response to therapy, but pharmacogenomic studies of patients treated with TOR are lacking. In this study, we examined individual variability in sulfation of 4-hydroxy TOR (4 OH TOR) (the active metabolite of TOR) in human liver cytosols from 104 subjects and found approximately 30-fold variation in activity. 4-OH TOR sulfation was significantly correlated (r = 0.98, P < 0.0001) with beta-naphthol sulfation (diagnostic for SULT1A1) but not with 17beta estradiol sulfation, a diagnostic substrate for SULT1E1(r = 0.09, P = 0.34). Examination of recombinant sulfotransferases (SULTs) revealed that SULT1A1 and SULT1E1 catalyzed 4-OH TOR sulfation, with apparent Km values of 2.6 and 6.4 MUM and Vmax values of 8.5 and 5.5 nmol x min(-1) x mg protein(-1), respectively. 4-OH TOR sulfation was inhibited by 2,6-dichloro-4-nitrophenol (IC50 = 2.34 +/- 0.19 MUM), a specific inhibitor of SULT1A1. There was also a significant association between SULT1A1 genotypes and copy number and 4-OH TOR sulfation in human liver cytosols. These results indicate that variability in sulfation could contribute to response to TOR in the treatment of breast and prostate cancer. PMID- 22434875 TI - R-CHIE: a web server and R package for visualizing RNA secondary structures. AB - Visually examining RNA structures can greatly aid in understanding their potential functional roles and in evaluating the performance of structure prediction algorithms. As many functional roles of RNA structures can already be studied given the secondary structure of the RNA, various methods have been devised for visualizing RNA secondary structures. Most of these methods depict a given RNA secondary structure as a planar graph consisting of base-paired stems interconnected by roundish loops. In this article, we present an alternative method of depicting RNA secondary structure as arc diagrams. This is well suited for structures that are difficult or impossible to represent as planar stem-loop diagrams. Arc diagrams can intuitively display pseudo-knotted structures, as well as transient and alternative structural features. In addition, they facilitate the comparison of known and predicted RNA secondary structures. An added benefit is that structure information can be displayed in conjunction with a corresponding multiple sequence alignments, thereby highlighting structure and primary sequence conservation and variation. We have implemented the visualization algorithm as a web server R-chie as well as a corresponding R package called R4RNA, which allows users to run the software locally and across a range of common operating systems. PMID- 22434876 TI - Grinder: a versatile amplicon and shotgun sequence simulator. AB - We introduce Grinder (http://sourceforge.net/projects/biogrinder/), an open source bioinformatic tool to simulate amplicon and shotgun (genomic, metagenomic, transcriptomic and metatranscriptomic) datasets from reference sequences. This is the first tool to simulate amplicon datasets (e.g. 16S rRNA) widely used by microbial ecologists. Grinder can create sequence libraries with a specific community structure, alpha and beta diversities and experimental biases (e.g. chimeras, gene copy number variation) for commonly used sequencing platforms. This versatility allows the creation of simple to complex read datasets necessary for hypothesis testing when developing bioinformatic software, benchmarking existing tools or designing sequence-based experiments. Grinder is particularly useful for simulating clinical or environmental microbial communities and complements the use of in vitro mock communities. PMID- 22434877 TI - Sequencing of RDR6-dependent double-stranded RNAs reveals novel features of plant siRNA biogenesis. AB - Biogenesis of trans-acting siRNAs (tasiRNAs) is initiated by miRNA-directed cleavage of TAS gene transcripts and requires RNA-dependent RNA polymerase 6 (RDR6) and Dicer-like 4 (DCL4). Here, we show that following miR173 cleavage the entire polyadenylated parts of Arabidopsis TAS1a/b/c and TAS2 transcripts are converted by RDR6 to double-stranded (ds)RNAs. Additionally, shorter dsRNAs are produced following a second cleavage directed by a TAS1c-derived siRNA. This tasiRNA and miR173 guide Argonaute 1 complexes to excise the segments from TAS2 and three TAS1 transcripts including TAS1c itself to be converted to dsRNAs, which restricts siRNA production to a region between the two cleavage sites. TAS1c is also feedback regulated by a cis-acting siRNA. We conclude that TAS1c generates a master siRNA that controls a complex network of TAS1/TAS2 siRNA biogenesis and gene regulation. TAS1/TAS2 short dsRNAs produced in this network are processed by DCL4 from both ends in distinct registers, which increases repertoires of tasiRNAs. PMID- 22434878 TI - Interaction of two photoreceptors in the regulation of bacterial photosynthesis genes. AB - The expression of photosynthesis genes in the facultatively photosynthetic bacterium Rhodobacter sphaeroides is controlled by the oxygen tension and by light quantity. Two photoreceptor proteins, AppA and CryB, have been identified in the past, which are involved in this regulation. AppA senses light by its N terminal BLUF domain, its C-terminal part binds heme and is redox-responsive. Through its interaction to the transcriptional repressor PpsR the AppA photoreceptor controls expression of photosynthesis genes. The cryptochrome-like protein CryB was shown to affect regulation of photosynthesis genes, but the underlying signal chain remained unknown. Here we show that CryB interacts with the C-terminal domain of AppA and modulates the binding of AppA to the transcriptional repressor PpsR in a light-dependent manner. Consequently, binding of the transcription factor PpsR to its DNA target is affected by CryB. In agreement with this, all genes of the PpsR regulon showed altered expression levels in a CryB deletion strain after blue-light illumination. These results elucidate for the first time how a bacterial cryptochrome affects gene expression. PMID- 22434879 TI - Mutually exclusive splicing regulates the Nav 1.6 sodium channel function through a combinatorial mechanism that involves three distinct splicing regulatory elements and their ligands. AB - Mutually exclusive splicing is a form of alternative pre-mRNA processing that consists in the use of only one of a set of two or more exons. We have investigated the mechanisms involved in this process for exon 18 of the Na(v) 1.6 sodium channel transcript and its significance regarding gene-expression regulation. The 18N exon (neonatal form) has a stop codon in phase and although the mRNA can be detected by amplification methods, the truncated protein has not been observed. The switch from 18N to 18A (adult form) occurs only in a restricted set of neural tissues producing the functional channel while other tissues display the mRNA with the 18N exon also in adulthood. We demonstrate that the mRNA species carrying the stop codon is subjected to Nonsense-Mediated Decay, providing a control mechanism of channel expression. We also map a string of cis elements within the mutually exclusive exons and in the flanking introns responsible for their strict tissue and temporal specificity. These elements bind a series of positive (RbFox-1, SRSF1, SRSF2) and negative (hnRNPA1, PTB, hnRNPA2/B1, hnRNPD-like JKTBP) splicing regulatory proteins. These splicing factors, with the exception of RbFox-1, are ubiquitous but their levels vary during development and differentiation, ensuing unique sets of tissue and temporal levels of splicing factors. The combinatorial nature of these elements is highlighted by the dominance of the elements that bind the ubiquitous factors over the tissue specific RbFox-1. PMID- 22434880 TI - Identification and classification of bacterial Type III toxin-antitoxin systems encoded in chromosomal and plasmid genomes. AB - Toxin-antitoxin systems are widespread in bacteria and archaea. They perform diverse functional roles, including the generation of persistence, maintenance of genetic loci and resistance to bacteriophages through abortive infection. Toxin antitoxin systems have been divided into three types, depending on the nature of the interacting macromolecules. The recently discovered Type III toxin-antitoxin systems encode protein toxins that are inhibited by pseudoknots of antitoxic RNA, encoded by short tandem repeats upstream of the toxin gene. Recent studies have identified the range of Type I and Type II systems within current sequence databases. Here, structure-based homology searches were combined with iterative protein sequence comparisons to obtain a current picture of the prevalence of Type III systems. Three independent Type III families were identified, according to toxin sequence similarity. The three families were found to be far more abundant and widespread than previously known, with examples throughout the Firmicutes, Fusobacteria and Proteobacteria. Functional assays confirmed that representatives from all three families act as toxin-antitoxin loci within Escherichia coli and at least two of the families confer resistance to bacteriophages. This study shows that active Type III toxin-antitoxin systems are far more diverse than previously known, and suggests that more remain to be identified. PMID- 22434881 TI - Deep annotation of mouse iso-miR and iso-moR variation. AB - With a dataset of more than 600 million small RNAs deeply sequenced from mouse hippocampal and staged sets of mouse cells that underwent reprogramming to induced pluripotent stem cells, we annotated the stem-loop precursors of the known miRNAs to identify isomoRs (miRNA-offset RNAs), loops, non-preferred strands, and guide strands. Products from both strands were readily detectable for most miRNAs. Changes in the dominant isomiR occurred among the cell types, as did switches of the preferred strand. The terminal nucleotide of the dominant isomiR aligned well with the dominant off-set sequence suggesting that Drosha cleavage generates most miRNA reads without terminal modification. Among the terminal modifications detected, most were non-templated mono- or di-nucleotide additions to the 3'-end. Based on the relative enrichment or depletion of specific nucleotide additions in an Ago-IP fraction there may be differential effects of these modifications on RISC loading. Sequence variation of the two strands at their cleavage sites suggested higher fidelity of Drosha than Dicer. These studies demonstrated multiple patterns of miRNA processing and considerable versatility in miRNA target selection. PMID- 22434882 TI - The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP. AB - The homologous cellular coactivators p300 and CBP contain intrinsic lysine acetyl transferase (termed HAT) activity. This activity is responsible for acetylation of several sites on the histones as well as modification of transcription factors. In a previous study, we found that HBZ, encoded by the Human T-cell Leukemia Virus type 1 (HTLV-1), binds to multiple domains of p300/CBP, including the HAT domain. In this study, we found that HBZ inhibits the HAT activity of p300/CBP through the bZIP domain of the viral protein. This effect correlated with a reduction of H3K18 acetylation, a specific target of p300/CBP, in cells expressing HBZ. Interestingly, lower levels of H3K18 acetylation were detected in HTLV-1 infected cells compared to non-infected cells. The inhibitory effect of HBZ was not limited to histones, as HBZ also inhibited acetylation of the NF kappaB subunit, p65, and the tumor suppressor, p53. Recent studies reported that mutations in the HAT domain of p300/CBP that cause a defect in acetylation are found in certain types of leukemia. These observations suggest that inhibition of the HAT activity by HBZ is important for the development of adult T-cell leukemia associated with HTLV-1 infection. PMID- 22434883 TI - Buffering and proteolysis are induced by segmental monosomy in Drosophila melanogaster. AB - Variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segments (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined; it is the leading cause of miscarriages and mental retardation and a hallmark of cancer. However, despite their documented importance in disease, the effects of aneuploidies on the transcriptome remain largely unknown. We have examined the expression effects of seven heterozygous chromosomal deficiencies, both singly and in all pairwise combinations, in Drosophila melanogaster. The results show that genes in one copy are buffered, i.e. expressed more strongly than the expected 50% of wild-type level, the buffering is general and not influenced by other monosomic regions. Furthermore, long genes are significantly more highly buffered than short genes and gene length appears to be the primary determinant of the buffering degree. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Thus, enhanced proteolysis appears to be a general response to aneuploidy. PMID- 22434884 TI - Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization. AB - Phase variation of surface structures occurs in diverse bacterial species due to stochastic, high frequency, reversible mutations. Multiple genes of Campylobacter jejuni are subject to phase variable gene expression due to mutations in polyC/G tracts. A modal length of nine repeats was detected for polyC/G tracts within C. jejuni genomes. Switching rates for these tracts were measured using chromosomally-located reporter constructs and high rates were observed for cj1139 (G8) and cj0031 (G9). Alteration of the cj1139 tract from G8 to G11 increased mutability 10-fold and changed the mutational pattern from predominantly insertions to mainly deletions. Using a multiplex PCR, major changes were detected in 'on/off' status for some phase variable genes during passage of C. jejuni in chickens. Utilization of observed switching rates in a stochastic, theoretical model of phase variation demonstrated links between mutability and genetic diversity but could not replicate observed population diversity. We propose that modal repeat numbers have evolved in C. jejuni genomes due to molecular drivers associated with the mutational patterns of these polyC/G repeats, rather than by selection for particular switching rates, and that factors other than mutational drift are responsible for generating genetic diversity during host colonization by this bacterial pathogen. PMID- 22434885 TI - A robust PCR primer design platform applied to the detection of Acidobacteria Group 1 in soil. AB - Environmental biosurveillance and microbial ecology studies use PCR-based assays to detect and quantify microbial taxa and gene sequences within a complex background of microorganisms. However, the fragmentary nature and growing quantity of DNA-sequence data make group-specific assay design challenging. We solved this problem by developing a software platform that enables PCR-assay design at an unprecedented scale. As a demonstration, we developed quantitative PCR assays for a globally widespread, ecologically important bacterial group in soil, Acidobacteria Group 1. A total of 33,684 Acidobacteria 16S rRNA gene sequences were used for assay design. Following 1 week of computation on a 376 core cluster, 83 assays were obtained. We validated the specificity of the top three assays, collectively predicted to detect 42% of the Acidobacteria Group 1 sequences, by PCR amplification and sequencing of DNA from soil. Based on previous analyses of 16S rRNA gene sequencing, Acidobacteria Group 1 species were expected to decrease in response to elevated atmospheric CO(2). Quantitative PCR results, using the Acidobacteria Group 1-specific PCR assays, confirmed the expected decrease and provided higher statistical confidence than the 16S rRNA gene-sequencing data. These results demonstrate a powerful capacity to address previously intractable assay design challenges. PMID- 22434886 TI - Collaborative coupling between polymerase and helicase for leading-strand synthesis. AB - Rapid and processive leading-strand DNA synthesis in the bacteriophage T4 system requires functional coupling between the helicase and the holoenzyme, consisting of the polymerase and trimeric clamp loaded by the clamp loader. We investigated the mechanism of this coupling on a DNA hairpin substrate manipulated by a magnetic trap. In stark contrast to the isolated enzymes, the coupled system synthesized DNA at the maximum rate without exhibiting fork regression or pauses. DNA synthesis and unwinding activities were coupled at low forces, but became uncoupled displaying separate activities at high forces or low dNTP concentration. We propose a collaborative model in which the helicase releases the fork regression pressure on the holoenzyme allowing it to adopt a processive polymerization conformation and the holoenzyme destabilizes the first few base pairs of the fork thereby increasing the efficiency of helicase unwinding. The model implies that both enzymes are localized at the fork, but does not require a specific interaction between them. The model quantitatively reproduces homologous and heterologous coupling results under various experimental conditions. PMID- 22434887 TI - Real-time monitoring of RAG-catalyzed DNA cleavage unveils dynamic changes in coding end association with the coding end complex. AB - During V(D)J recombination, the RAG1/2 recombinase is thought to play an active role in transferring newly excised recombination ends from the RAG post-cleavage complex (PCC) to the non-homologous end joining (NHEJ) machinery to promote appropriate antigen receptor gene assembly. However, this transfer mechanism is poorly understood, partly because of the technical difficulty in revealing weak association of coding ends (CEs) with one of the PCCs, coding end complex (CEC). Using fluorescence resonance energy transfer (FRET) and anisotropy measurement, we present here real-time monitoring of the RAG1/2-catalyzed cleavage reaction, and provide unequivocal evidence that CEs are retained within the CEC in the presence of Mg(2+). By examining the dynamic fluorescence changes during the cleavage reaction, we compared the stability of CEC assembled with core RAG1 paired with full-length RAG2, core RAG2 or a frameshift RAG2 mutant that was speculated to destabilize the PCC, leading to increased aberrant joining. While the latter two CECs exhibit similar stability, the full-length RAG2 renders a less stable CEC unless H3K4me3 peptides are added. Interestingly, the RAG2 mutant appears to modulate the structure of the RAG-12RSS pre-cleavage complex. Thus, the fluorescence-based detection offers a sensitive, quantitative and continuous assessment of pre-cleavage complex assembly and CEC stability. PMID- 22434888 TI - Mammalian HCA66 protein is required for both ribosome synthesis and centriole duplication. AB - Ribosome production, one of the most energy-consuming biosynthetic activities in living cells, is adjusted to growth conditions and coordinated with the cell cycle. Connections between ribosome synthesis and cell cycle progression have been described, but the underlying mechanisms remain only partially understood. The human HCA66 protein was recently characterized as a component of the centrosome, the major microtubule-organizing center (MTOC) in mammalian cells, and was shown to be required for centriole duplication and assembly of the mitotic spindle. We show here that HCA66 is also required for nucleolar steps of the maturation of the 40S ribosomal subunit and therefore displays a dual function. Overexpression of a dominant negative version of HCA66, accumulating at the centrosome but absent from the nucleoli, alters centrosome function but has no effect on pre-rRNA processing, suggesting that HCA66 acts independently in each process. In yeast and HeLa cells, depletion of MTOC components does not impair ribosome synthesis. Hence our results suggest that both in yeast and human cells, assembly of a functional MTOC and ribosome synthesis are not closely connected processes. PMID- 22434890 TI - When indecision is a decision and inaction is an action. PMID- 22434889 TI - Mechanism of strand displacement synthesis by DNA replicative polymerases. AB - Replicative holoenzymes exhibit rapid and processive primer extension DNA synthesis, but inefficient strand displacement DNA synthesis. We investigated the bacteriophage T4 and T7 holoenzymes primer extension activity and strand displacement activity on a DNA hairpin substrate manipulated by a magnetic trap. Holoenzyme primer extension activity is moderately hindered by the applied force. In contrast, the strand displacement activity is strongly stimulated by the applied force; DNA polymerization is favoured at high force, while a processive exonuclease activity is triggered at low force. We propose that the DNA fork upstream of the holoenzyme generates a regression pressure which inhibits the polymerization-driven forward motion of the holoenzyme. The inhibition is generated by the distortion of the template strand within the polymerization active site thereby shifting the equilibrium to a DNA-protein exonuclease conformation. We conclude that stalling of the holoenzyme induced by the fork regression pressure is the basis for the inefficient strand displacement synthesis characteristic of replicative polymerases. The resulting processive exonuclease activity may be relevant in replisome disassembly to reset a stalled replication fork to a symmetrical situation. Our findings offer interesting applications for single-molecule DNA sequencing. PMID- 22434891 TI - More than vigilance: protecting children from harm. PMID- 22434892 TI - Lipid resuscitation: listening to our patients and learning from our models. PMID- 22434893 TI - Variability indices of processed electroencephalography and electromyography. PMID- 22434894 TI - Neuroanesthesiology: then & now. PMID- 22434895 TI - A different kind of vigilance. PMID- 22434896 TI - Wall building. PMID- 22434897 TI - Intravenous lipid infusion restores consciousness associated with olanzapine overdose. PMID- 22434898 TI - Clinical experience: a potential hazard. PMID- 22434899 TI - Tracheal Intubation with the Pentax-AWS in Morbidly Obese Patients. PMID- 22434900 TI - A simple rewarming method to restore pulse oximeter signal detection. PMID- 22434901 TI - Spinal cord angiography and Rene Djindjian. PMID- 22434902 TI - Mechanical thrombectomy cannot be considered as first-line treatment for cerebral venous thrombosis. PMID- 22434903 TI - Author's response to: "A model is not just any model". PMID- 22434904 TI - Pre-intervention cerebral blood volume predicts outcomes in patients undergoing endovascular therapy for acute ischemic stroke. AB - BACKGROUND: Pre-intervention perfusion imaging is increasingly becoming part of stroke triage. Small studies supporting imaging based patient selection have been published. The goal of this larger study was to determine if perfusion imaging could impact on functional outcomes in patients undergoing stroke interventions. METHODS: All patients who had undergone endovascular therapy for anterior circulation strokes over a 7 year period were retrospectively analyzed. The pre intervention perfusion imaging was assessed for size of cerebral blood volume (CBV), cerebral blood flow and mean transit time (MTT) abnormalities. A perfusion mismatch for irreversible versus reversible ischemia was based on CBV and MTT. Clinical outcome and mortality were based on the 90 day modified Rankin Scale. An analysis of the pre-intervention perfusion parameters was then performed to determine any impact on functional outcomes. RESULTS: 110 patients underwent endovascular therapy for anterior circulation strokes. A younger age and lower National Institutes of Health Stroke Scale score were important clinical predictors of favorable outcome (modified Rankin Scale <= 2). The extent of the CBV abnormality and percentage of CBV/MTT mismatch were the strongest imaging predictors of outcome and mortality. A CBV area of 229.5 mm(2) (+/- 290) was seen for favorable outcomes versus 968 mm(2) (+/- 1173) for poor outcomes (p<0.0001). A CBV/MTT mismatch of 91% (+/- 10.7) was seen for favorable outcomes versus 72.5% (+/- 31.6) for poor outcomes (p=0.0001). The CBV area was 273 mm(2) (+/- 392) in patients without mortality versus 1401.1 mm(2) (+/- 1310) in patients with mortality (p<0.0001). Patients who survived had a mean CBV/MTT mismatch of 90.2% (+/- 12.5) versus 61.1% (+/- 35.2) for those who did not (p<0.0001). A CBV lesion approximately greater than one-third of the middle cerebral artery distribution predicted a poor outcome and mortality. CONCLUSION: The extent of pre intervention CBV abnormality is a strong predictor of functional outcomes following endovascular stroke therapy. This information can aid in patient selection and improve procedure efficacy. PMID- 22434905 TI - A model is not just any model. PMID- 22434906 TI - Mechanical thrombectomy as the primary treatment for acute basilar artery occlusion: experience from 5 years of practice. AB - BACKGROUND: Most studies of the treatment for acute basilar occlusion focus on intravenous or intra-arterial thrombolysis whereas data on mechanical thrombectomy as the preferred treatment for acute basilar occlusion are scarce. In this study, data are presented on 28 patients treated with mechanical thrombectomy as the preferred treatment for basilar artery occlusion. METHODS: Retrospective study comprising all patients who were treated for acute basilar occlusion at the Karolinska University Hospital from September 2005 to November 2010. Favorable outcome was defined as a modified Rankin score of <=2 at 3-8 months after thrombectomy. RESULTS: Of 28 patients treated with mechanical thrombectomy, the proportion reaching a favorable outcome was 57% (95% CI 37% to 75%), and if there were no signs of acute infarction prior to treatment the proportion was 73% (95% CI 50% to 89%). Only 21% died (95% CI 8% to 41%). CONCLUSIONS: The results for mechanical thrombectomy for basilar artery occlusion were superior to those presented previously for intravenous and intra-arterial thrombolysis. The study suggests that mechanical thrombectomy is a method distinct from therapies based on thrombolysis and that any randomized clinical trial on treatment for acute basilar occlusion must consider mechanical thrombectomy as a separate entity. PMID- 22434908 TI - Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells. AB - Under the instruction of cell-fate-determining, DNA-binding transcription factors, chromatin-modifying enzymes mediate and maintain cell states throughout development in multicellular organisms. Currently, small molecules modulating the activity of several classes of chromatin-modifying enzymes are available, including clinically approved histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors. We describe the genome-wide expression changes induced by 29 compounds targeting HDACs, DNMTs, histone lysine methyltransferases (HKMTs), and protein arginine methyltransferases (PRMTs) in pancreatic alpha- and beta-cell lines. HDAC inhibitors regulate several hundred transcripts irrespective of the cell type, with distinct clusters of dissimilar activity for hydroxamic acids and orthoamino anilides. In contrast, compounds targeting histone methyltransferases modulate the expression of restricted gene sets in distinct cell types. For example, we find that G9a/GLP methyltransferase inhibitors selectively up-regulate the cholesterol biosynthetic pathway in pancreatic but not liver cells. These data suggest that, despite their conservation across the entire genome and in different cell types, chromatin pathways can be targeted to modulate the expression of selected transcripts. PMID- 22434909 TI - Comparative genomics of Ceriporiopsis subvermispora and Phanerochaete chrysosporium provide insight into selective ligninolysis. AB - Efficient lignin depolymerization is unique to the wood decay basidiomycetes, collectively referred to as white rot fungi. Phanerochaete chrysosporium simultaneously degrades lignin and cellulose, whereas the closely related species, Ceriporiopsis subvermispora, also depolymerizes lignin but may do so with relatively little cellulose degradation. To investigate the basis for selective ligninolysis, we conducted comparative genome analysis of C. subvermispora and P. chrysosporium. Genes encoding manganese peroxidase numbered 13 and five in C. subvermispora and P. chrysosporium, respectively. In addition, the C. subvermispora genome contains at least seven genes predicted to encode laccases, whereas the P. chrysosporium genome contains none. We also observed expansion of the number of C. subvermispora desaturase-encoding genes putatively involved in lipid metabolism. Microarray-based transcriptome analysis showed substantial up-regulation of several desaturase and MnP genes in wood-containing medium. MS identified MnP proteins in C. subvermispora culture filtrates, but none in P. chrysosporium cultures. These results support the importance of MnP and a lignin degradation mechanism whereby cleavage of the dominant nonphenolic structures is mediated by lipid peroxidation products. Two C. subvermispora genes were predicted to encode peroxidases structurally similar to P. chrysosporium lignin peroxidase and, following heterologous expression in Escherichia coli, the enzymes were shown to oxidize high redox potential substrates, but not Mn(2+). Apart from oxidative lignin degradation, we also examined cellulolytic and hemicellulolytic systems in both fungi. In summary, the C. subvermispora genetic inventory and expression patterns exhibit increased oxidoreductase potential and diminished cellulolytic capability relative to P. chrysosporium. PMID- 22434912 TI - Geometry, epistasis, and developmental patterning. AB - Developmental signaling networks are composed of dozens of components whose interactions are very difficult to quantify in an embryo. Geometric reasoning enumerates a discrete hierarchy of phenotypic models with a few composite variables whose parameters may be defined by in vivo data. Vulval development in the nematode Caenorhabditis elegans is a classic model for the integration of two signaling pathways; induction by EGF and lateral signaling through Notch. Existing data for the relative probabilities of the three possible terminal cell types in diverse genetic backgrounds as well as timed ablation of the inductive signal favor one geometric model and suffice to fit most of its parameters. The model is fully dynamic and encompasses both signaling and commitment. It then predicts the correlated cell fate probabilities for a cross between any two backgrounds/conditions. The two signaling pathways are combined additively, without interactions, and epistasis only arises from the nonlinear dynamical flow in the landscape defined by the geometric model. In this way, the model quantitatively fits genetic experiments purporting to show mutual pathway repression. The model quantifies the contributions of extrinsic vs. intrinsic sources of noise in the penetrance of mutant phenotypes in signaling hypomorphs and explains available experiments with no additional parameters. Data for anchor cell ablation fix the parameters needed to define Notch autocrine signaling. PMID- 22434910 TI - Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B cell responses with age. AB - T cell-dependent B-cell responses decline with age, suggesting defective CD4 T cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both P < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all P < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (P = 0.002), which inversely correlated with the expression of CD40L (r = 0.65, P = 0.002), ICOS (r = 0.57, P = 0.008), and IL-4 (r = 0.66, P = 0.001). In CD4 KO mice reconstituted with DUSP4 OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (P = 0.003) and the production of ova-specific antibodies (P = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (P < 0.001), IL-4 (P = 0.007), and IL 21 (P = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (P = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses. PMID- 22434913 TI - Outcome and relapse risks of thrombotic thrombocytopaenic purpura: an Egyptian experience. AB - BACKGROUND: Thrombotic thrombocytopaenic purpura (TTP) is a rare life-threatening disease. Plasma exchange has significantly decreased the mortality from this disease, which still tends to recur in a substantial proportion of patients. This study describes the clinical spectrum and response to treatment and explores the risks of relapse in a cohort of patients. METHODS: Patients treated for TTP at the Clinical Haematology Unit, Cairo University, Egypt, between 2000 and 2008 were identified. Complete demographic, clinical history and full clinical examination, laboratory, treatment modalities and duration, and outcome data were collected and analysed. The follow-up duration was 24 months. RESULTS: 30 patients; 13 men (43%) and 17 women (57%) with a median age of 42 years were treated for 46 episodes of TTP. The median duration of disease onset to diagnosis for the first episode was 7 days. Twenty-three patients (76.66%) were diagnosed as idiopathic primary and seven patients (23.33%) were secondary TTP. Four patients died during the first 24 h. Of the 26 patients, 22 (85.6%) achieved remission with an average of 7.55 plasma exchange sessions, Another nine patients had 25 relapses (mean 2.7). Splenectomy was performed in three patients (11.5%). The 24-month overall survival was 80%. The initial low platelet count and high LDH were the only two statistically significant relapse predictors. CONCLUSIONS: The current results conform to the reported literature on the outcome of TTP. The very early mortality due to late referral highlights the need of education about the disease among primary healthcare providers. PMID- 22434914 TI - Quality of secondary prevention measures in TIA patients: a retrospective cohort study. AB - OBJECTIVE: Pharmacological and lifestyle interventions are recommended for the reduction of stroke risk in people who have had a transient ischaemic attack (TIA). This study aimed to investigate the quality of secondary stroke prevention in primary care following diagnosis of TIA in a specialist clinic. METHODS: Quality standards were identified from the Royal College of Physicians (RCP) national clinical guideline for stroke and the general practice Quality and Outcomes Framework (QOF) indicators. Patients who were diagnosed with TIA between February and October 2009 were identified from a TIA clinic database. Achievement of quality standards was assessed 12-24 months following clinic attendance. RESULTS: General practices were sent structured data collection forms for 233 patients, and the response rate was 80% (n=186). Complete data were available for 163 eligible patients (70%). Overall, 94% were prescribed antithrombotic medication. QOF standards were achieved by 82% for blood pressure (<=150/90 mm Hg) and 61% for total cholesterol (<=5.0 mmol/l). RCP standards were achieved by 35% for blood pressure (<=130/80 mm Hg) and 28% for total cholesterol (<4.0 mmol/l). RCP standards for the provision of dietary and exercise advice were achieved by 29% and 34% of patients, respectively. CONCLUSION: Only a minority of TIA patients achieved RCP standards whereas QOF standards were generally well achieved. Substantial benefits in terms of stroke prevention stand to be gained if risk factors are managed in line with more stringent RCP standards. PMID- 22434915 TI - A neural circuitry linking insulin resistance to depressed mood. AB - OBJECTIVE: Insulin resistance (IR) confers risk for Type 2 diabetes and is associated with depressed mood. Neurons within the ventral striatum (VS) are sensitive to insulin levels and show altered function in the context of both IR and depression. Hence, VS may represent a critical component of a neural circuitry linking IR to depressed mood. METHODS: Ninety adults (aged 30-50 years) free from major psychiatric illnesses and diabetes participated. Fasting blood was sampled, and participants completed a set of questionnaires (including the Beck Depression Inventory-II). Participants also underwent resting-state functional magnetic resonance imaging of the brain. Seed-based connectivity analyses, centered on VS, were conducted to examine how resting-state interregional connectivity patterns covaried with IR and depressed mood. RESULTS: Higher levels of IR covaried with increased connective strength between the left VS and two regions: the insula and the anterior midcingulate cortex (aMCC). Moreover, aMCC-VS connectivity predicted depressed mood (b = 0.93, standard error = 0.36, F(change)(1,81) = 6.54, p = .01). Finally, aMCC-VS connectivity was shown by Monte Carlo analysis to mediate the relationship between IR and depressed mood (a*b indirect effect = 0.16, confidence interval = 0.005-0.39, p = .03). CONCLUSIONS: IR relates to changes in the functional connectivity between VS and aMCC. These changes in interregional communication partly account for the coupling of IR to depressed mood in otherwise healthy adults. These findings are relevant for understanding bidirectional associations between diabetes risk and depressed mood. PMID- 22434916 TI - Combining psychosocial data to improve prediction of cardiovascular disease risk factors and events: The National Heart, Lung, and Blood Institute--sponsored Women's Ischemia Syndrome Evaluation study. AB - BACKGROUND: There is overlap among psychosocial predictors of cardiovascular disease (CVD). The usefulness of combining psychosocial variables as risk markers for CVD needs investigation. METHODS: Participants were 493 women in the NHLBI WISE study. Multivariate combination of Beck Depression Inventory (BDI), State Trait Anxiety Inventory (STAI), Social Network Index (SNI), and Cook-Medley hostility subscales was evaluated, and principal components analysis also conducted. Relationships of composite psychosocial risk markers to CVD events and risk factors were assessed. RESULTS: The multivariate block of SNI, Cook-Medley Hostile Affect subscale, STAI, and BDI predicted CVD events (chi(2) = 27.8, df = 6, p < .001). Scalewise factor analysis revealed 2 factors: negative affectivity (NA) and hostility (explained variance, 45.6% and 17.1%, respectively). NA was associated with BMI (beta [SE] = 0.18 [0.09], p = .04), hostility with metabolic syndrome (exp(beta) = 0.60 [0.28], p = .04). Both factors were associated with blood pressure (BP): NA with SBP (beta = 2.53 [1.04], p = .02) and DBP (beta = 1.66 [0.60], p = .02); hostility with SBP (beta = 2.72 [1.13], p = .02) and DBP (beta = 1.83 [0.65], p = .005). Neither factor predicted CVD events. Original scales predicted CVD events: lower SNI (HR = 0.74, CI = 0.57-0.96), lower Hostile Affect (HR = 0.80, CI = 0.56-1.03), and higher BDI (HR = 1.33, CI = 1.08-1.74). CONCLUSIONS: In women with suspected ischemia, multivariate combination of psychosocial risk markers predicts CVD events; derived psychosocial factors were associated with CVD risk factors but not events. Measuring common variance among psychosocial variables may be a useful research strategy. PMID- 22434917 TI - Mood problems increase the risk of mortality in patients with lacunar infarcts: the SMART-MR study. AB - OBJECTIVE: A relationship between depression and mortality has been well established, but underlying mechanisms remain unclear. We investigated the influence of cerebral small vessel disease (CSVD), characterized by white matter lesions (WMLs) and lacunar infarcts, on the relationship between mood mortality during 6 years follow-up. METHODS: Mood problems were assessed with the mental component summary of the 36-item Short-Form Medical Outcomes Study in 1110 patients with symptomatic atherosclerotic disease (mean age 59 years). Volumetric WML estimates were obtained with 1.5-T magnetic resonance imaging; lacunar infarcts were scored visually. Cox regression models were adjusted for age, sex, vascular risk, physical functioning, antidepressants and infarcts. We adjusted for CSVD to examine whether it may be an intermediate or confounding factor. Second, we added interaction terms to investigate whether associations differed between patients with CSVD (absent/present). RESULTS: Patients in the lowest quartile of mental functioning, representing most severe mood problems, were at higher, although not significant, risk of death (hazard ratio [HR] = 1.47, 95% confidence interval [CI] = 0.94-2.30) compared with patients in higher quartiles. Adjustment for CSVD did not change this association. Lacunar infarcts, not WML, modified the association of mood problems with mortality (p value for interaction = .01); mood problems strongly increased the risk of mortality in patients with lacunar infarcts (HR = 2.75, 95% CI = 1.41-5.38) but not in those without it (HR = 0.78, 95% CI = 0.39-1.57). CONCLUSIONS: Patients with lacunar infarcts may be especially vulnerable for the effect of mood problems on mortality. PMID- 22434918 TI - Depression in premenopausal women with HSDD: baseline findings from the HSDD Registry for Women. AB - OBJECTIVE: Hypoactive sexual desire disorder (HSDD) is a multifactorial disorder that is affected by, and may affect, mental health. Data are from the HSDD Registry for Women, a large multicenter observational study of US women with clinically diagnosed generalized, acquired HSDD. We analyzed complete baseline data from 1088 premenopausal women. METHODS: Validated measures of sexual function and distress, physical and mental health, and depression symptoms were obtained from participant and clinician questionnaires. Depression was defined as having a current diagnosis, symptoms (by Patient Health Questionnaire), or use of antidepressant (AD) medication. RESULTS: Thirty-four percent met criteria for current depression, of whom 56% took AD medication. Depressed women were less happy with their relationship, had greater difficulty forming or maintaining relationships, and decreased partnered sex compared with nondepressed HSDD patients. Sexual function was significantly lower in women with current depression (p < .001) versus nondepressed women. Among AD users, those with inadequately treated depression had increased severity of HSDD (p = .02) and reduced sexual desire (p = .04) compared with women in remission. Otherwise, AD use was not associated with sexual function differences among women with HSDD and diagnosed depression. CONCLUSIONS: About one third of premenopausal women with HSDD presented with current symptoms or a diagnosis of depression. Women with HSDD and depression reported poorer relationships and sexual function compared with women with HSDD and no depression. AD use was associated with sexual dysfunction only among women with unresolved symptoms of depression, and conversely, current symptoms of depression were associated with more severe HSDD among AD users. PMID- 22434919 TI - Do the effects of psychological treatments on improving glycemic control in type 1 diabetes persist over time? A long-term follow-up of a randomized controlled trial. AB - OBJECTIVES: In a randomized controlled trial, adults with Type 1 diabetes and suboptimal glycemic control who received motivational enhancement therapy (MET) plus cognitive behavioral therapy (CBT) had a greater reduction in their 12-month hemoglobin A(1c) (Hb(A1c)) than those who received usual care (UC). We tested whether improvements in glycemic control persisted up to 4 years after randomization. METHODS: In the original trial, participants were randomized to UC (n = 121), 4 sessions of MET (n = 117), or 4 sessions of MET plus 8 sessions of CBT (n = 106). Of the 344 patients who participated in the original trial, 260 (75.6%) consented to take part in this posttrial study. A linear mixed model was fitted to available measurements to assess whether intervention effects on Hb(A1c) at 12 months were sustained at 2, 3, and 4 years. RESULTS: Estimated mean Hb(A1c) level was lower for participants in the two intervention arms when compared with UC at 2, 3, and 4 years, but none of the differences were statistically significant. At 4 years, estimated mean Hb(A1c) level for MET plus CBT was 0.28% (95% confidence interval = -0.22% to 0.77%) lower than that for UC, and estimated mean Hb(A1c) level for MET was 0.17% (95% confidence interval = 0.33% to 0.66%) lower than that for UC. CONCLUSIONS: There was no evidence of benefit for patients randomized to MET plus CBT at 2, 3, or 4 years. Larger studies are needed to estimate long-term treatment effects with greater precision. Current models of psychological treatments in diabetes may need to be intensified or include maintenance sessions to maintain improvements in glycemic control. PMID- 22434920 TI - Gamma-ray rejection, or detection, with gadolinium as a converter. AB - Gadolinium is a competent neutron conversion material for neutron detection due to its extremely high neutron capture cross section. It differs from the other neutron reactive materials by emitting large amounts of low-energy electrons for the consequent signal generation in a detector. Such low-energy electrons, though abundant, are prone to be contaminated by internal and/or external gamma rays, such as the activated 43.0 keV K-X rays, given the high atomic number of gadolinium. While the 43.0 keV K-X ray ought to be rejected as it originates in part from the external gamma rays when neutron detection is concerned, the ability to separate this energy line from other signals points to a practical mode of gamma-ray detection by a thin-film semiconductor with gadolinium as a converter. In this paper, a gamma-ray discrimination scheme for neutron detection is studied, which also provides insight into gamma-ray detection with a small semiconductor device with gadolinium as a converter, in line with the same principle of isolating the K-X rays activated by high- or medium-energy gamma rays. PMID- 22434921 TI - A simple well-logging tool using boron-lined sodium iodide scintillators and an 241Am-Be neutron source. AB - A couple of 2-inch by 2-inch right cylinder sodium iodide scintillators and an Am Be radioisotope neutron source have been used in a neutron porosity well-logging tool to explore the variation of hydrogen contents in a prototype formation. Both Monte Carlo N-particle transport code simulation and experimental results of the near- to far-detector responses confirm the reliable sensitivity of proposed tool to the formation porosity. PMID- 22434922 TI - Air kerma to Hp(3) conversion coefficients for a new cylinder phantom for photon reference radiation qualities. AB - The International Organization for Standardization (ISO) has issued a standard series on photon reference radiation qualities (ISO 4037). In this series, no conversion coefficients are contained for the quantity personal dose equivalent at a 3 mm depth, H(p)(3). In the past, for this quantity, a slab phantom was recommended as a calibration phantom; however, a cylinder phantom much better approximates the shape of a human head than a slab phantom. Therefore, in this work, the conversion coefficients from air kerma to H(p)(3) for the cylinder phantom are supplied for X- and gamma radiation qualities defined in ISO 4037. PMID- 22434923 TI - Natural radioactivity and external dose assessment of surface soils in Vietnam. AB - In this study, natural radioactivity in surface soils of Vietnam and external dose assessment to human population, deduced from activities of (226)Ra, (232)Th and (40)K nuclides, were determined. From 528 soil samples collected in 63 provinces of Vietnam, including five centrally governed cities, the average activities were obtained and equal to 42.77 +/- 18.15 Bq kg(-1) for (226)Ra, 59.84 +/- 19.81 Bq kg(-1) for (232)Th and 411.93 +/- 230.69 Bq kg(-1) for (40)K. The outdoor absorbed dose rates (OADRs) in air at 1 m above the ground level for 63 provinces were calculated, and their average value was 71.72 +/- 24.72 nGy h( 1), with a range from 17.45 to 149.40 nGy h(-1). The population-weighted OADR of Vietnam was 66.70 nGy h(-1), which lies in the range of 18-93 nGy h(-1) found in the World. From the OADRs obtained, it was estimated that the outdoor annual effective dose and indoor annual effective dose to the population were 0.082 and 0.458 mSv, which are higher than the corresponding values 0.07 and 0.41 mSv, respectively, of the World. The radium equivalent activity Ra(eq) and the external hazard index H(ex) of surface soils of Vietnam are lower than the corresponding permissible limits of 370 Bq kg(-1) and 1, respectively. Therefore, soil from Vietnam is safe for the human population when it is used as a building material. PMID- 22434924 TI - Characterisation of a setup for mixed beam exposures of cells to 241Am alpha particles and X-rays. AB - Exposure of humans to mixed fields of high- and low-linear energy transfer (LET) radiation occurs in many situations-for example, in urban areas with high levels of indoor radon as well as background gamma radiation, during airplane flights or certain forms of radiation therapy. From the perspective of health risk associated with exposure to mixed fields, it is important to understand the interactions between different radiation types. In most cellular investigations on mixed beams, two types of irradiations have been applied sequentially. Simultaneous irradiation is the desirable scenario but requires a dedicated irradiation facility. The authors have constructed a facility where cells can be simultaneously exposed to (241)Am alpha particles and 190-kV X-rays at 37 degrees C. This study presents the technical details and the dosimetry of the setup, as well as validates the performance of the setup for clonogenic survival in AA8 Chinese hamster ovary cells. No significant synergistic effect was observed. The relative biological effectiveness of the alpha particles was 2.56 for 37 % and 1.90 for 10 % clonogenic survival. PMID- 22434925 TI - Detection of bremsstrahlung radiation of 90Sr-90Y for emergency lung counting. AB - This study explores the possibility of developing a field-deployable (90)Sr detector for rapid lung counting in emergency situations. The detection of beta emitters (90)Sr and its daughter (90)Y inside the human lung via bremsstrahlung radiation was performed using a 3" * 3" NaI(Tl) crystal detector and a polyethylene-encapsulated source to emulate human lung tissue. The simulation results show that this method is a viable technique for detecting (90)Sr with a minimum detectable activity (MDA) of 1.07 * 10(4) Bq, using a realistic dual shielded detector system in a 0.25-uGy h(-1) background field for a 100-s scan. The MDA is sufficiently sensitive to meet the requirement for emergency lung counting of Type S (90)Sr intake. The experimental data were verified using Monte Carlo calculations, including an estimate for internal bremsstrahlung, and an optimisation of the detector geometry was performed. Optimisations in background reduction techniques and in the electronic acquisition systems are suggested. PMID- 22434926 TI - Determination of relevant parameters for the use of electronic dosemeters in pulsed fields of ionising radiation. AB - Active electronic dosemeters using counting techniques are used for radioprotection purposes in pulsed radiation fields in X-ray diagnostics or therapy. The disadvantage of the limited maximum measurable dose rate becomes significant in these radiation fields and leads to some negative effects. In this study, a set of relevant parameters for a dosemeter is described, which can be used to decide whether it is applicable in a given radiation field or not. The determination of these relevant parameters-maximum measurable dose rate in the radiation pulse, dead time of the dosemeter, indication per counting event and measurement cycle time-is specified. The results of the first measurements on the determination of these parameters for an electronic personal dosemeter of the type Thermo Fisher Scientific EPD Mk2 are shown. PMID- 22434927 TI - Continuous electromagnetic radiation monitoring in the environment: analysis of the results in Greece. AB - Non-ionising radiation-monitoring networks were initiated as a result of the public concerns about the potential health effects from telecommunication emissions. In the present study, the data acquired from such networks in Greece are used to assess the changes in the outdoor electromagnetic environment with respect to location and time. The study shows that there is a statistically significant difference between the urban (median electric field: 1.1 V m(-1)) and the rural (median electric field: 0.3 V m(-1)) installations of monitoring units and also shows that there is a median diurnal variation (daily maximum to minimum) of 20.2 and 33.8 % for the broadcasting and mobile telecommunication emissions, respectively. Moreover, there is a difference in the electric field between daytime and night, but not between morning and afternoon. The results are in line with previously published data from spot measurements, monitoring networks and personal exposimeter studies performed in several European countries. PMID- 22434928 TI - Differentiation between benign and malignant breast tumors using kinetic features of real-time harmonic contrast-enhanced ultrasound. AB - BACKGROUND: Contrast-enhanced ultrasound (CEUS) has gained interest because of its ability to gather vascular information in diverse organs. There is still a subject of debate concerning its value in breast lesions, especially as a differential diagnostic tool. PURPOSE: To investigate whether kinetic parameters of CEUS can differentiate between malignant and benign breast lesions. MATERIAL AND METHODS: We evaluated 75 malignant and 21 benign lesions in the breast or axilla. Contrast harmonic imaging (CHI) US was performed after the injection of a bolus dose of 2.4 mL of Sono Vue(r) (Bracco, Milano, Italy). The following parameters were calculated for kinetic analysis: initial slope, time to peak enhancement, wash-out ratios W(21) and W(50) (relative decrease in signal intensity from the peak enhancement to 21 s and 50 s, respectively). RESULTS: A significant difference was found between the benign and malignant lesions in time to-peak (P value <0.05) and wash-out ratios W(21) (P value <0.001) and W(50) (P value <0.001). The mean time-to-peak was 9.3 s for malignant and 14.6 s for benign lesions. The mean signal drop from peak to signal intensity measured at 50 s was 85% for malignant and 66% for benign lesions. There was no difference in absolute values of peak signal intensity and initial slope. The most significant difference between standardized benign and malignant wash-out curves was found at 21 s but statistical significance was reached in the range of 14-50 s. CONCLUSION: Real-time CEUS can evolve into a new non-invasive option for differentiate malignant from benign breast lesions. PMID- 22434929 TI - Endovascular treatment of eight renal artery aneurysms. AB - BACKGROUND: Renal artery aneurysms (RAA) are a relatively rare vascular entity. Treatment could be either surgical or via an endovascular route. The main aim of therapy is to prevent lethal rupture. PURPOSE: To evaluate the angiographic and clinical results after endovascular treatment (EVT) of eight renal artery aneurysms. MATERIAL AND METHODS: From January 2000 to June 2011, 18 patients presented with 18 renal artery aneurysms. One was classified as Rundback type I, 15 were type II, and two aneurysms were type III. Endovascular treatment was considered unsafe in 10 cases (all were Rundback type II), and were referred to surgery. The remaining eight aneurysms were treated endovascularly during altogether nine sessions. Among these, four patients were asymptomatic, three were hypertensive, and one presented with ipsilateral flank pains. Aneurysmal sac diameter varied between 12 and 50 mm. EVT included selective coil embolization in five cases, covered stents in two cases, and parent artery occlusion in one. RESULTS: Follow-up with CT angiography was obtained in all endovascularly treated aneurysms (range 6-54 months, mean 15 months). Complete durable occlusion was achieved in all aneurysms except one, which showed re-expansion after 20 months and was retreated with covered stent implantation. Clinically silent, branch occlusion occurred after four procedures with subsequent limited (less than 25%) ischemic parenchymal loss. All patients were discharged with preserved renal function. Clinical improvement was noted in all symptomatic patients. CONCLUSION: Endovascular treatment of renal artery aneurysms is an adequate treatment and can be proposed, if feasible, as first step. PMID- 22434930 TI - The evolution of the cerebral blood volume abnormality in patients with ischemic stroke: a CT perfusion study. AB - BACKGROUND: Accurate identification of the acute infarct core abnormality is important for guiding acute stroke treatment. Abnormality volumes from diffusion weighted MRI (DWI) and CT perfusion (CTP)-cerebral blood volume (CBV) are highly correlated. DWI lesions have been shown to be reversible at 24 h. PURPOSE: To examine the temporal profile of the CT perfusion (CTP)-derived CBV abnormality out to 7 days post ischemic stroke. MATERIAL AND METHODS: Twenty-six patients were included. Group A (n = 13) underwent a non-contrast CT (NCCT), CTP/CT angiography (CTA) within 6 h of stroke onset, CTP/CTA at 24 h, and CTP/NCCT at 5 7 days post stroke. Group B (n = 13) underwent a NCCT, CTP/CTA within 6 h of stroke onset, and NCCT at 5-7 days. Recanalization status was established in all patients. For both groups, infarct volumes were traced on 5-7 day NCCT images and superimposed onto all CTP-CBV functional maps to determine CBV. Group B (n = 13) admission images were used to define CBV infarct thresholds for gray and white matter. CBV-lesion over-estimation was determined for Group A using the thresholds from Group B. RESULTS: CBV (mL.100g(- 1); mean +/- stdev) for gray/white matter, within confirmed infarcted regions (CBV(I)) at admission, 24 h, and 5-7 days were 1.82 +/- 0.56, 1.56 +/- 0.42, 1.75 +/- 0.31, and 1.38 +/- 0.65, 1.13 +/- 0.31, 1.32 +/- 0.44, respectively, when averaged over all patients (P > 0.05). Four patients had tissue time-density curves from ischemic lesions (TDC(i)) with an incomplete contrast medium wash-out phase (truncation) at admission and/or 24 h. Compared to admission, gray matter CBV(I) was higher at 5 7 days for patients with TDC(i) truncation (P < 0.05). There were no significant CBV(I) increases for the eight patients without truncation (P > 0.05). Over estimation of acute CBV lesion was present in 3/4 (75%) and 1/9 (11%) of patients with/without TDC(i) truncation, respectively. CONCLUSION: CTP-derived CBV lesion reversal is associated with TDC(i) truncation during the acute stroke phase. PMID- 22434931 TI - Interactions between mood and the structure of semantic memory: event-related potentials evidence. AB - Recent evidence suggests that affect acts as modulator of cognitive processes and in particular that induced mood has an effect on the way semantic memory is used on-line. We used event-related potentials (ERPs) to examine affective modulation of semantic information processing under three different moods: neutral, positive and negative. Fifteen subjects read 324 pairs of sentences, after mood induction procedure with 30 pictures of neutral, 30 pictures of positive and 30 pictures of neutral valence: 108 sentences were read in each mood induction condition. Sentences ended with three word types: expected words, within-category violations, and between-category violations. N400 amplitude was measured to the three word types under each mood induction condition. Under neutral mood, a congruency (more negative N400 amplitude for unexpected relative to expected endings) and a category effect (more negative N400 amplitude for between- than to within-category violations) were observed. Also, results showed differences in N400 amplitude for both within- and between-category violations as a function of mood: while positive mood tended to facilitate the integration of unexpected but related items, negative mood made their integration as difficult as unexpected and unrelated items. These findings suggest the differential impact of mood on access to long-term semantic memory during sentence comprehension. PMID- 22434932 TI - The structure of the TLR5-flagellin complex: a new mode of pathogen detection, conserved receptor dimerization for signaling. AB - Knowledge about how Toll-like receptors (TLRs) recognize pathogenic ligands is critical to understanding how these receptors are activated and to designing therapeutic compounds that target this family of receptors for inflammatory diseases. The crystal structure of TLR5 in complex with its bacterial ligand flagellin revealed that the ligand-binding mode for TLR5 is distinct from that of previously characterized TLRs. Nevertheless, like other TLRs, TLR5 forms a dimer in response to ligand binding. This work contributes to our current knowledge of TLR function and further demonstrates the ability of TLRs to couple versatile ligand recognition to a conserved receptor signaling mechanism. PMID- 22434933 TI - Cellular inhibitors of apoptosis are global regulators of NF-kappaB and MAPK activation by members of the TNF family of receptors. AB - Tumor necrosis factor (TNF) family members are essential for the development and proper functioning of the immune system. TNF receptor (TNFR) signaling is mediated through the assembly of protein signaling complexes that activate the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways in a ubiquitin-dependent manner. The cellular inhibitor of apoptosis (c IAP) proteins c-IAP1 and c-IAP2 are E3 ubiquitin ligases that are recruited to TNFR signaling complexes through their constitutive association with the adaptor protein TNFR-associated factor 2 (TRAF2). We demonstrated that c-IAP1 and c-IAP2 were required for canonical activation of NF-kappaB and MAPK by members of the TNFR family. c-IAPs were required for the recruitment of inhibitor of kappaB kinase beta (IKKbeta), the IKK regulatory subunit NF-kappaB essential modulator (NEMO), and RBCK1/Hoil1-interacting protein (HOIP) to TNFR signaling complexes and the induction of gene expression by TNF family members. In contrast, TNFRs that stimulated the noncanonical NF-kappaB pathway triggered translocation of c IAPs, TRAF2, and TRAF3 from the cytosol to membrane fractions, which led to their proteasomal and lysosomal degradation. Finally, we established that signaling by B cell-activating factor receptor 3 induced the cytosolic depletion of TRAF3, which enabled noncanonical NF-kappaB activation. These results define c-IAP proteins as critical regulators of the activation of NF-kappaB and MAPK signaling pathways by members of the TNFR superfamily. PMID- 22434935 TI - Using video feedback to improve early father-infant interaction: a pilot study. AB - Preventive interventions with parents of infants have tended to focus on mothers. Recent research focused on fathers suggests that their involvement in interventions might enhance effectiveness. One effective approach with mothers is the brief, home-based Video-feedback Intervention to promote Positive Parenting (VIPP). This paper is a report of a pilot study of VIPP with fathers to assess its feasibility. Five fathers were recruited from an existing longitudinal study of parents. The primary outcome was acceptability, assessed using a semi structured questionnaire after completion of the intervention. All fathers completed all sessions of the intervention. Fathers rated the intervention as having had a significant impact on their understanding of their child's thoughts and feelings, and as having improved their communication and relationship with their baby. Fathers' feedback was generally positive. The flexibility to conduct sessions at home (or at fathers' places of work) and the flexible timing of sessions were identified as fundamental to successful delivery. The results of this pilot study are encouraging, as VIPP with fathers was feasible. In light of the modest sample size, and the use of a non-clinical sample, the intervention must be evaluated with larger, clinical samples to evaluate its efficacy with fathers. PMID- 22434934 TI - Cannabinoids induce pancreatic beta-cell death by directly inhibiting insulin receptor activation. AB - Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic beta cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate-binding protein alpha subunit Galpha(i). Galpha(i) inhibited the kinase activity of the insulin receptor in beta cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad was reduced and its apoptotic activity was stimulated, leading to beta-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors enhanced insulin receptor signaling after injury, leading to reduced blood glucose concentrations and activation of Bad, which increased beta-cell survival. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and suggest a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors. PMID- 22434936 TI - Colorectal stents orient specimens and induce artifacts that mimic Crohn disease. AB - Colorectal malignancies may be stented to alleviate obstruction. The stent is a polarized and braided network of metallic wires. Pathology associated with colorectal stents is yet to be described. The authors reviewed 7 cases involving stented colorectal segments from patients lacking clinical suspicion of Crohn disease. In 4 cases, orientation of the specimens and stents matched the corresponding anatomic landmarks. In 3 cases, the specimens lacked helpful anatomic landmarks, and orientation was possible only after correlating with the intrinsic polarity of the stents. Stented areas showed artifacts resembling Crohn disease, including rounded cobblestones, pseudopolyps, and simple fissures, as well as unique artifacts including rhomboid cobblestones, complex fissures, oblique fissures with remarkably straight edges, and conical fragments of tissue that appeared to float. Crohn disease was misdiagnosed in 1 case in which the stent was removed intraoperatively and was never received. Colorectal stents help orient ambiguous specimens and induce patterned injury that can be confused with Crohn disease. PMID- 22434937 TI - Penalized likelihood methods for estimation of sparse high-dimensional directed acyclic graphs. AB - Directed acyclic graphs are commonly used to represent causal relationships among random variables in graphical models. Applications of these models arise in the study of physical and biological systems where directed edges between nodes represent the influence of components of the system on each other. Estimation of directed graphs from observational data is computationally NP-hard. In addition, directed graphs with the same structure may be indistinguishable based on observations alone. When the nodes exhibit a natural ordering, the problem of estimating directed graphs reduces to the problem of estimating the structure of the network. In this paper, we propose an efficient penalized likelihood method for estimation of the adjacency matrix of directed acyclic graphs, when variables inherit a natural ordering. We study variable selection consistency of lasso and adaptive lasso penalties in high-dimensional sparse settings, and propose an error-based choice for selecting the tuning parameter. We show that although the lasso is only variable selection consistent under stringent conditions, the adaptive lasso can consistently estimate the true graph under the usual regularity assumptions. PMID- 22434938 TI - The use of magnetic nanoparticles in thermal therapy monitoring and screening: Localization and imaging (invited). AB - Magnetic nanoparticles have many diagnostic and therapeutic applications. A method termed magnetic spectroscopy of nanoparticle Brownian motion (MSB) was developed to interrogate in vivo the microscopic environment surrounding magnetic nanoparticles. We can monitor several effects that are important in thermal therapy and screening including temperature measurement and the bound state distribution. Here we report on simulations of nanoparticle localization. Measuring the spatial distribution of nanoparticles would allow us to identify ovarian cancer much earlier when it is still curable or monitor thermal therapies more accurately. We demonstrate that with well-designed equipment superior signal to noise ratio (SNR) can be achieved using only two harmonics rather than using all the harmonics containing signal. Alternatively, smaller magnetic field amplitudes can be used to achieve the same SNR. The SNR is improved using fewer harmonics because the noise is limited. PMID- 22434939 TI - Tracer design for magnetic particle imaging (invited). AB - Magnetic particle imaging (MPI) uses safe iron oxide nanoparticle tracers to offer fundamentally new capabilities for medical imaging, in applications as vascular imaging and ultra-sensitive cancer therapeutics. MPI is perhaps the first medical imaging platform to intrinsically exploit nanoscale material properties. MPI tracers contain magnetic nanoparticles whose tunable, size dependent magnetic properties can be optimized by selecting a particular particle size and narrow size-distribution. In this paper we present experimental MPI measurements acquired using a homemade MPI magnetometer: a zero-dimensional MPI imaging system designed to characterize tracer performance by measuring the derivative of the time-varying tracer magnetization, M'(H(t)), at a driving frequency of 25 kHz. We show that MPI performance is optimized by selecting phase pure magnetite tracers of a particular size and narrow size distribution; in this work, tracers with 20 nm median diameter, log-normal distribution shape parameter, sigma(v), equal to 0.26, and hydrodynamic diameter equal to 30 nm showed the best performance. Furthermore, these optimized MPI tracers show 4 * greater signal intensity (measured at the third harmonic) and 20% better spatial resolution compared with commercial nanoparticles developed for MRI. PMID- 22434940 TI - Assessment of the innervation pattern of oral squamous cell carcinoma using neural protein gene product (9.5)-An immunocytochemical study. AB - BACKGROUND: This study was carried out to assess the innervation patterns in oral cancer using the general neuronal marker protein gene product 9.5 (PGP 9.5) and to find an explanation for why oral cancer tends to be painless in the early stages. MATERIALS AND METHODS: Tumor tissue from 30 unselected patients with oral squamous cell carcinoma was evaluated for this study. PGP 9.5 was used to localize nerve fibers in oral squamous cell carcinoma. An indirect immunofluorescence technique using biotin/FITC streptavidin detection system was used on paraffin wax sections of tumor tissue fixed in neutral buffered formalin. RESULTS: There was no PGP9.5 immunoreactivity in the normal tissue adjacent to the tumor in 18 cases out of 30 (60%). In 12/30 of oral squamous cell carcinoma, preexisting nerve fibers were detected in tissue stroma adjacent to the cancer tissue. Labeled nerve fibers between tumor cells were detected only in 2 out of the 30 cases. CONCLUSION: There are no apparent patterns of innervations in the cancer tissues themselves, but there are innervations patterns in the surrounding tissue, which presumably represents preexisting nerves. These results may partly explain why oral cancer tends to be painless in the early stages. PMID- 22434941 TI - Expression of vascular endothelial growth factor and microvessel density in oral tumorigenesis. AB - CONTEXT: Significant increase in vascularity occurs during the transition from normal oral mucosa, through differing degrees of dysplasia, to invasive squamous cell carcinoma (SCC). AIMS: To evaluate microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in oral tumorigenesis and correlate it with the clinicopathological characteristics. SETTINGS AND DESIGN: VEGF expression and MVD were quantified immunohistochemically using anti-VEGF and anti CD34 antibody. MATERIALS AND METHODS: For this study we used a total of 60 archival specimens, including 10 normal oral mucosa (NOM), 7 mild epithelial dysplasia (Mild ED), 8 moderate epithelial dysplasia (Mod ED), 5 severe epithelial dysplasia (SED), 14 well-differentiated SCC, 11 moderately differentiated SCC, and 5 poorly-differentiated SCC. VEGF expression was assessed in relation to the localization, intensity, and area of the immunohistochemically stained cells. MVD was evaluated using the Image-Pro((r)) Plus software. STATISTICAL ANALYSIS: One-way ANOVA (F test) was carried out for comparing the parameters for multiple groups such as different histopathological grades of dysplasia and carcinoma. Comparison between groups was carried out using the Student's 't' test. Correlations between VEGF score and MVD were estimated using the Karl Pearson coefficient of correlation. RESULTS: VEGF and MVD appeared to increase with disease progression and were statistically higher in oral SCC than in epithelial dysplasia and normal buccal mucosa. There was significant correlation between VEGF expression and MVD. CONCLUSIONS: These findings indicate that VEGF expression is upregulated during head and neck tumorigenesis. PMID- 22434942 TI - Stem cell therapy in oral and maxillofacial region: An overview. AB - Cells with unique capacity for self-renewal and potency are called stem cells. With appropriate biochemical signals stem cells can be transformed into desirable cells. The idea behind this article is to shortly review the obtained literature on stem cell with respect to their properties, types and advantages of dental stem cells. Emphasis has been given to the possibilities of stem cell therapy in the oral and maxillofacial region including regeneration of tooth and craniofacial defects. PMID- 22434943 TI - Oral pyogenic granuloma: Various concepts of etiopathogenesis. AB - Pyogenic granuloma or granuloma pyogenicum is a well-known oral lesion. The name pyogenic granuloma is a misnomer since the condition is not associated with pus and does not represent a granuloma histologically. Pyogenic granuloma of the oral cavity is known to involve the gingiva commonly. Extragingivally, it can occur on the lips, tongue, buccal mucosa, palate, and the like. A history of trauma is common in such sites. The etiology of the lesion is not known, though it was originally believed to be a botryomycotic infection. It is theorized that pyogenic granuloma possibly originates as a response of tissues to minor trauma and/or chronic irritation, thus opening a pathway for invasion of nonspecific microorganisms, although microorganisms are seldom demonstrated within the lesion. Pathogenesis of pyogenic granuloma is still debatable. Medline and PubMed databases were searched under the following key terms: Pathogenesis of oral pyogenic granuloma, pyogenic granuloma, and oral pyogenic granuloma. This search was limited to articles on human/animal studies which were published in English language. After reviewing the searched articles, the relevant articles were selected for the present review. Through this article, we have tried to summarize and present all the concepts of pathogenesis related to this most common and most mysterious oral lesion. PMID- 22434944 TI - Evolution of dental informatics as a major research tool in oral pathology. AB - Bioinformatics is a relatively new field of science that incorporates the principles of biology and computer science. It is mainly concerned with collecting, storing, and retrieving data from large databases. Ever since the successful completion of the Human Genome Project, there has been an exponential growth in the volumes of biological data that is being generated worldwide. The evolution of bioinformatics has made it possible to access these databases and apply the information for better research. One discipline that has been benefitted from the advent of bioinformatics is oral pathology. Oral pathology is a branch of dentistry which deals with the diseases of the head and neck region. Remarkable progress has been made in the diagnosis and treatment of diseases with the aid of bioinformatics. This article attempts to review the evolution and progress of dental informatics as a specialty and its applications in oral pathology. PMID- 22434945 TI - Second primary oral melanoma: A rare presentation. AB - Melanomas are neoplasms of melanocytic origin. They are aggressive neoplasms with an unpredictable behavior, and can involve virtually any organ of the body. Oral melanomas are very rare and have an extremely poor prognosis. Early diagnosis and prompt treatment is the key to reduce the morbidity and mortality. A second primary tumor is a new primary tumor developing in a person with a history of tumor, in a new site or tissue and subsequent to the initial tumor. Patients with previous history of melanoma are associated with a higher risk of developing second primaries. A case of second primary oral melanoma in a 55-year-old female is reported here. The anachronistic presentation of the primary and the second primary lesions make this case clinically interesting. Noteworthy immunohistochemical findings were recorded, HMB-45 positive and S-100 negative. PMID- 22434946 TI - Paget's disease of the mandible. AB - Paget's disease (PD) is a chronic progressive disease of the bone characterized by abnormal bone resorption and deposition affecting either single bone (monostotic) or many bones (polyostotic) with uncertain etiology. We report a case of isolated mandibular involvement in a 65-year-old female patient, clinically asymptomatic with abnormally increased alkaline phosphatase level (1 368.1 U/l). Although prevalence of PD is common in western countries, but rare in Asian chapter, that too isolated mandibular involvement, considering this fact, we report this case of PD for documentation. PMID- 22434947 TI - Calcifying epithelial odontogenic tumor (Pindborg tumor) without calcification: A rare entity. AB - The calcifying epithelial odontogenic tumor is a rare benign odontogenic tumor that was first described by Pindborg in 1955. It accounts for less than 1% of all odontogenic neoplasms. The tumor is characterized histologically by the presence of polygonal epithelial cells, calcification, and eosinophilic deposits resembling amyloid. Noncalcifying Pindborg tumor is very rare and only three cases have been documented in the English language literature so far. We present an additional case of noncalcifying Pindborg tumor and review the previously reported cases. Because noncalcifying Pindborg tumor is believed to be an aggressive variant, a definitive resection of the tumor with tumor-free surgical margins and long-term follow-up is recommended. PMID- 22434948 TI - Metastasizing granular cell ameloblastoma. AB - Ameloblastoma is a slow growing odontogenic epithelial tumor of jaw. It accounts for 1% of all tumors and cysts arising in maxilla and mandible. Although it is locally invasive and has a marked tendency to recur, metastasis is rare. Of the various histological patterns of ameloblastoma, the granular cell type is extremely rare accounting for 4% of ameloblastomas. We report a case of granular cell ameloblastoma with metastasis to the cervical lymph node presenting in a 40 year-old Indian female. PMID- 22434949 TI - Bilateral fusion of mandibular second premolar and supernumerary tooth: A rare case report. AB - Fusion is the union of two normally separated tooth germs resulting in the formation of a single large tooth. The prevalence of this anomaly is less than 1% and most common in the primary dentition, in the incisor-canine region. Fusions are almost always unilateral, but few cases of bilateral fusions have been reported. The purpose of this article is to report a rare case of bilateral fusion of mandibular second premolar with supernumerary tooth. PMID- 22434950 TI - Paradental cyst associated with supernumerary tooth fused with third molar: A rare case report. AB - Fusion is the union of two tooth buds that are normally separated. Fusion is more frequent in deciduous teeth, particularly in the anterior region. The etiology of fusion is not known. It has been suggested that the pressure of adjacent dental follicles produces their contact and fusion before calcification. There is no difference between men and women in incidence. The term paradental cyst means that such type of cysts that are close proximity with the root of a tooth. A history of recurrent pericoronitis is reported usually and there is often the presence of a communication between the periodontal pocket and the cyst. We present a rare case report where in partially erupted mandibular third molar is fused horizontally with a supernumerary tooth with paradental cyst. PMID- 22434951 TI - Salivary duct carcinoma of the parotid gland. AB - Salivary duct carcinoma of the parotid gland is an uncommon tumor, highly aggressive. About 200 cases have been reported in the English literature. Pathomorphologically, these tumors showed great similarities to ductal carcinoma of the female breast, which is why they described this tumor as "salivary duct carcinoma." The authors describe a new case of salivary duct carcinoma of the parotid gland. We present the case of a 50-year-old patient with progressive facial paralysis. The MRI examination of the head showed two ill-defined formations. A malignant tumor was strongly suspected, so that a total left parotidectomy with excision of the adjacent facial nerve and left lymph node dissection was performed. Microscopic examination concluded to a salivary duct carcinoma of the left parotid gland negative with Her2/neu antibody with lymph node metastasis. There were no recurrences or metastases within 3 years of follow up. Salivary duct carcinoma of the parotid gland is a rare tumor with an aggressive behavior. This is due to its propensity to infiltrate distant organs. The diagnosis is based on microscopic examination. Treatment modalities are non consensual, but some authors advocate the necessity of aggressive approach, especially in tumors negative with Heur2/neu antibody. This is due to the fact that the overexpression of this antigen was reported to be associated with a poor prognosis. PMID- 22434952 TI - High-grade mucoepidermoid carcinoma of maxillary sinus. AB - Malignant tumors of the paranasal sinus are uncommon, constituting less than 1% of all malignancies and 3% of all head and neck cancers. Nonsquamous cancers of the maxillary sinus are even rarer as is evident from the limited data available on the clinical characteristics and outcomes. Mucoepidermoid carcinoma accounts for 13% of all malignancies occurring in maxillary sinus. We report a rare case of high-grade mucoepidermoid carcinoma of maxillary sinus in a 45-year-old female along with review of the literature. PMID- 22434953 TI - Drug induced oral erythema multiforme: A rare and less recognized variant of erythema multiforme. AB - Oral erythema multiforme (EM) is considered as a third category of EM other than EM minor and major. Patients present with oral and lip ulcerations typical of EM but without any skin target lesions. It has been reported that primary attacks of oral EM is confined to the oral mucosa but the subsequent attacks can produce more severe forms of EM involving the skin. Hence, it is important to identify and distinguish them from other ulcerative disorders involving oral cavity for early management. This article reports two cases of oral EM that presented with oral and lip ulcerations typical of EM without any skin lesions and highlights the importance of early diagnosis and proper management. PMID- 22434954 TI - Basaloid squamous cell carcinoma. PMID- 22434955 TI - Ameloblastic carcinoma: Sometimes a challenge. PMID- 22434956 TI - Evaluation of pre-service training on integrated management of neonatal and childhood illness in ethiopia. AB - BACKGROUND: The Integrated Management of Newborn and Childhood Illness strategy equips health workers with essential knowledge and skills to effectively manage sick children with common neonatal and childhood diseases. Since in-service training is very demanding to achieve the desired coverage of training of health workers, pre-service training is taken as a solution. At the time of the survey, most public and some private health professionals' training institutions were conducting pre-service training. However, several concerns have been expressed on the training. Therefore, this survey was conducted to assess the status of pre service Integrated Management of New-born and Childhood Illness training. METHODS: A cross sectional survey on health professional training institutes/schools to evaluate pre-service Integrated Management of Newborn and Childhood Illness training was conducted in November 2007. Data was collected using pre-tested questionnaires, focused group interviews with teachers and students, observation of students while managing sick children using Integrated Management of Newborn and Childhood Illness guidelines, and reviews of pediatric course outlines and other teaching/learning materials. Data was entered in computer and analyzed using SPSS for Windows version 12.0.1. RESULTS: Twenty nine health professionals' training institutions (34 academic programs) which have started pre-service training were included in the survey. Of the 34 programs 22 were diploma nursing, 6 Bachelor of Sciences nursing, 4 health officer and the remaining two medicine. Thirty (88.2%) programs have integrated it in their curriculum. All academic programs had at least one fulltime staff for Integrated Management of Newborn and Childhood Illness classroom instruction. Twenty nine (85.3%) programs had staff trained in case management skills. All the 34 academic programs taught health workers skills, 28(82.3%) used mixed approach. Integrated Management of Newborn and Childhood Illness was either incorporated for 21 (61.8%) or added to the previous teaching 11 (32.3%). The instructor to student ratio was low for most of the schools. Main challenges encountered in the pre service teaching were constraints with trained staff and other resources each by 28 (82.3%) programs. Integrated Management of Newborn and Childhood Illness was included in student evaluation by all programs (100%). All students and instructors (100%) rated that Integrated Management of Newborn and Childhood Illness concept is very relevant or extremely relevant but majority said the time given was short. The over all mean score of students clinical practice was 63.5%. CONCLUSION: This study demonstrated that Integrated Management of Newborn and Childhood Illness was introduced into the teaching programs of most health professional training institutions. The most preferred teaching style was the mixed approach. Group discussion and demonstration were commonly used methods and Integrated Management of Newborn and Childhood Illness questions were included in students' evaluation in almost all programs. Shortage of IMNCI trained staff and teaching materials were major challenges. The use of teaching materials prepared for pre-service training like handbook and model chapter was limited. Instructors and students attitude towards IMNCI was very good. The students overall performance in managing sick child as per the IMNCI guidelines was above average. We recommend that the respective bodies at every level make every effort to strengthen IMNCI pre-service teaching through revisiting curricula, facilitating staff training, availing teaching materials and allocating adequate time. Exploring for an alternative/innovative and sustainable training approach is an assignment for all. PMID- 22434957 TI - Knowledge about Obstetric Danger Signs among Pregnant Women in Aleta Wondo District, Sidama Zone, Southern Ethiopia. AB - BACKGROUND: Raising awareness of women on danger signs of pregnancy, childbirth and the postpartum period is crucial for safe motherhood. In Ethiopia, a country where maternal morbidity and mortality is high little is known about knowledge level of pregnant women on obstetric danger signs. The objective of this study was to assess pregnant women's knowledge about obstetric danger signs in Aleta Wondo district, Sidama Zone, South Ethiopia. METHODS: A community based cross sectional study was conducted from January 18 - February 20, 2007, on a sample of 812 pregnant women selected from, 8 rural and 2 urban Kebeles. A structured pre tested questionnaire was used to collect quantitative data on socio-demographic characteristics, obstetric history, and knowledge about danger signs of pregnancy, childbirth and post partum period. Qualitative data was collected through focus group discussion with pregnant women and in-depth interview with traditional birth attendants. The collected data were analyzed using SPSS for Windows version 12.0.1. RESULTS: Seven hundred forty three pregnant women participated in the study making a response rate of 92%. Out of the 743 pregnant women who participated in this study 226 (30.4%), 305(41.3%) and 279(37.7%) knew at least two danger signs during pregnancy, childbirth and postpartum period, respectively. Being urban resident was consistently found to be strongly associated with mentioning at least two danger signs of pregnancy (OR=4.1; 95% CI: 2.4, 7.0), child birth (OR=3.3; 95% CI: 1.8, 6.1), and postpartum period (OR=8.4; 95% CI: 4.5, 15.4). CONCLUSION: This study indicated that the knowledge level of pregnant women about obstetric danger signs (during pregnancy, childbirth and postpartum period) was low and affected by residential area. Therefore, the identified deficiencies in awareness should be addressed through maternal and child health services by designing an appropriate strategies including provision of targeted information, education and communication. PMID- 22434958 TI - Patterns of diabetic complications at jimma university specialized hospital, southwest ethiopia. AB - BACKGROUND: Diabetes Mellitus is common metabolic disease worldwide. Its complications in the Ethiopian care setup has not been well documented. The objective of this study was to assess the pattern and distribution of diabetic complications among patients having follow-up at Jimma University specialized Hospital diabetic clinic. METHODS: A cross sectional study based on record review of 305 patients, selected using systematic sampling with replacement was carried out in October 2008. The data were analyzed using SPSS for Windows version 13.0. RESULTS: Larger proportion, 189 (62.0%), of patients had type II diabetes and 163 (53.4%) of them were diabetic for less than 5 years. Seventy three of the 76 (96.1%) patients with type II diabetes mellitus had hypertension. Acute complications were observed in 93 (30.5%) of the patients of which Diabetic Ketoacidosis was documented in 66(71.0%). Forty eight (45.7%) of patients had proteinuria, 90 (29.5%) had peripheral neuropathy, 13(6.8%) had impotence. Diabetic foot ulcer, skin and/or subcutaneous tissue infection, dental problems and tuberculosis were documented in 14(4.5%), 31(10.0%), 31(10.0%), and 17(5.6%) patients, respectively. Any of the chronic complications were not different by sex of the patient but age had statistically significant association with hypertension, visual disturbance and neuropathy (p< 0.05). Type of diabetes had statistically significant association with all the tested complications except infection (P<0.05) where most of the complications occurred in type II diabetics. Statistically significant association was observed between the duration of the diabetes and impotence and visual disturbances (p < 0.05). CONCLUSION: The majority of patients were type II diabetics. Acute complications were observed more commonly among type I diabetics and DKA was the commonest acute complication. The frequency of chronic complications was high. Increased occurrence of retinopathy, peripheral neuropathy, hypertension and nephropathy was observed with longer duration of illness. Impotence and diabetic nephropathy were more common in type II diabetics. The study showed that age, sex, type of diabetes mellitus and duration of diabetes were significantly associated with the development of diabetic complications. PMID- 22434959 TI - Microbial load, prevalence and antibiograms of salmonella and Shigella in lettuce and green peppers. AB - BACKGROUND: Human food borne infections traditionally are acquired through the ingestion of foods of animal origin. Fresh fruits and vegetables are major vehicles for the transmission of the food-borne infections. In Ethiopia, there is a tradition of consuming raw vegetables, particularly lettuce and green pepper, without adequate treatment. The objective of this study was to investigate the microbial load of fresh lettuce and green pepper, used as salad vegetables, and to assess the prevalence and antibiotic resistance of Salmonella and Shigella spp. isolated from lettuce and green pepper. METHODS: A total of eighty samples of lettuce and green peppers were purchased from different outlets in Addis Ababa and analyzed for their load of various microbial groups and flora analysis was conducted following standard microbiological methods. The presence of Salmonella and Shigella and their antibiotic resistance was also determined. RESULTS: Over 90% of the vegetable samples had aerobic mesophilic counts of >= log 6 cfu/g. Ninety seven percent of the lettuce and 58% of the green pepper samples had enterobacteraceae counts of >= log 5 cfu/g. Coliforms were encountered at counts >= log 4 cfu/g in 48% and 35% of lettuce and green pepper samples, respectively. Over 80% of vegetable samples harbored staphylococci with counts ranging from log 4 to log 6 cfu/g. More than 88% of lettuce and 18% of green pepper samples had yeast and mold counts >= log 4 cfu/g. The aerobic mesophilic flora of the vegetable samples was dominated by Bacillus and Micrococcus spp. Salmonella and Shigella were isolated from eight (10%) and 24 (30%) samples, respectively. All of the Salmonella and 97% of Shigella isolates showed resistance to penicillin. Ampicillin resistance was observed in 42% of Salmonella and 79% of Shigella isolates. Multiple drug resistance was seen in 8 and 24 isolates of Salmonella and Shigella isolates, respectively. CONCLUSION: The majority of lettuce and green pepper samples had high microbial load and multiple drug resistant pathogens were also isolated from some samples. As lettuce and green pepper, when used as salad vegetables, do not get any further heat treatment, thorough washing and considerably longer exposure of the vegetables to food grade chemicals is recommended to kill pathogens and significantly reduce the microbial load. PMID- 22434960 TI - Factors Associated with Perceived Continuation of Females' Genital Mutilation among Women in Ethiopia. AB - BACKGROUND: Females genital mutilation is one of the harmful traditional practices affecting the health of women and children. It has a long-term physiological, sexual and psychological effect on women. Females' genital mutilation still remains to be a serious problem for large proportion of women in most sub-Saharan Africa countries including Ethiopia. The objective of the study was to identify the main factors contributing to the support for the continuation of female genital mutilations in Ethiopia. METHODS: This study was conducted based on secondary data obtained from the Ethiopian Demographic and Health Survey 2005. A two-stage stratified cluster sampling design was applied for selecting the sampling units. Both descriptive and binary logistic regression analyses were used to analyse the data using SPSS for Windows version 16. RESULTS: The results on both descriptive and logistic regression model revealed that predictor variables like education, religion, residence, knowledge on ways of HIV transmission and region play significant role in determining the dependent variable. As a result, all predictor variables were strongly associated with the dependent variable. Regarding the fit of the model, support for the continuation of FGM, decreased with increase in education status. Furthermore, Muslim among other religions, and Somali and Afar among other regions, were more likely to support for the continuation of FGM. CONCLUSION: There was low awareness with less education status, Somali and Afar regions, rural residence, and Muslim religion were predictors of continuation of females' genital mutilation. PMID- 22434961 TI - Assessment of HIV Post-Exposure Prophylaxis Use Among Health Workers of Governmental Health Institutions in Jimma Zone, Oromiya Region, Southwest Ethiopia. AB - BACKGROUND: Infection with Human Immunodeficiency Virus is a serious public health problem costing the lives of many people including health workers. Hence, Ethiopia has developed guideline on the prevention of infection in health institutions in July 2004 and also employed the use of post exposure prophylaxis since the implementation of free antiretroviral in January 2005. However in the country, specifically in Jimma zone, published studies showing the clear picture about HIV post exposure prophylaxis in the work place were non-existent. Therefore, this study was conducted to assess the knowledge, practice and factors associated to HIV post-exposure prophylaxis use among health workers of governmental health institutions in the Zone. METHODS: A cross-sectional survey employing quantitative and qualitative methods was conducted from October to December 2008. Two hundred fifty four health workers participated in the quantitative study. Health workers for focus group discussion and key informants for in-depth interviews were identified with the help of administrators/ HIV/AIDs coordinators of the two administrative health bureaus and institutions included in the study. The quantitative data were entered and cleaned using Epi Info version 6.4 and analysed using SPSS for windows version 11.0. Descriptive statistics and chi-square test was employed to assess association among variables. P-value less than 0.05 was considered statistically significant. RESULTS: Among the total 254 participants, 213 (83.9%) had inadequate knowledge about post exposure prophylaxis of HIV and 174 (68.5%) had ever been exposed to HIV risk conditions. Out of 174 health workers exposed to HIV risk, 105 (60.3%) sustained needle prick/cut by sharps, 77 (44.3%) to blood and 68 (39.1%) exposed to patients' body fluid. Perceived causes of exposure were; high workload 77 (44.3%), lack of protective barriers 58 (33.3%) and lack of knowledge on standard precautions 31 (17.8%). One hundred forty two (81.6%) of those exposed did not use post-exposure prophylaxis. Lack of information about the existence of post exposure prophylaxis service 48 (33.8%), fear of stigma and discrimination 46 (32.4%), lack of understanding the value of reporting 33 (23.2%) and lack of support and encouragement to report 29 (20.4%) were the reasons for not using. Moreover, formal (separate) HIV post-exposure prophylaxis centre with proper guideline was non-existent in the study areas. CONCLUSIONS: In general, findings of the quantitative and qualitative study revealed that the knowledge of health workers about post exposure prophylaxis against HIV is inadequate. Though many of the studied health workers had HIV risk exposure, only few used post-exposure prophylaxis. Therefore, establishing a 24 hours accessible formal post-exposure prophylaxis centre with proper guideline is recommended. Health institutions are also advised to raise awareness of their employees on post exposure prophylaxis. PMID- 22434962 TI - Correlates of Selected Indices of Physical Fitness And Duration of Incarceration among Inmates in Some Selected Nigeria Prisons. AB - BACKGROUND: Incarceration has been associated with reduced physical activity. However, physical inactivity is a major cause of morbidity and mortality. The aim of the present study was therefore, to evaluate the incidence and relationship between the measures of physical fitness and the duration of incarceration in of inmates in Kano-Nigeria prisons. METHOD: A cross-sectional study was done to determine the relationship between the measures of physical fitness and the duration of incarceration of inmates in Kano prisons. Subjects' physical fitness level (cardio-respiratory fitness, body mass index and waist circumference) was assessed using standardized protocols. Simple percentage, Pearson moment correlation test and student's t-test were used to analyze variables of interest. RESULT: One hundred and sixteen inmates; 108 (93.1%) males and 8 (6.9%) females participated in the study. The study revealed high (93.1%) prevalence of low cardio-respiratory fitness among inmates and significant correlation between the selected indices of physical fitness (cardio-respiratory fitness, body mass index and waist circumference) and duration of incarceration. CONCLUSION: The prevalence of low cardio-respiratory fitness was high among inmates and long period of inadequate physical activity may be implicated as causative factor of low physical fitness among inmates in Kano prison. Prison administration and staff should encourage healthy inmate behavior. Provision of adequate facilities to encourage physical activity and sports participation is highly needed. PMID- 22434963 TI - The road to maternal death in rural southwest ethiopia. AB - The study explored cultural beliefs and practices contributing to maternal deaths together with maternal deaths reviews as testimonial. Six maternal deaths were retrospectively observed in rural southwest Ethiopia. Four of the 6 deaths occurred due to direct obstetric causes. Substandard primary and referral care, not understanding the severity of the problem, and lack of transport were the major themes identified as contributing factors. The result highlighted the need to improving primary health care, to strengthen referral system and community education. PMID- 22434964 TI - Factors influencing antenatal care service utilization in hadiya zone. AB - BACKGROUND: In Ethiopia, the levels of maternal and infant morbidity and mortality are among the highest in the world. This is attributed to, among other factors, none use of modern health care services by women in Ethiopia. According to the 2005 Ethiopian Demographic Health Survey, more than seven in ten mothers did not receive antenatal care at all. Therefore, the objective of this study was to explore factors influencing antenatal care services utilization in Southern Ethiopia. METHODS: A community-based cross sectional study was conducted in Hadiya Zone of Southern Ethiopia from January to February 2009. A multi stage sampling technique was used to select the study population in one urban and five rural kebeles. Analysis was done using SPSS for windows version 16. RESULT: This study revealed that antenatal care service utilization in the study area was 86.3%. However, from those who attended antenatal care service 406 (68.2%) started antenatal care visit during the second trimester of pregnancy and significant proportion 250 (42%) had less than four visits. Maternal age, husband attitude, family size, maternal education, and perceived morbidity were major predictors of antenatal care service utilization. CONCLUSION: Though the antenatal care service utilization is high in the study population, four in ten of the mothers did not have the minimum number of visits recommended by World Health Organization. Promoting information, education and communication in the community is recommended to favorably affect the major predictors of antenatal care service utilization. PMID- 22434965 TI - Child spacing and fertility planning behavior among women in mana district, jimma zone, South west ethiopia. AB - BACKGROUND: Short birth intervals and unintended pregnancies pose serious health risks to mothers and their infants by causing unnecessary high risk of pregnancy related complications and self induced abortions. The objective of the study was to assess the child spacing and fertility planning behavior of women in Mana district, Jimma zone. METHODS: A cross-sectional survey was conducted from July 18 - August 17, 2008 on 645 women who had a live birth in the three years prior to the survey. A simple random sampling technique was used to identify eligible women. A pre-tested structured questionnaire was used for data collection. Data were analyzed using SPSS for windows version 15. Frequency distributions, cross tabulation, and logistic regression analysis were performed. RESULTS: Analysis of birth intervals for women with non first births showed that 27% of births occurred within less than 24 months after a previous birth, showing that a considerable proportion of births were not adequately spaced to promote maternal and child health. About 39% of women reported that their recent pregnancy was unintended. Women with unintended pregnancy are more likely to be illiterate (OR=1.85,95%CI,1.23-2.79), have four or more living children(OR=2.77,95% CI,1.77 4.33), had a previous birth interval of less than 24 months(OR=1.78,95% CI(1.19 2.69), have never used contraception (OR=4.53, 95% CI, 3.05-6.75) and did not desire any more children (OR=1.84, 95% CI, 1.23-2.76). CONCLUSION: The study showed that an inadequate child spacing and high level of unintended pregnancy among considerable proportion of the study population. Unintended pregnancy and short birth intervals can pose serious health risks to mothers and their infants by causing unnecessary high risk of pregnancy related complications. Thus, improving access to safe and voluntary family planning counseling and services is essential to reduce the high level of unintended pregnancy and short birth intervals. PMID- 22434966 TI - Knowledge, attitude and practice of emergency contraception among graduating female students of jimma university, southwest ethiopia. AB - BACKGROUND: Emergency contraception refers to methods that women can use to prevent pregnancy after unprotected sexual intercourse, method failure or incorrect use. Unwanted pregnancy followed by unsafe abortion can be avoided by using different contraceptive methods including emergency contraceptives. The objective of this study was to assess the knowledge, attitude and practice of emergency contraception among graduating female students of Jimma University main campus. METHODS: A cross-sectional study was conducted in Jimma University main campus in 2009. The calculated sample size was allocated to each faculty proportions to size of female students. Then within the faculty the sample unit was selected by using simple random sampling technique. Data was collected using self administered questionnaire and analyzed using SPSS for widow version 16.0. RESULTS: A total of 389 (96.5%) volunteered graduating female students participated in the study. One hundred sixty three (41.9%) were ever heard of Emergency Contraceptive, only 11(6.8%) used the method. The common sources of information were friends 60 (36.5%), radio 37 (22.8%) and television 20 (12.3%). One hundred sixteen (71.2%) agreed to use Emergency Contraceptive when they practice unintended sexual intercourse. CONCLUSION: Awareness and use of emergency contraception among graduating female students of Jimma University was low. There is a need to educate adolescents about emergency contraceptives, with emphasis on available methods and correct timing of use. PMID- 22434967 TI - The pattern of cardiac diseases at the cardiac clinic of jimma university specialised hospital, South west ethiopia. AB - BACKGROUND: Rheumatic heart disease is the commonest cardiac disease in most sub Saharan African countries, followed by hypertensive heart disease which is rising along with the other non-communicable diseases. However the pattern in our setting is not known. This study aimed to determine the pattern of cardiac diseases among adult patients on follow-up at the cardiac follow-up clinic of Jimma University Specialized Hospital. METHODS: A cross-sectional study was conducted on cardiac patients who are newly enrolled to the cardiac follow up clinic of Jimma university specialized hospital during a five year period from 2003 to 2008. Out of the total 837 cases that were newly enrolled to the clinic in the five year period, 781 patients who had complete record about etiologic diagnosis were included in the study. The data were collected using structured record review checklist. The collected data were then analyzed using SPSS for windows version 12.0. RESULTS: Rheumatic heart disease was the diagnosis in 256 (32.8%) of the cardiac cases on follow-up followed by hypertensive heart disease and cardiomyopathy accounting for 189 (24.2%) and 158 (20.2%) of cases, respectively. Among Rheumatic heart disease patients; male to female ratio was 0.86:1 and the mean age was 31.4 years. One hundred ninety three (75.4%) of the cases with rheumatic heart disease had echocardiographic report that showed valve(s) involvements of pure MS in 99 (51.3%) and combined MS, MR in 49 (25.4%). Overall, hypertension contributed for a total of 241 (30.9%) of cardiac patients that included 189 (24.2%) hypertensive heart disease and 52 (6.7%) as one major risk factor for ischemic heart disease. CONCLUSION: Rheumatic, hypertensive and cardiomyopathic heart diseases accounted for more than three-quarters of cardiac diseases in the study population. This study highlighted the need for further study to determine the burden at community setting. PMID- 22434968 TI - Clinical effects of yoga on asthmatic patients: a preliminary clinical trial. AB - BACKGROUND: Asthma is one of the commonest respiratory diseases in Jimma area as well as a significant disease burden worldwide costing billions of dollars. Anti asthmatic drugs that are available in the market are expensive and have adverse effects. Thus, it is wise to look for an adjunct therapy to alleviate these problems. Therefore, the main aim of this study is to see the effect of yoga on patterns of clinical features, peak expiratory flow rates and use of drugs in asthmatic patients. METHODS: A preliminary controlled clinical trial study was conducted on 24 volunteer asthmatic patients who were getting support at the missionary of charity. They were grouped in yoga and control groups. An Indian yoga expert through a translator conducted the training on yogic practice, yogic posture, breath slowing technique and discussion at the end. Then, the yoga groups were supervised for four weeks taking yoga exercise daily for 50 minutes. Peak expiratory flow rate was taken using the mini Wright peak flow meter and vital signs were measured in both groups. Data were analyzed using web based Graph pad quick calcs statistical software. RESULTS: The male to female ratio was 1:1 in both cases and control groups, 8(66.7%) were Christian and 9 (75.0%) were farmers. The yoga group showed 66.7% reduction in the use of salbutamole puff and 58.3% salbutamole tablets. There was a 10% increment in the PEFR in the yoga group while only 2% in the control group. There was statistically significant reduction in day and night asthma attacks in the yoga group. CONCLUSION: Yoga exercise among asthmatic patients resulted in a decreased number of day and night attacks and use of drugs. It also shows significant improvement in the peak expiratory flow rate. Further large scale study is recommended. PMID- 22434969 TI - Reasons and outcomes of admissions to the medical wards of jimma university specialized hospital, southwest ethiopia. AB - BACKGROUND: Non-communicable diseases are the main reasons for admission to the medical wards in high-income countries. While in low and middle income countries communicable diseases are the main reasons for admission to the medical wards. However, in some low and middle income countries the reasons for admission are changing from communicable diseases to non-communicable diseases. But, data on reasons for admission to the medical wards of low income countries is scarce. Therefore, this study takes one year data from a low income country referral hospital aiming at describing the recent reasons and outcomes of medical admissions to see whether there is a change in reasons for admission and the outcome. METHODS: A retrospective study examined patient case notes and ward registration books of medical admissions at Jimma University Specialized Hospital from January 1, 2008 to December 31, 2008. Socio-demographic variables, reasons and outcomes of admission were some of the variables recorded during the data collection. The International Statistical Classification of Disease was used for sorting and categorizing the diagnosis. The data was then analyzed using SPSS windows version 13.0. RESULT: A total of 610 patient case notes were reviewed. The mean age of the patients was 36 years (SD +/- 15.75). The highest number of admissions 218 (35.7%) was among the age groups 21 to 30 years. Communicable diseases; namely severe community acquired pneumonia 139(22.8%), all infectious and parasitic diseases category 100 (16.4%), and pyogenic as well as chronic meningitis 80(13.1%) were the most common reasons for admission. The death rate among patients admitted to the medical wards was 12.6%. CONCLUSIONS: Communicable diseases were still the common reasons for medical admissions at Jimma University Specialized Hospital. The outcome of medical admissions has not changed over sixteen years. PMID- 22434970 TI - Risk Factors for Cardiovascular Diseases among Diabetic Patients In Southwest Ethiopia. AB - BACKGROUND: Studies on cardiovascular risk factors among diabetic persons in Ethiopia are lacking. The objective of this study was to determine the prevalence of the cardiovascular risk factors (hypertension, obesity, physical inactivity, dyslipidemia and smoking) among diabetic patients at the diabetic clinic of Jimma University Specialized Hospital. METHODS: A cross-sectional study was conducted from October to December 2007. Three hundred one individuals were randomly selected from 950 patients on follow-up. Data were collected using a structured format and appropriate equipments and reagents. Laboratory data were recorded in a separate checklist. The data were entered into SPSS for Windows version 12. Multivariate regression analysis was carried out to identify predictors of hypertension, obesity and dyslipidemia. RESULTS: Two hundred and fifty six (85.1%) of the sample participated in the study. The prevalence of hypertension, obesity, dyslipidemia, physical inactivity and current smoking was 46.5%, 23.4%, 63.5%, 55.1% and 5.5% respectively. Age >= 45 years, type 2 diabetes and obesity were predictors of hypertension. Females were less likely to be hypertensive (OR =2.26, 3.37, 3.79 and 0.48 respectively). Type 2 diabetics and females were more while rural diabetics were less likely to be obese. (OR =6.08, 4.17 and 0.37 respectively). Female gender, hypertension and fasting blood glucose >= 180mg/dl were predictors of dyslipidemia. Alcohol users were less likely to be dyslipidemic. (OR =4.25, 3.5, 3.56 and 0.39, respectively) CONCLUSION: Hypertension, obesity, dyslipidemia and physical inactivity were common while smoking was uncommon among diabetic patients in Jimma University Specialized Hospital. Type 2 DM was a predictor of hypertension and obesity. Diabetic women were more likely to be obese and dyslipidemic. We recommend screening and management of these risk factors. PMID- 22434971 TI - Impact assessment of gilgel gibe hydroelectric dam on schitosomiasis: a cross sectional study in southwest ethiopia. AB - BACKGROUND: Intestinal schistosomiasis is prevalent in East Africa including Ethiopia. Constructed five years back, Gilgel Gibe dam is suspected to harbor the intermediate host for transmission of schistosomiasis. The objective of this study was to determine the prevalence of intestinal schistosomiasis and risk factors among school children. METHODS: A comparative cross-sectional study was carried out in October 2008 in four Woredas bordering Gilgel Gibe dam, within 10 kilometers, and Bulbul, which is 30 Kms away from the dam. Children attending grades 1-8 in the schools located adjacent to the dam constituted the cases and those living in Bulbul constitute the controls. Using Epinfo version 6.0 for cross-sectional study, a sample size of 937 was determined. Sample size allocation was done 2:1 for cases and control. After interview, stool sample was collected and analyzed. Screening for the presence of intermediate host and physiochemical analyses of selected water bodies along the major water contact sites of the reservoir was also done Data were entered into computer and analyzed using SPSS for windows version 13.0.1. RESULTS: Out of 624 sampled cases and 312 controls, 585 and 270 participated in the study giving a response rate of 93.8% and 86.5%, respectively. Four hundred seventy four (81.0% of the cases and 203 (75.2%) controls use latrine regularly. On stool examination, 406 (47.5%) children, 295 (50.4%) cases and 111 (41.1%) controls) were positive to intestinal parasites but only two children, both from the control groups, were positive for Schistosoma mansoni. The three river water samples on which malacological survey was done had similar physicochemical characteristics in many ways except high conductivity, pH and percent of dissolved oxygen concentration (milligram per liter) at one site where uninfected Biomphilaria Pfeifferi was found CONCLUSION: The study revealed that schistosomiasis is not yet a problem at Gilgel-Gibe dam. But, continuous surveying is required as the intermediate host is prevalent, the water bodies are suitable for the intermediate host and cases of schistosomiasis are identified 30 kms away the dam, in control area. PMID- 22434972 TI - Microbial flora and food borne pathogens on minced meat and their susceptibility to antimicrobial agents. AB - BACKGROUND: Food-borne pathogens are the leading cause of illness and death in developing countries. Changes in eating habits, mass catering, unsafe food storage conditions and poor hygiene practices are major contributing factors to food associated illnesses. In Ethiopia, the widespread habit of raw beef consumption is potential cause for food borne illnesses. The present study aimed at investigating the microbial quality of meat available in common retail shops, restaurants and abattoir of Jimma City and determining susceptibility pattern of bacterial isolates. METHOD: A total of 165 samples from food establishments, butcher shops and a slaughter houses were processed and analyzed for the presence of indicator bacterial and potential food pathogens using standards methods. Antimicrobial susceptibility test was performed for Salmonella, Shigella and Staphylococcus aureus isolates using Kirby-Bauer disk diffusion method. RESULTS: A total of 165 samples were collected from twenty four hotels and five butchers and an abattoir. Various food borne pathogens were isolated in 13 (43.3%) and indicator organisms in 29 (96.7%) out of the thirty food establishments (hotels, butchery and abattoir). Overall, ten different bacterial species were isolated which included, proteus spp 89 (53.9%), E. coli 44 (26.6%), Providencia spp 23 (13.9%) Citrobacter spp 15(9%), Pseudomonas spp 9 (5.5%), Klebsiella spp 2 (1.2%), Enterobacter spp 2 (1.2%), Salmonella spp 2(1.2%), and Shigella species 1 (0.6%). Out of the 44 E. coli isolates 37 (84%) were thermo tolerant E. coli and out of the gram positive organisms identified 20 (12.1%) were Staphylococcus aureus isolates. From the two Salmonella isolates one was susceptible against all 12 tested antimicrobials, while the other to all the 11 except cephalexin. Shigella dysentery was resistant only to co-trimoxazole and tetracycline. Out of the 20 S. aureus isolates, 90% showed resistance to oxacillin, 85% to ampicillin, 65% to erythromycin, 60% to amoxicillin, 35% to streptomycin, and 20% to vancomycin and all isolates were sensitive to co-trimoxazole (100%). In this study, 90% (18/20) of the S. aureus isolates were Methicillin Resistant Staphylococcus aureus. CONCLUSION: In this study high percentage of indicator organisms as well as food borne pathogens were identified, which shows unhygienic condition of handling and processing in the food establishments. Our data also confirmed the presence of resistant food pathogens; particularly Staphylococcus aureus isolates which are Methicillin Resistant Staphylococcus aureus and multidrug resistant that emphasizes close follow up in the utilization of antibiotics. Therefore, meat handlers and sellers should be educated on the adverse effect of lack of proper personal, environmental hygiene and sanitation. In addition, consumers should be made aware of the risk of consuming raw and inadequately cooked meat. PMID- 22434973 TI - Incidence, causes and outcome of obstructed labor in jimma university specialized hospital. AB - BACKGROUND: Obstructed labor is one of the common preventable causes of maternal and perinatal morbidity and mortality in developing countries. Africa has the highest maternal mortality in the world, estimated at an average of about 1,000 deaths per 100,000 live births. This study was conducted to assess the incidence, causes and outcome of obstructed labor in Jimma University Specialized Hospital. METHODS: Hospital-based, cross-sectional study was conducted on all mothers who were admitted and delivered in the labor ward of Jimma University Specialized Hospital from November 1, 2008 to April 30, 2009. Data was collected using structured questionnaire and checklist, and then analyzed using SPSS for windows version 16.0. RESULTS: The incidence of obstructed labor was 12.2%. Out of these 61.5% did not have antenatal care follow-up. Most of the cases, accounting for 145(81.0%), 160 (89.4%) and 170 (93.9%) were referred from health centers, visited the hospital after at least 12 hours of labor and came from a distance of more than 10 kilometers, respectively. The causes of obstructed labor were cephalo-pelvic disproportion in 121(67.6%) and malpresentation in 50 (27.9%) of the cases. The commonest maternal complications observed were uterine rupture in 55 (45.1%) and sepsis in 48 (39.3%) of the cases with complications. Forty-five point eight percent of fetuses were born alive and all had low first minute APGAR score. CONCLUSION: The incidence of obstructed labor was high with high rate of complications. The antenatal care follow-up practice was also found to be low. Improved antenatal care coverage, good referral system, and availing comprehensive obstetric care in nearby health institution are recommended to prevent obstructed labor and its complications. PMID- 22434974 TI - Maternal height as an independent risk factor for neonatal size among adolescent bengalees in kolkata, India. AB - BACKGROUND: Low Birth Weight is a major public health problem in developing countries. The causes of LBW are multifactorial including complication during pregnancy, genetic, environmental, social-cultural, demographic and nutritional variables. Comparison of anthropometric risk factors for neonatal size of adolescent mothers are lacking from West Bengal. Therefore, this study was undertaken to identify maternal anthropometric characteristics, which most strongly influence neonate weight and length among Bengalee mothers. METHODS: A hospital based cross-sectional study was undertaken during 2004 in a Government general hospital in South Kolkata, India. A total of 76 adolescent (age<20years) pregnant women were enrolled from obstetric ward who were admitted for delivery. Due to 4 perinatal deaths; a total of 72 adolescent mother- baby pairs were included in this analysis. Anthropometric measurements were undertaken immediately after delivery following stabilization as well maternal body mass index (BMI) was calculated using standard formula. RESULTS: The prevalence of low birth weight (LBW) in the present study was 52.8%. The results revealed that 30.6% of mothers were undernourished (BMI<19.8 kg/m(2)). It was noted that about 64% of undernourished mothers delivered LBW baby. Linear regression analyses of neonatal weight and length as dependent variables revealed that in both cases, maternal height had the most significant impact. It showed 12.9% (birth weight) and 16.1% (birth length) of variation. Moreover, the proportion of LBW was 75%, 52.3% and 25% among short (height <=145 cm), average (146-155cm) and tall (>155cm) mothers (x(2)=6.855, p<0.01), respectively. Short mothers had 2.74 and 9.0 fold greater risk of delivering LBW baby than average and tall mothers. In contrast, mean birth weight and length of baby was lower in short mother than their counterparts. CONCLUSION: This study revealed that maternal height had the strongest significant impact on neonate size. This strong association could have serious health implications for Bengalee adolescent mothers. However, since this is a preliminary finding, it needs validation using a larger sample of adolescent mothers. PMID- 22434975 TI - Sexual practices and their development pattern among jimma university students. AB - BACKGROUND: Traditional views of sexual behaviors are frequently changing as the factors influencing them are changing. Therefore, assessing sexual practices that are not part of the tradition would be necessary. The objective of this study was to identify the types of sexual practices, their development pattern and how these development patterns expose students to sexually transmitted infections and unplanned pregnancy. METHODS: A cross-sectional survey was conducted on a sample of 1986 (1612 males, 365 females, and with 9 subjects' gender not indicated) Jimma university students in August 2009 with their age ranging from 17-45 years (median = 20). Quantitative data was collected using a piloted, precoded questionnaire and qualitative data was collected from six focus group discussions. Logistic regression and descriptive statistics were computed and qualitative findings were triangulated with quantitative findings. P-value less than 0.05 was considered significant. RESULTS: Practice of penile to vaginal intercourse, masturbation, kissing, oral sex, and anal sex were reported by 567 (28.9%), 688 (36.7%), 840 (42.4%), 179 (9.2%) and 83 (4.3%) of the respondents, respectively. Respondents had two years (one year with and one year without condom) of sexual experience before marriage. Sixty percent of those who had sexual experience were exposed to sexually transmitted infections and 46.6% were exposed to both unplanned pregnancy and sexually transmitted infections. Forty seven percent of those who practiced oral sex and 29% of those who practiced anal sex did not consider their acts as sexual intercourse. CONCLUSIONS: University students are high risk groups that need more focused research and concerted health care. The term 'sexual intercourse' should be consciously defined for its future use in Ethiopia. Furthermore, Service providers and researchers should address all types of sexual practices. PMID- 22434976 TI - Boy/Girl friend and virginity values, and stigma related to condom among jimma university students. AB - BACKGROUND: Individual factors such as the value given to virginity and boy/ girl friend, and stigma attached to condom can strongly affect success in preventing early sexual initiation and in using condom consistently. To the best knowledge of the authors, no literature was available in Ethiopia on these issues until the time of this study. The objective of this study was to assess the value given to virginity, boy/ girl friend, and stigma related to condom access and use. METHODS: A cross-sectional survey was conducted on a random sample of 1986 students in May 2009 in Jimma University using both qualitative and quantitative techniques. Data were collected using piloted and pre-coded questionnaire and from six focus group discussions. Quantitative data were analyzed using SPSS for windows version 13 where descriptive statistics, ANOVA, and t-test were computed. P-value less than 0.05 was considered statistically significant and effect size was measured in Eta squared. The qualitative data findings were triangulated with the quantitative ones. RESULTS: Of 1986 respondents, 1612 (81.2%) were males, 365 (18.4%) females and 9 (0.4%) their gender not indicated. The age of respondents ranged from 17- 45 years with median of 20 years. Virginity value-scores were significantly lower among females (p< 0.001, Eta squared= 0.023). In contrast to many males, most females appeared to be not concerned about virginity during the focus group discussions. Many respondents of both genders reported that boy/girl friend is very important in campus life. Although the stigma to condom was slightly higher among females (p< 0.001, Eta squared= 0.009), most respondents of both genders had a stigmatizing attitude. CONCLUSION: Lower virginity value among females with high value given to boy/girl friend appeared to indicate the liberalization of sex. Liberalization of sex and stigma to condom were occurring together. Sex educators targeting university students should focus on problems of liberalized unprotected sex in relation to success in life. PMID- 22434977 TI - Outcome of presumptive versus rapid diagnostic tests-based management of childhood malaria - pneumonia overlap in urban Nigeria: a pilot quasi experimental study. AB - BACKGROUND: Symptoms of malaria and pneumonia overlap in African under-five children and the integrated management of childhood illness strategy require that such children be managed presumptively with both antibiotics and antimalarials. A 2003 WHO expert meeting recommended the evaluation of malaria rapid diagnostic test in the management of children with this overlap, but this has not been evaluated. Therefore, the objective of this study was to compare the clinical outcome of presumptive versus malaria rapid diagnostic test-based management of childhood malaria-pneumonia overlap in Nigeria. METHODS: A pilot quasi experimental study was conducted November 2009 through February 2010 in an urban comprehensive health centre in Ogun, South-Western Nigeria. First, 50 children with malaria-pneumonia symptom overlap were consecutively enrolled and treated presumptively with antibiotics and antimalarials irrespective of malaria test result (control arm).Then, another 50 eligible children were enrolled and treated with antibiotics with/out antimalarials based on rapid diagnostic test result (intervention arm). Primary endpoint: clinical cure at day-5. The data were analyzed using Epi Info version 3.4.1. RESULTS: The intervention and control arms did not differ significantly regarding patient demographic and clinical characteristics. Clinical cure rate was slightly higher in children managed presumptively 49 (98%) than those managed rapid diagnostic test -based 47 (94%) (P = 0.31). However, rapid diagnostic test -based treated children had lower risk of receiving antimalarials compared to those treated presumptively (48% vs. 100%), (P = <0.001; relative risk 2.08, CI 1.56 to 2.78). No death or severe complications were recorded in either group at day-5 follow-up. CONCLUSION: Outcome of rapid diagnostic test-based treatment is not inferior to presumptive management in children with malaria-pneumonia symptom overlap. More extensive studies with larger sample sizes are needed. PMID- 22434978 TI - Knowledge and practice of malaria prevention methods among residents of arba minch town and arba minch zuria district, southern ethiopia. AB - BACKGROUND: To date, there is no effective vaccine or no effective drug for mass chemoprophylaxis against malaria. Thus, proper know-how and use of prevention methods is crucial. This study aims to assess the knowledge and practice of malaria prevention methods among the residents of Arba Minch area, Southern Ethiopia. METHODS: A community-based cross-sectional study that utilized a two stage sampling was conducted from January 22 to February 1, 2007 on a sample of 454 household heads or their deputies. SPSS 16 for windows was used for data analysis. Chi-square and Fisher's exact probability tests were used to assess the association of selected variables with place of residence. RESULTS: Majority (86.8%) of the respondents mentioned fever as a symptom of malaria, and 98.2% of the respondents reported mosquito bite as the cause of malaria. Three hundred and eighty four (84.6%) of the respondents mentioned mosquito nets as protective measures against mosquito bites. The protective measure mostly used by the respondents or other household members in the last 12 months was mosquito net (73.3%) followed by aerosol insecticide (13%) with the former being used more in rural areas and the latter in urban areas. CONCLUSION: The study subjects' awareness regarding the cause, symptoms and preventive measures of malaria was high. Use of mosquito net as protective measure against mosquito bites in the last 12 months was high. However, use of other preventive measures was low. Behavioral change communication is required to increase the use of other preventive measures along with mosquito nets. PMID- 22434979 TI - Knowledge, attitude and practice of emergency contraceptives among adama university female students. AB - BACKGROUND: Unwanted pregnancy followed by unsafe abortion is one of the major worldwide health problems, which has many negative consequences on the health and well-being of women. Information about women's knowledge, attitude and practice of emergency contraceptives plays a major role in the reduction of unwanted pregnancy; however, there are no studies about this issue in the study area. This study assessed Adama University female students' knowledge, attitude and practice of emergency contraceptives. METHOD: A cross-sectional study design was employed from February 1 to 30/2009, on 660 regular undergraduate female students of Adama University. Data were entered and analyzed using SPSS for windows version 16.0. Logistic regression was used to identify the association between variables and emergency contraceptive knowledge, attitude and practice. P-value less than 0.05 at 95% CI was taken for statistical significance. RESULTS: Of the total, 660 respondents, 194(29.4%) were sexually active, 63(9.4%) had history of pregnancy and 49(7.4%) had history of abortion. About 309 (46.8%) of the students had heard about emergency contraceptives and from those who heard emergency contraceptives, 27.2% had good knowledge. Majority, four hundred fifteen (62.9%) of the students had positive attitude towards it. However, only 31(4.7%) had used emergency contraceptive methods. CONCLUSION: This study demonstrated lack of awareness, knowledge and utilization of emergency contraceptives among Adama University female students. Hence behavioral change strategies should be considered by responsible bodies to improve knowledge and bring attitudinal change on use of emergency contraception. PMID- 22434980 TI - Invasive Bacterial Pathogens and their Antibiotic Susceptibility Patterns in Jimma University Specialized Hospital, Jimma, Southwest Ethiopia. AB - BACKGROUND: Presence of microorganisms in the circulating blood whether continuously or intermittently is a threat to every organ in the body. Approximately 200,000 cases of bacteraemia occur annually with mortality rates ranging from 20-50%. Early diagnosis and appropriate treatment of these infections can make the difference between life and death. The aim of the present study was to determine the bacterial flora of the blood stream infections and their antibiotic susceptibility pattern. METHODS: A cross sectional study was conducted on 260 adult febrile patients in Jimma University Specialized Hospital from 27 October 2009 to 26 March 2010. The positive blood cultures were examined and the organisms were identified as per standard procedures. Antimicrobial testing was performed for all isolates by disk diffusion techniques, according to Clinical Laboratory Standards Institute guide lines. The data was analyzed using SPSS for windows version 16 and Microsoft Office Excel. RESULTS: From the total of two hundred sixty blood specimens only 23(8.8%) were positive to seven different types of bacteria. The isolated bacteria were: Coagulase negative staphylococci 6(26.1%), S. aureus 5 (21.7%), S. pyogens 3 (13.0%), E. coli 4(17.4%), K. pneumoniae 3(13.0%), Salmonella spp. 1(4.3%), and Citrobacter spp. 1(4.3%). The isolates showed high rates of resistance to most antibiotics tested. The range of resistance for gram positive bacteria were 0% to 85.7%, and for gram negative from 0% to 100%. None of the isolates were resistance to ciprofloxacin and ceftriaxone. CONCLUSION: Our study result showed the presence of invasive bacterial pathogens with high rate of resistance to most commonly used antibiotics used to treat bacterial infections. Therefore, timely investigation of bacterial flora of the blood stream infections and monitoring of their antibiotic resistance pattern plays an important role in reduction of the incidence of blood stream infections. PMID- 22434981 TI - Indoor air bacterial load and antibiotic susceptibility pattern of isolates in operating rooms and surgical wards at jimma university specialized hospital, southwest ethiopia. AB - BACKGROUND: Surgical site infection is the second most common health care associated infection. One of the risk factors for such infection is bacterial contamination of operating rooms' and surgical wards' indoor air. In view of that, the microbiological quality of air can be considered as a mirror of the hygienic condition of these rooms. Thus, the objective of this study was to determine the bacterial load and antibiotic susceptibility pattern of isolates in operating rooms' and surgical wards' indoor air of Jimma University Specialized Hospital. METHODS: A cross sectional study was conducted to measure indoor air microbial quality of operating rooms and surgical wards from October to January 2009/2010 on 108 indoor air samples collected in twelve rounds using purposive sampling technique by Settle Plate Method (Passive Air Sampling following 1/1/1 Schedule). Sample processing and antimicrobial susceptibility testing were done following standard bacteriological techniques. The data was analyzed using SPSS version 16 and interpreted according to scientifically determined baseline values initially suggested by Fisher. RESULTS: The mean aerobic colony counts obtained in OR-1(46cfu/hr) and OR-2(28cfu/hr) was far beyond the set 5-8cfu/hr acceptable standards for passive room. Similarly the highest mean aerobic colony counts of 465cfu/hr and 461cfu/hr were observed in Female room-1 and room-2 respectively when compared to the acceptable range of 250-450cfu/hr. In this study only 3 isolates of S. pyogenes and 48 isolates of S. aureus were identified. Over 66% of S. aureus was identified in Critical Zone of Operating rooms. All isolates of S. aureus showed 100% and 82.8% resistance to methicillin and ampicillin respectively. CONCLUSION: Higher degree of aerobic bacterial load was measured from operating rooms' and surgical wards' indoor air. Reducing foot trafficking, improving the ventilation system and routine cleaning has to be made to maintain the aerobic bacteria load with in optimal level. PMID- 22434982 TI - Bacteriological and physicochemical quality of drinking water and hygiene sanitation practices of the consumers in bahir dar city, ethiopia. AB - BACKGROUND: Lack of safe drinking water, basic sanitation, and hygienic practices are associated with high morbidity and mortality from excreta related diseases. The aims of this study were to determine the bacteriological and physico-chemical quality of drinking water and investigate the hygiene and sanitation practices of the consumers in Bahir Dar City, Ethiopia. METHODS: A cross sectional prospective study was conducted in Bahir Dar City from October-December, 2009. Water samples were collected from 35 private taps and 35 household water containers for bacteriological analysis. The turbidity, pH, temperature and turbidity were measured immediately after collection. Finally, the hygiene-sanitation practices of the consumers were surveyed using interview. RESULTS: Twenty seven (77.1%) of the household water samples had high total coliforms counts. Twenty (57.1%) household water samples and 9 (25.7%) of the tap water samples had no residual free chlorine. Sixteen (45.7%) household water samples had very high risk score to thermotolerant coliforms. Eight (22.9%) tap water samples had low risk score for total coliforms whereas 21(60%) tap water had very low risk score for thermotolerant coliforms. Twelve (34.3%) of the consumers collect water without contact with their hand and 9(25.7%) wash their hands with soap after visiting toilet. CONCLUSION: Water supplies at tap and household water containers were contaminated with bacteria. Poor sanitation, low level of hygiene, uncontrolled treatment parameters are the causes for contamination. Control of physico chemical parameters and promoting good hygiene and sanitation are recommended. PMID- 22434983 TI - The structure and reliability of the amharic version of the hospital anxiety and depression scale in orphan adolescents in addis ababa. AB - BACKGROUND: The Hospital Anxiety and Depression Scale was developed as a self assessment tool to identify anxiety and depression in patients of age 16-65 years. Its use in younger age groups and illiterate populations is not well examined. The purpose of this study was to examine the structure, reliability, and applicability of its Amharic version in a community sample of early orphan adolescents. METHODS: Secondary data primarily collected from randomly selected 804 orphans using the Amharic version of the Hospital Anxiety and Depression Scale by interview technique in March 2010 in Addis Ababa was used with permission. Confirmatory factor analysis with principal components extraction and oblique rotation (delta=0) was computed. The internal consistency of the subscales was assessed using Cronbach's alpha and the correlation between the subscales was assessed using Pearson correlation. RESULTS: In the whole sample (age 11-18 years), two factors: anxiety and depression, explaining a total of 45.9% of the variance were found. In the 11-15 years sub-sample, the same two factors were extracted explaining a total of 45.7% of the variance. The Amharic HADS had Cronbach's alpha of 0.81 and 0.76 in the whole sample for the anxiety and depression sub-scales, respectively. In the 11-15 years sub-sample the corresponding alpha values for anxiety and depression scales were 0.80 and 0.77, respectively. The correlation between the anxiety and the depression subscales were 0.66 (p<0.001) and 0.67 (p< 0.001) for the whole sample and for the 11-15 years group, respectively. CONCLUSION: Administering the Amharic version of the Hospital Anxiety and Depression Scale by interviewers gave meaningful data starting from the age of 11 suggesting successful applicability of the scale with further validation. PMID- 22434984 TI - Khat chewing and mental distress: a community based study, in jimma city, southwestern ethiopia. AB - BACKGROUND: Khat (Catha edulis) contains a psychoactive substance, cathinone, which produces central nervous system stimulation analogous to amphetamine. It is believed that khat chewing has a negative impact on the physical and mental health of individuals as well as the socioeconomic condition of the family and the society at large. There is lack of community based studies regarding the link between khat use and poor mental health. The objective of this study was to evaluate the association between khat use and mental distress and to determine the prevalence of mental distress and khat use in Jimma City. METHODS: A cross sectional community-based study was conducted in Jimma City from October 15 to November 15, 2009. The study used a structured questionnaire and Self Reporting Questionnaire-20 designed by WHO and which has been translated into Amharic and validated in Ethiopia. By multi stage sampling, 1200 individuals were included in the study. Data analysis was done using SPSS for window version 13. RESULTS: The Khat use prevalence was found to be 37.8% during the study period. Majority of the khat users were males (73.5%), age group 18-24 (41.1%), Muslims (46.6%), Oromo Ethnic group (47.2%), single (51.4%), high school students (46.8%) and employed (80%). Using cut-off point 7 out of 20 on the Self Reporting Questionnaire-20, 25.8% of the study population was found to have mental distress. Males (26.6%), persons older than 55 years (36.4%), Orthodox Christians (28.4%), Kefficho Ethnic groups (36.4%), widowed (44.8%), illiterates (43.8%) and farmers (40.0%) had higher rates of mental distress. We found that mental distress and khat use have significant association (34.7% Vs 20.5%, P<0.001). There was also significant association between mental distress and frequency of khat use (41% Vs 31.1%, P<0.001) CONCLUSION: The high rate of khat use among the young persons calls for public intervention to prevent more serious forms of substance use disorders. Our findings suggest that persons who use khat suffer from higher rates of mental distress. However, causal association could not be established due to cross-sectional study design. PMID- 22434985 TI - Patients' preoperative expectation and outcome of cataract surgery at jimma university specialized hospital -department of ophthalmology. AB - BACKGROUND: Patient's satisfaction for a given treatment is an important clinical outcome because a satisfied patient is more likely to comply with treatments, attend follow-ups and advocate the service to others. Therefore, knowing patients' expectations before a planned procedure or treatment and the actual level of satisfaction and fulfillment of their initial expectations thereafter is much helpful. As far as the knowledge and experience of the researchers is concerned, there has not been any study conducted in Ethiopia to find out about patients' preoperative expectations and postoperative level of satisfaction for actual outcomes. This study was therefore, conducted to describe and find out the relationship between preoperative expectations of cataract patients and the actual postoperative experience and their satisfaction level following the surgery at ophthalmology department in Jimma University Specialized Hospital. METHODS: A prospective cohort study of patients undergoing first eye cataract surgery was conducted from July 10 to Oct., 10, 2007 in the Ophthalmology department of Jimma University Specialized Hospital. Detailed interviews that included general and vision specific health status measures and patients' preoperative expectations for cataract surgery outcomes were performed followed by visual acuity testing. Postoperatively, visual acuity testing was taken again and patients' level of satisfaction with attained postoperative vision was assessed. Data were collected and filled in a separate questionnaire form for each patient, and entered into a computer and analyzed using SPSS for Windows version 12.0. RESULTS: Of the 200 patients operated for cataract, 179 (89.5%) were followed for the whole five weeks. The average expected preoperative Visual Function-15 score was 96.3, compared to an achieved (postoperative) Visual Function-15 score of just 96.2. However, the most unrealistic expectations observed were reading small prints and doing fine handiwork. The final pinhole visual acuity postoperatively was <= 6/18 in 126 (70.4%) patients. Of the 78 (39%) patients who were bilaterally blind preoperatively, 5 (2.5%) patients remained blind postoperatively. CONCLUSIONS: Significant improvements were obtained in clinical, functional, and perceived vision by cataract surgery involving extracapsular cataract extraction with posterior chamber intraocular lens implantations. Expectations regarding visual functioning after cataract surgery were very high, and in most cases and in most cases they were fulfilled. PMID- 22434986 TI - Characterization of mosquito breeding sites in and in the vicinity of tigray microdams. AB - BACKGROUND: Malaria vector control in Ethiopia has a history of more than 50 years, but malaria remains a major cause of morbidity and mortality in Ethiopia. Thus, targeting the control program on the larval stage is of paramount importance. This study aimed to characterize the aquatic habitats of vector mosquito larvae associated with micro-dams. METHODS: Cross-sectional larval survey was conducted on six micro-dams in Tigray, Northern Ethiopia in 2005/06. The study area on each dam was divided into eight zones. Immature stages of mosquitoes were collected using standard dippers. The physico-chemical characteristics of the aquatic habitats were measured onsite. RESULTS: A total of 301 aquatic habitats were surveyed for mosquito larvae; in 32.56% (n=301) only Anopheles, in 27.91% only Culex, both genera were found mixed in 21.59% and no mosquito larvae were found in 17.94%. The findings depicted that dissolved oxygen (r = 0.34, p =0.04), pH (r = 0.35, p =0.03), conductivity (r = 0.36, p =0.03), vegetation (F = 3.54, p =0.002), microhabitat (F = 2.65, p =0.04), fauna and bottom surface of the water body were positively associated and important in explaining the presence and abundance of Culex. On the other hand, dissolved oxygen (r = 0.39, p =0.02), pH (r = 0.42, p =0.008), vegetation (F = 5.6, p =0.000), water transparency (F = 2.72, p =0.00), rainfall (F = 2.22, p = 0.027) and fauna were positively associated and important in explaining the presence and abundance of Anopheles. CONCLUSION: The findings of this study suggest that both biotic (vegetation and fauna) and abiotic (chemical and physical) factors play a significant role in larvae's habitat preference in both Culex and Anopheles. PMID- 22434987 TI - Hepatitis B and C Viruses Infections and Their Association with Human Immunodeficiency Virus: A Cross-Sectional Study among Blood Donors in Ethiopia. AB - BACKGROUND: Since the introduction of Highly Active Anti-Retroviral Therapy and the dramatic improvement in the prognosis of individuals with Human Immunodeficiency Virus, liver disease due to chronic viral hepatitis has become as important cause of morbidity and mortality in co-infected individuals. The objective of the study was to determine the Sero-prevalence of Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency Virus and the association of the virus with Hepatitis B Virus and Hepatitis C Virus infection. As Human Immunodeficiency Virus and Hepatitis B Virus infections are highly prevalent and they are among the major public health concern in developing countries including Ethiopia investigating this problem is of paramount benefit. Although studies on co-infection of Hepatitis C Virus and Human Immunodeficiency Virus have clearly identified adverse effects of co-infection, the prevalence of Hepatitis C Virus infection and the association with Human Immunodeficiency Virus in developing countries including Ethiopia has not been know for sure. METHOD: A cross sectional study was conducted from January 1 to 31, 2010, in Jimma University specialized hospital Blood Bank. The inclusion criteria of the study was adult who donated blood to Jimma University specialized hospital blood bank any time from establishment of the unit until January 2010 and whose record was retrieved. Accordingly 9,204 adults were included of which 6,063 were selected by lottery method. Data on socio-demographic variables (age and sex), laboratory test result for Hepatitis B surface Antigen, anti-Hepatitis C Virus antibody, anti-Human Immunodeficiency Virus 1 antibody, and Rapid Plasma Reagin tests were collected using structured questionnaire. After the data were collected, they were entered into a computer and analyzed using SPSS -16 for windows. P-Value of < 0.05 was taken to be statistically significant. RESULTS: The prevalence rate of Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency Virus and syphilis infection were 2.1%, 0.2%, 2.1% and 0.7%, respectively. Sex and age had statistically significant association with Human Immunodeficiency and Hepatitis B virus infections where females were less likely to be infected. As age increases above 20 years, the risk of infection with Human Immunodeficiency Virus or Hepatitis B Virus increases. There was no association between Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency Virus. CONCLUSION: the prevalence rate of Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency Virus infections among blood donors in Jimma University specialized hospital were lower as compared to previous studies, in addition there was no association between Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency Virus. Thus, community based study should be conducted to confirm the relationship of Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency Virus. PMID- 22434988 TI - Factors affecting unmet need for family planning in southern nations, nationalities and peoples region, ethiopia. AB - BACKGROUND: High fertility and low contraceptive prevalence characterize Southern Nations, Nationalities and Peoples Region. In such populations, unmet needs for contraception have a tendency to be high, mainly due to the effect of socio economic and demographic variables. However, there has not been any study examining the relationship between these variables and unmet need in the region. This study, therefore, identifies the key socio- demographic determinants of unmet need for family planning in the region. METHODS: The study used data from the 2000 and 2005 Ethiopian Demographic and Health Surveys. A total of 2,133 currently married women age 15-49 from the 2000 survey and 1,988 from the 2005 survey were included in the study. Unmet need for spacing, unmet need for limiting and total unmet need were used as dependent variables. Socio- demographic variables (respondent's age, age at marriage, number of living children, sex composition of living children, child mortality experience, place of residence, respondent's and partner's education, religion and work status) were treated as explanatory variables and their relative importance was examined on each of the dependent variables using multinomial and binary logistic regression models. RESULTS: Unmet need for contraception increased from 35.1% in 2000 to 37.4% in 2005. Unmet need for spacing remained constant at about 25%, while unmet need for limiting increased by 20% between 2000 and 2005. Age, age at marriage, number of living children, place of residence, respondent's education, knowledge of family planning, respondent's work status, being visited by a family planning worker and survey year emerged as significant factors affecting unmet need. On the other hand, number of living children, education, age and age at marriage were the only explanatory variables affecting unmet need for limiting. Number of living children, place of residence, age and age at marriage were also identified as factors affecting total unmet need for contraception. CONCLUSION: unmet need for spacing is more prevalent than unmet need for limiting. Women with unmet need for both spacing and limiting are more likely to be living in rural areas, have lower level of education, lower level of knowledge about family planning methods, have no work other than household chores, and have never been visited by a family planning worker. In order to address unmet need for family planning in the region, policy should set mechanisms to enforce the law on minimum age for marriage, improve child survival and increase educational access to females. In addition, the policy should promote awareness creation about family planning in rural areas. PMID- 22434989 TI - Surgical site infection rate and risk factors among obstetric cases of jimma university specialized hospital, southwest ethiopia. AB - BACKGROUND: Surgical Site infections are the second most frequently reported infections of all nosocomial infections among hospital patients. Among surgical patients in obstetrics, Surgical Site Infections were the most common nosocomial infections and the rate is higher in sub-Saharan Africa. There has not been a study which documented the extent of the problem in the study area; hence the objective of this study was to determine the surgical site infection rate among women having surgery for delivery in obstetrics of Jimma University Specialized Hospital (JUSH) from April 1, 2009 to March 31, 2010. METHODS: A prospective descriptive study design was conducted with the aim of determining the surgical site infection rate on all 770 women who had surgery for delivery from April 1, 2009 to March 31, 2010 in obstetric ward of the Hospital. Data on history of the patient, patient specific demographic information on potential risk factors and the occurrence of Surgical Site infections in the first 30 days following surgery were collected using pretested data collection form. In addition, relevant data were also abstracted from the operation logbook of the cases. Then data were cleaned, edited and fed to computer and analyzed using SPSS for window version 16.0. Finally Statistical test for significance was employed using chi-squared (X (2)) where appropriate at 5% level of significance. RESULTS: The mean (+/-SD) of the subjects' age was 26(+/-7) years and the majority of the women were from the rural areas (72.7%). The overall surgical site infection rate was 11.4%. Of those who had surgical site infections, 64.8% had clean-contaminated wound and 35.2% had contaminated /dirty wounds. Wound class at time of surgery has a statistically significant association with Surgical Site infections (p <0.001).The Surgical Site infections rate was similar for cesarean section and abdominal hysterectomy but higher for destructive delivery under direct vision. Majority of the operations were made for emergency Obstetric conditions (96.6%) and the Surgical Site Infections rate was two times higher compared to that of elective surgery. Chorioamnionitis, presence of meconium, large intraoperative blood loss and Perioperative blood transfusion were associated with increased severity of SSIs with p < 0.001. Absence of antenatal care follow up was also associated with increased severity of Surgical Site Infections. CONCLUSION: It has been revealed that Surgical Site Infections rates are higher than acceptable standards indicating the need for improving Antenatal care, increasing the number of skilled birth attendants at the local clinics, increasing basic and comprehensive emergency obstetric care services, applying improved surgical techniques and improving infection prevention practices to decrease infection rate to acceptable standard. PMID- 22434990 TI - Human intestinal schistosomiasis in communities living near three rivers of jimma town, South Western ethiopia. AB - BACKGROUND: Schistosoma mansoni is one of the parasites with high public and medical importance in Ethiopia. However, information is scarce about S. mansoni epidemiology in people living with higher risk of infection in Jimma town. This study was designed to determine point prevalence, intensity and risk factors of S. mansoni infection among residents nearby three rivers of Jimma town and assess the rate of Biomphalaria species shading cercariae from January to April, 2007. METHODS: A cross-sectional study was conducted in communities residing nearby three rivers of Jimma town. Structured questionnaires were used to collect data on socio- demographic and behavioral risk factors. After physical examination, stool samples were collected from 517 study participants and processed with Kato Katz technique for microscopic examination and quantification of egg load. Snails were collected for identification of Biomphalaria species and then checked for cercarial shading. RESULTS: The prevalence of S. mansoni was 26.3 % with intensity ranging 24 to 936 eggs per gram of stool. Participants in the age group 10-19 years, OR = 2.19 (95% CI; 1.10 - 4.34), and those living near the Awetu River, OR = 2.67 (95% CI; 1.06 - 6.75), had higher risk of S. mansoni infection. Moreover, water contact while crossing a river, OR = 3.77 (95% CI; 1.79 - 7.95), and swimming, OR = 2.59 (95% CI; 1.37 - 4.91, was significantly associated with infection. Biomphalaria snails collected from Chore and Awetu Rivers shaded higher rate of cercariae compared with Kito River. CONCLUSION: A moderate prevalence of S. mansoni infection was shown in the study population. Infection rate among the residents correlated with rate of cercarial shading Biomphalaria snails. Treatment of targeted groups, appropriate health education and environmental measures (e.g. snail control) are needed to improve the situation. PMID- 22434991 TI - The quality of care provided to patients with chronic non-communicable diseases: a retrospective multi-setup study in jimma zone, southwest ethiopia. AB - BACKGROUND: Chronic Non-Communicable Diseases are among the major causes of morbidity and mortality worldwide. However, access to and quality of health care for patients is very low in developing countries including Ethiopia. Hospitals and Health Centers are the main sources of health care for such patients in Ethiopia. In this study we assessed the quality of care patients with Chronic Non Communicable Diseases received in hospital and health center setups. METHODS: A retrospective multi-setup study was conducted in Jimma University Specialized Hospital and four Health Centers in Jimma Zone from February to March 2010. A total of 52 process indicators of quality covering three disease conditions: Diabetes, Hypertension and Epilepsy were measured by reviewing randomly selected medical records. Quality of care was measured as a proportion of recommended components of care actually provided to patients. And also outcome and structural measures were assessed to supplement process measures of quality. RESULTS: Six hundred seventy four medical records were reviewed. Recommended care components were actually provided to patients in 35.1% (95% CI:34.1%, 36.0%), 38.5% (95% CI:37.5%, 39.5%) and 60.1% (95% CI:59.3%, 61.0%) of times on which patients were eligible, among patients with Diabetes, Hypertension and Epilepsy, respectively. After case mix adjustment, it was found that 45.9% (95% CI:45.4%, 46.5%) of recommended components of care was actually provided to patients. This was 45.1% (95% CI:44.4%, 45.8%) in the hospital and 30.5% (95% CI:29.7%, 31.3%) in the health centers. Among patients for whom outcome data was available, optimal level of disease control was achieved only for 47 (30.5%), 40 (38.5%) and 193 (52.9%) of patients with Diabetes, Hypertension and Epilepsy, respectively. CONCLUSION: The quality of care provided to patients with Chronic Non-Communicable Diseases is very low in both settings though it is relatively better in Jimma University Specialized Hospital. Therefore, a continuous process of quality improvement is recommended in both settings. PMID- 22434992 TI - Risk Factors of Active Tuberculosis in People Living with HIV/AIDS in Southwest Ethiopia: A Case Control Study. AB - BACKGROUND: Determinants of active tuberculosis among People Living with HIV/AIDS (PLHA) are not well elucidated in countries with limited resources. The objective of this study was to assess distal and proximate determinants of active tuberculosis among people living with HIV/AIDS in southwest Ethiopia. METHODS: A case-control study was conducted from January to March, 2009 in South West Ethiopia. The study population consisted of 162 cases and 647 controls. Cases were adult people living with HIV/AIDS who developed active pulmonary tuberculosis and controls were people living with HIV/AIDS without active tuberculosis. An interviewer administered structured questionnaire was used to collect information on potential risk factors. RESULTS: After adjustment for potential confounders, male gender (OR=1.7; 95%CI: 1.1, 2.7), a low level of education (OR=2.8; 95% CI: 1.1, 7.1), a body mass index less than 18.5 kg/m2 (OR=4.1; 95% CI: 2.3, 7.4), hemoglobin level less than 10.0 g/dl (OR=2.8; 95%CI: 1.5, 5.2), a CD4 lymphocyte count less than 200 cells/uL (OR=9.8'95% CI: 5.5, 17.5), a WHO clinical stage IV (OR=4.3; 95% CI: 2.6, 6.8), not taking antiretroviral treatment (OR=3.1; 95%CI: 1.9,4.9), an infection with helminthes (OR=2.2; 95% CI: 1.4, 3.4), a history of contact with a tuberculosis patient in the family (OR=2.0; 95% CI: 1.2, 3.3), and living in a house made of mud wall (OR=3.7; 95% CI: 1.5, 7.5) were independently associated with the development of active tuberculosis in people living with HIV/AIDS. CONCLUSION: All people living with HIV/AIDS should be screened for tuberculosis but in the presence of the risk factors mentioned above, intensified screening is recommended. PMID- 22434993 TI - Bacterial uropathogens in urinary tract infection and antibiotic susceptibility pattern in jimma university specialized hospital, southwest ethiopia. AB - BACKGROUND: Urinary tract infection (UTI) is one of the most common bacterial infections encountered by clinicians in developing countries. Area-specific monitoring studies aimed to gain knowledge about the type of pathogens responsible for urinary tract infections and their resistance patterns may help the clinician to choose the correct empirical treatment. Therefore, the aim of this study was to determine the type and antibiotic resistance pattern of the urinary pathogens isolated from patients attending Jimma University Specialized Hospital from April to June 2010. METHODS: A hospital based cross sectional stud was conducted and urine samples were collected using the mid-stream "clean catch" method from 228 clinically-suspected cases of urinary tract infections and tested bacteriologically using standard procedures. Antimicrobial susceptibility test was performed for the isolated pathogens using Kirby-Bauer disk diffusion method according to Clinical and Laboratory Standards Institute guidelines. RESULTS: Significant bacteria were detected from 9.2% of the total patients. The most common pathogens isolated were Escherichia coli (33.3%), Klebsiella pneumoniae (19%) and S. saprophyticus (14.3%). E. coli and Klebsiella pneumoniae showed the highest percentage of resistance to ampicillin and amoxacillin (100%) however, all isolates of E. coli and K. pneumoniae were susceptible to ciprofloxacin. S. saprophyticus and S. aureus were resistant to ampicillin (100%) and amoxicillin (66.7%). For all UTI isolates, least resistance was observed against drugs such as ceftriaxone, gentamycin and chloramphenicol. CONCLUSION: This study finding showed that E. coli isolates were the predominant pathogens and the presence of bacterial isolates with very high resistance to the commonly prescribed drugs that in turn leaves the clinicians with very few alternative options of drugs for the treatment of UTIs. As drug resistance among bacterial pathogens is an evolving process, routine surveillance and monitoring studies should be conducted to provide physicians knowledge on the updated and most effective empirical treatment of UTIs. PMID- 22434994 TI - Hypertensive disorders of pregnancy in jimma university specialized hospital. AB - BACKGROUND: Hypertensive disorders represent the most common medical complications of pregnancy with a reported incidence between 5 and 10%. The disorders are major causes of maternal and perinatal morbidities and mortalities. This study was conducted to determine the pattern and outcomes of pregnancies complicated by hypertensive disorders. METHODS: Hospital based cross-sectional study was conducted on all mothers who gave birth in the labor ward of Jimma University Specialized Hospital from April 1, 2009 to March 31, 2010. Data was collected by interviewing the mothers and review of their medical records using structured questionnaire and checklist, respectively. Data analysis was performed using SPSS for windows version 16.0. RESULT: Majority (52.5%) of the mothers were in the age group of 25 - 34 years. The overall prevalence of hypertensive disorders of pregnancy was 8.5%. Severe preeclampsia accounted for 51.9% of the cases followed by eclampsia (23.4%). Residential area of the mothers (urban/rural) was found to have statistically significant association with severity of the disorder. Most (66.5% and 74.7%) of the mothers were nulliparous and had antenatal care follow-up during the index pregnancy, respectively. Antenatal care follow-up and parity had no statistically significant association with severity of the disease. The case fatality rate of hypertensive disorders of pregnancy was 1.3% with perinatal mortality of 317.1/1000 births. CONCLUSION: Pregnancies complicated by hypertensive disorders have poor maternal and perinatal outcomes and rural women were more affected. Quality antenatal care services with good obstetric and neonatal care at delivery are essential for early recognition and management of hypertensive disorders of pregnancy. PMID- 22434995 TI - Magnitude and pattern of injury in jimma university specialized hospital, South west ethiopia. AB - BACKGROUND: Injury statistics in Ethiopia provides little knowledge about its magnitude and related information needed for prevention. This study, therefore, aims to determine the magnitude and pattern of injury in Jimma University Specialized Hospital (JUSH). METHODS: A retrospective review of records of all injured patients seen at surgical outpatient department from April 09, 2010 to January 07, 2011; was conducted in January 2011. Data were collected using a structured checklist that was developed by adapting the World Health Organization instrument. Five degree holder nurses collected the data while investigators closely supervised. Socio demographic characteristics of the patients and injury related information were collected. Data were analyzed using SPSS for windows version 16.0. RESULTS: Of 13500 patients who visited surgical outpatient department of JUSH during the study period, 1102(8.2%) were injury cases. The commonest mechanism of injury was blunt assault, 341(30.9%), followed by road traffic accident, 334(30.3). Fracture was the leading outcome of injury, 454(41.2%), followed by bruise or skin laceration, 404(36.7%). Significantly more males had cut, (AOR=2.0; 95% CI=1.2, 3.3) and stab, (AOR=3.0; 95% CI=1.6, 5.7), injuries compared to females. Conversely, significantly fewer males had burn, (AOR=0.4, 95% CI=0.2, 0.8) and road traffic accident, (AOR=0.7, 95% CI=0.5, 0.9), than females. Most, 715(95.8%), patients were presented to the hospital within one week. The commonest functional limitations were; difficulty to use hands, 312(28.3%) and difficulty to use legs, 217(19.7%). Eighty three, (7.5%) of the patients died and road traffic accident alone accounted for almost half, 179 (49.7%), of the severe injuries. CONCLUSION: The magnitude of injury in the hospital was considerably high. Age and sex were predictors of injury. Appropriate prevention strategies should be designed and implemented against assault, road traffic accident and cut by sharp tool. PMID- 22434996 TI - Prevalence and predictors of intestinal helminthiasis among school children in jimma zone; a cross-sectional study. AB - BACKGROUND: Globally, millions of people suffer from intestinal parasitic infections. These infections are among the most common resulting in considerable morbidity and mortality. In Ethiopia and particularly in Jimma and its surroundings intestinal parasitic infections are highly prevalent because of low living standards and poor environmental sanitation. The objective of the survey was to determine the prevalence and predictors of intestinal parasitosis among school children in four woredas of Jimma zone surrounding Gilgel gibe hydraulic dam and serve as a base line data to help evaluate health promoting activities for the future and monitor those already delivered to the community. METHODS: A cross-sectional study was carried out in October, 2008 in four Woredas of Jimma zone bordering Gilgel Gibe Dam. Children attending grades 1-8 in the schools located within 10 Kms ofthe Dam in the four bordering woredas and those living 30 Kms away from the shore line were the study subjects. Six hundred twenty four and 321 children were selected from the schools around Gilgel Gibe dam and from the schools in Bulbul, respectively. Data on background of participant was collected and stool specimen collected and processed. Data were filtered and entered into computer then analyzed using SPSS for windows version 13.0.1. RESULTS: Of the 937 selected individuals, 855 participated in the study giving a response rate of 91.2%. The prevalence of intestinal parasitosis was 47.1% where 174 (20%) had Ascaris lumbricoides monoinfection; 4.3% had dual infection involving Ascaris lumbricoides and hookworm and 0.2% had triple infection but all the infections were of light intensity. In addition, there was no association between prevalence of intestinal parasitosis with availability or regular use of latrine and clinical symptoms. CONCLUSION: The prevalence and intensity of intestinal parasites in the study area is lower than national, urban and rural setting of Jimma zone. These might be due to a better awareness of the study community on prevention of intestinal parasitosis following increased health promoting activities in the area, delivered through various activities of Jimma Public health training program. PMID- 22434997 TI - Bacteraemia among severely malnourished children in jimma university hospital, ethiopia. AB - BACKGROUND: Sever acute malnutrition severely suppresses every component of the immune system leading to increased susceptibility and severity to infection. However, symptoms and signs of infections are often unapparent making prompt clinical diagnosis and early treatment very difficult. The aim of the study was to determine the magnitude of bacteraemia and antimicrobial sensitivity among severely malnourished children. METHODS: Severely malnourished children admitted in Jimma University Specialized Hospital were enrolled between October, 2009 to May, 2010. Blood samples were collected, processed and bacterial isolates were identified using standard bacteriological procedures. Then, antibiotic susceptibility pattern of the isolates was determined by using Kirby-Bauer technique. RESULTS: Bacteraemia was seen in 35 (20.6%) of the 170 study subjects. There were a total of 35 bacterial isolates, Gram positive bacteria constitute 24(68.6%) of the isolates, where Staphylococcus aureus was the leading Gram positive isolate while Klebsiella species were the dominant Gram negative isolates. Twelve (7.1%) children died and 4 (33.3%) of them had bacteraemia. While susceptibility was more than 80% to Gentamicin, Ciprofloxacin and Ceftriaxone, increased level of resistance was documented to commonly used antibiotics, such as Amoxycillin, Co-trimoxazole and Chloramphenicol. CONCLUSION: High prevalence of bacteraemia with predominating Gram positive isolates and increased level of resistance to commonly used antibiotics was shown among severely malnourished children in Jimma. Further studies are required to revise the current guideline for antibiotic choice. PMID- 22434998 TI - Knowledge and information on psychological, physiological and gynaecological problems among adolescent schoolgirls of eastern India. AB - BACKGROUND: Sex education aims to reduce the risks of potentially negative outcome from sexual behavior such as fear and stigma of menstruation, unwanted and unplanned pregnancies and sexually transmitted infections including HIV. Hence, this study was conducted to determine sex education knowledge level of school going adolescents in semi urban area of Midnapore, West Bengal, India. METHODS: A cross-sectional study was conducted in two selected premier secondary school of girls in the Midnapore Town from September - October 2007. A total of 521 adolescent aged 10-19 years were selected randomly from two secondary schools of girls. However, schools were selected purposively. All information was collected by using open-ended pre-tested questionnaire. RESULTS: Of the total subjects 94.2% of them were in the age of 13-16 years. Nearly, 94% respondents reported their age at menarche and maximum i.e. 54% respondents experienced in the age of 11 - 13 years. It was observed that 18%, 60.7% and 21.3% of the respondents had good knowledge, moderate or some knowledge and very poor knowledge of puberty, pubertal problems and their prevention. Thirty three percent said that they had faced one or some other kind of physical problems and out of them 60% indicated that they had visited to a doctor for their problems. The suffering of any gynecological problems had 2.48 (95% CI: 1.42 - 4.36) and 1.94 (95% CI: 1.01 - 3.73) times greater among subjects with little or some knowledge and minimum or no knowledge compare to subjects with good knowledge of sex education. CONCLUSION: Thus, the results show that not only knowledge regarding sex education was poor among the subjects but also their knowledge regarding sexual infections including AIDS was not satisfactory. School based sex education programs are particularly good at providing information, skills development and attitude clarification in more formal way through lesson within the curriculum. Therefore, appropriate sex education program should be initiated from the adolescence to prevent health hazards. PMID- 22434999 TI - Seasonal Variation of Intestinal Parasitic Infections Among HIV-Positive Patients in Benin City, Nigeria. AB - BACKGROUND: There are a number of conflicting studies on the prevalence of intestinal parasitic infections in HIV infection with regards to different seasons. This study was conducted to determine seasonal influence on the prevalence of intestinal parasitic infections in HIV-positive persons in Benin City, Nigeria. METHODS: Stool specimens from 2000 HIV-positive patients and 500 controls (HIV-negative individuals) were examined for ova, cysts or parasites using standard procedures. RESULTS: More intestinal parasitic infections were observed in the rainy season (17.6%) than the dry season (12.3%) (OR = 1.526, 95% CI = 1.184, 1.967, p = 0.0013). Male patients (18.3) had more episodes of intestinal parasitic infections than their female (13.7) counterparts (OR = 1.403, 95% CI = 1.092, 1.803, p = 0.0096). CONCLUSION: Cryptosporidium species and Strongyloides stercoralis were the only parasitic agents that were associated with rainy season. PMID- 22435000 TI - Effects of aerobic exercise in the management of erectile dysfunction: a meta analysis study on randomized controlled trials. AB - BACKGROUND: Penile erection is a hemodynamic process involving increased arterial inflow and restricted venous outflow, coordinated with corpus cavernosum and penile arterial smooth muscle relaxation. Any problem in this mechanism results in Erectile Dysfunction and its etiology is generally multifactorial. This study is aimed at determining the objective outcome of aerobic training in the management of Erectile Dysfunction of arterogenic origin using Meta analysis. METHODS: Relevant publications were searched up to November 2010 in the MEDLINE (PubMed) database. The citation lists of randomized controlled trials on the effect of aerobic training and Erectile Dysfunction management using the International Index of Erectile Function (IIEF) as treatment outcome measure. Studies on different operative techniques on the effects of aerobic training for men with Erectile Dysfunction due to arterogenic Erecile Dysfunction were selected. Data on participants' characteristics, study quality, population, intervention, treatment outcome were collected and analyzed. RESULTS: There were 5 randomized controlled studies using the International Index of Erectile Function as measure of treatment outcome. A total of 385 subjects were involved in 5 studies; results indicated significant effect of aerobic training on Erecile Dysfunction (t=5.856, p= .000) at p< 0.05. CONCLUSION: Subjects with arterogenic Erectile Dysfunction might benefit from aerobic training. More randomized controlled studies in this area are warranted. PMID- 22435001 TI - Severe organophosphate poisoning with delayed cholinergic crisis, intermediate syndrome and organophosphate induced delayed polyneuropathy on succession. AB - Organophosphate compounds are the organic derivatives of Phosphorous containing acids and their effect on neuromuscular junction and Autonomic Synapses is clinically important. After exposure these agents cause acute and sub acute manifestations depending on the type and severity of the agents like Acute Cholinergic Manifestations, Intermediate Syndrome with Nicotinic features and Delayed Central Nervous System Complications. The patient reported here had severe Organophosphate Poisoning with various rare complications on a succession. This is the first report of Organophosphates Poisoning complicated by Intermediate Syndrome and Organophosphate Induced Delayed Polyneuropathy in Ethiopia and it is reported to increase awareness of health care workers on these rare complications of a common problem. PMID- 22435002 TI - Idiopathic masseter muscle hypertrophy. AB - Benign Masseteric Hypertrophy is a relatively uncommon condition that can occur unilaterally or bilaterally. Pain may be a symptom, but most frequently a clinician is consulted for cosmetic reasons. In some cases prominent Exostoses at the angle of the mandible are noted. Although it is tempting to point to Malocclusion, Bruxism, clenching, or Temporomandibular joint disorders, the etiology in the majority of cases is unclear. Diagnosis is based on awareness of the condition, clinical and radiographic findings, and exclusion of more serious Pathology such as Benign and Malignant Parotid Disease, Rhabdomyoma, and Lymphangioma. Treatment usually involves resection of a portion of the Masseter muscle with or without the underlying bone. PMID- 22435003 TI - Assessment of Effective Coverage of HIV Prevention of Pregnant Mother to Child Transimission Services in Jimma Zone, South West Ethiopia. AB - BACKGROUND: Coverage assessment of prevention of Pregnant Mother to Child Transmission (PMTCT) of HIV service is useful to measure the health system effort or performance of health service delivery function and to influence decisions. The objective of this study was to assess effective coverage level for prevention of Pregnant Mother to Child Transmission services in Jimma University Hospital. METHODS: Health institution based cross-sectional quantitative and qualitative study was conducted on prevention of Pregnant Mother to Child Transmission of HIV services. RESULTS: Out of total 1904 pregnant women who received at least one antenatal care service, 1472 (77.3%) were covered with PMTCT service in 2005 in Jimma University Hospital. The overall PMTCT service coverage for the target group in the Jimma Zone was 1.1 %. The prevalence of positive HIV blood test among pre counseled women was 101 (6.9%). Of all HIV positive pregnant women 62(61.3%) were taking Neverapine at home. CONCLUSION: From the data obtained, it was observed that PMTCT service coverage was low. Thus, we recommended that the services to be strengthened, for a better achievement and optimizing coverage. PMID- 22435004 TI - Assessment of effective coverage of voluntary counseling and testing services in major health facilities of jimma zone, South ethiopia. AB - BACKGROUND: Coverage assessment of Voluntary Counseling and Testing (VCT) service is useful to measures the health system effort or performance of health service delivery function and to influence decisions. The objective of this study was to assess effective coverage level for Voluntary Counseling and testing services in major health facilities of Jimma Zone. METHODS: Health institution based cross sectional quantitative and qualitative study on health facilities that provide voluntary Counseling and testing services. RESULTS: The over all HIV/AIDS service package indicators availability coverage were 45.5% across the zone. The over all coverage for target population were 1.3%. The primary health care centers served only 18% of total registered Voluntary Counseling and Testing service users. Out of total positive serostatus clients, only 5% received condom. The coverage for post result counseling was 98.7% for all tested clients. Seventy-four (1.3%) of clients who were tested for HIV did not returned to know their results. CONCLUSION: This study demonstrated that effective coverage of Voluntary Counseling and Testing service was very low based on the providers view and records available. Thus we recommended that the services has to be strengthened, supervised and monitored to have a better achievement and improving the coverage status in addition to scaling up the services in the Zone. PMID- 22435005 TI - Job satisfaction and its determinants among health workers in jimma university specialized hospital, southwest ethiopia. AB - BACKGROUND: Human power is the back bone for the provision of quality health care for the population. High level of professional satisfaction among health workers earns high dividends such as higher worker force retention and patients satisfaction. There is limited amount of literature in the areas related to factors affecting job satisfaction and retention. The objective of this study was to determine the job satisfaction of health professionals working in Jimma University Specialized Hospital and factors affecting their level of satisfaction. METHOD: A cross-sectional study was conducted to determine the level and factors affecting job satisfaction and retention of health professionals working in Jimma University Specialized Hospital. The study was conducted from March to October 2009 and included all categories of health professionals working in the hospital during the study period. Data was collected using self administered questionnaire and focus group discussion. After the data was collected, it was entered into a computer and analyzed using SPSS version16.0 windows statistical software. Chi-square tests were made to evaluate association of different variables with job satisfaction, and P-value < 0.05, at 95% CI was taken as cut off point for statistical significance. RESULTS: A total of 145 health professionals have responded for the self administered questionnaire. The result showed that sixty seven (46.2%) of the health workers are dissatisfied with their job. The major reasons reported for their dissatisfaction were lack of motivation, inadequate salary, insufficient training opportunities and inadequate number of human resources. Only sixty (41.4%) health professionals were satisfied with their job, the major reasons given were getting satisfaction from helping others and professional gratification. Suggestion given by the respondents to improve job satisfaction and increase retention rate included motivation of staff through different incentives such us bonus, house allowance, salary increment, establishing good administration management system and improving hospital facilities and infrastructure. CONCLUSION: Job satisfaction of health professionals in Jimma University Specialized Hospital was found to be low. Responsible bodies should devise mechanisms to improve job satisfaction and retention of health professional so as to improve the healthcare services of the hospital. PMID- 22435006 TI - Presence and use of legislative guidelines for the distribution of decentralized decision making authority in the jimma zone health system, southwest ethiopia. AB - BACKGROUND: Decentralization ultimately involves the execution of most health care activities at lower levels of the health system. However, when poorly implemented, decentralization can create confusion about roles and responsibilities. Therefore, the objective of this study was to assess the presence and use of legislative guidelines depicting the distribution of decentralized authority for decision making in the Jimma Zone health system, Southwest Ethiopia. METHODS: A cross sectional study employing both qualitative and quantitative methods was undertaken from 16(th) January to 15(th) March 2007 in Jimma Zone. Health managers at relevant departments of the Federal Ministry of Health, Oromia Regional Health Bureau (RHB), Jimma Zonal Health Department, 13 Woreda Health Offices of Jimma Zone and the health centers and health posts in these districts were included in the study. Data was collected using interview guides and self administered structured questionnaires prepared for each level of the health system. Tape-recorded qualitative data was transcribed and analyzed using thematic framework approach while SPSS for windows version 12.0.1 was used to analyze the quantitative data obtained. RESULTS: According to the regional guidelines, ensuring achievement of regional health service targets is the responsibility of the RHB. This was clear to 97 (97.9%) of the health managers included in this study. However, almost equivalent proportion of the respondents, 95 (95.9%) agreed that the FMOH should be responsible for this. Similarly, 71 (73.9%) of the health managers knew that approval of health budgets and efforts for local resource generation is the responsibility of the Woreda Administrative Council while the remaining 27.1% were uncertain or disagreed about this regional direction. Such confusions were observed in almost every functional area. Moreover, legislative guidelines were not available in most of the district health offices and health facilities. CONCLUSION: Legislative guidelines depicting the distribution of decentralized authority in decision making in the health system were prepared at national and regional levels. However, the findings of this study suggested that health managers in the Jimma Zone health system did not appear to have the right perceptions about roles and responsibilities of the various levels. It is, therefore, very important to clarify such confusions along with capacity building efforts to match the changing roles of each level. PMID- 22435007 TI - Assessment of quality of care delivered for infectious pulmonary tuberculosis patients in jimma zone, South west ethiopia. AB - BACKGROUND: Providing quality of care for infectious pulmonary tuberculosis patients is crucial in prevention and control of the disease. However, little is known about the existing quality of care in such services. The objective of the study was to assess the quality of care delivered for infectious pulmonary tuberculosis patient in Jimma Zone, South West Ethiopia. METHODS: Facility based cross- sectional study was conducted from January- February 2008 in 10 public health facilities in Jimma Zone. Facility audit was carried out to assess structural quality. Twenty providers were interviewed and records of 299 smear positive patients registered for 1 year was reviewed. Data were entered and analyzed using SPSS 11.0 for windows statistical software and findings at 95% CI and p value of 0.05 were reported as statistically significant. RESULTS: The results of the study showed that all the three quality dimensions were graded as poor in all the study health facilities and overall 66.0% of TB patients receive poor quality care. Four variables were identified that significantly predicted treatment success, i.e. conformity to the recommended schedule of sputum smear microscopy, conformity to DOTS drug regimen during both intensive and continuation phase of therapy and quality of registration of patients' medical records. CONCLUSION: This study revealed that most of the problems could be managed at local level, while a few needs further discussion with other management bodies. Success of anti tuberculosis therapy could be ensured through strict adherence to all the elements of DOTS strategy, with special emphasis on the 4 variables that significantly predicted treatment success in the present study. PMID- 22435008 TI - Assessment of quality of health care in jimma zone, southwest ethiopia. AB - BACKGROUND: Quality of care is an important aspect of health care delivery system that is given a priority. Quality is a multidimensional concept that has been defined in various ways. Variation in quality of care between different health care facilities is thought to reflect differences in efficiency and other organizational factors. There was no adequate study related to quality of health care in Jimma zone. Therefore, the objective of this study was to assess quality of health care in Jimma zone. METHODS: A cross sectional quantitative study design was employed to assess the quality of care with respect to structure, care process and customer satisfaction involving 640 patients and 96 care providers in Jimma zone, southwest Ethiopia. Data were collected using an interview questionnaire and observation checklist devised by the investigators. RESULTS: The study showed that, on average, the studied institutions fulfilled 153(70.4%) of the health human power need. They also fulfilled 86(62.8%) of major equipment requirement against the national standard. The composite average satisfaction level of patients was 89.1% and that of the care providers was 86.7%. Nevertheless, the respect given to patients by care providers was rated as poor. A significant proportion, 39(48.2%) of the care providers were assessed as low performance. CONCLUSIONS: Majority of study subjects rated the overall quality of care as "good". However the observation revealed that the human aspect of care was "poor". In addition, the health institutions were facing shortage of human and material resources. Thus it was recommended that the responsible bodies at the 3 levels should take actions for improving institutional capacity and performance of care providers in order to improve quality of care. PMID- 22435009 TI - Private hospital sector development: an exploratory study on providers perspective in addis ababa, ethiopia. AB - BACKGROUND: Over the past decade there is a trend of fast development in the private hospital sector in Ethiopia. This important component of the health care system has received policy attention and federal government is a promoter for private health care. Yet lack of basic data on the factors affecting the growth of private health care provision in the country and no studies are available on this issue in Ethiopia. The aim of this study is to get some preliminary insights on the factors affecting the growth and development of private hospital sector in Addis Ababa, Ethiopia with perspective of provider. METHODS: A hospital based qualitative study was conducted in 25 for-profit hospitals in Addis Ababa using key informant in-depth interviews and secondary data was collected from Federal Ministry of Health and Addis Ababa City Health Administration and private hospital providers. RESULTS: The findings of the study suggest that private hospital sector is expanding significantly in recent years in Ethiopia. The active role of government is a catalyst for the growth of private facilities in the country. Factors outside the health are growing disposable income, improvements in literacy, road networks, population growth and long standing diseases, all contribute to the trend. But private providers are facing many problems, like availability of trained manpower, escalation of costs, availability and quality of drugs and financing mechanisms. CONCLUSION: Private hospital sector is expanding in Ethiopia. But private providers are vulnerable to imperfections in the existing market structure. Government and professional bodies need to make a concerted effort to address these issues and design appropriate strategies to promote and regulate this sector effectively. PMID- 22435010 TI - Utilization of health information system at district level in jimma zone oromia regional state, South west ethiopia. AB - INTRODUCTION: Information systems are increasingly important for measuring and improving the quality and coverage of health services. Reliable and timely health information is vital for operational and strategic decision making that save lives and enhances health. In Ethiopia information quality and use remain weak, particularly at district health offices and primary health care facilities to facilitate decision making. Therefore, the objective of this study is to assess the utilization of health information systems at District level in Jimma Zone, southwest Ethiopia. METHODS: A cross sectional study was conducted in all health institutions by interviewing heads/ units/departments of District Health Office, Health Center and Health Post from January to February, 2009. Quantitative and qualitative data were collected using structured questionnaires, check lists, observation and interview guide by trained data collectors. Data was analyzed using SPSS version 16 and descriptive and logistic regression analysis was carried out. RESULTS: The finding of the study revealed that utilization of health information was 119(32.9%) in all the study units/departments. The major source of data was routine and vertical program report from public institutions. The utilization of information was affected by many factors but from variables studied only documentation of data, catchment population profile charts presentation and quarter plan performance monitoring was found significant at 95 % level of significance. CONCLUSION: The study identified that the implementation of health data/information and utilization of health information system was found to be far below the national expectation. Activities are poorly coordinated at the districts and primary health units where data was generated initially. Therefore, in-service training and updating of staff involved in health information system (HIS) at district, strengthening health information system inputs, timely and concrete feedbacks with establishment of functional health management information system (HMIS). PMID- 22435011 TI - Assessment of Production and Distribution of Printed Information Education Communication (IEC) Materials in Ethiopia and Utilization in the Case of Jimma Zone, Oromiya National Regional State: A Cross Sectional Study. AB - BACKGROUND: Health promotion and health education activities rely on a variety of well designed and effective printed Information Education Communication materials to help ensure success. However, in Ethiopia, there is no well established evidence that shows the extent to which printed Information Education Communication materials are produced distributed, utilized and the existing needs and gaps. Therefore, the objective of this study was to assess the process of printed Information Education Communication materials production, distribution and utilization and to identify current Information Education Communication needs and gaps. METHODS: Cross sectional study combining quantitative and qualitative approaches was conducted at Federal, Regional (Oromiya), zonal (Jimma) and facility levels. Fourteen health centers within Jimma Zone were randomly selected and 303 health workers working in these health centers were included in the study. Purposive sampling technique was used to identify respondents for in-depth interview. The quantitative data were analyzed by SPSS for windows version 16.0. RESULTS: The materials designed both by the Health Education Extension Center and Oromiya Regional Health Bureau were not fully culture sensitive. Information Education Communication materials inventories had not been practiced, particularly at zonal and health center levels. Furthermore, at zonal and health center level, there were no safe storage places. Chronic shortage of Information Education Communication materials was reported consistently. Only 206 (68.0%) of the participants had ever used printed Information Education Communication material. 146 (48.2%) and 29 (9.6%) of the participants were rated the IEC material they have seen as very good in terms of understablity and the extent to which it takes the local context into account, respectively. Participants who were nurse and laboratory technologist were 0.35 and 0.23 times less likely to use IEC materials than environmental Health experts [AOR=0.35, 95% CI: 0.14-0.85] and [AOR=0.23, 95%CI: 0.07-0.79], respectively. Graduates of private colleges were 10 times more likely to report utilization of IEC materials than graduates of government institutions [AOR=10.46, 95% CI: 3.47-31.50]. CONCLUSION: This study revealed that design, production, distribution and utilization of printed Information Education Communication materials were not in line with the underlying principles of Information Education Communication material development. Thus, all concerned institutions and individuals should work towards to improvement. PMID- 22435012 TI - Health services utilization and associated factors in jimma zone, South west ethiopia. AB - BACKGROUND: In Ethiopia, utilization of health services remains low and unevenly distributed. To ensure appropriate health care use, we need to understand factors affecting health care use, and the reasons for low levels of utilization among our community. The objective of the study was to assess utilization of health services and associated factors in Jimma zone, south west Ethiopia. METHODS: A cross sectional data was collected from January 15 to February 08, 2007 in Jimma zone. First, four districts were selected by lottery method. Then 2 'kebeles' from each district were selected randomly and households were selected by systematic sampling. A total of 836 households were studied. The data were cleaned, coded and entered into computer and analyzed using SPSS for windows version 12.0. Bivariate analysis and logistic regression were conducted and a significance level of 5% was considered for interpretation. RESULTS: The health services utilization rate was found to be 45.6%. After controlling confounders using logistic regression; sex (OR=0.23), marital status (OR=8.1), household income (OR=0.70), socioeconomic status (OR=3.5), presence of disabling health problem (OR=3.3), presence of an illness episode (OR=28.3), perceived transport cost (OR=3.6), perceived treatment cost (OR=0.15) and distance to the nearest health center or hospital (OR=2.9) were found to be predictors of utilization of health care. CONCLUSION: It has been shown that utilization level was not satisfactory. Thus, we recommend that the level of health service utilization should be improved by improving predictors of health care use like physical accessibility. PMID- 22435013 TI - Factors Associated with Readiness to VCT Service Utilization among Pregnant Women Attending Antenatal Clinics in Northwestern Ethiopia: A Health Belief Model Approach. AB - BACKGROUND: One of the consequences of Human Immunodeficiency Virus infection in women is the transmission of the virus to their children. Voluntary counseling and testing is an entry point for prevention of mother to child transmission). This study therefore, investigated readiness to Voluntary counseling and testing service utilization and associated factors among pregnant women attending antenatal care clinics using a health belief model. METHODS: Health institution based cross-sectional study supplemented with qualitative method was conducted at Debremarkos town from February 15 to March 25, 2008. A total of 418 Antenatal care clients were interviewed. In addition four focus group discussion and five in-depth interviews were performed. RESULTS: Out of 418 pregnant women 254(60.8%) had heard of, Voluntary counseling and testing of these 141 (55.5%) were not ready to use. R Voluntary counseling and testing eadiness of women to utilize Voluntary counseling and testing was significantly associated with knowledge on mother to child transmission, gravidity, gestational age, occupation and educational status. Most women 161 (63.4%) had low perceived susceptibility to HIV and 199(78.3%) had high perceived barrier to Voluntary counseling and testing. The qualitative result showed spouse's disapproval, fear of blood drawing and knowing HIV status, stigma and discrimination were mentioned as barriers. Among the HBM constructs, perceived susceptibility, benefit, barrier and self efficacy were important predictors of women's readiness to. Voluntary counseling and testing CONCLUSION: This study showed pregnant women's readiness to utilize is l Voluntary counseling and testing ow. It is useful hence, to implement Information Education Communication/Behavioral Change Communication strategies to increase readiness. The use of behavioral model will likely assist the intervention. PMID- 22435014 TI - Utilization of case presentations in medical microbiology to enhance relevance of basic science for medical students. AB - BACKGROUND: Small-group case presentation exercises (CPs) were created to increase course relevance for medical students taking Medical Microbiology (MM) and Infectious Diseases (ID) METHODS: Each student received a unique paper case and had 10 minutes to review patient history, physical exam data, and laboratory data. Students then had three minutes to orally present their case and defend why they ruled in or out each of the answer choices provided, followed by an additional three minutes to answer questions. RESULTS: Exam scores differed significantly between students who received the traditional lecture-laboratory curriculum (Group I) and students who participated in the CPs (Group II). In MM, median unit exam and final exam scores for Group I students were 84.4% and 77.8%, compared to 86.0% and 82.2% for Group II students (P<0.018; P<0.001; Mann-Whitney Rank Sum Test). Median unit and final ID exam scores for Group I students were 84.0% and 80.0%, compared to 88.0% and 86.7% for Group II students (P<0.001; P<0.001). CONCLUSION: Students felt that the CPs improved their critical thinking and presentation skills and helped to prepare them as future physicians. PMID- 22435015 TI - Glycemia and cardiovascular risk: challenging evidence based medicine. AB - Optimal glycemic control is well known to reduce effectively the risk of micro vascular complications both in type 1 and type 2 diabetes mellitus. However the role of glycemic control in decreasing the risk of myocardial infarction and ischemic stroke, the leading causes of death in patients with diabetes, has been so far controversial. In this review, based on data recently reported from large interventional studies, we discuss the possible causal relationship between glycemia and cardiovascular outcomes in type 1 and type 2 diabetes. Strict glycemic control right from the diagnosis of the disease may be effective in reducing long term incidence of cardiovascular (CV) disease in both T1 and T2 diabetics. Nevertheless such a strategy could be potentially harmful for T2 diabetics with long duration of sub optimal glycemic control and already established CV complications. Treatment targets in these patients should be individualized taking into account other aspects of glycemic control and diabetes complications such as hypoglycemia and autonomic neuropathy. PMID- 22435016 TI - Pregnancy-related low back pain. AB - Pregnancy related low back pain is a common complaint among pregnant women. It can potentially have a negative impact on their quality of life. The aim of this article is to present a current review of the literature concerning this issue.By using PubMed database and low back pain, pelvic girdle pain, pregnancy as keywords, abstracts and original articles in English investigating the diagnosis treatment of back pain during pregnancy were searched and analyzedLow back pain could present as either a pelvic girdle pain between the posterior iliac crest and the gluteal fold or as a lumbar pain over and around the lumbar spine. The source of the pain should be diagnosed and differentiated early.The appropriate treatment aims to reduce the discomfort and the impact on the pregnant womans quality of life. This article reveals the most common risk factors, as well as treatment methods, which may help to alleviate the pain. Some suggestions for additional research are also discussed. PMID- 22435017 TI - Electrical Impedance Tomography: a new study method for neonatal Respiratory Distress Syndrome? AB - Treatment of cardiorespiratory system diseases is a procedure that usually demands data collection on terms of the anatomy and the operation of the organs that are under study. Electrical Impedance Tomography (EIT) is an alternative approach, in comparison to existing techniques. With EIT electrodes are placed in the perimeter of the human body and images of the estimated organ are reconstructed, using the measurement of its impendence (or resistance) distribution and determining its alteration through time, while at the same time the patient is not exposed to ionizing radiation. Its clinical use presupposes the correct placement of the electrodes over the perimeter of the human body, the rapid data collection and electrical safety. It is a low cost technique and it is implemented near the patient. It is able to determine the distribution of ventilation, blood supply, diffused or localized lung defects, but it can also estimate therapeutic interventions or alteration to assisted ventilation of the neonate. EIT was developed at the beginning of the 1980s, but it has only recently begun to be implemented on neonates, and especially in the study of their respiratory system function. The low rate of image analysis is considered to be a drawback, but it is offset by the potential offered for the estimation of lungs' function (both under normal and pathological conditions), since ventilation and resistance are two quite similar concepts. In this review the most important studies about EIT are mentioned as a method of estimating respiratory distress syndrome in neonates. In terms of the above mentioned development, it is supposed that this technique will offer a great amount of help to the doctor in his / her estimations of the cardiorespiratory system and to his / her selection of the best intervening strategies. PMID- 22435018 TI - Dietary interventions for primary allergy prevention in infants. AB - Allergy prevention remains a vexing problem. Food sensitization frequently occurs early in life and is often the first sign of future atopic disease. Therefore, interventions to prevent food allergies and the development of the atopic phenotype are best made early in life. The results of studies regarding the effects of breast-feeding and the prevention of allergy remain inconclusive. Several factors in breast milk either induce or protect against food allergies. Probiotic and prebiotic supplemented whey hydrolysate formulas need further research in order to determine the future of this intervention in the prevention of food allergies. Several dietary manipulations in infancy, such as prolonged breast feeding, maternal avoidance diets during pregnancy and lactation, the use of hypoallergenic formulas, have been proposed as ways of altering the Th1/Th2 balance in infants, with varying degrees of success. Studies have examined whether food atopy can be prevented by controlling the intake of highly allergenic foods by a high-risk infant from a variety of sources, that is, both direct ingestion and indirect ingestion through the breast milk. The previous studies showed that in high risk infants who are unable to be completely breast fed, there is evidence that prolonged feeding with a hydrolysed formula compared to a cow's milk formula reduces infant and childhood allergy and infant cow's milk allergy ,while other studies reported that an antigen avoidance diet for high risk mothers is unlikely to reduce the atopic diseases in their children substantially, and that such a diet may adversely affect maternal and/or fetal nutrition. PMID- 22435020 TI - Network-centric Analysis of Genetic Predisposition in Diabetic Nephropathy. AB - Diabetic nephropathy is a serious, long-term complication of diabetes and the leading cause of end-stage renal disease throughout the world. Although this disease is progressively imposing a heavier burden on the health care system, in many aspects it remains poorly understood. In addition to environmental influences, there is abundant evidence in support of genetic susceptibility to microvascular complications of nephropathy in diabetic patients. Familial clustering of phenotypes such as end-stage renal disease, albuminuria and kidney disease have been reported in large scale population studies throughout the world demonstrating strong contribution of inherited factors. Recent genome-wide linkage scans identified several chromosomal regions that are likely to contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under linkage peaks. In this review we have extracted from the literature the most promising candidate genes thought to confer susceptibility to diabetic nephropathy and mapped them to affected pathways by using network-centric analysis. Several of the top susceptibility genes have been identified as network hubs and bottlenecks suggesting that they might be important agents in the onset of diabetic nephropathy. PMID- 22435019 TI - Current options in inguinal hernia repair in adult patients. AB - Inguinal hernia is a very common problem. Surgical repair is the current approach, whereas asymptomatic or minimally symptomatic hernias may be good candidate for watchful waiting. Prophylactic antibiotics can be used in centers with high rate of wound infection. Local anesthesia is a suitable and economic option for open repairs, and should be popularized in day-case setting. Numerous repair methods have been described to date. Mesh repairs are superior to "nonmesh" tissue-suture repairs. Lichtenstein repair and endoscopic/laparoscopic techniques have similar efficacy. Standard polypropylene mesh is still the choice, whereas use of partially absorbable lightweight meshes seems to have some advantages. PMID- 22435021 TI - Lipopolysaccharide and hypoxia significantly alters interleukin-8 and macrophage chemoattractant protein-1 production by human fibroblasts but not fibrosis related factors. AB - Besides extracellular matrix production, fibroblasts are able to produce various cytokines. Their ubiquitous position makes fibroblasts appropriate cells for sensing various noxious stimuli and for attracting immune cells in the affected area. In the present study the effect of lipopolysaccharide (LPS) and cobalt chloride (CoCl(2)) on the above fibroblasts functions were evaluated in primary human skin fibroblasts cultures. Collagen, matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1, transforming growth factor-beta1, interleukin 8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) were measured in fibroblasts culture supernatants. Fibroblasts proliferation and viability were assessed as well. Hypoxia inducible factor-1alpha and the phosphorylated p65 portion of NF-kappaB were assessed in fibroblasts protein extracts. LPS and CoCl(2) had a minor effect on fibrosis related factors in human primary fibroblasts, possibly due to the absence of interplay with other cell types in the used experimental system. On the contrary both LPS and CoCl(2) increased significantly IL-8. LPS also increased considerably MCP-1, but CoCl(2) decreased it. Thus LPS and CoCl(2) induce a sentinel, nevertheless not identical, phenotype in primary human fibroblasts. The last disparity could result in different body response to infectious or hypoxic noxious stimuli. PMID- 22435022 TI - Are vascular disorders a common cause of erectile dysfunction in non hypogonadal, non neuropsychiatric patients? AB - OBJECTIVES: Pharmacological Color Duplex Ultrasonography (PCDU) is a technique used as an advanced investigation of erectile dysfunction (ED) causes. Aim of the study was to determine, if frequency of vascular disorders in ED patients justifies routine use of PCDU. MATERIALS AND METHODS: Seventy six patients aged 25-69 years with moderate to severe ED, free neuropsychiatric history and normal hormones were included in the study. The investigation consisted of basic ED work up and penile PCDU. Erection vascular parameters were determined. RESULTS: In the younger group (<=45 years), 12% of patients demonstrated mild arterial insufficiency and none venous leakage, with only two patients not achieving hard erection. In the older group, 19.6% of patients demonstrated mild to moderate arterial insufficiency and 5.9% severe. Venous leakage was detected in 7.84%. Most patients (74.6%) achieved normal erection and 66.7% had normal PCDU parameters. CONCLUSIONS: Vascular disorders were not found the primary cause of ED, especially among younger patients. PCDU is an advanced ED investigation, which should be applied only in vascular high risk cases. PMID- 22435023 TI - The use of fibrin sealant after total thyroidectomy for benign disease obviates the need for routine drainage. Results of a randomized controlled trial. AB - BACKGROUND: Drains are usually left after thyroid surgery to prevent formation of hematoma and seroma in the thyroid bed. This prospective randomized clinical trial was conducted to evaluate the necessity of drainage after total thyroidectomy for benign thyroidal disorders. METHODS: The patients were assigned randomly into two groups (group 1: with suction drain, group 2: fibrin glue). In the study, operating time, postoperative pain, the total amount of intramuscular analgesic administration, hospital stay, complications (such as wound infection, seroma, bleeding, hematoma, recurrent laryngeal nerve palsy or hypoparathyroidism), were recorded. RESULTS: The drained group (group 1) consisted of 2 men and 48 women with a mean age of 47.76+/-11.22 years. The nondrained (plus fibrin sealant)( group 2) (comprised of 10 men and 40 women with a mean age of 44.72+/-11.32 years. There was no significant difference in the gender, age, hormonal status and histopathological results of the patients between the two groups (P=0.18, P=0.36, P=0.28 and P=0.40, respectively). The operations performed were total thyroidectomy in all patients. Twenty-five patients (50%) in the non-drained group did not need intramuscular analgesic, whereas 15 patients (30%) did not in the drained group (P=0.01). In addition, the mean amount of intramuscular analgesic requirement was significantly less in the non-drained group than in the drained group (P=0.02). The complication rates were similar between the two groups. One case of hematoma (2%), two cases of seroma (4%) and three cases of transient hypoparathyroidism (6%) occurred in the non drained group, whereas one case of hematoma (2%), two cases of seroma (4%), two cases of wound infections (4%) and two cases of transient hypoparathyroidism (4%) occurred in the drained group (P=0.69). No patient needed surgical revision or re operation for any complication and all complications were successfully managed conservatively. CONCLUSION: Routine drainage of thyroid bed following thyroid surgery may not be necessary. Not draining the wound results in lesser morbidity and decreased hospital stay. PMID- 22435024 TI - Socioeconomic evaluation of the treatment of ureteral lithiasis. AB - BACKGROUND AND AIM: This study attempts to estimate the socioeconomic differences between three major alternatives for the management of upper and lower ureteral lithiasis. MATERIAL AND METHODS: Two hundred and forty patients with upper and lower ureteral lithiasis, have been studied retrospectively, divided in six equal groups of forty. These patients have been treated either by extracorporeal shockwave lithotripsy (SWL), or with ureteroscopy with semirigid ureteroscope and the use of pneumatic lithoclast, or with ureteroscopy with flexible ureteroscope and the use of Holmium YAG Laser. For cost calculation, the reimbursement fee paid by insurance to the hospital was taken into account. For the estimation of the social burden, the length of hospital stay and the number of outpatient visits have been included as countable parameters. RESULTS: The percentage of effective stone removal for upper ureter was 81.0% for SWL, 62.5% for ureteroscopy with semirigid ureteroscope and the use of pneumatic lithoclast and, 82.5% for ureteroscopy with flexible ureteroscope and the use of Holmium YAG Laser. The same percentages for lower ureter were 82.5%, 92.5% and 97.5% respectively. The cost of stone removal for both the upper and lower ureter using extracorporeal lithotripsy was significantly higher compared to the other two procedures (median cost for upper ureter 828 ? vs 474.50 ? and 396 ? respectively, and for lower ureter 826 ? vs 396 ? and 271 ?, p<0.001). Regarding the social aspect, SWL is mainly an outpatient procedure, requiring a short hospital stay (for upper ureter 1.63 vs 2.48 and 2.45 respectively and for lower ureter 1.35 vs 2.43 and 2.13days), but needing more and prevailing clinic visits (for upper ureter 1.43 vs 1.45 and 1 respectively and for lower ureter 1.45 vs 1.15 and 0.55 visitsgive numbers, compare), both in outpatient and in accident and emergency (A&E) department. CONCLUSION: The increase in the expenses with regard to health management indicates the necessity of cost accounting the health programs including the medical procedures as a means to improve the relation between cost and benefit. PMID- 22435025 TI - Percutaneous ultrasound-guided renal biopsy in children: a single centre experience. AB - BACKGROUND AND AIM: The contribution of renal biopsy is of major importance in many renal diseases in children. In our study we aimed to evaluate retrospectively the indications, safety, efficacy and the spectrum of histopathological findings of percutaneous ultrasound-guided renal (PRB) biopsy during a 7 year period as well as to analyze specific groups of renal patients. PATIENTS AND METHODS: A total of 84 renal biopsies were performed in 81 children. Demographic data, clinical symptoms at presentation, indications for renal biopsy, laboratory findings, complications of the procedure and histological diagnosis were obtained from all patients who underwent PRB. RESULTS: The commonest indication for biopsy accounted was steroid resistant, steroid dependent or frequent relapsing idiopathic nephrotic syndrome (INS). Subcapsular hematoma presented 11% of the patients, but none of them needed blood transfusion. Adequate renal tissue sample was obtained in 97.7% of the renal biopsies. In 80% the histopathology revealed glomerular diseases. The most frequent types of biopsy-proven renal diseases were: focal segmental glomerulosclerosis (FSGS) (15%), IgA nephropathy (13.5%), minimal change disease (10%), various stages of lupus nephritis (8.5%), Henoch-Schonlein nephritis (7.5%), membranous glomerulonephritis (7.5%), mesangioproliferative glomerulonephritis (6%), post-infectious glomerulonephritis (6%), hemolytic uremic syndrome (5%), tubulointerstitial nephropathies (3.5%), acute tubular necrosis 2.5%. Among the 28 cases of INS, FSGS accounted for 43%. The leading histopathological pattern found in patients with recurrent episodes of gross haematuria was IgAN (84.5%). Among 7 cases of lupus nephritis, the observed histological types were: IV+V in 3/7, IIIA in 3/7 (43%) and IIB in 1/7. CONCLUSIONS: Our study shows that percutaneous ultrasound-guided renal biopsy is a safe, reliable and effective technique in children. It also provides updated information for childhood renal disease pattern. PMID- 22435026 TI - Scintigraphic evaluation of small intestinal transit in the streptozotocin induced diabetic rats. AB - AIM: Small intestine (SI) transit in the streptozotocin (STZ) induced diabetic rats were examined by using 99mTc-mebrofenin scintigraphy. MATERIALS AND METHODS: Wistar albino rats (mean body weight: 220+/-12 g) were studied for both control (n=10) and diabetes mellitus (DM) (n=10) groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg(-1) body weight. SI transit time was assessed by measuring arrival times of 99mTc-mebrofenin from duodenum to caecum. RESULTS: The mean transit time of 99mTc- mebrofenin was 67.8+/-11 min in control group. The mean transit time of SI was prolonged in STZ induced diabetic animals with (111.9+/-12.5, p=0.01). There was significant correlation between small intestinal transit time and blood glucose level (r: 0.73, p=0.01). CONCLUSION: We observed that SI transit was prolonged in diabetic animals using 99mTc- mebrofenin, and additionally this technique is a readily available method for the detection of transit abnormalities in animal experiment. PMID- 22435027 TI - White Matter Lesions in Femoral Head Osteonecrosis patients: Manifestation of vascular disease or not? AB - BACKGROUND: Osteonecrosis has been associated with the presence of white matter lesions. The objective of this study was to investigate the association between macro- and micro- vascular disease and white matter lesions. METHODS: Sixty-four patients with femoral head osteonecrosis were assessed during a cross sectional study in our university-based hospital. A vascular 'profile' was obtained for each patient and included measurement of plasma lipids, fundoscopic examination and common carotid artery triplex ultrasonography. All patients had brain MRI to assess for presence of white matter lesions. The two groups formed, with and without white matter lesions, were compared in order to define the association between white matter lesions and vascular disease. RESULTS: Patients without white matter lesions had more frequently corticosteroid induced osteonecrosis. There was no difference in the two groups with respect to intima media thickness and ApoB/ApoA1 ratio. Only one of our patients demonstrated retinopathy. CONCLUSIONS: There is no evidence of concurrent macro- and micro- vascular pathology in young patients with white matter lesions and femoral head osteonecrosis. Cortisone appears to have a 'protective' effect against occurrence of white matter lesions. PMID- 22435028 TI - Bilateral asymptomatic giant renal artery aneurysm. AB - The incidence of renal artery aneurysm is very low. Approximately in 20% of these patients hypertension is observed. The diameter of aneurysm increases with accompanying complication rates. The most feared complication is rupture. The risk of rupture also increases with the diameter of aneurysm. We report an aneurysm with the biggest diameter reported in the literature. The patient had a 12 cm-diameter of aneurysm in one kidney and did not show any symptoms including hypertension until she was seventy years old. PMID- 22435029 TI - Oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus in Northern Greece. AB - Resistance to oseltamivir was observed to influenza A pandemic (H1N1) 2009 virus strains, isolated from two patients in North Greece. Investigations showed resistant viruses with the neuraminidase (NA) 275Y genotypes. Pandemic A (H1N1) 2009 virus should be closely monitored for emergence of resistant variants. PMID- 22435030 TI - Video capsule endoscopy findings in subacute superior mesenteric vein thrombosis. AB - BACKGROUND: Subacute superior mesenteric vein thrombosis is a rare ischemic intestinal disease which is often characterized by delayed diagnosis due to obscure clinical picture. CASE REPORT: A 67-year-old woman who presented chronic abdominal pain with mild nausea due to superior mesenteric vein thrombosis was submitted to video capsule endoscopy. We describe, for the first time, the video capsule endoscopy findings in this patient. CONCLUSION: We emphasize the role of this new technology in the diagnosis of suspected ischemic intestinal diseases. PMID- 22435031 TI - Identification of a mutation in the MTM1 gene, associated with X-linked myotubular myopathy, in a Greek family. AB - X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually characterized by severe hypotonia and respiratory insufficiency at birth, in affected, male infants. The disease is causally associated with mutations in the MTM1 gene, coding for phosphatase myotubularin. We report a severe case of XLMTM with a novel mutation, at a donor splicing site (c.1467+1G) previously associated with severe phenotype. The mutation was also identified in the patient's mother, providing an opportunity for sound genetic counseling. PMID- 22435032 TI - Spontaneous intramural esophageal hematoma. PMID- 22435033 TI - Prevalence and sociodemographic correlates of addictive substances use among medical school students. PMID- 22435034 TI - Spontaneous pneumothorax complicating sunitinib therapy. PMID- 22435035 TI - Surgical treatment of gastrointestinal stromal tumour of jejunum. PMID- 22435036 TI - Sweet's syndrome associated with upper respiratory tract streptococcal infection: "wait-and-see" strategy or anecdotal use of corticosteroids? PMID- 22435037 TI - Posterior dislocation of the sternoclavicular joint. PMID- 22435038 TI - Renal artery pseudoaneurysm after partial nephrectomy. PMID- 22435039 TI - Long-term safety and efficiency of endovascular repair in an adolescent patient with post-traumatic aortic pseudoaneurysm. PMID- 22435040 TI - Treatment with risperidone and venlafaxine of a patient with double-coded diagnosis of body dysmorphic disorder and delusional disorder somatic type. PMID- 22435041 TI - Low aqueous humor ghrelin levels in open-angle glaucoma patients may correlate with Helicobacter pylori-associated apoptotic mechanisms. PMID- 22435042 TI - Early enteral nutrition positively influences endocrine function in traumatic brain injury patients. PMID- 22435043 TI - Anion Cluster: Assembly of Dihydrogen Phosphates for the Formation of a Cyclic Anion Octamer. AB - Structural characterization of a dihydrogen phosphate complex of triprotonated tris[2-(2-thienylmethylamino)ethyl] amine shows that eight dihydrogen phosphate anions are assembled around the host by strong interactions of H-bond donors and acceptors to form a new type of cyclic anion octamer as (H(2)PO(4) (-))(8), an analogy of cyclic water octamer. The presence of an anion cluster has also been identified by electrospray ionization mass spectrometry and (31)P NMR experiments. PMID- 22435044 TI - Prepared to react? Assessing the functional capacity of the primary health care system in rural Orissa, India to respond to the devastating flood of September 2008. AB - BACKGROUND: Early detection of an impending flood and the availability of countermeasures to deal with it can significantly reduce its health impacts. In developing countries like India, public primary health care facilities are frontline organizations that deal with disasters particularly in rural settings. For developing robust counter reacting systems evaluating preparedness capacities within existing systems becomes necessary. OBJECTIVE: The objective of the study is to assess the functional capacity of the primary health care system in Jagatsinghpur district of rural Orissa in India to respond to the devastating flood of September 2008. METHODS: An onsite survey was conducted in all 29 primary and secondary facilities in five rural blocks (administrative units) of Jagatsinghpur district in Orissa state. A pre-tested structured questionnaire was administered face to face in the facilities. The data was entered, processed and analyzed using STATA((r)) 10. RESULTS: Data from our primary survey clearly shows that the healthcare facilities are ill prepared to handle the flood despite being faced by them annually. Basic utilities like electricity backup and essential medical supplies are lacking during floods. Lack of human resources along with missing standard operating procedures; pre-identified communication and incident command systems; effective leadership; and weak financial structures are the main hindering factors in mounting an adequate response to the floods. CONCLUSION: The 2008 flood challenged the primary curative and preventive health care services in Jagatsinghpur. Simple steps like developing facility specific preparedness plans which detail out standard operating procedures during floods and identify clear lines of command will go a long way in strengthening the response to future floods. Performance critiques provided by the grass roots workers, like this one, should be used for institutional learning and effective preparedness planning. Additionally each facility should maintain contingency funds for emergency response along with local vendor agreements to ensure stock supplies during floods. The facilities should ensure that baseline public health standards for health care delivery identified by the Government are met in non-flood periods in order to improve the response during floods. Building strong public primary health care systems is a development challenge. The recovery phases of disasters should be seen as an opportunity to expand and improve services and facilities. PMID- 22435045 TI - Comparing the Iowa and soochow gambling tasks in opiate users. AB - The Iowa Gambling Task (IGT) is in many respects the gold standard for demonstrating decision making in drug using groups. However, it is not clear how basic task properties such as the frequency and magnitude of rewards and losses affect choice behavior in drug users and even in healthy players. In this study, we used a variant of the IGT, the Soochow Gambling Task (SGT), to observe choice behavior in opiate users and healthy decision makers in a task where reward frequency is not confounded with the long-term outcome of each alternative. In both opiate users (n = 26) and healthy controls (n = 27), we show that reward frequency strongly influences choice behavior in the IGT and SGT. Neither group showed a consistent preference across tasks for alternatives with good long-term outcomes, but rather, subjects appeared to prefer alternatives that win most frequently. We interpret this as evidence to suggest that healthy players perform better than opiate users on the IGT because they are able to utilize gain-loss frequencies to guide their choice behavior on the task. This challenges the previous notion that poorer performance on the IGT in drug users is due to an inability to be guided by future consequences. PMID- 22435046 TI - Decisions from experience: adaptive information search and choice in younger and older adults. AB - In real-world decision making, choice outcomes, and their probabilities are often not known a priori but must be learned from experience. The dopamine hypothesis of cognitive aging predicts that component processes of experience-based decision making (information search and stimulus-reward association learning) decline with age. Many existing studies in this domain have used complex neuropsychological tasks that are not optimal for testing predictions about specific cognitive processes. Here we used an experimental sampling paradigm with real monetary payoffs that provided separate measures of information search and choice for gains and losses. Compared with younger adults, older adults sought less information about uncertain risky options. However, like younger adults, older participants also showed evidence of adaptive decision making. When the desirable outcome of the risky option was rare (p = 0.10 or 0.20), both age groups engaged in more information search and made fewer risky choices, compared with when the desirable outcome of the risky option was frequent (p = 0.80 or 0.90). Furthermore, loss options elicited more sampling and greater modulation of risk taking, compared with gain options. Overall, these findings support predictions of the dopamine hypothesis of cognitive aging, but they also highlight the need for additional research into the interaction of age and valence (gain vs. loss) on experience-based choice. PMID- 22435047 TI - The importance of combinatorial gene expression in early Mammalian thalamic patterning and thalamocortical axonal guidance. AB - The thalamus is essential for sensory perception. In mammals, work on the mouse has taught us most of what we know about how it develops and connects to the cortex. The mature thalamus of all mammalian species comprises numerous anatomically distinct collections of neurons called nuclei that differ in function, connectivity, and molecular constitution. At the time of its initial appearance as a distinct structure following neural tube closure, the thalamus is already patterned by the regional expression of numerous regulatory genes. This patterning, which lays down the blueprint for later development of thalamic nuclei, predates the development of thalamocortical projections. In this review we apply novel analytical methods to gene expression data available in the Allen Developing Mouse Brain Atlas to highlight the complex organized molecular heterogeneity already present among cells in the thalamus from the earliest stages at which it contains differentiating neurons. This early patterning is likely to invest in axons growing from different parts of the thalamus the ability to navigate in an ordered way to their appropriate area in the cerebral cortex. We review the mechanisms and cues that thalamic axons use, encounter, and interpret to attain the cortex. Mechanisms include guidance by previously generated guidepost cells, such as those in the subpallium that maintain thalamic axonal order and direction, and axons such as those of reciprocal projections from intermediate structures or from the cortex itself back toward the thalamus. We show how thalamocortical pathfinding involves numerous guidance cues operating at a series of steps along their route. We stress the importance of the combinatorial actions of multiple genes for the development of the numerous specific identities and functions of cells in this exquisitely complex system and their orderly innervation of the cortex. PMID- 22435048 TI - Three functional facets of calbindin D-28k. AB - Many neurons of the vertebrate central nervous system (CNS) express the Ca(2+) binding protein calbindin D-28k (CB), including important projection neurons like cerebellar Purkinje cells but also neocortical interneurons. CB has moderate cytoplasmic mobility and comprises at least four EF-hands that function in Ca(2+) binding with rapid to intermediate kinetics and affinity. Classically it was viewed as a pure Ca(2+) buffer important for neuronal survival. This view was extended by showing that CB is a critical determinant in the control of synaptic Ca(2+) dynamics, presumably with strong impact on plasticity and information processing. Already 30 years ago, in vitro studies suggested that CB could have an additional Ca(2+) sensor function, like its prominent acquaintance calmodulin (CaM). More recent work substantiated this hypothesis, revealing direct CB interactions with several target proteins. Different from a classical sensor, however, CB appears to interact with its targets both, in its Ca(2+)-loaded and Ca(2+)-free forms. Finally, CB has been shown to be involved in buffered transport of Ca(2+), in neurons but also in kidney. Thus, CB serves a threefold function as buffer, transporter and likely as a non-canonical sensor. PMID- 22435049 TI - AKT/GSK3 signaling pathway and schizophrenia. AB - Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3beta in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms. PMID- 22435050 TI - Modeling neural differentiation on micropatterned substrates coated with neural matrix components. AB - Topographical and biochemical characteristics of the substrate are critical for neuronal differentiation including axonal outgrowth and regeneration of neural circuits in vivo. Contact stimuli and signaling molecules allow neurons to develop and stabilize synaptic contacts. Here we present the development, characterization and functional validation of a new polymeric support able to induce neuronal differentiation in both PC12 cell line and adult primary skin derived precursor cells (SKPs) in vitro. By combining a photolithographic technique with use of neural extracellular matrix (ECM) as a substrate, a biocompatible and efficient microenvironment for neuronal differentiation was developed. PMID- 22435051 TI - Cholinergic modulation of the CAN current may adjust neural dynamics for active memory maintenance, spatial navigation and time-compressed replay. AB - Suppression of cholinergic receptors and inactivation of the septum impair short term memory, and disrupt place cell and grid cell activity in the medial temporal lobe (MTL). Location-dependent hippocampal place cell firing during active waking, when the acetylcholine level is high, switches to time-compressed replay activity during quiet waking and slow-wave-sleep (SWS), when the acetylcholine level is low. However, it remains largely unknown how acetylcholine supports short-term memory, spatial navigation, and the functional switch to replay mode in the MTL. In this paper, we focus on the role of the calcium-activated non specific cationic (CAN) current which is activated by acetylcholine. The CAN current is known to underlie persistent firing, which could serve as a memory trace in many neurons in the MTL. Here, we review the CAN current and discuss possible roles of the CAN current in short-term memory and spatial navigation. We further propose a novel theoretical model where the CAN current switches the hippocampal place cell activity between real-time and time-compressed sequential activity during encoding and consolidation, respectively. PMID- 22435052 TI - In vivo Large-Scale Cortical Mapping Using Channelrhodopsin-2 Stimulation in Transgenic Mice Reveals Asymmetric and Reciprocal Relationships between Cortical Areas. AB - We have mapped intracortical activity in vivo independent of sensory input using arbitrary point channelrhodopsin-2 (ChR2) stimulation and regional voltage sensitive dye imaging in B6.Cg-Tg (Thy1-COP4/EYFP)18Gfng/J transgenic mice. Photostimulation of subsets of deep layer pyramidal neurons within forelimb, barrel, or visual primary sensory cortex led to downstream cortical maps that were dependent on synaptic transmission and were similar to peripheral sensory stimulation. ChR2-evoked maps confirmed homotopic connections between hemispheres and intracortical sensory and motor cortex connections. This ability of optogentically activated subpopulations of neurons to drive appropriate downstream maps suggests that mechanisms exist to allow prototypical cortical maps to self-assemble from the stimulation of neuronal subsets. Using this principle of map self-assembly, we employed ChR2 point stimulation to map connections between cortical areas that are not selectively activated by peripheral sensory stimulation or behavior. Representing the functional cortical regions as network nodes, we identified asymmetrical connection weights in individual nodes and identified the parietal association area as a network hub. Furthermore, we found that the strength of reciprocal intracortical connections between primary and secondary sensory areas are unequal, with connections from primary to secondary sensory areas being stronger than the reciprocal. PMID- 22435053 TI - An agonist-antagonist cerebellar nuclear system controlling eyelid kinematics during motor learning. AB - The presence of two antagonistic groups of deep cerebellar nuclei neurons has been reported as necessary for a proper dynamic control of learned motor responses. Most models of cerebellar function seem to ignore the biomechanical need for a double activation-deactivation system controlling eyelid kinematics, since most of them accept that, for closing the eyelid, only the activation of the orbicularis oculi (OO) muscle (via the red nucleus to the facial motor nucleus) is necessary, without a simultaneous deactivation of levator palpebrae motoneurons (via unknown pathways projecting to the perioculomotor area). We have analyzed the kinetic neural commands of two antagonistic types of cerebellar posterior interpositus neuron (IPn) (types A and B), the electromyographic (EMG) activity of the OO muscle, and eyelid kinematic variables in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. We addressed the hypothesis that the interpositus nucleus can be considered an agonist-antagonist system controlling eyelid kinematics during motor learning. To carry out a comparative study of the kinetic-kinematic relationships, we applied timing and dispersion pattern analyses. We concluded that, in accordance with a dominant role of cerebellar circuits for the facilitation of flexor responses, type A neurons fire during active eyelid downward displacements-i.e., during the active contraction of the OO muscle. In contrast, type B neurons present a high tonic rate when the eyelids are wide open, and stop firing during any active downward displacement of the upper eyelid. From a functional point of view, it could be suggested that type B neurons play a facilitative role for the antagonistic action of the levator palpebrae muscle. From an anatomical point of view, the possibility that cerebellar nuclear type B neurons project to the perioculomotor area-i.e., more or less directly onto levator palpebrae motoneurons-is highly appealing. PMID- 22435054 TI - Acquisition of "Start" and "Stop" response thresholds in peak-interval timing is differentially sensitive to protein synthesis inhibition in the dorsal and ventral striatum. AB - Time-based decision-making in peak-interval timing procedures involves the setting of response thresholds for the initiation ("Start") and termination ("Stop") of a response sequence that is centered on a target duration. Using intracerebral infusions of the protein synthesis inhibitor anisomycin, we report that the acquisition of the "Start" response depends on normal functioning (including protein synthesis) in the dorsal striatum (DS), but not the ventral striatum (VS). Conversely, disruption of the VS, but not the DS, impairs the acquisition of the "Stop" response. We hypothesize that the dorsal and ventral regions of the striatum function as a competitive neural network that encodes the temporal boundaries marking the beginning and end of a timed response sequence. PMID- 22435055 TI - Involvement of the insular cortex in regulating glucocorticoid effects on memory consolidation of inhibitory avoidance training. AB - Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC) to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor (GR) agonist RU 28362 (3 or 10 ng in 0.5 MUl) infused bilaterally into the IC of male Sprague-Dawley rats immediately after one-trial inhibitory avoidance training dose-dependently enhanced 48 h retention performance. Moreover, training on the inhibitory avoidance task increased neuronal activity of the IC, as assessed by an increased number of cells expressing immunoreactivity for phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). However, systemic administration of a memory-enhancing dose of corticosterone (1 mg/kg) after inhibitory avoidance training rapidly reduced the number of pERK1/2-positive cells in the IC, suggesting that glucocorticoid administration reduces overall neuronal activity of the IC. To investigate which components of the inhibitory avoidance training experience were influenced by the intra-IC glucocorticoid administration, in the last experiment rats were trained on a modified inhibitory avoidance task in which context exposure and footshock training occur on two sequential days. RU 28362 administration into the IC enhanced later retention when infused immediately after either the context or footshock training. Thus, these findings indicate that the IC mediates glucocorticoid effects on the consolidation of memory of different components of inhibitory avoidance training and suggest that the IC might be an important element of the rodent brain network involved in emotional regulation of learning and memory. PMID- 22435056 TI - Moving a Rubber Hand that Feels Like Your Own: A Dissociation of Ownership and Agency. AB - During voluntary hand movement, we sense that we generate the movement and that the hand is a part of our body. These feelings of control over bodily actions, or the sense of agency, and the ownership of body parts are two fundamental aspects of the way we consciously experience our bodies. However, little is known about how these processes are functionally linked. Here, we introduce a version of the rubber hand illusion in which participants control the movements of the index finger of a model hand, which is in full view, by moving their own right index finger. We demonstrated that voluntary finger movements elicit a robust illusion of owning the rubber hand and that the senses of ownership and agency over the model hand can be dissociated. We systematically varied the relative timing of the finger movements (synchronous versus asynchronous), the mode of movement (active versus passive), and the position of the model hand (anatomically congruent versus incongruent positions). Importantly, asynchrony eliminated both ownership and agency, passive movements abolished the sense of agency but left ownership intact, and incongruent positioning of the model hand diminished ownership but did not eliminate agency. These findings provide evidence for a double dissociation of ownership and agency, suggesting that they represent distinct cognitive processes. Interestingly, we also noted that the sense of agency was stronger when the hand was perceived to be a part of the body, and only in this condition did we observe a significant correlation between the subjects' ratings of agency and ownership. We discuss this in the context of possible differences between agency over owned body parts and agency over actions that involve interactions with external objects. In summary, the results obtained in this study using a simple moving rubber hand illusion paradigm extend previous findings on the experience of ownership and agency and shed new light on their relationship. PMID- 22435057 TI - Music training enhances rapid neural plasticity of n1 and p2 source activation for unattended sounds. AB - Neurocognitive studies have demonstrated that long-term music training enhances the processing of unattended sounds. It is not clear, however, whether music training also modulates rapid (within tens of minutes) neural plasticity for sound encoding. To study this phenomenon, we examined whether adult musicians display enhanced rapid neural plasticity compared to non-musicians. More specifically, we compared the modulation of P1, N1, and P2 responses to standard sounds between four unattended passive blocks. Among the standard sounds, infrequently presented deviant sounds were presented (the so-called oddball paradigm). In the middle of the experiment (after two blocks), an active task was presented. Source analysis for event-related potentials (ERPs) showed that N1 and P2 source activation was selectively decreased in musicians after 15 min of passive exposure to sounds and that P2 source activation was found to be re enhanced after the active task in musicians. Additionally, ERP analysis revealed that in both musicians and non-musicians, P2 ERP amplitude was enhanced after 15 min of passive exposure but only at the frontal electrodes. Furthermore, in musicians, the N1 ERP was enhanced after the active discrimination task but only at the parietal electrodes. Musical training modulates the rapid neural plasticity reflected in N1 and P2 source activation for unattended regular standard sounds. Enhanced rapid plasticity of N1 and P2 is likely to reflect faster auditory perceptual learning in musicians. PMID- 22435058 TI - Flexible recruitment of semantic richness: context modulates body-object interaction effects in lexical-semantic processing. AB - Body-object interaction (BOI) is a semantic richness variable that measures the perceived ease with which the human body can physically interact with a word's referent. Lexical and semantic processing is facilitated when words are associated with relatively more bodily experience. To date, BOI effects have only been examined in the context of one semantic categorization task (SCT; is it imageable?). It has been argued that semantic processing is dynamic and can be modulated by context. We examined these influences by testing how task knowledge modulated BOI effects. Participants discriminated between the same sets of entity (high- and low-BOI) and action words in each of four SCTs. Task framing was manipulated: participants were told about one (is it an action? vs. is it an entity?) or both (action or entity? vs. entity or action?) categories of words in the decision task. Facilitatory BOI effects were only observed when participants knew that "entity" was part of the decision category. That BOI information was only useful when participants had expectations that entity words would be presented suggests a strong role for the decision context in lexical-semantic processing, and supports a dynamic view of conceptual knowledge. PMID- 22435059 TI - The stomatogastric nervous system as a model for studying sensorimotor interactions in real-time closed-loop conditions. AB - The perception of proprioceptive signals that report the internal state of the body is one of the essential tasks of the nervous system and helps to continuously adapt body movements to changing circumstances. Despite the impact of proprioceptive feedback on motor activity it has rarely been studied in conditions in which motor output and sensory activity interact as they do in behaving animals, i.e., in closed-loop conditions. The interaction of motor and sensory activities, however, can create emergent properties that may govern the functional characteristics of the system. We here demonstrate a method to use a well-characterized model system for central pattern generation, the stomatogastric nervous system, for studying these properties in vitro. We created a real-time computer model of a single-cell muscle tendon organ in the gastric mill of the crab foregut that uses intracellular current injections to control the activity of the biological proprioceptor. The resulting motor output of a gastric mill motor neuron is then recorded intracellularly and fed into a simple muscle model consisting of a series of low-pass filters. The muscle output is used to activate a one-dimensional Hodgkin-Huxley type model of the muscle tendon organ in real-time, allowing closed-loop conditions. Model properties were either hand tuned to achieve the best match with data from semi-intact muscle preparations, or an exhaustive search was performed to determine the best set of parameters. We report the real-time capabilities of our models, its performance and its interaction with the biological motor system. PMID- 22435060 TI - Models of the aging brain structure and individual decline. AB - The aging brain's structural development constitutes a spatiotemporal process that is accessible by MR-based computational morphometry. Here we introduce basic concepts and analytical approaches to quantify age-related differences and changes in neuroanatomical images of the human brain. The presented models first address the estimation of age trajectories, then we consider inter-individual variations of structural decline, using a repeated measures design. We concentrate our overview on preprocessed neuroanatomical images of the human brain to facilitate practical applications to diverse voxel- and surface-based structural markers. Together these methods afford analysis of aging brain structure in relation to behavioral, health, or cognitive parameters. PMID- 22435061 TI - A Collection of Pseudo-Words to Study Multi-Talker Speech Intelligibility without Shifts of Spatial Attention. AB - A new collection of pseudo-words was recorded from a single female speaker of American English for use in multi-talker speech intelligibility research. The pseudo-words (known as the KARG collection) consist of three groups of single syllable pseudo-words varying only by the initial phoneme. The KARG method allows speech intelligibility to be studied free of the influence of shifts of spatial attention from one loudspeaker location to another in multi-talker contexts. To achieve this, all KARG pseudo-words share the same concluding rimes, with only the first phoneme serving as a distinguishing identifier. This ensures that listeners are unable to correctly identify the target pseudo-word without hearing the initial phoneme. As the duration of all the initial phonemes are brief, much shorter than the time required to spatially shift attention, the KARG method assesses speech intelligibility without the confound of shifting spatial attention. The KARG collection is available free for research purposes. PMID- 22435062 TI - On some unwarranted tacit assumptions in cognitive neuroscience. AB - The cognitive neurosciences are based on the idea that the level of neurons or neural networks constitutes a privileged level of analysis for the explanation of mental phenomena. This paper brings to mind several arguments to the effect that this presumption is ill-conceived and unwarranted in light of what is currently understood about the physical principles underlying mental achievements. It then scrutinizes the question why such conceptions are nevertheless currently prevailing in many areas of psychology. The paper argues that corresponding conceptions are rooted in four different aspects of our common-sense conception of mental phenomena and their explanation, which are illegitimately transferred to scientific enquiry. These four aspects pertain to the notion of explanation, to conceptions about which mental phenomena are singled out for enquiry, to an inductivist epistemology, and, in the wake of behavioristic conceptions, to a bias favoring investigations of input-output relations at the expense of enquiries into internal principles. To the extent that the cognitive neurosciences methodologically adhere to these tacit assumptions, they are prone to turn into a largely a-theoretical and data-driven endeavor while at the same time enhancing the prospects for receiving widespread public appreciation of their empirical findings. PMID- 22435063 TI - Facilitated assessment of tissue loss following traumatic brain injury. AB - All experimental models of traumatic brain injury (TBI) result in a progressive loss of brain tissue. The extent of tissue loss reflects the injury severity and can be measured to evaluate the potential neuroprotective effect of experimental treatments. Quantitation of tissue volumes is commonly performed using evenly spaced brain sections stained using routine histochemical methods and digitally captured. The brain tissue areas are then measured and the corresponding volumes are calculated using the distance between the sections. Measurements of areas are usually performed using a general purpose image analysis software and the results are then transferred to another program for volume calculations. To facilitate the measurement of brain tissue loss we developed novel algorithms which automatically separate the areas of brain tissue from the surrounding image background and identify the ventricles. We implemented these new algorithms by creating a new computer program (SectionToVolume) which also has functions for image organization, image adjustments and volume calculations. We analyzed brain sections from mice subjected to severe focal TBI using both SectionToVolume and ImageJ, a commonly used image analysis program. The volume measurements made by the two programs were highly correlated and analysis using SectionToVolume required considerably less time. The inter-rater reliability was high. Given the extensive use of brain tissue loss measurements in TBI research, SectionToVolume will likely be a useful tool for TBI research. We therefore provide both the source code and the program as attachments to this article. PMID- 22435064 TI - REACH MUSC: A Telemedicine Facilitated Network for Stroke: Initial Operational Experience. AB - REACH Medical University of South Carolina (MUSC) provides stroke consults via the internet in South Carolina. From May 2008 to April 2011 231 patients were treated with intravenous (IV) thrombolysis and 369 were transferred to MUSC including 42 for intra-arterial revascularization [with or without IV tissue plasminogen activator (tPA)]. Medical outcomes and hemorrhage rates, reported elsewhere, were good (Lazaridis et al., 2011). Here we report operational features of REACH MUSC which covers 15 sites with 2,482 beds and 471,875 Emergency Department (ED) visits per year. Eight Academic Faculty from MUSC worked with 165 different physicians and 325 different nurses in the conduct of 1085 consults. For the 231 who received tPA, time milestones (in minutes) were: Onset to Door: 62 (mean), 50 (median); Door to REACH Consult: 43 and 33, Consult Request to Consult Start: was 9 and 7, Consult Start to tPA Decision: 31 and 25; Decision to Infusion: 20 and 14, and total Door to Needle: 98 and 87. The comparable times for the 854 not receiving tPA were: Onset to Door: 140 and 75; Door to REACH Consult: 61 and 41; Consult Request to Consult Start: 9 and 7, Consult Start to tPA Decision: 27 and 23. While the consultants respond to consult requests in <10, there is a long delay between arrival and Consult request. Tracking of operations indicates if we target shortening Door to Call time and time from tPA decision to start of drug infusion we may be able to improve Door to Needle times to target of <60. The large number of individuals involved in the care of these patients, most of whom had no training in REACH usage, will require novel approaches to staff education in ED based operations where turnover is high. Despite these challenges, this robust system delivered tPA safely and in a high fraction of patients evaluated using the REACH MUSC system. PMID- 22435065 TI - Iron-based microbial ecosystem on and below the seafloor: a case study of hydrothermal fields of the southern mariana trough. AB - Microbial community structures in deep-sea hydrothermal vents fields are constrained by available energy yields provided by inorganic redox reactions, which are in turn controlled by chemical composition of hydrothermal fluids. In the past two decades, geochemical and microbiological studies have been conducted in deep-sea hydrothermal vents at three geographically different areas of the Southern Mariana Trough (SMT). A variety of geochemical data of hydrothermal fluids and an unparalleled microbiological dataset of various samples (i.e., sulfide structures of active vents, iron-rich mats, borehole fluids, and ambient seawater) are available for comparative analyses. Here, we summarize the geochemical and microbiological characteristics in the SMT and assess the relationship between the microbial community structures and the fluid geochemistry in the SMT by thermodynamic modeling. In the high temperature vent fluids, aerobic sulfide-oxidation has the potential to yield large amounts of bioavailable energy in the vent fluids, which is consistent with the detection of species related to sulfide-oxidizing bacteria (such as Thiomicrospira in the Gammaproteobacteria and Sulfurimonas in the Epsilonproteobacteria). Conversely, the bioavailable energy yield from aerobic iron-oxidation reactions in the low temperature fluids collected from man-made boreholes and several natural vents were comparable to or higher than those from sulfide-oxidation. This is also consistent with the detection of species related to iron-oxidizing bacteria (Mariprofundus in the Zetaproteobacteria) in such low-temperature samples. The results of combination of microbiological, geochemical, and thermodynamic analyses in the SMT provide novel insights into the presence and significance of iron-based microbial ecosystems in deep-sea hydrothermal fields. PMID- 22435066 TI - Genomic diversification of enterococci in hosts: the role of the mobilome. AB - Enterococci are ubiquitous lactic acid bacteria, possessing a flexible nature that allows them to colonize various environments and hosts but also to be opportunistic pathogens. Many papers have contributed to a better understanding of: (i) the taxonomy of this complex group of microorganisms; (ii) intra-species variability; (iii) the role of different pathogenicity traits; and (iv) some markers related to the character of host-specificity, but the reasons of such incredible success of adaptability is still far from being fully explained. Recently, genomic-based studies have improved our understanding of the genome diversity of the most studied species, i.e., E. faecalis and E. faecium. From these studies, what is becoming evident is the role of the mobilome in adding new abilities to colonize new hosts and environments, and eventually in driving their evolution: specific clones associated with human infections or specific hosts can exist, but probably the consideration of these populations as strictly clonal groups is only partially correct. The variable presence of mobile genetic elements may, indeed, be one of the factors involved in the evolution of one specific group in a specific host and/or environment. Certainly more extensive studies using new high throughput technologies are mandatory to fully understand the evolution of predominant clones and species in different hosts and environments. PMID- 22435067 TI - Role of Human TRIM5alpha in Intrinsic Immunity. AB - Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV 1) does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5alpha was identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfortunately, human TRIM5alpha is almost powerless to restrict HIV-1. However, human TRIM5alpha potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating that human TRIM5alpha represents the restriction factor previously designated as Ref1. African green monkey TRIM5alpha represents another restriction factor previously designated as Lv1, which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B-box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, and TRIM5alpha is thought to degrade viral core via ubiquitin-proteasome-dependent and -independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY domain, which is a determinant of species-specific retrovirus restriction by TRIM5alpha. On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core. A single amino acid difference in the surface-exposed loop between alpha-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA affects viral sensitivity to human TRIM5alpha and was also shown to be associated with viral load in West African HIV-2 patients, indicating that human TRIM5alpha is a critical modulator of HIV-2 replication in vivo. Interestingly, L6/7 of CA corresponds to the MLV determinant of sensitivity to mouse factor Fv1, which potently restricts N-tropic MLV. In addition, human genetic polymorphisms also affect antiviral activity of human TRIM5alpha. Recently, human TRIM5alpha was shown to activate signaling pathways that lead to activation of NF-kappaB and AP-1 by interacting with TAK1 complex. TRIM5alpha is thus involved in control of viral infection in multiple ways. PMID- 22435068 TI - Tegument Proteins of Kaposi's Sarcoma-Associated Herpesvirus and Related Gamma Herpesviruses. AB - A herpesvirus virion is composed of a viral genomic DNA-containing capsid surrounded by a viral envelope with glycoprotein spikes on its surface. Located between the capsid and the outer viral envelope is the virion tegument layer. Though the majority of the virion proteins are located in the tegument, this layer is less studied and was thought to be an amorphous structure. Over the last decade, a number of studies have indicated the presence of organized tegument structures across the spectrum of herpesviruses, implicating tegument components in critical steps governing the viral life cycle. In the case of Kaposi's sarcoma associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, several functions exerted by tegument proteins at different stages of the viral life cycle, inclusive of primary de novo infection and virion assembly, have been identified over the last several years. In this review, KSHV tegument components are cataloged and the occurrence of organized tegument structures in KSHV, built through interactions amongst the different virion proteins, is discussed in depth. The significant functional roles of the KSHV tegument proteins at different stages of the viral life cycle are elaborated under separate headings. Definitive functional roles exerted by tegument proteins of related gamma herpesviruses are also discussed. Since tegument proteins play key roles during viral assembly, viral entry, and represent an important interface for virus-host interactions, further research in this area should provide detailed insights into the functional capacity of the KSHV tegument, resulting in a better understanding of the viral life cycle. PMID- 22435069 TI - Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift. AB - This paper describes a new program SnpSift for filtering differential DNA sequence variants between two or more experimental genomes after genotoxic chemical exposure. Here, we illustrate how SnpSift can be used to identify candidate phenotype-relevant variants including single nucleotide polymorphisms, multiple nucleotide polymorphisms, insertions, and deletions (InDels) in mutant strains isolated from genome-wide chemical mutagenesis of Drosophila melanogaster. First, the genomes of two independently isolated mutant fly strains that are allelic for a novel recessive male-sterile locus generated by genotoxic chemical exposure were sequenced using the Illumina next-generation DNA sequencer to obtain 20- to 29-fold coverage of the euchromatic sequences. The sequencing reads were processed and variants were called using standard bioinformatic tools. Next, SnpEff was used to annotate all sequence variants and their potential mutational effects on associated genes. Then, SnpSift was used to filter and select differential variants that potentially disrupt a common gene in the two allelic mutant strains. The potential causative DNA lesions were partially validated by capillary sequencing of polymerase chain reaction-amplified DNA in the genetic interval as defined by meiotic mapping and deletions that remove defined regions of the chromosome. Of the five candidate genes located in the genetic interval, the Pka-like gene CG12069 was found to carry a separate pre mature stop codon mutation in each of the two allelic mutants whereas the other four candidate genes within the interval have wild-type sequences. The Pka-like gene is therefore a strong candidate gene for the male-sterile locus. These results demonstrate that combining SnpEff and SnpSift can expedite the identification of candidate phenotype-causative mutations in chemically mutagenized Drosophila strains. This technique can also be used to characterize the variety of mutations generated by genotoxic chemicals. PMID- 22435070 TI - The metamorphosis of amphibian toxicogenomics. AB - Amphibians are important vertebrates in toxicology often representing both aquatic and terrestrial forms within the life history of the same species. Of the thousands of species, only two have substantial genomics resources: the recently published genome of the Pipid, Xenopus (Silurana) tropicalis, and transcript information (and ongoing genome sequencing project) of Xenopus laevis. However, many more species representative of regional ecological niches and life strategies are used in toxicology worldwide. Since Xenopus species diverged from the most populous frog family, the Ranidae, ~200 million years ago, there are notable differences between them and the even more distant Caudates (salamanders) and Caecilians. These differences include genome size, gene composition, and extent of polyploidization. Application of toxicogenomics to amphibians requires the mobilization of resources and expertise to develop de novo sequence assemblies and analysis strategies for a broader range of amphibian species. The present mini-review will present the advances in toxicogenomics as pertains to amphibians with particular emphasis upon the development and use of genomic techniques (inclusive of transcriptomics, proteomics, and metabolomics) and the challenges inherent therein. PMID- 22435071 TI - The Italian SEME Surveillance System of Severe Mental Disorders Presenting to Community Mental Health Services. AB - Mental health is recognized worldwide as a major public health priority for the twenty-first century. Different actions are needed, including developing or strengthening national mental health information systems, based on standardized indicators that allow national and international monitoring. In 2008, the national Centre for Disease prevention and Control of the Italian Ministry of Health and the Mental Health Unit of the Italian National Institute of Health (INIH) jointly launched a mental health information system named SEME (an Italian acronym meaning 'mental health epidemiological surveillance') based upon data collected from trained psychiatrists working in 22 selected sentinel community mental health centers distributed across Italy and covering a total population of 1,941,853 inhabitants, in order to collect and report site-level information on first-contact patients suffering from specific severe mental disorders (schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, bipolar I disorder, anorexia nervosa, major depressive episode with psychotic symptoms or suicide attempt). Strengths of the system are the high reliability of diagnoses and the use of a web-based technique for data collection with data entry forms designed for ease of completion. During the first year of implementation of this system, a total of 343 first-contact patients met criteria for one of the severe mental disorders under surveillance. As the system includes standardized instruments to measure psychiatric symptoms and psychosocial functioning, it may facilitate health services research based on longitudinal measurements aimed at evaluating the continuity of psychiatric care and the effectiveness of innovative therapeutic and rehabilitative programs. PMID- 22435072 TI - Incidence of therapy-related acute leukaemia in mitoxantrone-treated multiple sclerosis patients in Germany. AB - BACKGROUND: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed. METHODS AND RESULTS: In a retrospective meta-analysis from six centres, we observed six cases of acute myeloid leukaemia (AML) (incidence 0.41% for patients with mean follow up after end of treatment of 3.6 years, n = 1.156; incidence 0.25% for all patients, n = 2.261). Potential influencing factors such as myelotoxic or glucocorticosteroid pretreatment/cotreatment were present in all but one case of TRAL. Between 1990 and 2010, 11 cases of TRAL were reported to the Drug Commission of the German Medical Association (estimated risk of 0.09 0.13%). CONCLUSIONS: Regional differences in reported TRAL incidence may point to confounding cofactors such as administration protocols and cotreatments. PMID- 22435073 TI - Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? AB - It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength of the evidence limits definite conclusions. It was concluded that some evidence supports the possibility of a disease-modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are needed to confirm this. PMID- 22435074 TI - From injection therapies to natalizumab: views on the treatment of multiple sclerosis. AB - Discoveries of the mechanisms that underlie the pathogenesis of multiple sclerosis have been acquired at an impressive rate over the last few decades and, as a consequence, a growing number of treatments are becoming available for this disease. This review first analyzes the experience from the early stages of the disease-modifying therapies, then, expanding on the concept of early treatment for improved outcomes, it focuses on natalizumab and its major complication, progressive multifocal leukoencephalopathy. We offer views on the risks associated with the use of natalizumab by underscoring the importance of the JC virus serology and by providing preliminary data on our experience with the extended interval dosing of natalizumab. This approach, which advocates individualized treatment plans, raises the question of the minimum effective natalizumab dose. Extended interval dosing suggests efficacy can be maintained while providing advantages of costs and convenience over regular monthly dosing. More data examining this strategy are necessary. PMID- 22435075 TI - Health-related quality of life as an outcome variable in Parkinson's disease. AB - In the past three decades, health-related quality of life (HRQoL) has become an outcome variable in Parkinson's disease clinical trials. This review considers the measuring tools that have been developed, suitability of data reporting, complexity of outcome interpretation, and clinical application to provide evidence regarding available therapeutic interventions to date. In the introduction, different terms regarding quality of life are clearly defined. The methodology section offers an overview of generic, disease specific, and recommended HRQoL scales in Parkinson's disease and the most important psychometric attributes a scale should meet. The interpretation of HRQoL outcomes is complex and not intuitive. Thus, appropriate reporting of data is crucial in order to calculate relative change, a result that facilitates understanding to what extent an intervention is beneficial. The concept of minimally important change/difference is explained as well as the different approaches to its calculation (anchor-based and distribution-based methods). In the results section, a brief overview of the impact on HRQoL of currently available treatments in Parkinson's disease is provided. Special emphasis is given to data assessment, highlighting reports that helped understanding of the clinical significance of the intervention and therefore aided in making therapeutic decisions. The discussion section emphasizes the need for more clinical trials with HRQoL as a primary outcome and standardized reporting in order to further our understanding of the complexity of treatment effects and make evidence-based clinical decisions regarding HRQoL in patients with Parkinson's disease. PMID- 22435076 TI - Neuroimaging of motor neuron diseases. AB - It is agreed that conventional magnetic resonance imaging (MRI) of the brain and spine is one of the core elements in the differential diagnostic work up of patients with clinical signs of motor neuron diseases (MNDs), for example amyotrophic lateral sclerosis (ALS), to exclude MND mimics. However, the sensitivity and specificity of MRI signs in these disorders are moderate to low and do not have an evidence level higher than class IV (good clinical practice point). Currently computerized MRI analyses in ALS and other MNDs are not techniques used for individual diagnosis. However, they have improved the anatomical understanding of pathomorphological alterations in gray and white matter in various MNDs and the changes in functional networks by quantitative comparisons between patients with MND and controls at group level. For multiparametric MRI protocols, including T1-weighted three-dimensional datasets, diffusion-weighted imaging and functional MRI, the potential as a 'dry' surrogate marker is a subject of investigation in natural history studies with well defined patients. The additional value of MRI with respect to early diagnosis at an individual level and for future disease-modifying multicentre trials remains to be defined. There is still the need for more longitudinal studies in the very early stages of disease or when there is clinical uncertainty and for better standardization in the acquisition and postprocessing of computer-based MRI data. These requirements are to be addressed by establishing quality-controlled multicentre neuroimaging databases. PMID- 22435077 TI - Management of pediatric femoral shaft fractures with long intramedullary kirshner wires. PMID- 22435078 TI - Gender and Socio-economic Differences in Daily Smoking and Smoking Cessation Among Adult Residents in a Greek Rural Area. AB - Despite the well-known health risks, smoking is still highly prevalent worldwide. Greece has the highest level of adult smoking rate (40%) across the European Union. We investigated gender and socio-economic differences in daily smoking and smoking cessation among Greek adults. We conducted a cross-sectional survey between October and November 2009 in 434 adults residing in a Greek rural area. Data were collected with the use of the World Health Organization Global Adult Tobacco Survey (WHO GATS) Core Questionnaire. Respondents were classified into smokers (if they had smoked at least 100 cigarettes in their lifetime and continued to smoke) or non-smokers. Overall, 58.1% (n=252) were smokers (58.5% male, n=127 and 57.8% female, n=125); 51.2% (n=222) were younger than 18 years old when they started smoking. Men tended to start smoking at a younger age, to smoke more cigarettes/day and to have smoked a greater average of cigarettes during the last 5 days. Overall, 82.5% of smokers attempted to stop smoking a year prior to the study, with women having a greater difficulty in quitting smoking. The main source of information on smoking was the mass media (73.5%) and books (53.7%), whereas doctors and other health professionals were the least listed source of relative information (27.7 and 8.1%, respectively). Smoking rates among Greek adults were high, but a considerable number of individuals who smoked, wished to quit and had attempted to do so. Smoking cessation clinics are not perceived as a valuable support in quitting effort. PMID- 22435079 TI - Soft Tissue Attenuation Patterns Associated with Upright Acquisition SPECT Myocardial Perfusion Imaging: A Descriptive Study. AB - BACKGROUND: Little is known about soft tissue attenuation artifacts when an upright patient-position SPECTmyocardial perfusion imaging (MPI) system is used. In this investigation we sought to describe the patterns and frequency of attenuation artifacts associated with this type of instruments and we explored the impact of gender and body habitus on these artifacts. METHODS: In a cross sectional study, we described the prevalence of various soft-tissue attenuation patterns in 212 normal SPECT-MPI studies acquired with an upright patient position imaging system. RESULTS: In these 212 normal, clinically-indicated, upright-acquisition SPECT-MPIs the attenuation patterns observed were: anterior (6.1%), inferior (63.7%) and lateral (24.1%). Though uncommon, anterior attenuation trended to being more prevalent among women [9.5% vs. 3.4%, P=0.07] and was independently associated with chest circumference. Lateral attenuation was more common among women [34.7% vs. 15.4%, p=0.001] and was strongly associated with obesity (p<0.001). Inferior attenuation was more prevalent among men than women (75.2% vs. 49.5% respectively, P<0.001). CONCLUSIONS: Soft-tissue attenuation artifacts are common in upright-acquisition SPECT-MPI. Recognizing the frequency of these attenuation patterns and their interaction with gender and body habitus is critical for the accurate interpretation of SPECT-MPI. PMID- 22435080 TI - Protein-Signaled Guided Bone Regeneration Using Titanium Mesh and Rh-BMP2 in Oral Surgery: A Case Report Involving Left Mandibular Reconstruction after Tumor Resection. AB - Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive protein approved for use in oral and maxillofacial defect reconstruction. Growth factors act as mediators of cellular growth on morphogenesis and mythogenesis phases. Utilized as recombinant proteins, these growth factors need the presence of local target cells capable of obtaining the required results. This cell population may be present at the wound site or added to scaffolding material before implantation at the surgical site.The aim of this study is to evaluate the clinical and radiographic results of a reported case with a large bone defect, treated with an absorbable collagen sponge, rhBMP-2 and a titanium plate and mesh. The Authors want to report a case which shows the resulting effectiveness of the rhBMP2 action regarding a large, mandibular defect reconstruction. This case also shows how the removal of a rare tumor such as a ghost cell tumor of the jaw may be treated without harvesting bone from another body site. A quick diagnosis of the lesions is important in order to perform the most suitable treatment. The Authors also underline the clinical and histological steps to insure the correct treatment is carried out to solve the case.Moreover, from results obtained from this case, it is possible to highlight several clinical benefits for the patient by adding rhBMP-2 to the common allograft to not only have alveolar reconstruction defects and sinus floor augmentation, but also to have alveolar cleft reconstruction and to treat segmental defects. PMID- 22435081 TI - The value of fundoscopy in general practice. AB - BACKGROUND: Many of the common systemic diseases present characteristic changes in the fundus of the eye, but fundoscopy is often performed by an ophthalmologist. Our purpose was to assess the value of fundoscopy for the general practitioners (GPs) regarding the diagnosis and management of the cases which they face in daily practice. METHODS: 689 patients were referred by GPs to the outpatient ophthalmology department for fundoscopy during the year 2010. The causes of this referral, the results of ophthalmoscopy and its significance in the final diagnosis were recorded and analyzed. RESULTS: In 22 patients (3.1%), fundoscopy revealed optic disc edema. In 7 patients with head trauma (9.7%), fundoscopy revealed intravitreous haemorrhage and Berlin edema. From the patients with photopsias or floaters, 5 (10.2%) had retinal detachment. Finally, in cases with diabetes mellitus or hypertension, ophthalmoscopy was very important to detect the existence and grade the degree of diabetic or hypertensive retinopathy, if they appeared, and as a result to evaluate the prognosis of the disease. CONCLUSIONS: Fundoscopy is fundamental for the GP, as it may help to confirm or exclude the diagnosis of many common diseases. Nevertheless, there are clinical entities where ophthalmoscopy should be performed by an ophthalmologist, in order to be more specific and accurate, and GP should be able to recognise these cases. PMID- 22435082 TI - Immune Reconstitution During the First Year of Antiretroviral Therapy of HIV-1 Infected Adults in Rural Burkina Faso. AB - There are no data on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected adults in rural Burkina Faso. We therefore assessed CD4(+) T-cell counts and HIV-1 plasma viral load (VL), the proportion of naive T-cells (co expressing CCR7 and CD45RA) and T-cell activation (expression of CD95 or CD38) in 61 previously untreated adult patients from Nouna, Burkina Faso, at baseline and 2 weeks, 1, 3, 6, 9 and 12 months after starting therapy. Median CD4(+) T-cell counts increased from 174 (10(th)-90(th) percentile: 33-314) cells/ul at baseline to 300 (114- 505) cells/ul after 3 months and 360 (169-562) cells/ul after 12 months of HAART. Median VL decreased from 5.8 (4.6- 6.6) log10 copies/ml at baseline to 1.6 (1.6-2.3) log10 copies/ml after 12 months. Early CD4(+) T-cell recovery was accompanied by a reduction of the expression levels of CD95 and CD38 on T-cells. Out of 42 patients with complete virological follow-up under HAART, 19 (45%) achieved concordant good immunological (gain of >=100 CD4(+) T-cells/ul above baseline) and virological (undetectable VL) responses after 12 months of treatment (intention-to-treat analysis). Neither a decreased expression of the T cell activation markers CD38 and CD95, nor an increase in the percentage of naive T-cells reliably predicted good virological treatment responses in patients with good CD4(+) T-cell reconstitution. Repeated measurement of CD4(+) T-cell counts during HAART remains the most important parameter for immunologic monitoring. Substitution of repeated VL testing by determination of T-cell activation levels (e.g., CD38 expression on CD8(+) T-cells) should be applied with caution. PMID- 22435083 TI - Controlled electroporation of the plasma membrane in microfluidic devices for single cell analysis. AB - Chemical cytometry on a single cell level is of interest to various biological fields ranging from cancer to stem cell research. The impact chemical cytometry can exert in these fields depends on the dimensionality of the retrievable analytes content. To this point, the number of different analytes identifiable and additionally their subcellular localization is of interest. To address this, we present an electroporation based approach for selective lysis of only the plasma membrane, which permits analysis of the dissolved cytoplasm, while reducing contributions from the nucleus and membrane bound fractions of the cell analytes. The use of 100 MUs long pulse and a well defined DC electric field gradient of ~4.5 kV.cm(-1) generated by 3D electrodes initiates release of a cytoplasm marker in ?1 s, while retaining nuclear fluorescence markers. PMID- 22435084 TI - Expression levels of novel cytokine IL-32 in periodontitis and its role in the suppression of IL-8 production by human gingival fibroblasts stimulated with Porphyromonas gingivalis. AB - BACKGROUND: IL-32 was recently found to be elevated in the tissue of rheumatoid arthritis and inflammatory bowel disease. Periodontitis is a chronic inflammatory disease caused by polymicrobial infections that result in soft tissue destruction and alveolar bone loss. Although IL-32 is also thought to be associated with periodontal disease, its expression and possible role in periodontal tissue remain unclear. Therefore, this study investigated the expression patterns of IL 32 in healthy and periodontally diseased gingival tissue. The expression of IL-32 in cultured human gingival fibroblasts (HGF) as well as effects of autocrine IL 32 on IL-8 production from HGF were also examined. METHODS: Periodontal tissue was collected from both healthy volunteers and periodontitis patients, and immunofluorescent staining was performed in order to determine the production of IL-32. Using real-time PCR and ELISA, mRNA expression and protein production of IL-32 in HGF, stimulated by Porphyromonas gingivalis (Pg), were also investigated. RESULTS: Contrary to our expectation, the production of IL-32 in the periodontitis patients was significantly lower than in the healthy volunteers. According to immunofluorescent microscopy, positive staining for IL 32 was detected in prickle and basal cell layers in the epithelium as well as fibroblastic cells in connective tissue. Addition of fixed Pgin vitro was found to suppress the otherwise constitutive expression of IL-32 mRNA and protein in HGF. However, recombinant IL-32 in vitro inhibited the expression of IL-8 mRNA by HGF stimulated with Pg. Interestingly, anti-IL-32 neutralizing antibody upregulated the IL-8 mRNA expression in non-stimulated HGF, indicating that constitutive expression of IL-32 in HGF suppressed IL-8 mRNA expression in the absence of bacterial stimulation. CONCLUSION: These results indicate that IL-32 is constitutively produced by HGF which can be suppressed by Pg and may play a role in the downregulation of inflammatory responses, such as IL-8 production, in periodontal tissue. PMID- 22435085 TI - Inactivating alternative NADH dehydrogenases: enhancing fungal bioprocesses by improving growth and biomass yield? AB - Debate still surrounds the physiological roles of the alternative respiratory enzymes found in many fungi and plants. It has been proposed that alternative NADH:ubiquinone oxidoreductases (NADH dehydrogenases) may protect against oxidative stress, conversely, elevated activity of these enzymes has been linked to senescence. Here we show that inhibition of these enzymes in a fungal protein expression system (Aspergillus niger) leads to significantly enhanced specific growth rate, substrate uptake, carbon dioxide evolution, higher protein content, and more efficient use of substrates. These findings are consistent with a protective role of the NADH dehydrogenases against oxidative stress, thus, when electron flow via these enzymes is blocked, flux through the main respiratory pathway rises, leading to enhanced ATP generation. We anticipate that our findings will stimulate further studies in fungal and plant cultures leading to significant improvements in these expression systems, and to deeper insights into the cellular roles of alternative respiration. PMID- 22435086 TI - How well do the substrates KISS the enzyme? Molecular docking program selection for feruloyl esterases. AB - Molecular docking is the most commonly used technique in the modern drug discovery process where computational approaches involving docking algorithms are used to dock small molecules into macromolecular target structures. Over the recent years several evaluation studies have been reported by independent scientists comparing the performance of the docking programs by using default 'black box' protocols supplied by the software companies. Such studies have to be considered carefully as the docking programs can be tweaked towards optimum performance by selecting the parameters suitable for the target of interest. In this study we address the problem of selecting an appropriate docking and scoring function combination (88 docking algorithm-scoring functions) for substrate specificity predictions for feruloyl esterases, an industrially relevant enzyme family. We also propose the 'Key Interaction Score System' (KISS), a more biochemically meaningful measure for evaluation of docking programs based on pose prediction accuracy. PMID- 22435087 TI - Experimental validation of an extended Jones matrix calculus model to study the 3D structural orientation of the collagen fibers in articular cartilage using polarization-sensitive optical coherence tomography. AB - We report results to verify a theoretical framework to analyze the 3D depth-wise structural organization of collagen fibers in articular cartilage using polarization-sensitive optical coherence tomography. Apparent birefringence data obtained from multi-angle measurements using a time domain polarization-sensitive optical coherence tomography system has been compared with simulated data based on the extended Jones matrix calculus. Experimental data has been shown to agree with the lamellar model previously proposed for the cartilage microstructure based on scanning electron microscopy data. This tool could have potential application in mapping the collagen structural orientation information of cartilage non-invasively during arthroscopy. PMID- 22435088 TI - Endovascular optical coherence tomography intensity kurtosis: visualization of vasa vasorum in porcine carotid artery. AB - Application of speckle variance optical coherence tomography (OCT) to endovascular imaging faces difficulty of extensive motion artifacts inherently associated with arterial pulsations in addition to other physiological movements. In this study, we employed a technique involving a fourth order statistical method, kurtosis, operating on the endovascular OCT intensity images to visualize the vasa vasorum of carotid artery in vivo and identify its flow dynamic in a porcine model. The intensity kurtosis technique can distinguish vasa vasorum from the surrounding tissues in the presence of extensive time varying noises and dynamic motions of the arterial wall. Imaging of vasa vasorum and its proliferation, may compliment the growing knowledge of structural endovascular OCT in assessment and treatment of atherosclerosis in coronary and carotid arteries. PMID- 22435089 TI - Multicolour single molecule imaging on cells using a supercontinuum source. AB - Multicolour single molecule fluorescence imaging enables the study of multiple proteins in the membranes of living cells. We describe the use of a supercontinuum laser as the excitation source, show its comparability with multiplexed single-wavelength lasers and demonstrate that it can be used to study membrane proteins such as the ErbB receptor family. We discuss the benefits of white-light sources for single molecule fluorescence, in particular their ease of use and the freedom to use the most appropriate dye without being constrained by available laser wavelengths. PMID- 22435090 TI - Compensation method for obtaining accurate, sub-micrometer displacement measurements of immersed specimens using electronic speckle interferometry. AB - We proposed and validated a compensation method that accounts for the optical distortion inherent in measuring displacements on specimens immersed in aqueous solution. A spherically-shaped rubber specimen was mounted and pressurized on a custom apparatus, with the resulting surface displacements recorded using electronic speckle pattern interferometry (ESPI). Point-to-point light direction computation is achieved by a ray-tracing strategy coupled with customized B spline-based analytical representation of the specimen shape. The compensation method reduced the mean magnitude of the displacement error induced by the optical distortion from 35% to 3%, and ESPI displacement measurement repeatability showed a mean variance of 16 nm at the 95% confidence level for immersed specimens. The ESPI interferometer and numerical data analysis procedure presented herein provide reliable, accurate, and repeatable measurement of sub micrometer deformations obtained from pressurization tests of spherically-shaped specimens immersed in aqueous salt solution. This method can be used to quantify small deformations in biological tissue samples under load, while maintaining the hydration necessary to ensure accurate material property assessment. PMID- 22435091 TI - Determining the optical properties of a gelatin-TiO(2) phantom at 780 nm. AB - Tissue phantoms play a central role in validating biomedical imaging techniques. Here we employ a series of methods that aim to fully determine the optical properties, i.e., the refractive index n, absorption coefficient MU(a), transport mean free path [Formula: see text], and scattering coefficient MU(s) of a TiO(2) in gelatin phantom intended for use in optoacoustic imaging. For the determination of the key parameters MU(a) and [Formula: see text], we employ a variant of time of flight measurements, where fiber optodes are immersed into the phantom to minimize the influence of boundaries. The robustness of the method was verified with Monte Carlo simulations, where the experimentally obtained values served as input parameters for the simulations. The excellent agreement between simulations and experiments confirmed the reliability of the results. The parameters determined at 780 nm are [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]The asymmetry parameter g obtained from the parameters [Formula: see text] and [Formula: see text] is 0.93, which indicates that the scattering entities are not bare TiO(2) particles but large sparse clusters. The interaction between the scattering particles and the gelatin matrix should be taken into account when developing such phantoms. PMID- 22435092 TI - Mechanisms of nanoparticle-mediated photomechanical cell damage. AB - Laser-assisted killing of gold nanoparticle targeted macrophages was investigated. Using pressure transient detection, flash photography and transmission electron microscopy (TEM) imaging, we studied the mechanism of single cell damage by vapor bubble formation around gold nanospheres induced by nanosecond laser pulses. The influence of the number of irradiating laser pulses and of particle size and concentration on the threshold for acute cell damage was determined. While the single pulse damage threshold is independent of the particle size, the threshold decreases with increasing particle size when using trains of pulses. The dependence of the cell damage threshold on the nanoparticle concentration during incubation reveals that particle accumulation and distribution inside the cell plays a key role in tissue imaging or cell damaging. PMID- 22435093 TI - Remote switching of cellular activity and cell signaling using light in conjunction with quantum dots. AB - Stimulating cells by using light is a non-invasive technique that provides flexibility in probing different locations while minimizing unintended effects on the system. We propose a new way to make cells photosensitive without using genetic or chemical manipulation, which alters natural cells, in conjunction with Quantum Dots (QDs). Remote switching of cellular activity by optical QD excitation is demonstrated by integrating QDs with cells: CdTe QD films with prostate cancer (LnCap) cells, and CdSe QD films and probes with cortical neurons. Changes in membrane potential and ionic currents are recorded by using the patch-clamp method. Upon excitation, the ion channels in the cell membrane were activated, resulting in hyperpolarization or depolarization of the cell. PMID- 22435094 TI - Hemodynamic and morphological vasculature response to a burn monitored using a combined dual-wavelength laser speckle and optical microangiography imaging system. AB - A multi-functional imaging system capable of determining relative changes in blood flow, hemoglobin concentration, and morphological features of the blood vasculature is demonstrated. The system combines two non-invasive imaging techniques, a dual-wavelength laser speckle contrast imaging (2-LSI) and an optical microangiography (OMAG) system. 2-LSI is used to monitor the changes in the dynamic blood flow and the changes in the concentration of oxygenated (HbO), deoxygenated (Hb) and total hemoglobin (HbT). The OMAG system is used to acquire high resolution images of the functional blood vessel network. The vessel area density (VAD) is used to quantify the blood vessel network morphology, specifically the capillary recruitment. The proposed multi-functional system is employed to assess the blood perfusion status from a mouse pinna before and immediately after a burn injury. To our knowledge, this is the first non invasive, non-contact and multifunctional imaging modality that can simultaneously measure variations of several blood perfusion parameters. PMID- 22435095 TI - Clinical evaluation of melanomas and common nevi by spectral imaging. AB - A clinical trial on multi-spectral imaging of malignant and non-malignant skin pathologies comprising 17 melanomas and 65 pigmented common nevi was performed. Optical density data of skin pathologies were obtained in the spectral range 450 950 nm using the multispectral camera Nuance EX. An image parameter and maps capable of distinguishing melanoma from pigmented nevi were proposed. The diagnostic criterion is based on skin optical density differences at three fixed wavelengths: 540nm, 650nm and 950nm. The sensitivity and specificity of this method were estimated to be 94% and 89%, respectively. The proposed methodology and potential clinical applications are discussed. PMID- 22435096 TI - Dynamic OCT measurement of corneal deformation by an air puff in normal and cross linked corneas. AB - A new technique is presented for the non-invasive imaging of the dynamic response of the cornea to an air puff inducing a deformation. A spectral OCT instrument combined with an air tonometer in a non-collinear configuration was used to image the corneal deformation over full corneal cross-sections, as well as to obtain high speed measurements of the temporal evolution of the corneal apex. The entire deformation process can be dynamically visualized. A quantitative analysis allows direct extraction of several deformation parameters, such as amplitude, diameter and volume of the maximum deformation, as well as duration and speed of the increasing deformation period and the recovery period. The potential of the technique is demonstrated on porcine corneas in vitro under constant IOP for several conditions (untreated, after riboflavin instillation and under cross linking with ultraviolet light), as well as on human corneas in vivo. The new technique has proved very sensitive to detect differences in the deformation parameters across conditions. We have confirmed non-invasively that Riboflavin and UV-cross-linking induce changes in the corneal biomechanical properties. Those differences appear to be the result of changes in constituent properties of the cornea, and not a consequence of changes in corneal thickness, geometry or IOP. These measurements are a first step for the estimation of the biomechanical properties of corneal tissue, at an individual level and in vivo, to improve diagnosis and prognosis of diseases and treatments involving changes in the biomechanical properties of the cornea. PMID- 22435097 TI - A handheld laser scanning confocal reflectance imaging-confocal Raman microspectroscopy system. AB - Confocal reflectance microscopy and confocal Raman spectroscopy have shown potential for non-destructive analysis of samples at micron-scale resolutions. Current studies utilizing these techniques often employ large bench-top microscopes, and are not suited for use outside of laboratory settings. We have developed a microscope which combines laser scanning confocal reflectance imaging and confocal Raman spectroscopy into a compact handheld probe that is capable of high-resolution imaging and spectroscopy in a variety of settings. The compact size of the probe is largely due to the use of a MEMS mirror for beam scanning. The probe is capable of axial resolutions of up to 4 MUm for the confocal imaging channel and 10 MUm for the confocal Raman spectroscopy channel. Here, we report instrument design, characterize optical performance, and provide images and spectra from normal skin to demonstrate the instrument's capabilities for clinical diagnostics. PMID- 22435098 TI - Logarithmic intensity and speckle-based motion contrast methods for human retinal vasculature visualization using swept source optical coherence tomography. AB - We formulate a theory to show that the statistics of OCT signal amplitude and intensity are highly dependent on the sample reflectivity strength, motion, and noise power. Our theoretical and experimental results depict the lack of speckle amplitude and intensity contrasts to differentiate regions of motion from static areas. Two logarithmic intensity-based contrasts, logarithmic intensity variance (LOGIV) and differential logarithmic intensity variance (DLOGIV), are proposed for serving as surrogate markers for motion with enhanced sensitivity. Our findings demonstrate a good agreement between the theoretical and experimental results for logarithmic intensity-based contrasts. Logarithmic intensity-based motion and speckle-based contrast methods are validated and compared for in vivo human retinal vasculature visualization using high-speed swept-source optical coherence tomography (SS-OCT) at 1060 nm. The vasculature was identified as regions of motion by creating LOGIV and DLOGIV tomograms: multiple B-scans were collected of individual slices through the retina and the variance of logarithmic intensities and differences of logarithmic intensities were calculated. Both methods captured the small vessels and the meshwork of capillaries associated with the inner retina in en face images over 4 mm(2) in a normal subject. PMID- 22435099 TI - Advances in optics for biotechnology, medicine and surgery. AB - The editors introduce the Biomedical Optics Express feature issue, "Advances in Optics for Biotechnology, Medicine and Surgery," which includes 12 contributions from attendees of the 2011 conference Advances in Optics for Biotechnology, Medicine and Surgery XII. PMID- 22435100 TI - Optical coherence tomography for the identification of musculoskeletal structures of the spine: a pilot study. AB - Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine requiring in severe cases invasive surgery. Here, we explore the potential of optical coherence tomography (OCT) as a guiding tool for novel fusionless minimally invasive spinal surgeries on an ex vivo porcine model. We show that OCT, despite its limited penetration depth, may be used to precisely locate structures such as growth plate, bone and intervertebral disk using relative attenuation coefficients. We further demonstrate a segmentation algorithm that locates growth plates automatically on en-face OCT reconstructions. PMID- 22435101 TI - Infinite space Green's function of the time-dependent radiative transfer equation. AB - This study contains the derivation of an infinite space Green's function of the time-dependent radiative transfer equation in an anisotropically scattering medium based on analytical approaches. The final solutions are analytical regarding the time variable and given by a superposition of real and complex exponential functions. The obtained expressions were successfully validated with Monte Carlo simulations. PMID- 22435102 TI - Modeling boundary measurements of scattered light using the corrected diffusion approximation. AB - We study the modeling and simulation of steady-state measurements of light scattered by a turbid medium taken at the boundary. In particular, we implement the recently introduced corrected diffusion approximation in two spatial dimensions to model these boundary measurements. This implementation uses expansions in plane wave solutions to compute boundary conditions and the additive boundary layer correction, and a finite element method to solve the diffusion equation. We show that this corrected diffusion approximation models boundary measurements substantially better than the standard diffusion approximation in comparison to numerical solutions of the radiative transport equation. PMID- 22435103 TI - Wavelet denoising of multiframe optical coherence tomography data. AB - We introduce a novel speckle noise reduction algorithm for OCT images. Contrary to present approaches, the algorithm does not rely on simple averaging of multiple image frames or denoising on the final averaged image. Instead it uses wavelet decompositions of the single frames for a local noise and structure estimation. Based on this analysis, the wavelet detail coefficients are weighted, averaged and reconstructed. At a signal-to-noise gain at about 100% we observe only a minor sharpness decrease, as measured by a full-width-half-maximum reduction of 10.5%. While a similar signal-to-noise gain would require averaging of 29 frames, we achieve this result using only 8 frames as input to the algorithm. A possible application of the proposed algorithm is preprocessing in retinal structure segmentation algorithms, to allow a better differentiation between real tissue information and unwanted speckle noise. PMID- 22435104 TI - Quantitative comparison of optimized nanorods, nanoshells and hollow nanospheres for photothermal therapy. AB - The purpose of this study is to get more efficient gold nanoparticles, for necrosis of cancer cells, in photothermal therapy. Therefore a numerical maximization of the absorption efficiency of a set of nanoparticles (nanorod, nanoshell and hollow nanosphere) is proposed, assuming that all the absorbed light is converted to heat. Two therapeutic cases (shallow and deep cancer) are considered. The numerical tools used in this study are the full Mie theory, the discrete dipole approximation and the particle swarm optimization. The optimization leads to an improved efficiency of the nanoparticles compared with previous studies. For the shallow cancer therapy, the hollow nanosphere seems to be more efficient than the other nanoparticles, whereas the hollow nanosphere and nanorod, offer comparable absorption efficiencies, for deep cancer therapy. Finally, a study of tolerance for the size parameters to guarantee an absorption efficiency threshold is included. PMID- 22435105 TI - Fiber laser-microscope system for femtosecond photodisruption of biological samples. AB - We report on the development of a ultrafast fiber laser-microscope system for femtosecond photodisruption of biological targets. A mode-locked Yb-fiber laser oscillator generates few-nJ pulses at 32.7 MHz repetition rate, amplified up to ~125 nJ at 1030 nm. Following dechirping in a grating compressor, ~240 fs-long pulses are delivered to the sample through a diffraction-limited microscope, which allows real-time imaging and control. The laser can generate arbitrary pulse patterns, formed by two acousto-optic modulators (AOM) controlled by a custom-developed field-programmable gate array (FPGA) controller. This capability opens the route to fine optimization of the ablation processes and management of thermal effects. Sample position, exposure time and imaging are all computerized. The capability of the system to perform femtosecond photodisruption is demonstrated through experiments on tissue and individual cells. PMID- 22435106 TI - OCT methods for capillary velocimetry. AB - TO DATE, TWO MAIN CATEGORIES OF OCT TECHNIQUES HAVE BEEN DESCRIBED FOR IMAGING HEMODYNAMICS: Doppler OCT and OCT angiography. Doppler OCT can measure axial velocity profiles and flow in arteries and veins, while OCT angiography can determine vascular morphology, tone, and presence or absence of red blood cell (RBC) perfusion. However, neither method can quantify RBC velocity in capillaries, where RBC flow is typically transverse to the probe beam and single file. Here, we describe new methods that potentially address these limitations. Firstly, we describe a complex-valued OCT signal in terms of a static scattering component, dynamic scattering component, and noise. Secondly, we propose that the time scale of random fluctuations in the dynamic scattering component are related to red blood cell velocity. Analysis was performed along the slow axis of repeated B-scans to parallelize measurements. We correlate our purported velocity measurements against two-photon microscopy measurements of RBC velocity, and investigate changes during hypercapnia. Finally, we image the ischemic stroke penumbra during distal middle cerebral artery occlusion (dMCAO), where OCT velocimetry methods provide additional insight that is not afforded by either Doppler OCT or OCT angiography. PMID- 22435107 TI - Complete complex conjugate resolved heterodyne swept source optical coherence tomography using a dispersive optical delay line: erratum. AB - We correct an error in our previous paper [Biomed. Opt. Express 2, 1218 (2011)] which led to an erroneous conclusion that a dispersive optical delay line (DODL) used in a swept source optical coherence tomography (SSOCT) system generated a pure phase modulation allowing for complex conjugate artifact removal in Fourier domain OCT via optical heterodyning. We now understand that an alternate phenomenon known as coherence revival was responsible for the observed phase modulation, while the DODL provided a compact means of generating a large group delay with readily adjustable group velocity dispersion compensation. PMID- 22435108 TI - Complex conjugate resolved heterodyne swept source optical coherence tomography using coherence revival. AB - We describe a simple and low-cost technique for resolving the complex conjugate ambiguity in Fourier domain optical coherence tomography (OCT) that is applicable to many swept source OCT (SSOCT) systems. First, we review the principles of coherence revival, wherein an interferometer illuminated by an external cavity tunable laser (ECTL) exhibits interference fringes when the two arms of the interferometer are mismatched by an integer multiple of the laser cavity length. Second, we report observations that the spectral interferogram obtained from SSOCT systems employing certain ECTLs are automatically phase modulated when the arm lengths are mismatched this way. This phase modulation results in a frequency shifted interferogram, effectively creating an extended-depth heterodyne SSOCT system without the use of acousto-optic or electro-optic modulators. We suggest that this phase modulation may be caused by the ECTL cavity optical pathlength varying slightly over the laser sweep, and support this hypothesis with numerical simulations. We also report on the successful implementation of this technique with two commercial swept source lasers operating at 840nm and 1040nm, with sweep rates of 8kHz and 100kHz respectively. The extended imaging depth afforded by this technique was demonstrated by measuring the sensitivity fall-off profiles of each laser with matched and mismatched interferometer arms. The feasibility of this technique for clinical systems is demonstrated by imaging the ocular anterior segments of healthy human volunteers. PMID- 22435109 TI - Sequential Turning Acquisition and Reconstruction (STAR) method for four dimensional imaging of cyclically moving structures. AB - Optical coherence tomography allows for dynamic, three-dimensional (3D+T) imaging of the heart within animal embryos. However, direct 3D+T imaging frame rates remain insufficient for cardiodynamic analysis. Previously, this limitation has been addressed by reconstructing 3D+T representations of the beating heart based on sets of two-dimensional image sequences (2D+T) acquired sequentially at high frame rate and in fixed (and parallel) planes throughout the heart. These methods either require additional hardware to trigger the acquisition of each 2D+T series to the same phase of the cardiac cycle or accumulate registration errors as the slices are synchronized retrospectively by pairs, without a gating signal. Here, we present a sequential turning acquisition and reconstruction (STAR) method for 3D+T imaging of periodically moving structures, which does not require any additional gating signal and is not prone to registration error accumulation. Similarly to other sequential cardiac imaging methods, multiple fast image series are consecutively acquired for different sections but in between acquisitions, the imaging plane is rotated around the center line instead of shifted along the direction perpendicular to the slices. As the central lines of all image sequences coincide and represent measurements of the same spatial position, they can be used to accurately synchronize all the slices to a single inherent reference signal. We characterized the accuracy of our method on a simulated dynamic phantom and successfully imaged a beating embryonic rat heart. Potentially, this method can be applied for structural or Doppler imaging approaches with any direct space imaging modality such as computed tomography, ultrasound, or light microscopy. PMID- 22435110 TI - Dual-modality fluorescence and full-field optical coherence microscopy for biomedical imaging applications. AB - Full-field optical coherence microscopy (FFOCM) is a high-resolution interferometric technique that is particularly attractive for biomedical imaging. Here we show that combining it with structured illumination fluorescence microscopy on one platform can increase its versatility since it enables co localized registration of optically sectioned reflectance and fluorescence images. To demonstrate the potential of this dual modality, a fixed and labeled mouse retina was imaged. Results showed that both techniques can provide complementary information and therefore the system could potentially be useful for biomedical imaging applications. PMID- 22435111 TI - Noble J. David, MD (1927-2011). PMID- 22435112 TI - Bone marrow transplant options and preferences in a sickle cell anemia cohort on chronic transfusions. AB - BACKGROUND: Bone marrow transplantation (BMT) using human leukocyte antigen (HLA) matched sibling donors can be curative for children with sickle cell anemia (SCA). However, minimal data exist regarding availability of HLA-identical matched siblings for transplant-eligible children, and family interest in pursuing transplantation. METHODS: We retrospectively analyzed a pediatric SCA cohort receiving chronic transfusions between July 2004 and January 2011. Data were analyzed regarding the number of full siblings and half-siblings, availability, and family interest in HLA testing the full siblings, and interest in proceeding with HLAmatched transplantation. RESULTS: Among 113 patients, 46 (41%) had at least 1 full sibling and 40 (35%) had an unaffected full sibling who could serve as a BMT donor. The families of 23 of these patients (58%) agreed to HLA-type sibling, 8 of whom (35%) were matched. Transfusion indications for families agreeing to HLA typing included stroke (46%) abnormal TCD (29%), acute chest syndrome (21%), and other CNS reasons (4%). Common reasons to decline HLA typing or transplantation included fear of the process, toxicities of the procedure, and comfort with current quality of life on transfusions. Only 8 of 113 (7%) were eligible for matched BMT, and only 3 (3%) underwent HLA-matched transplantation. Two unmatched children received haploidentical transplantation. CONCLUSIONS: Most families of children with SCA on chronic transfusions choose to proceed with HLA typing. However, when a matched sibling was identified, most families declined to proceed with matched-sibling transplantation. Discussing BMT as a treatment option, offering HLA typing and identifying barriers may improve acceptance of this treatment modality. PMID- 22435113 TI - Isolation and characterization of heavy-metal resistant microbes from roadside soil and phylloplane. AB - Contamination by heavy metals is one of the major environmental problems in many countries and these contaminants reach from various sources such as traffic cars and other activities. Soil and phylloplane samples were collected from eight traffic and two non-traffic sites in Sohag city, Egypt. Heavy metal contents of Cd2+, Zn2+ and Pb2+ of soil and phylloplane samples were determined and revealed high levels of Zn2+ and Pb2+ in traffic samples. A total of 112 bacterial and 62 fungal isolates were obtained from soil and phylloplane. Bacterial isolates were characterized on the basis of morphological, physicochemical and biochemical characteristics; and 16S rRNA gene sequences. Fungal isolates were identified according to morphological characterization. Minimal inhibitory concentrations (MICs) of Cd2+, Zn2+ and Pb2+ for each isolate were detected. All bacterial and fungal isolates demonstrated resistance to lead with MICs >0.528 mM and >0.211, respectively. Moreover, the maximum MICs of cadmium and zinc for bacteria were 0.821 mM and 1.471 mM, respectively, where as, MICs for fungi were 0.328 mM and 0.588 mM, respectively. The most resistant bacterial and fungal isolates were Pseudomonas aeruginosa RA65 and Penicillium corylophyllum, respectively. Therefore, P. aeruginosa RA65 was selected for further investigations. Growth curve study showed that 0.264 mM lead had no efficiently effect on the growth of P. aeruginosa RA65. Plasmid isolation evidenced by transformation studies indicated that P. aeruginosa RA65 harbored a single plasmid (~9.5 kb) which mediated heavy meal resistance. Consequently, these microbial isolates could be potentially used in bioremediation of heavy metal-contaminated environment. PMID- 22435114 TI - Group cognitive behavior therapy for children with high-functioning autism spectrum disorders and anxiety: a randomized trial. AB - BACKGROUND: Children with high-functioning autism spectrum disorders (ASD) are at high risk for developing significant anxiety. Anxiety can adversely impact functioning across school, home and community environments. Cognitive behavioral therapies (CBT) are frequently used with success for children with anxiety symptoms. Modified CBT interventions for anxiety in children with ASD have also yielded promising results. METHODS: Fifty children with high-functioning ASD and anxiety were randomizedto group CBT or treatment-as-usual (TAU) for 12 weeks. Independent clinical evaluators, blind to condition, completed structured interviews (Anxiety Disorders Interview Schedule - Parent Version;ADIS-P) pre- and post-intervention condition. RESULTS: Forty-seven children completed either the CBT or TAU condition. Results indicated markedly better outcomes for the CBT group. Significant differences by group were noted in Clinician Severity Ratings, diagnostic status, and clinician ratings of global improvement. In the intent-to treat sample, 10 of 20 children (50%) in the CBT group had a clinically meaningful positive treatment response, compared to 2 of 23 children (8.7%) in the TAU group. CONCLUSIONS: Initial results from this randomized, designed treatment study suggest that agroup CBT intervention specifically developed for children with ASD may be effective in decreasing anxiety. Limitations of this study include small sample size, lack of an attention control group, and use of outcome measures normed with typically developing children PMID- 22435115 TI - Reflections: neurology and the humanities. The girl with the dromedary gait. PMID- 22435116 TI - Mucosal immune responses induced by transcutaneous vaccines. AB - The skin has been investigated as a site for vaccine delivery only since the late 1990s. However, much has been discovered about the cell populations that reside in the skin, their active role in immune responses, and the fate of trans- cutaneously applied antigens. Transcutaneous immunization (TCI) is a safe, effective means of inducing immune responses against a number of pathogens. One of the most notable benefits of TCI is the induction of immune responses in both systemic and mucosal compartments. This chapter focuses on the transport of antigen into and beyond intact skin, the cutaneous sentinel cell populations that play a role in TCI, and the types of mucosal immune responses that have been generated. A number of in vivo studies in murine models have provided information about the broad responses induced by TCI. Cellular and humoral responses and protection against challenge have been noted in the gastrointestinal, reproductive, and respiratory tracts. Clinical trials have demonstrated the benefits of this vaccine delivery route in humans. As with other routes of immunization, the type of vaccine formulation and choice of adjuvant may be critical for achieving appropriate responses and can be tailored to activate specific immune-responsive cells in the skin to increase the efficacy of TCI against mucosal pathogens. PMID- 22435117 TI - Health policy and the dental implant practitioner. PMID- 22435118 TI - EHRs: it's not about technology; it's how you use it. PMID- 22435119 TI - Tadeusz Reichstein (1897-1996): a cofounder of modern steroid treatment in dermatology. AB - Corticosteroids, which revolutionized dermatologic therapy a half century ago, owe their beginnings to Tadeusz Reichstein (1897-1996), who was born in Poland but emigrated in 1905 with his family to Switzerland. Between 1934 and 1944, he isolated and elucidated the chemical structure of 29 pure substances from the extract of the adrenal cortex. All of them turned out to be steroid derivatives, including corticosterone and hydrocortisone. In 1950, the Karolinska Institute in Stockholm awarded the Nobel Prize in Physiology or Medicine to Tadeusz Reichstein, along with Edward Kendall (1886-1972) and Phillip Hench (1896-1965), for their discoveries relating to the hormones of the adrenal cortex, their structures, and their biologic effects. In 1953, Reichstein isolated the pure crystalline form of a substance with a strong effect on electrolyte and water balance--aldosterone. Reichstein was an author or coauthor of 635 papers, the last ones at the age of 97. He described himself as "a Swiss of Polish-Jewish descent," but his scientific achievements made him a world citizen. PMID- 22435121 TI - DNA methylation biomarkers for colorectal carcinoma and adenomatous polyps. PMID- 22435120 TI - Black widow spider bite: a case study. PMID- 22435123 TI - Genes methylated in cancer that are resistant to activation by DNA demethylating agents and histone deacetylase inhibitors. PMID- 22435122 TI - Fibrocytes: a potential therapeutic cell population in chronic wounds. PMID- 22435124 TI - Inflammation and age-dependent DNA demethylation. PMID- 22435125 TI - Request for pictures of rabies vaccine bait. PMID- 22435126 TI - Opportunity: new program to help practices increase preventive care for pets. PMID- 22435127 TI - Guidelines promote preventive care. PMID- 22435128 TI - Economic concerns push AVMA into action: leadership conference inspires, informs members. PMID- 22435129 TI - Pending regulations put future of GHLIT in doubt. PMID- 22435130 TI - AVMA updates model practice act: delegates also act on rabies vaccine waivers, abuse reports. PMID- 22435131 TI - Extralabel drug use policy revised: AVMA to send FDA comments on new antimicrobial order. PMID- 22435132 TI - Human-animal bond to be emphasized at 2013 AVMA convention. PMID- 22435133 TI - Leadership development program in transition. PMID- 22435134 TI - Balloting for Executive Board election commences: Howe declared District VII winner, District IX undecided. PMID- 22435135 TI - New program helps practices become cat-friendly: Program offers educational resources, certification at silver or gold level. PMID- 22435136 TI - State cuts put colleges in precarious situation: academic, veterinary leaders discuss potential solutions. PMID- 22435137 TI - USDA reducing offices, employees. PMID- 22435138 TI - CRWAD dedicated to Simmons: animal disease researchers convene, honor their own. PMID- 22435139 TI - Residual ordered structure in denatured proteins and the problem of protein folding. AB - Structural characteristics of numerous globular proteins in the denatured state have been reviewed using literature data. Recent more precise experiments show that in contrast to the conventional standpoint, proteins under strongly denaturing conditions do not unfold completely and adopt a random coil state, but contain significant residual ordered structure. These results cast doubt on the basis of the conventional approach representing the process of protein folding as a spontaneous transition of a polypeptide chain from the random coil state to the unique globular structure. The denaturation of proteins is explained in terms of the physical properties of proteins such as stability, conformational change, elasticity, irreversible denaturation, etc. The spontaneous renaturation of some denatured proteins most probably is merely the manifestation of the physical properties (e.g., the elasticity) of the proteins per se, caused by the residual structure present in the denatured state. The pieces of the ordered structure might be the centers of the initiation of renaturation, where the restoration of the initial native conformation of denatured proteins begins. Studies on the denaturation of proteins hardly clarify how the proteins fold into the native conformation during the successive residue-by-residue elongation of the polypeptide chain on the ribosome. PMID- 22435140 TI - Angiogenic response of advanced glycation end products (AGEs) involves PPARgamma. AB - Diabetes is associated with increased formation of advanced glycation end products (AGEs), which have been implicated in micro and macrovascular complications of diabetes. Our earlier reports showed proangiogenic effect of AGE bovine serum albumin (BSA). In order to understand the mechanism of AGE-mediated angiogenesis, the possibility of involvement of peroxisome prolifeator activated receptor (PPAR) gamma, a ligand activated transcription factor was examined. The angiogenic effect was studied in chick chorio allantoic membrane (CAM) and by analyzing angiogenic markers in human umbilical vein endothelial cells (HUVECs) in culture. The involvement of PPAR y was investigated using synthetic PPAR gamma agonist GW 1929 and antagonist GW 9662 and by RT-PCR. In CAM assay, PPAR gamma antagonist GW 9662 reversed the AGE-induced effect on vascularity. In HUVECs in culture, GW 9662 reversed the effect of AGE-BSA and decreased the expression of CD 31, E-Selectin and VEGF. RT-PCR analysis showed that treatment with AGE-BSA caused upregulation of PPAR gamma mRNA levels. The reversal of the effect of AGE on angiogenesis by treatment with PPAR gamma antagonists and up-regulation of PPAR gamma gene in HUVECs treated with AGE-BSA suggested the possible involvement of PPAR gamma-dependent downstream pathway in mediating the angiogenic effect of AGE. PMID- 22435141 TI - An association study of single nucleotide polymorphisms of the FOXP3 intron-1 and the risk of Psoriasis vulgaris. AB - Psoriasis vulgaris (PV) is a common autoimmune disease that involves the dysfunction of CD4+CD25+ regulatory T cells. FOXP3 is a key transcription factor in the development and function of CD4+CD25+ regulatory T cells. Previous studies have demonstrated a genetic association between the FOXP3 gene and some autoimmune diseases. To elucidate the association between the FOXP3 gene and the risk of PV, 408 patients diagnosed with PV and 363 age and sex-matched healthy controls from a cohort of the Chinese majority Han population were recruited. Four single nucleotide polymorphisms (rs2232365, rs3761547, rs3761548 and rs3761549) of the FOXP3 gene were analyzed using the polymerase chain reaction and ligase detection reaction. The major allele of three single nucleotide polymorphisms (SNPs - rs2232365 A, rs3761547 A and rs3761549 C) were associated with an increased risk of PV in a clinical subgroup of female patients, who were less than 40 yrs of age, had a family history of the disease and did not have disease complications (p < 0.05 for all parameters). The haplotype was structured between rs3761547 and rs3761549. An increased risk of PV was observed in haplotype A/A-T/T (p = 0.0055; adjusted OR = 3.188; 95% CI = 0.4354-23.34) and A/G-C/C (p = 0.0082; adjusted OR = 1.288; 95% CI = 0.1529-10.85) between rs3761547 and rs3761549. A synergistic effect was found among the three SNPs. Subjects with the rs2232365AA- rs3761547 AG + GG genotype were more susceptible to PV (p = 0.0393; OR = 2.90; 95% CI = 1.05-7.97). No correlation was found between rs3761548 and the onset of PV. Therefore, the FOXP3 polymorphisms appear to contribute to the risk of psoriasis among the Chinese majority Han population. These findings may aid in our understanding of the pathogenesis of psoriasis. PMID- 22435142 TI - Cloning and characterization of a gene encoding novel zinc finger protein transcription factor induced under water deficit stress from rice (Oryza sativa) cv. N-22. AB - A gene OsZnI encoding Cys3/His1-type zinc finger protein was isolated from the water stress-induced cDNA library of rice (Oryza sativa) cv. N-22, an early maturing, deep-rooted, drought-tolerant genotype adapted to upland conditions. The in-silico analysis revealed an insert of 800 bp with an ORF of 663 nucleotides, encoding 221 amino acids. OsZnI had three distinct features--nuclear localization signal (NLS) present in Arg152-Arg168, Zn finger domain between 185 193 amino acids and 12 amino acids conserved domain in 71-82 amino acids homologous to LEA motif, and belonged to C-type family of Zn finger protein. OsZnI showed induced expression under water deficit stress. PMID- 22435143 TI - Purification and characterization of Mn-peroxidase from Musa paradisiaca (banana) stem juice. AB - Mn-peroxidase (MnP), a biotechnologically important enzyme was purified for the first time from a plant source Musa paradisiaca (banana) stem, which is an agro waste easily available after harvest of banana fruits. MnP was earlier purified only from the fungal sources. The enzyme was purified from stem juice by ultrafiltration and anion-exchange column chromatography on diethylamino ethylcellulose with 8-fold purification and purification yield of 65%. The enzyme gave a single protein band in SDS-PAGE corresponding to molecular mass 43 kDa. The Native-PAGE of the enzyme also gave a single protein band, confirming the purity of the enzyme. The UV/VIS spectrum of the purified enzyme differed from the other heme peroxidases, as the Soret band was shifted towards lower wavelength and the enzyme had an intense absorption band around 250 nm. The K(m) values using MnSO4 and H2O2 as the substrates of the purified enzyme were 21.0 and 9.5 microM, respectively. The calculated k(cat) value of the purified enzyme using Mn(II) as the substrate in 50 mM lactate buffer (pH 4.5) at 25 degrees C was 6.7s(-1), giving a k(cat)/K(m) value of 0.32 microM(-1)s(-1). The k(cat) value for the MnP-catalyzed reaction was found to be dependent of the Mn(III) chelator molecules malonate, lactate and oxalate, indicating that the enzyme oxidized chelated Mn(II) to Mn(III). The pH and temperature optima of the enzyme were 4.5 and 25 degrees C, respectively. The enzyme in combination with H2O2 liberated bromine and iodine in presence of KBr and KI respectively. All these enzymatic characteristics were similar to those of fungal MnP. The enzyme has the potential as a green brominating and iodinating agent in combination with KBr/KI and H2O2. PMID- 22435144 TI - Purification and characterization of phytase with a wide pH adaptation from common edible mushroom Volvariella volvacea (Straw mushroom). AB - A novel phytase with a molecular mass of 14 kDa was isolated from fresh fruiting bodies of the common edible mushroom Volvariella volvacea (Straw mushroom). The isolation procedure involved successive chromatography on DEAE-cellulose, CM cellulose, Affi-gel blue gel, Q-Sepharose and Superdex-75. The enzyme was a monomeric protein and was unadsorbed on DEAE-cellulose, CM-cellulose and Affi-gel blue gel, but was adsorbed on Q-Sepharose. The enzyme was purified 51.6-fold from the crude extract with 25.9% yield. Its N-terminal amino acid sequence GEDNEHDTQA exhibited low homology to the other reported phytases. The optimal pH and temperature of the purified enzyme was 5 and 45 degrees C, respectively. The enzyme was quite stable over the pH range of 3.0 to 9.0 with less than 30% change in its activity, suggesting that it can be used in a very wide pH range. The enzyme exhibited broad substrate selectivity towards various phosphorylated compounds, but lacked antifungal activity against tested plant pathogens. PMID- 22435145 TI - Antihyperglycemic and antioxidant effect of hydroethanolic extract of Butea monosperma bark in diabetic mice. AB - The antihyperglycemic, antihyperlipidemic and antioxidative properties of hydroethanolic extract of Butea monosperma bark were investigated in alloxan induced diabetic mice. Alloxan administration resulted in higher blood glucose level and reduced hepatic glycogen content as compared to normal animals. Besides, serum lipid profile parameters such as total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol were also found to be significantly elevated, whereas the level of high density lipoprotein (HDL) cholesterol was markedly reduced in diabetic animals. Oxidative damage in the tissues of diabetic mice was evidenced by a marked increase in the level of thiobarbituric acid reactive substances (TBARS), distinct decrease in reduced glutathione (GSH) content and declined activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). The daily treatment of diabetic animals with crude extract of B. monosperma bark (300 mg kg(-1)) for 45 days significantly lowered blood glucose level and elevated hepatic glycogen content, bringing the values close to those observed in normal control and glibenclamide treated diabetic mice. Furthermore, the level of various lipid profile parameters was also reversed towards normal. TBARS and GSH also restored towards normal and the declined activity of antioxidant enzymes in diabetic animals was also normalized in crude extract administered mice, thus indicating the antioxidant efficacy of the drug in diabetes-induced oxidative damage. Significant antihyperglycemic and antioxidant potential of the crude extract of B. monosperma bark indicated that it may find use in the management of diabetes and resultant oxidative stress. PMID- 22435146 TI - Pre-treatment of seeds with static magnetic field ameliorates soil water stress in seedlings of maize (Zea mays L.). AB - The effect of magnetic field (MF) treatments of maize (Zea mays L.) var. Ganga Safed 2 seeds on the growth, leaf water status, photosynthesis and antioxidant enzyme system under soil water stress was investigated under greenhouse conditions. The seeds were exposed to static MFs of 100 and 200 mT for 2 and 1 h, respectively. The treated seeds were sown in sand beds for seven days and transplanted in pots that were maintained at -0.03, -0.2 and -0.4 MPa soil water potentials under greenhouse conditions. MF exposure of seeds significantly enhanced all growth parameters, compared to the control seedlings. The significant increase in root parameters in seedlings from magnetically-exposed seeds resulted in maintenance of better leaf water status in terms of increase in leaf water potential, turgor potential and relative water content. Photosynthesis, stomatal conductance and chlorophyll content increased in plants from treated seeds, compared to control under irrigated and mild stress condition. Leaves from plants of magnetically-treated seeds showed decreased levels of hydrogen peroxide and antioxidant defense system enzymes (peroxidases, catalase and superoxide dismutase) under moisture stress conditions, when compared with untreated controls. Mild stress of -0.2 MPa induced a stimulating effect on functional root parameters, especially in 200 mT treated seedlings which can be exploited profitably for rain fed conditions. Our results suggested that MF treatment (100 mT for 2 h and 200 for 1 h) of maize seeds enhanced the seedling growth, leaf water status, photosynthesis rate and lowered the antioxidant defense system of seedlings under soil water stress. Thus, pre sowing static magnetic field treatment of seeds can be effectively used for improving growth under water stress. PMID- 22435147 TI - Echoguided pair technique in diagnosis and treat-ment of abdominal hydatid cystic disease in Egyptian patients: clnical and ultrasonographic follow up. AB - The introduction of the percutaneous puncture, aspiration, injection of scolecidal agent and reaspiration (PAIR) technique is gaining an increasing acceptance in diagnosis and treatment of abdominal cystic hydatid disease (CHD). Thirty-three patients (12 male & 21 female with age between 15 and 70 years) had 46 cysts in liver, spleen and kidneys (75.7%, 18.2% & 6.1% respectively). Puncture, aspiration, injection of 95% sterile alcohol for 20 minutes and reaspiration (PAIR) was used for treatment of hydatid cysts of different types and sizes. Follow up both clinically and ultrasonographically was done over a period of 2 years. The commonest ultrasound picture was type la (overall echofree) in 80.4%, commonly in the liver (75.7%) mainly in the right lobe (88%). Improvement of symptoms had occurred its 85% within 3 weeks. As regards ultrasound follow up of 41 non-complicated cysts within the 1st six months, was disappearance of 5 cysts, 34 reduced in size and 36 showed different grades of solidification. After 1.5 year 10 more cysts disappeared while the pseudotumour appearance was shown in remaining 26 cysts. Ultrasound follow up of the 5 infected cysts revealed complete cure within a period of 8-16 weeks in 4 of them. The last patient discontinued drainage therapy and was referred to surgery. This makes ultrasound cure reaching 97%. Minor complications were skin reaction only in 2 patients (6%). No fatal anaphylaxis cyst recurrence or rupture into the peritoneal cavity or bleeding from renal or splenic puncturing. PAIR technique under ultrasonographic guidance is the first choice method for treatment of abdominal CHD especially in the developing countries and inoperable hydatid cysts. PMID- 22435148 TI - The ecological differences between Bulinus beccari, the intermediate host of Schistsoma haematobium and Biomphalaria pfeifferi the intermediate host of S. mansoni in in Jazan Region, Saudi Arabia. AB - Bulinus beccari, intermediate host of Schistsoma haematobium, and Biomphalaria pfeifferi, intermediate host of S. mansoni have different geographical distribution in Jazan Region. The role of rain fall, ionic composition of water. water temperature and pH Grades were studied. Fluctuation of snail population densities were accompanied with corresponding fluctuation rates of rainfall. B. pfeifferi showed a wider and heavier shell than B. beccari, which might enable it to resist the effects of flash floods. B. beccari showed a higher tolerance of total dissolved solids and calcium carbonate than B. pfeifferi. Average maximum tolerated concentration of dissolved solids and calcium carbonate for B. beccari was 1254ppm and 813ppm, while that of B. pfeifferi was 455ppm and 603ppm. Average water temperature of B. beccari habitats was 25-36.3 degrees C while that of B. pfeifferi was 25-28 degrees C. No significant statistical difference in different pH grades was observed. PMID- 22435149 TI - Malaria drug resistant: current situation with reference to Saudi Arabia (review). AB - Malaria is a chronic disease caused by parasitic protozoa of plasmodia species. Four plasmodium species are causing malaria to human (P. vivax P. ovale, P. malariae and P. falciparum). Malaria classifies as one of the most serious diseases in tropical and subtropical countries and p. falciparum represents the major cause of death by malaria species. Approximately 40% of the world population resides in areas of active malaria transmission. Treatment and prophylaxis measures are important to reduce morbidity and mortality rate of infection. In last two decades, a significant number of malaria drug resistance cases (mainly P. falciparum) were reported in endemic areas against choroquine components. Parasite showed enormous amount of antigenic variation under immune pressure leading to emergence of vaccine resistant strains. Similarly, under drug pressure it allows mutations to settle in the target genes. It is becoming more and clearer that with the continuous exposure to a drug, the parasite accumulates more and more number of mutations in these genes. Artemisinin is the only available drug that is globally effective. This review concentrates on the current situation of malaria drug resistance including epidemiological distribution, the mechanism of how the malaria resists certain drugs and the role of recent advances facilities in molecular biology to evaluate the impact on drug resistance of new drug-based strategies in Saudi Arabia. PMID- 22435150 TI - Vectorial competence of Phlebotomus papatasi (Diptera: Psychodidae) to transmit two old world Leishmania species: Leishmania major and L. Tropica. AB - The vectorial competence of Phlebotomus papatasi for two old world Leishmania species, L. major & L. tropica was investigated. Phlebotomus papatasi originally collected from Suez Governorate, were membrane fed on homogenized hamster's lesion infected with L. major, MHOM/EG/06/RTC-63, and L. tropica, MGER/EG/06/RTC 74 identified from patients with suspected CL in Northern Sinai, Egypt. Fed flies were dissected at different time intervals and examined microscopically to determine the infection rate and parasite intensity. The feeding rate of P. papatasi on L. major (58.69%) was found higher than on L. tropica (45.99%). Infection rate with L. major (60.19%) was significantly higher than that with L. tropica (39.73%). Transmission by bites in case of P. papatasi/L. tropica failed. A characteristic L. major lesion was developed on the foot pads region 120 days post infective bites on healthy hamster. It is therefore concluded that P. papatasi is a much more effective vector for L. major than for L. tropica. PMID- 22435151 TI - The impact of three anopheline mosquito species in Toshka, on the introduction of chloroquine resistant P. falciparum to Egypt. AB - Malaria still tops the prevalent human arthropod-borne diseases. In Egypt, sporadic cases of human malaria were reported with a focus in Al-Fayoum. Besides, many Egyptian Anopheles species were reported allover which are either malaria vectors or incriminated ones. This study recorded An. multicolor, An. sergentii, and An. algeriensis in Toshka. Many authors reported that A. sergentii is a malaria-vector and A. multicolor is a suspected vector. Consquently, the endemicity of Chloroquine resistant Plasmodium falciparum on the Egyptian Sudanese border pave the way for malignant malaria transmission particularly among travelers returning back from Sudan. PMID- 22435152 TI - Liver metastases in Egyptian patients with colorectal cancer: incidence and clinico-pathological predictors. AB - Carcinoma of the large bowel is the fourth commonest cancer worldwide. The most frequent site for metastasis is the liver. Overall 30% of patients develop liver metastasis during the course of their illness; of these, 23% to 47% are synchronous lesions. These data are based on western studies. No data are published on patients with colorectal cancer from Egypt. We aimed to assess the incidence of colorectal liver metastasis in Egyptian patients and to evaluate the differences in the clinicopathological features and tumor behavior in patients with and without liver metastasis. One hundred forty eight patients were prospectively enrolled in the study. Patients were classified into metastatic group (n=78) and non metastatic group (n=70). In the two groups macroscopic features compared including: tumor size (2 cm, 2-5 cm, and >5 cm), site of primary tumor, side of liver involved, clinical symptoms and liver profile. Carcino-embryonic antigen (CEA) and cancer antigen (CA19.9) levels were recorded. At microscopy, tumor differentiation, invasion and nodal status were evaluated. No difference was found in the distribution of the primary site and size of the tumor. Jaundice, hepatomegaly and ascites were significantly higher in patients with liver metastases. Patients with liver metastasis had higher levels of CEA, CA19.9, higher frequency of vascular invasion and nodal involvement. PMID- 22435153 TI - Effect of splenectomy on liver regeneration and function following partial hepatectomy: experimental study. AB - The presence of enough remaining functioning liver parenchyma to avoid life threatening post-operative liver failure is a major prerequisite for hepatic resection in patients with hepato-biliary carcinoma. There are clinical reports which confirm the beneficial clinical effects of splenectomy on integrity of the residual liver following liver resection for hepatocellular carcinoma in cirrhotic patients with hypersplenism and portal hypertension. This experimental study was designed on hamsters to evaluate the proliferative capacity and function of the remaining liver lobes; in which splenectomy was done simultaneously with partial hepatectomy compared with those in which splenectomy was not done. Forty hamsters were divided into two groups: GI; in which partial hepatectomy was performed without splenectomy and the GII; in which animals were subjected to partial hepatectomy with prior splenectomy. Animals from each group were subjected to liver biopsy from the remaining lobes 48, 72 hours and one week after surgery. Also, serum alanine aminotransferase (ALT) and total bilirubin were tested before, 48, 72 hours and one week after hepatectomy. Hepatic regeneration in the remaining lobes was assessed through histo-pathological study, DNA ploidy of the hepatic nuclei using computerized image analysis system and determining of the labeling index of the nuclear factor NF Kappa B (P105), a novel monoclonal antibody specific for P105 protein by immunohistochemistry. In GII: induction of NK kappa B (P105) labeling index showed maximum expression depending on the regenerative capacity of the remaining liver lobes. In contrast, in GI; liver regeneration was slow. Also, changes in liver function of GII indicated that splenectomy prior hepatecotomy may minimize dysfunction in the remaining hypertrophied liver lobes. PMID- 22435154 TI - Acute cases of toxocariasis classified by IGG antibodies avidity in Venezuela. PMID- 22435155 TI - Larval habitat, ecology, seasonal abundance and vectorial role in malaria transmission of Anopheles arabiensis in Jazan Region of Saudi Arabia. AB - Studies on the ecology and role in malaria transmission of the local anopheline fauna of An. arabiensis, was undertaken at the Red Sea coastal plain, the Tihama, in Saudi Arabia, an area of moderate malaria endemicity. Studies were carried out over a 13 months period from March 2007, by larval collection and by adult collection using pyrethrum knockdown (PKD), and CDC light-traps at 9 s sites. In total 479,520 mosquitoes of 14 species collected seven anopheles species were identified: An. gambiae s.l Giles, An. dthali Patton, An. pretoriensis Theobald, An. sergentii Theobald, An. multicolour, An. rhodesiensis rupicola Lewis, and An. turkhudi Liston. An. gambiae was the most predominant species. An. arabiensis Patton was identified by PCR as the only member of the An. gambiae complex present. A survey of mosquito breeding sites showed that suitable sites for both An. arabiensis and other anophelines existed all year round. Larvae of An. arabiensis, An. dthali and An. pretoriensis were found every month. In addition to the more typical breeding sites, An. arabiensis larvae were found in rock pools and in domestic water containers and tanks. An. arabiensis was the predominant anopheline species found resting in human habitations but despite its endophily, only 40% bloodmeals were of human origin. The source(s) of the remainder was (were) unknown. Despite its predominance in larval collections, few adult An., dthali and An. pretoriensis were caught in PKD, indicating a zoophilic preference. Other anophelines were rarely found. Sporozoite rate in An. arabiensis was 0.61%, based on 21 posities. None was found in others. PMID- 22435156 TI - Study the protein content differences between common argasid species found in Egypt. AB - This work showed protein analysis differentiates between the argasid tick species. Protein band numbers found in the different ticks were 15, 12, 8 and 14 bands of Argas persicus, A. hermanni, A. arborius, and the Ornithodorus savignyi respectively. The proteins with molecular weights 410 and 17 kD were found only in A. persicus. One protein with M.W 126 kD was found in O. savignyi. The absence of the protein with MW 88 kDa is only shown in A. hermanni. A. arborius, only eight protein bands are shown and the nonexistence proteins Mw were (181, 77, 21, 15.6 and 8.66 kDa) which are found in the other tick samples. PMID- 22435157 TI - Bioremediation of heavy metal toxicity from factory effluents by transconjugants bacteria. AB - The presence of heavy metals in aquatic environments is known to cause severe damage to aquatic life, beside the fact that these metals kill microorganisms during biological treatment of wastewater with a consequent delay of the process of water purification. Most of the heavy metal salts are soluble in water and form aqueous solutions and consequently cannot be separated by ordinary physical means of separation. Five bacterial strains were used in this study. Bacterial strains were marking using 10 antibiotics and 7 heavy metals to be use as a selectable markes in conjugation process. Mating were performed using five bacterial strains. These strains were genetically marking in relation to their tolerance to the different antibiotics and heavy metals. All matings between bacterial strains were successes. The biosorption capacities for all heavy metals determined were higher for some metals than others. The transconjugants strain Tr5 resulted from mating between the parental bacterial strains (B-6bs X B-21) was more efficient in molybdenum uptake than all bacterial strains when supplementednutrient media wi th wastewater. Bacterial strains (B-21) appeared a good uptake of heavy metal ions (copper, cadmium, iron, cadmium and Lead) than other bacterial strains. This work highlights the potential of bacterial strains B-21 in uptake of heavy metals. The transconjugant strain Tr3 resulted from mating between parental bacterial strains (B-1584 X B-287) was more efficient in chromium uptake than all bacterial strains. PMID- 22435158 TI - Habitat characteristics for different freshwater snail species as determined biologically through macroinvertebrate information. AB - Macro-invertebrates including freshwater snails collected from 643 sites over 8 successive seasons among the River Nile, branches, main canals and certain drains in eight Egyptian Governorates. Thirteen snail species and one bivalve species were identified. The most distributed were Lanistus carinatus and Physa acuta while the most abundant were Cleopatra bulimoides and Physa acuta during the whole study. The sites that harbored each snail species in all the examined water courses were grouped seasonally and their biological assessment was determined by their minimum and maximum total point similarity percentage to that of the corresponded reference site and mean of the total points. Habitats for most snail species attained minimum total point's similarity percentage less than 21% (very poor habitat) during autumn and winter then spring while during summer very poor habitat was harbored by only few snail species. P. acuta was the only survived snails in habitat which attained 0 as a minimum total point's similarity percentage during two seasons and L. carinatus and Succinea cleopatra during one season. With respect to medically important snails very poor sites constituted 23% of Biomphalaria alexandrina sites, 14% of Lymnaea natalensis and 9.4% of Bulinus truncatus sites. The studied macroinvertebrate matrices, total number of organisms, taxa richness, the Ephemeroptera, Plecoptera, and Trichoptera (EPT) index, ratio of EPT index to chironomidae, ratio of scraper to filtering collector, contribution of dominant macroinvertebrate major group, comparison revealed descending tolerances from B. alexanrina followed by L. natalensis then B. truncates, but Hilsenhoff Biotic Index (HBI) showed the same tolerance to organic pollution. PMID- 22435159 TI - Active enhancement of Bacillus thuringiensis subsp-israelensis toxins and protein purification. AB - Bacillus thuringiensis sub sp. ilsraelensis de Barjac, that produce insecticidal protein endotoxins are used for mosquito control. The bacterium produces several Cry and Cytoxins that individually show activity against mosquitoes. A CryllA protein IA848, which corresponds to the first 848 amino acids from N-terminal of CryllA-gene was purified from E. coli by Ni-NTA affinity isolation, Q-Sepharose Fast-Flow chromatography & Super-200 size exclusion chromatography. It was determined using laboratory bioassays that the purified-IA848 protein has good insecticidal competitive binding bioassays show that IA848 does not compete with CryIAb for binding to the brush border membrane vesicles (BBM) of the Aedes aegyptiborer and does not compete with CryIAb at concentrations below 400-fold excess of unlabeled CryIAb for binding to the peritrophic matrix (PM) of the insect. This IA848 proved good competitive in control strategies. CryllA protein purification demonstrate molecular mechanism by which CytIA synergizes or suppresses resistance to toxins by providing a binding site for CryIIAa that resulted in an efficient formation of CryIIAa pre-pore that inserts into membranes and forms ionic pores. PMID- 22435160 TI - Single incision tans-umbilical laparoscopic cholecystectomy using conventional laparoscopic instruments: initial experience of single institute. AB - Laparoscopic cholecystectomy (LC) had been considered the gold standard treatment for symptomatic gall bladder (GB) stones. Single incision laparoscopic cholecystectomy (SILC) was emerged as a less invasive alternative with better cosmesis and less post operative pain. This study evaluated the feasibility, safety, advantages and complications of SILC using the conventional laparoscopic instruments. A total of 52 patients (47 females and 5 males) with symptomatic GB stones underwent elective SILC using the conventional laparoscopic instruments. The mean operative time was 61.75 min and the mean estimated blood loss was 17.21 ml. Gall bladder perforation occurred in 5 cases (9.6%) in which 3 cases calculi spillage occurred. Troublesome cystic artery bleeding occurred in 2 cases (3.8%) while gall bladder bed bleeding happened in 1 case (1.9%). An intraoperative cholangiogram was performed in 3 cases and a drain was inserted in one case. No conversions of the technique occurred. 49 patients discharged in the first post operative day and 3 patients (5.8 %) in the 2nd day. Three month post operative wound length was an average of 1.58 cm while patient satisfaction of the surgery was an average of 9.32. PMID- 22435161 TI - Parasite community of wild and cultured Oreochromis niloticus from Lake Manzalah, Egypt. AB - A total of 323 O. niloticus (168 wild fishes and 155 cultured fishes) were collected from Lake Manzala, Egypt from July to September 2010. The fish samples were examined for both ectoparasites and endoparasites. The parasite community of wild and cultured, O. niloticus consisted of ten parasitic species, one protozoon (Trichodina spp.), six monogenea (Cichlidogyrus sclerosus, C. thurstonae, C. halli typicus, C. tilapiae, C. ergensi, C. tiberianus), one acanthocephalan (Acanthogyrus (Acanthosentis) tilapiae) and two crustacean species (Lernaea cyprinacea and Ergasilus sp.). Mean parasite species richness significantly differed between wild (4.9 +/- 0.3) and cultured (6.6 +/- 0.8). The overall prevalence of infection in cultured O. niloticus (54.84%) was significantly higher as compared to that in wild fish (39.9%). The most prevalent parasite was C. thurstonae (37.46%) and C. sclerosus (35.91%) while the less prevalent one was Ergasilus sp. (14.55%). Host sex and host body size significantly affect parasitism in most parasite species. PMID- 22435162 TI - Interactions of Spodoptera littoralis haemocytes following injection with the entomopathogenic fungi: Beauveria bassiana and Nomuraea rileyi. AB - This study compared the cellular interactions of Spodopteralittoralis haemocytes with two virulence-different entomopathogenic fungi: Beauveriabassiana and Nomuraearileyi. Using light and transmission microscopy, five types of haemocytes namely, prohaemocytes (PRs), plasmatocytes (PLs), granulocytes (GRs), spherule cells (SPs) and oenocytoids (OEs) were identified in the 6th instar larvae. PRs and PLs were found in the haemopoietic tissue. Intra-haemocoelic injection of blastospores induced ultrastructural alterations in the cytoplasm and nuclei of circulating haemocytes of treated larvae. Different responses were observed in the populations of haemocyte types following injection with the tested fungi. The most important changes were the decrease of the numers of GRs accompanied with increase in SPs at 12-48h following injection with B. bassiana, whereas, a decrease of PLs with a commitment increase inSPs and OEs were observed at most time intervals after injection with N. rileyi. Both fungi provoked a decrease of the total number of haemocytes at 48h followed by an increase at 72h post injection. In vivo assay showed that the GRs and PLs actively phagocytised fungal blastospores. There was a time-dependent decrease and increase in the phagocytosis activity after injection of B. bassiana and N. Rileyi, respectively. In B. bassiana-injected insects, the numbers nodules increased significantly at 6 48h in comparison with the controls post-injection. In N. rileyi-injected insects, nodules increased significantly only at 72h post-injection. No cellular encapsulation was observed in any of the examined insects. PMID- 22435163 TI - Chemical and biological assessment for Egyptian surface freshwater environment with reference to human activities. AB - The Egyptian freshwater was assessed in the River Nile, branches, main canals and certain drainages in eight Governorates, over eight successive seasons starting from spring 2008. Chemical assessment was made through ten parameters and the biological one was made through macro-invertebrates information. Results showed that means of Cd, Pb, Cu, Hg, Mn, Fe, Ni, Na, K & Ca varied in watercourses seasonally within somewhat narrow ranges, which may exceed the level of concern but with some elevations in branches, Rayahs and canals during certain seasons. Sites showed chemical levels over the permissible one or those gain total points < or = 6.3 according to the biological assessment indicate that very poor habitat or those of Hilsenhoff Biotic Index (HBI) equal to 7-10 indicate that organic pollution were observed in all the studied watercourses reflecting hazard non point source pollution. Damietta branch in the region of Damietta city characterized with elevations in the concentration of most chemicals examined. The percentages of sites that showed chemical level over the permissible one were 70.56% for K, 54.08% for Cu, 50.08% for Na, 22.08% for Cd, 11.36% for Fe, 5.6% for Pb, 1.92% for Ni, 1.12% for Mn, 0.16% for Ca and at last 0.0736% for Hg. The biological assessment was more able to define more polluted sites than did the chemical one. Human activity data revealed that each of the drains, Giza and Qalyubia canals showed the highest item conduction (animal or plant waste, macroscopic pollution and presence of bridges or barriers) and this was co parallel with their highest pollution recordation. PMID- 22435164 TI - Screening for metabolic liver diseases crucial to increase SVR to patients with CHC. AB - Liver diseases and its complications is common health problem worldwide. The emergence of metabolic disorders as a cause after exclusion of viral hepatitis nowadays is important. This is retrospective study on 200 patient's age range from 6months to 18 years old (50 females and 150 males). The patients divided into 2 groups according to age < 5 years & >5 years and all investigations done was collected and statistically processed. Abdominal enlargement was observed in 166/200 of all patients, 48/166 (67.6%) in patients <5 years old and 118/166 (91.5%) in patients >5 years old with statistical significant, jaundice was present in 34/200 of patients, 23/34 (32.4%) in patients <5 years old and 11/34(8.5%) in patients >5 years old, with statistical significant difference, CBC was normal in 58/200 of all age groups. 10/58 (14.1%) in patients <5 years old, 48/58 (73.2%) in patients <5 years old, with statistical significant difference and abnormal CBC in 142/200 (61/142, 62.8%) in age group > 5 years old, 81/142 (85.9%) in age group <5 years. Metabolic disorders was normal in 124/200 of all age groups, 23/124 (32.4%) in patients <5 years old. Metabolic disorders was abnormal in 76/200 of all, 48/76(67.6%) in patients >5 years old and 28/76 (21.7%) in patients < 5 years old, with statistical significant difference & for both age groups. The sensitivity of modalities used in the diagnosis of liver disease was as follow for US, study of metabolic profile, abnormal liver functions and abnormal CBC, 83.1%, 65.2%, 61.6% and 66.1% consequently. PMID- 22435165 TI - Conservative surgery in patients with malignant ovarian germ cell tumours. AB - Conservative surgery with adjuvant chemotherapy has made the preservation of fertility even in patient with advanced disease. The increase in cure rate has shifted to research for the long term menstrual reproductive and gynecologic outcome in these patients. The current study is retrospective for 25 cases of ovarian malignant germ cell tumor from January 2006 to January 2011, at El Hussian and Sayed Galal University Hospitals. The uterus and contralateral ovary were retained to preserve ovarian function with or without chemotherapy, followed up for two years. The mean age of most patients ranged from 15-28 years (average 21.5 years). According to International Federation of Gynecology and Obstetrics, the histological subtypes were ten dysgerminoma (40%). Five immature teratoma (20%), three endodermal sinus tumor (12%), four mixed germ cell tumor (16%) three embryonic cell tumours (12%). Stage I: tumors 15 cases (60%), Stage II: tumors one case (4%), Stage III tumors 6 cases (24%), Stage IV tumors 3 cases (12%). Adjuvant chemotherapy was administered to 15 cases 60% and followed up for two years. There were two recurrences, one died at 7th day postoperative of massive pulmonary embolism with past history of D.V.T, five healthy live births in the chemotherapy group without birth defects, and one infertility case 4%. PMID- 22435166 TI - Placental alkaline phosphatase activity and its relation to foetal growth and nutrition in appropriate and small for gestational age newborns at term. AB - The placental alkaline phosphatase (PAP) activity progressively rises as pregnancy advances, possibly, because of its increasing synthesis by placental tissue. The present study examined the relationship between placental alkaline phosphatase activity and the biochemical indices of foetal nutrition (cord blood glucose, albumin) and growth (neonatal birth weight). Placental and umbilical cord blood samples were collected from 56 term deliveries 30 of them were appropriate for gestational age (AGA) and 26 were small for gestational age(SGA) and prepared for placental alkaline phosphatase assay, glucose and albumin estimations using standard procedures. The birth weights of the neonates at term were taken and recorded. Correlation analyses of the data obtained show significant positive relationships between PAP and cord blood glucose, albumin and birth weight in AGA newborn (r2 = 0.86, 0.71, 0.68 p<0.05) and (r2 = 0.69, 0.81, 0.73 p<0.05) in SGA newborn but no significant relationship with gestational age, also there was significant statistical difference between both groups in level of PAP, glucose and albumin. PMID- 22435167 TI - Corvus R. ruficollis (desert or brown necked raven): a reservoir host for zoonotic parasites in Egypt. AB - Egypt includes many desert and rural areas. The small uptown fertile areas are placed under illegal enormous pressure of existing resources, where intensive agricultural practices are performed in combination with high population densities. The brown necked ravens (Corvus ruficollis) are attracted in huge numbers to such areas. The birds are omnivorous, very aggressive pest and seriously affect human welfare. The study focused on zoonotic role of ravens. PMID- 22435168 TI - Combined effect of three insect growth regulators on the digestive enzymatic profiles of Callosobruchus maculatus (Coleoptera: Bruchidae). AB - Insect growth regulators (IGRs) are insecticides that mimic insect produced hormones by regulatingdevelopmental process. Theyhave little or no mammalian toxicity, and are considered reduced-risk insecticides that are often exempt from tolerance requirements of regulatory agencies. IGRs, especially, chlorfluazuron, hydroprene and hexaflumuron (benzoylphenylurea) are currently studied because of possibility of using in stored products protection. Many of IGRs compounds usedin insect pests control are known to affect digestive enzymes. Chlorfluazuron, hydroprene and hexaflumuronwere tested topically at doses of 0.25%, 0.5%&1% for chlorfluazuron and hydroprene and 0.5, 1 & 2 microg/ml of hexaflumuron to investigate its effects on the activities of the digestive enzymes protease, amylase and lipase in Callosobruchusmaculatus larvae, which were affected by IGRs individually and in combination. When combined, the effect was more sever at low concentration. There were statistically significant differences (P < or = 0.05) in enzyme activities in combined and individual treatments. Combination three IGRs caused a two-fold decrease in enzyme activity even at reduced concentration. Clear dose-response relationships were established with respect to enzyme activity. A synergistic effect of IGRs was found by combination of low doses. These effects are most pronounced in early instars. PMID- 22435169 TI - Influence of serum cortisol levels on glycemic control in children with type 1 diabetes. AB - The association between plasma glucose (PG), HbA1c and serum cortisol levels in children with type 1 diabetes was investigated to determine the influence of serum cortisol on their glycemic control. A total of 45 children, aged 10-15 years, with type 1 diabetes for at least 3 years of diabetes were studied. Most of them did not have pancreatic beta-cell function. The cortisol levels among all patients were stratified according to fasting plasma glucose levels (50-99, 100 199, 200-299, & > or = 300 mg/dL), and the HbAlc levels (<7.0, 7.0-7.9, 8.0-8.9, & > or = 9%). The mean fasting PG, HbA1c and serum cortisol levels were 174 +/- 97 mg/dL, 7.7 +/- 1.3% and 23.04 +/- 16.6 ug/dl, respectively. The cortisol levels were highly correlated with PG levels (r =0.553, P < 0.0001) and mildly correlated with HbA1c levels (r=0.301, P=0.0192). Patients with high PG levels gave significantly higher cortisol levels as compared to those with lower PG levels (18.4 +/- 7.3, 26.8 +/- 18.3, 31.4 +/- 17.0 & 36.3 +/- 17.2ug/dl, P=0.0009). There were no significant differences in serum cortisol levels among patients stratified according to HbA1c levels (P=0.1566), however, patients with HbA1c levels > or = 9% had significantly higher cortisol levels than those with HbA1c levels<7% (32.6 +/- 14.4 vs. 21.8 +/- 11.3ug/dl, P=0.0291). PMID- 22435170 TI - Interrelation of antioxidant, anticancer and antilieshmania effects of some selected Egyptian plants and their phenolic constituents. AB - Medicinal plants are the most potential resource of new therapeutic agents. They are diverse, largely productive, biologically active and chemically unique; among their constituents "polyphenol compounds group" one of the main determinant factors in evaluating the pharmacological potentials i.e. polyphenols display an array of pharmacological properties such as antioxidant, immunostimulant, antitumor and antiparasitic effects. Cancer is a dreadful human disease, increasing with changing life style, nutrition and global warming while current available anticancer drugs cause serious side effects in most instances. Several reports suggested the relationship between antioxidant, anticancer and antiparasitic effects; they suggested that they act indirectly through promoting host resistance, restabilizing body equilibrim and conditioning body tissues in addition to their direct effect on certain parasites involved in cancer etiology. This work was conducted for estimation of total phenolic, flavonoids, phenylethanoid glycoside and iridoid content of twenty-three selected Egyptian plants as well as screening of their anticancer, antioxidant and antileishmanial effects, the overall gained results for suggest that the most suitable medicinal plant used as anticancer and antioxidant is Petrea volubilis L. which contain adequate mixture of total phenolic compounds 88.7 mg% and flavonoids 50.80 mg% and also suggest that flavonoid compounds are the category of phenolic compounds possess significant antioxidant and anticancer effects while the antilieshamnia screening revealed that Thymus decussatus Benth. extract exhibited the highest effect due to the presence of flavonoids and iridoids in adequate combination where iridoid compounds 201 mg% and flavonoid content was 128 mg%. PMID- 22435171 TI - Aedes aegypti re-emerging in Egypt: a review and what should be done? AB - Mosquitoes are main vectors of varieties of pathogenic agents affecting man and animals. There-emergencein Aswan and approach of Aedesa egypti, the vector of the Dengue hemorrhagic fever, Yellow fever and Chikungunya fever, which are encountered in Africa, needs to alert for this public health threat. The presence of Dengue and dengue hemorrhagic fever in Saudi Arabia is another issue. PMID- 22435172 TI - CRANIO: a 30-year perspectice in a 'contentious field'. PMID- 22435173 TI - A critical review of Dr. Charles S. Greene's article titled "Managing the Care of Patients with Temporomandibular Disorders: a new Guideline for Care" and a revision of the American Association for Dental Research's 1996 policy statement on temporomandibular disorders, approved by the AADR Council in March 2010, published in the Journal of the American Dental Association September 2010. AB - Dr. Charles Greene's article, "Managing the Care of Patients with TMDs A New Guideline for Care," and the American Association for Dental Research's (AADR) 2010 Policy Statement on Temporomandibular Disorders, published in the Journal of the American Dental Association (JADA) September 2010, are reviewed in detail. The concept that all temporomandibular disorders (TMDs) should be lumped into one policy statement for care is inappropriate. TMDs are a collection of disorders that are treated differently, and the concept that TMDs must only be managed within a biopsychosocial model of care is inappropriate. TMDs are usually a musculoskeletal orthopedic disorder, as defined by the AADR. TMD orthopedic care that is peer-reviewed and evidence-based is available and appropriate for some TMDs. Organized dentistry, including the American Dental Association, and mainstream texts on TMDs, support the use of orthopedics in the treatment of some TMDs. TMDs are not psychological or social disorders. Informed consent requires that alternative care is discussed with patients. Standard of care is a legal concept that is usually decided by a court of law and not decided by a policy statement, position paper, guidelines or parameters of care handed down by professional organizations. The 2010 AADR Policy Statement on TMD is not the standard of care in the United States. Whether a patient needs care for a TMD is not decided by a diagnostic test, but by whether the patient has significant pain, dysfunction and/or a negative change in quality of life from a TMD and they want care. Some TMDs need timely invasive and irreversible care. PMID- 22435174 TI - Changes in condylar position using different types of splints with and without a chinstrap: a case-control study. AB - The aim of this case-control study was to analyze and quantify if there is a different mechanical effect of stabilization and pivot splints with uni- or bilateral pivot of different heights and with and without an additional chinstrap, on the vertical, sagittal, and horizontal condyle position. A stabilization splint and splints with unilateral or bilateral posterior pivot support of 0.6 mm or 1.9 mm height were used with and without a chinstrap individually adjusted to 5N per side. Electronic-condylar-position-analysis was performed using an ultrasound-based jaw-tracking system with an accuracy of 0.1 mm. Manual guided central position served as the reference point. Participants were 40 functional, asymptomatic volunteers with a mean age of 33.9 years. Main effect splint design (stabilization, uni-, bilateral pivot) was not significant. Pivoting height was reported as significant (p < or = 0.02) in all axes. Use of the chinstrap was significant (p < or = 0.03) in the X- and Y- axis, but not significant in the Z-axis. A post-hoc test revealed that use of a chinstrap led to significantly (p = 0.003) less anterior and significantly (p = 0.002) more inferior condyle displacement. Results indicate that the use of pivot splints only in combination with a chinstrap lead to a distractive effect of the condyles. PMID- 22435175 TI - Alignment of biological apatite crystallites at first molar in human mandible cortical bone. AB - The aim of this study was to quantitatively clarify the c-axis alignment of biological apatite (BAp) crystallites (hereafter referred to as BAp alignment) in the cortical bone of the human mandible first molar. Six mandible specimens were collected from the cadavers of six dentulous Japanese adults (mean age, 63.0 +/- 12.1 years) held at the Department of Anatomy, Tokyo Dental College. A microbeam x-ray diffraction system was used to determine BAp alignment in the mesiodistal direction. Bone mineral density (BMD) was also measured using 3-dimensional trabecular structure measurement software. The results showed that the degree of BAp alignment in the mesiodistal direction was low in the alveolar area and high at the base of the mandible, suggesting that BAp alignment in the alveolar area is affected by occlusal force. Moreover, it was observed that the correlation between BAp alignment and BMD was small, indicating that BAp alignment and BMD could be independent factors. Therefore, determining BAp alignment was important in the evaluation of bone quality, including bone strength. PMID- 22435176 TI - Comparison of normal permanent and primary dentition sagittal tooth-crown inclinations of Japanese females. AB - The purpose of this study was to clarify the characteristics of permanent and primary tooth-crown inclinations. Landmark points from cephalograms and dental casts of two groups; 23 women (mean 20.3 +/- 3.3 years) and 11 girls (mean 5.2 +/ 0.1 years) were digitized, and the coordinates were integrated and transformed to a standardized plane. The 3-dimensional crown inclinations were projected on the sagittal plane, and the angles between the tooth vectors and the FH plane were calculated. An independent-group t-test was used to test for group differences of each tooth inclination, and correlation coefficients were generated for the inclination angles among the permanent and primary teeth. Most maxillary tooth-crown inclinations showed significant age-related differences, while only the second premolar and primary second molar differed significantly in the mandible. The maxillary molars were parallel to the corresponding mandibular molars and correlated with each other, but the primary molars were not. Significant correlations were found between inclinations of most permanent teeth, but not the primary teeth. Maxillary tooth-crown inclinations change during growth, but tooth-crown inclinations of the mandibular teeth do not. PMID- 22435177 TI - The prognosis of myofascial pain syndrome (MPS) during a fixed orthodontic treatment. AB - Among treatments in the literature for myofascial pain syndrome (MPS), the most reliable therapies in dentistry are spray and stretch, and, although less frequently used, anesthetic injection. Adult MPS subjects are often treated using fixed orthodontic therapy for resolution of malocclusion. There is no clarity in the literature on the prognosis of MPS during orthodontic therapy. The purpose of this study was to analyze the prognosis of MPS during orthodontic treatment of subjects with malocclusion, initially diagnosed as having MPS. The analysis covered the medical records of 91 young adult Caucasians scheduled for orthodontic treatment for various malocclusions. Thirty-seven of the patients were initially diagnosed as also having MPS (T0). Thirty patients began the orthodontic treatment and were recalled for a re-evaluation of MPS after dental alignment and dental class correction was achieved (T1). A wait-and-see strategy was applied in seven subjects who were included as the control subjects. They received no treatment for MPS. At T1, a statistically significant decrease was observed in the study group in the presence of any clicking or creaking noises from the jaw joint, a significant jaw joint and jaw muscle pain reduction, and a quality of life improvement. Among patients who were depressed at the beginning of treatment, the majority felt better at the follow-up evaluation. On muscular palpation, a statistically significant decrease was found on the visual analogic scale value of the middle fibers of the temporalis muscle, temporalis tendon, clavicular and sternal division of the sternocleidomastoid muscle, masseter muscles, and posterior cervical muscles. The temporalis and the masseter muscles showed a significant decrease in the number of subjects with trigger points (TrPs) in all areas in the study group, after treatment. The digastric and sternocleidomastoid muscles also showed a significant reduction in the number of subjects with TrPs. Subjects with MPS and malocclusion were treated using a fixed orthodontic treatment. They showed improvement, although no resolution, in the signs and symptoms of MPS, compared with the untreated control group. PMID- 22435178 TI - Evaluation of the palatal bone for placement of orthodontic mini-implants in Japanese adults. AB - Mini-implants are increasingly being used for orthodontic anchorage in the palate. The anatomical structure of the jaw must be properly evaluated prior to use; however, there are a few research reports providing basic data regarding the palate. Bone thickness was measured and bone morphology evaluated in the palates of Japanese people. The palates of five Japanese adult cadavers and 15 skulls were examined. The samples were imaged and measured using the micro-CT system. In the mid-palatine suture region, the cortical bone had a complex mesh-like structure and was thicker than surrounding areas. Cortical bone thickness varied depending on the site. The mid-palatine suture region is an ideal site for mini implant insertion; however, because bone and cortical bone thickness markedly decrease in the lateral region, careful attention should be paid when inserting mini-implants in the mid-palatine suture. PMID- 22435179 TI - Integration of participatory approaches into surveillance systems. AB - Animal health surveillance is essential for protecting public health, enhancing access to international markets for animals and their products, and improving animal health, production and welfare. It is of vital importance for protecting and improving the livelihoods of diverse groups of livestock keepers and stakeholders in livestock value chains. Surveillance systems consist of sets of complementary components which generate information to inform risk assessment, decision-making and policy formulation for both national programmes and international trade. Participatory approaches have the potential to add value to surveillance systems by enhancing their performance, especially their sensitivity and timeliness, and encouraging the inclusion of marginalised groups. This paper summarises key considerations in the assessment and design of animal health surveillance and discusses how participatory approaches can be integrated into comprehensive surveillance systems, leading to a more effective overall outcome for both domestic and international purposes. PMID- 22435180 TI - The influence of economic indicators, poultry density and the performance of veterinary services on the control of high-pathogenicity avian influenza in poultry. AB - High-pathogenicity avian influenza (HPAI) and low-pathogenicity notifiable avian influenza (LPNAI) in poultry are notifiable diseases that must be reported to the World Organisation for Animal Health (OIE). There are variations between countries' responses to avian influenza (AI) outbreak situations based on their economic status, diagnostic capacity and other factors. The objective of this study was to ascertain the significant association between HPAI control data and a country's poultry density, the performance of its Veterinary Services, and its economic indicators (gross domestic product, agricultural gross domestic product, gross national income, human development index and Organisation for Economic Co operation and Development [OECD] status). Results indicate that as poultry density increases for least developed countries there is an increase in the number and duration of HPAI outbreaks and in the time it takes to eradicate the disease. There was no significant correlation between HPAI control and any of the economic indicators except membership of the OECD. Member Countries, i.e. those with high-income economies, transparency and good governance, had shorter and significantly fewer HPAI outbreaks, quicker eradication times, lower mortality rates and higher culling rates than non-OECD countries. Furthermore, countries that had effective and efficient Veterinary Services (as measured by the ratings they achieved when they were assessed using the OIE Tool for the Evaluation of Performance of Veterinary Services) had better HPAI control measures. PMID- 22435181 TI - A qualitative risk assessment methodology for scientific expert panels. AB - Risk assessment can be either quantitative, i.e. providing a numeric estimate of the probability of risk and the magnitude of the consequences, or qualitative, using a descriptive approach. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES), formerly the French Food Safety Agency (AFSSA), bases its assessments on the opinions of scientific panels, such as the ANSES Animal Health Scientific Panel (AH-SP). Owing to the lack of relevant data and the very short period of time usually allowed to assess animal health risks on particular topics, this panel has been using a qualitative risk method for evaluating animal health risks or crises for the past few years. Some experts have drawn attention to the limitations of this method, such as the need to extend the range of adjectives used for the lower probabilities and to develop a way to assess consequences. The aim of this paper is to describe the improved method now established by the AH-SP, taking into account the limitations of the first version. The authors describe a new set of levels for probabilities, as well as the items considered when addressing either animal or human health consequences. PMID- 22435182 TI - [Economic management of health crises affecting production animals in Europe]. AB - The importance of animal health crises has considerably increased over the last few years. When a crisis occurs, farmers can receive financial support through various public, private and mixed compensation schemes. Economic losses resulting from diseases may be direct and indirect. If a disease is covered by European Union regulations then countries have a legal obligation to partly compensate farmers for direct losses, either directly through the national budget, or through a specific fund. The European Veterinary Fund also co-finances these losses. Only a few countries provide compensation for indirect losses. The private insurance sector also provides protection against some direct and indirect losses but the risks covered are variable. To encourage farmers to subscribe to this kind of insurance, some public authorities provide subsidies to help pay the premium. Insurance companies do not generally cover the risks linked to contagious diseases, but some companies do extend cover to include this type of risk. Several alternatives, such as mutual funds, are available to improve risk coverage. There is a lack of harmonisation among the various compensation schemes of different countries. Public authorities cannot provide full compensation, but mutual funds and private insurance companies are alternatives that should be further investigated and their use should be extended to other countries. A classification of diseases would harmonise the situation at the European level. PMID- 22435183 TI - An assessment of the feasibility of a poultry tracing scheme for smallholders in Vietnam. AB - Tracing movements could assist the implementation of bio-containment measures during a disease outbreak. To evaluate the potential for implementing a tracing system for a poultry supply chain in northern Vietnam, a four-month longitudinal study was conducted to identify marketing practices associated with poultry traceability. Poultry sold in batches were traced between farms and markets, and their traceability was assessed upon market arrival. A total of 315 batches were released from the farms; 37% arrived at a market, from which 57.3% were 'traceable'. The results of the multivariable analysis showed that traceability was associated with farms operating through no more than two traders (Odds ratio [OR] = 5.97, 95% CI 1.15-30.92) and batches brought to the market on the day of purchase (OR = 4.05, 95% CI 1.23-13.27). No specific incentives were provided to farmers or traders. Results suggest that there is potential for implementing a poultry traceability scheme, although the tracing methodology should be refined. PMID- 22435184 TI - Animal Health Ireland: providing national leadership and coordination of non regulatory animal health issues in Ireland. AB - Livestock production plays an important role in the Irish economy. Regulatory animal health issues are the responsibility of government, but until recently there has been no national coordination of non-regulatory animal health issues. This gap has recently been filled with the establishment of Animal Health Ireland (AHI), a not-for-profit, partnership-based organisation providing national leadership and coordination of non-regulatory animal health issues in Ireland. Animal Health Ireland provides benefits to livestock producers and processors by providing the knowledge, education and coordination required to establish effective control strategies, both on-farm and nationally. This paper presents a brief overview of the context for AHI, and of its establishment and initial activities. Non-regulatory animal health issues have been prioritised. A series of work programmes (each focusing on a high-priority issue) have been established. Partnership is critical to success, both for AHI as an organisation and for effective farm-level transfer of knowledge. This model for national leadership and coordination of non-regulatory animal health issues may be of relevance elsewhere. PMID- 22435185 TI - Developing a disease prevention strategy in the Caribbean: the importance of assessing animal health-related risks at regional level. AB - In 2009 CaribVET conducted a survey among Caribbean national Veterinary Services to assess perceptions of risk assessment and to identify the principal exotic diseases of concern in the region and their means of introduction. The results showed that the introduction of live animals was considered the most likely route of introduction of exotic animal pathogens, followed by the uncontrolled introduction of animal products by boat passengers. The results were used to define a regional strategy for assessing animal health risks that highlights the importance of within-region exchanges. PMID- 22435186 TI - Sustainable control of zoonotic pathogens in wildlife: how to be fair to wild animals? AB - Wildlife may harbour infectious pathogens that are of zoonotic concern. However, culling such reservoir populations to mitigate or control the transmission of these pathogens to humans has proved disappointingly inefficient. Alternatives are still in an experimental stage of development. They include vaccination, medication, contraception and environmental manipulation, including fencing and biosecurity measures. This review examines the general concepts involved in the control of wildlife diseases and presents relevant case studies. Since wildlife disease control inevitably involves interfering with wildlife ecology, this is a complex goal whose attempts at realisation should be supervised by a scientific organisation. Most approaches within natural ecosystems should first be carefully tested in trials that are progressively extended to a larger scale. Finally, all measures that aim to prevent infection in humans (such as personal hygiene or vaccination) or that encourage us to avoid infectious contacts with wildlife should be recommended. PMID- 22435187 TI - A feasibility study for the establishment of a national wildlife health centre in Sri Lanka. AB - Sri Lanka is a tropical nation within a zoogeographic zone that is at high risk for infectious disease emergence. In 2010, a study was conducted on the feasibility of enhancing capacity in Sri Lanka to manage wildlife diseases through the establishment of a national wildlife health centre. The Canadian Cooperative Wildlife Health Centre was assessed as a potential model for adaptation in Sri Lanka. Interviews and group meetings were conducted with potential key participants from the Sri Lankan Departments of Wildlife Conservation and Animal Production and Health, and the Faculty of Veterinary Medicine and Animal Science of the University of Peradeniya. In addition, site visits were made to potentially participating facilities and the literature on best practices in building scientific capacity was consulted. With strategic enhancements in education and training, additional personnel, improvements in transportation and diagnostic facilities, and central coordination, Sri Lanka appears very well positioned to establish a sustainable wildlife health centre and programme. PMID- 22435188 TI - Establishing a European network for wildlife health surveillance. AB - Surveillance of wildlife health in Europe remains informal and reporting wildlife diseases is not yet coordinated among countries. At a meeting in Brussels on 15 October 2009, delegates from 25 countries provided an overview of the current status of wildlife health surveillance in Europe. This showed that every year in Europe over 18,000 wild animals are examined as part of general surveillance programmes and over 50,000 wild animals are examined in the course of targeted surveillance. The participants at the Brussels meeting agreed to set up a European network for wildlife health surveillance. The goals of this network, which was established in February 2010, are to improve procedures for the rapid exchange of information, harmonise procedures for investigation and diagnosis of wildlife diseases, share relevant expertise, and provide training opportunities for wildlife health surveillance. PMID- 22435189 TI - Ranking control options for tropical theileriosis in at-risk dairy cattle in Tunisia, using benefit-cost analysis. AB - An economic evaluation of various control programmes against Theileria annulata infection was conducted on a sample of 49 Tunisian dairy farms where clinical cases of tropical theileriosis had been recorded during the summer. Indicators of morbidity and the prevalence of infection, as well as production and demographic indicators (recorded in the present survey ortaken from secondary sources), were used to rank the potential costs and benefits of various control programmes for tropical theileriosis over a time horizon of 15 years. Three options were considered, i.e. vaccination with a local attenuated cell-line vaccine; partial barn upgrading, based on first roughcasting then smoothing all the walls of the animal premises (inner and outer surfaces); and applying acaricides to control the vector tick population on the cattle. The most important loss from this disease, representing between 22% and 38% of the overall losses, is the loss in milk yield from carriers of T. annulata. Upgrading barns produced the highest mean benefit-cost ratio (1.62 to 3.71), while the ratios for vaccination and acaricides ranged from 0.20 to 1.19 and 0.32 to 0.88, respectively. However, the benefit-cost ratio of vaccination increased (from 1.65 to 5.41), when the costs due to carrier state infection, which vaccination does not prevent, were ignored. Upgrading barns is a sustainable eradication policy against tropical theileriosis, based on a single investment, and is environmentally friendly. This control option should be encouraged by national Veterinary Authorities in regions where tropical theileriosis is transmitted by a domestic endophilic tick. PMID- 22435190 TI - Climate change, zoonoses and India. AB - Economic trends have shaped our growth and the growth of the livestock sector, but atthe expense of altering natural resources and systems in ways that are not always obvious. Now, however, the reverse is beginning to happen, i.e. environmental trends are beginning to shape our economy and health status. In addition to water, air and food, animals and birds play a pivotal role in the maintenance and transmission of important zoonotic diseases in nature. It is generally considered that the prevalence of vector-borne and waterborne zoonoses is likely to increase in the coming years due to the effects of global warming in India. In recent years, vector-borne diseases have emerged as a serious public health problem in countries of the South-East Asia region, including India. Vector-borne zoonoses now occur in epidemic form almost on an annual basis, causing considerable morbidity and mortality. New reservoir areas of cutaneous leishmaniosis in South India have been recognised, and the role of climate change in its re-emergence warrants further research, as does the role of climate change in the ascendancy of waterborne and foodborne illness. Similarly, climate change that leads to warmer and more humid conditions may increase the risk of transmission of airborne zoonoses, and hot and drier conditions may lead to a decline in the incidence of disease(s). The prevalence of these zoonotic diseases and their vectors and the effect of climate change on important zoonoses in India are discussed in this review. PMID- 22435191 TI - Triggers for foot and mouth disease vaccination in the United States. AB - In the United States, the national policy for foot and mouth disease (FMD) vaccination lacks clarity. To better understand what potential Incident Commanders see as important 'triggers' or factors to consider for implementing vaccination as a control strategy, the authors presented seven such individuals with an FMD outbreak scenario that started in north-western Illinois and spread across state lines by the end of the fifth week. The scenario had four infected premises at the end of week one, 13 at the end of week two, and 60 (including both infected and previously depopulated premises) by the end of week five. Two individuals favoured vaccination the first week of the outbreak scenario, one did not want to vaccinate during the scenario, and the remainder wanted vaccination at some time during the scenario. Respondents ranked nine specific factors to take into consideration when deciding whether or not to vaccinate. Of these, the capability to manage the outbreak by stamping out ranked first. Many of the issues raised in this report are applicable to other countries that are currently FMD-free without vaccination. PMID- 22435192 TI - Five years' experience of classical swine fever polymerase chain reaction ring trials in France. AB - Since 2004, the French National Reference Laboratory for classical swine fever (CSF) has conducted an annual proficiency test (PT) to evaluate the ability of local veterinary laboratories to perform real-time polymerase chain reaction (PCR) for CSF virus. The results of five years of testing (2004-2008) are described here. The PT was conducted under blind conditions on 20 samples. The same batch of samples was used for all five years. The number of laboratories that analysed the samples increased from four in 2004 to 13 in 2008. The results of the PT showed the following: cross-contamination between samples and deficiencies in RNA preparation can occur even in experienced laboratories; sample homogeneity should be checked carefully before selection; samples stored at-80 degrees C for several years remain stable; and poor shipment conditions do not damage the samples with regard to detection of CSF virus genome. These results will enable redesign of the panel to improve the overall quality of the PT, which will encourage laboratories to check and improve their PCR procedures and expertise. This is an excellent way to determine laboratory performance. PMID- 22435193 TI - The first International Standard anti-Brucella melitensis Serum. AB - The World Organisation for Animal Health (OIE) requested an International Standard anti-Brucella melitensis Serum (ISaBmS) to standardise diagnostic tests and reagents for sheep and goats. The agreed criteria were the highest dilution (in negative serum) of the standard which must give a positive result and the lowest dilution (in negative serum) which must simultaneously give a negative result. The two dilutions for each assay were, respectively: indirect enzyme linked immunosorbent assay (iELISA) 1/64 and 1/750, competitive ELISA (cELISA) 1/8 and 1/300, fluorescent polarisation assay (FPA) 1/16 and 1/200, Rose Bengal test (RBT) 1/16 and 1/200. The OIE International Standard Serum (OIEISS) will remain the primary standard for the RBT; the ISaBmS is an additional standard. It was impossible to set criteria for the complement fixation test, therefore the OIEISS will remain the primary standard. The ISaBmS can be used to standardise iELISA, cELISA and FPA to diagnose sheep and goat brucellosis. This standard should facilitate harmonisation of tests used for brucellosis surveillance and international trade in these species. PMID- 22435194 TI - The utility of polymerase chain reaction for diagnosis of lumpy skin disease in cattle and water buffaloes in Egypt. AB - An outbreak of lumpy skin disease (LSD) occurred among cattle and water buffaloes in Egypt in 2006. Polymerase chain reaction (PCR) and the agar gel precipitation test (AGPT) were compared. Eight of ten (80%) tissue specimens from diseased cattle were positive with AGPT while 100% were positive with PCR. Of ten tissue specimens from diseased water buffaloes, 70% were positive with AGPT while 100% were positive with PCR. Ten milk samples were obtained from diseased water buffaloes; PCR detected nucleic acid of LSD virus (LSDV) in 50% while AGPT failed to detect LSDV antigen. Water buffaloes are susceptible to LSDV infection. The clinical signs of LSD were less severe in water buffaloes, but the virus was excreted in their milk. Diagnosis of LSD outbreaks by PCR will facilitate rapid application of control measures. Mass vaccination should be applied in both cattle and water buffaloes in Egypt using an effective specific vaccine against LSD, such as the attenuated Neethling strain vaccine or a recombinant vaccine. PMID- 22435195 TI - Comparative efficacy of candling and glass plate compression for detection of diphyllobothriosis in rainbow trout (Oncorhynchus mykiss) musculature. AB - The efficiency of the direct candling technique on fillets (candling 1) was compared with examination of cuts 4 mm thick or less (candling 2) and glass plate compression for the detection of plerocercoids of Diphyllobothrium spp. in muscles of rainbow trout, Oncorhynchus mykiss. Application of the three procedures gave the following results (percentage of infected fish/percentage of isolated plerocercoids): candling 1: 40.9/22, candling 2: 29.5/18.8, glass plate compression: 29.5/59.2, and combination of candling 1 and 2: 70.5/40.8. The combination of the three techniques yielded 100% sensitivity: 44 infected fish were detected of 77 trout examined. When different regions of the musculature were compared using the three techniques, a high density of plerocercoids and the highest percentage of infection (90.9%; 40 infected trout) were detected in the ventral musculature. Candling 1, candling 2 and glass plate compression on the ventral musculature gave the following case numbers and percentages, respectively, for the total of 44 cases: 9 (20.5%), 9 (20.5%), and 22 (50%). PMID- 22435196 TI - Assessment of national strategies for control of high-pathogenicity avian influenza and low-pathogenicity notifiable avian influenza in poultry, with emphasis on vaccines and vaccination. AB - Twenty-nine distinct epizootics of high-pathogenicity avian influenza (HPAI) have occurred since 1959. The H5N1 HPAI panzootic affecting Asia, Africa and Eastern Europe has been the largest among these, affecting poultry and/or wild birds in 63 countries. A stamping-out programme achieved eradication in 24 of these epizootics (and is close to achieving eradication in the current H5N2 epizootic in South African ostriches), but vaccination was added to the control programmes in four epizootics when stamping out alone was not effective. During the 2002 to 2010 period, more than 113 billion doses of avian influenza (AI) vaccine were used in at-risk national poultry populations of over 131 billion birds. At two to three doses per bird for the 15 vaccinating countries, the average national vaccination coverage rate was 41.9% and the global AI vaccine coverage rate was 10.9% for all poultry. The highest national coverage rate was nearly 100% for poultry in Hong Kong and the lowest national coverage was less than 0.01% for poultry in Israel and The Netherlands. Inactivated AI vaccines accounted for 95.5% and live recombinant virus vaccines for 4.5% of the vaccines used. Most of these vaccines were used in the H5N1 HPAI panzootic, with more than 99% employed in the People's Republic of China, Egypt, Indonesia and Vietnam. Implementation of vaccination in these four countries occurred after H5N1 HPAI became enzootic in domestic poultry and vaccination did not result in the enzootic infections. Vaccine usage prevented clinical disease and mortality in chickens, and maintained rural livelihoods and food security during HPAI outbreaks. Low pathogenicity notifiable avian influenza (LPNAI) became reportable to the World Organisation for Animal Health in 2006 because some H5 and H7 low-pathogenicity avian influenza (LPAI) viruses have the potential to mutate to HPAI viruses. Fewer outbreaks of LPNAI have been reported than of HPAI and only six countries used vaccine in control programmes, accounting for 8.1% of the total H5/H7 AI vaccine usage, as compared to 91.9% of the vaccine used against HPAI. Of the six countries that have used vaccine to control LPNAI, Mexico, Guatemala, El Salvador and Italy have been the biggest users. In countries with enzootic HPAI and LPNAI, development and implementation of exit strategies has been difficult. PMID- 22435197 TI - Mortality rate and clinical features of highly pathogenic avian influenza in naturally infected chickens in Bangladesh. AB - A retrospective study was performed to assess the mortality rates and clinical signs in commercial and backyard chickens naturally infected with the highly pathogenic avian influenza (HPAI) H5N1 virus in Bangladesh. All of the 33 commercial and 25 backyard farms, recorded during the first wave of HPAI outbreaks (January to November 2007) in Bangladesh, were enrolled in this study. The farm profile data, stock information and major clinical signs recognised by the farmers and/or farm attendants, were collected through a prototype questionnaire. The investigating veterinarians' retrospective appraisals of the clinical signs were recorded by interview. After the clinical onset, the incidence rates of mortality in breeder, commercial broiler, commercial layer and backyard chickens were, respectively: 0.0215, 0.0341, 0.0179 and 0.0703 per chicken-day at risk. The four major clinical signs observed were cyanotic combs and wattles, oedema of the head and face, drowsiness and huddling and ecchymotic discoloration of the leg shanks. The first sign (cyanotic combs and wattles) was equally observed in chickens from commercial and backyard farms (p = 0.44) but the second (oedema of the head and face) was more common in backyard farms (p = 0.03). PMID- 22435198 TI - Control strategies for peste des petits ruminants in small ruminants of India. AB - Peste des petits ruminants (PPR) is a contagious viral disease of small ruminants. It is endemic in several African, Middle Eastern and Asian countries, including India. India has recently taken comprehensive steps to deal with PPR through the development and production of potent vaccines and monoclonal-antibody based diagnostic kits, while also gathering baseline information on the disease situation and human resources. As a result, PPR can now be controlled by focused vaccinations in high-risk populations of sheep and goats, followed by mass vaccination campaigns. Mass vaccination campaigns must achieve high levels of herd immunity (70% to 80%) to block the epidemic cycle of the virus. With the tools currently available, disease control and subsequent eradication programmes for PPR may be a feasible option, following the example of the National Rinderpest Eradication Programme, which has successfully eradicated rinderpest from India. An understanding of the cultural and socio-economic circumstances of goat and sheep owners and a keen watch on the endemic nature of PPR in neighbouring countries will enhance the success of this approach. Coordinated efforts from all stakeholders, combined with proper funding and execution of control programmes, will be needed to achieve the goal of a PPR-free India. In addition, the availability of effective combined vaccines of PPR with goat pox or sheep pox offers a cost-effective way of simultaneously launching control programmes against all three of these diseases. PMID- 22435199 TI - Sero-epidemiological study of peste des petits ruminants in sheep and goats in India between 2003 and 2009. AB - This study describes the serosurveillance of peste des petits ruminants (PPR) in sheep and goats that was carried out between 2003 and 2009 using serum samples from animals suspected of PPR that were submitted to the Rinderpest and Allied Disease Laboratory (Division of Virology of the Indian Veterinary Research Institute [IVRI]). A total of 2,197 serum samples from sheep and 2,687 from goats were screened for PPR virus (PPRV) antibody using a monoclonal antibody-based competitive enzyme-linked immunosorbent assay developed at IVRI. Screening of the 4,884 serum samples showed that the prevalence of PPRV antibody in sheep and goats was 41.01% (95% confidence interval [CI]: 31.86 to 50.16) and 46.11% (95% CI: 37.18 to 55.04), respectively, with an overall prevalence of 43.56% (95% CI: 36.78 to 50.34) during the period. This indicates increased and widespread infection with the virus in India compared with earlier reports, which is attributed to the variations in sheep and goat husbandry practices in different regions, the agro-climatic conditions, the topography of different states, the socio-economic status of individual farmers and the migration of livestock in India. PMID- 22435200 TI - [Landscape components favouring the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina)]. AB - The authors studied the landscape components that favour the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina). They made spatial locations of anthrax outbreaks diagnosed by registered veterinary laboratories in the study area's zone of influence. As variables for study, they differentiated areas that are flooded for 20% of the time or more from primary and secondary runoff channels. They also identified areas with low-productivity pasture. Logistic regression analysis of farm populations revealed that landscape components favouring the occurrence of anthrax outbreaks are shared runoff channels (odds ratio (OR) = 2.3; confidence interval (CI) = 1.2; 4.7) and > or = 40% low-productivity pasture (OR = 5.4; CI = 3.5; 8.3). Contrary to initial assumptions, susceptibility to flooding was not a significant variable (OR = 1.1; CI = 0.5; 2.1). The authors concluded that the first step in decision-making and ensuring more efficient implementation of future anthrax control and eradication plans was to identify risk variables. PMID- 22435201 TI - Trapping as an alternative method of eradicating classical swine fever in a wild boar population in Bulgaria. AB - Between August and November 2009, eight cases of classical swine fever (CSF) occurred in young wild boar in a 25-km2 oak forest3 km south of the river Danube in the north-eastern part of Bulgaria. The wild boar population within the affected area was estimated to be 156 animals, or approximately six boar per km2. To control and eradicate the disease, and in addition to vaccination and hunting, trapping was used to reduce the boar population to below two animals per km2. In total, 124 wild boar were removed from the infected area within three months. Of these, 119 were trapped. In this paper, the authors present trapping as a successful tool to eradicate CSF from an area where hunting and vaccination alone might not be sufficient. Up to seven wild boar could be trapped in a single trap. Furthermore, the spread of CSF virus to the local domestic pig population and to wild boar in neighbouring areas was prevented. By decreasing the wild boar population to fewer than two animals per km2, it was assumed that the virus would no longer circulate and the disease would fade out. In fact, no further CSF cases were diagnosed afterwards. Under Bulgarian and similar conditions, trapping seems to be a more reliable method than hunting for reducing a wild boar population within a short period of time. Furthermore, trapping may be used alone or in combination with hunting, depending on the situation. PMID- 22435202 TI - Infestation of tracer lambs by Fasciola hepatica in Tunisia: determining periods for strategic anthelmintic treatments. AB - Ovine fasciolosis causes high morbidity and mortality rates, resulting in large economic losses to the sheep industry in northern Tunisia. The authors surveyed ovine fasciolosis (Fasciola hepatica infestation) in a Barbarine sheep flock in the humid region of Tunisia (Sejnane, Governorate of Bizerte) over two consecutive years, 2004 to 2005. To assess the dynamics of fluke infestation, a total of 36 tracer lambs were introduced into the flock successively, in groups of three, every two months, and their infestations were monitored by coproscopy and necropsy. Coproscopic analysis revealed high mean percentages of infestation of 60% and 65% for flock lambs and ewes, respectively. Similarly, a high percentage of infestations was recorded in the tracer lambs (more than 70%) post mortem. Significant fluctuations in infestation dynamics were observed in the tracer lambs, and three distinct infestation periods were identified: a period of very low, non-constant infestation risk during the warm period (from July to October); a high-risk period from March to June, and a third period with a variable but constant infestation risk (from November to February). Based on these results, the authors propose strategic flukicide treatments with triclabendazole, aimed at reducing mollusc infestation and subsequent pasture contamination by metacercariae, during two main periods: in September and in February, just before the reactivation of the molluscs from aestivation and hibernation, respectively. PMID- 22435203 TI - Ornithobacterium rhinotracheale and Mycoplasma synoviae in broiler chickens in Jordan. AB - A cross-sectional study was conducted from November 2008 to July 2010 in commercial broiler flocks in southern (n = 50) and northern (n = 50) areas of Jordan, to determine the flock-level prevalence of Ornithobacterium rhinotracheale (ORT) and Mycoplasma synoviae (MS) infections. Tracheal swabs were collected from commercial broilers with respiratory disease and tested by polymerase chain reaction. In total, 21% (95% CI: 18-45%) and 25% (95% CI: 20 51%) of commercial broiler flocks were positive for ORT and MS, respectively. In the southern areas the prevalence of flocks with positive tracheal swabs for ORT and MS was 16% and 10%; in the northern areas the prevalence was 26% and 40%, respectively. Of the flocks tested, 7% were infected with ORT and MS simultaneously. Further epidemiological studies are recommended to determine risk factors and evaluate the economic consequences of ORT and MS infections in the region. Furthermore, studies are required to isolate ORT and MS and develop vaccines against the local field isolates. PMID- 22435204 TI - Chlamydophila psittaci and Chlamydophila pecorum infections in goats and sheep in Egypt. AB - The aim of this study was to investigate the epidemiology of chlamydiosis in free ranging asymptomatic and diarrhoeic sheep and goats in Egypt. Faecal swabs were examined for the presence of Chlamydiae by culture in Vero cells and chick embryos, and staining with Gimenez, direct fluorescein-conjugated monoclonal antibodies, and immunoperoxidase. Specific chlamydial DNA was identified by amplification of the omp2 gene. The asymptomatic goats were 50% positive for the presence of the omp2 gene of the family Chlamydiaceae, and all isolates were Chlamydophila psittaci. The percentage of diseased goats in which Chlamydiaceae were identified was 16.2%, and all were positive for Cp. psittaci. Of the asymptomatic sheep, 6.7% were positive for the omp2 gene of the family Chlamydiaceae, and again all were positive for Cp. psittaci. In contrast, 42.9% of the samples that were collected from the diseased sheep were positive for Chlamydiaceae, of which 25.7% were Cp. psittaci and 4.8% Cp. pecorum. PMID- 22435205 TI - First detection of the equine herpesvirus 1 neuropathogenic variant in Brazil. AB - This report describes the first detection of an equine herpesvirus 1 (EHV-1) neuropathogenic variant (G2254/D752) in Brazil from a case of fatal equine herpesvirus myeloencephalopathy (EHM) in a mare. The results of nucleotide sequencing of the EHV-1 ORF30 gene showed that two other Brazilian EHV-1 isolates from EHM cases are representatives of the non-neuropathogenic variant (A2254/N752), suggesting that other unidentified factors are probably also involved in the neuropathogenicity of EHV-1 in horses. These findings will contribute to the epidemiological knowledge of EHV-1 infection in Brazil. PMID- 22435206 TI - Serum lipid and lipoprotein patterns of Iranian horses. AB - Patterns of serum biochemical parameters vary among horse breeds. The objective of the present study was to compare serum lipoproteins of Iranian Caspian ponies with those of other horses (Arabs and Thoroughbreds) in the Iranian region. Serum lipoprotein values were determined by agar-agarose gel electrophoresis and measured by scan densitometry. Moreover, serum triglyceride and cholesterol concentrations were determined and the results were analysed by one-way analysis of variance. Serum triglyceride and cholesterol values were 1.13 +/- 0.23 and 2.38 +/- 0.18 mmol/l in Caspian ponies, 1.96 +/- 0.49 and 1.92 +/- 0.25 mmol/l in Arab horses and 1.38 +/- 0.26 and 2.17 +/- 0.53 mmol/l in Thoroughbred horses. The relative percentages of alpha- (72.63 +/- 17.76%) and beta-lipoproteins (29.10 +/- 5.49%) in serum electrophoretic tracings from Caspian ponies were not significantly different from those of other horses (p > 0.05). The lipoprotein phenotype in Caspian ponies may be useful for evaluating metabolic diseases. PMID- 22435207 TI - Modern pig farming in the People's Republic of China: growth and veterinary challenges. AB - Cyclical oversupply and non-profitability situations have led to pig industry consolidations in the People's Republic of China, with many smaller farmers leaving the industry. In 2007, pork supply worsened due to outbreaks of 'high fever blue-ear disease', a complex disease issue that includes highly virulent porcine reproductive and respiratory syndrome, porcine circovirus and classical swine fever. Best estimates suggest that 50 million pigs were affected. More recent natural disasters (earthquakes/freezing winters) have also limited pig production in some areas. Overall expansion of the Chinese breeding herd is now continuing at a good pace and is likely to be sufficient to supply the predicted 7% annual increase in demand for pork. High prices of feed ingredients (cereals and soybean) continue to create cost-of-production issues. Authorities have instigated many helpful measures over the past decade, including insurance for farm breeder stock, direct subsidies for farm expansions and breeding programmes, free supplies of some vaccines, and taxation exemptions. Specific challenges remaining include: the high levels of spread, persistence and on-farm impact of key virus infections on single-site farm systems; the variable titre and potency of some local vaccines; the low level of technical capacity in laboratories and the lack of training and expertise among farm staff; and the lack of a distinctive representative voice for pig farmers. PMID- 22435208 TI - Organic livestock production: an emerging opportunity with new challenges for producers in tropical countries. AB - Agrochemicals, veterinary drugs, antibiotics and improved feeds can increase the food supply while minimising production costs in various livestock production systems around the world. However, these days, quality-conscious consumers are increasingly seeking environmentally safe, chemical-residue-free healthy foods, along with product traceability and a high standard of animal welfare, which organic production methods are said to ensure. Organic production is not only a challenge for producers in developing countries, it offers new export opportunities as well. Organic agriculture is practised by 1.8 million producers in 160 countries, and production of organically grown food continues to increase steadily by 15% per year. Most tropical countries are now exporting organic agricultural products but, apart from organic beef from Brazil and Argentina, organic livestock products are yetto take off. Most trade in organic livestock products is restricted to the European Union and other developed nations. Nevertheless, tropical countries cannot afford to neglect this emerging system of animal production. Organic production is knowledge- and management-intensive. Producers must be well versed in organic production standards, principles and practices, which require a high degree of knowledge and skill. In organic production, it is not simply the final product but the whole production process that must be inspected and approved by the accredited certification bodies. Organic livestock farming is still evolving, and further research is needed to make it sustainable. In this paper, the authors review the prospects of organic animal husbandry and its possible constraints in developing and tropical countries. PMID- 22435209 TI - A Kodak moment, or a century. PMID- 22435210 TI - Jack be nimble. Jill, too. PMID- 22435211 TI - Have a heart, obey the rules. PMID- 22435212 TI - A good idea! Keeping workers alert and patients safe. PMID- 22435213 TI - Legal woes. Lawsuits are stressing docs. PMID- 22435214 TI - Safety first. Unique partnership with feds boosts worker safety. PMID- 22435215 TI - #Disasterplan@hospital relies on social media. PMID- 22435216 TI - Please doc, stay. Give docs a reason to set up shop. PMID- 22435217 TI - Lessons learned in Medicare demos. PMID- 22435218 TI - Good-bye to paper. PMID- 22435219 TI - iGovernance: Hospitals are replacing the often haphazard approach of choosing IT projects with a much more formal and disciplined process. PMID- 22435220 TI - Keeping score on quality matters. Interview by Bob Kehoe. PMID- 22435221 TI - Observation units: a tightrope act. PMID- 22435222 TI - The evolution of palliative care. PMID- 22435223 TI - Meaningful use: lessons from the front. PMID- 22435224 TI - This Bud's for you. PMID- 22435225 TI - Managing workforce costs. PMID- 22435226 TI - Editorial: Broadening implementation of a preventive ethics approach. AB - We find the PE approach as part of the VA's IE program an excellent model from which all can learn. We have offered some additional issues for consideration on the basis of our own work and that of others. We hope that the combination of those ideas and the work of Foglia et al. will further advance the promotion and adoption of PE as a means to improve quality and minimize the occurrence of potentially harmful ethics conflicts. PMID- 22435227 TI - Preventive ethics: addressing ethics quality gaps on a systems level. AB - BACKGROUND: Preventive ethics (PE) is a key component of IntegratedEthics (IE), an innovative model developed by the Veterans Health Administration (VA)'s National Center for Ethics in Health Care which establishes a comprehensive, systematic, integrated approach to ethics in health care organizations. Since early 2008, IE has been implemented throughout all 153 medical centers and 21 regional networks within the US Department of Veterans Affairs (VA) health care system. ISSUES: A STEP-BY-STEP APPROACH TO ETHICS QUALITY IMPROVEMENT: PE employs a systematic, step-by-step process improvement approach called ISSUES: Identify an issue, Study the issue, Select a strategy, Undertake a plan, Evaluate and adjust, and Sustain and spread. After the ethics quality gap is described, a measureable and achievable improvement goal based on the gap is developed. One of the most challenging aspects of describing an ethics quality gap is to establish an appropriate ethical standard on which to base the operational definition of best ethics practice. PRACTICAL STEPS TO DEVELOPING A PREVENTIVE ETHICS FUNCTION: Within the VA's IE model, PE is situated as a subcommittee of the IE council, which is chaired by the facility director (equivalent to a hospital chief executive officer) and oversees all aspects of the organization's ethics program, including ethical leadership, ethics consultation, and PE. Each VA medical center is required to have a PE team led and managed by a PE coordinator and may need to address ethics issues across the full range of health care ethics domains. CONCLUSIONS: The VA's IE model establishes a robust conceptual framework, along with concrete tools and resources, to integrate PE concepts into the day-to-day operations of a health care organization and is directly transferrable to other health care organizations and systems. PMID- 22435228 TI - A case study on the safety impact of implementing smart patient-controlled analgesic pumps at a tertiary care academic medical center. AB - BACKGROUND: As with the use of any therapy involving opioids, patient-controlled analgesia (PCA)-related errors can lead to overdose and even death. "Smart" (computerized) pumps have medication safety enhancements, particularly those related to operator errors during administration, to improve overall safety and efficacy. After the occurrence of PCA-related errors that occurred at a tertiary care academic medical center, an analysis of PCA errors was conducted. The introduction of smart pumps was identified as a possible solution, and the medical center adopted the technology in 2006. A study was conducted to investigate the impact of implementation. METHODS AND RESULTS: The study had three primary objectives: (1) to evaluate history logs stored in the smart PCA pumps to characterize the nature of hard and soft stop alerts and identify potential errors that may have been averted, (2) to examine the impact of smart PCA pumps on voluntarily reported PCA therapy-related errors, and (3) to assess nursing perceptions regarding the improvement in safety due to the introduction of smart PCA pumps. The smart pumps potentially prevented 159 errors for the January-June 2007 period; upper hard limits had the most number of alerts, representing avoidance of errors with the greatest potential to be detrimental to the patient. In addition, pump-programming errors due to wrong concentration were eliminated after implementation. Finally, nursing staff perceived smart pumps to be valuable in improving patient safety. CONCLUSIONS: Smart PCA pumps had an important positive impact on PCA-related patient safety at the medical center. Other facilities should adopt PCA devices with additional safety features such as bar-code verification of the drug and concentration, as well as dosage limits, to prevent pump-programming errors. PMID- 22435229 TI - The costs of adverse drug events in community hospitals. AB - BACKGROUND: Adverse drug events (ADEs) occur often in hospitals, causing high morbidity and a longer length of stay (LOS), and are costly. However, most studies on the impact of ADEs have been conducted in tertiary referral centers, which are systematically different than community hospitals, where the bulk of care is delivered, and most available data about ADE costs in any setting are dated. Costs in community settings are generally lower than in academic hospitals, and the costs of ADEs might be as well. To assess the additional costs and LOS associated with patients with ADEs, a multicenter retrospective cohort study was conducted in six community hospitals with 100 to 300 beds in Massachusetts during a 20-month observation period (January 2005-August 2006). METHODS: A random sample of 2,100 patients (350 patients per study site) was drawn from a pool of 109,641 patients treated within the 20-month observation period. Unadjusted and adjusted cost of ADEs as well as LOS were calculated. RESULTS: ADEs were associated with an increased adjusted cost of $3,420 and an adjusted increase in length of stay (LOS) of 3.15 days. For preventable ADEs, the respective figures were +$3,511 and +3.37 days. The severity of the ADE was also associated with higher costs--the costs were +$2,852 for significant ADEs (LOS +2.77 days), +$3,650 for serious ADEs (LOS +3.47 days), and +$8,116 for life threatening ADEs (LOS +5.54 days, all p < .001). CONCLUSIONS: ADEs in community hospitals cost more than $3,000 dollars on average and an average increase of LOS of 3.1 days--increments that were similar to previous estimates from academic institutions. The LOS increase was actually greater. A number of approaches, including computerized provider order entry and bar coding, have the potential to improve medication safety. PMID- 22435230 TI - He thought the "lady in the door" was the "lady in the window": a qualitative study of patient identification practices. AB - BACKGROUND: Accurate patient identification (PT ID) is a key component in hospital patient safety practices and was addressed by one of the first six Joint Commission National Patient Safety Goals, which were introduced in 2003. Although the literature on patient safety practices is replete with discussion of strategies for improvement, less is known about frontline providers' subjective views. A qualitative study was conducted to examine the subjective views and experiences of nurses and residents regarding PT ID at an urban teaching hospital. METHODS: Some 15 registered nurses and 15 residents were interviewed between August 2009 and June 2010. Transcripts were analyzed using qualitative methodologies. FINDINGS: Although residents and nurses viewed PT ID as crucial to patient safety, they cited time pressures; confidence in their ability to informally identify patients; and a desire to deliver personal, humanistic care as reasons for not consistently verifying patient identification. Nurses expressed concern about annoying, offending, and/or alienating patients by repeatedly checking wristbands and asking date of birth, in the belief that excessive patient identification practices could undermine trust. Residents relied on nurses to check ID and preferred to greet the patient by name, a practice that they viewed as more consistent with their professional identity. Referring to patients by their room number and location was cited as a commonly used practice of PT ID and a contributor to errors in identification. CONCLUSIONS: Nurses and residents are aware of the importance and requirements to verify PT ID, but their adherence is mitigated by a variety of factors, including assessment of necessity or risk, impact on their relationship with the patient, and practices in place in the hospital environment that protect patient privacy. PMID- 22435231 TI - Implementing a perioperative handoff tool to improve postprocedural patient transfers. AB - Handoffs in the perioperative setting--the period during which the patient leaves the operating room (OR) and arrives at the postanesthesia care unit (PACU) or intensive care unit (ICU)--have received little attention. A perioperative handoff tool consisting of an OR-to-ICU/PACU protocol and checklists incorporates a defined process, a specified team structure, a procedure for technology transfer, and clearly defined information elements to share. The tool could be applied to any periprocedural setting in which a patient is physically transferred from the procedural location (with the associated procedural team) to a postprocedural care unit with a different care team. PMID- 22435232 TI - Promising AI. PMID- 22435233 TI - Coming to grips with SEMS. PMID- 22435234 TI - My first confined space experience. PMID- 22435235 TI - Doing your homework before the purchase. PMID- 22435236 TI - How to comply with respiratory protection standards. PMID- 22435237 TI - Produce safety: from the ground up. PMID- 22435238 TI - A new challenge for drug-free workplace programs. PMID- 22435239 TI - Visual communications & spill containment strategies and techniques. PMID- 22435240 TI - Boosting your safety immune system. PMID- 22435241 TI - Birth risk indicators for maternal and neonatal health: Songkla Center Hospital perspective. AB - OBJECTIVE: The aim of the present study was to examine the maternal and neonatal birth risk indicator and their relationship with the outcome of pregnancy. MATERIAL AND METHOD: This retrospective descriptive study was conducted in a selective month of 2008, 2009, and 2010. The birth risk indicators of maternal and neonatal health were collected from the medical records. RESULTS: There were 385, 349 and 334 deliveries in a selective month of 2008, 2009, and 2010. There was neither maternal mortality, nor cardiovascular failure in the present study period. Three main indication of inductions of labor were premature rupture of membrane (up to 4.0%), diabetes mellitus (up to 2.0%), and postdate (up to 1.3%). The first two conditions had statistical significance in September 2009 (p = 0.0334 and 0.0053 respectively). Whereas, the three major indications of cesarean section were previous cesarean section (12.5 to 21.9%), failure to progress due to protracted/arrest of labor pattern with/without rupture of membrane and augmented labor (2.4 to 7.5%), and fetal distress (1.1 to 4.2%). The rates of low birth weight, less than 2,500 grams, were varied from 5.2 to 6.9%. The respiratory distress syndrome (RDS) related to repeat cesarean section was encountered up to 3.6%, as well as the RDS related to induction of labor was up to 1.6%. CONCLUSION: The birth risk indicators reflect the outcome of pregnancy, however the development of additional key indicators for perinatal health care outcome are required. PMID- 22435242 TI - False positive rate of serum markers for Down syndrome screening: does transportation have any effect? AB - OBJECTIVE: To determine the false positive rate of serum markers for Down syndrome screening caused by transportation by analyzing samples sent from different hospitals at various distances. MATERIAL AND METHOD: The database of serum markers between March 2008 and August 2010 was retrieved from Maternal Fetal the Medicine unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University. The tests were performed using Delfia Xpress system. The cut off value for positive test result was 1 in 250. RESULT: Two thousand six hundred thirty one samples from hospitals located at various distances ranging from 0 to 449 km were assessed. The overall positive results were 6.1%, ranging from 5.6% among the hospitals near the laboratory to 15.4% among the hospitals far away from the laboratory (p-value < 0.001). The samples from the remote hospitals had significantly higher levels of free beta hCG than those from nearby hospitals (p-value = 0.003). CONCLUSION: The samples transported from the hospitals far from the laboratory need better storage and shipping procedure to avoid high false positive rate, which leads to unnecessary invasive prenatal diagnosis procedure. PMID- 22435243 TI - Diabetes self-management, fasting blood sugar and quality of life among type 2 diabetic patients with foot ulcers. AB - BACKGROUND: Diabetic foot ulcers have a negative impact on quality of life and diabetes self-management of the condition is a key component of diabetes treatment. However no study has yet been conducted to determine the relationship between diabetes self-management, fasting blood sugar and quality of life among type 2 diabetic patients with foot ulcers in Thailand. OBJECTIVE: To examine the relationship between diabetes self-management, fasting blood sugar and quality of life (QOL) among type 2 diabetic patients with foot ulcers who received the diabetes treatment in King Chulalongkorn Memorial Hospital, Thailand. MATERIAL AND METHOD: This was a cross-sectional study of 80 participants with type 2 diabetes who had foot ulcers in King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Participants with diabetic foot ulcers were given a questionnaire regarding demographic data, fasting blood sugar, diabetes self-management and quality of life. Self-management was assessed by evaluating dietary intake, exercise, medication, self-monitoring, hygienic and foot care. WHOQOL-BREF-THAI, comprising of 26 items, was used to investigate quality of life. A purposive sampling technique was used for selecting patients from two outpatient departments, surgical and rehabilitation. Data were collected between September 2009 and October 2010. Simple descriptive statistics were used to provide the basic information and Pearson's product moment was applied. RESULTS: The majority (51.3%) of study participants were males and in the age group of > 60 years (50%). Over half (61.5%) of the participants had a severity of foot ulcer at the first level. The analysis revealed that there was a negative significant association between fasting blood sugar and quality of life (r = -0.30, p < 0.05). Furthermore, diabetes self-management had a significant association with quality of life (r = 0.35, p < 0.05). CONCLUSION: The results in the present study suggest that good quality of life is significantly related to good diabetes self-management and fasting blood sugar control in type 2 diabetes patients with foot ulcers. Therefore, these patients should be encouraged to perform self management for controlling their blood sugar and improving their quality of life. PMID- 22435244 TI - Lipid profile changes in Thai HIV and tuberculosis co-infected patients receiving non-nucleoside reverse transcriptase inhibitors-based antiretroviral therapy. AB - OBJECTIVE: To study and compare the pattern of lipid profile changes in Thai HIV and tuberculosis (TB) co-infected patients after receiving two non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based antiretroviral therapy (ART). MATERIAL AND METHOD: From an open label, randomized, comparative trial comparing treatment outcome between HIV and TB co-infected patients receiving nevirapine (NVP) or efavirenz (EFV) combined with stavudine and lamivudine, patient's body mass index (BMI), CD4 cell count, plasma HIV-1 RNA, fasting blood glucose, plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglyceride (TG) were collected at baseline, 24, and 48 weeks of ART. RESULTS: Of the 121 patients included in the present study, mean (SD) age was 36.9 (8.4) years and 66% were male. After 48 weeks of ART the median (IQR) percentage of TC, LDL-C, HDL-C and TG values were 21.1% (5.4-40.7), 23.5% (-0.8-49.8), 22.7% (0-50) and -1.0% (-34.6-32.2) respectively. The median (IQR) percentage change of the HDL-C value was significantly higher in NVP-based than EFV-based ART (31.9 [9.6-50.0] vs. 12.2 [ 8.8-51.2]; p = 0.03). The proportions of patients with high TC (21.5%) and high LDL-C (29.2%) increased and low HDL-C (11.6%) decreased significantly at 48 weeks of ART compared to baseline (all, p < 0.01). The proportions of patients with high TC, high TG and low HDL-C were significantly higher in the EFV group than in the NVP group (p = 0.03 for high TC, p = .01 for high TG and p < 0.01 for low HDL C). CONCLUSION: NNRTI-based ART is associated with increases of TC, LDL-C and HDL C values in Thai HIV and TB co-infected patients. More favorable lipid profile is observed in NVP-based than EFV-based ART. PMID- 22435245 TI - Nosocomial bloodstream infection in Songklanagarind Hospital: outcome and factors influencing prognosis. AB - OBJECTIVE: To determine epidemiology, microbiology, outcome, and factor influencing mortality in nosocomial bloodstream infection in Songklanagarind Hospital. MATERIAL AND METHOD: Retrospective study in adult patients who were hospitalized at Songklanagarind Hospital with positive blood culture after 48 hours of admission was conducted. The present study duration was between 1 August and 30 November 2008. RESULTS: There were 138 episodes of nosocomial blood stream infection in 117 patients, the prevalence of 11.6/1,000 admissions. The mean age of patients was 54.8 years (range 12 to 88 years) and males comprised of 60.9%. Hematologic malignancy was the most common underlying condition of the patients (27.5%) while 30.4% of patients had no underlying disease. The three common primary infections were lower respiratory tract (13.9%), urinary tract (12.4%) and skin and soft tissue (6.5%), whereas the unknown site of infection had accounted for 80 episodes (62.0%). The leading pathogens of nosocomial bacteremia were E. coli 17.4%, S. aureus 15.2%, K. pneumoniae 12.3% and P. aeruginosa 10.3%. Vanocomycin was dominantly sensitive to gram positive cocci, while about half (52.4%) of S. aureus had methicillin resistance. The variety of resistance had encountered for example P. aeruginosa (7.1%) to imipenem and majority of A. baumannii to aminoglycosides, fluoroquinolones and carbapenems. Overall mortality was 28.3% but mortality due directly to bacteremia was 13.8%. Univariate and multivariate analyses showed liver cirrhosis and lower respiratory tract infection to be associated with increased mortality. CONCLUSION: The prevalence of nosocomial blood stream infection had slightly sideway down, while the mortality was stable, compared with several reports in the last two decades. The gram negative bacteria had a high proportion of antibiotic resistance. PMID- 22435246 TI - The low prevalence of primary restless legs syndrome in Thai Parkinson's disease patients at Chulalongkorn University Hospital. AB - OBJECTIVE: There have been many studies of the prevalence of restless legs syndrome (RLS) in Parkinson's disease (PD). Some studies found a lower prevalence than in comparable groups in the general population while others reported more RLS. The present study was designed to determine the prevalence of primary RLS in Thai PD patients. MATERIAL AND METHOD: PD patients were interviewed for RLS symptoms and were excluded if they had a malignancy, endstage renal disease, neuropathy, a history of spinal cord diseases or were pregnant. Serum ferritin levels were measured. RESULTS: Three out of 183 patients interviewed (1.6%) had symptoms consistent with RLS. When one patient who had a serum ferritin level of 31.9 ng/ml is excluded, the prevalence falls to 0.98%. None of the following variables were significantly different in patients with and without RLS: age, gender age at onset of PD, duration of PD, Hoehn and Yahr stage, serum ferritin level and dose and duration of dopaminergic medication. None of the patients who have had subthalamic nucleus deep brain stimulation (n = 5) had RLS. CONCLUSION: The prevalence of RLS in Thai PD patients was found to be much lower than in most of the previous studies, especially those conducted in Europe and America. PMID- 22435247 TI - The relative false negative rate of isosulfan blue in detecting sentinel lymph nodes in early breast cancer. AB - OBJECTIVE: To determine the false negative rate of the isosulfan blue injection method of SLN detection in early breast cancer, relative to that of the combined blue dye and radiocolloid injection method. MATERIAL AND METHOD: Seventy women with early breast cancer underwent the combined method of SLN detection during the period between September 2007 and December 2008. Standard criteria for each method were used to identify SLNs. Each SLN was labeled as identified by the blue dye, the radiocolloid and as being positive or negative for cancer cells. RESULTS: Subjects were 50 years old with tumors of size 2.3 cm on the average. The average number of SLNs harvested was 2.5 nodes per subject. The detection rate for the isosulfan blue method was 91% (64/70). The relative false negative rate of the blue dye was zero (0/64). CONCLUSION: Experienced surgeons who use the isosulfan blue method of SLN detection in early breast cancer can be reasonably confident that the false negative rate of the isosulfan blue method was similar to that of the combined method. PMID- 22435248 TI - Single dose of gabapentin for prophylaxis intrathecal morphine-induced pruritus in orthopedic surgery: a randomized controlled trial. AB - OBJECTIVE: Gabapentin has an antipruritus effect, which its efficacy in reducing pruritus induced by intrathecal morphine has not been well documented. The purpose of the present study was to know if a single smaller dose of gabapentin could decrease the intrathecal morphine-induced pruritus. MATERIAL AND METHOD: One hundred sixty eight patients from the 180 recruited patients fulfilled the trial requirement and were scheduled for orthopedic surgery under spinal anesthesia using 0.5% isobaric bupivacaine and 0.2 mg preservative-free morphine. The patients were divided into two groups, each of 84 subjects and received either gabapentin 600 mg or a placebo, two hours preoperatively, in a prospective, randomized, double-blind, placebo-controlled trial. The pruritus was evaluated at 1, 2, 3, 4, 6, 9, 12 and 24 hours after intrathecal morphine administration. Adverse events were noted. RESULTS: The overall incidence of pruritus was not significantly different between the two groups while the incidence and severity of pruritus was significantly decreased in the gabapentin group at four hours after intrathecal morphine injection (18 of 84 subjects, 21.4% vs. 35 of 84 subjects, 41.7%; p = 0.008 and 0.045 respectively). The urinary retention was significantly higher in the study group compared to the placebo group (50.0% (42 of 84 subjects) vs. 33.3% (28 of 84 subjects) p = 0.042). CONCLUSION: Preoperative gabapentin 600 mg did not significantly reduce the postoperative intrathecal morphine-induced pruritus. PMID- 22435249 TI - The use of continuous thoracic paravertebral nerve block under direct vision for postoperative pain management in thoracic surgery. AB - OBJECTIVE: The purpose of the present study was to determine the quality of analgesia of continuous thoracic paravertebral nerve block after thoracic surgery by inserting a catheter under direct vision and assessing complications related to the analgesia technique. MATERIAL AND METHOD: Thirty patients with ASA I-III scheduled for pulmonary resection were enrolled in the present prospective study. Posterolateral thoracotomy was done by one surgeon. At the end of the operation before chest closure, a 16 G Touhy needle was inserted under direct vision at distance 5 cm from midline below incision interspace. The needle was advanced slowly until its tip bulged into the potential space, which is called paravertebral space, beneath the parietal pleura. Then, passing a catheter until the distal tip laid two to three intercostal spaces above the incision. A bolus of 15 to 20 ml of 0.5% levobupivacaine was given via a catheter and a continuous infusion with 0.25% levobupivacaine at rate 0.1 ml/kg/hr. Rescue treatment consisted of intravenous morphine and oral analgesic drugs. Numeric rating scale (NRS at rest, movement and cough), an amount of morphine consumption and complications related to analgesia were assessed at 2, 6, 12, 24, 48, 72, and 96 hours after operation. RESULTS: All patients completed the present study. The median numeric rating scale at rest in 24, 48, 72 and 96 hours after the operation was 2 (0-3), 0.5 (0-2),0 (0-2) and 0 (0-1) whereas the median numeric rating scale at deep breathing and coughing was 3.5 (2-5), 2 (2-4), 2 (1-3) and 2 (0-2). The median cumulative morphine consumption in 48 and 72 hours was 2 (0-4) and 3 (0-6) mg. Ten patients did not require additional morphine during the postoperative period. One patient experienced hypotension after a bolus of levobupivacaine for a few hours and recovered after supportive treatment. CONCLUSION: The use of continuous thoracic paravertebral blockade under direct vision technique offered satisfactory pain control and less complications. It could be considered as an alternative when thoracic epidural block is difficult to access. PMID- 22435250 TI - The usage of a hand-made chair at home for children with moderate to severe cerebral palsy: preliminary study. AB - BACKGROUND: Specially designed chairs are expensive. A hand-made chair easily constructed from recycled material can be an alternative option. However data on the feasibility of hand-made chair use at home is limited. The present study aimed to explore the usage of a hand-made chair at home in children with moderate to severe motor disabilities. MATERIAL AND METHOD: Seventeen children with cerebral palsy were recruited. Main caregivers were interviewed regarding the possibility of using the chair at home. Home visits and observations were also performed to explain how the chair had been used at home. RESULTS: Nine children (52.9%) used the chair everyday. Seven of these nine children were seated at least 30 minutes each time and two to three times per day. The total time that children spent on the hand-made chair each day ranged from 10 to 90 minutes. CONCLUSION: The severity of disability and main caregivers' workload may explain an inadequate usage of the hand-made chair. A few modifications may help to improve the applicability of the hand-made chair. PMID- 22435251 TI - Snake scope camera assisted endotracheal intubation: a procedural skills training in cadaver to prepare preclinical students for their clerkships. AB - OBJECTIVE: Preparing students to perform specific procedures on patients presents a challenge of student confidence in performing these tasks. This descriptive study determined the ability of the medical students to perform a basic clinical task after a short hands-on training workshop in cadavers. This basic procedural skills training was an attempt for developing conceptual understanding and increasing procedural skills in endotracheal intubation of the medical students. MATERIAL AND METHOD: The students were trained to perform two different endotracheal intubations, uncomplicated intubation, and a traumatic difficult airway scenario. The training session consisted of two methods of endotracheal intubation, oral intubations using direct laryngoscopy (DL) in two cadavers with uncomplicated airway and the Flexible Snake Scope camera (FSSC) assisted nasal intubation procedures in two cadavers simulated trauma victims with difficult airway. In the assessment session, the students performed one timed trial with each device. All four cadavers were changed but the scenarios were the same. The groups of the medical students were randomly assigned to perform the tasks in one of two cadavers of the two scenarios. RESULTS: Thirty-two medical students participated in this training and assessment. The training session and the assessment lasted five hours and three hours respectively. No student was asked to perform the second trial. The average time for successful intubation with DL was 32.7 seconds (SD, 13.8 seconds) and for FSSC was 127.0 seconds (SD, 32.6 seconds). The intubation failure rate was 0% for the entire study. CONCLUSION: The medical students have the ability to accomplish a basic clinical task after a short hands-on training workshop. PMID- 22435252 TI - Cost-effectiveness analysis of manual small incision cataract surgery (MSICS) and phacoemulsification (PE). AB - BACKGROUND: Cataract is the most common cause of blindness, responsible for 50 to 80% of all blindness in South-East Asia. Method of cataract surgery that has cost effective, low technology procedure and a low complication rate in the shortest amount of time is needed. This study provides the useful resources comparing clinical outcomes and cost of phacoemulsification (PE) and manual small incision cataract surgery (MSICS) based on hospital perspective. OBJECTIVE: To compare the costs and effectiveness of two-cataract-surgery methods, MSICS and PE, using the hospital's perspective. SETTING: Department of Ophthalmology, Phrapoklao hospital, Thailand. MATERIAL AND METHOD: This study was prospective and comparative. Data was collected from medical charts and through patient interviews using data collection forms. Labor material and capital cost were recorded for both surgical methods. The effectiveness was measured in visual acuity (VA), astigmatism and complications occurring at 90 days after surgery. RESULTS: The average total cost was 10,043.81 bath/case for MSICS and 11,590.72 bath/case for PE. After 90 days after surgery, the average VA of MSICS and PE groups were 0.83 +/- 0.225 (0.10-1.00) and 0.76 +/- 0.268 (0.06-1.00). There was no statistically significant difference in both groups. The average astigmatism at 90 days after surgery was 1.01 +/- 0.733 (0.00-3.50) D and 0.99 +/- 0.713 (0.00-4.25) D for MSICS and PE method. The average change in astigmatism was 0.15 and 0.20 D for the MSICS and PE groups. The intraoperative complication was vitreous loss (1.40%) in the PE group. The postoperative complication was corneal edema (5.60%) in the MSICS group. There was no statistically significant difference in the number of postoperative complications in both groups (p = 0.16). CONCLUSION: The effectiveness of MSICS and PE methods was not significantly different, but PE method had higher costs. Therefore, MSICS has better cost-effectiveness than PE thus, MSICS should be a preferred cataract surgery method to PE method, based on the hospital's perspective. PMID- 22435253 TI - CT appearances of post-radiation livers in patients with unresectable cholangiocarcinoma. AB - OBJECTIVE: To characterize the computed tomographic (CT) findings of post radiation livers and the interval changes in patients with unresectable cholangiocarcinoma. MATERIAL AND METHOD: Thirteen patients with unresectable cholangiocarcinoma who received concurrent chemoradiation with conformal radiotherapy technique (50 to 66 Gy, 2 Gy/fraction) were included in the present study. CT at pre-radiation and sequential follow-up at 1, 3, 6, 9 and 12 months were retrospectively reviewed by two abdominal radiologists to identify CT characteristics of post-radiation liver and the interval changes. RESULTS: CT at pre-radiation and sequential follow-up at 1, 3, 6, 9 and 12 months were available in 92.3%, 100%, 76.9%, 53.8%, 30.8% and 23.1%, respectively. Post-radiation livers showed sharply-delineated, hypodense radiation areas, which were well related with the isodose line of 35 to 56 Gy (mean = 44.4 +/- 6.55 Gy). These radiation areas were mostly appreciated on portal venous phase at 1-month follow up study in 12 of 13 (92.3%) patients and these were gradually less defined in subsequent studies. Progressive decrease size of radiation areas with persistent enhancement on delayed phase images were recognized. Progression of hepatic cortical irregularity was seen in four (30.8%) patients, as well as pulmonary fibrosis of lung bases. CONCLUSION: Post-radiation liver in patients with unresectable cholangiocarcinoma showed a sharply-defined, hypodense radiation area, which was mostly appreciated in 1-month follow-up CT and was gradually less defined in subsequent studies with evidence of progressive atrophic change. PMID- 22435254 TI - Skin toxicity and cosmesis after hypofractionated whole breast irradiation for early breast cancer. AB - OBJECTIVE: To assess and compare the impact on skin reactions and cosmesis between hypofractionated whole breast and conventional irradiation for early breast cancer. MATERIAL AND METHOD: Seventy-three patients with operable breast cancer (pT1-3pN0-1M0) who underwent breast-conserving surgery were assigned for irradiation to either conventional arm (50 Gy in 25 fractions) with a sequential electron boost of 15-16 Gy over five weeks or hypofractionated arm (43.2 Gy in 16 fractions) with a concomitant electron boost of 0.6 Gy over three weeks. RESULTS: At 3-week follow-up, skin toxicities in the hypofractionated arm were significantly worse than that seen in the conventional arm, while at 6-week follow-up, the percentages of skin toxicities in the conventional arm were higher After a median follow-up of six months, there was no significant difference in skin toxicities between the two treatment groups. In addition, there were no significant differences in the mean scores of cosmetic outcome for patients between two regimens. CONCLUSION: This hypofractionated radiotherapy regimen of 43.2 Gy in 16 fractions with a concomitant electron boost showed good results in terms of normal tissue effects and cosmesis. A long-term follow-up is needed to confirm these favorable results. PMID- 22435255 TI - Model development for substance abusing surveillance system in communities. AB - BACKGROUND: There is growing evidence that the number of substance abusers have increased. Use of public health surveillance system in substance abuse at the community level is limited. OBJECTIVE: Study and develop a suitable Model for Substance Abusing Surveillance System (MSASS) in communities. MATERIAL AND METHOD: Thirty-eight volunteers, including five direct responsible officers, five local leaders, five people representatives and four university specialists participated in the development of the model. The present study utilized ten sets of database, reported on a monthly basis. These included substance abuse arrested cases, substance abuse treatment seekers, anonymous notification of drug abuse, notification of obstacles and problems of the responsible organizations and notification of substance abuse by the local community leaders. The seven approaches of the model included situational analysis, prototype design, trial test, system design, system running test, model improvement and model dissemination. The study was conducted in 47 communities in four sub-districts in Phakdichumphon District, Chaiyaphum Province. RESULTS: The MSASS model application was created at the community level. The model assessed and monitored substance abuse practices of population aged 12 to 65 years and triggered prevention and control actions in communities. The five important constituents of the model were 1) organizations of substance abuse networks, 2) indicators of substance abuse situations, 3) criteria for investigation of magnitude of the problems, 4) data collection tools and 5) dissemination of information. The model comprised of six core activities (detection, registration, confirmation, reporting, analysis and feedback) and four support activities (communication through meeting and brainstorming, training, supervision and resource-provision). After one year the authors were able to develop indicators and criteria for measuring magnitude of the substance abuse problems. The current developed MSASS was effective in terms of representativeness (93.0%), sensitivity (92.7%), timeliness (84.7%), prediction ability (84.5%), acceptability (82.5%), simplicity (82.5%) and validity (80.3%). CONCLUSION: The developed MSASS is an effective form of public health surveillance suitable for communities at a district level. PMID- 22435256 TI - The effect of squad leader mentors through short message services for mobile phones in promoting safe sex among first (central) army area conscripts of Thailand. AB - BACKGROUND: Conscripts are a vulnerable population group for HIV infection. Their serostatus has been monitored in Thailand as part of the national sentinel surveillance since 1997. Given the nature of the military environment, an innovative program is needed to promote safe sex to reduce the rate of sexually transmitted infections (STIs) and HIV. OBJECTIVE: The present study proposed to evaluate the program of "Squad Leader Mentors through Short Message Services on Mobile Phones" in improving the required knowledge, attitudes, and the safe sex practice among conscript groups. MATERIAL AND METHOD: A quasi-experimental design was applied in separate areas. The subjects were recruited by multistage sampling techniques. One hundred forty eight conscripts from the Lop Buri Military District were randomly selected to be the study group, and 114 conscripts from the Sara Buri Military District were the control group. The study and control groups were matched for background characteristics. The changes in knowledge, attitudes, and safe sex practice were measured by pre- and post-test questionnaires over a six-month period. RESULTS: There were significant changes in overall scores of knowledge of safe sex and STIs. Benefits of using SMS and squad leaders that acted as mentors in the study groups (p-value < 0.001**) were observed. The safe sex practices in the study group showed significant increase in condom use with risky partners such as sex workers and other men (p-value < 0.001**). Therefore, it is believe that conscripts can be mentors in promoting safe sex (p-value = 0.006*). CONCLUSION: The presented program can genuinely increase knowledge and practice of safe sex among conscripts in the study group. PMID- 22435257 TI - The integration of the applied Thai traditional medicine into hospitals of the current health delivery system: the development of an administrative/management model. AB - OBJECTIVE: Develop a model of administration/management of district/general hospitals in the Ministry of Public Health of Thailand to enable the medical services of Applied Thai Traditional Medicine to be integrated into the current Modern Medical (Health) System. MATERIAL AND METHOD: A prospective study of the various services of Applied Thai Traditional Medicine in relation to the needs of other related services of the hospitals and the health needs of the population of Huay Ploo District Hospital of Nakhon Pathom Province. The collection of data of services covered 12 months to enable the comparisons of changes that occurred during the period. The study was both quantitative and quantitative measures. RESULTS: There is a statistical difference in all aspects compared of the opinions of personnel related to the services of Thai Traditional Medicine before and after the interventions in the areas of knowledge, attitude, beliefs, and the support of the services rendered by Thai Traditional Medicine. The present study showed that more system diseases was seen before than after the interventions whereas the most common incidence of diseases was in the musculo-skeletal system when compared to those found in other systems. After the interventions, the patients' preferences in the methods of treatment were mixed, with several methods of treatment preferred and with the tendency to resort to Thai Traditional Medicine more than before the interventions. This was believed to be the result of changes in the hospital i.e. personnel from all service units after answering the questionnaires and voiced opinions were found to require more relevant competencies and in need of support from their superiors. The personnel surveyed wished that the planning and policies'goals succeed with efficiency The Administrators outlined the plan and strategies to move forward. With cooperation to solve problems, should any occur and with mutual role and coordination of personnel and services, the way towards solving problems should be beneficial as all sides participated in the undertakings. CONCLUSION: The management/administration of Government district/general hospitals under the Ministry of Public Heath aiming for an integration of all services of Applied Thai Traditional Medicine into services of Modern Medicine in Government Hospitals at the mentioned level was feasible and this undertaking would comply with the National Health Policy and WHO Guidelines. The present research study proposed that the Hospital uses health care services as a 'principal core' and other related sectors acted as supporting/promoting/and facilitating the principal core towards the best practice in health/medical care. The researchers wished to label the development of this model as "Huay Ploo Model", which will be a landmark. In addition, the Ministry may want to pursue a similar model as the administrative structures of all hospitals under the Ministry, under the Thai civil service system. The researchers also proposed the set-up of a Centre for Training and Learning within the hospital. It was also suggested that the Hospital should hold regular academic meetings of various forms to strengthen the knowledge, skill, and overall capacity of its personnel. PMID- 22435258 TI - Interrater reliability of Thai version of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (T-SCID II). AB - OBJECTIVE: Explore the interrater reliability of Thai version of Structured Clinical Interview for DSM-IV Personality Disorders (T-SCID-II). MATERIAL AND METHOD: Fifty-four psychiatric patients were assessed by seven psychiatrists. Each patient was interviewed independently and separately by two psychiatrists using T-SCID-II, with the second interview held within one to six weeks of the first. RESULTS: The Kappa value between the first and second raters with regard to the diagnosis of each personality disorder ranged from 0.70 for Depressive Personality Disorder to 0.90 for Obsessive-compulsive Personality Disorder with a mean of 0.81 for all the personality disorders. The mean trait intraclass correlation coefficient score was 0.90 and the summed score was 0.83. The overall interrater reliability was shown to be good across all the studies. CONCLUSION: Overall, Thai version of Structured Clinical Interview for DSM-IV Personality Disorders (T-SCID-II) showed between good and excellent reliability. Limitation of the present study and its generalizability was discussed. PMID- 22435259 TI - Functional and manometric outcomes after a congenital pouch colon reconstruction: report of a case. AB - Congenital pouch colon is a form of anorectal malformation, rarely reported outside north India. Hallmarks of this malformation are a short colon containing a large distal pouch with a fistula connecting to the urinary system. Herein, the authors report the case of a Thai male neonate with a congenital pouch colon type II who was initially misdiagnosed as a common imperforate anus. As a result, urinary tract infection and metabolic acidosis developed after a colostomy. A definitive surgery consisting of a tabularized coloplasty and an abdominoperineal pull-through was performed at one month of age. After closure of the colostomy, the child experienced transient loose stool with perineal excoriation for about three months and then gradually improved. At three years of age, the patient had normal bowel movements and adequate sensation, and a contrast enema showed a normal sized neorectum. An anal endosonogram revealed good localization of the rectum. A rectal manometry showed spontaneous rectal contraction and a complete rectoanal inhibitory reflex. The present case provides evidence suggesting that preservation of the native pouch colon is not contraindicated in this type of congenital pouch colon syndrome. PMID- 22435260 TI - Intravenous bisphosphonate therapy for children who have a traumatic fracture neck of femur and osteonecrosis: a case report. AB - BACKGROUND: Prognosis of traumatic osteonecrosis of femoral head in children is poor for either conservative treatment or surgical intervention. Intravenous bisphosphonate is an expecting medication to reduce femoral head resorption and to prevent femoral head collapse after traumatic osteonecrosis. This mechanism will reduce development of osteoarthritis and disability in the future. OBJECTIVE: Report the result of the effectiveness of intravenous bisphosphonate in treatment of a child with traumatic fracture neck of femur and developed osteonecrosis. MATERIAL AND METHOD: A case report was done between May 2008 and June 2010. The patient developed traumatic osteonecrosis of the right femoral head after multiple screws fixation in treatment of femoral neck fracture. Intravenous bisphosphonate was given every other month for two years. RESULTS: A 13-year-old girl who had a motorcycle accident developed avascular necrosis after multiple screws fixation of femoral neck fracture. After an intravenous bisphosphonate was given every other month for two years, the last follow-up showed good prognosis. PMID- 22435261 TI - Upper extremity deep vein thrombosis related to fatal massive pulmonary embolism after spinal surgery. AB - Upper extremity deep vein thrombosis (UEDVT) is an increasingly important clinical entity with potential for considerable morbidity, especially pulmonary embolism (PE). Here, the authors report a fatal case of the massive PE after spinal surgery, along with the UEDVT of superior vena cava (SVC). PMID- 22435262 TI - Acquired hypoprothrombinemia inducing bleeding in a girl with transient antiphospholipid antibody: case report. AB - BACKGROUND: Congenital or acquired prothrombin deficiency is a rare condition. CASE REPORT: A 2-year-7-month old Thai girl presented with ecchymosis, bleeding at both thighs and right ear lobe after a self-limited viral infection. RESULTS: The investigations revealed prolonged APTT and PT, prothrombin level 6% and positive anticardiolipin antibody 26.2 IU/mL. The 1:1 mixture of her plasma and normal plasma could not normalize her APTT and PT. The inhibitor to prothrombin determined by Bethesda method was 0.62 BU. She was responsive to 20 ml/kg of FFP transfusion, followed by 10 ml/kg at an interval of 12 h for three days and daily 500 units of prothrombin complex concentrate administration for three days. At two-week follow-up, she had no bleeding symptom, coagulation tests were normal, prothrombin level was normalized at 94%, no inhibitor to prothrombin was detected, and anticardiolipin antibody became negative. The additional DNA analysis of her prothrombin gene revealed nine different polymorphisms for which seven had been found in patients with congenital prothrombin deficiency and two were novel (4096T-->C, 4097T-->C). These single nucleotide polymorphisms are not the disease-causing mutations. In addition, neither known mutations inducing congenital prothrombin deficiency were identified. CONCLUSION: The acquired hypoprothrombinemia was concluded as the cause of bleeding in this reported patient. It might be caused by the transient low titer of antiphospholipid antibody, which was responsive to replacement therapy of FFP and prothrombin complex concentrate. PMID- 22435263 TI - 18F-FDG avid in uterine leiomyoma: a case report. AB - The author presents a case of 18F-FDG avid in uterine leiomyoma. A 32-year old female had Hodgkin's lymphoma stage IVb (the primary lesions at bilateral supraclavicular right paratracheal, subcarina, intraabdominal, bilateral iliac lymph nodes with liver spleen and bone marrow involvement). She was sent for 18F FDG PET/CT scan for detection of active lymphoma after chemotherapy treatment. The positive finding was hypermetabolic well defined round shape-enhanced lesion at posterior fundus. The SUV max (maximum value of Standard uptake value) was 6.3 and 2.0 x 1.9 CM in size. This lesion on CT finding is compatible with uterine leiomyoma. There is no other area of abnormal activity in the other body parts in the scan finding. After the PET/CT study, the patient was in remission of disease with no treatment. The planning is for follow-up CT. The knowledge of normal variation or false positive finding of 18F-FDG PET scan in order to get the exact diagnosis can dramatically alter the clinical course or plan of treatment. PMID- 22435264 TI - Drug interaction between valproic acid and meropenem: a case report. AB - Valproic acid and meropenam is commonly co-administrated in neurosurgical patients. Meropenem potentially decreases the valproic acid level, which may cause perioperative seizure. There has been no previous report of drug interaction between valproic acid and meropenem in Thailand. The authors report a patient who faced uncontrolled seizure after co-administrated valproic acid and meropenem. The level of valproic acid was assessed in different times after the administration of meropenem. Rapid decrease of valproic level was detected. However due to the administration of other antiepileptic agents, seizure did not develop. It is important for the physicians to recognize drug interaction between valproic acid and meropenem. Avoiding co-administration of both agents, valproic acid level monitoring and additive of other antiepileptic agents seem to be the appropriate solution. PMID- 22435265 TI - The psychological disturbances of the child undergoing surgery--from admission till beyond discharge. PMID- 22435266 TI - Pulmonary vascular tone and the anesthesiologist. PMID- 22435267 TI - Preoperative anxiety in children risk factors and non-pharmacological management. AB - It is important for anesthesiologists to appreciate the impact of preoperative anxiety in children. Not only does it cause suffering in many children prior to their surgical experience, it has a negative impact on their postoperative recovery and possibly long afterwards. Because of these concerns, continued research is warranted to seek ways of minimizing their fears in the perioperative setting. In this review, we will examine the risk factors for preoperative anxiety, tools for quantifying children and parent's anxiety, and strategies that may play a part in decreasing preoperative anxiety. Variables, which influence preoperative anxiety in children, include their age, temperament, prior hospital experience and parent coping abilities. This review will also explore issues surrounding parental presence during a child's anesthesia induction and how understanding child development can enhance their cooperativeness during the preoperative period, especially during anesthesia induction. Non-pharmacological interventions as a means of decreasing pediatric anxiety will be explored. Finally recent trends and new directions will be touched upon. PMID- 22435268 TI - Premedication of the child undergoing surgery. PMID- 22435269 TI - Emergence agitation in children--a view. PMID- 22435270 TI - Postoperative maladaptive behavioral changes in children. AB - Induction of anesthesia can be a very stressful period for a child and his family and can be associated with increased risk of psychological disturbances. These disturbances are categorized as preoperative anxiety, emergence delirium and postoperative behavioral changes. Several tools have been developed to measure these psychological manifestations as well as the baseline personality traits of these patients. Postoperative negative behavioral changes, such as sleep and eating disorders, separation anxiety, temper tantrum, aggression toward authorities, may occur in up to 60% of all children undergoing general anesthesia. Several studies found a strong association between these postoperative behavioral changes, the distress of the child on induction and his individual personality characteristics, although a cause-effect relationship could not be determined. Understanding the risk factors for behavior changes helps us determine the best way for prevention and treatment of these changes in the perioperative period. PMID- 22435271 TI - Perioperative management of the child with behavioral disorders. AB - Behavioral disorders can be a normal part of development of a child, or secondary to extraordinary life stresses or associated with a child's inherent disorder. In those children, each hospital visit represents a major challenge for the child, his parents and the hospital staff. Hence, a coordinated approach with a clear plan should be made in advance to minimize child's perioperative stress and to deliver a high quality service. PMID- 22435272 TI - The pregnant patient with pulmonary artery hypertension--a review. PMID- 22435273 TI - Preeclampsia, a new perspective in 2011. PMID- 22435274 TI - Low back pain as perceived by the pain specialist. PMID- 22435275 TI - Mitochondrial disorders--a review of anesthetic considerations. PMID- 22435276 TI - Mucopolysaccharidoses: anesthetic considerations and clinical manifestations. AB - Mucopolysaccharidosis (MPS) is a group of genetic disorders that presents challenges during anesthetic care and in particular difficulty with airway management. Patients should be managed by experienced anesthesiologists at centers that are familiar with these types of conditions. Rarely encountered disease states have been identified as important topics in the continuing education of clinical anesthesiologists. This review will define MPS, describe the pathophysiology of MPS, describe how patients with this rare lysosomal storage disorders have dysfunction of tissues, cite the incidence of MPS, list the clinical manifestations and specific problems associated with the administration of anesthesia to patients with MPS, present treatment options for patients with MPS, define appropriate preoperative evaluation and perioperative management of these patients, including, to anticipate potential postoperative airway problems. PMID- 22435277 TI - Contemporary anesthesia management for liver transplantation: a comparison of American and European methods. AB - This review article compares the organization of liver transplantation programs, anesthesia management and postoperative care in the United States and Europe. Liver transplantation is a definitive treatment for end-stage liver disease. The procedure is extremely complex and requires excellent surgical technique and experienced anesthesiologists who are able to provide precise management. Liver transplantation programs, which first started in the United States and a few years later in Europe, have quickly been able to achieve remarkable results. In the United States one organization, the United Network for Organ Sharing (UNOS) is responsible for the allocation of organs and data collection; in Europe there are various organizations with different levels of cooperation. The major difference between anesthesia management in the United States and Europe is the number of medications available for coagulation improvement. Substances such as prothrombin complex concentrate, fibrinogen, and antithrombin III allow for a greater flexibility in European anesthesia management. Thromboelastography, which is routinely used in the United States for overseeing coagulation, is now increasingly being used in Europe, and seems to be highly effective in providing precise information about coagulation. The overall ICU stay in Europe is longer than in the United States, and services such as maintenance of critical care, immunosuppression and nutrition are not separated in Europe. Despite these differences in liver transplantation programs, overall one-year patient survival rate is similar in the United States and in Europe, exceeding 85% in both. PMID- 22435278 TI - Induced hypocapnia is effective in treating pulmonary hypertension following mitral valve replacement. AB - BACKGROUND: Mitral valve stenosis is often associated with increased pulmonary vascular resistance resulting in pulmonary hypertension, which may lead to or exacerbate right heart dysfunction. Hypocapnia is a known pulmonary vasodilator. The purpose of this study was to evaluate whether induced hypocapnia is an effective treatment for pulmonary hypertension following elective mitral valve replacement in adults. METHODS: In a prospective, crossover controlled trial, 8 adult patients with mitral stenosis were studied in the intensive care unit following elective mitral valve replacement. Hypocapnia was induced by removal of previously added dead space. Normocapnic (baseline), hypocapnic and recovery hemodynamic parameters including cardiac output, pulmonary vascular resistance, pulmonary artery pressure and systemic oxygen delivery and consumption were recorded. RESULTS: Moderate hypocapnia (an end-tidal carbon dioxide concentration reduced to 28 +/- 5 mmHg) resulted in decreases in pulmonary vascular resistance and mean pulmonary artery pressure of 33% and 25%, respectively. Hypocapnia had no other hemodynamic or respiratory effects. The changes in pulmonary vascular resistance and mean pulmonary artery pressure were reversible. CONCLUSION: Moderate hypocapnia was effective in decreasing pulmonary vascular tone in adults following mitral valve replacement. The application of this maneuver in the immediate postoperative period may provide a bridge until pulmonary vascular tone begins to normalize following surgery. PMID- 22435279 TI - Clevidipine for controlled hypotension during spinal surgery in adolescents. AB - INTRODUCTION: Clevidipine is an ultra-shorting acting, intravenous calcium channel antagonist of the dihydropyridine class. Metabolism by blood and tissue esterases results in a half-life of 1-2 minutes thereby allowing easy titration by i.v. administration. We present preliminary experience with this novel agent to provide controlled hypotension (CH) in a cohort of adolescents undergoing posterior spinal fusion. METHODS: The records of patients < or = 18 years of age who received clevidipine for CH were retrospectively reviewed. Demographic data included age, weight, gender, and co-morbid disease processes. Information regarding clevidipine included the initial infusion rate, time to achieve the target mean arterial pressure (MAP), the maintenance infusion rate, the average infusion rate, and the duration of administration. Hemodynamic information included the starting MAP and heart rate (HR) as well as the MAP and HR during the clevidipine infusion. Adverse effects related to clevidipine included excessive hypotension (need to discontinue the infusion or the need for a fluid bolus or administration of a vasopresor), tachycardia (20% increase in HR or the administration of a beta-adrenergic antagonist) and elevated serum triglyceride level. RESULTS: The study cohort included 20 patients, ranging in age from 14 to 18 years and in weight from 46 to 96 kgs. To provide acceptable conditions for evoked potential monitoring, a total i.v. anesthetic technique was used. Propofol was started at 100 microg/kg/min and titrated to maintain the bispectral index at 40-60. Remifentanil was started at 0.1 microg/kg/min and increased up to 0.3 microg/kg/min as needed to control MAP. If the MAP was > or = 65 mmHg, clevidipine was added to maintain the MAP at 50-65. The clevidipine infusion was started at 0.5-1 microg/kg/min and increased in increments of 0.5-1 microg/kg/min every 2-3 minutes to achieve the desired MAP. The target MAP was achieved within 5 minutes in 15 of the 20 patients and within 10 minutes in the other 5 patients. The maintenance infusion rate of clevidipine varied from 1-5 microg/kg/min (2.9 +/- 0.7 microg/kg/min). With the administration of clevidipine, HR increased from a baseline of 76 +/- 14 to 92 +/- 11 beats/minute (p < 0.05). The HR increase was > or = 20 beats/minute in 4 patients. Intermittent doses of metoprolol were used in 3 patients to control the HR increase. No excessive hypotension was noted. A triglyceride level was drawn in 6 patients who received clevidipine with propofol and was elevated in 3 patients (> or = 150 mg/dL, high level 328 mg/dL). When the clevidipine infusion was discontinued, MAP returned to baseline within 5 minutes in 16 of the 20 patients and within 10 minutes in the other 4 patients. DISCUSSION: Clevidipine effectively controlled MAP and provided CH. Mild tachycardia was noted in some patients with the occasional need for a beta adrenergic antagonist. No episodes of excessive hypotension were noted. Given its short half-life, clevidipine can be rapidly titrated to provide CH when changing levels of sympathetic stimulation may occur. Should inadvertent hypotension occur, its short duration of action offers an additional advantage over several other i.v. antihypertensive agents. PMID- 22435280 TI - Effect of propofol titration v/s bolus during induction of anesthesia on hemodynamics and bispectral index. AB - BACKGROUND: Propofol when given as 2 mg/kg IV bolus for induction of anesthesia is known to cause hypotension requiring vasopressors. The objective of our study was to compare Propofol 2 mg/kg single IV bolus (Precalculated group, PG) with the titration of Propofol (Titration group, TG) to clinical parameters as 10 mg IV increments every 3 seconds on hemodynamic Parameters and Bispectral Index (BIS), during induction. The effect of titration on dose requirement for induction was also evaluated. METHODS: Effects on Hemodynamic parameters [Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP)], and vasopressors use were recorded at baseline and every 2 minute intervals for 10 minutes. The percent difference in HR, SBP, DBP, and MAP from baseline at 2, 4, 6, 8 and 10 minutes were calculated, to determine the effect on hemodynamic parameters. BIS was recorded at baseline, after injection of Propofol, at intubation and at 10 minutes. Dose requirement of Propofol in TG was also recorded. RESULTS: At 2 and 4 minutes, SBP decreased in PG by 21% and 18% vs. 11% and 9% in TG (p = .00 & .02); DBP decreased by 17% and 15% in PG vs. 5% and 4% in TG (p = .02 & .03); MAP decreased by 19% and 17% in PG vs. 5% and 4% in TG (p = .00 & .01). Vasopressors were required in 14/43 patients in PG vs. 5/41 in TG (p = .03). Titration resulted in 30% reduction in dose. CONCLUSION: Titration of Propofol reduces hemodynamic changes, dose requirement and is able to achieve same level of BIS as in bolus. PMID- 22435281 TI - Ultrasound confirmation of laryngeal mask airway placement correlates with fiberoptic laryngoscope findings. AB - BACKGROUND: Correct placement of a laryngeal mask airway (LMA) requires confirmation to appreciate the adequacy of laryngeal seal and pulmonary ventilation. OBJECTIVES: The present study was designed to assess the feasibility of ultrasound use for confirmation of correct placement of LMA and its correlation with fiberoptic laryngoscopy as a confirmation tool for LMA position. MATERIALS AND METHODS: 31 ASA I and II patients scheduled for same day surgery under general anesthesia underwent standard general anesthetic technique with AuraOnce or AuraFlex Disposable Laryngeal Mask Airways. The position of the LMA cuff was confirmed by transverse neck ultrasound (USG), and reconfirmed with intra-LMA fiberoptic laryngoscopy (FOL). RESULTS: The ultrasound grade of LMA position strongly correlated positively with the fiberoptic grade of LMA position (r = 0.92; p < 0.0001). This correlation was obtained immediately after LMA placement, as well as just before LMA removal. The Bland-Altman scatter plot showed insignificant differences between the two grading systems with small and good limits of agreement (-0.63 to +0.57). CONCLUSION: Ultrasound examination can replace fiberoptic examination for confirmation of the correct placement of an LMA. Additionally, non-invasive ultrasound examination can further give insight into the cause of airway/ventilation events that may be interfering with the LMA placement and ventilation. PMID- 22435282 TI - Anesthetic management of a morbidly obese parturient undergoing cesarean section. PMID- 22435283 TI - The administration of general anesthesia to a patient with croup. AB - Croup in a young child may lead to severe airway narrowing, and would present a severe risk for administration of anesthesia. To the best of our knowledge, there have been no previous case reports of patients undergoing general anesthesia with croup. In our report, we describe a case of a 31 month old child with croup who required anesthesia. PMID- 22435284 TI - Intraoperative coronary artery vasospasm: a twist in the tale! AB - The cause of variant angina is localized hyperresponsiveness of the vascular smooth muscle cells caused by non-specific stimuli of vasoconstriction. Autonomic imbalance can be one of the mechanisms of spontaneous vasospasm, and sympathetic or parasympathetic stimulation can induce Coronary Artery Spasm (CAS). Although various reports of CAS events have been described, episodes associated with untwisting or manipulation of a visceral structure remains unique. We report one such case of CAS in association with intraoperative untwisting of a torted ovarian cyst treated with intracoronary nitroglycerine in the catheterization laboratory. Vasospastic or variant angina is a well known clinical condition first described by prinzmetal and colleagues, characterized by CAS in normal and diseased coronary arteries. General anesthesia can be a triggering event. This case demonstrates unique etiology in that spasm was provoked by surgical manipulation of a torted ovarian cyst. CAS has been implicated as a cause of sudden, unexpected circulatory collapse and death during surgery, cardiopulmonary bypass, and other non-cardiac surgical procedures. There are few reports of coronary vasospasm during regional anesthesia and neuroaxial block. Many factors are involved in the occurrences of perioperative CAS including activated sympathetic activity, activated parasympathetic activity, cocaine, alkalosis, hypercalcemia, magnesium deficiency, succinylcholine, vasopressors, essential hypertension, Hyperthyroidism, epidural anesthesia, spinal anesthesia, smoking, lipid metabolic disorder, coronary artery aneurysm, commercial weight loss products. We describe a rare case of CAS during general anesthesia, in a patient with no past history of coronary artery disease, possibly provoked by surgical manipulation ofa torted ovarian cyst, which was diagnosed and treated promptly via cardiac catheterization. Intraoperative coronary artery vasospasm: a twist in the tale! PMID- 22435285 TI - Deceptive level after intrathecal block for cesarean section in a patient with prior abdominoplasty--a case report. AB - Abdominoplasty is performed in an increasing number of patients, both male and female. The removal and hence rearrangement of abdominal skin may make assessment of the dermatome level of a subarachnoid block difficult. Also patients may hesitate, or even forget, to reveal cosmetic surgeries during the preanesthetic interview. Therefore it is important to maintain a high index of suspicion in patients who have had bariatric surgery. In this report we present the case of a deceptive anesthetic level in a parturient with an undisclosed history of abdominoplasty who presented for Cesarean section. PMID- 22435286 TI - Anesthetic management of children with Rubinstein-Taybi syndrome--case reports. AB - A limited number of cases of anesthetic management of Rubinstein-Taybi Syndrome (RTS) have been reported since this syndrome was first diagnosed in 1963. After some well-publicized complications following anesthesia for patients with RTS, there has been great interest in avoiding all precipitant factors and careful monitoring during intraoperative and postoperative periods. This case series examines the cases of three pediatric patients with RTS who presented to the Children's Hospital of Michigan for different surgeries. We aim in this study to share information about this rare syndrome and to emphasize how this case series allowed us to improve our anesthetic management. In each case, we adjusted our techniques using information from preceding cases to avoid complications in the following encounter. PMID- 22435287 TI - Broken piece of LMA-ProSeal introducer: an unusual cause of airway obstruction. PMID- 22435288 TI - [Biochemical mechanisms of neurotoxicity caused by cadmium]. AB - Cadmium (Cd), which belongs to the heavy metals, is one of the major polluting component of human and animal environment. Exposure to cadmium can lead to absorption of the compounds to the organism and consequently, the toxic effects in the nervous system. The paper presents various views on the biochemical mechanisms of neurotoxicity caused by cadmium. This paper describes the disturbances in the cellular antioxidant system, generation of reactive oxygen and nitrogen species, changes in energy production in the metabolic pathways, changes in the metabolism of biogenic amines, neurotransmitter amino acids and calcium ions and inhibition of enzymatic proteins. PMID- 22435289 TI - [Analysis of notifications on exceeding of the acceptable level of histamine according to the RASFF reports]. AB - The histamine is biogenic amine produced in considerable amounts in fish and fish products contaminated with bacteria. Histamine content in fish should not exceed 200 mg/kg, higher levels can cause poisoning and the concentrations above 1000 mg/kg are toxic and may be dangerous for man. The Rapid Alert System for Food and Feed (RASFF) notifies the exceedances of the permissible level of histamine. In the years 2003-2009 there have been 272 notifications, including 72 alarm and 178 information. High histamine content in tuna exceeding the permissible level up to more than 40-fold (8299 mg/kg), in coryfena (mahi-mahi), more than 17-fold (3490 mg/kg), sardines 9-fold (1820 mg/kg), anchovii (anchovies) and 8-fold (1630 mg/kg) and fish sauce over a 7-fold (1467 mg/kg) was observed. PMID- 22435290 TI - [Studies on primary aromatic amines (PAAs) migration from multi-layer plastic food packaging by HPLC method]. AB - The aim of this study was to identify of primary aromatic amines (PAAs) and to determine their migration from plastic food packaging. The magnitude of the migration of these substances from plastic food packaging consists a base for the evaluation of their compliance with the requirements of EU legislation and hazard for human health taking into account their migration into food. The unprinted and printed multi-layer plastic packaging (laminates), domestic and imported, were examined in these studies. PAAs migration tests from the laminates into food simulant (3% acetic acid) was performed according to the appropriate procedures recommended in the EU for testing migration from food contact articles under standard conditions reflecting the real use of laminates (10 days, 40 degrees C) and under ,, worst case scenario" conditions (2 h, 70 degrees C). PAAs present in migration solutions were concentrated on SPE columns and then seven PAAs (aniline, 1,3-phenylenediamine, 2, 6-toluenediamine, 2,4-toluenediamine, 4,4' oxydianiline, 4,4'-methylenedianiline and 3,3 '-dimethylbenzidyne) were identified and determined by previously validated HPLC-DAD method. Depending on the migration conditions the PAAs content was different. When the "worst case scenario" conditions were applied the migration of 4,4 '-methylenedianiline (4,4 '-MDA) ranged from below detection limit (LOD = 0.51 microg/kg) up to 9.86 microg/kg, and aniline was released in the range from below detection limit (LOD = 0,98 microg/kg) up to 7.04 microg/kg. In two laminate samples of eight examined, the sum of PAAs (aniline and 4,4'-MDA) was 13.32 microg/kg and 14.72 microg/kg showing that the permitted limit (10 microg/kg) was exceeded. In the standard conditions, the migration of aniline and 4,4'-MDA was significantly lower Regarding the carcinogenic potential of PAAs, the laminates causing the amines migration above the permitted limit should not be used as food packaging. PMID- 22435291 TI - [Studies and safety evaluation of aflatoxins in herbal plants]. AB - Herbs and herbal products are commonly used in food and pharmaceutical industries. The aim of this study was to test herbal plants for contamination with aflatoxins (AF), genotoxic, cancerogenic and hepatotoxic compounds which can cause immunotoxic and allergic effects as well as growth disorders. Aflatoxins were determined by high performance liquid chromatography (HPLC) with post column derivatization involving bromination with pyridinium hydrobromide perbromide (PBPB). Extracts was cleaned-up by immunoaffinity columns (IAC). The contents of aflatoxins B, B, G, and G, in more than 500 herbal plants samples mainly from Eastern Poland were investigated. Samples were supplied by manufacturers (herbal facilities) in 2006-2010 years. In all the evaluated samples the levels of aflatoxins above the detection limits of methods applied were not observed: for AF B1--0.2 microg/kg; AF B2--0.03 microg/kg; AF G1--0.3 microg/kg; AF G2--0.03 microg/kg (PN-EN 14123) and for AF B1--0.15 microg/kg (Ph. Eur.6, 2008:2.8.18). All the herbal plants tested for contamination with aflatoxins should be considered safe, which indicates that manufacturers used good manufacturing practices during drying and storage of raw materials. PMID- 22435292 TI - [The content of phenolic compounds and antioxidant activity ready to eat desserts for infants]. AB - The aim of this study was to determine the content of phenolic compounds and antioxidant activity in ready-to-eat desserts for babies. The experimental material consisted of six kinds of fruit desserts taken from the market in 2008, in which the content of dry matter phenolic compounds and antioxidant activity levels on the basis of free radical quenching ability ABTS were determined. The largest share of dry matter was found in apricot mousse with apples and bananas (16.9%). The largest amounts of phenolic compounds were found in the cream with apple and wild rose (186.3 mg/100 g) and apple with forest fruits (170.7 mg/100 g). The highest antioxidant activity among the desserts was determined in cream with apple and wild rose (14.2 micromol Trolox/g) and apple mousse with peaches (12.8 micromol Trolox/g). The antioxidant capacity of the remaining examined puree was slightly lower and ranged from 11.4-11.7 micromol Trolox/g. PMID- 22435293 TI - [Dietary intake of n-3 polyunsaturated fatty acids in healthy adults in relation to current recommended intake]. AB - The health benefits of n-3 PUFA and especially long-chain n-3 PUFA are well recognized and recommendation of their dietary intake for general population are elaborated However, there is still a need for assessment of LCn-3 PUFA intake in different population groups. The aim of this study was to assess intake of n-3 PUFA, particularly long-chain n-3PUFA (LCn-3 PUFA) and to identify their major sources in diets of healthy subjects. The studied group consisted of 182 adults, both men and women. Assessment of n-3 PUFA dietary intake was based on individual 3-day records. Data were analyzed using updated polish food composition tables and "Dieta 2" and "Dieta 4" Software. It was found, that more than 40% of studied subjects consumed daily less than 1 g ALA, about 50%--less than 100 mg LCn-3 PUFA and about 60% less than 10 mg DHA. PMID- 22435294 TI - [Evaluation of antioxidant vitamins intake by students of Warsaw University of Life Science]. AB - The aim of this study was the assessment of antioxidant vitamins intake among students of the Faculty of Human Nutrition and Consumer Sciences of Warsaw University of Life Science. The investigation was done among 145 students at the age 21-28 in the 2008 year. Data about food intake were collected using a 3-day dietary records method. On this basis intake of vitamin A, beta-carotene, vitamin E and C was calculated The results shows that the quantity of antioxidant vitamins was adequate for vitamin C (64 mg/d, 102% EAR), but for vitamin A and E was higher then recommended value (698 microg retinol equivalent/d, 135% EAR and 11,5 mg tocopherol equivalent/d, 138% of AI). About 12-15% students used supplements, providing additional 574 microg vitamin A, 116 mg vitamin C and 4 mg vitamin E. It covered together with food intakes 260%, 298% EAR value and 199% of AI value, in case of vitamin E. In smokers, for which recommendations of intake antioxidant vitamins are slightly different, it was found too low their intake. PMID- 22435295 TI - [Evaluation of Poznan kayakers' nutritional knowledge on rich sources of vitamins and minerals]. AB - The aim of this work was to evaluate the nutritional knowledge of Poznan kayakers and canoers on rich sources of vitamins and minerals. A questionnare on the knowledge about rich sources of vitamins and minerals were filled in by a group of 108 Poznan canoers and kayakers of both gender The statistical analysis of the results was conducted with the use of the computer program SPSS 11,5. for Windows. The population was divided according to gender. The sportsmen questioned differed in a statistically significant way in regard to their sports class, type of boat (kayak or canoe) and the distance on which they usually swam during competitions. Gender had statistically significant influence on the answers to two questions, namely whether fruits are a rich source of B vitamins and if poultry is a rich source of iron. The male kayakers and canoers answered both of the questions better than the female kayakers. The nutritional knowledge of Poznan kayakers and canoers on rich sources of vitamins and minerals should be described as extensive, but not systematic enough. PMID- 22435296 TI - [Assessment of frequency of consumption of selected sources of dietary fibre by students]. AB - The study deals with the evaluation of the frequency of food products consumption that are a source of dietary fiber in the diet of students. Survey was conducted in May 2010 among 96 second-year students of 'Food Processing Technology and Human Nutrition' at the University of Rzeszow. The Block's questionnaire was used to assess the frequency of consumption of selected sources of dietary fiber. In order to determine the frequency of consumption of fruits, fruit juices, salads, potatoes, legumes, white bread, dark bread and other cereal products the 5-degree scale with verbal terms (less than once per week--0 points, roughly once a week- 1 point, 2-3 times per week - 2 points, 4-6 times per week--3 points, every day- 4 points) was used. It was found that none of the examined persons, both women and men, had a sufficient consumption of fiber in the diet. The main source of dietary fiber in the diet of the examined students were white and dark bread and potatoes. A small percentage of the examined persons consume fruits and vegetables in their daily diet. PMID- 22435297 TI - Evaluation for magnesium and vitamin B6 supplementation among Polish elite athletes. AB - Contemporary sport requires a lot of effort from sportsmen, frequently exceeding their maximum physical and mental efficiency. Athletes often report poor dietary habits and reach for magnesium and vitamin B supplements to avoid dietary deficiencies. The aim of this study was to determine magnesium and vitamin B6 content in daily food rations of Polish athletes and to verify the justification of diet supplementation. Magnesium and vitamin B6 concentrations were determined in 62 collected and 12 reconstructed daily food rations of elite Polish runners. Flame atomic absorption spectrometry and HPLC methods were used for quantification of magnesium and vitamin B6, respectively. The analyzed female diets provided daily 256 +/- 111 mg of magnesium and 2.04 +/- 0.63 mg of vitamin B6 whereas male diets provided 284 +/- 58 mg of magnesium and 2.12 +/- 0.68 mg of vitamin B6. Computer analysis calculated 159-181% higher content o magnesium and vitamin B6 comparing to determined laboratory values. The results of this study indicate that in the analyzed daily food rations of athletes low magnesium intake was observed, thus diet supplementation with this mineral may be justified. Daily food rations fulfilled RDA for vitamin B6, thus supplementation with this vitamin was not justified. PMID- 22435298 TI - [Nutritional value of daily food rations in 10 year old children with different body weight]. AB - The study objective was to assess the number and type of the daily consumed meals and to make a comparison between energetic and nutritional value in the meals consumed by children with normal and excessive body weight. A study was conducted in a group of 280 children aged 10 years (141 girls and 139 boys) in Bialystok. A 24 h dietary recall was taken of the day preceding the examination in order to perform a quantitative evaluation of daily food rations. Taking into consideration the particular meals, the energetic value and the content of basic dietary nutrients. Also cholesterol and fiber were evaluated, using the computer program Diet 2.0 developed in the Institute of Food and Nutrition in Warsaw. In the tested groups, a four-meal model predominated and the afternoon snack was most frequently missed. As many as 95% of children with normal body weight and 100% of children with excessive body weight admitted irregular eating between meals. The proportion in energy delivery from the respective meals was disturbed and nutritional abnormalities were found especially in the overweighted and obese children. PMID- 22435299 TI - [Depression, overweight and perceived body image among adolescents living in suburban areas]. AB - The aim of the article is to explore the association between depression and overweight among adolescents living in suburban areas and to verify to what extend the acceptance of body image may be a mediating factor. The study was conducted on the sample of 322 students (girls--51.2%, boys--48.8%) aged 16 - 19 years attending two senior high schools in Radzymin. Overweight was measured by Body Mass Index (BMI) and according to WHO recommendations the following categories were established: BMI < 20--underweight, 20 < BMI < 25--normal weight, BMI > 25--overweight or obese. A question about the acceptance of body image contained four possible answers: I'm okay/I do not weight properly, but I accept myself/I do not accept myself, I'm too thin/I do not accept myself, I'm to thick. Beck Depression Inventory (BDI) was used for measure the level of depression. Unexpectedly, our investigations found association between depression and overweight only for boys. In turn, the girls, as expected, lower accepted their body image than boys. Moreover a considerable percents of girls whose weight was normal, and even those with underweight, perceived themselves as thick. The association between acceptance of body image and depression was confirmed only for girls. Our study suggests that the lack of acceptance of body image, especially by girls, to greater extend causes the appearance of depression than real overweight. PMID- 22435300 TI - [Assessment of sociodemographic and nutritional status of lung cancer patients]. AB - Low sociodemographic status positively correlates with the risk of lung cancer. Nutritional status assessed during diagnosis of cancer may be a useful predictive factor for response to therapy and influences the quality of life and life expectancy after oncological therapy. The aim of this study was to assess the sociodemographic and nutritional status of patients. Lower Silesian Centre of Lung Diseases, diagnosed with lung cancer. 81 cases and 125 subjects formed the control group were included in this study. The questionnaire about sociodemographic status was performed among all respondents as well as MNA questionnaire and anthropometric measurements for evaluating nutritional status. Lower level of education, lower employment status and more frequent tobacco addiction was found in patient group then in control individuals. Nutritional status of patients was worse than the control group, which has been demonstrated mainly through a MNA questionnaire and arm circumference measurements. The risk of malnutrition or diagnosed malnutrition found in most patients assessed by MNA test may increase the likelihood of complications during treatment. PMID- 22435301 TI - [The influence of bisphenol A and of combined exposure to X-rays and bisphenol A to somatic cells of the bone marrow and liver of mice]. AB - The aim of study was to estimate the effects of bisphenol A (BPA) and combined exposure to X-rays and BPA to somatic cells of the bone marrow and liver of mice. Male mice Pzh: Sfis were irradiated with 0.05 Gy or treated with BPA (5 mg/kg mc, 10 mg/kg mc, 20 mg/kg mc) or exposed to a combination of both (0.05 Gy + 5 mg/kg BPA) for 8 weeks. Samples were taken at 24h, 1, 4 and 8 weeks after the end of exposure. Our study showed, that BPA can induce, measured by Comet assay, DNA damage in limphocytes of the bone marrow. The induction of DNA damage in somatic cells of the liver was not detected. After combined exposure to both agents a greater migration of DNA in cells of both organs than after the exposure to bisphenol A alone was observed. Probably the X-rays intensify the genotoxicity of BPA. PMID- 22435302 TI - [Preferences of the powdered spices choice to the meal by professionally working persons in relation to the innovative changes in their manufacturing]. AB - The objective of this study was to evaluate preferences and frequency choice of commercially available powdered spices, applied to the dishes prepared at home by professionally working persons as well as factors which determine the acceptance of innovative changes in relation to the number and type of components used for their manufacturing. It was shown that above 80% mixtures of spices contained except vegetable spices also other flavourings, spice-products and functional additives but mostly monosodium glutamate (MSG) and sodium chloride. The respondents mostly accepted multicomponent powdered spices, manufactured with the application of new technologies which permitted creation original tastes and next their health-promoting role as well as convenience in use however, without changes in recipe. The women declared that to the dishes prepared at home usually applied herb spices. Conversely, the men mostly liked and often chose spices with savoury and distinctive taste and most willingly multicomponent ones which were suitable for flavour improvement of many dishes. PMID- 22435303 TI - [The influence of thermal and chemical processes on the content and structure of humic acids--the basic ingredient of peat preparations]. AB - Water extracts with supplement NaOH, Na2CO3 and NaCl obtained in different temperatures from peat of low type were examined. These extracts are the basic ingredient of peat preparation applicable in cosmetics and therapeutics (pastes, gels, emulsions, oinments, tonics, creams. The continuous absorption spectra of humid compounds in the UV-VIS and LR range in the extracts were developed. In the differential 4th degree absorption spectra in the range UV-VIS the typical wavelengths were compared with separated absorption peaks of examined and standard humic acids. The quantitative proportions among acids in these extracts were determined. Also absorptions bands corresponding to characteristic functional groups and chemical bonds were determined. On the basis of the analysis of UV-VIS and IR absorption spectra the influence of temperature and non organic compounds supplementation on the structure (the bonds types, functional groups, molecular helicity inversion) and the content of humic compounds in water extracts was evaluated. PMID- 22435304 TI - Dissemination of knowledge and information: rethinking the model. PMID- 22435305 TI - Health and immigration. PMID- 22435306 TI - Nursing research with refugee claimants: promoting the protection of human rights. PMID- 22435307 TI - Immigrant and refugee social networks: determinants and consequences of social support among women newcomers to Canada. AB - Recent immigrants and refugees (newcomers) vary on many dimensions but do share similar challenges. Newcomers must rebuild social networks to obtain needed social support but often face social exclusion because of their race, language, religion, or immigrant status. In addition, most have limited access to personal, social, and community resources. Effects of situational and personal variables on the benefits and limitations associated with the social networks of female newcomers were explored through interviews and focus groups with 87 women from 7 communities. Using thematic analysis, the authors identify 5 sources of informal support across all 7 communities, which were almost exclusively limited to co ethnic relationships, and the types of support, limitations, and reciprocity within each. Perceived support was strongest from family and close friends and, when support from close relationships was unavailable, from primary care providers. The results suggest that co-ethnic peer support networks may be overwhelmed in newcomer communities because of their limited size and resources. PMID- 22435308 TI - Social support for breast cancer management among Portuguese-speaking immigrant women. AB - Breast cancer is one of the most commonly diagnosed types of cancer among women in Canada. Much health sciences research has examined this topic. The importance of formal and informal social support in managing breast cancer has received particular attention, but research with immigrant women has been limited. This article presents the findings of an applied ethnographic study conducted in Toronto, Canada, with 12 Portuguese-speaking women from Brazil, Portugal, and Angola about their need for, access to, and use of social support in the management of breast cancer. The key findings pertain to cancer-related fears and stigma that restrict access to and use of informal social support, barriers to obtaining formal social support, and women's resilience in the context of limited informal and formal social support. Implications for healthcare providers are presented at micro, meso, and macro levels. PMID- 22435309 TI - The health of women temporary agricultural workers in Canada: a critical review of the literature. AB - Among high-income countries such as Canada, there is growing dependency on "low skilled" temporary foreign workers in a variety of sectors. The purpose of this review is to critically synthesize and analyze the theoretical and empirical literature on gendered and temporary migration in the context of globalization and the health of temporary agricultural workers, particularly women in Canadian programs. While the social sciences literature contains well-developed conceptualizations of gendered migration, the research has focused on women in feminized occupations such as domestic work. Multidisciplinary searches produced only 11 research and review publications on the gendered constraints or health of temporary agricultural workers in Canada. Further investigation is needed to explore and integrate the strengths, resiliencies, and health-care needs of women migrant agricultural workers in Canada, as well as the barriers they face, within the intersecting and gendered forces of inequities at all levels: local, national, and global. PMID- 22435310 TI - Population health intervention research in Canada: catalyzing research through funding. PMID- 22435311 TI - The birthing experiences of rural Aboriginal women in context: implications for nursing. AB - It has been established that the birthing experiences and outcomes of rural women are shaped by poverty, isolation, limited economic opportunities, and diminishing maternity services. We lack research into how these dynamics are compounded by intersecting forms of oppression faced by Aboriginal women, to impact on their birthing experiences and outcomes. The findings of this study of rural Aboriginal maternity care in 4 communities in British Columbia show how diminishing local birthing choices and women's struggles to exert power, choice, and control are influenced by centuries of colonization. The research questions focus on rural Aboriginal women's experiences of birthing and maternity care in this neocolonial context and their desire for supportive birthing environments. A community-based participatory and ethnographic design was employed. Individual interviews, focus groups, and participant observation were the primary data sources. Although the women's experiences in each community were shaped by distinct histories and traditions, economics, politics, and geographies, the impacts of colonization and medical paternalism and the struggle for control of women's bodies during birth intersect, placing additional stress on women. The implications for nurses of accounting for the intersecting dynamics that shape Aboriginal women's experiences and birth outcomes are discussed. PMID- 22435312 TI - Arkansas payment improvement...improving! PMID- 22435313 TI - Hopkins' rules. PMID- 22435314 TI - Legally speaking: Social media and on-line conduct policies for medical practices. PMID- 22435315 TI - Social tool or trap? Social media offers physicians a mixed bag of delights and dangers. PMID- 22435316 TI - Cricoid chondronecrosis: a complication of endotracheal intubation. AB - Stenosis of the subglottic area is a common complication of endotracheal intubation and external blunt trauma. Chondronecrosis of the cricoid cartilage is a rare but known complication of neck radiotherapy for laryngeal carcinoma. It has also been reported as a complication of prolonged endotracheal intubation. The clinical and bronchoscopic findings are non-specific and the diagnosis can not be accurately established without surgical evidence or computed tomographic (CT) findings. In addition to technical issues related intubation, multiple anatomic and host factors can contribute to the pathogenesis of this uncommon entity. In this report, we describe the clinical and radiographic findings of a recent case and review the literature. To our knowledge, this is the second case of cricoid chondronecrosis in an adult patient occurring after only a few hours of intubation. PMID- 22435317 TI - In vitro evaluation of the Spectra early caries detection system. AB - OBJECTIVE: The goal of this study was to perform an in vitro evaluation of the Spectra, a new caries detector that uses light-induced fluorescence of healthy tooth structure and bacterial pigments to optically detect caries. The Spectra generates a storable color map image of examined tooth surfaces which shows areas of enamel and dentin caries. In this study, Spectra readings of occlusal surfaces were compared to clinical, radiographic, and histological assessments of caries. METHODS: Two examiners evaluated 41 extracted molars. The teeth were radiographed and then visually assessed. The International Caries Detection and Assessment System (ICDAS) was used to classify the extent of caries. The teeth were then sectioned and assigned a histological score based on the extension of caries into enamel or dentin. RESULTS: Teeth lacking radiographic caries had a mean Spectra reading of 1.5. Teeth having radiographic caries had a mean Spectra reading of 2.0. This difference was statistically significant. In general, higher ICDAS scores were associated with higher Spectra readings. Teeth with histologically evident deep dentin caries had significantly higher Spectra readings than intact teeth or teeth with superficial enamel demineralization. Spectra assessment of occlusal caries agrees with clinical and radiographic methods. CONCLUSION: Spectra images illustrate the full spectrum of caries severity, from enamel demineralization to dentin decay. The Spectra is a promising technology for the diagnosis and for monitoring the progression of occlusal caries. PMID- 22435318 TI - Novel clinical applications of Colgate Sensitive Pro-Relief in the management of dentin hypersensitivity. PMID- 22435319 TI - Evaluation of the sensitivity of a digital plaque imaging system on different tooth surfaces. AB - OBJECTIVE: The study aimed to test the sensitivity of digital plaque imaging in distinguishing the effectiveness of test and control mouthwashes for different groups of tooth surfaces. METHODS: The study was a double-blind, parallel, randomized, controlled clinical trial. Sixty subjects underwent scaling and polishing after recruitment, and attended their baseline examination after a washout phase of a minimum of seven days. They were then randomly assigned to one of two mouthwashes: 1) 0.05% CPC mouthwash; and 2) matching placebo mouthwash without CPC. Both groups were asked to use their assigned mouthwash and to refrain from any other oral hygiene measures for a period of eight days. At the baseline and day 8 visits, digital images of tooth surfaces were captured using Quantitative Light-induced Fluorescence (QLF) imaging, and plaque area as a percentage of the tooth surface was measured. Comparisons were carried out between the products for different groups of tooth surfaces. The data generated by the software were validated by a manual plaque outlining technique. RESULTS: Fifty-eight (58) subjects completed the study. More plaque was detected on the facial surfaces for the whole mouth (42.88% coverage for CPC and 46.45% for placebo) than the whole mouth lingual surfaces (7.23% coverage for CPC and 11.10% for placebo). Significant differences were observed between the products for the following areas: all tooth surfaces (p = 0.032), anterior lingual (p = 0.005), posterior lingual (p = 0.003), and whole mouth lingual (p = 0.001), whereas there were no differences between the products for anterior facial, anterior (facial & lingual), posterior facial, posterior (facial & lingual), and whole mouth facial. A strong correlation (R = 0.793, p < 0.001) was observed between the data (mean difference of percentage plaque coverage) generated by the analyzing program and that from the manual plaque outlining technique. CONCLUSION: The digital plaque imaging system was able to distinguish between the products when looking at the whole mouth. Digital imaging was better able to separate the groups when examining the lingual surfaces than facial. PMID- 22435320 TI - Comparison of two power interdental cleaning devices on plaque removal. AB - OBJECTIVE: The objective of this randomized, single-use, single-blind, two-group, parallel clinical trial was to evaluate the supragingival plaque removal efficacy of two power interdental devices combined with a manual toothbrush. METHODS: Eighty-two (82) subjects completed the study. Subjects were randomly assigned to one of two groups: Waterpik Water Flosser (WF) plus manual tooth brushing or Sonicare Air Floss (AF) plus manual tooth brushing. Pre-brushing and interdental cleaning scores were obtained using the Rustogi Modified Navy Plaque Index (RMNPI). Subjects were instructed on the use of the manual toothbrush and assigned an interdental product. Post-brushing and interdental cleaning scores were obtained after a supervised two-minute brushing and use of the interdental device. Scores were recorded for whole mouth, marginal, approximal, facial, and lingual regions for each subject. RESULTS: There were no differences in the pre cleaning plaque scores for whole mouth, marginal, approximal, facial, or lingual regions. Both groups showed significant reductions in plaque from baseline for all regions. The WF group demonstrated significantly higher reductions as measured by the RMNPI compared to the AF for whole mouth (74.9% vs. 57.5%), marginal (58.6% vs. 36.7%), approximal (92.1% vs. 77.4%), facial (83.6% vs. 69.1%), and lingual (65.7% vs. 45.4%). CONCLUSION: The use of the Waterpik Water Flosser removes significantly more plaque from tooth surfaces (whole mouth, marginal, approximal, facial, and lingual) than the Sonicare Air Floss when used with a manual toothbrush. PMID- 22435321 TI - Comparison of two power interdental cleaning devices on the reduction of gingivitis. AB - OBJECTIVE: The objective of this study was to compare the reduction of gingivitis by two power interdental devices combined with a manual toothbrush. METHODS: Eighty-two subjects completed this randomized, four-week, single-blind, two-group parallel clinical study. Subjects were randomly assigned to one of two groups: Waterpik Water Flosser (WF) plus manual tooth brushing or Sonicare Air Floss (AF) plus manual tooth brushing. Subjects were provided written and verbal instructions for all products at the baseline visit and instructions were reviewed at the two-week (W2) visit. Data were evaluated for whole mouth, lingual, and facial areas for gingivitis and bleeding on probing. Plaque data were evaluated for whole mouth, lingual, facial, approximal, and marginal areas of the tooth. Gingivitis, bleeding on probing, and plaque were scored at baseline (BSL), two weeks, and four weeks (W4). RESULTS: Both groups showed significant reductions in gingivitis, bleeding on probing, and plaque from baseline for all regions and time points measured (p < 0.001). The WF group was significantly more effective than the AF group at reducing plaque and gingivitis at W2 and W4 for all areas measured (p <0.001). At W4, the WF group was 80% more effective than AF for whole mouth gingivitis reduction, and twice as effective for the lingual region. In terms of plaque removal at W4, the WF group was 70% more effective for whole mouth (50.9% vs. 30%), 60% for approximal area (76.7% vs. 48%), and 47% for facial (52.8% vs. 35.9%) surfaces. The WF was twice as effective for lingual areas and more than three times as effective for marginal areas vs. the AF group (p <0.001). Results for bleeding on probing showed the WF group was numerically better than the AF group for all areas and time points, with these improvements being statistically significance for whole mouth (p = 0.02) and facial area (p = 0.004) at W2, and for the facial area (p = 0.02) at W4. CONCLUSION: The Waterpik Water Flosser is significantly more effective than Sonicare Air Floss for reducing gingivitis and plaque. PMID- 22435322 TI - Laboratory interproximal access efficacy of four elmex caries protection toothbrushes. AB - OBJECTIVE: The purpose of this research was to evaluate five toothbrushes in a laboratory assay that determines the ability of toothbrush bristles to penetrate and remove artificial plaque from interproximal sites. Interproximal access efficacy (IAE), using the laboratory method employed, has been predictive of clinical plaque removal. METHODS: The toothbrushes tested were four elmex Caries Protection (SOFT, SOFT Short Head, MEDIUM, and MEDIUM Short Head) and the American Dental Association's (ADA) standard. Simulated anterior and posterior teeth were covered with a pressure-sensitive artificial plaque substrate. Efficacy was evaluated by using the test products to brush the simulated teeth using horizontal and vertical motions with a brushing pressure of 250 g. The maximum width of plaque removed from around the simulated teeth is defined as IAE. Twenty-four tests were conducted on each toothbrush product group. Test results were statistically analyzed using ANOVA and the post hoc Tukey test. RESULTS: In all assays conducted, the four elmex Caries Protection toothbrushes had a superior overall IAE (p < 0.001) compared to the ADA standard toothbrush. There were no statistically significant differences in the overall IAE means between the four elmex Caries Protection toothbrushes. CONCLUSION: The elmex Caries Protection toothbrushes are predicted to have superior clinical plaque removal efficacy compared to the ADA standard toothbrush. PMID- 22435323 TI - Health effects of uranium: new research findings. AB - Recent plans for a nuclear renaissance in both established and emerging economies have prompted increased interest in uranium mining. With the potential for more uranium mining worldwide and a growth in the literature on the toxicology and epidemiology of uranium and uranium mining, we found it timely to review the current state of knowledge. Here, we present a review of the health effects of uranium mining, with an emphasis on newer findings (2005-2011). Uranium mining can contaminate air, water, and soil. The chemical toxicity of the metal constitutes the primary environmental health hazard, with the radioactivity of uranium a secondary concern. The update of the toxicologic evidence on uranium adds to the established findings regarding nephrotoxicity, genotoxicity, and developmental defects. Additional novel toxicologic findings, including some at the molecular level, are now emerging that raise the biological plausibility of adverse effects on the brain, on reproduction, including estrogenic effects, on gene expression, and on uranium metabolism. Historically, most epidemiology on uranium mining has focused on mine workers and radon exposure. Although that situation is still overwhelmingly true, a smaller emerging literature has begun to form around environmental exposure in residential areas near uranium mining and processing facilities. We present and critique such studies. Clearly, more epidemiologic research is needed to contribute to causal inference. As much damage is irreversible, and possibly cumulative, present efforts must be vigorous to limit environmental uranium contamination and exposure. PMID- 22435324 TI - Genotoxicity of metal nanoparticles. AB - Nanotechnology is currently used in industry, medicine, and military applications, as well as in more than 300 commercial products. Yet, the same properties that make these particles exciting for technology also make them daunting public health concerns because their toxicity is unknown and relatively unexplored. Increased attention is being placed on the study of metal particle genotoxicity; however, a lot of unknowns remain about their effects and the mechanisms. In this article, we highlight some metal and metal oxide nanoparticles of interest and discuss the current in vivo and in vitro studies of genotoxic effects. Many metal nanoparticles were found to cause chromosomal aberrations, DNA strand breaks, oxidative DNA damage, and mutations. Inconsistencies are found in the literature, however, thus drawing conclusions is difficult due to a variety of factors. Therefore, the areas requiring further attention are highlighted and recommendations to improve our understanding of the genotoxic potential are addressed. PMID- 22435325 TI - Ehrlichia species, probable emerging human pathogens in sub-Saharan Africa: environmental exacerbation. AB - Ehrlichiae are obligate intracellular Gram-negative tick-borne bacteria that are responsible for life-threatening emerging human zoonoses and diseases of veterinary importance worldwide, collectively called ehrlichioses. The genus Ehrlichia consists of five recognized species, including E. canis, E. chaffeensis, E. ewingii, E. muris, and E. ruminantium. The recent discoveries of Ehrlichia species in new areas and of tick species that were previously thought to be uninfected by these agents have suggested that these agents may have wider distribution than originally thought. Environmental factors like temperature, migration, control failure, and host population have been known to exacerbate the spread of Ehrlichia species. Human cases of moderate to severe disease caused by E. chaffeensis have been reported mainly in North America. In this article, we present an overview of ehrlichiae as emerging pathogens in sub-Saharan Africa, where E. ruminantium, the causative agent of heartwater, a disease of domestic and wild ruminants, is most established. Molecular evidence indicates that E. ruminantium may be an emerging pathogen of a life-threatening human disease. Ehrlichia ruminantium is considered an agricultural biothreat, with several strains reported throughout sub-Saharan Africa, where the infection is considered endemic. Understanding the diversity of E. ruminantium and other Ehrlichia species from all geographically distinct areas of sub-Saharan Africa may enhance our knowledge of the pathogenesis and epidemiology of these pathogens. PMID- 22435326 TI - A review of the toxicity of chemical dispersants. AB - Chemical dispersants are a mixture of various surfactants and solvents. Most dispersants are proprietary, and the complete composition is not often public knowledge. Chemical dispersants used for the cleanup and containment of crude oil toxicity became a major concern after the 2010 Deepwater Horizon oil crisis in the Gulf of Mexico. During the crisis, millions of liters of chemical dispersants (Corexit 9527 and 9500) were used--the largest known application of dispersants in the field. As of February 2011, 38 peer-reviewed articles were available on the toxicity of 35 different chemical dispersants. Nalco, BP, Shell, and Total Special Fluids manufacture a variety of chemical dispersants. Most notably, Nalco manufactures Corexit 9527 and 9500, and 19 miscellaneous dispersants are manufactured by others. Most studies examined the lethality of the dispersants. Several nonlethal end points were considered, including the effect on predator/prey recognition, enzyme activity changes, effects on hatchability, and the threshold for bradycardia. The animals studied included Daphnia (small planktonic crustaceans), anemones, corals, crustaceans, starfish, mollusks, fish, birds, and rats. Studies in birds and mammals are distinctly lacking. The variety of chemical dispersants, the variability in test methods, and the lack of distinct species overlap between studies make it difficult to compare and deduce which dispersant is most toxic and which is least. Here, we offer some attempt at comparing Corexit 9527 and 9500 (because these have had the largest field application), but significantly more research is needed before clear conclusions can be drawn. PMID- 22435327 TI - Estimation of the possible flood discharge and volume of stormwater for designing water storage. AB - The shortage of good-quality water resources is an important issue in arid and semiarid zones. Stormwater-harvesting systems that are capable of delivering good quality wastewater for non-potable uses while taking into account environmental and health requirements must be developed. For this reason, the availability of water resources of marginal quality, like stormwater, can be a significant contribution to the water supply. Current stormwater management practices in the world require the creation of control systems that monitor quality and quantity of the water and the development of stormwater basins to store increased runoff volumes. Public health and safety considerations should be considered. Urban and suburban development, with the creation of buildings and roads and innumerable related activities, turns rain and snow into unwitting agents of damage to our nation's waterways. This urban and suburban runoff, legally known as stormwater, is one of the most significant sources of water pollution in the world. Based on various factors like water quality, runoff flow rate and speed, and the topography involved, stormwater can be directed into basins, purification plants, or to the sea. Accurate floodplain maps are the key to better floodplain management. The aim of this work is to use geographic information systems (GIS) to monitor and control the effect of stormwater. The graphic and mapping capabilities of GIS provide strong tools for conveying information and forecasts of different storm-water flow and buildup scenarios. Analyses of hydrologic processes, rainfall simulations, and spatial patterns of water resources were performed with GIS, which means, based on integrated data set, the flow of the water was introduced into the GIS. Two cases in Israel were analyzed--the Hula Project (the Jordan River floods over the peat soil area) and the Kishon River floodplains as it existed in the Yizrael Valley. PMID- 22435328 TI - [The number of circulating fibrocytes of skeletal muscle in rats after contusion]. AB - OBJECTION: To investigate the time-dependent appearance of circulating fibrocytes of skeletal muscle in rats after contusion. METHODS: The model of skeletal muscle wound was established in rat. The circulating fibrocytes in contused skeletal muscle were detected by CD45 and procollagen I double immunofluorescence staining method. RESULTS: In the control group, CD45- and procollagen I-positive cells were not detected in skeletal muscle. A few CD45 cells were observed aged from 6 h to 1 d after contusion. A few CD45- and procollagen I-positive cells (fibrocytes) initially gathered in injury area 3d after injury. The ratio of positive fibrocytes significantly increased 5 d after injury. The ratio of fibrocytes was highest at 7 d after contusion and then decreased. The volume of fibrocytes showed bigger with injury time increase compared with 3 d group. The expression of procollagen I and CD45 were weakened at 14d after injury. CONCLUSION: The circulating fibrocytes are detected in contused skeletal muscle in time-dependent pattern. Circulating fibrocytes may be a marker in the wound age determination for contused skeletal muscle. PMID- 22435329 TI - [Changes of biomechanical properties of soft tissues in underwater corpse for postmortem interval estimation]. AB - OBJECTIVE: To explore the postmortem changes of biomechanical properties of underwater corpses and value for estimating postmortem interval. METHODS: SD rats were sacrificed by cervical vertebra dislocation and stored in the water at constant temperature. The vessel wall, skin, muscle, small intestine and colon were sampled at different postmortem time points (0h, 6h, 12h, 18h, 24h, 30h, 36h, 42h, 48h, 60h, 72h, 96h, 120h, 144h, 168h, 192h). The biomechanics properties of different soft tissues including ultimate load, strain, maximum stress were measured by electronic universal material testing machine. RESULTS: Except for the vessel wall, the biomechanics properties of skin, muscle, small intestine and colon showed linear decrease gradually after death. Each tissue displayed its obvious "window period" for PMI estimation. CONCLUSION: The time sequential changes of biomechanical property parameters of soft tissue in underwater corpses are significantly correlated with PMI and it could be a simple and quantitive new technology for estimating PMI. The specific heat capacity of the heat-eliminating medium around the corpses probably is one of the physical factors to influence algor mortis, autolysis, putrefaction and biomechanics properties. PMID- 22435330 TI - [Effects of restraint position on changes of diaphragmatic mechanical characteristic in rats]. AB - OBJECTIVE: To observe effects of restraint position on the changes of diaphragmatic mechanical characteristic in rats, and try to explore the role of nitric oxide (NO). METHODS: Rat model of restraint position was established. Rats were divided into control group, restraint position 12h and 24h groups. The markers of respiratory functions in vivo and the biomechanical markers of diaphragmatic characteristic ex vivo were evaluated. Serum NO levels were measured with spectrophotometry. The expressions of nNOS and iNOS mRNA in diaphragm were detected using RT-PCR. RESULTS: Compared with control group, respiratory rate, tidal volume and minute ventilation were significantly decreased in the restraint position 12h and 24h groups. Pt of diaphragm significantly decreased and force-generating capacity reduced at low frequency stimulation in 12h group. Force-generating capacity over the full range reduced at low and high frequency stimulation in 24h group. Pt of diaphragm in control and restraint position groups increased after L-NNA pre-incubation. Force frequency relationship after L-NNA pre-incubation reduced in 24h group. NO level in serum increased significantly in the restraint position groups. Diaphragmatic nNOS mRNA expression was upregulated significantly in the restraint position groups. CONCLUSION: Restraint position induces the decreasement of diaphragmatic contractility and the decreasement is mediated by NO from diaphragm or circulation blood. PMID- 22435331 TI - [Expression of FAPalpha and TGF-beta1 in sudden deaths due to acute myocardial ischemia]. AB - OBJECTIVE: To explore the expression of fibroblast activation protein alpha (FAPalpha) and transforming growth factor-beta1 (TGF-beta1) in myocardial cytoplasm for the cases of sudden death due to acute myocardial ischemia. METHODS: The heart tissues of 47 cases were collected. All cases were divided into three groups: control group, acute myocardial infarction group and recurrent myocardial infarction group. FAPalpha and TGF-beta1 expressions were explored in myocardial cytoplasm by immunohistochemistry technology. The staining results were collected by image analysis system and then the positive area ratio and average optical density were detected. The positive signal differences were compared among the groups. RESULTS: Strong FAPalpha and TGF-beta1 expressions were detected in myocardial cytoplasm in both acute and recurrent myocardial infarction groups. The expression of FAPalpha was not detected in myocardial cytoplasm in control group and TGF-beta1 expression showed a weak positive result. FAPalpha and TGF-beta1 expressions showed the statistical difference (P < 0.05) in myocardial infarction (acute and recurrent) groups and control group. CONCLUSION: FAPalpha and TGF-beta1 can be the diagnostic markers for determing acute myocardial infarction. PMID- 22435332 TI - [Analysis of variation of Han male adolescent bone development in Hainan, Henan and Zhejiang provinces]. AB - OBJECTIVE: To study the difference of bone development of the Han male adolescents in Hainan, Henan and Zhejiang provinces. METHODS: All radiographs including sternal end of clavicle, pelvis and six main bone joints taken from 877 Han male adolescents aged between 12.00 and 20.00 in Hainan, Henan and Zhejiang provinces were reviewed. Twenty-four indices of skeletal development were analyzed based on "The Grading Standards" of skeletal growth of teenagers and then the bone age were calculated using mathematical model functions. The ratios of the bone age and the chronological age were then analyzed by statistical software. RESULTS: The development of Hainan male adolescents' skeleton were about 1.09 years and 1.26 years earlier than that in Henan and Zhejiang at the age group of 12.00-12.99 years. The development of Hainan male adolescents' skeleton were about 0.70 years and 1.38 years earlier than that in Henan and Zhejiang at the age group of 13.00-13.99 years, while the development of Henan male adolescents' skeleton were about 0.68 years earlier than that in Zhejiang in this age group. The development of Hainan male adolescents' skeleton were about 0.79 years later than that in Henan at the age group of 18.00-18.99 years. The development of Hainan male adolescents' skeleton were about 0.70 years and 0.95 years later than that in Henan and Zhejiang at the age group of 19.00-20.00 years. CONCLUSION: There are significant differences in the skeleton development of Han male adolescents between the provinces of Hainan, Henan and Zhejiang. These results provide potential value for the practice of forensic medicine, anthropology and clinical medicine. PMID- 22435333 TI - [Application of contrast vision in identifying the malingering decreased vision]. AB - OBJECTIVE: To study the application value of contrast vision in identifying the malingering decreased vision in the practice of clinical forensic medicine. METHODS: Thirty-one young and middle aged volunteers were selected and divided randomly into group 1 (16 persons with 32 eyes) and group 2 (15 persons with 30 eyes). The optotype contrast was 100%, 25%, 10% and 5%, respectively. The contrast vision of group 1 was tested. The contrast vision of group 2 was tested as follows: (1) the volunteers cooperated without inspector's interference; (2) the volunteers cooperated under inspector's interference; (3) the volunteers disguised decreased vision without inspector's interference; (4) the volunteers disguised decreased vision under inspector's interference. The data was then analyzed by statistics. RESULTS: There was a close correlation between contrast vision and contrast. As the contrast decreased, the vision acuity also decreased. The contrast vision curve of former two methods showed a good reproducibility while the contrast vision curve of latter two methods had a bad reproducibility. CONCLUSION: The repetition of contrast curve with or without inspector's interference can be used to discriminate malingering vision. The acquired contrast curves can be provided to the court as direct evidence and can help enhance the verification conclusion. PMID- 22435334 TI - [Characteristics and distribution of ERP by different field stimulation]. AB - OBJECTIVE: To study the variation of latency and amplitude of the event related potential (ERP) and its distribution in human scalp when the normal subjects were stimulated with different visual fields. METHODS: The ERP recorded in scalp with the stimulation of 10 degrees visual field and 60 degrees visual field respectively in 20 healthy volunteers with normal visual function. RESULTS: Two different visual field stimulation may evoke the different exogenous components P1 (70-125 ms), N1 (90-170 ms), P2 (140-220 ms) and endogenous components N2 (190 280 ms) and P3 (290-430 ms). The latencies of all the components evoked by 10 degrees visual field were shorter than that of the 60 degrees visual field while the amplitudes of N1 and N2 were lower and appeared over the extensive encephalic region; and the amplitudes of the P1, P2 and P3 were higher and appeared in occipitotemporal, prefrontal and occipital region, respectively. CONCLUSION: Two different visual field stimulation may evoke all the ERP components with significant differences in the latency, amplitude and distribution. The differences may reflect the different visual information integration and processing in human brain during the different visual field stimulation. PMID- 22435335 TI - [Reliability of the Violence Risk Scale of Chinese version]. AB - OBJECTIVE: To introduce and revise the Violence Risk Scale (VRS) for assessing violence risk and risk change, and to examine the reliability of Violence Risk Scale of Chinese version(VRS-C). METHODS: The original English version of the VRS was translated into Chinese according to established translation procedures. To examine the scorer reliability the 14 cases assessed by 3 assessors separately. One hundred and twenty-five patients with mental disorders from 3 different institutions in Sichuan province (Refined Control Ward in Ankang Hospital, Department of Forensic Psychiatry, Institute of Forensic Science and Mental Health Center of West China Hospital) were collected to examine the reliability of VRS-C. RESULTS: The results showed moderately good scale reliability of the VRS-C, with 0.80 of ICC for scorer reliability. All items have significant consistence with Cronbach's alpha coefficient as 0.921, split-half reliability as 0.906 and item total correlation as 0.246-0.849. CONCLUSION: The reliability of the VRS-C version is acceptable. PMID- 22435336 TI - [Typing and polymorphism analysis of 16 STR loci on X chromosome]. AB - OBJECTIVE: To develop a PCR-based X-STR kit for typing of 16 X-STR loci and investigate the polymorphisms of the X-STR markers. METHODS: Sixteen STR loci (GATA 165B12, DXS101, GATA 172D05, HPRTB, DXS981, DXS8378, DXS6795, GATA 31E08, DXS6809, DXS6803, DXS9902, DXS6807, DXS7423, DXS7133, DXS6810 and DXS7132) located on X chromosome were selected. The primers for multiplex PCR were designed by Primer Premier 5.0 software and labeled by four fluorescences (FAM, HEX, TAMRA and ROX). The developed multiplex PCR system was used for investigating the polymorphisms of the X-STR markers in Han populations. RESULTS: The 16-plex amplification system named IDtyper X-16 was successfully developed and validated. Among the 16 X-STR loci, DXS7133 and DXS7423 were found to be moderately polymorphic and the other 14 X-STR markers were highly polymorphic (P1C > 0.5, H > 0.5). The cumulative discrimination power in females and in males were 0.999 999 999 999 97 and 0.999 999 993 respectively in Han population. The combined power of exclusion in trios and in duos were 0.999 999 93 and 0.999990, respectively. CONCLUSION: The IDtyper X-16 kit is highly valuable in forensic science and is suitable for paternity testing in disputed cases. PMID- 22435337 TI - [Degenerate oligonucleotide primed-PCR technology establishment and its sensitivity test analysis]. AB - OBJECTIVE: To establish a whole genome amplification testing system based on degenerate oligonucleotide primed-PCR (DOP-PCR) and to explore its reliability and sensitivity. METHODS: DOP-PCR amplified production was detected by fluorescent labeled multiplex STR amplification and capillary electrophoresis detection system to determine reliability and sensitivity of DOP-PCR system. RESULTS: DOP-PCR system was successfully established and the detection sensitivity reached 5 cells (30 pg) by pretreatment of DOP-PCR and then detection of STR genotyping. CONCLUSION: The system established in this study is reliable and more testing sensitive for forensic trace evidence. PMID- 22435338 TI - [Screening and confirmation of psychotropic drugs in blood and urine by HPLC-LTQ Orbitrap MS]. AB - OBJECTIVE: To establish a screening and confirmation method for psychotropic drugs and their metabolites in human blood and urine by HPLC-LTQ Orbitrap MS. METHODS: The samples were pretreated with Sirocco protein precipitation plate, and then analyzed by HPLC-LTQ Orbitrap MS. The method was validated in terms of the limit of detection (LOD). An accurate mass database was created for psychotropic drugs screening. RESULTS: The LOD for most of 56 determined compounds was < or = 0.1 ng/mL. The accurate mass database included the accurate mass information of 61 psychotropic drugs. CONCLUSION: The method is accurate, rapid, sensitive and the database is suitable for psychotropic drugs screening and confirmation. PMID- 22435339 TI - [Correlation of disability degree and Tile type of pelvic fracture caused by traffic accidents]. AB - OBJECTIVE: To analyze the relevance of Tile type of pelvic fracture and the degree of disability and explore how to understand the malunion and severe malunion of pelvic fracture for the injured in the traffic accidents. METHODS: Eighty-six cases of pelvic fractures caused by traffic accidents from August 2008 to August 2011 in Forensic Judical Appraisal Institute of Suzhou Municipal Hospital were collected. At first, the grade of disability for every case was evaluated by 3 senior forensic experts independently. Then, the Tile type of pelvic fractures for every case was determined by 3 radiologists independently. At last, the correlation of the types of the fracture with the grades of disabilities was analyzed. RESULTS: In all the cases there were 19 cases determined as A-type fracture and evaluated as non-grade disability. There were 43 cases determined as B-type fracture. And in these cases there were 41 cases determined as tenth grade of disability, one case as non-grade disability and one case as ninth grade disability. There were 24 cases determined as C-type fracture. And in these cases there were 14 cases evaluated as tenth grade disability and 10 cases evaluated as ninth grade disability. There was a correlation between the grade of disability and the type of the fracture (r = 0.760). CONCLUSION: The disability degree caused by pelvic fracture correlates significantly with the type of the fracture. The finding is potentially useful to understand the malunion and severe malunion of pelvic fracture in forensic practice. PMID- 22435340 TI - [Research status and prospects of DNA test on difficult specimens]. AB - This paper reviews the advances of DNA detection on three types of difficult biological specimens including degraded samples, trace evidences and mixed samples. The source of different samples, processing methods and announcements were analyzed. New methods such as mitochondrial test system, changing the original experimental conditions, low-volume PCR amplification and new technologies such as whole genome amplification techniques, laser capture micro dissection, and mini-STR technology in recent years are introduced. PMID- 22435341 TI - Chiral crystallization of a heterodinuclear Ni-Ln series: comprehensive analysis of the magnetic properties. AB - Four heterodinuclear (H(2)O)(2)NiL-Ln(NO(3))(3) complexes (Ln = Tb, Dy, Er, Yb) with a double phenoxo bridge coming from the dideprotonated Schiff-base ligand are synthesized and characterized by crystal and powder X-ray diffraction studies. This series of compounds devoid of any chiral center, crystallizes in a noncentrosymmetric space group P2(1), as the previously described (H(2)O)(2)NiL Gd(NO(3))(3) equivalent. All four complexes are ferromagnetically coupled. If this behavior is clearly shown by the chi(M)T increase at low temperature in the case of the Ni-Tb and Ni-Dy complexes, it necessitates the preparation of the Zn Er and Zn-Yb equivalent entities to be evidenced in the case of the Ni-Er and Ni Yb complexes. Out-of-phase susceptibility signals are found in the four cases, but the SMM behavior is neither confirmed, nor completely studied because of the presence of fast quantum tunnelling at zero field. Thorough ab initio multiconfiguration calculations are carried out, achieving a realistic account of ligand field effects, exchange coupling and magnetic anisotropy in the discussed systems. The calculations reveal the ferromagnetic intercenter exchange coupling, the interplay with spin-orbit effects leading to a Ising-like scheme of the lowest levels. The ab initio simulation of the magnetic susceptibility is in semiquantitative agreement with experimental data, certifying the reasonableness of the theoretical treatments in obtaining valuable information for the interacting mechanisms. The anisotropy is accounted for by drawing polar diagrams of state-specific magnetization functions, obtained by handling of the data resulting from ab initio calculations including the spin-orbit effects. Supplementary, Density Functional Theory (DFT) calculations are carried out, presenting new methodological clues and assessments. The DFT is not perfectly adequate for lanthanide systems because of orbital pseudodegeneracy issues. However, we show that in particular circumstances the DFT can be partly used, succeeding here in mimicking different orbital configurations of the Ni-Tb system. The DFT seems to offer reasonable estimations of exchange coupling parameters, while it remains problematic in the complete account of Ligand Field splitting. The Paper presents unprecedented methodological advances and correlations with phenomenological and heuristic interpretation of experimental data, taking into focus relevant d-f systems constructed with a prototypical binucleating ligand. PMID- 22435342 TI - Clinical diagnosis: a topic worth revisiting for pharmacovigilance. PMID- 22435343 TI - Safety of flecainide. AB - Flecainide is a class Ic antiarrhythmic agent that has an important role as part of rhythm control strategies in patients with atrial fibrillation (AF). Early clinical data on the use of flecainide showed an increase in arrhythmias and mortality compared with placebo in patients with a previous myocardial infarction and asymptomatic or mildly symptomatic ventricular arrhythmias. These findings only apply to a specific group of patients with left ventricular dysfunction and ischaemic heart disease, but had a negative impact on the use of class Ic antiarrhythmics across all indications and patient groups. The aim of this review was to evaluate the available safety data for flecainide in the literature and to assess its current use in patients with AF. Current European guidelines now recommend the use of flecainide in carefully selected groups of patients with AF who do not have structural heart disease. This includes for the cardioversion of recent-onset AF, pretreatment prior to direct current cardioversion, out-of hospital acute oral therapy ('pill-in-the-pocket' approach) and for the ongoing maintenance of sinus rhythm. Potential cardiac adverse effects of flecainide include proarrhythmia, conduction abnormalities and negative inotropic effects. Dizziness is the most frequent non-cardiac side effect, followed by blurred vision and difficulty focusing; these are almost all mild, transient and tolerable. Data from recent clinical trials in patients with supraventricular arrhythmias suggest that flecainide has a good tolerability profile in groups of appropriately selected patients. Caution is required when using flecainide in patients with renal dysfunction, and there are a number of drug interactions, but these are well documented and manageable. Overall, flecainide is a good choice for the pharmacological management of AF. It has a good safety record and low incidence of adverse effects, rare end-organ toxicity and a low risk of ventricular proarrhythmia. To ensure that the benefits of treatment outweigh any potential risks, careful patient selection and monitoring is required. PMID- 22435344 TI - Vaccine-based subgroup analysis in VigiBase: effect on sensitivity in paediatric signal detection. AB - BACKGROUND: Data mining of spontaneously reported adverse drug reactions (ADRs), using measures of disproportionality, is a valuable first evaluation step for drug safety signal detection. Of all ADRs reported for children and adolescents within VigiBase, vaccine-ADR pairs comprise more than half of the reports. ADRs concerning vaccines differ with respect to type and seriousness from other drugs, and therefore may influence signal detection for non-vaccine drugs if not accounted for appropriately. The potential influence of vaccines on safety signal detection for drugs was recently raised by the CIOMS Working Group VIII, who proposed that it may be appropriate to undertake automatic signal detection using both medicines and vaccines, and some analysis using vaccines only. However, it has not described for which types of ADRs or drugs subgroup analysis is beneficial. OBJECTIVE: The aim of the study was to study the methodological aspects concerning the influence of a high prevalence of vaccine-related ADRs on signal detection within paediatric ADR data. METHODS: We analysed all paediatric Individual Case Safety Reports (ICSRs) received by VigiBase between 2000 and 2006, and calculated the reporting odds ratio (ROR) for all unique drug-ADR pairs with at least three reports. The ROR was additionally calculated in subgroups of vaccine-ADR pairs and non-vaccine-ADR pairs and further in different age groups. A proportional change in the ROR for the different subgroups was calculated and the change in the number of signals of disproportional reporting (SDRs) after subgroup analysis was assessed. RESULTS: Of all paediatric ICSRs (N = 218 840, of which 117 877 were vaccine-related), a total of 26 203 unique drug-ADR pairs were eligible for inclusion (5586 vaccine-related). A total of 1637 vaccine-related SDRs and 13 375 non-vaccine-related SDRs were detected in the crude analysis. Subgroup analysis by restricting to either vaccines or non-vaccines revealed 494 additional SDRs for vaccines (+30.2%) and 821 additional SDRs for non-vaccines (+6.1%). Subgroup analyses were only beneficial for non-vaccines if the ADR of interest was reported uncommonly for non-vaccines and beneficial for vaccines if the ADR was reported uncommonly for vaccines. Subgroup analysis for ADRs that were reported commonly for either vaccines or non-vaccines led to the disappearance of 272 SDRs for vaccines and 2721 SDRs for non-vaccines. We could empirically derive a model that predicts the change in ROR in the subgroups based on the proportion of vaccines within the total dataset. CONCLUSION: The high proportion of vaccine-related reports within paediatric ADR data has a large and mathematically predictable impact on signal detection in paediatric ADR data. Subgroup analysis reveals new SDRs that potentially represent genuine safety signals. The most inclusive and sensitive signal detection method would be the combination of a crude and subgroup-based data mining approach, based on the ratio between the proportion of vaccines within the ADR of interest and within all other ADRs. PMID- 22435345 TI - Attentional factors in conceptual congruency. AB - Conceptual congruency effects are biases induced by an irrelevant conceptual dimension of a task (e.g., location in vertical space) on the processing of another, relevant dimension (e.g., judging words' emotional evaluation). Such effects are a central empirical pillar for recent views about how the mind/brain represents concepts. In the present paper, we show how attentional cueing (both exogenous and endogenous) to each conceptual dimension succeeds in modifying both the manifestation and the symmetry of the effect. The theoretical implications of this finding are discussed. PMID- 22435346 TI - Technology limits for reducing EU transport sector CO2 emissions. AB - Using a new data set describing the techno-economic characteristics of current and projected future transport technologies and a synthesis of existing transport demand models, lifecycle CO(2) emissions from 27 EU countries (EU27) were estimated in the absence and presence of new policy interventions to 2050. Future CO(2) emissions are strongly dependent on geographical scope and economic growth assumptions, and to a lesser extent on uncertainties in technology characteristics, but in the absence of new policy intervention they continue to rise from present-day values in all three scenarios examined. Consequently, EU27 emissions goals, which may require a 60% decrease in transport sector greenhouse gas emissions from year-1990 values by 2050, will be difficult to meet. This is even the case under widespread adoption of the most promising technologies for all modes, due primarily to limitations in biofuel production capacity and a lack of technologies that would drastically reduce CO(2) emissions from heavy trucks and intercontinental aviation. PMID- 22435348 TI - The use of multiple dietary supplements. AB - Dietary supplements are widely used in the belief that they confer additional benefit to health and longevity. Most people take one or two supplements but some take far more. What evidence is there to support use of multiple supplements and how should we advise patients who are using them? This case report gives a framework to address this issue with patients. PMID- 22435347 TI - Engineered proteins: redox properties and their applications. AB - Oxidoreductases and metalloproteins, representing more than one third of all known proteins, serve as significant catalysts for numerous biological processes that involve electron transfers such as photosynthesis, respiration, metabolism, and molecular signaling. The functional properties of the oxidoreductases/metalloproteins are determined by the nature of their redox centers. Protein engineering is a powerful approach that is used to incorporate biological and abiological redox cofactors as well as novel enzymes and redox proteins with predictable structures and desirable functions for important biological and chemical applications. The methods of protein engineering, mainly rational design, directed evolution, protein surface modifications, and domain shuffling, have allowed the creation and study of a number of redox proteins. This review presents a selection of engineered redox proteins achieved through these methods, resulting in a manipulation in redox potentials, an increase in electron-transfer efficiency, and an expansion of native proteins by de novo design. Such engineered/modified redox proteins with desired properties have led to a broad spectrum of practical applications, ranging from biosensors, biofuel cells, to pharmaceuticals and hybrid catalysis. Glucose biosensors are one of the most successful products in enzyme electrochemistry, with reconstituted glucose oxidase achieving effective electrical communication with the sensor electrode; direct electron-transfer-type biofuel cells are developed to avoid thermodynamic loss and mediator leakage; and fusion proteins of P450s and redox partners make the biocatalytic generation of drug metabolites possible. In summary, this review includes the properties and applications of the engineered redox proteins as well as their significance and great potential in the exploration of bioelectrochemical sensing devices. PMID- 22435349 TI - Informing the public responsibly about herbal medicine. AB - The current popularity requires reliable information in this sector to minimize harm and maximize benefit. Currently there are only very few such sources of information aimed at the lay public. Instead, we have a plethora of seriously misleading texts. In the interest of public health, we need reliable, unbiased, and easily accessible information. PMID- 22435350 TI - Investigation of modulation of the alpha-2 receptor in tetrahydropalmatine (THP) analgesia in male Sprague-Dawley rats. AB - The increased use of nutraceuticals over the past 20 years makes it essential to know the effects these may have with anesthetics and analgesics (Kaye et al., 2000). Tetrahydropalmatine (THP), a derivative of the herb corydalis, may have analgesic properties (Hu & Jin, 2000a; Wei, Zou, Young, Dubner, & Ren, 1999); however, the mechanism of action is unclear. We proposed that THP may modulate alpha-2 receptors and interact with dexmedetomidine, a known alpha-2-receptor agonist, used for sedation. Fifty-five male Sprague-Dawley rats, divided into five groups, were administered the following by intraperitoneal injection: (1) vehicle, (2) dexmedetomidine, (3) THP, (4) THP and yohimbine, and (5) THP and dexmedetomidine. A baseline measurement of hot-plate latency was recorded, followed by an injection of appropriate compound(s). Testing occurred at 5, 10, 30, and 60 min after injections. Repeated measures ANOVA suggested a significant difference among groups (f = 8.09; p = 0.00). Post hoc Bonferroni suggested that THP significantly prolonged reaction time on the hot plate compared to vehicle (p =. 037). Rats injected with THP and yohimbine did not have significantly shorter latency times compared to those injected with THP alone suggesting that THP does not modulate alpha-2 receptors. Finally, rats injected with THP and dexmedetomidine did not demonstrate a significantly increased latency time compared to THP alone, suggesting no additive effect of THP. PMID- 22435351 TI - Panax ginseng may improve some symptoms of attention-deficit hyperactivity disorder. AB - OBJECTIVE: In this open trial, Panax ginseng, a serotonin and norepinephrine reuptake inhibitor, actually used as an antidepressant, has been investigated for its efficacy in the treatment of attention-deficit hyperactivity disorder (ADHD) patients. METHOD: Three 14-17-year-old male psychiatric outpatients, diagnosed with ADHD disattention type have been rated at baseline and while taking Panax ginseng to determine its efficacy as a treatment for ADHD. Improvement was determined using comparisons of Conners' parent ratings. RESULTS: Patients' mean scores improved for Conners' hyperactivity, inattention, and immaturity factors. CONCLUSIONS: Although the sample size is very small and generalization is very difficult, this observation indicates that Panax ginseng may be a slightly effective treatment for ADHD. PMID- 22435352 TI - Inhibitory effects of St. John's Wort on inflammation: ignored potential of a popular herb. AB - St. John's wort (Hypericum perforatum L., family Hypericaceae) is a flowering herb, which has been used traditionally for decades in Europe and other parts of the world for the treatment of depressive mood disorders. A number of clinical trials support its application in the treatment of depressive mood symptoms. Although not commonly known for this use, St John's wort is also reputed for its usefulness in inflammatory conditions such as sciatica and fibromyalgia. This article discusses evidence from in vitro and in vivo studies supporting a possible use of St. John's wort as an anti-inflammatory remedy, in addition to its well-known antidepressant effects. PMID- 22435353 TI - Do dietary supplements help promote weight loss? AB - As two-thirds of the US population is overweight or obese, new strategies are needed to help individuals safely and effectively lose weight. One option is to use dietary supplements, but not all supplements that are touted for weight loss have published clinical support for efficacy. The purpose of this article was to identify all published articles on dietary supplements for weight loss. Effectiveness of these supplements was defined as promoting 1-2 lb of weight loss each week. Although several dozen different dietary supplements are sold, only 14 published studies were identified. Four individual ingredients and three blends of ingredients were considered to be effective. Additionally, we compared weight loss from these dietary supplements to over-the-counter (OTC) orlistat (alliTM, GlaxoSmithKline, Brentford, UK). Five single ingredients and three blends of ingredients produced more weight loss than OTC orlistat. Persons who use dietary supplements for weight management, counsel patients on how to lose weight, and retailers who sell dietary supplements, should become familiar with those supplements only that are effective at producing weight loss to assure the best results. PMID- 22435354 TI - An evidence-based systematic review of green-lipped mussel (Perna canaliculus) by the Natural Standard Research Collaboration. AB - This paper is an evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. SEARCH STRATEGY: To prepare each Natural Standard review, electronic searches are conducted in nine databases, including AMED, CANCERLIT, CINAHL, CISCOM, the Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts, Medline, and NAPRALERT. Search terms include the common name(s), scientific name(s), and all listed synonyms for each topic. Hand searches are conducted of 20 additional journals (not indexed in common databases), and of bibliographies from 50 selected secondary references. No restrictions are placed on language or quality of publications. Researchers in the field of complementary and alternative medicine (CAM) are consulted for access to additional references or ongoing research. SELECTION CRITERIA: All literature is collected pertaining to efficacy in humans (regardless of study design, quality, or language), dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory assays, and mechanism of action (in vitro, animal research, human data). Standardized inclusion/exclusion criteria are utilized for selection. DATA ANALYSIS: Data extraction and analysis are performed by healthcare professionals conducting clinical work and/or research at academic centers, using standardized instruments that pertain to each review section (defining inclusion/exclusion criteria and analytic techniques, including validated measures of study quality). Data are verified by a second reviewer. REVIEW PROCESS: A blinded review is conducted by multidisciplinary research-clinical faculty at major academic centers with expertise in epidemiology and biostatistics, pharmacology, toxicology, CAM research, and clinical practice. In cases of editorial disagreement, a three member panel of the Editorial Board addresses conflicts, and consults experts when applicable. Authors of studies are contacted when clarification is required. PMID- 22435355 TI - Medical image registration: a review. AB - This paper presents a review of automated image registration methodologies that have been used in the medical field. The aim of this paper is to be an introduction to the field, provide knowledge on the work that has been developed and to be a suitable reference for those who are looking for registration methods for a specific application. The registration methodologies under review are classified into intensity or feature based. The main steps of these methodologies, the common geometric transformations, the similarity measures and accuracy assessment techniques are introduced and described. PMID- 22435356 TI - Ionic liquids: differential scanning calorimetry as a new indirect method for determination of vaporization enthalpies. AB - Differential scanning calorimetry (DSC) has been used to measure enthalpies of synthesis reactions of the 1-alkyl-3-methylimidazolium bromide [C(n)mim][Br] ionic liquids from 1-methylimidazole and n-alkyl bromides (with n = 4, 5, 6, 7, and 8). The optimal experimental conditions have been elaborated. Enthalpies of formation of these ionic liquids in the liquid state have been determined using the DSC results according to the Hess Law. The ideal-gas enthalpies of formation of [C(n)mim][Br] were calculated using the methods of quantum chemistry. They were used together with the DSC results to derive indirectly the enthalpies of vaporization of the ionic liquids under study. In order to validate the indirect determination, the experimental vaporization enthalpy of [C(4)mim][Br] was measured by using a quartz crystal microbalance (QCM). The combination of reaction enthalpy measurements by DSC with modern high-level first-principles calculations opens valuable indirect thermochemical options to obtain values of vaporization enthalpies of ionic liquids. PMID- 22435357 TI - Retrospective case series of outcomes following spinal cord infarction. AB - BACKGROUND AND PURPOSE: There are very few studies of functional and rehabilitation outcomes in patients with spinal cord injury (SCI) owing to infarction. METHODS: Retrospective chart review of consecutive admissions to a tertiary medical unit specializing in SCI rehabilitation, Melbourne, Australia. All admissions between 1 January 1995 and 31 December 2008 with a recent onset of SCI owing to ischaemia were included. Outcome measures included the following: demographic characteristics, American Spinal Injury Association (ASIA) Impairment Scale (AIS), length of stay (LOS), medical complications, accommodation, support services, continence, mobility and Functional Independence Measure (FIM) motor scores. Outcome measures recorded at admission, discharge and at 12 months post discharge. RESULTS: Forty-four patients were admitted for rehabilitation (men = 26, 59%), with a median age of 72 years (interquartile range [IQR], 62-79). On admission, 41 (93%) patients had paraplegia. The majority of patients (n = 33, 75%) had an incomplete SCI. Aetiology was vascular in 19 (43%) patients, idiopathic in 11 (25%) and other in 14 (33%). The median LOS in rehabilitation was 85 days (IQR, 24-129). The most common complications were pain (n = 34, 77%), urinary tract infection (n = 25, 57%), spasticity (n = 12, 27%), cardiac failure (n = 11, 25%) and pneumonia (n = 9, 20%). At rehabilitation discharge most patients (n = 35, 80%) had no change in their AIS grade. Despite this, the FIM motor subscale on admission (median = 28; IQR, 21-34) had significantly improved (P < 0.0000) by discharge (median = 66; IQR 42-78). CONCLUSION: Despite their comorbidities and limited change in AIS, these patients had significant improvement in functional abilities during impatient rehabilitation. PMID- 22435361 TI - Anosognosia and neglect respond differently to the same treatments. AB - Different techniques, such as optokinetic stimulation, adaptation to prismatic shift of the visual field to the right, or transcutaneous electrical nerve stimulation (TENS), have been shown to alleviate neglect, at least temporarily. We assessed the effect of these techniques on anosognosia and whether their therapeutic effect, if any, matches that on neglect. The effect of the three types of treatment on anosognosia and neglect was investigated in five patients presenting with both severe anosognosia and neglect. Patient 1 was treatment responsive to anosognosia but not to neglect, whereas patients 4 and 5 showed the reverse pattern, i.e., they were treatment responsive to neglect but not to anosognosia. This "treatment response bias" proved to be a valid means to investigate different effects of treatments in the same patient. PMID- 22435362 TI - Congenital high airway obstruction syndrome in the breech presentation managed by ex utero intrapartum treatment procedure after intraoperative external cephalic version. AB - Congenital high airway obstruction syndrome (CHAOS) caused by laryngeal atresia was diagnosed by prenatal ultrasound in a male fetus at 26 weeks of gestation. Findings included massive ascites, subcutaneous edema, enlarged hyperechogenic lungs with diaphragmatic inversion, dilated trachea, polyhydramnios, and breech presentation. Those findings of CHAOS spontaneously returned to normal by 33 weeks of gestation. However, the placenta was localized to the anterior uterine wall. In addition, the fetal position had been breech until delivery. At 36 weeks of gestation, a planned ex utero intrapartum treatment (EXIT) procedure was performed following intraoperative external cephalic version (ECV) in which the fetus was approached from the posterior wall of the uterus. Laryngoscopy revealed the predicted laryngeal obstruction, and tracheostomy was placed. Intraoperative ECV may be a useful technique in breech presentation before EXIT procedure. PMID- 22435363 TI - Substance use and sexual risk behaviour among HIV-positive men who have sex with men in specialized out-patient clinics. AB - OBJECTIVES: Unprotected sexual intercourse between men who have sex with men (MSM) is the most common route of HIV infection in Germany. Approximately 70% of newly infected people are MSM. Substance use is a determinant of sexual risk behaviour in the general population, but also in the MSM subpopulation. There are only a few studies, from the USA, on the correlation between substance use and sexual risk behaviour in HIV-infected MSM in specialized care. METHODS: In a German sample of 445 HIV-infected MSM treated in specialized out-patient clinics, the influence of substance use on sexual risk behaviour was investigated. Information was obtained from subjects using self-report questionnaires and a structured interview. RESULTS: Recreational drug use was common. The prevalences of cannabis addiction (4.5%), harmful use of cannabis (4.3%) and harmful use of dissociative anaesthetics (0.4%) were higher than in the general German male population. A substantial proportion of patients reported unprotected insertive (32.9%) and receptive (34.6%) anal intercourse during the last 12 months. Use of cannabis, amyl nitrite, dissociative anaesthetics, cocaine, amphetamines and erectile dysfunction medication was significantly correlated with unprotected sexual contacts. Substance use in the context of sexual activity significantly increased sexual risk behaviour. CONCLUSIONS: Substance use, especially in the context of sexual activity, should be taken into account when developing new prevention and intervention programmes aimed at reducing sexual risk behaviour in HIV-infected MSM currently in specialized care. PMID- 22435365 TI - Open wide! Dental settings are an untapped resource for substance misuse screening and brief intervention. PMID- 22435364 TI - Cardiac protein changes in ischaemic and dilated cardiomyopathy: a proteomic study of human left ventricular tissue. AB - The development of heart failure (HF) is characterized by progressive alteration of left ventricle structure and function. Previous works on proteomic analysis in cardiac tissue from patients with HF remain scant. The purpose of our study was to use a proteomic approach to investigate variations in protein expression of left ventricle tissue from patients with ischaemic (ICM) and dilated cardiomyopathy (DCM). Twenty-four explanted human hearts, 12 from patients with ICM and 12 with DCM undergoing cardiac transplantation and six non-diseased donor hearts (CNT) were analysed by 2DE. Proteins of interest were identified by mass spectrometry and validated by Western blotting and immunofluorescence. We encountered 35 differentially regulated spots in the comparison CNT versus ICM, 33 in CNT versus DCM, and 34 in ICM versus DCM. We identified glyceraldehyde 3 phophate dehydrogenase up-regulation in both ICM and DCM, and alpha-crystallin B down-regulation in both ICM and DCM. Heat shock 70 protein 1 was up-regulated only in ICM. Ten of the eleven differentially regulated proteins common to both aetiologies are interconnected as a part of a same network. In summary, we have shown by proteomics analysis that HF is associated with changes in proteins involved in the cellular stress response, respiratory chain and cardiac metabolism. Although we found altered expression of eleven proteins common to both ischaemic and dilated aetiology, we also observed different proteins altered in both groups. Furthermore, we obtained that seven of these eleven proteins are involved in cell death and apoptosis processes, and therefore in HF progression. PMID- 22435366 TI - Auxin: a regulator of cold stress response. AB - The growth hormone auxin regulates essentially all aspects of plant developmental processes under optimum condition. However, as a sessile organism, plants encounter both optimal and non-optimal conditions during their life cycle. Various biotic and abiotic stresses affect the growth and development of plants. Although several phytohormones, such as salicylic acid, jasmonate and ethylene, have been shown to play central roles in regulating the plant development under biotic stresses, the knowledge of the role of hormones, particularly auxin, in abiotic stresses is limiting. Among the abiotic stresses, cold stress is one of the major stress in limiting the plant development and crop productivity. This review focuses on the role of auxin in developmental regulation of plants under cold stress. The emerging trend from the recent experiments suggest that cold stress induced change in the plant growth and development is tightly linked to the intracellular auxin gradient, which is regulated by the polar deployment and intracellular trafficking of auxin carriers. PMID- 22435367 TI - Industry support of CME--are we at the tipping point? PMID- 22435368 TI - The potential for cost savings through bundled episode payments. PMID- 22435369 TI - A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. AB - BACKGROUND: Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. METHODS: In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). RESULTS: The three treatment groups each comprised 25 patients. The mean (+/-SD) NIHSS score at baseline for all patients was 14.4+/-2.6, and the time to treatment was 2.9+/-0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). CONCLUSIONS: Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.). PMID- 22435370 TI - Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. AB - BACKGROUND: Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727). METHODS: In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter [2.6 mmol per liter]) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43. The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile. RESULTS: Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of -39.2, -53.7, and -61.0 percentage points, respectively, as compared with placebo (P<0.001 for all comparisons). CONCLUSIONS: In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.). PMID- 22435371 TI - Membranoproliferative glomerulonephritis--a new look at an old entity. PMID- 22435372 TI - Monogenic mitochondrial disorders. PMID- 22435373 TI - Images in clinical medicine. Kerion celsi. PMID- 22435374 TI - Case records of the Massachusetts General Hospital. Case 9-2012. A 67-year-old man with a persistently elevated PSA level. PMID- 22435375 TI - Lowering plasma cholesterol by raising LDL receptors--revisited. PMID- 22435376 TI - Tumor-cell death, autophagy, and immunity. PMID- 22435378 TI - Dronedarone in high-risk permanent atrial fibrillation. PMID- 22435379 TI - Dronedarone in high-risk permanent atrial fibrillation. PMID- 22435380 TI - Dronedarone in high-risk permanent atrial fibrillation. PMID- 22435381 TI - Dronedarone in high-risk permanent atrial fibrillation. PMID- 22435382 TI - Eculizumab in a patient with dense-deposit disease. PMID- 22435383 TI - Eculizumab for the treatment of dense-deposit disease. PMID- 22435384 TI - Eculizumab and refractory membranoproliferative glomerulonephritis. PMID- 22435385 TI - Videos in clinical medicine. Emergency pericardiocentesis. PMID- 22435386 TI - Images in clinical medicine. Kayser-Fleischer rings in Wilson's disease. PMID- 22435387 TI - Retinal vascular calibre as a predictor of incidence and progression of diabetic retinopathy. AB - Recent advances in retinal photographic imaging techniques have allowed objective and precise measurement of subtle vascular characteristics in the retina, including the retinal vessel calibre (diameter). Data from population-based and clinic-based studies show that changes in retinal calibre are associated with systemic vascular risk factors and might reflect early microcirculatory alterations in people with diabetes prior to the onset of clinically significant complications, such as diabetic retinopathy. Prospective studies suggest that in people with type 1 diabetes, wider retinal venules are associated with progression of mild to more severe levels of retinopathy, including proliferative retinopathy. Thus, studying retinal vascular calibre changes might offer the potential to improve our understanding of the early pathophysiological pathways of diabetic retinopathy, potentially allowing the development of novel therapies. Future research is still needed to assess the ability of retinal vessel calibre measures to provide clinically useful prognostic information that might add to risk prediction of diabetic retinopathy over and above the contribution from traditional risk factors, including glycaemic levels and the duration of diabetes. PMID- 22435388 TI - Influence of the hydrophilic-lipophilic balance of sunscreen emulsions on their water resistance property. AB - The use of sunscreens with sun protective cloths is the photoprotection way mostly used by Occidentals. During sweating or a bath, those products should be still efficient. As the emulsion is the mostly used type of product format, it is essential that the scientist knows how to formulate an emulsion which will be water resistant. The HLB (hydrophilic-lipophilic balance) of a formulation has high influence on this characteristic. PMID- 22435389 TI - Prebiopsy magnetic resonance spectroscopy and imaging in the diagnosis of prostate cancer. AB - INTRODUCTION: Existing screening investigations for the diagnosis of early prostate cancer lack specificity, resulting in a high negative biopsy rate. There is increasing interest in the use of various magnetic resonance methods for improving the yield of transrectal ultrasound-guided biopsies of the prostate in men suspected to have prostate cancer. We review the existing status of such investigations. METHODS: A literature search was carried out using the Pubmed database to identify articles related to magnetic resonance methods for diagnosing prostate cancer. References from these articles were also extracted and reviewed. RESULTS: Recent studies have focused on prebiopsy magnetic resonance investigations using conventional magnetic resonance imaging, dynamic contrast enhanced magnetic resonance imaging, diffusion weighted magnetic resonance imaging, magnetization transfer imaging and magnetic resonance spectroscopy of the prostate. This marks a shift from the earlier strategy of carrying out postbiopsy magnetic resonance investigations. Prebiopsy magnetic resonance investigations has been useful in identifying patients who are more likely to have a biopsy positive for malignancy. CONCLUSIONS: Prebiopsy magnetic resonance investigations has a potential role in increasing specificity of screening for early prostate cancer. It has a role in the targeting of biopsy sites, avoiding unnecessary biopsies and predicting the outcome of biopsies. PMID- 22435390 TI - Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development. AB - Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies. PMID- 22435391 TI - Subclinical hypothyroidism and homeostatic disturbances: case report and literature review. AB - Abnormalities of coagulation have been reported in patients with thyroid dysfunction, although there is no clear information to explain the mechanism behind such irregularities. We are presenting a case of subclinical hypothyroidism that came with coagulation disturbance (hypocoagulation). Her symptoms resolved with leothyroxin in 4 weeks. Further studies are needed to clear the pathogenesis of the coagulation disturbance in such setting. The article also outlines some patents on hypothyroidism and hyperthyroidism. PMID- 22435392 TI - Current updates in the medical management of obesity. AB - Obesity is a chronic medical condition that is expected to become an indirect but leading cause of mortality and morbidity. Obesity results in type 2 diabetes mellitus, insulin resistance, hypertension, dyslipidemia, coronary heart disease. These factors contribute to cardiovascular disease that is a leading cause of death. Therefore, the approach to obesity therapy should be designed to reduce cardiovascular disease risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small. For more effective weight loss, individuals have shown to benefit from anti-obesity medications. Anti-Obesity therapy is considered for individuals with a body mass index greater than 30 kg/m2 or ranging from 25 to 30 kg/m2, or individuals with co-morbid conditions. Recent anti-obese medications affect biological mechanisms that suppress appetite and absorb nutrients to regulate body weight. In this review, we discuss the FDA approved anti-obesity drugs and recent patents which include phentermine/topiramate, pramlintide, lorcaserin, AOD9604, oleoyl-estrone, trk-beta antagonists and melanin concentrating hormone that can reduce adiposity at the molecular level. PMID- 22435393 TI - The novel use of GLP-1 analogue and insulin combination in type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a global public health problem. Due to the progressive nature of the disease, a combination(s) of two or more drugs acting on different pathophysiological process is often necessary to achieve early and sustained achievement of individualized glycemic targets. At the same time, choosing the safest option to avoid hypoglycemia is of paramount importance. GLP 1 analogues are a relatively recent class of anti-diabetic drugs, and are highly effective with an acceptable safety profile. Attempts have been made to combine GLP-1 analogues with basal insulin for management of T2DM. Presently GLP-1 analogues like exenatide/long acting exenatide and liraglutide have been co administered with basal insulin like glargine and detemir respectively, and are approved by regulatory agencies. Currently a fixed dose combination (FDC) of insulin degludec and liraglutide is under development. GLP-1 analogue and insulin as FDC or by co-administration, is a rational method of controlling fasting and postprandial glucose effectively. The efficacy and safety of this combination has been studied in a wide population with promising outcomes. Innovative use of GLP 1 analogues beyond diabetes is also being attempted, and a variety of patents are filed or granted for the same. This review summarizes the current status of GLP-1 and insulin combination in the management of T2DM and highlights the new frontiers in research involving GLP-1. Patents on combination of GLP-1 and insulin which were granted earlier, and the ones which have been applied for, are also discussed. PMID- 22435394 TI - Macrocycle formation by proton-template-induced dimerization of complexes with (alkoxoimino)pyridine. AB - The existence of a strong hydrogen bond between two molecules of an (alkoxoimino)pyridinemanganese(I) complex induces their dimerization and the formation of a metallamacrocycle. The expected intramolecular attack of the alkoxo moiety is disfavored. PMID- 22435395 TI - Triaspartate: a model system for conformationally flexible DDD motifs in proteins. AB - Understanding the interactions that govern turn formation in the unfolded state of proteins is necessary for a complete picture of the role that these turns play in both normal protein folding and functionally relevant yet disordered linear motifs. It is still unclear, however, whether short peptides can adopt stable turn structures in aqueous environments in the absence of any nonlocal interactions. To explore the effect that nearest-neighbor interactions and the local peptide environment have on the turn-forming capability of individual amino acid residues in short peptides, we combined vibrational (IR, Raman, and VCD), UV CD, and (1)H NMR spectroscopies in order to probe the conformational ensemble of the central aspartic acid residue of the triaspartate peptide (DDD). The study was motivated by the recently discovered turn propensities of aspartic acid in GDG (Hagarman; et al. Chem.-Eur. J. 2011, 17, 6789). We investigated the DDD peptide under both acidic and neutral conditions in order to elucidate the effect that side-chain protonation has on the conformational propensity of the central aspartic acid residue. Amide I' profiles were analyzed in terms of two dimensional Gaussian distributions representing conformational subdistributions in Ramachandran space. Interestingly, our results show that while the protonated form of the DDD peptide samples various turn-like conformations similar to GDG, deprotonation of the peptide eliminates this propensity for turns, causing the fully ionized peptide to exclusively sample pPII and beta-strand-like structures. To further explore the factors stabilizing these more extended conformations in fully ionized DDD, we analyzed the temperature dependence of both the UV-CD spectrum and the (3)J(H(N),H(alpha)) coupling constants of the two amide protons (N- and C-terminal) in terms of a simple two-state (pPII-beta) thermodynamic model. Thus, we were able to obtain the enthalpic and entropic differences between the pPII and beta-strand conformations of the central and C-terminal residue. For the central residue, we obtained DeltaH(3) = -12.0 kJ/mol and DeltaS(3) = -73.8 J/mol.K, resulting in a much larger room-temperature Gibbs free energy of 10.0 kJ/mol, which effectively locks the C-terminal in a beta-like conformation. A comparison of the temperature dependence of the chemical shifts reveals that there is indeed some type of protection of the amide protons from solvent in ionized DDD. This finding and several other lines of evidence suggest that both conformations of ionized DDD are stabilized by hydrogen bonding between the carboxylate groups of the central and C-terminal residue and the respective amide protons. These hydrogen bonds can be expected to be eliminated by side chain protonation and substituted by hydrogen bonds between the N-terminal amide proton and the C-terminal carbonyl group as well as between the central aspartate side chain and the N-terminal amide proton. Hence, our results are indicative of a pH-induced switch in hydrogen-bonding patterns of aspartic acid motifs. PMID- 22435396 TI - Letter to the editor: electromagnetic hypersensitivity. PMID- 22435397 TI - Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients. AB - BACKGROUND AND PURPOSE: Dopamine dysregulation in restless legs syndrome (RLS) may be varied by the severity of RLS, which could contribute to the conflicting results from previous functional neuroimaging studies on the central dopaminergic neurotransmission of RLS. The aim of this study was to observe whether reduced striatal dopaminergic neurotransmission is associated with moderate to moderately severe RLS. METHODS: Thirteen elderly patients with RLS and 12 normal elderly controls were enrolled in the study. All the subjects were dopaminergic-drug naive and twelve patients with RLS had the severity of moderate to moderately severe degree based on the International Restless Legs Syndrome Study Group (IRLSSG) Severity Scale. We compared dopamine transporter density (DAT) availability and D2 receptor density in the striatum between patients with RLS and controls using [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane single photon emission computed tomography (SPECT) and [(123)I]iodobenzamide SPECT. RESULTS: Dopamine transporter density of patients with RLS was increased in the caudate (P = 0.037), posterior putamen (P = 0.041), and entire striatum (P = 0.046) compared with that of normal controls. DAT density was higher in the anterior putamen of patients with RLS than controls, although statistically not significant (P = 0.079). There was no difference in the D2 receptor density between patients with RLS and normal controls in the whole striatum or any of subregions. CONCLUSIONS: Dysregulation rather than simple upregulation or downregulation of central dopaminergic neurotransmission may underlie the pathogenesis of RLS, and decreased dopaminergic neurotransmission may cause moderate to moderately severe RLS in the elderly. PMID- 22435398 TI - Osteocalcin as a predictor of the metabolic syndrome in older persons: a population-based study. AB - BACKGROUND: Recent evidence indicates that the osteoblast-derived protein osteocalcin is able to influence adiposity and glucose homeostasis in mice. Little is known about this relationship in humans. OBJECTIVE: To investigate the association of plasma osteocalcin levels with the metabolic syndrome in a community-dwelling cohort of older persons in the Netherlands. DESIGN AND PARTICIPANTS: Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing multidisciplinary cohort study in a representative sample of the older Dutch population (>=65 years old). A total of 1284 subjects (629 men and 655 women) between the age of 65 and 88 years participated in this study. MEASUREMENTS: Metabolic syndrome (U.S. National Cholesterol Education Program definition) and its individual components were assessed as well as plasma osteocalcin levels. RESULTS: Among the participants, the prevalence of the metabolic syndrome was 37.1%. The median osteocalcin level was 2.0 nmol/l. Plasma osteocalcin was inversely associated with the metabolic syndrome. The odds ratio (OR) was 3.68 with 95% confidence interval (CI) 2.53-5.34 for the lowest osteocalcin quartile compared to the highest quartile. The association between osteocalcin and the metabolic syndrome was mainly determined by high triglycerides, low HDL, waist circumference and hypertension. CONCLUSION: Low plasma osteocalcin levels are strongly associated with the metabolic syndrome in an older community-dwelling population. PMID- 22435399 TI - Development of stabilized itraconazole nanodispersions by using high-gravity technique. AB - PURPOSE: For large scale preparation of stabilized itraconazole (ITZ) nanodispersions to improve the dissolution rate. METHOD: High-gravity technique was employed to produce ITZ nanodispersions. RESULTS: Stabilizer had a significant effect on the stability of drug nanoparticles. Hydroxypropylmethylcellulose was found to be the most effective stabilizer to prevent drug nanoparticles from aggregation. ITZ nanoparticles with an average size of 210 nm were obtained. Mannitol was the suitable carrier matrix for improving the flowability and the dissolution rate of ITZ nanodispersion. The effects of operating variables on the particle size distribution were investigated in detail. The stability of ITZ nanodispersions was characterized by scanning electron microscopy, X-ray diffraction, Fourier transform-infrared spectroscopy, differential scanning calorimetry, and in vitro dissolution studies. After 6 months storage, the nanodispersion showed unchanged particles size, morphology, crystal state, chemical structure, and dissolution. In vitro dissolution rate indicated that the nanodispersion could significantly enhance the dissolution rate when compared to the commercial available Sporanox capsules. The nanodispersion achieved 70% of drug dissolution in 10 min, whereas the Sporanox capsules only dissolved 20% during the same period. CONCLUSION: This study demonstrated that high-gravity technique is a promising method for large scale production of nanodispersions to enhance the dissolution rate of poorly water-soluble drugs. PMID- 22435400 TI - Growth of protein crystals in hydrogels prevents osmotic shock. AB - High-throughput protein X-ray crystallography offers a significant opportunity to facilitate drug discovery. The most reliable approach is to determine the three dimensional structure of the protein-ligand complex by soaking the ligand in apo crystals. However, protein apo crystals produced by conventional crystallization in a solution are fatally damaged by osmotic shock during soaking. To overcome this difficulty, we present a novel technique for growing protein crystals in a high-concentration hydrogel that is completely gellified and exhibits high strength. This technique allowed us essentially to increase the mechanical stability of the crystals, preventing serious damage to the crystals caused by osmotic shock. Thus, this method may accelerate structure-based drug discoveries. PMID- 22435401 TI - Controlled growth of polyaniline fractals on HOPG through potentiodynamic electropolymerization. AB - Polyaniline (PANI) in fractal dimension has been electrodeposited reproducibly on highly oriented pyrolytic graphite (HOPG) from 0.2 M aniline in 1 M aqueous HCl solution by potentiodynamic sweeping in the range of -0.2 to 0.76 V vs Ag/AgCl at room temperature. Fractal growth of PANI dendrimers is affected by diffusion limited polymerization (DLP) at a sweep rate of 15 mV s(-1) for 43 min. This type of PANI dendrimer is prepared for the first time on such large area HOPG substrate by electrochemical technique using rather simple cell setup. The fractal dimension has been determined by chronoamperometry (CA) and box counting technique and is found to vary from 1.4 to 1.9 with the duration of electropolymerization. The sweep rate, terminal oxidation potential, and the diverse surface anisotropy of the HOPG surface are found to be crucial factors in controlling the growth of such PANI fractals. PMID- 22435402 TI - On the spatial foundations of the conceptual system and its enrichment. AB - A theory of how concept formation begins is presented that accounts for conceptual activity in the first year of life, shows how increasing conceptual complexity comes about, and predicts the order in which new types of information accrue to the conceptual system. In a compromise between nativist and empiricist views, it offers a single domain-general mechanism that redescribes attended spatiotemporal information into an iconic form. The outputs of this mechanism consist of types of spatial information that we know infants attend to in the first months of life. These primitives form the initial basis of concept formation, allow explicit preverbal thought, such as recall, inferences, and simple mental problem solving, and support early language learning. The theory details how spatial concepts become associated with bodily feelings of force and trying. It also explains why concepts of emotions, sensory concepts such as color, and theory of mind concepts are necessarily later acquisitions because they lack contact with spatial descriptions to interpret unstructured internal experiences. Finally, commonalities between the concepts of preverbal infants and nonhuman primates are discussed. PMID- 22435403 TI - Investigating the impact of parental status and depression symptoms on the early perceptual coding of infant faces: an event-related potential study. AB - Infant faces are highly salient social stimuli that appear to elicit intuitive parenting behaviors in healthy adult women. Behavioral and observational studies indicate that this effect may be modulated by experiences of reproduction, caregiving, and psychiatric symptomatology that affect normative attention and reward processing of infant cues. However, relatively little is known about the neural correlates of these effects. Using the event-related potential (ERP) technique, this study investigated the impact of parental status (mother, non mother) and depression symptoms on early visual processing of infant faces in a community sample of adult women. Specifically, the P1 and N170 ERP components elicited in response to infant face stimuli were examined. While characteristics of the N170 were not modulated by parental status, a statistically significant positive correlation was observed between depression symptom severity and N170 amplitude. This relationship was not observed for the P1. These results suggest that depression symptoms may modulate early neurophysiological responsiveness to infant cues, even at sub-clinical levels. PMID- 22435404 TI - Sonoclot(r) evaluation of single- and multiple-dose subcutaneous unfractionated heparin therapy in healthy adult dogs. AB - BACKGROUND: Heparin therapy is difficult to monitor due to variation in animal response. While laboratory measurements of activated partial thromboplasin time (aPTT) and Anti-Xa activity (AXA) accurately describe heparin effect, their availability is limited. HYPOTHESIS: Sonoclot analysis would be as sensitive as AXA and aPTT to monitor effects of unfractionated heparin (UFH) in healthy adult dogs. ANIMALS: Six adult mixed-breed dogs. METHODS: A prospective study design was employed. On day 1, baseline samples were collected (CBC, PT, aPTT, and Sonoclot), and UFH (300 U/kg SC) was administered to 6 dogs following an IV loading dose of 50 U/kg. Sonoclot and aPTT were performed hourly for 12 hours. AXA was assayed at hours 3, 6, 9, and 12. UFH (300 U/kg q8 h SC) was administered at 12 hours, and subsequently (q8 h) for 2 additional days. On day 4, a final dose of UFH was administered, and a sampling protocol identical to day 1 was performed. RESULTS: Sonoclot activated clotting time (ACT) and clot rate (CR) correlated with AXA (R = 0.69, R = 0.65, respectively, P < .001), although to a lesser degree than aPTT (R = 0.75, P < .001). Linear regression using ACT and CR as covariates indicated a stronger correlation with AXA (R = 0.73, P < .001). ACT values strongly correlated with aPTT (R = 0.87, P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of UFH to healthy dogs results in progressive changes in Sonoclot values. AXA was correlated with a combination of ACT and CR and with aPTT. Sonoclot may play a role in monitoring UFH therapy; however, prospective studies evaluating its utility in clinical cases are warranted. PMID- 22435406 TI - Improved strategies for HIV diagnosis among men who have sex with men (MSM) in Buenos Aires, Argentina, a population with a high prevalence and incidence of HIV infection. AB - BACKGROUND: In Argentina, HIV diagnosis in adults is made using one or two enzyme immunoassay tests and a confirmatory test. These strategies may fail to identify infected individuals during early primary infection, which represents an important public health problem among groups with a high HIV incidence, such as men who have sex with men (MSM) (6.3% persons/year). The general objective of this study was to contribute to reducing HIV transmission among MSM through the identification of antibody-negative, nucleic acid-positive individuals. FINDINGS: A total of 1549 MSM were recruited for an HIV seroprevalence study. A total of 161 (10.4%) MSM were HIV-positive and 14 (0.9%) were indeterminate. Among the 1374 negative individuals, 16 (1.2%) exhibited reactive results in the screening assay. Indeterminate Western blot (WB) samples and negative WB samples (with discordant results in the screening) were analysed to detect HIV nucleic acid by viral load testing. Up to 23.1% of HIV-indeterminate WB samples and 7.1% of HIV negative WB samples with discordant results in the screening assays had detectable nucleic acid. Overall, 14.8% of the samples with discordant or indeterminate results were identified as HIV-positive using direct diagnosis. With the identification of four new cases using the nucleic acid detection test, the HIV prevalence in MSM increased by 0.3% (from 10.4 to 10.7%). CONCLUSIONS: The results of this study suggest the importance of including nucleic acid detection in the HIV algorithm for MSM with HIV-indeterminate WB results and those with HIV-negative WB results and discordant results in screening assays, in order to decrease HIV transmission among this population with a high HIV prevalence and incidence. PMID- 22435405 TI - Histamine: an undercover agent in multiple rare diseases? AB - Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G-protein coupled receptors. Thus, histamine-related effects are the results of highly interconnected and tissue-specific signalling networks. Consequently, alterations in histamine-related factors could be an important part in the cause of multiple rare/orphan diseases. Bearing this hypothesis in mind, more than 25 rare diseases related to histamine physiopathology have been identified using a computationally assisted text mining approach. These newly integrated data will provide insight to elucidate the molecular causes of these rare diseases. The data can also help in devising new intervention strategies for personalized medicine for multiple rare diseases. PMID- 22435407 TI - Ultrastructural immunolocalization of dentin matrix protein 1 on Sharpey's fibers in monkey tooth cementum. AB - Despite the importance of dentin matrix protein 1 (DMP1) in the formation of mineralized tissue, including dentinogenesis and osteogenesis, its precise role in cementogenesis remains to be clarified fully. The purpose of our study was to demonstrate the ultrastructural immunolocalization of DMP1 in monkey molar tooth cementum. Japanese Macaca fuscata monkeys were fixed by perfusion. The upper molar teeth and accompanying periodontium then were dissected and demineralized with EDTA. Cryosections were obtained, incubated in anti-DMP1 polyclonal antibody, and processed by immunoperoxidase and immunogold labeling. Intense immunoperoxidase staining for DMP1 was observed in acellular extrinsic fiber cementum, particularly in Sharpey's fibers. Cementocyte lacunae with canaliculi showed DMP1 staining in the apical region of the tooth root. Electron immunomicroscopy revealed the close proximity of DMP1 to collagen fibrils in Sharpey's fibers at the mineralization front. Intense immunogold labeling was localized on the walls of the cementocyte lacunae in cellular cementum. These results should contribute to better understanding of the role of DMP1, not only in Sharpey's fiber biomineralization, but also in the maintenance of the cementocyte lacunar space in cementum. PMID- 22435408 TI - Public health impacts of combustion emissions in the United Kingdom. AB - Combustion emissions are a major contributor to degradation of air quality and pose a risk to human health. We evaluate and apply a multiscale air quality modeling system to assess the impact of combustion emissions on UK air quality. Epidemiological evidence is used to quantitatively relate PM(2.5) exposure to risk of early death. We find that UK combustion emissions cause ~13,000 premature deaths in the UK per year, while an additional ~6000 deaths in the UK are caused by non-UK European Union (EU) combustion emissions. The leading domestic contributor is transport, which causes ~7500 early deaths per year, while power generation and industrial emissions result in ~2500 and ~830 early deaths per year, respectively. We estimate the uncertainty in premature mortality calculations at -80% to +50%, where results have been corrected by a low modeling bias of 28%. The total monetized life loss in the UK is estimated at L6-62bn/year or 0.4-3.5% of gross domestic product. In Greater London, where PM concentrations are highest and are currently in exceedance of EU standards, we estimate that non UK EU emissions account for 30% of the ~3200 air quality-related deaths per year. In the context of the European Commission having launched infringement proceedings against the UK Government over exceedances of EU PM air quality standards in London, these results indicate that further policy measures should be coordinated at an EU-level because of the strength of the transboundary component of PM pollution. PMID- 22435409 TI - Pain relief assessment by aromatic essential oil massage on outpatients with primary dysmenorrhea: a randomized, double-blind clinical trial. AB - AIM: This study assessed the effectiveness of blended essential oils on menstrual cramps for outpatients with primary dysmenorrhea and explored the analgesic ingredients in the essential oils. MATERIAL AND METHODS: A randomized, double blind clinical trial was conducted. Forty-eight outpatients were diagnosed with primary dysmenorrhea by a gynecologist and had 10-point numeric rating scales that were more than 5. The patients were randomly assigned to an essential oil group (n = 24) and a synthetic fragrance group (n = 24). Essential oils blended with lavender (Lavandula officinalis), clary sage (Salvia sclarea) and marjoram (Origanum majorana) in a 2:1:1 ratio was diluted in unscented cream at 3% concentration for the essential oil group. All outpatients used the cream daily to massage their lower abdomen from the end of the last menstruation continuing to the beginning of the next menstruation. RESULTS: Both the numeric rating scale and the verbal rating scale significantly decreased (P < 0.001) after one menstrual cycle intervention in the two groups. The duration of pain was significantly reduced from 2.4 to 1.8 days after aromatherapy intervention in the essential oil group. CONCLUSION: Aromatic oil massage provided relief for outpatients with primary dysmenorrhea and reduced the duration of menstrual pain in the essential oil group. The blended essential oils contain four key analgesic components that amount to as much as 79.29%; these analgesic constitutes are linalyl acetate, linalool, eucalyptol, and beta-caryophyllene. This study suggests that this blended formula can serve as a reference for alternative and complementary medicine on primary dysmenorrhea. PMID- 22435410 TI - Feverfew for migraine prophylaxis: a systematic review. AB - Feverfew has been studied for the treatment of migrane in several studies and the pharmacologic mechanisms are preliminarily understood. We performed a systematic review of randomized controlled trials and present the clinical findings and potential implications. The modality of data collection and reporting in the individual studies does not support a pooling of results, but does suggest benefit of feverfew in migraine prophylaxis for at least subsets of the population with the disorder. Pharmacologically, there is some potential for concern with long-term dosing given its cyclooxygenase-2 inhibiting effects and longer-term studies will be needed to ameliorate these concerns in coronary disease patients. PMID- 22435411 TI - Inhibition of paclitaxel metabolism in vitro in human hepatocytes by Ginkgo biloba preparations. AB - Since the late 1980s, chemotherapy-induced cognitive impairment, also known as "chemobrain", has been a recognized side effect in patients undergoing cancer treatment ( Matsuda et al., 2005 ). Although products containing Ginkgo biloba may be used by patients undergoing chemotherapy with paclitaxel and other agents, the potential for an herb-drug interaction with this combination has not been adequately explored. This report describes the inhibition of paclitaxel metabolism by Ginkgo preparations in vitro in human hepatocytes. Hydrolyzate of Ginkgo extract (10-100 mM in terpene lactone concentration) caused a dose dependent inhibition of the 6alpha -hydroxylation of paclitaxel, the enzymatic activity responsible for the majority of the clearance of that drug in clinical applications; parent extract had no effect. Contrary to the assumed therapeutic benefit of Ginkgo, its concomitant use with paclitaxel could result in elevated blood levels of the chemotherapeutic, with attendant exacerbation of cognitive impairment and other toxic effects associated with cancer therapy. PMID- 22435412 TI - Investigations on the effect of flavonoids from banana, Musa paradisiaca L. on lipid metabolism in rats. AB - Oral administration of flavonoids extracted from unripe fruits of Musa paradisiaca showed significant hypolipidemic activities in male rats (Sprague Dawley strain) at a dose of 1 mg/100 g body weight (BW)/day. Concentrations of cholesterol, phospholipids, free fatty acids, and triglycerides showed significant decrease in the serum, liver, kidney, and brain of experimental animals. HMG CoA reductase activity was found to be enhanced, while activities of glucose-6-phosphate dehydrogenase and malate dehydrogenase were significantly reduced. Activities of lipoprotein lipase and plasma LCAT showed significant enhancement. A significant increase in the concentrations of hepatic and fecal bile acids and fecal neutral sterols was also observed indicating a higher rate of degradation of cholesterol. The present study indicates that although there is an increase in the rate of synthesis of cholesterol in the liver, the process of degradation exceeds the rate of synthesis. PMID- 22435413 TI - Practices, attitudes, and beliefs regarding dietary supplements among Florida's dietitians and nurses. AB - This study investigated the practices, attitudes, and beliefs of Florida's nurses and dietitians regarding dietary supplements (DS). Eighty-nine dietitians and 64 nurses responded to a self-reported online survey about nutrient-based supplements, defined as nutrients taken to supplement the diet for enhancing health, and herbal supplements, defined as plants used for enhancing health rather than food seasoning. Personal use of nutrient-based supplements for treatment of a health condition was higher among nurses (67%) than dietitians (42%) (p <. 05). However, dietitians recommended nutrient-based supplements more often than nurses (p <. 05). Both groups used fewer herbal than nutrient-based supplements (p <. 001). More nurses than dietitians believed herbal supplements to be effective (p <. 05). Practice trends regarding DS identified among Florida's dietitians and nurses can be a reference for states and countries in which the number of older adults is growing. PMID- 22435414 TI - The essentials of essential fatty acids. AB - All fats, including saturated fatty acids, have important roles in the body. However, the most important fats are those that the body cannot make and thus must come from the food we eat. These essential fatty acids (EFAs) are based on linoleic acid (omega-6 group) and alpha-linolenic acid (omega-3 group). We need both groups of essential fatty acids to survive. For various reasons EFA deficiency is common in the general population, as is a disproportionate intake of omega-6 fatty acids over omega-3 fatty acids. As such, it is important to eat the right foods to make sure that you're taking in enough and the right kinds of the essential fatty acids. However, there is much more to the story. Studies have shown that increasing the intake of certain essential fatty acids, either alone or in combination with other fats and compounds, can increase health, help in treating certain diseases, and even improve body composition, mental and physical performance. PMID- 22435415 TI - An evidence-based systematic review of bilberry (Vaccinium myrtillus) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22435420 TI - Which is the best method to estimate the actual ureteral length in patients undergoing ureteral stent placement? AB - OBJECTIVES: To define the best modality for estimating ureteral length in patients undergoing ureteral stent placement. METHODS: This study enrolled 151 patients (169 ureters) undergoing stent insertion. In all of them, an intravenous urography and non-contrast computed tomography were carried out. The actual ureteral length was determined by direct measurement using a 5-Fr ureteral catheter. A multivariate analysis evaluated the association between the ureteral length and each of the following parameters: body height, body surface area, ureteral trace by intravenous urography, linear distance (liner distance 1) from the ureteropelvic junction to the ureterovesical junction by intravenous urography, linear distance (liner distance 2) from the mid kidney to the ureterovesical junction by intravenous urography, and the distance from the level of the renal vein to the ureterovesical junction by axial computed tomography (axial computed tomography distance). RESULTS: The mean actual ureteral length was 23.2 cm (median 24 cm, range 16-29 cm). The Spearman correlation coefficients for body height, body surface area, ureteral trace, liner distance 1, liner distance 2 and axial computed tomography distance were 0.3126, 0.3076, 0.4541, 0.5230, 0.4796 and 0.6168, respectively. Axial computed tomography distance showed the best correlation with the actual ureteral length. CONCLUSION: The axial computed tomography distance as calculated by the axial computed tomography can more reliably predict the actual ureteral length than other parameters. Further studies are required to show the best method for estimating the actual ureteral length in patients undergoing ureteral stent placement. PMID- 22435421 TI - Plasma exchange and rituximab treatment for lenalidomide-associated cold agglutinin disease. AB - BACKGROUND: Lenalidomide is an amino-substituted analog of thalidomide with potent immunomodulatory properties. The drug has been widely used for treatment of multiple myeloma and myelodysplastic syndrome (MDS) associated with 5q abnormality. The most common side effects are cytopenias, infections, and deep venous thrombosis. CASE STUDY: We report a clinical observation of severe autoimmune hemolytic anemia (AIHA) due to cold agglutinin disease (CAD) that developed 11 days after initiation of lenalidomide treatment in a patient with MDS who relapsed after allogeneic bone marrow transplantation. RESULTS: CAD was diagnosed by the presence of hemolytic variables and cold agglutinin detected in patient's plasma. The antibody screen, which was performed at 37 degrees C, was negative throughout. The direct antiglobulin test was positive only for complement (C3d). These findings supported the diagnosis of CAD associated with lenalidomide administration. Other causes of hemolysis including ABO incompatibility and infectious etiologies were ruled out. Rituximab therapy in conjunction with daily plasma exchange decreased the rate of hemolysis and transfusion requirement in our case. CONCLUSION: In addition to warm AIHA, lenalidomide use can also be associated with development of CAD. Rituximab given in conjunction with plasma exchange can be effective in treating CAD in this setting. PMID- 22435422 TI - Large linear papular eruption on the forearm. Diagnosis: Lichen striatus. PMID- 22435423 TI - Dermatoses secondary to Asian cultural practices. AB - Although Asian cultural practices, such as acupuncture and threading, are widely used, there is limited medical literature describing their cutaneous effects and complications. This review briefly describes therapeutic cultural practices (traditional Chinese medicine, acupuncture, cupping, moxibustion, coining, Ayurveda, and aromatherapy) and cosmetic cultural practices (hair oils, henna, bindis, saris, and threading), with particular attention to dermatoses secondary to these practices. Traditional Chinese medicine and Ayurveda may cause heavy metal toxicity, severe cutaneous adverse reactions, and contact dermatitis. Cupping, moxibustion, and coining lead to dermatoses that may be mistaken for abuse by people unfamiliar with the practices. Hair oils may cause contact dermatitis and folliculitis. Paraphenylenediamine in black henna and bindi dyes and adhesives can cause severe allergic contact dermatitis. The drawstring in saris causes frictional irritation, which can lead to tinea corporis, koebnerization, and even squamous cell carcinoma. Threading may cause folliculitis, impetigo, and verrucae. The increasing prevalence of Asian cultural practices, which are performed inside and outside of Asia in this era of globalization, demands that dermatologists be familiar with the secondary dermatoses that may develop. PMID- 22435424 TI - Myeloid leukemia cutis in the setting of myelodysplastic syndrome: a crucial dermatological diagnosis. AB - Cutaneous involvement by myeloid leukemic cells is an unusual phenomenon. Clinical manifestations vary from erythematous papules to plum-colored plaques and nodules that may become purpuric and ulcerate. The definitive diagnosis of myeloid leukemia cutis requires the analysis of biopsy specimens using immunohistochemical staining to determine the expression of selective cell surface markers. We will review myeloid leukemia when first evident in the skin, particularly in the setting of myelodysplastic syndrome. The diagnosis of leukemia cutis in patients with myelodysplastic syndrome is indicative of concomitant or impending acute leukemic transformation. The early recognition and accurate identification of leukemic skin infiltrates in myelodysplastic patients is crucial, as this finding can have significant therapeutic and prognostic implications. PMID- 22435425 TI - The roles of cells and cytokines in the pathogenesis of psoriasis. AB - Psoriasis is considered an immune chronic disease in which T cells are accepted as important. Nowadays, it is believed that psoriasis is most likely a T helper (Th)1/Th17 induced inflammatory disease. However, some other cells, such as endothelial cells, dendritic cells, monocytic cells, neutrophils, keratinocytes, and several cytokines, appear to have, at different stages of the disease, an important role in its pathogenesis. For instance, the response to psoriasis therapy is dependent not only on the inactivation of Th1 and Th17 immune responses but also on the inactivation of dendritic cell products. Moreover, interleukin (IL)-23 deregulation appears to be an independent factor in the pathogenesis of psoriasis. Indeed, currently, the IL-23/Th17 axis is believed to be crucial in psoriasis pathogenesis, and its inhibition appears to be important for therapeutic achievement. This review presents the roles and interactions of cells and cytokines that are related to psoriasis pathogenesis. PMID- 22435426 TI - Progressive cribriform and zosteriform hyperpigmentation: a clinicopathologic study. AB - BACKGROUND: Progressive cribriform and zosteriform hyperpigmentation (PCZH) is a disorder of pigmentation. Although several cases of PCZH have been reported, no clinicopathologic studies of the condition have been published in the English language literature. OBJECTIVES: The purpose of this study was to determine the clinical characteristics and histologic findings of PCZH. METHODS: Between 1999 and 2009, 30 patients were diagnosed with PCZH in our Department of Dermatology. Medical records, clinical photographs, and pathologic findings for each patient were retrospectively reviewed. RESULTS: The patients included 16 men and 14 women. The mean age at onset was 14.27 years. The trunk was the most common site of involvement. Microscopic examination showed an increased level of melanin pigment in the basal cell layer compared with adjacent normal skin, although no significant difference existed in the number of melanocytes. Pigmentary incontinence was observed in 13 of 30 cases. CONCLUSIONS: There was no significant difference in prevalence, age at onset, and duration of lesions between male and female patients with PCZH. The lesions corresponded to the lines of Blaschko and were localized rather than exhibiting diffuse patterns. A common feature of the histopathologic findings was higher melanin content in the lesions than in normal skin but with no significant difference in the number of melanocytes. PMID- 22435427 TI - Evaluation of a newly-developed immunochromatography strip test for diagnosing dermatophytosis. AB - BACKGROUND: Traditionally, dermatophytosis, a common disease affecting millions of people world-wide, has been diagnosed by direct microscopy and fungal culture. The immunochromatography (ICG) strip test was recently developed. METHODS: We compared the performance of the ICG strip test for the detection of dermatophytes in samples from human skin and nails with direct microscopy. The 160 samples, consisting of 88 skin and 72 nail specimens, were subjected to direct microscopy study using a 20% KOH solution and to examination with the ICG strip test. Of 160 samples, 18 were examined by fungal culture using Sabouraud dextrose agar medium. RESULTS: We found that the overall sensitivity and specificity of the ICG test were 83.5% and 66.7%; they were 82.1% and 76.2% for the 88 skin and 85.4% and 58.3% for the 72 nail specimens, respectively. CONCLUSIONS: Our findings indicate that the efficacy of the ICG test is comparable to direct microscopy for the detection of dermatophytes. Performance of the assay was easy, and results were available quickly. We suggest that it is an effective tool for dermatophytosis screening. PMID- 22435428 TI - Dermatophyte infections mimicking other skin diseases: a 154-person case survey of tinea atypica in the district of Cagliari (Italy). AB - BACKGROUND: Although usually simple, the diagnosis of dermatophyte infection is sometimes neglected. An observational study has been realized to evaluate the role of corticosteroid exposure (tinea incognito) and of other primary characteristics of the dermatophytosis that from onset mimic other diseases and mislead an unexperienced physician. MATERIALS AND METHODS: Between 1990 and 2009, all cases of atypical dermatophytosis mimicking other skin diseases were collected from the more general number of dermatophyte infections diagnosed at the Dermatology Department of Cagliari University, Italy. RESULTS: One-hundred and fifty-four cases (71 male/83 female, 2-81 years old) were studied, with a median of 7 cases/year. The most observed clinical forms were those mimicking impetigo, eczematous dermatitis, lupus erythematosus, polymorphous light eruption, psoriasis, and rosacea. The identified dermatophytes were: Microsporum canis (70 cases), Trichophyton rubrum (43 cases), Trichophyton mentagrophytes var. mentagrophytes (29 cases), Trichophyton mentagrophytes var. interdigitale (six cases), Microsporum gypseum (three cases), Epidermophyton floccosum (two cases), and Trichophyton verrucosum (one case). Diagnostic difficulties are discussed, with special attention to the origin of the pathomorphosis. CONCLUSIONS: In our experience, clinical atypia is not a mere consequence of corticosteroid therapy but present at the very onset of the illness, due to the variable dermatophyte invasive capacity, the site of invasion, physiological individual, and/or acquired condition, such as excessive washing or sun exposure. Therefore, we suggest using the term "tinea atypica" rather than "tinea incognito" to include all forms of dermatophytosis that do not present the classic features for both primary and secondary pathomorphosis. PMID- 22435429 TI - Self-medication and adherence to treatment in psoriasis. AB - BACKGROUND: Self-medication and non-adherence to treatment are very common practice. This often implies bad results for the patients, as well as for the physicians. Several studies suggest that up to 30-40% of the population is non adherent to treatments. This problem generates 5% of all hospitalizations, having caused about 45,000 deaths in 2007 in Argentina. MATERIALS AND METHODS: A 21 question survey was carried out among 176 patients with psoriasis in the Psoriasis Center at the Fernandez Hospital in Buenos Aires, Argentina. RESULTS: Seventy-seven percent of the patients were non-adherent to treatment, and 33% were self-medicated. The two groups combined accounted for 82% of the population studied. We found no significant differences among the variables studied in either the non-adherence or the combined group, although males comprised 67% and females 33% of the self-medicated group, and that difference was statistically significant (P<0.025). CONCLUSIONS: Self-care is a very complex behavior to be explained by a single cause, which clearly makes it a multifactorial problem. In our view, patient education, the physician-patient relationship, and availability of more effective therapeutic options would be significant factors in modifying a deep-rooted behavior pattern. PMID- 22435430 TI - Amelanotic melanomas presenting as red skin lesions: a diagnostic challenge with potentially lethal consequences. AB - OBJECTIVE: To characterize epidemiologic and clinical features of red primary amelanotic melanomas, an atypical presentation of melanoma that is underemphasized in patient and physician education. PATIENTS AND METHODS: Review of a prospectively collected melanoma database identified 46 patients with red amelanotic melanomas, whose clinical features were compared with 329 patients with pigmented melanomas from the same database and same timeframe from January 1964 to September 2005. RESULTS: Red amelanotic melanomas represented 3.9% of all melanomas recorded in our database and accounted for nearly 70% of amelanotic melanomas. Melanoma was included in the clinical differential diagnosis in 32% of red amelanotic melanomas vs. 94% of pigmented melanomas (P<0.001). Red amelanotic melanomas more commonly underwent shave biopsy (55 vs. 12%, P<0.001) and more likely had positive deep margins (35 vs. 9%, P<0.001) but had comparable risks of metastasis and mortality. CONCLUSION: Red amelanotic melanomas are often misdiagnosed clinically but carry a mortality risk comparable to pigmented melanomas. Clinicians screening for melanoma should be more vigilant in considering melanoma in the differential diagnosis of red skin lesions. PMID- 22435431 TI - Characterization of TGM1 c.984+1G>A mutation identified in a homozygous carrier of lamellar ichthyosis. AB - BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare, nonsyndromic, heterogeneous disorder of cornification. It is divided into three clinical subtypes: lamellar ichthyosis (LI); congenital ichthyosiform erythroderma; and harlequin ichthyosis. In the majority of patients, LI is caused by transglutaminase-1 (TGase1) deficiency resulting from mutations in both copies of the transglutaminase 1 (TGM1) gene in chromosome 14. CASE REPORT: We report a patient with a severe LI phenotype who has a homozygous putative splicing mutation in the TGM1 gene. Our aim is to assess the pathologic effect of the TGM1 c.984+1G>A by splicing assays and bioinformatic tools. RESULTS: c.984+1G>A mutation created two alternative TGM1 mRNA splice variants that included 30 or 32 nucleotides of the 5' of intron 6. At the protein level, the partial in-frame aberrant transcript retaining 30 bp of intron 6 led to the insertion of 10 amino acids (p.Met329_Val330ins10) at the catalytic core domain of TGM1 protein (codons 247-572), whereas the transcript with the insertion of 32 nucleotides is predicted to encode a truncated protein (p.Val330MetfsX12). CONCLUSION: Our splicing assay, together with bioinformatic prediction tools, supports the pathological effect of the recently identified c.984+1G>A mutation in the TGM1 gene and unravels the molecular mechanism by which c.984+1G>A acts. PMID- 22435432 TI - An unusual presentation of filariasis: cytology solves the puzzle. PMID- 22435433 TI - Unusual clinical presentation of sporotrichosis in three members of one family. AB - INTRODUCTION: Sporotrichosis is a mycosis caused by the dimorphic fungus Sporothrix spp., and the primary mode of transmission is traumatic inoculation of fungus conidia from plants and other organic matter. METHODS: Sporotrichosis was established in a cat and in three members of one family from a rural area, by fungal growth in culture. RESULTS: The cutaneous lesions developed on the lower buttock and limbs with no report of any injury. CONCLUSION: Although sporotrichosis should be considered for differential diagnosis in people working with soil and plants, cases of chronic lesions on skin of cats and in households is probably a new epidemiological approach in a given geographic region. PMID- 22435434 TI - Periumbilical perforating pseudoxanthoma elasticum--an acquired perforating disorder. PMID- 22435435 TI - Merkel cell polyomavirus DNA detection in a patient with Merkel cell carcinoma and multiple other skin cancers. PMID- 22435436 TI - Mobile encapsulated lipoma. PMID- 22435437 TI - Facial extensive recurrent basal cell carcinoma: successful treatment with photodynamic therapy and imiquimod 5% cream. AB - BACKGROUND: Management of facial extensive recurrent basal cell carcinoma can be a challenge for dermatologists. Although the preferred technique is usually Mohs surgery, sometimes the patient's condition or predicted aggressive surgery make other options advisable. METHODS: We describe a case of a giant recurrent basal cell carcinoma in the face of an old woman successfully treated by combined therapy with MAL-photodynamic therapy and topical 5%. RESULTS: The patient remains well and with no sign of the tumor, with very good cosmetic result two years after treatment. CONCLUSIONS: Management of extensive facial basal cell carcinoma with combined therapies, as photodynamic therapy followed by topical imiquimod, can be an option for selected cases such as ours. PMID- 22435438 TI - Comparative evaluation of griseofulvin, terbinafine and fluconazole in the treatment of tinea capitis. AB - Tinea capitis (TC) is a common childhood fungal infection which, if untreated, can cause long-term scarring. A number of antifungal drugs with proven efficacy are available for the treatment of TC. However, varying dosage schedules, changes in epidemiology, and rising drug resistance are factors that hamper treatment in some cases. A prospective, non-blinded, cross-sectional study of three commonly used drugs (terbinafine, griseofulvin, and fluconazole) was undertaken in children aged <=12 years, presenting to a pediatric superspecialty hospital. The comparative efficacies of these three drugs were evaluated. A total of 75 patients (25 in each treatment group) who completed the designated treatment protocol were included in the final analysis. Of these, 60% had non-inflammatory TC and 56% had an ectothrix pattern on hair microscopy. Trichophyton violaceum was the most commonly isolated fungus. Cure rates of 96%, 88%, and 84% were achieved with griseofulvin, terbinafine, and fluconazole, respectively. Overall, seven patients required prolonged therapy. No side effects to therapy were seen. Griseofulvin remains the drug of choice in the treatment of TC. Terbinafine was the second best agent and offered the advantage of a shorter course of therapy. Fluconazole had comparatively low cure rates but was easier to administer than the other two medications. PMID- 22435439 TI - Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea. AB - A 2006 article published in the International Journal of Dermatology reported that oral zinc sulfate 100 mg three times daily was associated with improvement in the severity of facial rosacea (Sharquie et al. 2006; 45: 857-861). The current study was undertaken to further assess the role of zinc in the management of rosacea. This was a randomized, double-blind trial of 220 mg of zinc sulfate twice daily for 90 days in patients with moderately severe facial rosacea at baseline. Subjects were recruited in the Upper Midwest USA between August 2006 and April 2008, and followed until July 2008. Forty-four subjects completed the trial (22 in each arm). Rosacea improved in both groups. There were no differences in magnitude of improvement based on rosacea severity scores between subjects receiving zinc sulfate and subjects receiving placebo (P=0.284). Serum zinc levels were higher in subjects receiving zinc (P<0.001). Oral zinc sulfate was not associated with greater improvement in rosacea severity compared with placebo in this study. Additional studies are needed to determine what role oral zinc may have in the management of rosacea. PMID- 22435440 TI - Oxymatrine inhibits collagen synthesis in keloid fibroblasts via inhibition of transforming growth factor-beta1/Smad signaling pathway. AB - BACKGROUND: Keloids are benign dermal tumors characterized by fibroblastic proliferation and excessive accumulation of collagen. Oxymatrine (OMT) is an alkaloid extracted from the Chinese herb Sophora japonica with capacities of anti fibrosis. OBJECTIVE: To evaluate the effects of OMT on collagen production and to explore its mechanisms. METHODS: OMT was applied to human keloid fibroblasts in vitro. Collagen, transforming growth factor (TGF)-beta1, TGF-beta receptor, and Smads were analyzed by Western Blot, reverse transcription polymerase chain reaction, and immunofluorescence. RESULTS: We found that both collagen synthesis and Smad3 production were significantly suppressed in a dose-dependent administration of OMT. However, expression of TGF-beta1, TGF-beta receptor1, TGF beta receptor2, Smad4, and Smad7 was unchanged. We also found that OMT reversed phosphorylation and nuclear translocation of Smad3 induced by TGF-beta1. CONCLUSIONS: OMT inhibited collagen synthesis, which might be associated with TGF beta/Smad signaling pathway. These findings suggest that OMT may be a promising candidate to prevent keloid and other fibrotic diseases. PMID- 22435441 TI - Use of intense pulse light for acne vulgaris in Indian skin--a case series. AB - BACKGROUND: Intense pulse light (IPL) has become extremely popular in Indian cosmetology circles. Yet, literature is silent on its effect in heavily melanized skin. OBJECTIVE: A descriptive study to gauge the effect of IPL on acne vulgaris in Indian patients done in a tertiary care center in south India. MATERIALS AND METHODS: Patients with moderate to severe acne vulgaris were given a maximum of five sittings of IPL treatment. Lesion counts were performed and photographs compared before and after treatment. RESULTS: IPL was offered to 10 patients with acne vulgaris. Two patients dropped out, seven patients had a good response after a mean of 3.4 sittings; 87.5% patients expressed satisfaction with the procedure. No adverse effects were noted. CONCLUSION: IPL serves a useful role in the treatment of acne vulgaris and could reduce treatment costs and pill burden. There is no increased risk of side effects with IPL on Indian skin with standard care. PMID- 22435442 TI - Historical notes on endemic pemphigus in South America. PMID- 22435443 TI - Dermatoscopic findings in the most frequent onychopathies: descriptive analysis of 500 cases. PMID- 22435444 TI - Overexpression of monocyte chemoattractant protein-1 in the overlying epidermis of multicentric reticulohistiocytosis lesions: a case report. PMID- 22435447 TI - Halogenated xenon cyanides ClXeCN, ClXeNC, and BrXeCN. AB - We report on the preparation and characterization of three new noble-gas molecules ClXeCN, ClXeNC, and BrXeCN. These molecules are synthesized by 193 nm photolysis and thermal annealing of ClCN and BrCN in a xenon matrix. The absorption spectra are measured in the mid- and far-infrared regions, and the assignment is supported by isotope substitution and quantum chemical calculations at the B3LYP and MP2 levels of theory. The present results demonstrate a way to prepare other noble-gas molecules of this type. PMID- 22435448 TI - Oxytocin in the heart regeneration. AB - We have demonstrated that entire oxytocin (OT) system is synthesized in the rat and human heart and this hormone is implicated in several cardiac functions including stem cells differentiation into cardiomyocytes. These observations led us to the invention of OT as an inducer of cardiomyogenesis (US20060205636A1). We also proposed the use of OT, its functional derivatives, and/or physiological precursors as well as nucleic acids capable of encoding OT as cell differentiating and useful agents for treating or preventing diseases, such as heart diseases associated with loss of cardiomyocytes. The invention is relevant to the use of OT or OT-related compounds. OT is claimed as an inducer that promotes the differentiation of non-cardiomyocytes (e.g. stem/progenitor cells) in situ, which can be used to repair, restore or fortify damaged cardiac tissue or in cell culture in order to provide material for cell or tissue grafting in the heart. Recent reports documented the significant progress in the research on the role of OT in cardiovascular regulation. Most of the results are consistent with the postulated cardioprotective role of OT. In this review, new data are discussed in the context of the main points presented in the invention. PMID- 22435449 TI - HDL-C levels and cardiovascular disease: more is not always better! AB - HMG-CoA reductase inhibitors have consistently demonstrated a relative risk reduction of death and myocardial infarction ranging between 29 and 35%. Nevertheless, in spite of significant improvement in prevention, cardiovascular disease remains the main cause of morbidity and mortality in industrialized countries. This significant residual risk observed in approximately 70% of patients under optimal anti-atherosclerotic therapies, warrants the exploration and development of alternative cardiovascular drugs. Specifically, HDL-C levels have been inversely correlated with the incidence of cardiovascular disease and an estimated 1 mg/dl higher HDL-C is associated with a 2% lower risk for men and a 3% lower risk for women. However, HDL-C-C pharmacological induced increases presented contradicting results regarding atherosclerotic development and in some cases increased cardiovascular mortality. In this review, we will focus on the structure and metabolism of HDL-C and patents related to HDL-C levels and cardiovascular disease along with the possible role of HDL-C increasing therapies in the future primary and secondary prevention of cardiovascular disease. PMID- 22435450 TI - Stent selection in patients with myocardial infarction: drug eluting, biodegradable polymers or bare metal stents? AB - Percutaneous coronary intervention (PCI) has been increasingly used in the last years during interventional procedures in patients with acute coronary syndromes (ACS) including ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). In patients with either STEMI, NSTEMI, high risk ACS with EKG changes or cardiac enzymes rises; PCI with bare metal stent (BMS) implantation has been associated with a significant improvement in clinical outcome. Therefore, BMS implantation during primary PCI in STEMI has become a standard of practice. With the introduction of drug eluting stents (DESs) in this decade, the use of these new devices instead of BMSs in patients with STEMI has emerged as a rational PCI alternative in this particular subgroup of patients. In spite of the unquestionable benefits of DESs in terms of reduction of restenosis and TVR, specific concerns have arisen with regard to their long-term safety. High incidence of very late stent thrombosis has been described with these devices, and special attention should be paid in patients with unstable coronary lesions, in which plaque composition and remodeling may play a main role in their safety and long-term outcome. Intraluminal thrombus caused by plaque rupture is the most frequent mechanism of STEMI, in which the necrotic core and thin fibrous cap play a major role. In this context, the use of first DESs designs may be futile or even unsafe because delayed healing may further contribute to plaque instability. Adjunctive invasive imaging tools can improve stent deployment and safety outcome in these lesions with intravascular findings of plaque instability. Recently, other players such as new dedicated antithrombotic BMS designs, including selfexpanding stents or drug-eluting coated balloons, are exploring their potential indications in patients with ACS and myocardial infarction. This paper reports and discusses new stent devices and adjunctive pharmacologic agents. It also mentions and describes the recent patents of devices invented to use in these complex lesions subsets. PMID- 22435451 TI - Simultaneous bioluminescent immunoassay of serum total and IgG-bound prolactins. AB - Novel dual-analyte single-well bioluminescence immunoassay (BLIA) for total and IgG-bound prolactins was developed on the base of Ca(2+)-regulated photoprotein obelin mutants with altered color and kinetics of bioluminescence signal as reporters. The mutants W92F-H22E and Y138F were chemically conjugated with monoclonal mouse anti-hPRL and anti-hIgG immunoglobulins and thus displayed signals from total prolactin and IgG-bounded prolactin (macroprolactin) correspondingly. Bioluminescence of the reporters was simultaneously triggered by a single injection of Ca(2+) solution and discriminated via bioluminescent signal spectral and time resolution. The developed microplate-based immunoassay allows detection of two prolactin forms in crude serum without additional manipulations (e.g., gel chromatography or PEG-precipitation). Total prolactin bioluminescence immunoassay in standard, control, and clinical sera offers high sensitivity and reproducibility. The BLIA results show good correlation with those obtained by RIA and immunoassay after gel chromatography. PMID- 22435452 TI - Screening methods for influenza antiviral drug discovery. AB - INTRODUCTION: Influenza antiviral high-throughput screens have been extensive, and yet no approved influenza antivirals have been identified through high throughput screening. This underscores the idea that development of successful screens should focus on the exploitation of the underrepresented viral targets and novel, therapeutic host targets. AREAS COVERED: The authors review conventional screening applications and emerging technologies with the potential to enhance influenza antiviral discovery. Real-world examples from the authors' work in biocontained environments are also provided. Future innovations are discussed, including the use of targeted libraries, multiplexed assays, proximity based endpoint methods, non-laboratory-adapted virus strains, and primary cells, for immediate physiological relevance and translational applications. EXPERT OPINION: The lack of successful anti-influenza drug discovery using high throughput screening should not deter future efforts. Increased understanding of the functions of viral targets and host-pathogen interactions has broadened the target reservoir. Future screening efforts should focus on identifying new drugs against unexploited viral and host targets using currently developed assays, and on the development of novel, innovative assays to discover new drugs with novel mechanisms. Innovative screens must be designed to identify compounds that specifically inhibit protein-protein or protein-RNA interactions or other virus/host factor interactions that are crucial for viral replication. Finally, the use of recent viral isolates, increased biocontainment (for highly-pathogenic strains), primary cell lines, and targeted compound libraries must converge in efficient high-throughput primary screens to generate high-content, physiologically-relevant data on compounds with robust antiviral activity. PMID- 22435453 TI - Melting of hydrogen bonds in uracil derivatives probed by infrared spectroscopy and ab initio molecular dynamics. AB - The thermal response of hydrogen bonds is a crucial aspect in the self-assembly of molecular nanostructures. To gain a detailed understanding of their response, we investigated infrared spectra of monomers and hydrogen-bonded dimers of two uracil-derivative molecules, supported by density functional theory calculations. Matrix isolation spectra of monomers, temperature dependence in the solid state, and ab initio molecular dynamics calculations give a comprehensive picture about the dimer structure and dynamics of such systems as well as a proper assignment of hydrogen-bond affected bands. The evolution of the hydrogen bond melting is followed by calculating the C?O...H-N distance distributions at different temperatures. The result of this calculation yields excellent agreement with the H-bond melting temperature observed by experiment. PMID- 22435454 TI - Meta-analysis of the cystatin C(CST3) gene G73A polymorphism and susceptibility to Alzheimer's disease. AB - BACKGROUND: The association between cystatin C(CST3) gene (rs1064039) G73A polymorphism and Alzheimer's disease (AD) is controversial. The objective of the study was to investigate the possible association between CST3 G73A polymorphism and AD. METHOD: We performed a meta-analysis pooling data from all relevant studies including 2,410 cases and 2,539 controls. We applied a random-effects or fixed-effects model to combine odds ratio (OR) and 95% confidence intervals (95% CI). RESULTS: Positive associations of the CST3 G73A polymorphism with AD risk were found in allele comparison A versus G (OR = 1.61, 95% CI = 1.19-2.18), dominant model AG + GG versus AA (OR = 0.63, 95% CI = 0.47-0.86), and homozygote comparison AA versus GG (OR = 1.61, 95% CI = 1.19-2.18). In subgroup analysis stratified by ethnicity, significant associations were also demonstrated in Caucasians under allele comparison (OR = 1.17, 95% CI = 1.02-1.33), dominant genetic (OR = 0.59, 95% CI = 0.40-0.86) model, and homozygote comparison (OR = 1.73, 95% CI = 1.18-2.54), but not in Asians. In subgroup analysis according to the age of onset, 73A allele (A versus G) was significantly associated with susceptibility to AD in Caucasians (OR = 1.26, 95% CI = 1.06-1.50), However, no association was found in Asians. CONCLUSION: The CST3 G73A polymorphism is associated with AD in Caucasian populations, but not in Asians. PMID- 22435455 TI - Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children. AB - OBJECTIVE: C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate and plays a key role in endochondral growth. Its amino-terminal propeptide (NTproCNP) is an equimolar product of CNP biosynthesis and is easily measured in plasma. Preliminary studies suggest that NTproCNP levels correlate with height velocity in sheep and children. The objectives of the study were to correlate NTproCNP levels with height velocity and to define the reference range for plasma CNP and NTproCNP across childhood. DESIGN: This was a prospective, cross-sectional, observational study of healthy children. PATIENTS: Participants were 258 healthy children between 2 months and 20 years of age. MEASUREMENTS: Anthropometrics were obtained and CNP and NTproCNP levels were determined by radioimmunoassay. RESULTS: For both sexes, CNP and NTproCNP levels were high in infancy, lower in early childhood, rising during puberty, then falling to low adult levels. Levels of NTproCNP peaked at 14.1 years in boys and 11.9 years in girls, coincident with the age of peak height velocity. Levels of NTproCNP varied with pubertal status, peaking at genital Tanner stage IV in boys and III in girls. There was a highly significant correlation between NTproCNP and height velocity. CONCLUSIONS: C-type natriuretic peptide plays an integral role in endochondral growth. We show here that CNP synthesis (as measured by NTproCNP levels in plasma) is closely related to linear growth in healthy children at all ages. We propose NTproCNP as a biomarker of linear growth. PMID- 22435456 TI - Reliability, sensitivity and validity of the assistant referee intermittent endurance test (ARIET) - a modified Yo-Yo IE2 test for elite soccer assistant referees. AB - We examined the reliability and validity of the assistant referee intermittent endurance test (ARIET), a modified Yo-Yo IE2 test including shuttles of sideways running. The ARIET was carried out on 198 Italian (Serie A-B, Lega-Pro and National Level) and 47 Danish elite soccer assistant referees. Reproducibility was tested for 41 assistant referees on four occasions each separated by one week. The ARIET intraclass correlation coefficients and typical error of measurement ranged from 0.96 to 0.99 and 3.1 to 5.7%, respectively. ARIET performance for Serie A and B was 23 and 25% greater than in Lega-Pro (P < 0.001). The lowest cut-off value derived from receiving operator characteristic discriminating Serie A-B from Lega-Pro was 1300 m. The ARIET performance was significantly correlated with VO(2max) (r = 0.78, P < 0.001), %HR(max) after 4 min of ARIET (r = - 0.81, P < 0.001) and Yo-Yo IR1 performance (r = 0.95, P < 0.001), but not sprint performance (r = -0.15; P = 0.58). The results showed that ARIET is a reproducible and valid test that is able to discriminate between assistant referees of different competitive levels. The lack of correlation with sprinting ability and close correlations with aerobic power, intermittent shuttle running and sub-maximal ARIET heart rate loading provide evidence that ARIET is a relevant test for assessment of intermittent endurance capacity of soccer assistant referees. PMID- 22435457 TI - Factors associated with a strictly undetectable viral load in HIV-1-infected patients. AB - OBJECTIVES: The aim of the study was to identify factors associated with a strictly undetectable viral load (VL) using a routine sensitive real-time polymerase chain reaction (RT-PCR) technology. METHODS: From a large prospective cohort, 1392 patients with a VL<50 HIV-1 RNA copies/mL while receiving a three drug suppressive regimen for at least 1 year were included in a cross-sectional analysis. Patients were classified into three groups and compared by univariate and multivariate analysis: 479 patients with a strictly undetectable VL (group 1; 34%), 617 patients with detectable VL below the threshold of 20 copies/mL (group 2; 44%), and 296 patients with a VL of 20-50 copies/mL (group 3; 12%). RESULTS: Comparing groups 1 and 2, VL zenith<5 log(10) copies/mL [odds ratio (OR) 1.51; 95% confidence interval (CI) 1.15-1.99; P=0.003], current CD4 T-cell count<500 cells/MUL (OR 1.44; 95% CI 1.08-1.92; P=0.01), and duration of viral suppression<50 copies/mL longer than 2 years (OR 2.32; 95% CI 1.20-4.54; P=0.01) were associated with undetectable VL. Comparing groups 1 and 3, VL zenith<5 log(10) copies/mL (OR 2.48; 95% CI 1.75-3.50; P<0.001), duration of viral suppression<50 copies/mL longer than 1 year (OR 3.33; 95% CI 1.66-6.66; P=0.0006), and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (OR 1.45; 95% CI 1.03-2.04; P=0.03) were associated with undetectable VL. No individual drug effect was found within NNRTI molecules. CONCLUSIONS: Longer duration of viral suppression<50 copies/mL, lower viral load zenith and NNRTI-based regimen were independently associated with a strictly undetectable viral load. This routinely used RT-PCR assay may prove to be a valuable tool in further large-scale studies. PMID- 22435458 TI - Manipulating interfacial polymer structures through mixed surfactant adsorption and complexation. AB - The effects of a nonionic alcohol ethoxylate surfactant, C(13)E(7), on the interactions between PVP and SDS both in the bulk and at the silica nanoparticle interface are studied by photon correlation spectroscopy, solvent relaxation NMR, SANS, and optical reflectometry. Our results confirmed that, in the absence of SDS, C(13)E(7) and PVP are noninteracting, while SDS interacts strongly both with PVP and C(13)E(7) . Studying interfacial interactions showed that the interfacial interactions of PVP with silica can be manipulated by varying the amounts of SDS and C(13)E(7) present. Upon SDS addition, the adsorbed layer thickness of PVP on silica increases due to Coulombic repulsion between micelles in the polymer layer. When C(13)E(7) is progressively added to the system, it forms mixed micelles with the complexed SDS, reducing the total charge per micelle and thus reducing the repulsion between micelle and the silica surface that would otherwise cause the PVP to desorb. This causes the amount of adsorbed polymer to increase with C(13)E(7) addition for the systems containing SDS, demonstrating that addition of C(13)E(7) hinders the SDS-mediated desorption of an adsorbed PVP layer. PMID- 22435459 TI - Intravesical application of lidocaine and sodium bicarbonate in the treatment of obstructive idiopathic lower urinary tract disease in cats. AB - BACKGROUND: In human patients with interstitial cystitis, intravesical instillation of alkalinized lidocaine sometimes is associated with sustained amelioration of symptoms beyond the acute treatment phase. Interstitial cystitis shares many features in common with feline idiopathic cystitis. OBJECTIVE: To evaluate whether intravesical instillation of alkalinized lidocaine decreases recurrence of urethral obstruction and severity of clinical signs in cats with obstructive idiopathic LUTD. ANIMALS: Twenty-six cats with obstructive idiopathic LUTD. Twelve cats in case group (treatment with alkalinized lidocaine) and 14 control cats (treatment with placebo or standard treatment). METHODS: Cats were randomly assigned to treatment (2 or 4 mg/kg lidocaine and sodium bicarbonate) or placebo groups (0.2 mL/kg saline solution and sodium bicarbonate). The intravesical instillation was done once a day for 3 days. Some cats underwent standard treatment only (indwelling urinary catheter for 3 days without intravesical instillations). A 2-week, 1-month, and 2-month follow-up after treatment was made using a questionnaire. The recurrence rate and amelioration scores of clinical signs were assessed and compared. RESULTS: Recurrence of urethral obstruction was 58% (7/12) in the case group and 57% (8/14) in the control group. Amelioration scores were similar between the 2 groups. CONCLUSION AND CLINICAL IMPORTANCE: Intravesical administration of lidocaine for up to 3 consecutive days had no apparent beneficial effect on decreasing recurrence rate and severity of clinical signs in cats with obstructive idiopathic LUTD. PMID- 22435462 TI - Suppressive effect of pregnant serum on murine dendritic cell function. AB - AIM: Tolerance to the semi-allogenic fetal graft by the maternal immune system is a medical enigma. Many aspects of immunoregulation at the feto-maternal interface have been clarified, but systemic effects of pregnancy on the immune system are still elusive. The present study was undertaken to determine whether mid pregnancy mouse serum has an inhibitory effect on dendritic cells (DC) function. MATERIAL AND METHODS: Mid-gestational sera were obtained from allogenic pregnant Balb/c mice (Balb/c * C57BL/6) on days 9-11 of gestation. Splenic DC were purified from Balb/c mice, and treated with mid-pregnancy mouse serum. Antigen pulsed DC were injected into mice palms. After 5 days, draining lymph nodes were removed, cultured in the presence of cognate antigen, and proliferation of responding cells was measured by (3)H-thymidin incorporation. Interleukin (IL)-10 and interferon-gamma (IFN-gamma) production by stimulated lymph node antigen specific cells was also measured in culture supernatants using sandwich ELISA. RESULTS: Treatment of DC with pregnant mouse serum markedly blocked their ability to induce antigen-specific lymphocyte proliferation and IFN-gamma and IL-10 production by primed lymph node cells in comparison with non-pregnant serum treated DC. CONCLUSION: Pregnant mouse serum has an inhibitory effect on DC capacity to induce antigen-specific proliferation and cytokine secretion by lymph node cells. The suppressive effects of pregnant serum on DC could be considered as one of the mechanisms responsible for the systemic immunomodulation observed during pregnancy. PMID- 22435461 TI - Lipid dynamics and protein-lipid interactions in 2D crystals formed with the beta barrel integral membrane protein VDAC1. AB - We employ a combination of (13)C/(15)N magic angle spinning (MAS) NMR and (2)H NMR to study the structural and functional consequences of different membrane environments on VDAC1 and, conversely, the effect of VDAC1 on the structure of the lipid bilayer. MAS spectra reveal a well-structured VDAC1 in 2D crystals of dimyristoylphosphatidylcholine (DMPC) and diphytanoylphosphatidylcholine (DPhPC), and their temperature dependence suggests that the VDAC structure does not change conformation above and below the lipid phase transition temperature. The same data show that the N-terminus remains structured at both low and high temperatures. Importantly, functional studies based on electrophysiological measurements on these same samples show fully functional channels, even without the presence of Triton X-100 that has been found necessary for in vitro-refolded channels. (2)H solid-state NMR and differential scanning calorimetry were used to investigate the dynamics and phase behavior of the lipids within the VDAC1 2D crystals. (2)H NMR spectra indicate that the presence of protein in DMPC results in a broad lipid phase transition that is shifted from 19 to ~27 degrees C and show the existence of different lipid populations, consistent with the presence of both annular and bulk lipids in the functionally and structurally homogeneous samples. PMID- 22435463 TI - Biomarkers for genome instability in some genetic disorders: a pilot study. AB - CONTEXT: The study of genome integrity in some genetic disorders has diagnostic and prognostic importance because of the evident relationship between genome instability and both DNA repair deficiencies and cancer predisposition. OBJECTIVE: The objective was to compare the chromosomal and DNA damage responses in lymphocytes from patients with Nijmegen breakage syndrome (NBS), Fanconi anemia (FA) and Williams-Beuren syndrome (WBS) to find additional biomarkers of genome instability. METHODS: The cytogenetic approaches were combined with the alkaline Comet assay to estimate genome integrity in cultured or freshly isolated and H(2)O(2)-treated lymphocytes. RESULTS: Basal frequencies of chromosome aberrations were significantly increased in NBS/FA probands and NBS heterozygous carriers. The NBS diagnosis was confirmed by detecting site-specific rearrangements, while the mitomycin C (MMC)-stress test was highly positive in a FA patient. Among patients with suspected WBS, 12 individuals had a 7q11.23 microdeletion. In the Comet assay, genome instability was revealed in all three disorders, impaired capacity to repair oxidative damage being observed in NBS and WBS in contrast to FA and controls. CONCLUSION: The results indicate that the estimates of DNA damage response may be proposed as efficient biomarkers for detecting and characterizing genome instability in the genetic disorders under study. PMID- 22435466 TI - Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes. AB - The absence of a fall in circulating progesterone levels has led to the concept that human labour is associated with 'functional progesterone withdrawal' caused through changes in the expression or function of progesterone receptor (PR). At the time of labour, the human uterus is heavily infiltrated with inflammatory cells, which release cytokines to create a 'myometrial inflammation' via NF kappaB activation. The negative interaction between NF-kappaB and PR, may represent a mechanism to account for 'functional progesterone withdrawal' at term. Conversely, PR may act to inhibit NF-kappaB function and so play a role in inhibition of myometrial inflammation during pregnancy. To model this inter relationship, we have used small interfering (si) RNA-mediated knock-down of PR in human pregnant myocytes and whole genome microarray analysis to identify genes regulated through PR. We then activated myometrial inflammation using IL-1beta stimulation to determine the role of PR in myometrial inflammation regulation. Through PR-knock-down, we found that PR regulates gene networks involved in myometrial quiescence and extracellular matrix integrity. Activation of myometrial inflammation was found to antagonize PR-induced gene expression, of genes normally upregulated via PR. We found that PR does not play a role in repression of pro-inflammatory gene networks induced by IL-1beta and that only MMP10 was significantly regulated in opposite directions by IL-1beta and PR. We conclude that progesterone acting through PR does not generally inhibit myometrial inflammation. Activation of myometrial inflammation does cause 'functional progesterone withdrawal' but only in the context of genes normally upregulated via PR. PMID- 22435467 TI - Fragmentation analysis of water-soluble atmospheric organic matter using ultrahigh-resolution FT-ICR mass spectrometry. AB - Isolated water-soluble atmospheric organic matter (AOM) analytes extracted from radiation fogwater samples were analyzed using collision induced dissociation with ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Tandem mass analysis was performed on several mass ranges between 100 and 400 Da to characterize the functional groups of AOM species. Compounds containing nitrogen and/or sulfur were targeted because of the high number of oxygen atoms contained in their molecular formulas. Due to the large number of isobaric ions in the precursor isolation ranges, large numbers of product ions resulted from collision induced dissociation. Common neutral losses were assigned by matching the molecular formulas of the expected product ions with the detected product ions within the appropriate mass spectra. Since polar functional groups are expected to affect the hygroscopic properties of aerosols, the losses of H(2)O, CO(2), CH(3)OH, HNO(3), CH(3)NO(3), SO(3), SO(4) and combinations of these were specifically targeted. Among the 421 compounds studied, the most frequently observed neutral losses were CO(2) (54%), H(2)O (43%) and CH(3)OH (40%). HNO(3) losses were observed for 63% of the studied nitrogen containing compounds and 33% of the studied compounds containing both nitrogen and sulfur. SO(3) losses were observed for 85% of the studied sulfur containing compounds and 42% of studied compounds containing both nitrogen and sulfur. A number of molecular formulas matching those of monoterpene ozonolysis SOA were observed; they include organonitrates, organosulfates, and nitroxy organosulfates. Overall, the results of fragmentation analysis of 400+ individual molecular precursors elucidate the complexity and multifunctional nature of the isolated water-soluble AOM. PMID- 22435468 TI - Aggregation of pre-implantation embryos improves establishment of parthenogenetic stem cells and expression of imprinted genes. AB - Parthenogenetic embryonic stem cells (PgES) might advance cell replacement therapies and provide a valuable in vitro model system to study the genomic imprinting. However, the differential potential of PgES cells was limited. It could result from relative low heterology of PgES cells compared with ES cells from fertilization (fES), which produce different expression of most imprinted genes. Here, we described the establishment of PgES cells by aggregating parthenogenetic embryos at the 8-cell stage (aPgES cells), which may increase heterozygy. We found that derivation of aPgES cells in association with an increased number of inner cell mass cells by aggregating was more efficient than that of PgES cells from a single parthenogenetic blastocyst. The aPgES cells have normal karyotype, stain positive for alkaline phosphatase, express high levels of ES cell markers and can differentiate into teratomas composed of the three germ layers. Moreover, compared with PgES cells, the more highly upregulated paternally expressed imprinted genes were observed in aPgES cells, the same change was not shown in aPg blastocysts. This suggested that the aggregation induced effect could modify the expression of paternally expressed imprinted genes. Our studies showed that aPgES cells, the expression of imprinted genes in which more closely resemble fES cells than PgES cells, would contribute to all organs and avoiding immuno-rejection, which may provide invaluable material for regeneration medicine. PMID- 22435469 TI - Periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: Report of three initial cases. AB - OBJECTIVES: To report a novel cell therapy using autologous adipose tissue derived regenerative cells for male stress urinary incontinence caused by urethral sphincteric deficiency, and the outcomes in the initial cases undergoing periurethral injection of adipose tissue-derived regenerative cells. METHODS: Three patients with moderate stress incontinence after radical prostatectomy and holmium laser enucleation of the prostate were enrolled. Adipose tissue-derived regenerative cells were isolated from the abdominal adipose tissue by using the Celution system. Subsequently, the isolated adipose tissue-derived regenerative cells, and a mixture of adipose tissue-derived regenerative cells and adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. Short-term outcomes during a 6-month follow up were assessed by a 24-h pad test, a validated patient questionnaire, urethral pressure profile, transrectal ultrasonography and magnetic resonance imaging. RESULTS: Urinary incontinence progressively improved after 2 weeks of injection up to 6 months in terms of decreased leakage volume, decreased frequency and amount of incontinence, and improved quality of life. Both maximum urethral closing pressure and functional profile length increased. Magnetic resonance imaging suggested a sustained presence of the injected adipose tissue. Enhanced ultrasonography showed a progressive increase in the blood flow to the injected area. No significant adverse events were observed peri- and postoperatively. CONCLUSION: These preliminary findings suggest that periurethral injection of the autologous adipose tissue-derived regenerative cells is a safe and feasible treatment modality for male stress urinary incontinence. PMID- 22435470 TI - Effect of sodium lauryl sulfate on recurrent aphthous stomatitis: a randomized controlled clinical trial. AB - OBJECTIVE: To compare the effects of sodium lauryl sulfate (SLS)-free and SLS containing dentifrice in patient with recurrent aphthous stomatitis (RAS). MATERIALS AND METHODS: The design of this study was a double-blind crossover trial. The 90 subjects were divided into three groups: group I used SLS-free (a commercially available SLS-free dentifrice) and SLS-A (SLS-free + 1.5% SLS), group II used SLS-A and SLS-B (a commercially available 1.5% SLS-containing dentifrice), and group III used SLS-free and SLS-B. The subjects used one of the two assigned dentifrices for 8 weeks and then the other for the following 8 weeks. The order of the dentifrices used was selected at random, and there was a 2-week washout period between the two phases. The clinical parameters (number of ulcers, number of episodes, duration of ulcers, mean pain score) were compared between the two phases for each group. RESULTS: The number of ulcers and episodes did not differ significantly between SLS-A, SLS-B, and SLS-free. Only duration of ulcers and mean pain score was significantly decreased during the period using SLS-free. CONCLUSION: Although SLS-free did not reduce the number of ulcers and episodes, it affected the ulcer-healing process and reduces pain in daily lives in patients with RAS. PMID- 22435471 TI - The role of the skin irritation response in polysensitization to fragrances. AB - BACKGROUND: Contact allergy to fragrance chemicals is an increasing problem. Polysensitization is likely to be a phenotype of increased susceptibility to contact allergy. The factors that play a role in polysensitization are largely unknown. Identifying these risk factors is important with regard to future studies on the aetiology of contact allergy. OBJECTIVES: To investigate whether enhanced skin irritability is a risk factor for the development of polysensitization to fragrance chemicals. METHODS: One hundred participants characterized by fragrance contact allergy were included in our study. The participants were patch tested on the back with 25 individual fragrance chemicals and fragrance mixes I and II, and on the upper arm with sodium lauryl sulfate (SLS) (consisting of SLS concentrations of 0.45%, 0.67%, 1%, and 1.5%). Reading of both tests was performed during the following visits at days 2, 3, and 7. The response to SLS was monitored by measuring transepidermal water loss (TEWL). Polysensitization was defined as three or more allergic reactions to non-cross reacting fragrance chemical allergens. RESULTS: Individuals with polysensitization showed significantly higher irritation responses to SLS 1% and 1.5% as assessed by TEWL. CONCLUSIONS: We found an enhanced skin irritation response to be a risk factor for the development of polysensitization to fragrance chemicals. PMID- 22435472 TI - Reverse pharmacology. PMID- 22435473 TI - Enhancing FDA's post-market surveillance of dietary supplements: two simple steps to build capacity. AB - Up to 52% of Americans spend $20 billion annually on dietary supplements, which rank among the top suspected causes of poisoning among adults. The recent recall by the US Food and Drug Administration (FDA) of a top-selling supplement linked to liver toxicity highlights the need for post-market surveillance. Unfortunately the agency is ill equipped to provide such surveillance, only recording about 1% of all adverse events. Poison control centers may be detecting 10 times more adverse events but are not forwarding them to the FDA. The FDA could increase its post-market surveillance capacity by coordinating with poison control centers and by utilizing external researchers. PMID- 22435474 TI - Calcium fructoborate: plant-based dietary boron for human nutrition. AB - The main objective of this paper is to evaluate the scientific evidence on the form of organic boron, calcium fructoborate (CF), including health dates, dietary needs, pharmacology, experts opinion, research papers, clinical evidence, and dosing. CF is a natural product with effects in oxidative metabolism and cell apoptosis. We review the biological and biochemical action of chemical natural identical entity of CF. This mini review provides support for future clinical research. PMID- 22435475 TI - Antihyperglycemic and antioxidant activities of medicinal plant Stereospermum suaveolens in streptozotocin-induced diabetic rats. AB - The ethanol extract of Stereospermum suaveolens (EESS) bark was evaluated for its antihyperglycemic in addition to antioxidant effects in streptozotocin (STZ) induced diabetic rats by acute and subacute models at dose levels of 200 and 400 mg/kg body weight, given orally. The ethanol extract showed a significant reduction in fasting blood glucose levels when compared to the standard drug, oral Glibenclamide (0.5 mg/kg body weight). The serum of rats treated with ethanol extract showed decreased levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, serum alkaline phosphatase, bilirubin, creatinine, urea, total cholesterol, triglycerides, and increased level of total proteins. EESS showed reduction in thiobarbituric acid reactive substances level and significantly increased the body weight (P < .001), glycogen, reduced glutathione, superoxide dismutase, and catalase activities, compared with STZ diabetic control in a dose-dependent manner. This finding shows that the ethanol extract of Stereospermum suaveolens exhibits potent antihyperglycemic and antioxidant properties. PMID- 22435476 TI - Herbals medicine also effective in treatment of premenstrual dysphoric disorder (PMDD)? PMID- 22435477 TI - Identification of marker genes for lipid-lowering effect of a short-chain fructooligosaccharide by DNA microarray analysis. AB - Administration of short-chain fructooligosaccharide (scFOS) is known to lower serum triglyceride levels in rats fed a high-fat diet, but the molecular mechanisms remain unclear. This study aimed to identify marker genes for lipid lowering effect of scFOS administration. The changes in hepatic gene expressions in rats fed scFOS were investigated using DNA microarray and quantitative RT-PCR analysis. The DNA microarray showed that phytanoyl-CoA 2-hydroxylase 2 (Phyh2), lipoprotein lipase (Lpl) and tyrosine aminotransferase (Tat) were significantly affected by scFOS administration (p < .05). Since Lpl is involved in lipid metabolism, the up-regulation of Lpl in the liver can be a potential marker of the lipid-lowering effect of scFOS. PMID- 22435478 TI - Morphological and reproductive characterization in hyacinth bean, Lablab purpureus (L.) sweet germplasm with clinically proven nutraceutical and pharmaceutical traits for use as a medicinal food. AB - The hyacinth bean, Lablab purpureus, is used throughout Asia and Africa for human food and medicine with potential to be a source of nutraceuticals and pharmaceuticals. Hyacinth bean accessions were grown in Griffin, Georgia, from 2002 to 2004 and characterized for agronomic traits including branching, foliage, plant size, days to 50% maturity, and seed reproduction. The plants regenerated a range reaching more than 4,000 seeds. Assessment of variation was determined using principal component analysis. This paper also discusses evidence from literature reviews regarding clinical trials supporting possible uses of various hyacinth bean phytochemicals as nutraceuticals and pharmaceuticals. Hyacinth bean seeds and pods could be used as famine food worldwide where humans suffer from malnourishment and disease. The purposes of this study are to characterize regenerating hyacinth bean genetic resources for branching, foliage, plant size, days to 50% maturity, seed production, and flower traits, as well as to discuss evidence from clinical trials supporting potential uses of various hyacinth bean containing phytochemicals as medicinal food, nutraceuticals, and pharmaceuticals. PMID- 22435479 TI - Smoking and supplement use among men in a rural population. AB - BACKGROUND: Few studies have investigated supplement use in relation to smoking among men in a rural population. METHODS: We analyzed responses about the use of supplements from a cross-sectional, population-based sample of 4,502 North Dakota men. RESULTS: 48% of respondents reported supplement use. After adjustment for confounders, supplement users were significantly more likely to be nonsmokers or former smokers than smokers (p < .0001) and to consume five or more daily servings of fruits and vegetables (p = .0003). CONCLUSION: Compared to nonsmoking rural men, supplement use is significantly less common among rural smokers. Rural smokers also are less likely to consume five or more daily servings of fruits and vegetables and may be at greater risk of vitamin deficiency. PMID- 22435480 TI - An evidence-based systematic review of bee pollen by the Natural Standard Research Collaboration. AB - An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22435481 TI - Vibrational coupling between helices influences the amide I infrared absorption of proteins: application to bacteriorhodopsin and rhodopsin. AB - The amide I spectrum of multimers of helical protein segments was simulated using transition dipole coupling (TDC) for long-range interactions between individual amide oscillators and DFT data from dipeptides (la Cour Jansen et al. J. Chem. Phys.2006, 125, 44312) for nearest neighbor interactions. Vibrational coupling between amide groups on different helices shift the helix absorption to higher wavenumbers. This effect is small for helix dimers (1 cm(-1)) at 10 A distance and only moderately affected by changes in the relative orientation between the helices. However, the effect becomes considerable when several helices are bundled in membrane proteins. Particular examples are the 7-helix membrane proteins bacteriorhodopsin (BR) and rhodopsin, where the upshift is 4.3 and 5.3 cm(-1), respectively, due to interhelical coupling within a BR monomer. A further upshift of 4.0 cm(-1) occurs when BR monomers associate to trimers. We propose that interhelical vibrational coupling explains the experimentally observed unusually high wavenumber of the amide I band of BR. PMID- 22435482 TI - Methodological challenges in the study of dental occlusion. AB - This narrative review describes the methodological challenges in the study of dental occlusion. The reigning confusion about the scope of this topic is discussed, and a conceptual framework for understanding dental occlusion research is suggested. The characteristics of clinical studies used in the study of dental occlusion are presented within this proposed framework consisting of a triad comprising the relative positions of the teeth-mandible-maxilla, the oral functions and oral appearance. Challenges in the preparation for a clinical study of dental occlusion are reviewed, which include a discourse on the objectives of a clinical study and appropriateness of different study designs. Guidelines are provided for the conduct of studies with a central focus on dental occlusion and diagnostic tests, prognosis, therapy and aetiology, respectively. Summarising chapters present methodological challenges in designing a clinical study of dental occlusion and threats to the proper conduct of a clinical study. PMID- 22435483 TI - Role of microRNAs in the regulation of drug metabolizing and transporting genes and the response to environmental toxicants. AB - INTRODUCTION: MicroRNAs (miRNAs) comprise a family of short non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Rapidly growing evidence indicates that miRNAs play a key role in drug (xenobiotic) metabolism. AREAS COVERED: This review summarizes the current knowledge of the role of miRNAs in the regulation of drug (xenobiotic) metabolizing genes and the cellular responses to exposure to exogenous toxicants. The literature search was performed using the PubMed database (up to March 2012). EXPERT OPINION: miRNAs play a major role in control of the proper functioning of the cellular drug metabolizing system. Emerging evidence indicates that exposure to environmental and occupational toxicants and therapeutic drugs may alter the expression of miRNAs, including those that regulate the expression of drug metabolizing genes. This suggests that drug-induced (xenobiotic-induced) miRNA abnormalities may be one of the underlying mechanisms in the pathogenesis of exposure-related pathologies, and that miRNAs may be potential non-invasive biomarkers of exposure and indicators of the severity of tissue injury induced by toxicants. Also, the evaluation of the expression of miRNAs may be applied for the chemical and drug safety assessment. Additionally, differences in the expression of miRNAs that target drug metabolizing genes may be important determinants for inter-individual differences in sensitivity to toxicants and can serve as critical biomarkers for identifying subpopulations sensitive to exposure. PMID- 22435485 TI - 9-Oxidophenalenone: a noninnocent beta-diketonate ligand? AB - The redox systems [Ru(L)(bpy)(2)](k), [Ru(L)(2)(bpy)](m), and [Ru(L)(3)](n) containing the potentially redox-active ligand 9-oxidophenalenone = L(-) were investigated by spectroelectrochemistry (UV-vis-near-IR and electron paramagnetic resonance) in conjunction with density functional theory (DFT) calculations. Compounds [Ru(L(-))(bpy)(2)]ClO(4) ([1]ClO(4)) and [Ru(L(-))(2)(bpy)]ClO(4) ([2]ClO(4)) were structurally characterized. In addition to establishing electron transfer processes involving the Ru(II)/Ru(III)/Ru(IV) and bpy(0)/bpy(*-) couples, evidence for the noninnocent behavior of L(-) was obtained from [Ru(IV)(L(*))(L(-))(bpy)](3+), which exhibits strong near-IR absorption due to ligand-to-ligand charge transfer. In contrast, the lability of the electrogenerated anion [Ru(L)(2)(bpy)](-) is attributed to a resonance situation [Ru(II)(L(*2-))(L(-))(bpy)](-)/[Ru(II)(L(-))(2) (bpy(*-))](-), as suggested by DFT calculations. PMID- 22435484 TI - Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation. AB - Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation. PMID- 22435486 TI - Lectins identify glycan biomarkers on glioblastoma-derived cancer stem cells. AB - Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Despite aggressive therapy with surgery, radiotherapy, and chemotherapy, nearly all patients succumb to disease within 2 years. Several studies have supported the presence of stem-like cells in brain tumor cultures that are CD133-positive, are capable of self-renewal, and give rise to all cell types found within the tumor, potentially perpetuating growth. CD133 is a widely accepted marker for glioma-derived cancer stem cells; however, its reliability has been questioned, creating a need for other identifiers of this biologically important subpopulation. We used a panel of 20 lectins to identify differences in glycan expression found in the glycocalyx of undifferentiated glioma-derived stem cells and differentiated cells that arise from them. Fluorescently labeled lectins that specifically recognize alpha-N-acetylgalactosamine (GalNAc) and alpha-N-acetylglucosamine (GlcNAc) differentially bound to the cell surface based on the state of cellular differentiation. GalNAc and GlcNAc were highly expressed on the surface of undifferentiated cells and showed markedly reduced expression over a 12-day duration of differentiation. Additionally, the GalNAc-recognizing lectin Dolichos biflorus agglutinin was capable of specifically selecting and sorting glioma-derived stem cell populations from an unsorted tumor stock and this subpopulation had proliferative properties similar to CD133(+) cells in vitro and also had tumor-forming capability in vivo. Our preliminary results on a single cerebellar GBM suggest that GalNAc and GlcNAc are novel biomarkers for identifying glioma-derived stem cells and can be used to isolate cancer stem cells from unsorted cell populations, thereby creating new cell lines for research or clinical testing. PMID- 22435496 TI - Maternal serum C-reactive protein in early pregnancy and occurrence of preterm premature rupture of membranes and preterm birth. AB - AIM: The aim of this study was to determine the relationship between maternal serum C-reactive protein (CRP) levels in the first 20 weeks of pregnancy and later occurrence of preterm premature rupture of membranes and preterm birth. MATERIAL AND METHODS: A prospective cohort study that measured maternal serum CRP levels in 778 pregnant women in the first half of pregnancy was performed in the city of Noor (north Iran), and included follow-up of patients up to time of delivery. Preterm premature rupture of membranes and preterm birth were defined as the occurrence of membranes rupture and birth, respectively before 37 weeks of gestation. RESULTS: Of the 778 pregnancies studied, 19 (2.41%) preterm premature rupture of membranes and 58 (7.3%) preterm births were seen. Median CRP levels in preterm premature rupture of membranes and preterm birth cases were much higher than in term deliveries (7 and 6.8 respectively vs 2.4 mg/L; 66.67 and 64.76, respectively vs 24.38 nmol/L). CRP levels >4 mg/L had statistically significant relationships with preterm premature rupture of membranes (OR 5.91, 95% CI 2.07 16.89) and preterm birth (OR 8.95, 95% CI 4.60-17.43). With a cut-off level of 4 mg/L of CRP, sensitivity, specificity, and likelihood ratios (LR(+) and LR(-) ) for preterm birth were 81, 70, 2.70, 0.28%, respectively, and for preterm premature rupture of membranes they were 79, 67, 2.41 and 0.31%, respectively. CONCLUSION: It seems that the inflammatory marker, CRP, can be used in the early stages of pregnancy to identify women at risk of experiencing preterm premature rupture of membranes and preterm birth. PMID- 22435497 TI - Evidence for tissue iron overload in long-term hemodialysis patients and the impact of withdrawing parenteral iron. AB - BACKGROUND/AIMS: Erythropoiesis in long-term hemodialyzed (LTH) patients is supported by erythropoietin (rHuEpo) and intravenous (IV) iron. This treatment may end up in iron overload (IO) in major organs. We studied such patients for the parameters of IO in the serum and in major organs. METHODS: Patients were treated with rHuEpo (6-8 x 10(3) units * 1-3/wk) and IV 100 mg ferric saccharate. RESULTS: Of 115 patients, 21 had serum ferritin (SF) > 1000 ng/mL. This group was further analyzed. Their SF and transferrin saturation (TSAT) were 2688 +/- 1489 ng/mL and 54.2 +/- 32.7%, respectively (vs. 125-360 ng/mL and 20-50% in normal controls). Serum hepcidin was 60.1 +/- 29.5 nm (vs. 10.61 +/- 6.44 nm in controls) (P < 0.001). Nineteen patients had increased malonyldialdehyde, a product of lipid peroxidation, indicating oxidative stress. T2* MRI disclosed in 19 of 21 patients moderate to severe IO in the liver and spleen, in three of eight patients in the pancreas, but in no patient in the heart. After stopping IV iron for a mean of 12 months, while continuing rHuEpo, the mean SF decreased in 11 patients to 1682 ng/mL and the mean TSAT decreased to 28%, whereas hemoglobin did not change indicating that tissue iron was utilized. CONCLUSION: High SF correlates with IO in the liver and spleen, but not in the heart. PMID- 22435498 TI - Systematic evaluation of land use regression models for NO2. AB - Land use regression (LUR) models have become popular to explain the spatial variation of air pollution concentrations. Independent evaluation is important. We developed LUR models for nitrogen dioxide (NO(2)) using measurements conducted at 144 sampling sites in The Netherlands. Sites were randomly divided into training data sets with a size of 24, 36, 48, 72, 96, 108, and 120 sites. LUR models were evaluated using (1) internal "leave-one-out-cross-validation (LOOCV)" within the training data sets and (2) external "hold-out" validation (HV) against independent test data sets. In addition, we calculated Mean Square Error based validation R(2)s. The mean adjusted model and LOOCV R(2) slightly decreased from 0.87 to 0.82 and 0.83 to 0.79, respectively, with an increasing number of training sites. In contrast, the mean HV R(2) was lowest (0.60) with the smallest training sets and increased to 0.74 with the largest training sets. Predicted concentrations were more accurate in sites with out of range values for prediction variables after changing these values to the minimum or maximum of the range observed in the corresponding training data set. LUR models for NO(2) perform less well, when evaluated against independent measurements, when they are based on relatively small training sets. In our specific application, models based on as few as 24 training sites, however, achieved acceptable hold out validation R(2)s of, on average, 0.60. PMID- 22435499 TI - Reliability of high- and low-field magnetic resonance imaging systems for detection of cartilage and bone lesions in the equine cadaver fetlock. AB - REASONS FOR PERFORMING STUDY: To determine the reliability of 2 magnetic resonance imaging (MRI) systems for detection of cartilage and bone lesions of the equine fetlock. OBJECTIVES: To test the hypotheses that lesions in cartilage, subchondral and trabecular bone of the equine fetlock verified using histopathology can be detected on high- and low-field MR images with a low incidence of false positive or negative results; that low-field images are less reliable than high-field images for detection of cartilage lesions; and that combining results of interpretation from different pulse sequences increases detection of cartilage lesions. METHODS: High- and low-field MRI was performed on 19 limbs from horses identified with fetlock lameness prior to euthanasia. Grading systems were used to score cartilage, subchondral and trabecular bone on MR images and histopathology. Sensitivity and specificity were calculated for images. RESULTS: High-field T2*-weighted gradient echo (T2*W-GRE) and low-field T2-weighted fast spin echo (T2W-FSE) images had high sensitivity but low specificity for detection of cartilage lesions. All pulse sequences had high sensitivity and low-moderate specificity for detection of subchondral bone lesions and moderate sensitivity and moderate-high specificity for detection of trabecular bone lesions (histopathology as gold standard). For detection of lesions of trabecular bone low-field T2*W-GRE images had higher sensitivity and specificity than T2W-FSE images. CONCLUSIONS: There is high likelihood of false positive results using high- or low-field MRI for detection of cartilage lesions and moderate-high likelihood of false positive results for detection of subchondral bone lesions compared with histopathology. Combining results of interpretation from different pulse sequences did not increase detection of cartilage lesions. MRI interpretation of trabecular bone was more reliable than cartilage or subchondral bone in both MR systems. POTENTIAL RELEVANCE: Independent interpretation of a variety of pulse sequences may maximise detection of cartilage and bone lesions in the fetlock. Clinicians should be aware of potential false positive and negative results. PMID- 22435500 TI - Chemistry of aqueous silica nanoparticle surfaces and the mechanism of selective peptide adsorption. AB - Control over selective recognition of biomolecules on inorganic nanoparticles is a major challenge for the synthesis of new catalysts, functional carriers for therapeutics, and assembly of renewable biobased materials. We found low sequence similarity among sequences of peptides strongly attracted to amorphous silica nanoparticles of various size (15-450 nm) using combinatorial phage display methods. Characterization of the surface by acid base titrations and zeta potential measurements revealed that the acidity of the silica particles increased with larger particle size, corresponding to between 5% and 20% ionization of silanol groups at pH 7. The wide range of surface ionization results in the attraction of increasingly basic peptides to increasingly acidic nanoparticles, along with major changes in the aqueous interfacial layer as seen in molecular dynamics simulation. We identified the mechanism of peptide adsorption using binding assays, zeta potential measurements, IR spectra, and molecular simulations of the purified peptides (without phage) in contact with uniformly sized silica particles. Positively charged peptides are strongly attracted to anionic silica surfaces by ion pairing of protonated N-termini, Lys side chains, and Arg side chains with negatively charged siloxide groups. Further, attraction of the peptides to the surface involves hydrogen bonds between polar groups in the peptide with silanol and siloxide groups on the silica surface, as well as ion-dipole, dipole-dipole, and van-der-Waals interactions. Electrostatic attraction between peptides and particle surfaces is supported by neutralization of zeta potentials, an inverse correlation between the required peptide concentration for measurable adsorption and the peptide pI, and proximity of cationic groups to the surface in the computation. The importance of hydrogen bonds and polar interactions is supported by adsorption of noncationic peptides containing Ser, His, and Asp residues, including the formation of multilayers. We also demonstrate tuning of interfacial interactions using mutant peptides with an excellent correlation between adsorption measurements, zeta potentials, computed adsorption energies, and the proposed binding mechanism. Follow-on questions about the relation between peptide adsorption on silica nanoparticles and mineralization of silica from peptide stabilized precursors are raised. PMID- 22435503 TI - Inflammatory bowel disease in the 21(st) century in China: turning challenges into opportunities. AB - Inflammatory bowel disease (IBD) has been an international hot spot for research for a long period of time. In China, the prevalence of IBD is rapidly increasing in recent years, mimicking the same fast growing footsteps of the developed world. Chinese literature of the 20(th) century shows that the total number of IBD cases increased by approximately 2.5-fold over the previous decade, in particular a 15.7-fold in patients with Crohn's disease (CD). Articles on basic research have increased 4.3-fold, with a particular 9.9-fold increase on immunological mechanisms. The predominantly Traditional Chinese Medicine (TCM) related clinical trials implied tendency to use a combination of Western Medicine and TCM in the management of Chinese IBD patients. IBD research and collaborations overseas have been markedly promoted since the Chinese Organization for the Study of Inflammatory Bowel Disease (COIBD) was founded at the beginning of the 21(st) century. From the second decade of the century onwards, we need to focus on the research hot spots to catch up with the rapid advances worldwide. Big challenges and present achievements provide us with great opportunities for further developments of the study on IBD. The development of some novel target pathogenic factors of the disease will provide us with more effective roll for modern management and optimistic treatment of IBD during this century. PMID- 22435501 TI - Condylomata, cytological abnormalities and human papillomavirus infection in the anal canal in HIV-infected men. AB - BACKGROUND: Genital infections with low-risk (LR) and high-risk (HR) human papillomavirus (HPV) genotypes are associated with ano-genital condylomata and anal squamous cell cancer. HPV-related pathologies in HIV-infected men are a serious concern. In this study, the prevalence of anal condylomata and their association with cytological abnormalities and HPV infection in the anal canal in HIV-infected men [men who have sex with men (MSM) and heterosexuals] were estimated. METHODS: This was a cross-sectional study based on the first visits of patients in the Can Ruti HIV-positive Men (CARH.MEN) cohort. Anal condylomata were assessed by clinical and proctological examination. Samples from the anal canal were collected for HPV genotyping and cytological diagnoses. RESULTS: A total of 640 HIV-infected men (473 MSM and 167 heterosexuals) were included in the study. The overall prevalence of anal condylomata was 25% [157 of 640; 95% confidence interval (CI) 21-28%]; in MSM it was 28% and in heterosexuals it was 15% [odds ratio (OR) 2.2; 95% CI 1.4-3.5]. In patients with anal condylomata, HPV infection in the anal canal was more prevalent (92% vs. 67% in those without anal condylomata; OR 8.5; 95% CI 3.2-22). This higher HPV prevalence involved at least two HPV genotypes (OR 4.0; 95% CI 2.2-7.1), mainly HR genotypes (OR 3.3; 95% CI 1.7-6.4). Similarly, the cumulative prevalence of HPV-6 and HPV-11 was higher in patients with anal condylomata (63% vs. 19% in those without anal condylomata). Having anal condylomata was associated with higher prevalences of cytological abnormalities (83% vs. 32% in those without anal condylomata; OR 6.9; 95% CI 3.8 12.7) and high-grade squamous intraepithelial lesions (HSILs) (9% vs. 3% in those without anal condylomata; OR 9.0; 95% CI 2.9-28.4) in the anal canal. CONCLUSIONS: HIV-infected men with anal condylomata were at risk of presenting HSILs and harbouring multiple HR HPV infections in the anal canal. Although MSM presented the highest prevalence of anal condylomata, heterosexual men also had a clinically important prevalence. Our findings emphasize the importance of screening and follow-up for condylomata in the anal canal in HIV-infected men. PMID- 22435504 TI - Once-daily versus multiple-daily mesalamine for patients with ulcerative colitis: a meta-analysis. AB - OBJECTIVE: To systematically review the efficacy and safety of once-daily (OD) mesalamine for the treatment of ulcerative colitis (UC) compared with multiple daily (MD) mesalamine. METHODS: Electronic databases up to July 2011 were searched for related studies evaluating the efficacy of OD vs MD for treatment of UC. Only randomized controlled trials (RCTs) were considered eligible. Remission rates or relapse rates were analyzed using intention-to-treat (ITT) and per protocol (PP) analysis. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated. Publication bias was assessed with a funnel plot. RESULTS: Overall 10 RCTs including 9 full-text manuscripts and one abstract met the inclusion criteria. OD dosing of mesalamine was shown to be as effective as MD dosing for the maintenance of clinical remission in patients with quiescent UC (RR = 1.00, 95% CI 0.89-1.12) by ITT analysis. For active UC, a mild but significant benefit was achieved by OD dosing compared with MD dosing (RR = 0.80, 95% CI 0.64-0.99). Total adverse events were similar using OD and MD mesalamine in quiescent UC (RR = 1.06, 95% CI 0.93-1.20). Compliance with OD was slightly better than with MD (RR = 0.92, 95% CI 0.82-1.03). CONCLUSIONS: OD mesalamine is as effective and has a comparable safety profile as MD regimens for the maintenance treatment of UC, and is even more effective for inducing remission in active UC. PMID- 22435505 TI - Promoter methylation regulates cigarette smoke-stimulated cyclooxygenase-2 expression in esophageal squamous cell carcinoma. AB - OBJECTIVE: Cigarette smoke extracts (CSE) could promote esophageal squamous cell carcinoma (ESCC) through upregulation of cyclooxygenase-2 (COX-2) expression. Promoter methylation mediates the transcriptional modulation of the COX-2 gene. The aim of the study was to explore whether COX-2 promoter methylation regulated COX-2 expression and functional activity in ESCC exposed to CSE. METHODS: The methylation status of COX-2 promoter in two human ESCC cell lines, EC109 and TE 1, was examined using bisulfite sequencing analysis. COX-2 mRNA and protein expression were detected by reverse-transcription polymerase chain reaction and Western blot. Prostaglandin E2 (PGE2) was examined by enzyme linked immunosorbent assay (ELISA). RESULTS: The promoter was hypermethylated in TE-1 which had a low level of COX-2 expression and was hypomethylated in EC109 with a relatively high level of COX-2 expression. Stimulation by cigarette smoke ethanol extract (EE) resulted in increased COX-2 expression in EC109, but not in TE-1. Treatment with 5-aza-2'-deoxycytidine (5-aza-DC) demethylated the promoter and upregulated COX-2 expression as well as PGE(2) production in TE-1, especially followed by EE stimulation. No significant effect was observed in EC109. CONCLUSION: These findings suggest that promoter methylation may be one of the mechanisms regulating COX-2 expression in ESCC in response to stimulation of CSE. PMID- 22435506 TI - Clinical prognostic variables in young patients (under 40 years) with hepatitis B virus-associated hepatocellular carcinoma. AB - OBJECTIVE: The aim of this study was to determine the impact of hepatocelluar carcinoma (HCC) screening in chronic hepatitis B patients who did not meet the current screening recommendations. METHODS: Patients who were admitted to Bellevue Hospital Center with HCC were assessed for risk factors, cirrhosis and tumor-specific factors. Eligibility for liver transplantation or resection with favorable outcome was determined by applying Milan criteria. RESULTS: In all 93 patients were diagnosed with hepatitis B virus (HBV)-associated HCC, 18 of whom were under 40 years. Cirrhosis was infrequently associated with HCC in this group, with most cancers occurring in non-cirrhotic patients (12/18, 66.7%). No patient developed HCC outside the American Association for the Study of Liver Diseases (AASLD) cancer screening recommendations (young age, non-cirrhotic) were eligible for liver transplantation or resection with favorable outcomes (within Milan criteria). However, HCC patients who were diagnosed within AASLD screening recommendations did meet Milan criteria in 17.3% (14/81) patients. CONCLUSIONS: Current guidelines for HCC screening in patients with HBV may lead to a delay in diagnosis in non-cirrhotic patients under 40 years. Consideration should be given to modifying current recommendations to advocate entering HBV patients into a cancer-screening program at young age. PMID- 22435507 TI - Efficacy of fenofibrate in Chinese patients with primary biliary cirrhosis partially responding to ursodeoxycholic acid therapy. AB - OBJECTIVE: To investigate the efficacy of fenofibrate combination therapy in Chinese patients with primary biliary cirrhosis (PBC) who had a partial response to standard dose of ursodeoxycholic acid (UDCA) for at least one year. METHODS: PBC patients were treated with UDCA (13-15 mg/kg/day) for more than one year. The biochemical response to UDCA treatment was evaluated after treatment. Fenofibrate (200 mg/day) was added to 22 patients with partial response to UDCA. RESULTS: In patients with partial response to UDCA, serum alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase levels significantly decreased after 3-month combination therapy of UDCA and fenofibrate, 68% of these patients even reached normal ALP level. Serum triglyceride (TG) and cholesterol levels were improved, and alanine transaminase (ALT) and aspartate transaminase (AST) were also decreased during the combination therapy. However, fenofibrate had no significant effect on serum bilirubin levels. The improvement of liver biochemical tests was maintained in some patients with long-term therapy (at least 6 months). No obvious adverse effects were observed in patients taking fenofibrate. CONCLUSIONS: Fenofibrate is effective for improving liver biochemical tests in patients who have partial response to UDCA monotherapy. It is worth exploring the efficacy of fenofibrate on histological changes in PBC patients. PMID- 22435508 TI - Fractalkine as a marker for assessment of severe acute pancreatitis. AB - OBJECTIVE: The aim of this study was to study the role of fractalkine (FKN) in the development of severe acute pancreatitis (SAP) in animal model. METHODS: Serum FKN levels in rat model (control, SAP6 h, 16 h, 24 h and 48 h) were determined by enzyme-linked immunosorbent assay. FKN mRNA and protein levels in the pancreas tissue were measured by reverse transcription polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry. RESULTS: Serum FKN level in the SAP rat increased significantly (P < 0.05 compared with the control group). FKN mRNA and protein levels in pancreas and lung increased significantly and reached the peak at 16 h after the induction of SAP, while those in kidney reached the peak at 48 h. Immunohistochemistry showed the overexpression of FKN in pancreas, lung and kidney tissue. CONCLUSION: FKN involves in the progression of SAP and might be a valuable marker for the assessment of SAP. PMID- 22435509 TI - Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. AB - OBJECTIVE: The aim of this prospective study was to compare the efficacy of the first-line lansoprazole-based sequential therapy and concomitant therapy (lansoprazole, amoxicillin, clarithromycin and metronidazole) for Helicobacter pylori (H. pylori) eradication. METHODS: A total of 169 patients with H. pylori infection were randomly assigned to either the sequential therapy group (n = 85) or the concomitant therapy group (n = 84). A follow-up endoscopy or urea breath test was examined at least 12 weeks after eradication. RESULTS: Comparable H. pylori eradication rate was observed in both the sequential therapy and concomitant therapy groups by either intention-to-treat analysis [sequential 80.0% (68/85) vs concomitant 88.1% (74/84); P = 0.27] or per protocol analysis [sequential, 85.3% (64/75) vs concomitant, 94.6% (70/74); P = 0.60]. Adverse effects were reported and good compliance was observed in both groups (P = 0.72). Although dual antibiotics resistance affected the therapeutic efficacy of sequential therapy (P = 0.03), not concomitant therapy (P = 0.74), it was not an independent factor for predicting the treatment outcome. CONCLUSION: First-line lansoprazole-based sequential and concomitant therapy were well-tolerated and comparable in terms of their H. pylori eradication rate. PMID- 22435510 TI - Endoscopic removal of a long sharp metallic foreign body by a snared magnet: an attractive solution. PMID- 22435511 TI - Nanoscale clustering of carbohydrate thiols in mixed self-assembled monolayers on gold. AB - Self-assembled monolayers (SAMs) bearing pendant carbohydrate functionality are frequently employed to tailor glycan-specific bioactivity onto gold substrates. The resulting glycoSAMs are valuable for interrogating glycan-mediated biological interactions via surface analytical techniques, microarrays, and label-free biosensors. GlycoSAM composition can be readily modified during assembly by using mixed solutions containing thiolated species, including carbohydrates, oligo(ethylene glycol) (OEG), and other inert moieties. This intrinsic tunability of the self-assembled system is frequently used to optimize bioavailability and antibiofouling properties of the resulting SAM. However, until now, our nanoscale understanding of the behavior of these mixed glycoSAMs has lacked detail. In this study, we examined the time-dependent clustering of mixed sugar + OEG glycoSAMs on ultraflat gold substrates. Composition and surface morphologic changes in the monolayers were analyzed by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM), respectively. We provide evidence that the observed clustering is consistent with a phase separation process in which surface-bound glycans self-associate to form dense glycoclusters within the monolayer. These observations have significant implications for the construction of mixed glycoSAMs for use in biosensing and glycomics applications. PMID- 22435512 TI - Safety and tolerability of intermittent androgen deprivation therapy: a literature review. AB - Androgen deprivation therapy is commonly used in men with advanced prostate cancer; however, it is associated with many short- and long-term side-effects. Intermittent androgen deprivation therapy was first suggested as an alternative regimen in the early 1990s and is now part of treatment guidelines as a result of its ability to reduce adverse events associated with continuous androgen deprivation therapy without decreasing its efficacy. Although many publications evaluated intermittent androgen deprivation therapy's efficacy, the safety and tolerability information of this regimen is relatively limited. The goal of this literature review was to analyze clinical trials that have reported safety and tolerability data in prostate cancer patients treated with intermittent androgen deprivation therapy, as well as assessing quality of life outcomes. A literature search was carried out using biomedical and pharmaceutical databases for published information comparing intermittent androgen deprivation therapy with continuous androgen deprivation therapy. A total of 13 randomized and non randomized studies were selected and reviewed based on their relevance to the safety, tolerability and quality of life of intermittent androgen deprivation therapy. Benefits for intermittent androgen deprivation therapy were observed for the short-term side-effects (hot flushes and sexual functions) mainly during the off-treatment phase, whereas the data for the long-term side-effects were not as conclusive. Quality of life evaluations are more in support of intermittent androgen deprivation therapy. Although there are some safety, tolerability and quality of life benefits associated with intermittent androgen deprivation therapy, the overall evidence is still limited. PMID- 22435513 TI - Investigation into the mechanism of anti-asthmatic action of Moringa oleifera. AB - We have studied the possible mechanism of the antiasthmatic action of Moringa oleifera seed kernel ethanolic extract (EXMO, 400 mg/kg). EXMO produced an increase in the Preconvulsion Dyspnea time induced by histamine and acetylcholine aerosol, a significant reduction in the elevated eosinophil and monocyte counts in the Broncho-Alveolar Lavage fluid of sensitized guinea pigs, reduction in the paw edema volume as compared to the control rats, and decrease in the elevated histamine release from the sensitized guinea pig lungs. The pD(2) values of histamine in tracheal chain and taenia coli were significantly greater and that in lung strip was lower in the sensitized animals and treatment with EXMO significantly decreased pD(2) values in all three preparations. Our data suggest inhibition of the immediate hypersensitive reaction, histamine release, and the infiltration of various inflammatory cells as possible antiasthmatic mechanisms of action. PMID- 22435514 TI - Artichoke leaf juice contains antihypertensive effect in patients with mild hypertension. AB - Lifestyle modifications are effective for the management and prevention of hypertension. We conducted a randomized, placebo-controlled trial to evaluate the efficacy of an oral concentrated leaf juice of artichoke (Cynara scolymus L.; CS) in patients with mild hypertension (systolic blood pressure [SBP]/diastolic blood pressure [DBP], 140-159/90-99 mmHg). Subjects were randomized into a placebo and two drug groups that received 50 and 100 mg of artichoke juice concentrate. After 12 weeks, SBP significantly reduced as compared with the baseline data in case groups and DBP was significantly lower from the baseline as compared with the placebo group. It is concluded that the use of artichoke juice concentrate may have a blood pressure-lowering effect in mild hypertension. PMID- 22435515 TI - First preliminary results of an observation of Panax ginseng treatment in patients with autistic disorder. AB - Autism is a pervasive developmental disorder, with impairments in reciprocal social interaction and verbal and nonverbal communication. There is often the need of psychopharmacological intervention in addition to psychobehavioral therapies, but benefits are limited by adverse side effects. For that reason, Panax ginseng, which is comparable with Piracetam, a substance effective in the treatment of autism, was investigated for possible improvement of autistic symptoms. There was some improvement, which suggests some benefits of Panax ginseng, at least as an add-on therapy. PMID- 22435517 TI - Open the doorway: how can physicians find out what dietary supplements their patients are actually taking, and why should they? PMID- 22435516 TI - Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose. AB - ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients. PMID- 22435518 TI - Prickly pear as food and medicine. PMID- 22435519 TI - Advising consumers about dietary supplements: lessons from cranberry products. AB - Consumers are continuing to incorporate dietary supplements as part of their routine health care. Yet, even as the market continues to grow, questions regarding safety, efficacy, and quality remain. Clinicians are increasingly being asked to advise their patients about the safe and efficacious use of such products. Cranberry is a commonly encountered supplement that has been studied comprehensively. We review some of the findings from the evaluation of cranberry as a dietary supplement and suggest how such findings can be shared effectively with patients and consumers. PMID- 22435520 TI - Response of carcinoma in situ (actinic keratosis) to green tea concentrate plus capsicum. AB - A single case of carcinoma in situ (actinic keratosis) was treated topically with a patch consisting of an aqueous paste of a commercially available mixture (50:1) of green tea concentrate plus Capsicum (Capsol-T(r)) for approximately 14 days. The carcinoma responded by the formation of apoptotic blisters whereas surrounding normal tissue showed no response. A second untreated carcinoma 17 cm distant from the treated area also responded indicative of a systemic action of the substance. PMID- 22435521 TI - An evidence-based systematic review of amaranth (Amaranthus spp.) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22435527 TI - Motor function after dorsal rhizotomy. PMID- 22435528 TI - Serum markers of apoptosis in the early period of heart transplantation. AB - CONTEXT AND OBJECTIVE: To assess the relationship between levels of serum markers of apoptosis and rejection grades in heart transplant (HTx). MATERIALS AND METHODS: A prospective study was conducted in 91 HTx. We correlated apoptosis markers and biopsy samples. The apoptosis markers were: TRAIL, TRAIL-R1, TRAIL R2, TRAIL-R3, TRAIL-R4, sFas, sTNF-R1 and sTNF-R2. RESULTS: The only significant correlation with rejection grade was sFas (r=0.329; p=0.005). Cyclosporine showed a proapoptotic effect (sTNF-R1 0.02 and sTNF-R2 0.02) and everolimus an antiapoptotic effect (sTNF-R1 r= -0.523; p=0.0001 and sTNF-R2 r= -0.405; p=0.0001). CONCLUSIONS: The utility of specific apoptosis markers in peripheral blood for diagnosis of acute cellular rejection is low. Everolimus may have an anti-apoptotic effect. PMID- 22435529 TI - Phase diagram and structures in mixtures of poly(styrenesulfonate anion) and alkyltrimethylammonium cations in water: significance of specific hydrophobic interaction. AB - Mixtures of polyelectrolytes and oppositely charged surfactants show very rich phase behavior that is influenced by surfactant-ion and polyion properties and by water content. A general feature is associative phase separation as a result of strong electrostatic interactions, whereas the effect of eventual more specific interactions (e.g., hydrophobic) has not been thoroughly investigated. In this paper, we report a detailed study on phase behavior and structures in poly(styrenesulfonate anion) (PSS(-))-cetyltrimethylammonium cation (CTA(+)) water mixtures that are characterized by a hydrophobic interaction between the styrene groups of PSS(-) and the micelle interior. Structures of various phases were determined by small-angle X-ray scattering, and results indicated the presence of a disordered micellar and an ordered hexagonal phase; no cubic phase was found. The general conclusion is that the highlighted hydrophobic interaction promotes dissolution of CTAPSS when the polyion salt is added and provides further stabilization of the dense phase when the surfactant salt is added. PMID- 22435530 TI - Mesenchymal stem cells conditioned with glucose depletion augments their ability to repair-infarcted myocardium. AB - Mesenchymal stem cells (MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57BL/6 mice were characterized for gene expression of IGF-1, FGF-2, VEGF, SIRT-1, AKT, p16(INK4a) , p21 and p53 along with measurements of population doubling (PD), superoxide dismutase (SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre conditioned with glucose depletion to enhance age affected function. Pre conditioning of aged MSCs led to an increase in expression of IGF-1, AKT and SIRT 1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre-conditioned aged MSCs, myocardial infarction (MI) was induced in 24 months old C57BL/6 wild type mice and GFP expressing untreated and pre-conditioned aged MSCs were transplanted. Hearts transplanted with pre-conditioned aged MSCs showed increased expression of paracrine factors, such as IGF-1, FGF-2, VEGF and SDF-1alpha. This was associated with significantly improved cardiac performance as measured by dp/dt(max), dp/dt(min), LVEDP and LVDP, declined left ventricle (LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre-conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium. PMID- 22435531 TI - Systems model of physician professionalism in practice. AB - RATIONALE: This article proposes a systems level conceptualization of physician professionalism that is embedded in and results from the characteristics of the organizations in which doctors work such as hospitals, group practices and physician organizations. AIMS AND OBJECTIVES: The goal of this study was to develop and test the systems model of professionalism. METHODS: In total, 25 interviews were conducted in Minneapolis and Miami. Job titles of the subjects included hospital presidents, medical directors, chairs of hospital departments, quality and safety directors, chief of quality improvement and practising physicians. The data from the interviews were coded and then sorted by members of the study team into major and minor themes. RESULTS: Virtually, all of the subjects were readily able to confirm aspects of the model by providing real-life examples of factors at the practice, hospital and market levels that they believed strongly influenced the extent to which physicians adhere, or fail to adhere, to the professional norms. CONCLUSIONS: The systems model of professionalism was consistent with the views and experiences of physicians and administrators in two different geographic regions of the USA. If born out by further research, this model has implications for interventions aimed at improving professionalism as well as for professionalism as a field of study. PMID- 22435532 TI - Evaluation of N-acetilglucosaminidase and myeloperoxidase activity in patients with endometriosis-related infertility undergoing intracytoplasmic sperm injection. AB - AIM: Inflammation is as an important factor in ovulation with the active participation of leucocytes and their inflammatory mediators. The present study was performed to compare the activity of the inflammatory enzymes myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) in patients with endometriosis-related infertility and in normally ovulating women undergoing intracytoplasmic sperm injection (ICSI). MATERIAL AND METHODS: This prospective study included infertile women undergoing ICSI treatment. These women were divided into two groups: endometriosis anovulation (n = 18) and normally ovulating (n = 20). NAG and MPO activity was evaluated colorimetrically in serum and in follicular fluids obtained at the time of oocyte retrieval. RESULTS: There was a significant correlation between the serum and follicular fluid activities of NAG and MPO (tau = 0.256, P = 0.025; and tau = -0.234, P = 0.041; respectively). Both serum and follicular fluid NAG activities were higher in patients with endometriosis compared to the control group (P < 0.001). MPO follicular fluid activity was lower in patients with endometriosis compared to normally ovulating women (P = 0.016). CONCLUSION: Infertile patients with endometriosis show a distinct pattern of serum and follicular fluid macrophage/neutrophil activation compared to normally ovulating women undergoing ICSI, which may reflect the role of immune and inflammatory alterations in endometriosis-related infertility. PMID- 22435533 TI - Homogeneous CO2 reduction by Ni(cyclam) at a glassy carbon electrode. AB - The homogeneous CO(2) reduction activity of several nickel cyclam complexes was examined by cyclic voltammetry and controlled potential electrolysis. CO production with high efficiency from unsubstituted Ni(cyclam) was verified, while the activity was found to be attenuated with methyl substitution of the amines on the cyclam ring. Reactivity with CO(2) was also probed using density functional theory (DFT) calculations. The relative CO(2) binding energies to the Ni(I) state obtained from DFT were found to match well with the experimental results and shed light on the possible importance of the isomeric form of Ni(cyclam) in determining the catalytic activity. PMID- 22435534 TI - Practical dietary management of protein energy malnutrition in young children with cow's milk protein allergy. AB - Cow's milk protein allergy (CMPA) affects between 1.9 and 4.9% of infants and young children. This food allergy requires the complete elimination of cow's milk and its derivatives, impacting on nutritional status. The risk of having protein energy malnutrition (PEM) in children with CMPA has been well documented. In 2007, the World Health Organisation published guidelines on the dietary management of PEM, which has impacted on the recommendations and composition on specialist feeds for many chronic diseases, but not on CMPA. The main change in management of the child with PEM is the protein energy ratio and energy requirements. The ideal protein energy ratio lies between 8.9 and 11.5%, which would ensure a deposition of about 70% lean and 30% fat mass. In addition, for optimal catch-up growth between 5 and 10 g/kg/day, energy requirements should be between 105 and 126 kcal/kg/day. Although most current hypoallergenic formulas fall well within the recommendation for protein, there is a problem in achieving energy requirements. As a result, modular additions are often made, disturbing the protein energy ratio or feeds are concentrated, which impacts on osmolality. We therefore aimed to review current guidelines on PEM and how these can be applied in the management of the malnourished child with CMPA. PMID- 22435535 TI - AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells. AB - Reprogramming of energetic metabolism is a phenotypic trait of cancer in which mitochondrial dysfunction represents a key event in tumour progression. In the present study, we show that the acquisition of the tumour-promoting phenotype in colon cancer HCT116 cells treated with oligomycin to inhibit ATP synthase is exerted by repression of the synthesis of nuclear-encoded mitochondrial proteins in a process that is regulated at the level of translation. Remarkably, the synthesis of glycolytic proteins is not affected in this situation. Changes in translational control of mitochondrial proteins are signalled by the activation of AMPK (AMP-activated protein kinase) and the GCN2 (general control non derepressible 2) kinase, leading also to the activation of autophagy. Changes in the bioenergetic function of mitochondria are mimicked by the activation of AMPK and the silencing of ATF4 (activating transcription factor 4). These findings emphasize the relevance of translational control for normal mitochondrial function and for the progression of cancer. Moreover, they demonstrate that glycolysis and oxidative phosphorylation are controlled at different levels of gene expression, offering the cell a mechanistic safeguard strategy for metabolic adaptation under stressful conditions. PMID- 22435536 TI - Fluoroquinolone disposition: identification of the contribution of renal secretory and reabsorptive drug transporters. AB - INTRODUCTION: Fluoroquinolones (FQs) exist as charged molecules in blood and urine making their absorption, distribution, and elimination likely to be influenced by active transport mechanisms. Greater understanding of in vivo FQ clearance mechanisms should help improve the predictability of drug-drug interactions, enhance the clinical safety and efficacy, and aid future novel drug design strategies. AREAS COVERED: The authors present an overview of FQ development and associated drug-drug interactions, followed by systematic quantitative review of the physicochemical and in vivo pharmacokinetic properties for 15 representative FQs using historical clinical literature. These results were correlated with in vitro studies implicating drug transporters in FQ clearance to link clinical and in vitro evidence supporting the contribution of drug transport mechanisms to FQ disposition. Specific transporters likely to handle FQs in human renal proximal tubule cells are also identified. EXPERT OPINION: Renal handling, that is, tubular secretion and reabsorption, appears to be the main determinant of FQ plasma half-life, clinical duration of action, and drug-drug interactions. Due to their zwitterionic nature, FQs are likely to interact with organic anion and cation transporters within the solute carrier (SLC) superfamily, including OAT1, OAT3, OCT2, OCTN1, OCTN2, MATE1, and MATE2. The ATP-binding cassette (ABC) transporters MDR1, MRP2, MRP4, and BCRP also may interact with FQs. PMID- 22435538 TI - Fabrication of alternating multilayer films of graphene oxide and carbon nanotube and its application in mechanistic study of laser desorption/ionization of small molecules. AB - Graphene, graphene oxide (GO), and multi-walled carbon nanotube (MWCNT) have been actively explored as matrix for laser desorption/ionization mass spectrometry (LDI-MS) in place of conventional organic matrix. Recently, the GO/MWCNT double layer films on a solid substrate showed excellent applicability in small molecule analysis, enzyme activity assay and tissue imaging. In the present study, LDI processes of small molecules on multilayers of alternating MWCNT and GO hybrid films were thoroughly investigated. We found that the LDI efficiency of small molecules was affected by thickness, assembly sequence and surface roughness of the hybrid films that were controlled by varying the number of layer-by-layer (LBL) assembly cycles. The study would provide useful basic information to develop an efficient LDI-MS platform based on carbon nanomaterials. PMID- 22435539 TI - Non-carious cervical lesions and occlusion: a systematic review of clinical studies. AB - Non-carious cervical lesions (NCCLs) are a group of lesions that affect the cervical area of the teeth. Different aetiological factors have been reported, among them tooth brushing force, erosive agents and occlusal forces. The aim of this study was to ascertain, by means of a systematic review, the association between NCCLs and occlusion. A search was performed in the MEDLINE database, retrieving a total of 286 articles. After title and abstract screening, the clinical investigations were read in full to select those that evaluated the occlusal aspects of NCCL aetiology. This systematic review describes the results of three prospective and 25 cross-sectional studies. As there is an extreme heterogeneity in design, diagnostic criteria, forms of analysis and associated factors, a meta-analysis was not possible. The wide variety of classification and diagnostic criteria reflects a high range of reported prevalence. An extensive heterogeneity of independent variables was noted, even in occlusal analysis, which helps to mask any conclusion about the role of occlusion in NCCL aetiology. The literature reveals that studies on this topic are subject to a substantial amount of bias, such as evaluation (use of non-blinded examiners) and confounding bias (no control of others aetiological factors). Up to now, it has been impossible to associate NCCLs with any specific causal agent, and the role of occlusion in the pathogenesis of non-carious cervical lesions seems as yet undetermined. Therefore, additional studies, properly designed to diminish bias, are warranted. PMID- 22435540 TI - Chemoenzymatic reversible immobilization and labeling of proteins without prior purification. AB - Site-specific chemical modification of proteins is important for many applications in biology and biotechnology. Recently, our laboratory and others have exploited the high specificity of the enzyme protein farnesyltransferase (PFTase) to site-specifically modify proteins through the use of alternative substrates that incorporate bioorthogonal functionality including azides and alkynes. In this study, we evaluate two aldehyde-containing molecules as substrates for PFTase and as reactants in both oxime and hydrazone formation. Using green fluorescent protein (GFP) as a model system, we demonstrate that the purified protein can be enzymatically modified with either analogue to yield aldehyde-functionalized proteins. Oxime or hydrazone formation was then employed to immobilize, fluorescently label, or PEGylate the resulting aldehyde-containing proteins. Immobilization via hydrazone formation was also shown to be reversible via transoximization with a fluorescent alkoxyamine. After characterizing this labeling strategy using pure protein, the specificity of the enzymatic process was used to selectively label GFP present in crude E. coli extract followed by capture of the aldehyde-modified protein using hydrazide-agarose. Subsequent incubation of the immobilized protein using a fluorescently labeled or PEGylated alkoxyamine resulted in the release of pure GFP containing the desired site specific covalent modifications. This procedure was also employed to produce PEGylated glucose-dependent insulinotropic polypeptide (GIP), a protein with potential therapeutic activity for diabetes. Given the specificity of the PFTase catalyzed reaction coupled with the ability to introduce a CAAX-box recognition sequence onto almost any protein, this method shows great potential as a general approach for selective immobilization and labeling of recombinant proteins present in crude cellular extract without prior purification. Beyond generating site-specifically modified proteins, this approach for polypeptide modification could be particularly useful for large-scale production of protein conjugates for therapeutic or industrial applications. PMID- 22435541 TI - Highly active and stable Ni-Fe bimetal prepared by ball milling for catalytic hydrodechlorination of 4-chlorophenol. AB - A novel Ni-Fe bimetal with high dechlorination activity for 4-chlorophenol (4-CP) was prepared by ball milling (BM) in this study. Increasing Ni content and milling time greatly enhanced the dechlorination activity, which was mainly attributed to the homogeneous distribution of Ni nanoparticles (50-100 nm) in bulk Fe visualized by scanning electron microscopy/energy dispersive X-ray spectrometry (SEM/EDS) with image mapping. In comparison with the Ni-Fe bimetal prepared by a chemical solution deposition (CSD) process, the ball milled Ni-Fe bimetal possessed high dechlorination activity and stability before being used up. Dechlorination kinetics indicated that the dechlorination rates of 4-CP increased with increasing Ni-Fe dose but decreased with increasing solution pH. Solution pH had a significant effect on the dechlorination of 4-CP and the passivation of the Ni-Fe bimetal. The enhanced pH during the dechlorination process significantly accelerated the formation of passivating film on the bimetallic surface. The Ni-Fe bimetal at the dose of 60 g/L was reused 10 times without losing dechlorination activity for 4-CP at initial pH less than 6.0, but the gradual passivation was observed at initial pH above 7.0. PMID- 22435542 TI - Dynamic respiratory endoscopy of Standardbred racehorses during qualifying races. AB - REASON FOR PERFORMING STUDY: Examination of the equine upper airway during racing has not previously been documented. OBJECTIVE: To describe the feasibility and appearance of the upper airways by overground respiratory endoscopic examination during racing conditions. METHODS: Overground videoendoscopic examinations were performed on 46 Standardbred racehorses during qualifying races. Examined horses' speeds were recorded throughout the race with a portable GPS device. RESULTS: The procedure did not interfere with performance as there were no significant differences in race times between races in which horses were examined with the endoscope in place and prior unexamined races. Airway obstructions during or after the race were documented in 21 horses. Most previously reported causes of upper airway obstruction were observed; surprisingly bilateral ventro-medial arytenoid displacement (VMAD; n = 5) was seen during exercise as frequently as dorsal displacement of the soft palate (DDSP). Although DDSP (n = 10) was the most common diagnosis made, many displacements (n = 5) occurred after the race. Horses that demonstrated DDSP after the race had slower speeds than unaffected horses during the race. CONCLUSIONS: Racing endoscopy permits the diagnosis of upper airway obstructions without affecting performance. The occurrence of DDSP immediately after exercise may be clinically relevant. During racing VMAD may be an important anomaly. POTENTIAL RELEVANCE: Racing endoscopy could be used to correlate the sensitivity of diagnostic endoscopy during race-training or treadmill examination. The pathogenesis and significance of VMAD deserves further investigation. PMID- 22435543 TI - Motor function after selective dorsal rhizotomy: a 10-year practice-based follow up study. AB - AIM: The aim of this study was to explore changes in motor function up to 10 years after selective dorsal rhizotomy (SDR). METHOD: The participants comprised 29 children (20 males, nine females) with bilateral spastic diplegia who were consecutively operated on at a median age of 4 years and 3 months and followed until a median age of 15 years. SDR was combined with physiotherapy and regular follow-up visits. The distribution of preoperative Gross Motor Function Classification System (GMFCS) levels was as follows: I, n=1; II, n=7; III, n=8; IV, n=12; and V, n=1. Muscle tone in hip flexors, hip adductors, knee flexors, and plantar flexors was assessed with the modified Ashworth scale, passive range of motion in hip abduction, popliteal angle, maximum knee extension, dorsiflexion of the foot was measured with a goniometer, and gross motor function was assessed using the Gross Motor Function Measure (GMFM-66). The results were compared with preoperative values, taking into account age at the time of SDR. RESULTS: After 10 years, muscle tone in hip flexors, hip adductors, knee flexors and plantar flexors was normalized in 19, 24, 13 and 23 participants respectively; mean change in passive range of motion ranged from -2.0 degrees to 8.6 degrees , and the mean increase in GMFM-66 was 10.6. Changes in GMFM-66 were associated with preoperative GMFCS level and GMFM-66 scores. INTERPRETATION: Children who underwent SDR and physiotherapy and were regularly followed up by an experienced team showed improved gross motor function for up to 10 years postoperatively. PMID- 22435544 TI - Celebrating 25 years of NF-kappaB research. PMID- 22435545 TI - NF-kappaB: where did it come from and why? AB - The vast majority of research on nuclear factor kappaB (NF-kappaB) signaling in the past 25 years has focused on its roles in normal and disease-related processes in vertebrates, especially mice and humans. Recent genome and transcriptome sequencing efforts have shown that homologs of NF-kappaB transcription factors, inhibitor of NF-kappaB (IkappaB) proteins, and IkappaB kinases are present in a variety of invertebrates, including several in phyla simpler than Arthropoda, the phylum containing insects such Drosophila. Moreover, many invertebrates also contain genes encoding homologs of upstream signaling proteins in the Toll-like receptor signaling pathway, which is well-known for its downstream activation of NF-kappaB for innate immunity. This review describes what we now know or can infer and speculate about the evolution of the core elements of NF-kappaB signaling as well as the biological processes controlled by NF-kappaB in invertebrates. Further research on NF-kappaB in invertebrates is likely to uncover information about the evolutionary origins of this key human signaling pathway and may have relevance to our management of the responses of ecologically and economically important organisms to environmental and adaptive pressures. PMID- 22435546 TI - NF-kappaB regulation: lessons from structures. AB - The signaling module that specifies nuclear factor-kappaBeta (NF-kappaB) activation is a three-component system: NF-kappaB, inhibitor of NF-kappaBeta (IkappaBeta), and IkappaBeta kinase complex (IKK). IKK receives upstream signals from the surface or inside the cell and converts itself into a catalytically active form, leading to the destruction of IkappaB in the inhibited IkappaB:NF kappaB complex, leaving active NF-kappaB free to regulate target genes. Hidden within this simple module are family members that all can undergo various modifications resulting in expansion of functional spectrum. Three-dimensional structures representing all three components are now available. These structures have allowed us to interpret cellular observations in molecular terms and at the same time helped us to bring forward new concepts focused towards understanding the specificity in the NF-kappaB activation pathway. PMID- 22435547 TI - It takes two to tango: IkappaBs, the multifunctional partners of NF-kappaB. AB - The inhibitory IkappaB proteins have been discovered as fundamental regulators of the inducible transcription factor nuclear factor-kappaB (NF-kappaB). As a generally excepted model, stimulus-dependent destruction of inhibitory IkappaBs and processing of precursor molecules, both promoted by components of the signal integrating IkappaB kinase complex, are the key events for the release of various NF-kappaB/Rel dimers and subsequent transcriptional activation. Intense research of more than 20 years provides evidence that the extending family of IkappaBs act not simply as reversible inhibitors of NF-kappaB activation but rather as a complex regulatory module, which assures feedback regulation of the NF-kappaB system and either can inhibit or promote transcriptional activity in a stimulus dependent manner. Thus, IkappaB and NF-kappaB/Rel family proteins establish a complex interrelationship that allows modulated NF-kappaB-dependent transcription, tailored to the physiological environment. PMID- 22435548 TI - Regulation of NF-kappaB by ubiquitination and degradation of the IkappaBs. AB - The nuclear factor-kappaB (NF-kappaB) signaling pathway is a busy ground for the action of the ubiquitin-proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IkappaBs) that bind NF-kappaB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IkappaB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IkappaB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF(beta-TrCP) . The F-box component of this E3, beta-TrCP, recognizes the IkappaB degron formed following phosphorylation by IKK and thus couples IkappaB phosphorylation to ubiquitination. SCF(beta-TrCP) -mediated IkappaB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IkappaBalpha within a few minutes of cell stimulation. In vivo ablation of beta-TrCP results in accumulation of all the IkappaBs and complete NF-kappaB inhibition. As many details of IkappaB-beta-TrCP interaction have been worked out, the development of beta-TrCP inhibitors might be a feasible therapeutic approach for NF-kappaB-associated human disease. However, we may still need to advance our understanding of the mechanism of IkappaB degradation as well as of the diverse functions of beta-TrCP in vivo. PMID- 22435549 TI - Ubiquitination in signaling to and activation of IKK. AB - A role for polyubiquitination in the activation of inhibitor of NF-kappaB (IkappaB) kinase (IKK) through a proteasome-independent mechanism was first reported in 1996, but the physiological significance of this finding was not clear until 2000 when TRAF6 was found to be a ubiquitin E3 ligase that catalyzes lysine-63 (K63) polyubiquitination. Since then, several proteins known to regulate IKK have been linked to the ubiquitin pathway. These include the deubiquitination enzymes CYLD and A20 that inhibit IKK, and the ubiquitin binding proteins NEMO and TAB2 which are the regulatory subunits of IKK and TAK1 kinase complexes, respectively. Now accumulating evidence strongly supports a central role of K63 polyubiquitination in IKK activation by multiple immune and inflammatory pathways. Interestingly, recent research suggests that some alternative ubiquitin chains such as linear or K11 ubiquitin chains may also play a role in certain pathways such as the TNF pathway. Here I present a historical narrative of the discovery of the role of ubiquitin in IKK activation, review recent advances in understanding the role and mechanism of ubiquitin-mediated IKK activation, and raise some questions to be resolved in future research. PMID- 22435550 TI - Regulation of NF-kappaB by deubiquitinases. AB - The nuclear factor-kappaB (NF-kappaB) pathway is a critical regulator of innate and adaptive immunity. Noncanonical K63-linked polyubiquitination plays a key regulatory role in NF-kappaB signaling pathways by functioning as a scaffold to recruit kinase complexes containing ubiquitin-binding domains. Ubiquitination is balanced by deubiquitinases that cleave polyubiquitin chains and oppose the function of E3 ubiquitin ligases. Deubiquitinases therefore play an important role in the termination of NF-kappaB signaling and the resolution of inflammation. In this review, we focus on NF-kappaB regulation by deubiquitinases with an emphasis on A20 and CYLD. Deubiquitinases and the ubiquitin/proteasome components that regulate NF-kappaB may serve as novel therapeutic targets for inflammatory diseases and cancer. PMID- 22435551 TI - The noncanonical NF-kappaB pathway. AB - The noncanonical nuclear factor-kappaB (NF-kappaB) signaling pathway mediates activation of the p52/RelB NF-kappaB complex and, thereby, regulates specific immunological processes. This NF-kappaB pathway relies on the inducible processing of NF-kappaB2 precursor protein, p100, as opposed to the degradation of IkappaBalpha in the canonical NF-kappaB pathway. A central signaling component of the noncanonical NF-kappaB pathway is NF-kappaB-inducing kinase (NIK), which functions together with a downstream kinase, IKKalpha (inhibitor of NF-kappaB kinase alpha), to induce phosphorylation-dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF-kappaB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF-kappaB pathway. PMID- 22435552 TI - Regulation of NF-kappaB by the CARD proteins. AB - Scaffold proteins play pivotal roles in the regulation of signal transduction pathways by connecting upstream receptors to downstream effector molecules. During the last decade, many scaffold proteins that contain caspase-recruitment domains (CARD) have been identified. Investigating the roles of CARD proteins has revealed that many of them play crucial roles in signaling cascades leading to activation of nuclear factor-kappaB (NF-kappaB). In this review, we discuss the contributions of CARD proteins to NF-kappaB activation in various signaling cascades. In particular, we share some of our personal experiences during the initial investigation of the functions of the CARMA family of CARD proteins and then summarize the roles of these proteins in signaling pathways induced by antigen receptors, G protein-coupled receptors, receptor tyrosine kinase, and C type lectin receptors in the context of recent progress in these field. PMID- 22435553 TI - The atypical PKCs in inflammation: NF-kappaB and beyond. AB - From the very early days of nuclear factor-kappaB (NF-kappaB) research, it was recognized that different protein kinase C (PKC) isoforms might be involved in the activation of NF-kappaB. Pharmacological tools and pseudosubstrate inhibitors suggested that these kinases play a role in this important inflammatory and survival pathway; however, it was the analysis of several genetic mouse knockout models that revealed the complexity and interrelations between the different components of the PB1 network in several cellular functions, including T-cell biology, bone homeostasis, inflammation associated with the metabolic syndrome, and cancer. These studies unveiled, for example, the critical role of PKCzeta as a positive regulator of NF-kappaB through the regulation of RelA but also its inflammatory suppressor activities through the regulation of the interleukin-4 signaling cascade. This observation is of relevance in T cells, where p62, PKCzeta, PKClambda/iota, and NBR1 establish a mesh of interactions that culminate in the regulation of T-cell effector responses through the modulation of T-cell polarity. Many questions remain to be answered, not just from the point of view of the implication for NF-kappaB activation but also with regard to the in vivo interplay between these pathways in pathophysiological processes like obesity and cancer. PMID- 22435554 TI - IkappaB kinase regulation of the TPL-2/ERK MAPK pathway. AB - Nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) activation play central roles in the induction of gene expression in innate immune cells following pathogen recognition. TPL-2 (tumor progression locus 2) is the MAP 3-kinase component of an ERK-1/2 (extracellular signal-regulated kinase 1/2) MAPK pathway activated by Toll-like receptor and tumor necrosis factor receptor family stimulation. In this review, we discuss results obtained from our laboratory and others that show that TPL-2 signaling function is directly controlled by the inhibitor of NF-kappaB (IkappaB) kinase (IKK) complex. Significantly, this means that IKK controls both NF-kappaB and ERK activation. TPL-2 is stoichiometrically complexed with the NF-kappaB inhibitory protein, NF kappaB1 p105, and the ubiquitin-binding protein ABIN-2, both of which are required to maintain TPL-2 protein stability. Binding to p105 also prevents TPL-2 from phosphorylating MEK (MAPK/ERK kinase), its downstream target. Agonist stimulation releases TPL-2 from p105-inhibition by IKK-mediated phosphorylation of p105, which triggers degradation of p105 by the proteasome. This facilitates TPL-2 phosphorylation of MEK, in addition to liberating p105-associated Rel subunits to translocate into the nucleus. We also examine evidence that TPL-2 is critical for the induction of inflammation and may play a role in development and/or progression of certain types of cancer. Finally, we consider the potential of TPL-2 as an anti-inflammatory drug target for treatment of certain types of inflammatory disease and cancer. PMID- 22435555 TI - NF-kappaB and chromatin: ten years on the path from basic mechanisms to candidate drugs. AB - Release of nuclear factor kappaBeta (NF-kappaB) dimers from the inhibitors of NF kappaBeta (IkappaBs) and their subsequent nuclear translocation are only the initial events leading to the induction of NF-kappaB-regulated genes. Once in the nucleus, NF-kappaB dimers must gain access to their cognate sites in target genes. While some sites are found in a constitutively accessible state, many others are associated with nucleosomal histones in a manner that prevents NF kappaB binding. Binding to such sites requires specific chromatin remodeling events driven by functionally cooperating transcription factors. Ten years of research on the complex interplay between chromatin and NF-kappaB led to some major successes, most notably the identification of the specific sequence features or trans-acting factors controlling the state of accessibility of kappaB sites, as well as the dissection of the mechanisms and players involved in the opening of occluded sites. Moreover, attempts at identifying mechanism-based compounds that inhibit the activation of selected subsets of NF-kappaB-dependent genes acting on chromatin-regulated transitions are starting to give initial promising results in preclinical tests. PMID- 22435556 TI - Dimer-specific regulatory mechanisms within the NF-kappaB family of transcription factors. AB - A fundamental feature of the transcriptional response to an nuclear factor-kappaB (NF-kappaB)-inducing stimulus is that the response is highly selective and limited to the activation of only a subset of potential NF-kappaB target genes. One major contributor to selectivity of the response is likely to be the capacity of different NF-kappaB dimers to regulate different sets of target genes. The NF kappaB family of transcription factors consists of five proteins, RelA, c-Rel, RelB, p50, and p52, which assemble into several homodimeric and heterodimeric species. Studies of mutant mouse strains have revealed that each family member, and perhaps each dimer, carries out unique functions in regulating transcription in cells of the immune system and in many other cell types. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins. Unique DNA binding specificities and affinities make additional contributions to selectivity of the response, with growing evidence that some NF-kappaB dimers can adopt different conformations and thereby function differently when bound to different DNA sequences. Despite significant advances, our knowledge remains limited and many years of additional work will be needed to fully understand how the dimer specific functions of NF-kappaB contribute to transcriptional selectivity. PMID- 22435557 TI - MicroRNAs, new effectors and regulators of NF-kappaB. AB - Since its discovery 25 years ago, nuclear factor-kappaB (NF-kappaB) has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory. Activation of NF-kappaB initiates an elaborate genetic program. Some of the NF-kappaB-driven genes do not encode proteins but rather are precursors to microRNAs. These microRNAs play important roles in the regulation of the inflammatory process, some being inhibitory and others activating. Here, we discuss both the regulation of their expression and the function of some of these non-coding RNA genes. We also include a personal discussion of how NF-kappaB was first discovered. PMID- 22435558 TI - Lessons from mathematically modeling the NF-kappaB pathway. AB - Mathematical modeling has proved to be a critically important approach in the study of many complex networks and dynamic systems in physics, engineering, chemistry, and biology. The nuclear factor kappaB (NF-kappaB) system consists of more than 50 proteins and protein complexes and is both a highly networked and dynamic system. To date, mathematical modeling has only addressed a small fraction of the molecular species and their regulation, but when employed in conjunction with experimental analysis has already led to important insights. Here, we provide a personal account of studying how the NF-kappaB signaling system functions using mathematical descriptions of the molecular mechanisms. We focus on the insights gained about some of the key regulatory components: the control of the steady state, the signaling dynamics, and signaling crosstalk. We also discuss the biological relevance of these regulatory systems properties. PMID- 22435560 TI - NF-kappaB function in B lymphocytes. AB - NF-kappaB proteins were identified in the search for mechanisms that regulate B lymphocyte-specific transcription of immunoglobulin kappa light chain genes. Twenty-five years later, though the function of the kappaB site in the enhancer remains enigmatic, NF-kappaB proteins have been shown to have important roles in B-cell development, maintenance, and function. In this review, we summarize the functions of NF-kappaB in B cells. An overview of B-cell biology that identifies stages in the life of B lymphocytes for the general reader is followed by three sections that examine the role of NF-kappaB family of proteins in B-cell development, mature B-cell survival and B-cell function. We endeavor throughout to suggest mechanisms and implications of the wide-ranging observations that have been made and conclude by highlighting the need to understand NF-kappaB-mediated gene expression in more depth. PMID- 22435559 TI - IKK biology. AB - The inhibitor of nuclear factor-kappaB (IkappaB) kinase (IKK) complex is the master regulator of the NF-kappaB signaling pathway. The activation of the IKK complex is a tightly regulated, highly stimulus-specific, and target-specific event that is essential for the plethora of functions attributed to NF-kappaB. More recently, NF-kappaB-independent roles of IKK members have brought increased complexity to its biological function. This review highlights some of the major advances in the studies of the process of IKK activation and the biological roles of IKK family members, with a focus on NF-kappaB-independent functions. Understanding these complex processes is essential for targeting IKK for therapeutics. PMID- 22435561 TI - NF-kappaB subunit specificity in hemopoiesis. AB - Although the diverse functions served by the nuclear factor-kappaB (NF-kappaB) pathway in virtually all cell types are typically employed to deal with stress responses, NF-kappaB transcription factors also play key roles in the development of hemopoietic cells. This review focuses on how NF-kappaB transcription factors control various aspects of thymic T-cell and myeloid cell differentiation that include its roles in hemopoietic precursors, conventional alphabeta T cells, CD4(+) regulatory T cells, natural killer T cells, gammadelta T cells, macrophages, and dendritic cells. PMID- 22435562 TI - Dynamic roles for NF-kappaB in HTLV-I and HIV-1 retroviral pathogenesis. AB - Viruses and hosts are involved in a continuing 'arms race'. The body deploys multiple defenses; however, viruses utilize generally superior and more rapidly evolving tactics for negating host immune surveillance and viral clearance. In the case of the two major pathogenic human retroviruses, human immunodeficiency virus-1 (HIV-1) and human T-lymphotrophic virus-I (HTLV-I), the nuclear factor kappaB (NF-kappaB) transcription factor plays a key role in the host's anti-viral responses involving both the innate and adaptive arms of the immune response. Similarly, these retroviruses capably exploit NF-kappaB for their replication, spread, and pathogenic functions. In this review, we discuss the dynamic and intimate interplay that occurs between NF-kappaB and the HTLV-I and HIV-1 retroviral pathogens. PMID- 22435564 TI - Regulation of cell death and autophagy by IKK and NF-kappaB: critical mechanisms in immune function and cancer. AB - The cellular response to survive or to undergo death is fundamental to the benefit of the organism, and errors in this process can lead to autoimmunity and cancer. The transcription factor nuclear factor kappaB (NF-kappaB) functions to block cell death through transcriptional induction of genes encoding anti apoptotic and antioxidant proteins. This is essential for survival of activated cells of the immune system and for cells undergoing a DNA damage response. In Ras transformed cells and tumors as well as other cancers, NF-kappaB functions to suppress apoptosis--a hallmark of cancer. Critical prosurvival roles for inhibitor of NF-kappaB kinase (IKK) family members, including IKKepsilon and TBK1, have been reported, which are both NF-kappaB-dependent and -independent. While the roles of NF-kappaB in promoting cell survival in lymphocytes and in cancers is relatively clear, evidence has been presented that NF-kappaB can promote cell death in particular contexts. Recently, IKK was shown to play a critical role in the induction of autophagy, a metabolic response typically associated with cell survival but which can lead to cell death. This review provides an historical perspective, along with new findings, regarding the roles of the IKK and NF-kappaB pathways in regulating cell survival. PMID- 22435563 TI - DNA damage-dependent NF-kappaB activation: NEMO turns nuclear signaling inside out. AB - The dimeric transcription factor nuclear factor kappaB (NF-kappaB) functions broadly in coordinating cellular responses during inflammation and immune reactions, and its importance in the pathogenesis of cancer is increasingly recognized. Many of the signal transduction pathways that trigger activation of cytoplasmic NF-kappaB in response to a broad array of immune and inflammatory stimuli have been elaborated in great detail. NF-kappaB can also be activated by DNA damage, though relatively less is known about the signal transduction mechanisms that link DNA damage in the nucleus with activation of NF-kappaB in the cytoplasm. Here, we focus on the conserved signaling pathway that has emerged that promotes NF-kappaB activation following DNA damage. Post-translational modification of NF-kappaB essential modulator (NEMO) plays a central role in linking the cellular DNA damage response to NF-kappaB via the ataxia telangiectasia mutated (ATM) kinase. Accumulating evidence suggests that DNA damage-dependent NF-kappaB activation may play significant biological roles, particularly during lymphocyte differentiation and progression of human malignancies. PMID- 22435565 TI - Role of NF-kappaB in epithelial biology. AB - Since its discovery, nuclear factor-kappaB (NF-kappaB) has been recognized as a critical regulator of immune responses. While early studies focused on studying the role of NF-kappaB in the development and function of immune cells, more recently the function of the inhibitor of NF-kappaB kinase (IKK)/NF-kappaB pathway in non-immune cells has gained increased attention. Studies in genetic mouse models were instrumental in dissecting the cell-specific functions of NF kappaB and provided experimental evidence that NF-kappaB signaling in epithelial cells is important for the maintenance of immune homeostasis in barrier tissues such as the skin and the intestine. Increased activation of IKK/NF-kappaB triggered cytokine expression by the epithelial cells, resulting in exacerbated tissue inflammatory responses. NF-kappaB inhibition in keratinocytes triggered severe tumor necrosis factor-dependent skin inflammation and epidermal hyperplasia, while inhibition of IKK/NF-kappaB signaling in intestinal epithelial cells disturbed the intestinal barrier and triggered severe chronic colon inflammation. Therefore, epithelial NF-kappaB signaling performs critical 'peace keeping' functions in barrier tissues at the interface with the environment by regulating cell survival, barrier integrity, and the immunological and anti microbial responses of epithelial cells. Improved understanding of epithelial NF kappaB functions may hold the key for elucidating the etiology and pathophysiology of chronic inflammatory diseases in epithelial tissues. PMID- 22435567 TI - NF-kappaB and the link between inflammation and cancer. AB - The nuclear factor-kappaB (NF-kappaB) transcription factor family has been considered the central mediator of the inflammatory process and a key participant in innate and adaptive immune responses. Coincident with the molecular cloning of NF-kappaB/RelA and identification of its kinship to the v-Rel oncogene, it was anticipated that NF-kappaB itself would be involved in cancer development. Oncogenic activating mutations in NF-kappaB genes are rare and have been identified only in some lymphoid malignancies, while most NF-kappaB activating mutations in lymphoid malignancies occur in upstream signaling components that feed into NF-kappaB. NF-kappaB activation is also prevalent in carcinomas, in which NF-kappaB activation is mainly driven by inflammatory cytokines within the tumor microenvironment. Importantly, however, in all malignancies, NF-kappaB acts in a cell type-specific manner: activating survival genes within cancer cells and inflammation-promoting genes in components of the tumor microenvironment. Yet, the complex biological functions of NF-kappaB have made its therapeutic targeting a challenge. PMID- 22435568 TI - Unexpected bilayer formation in Langmuir films of nucleolipids. AB - Langmuir monolayers have been extensively investigated by various experimental techniques. These studies allowed an in-depth understanding of the molecular conformation in the layer, phase transitions, and the structure of the multilayer. As the monolayer is compressed and the surface pressure is increased beyond a critical value, usually occurring in the minimal closely packed molecular area, the monolayer fractures and/or folds, forming multilayers in a process referred to as collapse. Various mechanisms for monolayer collapse and the resulting reorganization of the film have been proposed, and only a few studies have demonstrated the formation of a bilayer after collapse and with the use of a Ca(2+) solution. In this work, Langmuir isotherms coupled with imaging ellipsometry and polarization modulation infrared reflection absorption spectroscopy were recorded to investigate the air-water interface properties of Langmuir films of anionic nucleolipids. We report for these new molecules the formation of a quasi-hexagonal packing of bilayer domains at a low compression rate, a singular behavior for lipids at the air-water interface that has not yet been documented. PMID- 22435566 TI - Pathogenetic importance and therapeutic implications of NF-kappaB in lymphoid malignancies. AB - Derangement of the nuclear factor kappaB (NF-kappaB) pathway initiates and/or sustains many types of human cancer. B-cell malignancies are particularly affected by oncogenic mutations, translocations, and copy number alterations affecting key components the NF-kappaB pathway, most likely owing to the pervasive role of this pathway in normal B cells. These genetic aberrations cause tumors to be 'addicted' to NF-kappaB, which can be exploited therapeutically. Since each subtype of lymphoid cancer utilizes different mechanisms to activate NF-kappaB, several different therapeutic strategies are needed to address this pathogenetic heterogeneity. Fortunately, a number of drugs that block signaling cascades leading to NF-kappaB are in early phase clinical trials, several of which are already showing activity in lymphoid malignancies. PMID- 22435569 TI - CNS activity of aqueous extract of root of Cissus quadrangularis Linn. (Vitaceae). AB - In Ayurveda, Cissus quadrangularis Linn. is used to treat anorexia, asthma, sickle cell, colds, pain, and malaria. Aqueous C. quadrangularis extract was evaluated in vivo for its antiepileptic activity by using the maximal electroshock and isonicotinic hydrazide acid models, for its analgesic activity by using the hot plate method, and for its smooth muscle relaxant activity by using the rotarod method. Adult male Swiss mice were used for this study and animals were divided into 6 animals per group. Doses of 250 mg/kg body weight and 500 mg/kg body weight protected the mice against maximal electroshock seizure, and delayed the onset time of seizures induced by isonicotinic hydrazide acid. Prominent analgesic activity was observed using the hot plate method. The paw licking time was delayed significantly. The extract also displayed prominent smooth muscle relaxant activity. The results suggest that the aqueous extracts of C. quadrangularis roots possess anticonvulsant, analgesic, and smooth muscle relaxant properties. PMID- 22435570 TI - Effect of coriander seed powder (CSP) on 1, 2-dimethyl hydrazine-induced changes in antioxidant enzyme system and lipid peroxide formation in rats. AB - The effect of coriander seed powder (CSP), a culinary spice, on dimethyl hydrazine (DMH)-induced oxidative stress and toxicity in rats was investigated. Six groups of 6 male rats each were maintained for 12 weeks as (a) Control; (b) DMH (60 mg/kg body weight) injected; (c) 5% CSP incorporated diet; (d) 5% CSP incorporated diet + DMH; (e) 10% CSP incorporated diet; and (f) 10% CSP incorporated diet + DMH. The rats were sacrificed after 12 weeks. The results revealed that DMH administration lead to an increase in hepatic lipid peroxidation associated with reduction in levels of glutathione (GSH), activity of superoxide dismutase (SOD), and catalase and glucose-6-phosphate dehydrogenase. The coadministration of CSP and DMH diminished the hepatic malondialdehyde (MDA) significantly as compared to DMH-alone administered rats. The intake of coriander seeds at 10% level also enhanced the hepatic GSH-redox system by elevating GSH-Px, GSSGR, and GST activities. The DMH-induced decline in SOD and catalase activities was brought to normal by 10% CSP. The coadministration of CSP and the DMH produced a significant reduction in MDA and enhancement in catalase activity as compared to control. Coriander powder at 5% and 10% levels produced a significant rise in colonic catalase and GSH-Px. The coriander seeds produced significant beneficial effects by reducing the DMH induced oxidative stress and enhancing the tissue levels of antioxidant/detoxification agent in tissues. PMID- 22435571 TI - A normative study of the components of niprisan--an herbal medicine for sickle cell anemia. AB - Niprisan(r) is an herbal medicine for sickle cell anemia developed in the National Institute for Pharmaceutical Research and Development (NIPRD). It is prepared from pepper seeds [Piper guineense Schum. & Thonn., Piperaceae], clove flower buds [Eugenia caryophyllata Thunb., Myrtaceae], caprium stem [Pterocarpus osun (L.) Craib., Fabaceae], sorghum leaves [Sorghum bicolor (L.) Moench. Poaceae], and "trona" The components were sourced from food dealers and herbalists prequalified as suppliers by the Institute's department of Medicinal Plant Research and Traditional Medicine (MPRTM), based on the criteria proposed by World Health Organization (WHO, 1998. Quality control methods for medicinal plant materials, pp. 1-115. Geneva: WHO) for the collection and handling of medicinal plant materials. The aim of the work is to establish limits for features that will influence decisions on the components. The paper describes and quantifies as per WHO guidelines of 1998 and British Pharmacopoeia (British Pharmacopoeia, 2004 . Volume IV. The Stationery Office Limited, London. Appendix II D, Atomic spectrophotometry: emission and absorption, pp. A143-145. Determination of pH, pp. A143-145; Appendix VL, Determination of pH Values, pp. A199-A200, 2004.), the most striking features of these components and demonstrates that all, except Eugenia caryophyllata, exist in more than one variety. The results, including the occasional presence of lead in trona, are discussed in the context of good manufacturing practice (GMP). PMID- 22435572 TI - Podophyllum hexandrum as a potential botanical supplement for the medical management of nuclear and radiological emergencies (NREs) and free radical mediated ailments: leads from in vitro/in vivo radioprotective efficacy evaluation. AB - Management of radiation-induced reactive oxygen/nitrogen species requires a holistic approach to mitigate the deleterious effects of free radicals. Flora of the Himalayas, which prevails under extreme climatic conditions, has been explored for its potential utility to develop radioprotective drugs. The Himalayan high altitude medicinal plant, Podophyllum hexandrum Royle, was selected on the basis of its unique properties, and a novel fractionated nonpolar extract (REC-2003) was prepared and evaluated for radioprotective efficacy, in vitro as well as in vivo. The free radical scavenging activity of REC-2003 was found to be > 75% (20 MUg/ml) with maximum superoxide scavenging activity (57.56 +/- 1.38%) recorded at 1 mg/ml concentration (tetrazolium-based estimation). More than 30% inhibition of nitric oxide radicals was observed at concentrations > 0.5 mg/ml, while hydroxyl radical scavenging activity (deoxy-D-ribose assay) exhibited a dose-dependent (100-600 MUg/ml) increase. Significantly high (90%) protection to human erythrocytes was observed at 75 MUg/ml, which was found to be the most optimized dose. Similarly, more than 90% inhibition was observed against lipid peroxidation (evaluated by estimating levels of malondialdehyde). The significant antihemolytic potential of REC-2003 could be attributed to its ability to scavenge free radicals, reduce peroxidative stress on lipid membranes, and render protection to DNA (evaluated using plasmid relaxation assay). All these activities holistically contributed toward the radioprotective ability. REC 2003 (8 mg/kg BW; intraperitoneal (i.p.), -30 min) rendered > 80% total-body protection in Swiss Albino Strain 'A' mice [against lethal radiation (10 Gy)] in a 30-day survival assay. Phytochemical characterization of the constituents of REC-2003 revealed the presence of polyphenolics (flavonoids). The characterized constituents also included the aryl-tetralin lignans like podophyllotoxin, its glycoside, 4'-demethyl derivative, and epi-podophyllotoxin. The optimized requisite single dose (8 mg/KgBW; i.p., -30 min) for obtaining significant radioprotection is reasonably low and establishes its future utility as a dietary supplement in the medical management of free radical-mediated diseases and specifically for rescue missions during nuclear and radiological emergencies (NREs). PMID- 22435573 TI - Potential effects of dietary folate supplementation on oral carcinogenesis, development and progression. AB - Folates are associated with a variety of human health benefits, while folate deficiency has been identified as a potential risk factor for many health problems and cancers, due to its role in dysregulation of DNA synthesis, repair and methylation. The US Food and Drug Administration adopted requirements for folate fortification in some food products, which has resulted in an increase in mean dietary folate intake and a concomitant reduction in the incidence of adverse health effects associated with folate deficiency. This includes a significant reduction in the incidence of folate deficiency-associated birth defects, such as spina bifida. PMID- 22435574 TI - Hippophae leaf extract concentration regulates antioxidant and prooxidant effects on DNA. AB - Extracts from Hippophae leaves constitute some commonly consumed beverages such as tea and wine. We had developed an extract of Hippophae leaves (SBL-1), which was rich in quercetin, had antimutagenic effects, radioprotective effects, and countered radiation-induced gene conversion in Saccharomyces cerevisiae. This study was designed to investigate the action of SBL-1 on guanine cytosine (GC) rich nascent and mouse genomic DNA in vitro. The human and mouse liver DNA have about 43% GC content. Our results showed that at small concentration SBL-1 protected nascent as well as genomic DNA, while at large concentration SBL-1 damaged both types of DNA. The concentration of SBL-1 that protected DNA also demonstrated higher free radical scavenging activity. The reducing power of SBL-1 was greater than its free radical scavenging activity. The greater reducing power may have reduced the trace metals present in the SBL-1, leading to generation of hydroxyl radicals via Fenton reaction. The increased proportion of unscavenged hydroxyl radicals with increase in SBL-1 concentration may have been responsible for DNA damage or prooxidant effect of SBL-1 in vitro. This study suggests that the dietary supplements prepared from Hippophae should have low metal content. PMID- 22435575 TI - Effectiveness of B vitamins on the control of hypertension and stroke events of SHRSP rats. AB - The spontaneously hypertensive stroke-prone rat (SHRSP) is a recognized animal model for the study of severe hypertension and stroke, being characterized by presenting an elevated tissue levels of free radicals. Therefore, this study has the main goal to identify the effect of B vitamins, closely associated to the control of oxidative stress, on SHRSP rats. After 10 days (baseline period), the animals, 18 SHRSP rats at 18 weeks of age, were divided into three groups with six rats treated with riboflavin (B2), six treated with pyridoxine (B6) plus folic acid (B9), and control. Body weight, water and food intake, diuresis, sensory-motor responses, and systolic blood pressure of all the rats were determined daily. Physical aspects of whole body (i.e., distribution and coloring of hair, skin and mucosa, and an eventual presence of bleeding, stains, cracks, or opacification) and behavior were equally monitored. The data were evaluated by ANOVA two-way and p < .05 was considered significant. The supraphysiologic doses did not cause toxic effects. There was a significant decrease of systolic blood pressure, homocysteine, and malondialdehyde (MDA) blood levels in animals under B vitamin supplementation. The treatment also inhibited the neurological signs of an ischemic attack (unbalance, ataxia, and convulsions). The findings reported here suggest that B vitamin therapy was effective for the control of systolic blood pressure and oxidative stress. Hence, it could be thought as one of the alternative therapies to prevent the occurrence of stroke. PMID- 22435576 TI - An evidence-based systematic review of amylase inhibitors by the Natural Standard Research Collaboration. AB - An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22435592 TI - Generation of transgenic plantain (Musa spp.) with resistance to plant pathogenic nematodes. AB - Plant parasitic nematodes impose a severe constraint on plantain and banana productivity; however, the sterile nature of many cultivars precludes conventional breeding for resistance. Transgenic plantain cv. Gonja manjaya (Musa AAB) plants, expressing a maize cystatin that inhibits nematode digestive cysteine proteinases and a synthetic peptide that disrupts nematode chemoreception, were assessed for their ability to resist nematode infection. Lines were generated that expressed each gene singly or both together in a stacked defence. Nematode challenge with a single species or a mixed population identified 10 lines with significant resistance. The best level of resistance achieved against the major pest species Radopholus similis was 84% +/- 8% for the cystatin, 66% +/- 14% for the peptide and 70% +/- 6% for the dual defence. In the mixed population, trial resistance was also demonstrated to Helicotylenchus multicinctus. A fluorescently labelled form of the chemodisruptive peptide underwent retrograde transport along certain sensory dendrites of R. similis as required to disrupt chemoreception. The peptide was degraded after 30 min in simulated intestinal fluid or boiling water and after 1 h in nonsterile soil. In silico sequence analysis suggests that the peptide is not a mammalian antigen. This work establishes the mode of action of a novel nematode defence, develops the evidence for its safe and effective deployment against multiple nematode species and identifies transgenic plantain lines with a high level of resistance for a proposed field trial. PMID- 22435593 TI - Re: Naftopidil vs silodosin in medical expulsive therapy for ureteral stones: a randomized controlled study in Japanese male patients. PMID- 22435594 TI - Quality of life in children and adolescents post-TBI: a systematic review and meta-analysis. AB - Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in children and adolescents in first-world nations. Research from our team investigating adult survivors of pediatric TBI indicate that survivors of severe TBI are particularly vulnerable to global impairments, including poorer school performance, greater employment difficulties, poor quality of life (QoL), and increased risk of mental health problems. Investigation into less observable consequences, including QoL, has emerged recently as an important outcome to assess in TBI populations. The status of QoL in pediatric TBI populations is mixed, likely a reflection of the varied methodological and theoretical perspectives on QoL. AIM: This systematic study will clarify the nature of QoL in survivors of pediatric TBI, and identify predictors of QoL in this group. Of 419 articles identified, 11 studies met our inclusion criteria, and 9 were ultimately analyzed in this review. Four studies reported good QoL and 5 poor QoL. The difference between good and poor QoL was statistically significant due to TBI severity [chi-square(3)=77.38, p<0.001], timing of outcome assessment [chi square(1)=565, p<0.001], and definition of QoL [chi-square(3)=34.73, p<0.001]. The odds of having a poor QoL increased 5.8 times (RR=1.21) when injuries were more severe. Good outcomes are contingent on milder injuries, proxy reporting, and early assessment, whereas poor outcomes reflect more severe injuries and later assessment (<= 6 months versus >= 1 year post-trauma, respectively). PMID- 22435595 TI - Short-term toxic effects of naphthalene and pyrene on the common prawn (Palaemon serratus) assessed by a multi-parameter laboratorial approach: mechanisms of toxicity and impairment of individual fitness. AB - The short-term (96 h) toxic effects of two polycyclic aromatic hydrocarbons (PAHs), naphthalene (NAP) and pyrene (PYR), on the common prawn (Palaemon serratus) were investigated in laboratory bioassays, including a fitness related assay based on the post-exposure swimming velocity. Other effect criteria were biomarkers of neurotoxicity, oxidative stress and bioenergetics, and mortality. In the range of concentrations tested (NAP: 0.13-8 mg/L; PYR: 0.006-0.4 mg/L), both PAHs impaired the swimming velocity, induced oxidative stress and damage, and changed the activity of lactate dehydrogenase and isocitrate dehydrogenase. NAP also caused mortality (96 h-LC50=3.5 mg/L). Thus, both PAHs were able to cause toxic effects on P. serratus after a short period of exposure through the water, including the reduction of individual fitness. PYR was five folds more effective in reducing the swimming velocity of P. serratus than NAP. These findings are of interest for the marine ecological risk assessment of oil spills. PMID- 22435596 TI - Supramolecular and redox chemistry of tetrathiafulvalene monocarboxylic acid with hydrogen-bonded pyridine and bipyridine molecules. AB - Although tetrathiafulvalene derivatives (TTFs) have been used as the redox-active unit in a lot of ion responsive receptors, only a few such examples of TTF carboxylic acids have been reported, especially about the responses to neutral organic molecules. In this work, electrochemical and spectral properties of dimethylthio-tetrathiafulvalene monocarboxylic acid (DMT-TTFCOOH) have been studied by both experimental methods and quantum chemical calculations. A square mechanism of proton transfer and electron transfer equilibriums was proposed. It is noteworthy that the process of oxidizing the TTF moiety of DMT-TTFCOOH could be controlled to obtain TTF(*+) radical cation or TTF(2+) dication by choosing suitable oxidizing reagents. Supramolecular responsive properties of DMT-TTFCOOH to py/bpy were investigated by cyclic voltammetry and (1)H NMR spectra. The results showed that the compound DMT-TTFCOOH is an electrochemically sensitive hydrogen bonding donor that can detect a tiny difference in the hydrogen bonding acceptor molecules. The theoretical calculations further confirm the results. The hydrogen-bonding structure of DMT-TTFCOOH-bpy in crystal was solved by X-ray diffraction analysis. PMID- 22435597 TI - Periodic trends in hexanuclear actinide clusters. AB - Four new Th(IV), U(IV), and Np(IV) hexanuclear clusters with 1,2 phenylenediphosphonate as the bridging ligand have been prepared by self-assembly at room temperature. The structures of Th(6)Tl(3)[C(6)H(4)(PO(3))(PO(3)H)](6)(NO(3))(7)(H(2)O)(6).(NO(3))(2).4H(2)O (Th6 3), (NH(4))(8.11)Np(12)Rb(3.89)[C(6)H(4)(PO(3))(PO(3)H)](12)(NO(3))(24).15H(2)O (Np6-1), (NH(4))(4)U(12)Cs(8)[C(6)H(4)(PO(3))(PO(3)H)](12)(NO(3))(24).18H(2)O (U6 1), and (NH(4))(4)U(12)Cs(2)[C(6)H(4)(PO(3))(PO(3)H)](12)(NO(3))(18).40H(2)O (U6 2) are described and compared with other clusters of containing An(IV) or Ce(IV). All of the clusters share the common formula M(6)(H(2)O)(m)[C(6)H(3)(PO(3))(PO(3)H)](6)(NO(3))(n)((6-n)) (M = Ce, Th, U, Np, Pu). The metal centers are normally nine-coordinate, with five oxygen atoms from the ligand and an additional four either occupied by NO(3)(-) or H(2)O. It was found that the Ce, U, and Pu clusters favor both C(3i) and C(i) point groups, while Th only yields in C(i), and Np only C(3i). In the C(3i) clusters, there are two NO(3)(-) anions bonded to the metal centers. In the C(i) clusters, the number of NO(3)(-) anions varies from 0 to 2. The change in the ionic radius of the actinide ions tunes the cavity size of the clusters. The thorium clusters were found to accept larger ions including Cs(+) and Tl(+), whereas with uranium and later elements, only NH(4)(+) and/or Rb(+) reside in the center of the clusters. PMID- 22435598 TI - Randomized controlled study comparing effect of magnesium sulfate with placebo on fetal umbilical artery and middle cerebral artery blood flow in mild preeclampsia at >= 34 weeks gestational age. AB - AIMS: The aim of this study was to evaluate whether prophylactic magnesium sulfate given in women with mild preeclampsia or gestational hypertension brings any significant change in umbilical artery and fetal middle cerebral artery pulsatility index. MATERIAL AND METHODS: Forty-eight women with gestational age greater than 34 weeks with mild preeclampsia or gestational hypertension were randomly assigned to receive either magnesium sulfate or placebo. Pre- and post magnesium sulfate pulsatility index of umbilical and fetal middle cerebral artery were compared by Mann-Whitney U-test between the groups. Within-group comparison was conducted using Wilcoxon's signed rank test. RESULTS: There was a significant reduction in the post-magnesium sulfate umbilical artery pulsatility index in the intervention group (median 0.88 [0.82-1.03]) when compared to the placebo group (median 1.00 [0.89-1.10]). Post-magnesium sulfate fetal middle cerebral artery pulsatility index in the intervention group (median 1.78 [1.63-1.98]) did not show a significant change compared to the placebo group (median 1.65 [1.42 1.91]). Within-group comparison showed change in both variables after treatment in the intervention group. CONCLUSION: Magnesium sulfate produces a significant decrease in fetal umbilical artery and middle cerebral artery pulsatility index. PMID- 22435600 TI - Tobacco control: up in smoke in Europe? PMID- 22435599 TI - Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials. AB - Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization. PMID- 22435601 TI - Deletion of angiotensin II type 1 receptor gene or scavenge of superoxide prevents chronic alcohol-induced aortic damage and remodelling. AB - To investigate whether chronic alcohol consumption induces vascular injury via angiotensin II (Ang II) type 1 (AT1) receptor-dependent superoxide generation, male transgenic mice with knockout of AT1 gene (AT1-KO) and age-matched wild-type (WT) C57BL/6 mice were pair-fed a modified Lieber-DeCarli alcohol or isocaloric maltose dextrin control liquid diet for 2 months. Ethanol content (%, W/V) in the diet was 4.8 (34% of total calories) at initiation, and gradually increased up to 5.4 (38% of total calories). For some WT mice with and without alcohol treatment, superoxide dismutase mimetic (MnTMPyP) was given simultaneously by intraperitoneal injection at 5 mg/kg body weight daily for 2 months. At the end of studies, aortas were harvested for histopathological and immunohistochemical examination. Significant increases in the wall thickness and structural disarrangement of aorta were found in alcohol group, along with significant increases in aortic oxidative and/or nitrosative damage, expressions of NADPH oxidases (NOXs), inflammatory response, cell death and proliferation, and remodelling (fibrosis). However, these pathological changes were completely attenuated in alcohol-treated AT1-KO mice or in alcohol-treated WT mice that were also simultaneously treated with MnTMPyP for 2 months. These results suggest that chronic alcohol consumption may activate NOX via Ang II/AT1 receptor, to generate superoxide and associated peroxynitrite that in turn causes aortic nitrosative damage, inflammation, cell death and proliferation, and remodelling. Therefore, blocking Ang II/AT1 system or scavenging superoxide may become a potential preventive and/therapeutic approach to alcoholic vascular damage. PMID- 22435602 TI - A novel macroporous polyvinyl alcohol scaffold promotes chondrocyte migration and interface formation in an in vitro cartilage defect model. AB - Scaffold-cartilage integration is critical for the clinical success of a scaffold used for the repair of a focal cartilage defect. In this study, a macroporous polyvinyl alcohol (PVA) scaffold was found to facilitate chondrocyte infiltration and interfacial matrix formation in a juvenile bovine in vitro cartilage defect model. These results were found to depend on the press-fit between the scaffold and the cartilage, pretreatment of the cartilage with collagenase prior to scaffold insertion, and chondrocyte preseeding of the scaffold. Infiltrated and preseeded chondrocytes in the scaffold survived for 6 weeks in culture and resulted in sufficient matrix at the interface to significantly increase the interface shear strength 30-fold that compared favorably with the interface shear strength of cartilage-cartilage constructs. The ability of this macroporous PVA scaffold to form a stable interface with articular cartilage demonstrates the potential use of this scaffold design for focal cartilage defect repair. PMID- 22435603 TI - Dental occlusion, body posture and temporomandibular disorders: where we are now and where we are heading for. AB - The aim of this investigation was to perform a review of the literature dealing with the issue of relationships between dental occlusion, body posture and temporomandibular disorders (TMD). A search of the available literature was performed to determine what the current evidence is regarding: (i) The physiology of the dental occlusion-body posture relationship, (ii) The relationship of these two topics with TMD and (iii) The validity of the available clinical and instrumental devices (surface electromyography, kinesiography and postural platforms) to measure the dental occlusion-body posture-TMD relationship. The available posturographic techniques and devices have not consistently found any association between body posture and dental occlusion. This outcome is most likely due to the many compensation mechanisms occurring within the neuromuscular system regulating body balance. Furthermore, the literature shows that TMD are not often related to specific occlusal conditions, and they also do not have any detectable relationships with head and body posture. The use of clinical and instrumental approaches for assessing body posture is not supported by the wide majority of the literature, mainly because of wide variations in the measurable variables of posture. In conclusion, there is no evidence for the existence of a predictable relationship between occlusal and postural features, and it is clear that the presence of TMD pain is not related with the existence of measurable occluso-postural abnormalities. Therefore, the use instruments and techniques aiming to measure purported occlusal, electromyographic, kinesiographic or posturographic abnormalities cannot be justified in the evidence-based TMD practice. PMID- 22435604 TI - Hydrogen-bond strengthening upon photoinduced electron transfer in ruthenium anthraquinone dyads interacting with hexafluoroisopropanol or water. AB - Quinones play a key role as primary electron acceptors in natural photosynthesis, and their reduction is known to be facilitated by hydrogen-bond donors or protonation. In this study, the influence of hydrogen-bond donating solvents on the thermodynamics and kinetics of intramolecular electron transfer between Ru(bpy)(3)(2+) (bpy = 2,2'-bipyridine) and 9,10-anthraquinone redox partners linked together via one up to three p-xylene units was investigated. Addition of relatively small amounts of hexafluoroisopropanol to dichloromethane solutions of these rigid rodlike donor-bridge-acceptor molecules is found to accelerate intramolecular Ru(bpy)(3)(2+)-to-anthraquinone electron transfer substantially because anthraquinone reduction occurs more easily in the presence of the strong hydrogen-bond donor. Similarly, the rates for intramolecular electron transfer are significantly higher in acetonitrile/water mixtures than in dry acetonitrile. In dichloromethane, an increase in the association constant between hexafluoroisopropanol and anthraquinone by more than 1 order of magnitude following quinone reduction points to a significant strengthening of the hydrogen bonds between the hydroxyl group of hexafluoroisopropanol and the anthraquinone carbonyl functions. The photoinduced intramolecular long-range electron transfer process thus appears to be followed by proton motion; hence the overall photoinduced reaction may be considered a variant of stepwise proton-coupled electron transfer (PCET) in which substantial proton density (rather than a full proton) is transferred after the electron transfer has occurred. PMID- 22435605 TI - A new perspective on blame culture: an experimental study. AB - OBJECTIVES: Recently, a range of different institutions worldwide has identified the 'culture of blame' and the fear of being punished as the principal reasons for the lack of medical error reporting and, consequently, of their reiteration and of the poor quality of patient care. Despite much theoretical debate, there currently exist no experimental studies that directly investigate the presence and pervasiveness of the blame and punishment culture in health care contexts. In order to document empirical evidence for this culture in medicine and nursing, we conducted an experimental study asking physicians and nurses to express their fear of blame or punishment in the context of having made an error that would cause: (i) no; (ii) mild; (iii) severe consequences; or (iv) the death of the patient. METHODS: Two hundred and forty-nine health care providers (38 physicians, 11 medical students, 127 nurses and 73 nursing students) were included in the study. Two main data emerged: first, in general, the fear of being blamed is higher than the fear of being punished. Second, while the fear of being blamed is equally distributed among all participants, the fear of being punished varies according to the experience of subjects (it is higher in nursing students than in seniors nurses) and to their professional role (student and senior nurses are more susceptible to it than medical students and senior physicians). CONCLUSION: Given the relevance of these factors in medical error reporting and the evidence that they are so deep-seated not only in senior professionals, but also in students, we argue that an educational approach, together with an organization-based intervention, is desirable to shape cultural attitudes of health care providers in the direction of a 'safety culture'. PMID- 22435606 TI - Dabigatran or warfarin for the prevention of stroke in atrial fibrillation? A closer look at the RE-LY trial. AB - INTRODUCTION: In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE LY) trial, dabigatran 150 mg was shown to be superior to warfarin for the prevention of stroke or systemic embolism. However, there are some concerns with the RE-LY trial, such as its open-label design, potential unblinding of "blinded" adjudicators, the use of concomitant warfarin-aspirin (ASA), the disparity between baseline use of nonselective NSAIDs; the high unequal rate of drop-outs; unaccounted drop-ins; high rates of major bleeds in warfarin-treated patients, despite being a low risk population; and rates of major bleeds that do not match historic warfarin trials. Furthermore, although dabigatran offers potential advantages versus warfarin, there are disadvantages that must be taken into consideration before a patient is switched from the latter to the former. This review will summarize the flaws of the RE-LY trial as well as the clinically important advantages and disadvantages of dabigatran and warfarin. AREAS COVERED: This review examines the differences between dabigatran and warfarin in terms of side effects, drug-drug interactions, drug-food interactions, and potential reasons for using one anticoagulant rather than the other. The main focus of this review is a discussion of the design, procedures and results of the RE-LY trial. EXPERT OPINION: There seem to be major flaws with the RE-LY trial. A double blinded trial should be performed testing dabigatran against warfarin to verify the results of the RE-LY trial. PMID- 22435607 TI - The distribution of Escherichia coli serovars, virulence genes, gene association and combinations and virulence genes encoding serotypes in pathogenic E. coli recovered from diarrhoeic calves, sheep and goat. AB - Ruminants, especially cattle, have been implicated as a principal reservoir of one of the enterovirulent Escherichia coli pathotypes. The detection of the virulence genes in diarrhoeic calves and small ruminants has not been studied in Egypt. To determine the occurrence, serotypes and the virulence gene markers, stx1, stx2, hylA, Flic(h7) , stb, F41, K99, sta, F17, LT-I, LT-II and eae, rectal swabs were taken from diarrhoeic calves, sheep and goats and subjected to bacterial culture and PCR. The E. coli prevalence rate in the diarrhoeic animals was 63.6% in calves, 27.3% in goat and 9.1% in sheep. The 102 E. coli strains isolated from the calves, goat and sheep were 100% haemolytic non-verotoxic and fitted into the Eagg group. The isolates belonged to seven O serogroups (O25, O78, O86, O119, O158, O164 and O157). The eae gene was detected in six of the strains isolated from the calves. The 102 bovine, ovine and caprine E. coli strains isolated in this study were negative for stx1, stx2, F41, LT-I and Flic(h7) genes. The highest gene combinations were found to occur in the form of 24/102 isolates (23.5%) that carried the F17 gene predominantly associated with eaeA, hylA, K99 and Stb genes in the calves, while the hylA, K99 and Sta were the only genes found to be in conjunction in both calves and goats (6/102; 5.9% each). Our data show that in Egypt, large and small ruminants could be a potential source of infection in humans. PMID- 22435609 TI - Leaf protein concentrate as food supplement from arid zone plants. AB - In arid and semi-arid areas where prevalence of droughts and famines is a recurring feature, forest cover can in general make valuable contributions to food security and provide income to the rural poor. Protein and calorie malnutrition is widespread in these areas leading to high child mortality rate. Plant species can play an important role in overcoming this by being used as a source of leaf protein concentrate (LPC), a highly nutritious food. LPC should be considered seriously as it can serve as an additional protein source in the case of non-ruminants and man, especially in drought prone areas. The use of LPC in developing countries as an alternative protein source to fishmeal in broiler diet holds tremendous promise as it can substantially lower high cost of fishmeal and eventually the acute shortage of animal protein supply. Potential tropical plants for LPC production have been evaluated and selected for further research by United States Department of Agriculture. The present study was aimed to determine the potential of arid zone plants for preparation of LPC. Extraction characteristics of the several plant species have been studied and the quality of LPC prepared from them was investigated. Different fractions, chloroplastic and cytoplasmic proteins, were analyzed for their crude protein contents. Analysis of LPC shows considerable differences in their protein contents, which was found to range from 13.7 to 88.9%. Based on this, Achyranthes aspera and Tephrosia purpurea were found to be the best suited plants for LPC preparation. PMID- 22435610 TI - Analgesic and antipyretic activities of ethanol extract of Stereospermum suaveolens. AB - Ethanol extract from the stem bark of Stereospermum suaveolens (Roxb.) DC (Bignoniaceae), given orally at the doses of 200 and 400 mg/kg body weight, was assessed for analgesic and antipyretic properties on different experimental animal models. Administration of ethanol extract of Stereospermum suaveolens (EESS) produced significant (p < .05, p < .001) dose-dependent analgesic effect in the tail flick, hot plate, and tail clip (central) as well as in acetic acid induced writhing (peripheral) nociceptive tests in mice, suggesting the involvement of both central and peripheral mechanisms in alleviating the pain response. In the current study, indomethacin, aspirin, and morphine were used as the standard analgesic drugs. In addition, EESS also exhibited a significant (p < .05, p < .001) dose-dependent antipyretic response in Brewer's yeast-induced pyrexia in rats and the results were comparable with that of paracetamol, a standard antipyretic agent. These results showed that the EESS possesses potent analgesic and antipyretic activity by dose-dependent manner, in various experimental animal models. PMID- 22435608 TI - Chemistry and biology of multicomponent reactions. PMID- 22435611 TI - Analytical characterization of Hempseed (seed of Cannabis sativa L.) oil from eight regions in China. AB - In this study, eight cultivars of hempseed were collected from different regions of China for analysis of physiochemical properties and chemical composition, as well as for seed indexes and proximate composition of seed kernel. The results indicated that Yunma No. 1 and Bama Huoma, with more than 50% oil and 30% protein in dehulled seed, could be considered as oil extraction material and protein source with respect to kernel yield. Iodine values ranging from 153.6 to 169.1 g/100 g reflected the high degree of unsaturation. The concentration of unsaturated fatty acids exceeded 90%, higher than most conventional vegetable oils. Moreover, polyunsaturated fatty acids ranged from 76.26% to 82.75% and were mainly composed of linoleic acid and alpha-linolenic acid with a ratio close to 3:1. gamma-Tocopherol was found at an average concentration of 28.23 mg/100 g of hempseed oil. The results indicated that hempseed oil is a potentially valuable vegetable oil. PMID- 22435612 TI - Inhibition of oral cancer growth in vitro is modulated through differential signaling pathways by over-the-counter proanthocyanidin supplements. AB - BACKGROUND: Approximately 30,000 people are diagnosed with oral cancer annually in the United States. Recent evidence suggests that nutrition may play a more complex role in the prevention of oral cancers than previously believed. Proanthocyanidins (PACs) are a class of compounds found in normal dietary foods that exhibit chemopreventive properties and chemotherapeutic potential. Recently preliminary evidence suggests that PACs inhibit the proliferation of oral cancer cell lines. The primary goal of this study was to elucidate the mechanisms responsible for previous observations that grape seed-derived PACs significantly inhibited oral cancer proliferation. METHODS: Using the well-characterized oral squamous cell carcinoma cell lines, CAL27 and SCC25, as well as nontumorigenic cell lines, a series of in vitro assays was performed to quantify the temporal and dose-specific growth inhibitory properties of PAC on oral cancers. In addition, quantitative analysis of mRNA from key intracellular signaling pathway molecules, involved in both cell-cycle control and apoptosis, were analyzed using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). RESULTS: This study found that oral cancer proliferation was inhibited by 24 hours in the PAC concentration range of 50-70 MUg/mL with concomitant decreases in mRNA expression of specific cell-cycle regulators, and increases in the expression of apoptosis specific molecules, such as caspase-2 and caspase-8. CONCLUSION: These results may represent the first demonstration of simultaneous, temporal inhibition of cell-cycle signaling pathways with the activation of specific apoptosis-related signaling pathways within oral cancers in response to PAC, lending further support to the concept that PACs may be promising candidates for adjuvant or complementary therapies for oral cancer patients. PMID- 22435613 TI - A randomized placebo-controlled crossover trial of aloe vera on bioavailability of vitamins C and B(12), blood glucose, and lipid profile in healthy human subjects. AB - Several factors limit the absorption and bioavailability of vitamins. Vitamin C, a commonly used water-soluble supplement reduces the risk of disease. Vitamin B(12) is necessary for the development of RBC, growth, and nervous system. Vitamin B(12) deficiency is common among elderly. Thus, agents that improve bioavailability of vitamin C and B(12), especially in older individuals would be important. Aloe Vera is a botanical with immunomodulatory properties. Aloe is processed using the hand-filleted technique or whole leaf procedure. The aim of this study is to examine the effect of two different aloe vera preparations (aloe inner leaf gel, [AG] and aloe whole leaf decolorized gel, [AL]) compared to placebo on the bioavailability of vitamins, C and B(12), in healthy human volunteers in a randomized crossover trial. Subjects (n = 15) received in a random fashion either aloe whole leaf extract (AL with vitamins B(12), 1 mg and vitamin C 500 mg) or aloe fillet gel (AG with B(12) 1 mg and vitamin C 500 mg) or water (with vitamin B(12) 1 mg and vitamin C 500 mg). Blood was obtained fasting, followed by 1, 2, 4, 6, 8, and 24 hours postingestion of aloe/water. When given with vitamins C and B(12), AG significantly increased plasma oxygen radical absorbance capacity (ORAC) at both 4 and 24 hours and AL at 4 hours compared to baseline and placebo. AG significantly increased plasma vitamin C at 4, 6, 8, and 24 hours and AL at 4 and 6 hours compared to baseline and placebo (p <.01). Also, both aloes significantly increased serum vitamin B(12) levels at 1 and 2 hours compared to baseline and placebo (p <.01). Thus, AG and AL preparations are safe, well tolerated, and enhance the bioavailability of vitamins C and B(12) and antioxidant potential. PMID- 22435614 TI - Omega-3 but not omega-6 unsaturated fatty acids inhibit the cancer-specific ENOX2 of the HeLa cell surface with no effect on the constitutive ENOX1. AB - Epidemiological and laboratory studies suggest that dietary fatty acids (oleic acid (in olive oil), eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) (in fish oil)) play important roles in carcinogenesis. The most potent antitumor effects of all fatty acids are given by fatty acid conjugated linoleic acid (CLA). The antitumor effects of CLA may be mediated through enhanced apoptosis. While CLA, EPA, and DHA (omega-3 polyunsaturated fatty acids) have inhibitory effects on cancer cells, omega-6 fatty acids have often shown negative or potentiating effects on cancer cells. Linoleic acid (an omega-6) is desaturated in the cell by delta 6 and 5 destaturases to form arachidonic acid. COX 1 and 2 isoforms then act on arachidonic acid to form prostaglandins and other related regulatory molecules. It is normally thought that what is important to the development of the cancerous phenotype is some balance of these various metabolites. In experiments with surface NOX proteins released from HeLa cells, spectrophotometric measurements of the oxidation of NADH revealed inhibition of the cancer-specific ENOX2 activity by CLA and the omega-3 fatty acids, eicosapentaenoic, docosahexaenoic, and alpha-linolenic acids. The constitutive ENOX1 activity was not inhibited. In contrast, the omega-6 fatty acids, linoleic acid, and arachidonic acid inhibited neither ENOX1 nor ENOX2. The findings indicate the possibility that a direct effect of CLA and omega-3 fatty acids on ENOX2 may be responsible for the potent activity of CLA and omega-3 fatty acids in cancer prevention and therapy. PMID- 22435615 TI - An evidence-based systematic review of spearmint by the natural standard research collaboration. AB - An evidence-based systematic review of spearmint (Mentha spicata, Mentha viridis) including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 22435616 TI - Quantitative assessment of the sulfuric acid contribution to new particle growth. AB - The Nano Aerosol Mass Spectrometer (NAMS) was deployed to rural/coastal and urban sites to measure the composition of 20-25 nm diameter nanoparticles during new particle formation (NPF). NAMS provides a quantitative measure of the elemental composition of individual, size-selected nanoparticles. In both environments, particles analyzed during NPF were found to be enhanced in elements associated with inorganic species (nitrogen, sulfur) relative to that associated with organic species (carbon). A molecular apportionment algorithm was applied to the elemental data in order to place the elemental composition into a molecular context. These measurements show that sulfate constitutes a substantial fraction of total particle mass in both environments. The contribution of sulfuric acid to new particle growth was quantitatively determined and the gas-phase sulfuric acid concentration required to incorporate the measured sulfate fraction was calculated. The calculated values were compared to those calculated by a sulfuric acid proxy that considers solar radiation and SO(2) levels. The two values agree within experimental uncertainty. Sulfate accounts for 29-46% of the total mass growth of particles. Other species contributing to growth include ammonium, nitrate, and organics. For each location, the relative amounts of these species do not change significantly with growth rate. However, for the coastal location, sulfate contribution increases with increasing temperature whereas nitrate contribution decreases with increasing temperature. PMID- 22435617 TI - What is the role of the interfacial interaction in the slow relaxation of nanometer-thick polymer melts on a solid surface? AB - At the nanoscale and interfaces, the relaxation behavior of polymer melts, which affects the polymer's long-term performance in many important applications, is very different from that in the bulk. The role of polymer-substrate interfacial interaction, which does not have a bulk counterpart, has not been fully understood to date. In this study, the relaxation of nanometer-thick perfluoropolyether melts on a silicon wafer has been investigated by water contact angle measurement. The polymer-substrate interactions have been systematically changed by tailoring the polymer structure to clarify the effect of the interfacial interaction. The experimental results show that (1) when there is attractive interaction at the interface, some polymers are anchored to the substrate and others are free, (2) the attractive interfacial interaction drives the free polymers to relax at the interface, and (3) the relaxation is much slower than in the bulk, which has been attributed to the low mobility of the anchored polymer chains and the motional cooperativity between anchored and free polymer chains in the nanometer-thick films. PMID- 22435618 TI - Granulomatous slack skin disease: a review, in comparison with mycosis fungoides. AB - Granulomatous slack skin (GSS) is a rare cutaneous disorder characterized by the evolution of circumscribed erythematous loose skin masses, especially in the body folds, and histologically by a loss of elastic fibers and granulomatous T-cell infiltrates. This disease is often associated with preceding or successive lymphoproliferative malignancies, especially Mycosis Fungoides (MF) and Hodgkin's Disease (HD). Whether Granulomatous Slack Skin Disease is a benign disorder, an unusual host reaction or a precursor of malignant lymphoma or an indolent Cutaneous T-cell Lymphoma (CTCL) in itself, is still a controversy. This article reviews its literature on the etiology, clinical findings, and treatment of Granulomatous Slack Skin Disease. It also concentrates on its association with Hodgkin's disease and its comparison with Mycosis Fungoides and Sezary Syndrome. PMID- 22435619 TI - Meta-analysis of clinical trials on traditional Chinese herbal medicine for treatment of persistent allergic rhinitis. AB - BACKGROUND: Chinese herbal medicine (CHM) has been used for the prevention and treatment of persistent allergic rhinitis (PAR), but results are still equivocal. This study was to assess the clinical effectiveness of CHM in patients with PAR. MATERIALS AND METHODS: Databases searched included articles published in the Cochrane library, MEDLINE, EMBASE, China National Knowledge Infrastructure, and Wanfang database from 1999 to 2011. The studies included were randomized controlled trials (RCTs) comparing CHM to placebo if they included patients with PAR. The main outcomes were the changes in the standardized mean difference (SMD) of nasal symptom scores and total serum IgE level. Methodological quality was assessed by the modified Jadad's scale. RESULTS: Seven RCTs with 533 patients were identified and analyzed. In the meta-analysis, CHM reduced the total nasal symptom scores compared to placebo (SMD, -1.82; 95% confidence interval [CI], 3.03 to -0.62; P = 0.003). The effect estimate was in favor of the CHM intervention (SMD, -1.09; 95% CI, -2.74 to 0.55) in reducing the total serum IgE level, although this was not significant (P = 0.19). CONCLUSIONS: CHM interventions appear to have beneficial effects in patients with PAR. However, the published efficacy studies are too small to draw firm conclusion. PMID- 22435620 TI - Mapping QTL for fat area ratios and serum leptin concentrations in a Duroc purebred population. AB - The reduction of extra subcutaneous, intermuscular and abdominal fat is important to increase the carcass lean percentage of pigs. Image analyses of fat area ratios were effective for estimation of separated fat in pig carcasses. Serum concentrations of leptin are useful as physiological predictors of fat accumulation in pigs. The objectives of the present study were to perform a quantitative trait locus (QTL) analysis for fat area ratios and serum leptin concentrations in a Duroc purebred population. Pigs (n = 226 to 538) were measured for fat area ratios of carcass cross-sections at the fifth to sixth thoracic vertebrae, half body length and last thoracic vertebra using an image analysis system, and serum leptin concentration. In total, animals were genotyped for 129 markers and used for QTL analysis. For fat area ratios, four significant and 12 suggestive QTLs were detected on chromosomes 1, 6, 7, 8, 9, 12 and 13. Significant QTLs were detected on the same region of chromosome 6, which was located near a leptin receptor gene. For serum leptin concentrations, two significant and two suggestive QTLs were detected on chromosomes 6, 9, and 16, and the QTLs on chromosome 6 were also in the same region for fat area ratios. PMID- 22435621 TI - Genetic variation in the 5'UTR of the KRT2.13 gene of sheep. AB - KRT2.13 is a type II keratin wool intermediate filament (IF) protein. Extensive variation was revealed in the 5' untranslated region (UTR) of the ovine KRT2.13 gene (KRT2.13) using polymerase chain reaction - single strand conformational polymorphism (PCR-SSCP) analysis. Nine unique PCR-SSCP patterns were obtained with individual sheep having either one (homozygous), or a combination of two (heterozygous) of these patterns. Seven of the amplicons that produced the apparently homozygous patterns were successfully sequenced (GenBank FJ217670 - FJ217676), revealing eight single nucleotide insertions, 10 single nucleotide substitutions, a nucleotide deletion and a 16 nucleotide insertion that occurred in only one of the sequences. The seven sequences showed between 85% and 95% homology to the previously identified KRT2.13 sequence (GenBank X72379). This study emphasizes the power of PCR-SSCP analysis in genotyping, as this extensive variation was found in only 100 sheep, of a variety of breeds. Since variation in the 5'UTR of genes may affect their expression, this genetic variation needs to be further studied to establish its role if any, in influencing gene expression and consequently wool traits. PMID- 22435622 TI - Genetic variability of maternal effect on body measurements and its intra- and inter-genetic relationship with direct effect in Japanese Black calves. AB - This study was conducted to evaluate the importance of maternal effect on body measurement traits at an early stage of growth, and to estimate the genetic relationships between direct and maternal effects and among body measurement traits at 0 month (0-mo) and 4 months (4-mo) of age in a population of Japanese Black calves. Body measurements and body weight of 889 Japanese Black calves were estimated with the use of an animal model by the Residual Maximum Likelihood procedure. Direct heritabilities were low to moderate, ranging between 0.17 +/- 0.09 and 0.48 +/- 0.13 at 0-mo, and slightly lower, ranging between 0.15 +/- 0.07 and 0.33 +/- 0.13 at 4-mo. Estimated maternal heritabilities were low to moderate, ranging between 0.08 +/- 0.07 and 0.33 +/- 0.07 at 0-mo and 0.13 +/- 0.06 to 0.33 +/- 0.06 at 4-mo. The direct genetic correlations between 0-mo and 4 mo were moderate to highly positive, ranging from 0.53 +/- 0.23 to 0.96 +/- 0.09. The estimated direct genetic correlation of chest width with other width traits was low and positive at both ages, whereas with hip width it was high and positive (0.80 +/- 0.09) at 0-mo, suggesting that simultaneous improvement of body width of the front and back parts is possible. Maternal genetic effects were relatively independent of direct genetic effects for body measurement traits and can be considered in genetic evaluation. PMID- 22435623 TI - Relation of reproductive performances and rectal palpation for luteum function of heifers 7 days after estrus. AB - Diagnosis of corpus luteum (CL) function by rectal palpation (RP) has been widely used for recipient selection of embryo transfer (ET), a technology essential for genetic improvements in cattle. To examine the accuracy of RP diagnosis method, the relationship between RP-based CL function and reproductive performance was compared in this study. In Experiment 1, CL of Holstein heifers on day 7 after estrus was classified into functional or hypoplastic by RP, and the results were compared with ultrasonographic (US) images and plasma progesterone (P4) levels. As a result, heifers with functional CL judged by RP had a mean maximum CL diameter of 20.1 +/- 3.1 mm on US and a mean P4 concentration of 8.1 +/- 2.3 ng/mL. These values were significantly greater than those of heifers with hypoplastic CL (12.4 +/- 5.4 mm, 4.0 +/- 2.8 ng/mL) (P < 0.001). In Experiment 2, the length of the estrus cycle was examined between functional CL and hypoplastic CL. The rate of heifers with a normal estrus cycle length with 18-25 days was significantly lower with hypoplastic CL than with functional CL (16/24 vs. 43/46, P < 0.01). In Experiment 3, 543 inseminated heifers were similarly classified by CL function by RP 7 days after estrus. The heifers with functional CL showed higher pregnancy rate compared with the heifers with hypoplastic CL (75.2 vs. 47.9%, P < 0.0001). Finally, the CL function of 66 heifers was examined by RP on day 7 post-estrus, and ET was performed in 49 (74.2%) heifers with functional CL. As a result, 27 (55.1%) of them became pregnant. Taken together, these results reconfirm that RP on day 7 after estrus is useful for selection of heifers with functional CL. PMID- 22435624 TI - Effect of roll clearance of mechanical processing of corn silage harvested at the black-line stage of maturity on carbohydrate and protein utilization in dairy cows. AB - The experiment was conducted to evaluate the effect of roll clearance of mechanical processing of whole plant corn silage (CS) on carbohydrate and protein utilization in dairy cows. Treated CS was harvested at the black-line stage of maturity and chopped at a theoretical length of cut (TLC) of 9.5 mm without processing or at a TLC of 19 mm with processing at a roll clearance of 1, 3 and 5 mm. Four ruminally and duodenally cannulated dry cows were assigned to a 4 * 4 Latin square design for 14-day periods. Cows were fed diets containing 77% CS and 23% soybean meal (dry matter basis) to equalize the crude protein supply. Mechanical processing had no significant effect on dry matter intake and neutral detergent fiber digestibility. Ruminal and total tract starch digestibility and total digestible nutrients tended to be higher with processing at a roll clearance of 1 or 3 mm than at 5 mm. Microbial nitrogen efficiency in cows did not differ among all treatment groups. These results suggest that when CS is harvested at the black-line stage of maturity, roll clearance should be 3 mm or less with a TLC of 19 mm. PMID- 22435625 TI - Digestibility, ruminal fermentation, nitrogen balance and methane production in Holstein steers fed diets containing soy sauce cake at 10 or 20%. AB - Two feeding trials were performed to evaluate the effect of soy sauce cake (SSC) on digestibility, ruminal fermentation and nitrogen (N) balance as well as methane production in Holstein steers. Six animals received a diet without or with the SSC at 10% (Experiment 1) and 20% (Experiment 2) in a 2 * 2 crossover design with a balance trial and respiratory exchange measurement. The SSC feeding showed a strongly inhibitory effect on methane production when its proportion was elevated up to 20%. The digestibility of nutrients with the 10% SSC treatment was similar to that of the control, whereas that for the 20% SSC treatment was significantly decreased in comparison with the control. The 20% SSC treatment also inhibited ruminal fermentation. A lower N partition to urine and a higher N partition to retention were observed in the animals receiving the 20% SSC treatment. These results suggested that SSC feeding at 20% suppressed methane production and changed the N balance; however, the feeding level of 20% caused deterioration in some productive aspects, such as nutrient digestibility and ruminal fermentation. In addition, a feeding level of SSC at 10% of the diet should be considered a reasonable level in cattle. PMID- 22435626 TI - Seasonal changes of the mineral contents in the rumen of wild Yeso sika deer (Cervus nippon yesoensis). AB - The rumen contents were collected from 36 wild Yeso sika deer (Cervus nippon yesoensis) captured by deer culling or by hunting in the spring, summer, autumn and winter in Hokkaido, Japan. Botanical classification was conducted, and the contents of mineral (calcium (Ca), phosphorus (P), potassium (K), sodium (Na), iron (Fe), copper (Cu) and zinc (Zn)) were measured. The animals were captured around pastures or fallow field areas in the Kushiro area. The rumen contents consisted of grasses and Sasa sp. leaves regardless of the season. Leaves and bark were ingested in the spring, autumn and winter. The macro-mineral contents in the rumen showed seasonal changes. In the summer, the Ca, K and P contents were high, and the Na content was low. There were no seasonal changes in the Fe content. The P, Na and Fe contents were higher than the animals' requirements. In a future survey, it is needed to determine the mineral contents of the food ingested by wild Yeso sika deer. PMID- 22435627 TI - Effects of bisphenol A administration to pregnant mice on serum Ca and intestinal Ca absorption. AB - Bisphenol A (BPA) is a xenoestrogen commonly used in food storage plastics. The present study was conducted to clarify the effects of BPA administration to pregnant mice on serum calcium (Ca) and Ca metabolism of the gut and kidney. From 6.5 to 16.5 days post coitus (dpc), pregnant mice were administered at 2 mg or 20 mg/kg body weight/day of BPA. Serum Ca was decreased in mice treated with 20 mg BPA at 17.5 dpc, but no remarkable differences were detected in the alkaline phosphatase activity and vitamin D receptor protein expression in the duodenum and jejunum. The messenger RNA (mRNA) expressions of calcium binding protein (CaBP-9k) and active vitamin D synthesis enzyme (CYP27B1) in the kidney were increased in mice treated with 20 mg BPA. The mRNA expressions of occludin and junction adherence molecular A (JAM-A) in the duodenum and ileum, which regulate paracellular transport, were increased in mice treated with 20 mg BPA. However, the administration of 2 mg BPA had no effect on serum Ca and mRNA expressions of relative genes in Ca metabolism. These results imply that BPA administration at 20 mg/kg body weight/day during pregnancy decreases serum Ca in pre-delivery mice, which may be partly due to decreased paracellular Ca absorption. PMID- 22435628 TI - The effect of lighting conditions on the rhythmicity of growth hormone secretion in Holstein steers. AB - Growth hormone (GH) secretion regularity and the effects of lighting condition and GH-releasing hormone (GHRH) on GH release were determined in steers. First, steers were kept under 12:12 L : D conditions (light: 06.00-18.00 hours). The animals were then subjected to a 1-h advancement in lighting on/off conditions (05.00 and 17.00 hours, respectively). Blood was sampled for 24 h at 1-h interval on the seventh day of each condition. Second, GHRH was injected intravenously (IV) at 12.00 and 00.00 hours under 12:12 L : D and blood was sampled at 15-min interval for 4-h (1 h before and 3 h after the injection). Plasma GH concentrations were measured by a radioimmunoassay. Periodicity of GH secretory profile was calculated by power spectrum analysis using the maximum entropy method. Plasma GH concentrations showed a characteristic pattern consisting of four distinct peaks. Mean periodicity of GH secretory profile was 5.7 h, and it was not altered by any change in lighting conditions. IV injection of GHRH increased GH secretion during the day and night. The increase in GH secretory volume after GHRH injection during the night was equal to that during the day. The present results suggest that GH secreted from the anterior pituitary have regularity in steers. PMID- 22435629 TI - The effects of replacement of antibiotics with by-products of oriental medicinal plants on growth performance and meat qualities in fattening pigs. AB - The effect of by-products of oriental medicinal plants (OMP; T1) containing 0.03% herb extracts (T2) or 0.1% aminolevulinic acid (T3) on the production performance of swine during the finishing period and on its meat quality were investigated. No significant differences were found in the weight gain, feed intake and feed conversion rate among the tested groups (P > 0.05). But the treated group showed higher (P < 0.05) moisture and ash and lower protein than the control group. The T3 group showed a lower meat cholesterol content (38.42 mg/100 g) compared to the other groups (P < 0.05). The vitamin E content of the muscle in the treated groups was higher compared to the control group. No antibiotic content was detected in all treated and control samples. The values of the volatile basic nitrogen (VBN) and thiobarbituric acid reactive substance (TBARS) of the treated groups were significantly lower (P < 0.01) than the control group. The treated groups had significantly better (P < 0.05) sensory-test scores for color, flavor, off-flavor and total acceptability compared to the control group. PMID- 22435630 TI - Differences in mRNA expression of calpains, calpastatin isoforms and calpain/calpastatin ratios among bovine skeletal muscles. AB - Messenger RNA (mRNA) expression of calpain-1 (u-calpain), -2 (m-calpain), -3 (p94), small subunit (calpain-4; 28 kDa), and three types of calpastatin (CSTN) isoform were investigated for 10 skeletal muscles of Holstein cattle by real-time and/or semi-quantitative reverse transcription polymerase chain reaction. Noticeably, effect of muscle type was observed on 28 kDa expression (P < 0.001) with a tendency of higher 28 kDa expression in myosin heavy chain (MyHC)-2x-rich muscles compared to MyHC-slow-rich muscles. The CSTN-I and -III expression in Longissimus thoracis (LT) showed the lowest value among the muscles tested. Moreover, 28 kDa/CSTN-I ratio was higher in the diaphragm (DP), psoas major (PM), and LT than those in the lingual muscles (TN), masseter (MS) and pectoralis (PP) (P < 0.05). Calpain-1/CSTN I, calpain-2/CSTN I in LT and PM were higher than that in TN (P < 0.05). Calpain-3/CSTN-I and -III in LT and/or PM showed higher values than that in TN (P < 0.05). These results indicated that the calpain and CSTN expressions are regulated by muscle type, suggesting especially by muscle fiber type. Calpains/CSTN-I ratios, especially 28 kDa/CSTN-I, may account for higher extent of post mortem proteolysis previously observed in LT and PM muscles. PMID- 22435631 TI - Common nucleotide sequence of structural gene encoding fibroblast growth factor 4 in eight cattle derived from three breeds. AB - Fibroblast growth factor 4 (FGF4) is considered as a crucial gene for the proper development of bovine embryos. However, the complete nucleotide sequences of the structural genes encoding FGF4 in identified breeds are still unknown. In the present study, direct sequencing of PCR products derived from genomic DNA samples obtained from three Japanese Black, two Japanese Shorthorn and three Holstein cattle, revealed that the nucleotide sequences of the structural gene encoding FGF4 matched completely among these eight cattle. On the other hand, differences in the nucleotide sequences, leading to substitutions, insertions or deletions of amino acid residues were detected when compared with the already reported sequence from unidentified breeds. We cannot rule out a possibility that the structural gene elucidated in the present study is widely distributed in cattle. To the best of our knowledge, this is the first determination of the complete nucleotide sequence of the structural gene encoding bovine FGF4 in identified breeds. PMID- 22435632 TI - Chemerin analog regulates energy metabolism in sheep. AB - Accumulating data suggest a relationship between chemerin and energy metabolism. Our group previously described gene cloning, expression analysis and the regulatory mechanism of chemerin and its own receptor in mice and cattle. The objective of the present study was to investigate the physiological effect of chemerin on endocrine changes and energy metabolism in sheep using a biologically stable chemerin analog. The chemerin analog was intravenously administrated (100 or 500 ug/head) to sheep, and plasma insulin and metabolites (glucose, nonesterified fatty acids (NEFA), triglyceride, total cholesterol and high density lipoprotein (HDL) cholesterol) were analyzed. The chemerin analog dramatically increased the insulin levels, and glucose levels were decreased. NEFA levels were slightly decreased at 20 min but then increased gradually from 60 to 180 min after analog administration. In addition, injection of the chemerin analog immediately increased triglyceride and total cholesterol but not HDL levels. These results suggested that chemerin analog regulated insulin secretion related to glucose metabolism and the release of triglycerides in sheep in vivo. This study provides new information about endocrine and metabolic changes in response to chemerin in sheep. PMID- 22435633 TI - Analysis of preference for domestic grass-fed beef in Japanese youths. AB - A questionnaire based on sensory evaluation of completely domestic grass-fed beef was carried out on 157 Japanese undergraduate students aged between 18 and 22 years in Kitasato University. The sensory evaluation sheet consisted of 10 questions concerning preference for domestic grass-fed beef, and three demographic/lifestyle questions. Using principal component analysis and cluster analysis, the respondents were divided into four groups (G1-G4). G1 accepted almost all properties. G2 accepted most properties but disliked chewiness. G3 accepted juiciness and flavor but disliked the color and texture of the meat. G4 tended to dislike almost all properties. According to chi-square test, most G2 people statistically liked other commercial beef and G4-people had neutral and negative impressions. G1- or G3-people did not have any significant tendency as regards beef preference. These results indicate that most of the young respondents who preferred domestic grass-fed beef could not accept its texture, and some respondents could accept its juiciness and flavor. It is also suggested that a part of the people who like commercial beef do not prefer chewiness of grass-fed beef. Such information will aid grass-fed beef cattle breeders, producers and packers to improve the quality of beef and its evaluation. PMID- 22435634 TI - Peripheral neuropathy associated with mitochondrial disease in children. AB - Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease. PMID- 22435635 TI - Analysis of three Xanthomonas axonopodis pv. citri effector proteins in pathogenicity and their interactions with host plant proteins. AB - Xanthomonas axonopodis pv. citri, the bacterium responsible for citrus canker, uses effector proteins secreted by a type III protein secretion system to colonize its hosts. Among the putative effector proteins identified for this bacterium, we focused on the analysis of the roles of AvrXacE1, AvrXacE2 and Xac3090 in pathogenicity and their interactions with host plant proteins. Bacterial deletion mutants in avrXacE1, avrXacE2 and xac3090 were constructed and evaluated in pathogenicity assays. The avrXacE1 and avrXacE2 mutants presented lesions with larger necrotic areas relative to the wild-type strain when infiltrated in citrus leaves. Yeast two-hybrid studies were used to identify several plant proteins likely to interact with AvrXacE1, AvrXacE2 and Xac3090. We also assessed the localization of these effector proteins fused to green fluorescent protein in the plant cell, and observed that they co-localized to the subcellular spaces in which the plant proteins with which they interacted were predicted to be confined. Our results suggest that, although AvrXacE1 localizes to the plant cell nucleus, where it interacts with transcription factors and DNA binding proteins, AvrXacE2 appears to be involved in lesion-stimulating disease 1 mediated cell death, and Xac3090 is directed to the chloroplast where its function remains to be clarified. PMID- 22435636 TI - The effect of cigarette smoking on allergic conditions in Maltese children (ISAAC). AB - Maltese children are frequently exposed to tobacco smoke through passive and personal smoking. In the phase 3 ISAAC study questionnaire, we enquired about passive smoking to the parents of 3816 (80% response rate) 5- to 8-yr-old children and about passive and personal smoking to 4139 (90% response rate) 13- to 15-yr-old participating children. Thirty-one percent of 5- to 8-yr olds were passive smokers with their father more likely to be the smoker (p < 0.0001). Maternal smoking in the first year of the child's life resulted in the children having an increased chance of wheezing 'ever' (p < 0.001), exercise-induced wheezing (p < 0.05) and being diagnosed with asthma (p < 0.0001). Current smoking by the mother also led to the child having current rhinitis (p < 0.001). Fifty one percent of 13- to 15-yr olds were passive smokers again with the father more likely to be the smoker (p < 0.0001). Maternal (p < 0.0001) and paternal smoking (p < 0.05) resulted in the children having an increased chance of wheezing sometime in their life, exercise-induced wheezing, nocturnal cough, and being diagnosed with asthma. Current smoking by the mother was more common in children having current rhinitis (p < 0.05), while current smoking by both mother and/or father led to itchy/watery eyes accompanying rhinitis (p < 0.05). Recurrent itchy rashes were also more likely in passive smokers (p < 0.001). Personal smoking by the 13- to 15-yr olds (8.15% boys vs. 8.8% girls ns ) resulted in a higher cumulative prevalence of wheezing (p < 0.0001), rhinitis (p < 0.05), and recurrent itchy rash (p < 0.001) but only affected current prevalence of wheezing (p < 0.0001). These smokers were more likely to experience exercise-induced wheezing (p < 0.0001), nocturnal cough (p < 0.0001), and being diagnosed with asthma (p < 0.05) and eczema (p < 0.001). Children smoking more than 10 cigarettes/day persisted with wheezing (p = 0.04) had more frequent episodes of exercise-induced wheeze (p = 0.04), nocturnal cough (p < 0.0001), and rhinoconjunctivitis (p = 0.02) than milder smokers. Smoking seems to be affecting childhood allergies in Maltese children quite significantly. PMID- 22435640 TI - Ovine PrP transgenic Drosophila show reduced locomotor activity and decreased survival. AB - Drosophila have emerged as a model system to study mammalian neurodegenerative diseases. In the present study we have generated Drosophila transgenic for ovine PrP (prion protein) to begin to establish an invertebrate model of ovine prion disease. We generated Drosophila transgenic for polymorphic variants of ovine PrP by PhiC31 site-specific germ-line transformation under expression control by the bi-partite GAL4/UAS (upstream activating sequence) system. Site-specific transgene insertion in the fly genome allowed us to test the hypothesis that single amino acid codon changes in ovine PrP modulate prion protein levels and the phenotype of the fly when expressed in the Drosophila nervous system. The Arg(154) ovine PrP variants showed higher levels of PrP expression in neuronal cell bodies and insoluble PrP conformer than did His(154) variants. High levels of ovine PrP expression in Drosophila were associated with phenotypic effects, including reduced locomotor activity and decreased survival. Significantly, the present study highlights a critical role for helix-1 in the formation of distinct conformers of ovine PrP, since expression of His(154) variants were associated with decreased survival in the absence of high levels of PrP accumulation. Collectively, the present study shows that variants of the ovine PrP are associated with different spontaneous detrimental effects in ovine PrP transgenic Drosophila. PMID- 22435641 TI - Validation of a novel molecular dynamics simulation approach for lipophilic drug incorporation into polymer micelles. AB - Polymer micelles can be used to facilitate the aqueous solubilization of lipophilic, poorly water-soluble compounds and drugs. Even if the evaluation of the efficiency of drug incorporation into such micelles can be tested experimentally, a theoretical approach based on molecular simulation can constitute a useful tool that reduces time and cost. Here we present a promising method, based on molecular dynamics simulation, for the calculation of the Flory Huggins interaction parameters as a measure of the potential for drug incorporation into polymer micelles. The data from modeling are validated on four drug compounds with different physical-chemical properties by means of a comparison with the data obtained from experiments. PMID- 22435642 TI - Stress significantly increases mortality following a secondary bacterial respiratory infection. AB - A variety of mechanisms contribute to the viral-bacterial synergy which results in fatal secondary bacterial respiratory infections. Epidemiological investigations have implicated physical and psychological stressors as factors contributing to the incidence and severity of respiratory infections and psychological stress alters host responses to experimental viral respiratory infections. The effect of stress on secondary bacterial respiratory infections has not, however, been investigated. A natural model of secondary bacterial respiratory infection in naive calves was used to determine if weaning and maternal separation (WMS) significantly altered mortality when compared to calves pre-adapted (PA) to this psychological stressor. Following weaning, calves were challenged with Mannheimia haemolytica four days after a primary bovine herpesvirus-1 (BHV-1) respiratory infection. Mortality doubled in WMS calves when compared to calves pre-adapted to weaning for two weeks prior to the viral respiratory infection. Similar results were observed in two independent experiments and fatal viral-bacterial synergy did not extend beyond the time of viral shedding. Virus shedding did not differ significantly between treatment groups but innate immune responses during viral infection, including IFN-gamma secretion, the acute-phase inflammatory response, CD14 expression, and LPS induced TNFalpha production, were significantly greater in WMS versus PA calves. These observations demonstrate that weaning and maternal separation at the time of a primary BHV-1 respiratory infection increased innate immune responses that correlated significantly with mortality following a secondary bacterial respiratory infection. PMID- 22435643 TI - A field test for host fruit odour discrimination and avoidance behaviour for Rhagoletis pomonella flies in the western United States. AB - Prezygotic isolation due to habitat choice is important to many models of speciation-with-gene-flow. Habitat choice is usually thought to occur through positive preferences of organisms for particular environments. However, avoidance of non-natal environments may also play a role in choice and have repercussions for post-zygotic isolation that preference does not. The recent host shift of Rhagoletis pomonella (Diptera: Tephritidae) from downy hawthorn, Crataegus mollis, to introduced apple, Malus domestica, in the eastern United States is a model for speciation-with-gene-flow. However, the fly is also present in the western United States where it was likely introduced via infested apples <= 60 years ago. R. pomonella now attacks two additional hawthorns in the west, the native C. douglasii (black hawthorn) and the introduced C. monogyna (English ornamental hawthorn). Flight tunnel tests have shown that western apple-, C. douglasii- and C. monogyna-origin flies all positively orient to fruit volatile blends of their respective natal hosts in flight tunnel assays. Here, we show that these laboratory differences translate to nature through field-trapping studies of flies in the state of Washington. Moreover, western R. pomonella display both positive orientation to their respective natal fruit volatiles and avoidance behaviour (negative orientation) to non-natal volatiles. Our results are consistent with the existence of behaviourally differentiated host races of R. pomonella in the west. In addition, the rapid evolution of avoidance behaviour appears to be a general phenomenon for R. pomonella during host shifts, as the eastern apple and downy hawthorn host races also are antagonized by non-natal fruit volatiles. PMID- 22435645 TI - Regionally different immunoreactivity for Smurf2 and pSmad2/3 in TDP-43-positive inclusions of amyotrophic lateral sclerosis. AB - AIMS: Smad ubiquitination regulatory factor-2 (Smurf2), an E3 ubiquitin ligase, can interact with Smad proteins and promote their ubiquitin-dependent degradation, thereby controlling the cellular levels of these signalling mediators. We previously reported that phosphorylated Smad2/3 (pSmad2/3) was sequestered in transactive response DNA-binding protein-43 (TDP-43) inclusions in the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Recent biochemical and immunohistochemical studies on spinal cord and brain of ALS patients demonstrated that the composition of the TDP-43 inclusions is regionally distinct, suggesting different underlying pathogenic processes. We aimed to elucidate regional differences in pathomechanisms and composition of TDP-43 inclusions in relation to pSmad2/3 and Smurf2. METHODS: The spinal cord and brain tissues of 13 sporadic ALS (SALS) patients were investigated using immunohistochemical analysis. RESULTS: TDP-43-positive inclusions in lower motor neurones of SALS patients were immunopositive for Smurf2 and pSmad2/3. Multiple immunofluorescence staining for Smurf2, pSmad2/3, TDP-43 and ubiquitin revealed co-localization of these four proteins within the inclusions in lower motor neurones of SALS patients. Furthermore, the loss of nuclear pSmad2/3 immunoreactivity was observed in cells bearing TDP-43 inclusions. In contrast, TDP-43-positive inclusions in the extramotor neurones in the brain of SALS patients were noticeably negative for Smurf2 and pSmad2/3. In addition, pSmad2/3 immunoreactivity was preserved in the nuclei of inclusion-bearing cells. CONCLUSIONS: This regional difference in the expression of Smurf2 and pSmad2/3 within TDP-43-positive inclusions might be one of the pathomechanisms underlying the loss of lower motor neurones and comparatively spared cortical neurones seen in ALS. PMID- 22435644 TI - Acute neuroimmune modulation attenuates the development of anxiety-like freezing behavior in an animal model of traumatic brain injury. AB - Chronic anxiety is a common and debilitating result of traumatic brain injury (TBI) in humans. While little is known about the neural mechanisms of this disorder, inflammation resulting from activation of the brain's immune response to insult has been implicated in both human post-traumatic anxiety and in recently developed animal models. In this study, we used a lateral fluid percussion injury (LFPI) model of TBI in the rat and examined freezing behavior as a measure of post-traumatic anxiety. We found that LFPI produced anxiety-like freezing behavior accompanied by increased reactive gliosis (reflecting neuroimmune inflammatory responses) in key brain structures associated with anxiety: the amygdala, insula, and hippocampus. Acute peri-injury administration of ibudilast (MN166), a glial cell activation inhibitor, suppressed both reactive gliosis and freezing behavior, and continued neuroprotective effects were apparent several months post-injury. These results support the conclusion that inflammation produced by neuroimmune responses to TBI play a role in post traumatic anxiety, and that acute suppression of injury-induced glial cell activation may have promise for the prevention of post-traumatic anxiety in humans. PMID- 22435646 TI - Effectiveness of a brief condom promotion program in reducing risky sexual behaviours among African American men. AB - RATIONALE: The prevention of human immunodeficiency virus/sexually transmitted diseases remains a significant global public health issue, especially among vulnerable populations. AIMS AND OBJECTIVES: To promote condom use skills among young urban African American men. METHODS: As a pilot study, a randomized controlled trial was conducted among 136 African American men aged 18-24 years recruited from urban communities in Chicago. Participants assigned to the intervention received 45-60 minutes of a one-on-one single-session condom promotion program delivered by trained facilitators while those assigned to the attention-matched comparison condition received a general health program. Longitudinally, 115 (85%) and 120 (88%) participants completed the 3-month and 6 month follow-up surveys, respectively. RESULTS: Overall, the study results indicate that positive effects were observed from baseline to 6-month follow-up for intervention participants relative to comparison condition participants for prior condom use (1.23-1.82 versus 1.34-0.97); condom use intention (2.51-3.19 versus 2.69-2.21); perceived condom availability (3.44-3.72 versus 3.42-3.38); positive reasons to use condoms (2.82-3.08 versus 2.95-1.99); favourable condom use attitude (2.41-2.69 versus 2.49-1.95); barriers to condom use (1.33-0.79 versus 1.25-1.85); and negative condom use attitude (1.45-0.66 versus 1.33-1.39), respectively. CONCLUSIONS: We conclude that a brief single-session condom promotion program is effective in preventing high-risk sexual behaviours among urban young adult African American men. PMID- 22435647 TI - Isolation of (CO)1- and (CO2)1- radical complexes of rare earths via Ln(NR2)3/K reduction and [K2(18-crown-6)2]2+ oligomerization. AB - Deep-blue solutions of Y(2+) formed from Y(NR(2))(3) (R = SiMe(3)) and excess potassium in the presence of 18-crown-6 at -45 degrees C under vacuum in diethyl ether react with CO at -78 degrees C to form colorless crystals of the (CO)(1-) radical complex, {[(R(2)N)(3)Y(MU-CO)(2)][K(2)(18-crown-6)(2)]}(n), 1. The polymeric structure contains trigonal bipyramidal [(R(2)N)(3)Y(MU-CO)(2)](2-) units with axial (CO)(1-) ligands linked by [K(2)(18-crown-6)(2)](2+) dications. Byproducts such as the ynediolate, [(R(2)N)(3)Y](2)(MU-OC=CO){[K(18-crown 6)](2)(18-crown-6)}, 2, in which two (CO)(1-) anions are coupled to form (OC=CO)(2-), and the insertion/rearrangement product, {(R(2)N)(2)Y[OC(?CH(2))Si(Me(2))NSiMe(3)]}[K(18-crown-6)], 3, are common in these reactions that give variable results depending on the specific reaction conditions. The CO reduction in the presence of THF forms a solvated variant of 2, the ynediolate [(R(2)N)(3)Y](2)(MU-OC=CO)[K(18-crown-6)(THF)(2)](2), 2a. CO(2) reacts analogously with Y(2+) to form the (CO(2))(1-) radical complex, {[(R(2)N)(3)Y(MU-CO(2))(2)][K(2)(18-crown-6)(2)]}(n), 4, that has a structure similar to that of 1. Analogous (CO)(1-) and (OC=CO)(2-) complexes of lutetium were isolated using Lu(NR(2))(3)/K/18-crown-6: {[(R(2)N)(3)Lu(MU-CO)(2)][K(2)(18 crown-6)(2)]}(n), 5, [(R(2)N)(3)Lu](2)(MU-OC=CO){[K(18-crown-6)](2)(18-crown-6)}, 6, and [(R(2)N)(3)Lu](2)(MU-OC=CO)[K(18-crown-6)(Et(2)O)(2)](2), 6a. PMID- 22435648 TI - Cost-effectiveness analysis of palivizumab among pre-term infant populations covered by Medicaid in the United States. AB - OBJECTIVE: Medicaid infants are at high risk of severe respiratory syncytial virus (RSV) disease. The study objective was to estimate the cost-effectiveness of palivizumab in a Medicaid population. METHODS: A societal cost-utility analysis was conducted of prophylaxis with palivizumab vs no prophylaxis among four groups of premature infants: (1) <32 weeks gestational age (wGA) and <= 6 months chronologic age (CA); (2) 32-34 wGA, <= 3 months CA with 2009 American Academy of Pediatrics (AAP) risk factors (RF); (3) 32-35 wGA, <= 6 months CA with 2006 AAP RF; and (4) 32-35 wGA, <= 6 months CA with <= 1 RF. Full dosing of palivizumab was assumed throughout the RSV season (consistent with the FDA approved label). All costs were in 2010 US dollars. The societal public payer spend for palivizumab was estimated using Medicaid reimbursement methodologies for the top 10 palivizumab-using states in 2010 minus mandatory manufacturer rebates. This study reports the incremental cost-effectiveness ratios (ICERs) in cost per quality-adjusted life-year (QALY) gained. Sensitivity and probabilistic analyses were also conducted. RESULTS: Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32-34 wGA with 2009 AAP RF ($16,037 per QALY) and in infants 32-35 wGA with 2006 AAP RF ($38,244 per QALY). The ICER for infants 32-35 wGA with <= 1 RF was $281,892 per QALY. Influential variables in the sensitivity analysis included the background rate of RSV hospitalization, the cost of palivizumab, and the efficacy of palivizumab. KEY LIMITATIONS: These results are not generalizable to commercially insured infants or infants outside of the US. CONCLUSIONS: This is the first cost-utility analysis of palivizumab in a Medicaid population. Palivizumab, when dosed consistent with the FDA-approved labeling, was either cost-saving or cost effective among current guideline-eligible infants in the Medicaid population. Palivizumab did not demonstrate cost-effectiveness in 32-35 wGA infants with <= 1 RF. PMID- 22435649 TI - Evaluation of the LIM homeobox genes LHX6 and LHX8 as candidates for Tourette syndrome. AB - The etiology and pathophysiology of Tourette Syndrome (TS) remain poorly understood. Multiple lines of evidence suggest that a complex genetic background and the cortico-striato-thalamo-cortical circuit are involved. The role of Lhx6 and Lhx8 in the development of the striatal interneurons, prompted us to investigate them as novel candidate genes for TS. We performed a comparative study of the expression of Lhx6 and Lhx8 and investigated genetic association with TS using two samples of trios (TSGeneSEE and German sample - 222 families). We show that Lhx6 and Lhx8 expression in the forebrain is evolutionarily conserved, underlining their possible importance in TS-related pathophysiological pathways. Our tagging-single nucleotide polymorphism (tSNP)-based association analysis was negative for association with LHX8. However, we found positive association with LHX6 in the TSGeneSEE sample (corrected P-value = 0.006 for three-site haplotype around SNP rs3808901) but no association in the sample of German families. Interestingly, the SNP allele that was identified to be significantly associated in the TSGeneSEE dataset, showed an opposite trend of transmission in the German dataset. Our analysis of the correlation of the LHX6 region with individual ancestry within Europe, revealed the fact that this particular SNP demonstrates a high degree of population differentiation and is correlated with the North to South axis of European genetic variation. Our results indicate that further study of the LHX6 gene in relation to the TS phenotype is warranted and suggest the intriguing hypothesis that different genetic factors may contribute to the etiology of TS in different populations, even within Europe. PMID- 22435650 TI - Synthesis and biological evaluation of heterocyclic ring-fused betulinic acid derivatives as novel inhibitors of osteoclast differentiation and bone resorption. AB - A series of betulinic acid (BA) derivatives were designed and synthesized by introducing various fused heterocyclic rings at C-2 and C-3 positions. Their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated by using a cell-based tartrate-resistant acid phosphatase (TRAP) activity assay. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with BA. The most potent compound, 20, showed 66.9% inhibition even at the low concentration of 0.1 MUM, which was about 200-fold more potent than the lead compound BA. What's more, the cytotoxicity assay on RAW264.7 suggested that the inhibition of 20 on osteoclast differentiation did not result from its cytotoxicity. The primary mechanistic study indicated that 20 could inhibit osteoclastogenesis-related marker gene expression levels of cathepsin K and TRAP. More importantly, 20 could attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent. PMID- 22435651 TI - Water oxidation catalyzed by the tetranuclear Mn complex [Mn(IV)4O5(terpy)4(H2O)2](ClO4)6. AB - The tetranuclear manganese complex [Mn(IV)(4)O(5)(terpy)(4)(H(2)O)(2)](ClO(4))(6) (1; terpy = 2,2':6',2"-terpyridine) gives catalytic water oxidation in aqueous solution, as determined by electrochemistry and GC-MS. Complex 1 also exhibits catalytic water oxidation when adsorbed on kaolin clay, with Ce(IV) as the primary oxidant. The redox intermediates of complex 1 adsorbed on kaolin clay upon addition of Ce(IV) have been characterized by using diffuse reflectance UV/visible and EPR spectroscopy. One of the products in the reaction on kaolin clay is Mn(III), as determined by parallel-mode EPR spectroscopic studies. When 1 is oxidized in aqueous solution with Ce(IV), the reaction intermediates are unstable and decompose to form Mn(II), detected by EPR spectroscopy, and MnO(2). DFT calculations show that the oxygen in the mono-MU-oxo bridge, rather than Mn(IV), is oxidized after an electron is removed from the Mn(IV,IV,IV,IV) tetramer. On the basis of the calculations, the formation of O(2) is proposed to occur by reaction of water with an electrophilic manganese-bound oxyl radical species, (*)O-Mn(2)(IV/IV), produced during the oxidation of the tetramer. This study demonstrates that [Mn(IV)(4)O(5)(terpy)(4)(H(2)O)(2)](ClO(4))(6) may be relevant for understanding the role of the Mn tetramer in photosystem II. PMID- 22435652 TI - Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands. AB - INTRODUCTION: Adenosine exerts its effects by interacting with G-protein coupled receptors (GPCR) namely A(1), A(2A), A(2B) and A(3), respectively. These are involved in several diseases, for example and most importantly, Parkinson's disease, ischemia and inflammation. There is high interest in the development of potent and selective ligands for these adenosine receptor (AR) subtypes, primarily for their therapeutic potential but also as pharmacological tools in receptor studies. AREAS COVERED: This paper concentrates on reviewing the therapeutic potential of A(2) and A(3) ARs, which represent the most interesting subtypes of recent years. A general description of each receptor is reported with novel agonist and antagonist structures, patented in 2008 - 2011. PubMed and Free Patents Online databases were principally used to collect all the material. EXPERT OPINION: In the past years, by modulating A(2) and A(3)ARs, several new possible therapeutic applications were discovered. For this reason, research concerning AR ligands is still of great interest. In particular, few potent and selective A(2B) agonists and antagonists are actually reported and a clear SAR (structure-activity relationship) profile lacks for this AR subtype. At the A(3)AR, allosteric modulation may prevent problems related to the high difference between rat and human orthosteric sites and simplify the preclinical studies on A(3)AR. PMID- 22435654 TI - Novel active personal nanoparticle sampler for the exposure assessment of nanoparticles in workplaces. AB - A novel active personal nanoparticle sampler (PENS), which enables the collection of both respirable particulate mass (RPM) and nanoparticles (NPs) simultaneously, was developed to meet the critical demand for personal sampling of engineered nanomaterials (ENMs) in workplaces. The PENS consists of a respirable cyclone and a micro-orifice impactor with the cutoff aerodynamic diameter (d(pa50)) of 4 MUm and 100 nm, respectively. The micro-orifice impactor has a fixed micro-orifice plate (137 nozzles of 55 MUm in the inner diameter) and a rotating, silicone oil coated Teflon filter substrate at 1 rpm to achieve a uniform particle deposition and avoid solid particle bounce. A final filter is used after the impactor to collect the NPs. Calibration results show that the d(pa50) of the respirable cyclone and the micro-orifice impactor are 3.92 +/- 0.22 MUm and 101.4 +/- 0.1 nm, respectively. The d(pa50) at the loaded micro-Al(2)O(3) mass of 0.36-3.18 mg is shifted to 102.9-101.2 nm, respectively, while it is shifted to 98.9-97.8 nm at the loaded nano-TiO(2) mass of 0.92-1.78 mg, respectively. That is, the shift of d(pa50) due to solid particle loading is small if the PENS is not overloaded. Both NPs and RPM concentrations were found to agree well with those of the IOSH respirable cyclone and MOUDI. By using the present PENS, the collected samples can be further analyzed for chemical species concentrations besides gravimetric analysis to determine the actual exposure concentrations of ENMs in both RPM and NPs fractions in workplaces, which are often influenced by the background or incident pollution sources. PMID- 22435653 TI - Biofunctionalized calcium phosphate cement to enhance the attachment and osteodifferentiation of stem cells released from fast-degradable alginate-fibrin microbeads. AB - Stem cell-encapsulating microbeads could be mixed into a paste such as calcium phosphate cement (CPC), where the microbeads could protect the cells from the mixing and injection forces. After being placed, the microbeads could quickly degrade to release the cells throughout the scaffold, while creating macropores. The objectives of this study were to (1) construct alginate-fibrin microbeads encapsulating human umbilical cord mesenchymal stem cells (hUCMSCs) embedded in the surface of novel biofunctionalized CPC and (2) investigate microbead degradation, cell release, and osteodifferentiation on CPC. Hydrogel microbeads were fabricated that encapsulated hUCMSCs at 1*10(6) cells/mL. CPC was biofunctionalized with fibronectin (Fn) and Arg-Gly-Asp (RGD). Four scaffolds were tested: CPC control, CPC mixed with Fn, CPC mixed with RGD, and CPC grafted with RGD. The degradable microbeads released hUCMSCs at 7 days, which attached to CPC. Adding Fn or RGD to CPC greatly improved cell attachment. CPC grafted with RGD showed the fastest cell proliferation, with cell density being ninefold that on CPC control. The released hUCMSCs underwent osteodifferentiation. Alkaline phosphatase, osteocalcin, collagen 1, and runt-related transcription factor 2 (Runx2) gene expression increased by 10 to 30 fold at 7-21 days, compared with day 1. The released cells on CPC synthesized bone minerals, with the mineralization amount at 21 days being two orders of magnitude higher than that at 7 days. In conclusion, alginate-fibrin microbeads embedded in CPC surface were able to quickly release the hUCMSCs that attached to biofunctionalized CPC. Incorporating Fn and RGD into CPC greatly improved cell function, and CPC grafted with RGD had the fastest cell proliferation. The released cells on CPC differentiated into the osteogenic lineage and synthesized bone minerals. The new biofunctionalized CPC with hUCMSC-encapsulating microbeads is promising for bone regeneration applications. PMID- 22435655 TI - The preferences of people with diabetes for diabetic retinopathy screening. PMID- 22435657 TI - Nitrogen-doped titanate-anatase core-shell nanobelts with exposed {101} anatase facets and enhanced visible light photocatalytic activity. AB - Anatase TiO(2) with specifically exposed facets has been extensively studied for maximizing its photocatalytic activity. However, most previous preparation methods involve high-pressure processing and corrosive chemicals. Few works have been conducted on hierarchical composite nanostructures assembled from well defined TiO(2) nanocrystals. Here, we report a facile method for the preparation of nitrogen-doped titanate-anatase core-shell nanobelts. Anatase nanorods with specifically exposed {101} facets were obtained from a simple evaporation induced, self-assembly (EISA) process and coupled with another semiconductor photocatalyst. The composite material with improved visible-light-harvesting ability, high charge-hole mobility, and low electron-hole recombination exhibited high photocatalytic performance and stability. The results presented here will make significant contributions toward the development of delicate composite photocatalysts for photocatalytic water purification and solar energy utilization. PMID- 22435658 TI - Cow's milk and ovalbumin-specific IgG and IgA in children with eczema: low beta lactoglobulin-specific IgG4 levels are associated with cow's milk allergy. AB - Tolerance to allergens may partly depend on allergen-specific IgG and IgG subclasses and IgA antibodies. We investigated whether specific IgG and IgG subclasses and IgA antibodies to beta-lactoglobulin, alpha-casein, and ovalbumin differed between infants who had verified cow's milk allergy (CMA) and infants with cow's milk (CM)-associated eczema, but negative CM oral challenge. The study population comprised 95 infants with clinical eczema that was by history associated with the consumption of CM. After an elimination period, a double blind, placebo-controlled (DBPC) CM oral challenge confirmed CMA in 45 infants. Skin prick tests (SPT) were performed with CM and hen's egg. Serum levels of IgE antibodies to CM and hen's egg were measured with UniCAP (Phadia, Uppsala, Sweden), and levels of IgA, IgG, IgG1, and IgG4 antibodies to beta-lactoglobulin, alpha-casein, and ovalbumin were measured with enzyme-linked immunosorbent assay. We observed that infants with CMA had lower IgG4 levels to beta-lactoglobulin than infants with negative DBPC CM challenge (p = 0.004). Positive CM SPT was associated with lower IgG4 levels to alpha-casein (p = 0.04). The relation of CM IgE to beta-lactoglobulin and alpha-casein IgG4 was higher in CMA than in infants with negative challenge (p < 0.002 and 0.0001). Positive egg SPT was associated with elevated levels of specific IgG to ovalbumin, beta-lactoglobulin, and alpha casein as well as IgA to alpha-casein (p < 0.04). Our study thus shows that low beta-lactoglobulin-specific serum IgG4 levels may differentiate eczematous infants with CMA from infants who have eczema with only suspected association with CM. PMID- 22435662 TI - Ligand-triggered resistance to molecular targeted drugs in lung cancer: roles of hepatocyte growth factor and epidermal growth factor receptor ligands. AB - Recent advances in molecular biology have led to the identification of new molecular targets, such as epidermal growth factor receptor ( EGFR ) mutations and echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene, in lung cancer. Dramatic response has been achieved with EGFR inhibitors (gefitinib and erlotinib) and an ALK inhibitor (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to molecular targeted drugs include gatekeeper mutations in the target gene and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand-triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. Moreover, EGFR ligands activate EGFR and downstream pathways and trigger resistance to crizotinib in EML4-ALK lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling in EGFR -mutant lung cancer and ALK signaling in EML4-ALK lung cancer) and ligand triggered bypass signals (HGF-Met and EGFR ligands-EGFR, respectively) must be simultaneously blocked to avoid the resistance. This review focuses specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies that are under development for overcoming resistance to molecular targeted drugs in lung cancer. PMID- 22435660 TI - In vitro stretch injury induces time- and severity-dependent alterations of STEP phosphorylation and proteolysis in neurons. AB - Striatal-enriched tyrosine phosphatase (STEP) has been identified as a component of physiological and pathophysiological signaling pathways mediated by N-methyl-d aspartate (NMDA) receptor/calcineurin/calpain activation. Activation of these pathways produces a subsequent change in STEP isoform expression or activation via dephosphorylation. In this study, we evaluated changes in STEP phosphorylation and proteolysis in dissociated cortical neurons after sublethal and lethal mechanical injury using an in vitro stretch injury device. Sublethal stretch injury produces minimal changes in STEP phosphorylation at early time points, and increased STEP phosphorylation at 24 h that is blocked by the NMDA receptor antagonist APV, the calcineurin-inhibitor FK506, and the sodium channel blocker tetrodotoxin. Lethal stretch injury produces rapid STEP dephosphorylation via NR2B-containing NMDA receptors, but not calcineurin, and a subsequent biphasic phosphorylation pattern. STEP(61) expression progressively increases after sublethal stretch with no change in calpain-mediated STEP(33) formation, while lethal stretch injury results in STEP(33) formation via a NR2B-containing NMDA receptor pathway within 1 h of injury. Blocking calpain activation in the initial 30 min after stretch injury increases the ratio of active STEP in cells and blocks STEP(33) formation, suggesting that STEP is an early substrate of calpain after mechanical injury. There is a strong correlation between the amount of STEP(33) formed and the degree of cell death observed after lethal stretch injury. In summary, these data demonstrate that previously characterized pathways of STEP regulation via the NMDA receptor are generally conserved in mechanical injury, and suggest that calpain-mediated cleavage of STEP(33) should be further examined as an early marker of neuronal fate after stretch injury. PMID- 22435663 TI - Single-particle SEM-EDX analysis of iron-containing coarse particulate matter in an urban environment: sources and distribution of iron within Cleveland, Ohio. AB - The physicochemical properties of coarse-mode, iron-containing particles and their temporal and spatial distributions are poorly understood. Single-particle analysis combining X-ray elemental mapping and computer-controlled scanning electron microscopy (CCSEM-EDX) of passively collected particles was used to investigate the physicochemical properties of iron-containing particles in Cleveland, OH, in summer 2008 (Aug-Sept), summer 2009 (July-Aug), and winter 2010 (Feb-March). The most abundant classes of iron-containing particles were iron oxide fly ash, mineral dust, NaCl-containing agglomerates (likely from road salt), and Ca-S containing agglomerates (likely from slag, a byproduct of steel production, or gypsum in road salt). The mass concentrations of anthropogenic fly ash particles were highest in the Flats region (downtown) and decreased with distance away from this region. The concentrations of fly ash in the Flats region were consistent with interannual changes in steel production. These particles were observed to be highly spherical in the Flats region, but less so after transport away from downtown. This change in morphology may be attributed to atmospheric processing. Overall, this work demonstrates that the method of passive collection with single-particle analysis by electron microscopy is a powerful tool to study spatial and temporal gradients in components of coarse particles. These gradients may correlate with human health effects associated with exposure to coarse-mode particulate matter. PMID- 22435664 TI - Alterations in renal iron metabolism caused by a copper/zinc-superoxide dismutase deficiency. AB - Copper/zinc-superoxide dismutase knockout (SOD1 KO) mice have been extensively used as an experimental animal model of pathology associated with oxidative stress. The mice spontaneously develop mild chronic hemolytic anaemia (HA). We previously reported that the kidneys of these types of mice contain massive amounts of iron. In this study, to clarify the role of the kidney for iron metabolism under HA, changes in the levels of expression and functions of iron related proteins were examined. In SOD1 KO mice kidneys, protein levels of iron transporters, the iron-responsive element (IRE)-binding activity of IRP1 and the levels of phosphorylation of IRP1 are all increased. These findings indicate that oxidative stress caused by a SOD1 deficiency probably enhances the phosphorylation of and the conversion of IRP1 to the IRE-binding form, which may accelerate the reabsorption of iron by renal tubular cells. Kidney could play an important role in iron homeostasis under conditions of HA. PMID- 22435665 TI - Fitness trade-offs and the maintenance of alternative male morphs in the bulb mite (Rhizoglyphus robini). AB - Alternative reproductive phenotypes (ARPs) occur across a wide range of taxa. Most ARPs are conditionally expressed in response to a cue, for example body size, that reliably correlates with the status of the environment: individuals below the (body size) threshold then develop into one morph, and individuals above the threshold develop into the alternative morph. The environmental threshold model provides a theoretical framework to understand the evolution and maintenance of such ARPs, yet no study has examined the underlying fitness functions that are necessary to realize this. Here, we empirically examined fitness functions for the two male morphs of the bulb mite (Rhizoglyphus robini). Fitness functions were derived in relation to male size for solitary males and in relation to female size under competition. In both cases, the fitness functions of the two morphs intersected, and the resulting fitness trade-offs may play a role in the maintenance of this male dimorphism. We furthermore found that competition was strongest between males of the same morph, suggesting that fitness trade-off in relation to male size may persist under competition. Our results are a first step towards unravelling fitness functions of ARPs that are environmentally cued threshold traits, which is essential for understanding their maintenance and in explaining the response to selection against alternative morphs. PMID- 22435666 TI - The NADPH oxidase-mediated production of hydrogen peroxide (H(2)O(2)) and resistance to oxidative stress in the necrotrophic pathogen Alternaria alternata of citrus. AB - It has become increasingly apparent that the production of reactive oxygen species (ROS) by the NADPH oxidase (Nox) complex is vital for cellular differentiation and signalling in fungi. We cloned and characterized an AaNoxA gene of the necrotrophic fungus Alternaria alternata, which encodes a polypeptide analogous to mammalian gp91(phox) and fungal Noxs implicated in the generation of ROS. Genetic analysis confirmed that AaNoxA is responsible for the production of ROS. Moreover, deletion of AaNoxA in A. alternata resulted in an elevated hypersensitivity to hydrogen peroxide (H(2)O(2)), menadione, potassium superoxide (KO(2)), diamide and many ROS-generating compounds. The results implicate the involvement of AaNoxA in cellular resistance to ROS stress. The impaired phenotypes strongly resemble those previously seen for the ap1 null mutant defective in a YAP1-like transcriptional regulator and for the hog1 mutant defective in a HOG1-like mitogen-activated protein (MAP) kinase. The noxA null mutant was also hypersensitive to Nox inhibitors, nitric oxide (NO(.)) donors and NO(.) synthase inhibitors, implying a role of AaNoxA in the NO(.) signalling pathway. Expression of AaNoxA was activated by H(2)O(2), menadione, KO(2), NO(.) donors and L-arginine (a substrate for NO(.) synthase). AaNoxA may be able to sense and respond to both ROS and nitric oxide. Moreover, AaNoxA is required for normal conidiation and full fungal virulence. AaNoxA promoted the expression of the AaAP1 and AaHOG1 genes in A. alternata. Inactivation of AaNoxA greatly reduced the transcriptional activation of AaAP1 in response to ROS stress. Thus, we conclude that the regulatory functions of AaNoxA conferring ROS resistance are modulated partially through the activation of the YAP1- and HOG1 MAP kinase mediated signalling pathways. PMID- 22435667 TI - Staphylococcus aureus biofilm formation and antibiotic susceptibility tests on polystyrene and metal surfaces. AB - AIM: We compared the MBECTM-HTP assay plates made of polystyrene with metal discs composed of TMZF((r)) and CrCo as substrates for biofilm formation. METHODS AND RESULTS: Staphylococcus aureus was grown on polystyrene and on metal discs made of titanium and chrome-cobalt. Antibiotic susceptibility was assessed by examining the recovery of cells after antibiotic exposure and by measuring the biofilm inhibitory concentration (BIC). The minimal inhibitory concentration (MIC) was assessed with planktonic cells. Bacterial growth was examined by scanning electron microscopy. The antibiotic concentration for biofilm inhibition (BIC) was higher than the MIC for all antibiotics. Microscopic images showed the biofilm structure characterized by groups of cells covered by a film. CONCLUSIONS: All models allowed biofilm formation and testing with several antibiotics in vitro. Gentamicin and rifampicin are the most effective inhibitors of Staph. aureus biofilm-related infections. We recommend MBECTM-HTP assay for rapid testing of multiple substances and TMZF((r)) and CrCo discs for low throughput testing of antibiotic susceptibility and for microscopic analysis. SIGNIFICANCE AND IMPACT OF THE STUDY: In vitro assays can improve the understanding of biofilms and help developing methods to eliminate biofilms from implant surfaces. One advantage of the TMZF((r)) and CrCo discs as biofilm in vitro assay is that these metals are commonly used for orthopaedic implants. These models are usable for future periprosthetic joint infection studies. PMID- 22435668 TI - Service delivery characteristics associated with contraceptive use among youth clients in integrated voluntary counseling and HIV testing clinics in Kenya. AB - Youth attending voluntary counseling and HIV testing (VCT) services often have unmet need for contraception. Integrated family planning (FP) and HIV services can address dual HIV and unintended pregnancy prevention needs. However, little is known about which VCT service characteristics, such as quality of care, strength of FP-HIV service integration, and youth-friendliness, affect contraceptive behavior. This study explores the facility- and provider-level characteristics that may be associated with same day uptake or intention to use contraception after a VCT visit, and contraceptive use three months later among youth clients, controlling for client characteristics. This was a descriptive study conducted in 20 integrated VCT clinics across Kenya. Data collection included 20 structured clinic observations, 349 baseline interviews with male and female clients aged 15-24 after their VCT visit plus 277 follow-up interviews with clients three months later, and interviews with 46 providers who served the clients at the study clinics. Client, provider, and structured observation data were linked and multi-level logistic path models were used for analyses. Results revealed little evidence of specific service characteristics being associated with contraceptive behavior. However, VCT providers were not routinely screening for risk of unintended pregnancy or counseling on contraception. Results are likely a reflection of suboptimal integrated services. The clinics were serving youth with unmet contraceptive need and therefore integrated services should be strengthened overall to ensure no missed opportunities. PMID- 22435669 TI - Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead. AB - Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G. J. Med. Chem. 2008, 51, 7417-7427) were performed, including the replacement of the trans-styryl moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol 4-yl)-N-hydroxyacrylamide (12, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the in vitro safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP 3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (t1/2), plasma stability (t1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and in vivo half life. PMID- 22435670 TI - Nonirritant intradermal skin test concentrations of ciprofloxacin, clarithromycin, and rifampicin. AB - BACKGROUND: Intradermal skin testing of the clinically important antibiotics ciprofloxacin, clarithromycin, and rifampicin in the case of suspected allergies to antibiotics is poorly standardized. For clinical practice, standardized procedures and protocols are desired. METHODS: Fifteen healthy volunteers were tested with different concentrations of the antibiotics as well as with appropriate controls. Test readings included wheal area measured by digital image analysis and blood flow increase measured by laser Doppler flowmetry (LDF). To reduce interpersonal variability, test results were normalized with the individual controls using a novel protocol. RESULTS: Nonirritating concentrations of the three antibiotics (ciprofloxacin ~0.0067 mg/ml, clarithromycin ~0.05 mg/ml, rifampicin ~0.002 mg/ml) could be defined for healthy volunteers. Laser Doppler flowmetry generates comparable results to wheal area measurement. Normalization of the test results is necessary and can be applied in a practical algorithm. CONCLUSIONS: Standardized skin testing to detect sensitization to broadly used nonbetalactam antibiotics was presented and should be applied in truly sensitized patients. This approach should help to minimize the inter- and intraindividual differences in reactivity. PMID- 22435671 TI - Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. AB - Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype. PMID- 22435672 TI - A glycosynthase derived from an inverting GH19 chitinase from the moss Bryum coronatum. AB - BcChi-A, a GH19 chitinase from the moss Bryum coronatum, is an endo-acting enzyme that hydrolyses the glycosidic bonds of chitin, (GlcNAc)(n) [a beta-1,4-linked polysaccharide of GlcNAc (N-acetylglucosamine) with a polymerization degree of n], through an inverting mechanism. When the wild-type enzyme was incubated with alpha-(GlcNAc)2-F [alpha-(GlcNAc)(2) fluoride] in the absence or presence of (GlcNAc)(2), (GlcNAc)(2) and hydrogen fluoride were found to be produced through the Hehre resynthesis-hydrolysis mechanism. To convert BcChi-A into a glycosynthase, we employed the strategy reported by Honda et al. [(2006) J. Biol. Chem. 281, 1426-1431; (2008) Glycobiology 18, 325-330] of mutating Ser(102), which holds a nucleophilic water molecule, and Glu(70), which acts as a catalytic base, producing S102A, S102C, S102D, S102G, S102H, S102T, E70G and E70Q. In all of the mutated enzymes, except S102T, hydrolytic activity towards (GlcNAc)(6) was not detected under the conditions we used. Among the inactive BcChi-A mutants, S102A, S102C, S102G and E70G were found to successfully synthesize (GlcNAc)(4) as a major product from alpha-(GlcNAc)(2)-F in the presence of (GlcNAc)(2). The S102A mutant showed the greatest glycosynthase activity owing to its enhanced F( ) releasing activity and its suppressed hydrolytic activity. This is the first report on a glycosynthase that employs amino sugar fluoride as a donor substrate. PMID- 22435673 TI - Post-discharge tobacco cessation rates among hospitalized US veterans with and without diabetes. AB - AIMS: Smoking is a major risk factor for cardiovascular complications among patients with diabetes. Hospitalization has been shown to enhance cessation rates. The purpose of this study was to compare 6-month post-hospitalization tobacco cessation rates among US veterans with and without diabetes. METHODS: This was a longitudinal study among inpatient veterans who used tobacco in the past month (n = 496). Patients were recruited and surveyed from three Midwestern Department of Veterans Affairs hospitals during an acute-care hospitalization. They were also asked to complete a follow-up survey 6 months post-discharge. Bivariate- and multivariable-adjusted analyses were conducted to determine differences in tobacco cessation rates between patients with and without a diagnosis of diabetes. RESULTS: The mean age of patients was 55.2 years and 62% were white. Twenty-nine per cent had co-morbid diabetes. A total of 18.8% of patients with diabetes reported tobacco cessation at 6 months compared with 10.9% of those without diabetes (P = 0.02). Cotinine-verified cessation rates were 12.5 vs. 7.4% in the groups with and without diabetes, respectively (P = 0.07). Controlling for psychiatric co-morbidities, depressive symptoms, age, self-rated health and nicotine dependence, the multivariable-adjusted logistic regression showed that patients with diabetes had three times higher odds of 6-month cotinine-verified tobacco cessation as compared with those without diabetes (odds ratio 3.17, P = 0.005). CONCLUSIONS: Post-hospitalization rates of smoking cessation are high among those with diabetes. Intensive tobacco cessation programmes may increase these cessation rates further. PMID- 22435674 TI - Structure and properties of new mixed-valent [Mn(III)2Mn(IV)3Ln(III)5O5] complexes (Ln(III) = Tm(III), Lu(III), and Yb(III)). AB - By using 2'-hydroxyacetophenoxime, a new family of complexes with an [Mn(III)(2)Mn(IV)(3)Ln(5)O(5)] core was obtained with Ln = Tm (1), Lu (2), and Yb (3). Heterometallic Mn/Tm and Mn/Lu combinations have had no precedence so far. Studies of the magnetic properties indicate the presence of intracomplex antiferromagnetic interactions in 1 and 3, as well as a dominating ferromagnetic interaction between Mn(III) and Mn(IV) spins in 2, leading to an S(T) = 5/2 ground state. PMID- 22435675 TI - Understanding dry eye disease: a managed care perspective. AB - Dry eye disease (DED) is a multifactorial disorder that results in eye discomfort, visual disturbance, and often ocular surface damage. This supplement to The American Journal of Managed Care discusses the prevalence of DED and the economic burden associated with DED. The etiology and pathophysiology of DED will also be discussed, including disease progression and impact on the patient's quality of life. With greater understanding of the pathophysiology of DED, there are numerous available therapies/strategies for the management of the disorder, ranging from artificial tear substitutes, anti-inflammatory agents, secretagogues, punctal plugs, and systemic immunosuppressives, to surgery. This activity will aim to provide managed healthcare professionals with an understanding of when and how to use these different strategies to reduce morbidity and prevent complications. PMID- 22435676 TI - Analysis of subtelomeric virulence gene families in Plasmodium falciparum by comparative transcriptional profiling. AB - The Plasmodium falciparum genome is equipped with several subtelomeric gene families that are implicated in parasite virulence and immune evasion. Members of these families are uniformly positioned within heterochromatic domains and are thus subject to variegated expression. The best-studied example is that of the var family encoding the major parasite virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 undergoes antigenic variation through switches in mutually exclusive var gene transcription. var promoters function as crucial regulatory elements in the underlying epigenetic control strategy. Here, we analysed promoters of upsA, upsB and upsC var, rifA1-type rif, stevor, phist and pfmc-2tm genes and investigated their role in endogenous gene transcription by comparative genome-wide expression profiling of transgenic parasite lines. We find that the three major var promoter types are functionally equal and play an essential role in singular gene choice. Unlike var promoters, promoters of non var families are not silenced by default, and transcription of non-var families is not subject to the same mode of mutually exclusive transcription as has been observed for var genes. Our findings identified a differential logic in the regulation of var and other subtelomeric virulence gene families, which will have important implications for our understanding and future analyses of phenotypic variation in malaria parasites. PMID- 22435677 TI - Properties of cartilage engineered from elderly human chondrocytes for articular surface repair. AB - Numerous studies on engineering cartilage utilizing chondrocytes from juvenile animal sources have been reported. However, there are many unknown aspects of engineering cartilage using human chondrocytes-especially from middle-aged or elderly adults-which are critical for clinical application of tissue engineering in the field of orthopedic surgery. The primary aim of this study was to engineer neocartilage tissue from 50-60-year-old human chondrocytes in comparison to engineered cartilage made from juvenile swine chondrocytes (JSCs). Articular chondrocytes from middle-aged, nonarthritic humans and juvenile swine were isolated and placed in culture for expansion. The chondrocytes (passage 1) were mixed in fibrin gel at 40-60*10(6) cells/mL until polymerization. Cells/nodule constructs and devitalized cartilage-cells/hydrogel-devitalized cartilage constructs (three-layered model) were implanted into subcutaneous pockets of nude mice for 12, 18, and 24 weeks. The specimens were evaluated histologically, biochemically, and biomechanically. This allowed for direct comparison of the cartilage engineered from human versus swine cells. Histological analysis demonstrated that samples engineered utilizing chondrocytes from middle-aged adults accumulated basophilic, sulfated glycosaminoglycans (sGAG), and abundant type II collagen around the cells in a manner similar to that seen in samples engineered using JSCs at all time points. Biochemical analysis revealed that samples made with human cells had about 40%-60% of the amount hydroxyproline of native human cartilage, a trend parallel to that observed in the specimens made with swine chondrocytes. The amount of sGAG in the human chondrocyte specimens was about one-and-a-half times the amount in native human cartilage, whereas the amount in the samples made with swine chondrocytes was always less than native cartilage. The biomechanical analysis revealed that the stiffness and tensile of samples made with human cells were in a pattern similar to that seen with swine chondrocytes. This study demonstrates that chondrogenesis using articular chondrocytes from middle-aged adults can be achieved in a predictable and reliable manner similar to that shown in studies using cells from juvenile animals and can form the basis of engineering cartilage with degradable scaffolds in this patient population. PMID- 22435679 TI - Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. AB - BACKGROUND: Excessive oxidative stress and lipid peroxidation have been demonstrated to play important roles in the production of liver damage. L carnitine is a natural substance and acts as a carrier for fatty acids across the inner mitochondrial membrane for subsequent beta-oxidation. It is also an antioxidant that reduces metabolic stress in the cells. Recent years L-carnitine has been proposed for treatment of various kinds of disease, including liver injury. This study was conducted to evaluate the protective effect of L-carnitine against hydrogen peroxide (H2O2)-induced cytotoxicity in a normal human hepatocyte cell line, HL7702. METHODS: We analyzed cytotoxicity using MTT assay and lactate dehydrogenase (LDH) release. Antioxidant activity and lipid peroxidation were estimated by reactive oxygen species (ROS) levels, activities and protein expressions of superoxide dismutase (SOD) and catalase (CAT), and malondialdehyde (MDA) formation. Expressions of peroxisome proliferator-activated receptor (PPAR)-alpha and its target genes were evaluated by RT-PCR or western blotting. The role of PPAR-alpha in L-carnitine-enhanced expression of SOD and CAT was also explored. Statistical analysis was performed by a one-way analysis of variance, and its significance was assessed by Dennett's post-hoc test. RESULTS: The results showed that L-carnitine protected HL7702 cells against cytotoxity induced by H2O2. This protection was related to the scavenging of ROS, the promotion of SOD and CAT activity and expression, and the prevention of lipid peroxidation in cultured HL7702 cells. The decreased expressions of PPAR-alpha, carnitine palmitoyl transferase 1 (CPT1) and acyl-CoA oxidase (ACOX) induced by H2O2 can be attenuated by L-carnitine. Besides, we also found that the promotion of SOD and CAT protein expression induced by L-carnitine was blocked by PPAR alpha inhibitor MK886. CONCLUSIONS: Taken together, our findings suggest that L carnitine could protect HL7702 cells against oxidative stress through the antioxidative effect and the regulation of PPAR-alpha also play an important part in the protective effect. PMID- 22435681 TI - Applications of fluorescence spectroscopy for predicting percent wastewater in an urban stream. AB - Dissolved organic carbon (DOC) is a significant organic carbon reservoir in many ecosystems, and its characteristics and sources determine many aspects of ecosystem health and water quality. Fluorescence spectroscopy methods can quantify and characterize the subset of the DOC pool that can absorb and re-emit electromagnetic energy as fluorescence and thus provide a rapid technique for environmental monitoring of DOC in lakes and rivers. Using high resolution fluorescence techniques, we characterized DOC in the Tualatin River watershed near Portland, Oregon, and identified fluorescence parameters associated with effluent from two wastewater treatment plants and samples from sites within and outside the urban region. Using a variety of statistical approaches, we developed and validated a multivariate linear regression model to predict the amount of wastewater in the river as a function of the relative abundance of specific fluorescence excitation/emission pairs. The model was tested with independent data and predicts the percentage of wastewater in a sample within 80% confidence. Model results can be used to develop in situ instrumentation, inform monitoring programs, and develop additional water quality indicators for aquatic systems. PMID- 22435682 TI - The outcome after severe bronchiolitis is related to gender and virus. AB - The association between bronchiolitis in the first year of life and subsequent asthma, atopy, airway obstruction and bronchial hyper-responsiveness (BHR) is unsettled. Genetic predispositions, pre-morbid lung function, environmental interactions and altered immunological responses are risk factors that have been studied. The aim of this study was to assess lung function, BHR and the occurrence of asthma and atopy 11 yr after hospitalization for bronchiolitis in the first year of life, particularly focusing on the role of gender and virus involved. The study included 121 of 131 (92%) children hospitalized for bronchiolitis, 90 (74%) respiratory syncytial virus (RSV)-positive children and 141 children in an age-matched and unselected control group. At follow-up, current asthma was more common after RSV-negative bronchiolitis compared to controls (35.5% vs. 9.2%; p < 0.001), but not after RSV bronchiolitis (15.6%; p = 0.144). Higher BHR and an obstructive lung function pattern were observed after bronchiolitis, the latter most prominent after RSV-negative bronchiolitis. Higher BHR was confined to boys, but present in both the RSV-positive and RSV-negative groups (p = 0.007 and 0.003, respectively). Asthma after bronchiolitis was not associated with atopy. Atopy was similarly distributed between the RSV-positive and RSV-negative bronchiolitis groups and the control group. This study has shown that gender and type of virus are important factors to consider when addressing later development of asthma, BHR and lung function after hospitalization for bronchiolitis in early life. PMID- 22435680 TI - Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. AB - BACKGROUND: Chronic lung diseases contribute significantly to the morbidity and mortality of the population. There are few effective treatments for many chronic lung diseases, and even fewer therapies that can arrest or reverse the progress of the disease. DESIGN: In this review, we present the current state of regenerative therapies for the treatment of chronic lung diseases. We focus on endothelial progenitor cells, mesenchymal stem cells, and endogenous lung stem/progenitor cells; summarize the work to date in models of lung diseases for each of these therapies; and consider their potential benefits and risks as viable therapies for patients with lung diseases. CONCLUSIONS: Cell-based regenerative therapies for lung diseases offer great promise, with preclinical studies suggesting that the next decade should provide the evidence necessary for their ultimate application to our therapeutic armamentarium. PMID- 22435683 TI - Protective effect of Homer 1a against hydrogen peroxide-induced oxidative stress in PC12 cells. AB - Oxidative stress-induced cell damage is involved in many neurological diseases. Homer protein, as an important scaffold protein at postsynaptic density, regulates synaptic structure and function. Here, we reported that hydrogen peroxide (H(2)O(2)) induced the expression of Homer 1a. Down-regulation of Homer 1a with a specific small interfering RNA (siRNA) exacerbated H(2)O(2)-induced cell injury. Up-regulation of Homer 1a by lentivirus transfection did not affect the anti-oxidant activity, but significantly reduced the reactive oxygen species (ROS) production and lipid peroxidation after H(2)O(2)-induced oxidative stress. Overexpression of Homer 1a attenuated the loss of mitochondrial membrane potential (MMP) and ATP production induced by H(2)O(2), and subsequently inhibited mitochondrial dysfunction-induced cytochrome c release, increase of Bax/Bcl-2 ratio and caspase-9/caspase-3 activity. Furthermore, in the presence of BAPTA-AM, an intracellular free-calcium (Ca(2+)) chelator, overexpression of Homer 1a had no significant effects on H(2)O(2)-induced oxidative stress. These results suggest that Homer 1a has protective effects against H(2)O(2)-induced oxidative stress by reducing ROS accumulation and activation of mitochondrial apoptotic pathway, and these protective effects are dependent on the regulation of intracellular Ca(2+) homeostasis. PMID- 22435684 TI - Transient complex interactions of mammalian peroxisomes without exchange of matrix or membrane marker proteins. AB - Peroxisomes and mitochondria show a much closer interrelationship than previously anticipated. They co-operate in the metabolism of fatty acids and reactive oxygen species, but also share components of their fission machinery. If peroxisomes - like mitochondria - also fuse in mammalian cells is a matter of debate and was not yet systematically investigated. To examine potential peroxisomal fusion and interactions in mammalian cells, we established an in vivo fusion assay based on hybridoma formation by cell fusion. Fluorescence microscopy in time course experiments revealed a merge of different peroxisomal markers in fused cells. However, live cell imaging revealed that peroxisomes were engaged in transient and long-term contacts, without exchanging matrix or membrane markers. Computational analysis showed that transient peroxisomal interactions are complex and can potentially contribute to the homogenization of the peroxisomal compartment. However, peroxisomal interactions do not increase after fatty acid or H(2) O(2) treatment. Additionally, we provide the first evidence that mitochondrial fusion proteins do not localize to peroxisomes. We conclude that mammalian peroxisomes do not fuse with each other in a mechanism similar to mitochondrial fusion. However, they show an extensive degree of interaction, the implication of which is discussed. PMID- 22435685 TI - Novel regulation of checkpoint kinase 1: Is checkpoint kinase 1 a good candidate for anti-cancer therapy? AB - DNA-damaging strategies, such as radiotherapy and the majority of chemotherapeutic therapies, are the most frequently used non-surgical anti-cancer therapies for human cancers. These therapies activate DNA damage/replication checkpoints, which induce cell-cycle arrest to provide the time needed to repair DNA damage. Due to genetic defect(s) in the ATM (ataxia-telangiectasia mutated) Chk2-p53 pathway, an ATR (ATM- and Rad3-related)-Chk1-Cdc25 route is the sole checkpoint pathway in a majority of cancer cells. Chk1 inhibitors are expected to selectively induce the mitotic cell death (mitotic catastrophe) of cancer cells. However, recent new findings have pointed out that Chk1 is essential for the maintenance of genome integrity even during unperturbed cell-cycle progression, which is controlled by a variety of protein kinases. These observations have raised concerns about a possible risk of Chk1 inhibitors on the clinics. In this review, we summarize recent advances in Chk1 regulation by phosphorylation, and discuss Chk1 as a molecular target for cancer therapeutics. PMID- 22435687 TI - Virtual dermatohistopathology at http://www.pathowiki.org. AB - PATHOWIKI (http://www.pathowiki.org) is a new specialized information system in the form of a web-based wiki with content from all sub-disciplines of human pathology. Essential components are articles and specimens which are located thematically in dermatopathology. The project is presented on the basis of impressive examples and possibilities. The ability to link all kinds of content and integrate pattern analysis theories creates an effective tool for teaching and training in dermatopathology. Collaborative work ensures the effective usage of available resources and a continually growing amount of content, the quality of which depends on the number of users and should be as high as possible. Therefore, all interested colleagues are invited to support the project. PMID- 22435693 TI - Eruptive multiple Spitz nevi in a patient with epilepsy and drug addiction. PMID- 22435694 TI - Surgery for pilonidal sinus. PMID- 22435698 TI - [Intracutaneous nodules in a three-year-old girl. Leukemia cutis]. PMID- 22435702 TI - Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions. AB - BACKGROUND: Risk indicators of indolent systemic mastocytosis (ISM) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa (UP)] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid (MIMA) and methylhistamine (MH) to select patients for bone marrow investigations to diagnose ISM. METHODS: Retrospective data analysis of all adults, in whom bone marrow investigations were performed to diagnose ISM, was carried out. RESULTS: In total, 142 patients were included. SM was absent in all 44 patients with tryptase <10 MUg/l, in 45 of 98 (46%) patients with tryptase >=10 MUg/l and in 18 of 52 patients (35%) with tryptase >20 MUg/l. Above 43 MUg/l, all patients had ISM (n = 11). Male gender, insect venom anaphylaxis as presenting symptom, tryptase, MIMA, and MH were independent ISM predictors. If tryptase was >=10 MUg/l, the diagnostic accuracy of MIMA and MH was high (areas under the ROC curve 0.92). CONCLUSIONS: In suspected patients without UP, the ISM risk is very low (if present at all) if tryptase is <10 MUg/l. If tryptase is >=10 MUg/l, this risk depends on MIMA and MH, being low if these are normal, but high if these are elevated. Male gender and insect venom anaphylaxis are additional risk indicators. We recommend refraining from bone marrow examinations in suspected patients without UP if tryptase is <10 MUg/l. Our results question the reliability of the minor diagnostic World Health Organization criterion of tryptase >20 MUg/l. PMID- 22435703 TI - Comparative analysis of encephalization in mammals reveals relaxed constraints on anthropoid primate and cetacean brain scaling. AB - There is a well-established allometric relationship between brain and body mass in mammals. Deviation of relatively increased brain size from this pattern appears to coincide with enhanced cognitive abilities. To examine whether there is a phylogenetic structure to such episodes of changes in encephalization across mammals, we used phylogenetic techniques to analyse brain mass, body mass and encephalization quotient (EQ) among 630 extant mammalian species. Among all mammals, anthropoid primates and odontocete cetaceans have significantly greater variance in EQ, suggesting that evolutionary constraints that result in a strict correlation between brain and body mass have independently become relaxed. Moreover, ancestral state reconstructions of absolute brain mass, body mass and EQ revealed patterns of increase and decrease in EQ within anthropoid primates and cetaceans. We propose both neutral drift and selective factors may have played a role in the evolution of brain-body allometry. PMID- 22435704 TI - A novel lanreotide-encoded micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors. AB - Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(epsilon caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 +/- 0.4 nm, high drug encapsulation (87.1 +/- 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2 positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors. PMID- 22435705 TI - Prospecting for ice association: characterization of freeze-thaw selected enrichment cultures from latitudinally distant soils. AB - Freeze-thaw stress has previously been shown to alter soil community structure and function. We sought to further investigate this stress on enriched microbial consortia with the aim of identifying microbes with ice-associating adaptations that facilitate survival. Enrichments were established to obtain culturable psychrotolerant microbes from soil samples from the latitudinal extremes of the Canadian Shield plateau. The resulting consortia were subjected to consecutive freeze-thaw cycles, and survivors were putatively identified by their 16S rRNA gene sequences. Even though the northerly site was exposed to longer, colder winters and large spring-time temperature fluctuations, the selective regime similarly affected both enriched consortia. Quantitative PCR and metagenomic sequencing were used to determine the frequency of a subset of the resistant microbes in the original enrichments. The metagenomes showed 22 initial genera, only 6 survived and these were not dominant prior to selection. When survivors were assayed for ice recrystallization inhibition and ice nucleation activities, over 60% had at least one of these properties. These phenotypes were not more prevalent in the northern enrichment, indicating that regarding these adaptations, the enrichment strategy yielded seemingly functionally similar consortia from each site. PMID- 22435706 TI - Self-assembly of discrete M6L8 coordination cages based on a conformationally flexible tripodal phosphoric triamide ligand. AB - Reactions of a tripodal ligand, N,N',N"-tris(3-pyridinyl)phosphoric triamide (TPPA), and a series of transition-metal ions result in the assembly of five discrete M(6)L(8) coordination cages [M(6)(TPPA)(8)(H(2)O)(12)](ClO(4))(12).57H(2)O [M = Ni(2+) (1), Co(2+) (2), Zn(2+) (3), Cd(2+) (4)] and [Pd(6)(TPPA)(8)]Cl(12).22H(2)O (5). X-ray structural analyses reveal that the cages have large internal cavities and flexible windows. The flexible ligand TPPA adopts the syn conformation in cages 1-4, but it transforms to the anti conformation in cage 5. Because of the conformational transformation, the sizes of the windows and the volume of the internal cavity of cage 5 are increased. (1)H NMR and electrospray mass spectrometric studies show that cage 5 maintains its structural integrity in solution. Additionally, compounds 3 and 4 exhibit strong blue fluorescent emissions, which are 1 order of magnitude higher than that of the free ligand. PMID- 22435707 TI - Kinetic analysis of FTO (fat mass and obesity-associated) reveals that it is unlikely to function as a sensor for 2-oxoglutarate. AB - Genomewide-association studies have revealed that SNPs (single nucleotide polymorphisms) in FTO (fat mass and obesity-associated) are robustly associated with BMI (body mass index) and obesity. FTO is an Fe(II) 2-OG (2-oxoglutarate) dependent dioxygenase that can demethylate 3-meT (3-methylthymine) in single stranded DNA, as well as 3-meU (3-methyluracil) and N6-methyl adenosine in RNA. In the present paper we describe the development of an RNase-cleavage assay measuring the demethylation activity of FTO on 3-meU. RNase A cleaves at the 3' end of pyrimidines, including uracil, and a methyl group at position three of uracil inhibits cleavage. An oligonucleotide probe was designed consisting of a DNA stem, an RNA loop containing a single 3-meU as the only RNase A-cleavage site, a fluorescent reporter on one end and a quencher at the other end. FTO demethylation of the unique 3-meU enables RNase A cleavage, releasing the quencher and enabling a fluorescent signal. In the presence of excess RNase A, FTO activity is limiting to the development of fluorescent signal, which can be read continuously and is able to discriminate between wild-type and the catalytically dead R316Q FTO. 2-OG is a co-substrate of FTO and, as a metabolite in the citric acid cycle, is a marker of intracellular nutritional status. The assay described in the present paper was used to measure, for the first time, the K(m) of FTO for 2-OG. The K(m) of 2.88 MUM is up to 10-fold lower than the estimated intracellular concentrations of 2-OG, rendering it unlikely that FTO functions as a sensor for 2-OG levels. PMID- 22435708 TI - Identification of a class of novel tubulin inhibitors. AB - We previously developed a series of anticancer agents based on cyclooxygenase-2 (COX-2) inhibitor nimesulide as a lead compound. However, the molecular targets of these agents still remain unclear. In this study, we synthesized a biotinylated probe based on a representative molecule of the compound library and performed protein pull-down assays to purify the anticancer targets of the compound. Via proteomic approaches, the major proteins bound to the probe were identified to be tubulin and heat shock protein 27 (Hsp27), and the compound inhibited tubulin polymerization by binding at the colchicine domain. However, the tubulin inhibitory effect of the compound activated the Hsp27 phosphorylation and possibly overrode the direct Hsp27 inhibitory effects, which made it difficult to solely validate the Hsp27 target. Taken together, the compound was a dual ligand of tubulin and Hsp27, inhibited tubulin polymerization, and had the potential to be a class of new chemotherapeutic agents. PMID- 22435709 TI - The impact of insulin administration during the mixed meal tolerance test. AB - AIMS: The mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test. METHODS: Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin. RESULTS: The 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (>= 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C peptide was highly correlated to 90-min serum C-peptide during the test (r = 0.97, P < 0.0001). A fasting serum C-peptide >= 0.07 nmol/l was the optimal cut off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide >= 0.2 nmol/l). CONCLUSIONS: Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients. PMID- 22435710 TI - Estrone is neuroprotective in rats after traumatic brain injury. AB - In various animal and human studies, early administration of 17beta-estradiol, a strong antioxidant, anti-inflammatory, and anti-apoptotic agent, significantly decreases the severity of injury in the brain associated with cell death. Estrone, the predominant estrogen in postmenopausal women, has been shown to be a promising neuroprotective agent. The overall goal of this project was to determine if estrone mitigates secondary injury following traumatic brain injury (TBI) in rats. Male rats were given either placebo (corn oil) or estrone (0.5 mg/kg) at 30 min after severe TBI. Using a controlled cortical impact device in rats that underwent a craniotomy, the right parietal cortex was injured using the impactor tip. Non-injured control and sham animals were also included. At 72 h following injury, the animals were perfused intracardially with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for TUNEL-positive cells. Estrone decreased cortical lesion volume (p<0.01) and neuronal injury (p<0.001), and it reduced cerebral cortical levels of TUNEL-positive staining (p<0.0001), and decreased numbers of TUNEL-positive cells in the corpus callosum (p<0.03). We assessed the levels of beta-amyloid in the injured animals and found that estrone significantly decreased the cortical levels of beta-amyloid after brain injury. Cortical levels of phospho-ERK1/2 were significantly (p<0.01) increased by estrone. This increase was associated with an increase in phospho-CREB levels (p<0.021), and brain-derived neurotrophic factor (BDNF) expression (p<0.0006). In conclusion, estrone given acutely after injury increases the signaling of protective pathways such as the ERK1/2 and BDNF pathways, decreases ischemic secondary injury, and decreases apoptotic-mediated cell death. These results suggest that estrone may afford protection to those suffering from TBI. PMID- 22435711 TI - Antidepressant use during pregnancy and the risk of pregnancy-induced hypertension. AB - AIM: Due to their effect on altering physiological interactions between vasodilator and vasoconstrictor autacoids in normal pregnancies, antidepressants may be associated with the risk of pregnancy-induced hypertension. We evaluated the impact of antidepressant use during pregnancy on the risk of pregnancy induced hypertension. METHODS: We conducted a nested case-control study within the Quebec Pregnancy Registry, built by linkage of provincial medical, pharmaceutical, hospital and birth databases. We identified 1216 women with a diagnosis of pregnancy-induced hypertension with or without pre-eclampsia and with no history of hypertension before pregnancy. We randomly selected 10 controls for each case, matched on case index date (date of diagnosis) and gestational age. Odds ratios (OR) were calculated using conditional logistic regression models, adjusting for sociodemographic characteristics, maternal depression, anxiety, other chronic conditions, medication use and health service utilization. RESULTS: Among cases, 45 (3.7%) had used antidepressants during pregnancy compared with 300 (2.5%) in the control group (OR 1.52, 95% CI 1.10, 2.09). After adjusting for potential confounders, use of antidepressants during pregnancy was significantly associated with increased risk of pregnancy-induced hypertension (OR 1.53, 95% CI 1.01, 2.33). In stratified analyses, use of selective serotonin re-uptake inhibitors (OR 1.60, 95% CI 1.00, 2.55), and more specifically, paroxetine (OR 1.81, 95% CI 1.02, 3.23) was associated with risk of pregnancy-induced hypertension. CONCLUSIONS: Women who use antidepressants during pregnancy are at increased risk of pregnancy-induced hypertension with or without pre-eclampsia above and beyond the risk that could be attributed to their depression or anxiety disorders. PMID- 22435712 TI - The promoter architectural landscape of the Salmonella PhoP regulon. AB - The DNA-binding protein PhoP controls virulence and Mg2+ homeostasis in the Gram negative pathogen Salmonella enterica serovar Typhimurium. PhoP regulates expression of a large number of genes that differ both in their ancestry and in the biochemical functions and physiological roles of the encoded products. This suggests that PhoP-regulated genes are differentially expressed. To understand how a bacterial activator might generate varied gene expression behaviour, we investigated the cis-acting promoter features (i.e. the number of PhoP binding sites, as well as their orientation and location with respect to the sites bound by RNA polymerase and the sequences that constitute the PhoP binding sites) in 23 PhoP-activated promoters. Our results show that natural PhoP-activated promoters utilize only a limited number of combinations of cis-acting features--or promoter architectures. We determine that PhoP activates transcription by different mechanisms, and that ancestral and horizontally acquired PhoP-activated genes have distinct promoter architectures. PMID- 22435713 TI - Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance. AB - BACKGROUND: Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB). Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis. RESULTS: Here we propose a novel measure--Codon Deviation Coefficient (CDC)--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance. CONCLUSIONS: As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions. PMID- 22435714 TI - Early-term effect of adult chondrocyte transplantation in an osteoarthritis animal model. AB - In this study, we investigated the efficacy of the transplantation of autologous articular chondrocytes seeded onto a hyaluronan-based scaffold, known as Hyaff((r))-11, on the treatment of early cartilage lesions in a rabbit osteoarthritis (OA) model. The hypothesis of the study was that this treatment could enhance cartilage repair after OA induction. OA was surgically induced by Anterior Cruciate Ligament Transection (ACLT) in thirty rabbits. Animals were divided into three groups, according to treatment: group 1: ACLT; group 2: Chondrocytes+Hyaff-11; and group 3: Hyaff-11 alone. The animals were euthanized, respectively, at 3 and 6 months after the treatment. Histomorphometrical analyses were performed by means of fibrillation index, cartilage thickness, and subchondral bone thickness evaluations. Histological appearance was scored according to Modified Kraus' Mankin and Osteoarthritis Research Society International (OARSI) scores. Immunohistochemical analyses were carried out for type I and II collagens, MMP-1, and MMP-3. A comparison between groups and follow up for each outcome was performed with the general linear model with Sidak correction. Histomorphometrical evaluations at 3 and 6 months demonstrated that OA lesions became significantly worse followed by Hyaff-11 treatment, whereas Chondrocytes+Hyaff-11 treatment had the best overall subjective grade. Overall raw histological scores demonstrated a significant improvement with chondro hyaluronic acid (HA) treatment at 3 months compared with HA in cartilage repair processes. Immunohistochemical analyses displayed a strong positivity for type II collagen in the Chondrocytes+Hyaff-11group at 3 months compared with the HA group. No staining was observed in MMP-3 expression in this group at any experimental point. The use of Chondrocytes+Hyaff-11 for the treatment of early OA lesions produced, already at 3 months, a repair tissue showing better macroscopic, histological, and immunohistochemical results than those observed after Hyaff-11 treatment. Thus, the transplantation of Chondrocytes+Hyaff-11 would seem to be advocated in the very early stage of the OA disease when a precocious action is mandatory. PMID- 22435715 TI - Two new antimicrobial flavanes from dragon's blood of Dracaena cambodiana. AB - Two new flavonoids, named cambodianins D (1) and E (2), together with two known flavanes (2S)-7,4'-dihydroxy-6,8-dimethylflavane (3) and (2S)-7,3'-dihydroxy-4' methoxy-8-methylflavane (4), were isolated from dragon's blood of Dracaena cambodiana. The new compounds were determined by HR-ESI-MS and spectroscopic techniques (UV, IR, 1D, and 2D NMR). Compounds 1-3 exhibited antimicrobial activities. PMID- 22435717 TI - Assessment of quality of life in pregnant Japanese women: comparison of hospitalized, outpatient, and non-pregnant women. AB - This cross-sectional study explored the comfort and quality of life in hospitalized, preterm, pregnant women compared with pregnant outpatients, and identified the relationship between comfort, quality of life, and hospitalization. Two-hundred-and-twenty-one hospitalized pregnant women who met the inclusion criteria were recruited from obstetric units, and 1015 outpatient pregnant women were recruited from obstetric outpatient units in Japan. The women were questioned on six domains of the Japanese Short-Form-36 version 2 (bodily pain, general health, vitality, role emotional, social functioning, and mental health) and on their subjective comfort. A total of 189 hospitalized pregnant women and 503 low-risk pregnant women were analyzed. Subjective comfort and all six domains of health-related quality of life showed significantly lower scores for hospitalized women than outpatient women (P < 0.05-0.001). The mean differences in social functioning and role-emotional domains between the two groups were particularly marked. The result of this study suggests that these patients require positive psychological support to improve their comfort and quality of life. PMID- 22435718 TI - Contrast-enhanced 3D FIESTA imaging in Tolosa-Hunt syndrome. PMID- 22435719 TI - Rapid magnetic biomonitoring and differentiation of atmospheric particulate pollutants at the roadside and around two major industrial sites in the U.K. AB - Emissions of particulate matter (PM) from vehicle and industrial sources constitute a hazard to human health. Here, we apply biomagnetic monitoring to (a) discriminate between potential PM(10) sources around a steelworks and (b) examine magnetic source differentiation for a combined, U.K.-based, magnetic data set (steelworks, roadside, power-generating site). Tree leaves (sampled September 2009, as passive PM receptors) and putative sources were subjected to rapid magnetic characterization (magnetic remanence measurements). Fuzzy cluster analysis of the combined data set identified three clusters, showing that particulates emitted from vehicle fleets (e.g., diesel/petrol), and from different industrial processes can be magnetically differentiated. Cluster analysis of the steelworks leaf receptors and potential sources identified seven magnetic groupings. Leaves from one PM "hotspot" showed no affinity with any available source sample, suggesting an as yet untested PM source. These data indicate the value of fast, inexpensive magnetic techniques for particulate source discrimination and indication of "missing" sources. PMID- 22435720 TI - [Ni(phen)3]2Sb18S29: a novel three-dimensional framework thioantimonate(III) templated by [Ni(phen)3] complexes. AB - A novel thioantimonate(III), namely, [Ni(phen)(3)](2)Sb(18)S(29) (1; phen = 1,10 phenanthroline), has been solvothermally synthesized. Its structure features a three-dimensional framework with the largest channels in thioantimonates. The chiral [Ni(phen)(3)](2+) cations and the Sb:S ratio (1:1.611) in 1 are unique among those in the reported thioantimonates. The thermal stability, optical properties, and electric conductivity as well as the theoretical band structure and density of state of 1 have also been studied. PMID- 22435723 TI - Linear granuloma annulare in an infant--an unusual clinical presentation. PMID- 22435724 TI - Self monitoring of glucose in Type 2 diabetes: guidelines fail to reflect evidence. PMID- 22435726 TI - Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death. AB - The life-long homeostasis of memory CD8(+) T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8(+) CD28(-) T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8(+) CD28(-) T cells have not yet been elucidated. In this study, we demonstrate that the miR-23~24~27 cluster is up-regulated during post-thymic CD8(+) T-cell differentiation in humans. The increased expression of miR-24 in CD8(+) CD28(-) T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8(+) CD28(-) when compared to CD8(+) CD28(+) T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8(+) CD28(-) T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide mediated apoptosis of CD8(+) CD28(-) T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8(+) CD28(-) T cells in humans. PMID- 22435727 TI - Effect of lactose on gut microbiota and metabolome of infants with cow's milk allergy. AB - Allergic infants have an unusual gastrointestinal microbiota with low numbers of Bifidobacterium/Lactobacilli and high levels of Clostridium, staphylococci and Escherichia coli. Hydrolyzed formula used to treat these infants is deprived of lactose that instead may influence the gut microbial composition. The aim of the present study is to investigate the influence of lactose on the composition of the gut microbiota and metabolome of infants with cow's milk allergy. Infants prospectively enrolled received an extensively hydrolyzed formula with no lactose for 2 months followed by an identical lactose-containing formula for an additional 2 months. Healthy, age-gender-matched infants were used as controls. The following determinations were performed before and after the introduction of lactose in the diet: enumeration of cells present in the feces using FISH, counts of viable bacterial cells and gas-chromatography mass spectrometry/solid-phase microextraction analysis. The addition of lactose to the diet significantly increases the counts of Bifidobacteria and lactic acid bacteria (p < 0.01), decreases that of Bacteroides/clostridia (p < 0.05) reaching counts found in healthy controls; lactose significantly increases the concentration of total short-chain fatty acids (p < 0.05). The addition of lactose to an extensively hydrolyzed formula is able to positively modulate the composition of gut microbiota by increasing the total fecal counts of Lactobacillus/Bifidobacteria and decreasing that of Bacteroides/Clostridia. The positive effect is completed by the increase of median concentration of short chain fatty acids, especially for acetic and butyric acids demonstrated by the metabolomic analysis. PMID- 22435728 TI - Suicide attempt with an overdose of imatinib. PMID- 22435730 TI - Importance of the icmN gene in the growth of Legionella pneumophila in amoebic cells at low temperature. AB - Legionella pneumophila grows in amoebae and has achieved the ability to grow at various temperatures, although the mechanisms controlling this ability remain poorly understood. The Icm/Dot type IVB secretion system is composed of more than 25 proteins and is known to be essential for intracellular growth. The role of the icmN gene in intracellular multiplication and the effects of culture temperatures on it are not precisely understood. We conducted our investigation using an icmN mutant made by gene replacement mutagenesis. Intracellular growth of the mutant was impaired both in mammalian macrophages and amoeba at 37 degrees C. In particular, intracellular growth in amoebae was completely impaired at 25 degrees C. It was found that genes from icmN to icmC formed an operon, i.e., icmN, -M, -L, -E, -G, -C,, and the promoter activity of the icmN operon was stronger at 25 than at 37 degrees C. It was suggested that icmM and its downstream genes had a secondary promoter that enables icmN mutant grow in amoebae at lower temperatures and macrophages at 37 degrees C. These results show that the icmN promoter has a low temperature inducible nature, and gene products of the icmN operon require high expression for bacterial proliferation at low temperatures within amoeba. PMID- 22435729 TI - Utilization and costs of health care after geriatric traumatic brain injury. AB - Despite the growing number of older adults experiencing traumatic brain injury (TBI), little information exists regarding their utilization and cost of health care services. Identifying patterns in the type of care received and determining their costs is an important first step toward understanding the return on investment and potential areas for improvement. We performed a health care utilization and cost analysis using the National Study on the Costs and Outcomes of Trauma (NSCOT) dataset. Subjects were persons 55-84 years of age with TBI treated in 69 U.S. hospitals located in 14 states (n=414, weighted n=1038). Health outcomes, health care utilization, and 1-year costs of care following TBI in 2005 U.S. dollars were estimated from hospital bills, patient surveys, medical records, and Medicare claims data. The subjects were further analyzed in three subgroups (55-64, 65-74, and 75-84 years of age). Unadjusted cost models were built, followed by a second set of models adjusting for demographic and pre injury health status. Those in the oldest category (75-84 years) had significantly higher numbers of re-hospitalizations, home health care visits, and hours per week of unpaid care, and significantly lower numbers of physician and mental health professional visits than younger age groups (age 55-64 and 65-74 years). Significant age-related differences were seen in all health outcomes tested at 12 months post-injury except for incidence of depressive symptoms. One year total treatment costs did not differ significantly across age categories for brain-injured older adults in either the unadjusted or adjusted models. The unadjusted total mean 1-year cost of care was $77,872 in persons aged 55-64 years, $76,903 in persons aged 65-74 years, and $72,733 in persons aged 75-84 years. There were significant differences in cost drivers among the age groups. In the unadjusted model index hospitalization costs and inpatient rehabilitation costs were significantly lower in the oldest age category, while outpatient care costs and nursing home stays were lower in the younger age categories. In the adjusted model, in addition to these cost drivers, re-hospitalization costs were significantly higher among those 75-84 years of age, and receipt of informal care from friends and family was significantly different, being lowest among those aged 65-74 years, and highest among those aged 75-84 years. Identifying variations in care that these patients are receiving and determining the costs versus benefits is an important next step in understanding potential areas for improvement. PMID- 22435731 TI - MiR-21 regulates epithelial-mesenchymal transition phenotype and hypoxia inducible factor-1alpha expression in third-sphere forming breast cancer stem cell-like cells. AB - Cancer stem cells (CSCs) are predicted to be critical drivers of tumor progression due to their "stemness", but the molecular mechanism of CSCs in regulating metastasis remains to be elucidated. Epithelial-mesenchymal transition (EMT), hypoxia-inducible factor (HIF)-1alpha, and miR-21, all of which contribute to cell migration for metastasis, are interrelated with CSCs. In the present study, third-sphere forming (3-S) CSC-like cells, which showed elevated CSC surface markers (ALDH1(+) and CD44(+)/CD24(-/low)) and sphereforming capacity as well as migration and invasion capacities, were cultured and isolated from breast cancer MCF-7 parental cells, to evaluate the role of miR-21 in regulating the CSC like cell biological features, especially EMT. EMT, which was assessed by overexpression of mesenchymal cell markers (N-cadherin, Vimentin, alpha-smooth muscle actin [alpha-SMA]) and suppression of epithelial cell marker (E-cadherin), was induced in 3-S CSC-like cells. Moreover, both of HIF-1alpha and miR-21 were upregulated in the CSC-like cells. Interestingly, antagonism of miR-21 by antagomir led to reversal of EMT, downexpression of HIF-1alpha, as well as suppression of invasion and migration, which indicates a key role of miR-21 involved in regulate CSC-associated features. In conclusion, we demonstrated that the formation of CSC-like cells undergoing process of EMT-like associated with overexpression of HIF-1alpha, both of which are regulated by miR-21. PMID- 22435732 TI - Grading amino acid properties increased accuracies of single point mutation on protein stability prediction. AB - BACKGROUND: Protein stabilities can be affected sometimes by point mutations introduced to the protein. Current sequence-information-based protein stability prediction encoding schemes of machine learning approaches include sparse encoding and amino acid property encoding. Property encoding schemes employ physical-chemical information of the mutated protein environments, however, they produce complexity in the mean time when many properties joined in the scheme. The complexity introduces noises that affect machine learning algorithm accuracies. In order to overcome the problem we described a new encoding scheme that graded twenty amino acids into groups according to their specific property values. RESULTS: We employed three predefined values, 0.1, 0.5, and 0.9 to represent 'weak', 'middle', and 'strong' groups for each amino acid property, and introduced two thresholds for each property to split twenty amino acids into one of the three groups according to their property values. Each amino acid can take only one out of three predefined values rather than twenty different values for each property. The complexity and noises in the encoding schemes were reduced in this way. More than 7% average accuracy improvement was found in the graded amino acid property encoding schemes by 20-fold cross validation. The overall accuracy of our method is more than 72% when performed on the independent test sets starting from sequence information with three-state prediction definitions. CONCLUSIONS: Grading numeric values of amino acid property can reduce the noises and complexity of input information. It is in accordance with biochemical concepts for amino acid properties and makes the input data simplified in the mean time. The idea of graded property encoding schemes may be applied to protein related predictions with machine learning approaches. PMID- 22435733 TI - The toxin/immunity network of Burkholderia pseudomallei contact-dependent growth inhibition (CDI) systems. AB - Burkholderia pseudomallei is a category B pathogen and the causative agent of melioidosis--a serious infectious disease that is typically acquired directly from environmental reservoirs. Nearly all B. pseudomallei strains sequenced to date (> 85 isolates) contain gene clusters that are related to the contact dependent growth inhibition (CDI) systems of gamma-proteobacteria. CDI systems from Escherichia coli and Dickeya dadantii play significant roles in bacterial competition, suggesting these systems may also contribute to the competitive fitness of B. pseudomallei. Here, we identify 10 distinct CDI systems in B. pseudomallei based on polymorphisms within the cdiA-CT/cdiI coding regions, which are predicted to encode CdiA-CT/CdiI toxin/immunity protein pairs. Biochemical analysis of three B. pseudomallei CdiA-CTs revealed that each protein possesses a distinct tRNase activity capable of inhibiting cell growth. These toxin activities are blocked by cognate CdiI immunity proteins, which specifically bind the CdiA-CT and protect cells from growth inhibition. Using Burkholderia thailandensis E264 as a model, we show that a CDI system from B. pseudomallei 1026b mediates CDI and is capable of delivering CdiA-CT toxins derived from other B. pseudomallei strains. These results demonstrate that Burkholderia species contain functional CDI systems, which may confer a competitive advantage to these bacteria. PMID- 22435735 TI - Natural-source d-alpha-tocopheryl acetate inhibits oxidant stress and modulates atopic asthma in humans in vivo. AB - BACKGROUND: Asthma is associated with oxidant stress and diminished antioxidant defenses. Yet, the mechanistic role of oxidant stress and antioxidant supplementation in human asthmatics remains uncertain. We determined the effect of high doses of the antioxidant natural-source d-alpha-tocopheryl acetate for 16 weeks on allergen-induced airway oxidant stress, inflammation, and bronchial responsiveness to methacholine and allergen in atopic asthmatics in vivo. METHODS: Thirty-three mild atopic asthmatics underwent bronchoscopy with baseline bronchoalveolar lavage and segmental allergen challenge. The allergen-challenged airway was lavaged 24 h later. At least 3 weeks later, patients underwent inhaled challenges with methacholine and specific allergen. Volunteers took 1500 IU of natural-source d-alpha-tocopheryl acetate daily for at least 16 weeks. At the end of the treatment, the two bronchoscopies and inhaled methacholine and allergen challenges were repeated. F(2)-isoprostanes, specific markers of oxidant stress, and selected Th1 and Th2 cytokines were analyzed in the lavage fluid. RESULTS: Following supplementation of natural-source d-alpha-tocopheryl acetate, plasma concentrations of alpha-tocopherol increased and gamma-tocopherol decreased. Both baseline and allergen-induced F(2)-isoprostanes significantly decreased, providing biochemical evidence for an antioxidant effect. Natural-source d-alpha tocopheryl acetate reduced allergen-provoked concentrations of interleukin 3 and interleukin 4 and augmented levels of interleukin 12 in bronchoalveolar lavage fluid. Natural-source d-alpha-tocopheryl acetate improved airway responsiveness to methacholine but did not alter airway reactivity to specific allergen. CONCLUSIONS: Inhibition of oxidant stress by natural-source d-alpha-tocopheryl acetate modulates allergic inflammation and airway hyperresponsiveness in human atopic asthmatics in vivo. These results need to be confirmed by a randomized placebo-controlled trial. PMID- 22435736 TI - Transformation of bisphenol A and alkylphenols by ammonia-oxidizing bacteria through nitration. AB - Transformation of bisphenol A (BPA) by ammonia-oxidizing bacteria (AOB) Nitrosomonas europaea ATCC 19718 was investigated. On the basis of the ultraperformance liquid chromatography (UPLC) coupled to quadrupole time-of flight mass spectrometry (Q-TOF MS) and nuclear magnetic resonance analysis, we found N. europaea could transform BPA into nitro- and dinitro-BPA, suggesting that abiotic nitration between the biogenic nitrite and BPA played a major role in the transformation of BPA in the batch AOB system. Nitrite concentrations, temperature, and pH values were the major factors to influence the reaction rate. Furthermore, the yeast estrogenic screening assay showed that the formed nitro- and dinitro-BPA had much less estrogenic activity as compared with its parent compound BPA. Similar reactions of abiotic nitration were considered for 4-n nonylphenol (nNP) and 4-n-octylphenol (nOP) since nitro-nNP and nitro-nOP were detected by UPLC-Q-TOF MS. In addition, results from the local wastewater treatment plant (WWTP) showed the occurrence of nitro-BPA and dinitro-BPA during the biological treatment process and in the effluent, indicating that nitration of BPA is also a pathway for removal of BPA. Results of this study provided implication that AOB in the WWTPs might contribute to removal of selected endocrine-disrupting compounds (EDCs) through abiotic nitritation. PMID- 22435737 TI - Plexiform fibrohistiocytic tumour: morphological changes and challenges in assessment of recurrent and metastatic lesions. PMID- 22435738 TI - Synthesis and characterization of high-throughput nanofabricated poly(4-hydroxy styrene) membranes for in vitro models of barrier tissue. AB - Commercially available permeable supports with microporous membranes have led to significant improvements in the culture of polarized cells because they permit them to feed basolaterally and thus carry out metabolism in a more in vivo-like setting. The porous nature of these membranes enables permeability measurements of drugs or biomolecules across the cellular barrier. However, current porous membranes have a high flow resistance due to great thickness (20-40 MUm), low porosity, and a wide pore size distribution with tortuous diffusion paths, which make them low-throughput for permeability studies. Here we describe an alternate platform that is more flexible, allows for more control over physical parameters of the membranes, and is high-throughput. This study reports on the synthesis, nanofabrication, and surface characterization of a 3-MUm-thick transparent membrane based on poly(4-hydroxy styrene) (PHOST). The membranes are nanofabricated using electron beam lithography and deep ion plasma etching to achieve an organized array of straight pores from 50 to 800 nm in diameter, with at least 23 times less flow resistance. It also shows for the first time the potential utility of PHOST as a cell culture substrate without cytotoxicity, and suitability for nanofabrication processes due to temperature stability. PMID- 22435739 TI - Ruthenium-phenothiazine electron transfer dyad with a photoswitchable dithienylethene bridge: flash-quench studies with methylviologen. AB - A molecular ensemble composed of a phenothiazine (PTZ) electron donor, a photoisomerizable dithienylethene (DTE) bridge, and a Ru(bpy)(3)(2+) (bpy = 2,2' bipyridine) electron acceptor was synthesized and investigated by optical spectroscopic and electrochemical means. Our initial intention was to perform flash-quench transient absorption studies in which the Ru(bpy)(3)(2+) unit is excited selectively ("flash") and its (3)MLCT excited state is quenched oxidatively ("quench") by excess methylviologen prior to intramolecular electron transfer from phenothiazine to Ru(III) across the dithienylethene bridge. However, after selective Ru(bpy)(3)(2+1)MLCT excitation of the dyad with the DTE bridge in its open form, (1)MLCT -> (3)MLCT intersystem crossing on the metal complex is followed by triplet-triplet energy transfer to a (3)pi-pi* state localized on the DTE unit. This energy transfer process is faster than bimolecular oxidative quenching with methylviologen at the ruthenium site (Ru(III) is not observed); only the triplet-excited DTE then undergoes rapid (10 ns, instrumentally limited) bimolecular electron transfer with methylviologen. Subsequently, there is intramolecular electron transfer with PTZ. The time constant for formation of the phenothiazine radical cation via intramolecular electron transfer occurring over two p-xylene units is 41 ns. When the DTE bridge is photoisomerized to the closed form, PTZ(+) cannot be observed any more. Irrespective of the wavelength at which the closed isomer is irradiated, most of the excitation energy appears to be funneled rapidly into a DTE-localized singlet excited state from which photoisomerization to the open form occurs within picoseconds. PMID- 22435740 TI - (1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans. AB - G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway. PMID- 22435741 TI - Oral sumatriptan and almotriptan--delimiting the MAOI effect. AB - OBJECTIVES/BACKGROUND: (1) To investigate whether a parsimonious model for sumatriptan pharmacokinetics can apply to oral administration; (2) for a successful model, whether a monoamine oxidase A inhibitor (MAOI-A) perturbs it; and (3) whether such a model is generalizable to oral almotriptan. These goals respond to statements in US product labeling. METHODS: Extension of a previous model for subcutaneous sumatriptan. Numerical solutions to 3 concurrent differential equations were found, with prospective criteria for model acceptance based upon comparison with clinically observed data. RESULTS: The model was successfully extended by inserting a time factor into the absorption phase. This extension was robust: it imitated clinical data for 3 oral sumatriptan dose sizes (both without and with a concomitant MAOI-A) and also for oral almotriptan. CONCLUSION: A model for oral sumatriptan pharmacokinetics can be found using the differential calculus, and it is generalizable to oral almotriptan. The model suggests that an MAOI-A probably has greater effect on elimination kinetics than first-pass metabolism, and that this interaction appears to be overstated in product labeling. PMID- 22435742 TI - Larval settlement and metamorphosis of the mussel Mytilus coruscus in response to natural biofilms. AB - Settlement and metamorphosis of pediveliger larvae of Mytilus coruscus in response to natural biofilms was investigated in the laboratory. Pediveliger larvae settled and metamorphosed in response to biofilms and post-larval settlement and metamorphosis increased with biofilm age. The activity of the biofilm was positively correlated with biofilm age, dry weight, bacterial density and diatom density, but had no apparent relationship with chlorophyll a concentration. The change in bacterial community composition corresponding to biofilm age may explain differences in the age-dependent inducing activities of biofilms, which in turn may play an important role in larval settlement in this species. PMID- 22435743 TI - 2-Methoxy-5-amino-N-hydroxybenzamide, a derivative of mesalamine, inhibits colon cancer cell growth through cyclo-oxygenase-2-dependent and -independent mechanisms. AB - COX-2 (cyclo-oxygenase-2) and PGE2 (prostaglandin E2) play a key role in sustaining CRC (colorectal cancer) cell growth and survival. Indeed, the use of agents targeting the COX-2/PGE2 axis has been associated with a reduction in the development of CRC in both humans and murine models of colon carcinogenesis. In the present study, we investigated whether 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a derivative of mesalamine that inhibits CRC cell growth both in vitro and in vivo, negatively regulates COX-2/PGE2 expression in CRC cells and assessed whether the 2-14-mediated anti-neoplastic effect is strictly dependent on the inhibition of this pathway. Our results show that 2-14 blocks the growth and enhances the death of HT-115, a CRC cell line overexpressing COX 2, and that these effects associate with inhibition of COX-2 but not COX-1. 2-14 also down-regulates TNFalpha (tumour necrosis factor alpha)-induced COX-2 in HT 29 cells as well as COX-2/PGE2 expression in ex vivo cultures of human CRC explants. Similarly, 2-14 reduces COX-2, but not COX-1, in tumoural areas developing in a mouse model of CAC (colitis-associated colon cancer). Finally, we show that 2-14 exhibits in vitro and in vivo anti-mitogenic effects in DLD-1, a COX-deficient CRC cell line. Taken together, these results suggest that 2-14 inhibits CRC cell growth through COX-2-dependent and -independent mechanisms. PMID- 22435745 TI - Hypertension control in ambulatory care patients with diabetes. AB - PURPOSE: Hypertension (HTN) control among diabetics is essential to preventing macrovascular complications. We investigated correlates of HTN control among a national sample of 1313 patients with diabetes receiving care in ambulatory care settings. METHODS: The current study employed extant data from the 2008 National Ambulatory Care Survey. Multivariate logistic regression analyses were employed to examine the relationship between HTN control and candidate covariates, including race, income, provider, and facility characteristics, and patient demographic and health status indicators among patients with diabetes receiving care in ambulatory care facilities. RESULTS: Approximately 28.7% of patients achieved HTN control at the level of 130/80 mm Hg and 57.0% at 140/90 mm Hg. Patients seen at physician offices or academic medical center/hospital settings had greater probability of HTN control compared with outpatient departments and community health centers. Patients seen in academic medical centers or other hospital settings had the greatest probability of control (47.9% at 130/80 mm Hg and 70% at 140/90 mm Hg, P < .0001). Despite being more likely to be on antihypertensive medications, black patients with diabetes had the lowest probability of HTN control at the level of 140/90 mm Hg (41.1%) or 130/80 mm Hg (19.0%) compared with other race/ethnic groups (P < .0001). CONCLUSIONS: Patients with diabetes seen in diverse primary care settings had a low probability of having blood pressure (BP) controlled to the recommended levels. Care setting specific policies may prove useful in improving BP control. Continued attention is still warranted for racial and ethnic disparities in HTN control. PMID- 22435746 TI - Preventive care and health behaviors among overweight/obese men in HMOs. AB - OBJECTIVES: To examine potential weight-related disparities in receipt of preventive screening exams and to compare several quality indicators and health behaviors among overweight/obese men and healthy-weight men enrolled in 2 large managed care plans. STUDY DESIGN: Cross-sectional analysis nested within a diverse cohort of men participating in the California Men's Health Study (CMHS) (N = 80,771). METHODS: We extracted utilization of serum cholesterol, triglycerides, glucose, glycosylated hemoglobin, sigmoidoscopy exams, and prostatespecific antigen tests from health plan electronic sources. CMHS survey data provided information about diet and physical activity. Adjusted odds ratios and 95% confidence intervals were estimated to assess the association of screening exams and behaviors with categories of body mass index (BMI). RESULTS: Tests for cholesterol, glucose, and diabetes control increased across categories of BMI, while overweight and obese men were less likely to undergo screening exams for colorectal and prostate cancer. Smoking and alcohol consumption were less frequent among overweight/obese men; however, they reported diets higher in fat and lower in fruits and vegetables, and were much less likely to report moderate/vigorous activity and much more likely to be sedentary. CONCLUSIONS: Managed care organizations might reduce weight-related health risks and disparities in care with targeted efforts to promote cancer screenings, healthy diets, and physical activity among overweight and obese patients. PMID- 22435747 TI - Economic evaluation of plerixafor for stem cell mobilization. AB - INTRODUCTION: Autologous peripheral stem cell transplantation (ASCT) with high dose chemotherapy is a preferred treatment for relapsed non- Hodgkin lymphoma (NHL) patients. Estimated failure rates with current stem cell mobilization (SCM) regimens are 5% to 30%. Granulocyte colony-stimulating factor (G-CSF) with plerixafor (G P) is superior to G-CSF alone for SCM in heavily pretreated NHL patients. OBJECTIVES: To conduct a cost-utility evaluation of G P versus G-CSF as a method for SCM in patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of NHL. METHODS: A Markov model simulated the care process of DLBCL patients undergoing ASCT using data from the Washington University site of the plerixafor phase III study. Other data and utilities were taken from the literature. Costs were Medicare allowable. Using microsimulation we estimated the incremental cost-utility ratio (ICUR) over the patient's remaining lifetime. RESULTS: The expected lifetime cost of providing care for DLBCL patients using G P was $25,567 more than G-CSF, but they accumulated 1.74 more quality-adjusted life-years (QALYs) for an ICUR of $14,735 per QALY. In sensitivity analyses this result was robust to clinically relevant changes in assumptions. CONCLUSIONS: Using G P for SCM in ASCT of patients with DLBCL meets accepted standards of cost effectiveness, primarily because of its effectiveness in SCM. PMID- 22435748 TI - Systematic review of comparative effectiveness data for oncology orphan drugs. AB - OBJECTIVES: To systematically assess clinical and economic evidence for oncology orphan drugs marketed in the United States and to highlight the challenges and opportunities for evidence development within this pharmaceutical category. STUDY DESIGN: Systematic review. METHODS: We conducted systematic literature searches of the Medline and Embase databases for clinical and cost-effectiveness studies published before June 2010 for all oncology orphan drugs marketed in the United States. We used the Grading of Recommendations Assessment, Development and Evaluation method and the Quality of Health Economic Studies criteria to assess the quality of the selected studies. RESULTS: We identified 60 randomized controlled trials and 21 cost-effectiveness analyses to support 47 oncology orphan drugs. A total of 21 drugs had moderate or high-quality bodies of clinical evidence, 11 had low-quality or very low quality clinical evidence, and 15 drugs could not be evaluated because we were unable to identify clinical evidence that met our inclusion criteria. The Spearman rank correlation coefficient for the level of evidence for oncology orphan drugs and disease prevalence was 0.3 (95% confidence interval, 0.0-0.5). The cost-effectiveness analyses received quality scores between 72 and 100 (range 0-100), with a mean score of 85. CONCLUSIONS: The results of our study show that oncology orphan drugs marketed in the United States have varying levels and quality of clinical evidence and a paucity of evidence regarding economic value. Innovative analytic and policy approaches are needed to develop and implement a decision-making framework for this pharmaceutical category that is consistent with evidence-based medicine and comparative effectiveness research. PMID- 22435749 TI - Protein quantification of UDP-glucuronosyltransferases 1A1 and 2B7 in human liver microsomes by LC-MS/MS and correlation with glucuronidation activities. AB - The aims of this study were to quantify absolute protein levels of uridine 5' diphosphate-glucuronosyltransferases (UGTs) 1A1 and 2B7 in human liver microsomes (HLMs) and to investigate their correlation with marker activities. A quantification method for UGT1A1 and UGT2B7 in HLMs was developed. Unique tryptic peptides of UGT1A1 and UGT2B7 in tryptically digested HLMs were simultaneously quantified by liquid chromatography (LC) equipped with tandem mass spectrometry (MS) using corresponding stable isotope-labelled peptides as internal standards. Bovine serum albumin was used as a blank matrix for calibration curve samples. Our procedure had good digestion efficiency, sensitivity, calibration curve linearity, and reproducibility of digestion to quantification. In 16 individual HLMs, the protein levels of UGT1A1 and UGT2B7 ranged from 6.50 to 44.6 pmol/mg and 4.45 to 18.2 pmol/mg, respectively. Estradiol 3beta-glucuronidation correlated strongly with the UGT1A1 level, indicating its high reliability as a reaction marker. Both morphine 3-O- and 6-O-glucuronidation significantly correlated with UGT2B7 level. However, the intercept of the linear regression clearly indicates that morphine glucuronidation was mediated by other UGT isoforms in addition to UGT2B7. PMID- 22435750 TI - Adverse associations of increases in television viewing time with 5-year changes in glucose homoeostasis markers: the AusDiab study. AB - BACKGROUND: Television viewing time is associated cross-sectionally with abnormal glucose tolerance and diabetes risk; however, the impact of changes in television viewing time on glycaemic measures is less understood. We examined relationships of 5-year change in television viewing time with 5-year change in glucose homeostasis markers. METHODS: Participants in the Australian Diabetes, Obesity and Lifestyle study with data available at the 1999-2000 baseline and the 2004 2005 follow-up were included (4870; 45% men). Television viewing time (h/week) was assessed by questionnaire. Fasting plasma glucose, serum insulin and 2-h plasma glucose were obtained from an oral glucose tolerance test. Beta-cell function and insulin resistance were ascertained using the homeostasis model assessment 2-calculator. Associations of change in television viewing time with changes in glucose homeostasis markers were examined using linear regression models [beta-coefficients (95% CI)]. Adjustments included baseline measures of age, television viewing time and glycaemic marker, and baseline and 5-year change in diet quality, energy intake, physical activity and waist circumference. RESULTS: For every 5-h per week increase in television viewing time from baseline to 5-year follow-up, changes in glucose homeostasis markers were observed: among women there was a significant increase in fasting plasma glucose [0.01 (0.00 0.02) mmol/l] insulin resistance [0.03 (0.01-0.05)] and insulin secretion [1.07 (0.02-2.12) %]; insulin levels increased [men: 1.20 (0.30-2.09); women: 1.06 (0.32-1.80) pmol/l]; in men, 2-h plasma glucose levels increased [0.06 (0.01-0.1) mmol/l]. CONCLUSION: Five-year increases in television viewing time were associated adversely with changes in glucose homeostasis markers. These findings add to earlier cross-sectional evidence that television viewing time can be associated with biomarkers of diabetes risk. PMID- 22435751 TI - Synthesis and photodynamics of fluorescent blue BODIPY-porphyrin tweezers linked by triazole rings. AB - Novel zinc porphyrin tweezers in which two zinc porphyrins were connected with pi conjugated boron dipyrromethenes (BDP meso-Por(2) and BDP beta-Por(2)) through triazole rings were synthesized to investigate the photoinduced energy transfer and electron transfer. The UV-vis spectrum of BDP beta-Por(2) which has less bulky substituents than BDP meso-Por(2) exhibits splitting of the Soret band as a result of the interaction between porphyrins of BDP beta-Por(2) in the excited state. Such interaction between porphyrins of both BDP beta-Por(2) and BDP meso Por(2) is dominant at room temperature, while the coordination of the nitrogen atoms of the triazole rings to the zinc ions of the porphyrins occurs at low temperature. The conformational change of the BDP-porphyrin composites was confirmed by the changes in UV-vis and fluorescence spectra depending on temperature. Photodynamics of BDP meso-Por(2) and BDP beta-Por(2) has also been investigated by laser flash photolysis. Efficient singlet-singlet energy transfer from the ZnP to the pi-conjugated BDP moiety of both BDP meso-Por(2) and BDP beta Por(2) occurred in opposite direction as compared to energy transfer from conventional BDP to ZnP due to the pi-conjugation in nonpolar toluene. In polar benzonitrile, however, additional electron transfer occurred along with energy transfer. PMID- 22435752 TI - Long-term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system. AB - Recent societal acceptance of cannabinoids as recreational and therapeutic drugs has posed a potential hazard to male reproductive health. Mammals have a highly sophisticated endogenous cannabinoid (ECS) system that regulates male (and female) reproduction and exo-cannabinoids may influence it adversely. Therefore it is imperative to determine their effects on male reproduction so that men can make informed choices as to their use. Here, an animal model was used to administer HU210, a synthetic analogue of Delta9-tetrahydrocannabinol (THC) and potent cannabinoid receptor (CB) agonist to determine its effects on reproductive organ weights, spermatogenesis, testicular histology and sperm motility. Its effects on the physiological endocannabinoid system were also investigated. Spermatogenesis was markedly impaired with reductions in total sperm count after 2 weeks of exposure. Spermatogenic efficiency was depleted, and Sertoli cell number decreased as exposure time increased with seminiferous tubules showing germ cell depletion developing into atrophy in some cases. Sperm motility was also adversely affected with marked reductions from 2 weeks on. HU210 also acted on the sperm's endocannabinoid system. Long-term use of exo-cannabinoids has adverse effects on both spermatogenesis and sperm function. These findings highlight the urgent need for studies evaluating the fertility potential of male recreational drug users. HU210, a selective agonist for CB1 and CB2 cannabinoid receptors impairs spermatogenesis and sperm motility and deregulates the endocannabinoid system. PMID- 22435753 TI - The bacterial protein Hfq: much more than a mere RNA-binding factor. AB - Most of the sequenced bacterial genomes contain a gene encoding a protein known as Hfq that resembles the eukaryotic RNA-binding proteins of the LSm family. It was originally identified in Escherichia coli as a host factor required for replication of the Qbeta RNA phage. In this review, we present a comprehensive summary of 40 years of investigation to learn that Hfq is an influential, though not essential, global regulator of gene expression in bacteria and that this feature is undoubtedly linked to Hfq's RNA-binding properties. This protein intervenes in different RNA transactions, notably the promotion of antisense interactions between messenger RNAs and small regulatory RNAs. Yet, several aspects of its molecular mechanism remain not understood. In addition, mechanistic studies have been exclusively carried out in enterobacterial models, highlighting the need to expand the research on Hfq function to other taxons. Upon reviewing the genetic, structural, biochemical, and biological aspects of this extraordinary protein, we discuss recent findings on interactions with macromolecules other than RNA suggesting a broader participation of Hfq in major steps in the flow of genetic information. We show that, although significant progress has been achieved to elucidate Hfq role at the molecular level, many open questions remain. PMID- 22435754 TI - Mechanical characterization of the injured spinal cord after lateral spinal hemisection injury in the rat. AB - The glial scar formed at the site of traumatic spinal cord injury (SCI) has been classically hypothesized to be a potent physical and biochemical barrier to nerve regeneration. One longstanding hypothesis is that the scar acts as a physical barrier due to its increased stiffness in comparison to uninjured spinal cord tissue. However, the information regarding the mechanical properties of the glial scar in the current literature is mostly anecdotal and not well quantified. We monitored the mechanical relaxation behavior of injured rat spinal cord tissue at the site of mid-thoracic spinal hemisection 2 weeks and 8 weeks post-injury using a microindentation test method. Elastic moduli were calculated and a modified standard linear model (mSLM) was fit to the data to estimate the relaxation time constant and viscosity. The SLM was modified to account for a spectrum of relaxation times, a phenomenon common to biological tissues, by incorporating a stretched exponential term. Injured tissue exhibited significantly lower stiffness and elastic modulus in comparison to uninjured control tissue, and the results from the model parameters indicated that the relaxation time constant and viscosity of injured tissue were significantly higher than controls. This study presents direct micromechanical measurements of injured spinal cord tissue post injury. The results of this study show that the injured spinal tissue displays complex viscoelastic behavior, likely indicating changes in tissue permeability and diffusivity. PMID- 22435755 TI - PKC-delta mediates interferon-alpha-induced apoptosis through c-Jun NH2-terminal kinase activation. AB - BACKGROUND: Interferon-alpha (IFN-alpha) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-alpha induced a sustained activation of c-Jun NH2 terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-alpha-initiated activation of JNK1. RESULTS: IFN-alpha caused activation of PKC-delta in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-delta. The dominant-negative form of mutant PKC-delta (dnPKC-delta) reduced the IFN-alpha induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (DeltaPsim), and increase in propidium iodide (PI) positive cells. The IFN-alpha-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-delta inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-delta enhanced the IFN-alpha-induced TRAIL promoter activity and loss of DeltaPsim in Daudi B lymphoma cells. In addition, IFN-alpha-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-delta. CONCLUSIONS: IFN alpha induced JNK1 activation via PKC-delta, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of DeltaPsim and increase in PI positive cells. The IFN-alpha induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC delta-mediated signaling component(s). PMID- 22435756 TI - Survey of Australian practitioners' provision of healthy lifestyle advice to clients who are obese. AB - Obesity is a global issue, with healthcare practitioners increasingly involved in clinical interactions with people who are overweight or obese. These interactions are opportunities to provide evidence-based healthy lifestyle advice, and impact on public health. This study used a cross-sectional survey of Australian healthcare practitioners to investigate what influenced the provision of healthy lifestyle advice to obese and overweight clients. A modified theory of planned behavior was used to explore knowledge translation processes. Knowledge translation was linked to three factors: (i) a healthcare practitioner's education and confidence in the currency of their knowledge; (ii) personal characteristics - whether they accepted that providing this advice was within their domain of practice; and (iii) the existence of organizational support structures, such as access to education, and best practice guidelines. To fulfill the potential role healthcare practitioners can play in the provision of evidence based health promotion advice requires organizations to provide access to practice guidelines and to instill a belief in their workforce that this is a shared professional domain. PMID- 22435757 TI - Loss of FlhE in the flagellar Type III secretion system allows proton influx into Salmonella and Escherichia coli. AB - flhE belongs to the flhBAE flagellar operon in Enterobacteria, whose first two members function in Type III secretion (T3S). In Salmonella enterica, absence of FlhE affects swarming, but not swimming, motility. Based on a chance observation of a 'green' colony phenotype of flhE mutants on pH indicator plates containing glucose, we have established that this phenotype is associated with lysis of flagellated cells in an acidic environment created by glucose metabolism. The flhE mutant phenotype of Escherichia coli is similar overall to that of S. enterica but is seen in the absence of glucose and, unlike in S. enterica, causes a substantial growth defect. flhE mutants have a lowered cytoplasmic pH in both bacteria, indicative of a proton leak. GFP reporter assays indicate that the leak is dependent on the flagellar system, is present before the T3S system switches to secretion of late substrates, and gets worse after the switch and upon filament assembly, leading to cell lysis. We show that FlhE is a periplasmic protein that co-purifies with flagellar basal bodies. FlhE may act as a plug or a chaperone to regulate proton flow through the flagellar T3S system. PMID- 22435759 TI - A novel role for interleukin-1 receptor signaling in the developmental regulation of immune responses to endotoxin. AB - Neonatal Innate immunity is distinct compared with later ages with some inflammatory cytokines produced in excess of adult levels in response to microbial products such as lipopolysaccharide (LPS). The molecular mechanisms underpinning this specific pattern of neonatal immunity are unknown. In this study, we compared gene expression and cytokine production from LPS stimulated mononuclear cell cultures from 60 individuals at birth and at 12-months. Neonatal mononuclear cell responses were characterized by high levels of IL-1beta, IL-10, and IFNgamma compared with mononuclear cell responses at 12 months. Microarray analysis of gene expression revealed widespread differences between the neonatal versus infant LPS response. We found expression of a subset of interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) signaling genes was highly expressed in the neonatal period and rapidly down regulated by 12 months. The data suggest that IL-1R1 expression in the neonatal period provides an additional level of Myd88-dependent signaling during this period of heighted susceptibility to infection. PMID- 22435758 TI - Microencapsulation of small intestinal neuroendocrine neoplasm cells for tumor model studies. AB - Basic cancer research is dependent on reliable in vitro and in vivo tumor models. The serotonin (5-HT) producing small intestinal neuroendocrine tumor cell line KRJ-1 has been used in in vitro proliferation and secretion studies, but its use in in vivo models has been hampered by problems related to the xeno-barrier and tumor formation. This may be overcome by the encapsulation of tumor cells into alginate microspheres, which can function as bioreactors and protect against the host immune system. We used alginate encapsulation of KRJ-1 cells to achieve long term functionality, growth and survival. Different conditions, including capsule size, variations in M/G content, gelling ions (Ca(2+) /Ba(2+)) and microcapsule core properties, and variations in KRJ-1 cell condition (single cells/spheroids) were tested. Viability and cell growth was evaluated with MTT, and confocal laser scanner microscopy combined with LIVE/DEAD viability stains. 5-HT secretion was measured to determine functionality. Under all conditions, single cell encapsulation proved unfavorable due to gradual cell death, while encapsulation of aggregates/spheroids resulted in surviving, functional bioreactors. The most ideal spheroids for encapsulation were 200-350 MUm. Long-term survival (>30 days) was seen with solid Ca(2+) /Ba(2+) microbeads and hollow microcapsules. Basal 5 HT secretion was increased (sixfold) after hollow microcapsule encapsulation, while Ca(2+) /Ba(2+) microbeads was associated with normal basal secretion and responsiveness to cAMP/PKA activation. In conclusion, encapsulation of KRJ-1 cells into hollow microcapsules produces a bioreactor with a high constitutively activate basal 5-HT secretion, while Ca(2+) /Ba(2+) microbeads provide a more stable bioreactor similar to non-encapsulated cells. Alginate microspheres technology can thus be used to tailor different functional bioreactors for both in vitro and in vivo studies. PMID- 22435760 TI - Angiosarcoma of graft nephrectomy site: genetic profiling reveals recipient origin. PMID- 22435761 TI - Controlled Attenuation Parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography. AB - BACKGROUND: Accurate tools for the noninvasive detection of hepatic steatosis are needed. The Controlled Attenuation Parameter (CAP) specifically targets liver steatosis using a process based on transient elastography. METHODS: Patients with chronic liver disease and body mass index (BMI) >=28 kg/m(2) underwent biopsy and liver stiffness measurement (LSM) with simultaneous CAP determination using the FibroScan((r)) M probe. The performance of the CAP for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROC). RESULTS: A total of 153 patients were included: 69% were male, median BMI was 32 kg/m(2); 47% had nonalcoholic fatty liver disease (NAFLD); and 65% had significant (>=10%) steatosis. The CAP was significantly correlated with the percentage of steatosis (rho = 0.47) and steatosis grade (rho = 0.51; both P < 0.00005). The median CAP was higher among patients with significant steatosis (317 [IQR 284-339] vs. 250 [227-279] dB/m with <10% steatosis; P < 0.0005) and the AUROC for this outcome was 0.81 (95% CI 0.74-0.88). At a cut-off of 283 dB/m, the CAP was 76% sensitive, 79% specific, and had positive and negative predictive values of 87% and 64%, respectively. CAP performance was not influenced by measurement variability, but was higher in patients with mild (F0-F1) fibrosis (AUROC 0.89 vs. 0.72 with F2-F4; P = 0.03). The AUROCs of the CAP for >=5%, >33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively. CONCLUSIONS: The CAP is a promising tool for the noninvasive detection of hepatic steatosis. Advantages of CAP include its ease of measurement, operator-independence and simultaneous availability with LSM for fibrosis assessment. PMID- 22435762 TI - A comparison of the clavam biosynthetic gene clusters in Streptomyces antibioticus Tu1718 and Streptomyces clavuligerus. AB - The production of clavam metabolites has been studied previously in Streptomyces clavuligerus , a species that produces clavulanic acid as well as 4 other clavam compounds, but the late steps of the pathway leading to the specific end products are unclear. The present study compared the clavam biosynthetic gene cluster in Streptomyces antibioticus , chosen because it produces only 2 clavam metabolites and no clavulanic acid, with that of S. clavuligerus. A cosmid library of S. antibioticus genomic DNA was screened with a clavaminate synthase-specific probe based on the corresponding genes from S. clavuligerus, and 1 of the hybridizing cosmids was sequenced in full. A clavam gene cluster was identified that shows similarities to that of S. clavuligerus but also contains a number of novel genes. Knock-out mutation of the clavaminate synthase gene abolished clavam production in S. antibioticus, confirming the identity of the gene cluster. Knock out mutation of a novel gene encoding an apparent oxidoreductase also abolished clavam production. A potential clavam biosynthetic pathway consistent with the genes in the cluster and the metabolites produced by S. antibioticus, and correspondingly different from that of S. clavuligerus, is proposed. PMID- 22435763 TI - Rural health research: what sort of investment is needed? PMID- 22435764 TI - 'Making evidence count': a framework to monitor the impact of health services research. AB - OBJECTIVES: The objective of this study is to develop a framework to measure the impact of primary health care research, describe how it could be used and propose a method for its validation. DESIGN: Literature review and critical appraisal of existing models of research impact, and integration of three into a comprehensive impact framework. SETTING: Centre of Research Excellence focusing on access to primary health care services in Australia. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Health Services Research Impact Framework, integrating the strengths of three existing models of research impact. CONCLUSION: In order to ensure relevance to policy and practice and to provide accountability for funding, it is essential that the impact of health services research is measured and monitored over time. Our framework draws upon previously published literature regarding specific measures of research impact. We organise this information according to the main area of impact (i.e. research related, policy, service and societal) and whether the impact originated with the researcher (i.e. producer push) or the end-user (i.e. user pull). We propose to test the utility of the framework by recording and monitoring the impact of our own research and that of other groups of primary health care researchers. PMID- 22435765 TI - Do clinical pathways enhance access to evidence-based acute myocardial infarction treatment in rural emergency departments? AB - OBJECTIVE: The objective of this study is to measure the impact of a five-step implementation process for an acute myocardial infarction (AMI) clinical pathway (CPW) on thrombolytic administration in rural emergency departments. DESIGN: Cluster randomised controlled trial. SETTING: Six rural Victorian emergency departments participated. INTERVENTION: The five-step CPW implementation process comprised (i) engaging clinicians; (ii) CPW development; (iii) reminders; (iv) education; and (v) audit and feedback. MAIN OUTCOME MEASURES: The impact of the intervention was assessed by measuring the proportion of eligible AMI patients receiving a thrombolytic and time to thrombolysis and electrocardiogram. RESULTS: Nine hundred and fifteen medical records were audited, producing a final sample of 108 patients eligible for thrombolysis. There was no significant difference between intervention and control groups for median door-to-needle time (29 mins versus 29 mins; P = 0.632), proportion of those eligible receiving a thrombolytic (78% versus 84%; P = 0.739), median time to electrocardiogram (7 mins versus 6 mins; P = 0.669) and other outcome measures. Results showed superior outcome measures than other published studies. CONCLUSIONS: The lack of impact of the implementation process for a chest pain CPW on thrombolytic delivery or time to electrocardiogram in these rural hospitals can be explained by a ceiling effect in outcome measures but was also compromised by the small sample. Results suggest that quality of AMI treatment in rural emergency departments (EDs) is high and does not contribute to the worse mortality rate reported for AMIs in rural areas. PMID- 22435766 TI - Potential of pharmacists to help reduce the burden of poorly managed cardiovascular risk. AB - INTRODUCTION: Rural areas require better use of existing health professionals to ensure capacity to deliver improved cardiovascular outcomes. Community pharmacists (CPs) are accessible to most communities and can potentially undertake expanded roles in prevention of cardiovascular disease (CVD). OBJECTIVE: This study aims to establish frequency of contact with general practitioners (GPs) and CPs by patients at high risk of CVD or with inadequately controlled CVD risk factors. DESIGN, SETTING AND PARTICIPANTS: Population survey using randomly selected individuals from the Wimmera region electoral roll and incorporating a physical health check and self-administered health questionnaire. Overall, 1500 were invited to participate. RESULTS: The participation rate was 51% when ineligible individuals were excluded. Nine out of 10 participants visited one or both types of practitioner in the previous 12 months. Substantially more participants visited GPs compared with CPs (88.5% versus 66.8%). With the exception of excess alcohol intake, the median number of opportunities to intervene for every inadequately controlled CVD risk factor and among high risk patient groups at least doubled for the professions combined when compared with GP visits alone. CONCLUSION: Opportunities exist to intervene more frequently with target groups by engaging CPs more effectively but would require a significant attitude shift towards CPs. Mechanisms for greater pharmacist integration into primary care teams should be investigated. PMID- 22435767 TI - Is personality the missing link in understanding recruitment and retention of rural general practitioners? AB - CONTEXT: Little is known about the role of personality and related constructs in general practitioners' (GPs) choices of geographic location of medical practice. There is however some theory suggesting a role for personality in career decision making and some limited empirical evidence that this applies in medical career decisions. PURPOSE: The aim of this study is to gain insight into whether personality plays a role in GPs' decisions to work in rural areas and the length of time that they intend to remain as a rural practitioner. METHOD: Samples of rural (n=372) and urban (n=100) GPs from New South Wales (Australia) completed the Neuroticism, Extraversion, Openness--Five Factor Inventory (NEO-FFI) and Adjective Checklist personality instruments and answered questions about demographics and rural upbringing. FINDINGS: Rural GPs scored, on average, more highly than urban GPs with respect to conscientiousness and agreeableness but lower on openness, which can also be taken to mean a more 'down-to-earth' personality. Personality together with age, gender, experience as a GP, time in current location and rural childhood yield an area under the receiver operating characteristic curve of 0.81 in discriminating rural from urban GPs. Among rural GPs openness (P=0.007) was positively correlated with intended longevity as a rural doctor as was nurturing (P=0.06). CONCLUSIONS: Personality appears to play some role both in discriminating rural from urban GPs and in how long existing rural GPs intend to remain as rural GPs. Consideration of personality might assist in selection of individuals who will better fit the professional and social environment of rural life. PMID- 22435768 TI - Nature or nurture: the effect of undergraduate rural clinical rotations on pre existent rural career choice likelihood as measured by the SOMERS Index. AB - OBJECTIVE: Do undergraduate rural clinical rotations increase the likelihood of medical students to choose a rural career once pre-existent likelihood is accounted for? DESIGN: A prospective, controlled quasi-experiment using self paired scores on the SOMERS Index of rural career choice likelihood, before and after 3 years of clinical rotations in either mainly rural or mainly urban locations. SETTING: Monash University medical school, Australia. PARTICIPANTS: Fifty-eight undergraduate-entry medical students (35% of the 2002 entry class). MAIN OUTCOME MEASURES: The SOMERS Index of rural career choice likelihood and its component indicators. RESULTS: There was an overall decline in SOMERS Index score (22%) and in each of its components (12-41%). Graduating students who attended rural rotations were more likely to choose a rural career on graduation (difference in SOMERS score: 24.1 (95% CI, 15.0-33.3) P<0.0001); however, at entry, students choosing rural rotations had an even greater SOMERS score (difference: 27.1 (95% CI, 18.2-36.1) P<0.0001). Self-paired pre-post reductions in likelihood were not affected by attending mainly rural or urban rotations, nor were there differences based on rural background alone or sex. CONCLUSIONS: While rural rotations are an important component of undergraduate medical training, it is the nature of the students choosing to study in rural locations rather than experiences during the course that is the greater influence on rural career choice. In order to improve the rural medical workforce crisis, medical schools should attract more students with pre-existent likelihood to choose a rural career. The SOMERS Index was found to be a useful tool for this quantitative analysis. PMID- 22435769 TI - Treatment via videoconferencing: a pilot study of delivery by clinical psychology trainees. AB - OBJECTIVE: This pilot study explored the outcomes of clinical psychology trainees delivering treatments via videoconferencing. DESIGN: A noncurrent, multiple baseline across subjects and settings. SETTING: University outpatient psychology clinic. PARTICIPANTS: Six clients (two men and four women) with an anxiety or depressive disorder were randomly assigned to received six sessions of individual therapy (either via videoconferencing or face to face) from a male or female clinical psychology trainee. MAIN OUTCOME MEASURES: Participants provided daily ratings (0-10) of subjective distress/well-being via text messaging, and at pre-, post-, and 1 month follow-up of treatment, completed the Depression Anxiety Stress Scales and the Outcome Questionnaire-45. Along with the trainees, participants also provided feedback on the therapy experience. RESULTS: The subjective well-being of all participants improved, and all videoconferencing participants showed a statistically and clinically significant reduction in symptomology and gains in general life functioning. Feedback comments were positive. CONCLUSIONS: This study suggests that there is value in clinical psychology trainees gaining experience in the delivery of treatments via videoconferencing. Further study is needed to demonstrate the potential for university clinics to deliver mental health services, via this modality, to rural and remote areas. PMID- 22435770 TI - Behavioural activation for the treatment of rural adolescents with depression. PMID- 22435771 TI - Dislocated crystalline lens in an Aboriginal patient. PMID- 22435773 TI - Electron transfer dynamics of iridium oxide nanoparticles attached to electrodes by self-assembled monolayers. AB - Self-assembled monolayers (SAMs) of carboxylated alkanethiolates (-S(CH(2))(n 1)CO(2)(-)) on flat gold electrode surfaces are used to tether small (ca. 2 nm d.) iridium(IV) oxide nanoparticles (Ir(IV)O(X) NPs) to the electrode. Peak potential separations in cyclic voltammetry (CV) of the nanoparticle Ir(IV/III) wave, in pH 13 aqueous base, increase with n, showing that the Ir(IV/III) apparent electron transfer kinetics of metal oxide sites in the nanoparticles respond to the imposed SAM electron transfer tunneling barrier. Estimated apparent electron transfer rate constants (k(app)(0)) for n = 12 and 16 are 9.8 and 0.12 s(-1). Owing to uncompensated solution resistance, k(app)(0) for n = 8 was too large to measure in the potential sweep experiment. For the cathodic scans, coulometric charges under the Ir(IV/III) voltammetric waves were independent of potential scan rate, suggesting participation of all of the iridium oxide redox sites (ca. 130 per NP) in the NPs. These experiments show that it is possible to control and study electron transfer dynamics of electroactive nanoparticles including, as shown by preliminary experiments, that of the electrocatalysis of water oxidation by iridium oxide nanoparticles. PMID- 22435774 TI - Improving the application of vertebrate trait-based frameworks to the study of ecosystem services. AB - 1. Examining the consequences of environmental change for the provision of ecosystem services can be facilitated through trait-based frameworks that consider linkages between traits that influence a species' response to change and traits that determine its effect on ecosystem services. 2. Developing these frameworks requires a systematic approach to trait selection and addressing the interrelationships among the scale of the environmental change, area of ecosystem service provision and the most appropriate traits for analysis. 3. We examine key issues in the application of trait approaches to vertebrates, drawing specifically on the substantial progress made in this area for plants. We argue that vertebrate ecologists need to develop more coherent and systematic trait based approaches that are broadly applicable. 4. We present a new framework for selecting response and effect traits to link environmental change with ecosystem services. An empirical example of each step in the framework is provided using birds as a case study, linking the environmental change of loss of tree cover with the ecosystem service of invertebrate pest regulation in apple orchards. We found that as tree cover around orchards increased so did the abundance and foraging rate of bird species that pursue invertebrates in flight, and this may help reduce the abundance of certain pests of apples (e.g. adult stages of Cydia pomonella and Helicoverpa armigera). 5. Implementing a systematic and transparent approach to trait selection should further refine the development of trait-based approaches for vertebrates. PMID- 22435775 TI - Xylem- and phloem-based transport of CuO nanoparticles in maize (Zea mays L.). AB - This work reports on the toxicity of CuO nanoparticles (NPs) to maize (Zea mays L.) and their transport and redistribution in the plant. CuO NPs (100 mg L(-1)) had no effect on germination, but inhibited the growth of maize seedlings; in comparison the dissolved Cu(2+) ions and CuO bulk particles had no obvious effect on maize growth. CuO NPs were present in xylem sap as examined by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS), showing that CuO NPs were transported from roots to shoots via xylem. Split-root experiments and high-resolution TEM observation further showed that CuO NPs could translocate from shoots back to roots via phloem. During this translocation, CuO NPs could be reduced from Cu (II) to Cu (I). To our knowledge, this is the first report of root-shoot-root redistribution of CuO NPs within maize. The current study provides direct evidence for the bioaccumulation and biotransformation of CuO NPs (20-40 nm) in maize, which has significant implications on the potential risk of NPs and food safety. PMID- 22435776 TI - Longitudinal in vivo imaging to assess blood flow and oxygenation in implantable engineered tissues. AB - The functionality of vascular networks within implanted prevascularized tissues is difficult to assess using traditional analysis techniques, such as histology. This is largely due to the inability to visualize hemodynamics in vivo longitudinally. Therefore, we have developed dynamic imaging methods to measure blood flow and hemoglobin oxygen saturation in implanted prevascularized tissues noninvasively and longitudinally. Using laser speckle imaging, multispectral imaging, and intravital microscopy, we demonstrate that fibrin-based tissue implants anastomose with the host (severe combined immunodeficient mice) in as short as 20 h. Anastomosis results in initial perfusion with highly oxygenated blood, and an increase in average hemoglobin oxygenation of 53%. However, shear rates in the preformed vessels were low (20.8+/-12.8 s(-1)), and flow did not persist in the vast majority of preformed vessels due to thrombus formation. These findings suggest that designing an appropriate vascular network structure in prevascularized tissues to maintain shear rates above the threshold for thrombosis may be necessary to maintain flow following implantation. We conclude that wide-field and microscopic functional imaging can dynamically assess blood flow and oxygenation in vivo in prevascularized tissues, and can be used to rapidly evaluate and improve prevascularization strategies. PMID- 22435778 TI - Pharmacokinetics of paroxetine, a selective serotonin reuptake inhibitor, in Grey parrots (Psittacus erithacus erithacus): influence of pharmaceutical formulation and length of dosing. AB - Paroxetine, a selective serotonin reuptake inhibitor, may be beneficial in the treatment of behavioural disorders in pet birds. The lack of pharmacokinetic data and clinical trials currently limits the use of this drug in clinical avian practice. This paper evaluates the pharmacokinetic properties and potential side effects of single and repeated dosing of paroxetine in Grey parrots (Psittacus erithacus erithacus). Paroxetine pharmacokinetics were studied after single i.v. and single oral dosing, and after repeated oral administration during 1 month. Plasma paroxetine concentrations were determined by liquid chromatography-tandem mass spectrometry. No undesirable side effects were observed during the study. Pharmacokinetic analysis revealed a quick distribution and rapid elimination after i.v. administration. Oral administration of paroxetine HCl dissolved in water resulted in a relatively slow absorption (T(max)=5.9+/-2.6 h) and a low bioavailability (31+/-15%). Repeated administration resulted in higher rate of absorption, most likely due to a saturation of the cytochrome P450-mediated first pass metabolism. This study shows that oral administration of paroxetine HCl (4 mg/kg twice daily) in parrots results in plasma concentrations within the therapeutic range recommended for the treatment of depressions in humans. Further studies are needed to demonstrate the clinical efficacy of this dosage regimen in parrots with behavioural disorders. PMID- 22435779 TI - High-intensity exercise attenuates postprandial lipaemia and markers of oxidative stress. AB - Regular exercise can reduce the risk of CVD (cardiovascular disease). Although moderate-intensity exercise can attenuate postprandial TAG (triacylglycerol), high-intensity intermittent exercise might be a more effective method to improve health. We compared the effects of high-intensity intermittent exercise and 30 min of brisk walking on postprandial TAG, soluble adhesion molecules and markers of oxidative stress. Nine men each completed three 2-day trials. On day 1, subjects rested (control), walked briskly for 30 min (walking) or performed 5*30 s maximal sprints (high-intensity). On day 2, subjects consumed a high-fat meal for breakfast and 3 h later for lunch. Blood samples were taken at various times and analysed for TAG, glucose, insulin, ICAM-1 (intracellular adhesion molecule 1), VCAM-1 (vascular adhesion molecule-1), TBARS (thiobarbituric acid- reactive substances), protein carbonyls and beta-hydroxybutyrate. On day 2 of the high intensity trial, there was a lower (P<0.05) incremental TAG AUC (area under the curve; 6.42+/-2.24 mmol/l per 7 h) compared with the control trial (9.68+/-4.77 mmol/l per 7 h) with no differences during day 2 of the walking trial (8.98+/ 2.84 mmol/l per 7 h). A trend (P=0.056) for a reduced total TAG AUC was also seen during the high-intensity trial (14.13+/-2.83 mmol/l per 7 h) compared with control (17.18+/-3.92 mmol/l per 7 h), walking showed no difference (16.33+/-3.51 mmol/l per 7 h). On day 2 of the high-intensity trial plasma TBARS and protein carbonyls were also reduced (P<0.05) when compared with the control and walking trials. In conclusion, high-intensity intermittent exercise attenuates postprandial TAG and markers of oxidative stress after the consumption of a high fat meal. PMID- 22435780 TI - Meat intake frequency and anemia in Japanese children and adolescents. AB - The consumption of meat products is considered to be a feasible solution to prevent anemia, which is a critical health problem. The present study assessed hematological parameters and the prevalence of anemia in Japanese children and adolescents, and examined the association with the frequency of meat intake. Data from the Shunan Children Health Cohort Study were analyzed. The participants included male and female residents, 3373 children (aged 10-11 years), and 3085 adolescents (aged 13-14 years). The frequency of meat intake was determined with a questionnaire, and blood samples were analyzed. Anemia was defined according to the criteria of the World Health Organization. The prevalence of anemia in children was 3.6% and 2.5% in girls and boys, respectively, and in adolescents, it was 4.5% in girls and 0.8% in boys. The frequency of meat intake did not show a positive association with the hematological indices or the prevalence of anemia. These results suggest that the promotion of meat consumption is not an effective strategy to decrease anemia, and that other approaches are necessary to prevent anemia in this population. PMID- 22435781 TI - Incidence and costs of severe hypoglycaemia requiring attendance by the emergency medical services in South Central England. AB - AIMS: The aim was to estimate the incidence of severe hypoglycaemia requiring emergency ambulance assistance, its management and associated costs. METHODS: A retrospective observational study used routinely collected data for a 1-year period from December 2009 to November 2010 from the South Central Ambulance Service National Health Service Trust, UK. The main outcome was episodes reported by ambulance personnel and costs were estimated from published data. RESULTS: During the 1-year study period, 398,409 emergency calls were received, of which 4081 (1.02%) were coded as hypoglycaemia. The overall numbers (and annual rate) of hypoglycaemia recorded among people >= 15 years with presumed diabetes was 3962 (2.1%), but for those aged 15-35 years was 516 (7.5%) and for those aged >= 65 years was 1886 (1.9%). Of those attended, 1441 (35.3%) were taken to hospital. The estimated total cost of initial ambulance attendance and treatment at scene was L553,000; if transport to hospital was necessary, the additional ambulance costs were L223,000 plus emergency department costs of L140,000; and the cost of primary care follow-up was estimated as L61,000. The average cost per emergency call was L263. The estimated annual cost of emergency calls for severe hypoglycaemia is L13.6m for England. CONCLUSIONS: Our estimates suggest prevalence of severe hypoglycaemia attended by the emergency services is high in younger age groups and lower for older age groups, although the absolute numbers of severe events in older age groups contribute substantially to the overall costs of providing emergency assistance for hypoglycaemia. PMID- 22435782 TI - Enhancement of fluoride activity against Streptococcus mutans biofilms by a substance separated from Polygonum cuspidatum. AB - Polygonum cuspidatum is a plant with spreading rhizomes and numerous reddish brown stems that has been used in Korean folk medicine to improve oral hygiene. Nevertheless, there are no reports related to its possible effect on the virulence of dental biofilms. In this study, the ability of a fraction (F1) separated from P. cuspidatum, alone or in combination with fluoride, to disrupt virulence factors and the composition of Streptococcus mutans biofilms was examined. F1 was mainly composed of resveratrol, emodin and physcion (approximately 16.2%, 18.9% and 2.07% of the weight of F1, respectively). F1 showed inhibitory effects on acid production and F-ATPase activity of S. mutans in biofilms, and could enhance fluoride activity against acid production and acid tolerance of S. mutans in biofilms. When S. mutans biofilms were briefly treated with F1 (10 min, a total of five times), the biomass accumulation, water insoluble polysaccharides and intracellular iodophilic polysaccharides were reduced. Furthermore, the fluoride activity against biomass accumulation was enhanced by F1. These results suggest that F1 may be useful in the control of dental biofilms and in improving the cariostatic properties of fluoride without increasing its exposure. PMID- 22435783 TI - Back-scattered electron imaging combined with EBSD technique for characterization of pearlitic steels. AB - Microstructure of pearlitic steels subjected different heat treatments were characterized combining the usage of back-scattered electron imaging and electron backscatter diffraction in a scanning electron microscope. The results indicated that the method used in current study enabled the acquisition of pearlite nodule, colony and interlamellar spacing of pearlite structure only through sample preparation of one time. Both the morphology of pearlite lamellae and the crystallographic orientation of ferrite matrix can be released in back-scattered electron imaging image and electron backscatter diffraction micrograph acquired at the same region. The definitions of pearlite colony and the low-angle boundaries existed in ferrite matrix were also discussed based on this method. PMID- 22435784 TI - The use of heparin for preventing miscarriage. AB - Recommendations for the use of heparin for preventing miscarriage are recently rapidly changing based on evidenced based prospective studies. At present either heparin or low molecular weight heparin (LMWH) is recommended for the antiphospholipid syndrome (APS). However criteria for diagnosing APS have become much stricter. The exact timing of the heparin is still being evaluated since it is not clear if the main therapeutic effect is in inhibition of thrombosis when the heparin could be started at the time in the first trimester when the platelets become thrombophilic or does its main role in improving implantation in which it would be started shortly before or shortly after ovulation. Possibly heparin is superior to LMWH in improving the implantation process though more studies are needed to corroborate or refute this suggestion. At present inherited thrombophilias are not considered a cause of first trimester miscarriage and thus measuring these factors are not recommended. There is no evidence that heparin has any benefit in preventing miscarriage from unexplained causes. Heparin is effective alone and there does not appear to be any extra benefit from adding aspirin (or even aspirin may negate some of its benefits). PMID- 22435785 TI - TSI assay utilization: impact on costs of Graves' hyperthyroidism diagnosis. AB - OBJECTIVES: Thyroid-stimulating immunoglobulins (TSIs) are autoantibodies that bind to the thyroid-stimulating hormone (TSH) receptor on thyroid cells, resulting in Graves' disease (GD), the most common cause of hyperthyroidism. Recently published guidelines recognize the value of anti-TSH receptor antibodies, and a TSI test with high sensitivity and specificity for GD, recently cleared by the US Food and Drug Administration, is now available. Despite this, existing diagnostic algorithms for hyperthyroidism do not currently include TSI testing except in specific cases like pregnancy. The objectives of this analysis are to understand whether incorporating a test that specifically detects TSIs into existing algorithms results in cost savings and reduces time to diagnosis for payers and managed care organizations. STUDY DESIGN: An evidence-based economic model was developed to determine the average time to diagnosis and annual costs associated with various diagnostic algorithms for GD in a population of 100,000 managed care enrollees. Diagnostic algorithms used in current practice and hypothetical algorithms that include the TSI test were identified using published clinical guidelines and interviews with practicing endocrinologists. The model estimates costs of current and TSI test-based diagnostic algorithms using payment amounts for laboratory tests, procedures, and physician visits. RESULTS: Compared with non-TSI algorithms, 100% use of algorithms that include the TSI test result in 46% faster time to diagnosis and generate 47% overall cost savings due in large part to reductions in costly procedures and specialist office visits. CONCLUSIONS: Incorporation and early utilization of the TSI in vitro diagnostic test into current diagnostic algorithms confers cost savings and shortens time to diagnosis. PMID- 22435786 TI - Impact of cost-sharing on treatment augmentation in patients with depression. AB - OBJECTIVES: Many patients with depression do not respond to first-line antidepressant therapy and may require augmentation with another concurrent treatment such as a second antidepressant, a stimulant, a mood stabilizer, or a second-generation antipsychotic (SGA). The objective of this study was to examine the relationship between patient cost-sharing and the use of augmentation among a sample of commercially insured patients. STUDY DESIGN: Retrospective observational study of adult patients diagnosed with depression and receiving antidepressant therapy (n = 48,807). METHODS: Logistic regression models estimated the likelihood of augmentation as a function of patient cost-sharing amounts. An alternative-specific conditional logit model of the likelihood of each augmentation class, varying the cost-sharing prices faced for each class, was also estimated. All models controlled for sociodemographic characteristics, physical and mental comorbidities, health plan type, and year of index antidepressant therapy initiation. RESULTS: The range of mean copayments paid by patients for augmentation therapy was from $27.05 (antidepressant) to $38.81 (SGA). A $10- higher cost-sharing index for all augmentation classes was associated with lower odds of augmentation (adjusted odds ratio = 0.85; 95% confidence interval 0.79-0.91). Doubling the costsharing amount for each augmentation class was associated with a smaller percentage of patients utilizing each class of augmentation therapy. CONCLUSIONS: Employers and payers should consider the relationship between cost-sharing and medication utilization patterns of patients with depression. PMID- 22435787 TI - The impact of hospitalists on length of stay and costs: systematic review and meta-analysis. AB - BACKGROUND: Hospital medicine has undergone remarkable growth since its creation. Most (but not all) of the published literature demonstrates better outcomes for patients cared for by hospitalists. PURPOSE: We performed a systematic review and meta-analysis to estimate the magnitude of the impact of hospitalists on length of stay (LOS) and cost. DATA SOURCES: Medline/PubMed. STUDY SELECTION: Articles published through February 2011 comparing outcomes (LOS and/or cost) of hospitalists with others. DATA EXTRACTION: Two reviewers independently searched for abstracted information. We also contacted individual authors to provide us with missing data. DATA SYNTHESIS: We used a random-effects model. RESULTS: A total of 502 abstracts were initially identified and 17 studies of 137,561 patients were included in the final analysis. LOS was significantly shorter in the hospitalist group compared with the non-hospitalist group, with a mean difference of -0.44 days (95% confidence interval [CI] -0.68 to -0.20, P < .001). In studies that compared a (non-resident) hospitalist service with a (non resident) non-hospitalist service, LOS was also significantly shorter in the hospitalist group (mean difference -0.69 days [95% CI -0.93 to -0.46, P < .001]). Cost was not found to be significantly different (11 studies). There was significant heterogeneity between studies and we found no evidence of publication bias. CONCLUSIONS: Despite its limitations, our analysis supports the conclusion that hospitalists significantly reduce LOS without increasing costs. These findings can be used to define and measure expectations of performance for hospital medicine groups. PMID- 22435788 TI - Implementation of paperless credentialing in a multi-state managed care organization. AB - OBJECTIVES: To evaluate the impact of paperless provider credentialing in a multi state managed care organization. STUDY DESIGN: Implementation took place from June to October of 2009. A total of 6220 providers were credentialed during this study period and selected for analysis. We used an interrupted time-series design, centered the data on implementation, and then compared efficiency rates for the 14 weeks before implementation of paperless credentialing to efficiency rates for the 14 weeks after implementation. LIMITATIONS: The absence of a control group and a relatively short observation period are potential threats to validity. METHODS: The main unit of analysis was the provider credentialing file. We compared quality review pass rates, processing time (in days), and processing cost per file before and after paperless credentialing implementation. RESULTS: The percentage of files passing quality review increased from 83% to 92%. The turnaround time for the credentialing process dropped from 53 calendar days to 36 calendar days. CONCLUSIONS: Implementation of electronic credentialing appears to significantly improve processing efficiency. Indeed, credentialing seems to be a particularly promising area for adoption of electronic records in an administrative setting. PMID- 22435789 TI - Financial incentives and use of Cesarean delivery: Taiwan birth data 2003 to 2007. AB - OBJECTIVES: The Cesarean section (CS) rate in Taiwan has exceeded 30% since 2000. To lower the CS rate, the Bureau of National Health Insurance in Taiwan raised the payment for vaginal delivery (VD) in May 2005, and also increased the insured's copayment for elective CS in May 2006. This study clarifies the influences of these financial incentives, and explores whether the 2 policies lowered the CS rate. STUDY DESIGN: The materials used are birth cases obtained from a systematic sampling of the original inpatient claim data in the National Health Insurance research database between 2003 and 2007. The empirical analysis of this study groups the birth data into 4 types: VD, unplanned CS, planned CS, and elective CS. METHODS: The 4 delivery types represent the dependent variable. A multinomial logistic regression model was adopted as the empirical method. The policy changes, hospital attributes, and insured status were considered independent variables. RESULTS: Results indicate that the supply-side policy change in May 2005 reduced the number of CS cases. However, the policy effect was not very significant, and the CS rate decreased mainly because of planned CS cases. The demand-side policy change in May 2006 did not lower the rate of elective CS. CONCLUSIONS: The results imply that the financial incentives were not the main consideration for both the demand and supply sides. To encourage more VDs and lower the CS rate, the authorities could consider mechanisms other than adjusting the payment or changing the copayment. PMID- 22435791 TI - Effects of fuel additives on the thermal cracking of n-decane from reactive molecular dynamics. AB - Thermal cracking of n-decane and n-decane in the presence of several fuel additives are studied in order to improve the rate of thermal cracking by using reactive molecular dynamics (MD) simulations employing the ReaxFF reactive force field. From MD simulations, we find the initiation mechanisms of pyrolysis of n decane are mainly through two pathways: (1) the cleavage of a C-C bond to form smaller hydrocarbon radicals, and (2) the dehydrogenation reaction to form an H radical and the corresponding decyl radical. Another pathway is the H-abstraction reactions by small radicals including H, CH(3), and C(2)H(5). The basic reaction mechanisms are in good agreement with existing chemical kinetic models of thermal decomposition of n-decane. Quantum mechanical calculations of reaction enthalpies demonstrate that the H-abstraction channel is easier compared with the direct C-C or C-H bond-breaking in n-decane. The thermal cracking of n-decane with several additives is further investigated. ReaxFF MD simulations lead to reasonable Arrhenius parameters compared with experimental results based on first-order kinetic analysis. The different chemical structures of the fuel additives greatly affect the apparent activation energy and pre-exponential factors. The presence of diethyl ether (DEE), methyl tert-butyl ether (MTBE), 1-nitropropane (NP), 3,6,9-triethyl-3,6,9-trimethyl-1,2,4,5,7,8-hexaoxonane (TEMPO), triethylamine (TEA), and diacetonediperodixe (DADP) exhibit remarkable promoting effect on the thermal cracking rates, compared with that of pure n-decane, in the following order: NP > TEMPO > DADP > DEE (~MTBE) > TEA, which coincides with experimental results. These results demonstrate that reactive MD simulations can be used to screen for fuel additives and provide useful information for more comprehensive chemical kinetic model studies at the molecular level. PMID- 22435790 TI - Diversity in prokaryotic glycosylation: an archaeal-derived N-linked glycan contains legionaminic acid. AB - VP4, the major structural protein of the haloarchaeal pleomorphic virus, HRPV-1, is glycosylated. To define the glycan structure attached to this protein, oligosaccharides released by beta-elimination were analysed by mass spectrometry and nuclear magnetic resonance spectroscopy. Such analyses showed that the major VP4-derived glycan is a pentasaccharide comprising glucose, glucuronic acid, mannose, sulphated glucuronic acid and a terminal 5-N-formyl-legionaminic acid residue. This is the first observation of legionaminic acid, a sialic acid-like sugar, in an archaeal-derived glycan structure. The importance of this residue for viral infection was demonstrated upon incubation with N-acetylneuraminic acid, a similar monosaccharide. Such treatment reduced progeny virus production by half 4 h post infection. LC-ESI/MS analysis confirmed the presence of pentasaccharide precursors on two different VP4-derived peptides bearing the N glycosylation signal, NTT. The same sites modified by the native host, Halorubrum sp. strain PV6, were also recognized by the Haloferax volcanii N-glycosylation apparatus, as determined by LC-ESI/MS of heterologously expressed VP4. Here, however, the N-linked pentasaccharide was the same as shown to decorate the S layer glycoprotein in this species. Hence, N-glycosylation of the haloarchaeal viral protein, VP4, is host-specific. These results thus present additional examples of archaeal N-glycosylation diversity and show the ability of Archaea to modify heterologously expressed proteins. PMID- 22435792 TI - The 2002-2007 trends of prevalence of asthma, allergic rhinitis and eczema in Irish schoolchildren. AB - BACKGROUND: Irish adolescents have the third highest asthma prevalence in the world. Few data examine trends of prevalence of asthma and allergic disorders in younger Irish children. We compared the prevalence of asthma, allergic rhinitis and eczema in school children, aged 6-9 in 2002 and 2007. METHODS: In two cross sectional studies, parents of children aged 6-9, completed identical ISAAC-based questionnaires in the same 24 Cork City schools in 2002 (n = 1474, response rate = 74.8%) and in 2007 (n = 1535, response rate = 76.2%). RESULTS: The prevalence of asthma in our study population of schoolchildren, aged 6-9 remained stable in 2007 (23.5%) since the 2002 finding of 21.7% (p = 0.27). Significant increases were found in the prevalence of rhino-conjunctivitis (7.6-10.6%, p = 0.005) and eczema (8.9-13.5%, p < 0.001). In 2007, male preponderance for suffering the symptoms of current asthma existed (M:F 1.2:1, p = 0.075), although it had lost its significance since 2002 (M:F 1.5:1, p < 0.001). M:F ratio for most allergic rhinitis related symptoms moved from equal sex distribution to male predominance (nasal problems ever: 2002 - M:F, 1.1:1, p = 0.117; 2007 - M:F, 1.2:1, p = 0.012, current rhinitis: 2002 - M:F 1.2:1, p = 0.98; 2007 M:F 1.3:1, p = 0.009, hay fever ever: 2002 - M:F 1:1, p = 0.57; 2007 - M:F 1.5:1, p = 0.007). The sex specific prevalence of rhino-conjunctivitis and the severity of symptoms suffered, remained equally sex distributed in both timeframes. From 2002 to 2007, the prevalence of all the reported symptoms of eczema were equally distributed between the sexes, while lifetime prevalence of eczema moved from male predominance to equal distribution. CONCLUSION: The prevalence of asthma in 6-9 yr old Cork schoolchildren remained static between 2002 and 2007; however, rhino conjunctivitis and eczema have become increasingly prevalent. Co-morbidity of allergic conditions continues to pose a considerable health burden in this young population. We also demonstrated an alteration in the sex-specific profile of current asthma and lifetime allergic rhinitis towards equalization in distribution. PMID- 22435793 TI - Intracranial pressure monitoring in severe traumatic brain injury in latin america: process and methods for a multi-center randomized controlled trial. AB - In patients with severe traumatic brain injury (TBI), the influence on important outcomes of the use of information from intracranial pressure (ICP) monitoring to direct treatment has never been tested in a randomized controlled trial (RCT). We are conducting an RCT in six trauma centers in Latin America to test this question. We hypothesize that patients randomized to ICP monitoring will have lower mortality and better outcomes at 6-months post-trauma than patients treated without ICP monitoring. We selected three centers in Bolivia to participate in the trial, based on (1) the absence of ICP monitoring, (2) adequate patient accession and data collection during the pilot phase, (3) preliminary institutional review board approval, and (4) the presence of equipoise about the value of ICP monitoring. We conducted extensive training of site personnel, and initiated the trial on September 1, 2008. Subsequently, we included three additional centers. A total of 176 patients were entered into the trial as of August 31, 2010. Current enrollment is 81% of that expected. The trial is expected to reach its enrollment goal of 324 patients by September of 2011. We are conducting a high-quality RCT to answer a question that is important globally. In addition, we are establishing the capacity to conduct strong research in Latin America, where TBI is a serious epidemic. Finally, we are demonstrating the feasibility and utility of international collaborations that share resources and unique patient populations to conduct strong research about global public health concerns. PMID- 22435794 TI - Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients. AB - BACKGROUND: The role of serotonin transporter (SERT) gene polymorphism in irritable bowel syndrome (IBS) has been demonstrated. However, the expression of SERT mRNA and proteins in the colonic mucosa with different 5-HTT gene-linked polymorphic region (5-HTTLPR) genotypes remains unknown. We examined SERT mRNA and protein levels in colon biopsies from patients with different 5-HTTLPR genotypes and evaluated the links between the polymorphism and the expression levels. METHODS: Two hundred and fifty-four patients with IBS and 120 healthy subjects were studied. DNA samples were extracted from peripheral blood and genotyped by polymerase chain reaction (PCR). SERT mRNA and protein levels were evaluated by quantitative real time PCR and western blotting. The promoter efficiency of the serotonin transporter promoter (SERT-P) was evaluated with luciferase reporter system. KEY RESULTS: The frequency of the L/L genotype in C IBS group was significantly higher than that in the control and D-IBS. However, the S/S genotype in D-IBS was significantly higher than that in C-IBS. The transcriptional efficiency of the L/L genotype was significantly higher than that in the L/S and S/S genotype. Patients with the L/L genotype demonstrated increased production of the SERT protein when compared with L/S and S/S patients. The l variant increased SERT promoter activity by 2.43-fold when compared with the s variant. CONCLUSIONS & INFERENCES: Polymorphism in the promoter region of the SERT gene can influence the expression of SERT mRNA and the levels of the SERT protein in the colonic mucosa, thereby playing a key role in motility related symptoms of IBS patients. PMID- 22435795 TI - Emission and atmospheric transport of particulate PAHs in Northeast Asia. AB - The emission, concentration levels, and transboundary transport of particulate polycyclic aromatic hydrocarbons (PAHs) in Northeast Asia were investigated using particulate PAH measurements, the newly developed emission inventory (Regional Emission inventory in ASia for Persistent Organic Pollutants version, REAS-POP), and the chemical transport model (Regional Air Quality Model ver2 for POPs version, RAQM2-POP). The simulated concentrations of the nine particulate PAHs agreed well with the measured concentrations, and the results firmly established the efficacy of REAS/RAQM2-POP. It was found that the PAH concentrations in Beijing (China, source region), which were emitted predominantly from domestic coal, domestic biofuel, and other transformations of coal (including coke production), were approximately 2 orders of magnitude greater than those monitored at Noto (Japan, leeward region). In Noto, the PAH concentrations showed seasonal variations; the PAH concentrations were high from winter to spring due to contributions from domestic coal, domestic biofuel, and other transformations of coal, and low in summer. In summer, these contribution were decrease, instead, other sources, such as the on-road mobile source, were relatively increased compared with those in winter. These seasonal variations were due to seasonal variations in emissions from China, as well as transboundary transport across the Asian continent associated with meteorological conditions. PMID- 22435796 TI - Molecular diversity, population structure, and linkage disequilibrium in a worldwide collection of tobacco (Nicotiana tabacum L.) germplasm. AB - BACKGROUND: The goals of our study were to assess the phylogeny and the population structure of tobacco accessions representing a wide range of genetic diversity; identify a subset of accessions as a core collection capturing most of the existing genetic diversity; and estimate, in the tobacco core collection, the extent of linkage disequilibrium (LD) in seven genomic regions using simple sequence repeat (SSR) markers. To this end, a collection of accessions were genotyped with SSR markers. Molecular diversity was evaluated and LD was analyzed across seven regions of the genome. RESULTS: A genotyping database for 312 tobacco accessions was profiled with 49 SSR markers. Principal Coordinate Analysis (PCoA) and Bayesian cluster analysis revealed structuring of the tobacco population with regard to commercial classes and six main clades were identified, which correspond to "Oriental", Flue-Cured", "Burley", "Dark", "Primitive", and "Other" classes. Pairwise kinship was calculated between accessions, and an overall low level of co-ancestry was observed. A set of 89 genotypes was identified that captured the whole genetic diversity detected at the 49 loci. LD was evaluated on these genotypes, using 422 SSR markers mapping on seven linkage groups. LD was estimated as squared correlation of allele frequencies (r2). The pattern of intrachromosomal LD revealed that in tobacco LD extended up to distances as great as 75 cM with r2 > 0.05 or up to 1 cM with r2 > 0.2. The pattern of LD was clearly dependent on the population structure. CONCLUSIONS: A global population of tobacco is highly structured. Clustering highlights the accessions with the same market class. LD in tobacco extends up to 75 cM and is strongly dependent on the population structure. PMID- 22435797 TI - Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo controlled trial. PMID- 22435798 TI - Clinical assessment of the accuracy of blood glucose measurement devices. AB - OBJECTIVES: Blood glucose meters for patient self-measurement need to comply with the accuracy standards of the ISO 15197 guideline. We investigated the accuracy of the two new blood glucose meters BG*Star and iBG*Star (Sanofi-Aventis) in comparison to four other competitive devices (Accu-Chek Aviva, Roche Diagnostics; FreeStyle Freedom Lite, Abbott Medisense; Contour, Bayer; OneTouch Ultra 2, Lifescan) at different blood glucose ranges in a clinical setting with healthy subjects and patients with type 1 and type 2 diabetes. BGStar and iBGStar are employ dynamic electrochemistry, which is supposed to result in highly accurate results. METHODS: The study was performed on 106 participants (53 female, 53 male, age (mean +/- SD): 46 +/- 16 years, type 1: 32 patients, type 2: 34 patients, and 40 healthy subjects). Two devices from each type and strips from two different production lots were used for glucose assessment (~200 readings/meter). Spontaneous glucose assessments and glucose or insulin interventions under medical supervision were applied to perform measurements in the different glucose ranges in accordance with the ISO 15197 requirements. Sample values <50 mg/dL and >400 mg/dL were prepared by laboratory manipulations. The YSI glucose analyzer (glucose oxidase method) served as the standard reference method which may be considered to be a limitation in light of glucose hexokinase-based meters. RESULTS: For all devices, there was a very close correlation between the glucose results compared to the YSI reference method results. The correlation coefficients were r = 0.995 for BGStar and r = 0.992 for iBGStar (Aviva: 0.995, Freedom Lite: 0.990, Contour: 0.993, Ultra 2: 0.990). Error-grid analysis according to Parkes and Clarke revealed both 100% of the readings to be within the clinically acceptable areas (Clarke: A + B with BG*Star (100 + 0), Aviva (97 + 3), and Contour (97 + 3); and 99.5% with iBG*Star (97.5 + 2), Freedom Lite (98 + 1.5), and Ultra 2 (97.5 + 2)). CONCLUSIONS: This study demonstrated the very high accuracy of BG*Star, iBG*Star, and the competitive blood glucose meters in a clinical setting. PMID- 22435799 TI - Editor's Choice. Caring in nursing. PMID- 22435800 TI - Effects on 3-mercaptohexan-1-ol precursor concentrations from prolonged storage of Sauvignon blanc grapes prior to crushing and pressing. AB - Formation of wine thiol precursors is a dynamic process, which can be influenced by vineyard and winery processing operations. With the aim of increasing thiol precursor concentrations, a study of the effects of storing machine-harvested Sauvignon blanc grapes prior to crushing and pressing was undertaken on a commercial scale. 3-Mercaptohexan-1-ol (3-MH) precursors, 2-S glutathionylcaftaric acid (grape reaction product, GRP), glutathione (GSH) and a number of C6 compounds were assessed at several time points during the experiment. The concentration of the cysteine precursor to 3-MH doubled within 8 h and tripled after 30 h while the GSH and cysteinylglycine precursors increased in concentration roughly 1.5 times. (E)-2-Hexenal and GSH levels decreased as thiol precursors, GRP and C6 alcohols increased during storage. Principal component analysis revealed that precursors contributed to most of the variation within the samples over the storage period, with additional influence, primarily from GSH and GRP, as well as (E)-2-hexenal and (Z)-3-hexen-1-ol. Early storage time points were associated with higher concentrations of GSH and some unsaturated C6 compounds while longer storage times were most closely associated with higher thiol precursor and GRP concentrations. This study provides a detailed overview of interactions related to thiol precursor formation on a commercial scale and highlights the ability to manipulate precursor concentrations prior to grape crushing. PMID- 22435801 TI - The significance of ICG-R15 in predicting hepatic toxicity in patients receiving radiotherapy for hepatocellular carcinoma. AB - AIM: To evaluate whether the retention rate of indocyanine green 15 min after administration (ICG-R15) could predict radiation hepatotoxicity in patients treated with radiotherapy (RT) for hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed data of 146 HCC patients treated with RT between February 1994 and December 2008. The ICG-R15 was measured within 1 month prior to the start of RT. Radiation hepatotoxicity was evaluated by incidence of radiation induced liver disease (RILD) between 2 weeks and 3 months after completion of RT. We analysed the correlation between the incidence rate of RILD and the ICG-R15 before RT (pre-RT ICG-R15). RESULTS: The classic and non-classic RILD occurred in 15 patients (10.3%): classic type in five patients (3.4%) and non-classic RILD in 10 patients (6.9%). A positive correlation was shown between the probability of RILD and increase in pre-RT ICG-R15 (P < 0.0001). Univariate analysis indicated that cut-off value of pre-RT ICG-R15 could predict RILD significantly. The incidence of RILD for the patients with 22% or higher pre-RT ICG-R15 levels was 40.7% as compared to 3.4% for those with levels lower than 22% (P < 0.0001). There was no clinical factor that significantly affected RILD in univariate analysis. Multivariate analysis indicated that the pre-RT ICG-R15 value was the only significant factor affecting RILD (P < 0.0001). CONCLUSION: These results suggest that pre-RT ICG-R15 could be a useful factor in predicting radiation hepatotoxicity in HCC patients treated with RT. PMID- 22435802 TI - Severe motor disability affects functional cortical integration in the context of brain-computer interface (BCI) use. AB - The purpose of this study was to investigate cortical interaction between brain regions in people with and without severe motor disability during brain-computer interface (BCI) operation through coherence analysis. Eighteen subjects, including six patients with cerebral palsy (CP) and three patients with amyotrophic lateral sclerosis (ALS), participated. The results showed (1) the existence of BCI performance difference caused by severe motor disability; (2) different coherence patterns between participants with and without severe motor disability during BCI operation and (3) effects of motor disability on cortical connections varying in the brain regions for the different frequency bands, indicating reduced cortical differentiation and specialisation. Participants with severe neuromuscular impairments, as compared with the able-bodied group, recruited more cortical regions to compensate for the difficulties caused by their motor disability, reflecting a less efficient operating strategy for the BCI task. This study demonstrated that coherence analysis can be applied to examine the ways cortical networks cooperate with each other during BCI tasks. PRACTITIONER SUMMARY: Few studies have investigated the electrophysiological underpinnings of differences in BCI performance. This study contributes by assessing neuronal synchrony among brain regions. Our findings revealed that severe motor disability causes more cortical areas to be recruited to perform the BCI task, indicating reduced cortical differentiation and specialisation. PMID- 22435803 TI - Chemical constituents and bioactivities of the plants of genus Flemingia Roxb. et Ait. (Leguminosae). AB - The genus Flemingia Roxb. et Ait. (Leguminosae) has been used for disease prevention and therapy in China since ancient times. So the material basis of the pharmacological activity in the genus Flemingia should be clear for how to use this kind of traditional Chinese medicines more reasonably in pharmacology. Therefore, this review gives an account of the current knowledge on the chemical constituents, biological activities and pharmacological properties of the plants of the genus. Several different classes of compounds were previously isolated, which the main groups are flavones, particularly prenylated flavones, and triterpenes accompanied with sterols, anthraquinones, and others. The names and structures of the chemical constituents are given in this review. In addition, the pharmacological effects of the extracts and individual compounds (mainly for flavones) derived from the genus plants have been found, including neuroprotection, anti-inflammation, anti-oxidation, cytotoxicity, hormone-like effects, antimicrobial activities, and so on. PMID- 22435804 TI - Calcium signalling remodelling and disease. AB - A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease. PMID- 22435805 TI - Metabolic sensors and their interplay with cell signalling and transcription. AB - There is an intimate, yet poorly understood, link between cellular metabolic status, cell signalling and transcription. Central metabolic pathways are under the control of signalling pathways and, vice versa, the cellular metabolic profile influences cell signalling through the incorporation of various metabolic sensors into the signalling networks. Thus information about nutrients availability directly and crucially influences crucial cell decisions. In the present review, I summarize our current knowledge of various metabolic sensors and give some examples of the integration of metabolically derived inputs into the signalling system and the regulation of transcription. I also discuss the Warburg effect where the cross-talk between metabolism and signalling is used to orchestrate rapid cell growth and division. It is becoming clear that future research will concentrate on the collection of small-molecule metabolites, whose concentration fluctuates in response to cellular energy levels, searching for their sensors that connect them to the signalling and transcriptional networks. PMID- 22435806 TI - Dynamic clustering of IP3 receptors by IP3. AB - The versatility of Ca2+ as an intracellular messenger stems largely from the impressive, but complex, spatiotemporal organization of the Ca2+ signals. For example, the latter when initiated by IP3 (inositol 1,4,5-trisphosphate) in many cells manifest hierarchical recruitment of elementary Ca2+ release events ('blips' and then 'puffs') en route to global regenerative Ca2+ waves as the cellular IP3 concentration rises. The spacing of IP3Rs (IP3 receptors) and their regulation by Ca2+ are key determinants of these spatially organized Ca2+ signals, but neither is adequately understood. IP3Rs have been proposed to be pre assembled into clusters, but their composition, geometry and whether clustering affects IP3R behaviour are unknown. Using patch-clamp recording from the outer nuclear envelope of DT40 cells expressing rat IP3R1 or IP3R3, we have recently shown that low concentrations of IP3 cause IP3Rs to aggregate rapidly and reversibly into small clusters of approximately four IP3Rs. At resting cytosolic Ca2+ concentrations, clustered IP3Rs open independently, but with lower open probability, shorter open duration and lesser IP3-sensitivity than lone IP3Rs. This inhibitory influence of clustering on IP3R is reversed when the [Ca2+]i (cytosolic free Ca2+ concentration) increases. The gating of clustered IP3Rs exposed to increased [Ca2+]i is coupled: they are more likely to open and close together, and their simultaneous openings are prolonged. Dynamic clustering of IP3Rs by IP3 thus exposes them to local Ca2+ rises and increases their propensity for a CICR (Ca2+-induced Ca2+ rise), thereby facilitating hierarchical recruitment of the elementary events that underlie all IP3-evoked Ca2+ signals. PMID- 22435807 TI - From beads on a string to the pearls of regulation: the structure and dynamics of chromatin. AB - The assembly of eukaryotic chromatin, and the bearing of its structural organization on the regulation of gene expression, were the central topics of a recent conference organized jointly by the Biochemical Society and Wellcome Trust. A range of talks and poster presentations covered topical aspects of this research field and illuminated recent advances in our understanding of the structure and function of chromatin. The two-day meeting had stimulating presentations complemented with lively discourse and interactions of participants. In the present paper, we summarize the topics presented at the meeting, in particular highlighting subjects that are reviewed in more detail within this issue of Biochemical Society Transactions. The reports bring to life the truly fascinating molecular and structural biology of chromatin. PMID- 22435808 TI - DNA structure, nucleosome placement and chromatin remodelling: a perspective. AB - A major question in chromatin biology is to what extent the sequence of DNA directly determines the genetic and chromatin organization of a eukaryotic genome? We consider two aspects to this question: the DNA sequence-specified positioning of nucleosomes and the determination of NDRs (nucleosome-depleted regions) or barriers. We argue that, in budding yeast, while DNA sequence specified nucleosome positioning may contribute to positions flanking the regions lacking nucleosomes, DNA thermodynamic stability is a major component determinant of the genetic organization of this organism. PMID- 22435809 TI - H1 and HMGB1: modulators of chromatin structure. AB - Histone H1 and HMGB1 (high-mobility group protein B1) are the most abundant chromosomal proteins apart from the core histones (on average, one copy per nucleosome and per ten nucleosomes respectively). They are both highly mobile in the cell nucleus, with high on/off rates for binding. In vivo and in vitro evidence shows that both are able to organize chromatin structure, with H1 binding resulting in a more stable structure and HMGB1 binding in a less stable structure. The binding sites for H1 and HMGB1 in chromatin are partially overlapping, and replacement of H1 by HMGB1 through the highly dynamic nature of their binding, possibly facilitated by interaction between them, could result in switching of chromatin states. Binding of HMGB1 to DNA or chromatin is regulated by its long and highly acidic tail, which is also involved in H1 binding. The present article focuses mainly on HMGB1 and its interaction with chromatin and H1, as well as its chaperone role in the binding of certain transcription factors (e.g. p53) to their cognate DNA. PMID- 22435810 TI - Nucleosome recognition and spacing by chromatin remodelling factor ISW1a. AB - Nucleosomes are actively positioned along DNA by ATP-dependent, chromatin remodelling factors. A structural model for the ISW1a chromatin remodelling factor from Saccharomyces cerevisiae in complex with a dinucleosome substrate was constructed from the X-ray structures of ISW1a (DeltaATPase) with and without DNA bound, two different cryo-EM (cryo-electron microscopy) structures of ISW1a (DeltaATPase) bound to a nucleosome, and site-directed photo-cross-linking analyses in solution. The X-ray structure of ISW1a (DeltaATPase) with DNA bound suggests that DNA sequence may be involved in nucleosome recognition and thereby specificity of promoter interaction. The model suggests how the highly ordered nucleosome arrays observed by mapping nucleosomes in genes and their promoter regions could be generated by a chromatin remodelling factor. PMID- 22435811 TI - Deciphering how the chromatin factor RCC1 recognizes the nucleosome: the importance of individuals in the scientific discovery process. AB - The nucleosome repeating unit of chromatin is the target of chromatin enzymes and factors that regulate gene activity in a eukaryotic cell. How the nucleosome is recognized by chromatin enzymes and factors is poorly understood, even though such interaction is fundamental to gene regulation and chromatin biology. My laboratory recently determined the structural basis for how the RCC1 (regulator of chromosome condensation 1) chromatin factor binds to the nucleosome, including the first atomic crystal structure of a chromatin protein complexed with the nucleosome core particle. I describe here how we developed and investigated structural models for RCC1 binding to the nucleosome using biochemical methods and how we crystallized the 300 kDa complex of RCC1 with the nucleosome core particle. This article highlights the contributions made by key laboratory members and explains our thinking and rationale during the discovery process. PMID- 22435812 TI - Histone transfer among chaperones. AB - The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly. PMID- 22435813 TI - Cancer and the bromodomains of BAF180. AB - Chromatin remodelling complexes alter the structure of chromatin and have central roles in all DNA-templated activities, including regulation of gene expression and DNA repair. Mutations in subunits of the PBAF (polybromo/Brg1-associated factor) or SWI/SNF-B remodelling complex, including BAF180, are frequently associated with cancer. There are six potential acetyl-lysine-binding BDs (bromodomains) in BAF180, which may function to target the PBAF complex to promoters or sites of DNA repair. In the present review, we discuss what is currently known about the BDs of BAF180 and their potential significance in cancer. PMID- 22435814 TI - Histone marks: repairing DNA breaks within the context of chromatin. AB - Inherited or acquired defects in detecting, signalling or repairing DNA damage are associated with various human pathologies, including immunodeficiencies, neurodegenerative diseases and various forms of cancer. Nuclear DNA is packaged into chromatin and therefore the true in vivo substrate of damaged DNA occurs within the context of chromatin. Our work aims to decipher the mechanisms by which cells detect DNA damage and signal its presence to the DNA-repair and cell cycle machineries. In particular, much of our work has focused on DNA DSBs (double-strand breaks) that are generated by ionizing radiation and radiomimetic chemicals, and which can also arise when the DNA replication apparatus encounters other DNA lesions. In the present review, we describe some of our recent work, as well as the work of other laboratories, that has identified new chromatin proteins that mediate DSB responses, control SDB processing or modulate chromatin structure at DNA-damage sites. We also aim to survey several recent advances in the field that have contributed to our understanding of how particular histone modifications and involved in DNA repair. It is our hope that by understanding the role of chromatin and its modifications in promoting DNA repair and genome stability, this knowledge will provide opportunities for developing novel classes of drugs to treat human diseases, including cancer. PMID- 22435815 TI - Active nucleosome positioning beyond intrinsic biophysics is revealed by in vitro reconstitution. AB - Genome-wide nucleosome maps revealed well-positioned nucleosomes as a major theme in eukaryotic genome organization. Promoter regions often show a conserved pattern with an NDR (nucleosome-depleted region) from which regular nucleosomal arrays emanate. Three mechanistic contributions to such NDR-array-organization and nucleosome positioning in general are discussed: DNA sequence, DNA binders and DNA-templated processes. Especially, intrinsic biophysics of DNA sequence preferences for nucleosome formation was prominently suggested to explain the majority of nucleosome positions ('genomic code for nucleosome positioning'). Nonetheless, non-histone factors that bind DNA with high or low specificity, such as transcription factors or remodelling enzymes respectively and processes such as replication, transcription and the so-called 'statistical positioning' may be involved too. Recently, these models were tested for yeast by genome-wide reconstitution. DNA sequence preferences as probed by SGD (salt gradient dialysis) reconstitution generated many NDRs, but only few individual nucleosomes, at their proper positions, and no arrays. Addition of a yeast extract and ATP led to dramatically more in vivo-like nucleosome positioning, including regular arrays for the first time. This improvement depended essentially on the extract and ATP but not on transcription or replication. Nucleosome occupancy and close spacing were maintained around promoters, even at lower histone density, arguing for active packing of nucleosomes against the 5' ends of genes rather than statistical positioning. A first extract fractionation identified a direct, specific, necessary, but not sufficient role for the RSC (remodels the structure of chromatin) remodelling enzyme. Collectively, nucleosome positioning in yeast is actively determined by factors beyond intrinsic biophysics, and in steady-state rather than at equilibrium. PMID- 22435816 TI - Conserved activation pathways in G-protein-coupled receptors. AB - GPCRs (G-protein-coupled receptors) are seven-transmembrane helix proteins that transduce exogenous and endogenous signals to modulate the activity of downstream effectors inside the cell. Despite the relevance of these proteins in human physiology and pharmaceutical research, we only recently started to understand the structural basis of their activation mechanism. In the period 2008-2011, nine active-like structures of GPCRs were solved. Among them, we have determined the structure of light-activated rhodopsin with all the features of the active metarhodopsin-II, which represents so far the most native-like model of an active GPCR. This structure, together with the structures of other inactive, intermediate and active states of rhodopsin constitutes a unique structural framework on which to understand the conserved aspects of the activation mechanism of GPCRs. This mechanism can be summarized as follows: retinal isomerization triggers a series of local structural changes in the binding site that are amplified into three intramolecular activation pathways through TM (transmembrane helix) 5/TM3, TM6 and TM7/TM2. Sequence analysis strongly suggests that these pathways are conserved in other GPCRs. Differential activation of these pathways by ligands could be translated into the stabilization of different active states of the receptor with specific signalling properties. PMID- 22435817 TI - Insights into the activation mechanism of the visual receptor rhodopsin. AB - Recent advances in the structural biology of GPCRs (G-protein-coupled receptors) have provided insights into their structure and function. Comparisons of the visual and ligand-activated receptors highlight the unique elements of rhodopsin that allow it to function as a highly sensitive dim-light photoreceptor in vertebrates, as well as the common elements that it shares with the large class A GPCR family. However, despite progress, a number of questions remain unanswered about how these receptors are activated. PMID- 22435818 TI - G-protein-coupled receptor dynamics: dimerization and activation models compared with experiment. AB - Our previously derived models of the active state of the beta2-adrenergic receptor are compared with recently published X-ray crystallographic structures of activated GPCRs (G-protein-coupled receptors). These molecular dynamics-based models using experimental data derived from biophysical experiments on activation were used to restrain the receptor to an active state that gave high enrichment for agonists in virtual screening. The beta2-adrenergic receptor active model and X-ray structures are in good agreement over both the transmembrane region and the orthosteric binding site, although in some regions the active model is more similar to the active rhodopsin X-ray structures. The general features of the microswitches were well reproduced, but with minor differences, partly because of the unexpected X-ray results for the rotamer toggle switch. In addition, most of the interacting residues between the receptor and the G-protein were identified. This analysis of the modelling has also given important additional insight into GPCR dimerization: re-analysis of results on photoaffinity analogues of rhodopsin provided additional evidence that TM4 (transmembrane helix 4) resides at the dimer interface and that ligands such as bivalent ligands may pass between the mobile helices. A comparison, and discussion, is also carried out between the use of implicit and explicit solvent for active-state modelling. PMID- 22435819 TI - Kinesin backsteps. AB - Kinesin-1 is a walking machine that takes ~8 nm steps along microtubules. Some aspects of the molecular mechanism of walking are now clear, but many are not. In the present paper, we discuss currently controversial points, focusing on the pathways by which kinesin takes occasional backsteps. Backsteps represent failures of the forwards-biasing mechanism. By studying the mechanochemistry of backstepping, one can learn much about the underlying molecular mechanisms responsible for forwards directional bias in the walking action. PMID- 22435820 TI - Structural insights into specificity and diversity in mechanisms of ubiquitin recognition by ubiquitin-binding domains. AB - UBDs [Ub (ubiquitin)-binding domains], which are typically small protein motifs of <50 residues, are used by receptor proteins to transduce post-translational Ub modifications in a wide range of biological processes, including NF-kappaB (nuclear factor kappaB) signalling and proteasomal degradation pathways. More than 20 families of UBDs have now been characterized in structural detail and, although many recognize the canonical Ile44/Val70-binding patch on Ub, a smaller number have alternative Ub-recognition sites. The A20 Znf (A20-like zinc finger) of the ZNF216 protein is one of the latter and binds with high affinity to a polar site on Ub centred around Asp58/Gln62. ZNF216 shares some biological function with p62, with both linked to NF-kappaB signal activation and as shuttle proteins in proteasomal degradation pathways. The UBA domain (Ub-associated domain) of p62, although binding to Ub through the Ile44/Val70 patch, is unique in forming a stable dimer that negatively regulates Ub recognition. We show that the A20 Znf and UBA domain are able to form a ternary complex through independent interactions with a single Ub molecule, supporting functional models for Ub as a 'hub' for mediating multi-protein complex assembly and for enhancing signalling specificity. PMID- 22435821 TI - Structural and dynamic aspects of Ca2+ and Mg2+ binding of the regulatory domains of the Na+/Ca2+ exchanger. AB - Intracellular Ca2+ regulates the activity of the NCX (Na+/Ca2+ exchanger) through binding to the cytosolic CBD (Ca2+-binding domain) 1 and CBD2. In vitro studies of the structure and dynamics of CBD1 and CBD2, as well as studies of their kinetics and thermodynamics of Ca2+ binding, greatly enhanced our understanding of NCX regulation. We describe the fold of the CBDs in relation to other known structures and review Ca2+ binding of the different CBD variants from a structural perspective. We also report on new findings concerning Mg2+ binding to the CBDs and finally we discuss recent results on CBD1-CBD2 interdomain interactions. PMID- 22435822 TI - Dynamics in transient complexes of redox proteins. AB - Recent studies have provided experimental information about the initial stage of protein complex formation, the encounter complex. This stage is particularly important in the weak and transient complexes formed between electron transfer proteins and their partners. These studies are discussed and the role of the encounter complex is interpreted in terms of the specific requirements that the biological function puts on these complexes. PMID- 22435823 TI - Conformational dynamics and thermodynamics of protein-ligand binding studied by NMR relaxation. AB - Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein-ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions. PMID- 22435824 TI - Understanding how small helical proteins fold: conformational dynamics of Im proteins relevant to their folding landscapes. AB - Understanding the mechanism of folding of small proteins requires characterization of their starting unfolded states and any partially unfolded states populated during folding. Here, we review what is known from NMR about these states of Im7, a 4-helix bundle protein that folds via an on-pathway intermediate, and show that there is an alignment of non-native structure in urea unfolded Im7 with the helices of native Im7 that is a consequence of hydrophobic helix-promoting residues also promoting cluster-formation in the unfolded protein. We suggest that this kind of alignment is present in other proteins and is relevant to how native state topology determines folding rates. PMID- 22435825 TI - Morphogenesis of a protein: folding pathways and the energy landscape. AB - Current knowledge on the reaction whereby a protein acquires its native three dimensional structure was obtained by and large through characterization of the folding mechanism of simple systems. Given the multiplicity of amino acid sequences and unique folds, it is not so easy, however, to draw general rules by comparing folding pathways of different proteins. In fact, quantitative comparison may be jeopardized not only because of the vast repertoire of sequences but also in view of a multiplicity of structures of the native and denatured states. We have tackled the problem of the relationships between the sequence information and the folding pathway of a protein, using a combination of kinetics, protein engineering and computational methods, applied to relatively simple systems. Our strategy has been to investigate the folding mechanism determinants using two complementary approaches, i.e. (i) the study of members of the same family characterized by a common fold, but substantial differences in amino acid sequence, or (ii) heteromorphic pairs characterized by largely identical sequences but with different folds. We discuss some recent data on protein-folding mechanisms by presenting experiments on different members of the PDZ domain family and their circularly permuted variants. Characterization of the energetics and structures of intermediates and TSs (transition states), obtained by Phi-value analysis and restrained MD (molecular dynamics) simulations, provides a glimpse of the malleability of the dynamic states and of the role of the topology of the native states and of the denatured states in dictating folding and misfolding pathways. PMID- 22435826 TI - The role of the extracellular loops of the CGRP receptor, a family B GPCR. AB - The CGRP (calcitonin gene-related peptide) receptor is a family B GPCR (G-protein coupled receptor). It consists of a GPCR, CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activity-modifying protein 1). RAMP1 is needed for CGRP binding and also cell-surface expression of CLR. There have been few systematic studies of the ECLs (extracellular loops) of family B GPCRs. However, they are likely to be especially important for the interaction of the N termini of the peptide agonists that are the natural agonists for these receptors. We have carried out alanine scans on all three ECLs of CLR, as well as their associated juxtamembrane regions. Residues within all three loops influence CGRP binding and receptor activation. Mutation of Ala203 and Ala206 on ECL1 to leucine increased the affinity of CGRP. Residues at the top of TM (transmembrane) helices 2 and 3 influenced CGRP binding and receptor activation. L351A and E357A in TM6/ECL3 reduced receptor expression and may be needed for CLR association with RAMP1. ECL2 seems especially important for CLR function; of the 16 residues so far examined in this loop, eight residues reduce the potency of CGRP at stimulating cAMP production when mutated to alanine. PMID- 22435827 TI - The mechanical properties of kinesin-1: a holistic approach. AB - During the last 25 years, a vast amount of research has gone into understanding the mechanochemical cycle of kinesin-1 and similar processive motor proteins. An experimental method that has been widely used to this effect is the in vitro study of kinesin-1 molecules moving along microtubules while pulling a bead, the position of which is monitored optically while trapped in a laser focus. Analysing results from such experiments, in which thermally excited water molecules are violently buffeting the system components, can be quite difficult. At low loads, the effect of the mechanical properties of the entire molecule must be taken into account, as stalk compliance means the bead position recorded is only weakly coupled to the movement of the motor domains, the sites of ATP hydrolysis and microtubule binding. In the present review, findings on the mechanical and functional properties of the various domains of full-length kinesin-1 molecules are summarized and a computer model is presented that uses this information to simulate the motion of a bead carried by a kinesin molecule along a microtubule, with and without a weak optical trap present. A video sequence made from individual steps of the simulation gives a three-dimensional visual insight into these types of experiment at the molecular level. PMID- 22435828 TI - The ERMES complex and ER-mitochondria connections. AB - Cellular organelles need to communicate in order to co-ordinate homoeostasis of the compartmentalized eukaryotic cell. Such communication involves the formation of membrane contact sites between adjacent organelles, allowing privileged exchange of metabolites and information. Using a synthetic protein designed to artificially tether the ER (endoplasmic reticulum) to mitochondria, we have discovered a yeast protein complex naturally involved in establishing and maintaining contact sites between these two organelles. This protein complex is physiologically involved in a plethora of mitochondrial processes, suggesting that ER-mitochondria connections play a central co-ordinating role in the regulation of mitochondrial biology. Recent biochemical characterization of this protein complex led to the discovery that GTPases of the Miro family are part of ER-mitochondria connections. The yeast Miro GTPase Gem1 localizes to ER mitochondria interface and influences the size and distribution of mitochondria. Thus Miro GTPases may serve as regulators of the ER-mitochondria connection. PMID- 22435829 TI - 14-3-3 protein and ATRAP bind to the soluble class IIB phosphatidylinositol transfer protein RdgBbeta at distinct sites. AB - PITPs (phosphatidylinositol transfer proteins) are characterized by the presence of the PITP domain whose biochemical properties of binding and transferring PI (phosphatidylinositol) are well studied. Despite their wide-spread expression in both unicellular and multicellular organisms, they remain functionally uncharacterized. An emerging theme is that individual PITPs play highly specific roles in either membrane trafficking or signal transduction. To identify specific roles for PITPs, identification of interacting molecules would shed light on their molecular function. In the present paper, we describe binding partners for the class IIB PITP RdgBbeta (retinal degeneration type Bbeta). RdgBbeta is a soluble PITP but is unique in that it contains a region of disorder at its C terminus following its defining N-terminal PITP domain. The C-terminus of RdgBbeta is phosphorylated at two serine residues, Ser274 and Ser299, which form a docking site for 14-3-3 proteins. Binding to 14-3-3 proteins protects RdgBbeta from degradation that occurs at the proteasome after ubiquitination. In addition to binding 14-3-3, the PITP domain of RdgBbeta interacts with the Ang II (angiotensin II)-associated protein ATRAP (Ang II receptor-associated protein). ATRAP is also an interacting partner for the AT1R (Ang II type 1 receptor). We present a model whereby RdgBbeta functions by being recruited to the membrane by ATRAP and release of 14-3-3 from the C-terminus allows the disordered region to bind a second membrane to create a membrane bridge for lipid transfer, possibly under the control of Ang II. PMID- 22435830 TI - Chloroplast lipid synthesis and lipid trafficking through ER-plastid membrane contact sites. AB - Plant chloroplasts contain an intricate photosynthetic membrane system, the thylakoids, and are surrounded by two envelope membranes at which thylakoid lipids are assembled. The glycoglycerolipids mono- and digalactosyldiacylglycerol, and sulfoquinovosyldiacylglycerol as well as phosphatidylglycerol, are present in thylakoid membranes, giving them a unique composition. Fatty acids are synthesized in the chloroplast and are either directly assembled into thylakoid lipids at the envelope membranes or exported to the ER (endoplasmic reticulum) for extraplastidic lipid assembly. A fraction of lipid precursors is reimported into the chloroplast for the synthesis of thylakoid lipids. Thus polar lipid assembly in plants requires tight co ordination between the chloroplast and the ER and necessitates inter-organelle lipid trafficking. In the present paper, we discuss the current knowledge of the export of fatty acids from the chloroplast and the import of chloroplast lipid precursors assembled at the ER. Direct membrane contact sites between the ER and the chloroplast outer envelopes are discussed as possible conduits for lipid transfer. PMID- 22435831 TI - The relationship between ER-multivesicular body membrane contacts and the ESCRT machinery. AB - Activated EGFR (epidermal growth factor receptor) undergoes ESCRT (endosomal sorting complex required for transport)-mediated sorting on to ILVs (intraluminal vesicles) of endosomes before degradation in the lysosome. Sorting of endocytosed EGFR on to ILVs removes the catalytic domain of the EGFR from the cytoplasm, resulting in termination of receptor signalling. EGFR signalling is also subject to down-regulation through receptor dephosphorylation by the ER (endoplasmic reticulum)-localized PTP1B (protein tyrosine phosphatase 1B). PTP1B on the cytoplasmic face of the ER interacts with endocytosed EGFR via direct membrane contacts sites between the ER and endosomes. In the present paper, we review the relationship between ER-endosome membrane contact sites and ILV formation, and their potential role in the regulation of EGFR sorting on to ILVs, through PTP1B mediated dephosphorylation of both EGFR and components of the ESCRT machinery. PMID- 22435832 TI - The oxysterol-binding protein superfamily: new concepts and old proteins. AB - The Kes1 OSBP (oxysterol-binding protein) is a key regulator of membrane trafficking through the TGN (trans-Golgi network) and endosomal membranes. We demonstrated recently that Kes1 acts as a sterol-regulated rheostat for TGN/endosomal phosphatidylinositol 4-phosphate signalling. Kes1 utilizes its dual lipid-binding activities to integrate endosomal lipid metabolism with TORC1 (target of rapamycin complex 1)-dependent proliferative pathways and transcriptional control of nutrient signalling. PMID- 22435833 TI - Fourteen-electron ring model and the anomalous magnetic circular dichroism of meso-triarylsubporphyrins. AB - The MCD spectra of meso-triarylsubporphyrins show a sign anomaly which is correlated with the acceptor properties of the aryl substituent. From the spectra, magnetic moments of the excited states are determined. In the context of a simplified orbital model, the sign change is attributed to the quenching of the magnetic moment of the LUMO by acceptor orbitals of the substituent. The actual calculation of this moment presents a major challenge to computational methods. It is shown that wave function techniques based on CASSCF underestimate the covalency effects that are responsible for the quenching. In contrast, a CI method based on DFT orbitals yields excellent results, which fully support the orbital model. PMID- 22435834 TI - Developing red-emissive ruthenium(II) complex-based luminescent probes for cellular imaging. AB - Ruthenium(II) complexes have rich photophysical attributes, which enable novel design of responsive luminescence probes to selectively quantify biochemical analytes. In this work, we developed a systematic series of Ru(II)-bipyrindine complex derivatives, [Ru(bpy)(3-n)(DNP-bpy)(n)](PF(6))(2) (n = 1, 2, 3; bpy, 2,2' bipyridine; DNP-bpy, 4-(4-(2,4-dinitrophenoxy)phenyl)-2,2'-bipyridine), as luminescent probes for highly selective and sensitive detection of thiophenol in aqueous solutions. The specific reaction between the probes and thiophenol triggers the cleavage of the electron acceptor group, 2,4-dinitrophenyl, eliminating the photoinduced electron transfer (PET) process, so that the luminescence of on-state complexes, [Ru(bpy)(3-n)(HP-bpy)(n)](2+) (n = 1, 2, 3; HP-bpy, 4-(4-hydroxyphenyl)-2,2'-bipyridine), is turned on. We found that the complex [Ru(bpy)(DNP-bpy)(2)](2+) remarkably enhanced the on-to-off contrast ratio compared to the other two (37.8 compared to 21 and 18.7). This reveals a new strategy to obtain the best Ru(II) complex luminescence probe via the most asymmetric structure. Moreover, we demonstrated the practical utility of the complex as a cell-membrane permeable probe for quantitative luminescence imaging of the dynamic intracellular process of thiophenol in living cells. The results suggest that the new probe could be a very useful tool for luminescence imaging analysis of the toxic thiophenol in intact cells. PMID- 22435835 TI - Nurse-run, telephone-based outreach to improve lipids in people with diabetes. AB - BACKGROUND: There is a need for randomized, prospective trials of case management interventions with resource utilization analyses. OBJECTIVES: To determine whether algorithm-driven telephone care by nurses improves lipid control in patients with diabetes. DESIGN: Prospective, randomized, controlled trial. PARTICIPANTS: Adults with diabetes at a federally funded community health center were randomly assigned to intervention (n = 381) or usual-care (n = 381) groups. INTERVENTIONS: Nurses independently initiated and titrated lipid therapy and promoted behavioral change through motivational interviewing and self-management techniques. Other parameters of diabetes care were addressed based on time constraints. MAIN MEASURES: The primary outcome was the proportion of patients with a low-density lipoprotein (LDL) less than 100 mg/dL. Secondary outcomes included the number of hospital admissions, total hospital charges per patient, and the proportion of patients meeting other lipid, glycemic, and blood pressure guidelines. KEY RESULTS: The percent of patients with an LDL < 100 mg/dL increased from 52.0% to 58.5% in the intervention group and decreased from 55.6% to 46.7% in the control group (P < .01). Average cost per patient to the healthcare system was less for the intervention group ($6600 vs $9033, P = .03). Intervention patients trended toward fewer hospital admissions (P = .06). The intervention did not affect glycemic and blood pressure outcomes. CONCLUSIONS: Nurses can improve lipid control in patients with diabetes in a primarily indigent population through telephone care using moderately complex algorithms, but a more targeted approach is warranted. Telephone-based outreach may decrease resource utilization, but more study is needed. PMID- 22435836 TI - A dementia care management intervention: which components improve quality? AB - OBJECTIVES: To analyze whether types of providers and frequency of encounters are associated with higher quality of care within a coordinated dementia care management (CM) program for patients and caregivers. DESIGN: Secondary analysis of intervention-arm data from a dementia CM cluster-randomized trial, where intervention participants interacted with healthcare organization care managers (HOCMs), community agency care managers (CACMs), and/ or healthcare organization primary care providers (HOPCPs) over 18 months. METHODS: Encounters of 238 patient/caregivers (dyads) with HOCMs, CACMs, and HOPCPs were abstracted from care management electronic records. The quality domains of assessment, treatment, education/support, and safety were measured from medical record abstractions and caregiver surveys. Mean percentages of met quality indicators associated with exposures to each provider type and frequency were analyzed using multivariable regression, adjusting for participant characteristics and baseline quality. RESULTS: As anticipated, for all 4 domains, the mean percentage of met dementia quality indicators was 15.5 to 47.2 percentage points higher for dyads with HOCM- only exposure than for dyads with none (all P < .008); not anticipated were higher mean percentages with increasing combinations of provider-type exposure-up to 73.7 percentage points higher for safety (95% confidence interval 65.2%-82.1%) with exposure to all 3 provider types compared with no exposure. While greater frequency of HOCM-dyad encounters was associated with higher quality (P < .04), this was not so for other provider types. CONCLUSIONS: HOCMs' interactions with dyads was essential for dementia care quality improvement. Additional coordinated interactions with primary care and community agency staff yielded even higher quality. PMID- 22435837 TI - Hospital readmission rates in Medicare Advantage plans. AB - OBJECTIVES: To compute a benchmark for tracking readmission rates among patients enrolled in Medicare's private comprehensive Medicare Advantage (MA) plans and to develop preliminary comparisons with the fee-for-service (FFS) readmission rates. STUDY DESIGN: Descriptive data presentation with analytic discussion. METHODS: We computed a benchmark for rehospitalization rates among MA patients using data from a commercial registry. To compare readmission rates between FFS and MA patients, we analyzed differences in demographics, geography, time period, entitlement status, and risk of readmission based on major diagnosis associated with the admission and the presence of complicating conditions. RESULTS: We found an unadjusted 30-day hospital readmission rate in the MA sample of 14.5% in 2006 2008. Results from contemporaneous comparisons between FFS and MA in the 2006 2008 period showed MA 30-day readmission rates were 22% lower than FFS readmission rates, before risk or other adjustments. After adjusting for risk of readmission (using distributions of major diagnosis codes and their respective likelihoods of readmission) and excluding patients under age 65 years (ie, those entitled to Medicare because of disability) from the comparison, we estimated that 30-day readmission rates for MA patients were approximately 13% to 20% lower than those for FFS patients in the 2006-2008 period. CONCLUSIONS: We measured substantial differences in the risk-adjusted rates of hospital readmission among Medicare FFS and MA patients in our samples. PMID- 22435838 TI - Early evaluations of the medical home: building on a promising start. AB - OBJECTIVES: To systematically review the current evidence on the patient-centered medical home (PCMH, or medical home), which aims to reinvigorate primary care and achieve the triple aim of better quality, improved experience, and lower costs. STUDY DESIGN: Systematic review of quantitative evidence on the PCMH. METHODS: Out of 498 studies published or disseminated from January 2000 to September 2010 on US-based interventions, 14 evaluations of 12 interventions met our inclusion criteria: (1) tested a practice-level intervention with 3 or more of 5 key PCMH components and (2) conducted a quantitative study of one of the triple aim outcomes or of healthcare professional experience. We synthesized findings on interventions that were evaluated using rigorous methods. We also provide guidance to structure future evaluations to maximize learning. RESULTS: The interventions most often cited to support the medical home can be viewed as precursors to the medical home. Evaluations of 6 of these interventions provided rigorous evidence on 1 or more outcomes. This evidence indicates some favorable effects on all 3 triple aim outcomes, a few unfavorable effects on costs, and many inconclusive results. CONCLUSIONS: Although the PCMH is a promising innovation, rigorous quantitative evaluations and comprehensive implementation analyses are needed to assess effectiveness and refine the model to meet stakeholders' needs. Findings from future evaluations will help guide the substantial efforts practices and payers invest to adopt the PCMH with the goal of achieving the triple aim outcomes. PMID- 22435839 TI - Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator. AB - Outcome prediction following severe traumatic brain injury (sTBI) is a widely investigated field of research. A major breakthrough is represented by the IMPACT prognostic calculator based on admission data of more than 8500 patients. A growing body of scientific evidence has shown that clinically meaningful biomarkers, including glial fibrillary acidic protein (GFAP), ubiquitin C terminal hydrolase-L1 (UCH-L1), and alphaII-spectrin breakdown product (SBDP145), could also contribute to outcome prediction. The present study was initiated to assess whether the addition of biomarkers to the IMPACT prognostic calculator could improve its predictive power. Forty-five sTBI patients (GCS score<=8) from four different sites were investigated. We utilized the core model of the IMPACT calculator (age, GCS motor score, and reaction of pupils), and measured the level of GFAP, UCH-L1, and SBDP145 in serum and cerebrospinal fluid (CSF). The forecast and actual 6-month outcomes were compared by logistic regression analysis. The results of the core model itself, as well as serum values of GFAP and CSF levels of SBDP145, showed a significant correlation with the 6-month mortality using a univariate analysis. In the core model, the Nagelkerke R(2) value was 0.214. With multivariate analysis we were able to increase this predictive power with one additional biomarker (GFAP in CSF) to R(2)=0.476, while the application of three biomarker levels (GFAP in CSF, GFAP in serum, and SBDP145 in CSF) increased the Nagelkerke R(2) to 0.700. Our preliminary results underline the importance of biomarkers in outcome prediction, and encourage further investigation to expand the predictive power of contemporary outcome calculators and prognostic models in TBI. PMID- 22435842 TI - Solid-state NMR study of Li-assisted dehydrogenation of ammonia borane. AB - The mechanism of thermochemical dehydrogenation of the 1:3 mixture of Li(3)AlH(6) and NH(3)BH(3) (AB) has been studied by the extensive use of solid-state NMR spectroscopy and theoretical calculations. The activation energy for the dehydrogenation is estimated to be 110 kJ mol(-1), which is lower than for pristine AB (184 kJ mol(-1)). The major hydrogen release from the mixture occurs at 60 and 72 degrees C, which compares favorably with pristine AB and related hydrogen storage materials, such as lithium amidoborane (LiNH(2)BH(3), LiAB). The NMR studies suggest that Li(3)AlH(6) improves the dehydrogenation kinetics of AB by forming an intermediate compound (LiAB)(x)(AB)(1-x). A part of AB in the mixture transforms into LiAB to form this intermediate, which accelerates the subsequent formation of branched polyaminoborane species and further release of hydrogen. The detailed reaction mechanism, in particular the role of lithium, revealed in the present study highlights new opportunities for using ammonia borane and its derivatives as hydrogen storage materials. PMID- 22435840 TI - Unraveling the relationship between aeroallergen sensitization, gender, second hand smoke exposure, and impaired lung function. AB - BACKGROUND: Contradictory findings on the differential effects of second-hand smoke (SHS) on lung function in girls and boys may result from masked relationships between host and environmental factors. Allergic sensitization may augment the relationship between SHS and decreased lung function, although its role in relation to the inconsistent gender differences in children has not been elucidated. HYPOTHESIS: We hypothesize that there will be differences between boys and girls related to early-life allergic sensitization and exposure to SHS on pulmonary function later in childhood. METHODS: Participants in this study (n = 486) were drawn from the Cincinnati Childhood Allergy and Air Pollution (CCAAPS) birth cohort study consisting of 46% girls. Allergic sensitization was assessed by skin prick test (SPT) to 15 aeroallergens at ages 2, 4, and 7, while pulmonary function and asthma diagnosis occurred at age 7. SHS exposure was measured by hair cotinine at ages 2 and/or 4. Gender differences of SHS exposure on pulmonary function among children with positive SPTs at ages 2, 4, and 7 as well as first- and higher-order interactions were examined by multiple linear regression. Interactions significant in the multivariate models were also examined via stratification. Comparisons within and between stratified groups were assessed by examining the slope of the parameter estimates/beta coefficients and associated p-values and confidence intervals. RESULTS: Increased cotinine levels were significantly associated with decreases in FEV(1) (-0.03 l, p < 0.05), peak expiratory flow (-0.07 l/s, p < 0.05), and FEF (25-75%) (-0.06 l/s, p < 0.01). The interaction between cotinine and sensitization at age 2 was borderline significant (p = 0.10) in the FEF(25-75%) model and showed an exposure response effect according to the number of positive SPTs at age 2; zero (-0.06 l/s, p < 0.01), one (-0.09 l/s, p < 0.05), or two or more positive SPTs (-0.30 l/s, p < 0.01). Despite increased polysensitization among boys, the association between cotinine and FEF(25-75%) among girls, with two or more positive SPTs at age 2, showed the greatest deficits in FEF(25-75%) (-0.34 l/s vs. -0.05 l/s and 0.06 l/s for non-sensitized girls and boys, respectively. Girls with two or more positive SPTs showed a twofold greater decrease in FEF(25-5%) (-0.34 l/s; 95% CI: -0.55, -0.13) compared to boys with the same degree of allergic sensitization ( 0.18 l/s; 95% CI: -0.41, 0.06), although this difference was not statistically significant. CONCLUSIONS: Reductions in lung function were observed among children exposed to SHS, and the number of aeroallergen-positive SPTs at age 2 modifies this relationship. Girls experiencing early childhood allergic sensitization and high SHS exposure are at greater risk of decreased lung function later in childhood compared to non-sensitized girls and boys and demonstrate greater deficits compared to boys with similar degrees of sensitization. PMID- 22435843 TI - Journey to the edges: social structures and neural maps of inter-group processes. AB - This article explores boundaries of the intellectual map of inter-group processes, going to the macro (social structure) boundary and the micro (neural systems) boundary. Both are illustrated by with my own and others' work on social structures and on neural structures related to inter-group processes. Analysing the impact of social structures on inter-group processes led to insights about distinct forms of sexism and underlies current work on forms of ageism. The stereotype content model also starts with the social structure of inter-group relations (interdependence and status) and predicts images, emotions, and behaviours. Social structure has much to offer the social psychology of inter group processes. At the other, less explored boundary, social neuroscience addresses the effects of social contexts on neural systems relevant to inter group processes. Both social structural and neural analyses circle back to traditional social psychology as converging indicators of inter-group processes. PMID- 22435844 TI - Gaining control over responses to implicit attitude tests: Implementation intentions engender fast responses on attitude-incongruent trials. AB - The present research investigated whether forming implementation intentions could promote fast responses to attitude-incongruent associations (e.g., woman-manager) and thereby modify scores on popular implicit measures of attitude. Expt 1 used the Implicit Association Test (IAT) to measure associations between gender and science versus liberal arts. Planning to associate women with science engendered fast responses to this category-attribute pairing and rendered summary scores more neutral compared to standard IAT instructions. Expt 2 demonstrated that forming egalitarian goal intentions is not sufficient to produce these effects. Expt 3 extended these findings to a different measure of implicit attitude (the Go/No-Go Association Task) and a different stereotypical association (Muslims terrorism). In Expt 4, managers who planned to associate women with superordinate positions showed more neutral IAT scores relative to non-planners and effects were maintained 3 weeks later. In sum, implementation intentions enable people to gain control over implicit attitude responses. PMID- 22435845 TI - Cognitive self-affirmation inclination: an individual difference in dealing with self-threats. AB - The current research shows that people differ in their inclination to use positive self-images when their self is threatened (i.e., cognitive self affirmation inclination, CSAI). Just as self-affirmation manipulations do, the use of positive self-images induces open mindedness towards threatening messages. The aim of the current studies was to show the meaning, stability, and effects of this new individual difference measure. A cross-sectional study among smokers (Study 1) showed that people with a strong CSAI perceived more negative consequences from smoking, suggesting open mindedness. Study 2 showed the stable and reliable character of the CSAI scale. Study 3 showed that the scale had an overlap of 18% with another self-related construct (self-efficacy) and no relation with self-consciousness. Study 4 showed that for induced self-threats a strong CSAI led to the same pattern of persuasion as found in earlier studies on self-affirmation manipulations. Study 5 showed that a self-affirmation manipulation did not have any effect for those participants with a strong self affirmation inclination, probably because they already had access to positive self-images. Study 6 showed that self-reported positive self-images mediated the effect of self-affirmation inclination on persuasion. PMID- 22435846 TI - On conviction's collective consequences: integrating moral conviction with the social identity model of collective action. AB - This article examines whether and how moral convictions predict collective action to achieve social change. Because moral convictions - defined as strong and absolute stances on moral issues - tolerate no exceptions, any violation motivates individuals to actively change that situation. We propose that moral convictions have a special relationship with politicized identities and collective action because of the potentially strong normative fit between moral convictions and the action-oriented content of politicized identities. This effectively integrates moral conviction with the Social Identity Model of Collective Action (Van Zomeren, Postmes, & Spears, 2008), which predicts that, on the basis of a relevant social identity, group-based anger and efficacy predict collective action. Results from two studies indeed showed that moral convictions predicted collective action intentions (Study 1-2) and collective action (Study 2) through politicized identification, group-based anger, and group efficacy. We discuss theoretical and practical implications of our integrative model. PMID- 22435847 TI - Mobilizing support for the extreme right: a discursive analysis of minority leadership. AB - This study uses a tripolar model of minority influence to investigate social category constructions of extreme right politicians. The analysis focuses on Geert Wilders, leader of the extreme right Party For Freedom (PVV) in the Netherlands. It is examined how this popular politician construes the interdependent relations between himself, the population, and mainstream politicians, and discursively manages his controversial standpoints and proposals. Four parliamentary debates are analysed. The analysis shows that by defining national identity, Wilders invokes a self-image as a prototypical member of the population. Furthermore, and in contrast to other politicians, Wilders works up a self-image of a responsible and realistic politician who is group oriented. In addition, the analysis suggests that being a minority can be of strategic political value and therefore a position to foster. The relevance of the analysis for social psychological approaches to leadership and political minorities is discussed. PMID- 22435848 TI - You want to give a good impression? Be honest! Moral traits dominate group impression formation. AB - Research has shown that warmth and competence are core dimensions on which perceivers judge others and that warmth has a primary role at various phases of impression formation. Three studies explored whether the two components of warmth (i.e., sociability and morality) have distinct roles in predicting the global impression of social groups. In Study 1 (N= 105) and Study 2 (N= 112), participants read an immigration scenario depicting an unfamiliar social group in terms of high (vs. low) morality, sociability, and competence. In both studies, participants were asked to report their global impression of the group. Results showed that global evaluations were better predicted by morality than by sociability or competence-trait ascriptions. Study 3 (N= 86) further showed that the effect of moral traits on group global evaluations was mediated by the perception of threat. The importance of these findings for the impression formation process is discussed. PMID- 22435850 TI - Effects of aging on cholinergic neuromuscular transmission in isolated small intestine of ad libitum fed and calorically-restricted rats. AB - BACKGROUND: Age-associated losses of enteric neurons have been described. In rat ileum, myenteric neurons lost during aging have been reported to be predominantly cholinergic, and caloric restriction (CR) has been shown to protect against these losses. Cholinergic myenteric neurons include excitatory motor neurons, so the aim of this work was to determine whether neuronal loss in ad libitum (AL)-fed animals is reflected in dysfunctional cholinergic neuromuscular transmission, and if CR reduces any such dysfunction. METHODS: Effects of electrical field stimulation (EFS) and applied acetylcholine (ACh) were examined in the longitudinal muscle of isolated ileal segments from 6-month-old rats and from 13- and 24-month-old rats fed either AL or CR diets. KEY RESULTS: Contractile responses to EFS were abolished by atropine and potentiated by the acetylcholinesterase inhibitor, eserine. Frequency-response relationships were not significantly different amongst the three age-groups. Sensitivity to applied ACh, however, was three-fold lower in the oldest animals (P < 0.05). Eserine potentiated responses to ACh; there were no statistically significant differences amongst the sensitivities to ACh in its presence. No significant differences between AL- and CR-fed animals were measured, although variability was less in CR fed than in AL-fed groups. CONCLUSIONS & INFERENCES: The cholinergic system supplying the rat ileum longitudinal muscle did not appear to be impaired in old age. Decreased sensitivity to applied ACh in old tissues may have been due to increased acetylcholinesterase activity. Caloric restriction had no significant effect on responses to EFS or applied ACh. The implications of these results are discussed. PMID- 22435851 TI - Gravitational and magnetic field variations synergize to cause subtle variations in the global transcriptional state of Arabidopsis in vitro callus cultures. AB - BACKGROUND: Biological systems respond to changes in both the Earth's magnetic and gravitational fields, but as experiments in space are expensive and infrequent, Earth-based simulation techniques are required. A high gradient magnetic field can be used to levitate biological material, thereby simulating microgravity and can also create environments with a reduced or an enhanced level of gravity (g), although special attention should be paid to the possible effects of the magnetic field (B) itself. RESULTS: Using diamagnetic levitation, we exposed Arabidopsis thaliana in vitro callus cultures to five environments with different levels of effective gravity and magnetic field strengths. The environments included levitation, i.e. simulated MUg* (close to 0 g* at B = 10.1 T), intermediate g* (0.1 g* at B = 14.7 T) and enhanced gravity levels (1.9 g* at B = 14.7 T and 2 g* at B = 10.1 T) plus an internal 1 g* control (B = 16.5 T). The asterisk denotes the presence of the background magnetic field, as opposed to the effective gravity environments in the absence of an applied magnetic field, created using a Random Position Machine (simulated MUg) and a Large Diameter Centrifuge (2 g).Microarray analysis indicates that changes in the overall gene expression of cultured cells exposed to these unusual environments barely reach significance using an FDR algorithm. However, it was found that gravitational and magnetic fields produce synergistic variations in the steady state of the transcriptional profile of plants. Transcriptomic results confirm that high gradient magnetic fields (i.e. to create MUg* and 2 g* conditions) have a significant effect, mainly on structural, abiotic stress genes and secondary metabolism genes, but these subtle gravitational effects are only observable using clustering methodologies. CONCLUSIONS: A detailed microarray dataset analysis, based on clustering of similarly expressed genes (GEDI software), can detect underlying global-scale responses, which cannot be detected by means of individual gene expression techniques using raw or corrected p values (FDR). A subtle, but consistent, genome-scale response to hypogravity environments was found, which was opposite to the response in a hypergravity environment. PMID- 22435852 TI - The impact of continuous subcutaneous insulin infusion on glycaemic control in children and adolescents: a regional review in North East England using a bio modelling approach. PMID- 22435853 TI - Evaluation of antimicrobial effects of novel implant materials by testing the prevention of biofilm formation using a simple small scale medium-throughput growth inhibition assay. AB - Staphylococcal colonization of implants is a serious complication of orthopaedic surgery. Anti-infectious modification of implant surfaces may serve to prevent bacterial colonization. The authors set out to develop an in vitro test system for the analysis of prevention of biofilm formation by Staphylococcus epidermidis and Staphylococcus aureus on implant materials. Biofilm growth was monitored over 10 days on titanium disks in order to develop appropriate test parameters. Bacterial cell counts following ultrasonic treatment of the colonized samples were compared with scanning electron microscope images of the specimens. Copper ion containing surfaces (ie copper [Cu] and inter-metallic Ti-Cu films) were used for growth inhibition assays: copper ion releasing specimens led to reduced bacterial numbers in biofilms and decreased bacterial persistence in the model used. The assay used represents an inexpensive and quick in vitro screen for the antibacterial effects of novel implant surface materials. PMID- 22435854 TI - Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. AB - BACKGROUND: There is no established management algorithm for portal vein thrombosis (PVT) in cirrhotic patients. The aim of our study was to prospectively evaluate anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT. METHODS: Cirrhotics with non-malignant PVT were included. Low weight molecular heparin anticoagulation was considered in all; TIPS was indicated if thrombosis progressed or anticoagulation was contraindicated. Patients who were not anticoagulated nor received TIPS served as controls. RESULTS: Fifty-six patients (of whom 21 controls) were included. PVT was occlusive in 11/35, with extension to the superior mesenteric or splenic vein in 13/35. In the study group 33 patients were anticoagulated, with a recanalization rate of 36% (12/33) compared with 1/21 among controls. A time interval between appearance of thrombosis and anticoagulation < 6 months predicted chance of repermeation. Thrombus progression occurred in 15/21 non anticoagulated patients and in 5/33 anticoagulated patients (P < 0.001). TIPS was placed in six patients. There were five variceal bleedings and two intestinal venous ischaemia episodes in the control group, compared with one variceal bleeding episode in the study group. CONCLUSIONS: In cirrhotics with PVT, a treatment algorithm using anticoagulation and TIPS achieves a good chance of complete repermeation, reduces portal hypertensive complications, and decreases the rate of thrombosis progression. PMID- 22435855 TI - Risk factors related to hazardous alcohol consumption among Korean men with hypertension. AB - The present study examines the alcohol consumption behaviors and risk factors related to hazardous alcohol consumption in men with hypertension in South Korea. The participants were 490 Korean hypertensive men > 20 years of age. The Alcohol Use Disorders Identification Test was used to detect hazardous alcohol consumption. The majority of the participants were current drinkers, and 37.4% were hazardous drinkers. However, very few participants had received consultation about alcohol consumption. Of the participants, 37.7% were current smokers, and almost half of them smoked more than one pack of cigarettes daily. The hazardous drinkers smoked much more than the normal drinkers, and their stress levels were higher than that of normal drinkers. Participants aged 40-49 and 50-59 years (odds ratio = 7.91, 95% confidence interval = 1.50-41.70; odds ratio = 7.57, 95% confidence interval = 1.31-43.70), those without stroke (odds ratio = 4.86, 95% confidence interval = 1.33-17.77), and current smokers (odds ratio = 4.24, 95% confidence interval = 2.00-8.98) were more likely to be involved in hazardous alcohol consumption. Successful blood pressure management will necessitate the education of such hypertensive men with consideration of their risk factors. PMID- 22435856 TI - Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. AB - OBJECTIVES: Lactate clearance (LC) and central venous oxygen saturation (ScvO(2)) have been proposed as goals of early sepsis resuscitation. The authors sought to determine the agreement and prognostic value of achieving ScvO(2) or LC goals in septic shock patients undergoing emergency department (ED)-based early resuscitation. METHODS: This was a preplanned analysis of a multicenter ED randomized controlled trial of early sepsis resuscitation targeting three variables: central venous pressure, mean arterial pressure, and either ScvO(2) or LC. Inclusion criteria included suspected infection, two or more systemic inflammation criteria, and either systolic blood pressure of <90 mm Hg after intravenous fluid bolus or lactate level of >4 mmol/L. Both ScvO(2) and LC were measured simultaneously. The ScvO(2) goal was defined as >=70%. Lactate was measured at enrollment and every 2 hours until the goal was reached or up to 6 hours. LC goal was defined as a decrease of >=10% from initial measurement. The primary outcome was in-hospital mortality. RESULTS: A total of 203 subjects were included, with an overall mortality of 19.7%. Achievement of the ScvO(2) goal only was associated with a mortality rate of 41% (9/22), while achievement of the LC goal only was associated with a mortality rate of 8% (2/25; proportion difference = 33%; 95% confidence interval [CI] = 9% to 55%). No agreement was found between goal achievement (kappa = -0.02), and exact test for matched pairs demonstrated no significant difference between discordant pairs (p = 0.78). CONCLUSIONS: No agreement was found between LC and ScvO(2) goal achievement in early sepsis resuscitation. Achievement of a ScvO(2) >= 70% without LC >= 10% was more strongly associated with mortality than achievement of LC >= 10% with failure to achieve ScvO(2) >= 70%. PMID- 22435857 TI - Point-of-care urine albumin:creatinine ratio is associated with outcome in emergency department patients with sepsis: a pilot study. AB - OBJECTIVES: Sepsis is characterized by an initial systemic proinflammatory response leading to endothelial damage and increased capillary permeability. The authors conducted a pilot study to determine if microalbuminuria, measured by the urine albumin:creatinine ratio (ACR), was associated with outcome in emergency department (ED) sepsis patients. METHODS: This was an observational cohort study of a convenience sample of adult patients presenting to two EDs over 10 months with sepsis (two or more systemic inflammatory response syndrome [SIRS] criteria and suspected infection). Those who received a urinalysis were prospectively enrolled. Patients with anuria, grossly contaminated specimens, or concurrent noninfectious diagnoses were excluded. Urine ACR was measured on a point-of-care (POC) device. The primary study outcome was ED disposition (three groups): treated and discharged, admitted to the floor, or admitted to the intensive care unit (ICU). Kruskal-Wallis testing was used to compare ACR based on disposition. Variables associated with ACR were identified by Spearman rank correlation or Mann-Whitney rank-sum testing. A post hoc subgroup analysis of patients with and without a genitourinary (GU) source of infection was also performed. RESULTS: A total of 121 patients were screened, and 29 (24%) were excluded; 92 patients met criteria (mean +/- SD age, 51.2 +/- 17.0 years; 51 [55%] had severe sepsis, three [3%] had septic shock). There were three in-hospital deaths. Median ACR for patients treated and discharged (n = 22), admitted to floor (n = 50), and admitted to ICU (n = 20) was 2.54 (interquartile range [IQR] = 0.89 to 6.16) versus 2.8 (IQR = 1.69 to 8.8) versus 12.15 (IQR = 4.76 to 20.95), respectively (p = 0.0049). Age, serum creatinine, and GU source of infection were associated with ACR. ACR was significantly associated with disposition among patients without a GU source of infection (p = 0.003), but not among patients with a GU source (p = 0.3744). CONCLUSIONS: In this pilot study, microalbuminuria measured by POC ACR was associated with disposition in ED patients with sepsis or severe sepsis. Larger studies using more robust outcomes comparing ACR with validated sepsis biomarkers are needed to elaborate on these results. PMID- 22435858 TI - Crocodile oil enhances cutaneous burn wound healing and reduces scar formation in rats. AB - OBJECTIVES: This study was performed to evaluate the burn wound-healing efficacy of crocodile oil from Crocodylus siamensis by employing deep second-degree burns in a Wistar rat model. METHODS: Twenty-four rats were assigned equally into four groups using a random-number table, and two burns were created on the dorsum of each animal except for the sham group. The three treatment groups received with saline solution (12 burns, served as negative control), silver sulfadiazine (12 burns, served as positive control), or crocodile oil (12 burns). Silver sulfadiazine cream was used as standard care, and the treatments were repeated twice daily for 28 days. After day 28 the animals were euthanized and the wounds were removed for quantitative real-time polymerase chain reaction, histologic, and immunohistochemical study. RESULTS: Crocodile oil accelerated the wound healing process as indicated by a significant decrease in wound closure time in comparison to the burn control and silver sulfadiazine treatment groups. Histologic results showed well-organized and distributed skin structure and collagen deposition in the animals treated with crocodile oil. Transforming growth factor-beta1 (TGF-beta1), a key cytokine promoting scarring, was also observed to play a role in the burn wound healing. Immunohistochemical staining results showed the negative expression of TGF-beta1 and Smad3 in the 28-days postburn skin of crocodile oil group versus positive in the epidermis of burn controls. Compared to the burn control group, expressions of TGF-beta1 and Smad3 mRNA decreased significantly (p < 0.01) in the 28-days-postburn skin of the crocodile oil group. CONCLUSIONS: Our results showed that crocodile oil could enhance cutaneous burn wound healing and reduce scar formation in rats, which might be related to TGF-beta1/Smad3 signaling. PMID- 22435859 TI - Mobile pediatric emergency response team: patient satisfaction during the novel H1N1 influenza outbreak. AB - OBJECTIVES: The objective was to determine child caregiver satisfaction with a nontraditional pediatric emergency department (ED) venue during the 2009 novel H1N1 influenza outbreak. METHODS: Between May 1 and 7, 2009, the Texas Children's Hospital (TCH) ED used a six-bed outdoor facility, the Mobile Pediatric Emergency Response Team (MPERT), to evaluate patients with suspected novel H1N1 influenza. Parents and caregivers of patients evaluated in the MPERT were surveyed by telephone using a validated questionnaire to evaluate satisfaction with the facility. RESULTS: Of 353 patients, 155 caregivers (44%) completed questionnaires; 127 had wrong numbers, 71 did not answer, and 15 were on a no call list. Survey responders felt that nurses and doctors explained concepts well (nurses 92%, doctors 94%), 91% felt TCH prepared them well for taking care of their children at home, 94% were satisfied with the medical care received, and 88% were not bothered by the outdoor setting. When asked to rate their MPERT experience on a scale of 0 (worst possible) to 10 (best possible), the median score was 9 (range 1 to 10). CONCLUSIONS: The MPERT facility alleviated patient volume surge and potentially prevented transmission during H1N1 outbreak. While these were health care provider goals, caregiver expectations were also met. Caregivers perceived MPERT as an acceptable alternative to receiving care in the regular ED, felt that physicians and nurses communicated well, and felt that medical care was good to excellent. Use of the MPERT did not negatively affect overall caregiver satisfaction with TCH. These findings suggest that families of pediatric patients are amenable to nontraditional ED venues during periods of ED crowding. PMID- 22435860 TI - Effect of a mass casualty incident: clinical outcomes and hospital charges for casualty patients versus concurrent inpatients. AB - OBJECTIVES: A mass casualty incident (MCI) may strain a health care system beyond surge capacity, affecting patterns of care for casualties and other patients. Prior studies of MCIs have assessed clinical care for casualty patients, but have not examined outcomes or expenditures for noncasualty inpatients in the same time period. METHODS: This was a retrospective analysis of administrative hospital claims in a state where an MCI with over 200 casualties occurred; two hospitals that admitted casualties of >5% of their inpatient capacity were studied. The "surge period" was defined as 7 days after the MCI. Using diagnostic codes, patients admitted on the MCI day with diagnoses of burns or inhalation injury were included in the "MCI surge cohort." Patients admitted within a time frame of 7 days prior to 7 days after the MCI who were inpatients during the surge period were included in the "non-MCI surge cohort." The authors compared the MCI and non MCI surge cohorts to a mutually exclusive reference cohort (all inpatients during 6 weeks prior to the MCI), regarding key outcomes of hospital length of stay (LOS) and hospital charges adjusted for age, sex, race/ethnicity, and severity of illness. RESULTS: Fifty-five patients met criteria for the MCI surge cohort, 1,369 for the non-MCI surge cohort, and 5,980 for the reference group. Compared with the reference group and adjusted for covariates, the mean (+/-SD) hospital LOS was 4.90 (+/-1.85) days longer for the MCI surge cohort (95% confidence interval [CI] = 1.67 to 8.84) and 1.34 (+/-0.16) days longer for the non-MCI surge cohort (95% CI = 1.00 to 1.65). The MCI cohort also had significantly longer mean hospital LOS than the non-MCI surge cohort (difference = 3.56 days; 95% CI = 0.36 to 7.36). Also adjusted for covariates, mean (+/-SD) total hospital charges for the MCI surge cohort were $22,349 (+/-$8,342) greater than for the reference group (95% CI = $8,182 to $39,485). Mean (+/-SD) charges for the non MCI surge cohort were $4,028 (+/-$633) greater than for the reference group (95% CI = $2,792 to $5,196). The MCI cohort also had higher mean total charges than the non-MCI surge cohort (difference = $18,321; 95% CI = $4,488 to $34,980). CONCLUSIONS: When adjusted for severity of illness, casualty patients and noncasualty patients receiving concurrent hospital care have significantly longer LOS and higher charges than typical hospital patients at times unaffected by MCIs. Spillover effects from MCIs for noncasualty patients have not been previously described and have implications for clinical and hospital management in MCI and other high-surge circumstances. PMID- 22435861 TI - Use of kiosks and patient understanding of opt-out and opt-in consent for routine rapid human immunodeficiency virus screening in the emergency department. AB - OBJECTIVES: The objective was to evaluate patient acceptance and understanding of nontargeted opt-out and opt-in rapid human immunodeficiency virus (HIV) screening using computerized kiosks in the emergency department (ED). METHODS: This study was a prospective quasi-experiment in an urban hospital with an annual ED and urgent care census of 120,000 visits. During medical screening, patients 13 years and older were offered rapid HIV screening using kiosks and opt-out consent (October 2009) or opt-in consent (December 2009). Random time blocks were used to administer structured surveys to evaluate patient understanding of the testing process. RESULTS: During the opt-out phase, 6,602 were offered testing, and of these 3,993 (61%) did not opt-out and 886 (13%) completed screening. During the opt-in phase, 5,781 were offered testing, and of these 930 (16%) opted-in and 389 (7%) completed screening (absolute difference = 6%, 95% confidence interval [CI] = 5% to 8%). During the opt-out phase, 330 patients completed the survey. Of these, 201 (61%) did not opt-out, but 108 (54%, 95% CI = 47% to 61%) responded that they had not been informed about an HIV test. Of the 84 patients who had been informed, 32 (38%, 95% CI = 28% to 49%) responded that they had not agreed to an HIV test. During the opt-in phase, 416 completed the survey. Of these, 80 (19%) agreed to testing and two (3%, 95% CI = 0.3% to 9%) responded that they had not been informed about an HIV test. Of the 74 patients who had been informed, only two (3%, 95% CI = 0.3% to 9%) responded that they had not agreed to an HIV test. CONCLUSIONS: Computerized kiosks can be successfully used to perform nontargeted rapid HIV screening in EDs. However, when using this approach, patient understanding of opt-in consent is significantly better than opt-out consent. PMID- 22435862 TI - Outcomes of early, late, and no admission to the intensive care unit for patients hospitalized with community-acquired pneumonia. AB - OBJECTIVES: The objective was to compare outcomes associated with early, late, and no admission to the intensive care unit (ICU) for patients hospitalized with community-acquired pneumonia (CAP). METHODS: This was a post hoc analysis of the original data from the Emergency Department Community-Acquired Pneumonia (EDCAP) and Pneumocom-1 prospective multicenter cohort studies of adult patients hospitalized with CAP. Propensity score-adjusted analysis was used to compare 28 day mortality and hospital length of stay (LOS) for 199, 144, and 2,215 patients with early (i.e., ICU admission on the day of emergency department [ED] presentation), late, and no ICU admission. RESULTS: Unadjusted 28-day mortality rates were 13.1, 19.4, and 5.7% for early, late, and no ICU admissions, respectively (p < 0.001). After adjusting for quintile of propensity score, the odds of 28-day mortality were higher for late ICU admissions relative to early ICU admissions (odds ratio [OR] = 2.63; 95% confidence interval [CI] = 1.42 to 4.90), and no ICU admissions (OR = 3.40; 95% CI = 2.11 to 5.48), but did not differ between early and no ICU admissions (OR = 1.29; 95% CI = 0.79 to 2.09). The median hospital LOS was 10 days for early (interquartile range [IQR] = 7 to 18), 15 days for late (IQR 9 to 23), and 6 days (IQR 4 to 9) for no ICU admissions (p < 0.001). CONCLUSIONS: This study suggests that late but not early admission to the ICU is associated with higher 28-day mortality for patients hospitalized with CAP. Patients admitted to the ICU have longer hospital LOS in comparison to those managed on the wards, particularly if they are admitted late to the ICU. PMID- 22435863 TI - Outcomes of community-dwelling seniors vary by type of emergency department. AB - OBJECTIVES: The specific objectives were: 1) to compare the characteristics and 6 month outcomes of community-dwelling seniors in Quebec, Canada, who visited three different emergency department (ED) types and 2) to explore whether the differences in outcomes by ED type were seen among subgroups of seniors. METHODS: The three types of ED were most specialized, less community-oriented (n = 12); moderately specialized, less community-oriented (n = 28); and least specialized, more community-oriented (n = 28). Administrative databases were used to create a cohort of 223,120 seniors who visited these 68 EDs during a 14-month period. Using a multilevel approach, the following patient characteristics were compared across ED types: sociodemographic (age, sex, urban vs. rural residence, proximity to ED); medical diagnoses and comorbidity burden; and utilization of hospital and physician services during the 16 months before the index ED visit. Cox regression analysis was used to model the relationships between ED type and two 6-month outcomes, adjusting for patient characteristics: 1) serious outcomes (death, acute or long term-care admission) among all individuals who made an index visit and 2) outpatient ED visits (without hospital admission) among those discharged either from the ED or hospital. Interactions between ED type and patient age, sex, urban-rural residence, and comorbidity burden were explored. RESULTS: Compared to patients treated at the least specialized EDs, those at the most specialized EDs were more often urban-dwelling, resided outside the health service area of the ED, and had the highest disease burden and prior specialist utilization. Those treated at the moderately specialized EDs were intermediate between these two groups. During the 6 months after the ED visit, the rate of serious outcomes was higher and the rate of outpatient ED visits was lower for the most specialized compared to the least specialized EDs, even after adjustment for patient characteristics. The differences in these outcomes by ED type were attenuated among older patients and those with greater comorbidity. CONCLUSIONS: More vulnerable community-dwelling seniors tend to be treated in more specialized EDs, which have worse linkages to community services. Improved linkages between more specialized EDs and the community (physicians, home care, and other services) and increased access to community services may improve outcomes in this population. Seniors treated at more specialized EDs were more likely to experience serious outcomes, but were less likely to make a return outpatient ED visit. PMID- 22435864 TI - The delivery of a health promotion intervention by a public health promotion specialist improves patient satisfaction in the emergency department. AB - OBJECTIVES: The objective was to introduce a public health promotion specialist (PHPS) into the hospital emergency department (ED) to provide a brief health promotion intervention to patients and to determine the effect of the initiative on patient satisfaction. METHODS: Patients in the intervention group were offered and received a 5- to 10-minute presentation about exercise, heart health, healthy eating on a budget, or weight control by a trained PHPS. Patients in the control group received usual ED care. Both groups completed the patient satisfaction instrument. Ordinal logistic regression models were used to compare the two groups on patient satisfaction questions and to identify predictors of the likelihood of patients referring others to the ED. RESULTS: Subjects in the intervention group were more likely to rate the services as great in areas of patient satisfaction such as provider listening, staff being friendly and helpful, comfort and safety, and privacy. Those in the intervention group were three times more likely than those in the control group to state that they would refer others to the ED. CONCLUSIONS: Health promotion and disease prevention interventions carried out by PHPS in the ED can improve patient satisfaction. PMID- 22435865 TI - A systematic review of emergency department technology-based behavioral health interventions. AB - OBJECTIVES: This systematic review evaluated the evidence for use of computer technologies to assess and reduce high-risk health behaviors in emergency department (ED) patients. METHODS: A systematic search was conducted of electronic databases, references, key journals, and conference proceedings. Studies were included if they evaluated the use of computer-based technologies for ED-based screening, interventions, or referrals for high-risk health behaviors (e.g., unsafe sex, partner violence, substance abuse, depression); were published since 1990; and were in English, French, or Spanish. Study selection and assessment of methodologic quality were performed by two independent reviewers. Data extraction was performed by one reviewer and then independently checked for completeness and accuracy by a second reviewer. RESULTS: Of 17,744 unique articles identified by database search, 66 underwent full-text review, and 20 met inclusion criteria. The greatest number of studies targeted alcohol/substance use (n = 8, 40%), followed by intentional or unintentional injury (n = 7, 35%) and then mental health (n = 4, 20%). Ten of the studies (50%) were randomized controlled trials; the remainder were observational or feasibility studies. Overall, studies showed high acceptability and feasibility of individual computer innovations, although study quality varied greatly. Evidence for clinical efficacy across health behaviors was modest, with few studies addressing meaningful clinical outcomes. Future research should aim to establish the efficacy of computer-based technology for meaningful health outcomes and to ensure that effective interventions are both disseminable and sustainable. CONCLUSIONS: The number of studies identified in this review reflects recent enthusiasm about the potential of computers to overcome barriers to behavioral health screening, interventions, and referrals to treatment in the ED. The available literature suggests that these types of tools will be feasible and acceptable to patients and staff. PMID- 22435866 TI - When an event sparks behavior change: an introduction to the sentinel event method of dynamic model building and its application to emergency medicine. AB - Experiencing a negative consequence related to one's health behavior, like a medical problem leading to an emergency department (ED) visit, can promote behavior change, giving rise to the popular concept of the "teachable moment." However, the mechanisms of action underlying this process of change have received scant attention. In particular, most existing health behavior theories are limited in explaining why such events can inspire short-term change in some and long-term change in others. Expanding on recommendations published in the 2009 Academic Emergency Medicine consensus conference on public health in emergency medicine (EM), we propose a new method for developing conceptual models that explain how negative events, like medical emergencies, influence behavior change, called the Sentinel Event Method. The method itself is atheoretical; instead, it defines steps to guide investigations that seek to relate specific consequences or events to specific health behaviors. This method can be used to adapt existing health behavior theories to study the event-behavior change relationship or to guide formulation of completely new conceptual models. This paper presents the tenets underlying the Sentinel Event Method, describes the steps comprising the process, and illustrates its application to EM through an example of a cardiac related ED visit and tobacco use. PMID- 22435867 TI - Novel metrics for quality of hospital surge capacity. PMID- 22435868 TI - Optimizing clinical operations as part of a global emergency medicine initiative in Kumasi, Ghana: application of Lean manufacturing principals to low-resource health systems. AB - BACKGROUND: Although many global health programs focus on providing clinical care or medical education, improving clinical operations can have a significant effect on patient care delivery, especially in developing health systems without high level operations management. Lean manufacturing techniques have been effective in decreasing emergency department (ED) length of stay, patient waiting times, numbers of patients leaving without being seen, and door-to-balloon times for ST elevation myocardial infarction in developed health systems, but use of Lean in low to middle income countries with developing emergency medicine (EM) systems has not been well characterized. OBJECTIVES: To describe the application of Lean manufacturing techniques to improve clinical operations at Komfo Anokye Teaching Hospital (KATH) in Ghana and to identify key lessons learned to aid future global EM initiatives. METHODS: A 3-week Lean improvement program focused on the hospital admissions process at KATH was completed by a 14-person team in six stages: problem definition, scope of project planning, value stream mapping, root cause analysis, future state planning, and implementation planning. RESULTS: The authors identified eight lessons learned during our use of Lean to optimize the operations of an ED in a global health setting: 1) the Lean process aided in building a partnership with Ghanaian colleagues; 2) obtaining and maintaining senior institutional support is necessary and challenging; 3) addressing power differences among the team to obtain feedback from all team members is critical to successful Lean analysis; 4) choosing a manageable initial project is critical to influence long-term Lean use in a new environment; 5) data intensive Lean tools can be adapted and are effective in a less resourced health system; 6) several Lean tools focused on team problem-solving techniques worked well in a low-resource system without modification; 7) using Lean highlighted that important changes do not require an influx of resources; and 8) despite different levels of resources, root causes of system inefficiencies are often similar across health care systems, but require unique solutions appropriate to the clinical setting. CONCLUSIONS: Lean manufacturing techniques can be successfully adapted for use in developing health systems. Lessons learned from this Lean project will aid future introduction of advanced operations management techniques in low- to middle-income countries. PMID- 22435869 TI - Application of statistical process control to physician-specific emergency department patient satisfaction scores: a novel use of the funnel plot. AB - OBJECTIVES: Emergency department (ED) patient satisfaction remains a high priority for many hospitals. Patient surveys are a common tool for measuring patient satisfaction, and process improvement efforts are aimed at improving patient satisfaction scores. In some institutions, patient satisfaction scores can be calculated for each emergency physician (EP). ED leaders are faced with the task of interpreting individual as well as group physician scores to identify opportunities for improvement. Analysis of these data can be challenging because of the relatively small numbers of returned surveys assignable to a single physician, variable numbers of surveys returned for each physician and high standard deviations (SDs) for individual physician scores. The objective was to apply statistical process control methodology to analyze individual as well as group physician patient satisfaction scores. The novel use of funnel plots to interpret individual physician patient satisfaction scores, track individual physician scores over two successive 8-month periods, and monitor physician group performance is demonstrated. METHODS: Patient satisfaction with physicians was measured using Press Ganey surveys for a 65,000-volume ED over two successive 8 month periods. Using funnel plots, individual physician patient satisfaction scores were plotted against the number of surveys completed for each physician for each 8-month period. Ninety-fifth and 99th percentile control limits were displayed on the funnel plots to illustrate individual physician patient satisfaction scores that are within, versus those that are outside of, expected random variation. Control limits were calculated using mean patient satisfaction scores and SDs for the entire group of physicians. Additional funnel plots were constructed to demonstrate changes in individual physicians' patient satisfaction scores as a function of increasing numbers of returned surveys and to illustrate changes in the group's patient satisfaction scores between the first and second 8 month intervals after the institution of process improvement efforts aimed at improving patient satisfaction. RESULTS: For the first 8-month period, 34,632 patients were evaluated in and discharged from the ED, with 581 surveys returned for 21 physicians. The mean (+/-SD) overall group physician patient satisfaction score was 81.8 (+/-24.7). Returned surveys per physician ranged from 2 to 58. For the second period, 34,858 patients were evaluated and discharged from the ED, with 670 patient satisfaction surveys returned for 20 physicians. The mean (+/ SD) overall physician score for all surveys returned during the second period was 85.0 (+/-22.2). Returned surveys per physician ranged from 8 to 65. CONCLUSIONS: The application of statistical control methodology using funnel plots as a means of analyzing ED group and physician patient satisfaction scores was possible. The authors believe that using funnel plots to analyze scores graphically can rapidly help determine the significance of individual physician patient satisfaction scores. In addition, serial funnel plots may prove to be useful as a means of measuring changes in patient satisfaction, particularly in response to quality improvement interventions. PMID- 22435870 TI - Can novice sonographers accurately locate an endotracheal tube with a saline filled cuff in a cadaver model? A pilot study. AB - BACKGROUND: No single confirmatory device can accurately distinguish between endotracheal, endobronchial, and esophageal intubation. Bedside ultrasound (US) shows promising potential for endotracheal tube (ETT) verification. Image acquisition depends on the approach used and the experience of the sonographer. Air within the trachea remains a challenge for interpretation of US images. Insufflation of the ETT cuff with saline helps overcome this difficulty and allows easy visualization of the cuff. This novel approach has not been studied in ETT verification among novice sonographers. OBJECTIVES: The objective was to evaluate the accuracy of novice sonographers in identifying proper ETT location and depth using US visualization of a saline-filled cuff. METHODS: Eight pediatric emergency medicine (PEM) fellows without prior training in airway bedside US participated in this prospective pilot study. Baseline US knowledge was assessed using a pretraining questionnaire. Fellows received a 20-minute didactic training session focused on airway US, followed by a 30-minute practice session. Using a linear US probe placed at the suprasternal notch, fellows identified the saline-filled cuff of an ETT in both the trachea and the esophagus. Following training, the ETT was placed in either the esophagus or the trachea of the cadaver model by the principal investigator. ETT depth (adequacy) was confirmed by chest radiograph. Each PEM fellow, blinded to the placement of the ETT, used bedside US to determine ETT location and depth. If placement was determined to be tracheal, the fellow was asked to comment on adequacy of tube placement. Adequate placement was defined as complete visualization of the ETT cuff within the trachea at the suprasternal notch. This was used as a surrogate for correct depth. This study sequence was repeated five times for each trainee, following varying placement of the ETT in the trachea or esophagus. RESULTS: The PEM fellows displayed limited baseline knowledge of US prior to receiving the training module (average score of 50% on pretest questionnaire). None had any prior airway bedside US experience. Following training, PEM fellows correctly identified ETT location in 39 of 40 scans, with a sensitivity of 96% (23 of 24) for identifying tracheal location. The tube depth was correctly identified in 22 of 23 scans identified as tracheal intubations. CONCLUSIONS: PEM fellows, lacking formal airway bedside US training, were able to identify the location and depth of a saline-filled ETT above or at the suprasternal notch in an adult cadaver model following a 50-minute teaching module. Filling the ETT cuff with saline allowed novice sonographers to accurately visualize the ETT within the trachea. PMID- 22435873 TI - Compassion fatigue in family caregivers: a Wilsonian concept analysis. AB - AIM: An analysis of the concept of compassion fatigue in family caregivers. BACKGROUND: The term 'compassion fatigue' is predominantly used with professional caregivers, such as nurses, doctors and social workers. Secondary traumatic stress, burnout, and other related terms are often cited in the literature in conjunction with compassion fatigue. Although compassion fatigue is linked to professional caregivers as a result of exposure to traumatizing events, minimal knowledge has been developed regarding its presence in family caregivers. DATA SOURCES: Literature published between 1980-2010 from the humanities, nursing and the social sciences, including psychology, sociology, social work, and religion, was reviewed. Data sources included dictionaries, newspapers and multiple academic databases, such as Academic Search Complete, Atla, CINAHL, PsychInfo, and PubMed. REVIEW METHODS: Wilson's concept analysis strategy was employed to frame the analysis of compassion fatigue, using model, contrary, related, and borderline cases to illustrate the concept's meaning in relation to family caregivers. RESULTS: Analysis revealed that the concept is predominantly used in relation to healthcare providers. Parallels are drawn between the role of healthcare providers and family caregivers. Compassion fatigue occurs when a care giving relationship founded on empathy potentially results in a deep psychological response to stress that progresses to physical, psychological, spiritual, and social exhaustion in the family caregiver. CONCLUSION: This concept analysis clarified the definition and revealed that the concept of compassion fatigue has potential use with family caregivers. Implications for practice and research are identified. PMID- 22435872 TI - Two types of burst firing in gonadotrophin-releasing hormone neurones. AB - Gonadotrophin-releasing hormone (GnRH) neurones fire spontaneous bursts of action potentials, although little is understood about the underlying mechanisms. In the present study, we report evidence for two types of bursting/oscillation driven by different mechanisms. Properties of these different types are clarified using mathematical modelling and a recently developed active-phase/silent-phase correlation technique. The first type of GnRH neurone (1-2%) exhibits slow (~0.05 Hz) spontaneous oscillations in membrane potential. Action potential bursts are often observed during oscillation depolarisation, although some oscillations were entirely subthreshold. Oscillations persist after blockade of fast sodium channels with tetrodotoxin (TTX) and blocking receptors for ionotropic fast synaptic transmission, indicating that they are intrinsically generated. In the second type of GnRH neurone, bursts were irregular and TTX caused a stable membrane potential. The two types of bursting cells exhibited distinct active phase/silent-phase correlation patterns, which is suggestive of distinct mechanisms underlying the rhythms. Further studies of type 1 oscillating cells revealed that the oscillation period was not affected by current or voltage steps, although amplitude was sometimes damped. Oestradiol, an important feedback regulator of GnRH neuronal activity, acutely and markedly altered oscillations, specifically depolarising the oscillation nadir and initiating or increasing firing. Blocking calcium-activated potassium channels, which are rapidly reduced by oestradiol, had a similar effect on oscillations. Kisspeptin, a potent activator of GnRH neurones, translated the oscillation to more depolarised potentials, without altering period or amplitude. These data show that there are at least two distinct types of GnRH neurone bursting patterns with different underlying mechanisms. PMID- 22435874 TI - Brazilian Ministry of Agriculture, Livestock and Food Supply (MAPA): strategies to tackle chemical food safety issues. PMID- 22435875 TI - Reactions of CH3SH and CH3SSCH3 with gas-phase hydrated radical anions (H2O)n(* ), CO2(*-)(H2O)n, and O2(*-)(H2O)n. AB - The chemistry of (H(2)O)(n)(*-), CO(2)(*-)(H(2)O)(n), and O(2)(*-)(H(2)O)(n) with small sulfur-containing molecules was studied in the gas phase by Fourier transform ion cyclotron resonance mass spectrometry. With hydrated electrons and hydrated carbon dioxide radical anions, two reactions with relevance for biological radiation damage were observed, cleavage of the disulfide bond of CH(3)SSCH(3) and activation of the thiol group of CH(3)SH. No reactions were observed with CH(3)SCH(3). The hydrated superoxide radical anion, usually viewed as major source of oxidative stress, did not react with any of the compounds. Nanocalorimetry and quantum chemical calculations give a consistent picture of the reaction mechanism. The results indicate that the conversion of e(-) and CO(2)(*-) to O(2)(*-) deactivates highly reactive species and may actually reduce oxidative stress. For reactions of (H(2)O)(n)(*-) with CH(3)SH as well as CO(2)(* )(H(2)O)(n) with CH(3)SSCH(3), the reaction products in the gas phase are different from those reported in the literature from pulse radiolysis studies. This observation is rationalized with the reduced cage effect in reactions of gas phase clusters. PMID- 22435876 TI - Evaluation of multiplexed PCR and liquid-phase array for identification of respiratory fungal pathogens. AB - Invasive fungal infections are the cause of serious morbidity and high mortality in immunocompromised patients. Early laboratory diagnostic options remain limited; however, rapid detection and accurate identification may improve outcome. Herein, multiplexed PCR followed by liquid-phase array was evaluated for detection and identification of common respiratory fungal pathogens, including Aspergillus fumigatus, Rhizopus microsporus, Scedosporium apiospermum and Fusarium solani. The limit of detection ranged 0.1-1 ng of DNA, depending on the fungus being tested. Primer cross-reactivity was seen for some fungi: Aspergillus flavus primers detected Aspergillus oryzae; Scedosporium apiospermum primers detected Paecilomyces lilacinus, and Aspergillus terreus primers detected S. apiospermum. PCR followed by liquid-phase array is potentially useful for the identification of clinically relevant fungal pathogens. PMID- 22435878 TI - Cryptococcal osteomyelitis of the scapula and rib in an immunocompetent patient. AB - Cryptococcal osteomyelitis is extremely rare and almost always occurs in immunocompromised patients. We describe a case of osteomyelitis due to Cryptococcus neoformans involving both scapula and rib in an immunocompetent and previously healthy patient. The patient received treatment with amphotericin B deoxycholate and flucytosine for 4 weeks, followed by oral fluconazole 400 mg per day for 8 weeks and 200 mg per day for 9 months. The 12-month course of antifungal therapy resulted in complete clinical recovery and undetectable serum cryptococcal antigen. Cryptococcal osteomyelitis should be suspected in any immunocompetent patient with osteolytic lesions on radiological images. PMID- 22435877 TI - Risk factors for mortality in patients with mucormycosis. AB - Optimal clinical care and clinical investigation of patients with mucormycosis are limited by absence of controlled trials, and absence of well-defined predictors of mortality or clinical response. The Deferasirox-AmBisome Therapy for mucormycosis (DEFEAT Mucor) study was the first randomized clinical trial conducted on patients with mucormycosis, and demonstrated that adjunctive deferasirox therapy did not improve outcomes of the disease. The current study describes clinical factors from the 20 patients enrolled to identify those associated with 90-day mortality of the 11 (55%) patients who died by day 90. Age, diabetes mellitus, transplant status, or antifungal therapy were not associated with mortality. However, active malignancy or neutropenia at enrollment were associated with increased mortality. Pulmonary infection was linked with lower Kaplan-Meier survival compared to non-pulmonary infection. Higher baseline serum concentrations of iron and ferritin were also associated with mortality. No patient who progressed clinically during the first 14 days of study therapy survived; however, many patients who clinically improved during that time did not survive to 90 days. In contrast, day 30 clinical response was predictive of 90-day survival. These factors may be useful in defining enrollment randomization stratification critieria for future clinical trials, and in supporting clinical care of patients with mucormycosis. PMID- 22435879 TI - Majocchi's granuloma: a symptom complex caused by fungal pathogens. AB - Majocchi's granuloma (MG) is a well-recognized but uncommon infection of dermal and subcutaneous tissues that is caused by mold fungi. Although primarily caused by keratinophilic dermatophytes such as anthropophilic Trichophyton rubrum, species from the Aspergillus and Phoma genera have been occasionally detected as etiologic agents of MG. In both healthy individuals and immunocompromised hosts, MG often presents as nodules, plaques, and papules on areas that are prone to trauma. Although MG generally appears on the upper and lower extremities (forearms, hands, legs, or ankles), it occasionally appears on the scalp and face. The clinical, mycologic, and/or cytologic diagnosis should be confirmed by the demonstration of perifollicular granulomatous inflammation by histologic examination. This review focuses on the clinical presentation, pathogenesis, laboratory diagnostic methods (including the Tzanck smear test), etiologic agents, histopathologic characteristics, and therapeutic approaches to the treatment of MG. PMID- 22435880 TI - Mechanical properties of Si nanowires as revealed by in situ transmission electron microscopy and molecular dynamics simulations. AB - Deformation and fracture mechanisms of ultrathin Si nanowires (NWs), with diameters of down to ~9 nm, under uniaxial tension and bending were investigated by using in situ transmission electron microscopy and molecular dynamics simulations. It was revealed that the mechanical behavior of Si NWs had been closely related to the wire diameter, loading conditions, and stress states. Under tension, Si NWs deformed elastically until abrupt brittle fracture. The tensile strength showed a clear size dependence, and the greatest strength was up to 11.3 GPa. In contrast, under bending, the Si NWs demonstrated considerable plasticity. Under a bending strain of <14%, they could repeatedly be bent without cracking along with a crystalline-to-amorphous phase transition. Under a larger strain of >20%, the cracks nucleated on the tensed side and propagated from the wire surface, whereas on the compressed side a plastic deformation took place because of dislocation activities and an amorphous transition. PMID- 22435881 TI - 3D graphene-cobalt oxide electrode for high-performance supercapacitor and enzymeless glucose detection. AB - Using a simple hydrothermal procedure, cobalt oxide (Co(3)O(4)) nanowires were in situ synthesized on three-dimensional (3D) graphene foam grown by chemical vapor deposition. The structure and morphology of the resulting 3D graphene/Co(3)O(4) composites were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and Raman spectroscopy. The 3D graphene/Co(3)O(4) composite was used as the monolithic free-standing electrode for supercapacitor application and for enzymeless electrochemical detection of glucose. We demonstrate that it is capable of delivering high specific capacitance of ~1100 F g(-1) at a current density of 10 A g(-1) with excellent cycling stability, and it can detect glucose with a ultrahigh sensitivity of 3.39 mA mM(-1) cm(-2) and a remarkable lower detection limit of <25 nM (S/N = 8.5). PMID- 22435882 TI - Carotid disease in acute ischemic stroke patients of northern Israel. AB - BACKGROUND: Carotid disease complicated by thrombosis or embolism is a frequent cause of acute ischemic stroke. The aim of the study was to determine factors associated with carotid disease in patients suffering from acute ischemic stroke in northern Israel. METHODS: Participants were 1378 acute ischemic stroke patients, including 671 patients with and 707 patients without carotid plaques, as defined by cervical ultrasound. RESULTS: Logistic regression analysis of possible predictors revealed that age, male gender, diabetes, hyperlipidemia, and smoking were independent predictors for the presence of carotid plaque. Male gender was independently associated with the increased prevalence of carotid stenosis of 50% or more, as well as with symptomatic carotid plaques. Age was found to be the only independent factor influencing the extent (bilateral vs unilateral) of carotid disease among acute ischemic stroke patients in northern Israel. Although ethnicity was initially found to have an influence on the prevalence of carotid plaques (higher among Jews than Arabs), no such influence was found after logistic regression. CONCLUSION: Our findings emphasize that demographic characteristics (age, gender) and vascular risk factors (diabetes, smoking and hyperlipidemia) rather than ethnic disparities are important determinants of carotid disease in acute ischemic stroke patients in northern Israel. PMID- 22435883 TI - Care by cell phone: text messaging for chronic disease management. AB - OBJECTIVES: To assess the feasibility of engaging adults with diabetes in self management behaviors between clinic visits by using cell phone text messaging to provide blood sugar measurement prompts and appointment reminders. STUDY DESIGN: Quasi-experimental pilot among adult diabetic patients with cell phones who receive regular care at a federally qualified community health center in Denver, Colorado, which serves a population that is predominantly either uninsured (41%) or on Medicaid or Medicare (56%). METHODS: Patients (N = 47) received text message prompts over a 3-month period. Blood sugar readings were requested 3 times per week (Monday, Wednesday, and Friday). Reminders were sent 7, 3, and 1 day(s) before each scheduled appointment. Acknowledgments were returned for all patient-sent messages. Focus groups were conducted in English and Spanish with selected patients (n = 8). RESULTS: Patients of all ages were active participants. Correctly formatted responses were received for 67.3% of 1585 prompts. More than three-fourths (79%) of the cohort responded to more than 50% of their prompts. The appointment analysis was underpowered to detect significant changes in attendance. Participants reported increased social support, feelings that the program "made them accountable," and increased awareness of health information. Two-thirds (66%) of patients provided glucose readings when prompted during the study, compared with 12% at 2 preceding clinic visits. CONCLUSIONS: For certain patients, cell phone-based text messaging may enhance chronic disease management support and patient-provider communications beyond the clinic setting. PMID- 22435884 TI - EHRs in primary care practices: benefits, challenges, and successful strategies. AB - OBJECTIVES: To understand the current use of electronic health records (EHRs) in small primary care practices and to explore experiences and perceptions of physicians and staff toward the benefits, challenges, and successful strategies for implementation and meaningful use of advanced EHR functions. STUDY DESIGN: Qualitative case study of 6 primary care practices in Virginia. METHODS: We performed surveys and in-depth interviews with clinicians and administrative staff (N = 38) and observed interpersonal relations and use of EHR functions over a 16-month period. Practices with an established EHR were selected based on a maximum variation of quality activities, location, and ownership. RESULTS: Physicians and staff report increased efficiency in retrieving medical records, storing patient information, coordination of care, and office operations. Costs, lack of knowledge of EHR functions, and problems transforming office operations were barriers reported for meaningful use of EHRs. Major disruption to patient care during upgrades and difficulty utilizing performance tracking and quality functions were also reported. Facilitators for adopting and using advanced EHR functions include team-based care, adequate technical support, communication and training for employees and physicians, alternative strategies for patient care during transition, and development of new processes and work flow procedures. CONCLUSIONS: Small practices experience difficulty with implementation and utilization of advanced EHR functions. Federal and state policies should continue to support practices by providing technical assistance and financial incentives, grants, and/or loans. Small practices should consider using regional extension center services and reaching out to colleagues and other healthcare organizations with similar EHR systems for advice and guidance. PMID- 22435885 TI - Adaptation and psychometric properties of the PACIC short form. AB - OBJECTIVES: The Patient Assessment of Chronic Illness Care (PACIC) is a widely used instrument to evaluate the quality and patient-centeredness of chronic illness care based on the Chronic Care Model (CCM). It is a validated and reliable instrument which consists of 20 items. Additionally, a short form with 11 items was developed. The aim of this study was to translate this short form into German and examine the psychometric properties among patients with a chronic illness in Germany. STUDY DESIGN: Observational study design. METHODS: We performed a translation and cultural adaptation of the PACIC short form into German. The German version was externally validated with the 20-item PACIC. Cronbach a, descriptive statistics, and principal component analysis were used to assess psychometric properties. RESULTS: In total, 264 primary care patients completed the PACIC short form. The PACIC short form showed good convergent construct validity to the 20-item PACIC (Spearman rank correlation 0.82, P < .001) and high internal consistency (Cronbach a 0.87). Principal component analysis underlined the 1-dimensional structure of the instrument. No correlation between the mean overall score of the PACIC short form and the number of chronic conditions (r = 0.068; P = .273) was found. CONCLUSIONS: The PACIC short form showed good to very good psychometric properties and reliable measures regarding patient assessment of receiving care congruent with the CCM. It is a less burdensome instrument which can be used for further research of patients with more than 1 chronic condition. PMID- 22435886 TI - Identifying patients with osteoporosis or at risk for osteoporotic fractures. AB - OBJECTIVES: To test the validity of using administrative data to identify patients with osteoporosis or low bone mineral density (BMD) and high risk for osteoporotic fractures. STUDY DESIGN: We conducted a retrospective cohort study. METHODS: We analyzed data from a managed care plan in Massachusetts. We developed 6 case-identification algorithms based on number of osteoporosis (OP) diagnoses, clinical setting of the OP diagnosis, timing of the OP diagnosis relative to BMD test, and clinical fracture risk factors adapted from the World Health Organization Fracture Risk Assessment Tool. We validated the algorithms against BMD results and calculated sensitivity, specificity, and positive predictive value (PPV) against 2 diagnostic criteria (T-score <=--2.5 and T-score <=--2.0). RESULTS: When compared against the first criterion (T-score <=--2.5), the sensitivity of algorithm (35% to 80%), specificity (65% to 93%), PPV (44% to 63%), and adding fracture risk factors did not improve case identification. When compared against the expanded criterion (T-score <=--2.0), we found the sensitivity of the algorithms ranged from 23% to 63%, specificity from 72% to 95%, and PPV from 67% to 83%. Including fracture risk in the expanded OP criterion improved case identification, and the algorithms achieved the highest PPV: 70% to 85%. CONCLUSIONS: Identifying patients with OP or low BMD and high risk for osteoporotic fractures is possible in administrative data if using information about both OP diagnoses and fracture risk profile. PMID- 22435887 TI - Systematic review of the impact of worksite wellness programs. AB - OBJECTIVES: To analyze the impact of worksite wellness programs on health and financial outcomes, and the effect of incentives on participation. METHODS: Sources were PubMed, CINAHL and EconLit, Embase, Web of Science, and Cochrane for 2000-2011. We examined articles with comparison groups that assessed health related behaviors, physiologic markers, healthcare cost, and absenteeism. Data on intervention, outcome, size, industry, research design, and incentive use were extracted. RESULTS: A total of 33 studies evaluated 63 outcomes. Positive effects were found for threefourths of observational designs compared with half of outcomes in randomized controlled trials. A total of 8 of 13 studies found improvements in physical activity, 6 of 12 in diet, 6 of 12 in body mass index/weight, and 3 of 4 in mental health. A total of 6 of 7 studies on tobacco and 2 of 3 on alcohol use found significant reductions. All 4 studies on absenteeism and 7 of 8 on healthcare costs estimated significant decreases. Only 2 of 23 studies evaluated the impact of incentives and found positive health outcomes and decreased costs. CONCLUSIONS: The studies yielded mixed results regarding impact of wellness programs on healthrelated behaviors, substance use, physiologic markers, and cost, while the evidence for effects on absenteeism and mental health is insufficient. The validity of those findings is reduced by the lack of rigorous evaluation designs. Further, the body of publications is in stark contrast to the widespread use of such programs, and research on the effect of incentives is lacking. PMID- 22435888 TI - Deposition gene transfection using bioconjugates of DNA and thermoresponsive cationic homopolymer. AB - A poly(N,N-dimethylaminoethylmethacrylate) (PDMAEMA) homopolymer with both thermoresponsive and cationic characteristics was applied to a vector for use in deposition transfection. PDMAEMA with a molecular weight of 2.5 * 10(5) g mol(-1) was synthesized by photoinduced radical polymerization. Polyplexes approximately 750 nm in size were formed by mixing PDMAEMA with luciferase-encoding plasmid DNA. The polyplexes had a lower critical solution temperature (LCST) of approximately 30 degrees C. In addition, they exhibited excellent adsorption and durability on a polystyrene surface, as confirmed by a surface chemical compositional analysis. When HeLa cells and primary cells were cultured on a substrate coated with the polyplexes, high transgene expression and cell viability of more than 90% were obtained at low charge ratios (PDMAEMA/plasmid DNA ratio) ranging from 2 to 8. In addition, transgene expression was sustained for over 2 weeks post-transfection whereas decreased expression was observed 5 days post-transfection when the conventional solution-mediated transfection method was used. Thus, high and sustained transgene expression as well as high cell viability can be realized by using small amounts of PDMAEMA as a deposition transfection material. PMID- 22435889 TI - Family caregiver participation in hospice interdisciplinary team meetings: how does it affect the nature and content of communication? AB - Collaboration between family caregivers and health care providers is necessary to ensure patient-centered care, especially for hospice patients. During hospice care, interdisciplinary team members meet biweekly to collaborate and develop holistic care plans that address the physical, spiritual, psychological, and social needs of patients and families. The purpose of this study was to explore team communication when video-conferencing is used to facilitate the family caregiver's participation in a hospice team meeting. Video-recorded team meetings with and without family caregiver participation were analyzed for communication patterns using the Roter Interaction Analysis System. Standard meetings that did not include caregivers were shorter in duration and task-focused, with little participation from social workers and chaplains. Meetings that included caregivers revealed an emphasis on biomedical education and relationship-building between participants, little psychosocial counseling, and increased socioemotional talk from social workers and chaplains. Implications for family participation in hospice team meetings are highlighted. PMID- 22435890 TI - tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury. AB - Traumatic brain injury (TBI) is associated with loss of autoregulation due to impaired responsiveness to cerebrovascular dilator stimuli, which leads to cerebral hypoperfusion and neuronal impairment or death. Upregulation of tissue plasminogen activator (tPA) post-TBI exacerbates loss of cerebral autoregulation and NMDA-receptor-mediated impairment of cerebral hemodynamics, and enhances excitotoxic neuronal death. However, the relationship between NMDA-receptor activation, loss of autoregulation, and neurological dysfunction is unclear. Here, we evaluated the potential therapeutic efficacy of a catalytically inactive tPA variant, tPA S481A, that acts by competing with wild-type tPA for binding, cleavage, and activation of NMDA receptors. Lateral fluid percussion brain injury was produced in anesthetized piglets. Pial artery reactivity was measured via a closed cranial window, and cerebrospinal fluid (CSF) extracellular signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) was quantified by enzyme-linked immunosorbent assay (ELISA). tPA-S481A prevented impairment of cerebral autoregulation and reduced histopathologic changes after TBI by inhibiting upregulation of the ERK isoform of MAPK. Treatment with this tPA variant provides a novel approach for limiting neuronal toxicity caused by untoward NMDA-receptor activation mediated by increased tPA and glutamate following TBI. PMID- 22435891 TI - Planar-chiral metal complexes comprised of square-planar metal and achiral tetradentate ligands: design, optical resolution, and thermodynamics. AB - Planar-chiral palladium complexes {[[N,N'-[1,4-butanediylbis(oxy-7,1 naphthalenediyl)]bis(2-pyridinecarboxamidato)](2-) kappaN(1),kappaN(1)',kappaN(2),kappaN(2)']palladium (PdL(4)) and [[2,2'-[1,4 butanediylbis[[(oxy-7,1-naphthalenediyl)imino]methyl]]dipyrrolato](2-) kappaN(1),kappaN(1)',kappaN(2),kappaN(2)']palladium (PdL(5))} were synthesized from achiral tetradentate ligands N,N'-[1,4-butanediylbis(oxy-7,1 naphthalenediyl)]bis(2-pyridinecarboxamide) (H(2)L(4)) and N,N'-bis[(1H-pyrrol-2 yl)methylidene]-7,7'-(1,4-butanediyldioxy)bis(1-naphthalenamine) (H(2)L(5)) bearing two dissymmetric bidentate units at both ends and a Pd(II) ion, respectively. The palladium complexes were crystallized in the monoclinic space group P2(1)/n with the unit cell parameters a = 16.5464(6) A, b = 11.3534(4) A, c = 17.6697(7) A, beta = 115.5300(10) degrees , and Z = 4 for PdL(4) and a = 17.2271(8) A, b = 10.1016(5) A, c = 17.9361(9) A, beta = 105.6310(10) degrees , and Z = 4 for PdL(5). The planar-chiral structures of PdL(4) and PdL(5) were confirmed by single-crystal X-ray analyses, resulting in the fact that the crystals were racemic mixtures. The racemic mixtures were successfully resolved by using chiral high-performance liquid-chromatography techniques. Racemizations of the complexes were found to be drastically dependent on the arrangement of the charged or uncharged metal-binding N atoms of the ligands. PMID- 22435892 TI - Self-monitoring of blood glucose in patients with diabetes who do not use insulin -are guidelines evidence-based? AB - AIMS: To evaluate if clinical practice guideline recommendations regarding self monitoring of blood glucose in patients with diabetes not using insulin follow the principles of evidence-based medicine. METHODS: After a search from 1999 to 2011, 18 clinical practice guidelines were included. Recommendations regarding self-monitoring of blood glucose were graded on a scale from one (strongly against self-monitoring) to four (strongly in favour of self-monitoring) and compared with the similarly graded conclusions of systematic reviews that were cited by the clinical practice guidelines. We also investigated how clinical practice guideline characteristics, for example funding sources, and quality of references cited could be related to the guideline recommendations. RESULTS: The clinical practice guidelines cited in total 15 systematic reviews, 14 randomized controlled trials, 33 non-randomized controlled trials papers and 18 clinical practice guidelines or position statements. The clinical practice guideline recommendations had an average grade of 3.4 (range 2.0-4.0). Higher grades were seen for clinical practice guidelines that acknowledged industry funding (mean value 4.0) or were issued by organizations depending on private funding (mean value 3.6 vs. 3.0 for governmental funding). The conclusions of the 15 systematic reviews had a mean grade of 2.2 (range 1.0-3.8). Systematic reviews with low grades were less cited. In total, 21 randomized controlled trials were included in the systematic reviews. Approximately half of these evaluated an educational intervention where the effect of self-monitoring of blood glucose could not be clearly isolated. CONCLUSIONS: Clinical practice guidelines were more in favour of self-monitoring use than the systematic reviews that were cited. The citation practice was non-systematic and industry funding seemingly led to a more positive attitude towards use of self-monitoring of blood glucose. PMID- 22435893 TI - Off-hour effects on stroke care and outcome in stroke centres. AB - BACKGROUND AND PURPOSE: Poorer stroke care processes and outcomes have been reported for acute stroke patients arriving at centres during off hours and weekends. OBJECTIVE: To compare each step of the continuous specialized care that Stroke Centres (SC) provide according to time of admission and final outcome. METHODS: Observational study of consecutive stroke patients admitted to SC during 2008 and 2009. Patients were classified into two groups according to their arrival time: Work Hours (WH) and Off Hour (OH) (weekends and any time other than 8:00 am to 3:00 pm on weekdays). Differences in time to diagnostic procedures, tPA administration, stroke outcome [modified Rankin Scale, (mRS)] and in-hospital fatality rates were analysed. RESULTS: A total of 912 patients were admitted. Data from 674 patients fulfilling study criteria were analysed. A total of 434 (64.4%) patients arrived during OH. No differences in stroke severity were found when comparing OH and WH. Time to blood test results was higher for WH (median 67 min vs. 47 min; P < 0.01), but time to cranial CT scan was similar. Intravenous tPA was administered to 58 (16.4%) OH vs. 26 (13.1%) WH patients (P = 0.33). OH arrival was not associated with poorer outcome (mRS >= 3) at discharge (32.8% vs. 37%; P = 0.27), or at the 3-month follow-up (30.6% vs. 27.6%, P = 0.52). No differences were found for in-hospital fatality rates (5.8% vs. 5.4%, P = 1.00). CONCLUSIONS: The care provided by SC with neurologists on call 24/7 prevents differences in outcomes associated with time of admission and guarantees equal attention to stroke patients. PMID- 22435894 TI - Leukotriene D4 bronchial provocation test: methodology and diagnostic value. AB - BACKGROUND: Although leukotriene D4 (LTD4) is a potent bronchoconstrictor, little is known about airway responsiveness to LTD4 in asthmatics with different inflammation phenotypes. OBJECTIVES: To establish the methodology and investigate the distribution characters of airway responsiveness, diagnostic value and safety of LTD4 bronchial provocation test. METHODS: LTD4 bronchial provocation tests were performed in 62 asthmatics and 21 normal controls. Airway responsiveness was assessed based on the cumulative dosage causing a 20% fall in FEV(1) (PD(20)FEV(1)-LTD4) and was expressed as (median, interquartile range). The fall in spirometric parameters was plotted showing the distribution characters. The diagnostic value was assessed using receiver operation characteristic (ROC) curve. All adverse events were recorded during the test. RESULTS: Airway responsiveness to LTD4 was significantly higher in asthmatics (0.410 nmol, 0.808 nmol) as compared with normal controls (5.00 nmol, 0.00 nmol). The decrease in spirometric parameters varied after bronchoprovocation, which was negatively correlated with PD(20)FEV(1)-LTD4, among which FEV(1) had a maximal slope (r = 0.524, P = 0.000). High diagnostic value (AUC: 0.914, 95%CI: [0.855, 0.974]) was revealed by ROC curve. The major adverse events were dyspnea (82.3%), chest tightness (72.6%), wheezing (32.3%) and coughing (25.8%) in asthmatics, which could overall be recovered within 15.0 minutes after inhalation of 200 ~ 400 mcg salbutamol MDI. No serious adverse event was reported. CONCLUSION: The established procedure of LTD4 bronchial provocation test is effective in the diagnosis of asthma and is well tolerated. Future studies are necessary to provide more evidences in terms of safety and efficacy. This may be helpful upon further application in clinical practice. PMID- 22435895 TI - Cyanobacteria cause black staining of the National Museum of the American Indian Building, Washington, DC, USA. AB - Microbial deterioration of stone is a widely recognised problem affecting monuments and buildings all over the world. In this paper, dark-coloured staining, putatively attributed to microorganisms, on areas of the National Museum of the American Indian Building, Washington, DC, USA, were studied. Observations by optical and electron microscopy of surfaces and cross sections of limestone indicated that biofilms, which penetrated up to a maximum depth of about 1 mm, were mainly composed of cyanobacteria, with the predominance of Gloeocapsa and Lyngbya. Denaturing gradient gel electrophoresis analysis revealed that the microbial community also included eukaryotic algae (Trebouxiophyceae) and fungi (Ascomycota), along with a consortium of bacteria. Energy-dispersive X ray spectroscopy analysis showed the same elemental composition in stained and unstained areas of the samples, indicating that the discolouration was not due to abiotic chemical changes within the stone. The dark pigmentation of the stone was correlated with the high content of scytonemin, which was found in all samples. PMID- 22435896 TI - Why choose a career in nursing? AB - AIM: This paper examines the prevalence of various career-choice motives given by nursing students in two national cohorts at the beginning and end of their education respectively and how these motives are interrelated and associated with perceived career-choice stress. BACKGROUND: Several international studies have identified various motives for choosing nursing. The degree to which motives are autonomous or controlled affects an individual's professional development and health. Earlier research on career choice has used small non-representative samples. DESIGN: Cross-sectional survey. METHODS: This was a study of all Swedish undergraduate nursing students in their first (n = 1697) or last (n = 1150) year. The data for this study were collected in 2002, forming the baseline of a prospective longitudinal study where data were collected annually between 2002 2010. Data analysis included descriptive statistics, exploratory factor analysis and multiple regression analysis. RESULTS: A model incorporating three factors explained 50-60% of the variance in motives for becoming a nurse. 'Genuine interest' was ranked highest, followed by 'practical reasons'. Only a small group of students gave nursing as 'default choice'. Fewer autonomous motives for choosing nursing were associated with perceived career-choice stress. CONCLUSION: We suggest that it is imperative for nurse educators to identify students who lack autonomy. Supporting students' autonomy is likely to improve educational outcome, enable professional socialization and decrease professional turnover. Future research on students' motivation in relation to educational outcome and professional turnover as well as quality of patient care is needed. PMID- 22435897 TI - Quantitative genome re-sequencing defines multiple mutations conferring chloroquine resistance in rodent malaria. AB - BACKGROUND: Drug resistance in the malaria parasite Plasmodium falciparum severely compromises the treatment and control of malaria. A knowledge of the critical mutations conferring resistance to particular drugs is important in understanding modes of drug action and mechanisms of resistances. They are required to design better therapies and limit drug resistance.A mutation in the gene (pfcrt) encoding a membrane transporter has been identified as a principal determinant of chloroquine resistance in P. falciparum, but we lack a full account of higher level chloroquine resistance. Furthermore, the determinants of resistance in the other major human malaria parasite, P. vivax, are not known. To address these questions, we investigated the genetic basis of chloroquine resistance in an isogenic lineage of rodent malaria parasite P. chabaudi in which high level resistance to chloroquine has been progressively selected under laboratory conditions. RESULTS: Loci containing the critical genes were mapped by Linkage Group Selection, using a genetic cross between the high-level chloroquine resistant mutant and a genetically distinct sensitive strain. A novel high resolution quantitative whole-genome re-sequencing approach was used to reveal three regions of selection on chr11, chr03 and chr02 that appear progressively at increasing drug doses on three chromosomes. Whole-genome sequencing of the chloroquine-resistant parent identified just four point mutations in different genes on these chromosomes. Three mutations are located at the foci of the selection valleys and are therefore predicted to confer different levels of chloroquine resistance. The critical mutation conferring the first level of chloroquine resistance is found in aat1, a putative aminoacid transporter. CONCLUSIONS: Quantitative trait loci conferring selectable phenotypes, such as drug resistance, can be mapped directly using progressive genome-wide linkage group selection. Quantitative genome-wide short-read genome resequencing can be used to reveal these signatures of drug selection at high resolution. The identities of three genes (and mutations within them) conferring different levels of chloroquine resistance generate insights regarding the genetic architecture and mechanisms of resistance to chloroquine and other drugs. Importantly, their orthologues may now be evaluated for critical or accessory roles in chloroquine resistance in human malarias P. vivax and P. falciparum. PMID- 22435898 TI - Three-dimensional analysis and computer modeling of the capillary endothelial vesicular system with electron tomography. AB - OBJECTIVE: We examined the three-dimensional organization of the endothelial vesicular system with TEM tomography of semi-thick sections. MATERIALS AND METHODS: Mouse abdominal muscle capillaries were perfused with terbium to label vesicular compartments open to the luminal surface. The tissue was prepared for TEM and semi-thick (250 nm) sections were cut. Dual axis tilt series, collected from +60 degrees to -60 degrees at 1 degrees increments, were acquired in regions of labeled abluminal caveolae. These tomograms were reconstructed and analyzed to reveal three-dimensional vesicular associations not evident in thin sections. RESULTS: Reconstructed tomograms revealed free vesicles, both labeled and unlabeled, in the endothelial cytoplasm as well as transendothelial channels that spanned the luminal and abluminal membranes. A large membranous compartment connecting the luminal and abluminal surfaces was also present. Computer modeling of tomographic data and video animations provided three-dimensional perspectives to these structures. CONCLUSIONS: Uncertainties associated with other three dimensional methods to study the capillary wall are remedied by tomographic analysis of semi-thick sections. Transendothelial channels of fused vesicles and free cytoplasmic vesicles give credence to their role as large pores in the transport of solutes across the walls of continuous capillaries. PMID- 22435899 TI - Yentl resurgat: inadequate management of cardiovascular risk in women. PMID- 22435900 TI - Legionella pneumophila lung abscess associated with immune suppression. AB - Legionella species are a common cause of community-acquired pneumonia, infrequently complicated by cavitary disease. We describe Legionella pneumophila pneumonia and abscess formation in an immunosuppressed patient receiving corticosteroid therapy for metastatic breast carcinoma. The predisposing role of corticosteroids is discussed and the management of this complication is reviewed. PMID- 22435901 TI - Safety of withholding anticoagulation in patients with mechanical prosthetic valves and intracranial haemorrhage. AB - Patients with prosthetic heart valves require lifelong anticoagulation to prevent thromboembolism. When they have intracranial haemorrhage, anticoagulation has to be withheld. This study was aimed to identify safety duration and complications of anticoagulation withholding in patients with prosthetic heart valves and intracranial haemorrhage. This was a retrospective descriptive study in 26 prosthetic heart valve patients hospitalised in Srinagarind Hospital, Khon Kaen University because of intracranial haemorrhage from 2003 to 2008. Range of anticoagulation withholding was 1 to 26 days with mean 8.5 +/- 7.7 days. Most patients (84.6%) were withheld anticoagulation for less than 14 days. There were five in-hospital deaths mostly within 3 days of admission from severe intracranial haemorrhage. No data of reintroduction of anticoagulation was found in three patients because they were lost to follow up. One patient had right basal ganglia infarction after 7 days of anticoagulation withholding. Prosthetic heart valve dysfunction was suspected in one patient who withheld anticoagulant for 76 days. Discontinuation of anticoagulation in patients with prosthetic heart valves and intracranial haemorrhage for less than 7 days was associated with low thromboembolic risk and there was no clinical evidence of prosthetic heart valve dysfunction when anticoagulation was withheld for less than 14 days. PMID- 22435902 TI - Allergic bronchopulmonary aspergillosis: a reversible cause of complete lung collapse. PMID- 22435903 TI - Patent foramen ovale and paradoxical cerebral embolism in a young woman. PMID- 22435904 TI - 'Prolactinoma: are dopamine agonists still first choice?'. PMID- 22435906 TI - Diet-induced obesity resistance of Kv1.3-/- mice is olfactory bulb dependent. AB - Gene-targeted deletion of the voltage-gated potassium channel, Kv1.3 (Kv1.3-/-), increases olfactory sensitivity and discriminatory ability, and causes resistance to diet-induced obesity (DIO) in mice. The present study aimed to determine whether the enhanced olfactory ability of the Kv1.3-/- mouse contributes to the resistance to DIO. Kv1.3+/+ and Kv1.3-/- mice were subject to bilateral olfactory bulbectomy (OBX) or sham surgery at 9 weeks of age and placed on either a control chow diet or a 32% moderately high-fat diet (MHF). Caloric and water intake, locomotor activity and oxygen consumption were monitored after 5 weeks of diet treatment. At the end of 26 weeks of diet treatment, fat pad weight and blood chemistry were evaluated. Kv1.3+/+ mice exhibited a significant increase in weight, adiposity, fasting glucose and fasting leptin in response to the MHF diet, with or without OBX. When treated with a MHF-diet, Kv1.3-/- mice gained significantly less weight than Kv1.3+/+ mice and exhibited a significant increase in light phase metabolism. OBX of Kv1.3-/- mice prevented the resistance to DIO and concomitant up-regulation of light phase metabolism at the same time as decreasing dark phase metabolism and total energy expenditure. These findings suggest that pathways activated in Kv1.3-/- that increased energy expenditure and led to resistance to DIO are olfactory bulb dependent. Thus, these findings add to a growing body of evidence suggesting that the olfactory system can modulate the pathways involved in the regulation of energy balance. PMID- 22435907 TI - Adherence and dosing frequency of common medications for cardiovascular patients. AB - OBJECTIVES: To compare adherence between once-daily (QD) and twice-daily (BID) dosing with chronic-use prescription medications used by patients with cardiovascular disease. STUDY DESIGN: Retrospective cohort database analysis. METHODS: Analysis consisted of 1,077,474 patients aged >18 years with a prescription index date from January 1 to December 31, 2007, for an antidiabetic, antihyperlipidemic, antiplatelet, or cardiac agent with QD or BID dosing. Adherence (medication possession ratio [MPR]) was the number of days of medication supplied between the first prescription fill date and the subsequent 365 days divided by 365 days. Overall mean MPR and comparisons between dosing frequency groups were assessed with a generalized estimating equation. Covariates included age at index date, gender, Charlson comorbidity index, therapeutic class, dosing frequency, and the interaction between therapeutic class and dosing frequency group. RESULTS: Overall, the adjusted mean MPR +/- standard error (SE) value for QD agents was 13.6% greater than BID agents (0.66 +/- 0.0006 vs 0.57 +/ 0.0016; P <.01). The adjusted mean MPR value for QD agents was 2.9%, 17.5%, and 29.4% greater than BID agents in the antidiabetic, antihyperlipidemic, and antiplatelet therapeutic classes, respectively. For cardiac agents, the adjusted mean MPR value was similar between QD and BID agents. Carvedilol represented approximately 80% of the cardiac agents in the BID group. The adjusted mean MPR +/- SE for carvedilol phosphate QD was 0.73 +/- 0.0024 and 0.65 +/- 0.0027 for carvedilol BID (11% difference; P <.01). CONCLUSIONS: In this large analysis, the QD dosing regimen was related to greater adherence versus a BID regimen. PMID- 22435908 TI - Reducing long-term cost by transforming primary care: evidence from Geisinger's medical home model. AB - OBJECTIVES: To estimate cost savings associated with ProvenHealth Navigator (PHN), which is an advanced model of patient-centered medical homes (PCMHs) developed by Geisinger Health System, and determine whether those savings increase over time. STUDY DESIGN: A retrospective claims data analysis of 43 primary care clinics that were converted into PHN sites between 2006 and 2010. The study population included Geisinger Health Plan's Medicare Advantage plan enrollees who were 65 years or older treated in these clinics (26,303 unique members). METHODS: Two patient-level multivariate regression models (with and without interaction effects between prescription drug coverage and PHN exposure) with member fixed effects were used to estimate the effect of members' exposure to PHN on per-member per-month total cost, controlling for member risk, seasonality, yearly trend, and a set of baseline clinic characteristics. RESULTS: In both models, a longer period of PHN exposure was significantly associated with a lower total cost. The total cumulative cost savings over the study period was 7.1% (95% confi dence interval [CI] 2.6-11.6) using the model with the prescription drug coverage interaction effects and 4.3% (95% CI 0.4-8.3) using the model without the interaction effects. Corresponding return on investment was 1.7 (95% CI 0.3-3.0) and 1.0 (95% Cl -0.1 to 2.0), respectively. CONCLUSIONS: Our finding suggests that PCMHs can lead to significant and sustainable cost savings over time. PMID- 22435909 TI - What determines successful implementation of inpatient information technology systems? AB - OBJECTIVES: To identify the factors and strategies that were associated with successful implementation of hospital-based information technology (IT) systems in US Department of Veterans Affairs (VA) hospitals, and how these might apply to other hospitals. STUDY DESIGN: Qualitative analysis of 118 interviews conducted at 7 VA hospitals. The study focused on the inpatient setting, where nurses are the main patient-care providers; thus, the research emphasized the impact of Computerized Patient Record System and Bar Code Medication Administration on nurses. Hospitals were selected to represent a range of IT implementation dates, facility sizes, and geography. The subjects included nurses, pharmacists, physicians, IT staff, and managers. Interviews were guided by a semi-structured interview protocol, and a thematic analysis was conducted, with initial codes drawn from the content of the interview guides. Additional themes were proposed as the coding was conducted. RESULTS: Five broad themes arose as factors which affected the process and success of implementation: (1) organizational stability and implementation team leadership, (2) implementation timelines, (3) equipment availability and reliability, (4) staff training, and (5) changes in work flow CONCLUSIONS: Overall IT implementation success in the VA depended on: (1) whether there was support for change from both leaders and staff, (2) development of a gradual and flexible implementation approach, (3) allocation of adequate resources for equipment and infrastructure, hands-on support, and deployment of additional staff, and (4) how the implementation team planned for setbacks, and continued the process to achieve success. Problems that developed in the early stages of implementation tended to become persistent, and poor implementation can lead to patient harm. PMID- 22435910 TI - IT-enabled systems engineering approach to monitoring and reducing ADEs. AB - OBJECTIVES: To develop and pilot-test a Web-based implementation of a team resource management (TRM) intervention to improve medication safety in primary care. STUDY DESIGN: Randomized controlled trial. METHODS: Eight practices were randomized to either the Web-based TRM or usual practice (4 practices in each group). Primary outcome was adverse drug events (ADEs) in older adults, ascertained using a trigger tool chart review at two 12-month periods (before and after the intervention). The prospective TRM approach, designed to inculcate ownership and empowerment, facilitates systematic appraisal of risk and error reduction. This approach uses the highly adaptable and transferable Safety Enhancement and Monitoring Instrument that is Patient Centered. RESULTS: The rate of ADEs decreased from 25.8 to 18.3 per 100 patients per year in the intervention group. The rate was virtually unchanged in the control group (24.3 vs 24.8). In an analysis of covariance at the practice level, being in the intervention group was associated with a lower rate of ADEs. The interaction between time (preintervention vs postintervention) and group (intervention vs control) was not signifi cant (P = .104) but showed a trend toward a decrease in the intervention group compared with the control group over time. CONCLUSIONS: The Web-based TRM intervention proved feasible and demonstrated potential for effectiveness in various ambulatory settings. This pilot study was limited by small size and short follow-up period. Future studies should test the intervention on a larger scale over a longer period of time and should explore methods for overcoming common barriers to change. PMID- 22435911 TI - Up-conversion cell imaging and pH-induced thermally controlled drug release from NaYF4/Yb3+/Er3+@hydrogel core-shell hybrid microspheres. AB - In this study, we report a new controlled release system based on up-conversion luminescent microspheres of NaYF(4):Yb(3+)/Er(3+) coated with the smart hydrogel poly[(N-isopropylacrylamide)-co-(methacrylic acid)] (P(NIPAM-co-MAA)) (prepared using 5 mol % of MAA) shell. The hybrid microspheres show bright up-conversion fluorescence under 980 nm laser excitation, and turbidity measurements show that the low critical solution temperature of the polymer shell is thermo- and pH dependent. We have exploited the hybrid microspheres as carriers for Doxorubicin hydrochloride (DOX) due to its stimuli-responsive property as well as good biocompatibility via MTT assay. It is found that the drug release behavior is pH triggered thermally sensitive. Changing the pH to mildly acidic condition at physiological temperature deforms the structure of the shell, causing the release of a large number of DOX from the microspheres. The drug-loaded microspheres exhibit an obvious cytotoxic effect on SKOV3 ovarian cancer cells. The endocytosis process of drug-loaded microspheres is observed using confocal laser scanning microscopy and up-conversion luminescence microscopy. Meanwhile, the as prepared NaYF(4):Yb(3+)/Er(3+)@SiO(2)@P(NIPAM-co-MAA) microspheres can be used as a luminescent probe for cell imaging. In addition, the extent of drug release can be monitored by the change of up-conversion emission intensity. These pH-induced thermally controlled drug release systems have potential to be used for in vivo bioimaging and cancer therapy by the pH of the microenvironment changing from 7.4 (normal physiological environment) to acidic microenvironments (such as endosome and lysosome compartments) owing to endocytosis. PMID- 22435912 TI - Minimally invasive follicular thyroid carcinoma developed in dyshormonogenetic multinodular goiter due to thyroid peroxidase gene mutation. AB - BACKGROUND: The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has only been reported in one patient harboring mutations in the thyroid peroxidase (TPO) gene. PATIENT FINDINGS: We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of levothyroxine treatment and consequently normal thyrotropin (TSH) levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland. SUMMARY: Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG. CONCLUSIONS: Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma. PMID- 22435913 TI - Pancreatic metastasis arising from a BRAF(V600E)-positive papillary thyroid cancer: the role of endoscopic ultrasound-guided biopsy and response to sorafenib therapy. AB - BACKGROUND: Lungs and bones are the most common sites for distant metastases from papillary thyroid cancer (PTC). Metastases to the pancreas are extremely rare. Here we present a man with pancreatic metastases from PTC, report our experience with sorafenib therapy, and discuss the role of endoscopic ultrasound (EUS) guided biopsy in its diagnosis. PATIENT FINDINGS: A 56-year-old man underwent total thyroidectomy, right-modified neck dissection, and radioactive iodine (RAI) remnant ablation for PTC at age 47 years (in 2002). Between 2002 and 2007, he had three more neck surgeries, two RAI therapies, and external beam radiotherapy for persistent and subsequently metastatic PTC. In 2008, a computed tomography/positron emission tomography (CT/PET) scan showed an 18F fluorodeoxyglucose (FDG)-avid pancreatic focus. Magnetic resonance imaging (MRI) revealed a pancreatic nodule at the same location. An EUS-guided biopsy confirmed the diagnosis of pancreatic metastasis from PTC, and molecular studies showed positive BRAF(V600E) mutation. He was treated with sorafenib for 6 months. Although a lung CT scan done 2 months after initiation of sorafenib suggested stability of the disease, MRI studies done at 3 and 6 months showed clear progression with an increase in the size of the lung and pancreatic metastases. Subsequently, he developed liver, bone, and omental metastases. He died in July 2011, 9 years and 8 months after the initial diagnosis of PTC and 20 months after discovery of the pancreatic metastasis. SUMMARY: A middle-aged man with PTC developed lung metastases despite multiple surgeries and RAI therapies. Seven years after the initial diagnosis, a pancreatic metastasis was accidentally discovered. Both the metastasis and the primary thyroid tumor are positive for BRAF(V600E) mutation. The lung and pancreatic metastases progressed while the patient was receiving sorafenib for 6 months, and the patient died 20 months after diagnosis of pancreatic metastasis. CONCLUSION: PTC rarely metastasizes to the pancreas. In this patient, an FDG PET scan and EUS-guided biopsy played important roles in the diagnosis. PTC metastases to the pancreas usually occur in otherwise advanced disease. In the patient presented here, sorafenib may have slowed disease progression but the overall utility of tyrosine kinase inhibitors in pancreatic metastases from PTC is not clear. PMID- 22435914 TI - American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer. AB - BACKGROUND: Cervical lymph node metastases from differentiated thyroid cancer (DTC) are common. Thirty to eighty percent of patients with papillary thyroid cancer harbor lymph node metastases, with the central neck being the most common compartment involved. The goals of this study were to: (1) identify appropriate methods for determining metastatic DTC in the lateral neck and (2) address the extent of lymph node dissection for the lateral neck necessary to control nodal disease balanced against known risks of surgery. METHODS: A literature review followed by formulation of a consensus statement was performed. RESULTS: Four proposals regarding management of the lateral neck are made for consideration by organizations developing management guidelines for patients with thyroid nodules and DTC including the next iteration of management guidelines developed by the American Thyroid Association (ATA). Metastases to lateral neck nodes must be considered in the evaluation of the newly diagnosed thyroid cancer patient and for surveillance of the previously treated DTC patient. CONCLUSIONS: Lateral neck lymph nodes are a significant consideration in the surgical management of patients with DTC. When current guidelines formulated by the ATA and by other international medical societies are followed, initial evaluation of the DTC patient with ultrasound (or other modalities when indicated) will help to identify lateral neck lymph nodes of concern. These findings should be addressed using fine-needle aspiration biopsy. A comprehensive neck dissection of at least nodal levels IIa, III, IV, and Vb should be performed when indicated to optimize disease control. PMID- 22435915 TI - Isoelectronic doping of graphdiyne with boron and nitrogen: stable configurations and band gap modification. AB - Graphdiyne, consisting of sp- and sp(2)-hybridized carbon atoms, is a new member of carbon allotropes which has a natural band gap ~1.0 eV. Here, we report our first-principles calculations on the stable configurations and electronic structures of graphdiyne doped with boron-nitrogen (BN) units. We show that BN unit prefers to replace the sp-hybridized carbon atoms in the chain at a low doping rate, forming linear BN atomic chains between carbon hexagons. At a high doping rate, BN units replace first the carbon atoms in the hexagons and then those in the chains. A comparison study indicates that these substitution reactions may be easier to occur than those on graphene which composes purely of sp(2)-hybridized carbon atoms. With the increase of BN component, the band gap increases first gradually and then abruptly, corresponding to the transition between the two substitution motifs. The direct-band gap feature is intact in these BN-doped graphdiyne regardless the doping rate. A simple tight-binding model is proposed to interpret the origin of the band gap opening behaviors. Such wide-range band gap modification in graphdiyne may find applications in nanoscaled electronic devices and solar cells. PMID- 22435916 TI - The Jefferson Scale of Physician Empathy: a preliminary psychometric study and group comparisons in Korean physicians. AB - BACKGROUND: Empathy is an important element of professionalism in medicine. Thus, evaluation and enhancement empathy in physicians is important, regardless of geographical boundaries. AIM: This study was designed to evaluate the psychometrics of a Korean version of the Jefferson Scale of Physician Empathy (JSPE) among Korean physicians. METHODS: The Korean version of JSPE was completed by 229 physicians in Korea. RESULTS: Item-total score correlations were all positive and statistically significant. Cronbach's coefficient alpha was 0.84. The mean score was 98.2 (SD = 12.0), which was lower than that reported for American and Italian physicians. The emerged factor structure of the translated version was somewhat similar to that reported for American physicians, although the order was different. Significant differences in the mean empathy scores were observed between men and women and among physicians in different specialties. CONCLUSION: Our findings provide evidence in support of reliability and construct validity of the Korean version of JSPE for assessing empathy among Korean physicians. The disparity between Korean physicians and physicians from other countries may be explained by differences in the culture of medical education and medical practice. It suggests an exploration of cross-cultural differences in physician empathy. PMID- 22435917 TI - Who will be the faculty of the future? Results of a 5-year study growing educators using an immersive third postgraduate year (PGY-3) faculty development mini-fellowship. AB - BACKGROUND: Residency education requires large numbers of skilled teaching faculty. Potential faculty can often be identified during residency training. AIMS: Employ a 4-week immersive faculty development mini-fellowship to enhance the teaching skills of selected PGY-3 residents and study outcomes over 5 years. METHODS: PGY-3 residents were competitively selected and completed the 4-week curriculum to increase skills in precepting, small group teaching, large group teaching, learner feedback/assessment, academic career development, and research. RESULTS: Fifteen residents completed the mini-fellowship over the 5-year study period. The curriculum was rated highly by the residents with mean ratings of curriculum components ranging from 4.5 to 4.9 on a 5-point scale. Eight residents (53%) were selected for faculty positions compared to a usual selection rate of 11%. Compared to new faculty without mini-fellowship completion, program directors rated the residents completing the mini-fellowship as better prepared to perform learner feedback (4.1 vs. 3.0, p <= 0.01) and to understand the conduct of research (3.6 vs. 2.5 p <= 0.01). CONCLUSIONS: This study demonstrates short-term success at growing faculty with enhanced teaching skills during residency. While long-term retention in academic medicine cannot be predicted, this program represents one method to mitigate shortages of qualified junior residency faculty. PMID- 22435918 TI - Twelve tips for supervising research students. AB - BACKGROUND: Research supervision is a task that requires a set of abilities and skills. Many academics begin research supervision as novices and develop their abilities and skills through experience over time. AIM: We aim to provide advice about research supervision to prospective supervisors. METHODS: We used critical reflection of our experiences, including feedback received from students under supervision as well as advice from the literature to develop these tips. RESULTS: Twelve tips are presented to assist faculty with research supervision. CONCLUSION: Research supervision is an important component of many medical academics' work. Beginning supervisors need to understand the dynamics and practicalities of supervision before they embark on this process. PMID- 22435919 TI - Global health training starts at home: a unique US-based global health clinical elective for residents. AB - BACKGROUND: Many physicians planning to work in global health lack adequate formal training. Globalized cities create opportunities to integrate global health training into residency programs, preparing clinicians for less supported experiences abroad. AIM: To develop a clinical elective to advance residents' knowledge and skills in global health and fieldwork abroad. METHODS: Two-week comprehensive elective was offered to PGY2 combined medicine-pediatrics residents. We incorporated clinical exposures and global health topics. Global health experts were involved as teachers and preceptors. Clinical exposure included: tropical medicine with laboratory sessions; travel medicine; tuberculosis; immigrant and continuity; and human rights clinics. Didactic components and supplemental readings included socio-political issues, global public health, and health challenges of populations from developing regions. We assessed resident satisfaction using questionnaires and focus groups. RESULTS: Residents reported usefulness and relevance of sessions and topics as (4) very good (scale: (1) poor to (5) excellent), and quality of sessions and teaching as very good to excellent (4.2). Residents' baseline knowledge and understanding of global health issues improved by around 50%. CONCLUSION: Our experience supports the feasibility and usefulness of clinical and didactic training in global health issues at home. A multidisciplinary approach, collaboration with academic and non academic institutions, experienced faculty, and departmental commitment are vital. PMID- 22435920 TI - Structure, agency, and sexual development of Latino gay men. AB - There is a high prevalence of childhood sexual abuse and HIV among Latino gay men, with limited proven HIV prevention interventions. This study used qualitative methods to explicate earlier findings showing differential health outcomes among Latino gay men who had no sex, voluntary, or forced sex before age 16. Analyses of in-depth interviews with 27 Latino gay men revealed that structural factors in childhood contribute to their developing sexuality by enhancing or inhibiting a sense of agency. Agency is essential for making decisions that are in line with their intentions to have healthy sexual lives. Findings suggest that interventions should focus on developing a sense of sexual agency among Latino gay men by (a) increasing their recognition of structural factors that contribute to feelings of worthlessness in order to relocate internalized blame and homophobia to external structural forces, (b) facilitating awareness of the social structural oppressions that lead to psychological and sexual risk in order to enhance their options for sexual health, and (c) shifting from individually focused constructions of sexual health to those that consider the structural factors that reduce agency and contribute to diminished sexual health among Latino gay men. PMID- 22435921 TI - Influence of fungal endophyte infection on phenolic content and antioxidant activity in grasses: interaction between Lolium perenne and different strains of Neotyphodium lolii. AB - Lolium perenne is a major forage and turf grass, which is often naturally infected with a "wild-type" strain (E(WT)) of the fungal endophyte Neotyphodium lolii , establishing a symbiotic relationship. In this study, the impacts of different strains wild type E(WT), AR1 (E(AR1)) and AR37 (E(AR37)), of N. lolii on the phenolic profile, phenolic content, and antioxidant capacity of L. perenne were examined. Samples could be ranked according to their phenol content as follows: E(AR1) > E(AR37) >= E(-) > E(WT). Radical-scavenging assays showed the same relative ranking of extracts. Flavonoid glycosides and hydroxycinnamic acids were the most abundant polyphenols in L. perenne extracts. Chlorogenic acid and its derivatives were the major compounds responsible for the antioxidant activity. Infection with N. lolii significantly influenced L. perenne phenolic content and antioxidant activity. In conclusion, changes in phenolic composition were merely quantitative. Endophyte infection can have zero, positive, or negative effect on phenol content depending on the endophyte strain. PMID- 22435922 TI - Oxidative stress in the airways of children with asthma and allergic rhinitis. AB - INTRODUCTION: Even though it is well known that oxidant stress plays an important role in the pathogenesis of asthma, less is known about allergic rhinitis. Moreover, it is not known whether the co-existence of the two diseases augments the level of oxidant stress within a united airway concept. AIM: To define the level of oxidative stress in children with asthma and/or allergic rhinitis in nasal and oral exhaled breath condensates (EBC) of children. METHOD: Children aged 6-18 years with asthma (n = 28), allergic rhinitis (n = 17), asthma and allergic rhinitis (n = 100), and healthy controls (n = 74) were enrolled in the study. Levels of malondialdehyde (MDA) as a marker of oxidative stress and reduced glutathione (GSH) as an antioxidant were measured by High-Performance Liquid Chromatography in the EBC. RESULTS: Malondialdehyde levels were higher, and GSH levels were lower in all patient groups compared to healthy controls in both nasal and oral EBC samples (p < 0.01) but there were no differences among the different patient groups. Interestingly, oral MDA levels were lower in patients with asthma and allergic rhinitis [17.78 nM (11.62-23.94)] compared to patients with asthma only [25.71 nM (18.81-32.61)] (p < 0.01). DISCUSSION: Both asthma and allergic rhinitis are associated with increased oxidative stress in the airways in children. However, the co-existence of the two diseases does not augment the oxidant stress further. PMID- 22435923 TI - Maternal age and elective cesarean section in a low-risk population. AB - OBJECTIVE: To examine the association between maternal age and elective cesarean section in primiparous and para one women in a low-risk population. DESIGN: Population-based registry study. SETTING: Norway. POPULATION: The source population was all mothers giving birth to their first or second child from 1 January 1999 to 31 December 2006. The final study population comprised 229 370 primiparous and para one low-risk mothers. METHODS: Data were extracted from the Medical Birth Registry of Norway. We constructed a low-risk population by excluding pregnancies with medical conditions associated with elective cesarean section and maternal age. The association between maternal age and elective cesarean was analysed by relative-risk models. MAIN OUTCOME MEASURES: Elective cesarean section. RESULTS: In this low-risk population, the proportion of cesarean section was 9%, and 27% of these were elective. Cesarean delivery increased substantially with increasing maternal age, especially elective cesarean section. In primipara, elective cesarean section increased from 0.6 to 7.5% of all deliveries, corresponding to a relative risk of 11.7 (95% confidence interval 8.9-15.4) in women >= 40 years relative to 20-24 years. When comparing women >= 40 years with those aged below 25 years, the relative risk in para one without previous cesarean section was 4.5 (95% confidence interval 3.5-5.8; the proportion increasing from 1.4 to 6.2%), while in para one with previous cesarean section it was 2.9 (95% confidence interval 2.4-3.6; the proportion increasing from 17.5 to 51.5%). CONCLUSIONS: We found a close association between maternal age and elective cesarean section in a low-risk population. PMID- 22435924 TI - An exact solution of transient equations describing slow axonal transport. AB - An exact analytical solution of equations describing slow axonal transport of cytoskeletal elements (CEs) injected in an axon is presented. The equations modelling slow axonal transport are based on the stop-and-go hypothesis. The simplest model implementing this hypothesis postulates that CEs switch between pausing and running kinetic states, and that the probabilities of CE transition between these two states are described by first-order rate constants. It is assumed that initially CEs are injected such that they form a uniform pulse of a given width. All injected CEs are initially attributed to the pausing state. It is shown that within 30 s kinetic processes redistribute CEs between pausing and running states; after that the process occurs under quasi-equilibrium conditions. The parameter accessible to experiments is the total concentration of CEs (pausing plus running). As the initial rectangular-shaped pulse moves, it changes its shape to become a bell-shaped wave that spreads out as it propagates. The wave's amplitude is decreasing during the wave's propagation. It is also shown that the system forgets its initial condition, meaning that if one starts with pulses of different widths, after sometime they converge to the same bell-shaped wave. PMID- 22435925 TI - Reduced urinary glutamate levels are associated with the frequency of migraine attacks in females. AB - BACKGROUND AND PURPOSE: Recent evidences indicate that glutamatergic homeostasis disorders are implicated in the pathogenesis of migraine. In particular, plasma and cerebrospinal fluid glutamate levels seem to be altered in migraine patients. However, the impacts of glutamate on migraine and especially on aura symptoms, alterations in the frequency of migraine attacks as well as investigations on glutamate on migraine-related metabolic dysfunctions, like hyperinsulinaemia, and an atherogenic lipid profile remain elusive to date. The aim of the present study was to investigate the impact of glutamate on migraine and related metabolic dysfunctions. METHODS: We investigated the urinary glutamate levels of female migraineurs (n = 48) in the interictal phase and healthy controls (n = 48). Parameters of the insulin- and lipid metabolism, inflammatory parameters and anthropometric parameters were additionally determined. RESULTS: Urinary glutamate levels of female migraineurs were significantly decreased with respect to the control group. Logistic regression revealed an odds ratio of 4.04 for migraine. We found a significant correlation with the time-period of patients' last attack and a significant inverse correlation with the annual frequency of migraine attacks. Other parameters of the insulin- and lipid metabolism, anthropometric and inflammatory parameters showed no significant correlation with glutamate levels. CONCLUSION: We show here that female migraineurs exhibit decreased urinary glutamate levels which are associated with a 4.04-fold higher risk for migraine and correlated with patients' frequency of migraine attacks. PMID- 22435926 TI - Spondylodiscitis: standards of current treatment. AB - BACKGROUND: Spinal infections are an important clinical problem that often require aggressive medical therapy, and sometimes even surgery. Known risk factors are advanced age, diabetes mellitus, rheumatoid arthritis, immunosuppression, alcoholism, long-term steroid use, concomitant infections, poly-trauma, malignant tumor, and previous surgery or invasive procedures (discography, chemonucleolysis, and surgical procedures involving or adjacent to the intervertebral disc space). The most common level of involvement is at the lumbar spine, followed by the thoracic, cervical and sacral levels: lesions at the thoracic spine tend to lead more frequently to neurological symptoms. OBJECTIVE: The aim of the current paper is to describe current evidence-based standards of therapy in the management of SD by emphasizing pharmacological therapy and principles and indications for bracing and surgery. METHODS: A PubMed and Google Scholar search using various forms and combinations of the key words: spondylodiscitis, spine, infection, therapy, surgery, radiology, treatment. Reference citations from publications identified in the literature search were reviewed. Publications highlighted in this article were extracted based on relevancy to established, putative, and emerging diagnostic and therapeutic standards, either conservative (antibiotic therapy and bracing) or surgical. FINDINGS: To date, conservative therapy, based on targeted antibiotic therapy plus bracing, represents the mainstay in the management of SD. Proper diagnosis and tailored therapy can improve clinical results and decrease the chance of failure. Surgery should be an option only for patients with complications of this disease, namely deformity, neural compression and neurological compromise. Current standards in the setting of SD are continuously evolving, as can be seen in the recent advances in the field of radiological diagnostics, and the use of growth factors and cell-therapy strategies to promote infection eradication and bone healing after surgery. PMID- 22435927 TI - Validation of Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance. AB - BACKGROUND: As part of a pilot U.S. inhibitor surveillance project initiated at the Centers for Disease Control and Prevention (CDC) in 2006, a centralized inhibitor measurement was instituted. OBJECTIVE: To validate a modified method for inhibitor measurement suitable for surveillance of treated and untreated patients. METHODS/RESULTS: In all, 710 subjects with hemophilia A were enrolled; 122 had a history of inhibitor (HI). Nijmegen-Bethesda assay (NBA) results on 50 split specimens shipped on cold packs and frozen were equivalent (r=0.998). Because 55% of 228 initial specimens had factor (F)VIII activity (VIII:C) present, a heat treatment step was added. Heating specimens to 56 degrees C for 30 min and centrifuging removed FVIII, as demonstrated by a reduction of VIII:C and FVIII antigen to <1 U dL(-1) in recently treated patients. Among specimens inhibitor-negative before heating, one of 159 with negative HI and five of 30 with positive HI rose to >= 0.5 Nijmegen-Bethesda units (NBU) after heating. Correlation of heated and unheated inhibitor-positive specimens was 0.94 (P=0.0001). The modified method had a coefficient of variation (CV) for a 1 NBU positive control of 10.3% and for the negative control of 9.8%. Based on results on 710 enrollment specimens, a positive CDC inhibitor was defined as >= 0.5 NBU. Results were similar when 643 post-enrollment specimens were included. Of 160 enrolled hemophilia B patients, two had HI. All others had NBU <= 0.2 at enrollment. CONCLUSION: The CDC experience demonstrates that this modified NBA can be standardized to be within acceptable limits for clinical tests and can be used for national surveillance. PMID- 22435928 TI - Insulin secretion based on the late oral glucose tolerance test period and incident diabetes: the San Antonio Heart Study. AB - AIMS: The Insulinogenic Index from 0 to 30 min (DeltaI (0-30) /DeltaG(0-30) ), a measure of insulin secretion derived from the early period of the oral glucose tolerance test, predicts future diabetes. However, there are few data on secretory measures from the late oral glucose tolerance test period. We therefore investigated the association of the ratio of the area under the insulin curve to the area under the glucose curve from 60 to 120 min (I/G(AUC 60-120) ) with incident diabetes. METHODS: Participants were 1540 Mexican Americans and non Hispanic whites in the San Antonio Heart Study who were free of diabetes at baseline. We analysed indices of sensitivity (Matsuda index) and secretion from the early (DeltaI(0-30) /DeltaG(0-30) ) and late oral glucose tolerance test periods (I/G(AUC 60-120) ). RESULTS: A total of 179 participants developed diabetes after 7.5 years. I/G(AUC 60-120) was an independent predictor of diabetes [odds ratio * 1 SD unit increase, 0.37 (0.26-0.54)] in a model that also included age, sex, ethnicity, body mass index, family history of diabetes, Matsuda index and (DeltaI (0-30) /DeltaG(0-30) ) as covariates. I/G(AUC 60-120) increased the C statistic (a test of discrimination) of the model (0.882 vs. 0.875, P=0.044). I/G(AUC 60-120) correctly reclassified one-fifth of individuals with moderate and strong risks of future diabetes. The net reclassification improvement was 0.13 (P<0.001) and the integrated discrimination improvement was 0.033 (P<0.001). CONCLUSIONS: An insulin secretory measure derived from the late oral glucose tolerance test period is useful for classifying individuals at risk of future diabetes independently of other risk factors, including insulin sensitivity and a secretory measure from the early oral glucose tolerance test period. PMID- 22435929 TI - Quantifying dental biofilm growth using cross-polarization optical coherence tomography. AB - AIMS: Quantifying the ex vivo growth of complex multispecies dental biofilms using cross-polarization 1310-nm optical coherence tomography (CP-OCT) system was investigated. METHODS AND RESULTS: Bacterial microcosms, which were derived from plaque samples of paediatric subjects, were incubated in a biofilm reactor system containing discs of different dental materials for 72 h with daily sucrose pulsing (5*). CP-OCT analysis of biofilm mass was validated with crystal violet (CV) assays at various growth stages of these complex biofilms. CP-OCT was able to filter out the back-reflected signals of water layers in the hydrated biofilm and allowed for direct biofilm quantification. The overall depth-resolved scattering intensity of the biofilm showed very strong positive correlation with CV assay quantification (Spearman's rho = 0.92) during the growth phase of the biofilm. CONCLUSION: CP-OCT was able to quantify the mass of the biofilm by measuring the overall depth-resolved scattering of the biofilm. SIGNIFICANCE AND IMPACT OF THE STUDY: CP-OCT has the ability to nondestructively monitor biofilm growth and elucidate the growth characteristics of these microcosms on different dental material compositions. PMID- 22435930 TI - Potential T cell epitopes of Mycobacterium tuberculosis that can instigate molecular mimicry against host: implications in autoimmune pathogenesis. AB - BACKGROUND: Molecular mimicry between microbial antigens and host-proteins is one of the etiological enigmas for the occurrence of autoimmune diseases. T cells that recognize cross-reactive epitopes may trigger autoimmune reactions. Intriguingly, autoimmune diseases have been reported to be prevalent in tuberculosis endemic populations. Further, association of Mycobacterium tuberculosis (M. tuberculosis) has been implicated in different autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Although, in silico analyses have identified a number of M. tuberculosis specific vaccine candidates, the analysis on prospective cross-reactive epitopes, that may elicit autoimmune response, has not been yet attempted. Here, we have employed bioinformatics tools to determine T cell epitopes of homologous antigenic regions between M. tuberculosis and human proteomes. RESULTS: Employing bioinformatics tools, we have identified potentially cross-reactive T cell epitopes restricted to predominant class I and II alleles of human leukocyte antigens (HLA). These are similar to peptides of mycobacterial proteins and considerable numbers of them are promiscuous. Some of the identified antigens corroborated with established autoimmune diseases linked with mycobacterial infection. CONCLUSIONS: The present study reveals many target proteins and their putative T cell epitopes that might have significant application in understanding the molecular basis of possible T cell autoimmune reactions during M. tuberculosis infections. PMID- 22435932 TI - The effect of cognitive behavior therapy on decision making in adolescents who self-harm: a pilot study. AB - Research shows poor decision making in adolescents who self-harm and a positive correlation between decision-making abilities and duration since last self-harm episode. This exploratory study investigated whether decision making in self harming adolescents could be improved through treatment with a novel cognitive behavior therapy (CBT). It also investigated whether improvement in decision making following treatment was linked to self-harm cessation. Adolescent self harmers receiving CBT (n = 24) or no treatment (n = 9) and healthy controls (n = 22) were longitudinally compared on the Iowa gambling task (IGT). Significant IGT improvements were only observed for adolescents who self-harm following CBT. CBT may benefit adolescent self-harmers and generate decision-making improvements. PMID- 22435933 TI - Enhancement of thermoelectric properties by modulation-doping in silicon germanium alloy nanocomposites. AB - Modulation-doping was theoretically proposed and experimentally proved to be effective in increasing the power factor of nanocomposites (Si(80)Ge(20))(70)(Si(100)B(5))(30) by increasing the carrier mobility but not the figure-of-merit (ZT) due to the increased thermal conductivity. Here we report an alternative materials design, using alloy Si(70)Ge(30) instead of Si as the nanoparticles and Si(95)Ge(5) as the matrix, to increase the power factor but not the thermal conductivity, leading to a ZT of 1.3 +/- 0.1 at 900 degrees C. PMID- 22435935 TI - Development of an aging society is a common feature of modern industrialized countries. Preface. PMID- 22435936 TI - Long-term multiple risk factor interventions in Japanese elderly diabetic patients: the Japanese Elderly Diabetes Intervention Trial--study design, baseline characteristics and effects of intervention. AB - AIM: To evaluate long-term, multiple risk factor intervention on physical, psychological and mental prognosis, and development of complications and cardiovascular disease in elderly type 2 diabetes patients. METHODS: Our randomized, controlled, multicenter, prospective intervention trial included 1173 elderly type 2 diabetes patients who were enrolled from 39 Japanese institutions and randomized to an intensive or conservative treatment group. Glycemic control, dyslipidemia, hypertension, obesity, diabetic complications and atherosclerotic disease were measured annually. Instrumental activity of daily living, cognitive impairment, depressive symptoms and diabetes burden were assessed at baseline and 3 years. RESULTS: There was no significant difference in clinical or cognitive parameters at baseline between the two groups. The prevalence of low activities of daily living, depressive symptoms and cognitive impairment was 13%, 28% and 4%, respectively, and was similar in the two groups. A small, but significant difference in HbA1c between the two groups was observed at 1 year after the start of intervention (7.9% vs 8.1%, P < 0.05), although this significant difference was not observed after the second year. With the exception of coronary revascularization, there was no significant difference in fatal or non-fatal events between the two groups. Composite events were also similar in the two groups. CONCLUSIONS: This study showed no significant differences in fatal or non fatal events between intensive and conventional treatment. The present study might clarify whether treatment of risk factors influences function and quality of life in elderly diabetic patients. PMID- 22435937 TI - Non-high-density lipoprotein cholesterol: an important predictor of stroke and diabetes-related mortality in Japanese elderly diabetic patients. AB - AIMS: To evaluate the association of low-density lipoprotein, high-density lipoprotein and non-high-density lipoprotein cholesterol with the risk of stroke, diabetes-related vascular events and mortality in elderly diabetes patients. METHODS: This study was carried out as a post-hoc landmark analysis of a randomized, controlled, multicenter, prospective intervention trial. We included 1173 elderly type 2 diabetes patients (aged >= 65 years) from 39 Japanese institutions who were enrolled in the Japanese elderly diabetes intervention trial study and who could be followed up for 1 year. A landmark survival analysis was carried out in which follow up was set to start 1 year after the initial time of entry. RESULTS: During 6 years of follow up, there were 38 cardiovascular events, 50 strokes, 21 diabetes-related deaths and 113 diabetes-related events. High low-density lipoprotein cholesterol was associated with incident cardiovascular events, and high glycated hemoglobin was associated with strokes. After adjustment for possible covariables, non-high-density lipoprotein cholesterol showed a significant association with increased risk of stroke, diabetes-related mortality and total events. The adjusted hazard ratios (95% confidence intervals) of non-high-density lipoprotein cholesterol were 1.010 (1.001-1.018, P = 0.029) for stroke, 1.019 (1.007-1.031, P < 0.001) for diabetes related death and 1.008 (1.002-1.014; P < 0.001) for total diabetes-related events. CONCLUSIONS: Higher non-high-density lipoprotein cholesterol was associated with an increased risk of stroke, diabetes-related mortality and total events in elderly diabetes patients. PMID- 22435938 TI - Relations of nutritional intake to age, sex and body mass index in Japanese elderly patients with type 2 diabetes: the Japanese Elderly Diabetes Intervention Trial. AB - AIM: To determine the status of nutritional intake in elderly Japanese patients with type 2 diabetes aged 65 years or older, and to clarify relations of nutritional intake to age, sex and body mass index (BMI). DESIGN: Clinical parameters and nutritional intake were investigated and compared in 912 (417 men, 495 women) elderly Japanese patients with type 2 diabetes registered to the Japanese Elderly Diabetes Intervention Trial. RESULTS: The mean daily energy intake of patients was 1802 kcal in men and 1661 kcal in women, respectively. The energy intakes per kilogram of standard bodyweight in both sexes and the energy intakes per kilogram of present bodyweight in men increased significantly with age. The protein : fat : carbohydrate (PFC) energy ratio (%E) was 15.2:25.4:59.5 in men, and 15.7:25.8:58.6 in women, respectively. Grain, oil, alcohol and soft drink intakes were higher in men than in women. Potato, fruit and green vegetable intakes were higher in women than in men. Fruit intake showed a significant age related increase in men. In women, there was an age-related significant decrease of meat intake. An increase of BMI correlated with a significant increase in bodyweight, waist circumference, hip circumference, waist-to-hip ratio, triglycerides and diastolic blood pressure. The mean energy intake of three BMI groups, lean (BMI < 18.5 kg/m(2)), normal (18.5 kg/m(2) /=7.4% enrolled in the Japanese Elderly Diabetes Intervention Trial (J-EDIT). The participants were divided into four groups by the percentage of total energy intake (%E) of carbohydrate (C1: less than 55%E, C2: 55%E or more and less than 60%E, C3: 60%E or more and less than 65%E, and C4: 65%E or more). Relations of %E of carbohydrate to HbA1c and other metabolic parameters, energy intake and nutritional intake were examined. Furthermore, the subjects were divided into four categories by HbA1c levels by quartile method (Q1: less than 7.90%, Q2: 7.90% or more and less than 8.30%, Q3: 8.30% or more and less than 8.80%, Q4: 8.80% or more). Relations of HbA1c to other metabolic parameters, energy intake and nutritional intake were examined. RESULTS: The mean HbA1c levels in the four groups were C1: 8.40%, C2: 8.50%, C3: 8.41% and C4: 8.36% in men, and C1: 8.51%, C2: 8.47%, C3: 8.35% and C4: 8.52% in women, respectively. There were no significant differences and linear trend in HbA1c levels across groups. The mean triglyceride levels were in the range of 122 128 mg/dL in men from C1 to C3, although it was significantly higher in C4 (177 mg/dL). The mean triglyceride levels were in the range of 128-136 mg/dL in women from C1 to C3, although it was significantly higher in Q4 (150 mg/dL). Amounts of protein and fat intakes decreased with an increase of %E of carbohydrate, although amount of carbohydrate intake did not change significantly. As a result, %E of protein and fat, and energy intake decreased in both men and women with an increase in %E of carbohydrate. Among the four quartiles divided by HbA1c levels, there were no significant differences in energy intake and PFC energy ratio. CONCLUSIONS: The present study suggests that, within the range studied, the carbohydrate energy ratio has no correlation with HbA1c levels. However, serum triglyceride levels increased and high-density lipoprotein cholesterol levels decreased significantly, with an increase of %E of carbohydrate in men, and the same tendencies were observed in women. Furthermore, in patients with 65%E or more of carbohydrate, serum triglyceride levels exceeded 150 mg/dL, which is the recommended treatment target for diabetic patients. These results suggest that the ideal %E of carbohydrate for Japanese elderly type 2 diabetes is less than 65. The lower limit of %E of carbohydrate could not be determined from the present study. PMID- 22435940 TI - Effects of total and green vegetable intakes on glycated hemoglobin A1c and triglycerides in elderly patients with type 2 diabetes mellitus: the Japanese Elderly Intervention Trial. AB - AIM: Many reports have shown that vegetable intake is effective in inhibiting the onset and progression of diabetes mellitus, although the amount of vegetable intake required to be effective remains as unclear. The present study therefore aimed to clarify the relationship between the amount of vegetable intake and glycated hemoglobin A1c (HbA1c) and other metabolic parameters using male Japanese type 2 diabetic patients aged 65 years or older as subjects. METHOD: Participants were 417 male type 2 diabetic patients aged 65 years or older enrolled in the Japanese Elderly Diabetes Intervention Trial. Dietary intakes were measured by using the Food Frequency Questionnaires method. The patients were divided into five groups by their daily total vegetable intake (A1: ~100 g, A2: 100~150 g, A3: 150~200 g, A4: 200~300 g, A5: 300 g~), and compared HbA1c and other metabolic parameters. Furthermore, the relationship between daily green vegetable intake and HbA1c and other metabolic parameters were examined among five groups divided by quintile methods. RESULTS: There were significant decreases in HbA1c, triglycerides and waist circumference with an increase of total vegetable intake. A significant decrease of HbA1c levels was observed in patients with a daily total vegetable intake of 150 g or more. Furthermore, there was a significant decrease of serum triglyceride levels in patients with a total vegetable intake of 200 g or more. HbA1c levels showed a decreasing tendency with the increase of green vegetable intake, and HbA1c levels in the Q1 group (green vegetable intake: less than 40 g) was significantly higher than those in the other four groups (anovaP = 0.025). In addition, there were significant decreases of body mass index, triglyceride levels and waist circumference with the increase of green vegetable intake. Triglyceride levels decreased significantly from the Q3 group (green vegetable intake: 70 g or more) to the Q5 group (green vegetable intake: 130 g or more; anovaP = 0.016). In the group with a lower intake of total vegetables and green vegetables, the protein energy ratio decreased significantly. As a result, the fat energy ratio and energy intake tended to increase with the decrease of total and green vegetable intakes. Furthermore, intake of grains, sweets and alcoholic beverages increased with the decrease of total vegetable intake. In contrast, intake of nuts, potatoes, sugar, legumes, fruit, seaweed and fish increased with the increase of total vegetable intake CONCLUSIONS: Daily total vegetable intake of 200 g or more, and green vegetable intake of 70 g or more correlated with improved control of HbA1c and triglyceride levels in elderly type 2 diabetes patients through achieving a well-balanced diet. PMID- 22435941 TI - Dietary pattern and mortality in Japanese elderly patients with type 2 diabetes mellitus: does a vegetable- and fish-rich diet improve mortality? An explanatory study. AB - AIM: To assess the effect of dietary patterns on all deaths and diabetes-related deaths in the Japanese Elderly Diabetes Intervention Trial (J-EDIT). METHODS: We investigated relationships between that of overall mortality and dietary pattern, and diabetes-related deaths and dietary pattern as observed among 912 registered cases of the J-EDIT study, which is a prospective follow-up study of elderly Japanese type 2 diabetic patients. RESULTS: Factor analysis with the factor number 3 led to deriving three dietary patterns (healthy type, snack type and greasy type). The relationship between these patterns and overall mortality or diabetes-related death was investigated. Although not statistically significant, there was a lower tendency of overall mortality and diabetes-related deaths for the healthy type dietary pattern. When the tendencies of overall mortality were analyzed for "young-old," who are younger than 75 years-of age, and "old-old" of over 75 years-of-age, the mortality rate for the greasy type and healthy type dietary patterns were nearly the same and higher than the snack type dietary pattern in young-old. In contrast, in old-old, a higher mortality rate was reported for the greasy type dietary pattern and a lower mortality rate was reported for the healthy type dietary pattern. The hazard ratio by Cox regression analysis for greasy type to healthy type in old-old was 3.03 (P = 0.04, CI 1.07 8.57). Furthermore, in old-old, as vegetable consumption increased, the lower the tendency foroverall mortality, and the more fish that was consumed, the overall mortality significantly decreased (P = 0.020) in the tertile. CONCLUSIONS: The greasy type dietary pattern with an increased amount of sugar, fat and meat led to poor life prognosis for elderly Japanese type 2 diabetic patients. The healthy type dietary pattern rich in vegetable and fish, which is similar to the Mediterranean diet and Dietary Approach to Stop Hypertension diet, was suggested to improve life prognosis. PMID- 22435942 TI - Lower physical activity, but not excessive calorie intake, is associated with metabolic syndrome in elderly with type 2 diabetes mellitus: the Japanese Elderly Diabetes Intervention Trial. AB - AIM: A decline in physical activity has been shown to be associated with metabolic syndrome (MetS), leading to cardiovascular events. However, this is difficult to manage well in the elderly with multiple atherosclerotic risk factors. In this study, we investigated the correlation between physical activity and clinical parameters in the presence and absence of MetS in Japanese elderly subjects with type 2 diabetes mellitus (T2DM). In addition, we determined which factor, calorie intake or physical activity, mainly contributes to the prevalence of MetS. METHODS: Cross-sectional analysis of 846 consecutive Japanese elderly (408 men and 438 women, mean age 68.7 years) was carried out at the time of enrolment (2000-2002) in the Japanese Elderly Diabetes Intervention Trial. Their level of physical activity was evaluated using the Baecke questionnaire, consisting of three components: work, sports and leisure. Total activity score (TAS) as the sum of each activity score was divided into four quartiles (Q1 to Q4). RESULTS: After adjustment for age and sex, there was a positive association of TAS with high-density lipoprotein cholesterol, although no significant correlation between other lipid parameters and TAS was found. In addition, fasting plasma glucose, insulin level and physical measurements, such as waist circumference, waist/hip ratio and body mass index, were inversely associated with TAS. Although no correlation between TAS and cognitive function Mini-Mental State Examination was found, TAS was positively associated with instrumental ADL and negatively associated with geriatric depression score (GDS), suggesting that a decline in physical activity in the elderly is associated with depressed mood rather than a decline of cognitive function. Total calorie intake appeared to increase according to TAS; however, this did not reach statistical significance. In a subanalysis comparing the presence and absence of MetS, the TAS grade in the MetS group was significantly lower than that in the non-MetS group, although there was no significant difference in total calorie intake between the groups. CONCLUSION: These results showed that lower physical activity, but not excessive calorie intake, is independently associated with the prevalence of MetS in the elderly with T2DM. In our routine work, encouraging physical activity might contribute to preventing MetS and subsequent atherosclerotic disease in the elderly, rather than strict management of abnormal laboratory parameters using multiple drugs. PMID- 22435943 TI - Lower physical activity is a strong predictor of cardiovascular events in elderly patients with type 2 diabetes mellitus beyond traditional risk factors: the Japanese Elderly Diabetes Intervention Trial. AB - AIM: It is well known that a decline in physical activity is associated with lifestyle-related diseases including cardiovascular (CV) events. However, little is known about the association between physical activity and CV events in elderly patients, because recent accumulating reports have mainly dealt with middle-aged populations. In this study, we investigated the correlation between physical activity and CV events in Japanese elderly patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 938 Japanese elderly patients with T2DM (447 men and 491 women, mean age 71.9 years) enrolled (2000-2002) in the Japanese Elderly Diabetes Intervention Trial (J-EDIT) were used in this study. Physical activity consisting of three components, work, sports and leisure-time, of their lifestyle was evaluated using the Baecke questionnaire at baseline. Total activity score (TAS) as a sum of each activity score was divided into four quartiles (Q1 to Q4). RESULTS: During a follow-up period of 65.2 months, 165 events and 71 deaths in total occurred. Higher TAS grade was associated with reduced risk of all events (hazard ratios: 0.82, 0.77 and 0.54 in Q2, Q3 and Q4, respectively) with statistical significance. Even after multivariate adjustment for covariates, higher TAS grade was a strong predictor of all events, and the prediction by TAS of cerebrovascular events was more effective than that of cardiac events. In contrast, all-cause mortality gradually decreased according to TAS grade; however, no statistical significance was found. Among the four grades of TAS, no significant change in several parameters, such as profiles of lipid and glucose metabolism, blood pressure, physical measurements, cognitive function and depression scale, was found throughout the follow-up period, suggesting that the higher level of physical activity itself was associated with the risk reduction of primary events. CONCLUSION: Lower physical activity is a strong and independent predictor of all CV events in the elderly with T2DM beyond traditional risk factors. In addition to strict management of each atherosclerotic risk factor, engagement with patients to augment and maintain the level of physical activity in their lifestyle is also essential in clinical practice. PMID- 22435944 TI - Effective prevention of cardiovascular disease and diabetes-related events with atorvastatin in Japanese elderly patients with type 2 diabetes mellitus: adjusting for treatment changes using a marginal structural proportional hazards model and a rank-preserving structural failure time model. AB - AIM: To assess the preventive effect of atorvastatin on cardiovascular disease and on diabetes-related events in elderly type 2 diabetic patients enrolled in the Japanese Elderly Diabetes Intervention Trial (J-EDIT). METHODS: Data were obtained from 1173 patients aged 65-84 years who were enrolled in the J-EDIT. Patients were followed prospectively for 6 years to determine the effects of atorvastatin on serum cholesterol levels, and cardiovascular and diabetes-related events. Because the study protocol allowed atorvastatin to be prescribed according to the clinical needs of each patient, we regarded the J-EDIT data as if they came from a cohort study. We adjusted for clinical characteristics during the study as time-dependent confounders using two methods, inverse-probability-of treatment (IPT) weighting and g-estimation method. RESULTS: The total follow-up period was 5310.8 person-years (5.7 years of median follow up), during which 202 patients received atorvastatin treatment. Atorvastatin was associated with moderate reductions in cholesterol levels: 24.2 mg/dL for total cholesterol, 22.9 mg/dL for low-density lipoprotein (LDL) cholesterol and 24.3 mg/dL for non-high density lipoprotein cholesterol at the first post-treatment year. As a result, the proportion of patients who achieved targeted levels of LDL cholesterol clearly increased after atorvastatin treatment. Eight patients in 476.6 person years among atorvastatin-treated and 113 untreated patients in 4721.4 person years had cardiovascular events (the composite end-point of fatal/non-fatal myocardial infarction, angina pectoris, coronary intervention, and fatal/non fatal cerebrovascular disease); hazard ratio (HR) = 0.48, 95% confidence interval (CI) = 0.19-1.16, P = 0.10, and HR = 0.32, 95% CI = 0.05-1.87, P = 0.21 from IPT weighting and g-estimation method, respectively. Furthermore, seven in 475.0 person-years among atorvastatin-treated and 149 untreated patients in 4682.4 person-years had diabetes-related events (the composite end-point of sudden death, renal failure death, death as a result of hyperglycemia or hypoglycemia, diabetic gangrene and congestive heart failure in addition to cardiovascular event); HR = 0.30, 95% CI = 0.12-0.77, P = 0.01, and HR = 0.40, 95% CI = 0.09 0.89, P = 0.03 from IPT weighting and g-estimation method, respectively. When cardiovascular events were further differentiated into coronary vascular and cerebrovascular events, atorvastatin especially decreased the cerebrovascular risk. CONCLUSION: The use of atorvastatin to lower cholesterol levels in elderly Japanese patients with type 2 diabetes mellitus appears to reduce the risk of cardiovascular and diabetes-related events. PMID- 22435945 TI - Risk factors associated with cognitive decline in the elderly with type 2 diabetes: baseline data analysis of the Japanese Elderly Diabetes Intervention Trial. AB - AIM: Recent evidence has shown that type 2 diabetes mellitus (T2DM) in the elderly is a risk factor for cognitive dysfunction or dementia. However, the precise mechanisms have not yet been elucidated. In the current study, we attempted to elucidate the association of clinical indices and diabetic complications at baseline with cognitive declines after 6-year follow up in type 2 diabetic elderly. METHODS: The subjects were 261 participants who were administered the Mini-Mental State Examination (MMSE) at baseline and after 6 years, at the end of the observation period. The cognitive decline was determined as a 5-point or greater decline in MMSE scores during the observation period. Logistic regression analysis to find the factors associated with cognitive decline, adjusted for age and sex, were carried out, and factors with P-values of less than 0.2 were included in four models of multiple logistic regression analysis. RESULTS: We found that the existence of diabetic nephropathy, higher systolic blood pressure and higher serum triglycerides (or lower high-density lipoprotein cholesterol) at baseline were significantly associated with cognitive declines after 6 years in Japanese elderly diabetics in all four models. CONCLUSION: The comorbidity of diabetic nephropathy, hypertension and hypertriglyceridemia at baseline were associated with more than 5-point declines in MMSE. Elucidation of the underlying mechanisms of this association is warranted. PMID- 22435946 TI - Risk factors associated with cognitive decline in the elderly with type 2 diabetes: pooled logistic analysis of a 6-year observation in the Japanese Elderly Diabetes Intervention Trial. AB - AIM: Considerable attention has been paid to the association between type 2 diabetes mellitus (T2DM) and cognitive dysfunction in the elderly. T2DM is often comorbid with several other metabolic disturbances, including hypertension and dyslipidemia. These comorbid diseases might be associated with cognitive impairment. Many clinical indices should be included as variables for the association with cognitive decline. In the current study, we tried to identify the associated factors with cognitive decline during a 6-year period in elderly T2DM considering the changes in the clinical indices during the follow-up period. METHODS: The subjects in the present study were 63 Japanese Elderly Interventional Trial participants who were administered the Mini-Mental State Examination at baseline, at the third year, and at the end of the 6-year follow up period. We applied the pooled logistic analysis method to consider the changes in clinical indices during the observation period and tried to identify the factors associated with cognitive decline during the 6 years in elderly type 2 diabetics using repeated measured data for glycated hemoglobin A1c, blood pressure and serum lipids. RESULTS: In the current study, low high-density lipoprotein-cholesterol and higher diastolic blood pressure were significantly associated with cognitive decline by pooled logistic analysis in the 6-year observation of older diabetic subjects. Higher glycated hemoglobin A1c had a tendency toward association with cognitive decline. CONCLUSION: The results suggest that comprehensive management of diabetes, including dyslipidemia and hypertension, might contribute to the prevention of declines in cognitive function in older diabetic patients. PMID- 22435947 TI - Risk factors for a 6-year decline in physical disability and functional limitations among elderly people with type 2 diabetes in the Japanese Elderly Diabetes Intervention Trial. AB - AIM: Type 2 diabetes increases the risk of disability. The purpose of this study was to clarify the explanatory factors for disability in Japanese diabetic elderly. METHODS: The 6-year decline in physical disability and functional limitations was investigated among 317 elderly people with type 2 diabetes recruited in a large-scale prospective study of the Japanese Elderly Diabetes Intervention Trial. Information about diabetes, blood examinations and complications was obtained, and basic activities of daily living (ADL) and instrumental ADL (IADL) were assessed by total score of the Barthel index and the Tokyo Metropolitan Institute of Gerontology Index of Competence, respectively. RESULTS: After 6 years of follow up, 13.6% of patients had developed a new ADL disability and 38.3% had developed a new functional impairment. In the 65-74 years age group, basic ADL decreased only in males, whereas females became functionally impaired. In the 75-84 years age group, basic and IADL decreased in both males and females. Older age and metabolic syndrome were prognostic for impairment of basic ADL, whereas baseline IADL problems, lower cognitive function, physical inactivity and insulin therapy were significant predictors of a future decline in the IADL. CONCLUSION: This study identified several factors predicting the future decline of basic ADL and IADL in diabetic elderly patients, and provided a conceptual framework that might help to clarify the pathways leading to disability. Because the specific causes of each functional problem are modifiable, comprehensive treatment and care are needed to allow Japanese diabetic elderly patients to have more favorable living conditions. PMID- 22435948 TI - Factors associated with progression of diabetic nephropathy in Japanese elderly patients with type 2 diabetes: sub-analysis of the Japanese Elderly Diabetes Intervention Trial. AB - AIM: Diabetic nephropathy is a serious complication in patients with type 2 diabetes. The aim of this study was to explore the factors associated with the progression of this complication in elderly patients with type 2 diabetes. METHODS: This retrospective study of a subgroup of patients registered with the Japanese Elderly Diabetes Intervention Trial included 621 Japanese patients with type 2 diabetes mellitus (age >= 65 years, 346 with normoalbuminuria, 190 with microalbuminuria and 85 with overt proteinuria). Multivariate Cox proportional hazard regression model with a backward stepwise procedure was applied to select factors with significant effects on worsening of nephropathy stage and the doubling of serum creatinine. RESULTS: During the follow up (median 52 months), 21% of patients progressed from normoalbuminuria and microalbuminuria to a worse nephropathy stage. Aging, female sex and high-density lipoprotein cholesterol were identified as independent and significant factors that worsen nephropathy stage. Also, 6.1% of patients showed doubling of serum creatinine during follow up. A positive history of cardiovascular disease, hyperuricemia and conventional therapy were identified as significant factors involved in the doubling of serum creatinine. The cumulative incidence of the doubling of serum creatinine was significantly lower in the intensive therapy group than the conventional therapy group (P = 0.016), although that of progression of nephropathy stage was similar in the two groups. CONCLUSIONS: We identified several factors associated with the progression of diabetic nephropathy in elderly patients with type 2 diabetes. The results suggest that multiple risk factor intervention seems important in preventing deterioration of renal dysfunction. PMID- 22435950 TI - Long-term risk factors for diabetic retinopathy and diabetic maculopathy in elderly Japanese patients with type 2 diabetes mellitus. PMID- 22435949 TI - Prevalence and risk factors for diabetic maculopathy, and its relationship to diabetic retinopathy in elderly Japanese patients with type 2 diabetes mellitus. AB - AIMS: To determine the prevalence of diabetic retinopathy and diabetic maculopathy in Japanese patients older than 65 years-of-age with type 2 diabetes mellitus. In addition, to determine the relationship between the severity of retinopathy and maculopathy, and the risk factors for these conditions in Japanese patients with the same characteristics. METHODS: This was a cross sectional study carried out at the enrolment of patients who participated in a randomized controlled trial. A total of 960 eyes of 960 Japanese patients with type 2 diabetes who were >= 65 years-of-age were analyzed. RESULTS: Our data showed that there was a correlation between the severity of retinopathy and the severity of maculopathy. The risk factors for the severity of retinopathy were different from the risk factors for the severity of maculopathy. The age, duration of diabetes, systemic pulse pressure, fasting insulin, insulin treatment of diabetes, high-density lipoprotein cholesterol, microalbumin-to-creatinine ratio and history of cerebrovascular disease all contributed significantly to the severity of retinopathy. The duration of diabetes, insulin treatment and microalbumin-to-creatinine ratio were correlated with the severity of maculopathy. CONCLUSIONS: The risk factors related to diabetic retinopathy and maculopathy in Japanese patients with type 2 diabetes mellitus aged >= 65 years were different from that in other countries. Our data also showed that the certain risk factors for retinopathy differ from those associated with maculopathy. PMID- 22435951 TI - Effect of multidisciplinary pre-dialysis education in advanced chronic kidney disease: Propensity score matched cohort analysis. AB - AIM: The mortality and morbidity of end-stage renal failure patients remains high despite recent advances in pre-dialysis care. Previous studies suggesting a positive effect of pre-dialysis education were limited by unmatched comparisons between the recipients and non-recipients of education. The present study aimed to clarify the roles of the multidisciplinary pre-dialysis education (MPE) in chronic kidney disease patients. METHODS: We performed a retrospective single centre study, enrolling 1218 consecutive pre-dialysis chronic kidney disease patients, between July 2007 and Feb 2008 and followed them up to 30 months. By using propensity score matching, we matched 149 recipient- and non-recipient pairs from 1218 patients. The incidences of renal replacement therapy, mortality, cardiovascular event and infection were compared between recipients and non recipients of MPE. RESULTS: Renal replacement therapy was initiated in 62 and 64 patients in the recipients and non-recipients, respectively (P > 0.05). The MPE reduced unplanned urgent dialysis (8.7% vs 24.2%, P < 0.001) and shortened hospital days (2.16 vs 5.05 days/patient per year). MPE recipients had a better metabolic status at the time of initiating renal replacement therapy. Although no significant survival advantage from MPE was exhibited, MPE recipients had lower incidence of cardiovascular events (adjusted hazard ratio, 0.24; 95% confidence interval (CI), 0.08 to 0.78; P = 0.017), and a tendency toward a lower infection rate (adjusted hazard ratio, 0.44; 95% CI, 0.17 to 1.11; P = 0.083). CONCLUSION: MPE was associated with better clinical outcomes in terms of urgent dialysis, cardiovascular events and infection. PMID- 22435952 TI - Mechanistic aspects of hydrosilylation catalyzed by (ArN=)Mo(H)(Cl)(PMe3)3. AB - The reaction of (ArN=)MoCl(2)(PMe(3))(3) (Ar = 2,6-diisopropylphenyl) with L Selectride gives the hydrido-chloride complex (ArN=)Mo(H)(Cl)(PMe(3))(3) (2). Complex 2 was found to catalyze the hydrosilylation of carbonyls and nitriles as well as the dehydrogenative silylation of alcohols and water. Compound 2 does not show any productive reaction with PhSiH(3); however, a slow H/D exchange and formation of (ArN=)Mo(D)(Cl)(PMe(3))(3) (2(D)) was observed upon addition of PhSiD(3). Reactivity of 2 toward organic substrates was studied. Stoichiometric reactions of 2 with benzaldehyde and cyclohexanone start with dissociation of the trans-to-hydride PMe(3) ligand followed by coordination and insertion of carbonyls into the Mo-H bond to form alkoxy derivatives (ArN=)Mo(Cl)(OR)(PMe(2))L(2) (3: R = OCH(2)Ph, L(2) = 2 PMe(3); 5: R = OCH(2)Ph, L(2) = eta(2)-PhC(O)H; 6: R = OCy, L(2) = 2 PMe(3)). The latter species reacts with PhSiH(3) to furnish the corresponding silyl ethers and to recover the hydride 2. An analogous mechanism was suggested for the dehydrogenative ethanolysis with PhSiH(3), with the key intermediate being the ethoxy complex (ArN=)Mo(Cl)(OEt)(PMe(3))(3) (7). In the case of hydrosilylation of acetophenone, a D-labeling experiment, i.e., a reaction of 2 with acetophenone and PhSiD(3) in the 1:1:1 ratio, suggests an alternative mechanism that does not involve the intermediacy of an alkoxy complex. In this particular case, the reaction presumably proceeds via Lewis acid catalysis. Similar to the case of benzaldehyde, treatment of 2 with styrene gives trans-(ArN=)Mo(H)(eta(2) CH(2)?CHPh)(PMe(3))(2) (8). Complex 8 slowly decomposes via the release of ethylbenzene, indicating only a slow insertion of styrene ligand into the Mo-H bond of 8. PMID- 22435953 TI - Kinetics of elementary steps in the reactions of atomic bromine with isoprene and 1,3-butadiene under atmospheric conditions. AB - Laser flash photolysis of CF(2)Br(2) has been coupled with time-resolved detection of atomic bromine by resonance fluorescence spectroscopy to investigate the gas-phase kinetics of early elementary steps in the Br-initiated oxidations of isoprene (2-methyl-1,3-butadiene, Iso) and 1,3-butadiene (Bu) under atmospheric conditions. At T >= 526 K, measured rate coefficients for Br + isoprene are independent of pressure, suggesting that hydrogen transfer (1a) is the dominant reaction pathway. The following Arrhenius expression adequately describes all kinetic data at 526 K <= T <= 673 K: k(1a)(T) = (1.22 +/- 0.57) * 10(-11) exp[(-2100 +/- 280)/T] cm(3) molecule(-1) s(-1) (uncertainties are 2sigma and represent precision of the Arrhenius parameters). At 271 K <= T <= 357 K, kinetic evidence for the reversible addition reactions Br + Iso <-> Br-Iso (k(1b), k(-1b)) and Br + Bu <-> Br-Bu (k(3b), k(-3b)) is observed. Analysis of the approach to equilibrium data allows the temperature- and pressure-dependent rate coefficients k(1b), k(-1b), k(3b), and k(-3b) to be evaluated. At atmospheric pressure, addition of Br to each conjugated diene occurs with a near gas-kinetic rate coefficient. Equilibrium constants for the addition/dissociation reactions are obtained from k(1b)/k(-1b) and k(3b)/k(-3b), respectively. Combining the experimental equilibrium data with electronic structure calculations allows both second- and third-law analyses of thermochemistry to be carried out. The following thermochemical parameters for the addition reactions 1b and 3b at 0 and 298 K are obtained (units are kJ mol(-1) for Delta(r)H and J mol(-1) K(-1) for Delta(r)S; uncertainties are accuracy estimates at the 95% confidence level): Delta(r)H(0)(1b) = -66.6 +/- 7.1, Delta(r)H(298)(1b) = -67.5 +/- 6.6, and Delta(r)S(298)(3b) = -93 +/- 16; Delta(r)H(0)(3b) = -62.4 +/- 9.0, Delta(r)H(298)(3b) = -64.5 +/- 8.5, and Delta(r)S(298)(3b) = -94 +/- 20. Examination of the effect of added O(2) on Br kinetics under conditions where reversible adduct formation is observed allows the rate coefficients for the Br Iso + O(2) (k(2)) and Br-Bu + O(2) (k(4)) reactions to be determined. At 298 K, we find that k(2) = (3.2 +/- 1.0) * 10(-13) cm(3) molecule(-1) s(-1) independent of pressure (uncertainty is 2sigma, precision only; pressure range is 25-700 Torr) whereas k(4) increases from 3.2 to 4.7 * 10(-13) cm(3) molecule(-1) s(-1) as the pressure increases from 25 to 700 Torr. Our results suggest that under atmospheric conditions, Br-Iso and Br-Bu react with O(2) to produce peroxy radicals considerably more rapidly than they undergo unimolecular decomposition. Hence, the very fast addition reactions appear to control the rates of Br initiated formation of Br-Iso-OO and Br-Bu-OO radicals under atmospheric conditions. The peroxy radicals are relatively weakly bound, so conjugated diene regeneration via unimolecular decomposition reactions, though unimportant on the time scale of the reported experiments (milliseconds), is likely to compete effectively with bimolecular reactions of peroxy radicals under relatively warm atmospheric conditions as well as in 298 K competitive kinetics experiments carried out in large chambers. PMID- 22435954 TI - Tissue kallikrein promotes cardiac neovascularization by enhancing endothelial progenitor cell functional capacity. AB - Tissue kallikrein (TK) has been demonstrated to improve neovasculogenesis after myocardial infarction (MI). In the present study, we examined the role and underlying mechanisms of TK in peripheral endothelial progenitor cell (EPC) function. Peripheral blood-derived mononuclear cells containing EPCs were isolated from rat. The in vitro effects of TK on EPC differentiation, apoptosis, migration, and vascular tube formation capacity were studied in the presence or absence of TK, kinin B(2) receptor antagonist (icatibant), and phosphatidylinositol-3 kinase inhibitor (LY294002). Apoptosis was evaluated by flow-cytometry analysis using Annexin V-FITC/PI staining, as well as western-blot analysis of Akt phosphorylation and cleaved caspase-3. Using an MI mouse model, we then examined the in vivo effects of human TK gene adenoviral vector (Ad.hTK) administration on the number of CD34(+)Flk-1(+) progenitors in the peripheral circulation, heart tissue, extent of vasculogenesis, and heart function. Administration of TK significantly increased the number of Dil-LDL/UEA-lectin double-positive early EPCs, as well as their migration and tube formation properties in vitro. Transduction of TK in cultured EPCs attenuated apoptosis induced by hypoxia and led to an increase in Akt phosphorylation and a decrease in cleaved caspase-3 levels. The beneficial effects of TK were blocked by pretreatment with icatibant and LY294002. The expression of recombinant human TK in the ischemic mouse heart significantly improved cardiac contractility and reduced infarct size 7 days after gene delivery. Compared with the Ad.Null group, Ad.hTK reduced mortality and preserved left ventricular function by increasing the number of CD34(+)Flk-1(+) EPCs and promoting the growth of capillaries and arterioles in the peri-infarct myocardium. These data provide direct evidence that TK promotes vessel growth by increasing the number of EPCs and enhancing their functional properties through the kinin B(2) receptor-Akt signaling pathway. PMID- 22435955 TI - Changes in emotional empathy, affective responsivity, and behavior following severe traumatic brain injury. AB - This study was designed to examine the relationship between deficits in empathy, emotional responsivity, and social behavior in adults with severe traumatic brain injury (TBI). A total of 21 patients with severe TBI and 25 control participants viewed six film clips containing pleasant, unpleasant, and neutral content whilst facial muscle responses, skin conductance, and valence and arousal ratings were measured. Emotional empathy (the Balanced Emotional Empathy Scale, BEES: self report) and changes in drive and control in social situations (The Current Behaviour Scale, CBS: relative report) were also assessed. In comparison to control participants, those in the TBI group reported less ability to empathize emotionally and had reduced facial responding to both pleasant and unpleasant films. They also exhibited lowered autonomic arousal, as well as abnormal ratings of valence and arousal, particularly to unpleasant films. Relative reported loss of emotional control was significantly associated with heightened empathy, while there was a trend to suggest that impaired drive (or motivation) may be related to lower levels of emotional empathy. The results represent the first to suggest that level of emotional empathy post traumatic brain injury may be associated with behavioral manifestations of disorders of drive and control. PMID- 22435956 TI - Prefrontal cortex rTMS enhances action naming in progressive non-fluent aphasia. AB - BACKGROUND AND PURPOSE: Progressive non-fluent aphasia (PNFA) is a neurodegenerative disorder that is characterized by non-fluent speech with naming impairment and grammatical errors. It has been recently demonstrated that repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) improves action naming in healthy subjects and in subjects with Alzheimer's disease. PURPOSE: To investigate whether the modulation of DLPFC circuits by rTMS modifies naming performance in patients with PNFA. METHODS: Ten patients with a diagnosis of PNFA were enrolled. High-frequency rTMS was applied to the left and right DLPFC and the sham (i.e. placebo) condition during object and action naming. A subgroup of patients with semantic dementia was enrolled as a comparison group. RESULTS: A repeated-measure anova with stimulus site (sham, left and right rTMS) showed significant effects. Action naming performances during stimulation of both the left and right DLPFC were better than during placebo stimulation. No facilitating effect of rTMS to the DLPFC on object naming was observed. In patients with a diagnosis of semantic dementia, no effect of stimulation was reported. CONCLUSIONS: Our study demonstrated that rTMS improved action naming in subjects with PNFA, possibly due to the modulation of DLPFC pathways and a facilitation effect on lexical retrieval processes. Future studies on the potential of a rehabilitative protocol using rTMS applied to the DLPFC in this orphan disorder are required. PMID- 22435957 TI - The neurotoxicity of intrathecal lidocaine is enhanced in postpartum compared to virgin rats. AB - During the perinatal period, the pharmacokinetics and pharmacodynamics of drugs may be altered. Data about the neurotoxicity of intrathecal local anesthetics in the peripartum period are lacking. So we hypothesized that the neurotoxicity of intrathecal lidocaine during perinatal period may be changed. Therefore, we designed the present study to determine whether the neurotoxicity of intrathecal lidocaine in postpartum rats would be different from that in nonpregnant, virgin rats. Postpartum and nonpregnant rats randomly received an intrathecal infusion of lidocaine 50 mg/mL in saline, lidocaine 20 mg/mL in saline, or saline for 1 h at a rate of 1 MUL/min. Four days after drug infusion, the rats were assessed for persistent impairment of sensory and motor function (MF) using the tail-flick (TF) test, paw pressure test, and MF score. Spinal cords and nerve roots were obtained for light and electron microscopic examinations, and the injury scores were compared between groups. The TF latencies and the mean nerve injury scores of the postpartum group were significantly higher than those of nonpregnant group. Lidocaine induced a dose-dependent impairment in TF latencies and nerve injury scores. There was no significant interaction between postpartum and the drug. Our results suggest that the neurotoxicity of intrathecal lidocaine is enhanced in rats during the early postpartum period compared with nonpregnant, virgin rats. PMID- 22435958 TI - Observation of absorption-dominated bonding dark plasmon mode from metal insulator-metal nanodisk arrays fabricated by nanospherical-lens lithography. AB - Plasmon hybridization modes are observed in the extinction spectra of a metal insulator-metal (MIM) nanodisk array fabricated using nanospherical-lens lithography. Two distinct hybridization modes are observed in this vertically aligned configuration. Theoretical simulation indicates that the bonding mode located at a lower energy level exhibits an antiphase charge distribution and corresponds to the dark plasmon mode. This is vastly different compared to antibonding dark plasmon mode observed in the conventional dimer configuration. The observed mode is tunable over a wide spectral range simply by varying the insulator thickness and the diameters of the MIM nanodisks. Absorption is the dominating extinction process for the dark plasmon, while scattering dominates the bright plasmon mode. The ability to experimentally measure and tune dark plasmon modes using a MIM configuration should catalyze more novel studies that take full advantages of the absorption-dominated dark plasmon mode. PMID- 22435959 TI - Recognizing pitfalls in virtual screening: a critical review. AB - The aim of virtual screening (VS) is to identify bioactive compounds through computational means, by employing knowledge about the protein target (structure based VS) or known bioactive ligands (ligand-based VS). In VS, a large number of molecules are ranked according to their likelihood to be bioactive compounds, with the aim to enrich the top fraction of the resulting list (which can be tested in bioassays afterward). At its core, VS attempts to improve the odds of identifying bioactive molecules by maximizing the true positive rate, that is, by ranking the truly active molecules as high as possible (and, correspondingly, the truly inactive ones as low as possible). In choosing the right approach, the researcher is faced with many questions: where does the optimal balance between efficiency and accuracy lie when evaluating a particular algorithm; do some methods perform better than others and in what particular situations; and what do retrospective results tell us about the prospective utility of a particular method? Given the multitude of settings, parameters, and data sets the practitioner can choose from, there are many pitfalls that lurk along the way which might render VS less efficient or downright useless. This review attempts to catalogue published and unpublished problems, shortcomings, failures, and technical traps of VS methods with the aim to avoid pitfalls by making the user aware of them in the first place. PMID- 22435960 TI - Quantitative underwater 3D motion analysis using submerged video cameras: accuracy analysis and trajectory reconstruction. AB - In this study we aim at investigating the applicability of underwater 3D motion capture based on submerged video cameras in terms of 3D accuracy analysis and trajectory reconstruction. Static points with classical direct linear transform (DLT) solution, a moving wand with bundle adjustment and a moving 2D plate with Zhang's method were considered for camera calibration. As an example of the final application, we reconstructed the hand motion trajectories in different swimming styles and qualitatively compared this with Maglischo's model. Four highly trained male swimmers performed butterfly, breaststroke and freestyle tasks. The middle fingertip trajectories of both hands in the underwater phase were considered. The accuracy (mean absolute error) of the two calibration approaches (wand: 0.96 mm - 2D plate: 0.73 mm) was comparable to out of water results and highly superior to the classical DLT results (9.74 mm). Among all the swimmers, the hands' trajectories of the expert swimmer in the style were almost symmetric and in good agreement with Maglischo's model. The kinematic results highlight symmetry or asymmetry between the two hand sides, intra- and inter-subject variability in terms of the motion patterns and agreement or disagreement with the model. The two outcomes, calibration results and trajectory reconstruction, both move towards the quantitative 3D underwater motion analysis. PMID- 22435961 TI - Healthcare continuity from hospital to territory in Lombardy: TELEMACO project. AB - OBJECTIVES: To verify implementation and use of TELEMACO (TELEMedicina Ai piccoli COmunilombardi; http://www.telemaco.regione.lombardia.it/), which provides specialized continuity of care with innovative healthcare services in remote areas of the Lombardy region of Italy; to design a network in the territory for sharing of continuityof- care programs; and to allow the relevant health authorities to collect cost data to establish a model for sustainable pricing for implementing these services. METHODS: TELEMACO provides home-based telemanagement services for patients with chronic heart failure and chronic obstructive pulmonary disease (COPD), as well as second-opinion teleconsultations in cardiology, dermatology, diabetology, and pulmonology for general practitioners and second-opinion teleconsultations on digital images in cases of traumatic brain injury and stroke. A total of 2 service centers, 10 cardiology and pneumology departments, 30 specialists, 176 general practitioners, 40 nurses, 2 emergency departments, and 2 consultant hospitals were involved. RESULTS: A total of 166 patients with chronic heart failure and 474 patients with COPD were enrolled. There were 4830, 51, and 44 second-opinion teleconsultations for cardiologic, dermatologic, and diabetic conditions, respectively. There were 147 second-opinion teleconsultations on digital images, 68 for stroke, and 79 for traumatic brain injury. Implementation of TELEMACO introduced innovations in working methods and provided evidence to the health authorities for allocating funds for such services. CONCLUSIONS: TELEMACO provided evidence that there is a growing need for home management of patients using telemedicine, a common and efficacious approach that can ensure care continuity, especially in chronic diseases. PMID- 22435962 TI - Off-label use of antipsychotic medications in Medicaid. AB - OBJECTIVES: To determine how often antipsychotics are prescribed off-label to adults without schizophrenia or bipolar disorder who are enrolled in Medicaid, which pays for more than 70% of antipsychotic prescriptions in the United States. STUDY DESIGN: Retrospective analysis of 2003 administrative data from 42 state Medicaid programs. METHODS: Continuously enrolled patients with at least 1 prescription for an antipsychotic medication were identified. For these patients, inpatient and outpatient records were checked for any diagnosis of schizophrenia or bipolar disorder; those without any such diagnoses were considered to have received these medications off-label. Offlabel antipsychotic use was compared across sociodemographic groups (age, race/ethnicity, sex). Multivariate logistic regression models identified characteristics associated with off-label use. RESULTS: Of the 372,038 individuals given an antipsychotic medication, 214,113 (57.6%) received these agents for off-label disorders. Off-label use among patients receiving an antipsychotic was more prevalent among individuals under age 21 years (75.9%) and those 65 years and older (64.8%) than it was among those aged 21 to 64 years (49.0%). Rates of off-label use were relatively high for Hispanics (65.7%) and low for African Americans (52.3%) compared with whites (58.2%). Off-label use was most common among patients receiving risperidone and least common among patients receiving clozapine. CONCLUSIONS: Off-label use of antipsychotic medications is common, particularly among the elderly and children/adolescents. Given that these drugs are expensive, have potentially severe side effects, and have limited evidence supporting their effectiveness off label, they should perhaps be used with greater caution. PMID- 22435963 TI - Clinical pathways for oncology: more rigor needed when evaluating models. PMID- 22435964 TI - The promise and peril of healthcare forecasting. AB - Health plans and physician groups increasingly use sophisticated tools to predict individual patient outcomes. Such analytics will accelerate as US medicine enters the digital age. Promising applications of forecasting include better targeting of disease management as well as innovative patient care approaches such as personalized health insurance and clinical decision support systems. In addition, stakeholders will use predictions to advance their organizational agendas, and unintended consequences could arise. Forecasting-based interventions might have uncertain effectiveness, focus on cost savings rather than long-term health, or specifically exclude disadvantaged populations. Policy makers, health plans, and method developers should adopt strategies that address these concerns in order to maximize the benefit of healthcare forecasting on the long-term health of patients. PMID- 22435965 TI - Impact of an online prescription management account on medication adherence. AB - OBJECTIVES: To assess medication adherence rates of patients utilizing an online prescription management account compared with nonusers. STUDY DESIGN: A retrospective analysis was conducted using de-identified pharmacy claims data from a pharmacy benefit manager covering the period from April 1, 2009, to March 31, 2011. Patients who were continuously eligible throughout the study period and that had at least 1 prescription fill for any of the 8 therapeutic groups examined in the study were selected for inclusion. METHODS: Adherence was assessed by measuring the proportion of days covered (PDC). Propensity score matching was utilized to minimize differences in age, gender, chronic condition score, copay, household income, and urban locality between the users and nonusers groups. Results were reported for all therapeutic groups combined, as well as by individual therapeutic group. RESULTS: Overall, patients utilizing the online account had a significantly higher weighted average PDC (73.19% vs 61.64%, P <.0001). Users also had a higher average PDC for each individual therapeutic group, although the beta-blocker group was not statistically significant. The percentage of patients achieving an average PDC of >80% was also found to be greater in the users group across each therapeutic group and overall. CONCLUSIONS: Patients who utilized an online prescription management account had higher rates of medication adherence as compared with nonusers. Additional studies are needed to assess which specific components of the prescription management account have the biggest impact on adherence. PMID- 22435966 TI - Optimal approach to improving trauma triage decisions: a cost-effectiveness analysis. AB - OBJECTIVES: To identify the optimal target of a future intervention to improve physician decision making in trauma triage. STUDY DESIGN: Comparison of incremental costeffectiveness ratios (ICERs) of current practice with hypothetical interventions targeting either physicians' decisional thresholds (attitudes toward transferring patients to trauma centers) or perceptual sensitivity (ability to identify patients who meet transfer guidelines). METHODS: Taking the societal perspective, we constructed a Markov decision model, drawing estimates of triage patterns, mortality, utilities, and costs from the literature. We assumed that an intervention to change the decisional threshold would reduce undertriage but also increase overtriage more than an intervention to change perceptual sensitivity. We performed a series of 1-way sensitivity analyses and studied the most influential variables in a Monte Carlo simulation. RESULTS: The ICER of an intervention to change perceptual sensitivity was $62,799 per qualityadjusted life-year (QALY) gained compared with current practice. The ICER of an intervention to change the decisional threshold was $104,975/ QALY gained compared with an intervention to change perceptual sensitivity. These findings were most sensitive to the relative cost of hospitalizing patients with moderate to severe injuries and their relative risk of dying at non-trauma centers. In probabilistic sensitivity analyses, at a willingness-to-pay threshold of $100,000/QALY gained, there was a 62% likelihood that an intervention to change perceptual sensitivity was the most cost-effective alternative. CONCLUSIONS: Even a minor investment in changing decision making in trauma triage could greatly improve quality of care. The optimal intervention depends on the characteristics of the individual trauma systems. PMID- 22435967 TI - Maternal hypothyroidism decreases progesterone receptor expression in the cortical subplate of foetal rat brain. AB - Steroid hormones exert profound effects on the development of brain areas controlling complex cognitive function in adulthood. One class, progestins, may contribute by acting on the progestin receptor (PR), which is transiently expressed in a critical layer of developing cortex: the subplate. PR expression in the subplate coincides with the establishment of ongoing cortical connectivity and may play an important organisational role. Identification of the factor(s) that regulate the precise timing of PR expression within subplate may help elucidate the function of PR. Thyroid hormone may interact with hormone response elements within the PR gene. The present study examined the effects of maternal hypothyroidism on levels of PR immunoreactivity (PR-IR) within the foetal subplate. Pregnant rats were made hypothyroid by the administration of methimazole and potassium perchlorate in drinking water. Maternal hypothyroidism significantly decreased PR-IR within the foetal subplate. Using the incorporation of 5-bromo-2'-deoxyuridine (BrDU) during subplate cell neurogenesis (embryonic day 13.5) to determine subplate cell survival in hypothyroid animals, we found that decreases in PR-IR cannot be attributed to significant subplate cell loss but are more likely the result of altered PR expression. Gestational thyroxine replacement to hypothyroid dams prevented the decrease in PR-IR within the subplate. These results identify thyroid hormone as a potential factor in the regulation of PR expression in the developing brain. These results are consistent with the idea that endocrine cross-talk between progesterone and thyroid hormone may be one mechanism by which maternal hypothyroidism alters normal cortical development. PMID- 22435968 TI - Effect of endotoxin and allergens on neonatal lung function and infancy respiratory symptoms and eczema. AB - BACKGROUND: Exposure to endotoxin and allergens in house dust has been found to be associated with childhood wheeze and asthma. Neonatal lung function is rarely examined in relation to this exposure. OBJECTIVES: To assess the association between exposure to endotoxin, house dust mite and cat allergens and neonatal lung function, and respiratory symptoms and eczema in infancy. METHODS: In the Wheezing Illnesses Study Leidsche Rijn (WHISTLER) birth cohort study, levels of endotoxin, house dust mite allergens, and cat allergen have been measured in dust samples collected in the child's home. Lung function was measured before age 2 months, and respiratory symptoms and eczema were recorded in a daily diary during the first year of life. Associations of lung function (N = 302), respiratory symptoms (N = 361), and eczema (N = 342) with endotoxin and allergen levels have been studied by means of linear and logistic regression, respectively. RESULTS: Mattress dust endotoxin was associated with a significant increase in neonatal respiratory compliance [adjusted mean difference (95% confidence interval) 2.31 (0.33; 4.29) ml/kPa per interquartile range increase in exposure] and a non significant decrease in neonatal airway resistance [0.32 (-0.77; 0.14) kPa/l/s]. There were no associations between allergen exposure and neonatal lung function and respiratory symptoms. CONCLUSIONS: Environmental exposure to endotoxin may have an important role in the development of lung function. PMID- 22435969 TI - Association between COX-2 rs2745557 polymorphism and prostate cancer risk: a systematic review and meta-analysis. AB - BACKGROUND: Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). The COX-2 polymorphism rs2745557 (+202 C/T) has been extensively investigated as a potential risk factor for PCa, but the results have thus far been inconclusive. This meta-analysis was performed to derive a more precise estimation of the association. METHODS: A comprehensive search was conducted to identify all case-control studies of COX-2 rs2745557 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Statistical analyses were performed by Review Manage, version 5.0 and Stata 10.0. RESULTS: A total of 8 available studies were considered in the present meta-analysis, with 11356 patients and 11641 controls for rs2745557. When all groups were pooled, there was no evidence that rs2745557 had significant association with PCa under co-dominant, recessive, over-dominant, and allelic models. However, our analysis suggested that rs2745557 was associated with a lower PCa risk under dominant model in overall population (OR=0.85, 95%CI=0.74 0.97, P=0.02). When stratifying for race, there was a significant association between rs2745557 polymorphism and lower PCa risk in dominant model comparison in the subgroup of Caucasians (OR=0.86, 95%CI=0.75-0.99, P=0.04), but not in co dominant, recessive, over-dominant and allelic comparisons. CONCLUSION: Based on our meta-analysis, COX-2 rs2745557 was associated with a lower PCa risk under dominant model in Caucasians. PMID- 22435970 TI - Immunoregulatory effects of isotretinoin in patients with acne. AB - BACKGROUND: In vitro studies have shown that retinoids influence T-cell differentiation. OBJECTIVES: To study the effect of isotretinoin on T-cell differentiation markers in patients with acne. METHODS: A total of 37 patients with acne vulgaris (25 female, 12 male, age 19.6 +/- 3.7 years) and 30 age- and sex-matched healthy controls (19 female, 11 male, age 20.5 +/- 4.4 years) were included in the study. Screening for biochemical parameters in serum samples were done just before initiation (pretreatment) and after 3 months of isotretinoin treatment (post-treatment) in the acne group. RESULTS: Baseline levels of tumour necrosis factor (TNF)-alpha (P<0.0001), interleukin (IL)-4 (P<0.0001), IL-17 (P<0.0001) and interferon (IFN)-gamma (P=0.002) were significantly higher in the acne group compared with the control group. TNF-alpha (P<0.0001), IL-4 (P<0.0001), IL-17 (P<0.0001) and IFN-gamma (P<0.0001) levels decreased after isotretinoin treatment. TNF-alpha and IL-4 values after isotretinoin treatment were similar to those of the control group. However, levels of IL-17 (P<0.0001) after isotretinoin treatment were higher than those of the control group, despite a significant decline after treatment. Levels of IFN-gamma (P<0.0001) after isotretinoin treatment were lower than those of the control group. CONCLUSIONS: This study shows that isotretinoin treatment significantly decreases TNF, IL-4, IL-17 and IFN-gamma levels in patients with acne. We failed to show that isotretinoin redirects naive T helper (Th) differentiation preferentially towards the Th2 cell lineage. PMID- 22435971 TI - Calpain-2 expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer. AB - Ovarian cancer is routinely treated with surgery and platinum-based chemotherapy. Resistance is a major obstacle in the efficacy of this chemotherapy regimen and the ability to identify those patients at risk of developing resistance is of considerable clinical importance. The expression of calpain-1, calpain-2 and calpastatin were determined using standard immunohistochemistry on a tissue microarray of 154 primary ovarian carcinomas from patients subsequently treated with platinum-based adjuvant chemotherapy. High levels of calpain-2 expression was significantly associated with platinum resistant tumours (P = 0.031). Furthermore, high expression of calpain-2 was significantly associated with progression-free (P = 0.049) and overall survival (P = 0.006) in this cohort. The association between calpain-2 expression and overall survival remained significant in multivariate analysis accounting for tumour grade, stage, optimal debulking and platinum sensitivity (hazard ratio = 2.174; 95% confidence interval = 1.144-4.130; P = 0.018). The results suggest that determining calpain-2 expression in ovarian carcinomas may allow prognostic stratification of patients treated with surgery and platinum-based chemotherapy. The findings of this study warrant validation in a larger clinical cohort. PMID- 22435972 TI - Feather meal: a previously unrecognized route for reentry into the food supply of multiple pharmaceuticals and personal care products (PPCPs). AB - Antimicrobials used in poultry production have the potential to bioaccumulate in poultry feathers but available data are scarce. Following poultry slaughter, feathers are converted by rendering into feather meal and sold as fertilizer and animal feed, thereby providing a potential pathway for reentry of drugs into the human food supply. We analyzed feather meal (n = 12 samples) for 59 pharmaceuticals and personal care products (PPCPs) using EPA method 1694 employing liquid chromatography tandem mass spectrometry (LC/MS/MS). All samples tested positive and six classes of antimicrobials were detected, with a range of two to ten antimicrobials per sample. Caffeine and acetaminophen were detected in 10 of 12 samples. A number of PPCPs were determined to be heat labile during laboratory simulation of the rendering process. Growth of wild-type E. coli in MacConkey agar was inhibited by sterilized feather meal (p = 0.01) and by the antimicrobial enrofloxacin (p < 0.0001) at levels found in feather meal. Growth of a drug-resistant E. coli strain was not inhibited by sterilized feather meal or enrofloxacin. This is the first study to detect antimicrobial residues in feather meal. Initial results suggest that more studies are needed to better understand potential risks posed to consumers by drug residues in feather meal. PMID- 22435973 TI - A Turkish study on menarche and menstrual experiences and their effects on attitudes towards menopause. AB - The purpose of this study was to investigate women's menarche and menstrual experiences and their effects on attitudes towards menopause. This research was planned as cross-sectional. A total of 300 women who had applied for a physical examination at the Maternity and Gynecology and Children's Hospital of Ordu province of Turkey were recruited for the study using the convenience sampling method. The study was conducted between 16 April and 28 May 2008. The research data were gathered using the Menopause Attitude Scale and a questionnaire. The average score for women on the Menopause Attitude Scale was 37.85 +/- 10.34. Significant differences were found between attitudes of women towards menopause and the information they had received before menarche about menstruation (P = 0.024), the meaning of menstruation (P = 0.014), the interval time between menstrual periods (P = 0.017), problems experienced before menstruation (P = 0.035) and the desire of some women to continue menstruating and delay menopause (P = 0.005). Results of this study showed that more than half of the women had negative attitudes towards menopause. In order to help girls and women develop positive attitudes about menarche, menstruation and menopause, they need to have access to information during all phases of these important physical changes. PMID- 22435974 TI - Factors that affect self-care behaviour of female high school students with dysmenorrhoea: a cluster sampling study. AB - The purpose of this study was to identify factors that affect the self-care behaviour of female high school students with dysmenorrhoea. This cross-sectional study utilized a questionnaire-based survey to understand the self-care behaviour of female high school students dysmenorrhoeal, along with the factors that affect this behaviour. A cluster random sampling method was adopted and questionnaires were used for data collection. Study participants experienced a moderate level of discomfort from dysmenorrhoea, and perceived dysmenorrhoea as serious. This investigation finds that cues to action raised perceived susceptibility to dysmenorrhoea and the perceived effectiveness of self-care behaviour and, therefore, increased the adoption of self-care behaviour. Hence, school nurses should offer female high school students numerous resources to apply correct self care behaviour. PMID- 22435975 TI - Symptom distress of Jordanian patients with cancer receiving chemotherapy. AB - The purpose of this study was to explore the prevalence of symptom distress among Jordanian patients with cancer who are receiving chemotherapy. A total of 112 patients with cancer were evaluated using the Distress Thermometer and clinical symptom problem list, and Demographic and Clinical Characteristic Data Sheet. Patients in the sample were mostly female, and recently diagnosed with cancer during the past 6 months, with a variety of types of cancer with breast cancer being the most common. Patients reported several symptoms with nausea, fatigue, anorexia and daily activity disorder being reported most frequently. Most of the patients (71%) reported distress at a clinically significant level. Distress was correlated with clinical characteristics as treatment number and time. Problems in the areas of family relationships, emotional functioning and physical functioning were associated with higher reports of distress. Identification of the presence of distress is the first step towards referral and treatment of the symptoms that may contribute to the distress of the patient with cancer. PMID- 22435976 TI - Symptom patterns, duration and responses in newly diagnosed patients with heart failure. AB - This study investigated the symptom patterns and duration and associated predictors occurring prior to first heart failure (HF) admission. Data from the Managing Cardiac Function (MACARF) program from January to December 2007 were reviewed in relation to preadmission symptoms and contacts with health professionals. Patients (n = 242) were aged 78.7 years (SD 12 years), male (54%) and married (45%). Patients experienced up to seven symptoms (Mean 2.7, SD 1.4) for a median of 4.47 days (range 1-7) before admission, most commonly increased dyspnoea on exertion (88%), and for the shortest duration chest discomfort. Less than half (48%) contacted a health professional before hospitalization, most often a general practitioner (37%). The duration patients experienced before presenting to hospital was increased if they presented during business hours (beta = 2.68) or the evening (beta = 1.88) (and therefore less from midnight to 8:30 am), or with a change in symptom (beta = 1.4), whereas duration was reduced by chest discomfort (beta = -2.01) and older age (beta = -0.07). There is a significant time window during which patients and health professionals may detect and act on worsening HF symptoms. Newly diagnosed patients with HF need support to recognize and respond to these symptoms to avoid hospital admission. PMID- 22435977 TI - Differences between patients' expectations and satisfaction with nursing care in a private hospital in Jordan. AB - A descriptive correlation study was conducted to describe the differences between patient expectations and satisfaction with nursing care, and to determine the relationships among patient's satisfaction with nursing care and selected sociodemographic variables. A convenience sample of 250 patients with different medical, surgical and gynaecologic diagnoses was recruited to participate in the study, which was carried out at a private hospital in Amman. Two research instruments and a sociodemographic data form were used for data collection: The Patient Expectations Questionnaire and Patient Satisfaction with Nursing Care Quality Questionnaire. The results indicated that patients were more satisfied with technical and ethical aspects of nursing care whereas they were less satisfied with nursing care during the night shift as well as with professional information provided by the nurses. The difference between patients' expectations and satisfaction was statistically significant. Patients' opinions regarding their expectations and their satisfaction with nursing care can be considered as an important opportunity for nurses to plan and implement appropriate strategies that improve the quality of nursing care. PMID- 22435978 TI - Depression and caregiver burden experienced by caregivers of Jordanian patients with stroke. AB - Many stroke survivors will be cared for at home, primarily by their relatives. Providing care to a family member with a chronic disabling disease can be both emotionally and physically distressing for the caregivers. The purpose of this study was to investigate the relationship between patients' characteristics, duration of caregiving, daily caregiving time, caregiver's characteristics, caregiver depression and burden in caregivers of patients with stroke. A cross sectional design was used with a convenience sample of 116 subjects. The Center of Epidemiologic Studies of Depression and the Caregiver Strain Index were used to identify caregiver depression and burden, respectively. Logistic regression analysis identified the influence of independent variables on caregiver depression and caregiver burden. Caregivers had high scores for depression and burden indices. Caregivers' health, receiving professional home health care and caregivers' burden were related to caregiver depression. Functional disabilities of patients with stroke and depression of caregivers were related to caregiver burden. To decrease caregiver depression and burden, nurses must provide caregivers with instructions for home management of patients with stroke. Development of specialized stroke home health services in Jordan that targets patients with stroke and their caregivers are recommended. PMID- 22435979 TI - Secondary traumatic stress and associated factors among Japanese nurses working in hospitals. AB - Nurses can experience secondary traumatic events while caring for patients. However, the severity of this issue is underestimated in Japan. To evaluate the prevalence and factors associated with secondary traumatic stress among general hospital nurses, we carried out a cross-sectional study at a general hospital in August 2006. The rate of experiencing secondary trauma was 90.3% (159 of 176 nurses; 52.1% response rate). The median score of the Impact of Event Scale Revised was 4.0 (range, 0-56). In multiple regression analyses, variables correlated with the Impact of Event Scale included neuroticism, trauma severity and feelings of self-reproach. It is necessary to develop support systems for nurses at risk for secondary traumatic stress. PMID- 22435980 TI - The effectiveness of aromatherapy massage using lavender oil as a treatment for infantile colic. AB - The aim of this paper was to investigate the effect of aromatherapy massage using lavender oil as a possible treatment for this condition. This research was carried out on a group of 40 infants between 2 and 6 weeks of age with a gestational age of 38-42 weeks and normal development and growth. All the infants weighed between 2500 and 4000 g at birth and all exhibited the signs of colic. Infants in the treatment group received abdominal massage by their mothers using lavender oil, while those in the control group were not subject to an intervention. The infants in both control and treatment groups were monitored once a week by the researchers, in total five times. The effect of the massage was measured in terms of changes in the length of time the infants cried per week. The use of aromatherapy massage using lavender oil was found to be effective in reducing the symptoms of colic. PMID- 22435981 TI - The effect of education given to patients with type 2 diabetes mellitus on self care. AB - This research was performed as a single group pretest--posttest experimental design to determine the effect of education given to patients with type 2 diabetes mellitus on self-care. The research was performed between October 2007 and June 2008 in the Internal Medicine Outpatient Clinics located in A and B Blocks of Erzincan State Hospital. The research population included 100 patients with type 2 diabetes mellitus who attended the above mentioned units between the specified dates and met the inclusion criteria. Patients were subjected to a pretest using a patient identification form, Diabetes Self-Care Scale (DSCS) form in Turkish language and metabolic control parameters. A statistically significant difference was found between the mean values of pre-education and posteducation DSCS scores with an increase in mean posteducation scores. These results demonstrate that the education given to patients improves their self-care and metabolic control variables. PMID- 22435982 TI - The influence of the professionalism behaviour of nurses working in health institutions on job satisfaction. AB - This study was carried out with the aim of determining the effect of the professional behaviour of nurses on their job satisfaction. The sample of the study included 531 nurses working in university, state and private hospitals in Turkey. Data were collected using two questionnaires which included the demographic characteristics of nurses, a Behavioral Inventory Form for Professionalism in Nursing (BIPN) and the Minnesota Satisfaction Questionnaire. The results from the BIPN showed that the mean score of nurses was low. The mean score of job satisfaction was at a medium level. The relationship between job satisfaction and professionalism was found to be statistically significant and in the positive direction. Based on this result, in order to increase job satisfaction, increasing the performance of arrangements directed towards the development of professional behaviour that is found within the scope of the professionalism scale is recommended. PMID- 22435983 TI - Nominal group technique: an effective method for obtaining group consensus. AB - This paper aims to demonstrate the versatility and application of nominal group technique as a method for generating priority information. Nominal group technique was used in the context of four focus groups involving clinical experts from the emergency department (ED) and obstetric and midwifery areas of a busy regional hospital to assess the triage and management of pregnant women in the ED. The data generated were used to create a priority list of discussion triggers for the subsequent Participatory Action Research Group. This technique proved to be a productive and efficient data collection method which produced information in a hierarchy of perceived importance and identified real world problems. This information was vital in initiating the participatory action research project and is recommended as an effective and reliable data collection method, especially when undertaking research with clinical experts. PMID- 22435984 TI - Nurses' perceptions of risk from emerging respiratory infectious diseases: a Singapore study. AB - The recent emergence of virulent respiratory infectious diseases such as Severe Acute Respiratory Syndrome (SARS) and Influenza A/H1N1 viruses predisposes nurses to occupational risks. This qualitative study investigated how Chinese Singaporean nurses perceived the risks of exposure to these infectious diseases and the factors that influenced this risk perception. Data were collected through face-to-face interviews and were analyzed using Braun and Clarke's process of thematic analysis. Three themes emerged: living with risk; the experience of SARS; and acceptance of risk. The nature of nursing work was perceived to place participants at risk of infection. Another significant finding of this study is that the government's, organizations' and nurses' perceptions of new emerging respiratory infectious diseases were influenced by their previous experience with SARS. Similar to previous studies, nurses working at the 'front line' believed that infection from these diseases was an unavoidable occupational hazard. PMID- 22435985 TI - Health related quality of life and the support needs of carers of cardiac surgical patients: an exploratory study. AB - In this descriptive, repeated-measures study, we assessed changes in Health Related Quality of Life (HRQL) of cardiac surgical patients' caregivers over time and their need for support. Ninety-six primary carers of cardiac patients who had received elective surgery at one tertiary referral hospital were recruited. The majority were female spouses of patients who had undergone bypass and/or cardiac valve surgery. Participants completed a self-administered questionnaire that included the SF-36v2 quality of life health survey and asked about their need for support 6 weeks and 6 months following patient discharge. Carers reported a significant improvement in five out of eight HRQL dimensions (Physical functioning, Physical role, Vitality, Social functioning, Role-emotional) over the study period (P < 0.05). Those who completed the survey at 6 weeks but not 6 months reported higher scores across all dimensions. Carers' need for support need was higher at 6 weeks than 6 months. PMID- 22435986 TI - Distracting children during blood draw: looking through distraction cards is effective in pain relief of children during blood draw. AB - This study aims to investigate the effects of distraction method by way of looking through distraction cards/Flippits(r) to reduce procedural pain and anxiety during blood draw. In this method we distract attention of the children with distraction cards/Flippits(r). Flippits(r) consist of various eye-catching pictures and shapes. Then we asked the children questions about the cards during the blood draw procedure that he or she can only answer if he or she examines the cards carefully. This study is a prospective, randomized controlled trial. The sample consisted of 123 children of ages between 6 and 12. We randomly assigned subjects into two groups. Group 1 received no intervention, whereas Group 2 received distraction in the form of looking through distraction cards/Flippits(r). Pre-procedural and procedural anxiety was assessed using the anxiety scale from the Children's Anxiety and Pain Scales by parents' and observer's report. Procedural pain was assessed using Faces Pain Scale-Revised by children, parent and observer reports. Results show that pre-procedural anxiety did not differ significantly. However, the experimental group had significantly lower pain levels than the control group during the blood draw procedure. Also experimental group had significantly lower anxiety levels than the control group. PMID- 22435987 TI - The determinants of leaf turgor loss point and prediction of drought tolerance of species and biomes: a global meta-analysis. AB - Increasing drought is one of the most critical challenges facing species and ecosystems worldwide, and improved theory and practices are needed for quantification of species tolerances. Leaf water potential at turgor loss, or wilting (pi(tlp) ), is classically recognised as a major physiological determinant of plant water stress response. However, the cellular basis of pi(tlp) and its importance for predicting ecological drought tolerance have been controversial. A meta-analysis of 317 species from 72 studies showed that pi(tlp) was strongly correlated with water availability within and across biomes, indicating power for anticipating drought responses. We derived new equations giving both pi(tlp) and relative water content at turgor loss point (RWC(tlp) ) as explicit functions of osmotic potential at full turgor (pi(o) ) and bulk modulus of elasticity (epsilon). Sensitivity analyses and meta-analyses showed that pi(o) is the major driver of pi(tlp) . In contrast, epsilon plays no direct role in driving drought tolerance within or across species, but sclerophylly and elastic adjustments act to maintain RWC(tlp,) preventing cell dehydration, and additionally protect against nutrient, mechanical and herbivory stresses independent of drought tolerance. These findings clarify biogeographic trends and the underlying basis of drought tolerance parameters with applications in comparative assessments of species and ecosystems worldwide. PMID- 22435988 TI - Nonsuicidal self-injury and gender: patterns of prevalence, methods, and locations among adolescents. AB - Nonsuicidal self-injury (NSSI) among adolescents is a growing concern. However, little is known about gender and features of this behavior. Gender differences in NSSI among a sample of 7,126 adolescents were investigated, 1,774 of whom reported having engaged in NSSI. Gender differences in prevalence, method, and location of NSSI were examined. Findings revealed that females reported higher rates of NSSI, more cutting and scratching, and more injuries to arms and legs than their male counterparts. Males reported more burning and hitting-type behavior, as well as injuries to the chest, face, or genitals. This highlights an interesting pattern of NSSI, which future research should consider to accurately examine NSSI in females and males. PMID- 22435989 TI - Chemical and biological properties of frequent screening hits. AB - High-throughput screening (HTS) has become an important technology for the drug discovery process. It has been noted that certain compounds frequently appear as hits in many screening campaigns. By mining an HTS database covering large chemical space and diverse biological functions, we identified many novel chemical features, as well as several biological processes that were associated with a significant portion of frequent hits. However, we also noted that several marketed drugs also contained characteristics that commonly were associated with frequent hits. This observation suggested that current generally employed strategies for triaging compounds may result in the removal of compounds with desirable properties. Therefore, we developed a novel strategy that overlaid chemical scaffolds and biological processes, along with empirical hit frequency data, in order to provide a more functional frequent hit triage strategy; the risk of removing biologically relevant frequent hits was reduced compared to the typical empirical hit frequency-based filtering strategy. PMID- 22435990 TI - A transient expression assay for the in planta efficacy screening of an antimicrobial peptide against grapevine bacterial pathogens. AB - AIMS: Natural and synthetic antimicrobial peptides (AMPs) are of increasing interest as potential resistance conferring elements in plants against pathogen infection. The efficacy of AMPs against pathogens is prescreened by in vitro assays, and promising AMP candidates are introduced as transgenes into plants. As in vitro and in planta environments differ, a prescreening procedure of the AMP efficacy in the plant environment is desired. Here, we report the efficacy of the purified synthetic peptide D4E1 against the grapevine-infecting bacterial pathogens Agrobacterium vitis and Xylophilus ampelinus in vitro and describe for the first time an in planta prescreening procedure based on transiently expressed D4E1. METHODS AND RESULTS: The antimicrobial effect of D4E1 against Ag. vitis and X. ampelinus was shown by a reduction in colony-forming units in vitro in a traditional plate-based assay and by a reduction in bacterial titres in planta as measured by quantitative real-time PCR (qPCR) in grapevine leaves transiently expressing D4E1. A statistically significant reduction in titre was shown for X. ampelinus, but for Ag. vitis, a significant reduction in titre was only observed in a subset of plants. CONCLUSIONS: The titres of both grapevine-infecting bacterial pathogens were reduced in an in vitro assay and for X. ampelinus in an in planta assay by D4E1 application. This widens the applicability of D4E1 as a potential resistance-enhancing element to additional pathogens and in a novel plant species. SIGNIFICANCE AND IMPACT OF THE STUDY: D4E1 is a promising candidate to confer enhanced resistance against the two tested grapevine bacterial pathogens, and the applied transient expression system proved to be a valuable tool for prescreening of D4E1 efficacy in an in planta environment. The described prescreening procedure can be used for other AMPs and might be adapted to other plant species and pathogens before the expensive and tedious development of stably transgenic lines is started. PMID- 22435991 TI - Indocyanine green-augmented diode laser treatment of port-wine stains: clinical and histological evidence for a new treatment option from a randomized controlled trial. AB - BACKGROUND: Complete clearance of port-wine stains (PWS) is difficult to achieve, mainly because of the resistance of small blood vessels to laser irradiation. Indocyanine green (ICG)-augmented diode laser treatment (ICG+DL) may overcome this problem. OBJECTIVES: To evaluate the feasibility of ICG+DL therapy of PWS and to compare the safety and efficacy of ICG+DL with the standard treatment, flashlamp-pumped pulsed dye laser (FPDL). METHODS: In a prospective randomized controlled clinical study, 31 patients with PWS were treated with FPDL (lambda(em)=585 nm, 6 J cm(-2) , 0.45 ms pulse duration) and ICG+DL (lambda(em)=810 nm, 20-50 J cm(-2) , 10-25 ms pulse duration, ICG-concentration: 2 mg kg(-1) body weight) in a split-face modus in one single treatment setting that included histological examination (haematoxylin and eosin, CD34). Two blinded investigators and the patients assessed clearance rate, cosmetic appearance and side-effects up to 3 months after treatment. RESULTS: ICG+DL therapy induced photocoagulation of medium and large blood vessels (>20 MUm diameter) but not of small blood vessels. According to the investigators' assessment, clearance rates and cosmetic appearance were better after ICG+DL therapy than after FPDL treatment (P=0.114, P=0.291, respectively), although not up to a statistically significant level, whereas patients considered these parameters superior (P=0.003, P=0.006, respectively). On a 10-point scale indicating pain during treatment, patients rated ICG+DL to be more painful (5.81 +/- 2.12) than FPDL treatment (1.61 +/- 1.84). CONCLUSION: ICG+DL represents a new and promising treatment modality for PWS, but laser parameters and ICG concentration need to be further optimized. PMID- 22435992 TI - Behavioral functioning and treatment adherence in pediatric eosinophilic gastrointestinal disorders. AB - OBJECTIVE: To examine behavioral predictors of treatment adherence in patients with eosinophilic gastrointestinal disorders (EGID). METHODS: Participants were 96 patients 2.5-18 yr of age with eosinophilic esophagitis or eosinophilic gastroenteritis and their caregivers (mother, father). We assessed maternal and paternal report of child/adolescent internalizing symptoms (e.g., anxiety, depression) and externalizing symptoms (e.g., aggression, anger) using the Behavior assessment system for children, 2nd edition (BASC-2). A multi-informant adherence assessment approach and an 80% cut point were used to classify patients as adherent or non-adherent. RESULTS: Sociodemographic predictors did not distinguish between adherent and non-adherent patients. Maternal report of internalizing symptoms significantly correlated with non-adherence (p < 0.001). Post hoc probing revealed a significant contribution of depression, with depressed patients being more likely (OR = 7.27; p < 0.05) to be non-adherent than non-depressed patients. Paternal report of internalizing and externalizing symptoms was not associated with non-adherence. CONCLUSIONS: Maternal report of patient internalizing behavioral symptoms, particularly depression, is significantly associated with non-adherence in patients with EGID. These symptoms are potential risk factors and should be considered when assessing and treating non-adherence. Clinical care of patients with EGID should include routine screening for depression. PMID- 22435993 TI - Introduction to the special section on "Femto10. The Madrid Conference on Femtochemistry". PMID- 22435994 TI - The Custom Endosteal Implant (CEI): Histology and Case Report of a Retrieved Maxillary Custom Osseous-Integrated Implant Nine Years in Service. AB - Abstract The Custom Endosteal Implant (CEI) is a custom-cast osseo-integrated implant that over the years has evolved to replace the "old" fibro-integrated subperiosteal variant. This newly developed implant achieves osseous integration by utilizing a hydroxyapatite (HA) coating plus a specialized grafting technique that produces much improved success rates relative to its fibro-integrated subperiosteal predecessor. This case reported herewith represents a maxillary CEI implant that was placed and in functional service for nine years before later being retrieved and processed for histologic examination subsequent to the patient's demise. In addition, due to infection that occurred shortly after placement, an early provisional procedure with fluoridated HA was also performed. Histologic analysis of the post-mortem specimen revealed fully integrated new bone formation intimately surrounding the previously dehisced implant strut. The latter had previously been decontaminated and grafted with a thin layer of fluorapatite (FA) material. Results including histologic analysis confirmed complete osseous-integration of the implant following successful FA graft revision. PMID- 22435997 TI - Redox energetics of hypercloso boron hydrides B(n)H(n) (n = 6-13) and B12X12 (X = F, Cl, OH, and CH3). AB - The reduction potentials (E degrees (Red) versus SHE) of hypercloso boron hydrides B(n)H(n) (n = 6-13) and B(12)X(12) (X = F, Cl, OH, and CH(3)) in water have been computed using the Conductor-like Polarizable Continuum Model (CPCM) and the Solvation Model Density (SMD) method for solvation modeling. The B3LYP/aug-cc-pvtz and M06-2X/aug-cc-pvtz as well as G4 level of theory were applied to determine the free energies of the first and second electron attachment (DeltaG(E.A.)) to boron clusters. The solvation free energies (DeltaG(solv)) greatly depend on the choice of the cavity set (UAKS, Pauling, or SMD) while the dependence on the choice of exchange/correlation functional is modest. The SMD cavity set gives the largest DeltaDeltaG(solv) for B(n)H(n)(0/-) and B(n)H(n)(-/2-) while the UAKS cavity set gives the smallest DeltaDeltaG(solv) value. The E degrees (Red) of B(n)H(n)(-/2-) (n = 6-12) with the G4/M06 2X(Pauling) (energy/solvation(cavity)) combination agrees within 0.2 V of experimental values. The experimental oxidative stability (E(1/2)) of B(n)X(n)(2 ) (X = F, Cl, OH, and CH(3)) is usually located between the values predicted using the B3LYP and M06-2X functionals. The disproportionation free energies (DeltaG(dpro)) of 2B(n)H(n)(-) -> B(n)H(n) + B(n)H(n)(2-) reveal that the stabilities of B(n)H(n)(-) (n = 6-13) to disproportionation decrease in the order B(8)H(8)(-) > B(9)H(9)(-) > B(11)H(11)(-) > B(10)H(10)(-). The spin densities in B(12)X(12)(-) (X = F, Cl, OH, and CH(3)) tend to delocalize on the boron atoms rather than on the exterior functional groups. The partitioning of DeltaG(solv)(B(n)H(n)(2-)) over spheres allows a rationalization of the nonlinear correlation between DeltaG(E.A.) and E degrees (Red) for B(6)H(6)(-/2-), B(11)H(11)(-/2-), and B(13)H(13)(-/2-). PMID- 22435995 TI - Elastin overexpression by cell-based gene therapy preserves matrix and prevents cardiac dilation. AB - After a myocardial infarction, thinning and expansion of the fibrotic scar contribute to progressive heart failure. The loss of elastin is a major contributor to adverse extracellular matrix remodelling of the infarcted heart, and restoration of the elastic properties of the infarct region can prevent ventricular dysfunction. We implanted cells genetically modified to overexpress elastin to re-establish the elastic properties of the infarcted myocardium and prevent cardiac failure. A full-length human elastin cDNA was cloned, subcloned into an adenoviral vector and then transduced into rat bone marrow stromal cells (BMSCs). In vitro studies showed that BMSCs expressed the elastin protein, which was deposited into the extracellular matrix. Transduced BMSCs were injected into the infarcted myocardium of adult rats. Control groups received either BMSCs transduced with the green fluorescent protein gene or medium alone. Elastin deposition in the infarcted myocardium was associated with preservation of myocardial tissue structural integrity (by birefringence of polarized light; P < 0.05 versus controls). As a result, infarct scar thickness and diastolic compliance were maintained and infarct expansion was prevented (P < 0.05 versus controls). Over a 9-week period, rats implanted with BMSCs demonstrated better cardiac function than medium controls; however, rats receiving BMSCs overexpressing elastin showed the greatest functional improvement (P < 0.01). Overexpression of elastin in the infarcted heart preserved the elastic structure of the extracellular matrix, which, in turn, preserved diastolic function, prevented ventricular dilation and preserved cardiac function. This cell-based gene therapy provides a new approach to cardiac regeneration. PMID- 22435998 TI - Ultrasound contrast agents: updated data on safety profile. AB - Contrast echocardiography represents a major technological advancement in the constantly evolving field of cardiovascular imaging. Over the last twenty years numerous studies have been published, illustrating the incremental value of contrast implementation into a variety of clinical scenarios. However, serious concerns have been raised about contrast safety profile, mainly based on postmarketing observational data and several animal studies. The latter have investigated contrast bio effects under experimental conditions that are not consistent with daily clinical practice. On the other hand, numerous clinical trials with large registries have proven otherwise. Not only contrast agents are efficient, but they also demonstrate a remarkable safety profile. So the question is: should we fear contrast utilization or should we consider them as an adjunctive and indispensable clinical tool for daily bedside practice? PMID- 22435999 TI - (Thio)urea organocatalyst equilibrium acidities in DMSO. AB - Bordwell's method of overlapping indicators was used to determine the pK(a) values of some of the most popular (thio)urea organocatalysts via UV spectrophotometric titrations. The incremental effect of CF(3) groups on acidic strength was also investigated. The pK(a)'s are in the range of 8.5-19.6. The results may lead to a better understanding of noncovalent organocatalysis and may aid in future catalyst development. PMID- 22436000 TI - Impact of assistive technology on family caregivers of children with physical disabilities: a systematic review. AB - PURPOSE: To systematically review the literature on the effects of assistive technology (AT) on family caregivers of children with physical disabilities. METHOD: Electronic searches of Medline, CINAHL Plus, PubMed, and PsychInfo were conducted. The main search terms were AT, caregiver, physical disability, cerebral palsy and quality of life. Studies were included if they related to the impact of AT on the family caregiver of children with physical impairment. Data extraction and quality assessments were conducted by three reviewers. RESULTS: Five articles were eligible for inclusion. Two studies rated weak quality of evidence (level 5), two studies rated moderate quality of evidence (level 3), and one article was a systematic review, rating high level of quality (level 1). A paucity of literature, small sample sizes, descriptive study designs and weak methodological quality meant a narrative review was possible. Three articles reported that AT lightened caregiver assistance in the areas of mobility, self- care and social function. CONCLUSIONS: Evidence suggests that AT has a positive impact on children with physical impairments and their caregivers. Future studies in this area could include valid and reliable outcome measures of AT use and the psychological impacts of AT on caring for a child with physical impairments. PMID- 22436001 TI - Ordering of epitaxial quantum dots on nanomembranes. AB - Semiconductor nanomembranes (NMs) provide fascinating opportunities to create unique structures and electronic devices owing to their mechanical flexibility. A fascinating question is whether the growth mediated by such flexibility can lead to the formation of ordered epitaxial surface nanostructures. By using computational modeling, we investigate the energetics of ordering of SiGe quantum dots (QDs) on both Si(001) and Si(111) NMs. We calculate the interaction energies for quantum dots grown on one side and on both sides of the NM and assembled in a square lattice for the Si(001) surface and in a hexagonal lattice for the Si(111) surface. Our calculations show that for QDs grown on the Si(001) NM the interaction energy possesses a minimum at a well-defined spacing only when the QDs are positioned on both sides in a square array and aligned along the [110] direction. The predicted QD ordering, spacing, and other features are in excellent agreement with recent experimental results. For QDs grown on the Si(111) NM, our calculations predict that ordered QDs can be achieved for both one-side and both-side growth, albeit with different QD spacings. The present work suggests that semiconductor NMs are a fascinating template for the self assembled growth of ordered QDs. PMID- 22436002 TI - Patient-specific modelling of the foot: automated hexahedral meshing of the bones. AB - Subject-specific finite element modelling is a powerful tool for carrying out controlled investigations of the effects of geometric and material property differences on performance and injury risk. Unfortunately, the creation of suitable meshes for these models is a challenging and time-intensive task. This paper presents an automated method of generating fully hexahedral meshes of the bones of the feet which requires only surface representations as inputs. The method is outlined and example meshes, using two human feet and the foot of a Japanese macaque, are given to demonstrate its flexibility. Mesh quality is also evaluated for the calcaneus, first metatarsal, navicular and talus. Streamlining the generation of finite element meshes of the foot will ease investigations into the patient-specific biomechanics of injury. PMID- 22436003 TI - Combined therapy with PJ34, a poly(ADP-ribose)polymerase inhibitor, reduces tissue plasminogen activator-induced hemorrhagic transformations in cerebral ischemia in mice. AB - Recombinant tissue-type plasminogen activator (rt-PA) is presently the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke. Although reperfusion of ischemic tissue is essential, the use of rt-PA is limited due to its narrow therapeutic window and risk of hemorrhagic transformations. Recent studies have shown that rt-PA amplifies the post-ischemic activation of the nuclear enzyme poly(ADP-ribose)polymerase (PARP). This enzyme has been shown to contribute to both the breakdown of the blood brain barrier and spontaneous hemorrhagic transformations after ischemia. We therefore examined the capacity of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino) acetamide hydrochloride), a potent inhibitor of PARP, to reduce the hemorrhagic transformations that occur after rt-PA in mice with permanent focal cerebral ischemia. Ischemia was produced by intraluminal occlusion of the left middle cerebral artery and treated with vehicle, rt-PA (10 mg/kg, i.v., 6 h after occlusion) or rt-PA plus PJ34 (3, 6 or 12 mg/kg, i.p., at ischemia onset and 4 h later). Hemorrhagic transformations, neurological examination, and infarct volumes were evaluated 48 h after the onset of ischemia. Delayed administration of rt-PA resulted in increased hemorrhagic transformations and aggravated the neurological deficit. Giving PJ34 (3 mg/kg) markedly reduced the hemorrhagic transformations, an effect not owing to a modification of matrix metalloprotease activity. Furthermore, PJ34 improved the neurological functions of rt-PA-treated ischemic mice. To conclude, the PARP inhibitor PJ34 makes rt-PA safer in experimental ischemic stroke. PMID- 22436004 TI - Understanding lacunar stroke: also an epidemiological challenge. PMID- 22436005 TI - Novel polysome messages and changes in translational activity appear after induction of adipogenesis in 3T3-L1 cells. AB - BACKGROUND: Control of translation allows for rapid adaptation of the cell to stimuli, rather than the slower transcriptional control. We presume that translational control is an essential process in the control of adipogenesis, especially in the first hours after hormonal stimulation. 3T3-L1 preadipocytes were cultured to confluency and adipogenesis was induced by standard protocols using a hormonal cocktail. Cells were harvested before and 6 hours after hormonal induction. mRNAs attached to ribosomes (polysomal mRNAs) were separated from unbound mRNAs by velocity sedimentation. Pools of polysomal and unbound mRNA fractions were analyzed by microarray analysis. Changes in relative abundance in unbound and polysomal mRNA pools were calculated to detect putative changes in translational activity. Changes of expression levels of selected genes were verified by qPCR and Western blotting. RESULTS: We identified 43 genes that shifted towards the polysomal fraction (up-regulated) and 2 genes that shifted towards free mRNA fraction (down-regulated). Interestingly, we found Ghrelin to be down-regulated. Up-regulated genes comprise factors that are nucleic acid binding (eIF4B, HSF1, IRF6, MYC, POLR2a, RPL18, RPL27a, RPL6, RPL7a, RPS18, RPSa, TSC22d3), form part of ribosomes (RPL18, RPL27a, RPL6, RPL7a, RPS18, RPSa), act on the regulation of translation (eIF4B) or transcription (HSF1, IRF6, MYC, TSC22d3). Others act as chaperones (BAG3, HSPA8, HSP90ab1) or in other metabolic or signals transducing processes. CONCLUSIONS: We conclude that a moderate reorganisation of the functionality of the ribosomal machinery and translational activity are very important steps for growth and gene expression control in the initial phase of adipogenesis. PMID- 22436006 TI - Working memory and verbal fluency in simultaneous interpreters. AB - We investigated working memory and verbal fluency in simultaneous interpreters, expecting to find enhanced working memory and semantic processing in interpreters relative to others fluent in a second language. The interpreters (n = 15) outperformed the control group (n = 35) on semantic fluency and most measures of working memory; their advantage over teachers of a foreign language (n = 15) approached, but did not reach, statistical significance. Our findings suggest that, while proficiency in a foreign language may enhance fluency and working memory skills, simultaneous interpreters have semantic processing and working memory capacities greater than those expected from mere proficiency in a foreign language. PMID- 22436007 TI - Successful hemostasis by embolization in a case of uncontrollable arterial bleeding following posterior tension-free vaginal mesh procedure puncture. AB - An 82-year-old woman presented to our hospital in April 2009 complaining of sensations of a descending bladder and residual urine, and frequent urination. She had given birth to two children. She had undergone simple total hysterectomy for uterine myoma at another hospital in 1974 and anterior colporrhaphy for anterior vaginal wall prolapse, also at another hospital, in 2008. On presentation, examination with the pelvic organ prolapse quantitative system revealed a stage-III cuff scar prolapse and cystocele. A cystogram revealed a cystocele. We report here a tension-free vaginal mesh (TVM) procedure and the development of arterial bleeding following the third puncture for posterior TVM, which could not be controlled through the operative field but was successfully stopped by embolization. PMID- 22436008 TI - 'Candidatus Arthromitus' revised: segmented filamentous bacteria in arthropod guts are members of Lachnospiraceae. AB - The name Arthromitus has been applied collectively to conspicuous filamentous bacteria found in the hindguts of termites and other arthropods. First observed by Joseph Leidy in 1849, the identity of these filaments has remained contentious. While Margulis and colleagues declared them to be a life stage of Bacillus cereus, others have assumed them to belong to the same lineage as the segmented filamentous bacteria (SFB) from vertebrate guts, a group that has garnered much attention due to their unique ability to specifically modulate their host's immune response. Both SFB and Arthromitus filaments from arthropod guts were grouped under provisional name 'Candidatus Arthromitus' by Snel and colleagues as they share a striking similarity in terms of their morphology and close contact to the host gut wall. While SFB form a distinct lineage within the family Clostridiaceae, the identity of the filaments from arthropod guts remains elusive. Using whole-genome amplification of single filaments capillary picked from termite guts and fluorescence in situ hybridization of 16S rRNA with group specific oligonucleotide probes, we show that they represent a monophyletic lineage within the family Lachnospiraceae distinct from that of SFB. Therefore, 'Candidatus Arthromitus' can no longer be used for both groups. Given the historic precedence, we propose to reserve this name for the filaments that were originally described by Leidy. For the SFB from vertebrate guts, we propose the provisional name 'Candidatus Savagella' in honour of the American gut microbiologist Dwayne C. Savage, who was the first to describe that important bacterial group. PMID- 22436009 TI - Phosphoproteome profiling of substantia nigra and cortex regions of Alzheimer's disease patients. AB - Alzheimer's disease (AD) is the most common form of dementia and cognitive impairment usually characterized by widespread neurodegeneration throughout the association cortex, limbic system and hippocampus. Aberrant protein phosphorylation is a defining pathological hallmark of AD and implicated in the dysregulation of major cellular processes through highly dynamic and complex signaling pathways. Here in, we demonstrate 81 proteins, of 600 spots selected, unambiguously identified as phosphorylated, providing a partial phosphoproteome profile of AD substantia nigra and cortex and respective control brain regions. More importantly, abnormal phosphorylation signal intensity of nine physiologically important proteins observed can profoundly affect cell metabolism, signal transduction, cytoskeleton integration, and synaptic function and accounts for biological and morphological alterations. Our studies employed two-dimensional gel electrophoresis for protein separation, Pro-Q((r)) Diamond phosphoprotein staining and electrospray ionization quadrupole time of flight tandem MS for protein identification. NetPhosk 1.0 is used for the confirmation of protein modification status as well known/putative phosphoproteins. A further insight into the links among the identified phosphoproteins and functional roles STRING 8.3, KEGG and REACTOME pathway databases were applied. The present quantitative phosphoproteomic analysis can be supportive in establishing a broad database of potential protein targets of abnormal phosphorylation in AD brain. PMID- 22436010 TI - Polydatin suppresses ultraviolet B-induced cyclooxygenase-2 expression in vitro and in vivo via reduced production of reactive oxygen species. PMID- 22436011 TI - Serotonin is critical for rewarded olfactory short-term memory in Drosophila. AB - The biogenic amines dopamine, octopamine, and serotonin are critical in establishing normal memories. A common view for the amines in insect memory performance has emerged in which dopamine and octopamine are largely responsible for aversive and appetitive memories. Examination of the function of serotonin begins to challenge the notion of one amine type per memory because altering serotonin function also reduces aversive olfactory memory and place memory levels. Could the function of serotonin be restricted to the aversive domain, suggesting a more specific dopamine/serotonin system interaction? The function of the serotonergic system in appetitive olfactory memory was examined. By targeting the tetanus toxin light chain (TNT) and the human inwardly rectifying potassium channel (Kir2.1) to the serotonin neurons with two different GAL4 driver combinations, the serotonergic system was inhibited. Additional use of the GAL80(ts1) system to control expression of transgenes to the adult stage of the life cycle addressed a potential developmental role of serotonin in appetitive memory. Reduction in appetitive olfactory memory performance in flies with these transgenic manipulations, without altering control behaviors, showed that the serotonergic system is also required for normal appetitive memory. Thus, serotonin appears to have a more general role in Drosophila memory, and implies an interaction with both the dopaminergic and octopaminergic systems. PMID- 22436012 TI - Heritability and genetic correlations of obesity-related phenotypes among Roma people. AB - BACKGROUND: The Roma people are particularly vulnerable to developing obesity and related diseases, due to their social and ethnic backgrounds. However, little is known about the genetic and/or environmental factors affecting the variability of obesity-related traits among the Roma population. AIM: The aim of the present study was to estimate heritabilities and common genetic and environmental influences of obesity-related phenotypes in a sample of Roma people living in the Greater Bilbao region (Basque Country; Spain). SUBJECTS AND METHODS: Three hundred and seventy-two individuals from 50 large, extended and highly consanguineous pedigrees were phenotyped for anthropometric traits related to obesity. Heritability estimates were assessed for all quantitative traits and bivariate analyses were conducted to assess the phenotypic, genetic and environmental correlations among these traits. RESULTS: Significant heritable components (p<0.01) ranging from 0.25-0.68 exist for the studied phenotypes. Heritability for WHR (h(2) =0.60) considerably surpasses the usual heritability estimates on family-based studies ( <0.30). Measures of overall fatness (BMI, CF and SF) show stronger correlations with each other than body fat distribution traits (WHR, CI and TER). CONCLUSIONS: The study concluded that the Greater Bilbao Roma population is genetically predisposed to abdominal fat distribution. Variation in body mass is highly associated with variation in adiposity. However, overall fatness and adiposity distribution does not seem to share major common genetic factors, although common environmental factors operate between them. PMID- 22436014 TI - Bi-fluorescence imaging for estimating accurately the nuclear condition of Rhizoctonia spp. AB - AIMS: To simplify the determination of the nuclear condition of the pathogenic Rhizoctonia, which currently needs to be performed either using two fluorescent dyes, thus more costly and time-consuming, or using only one fluorescent dye, thus less accurate. METHODS AND RESULTS: A red primary fluorescence (autofluorescence) of the hyphal cell walls and septa of Rhizoctonia spp. with green excitation is evidenced in Rhizoctonia spp. This property is exploited and combined for the first time with a conventional DAPI fluorescence to accurately determine the nuclear condition of Rhizoctonia. This bi-fluorescence imaging strategy depicted the nuclear condition in Rhizoctonia spp. more accurately than the conventional DAPI fluorescence used alone and was validated against isolates previously genotyped by DNA sequencing. CONCLUSIONS: We demonstrated that the bi fluorescence imaging strategy was safe, accurate and simple to perform and interpret. SIGNIFICANCE AND IMPACT OF THE STUDY: The developed bi-fluorescence imaging strategy provides a sensitive tool for determining the nuclear condition of Rhizoctonia strains. Its simplicity is a key advantage when there are numerous cultures to be examined. PMID- 22436015 TI - Shear induced collateral artery growth modulated by endoglin but not by ALK1. AB - Transforming growth factor-beta (TGF-beta) stimulates both ischaemia induced angiogenesis and shear stress induced arteriogenesis by signalling through different receptors. How these receptors are involved in both these processes of blood flow recovery is not entirely clear. In this study the role of TGF-beta receptors 1 and endoglin is assessed in neovascularization in mice. Unilateral femoral artery ligation was performed in mice heterozygous for either endoglin or ALK1 and in littermate controls. Compared with littermate controls, blood flow recovery, monitored by laser Doppler perfusion imaging, was significantly hampered by maximal 40% in endoglin heterozygous mice and by maximal 49% in ALK1 heterozygous mice. Collateral artery size was significantly reduced in endoglin heterozygous mice compared with controls but not in ALK1 heterozygous mice. Capillary density in ischaemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared with controls. To provide mechanistic evidence for the differential role of endoglin and ALK1 in shear induced or ischaemia induced neovascularization, murine endothelial cells were exposed to shear stress in vitro. This induced increased levels of endoglin mRNA but not ALK1. In this study it is demonstrated that both endoglin and ALK1 facilitate blood flow recovery. Importantly, endoglin contributes to both shear induced collateral artery growth and to ischaemia induced angiogenesis, whereas ALK1 is only involved in ischaemia induced angiogenesis. PMID- 22436016 TI - Graph mining for SAR transfer series. AB - The transfer of SAR information from one analog series to another is a difficult, yet highly attractive task in medicinal chemistry. At present, the evaluation of SAR transfer potential from a data mining perspective is still in its infancy. Only recently, a first computational approach has been introduced to evaluate SAR transfer events. Here, a substructure relationship-based molecular network representation has been used as a starting point to systematically identify SAR transfer series in large compound data sets. For this purpose, a methodology is introduced that consists of two stages. For graph mining, an algorithm has been designed that extracts all parallel series from compound data sets. A parallel series is formed by two series of analogs with different core structures but pairwise corresponding substitution patterns. The SAR transfer potential of identified parallel series is then evaluated using a scoring function that emphasizes corresponding potency progression over many analog pairs and large potency ranges. The substructure relationship-based molecular network in combination with the graph mining algorithm currently represents the only generally applicable approach to systematically detect SAR transfer events in large compound data sets. The combined approach has been evaluated on a large number of compound data sets and shown to systematically identify SAR transfer series. PMID- 22436017 TI - Effect of menstrual blood-derived stromal stem cells on proliferative capacity of peripheral blood mononuclear cells in allogeneic mixed lymphocyte reaction. AB - AIM: Menstrual blood stromal stem cells (MBSCs) have been demonstrated to exhibit stem cell properties such as the capability for self-renewal and multipotency, allowing for multilineage differentiation. In addition, this cell type has various immunomodulatory effects. In this study, we examined the potential effect of MBSCs on proliferation of peripheral blood mononuclear cells (PBMCs) in allogeneic mixed lymphocyte reaction (MLR). MATERIALS AND METHODS: Menstrual blood was collected from healthy donors after menstrual blood flow initiated and its mononuclear cell fraction was separated. Cells were subsequently cultured and adherent cells were allowed to propagate and used as stem cells. Flowcytometric immunophenotyping was performed using a panel of monoclonal antibodies including CD44, CD45, CD34, CD9, CD29, CD10, CD38, CD105, CD73, CD133, STRO-1 and Oct-4A. For functional analysis, PBMCs were co-cultured with MBSCs, collected after 4 days and added to allogeneic PBMCs. 2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H tetrazolium-5-carboxanilide (XTT) assay was carried out to evaluate cell proliferation. RESULTS: MBSCs showed surface and intracellular markers of mesenchymal stem cells with the exception of the high expression of Oct-4A. MBSCs affected the proliferative response of PBMC in a dose-dependent manner. At ratio of 1:1 to 1:2, MBSCs inhibited, while at lower ratios (1:32 to 1:64) stimulated the proliferative capacity of allogeneic PBMCs. CONCLUSION: According to the present study, MBSCs exert their immunoregulatory effects on allogeneic PBMCs in a dose-dependent manner. This finding can be considered as a valuable point in future cell therapy strategies, when this cell population is used. PMID- 22436018 TI - Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis. AB - BACKGROUND: The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown METHODS: To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-beta. RESULTS: The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-beta and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. In vitro, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25(hi) CD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-beta to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation. CONCLUSION: In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease. PMID- 22436019 TI - Determination of pKa and forced degradation of the indoloquinoline antimalarial compound cryptolepine hydrochloride. AB - The study was aimed at determining the acid dissociation constant of cryptolepine hydrochloride and its degradation under stressed conditions. The pKa was determined using buffers in the pH range 10.4-11.6 by spectrophotometry at controlled measurement temperature (20 +/- 0.5 degrees C). The stability of the compound was investigated under various stressed conditions including neutral, acid, alkaline, light, dry heat and oxidation at different temperatures. Degradation products were analysed by HPLC. The calculated pKa values (uncorrected and corrected for ionic strength) were 11.09 +/- 0.03 and 10.99 +/- 0.05, respectively. A graphical approach yielded an uncorrected pKa value of 11.07. Degradation of the compound in water, 0.1 M HCl, 0.1 M NaOH and 3% hydrogen peroxide followed a first order reaction. With proper temperature control and maintenance of uniform ionic strength, a reproducible pKa of cryptolepine is obtainable by spectrophotometry. The compound was found to be highly susceptible to oxidation and relatively stable in neutral and acidic conditions but less so in a basic medium. There were no significant changes in concentration of samples exposed to light and dry heat at 60 degrees C over the study period. PMID- 22436020 TI - Overall versus individual changes for otoacoustic emissions and audiometry in a noise-exposed cohort. AB - OBJECTIVE: For a noise-exposed group of workers, group-averaged and individual changes were compared for pure-tone audiometry, transient-evoked otoacoustic emissions (TEOAEs), and distortion product otoacoustic emissions (DPOAEs) in order to see if they exhibit the same pattern in time. DESIGN: Baseline and 17 months follow-up hearing status was examined with pure-tone audiometry, TEOAEs, and DPOAEs. STUDY SAMPLE: A total of 233 noise-exposed employees were measured, while 60 subjects from this group contributed to test-retest reliability measures. RESULTS: Group-averaged changes and individual shifts followed similar patterns: decreases for audiometry at 6-8 kHz and DPOAE at 1.5 kHz, and enhancements for DPOAE at 3 kHz. TEOAEs showed an overall deterioration while both individual deteriorations and enhancements were larger than chance. DPOAE at 6 kHz showed the largest group-averaged change, while the number of individual shifts was not significant. There were no clear relations between changes in audiometry and changes in OAE. CONCLUSION: Significant individual OAE changes do not necessarily follow the same pattern as the group-averaged results. This limits the applicability of OAE testing for the monitoring of individual subjects. Furthermore, hearing deterioration might manifest itself in a local enhancement of otoacoustic emissions and not only in the form of decreases in amplitude. PMID- 22436021 TI - Myrtenal ameliorates diethylnitrosamine-induced hepatocarcinogenesis through the activation of tumor suppressor protein p53 and regulation of lysosomal and mitochondrial enzymes. AB - Myrtenal is a novel class of compound belongs to monoterpenes found predominantly in mint, pepper, etc., and it was shown to have excellent pharmacological activities against many diseases among which cancer is imperative. Hepatocellular carcinoma is a primary malignancy of the hepatocytes, which rapidly leads to death in short periods. The aim of this study was to investigate the possible therapeutic efficiency of myrtenal against diethylnitrosamine-induced experimental hepatocarcinogenesis by analyzing the key enzymes of carbohydrate metabolism, lysosomal and mitochondrial TCA cycle enzymes, and also the possible role of tumor suppressor protein p53, and scanning electron microscopic studies. The results revealed that myrtenal significantly ameliorated the altered enzymes of carbohydrate metabolism, lysosomal and mitochondrial enzymes, and interestingly the tumor suppressor protein p53 was found to be significantly accumulated in myrtenal-treated animals, which inevitably confirms that myrtenal has a prominent role in preventing the liver cancer during treatment. Furthermore, the antineoplastic property was well evidenced by the mRNA expression of p53 protein by the reverse-transcriptase polymerase chain reaction and immunoblot analysis. The observed anticancer property of myrtenal may be due to the involvement and expression of p53 and influence in the mitochondrial and lysosomal membrane integrity and also interference in the gluconeogenesis process of cancer cells. Our results suggest that myrtenal is very efficient and useful compound in the treatment of liver cancer in future. PMID- 22436022 TI - Validation of a heterogeneous elastic-biphasic model for the numerical simulation of the PDL. AB - An elastic-biphasic model for the simulation of the periodontal ligament (PDL) and the adjacent tooth is presented and investigated. The PDL is modelled as a biphasic material following the work of Ehlers and Markert (2001 ), whereas the tooth is modelled as a linear elastic body. A spatial discretisation scheme is proposed based on mixed finite elements for the spatial discretisation. Due to nonlinearity in the model, a predictor-corrector scheme is employed as a temporal discretisation scheme. In order to validate the PDL model, in vitro measurements are compared with numerical simulations. The numerical simulations are performed using geometries resulting from micro-CT scanner of the same porcine tooth, which was employed for the in vitro measurements. PMID- 22436023 TI - Perspective-taking and depth of theory-of-mind reasoning in sequential-move games. AB - Theory-of-mind (ToM) involves modeling an individual's mental states to plan one's action and to anticipate others' actions through recursive reasoning that may be myopic (with limited recursion) or predictive (with full recursion). ToM recursion was examined using a series of two-player, sequential-move matrix games with a maximum of three steps. Participants were assigned the role of Player I, controlling the initial and the last step, or of Player II, controlling the second step. Appropriate for the assigned role, participants either anticipated or planned Player II's strategy at the second step, and then determined Player I's optimal strategy at the first step. Participants more readily used predictive reasoning as Player II (i.e., planning one's own move) than as Player I (i.e., anticipating an opponent's move), although they did not differ when translating reasoning outcome about the second step to optimal action in the first step. Perspective-taking influenced likelihood of predictive reasoning, but it did not affect the rate at which participants acquired it during the experimental block. We conclude that the depth of ToM recursion (related to perspective-taking mechanisms) and rational application of belief-desire to action (instrumental rationality) constitute separate cognitive processes in ToM reasoning. PMID- 22436024 TI - Post-transcriptional regulatory networks play a key role in noise reduction that is conserved from micro-organisms to mammals. AB - RNA-binding proteins (RBPs) are core regulators of mRNA transcript stability and translation in prokaryotes and eukaryotes alike. Genome-wide studies in yeast have shown intriguing relationships between the expression dynamics of RBPs, the structure of post-transcriptional regulatory networks of RBP-mRNA binding interactions and noise reduction in post-transcriptionally regulated expression profiles. In the present study, we assembled and compared the genomic properties of RBPs and integrated transcriptional and post-transcriptional regulatory networks in four species: Escherichia coli, yeast, mouse and human. We found that RBPs are consistently regulated to have minimal levels of protein noise, that known noise-buffering network motifs are enriched in the integrated networks and that post-transcriptional feedback loops act as regulators of other regulators. These results support a general model where RBPs are the key regulators of stochastic noise-buffering in numerous downstream cellular processes. The currently available datasets do not allow clarification of whether post transcriptional regulation by RBPs and by noncoding RNAs plays a similar or distinct role, although we found evidence that specific combinations of transcription factors, RBPs and micro-RNAs jointly regulate known disease pathways in humans, suggesting complementarity rather than redundancy between both modes of post-transcriptional regulation. PMID- 22436025 TI - Thermal inkjet printing in tissue engineering and regenerative medicine. AB - With the advantages of high throughput, digital control, and highly accurate placement of cells and biomaterial scaffold to the desired 2D and 3D locations, bioprinting has great potential to develop promising approaches in translational medicine and organ replacement. The most recent advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review. Bioprinting has no or little side effect to the printed mammalian cells and it can conveniently combine with gene transfection or drug delivery to the ejected living systems during the precise placement for tissue construction. With layer-by-layer assembly, 3D tissues with complex structures can be printed using scanned CT or MRI images. Vascular or nerve systems can be enabled simultaneously during the organ construction with digital control. Therefore, bioprinting is the only solution to solve this critical issue in thick and complex tissues fabrication with vascular system. Collectively, bioprinting based on thermal inkjet has great potential and broad applications in tissue engineering and regenerative medicine. This review article introduces some important patents related to bioprinting of living systems and the applications of bioprinting in tissue engineering field. PMID- 22436026 TI - Structural and functional properties, chaperone activity and posttranslational modifications of alpha-crystallin and its related subunits in the crystalline lens: N-acetylcarnosine, carnosine and carcinine act as alpha- crystallin/small heat shock protein enhancers in prevention and dissolution of cataract in ocular drug delivery formulations of novel therapeutic agents. AB - Cataract is a leading cause of blindness worldwide and is responsible for ~40-80% of the estimated 45 million cases of blindness that occur across the globe. In addition to providing refractive properties to the lens for focusing the image, it is believed that the molecular chaperone function of alpha-crystallin is essential in preventing the light scattering due to aggregation of other proteins and thus in the maintenance of lens transparency and thereby prevention of cataract. By now, it is fairly acknowledged that chaperoning ability of alpha crystallin is instrumental in the maintenance of crystalline lens transparency, and decreased chaperone-like activity of alpha-crystallin is associated with various types and stages of cataract. A better pharmacological targeting of safeguarding the alpha-crystallin chaperone activity may aid the development of therapeutic strategies that could evade the need for cataract surgery and revive lens transparency of the cataractous lenses. This article originally summarizes the significance of modulation and enhancing of alpha-crystallin chaperone activity with imidazole-containing dipeptides N-acetylcarnosine, carnosine and carcinine in consequence to prevent, delay or dissolve the human cataract. A growing evidence and discussion of recent patents are presented in this study that demonstrate the ability of N-acetylcarnosine (lubricant eye drops) or carcinine (lubricant eye drops) (universal antioxidant and deglycation agent) resistant to enzymatic hydrolysis with carnosinase to act as pharmacological chaperones, to decrease oxidative stress and ameliorate oxidative and excessive glycation stress-related eye disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for age-related cataracts, age related macular degeneration (AMD) and ocular complications of diabetes (OCD). The therapeutic strategies are highlighted in the study for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human age-related eye disease, such as cataracts and advanced glycation tissue proteins - engineered systems. PMID- 22436027 TI - Recent advances in chitosan films for controlled release of drugs. AB - Chitosan is a versatile carrier for biologically active agent from a small molecule such as an antibiotic to macromolecules such as proteins and nucleic acids. In addition, drug delivery devices based on chitosan can be available in a variety of morphologies including films, fibers, nanoparticles and microspheres. Otherwise the inherent advantages of this polymer such as biocompatibility, tissue adhesions and hydrophilic nature, chitosan can be modified to accomplish a specific purpose, for example improves release kinetics. In this review, recent patents of chitosan-based film systems for drug delivery are presented and discussed. This review include matrix type systems, membrane coated systems and film forming solution. For each one of these systems, several examples of manufacture processes, bioactive agents to be delivered and specifics applications are considered. This work highlights the use of chitosan in the film technology for drug delivery, presenting examples of chitosan used in an unmodified state and examples of modifications of the polymer backbone. PMID- 22436028 TI - Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern? AB - BACKGROUND AND PURPOSE: Optic nerve involvement is frequent in mitochondrial disease, and retinal abnormalities are described in Parkinson's disease (PD). METHODS: We evaluated retinal nerve fiber layer (RNFL) thickness by optical coherence tomography in 43 patients with PD and in 86 age-matched controls. We considered separately the eyes ipsilateral and contralateral to the most affected body side in patients with PD. ancova analysis, Pearson test, and multiple regression analysis were used (P < 0.05). RESULTS: Patients with PD showed significantly thinner temporal RNFL thickness compared to controls (P = 0.004), more evident in the eye contralateral to the most affected body side. Average RNFL thickness significantly correlated with age in both controls and patients with PD (P-values ranging from 0.001 to 0.019), whereas in patients with PD RNFL thickness did not correlate with clinical variables. CONCLUSIONS: Our study reveals a loss of retinal nerve fibers in the temporal quadrant in PD, which is typically susceptible in mitochondrial optic neuropathies. PMID- 22436029 TI - Degree of dental anxiety in children with and without toothache: prospective assessment. AB - BACKGROUND: Few prospective studies on the anxiety of children in the dental office have been published. AIMS: To monitor dental anxiety levels in children with and without previous experience with toothache over a period of six consecutive visits. DESIGN: A longitudinal study was carried out involving 167 children treated at a public dental service. Levels of anxiety in the dental setting were assessed in children without toothache (G1) and those with toothache (G2) using the modified Venham picture test (VPT). Data acquisition was carried out over a 6-week period, with each child treated in the dental office once a week. Six assessments of anxiety were performed in the waiting room prior to dental treatment. RESULTS: A significant reduction in anxiety scores occurred between appointments in both groups. In the inter-group comparison, G2 had significantly higher anxiety scores than G1. Although statistically significant reductions in anxiety scores occurred through to the fifth appointment, a tendency toward stagnation in anxiety scores was observed beginning with the fourth appointment. CONCLUSIONS: Dental anxiety scores were reduced over the course of six appointments. Children with toothache had higher levels of dental anxiety than those that had never experienced toothache. PMID- 22436030 TI - Preparation of functional phosphorus zwitterions from activated alkanes, aldehydes, and tributylphosphine: synthesis of polysubstituted furo[3,2 c]coumarins. AB - A general preparation of new types of highly functional phosphorus zwitterions is realized via tandem three-component reactions using the corresponding functional alkanes, aldehydes, and Bu(3)P. Starting from our novel zwitterions as synthetic reagents with commercially available acid chlorides in a one-step procedure provides an attractive approach toward furo[3,2-c]coumarins. PMID- 22436031 TI - Impact of ligand modification on hydrogen photogeneration and light-harvesting applications using cyclometalated iridium complexes. AB - To explore structure-activity relationships with respect to light-harvesting behavior, a family of bis-cyclometalated iridium complexes [Ir(C^N)(2)(Hbpdc)] 2 5 (where C^N = 2-phenylbenzothiazole and its functionalized derivatives, and H(2)bpdc =2,2'-bipyridine-4,4'-dicarboxylate) was synthesized using a facile method. The photophysical and electrochemical properties of these complexes were investigated and compared to those of analogue 1 (C^N = (4-trifluoromethyl)-2 phenylbenzothiazole); they were also investigated theoretically using density functional theory. The molecular structures of complexes 2-4 were determined by X ray crystallography, which revealed typical octahedral coordination geometry. The structural modifications involved in the complexes were accomplished through the attributes of electron-withdrawing CF(3) and electron-donating NMe(2) substituents. The UV-vis spectra of these species, except for that of 5, displayed a broad absorption in the low-energy region, which originated from metal-to-ligand charge-transfer transitions. These complexes were found to exhibit visible-light-induced hydrogen production and light-to-electricity conversion in photoelectrochemical cells. The yield of hydrogen production from water using these complexes was compared, which revealed substantial dependences on their structures, particularly on the substituent of the cyclometalated ligand. Among the systems, the highest turnover number of 1501 was achieved with complex 2, in which the electron-withdrawing CF(3) substituent was connected to a phenyl ring of the cyclometalated ligand. The carboxylate anchoring groups made the complexes highly suitable for grafting onto TiO(2) (P25) surfaces for efficient electron transfer and thus resulted in an enhancement of hydrogen evolution compared to the unattached homogeneous systems. In addition, the combined incorporation of the electron-donating NMe(2) group and the electron withdrawing CF(3) substituent on the cyclometalated ligand caused complex 5 to not work well for hydrogen production. Their incorporation, however, enhanced the performance of 5 in the light-harvesting application in nanocrystalline TiO(2) dye-sensitized solar cells, which was attributed to the intense absorption in the visible region. PMID- 22436032 TI - Synthesis of 2,5-disubstituted oxazoles and oxazolines catalyzed by ruthenium(II) porphyrin and simple copper salts. AB - A novel and moderate synthesis of 2,5-disubstituted oxazoles and oxazolines involving ruthenium(II) porphyrin-copper chloride catalyzed cyclization was developed. These reactions using readily available benzene carboxylic acids and phenylethenes or phenylacetylenes are performed under mild conditions. The reactions proceed in series, giving rise to the formation of an intermolecular C N bond and an intramolecular C-O bond, which yield oxazole or oxazoline derivatives simultaneously. PMID- 22436033 TI - Dysfunction of mitotic cell division at shoot apices triggered severe growth abortion in interspecific hybrids between tetraploid wheat and Aegilops tauschii. AB - Common wheat is an allohexaploid species, derived through endoreduplication of an interspecific triploid hybrid produced from a cross between cultivated tetraploid wheat and the wild diploid relative Aegilops tauschii. Hybrid incompatibilities, including hybrid necrosis, have been observed in triploid wheat hybrids. A limited number of A. tauschii accessions show hybrid lethality in triploid hybrids crossed with tetraploid wheat as a result of developmental arrest at the early seedling stage, which is termed severe growth abortion (SGA). Despite the potential severity of this condition, the genetic mechanisms underlying SGA are not well understood. Here, we conducted comparative analyses of gene expression profiles in crown tissues to characterize developmental arrest in triploid hybrids displaying SGA. A number of defense-related genes were highly up regulated, whereas many transcription factor genes, such as the KNOTTED1-type homeobox gene, which function in shoot apical meristem (SAM) and leaf primordia, were down-regulated in the crown tissues of SGA plants. Transcript accumulation levels of cell cycle-related genes were also markedly reduced in SGA plants, and no histone H4-expressing cells were observed in the SAM of SGA hybrid plants. Our findings demonstrate that SGA shows unique features among other types of abnormal growth phenotypes, such as type II and III necrosis. PMID- 22436034 TI - Commentary: functional dyspepsia - is acupuncture the solution? PMID- 22436036 TI - Commentary: outcomes after escalation of infliximab in moderately active ulcerative colitis. PMID- 22436038 TI - Commentary: diagnostic medical radiation exposure in inflammatory bowel disease. PMID- 22436039 TI - Commentary: is CRP ready for use to indicate response or remission with infliximab in Crohn's? PMID- 22436041 TI - Commentary: long-term lubiprostone for constipation predominant IBS. PMID- 22436042 TI - Letter: thiopurines during pregnancy and intrauterine exposure to metabolites. PMID- 22436044 TI - Letter: TPMT activity and age in IBD patients. PMID- 22436046 TI - Transplantation of novel human GDF5-expressing CHO cells is neuroprotective in models of Parkinson's disease. AB - Growth/differentiation factor 5 (GDF5) is a neurotrophic factor that promotes the survival of midbrain dopaminergic neurons in vitro and in vivo and as such is potentially useful in the treatment of Parkinson's disease (PD). This study shows that a continuous supply of GDF5, produced by transplanted GDF5-overexpressing CHO cells in vivo, has neuroprotective and neurorestorative effects on midbrain dopaminergic neurons following 6-hydroxydopamine (6-OHDA)-induced lesions of the adult rat nigrostriatal pathway. It also increases the survival and improves the function of transplanted embryonic dopaminergic neurons in the 6-OHDA-lesioned rat model of PD. This study provides the first proof-of-principle that sustained delivery of GDF5 in vivo may be useful in the treatment of PD. PMID- 22436047 TI - Loeffler myocarditis in pre-B acute lymphoblastic leukaemia with t(5;14)(q31;q32). PMID- 22436048 TI - Familial diarrhea syndrome caused by an activating GUCY2C mutation. AB - BACKGROUND: Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis. METHODS: We used linkage analysis, based on arrays with single nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC C using HEK293T cells. RESULTS: We identified a heterozygous missense mutation (c.2519G->T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members. CONCLUSIONS: Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.). PMID- 22436049 TI - Financing graduate medical education--mounting pressure for reform. PMID- 22436050 TI - Registered nurse labor supply and the recession--are we in a bubble? PMID- 22436051 TI - Acetylcholine content and viability of cholinergic neurons are influenced by the activity of protein histidine phosphatase. AB - BACKGROUND: The first mammalian protein histidine phosphatase (PHP) was discovered in the late 90s of the last century. One of the known substrates of PHP is ATP-citrate lyase (ACL), which is responsible--amongst other functions- for providing acetyl-CoA for acetylcholine synthesis in neuronal tissues. It has been shown in previous studies that PHP downregulates the activity of ACL by dephosphorylation. According to this our present work focused on the influence of PHP activity on the acetylcholine level in cholinergic neurons. RESULTS: The amount of PHP in SN56 cholinergic neuroblastoma cells was increased after overexpression of PHP by using pIRES2-AcGFP1-PHP as a vector. We demonstrated that PHP overexpression reduced the acetylcholine level and induced cell death. The acetylcholine content of SN56 cells was measured by fast liquid chromatography-tandem mass spectrometry method. Overexpression of the inactive H53A-PHP mutant also induced cell damage, but in a significantly reduced manner. However, this overexpression of the inactive PHP mutant did not change the acetylcholine content of SN56 cells significantly. In contrast, PHP downregulation, performed by RNAi-technique, did not induce cell death, but significantly increased the acetylcholine content in SN56 cells. CONCLUSIONS: We could show for the first time that PHP downregulation increased the acetylcholine level in SN56 cells. This might be a potential therapeutic strategy for diseases involving cholinergic deficits like Alzheimer's disease. PMID- 22436052 TI - PGE(2) reverses G(s)-mediated inhibition of platelet aggregation by interaction with EP3 receptors, but adds to non-G(s)-mediated inhibition of platelet aggregation by interaction with EP4 receptors. AB - Prostaglandin E(2) (PGE(2)) has intriguing effects on platelet function in the presence of agents that raise cyclic adenosine 3'5'-monophosphate (cAMP). PGE(2) reverses inhibition of platelet aggregation by agents that stimulate cAMP production via a G(s)-linked receptor, but adds to the inhibition of platelet function brought about by agents that raise cAMP through other mechanisms. Here, we used the EP receptor antagonists DG-041 (which acts at the EP3 receptor) and ONO-AE3-208 (which acts at the EP4 receptor) to investigate the role of these receptors in mediating these effects of PGE(2). Platelet aggregation was measured in platelet-rich plasma obtained from healthy volunteers in response to adenosine diphosphate (ADP) using single platelet counting. The effects of a range of concentrations of PGE(2) were determined in the presence of (1) the prostacyclin mimetic iloprost, which operates through G(s)-linked IP receptors, (2) the cAMP PDE inhibitor DN9693 and (3) the direct-acting adenylate cyclase stimulator forskolin. Vasodilator-stimulated phosphoprotein (VASP) phosphorylation was also determined as a measure of cAMP. PGE(2) reversed the inhibition of aggregation brought about by iloprost; this was prevented in the presence of the EP3 antagonist DG-041, indicating that this effect of PGE(2) is mediated via the EP3 receptor. In contrast, PGE(2) added to the inhibition of aggregation brought about by DN9693 or forskolin; this was reversed by the EP4 antagonist ONO-AE3 208, indicating that this effect of PGE(2) is mediated via the EP4 receptor. Effects on aggregation were accompanied by corresponding changes in VASP phosphorylation. The dominant role of EP3 receptors circumstances where cAMP is increased through a Gs-linked mechanism may be relevant to the situation in vivo where platelets are maintained in an inactive state through constant exposure to prostacyclin, and thus the main effect of PGE(2) may be prothrombotic. If so, the results described here further support the potential use of an EP3 receptor antagonist in the control of atherothrombosis. PMID- 22436053 TI - Antenatal risk factors for postnatal depression: a prospective study of Chinese women at maternal and child health centres. AB - BACKGROUND: Risk factors for postnatal depression (PND) are under-explored in the Chinese populations. There is increasing recognition of the importance of identifying predictive factors during the antenatal period for PND. The present study aimed to identify the risk factors for postnatal depression in a community cohort of Chinese women with special focus on the antenatal risk factors. METHODS: Eight hundred and five Chinese women were interviewed during their third trimester of pregnancy and at around 2 months postnatally. Putative risk factors for PND were collected and the diagnosis of PND was confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders. The 2-month postnatal depression status was used as the dependent variable for univariate and multivariate analyses against putative risk factors. RESULTS: Marital dissatisfaction (Relative Risk = 8.27), dissatisfied relationship with mother-in-law (Relative Risk = 3.93), antenatal depressive symptomatology (Relative Risk = 3.90), and anxiety-prone personality (Relative Risk = 2.14) predicted PND in Chinese women independently. CONCLUSIONS: Chinese women tend to keep their own feelings and emotions and it is important to monitor Chinese pregnant women with these predictive risk factors so that PND can be identified early. PMID- 22436054 TI - Cytoplasmic RNA in undifferentiated neural stem cells: a potential label-free Raman spectral marker for assessing the undifferentiated status. AB - Raman microspectroscopy (rms) was used to identify, image, and quantify potential molecular markers for label-free monitoring the differentiation status of live neural stem cells (NSCs) in vitro. Label-free noninvasive techniques for characterization of NCSs in vitro are needed as they can be developed for real time monitoring of live cells. Principal component analysis (PCA) and linear discriminant analysis (LDA) models based on Raman spectra of undifferentiated NSCs and NSC-derived glial cells enabled discrimination of NSCs with 89.4% sensitivity and 96.4% specificity. The differences between Raman spectra of NSCs and glial cells indicated that the discrimination of the NSCs was based on higher concentration of nucleic acids in NSCs. Spectral images corresponding to Raman bands assigned to nucleic acids for individual NSCs and glial cells were compared with fluorescence staining of cell nuclei and cytoplasm to show that the origin of the spectral differences were related to cytoplasmic RNA. On the basis of calibration models, the concentration of the RNA was quantified and mapped in individual cells at a resolution of ~700 nm. The spectral maps revealed cytoplasmic regions with concentrations of RNA as high as 4 mg/mL for NSCs while the RNA concentration in the cytoplasm of the glial cells was below the detection limit of our instrument (~1 mg/mL). In the light of recent reports describing the importance of the RNAs in stem cell populations, we propose that the observed high concentration of cytoplasmic RNAs in NSCs compared to glial cells is related to the repressed translation of mRNAs, higher concentrations of large noncoding RNAs in the cytoplasm as well as their lower cytoplasm volume. While this study demonstrates the potential of using rms for label-free assessment of live NSCs in vitro, further studies are required to establish the exact origin of the increased contribution of the cytoplasmic RNA. PMID- 22436055 TI - Heme oxygenase-1 induction: the anti-inflammatory regime in organ transplant. PMID- 22436056 TI - Is impaired Kupffer cell function really important to the pathogenesis of nonalcoholic steatohepatitis? PMID- 22436057 TI - Asian consensus report on functional dyspepsia: necessary and ready? PMID- 22436058 TI - Differential prognostic impact of renal insufficiency on patients with hepatocellular carcinoma: a propensity score analysis and staging strategy. AB - BACKGROUND AND AIM: Renal insufficiency (RI) can coexist in patients with hepatocellular carcinoma (HCC). This study analyzed the prognostic impact of RI on patients with HCC and determined the optimal staging strategy for these patients. METHODS: RI was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). A total of 502 and 1701 HCC patients with and without RI, respectively, were enrolled. One-to-one matched patient cohorts according to treatments were built by using the propensity model. The prognostic ability of the Cancer of the Liver Italian Program, Barcelona Clinic Liver Cancer, Japan Integrated Scoring, and Taipei Integrated Scoring (TIS) systems in HCC patients with RI was compared by using the Akaike information criterion (AIC). RESULTS: For patients undergoing percutaneous ablation and transarterial chemoembolization (TACE), RI was significantly associated with decreased long-term survival (P = 0.001 and 0.004, respectively). In patients receiving resection and other treatments, there were no significant survival differences between patients with and without RI. With similar demographics generated in the propensity model, significantly decreased survival was found in patients with RI in the TACE group (P = 0.018), but not in the resection, percutaneous ablation, and other treatment groups. Among HCC patients with RI, the TIS system had the lowest AIC value. CONCLUSIONS: RI is often present in patients with HCC and predicts a poor outcome in patients undergoing TACE. The survival of HCC patients receiving resection, percutaneous ablation, and other treatments is not affected by RI. The TIS staging system is a more feasible prognostic model for HCC patients with RI. PMID- 22436059 TI - Education and Imaging. Gastrointestinal: A sheep in wolf's clothing. PMID- 22436060 TI - Education and Imaging. Gastrointestinal: A cutaneous clue to painless acute on chronic pancreatitis. PMID- 22436061 TI - Education and Imaging. Gastrointestinal: An unexpected cause of refractory iron deficiency anemia; Taenia SPP. on capsule endoscopy. PMID- 22436062 TI - Education and Imaging. Hepatobiliary and pancreatic: Hepatic actinomycosis. PMID- 22436063 TI - Education and Imaging. Hepatobiliary and pancreatic: Pancreatic mucosa-associated lymphoid tissue (MALT) lymphoma. PMID- 22436066 TI - High-dose fasudil preserves postconditioning against myocardial infarction under hyperglycemia in rats: role of mitochondrial KATP channels. AB - BACKGROUND: The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels. METHODS: Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR). RESULTS: Under normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 +/- 8%, 21 +/- 9% and 21 +/- 10% of AAR, respectively) compared with that in the control (42 +/- 7%). Under hyperglycemia, low-dose fasudil (40 +/- 11%) and diazoxide (44 +/- 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 +/- 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 +/- 13%). CONCLUSION: Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection. PMID- 22436067 TI - Methods for the guideline-based development of quality indicators--a systematic review. AB - BACKGROUND: Quality indicators (QIs) are used in many healthcare settings to measure, compare, and improve quality of care. For the efficient development of high-quality QIs, rigorous, approved, and evidence-based development methods are needed. Clinical practice guidelines are a suitable source to derive QIs from, but no gold standard for guideline-based QI development exists. This review aims to identify, describe, and compare methodological approaches to guideline-based QI development. METHODS: We systematically searched medical literature databases (Medline, EMBASE, and CINAHL) and grey literature. Two researchers selected publications reporting methodological approaches to guideline-based QI development. In order to describe and compare methodological approaches used in these publications, we extracted detailed information on common steps of guideline-based QI development (topic selection, guideline selection, extraction of recommendations, QI selection, practice test, and implementation) to predesigned extraction tables. RESULTS: From 8,697 hits in the database search and several grey literature documents, we selected 48 relevant references. The studies were of heterogeneous type and quality. We found no randomized controlled trial or other studies comparing the ability of different methodological approaches to guideline-based development to generate high-quality QIs. The relevant publications featured a wide variety of methodological approaches to guideline-based QI development, especially regarding guideline selection and extraction of recommendations. Only a few studies reported patient involvement. CONCLUSIONS: Further research is needed to determine which elements of the methodological approaches identified, described, and compared in this review are best suited to constitute a gold standard for guideline-based QI development. For this research, we provide a comprehensive groundwork. PMID- 22436069 TI - Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes. AB - WHAT IS KNOWN AND OBJECTIVE: Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitor therapies provide glycaemic control with reduced risks associated with weight gain or hypoglycaemia. Incretin therapies are compared with their mechanisms of action, effects on haemoglobin A(1C) (HbA(1C)), fasting plasma glucose (FPG), post prandial glucose (PPG), body weight, beta-cell function, cardiovascular biomarkers and in their safety profiles to aid clinicians in the selection of individualized pharmacotherapy for patients with type 2 diabetes. METHODS: Relevant articles for a systematic review were identified through PubMed. Randomized, head-to-head comparison studies among incretin therapies were identified and included in the review. Additionally, randomized, controlled monotherapy and combination therapy studies examining glycaemic and extraglycaemic effects of individual incretin therapies from 2007 to 2011 were reviewed. RESULTS AND DISCUSSION: Glucagon-like peptide-1 receptor agonists are generally preferred over DPP-4 inhibitors because of their greater effectiveness in reducing HbA(1C) , FPG and PPG excursions, and greater weight loss potentiation. As a monotherapy option, longer-acting GLP-1 RAs, including liraglutide and exenatide once-weekly, may be preferred at higher HbA(1C) because of their more pronounced effects on FPG. At lower/near normal HbA(1C) , a short acting GLP-1 RA, such as exenatide twice-daily, may be a better choice as its effects are more pronounced with PPG. Ideal patients or patient situations for DPP-4 inhibitors include patients who need minimal reduction in HbA(1C,) elderly patients, patients who are unwilling or unable to take an injectable agent, when GLP-1 RAs are contraindicated or when the patient will not benefit from weight loss. Treatment benefits common to all incretin-based therapies include minimal hypoglycaemia risk, potential preservation of beta-cell function and effective targeting of multiple organs underlying type 2 diabetes and of comorbidities commonly associated with type 2 diabetes, such as obesity and hypertension. WHAT IS NEW AND CONCLUSION: Key differences in mechanisms of action and in glycaemic and extra-glycaemic treatment outcomes exist among incretin therapies, both within the GLP-1 RA class, and between GLP-1 RAs and DPP-4 inhibitors. Clinical judgment acknowledging important differences among incretin therapies and treatment-related patient characteristics will aid in the selection of the appropriate incretin agent for individualized pharmacotherapy. PMID- 22436070 TI - Assessment of mechanical integrity for drug-eluting renal stent with micro-sized drug reservoirs. AB - The drug-eluting stent (DES) has become the gold standard worldwide for the treatment of cardiovascular diseases. In recent years, an innovative variation of the DES with micro-sized drug reservoirs has been introduced. It allows programmable drug delivery with both spatial and temporal control and has several potential advantages over traditional DESs. However, creating such reservoirs on the stent struts may weaken the structure of the stent scaffolding and compromise its mechanical integrity. In this study, we propose to use this innovative stent concept in the renal indication for potential treatment of both renal artery stenosis (upstream) and its associated kidney diseases (downstream) at the same time. The effects of these micro-sized drug reservoirs on several key clinically relevant functional attributes of the drug-eluting renal stent were systematically and quantitatively investigated. Finite element models were developed to predict the mechanical integrity of a balloon-expandable stent at various stages. Results show that (1) creating drug reservoirs on a stent could impact the stent fatigue resistance to certain degrees; (2) drug reservoirs on the stent crowns lead to greater loss in all key stent attributes than reservoirs on either bar arms or connectors and (3) the proposed optimised depot stent was proven to be feasible and could triple drug capacity than the current DESs, with marginal trade-off in its key clinical attributes. These results can serve as the guidelines to help future stent designs to achieve the best combination of stent structural integrity and smart drug delivery in the future. PMID- 22436071 TI - {Sn9[Si(SiMe3)3]3}- and {Sn8Si[Si(SiMe3)3]3}-: variations of the E9 cage of metalloid group 14 clusters. AB - The disproportionation reaction of the subvalent metastable halide SnBr proved to be a powerful synthetic method for the synthesis of metalloid cluster compounds of tin. Hence, the neutral metalloid cluster compound Sn(10)[Si(SiMe(3))(3)](6) (3) was synthesized from the reaction of SnBr with LiSi(SiMe(3))(3). In the course of the reaction anionic clusters might also be present, and we now present the first anionic cluster compound {Sn(8)E[Si(SiMe(3))(3)](3)}(-) (E = Si, Sn), where one position in the cluster core is occupied by a silicon or a tin atom, giving further insight into structural variations of E(9) cages in metalloid group 14 cluster compounds. PMID- 22436072 TI - Effect of age and COX-2-derived prostanoids on the progression of adult vascular dysfunction in the offspring of diabetic rats. AB - BACKGROUND AND PURPOSE: The present study was designed to determine how diabetes in pregnancy affects vascular function in their offspring, the influence of age and whether COX activation is involved in this effect. EXPERIMENTAL APPROACH: Relaxation responses to ACh were analysed in mesenteric resistance arteries from the offspring of control rats (O-CR) and those of diabetic rats (O-DR) at 3, 6 and 12 months of age. TxB2, PGE2 and PGF(2alpha) release were determined by enzyme immunoassay. COX-1 and COX-2 expression were measured by Western blot analysis. KEY RESULTS: O-DR developed hypertension from 6 months of age compared with O-CR. In O-DR, relaxation responses to ACh were impaired in all ages studied and were restored by COX-2 inhibition. TP receptor blockade (SQ29548) restored ACh relaxation in arteries from 3-month-old O-DR while TP and EP receptor blockade (SQ29548 + AH6809) was required to restore it in 6-month-old O-DR. In 12 month-old O-DR, ACh relaxation was restored when TP, EP and FP receptors were blocked (SQ29548 + AH6809 + AL8810). ACh-stimulated TxB2 was higher in all O-DR. ACh-stimulated PGE2 release was increased in arteries from 6- and 12-month-old O DR, whereas PGF(2alpha) was increased only in 12-month-old O-DR. COX-2, but not COX-1, expression was higher in O-DR than O-CR. CONCLUSIONS AND IMPLICATIONS: The results indicate an age-dependent up-regulation of COX-2 coupled to an enhanced formation of vasoconstrictor prostanoids in resistance arteries from O-DR. This effect plays a key role in the pathogenesis of endothelial dysfunction, which in turn could contribute to the progression of vascular dysfunction in these rats. PMID- 22436073 TI - From apnea and insomnia in Iceland to season and slow wave sleep. PMID- 22436075 TI - Independent and combined effects of carbohydrate and caffeine ingestion on aerobic cycling performance in the fed state. AB - The purpose of this study was to examine the independent and combined effects of carbohydrate and caffeine ingestion on performance and various physiological parameters during aerobic cycling (~1 h). Ten male cyclists (28 +/- 9 years, 73 +/- 6 kg, 66 +/- 9 mL.kg(-1).min(-1) maximal oxygen consumption) performed 20 min of steady-state (SS) cycling (60% peak power (W(max))) followed by a simulated 20 km time trial (TT) under placebo (PLA), carbohydrate (CHO), caffeine (CAF), and combined CAF-CHO conditions, all of which were performed in the fed state. CAF CHO improved TT performance by 3.4% +/- 2% (84 +/- 57 s) compared with PLA (p < 0.05), whereas no differences were detected among CHO, CAF, and PLA. The SS respiratory exchange ratio was elevated in CHO (0.92 +/- 0.03), CAF (0.96 +/- 0.07), and CAF-CHO (0.95 +/- 0.02) compared with PLA (0.89 +/- 0.03) (p < 0.05). Post-SS and post-TT blood glucose levels were also elevated in CAF-CHO (88.3 +/- 16.7 mg.dL(-1) and 111.2 +/- 33.5 mg.dL(-1), respectively) compared with PLA (74.5 +/- 9.8 mg.dL(-1) and 85.4 +/- 17.6 mg.dL(-1), respectively) (p < 0.05). Treatment conditions did not differentially impact SS pulmonary ventilation, oxygen consumption, heart rate, peak quadriceps muscle strength, rating of perceived exertion, or blood lactate. CAF and CHO improved TT performance when taken together but not independently. Although the present work did not yield any definitive physiological mechanisms for the performance findings, these data suggest that cyclists in the fed state should ingest carbohydrate and caffeine together to improve time trial performance. PMID- 22436076 TI - Gestational and postnatal protein deficiency affects postnatal development and histomorphometry of liver, kidneys, and ovaries of female rats' offspring. AB - Pre- and postnatal protein deficiency may lead to decreased foetal intra-uterine development and postnatal growth, which is common in developing countries. The present study aimed to investigate the consequences of a low-protein intake during gestation and postnatally on adult female rats' offspring. Female rats were given either a control or a protein-deficient diet throughout the gestation and lactation periods. A subset of females was killed at day 20 of pregnancy for foetal and placental measurements. Another subset of females farrowed and the number, length, and weight of the offspring were measured. After weaning, the offspring received the same diet as their dams until 70 days of age. They were sacrificed, and some organs were weighed and collected for histomorphometrical analyses. Placental weight and size and foetal weight were lower in protein deficient dams. The weight and length of pups at birth were also lower in the deficient group. The organs to body weight ratio were higher in the deficient animals at 70 days of age. The protein-deficient female offspring had a smaller ovarian area, greater numbers of primordial follicles and developing follicles per square millimetres of ovarian cortex, and no corpora lutea. The liver showed smaller nuclear diameter of the hepatocytes and height of the hepatocytes cords. The kidneys showed smaller cortical area with reduced glomerular number and diameter. These results provide the first evidence of the histomorphological changes of the association between gestational and postnatal protein deficiency in female rats' offspring. PMID- 22436077 TI - Transition-metal-free intramolecular N-arylations. AB - N-Substituted phenoxazines and related aza analogs have been prepared from N acetylated aryloxy anilides by transition-metal-free, base-catalyzed cyclization reactions. In the presence of a mixture of 10 mol % of N,N' dimethylethylenediamine (DMEDA) and 2 equiv of K(2)CO(3) in toluene at 135 degrees C the products are obtained in high yields. PMID- 22436078 TI - Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats. AB - Reduced intrahepatic nitric oxide (NO) bioavailability and increased cyclooxygenase-1 (COX-1)-derived vasoconstrictor prostanoids modulate the hepatic vascular tone in cirrhosis. We aimed at investigating the reciprocal interactions between NO and COX in the hepatic endothelium of control and cirrhotic rats. NO bioavailability (DAF-FM-DA staining), superoxide (O(2)(-)) content (DHE staining), prostanoid production (PGI(2) and TXA(2) by enzyme immunoassays) as well as COX expression (Western Blot), were determined in hepatic endothelial cells (HEC) from control and cirrhotic rats submitted to different experimental conditions: COX activation, COX inhibition, NO activation and NO inhibition. In control and cirrhotic HEC, COX activation with arachidonic acid reduced NO bioavailability and increased O(2)(-) levels. These effects were abolished by pre treating HEC with the COX inhibitor indomethacin. In control, but not in cirrhotic HEC, scavenging of O(2)(-) by superoxide dismutase (SOD) incubation partially restored the decrease in NO bioavailability promoted by COX activation. NO supplementation produced a significant and parallel reduction in PGI(2) and TXA(2) production in control HEC, whereas it only reduced TXA(2) production in cirrhotic HEC. By contrast, in control and cirrhotic HEC, NO inhibition did not modify COX expression or activity. Our results demonstrate that NO and COX systems are closely interrelated in HEC. This is especially relevant in cirrhotic HEC where COX inhibition increases NO bioavailability and NO supplementation induces a reduction in TXA(2). These strategies may have beneficial effects ameliorating the vasoconstrictor/vasodilator imbalance of the intrahepatic circulation of cirrhotic livers. PMID- 22436079 TI - Priming and stimulus-response learning in perceptual classification tasks. AB - Participants often respond more quickly and more accurately to a repeated stimulus compared to a non-repeated one, a phenomenon known as repetition priming. In semantic classification tasks priming appears to be largely attributable to the learning of stimulus-decision and stimulus-response associations, which allow participants to bypass many of the processes engaged during initial stimulus analysis. The current study tested whether stimulus response learning plays a similarly dominant role in priming that occurs in perceptual classification tasks. Unfamiliar objects were used as stimuli to reduce the influence of semantic processes on priming and the task switched for all test trials to eliminate stimulus-decision learning. The results showed across-task priming as measured by reaction time facilitation and improved accuracy when the response remained the same during the encoding and test phases. When the response switched, similar levels of reaction time facilitation were observed, but priming as measured by accuracy was significantly reduced and no longer significant. These findings indicate that stimulus-response learning contributes to priming in perceptual classification tasks, but does not play a dominant role. Significant stimulus-level learning that is independent of the task and response also occurs and likely indexes facilitated perceptual processing of the objects. PMID- 22436080 TI - Do gastrointestinal and respiratory signs and symptoms correlate with the severity of gastroesophageal reflux? AB - BACKGROUND: Gastroesophageal reflux (GER) is a disorder that is common by seen in childhood and may lead to severe complications. In this study, we ascertained the incidence of GER among the children who had typical and atypical complaints of GER and whether there was a difference between two groups comparing the findings of 24-hour pH-meter. METHODS: 39 out of 70 patients with typical and atypical GER symptoms were diagnosed as GER by 24-hour pH-meter monitoring. The patients were divided into three groups, those having gastrointestinal complaints, those having respiratory complaints and those having both gastrointestinal and respiratory symptoms. RESULTS: Evaluated the GER prevalence in these groups, it was found to be 60% in the gastrointestinal group, 48.6% in the respiratory group and 75% in the mixed group. When pH-meter measurements of GER positive patients were compared within the clinical groups, the fraction of time that pH was lower than 4 was found to be significantly higher in the mixed group (p = 0.004). CONCLUSIONS: The coexistence of gastrointestinal and respiratory symptoms in the patients with GER may be related to the severe reflux. PMID- 22436081 TI - The role of novelty in early word learning. AB - What mechanism implements the mutual exclusivity bias to map novel labels to objects without names? Prominent theoretical accounts of mutual exclusivity (e.g., Markman, 1989, 1990) propose that infants are guided by their knowledge of object names. However, the mutual exclusivity constraint could be implemented via monitoring of object novelty (see Merriman, Marazita, & Jarvis, 1995). We sought to discriminate between these contrasting explanations across two preferential looking experiments with 22-month-olds. In Experiment 1, infants viewed three objects: one name-known, two name-unknown. Of the two name-unknown objects, one was novel, and the other had been previously familiarized. The infants responded to hearing a novel label by increasing attention only to the novel, name-unknown object. In a second experiment in which the name-known object was absent, a novel label increased infants' attention to a novel object beyond baseline preference for novelty. The experiments provide clear evidence for a novelty-based mechanism. However, differences in the time course of disambiguation across experiments suggest that novelty processing may be influenced by contextual factors. PMID- 22436082 TI - Contradictory effects for prevention of depression and anxiety in residents in homes for the elderly: a pragmatic randomized controlled trial. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of a stepped care program to prevent the onset of depression and anxiety disorders in elderly people living in residential homes. METHODS: A pragmatic randomized controlled trial was conducted to compare the intervention with usual care in 14 residential homes in the Netherlands. A total of 185 residents with a minimum score of 8 on the Centre for Epidemiologic Studies Depression Scale, who did not meet the diagnostic criteria for a depressive or anxiety disorder, and were not suffering from severe cognitive impairment, were recruited between April 2007 and December 2008. They were randomized to a stepped-care program (N = 93) or to usual care (N = 92). The stepped-care participants sequentially underwent watchful waiting, a self-help intervention, life review, and a consultation with the general practitioner. The primary outcome measure was the incidence of a major depressive disorder (MDD) or anxiety disorder during a period of one year according to the Mini International Neuropsychiatric Interview. RESULTS: The intervention was not effective in reducing the incidence of the combined outcome of depression and anxiety (incidence rate ratio (IRR) = 0.50; 95% confidence interval (CI) = 0.23 1.12). However, the intervention was superior to usual care in reducing the risk of MDD incidence (IRR = 0.26; 95% CI = 0.12-0.80) contrary to anxiety incidence (IRR = 1.32; 95% CI = 0.48-3.62). CONCLUSIONS: These results suggest that the stepped-care program is effective in reducing the incidence of depression, but is not effective in preventing the onset of anxiety disorders in elderly people living in residential homes. PMID- 22436083 TI - A pilot open label prospective study of memantine monotherapy in adults with ADHD. AB - OBJECTIVES: Available pharmacotherapies treat some adults with ADHD inadequately. A small literature suggests that glutamate modulation could have effects on ADHD. METHODS: Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, was titrated to a maximum dose of 10 mg BID in 34 adult subjects aged 18-55 who met DSM-IV criteria for ADHD or ADHD NOS on structured interview. Twenty-eight subjects completed 12 weeks exposure. The Adult ADHD Investigator Symptom Report (AISRS), Clinical Global Impression (CGI), a neuropsychological battery sensitive to domains of executive function, and the CANTAB cognitive battery were administered. Paired t-tests compared treated and baseline scores. RESULTS: At week 12, AISRS data showed reduction in total symptoms (-17.5, P < 0.001), inattentive symptoms (-10.6, P < 0.001), and hyperactive symptoms (-6.9, P < 0.01). A total of 44% of subjects had CGI ratings of much or very much improved. Cognitive performance improved in measures of attention, working memory, and other selected executive domains by weeks 6 and 12 (each P < 0.05); simple reaction time declined by week 12 (P < 0.05). There were no severe adverse events, but mild adverse events were common and six subjects discontinued due to adverse effects. CONCLUSIONS: Memantine was largely well-tolerated and associated with improvement in ADHD symptoms and neuropsychological performance. Randomized studies are indicated to confirm whether memantine is a novel therapy for ADHD across the lifespan. PMID- 22436084 TI - Chitosan based mucoadhesive nanoparticles of ketoconazole for bioavailability enhancement: formulation, optimization, in vitro and ex vivo evaluation. AB - PURPOSE: The conventional dosage form of Ketoconazole (KZ) shows poor absorption due to rapid gastric emptying. Chitosan based mucoadhesive nanoparticles (NPs) of KZ were developed to efficiently release drug at its absorption window i.e. stomach and the site of action i.e. esophagus. METHOD: The NPs were prepared by ionic gelation method. Concentration of polymer, cross-linking agent and ratio of drug/polymer as well as polymer/cross linking agent were optimized. RESULTS: NPs had 69.16 +/- 5.91% mucin binding efficiency, particle size of 382.6 +/- 2.384 nm, zeta potential of +48.1 mv and entrapment efficiency of 59.84 +/- 1.088%. DSC thermogram indicated absence of any drug polymer interaction. The drug release was by controlled, non-fickian diffusion mechanism. Ex vivo diffusion studies were performed by emptying the stomach contents after 2 h to simulate in vivo gastric emptying. The results showed that drug diffusion from the solution across stomach mucosa stopped after emptying whereas that from the NPs continued upto 5 h. Hence we could conclude that the NPs must have adhered to the stomach mucosa and thereby would have been retained at this absorption site even after gastric emptying. CONCLUSION: The orally delivered KZ loaded mucoadhesive NPs can be used as an efficient carrier for delivering drug at its absorption window i.e. the stomach and the site of action i.e. esophagus even after gastric emptying. PMID- 22436085 TI - Climate effects of emission standards: the case for gasoline and diesel cars. AB - Passenger transport affects climate through various mechanisms involving both long-lived and short-lived climate forcers. Because diesel cars generally emit less CO(2) than gasoline cars, CO(2) emission taxes for vehicle registrations and fuels enhance the consumer preference for diesel cars over gasoline cars. However, with the non-CO(2) components, which have been changed and will be changed under the previous and upcoming vehicle emission standards, what does the shift from gasoline to diesel cars mean for the climate mitigation? By using a simple climate model, we demonstrate that, under the earlier emissions standards (EURO 3 and 4), a diesel car causes a larger warming up to a decade after the emissions than a similar gasoline car due to the higher emissions of black carbon and NO(X) (enhancing the O(3) production). Beyond a decade, the warming caused by a diesel car becomes, however, weaker because of the lower CO(2) emissions. As the latter emissions standards (EURO 5 and 6) are phased in, the short-term warming due to a diesel car becomes smaller primarily due to the lower black carbon emissions. Thus, although results are subject to restrictive assumptions and uncertainties, the switch from gasoline to diesel cars encouraged by CO(2) taxes does not contradict with the climate mitigation focusing on long-term consequences. PMID- 22436086 TI - What precipitates depression in African-American cancer patients? Triggers and stressors. AB - OBJECTIVE: This study examined general and cancer-related stressors of depression that are unique to African-American cancer patients. METHOD: The study used cohort design and mixed methods. Seventy-four breast and prostate cancer survivors including 34 depressed and 23 non-depressed African-Americans and 17 depressed whites were interviewed. Qualitative data analysis identified themes. The thematic codes were converted to a SPSS data set numerically. The Fisher's exact test was performed to examine group differences in the experience of stress. RESULTS: Significantly more depressed African-Americans experienced a dramatic reaction to a cancer diagnosis (p = 0.03) or had concerns about functional decline (p = 0.01), arguments with relatives or friends (p = 0.02), and unemployment status (p = 0.03) than did non-depressed African-Americans, who reacted to the cancer diagnosis as a matter of reality (p = 0.02). Significantly more depressed African-Americans talked about feeling shocked by a cancer diagnosis (p = 0.04) and being unable to do things that they used to do (p = 0.02) than did depressed whites. Qualitative analysis shed light on the extent of such group differences. SIGNIFICANCE OF RESULTS: Distress from the initial cancer diagnosis and functional decline were likely to have triggered or worsened depression in African-American cancer patients. This study highlighted racial differences in this aspect. It is critical to screen African-American cancer patients for depression at two critical junctures: immediately after the disclosure of a cancer diagnosis and at the onset of functional decline. This will enhance the chance of prompt diagnosis and treatment of depression in this underserved population. PMID- 22436087 TI - Time trends in social differences in nutrition habits of a Lithuanian population: 1994-2010. AB - BACKGROUND: During the post-communist transition period, political, economic, and social changes affected the lifestyles of the Lithuanian population, including their nutritional habits. However, people of lower socio-economic position were more vulnerable to these changes. The aim of the present study was to evaluate the trends in selected food habits of the Lithuanian adult population by their level of education and place of residence from 1994 to 2010. METHODS: The data were obtained from nine biannual cross-sectional postal surveys of Lithuanian health behaviours, beginning in 1994. Each survey used a randomly selected nationally representative sample of 3000 inhabitants aged 20-64 drawn from the population register. In total, 7358 men and 9796 women participated in these surveys. Questions about food consumption were included within all health behaviour questionnaires. RESULTS: During the transition period, use of vegetable oil in cooking and the frequency of consumption of fresh vegetables increased, use of butter on bread decreased, and the proportion of women drinking high-fat milk declined. Lithuanians with higher education reported more frequent use of vegetable oil in cooking as well as daily consumption of fresh vegetables than those with a lower level of education. Consumption of high-fat milk was inversely associated with educational background. In addition, the proportion of persons spreading butter on bread increased with higher education level. The greatest urban-rural difference was observed in high-fat milk consumption. The increase in the use of vegetable oil in cooking, and the reduction of spreading butter on bread was more evident among less educated and rural inhabitants. Meanwhile, a greater proportion of the rural population, compared to urban, reduced their use of butter on bread. Daily consumption of fresh vegetables increased most among highly educated Lithuanians. CONCLUSIONS: The data from our study indicate beneficial dietary changes among the Lithuanian adult population. In general, those with a higher level of education had healthier food habits than those with low education. The educational gradient in analyzed food habits, except the use of vegetable oil, enlarged. A higher proportion of the rural population, compared to urban, reduced their usage of butter on bread. However, consumption of high fat milk was greatest in the rural population. Our data highlight the need for future food and nutrition policies, as well as health promotion programmes, targeting the whole population, particularly those with lower education and living in rural areas. PMID- 22436088 TI - The application of principal component analysis to quantify technique in sports. AB - Analyzing an athlete's "technique," sport scientists often focus on preselected variables that quantify important aspects of movement. In contrast, coaches and practitioners typically describe movements in terms of basic postures and movement components using subjective and qualitative features. A challenge for sport scientists is finding an appropriate quantitative methodology that incorporates the holistic perspective of human observers. Using alpine ski racing as an example, this study explores principal component analysis (PCA) as a mathematical method to decompose a complex movement pattern into its main movement components. Ski racing movements were recorded by determining the three dimensional coordinates of 26 points on each skier which were subsequently interpreted as a 78-dimensional posture vector at each time point. PCA was then used to determine the mean posture and principal movements (PMk ) carried out by the athletes. The first four PMk contained 95.5 +/- 0.5% of the variance in the posture vectors which quantified changes in body inclination, vertical or fore aft movement of the trunk, and distance between skis. In summary, calculating PMk offered a data-driven, quantitative, and objective method of analyzing human movement that is similar to how human observers such as coaches or ski instructors would describe the movement. PMID- 22436091 TI - Nut consumption and risk of atrial fibrillation in the Physicians' Health Study. AB - BACKGROUND: Atrial Fibrillation is highly prevalent in clinical practice affecting approximately 2.3 million people in USA and 4.5 million people in European Union. The aim of the study was to examine the association between nut consumption and incident atrial fibrillation. METHODS: Prospective cohort of 21,054 male participants of Physicians' Health Study I. Nut consumption was estimated using food frequency questionnaire and incident atrial fibrillation was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risks of atrial fibrillation. RESULTS: The average age was 54.6 +/- 9.5 years (40.7-87.1). During a mean follow up of 20 years (median 24 years), 3,317 cases of atrial fibrillation occurred. The crude incidence rate was 7.6, 7.4, 8.2, 7.9, and 6.8 cases/1000 person-years for people reporting nut consumption of rarely/never, 1-3/month, 1/per week, 2-6/week, and >= 7/week, respectively. Multivariable adjusted hazard ratios (95% CI) for incident atrial fibrillation were 1.00 (ref), 1.00 (0.90-1.11), 1.09 (0.97-1.21), 1.07 (0.95 1.21), and 0.91 (0.70-1.17) for nut consumption from the lowest to the highest category of nut consumption (p for trend 0.26). No statistically significant association between nut consumption and atrial fibrillation was found when stratified by body mass index (BMI < 25 vs >= 25 kg/m2) or age (< 65 vs. >= 65 years). CONCLUSIONS: Our data did not show an association between nut consumption and incident atrial fibrillation among US male physicians. PMID- 22436092 TI - Screening for bipolar disorder with the Mood Disorders Questionnaire in patients diagnosed as major depressive disorder - the experience in China. AB - BACKGROUND: Bipolar disorder (BD) is often misdiagnosed as a major depressive disorder (MDD). This study aimed to test the usefulness of the screening tool, the Mood Disorders Questionnaire (MDQ), to identify BD patients misdiagnosed as MDD in Chinese clinical settings. METHODS: A total of 1487 patients treated for MDD were consecutively examined in 13 mental health centers in China. The patients' socio-demographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. The MDQ was completed by patients to identify symptoms characteristic of BD. DSM-IV diagnoses were established using the Mini International Neuropsychiatric Interview (MINI). RESULTS: Three hundred-nine of the 1487 patients (20.8%) satisfied DSM-IV criteria for BD; 118 (7.9%) for BD-I and 191 (12.8%) for BD-II on the MINI. The optimal cut-off point on the MDQ to differentiate BD from MDD was 3, while cut off points of 5 and 3 differentiated BD-I and BD-II from MDD, respectively. The maximum sensitivity was 0.31, 0.45 and 0.22 for differentiating BD, BD-I and BD II from MDD, respectively. CONCLUSIONS: The optimal cutoff points of the MDQ for screening BD in Chinese patients originally diagnosed as MDD were considerably lower than those in earlier studies. The routine clinical use of the MDQ as a screening scale for BD in Chinese patients treated for MDD does not seem to be justified. PMID- 22436093 TI - A new metric for quantifying performance impairment on the psychomotor vigilance test. AB - We have developed a new psychomotor vigilance test (PVT) metric for quantifying the effects of sleep loss on performance impairment. The new metric quantifies performance impairment by estimating the probability density of response times (RTs) in a PVT session, and then considering deviations of the density relative to that of a baseline-session density. Results from a controlled laboratory study involving 12 healthy adults subjected to 85 h of extended wakefulness, followed by 12 h of recovery sleep, revealed that the group performance variability based on the new metric remained relatively uniform throughout wakefulness. In contrast, the variability of PVT lapses, mean RT, median RT and (to a lesser extent) mean speed showed strong time-of-day effects, with the PVT lapse variability changing with time of day depending on the selected threshold. Our analysis suggests that the new metric captures more effectively the homeostatic and circadian process underlying sleep regulation than the other metrics, both directly in terms of larger effect sizes (4-61% larger) and indirectly through improved fits to the two-process model (9-67% larger coefficient of determination). Although the trend of the mean speed results followed those of the new metric, we found that mean speed yields significantly smaller (~50%) intersubject performance variance than the other metrics. Based on these findings, and that the new metric considers performance changes based on the entire set of responses relative to a baseline, we conclude that it provides a number of potential advantages over the traditional PVT metrics. PMID- 22436094 TI - Making sense of evidence in management decisions: the role of research-based knowledge on innovation adoption and implementation in healthcare. study protocol. AB - BACKGROUND: We know that patient care can be improved by implementing evidence based innovations and applying research findings linked to good practice. Successfully implementing innovations in complex organisations, such as the UK's National Health Service (NHS), is often challenging as multiple contextual dynamics mediate the process. Research studies have explored the challenges of introducing innovations into healthcare settings and have contributed to a better understanding of why potentially useful innovations are not always implemented in practice, even if backed by strong evidence. Mediating factors include health policy and health system influences, organisational factors, and individual and professional attitudes, including decision makers' perceptions of innovation evidence. There has been limited research on how different forms of evidence are accessed and utilised by organisational decision makers during innovation adoption. We also know little about how diverse healthcare professionals (clinicians, administrators) make sense of evidence and how this collective sensemaking mediates the uptake of innovations. METHODS: The study will involve nine comparative case study sites of acute care organisations grouped into three regional clusters across England. Each of the purposefully selected sites represents a variety of trust types and organisational contexts. We will use qualitative methods, in-depth interviews, observation of key meetings, and systematic analysis of relevant secondary data to understand the rationale and challenges involved in sourcing and utilising innovation evidence in the empirical setting of infection prevention and control. We will use theories of innovation adoption and sensemaking in organisations to interpret the data. The research will provide lessons for the uptake and continuous use of innovations in the English and international health systems. DISCUSSION: Unlike most innovation studies, which involve single-level analysis, our study will explore the innovation-adoption process at multiple embedded levels: micro (individual), meso (organisational), and macro (interorganisational). By comparing and contrasting across the nine sites, each with different organisational contexts, local networks, leadership styles, and different innovations considered for adoption, the findings of the study will have wide relevance. The research will produce actionable findings responding to the political and economic need for healthcare organisations to be innovation-ready. PMID- 22436095 TI - Factors associated with the use of St. John's wort among adults with depressive symptoms. AB - OBJECTIVE: To examine the association between access to conventional health care and the use of St. John's wort among adults who report depressive symptoms. STUDY DESIGN: Logistic secondary analysis of the Complementary and Alternative Medicine Supplement to the 2002 National Health Interview Survey (NHIS). STUDY POPULATION: Adults who report depressive symptoms and used St. John's wort (n = 246) were compared to nonusers with depressive symptoms (n = 5,111). RESULTS: After controlling for various sociodemographic and socioeconomic factors, depressed adults who could not afford needed medical care due to cost were nearly two times (AOR 1.92, 95% CI 1.38-2.67) more likely to use St. John's wort than those who could afford conventional medical care. Higher income, education, and health status were also positively associated with the use of St. John's wort. CONCLUSION: The growing use of complementary and alternative therapies in the US is widely interpreted as evidence of changing consumer tastes and dissatisfaction with conventional medical treatment for chronic conditions like depression. However, the rising costs of conventional therapies and diminishing access to health insurance may also play a role. PMID- 22436096 TI - Tropical American plants in the treatment of infectious diseases. AB - The increasingly diverse U.S. immigrant populations and the growing use of medicinal herbs create a need for health care professionals to expand their knowledge in this area. This is a review of tropical plants, Annona Muricata, Artemisia absinthium, Cinchona officinalis, Illicium verum, Momordica charantia, Opuntia streptacantha, Schinus terebinthifolius, and Tabebuia avellanedae (impetiginosa), commonly used by Latino and Haitian populations for the treatment of infectious disease. All the eight plants discussed here have one or more of the following: antibacterial, antiviral, antifungal, or antiparasitic properties. All of these plants are primarily known and used in the tropical region, but they are also readily available for purchase in the United States, specifically in the ethnic markets. This review discusses their traditional uses, chemical constituents, proven scientific evidence, and toxicities. PMID- 22436097 TI - Pharmacokinetic study of Noni fruit extract. AB - Many different products containing Noni (Morinda citrifolia) fruit extracts are sold throughout the world for health restoration and maintenance. Despite a large business enterprise fueling Noni's popularity, there is a lack of standardization of products and no scientific evidence of Noni's clinical efficacy and safety. There is also no evidence to indicate an optimal therapeutic dose or dosing interval. In an initial volunteer, scopoletin was identified as a bioactive marker of Noni exposure and a candidate for product standardization and pharmacokinetic studies. Subsequently, capsules containing the whole freeze-dried fruit of Noni were orally administered to nine healthy volunteers (3 per group) at doses of 1,500 mg (3 * 500 mg), 2,000 mg (4 * 500 mg) and 2,500 mg (5 * 500 mg). Plasma and urine samples were obtained from each subject prior to dosing and at 0.5, 1, 2, 4 and 8 h after dosing. Concentrations of scopoletin were determined by HPLC with PDA (scanning at 200-700 nm) and MS detection. Scopoletin rapidly enters the plasma after Noni ingestion, maintaining levels in the range of 0.5 to 5 ng/mL for at least 8 h after dosing. Scopoletin bioavailability appears to be low, with significant intersubject variability. We conclude that scopoletin can be used as a relatively specific marker of Noni exposure in the blood and particularly in urine when its pharmacokinetics is considered appropriately. PMID- 22436098 TI - Use of tryptophan-fortified hydrolyzed collagen for nutritional support. AB - Protein is essential for the maintenance of optimal health. Without adequate amounts of amino acids, organs become dysfunctional and ultimately death can result. Protein deficiency is a common problem in both adults and children. Numerous nutritional supplements have been developed to help optimize protein intake. The purpose of this paper is to describe the use of tryptophan-fortified hydrolyzed collagen for nutritional support in malnourished patients. PMID- 22436099 TI - Effects of turmeric extract on the pharmacokinetics of nifedipine after a single oral administration in healthy volunteers. AB - The effects of turmeric extracts on the pharmacokinetics of nifedipine were examined in 10 healthy volunteers. An open-label and randomized crossover study was performed at 2-week intervals. In the control experiment, after a 10 h overnight fast, 10 mg of nifedipine (Adalat(r) capsule) was administered orally and blood was collected at 0, 0.5, 1, 2, 3, 4, 5, 6, and 8 h. In the combination experiment, the volunteers were orally administered 10 mg of nifedipine together with six tablets containing concentrated turmeric extract (480 mg of curcuminoid per six tablets), which is the general daily dose, and blood was sampled as above. The time profile of the plasma concentration of nifedipine in the control was comparable to that in combination with turmeric extract, as were the pharmacokinetic parameters: that is, the mean ratio of turmeric extract/control group (90% confidence interval: CI); C(max), 0.98 (0.95, 1.01) and AUC(0 - infinity) 1.00 (0.98, 1.02). In addition, the volunteers all completed the study without any serious adverse events. Consumption of the turmeric extract did not affect the pharmacokinetics of nifedipine after a single oral administration. PMID- 22436100 TI - Essential concepts and vocabulary in herbal medicine. AB - Western-trained scientists and physicians can better understand herbal medicine if they learn the basic terminologies and essential concepts used by herbal practitioners around the globe to describe how herbs work on the body. Specific and general chemical actions, pharmacokinetics, and plant constituents (such as carotenoids and flavonoids) can all be used to understand how herbs work. Other important tools for understanding herbal medicine include organoleptic methods (personal sensory based information), such as heating and cooling effects, tastes, and physically felt actions. Tissue affinity is also an important method, one aspect of which is tissue-specific antioxidant effects. In addition, broad concepts from the Oriental traditions--such as the Chinese Yin and Yang, and the Ayurvedic Vata, Pitta, and Kapha--can and have been effectively used to organize and focus understanding and guide treatment. PMID- 22436101 TI - Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator. AB - Impeller speed was varied from 300 to 1500 rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300 rpm in the "bumpy" flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The "roping" flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 um that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700 rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of "roping" flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter. PMID- 22436102 TI - Re: methods of developing UWIN, the modified American Urological Association symptom score: A. B. Barqawi, K. F. Sullivan, E. D. Crawford, C. G. Roehrborn, A. Hughes, M. O'Leary, N. Stone and C. I. O'Donnell, J Urol 2011; 186: 940-944. PMID- 22436103 TI - Re: long-term infection outcomes after original antibiotic impregnated inflatable penile prosthesis implants: up to 7.7 years of followup: C. C. Carson, III, J. J. Mulcahy and M. R. Harsch, J Urol 2011; 185: 614-618. PMID- 22436104 TI - Methane emissions from a small wind shielded lake determined by eddy covariance, flux chambers, anchored funnels, and boundary model calculations: a comparison. AB - Lakes are large sources of methane, held to be responsible for 18% of the radiative forcing, to the atmosphere. Periods of lake overturn (during fall/winter) are short and therefore difficult to capture with field campaigns but potentially one of the most important periods for methane emissions. We studied methane emissions using four different methods, including eddy covariance measurements, floating chambers, anchored funnels, and boundary model calculations. Whereas the first three methods agreed rather well, boundary model estimates were 5-30 times lower leading to a strong underestimation of methane fluxes from aquatic systems. These results show the importance of ebullition as the most important flux pathway and the need for continuous measurements with a large footprint covering also shallow parts of lakes. Although fluxes were high, on average 4 mmol m(-2) d(-1) during the overturn period, water column microbial methane oxidation removed 75% of the methane and only 25% of potential emissions were released to the atmosphere. Hence, this study illustrates second the importance of considering methane oxidation when estimating the flux of methane from lakes during overturn periods. PMID- 22436105 TI - Polycyclic aromatic hydrocarbon (1-OHPG and 2-naphthol) and oxidative stress (malondialdehyde) biomarkers in urine among Korean adults and children. AB - Using the urinary biomarkers 1-hydroxypyrene-glucuronide (1-OHPG), 2-naphthol, and malondialdehyde (MDA), we evaluated seasonal and regional variations in polycyclic aromatic hydrocarbon (PAH) exposure and oxidative stress among Korean adults and children. In total, 322 children (175 male and 147 female) and 332 adults (47 male and 285 female) were recruited in two regions of Korea, one representing a metropolitan area (Seoul/Incheon) and the other an industrial (Pohang) area, from winter 2002 to spring 2003. The subjects voluntarily gathered their first morning urine void, which was immediately transported to our laboratory and stored at -20 degrees C. Urinary 1-OHPG was measured by synchronous fluorescence spectroscopy, 2-naphthol by HPLC, and urinary MDA by HPLC with a UV detector. The median urinary 1-OHPG concentration tended to be higher in the industrial region than in the metropolitan region (0.92 vs. 0.77 ng/mL; p=0.03), and higher in winter than in spring (0.95 vs. 0.73 ng/mL; p<0.001). The median 2-naphthol concentration was also higher in the industrial region than in the metropolitan region (21.0 vs. 12.3 ng/mL; p<0.0001), but was higher in spring than in winter (19.7 vs. 10.3 ng/mL; p<0.0001). The median MDA concentration was significantly higher in winter than in spring (2.19 vs. 1.03 MUmol/L; p<0.0001), whereas regional variation in MDA was observed only in female adults (p=0.02). In winter, the level of 1-OHPG was higher in children exposed to environmental tobacco smoke than in unexposed children (0.94 vs. 0.86 ng/mL; p=0.02). Our results indicate that both region and season can significantly influence the levels of PAH exposure and oxidative stress biomarkers. PMID- 22436106 TI - The mediating role of psychological capital on the association between occupational stress and depressive symptoms among Chinese physicians: a cross sectional study. AB - BACKGROUND: Although occupational stress is an identified predictor of depressive symptoms, the mechanism behind the association is not well understood. The purpose of this study was to examine how psychological capital (PsyCap), a positive psychological state, mediates the association between occupational stress and depressive symptoms among Chinese physicians. METHODS: A cross sectional survey was conducted in Liaoning Province, China, during September October 2010. Self-administered questionnaires including items on depressive symptoms assessed by the Center for Epidemiologic Studies Depression Scale, occupational stress assessed by the effort-reward imbalance scale and PsyCap estimated by a 24-item Psychological Capital Questionnaire, together with age, gender, marital status and education were distributed to 1300 physicians employed in large general hospitals. The final sample consisted of 998 participants. Asymptotic and resampling strategies were used to examine how PsyCap mediates the association between occupational stress and depressive symptoms. RESULTS: Both the effort/reward ratio (ERR) and overcommitment were significantly associated with depressive symptoms among male and female physicians. There was a gender difference in the mediating role of PsyCap on the occupational stress-depressive symptoms association. For male physicians, PsyCap did not mediate the association between occupational stress and depressive symptoms. For female physicians, ERR and overcommitment were negatively associated with PsyCap, and PsyCap was negatively associated with depressive symptoms. As a result, PsyCap significantly mediated the associations of ERR and overcommitment with depressive symptoms. The proportion of PsyCap mediation was 19.07% for ERR, and 24.29% for overcommitment. CONCLUSIONS: PsyCap could be a positive resource for combating depressive symptoms in Chinese physicians. In addition to reducing occupational stress, PsyCap development should be included in depression prevention and treatment strategies, especially for female physicians. PMID- 22436107 TI - Self-reported colorectal cancer screening of Medicare beneficiaries in family medicine vs. internal medicine practices in the United States: a cross-sectional study. AB - BACKGROUND: The benefit of screening for decreasing the risk of death from colorectal cancer (CRC) has been shown, yet many patients in primary care are still not undergoing screening according to guidelines. There are known variations in delivery of preventive health care services among primary care physicians. This study compared self-reported CRC screening rates and patient awareness of the need for CRC screening of patients receiving care from family medicine (FPs) vs. internal medicine (internists) physicians. METHODS: Nationally representative sample of non-institutionalized beneficiaries who received medical care from FPs or internists in 2006 (using Medicare Current Beneficiary Survey). The main outcome was the percentage of patients screened in 2007. We also examined the percentage of patients offered screening. RESULTS: Patients of FPs, compared to those of internists, were less likely to have received an FOBT kit or undergone home FOBT, even after accounting for patients' characteristics. Compared to internists, FPs' patients were more likely to have heard of colonoscopy, but were less likely to receive a screening colonoscopy recommendation (18% vs. 27%), or undergo a colonoscopy (43% vs. 46%, adjusted odds ratios [AOR], 95% confidence interval [CI]-- 0.65, 0.51-0.81) or any CRC screening (52% vs. 60%, AOR, CI--0.80, 0.68-0.94). Among subgroups examined, higher income beneficiaries receiving care from internists had the highest screening rate (68%), while disabled beneficiaries receiving care from FPs had the lowest screening rate (34%). CONCLUSION: Patients cared for by FPs had a lower rate of screening compared to those cared for by internists, despite equal or higher levels of awareness; a difference that remained statistically significant after accounting for socioeconomic status and access to healthcare. Both groups of patients remained below the national goal of 70 percent. PMID- 22436108 TI - Microsurgical treatment of spinal epidermoid and dermoid cysts in the lumbosacral region. AB - The aim of this study was to evaluate the characteristics and surgical outcome of spinal epidermoid and dermoid cysts in the lumbosacral spine. We reviewed 26 patients with spinal epidermoid and dermoid cysts (15 epidermoid and 11 dermoid) treated between October 2000 and December 2010. The latter 15 patients of this series underwent neurophysiological monitoring during surgery. Gross total resection of the tumour was achieved in 46.2% of patients, and 53.8% underwent subtotal resection. In 14 patients, the tumour capsule adhered so tightly to the neural structures that a section of the capsule remained in situ. After surgery, the Japanese Orthopaedic Association score improved in 80.8% of patients, remained stable in 15.4%, and declined in 3.8%. The average follow-up period was 53 months. Three patients developed recurrence of the tumour and 20 patients resumed a normal working life. Microsurgical techniques and intraoperative neurophysiological monitoring are practical and reliable methods for radical removal of spinal epidermoid and dermoid cysts that involve the conus medullaris and cauda equina. PMID- 22436109 TI - Patients' regrets after participating in a randomized controlled trials depended on their involvement in the decision making. AB - OBJECTIVE: To identify the factors associated with long-term regrets expressed a posteriori by randomized controlled trial (RCT) participants questioned about their decision to participate in an RCT. STUDY DESIGN AND SETTING: Participants were questioned 6 years on average after their inclusion in a breast cancer adjuvant therapy RCT. Among 115 women from 21 centers, 93 (81%) answered a self administered questionnaire based on the Decision Regret Scale (DRS). RESULTS: Mean DRS score was 16.8 (standard deviation=15.9); 43.0% of participants expressed mild regret, and 25.8% expressed moderate to strong regret. A quarter of the women (25.6%) said that the decision was taken by the doctor alone, and 13.5% said it was not consistent with their own wishes. In the multivariate ordinal regression analysis, an involuntarily passive role in decision making was found to be associated with greater regret (cumulative proportional odds ratio=7.3, 95% confidence interval=2.0-27.6), regardless of age and being allotted or not to the standard treatment in the RCT. CONCLUSION: Whether patients' regret depended on their level of participation in the decision making or vice versa could not be determined in this cross-sectional survey, but efforts should be made to ensure that patients' participation in trials is always based on an active personal decision. PMID- 22436110 TI - Merging organocatalysis with transition metal catalysis: highly stereoselective alpha-alkylation of aldehydes. AB - The unprecedented cooperative systems involving a diarylprolinol silyl ether with various Lewis acids have been found to effect the highly enantioselective intermolecular alpha-alkylation of aldehydes. A wide variety of aldehydes and alcohols can be transformed into the desired highly functionalized aldehydes in high yields, excellent enantioselectivities, and good diastereoselectivities at room temperature under mild conditions. PMID- 22436111 TI - Sexual violence by occupational forces during and after World War II: influence of experiencing and witnessing of sexual violence on current mental health in a sample of elderly Austrians. AB - BACKGROUND: Wartime rape is an atrocity with long-lasting impacts not only on victims but whole societies. In this brief report, we present data on experience and witness of sexual violence during World War II (WWII) and subsequent time of occupation and on indicators of mental health in a sample of elderly Austrians. METHODS: Interviews of 298 elderly Austrians from a larger epidemiological study on WWII traumatization were analyzed for the impact of experience and witness of sexual violence during the wartime committed by occupational forces. Interviews comprised a biographical/historical section and psychological measures (BSI, TLEQ, PCL-C). Participants were recruited in all nine provinces of Austria with respect to former zones of occupation (Western Allied/Soviet). RESULTS: Twelve persons reported direct experience of sexual violence, 33 persons witnessed such atrocities. One third of the victims and 18.2% of the witnesses reported post traumatic stress disorder (PTSD full/subthreshold). Sexual violence occurred more often in the former Soviet zone. Victims and witnesses displayed higher odds of post-traumatic symptoms and symptoms of depression and phobic fear than non victims. Furthermore, witnesses displayed higher levels of aggression compared to victims and non-witnesses. CONCLUSIONS: Our results corroborate previous findings that wartime rape has long-lasting effects over decades on current mental health and post-traumatic distress in victims and witnesses. We recommend integration of psychotraumatological knowledge on consequences of sexual violence on mental health into geriatric care and the education of dedicated personnel. PMID- 22436112 TI - Portable media players, preferred listening levels, earphones, and background noise. PMID- 22436114 TI - Auditory steady-state responses. AB - BACKGROUND: The auditory steady state response (ASSR) is an auditory evoked potential (AEP) that can be used to objectively estimate hearing sensitivity in individuals with normal hearing sensitivity and with various degrees and configurations of sensorineural hearing loss (SNHL). For this reason, many audiologists want to learn more about the stimulus and recording parameters used to successfully acquire this response, as well as information regarding how accurately this response predicts behavioral thresholds across various clinical populations. PURPOSE: The scientific goal is to create a tutorial on the ASSR for doctor of audiology (Au.D.) students and audiologists with limited (1-5 yr) clinical experience with AEPs. This tutorial is needed because the ASSR is unique when compared to other AEPs with regard to the type of terminology used to describe this response, the types of stimuli used to record this response, how these stimuli are delivered, the methods of objectively analyzing the response, and techniques used to calibrate the stimuli. A second goal is to provide audiologists with an understanding of the accuracy with which the ASSR is able to estimate pure tone thresholds in a variety of adult and pediatric clinical populations. DESIGN: This tutorial has been organized into various sections including the history of the ASSR, unique terminology associated with this response, the types of stimuli used to elicit the response, two common stimulation methods, methods of objectively analyzing the response, technical parameters for recording the ASSR, and the accuracy of ASSR threshold prediction in the adult and pediatric populations. In each section of the manuscript, key terminology/concepts associated with the ASSR are bolded in the text and are also briefly defined in a glossary found in the appendix. The tutorial contains numerous figures that are designed to walk the reader through the key concepts associated with this response. In addition, several summary tables have been included that discuss various topics such as the effects of single versus multifrequency stimulation techniques on the accuracy of estimating behavioral thresholds via the ASSR; differences, if any, in monaural versus binaural ASSR thresholds; the influence of degree and configuration of SNHL on ASSR thresholds; test-retest reliability of the ASSR; the influence of neuro-maturation on ASSR thresholds; and the influence of various technical factors (i.e., oscillator placement, coupling force, and the number of recording channels) that affect bone conducted ASSRs. CONCLUSION: Most researchers agree that, in the future, ASSR testing will play an important role in clinical audiology. Therefore, it is important for clinical audiologists and Au.D. students to have a good basic understanding of the technical concepts associated with the ASSR, a knowledge of optimal stimulus and recording parameters used to accurately record this response, and an appreciation of the current role and/or limitations of using the ASSR to estimate behavioral thresholds in infants with various degrees and configurations of hearing loss. PMID- 22436115 TI - Are two ears not better than one? AB - BACKGROUND: The decision to fit one or two hearing aids in individuals with binaural hearing loss has been debated for years. Although some 78% of U.S. hearing aid fittings are binaural (Kochkin , 2010), Walden and Walden (2005) presented data showing that 82% (23 of 28 patients) of their sample obtained significantly better speech recognition in noise scores when wearing one hearing aid as opposed to two. PURPOSE: To conduct two new experiments to fuel the monaural/binaural debate. The first experiment was a replication of Walden and Walden (2005), whereas the second experiment examined the use of binaural cues to improve speech recognition in noise. RESEARCH DESIGN: A repeated measures experimental design. STUDY SAMPLE: Twenty veterans (aged 59-85 yr), with mild to moderately severe binaurally symmetrical hearing loss who wore binaural hearing aids were recruited from the Audiology Department at the Bay Pines VA Healthcare System. DATA COLLECTION AND ANALYSIS: Experiment 1 followed the procedures of the Walden and Walden study, where signal-to-noise ratio (SNR) loss was measured using the Quick Speech-in-Noise (QuickSIN) test on participants who were aided with their current hearing aids. Signal and noise were presented in the sound booth at 0 degrees azimuth under five test conditions: (1) right ear aided, (2) left ear aided, (3) both ears aided, (4) right ear aided, left ear plugged, and (5) unaided. The opposite ear in (1) and (2) was left open. In Experiment 2, binaural Knowles Electronics Manikin for Acoustic Research (KEMAR) manikin recordings made in Lou Malnati's pizza restaurant during a busy period provided a typical real-world noise, while prerecorded target sentences were presented through a small loudspeaker located in front of the KEMAR manikin. Subjects listened to the resulting binaural recordings through insert earphones under the following four conditions: (1) binaural, (2) diotic, (3) monaural left, and (4) monaural right. RESULTS: Results of repeated measures ANOVAs demonstrated that the best speech recognition in noise performance was obtained by most participants with both ears aided in Experiment 1 and in the binaural condition in Experiment 2. CONCLUSIONS: In both experiments, only 20% of our subjects did better in noise with a single ear, roughly similar to the earlier Jerger et al (1993) finding that 8-10% of elderly hearing aid users preferred one hearing aid. PMID- 22436116 TI - Comparison of user volume control settings for portable music players with three earphone configurations in quiet and noisy environments. AB - BACKGROUND: Listening to music is one of the most common forms of recreational noise exposure. Previous investigators have demonstrated that maximum output levels from headphones can exceed safe levels. Although preferred listening levels (PLL) in quiet environments may be at acceptable levels, the addition of background noise will add to the overall noise exposure of a listener. Use of listening devices that block out some of the background noise would potentially allow listeners to select lower PLLs for their music. Although one solution is in the-ear earphones, an alternative solution is the use of earmuffs in conjunction with earbuds. PURPOSE: There were two objectives to this experiment. The first was to determine if an alternative to in-the-ear earphones for noise attenuation (the addition of earmuffs to earbuds) would allow for lower PLLs through a portable media player (PMP) than earbuds. The second was to determine if a surrounding background noise would yield different PLLs than a directional noise source. RESEARCH DESIGN: This was an experimental study. STUDY SAMPLE: Twenty four adults with normal hearing. DATA COLLECTION AND ANALYSIS: PLLs were measured for three earphone configurations in three listening conditions. The earphone configurations included earbuds, canal earphones, and earbuds in combination with hearing protection devices (HPDs). The listening conditions included quiet, noise from one loudspeaker, and noise from four surrounding loudspeakers. Participants listened in each noise and earphone combination for as long as they needed to determine their PLL for that condition. Once the participant determined their PLL, investigators made a 5 sec recording of the music through a probe tube microphone. The average PLLs in each noise and earphone combination were used as the dependent variable. Ear canal level PLLs were converted to free-field equivalents to compare to noise exposure standards and previously published data. RESULTS: The average PLL as measured in the ear canal was 74 dBA in the quiet conditions and 84 dBA in the noise conditions. Paired comparisons of the PLL in the presence of background noise for each pair of earphone configurations indicated significant differences for each comparison. An inverse relationship was observed between attenuation and PLL whereby the greater the attenuation, the lower the PLL. A comparison of the single noise source condition versus the surrounding noise condition did not result in a significant effect. CONCLUSION: The present work suggests that earphones that take advantage of noise attenuation can reduce the level at which listeners set music in the presence of background noise. An alternative to in-the-ear earphones for noise attenuation is the addition of earmuffs to earbuds. PMID- 22436117 TI - Dichotic listening performance in young adults using low-pass filtered speech. AB - BACKGROUND: Assessment of interaural asymmetry (IA) on dichotic listening tests becomes challenging when accuracy on one or both ears are at ceiling. Cognitive task demands are often increased to avoid this situation, raising the possibility that non-auditory-specific processes will further influence IA estimation. PURPOSE: To investigate the utility of low-pass filtered dichotic speech stimuli (dichotic filtered words [DFWs]) as a potential auditory-specific technique for increasing task difficulty in the dichotic listening paradigm. RESEARCH DESIGN: A prospective experimental study investigating differences in IA observed for a group of young adults on three dichotic listening tasks differentiated on the basis of stimulus type (unfiltered words, DFWs) and/or mode of test administration (divided attention [DIV]; directed attention [DIR]). STUDY SAMPLE: Thirty-two adults between 18 and 34 yr of age participated in the study. DATA COLLECTION AND ANALYSIS: Accuracy scores on each ear and normalized values of IA (via laterality index) served as dependent measures evaluated in a repeated measures ANOVA design. Correlation and regression analyses were carried out to investigate potential relationships between participants' behavioral accuracy to experimental stimuli and the magnitude of observed IA. Behavioral profiles of IA were constructed for each participant. RESULTS: Using a traditional DIV test mode, DFW stimuli produced a significantly larger right-ear advantage (REA) as compared to unfiltered speech. The magnitude of the average REA to DFW stimuli was not statistically different between DIV and DIR test modes for the group. Inspection of individual performances, however, revealed that out of the participants who demonstrated meaningful IA during DIV, approximately half produced the same or greater amount of IA during DIR whereas half showed a relative decrease. Participants' accuracy to left-sided stimuli was most related to the magnitude of observed IA across tasks. CONCLUSIONS: The utility of low pass filtered speech may be helpful in the evaluation of IA obtained during dichotic testing. PMID- 22436118 TI - Self-monitoring of listening abilities in normal-hearing children, normal-hearing adults, and children with cochlear implants. AB - BACKGROUND: Self-monitoring has been shown to be an essential skill for various aspects of our lives, including our health, education, and interpersonal relationships. Likewise, the ability to monitor one's speech reception in noisy environments may be a fundamental skill for communication, particularly for those who are often confronted with challenging listening environments, such as students and children with hearing loss. PURPOSE: The purpose of this project was to determine if normal-hearing children, normal-hearing adults, and children with cochlear implants can monitor their listening ability in noise and recognize when they are not able to perceive spoken messages. RESEARCH DESIGN: Participants were administered an Objective-Subjective listening task in which their subjective judgments of their ability to understand sentences from the Coordinate Response Measure corpus presented in speech spectrum noise were compared to their objective performance on the same task. STUDY SAMPLE: Participants included 41 normal-hearing children, 35 normal-hearing adults, and 10 children with cochlear implants. DATA COLLECTION AND ANALYSIS: On the Objective-Subjective listening task, the level of the masker noise remained constant at 63 dB SPL, while the level of the target sentences varied over a 12 dB range in a block of trials. Psychometric functions, relating proportion correct (Objective condition) and proportion perceived as intelligible (Subjective condition) to target/masker ratio (T/M), were estimated for each participant. Thresholds were defined as the T/M required to produce 51% correct (Objective condition) and 51% perceived as intelligible (Subjective condition). Discrepancy scores between listeners' threshold estimates in the Objective and Subjective conditions served as an index of self-monitoring ability. In addition, the normal-hearing children were administered tests of cognitive skills and academic achievement, and results from these measures were compared to findings on the Objective-Subjective listening task. RESULTS: Nearly half of the children with normal hearing significantly overestimated their listening in noise ability on the Objective-Subjective listening task, compared to less than 9% of the adults. There was a significant correlation between age and results on the Objective-Subjective task, indicating that the younger children in the sample (age 7-12 yr) tended to overestimate their listening ability more than the adolescents and adults. Among the children with cochlear implants, eight of the 10 participants significantly overestimated their listening ability (as compared to 13 of the 24 normal-hearing children in the same age range). We did not find a significant relationship between results on the Objective-Subjective listening task and performance on the given measures of academic achievement or intelligence. CONCLUSIONS: Findings from this study suggest that many children with normal hearing and children with cochlear implants often fail to recognize when they encounter conditions in which their listening ability is compromised. These results may have practical implications for classroom learning, particularly for children with hearing loss in mainstream settings. PMID- 22436119 TI - Psychosocial status of children with auditory processing disorder. AB - BACKGROUND: Children with hearing loss often exhibit reduced psychosocial status compared to children with normal hearing. It is reasonable to assume that psychosocial function may also be affected in children diagnosed with auditory processing disorder (APD). However, there are no published studies specifically addressing the psychosocial health of children with APD. PURPOSE: This investigation examined relationships between APD and psychosocial status, with an aim to examine nonauditory factors that may influence quality of life of children diagnosed with APD. RESEARCH DESIGN: A two-matched group design was employed. Participants and their mothers completed appropriate versions of the Dartmouth Primary Care Cooperative Information Project Charts for Adolescents (COOP-A), the Behavioral Assessment System for Children, Second Edition (BASC-2), and the Social Skills Rating System (SSRS). STUDY SAMPLE: Participants consisted of 19 children (aged 9.5-17.8 yr; mean = 11.9) diagnosed with APD and 20 gender- and age-matched (mean = 12.8 yr) children with no evidence of APD by history or audiological assessment. Primary caretakers (mothers) of the participants also completed psychosocial questionnaires according to their perception of their participating child's function. DATA COLLECTION AND ANALYSIS: Data were collected at a single visit, following APD diagnosis. Data from each questionnaire were analyzed using appropriate statistical methods for two-group comparisons. RESULTS: Analysis of child reports revealed significantly greater psychosocial difficulty in the APD group on subscales of the COOP-A and BASC-2. Increased problems in the APD group were also reported by parents on subscales of the COOP A, BASC-2, and SSRS. Eta-squared values for all significant findings indicated moderate to large effect sizes, suggesting findings may be generalized to other children in this age group. No between-group differences were found on any subscale for APD children with or without a confirmed or suspected language disorder. CONCLUSION: We found that children with APD exhibit increased psychosocial difficulty in several areas compared to children without APD. PMID- 22436120 TI - Tissue engineering and regenerative medicine -where do we stand? AB - Tissue Engineering (TE) in the context of Regenerative Medicine (RM) has been hailed for many years as one of the most important topics in medicine in the twenty-first century. While the first clinically relevant TE efforts were mainly concerned with the generation of bioengineered skin substitutes, subsequently TE applications have been continuously extended to a wide variety of tissues and organs. The advent of either embryonic or mesenchymal adult stem-cell technology has fostered many of the efforts to combine this promising tool with TE approaches and has merged the field into the term Regenerative Medicine. As a typical example in translational medicine, the discovery of a new type of cells called Telocytes that have been described in many organs and have been detected by electron microscopy opens another gate to RM. Besides cell-therapy strategies, the application of gene therapy combined with TE has been investigated to generate tissues and organs. The vascularization of constructs plays a crucial role besides the matrix and cell substitutes. Therefore, novel in vivo models of vascularization have evolved allowing axial vascularization with subsequent transplantation of constructs. This article is intended to give an overview over some of the most recent developments and possible applications in RM through the perspective of TE achievements and cellular research. The synthesis of TE with innovative methods of molecular biology and stem-cell technology appears to be very promising. PMID- 22436121 TI - Fidelity and moderating factors in complex interventions: a case study of a continuum of care program for frail elderly people in health and social care. AB - BACKGROUND: Prior studies measuring fidelity of complex interventions have mainly evaluated adherence, and not taken factors affecting adherence into consideration. A need for studies that clarify the concept of fidelity and the function of factors moderating fidelity has been emphasized. The aim of the study was to systematically evaluate implementation fidelity and possible factors influencing fidelity of a complex care continuum intervention for frail elderly people. METHODS: The intervention was a systematization of the collaboration between a nurse with geriatric expertise situated at the emergency department, the hospital ward staff, and a multi-professional team with a case manager in the municipal care services for older people. Implementation was evaluated between September 2008 and May 2010 with observations of work practices, stakeholder interviews, and document analysis according to a modified version of The Conceptual Framework for Implementation Fidelity. RESULTS: A total of 16 of the 18 intervention components were to a great extent delivered as planned, while some new components were added to the model. No changes in the frequency or duration of the 18 components were observed, but the dose of the added components varied over time. Changes in fidelity were caused in a complex, interrelated fashion by all the moderating factors in the framework, i.e., context, staff and participant responsiveness, facilitation, recruitment, and complexity. DISCUSSION: The Conceptual Framework for Implementation Fidelity was empirically useful and included comprehensive measures of factors affecting fidelity. Future studies should focus on developing the framework with regard to how to investigate relationships between the moderating factors and fidelity over time. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01260493. PMID- 22436122 TI - Identification of single nucleotide polymorphisms within the mtDNA genome of the domestic dog to discriminate individuals with common HVI haplotypes. AB - We sequenced the entire ~16 kb canine mitochondrial genome (mtGenome) of 100 unrelated domestic dogs (Canis lupus familiaris) and compared these to 246 published sequences to assess hypervariable region I (HVI) haplotype frequencies. We then used all available sequences to identify informative single nucleotide polymorphisms (SNPs) outside of the control region for use in further resolving mtDNA haplotypes corresponding to common HVI haplotypes. Haplotype frequencies in our data set were highly correlated with previous ones (e.g., F(ST)=0.02, r=0.90), suggesting the total data set reasonably reflected the broader dog population. A total of 128 HVI haplotypes was represented. The 10 most common HVI haplotypes (n=184 dogs) represented 53.3% of the sample. We identified a total 71 SNPs in the mtGenomes (external to the control region) that resolved the 10 most common HVI haplotypes into 63 mtGenome subhaplotypes. The random match probability of the dataset based solely on the HVI sequence was 4%, whereas the random match probability of the mtGenome subhaplotypes was <1%. Thus, the panel of 71 SNPs identified in this study represents a useful forensic tool to further resolve the identity of individual dogs from mitochondrial DNA (mtDNA). PMID- 22436123 TI - Mitochondrial DNA control region data from indigenous Angolan Khoe-San lineages. AB - Here we provide 129 complete mitochondrial control region sequences of indigenous Khoe-San individuals from Angola to contribute to the still underrepresented pool of data from Africa. The dataset consists of exclusively African lineages with a majority of Sub-Saharan haplogroups. The probability of a random match was calculated as 0.09. The data set comprises 21 haplotypes occurring more than once and 17 unique haplotypes. Upon publication, haplotypes were incorporated in the EMPOP database (www.empop.org; EMP00069) [1]. PMID- 22436124 TI - Genetic analysis of the 11 X-STR loci in Uigur population from China. PMID- 22436125 TI - Healthcare access and mammography screening in Michigan: a multilevel cross sectional study. AB - BACKGROUND: Breast cancer screening rates have increased over time in the United States. However actual screening rates appear to be lower among black women compared with white women. PURPOSE: To assess determinants of breast cancer screening among women in Michigan USA, focusing on individual and neighborhood socio-economic status and healthcare access. METHODS: Data from 1163 women ages 50-74 years who participated in the 2008 Michigan Special Cancer Behavioral Risk Factor Survey were analyzed. County-level SES and healthcare access were obtained from the Area Resource File. Multilevel logistic regression models were fit using SAS Proc Glimmix to account for clustering of individual observations by county. Separate models were fit for each of the two outcomes of interest; mammography screening and clinical breast examination. For each outcome, two sequential models were fit; a model including individual level covariates and a model including county level covariates. RESULTS: After adjusting for misclassification bias, overall cancer screening rates were lower than reported by survey respondents; black women had lower mammography screening rates but higher clinical breast examination rates than white women. However, after adjusting for other individual level variables, race was not a significant predictor of screening. Having health insurance or a usual healthcare provider were the most important predictors of cancer screening. DISCUSSION: Access to healthcare is important to ensuring appropriate cancer screening among women in Michigan. PMID- 22436126 TI - Does the cancer patient's disease stage matter? A comparative study of caregivers' mental health and health related quality of life. AB - OBJECTIVE: Cancer affects both patients and their caregivers. Caregiver burden may change during different stages of the patients' cancer trajectory. Limited research has focused on the impact of being a caregiver, assessed by the caregiver's mental health and quality of life (QOL) during the curative and the palliative phases of the patient's disease. The aim of this study is to compare caregivers of cancer patients during the curative and a palliative phases with respect to their mental health and health-related QOL. METHOD: This descriptive, cross-sectional study combines data from two studies. The first group consists of caregivers of patients with cancer in the late palliative phase and the second group consists of caregivers of outpatients with cancer who suffer from pain and/or use analgesics. Data were collected by means of standardized measures and analyzed with descriptive statistics. RESULTS: Based on this material, no significant differences in mental health and health- related QOL were revealed for caregivers of cancer patients in the palliative and the curative phases, respectively. Neither education level in the caregivers, nor the patients' functional status influenced caregivers' mental health or QOL. Younger caregivers seem to have better physical QOL. SIGNIFICANCE OF RESULTS: Being caregivers of cancer patients seems to have a similar pattern of impact on caregivers' mental health and quality of life regardless of the patient's disease stage. We share some reflections about the way in which the cancer stage is divided and the appropriateness of such selection for measuring caregivers' mental health and QOL. Additionally, we discuss the use of generic instruments for measuring specific contexts and particular samples. PMID- 22436127 TI - Arterial anomalies in arterial tortuosity syndrome: a sour-sweet pathology? PMID- 22436128 TI - Inorganic arsenic and basal cell carcinoma in areas of Hungary, Romania, and Slovakia: a case-control study. AB - BACKGROUND: Inorganic arsenic (iAs) is a potent carcinogen, but there is a lack of information about cancer risk for concentrations < 100 MUg/L in drinking water. OBJECTIVES: We aimed to quantify skin cancer relative risks in relation to iAs exposure < 100 MUg/L and the modifying effects of iAs metabolism. METHODS: The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) study, a case-control study, was conducted in areas of Hungary, Romania, and Slovakia with reported presence of iAs in groundwater. Consecutively diagnosed cases of basal cell carcinoma (BCC) of the skin were histologically confirmed; controls were general surgery, orthopedic, and trauma patients who were frequency matched to cases by age, sex, and area of residence. Exposure indices were constructed based on information on iAs intake over the lifetime of participants. iAs metabolism status was classified based on urinary concentrations of methylarsonic acid (MA) and dimethylarsinic acid (DMA). Associations were estimated by multivariable logistic regression. RESULTS: A total of 529 cases with BCC and 540 controls were recruited for the study. BCC was positively associated with three indices of iAs exposure: peak daily iAs dose rate, cumulative iAs dose, and lifetime average water iAs concentration. The adjusted odds ratio per 10-MUg/L increase in average lifetime water iAs concentration was 1.18 (95% confidence interval: 1.08, 1.28). The estimated effect of iAs on cancer was stronger in participants with urinary markers indicating incomplete metabolism of iAs: higher percentage of MA in urine or a lower percentage of DMA. CONCLUSION: We found a positive association between BCC and exposure to iAs through drinking water with concentrations < 100 MUg/L. PMID- 22436129 TI - The efficacy and safety of febuxostat for urate lowering in gout patients >=65 years of age. AB - BACKGROUND: The incidence of gout rises with increasing age. Management of elderly (>=65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial. METHODS: Hyperuricemic (serum urate [sUA] levels >= 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration.Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs). RESULTS: Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments. CONCLUSIONS: These data suggest that either dose of febuxostat is superior to commonly prescribed fixed doses of allopurinol (200/300 mg) in subjects >=65 years of age with high rates of renal dysfunction. In addition, in this high-risk population, ULT with either drug was well tolerated. TRIAL REGISTRATION: clinicaltrials.gov NCT#00430248. PMID- 22436130 TI - Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. AB - BACKGROUND: Diarrhea is recognized as a leading cause of morbidity and mortality among children under 5 years of age in low- and middle-income countries yet updated estimates of diarrhea incidence by age for these countries are greatly needed. We conducted a systematic literature review to identify cohort studies that sought to quantify diarrhea incidence among any age group of children 0-59 mo of age. METHODS: We used the Expectation-Maximization algorithm as a part of a two-stage regression model to handle diverse age data and overall incidence rate variation by study to generate country specific incidence rates for low- and middle-income countries for 1990 and 2010. We then calculated regional incidence rates and uncertainty ranges using the bootstrap method, and estimated the total number of episodes for children 0-59 mo of age in 1990 and 2010. RESULTS: We estimate that incidence has declined from 3.4 episodes/child year in 1990 to 2.9 episodes/child year in 2010. As was the case previously, incidence rates are highest among infants 6-11 mo of age; 4.5 episodes/child year in 2010. Among these 139 countries there were nearly 1.9 billion episodes of childhood diarrhea in 1990 and nearly 1.7 billion episodes in 2010. CONCLUSIONS: Although our results indicate that diarrhea incidence rates may be declining slightly, the total burden on the health of each child due to multiple episodes per year is tremendous and additional funds are needed to improve both prevention and treatment practices in low- and middle-income countries. PMID- 22436131 TI - Psychological well-being in relation to frailty: a frailty identity crisis? AB - BACKGROUND: Frailty can be defined as the presence of multiple, interacting medical and functional problems. Frailty is associated with psychiatric conditions but its relation to psychological well-being is unclear. A "frailty identity crisis" has been proposed as a maladaptive response to the sense of self as health deficits accumulate. We evaluated this so-called identity crisis by investigating associations between well-being, frailty, and mortality in community-dwelling older Canadians. METHODS: In this secondary analysis of the Canadian Study of Health and Aging (N = 5,703; age 70+), frailty was defined by an index of 33 health deficits. Psychological well-being was measured using Ryff's 18-item scale, with six domains (autonomy, personal growth, environmental mastery, positive relations, purpose in life, and self-acceptance). Cognition was measured using the Modified Mini-Mental State Examination. Associations between well-being, frailty, and mortality were measured using linear regression, adjusting for age, sex, education, cognition, and mental health. RESULTS: For each additional frailty-defining deficit, the psychological well-being score worsened by 0.3 points (0.29, 95% CI: 0.22-0.36, p < 0.001), independent of age, sex, education, cognition, and mental health. Among the six domains of well being, only "purpose in life" and "autonomy" were not associated with frailty (all others, p < 0.001). Worse psychological well-being was associated with five year mortality independent of age, sex, education, frailty, and mental health; this association was not statistically significant when adjusting for baseline cognition. CONCLUSIONS: Frailty was associated with low levels of well-being. Psychological well-being impaired by a frailty identity crisis may play an important role in defining subjective health in older adults. PMID- 22436132 TI - Assembly of spirooxindole derivatives containing four consecutive stereocenters via organocatalytic Michael-Henry cascade reactions. AB - A novel organocatalytic strategy for the synthesis of highly substituted spirocyclopentaneoxindoles was developed employing simple nitrostyrenes and 3 substituted oxindoles as starting materials. Michael-Henry cascade reactions, enabled through cinchona alkaloid organocatalysis, provided products in high yield and excellent enantioselectivity in a single step. PMID- 22436133 TI - Mechanical spectroscopy of nanocrystalline aluminum films: effects of frequency and grain size on internal friction. AB - Energy dissipation by internal friction is a property of fundamental interest for probing the effects of scale on mechanical behavior in nanocrystalline metallic films and for guiding the use of these materials in the design of high-Q micro/nanomechanical resonators. This paper describes an experimental study to measure the effects of frequency, annealing and grain size on internal friction at room temperature in sputter-deposited nanocrystalline aluminum films with thicknesses ranging from 60 to 120 nm. Internal friction was measured using a single-crystal silicon microcantilever platform that calibrates dissipation against the fundamental limits of thermoelastic damping. Internal friction was a weak function of frequency, reducing only by a factor of two over three decades of frequency (70 Hz to 44 kHz). Annealing led to significant grain growth and the average grain size of 100 nm thick films increased from 90 to 390 nm after annealing for 1 h at 450 (?)C. This increase in grain size was accompanied by a decrease in internal friction from 0.05 to 0.02. Taken together, these results suggest that grain-boundary sliding, characterized by a spectrum of relaxation times, contributes to internal friction in these films. PMID- 22436134 TI - Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells. AB - BACKGROUND: HuR, an RNA binding protein involved in the post-transcriptional regulation of a wide spectrum of mRNAs, has been demonstrated to be a determinant of carcinogenesis and tumor aggressiveness in several cancer types. In this study, we investigated the role of HuR in the apoptosis and in the chemoresistance induced by the widely used anticancer drug doxorubicin in human breast cancer cells (MCF-7). RESULTS: We showed that HuR acts in the early phase of cell response to doxorubicin, being induced to translocate into the cytoplasm upon phosphorylation. Reducing HuR levels diminished the apoptotic response to doxorubicin. Doxorubicin-induced apoptosis was also correlated with the presence of HuR in the cytoplasm. Rottlerin, which was able to block HuR nuclear export, had correspondingly antagonistic effects with doxorubicin on cell toxicity. The proapoptotic activity of HuR was not due to cleavage to an active form, as was previously reported. In in vitro selected doxorubicin resistant MCF-7 cells (MCF 7/doxoR) overexpressing the multidrug resistance (MDR) related ABCG2 transporter, we observed a significant HuR downregulation that was paralleled by a corresponding downregulation of HuR targets and by loss of rottlerin toxicity. Restoration of HuR expression in these cells resensitized MCF-7/doxoR cells to doxorubicin, reactivating the apoptotic response. CONCLUSIONS: The present study shows that HuR is necessary to elicit the apoptotic cell response to doxorubicin and that restoration of HuR expression in resistant cells resensitizes them to the action of this drug, thereby identifying HuR as a key protein in doxorubicin pharmacology. PMID- 22436135 TI - Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): early treatment results and study concepts. AB - BACKGROUND: Particle irradiation was established at the University of Heidelberg 2 years ago. To date, more than 400 patients have been treated including patients with primary brain tumors. In malignant glioma (WHO IV) patients, two clinical trials have been set up-one investigating the benefit of a carbon ion (18 GyE) vs. a proton boost (10 GyE) in addition to photon radiotherapy (50 Gy), the other one investigating reirradiation with escalating total dose schedules starting at 30 GyE. In atypical meningioma patients (WHO degrees II), a carbon ion boost of 18 GyE is applied to macroscopic tumor residues following previous photon irradiation with 50 Gy.This study was set up in order to investigate toxicity and response after proton and carbon ion therapy for gliomas and meningiomas. METHODS: 33 patients with gliomas (n = 26) and meningiomas (n = 7) were treated with carbon ion (n = 26) and proton (n = 7) radiotherapy. In 22 patients, particle irradiation was combined with photon therapy. Temozolomide-based chemotherapy was combined with particle therapy in 17 patients with gliomas. Particle therapy as reirradiation was conducted in 7 patients. Target volume definition was based upon CT, MRI and PET imaging. Response was assessed by MRI examinations, and progression was diagnosed according to the Macdonald criteria. Toxicity was classified according to CTCAE v4.0. RESULTS: Treatment was completed and tolerated well in all patients. Toxicity was moderate and included fatigue (24.2%), intermittent cranial nerve symptoms (6%) and single episodes of seizures (6%). At first and second follow-up examinations, mean maximum tumor diameters had slightly decreased from 29.7 mm to 27.1 mm and 24.9 mm respectively. Nine glioma patients suffered from tumor relapse, among these 5 with infield relapses, causing death in 8 patients. There was no progression in any meningioma patient. CONCLUSIONS: Particle radiotherapy is safe and feasible in patients with primary brain tumors. It is associated with little toxicity. A positive response of both gliomas and meningiomas, which is suggested in these preliminary data, must be evaluated in further clinical trials. PMID- 22436136 TI - Maternal depression and infant growth and development in British Pakistani women: a cohort study. AB - OBJECTIVES: Perinatal depression has been found to be a strong and independent risk factor for poor child growth and development in low-income South Asian populations. The authors aimed to study if there was a similar association in first and second-generation British women of Pakistani origin. DESIGN: A prospective cohort study. SETTING: The study was conducted in the North-West of England, in areas with high density of Pakistani-origin population. The subjects were recruited from Central Manchester Hospital in the City of Manchester and East Lancashire Hospital in Lancashire. PARTICIPANTS: 704 physically healthy women were assessed in two phases (screening and detailed assessment of high scorers and a proportion of low scorers) during the third trimester of pregnancy to obtain at birth a cohort of 63 infants of depressed mothers and 173 infants of psychologically well mothers. PRIMARY AND SECONDARY OUTCOME MEASURES: All infants were weighed and measured at birth and 6 months, and their development was assessed using the Bayley Scales of Infant Development-Third Edition. RESULTS: There was no difference in the birth weight or weight and height at 6 months of infants of depressed mothers versus infants of psychologically well mothers. The only significant difference between the two groups was in the infants' adaptive behaviour; infants of depressed mothers scored significantly lower than those of psychologically well mothers (mean difference 4.6, t=2.81, df 195, p=0.006). The associations remained significant after adjustment for socio-demographic factors by multivariate analyses. CONCLUSIONS: Prenatal depression is not associated with impaired growth in this sample of British Pakistani women. There is, however, an association of prenatal depression with parent-reported problems in the infants' adaptive behaviour. Further research is needed to understand various pathways through which maternal depression affects infant outcomes in low- and high-income settings. PMID- 22436137 TI - Phenotypic and genetic characterisation of bacterial sexually transmitted infections in Bissau, Guinea-Bissau, West Africa: a prospective cohort study. AB - BACKGROUND: Knowledge regarding characteristics and transmission of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium and antibiotic resistance in N gonorrhoeae in Guinea-Bissau, West Africa, is entirely lacking. OBJECTIVES: To characterise N gonorrhoeae, C trachomatis and M genitalium samples from Guinea-Bissau and to define bacterial populations, possible transmission chains and for N gonorrhoeae spread of antibiotic-resistant isolates. DESIGN: Prospective cohort study. SETTING: Two sexual health and family planning clinics, Bissau, Guinea-Bissau. PARTICIPANTS: Positive samples from 711 women and 27 men. MATERIAL AND METHODS: Positive samples for N gonorrhoeae (n=31), C trachomatis (n=60) and M genitalium (n=30) were examined. The gonococcal isolates were characterised with antibiograms, serovar determination and N gonorrhoeae multiantigen sequence typing (NG-MAST). The C trachomatis ompA gene and the M genitalium mgpB gene were sequenced, and phylogenetic analyses were performed. RESULTS: For N gonorrhoeae, the levels of resistance (intermediate susceptibility) to ciprofloxacin, erythromycin, rifampicin, ampicillin, tetracycline, penicillin G and cefuroxime were 10% (0%), 6% (10%), 13% (10%), 68% (0%), 74% (0%), 68% (16%) and 0% (84%), respectively. All isolates were susceptible to cefixime, ceftriaxone, spectinomycin and azithromycin, and the minimum inhibitory concentrations of kanamycin (range: 8-32 mg/l) and gentamicin (range: 0.75-6 mg/l) were low (no resistance breakpoints exist for these antimicrobials). 19 NG-MAST sequence types (STs) (84% novel STs) were identified. Phylogenetic analysis of the C trachomatis ompA gene revealed genovar G as most prevalent (37%), followed by genovar D (19%). 23 mgpB STs were found among the M genitalium isolates, and 67% of isolates had unique STs. CONCLUSIONS: The diversity among the sexually transmitted infection (STI) pathogens may be associated with suboptimal diagnostics, contact tracing, case reporting and epidemiological surveillance. In Guinea-Bissau, additional STI studies are vital to estimate the STI burden and form the basis for a national sexual health strategy for prevention, diagnosis and surveillance of STIs. PMID- 22436138 TI - Cancer and post-traumatic stress disorder: diagnosis, pathogenesis and treatment considerations. AB - OBJECTIVE: The purpose of this article was to review the literature regarding diagnosis, pathogenesis, and treatment of post-traumatic stress disorder (PTSD) associated with cancer. METHOD: We surveyed studies examining the validity of diagnostic scales commonly used to measure PTSD in patients with cancer. Neurobiological underpinnings of PTSD and cancer, including inflammation as the physiological mechanism linking these comorbidities, were examined. Psychopharmacologic and psychotherapeutic treatment of PTSD symptoms in patients with cancer was reviewed. In addition, potential drug-drug interactions between psychotropic medications commonly used to treat PTSD and anti-cancer agents were reviewed. RESULTS: Multiple studies demonstrated the validity of the PTSD Checklist Civilian Version (PCL-C) in diagnosing PTSD in patients with cancer. Research has shown that PTSD as defined in DSM-IV appears to be a better model for conceptualizing distress in patients with cancer than a generalized "distress" model. Epidemiologic studies have shown an increased incidence of PTSD associated with cancer; however, literature regarding characteristics of PTSD in patients with cancer is cross-sectional in nature. SIGNIFICANCE OF RESULTS: Future research focusing on longitudinal, prospective studies to identify patients at risk, determine causal or aggravating factors, and develop preventive interventions is needed. Further study of PTSD in patients with cancer may help increase recognition of this disorder, optimize treatment, and enhance the quality of life of these individuals. PMID- 22436139 TI - Rare hereditary diseases with defects in DNA-repair. AB - The human genome is constantly exposed to various sources of DNA damage. Ineffective protection from this damage leads to genetic instability which can ultimately give rise to somatic disease, causing mutations. Therefore our organism commands a number of highly conserved and effective mechanisms responsible for DNA repair. If these repair mechanisms are defective due to germline mutations in relevant genes, rare diseases with DNA repair deficiencies can arise. Today, a limited number of rare hereditary diseases characterized by genetic defects of DNA repair mechanisms is known, comprising ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy. Although heterogeneous in respect to selected symptoms, these rare disorders share many clinical features such as growth retardation, neurological disorders, premature ageing, skin alterations including abnormal pigmentation, telangiectasia, xerosis cutis, pathological wound healing as well as an increased risk of developing different types of cancer. Based on the clinical similarities of symptoms as well as the predominant diagnostic technology available, many of these rare disorders were formerly classified as genodermatoses with cancer predisposition or chromosomal breakage symptoms. These pathological conditions not only severely impair patients with these rare genetic diseases but also represent symptoms affecting large parts of the general population. PMID- 22436140 TI - The STAI-Y trait scale: psychometric properties and normative data from a large population-based study of elderly people. AB - BACKGROUND: Whereas the State-Trait Anxiety Inventory (STAI-Y) is probably the most widely used self-reported measure of anxiety, the lack of current norms among elderly people appears to be problematic in both a clinical and research context. The objective of the present study was to provide normative data for the STAI-Y trait scale from a large elderly cohort and to identify the main sociodemographic and health-related determinants of trait anxiety. METHODS: The STAI-Y trait scale was completed by 7,538 community-dwelling participants aged 65 years and over from the "Three City" epidemiological study. Trained nurses and psychologists collected information during a face-to-face interview including sociodemographic characteristics and clinical variables. RESULTS: The scale was found to have good internal consistency (Cronbach's alpha = 0.89). Norms were stratified for gender and educational level differentiating persons with and without depressive symptoms. Multivariate linear regression found the STAI-Y trait score to be significantly associated with female gender, psychotropic medication use, higher depressive symptoms, higher cognitive complaints, and with an interaction between subjective health and marital status. Age was not associated with the total score. CONCLUSION: This study provides norms for the STAI-Y trait scale in the general elderly population which are of potential use in both a clinical and research context. The present results confirm the importance of several factors previously associated with higher trait anxiety in the elderly. However, more research is needed to better understand the clinical specificities of anxiety in the elderly and the improvement of assessment. PMID- 22436141 TI - Pattern and levels of spending allocated to HIV prevention programs in low- and middle-income countries. AB - BACKGROUND: AIDS continues to spread at an estimated 2.6 new million infections per year, making the prevention of HIV transmission a critical public health issue. The dramatic growth in global resources for AIDS has produced a steady scale-up in treatment and care that has not been equally matched by preventive services. This paper is a detailed analysis of how countries are choosing to spend these more limited prevention funds. METHODS: We analyzed prevention spending in 69 low- and middle-income countries with a variety of epidemic types, using data from national domestic spending reports. Spending information was from public and international sources and was analyzed based on the National AIDS Spending Assessment (NASA) methods and classifications. RESULTS: Overall, prevention received 21% of HIV resources compared to 53% of funding allocated to treatment and care. Prevention relies primarily on international donors, who accounted for 65% of all prevention resources and 93% of funding in low-income countries. For the subset of 53 countries that provided detailed spending information, we found that 60% of prevention resources were spent in five areas: communication for social and behavioral change (16%), voluntary counselling and testing (14%), prevention of mother-to-child transmission (13%), blood safety (10%) and condom programs (7%). Only 7% of funding was spent on most-at-risk populations and less than 1% on male circumcision. Spending patterns did not consistently reflect current evidence and the HIV specific transmission context of each country. CONCLUSIONS: Despite recognition of its importance, countries are not allocating resources in ways that are likely to achieve the greatest impact on prevention across all epidemic types. Within prevention spending itself, a greater share of resources need to be matched with interventions that approximate the specific needs and drivers of each country's epidemic. PMID- 22436142 TI - Patient-reported treatment burden of chronic immune thrombocytopenia therapies. AB - BACKGROUND: Chronic immune thrombocytopenia (ITP) is a debilitating autoimmune disorder that causes a reduction in blood platelets and increased risk of bleeding. ITP is currently managed with various pharmacologic therapies and splenectomy.This study was conducted to assess patient perceived and reported treatment side effects, as well as the perceived burden or bother, and need to reduce or stop treatment, associated with these side effects among adult patients with chronic ITP. METHODS: A Web-enabled survey was administered to members of a US-based ITP patient support group. Patients reported demographic and clinical characteristics, ITP treatments' side effects for treatments received since diagnosed, level of bother (or distress), and need to reduce or stop treatment, associated with side effects. Current and past exposure was assessed for five specific treatment types: corticosteroids (CS), intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D), rituximab (RT), and splenectomy (SPL), as well as for other patient-referenced therapies (captured as "other"). RESULTS: The survey was completed by 589 patients; 78% female, 89% white, mean age 48 years (SD = 14.71), and 68% reported a typical low platelet count of < 50,000/MUL. Current or past treatment with CS was reported by 92% (n = 542) of patients, 56% (n = 322) for IVIg, 36% (n = 209) for anti-D, 36% (n = 213) for RT, and 39% (n = 227) for SPL. A substantial proportion of CS-treated patients reported side effects (98%, P < 0.05), were highly bothered by their side effects (53.1%, P < 0.05), and reported the need to stop or reduce treatment due to side effects (37.8%, P < 0.05). Among patients reporting side effects of treatment, significant associations were noted for the number of side effects, aggregate bother of reported side effects, and the need to stop or reduce treatment (all P < 0.05). CONCLUSIONS: Current ITP treatments, particularly corticosteroids, are associated with multiple bothersome side effects that may lead to patients stopping or reducing therapy. Open, informed and complete communication between clinician and patient regarding both the benefits and the side effects of ITP treatment may better prepare patients for their prescribed regimens. PMID- 22436143 TI - Using small molecule reagents to selectively modify epitopes based on their conformation. AB - PrP(Sc) is an infectious protein. The only experimentally verified difference between PrP(Sc) and its normal cellular isoform (PrP(C)) is conformational. This work describes an approach to determining the presence of surface exposed or sequestered amino acids present in the PrP(Sc) isoform. The N-hydroxysuccinimide esters of acetic acid and 4-trimethylammoniumbutyric acid were synthesized and reacted with detergent-solubilized brain extracts from Me7-infected mice, uninfected mice, 263K-infected hamsters or uninfected hamsters. These reaction mixtures were analyzed by western blots probed with the antibodies 3F4, 6D11, 7D9, AG4, AH6, GE8 or MAB5424. The 3F4, 6D11, AH6, and GE8 antibodies recognize an epitope that is encrypted in the PrP(Sc) isoform, but exposed in the PrP(C) isoform. These reagents permit the detection of prion infected brain extracts without the need for proteinase K digestion. In addition they can be used, with an appropriate antibody, to determine which amino acids of PrP(Sc) are exposed on the surface and which are encrypted, thus providing useful structural information. This approach was used to distinguish between the 263K and drowsy strains of hamster-adapted scrapie without the use of proteinase K. PMID- 22436144 TI - A phase II multi-institutional study assessing simultaneous in-field boost helical tomotherapy for 1-3 brain metastases. AB - BACKGROUND: Our research group has previously published a dosimetric planning study that demonstrated that a 60 Gy/10 fractions intralesional boost with whole brain radiotherapy (WBRT) to 30 Gy/10 fractions was biologically equivalent with a stereotactic radiosurgery (SRS) boost of 18 Gy/1 fraction with 30 Gy/10 fractions WBRT. Helical tomotherapy (HT) was found to be dosimetrically equivalent to SRS in terms of target coverage and superior to SRS in terms of normal tissue tolerance. A phase I trial has been now completed at our institution with a total of 60 enrolled patients and 48 evaluable patients. The phase II dose has been determined to be the final phase I cohort dose of 60 Gy/10 fractions. METHODS/DESIGN: The objective of this clinical trial is to subject the final phase I cohort dose to a phase II assessment of the endpoints of overall survival, intracranial control (ICC) and intralesional control (ILC). We hypothesize HT would be considered unsuitable for further study if the median OS for patients treated with the HT SIB technique is degraded by 2 months, or the intracranial progression-free rates (ICC and ILC) are inferior by 10% or greater compared to the expected results with treatment by whole brain plus SRS as defined by the RTOG randomized trial. A sample size of 93 patients was calculated based on these parameters as well as the statistical assumptions of alpha = 0.025 and beta = 0.1 due to multiple statistical testing. Secondary assessments of toxicity, health-related quality-of-life, cognitive changes, and tumor response are also integrated into this research protocol. DISCUSSION: To summarize, the purpose of this phase II trial is to assess this non-invasive alternative to SRS in terms of central nervous system (CNS) control when compared to SRS historical controls. A follow-up phase III trial may be required depending on the results of this trial in order to definitively assess non-inferiority/superiority of this approach. Ultimately, the purpose of this line of research is to provide patients with metastatic disease to the brain a shorter course, dose intense, non-invasive radiation treatment with equivalent or improved CNS control/survival and health related quality-of-life/toxicity profile when compared to SRS radiotherapy. TRIAL REGISTRATION: Clinicaltrials.gov - NCT01543542. PMID- 22436145 TI - Depressive symptoms among informal caregivers of older adults: insights from the Singapore Survey on Informal Caregiving. AB - BACKGROUND: This paper determines care recipient and caregiver characteristics and caregiving dimensions - associated with depression among caregivers of older adults, using path analysis and assesses whether the identified path model differs between spousal and adult child caregivers. METHODS: Data from 1,190 dyads comprising care recipients (community-dwelling adults aged >= 75 years with at least one activity of daily living (ADL) limitation) and caregivers (family member/friend most involved in providing care/ensuring provision of care to care recipient), who were interviewed through the Singapore Survey on Informal Caregiving (2010-2011), were used. Using path analysis, we assessed the direct and indirect associations between primary stressors (care recipient's ADL and instrumental ADL status, and memory and behavior problems), caregiver health status, receipt of assistance from a foreign domestic worker/maid, amount of caregiving, negative reaction to caregiving, caregiver's self-esteem, perceived emotional support, and caregiver depressive symptoms. RESULTS: Our analysis showed that primary stressors, receipt of assistance from a foreign domestic worker/maid, perceived emotional support, and caregiver health status were directly or indirectly associated with caregiver depressive symptoms, and this association was mediated by negative reaction to caregiving. Caregiver self esteem mediated the relationship between perceived emotional support and negative reaction to caregiving only among adult child caregivers. CONCLUSIONS: The results provide insights into factors associated with depressive symptoms among spousal and adult child caregivers, and help identify targeted interventions for improving caregiver mood. PMID- 22436146 TI - Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow up. AB - BACKGROUND: Conflicting results have been recently reported evaluating the relationship between pneumococcal vaccination and the risk of thrombotic vascular events. This study assessed the clinical effectiveness of the 23-valent polysaccharide pneumococcal vaccine (PPV23) against acute myocardial infarction and ischaemic stroke in older adults. METHODS: Population-based prospective cohort study conducted from December 1, 2008 until November 30, 2009, including all individuals >= 60 years-old assigned to nine Primary Care Centres in Tarragona, Spain (N = 27,204 individuals). Primary outcomes were hospitalisation for acute myocardial infarction and/or ischaemic stroke. All cases were validated by checking clinical records. The association between pneumococcal vaccination and the risk of each outcome was evaluated by Multivariable Cox proportional hazard models (adjusted by age, sex, influenza vaccine status, presence of comorbidities and cardiovascular risk factors). RESULTS: Cohort members were followed for a total of 26,444 person-years, of which 34% were for vaccinated subjects. Overall incidence rates (per 1000 person-years) were 4.9 for myocardial infarction and 4.6 for ischaemic stroke. In the multivariable analysis, vaccination was associated with a marginally significant 35% lower risk of stroke (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.42-0.99; p = 0.046). We found no evidence for an association between pneumococcal vaccination and reduced risk of myocardial infarction (HR: 0.83; 95% CI: 0.56-1.22; p = 0.347). CONCLUSIONS: Our data supports a benefit of PPV23 against ischaemic stroke among the general population over 60 years, suggesting a possible protective role of pneumococcal vaccination against some acute thrombotic events. PMID- 22436147 TI - CD4 lymphocyte dynamics in Tanzanian pulmonary tuberculosis patients with and without HIV co-infection. AB - BACKGROUND: The interaction of HIV and tuberculosis (TB) on CD4 levels over time is complex and has been divergently reported. METHODS: CD4 counts were assessed from time of diagnosis till the end of TB treatment in a cohort of pulmonary TB patients with and without HIV co-infection and compared with cross-sectional data on age- and sex-matched non-TB controls from the same area. RESULTS: Of 1,605 study participants, 1,250 were PTB patients and 355 were non-TB controls. At baseline, HIV was associated with 246 (95% CI: 203; 279) cells per MUL lower CD4 counts. All PTB patients had 100 cells per MUL lower CD4 counts than the healthy controls. The CD4 levels were largely unchanged during a five-month of TB treatment. HIV infected patients not receiving ART at any time and those already on ART at baseline had no increase in CD4 counts after 5 months of TB treatment, whereas those prescribed ART between baseline and 2 months, and between 2 and 5 months increased by 69 (22;117) and 110 (52; 168) CD4 cells per MUL after 5 months. CONCLUSIONS: The increase in circulating CD4 levels observed in PTB in patients is acquired after 2 months of treatment irrespective of HIV status. Initiation of ART is the strongest factor correlated with CD4 increase during TB treatment. TRIAL REGISTRATION NUMBER: Clinical trials.gov: NCT00311298. PMID- 22436148 TI - Heritability of shoulder ulcers and genetic correlations with mean piglet weight and sow body condition. AB - The objective of this paper was to estimate the heritability for shoulder ulcers and the genetic correlations between shoulder ulcers, mean piglet weight and sow body condition. The analyses were based on information on 5549 Norwegian Landrace sows and their 7614 purebred litters. The genetic analysis was performed using the Gibbs sampling method. Shoulder ulcers were analyzed as a threshold trait. Sow body condition and mean piglet weight were analyzed as linear traits. The heritability of shoulder ulcers was estimated at 0.25 (s.d. = 0.03). The heritability for sow body condition was estimated at 0.14 (s.d. = 0.02) and that for mean piglet weight at 0.23 (s.d. = 0.02). The genetic correlation between shoulder ulcers and sow body condition was negative (-0.59, s.d. = 0.09). The genetic correlation between shoulder ulcers and mean piglet weight was positive (0.23, s.d. = 0.10) and the genetic correlation between sow body condition and mean piglet weight was negative (-0.24, s.d. = 0.10). PMID- 22436149 TI - Genetic parameters between slaughter pig efficiency and growth rate of different body tissues estimated by computed tomography in live boars of Landrace and Duroc. AB - In this study, computed tomography (CT) technology was used to measure body composition on live pigs for breeding purposes. Norwegian Landrace (L; n = 3835) and Duroc (D; n = 3139) boars, selection candidates to be elite boars in a breeding programme, were CT-scanned between August 2008 and August 2010 as part of an ongoing testing programme at Norsvin's boar test station. Genetic parameters in the growth rate of muscle (MG), carcass fat (FG), bone (BG) and non carcass tissue (NCG), from birth to ~100 kg live weight, were calculated from CT data. Genetic correlations between growth of different body tissues scanned using CT, lean meat percentage (LMP) calculated from CT and more traditional production traits such as the average daily gain (ADG) from birth to 25 kg (ADG1), the ADG from 25 kg to 100 kg (ADG2) and the feed conversion ratio (FCR) from 25 kg to 100 kg were also estimated from data on the same boars. Genetic parameters were estimated based on multi-trait animal models using the average information restricted maximum likelihood (AI-REML) methodology. The heritability estimates (s.e. = 0.04 to 0.05) for the various traits for Landrace and Duroc were as follows: MG (0.19 and 0.43), FG (0.53 and 0.59), BG (0.37 and 0.58), NCG (0.38 and 0.50), LMP (0.50 and 0.57), ADG1 (0.25 and 0.48), ADG2 (0.41 and 0.42) and FCR (0.29 and 0.42). Genetic correlations for MG with LMP were 0.55 and 0.68, and genetic correlations between MG and ADG2 were -0.06 and 0.07 for Landrace and Duroc, respectively. LMP and ADG2 were clearly unfavourably genetically correlated (L: -0.75 and D: -0.54). These results showed the difficulty in jointly improving LMP and ADG2. ADG2 was unfavourably correlated with FG (L: 0.84 and D: 0.72), thus indicating to a large extent that selection for increased growth implies selection for fatness under an ad libitum feeding regime. Selection for MG is not expected to increase ADG2, but will yield faster growth of the desired tissues and a better carcass quality. Hence, we consider MG to be a better biological trait in selection for improved productivity and carcass quality. CT is a powerful instrument in conjunction with breeding, as it combines the high accuracy of CT data with measurements taken from the selection candidates. CT also allows the selection of new traits such as real body composition, and in particular, the actual MG on living animals. PMID- 22436150 TI - Genetic diversity and admixture among Canadian, Mountain and Moorland and Nordic pony populations. AB - As part of the requirements of the Convention on Biological Diversity, Canada has been investigating the genetic diversity of its native equine and pony populations. Along with examining four indigenous Canadian equine populations (Canadian horse, Lac La Croix pony, Newfoundland pony and Sable Island population), another 10 Mountain and Moorland, three Nordic, four horse and two feral equine populations (thought to have influenced some pony breeds) were also investigated. In total, 821 individuals were genotyped at 38 microsatellite loci. Results of the analysis of molecular variance indicated that 13.3% of genetic diversity was explained by breed differences, whereas 84.6% and 2.1% of diversity came from within and among individuals, respectively. The average effective number of alleles and allelic richness was the lowest in the Eriskay (2.51 and 3.98) and Lac La Croix (2.83 and 4.01) populations, whereas it was highest in the New Forest (4.31 and 6.01) and Welsh (4.33 and 5.87) breeds, followed closely by the Newfoundland-CDN (4.23 and 5.86) population. Expected heterozygosities varied from 0.61 in the Lac La Croix to 0.74 in the Welsh and in Newfoundland. Observed heterozygosities ranged from 0.57 in the Exmoor and 0.58 in the Sable Island herd to 0.77 in the Kerry Bog and 0.76 in the New Forest breeds. Structure and admixture analyses revealed that the most likely number of clusters was 21, although some substructure was also observed when K = 16, compared with the 24 predefined populations. Information gathered from this study should be combined with other available phenotypic and pedigree data to develop, or amend, a suitable conservation strategy for all populations examined. PMID- 22436151 TI - Genetic parameters for first lactation test-day milk flow in Holstein cows. AB - Genetic parameters for test-day milk flow (TDMF) of 2175 first lactations of Holstein cows were estimated using multiple-trait and repeatability models. The models included the direct additive genetic effect as a random effect and contemporary group (defined as the year and month of test) and age of cow at calving (linear and quadratic effect) as fixed effects. For the repeatability model, in addition to the effects cited, the permanent environmental effect of the animal was also included as a random effect. Variance components were estimated using the restricted maximum likelihood method in single- and multiple trait and repeatability analyses. The heritability estimates for TDMF ranged from 0.23 (TDMF 6) to 0.32 (TDMF 2 and TDMF 4) in single-trait analysis and from 0.28 (TDMF 7 and TDMF 10) to 0.37 (TDMF 4) in multiple-trait analysis. In general, higher heritabilities were observed at the beginning of lactation until the fourth month. Heritability estimated with the repeatability model was 0.27 and the coefficient of repeatability for first lactation TDMF was 0.66. The genetic correlations were positive and ranged from 0.72 (TDMF 1 and 10) to 0.97 (TDMF 4 and 5). The results indicate that milk flow should respond satisfactorily to selection, promoting rapid genetic gains because the estimated heritabilities were moderate to high. Higher genetic gains might be obtained if selection was performed in the TDMF 4. Both the repeatability model and the multiple-trait model are adequate for the genetic evaluation of animals in terms of milk flow, but the latter provides more accurate estimates of breeding values. PMID- 22436152 TI - Genetic parameters and environmental effects on temperament score and reproductive traits of Nellore cattle. AB - Animal temperament is a trait of economic relevance and its use as a selection criterion requires the identification of environmental factors that influence this trait, as well as the estimation of its genetic variability and interrelationship with other traits. The objectives of this study were to evaluate the effect of the covariates dam age at calving (ADC), long yearling age (YA) and long yearling weight (YW) on temperament score (T) and to estimate genetic parameters for T, scrotal circumference (SC) at long YA and age at first calving (AFC) in Nellore cattle participating in a selection program. The traits were analyzed by the restricted maximum likelihood method under a multiple-trait animal model. For all traits, contemporary group was included as a fixed effect and additive genetic and residual as random effects. In addition to these effects, YA, YW and ADC were considered for analyzing T. In the case of SC and AFC, the effect of long YW was included as a covariate. Genetic parameters were estimated for and between traits. The three covariates significantly influenced T. The heritability estimates for T, SC and AFC were 0.18 +/- 0.02, 0.53 +/- 0.04 and 0.23 +/- 0.08, respectively. The genetic correlations between T and SC, and T and AFC were -0.07 +/- 0.17 and -0.06 +/- 0.19, respectively. The genetic correlation estimated between SC and AFC was -0.57 +/- 0.16. In conclusion, a response to selection for T, SC and AFC is expected and selection for T does not imply correlated responses with the other traits. PMID- 22436153 TI - On the way to functional agro biodiversity: coat colour gene variability in goats. AB - Functional agro biodiversity defines the exploitation of biodiversity to provide ecosystem services, support sustainable agricultural production and benefit the regional and global environment and the public at large (ELN-FAB, 2009; www.eln_fab.eu). Tracking of animal products back to the breed of origin based on their genetic make-up undoubtedly falls in this category. The aim of this paper was to identify and validate a set of single nucleotide polymorphisms (SNPs) in goat coat colour genes, most of which have not been investigated before, to trace five goat populations of the Italian Alps and their product. Several regions of 28 genes influencing coat colour pathways were amplified in eight animals (two per breed). Sequence comparison revealed 48 SNPs and three INDEL (INsertion DELetion). No breed-specific alleles were detected; however, several SNPs showed an uneven frequency distribution between breeds. In BIO, the genotype frequency distribution of a non-synonymous SNP suggested a possible role of TYRP1 in brown eumelanic goat coat colour. A total of 29 independent SNPs in 20 genes were selected and used to allocate 159 minimally related goat samples using STRUCTURE 2.2 and GeneClass 2 software. STRUCTURE 2.2 assigns 99% of individuals to the correct breed considering the prior information on putative breed of origin for each sample and 81% using only the genotypic data. The three algorithms available in GeneClass 2 performed with nearly equal efficiency, with 86% and 87% correct allocations. All the methods yielded an average probability of assignment >0.92 and a specificity index >0.86. Despite their coat colour variability, individuals belonging to ORO were fully assigned, showing that, in the absence of a breed specific allele tied to coat colour, the best assignment resulted for the most genetically distinct breed. The lowest rate of correct assignment was observed in Verzaschese (73%), not ascertained in the breed panel used in the SNP discovery phase. PMID- 22436154 TI - Foetal life protein restriction in male mink (Neovison vison) kits lowers post weaning protein oxidation and the relative abundance of hepatic fructose-1,6 bisphosphatase mRNA. AB - Foetal life malnutrition has been studied intensively in a number of animal models. Results show that especially foetal life protein malnutrition can lead to metabolic changes later in life. This might be of particular importance for strict carnivores, for example, cat and mink (Neovison vison) because of their higher protein requirement than in other domestic mammals. This study aimed to investigate the effects of low protein provision during foetal life to male mink kits on their protein metabolism during the early post-weaning period of rapid growth and to investigate whether foetal life protein deficiency affects the response to adequate or deficient protein provision post weaning. Further, we intended to study whether the changes in the gene expression of key enzymes in foetal hepatic tissue caused by maternal protein deficiency were manifested post weaning. A total of 32 male mink kits born to mothers fed either a low-protein diet (LP), that is, 14% of metabolizable energy (ME) from protein (foetal low - FL), n = 16, or an adequate-protein (AP) diet, that is, 29% of ME from protein (foetal adequate - FA), n = 16) in the last 16.3 +/- 1.8 days of pregnancy were used. The FL offspring had lower birth weight and lower relative abundance of fructose-1,6-bisphosphatase (Fru-1,6-P2ase) and pyruvate kinase mRNA in foetal hepatic tissue than FA kits. The mothers were fed a diet containing adequate protein until weaning. At weaning (7 weeks of age), half of the kits from each foetal treatment group were fed an AP diet (32% of ME from protein; n = 8 FA and 8 FL) and the other half were fed a LP diet (18% of ME from protein; n = 8 FA and 8 FL) until 9.5 weeks of age, yielding four treatment groups (i.e. FA-AP, FA-LP, FL-AP and FL-LP). Low protein provision in foetal life lowered the protein oxidation post-weaning compared with the controls (P = 0.006), indicating metabolic flexibility and a better ability to conserve protein. This could not, however, be supported by changes in liver mass because of foetal life experience. A lower relative abundance of Fru-1,6-P2ase mRNA was observed (P < 0.05), being lower in 9.5-week-old FL than in FA kits. It can be concluded that foetal life protein restriction leads to changes in post-weaning protein metabolism through lower protein oxidation of male mink kits. PMID- 22436155 TI - Re-alimentation strategy to manoeuvre body condition and carcass characteristics in cull ewes. AB - Improvement in body condition and carcass traits through nutritional intervention was studied in cull ewes. Sixty-eight adult non-productive Malpura ewes (average body weight 26.7 +/- 0.33 kg) were randomly divided into four equal groups: G0 maintained on free grazing for 8 h on protected natural rangeland with ad libitum guar (Cyamopsis tetragonoloba) straw (GS) after grazing; G1, G2 and G3 fed with supplemental concentrate at the rate of 250 g, 2.5% of live weight (LW) and ad libitum, respectively. The experiment was continued for 90 days and daily feed intake, weekly LW and body condition score (BCS) were recorded. Intake and digestibility of nutrients were assessed by indicator method. Rumen fermentation attributes and blood biochemical profile were studied to assess the dietary effects and animals were slaughtered at the end of experiment for evaluation of carcass characteristics. Higher dry matter (DM) intake and improvement in plane of nutrition was observed in G2 and G3 with a higher LW gain (LWG) and improvement in BCS than in G0. The digestibility of DM, organic matter, CP, ADF and cellulose was higher (P < 0.05) in G2 and G3 than in G0. A lower ruminal pH and ammonia N but higher total N and trichloroacetic acid-precipitable N, an increase in holotrichs, spirotrichs and total protozoa population, increase in haemoglobin but decrease in serum total cholesterol and non-esterified fatty acids were observed in high-concentrate-fed groups. Carcass attributes revealed increase (P < 0.05) in empty LW, dressing yield, eye muscle area, subcutaneous and intramuscular fat, decrease in shear force value and higher (P < 0.05) protein content in Longissimus dorsi muscle in test groups than in the control. Above all, the G2 animals had better rumen environment and blood biochemical attributes and consumed more feed with enhanced digestibility that supported higher LWG at better feed conversion efficiency, improvement in BCS and carcass quality. Thus, re-alimentation of cull ewes with challenged feeding of concentrate at 2.5% of LW on a basal roughage diet for a period of 3 months may have promise for better economic return to the farmers with possibly meeting quality mutton for human consumption. PMID- 22436156 TI - Supplementation with l-carnitine downregulates genes of the ubiquitin proteasome system in the skeletal muscle and liver of piglets. AB - Supplementation of carnitine has been shown to improve performance characteristics such as protein accretion in growing pigs. The molecular mechanisms underlying this phenomenon are largely unknown. Based on recent results from DNA microchip analysis, we hypothesized that carnitine supplementation leads to a downregulation of genes of the ubiquitin proteasome system (UPS). The UPS is the most important system for protein breakdown in tissues, which in turn could be an explanation for increased protein accretion. To test this hypothesis, we fed sixteen male, four-week-old piglets either a control diet or the same diet supplemented with carnitine and determined the expression of several genes involved in the UPS in the liver and skeletal muscle. To further determine whether the effects of carnitine on the expression of genes of the UPS are mediated directly or indirectly, we also investigated the effect of carnitine on the expression of genes of the UPS in cultured C2C12 myotubes and HepG2 liver cells. In the liver of piglets fed the carnitine-supplemented diet, the relative mRNA levels of atrogin-1, E214k and Psma1 were lower than in those of the control piglets (P < 0.05). In skeletal muscle, the relative mRNA levels of atrogin-1, MuRF1, E214k, Psma1 and ubiquitin were lower in piglets fed the carnitine-supplemented diet than that in control piglets (P < 0.05). Incubating C2C12 myotubes and HepG2 liver cells with increasing concentrations of carnitine had no effect on basal and/or hydrocortisone-stimulated mRNA levels of genes of the UPS. In conclusion, this study shows that dietary carnitine decreases the transcript levels of several genes involved in the UPS in skeletal muscle and liver of piglets, whereas carnitine has no effect on the transcript levels of these genes in cultivated HepG2 liver cells and C2C12 myotubes. These data suggest that the inhibitory effect of carnitine on the expression of genes of the UPS is mediated indirectly, probably via modulating the release of inhibitors of the UPS such as IGF-1. The inhibitory effect of carnitine on the expression of genes of the UPS might explain, at least partially, the increased protein accretion in piglets supplemented with carnitine. PMID- 22436157 TI - Iron dextran treatment does not induce serum protein carbonyls in the newborn pig. AB - Oxidation of serum proteins can lead to carbonyl formation that alters their function and is often associated with stress-related diseases. As it is recommended that all pigs reared in modern production facilities be given supplemental iron at birth to prevent anemia, and metals can catalyze the carbonylation of proteins, the primary objective of this study was to determine whether standard iron dextran treatment was associated with enhanced serum protein oxidation in newborn piglets. Piglets were treated with 100 mg of iron dextran intramuscularly either on the day of birth, or on the third day after birth. Blood samples were collected from piglets 48 or 96 h after treatment and serum was harvested. For quantification, serum protein carbonyls were converted to hydrazones with dinitrophenyl hydrazine and analyzed spectrophotometrically. To identify and determine relative distribution of carbonylated proteins, serum protein carbonyls were derivatized with biotin hydrazide, separated by two dimensional polyacrylamide gel electrophoresis, stained with avidin-fluorescein and identified by mass spectrometry. The standard iron dextran treatment was associated with no increase in total oxidized proteins if given either on the first or third day of life. In addition, with a few noted exceptions, the overall distribution and identification of oxidized proteins were similar between control and iron dextran-treated pigs. These results indicate that while iron dextran treatment is associated with a marked increase in circulating iron, it does not appear to specifically induce the oxidation of serum proteins. PMID- 22436158 TI - Early vaccination with Improvac(r): effects on performance and behaviour of male pigs. AB - The aim of this study was to investigate the effect of giving a two-dose regimen of gonadotropin-releasing hormone vaccine, Improvac(r) (Pfizer Ltd), earlier than currently recommended, on performance and behaviour of growing/finishing pigs. Cross-bred male pigs (n = 192) were randomly allocated, within a litter, into four groups at birth: one group of pigs surgically castrated without anaesthesia before one week of age, a second group of early vaccinated pigs given Improvac at 10 and 14 weeks of age, a third group of standard vaccinated pigs given Improvac at 16 and 20 weeks of age, so that the second vaccination was given 4 to 6 weeks before slaughter as recommended by the manufacturer, and a fourth group of entire male pigs. The experiment started when the pigs were 12 weeks old and lasted until 25 weeks of age, when the pigs were slaughtered. The pigs were fed restrictedly. Daily weight gain and feed conversion during the entire raising period did not differ significantly between groups. Estimated lean meat content of early vaccinated and surgically castrated pigs was lower when compared with entire male pigs, whereas standard vaccinated pigs did not differ from entire males. Dressing percentage was higher in early vaccinated and surgically castrated pigs than in standard vaccinated and entire male pigs, partly because of lower size and weight of reproductive organs. For both groups of vaccinated pigs, both problematic and non-problematic behaviours decreased after their second injection, from the levels of entire males to those of surgically castrated pigs. After the second injection, pigs of both vaccination groups performed no mountings, in contrast with entire male pigs of the same age. Skin lesions at slaughter were fewer and less severe for vaccinated pigs compared with entire male pigs. No difference in income per carcass was observed for surgically castrated or vaccinated pigs. However, for entire male pigs the income was lower, as the payment system in Sweden also takes into consideration the additional cost for boar taint analyses and reduced payment for tainted carcasses. Under our experimental conditions, early vaccination with Improvac can be used as an alternative to the recommended schedule to minimise problematic behaviour with unaffected profitability. PMID- 22436159 TI - Alternative farrowing accommodation: welfare and economic aspects of existing farrowing and lactation systems for pigs. AB - There is growing societal pressure, expressed through government legislation and consumers' purchasing choices, to abolish livestock systems considered detrimental to farm animal welfare. Such systems include farrowing crates, which are behaviourally and physically restrictive for sows. Therefore, identifying less restrictive farrowing systems for commercial implementation has become an important focus of pig research. Despite numerous attempts to develop indoor alternatives to crates, there is as yet no universal acceptance of such systems at the commercial level. The primary concern is piglet survival, because often favourable figures are reported at the experimental level, but not replicated in commercial evaluation. Alternative farrowing systems should equal or surpass survival levels in conventional systems and perform consistently across a range of farm circumstances for widespread commercial implementation. In addition, it is important that alternatives consider ease of management, operator safety and economic sustainability. Utilising a large database of literature, 12 existing alternative indoor systems were identified and compared against each other, conventional crates and outdoor systems. An assessment of how well alternative systems satisfy the design criteria for meeting animals' biological needs was carried out by developing a welfare design index (WDI). The physical and financial performance of these systems was also evaluated and summarised. The derived WDI yielded values of 0.95 for conventional crates, with higher scores for commercial outdoor systems of 1.10 and indoor group farrowing or multi suckling systems (e.g. Thorstensson = 2.20). However, the high total piglet mortality (23.7% +/- s.e. 2.26) in indoor group systems compared with conventional crates (18.3% +/- s.e. 0.63) and outdoor systems (17.0% +/- s.e. 2.05), together with the added capital cost (92% more than conventional crates, 249% more than commercial outdoor huts), mainly as a result of extra building space provided per animal, question their feasibility to deliver from an economic perspective. Designed pen systems offered the best compromise, scoring 1.64 from the WDI, with a total piglet mortality of 16.6% (+/-s.e. 0.88) and capital costs and labour input more comparable to farrowing crates (17.5% more than crates). The critical review of different systems was hampered by the lack of comprehensive data and detailed system descriptions. When attempting to assess welfare and economic attributes of systems, there are certain caveats that require discussion, in particular weighting of the contribution of different design attributes to pig welfare, the relative importance of the sow and her piglets and the many potential confounding factors that arise. Also, when judging any system, it must be emphasised that the maternal characteristics of sows and the quality of stockpersonship will be integral to its success. PMID- 22436160 TI - Food preferences and aversions in human health and nutrition: how can pigs help the biomedical research? AB - The establishment of food preferences and aversions determines the modulation of eating behaviour and the optimization of food intake. These phenomena rely on the learning and memory abilities of the organism and depend on different psychobiological mechanisms such as associative conditionings and sociocultural influences. After summarizing the various behavioural and environmental determinants of the establishment of food preferences and aversions, this paper describes several issues encountered in human nutrition when preferences and aversions become detrimental to health: development of eating disorders and obesity, aversions and anorexia in chemotherapy-treated or elderly patients and poor palatability of medical substances and drugs. Most of the relevant biomedical research has been performed in rodent models, although this approach has severe limitations, especially in the nutritional field. Consequently, the final aim of this paper is to discuss the use of the pig model to investigate the behavioural and neurophysiological mechanisms underlying the establishment of food preferences and aversions by reviewing the literature supporting analogies at multiple levels (general physiology and anatomy, sensory sensitivity, digestive function, cognitive abilities, brain features) between pigs and humans. PMID- 22436161 TI - Adaptive response to Eimeria acervulina in rearing hens is affected by suboptimal incubation temperature and heat exposure in later life. AB - This study aimed to investigate whether suboptimal incubation (SI) temperature in weeks 1 and 3 of layer embryo incubation affects their development and post-hatch adaptive capacity during infectious challenges, by using Eimeria as a model infection under normal and immediately after more challenging environmental conditions of 72 h heat exposure. Eggs (n = 160 per treatment) were incubated at optimal (OI = 37.8 degrees C continuously) or suboptimal eggshell temperature (36.7 degrees C, 37.8 degrees C and 38.9 degrees C in weeks 1, 2 and 3, respectively). At day 33 of age, half the chickens of each incubation treatment were exposed to 72 h heat (35 degrees C), whereas the other half remained under control conditions (21 degrees C). At day 36 of age, all chickens were inoculated with 1 ml of a phosphate buffer saline solution containing 25 000 sporulated Eimeria acervulina oocysts/ml. The adaptive response to E. acervulina was measured by BW gain and FI from days 0 to 3 post infection (p.i.), days 3 to 5 p.i. and days 5 to 7 p.i., and by oocyst production (days 4 and 7 p.i.) and lesion scores in the duodenum (day 3, 4 and 7 p.i.). Our results demonstrated that SI temperatures in weeks 1 and 3 of incubation resulted in a reduction in yolk-free BW, chick length and navel condition. Moreover, SI temperature appeared to reduce the adaptive capacity to E. acervulina. This was demonstrated by tendencies to lower FI (P = 0.07) and BW gain (P = 0.08), more duodenal lesions (P = 0.09) and higher oocyst production (P = 0.02) after inoculation of E. acervulina. Higher lesion scores and faecal oocyst numbers were especially found when suboptimal incubation was combined with heat exposure preceding the infection. In conclusion, SI layer chickens tend to be less able to cope with an infectious challenge post hatch. PMID- 22436162 TI - Maize supplementation of Pelibuey sheep in a silvopastoral system: fodder selection, nutrient intake and resilience against gastrointestinal nematodes. AB - This trial evaluated the effect of maize supplementation on the ingestive behavior, nutrient intake and the resilience against gastrointestinal nematode (GIN) infection of hair sheep in a silvopastoral system containing tropical grasses and legume trees. In addition, it attempted to determine the metabolic cost of the natural GIN infection in supplemented and non-supplemented animals. Twenty-nine 3-month-old lambs (male and female), raised nematode free, were allocated to four groups: I-NS (infected, not supplemented, n = 8), I-S (infected, supplemented with maize at 1.5% live weight (LW), n = 7), T-NS (treated with moxidectin 0.2 mg/kg LW every 28 days, and not supplemented, n = 7) and T-S (treated with moxidectin and supplemented with maize at 1.5% LW, n = 7). During the 70-day trial, fodder intake, fodder selection, LW change (LWC), red blood cell counts (RBC), hemoglobin (Hb), hematocrit (Ht) and eggs per gram of feces (EPG) were measured every 14 days. Supplement consumption was recorded daily. Metabolizable energy (ME) and protein (MP) consumption from the feeds were estimated. Maize supplementation helped to improve the resilience of hair sheep lambs against GIN infections. The I-S and T-NS groups showed similar LWC, RBC, Hb and Ht (P > 0.05) and both were higher than those in the I-NS group (P < 0.05). No difference was found in EPG between the I-NS and the I-S groups (P > 0.05). No effect of sex was observed in the different variables. Although all groups showed low dry matter intake (DMI) (< 2% LW), supplemented groups (T-S and I-S) showed higher total DMI (fodder + maize; P < 0.05), hence higher ME and MP intakes than the non-supplemented groups (T-NS and I-NS). All groups showed similar fodder selection patterns. The estimated metabolic cost of parasitism was ME = 0.70 MJ/day and MP = 9.2 g/day in the I-S animals. Meanwhile, the cost in the I-NS animals was ME = 1.46 MJ/day and MP = 12.71 g/day. Maize supplementation was an economically viable strategy to control GIN compared with no intervention. PMID- 22436163 TI - Does increasing milk yield per cow reduce greenhouse gas emissions? A system approach. AB - Milk yield per cow has continuously increased in many countries over the last few decades. In addition to potential economic advantages, this is often considered an important strategy to decrease greenhouse gas (GHG) emissions per kg of milk produced. However, it should be considered that milk and beef production systems are closely interlinked, as fattening of surplus calves from dairy farming and culled dairy cows play an important role in beef production in many countries. The main objective of this study was to quantify the effect of increasing milk yield per cow on GHG emissions and on other side effects. Two scenarios were modelled: constant milk production at the farm level and decreasing beef production (as co-product; Scenario 1); and both milk and beef production kept constant by compensating the decline in beef production with beef from suckler cow production (Scenario 2). Model calculations considered two types of production unit (PU): dairy cow PU and suckler cow PU. A dairy cow PU comprises not only milk output from the dairy cow, but also beef output from culled cows and the fattening system for surplus calves. The modelled dairy cow PU differed in milk yield per cow per year (6000, 8000 and 10 000 kg) and breed. Scenario 1 resulted in lower GHG emissions with increasing milk yield per cow. However, when milk and beef outputs were kept constant (Scenario 2), GHG emissions remained approximately constant with increasing milk yield from 6000 to 8000 kg/cow per year, whereas further increases in milk yield (10 000 kg milk/cow per year) resulted in slightly higher (8%) total GHG emissions. Within Scenario 2, two different allocation methods to handle co-products (surplus calves and beef from culled cows) from dairy cow production were evaluated. Results showed that using the 'economic allocation method', GHG emissions per kg milk decreased with increasing milk yield per cow per year, from 1.06 kg CO2 equivalents (CO2eq) to 0.89 kg CO2eq for the 6000 and 10 000 kg yielding dairy cow, respectively. However, emissions per kg of beef increased from 10.75 kg CO2eq to 16.24 kg CO2eq due to the inclusion of suckler cows. This study shows that the environmental impact (GHG emissions) of increasing milk yield per cow in dairy farming differs, depending upon the considered system boundaries, handling and value of co products and the assumed ratio of milk to beef demand to be satisfied. PMID- 22436164 TI - Authentication of beef production systems using a metabolomic-based approach. AB - There is a need for new, non-invasive, rapid and reliable analytical methodologies that can easily be implemented and used for authentication of cattle production systems and the meat derived from them. Easily quantifiable markers could strengthen the current tracing methods for beef authentication. This study investigated the use of a nuclear magnetic resonance-based metabolomic approach as a tool to authenticate beef on the basis of the pre-slaughter production system. Urine and muscle samples were collected from animals fed either pasture outdoor, a barley-based concentrate indoor, silage followed by pasture outdoor or silage followed by pasture outdoor with concentrate over 1 year. A metabolomic analysis was performed on urine (n = 68) and muscle (n = 98) samples collected from animals on the different diets. The results showed that separation according to production system was possible indicating the potential use of this approach in beef authentication. Identification of the major discriminating peaks in urine led to the identification of potential markers of production system including creatinine, glucose, hippurate, pyruvate, phenylalanine, phenylacetylglycine and three unassigned resonances. PMID- 22436165 TI - Effect of water restriction on drinking behaviour and water intake in German black-head mutton sheep and Boer goats. AB - The present study was conducted to evaluate and compare the physiological responses of sheep and goats to water restriction using the deuterium dilution technique (D2O) to predict the total water intake (TWI) in both species. In two consecutive trials, 10 non-lactating Boer goats and 10 non-lactating German black head mutton ewes were each randomly allocated into a treatment and a control group. In the control groups (n = 5, for each species), water was offered ad libitum, whereas the treatment groups (n = 5, for each species) received water 3 h/day on experimental days 8 to 14 and 6 h every 2 days on experimental days 15 to 22. The respiratory rate, rectal temperature, body mass and drinking behaviour were also recorded. The TWI was estimated by D2O for each animal. Water restriction for 21 h/day or 42 h/2 days had no significant (P > 0.05) effect on water intake (WI), feed intake, WI to dry matter intake ratio or body mass in both species. The absence of differences between species in their WIs was also confirmed using D2O. However, sheep had higher respiratory rates and rectal temperatures than goats in both control and treatment groups. Both species showed the ability to tolerate a moderate water shortage by activating several physiological mechanisms and behavioural strategies. PMID- 22436166 TI - Pro-oxidant status and matrix metalloproteinases in apical lesions and gingival crevicular fluid as potential biomarkers for asymptomatic apical periodontitis and endodontic treatment response. AB - BACKGROUND: Oxidative stress and matrix metalloproteinases -9 and -2 are involved in periodontal breakdown, whereas gingival crevicular fluid has been reported to reflect apical status. The aim of this study was to characterize oxidant balance and activity levels of MMP -2 and -9 in apical lesions and healthy periodontal ligament; and second, to determine whether potential changes in oxidant balance were reflected in gingival crevicular fluid from asymptomatic apical periodontitis (AAP)-affected teeth at baseline and after endodontic treatment. METHODS: Patients with clinical diagnosis of AAP and healthy volunteers having indication of tooth extraction were recruited. Apical lesions and healthy periodontal ligaments, respectively, were homogenized or processed to obtain histological tissue sections. Matrix metalloproteinase -9 and -2 levels and/or activity were analyzed by Immunowestern blot, zymography and consecutive densitometric analysis, and their tissue localization was confirmed by immunohistochemistry. A second group of patients with AAP and indication of endodontic treatment was recruited. Gingival crevicular fluid was extracted from AAP-affected teeth at baseline, after endodontic treatment and healthy contralateral teeth. Total oxidant and antioxidant status were determined in homogenized tissue and GCF samples. Statistical analysis was performed using STATA v10 software with unpaired t test, Mann-Whitney test and Spearman's correlation. RESULTS: Activity of MMP-2 and MMP-9 along with oxidant status were higher in apical lesions (p < 0.05). Total oxidant status correlated positively with matrix metalloproteinase-2 and lesion size (p < 0.05). Gingival crevicular fluid showed significantly lower levels of total antioxidant status in diseased teeth at baseline compared to controls and endodontically-treated groups. CONCLUSIONS: Apical lesions display an oxidant imbalance along with increased activity of matrix metalloproteinase-2 and -9 and might contribute to AAP progression. Oxidant imbalance can also be reflected in GCF from AAP-affected teeth and was restored to normal levels after conservative endodontic treatment. These mediators might be useful as potential biomarkers for chair-side complementary diagnostic of apical status in GCF. PMID- 22436167 TI - Revisiting tuberculous pleurisy: pleural fluid characteristics and diagnostic yield of mycobacterial culture in an endemic area. AB - BACKGROUND: Tuberculous pleurisy is traditionally indicated by extreme lymphocytosis in pleural fluid and low yield of effusion culture. However, there is considerable inconsistency among previous study results. In addition, these data should be updated due to early effusion studies and advances in culture methods. METHODS: From January 2004 to June 2009, patients with tuberculous pleurisy were retrospectively identified from the mycobacteriology laboratories and the pathology and tuberculosis registration databases of two hospitals in Taiwan where tuberculosis is endemic. Pleural fluid characteristics and yields of mycobacterial cultures using liquid media were evaluated. RESULTS: A total of 382 patients with tuberculous pleurisy were identified. The median lymphocyte percentage of total cells in pleural fluids was 84% (IQR 64-95%) and 17% of cases had a lymphocyte percentage of <50%. The lymphocyte percentage was negatively associated with the probability of a positive effusion culture (OR 0.97; 95% CI 0.96 to 0.99). The diagnostic yields were 63% for effusion culture, 48% for sputum culture, 79% for the combination of effusion and sputum cultures, and 74% for histological examination of pleural biopsy specimens. CONCLUSION: The degree of lymphocyte predominance in tuberculous pleurisy was lower than was previously thought. The lymphocyte percentage in pleural fluid was negatively associated with the probability of a positive effusion culture. With the implementation of a liquid culture method, the sensitivity of effusion culture was much higher than has been previously reported, and the combination of effusion and sputum cultures provided a good diagnostic yield. PMID- 22436168 TI - The relationship between clinical outcomes and medication adherence in difficult to-control asthma. AB - Medication non-adherence and the clinical implications in difficult-to-control asthma were audited. Prescription issue data from 115 patients identified sub optimal adherence (<80%) in 65% of patients on inhaled corticosteroids (ICS) or combined ICS/long-acting beta2 agonist (LABA). In those using separate ICS and LABA, adherence to LABA (50%) was significantly better than to ICS (14.3%). Patients with sub-optimal ICS adherence had reduced FEV(1) and higher sputum eosinophil counts. Adherence ratio was an independent predictor of previous ventilation for acute severe asthma (p=0.008). The majority of patients with difficult-to-control asthma are non-adherent with their asthma medication. Non adherence is correlated with poor clinical outcomes. PMID- 22436169 TI - Poor air quality in classrooms related to asthma and rhinitis in primary schoolchildren of the French 6 Cities Study. AB - BACKGROUND: Relationships between indoor air quality (IAQ) found in schools and the allergic and respiratory health of schoolchildren have been insufficiently explored. A survey was conducted in a large sample of classrooms of primary schools in France to provide objective assessments of IAQ to which young schoolchildren are exposed in classrooms, and to relate exposure to major air pollutants found in classrooms to asthma and allergies of schoolchildren. METHODS: Concentrations of fine particles with aerodynamic diameter <=2.5 MUm (PM(2.5)), nitrogen dioxide (NO(2)) and three aldehydes were objectively assessed in 401 randomly chosen classrooms in 108 primary schools attended by 6590 children (mean age 10.4 years, SD +/-0.7) in the French 6 Cities Study. The survey incorporated a medical visit including skin prick testing (SPT) for common allergens, a test for screening exercise-induced asthma (EIA) and a standardised health questionnaire completed by parents. RESULTS: Children were differently exposed to poor air quality in classrooms, with almost 30% being highly exposed according to available standards. After adjusting for confounders, past year rhinoconjunctivitis was significantly associated with high levels of formaldehyde in classrooms (OR 1.19; 95% CI 1.04 to 1.36). Additionally, an increased prevalence of past year asthma was found in the classrooms with high levels of PM(2.5) (OR 1.21; 95% CI 1.05 to 1.39), acrolein (OR 1.22; 95% CI 1.09 to 1.38) and NO(2) (OR 1.16; 95% CI 0.95 to 1.41) compared with others. The relationship was observed mostly for allergic asthma as defined using SPT. A significant positive correlation was found between EIA and the levels of PM(2.5) and acrolein in the same week. CONCLUSIONS: In this random sample, air quality in classrooms was poor, varied significantly among schools and cities, and was related to an increased prevalence of clinical manifestations of asthma and rhinitis in schoolchildren. Children with a background of allergies seemed at increased risk. PMID- 22436170 TI - Ondasetron versus haloperidol for the treatment of postcardiotomy delirium: a prospective, randomized, double-blinded study. AB - BACKGROUND: To investigate the controlling efficacy of ondasetron and haloperidol in regard to the postcardiotomy delirium. METHODS: We included in this prospective, randomized, double-blinded study 80 patients who developed delirium after heart surgery with the application of heart lung-machine. The patients were divided into two, equally-sized groups, which on detection of delirium received ondasetron 8 mg iv or haloperidol 5 mg iv respectively. The statistical analysis compared the baseline and demographic characteristics of the two groups (age, gender, comorbidities, years of education, type of surgery etc.). RESULTS: Both ondasetron and haloperidol had very good delirium controlling effects, without statistically significant differences. DISCUSSION-CONCLUSIONS: Ondasetron and haloperidol are efficient agents as far as the treatment of postcardiotomy delirium is concerned. As, in addition, ondasetron bares milder side-effects, we believe this could be the agent of choice in patients developing postcardiotomy delirium in the future. PMID- 22436171 TI - Sporadic Creutzfeldt-Jakob disease: a description of two cases. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and devastating illness. It is the most frequently encountered form of the spongiform encephalopathies with 50 new cases a year in the UK. It presents with a myriad of symptoms reflecting central nervous system dysfunction and is characterized by a rapidly progressive dementia leading to death. The disease process can pose multiple challenges: diagnostic conundrums, complexities in management, and palliative care issues. Good coordinated care between services and information is paramount in adequate management and delivery of care for patients suffering from sCJD.Psychiatry services frequently become involved in the assessment and management of sCJD. PMID- 22436172 TI - Microarray-based method for screening of immunogenic proteins from bacteria. AB - BACKGROUND: Detection of immunogenic proteins remains an important task for life sciences as it nourishes the understanding of pathogenicity, illuminates new potential vaccine candidates and broadens the spectrum of biomarkers applicable in diagnostic tools. Traditionally, immunoscreenings of expression libraries via polyclonal sera on nitrocellulose membranes or screenings of whole proteome lysates in 2-D gel electrophoresis are performed. However, these methods feature some rather inconvenient disadvantages. Screening of expression libraries to expose novel antigens from bacteria often lead to an abundance of false positive signals owing to the high cross reactivity of polyclonal antibodies towards the proteins of the expression host. A method is presented that overcomes many disadvantages of the old procedures. RESULTS: Four proteins that have previously been described as immunogenic have successfully been assessed immunogenic abilities with our method. One protein with no known immunogenic behaviour before suggested potential immunogenicity.We incorporated a fusion tag prior to our genes of interest and attached the expressed fusion proteins covalently on microarrays. This enhances the specific binding of the proteins compared to nitrocellulose. Thus, it helps to reduce the number of false positives significantly. It enables us to screen for immunogenic proteins in a shorter time, with more samples and statistical reliability. We validated our method by employing several known genes from Campylobacter jejuni NCTC 11168. CONCLUSIONS: The method presented offers a new approach for screening of bacterial expression libraries to illuminate novel proteins with immunogenic features. It could provide a powerful and attractive alternative to existing methods and help to detect and identify vaccine candidates, biomarkers and potential virulence associated factors with immunogenic behaviour furthering the knowledge of virulence and pathogenicity of studied bacteria. PMID- 22436173 TI - The effect of obesity on spirometry tests among healthy non-smoking adults. AB - INTRODUCTION: The effects of obesity on pulmonary functions have not been addressed previously among Saudi population. We aim to study the effects of obesity on spirometry tests among healthy non-smoking adults. METHODS: A cross sectional study conducted among volunteers healthy non-smoking adults Subjects. We divided the subjects into two groups according to their BMI. The first group consisted of non-obese subjects with BMI of 18 to 24.9 kg/m2 and the second group consisted of obese subjects with BMI of 30 kg/m2 and above. Subjects underwent spirometry tests according to American thoracic society standards with measurement of the following values: the forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEF) and forced mid-expiratory flow (FEF25-75). RESULTS: The total subjects were 294 with a mean age of 32 years. There were 178 males and 116 females subjects. We found no significant differences in FEV1 (p value = 0.686), FVC (p value = 0.733), FEV1/FVC Ratio (p value = 0.197) and FEF25-75 (p value = 0.693) between the obese and non-obese subjects. However, there was significantly difference in PEF between the two groups (p value < 0.020). CONCLUSION: Obesity does not have effect on the spirometry tests (except PEF) among health non-smoking adults. We recommend searching for alternative diagnosis in case of findings abnormal spirometry tests results among obese subjects. PMID- 22436174 TI - Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance. AB - BACKGROUND: Life-threatening infections present major challenges for health systems in Malawi and the developing world because routine microbiologic culture and sensitivity testing are not performed due to lack of capacity. Use of empirical antimicrobial therapy without regular microbiologic surveillance is unable to provide adequate treatment in the face of emerging antimicrobial resistance. This study was conducted to determine antimicrobial susceptibility patterns in order to inform treatment choices and generate hospital-wide baseline data. METHODS: Culture and susceptibility testing was performed on various specimens from patients presenting with possible infectious diseases at Kamuzu Central Hospital, Lilongwe, Malawi. RESULTS: Between July 2006 and December 2007 3104 specimens from 2458 patients were evaluated, with 60.1% from the adult medical service. Common presentations were sepsis, meningitis, pneumonia and abscess. An etiologic agent was detected in 13% of patients. The most common organisms detected from blood cultures were Staphylococcus aureus, Escherichia coli, Salmonella species and Streptococcus pneumoniae, whereas Streptococcus pneumoniae and Cryptococcus neoformans were most frequently detected from cerebrospinal fluid. Haemophilus influenzae was rarely isolated. Resistance to commonly used antibiotics was observed in up to 80% of the isolates while antibiotics that were not commonly in use maintained susceptibility. CONCLUSIONS: There is widespread resistance to almost all of the antibiotics that are empirically used in Malawi. Antibiotics that have not been widely introduced in Malawi show better laboratory performance. Choices for empirical therapy in Malawi should be revised accordingly. A microbiologic surveillance system should be established and prudent use of antimicrobials promoted to improve patient care. PMID- 22436175 TI - Gene expression in Sinclair swine with malignant melanoma. AB - Sinclair swine develop an aggressive form of melanoma, which, in many cases, spontaneously regresses after a complete metastatic phase. We used Affymetrix GeneChip(r) Porcine Genome Arrays consisting of 24 123 probe sets to compare gene expression in white blood cells (WBCs) and various tissues including the liver, lungs, inguinal lymph nodes and spleen harvested from a Sinclair piglet afflicted by melanoma at birth and exhibiting metastatic lesions at weaning (6 weeks) with those from a full-sibling piglet that showed no incidence of melanoma at birth and weaning. The highest number (3489; ~14%) of significantly upregulated transcripts (fold change in gene expression >=2.0 and t-test P-value <=0.05) was observed in the liver, while the spleen exhibited the lowest number of upregulated transcripts (528; ~2%). Among significantly downregulated genes, the highest numbers were observed in the inguinal lymph nodes (3651; ~15%) and the least in WBCs (730; ~3%). Differentially expressed transcripts included genes involved in melanoma pathogenesis including SILV, TYR and RAB28. SILV was over expressed 784-, 430- and 164-fold, while TYR was over-expressed 138-, 81- and 28 fold in the liver, lungs and inguinal lymph nodes, respectively. Quantitative real-time RT-PCR (qRT-PCR) confirmed the microarray data of 12 selected differentially expressed sequences. These results suggest that significant changes in gene expression occur during metastasis of malignant melanoma in the Sinclair swine model. In addition, qRT-PCR analysis of the above 12 differentially expressed sequences was carried out on liver samples collected from 22 pigs (12 of which had melanoma during the first 6 weeks of life), and an ANOVA test contrasting absolute RNA expression between pigs with regressing, progressing and without tumors was significant for TYR, TACSTD1, MATP, GPNMB and CYP4A22, with P-values of 0.034, 0.015, 0.007, 0.050 and 0.022, respectively. PMID- 22436176 TI - A simple method for genomic selection of moderately sized dairy cattle populations. AB - An efficient algorithm for genomic selection of moderately sized populations based on single nucleotide polymorphism chip technology is described. A total of 995 Israeli Holstein bulls with genetic evaluations based on daughter records were genotyped for either the BovineSNP50 BeadChip or the BovineSNP50 v2 BeadChip. Milk, fat, protein, somatic cell score, female fertility, milk production persistency and herd-life were analyzed. The 400 markers with the greatest effects on each trait were first selected based on individual analysis of each marker with the genetic evaluations of the bulls as the dependent variable. The effects of all 400 markers were estimated jointly using a 'cow model,' estimated from the data truncated to exclude lactations with freshening dates after September 2006. Genotype probabilities for each locus were computed for all animals with missing genotypes. In Method I, genetic evaluations were computed by analysis of the truncated data set with the sum of the marker effects subtracted from each record. Genomic estimated breeding values for the young bulls with genotypes, but without daughter records, were then computed as their parent averages combined with the sum of each animal's marker effects. Method II genomic breeding values were computed based on regressions of estimated breeding values of bulls with daughter record on their parent averages, sum of marker effects and birth year. Method II correlations of the current breeding values of young bulls without daughter records in the truncated data set were higher than the correlations of the current breeding values with the parent averages for fat and protein production, persistency and herd-life. Bias of evaluations, estimated as a difference between the mean of current breeding values of the young bulls and their genomic evaluations, was reduced for milk production traits, persistency and herd-life. Bias for milk production traits was slightly negative, as opposed to the positive bias of parent averages. Correlations of Method II with the means of daughter records adjusted for fixed effects were higher than parent averages for fat, protein, fertility, persistency and herd-life. Reducing the number of markers included in the analysis from 400 to 300 did not reduce correlations of genomic breeding values for protein with current breeding values, but did slightly reduce correlations with means of daughter records. Method II has the advantages as compared with the method of VanRaden in that genotypes of cows can be readily incorporated into the Method II analysis, and it is more effective for moderately sized populations. PMID- 22436177 TI - Assessing priorities for conservation in Tuscan cattle breeds using microsatellites. AB - Preservation of rare genetic stocks requires assessment of within-population genetic diversity and between-population differentiation to make inferences on their degree of uniqueness. A total of 194 Tuscan cattle (44 Calvana, 35 Chianina, 25 Garfagnina, 31 Maremmana, 31 Mucca Pisana and 28 Pontremolese) individuals were genotyped for 34 microsatellite markers. Moreover, 56 samples belonging to Argentinean Creole and Asturiana de la Montana cattle breeds were used as an outgroup. Genetic diversity was quantified in terms of molecular coancestry and allelic richness. STRUCTURE analyses showed that the Tuscan breeds have well-differentiated genetic backgrounds, except for the Calvana and Chianina breeds, which share the same genetic ancestry. The between-breed Nei's minimum distance (Dm) matrices showed that the pair Calvana-Chianina was less differentiated (0.049 +/- 0.006). The endangered Tuscan breeds (Calvana, Garfagnina, Mucca Pisana and Pontremolese) made null or negative contributions to diversity, except for the Mucca Pisana contribution to allelic richness (CT = 1.8%). The Calvana breed made null or negative within-breed contributions (W = 0.0%; CW = -0.4%). The Garfagnina and Pontremolese breeds made positive contributions to between-breed diversity but negative and high within-breed contributions, thus suggesting population bottleneck with allelic losses and increase of homozygosity in the population. Exclusion of the four endangered Tuscan cattle breeds did not result in losses in genetic diversity (T = -0.7%; CT = -1.2%), whereas exclusion of the non-endangered breeds (Chianina and Maremmana) did (T = 2.1%; CT = 3.9%); the simple exclusion of the Calvana breed from the former group led to losses in genetic diversity (T = 0.47%; CT = 2.34%), indicating a diverse significance for this breed. We showed how quantifying both within-population diversity and between-population differentiation in terms of allelic frequencies and allelic richness provides different and complementary information on the genetic backgrounds assessed and may help to implement priorities and strategies for conservation in livestock. PMID- 22436178 TI - Random regression analyses using B-spline functions to model growth of Nellore cattle. AB - The objective of this study was to estimate (co)variance components using random regression on B-spline functions to weight records obtained from birth to adulthood. A total of 82 064 weight records of 8145 females obtained from the data bank of the Nellore Breeding Program (PMGRN/Nellore Brazil) which started in 1987, were used. The models included direct additive and maternal genetic effects and animal and maternal permanent environmental effects as random. Contemporary group and dam age at calving (linear and quadratic effect) were included as fixed effects, and orthogonal Legendre polynomials of age (cubic regression) were considered as random covariate. The random effects were modeled using B-spline functions considering linear, quadratic and cubic polynomials for each individual segment. Residual variances were grouped in five age classes. Direct additive genetic and animal permanent environmental effects were modeled using up to seven knots (six segments). A single segment with two knots at the end points of the curve was used for the estimation of maternal genetic and maternal permanent environmental effects. A total of 15 models were studied, with the number of parameters ranging from 17 to 81. The models that used B-splines were compared with multi-trait analyses with nine weight traits and to a random regression model that used orthogonal Legendre polynomials. A model fitting quadratic B splines, with four knots or three segments for direct additive genetic effect and animal permanent environmental effect and two knots for maternal additive genetic effect and maternal permanent environmental effect, was the most appropriate and parsimonious model to describe the covariance structure of the data. Selection for higher weight, such as at young ages, should be performed taking into account an increase in mature cow weight. Particularly, this is important in most of Nellore beef cattle production systems, where the cow herd is maintained on range conditions. There is limited modification of the growth curve of Nellore cattle with respect to the aim of selecting them for rapid growth at young ages while maintaining constant adult weight. PMID- 22436179 TI - Fe bioavailability from Fe-enriched yeast biomass in growing rats. AB - The Fe content in animal feeds is highly variable. The availability of Fe in feeds varies with the feed and the form in which Fe is present. The present study reports the effect of the addition of different concentrations of Fe from yeast biomass on Fe bioavailability and Fe level in rat liver, compared with a diet containing Fe-sulphate (Fe-sulphate) addition (control) and with a diet without any addition of Fe. Male Wistar rats were fed ad libitum for 10 days a diet with different levels of Fe-enriched yeast biomass (20, 35 and 50 mg of Fe), or Fe sulphate diet (50 mg of Fe) or without Fe addition. Faeces and urine were collected for Fe analyses during the last 5 days of the test period. The results clearly showed a highly significant (P < 0.001) better bioavailability of Fe from Fe-enriched yeast biomass, independent of the level of Fe in the diet. This was on average 36% higher than the availability of Fe from the Fe-sulphate-enriched diet. Liver Fe storage depended on the level of Fe in the diet from yeast biomass. A significantly lower amount of Fe was found to be incorporated in the liver in the group with an inorganic source of Fe (Fe-sulphate) in the diet. PMID- 22436180 TI - Apparent digestibility of wheat bran and extruded flax in horses determined from the total collection of feces and acid-insoluble ash as an internal marker. AB - Several studies have reported data on comparisons between two methods: the total collection of feces and the internal markers method. The aim of this study was to assess the apparent digestibility of two concentrates and to compare the apparent digestion coefficients using the total collection of feces and acid-insoluble ash (AIA) as the internal marker method. In 2009, six adult geldings aged between 3 and 11 years, with an average weight per trial of 543, 540 and 542 kg, respectively, were used to determine the apparent digestibility by means of three in vivo digestibility trials on hay, hay plus wheat bran (60 : 40) and hay plus extruded flax (80 : 20). Feces were collected over a 6-day period with a previous 14-day adaptation period. The three digestibility trials were carried out to determine the digestion coefficients of the three diets and, indirectly, of the two concentrates. The digestion coefficients of the diets were determined for the dry matter, organic matter, crude protein and gross energy, whereas the apparent digestion coefficients of the same parameters were calculated for wheat bran and extruded flax, by calculating the difference from the previous results. The data were analyzed using the Student t-test for paired samples. The digestion coefficients obtained were similar when the total collection of feces and the AIA method were used. Higher data variability, confirmed by a greater standard deviation, was observed using the AIA method to estimate the apparent digestion coefficients. It can be concluded that the use of AIA as an internal marker in digestibility trials on average leads to values similar to those obtained with the total collection of feces and can therefore be considered a less-expensive method to determine apparent digestion coefficients. Nevertheless, the total collection of feces should still be considered the best choice to determine the digestibility of some specific feedstuffs. PMID- 22436181 TI - N-alkanes v. ytterbium/faecal index as two methods for estimating herbage intake of dairy cows fed on diets differing in the herbage: maize silage ratio and feeding level. AB - The aim of this study was to compare the n-alkanes and the ytterbium (Yb)/faecal index techniques as two methods for estimating the herbage intake of dairy cows fed indoors on different herbage : supplement ratios and feeding levels. The supplement was a mixture of maize silage and soyabean meal (ratio of 87 : 13 on a dry matter (DM) basis). In all, four treatments were studied. The herbage : supplement ratio in the diet was 25 : 75, 50 : 50, 75 : 25 and 50 : 50 for treatments 1, 2, 3 and 4, respectively. Animals were offered for treatments 1, 2 and 3, 100% of ad libitum intake measured before the experiment and 70% of ad libitum intake for treatment 4. Cows were fed herbage in the morning and supplement in the evening. A total of six lactating Holstein dairy cows were used in a 4 * 4 Latin square with four 14-day periods. Herbage and supplement intakes, faecal output (FO), in vivo organic matter (OM) digestibility and faecal recovery of markers were measured on the last 5 days of each period. Intake was estimated with the two methods and from two faecal sampling techniques, that is, total faecal collection v. grab sampling during milking. Mean herbage intake as fed, or estimated from n-alkanes or from the Yb/faecal index was 7.7, 8.1 and 10.2 kg DM, respectively. The mean prediction error, expressed as a fraction of actual herbage intake, was 0.10 and 0.50 for the n-alkanes and Yb/faecal index methods, respectively. The n-alkanes method clearly showed much better accuracy than the Yb/faecal index method for estimating intake, irrespective of the faecal sampling method, herbage : silage proportion or feeding level. For the n-alkanes method, herbage intake was slightly overestimated (7%) when herbage proportion in the diet was high, due to a ratio of faecal C33 : C32 recovery >1. The high bias for the Yb/faecal index was due to the cumulative effect of overestimation of FO (mean recovery of Yb = 0.92) and underestimation of the diet indigestible fraction (-8%). Between-treatment variations of FO were on average well estimated by Yb. Between-treatment variations of OM digestibility estimated using the faecal index technique were lower than those observed in vivo. It is concluded that intake of grazing dairy cows receiving high levels of maize silage supplement should be estimated using the n-alkanes method. PMID- 22436182 TI - Effects of condensed tannins in wrapped silage bales of sainfoin (Onobrychis viciifolia) on in vivo and in situ digestion in sheep. AB - The objective of this study was to characterize the condensed tannins (CTs) in wrapped silage bales of sainfoin (Onobrychis viciifolia) and examine their potential action on in vivo and in situ digestive characteristics in sheep. Silage was made from sainfoin, cut at two phenological stages. The first phenological stage, at which silage was made, was from the first vegetation cycle at the end of flowering and the second stage silage was made from regrowth, 5 weeks after the first cut, but before flowering. The silages made from the two phenological stages were fed to 12 rumen-fistulated sheep in a crossover design. Of the 12 sheep, six received polyethylene glycol (PEG) to bind with and remove the effects of CT, whereas the other six were dosed with water. Organic matter digestibility, total-tract N digestibility and N (N) balance were measured over 6 days. Kinetic studies were performed on total N, ammonia N (NH3-N) and volatile fatty acids (VFAs) in rumen fluid before and 1.5, 3 and 6 h after feeding. The kinetics of degradation of dry matter and N from Dacron bags suspended in the rumen were also determined. Biological activity of CT (protein-binding capacity) and CT concentration were greater for the silage made from sainfoin at the early flowering stage. Total-tract N digestibility was increased by the addition of PEG (P < 0.001) to the sainfoin silage before flowering (P < 0.001). CTs decreased N excretion in urine (P < 0.05) and increased faecal N excretion (P < 0.001), but had no effect on body N retention, which is beneficial for the animal. Ruminal N degradability was smaller in the presence of active CT (P < 0.001) at both phenological stages; however, soluble N (P = 0.2060) and NH3-N (P = 0.5225) concentrations in rumen fluid remained unchanged. The results of this experiment indicate that CT in the sainfoin retain their ability to affect the nutritive value of preserved forage legumes. PMID- 22436183 TI - Metabolic regulation of fatty acid esterification and effects of conjugated linoleic acid on glucose homeostasis in pig hepatocytes. AB - Conjugated linoleic acids (CLAs) are geometric and positional isomers of linoleic acid (LA) that promote growth, alter glucose metabolism and decrease body fat in growing animals, although the mechanisms are poorly understood. A study was conducted to elucidate the effects of CLA on glucose metabolism, triglyceride (TG) synthesis and IGF-1 synthesis in primary culture of porcine hepatocytes. In addition, hormonal regulation of TG and IGF-1 synthesis was addressed. Hepatocytes were isolated from piglets (n = 5, 16.0 +/- 1.98 kg average body weight) by collagenase perfusion and seeded into collagen-coated T-25 flasks. Hepatocytes were cultured in William's E containing dexamethasone (10-8 and 10-7 M), insulin (10 and 100 ng/ml), glucagon (0 and 100 ng/ml) and CLA (1 : 1 mixture of cis-9, trans-11 and trans-10, cis-12 CLA, 0.05 and 0.10 mM) or LA (0.05 and 0.10 mM). Addition of CLA decreased gluconeogenesis (P < 0.05), whereas glycogen synthesis and degradation, TG synthesis and IGF-1 synthesis were not affected compared with LA. Increased concentration of fatty acids in the media decreased IGF-1 production (P < 0.001) and glycogen synthesis (P < 0.01), and increased gluconeogenesis (P < 0.001) and TG synthesis (P < 0.001). IGF-1 synthesis increased (P < 0.001) and TG synthesis decreased (P < 0.001) as dexamethasone concentration in the media rose. High insulin/glucagon increased TG synthesis. These results indicate that TG synthesis in porcine hepatocytes is hormonally regulated so that dexamethasone decreases and insulin/glucagon increases it. In addition, CLA decreases hepatic glucose production through decreased gluconeogenesis. PMID- 22436184 TI - Linoleic and alpha-linolenic acid as precursor and inhibitor for the synthesis of long-chain polyunsaturated fatty acids in liver and brain of growing pigs. AB - Studies suggested that in human adults, linoleic acid (LA) inhibits the biosynthesis of n-3 long-chain polyunsaturated fatty acids (LC-PUFA), but their effects in growing subjects are largely unknown. We used growing pigs as a model to investigate whether high LA intake affects the conversion of n-3 LC-PUFA by determining fatty acid composition and mRNA levels of Delta5- and Delta6 desaturase and elongase 2 and -5 in liver and brain. In a 2 * 2 factorial arrangement, 32 gilts from eight litters were assigned to one of the four dietary treatments, varying in LA and alpha-linolenic acid (ALA) intakes. Low ALA and LA intakes were 0.15 and 1.31, and high ALA and LA intakes were 1.48 and 2.65 g/kg BW0.75 per day, respectively. LA intake increased arachidonic acid (ARA) in liver. ALA intake increased eicosapentaenoic acid (EPA) concentrations, but decreased docosahexaenoic acid (DHA) (all P < 0.01) in liver. Competition between the n-3 and n-6 LC-PUFA biosynthetic pathways was evidenced by reductions of ARA (>40%) at high ALA intakes. Concentration of EPA (>35%) and DHA (>20%) was decreased by high LA intake (all P < 0.001). Liver mRNA levels of Delta5- and Delta6 desaturase were increased by LA, and that of elongase 2 by both ALA and LA intakes. In contrast, brain DHA was virtually unaffected by dietary LA and ALA. Generally, dietary LA inhibited the biosynthesis of n-3 LC-PUFA in liver. ALA strongly affects the conversion of both hepatic n-3 and n-6 LC-PUFA. DHA levels in brain were irresponsive to these diets. Apart from Delta6 desaturase, elongase 2 may be a rate-limiting enzyme in the formation of DHA. PMID- 22436185 TI - Expression and activities of hepatic cytochrome P450 (CYP1A, CYP2A and CYP2E1) in entire and castrated male pigs. AB - This study aimed to provide further insights into the mechanism of in vivo regulation of cytochrome P450 (CYP450) 1A, 2A and 2E1 activities in pigs with different levels of testicular steroids. Hepatic mRNA and protein expression and enzymatic activity of CYP1A, CYP2A and CYP2E1 were compared between entire male and castrated pigs. Castration was performed either surgically or immunologically. The pigs were divided into four groups. In the first group, piglets were surgically castrated without anaesthesia. Immunological castration was performed by vaccination with Improvac(r) (Pfizer Ltd). Vaccinated pigs were subdivided into two groups according to the vaccination regimen: early and standard vaccination. Pigs in the early vaccination group were vaccinated when aged 11 and 15 weeks. Pigs in the standard vaccination group were vaccinated when aged 17 and 21 weeks. In the control group, pigs remained intact throughout the study. Hepatic CYP450 mRNA expression, measured by real-time RT-PCR, differed significantly between groups for all isoforms measured: CYP1A2 (P = 0.002), 2A (P = 0.000) and 2E1 (P = 0.002). Lower CYP450 mRNA in entire male pigs suggests suppression of CYP1A2, CYP2A and CYP2E1 by testicular steroids at the transcriptional level. However, this suppression was not always reflected in decreased protein expression and activities of these isoforms, suggesting that at least some CYP450s (e.g. CYP2E1) are regulated by a post-transcriptional mechanism. PMID- 22436186 TI - Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers. AB - The effects of mycotoxins in the production of animal feed were investigated using broiler chickens. For the feeding trial, naturally Fusarium mycotoxin contaminated wheat was used, which mainly contained deoxynivalenol (DON). The main effects of DON are reduction of the feed intake and reduced weight gain of broilers. At the molecular level, DON binds to the 60 S ribosomal subunit and subsequently inhibits protein synthesis at the translational level. However, little is known about other effects of DON, for example, at the transcriptional level. Therefore, a microarray analysis was performed, which allows the investigation of thousands of transcripts in one experiment. In the experiment, 20 broilers were separated into four groups of five broilers each at day 1 after hatching. The diets consisted of a control diet and three diets with calculated, moderate concentrations of 1.0, 2.5 and 5.0 mg DON/kg feed, which was attained by exchanging uncontaminated wheat with naturally mycotoxin-contaminated wheat up to the intended DON concentration. The broilers were held at standard conditions for 23 days. Three microarrays were used per group to determine the significant alterations of the gene expression in the liver (P < 0.05), and qPCR was performed on the liver and the jejunum to verify the results. No significant difference in BW, feed intake or feed conversion rate was observed. The nutrient uptake into the hepatic and jejunal cells seemed to be influenced by genes: SLC2A5 (fc: -1.54, DON2.5), which facilitates glucose and fructose transport and SLC7A10 (fc: +1.49, DON5), a transporter of d-serine and other neutral amino acids. In the jejunum, the palmitate transport might be altered by SLC27A4 (fc: 1.87, DON5) and monocarboxylates uptake by SLC16A1 (fc: -1.47, DON5). The alterations of the SLC gene expression may explain the reduced weight gain of broilers chronically exposed to DON-contaminated wheat. The decreased expressions of EIF2AK3 (fc: -1.29, DON2.5/5) and DNAJC3 (fc: -1.44, DON2.5) seem to be related to the translation inhibition. The binding of DON to the 60 S ribosomal subunit and the subsequent translation inhibition might be counterbalanced by the downregulation of EIF2AK3 and DNAJC3. The genes PARP1, MPG, EME1, XPAC, RIF1 and CHAF1B are mainly related to single-strand DNA modifications and showed an increased expression in the group with 5 mg DON/kg feed. The results indicate that significantly altered gene expression was already occurring at 2.5 mg DON/kg feed. PMID- 22436187 TI - Nutritional regulation of body condition score at the initiation of the transition period in primiparous and multiparous dairy cows under grazing conditions: milk production, resumption of post-partum ovarian cyclicity and metabolic parameters. AB - The objective of this study was to investigate the effect of different body condition score (BCS) at 30 days before calving (-30 days) induced by a differential nutritional management from -100 days until -30 days on productive parameters, the interval to first ovulation and blood parameters in primiparous and multiparous Holstein cows under grazing conditions until 60 days post partum. The experimental arrangement was a randomized complete block design, where cows were blocked according to BW and expected calving date and then randomly assigned to different nutritional treatments from -100 to -30 days relative to calving to induce different BCS. As the assignment of cows to treatments was random, cows had to lose, maintain or gain BCS; thus, different planes of nutrition were offered with approximately 7, 14 or 20 kg dry matter per day. The BCS score was assessed every 15 days and animals were reassigned in order to achieve the desired BCS at -30 days. Only animals that responded to nutritional treatment were considered and this was defined as follows: primiparous and multiparous high cows (PH and MH) had to gain 0.5 points of BCS, primiparous low (PL) had to lose 0.5 points of BCS and multiparous low (ML) had to maintain BCS at least in two subsequent observations from -100 to -30 days. From -30 days to calving, primiparous and multiparous cows (P and M cows) were managed separately and cows were offered a diet once a day. From calving to 60 days post partum, cows of different groups grazed in separate plots a second year pasture. Cows were also supplemented individually with whole-plant maize silage and commercial concentrate. Cows had similar BCS at -100 days and differed after the nutritional treatment; however, all groups presented similar BCS at 21 days post partum. The daily milk production and milk yield at 60 days post partum was higher in M than P cows. The percentage of milk fat was higher in PH cows compared with PL cows. Concentrations of non-esterified fatty acids (NEFA) were affected by the BCS at 30 days within parity, and in PH cows the concentration of NEFA was higher than in PL cows. The concentrations of total protein were higher in M cows. A lower probability of cycling was found in PL than in PH cows (P < 0.05) and in ML than in MH cows (P < 0.05). Treatment affected various endocrine/metabolic profiles according to parity, suggesting that the metabolic reserves signal the productive/reproductive axis so as to induce a differential nutrient partitioning in adult v. first-calving cows. PMID- 22436188 TI - Effects of propylene glycol drenching before and after luteolysis on blood glucose, ovarian steroids and follicular dynamics in heifers. AB - The effect of propylene glycol drenching on ovarian and hormonal dynamics was studied in heifers. Five cycling heifers were used twice (as control and treatment) with crossover design. After the confirmation of ovulation (day 0), the heifers in the treatment group received propylene glycol on days 6, 7 and 8 as an oral drench (250 ml of 90% propylene glycol). On day 10, prostaglandin F2alpha (PGF2alpha), 15 mg per head of dinoprost, was administered intramuscularly to induce luteal regression followed by the follicular phase and then propylene glycol was again administered twice daily (500 ml/day) on days 10, 11 and 12. Palpation per rectum and ovarian ultrasonography were performed every other day from days 0 to 10, and daily after PGF2alpha administration until the subsequent ovulation (second ovulation) for analysis of follicular and luteal dynamics. Blood samples were also collected every other day from days 0 to 10, and then at 6 h intervals after PGF2alpha administration until the second ovulation. For the samples taken at 6-h intervals after PGF2alpha administration, the concentrations of glucose showed clear daily fluctuations in both groups. Changes in the plasma concentration of glucose in the treatment group were significantly (P < 0.05) higher than those of the control groups during the period between 0 and 72 h after PGF2alpha administration. No significant difference was detected in the growth of dominant follicles, maximum diameter of the ovulatory follicles and the changes in oestradiol and progesterone during the follicular phase between treatment and control groups. This study showed the clear daily fluctuations and stimulatory changes in the blood glucose concentrations at 24-h intervals during the short-term treatment of propylene glycol drenching in heifers. However, no significant changes in ovarian and hormonal dynamics were found under such metabolic conditions. PMID- 22436189 TI - Evaluation of chronic immune system stimulation models in growing pigs. AB - Two experiments (EXPs) were conducted to evaluate models of immune system stimulation (ISS) that can be used in nutrient metabolism studies in growing pigs. In EXP I, the pig's immune response to three non-pathogenic immunogens was evaluated, whereas in EXP II the pig's more general response to one of the immunogens was contrasted with observations on non-ISS pigs. In EXP I, nine growing barrows were fitted with a jugular catheter, and after recovery assigned to one of three treatments. Three immunogens were tested during a 10-day ISS period: (i) repeated injection of increasing amounts of Escherichia coli lipopolysaccharide (LPS); (ii) repeated subcutaneous injection of turpentine (TURP); and (iii) feeding grains naturally contaminated with mycotoxins (MYCO). In EXP II, 36 growing barrows were injected repeatedly with either saline (n = 12) or increasing amounts of LPS (n = 24) for 7 days (initial dose 60 MUg/kg body weight). Treating pigs with TURP and LPS reduced feed intake (P < 0.02), whereas feed intake was not reduced in pigs on MYCO. Average daily gain (ADG; kg/day) of pigs on LPS (0.50) was higher than that of pigs on TURP (0.19), but lower than that of pigs on MYCO (0.61; P < 0.01). Body temperature was elevated in pigs on LPS and TURP, by 0.8 degrees C and 0.7 degrees C, respectively, relative to pre ISS challenge values (39.3 degrees C; P < 0.02), but remained unchanged in pigs on MYCO. Plasma concentrations of interleukin-1beta were increased in pigs treated with LPS and TURP (56% and 55%, respectively, relative to 22.3 pg/ml for pre-ISS; P < 0.01), but not in MYCO-treated pigs. Plasma cortisol concentrations remained unchanged for pigs on MYCO and TURP, but were reduced in LPS-treated pigs (30% relative to 29.8 ng/ml for pre-ISS; P < 0.05). Red blood cell glutathione concentrations were lower in TURP-treated pigs (13% relative to 1.38 MUM for pre-ISS; P < 0.05), but were unaffected in pigs on LPS and MYCO. In EXP I, TURP caused severe responses including skin ulceration and substantial reductions in feed intake and ADG, whereas MYCO did not induce effective ISS. In EXP II, ISS increased relative organ weights, eye temperature, white blood cell count and plasma acute-phase proteins (P < 0.05), confirming that repeated injection with increasing amounts of LPS induced chronic and relatively mild ISS. Repeated injection with increasing amounts of LPS is a suitable model for studying nutrient metabolism and evaluating the efficacy of nutritional intervention during chronic ISS in growing pigs. PMID- 22436190 TI - Coronary angiography and percutaneous coronary intervention in the porcine model: a practical guide to the procedure. AB - Assessment of safety and efficacy within the porcine coronary artery model remains a standard requirement for new therapies delivered to the coronary arteries before proceeding to clinical testing. Human coronary procedures carry a very low mortality rate; however, procedural mortality for porcine experiments is often high, despite these animals being young and free of atherosclerosis. Some of these deaths are due to poor technique, and therefore avoidable. However, despite the wide use of this model, a systematic description of the procedure has never been published. This article will detail how porcine angiography and stent implantation is performed in our institution and will discuss the relevant differences between humans and pigs with regard to anaesthesia, pharmacotherapy, vascular access, catheter selection and angiographic views. Important variations to the technique that have been reported are also covered. PMID- 22436191 TI - Longitudinal analysis of acute-phase proteins in saliva in pig farms with different health status. AB - This study assesses the utility of saliva samples to monitor the time course of the acute-phase response to different viruses in pigs under field conditions by using time-resolved immunofluorometric assays (TR-IFMA). A total of 30 pigs from three different farms, located in Southeast Spain, were used. Farm 1 had outbreaks of porcine circovirus type 2, farm 2 had infections with porcine reproductive and respiratory syndrome virus and farm 3 had concomitant infections with both viruses. Serology was used to determine the time of seroconversion of pigs to two different pathogens. The levels of two acute-phase proteins (APPs), C reactive protein (CRP) and haptoglobin (Hp), were measured in saliva and serum samples and compared with pig's serology. Kinetic curves of both APPs across the study obtained in saliva samples were similar to those of serum, with R of 0.68 and 0.78 for CRP and Hp, respectively. The median CRP and Hp concentrations in saliva were higher around the theorized time of infection, according to previous experimental studies, and at seroconversion of animals. CRP increments were apparent 1 week before the increments obtained in Hp. These findings indicate that salivary APP concentrations, by using TR-IFMA, can be used in longitudinal studies as non-invasive early indicators of health status. PMID- 22436192 TI - Factors in pig production that impact the quality of dry-cured ham: a review. AB - This study reviews the factors of pig production that impact the quality of dry cured ham. When processing is standardized, the quality of the final dry-cured product is primarily determined by the quality of the meat before curing (green ham). This has been defined as the aptitude for seasoning and is determined by the green ham weight, adipose tissue quantity and quality, meat physico-chemical properties and the absence of visual defects. Various ante-mortem factors including pig age and weight, genetic type, diet, feeding strategy and slaughter conditions determine green ham properties such as the dynamics of water loss, salt intake and, as a consequence, proteolysis and lipolysis. Muscle conditions (pH, salt concentration, water content and availability, temperature) influence enzymatic activity and development of characteristic texture and flavor. Generally, hams of older and heavier pigs present better seasoning aptitude because of higher adiposity. Adiposity is also positively correlated with fat saturation, which is desired to avoid rancidity and oiliness. The fatty acid profile of tissue lipids can be manipulated by diet composition. Feeding strategy affects tissue accretion and protein turnover, thus directly impacting proteolysis. With respect to the impact of pig genotype on dry-cured ham quality, local breeds are generally considered more suitable for producing quality dry hams; however, the majority of dry-cured hams on the market today are from modern pig breeds raised in conventional systems, providing lean hams. The importance of all these factors of pig production is discussed and synthesized, with an emphasis on the main difficulties encountered in dry-cured ham production. PMID- 22436193 TI - Probiotics in milk replacer influence lamb immune function and meat quality. AB - This study was undertaken to assess the effect of milk replacer (MR) containing Lactobacillus acidophilus and a mix of Bifidobacterium animalis subsp. lactis and Bifidobacterium longum subsp. longum on lamb immune response and on lamb meat quality. A 6-week-trial was conducted on 40 male Comisana lambs, divided into four groups, fed maternal milk (MM), MR, MR with L. acidophilus supplementation (MRL) and MR with a mix (1 : 1) of B. animalis subsp. lactis and B. longum subsp. longum supplementations (MRB). Lambs fed MR containing a mix of bifidobacteria showed the highest in vivo cellular immune response to phytohemagglutinin, whereas MM and MRB showed the highest antibody response to ovalbumin. At day 11 of the trial, MRL displayed the highest value of Interleukin-10; differences disappeared among groups subsequently. Blood cholesterol levels in lambs fed MR containing L. acidophilus was almost halved compared with that found in MM and MR groups. Meat from artificially reared lambs was characterized by trans-11 18:1 and total conjugated 18:2n-6, whereas meat from the dam-suckled lambs was characterized by 14:0, cis-9 14:1 and 16:0. Polyunsaturated to saturated fatty acid ratio was higher in meat of MR, MRL and MRB than in MM lambs. Meat from artificially reared lamb fed MR containing probiotics showed an improved fatty acid profile for human diet. PMID- 22436194 TI - Mitochondrial respiratory and antioxidative enzyme activities in turkey meat. AB - Meat quality and (anti)oxidative metabolism of m. pectoralis superficialis (MPS), m. gastrocnemius (MG) and m. iliotibilialis lateralis (MIL) from turkey toms were analysed. After slaughter, pH of MPS and MG decreased and electrical conductivity of the MPS increased. The MG had generally higher pH values. The meat lightness (L) and redness (a) increased in MG and MPS after slaughter. The MPS always had higher L and lower a values. Mitochondrial respiratory activities (MRA) were higher in the MIL than the MPS. The activities of superoxide dismutase (SOD) and glutathione peroxidase, analysed in the MPS, increased and the glutathione reductase activity decreased after slaughter. Meat samples with lower pH24 h p.m. had higher drip loss and L values. The MRA were tendentially lower and the SOD activities higher in these samples. These results indicate a relation between the meat quality, the antioxidative metabolism and mitochondrial respiration. PMID- 22436195 TI - Access to and use of unauthorised online HIV self-tests by internet-using French speaking men who have sex with men. AB - OBJECTIVES: Although not authorised in France, HIV self-tests are easily available online. The authors questioned French-speaking internet-using men who have sex with men (MSM) concerning their access to and use of such tests. METHODS: Online questionnaire on sex websites and gay and HIV community websites. A multivariate logistic regression for rare events was used to identify factors associated with accessing self-tests. RESULTS: 9169 MSM completed the questionnaire. 2748 (30%) were aware of online self-tests, but only 82 of those aware and not already HIV positive (3.5%) declared having accessed one and only 69 using it. In the multivariate model, living one's sex-life with men in absolute secrecy (odds ratio (OR)=3.90, 95% CI 1.73 to 8.76), knowing of the tests via a sex partner (OR=3.42, CI 1.39 to 8.41) or an internet search engine (OR=2.18, CI 1.26 to 3.74) but not through the general (OR=0.21, CI 0.11 to 0.42) or the gay press (OR=0.34, CI 0.16 to 0.73), having unprotected anal intercourse with a casual partner in the preceding year (OR=1.90, CI 1.17 to 3.06), using self-tests for other diseases (OR=2.66, CI 1.43 to 4.90), using poppers (OR=2.23, CI 1.35 to 3.67) and doping products (OR=3.53, CI 1.55 to 8) in the preceding year, having done a traditional HIV test but not in the preceding year (OR=1.93, CI 1.14 to 3.32), never having had suicidal thoughts (OR=0.54, CI 0.32 to 0.90) and living in the provinces (OR=1.80, CI 1.01 to 3.25) were all independently associated with accessing self-tests. CONCLUSIONS: Although readiness to admit use of unauthorised medical products may have influenced results, few MSM aware of the existence of self-tests actually declared having accessed one. Accessing the self-test was independently associated with both living one's sex-life with men in total secrecy and having had unprotected anal intercourse in the last 12 months, indicating that autonomous self-testing may reduce barriers to testing for this vulnerable population. PMID- 22436196 TI - College students' condom use errors: who is experiencing breaking and slipping? PMID- 22436197 TI - Health inequalities among sexual minority youth: a need for sexual orientation and gender expression sensitive school environment. PMID- 22436198 TI - Pregnancy and contraceptive use among women participating in an HIV prevention trial in Tanzania. AB - OBJECTIVES: Information on pregnancy rates and factors associated with pregnancy and contraceptive use is important for clinical trials in women in sub-Saharan Africa where withdrawal of investigational products may be required in the event of pregnancy with a consequent effect on sample size and trial power. METHODS: A prospective cohort analysis of pregnancy and contraceptive use was conducted in Tanzanian women enrolled in a randomised placebo-controlled trial of herpes simplex virus-suppressive therapy with acyclovir to measure the effect on HIV incidence in HIV-negative women and on genital and plasma HIV viral load in HIV positive women. The cohort was followed every 3 months for 12-30 months. Women at each visit were categorised into users or non-users of contraception. Pregnancy rates and factors associated with pregnancy incidence and contraceptive use were measured. RESULTS: Overall 254 of 1305 enrolled women became pregnant at least once during follow-up (pregnancy rate: 12.0/100 person-years). Younger age, being unmarried, higher baseline parity and changes in contraceptive method during follow-up were independently associated with pregnancy. Having paid sex and being HIV positive were associated with lower risk of pregnancy. Uptake of contraception was associated with young age, being unmarried, occupation, parity and the number and type of sexual partners. CONCLUSIONS: Data on use of contraceptive methods and risk factors for pregnancy can help to guide decisions on trial eligibility and the need for additional counselling. Mandatory reliable contraceptive use in study participants may be required to reduce pregnancy rates in studies where pregnancy is contraindicated. PMID- 22436199 TI - Sex work and the public health impacts of the 2010 Olympic Games. AB - OBJECTIVES: The authors examined the impact of exposure to the 2010 Winter Olympics time period on outcomes measuring disruption of local sex work environments in Vancouver, Canada. METHODS: The authors conducted a before-and after study, using multivariable logistic regression, to assess the relationship between exposure to the Olympics period (19 January-14 March 2010) versus the post-Olympics period (1 April-1 July 2010) and outcomes. RESULTS: This study included 207 youth (14+ years) and adult sex workers (SWs) (Olympics: n=107; post Olympics: n=100). SWs in the two periods were statistically similar, with an overall median age of 33 years (IQR: 28-40), and 106 (51.2%) of indigenous ancestry or ethnic minority. In separate multivariable logistic regression models, the Olympics period remained statistically significantly associated with perceived heightened police harassment of SWs without arrest (adjusted ORs (AOR): 3.95, 95% CIs 1.92 to 8.14), decreased availability of clients (AOR: 1.97, 95% CIs 1.11 to 3.48) and increased difficulty meeting clients due to road closures/construction (AOR: 7.68, 95% CIs 2.46 to 23.98). There were no significantly increased odds in perceived reports of new (0.999), youth (0.536) or trafficked SWs (zero reports) in the Olympic period. CONCLUSIONS: To reduce potential adverse public health impacts of enhanced police harassment and displacement of local sex work markets, results suggest that evidence-based public health strategies need to be adopted for host cities of future events (eg, the London 2012 Olympic Games), such as the removal of criminal sanctions targeting sex work and the piloting and rigorous evaluation of safer indoor work spaces. PMID- 22436200 TI - Periconceptional changes in thyroid function: a longitudinal study. AB - BACKGROUND: Limitations in our current knowledge of normative physiologic changes in thyroid function during the periconception window narrow our ability to establish an optimal approach to screening and diagnosis of thyroid disease in pregnant women. The objective of this study was to characterize changes in thyroid function during the transition from the pre-pregnant to pregnant state in normal fertile women. METHODS: Women (N = 60) ages 30-42 years without a history of thyroid disease, who were planning pregnancy, were observed prospectively before and during early pregnancy. Thyroid function (thyroid stimulating hormone, TSH and free thyroxine, FT4) was measured before conception and between 6 and 9 weeks gestation. Pre-pregnancy samples were analyzed for thyroid antibodies. Bivariate analyses and longitudinal curves (general estimating equation models) were used to analyze changes in thyroid function during the periconception window by antibody status. RESULTS: Pre-pregnancy TSH values were significantly higher than early pregnancy TSH (p < 0.001), but FT4 values did not differ (p = 0.53). TSH declined as gestational age increased (P < 0.01). Thyroid antibody positive women had a higher pre-pregnancy TSH compared to antibody negative women (p < 0.01). Periconceptional change in thyroid function was more variable among women with antibodies (p < 0.001). 50% of women with elevated pre-pregnancy TSH values (TSH > 3.0 mIU/L) had normal TSH values (TSH < 2.5 mIU/L) in pregnancy. CONCLUSIONS: TSH values decline during the transition from pre-pregnancy to early pregnancy. The change in TSH appears to be less predictable in women with thyroid antibodies. Periconceptional changes in thyroid function should be considered in formulating prenatal thyroid screening guidelines. PMID- 22436201 TI - Adolescent chronic fatigue syndrome; a follow-up study displays concurrent improvement of circulatory abnormalities and clinical symptoms. AB - BACKGROUND: The pathophysiology of chronic fatigue syndrome (CFS) in adolescents is unknown, and the clinical course and prognosis is still questioned. Recent research indicates that abnormalities of autonomic cardiovascular control may play an important role. The aim of this research project was to perform a follow up study of adolescents with chronic fatigue syndrome, focusing on clinical symptoms and autonomic cardiovascular control. METHODS: 47 adolescents (12-18 years old) with CFS were recruited from the outpatient clinic at the Department of Pediatrics, Oslo University Hospital. In a primary visit and a follow-up visit (3-17 months later), we evaluated: a) a wide range of complaints and symptoms and b) cardiovascular variables at baseline and during a 20 degrees head-up tilt test (HUT). RESULTS: At the second visit, patients reported significant improvement regarding functional impairments, fatigue severity, muscular pain, concentration problems, post-exertional malaise and the problem of non-relieving rest. Also, at the second visit, baseline heart rate (HR), blood pressure, total peripheral resistance index (TPRI) and LF/HF (low-frequency:high-frequency heart rate variability ratio, an index of sinus node sympathovagal balance derived from spectral analyses of heart rate) were significant lower, and the increases in HR, mean blood pressure (MBP), diastolic blood pressure (DBP) and TPRI during tilt were significantly less pronounced as compared to the first visit. There was a significant correlation between changes in autonomic symptom score, fatigue severity score and functional impairment score from the first to the second visit. CONCLUSIONS: The majority of adolescents with CFS experienced an improvement over time in functional impairment, self-reported fatigue and additional symptoms, and a concurrent improvement of autonomic cardiovascular control. A possible connection between clinical symptoms and abnormal autonomic control in CFS might represent a focus for further research. PMID- 22436202 TI - Cough aerosol in healthy participants: fundamental knowledge to optimize droplet spread infectious respiratory disease management. AB - BACKGROUND: The Influenza A H1N1 virus can be transmitted via direct, indirect, and airborne route to non-infected subjects when an infected patient coughs, which expels a number of different sized droplets to the surrounding environment as an aerosol. The objective of the current study was to characterize the human cough aerosol pattern with the aim of developing a standard human cough bioaerosol model for Influenza Pandemic control. METHOD: 45 healthy non-smokers participated in the open bench study by giving their best effort cough. A laser diffraction system was used to obtain accurate, time-dependent, quantitative measurements of the size and number of droplets expelled by the cough aerosol. RESULTS: Voluntary coughs generated droplets ranging from 0.1 - 900 microns in size. Droplets of less than one-micron size represent 97% of the total number of measured droplets contained in the cough aerosol. Age, sex, weight, height and corporal mass have no statistically significant effect on the aerosol composition in terms of size and number of droplets. CONCLUSIONS: We have developed a standard human cough aerosol model. We have quantitatively characterized the pattern, size, and number of droplets present in the most important mode of person-to-person transmission of IRD: the cough bioaerosol. Small size droplets (< 1 MUm) predominated the total number of droplets expelled when coughing. The cough aerosol is the single source of direct, indirect and/or airborne transmission of respiratory infections like the Influenza A H1N1 virus. STUDY DESIGN: Open bench, Observational, Cough, Aerosol study. PMID- 22436203 TI - The CAMCOG for patients with Alzheimer's disease with low levels of education. PMID- 22436204 TI - Full employment: a solution for the job blackmail problem. PMID- 22436205 TI - Environmental justice and primary prevention of cancer: the odyssey and legacy of lorenzo tomatis. AB - Lorenzo Tomatis [1929-2007] devoted his private and professional life to the betterment of mankind. As a physician, scientist, and humanitarian he championed against the plight of social injustice and promoted the obvious benefits of primary prevention of diseases compared to treatments that prevent or delay disease progression, especially occupational cancers. An avowed student and scholar of literature, the arts, the history of medicine and science, and chemical carcinogenesis, he believed in and wrote about these issues throughout his storied life. Some of his achievements, with excerpts from his writings, especially on primary prevention and on social injustice, are highlighted herein. PMID- 22436206 TI - Labor and pollution prevention in Canada. AB - This article gives an account of Canadian Chemicals Policy over the past three decades, including the project for the "virtual elimination" of toxic chemicals and the federal government's Chemical Management Plan. The latter is what remained when the virtual elimination program achieved few results. The article then embarks on its central theme: explaining how the labor movement introduced the concept and the practice of Pollution Prevention (P2) to Canada, as well as its impact on legislation and policies over the use reduction of chemical pesticides. The Appendix is a glossary of terms and concepts used in the article. PMID- 22436207 TI - Medical interpretation for immigrant workers. AB - Foreign-born workers have high rates of occupational mortality and morbidity, despite downward trends for the U.S. workforce overall. They have limited access to health care services. Medical interpreters (MIs) facilitate care of acutely injured, low-English-proficiency (LEP) patients, including those sustaining occupational injuries. Our goal was to assess the potential for MIs to serve as advocates of LEP patients injured at work and to deliver preventive messages. We conducted interviews and a focus group of MIs regarding their attitudes toward foreign-born workers, knowledge of occupational health, and perceived roles. They were familiar with occupational injuries and sympathetic toward foreign-born workers, and they described their roles as conduits, cultural brokers, and advocates for hospitals, providers, and patients. More detailed and representative data would require a larger investigation. However, the time sensitive nature of policy-making at this point mandates that occupational health stakeholders participate in the national dialogue on standards, training, and licensure for MIs to promote improved access and quality of health care for LEP patients who have been injured at work. PMID- 22436208 TI - Identifying at-risk communities for action on cancer prevention: a case study in new brunswick (Canada) communities. AB - Health statistics reported by large geographic area such as province, state, county or health region offer little insight into disease conditions at the community level where people live and work, where occupational and environmental exposures occur, and where industrial emissions are often concentrated. This study investigated overall patterns of cancer incidence and socioeconomic status (SES) among 14 communities in the province of New Brunswick (Canada). A multivariate ordination technique, hierarchical clustering, and permutation procedures were used to identify and test significance of community clusters and whether the overall pattern of SES was correlated with patterns of cancer among communities. Communities with significantly high or significantly low overall rates of cancers were identified, patterns that were not related to SES. The potential influence of age, small populations, diagnostic screening, smoking and environmental risk factors contributing to locally elevated cancer rates are discussed. Cancer incidence reported at smaller spatial scales provides health officials and researchers with a basis for identifying communities potentially at risk and aids in the development of appropriate community-based risk reduction actions and cancer prevention. PMID- 22436212 TI - Dynamics of ampicillin-resistant Enterococcus faecium clones colonizing hospitalized patients: data from a prospective observational study. AB - BACKGROUND: Little is known about the dynamics of colonizing Enterococcus faecium clones during hospitalization, invasive infection and after discharge. METHODS: In a prospective observational study we compared intestinal E. faecium colonization in three patient cohorts: 1) Patients from the Hematology Unit at the University Hospital Basel (UHBS), Switzerland, were investigated by weekly rectal swabs (RS) during hospitalization (group 1a, n = 33) and monthly after discharge (group 1b, n = 21). 2) Patients from the Intensive Care Unit (ICU) at the University Medical Center Utrecht, the Netherlands (group 2, n = 25) were swabbed weekly. 3) Patients with invasive E. faecium infection at UHBS were swabbed at the time of infection (group 3, n = 22). From each RS five colonies with typical E. faecium morphology were picked. Species identification was confirmed by PCR and ampicillin-resistant E. faecium (ARE) isolates were typed using Multiple Locus Variable Number Tandem Repeat Analysis (MLVA). The Simpson's Index of Diversity (SID) was calculated. RESULTS: Out of 558 ARE isolates from 354 RS, MT159 was the most prevalent clone (54%, 100%, 52% and 83% of ARE in groups 1a, 1b, 2 and 3, respectively). Among hematological inpatients 13 (40%) had ARE. During hospitalization, the SID of MLVA-typed ARE decreased from 0.745 [95%CI 0.657-0.833] in week 1 to 0.513 [95%CI 0.388-0.637] in week 3. After discharge the only detected ARE was MT159 in 3 patients. In the ICU (group 2) almost all patients (84%) were colonized with ARE. The SID increased significantly from 0.373 [95%CI 0.175-0.572] at week 1 to a maximum of 0.808 [95%CI 0.768-0.849] at week 3 due to acquisition of multiple ARE clones. All 16 patients with invasive ARE were colonized with the same MLVA clone (p < 0.001). CONCLUSIONS: In hospitalized high-risk patients MT159 is the most frequent colonizer and cause of invasive E. faecium infections. During hospitalization, ASE are quickly replaced by ARE. Diversity of ARE increases on units with possible cross-transmission such as ICUs. After hospitalization ARE are lost with the exception of MT159. In invasive infections, the invasive clone is the predominant gut colonizer. PMID- 22436213 TI - The journey of resveratrol from yeast to human. AB - The natural polyphenolic compound resveratrol was first discovered in the 1940s. In the recent years, this compound received renewed interest as several findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction, and regulating longevity in lower organisms. Given the worldwide increase in age-related metabolic diseases the beneficial effects of resveratrol on metabolism and healthy aging in humans are currently a topic of intense investigation. PMID- 22436214 TI - The evolution of milk secretion and its ancient origins. AB - Lactation represents an important element of the life history strategies of all mammals, whether monotreme, marsupial, or eutherian. Milk originated as a glandular skin secretion in synapsids (the lineage ancestral to mammals), perhaps as early as the Pennsylvanian period, that is, approximately 310 million years ago (mya). Early synapsids laid eggs with parchment-like shells intolerant of desiccation and apparently dependent on glandular skin secretions for moisture. Mammary glands probably evolved from apocrine-like glands that combined multiple modes of secretion and developed in association with hair follicles. Comparative analyses of the evolutionary origin of milk constituents support a scenario in which these secretions evolved into a nutrient-rich milk long before mammals arose. A variety of antimicrobial and secretory constituents were co-opted into novel roles related to nutrition of the young. Secretory calcium-binding phosphoproteins may originally have had a role in calcium delivery to eggs; however, by evolving into large, complex casein micelles, they took on an important role in transport of amino acids, calcium and phosphorus. Several proteins involved in immunity, including an ancestral butyrophilin and xanthine oxidoreductase, were incorporated into a novel membrane-bound lipid droplet (the milk fat globule) that became a primary mode of energy transfer. An ancestral c lysozyme lost its lytic functions in favor of a role as alpha-lactalbumin, which modifies a galactosyltransferase to recognize glucose as an acceptor, leading to the synthesis of novel milk sugars, of which free oligosaccharides may have predated free lactose. An ancestral lipocalin and an ancestral whey acidic protein four-disulphide core protein apparently lost their original transport and antimicrobial functions when they became the whey proteins beta-lactoglobulin and whey acidic protein, which with alpha-lactalbumin provide limiting sulfur amino acids to the young. By the late Triassic period (ca 210 mya), mammaliaforms (mammalian ancestors) were endothermic (requiring fluid to replace incubatory water losses of eggs), very small in size (making large eggs impossible), and had rapid growth and limited tooth replacement (indicating delayed onset of feeding and reliance on milk). Thus, milk had already supplanted egg yolk as the primary nutrient source, and by the Jurassic period (ca 170 mya) vitellogenin genes were being lost. All primary milk constituents evolved before the appearance of mammals, and some constituents may have origins that predate the split of the synapsids from sauropsids (the lineage leading to 'reptiles' and birds). Thus, the modern dairy industry is built upon a very old foundation, the cornerstones of which were laid even before dinosaurs ruled the earth in the Jurassic and Cretaceous periods. PMID- 22436215 TI - Evolution of milk oligosaccharides and lactose: a hypothesis. AB - Mammalian milk or colostrum contains up to 10% of carbohydrate, of which free lactose usually constitutes more than 80%. Lactose is synthesized within lactating mammary glands from uridine diphosphate galactose (UDP-Gal) and glucose by a transgalactosylation catalysed by a complex of beta4-galactosyltransferase and alpha-lactalbumin (alpha-LA). alpha-LA is believed to have evolved from C type lysozyme. Mammalian milk or colostrum usually contains a variety of oligosaccharides in addition to free lactose. Each oligosaccharide has a lactose unit at its reducing end; this unit acts as a precursor that is essential for its biosynthesis. It is generally believed that milk oligosaccharides act as prebiotics and also as receptor analogues that act as anti-infection factors. We propose the following hypothesis. The proto-lacteal secretions of the primitive mammary glands of the common ancestor of mammals contained fat and protein including lysozyme, but no lactose or oligosaccharides because of the absence of alpha-LA. When alpha-LA first appeared as a result of its evolution from lysozyme, its content within the lactating mammary glands was low and lactose was therefore synthesized at a slow rate. Because of the presence of glycosyltransferases, almost all of the nascent lactose was utilized for the biosynthesis of oligosaccharides. The predominant saccharides in the proto lacteal secretions or primitive milk produced by this common ancestor were therefore oligosaccharides rather than free lactose. Subsequent to this initial period, the oligosaccharides began to serve as anti-infection factors. They were then recruited as a significant energy source for the neonate, which was achieved by an increase in the synthesis of alpha-LA. This produced a concomitant increase in the concentration of lactose in the milk, and lactose therefore became an important energy source for most eutherians, whereas oligosaccharides continued to serve mainly as anti-microbial agents. Lactose, in addition, began to act as an osmoregulatory molecule, controlling the milk volume. Studies on the chemical structures of the milk oligosaccharides of a variety of mammalian species suggest that human milk or colostrum is unique in that oligosaccharides containing lacto N-biose I (LNB) (Gal(beta1 -> 3)GlcNAc, type I) predominate over those containing N-acetyllactosamine (Gal(beta1 -> 4)GlcNAc, type II), whereas in other species only type II oligosaccharides are found or else they predominate over type I oligosaccharides. It can be hypothesized that this feature may have a selective advantage in that it may promote the growth of beneficial colonic bacteria, Bifidobacteria, in the human infant colon. PMID- 22436216 TI - Epigenetics: a possible role in acute and transgenerational regulation of dairy cow milk production. AB - A potential role for epigenetic mechanisms in the regulation of mammary function in the dairy cow is emerging. Epigenetics is the study of heritable changes in genome function that occur because of chemical changes rather than DNA sequence changes. DNA methylation is an epigenetic event that results in the silencing of gene expression and may be passed on to the next generation. However, recent studies investigating different physiological states and changes in milk protein gene expression suggest that DNA methylation may also play an acute, regulatory, role in gene transcription. This overview will highlight the role of DNA methylation in the silencing of milk protein gene expression during mastitis and mammary involution. Moreover, environmental factors such as nutrition may induce epigenetic modifications of gene expression. The current research investigating the possibility of in utero, hence cross-generational, epigenetic modifications in dairy cows will also be discussed. Understanding how the mammary gland responds to environmental cues provides a potential to enhance milk production not only of the dairy cow but also of her daughter. PMID- 22436217 TI - Bovine mammary stem cells: cell biology meets production agriculture. AB - Mammary stem cells (MaSC) provide for net growth, renewal and turnover of mammary epithelial cells, and are therefore potential targets for strategies to increase production efficiency. Appropriate regulation of MaSC can potentially benefit milk yield, persistency, dry period management and tissue repair. Accordingly, we and others have attempted to characterize and alter the function of bovine MaSC. In this review, we provide an overview of current knowledge of MaSC gained from studies using mouse and human model systems and present research on bovine MaSC within that context. Recent data indicate that MaSC retain labeled DNA for extended periods because of their selective segregation of template DNA strands during mitosis. Relying on this long-term retention of bromodeoxyuridine-labeled DNA, we identified putative bovine MaSC. These label-retaining epithelial cells (LREC) are in low abundance within mammary epithelium (<1%). They are predominantly estrogen receptor (ER)-negative and localized in a basal or suprabasal layer of the epithelium throughout the gland. Thus, the response of MaSC to estrogen, the major mitogen in mammary gland, is likely mediated by paracrine factors released by cells that are ER-positive. This is consistent with considerable evidence for cross-talk within and between epithelial cells and surrounding stromal cells. Excision of classes of cells by laser microdissection and subsequent microarray analysis will hopefully provide markers for MaSC and insights into their regulation. Preliminary analyses of gene expression in laser microdissected LREC and non-LREC are consistent with the concept that LREC represent populations of stem cells and progenitor cells that differ with regard to their properties and location within the epithelial layer. We have attempted to modulate the MaSC number by infusing a solution of xanthosine through the teat canal and into the ductal network of the mammary glands of prepubertal heifers. This treatment increased the number of putative stem cells, as evidenced by an increase in the percentage of LREC and increased telomerase activity within the tissue. The exciting possibility that stem cell expansion can influence milk production is currently under investigation. PMID- 22436218 TI - Does the circadian system regulate lactation? AB - Environmental variables such as photoperiod, heat, stress, nutrition and other external factors have profound effects on quality and quantity of a dairy cow's milk. The way in which the environment interacts with genotype to impact milk production is unknown; however, evidence from our laboratory suggests that circadian clocks play a role. Daily and seasonal endocrine rhythms are coordinated in mammals by the master circadian clock in the hypothalamus. Peripheral clocks are distributed in every organ and coordinated by signals from the master clock. We and others have shown that there is a circadian clock in the mammary gland. Approximately 7% of the genes expressed during lactation had circadian patterns including core clock and metabolic genes. Amplitude changes occurred in the core mammary clock genes during the transition from pregnancy to lactation and were coordinated with changes in molecular clocks among multiple tissues. In vitro studies using a bovine mammary cell line showed that external stimulation synchronized mammary clocks, and expression of the core clock gene, BMAL1, was induced by lactogens. Female clock/clock mutant mice, which have disrupted circadian rhythms, have impaired mammary development and their offspring failed to thrive suggesting that the dam's milk production was not adequate enough to nourish their young. We envision that, in mammals, during the transition from pregnancy to lactation the master clock is modified by environmental and physiological cues that it receives, including photoperiod length. In turn, the master clock coordinates changes in endocrine milieu that signals peripheral tissues. In dairy cows, it is clear that changes in photoperiod during the dry period and/or during lactation influences milk production. We believe that the photoperiod effect on milk production is mediated, in part by the 'setting' of the master clock with light, which modifies peripheral circadian clocks including the mammary core clock and subsequently impacts milk yield and may impact milk composition. PMID- 22436219 TI - Effects of continuous lactation and short dry periods on mammary function and animal health. AB - The dry period is required to facilitate cell turnover in the bovine mammary gland in order to optimize milk yield in the next lactation. Traditionally, an 8 week dry period has been a standard management practice for dairy cows based on retrospective analyses of milk yields following various dry period lengths. However, as milk production per cow has increased, transitioning cows from the nonlactating state to peak milk yield has grown more problematic. This has prompted new studies on dry period requirements for dairy cows. These studies indicate a clear parity effect on dry period requirement. First parity animals require a 60-day dry period, whereas lactations following later parities demonstrate no negative impact with 30-day dry period or even eliminating the dry period when somatotropin (ST) is also used to maintain milk yields. Shortened dry periods in first parity animals were associated with reduced mammary cell turnover during the dry period and early lactation and increased numbers of senescent cells and reduced functionality of lactating alveolar mammary cells postpartum. Use of ST and increased milking frequency postpartum reduced the impact of shortened dry periods. The majority of new intramammary infections occur during the dry period and persist into the following lactation. There is therefore the possibility of altering mastitis incidence by modifying or eliminating the dry period in older parity animals. As the composition of mammary secretions including immunoglobulins may be reduced when the dry period is reduced or eliminated, there is the possibility that the immune status of cows during the peripartum period is influenced by the length of the dry period. PMID- 22436220 TI - Host-defence-related proteins in cows' milk. AB - Milk is a source of bioactive molecules with wide-ranging functions. Among these, the immune properties have been the best characterised. In recent years, it has become apparent that besides the immunoglobulins, milk also contains a range of minor immune-related proteins that collectively form a significant first line of defence against pathogens, acting both within the mammary gland itself as well as in the digestive tract of the suckling neonate. We have used proteomics technologies to characterise the repertoire of host-defence-related milk proteins in detail, revealing more than 100 distinct gene products in milk, of which at least 15 are known host-defence-related proteins. Those having intrinsic antimicrobial activity likely function as effector proteins of the local mucosal immune defence (e.g. defensins, cathelicidins and the calgranulins). Here, we focus on the activities and biological roles of the cathelicidins and mammary serum amyloid A. The function of the immune-related milk proteins that do not have intrinsic antimicrobial activity is also discussed, notably lipopolysaccharide-binding protein, RNase4, RNase5/angiogenin and cartilage glycoprotein 39 kDa. Evidence is shown that at least some of these facilitate recognition of microbes, resulting in the activation of innate immune signalling pathways in cells associated with the mammary and/or gut mucosal surface. Finally, the contribution of the bacteria in milk to its functionality is discussed. These investigations are elucidating how an effective first line of defence is achieved in the bovine mammary gland and how milk contributes to optimal digestive function in the suckling calf. This study will contribute to a better understanding of the health benefits of milk, as well as to the development of high-value ingredients from milk. PMID- 22436221 TI - Cell-based models to test the effects of milk-derived bioactives. AB - The life science industries have a strong interest in screening for novel bioactives in complex mixtures like milk and dairy products. Food bioactives are not only important for public health in general, but also have potential therapeutic applications for the treatment of a number of diseases. To identify these novel bioactives, establishment of robust screening assays is essential. The use of in vitro cell-based models for screening and testing have the advantage that several concentrations of mixtures or specific compounds can be assayed at the same time in cells from specific tissues. Primary cell cultures from target organs or established cell lines can be used to identify the most sensitive cells. In addition, a large number of transfected cell lines with very specific sensitivities have been developed. Different endpoints inherent to basal or more sophisticated cellular functions can be investigated, such as cell viability, apoptosis, migration, intracellular signalling, regulation of gene expression, morphology and metabolic alterations. The gastrointestinal tract is an obvious target for bioactive molecules delivered through milk and dairy products, because it lies at the interface between dietary components in the lumen and the internal processes of the host. Identification of bioactive factors that affects proliferation or migration of epithelial cells may have potential applications in promoting gastrointestinal health in both humans and animals. The mammary gland is another target organ of considerable interest since it has been estimated that up to 50% of all newly diagnosed breast cancers may be related to dietary factors. A large number of gastrointestinal and mammary epithelial cell lines are commercially available, but in order to study some cellular functions, primary cultures of freshly isolated cells are often preferred, as established cell lines do not always express specialised properties in culture. PMID- 22436222 TI - Simultaneous estimation of daily weight and feed intake curves for growing pigs by random regression. AB - In this study, random regression models were used to estimate covariance functions between feed intake and BW in boars from the two breeds: the Norwegian Landrace and the Norwegian Duroc. In total, 1476 animals of the Norwegian Landrace breed and 1300 animals of the Norwegian Duroc breed had registrations on daily feed intake and growth from 54 to 180 days of age. Random regressions on the Legendre polynomials of age were used to describe genetic and permanent environmental curves in BW (up to the second order) and feed intake (up to the first order) for both the breeds. Heritabilities on BW increased over time for the Landrace (0.18 to 0.24), but were approximately constant for the Duroc (0.33 to 0.35). Average heritabilities for feed intake were approximately the same in both the breeds (0.09 to 0.11), and the estimates decreased over time, most pronounced in Duroc. On the basis of the current data, daily feed intake was seemingly controlled by the same genetic factors throughout the test period for Duroc; however, for Landrace, genetic correlations between test days decreased with increasing distance in time. For BW, the genetic correlations between test days were in general high, and did not go below 0.8 for any of the two breeds in this study. For both feed intake and BW, permanent environmental correlations between start and end of the test were reduced with increasing difference in days, most pronounced in Duroc. This study indicates that weight of the animal at the end of the test was more closely genetically correlated to feed intake of earlier periods compared with later periods of growth for both the breeds. This may be explained by the fact that BW is the cumulative growth of an individual, which is likely to be heavily affected by the feed intake during the most intense growth period. PMID- 22436223 TI - Impact of production strategies and animal performance on economic values of dairy sheep traits. AB - The objective of this study was to carry out a sensitivity analysis on the impact of various production strategies and performance levels on the relative economic values (REVs) of traits in dairy sheep. A bio-economic model implemented in the program package ECOWEIGHT was used to simulate the profit function for a semi extensive production system with the Slovak multi-purpose breed Improved Valachian and to calculate the REV of 14 production and functional traits. The following production strategies were analysed: differing proportions of milk processed to cheese, customary weaning and early weaning of lambs with immediate sale or sale after artificial rearing, seasonal lambing in winter and aseasonal lambing in autumn. Results of the sensitivity analysis are presented in detail for the four economically most important traits: 150 days milk yield, conception rate of ewes, litter size and ewe productive lifetime. Impacts of the differences in the mean value of each of these four traits on REVs of all other traits were also examined. Simulated changes in the production circumstances had a higher impact on the REV for milk yield than on REVs of the other traits investigated. The proportion of milk processed to cheese, weaning management strategy for lambs and level of milk yield were the main factors influencing the REV of milk yield. The REVs for conception rate of ewes were highly sensitive to the current mean level of the trait. The REV of ewe productive lifetime was most sensitive to variation in ewe conception rate, and the REV of litter size was most affected by weaning strategy for lambs. On the basis of the results of sensitivity analyses, it is recommended that economic values of traits for the overall breeding objective for dairy sheep be calculated as the weighted average of the economic values obtained for the most common production strategies of Slovak dairy sheep farms and that economic values be adjusted after substantial changes in performance levels of the traits. PMID- 22436224 TI - The potential use of n-alkanes, long-chain alcohols and long-chain fatty acids as diet composition markers: indoor validation with sheep and herbage species from the rangeland of Inner Mongolia of China. AB - To investigate the potential use of n-alkanes (alkanes), long-chain alcohols (alcohols) and long-chain fatty acids (acids) for estimating the diet composition of sheep, in a feeding trial. A total of 18 sheep were assigned randomly to three different diets (diet A, diet B and diet C) containing up to eight herbage species (Leymus chinensis, Leymus dasystachys, Elymus sibiricum, Chenopodium album, Puccinellia chinampoensis, Medicago sativa, Saussurea sinuata and Bromus inermis). Faecal recoveries of alkanes, alcohols and acids were determined, and diet compositions were estimated using different combinations of alkanes, alcohols and acids. The faecal concentrations of individual alkanes, alcohols and acids were corrected using the mean recovery of the dietary treatment that the respective animal belonged to (diet recovery), or the mean recovery across all dietary treatments (general recovery). In general, diets did not affect the faecal recovery values for alkanes, alcohols and acids, and no difference in accuracy was found between diet composition estimates based on dietary recovery and general recovery. The accuracy of diet composition estimates declined as the number of dietary components increased from four to eight herbage species (P < 0.001). Better (P < 0.05) estimates of diet composition were obtained with the combinations of two or three marker types instead of alkanes alone. Moreover, results showed that excluding minor diet components from the calculations decreased (P < 0.05) the accuracy of diet composition estimates, whereas including extra non-grazed herbage species did not reduce (P > 0.05) the quality of diet composition estimates. These results confirmed the usefulness of alkanes, alcohols and acids as markers for determining complex diet composition of sheep. However, a negative impact on the accuracy of diet composition estimates, caused by missing minor diet components from the calculation of diet composition, could happen when plant wax markers are used to estimate the diet composition of free ranging animals. PMID- 22436225 TI - In vitro study of dietary factors affecting the biohydrogenation shift from trans 11 to trans-10 fatty acids in the rumen of dairy cows. AB - On the basis of the isomer-specific effects of trans fatty acids (FA) on human health, and the detrimental effect of t10,c12-conjugated linoleic acid (CLA) on cows' milk fat production, there is a need to identify factors that affect the shift from trans-11 to trans-10 pathway during ruminal biohydrogenation of FA. This experiment was conducted in vitro and aimed at separating the effects of the diet of the donor cows from those of the fermentative substrate, which is necessary to prevent this shift. A total of four dry Holstein dairy cows were used in a 4 * 4 Latin square design. They received 12 kg of dry matter per day of four diets based on maize silage during four successive periods: the control diet (22% starch, <3% fat); the high-starch diet, supplemented with wheat plus barley (35% starch, <3% crude fat); the sunflower oil diet, supplemented with 5% of sunflower oil (20% starch, 7.6% crude fat); and the high-starch plus oil diet (33% starch, 7.3% crude fat). Ruminal fluid of each donor cow was incubated for 5 h with four substrates having similar chemical composition to the diets, replacing sunflower oil by pure linoleic acid (LA). The efficiency of isomerisation of LA to CLA was the highest when rumen fluids from cows receiving dietary oil were incubated with added LA. The shift from trans-11 to trans-10 isomers was induced in vitro by high-starch diets and the addition of LA. Oil supplementation to the diet of the donor cows increased this shift. Conversely, the trans-10 isomer balance was always low when no LA was added to incubation cultures. These results showed that a large accumulation of trans-10 FA was only observed with an adapted microflora, as well as an addition of non-esterified LA to the incubation substrate. PMID- 22436226 TI - Composition of free and adherent ruminal bacteria: inaccuracy of the microbial nutrient supply estimates obtained using free bacteria as reference samples and (15)N as the marker. AB - Previous studies have indicated that (15)N enrichment of solid-associated bacteria (SAB) may be predicted from the same value in liquid-associated bacteria (LAB). The aims of this study were to confirm this and to measure the error in the nutrient supply from SAB, when LAB are used as the reference sample. For this purpose, the chemical and amino acid (AA) compositions of both the bacterial populations were studied in four experiments carried out on different groups of three rumen cannulated wethers. Diets (one in Experiments 1 and 4 and three in Experiments 2 and 3) had forage-to-concentrate ratios (dry matter (DM) basis) between 2 : 1 and 40 : 60, and were consumed at intake levels between 40 and 75 g DM/kg (BW)(0.75). The bacteria samples were isolated after continuous infusion of ((15)NH(4))(2)SO(4) (40, 18, 30 and 25 mg (15)N/day, in Experiments 1 to 4, respectively) for at least 14 days. In all experiments, SAB had consistently higher concentrations of organic matter (826 v. 716 g/kg DM, as average) and total lipids (192 v. 95 g/kg DM, as average) than LAB. Similar CP concentrations of both populations were observed, except a higher concentration in SAB than in LAB in Experiment 3. A consistent (in Experiment 4 only as tendency) higher AA N/total N ratio (on average 17.5%) was observed in SAB than in LAB. The (15)N enrichment in SAB was systematically lower than in LAB. On the basis of the results of all studies a close relationship was found between the (15)N enrichment in SAB and LAB, which was shown irrespective of experiments. This relationship was established from Experiments 1 and 2 and the above cited previous results (n = 20; P < 0.001; R(2) = 0.996), and then confirmed from the results of Experiments 3 and 4. These relationships between SAB and LAB demonstrate that CP supply from SAB is underevaluated by, on average, 21.2% when LAB are used as the reference. This underevaluation was higher for true protein and even higher for the lipid supply (32.5% and 59.6%, respectively, as an average of the four experiments). Large differences in AA profile were observed between SAB and LAB. The prediction equation obtained using (15)N as the marker may be used to correct the errors associated with the traditional use of LAB as the reference sample, and therefore to obtain more accurate estimates of the microbial nutrient supply to the ruminants. PMID- 22436227 TI - Towards a better understanding of the respective effects of milk yield and body condition dynamics on reproduction in Holstein dairy cows. AB - The overall reproductive performance has decreased over the last decades, involving changes in cyclicity, oestrous behaviour and fertility. High milk yield (MY), low body condition score (BCS) and large body condition (BC) loss have been identified as risk factors. However, these effects are often confounded, as high MY and body lipid reserve mobilization are correlated. The aim of this study was to evaluate the respective effects of MY and BC on post-partum ovarian cyclicity, oestrus and fertility of Holstein cows. This study provides novel information, as MY and BC change were uncoupled in the overall dataset that included 98 lactations and milk progesterone profiles. Cows were assigned to two feeding level groups: high feed, which achieved high MY and moderate BC loss throughout lactation (8410 kg, -1.17 unit from calving to nadir BCS), and low feed, which limited MY and triggered a large BC loss (5719 kg, -1.54 unit). MY and BC had different effects at different stages of the reproductive process. Cyclicity as well as non-fertilization and early embryo mortality were mainly driven by body lipid reserves, whereas oestrous behaviour and late embryo mortality were related to MY. The results point to possible uncoupling between cyclicity, oestrus and early and late embryo survival allowing compensation along the reproductive process and leading to similar final reproductive performance. In compact calving systems, which require high pregnancy rates within a short period, higher MY strategies appear unsuitable even where BCS is maintained, owing to depressed oestrous behaviour and probably increased late embryo mortality, which delays rebreeding. Similarly, strategies that compromise cyclicity and fertility by excessively low BCS are unsuitable. PMID- 22436228 TI - Effect of glucose availability on glucose transport in bovine mammary epithelial cells. AB - Primary bovine mammary epithelial cells (BMEC) were cultured in media containing varying concentrations of glucose, to determine the effects of glucose availability on glucose transport and its mechanism in bovine mammary gland. The BMEC incubated with 10 and 20 mM glucose had twofold greater glucose uptake than that with 2.5 mM glucose (P < 0.05). Increased glucose availability enhanced the cell proliferation (P < 0.05). As the glucose uptake is mediated by facilitative glucose transporters (GLUTs), the expression of GLUT mRNA was investigated. Compared with the control (2.5 mM), 5 and 10 mM glucose did not influence the abundance of GLUT1 mRNA (P < 0.05), whereas 20 mM glucose decreased the GLUT1 mRNA expression in the BMEC (P < 0.05). The expression of GLUT8 mRNA was not affected by any concentration of glucose (P > 0.05). As GLUTs are coupled with hexokinases (HKs) in regulating glucose uptake, the expression of HKs and their activities were also studied. The HK activity was greater in 5, 10 and 20 mM glucose than that in 2.5 mM glucose (P < 0.05). The expression of HK2 mRNA rather than HK1 mRNA was detected in the BMEC; however, the abundance of HK2 mRNA was not elevated by any concentrations of glucose compared with control (P > 0.05). Furthermore, addition of 3-bromopyruvate (30, 50 or 70 MUM), an inhibitor of HK2, resulted in the decrease of glucose uptake and cell proliferation at both 2.5 and 10 mM glucose (P < 0.05). Therefore, the glucose concentrations may affect glucose uptake partly by altering the activity of HKs, and HK2 may play an important role in the regulation of glucose uptake in the BMEC. PMID- 22436229 TI - Effects of meloxicam (Metacam(r)) on post-farrowing sow behaviour and piglet performance. AB - Farrowing is an intrinsically risky process for both the sow and the piglets that can cause welfare and economic problems. The effects of the non-steroidal anti inflammatory drug meloxicam on post-farrowing behaviour of sows, and the performance of piglets were investigated. A total of 48 sows were randomly allocated at the day of farrowing (day 0) into two homogeneous groups regarding parity, and treated with either meloxicam or saline solution as placebo. For each sow, number of position changes, total time lying and standing or sitting, feed intake and rectal temperature (RT) were recorded during 3 days after farrowing. Piglets were individually weighed at farrowing and at weaning. The number of position changes did not show significant differences between treatments (P = 0.79). Sows spent significantly less time lying during day +3 after farrowing in the meloxicam group than in the placebo group (P = 0.04). Feed intake and RT showed a parity effect (P < 0.001 in both cases); however, no treatment effect was observed (P = 0.67 and P = 0.47, respectively). Pre-weaning mortality rate in piglets was not affected by treatment. In litters from multiparous sows, piglets of low birth weight (defined as percentile 15: BW <1180 g) had an average daily gain significantly higher in the meloxicam group than in the placebo group (196.6 +/- 7.2 v. 166.6 +/- 9.1 g/day; P = 0.03). Although the administration of meloxicam 90 min after farrowing showed a positive effect on the total time lying of the sows, additional investigations are required to better qualify relevant indicators of pain following farrowing in sows and to specify the analgesic effects of meloxicam on piglet performance. PMID- 22436230 TI - Characteristics of bruises in carcasses of cows sourced from farms or from livestock markets. AB - Bruises in cattle develop after the application of force, and they provide evidence for sub-optimal animal welfare. The aim of this study was to describe the gross characteristics of bruises in cows arriving at the slaughterhouse directly from farms or through the livestock market. The number of bruises and their distribution on the carcass as well as their severity, shape, size and colour were assessed post mortem in a slaughterhouse in Chile. A total of 258 cow carcasses were evaluated, and a total of 846 bruises were found on 243 of the carcasses. Cows that had passed through a livestock market (M-carcasses) had in total 563 bruises (mean 3.8 bruises/carcass, s.d. 2.0), whereas cows transported directly from farms (F-carcasses) had in total 283 bruises (mean 2.5 bruises/carcass, s.d. 1.8). The backs of F-carcasses had twice as many bruises as M-carcasses (32.9% and 16.2%, respectively), whereas bruises in the rib area were more frequently observed in M-carcasses (13.1%) than in F-carcasses (8.1%). Superficial bruises (grade 1) were the most frequently observed (66.2% of all bruises). Regarding the size of the bruises, 64 (7.6%) were classified as large, 271 (32.0%) as medium and 511 (60.4%) as small. Irregularly shaped bruises were the most frequent (91.1%, n = 771), followed by linear (3.8%, n = 32), circular (3.1%, n = 26) and tramline-shaped bruises (1.9%, n = 16). The latter were noticed only in M-carcasses, which may indicate that these animals were beaten more frequently with sticks or other rod-shaped objects. Fresh, bright red coloured bruises were found more frequently on all the animals (69.5% from farms and 70.5% from market) compared with bluish (29.7% and 29.3%, respectively) and yellow bruises (0.4% and 0.2%, respectively). The method of selling was significantly associated with the number of bruises on the carcass (P < 0.001) and the anatomical site (P < 0.05), but not with the severity, shape and colour of the bruises. Increased fat coverage reduced the severity of bruises (P < 0.001). This study shows that, in Chile, market animals have more bruises than those sourced directly from farms, and their distribution is different. More information about the causes of infliction may help reduce bruises and it may also improve their welfare. Further studies are required to elucidate whether the causes of the high bruising in the case of animals passing through markets are related only to extra handling (repeated loading, unloading, transportation, eventual mixing) or to the way of handling by personnel and inadequate design. PMID- 22436231 TI - Activity modulation of microbial enzymes by llama (Lama glama) heavy-chain polyclonal antibodies during in vivo immune responses. AB - Since they were first described in 1993, it was found that recombinant variable fragments (rVHHs) of heavy-chain antibodies (HCAbs) from Camelidae have unusual biophysical properties, as well as a special ability to interact with epitopes that are cryptic for conventional Abs. It has been assumed that in vivo raised polyclonal HCAbs (pHCAbs) should behave in a similar manner than rVHHs; however, this assumption has not been tested sufficiently. Furthermore, our own preliminary work on a single serum sample from a llama immunized with a beta lactamase, has suggested that pHCAbs have no special ability to down-modulate catalytic activity. In this work, we further explored the interaction of pHCAbs from four llamas raised against two microbial enzymes and analyzed it within a short and a long immunization plan. The relative contribution of pHCAbs to serum titer was found to be low compared with that of the most abundant conventional subisotype (IgG(1)), during the whole immunization schedule. Furthermore, pHCAbs not only failed to inhibit the enzymes, but also activated one of them. Altogether, these results suggest that raising high titer inhibitory HCAbs is not a straightforward strategy - neither as a biotechnological strategy nor in the biological context of an immune response against infection - as raising inhibitory rVHHs. PMID- 22436232 TI - Effect of release rate of the SF(6) tracer on methane emission estimates based on ruminal and breath gas samples. AB - The release rate (RR) of sulphur hexafluoride (SF(6)) gas from permeation tube in the rumen appears to be positively related with methane (CH(4)) emissions calculated using the SF(6) tracer technique. Gas samples of breath and ruminal headspace were collected simultaneously in order to evaluate the hypothesis that transactions of SF(6) in the rumen are the source for this relationship. Six non lactating dairy cows fitted with rumen cannulae were subdivided into two groups and randomly assigned to a two-period crossover design to permeation tubes with low RR (LRR = 1.577 mg/day) or two-times higher RR (HRR = 3.147 mg/day) RR. The cows were fed limited amounts of maize silage (80% ad libitum) split into two meals (40% at 0800 h and 60% at 1600 h). Each period consisted of 3-day gas sampling. Immediately before the morning feed and then each hour over 8 h, ruminal gas samples (50 ml) were withdrawn through the cannula fitted with stoppers to prevent opening. Simultaneously, 8-h integrated breath gas samples were collected over the same period. Ratios of concentration of CH(4)/SF(6), CO(2)/SF(6) and CO(2)/CH(4) and emission estimates of CH(4) and CO(2) were calculated for each sample source using the SF(6) tracer technique principles. The LRR treatment yielded higher (P < 0.001) ruminal CH(4)/SF(6) (by 1.79 times) and CO(2)/SF(6) (by 1.90 times) ratios than the HRR treatment; however, these differences were lower than the 2.0 times difference expected from the RR between the LRR and HRR. Consequently, the LRR treatment was associated with lower (P < 0.01) ruminal emissions of CH(4) over the 8-h collection period than with the HRR treatment (+11%), a difference also confirmed by the breath samples (+11%). RR treatments did not differ (P = 0.53) in ruminal or breath CO(2) emissions; however, our results confirm that the SF(6) tracer seems inappropriate for CO(2) emissions estimation in ruminants. Irrespective of the RR treatment, breath samples yielded 8% to 9% higher CH(4) emission estimates than the ruminal samples (P = 0.01). The relationship between rumen and breath sources for CH(4) emissions was better for LRR than for HRR treatment, suggesting that tracer performance decreases with the highest RR of SF(6) tested in our study (3.1 mg/day). A hypothesis is discussed with regard to the mechanism responsible for the relationship between RR and CH(4) emission estimates. The use of permeation tubes with small range in RR is recommended in animal experiments to decrease variability in CH(4) emission estimates using the SF(6) tracer technique. PMID- 22436233 TI - Effect of continuous v. daytime grazing on feed intake and growth of sheep grazing in a semi-arid grassland steppe. AB - In the Inner Mongolian steppe, China, sheep generally graze during daytime and are kept in yards overnight. Hence, nutrients are not returned to the grassland, which might reduce its long-term productivity. Furthermore, the restricted grazing time may limit forage intake and thus the performance of sheep. The aim of this study was therefore to evaluate the impact of continuous 24-h grazing (CG) v. the common daytime grazing (DG) on herbage mass (HM), feed quality, feed organic matter intake (OMI) and live weight gain (LWG) of sheep in the Inner Mongolian steppe. Experiments were carried out from July to September, between 2005 and 2007 on two 2-ha plots per grazing treatment. Each month, the external faecal marker titanium dioxide (TiO(2)) was orally administered to six sheep per plot on 10 consecutive days. Faecal grab samples were obtained from day 6 to 10 and analysed for CP concentrations to estimate digestibility of organic matter (dOM). Faecal TiO(2) concentrations were used to determine the total faecal output and hence OMI of sheep. Concomitant to faeces collection, HM and quality, as well as LWG of the animals were measured. HM and herbage quality did not differ between treatments. However, as the season progressed, concentrations of NDF, ADF and ADL increased, whereas HM and CP concentrations declined. HM and herbage quality parameters differed between years according to the annual precipitation. dOM was similar in CG (0.577) and DG (0.572) sheep, but it decreased from July (0.583) to September (0.558) and differed between years. Accordingly, the OMI of sheep was similar for both treatments across the entire grazing season and all study years. Although mean LWG differed between months and years, it was identical in CG (101.5 g/day) and DG sheep (101.8 g/day). Additional time on pasture during night does not increase feed intake or animal performance. Positive effects of a nutrient reflux on grassland productivity and herbage quality when animals remained on the plots overnight were not found, most likely because of the fact that sheep crowded together in one corner of the plots during darkness and faecal and urinary excretions were thus not evenly distributed across the entire pasture. Considering the risk of animal theft as well as the importance of sheep manure as fuel, the common penning of sheep at night seems to be an adequate management practice for pastoralists in the Inner Mongolian steppe. PMID- 22436234 TI - Outpatient-based massive weight loss body contouring: a review of 260 consecutive cases. AB - BACKGROUND: Massive weight loss (MWL), whether from bariatric surgery or self directed efforts, has become an increasingly-frequent reason for which patients present for body-contouring procedures. As the incidence of post-MWL surgery has increased, there has also been an increase in the frequency of outpatient ambulatory techniques for complex procedures. OBJECTIVES: The author describes his experience with MWL body contouring in an outpatient setting. METHODS: A retrospective review was performed of 260 consecutive patients who presented to the author's clinic for post-MWL body contouring in the author's accredited outpatient clinic. Many patients (n=150) underwent concurrent operations, for a total of 544 procedures. All patients received general anesthesia delivered by a board-certified anesthesiologist, received rigorous perioperative education, and were discharged on the day of operation. RESULTS: Of the 260 patients, 241 were women and 19 were men. The average patient age was 42 years (range, 19-70 years). Among the 544 procedures, the most common complication was minor wound separation. There were no wound infections and only one pulmonary embolism. There were no hospital readmissions and no deaths. CONCLUSIONS: With judicious patient selection, standardized perioperative teaching, and appropriate anesthesia, practitioners' advanced knowledge about complex MWL operations can allow them to perform these procedures safely and effectively in an accredited outpatient setting. LEVEL OF EVIDENCE: 4. PMID- 22436235 TI - Mirror on the wall: a study of women's perception of facial features as they age. AB - BACKGROUND: Facial aesthetic treatments are among the most popular cosmetic procedures worldwide, but the factors that motivate women to change their facial appearance are not fully understood. OBJECTIVES: The authors examine the relationships among the facial areas on which women focus most as they age, women's general self-perception, and the effect of their personal focus on "beauty points" on their perception of other women's faces. METHODS: In this prospective study, 200 women who presented to a cosmetic surgery outpatient clinic for consultation between December 2009 and February 2010 completed a questionnaire. The 200 participants were grouped by age: 20-29 years, 30-39, 40 49, and 50 or older (50 women in each group). They were asked which part of their face they focus on most when looking in the mirror, which part they notice most in other women (of different age groups), what they like/dislike most about their own face, and whether they wished to change any facial feature. RESULTS: A positive correlation was found between women's focal points and the areas they dislike or desire to change. Younger women focused mainly on their nose and skin, while older women focused on their periorbital area and jawline. Women focus on their personal focal points when looking at other women in their 20s and 30s, but not when looking at older women. CONCLUSIONS: Women presenting for cosmetic surgery consultation focus on the areas that they dislike most, which leads to a desire to change those features. The plastic surgeon must fully understand patients' expectations to select appropriate candidates and maximize satisfaction with the outcomes. PMID- 22436236 TI - Intraspinal rewiring of the corticospinal tract requires target-derived brain derived neurotrophic factor and compensates lost function after brain injury. AB - Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery of motor function following brain injury. After destruction of unilateral sensorimotor cortex, intact-side corticospinal tract formed sprouting fibres into the specific lamina of the denervated side of the cervical spinal cord, and made new contact with two types of spinal interneurons-segmental and propriospinal neurons. Anatomical and electrophysiological analyses revealed that this rewired corticospinal tract functionally linked to motor neurons and forelimb muscles. This newly formed corticospinal circuit was necessary for motor recovery, because transection of the circuit led to impairment of recovering forelimb function. Knockdown of brain derived neurotrophic factor in the spinal neurons or its receptor in the intact corticospinal neurons diminished fibre sprouting of the corticospinal tract. Our findings establish the anatomical, functional and molecular basis for the intrinsic capacity of neurons to form compensatory neural network following injury. PMID- 22436237 TI - Nitric oxide stress in sporadic inclusion body myositis muscle fibres: inhibition of inducible nitric oxide synthase prevents interleukin-1beta-induced accumulation of beta-amyloid and cell death. AB - Sporadic inclusion body myositis is a severely disabling myopathy. The design of effective treatment strategies is hampered by insufficient understanding of the complex disease pathology. Particularly, the nature of interrelationships between inflammatory and degenerative pathomechanisms in sporadic inclusion body myositis has remained elusive. In Alzheimer's dementia, accumulation of beta-amyloid has been shown to be associated with upregulation of nitric oxide. Using quantitative polymerase chain reaction, an overexpression of inducible nitric oxide synthase was observed in five out of ten patients with sporadic inclusion body myositis, two of eleven with dermatomyositis, three of eight with polymyositis, two of nine with muscular dystrophy and two of ten non-myopathic controls. Immunohistochemistry confirmed protein expression of inducible nitric oxide synthase and demonstrated intracellular nitration of tyrosine, an indicator for intra-fibre production of nitric oxide, in sporadic inclusion body myositis muscle samples, but much less in dermatomyositis or polymyositis, hardly in dystrophic muscle and not in non-myopathic controls. Using fluorescent double labelling immunohistochemistry, a significant co-localization was observed in sporadic inclusion body myositis muscle between beta-amyloid, thioflavine-S and nitrotyrosine. In primary cultures of human myotubes and in myoblasts, exposure to interleukin-1beta in combination with interferon-gamma induced a robust upregulation of inducible nitric oxide synthase messenger RNA. Using fluorescent detectors of reactive oxygen species and nitric oxide, dichlorofluorescein and diaminofluorescein, respectively, flow cytometry revealed that interleukin-1beta combined with interferon-gamma induced intracellular production of nitric oxide, which was associated with necrotic cell death in muscle cells. Intracellular nitration of tyrosine was noted, which partly co-localized with amyloid precursor protein, but not with desmin. Pharmacological inhibition of inducible nitric oxide synthase by 1400W reduced intracellular production of nitric oxide and prevented accumulation of beta-amyloid, nitration of tyrosine as well as cell death inflicted by interleukin-1beta combined with interferon-gamma. Collectively, these data suggest that, in skeletal muscle, inducible nitric oxide synthase is a central component of interactions between interleukin-1beta and beta-amyloid, two of the most relevant molecules in sporadic inclusion body myositis. The data further our understanding of the pathology of sporadic inclusion body myositis and may point to novel treatment strategies. PMID- 22436238 TI - Diaphragmatic hernia: a previously unreported association with Sotos syndrome. PMID- 22436239 TI - The association of polythelia with segmentation defects of the vertebrae. PMID- 22436240 TI - Set membership experimental design for biological systems. AB - BACKGROUND: Experimental design approaches for biological systems are needed to help conserve the limited resources that are allocated for performing experiments. The assumptions used when assigning probability density functions to characterize uncertainty in biological systems are unwarranted when only a small number of measurements can be obtained. In these situations, the uncertainty in biological systems is more appropriately characterized in a bounded-error context. Additionally, effort must be made to improve the connection between modelers and experimentalists by relating design metrics to biologically relevant information. Bounded-error experimental design approaches that can assess the impact of additional measurements on model uncertainty are needed to identify the most appropriate balance between the collection of data and the availability of resources. RESULTS: In this work we develop a bounded-error experimental design framework for nonlinear continuous-time systems when few data measurements are available. This approach leverages many of the recent advances in bounded-error parameter and state estimation methods that use interval analysis to generate parameter sets and state bounds consistent with uncertain data measurements. We devise a novel approach using set-based uncertainty propagation to estimate measurement ranges at candidate time points. We then use these estimated measurements at the candidate time points to evaluate which candidate measurements furthest reduce model uncertainty. A method for quickly combining multiple candidate time points is presented and allows for determining the effect of adding multiple measurements. Biologically relevant metrics are developed and used to predict when new data measurements should be acquired, which system components should be measured and how many additional measurements should be obtained. CONCLUSIONS: The practicability of our approach is illustrated with a case study. This study shows that our approach is able to 1) identify candidate measurement time points that maximize information corresponding to biologically relevant metrics and 2) determine the number at which additional measurements begin to provide insignificant information. This framework can be used to balance the availability of resources with the addition of one or more measurement time points to improve the predictability of resulting models. PMID- 22436241 TI - Suppression of ribosomal protein synthesis and protein translation factors by Peg interferon alpha/ribavirin in HCV patients blood mononuclear cells (PBMC). AB - BACKGROUND: We have previously reported the induction of many interferon stimulated genes (ISGs) in PBMC collected from patients infected with HCV at various times after initiation of interferon-ribavirin treatment using DNA microarrays to identify changes in gene expression with time. Almost as many genes are down regulated (suppressed) during interferon-ribavirin treatment as are up regulated. METHODS: DNA microarrays were analyzed by different software, including MAS5 (Affymetrix-Kegg) and GSEA (gene set enrichment analysis) to identify specific pathways both up regulated and down regulated. Data was assessed from a clinical trial, which was a microarray analysis from 68 patients. RESULTS: Up regulated genes included genes associated with NF-kb, toll like receptor cytokine -cytokine interaction, and complement and adhesion pathways. The most prominent pathway down regulated was that for ribosomal structural proteins, and eukaryotic translational factors. Down regulation of ribosomal protein genes continued through the treatment up to the last measurement, which was at day 28. CONCLUSIONS: This suppression of the protein synthetic apparatus might explain the long-term side effects of interferon-ribavirin, and explain a non-specific effect of interferon-ribavirin on viral protein synthesis. There was no evidence for unique transcription factors or micro RNA involvement. PMID- 22436242 TI - Transient severe aortic regurgitation and left ventricular dysfunction due to a stuck leaflet in a patient undergoing percutaneous transcatheter aortic valve implantation. AB - We report the case of a 78-year-old patient who underwent transcatheter aortic valve implantation. During the deployment, the leaflets of the implanted valve appeared to be stuck in calcium protruding from the native aortic leaflets, resulting in transient severe aortic regurgitation leading to cardiac arrest with successful cardiac resuscitation. Transient severe aortic regurgitation secondary to the mechanical failure of the deployed valve can lead to serious clinical consequences. PMID- 22436243 TI - Evolving characteristics of lung cancer: a surgical appraisal. AB - OBJECTIVE: Lung cancer management has changed due to emergence of new imaging techniques and of multimodal therapies. Our purpose was to analyse how lung cancer evolved in surgical practice. METHODS: The records of patients who underwent surgical resection for lung cancer from 1983 to 2006 in two centres were reviewed. Data were split into four time periods of 6 years. We analysed and compared the epidemiological, pathological and prognostic characteristics of each period. RESULTS: There were 832, 1148, 1493 and 1195 patients during the periods 1983-88, 1989-94, 1995-2000 and 2001-06, respectively. The main changed characteristics were increasing numbers of older patients, females, past history of another cancer and/or cardio-vascular disease, adenocarcinomas and undifferentiated large-cell carcinomas, smaller tumour size, T1-T2, N0 (47.2 61.2%) and neoadjuvant therapy (NAT) (3.8-24.9%). There were also a decreasing number of exploratory thoracotomies, pneumonectomies and adjuvant therapy (AT) (48.5-30%). The 5-year survival rates improved (34.5-46.3%, P < 10(-6)), mainly after lobectomy, and in the case of adenocarcinoma, N0 and N2 patients. Multivariate analysis confirmed that time trend was an independent factor of prognosis (P < 10(-6)), just as important as N involvement, complete resection (R0), tumour size, age, another cancer history and more significant than the type of resection, histology, NAT and AT. CONCLUSIONS: During the last 25 years, the clinico-pathological features of operated patients have progressively changed and the results following surgery improved. Earlier stage diagnosis might explain overall survival improvement, and play a more major role than associated peri operative treatments. Therefore, it is advisable to consider the time-related factor in future studies on lung cancer surgery. PMID- 22436244 TI - Evaluation of the use of lower body perfusion at 28 degrees C in aortic arch surgery. AB - OBJECTIVES: Although hypothermic circulatory arrest (HCA) and selective cerebral perfusion (SCP) are widely used for cerebral protection during aortic arch surgery, these strategies offer no protection for mesenteric ischaemia during prolonged circulatory arrest. This study explored mesenteric haemodynamics, metabolism, oxidative stress and inflammatory response levels during isolated SCP and combined cerebral and lower body perfusion (CLBP) in pigs. METHODS: Fourteen pigs (35-45 kg) were cooled on CPB to 28 degrees C. After 10 min of HCA, they were randomized to 60 min of isolated SCP (n = 7) and CLBP (n = 7) at low-flow pump rates: 10 ml/kg/min (SCP) and 20 ml/kg/min (LBP). Microspheres were injected at baseline, 5 and 60 min of SCP/CLBP and 5 and 60 min off CPB, to calculate mesenteric regional blood flow (RBF). Lactate levels and Oxy-DNA expression [fluorescence activated cell sorting (FACS)] in the portal venous blood were determined at the same time points. Semi-quantitative assessment of inflammatory cytokines was performed using real-time polymerase chain reaction (PCR) and immunhistochemical analyses. RESULTS: At baseline mesenteric, RBF was 61 +/- 31 ml/min/100 g in the jejunum and 78 +/- 43 ml/min/100 g in the colon. Whereas SCP provided a residual mesenteric RBF of 5%, CLBP offered 47% of the baseline jejunal (34 +/- 10 ml/min/100 g) and 68% of the colonic RBF (52 +/- 34 ml/min/100 g; P = 0.001). Lactate levels were significantly higher in then SCP group (15 +/- 2 vs. 11 +/- 3 mmol/l; P = 0.01). Oxy-DNA increased, reaching 137% of baseline (SCP) and 129% (CLBP) at 60 min SCP/CLBP, but recovered promptly during reperfusion. Real-time PCR revealed a massive increase in early cytokine expression vs. baseline, showing significant higher interleukin (IL) -6 (29 vs.2; P = 0.027) and COX-relative expression (7 vs. 3, P = 0.016) in the SCP group. Immunhistochemical analysis confirmed a higher immunological activity in the SCP group, showing more intensive signal for tumour necrosis factor-alpha, IL-6 and p38 when compared with the CLBP group. CONCLUSIONS: Low-flow CLBP provides a diminished but considerable mesenteric RBF, leading to lower lactate and oxidative stress levels and a diminished local inflammatory response reaction than isolated SCP. PMID- 22436245 TI - Studies of isolated global brain ischaemia: II. Controlled reperfusion provides complete neurologic recovery following 30 min of warm ischaemia - the importance of perfusion pressure. AB - OBJECTIVES: Neurologic injury after sudden death is likely due to a reperfusion injury following prolonged brain ischaemia, and remains problematic, especially if the cardiac arrest is unwitnessed. This study applies a newly developed isolated model of global brain ischaemia (simulating unwitnessed sudden death) for 30 min to determine if controlled reperfusion permits neurologic recovery. METHODS: Among the 17 pigs undergoing 30 min of normothermic global brain ischaemia, 6 received uncontrolled reperfusion with regular blood (n = 6), and 11 were reperfused for 20 min with a warm controlled blood reperfusate containing hypocalcaemia, hyper-magnesemia, alkalosis, hyperosmolarty and other constituents that were passed through a white blood cell filter and delivered at flow rates of 350 cc/min (n = 3), 550 cc/min (n = 2) or 750 cc/min (n = 6). Neurologic deficit score (NDS) evaluated brain function (score 0 = normal, 500 = brain death) 24 h post-reperfusion and 2,3,5-triphenyltetrazolium chloride (TTC) staining determined brain infarction. RESULTS: Regular blood (uncontrolled) reperfusion caused negligible brain O(2) uptake by IN Vivo Optical Spectroscopy (INVOS) (<10 15% O(2) extraction), oxidant damage demonstrated by raised conjugated diene (CD) levels (1.78 +/- 0.13 A233 mn), multiple seizures, 1 early death from brain herniation, high NDS (249 +/- 39) in survivors, brain oedema (84.4 +/- 0.6%) and extensive cerebral infarctions. Conversely, controlled reperfusion restored surface brain oxygen saturation by INVOS to normal (55-70%), but the extent of neurologic recovery was determined by the brain reperfusion pressure. Low pressure reperfusion (independent of flow) produced the same adverse functional, metabolic and anatomic changes that followed uncontrolled reperfusion in seven pigs (three at 350 cc/min, two at 550 and two at 750 cc/min). Conversely, higher reperfusion pressure in four pigs (all at 750 cc/min) resulted in NDS of 0-70* indicating complete (n = 2) or near complete (n = 2) neurological recovery, negligible CDs production (1.29 +/- 0.06 A233mn)*, minimal brain oedema (80.6 +/- 0.2%)* and no infarction by TTC stain. CONCLUSIONS: Brain injury can be avoided after 30 min of normothermic cerebral ischaemia if controlled reperfusion pressure is >50 mmHg, but the lower pressure (<50 mmHg) controlled reperfusion that is useful in other organs cannot be transferred to the brain. Moreover, INVOS is a poor guide to the adequacy of cerebral perfusion and the capacity of controlled brain reperfusion to restore neurological recovery. *P < 0.001 versus uncontrolled or low pressure controlled reperfusion. PMID- 22436246 TI - Severe tricuspid regurgitation after traumatic papillary muscle rupture. PMID- 22436247 TI - Studies of isolated global brain ischaemia: III. Influence of pulsatile flow during cerebral perfusion and its link to consistent full neurological recovery with controlled reperfusion following 30 min of global brain ischaemia. AB - OBJECTIVE: Brain damage is universal in the rare survivor of unwitnessed cardiac arrest. Non-pulsatile-controlled cerebral reperfusion offsets this damage, but may simultaneously cause brain oedema when delivered at the required the high mean perfusion pressure. This study analyses pulsatile perfusion first in control pigs and then using controlled reperfusion after prolonged normothermic brain ischaemia (simulating unwitnessed arrest) to determine if it might provide a better method of delivery for brain reperfusion. METHODS: Initial baseline studies during isolated brain perfusion in 12 pigs (six non-pulsatile and six pulsatile) examined high (750 cc/min) then low (450 cc/min) fixed flow before and after transient (30 s) ischaemia, while measuring brain vascular resistance and oxygen metabolism. Twelve subsequent pigs underwent 30 min of normothermic global brain ischaemia followed by either uncontrolled reperfusion with regular blood (n = 6) or pulsatile-controlled reperfusion (n = 6) before unclamping brain inflow vessels. Functional neurological deficit score (NDS; score: 0, normal; 500, brain death) was evaluated 24 h post-reperfusion. RESULTS: High baseline flow rates with pulsatile and non-pulsatile perfusion before and after transient ischaemia maintained normal arterial pressures (90-100 mmHg), surface oxygen levels IN Vivo Optical Spectroscopy (INVOS) and oxygen uptake. In contrast, oxygen uptake fell after 30 s ischaemia at 450 cc/min non-pulsatile flow, but improved following pulsatile perfusion, despite its delivery at lower mean cerebral pressure. Uncontrolled (normal blood) reperfusion after 30 min of prolonged ischaemia, caused negligible INVOS O(2) uptake (<10-15%), raised conjugated dienes (CD; 1.75 +/- 0.15 A(233 mn)), one early death, multiple seizures, high NDS (243 +/- 16) and extensive cerebral infarcts (2,3,5-triphenyl tetrazolium chloride stain) and oedema (84.1 +/- 0.6%). Conversely, pulsatile-controlled reperfusion pigs exhibited normal O(2) uptake, low CD levels (1.31 +/- 0.07 A(233 mn); P < 0.01 versus uncontrolled reperfusion), no seizures and a low NDS (32 +/- 14; P < 0.001 versus uncontrolled reperfusion); three showed complete recovery (NDS = 0) and all could sit and eat. Post-mortem brain oedema was minimal (81.1 +/- 0.5; P < 0.001 versus uncontrolled reperfusion) and no infarctions occurred. CONCLUSIONS: Pulsatile perfusion lowers cerebral vascular resistance and improves global O(2) uptake to potentially offset post-ischaemic oedema following high-pressure reperfusion. The irreversible functional and anatomic damage that followed uncontrolled reperfusion after a 30-min warm global brain ischaemia interval was reversed by pulsatile-controlled reperfusion, as its delivery resulted in consistent near complete neurological recovery and absent brain infarction. PMID- 22436248 TI - Characterization of non-technical skills in paediatric cardiac surgery: communication patterns. AB - OBJECTIVES: The management of non-technical skills in complex surgical domains, such as paediatric cardiac surgery, is being recognized as a major factor for both performance and safety. Communication patterns are very relevant for safety and were analysed in this human-factor observational study. METHODS: One behaviour observer taped and video-recorded the communication patterns for 10 consecutive paediatric open-heart cases, at a university institution, performed by variable, informal teams. Records were analysed for communication frequency, direction, type, content and pattern on the one hand, and on the other hand for factors influencing communication. RESULTS: A total of 10 167 communication flows were read, with an average of 1017 +/- 170.9 per procedure over an average duration of 136.15 +/- 19.52 min. The frequency of communication was maximal between the main surgeon and the scrub nurse (16% of all communications), followed by the main surgeon to the first surgical assistant (13.8%) and the main surgeon to the perfusionist (12.4%). Communication between the main surgeon and the anaesthetist was not more than 5%. Types of communication varied from requests, questions, answers, statements, informations and explanations, and being different for distinct staff roles: the main surgeon to the scrub nurse involved 84.2% requests, the main surgeon to the first surgical assistant 59.9% statements and the perfusionist to the main surgeon 65.4% answers. Communication patterns varied, being 'closed-loop' (with feedback and double-check) only between the main surgeon and the perfusionist, and mostly open among other team members. Communication-disturbing factors such as noise, technology-related events, resource-based problems and supervisory and training-related issues were also found. CONCLUSIONS: Communication is very frequent in paediatric cardiac surgery and shows a complex pattern. There is room for improvement, namely by a more formal and standardized communication flow structure that can be achieved with the help of behavioural, technological and organizational initiatives. PMID- 22436249 TI - Studies of isolated global brain ischaemia: I. A new large animal model of global brain ischaemia and its baseline perfusion studies. AB - OBJECTIVES: Neurological injury after global brain ischaemia (i.e. sudden death) remains problematic, despite improving cardiac survival. Unfortunately, sudden death models introduce unwanted variables for studying the brain because of multiple organ injury. To circumvent this, a new minimally invasive large animal model of isolated global brain ischaemia, together with baseline perfusion studies is described. METHODS: The model employs neck and small (3-4 inches) supra-sternal incisions to block inflow from carotid and vertebral arteries for 30 min of normothermic ischaemia. Neurological changes after 24 h in six pigs was compared with six Sham pigs assessing neurological deficit score (NDS, 0 = normal, 500 = brain death), brain oedema and cerebral infarction by 2,3,5 triphenyltetrazolium chloride (TTC) stain. Six other pigs had baseline perfusion characteristics in this new model evaluated at carotid flows of 750, 550 and 450 cc/min, with cerebral perfusion pressure, cerebral oximeter saturation [IN Vivo Optical Spectroscopy (INVOS)] and transcranial O(2) uptake measurements. RESULTS: The model never altered cardiac or pulmonary function, and six Sham pigs had normal (NDS = 0) neurological recovery without brain injury. Conversely, 24 h analysis showed that 30 min of global normothermic brain ischaemia caused multiple post-reperfusion seizures (P < 0.001 versus Sham), raised NDS (231 +/- 16; P < 0.001 versus Sham) in four of six survivors and caused marked post-brain oedema (P < 0.001 versus Sham) and extensive cerebral infarctions (TTC stain; P < 0.001 versus Sham). Baseline perfusion showed 750 cc/min flow rate produced normal INVOS levels and O(2) consumption at mean 90-100 mmHg carotid pressure. Carotid pressure and INVOS fell at mid- and low-flow rates. Although INVOS did not change, 450 cc/min flow lowered global O(2) consumption, which further decreased after transient ischaemia (30 s) and 5 min of reperfusion. CONCLUSIONS: This new isolated global brain model consistently caused anatomic, biochemical and functional neurological damage in pigs after 30 min of ischaemia. Flows of 750 cc/min maintained normal mean systemic arterial (90-100 mmHg) pressure, INVOS levels and O(2) consumption. Cerebral pressure and INVOS fell in mid- and low flow studies. A disparity existed between INVOS oxygen saturation and global O(2) consumption at lower flow rates of 450 cc/min following transient ischaemia, indicating that surface oxygen saturation measurement does not reflect global brain O(2) consumption. PMID- 22436250 TI - Direct communication between the right pulmonary artery and the left atrium: presenting with other congenital anomalies. PMID- 22436251 TI - Perceived exertion, comfort and working technique in professional computer users and associations with the incidence of neck and upper extremity symptoms. AB - BACKGROUND: The aim of this study was to investigate whether perceived exertion, perceived comfort and working technique is associated with the incidence of neck and upper extremity symptoms among professional computer users. METHODS: At baseline a self-administered questionnaire was distributed to 853 participants from 46 different work sites (382 men and 471 women) who, at baseline, had been free from neck and upper extremity symptoms during the preceding month. Work related exposures, individual factors, and symptoms from the neck and upper extremities were assessed. Observations of working technique were performed by ergonomists using an ergonomic checklist. Incidence data were collected by means of 10 monthly questionnaires, asking for information on the occurrence of neck, shoulder and arm/hand symptoms. Perceived exertion was rated on a modified Borg RPE scale ranging from 0 (very, very light) to 14 (very, very strenuous). Perceived comfort was rated on a 9-point scale ranging from -4 (very, very poor) to +4 (very, very good) in relation to the chair, computer screen, keyboard, and computer mouse. RESULTS: The median follow up time was 10.3 months. The incidence of symptoms from the neck, shoulders and arm/hands were 50, 24 and 34 cases per 100 person years, respectively.Higher perceived exertion in the neck, shoulder or arm/hands was associated with an increased risk of developing symptoms in the corresponding body region. Moreover, a dose-response relationship between the level of exertion and the risk of developing symptoms was recorded for all three regions. There was an association between low comfort and an increased risk for neck symptoms, but not for shoulder and arm/hand symptoms, although a trend towards such an association (not statistically significant) could be seen. Working technique was, in this study, not associated with the risk of developing symptoms in any of the investigated body regions. CONCLUSION: There was a strong association between high perceived exertion and the development of neck, shoulder, and arm/hand symptoms. Moreover, there was an association between poor perceived comfort and neck pain. Surveillance of computer users may include perceived exertion and comfort to target individuals at risk for neck and upper extremity symptoms. PMID- 22436252 TI - An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3. AB - BACKGROUND: Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. METHODS: All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. RESULTS: Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. CONCLUSION: A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family. PMID- 22436253 TI - Forensic pharmacovigilance. PMID- 22436254 TI - Evaluation of pharmacological evidence for forensic purposes. AB - A thorough analysis of a case that involves a medication that may have caused or contributed to an adverse outcome, or a comparison of two compounds in a patent dispute, requires consideration of many processes that affect the clinical effects of a medication. These include its chemical structure, its pharmacological actions (pharmacodynamics), the pharmaceutical formulation, and its absorption, distribution, metabolism, and excretion (pharmacokinetics). They also include analysis of clinical details, including the diagnosis, the quality of the prescribing decisions, the accuracy of the prescription, dispensing, and administration of medications, and how appropriately the case was managed, including monitoring. A causality assessment should be attempted for both the general case and the particular case. Knowledge of the systems that describe a medication's mechanisms of action (EIDOS) and the dose-relationships and time courses of adverse outcomes and individual susceptibilities to them (DoTS) can inform several aspects of the analysis. Reports should be written in clear English and should not contain statements that rely on expertise that the expert does not possess. PMID- 22436255 TI - Toxicological evidence in forensic pharmacology. AB - Laboratory evidence of the presence and concentration of a drug in a person who has come to harm is often helpful in forensic pharmacology, and may be crucial. However, its value depends on two critical interpretations by the expert. First, the expert must make a careful analysis of the relationship between the results as measured in the sample and the drug in the patient at the time that harm occurred. That is especially difficult with post-mortem samples. Secondly, the expert must syntheses the laboratory information with the available clinical history and clinical or pathological findings. Even in the most favourable circumstances, when the sample is correctly obtained, identified, and analyzed, it can be hard to say that beyond reasonable doubt a given concentration had a given effect. PMID- 22436256 TI - Case histories as evidence. AB - In courts case histories play a central part when a crime may have resulted from an effect of a prescribed drug; in civil cases where a person may have suffered damage from a drug; and in coroners' enquiries into the cause of unexplained deaths. The court must decide two important questions: 1. Can the suspected medication(s) cause this kind of effect? 2. Did it (or they) do so in this particular case? Many judges and coroners have not addressed these questions clearly and have not used expert witnesses consistently, on occasion disregarding scientific evidence. Courts need to appoint experts to explain and interpret the scientific evidence. Few judges are equipped to resolve contradictions between different experts. Brief accounts of five cases from four countries illustrate these points. The reluctance of legal processes to implicate drugs as a possible cause of violent behaviour leads to injustice. Courts must be required to obtain appropriate expert evidence, and be given independent data on which drugs can cause such behaviour. PMID- 22436257 TI - Epidemiological evidence in forensic pharmacovigilance. AB - Until recently epidemiological evidence was not regarded as helpful in determining cause and effect. It generated associations that then had to be explained in terms of bio-mechanisms and applied to individual patients. A series of legal cases surrounding possible birth defects triggered by doxylamine (Bendectin) and connective tissue disorders linked to breast implants made it clear that in some instances epidemiological evidence might have a more important role, but the pendulum swung too far so that epidemiological evidence has in recent decades been given an unwarranted primacy, partly perhaps because it suits the interests of certain stakeholders. Older and more recent epidemiological studies on doxylamine and other antihistamines are reviewed to bring out the ambiguities and pitfalls of an undue reliance on epidemiological studies. PMID- 22436258 TI - Forensic pharmacovigilance and substandard or counterfeit drugs. AB - Identification of harm in the form of adverse drug reactions that are caused by counterfeit or other substandard medicinal products by application of standard pharmacovigillance methods of registration, analysis and investigation could be forensic pharmacovigillance. As recent example of this type of forensic pharmacovigilance is the discovery and investigation into the adverse drug reactions caused by contaminated heparin in the USA in 2008 is discussed. PMID- 22436259 TI - Considerations on causality in pharmacovigilance. AB - Causality has been a topic of debate by philosophers, scientists, lawyers and for centuries. It is essential to define as precisely as possible all steps in the logical chain of events, since each may strengthen or confound an argument. Almost always there are issues of missing and conflicting data that need to be addressed specifically. In pharmacovigilance, as in many other situations, there is not just one possible causation for an effect but several. Each must be evaluated in the given context for probability. There is also likely to be a causal chain of events to the adverse effect under consideration, and each must be considered. In an individual patient diagnosis the components of patient history, clinical findings and various laboratory test findings are combined to point to the probability of the patho-physiological diagnosis, which in turn is related to possible causes with a strength determined by the constellation of findings. The established Bradford-Hill criteria are valuable in considering all the possible causal factors. Pharmacoepidemiology allows for population incidences of causes for particular effects and therefore provides an a priori probability listing for competing possible causes, or at least of one possible cause against the background of all others in a control group. Since adverse effects of medicines are generally rare, it is not possible to exclude drug causation in an individual by reliance on epidemiological evidence alone, only to argue that the incidence is below a level determined by statistical power, of the study or studies combined. Other areas of society are concerned with the process of causal inference, and this is especially true in legal cases in which judgements are made on possible personal injury by drugs. PMID- 22436260 TI - Writing reports for the courts. AB - In writing an expert report for any court or tribunal, account must be taken of that body's needs and where necessary of its strengths and weaknesses. The essential elements are truth, clarity and conciseness. The expert should indicate the nature and source of any standards that he applies. Above all he must beware of venturing into matters that lie in any sense outside his own defined area of expertise. PMID- 22436261 TI - Presenting evidence for the court. AB - The medical doctor is sometimes called upon to serve in the courts as expert witness. The work is challenging and has serious implications for the legal and justice system. The outcome of a case may adversely affect the lives of real people when the evidence is not presented appropriately. However, there is reluctance from doctors to participate in the court process. The health professional may not be trained in the art of being a court witness and while scientifically qualified, may not provide the due diligence in explaining the issues properly to the members of the court. Some of the issues that may affect the outcome of a legal case include late discovery of conflicts of interest, inability to communicate well and stick to scientific facts, the inefficiencies of the legal system, and testifying against a medical colleague. There is merit to recommend that all medical doctors must undergo theoretical and practical training when presented as expert witness in courts. Five cases are presented here as illustrations of doctors involved in court cases. PMID- 22436262 TI - Thrombogenicity of a new injectable biocompatible elastomer for aneurysm exclusion, compared to expanded polytetrafluoroethylene in a human ex vivo model. AB - OBJECTIVES: Customized aortic repair (CAR) is a new concept for endovascular aortic aneurysm repair in which a non-polymerised elastomer is injected to fill the aneurysm sac around a balloon catheter. Amongst other variables, the thrombogenicity of the elastomer should be tested, before further clinical experiments can take place. The aim of this human ex vivo study was to measure the thrombogenicity of the elastomer and to compare it to expanded polytetrafluoroethylene (ePTFE). DESIGN AND MATERIALS: In a validated ex vivo model, non-anticoagulated blood was drawn from the antecubital veins of 10 healthy donors with a 19-gauge needle. It was drawn through elastomer tubes and through ePTFE Gore-Tex vascular grafts, both 60 cm long and with an inner diameter of 3 mm. METHODS: Fibrinopeptide A (FPA) and P-selectin expression was measured in blood samples, collected at the end of the grafts. After the experiments, the deposition of platelets and fibrin onto the grafts was visualised by scanning electron microscopy. RESULTS: For these graft types, a progressive increase in FPA production was observed in time. No significant difference was observed between the elastomer and ePTFE grafts (p > 0.05). No increase in P-selectin expression, and thereby no platelet activation, was observed in the perfusate of either grafts (p > 0.05). By scanning electron microscopy, numerous platelet aggregates were observed on the ePTFE grafts, whereas just a few adhered platelets and no aggregates were observed in the elastomer grafts. CONCLUSIONS: The elastomer in its current formulation has a low thrombogenicity, comparable to ePTFE, making it an ideal substance for endovascular aneurysm sac filling. Further research should clarify the feasibility of CAR in vivo. PMID- 22436263 TI - Radiation-induced carotid stenotic lesions have a more stable phenotype than de novo atherosclerotic plaques. AB - OBJECTIVE: To identify plaque characteristics of carotid artery radiation-induced stenosis. MATERIALS AND METHODS: Nineteen carotid plaques were obtained during carotid endarterectomy (CEA) in 17 consecutive patients with prior cervical radiation therapy (XRT) (median interval 10 years) and compared with 95 matched control carotid plaques of patients without a history of XRT. The following histopathological factors were assessed: calcification, collagen, macrophages, smooth muscle cells, atheroma, microvessels and intraplaque haemorrhage. Association of individual histological parameters with XRT plaque was analysed through a multivariable regression model. RESULTS: Less infiltration of macrophages (6/19 versus 60/95, adjusted p = 0.003) and a smaller lipid core size (Atheroma >10%: 10/19 versus 80/95, adjusted p = 0.006) were independently associated with XRT plaque, compared to non-XRT plaques. CONCLUSIONS: Carotid stenotic lesions in patients with previous cervical radiation are less inflammatory and more fibrotic than carotid atherosclerotic lesions in non radiated patients. PMID- 22436264 TI - Muscle over mind? PMID- 22436265 TI - Younger is better for elective open abdominal aortic aneurysm repair, but.... PMID- 22436266 TI - NE-homocysteinyl-lysine isopeptide is associated with progression of peripheral artery disease in patients treated with folic acid. AB - OBJECTIVE: Folic acid (FA) administration can reduce plasma total homocysteine (tHcy); however, it fails to decrease cardiovascular events and progression of peripheral artery disease (PAD). NE-homocysteinyl-lysine isopeptide (NE-Hcy-Lys) is formed during catabolism of homocysteinylated proteins. We sought to investigate factors that determine the presence of NE-Hcy-Lys in PAD patients with hyperhomocysteinemia receiving FA. PATIENTS AND METHODS: We studied 131 consecutive PAD patients with tHcy > 15 MUmol l(-1) taking FA 0.4 mg d(-1) for 12 months. Serum NE-Hcy-Lys was determined by high-performance liquid chromatography (HPLC). We also measured interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), asymmetric dimethylarginine (ADMA) and 8-iso-prostaglandin F(2alpha) (8 iso-PGF(2alpha)). RESULTS: FA administration resulted in a 70.5% decrease in tHcy (p < 0.0001). However, serum NE-Hcy-Lys was detectable in 28 (21.4%) patients on FA who were more frequently current smokers and survivors of ischaemic stroke (p < 0.001). They had higher tHcy by 46.0%, PAI-1 by 51.7%, 8-iso-PGF(2alpha) by 59.1% and ADMA by 26.4% (all, p < 0.0001). The presence of NE-Hcy-Lys was associated with lower ankle-brachial index (ABI) values (p < 0.001) and higher prevalence of cardiovascular events (p < 0.001) following therapy. CONCLUSION: The presence of NE-Hcy-Lys in one-fifth of hyperhomocysteinemic individuals with PAD despite FA treatment is associated with progression of PAD and with increased ADMA formation, oxidative stress and hypofibrinolysis. PMID- 22436267 TI - New phenotypes for new breeding goals in pigs. AB - Pig breeders in the past have adopted their breeding goals according to the needs of the producers, processors and consumers and have made remarkable genetic improvements in the traits of interest. However, it is becoming more and more challenging to meet the market needs and expectations of consumers and in general of the citizens. In view of the current and future trends, the breeding goals have to include several additional traits and new phenotypes. These phenotypes include (a) vitality from birth to slaughter, (b) uniformity at different levels of production, (c) robustness, (d) welfare and health and (e) phenotypes to reduce carbon footprint. Advancements in management, genomics, statistical models and other technologies provide opportunities for recording these phenotypes. These new developments also provide opportunities for making effective use of the new phenotypes for faster genetic improvement to meet the newly adapted breeding goals. PMID- 22436268 TI - New phenotypes for new breeding goals in dairy cattle. AB - Cattle production faces new challenges regarding sustainability with its three pillars - economic, societal and environmental. The following three main factors will drive dairy cattle selection in the future: (1) During a long period, intensive selection for enhanced productivity has deteriorated most functional traits, some reaching a critical point and needing to be restored. This is especially the case for the Holstein breed and for female fertility, mastitis resistance, longevity and metabolic diseases. (2) Genomic selection offers two new opportunities: as the potential genetic gain can be almost doubled, more traits can be efficiently selected; phenotype recording can be decoupled from selection and limited to several thousand animals. (3) Additional information from other traits can be used, either from existing traditional recording systems at the farm level or from the recent and rapid development of new technologies and precision farming. Milk composition (i.e. mainly fatty acids) should be adapted to better meet human nutritional requirements. Fatty acids can be measured through a new interpretation of the usual medium infrared spectra. Milk composition can also provide additional information about reproduction and health. Modern milk recorders also provide new information, that is, on milking speed or on the shape of milking curves. Electronic devices measuring physiological or activity parameters can predict physiological status like estrus or diseases, and can record behavioral traits. Slaughterhouse data may permit effective selection on carcass traits. Efficient observatories should be set up for early detection of new emerging genetic defects. In the near future, social acceptance of cattle production could depend on its capacity to decrease its ecological footprint. The first solution consists in increasing survival and longevity to reduce replacement needs and the number of nonproductive animals. At the individual level, selection on rumen activity may lead to decreased methane production and concomitantly to improved feed efficiency. A major effort should be dedicated to this new field of research and particularly to rumen flora metagenomics. Low input in cattle production is very important and tomorrow's cow will need to adapt to a less intensive production environment, particularly lower feed quality and limited care. Finally, global climate change will increase pathogen pressure, thus more accurate predictors for disease resistance will be required. PMID- 22436269 TI - Turning science on robust cattle into improved genetic selection decisions. AB - More robust cattle have the potential to increase farm profitability, improve animal welfare, reduce the contribution of ruminant livestock to greenhouse gas emissions and decrease the risk of food shortages in the face of increased variability in the farm environment. Breeding is a powerful tool for changing the robustness of cattle; however, insufficient recording of breeding goal traits and selection of animals at younger ages tend to favour genetic change in productivity traits relative to robustness traits. This paper has extended a previously proposed theory of artificial evolution to demonstrate, using deterministic simulation, how choice of breeding scheme design can be used as a tool to manipulate the direction of genetic progress, whereas the breeding goal remains focussed on the factors motivating individual farm decision makers. Particular focus was placed on the transition from progeny testing or mass selection to genomic selection breeding strategies. Transition to genomic selection from a breeding strategy where candidates are selected before records from progeny being available was shown to be highly likely to favour genetic progress in robustness traits relative to productivity traits. This was shown even with modest numbers of animals available for training and when heritability for robustness traits was only slightly lower than that for productivity traits. When transitioning from progeny testing to a genomic selection strategy without progeny testing, it was shown that there is a significant risk that robustness traits could become less influential in selection relative to productivity traits. Augmentations of training populations using genotyped cows and support for industry-wide improvements in phenotypic recording of robustness traits were put forward as investment opportunities for stakeholders wishing to facilitate the application of science on robust cattle into improved genetic selection schemes. PMID- 22436270 TI - Nutritional strategies to combat Salmonella in mono-gastric food animal production. AB - Nutritional strategies to minimize Salmonella in food animal production are one of the key components in producing safer food. The current European approach is to use a farm-to-fork strategy, where each sector must implement measures to minimize and reduce Salmonella contamination. In the pre-harvest phase, this means that all available tools need to be used such as implementation of biosecurity measures, control of Salmonella infections in animals at the farm as well as in transport and trade, optimal housing and management including cleaning, disinfection procedures as well as efforts to achieve Salmonella-free feed production. This paper describes some nutritional strategies that could be used in farm control programmes in the major mono-gastric food production animals: poultry and pigs. Initially, it is important to prevent the introduction of Salmonella onto the farm through Salmonella-contaminated feed and this risk is reduced through heat treatment and the use of organic acids and their salts and formaldehyde. Microbiological sampling and monitoring for Salmonella in the feed mills is required to minimize the introduction of Salmonella via feed onto the farm. In addition, feed withdrawal may create a stressful situation in animals, resulting in an increase in Salmonella shedding. Physical feed characteristics such as coarse-ground meal to pigs can delay gastric emptying, thereby increasing the acidity of the gut and thus reducing the possible prevalence of Salmonella. Coarse-ground grains and access to litter have also been shown to decrease Salmonella shedding in poultry. The feed can also modify the gastro-intestinal tract microflora and influence the immune system, which can minimize Salmonella colonization and shedding. Feed additives, such as organic acids, short- and medium-chain fatty acids, probiotics, including competitive exclusion cultures, prebiotics and certain specific carbohydrates, such as mannan-based compounds, egg proteins, essential oils and bacteriophages, have the potential to reduce Salmonella levels when added to the feed. These nutritional strategies could be evaluated and used in farm control programmes. PMID- 22436271 TI - Genetic relationship between growth and reproductive traits in Nellore cattle. AB - The objective of this study was to evaluate the genetic relationship between postweaning weight gain (PWG), heifer pregnancy (HP), scrotal circumference (SC) at 18 months of age, stayability at 6 years of age (STAY) and finishing visual score at 18 months of age (PREC), and to determine the potential of these traits as selection criteria for the genetic improvement of growth and reproduction in Nellore cattle. The HP was defined as the observation that a heifer conceived and remained pregnant, which was assessed by rectal palpation at 60 days. The STAY was defined as whether or not a cow calved every year up to the age of 6 years, given that she was provided the opportunity to breed. The Bayesian linear threshold analysis via the Gibbs sampler was used to estimate the variance and covariance components applying a multitrait model. Posterior mean estimates of direct heritability were 0.15 +/- 0.00, 0.42 +/- 0.02, 0.49 +/- 0.01, 0.11 +/- 0.01 and 0.19 +/- 0.00 for PWG, HP, SC, STAY and PREC, respectively. The genetic correlations between traits ranged from 0.17 to 0.62. The traits studied generally have potential for use as selection criteria in genetic breeding programs. The genetic correlations between all traits show that selection for one of these traits does not imply the loss of the others. PMID- 22436272 TI - Genetic parameters for producer-recorded health data in Canadian Holstein cattle. AB - Health traits are of paramount importance for economic dairy production. Improvement in liability to diseases has been made with better management practices, but genetic aspects of health traits have received less attention. Dairy producers in Canada have been recording eight health traits (mastitis (MAST), lameness (LAME), cystic ovarian disease (COD), left displaced abomasum (LDA), ketosis (KET), metritis (MET), milk fever (MF) and retained placenta (RP)) since April 2007. Genetic analyses of these traits were carried out in this study for the Holstein breed. Edits on herd distributions of recorded diseases were applied to the data to ensure a sufficient quality of recording. Traits were analysed either individually (MAST, LAME, COD) or were grouped according to biological similarities (LDA and KET, and MET, MF and RP) and analysed with multiple-trait models. Data included 46 104 cases of any of the above diseases. Incidence ranged from 2.3% for MF to 9.7% for MAST. MET and KET also had an incidence below 4.0%. Variance components were estimated using four different sire threshold models. The differences between models resulted from the inclusion of days at risk (DAR) and a cow effect, in addition to herd, parity and sire effects. Models were compared using mean squared error statistic. Mean squared error favoured, in general, the sire and cow within sire model with regression on DAR included. Heritabilities on the liability scale were between 0.02 (MET) and 0.21 (LDA). There was a moderate, positive genetic correlation between LDA and KET (0.58), and between MET and RP (0.79). PMID- 22436273 TI - Nutritional value of white lupins (Lupinus albus) for broilers: apparent metabolisable energy, apparent ileal amino acid digestibility and production performance. AB - Two experiments were conducted to evaluate the nutritional value of three cultivars (Promore, Kiev mutant and Ultra) of white lupins (Lupinus albus L.) for broilers. In experiment 1, the apparent metabolisable energy (AME) and ileal amino acid digestibility coefficients of the three cultivars were determined. The cultivar effects were significant (P < 0.05) for AME, but the ileal amino acid digestibility coefficients were similar (P > 0.05) between cultivars. The AME value of Ultra cultivar was lower (P < 0.05) than those of Promore and Kiev mutant cultivars. In Experiment 2, using the AME and ileal digestible amino acid values determined in Experiment 1, diets containing 200 g/kg of lupin were formulated and the effects of feeding these diets on performance, digestive tract development and excreta quality of broiler starters were investigated. Weight gain, feed intake and feed per gain of broilers fed diets containing white lupins were similar (P > 0.05) to those fed the maize-soybean meal diet. The performance of birds fed diets containing different cultivars of white lupins was similar (P > 0.05). Several digestive tract parameters were influenced by the dietary inclusion of white lupins. In particular, the relative liver weight and the relative empty weights of small intestine and caeca in birds fed diets containing white lupins were higher (P < 0.05) than those fed the maize-soybean meal diet. No differences (P > 0.05) were observed in the excreta quality scores between the birds fed the maize-soybean meal diet and those fed diets containing white lupins. PMID- 22436274 TI - Ileal digestibility of amino acids of cassava, sweet potato, cocoyam and erythrina foliages fed to growing pigs. AB - Ileal digestibility in growing pigs fed starch-based diets with inclusion of four tropical leaves in a meal form was studied in a 5 * 5 Latin square design. Five diets were formulated with only casein as protein source in the basal diet (CAS), and casein plus dry cassava (CA) leaves, casein plus dry sweet potato (SP) leaves, casein plus dry cocoyam (CO) leaves and casein plus erythrina (ER) leaves in the other four diets. All diets contained the same amount of CP (14%), either provided by only CAS or a combination of casein and 250 g of leaf meal per kg of diet in the other diets. Leaves were separated manually from stems, and only the leaf part was used. A protein-free diet was fed during a sixth period in order to estimate the endogenous protein losses and calculate the CP- and amino-acid (AA) standardized ileal digestibility (SID) values. The values for the foliages were calculated according to the difference method, assuming no interaction between the foliage and the casein. The ileal tract apparent digestibility of CP, organic matter and energy was higher in diet CAS than in the other diets (P < 0.05). The SID of CP and AA was close to 0.950 for casein, whereas the SID of AA was markedly lower in the foliages; the SID of indispensable and dispensable AA was highest in CO (0.500 and 0.352) and lowest in ER (0.170 and 0.195); intermediate values were obtained for SPs (0.367 and 0.349) and CA (0.232 and 0.242) leaves. Accordingly, the SID of lysine was highest (0.538) for CO leaves and lowest (0.126) in ER leaves; intermediate values were measured for CA and SP leaves. These low SID values in foliage meals must be related to the high levels of dietary fibre and the presence of secondary metabolites (tannins). These results suggest that it is only possible to replace a fraction of the conventional protein sources such as soyabean meal by tropical foliages in growing pig diets with a preference for CO leaves. PMID- 22436275 TI - Estimation of the tryptophan requirement in piglets by meta-analysis. AB - There is no consensus concerning the Trp requirement for piglets expressed relative to Lys on a standardized ileal digestible basis (SID Trp : Lys). A meta analysis was performed to estimate the SID Trp : Lys ratio that maximizes performance of weaned piglets between 7 and 25 kg of BW. A database comprising 130 experiments on the Trp requirement in piglets was established. The nutritional values of the diets were calculated from the composition of feed ingredients. Among all experiments, 37 experiments were selected to be used in the meta-analysis because they were designed to express the Trp requirement relative to Lys (e.g. Lys was the second-limiting amino acid in the diet) while testing at least three levels of Trp. The linear-plateau (LP), curvilinear plateau (CLP) and asymptotic (ASY) models were tested to estimate the SID Trp : Lys requirement using average daily gain (ADG), average daily feed intake (ADFI) and gain-to-feed ratio (G : F) as response criteria. A multiplicative trial effect was included in the models on the plateau value, assuming that the experimental conditions affected only this parameter and not the requirement or the shape of the response to Trp. Model choice appeared to have an important impact on the estimated requirement. Using ADG and ADFI as response criteria, the SID Trp : Lys requirement was estimated at 17% with the LP model, at 22% with the CLP model and at 26% with the ASY model. Requirement estimates were slightly lower when G : F was used as response criterion. The Trp requirement was not affected by the composition of the diet (corn v. a mixture of cereals). The CLP model appeared to be the best-adapted model to describe the response curve of a population. This model predicted that increasing the SID Trp : Lys ratio from 17% to 22% resulted in an increase in ADG by 8%. PMID- 22436276 TI - Feed ingredients differing in fermentable fibre and indigestible protein content affect fermentation metabolites and faecal nitrogen excretion in growing pigs. AB - To study the fermentation characteristics of different non-conventional dietary fibre (DF) sources with varying levels of indigestible CP content and their effects on the production of fermentation metabolites and on faecal nitrogen (N) excretion, an experiment was conducted with 40 growing pigs (initial BW 23 kg) using wheat bran (WB), pea hulls (PH), pea inner fibres (PIF), sugar beet pulp (SBP) or corn distillers dried grains with solubles (DDGS). The diets also contained soya protein isolate, pea starch and sucrose, and were supplemented with vitamin-mineral premix. Faecal samples were collected for 3 consecutive days from day 10, fed with added indigestible marker (chromic oxide) for 3 days from day 13 and pigs were slaughtered on day 16 from the beginning of the experiment. Digesta from the ileum and colon were collected and analysed for short-chain fatty acids (SCFA) and ammonia (NH3) content. The apparent total tract N digestibility was the lowest (P < 0.001) in diets based on DDGS (74%), medium in diets with WB and SBP (76% each) and highest in those with PIF and PH (79% and 81%, respectively). Expressed per kg fermented non-starch polysaccharides (NSP), faecal N excretion was higher with DDGS and WB diets (130 and 113 g/kg NSP fermented, respectively) and lower with PIF, PH and SBP diets (42, 52 and 55 g/kg NSP fermented, respectively). The PH-based diets had the highest (P < 0.05) SCFA concentrations, both in the ileum and the colon (27 and 122 mMol/kg digesta, respectively). The highest NH3 concentration was also found in the colon of pigs fed with PH (132 mMol/kg digesta). Loading plot of principle component analysis revealed that the CP : NSP ratio was positively related with faecal N excretion and NH3 concentration in colon contents, whereas negatively related with SCFA concentration in colon contents. In conclusion, pea fibres and SBP increased SCFA and reduced NH3 concentration in the pig's intestine and reduced faecal N excretion, which makes pea fibres and SBP an interesting ingredient to use in pig diet to improve the positive effect of DF fermentation on the gastrointestinal tract and reduce faecal N excretion. PMID- 22436277 TI - Degradation of terpenes and terpenoids from Mediterranean rangelands by mixed rumen bacteria in vitro. AB - This in vitro study aimed at estimating the disappearance rates of 14 terpenes and terpenoids after 24-h incubation with mixed bacteria from caprine rumens. These compounds comprised nine monoterpene hydrocarbons (delta-3-carene, p cymene, beta-myrcene, (E)- and (Z)-beta-ocimene, alpha-phellandrene, alpha terpinene, gamma-terpinene and alpha-terpinolene), four oxygenated monoterpenes ((E)- and (Z)-linalool oxide, 4-terpinenol, alpha + gamma terpineol) and one sesquiterpene hydrocarbon (beta-cedrene). They were individually exposed to goat rumen microflora for 24 h in 70 ml culture tubes at an input level of 0.5 ml/l. Terpenoids were the least degraded, 100% of (E)-linalool oxide, 95% of (Z) linalool oxide, 91% of 4-terpinenol and 75% of terpineol remained intact after 24 h incubation. In contrast, alpha-terpinolene concentration in fermentation broth extracts was below quantification limit, thus indicating an extensive, if not complete, degradation by rumen bacteria. Only 2% of the initial amounts of alpha phellandrene were recovered. The other monoterpenes and beta-cedrene were partly degraded, with losses ranging from 67% for delta-3-carene to 90% for (E)-beta ocimene. The corresponding rates of disappearance were between 2.67 and 4.08 MUmol/ml inoculum per day. PMID- 22436278 TI - Supplementation with non-fibrous carbohydrates reduced fiber digestibility and did not improve microbial protein synthesis in sheep fed fresh forage of two nutritive values. AB - To determine whether non-fibrous carbohydrate (NFC) supplementation improves fiber digestibility and microbial protein synthesis, 18 Corriedale ewes with a fixed intake level (40 g dry matter (DM)/kg BW0.75) were assigned to three (n = 6) diets: F = 100% fresh temperate forage, FG = 70% forage + 30% barley grain and FGM = 70% forage + 15% barley grain + 15% molasses-based product (MBP, Kalori 3000). Two experimental periods were carried out, with late (P1) and early (P2) vegetative stage forage. For P2, ewes were fitted with ruminal catheters. Forage was distributed at 0900 h, 1300 h, 1800 h and 2300 h, and supplement added at 0900 h and 1800 h meals. Digestibility of the different components of the diets, retained N and rumen microbial protein synthesis were determined. At the end of P2, ruminal pH and N-NH3 concentration were determined hourly for 24 h. Supplementation increased digestibility of DM (P < 0.001) and organic matter (OM; P < 0.001) and reduced NDF digestibility (P = 0.043) in both periods, with greater values in P2 (P = 0.008) for the three diets. Daily mean ruminal pH differed (P < 0.05) among treatments: 6.33 (F), 6.15 (FG) and 6.51 (FGM). The high pH in FGM was attributed to Ca(OH)2 in MBP. Therefore, the decreased fiber digestibility in supplemented diets could not be attributed to pH changes. The mean ruminal concentration of N-NH3 was 18.0 mg/dl, without differences among treatments or sampling hours. Microbial protein synthesis was greater in P2 (8.0 g/day) than in P1 (6.1 g/day; P = 0.006), but treatments did not enhance this parameter. The efficiency of protein synthesis tended to be lower in supplemented groups (16.4, 13.9 and 13.4 in P1, and 20.8, 16.7 and 16.2 g N/kg digestible OM ingested in P2, for F, FG and FGM, respectively; P = 0.07) without differences between supplements. The same tendency was observed for retained N: 2.55, 1.38 and 1.98 in P1, and 2.28, 1.23 and 1.10 g/day in P2, for F, FG and FGM, respectively; P = 0.05). The efficiency of microbial protein synthesis was greater in P2 (P = 0.007). In conclusion, addition of feeds containing NFCs to fresh temperate forage reduced the digestibility of cell walls and did not improve microbial protein synthesis or its efficiency. An increase in these parameters was associated to the early phenological stage of the forage. PMID- 22436279 TI - Effects of alfalfa silage storage structure and roasting corn on ruminal digestion and microbial CP synthesis in lactating dairy cows. AB - The objective of this experiment was to quantify the effects of unroasted or roasted ground-shelled corn (GSC), when fed with alfalfa ensiled in bag, bunker, or O2-limiting tower silos on ruminal digestion and microbial CP synthesis in lactating dairy cows. The roasted corn was heat-treated in a propane-fired roasting system. Alfalfa was harvested as second cutting from fields with regrowth of the same maturity. A portion of each field was allotted to each silo. The diets with 3 * 2 factorial arrangement of treatments were fed to six multiparous rumen-cannulated Holstein cows in a cyclic change-over design with five 21-day periods. Experimental diets were comparable and averaged (on dry matter (DM) basis): 410 g/kg alfalfa silage (AS), 150 g/kg corn silage, 350 g/kg GSC, 50 g/kg soybean meal, 40 g/kg roasted soybeans, 177 g/kg CP, 264 g/kg NDF and 250 g/kg starch. Nutrient flow was quantified by the omasal sampling technique with use of three markers (Co, Yb and indigestible NDF). Continuous infusion of 10% atom excess (15NH4)2SO4 was used to label microbial CP. None of the interactions between storage structure of dietary AS and corn type were significant. DM intake was not different among dietary treatments, averaging 24.5 kg/day across diets. Means of ADF digested in the rumen for cows fed diets with AS from bag, bunker and O2-limiting tower silo were 2.1, 1.7 and 2.1 kg/day, respectively, and was lower in cows fed AS from the bunker silo. This response may partly be a reflection of the higher intake of ADF by cows fed AS ensiled in the O2-limiting tower silo compared with the bunker. There was a slightly greater supply of fermentable substrates for cows fed diets with roasted compared with unroasted GSC. The small increases in yield of milk protein and lactose observed in the previous production trial in cows fed diets containing roasted corn may have occurred because of greater supply of fermentable substrates. PMID- 22436280 TI - Comparison of three fluorescent CYP3A substrates in two vertebrate models: pig and Atlantic salmon. AB - We investigated in vitro inhibitory effects of ketoconazole (KTZ) on cytochrome P450 activity in microsomes from pigs and Atlantic salmon. The following enzymatic reactions were studied: 7-benzyloxyresorufin and 7-ethoxyresorufin O dealkylation (BROD and EROD, respectively), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD) and 7-benzyloxyquinoline O-debenzylation (BQOD). KTZ was a potent non-competitive inhibitor of BROD and BQOD in the microsomes from pigs, whereas in the microsomes from Atlantic salmon, these reactions were competitively inhibited by KTZ. BFCOD activity was inhibited by KTZ in a non competitive manner in both species. KTZ non-competitively inhibited EROD in Atlantic salmon, but not in porcine microsomes. The activity of BROD and BQOD was higher in male than that in female pigs, but the activity of BFCOD showed no sex related differences. PMID- 22436281 TI - Foetal bovine intermuscular adipose tissue exhibits histological and metabolic features of brown and white adipocytes during the last third of pregnancy. AB - This study reports the metabolic and morphological characteristics of bovine intermuscular adipose tissue (AT) throughout foetal growth. Our hypothesis was that the histological and molecular features of intermuscular AT would be different from those previously reported for foetal perirenal AT, based on its anatomical location near the muscle and the recent identification of two distinct adipocyte precursors in mouse AT depending on their locations. To address this question, intermuscular AT was sampled from Charolais and Blond d'Aquitaine foetuses at 180, 210 and 260 days post conception (dpc). The two bovine breeds were chosen because of the higher adiposity of Charolais than Blond d'Aquitaine cattle during the postnatal life. Regardless of the breed, adipocyte volume increased slightly (+38%, P < 0.01) with increasing foetal age. This was concomitant with a decrease (P < 0.05) in the activity of enzymes involved in de novo fatty acid (FA) synthesis (FA synthase and glucose-6-phosphate dehydrogenase) and FA esterification (glycerol-3-phosphate dehydrogenase) when expressed per million adipocytes, and with an increase (P ? 0.01) in mRNA abundances for uncoupling protein 1, adiponectin and leptin (LEP) between 180 and 260 dpc. No difference was observed in the adipocyte volume between breeds, which was consistent with the lack of major between-breed differences in mRNA abundances or activities of enzymes involved in lipid metabolism. The mRNA abundance of lipoprotein lipase was maintained across ages, suggesting a storage of circulating FA rather than of FA synthesized de novo. Plasma LEP increased with foetal age, but only in the Charolais breed (+71%, P ? 0.01), and was two- to threefold higher in Charolais than Blond d'Aquitaine foetuses. Regardless of the breed, bovine intermuscular AT contained predominantly unilocular adipocytes believed to be white adipocytes that were larger at 260 dpc than at 180 dpc. These data thus challenge current concepts of the largely brown nature of bovine foetal AT (based on histological and metabolic features of perirenal AT as previously reported a few days before or after birth). PMID- 22436282 TI - Use of different areas of pen by growing rabbits depending on the elevated platforms' floor-type. AB - The addition of platforms to rabbit cages increases their accessible area and provides rabbits greater freedom and mobility. Different types of platforms enable rabbits to situate themselves where they are most comfortable. The objective of this experiment was to analyse preference of growing rabbits between different areas of the pen depending on the elevated platforms' floor-type. Pens with a basic area of 0.84 m2 were equipped with platforms of 0.42 m2. Three types of flooring of the elevated platforms were used as treatments: deep-litter floor and an open wire-net floor (Experiment 1), and a deep-litter floor and a wire-net floor with a manure tray beneath it (Experiment 2). Growing rabbits (n = 168; 42 per treatment) between the ages of 5 and 11 weeks were studied, based on 24 h video recordings from infra-red cameras (one recording per week) applying scan sampling method with a frequency of 30 min. When the platform was deep-litter, significantly (P < 0.001) more rabbits used the area under the platform (53.7% and 54.3% in Experiments 1 and 2, respectively) than stayed on the platform (16.7% and 7.6%). In treatments of wire-net platform with and without tray beneath the platform also significantly (P < 0.001) more rabbits stayed under the platform (43.7% and 34.7%, respectively) than on the platform (19.5% and 29.9%, respectively). The differences from the expected 33.3% staying on the platform or under the platform were significant at least at the level of P < 0.05. The results show that the wire-net platform with the manure tray provides the optimal environment as it leads to the rabbits spreading themselves more evenly in the pen (i.e. the platform expands available floor area) without the risk of soiling from above, and without adverse effects on heat dissipation, and with the possibility of seeking cover when desired. PMID- 22436283 TI - The welfare of growing pigs in five different production systems: assessment of feeding and housing. AB - Ninety-one farms were visited over a 2-year period to assess the welfare of growing pigs in five different production systems found either in France or in Spain using the Welfare Quality(r) protocol. This study focused on animal-based measures as indicators of 'good feeding' and 'good housing'. Multiple Generalized Linear Mixed Models were performed for each measure to evaluate the differences between production systems and to detect possible causal factors. Pigs in the conventional system presented the lowest prevalence of poor body condition, whereas extensive Mallorcan Black pigs and extensive Iberian pigs were associated with a decreased prevalence of bursitis and pig dirtiness. The straw-bedded system presented a lower prevalence of bursitis, but poorer hygiene and more susceptibility of poor body condition than the conventional system. The age of the animals had a significant effect on the appearance of bursitis in the three intensive systems studied. The type of floor was a significant causal factor of bursitis and pig dirtiness in the conventional system and among intensive Iberian pigs. The feeding system was another causal factor of pig dirtiness on more than 50% of the body in the conventional system, whereas pig dirtiness on less than 50% of the body was influenced by the age of the animals. The prevalence of huddling animals in the conventional system was associated with the highest stocking densities and the lowest environmental temperatures. The results indicate that there were important differences between production systems based on animal-based indicators of the good feeding and housing principles. The recording of the age of the animals, type of floor, feeding system, stocking density and environmental temperature can be useful to predict the appearance of a given welfare measure of 'good housing' on a farm. PMID- 22436284 TI - Stunning pigs with nitrogen and carbon dioxide mixtures: effects on animal welfare and meat quality. AB - The aim of this study was to assess the effect of exposure to the gas mixtures of 70% nitrogen (N2) and 30% carbon dioxide (CO2; 70N30C), 80% N2 and 20% CO2 (80N20C) and 85% N2 and 15% CO2 (85N15C) on aversion, stunning effectiveness and carcass, as well as meat quality in pigs, and to compare them with the commercial stunning of 90% CO2 (90C). A total of 68 female pigs were divided into four groups and stunned with one of the gas mixtures. During the exposure to the gas, behavioural variables (retreat attempts, escape attempts, gasping, loss of balance, muscular excitation and vocalizations) were recorded, and at the end of the stunning, corneal reflex and rhythmic breathing were assessed. After slaughter, meat quality parameters such as pH at 45 min post mortem (pH45) and at 24 h post mortem (pHu), electrical conductivity, drip loss and colour, in the Longissimus thoracis (LT) and Semimembranosus (SM) muscles were measured, and the presence of ecchymosis on the hams was noted. The PROC MIXED and the PROC GENMOD of SAS(r) were used to analyse the parametric and binomial variables, respectively. The 'gas mixture' was always considered a fixed effect and the 'live weight' as a covariate. To assess the correlation between meat quality and behaviour measures, PROC CORR was used. Pigs exposed to 90C showed a higher percentage of escape attempts and gasping, a lower percentage of vocalization and shorter muscular excitation phase than pigs exposed to the other N2 and CO2 mixtures (P < 0.05). After stunning, no pig exposed to 90C showed corneal reflex or rhythmic breathing, whereas 85% and 92% of the animals exposed to N2 and CO2 mixtures showed corneal reflex and rhythmic breathing, respectively. Animals stunned with 80N20C and 85N15C had a lower pH45 (P < 0.01) than animals exposed to 90C. Electrical conductivity in the SM muscle was lower (P < 0.001) in 90C and 70N30C pigs than in 80N20C and 85N15C pigs, whereas in LT, it was lower (P < 0.05) in 90C pigs than in 85N15C. As the CO2 concentration of the gas mixture was decreased, the prevalence of exudative pork increased. Twenty-five percent of animals exposed to N2 and CO2 mixtures (n = 68) had ecchymosis in their carcasses, whereas no animal stunned with 90C had ecchymosis. In conclusion, although N2 and CO2 stunning exhibit fewer signs of aversion than 90C, their induction time to unconsciousness is longer, and this may negatively affect meat and carcass quality. PMID- 22436285 TI - Phytochemical complementarities among endophyte-infected tall fescue, reed canarygrass, birdsfoot trefoil and alfalfa affect cattle foraging. AB - We determined whether plant diversity and sequence of plant ingestion affected foraging when cattle chose from plants that varied in concentrations of alkaloids, tannins and saponins. We hypothesized cattle that ate high-alkaloid grasses (endophyte-infected tall fescue (TF) or reed canarygrass (RCG)) would prefer forages high in tannins (birdsfoot trefoil, BFT+) or saponins (alfalfa, ALF+), because tannins and saponins can bind to alkaloids, presumably reducing their absorption. We further hypothesized that forages with tannins or saponins consumed before, rather than after, foraging on high-alkaloid grasses would promote greater use of those grasses presumably by binding to alkaloids, thereby reducing their absorption. In Phase 1, cattle (n = 32) grazed on either high (+) or low (-) alkaloid grass (TF or RCG) pastures for 30 min each morning at 0600 h and were then offered a choice of BFT+, BFT-, ALF+ and ALF- for 60 min each day for 12 days. In Phase 2, cattle (n = 32) were first offered a choice of BFT+ or ALF+ for 30 min at 0600 h and then placed on grass (TF+ or -, or RCG+ or -) pastures for 60 min for 12 days. In both phases, we had four spatial replications of four treatments with 2 per calves assigned to each of the 16 replications per treatment combinations. Scan samples of individuals at 2-min intervals were used to determine incidence of foraging on each plant species (%). Cattle grazed more on RCG than on TF in Phases 1 (62% v. 27%; P = 0.0015) and 2 (71% v. 32%; P = 0.0005). In Phase 1, cattle that first foraged on RCG+ or TF- subsequently preferred ALF over BFT, whereas cattle offered RCG- or TF+ foraged on ALF and BFT equally. Foraging by cattle on RCG was cyclic during Phase 1, whereas cattle foraging on TF markedly decreased incidence of use of TF from 41% to only 16% by the end of the 12-day trial (P = 0.0029). Contrary to the cyclic (RCG) or steadily declining (TF) use of grasses in Phase 1, cattle steadily and dramatically increased foraging on both RCG and TF throughout Phase 2, when they first grazed BFT+ or ALF+ followed by high-alkaloid grasses (P = 0.0159). Our findings suggest that in plant species the sequence of ingestion influenced foraging behavior of cattle and that secondary compounds influenced those responses. PMID- 22436286 TI - Evaluation of long-chain alcohols as diet composition markers in goats grazing heathland areas. AB - An experiment was conducted to assess the potential of long-chain alcohols (LCOH), in alternative or combined with alkanes and long-chain fatty acids (LCFA), as faecal markers to estimate the diet composition of goats grazing heathland vegetation with associated improved pastures. A total of seven diets were offered across the grazing season. The diets were composed of mixtures of herb species (Lolium perenne and Trifolium repens) and woody species (Erica spp., Calluna vulgaris and Ulex gallii) in an attempt to simulate diet selection of goats on these complex vegetation areas. The diet composition was estimated using LCOH markers alone or combined with alkanes, LCFA and alkanes+LCFA, by least square optimization procedures. The data showed large differences between plant species in their LCOH profile. Generally, plant species showed higher LCOH concentrations than those of alkanes and lower than LCFA markers. Faecal recovery of LCOH was incomplete and increased in a linear manner (P < 0.001) with the carbon-chain length, and was influenced by diet composition and its digestibility. The diet composition estimates based on LCOH alone were more accurate (P < 0.05) than those using alkanes or LCFA alone. Results showed that the combination of LCOH with alkanes, LCFA and alkanes+LCFA resulted in more accurate (P < 0.05) estimates of diet composition, indicating that LCOH provided different discriminatory information to that of alkanes and LCFA, helping in the discrimination of the plant species used in this experiment. Results indicate that correction of faecal LCOH concentrations to incomplete faecal recovery is necessary to obtain more accurate estimates of diet composition. Nevertheless, it seemed that the use of a less accurate recovery correction on LCOH markers had a lower impact on the accuracy of estimates than that of alkanes and LCFA. PMID- 22436287 TI - Evaluating mountain goat dairy systems for conversion to the organic model, using a multicriteria method. AB - Organic farming conserves natural resources, promotes biodiversity, guarantees animal welfare and obtains healthy products from raw materials through natural processes. In order to evaluate possibilities of increasing organic animal production, this study proposes a farm-scale multicriteria method for assessing the conversion of dairy goat systems to the organic model. In addition, a case study in the Northern Sierra of Seville, southern Spain, is analysed. A consensus of expert opinions and a field survey are used to validate a list of potential indicators and issues for assessing the conversion, which consider not only the European Community regulations for organic livestock farming, but also agroecological principles. As a result, the method includes 56 variables integrated in nine indicators: Nutritional management, Sustainable pasture management, Soil fertility and contamination, Weed and pest control, Disease prevention, Breeds and reproduction, Animal welfare, Food safety and Marketing and management. The nine indicators are finally integrated in a global index named OLPI (Organic Livestock Proximity Index). Application of the method to a case study with 24 goat farms reveals an OLPI value of 46.5% for dairy goat farms located in mountain areas of southern Spain. The aspects that differ most from the agroecological model include soil management, animal nutrition and product marketing. Results of the case study indicate that the proposed method is easy to implement and is useful for quantifying the approximation of conventional farms to an organic model. PMID- 22436288 TI - Atomic structures of the eukaryotic ribosome. AB - Eukaryotic ribosomes are significantly larger and more complex than their prokaryotic counterparts. This parallels the increased complexity of the associated cellular machinery responsible for translation initiation, ribosome assembly, and the regulation of protein synthesis in eukaryotic cells. The recently determined crystal structures of the small (40S) and large (60S) ribosomal subunits and the 80S ribosome now provide an atomic description of this essential molecular machine and reveal its eukaryote-specific features. In this review, we discuss the common structural principles underlying the evolution of both ribosomal subunits. The recently obtained structural information provides a framework for further genetic, biochemical and structural studies of eukaryotic ribosomes. At the same time, it facilitates a direct comparison between prokaryotic and eukaryotic ribosomal features. PMID- 22436289 TI - Anterior mediastinal lymphangioma in an infant: diagnosis and surgical management. AB - Cystic lymphangioma is a rare lesion of the mediastinum. We present a patient with an antenatally detected mediastinal mass that appeared to regress during foetal life and was not demonstrated on early postnatal imaging. Acute severe respiratory distress at two months of age precipitated surgery with subsequent diagnosis of lymphangioma. PMID- 22436290 TI - LIF and sIL-2R plasma concentrations in IVF patients on the day of embryo transfer: predictive markers of IVF outcome. AB - Successful implantation is still the limiting step in IVF. We hypothesized that maternal plasma concentrations of certain cytokines at the time of embryo transfer could predict the likelihood of successful implantation and pregnancy. sIL-2R, IL-6, LIF, and MMP2 concentrations were measured in plasma from 160 IVF patients (natural and stimulated IVF cycles) on the morning of the embryo transfer (ET0) and 14 days later (ET+14). Patients were ultimately subdivided into four groups depending on the IVF treatment outcome (pregnancy failure, biochemical pregnancy, first-trimester miscarriage and normal term delivery). In natural and stimulated IVF cycles at ET0, sIL-2R concentrations were threefold higher in biochemical pregnancies than in pregnancy failures (P=0.020), and in natural cycles only, 2.5-fold higher in normal term deliveries than in pregnancy failures (P=0.023). Conversely, in natural and stimulated IVF cycles at ET0, LIF concentrations were one third lower in biochemical pregnancies/first-trimester miscarriages compared with pregnancy failures (P=0.042). We suggest that high sIL 2R and low LIF concentrations in maternal plasma on the morning of the embryo transfer might be associated with increased risks of early pregnancy loss, while a basal level of sIL-2R is necessary for normal term delivery outcome. Both cytokine measurements might therefore be useful in the management of IVF patients, and modulation of their concentrations could be investigated as a therapeutic alternative for women with abnormal concentrations at the time of embryo transfer. PMID- 22436291 TI - Experimental investigation of "hANP shot" using human atrial natriuretic peptide for myocardial protection in cardiac surgery. AB - BACKGROUND: We investigated myocardial protection by human atrial natriuretic peptide (hANP) during cardiac surgery without cardioplegia and determined whether suppression of myocardial ischemic reperfusion injury by hANP allows intraoperative aortic cross-clamp time to be prolonged. METHODS AND RESULTS: Thirty-two pigs were placed on cardiopulmonary bypass. Experimental pigs were divided into 4 groups: 15 min clamping; hANP 15 min clamping; 30 min clamping; and hANP 30 min clamping. In both hANP groups, a 100 MUg dose of hANP was administered after clamping. Left ventricular function, premature ventricular contractions (PVCs), histopathological studies, 8-isoprostane, myocardial Ca(2+), and ATP concentrations were determined. Comparison of the myocardial contractile force indicator E(max), in the 30 min groups, showed a significantly higher recovery rate in the hANP than in the control group. PVC numbers were significantly lower in the hANP than in the control groups for both arrest durations. On microscopic examination, hANP reduced ischemic reperfusion injury in the 30 min groups. The myocardial ATP level was significantly higher in the hANP 30 min than in the control 30 min group. Increases in 8-isoprostane and myocardial Ca(2+) concentrations were significantly inhibited in both hANP groups. CONCLUSIONS: This study demonstrated that hANP ameliorates ischemic reperfusion injury, improves postoperative myocardial contractility, and reduces reperfusion arrhythmias. We suggest that hANP allows aortic cross-clamping to be prolonged and thereby exerts a direct myocardial protective effect against cardiac arrest during cardiac surgery. PMID- 22436292 TI - Risk factors for positive depression screens in hospitalized cardiac patients. AB - BACKGROUND: Depression is common in patients with cardiac illness and is independently associated with elevated morbidity and mortality. There are screening guidelines for depression in cardiac patients, but the feasibility and cost-effectiveness of screening all cardiac patients is controversial. This process may be improved if a subset of cardiac patients at high risk for depression could be identified using information readily available to clinicians and screened. OBJECTIVE: To identify risk factors for a positive depression screen at the time of admission in hospitalized cardiac patients. METHODS: A total of 561 consecutively screened cardiac inpatients underwent the Patient Health Questionnaire-2 (PHQ-2). A prospective chart review was performed to assess potential risk factors for depression that would be readily available to front-line clinicians. Rates of risk factors were compared between patients with positive and negative PHQ-2 depression screens, and multivariate logistic regression was performed to assess whether specific risk factors were independently associated with positive screens. RESULTS: Of the 561 patients screened, 13.5% (n=76) had a positive depression screen (PHQ-2>=2). In the univariate analyses, several variables were associated with a positive depression screen. On multivariate analysis, an elevated white blood cell (WBC) count (>10*10(9) cells per liter) and prescription of an antidepressant on admission were independently associated with a positive depression screen, while current smoking showed a trend toward significance. CONCLUSION: Information on these three identified risk factors (WBC count, antidepressant use, and smoking) is readily available to clinicians, and patients with these diagnoses may represent a cohort who would benefit from targeted depression screening in certain settings. PMID- 22436293 TI - Azelnidipine, unique calcium channel blocker could prevent stress-induced cardiac dysfunction like alpha.beta blocker. AB - BACKGROUND: We have reported that alpha and beta adrenergic blockers could protect against emotional stress-induced cardiac dysfunction. Azelnidipine is a unique calcium blocker which does not increase heart rate. The purpose of this study is to evaluate the effect of azelnidipine to prevent stress-induced cardiac dysfunction. METHODS AND RESULTS: Rats premedicated with azelnidipine (0.3 mg/kg), labetalol (3 mg/kg), or vehicle, were restrained for 30 min (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) by echocardiography, blood pressure, and heart rate at the end of IMO and every 10 min for 60 min after IMO. During IMO, FAC in the labetalol group was significantly lower than that in the other two groups. At 20 min after IMO, FAC in the azelnidipine or labetalol group was significantly higher than that in the vehicle group (86 +/- 9%, 73 +/- 5% vs. 56 +/- 11%, p<0.05). During IMO, mean blood pressure in the azelnidipine or labetalol group was significantly lower than that in the vehicle group (107 +/- 5 mmHg, 106 +/- 17 mmHg vs. 124 +/- 5 mmHg, p<0.05). CONCLUSION: Acute administration of azelnidipine could prevent a sudden drop of cardiac function after acute stress like IMO. Azelnidipine might have a protective effect on stress-induced cardiac dysfunction like alpha and beta adrenergic blockers. PMID- 22436294 TI - Concentrations and correlations of disinfection by-products in municipal drinking water from an exposure assessment perspective. AB - Although disinfection by-products (DBPs) occur in complex mixtures, studies evaluating health risks have been focused in few chemicals. In the framework of an epidemiological study on cancer in 11 Spanish provinces, we describe the concentration of four trihalomethanes (THMs), nine haloacetic acids (HAA), 3 chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), four haloacetonitries, two haloketones, chloropicrin and chloral hydrate and estimate correlations. A total of 233 tap water samples were collected in 2010. Principal component analyses were conducted to reduce dimensionality of DBPs. Overall median (range) level of THMs and HAAs was 26.4 (0.8-98.1) and 26.4 (0.9-86.9) MUg/l, respectively (N=217). MX analysed in a subset (N=36) showed a median (range) concentration of 16.7 (0.8-54.1)ng/l. Haloacetonitries, haloketones, chloropicrin and chloral hydrate were analysed in a subset (N=16), showing levels from unquantifiable (<1 MUg/l) to 5.5 MUg/l (dibromoacetonitrile). Spearman rank correlation coefficients between DBPs varied between species and across areas, being highest between dibromochloromethane and dibromochloroacetic acid (r(s)=0.87). Principal component analyses of 13 DBPs (4 THMs, 9 HAAs) led 3 components explaining more than 80% of variance. In conclusion, THMs and HAAs have limited value as predictors of other DBPs on a generalised basis. Principal component analysis provides a complementary tool to address the complex nature of the mixture. PMID- 22436295 TI - Research on segmentation of dorsal diencephalon and ventral midbrain of zebrafish embryo based on active contour model. AB - Zebrafish is a valuable vertebrate model in life science research. In the zebrafish research, segmentation of zebrafish embryo images is a prerequisite for subsequent processing and analysis. Specifically, shape analysis of zebrafish's two important organs, the dorsal diencephalon and the ventral midbrain, is significant for studying the mutants caused by gene expression. Nevertheless, due to non-uniform intensity distribution and weak boundaries in dorsal diencephalon and ventral midbrain microscopic images, classical segmentation methods are unable to determine the precise boundaries. In this paper, a novel segmentation technique for zebrafish embryo images is proposed based on active contour model, which includes region based active contour model and geodesic active contour. Finally, the effectiveness of this approach is confirmed by the experimental results that the agreement between the algorithm and manual segmentation is more than 90%. PMID- 22436296 TI - Entropy based unsupervised Feature Selection in digital mammogram image using rough set theory. AB - Feature Selection (FS) is a process, which attempts to select features, which are more informative. In the supervised FS methods various feature subsets are evaluated using an evaluation function or metric to select only those features, which are related to the decision classes of the data under consideration. However, for many data mining applications, decision class labels are often unknown or incomplete, thus indicating the significance of unsupervised FS. However, in unsupervised learning, decision class labels are not provided. The problem is that not all features are important. Some of the features may be redundant, and others may be irrelevant and noisy. In this paper, a novel unsupervised FS in mammogram image, using rough set-based entropy measures, is proposed. A typical mammogram image processing system generally consists of mammogram image acquisition, pre-processing of image, segmentation, features extracted from the segmented mammogram image. The proposed method is used to select features from data set, the method is compared with the existing rough set based supervised FS methods and classification performance of both methods are recorded and demonstrates the efficiency of the method. PMID- 22436297 TI - Axonal transport analysis using Multitemporal Association Tracking. AB - Multitemporal Association Tracking (MAT) is a new graph-based method for multitarget tracking in biological applications that reduces the error rate and implementation complexity compared to approaches based on bipartite matching. The data association problem is solved over a window of future detection data using a graph-based cost function that approximates the Bayesian a posteriori association probability. MAT has been applied to hundreds of image sequences, tracking organelle and vesicles to quantify the deficiencies in axonal transport that can accompany neurodegenerative disorders such as Huntington's Disease and Multiple Sclerosis and to quantify changes in transport in response to therapeutic interventions. PMID- 22436298 TI - Fast leukocyte image segmentation using shadowed sets. AB - Leukocyte image segmentation acts as the foundation for all automated image based hematological disease recognition systems. Perfection in image segmentation is a necessary condition for improving the diagnostic accuracy in automated cytology. Even though much effort has been put in developing suitable segmentation routines, the problem still remains open in areas like pathological imaging. Clustering is an essential image segmentation procedure which segments an image into desired regions. This paper introduces a novel Shadowed C-means (SCM) clustering approach towards leukocyte segmentation in blood microscopic images. The segmented nucleus and cytoplasm of a leukocyte can be used for feature extraction which can lead to acute leukemia detection. Absence of parameter tuning in SCM with acceptable segmentation performance gives the proposed scheme an edge over standard cluster based segmentation techniques. Comparative analysis reveals that the proposed algorithm is fast and robust in segmenting stained blood microscopic images in the presence of outliers. PMID- 22436299 TI - Improving segmentation of 3D touching cell nuclei using flow tracking on surface meshes. AB - Automatic segmentation of touching cell nuclei in 3D microscopy images is of great importance in bioimage informatics and computational biology. This paper presents a novel method for improving 3D touching cell nuclei segmentation. Given binary touching nuclei by the method in Li et al. (2007), our method herein consists of several steps: surface mesh reconstruction and curvature information estimation; direction field diffusion on surface meshes; flow tracking on surface meshes; and projection of surface mesh segmentation to volumetric images. The method is validated on both synthesised and real 3D touching cell nuclei images, demonstrating its validity and effectiveness. PMID- 22436300 TI - Morphological analysis of zebrafish embryo tails. AB - Quantitative analysis of image-based phenotype is of significant importance in zebrafish image analysis and high-content screening. In this paper, an automatic analysis pipeline is proposed for quantification of the curvedness of zebrafish embryo tails. First, zebrafish embryos are extracted based on the active contour model, and then its skeleton line is generated by the principal graph algorithm. Several curvedness measures of tail skeleton are designed and compared, and experimental results show that joint consideration of the tail shape and its relative position relationship can result in better performance. The proposed pipeline has comparable performance to the manual analysis. PMID- 22436303 TI - Si solid-state quantum dot-based materials for tandem solar cells. AB - The concept of third-generation photovoltaics is to significantly increase device efficiencies whilst still using thin-film processes and abundant non-toxic materials. A strong potential approach is to fabricate tandem cells using thin film deposition that can optimise collection of energy in a series of cells with decreasing band gap stacked on top of each other. Quantum dot materials, in which Si quantum dots (QDs) are embedded in a dielectric matrix, offer the potential to tune the effective band gap, through quantum confinement, and allow fabrication of optimised tandem solar cell devices in one growth run in a thin-film process. Such cells can be fabricated by sputtering of thin layers of silicon rich oxide sandwiched between a stoichiometric oxide that on annealing crystallise to form Si QDs of uniform and controllable size. For approximately 2-nm diameter QDs, these result in an effective band gap of 1.8 eV. Introduction of phosphorous or boron during the growth of the multilayers results in doping and a rectifying junction, which demonstrates photovoltaic behaviour with an open circuit voltage (VOC) of almost 500 mV. However, the doping behaviour of P and B in these QD materials is not well understood. A modified modulation doping model for the doping mechanisms in these materials is discussed which relies on doping of a sub oxide region around the Si QDs. PMID- 22436304 TI - Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature. AB - BACKGROUND: Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the NF2 gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient. CASE PRESENTATION: We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing NF2, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including NF2 and MN1 (meningioma 1).Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing NF2 were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed MN1, PITPNB and TTC28. MN1, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (TEL/MN1) in human myeloid leukemias. Interestingly, Mn1-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, Mn1 regulates maturation and function of calvarial osteoblasts and is an upstream regulator of Tbx22, a gene associated with murine and human cleft palate. This suggests that deletion of MN1 in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities. CONCLUSIONS: Thus, our report describes a NF2 adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of MN1 deletion with abnormal craniofacial development and/or cleft palate in humans. PMID- 22436305 TI - Filming a live cell by scanning electrochemical microscopy: label-free imaging of the dynamic morphology in real time. AB - The morphology of a live cell reflects the organization of the cytoskeleton and the healthy status of the cell. We established a label-free platform for monitoring the changing morphology of live cells in real time based on scanning electrochemical microscopy (SECM). The dynamic morphology of a live human bladder cancer cell (T24) was revealed by time-lapse SECM with dissolved oxygen in the medium solution as the redox mediator. Detailed local movements of cell membrane were presented by time-lapse cross section lines extracted from time-lapse SECM. Vivid dynamic morphology is presented by a movie made of time-lapse SECM images. The morphological change of the T24 cell by non-physiological temperature is in consistence with the morphological feature of early apoptosis. To obtain dynamic cellular morphology with other methods is difficult. The non-invasive nature of SECM combined with high resolution realized filming the movements of live cells. PMID- 22436306 TI - The evidence-based pharmacotherapy of social anxiety disorder. AB - Social anxiety disorder (SAD) is a highly prevalent and often disabling disorder. This paper reviews the pharmacological treatment of SAD based on published placebo-controlled studies and published meta-analyses. It addresses three specific questions: What is the first-line pharmacological treatment of SAD? How long should treatment last? What should be the management of treatment-resistant cases? Based on their efficacy for SAD and common co-morbid disorders, tolerability and safety, selective serotonin reuptake inhibitors (SSRIs) and venlafaxine should be considered the first-line treatment for most patients. Less information is available regarding the optimal length of treatment, although individuals who discontinue treatment after 12-20 wk appear more likely to relapse than those who continue on medication. Even less empirical evidence is available to support strategies for treatment-resistant cases. Clinical experience suggests that SSRI non-responders may benefit from augmentation with benzodiazepines or gabapentin or from switching to monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase A, benzodiazepines or gabapentin. Cognitive-behavioural is a well-established alternative first line therapy that may also be a helpful adjunct in non-responders to pharmacological treatment of SAD. PMID- 22436307 TI - Virtual reality and robotics for stroke rehabilitation: where do we go from here? AB - Promoting functional recovery after stroke requires collaborative and innovative approaches to neurorehabilitation research. Task-oriented training (TOT) approaches that include challenging, adaptable, and meaningful activities have led to successful outcomes in several large-scale multisite definitive trials. This, along with recent technological advances of virtual reality and robotics, provides a fertile environment for furthering clinical research in neurorehabilitation. Both virtual reality and robotics make use of multimodal sensory interfaces to affect human behavior. In the therapeutic setting, these systems can be used to quantitatively monitor, manipulate, and augment the users' interaction with their environment, with the goal of promoting functional recovery. This article describes recent advances in virtual reality and robotics and the synergy with best clinical practice. Additionally, we describe the promise shown for automated assessments and in-home activity-based interventions. Finally, we propose a broader approach to ensuring that technology-based assessment and intervention complement evidence-based practice and maintain a patient-centered perspective. PMID- 22436308 TI - Nintendo wii sports and wii fit game analysis, validation, and application to stroke rehabilitation. AB - BACKGROUND: Interactive video gaming has become ubiquitous in the practice of rehabilitation. The Nintendo Wii is one such system. Interactive gaming can promote intensive task-based therapy in a manner that is motivating for the user. Widespread enthusiasm for consoles and their games prompted us to analyze the games for their rehabilitation elements related to improving balance and mobility for individuals poststroke. PURPOSE: The purpose of this article is to provide a game analysis for clinical application and evaluation of the game elements for research on interactive video gaming. METHODS: Using a team of game players and raters, 5 tables (1 for the Wii Sports and 4 for the Wii Fit) were developed and validated. The tables consist of 3 categories: game description, impairments targeted (strength, endurance, balance, and coordination), and feedback provided (knowledge of performance [KP] and knowledge of results [KR]). Two domain content experts established face validity. Construct validity was performed by 2 therapist-raters who had more than 15 years' clinical experience and postgraduate training in motor learning. Observations about the games including the fidelity of the interfaces, the nature of the feedback, and some of the challenges to adapting the games for rehabilitation are presented. RESULTS: An 80% agreement between raters set as the criterion for establishing the construct validity was met for feedback evaluation. There was 100% agreement on impairment ratings. Games provide a greater amount of KR compared with KP. CONCLUSION: Given the preponderance of KR, therapists will need to monitor motor performance. Adaptation of interactive video consoles for rehabilitation requires careful evaluation of the games' attributes using relevant rehabilitation construits. PMID- 22436309 TI - Game-based, portable, upper extremity rehabilitation in chronic stroke. AB - PURPOSE: This case series pilot study evaluates the efficacy of the Core:Tx gaming device on 2 chronic stroke survivors. METHODS: Intervention was provided 3 times a week for 3 weeks. Outcome measures, administered 1 week before and 1 week after intervention, included the Stroke Impact Scale (SIS), the Canadian Occupational Performance Measure (COPM), the Fugl-Meyer Assessment of Motor Recovery (Fugl-Meyer [FM]), and the Box and Block Test (BB). RESULTS: Participant A exhibited an 11-point increase on the SIS, a 1.2-point change on each of the performance and satisfaction scores of the COPM, a 1-point increase on the FM, and no change on the BB. Participant B exhibited a 3-point increase on the SIS and no change on the COPM, FM, or BB. CONCLUSIONS: The participants experienced increased quality of life, a greater propensity to use their affected arm, and enhanced task performance without exhibiting motor changes. Additionally, the Core:Tx gaming device was reported by the participants to be a motivating modality in the therapy setting. PMID- 22436310 TI - A pilot study of rhythm and timing training as a supplement to occupational therapy in stroke rehabilitation. AB - INTRODUCTION: Stroke is the leading cause of disability. A need exists for an effective intervention to enhance upper extremity (UE) motor abilities and activities of daily living (ADL) performance. OBJECTIVE: The objectives of this pilot study were to (1) determine the feasibility of adding Interactive Metronome (IM) to an occupational therapy (OT) program; and (2) determine changes in UE impairments, function, quality of life, and perceived physical performance ability and satisfaction using a combined IM + OT regimen compared with OT alone for adults with chronic stroke. METHODS: This pilot study (n=10) used a 2-group (OT or IM+OT) pretest-posttest design. The intervention involved 60 minutes of IM + OT or OT alone, 3 days a week for 10 weeks. Outcome measures included the UE Fugl-Meyer (impairment), the Arm Motor Ability Test (function), the Box and Block Test (function), Stroke Impact Scale (quality of life), and the Canadian Occupational Performance Measure (perceived performance ability and satisfaction). RESULTS: It was feasible to add IM to OT. The IM+OT group demonstrated decreased impairment and increased quality of life. However, the OT alone group demonstrated greater gains in function, perceived physical performance ability, and satisfaction. CONCLUSION: These findings suggest that rhythm and timing training using the IM is a feasible intervention to consider as part of therapy treatment. However, IM may fit best for prefunctional treatment, as it seemed to primarily decrease impairment. It may also serve as a supplement before or after treatment in order to maximize rehabilitation potential. Clinical implications and suggestions for future studies are provided. PMID- 22436311 TI - The therapeutic effect of outpatient use of a peroneal nerve functional electrical stimulation neuroprosthesis in people with stroke: a case series. AB - PURPOSE: Foot drop is a common problem following a stroke. Although peroneal nerve functional electrical stimulation (pFES) for foot drop has been shown to improve function and gait, the majority of studies have used daily stimulation. There are few studies to show benefit and guide practice for less frequent dosing. Therefore, the purpose of this study was to examine the effect of gait training with pFES on ambulation and lower extremity kinematics when used on a schedule consistent with usual care in an outpatient therapy clinic. METHODS: A pFES neuroprosthesis was used with overground gait training 3 times per week for 6 weeks in 2 subjects with foot drop due to chronic stroke (more than 6 months poststroke). Outcomes including functional gait (modified Emory Functional Ambulation Profile [mEFAP]), gait speed, and gait kinematics were assessed at baseline and at 6 weeks without the pFES (therapeutic effect). RESULTS: Both subjects demonstrated decreased ankle plantarflexion at initial heel contact during gait. Both subjects also showed decreased time to complete the mEFAP. Only 1 subject showed increased gait velocity. CONCLUSION: This case series suggests that the use of neuroprothesis pFES combined with overground gait training on a typical outpatient therapy schedule for 6 weeks may increase foot clearance during gait for persons with chronic stroke. Although the evidence is limited, it may be beneficial for clinicians to use pFES in creative ways during different aspects of treatment. PMID- 22436312 TI - Using sensors to measure activity in people with stroke. AB - PURPOSE: The purpose of this study was to determine the ability of a novel shoe based sensor that uses accelerometers, pressure sensors, and pattern recognition with a support vector machine (SVM) to accurately identify sitting, standing, and walking postures in people with stroke. METHODS: Subjects with stroke wore the shoe-based sensor while randomly assuming 3 main postures: sitting, standing, and walking. A SVM classifier was used to train and validate the data to develop individual and group models, which were tested for accuracy, recall, and precision. RESULTS: Eight subjects participated. Both individual and group models were able to accurately identify the different postures (99.1% to 100% individual models and 76.9% to 100% group models). Recall and precision were also high for both individual (0.99 to 1.00) and group (0.82 to 0.99) models. CONCLUSIONS: The unique combination of accelerometer and pressure sensors built into the shoe was able to accurately identify postures. This shoe sensor could be used to provide accurate information on community performance of activities in people with stroke as well as provide behavioral enhancing feedback as part of a telerehabilitation intervention. PMID- 22436313 TI - Reading and writing with aphasia in the 21st century: technological applications of supported reading comprehension and written expression. AB - PURPOSE: People with aphasia struggle to keep up with today's text-based communication, because of their reduced ability to comprehend and compose written messages. Therefore, the communication gap between people with aphasia and the communities around them continues to grow. The purpose of this article is to highlight the literature regarding supported reading comprehension and written expression techniques for people with aphasia and to discuss the role of these interventions in the context of Web-based communication and information sharing. METHODS: This article presents an overview of compensatory strategies that support reading comprehension such as aphasia-friendly text principles, pairing text with highly contextualized pictures, the notion of reading ramps, and written expression supports including word prediction, speech-to-text, and voice banking. Additionally, ideas for integrating these strategies into Web-based communication and information-sharing applications are reviewed. CONCLUSION: Speech-language pathologists must consider available Web-based communication strategies during the aphasia rehabilitation process. In particular, interventions designed to support the reading comprehension and written expression of people with aphasia should be adapted to meet the increasing trend to utilize Web-based technology to maintain or redefine social roles following a stroke. PMID- 22436314 TI - Superior colliculi involvement in poststroke unilateral spatial neglect: a pilot study. AB - PURPOSE: The neural mechanisms underlying unilateral spatial neglect (USN) are unclear. The superior colliculi (SC) may be involved in USN expression, and the spatial summation effect (SSE), where reaction times to bilateral stimuli are faster than to unilateral, may be a behavioral index of SC function. We determined the feasibility of investigating SC contribution to poststroke USN using the SSE in 3 groups. METHODS: Seven participants with left near extrapersonal space USN (USN+) following right hemisphere stroke, 10 without (USN ), and 10 controls were tested under binocular/monocular (right eye patched) conditions while responding to unilateral/bilateral stimuli. Control and USN- groups completed the SSE paradigm. RESULTS: Most USN+ participants were unable to initiate the SSE paradigm due to poor visual fi xation and demonstrated higher contrast sensitivity for left-sided stimuli. Controls showed an SSE (under both viewing conditions) while the USN- showed an abnormal SSE whereby reaction times to bilateral stimuli were faster than to unilateral-left but not to unilateral right stimuli (under both binocular/monocular conditions). CONCLUSION: This study is the fi rst to investigate SC contribution in poststroke USN using the SSE; we identifi ed higher contrast sensitivity to left-sided stimuli and poor fi xation in the USN+ group. These fi ndings suggest avenues for research that may lead to novel rehabilitation interventions. PMID- 22436315 TI - The crisis of stroke: experiences of patients and their family caregivers. AB - PURPOSE: Approximately 4.8 million stroke survivors are living in the community with some level of disability requiring the assistance of family caregivers. Stroke family caregivers are often unprepared for the demands required of them. The purpose of this grounded theory study was to explore the needs of stroke patients and their family caregivers as they transitioned through the stroke care continuum from acute care to inpatient rehabilitation to home. METHODS: Thirty eight participants, 19 recovering stroke patients (11 male, 8 female), 15 primary family caregivers (14 spouses, 1 mother), and 4 adult children were interviewed during their stay at a rehabilitation facility and within 6 months of discharge. Interview questions were loosely structured and focused on the stroke experience and how patients and caregivers were managing postdischarge. Data were analyzed using dimensional and comparative analysis. RESULTS: Findings were organized in a conceptual framework illustrating the trajectory of the crisis of stroke. Stroke survivors and their caregivers faced enormous challenges as they moved through 3 phases of the trajectory: the stroke crisis, expectations for recovery, and the crisis of discharge. Findings from this study suggest that as caregivers move through the phases of the trajectory, they do not have a good understanding of the role to which they are committing, and they are often underprepared to take on even the basic tasks to meet the patients' needs on discharge. CONCLUSION: Stroke survivors and their caregivers do not have adequate time to deal with the shock and crisis of the stroke event, let al.one the crisis of discharge and all of the new responsibilities with which they must deal. PMID- 22436316 TI - Introduction to a theoretical model based on embodied cognition: a pilot study of the diagnosis and treatment of hemiphobia. AB - PURPOSE: Neurorehabilitation programs have traditionally followed the mind-body dichotomy proposed by Descartes, which resulted in the creation of divergent theoretical frameworks. The purpose of this pilot study is to present a transdisciplinary proposal that integrates human experience via the embodied cognition concept, that is, to explore how the individual relates from their experiential totality. We illustrate this model with a case report: a woman with a physical imbalance caused by stroke, which we diagnose as an experiential disorder and we treat using a transdisciplinary approach. METHODS: The diagnosis is made in relation to the individual's intentionality when balancing; it is then subjected to an analysis based on embodied cognition. A transdisciplinary therapeutic approach consists of devising an intentionality that takes into consideration all intentional components of her balance. RESULTS: Through clinical practice based on embodied cognition, we identify an experiential disorder, which we name hemiphobia. This condition is characterized by avoidant motor behavior, hyperactivation of physiological tone, feelings of anxiety, and the suppression of reasoning during the motor task of balancing. We apply a transdisciplinary treatment incorporating intentionality as embodied cognition, body schema, body image, motor therapy, and metacognitive skills. This application improved her motricity skills in balancing and walking. CONCLUSIONS: The development of a theoretical model based on embodied cognition, in conjunction with the transdisciplinary treatment of hemiphobia, make a more profound and complex learning model possible to achieve the conscious integration of the motor function, the emotional variable, and the cognitive dimension as essential components of neurorehabilitation. PMID- 22436317 TI - [Correlation between TLR2 and TLR4 levels and adrenal gland response in trauma patients]. PMID- 22436318 TI - [Genetic determinants of acute renal damage risk and prognosis: a systematic review]. AB - INTRODUCTION: Acute renal damage (ARD) is a frequent syndrome in hospitalized patients. It is well accepted that ARD susceptibility and outcome are related to environmental risk factors and to the patient premorbid status. Recently, host factors have also been recognized as important in ARD predisposition and evolution. OBJECTIVE: To analyze genetic influences related to the risk and severity of ARD. DATA SOURCE: MEDLINE search. SELECTION OF STUDIES: articles published in English or Spanish between 1/1/1995 and 31/5/2011, analyzing the association between genic polymorphisms and (a) ARD susceptibility in patients versus healthy controls or within groups of patients; or (b) ARD severity. EXCLUSION CRITERIA: studies published only in abstract form, case reports or including patients less than 16 years of age, on chronic dialysis or having received a renal transplant. DATA EXTRACTION: at least one investigator analyzed each manuscript and collected the information using a predefined form. RESULTS: We identified 12 relevant studies that included 4835 patients. Eleven genes showed polymorphisms related to ARD susceptibility or severity. They were related to cardiovascular regulation (ACE I/D, eNOS, FNMT and COMT), inflammatory response (TNFalpha, IL10, IL6, HIP-1alpha, EPO), oxidative stress (NAPH oxidase) and lipid metabolism (APO E). Only APO E, ACE and AT1 receptor have been analyzed in more than one study. CONCLUSION: ARD susceptibility and severity is influenced by genetic factors, which are multiple and involve different physiopathological mechanisms. PMID- 22436319 TI - Ventrain: an ejector ventilator for emergency use. AB - BACKGROUND: A small, flow-regulated, manually operated ventilator designed for ventilation through a narrow-bore transtracheal catheter (TTC) has become available (Ventrain, Dolphys Medical BV, Eindhoven, The Netherlands). It is driven by a predetermined flow of oxygen from a high-pressure source and facilitates expiration by suction. The aim of this bench study was to test the efficacy of this new ventilator. METHODS: The driving pressure, generated insufflation, and suction pressures and also the suction capacity of the Ventrain were measured at different oxygen flows. The minute volume achieved in an artificial lung through a TTC with an inner diameter (ID) of 2 mm was determined at different settings. RESULTS: Oxygen flows of 6-15 litre min(-1) resulted in driving pressures of 0.5-2.3 bar. Insufflation pressures, measured proximal to the TTC, ranged from 23 to 138 cm H(2)O. The maximal subatmospheric pressure build-up was -217 cm H(2)O. The suction capacity increased to a maximum of 12.4 litre min(-1) at an oxygen flow of 15 litre min(-1). At this flow, the achievable minute volume through the TTC ranged from 5.9 to 7.1 litres depending on the compliance of the artificial lung. CONCLUSIONS: The results of this bench study suggest that the Ventrain is capable of achieving a normal minute volume for an average adult through a 2 mm ID TTC. Further in vivo studies are needed to determine the value of the Ventrain as a portable emergency ventilator in a 'cannot intubate, cannot ventilate' situation. PMID- 22436320 TI - Urogenital/pelvic pain in men. AB - PURPOSE OF REVIEW: The review is based on a Medline literature search using key words relating to male urogenital/pelvic pain for the years 2009-2011. RECENT FINDINGS: The review covers those studies relating to cause, ongoing mechanisms and treatments. SUMMARY: The review highlights that the patients are often polysymptomatic with multimodal/system issues that require a team approach that involves multiple specialties and multiple disciplines. PMID- 22436321 TI - Recognizing the value and needs of the caregiver in oncology. AB - PURPOSE OF REVIEW: This article reviews recent studies (published in 2010 and 2011) dealing with cancer caregivers' needs. The studies are organized by the phase of the illness trajectory studied and the association with demographic characteristics and quality-of-life outcomes. RECENT FINDINGS: The findings indicate that the major issues faced were: caregivers' needs for managing the psychological concerns of the patient as well as their own concerns, managing the patients' medical symptoms and side effects, and obtaining help with daily tasks. These needs vary across the patient's illness trajectory. Although fairly consistently mentioned during the end-of-life and bereavement phases, spiritual concerns caregivers are facing in cancer care were not systematically documented in other phases of survivorship. The caregivers' needs were often not satisfactorily met. Caregivers who are younger and lack social resources appear to report greater unmet needs and poorer quality of life. Caregivers' unmet needs are strong and consistent predictors of poor mental health. SUMMARY: The findings suggest that programs must be developed for caregivers who are younger and lack social resources and who report greater unmet needs and poorer quality of life. Also, future efforts need to include longitudinal studies that bridge survivorship and bereavement phases. PMID- 22436322 TI - The placebo in practice: how to use it in clinical routine. AB - PURPOSE OF REVIEW: Recent placebo literature provides the scientific basis for the different psychological factors that influence the outcome of a medical treatment. The aim of the present review is to summarize the recent findings of placebo research offering useful tools for everyday medical routine. RECENT FINDINGS: Treatment efficacy is influenced by the patient's expectations of therapeutic benefit. Indeed, positive or negative expectations may lead to symptom improvement or worsening, respectively. Therefore, in clinical practice, patients' expectations and beliefs need to be considered and controlled appropriately. In addition, previous experience influences the healing process, as shown by classical conditioning studies. This knowledge can be used to increase the effect of pharmacological or procedural treatments, to reduce drug intake, and to minimize psychological adverse events. Overall, a significant enhancement of the therapeutic outcome can be obtained by potentiating empathic communication and establishing a cooperative patient-provider relationship. SUMMARY: Placebo research provides solid scientific ground for all those psychological aspects that characterize every medical treatment. It also gives us information on the functioning of the human brain, with the possibility to exploit some of these mechanisms in routine medical practice. PMID- 22436323 TI - Ketamine for chronic noncancer pain: concerns regarding toxicity. AB - PURPOSE OF REVIEW: Ketamine misuse and abuse is on the increase. This review focuses on recent studies on ketamine toxicity in recreational users and possible implications for the use of ketamine in chronic pain therapy. RECENT FINDINGS: Urological toxicity, hepatotoxicity and cognitive deficits are all reported as adverse effects of the recreational use of ketamine. Urological toxicity and hepatotoxicity have been reported as adverse effects of ketamine in pain therapy. SUMMARY: These findings may have implications for the clinical use of ketamine in chronic noncancer pain conditions. Until safety issues are resolved, it is suggested that chronic pain treatment involving higher doses and repeated exposure to ketamine be restricted to the context of randomized, controlled trials or clinical audits. PMID- 22436324 TI - Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice. AB - Besides the receptor-mediated effects of pioglitazone, the involvement of nitric oxide (NO) has been previously demonstrated in some pioglitazone-induced central and peripheral effects. In the present study, the effects of acutely administered pioglitazone on pentylenetetrazole (PTZ)-induced seizures and involvement of NO were evaluated in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. A single dose of pioglitazone (10, 20, 40 and 80 mg/kg, p.o.) was administered either 2 or 4h prior to induction of seizures. For determination of possible role of peroxisome proliferator activated receptor gamma (PPAR-gamma) and nitric oxide pathway in this effect, the effects of a PPAR gamma antagonist, GW9662 (2 mg/kg); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.3, 1, 3, and 10 mg/kg); a specific iNOS inhibitor, aminoguanidine (100mg/kg, i.p.) or a nitric oxide precursor, L-arginine (30, 60, 100 and 200mg/kg, i.p.); each administered 15 min prior to pioglitazone, were investigated on the anticonvulsant effect of this drug. Administration of pioglitazone (40 and 80 mg/kg) increased the threshold of PTZ-induced seizure in a dose-dependent, and time-dependent manner. GW9662 reversed the anticonvulsant effect of pioglitazone (40 mg/kg). Acute administration of L-NAME (1, 3 and 10mg/kg) inhibited the anticonvulsant effect of pioglitazone (40 mg/kg), the same result was detected with aminoguanidine (100mg/kg); whereas L-arginine, in the noneffective dose (100mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of pioglitazone (20mg/kg). CONCLUSION: The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-gamma antagonist, and both a specific- and a non specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, L-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-gamma receptor-mediated pathway and also, at least partly, through the nitric oxide pathway. PMID- 22436325 TI - Comparison of granulometric methods and sampling strategies used in marine habitat classification and Ecological Status assessment. AB - Sediment particle size analysis (PSA) is routinely used to support benthic macrofaunal community distribution data in habitat mapping and Ecological Status (ES) assessment. No optimal PSA Method to explain variability in multivariate macrofaunal distribution has been identified nor have the effects of changing sampling strategy been examined. Here, we use benthic macrofaunal and PSA grabs from two embayments in the south of Ireland. Four frequently used PSA Methods and two common sampling strategies are applied. A combination of laser particle sizing and wet/dry sieving without peroxide pre-treatment to remove organics was identified as the optimal Method for explaining macrofaunal distributions. ES classifications and EUNIS sediment classification were robust to changes in PSA Method. Fauna and PSA samples returned from the same grab sample significantly decreased macrofaunal variance explained by PSA and caused ES to be classified as lower. Employing the optimal PSA Method and sampling strategy will improve benthic monitoring. PMID- 22436326 TI - What are the beliefs of pediatricians and dietitians regarding complementary food introduction to prevent allergy? AB - BACKGROUND: The timing of complementary food introduction is controversial. Providing information on the timing of dietary introduction is crucial to the primary prevention of food allergy. The American Academy of Pediatrics offers dietary recommendations that were updated in 2008. OBJECTIVE: Identify the recommendations that general pediatricians and registered dietitians provide to parents and delineate any differences in counselling. METHODS: A 9-item survey was distributed to pediatricians and dietitians online and by mail. Information on practitioner type, gender, length of practice and specific recommendations regarding complementary food introduction and exposure was collected. RESULTS: 181 surveys were returned with a 54% response rate from pediatricians. It was not possible to calculate a meaningful dietitian response rate due to overlapping email databases. 52.5% of all respondents were pediatricians and 45.9% were dietitians. The majority of pediatricians and dietitians advise mothers that peanut abstinence during pregnancy and lactation is unnecessary. Dietitians were more likely to counsel mothers to breastfeed their infants to prevent development of atopic dermatitis than pediatricians. Hydrolyzed formulas for infants at risk of developing allergy were the top choice of formula amongst both practitioners. For food allergy prevention, pediatricians were more likely to recommend delayed introduction of peanut and egg, while most dietitians recommended no delay in allergenic food introduction. CONCLUSIONS: In the prophylaxis of food allergy, pediatricians are less aware than dietitians of the current recommendation that there is no benefit in delaying allergenic food introduction beyond 4 to 6 months. More dietitians than pediatricians believe that breastfeeding decreases the risk of atopic dermatitis. Practitioners may benefit from increased awareness of current guidelines. PMID- 22436327 TI - T cell trafficking and metabolism: novel mechanisms and targets for immunomodulation. AB - Coordinated migratory events by naive and memory T cells are key to effective immunity. Naive T cells predominantly recirculate through secondary lymphoid tissue until antigen encounter, while primed T cells efficiently localize to antigen-rich lymphoid and non-lymphoid tissue. Tissue-selective targeting by primed T cells is achieved by a combination of inflammatory signals and tissue selective homing receptors acquired by T cells during activation and differentiation. A large number of molecular mediators and interactions promoting memory T cell migration to non-lymphoid sites of inflammation have been identified. Recently, additional antigen-driven mechanisms have been proposed, which orchestrate the targeted delivery of memory T cells to antigen-rich tissue. Importantly, recent studies have revealed that the T cell metabolic status influences their differentiation and homing patterns. We here summarize these key observations and discuss their relevance for the manipulation of immune anatomy in therapeutic settings. PMID- 22436328 TI - Patella fracture in a boy with bilateral inferior pole bipartite patellae. AB - We present the case of a 12 year old boy who had bilateral inferior pole fragment (Saupe type 1) bipartite patellae, and who sustained a traumatic separation through the right patella while playing basket ball, the left remaining asymptomatic. We have reviewed and discussed the previously published literature and case reports. PMID- 22436329 TI - Computed tomography based evaluation of the bone mineral density around the fixation area during knee ligament reconstructions: clinical relevance in the choice of fixation method. AB - INTRODUCTION: This study examined the bone density around the fixation area during knee ligament reconstructions and assessed how this clinical relevance can be applied to a firm construction for a reconstructed ligament. MATERIALS AND METHODS: Fifty consecutive patients (25 healthy men and 25 healthy women) were enrolled in this study. A quantitative computed tomography was used to determine the trabecular bone density at the 7 clinically relevant areas (anteromedial area of proximal tibia, anterolateral area of proximal tibia, posteromedial area of the proximal tibia, posterocentral area of the proximal tibia, posterolateral area of the proximal tibia, near femoral tunnel entrance of the ACL, near the femoral funnel entrance of the PCL). The means and standard deviations of the areas of interest were measured using a 10mm diameter circle and the bone density was compared. RESULTS: A comparison of the fixation areas in the proximal tibia, anteromedial area of proximal tibia showed the highest bone density and posterocentral area showed the lowest bone density. A comparison of the PCL tibial fixation with interference screws or trans-condylar fixation revealed the posterocentral area to have the lowest bone density. A comparison of the femoral fixation areas in the ACL and PCL reconstruction revealed no differences in bone density. CONCLUSION: The anteromedial area of the proximal tibia was most acceptable in the interference screw fixation and the posterocentral area had the lowest bone density in the proximal tibia. There were no differences in the femoral fixation areas in the ACL and PCL reconstruction. PMID- 22436330 TI - Numerical classification of curvilinear structures for the identification of pistol barrels. AB - This paper demonstrates a numerical pattern recognition method applied to curvilinear image structures. These structures are extracted from physical cross sections of cast internal pistol barrel surfaces. Variations in structure arise from gun design and manufacturing method providing a basis for discrimination and identification. Binarised curvilinear land transition images are processed with fast Fourier transform on which principal component analysis is performed. One way analysis of variance (95% confidence interval) concludes significant differentiation between 11 barrel manufacturers when calculating weighted Euclidean distance between any trio of land transitions and an average land transition for each barrel in the database. The proposed methodology is therefore a promising novel approach for the classification and identification of firearms. PMID- 22436331 TI - Kinetic characterization of newly discovered inhibitors of various constructs of human T-cell leukemia virus-1 (HTLV-1) protease and their effect on HTLV-1 infected cells. AB - BACKGROUND: Human T-cell leukemia virus-1 (HTLV-1) was the first identified human retrovirus and was shown to be associated with diseases such as adult T-cell leukemia lymphoma and tropical spastic paraparesis/HTLV-1 associated myelopathy. Retroviral proteases (PRs) are essential for viral replication by processing viral Gag and Gag-(Pro)-Pol polyproteins during maturation. Full-length HTLV-1 PR is 125 residues long; whether the C-terminal region is required for catalytic activity is still controversial. In this study, we characterized the effect of C terminal amino acids of HTLV-1 PR for PR activity and examined the binding of compounds identified by in silico screening. One compound showed inhibition against the virus in infected cells. METHODS: Truncated (116-, 121- and 122 residue) forms of HTLV-1 PR were prepared and proteins from expression of the genes were purified. In silico screening was performed by docking small molecules into the active site of HTLV-1 PR. The kinetic constants k(cat), K(m), k(cat)/K(m) and inhibition constants K(i) for inhibitors identified by the computational screening were determined. Western blot and ELISA analyses were used to determine the effect of the most potent PR inhibitors on HTLV-1 protein processing in infected cells. RESULTS: The constructs showed similar catalytic efficiency constants (k(cat)/K(m)); thus HTLV-1 PR C-terminal amino acids are not essential for full activity. Computational screening revealed new PR inhibitors and some were shown to be inhibitory in enzyme assays. In HTLV-1-infected cells, one of the small molecules inhibited HTLV-1 gag cleavage and decreased the amount of HTLV-1 p19 produced in the cells. CONCLUSIONS: We have identified an HTLV-1 PR inhibitor that is biologically functional. Inhibitor screening will continue to develop possible drugs for therapy of HTLV-1 infection. PMID- 22436332 TI - Microfluorescence analysis of nanostructuring inhomogeneity in optical fibers with embedded gallium oxide nanocrystals. AB - A spectroscopic protocol is proposed to implement confocal microfluorescence imaging to the analysis of microinhomogeneity in the nanocrystallization of the core of fibers belonging to a new kind of broadband fiber amplifier based on glass with embedded nanocrystals. Nanocrystallization, crucial for achieving an adequate light emission efficiency of transition metal ions in these materials, has to be as homogeneous as possible in the fiber to assure optical amplification. This requirement calls for a sensitive method for monitoring nanostructuring in oxide glasses. Here we show that mapping microfluorescence excited at 633 nm by a He-Ne laser may give a useful tool in this regard, thanks to quasi-resonant excitation of coordination defects typical of germanosilicate materials, such as nonbridging oxygens and charged Ge-O-Ge sites, whose fluorescence are shown to undergo spectral modifications when nanocrystals form into the glass. The method has been positively checked on prototypes of optical fibers--preventively characterized by means of scanning electron microscopy and energy dispersive spectroscopy--fabricated from preforms of Ni-doped Li2O-Na2O Sb2O3-Ga2O3-GeO2-SiO2 glass in silica cladding and subjected to heat treatment to activate gallium oxide nanocrystal growth. The method indeed enables not only the mapping of the crystallization degree but also the identification of drawing induced defects in the fiber cladding. PMID- 22436333 TI - Bee (Apis mellifera) venom produced toxic effects of higher amplitude in rat thoracic aorta than in skeletal muscle--an ultrastructural study. AB - In this study, changes produced in aorta and triceps surae muscle of Wistar rats as response to bee venom (BV) envenomation were analyzed by transmission electron microscopy and morphometry. A subchronic treatment of 30 days with daily doses of 700 MUg BV/kg and an acute-lethal treatment with a single dose of 62 mg BV/kg were performed. The subchronic treatment resulted in endothelial cell retraction, a thicker subendothelial layer, and thinner elastic laminae and musculoelastic layers in aorta, and thicker endothelium and basal laminae in skeletal muscle. In both tissues polymorphous, swollen mitochondria with disrupted cristae were observed. The acute treatment produced extensive endothelial lesions, breakdown of the collagen layer and migration of muscle cells toward the intima in the aorta, and dilatation of endoplasmic reticulum in the skeletal muscle cells. Mitochondria were almost devoid of cristae or with few circular cristae in the smooth muscle cells while most of the mitochondria presented abnormal circular cristae in the skeletal muscle cells. Degenerative alterations in the aorta were of higher intensity in our experiments-both the intima and media strongly responded to BV, in contrast to those found at the level of the skeletal muscle cells where a moderate degenerative myopathy was recorded. PMID- 22436334 TI - Calibration of piezoelectric positioning actuators using a reference voltage-to displacement transducer based on quartz tuning forks. AB - We use a piezoelectric quartz tuning fork to calibrate the displacement of ceramic piezoelectric scanners that are widely employed in scanning probe microscopy. We measure the static piezoelectric response of a quartz tuning fork and find it to be highly linear, nonhysteretic and with negligible creep. These performance characteristics, close to those of an ideal transducer, make quartz transducers superior to ceramic piezoelectric actuators. Furthermore, quartz actuators in the form of a tuning fork have the advantage of yielding static displacements comparable to those of local probe microscope scanners. We use the static displacement of a quartz tuning fork as a reference to calibrate the three axis displacement of a ceramic piezoelectric scanner. Although this calibration technique is a nontraceable method, it can be more versatile than using calibration grids because it enables characterization of the linear and nonlinear response of a piezoelectric scanner in a broad range of displacements, spanning from a fraction of a nanometer to hundreds of nanometers. In addition, the creep and the speed dependent piezoelectric response of ceramic scanners can be studied in detail. PMID- 22436335 TI - Improved focused ion beam target preparation of (S)TEM specimen--a method for obtaining ultrathin lamellae. AB - Specimen quality is vital to (scanning) transmission electron microscopy (TEM) investigations. In particular, thin specimens are required to obtain excellent high-resolution TEM images. Conventional focused ion beam (FIB) preparation methods cannot be employed to reliably create high quality specimens much thinner than 20 nm. We have developed a method for in situ target preparation of ultrathin TEM lamellae by FIB milling. With this method we are able to routinely obtain large area lamellae with coplanar faces, thinner than 10 nm. The resulting specimens are suitable for low kV TEM as well as scanning TEM. We have demonstrated atomic resolution by Cs-corrected high-resolution TEM at 20 kV on a FIB milled Si specimen only 4 nm thick; its amorphous layer measuring less than 1 nm in total. PMID- 22436336 TI - Electron diffraction based analysis of phase fractions and texture in nanocrystalline thin films, part III: application examples. AB - In this series of articles, a method is presented that performs (semi)quantitative phase analysis for nanocrystalline transmission electron microscope samples from selected area electron diffraction (SAED) patterns. Volume fractions and degree of fiber texture are determined for the nanocrystalline components. The effect of the amorphous component is minimized by empirical background interpolation. First, the two-dimensional SAED pattern is converted into a one-dimensional distribution similar to X-ray diffraction. Volume fractions of the nanocrystalline components are determined by fitting the spectral components, calculated for the previously identified phases with a priori known structures. These Markers are calculated not only for kinematic conditions, but the Blackwell correction is also applied to take into account dynamic effects for medium thicknesses. Peak shapes and experimental parameters (camera length, etc.) are refined during the fitting iterations. Parameter space is explored with the help of the Downhill-SIMPLEX. The method is implemented in a computer program that runs under the Windows operating system. Part I presented the principles, while part II elaborated current implementation. The present part III demonstrates the usage and efficiency of the computer program by numerous examples. The suggested experimental protocol should be of benefit in experiments aimed at phase analysis using electron diffraction methods. PMID- 22436337 TI - Pain relief is associated with decreasing postural sway in patients with non specific low back pain. AB - BACKGROUND: Increased postural sway is well documented in patients suffering from non-specific low back pain, whereby a linear relationship between higher pain intensities and increasing postural sway has been described. No investigation has been conducted to evaluate whether this relationship is maintained if pain levels change in adults with non-specific low back pain. METHODS: Thirty-eight patients with non-specific low back pain and a matching number of healthy controls were enrolled. Postural sway was measured by three identical static bipedal standing tasks of 90 sec duration with eyes closed in narrow stance on a firm surface. The perceived pain intensity was assessed by a numeric rating scale (NRS-11). The patients received three manual interventions (e.g. manipulation, mobilization or soft tissue techniques) at 3-4 day intervals, postural sway measures were obtained at each occasion. RESULTS: A clinically relevant decrease of four NRS scores in associated with manual interventions correlated with a significant decrease in postural sway. In contrast, if no clinically relevant change in intensity occurred (<= 1 level), postural sway remained similar compared to baseline. The postural sway measures obtained at follow-up sessions 2 and 3 associated with specific NRS level showed no significant differences compared to reference values for the same pain score. CONCLUSIONS: Alterations in self reported pain intensities are closely related to changes in postural sway. The previously reported linear relationship between the two variables is maintained as pain levels change. Pain interference appears responsible for the altered sway in pain sufferers. This underlines the clinical use of sway measures as an objective monitoring tool during treatment or rehabilitation. PMID- 22436338 TI - A preliminary investigation of unintentional POP emissions from thermal wire reclamation at industrial scrap metal recycling parks in China. AB - Thermal wire reclamation is considered to be a potential source of unintentional persistent organic pollutants (unintentional POPs). In this study, unintentional POP concentrations, including PCDD/Fs, dioxin like PCBs (dl-PCBs), polychlorinated naphthalenes (PCNs), hexachlorobenzene (HxCBz) and pentachlorobenzene (PeCBz), were quantified in flue gas and residual ash emissions from thermal wire reclamation at scrap metal dismantling parks in Zhejiang Province, China. The total average TEQ emissions of the investigated unintentional POPs from flue gas and residual ash in two typical scrap metal recycling plants ranged from 13.1 to 48.3ngTEQNm(-3) and 0.08 to 2.8ngTEQg(-1), respectively. The dominant PCDD/F congeners were OCDD, 1,2,3,4,6,7,8-HpCDD, OCDF and 1,2,3,4,6,7,8-HpCDF, while PCB-126 and PCB-169 were the main contributors to the toxicity of the dl-PCBs. There were clear differences in the distribution dl PCBs congeners contributing to the TEQ concentrations in the flue gas samples from the two plants. The PCN TEQs were dominated by PCN-66/67 and PCN-73. Although thermal wire reclamation in incinerators has been proposed as an alternative to open burning, there are still considerable environmental risks associated with regulated incinerators, and unintentional POP emissions from thermal wire reclamation sites need to be controlled by local government agencies. PMID- 22436339 TI - Nitrate-ion-selective exchange ability of layered double hydroxide consisting of MgII and FeIII. AB - In this study, layered double hydroxide (LDH) consisting of Mg(II) and Fe(III) (Mg/Fe-LDH) was synthesized by using a combination of coprecipitation with hydrothermal aging, and its anion-exchange properties were investigated. Through various analyses, the chemical formula of the proposed Mg/Fe-LDH was determined to be [Mg(0.76)Fe(0.24)(OH)(2)](Cl(-))(0.21)(CO(3)(2-))(0.02).0.76H(2)O. Furthermore, amorphous Fe(III) impurities were contained in the present Mg/Fe LDH. The proposed Mg/Fe-LDH exhibited clear selectivity for nitrate ions dissolved in water. This selectivity for nitrate ions can be explained by an anion-sieve effect by the existence of amorphous Fe(III) impurities. Our findings suggest that it is possible to synthesize LDHs with high selectivity for various anions by effective hybridizing Fe(III) impurities. PMID- 22436340 TI - Cerium(III) molybdate nanoparticles: Synthesis, characterization and radionuclides adsorption studies. AB - Cerium(III) molybdate nanostructure with average size about 40nm was prepared by adding cerium(III) chloride and ammonium molybdate solutions under varying conditions. The product was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA) and Brunauere Emmette Teller (BET) techniques. Ion exchange capacity of the sample for potassium ion and distribution coefficients (K(d)) for 23 metal ions were determined, the K(d) values for Tl(I), Pb(II), Th(IV), U(VI), and Cs(I) ions were found to be sufficiently high for their removal from various effluents. The adsorption behavior of the sample towards Cs(I)(134) species were studied. Finally, the binary separation of Dy(III)-U(VI), Sm(III)-Th(IV) and Cs(I)-Rb(I) and removal of Cs(I)(134) from the real sample were successfully achieved. PMID- 22436341 TI - Biodegradation of oxytetracycline by Pleurotus ostreatus mycelium: a mycoremediation technique. AB - Oxytetracycline (OTC) is administered in high doses to livestocks and enters the environmental compartments as a consequence of animal waste disposal. As a first step in setting up a useful mycoremediation technique, an OTC lab degradation test was performed in liquid medium using the ligninolytic fungus Pleurotus ostreatus. OTC disappearance in culture medium was clearly evident as early as the third day of exposure onwards, with an almost complete removal after 14d. The drug removal was mediated by fungal absorption in the mycelia, where the OTC molecule underwent a degradation step, as demonstrated by mass spectrometry analyses. A putative degradation product, ADOTC (2-acetyl-2-decarboxamido oxytetracycline) is proposed. Experimental conditions excluded OTC abiotic degradation; the degradation by extracellular laccase was also experimentally discarded. PMID- 22436342 TI - Effect of water composition on TiO2 photocatalytic removal of endocrine disrupting compounds (EDCs) and estrogenic activity from secondary effluent. AB - The effect of inorganic ions and dissolved organic matter (DOM) on the TiO(2) photocatalytic removal of estrogenic activity from secondary effluents of municipal wastewater treatment plants was investigated. The presence of HPO(4)(2 ), NH(4)(+), and HCO(3)(-) resulted in a significantly negative impact on the photocatalytic removal of estrogenic activity from synthetic water due to their strong adsorption on the surface of TiO(2). However, only a weak impact was noted during photocatalytic removal of estrogenic activity from secondary effluent with these ions added, since the presence of DOM in real wastewater played a more important role in inhibiting photocatalytic removal of estrogenic activity than inorganic ions. By investigating the effect of different DOM fractions on photocatalytic removal of estrogenic activity, polar compounds (PC) were found to cause a temporary increase in estrogenic activity during TiO(2) photocatalysis. Fluorescence spectroscopy and molecular weight (MW) analysis on secondary effluent spiked with PC during TiO(2) photocatalysis suggest that large MW organic matter (>4.5kDa) in secondary effluent, such as humic/fulvic acid, not only could play an important role in inhibiting photocatalytic removal of estrogenic activity but also is responsible for the temporary increase in estrogenic activity during the same process. PMID- 22436343 TI - Arsenate removal from simulated groundwater with a Donnan dialyzer. AB - A simple point of use (POU) device based on the theory of Donnan dialysis was developed for the removal of arsenate (As(V)) in the present study. A commercial anion exchange membrane was used as a semipermeable barrier between the feed and stripping solution (As(V)-spiked groundwater and a 12gL(-1) table salt solution, respectively). The proposed POU device could be operated 26 times before replacing the stripping solution. In each batch, approximately 80% of the arsenate anions were transported across the membrane within 24h, and the arsenic concentration of the stripping solution was finally more than 180 times greater than that of the treated water. Cations were well preserved in treated water; however, a slight increase in the sodium ion concentration was observed due to electrolyte leakage. Alternatively, the chloride ion concentration significantly increased at the expense of a loss of sulfate and bicarbonate. The quality of treated water was in compliance with drinking water standards. Membrane fouling was investigated, and a reduction in the As(V) removal rates was not observed when the membrane was used repeatedly. Our results showed that the proposed Donnan dialysis POU device could effectively remove arsenic from drinking water in rural areas in a sustainable manner. PMID- 22436344 TI - Timing of antenatal care for adolescent and adult pregnant women in south-eastern Tanzania. AB - BACKGROUND: Early and frequent antenatal care attendance during pregnancy is important to identify and mitigate risk factors in pregnancy and to encourage women to have a skilled attendant at childbirth. However, many pregnant women in sub-Saharan Africa start antenatal care attendance late, particularly adolescent pregnant women. Therefore they do not fully benefit from its preventive and curative services. This study assesses the timing of adult and adolescent pregnant women's first antenatal care visit and identifies factors influencing early and late attendance. METHODS: The study was conducted in the Ulanga and Kilombero rural Demographic Surveillance area in south-eastern Tanzania in 2008. Qualitative exploratory studies informed the design of a structured questionnaire. A total of 440 women who attended antenatal care participated in exit interviews. Socio-demographic, social, perception- and service related factors were analysed for associations with timing of antenatal care initiation using regression analysis. RESULTS: The majority of pregnant women initiated antenatal care attendance with an average of 5 gestational months. Belonging to the Sukuma ethnic group compared to other ethnic groups such as the Pogoro, Mhehe, Mgindo and others, perceived poor quality of care, late recognition of pregnancy and not being supported by the husband or partner were identified as factors associated with a later antenatal care enrolment (p < 0.05). Primiparity and previous experience of a miscarriage or stillbirth were associated with an earlier antenatal care attendance (p < 0.05). Adolescent pregnant women started antenatal care no later than adult pregnant women despite being more likely to be single. CONCLUSIONS: Factors including poor quality of care, lack of awareness about the health benefit of antenatal care, late recognition of pregnancy, and social and economic factors may influence timing of antenatal care. Community based interventions are needed that involve men, and need to be combined with interventions that target improving the quality, content and outreach of antenatal care services to enhance early antenatal care enrolment among pregnant women. PMID- 22436347 TI - Total exposure duration and proximity of cessation of cannabis use predict severity of sub-clinical psychotic symptoms among former users. AB - In a non-clinical military enrolment setting, former cannabis users (N=81), compared to substance-naive controls (N=132), endorsed markedly elevated rates of schizotypy subscale scores on the Schizotypal Personality Questionnaire (SPQ). Total duration of exposure and proximity of cessation of cannabis use also had an important impact on the severity of psychosis-like symptoms. PMID- 22436348 TI - Adolescent non-suicidal self-injury: a cross-national study of community samples from Italy, the Netherlands and the United States. AB - This study examined rates and correlates of non-suicidal self-injury (NSSI) across three non-clinical adolescent samples from different countries. Surveys were administered to 1862 adolescents (M(age)=15.69, S.D.=0.87) from Italy (n=827), the Netherlands (n=675), and United States (n=360), including measures of NSSI, substance use, internal (i.e., depressive symptoms, loneliness), and interpersonal factors (i.e., peer victimization, peer preference). After controlling for socio-demographic differences, similar prevalence of NSSI was found across the three samples, with approximately 24% of the adolescents reporting at least one NSSI episode within the last year. Multivariate logistic regressions showed that adolescents' victimization and higher levels of depressive symptoms and family-related loneliness were associated concurrently with NSSI comparably in all three samples. However, multi-group analyses indicated that the association between NSSI and substance use varied significantly across samples, indicating that NSSI related more strongly to substance use (i.e., cigarette smoking and frequent marijuana use) in the sample from the United States rather than the samples from the Netherlands and Italy. Findings provide evidence of NSSI and suggest high similarities in rates and correlates across samples from different countries. Future research should further explore NSSI cross-nationally. PMID- 22436349 TI - Family-based association study of cocaine- and amphetamine-regulated transcript (CARTPT) and protein interaction with C-kinase-1 (PICK1) genes in attention deficit hyperactivity disorder. PMID- 22436350 TI - Predictors for suicidal ideation after occupational injury. AB - Risk of suicide has been associated with trauma and negative life events in several studies. Our aim was to investigate the prevalence and risk factors of suicidal ideation, and the population attributable risk among workers after occupational injuries. We investigated workers who had been hospitalized for ?3 days after occupational injuries between February 1 and August 31, 2009. A self reported questionnaire including demographic data, injury condition, and the question of suicidal ideation was sent to 4498 workers at 3 months after their occupational injury. A total of 2001 workers (45.5%) completed the questionnaires and were included in final analysis. The prevalence of reporting suicidal ideation was 8.3%. After mutual adjustment, significant risk factors for suicidal ideation higher than "serious" in a self-rated severity scale (adjusted odds ratio, aOR=2.31; adjusted population attributable risk, aPAR=34.7%), total hospital stay for 8 days or longer (OR=1.98; aPAR=20.5%), intracranial injury (OR=2.30; aPAR=10.2%), and marriage status of being divorced/separated/widowed (OR=2.70; aPAR=10.0%). Three months after occupational injury, a significant proportion of workers suffered from suicidal ideation. Significant predictors of suicidal ideation after occupational injury included broken marriage, intracranial injury, injury severity, and total hospital stay. Identification of high risk subjects for early intervention is warranted. PMID- 22436351 TI - Age-of-onset of schizophrenic and obsessive-compulsive symptoms in patients with schizo-obsessive disorder. AB - Obsessive-compulsive symptoms (OCS) are prevalent, persistent, clinically significant phenomena in schizophrenia. To facilitate the understanding of their temporal interrelationship, we assessed age-of-onset of schizophrenic and obsessive-compulsive symptoms among 133 patients admitted to Tirat Carmel Mental Health Center (Israel) during the years 1999-2010 who met DSM-IV criteria for both schizophrenic disorder and obsessive-compulsive disorder (OCD). The mean age of-onset of the first clinically significant OCS was significantly earlier than the mean age-of onset of the first psychotic symptoms. An earlier onset of OCS was detected in men, but not in women. In sixty-four of 133 patients OCS preceded the first psychotic symptoms, in 37 patients OCS followed them, and in 32 patients OCS and psychotic symptoms occurred simultaneously. A sub-analysis of 52 first-episode schizophrenia patients revealed that OCS emerged approximately 3 years earlier than psychotic symptoms. Notably, schizo-obsessive patients had earlier mean age-of-onset of first psychotic symptoms than a comparative group of 113 non-OCD schizophrenia patients matched for age, gender and number of hospitalization. Earlier emergence of OCS than schizophrenic symptoms in schizo obsessive patients suggests that they are independent of psychosis and are not consequent to schizophrenia. In addition, the presence of OCS seems to modify clinical features of schizophrenia accounting for earlier onset of first psychotic symptoms, however a replication of these findings is needed. PMID- 22436352 TI - Lifetime mood symptoms and adult separation anxiety in patients with complicated grief and/or post-traumatic stress disorder: a preliminary report. AB - A minority of bereaved individuals experiences symptoms of complicated grief (CG) that are associated with significant distress and impairment. CG is currently under consideration for inclusion in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) and a major issue is whether or not it can be differentiated from major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The purpose of this study is to compare the clinical features of CG with those of PTSD and CG+PTSD. A total sample of 116 patients (66 PTSD, 22 CG and 28 CG+PTSD) was recruited. Assessments included: Structured Clinical Interview for DSM-IV Axis-I disorders (SCID-I/P), Inventory of Complicated Grief (ICG), Adult Separation Anxiety Questionnaire (ASA-27), Work and Social Adjustment Scale (WSAS), and Mood Spectrum-Self Report (MOODS-SR) lifetime version. CG was strongly associated with female gender. MDD comorbidity was more common among patients with CG while bipolar disorder was highest among those with PTSD+CG. Patients with CG+PTSD reported significantly higher ASA-27 scores compared to patients with either CG or PTSD alone. Patients with CG+PTSD or PTSD alone reported significantly higher scores on the manic component of the MOODS-SR. No significant differences were reported in the WSAS scores. Our results support differences between CG and PTSD that are important for the consideration of including CG as a new disorder in the DSM-V. PMID- 22436353 TI - The cerebellum and neuropsychiatric disorders. AB - Relative to non-human primates, in humans the cerebellum, and prefrontal cortex are brain regions which have undergone major evolutionary changes. In recent decades, progress in molecular biology and advances in the development of functional neuroimaging analysis have shown that the evolution of the human cerebellum was accompanied by the acquisition of more functions than were previously deduced from human post-mortem studies and animal experimentation. These new cerebellar functions included the control of attention and other cognitive functions, emotions and mood, and social behavior, which were all thought to represent cortical functions. The importance of this new view of cerebellar physiology has been confirmed by the frequency of neuropsychiatric disorders in individuals with cerebellar abnormalities. The information collected in this review emphasizes the importance of cerebellar studies in establishing the physiological substrate of mental diseases. PMID- 22436354 TI - Sitting with others: mental health self-help groups in northern Ghana. AB - BACKGROUND: Over the past four decades, there has been increasing interest in Self-Help Groups, by mental health services users and caregivers, alike. Research in high-income countries suggests that participation in SHGs is associated with decreased use of inpatient facilities, improved social functioning among service users, and decreased caregiver burden. The formation of SHGs has become an important component of mental health programmes operated by non-governmental organisations (NGOs) in low-income countries. However, there has been relatively little research examining the benefits of SHGs in this context. METHODS: Qualitative research with 18 SHGs, five local non-governmental organisations, community mental health nurses, administrators in Ghana Health Services, and discussions with BasicNeeds staff. RESULTS: SHGs have the potential to serve as key components of community mental health programmes in low-resource settings. The strongest evidence concerns how SHGs provide a range of supports, e.g., social, financial, and practical, to service users and caregivers. The groups also appear to foster greater acceptance of service users by their families and by communities at large. Membership in SHGs appears to be associated with more consistent treatment and better outcomes for those who are ill. DISCUSSION: This study highlights the need for longitudinal qualitative and quantitative evaluations of the effect of SHGs on clinical, social and economic outcomes of service users and their carers. CONCLUSIONS: The organisation of SHGs appears to be associated with positive outcomes for service users and caregivers. However, there is a need to better understand how SHGs operate and the challenges they face. PMID- 22436355 TI - Neuroprotective effects of chronic exposure of SH-SY5Y to low lithium concentration involve glycolysis stimulation, extracellular pyruvate accumulation and resistance to oxidative stress. AB - Recent studies suggest that lithium protects neurons from death induced by a wide array of neurotoxic insults, stimulates neurogenesis and could be used to prevent age-related neurodegenerative diseases. In this study, SH-SY5Y human neuronal cells were cultured in the absence (Con) or in the presence (Li+) of a low lithium concentration (0.5 mm Li2CO3, i.e. 1 mm lithium ion) for 25-50 wk. In the course of treatment, growth rate of Con and Li+ cells was regularly analysed using Alamar Blue dye. Resistance to oxidative stress was investigated by evaluating: (1) the adverse effects of high concentrations of lithium (4-8 mm) or glutamate (20-90 mm) on cell growth rate; (2) the levels of lipid peroxidation (TBARS) and total glutathione; (3) the expression levels of the anti-apoptotic Bcl-2 protein. In addition, glucose metabolism was investigated by analysing selected metabolites in culture media and cell extracts by 1H-NMR spectroscopy. As compared to Con, Li+ cells multiplied faster and were more resistant to stress, as evidenced by a lower dose-dependent decrease of Alamar Blue reduction and dose-dependent increase of TBARS levels induced by toxic doses of lithium and glutamate. Total glutathione content and Bcl-2 level were increased in Li+ cells. Glucose consumption and glycolytic activity were enhanced in Li+ cells and an important release of pyruvate was observed. We conclude that chronic exposure to lithium induces adaptive changes in metabolism of SH-SY5Y cells involving a higher cell growth rate and a better resistance to oxidative stress. PMID- 22436356 TI - Challenges in the implementation of evidence in stroke rehabilitation. PMID- 22436357 TI - Are recommendations regarding inpatient therapy intensity following acute stroke really evidence-based? AB - BACKGROUND: Recommendations regarding the daily minimum dose of therapy that patients should receive following stroke are included in many clinical practice guidelines. We examined the related literature to determine whether a specific evidence-based recommendation could be supported. METHOD: Six clinical practice guidelines were retrieved and examined to determine what recommendation, if any, had been made regarding the daily provision of therapy during inpatient rehabilitation. All studies cited by the guideline authors to support their recommendations were identified and retrieved. Studies in which treatment was (a) focused on motor recovery, (b) initiated during inpatient rehabilitation, and (c) provided within 3 months of stroke onset were reviewed in greater detail. RESULTS: Three of the 6 identified guidelines recommended daily minimum amounts of therapy, ranging from 45 to 60 minutes each day of occupational (OT) and physiotherapy (PT), and 3 made general statements indicating that increased intensity of therapy was either recommended or was not recommended. Among the 6 guidelines, 37 studies had been cited to support the recommendations. Of these, 15 were reviewed in detail. On average, patients in the control condition received 48 minutes of therapy per day while those in the experimental group received 63% more, or 78 minutes per day. Patients in the experimental group performed significantly better on the primary outcome in only 5 (33%) studies. CONCLUSIONS: We believe the evidence base cannot support a specific recommendation related to therapy intensity during inpatient rehabilitation following stroke. PMID- 22436358 TI - Barriers to the implementation of constraint-induced movement therapy into practice. AB - BACKGROUND AND PURPOSE: Constraint-induced movement therapy (CIMT) has been studied for many years in the treatment of the hemiplegic upper extremity (UE). However, there has been limited adoption of the protocol in daily practice. METHODS: In this article, we review the CIMT literature specifically for meta analysis, randomized controlled trials (RCTs), recent case reports, case series, and pilot studies of CIMT in the adult poststroke population to identify barriers to implementation. RESULTS: The following barriers have been identified: (a) limited generalizability, (b) resource intensity, (c) therapist factors, (d) patient factors, and (e) uncertainty regarding the emerging debate that the gains seen may be a result of intense, task-specific therapy focused on the use of the more affected UE and not specific to the protocol. CONCLUSIONS: CIMT has positive outcomes in the treatment of a select group of stroke survivors. Many national guidelines of stroke rehabilitation recommend that CIMT be used when appropriate, however adoption into practice has been limited. The issue of generalizability is being addressed by expanding protocol application to other populations. Resource intensity, with respect to cost and therapist time, is a major concern and has lead to the development of novel modes of service delivery. The benefit seen with CIMT may actually be the result of exposure to intense, task-specific therapy with a focus on the use of the more affected UE, but more research into this area is needed. PMID- 22436359 TI - Evidence to practice: botulinum toxin in the treatment of spasticity post stroke. AB - INTRODUCTION: Spasticity is a significant problem following stroke. Although there is extensive research examining the efficacy of botulinum toxin as a treatment, there are challenges in implementing its use. METHODS: The results from previously published randomized controlled trials and systematic reviews examining the use of botulinum toxin as a treatment for poststroke spasticity of the upper and lower limb and the shoulder are summarized. Several barriers to implementation are discussed. RESULTS: There is strong evidence that denervation of muscles, in the lower extremity and upper extremity post stroke, with botulinum toxin reduces focal spasticity. There is also strong evidence that it is associated with a small but significant improvement in gait velocity based on a recent meta-analysis. However, evidence that botulinum toxin injections are associated with improved function and improved quality of life is not as compelling. There is evidence that botulinum toxin injected into the subscapularis muscle can reduce spastic shoulder pain and improve passive range of motion of the hemiplegic shoulder. There are a number of challenges with botulinum toxin, including uncertainty over its role in improving motor dysfunction following stroke, the determination of which subsets of patients may benefit, the cost of treatment, and the identification of meaningful outcome measures. CONCLUSIONS: Botulinum toxin has been shown to be an effective treatment in reducing tone and managing spasticity post stroke. However, its effectiveness in improving function has been more controversial. PMID- 22436360 TI - Rehabilitation of individuals with severe stroke: synthesis of best evidence and challenges in implementation. AB - PURPOSE: The rehabilitation of patients who are recovering from severe stroke is associated with a substantial use of resources but limited potential for functional improvement. As a result, these individuals are not perceived as being ideal candidates for inpatient stroke rehabilitation. The objective of this review was to describe the evidence for and discuss some of the challenges of providing inpatient rehabilitation services for individuals with severe stroke. METHODS: A literature search was conducted to identify relevant studies. Studies were included if (a) inpatient rehabilitation was compared to other rehabilitation settings and (b) the study population included individuals with severe stroke-related disability. Following data abstraction, the methodological quality of randomized controlled trials (RCTs) that met inclusion criteria was assessed using the PEDro scale. RESULTS: Fourteen studies (including 4 RCTs) met inclusion criteria. Despite making limited functional improvement, persons with severe strokes who received inpatient rehabilitation had reduced mortality, decreased lengths of hospital stay, and increased likelihood of discharge home when compared to those who received rehabilitation in other settings. Rehabilitation on specialized stroke units resulted in better outcomes than other forms of inpatient rehabilitation for this group. CONCLUSION: Inpatient rehabilitation is beneficial for individuals with severe stroke. However, for this group, it may be necessary to rethink the emphasis on functional improvement and focus more on discharge planning. These individuals may still have restricted access to rehabilitation as a result of limited resources, the perception that they have poor rehabilitation potential, limited understanding of the goals of rehabilitation for this population, and a lack of research. PMID- 22436361 TI - Adherence to Canadian best practice recommendations for stroke care: assessment and management of poststroke depression in an Ontario rehabilitation facility. AB - BACKGROUND AND PURPOSE: Although Canadian best practice recommendations regarding assessment and management of poststroke depression (PSD) have been established, the degree to which these evidence-based guidelines have been translated into practice is not known. The objectives of the present study are to compare current and recommended best practice and examine possible reasons for identified care gaps. METHODS: Practice audit by chart review was performed to identify recorded screening, assessment, and treatment for PSD in patients discharged from a specialized inpatient rehabilitation program over a 6-month period. A questionnaire was administered to all clinical staff addressing current screening practices as well as opinions regarding the importance and feasibility of identification and treatment of PSD. RESULTS: Of 123 patients, 40 (32.5%) had been prescribed antidepressants at discharge. However, evidence of screening was found for 4.9% of patients; another 9.8% were referred for psychological consult. Treatment was associated with previous antidepressant use or history of depression, but not screening or assessment. Of the survey respondents, 56.2% were not aware of best practice recommendations. However, most felt screening and assessment to be important and treatment was regarded as both simple and effective. CONCLUSIONS: Despite potential benefit associated with identification and treatment of PSD and the availability of evidence-based best practice recommendations, PSD may remain unrecognized and undertreated. Given the juxtaposition of perceived importance with the lack of documented best practice, education regarding standardized screening and the development of consistent clinical protocols including roles and responsibilities in the identification, diagnosis, and treatment of PSD are underway. PMID- 22436362 TI - Adherence to Canadian Best Practice Recommendations for Stroke Care: vascular cognitive impairment screening and assessment practices in an Ontario inpatient stroke rehabilitation facility. AB - BACKGROUND: The Canadian Best Practice Recommendations for Stroke Care suggest that (1) all patients with stroke should be screened for cognitive impairment and (2) persons who are detected as having cognitive impairment on a screening test should receive additional cognitive assessment. The purpose of this study is to determine whether care in an Ontario inpatient stroke rehabilitation facility is consistent with these recommendations. METHODS: Stroke patients discharged from an inpatient stroke rehabilitation program located in Southwestern Ontario, Canada, from May to October 2009 were included in this study. Charts were reviewed to identify current screening and assessment practices. The percentages of patients formally screened and/or assessed as well as differences between those who were and were not screened are reported. RESULTS: The study included 123 patients (62 male; mean age = 67.3,SD 15.1). During inpatient rehabilitation, 82.9% of patients were screened using a formal cognitive screening instrument. Patients with cognitive and/or communication deficits were significantly less likely to be screened than those with intact cognitive and communicative abilities. Although 77.5% of those screened scored below the threshold for cognitive impairment, evidence of referral for a comprehensive cognitive assessment was found for only 3 patients. CONCLUSIONS: Although the majority of patients were screened for cognitive impairment while in inpatient rehabilitation, few patients were referred for a comprehensive diagnostic examination. On the basis of these results from a single inpatient stroke rehabilitation unit, it appears that specific cognitive deficits are likely underidentified in stroke rehabilitation patients in Ontario. PMID- 22436363 TI - Organized stroke rehabilitation in Canada: redefining our objectives. AB - INTRODUCTION: Evidence suggests that patients who receive care in organized stroke units experience better outcomes compared to patients who receive care in general rehabilitation units. As such, the Canadian Stroke Strategy has consistently included provision of "organized" stroke rehabilitation in their best practice recommendations for stroke care. However, recent research in Ontario suggests that development of organized stroke rehabilitation units has not led to the better patient outcomes that had been expected. METHODS: In this article, we review the evidence in favour of organized stroke rehabilitation units, assess the state of organized rehabilitation in Canada (as exemplified by care in Ontario), and discuss potential solutions for better application of best evidence and guideline recommendations for organized stroke care in Canada. RESULTS: The most up-to-date evidence in Canada suggests that best practice recommendations around organized stroke care are currently not adhered to well. However, further exploration suggests that some of the recommendations themselves may not be attainable as currently defined. CONCLUSIONS: It appears that organized stroke care is not available to many Canadians, and better application of recommendations is necessary. Still, re-evaluation of current recommendations may also be necessary to ensure that they fit with the reality of providing care in Canada. PMID- 22436364 TI - Efficacy of executive function interventions after stroke: a systematic review. AB - PURPOSE: Disorders in executive functions are common post stroke and play a critical role in predicting functional recovery. To establish best practice recommendations, it is necessary to appraise the evidence regarding specific executive function interventions post stroke. This systematic review aims to determine whether executive function intervention is more effective than no or alternative intervention in improving executive functions and functional abilities in the acute, subacute, and chronic stages post stroke. METHOD: A systematic review was performed up to January 2011 of MEDLINE, CINAHL, PsychINFO, OTseeker, and Cochrane databases. Eligible studies needed to include a cognitive intervention to remediate executive function impairments post stroke or to improve functional tasks compromised by these impairments. Methodological quality of randomized trials was rated by 2 authors. The level of evidence for each intervention, according to stage of recovery, was determined. RESULTS: Ten studies met inclusion criteria - 1 evaluating treatment in the subacute and 9 in the chronic stage. Limited evidence from the 1 study in the subacute stage (level 2b) and 9 studies (including 3 randomized controlled trials) in the chronic stage (level 2a) support using remedial (eg, computerized working memory training) and compensatory interventions (eg, problem-solving strategies, paging system) for improving executive functioning and, possibly, functional abilities. CONCLUSION: These findings suggest that persons with stroke may possibly benefit from specific executive function training and learn compensatory strategies to reduce the consequences of executive impairments. Further research is needed in acute and subacute stroke, when the impact of treatment is potentially great and where few studies have been undertaken. PMID- 22436365 TI - Shorter length of stay in the stroke unit: comparison between the 1990s and 2000s. AB - PURPOSE: The process ruling length of stay (LOS) in hospitals is complex, and changes over time in LOS have not been explored. The purpose of the study was to examine differences in LOS, use of and satisfaction with health-related services, and capacity in activities of daily living (ADLs) during the first year post stroke in 2 groups of patients with mild to moderate stroke who received care in the same stroke unit. METHOD: The patients (1993/96, n=40; 2006/07, n=43) in this study received care in the stroke unit at Karolinska University Hospital, Huddinge, Sweden. Data on LOS and on the use of health-related services were collected from the Stockholm County Council computerized registers. Satisfaction with health related services was assessed using a questionnaire covering different dimensions of care, while ADLs were assessed using Katz Extended Index of ADL. RESULTS: The LOS in the stroke unit was shorter in the 2006-2007 group (median 8 days) compared to the 1993-1996 group (13 days) (P < .001). Both groups were equally satisfied with health-related services received. A larger proportion of patients were independent in ADLs 3 months post stroke in the 2006-2007 group, but no difference was seen at 6 or 12 months post stroke. CONCLUSION: It seems possible to reduce the number of days spent in the stroke unit after mild to moderate stroke and instead spend days in a rehabilitation unit, and yet achieve similar patient satisfaction and faster recovery in ADL. PMID- 22436366 TI - Probing modifications of cortical excitability during stroke recovery with navigated transcranial magnetic stimulation. AB - OBJECTIVE: To follow cortical excitability changes during recovery from stroke with navigated transcranial magnetic stimulation (nTMS), in particular, to characterize changes of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), to correlate them with recovery of upper extremity function, and to detect possible shifts of cortical hand representations. METHODS: Single and paired pulse nTMS were delivered to the hemisphere with infarction and to the hemisphere without infarction in 14 first ever stroke patients at 1 (T1) and 3 months (T2) after stroke. Electromyographic responses to nTMS stimulation were recorded from the first dorsal interosseus muscles. nTMS was used to ensure an accurate coil repositioning in repeated measurements. Hand function recovery was clinically evaluated using the Action Research Arm Test (ARAT) and 9-hole peg test (9-HPT). RESULTS: SICI and ICF were modulated in both hemispheres during recovery. Inhibition in the hemisphere without infarction correlated significantly with the affected hand performance at T2; stronger disinhibition (poor inhibition) was associated with worse hand performance. Location of hand muscle representations was shifted in 3 well recovered patients out of 14 patients at T2. CONCLUSIONS: In line with earlier studies, disinhibition in the hemisphere without infarction may be related to poor recovery of the affected hand. Usage of the affected hand during stroke recovery seems to influence these cortical excitability changes. nTMS is a valuable tool for tracking muscle cortical representation changes during brain reorganization. PMID- 22436367 TI - Plexiform neurofibroma in an 8 year-old patient. PMID- 22436368 TI - Wernicke's encephalopathy secondary to hyperthyroidism and ingestion of thiaminase-rich products. PMID- 22436369 TI - Longitudinal study of in-hospital consultations with neurology in a tertiary hospital. A health care activity on the increase. AB - OBJECTIVE: In-hospital consultation (IHC) is a service that some medical specialties provide to others with the aim of resolving complications in patients admitted to different hospital units. The aim of this study is to perform a descriptive analysis and longitudinal study of IHCs received in our department during the last 5 years. METHOD: A retrospective study was conducted on the IHCs made within the period 2005-2009. The data analysed were as follows: department of origin of the IHC, reason for consult, date, priority of care, definitive diagnosis, need for follow-up, need for transfer, and the demographic data of the patients. RESULTS: There were a total of 1458 IHCs in the period studied. The mean age of the patients was 58.2 +/- 19.10 years, and 837 (57.6%) were males. The number of IHCs per year was: 2005: 263; 2006: 226; 2007: 239; 2007: 239, 2008: 329 and 2009: 401. The majority (86.8%) had normal priority, 8.5% high priority, and 4.7% were urgent. The Emergency Department (12%), Cardiology (10.9%), General Medicine (9.8%) and Psychiatry (8.9%) were the services with the highest demand. The most frequent reasons for consulting were loss of consciousness and epileptic seizures (24.6%), cerebral vascular disease (21.1%), and confusional states and cognitive impairment (13.4%). Over one third (36.8%) were resolved in the first consultation, and the remainder (63.8%) required follow up. Of all the cases assessed, 8.4% required transfer to Neurology. CONCLUSIONS: IHC is a complex activity that may not resolve all questions in a single visit. It involves a health care burden which is increasing annually. The increasing diagnostic complexity of the neurology, as well as the increasingly more specific treatments are the factors that lead to this higher demand. PMID- 22436370 TI - The neurologist facing pain in dementia. AB - INTRODUCTION: Ageing, a common background in dementia, is usually associated with painful disorders. Nevertheless, the use of analgesics is limited due to poor communication. On the other hand, dementia lesions are placed in the nociceptive pathways. For this reason, the painful experience becomes different and distinctive for every lesional type. COURSE: The lateral nociceptive pathway (lateral thalamic nuclei and primary parietal cortex), which is in charge of the primary pain perception, is preserved in dementia. Thereafter, the shear painful perception, including pain intensity and threshold, remains unmodified. Distinctly, the medial pain pathways are affected by dementia lesions. In this pathway are included: the intralaminar thalamic nuclei, the pons (locus ceruleus:LC), the mesencephalon (periaacueductal grey substance: PGS), the hypothalamus (paraventricular nuclei, mamilary tuberculum) and different areas of the parietal (primary, secondary, operculum), temporal (amigdala, hypoccampus) and frontal (anterior cingular: ACC). As a consequence, the features of pain executed by these areas will be compromised: the cognitive assessment, the mood and emotion inherent to pain, the pain memory or the autonomic responses are modified in dementia. Specifically, in Alzheimer's disease (AD) there is a reduction in the anticipatory and avoidance responses and also a flattening of the autonomic responses. These are essentially secondary to the degenerative changes in the medial temporal (pain memory) and ACC (cognitive and mood aspects) areas. In vascular dementias, there is a cortico-subcortical deafferentation secondary to the white matter lesions. The consequence is the presence of hyperpathy and hyperalgesia. In the frontotemporal dementias, there is a reduction in pain expressivity. It is linked to the lesions in the orbitofrontal and anterior temporal areas, which are responsible of the emotional aspects of pain. In Parkinson's disease, painful conditions are a common characteristic. They are attributed to an early lesion in the LC, which reduces its prominent antinociceptive activity. Finally, in the demented patients there is a lack of expectations to analgesic treatments. This means an absence of the placebo effect, which is, alongside the pharmacokinetic action, an inherent part of the analgesic response. The placebo response is related to activity in the ACC and PGS. Giving its lack, higher doses of analgesics are necessary in dementias. CONCLUSIONS: The assessment of pain in dementia is rather complex, which is the main reason for the scarcity of the analgesic treatment in dementias. It must be specific and systematic. For this purpose, the pain scales are a useful tool. For communicative patients, simple visual scales are helpful, meanwhile in the non communicative patients the multidimensional scales are the most suitable. By this means, the expressive, motor, emotional, functional and social interactions are evaluated. Pain may be responsible of progression and cognitive deterioration in dementia. This evolution could be reversible, and consequently it has to be foreseen in order to implement analgesic treatment. Trying to minimize adverse events, it has to be potent but closely monitored. PMID- 22436371 TI - Peripheral nerve blocks: a therapeutic alternative for hemicrania continua. AB - OBJECTIVES: A complete response to indomethacin is required for the diagnosis of hemicrania continua (HC). Nevertheless, patients may develop side effects leading to withdrawal of this drug. Several alternatives have been proposed with no consistent effectiveness. Both anaesthetic blocks of peripheral nerves and trochlear corticosteroid injections have been effective in some case reports. METHODS: Twenty-two patients with HC were assessed in a headache outpatient office. Physical examination included palpation of the supraorbital nerve (SON) and greater occipital nerve (GON) as well as of the trochlear area. RESULTS: In 14 patients, at least one tender point was detected. Due to indomethacin intolerance, at least one anaesthetic block of the GON or SON, or an injection of corticosteroids in the trochlear area, were performed in nine patients. Four of them were treated with a combination procedure. All these patients experienced total or partial improvement lasting from 2 to 10 months. CONCLUSION: Anaesthetic blocks or corticosteroid injections may be effective in HC patients showing tenderness of the SON, GON or trochlear area. PMID- 22436372 TI - High migraine prevalence in Parma: why? PMID- 22436373 TI - Children in public health nutrition. PMID- 22436374 TI - Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations confer resistance to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs) or a monoclonal antibody cetuximab. METHODS: NSCLC cells (cell lines HCC827, H292, H358, H1650, and H1975) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity, and apoptotic morphology were monitored by spectrophotometry, fluorimetry, and fluorescence microscopy. The combined effect of EGFR siRNA and different drugs was evaluated using a combination index. RESULTS: EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied, albeit with a different magnitude. The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs. The effects of siRNA probably correlate with the overall oncogenic significance of the receptor, which is only partly inhibited by the TKIs. The cells which showed weak response to TKIs, such as the H1975 cell line containing the T790M resistance mutation, were found to be responsive to siRNA knockdown of EGFR, as were cell lines with downstream TKI resistance mutations. The cell line HCC827, harboring an exon 19 deletion mutation, was more than 10-fold more sensitive to TKI proliferation inhibition and apoptosis induction than any of the other cell lines. Cetuximab alone had no relevant in vitro activity at concentrations obtainable in the clinic. The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines, independent of the EGFR mutation status (wild-type or sensitizing mutation or resistant mutation). The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA. CONCLUSIONS: EGFR knockdown by siRNA further decreases the cell growth of lung cancer cells that are treated with TKIs or cetuximab alone, confirming that single agent drug targeting does not achieve a maximal biological effect. The siRNA inhibits EGFR oncogenic activity that bypasses downstream "resistance" mutations such as KRAS and PTEN. The combined treatment of siRNA and EGFR inhibitory agents is additive. The combination of a potent, irreversible kinase inhibitor such as afatinib, with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers, including those with downstream resistance mutations. PMID- 22436375 TI - Molecular cloning and characterization of interleukin-1beta in half-smooth tongue sole Cynoglossus semilaevis. AB - As a member of the interleukin (IL)-1 family, IL-1beta is a prototypical proinflammatory cytokine, which plays a crucial role in immune responses. Herein, we reported the full length cDNA of IL-1beta in half-smooth tongue sole (Cynoglossus semilaevis). The csIL-1beta cDNA contained a 130 bp 5' UTR, a 417 bp 3' UTR and a 741 bp coding sequence (CDS) that translated into a polypeptide of 246 amino acids. The protein sequence included a typical IL-1 family signature and lacked an interleukin-converting enzyme (ICE) cut site. RT-PCR analysis indicated a broad expression of csIL-1beta, especially in immune-related organs. After injection with inactive Vibrio anguillarum, the expression of csIL-1beta was induced in the head kidney and spleen and reached the highest level at 8 h post injection. Higher expression of csIL-1beta was observed at gastrula stage, eye-bud stage and hatching stage and lower level of csIL-1beta mRNA was detected at metamorphic stage. The expression of csIL-1beta during development suggested IL-1beta might be involved not only in immunity but also development. Taken together, the present study indicated that csIL-1beta played an important role in immune responses and development like its mammalian counterparts, although species-specific features were present. PMID- 22436376 TI - Early exposure to probiotics in a canine model of atopic dermatitis has long-term clinical and immunological effects. AB - Probiotics modulate the immune response and may have protective effects against atopic dermatitis (AD). Clinical trials using dogs with spontaneous disease are limited by confounding factors such as different diets, environments and sensitizations while a more controlled evaluation is possible using experimental models. A validated model of canine AD showed that early exposure to Lactobacillus rhamnosus GG (LGG) significantly decreases allergen-specific IgE and partially prevents AD in the first 6 months of life. This study is a follow up three years after discontinuation of LGG. Clinical signs were evaluated after allergen challenge with ragweed, timothy, Dermatophagoides farinae. Allergen specific IgE, IL-10 and TGF-beta were measured on the 1st day of challenge, before allergen exposure. Normal dogs were included as controls. Analyses included seven dogs in the non-probiotic and nine in the probiotic litter. For clinical scores, a 2-Group * 9-Time Analysis of Variance showed significant effects of group (p=0.0003, probiotic=18 years under antihypertensive treatment attended in Spanish PC settings were included. BP control was regarded as optimum when BP values were <140/90mmHg in general population and <130/80mmHg in patients with diabetes, chronic renal disease or cardiovascular disease. BP control was also calculated for all patients when it was <140/90mmHg. RESULTS: A total of 12,961 hypertensive patients (52.0% women) with a mean age of 66.3 (+/-11.4) years were included. A percentage of 46.3 (95% CI: 45.4-47.1) presented good systolic BP and diastolic BP control; 61.1% (IC 95%: 60.2-61.9) of patients presented good BP control<140/90. A percentage of 63.6% was treated with combination therapy (44.1% with 2 drugs, 19.5% with 3 or more). BP control was significantly higher in evening measurements (50.4%) than in morning measurements (45.1%), and in patients who had taken the treatment before the visit (47.9%) compared with those who had not (30.5%). Factors such as not taking the medication before the visit, heavy alcohol consumption and dyslipemia were the risk factors mostly associated with a poor BP control (P<.001). CONCLUSIONS: Five out of 10 hypertensive patients treated in PC settings have an optimal BP control. The degree of control of arterial hypertension has improved with respect to the PRESCAP 2006 study. PMID- 22436385 TI - Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor. AB - BACKGROUND: Daclatasvir (BMS-790052) is an investigational molecule that inhibits the HCV NS5A protein and shows potent antiviral activity apparently across all HCV genotypes. Selection of drug resistance mutations has been reported only for HCV genotype 1, and no information exists for other HCV variants and/or in HIV HCV-coinfected individuals. METHODS: All interferon-alpha-naive, HIV-HCV coinfected patients newly attended at Hospital Carlos III (Madrid, Spain) in 2011 were identified. Changes reported to be associated with daclatasvir resistance in the in vitro replication system for HCV genotype/subtypes 1a/1b (M28T, Q30H/R, L31F/M/V, P32L and Y93C/H/N) were examined. RESULTS: A total of 78 HIV-HCV coinfected individuals as well as 635 NS5A sequences deposited at Los Alamos HCV database were analysed. None of the NS5A sequences from HCV-1a or HCV-3 showed changes associated with daclatasvir resistance. By contrast, all NS5A sequences from HCV-4 harboured L31M. The double mutant L31M+Y93H was found in 7% of HCV-1b and 13% of HCV-4. Finally, all NS5A sequences from HCV-1b and HCV-4 harboured changes at codon 28 (M28L) and 30 (L30R), which are of unknown significance. The rate of all these NS5A polymorphisms did not differ significantly when comparing HIV-HCV-coinfected patients and sequences from HCV-monoinfected subjects deposited at Los Alamos HCV database. CONCLUSIONS: Primary resistance mutations to daclatasvir, an investigational HCV NS5A inhibitor, are not seen in HCV-1a or in HCV-3 as natural polymorphisms. By contrast, they can be recognized in most HCV-1b and HCV-4 strains, regardless HIV coinfection. PMID- 22436386 TI - Selenium-containing naphthalimides as anticancer agents: design, synthesis and bioactivity. AB - Selenium analogues (4b-4h, and 4j) of two known sulfur compounds were synthesized and tested their anticancer activities. The selenium compound 4b had comparable activity with its sulfur analogue 4a, while DNA-binding study showed these two compounds had similar interaction with ct-DNA, the K(b) was 8.23 and 2.36, respectively. The primary results showed that most compounds had moderate anticancer activities with IC(50) values between 10(-6) and 10(-5) M. Another selenium analogue 4j showed the highest activity with the IC(50) values around 5.3 MUM against K562 and MCF-7 cell lines. More importantly, the organochalcogen compounds exhibited stronger anticancer activities against K562 cell line than the other cell lines tested. PMID- 22436387 TI - Synthesis and evaluation of [18F]fluororasagiline, a novel positron emission tomography (PET) radioligand for monoamine oxidase B (MAO-B). AB - The aim of this study was to synthesize and evaluate a novel fluorine-18 labeled analogue of rasagiline (6) as a PET radioligand for monoamine oxidase B (MAO-B). The corresponding non-radioactive fluorine-19 ligand, (1S,2S)-2-fluoro-N-(prop-2 yn-1-yl)indan-1-amine (4), was characterized in in vitro assays. The precursor compound (3aS,8aR)-3-(prop-2-yn-1-yl)-3,3a,8,8a-tetrahydroindeno[1,2 d][1,2,3]oxathiazole 2,2-dioxide (3) and reference standard 4 were synthesized in multi-step syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used in order to determine IC(50) values for compound 4 by use of an enzymatic assay employing kynuramine as substrate. Radiolabeling was accomplished by a two step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulphamidate group. Human whole hemisphere autoradiography (ARG) was performed with [(18)F]fluororasagiline. Blocking experiments with pirlindole (MAO A), L-deprenyl and rasagiline (MAO-B) were conducted to demonstrate the specificity of the binding. A positron emission tomography (PET) study was carried out in a cynomolgus monkey where time activity curves for whole brain and regions with high and low MAO-B activity were recorded. Radiometabolites were measured in monkey plasma using gradient HPLC. Compound 4 inhibited MAO-B with an IC(50) of 27 nM and MAO-A with an IC(50) of 2.3 MUM. Radiolabeling of precursor 3 and subsequent hydrolysis of the protecting group towards (1S,2S)-2-[(18)F]fluoro N-(prop-2-yn-1-yl)indan-1-amine (6) was successfully accomplished with an radiochemical yield of 40-70%, a radiochemical purity higher than 99% and a specific radioactivity higher than 200GBq/MUmol. ARG demonstrated selective binding for [(18)F]fluororasagiline (6) to MAO-B containing brain regions, for example, striatum. The initial uptake in the monkey brain was 250% SUV at 4 min post injection. The highest amounts of radioactivity were observed in the striatum and thalamus as expected whereas in the cortex and cerebellum lower levels were observed. Metabolite studies demonstrated 30% unchanged radioligand at 90 min post injection. Our investigations demonstrated that the new ligand [(18)F]fluororasagiline (6) binds specifically to MAO-B in vitro and has a MAO-B specific binding pattern in vivo. Thus, it could serve as a novel potential candidate for human PET studies. PMID- 22436388 TI - Thioglycine and L-thiovaline: biologically active H2S-donors. AB - Thioglycine and l-thiovaline are stable under acidic and basic conditions but in the presence of bicarbonate they liberate the gasotransmitter H(2)S. In cells both thioamino acids were proven to enhance cGMP formation and promote vasorelaxation in mouse aortic rings. Given that H(2)S is known to lower arterial hypertension, reduce oxidative stress and exhibit cardioprotective effects in preclinical models, H(2)S donors hold promise as novel treatments for cardiovascular diseases. PMID- 22436389 TI - Synthesis of new sulfonamides as lipoxygenase inhibitors. AB - The present study describes a convenient method for the synthesis of new lipoxygenase inhibitors, 4-(toluene-4-sulfonylamino)-benzoic acids from p-amino benzoic acid. Reaction of p-amino benzoic acid with p-toluenesulfonyl chloride provided thirteen N- and O-alkylation products 4a-4m in moderate to good yields. Lipoxygenase inhibition of newly formed sulfonamide derivatives was investigated and some of these compounds 4m, 4g, 4e, 4f and 4j showed good lipoxygenase inhibitory activities with IC(50) values ranged between 15.8 +/- 0.57 and 91.7 +/ 0.61 MUmol whilst all other compounds exhibited mild anti-lipoxygenase activities with IC(50) values ranged between 139.2 +/- 0.75 and 232.1 +/- 0.78 MUmol. N-alkylated products were more active against the enzyme than O-alkylated or both N- and O-alkylated ones. All synthesized sulfonamides were recrystallized in chloroform to give these title compounds which were characterized using FTIR, (1)H NMR, (13)C NMR, elemental analysis and single crystal X-ray diffraction techniques. PMID- 22436390 TI - Database of bioactive ring systems with calculated properties and its use in bioisosteric design and scaffold hopping. AB - A system for identification of bioisosteric scaffolds is presented. The system uses a database of over 7000 scaffolds extracted from bioactive molecules. Scaffolds in the database are characterized by their size, shape, pharmacophore features and several ADME descriptors. Also properties characterizing electron donating or -accepting power at connection vectors are considered. All these features are used as search criteria to find scaffolds with the most similar properties to the query. To guarantee fast processing the search is performed using topological descriptors only, but the system may be used to find optimal replacements of scaffolds also directly in the protein binding site. In this case a set of 3D conformations for the best 2D hits is generated and analogs optimally fitting the binding pocket are identified by overlap with the query ligand and by optimizing interactions with the protein. This tool is used at Novartis as an idea generator for identification of novel non-classical bioisosteric analogs in the drug discovery process. PMID- 22436391 TI - Identification of benzoylisoquinolines as potential anti-Chagas agents. AB - A set of three 3-benzoyl substituted isoquinolones was synthesized in good yields and assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease. Depending on the concentration evaluated, a greater or equivalent reduction in the number of bloodborne trypomastigotes compared to that observed with benznidazole, a drug currently used to attack the parasite, was observed for two of the samples. In order to assess the potential of the 3-benzoylisoquinolone nucleus as a possible scaffold in the design of novel anti-trypanosomal lead structures, a computational analysis was performed using structural and inhibition information from both functional and target assays archived in the online database, ChEMBL. Chemical space projection of the synthesized compounds along with 3067 structures with known activities against T. cruzi shows that the isoquinolones occupy a sparsely populated region of chemical space, indicating their potential for development as a novel class of trypanocidals. In addition, 2D and 3D structural similarity analyses revealed micromolar and submicromolar inhibitors of T. cruzi in ChEMBL with high similarity to the synthesized structures. PMID- 22436392 TI - Clostridium difficile infection in an Iranian hospital. AB - BACKGROUND: Clostridium difficile infection (CDI) is an important cause of morbidity and mortality internationally, yet there are important regional differences in the epidemiology and microbiology of disease. Most reports have come from North America and Europe, with limited information from other regions, including the Middle East. Given the changes in the epidemiology of CDI in developed countries, particularly associated with the dissemination of hypervirulent epidemic clones, an understanding of the epidemiology and microbiology of CDI in diverse regions is warranted. This study involved collection of stool samples from individuals with diarrhea at the Isfahan University of Medical Sciences Teaching Hospital, Isfahan, Iran, between October 2010 and March 2011. Selective enrichment culture for C. difficile was performed and isolates were characterised using ribotyping, PCR for the detection of tcdA, tcdB and cdtB genes, and tcdC sequence analysis. FINDINGS: Clostridium difficile was isolated from 19/89 (21%) stool samples of 17/86 (20%) patients. 13/17 (77%) cases of CDI were hospital-associated. Patients with CDI were significantly older (43 +/- 28y) than those with non-CDI diarrhea (24, +/- 26y)(P = 0.018). All isolates were toxigenic, and possessed genes encoding for toxins A and B. Six (32%) of 19 isolates also possessed cdtB. Twelve ribotypes were identified. Ribotype 078/toxinotype V was most common, accounting for 4 (21%) of isolates. A single isolate of a different toxinotype V ribotype was identified, as was a toxinotype XXIV isolate. The remaining isolates consisted of 9 different toxinotype 0 ribotypes. CONCLUSIONS: CDI is an important cause of diarrhea in patients in this hospital. The diversity of ribotypes was striking, and the number of different types suggests the presence of a broad range of strains in the community, the hospital or both. The predominance of toxinotype V strains, which have been associated with community-associated disease and food animals, was unexpected and possible sources of this type require further investigation. PMID- 22436393 TI - Getting more than they realized they needed: a qualitative study of women's experience of group prenatal care. AB - BACKGROUND: Pregnant women in Canada have traditionally received prenatal care individually from their physicians, with some women attending prenatal education classes. Group prenatal care is a departure from these practices providing a forum for women to experience medical care and child birth education simultaneously and in a group setting. Although other qualitative studies have described the experience of group prenatal care, this is the first which sought to understand the central meaning or core of the experience. The purpose of this study was to understand the central meaning of the experience of group prenatal care for women who participated in CenteringPregnancy through a maternity clinic in Calgary, Canada. METHODS: The study used a phenomenological approach. Twelve women participated postpartum in a one-on-one interview and/or a group validation session between June 2009 and July 2010. RESULTS: Six themes emerged: (1) "getting more in one place at one time"; (2) "feeling supported"; (3) "learning and gaining meaningful information"; (4) "not feeling alone in the experience"; (5) "connecting"; and (6) "actively participating and taking on ownership of care". These themes contributed to the core phenomenon of women "getting more than they realized they needed". The active sharing among those in the group allowed women to have both their known and subconscious needs met. CONCLUSIONS: Women's experience of group prenatal care reflected strong elements of social support in that women had different types of needs met and felt supported. The findings also broadened the understanding of some aspects of social support beyond current theories. In a contemporary North American society, the results of this study indicate that women gain from group prenatal care in terms of empowerment, efficiency, social support and education in ways not routinely available through individual care. This model of care could play a key role in addressing women's needs and improving health outcomes. PMID- 22436394 TI - Cannabis use and anticipatory pleasure as reported by subjects with early psychosis and community controls. AB - BACKGROUND: There is evidence of decreased pleasure and deficits in the anticipation of reward in both psychotic illness and drug addiction. Individuals with low anticipatory pleasure may preferentially engage in behaviours associated with immediate reward such as cannabis use. METHOD: Ninety-one psychosis patients and 91 controls without history of psychosis were administered the Temporal Experience of Pleasure Scale (TEPS), a self report which measures anticipatory and consummatory pleasure. Cannabis use diagnosis was assessed using the Structured Clinical Interview for DSM IV (SCID). Subjects reported the frequency of cannabis consumption and time since last use. RESULTS: Patients did not show a significant deficit in anticipatory or consummatory pleasure compared to controls; however, patients with an active cannabis-use disorder tended to have lower consummatory pleasure than controls with active cannabis disorder (p<.05). Patients who continued to use cannabis during treatment of their first episode of psychosis reported significantly lower anticipatory pleasure compared to those who had a lifetime cannabis diagnosis but were able to maintain abstinence (F(1,60)=5.6, p=.021). Frequency of cannabis use was negatively correlated to anticipatory and consummatory pleasure (Pearson R=-.46, -.48 respectively) in 37 patients currently using cannabis but not in 46 cannabis-using controls (partial R=-.04, -.07 respectively). CONCLUSION: Anticipatory pleasure may not be decreased in early psychosis patients. Lower hedonic response may be associated with persistent, heavy cannabis use in patients in the early phase of psychotic disorders. PMID- 22436395 TI - The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat. AB - Dual orexin receptor (OXR) antagonists emerge as a novel therapeutic class to treat insomnia that, based on anti-addictive effects of selective OXR type 1 antagonists in rats, might be associated with less abuse liability than commonly used gamma-aminobutyric acid (GABA) receptor modulators. Here, we studied the effects of the sleep-enabling dual OXR antagonist almorexant on conditioned place preference (CPP) and locomotor sensitization in rats. First, we compared almorexant to the GABA metabolite gamma-hydroxybutyrate (GHB), which is clinically used as a sleep-inducing drug and which is associated with mild abuse liability. Whereas conditioning with GHB induced significant place preference, conditioning with almorexant did not. Second, we tested the potential of almorexant to interfere with the conditioned rewarding or locomotor sensitizing effects related to psychostimulants or opiates. Almorexant attenuated the expression of CPP to high doses of cocaine (15 mg/kg) and d.l-amphetamine (2 mg/kg), but not to high dose of morphine (10 mg/kg). Conversely, almorexant interfered with the expression of locomotor sensitization to morphine, but not with that to cocaine and d.l-amphetamine. Third, we observed that chronic almorexant (12 d) treatment in morphine, cocaine or amphetamine pre-conditioned and locomotor-sensitized rats had no influence on the maintenance of CPP and locomotor sensitization when tested after almorexant washout. Our findings suggest that almorexant itself does not exert conditioned rewarding effects in the rat and that it may acutely interfere with the expression of CPP or locomotor sensitization in a drug-dependent manner (monoaminergic psychostimulants vs. opiates). PMID- 22436396 TI - Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step. AB - Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF alpha, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities. PMID- 22436397 TI - Socioeconomic inequalities in incidence of lung and upper aero-digestive tract cancer by age, tumour subtype and sex: a population-based study in Scotland (2000 2007). AB - BACKGROUND: Lung and upper aero-digestive tract (UADT) cancer risk is associated with socioeconomic inequality (SEI) but the degree of socioeconomic burden by age, tumour subtype, and sex is not known. METHODS: We reviewed 216,305 cases excluding non melanoma skin cancer (All Cancer) comprising 37,274 lung; 8216 head and neck; and 6534 oesophageal cancers from 2000 to 2007 classified into anatomical or morphology subtypes. Deprivation was measured using the Scottish Index of Multiple Deprivation and SEI was measured using the Slope Index of Inequality and the Relative Index of Inequality (RII). Analyses were partitioned by 5-year age group and sex. RII was adapted to rank tumour type contribution to All Cancer SEI and to examine subtype by age and sex simultaneously. Rank was defined as proportion of All Cancer SEI. RESULTS: All Cancer SEI was greater for males (RII=0.366; female RII=0.279); the combination of lung and UADT SEI contributed 91% and 81% respectively to All Cancer SEI. For both sexes lung and UADT subtypes showed significant SEI (P<0.001) except oesophageal adenocarcinoma in males (P=0.193); for females, SEI was borderline significant (P=0.048). Although RII rank differed by sex, all lung and larynx subtypes contributed most to All Cancer SEI with RII rank for oral cavity, oesophagus-squamous cell, and oropharynx following. For males 40-44 years, SEI increased abruptly peaking at 55 59 years. For females, SEI gradually peaked 10 years later. In both sexes, the SEI peak preceded peak incidence. CONCLUSION: SEI in lung and UADT cancers vary greatly by age, tumour subtype and sex; these variations are likely to largely reflect differences between the sexes in risk behaviours which vary by birth cohort and are socioeconomically patterned. PMID- 22436398 TI - A neonate with fever. PMID- 22436399 TI - The endocrine role of the skeleton: background and clinical evidence. AB - Based on the observation that diabetes, obesity, and hypogonadism influence bone metabolism, the existence of a feedback loop and a common regulation was postulated and an endocrine role ascribed to the skeleton. In the first part of this review, two pathways are described whereby adipose tissue acts on bone mass. In the first, leptin activates the sympathetic nervous system via serotonin and diminishes bone mass accrual. The second pathway functions via the activation of CART (CARTPT) and inhibits bone resorption. The first pathway leads to a decrease in bioactivity of the osteoblast-produced hormone osteocalcin (OC) (part 2). In its undercarboxylated form, OC acts on the three targets pancreas, adipose tissue, and gonads (part 3) and thereby causes an increase in insulin secretion and sensitivity, beta-cell proliferation, and male fertility. Insulin (part 4) is part of a recently discovered regulatory feedback loop between pancreas and osteoblasts. It is a strong counterplayer of leptin as it causes a decrease in OPG expression and enhances bone resorption and OC decarboxylation. Numerous clinical studies (part 5) have shown associations of total and undercarboxylated OC and markers of energy metabolism. Interventional studies, to date only performed in murine models, have shown positive effects of OC administration on energy metabolism. Whether bone tissue has an even further-reaching endocrine role remains to be elucidated. PMID- 22436400 TI - Low-dose estrogen combined oral contraceptives may negatively influence physiological bone mineral density acquisition during adolescence. AB - BACKGROUND: The aim was to evaluate changes of bone mineral density (BMD) and markers of bone turnover in healthy adolescents, and in adolescent users of combined oral contraceptives (COCs) with different ethinylestradiol (EE) contents. METHODS: In this prospective crossover study, 56 healthy females (15 19.5 years) with desire to use hormonal contraception were randomized to COC with either 30 or 15 MUg of EE in crossover design of 9-month intervention each in reverse order. Nonusers of the same age (n=28) served as controls. BMD at lumbar spine (LS), total femur, femoral neck, distal radius, and total body, and serum markers (N-propeptide of type I procollagen, and type I collagen C-telopeptide) were measured at baseline and after 9 and 18 months. RESULTS: In COC nonusers, BMD significantly increased at LS and radius, while markers decreased. In COC users, BMD did not increase, with the exception of LS BMD in the 30 MUg COC group (P<0.05). In the crossover design, a difference between the low- and very low dose COC users was found in LS BMD changes (P<0.05), where increase in BMD was more impaired in the 15 MUg COC users. The skeletal effects of COC remained significant after adjustments for age and smoking status. Markers declined faster in COC users during the first period, while they remained stable or even increased during the second 9 months. CONCLUSION: Physiological acquisition of LS BMD during adolescent age may be prevented by use of COC, especially those containing very low dose of EE. PMID- 22436401 TI - Socioeconomic parameters and mortality in Turner syndrome. AB - BACKGROUND: Turner syndrome (TS) is characterized by hypogonadism, short adult height, increased morbidity and mortality, contrasted by self-reported normal quality of life and perception of health. Small studies have indicated a similar level of education compared with the background population. AIM: To study the socioeconomic profile in TS and the impact of these factors on mortality. MATERIALS AND METHODS: Register study using Danish nationwide registries. Nine hundred and seventy-nine TS females and 94,850 controls were included. Information concerning cohabitation, motherhoods, level of education (bachelor degree), income, retirement, and death were obtained. One hundred and three TS and 5989 controls died during the study period. For the socioeconomic parameters, median age at first relevant episode was calculated. Income was analyzed using conditional logistic regression and the other parameters using Cox regression. RESULTS: In comparison with controls, TS had significantly fewer partnerships (hazard ratio (HR): 0.45), fewer motherhoods (HR: 0.18), and retired earlier (HR: 1.8). After the diagnosis of TS, the risk of retiring was increased. Educational attainment (HR: 1.0) as well as risk of unemployment was similar. Before the age of 30, low income was significantly more frequent; hereafter, it was similar to controls. Mortality was significantly increased (HR: 2.9) and slightly lower after adjustment for cohabitation and education (HR: 2.7). CONCLUSIONS: A divergent socioeconomic profile is apparent, with a reduced proportion of TS persons finding a partner and becoming mothers. The educational level was similar to controls. The increased mortality in TS was not materially affected after adjustment for cohabitation and education. PMID- 22436402 TI - Levels of C-peptide, body mass index and age, and their usefulness in classification of diabetes in relation to autoimmunity, in adults with newly diagnosed diabetes in Kronoberg, Sweden. AB - OBJECTIVE: C-peptide is a main outcome measure in treatment trials of diabetes. C peptide also has a role in the classification of diabetes, which is often difficult in adults and this is also increasingly recognised in adolescents and elders. AIM: We aimed to describe the levels of C-peptide in relation to age and body mass index (BMI) in a large population-based cohort of adults with newly diagnosed diabetes and compare the capabilities of C-peptide, age and BMI to discriminate between autoimmune and non-autoimmune diabetes. SUBJECTS AND METHODS: Blood samples from 1180 patients were analysed regarding islet cell antibody, glutamic acid decarboxylase antibody and fasting C-peptide (FCP). Receiver operating characteristics (ROC) curves were analysed to check the ability of age, BMI and C-peptide to discriminate between autoantibody-positive (Ab(+)) and -negative (Ab(-)) diabetes. RESULTS: Mean FCP was 0.73+/-0.5 (range 0.13-1.80) nmol/l in the Ab(+) and 1.42+/-0.9 (range 0.13-8.30) nmol/l in the Ab( ). FCP was 0.02 nmol/l higher per year increase in age at diagnosis of diabetes. Mean BMI was 26.0+/-4.8 (range 18.0-39.0) kg/m(2) in the Ab(+) and 28.9+/-5.3 (range 15.5-62.6) kg/m(2) in the Ab(-). FCP increased with age also within each BMI group. The highest area under the curve (AUC) in the ROC analysis was found for C-peptide, followed by age and BMI (0.78, 0.68 and 0.66 respectively). CONCLUSIONS: At diagnosis of diabetes, C-peptide was superior to age and BMI in discriminating between autoimmune and non-autoimmune diabetes. C-peptide increased significantly with BMI and age, latter also within each BMI group. Most of the adults had normal or high levels of C-peptide at presentation of diabetes among the autoimmune patients. PMID- 22436403 TI - Pain, sleeping problems and their many relatives. PMID- 22436404 TI - Targeting of prion-infected lymphoid cells to the central nervous system accelerates prion infection. AB - BACKGROUND: Prions, composed of a misfolded protein designated PrP(Sc), are infectious agents causing fatal neurodegenerative diseases. We have shown previously that, following induction of experimental autoimmune encephalomyelitis, prion-infected mice succumb to disease significantly earlier than controls, concomitant with the deposition of PrP(Sc) aggregates in inflamed white matter areas. In the present work, we asked whether prion disease acceleration by experimental autoimmune encephalomyelitis results from infiltration of viable prion-infected immune cells into the central nervous system. METHODS: C57Bl/6 J mice underwent intraperitoneal inoculation with scrapie brain homogenates and were later induced with experimental autoimmune encephalomyelitis by inoculation of MOG(35-55) in complete Freund's adjuvant supplemented with pertussis toxin. Spleen and lymph node cells from the co induced animals were reactivated and subsequently injected into naive mice as viable cells or as cell homogenates. Control groups were infected with viable and homogenized scrapie immune cells only with complete Freund's adjuvant. Prion disease incubation times as well as levels and sites of PrP(Sc) deposition were next evaluated. RESULTS: We first show that acceleration of prion disease by experimental autoimmune encephalomyelitis requires the presence of high levels of spleen PrP(Sc). Next, we present evidence that mice infected with activated prion experimental autoimmune encephalomyelitis viable cells succumb to prion disease considerably faster than do mice infected with equivalent cell extracts or other controls, concomitant with the deposition of PrP(Sc) aggregates in white matter areas in brains and spinal cords. CONCLUSIONS: Our results indicate that inflammatory targeting of viable prion-infected immune cells to the central nervous system accelerates prion disease propagation. We also show that in the absence of such targeting it is the load of PrP(Sc) in the inoculum that determines the infectivity titers for subsequent transmissions. Both of these conclusions have important clinical implications as related to the risk of prion disease contamination of blood products. PMID- 22436405 TI - Self-efficacy is independently associated with brain volume in older women. AB - BACKGROUND: ageing is highly associated with neurodegeneration and atrophy of the brain. Evidence suggests that personality variables are risk factors for reduced brain volume. We examine whether falls-related self-efficacy is independently associated with brain volume. METHOD: a cross-sectional analysis of whether falls related self-efficacy is independently associated with brain volumes (total, grey and white matter). Three multivariate regression models were constructed. Covariates included in the models were age, global cognition, systolic blood pressure, functional comorbidity index and current physical activity level. MRI scans were acquired from 79 community-dwelling senior women aged 65-75 years old. Falls-related self-efficacy was assessed by the activities-specific balance confidence (ABC) scale. RESULTS: after accounting for covariates, falls-related self-efficacy was independently associated with both total brain volume and total grey matter volume. The final model for total brain volume accounted for 17% of the variance, with the ABC score accounting for 8%. For total grey matter volume, the final model accounted for 24% of the variance, with the ABC score accounting for 10%. CONCLUSION: we provide novel evidence that falls-related self-efficacy, a modifiable risk factor for healthy ageing, is positively associated with total brain volume and total grey matter volume. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00426881. PMID- 22436406 TI - Biological meshes: a review of their use in abdominal wall hernia repairs. AB - PURPOSE: Biological meshes are mostly used in infected fields within complex abdominal wall hernia repairs. There is no consensus, however, on the most appropriate material to be used in a given situation. METHODS: A literature review of published articles reporting the utilization of biological meshes in ventral/incisional hernia repair was conducted. Data were analyzed to compare the recurrence rates obtained with biological meshes. MAIN FINDINGS: Only a few prospective comparative studies were identified. Most publications relate to AlloDerm(r), PermacolTM and SurgisisTM with data from other meshes insufficient to draw conclusions. AlloDerm has a 0-100% recurrence rate among studies. It compares poorly with Surgisis and results in an unfavorable outcome when used as a 'bridge prosthesis'. Permacol has consistent recurrence rates of 0-15%, whatever the patients' profiles or the context of infected fields, when considering the most relevant studies. The Surgisis results are more conflicting: the mesh exhibits low recurrence rates in clean fields, but in infected fields the recurrence rate is up to 39%. CONCLUSION: Taken together, these studies suggest that the cross-linked mesh, Permacol has the lowest failure rate and the longest time to failure, particularly in contaminated or infected fields. However, this data should be confirmed by large prospective randomized studies. PMID- 22436407 TI - Behavioral hearing thresholds between 0.125 and 20 kHz using depth-compensated ear simulator calibration. AB - OBJECTIVES: The purpose of this study was to obtain behavioral hearing thresholds for frequencies between 0.125 and 20 kHz from a large population between 10 and 65 yr old using a clinically feasible calibration method expected to compensate well for variations in the distance between the eardrum and an insert-type sound source. Previous reports of hearing thresholds in the extended high frequencies (>8 kHz) have either used calibration techniques known to be inaccurate or specialized equipment not suitable for clinical use. DESIGN: Hearing thresholds were measured from 352 human subjects between 10 and 65 yr old having clinically normal-hearing thresholds (<20 dB HL) up to 4 kHz. An otoacoustic emission probe fitted with custom sound sources was used, and the stimulus levels individually tailored on the basis of an estimate of the insertion depth of the measurement probe. The calibrated stimulus levels were determined on the basis of measurements made at various depths of insertion in a standard ear simulator. Threshold values were obtained for 21 frequencies between 0.125 and 20 kHz using a modified Bekesy technique. Forty-six of the subjects returned for a second measurement months later from the initial evaluation. RESULTS: In agreement with previous reports, hearing thresholds at extended high frequencies were found to be sensitive to age-related changes in auditory function. In contrast with previous reports, no gender differences were found in average hearing thresholds at most evaluated frequencies. Two aging processes, one faster than the other in time scale, seem to influence hearing thresholds in different frequency ranges. The standard deviation (SD) of test-retest threshold difference for all evaluated frequencies was 5 to 10 dB, comparable to that reported in the literature for similar measurement techniques but smaller than that observed for data obtained using the standard clinical procedure. CONCLUSIONS: The depth-compensated ear simulator-based calibration method and the modified Bekesy technique allow reliable measurement of hearing thresholds over the entire frequency range of human hearing. Hearing thresholds at the extended high frequencies are sensitive to aging and reveal subtle differences, which are not evident in the frequency range evaluated regularly (<=8 kHz). Previously reported gender-related differences in hearing thresholds may be related to ear-canal acoustics and the calibration procedure and not because of differences in hearing sensitivity. PMID- 22436408 TI - Electrophysiological properties of cochlear implantation in the gerbil using a flexible array. AB - OBJECTIVES: Cochlear implants (CI) perform especially well if residual acoustic hearing is retained and combined with the CI in the same ear (also termed hybrid or electric-acoustic stimulation). However, in most CI patients, residual hearing is at least partially compromised during surgery, and in some it is lost completely. At present, clinicians have no feedback on the functional status of the cochlea during electrode insertion. Development of an intraoperative physiological recording algorithm during electrode insertion could serve to detect reversible cochlear trauma and optimal placement relative to surviving hair cells. In this report, an animal model was used to assist in determining physiological markers for these conditions using a flexible electrode similar to human surgery. DESIGN: The animal model was the normal-hearing gerbil. The flexible electrodes had 1 to 2 platinum-iridium contacts embedded in a 200 um diameter silastic carrier. As control experiments some insertions were also made with much smaller (50 um diameter) rigid electrodes. In either case, the electrode was positioned at or just inside the round window membrane and subsequently advanced into the scala tympani longitudinally in 50 to 100 um increments. After each advancement, acoustic stimulation was used to elicit a cochlear microphonic (CM) and compound action potential (CAP). Stimuli were suprathreshold tone bursts of 1 to 16 kHz in octave steps with 2 msec rise and fall times and a 10 msec plateau. Anatomical integrity of the cochlea was subsequently assessed using a whole-mount preparation. RESULTS: In contrast with the CAP, which was relatively stable during insertion, the CM showed a variety of changes related to electrode movement. To tone bursts of 1 to 8 kHz the CM typically remained stable or increased during the insertion before contact with cochlear structures. After contact, the potentials often dropped dramatically. The CM to 16 kHz was the most variable; in some cases it increased but in other cases it decreased early in the insertion and later showed large and abrupt increases. In some instances, this pattern was seen to progressively lower frequencies as well. Histological analysis and the gerbil frequency map indicate that electrode travel was limited to the basal turn (~4 mm from the hook) and did not intrude into the characteristic frequency regions of most frequencies used. CONCLUSIONS: First, the CM provides a more sensitive indication of cochlear trauma than does the CAP. Second, stable or steady increases in the CM are a physiological marker for unimpeded travel through the scala tympani as the electrode approaches responding hair cells. Third, abrupt reductions in the CM across frequency are a physiological marker of contact with cochlear structures. Fourth, abrupt increases after a decline, which occurred primarily to 16 kHz but to a lesser degree to other frequencies as well, are a physiological marker for a release from contact. The interpretation is that as the tip of the electrode bends the shaft can move in the mediolateral dimension, sometimes contacting the basilar membrane and sometimes not. Overall, the results indicate that recordings during cochlear implantations can provide valuable feedback to the surgeon regarding electrode position and the integrity of surviving hair cells. PMID- 22436409 TI - A version of the TEN Test for use with ER-3A insert earphones. AB - OBJECTIVE: The aim of this study was to develop a version of the threshold equalizing noise (TEN) test for the diagnosis of dead regions for use with Etymotic ER-3A insert earphones. The use of such earphones is helpful when testing clients with asymmetric hearing loss or clients whose ear canals tend to collapse under the pressure of supra-aural headphones. It can also be useful when ambient noise levels are problematic. DESIGN: The spectral shape of the noise required to give equal masked thresholds at all frequencies, when expressed in dB HL, was derived by empirical measurements of the electrical output of audiometers using ER-3A earphones. To reduce the loudness of the noise and to minimize distortion generated in the audiometer or earphone, the noise was band-limited between 354 and 6500 Hz. In addition, the noise was synthesized using a method that leads to a low crest factor (ratio of peak to root mean square value). This further reduced audiometer/earphone distortion, and allowed higher levels per ERBN; ERBN is the equivalent rectangular bandwidth of the auditory filter at 1 kHz, as determined using young normally hearing subjects. The test tone frequencies were limited to the range 500 to 4000 Hz. Subjects with normal or near-normal hearing were tested using a noise level of 60 dB HL/ERBN, to assess whether the noise did lead to equal masked thresholds in dB HL for all audiometric frequencies from 500 to 4000 Hz. Thresholds in the TEN were measured using manual audiometry with a 2 dB final step size. RESULTS: The mean-masked thresholds varied by 1.3 dB across frequency when expressed in dB HL, and were close to the noise level per ERBN. CONCLUSION: This version of the TEN test can be used with ER-3A insert earphones. PMID- 22436410 TI - A multi-level study of the determinants of mental health service utilization. AB - BACKGROUND: Until now, research has focused on neighbourhood variations in mental health services and their relationships with local attributes, such as healthcare supply and socio-economic deprivation, without controlling for individual characteristics (age, sex, income, or education, for instance). Hence, this study is a major attempt to clarify the role played by individual and local attributes in the utilization of mental health services. The aim of this study was to disentangle individual and neighbourhood effects on mental health service use. METHODS: In this cross-sectional study, individual-level data on 423 participants with a frequent mental health disorder was recruited from the general population and linked to neighbourhood-level data at the census tract level from the 2006 Canadian Census. Neighbourhood variables included socio-economic deprivation, mean income, residential stability and the proportion of recent immigrants. Individual characteristics included gender, age, marital status, self-rated mental health and the number of diagnoses. Multi-level logistic regression was used to assess the effects of individual and neighbourhood characteristics simultaneously on mental health service use. RESULTS: The intraclass correlation coefficient indicated that 12.26% of the variance of mental health service utilization is at the neighbourhood level. Final analysis showed that at the individual level, being female, married, or self-rating mental health less than excellent increased healthcare use. At the neighbourhood level, deprived socio economic neighbourhood decreased health service use (OR=0.71, P<0.05), while residential stability increased use (OR=1.24, P<0.05). CONCLUSIONS: Individual and neighbourhood characteristics determine mental health service utilization. Taking both into consideration allows better targeting of health service policy and planning and enables more accurate needs-based resource allocation. However, future research should continue to investigate the pathway through which neighbourhood affects health service utilization. PMID- 22436411 TI - Prevalence of hypertension and associated risk factors in Benin. AB - BACKGROUND: Hypertension is one of the main risk factors of cardiovascular diseases. There has been a lack of data on this risk factor in the general population in Benin. The aim of this study was to determine the prevalence of hypertension and identify the associated risk factors in Benin. METHODS: A cross sectional study was conducted from July to August 2008 in Benin's 12 departments. The questionnaire and anthropometric measurements of the World Health Organization STEPWISE survey were used. The sample included 6853 subjects 25-64 years of age, randomly selected by five-stage random sampling. Blood pressure was measured using standard procedures. Data was processed and analyzed using EPI DATA and STATA 9.2 software. Prevalence levels were compared using Pearson's chi(2) and means with the Student t-test. Univariate and multivariate regression analysis, taking the sampling method into account, was used to identify risk factors. RESULTS: The sample comprised 49.5% females, the 25- to 34-year-old age group was the largest, and the mean age was 42.7+/-12.4 years. The prevalence of hypertension was 27.9% [95% CI: 26.3-29.5%], 77.5% of the subjects were unaware of their high blood pressure, and 81.6% had not taken their drugs two weeks before the survey. Prevalence of known hypertension was 6.9%, prevalence of treated hypertension 4.8%, and prevalence of controlled hypertension 1.9%. Age and obesity were significantly associated with hypertension. Department and profession were not associated with hypertension. CONCLUSION: This study showed a high prevalence of hypertension in the general population in Benin. Better management of this risk factor will contribute to reducing morbidity and mortality due to cardiovascular diseases. PMID- 22436412 TI - Circulating interleukin-6 levels correlate with residual HIV viraemia and markers of immune dysfunction in treatment-controlled HIV-infected patients. AB - BACKGROUND: Antiretroviral therapy (ART)-controlled HIV-infected patients have elevated levels of systemic inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6, which correlate with increased cardiovascular risk and/or mortality. Persistent low-level viral replication could be involved in this inflammatory state. We evaluated whether residual viral load (VL) correlated with the level of systemic inflammatory/immune markers in ART-controlled HIV-infected patients. METHODS: We evaluated 122 antiretroviral-controlled patients with VL 1 500 copies/ml for circulating levels of high-sensitivity (hs)CRP, hsIL-6, IL-8, soluble (s)CD14 and soluble tumour necrosis factor (TNF) receptors, sTNFR1 and sTNFR2. RESULTS: The patients were 80.3% men, the median age was 47 years, the median CD4(+) T-cell count was 519 cells/mm(3), the median nadir CD4(+) T-cell count was 180 cells/mm(3), the median VL was 28 copies/ml and the median body mass index was 23.3 kg/m(2). The median (range) values for IL-6, CRP, IL-8, sCD14, sTNFR1 and sTNFR2 were 0.685 pg/ml (0.15-5.46), 1.8 mg/l (0.2-9.7), 10.0 pg/ml (1.6-71.1), 1,174 ng/ml (214-3,145), 1,112 pg/ml (583-5,834) and 2,412 pg/ml (1,142-7,688), respectively. IL-6 values correlated positively with HIV VL (rho=0.217, P=0.017). The VL threshold value for significantly increased IL-6 was 31 copies/ml (P=0.023). IL-6 values correlated with markers of immune dysfunction: the CD4/CD8 ratio (rho=-0.248, P=0.011), CD4 nadir level (rho= 0.186, P=0.04) and nadir CD4/CD8 ratio (rho=-0.257, P=0.008). They negatively correlated with markers of immune activation sCD14 (rho=-0.236, P=0.011) and IL-8 (rho=-0.290, P=0.002). We found no correlation between VL and CRP or other markers of inflammation/immune dysfunction including sTNFR1, sTNFR2, sCD14 and IL 8. CONCLUSIONS: We report here that low-range IL-6 levels correlated with low range VL and inversely with sCD14 and IL-8. Our findings suggest that maintaining VL<30 copies/ml in HIV-infected patients might therefore reduce IL-6. PMID- 22436413 TI - Bilateral cochlear implantation in children: localization and hearing in noise benefits. AB - OBJECTIVE: The aim of this study was to report speech performance in quiet and in noise, sound localization with cochlear implanted children bilaterally. Their performances were compared also in unilateral conditions. In addition, speech and language evaluation was analyzed. METHODS: Twenty-three children implanted with Neurelec Digisonic SP devices in 3 tertiary centres were tested on a battery of speech perception tests in quiet and in noise. Localization was assessed by lateralization tasks (90 degrees and 30 degrees ). Progress in speech and language development and subjective assessment of benefit were assessed using several rating scales and questionnaires (categories of auditory perception, speech intelligibility rating, family participating rating scale). RESULTS: Children scored better when tested in bilateral conditions rather than in unilateral conditions. In quiet, the mean scores for the poorer and better side were 52% and 73%, respectively. In the bilateral condition, the mean score increased to 83%. In noise, the mean scores were 39% and 57% respectively, which increased to a mean of 70% in the bilateral condition. Nine children (<9 years) completed the +/-90 degrees lateralization task. For both unilateral conditions performance was not significantly different from chance level. In the bilateral condition, the mean score was 86%. The +/-30 degrees lateralization score was completed by eight of the older children (>9 years). The scores in the unilateral conditions were closed to chance level, but significantly better in the bilateral condition (mean of 86%). CONCLUSIONS: Performances in bilateral conditions were significantly better than in unilateral conditions on speech perception in quiet and in noise. Localization was significantly better when tested in the bilateral condition for +/-90 degrees lateralization task for the younger children and the +/-30 degrees task for the older children. All these results supported the hypothesis than bilateral cochlear implantation is more beneficial than unilateral implantation in children. PMID- 22436414 TI - Foreword. A revolution in cognitive neuroscience. PMID- 22436415 TI - Developmental cognitive neuroscience. PMID- 22436416 TI - Interactive specialization: a domain-general framework for human functional brain development? AB - A domain-general framework for interpreting data on human functional brain development is presented. Assumptions underlying the general theory and predictions derived from it are discussed. Developmental functional neuroimaging data from the domains of face processing, social cognition, word learning and reading, executive control, and brain resting states are used to assess these predictions. Finally, potential criticisms of the framework are addressed and challenges for the future presented. PMID- 22436417 TI - Near-infrared spectroscopy: a report from the McDonnell infant methodology consortium. AB - Near-infrared spectroscopy (NIRS) is a new and increasingly widespread brain imaging technique, particularly suitable for young infants. The laboratories of the McDonnell Consortium have contributed to the technological development and research applications of this technique for nearly a decade. The present paper provides a general introduction to the technique as well as a detailed report of the methodological innovations developed by the Consortium. The basic principles of NIRS and some of the existing developmental studies are reviewed. Issues concerning technological improvements, parameter optimization, possible experimental designs and data analysis techniques are discussed and illustrated by novel empirical data. PMID- 22436418 TI - Genetic and neural dissociation of individual responses to emotional expressions in human infants. AB - Interacting with others by interpreting and responding to their facial expressions is an essential and early developing social skill in humans. We examined whether and how variation in catechol-O-methyltransferase (COMT) and serotonin transporter (5-HTTLPR) genes is associated with 7-month-old infants' electrocortical responses to facial expressions. The results revealed that COMT variants are associated with differences in infants' brain responses to fearful faces over centro-parietal regions, whereas 5-HTTLPR variants are associated with differences in infants' brain responses to happy faces over fronto-temporal regions. Further support for differential associations of these gene variants with emotional processing came from our analysis of infant behavioral temperament: variation in COMT was associated with differences in infants' recovery from distress, whereas variation in 5-HTTLPR was associated with infants' smiling and laughter. This pattern of findings indicates that, in infancy, these genetic variants influence distinct brain systems involved in the processing of either positive or negative emotions. This has wide reaching implications for our understanding of how genetic variation biases specific brain mechanisms, giving rise to individual differences in emotional sensitivity and temperament. PMID- 22436419 TI - True- and false-belief reasoning in children and adults: an event-related potential study of theory of mind. AB - The understanding that another person's belief can differ from reality and that behaviour is guided by beliefs and not by reality reflects an important cornerstone in the development of a Theory of Mind. The present event-related potential (ERP) study had two aims: first, to reveal ERPs that distinguish between false- and true-belief reasoning and second, to investigate the neural changes in the development of false- and true-belief reasoning from childhood to adulthood. True- and false-belief cartoon stories were presented to adults and 6 8-year-old children. Results revealed two waveforms that differentiated between the two conditions: a late positive complex (LPC) associated with the reorientation from external stimuli to internal mental representations and a late anterior slow wave (LSW) associated with stimulus-independent processing of internal mental representations, a process that might be centrally involved in the decoupling mechanism. Additionally, we found developmental effects at an ERP level. Children showed a more posterior localization of the LPC and a broader frontal distribution of the LSW. The results may reflect developmental progress in conceptualizing the mental domain and support the idea that the cortical mentalizing network continues to develop even after children are able to master false beliefs. PMID- 22436420 TI - Severe paraneoplastic hypereosinophilia in metastatic renal cell carcinoma. AB - BACKGROUND: Renal cell carcinoma can cause various paraneoplastic syndromes including metabolic and hematologic disturbances. Paraneoplastic hypereosinophilia has been reported in a variety of hematologic and solid tumors. We present the first case in the literature of severe paraneoplastic hypereosinophilia in a patient with renal cell carcinoma. CASE PRESENTATION: A 46 year-old patient patient with a history of significant weight loss, reduced general state of health and coughing underwent radical nephrectomy for metastasized renal cell carcinoma. Three weeks after surgery, the patient presented with excessive peripheral hypereosinophilia leading to profound neurological symptoms due to cerebral microinfarction. Systemic treatment with prednisolone, hydroxyurea, vincristine, cytarabine, temsirolimus and sunitinib led to reduction of peripheral eosinophils but could not prevent rapid disease progression of the patient. At time of severe leukocytosis, a considerable increase of cytokines associated with hypereosinophilia was measurable. CONCLUSIONS: Paraneoplastic hypereosinophilia in patients with renal cell carcinoma might indicate poor prognosis and rapid disease progression. Myelosuppressive therapy is required in symptomatic patients. PMID- 22436421 TI - Differential expression of cancer associated proteins in breast milk based on age at first full term pregnancy. AB - BACKGROUND: First full term pregnancy (FFTP) completed at a young age has been linked to low long term breast cancer risk, whereas late FFTP pregnancy age confers high long term risk, compared to nulliparity. Our hypothesis was that proteins linked to breast cancer would be differentially expressed in human milk collected at three time points during lactation based on age at FFTP. METHODS: We analyzed breast milk from 72 lactating women. Samples were collected within 10 days of the onset of lactation (baseline-BL), two months after lactation started and during breast weaning (W). We measured 16 proteins (11 kallikreins (KLKs), basic fibroblast growth factor, YKL-40, neutrophil gelatinase-associated lipocalin and transforming growth factor (TGF) beta-1 and -2) associated with breast cancer, most known to be secreted into milk. RESULTS: During lactation there was a significant change in the expression of 14 proteins in women < 26 years old and 9 proteins in women > = 26 at FFTP. The most significant (p < .001) changes from BL to W in women divided by FFTP age (< 26 vs. > = 26) were in KLK3,6, 8, and TGFbeta2 in women < 26; and KLK6, 8, and TGFbeta2 in women > = 26. There was a significant increase (p = .022) in KLK8 expression from BL to W depending on FFTP age. Examination of DNA methylation in the promoter region of KLK6 revealed high levels of methylation that did not explain the observed changes in protein levels. On the other hand, KLK6 and TGFbeta1 expression were significantly associated (r2 = .43, p = .0050). CONCLUSIONS: The expression profile of milk proteins linked to breast cancer is influenced by age at FFTP. These proteins may play a role in future cancer risk. PMID- 22436422 TI - Cancer cell recognition--mechanical phenotype. AB - The major characteristics of cancer metastasis is the ability of the primary tumor cells to migrate by way of the blood or lymph vessels and to form tumors at multiple, distant sites. There are evidences that cancer progression is characterized by disruption and/or reorganization of cytoskeleton (i.e. cellular scaffold). This is accompanied by various molecular alterations influencing the overall mechanical resistance of cells. Current approach in diagnosis focuses mainly on microbiological, immunological, and pathological aspects rather than on the biomechanics of diseases. The determination of mechanical properties of an individual living cell has became possible with the development of local measurement techniques, such as atomic force microscopy, magnetic or optical tweezers. The advantage of them lies in the capability to measure living cells at a single cell level and in liquid conditions, close to natural environment. Here, we present the studies on mechanical properties of single cells originating from various cancers. The results show that, independently of the cancer type (bladder, melanoma, prostate, breast and colon), single cells are characterized by the lower Young's modulus, denoting higher deformability of cancerous cells. However, the obtained Young's modulus values were dependent on various factors, like the properties of substrates used for cell growth, force loading rate, or indentation depth. Their influence on elastic properties of cells was considered. Based on these findings, the identification of cancerous cells based on their elastic properties was performed. These results proved the AFM capability in recognition of a single, mechanically altered cell, also in cases when morphological changes are not visible. The quantitative analysis of cell deformability carried out using normal (reference) and cancerous cells and, more precisely, their characterization (qualitative and quantitative) can have a significant impact on the development of methodological approaches toward precise identification of pathological cells and would allow for more effective detection of cancer-related changes. PMID- 22436423 TI - Early results of systematic drug susceptibility testing in pulmonary tuberculosis retreatment cases in Cameroon. AB - BACKGROUND: The number of pulmonary tuberculosis (PTB) patients reported with resistance to first-line anti-tuberculosis drugs after a standardized retreatment regimen in Cameroon is increasing. Hence, the National Tuberculosis Control Program (NTP) implemented, in one of the ten Regions of the country, a pilot programme aimed at performing routine drug susceptibility testing (DST) for previously treated PTB cases. The objectives of the programme were to evaluate the feasibility of monitoring drug resistance among retreatment cases under programme conditions and to measure the presence and magnitude of anti-TB drug resistance in order to inform NTP policies. FINDINGS: This retrospective cohort study was conducted in the Littoral Region of Cameroon in 2009. It included all sputum smear positive (SM+) PTB cases registered for retreatment. TB cases were identified and classified according to World Health Organization (WHO) recommendations for national TB programs. Bacterial susceptibility testing to first-line anti-TB drugs was performed using standard culture methods. In 2009, 5,668 TB cases were reported in the Littoral Region, of which 438 (7.7%) were SM + PTB retreatment cases. DST results were available for 216 (49.4%) patients. Twenty six patients (12%) harbored multi-drug resistant (MDR) strains. Positive treatment outcome rates were particularly low in retreatment patients with MDR-TB (46.2%; 95% CI: 27.1-66.3). Thirteen MDR-TB patients were treated using a standardized MDR treatment regimen. Delivery of laboratory results took on average 17 (12-26) weeks. CONCLUSIONS: WHO-recommended routine DST in retreatment patients seems feasible in Cameroon. However, coverage needs to be improved through better management. Moreover, diagnostic delay should be shortened by introducing more rapid diagnostic tools. The high risk of MDR in standard regimen failure cases virtually rules out the standard retreatment regimen for such patients without prior DST. PMID- 22436424 TI - Changes in the body condition scores of Nigerian West African Dwarf sheep experimentally infected with mixed infections of Haemonchus contortus and Trichostrongylus colubriformis. AB - Weekly changes in body condition scores and body weights were determined in West African Dwarf sheep following trickle exposure to weekly escalating mixed infections with Haemonchus contortus and Trichostrongylus colubriformis starting with single doses of 500 infective larvae (L(3)) at wk1, 1000 L(3) at wk2, 2000 L(3) at wk3 and 4000 L(3) at wk4. Thirty-three animals were randomly assigned to two groups namely, Group 1 (n=27) and Group 2 (n=6). Group 1 animals were used for experimental infections and Group 2 animals served as uninfected controls. Body condition scores (BCS), body weights (BW), faecal egg counts (FEC) per gram of faeces and worm burden (Wb) were determined using standard procedures. Lambs in group 1 with epg <= 1000 were classified as strong responders (n=16), those with epg between 1000 and 10,000 as intermediate (n=5) and lambs with epg>10,000 on any sampling day were classified as weak responders (n=6). Based on this classification, the mean epg of lambs classified as strong responders was significantly lower (P<0.001) than the epg of lambs classified as weak responders. The body condition scores and body weights of the strong responder lambs were comparable with those of the uninfected control and they were significantly higher than those of the weak and intermediate responders from wk5 till the end of the experiment. There was an inverse and significant relationship between the average BCS of days 56 and 59 and the average FEC of days 56 and 59 (r(s)=-572; P=0.017; n=27) as well as with Wb (r(s)=-531; P=0.028; n=27). We concluded that changes in the body scores are good indicators of the intensity of gastrointestinal nematode infection in the Nigerian WAD sheep. PMID- 22436425 TI - The importance of vertical transmission of Neospora sp. in naturally infected horses. AB - Neospora spp. is a intracellular protozoan phylogenetically closely related to Toxoplasma gondii and Sarcocystis neurona, and it can infect horses leading to the development of reproductive or neurological diseases. We determined the presence of antibodies to Neospora sp. in mares at their parturition time and determine the frequency of vertical transmission in healthy foals to verify the importance of transplacental transmission. The samples were analyzed by indirect immunofluorescence antibody test, showing that seroprevalence in mares is higher than in foals and seropositive mares are likely to transmit the neosporosis to their offspring. This shows that endogenous challenge occurs in horses, and it suggests that this protozoan can be disseminated by means of transplacental transmission in horse species. PMID- 22436426 TI - Biological control of goat gastrointestinal helminthiasis by Duddingtonia flagrans in a semi-arid region of the northeastern Brazil. AB - The aim of this study was to test a pellet formulation in a sodium alginate matrix of Duddingtonia flagrans in the biological control of goat gastrointestinal helminths kept in a native pasture in a semi-arid region of Paraiba state, northeastern Brazil. An area of 2.4 ha was divided into three paddocks, where groups of seven goats ware formed. Each group received the following treatments during the months of March to August 2011: D. flagrans group, received 3g of pellets containing D. flagrans (AC001) for each 10 kg/l.w., twice a week; Moxidectin 0.2% group, received 0.2mg/kg of Moxidectin 0.2% orally, every 30 days; Control group, received 3g of pellets without fungi per 10 kg/l.w., twice a week. Each month, a tracer goat was placed in each group for 30 days and then sacrificed and necropsied. The D. flagrans group showed a greater reduction in EPG, increased weight gain, higher rates of packed cell volume and lower parasitic load burden in the tracer goats compared to Moxidectin 0.2% and Control groups. D. flagrans was efficient in controlling goat gastrointestinal helminthiasis in a semi-arid region of northeastern Brazil. PMID- 22436427 TI - Clinical placement and case study methodology: a complex affair. AB - Clinical placement is a valuable component of nursing education, helping students to authenticate, integrate and develop a range of nursing skills and knowledge. The diversity of nursing curricula throughout the world and the many models of clinical placement make this a difficult subject to research using typical qualitative and quantitative research methodologies. The potential for case study methodology to address the complexity of learning in the clinical environment is significant. This paper argues that Complexity Theory provides an interpretive paradigm that articulates well with case study methodology. This paper also provides an example of the development of a theoretical proposition based on pattern matching. Pattern matching is an approach to data analysis that encourages a consideration of predicted patterns with those that are empirically based. PMID- 22436428 TI - Monoamine oxidase A gene DNA hypomethylation - a risk factor for panic disorder? AB - The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Male subjects showed no or only very minor methylation with some evidence for relative hypomethylation at one CpG site in intron 1 in patients compared to controls. Female patients exhibited significantly lower methylation than healthy controls at 10 MAOA CpG sites in the promoter as well as in exon/intron 1, with significance surviving correction for multiple testing at four CpG sites (p<=0.001). Furthermore, in female subjects the occurrence of negative life events was associated with relatively decreased methylation, while positive life events were associated with increased methylation. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design. PMID- 22436429 TI - Performance of anti-deamidated gliadin peptides antibodies in celiac disease diagnosis. AB - OBJECTIVES: To assess the usefulness of anti-deamidated gliadin peptides antibodies (a-DGP), in the diagnostic of celiac disease (CD). PATIENTS AND METHODS: One hundred and three untreated CD patients (67 children and 36 adults) and 36 celiac patients under gluten-free diet were studied. Two hundred and seventy-four subjects served as controls (114 healthy blood donors, 80 healthy children and 80 patients with primary biliary cirrhosis). a-DGP (IgG and IgA) and anti-tissue transglutaminase antibodies (AtTG) were detected by enzyme-linked immunosorbent assay (Elisa). Anti-endomysium antibodies (AEA) were detected by indirect immunofluorescence on human umbilical cord. RESULTS: The sensitivitiy of IgG and IgA a-DGP were 94% and 97% respectively, compared to 96% for AEA and AtTG. The specificity of a-DGP was 93.6% for IgG and 92% for IgA. The specificity of AEA and AtTG were 100%. The frequency of IgG and IgA a-DGP was significantly higher in patients with CD than in control group (94% vs. 4.4%, P<10(-7); 97% vs. 8%, P<10(-7)). The frequency of IgG a-DGP was the same in children and adult (94%). The frequency of IgA a-DGP were similar in children and adults (95.5% vs. 100%). CONCLUSION: Our study shows that a-DGP increases neither the sensitivity nor the specificity of AEA and AtTG. PMID- 22436430 TI - Expression of epidermal growth factor receptor in canine osteosarcoma: association with clinicopathological parameters and prognosis. AB - Expression of epidermal growth factor receptor (EGFR) is associated with aggressive growth and metastasis of a range of tumours, including osteosarcomas (OS), although some studies have reported no relevance to clinicopathological events or prognosis. The present study evaluated EGFR mRNA and protein expression in a panel of OS cell lines, normal bones, frozen primary OS and tissue microarrays. EGFR expression was significantly elevated in primary OS compared to normal bones and in metastases of OS to the lungs in comparison with extrapulmonary sites. However, there were no clinical or pathological associations with mRNA expression levels in frozen tumours. Tissue microarray analysis demonstrated that a subset of canine OS with high EGFR expression was associated with significantly shorter survival times and disease-free intervals. Cytoplasmic expression of EGFR was present in 75% of metastases and was similar to expression in primary tumours. EGFR expression alone is not a reliable predictor of outcome and other markers are necessary for further prognostic stratification of dogs with OS. However, these findings suggest that a subset of dogs may benefit from anti-EGFR adjuvant therapies. PMID- 22436431 TI - Resin-bonded cantilever and twist-flex wire for maxillary incisor lost due to trauma. AB - A simple appliance to replace an 8-year-old's central incisor, which was decoronated after a trauma, is described. A natural tooth cantilevered pontic bonded to the adjacent central incisor may be an immediate solution. This appliance may be used when clinical conditions do not allow for the use of a conservative removable or fixed partial denture. PMID- 22436432 TI - Separating fact from fiction: use of high-level evidence from research syntheses to identify diseases and disorders associated with periodontal disease. AB - Correlations with periodontitis have been reported for several diseases, although the biological mechanisms that might lead to these putative correlations are generally unclear. This paper describes the most robust of these associations, on the basis of an evaluation of research syntheses (meta-analyses and systematic reviews) available up to June 2011. This high-level evidence indicates that individuals with periodontitis have a significantly higher risk of various other problems, including cardiovascular disease, diabetes mellitus, respiratory disease and preterm low-birth-weight deliveries. For some conditions, treatment of periodontitis leads to a reduction in the rates of the other disease, lending further support to the concept that the association is reversible. An understanding of these correlations is important to allow dental health care providers to inform patients with periodontitis of their increased risks and to counsel such patients to seek additional medical assessment or intervention, as indicated. PMID- 22436433 TI - Measurement of vascular wall attenuation: comparison of CT angiography using model-based iterative reconstruction with standard filtered back-projection algorithm CT in vitro. AB - OBJECTIVES: To compare the performance of model-based iterative reconstruction (MBIR) with that of standard filtered back projection (FBP) for measuring vascular wall attenuation. STUDY DESIGN: After subjecting 9 vascular models (actual attenuation value of wall, 89 HU) with wall thickness of 0.5, 1.0, or 1.5 mm that we filled with contrast material of 275, 396, or 542 HU to scanning using 64-detector computed tomography (CT), we reconstructed images using MBIR and FBP (Bone, Detail kernels) and measured wall attenuation at the center of the wall for each model. We performed attenuation measurements for each model and additional supportive measurements by a differentiation curve. We analyzed statistics using analyzes of variance with repeated measures. RESULTS: Using the Bone kernel, standard deviation of the measurement exceeded 30 HU in most conditions. In measurements at the wall center, the attenuation values obtained using MBIR were comparable to or significantly closer to the actual wall attenuation than those acquired using Detail kernel. Using differentiation curves, we could measure attenuation for models with walls of 1.0- or 1.5-mm thickness using MBIR but only those of 1.5-mm thickness using Detail kernel. We detected no significant differences among the attenuation values of the vascular walls of either thickness (MBIR, P=0.1606) or among the 3 densities of intravascular contrast material (MBIR, P=0.8185; Detail kernel, P=0.0802). CONCLUSIONS: Compared with FBP, MBIR reduces both reconstruction blur and image noise simultaneously, facilitates recognition of vascular wall boundaries, and can improve accuracy in measuring wall attenuation. PMID- 22436434 TI - Meta-analysis study of lymph node staging by 18 F-FDG PET/CT scan in non-small cell lung cancer: comparison of TB and non-TB endemic regions. AB - Lymph node staging in non-small cell lung cancer (NSCLC) is challenging and important for deciding treatment policy. The role of PET/CT scans in lymph node staging of NSCLC remains controversial when comparing TB and non-TB endemic regions. This study systematically reviews the literature regarding the diagnostic performance of PET/CT in lymph node staging of patients with NSCLC, and determines its pooled sensitivity and specificity. METHODS: The databases of PubMed, Medline, and Cochrane library were searched for relevant studies. Two reviewers independently assessed the methodological quality of each study. A meta analysis of the reported sensitivity and specificity of each study was performed. RESULTS: Seven of 86 studies were included. These studies had moderate to good methodological quality. Pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for patient-based analyses (five studies) were 66%, 92.7%, 5.86%, and 0.41%, respectively, and those for lesion-based analyses (six studies) were 59.4%, 96.5%, 9.37%, and 0.31%, respectively. Subanalysis of endemic regions of tuberculosis (TB) showed that these regions had lower sensitivity and similar specificity to non-TB endemic regions. CONCLUSION: PET/CT showed high specificity in the lymph node staging of NSCLC and lower sensitivity in TB endemic regions. PMID- 22436435 TI - The developing brain: from theory to neuroimaging and back. AB - Surprisingly little headway has been made towards understanding how brain growth maps onto mental growth during child development. This review aims at bridging and integrating recent human neuroscientific brain maturation findings with the conceptual thinking of theorists in the behavioural tradition of studying cognitive development. Developmental research in the field of internal control and self-regulation serves as a reference point for understanding the relation between brain maturation and mental growth. Using several recent neuroimaging findings as points in case, we show how a deeper appreciation of structural and functional neural development can be obtained from considering the traditional conceptual frameworks, and vice versa. We conclude that paradigmatic progress in developmental neuroscience can rely more on knowledge from developmental experimental psychology, and that developmental models of cognitive development can be constrained and articulated with more precision on the basis of knowledge of differential structural and functional brain maturation. PMID- 22436436 TI - Neural correlates of dyadic interaction during infancy. AB - This study examines the electrophysiological correlates of dyadic interaction in 14-month-old infants. Infants were presented with three conditions of live stimuli. A baseline condition involved the observation of moving geometric shapes. In a second condition the infant observed an adult performing movements that were not in reference to the infant and were not within the infant's proficient motor repertoire, such as dancing or hopping. A third condition involved face to face dyadic interactions in the context of an imitative game, where the infant and adult engaged in copying each other's hand and facial actions. Motor activity by the infant was controlled between conditions by synchronizing EEG with video frames of action. Infant EEG data was then edited offline to match in motor intensity across conditions. We expected mu rhythm (6-9 Hz) suppression during dyadic interactions relative to the amount of mu present in the baseline condition. This prediction was confirmed. We also observed suppressed mu in the interaction condition relative to the observation condition. The mu rhythm results suggest that infants at 14 months may well utilize a functioning mirroring system during dyadic interactions. PMID- 22436437 TI - Longitudinal development of prefrontal function during early childhood. AB - This is a longitudinal study on development of prefrontal function in young children. Prefrontal areas have been observed to develop dramatically during early childhood. To elucidate this development, we gave children cognitive shifting tasks related to prefrontal function at 3 years of age (Time 1) and 4 years of age (Time 2). We then monitored developmental changes in behavioral performance and examined prefrontal activation using near infrared spectroscopy. We found that children showed better behavioral performance and significantly stronger inferior prefrontal activation at Time 2 than they did at Time 1. Moreover, we demonstrated individual differences in prefrontal activation for the same behavioral tasks. Children who performed better in tasks at Time 1 showed significant activation of the right inferior prefrontal regions at Time 1 and significant activation of the bilateral inferior prefrontal regions at Time 2. Children who showed poorer performance at Time 1 exhibited no significant inferior prefrontal activation at Time 1 but significant left inferior prefrontal activation at Time 2. These results indicate the importance of the longitudinal method to address the link between cognitive and neural development. PMID- 22436438 TI - Learning to read shapes the activation of neural lexical representations in the speech recognition pathway. AB - It has been demonstrated that written and spoken language processing are tightly linked. Here we focus on the development of this relationship at the time children start reading and writing. We hypothesize that the newly acquired knowledge about graphemes shapes lexical access in neural spoken word recognition. A group of preliterate children (six years old) and two groups of beginning readers (six and eight years old) were tested in a spoken word identification task. Using word onset priming we compared behavioural and neural facilitation for target words in identical prime-target pairs (e.g., mon-monster) and in prime target pairs that varied in the first speech sound (e.g., non monster, Variation condition). In both groups of beginning readers priming was less effective in the Variation condition than in the Identity condition. This was indexed by less behavioural facilitation and enhanced P350 amplitudes in the event related potentials (ERPs). In the group of preliterate children, by contrast, both conditions did not differ. Together these results reveal that lexical access in beginning readers is based on more acoustic detail than lexical access in preliterate children. The results are discussed in the light of bidirectional speech and print interactions in readers. PMID- 22436439 TI - Life satisfaction questionnaire (Lisat-9): reliability and validity for patients with acquired brain injury. AB - The aim of this study was to determine the reliability and discriminant validity of the Dutch version of the life satisfaction questionnaire (Lisat-9 DV) to assess patients with an acquired brain injury. The reliability study used a test retest design, and the validity study used a cross-sectional design. The setting was the general rehabilitation centre. There were 159 patients over 18 years of age, with an acquired brain injury, in the chronic phase. The main outcome measures were weighted kappa of test and retest data on the nine questions of the Lisat-9 DV and significance levels of differences between subgroups of patients who are expected to differ in terms of Lisat-9 scores, on the basis of other instruments. The results were as follows: the reliability was moderate, with the weighted kappa ranging from 0.41 to 0.64. In terms of validity, subgroups of patients who were expected to differ in terms of the Lisat-9 domains did indeed differ significantly, except for the difference in the Lisat score for 'contact with friends and acquaintances' between subgroups defined by higher or lower scores on the corresponding domain of the Frenchay Activities Index. As there was a plausible explanation for not finding a significant difference between subgroups defined by one of the Frenchay Activities Index domains and significant differences were found between the subgroups defined by other instruments corresponding to the same domain, we conclude that the discriminant validity is good. The reliability was not clearly affected by cognitive disorder or aphasia. The conclusions were that the reliability of the Lisat-9 DV for patients with an acquired brain injury was moderate; the discriminant validity was good. PMID- 22436440 TI - Modified graded motor imagery for complex regional pain syndrome type 1 of the upper extremity in the acute phase: a patient series. AB - Complex regional pain syndrome (CRPS) is a pathologic condition in which the painful experience is disproportionate in time and intensity in comparison with the inciting event. At present, the pathophysiology of CRPS is not well understood. Several studies have indicated that cortical reorganization plays a role in the persistence of the symptoms. A new promising approach, graded motor imagery (GMI), seems to be effective, but there are limited data for the CRPS-1 upper extremity population. The aim of this study was to demonstrate the effectiveness of a modified GMI (mGMI) protocol based on the work of Moseley to reduce pain and enhance functional capacities for a population with nonchronic CRPS-1 of the upper extremity. The following outcome measures were used to assess the clinical effectiveness: pain (short form of the McGill Pain Questionnaire), grip force (Martin vigorimeter), perception of upper extremity function (Disabilities of the Arm, Shoulder and Hand Questionnaire), and patient's global impression of change. All outcomes at T4 were compared with the baseline data (T0) using the Mann-Whitney test and the chi test (nonparametric tests). Seven patients were recruited for the study. At the end of the mGMI (T4), we obtained significant results for the decrease in the pain experienced in the last 7 days (visual analog scale; P=0.046), improvement in the affected extremity grip force (P=0.042), and the patient's global impression of change (P=0.015). However, the data of the perception of upper extremity function (Disabilities of the Arm, Shoulder and Hand Questionnaire) were not clinically or statistically significant. Our results indicate that this mGMI protocol seems to be a promising therapeutic modality to reduce pain. However, more investigations are needed to determine whether mGMI has a significant impact on upper extremity function. PMID- 22436442 TI - Postictal psychosis and its electrophysiological correlates in invasive EEG: a case report study and literature review. AB - We identified two patients with medically refractory temporal lobe epilepsy, from whom intracranial EEG recordings were obtained at the time of postictal psychosis. Both patients had mesial temporal epilepsy associated with hippocampal sclerosis. In both patients, the postictal psychosis was associated with a continual "epileptiform" EEG pattern that differed from their interictal and ictal EEG findings (rhythmical slow wave and "abortive" spike-slow wave complex activity in the right hippocampus and lateral temporal cortex in case 1 and a periodic pattern of triphasic waves in the contacts recording activity from the left anterior cingulate gyrus). Some cases of postictal psychosis might be caused by the transient impairment of several limbic system structures due to the "continual epileptiform discharge" in some brain regions. Case 2 is the first report of a patient with TLE in whom psychotic symptoms were associated with the epileptiform impairment of the anterior cingulate gyrus. PMID- 22436443 TI - Reliability and validity of the PedsQLTM Generic Core Scales 4.0 for Chinese children with epilepsy. AB - This investigation examines the reliability and validity of the Chinese version of the PedsQL 4.0 Generic Core Scales for prognostic measures of pediatric epilepsy. The study comprised 163 parents whose children, between the ages of 2 and 18 years, were diagnosed with epilepsy. The parents were given a questionnaire to be completed on behalf of the child. Reliability was assessed by Cronbach's alpha analysis. Validity was assessed by the exploratory factor analysis and intercorrelation analysis between the four subscales as well as Student's t-test. The internal consistency reliability for Total Scale Score was 0.94 by Cronbach's alpha test. Four major factors were extracted by factor analysis. The scores from all sub-scales derived from healthy children were significantly higher than children with epilepsy (P<0.001). The reliability and validity of the parent proxy-report scales from the Chinese version of the PedsQLTM 4.0 Generic Core Scales effectively matched the original version and could be used to evaluate the health-related quality of life of children with epilepsy. PMID- 22436444 TI - An adaptive strategy for assessing regional consistency in multiregional clinical trials. AB - BACKGROUND: Unexpected regional difference in treatment effect has been reported in recent multiregional clinical trials (MRCTs). This may cause difficulty in interpreting results and can have regulatory implications such as marketing approvals and/or product labels in various markets. Careful consideration of consistency across regions and appropriate plans to address potential regional difference are necessary at the design stage. However, assessment of consistency in treatment effect is generally not the primary objective, and therefore, when there is no strong a priori reason to expect a regional difference, a MRCT is not usually designed to address the regional consistency. Unexpected regional finding may arise and increase the risk of ambiguous or controversial results at the end of the study. PURPOSE: To mitigate this risk, we propose an adaptive strategy for regional assessment based upon accumulated blinded data. METHODS: If review of accumulated blinded data shows unexpectedly severe imbalance in an intrinsic or extrinsic factor, and further assessment indicates that this factor could be a potential effect modifier as supported by biological plausibility or blinded correlation analysis, a stratified regional analysis controlled for this factor may be specified and documented before database lock. RESULTS: The proposed adaptive strategy can help with the interpretation of unexpected regional finding. A recent trial is used to illustrate the approach. LIMITATIONS: Even if the imbalanced factor may appear to explain away the regional difference, establishment of causal effect is usually difficult and requires more involved effort. CONCLUSIONS: This approach, by prespecifying the stratified analysis, can reduce the risk of post hoc exaggerated emphases across many possible exploratory analyses and provide greater confidence in the validity of the conclusions. If a causal effect can be established that the apparent regional difference is likely caused by this intrinsic or extrinsic factor, this prespecified analysis can also help guide clinical practice. PMID- 22436445 TI - Abietane diterpenes induce cytotoxic effects in human pancreatic cancer cell line MIA PaCa-2 through different modes of action. AB - Abietane diterpenes, especially those containing quinone moieties, are often reported to have cytotoxic effects on cancer cell lines. They deserve greater attention because several cancer chemotherapeutic agents also possess the quinone structural feature. To date, very little is known about their cytotoxic molecular modes of action. In the present study, five diterpenes, 7 alpha acetoxyroyleanone, horminone, royleanone, 7-ketoroyleanone and sugiol which have been previously isolated from the medicinal plant Peltodon longipes were shown to possess cytotoxic activity against the human pancreatic cancer cell line MIA PaCa 2. 7 alpha-Acetoxyroyleanone, horminone and royleanone were demonstrated to possess alkylating properties using the nucleophile 4-(4-nitrobenzyl)pyridine. However, no clear correlation between the alkylating properties and cytotoxicity of these diterpenes was observed. Furthermore, the relaxation activity of human DNA topoisomerases I and II was found to be influenced by these compounds, with 7 ketoroyleanone and sugiol being the most active. These two diterpenes preferentially inhibited topoisomerase I and exhibited lower IC(50) values than the classical topoisomerase I inhibitor camptothecin. Molecular docking studies revealed possible interactions of diterpenes with topoisomerase I, indicating that these compounds do not form the drug-enzyme-DNA covalent ternary complex as observed with camptothecin. A binding pocket located at the surface of the DNA interaction site was proposed. Moreover, the ability of the five diterpenes to generate DNA-strand breaks in single cells was confirmed using the alkaline comet assay. As expected, these diterpenes also influenced cell cycle progression and arrested cells in different phases of the cell cycle, primarily the G1/G0 and S phases. Interestingly, the diterpenes only exhibited a slight ability to induce apoptotic cell death and failed to generate intracellular reactive oxygen species. These results provide additional understanding of the cytotoxic effects of abietane diterpenes. Depending on their functional groups, we propose that abietane diterpenes utilise different mechanisms to induce cell death. PMID- 22436447 TI - Application of TDCR-Geant4 modeling to standardization of 63Ni. AB - As an alternative to the classical TDCR model applied to liquid scintillation (LS) counting, a stochastic approach based on the Geant4 toolkit is presented for the simulation of light emission inside the dedicated three-photomultiplier detection system. To this end, the Geant4 modeling includes a comprehensive description of optical properties associated with each material constituting the optical chamber. The objective is to simulate the propagation of optical photons from their creation in the LS cocktail to the production of photoelectrons in the photomultipliers. First validated for the case of radionuclide standardization based on Cerenkov emission, the scintillation process has been added to a TDCR Geant4 modeling using the Birks expression in order to account for the light emission nonlinearity owing to ionization quenching. The scintillation yield of the commercial Ultima Gold LS cocktail has been determined from double coincidence detection efficiencies obtained for (60)Co and (54)Mn with the 4pi(LS)beta-gamma coincidence method. In this paper, the stochastic TDCR modeling is applied for the case of the standardization of (63)Ni (pure beta(-)-emitter; E(max)=66.98 keV) and the activity concentration is compared with the result given by the classical model. PMID- 22436448 TI - Numerical modeling of large-area beta sources constructed from anodized-aluminum foils. AB - The numerical modeling of large-area beta sources constructed from anodized aluminum foils is described in this paper. Based on a realistic model for the activity depth distribution, theoretical lower and upper bounds for the efficiency and the transmission coefficient were calculated and used to analyze the comparison method recommended by ISO 8769 for measuring the surface emission rate. The analysis shows that this method can provide measurement results with relative standard uncertainties smaller than 3% for high energy beta emitters such as (90)Sr-(90)Y, (36)Cl and (204)Tl. PMID- 22436449 TI - Measurements of the half-life of 214Po and 218Rn using digital electronics. AB - The half-lives of (214)Po and (218)Rn have been measured. The radionuclides were produced in the decay of a (230)U source and the emitted alpha-particles were measured in nearly-2pi geometry with an ion-implanted planar silicon detector. The data acquisition was performed with a digitiser operated in list mode, saving the energy and time of detection (10 ns precision timestamp) of each event. The half-lives were deduced from the time differences between the alpha-decays populating the nuclide of interest and those corresponding to its decay. Different methods were applied, based on delayed coincidence counting and time interval distribution analysis. The resulting half-lives are 33.75 (15) ms for (218)Rn and 164.2 (6) MUs for (214)Po, both in agreement with some of the literature values, and obtained with higher precision in this work. PMID- 22436450 TI - The direct measurement of 57Co activity by the sum-peak method. AB - The direct measurement of the activities of (57)Co sources by application of the sum-peak method recently developed by Novkovic et al., is described in this paper. The comprehensive assessment of the uncertainty budget of the activity of the measured sources has been analyzed. The presented method is successfully tested using an HPGe spectrometer with efficiencies of 50%. The accuracy of this method is confirmed to be comparable with the commonly used methods of the activity measurement of (57)Co. PMID- 22436451 TI - Performance test and quality control of large area reference sources fabricated by the ink-jet printing technique. AB - Quantitative performance tests and evaluations were carried out for large area reference sources fabricated by the ink-jet printing technique developed by NMIJ/AIST. The present tests were performed quantitatively with emphasis on uniformity, surface emission rate and long-term stability. Some techniques to minimize the self-absorption and to control the amount of radioactivity were established. The prototype source fabricated in this study safely satisfies the requirements specified in ISO 8769. PMID- 22436452 TI - The effect of impurities on calculated activity in the triple-to-double coincidence ratio liquid scintillation method. AB - In the triple-to-double coincidence ratio (TDCR) method of liquid scintillation counting, unaccounted or improperly accounted impurities can result in lower-than expected or higher-than-expected recovered activities, depending on the counting efficiency of the nuclide of interest, the counting efficiency of the radionuclidic impurity, and the amount of impurity present. We describe these general dependences using a simple model. The trends predicted by the model are tested experimentally using a series of mixed (241)Am/(3)H and (63)Ni/(3)H sources. An "impurity surface" is derived to facilitate an intuitive grasp of impurity phenomena in TDCR. PMID- 22436453 TI - Designing the selenium and bladder cancer trial (SELEBLAT), a phase lll randomized chemoprevention study with selenium on recurrence of bladder cancer in Belgium. AB - BACKGROUND: In Belgium, bladder cancer is the fifth most common cancer in males (5.2%) and the sixth most frequent cause of death from cancer in males (3.8%). Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of bladder cancer. This suggests that selenium may also be suitable for chemoprevention of recurrence. METHOD: The SELEBLAT study opened in September 2009 and is still recruiting all patients with non-invasive transitional cell carcinoma of the bladder on TURB operation in 15 Belgian hospitals. Recruitment progress can be monitored live at http://www.seleblat.org. Patients are randomly assigned to selenium yeast (200 MUg/day) supplementation for 3 years or matching placebo, in addition to standard care. The objective is to determine the effect of selenium on the recurrence of bladder cancer. Randomization is stratified by treatment centre. A computerized algorithm randomly assigns the patients to a treatment arm. All study personnel and participants are blinded to treatment assignment for the duration of the study. DESIGN: The SELEnium and BLAdder cancer Trial (SELEBLAT) is a phase III randomized, placebo-controlled, academic, double-blind superior trial. DISCUSSION: This is the first report on a selenium randomized trial in bladder cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00729287. PMID- 22436454 TI - Alphavirus replicon vaccines. AB - The alphavirus replicon technology has been utilized for many years to develop vaccines for both veterinary and human applications. Many developments have been made to the replicon platform recently, resulting in improved safety and efficacy of replicon particle (RP) vaccines. This review provides a broad overview of the replicon technology and safety features of the system and discusses the current literature on RP and replicon-based vaccines. PMID- 22436455 TI - Heart failure with preserved ejection fraction: neither deformation nor timing are preserved. PMID- 22436456 TI - Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. AB - The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment. PMID- 22436457 TI - Synthetic lethal screen identifies NF-kappaB as a target for combination therapy with topotecan for patients with neuroblastoma. AB - BACKGROUND: Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. METHODS: We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. RESULTS: We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-kappaB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-kappaB target genes among the differentially altered genes, suggesting that NF-kappaB pathway was activated in the treated cells. Combination of topotecan and known NF-kappaB inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. CONCLUSIONS: Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-kappaB inhibitors in patients with high risk neuroblastoma. PMID- 22436458 TI - Qualitative risk analysis of introducing Batrachochytrium dendrobatidis to the UK through the importation of live amphibians. AB - The international amphibian trade is implicated in the emergence and spread of the amphibian fungal disease chytridiomycosis, which has resulted in amphibian declines and extinctions globally. The establishment of the causal pathogen, Batrachochytrium dendrobatidis (Bd), in the UK could negatively affect the survival of native amphibian populations. In recognition of the ongoing threat that it poses to amphibians, Bd was recently included in the World Organisation for Animal Health Aquatic Animal Health Code, and therefore is in the list of international notifiable diseases. Using standardised risk analysis guidelines, we investigated the likelihood that Bd would be introduced to and become established in wild amphibians in the UK through the importation of live amphibians. We obtained data on the volume and origin of the amphibian trade entering the UK and detected Bd infection in amphibians being imported for the pet and private collection trade and also in amphibians already held in captive pet, laboratory and zoological collections. We found that current systems for recording amphibian trade into the UK underestimate the volume of non-European Union trade by almost 10-fold. We identified high likelihoods of entry, establishment and spread of Bd in the UK and the resulting major overall impact. Despite uncertainties, we determined that the overall risk estimation for the introduction of Bd to the UK through the importation of live amphibians is high and that risk management measures are required, whilst ensuring that negative effects on legal trade are minimised. PMID- 22436459 TI - Batrachochytrium dendrobatidis infection of amphibians in the Donana National Park, Spain. AB - Amphibian chytridiomycosis, caused by infection with the non-hyphal, zoosporic chytrid fungus Batrachochytrium dendrobatidis (Bd), is an emerging infectious disease recognised as a cause of recent amphibian population declines and extinctions worldwide. The Donana National Park (DNP) is located in southwestern Spain, a country with widespread Bd infection. This protected area has a great diversity of aquatic habitats that constitute important breeding habitats for 11 native amphibian species. We sampled 625 amphibians in December 2007 and February to March 2008, months that correspond to the early and intermediate breeding seasons for amphibians, respectively. We found 7 of 9 sampled species to be infected with Bd and found differences in prevalence between sampling periods. Although some amphibians tested had higher intensities of infection than others, all animals sampled were apparently healthy and, so far, there has been no evidence of either unusually high rates of mortality or amphibian population declines in the DNP. PMID- 22436460 TI - Production of monoclonal antibodies specific to Macrobrachium rosenbergii nodavirus using recombinant capsid protein. AB - The gene encoding the capsid protein of Macrobrachium rosenbergii nodavirus (MrNV) was cloned into pGEX-6P-1 expression vector and then transformed into the Escherichia coli strain BL21. After induction, capsid protein-glutathione-S transferase (GST-MrNV; 64 kDa) was produced. The recombinant protein was separated using SDS-PAGE, excised from the gel, electro-eluted and then used for immunization for monoclonal antibody (MAb) production. Four MAbs specific to the capsid protein were selected and could be used to detect natural MrNV infections in M. rosenbergii by dot blotting, Western blotting and immunohistochemistry without cross-reaction with uninfected shrimp tissues or other common shrimp viruses. The detection sensitivity of the MAbs was 10 fmol ul-1 of the GST-MrNV, as determined using dot blotting. However, the sensitivity of the MAb on dot blotting with homogenate from naturally infected M. rosenbergii was approximately 200-fold lower than that of 1-step RT-PCR. Immunohistochemical analysis using these MAbs with infected shrimp tissues demonstrated staining in the muscles, nerve cord, gill, heart, loose connective tissue and inter-tubular tissue of the hepatopancreas. Although the positive reactions occurred in small focal areas, the immunoreactivity was clearly demonstrated. The MAbs targeted different epitopes of the capsid protein and will be used to develop a simple immunoassay strip test for rapid detection of MrNV. PMID- 22436461 TI - Myxobolus groenlandicus n. sp. (Myxozoa) distorting skeletal structures and musculature of Greenland halibut Reinhardtius hippoglossoides (Teleostei: Pleuronectidae). AB - A specimen of Greenland halibut Reinhardtius hippoglossoides (Walbaum, 1792) caught on the west coast of Greenland (Qasigiannguit) was found to possess serious pathological changes in the body musculature. A series of cartilaginous cylindrical structures organized symmetrically at the position of the proximal pterygiophores had changed the musculature and produced irreversible distortions (cavities and holes) in the fillet of the processed fish, leaving it with no value for the industry. Histopathological investigation showed that these structures consisted of hypertrophic cartilage containing numerous myxospore producing plasmodia. Morphometric and molecular analyses of the parasites showed that both spore morphology and rDNA sequences complied with characteristics of the genus Myxobolus, but no full affiliation with a known species could be found. The parasite is a previously undescribed species, and the name Myxobolus groenlandicus n. sp. is assigned to this new myxobolid. PMID- 22436462 TI - Waterborne zinc alters temporal dynamics of guppy Poecilia reticulata epidermal response to Gyrodactylus turnbulli (Monogenea). AB - The present study assessed the histological changes in the epidermis of Poecilia reticulata induced by the combined effects of an ectoparasite Gyrodactylus turnbulli and differing concentrations of waterborne zinc (Zn). Infected guppies were exposed to 0, 15, 30, 60, or 120 ug Zn l-1 and monitored over 3 wk during the exponential increase in parasite numbers on the fish. The fish epidermis responded within 3 d to G. turnbulli infection with a rapid increase in epidermal thickness and a modest increase in number, but not size or composition, of mucous cells. In contrast, in the presence of combined waterborne Zn and infection, mucous cell numbers declined rapidly. As the parasite numbers increased, the epidermis remained thicker than normal, and the number and size of mucous cells decreased. The addition of Zn led to a dramatic thickening of the epidermis during the exponential growth of the parasite population. Mucous cell numbers remained depressed. Temporal changes in mucous cell size were Zn concentration dependent. At 60 ug Zn l-1, cells returned to normal size as infection progressed, whereas they remained extremely small at 120 ug Zn l-1. Changes in mucin composition previously reported in response to Zn alone were subdued in the presence of the parasite except at 60 ug Zn l-1, where all cells contained only acidic mucins. Together these results demonstrate that, on exposure to both Zn and G. turnbulli infection, the epidermal response is initially a protective response to both stressors, and then mainly driven by the increased parasite burden. PMID- 22436463 TI - Non-lethal detection of DNA from Cichlidogyrus spp. (Monogenea, Ancyrocephalinae) in gill mucus of the Nile tilapia Oreochromis niloticus. AB - Infection of Nile tilapia Oreochromis niloticus by monogeneans of the genus Cichlidogyrus is harmful. Currently, diagnosis of this infection is based on invasive techniques and the identification of isolated parasites by their morphology. To facilitate diagnosis, we have developed a non-lethal polymerase chain reaction (PCR) test for detection of Cichlidogyrus spp. DNA in the gill mucus of O. niloticus, using 5 pairs of specific primers based on Cichlidogyrus sclerosus 28S rRNA (Cicly 1 to Cicly 5) which generate fragments of approximately 188, 180, 150, 159 and 189 bp, respectively. PCR specificity was tested using genomic DNA extracted individually from 175 isolated Cichlidogyrus spp., 75 Gyrodactylus cichlidarum and 75 endopararasitic Enterogyrus spp., as well as from 75 protozoans Trichodina spp. The Cicly primers were used to detect Cichlidogyrus spp. DNA in mucus from the gills of 23 Nile tilapia confirmed to be infected with the parasite. Negative controls consisted of 45 uninfected Nile tilapia. The limit of sensitivity of the assay was 1.2 ng of purified parasite DNA. The Cicly primers did not amplify DNA from the mucus of non-infected Nile tilapia, G. cichlidarum, Trichodina spp. or Enterogyrus spp. In all cases, the sensitivity and specificity of the test were 100%. The sequences of all the amplified fragments showed a high similarity to that of the 28S rRNA region of C. sclerosus (93 to 100% identical to GenBank Accession No. DQ157660.1). We provide evidence for a safe and non-invasive DNA-based diagnostic method for the presence of Cichlidogyrus in the gill mucus of O. niloticus. PMID- 22436464 TI - Extended geographic distribution of several Indo-Pacific coral reef diseases. AB - Other than coral bleaching, few coral diseases or diseases of other reef organisms have been reported from Japan. This is the first report of lesions similar to Porites ulcerative white spots (PUWS), brown band disease (BrB), pigmentation response (PR), and crustose coralline white syndrome (CCWS) for this region. To assess the health status and disease prevalence, qualitative and quantitative surveys (3 belt transects of 100 m2 each on each reef) were performed in March and September 2010 on 2 reefs of the Ginowan-Ooyama reef complex off Okinawa, and 2 protected reefs off Zamani Island, in the Kerama Islands 40 km west of Okinawa. Overall, mean (+/-SD) disease prevalence was higher in Ginowan-Ooyama (9.7 +/- 7.9%) compared to Zamami (3.6 +/- 4.6%). Porites lutea was most affected by PUWS at Ooyama (23.1 +/- 10.4 vs. 4.5 +/- 5.2%). White syndrome (WS) mostly affected Acropora cytherea (12. 5 +/- 18.0%) in Zamami and Oxipora lacera (10.2 +/- 10%) in Ooyama. Growth anomalies (GA) and BrB were only observed on A. cytherea (8.3 +/- 6.2%) and A. nobilis (0.8%) at Zamami. Black band disease affected Pachyseris speciosa (6.0 +/- 4.6%) in Ooyama only. Pigmentation responses (PR) were common in massive Porites in both localities (2.6 +/- 1.9 and 5.6 +/- 2.3% respectively). Crustose coralline white syndrome (CCWS) was observed in both localities. These results significantly expand the geographic distribution of PUWS, BrB, PR and CCWS in the Indo-Pacific, indicating that the northernmost coral reefs in the western Pacific are susceptible to a larger number of coral diseases than previously thought. PMID- 22436465 TI - Batrachochytrium dendrobatidis in amphibians confiscated from illegal wildlife trade and used in an ex situ breeding program in Brazil. AB - This paper describes an outbreak of chytridiomycosis affecting a group of Dendrobates tinctorius, a Neotropical anuran species, confiscated from the illegal wildlife trade and housed in a private zoo in Brazil as part of an ex situ breeding program. We examined histological sections of the skin of 30 D. tinctorius and 20 Adelphobates galactonotus individuals. Twenty D. tinctorius (66.7%) and none of the A. galactonotus were positive for Batrachochytrium dendrobatidis (Bd). Multiple development stages of Bd infection were observed. The reasons for the inter-specific difference in the rate of infection could not be determined, and further studies are advised. Because the examined population consisted of confiscated frogs, detailed epidemiological aspects could not be investigated, and the source of the fungus remains uncertain. The existence of ex situ amphibian populations is important for protecting species at higher risk in the wild, and ex situ amphibian conservation and breeding programs in Brazil may be established using confiscated frogs as founders. However, this paper alerts these programs to the urgency of strict quarantine procedures to prevent the introduction of potential pathogens, particularly Bd, into ex situ conservation programs. PMID- 22436466 TI - Covariance spectroscopy with a non-uniform and consecutive acquisition scheme for signal enhancement of the NMR experiments. AB - Two-dimensional covariance (COV2D) spectroscopy with non-uniform and consecutive acquisition (NUCA) scheme is introduced. This NUCA-COV2D method allows the number of t(1) points to be reduced by a factor of 1.5-3 without any broadening of the linewidth. Furthermore, the signal-to-noise ratio (S/N) can be increased up to 50%, which can further save experimental time by another factor of 2. This method has been demonstrated with model samples and the microcrystalline proteins. In all cases, the total experimental time can be reduced by a factor of 3-6, without any loss of resolution and S/N, with respect to what is necessary with the FT2D NMR. PMID- 22436467 TI - Detection of iron-labeled single cells by MR imaging based on intermolecular double quantum coherences at 14 T. AB - To evaluate the efficiency and feasibility of intermolecular multiple quantum coherence (iMQC) magnetic resonance (MR) imaging for single cell detection, we obtained intermolecular double quantum coherence (iDQC) and conventional gradient echo (GE) images of macrophage cells labeled by contrast agents in gel. The iDQC images obtained with echo-planar readout visualized the labeled cells effectively and with a higher contrast than seen in conventional GE images, especially at low planar resolutions and with thick slices. This implies that iDQC imaging with contrast agents could be a good alternative to conventional MR imaging for detecting labeled single cells or cell tracking under favorable conditions. PMID- 22436468 TI - Swedish high school students' knowledge and attitudes regarding fertility and family building. AB - BACKGROUND: Infertility is a serious problem for those who suffer. Some of the risks for infertility are preventable and the individual should therefore have knowledge of them. The purposes of this study were to investigate high-school students' knowledge about fertility, plans for family building and to compare views and knowledge between female and male students. METHODS: A questionnaire containing 34 items was answered by 274 students. Answers from male and female students were compared using student's t-test for normally distributed variables and Mann-Whitney U-test for non-normal distributions. The chi-square test was used to compare proportions of male and female students who answered questions on nominal and ordinal scales. Differences were considered as statistically significant at a p-value of 0.05. RESULTS: Analyses showed that 234 (85%) intended to have children. Female students felt parenthood to be significantly more important than male students: p = <0.01. The mean age at which the respondents thought they would like to start to build their family was 26 (+/- 2.9) years. Men believed that women's fertility declined significantly later than women did: p = <0.01. Women answered that 30.7% couples were involuntarily infertile and men answered 22.5%: p = <0.01. Females thought it significantly more likely that they would consider IVF or adoption than men, p = 0.01. Men felt they were more likely to abstain from having children than women: p = <0.01. Women believed that body weight influenced fertility significantly more often than men: p = <0.01 and men believed significantly more often that smoking influenced fertility: p = 0.03. Both female and male students answered that they would like to have more knowledge about the area of fertility. CONCLUSIONS: Young people plan to start their families when the woman's fertility is already in decline. Improving young people's knowledge about these issues would give them more opportunity to take responsibility for their sexual health and to take an active role in shaping political change to improve conditions for earlier parenthood. PMID- 22436469 TI - Effect of aggregation behavior of gelatin in aqueous solution on the grafting density of gelatin modified with glycidol. AB - The effect of aggregation behavior of gelatin in aqueous solution on the grafting density of glycidol grafted gelatin polymers (GGG polymers) was investigated. The grafting density was measured using the Van Slyke method by calculating the conversion rate of free - NH(2) groups of gelatin. The conversion rate reached peak values at 6% and 14% of the gelatin aqueous solution. SEM micrographs displayed a series of structural transitions (i.e., spherical, spindle, butterfly, irregular and dendritic aggregates) at varying concentrations from 2% to 16% (w/w) at an interval of 2% (w/w). The spindle aggregates reappeared at the concentrations of 6% and 14%. Viscosity measurements indicated that the physicochemical properties of the gelatin solution had changed with increasing concentration. UV and CD analysis indicated that hydrophobic interactions competed with hydrogen bonding, and the random coils partly transformed to beta sheet structure by changing the concentration. Zeta potential and pH data confirmed the increasing electrostatic repulsion associated with increasing the hydrophobic region. XPS analysis revealed that the elemental composition of the gelatin particle surface changed with variation in the aggregate structure, determining the monotonic variation of the grafting density with increasing concentration. Results demonstrate that aggregation behavior of gelatin in aqueous solution plays a crucial role in deciding the grafting density of gelatin modified products. PMID- 22436470 TI - [An editorial fellowship at Radiologia]. PMID- 22436471 TI - Characterization and determination of holin protein of Streptococcus suis bacteriophage SMP in heterologous host. AB - BACKGROUND: Holins are a group of phage-encoded membrane proteins that control access of phage-encoded endolysins to the peptidoglycan, and thereby trigger the lysis process at a precise time point as the 'lysis clock'. SMP is an isolated and characterized Streptococcus suis lytic phage. The aims of this study were to determine the holin gene, HolSMP, in the genome of SMP, and characterized the function of holin, HolSMP, in phage infection. RESULTS: HolSMP was predicted to encode a small membrane protein with three hydrophobic transmembrane helices. During SMP infections, HolSMP was transcribed as a late gene and HolSMP accumulated harmlessly in the cell membrane before host cell lysis. Expression of HolSMP in Escherichia coli induced an increase in cytoplasmic membrane permeability, an inhibition of host cell growth and significant cell lysis in the presence of LySMP, the endolysin of phage SMP. HolSMP was prematurely triggered by the addition of energy poison to the medium. HolSMP complemented the defective lambda S allele in a non-suppressing Escherichia coli strain to produce phage plaques. CONCLUSIONS: Our results suggest that HolSMP is the holin protein of phage SMP and a two-step lysis system exists in SMP. PMID- 22436472 TI - A call to action in consultation training. PMID- 22436473 TI - Barriers and facilitators to the implementation of Ontario's emergency department clinical decision unit pilot program: a qualitative study. AB - OBJECTIVE: In Ontario, clinical decision units (CDUs) were implemented as a pilot project in 2008 by the Ministry of Health and Long-Term Care as part of its strategy to reduce emergency department (ED) waiting times. Our objective was to describe general characteristics of the program at each of the participating sites and to examine barriers and facilitators to integrating CDUs into practice. METHODS: On-site small-group interviews were conducted in two phases with ED and hospital staff at participating sites, first at 8 to 12 weeks and again at 12 months postimplementation. Interview data were analyzed using the framework approach. Unstructured field notes and CDU clinical care protocols and documentation were also reviewed. RESULTS: The qualitative analysis identified 10 key themes related to integrating CDUs into EDs: shift in clinical and operational practice; administrative aspects of implementation; team building and stakeholder involvement; use of clinical care protocols; physical or virtual model of care; responsive ancillary services; involvement of specialist services; coordination with hospital and community supports; appropriate use of the CDU; and ongoing evaluation and monitoring. Each theme represents an important insight from the perspective of clinical and administrative staff at participating sites. CONCLUSION: The implementation of CDUs is a complex process, with no single preferred clinical care or operational model. This study identifies a number of key considerations relevant to the future implementation of CDUs. PMID- 22436474 TI - The utility of the prehospital electrocardiogram. AB - OBJECTIVES: The 12-lead electrocardiogram (ECG) can capture valuable information in the prehospital setting. By the time patients are assessed by an emergency department (ED) physician, their symptoms and any ECG changes may have resolved. We sought to determine whether the prehospital electrocardiogram (pECG) could influence ED management and how often the pECG was available to and reviewed by the ED physician. METHODS: A retrospective medical record review was conducted on a random sample of patients >= 18 years who had a prehospital 12-lead ECG and were transported to one of two tertiary care centres. Data were recorded onto a standardized data extraction tool. Three investigators independently compared the pECG to the first ECG obtained in the ED after patient arrival at the hospital. Any abnormalities not present on the ED ECG were adjudicated to ascertain whether they had the potential to change ED management. RESULTS: Of 115 ambulance runs selected, 47 had no pECG attached to the ambulance call record (ACR) and another 5 were excluded (one ST elevation myocardial infarction, one cardiac arrest, three ACR missing). Of the 63 pECGs reviewed, 16 (25%) showed changes not apparent on the initial ED ECG (kappa = 0.83; 95% CI 0.74-0.93), of which 12 had differences that might influence ED management (kappa = 0.76; 95% CI 0.72 0.82). Only one hospital record contained a copy of the pECG, despite the current protocol that paramedics print two copies of the pECG on arrival in the ED (one copy for the ACR and one to be handed to the medical personnel). None of 110 ED charts documented that the pECG was reviewed by the ED physician. CONCLUSION: The pECG has the potential to influence ED management. Improvement in paramedic and physician documentation and a formal pECG handover process appear necessary. PMID- 22436475 TI - Intra-articular lidocaine versus intravenous sedation for the reduction of anterior shoulder dislocations in the emergency department. AB - OBJECTIVE: The objective was to compare intra-articular lidocaine (IAL) versus intravenous sedation (IVS) for the reduction of acute, anterior shoulder dislocations in the emergency department (ED) in terms of ED length of stay, rate of successful reductions, patient satisfaction, and complications. METHODS: This was a prospective, randomized trial. Patients in the IAL group received 4 mg/kg (up to 200 mg) of 1% lidocaine injected into the glenohumeral joint using a lateral approach. Patients in the IVS group received medications for sedation as per the discretion of the treating physician. Follow-up was arranged within 2 weeks of the ED visit to assess for complications. RESULTS: Forty-four patients (25 IAL, 19 IVS) were included. This trial was stopped early owing to a combination of unexpected findings in success, resource limitations, and difficulty in patient enrolment. Median time from first physician assessment to patient discharge was not different between the IAL (170 minutes) group and the IVS (145 minutes) group (Delta -25 minutes; 95% CI -32, 70; p = 0.46). There was a significantly lower rate (p < 0.001) of successful closed reduction in the IAL group (48%) compared to the IVS group (100%). Patient satisfaction and physician ease of reduction were higher in the IVS group compared to the IAL group (p < 0.05). There were no reported complications in either group at time of reduction or follow-up. CONCLUSIONS: There was no difference in ED length of stay between groups. There was a lower rate of successful reductions and lower satisfaction scores in the IAL group. PMID- 22436476 TI - Bacterial contamination and cleanliness of emergency department ultrasound probes. AB - OBJECTIVES: As ultrasonography is increasingly used in the emergency department (ED), ultrasound equipment has become a potential threat to infection control. Improperly cleaned ultrasound probes may serve as a vector for pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). The primary objective of this study was to determine the prevalence of MRSA colonization on ultrasound probes used in a busy, urban ED. It was hypothesized that cultures of our ED ultrasound probes would yield a significant number of positive results for MRSA. METHODS: In this observational study, 11 ED ultrasound probes were randomly sampled on 10 different occasions. Samples were taken using a RODAC plate method and were cultured for MRSA and methicillin-sensitive Staphylococcus aureus (MSSA). On half of the randomly assigned sampling occasions, a visual inspection of each ultrasound probe for general cleanliness was conducted and recorded. Data were stratified by ultrasound location in the ED and analyzed using the Fisher exact test, with p < 0.05 deemed to be statistically significant. RESULTS: Of 110 samples, no isolates of MRSA were cultured. One probe yielded a positive culture for MSSA. Probes in the medicine, trauma, and pediatrics areas were found to be clean 65%, 33%, and 70% of the time, respectively. This variability in probe cleanliness by ED location was found to be statistically significant (p < 0.01). CONCLUSIONS: Contrary to our hypothesis, MRSA contamination of ultrasound probes was not found. This finding suggests that the spread of MRSA by ED ultrasound machines in a high-volume urban ED is unlikely. Further research at different centres with larger sample sizes is required before these results can be generalized. PMID- 22436477 TI - Teaching procedures: improving "see one, do one, teach one". PMID- 22436478 TI - Dopamine versus norepinephrine in the treatment of shock. AB - CLINICAL QUESTION: Which vasopressor agent, norepinephrine or dopamine, is superior in the treatment of shock? ARTICLE CHOSEN: De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89. STUDY OBJECTIVE: The authors of this study set out to compare 28-day mortality in patients with shock who were treated with either dopamine or norepinephrine as initial vasopressor therapy. The authors' secondary outcome measures included mortality beyond 28 days and adverse events associated with each agent. PMID- 22436479 TI - The weak eye. Intracranial aneurysm. PMID- 22436480 TI - Cardiac arrest in pregnancy and perimortem cesarean delivery: case report and discussion. AB - Cardiac arrest in pregnancy is a rare occurrence, particularly in the emergency department setting. The resuscitation of a pregnant patient in cardiac arrest is unique in a number of ways. Early identification and treatment of possible etiologies, appropriate response to the physiologic changes present in pregnancy, relief of potential vena cava obstruction by the gravid uterus, and expeditious preparation for possible cesarean delivery are important considerations for a successful resuscitation. We report and discuss the case of a pregnant patient with pulmonary edema and cardiac dysfunction who presented with severe hypoxemia and subsequent cardiac arrest and underwent a perimortem cesarean delivery and simultaneous fetal and maternal resuscitation in the emergency department. PMID- 22436481 TI - A sticky situation: management of spray polyurethane foam insulation in body orifices. AB - Spray polyurethane foam insulation is commonly used in the construction industry to fill gaps, seal, and insulate. We present three cases of intentional spray foam insertion in body orifices and discuss the management of such situations in the emergency department. This series includes a case of oral foam insertion used in a suicide attempt by suffocation and two cases of rectal insertion. All of these cases had potential long-term consequences; one was life-threatening. To our knowledge, this is the first published report on the medical management and removal of foam insulation from body orifices. In all three cases, the foam insulation material was successfully removed after allowing the material to harden. PMID- 22436482 TI - Hyperkalemia and atrial pacemakers: what can the electrocardiogram tell you? PMID- 22436483 TI - The development of emergency medicine in Ethiopia. PMID- 22436485 TI - The evolution of emergency medicine: the pressing need for "made in Canada" subspecialty training. PMID- 22436486 TI - Can lung cancer stem cells be targeted for therapies? AB - Lung cancer is the leading cause of cancer death, with a poor prognosis. Lung cancer stem cells (CSCs) are proposed as one of therapeutic targets for lung cancer. It is important to understand the exact role of lung CSC subpopulations in tumor initiation, recurrence, drug resistance and metastasis and explore biomarkers, signaling pathways and differentiation regulation specific to lung CSCs. Numerous measures targeting lung CSCs, e.g. genomics, proteomics and bioinformatics, have been used to investigate molecular mechanisms, eradicate cancer cells, and improve patient outcome. The present review overviewed the biological functions, biomarkers, signal pathways, differentiation regulation, genomics and proteomics, targeting roles of lung CSCs and related information on other CSCs as references. There are still a number of challenges to translate the research and understanding of lung CSCs to clinical applications and therapies, identify lung CSCs-specific and dynamic network biomarkers, study lung CSCs isolated from human samples, and clarify the source of lung CSCs. It is necessary to design effective therapies to target CSC biomarkers and signaling pathways, reverse drug resistance and induce differentiation of lung CSCs. Thus, lung CSCs as one of therapeutic target candidates for lung cancer need global forces and databases to integrate the genes, proteins, receptors, signal pathways and functions with clinical informatics and phenotypes together. PMID- 22436487 TI - Craniofacial fibrous dysplasia (CFD) of the maxilla in an 11-year old boy: a case report. AB - We present the case of a surgically treated 11-year old boy with a diagnosis of craniomaxillofacial fibrous dysplasia (CFD) in the maxillary sinus. When first seen in the outpatient clinic of our department he had minimal symptoms. After initial radiological diagnostics by computed tomography scans (CT-scans) the patient was treated operatively by radical excision of the tumor. The radiographs showed the typical intramedullary located and well-defined lesions, which eroded the cortical bone with the typical appearance of fibrous dysplasia. The histopathology showed the typical curved extending fibrous trabeculae in C, O and Y-shape which were embedded in a moderately cellular morphologically inconspicuous stroma, confirming the initial suspicion of fibrous dysplasia of the maxillary bone. Cone beam tomography was a valuable tool in determining the re-ossification of bone at the affected side. Local resection can be curative in limited disease. PMID- 22436488 TI - Sparing the posterior surgical site when planning radiation therapy for thoracic metastatic spinal disease. AB - BACKGROUND CONTEXT: Most patients with painful spinal metastases are sufficiently palliated by hypofractionated radiotherapy. However, a small group of patients will need surgical intervention to treat symptomatic spinal cord compression and/or gross mechanical instability. Irradiation of a (prospective) surgical area may lead to postsurgery complications, including wound dehiscence, infection, and chronic wound ulcers. Decreasing the radiation dose to the surgical area could reduce radiation-induced toxicity and associated surgical complications. PURPOSE: To investigate an alternative radiation technique designed to lower the surgical area dose while delivering an adequate target dose and minimal off-target dose. STUDY DESIGN: Comparison of radiation doses received by various anatomic structures after simulating irradiation with a routine posteroanterior single field (SF) technique and experimental multiple field (MF) technique in a setting of thoracic metastatic spinal disease. METHODS: The computed tomography (CT) data from six previously treated patients with a total of 10 thoracic spinal metastases were used to plan four radiation schemes (SF8 Gy; SF20 Gy; MF8 Gy; and MF20 Gy). Discrete anatomic structures were defined on CT data, including a posterior surgical area, and after simulation the doses received were calculated and compared for the 8 Gy and 20 Gy techniques. RESULTS: With the experimental MF technique, a clinically relevant dose could be delivered to the affected vertebra, whereas the dose received at the (prospective) surgical area could be significantly reduced compared with the SF technique. The dose received at the nontarget tissues fell below the threshold level for clinical relevance. CONCLUSIONS: This radiation planning study showed the feasibility of sparing the surgical area while delivering an adequate dose to affected vertebrae in thoracic metastatic spinal disease. PMID- 22436489 TI - Identification of in vitro HSC fate regulators by differential lipid raft clustering. AB - Most hematopoietic stem cells (HSC) in the bone marrow reside in a quiescent state and occasionally enter the cell cycle upon cytokine-induced activation. Although the mechanisms regulating HSC quiescence and activation remain poorly defined, recent studies have revealed a role of lipid raft clustering (LRC) in HSC activation. Here, we tested the hypothesis that changes in lipid raft distribution could serve as an indicator of the quiescent and activated state of HSCs in response to putative niche signals. A semi-automated image analysis tool was developed to map the presence or absence of lipid raft clusters in live HSCs cultured for just one hour in serum-free medium supplemented with stem cell factor (SCF). By screening the ability of 19 protein candidates to alter lipid raft dynamics, we identified six factors that induced either a marked decrease (Wnt5a, Wnt3a and Osteopontin) or increase (IL3, IL6 and VEGF) in LRC. Cell cycle kinetics of single HSCs exposed to these factors revealed a correlation of LRC dynamics and proliferation kinetics: factors that decreased LRC slowed down cell cycle kinetics, while factors that increased LRC led to faster and more synchronous cycling. The possibility of identifying, by LRC analysis at very early time points, whether a stem cell is activated and possibly committed upon exposure to a signaling cue of interest could open up new avenues for large-scale screening efforts. PMID- 22436490 TI - The expanding role of miR-302-367 in pluripotency and reprogramming. AB - MicroRNA (miRNA) has been shown to be essential for regulating cell fate and pluripotency; however, our knowledge of miRNA function in stem cells is incomplete due to experimental limitations and difficulties in identifying their physiological targets. Recent studies implicated hESC-expressed miRNAs (miR-302 367 and miR-371-373 clusters) in regulating BMP signaling and promoting pluripotency, suggesting that low levels of BMP signaling may promote pluripotency by preventing neural induction. A comprehensive list of miR-302-367 targets recently identified by genome-wide approaches suggests a number of additional cellular processes and signaling pathways whose regulation by miR-302 367 may promote pluripotency and reprogramming, such as cell cycle, epigenetic changes, metabolism and vesicular transfer. PMID- 22436492 TI - The relationship between rearfoot, tibial and hip kinematics in individuals with patellofemoral pain syndrome. AB - BACKGROUND: Excessive rearfoot eversion is thought to be a risk factor for patellofemoral pain syndrome development, based on theoretical rationale linking it to greater tibial internal rotation and hip adduction. This study aimed to establish the relationship of rearfoot eversion with tibial internal rotation and hip adduction during walking in individuals with and without patellofemoral pain syndrome. METHODS: Twenty-six individuals with patellofemoral pain syndrome and 20 controls (18-35years) participated. Each underwent instrumented three dimensional motion analysis during over-ground walking. Pearson's correlation coefficients (r) were calculated to establish the relationship of rearfoot eversion with tibial internal rotation and hip adduction (peak and range of motion). FINDINGS: Greater peak rearfoot eversion was associated with greater peak tibial internal rotation in the patellofemoral pain syndrome group (r=0.394, P=0.046). Greater rearfoot eversion range of motion was associated with greater hip adduction range of motion in the patellofemoral pain syndrome (r=0.573, P=0.002) and control (r=0.460, P=0.041) groups; and greater peak hip adduction in the control group (r=0.477, P=0.033). INTERPRETATION: Associations between greater rearfoot eversion and greater hip adduction indicate that interventions targeted at the foot or hip in individuals with patellofemoral pain syndrome may have similar overall effects on lower limb motion and clinical outcomes. The relationship between rearfoot eversion and tibial internal rotation identified in the patellofemoral pain syndrome group may be related to aetiology. However, additional prospective research is needed to confirm this. PMID- 22436491 TI - MicroRNAs in neuronal function and dysfunction. AB - MicroRNAs (miRNAs) are small noncoding RNA transcripts expressed throughout the brain that can regulate neuronal gene expression at the post-transcriptional level. Here, we provide an overview of the role for miRNAs in brain development and function, and review evidence suggesting that dysfunction in miRNA signaling contributes to neurodevelopment disorders such as Rett and fragile X syndromes, as well as complex behavioral disorders including schizophrenia, depression and drug addiction. A better understanding of how miRNAs influence the development of neuropsychiatric disorders may reveal fundamental insights into the causes of these devastating illnesses and offer novel targets for therapeutic development. PMID- 22436493 TI - Supportive care with art therapy, for patients in isolation during stem cell transplant. AB - OBJECTIVE: The aim of the art therapy study was twofold: 1) to identify the specific factors of the art therapy experience perceived as helpful by patients undergoing an allogenic hemopoietic stem cell transplant (HSCT); and 2) to establish an appropriate criterion for referral to art therapy among this population. METHOD: Between 2006 and 2010, a dedicated art therapist met all the patients who were referred to her by the hematologist. The art therapy approach and techniques are described. Outcome was evaluated by self-assessment, based on written questionnaires that were given to the patients before discharge. RESULTS: Seventy-four patients followed the weekly individual sessions during isolation and filled out the questionnaire. All of them defined the art therapy experience as "helpful" and specified in which way it had been helpful. Through a thematic analysis of the patients' written comments, three specific aspects of art therapy, which the patients found most helpful, were identified: (1) being able to calm down from anxiety, through the use of art therapy techniques (77.02%); (2) feeling free to express and share difficult feelings, which they had not communicated verbally (75.67%); and (3) establishing meaningful connections with their loved ones, through images made in art therapy (36.48%). Case illustrations are provided. SIGNIFICANCE OF RESULTS: The results suggest that referral to art therapy from the team might be helpful and appropriate: (1) when patients are anxious; (2) when they are uncommunicative and hide their feelings; and (3) when they feel disconnected from their loved ones at home. PMID- 22436495 TI - A perspicacious view. PMID- 22436494 TI - Struma ovarii associated with Pseudo-Meig's syndrome and high serum level of CA 125; a case report. AB - Struma ovarii is a rare form of ovarian neoplasm in a form of mature teratoma and is composed predominantly of thyroid tissue. In the literature review, there has only been 10 cases of this tumor, associated with ascites and pleural effusion (Meig's Syndrome) and increased CA125 so far. In such cases, the tumor mimics malignant ovarian tumor. In this article, the case of a 72-year-old symptomatic woman with a pelvic mass, pleural and peritoneal effusion and high level of serum CA125 is presented. Cytological evaluation for the pleural fluid was performed. She underwent hysterectomy and bilateral salpingo-oophorectomy. The result of pathologic diagnosis is presented in this paper. The patient was well in postoperative period and paraclinical tests including CA 125 were normal as well. PMID- 22436496 TI - Off-Pump versus Conventional Coronary Artery Bypass Grafting: A Meta-Analysis and Consensus Statement From The 2004 ISMICS Consensus Conference. AB - BACKGROUND: : The purpose of this evidence-based consensus statement is to systematically review and meta-analyze the randomized and nonrandomized evidence comparing off-pump (OPCAB) to conventional coronary artery bypass (CCAB) surgery and to provide consensus on the role of OPCAB in low- and high-risk surgical patients. METHODS AND RESULTS: : This consensus conference was conducted according to the American College of Cardiology (ACC)/American Heart Association (AHA) standards for development of clinical practice guidelines. The Steering Committee collated all published studies of OPCAB versus CCAB through May 2004 and developed six questions central to controversies surrounding OPCAB surgery in mortality, morbidity, and resource utilization. For mixed-risk patient populations, meta-analysis of 37 randomized clinical trials (3,369 patients, Level A) reported across a total of 53 papers, and two meta-analyses of nonrandomized trials (Level B) comparing OPCAB versus CCAB were identified. For high-risk patient populations, we performed a meta-analysis of 3 randomized and 42 nonrandomized trials (26,349 patients, Level B). CONCLUSION: : Meta-analysis of Level A and B evidence provided the basis for the following consensus statements in patients undergoing surgical myocardial revascularization: (1) OPCAB should be considered a safe alternative to CCAB with respect to risk of mortality [Class I, Level A]; (2) With appropriate use of modern stabilizers, heart positioning devices, and adequate surgeon experience, similar completeness of revascularization and graft patency can be achieved [Class IIa, Level A]; (3) OPCAB is recommended to reduce perioperative morbidity [Class I, Level A]; (4) OPCAB may be recommended to minimize midterm cognitive dysfunction [Class IIa, Level A]; (5) OPCAB should be considered as an equivalent alternative to CCAB in regard to quality of life [Class I, Level A]; (6) OPCAB is recommended to reduce the duration of ventilation, ICU and hospital stay, and resource utilization [Class I, Level A]; (7) OPCAB should be considered in high-risk patients to reduce perioperative mortality, morbidity, and resource utilization [Class IIa, Level B]. PMID- 22436497 TI - Routine off-pump coronary artery bypass: reasons for on-pump conversion. AB - OBJECTIVE: : To assess the feasibility of routine off-pump coronary artery bypass (OPCAB) and investigate risk factors for on-pump conversion. METHODS: : Between July 1, 2002, and June 30, 2004, OPCAB was attempted for all patients who required isolated coronary artery bypass in our institution. The perioperative results of patients were prospectively entered into a structured database, and the results were analyzed to identify the risks of requirement for cardiopulmonary bypass. RESULTS: : Off-pump coronary artery bypass was successfully performed in all but 9 patients, giving an OPCAB success rate of 97.3% (329/338). The reason for cardiopulmonary bypass was hemodynamic instability occurring during reoperative surgery in 7, and cardiogenic shock in 2. The OPCAB success rate was significantly higher in primary coronary artery bypass grafting (99.3%, 314/316) than in reoperative coronary artery bypass grafting (68.1%, 15/22; P < 0.0001), and higher in patients without cardiogenic shock (97.9%, 329/336) than in those with cardiogenic shock (0%, 0/2; P = 0.0005). Mean number of distal anastomoses performed under OPCAB was 3.5 +/- 1.4. There were 2 hospital deaths (0.6%). During a mean follow-up period of 1.0 +/- 0.4 years, 7 patients developed angina, which was treated with catheter intervention; there were no other cardiac events. CONCLUSION: : Routine OPCAB is feasible with acceptable short-term results. Patients undergoing reoperation or in persistent cardiogenic shock are more likely to require conversion to on-pump coronary artery bypass grafting. PMID- 22436498 TI - Transabdominal off-pump coronary artery bypass grafting using the right gastroepiploic artery. AB - BACKGROUND: : Anastomosis of the right gastroepiploic artery to vessels of the inferior wall of the heart can be performed using a transabdominal approach without sternotomy and without cardiopulmonary bypass. METHODS: : From July 1999 to December 2004, 18 patients presenting with only right coronary artery disease were operated on by the transabdominal approach using a pedicled right gastroepiploic artery graft. In 14 patients, it was a redo operation. In all redo patients, a patent graft to the anterior wall was present. Median EuroSCORE was 5 (range 1-13). The right descending posterior artery was grafted in 10 patients, the right coronary artery in 8 patients. RESULTS: : There was no hospital mortality and no conversion to sternotomy. Hospital morbidity consisted only of a right pleural hemothorax and a superficial wound infection. No blood transfusion was necessary in 16 (89%) patients. Hospital stay averaged 6 days.Follow-up is complete and averaged 2 years (range 0.5-5.5 years). There was no late mortality. Seventeen patients (94%) were asymptomatic. One patient who experienced return of angina 1 year after the procedure underwent a percutaneous transluminal coronary angioplasty of the right coronary artery. Thirteen patients underwent a stress test at median follow-up of 14 months without signs of myocardial ischemia. CONCLUSIONS: : Off-pump coronary bypass grafting using a right gastroepiploic artery by the transabdominal approach is a safe and effective procedure with a low hospital morbidity and excellent follow-up. In redo operations, this technique excludes the risk of damaging patent grafts to the left coronary system. PMID- 22436499 TI - Effects on lung function in patients undergoing coronary artery surgery on versus off cardiopulmonary bypass: a randomized trial. AB - BACKGROUND: : Coronary revascularization is associated with respiratory dysfunction and poor gas exchange postoperatively. Cardiopulmonary bypass (CPB) has been implicated as a possible explanation for this phenomenon. This study investigated respiratory function in patients undergoing coronary artery bypass grafting (CABG) on-CPB versus off-CPB to determine whether the off-CPB condition results in improved postoperative pulmonary function. METHODS: : Forty patients were randomized into 1 of 2 groups: CABG on-CPB (group A) or off-CPB (group B). Pulmonary function tests, including spirometry and diffusion studies, were performed preoperatively and on postoperative day 5. Arterial blood gases on 100% oxygen were taken preoperatively (TP1), 15 minutes after sternal closure (TP2), and 3 hours postoperatively (TP3). RESULTS: : The arterial partial pressure of oxygen (PaO2) on FiO2 1.0 decreased from 59.5 +/- 11.5 kPa and 55.7 +/- 12.2 kPa at TP1 to 39.5 +/- 16 kPa and 39.7 +/- 13 kPa at TP2 in groups A and B, respectively (P < 0.001), with no significant difference between groups. At TP3, the PaO2 partially recovered toward preoperative levels (P > 0.05).Spirometry revealed a significant reduction in FEV1 and FVC on the fifth postoperative day (P < 0.001), with no significant difference between groups. The corrected transfer factor for carbon monoxide reduced significantly in group A from 7.9 +/- 2.5 mmol.min . kPa preoperatively to 5.1 +/- 1.6 mmol.min . kPa postoperatively (P < 0.05). This reduction was not seen in group B. CONCLUSIONS: : Coronary artery surgery is associated with a marked reduction in lung function as measured by pulmonary function tests and PaO2. Diffusion studies revealed that on-CPB patients had significantly reduced diffusion capacities postoperatively compared with patients in the off-CPB group. PMID- 22436500 TI - A Comparative Study of Imaging Techniques in Aortic Dissection, DeBakey Type I: Intraoperative Live Three-Dimensional Epicardial Echocardiography, Multiplane Transesophageal Echocardiography, and Multislice Computed Tomography. AB - OBJECTIVE: : To compare the accuracy of intraoperative live 3-dimensional epicardial echocardiography, multiplane transesophageal echocardiography (TEE), and multislice computed tomography (MSCT) imaging in the detection of thoracic aortic dissection, site of intimal tear, and involvement of arch vessel. METHODS: : Of 24 patients studied from October 2003 to September 2004, 12 had aortic dissection. They were examined preoperatively with contrast material-enhanced MSCT and multiplane TEE. Intraoperative live 3-dimensional epicardial echocardiographic evaluation of the ascending aorta and arch was performed. Imaging results in terms of detection of aortic dissection, site of intimal tear, and involvement of coronary arteries and arch vessels were confirmed at intraoperative exploration by the operating surgeon as the reference standard. RESULTS: : Sensitivity in the detection of thoracic aortic dissection was 100% for all techniques. Specificity was 92%, 92%, and 100% for live 3-dimensional epicardial echocardiography, multiplane TEE, and MSCT imaging, respectively. In the assessment of aortic arch vessel involvement, sensitivity was 92%, 58%, and 92%, and specificity was 75%, 50%, and 83%, respectively. For the detection of the site of intimal tear, sensitivity was 92%,92%, and 58%, and specificity was 83%,75%, and 50%, respectively. CONCLUSION: : Intraoperative live 3-dimensional epicardial echocardiography is as valuable as multiplane TEE and MSCT imaging in the detection of thoracic aortic dissection. In the assessment of the aortic arch vessel involvement, MSCT and live 3-dimensional epicardial echocardiography are superior (P < 0.05), whereas live 3-dimensional epicardial echocardiography and TEE are superior in detection of site of intimal tear (P < 0.05). PMID- 22436501 TI - Cardioscopic Trans-septal Cryoablation of Left Atrium in Nonmitral Cases. AB - BACKGROUND: : A modified maze procedure in which trans-septal cardioscopy was used for cryoablation in the left atrium is described. METHODS: : The technique was used in 11 consecutive patients (9 men and 2 women, 56.5 +/- 19.8 years) with permanent atrial fibrillation (Af) and concomitant nonmitral cardiac or aortic disease: aortic valvular disease in 4 patients, atrial septal defect (ASD) in 2 patients, tricuspid regurgitation in 2 patients, acute aortic dissection in 1 patient, arch aneurysm in 1 patient, and coronary artery disease in 1 patient. The mean Af duration detected in 7 cases was 18.5 +/- 10.1 months. Partial sternotomy was used in aortic valve replacement, ASD closure, and tricuspid valve plasty, and fullsternotomy was used in aortic graft replacement and coronary artery bypass. Cardiopulmonary bypass was established, aortic cross-clamp was performed, a right atriotomy was created, a cryoablation probe and cardioscope (3 mm) were introduced into the left atrium through a 1-cm cut at the fossa ovalis or ASD, and cardioscopic left-atrial endocardial cryoablation was performed. The right-side maze procedure was conducted directly. The atrial appendages were excised in each case. RESULTS: : Left-atrial cardioscopic cryoablation required 25.0 +/- 5.5 minutes, and no deaths or procedure-related morbidities occurred. The mean follow-up period was 12 +/- 8.5 months. One patient with tricuspid regurgitation died of liver failure. With the exception of coronary and acute dissection cases, all patients have maintained a sinus rhythm. CONCLUSION: : Although experience is limited, videocardioscopic trans-septal left-atrial cryoablation is a viable method for nonmitral Af cases, and the partial sternotomy approach can be performed. PMID- 22436502 TI - Interleukin-10-819 promoter polymorphism in association with gastric cancer risk. AB - BACKGROUND: Potential functional allele T/C single nucleotide polymorphism (SNP) of Interleukin 10 (IL-10) promoter -819 (rs1800871) has been implicated in gastric cancer risk. We aimed to explore the role of T/C SNP of IL-10 -819 in the susceptibility to gastric cancer through a systematic review and meta-analysis. METHODS: Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 11 studies were ultimately eligible for the meta-analysis of IL-10 -819 T/C SNP. We adopted the most probably appropriate genetic model (recessive model). Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. RESULTS: IL-10 -819 TT genotype is associated with the overall reduced gastric cancer risk among Asians and even apparently observed among high quality subgroup Asians. IL-10-819 TT genotype is not statistically associated with the overall reduced gastric cancer susceptibility in persons with H. pylori infection compared with controls without H. pylori infection. IL-10 -819 TT genotype is reversely associated with diffuse-subtype risk but not in intestinal-subtype risk. IL-10 -819 TT genotype is not reversely associated with non-cardia or cardia subtype gastric cancer susceptibility. CONCLUSIONS: IL-10 -819 TT genotype seems to be more protective from gastric cancer in Asians. Whether IL-10 -819 TT genotype may be protective from gastric cancer susceptibility in persons infected with H. pylori or in diffuse-subtype cancer needs further exploring in the future well-designed high quality studies among different ethnicity populations. Direct sequencing should be more used in the future. PMID- 22436503 TI - Extracting energy and structure properties of glass-forming liquids from structural relaxation time. AB - A comprehensive examination of the kinetic liquid model (Wang et al 2010 J. Phys.: Condens. Matter 22 455104) is carried out by fitting the structural relaxation time of 26 different glass-forming liquids in a wide temperature range, including most of the well-studied materials. Careful analysis of the compiled reported data reveals that experimental inaccuracies should not be overlooked in any 'benchmark test' of relating theories or models (e.g. in Lunkenheimer et al 2010 Phys. Rev. E 81 051504). The procedure, accuracy, ability, and efficiency of the kinetic liquid model are discussed in detail and in comparison with other available fitting methods. In general, the kinetic liquid model could be verified by 17 of the 26 compiled data sets and can serve as a meaningful approximative method for analyzing these liquids. Nonetheless, further experimental examinations in a wide temperature range are needed and are called for. Through fitting, the microscopic details of these liquids are extracted, namely, the enthalpy, entropy, and cooperativity in structural relaxation, which may facilitate further quantitative analysis to both the liquidus and glassy states of these materials. PMID- 22436504 TI - The Bxb1 recombination system demonstrates heritable transmission of site specific excision in Arabidopsis. AB - BACKGROUND: The mycobacteriophage large serine recombinase Bxb1 catalyzes site specific recombination between its corresponding attP and attB recognition sites. Previously, we and others have shown that Bxb1 has catalytic activity in various eukaryotic species including Nicotiana tabacum, Schizosaccharomyces pombe, insects and mammalian cells. RESULTS: In this work, the Bxb1 recombinase gene was transformed and constitutively expressed in Arabidopsis thaliana plants harboring a chromosomally integrated attP and attB-flanked target sequence. The Bxb1 recombinase successfully excised the target sequence in a conservative manner and the resulting recombination event was heritably transmitted to subsequent generations in the absence of the recombinase transgene. In addition, we also show that Bxb1 recombinase expressing plants can be manually crossed with att flanked target transgenic plants to generate excised progeny. CONCLUSION: The Bxb1 large serine recombinase performs site-specific recombination in Arabidopsis thaliana germinal tissue, producing stable lines free of unwanted DNA. The precise site-specific deletion produced by Bxb1 in planta demonstrates that this enzyme can be a useful tool for the genetic engineering of plants without selectable marker transgenes or other undesirable exogenous sequences. PMID- 22436506 TI - Correlations between electrochemical behaviors and DNA photooxidative properties of non-steroidal anti-inflammatory drugs and their photoproducts. AB - Alkali-labile lesion to DNA photosensitized, via an electron transfer mechanism, by three non-steroidal anti-inflammatory drugs (NSAIDs), ketoprofen, tiaprofenic acid and naproxen and their photoproducts during drug photolysis, was investigated using (32)P-end labelled synthetic oligonucleotide. These photooxidative damages were correlated with the photophysical and electrochemical properties of drugs, appearing as the photosensitizer PS. Photophysical studies provided the excited state energies of the photosensitizer while their redox potentials and the relative stabilities of the PS(-) radical-anions were determined by cyclic voltammetry. On the basis of these data, we have calculated the Gibbs energy of photoinduced electron-transfer and evaluated the exergonicity of the oxidative photodamage. Moreover, kinetic control may be invoked according to the stabilities of PS(-). Applied to this NSAIDs family, the photoxidative damages through electron transfer mechanism were analyzed and a good correlation with photoredox and photobiological properties was established. PMID- 22436507 TI - Serial multiple biomarkers in the assessment of suspected acute coronary syndrome: multiple infarct markers in chest pain (MIMIC) study. AB - OBJECTIVE: To evaluate the accuracy of a 2-h serial multiple biomarker (SMB) protocol for exclusion of myocardial infarction (MI) in the Emergency Department. METHODS: A prospective, multicentre, observational study enrolled patients undergoing evaluation for possible MI. Blood samples at presentation and 2 h later were analysed for myoglobin, creatinine kinase-MB, troponin-I and B natriuretic peptide. Thrombolysis in Myocardial Infarction (TIMI) score and National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand (NHF/CSANZ) guideline for acute coronary syndrome were used to determine clinical risk. Primary outcome was MI diagnosed at index presentation. Secondary outcome was composite of all-cause mortality, MI and previously unplanned coronary revascularisation within 30 days. RESULTS: 1758 patients were recruited. 168 (11%) of 1501 with data sufficient for analysis had MI, and 223 (14%) of 1620 had a secondary outcome. SMB sensitivity and specificity were 0.90 (95% CI 0.84 to 0.94) and 0.41 (95% CI 0.39 to 0.44) for MI. For 30-day outcome, SMB sensitivity and specificity were 0.84 (95% CI 0.78 to 0.88) and 0.41 (95% CI 0.39 to 0.44), compared with standard 8-12 h troponin sensitivity and specificity of 0.79 (95% CI 0.73 to 0.84) and 0.96 (95% CI 0.95 to 0.97). Combined with risk scores, SMB had sensitivity and specificity for MI of 0.99 (0.96 to 1.00) and 0.11 (95% CI 0.09 to 0.12) for TIMI score 0, compared with 0.98 (95% CI 0.94 to 0.99) and 0.31 (95% CI 0.29 to 0.34) for NHF/CSANZ low/intermediate risk groups. CONCLUSIONS: SMB alone is not sufficiently sensitive to exclude MI. Combined with risk scoring, SMB appears to identify patients at lower risk. This requires prospective validation. PMID- 22436508 TI - The physiology of developmental changes in BOLD functional imaging signals. AB - BOLD fMRI (blood oxygenation level dependent functional magnetic resonance imaging) is increasingly used to detect developmental changes of human brain function that are hypothesized to underlie the maturation of cognitive processes. BOLD signals depend on neuronal activity increasing cerebral blood flow, and are reduced by neural oxygen consumption. Thus, developmental changes of BOLD signals may not reflect altered information processing if there are concomitant changes in neurovascular coupling (the mechanism by which neuronal activity increases blood flow) or neural energy use (and hence oxygen consumption). We review how BOLD signals are generated, and explain the signalling pathways which convert neuronal activity into increased blood flow. We then summarize in broad terms the developmental changes that the brain's neural circuitry undergoes during growth from childhood through adolescence to adulthood, and present the changes in neurovascular coupling mechanisms and energy use which occur over the same period. This information provides a framework for assessing whether the BOLD changes observed during human development reflect altered cognitive processing or changes in neurovascular coupling and energy use. PMID- 22436509 TI - Cerebral lateralization and early speech acquisition: a developmental scenario. AB - During the past ten years, research using Near-infrared Spectroscopy (NIRS) to study the developing brain has provided groundbreaking evidence of brain functions in infants. This paper presents a theoretically oriented review of this wealth of evidence, summarizing recent NIRS data on language processing, without neglecting other neuroimaging or behavioral studies in infancy and adulthood. We review three competing classes of hypotheses (i.e. signal-driven, domain-driven, and learning biases hypotheses) regarding the causes of hemispheric specialization for speech processing. We assess the fit between each of these hypotheses and neuroimaging evidence in speech perception and show that none of the three hypotheses can account for the entire set of observations on its own. However, we argue that they provide a good fit when combined within a developmental perspective. According to our proposed scenario, lateralization for language emerges out of the interaction between pre-existing left-right biases in generic auditory processing (signal-driven hypothesis), and a left-hemisphere predominance of particular learning mechanisms (learning-biases hypothesis). As a result of this completed developmental process, the native language is represented in the left hemisphere predominantly. The integrated scenario enables to link infant and adult data, and points to many empirical avenues that need to be explored more systematically. PMID- 22436510 TI - What can emerging cortical face networks tell us about mature brain organisation? AB - This opinion paper suggests that developmental neuroimaging studies investigating emerging cortical networks for specific cognitive functions can contribute substantially to our understanding of mature brain organisation. Based on a review of the literature on the neural correlates of face processing abilities, this paper shows how developmental neuroimaging can help resolve outstanding issues, such as whether specific brain regions actually start out by responding to specific stimulus classes, and how this response changes with development. It has been suggested for example, that improving specialisation in a particular brain regions may be the result of increasing connectivity with other network regions supporting the same cognitive function. Developmental neuroimaging studies are particularly well suited to disentangle the interplay between changes at different network levels, such as improving behavioural proficiencies and functional and structural brain development, as well as overall network configuration changes. However, much of the future progress will depend on whether developmental changes are assessed by combining multiple network observations. This paper makes specific suggestions as to how such a multifaceted approach may look like by exploring the suitability of different theoretical frameworks, such as the neural re-use theory or the neuroconstructivist approach for providing guiding principles for future research. PMID- 22436511 TI - Understanding the neural response to social rejection in adolescents with autism spectrum disorders: a commentary on Masten et al., McPartland et al. and Bolling et al. PMID- 22436512 TI - Neuroanatomical correlates of intellectual ability across the life span. AB - Attempts to correlate measures of intellectual ability with localized anatomical imaging features of the brain have yielded variable findings distributed across frontal, parietal, and temporal lobes. To better define the gray and white matter correlates of intellectual ability and the effects of sex and age, we analyzed the brains of 105 healthy individuals, ages 7-57 years, who had a Full Scale Intelligence Quotient (FSIQ) of 70 or higher. We examined associations of FSIQ with cortical thickness and with white matter volume throughout the cerebrum. Thinning of left ventromedial and right dorsolateral prefrontal cortices correlated significantly with FSIQ. Sex modified correlations of cortical thickness with FSIQ in the left inferior frontal, left cingulate, and right dorsomedial prefrontal cortices. Correlations of local white matter volumes with FSIQ varied by age, with adults showing inverse correlations of white matter volume with FSIQ in a large territory of right frontal white matter likely corresponding to fiber tracts of the superior corona radiata and superior longitudinal fasciculus. These findings corroborate the role of frontal and parietal association cortices and long association white matter fibers in higher intelligence and suggest ways in which the neuroanatomical correlates of higher intelligence may vary by sex and age. PMID- 22436513 TI - Acromegaly is associated with decreased skin transepidermal water loss and temperature, and increased skin pH and sebum secretion partially reversible after treatment. AB - BACKGROUND: Acromegaly is characterized by an acquired progressive somatic disfigurement, mainly involving the face and extremities, besides many other organ involvement. Wet and oily skin was described in acromegaly patients and it was attributed to hyperhidrosis and increased sebum production but this suggestion has not been evaluated with reliable methods. OBJECTIVE: The aim of this study was to examine the skin parameters of patients with acromegaly using measurements of skin hydration, sebum content, transepidermal water loss, pH and temperature and particularly the effects of 12 months of treatment on these parameters. METHODS: 52 patients with acromegaly and 24 healthy control subjects were included in this two blinded prospective study. Skin properties were measured on forehead and forearm by Corneometer CM825, Sebumeter SM810, Tewameter TM210 and Phmeter PH900 as non-invasive reliable measuring methods. Serum GH, IGF 1 and all measurements of skin properties on forehead and forearm were repeated at the end of the 3, and 6 months of therapy in 20 cases. Patients were treated with appropriate replacement therapy for deficient pituitary hormones. RESULTS: The sebum content and pH of the skin of acromegalic patients were significantly higher and transepidermal water loss and skin temperature were found to be significantly lower in acromegalic patients when compared to the control group both on forehead and forearm. GH and IGF-1 levels were positively correlated with sebum levels and negatively correlated with skin temperature on both forehead and forearm. The sebum levels of the patients were significantly decreased both on forehead and forearm at 3rd and 6th months of treatment. CONCLUSION: The present study demonstrated increased sebum secretion, decreased transepidermal water loss, alkali and hypothermic skin surface in patients with acromegaly by reliable methods for the first time. These data suggest that GH and/or IGF-I may have a modulatory role on several skin characteristics which can be at least partially reversible with treatment. PMID- 22436514 TI - Differences in the GH-IGF-I axis in children of different weight and fitness status. AB - OBJECTIVE: To determine if differences in the GH-IGF-I axis exist between children of high and low aerobic fitness who are obese or of normal weight. DESIGN: 124 children (ages 8-11) divided into four groups based on BMI and VO2max (mL O2/kg fat free mass(FFM)/min): normal weight--high-fit (NH), normal weight- low-fit (NL), obese--high-fit (OH), and obese--low-fit (OL). Height, weight, skinfolds, body mass index (BMI), body fat percentage and predicted VO2max (both ml/kg/min and ml/kg(FFM)/min) were assessed. Resting growth hormone (GH), total insulin-like growth factor 1 (total IGF-I), free insulin-like growth factor 1(free IGF-I), and insulin were measured using morning fasting blood samples. RESULTS: GH was greater in the NH group compared to the OL group only (p<0.01). No group differences existed for either total IGF-I (p=0.53) or free IGF-I (p=0.189). Insulin was greater in the OH and OL groups than the NH and NL groups (p<0.01). With groups combined (or overall), insulin and free IGF-I were related to fitness (insulin--ml/kg/min: r=-0.226, p<0.05 and ml/kg(FFM)/min: r=-0.212, p<0.05; free IGF-I--ml/kg/min: r=-0.219, p<0.01 and ml/kg(FFM)/min: r=-0.272, p<0.05). CONCLUSIONS: Fitness may contribute to the obesity related reduction of GH that may be involved with weight gain. PMID- 22436515 TI - Brachytherapy catheter spacing and stabilization technique. AB - PURPOSE/OBJECTIVES: To facilitate catheter spacing, implant stability, and patient comfort during multicatheter interstitial brachytherapy. METHODS AND MATERIALS: Uniform and consistent spacing of multiple interstitial implant catheters can be difficult because individual catheters may become displaced during the course of treatment. The authors have developed a brachytherapy catheter fixation method using Jackson-Pratt (JP) drains that can be used within wounds to maintain catheter spacing or on the skin surface for applicator fixation. JP drains are threaded over the implant needles to space and stabilize the implant geometry. The needles are then replaced with the usual brachytherapy catheters. RESULTS: Surgically directed ("open") placement of implant catheters is less prone to displacement when a drain connects and spaces the catheters in the wound. Fixation on the skin surface can also be achieved with the JP drains, which make the friction buttons optional. The soft drain material helps avoid discomfort and pressure injury sometimes associated with hard plastic buttons. Small (10 French) round JP drains are suitable for breast, and head and neck sites and larger 7*10-mm flat JP drains for extremity sarcomas, abdominal, or thoracic tumors. CONCLUSIONS: The complex brachytherapy devices fashioned from widely available surgical drains effectively guide and maintain geometry for multicatheter interstitial implants. Stable implant geometry leads to more reliable implementation of brachytherapy dosimetry. Patient comfort is improved and soft tissue injury from hard-edged buttons is avoided. PMID- 22436516 TI - Long-term outcome for very high-risk prostate cancer treated primarily with a triple modality approach to include permanent interstitial brachytherapy. AB - PURPOSE: To evaluate outcome in the most unfavorable subset of high-risk prostate cancer patients treated with a combination of supplemental external beam radiation therapy (EBRT) and brachytherapy. METHODS AND MATERIALS: Very high-risk prostate cancer was defined as follows: any Gleason score 10, Gleason score 8-9 with >50% of the biopsy cores positive for malignancy, Gleason score 8-9 with a prostate-specific antigen (PSA) >20ng/mL, any clinical stage T3, or any PSA >40ng/mL. One hundred thirty-one patients were identified who met the aforementioned criteria. The median followup was 6.6 years. One hundred twenty (91.6%) patients received supplemental EBRT and 100 (76.4%) received androgen deprivation therapy (median duration, 19.5 months; range, 4-36 months). The median postimplant day 0 D(90) (i.e., the minimum percentage of the prescription dose that covers the planning target volume) was 121.9% of prescription dose. Multiple clinical treatment and dosimetric parameters were evaluated for impact on the evaluated survival parameters. RESULTS: The median pretreatment PSA and Gleason score were 11.0ng/mL and 8. One hundred ten (84%) patients had a Gleason score >=8. At 9 and 12 years, the cause-specific survival, biochemical progression-free survival, and overall survival were 91.0% and 86.5%, 87.3% and 87.3%, and 70.5% and 60.5%, respectively. The most common cause of death was heart disease (22.2%) with deaths from nonprostate cancer (12.7%) and prostate cancer (8.3%) being less likely. CONCLUSIONS: Permanent interstitial brachytherapy usually with supplemental EBRT and androgen deprivation therapy results in excellent biochemical control and cause-specific survival in the most unfavorable subset of high-risk prostate cancer patients. Death from diseases of the heart was more than twice as likely as death from prostate cancer. PMID- 22436517 TI - Tumor control, eye preservation, and visual outcomes of ruthenium plaque brachytherapy for choroidal melanoma. AB - PURPOSE: To evaluate outcomes in patients with posterior choroidal melanoma treated with ruthenium ((106)Ru) brachytherapy. METHODS AND MATERIALS: A retrospective single institutional analysis of 83 of 94 consecutive patients who underwent (106)Ru brachytherapy was performed. Disease was mainly staged as small and medium-sized nonmetastatic melanoma. The main parameters evaluated were tumor control (local control [LC] and progression-free survival [PFS]) and ocular preservation (enucleation-free survival [EFS]). Besides, functional evaluation was performed and complications were described. RESULTS: The median follow-up was 39 (6-83) months. The median values of height and maximal basal diameter were 4.3 and 9.3mm, respectively. Median apical and basal doses were 100 and 307Gy, respectively. The actuarial 2-year LC, PFS, and EFS were 96.2%, 96.2%, and 95.5%, respectively. Actuarial 5-year LC, PFS, and EFS were 93.6%, 93.6%, and 84.1%, respectively. Preinsertion visual acuity (VA) maintenance was 34% (equal or better than before treatment). Approximately 56% of patients stayed with a minimum functional VA of 0.1 or more, from whom more than half stayed with 0.5 or more. Cataract was seen in 16% of treated eyes, and glaucoma was the rarest complication, with an incidence of 3%. CONCLUSIONS: Small- and medium-sized choroidal melanomas can be adequately treated with (106)Ru brachytherapy, with high rates of tumor control and ocular preservation. Moreover, acceptable incidence of complications such as glaucoma and cataract are seen, and a reasonable part of patients stay with a minimum functional VA. PMID- 22436518 TI - Evaluation of the visibility of a new thinner 125I radioactive source for permanent prostate brachytherapy. AB - PURPOSE: The 125I source currently used for prostate brachytherapy at St. James's Institute of Oncology is a standard size seed (~4.5mm in length and 0.8mm in diameter). A new, thinner seed is under evaluation. This is designed to be implanted using narrower needles, potentially reducing edema and improving the dose distribution. This study investigated the visibility of the thinner source on multimodality images and compared it with that of standard size seeds. METHODS AND MATERIALS: Images of dummy seeds of both thinner and standard size models were taken using ultrasound, fluoroscopy, computed tomography (CT), and magnetic resonance (MR) imaging. The ultrasound, fluoroscopy, and CT images were acquired with the seeds inserted into phantoms positioned in a water tank. The MR images were acquired using phantoms containing single seeds. The images were analyzed visually and quantitatively. The resolution of closely spaced seeds on CT images was investigated. RESULTS: The visibility of both seeds was similar on ultrasound, fluoroscopy, and MR images. On CT images, the thinner seeds give reduced artifacts and better resolution. CONCLUSIONS: The use of the thinner seed would have minimal effect on ultrasound and fluoroscopy imaging during treatment. However on CT images, the use of the thinner seeds may improve seed identification for post-treatment dosimetry. Further study is required into the suitability of MR images alone for post-treatment dosimetry. PMID- 22436519 TI - Calculating prescription doses for new sources by biologically effective dose matching. AB - PURPOSE: In current clinical practice, single isotopes, such as (125)I or (103)Pd, are used as single sources in prostate seed implants. A mixture of two radionuclides in the seeds has been proposed for prostate cancer treatment. This study investigates a method for determining the prescription dose for these new seeds using the biological effective dose (BED). METHODS: Ten prostate cancer cases previously treated using single radionuclide seeds were selected for this study. The BED distribution for these cases was calculated. Plans using other radionuclides were then calculated based on this BED distribution. Prescription values could then be obtained for the calculated plans. The method was verified by calculating the prescription dose for (103)Pd and (125)I and comparing to clinical values. The method was then applied to a hybrid seed that consisted of a mixture of (125)I and (103)Pd radionuclides, which deliver equal dose to 1cm from the source in water (50/50D@1 cm). A prescription BED value was also calculated. RESULTS: A prescription BED of 110 Gy was found to correlate to a prescription dose of 145, 120, and 137 Gy for (125)I, (103)Pd, and 50/50D@1 cm hybrid seeds, respectively. CONCLUSION: The method introduced in this article allows one to calculate the prescription dose for new and novel sources in brachytherapy. The method was verified by calculating a prescription dose for (125)I and (103)Pd radionuclides that coincides with values used clinically. PMID- 22436520 TI - [A pregnant woman without fetal heartsounds]. AB - A 31-year-old woman reported to a Malawian district hospital. She was pregnant of twins and in labour, and had received no prenatal care. There were no fetal heartsounds on examination. The patient spontaneously delivered 2 macerated stillbirths. A monochorionic placenta in 1 amniotic sack was seen with 2 entangled umbilical cords, a feared complication in monoamniotic monochorionic twin pregnancy. PMID- 22436521 TI - [A young woman with acute abdominal pain]. AB - A 21-year-old woman reported to the first aid with acute pain in the right lower abdomen since 5 days, diarrhoea and nausea. There was no fever or muscular guarding, and no signs of inflammation in the blood screening. An ultrasound and a CT-scan of the abdomen showed an ovoid, fatty mass compatible with an appendagitis epiploica. This self-limiting disease does not need treatment. PMID- 22436522 TI - [Age-specific treatment of femoral shaft fractures in children]. AB - In the treatment of femoral shaft fractures in children, the age, the anatomy of the epiphyseal plates, the vascularisation of the femoral head and the length of hospital stay play an important role. The degree in which a malposition after a femoral shaft fracture is corrected by growth depends on the size, the location and the type of dislocation, and on the residual growth potential of the child. In children up to the age of 4, treatment with traction followed by spica casting almost always gives good results. Children up to age 12 are preferably treated with elastic intramedullary nails, if necessary in combination with a spica cast. In special cases, plate osteosynthesis or external fixation can be used. Children older than 12 years are often too heavy for treatment using elastic nails. Because of the still open growth plate of the greater trochanter, the vascularisation of the femoral head and the diameter of the femur, a standard adult intramedullary nail is not always suitable. Recently, a smaller nail for adolescents was developed, which is currently being tested. PMID- 22436523 TI - [Colchicine has no negative effect on fertility and pregnancy]. AB - OBJECTIVE: To inventorise the possible development of infertility and pregnancy complications in patients with Familial Mediterranean Fever (FMF), on treatment with colchicine. DESIGN: Systematic review. METHOD: PubMed was searched for articles in English, describing the effects of colchicine on fertility and pregnancy in animals or humans. RESULTS: We found 73 articles, 13 of which matched the inclusion criteria. We selected another 12 articles via cross references and after evaluation by the co-authors. From these articles it appeared that colchicine inhibits the clinical symptoms of FMF and the development of amyloid deposits. No statistically significant effect was found of colchicine treatment on semen quality or hormone levels. Treatment with colchicine during pregnancy did not lead to severe complications. Both male and female patients who were treated with colchicine had a better prospect of maintaining fertility, compared with patients without this treatment. CONCLUSION: According to the literature selected, colchicine use has no demonstrable negative effect on fertility. If untreated, FMF itself can lead to amyloid deposits in the testis and ovary, resulting in infertility. Patients with FMF may safely continue to use colchicine throughout the reproductive phase of their life. PMID- 22436524 TI - [Family with fever after cleaning a sea aquarium]. AB - BACKGROUND: Improved aquarium techniques are enabling sea aquariums to imitate reality even better. This means that they sometimes contain known and unknown marine toxins. Aquarium keepers and their families may then develop potentially severe poisoning. CASE DESCRIPTION: A 37-year-old man presented at the Emergency Department with fever, hypotension and symptoms of a metallic taste in the mouth, nausea, headache, shivering and severe muscle cramps. Symptoms appeared after he had tried to remove a colony of Zoanthids (soft corals) from his aquarium by pouring boiling water over them. His wife (35-year-old) and two children (10-year old twins) had also inhaled the offensive-smelling steam coming from the aquarium and had similar symptoms. On physical examination, all family members had low blood pressure and fever > 38.5 degrees Celsius. Blood analysis showed leucocytosis and an elevated CRP. We diagnosed palytoxin poisoning. All family members recovered within 48 hours after receiving supportive therapy only. CONCLUSION: Manipulation of certain soft corals found in sea aquariums can cause emission of palytoxin. This may cause a potentially severe episode of poisoning. When working in a sea aquarium protective measures should be taken. There is no specific therapy for or antidote to palytoxin poisoning and for this reason, treatment is supportive. PMID- 22436525 TI - [Ethnic differences in laboratory results]. AB - Over the years the Netherlands has become a country with a population comprising over 20% of immigrants. Immigrants differ from natives in both biological and cultural aspects, amongst others in laboratory results, but also in level of participation in clinical trials, and treatment outcomes. It is important for physicians to keep these differences between ethnic groups in mind. The authors argue that specific reference ranges for subgroups should be established. PMID- 22436526 TI - [Trends in the use of primary radiotherapy for cancer in the Netherlands in patients with breast, prostate, rectal and lung tumours]. AB - OBJECTIVE: To provide insight in the application of radiotherapy as part of primary treatment of patients with cancer in the Netherlands. DESIGN: Retrospective, descriptive population-based study. METHOD: Data concerning patients with breast, prostate, rectal and non-small cell lung cancer were selected from the Netherlands Cancer Registry in 4 regions, covering 50% of the Dutch population. The selection concerned data from 1997-2008 and, except for prostate cancer, only patients without distant metastases were included. RESULTS: Between 1997 and 2008, the use of primary external radiotherapy increased approximately 7% in breast cancer patients and approximately 30% in rectal cancer patients. In the latter group preoperative radiotherapy strongly increased, while postoperative radiotherapy decreased. For prostate cancer there was an increase in brachytherapy (9%). The use of external beam radiotherapy in patients with prostate cancer and non-small cell lung cancer remained the same. Regional differences in the extent of use of radiotherapy for breast and rectal cancer clearly decreased. These differences remained limited for external beam radiotherapy in prostate and non-small cell lung cancer. Older patients less often received radiotherapy. CONCLUSION: The increase in use of radiotherapy for breast cancer is explained by the increase in breast conserving surgery. The trends in use in patients with rectal cancer and breast cancer are presumably related to the implementation of multidisciplinary practice guidelines. The implementation of these guidelines probably also contributed to the decrease in regional differences in the use of radiotherapy. PMID- 22436527 TI - [Clinical manifestations and hazards of brucellosis in the Netherlands]. AB - Brucellosis, a zoonotic infection characterised by undulant fever, has a low incidence in the Netherlands and is therefore rarely considered. We describe 3 patients aged 26, 47 and 56 years old; each presented with long-standing fever as predominant symptom after having travelled to an endemic area, Iraq or Turkey, 1 week to 4 months prior to manifestation of illness. They had similar symptoms: fever, weight loss, chills, night sweats and dry cough. Blood cultures of all patients became positive for gram-negative rods after 3-4 days of incubation. One patient had imported and consumed sheep-milk cheese from which a genetically indistinguishable Brucella strain was cultured. In another patient, identification of the bacterium proved difficult, resulting in delayed prescription of adequate antibiotic treatment. Serologic testing confirmed the diagnosis in this case. In the laboratory, there is a considerable risk of airborne transmission of the disease necessitating clear notification of the suspicion of brucellosis when material for culturing is submitted. PMID- 22436528 TI - [Willis and his circle]. AB - Thomas Willis (1621-1675) grew up in Wiltshire and studied medicine in Oxford, at a time when the city was besieged and then occupied by Parliamentarian troops. He started his career as a country doctor while concurrently taking part in informal gatherings with other scientists (William Petty, Christopher Wren and, later on, Robert Hooke, Richard Lower and Robert Boyle). They performed physical and chemical experiments and carried out a variety of tests on animals. After the restoration of the monarchy in 1660 Willis combined his practice with academic teaching. From then on he focused his studies on the structure and function of the brain, dissecting brains after removal from the skull and fixation in 'spirit of wine'. In his 'Cerebri anatome' of 1664, illustrated by Wren, he drew attention to the arterial circle at the base of the brain, including its physiological advantages. This arterial circle had been incompletely described by others in the past and fully, but only in writing, by Wepfer in 1658. PMID- 22436529 TI - [The medical specialist and quality standards: a plea for realism in an era of visible care]. AB - The outcome of medical practice is subject of growing interest. New media offer opportunities to search for specialists who offer the best treatment outcome. This information could stimulate competition in a positive manner, but it also increases the vulnerability of medical specialists. From this perspective, treatment outcome statistics should be presented realistically. Early cohort studies usually overestimate chances of success. The medical community should focus on the outcome of national registries or multicentre randomized studies when presenting reasonable outcome perspectives for their patients. PMID- 22436530 TI - Effect of moderate physical exercise on postural control among 65-74 years old men. AB - The aim of this study was to assess the changes in the postural control (PC) during quiet stance among elderly men with fatigue induced by moderate exercise, and to assess the relationships between changes in PC and somatic indices (body mass index (BMI), waist to hip ratio (WHR)), load during exercise, and post exercise blood lactate (BL) concentration. The study involved 17 elderly men (68.4+/-2.9 years of age, ranging between 65 and 74 years). Mean velocity of the center of pressure (COP) displacements was measured using a force plate both before and after fatigue induced by a cycle ergometer exercise. Following physical exercise, the mean velocity of the COP and its components, both in the sagittal and frontal plane, increased significantly. It was found that increasing BMI was associated with increasing exercise-induced changes in the mean velocity of the frontal plane. Additionally, BL level was positively correlated with changes in the mean velocity of the sagittal plane. Higher post-exercise values of the mean velocity of the COP may suggest a temporary increase in the risk of falls. Therefore, it seems advisable to caution the elderly men in regards to the increased risk of falling following exercise. Analysis showed that the changes in the PC as indicated by the increase in the COP displacements velocity may be related to the level of fatigue (as indicated by BL). Moreover, elderly men possessing a higher BMI may exhibit a tendency toward the greater increase in the postural sway after exercise-induced fatigue. PMID- 22436531 TI - Rocky. PMID- 22436532 TI - The value of serum CA125 for the development of virtual follow-up strategies for patients with epithelial ovarian cancer: a retrospective study. AB - BACKGROUND: Serum CA125 is routinely used in the follow up of ovarian cancer. The objective of the present study was to evaluate the usefulness of CA125 in the detection of ovarian cancer recurrence. METHODS: This retrospective case study was carried out at a tertiary gynaecological cancer centre in Australia. Patients with all cell types of epithelial ovarian cancer (EOC) treated between 2003 and2010 were considered eligible. We excluded patients whose aim of treatment was palliative, had no follow-up, had no pre-operative CA125 reading or had pre operative CA125 levels < 35 U/mL. After primary treatment, patients were followed up as per guidelines suggested by National Comprehensive Cancer Network (NCCN). We recorded if symptoms, findings from physical examination, imaging or serum CA125 levels led to the diagnosis of recurrence. An increase in CA125 levels to twice the postoperative nadir was considered as "doubling" at any time during follow up. RESULTS: Analysis is based on 56 patients who completed primary treatment and who presented for a total of 274 follow-up episodes. Of those, 29 patients (52%) developed a recurrence within the follow up period. Recurrence was diagnosed by CA125 alone in 14 of 29 patients (48%). CA125 was not elevated in 7 patients (24%) who recurred. Doubling of CA125 from nadir was observed in 27/29 patients. Of those 27 patients the doubling from nadir occurred within the normal range of 35 U/ml in 3 cases and outside the normal range in 24 cases. Multivariate analysis suggests that doubling of serum CA125 (OR 5.10, p 0.036) and nadir CA125 > 10 U/ml (OR 2.86, p 0.01) remained the only independent factors to predict ovarian cancer recurrence. CONCLUSIONS: The present paper proposes the validation of a novel CA125 algorithm aiming to detect recurrent EOC. These data may allow us to investigate novel ways of follow up that do not require a patient's physical attendance at a clinic (virtual follow-up). PMID- 22436533 TI - Comparison of the Addiction Severity Index (ASI) and the Global Appraisal of Individual Needs (GAIN) in predicting the effectiveness of drug treatment programs for pregnant and postpartum women. AB - This study conducts a within-subject comparison of the Addiction Severity Index (ASI) and the Global Appraisal of Individual Needs (GAIN) to assess change in alcohol and other drug treatment outcomes for pregnant and postpartum women. Data are from 139 women who were pregnant or who had children under 11 months old and were admitted to residential drug treatment, then re-interviewed 6 months postdischarge (83% follow-up rate). The ASI and GAIN change measures were compared on their ability to detect changes in alcohol and drug use, medical and HIV risk issues, employment issues, legal problems, family and recovery environment characteristics, and psychological/emotional issues. The measures were similar in their ability to detect treatment outcomes, and ASI and GAIN change scores were moderately correlated with each other. The GAIN scales had equal or slightly higher coefficient alpha values than the ASI composite scores. The GAIN also includes an HIV risk scale, which is particularly important for pregnant and postpartum women. These results suggest that the GAIN is comparable with the ASI and can be used for treatment research with pregnant and postpartum women. PMID- 22436534 TI - An anthropometric model to estimate neonatal fat mass using air displacement plethysmography. AB - BACKGROUND: Current validated neonatal body composition methods are limited/impractical for use outside of a clinical setting because they are labor intensive, time consuming, and require expensive equipment. The purpose of this study was to develop an anthropometric model to estimate neonatal fat mass (kg) using an air displacement plethysmography (PEA POD(r) Infant Body Composition System) as the criterion. METHODS: A total of 128 healthy term infants, 60 females and 68 males, from a multiethnic cohort were included in the analyses. Gender, race/ethnicity, gestational age, age (in days), anthropometric measurements of weight, length, abdominal circumference, skin-fold thicknesses (triceps, biceps, sub scapular, and thigh), and body composition by PEA POD(r) were collected within 1-3 days of birth. Backward stepwise linear regression was used to determine the model that best predicted neonatal fat mass. RESULTS: The statistical model that best predicted neonatal fat mass (kg) was: -0.012 0.064*gender + 0.024*day of measurement post-delivery -0.150*weight (kg) + 0.055*weight (kg)2 + 0.046*ethnicity + 0.020*sum of three skin-fold thicknesses (triceps, sub scapular, and thigh); R2 = 0.81, MSE = 0.08 kg. CONCLUSIONS: Our anthropometric model explained 81% of the variance in neonatal fat mass. Future studies with a greater variety of neonatal anthropometric measurements may provide equations that explain more of the variance. PMID- 22436535 TI - The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia. AB - Acute lymphoblastic leukaemia (ALL) occurs at all ages but is the most common cancer of childhood. The current treatment of paediatric ALL is highly successful with up to 90% children being cured. In contrast, survival rates for adult ALL are significantly lower at around 40%. The discovery and characterisation of genetic abnormalities have increased our understanding of the biology of the disease and provided important prognostic and predictive markers which have improved patient outcome. Not only is the spectrum of these aberrations vast but, due to advances in technology, continually expanding. A wide range of chromosomal and genomic abnormalities have been reported as being associated with patient outcome but only a subset are currently used to risk stratify patients. This review highlights the main genetic abnormalities which are used to manage patients with B-cell precursor ALL and discusses the evidence which has been accumulated on several newly described genomic abnormalities. PMID- 22436536 TI - Intranasal oxytocin administration is reflected in human saliva. AB - Following the discovery that intranasal administration of neuropeptides can reach the central nervous system, a growing number of studies applied intranasal oxytocin (OT) paradigms to demonstrate the positive effects of OT on social and emotional processes. The three-step paradigm typically included: OT administration, a 45-min waiting period, and approximately 1-h period of active drug effects when experimental manipulations are applied. Yet, this schedule has not been put to systematic validation. Utilizing a double-blind placebo-control within-subject design, ten individuals were administered OT or placebo and salivary OT was measured ten times, at baseline and nine times over four consecutive hours. OT administration induced substantial increases in salivary OT across the entire period. OT rose dramatically 15 min after administration (from 6.9 pg/ml at baseline to 1265.4 pg/ml), reached plateau at 45-120 min (range=131.6 and 105.3 pg/ml), and did not return to baseline by 4h. Results contribute to discussion on brain-periphery coordination of OT and highlight the need for further research on the temporal dynamics and durations of OT administration effects. PMID- 22436537 TI - [Assessment of the state and future of basic neonatal resuscitation equipment, in first-line health facilities in Senegal after 3years]. AB - BACKGROUND: Neonatal mortality is a major public health problem. The main causes are infections, prematurity and asphyxia at birth. In view of reducing this high mortality, primary healthcare facilities were equipped with basic equipment for the care of newborns and their key workers were trained in essential newborn care. Three years after this implementation, the present study assesses the state and conditions of use of this basic equipment intended for taking care of newborns at birth. METHOD: This assessment was conducted from 16 March to 3 April 2009. It was based on observations and interviews on a sample of healthcare facilities. RESULTS: Healthcare facilities were generally equipped with ventilator bags and masks (87%) (60/69). In more than half of the healthcare centers (20/38), they were not used often because the workers were renewed and not educated in their use. They were practically all in good condition. Eighty five percent (59/69) of healthcare facilities had at least one aspirator, generally adapted to newborns (negative pressure, 100 mmHg). The maintenance of the material was globally satisfactory because the aspirator bottles were most often clean. As for the aspirator tubes, they were always available but a few cases of supply rupture were observed in some healthcare centers. The warming table was available in only 52% (36/69) of healthcare facilities. Fifteen tables did not comply with initial specifications. CONCLUSION: This assessment highlights that the basic equipment intended for newborn care was generally available, functional and maintained well after 3 years. This strategy could be scaled up in order to contribute to reducing the newborn mortality. PMID- 22436538 TI - [Neonatal health indicators in a Senegalese rural district]. PMID- 22436539 TI - Blood mitochondrial DNA mutations in HIV-infected women and their infants exposed to HAART during pregnancy. AB - OBJECTIVES: Nucleo(s/t)ide reverse transcriptase inhibitors given to HIV-infected pregnant women to prevent vertical transmission may adversely affect mitochondrial DNA (mtDNA). We hypothesized that HAART-exposed/HIV-uninfected infants may show higher blood mtDNA mutation burden than controls born to HIV uninfected mothers. METHODS: Blood was collected from in-utero HIV/HAART-exposed infants and controls, as well as from a subset of their mothers. The presence of mtDNA A->C/T->G (AC/TG) mutations was measured by cloning and sequencing D-loop PCR amplicons. Relationships with maternal characteristics were examined. RESULTS: No significant difference was found between the percentage of HIV/HAART exposed infants with AC/TG mutations (N = 15/57, 26.3%) and controls (N = 10/70, 14.3%) before (P = 0.090) or after controlling for covariates (P = 0.058), although a tendency was observed. However, significantly more HIV/HAART-exposed mothers (N = 18/42, 42.9%) harboured AC/TG mutations compared with controls (N = 7/39, 17.9%) before (P = 0.015) and after (P = 0.012) controlling for covariates. AC/TG mutations were more prevalent in HIV/HAART-exposed mothers than in their infants (N = 42, 42.9 vs. 23.8%, P = 0.033), however, this difference disappeared after controlling for covariates. No difference was seen between control mothers and their infants (N = 39, both 17.9%). In HIV/HAART-exposed mothers, only a detectable HIV plasma viral load near delivery predicted AC/TG mutations. CONCLUSION: Our results suggest that HIV and/or HAART exposure are associated with increased prevalence of AC/TG mtDNA mutations in mothers and show a similar tendency in infants exposed during pregnancy. As accumulation of mtDNA mutations has been linked with aging and age-associated diseases, this may raise concerns in the long term for HIV and HAART-exposed populations. PMID- 22436540 TI - Neutrophilic eccrine hidradenitis in an HIV-1-infected patient. PMID- 22436541 TI - Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia. PMID- 22436542 TI - A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy. AB - BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. METHODS/DESIGN: A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. DISCUSSION: Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical function, and ultimately improving the health-related quality of life in men with prostate cancer receiving ADT. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00834392. PMID- 22436543 TI - Design and implementation of a virtual world training simulation of ICU first hour handover processes. AB - Nursing training for an Intensive Care Unit (ICU) is a resource intensive process. High demands are made on staff, students and physical resources. Interactive, 3D computer simulations, known as virtual worlds, are increasingly being used to supplement training regimes in the health sciences; especially in areas such as complex hospital ward processes. Such worlds have been found to be very useful in maximising the utilisation of training resources. Our aim is to design and develop a novel virtual world application for teaching and training Intensive Care nurses in the approach and method for shift handover, to provide an independent, but rigorous approach to teaching these important skills. In this paper we present a virtual world simulator for students to practice key steps in handing over the 24/7 care requirements of intensive care patients during the commencing first hour of a shift. We describe the modelling process to provide a convincing interactive simulation of the handover steps involved. The virtual world provides a practice tool for students to test their analytical skills with scenarios previously provided by simple physical simulations, and live on the job training. Additional educational benefits include facilitation of remote learning, high flexibility in study hours and the automatic recording of a reviewable log from the session. To the best of our knowledge, we believe this is a novel and original application of virtual worlds to an ICU handover process. The major outcome of the work was a virtual world environment for training nurses in the shift handover process, designed and developed for use by postgraduate nurses in training. PMID- 22436544 TI - Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis of biventricular vs. right ventricular pacing mode. AB - AIMS: For patients with refractory atrial fibrillation (AF) undergoing atrioventricular nodal ablation (AVNA), initial single-chamber right ventricular (RV)-only pacing is standard. Given the deleterious effects of chronic RV-only pacing, the impact of an initial biventricular (BiV) pacing strategy post ablation is of interest. METHODS AND RESULTS: We conducted a meta-analysis to determine the effect of BiV vs. RV-only pacing in patients undergoing AVNA for refractory atrial fibrillation. A search of multiple electronic databases identified 921 reports, which included four randomized controlled trials (n = 534). Mean New York Heart Association (NYHA) class was 2.3 and mean left ventricular ejection fraction (LVEF) was 44%. When compared with RV-only pacing, BiV pacing was not associated with reduced mortality [risk ratio 0.85, 95% confidence interval (CI) 0.40-1.82, P = 0.68]. In three studies comprised of patients with left ventricular systolic dysfunction (mean EF 41 +/- 3%), BiV pacing demonstrated a non-significant reduction in cardiac mortality (risk ratio 0.59, 95% CI 0.25-1.39; P = 0.23). Compared with RV-only pacing, BiV pacing was associated with significant improvement in symptoms [Minnesota Living with Heart Failure Questionnaire (MLWHFQ) 2.72 points fewer, 95% CI 1.45-3.99] and increased LVEF (+2.6%, 95% CI 1.69-3.44), but no significant change in 6 min walk distance (6MWD) (5.02 ms more, 95% CI -1.56 to 11.59; P = 0.13). CONCLUSIONS: In patients with refractory AF undergoing AVNA, BiV pacing was not associated with significantly improved survival when compared with RV-only pacing. A modest, but significant improvement in structural and functional response to BiV pacing was observed. PMID- 22436545 TI - Endoscopic Vascular Harvest in Coronary Artery Bypass Grafting Surgery: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2005. AB - OBJECTIVE: : This purpose of this consensus statement was to compare endoscopic vascular graft harvesting (EVH) with conventional open vascular harvesting (OVH) in adults undergoing coronary artery bypass grafting (CABG) surgery and to determine which resulted in improved clinical and resource outcomes. METHODS: : Before the consensus conference, the consensus panel reviewed the best available evidence, whereby systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of importance. Evidence-based statements were created, and consensus processes were used to determine the ensuing statements. The AHA/ACC system was used to label the level of evidence and class of recommendation. RESULTS: : The consensus panel agreed upon the following statements: CONCLUSIONS: : Given these evidence-based statements, the consensus panel stated that EVH should be the standard of care for patients who require saphenous vein grafts for coronary revascularization (Class I, Level B). Future research should address long-term safety, cost-effectiveness, and endoarterial harvest. PMID- 22436546 TI - Endoscopic vascular harvest in coronary artery bypass grafting surgery: a meta analysis of randomized trials and controlled trials. AB - OBJECTIVE: : This meta-analysis sought to determine whether endoscopic vascular graft harvesting (EVH) improves clinical and resource outcomes compared with conventional open graft harvesting (OVH) in adults undergoing coronary artery bypass surgery. METHODS: : A comprehensive search was undertaken to identify all randomized and nonrandomized trials of EVH versus OVH up to April 2005. The primary outcome was wound complications. Secondary outcomes included any other clinical morbidity and resource utilization. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences (SMD) and their 95% confidence intervals (95% CI) were analyzed. RESULTS: : Thirty-six trials of 9,632 patients undergoing saphenous vein harvest met the inclusion criteria (13 randomized; 23 nonrandomized). Risk of wound complications was significantly reduced by EVH compared with OVH (OR 0.31, 95% CI 0.23-0.41). Similarly, the risk of wound infections was significantly reduced (OR 0.23, 95% CI 0.20-0.53; P < 0.0001). Need for surgical wound intervention was also significantly reduced (OR 0.16, 95% CI 0.08-0.29). The incidence of pain, neuralgia, and patient satisfaction was improved with EVH compared with OVH. Postoperative myocardial infarction, stroke, reintervention for ischemia or angina recurrence, and mortality were not significantly different. Operative time was significantly increased (WMD 15.26 minutes; 95% CI 0.01, 30.51), hospital length of stay was reduced (WMD -0.85 days; 95% CI -1.55, -0.15), and readmissions were reduced (OR 0.53, 95% CI 0.29-0.98). Costs were insufficiently reported to allow for aggregate analysis. CONCLUSIONS: : Endoscopic vascular graft harvesting of the saphenous vein reduces wound complications and improves patient satisfaction and resource utilization. Further research is required to determine the incremental cost-effectiveness of EVH versus OVH. PMID- 22436547 TI - Right atrial surgery without caval snaring. AB - BACKGROUND: : During tricuspid valve replacement in a patient with previous mitral valve surgery, we made an incidental observation that the right atrium can be opened without caval snaring and without air entering the venous reservoir. We tested this hypothesis on an animal model. METHODS: : Two patients underwent right atrial surgery using percutaneous cannulation, and no air was entrained without caval snaring. This principle was tested in an animal model using 2 pigs weighing 80 kg each. Percutaneous cannulae were placed under epicardial echo guidance with their tips 4 cm from the right atrium. A "collapsible bag with air drainage system" was introduced into the venous return system to quantify air return from the superior vena cava (SVC) and inferior vena cava (IVC). Two types of percutaneous cannulae with (Cardiovations Quick Draw) and without (Biomedicus) proximal side holes were tested. RESULTS: : In the animal model using Biomedicus cannulae, upon opening the right atrium, air was entrained from the SVC cannula at 60 mL/minute with no air in the IVC. There was no difference in the amount of air between the two cannulae. Pressures measured were 5 cm of water in the IVC and -20 cm water in the SVC. Epicardial ultrasound demonstrated complete collapse of both vena cavae. Partial clamping of the SVC cannula reduced the amount of air to 60 cc/min, and placing a small straight clamp at the SVC atrial junction eliminated the air. No air was noted in IVC cannula. CONCLUSIONS: : Inferior vena caval drainage by percutaneous cannula does not entrain air with either type of cannula and without snaring (both in clinical cases and animal model). This might be explained by the presence of a competent Eustachian valve. However, the SVC is not immune to air. Minimal air (approximately 60 mL/minute) could be managed by partial clamping or completely be avoided by placing a small straight clamp without snaring. PMID- 22436548 TI - Prospective Evaluation of the St. Jude Medical Aortic Connector for Aortic-to Autologous Vessel Graft Anastomoses. AB - BACKGROUND: : Evolving technologies of proximal anastomosis devices meet the endeavor of surgeons to minimize manipulation of the ascending aorta during surgical myocardial revascularization. The objective of this study was to compare the patency rate of the saphenous vein coronary bypass grafts in which the proximal anastomoses were performed with automatic connector devices to the suture technique. METHODS: : From September 2002 through July 2003, 86 patients underwent coronary artery bypass grafting with at least 1 vein graft anastomosed to the ascending aorta with the Symmetry G2 connector. Six-month clinical and angiographic follow-up, including Core-Lab quantitative coronary angiography (QCA) and corrected TIMI frame count (CTFC), was performed. RESULTS: : Eighty patients had at least 1 connector successfully implanted. Freedom from MACE (cardiac mortality myocardial infarction and target vessel reintervention) was 72/80 (90%). Six patients underwent a target vessel reintervention on the connector grafts. Six-month (mean 193 +/- 36 days) angiography patency rates for the connector grafts were 72/81 (88.89%), 37/40 (92.5%) in sutured grafts, and 60/62 (96.8%) in arterial grafts. By QCA, 64/65 (98.5%) patent connector-grafts were free from more than 50% stenosis (1 connector-graft with a 51% stenosis). CTFC showed 65/65 (100%) patent connector-grafts with nonrestrictive flow. CONCLUSIONS: : Saphenous vein grafts anastomosed to the aorta with the Symmetry G2 connector have early and midterm patency rates comparable to the conventional sutured anastomoses. These results support the efficiency of the second generation of symmetry aortic connectors. PMID- 22436549 TI - Thoracic epidural anesthesia for coronary bypass surgery affects autonomic neural function and arrhythmias. AB - BACKGROUND: : In recent years, the invasiveness of coronary reconstruction has been markedly reduced. Awake off-pump coronary artery bypass (AOCAB), coronary bypass surgery with thoracic epidural anesthesia (TEA) without general anesthesia and cardiopulmonary bypass), has been reported in the literature. Because the details of this technique are still unclear, we evaluated its usefulness by examining the autonomic neural state and the incidence of arrhythmia. METHODS: : Fifty-five patients who underwent elective coronary artery bypass grafting (CABG) between April and December 2003 were included in the study. Patients who underwent CABG under high TEA alone comprised group A, those who underwent CABG under general anesthesia combined with TEA comprised group B, and those who underwent CABG under general anesthesia alone comprised group C. Holter electrocardiography was performed before and after surgery, and perioperative electrocardiograms were recorded (before surgery and during surgery, postoperative days 0-3, and postoperative day 7). On obtained electrocardiograms, the autonomic neural state was evaluated by analysis of heart rate variability, and the incidence of atrial fibrillation. RESULTS: : Concerning the autonomic neural state, sympathetic inhibition was observed during TEA in both groups A and B. After discontinuation of TEA, sympathetic activity recovered. Vagal activity was not inhibited in group A, but decreased during surgery and gradually recovered after surgery in group B. Evaluation of the balance between sympathetic and vagal activities showed that sympathetic activity became predominant rapidly on postoperative day 2 in group B but gradually after surgery in group A. The incidence of postoperative atrial fibrillation was the highest in group B. CONCLUSIONS: : In AOCAB, because there is no vagal inhibition, vagal dominance can be maintained after surgery. This may be associated with the lower incidence of postoperative atrial fibrillation in group A compared with group B. Further studies are necessary to evaluate the details of AOCAB. PMID- 22436550 TI - Evolution of Off-Pump Coronary Artery Bypass Grafting over 15 Years: A Single Institution Experience of 14,030 Cases. AB - BACKGROUND: : Off-pump coronary artery bypass grafting for multivessel disease is an important alternative to conventional myocardial revascularization using cardiopulmonary bypass. The development of exposure and stabilization techniques has made this surgery simple, safe, and routine. Experience with the technique, its evolution, the learning curve, and the pitfalls is presented. METHODS: : A retrospective analysis was made of 28,216 patients who underwent elective coronary artery bypass grafting over a 15-year period from January 1990 through December 2004. Isolated off-pump coronary artery bypass grafting was performed in 14,030 patients and on-pump coronary artery bypass grafting in 14,186 patients. The overall period was divided into 3 groups of 5 years each: group I (1990 1994), group II (1995-1999), and group III (2000-2004). Initially, off-pump coronary artery bypass grafting was performed selectively in high-risk patients (eg, atheromatous aorta, severe systemic impairment, chronic obstructive pulmonary disease, octogenarian). Recently (2000-2004), multivessel off-pump coronary artery bypass grafting has been performed electively in 96% to 98% of patients undergoing coronary artery bypass grafting. Patients' medical charts were reviewed for age, preoperative risk factors, operative findings, intraoperative conversion rate to cardiopulmonary bypass, postoperative complications, and length of hospital stay. RESULTS: : In the years 1990-1994 (group I), mostly high-risk cases and cases with left anterior descending coronary artery lesions were included for off-pump coronary artery surgery. In the years 1995-1999 (group II), patients with double and triple vessel disease presenting for coronary artery bypass surgery were accepted for off-pump surgery irrespective of preoperative risk factors. However, in the years 2000-2004 (group III), off-pump coronary artery bypass surgery was the first choice of approach for any patient presenting for coronary artery bypass surgery. The mean number of grafts was lower in off-pump cases than in on-pump cases in group I (2.0 +/- 0.4 vs. 3.2 +/- 0.80) and group II (2.6 +/- 0.6 vs. 3.3 +/- 0.4), whereas the mean number of grafts was higher in off-pump cases than in on-pump cases in group III (3.5 +/- 0.2 vs. 3.4 +/- 0.8). In groups I and II, the conversion to cardiopulmonary bypass was 5.2% and 5.9%, respectively. The conversion to cardiopulmonary bypass decreased to 1.7% in group III, which was statistically significant. Perioperative myocardial infarction was 5.2% in group I, 1.7% in group II, and 1.5% in group III. The difference between groups II and III was not statistically significant. Hospital mortality was higher in group I (5.2%) than in group II (1.2%) or III (1.1%). The difference between groups II and III was not statistically significant. Length of intensive care unit stay was 36 +/- 8 hours in group I, 28 +/- 7 hours in group II, and 20 +/- 8 hours in group III. These differences were statistically significant. Length of postoperative hospital stay was 8 +/- 2 days in group I, 7 +/- 2 days in group II, and 5 +/- 2 days in group III These differences were statistically significant. CONCLUSIONS: : As surgeons' experience matures, off-pump coronary artery bypass surgery permits total myocardial revascularization in virtually all patients with multivessel coronary artery disease. Despite a significant learning curve, evolution to routine off-pump coronary artery bypass with good patient outcomes can be achieved with careful patient selection during the "learning curve." The method is safe and reproducible, and patients benefit with shorter intensive care unit and hospital stays. PMID- 22436551 TI - Three-Dimensional Reconstruction of Ultrafast 16-Slice Computed Tomography Images and CT Angiography Versus Conventional Coronary Angiography at One Year in Multivessel Coronary Artery Bypass Surgery. AB - BACKGROUND: : The aim of this study was to evaluate and compare the postoperative graft patency assessment by multislice spiral computed tomography (MSCT) scan and conventional coronary angiography (CCA) in coronary artery bypass grafting (CABG) patients 1 year after surgery. METHODS: : Sixty-nine patients who underwent isolated CABG at least 1 year before the study, were subjected to both MSCT angiography with cardiac gating and CCA. The results were evaluated and compared. RESULTS: : There were 209 grafts in 69 patients. All grafts were evaluated by both MSCT angiography and CCA. Seventy-eight grafts were on the anterior wall, 83 on the lateral wall and 48 on the inferior wall of the heart.On MSCT angiography, all left internal mammary arteries were visualized with 3-dimensional reconstruction and found to be patent. Of 209 grafts, 11 grafts (5.26%) were blocked, 6 grafts on the lateral wall and 5 on the inferior wall. All patent grafts were correctly evaluated by MSCT angiography (specificity 100%). However, 2 grafts that were found to be patent on MSCT angiography were blocked on CCA (MSCT sensitivity 81.8%). CONCLUSIONS: : Postoperative evaluation of coronary bypass grafts is possible with very good resolution by MSCT angiography. This method allows evaluation of the bypass grafts and the quality of anastomosis with a noninvasive method that is comparable with CCA. PMID- 22436552 TI - Endoscopic lesser saphenous vein harvesting for coronary artery bypass grafting: first reported case. AB - Endoscopic vessel harvesting has become a widely used modality for harvesting venous and arterial conduits for coronary artery bypass grafting. Specifically, it has been used to harvest the greater saphenous vein, internal thoracic artery, and the radial artery. A case of endoscopic lesser saphenous vein harvesting for coronary artery bypass grafting is reported. PMID- 22436554 TI - Positron annihilation and relaxation dynamics from dielectric spectroscopy: poly(vinylmethylether). AB - We report on the temperature dependence of the lifetime of the ortho-positronium (o-Ps), tau(3), annihilation in amorphous polymer poly(vinylmethylether) (PVME) from positron annihilation lifetime spectroscopy (PALS). We show that the behavior of tau(3)(T) can be divided into five regions, each of them having a linear temperature dependence, and that the crossover PALS temperatures situated at T(b1)(G), 0.76T(g)(PALS), T(b1)(L) = 1.14T(g)(PALS) and T(b2)(L) = 1.37T(G)(PALS), and marking the discontinuity in the free volume microstructure are related to various dynamic features from neutron scattering (NS) and broadband dielectric spectroscopy (BDS). First, a slight change in the PALS response in the glassy PVME at T(b1)(G) is related to the onset of the excess wing in an apparent correspondence with the fast secondary beta motion from NS. A further slight bend in the liquid state at T(b1)(L) is related to a high frequency tail of the primary alpha process as well as to the slow secondary beta relaxation from BDS. In addition, it lies also in the vicinity of the crossover temperature, T(B)(betaKWW), in the spectral dispersion of the primary alpha process, indicating a connection of the change in the o-Ps lifetime with the variation in the width of the primary alpha relaxation times distribution. Finally, the tau(3) value at T(b2)(L) is close to the mean relaxation time of the primary alpha process, tau(alpha), in coincidence with the crossover in the secondary effective beta process between two regimes in the liquid PVME. All these relationships point to very close connections between the PALS response and the dynamic behavior of PVME, which can be explained in terms of the temperature dependence of the probability function of the liquid-like and the solid-like domains, as obtained from the two-order parameter (TOP) model description of the liquid to glass transition in glass-formers. PMID- 22436555 TI - Is the Brazilian pharmaceutical policy ensuring population access to essential medicines? AB - BACKGROUND: To evaluate medicine prices, availability and affordability in Brazil, considering the differences across three types of medicines (originator brands, generics and similar medicines) and different types of facilities (private pharmacies, public sector pharmacies and "popular pharmacies"). METHODS: Data on prices and availability of 50 medicines were collected in 56 pharmacies across six cities in Southern Brazil using the World Health Organization / Health Action International methodology. Median prices obtained were divided by international reference prices to derive the median price ratio (MPR). RESULTS: In the private sector, prices were 8.6 MPR for similar medicines, 11.3 MRP for generics and 18.7 MRP for originator brands, respectively. Mean availability was 65%, 74% and 48% for originator brands, generics and similar medicines, respectively. In the public sector, mean availability of similar medicines was 2 7 times higher than that of generics. Mean overall availability in the public sector ranged from 68.8% to 81.7%. In "popular pharmacies", mean availability was greater than 90% in all cities. CONCLUSIONS: Availability of medicines in the public sector does not meet the challenge of supplying essential medicines to the entire population, as stated in the Brazilian constitution. This has unavoidable repercussions for affordability, particularly amongst the lower socio-economic strata. PMID- 22436556 TI - Accumulation and depletion kinetics of erythromycin in rainbow trout (Oncorhynchus mykiss). AB - Erythromycin is an antimicrobial agent recommended for the control and treatment of diseases caused by gram-positive bacteria. Few studies, however, have determined the metabolic and pharmacokinetic aspects of this antimicrobial agent in fish. The aim of the present study, therefore, was to determine the accumulation and depletion time of erythromycin after administration of medicated feed containing 52 mg kg(-1) body weight day(-1) for 8 days in rainbow trout (Oncorhynchus mykiss). Results were analyzed following the European Agency for Evaluation of Medicinal Products guidelines. We measured a withdrawal time of 187 degrees C-day ( degrees C-day=water temperature*days), lower than the value (500 degrees C-day) recommended by Council Directive 2004/28/EC for veterinary medicinal products. Our results provide data to establish therapeutic regimens for the use of erythromycin in aquaculture. PMID- 22436557 TI - Predictors of caregiver distress among palliative home care clients in Ontario: evidence based on the interRAI Palliative Care. AB - OBJECTIVE: This study examines predictors of caregiver distress among community based palliative care clients. Analyses are based upon interRAI Palliative Care (interRAI PC) assessment data from palliative home care programs in three regions in Ontario, Canada. METHOD: The study sample involved all community-based palliative care clients in Ontario who were assessed with the interRAI PC as part of normal clinical practice during pilot implementation of the instrument between 2007 and 2009 (N = 3,929). The assessments were performed by trained case managers and were used as the basis for determining service needs to be addressed through services contracted from provider agencies. The main study outcome of interest was the presence of one or more indicators of caregiver distress: helper(s) unable to continue caring activities; primary informal helper expresses feelings of distress, anger, or depression; family or close friends report feeling overwhelmed by person's illness. RESULTS: Caregiver distress was evident among about 22% of palliative home care clients. Multivariate analyses identified included clinical instability (Changes in Health, End Stage disease, Signs and Symptoms [CHESS] scale), depressive symptoms, cognitive impairment, and positive outlook as significant client-level predictors. Significant caregiver characteristics included hours of informal care. Three service use/provider variables were significant predictors of caregiver distress: the specific home care agency, hospitalizations in the last 90 days, and nursing visits. SIGNIFICANCE OF RESULTS: Caregiver distress affects approximately one in five palliative care clients in the community. This may lead to a number of adverse outcomes for the caregiver and client. The experience of distress is affected by client, caregiver, and agency characteristics that are readily identified by the interRAI PC assessment instrument. The present results point to the need for a care planning protocol that may be used on a targeted basis for clients experiencing or at elevated risk of caregiver distress. PMID- 22436559 TI - Gender differences in patients with dizziness and unsteadiness regarding self perceived disability, anxiety, depression, and its associations. AB - BACKGROUND: It is known that anxiety and depression influence the level of disability experienced by persons with vertigo, dizziness or unsteadiness. Because higher prevalence rates of disabling dizziness have been found in women and some studies reported a higher level of psychiatric distress in female patients our primary aim was to explore whether women and men with vertigo, dizziness or unsteadiness differ regarding self-perceived disability, anxiety and depression. Secondly we planned to investigate the associations between disabling dizziness and anxiety and depression. METHOD: Patients were recruited from a tertiary centre for vertigo and balance disorders. Participants rated their global disability as mild, moderate or severe. They filled out the Dizziness Handicap Inventory and the two subscales of the Hospital Anxiety Depression Scale (HADS). The HADS was analysed 1) by calculating the median values, 2) by estimating the prevalence rates of abnormal anxiety/depression based on recommended cut-off criteria. Mann-Whitney U-tests, Chi-square statistics and odds ratios (OR) were calculated to compare the observations in both genders. Significance values were adjusted with respect to multiple comparisons. RESULTS: Two-hundred and two patients (124 women) mean age (standard deviation) of 49.7 (13.5) years participated. Both genders did not differ significantly in the mean level of self-perceived disability, anxiety, depression and symptom severity. There was a tendency of a higher prevalence of abnormal anxiety and depression in men (23.7%; 28.9%) compared to women (14.5%; 15.3%). Patients with abnormal depression felt themselves 2.75 (95% CI: 1.31-5.78) times more severely disabled by dizziness and unsteadiness than patients without depression. In men the OR was 8.2 (2.35-28.4). In women chi-square statistic was not significant. The ORs (95% CI) of abnormal anxiety and severe disability were 4.2 (1.9-8.9) in the whole sample, 8.7 (2.5-30.3) in men, and not significant in women. CONCLUSIONS: In men with vertigo, dizziness or unsteadiness emotional distress and its association with self-perceived disability should not be underestimated. Longitudinal surveys with specific pre-defined co-variables of self-perceived disability, anxiety and depression are needed to clarify the influence of gender on disability, anxiety and depression in patients with vertigo, dizziness or unsteadiness. PMID- 22436560 TI - How safe is oncoplastic breast conservation? Comparative analysis with standard breast conserving surgery. AB - AIM: Oncoplastic techniques are increasingly used to facilitate breast conservation and maintain breast aesthetics but evidence with regards to the oncological safety of oncoplastic breast conservation surgery (oBCS) remains limited. The aim of this study was to compare re-excision and local recurrence rates for oBCS with standard breast conserving surgery (sBCS). METHODS: From June 2003 to Feb 2010 data was obtained from contemporaneously recorded electronic patient records on patients who had oBCS and sBCS within a single breast cancer centre. Re-excision rates and local recurrence rates were compared. RESULTS: A total of 440 sBCS and 150 oBCS (in 146 women) were included in this study. Median tumour size and specimen weight was 21 mm and 67 g for oBCS and 18 mm and 40 g in the sBCS group (p < 0.001). Re-excision was 2.7% (4/150) and 13.4% (59/440) for oBCS and sBCS respectively (p < 0.001). At a median follow-up of 28 months, local relapse was 2.7% (4) and 2.2% (10) and distant relapse 1.3% (2) and 7.5% (33) for oBCS and sBCS respectively. CONCLUSIONS: Oncoplastic breast conserving techniques decrease re-excision rates. Early follow up data suggests oncological outcomes of oncoplastic breast conservation surgery are similar to standard breast conservation. PMID- 22436561 TI - The feeling of motivation in the developing brain. PMID- 22436562 TI - Addiction, adolescence, and the integration of control and motivation. AB - The likelihood of initiating addictive behaviors is higher during adolescence than during any other developmental period. The differential developmental trajectories of brain regions involved in motivation and control processes may lead to adolescents' increased risk taking in general, which may be exacerbated by the neural consequences of drug use. Neuroimaging studies suggest that increased risk-taking behavior in adolescence is related to an imbalance between prefrontal cortical regions, associated with executive functions, and subcortical brain regions related to affect and motivation. Dual-process models of addictive behaviors are similarly concerned with difficulties in controlling abnormally strong motivational processes. We acknowledge concerns raised about dual-process models, but argue that they can be addressed by carefully considering levels of description: motivational processes and top-down biasing can be understood as intertwined, co-developing components of more versus less reflective states of processing. We illustrate this with a model that further emphasizes temporal dynamics. Finally, behavioral interventions for addiction are discussed. Insights in the development of control and motivation may help to better understand - and more efficiently intervene in - vulnerabilities involving control and motivation. PMID- 22436563 TI - Closing the circle between perceptions and behavior: a cybernetic view of behavior and its consequences for studying motivation and development. AB - The dynamic aspect of behavior is exaggerated during social interactions such as sex, combat and rough-and-tumble play where the movements of the two animals involved continually influence one another. The behavioral 'markers' abstracted from this stream can greatly influence the conclusions drawn about the effects of experimental procedures and how changes during development are interpreted. By using methods of analysis that treat behaving systems as being dynamic and governed by negative feedback processes, the behavioral markers that are abstracted can more accurately reflect the underlying mechanisms. Using examples from rats engaged in play fighting, serious fighting and food defense, it is shown that motivational from non-motivational contributions to behavioral output and changes in that output with age can be discerned. For example, while sex differences in the frequency of initiating play by juvenile rats are shown to reflect differences in the motivation to engage in this behavior, sex differences in preferred motor patterns used during play do not. Rather, they reflect differences in perceptual and motor systems. Although an issue that is often neglected, we show that behavioral description, and the theoretical underpinnings of that description, is critical for the study of the mechanisms that produce and regulate behavior. PMID- 22436564 TI - The developmental psychopathology of motivation in adolescence. AB - Adolescence is a key period for the emergence of psychopathology, with many psychiatric disorders having their modal age-of-onset during this period. Relative to other periods of the lifespan, susceptibility to a number of psychiatric disorders is greatest during adolescence, particularly in females. In addition, disorders which emerge during adolescence appear to be more enduring and serious than those with a later onset. Although these psychiatric conditions may appear different from each other in terms of their associated behavioral signs or symptoms, this review will argue that they involve common alterations in motivational processes or disturbances in reward processing, although the direction of such changes (hypersensitivity vs. hyposensitivity to reward) and the stage of processing affected (reward anticipation vs. receipt) may differ across broader groupings of disorder. Recent behavioral, neuropsychological and neuroimaging research on reward processing in children, adolescents, and adults with these conditions will be described and evaluated. In addition, this article will consider what these studies tell us about their etiology and highlight gaps in our knowledge base. The review will also attempt to explain why adolescence is a period of elevated risk for the development of psychopathology, by discussing normative changes in reward processing in humans and animals. PMID- 22436565 TI - Development of the motivational system during adolescence, and its sensitivity to disruption by nicotine. AB - The brain continues to develop during adolescence, and exposure to exogenous substances such as nicotine can exert long-lasting adaptations during this vulnerable period. In order to fully understand how nicotine affects the adolescent brain it is important to understand normal adolescent brain development. This review summarizes human and animal data on brain development, with emphasis on the prefrontal cortex, for its important function in executive control over behavior. Moreover, we discuss how nicotine exposure during adolescence can disrupt brain development bearing long-term consequences on executive cognitive function in adulthood. PMID- 22436566 TI - Evaluating the rewarding nature of social interactions in laboratory animals. AB - Positive social interactions are essential for emotional well-being, healthy development, establishment and maintenance of adequate social structures and reproductive success of humans and animals. Here, we review the studies that have investigated whether forms of social interaction that occur in different phases of the lifespan of animals, i.e., maternal behavior, social play and sexual interaction are rewarding in rodents and non-human primates. We show that these three forms of social interaction can be used as incentive for place conditioning, lever pressing and maze learning, three setups that have been extensively used to study the rewarding properties of food and drugs of abuse and their neural underpinnings. The experience of positive social interactions during key developmental ages has profound and long-lasting effects on brain function and behavior in emotional, motivational and cognitive domains. For instance, pup interaction is more rewarding than cocaine for early postpartum dams and rats deprived of the opportunity to play during adolescence show social and cognitive impairments at adulthood. Furthermore, sexual behavior is only overtly rewarding when animals can control the rate at which the sexual interaction occurs. Last, we discuss how animal models contributed to our understanding of social reward mechanisms and its psychological components throughout development. PMID- 22436567 TI - Double helix: reciprocity between juvenile play and brain development. AB - This review summarizes what is presently known about the function, sexual differentiation, and neural circuitry of juvenile rough-and-tumble play. Juvenile rough-and-tumble play is a unique motivated behavior that is widespread throughout the mammalian order and usually occurs more often in males. Immediate early gene studies indicate that cortical and subcortical circuits, many of which are sensitive to sex steroid hormones, mediate juvenile play. Sex differences in rough-and-tumble play are controlled in part by neonatal exposure to androgens or their estrogenic metabolites. Studies indicate that testicular androgens during play are also necessary to stimulate male-like levels of play initiation. The resemblance of rough-and-tumble play to aggression and sexual behavior has led some to question whether male-typical adult behavior is contingent upon the experience of play. Attempts to control the amount of play through social isolation show that social experience during adolescence is critical for male typical adult behaviors to be expressed. This well-established finding, together with evidence that play induces neural plasticity, supports the hypothesis that juvenile play contributes to male-typical brain development that ultimately enables the expression of adult social and reproductive behavior. PMID- 22436568 TI - Testosterone levels correspond with increased ventral striatum activation in response to monetary rewards in adolescents. AB - Risk taking is an integral part of learning and development, particularly during adolescence the prevalence of risky behaviors peak. It is hypothesized that the tendency to take risks is related to pubertal maturation, where there is interplay between gonadal hormones, the neural mechanisms that underlie affective (e.g., reward) processing, and risky behavior. To test this hypothesis, fifty healthy adolescents (aged 10-16 years; 33 girls, 17 boys) at different stages of puberty performed a gambling task while lying in the MRI scanner, and provided saliva samples for hormone assessment. Gonadal hormone levels were correlated with the neural response to receiving a monetary reward. Results showed that testosterone level correlated positively with activation in the striatum for both boys and girls, suggesting that individual differences in hormones at puberty are related to the way adolescents respond to reward, which can ultimately affect risk-taking behavior. PMID- 22436569 TI - How the aging brain translates motivational incentive into action: the role of individual differences in striato-cortical white matter pathways. AB - The anticipation of reward enhances actions that lead to those rewards, but individuals differ in how effectively motivational incentives modulate their actions. Such individual differences are particularly prominent in aging. In order to account for such inter-individual variability among older adults, we approach the neurobiological mechanisms of motivated behavior from an individual differences perspective focusing on white matter pathways in the aging brain. Using analyses of probabilistic tractography seeded in the striatum, we report that the estimated strength of cortico-striatal and intra-striatal white matter pathways among older adults correlated with how effectively motivational incentives modulated their actions. Specifically, individual differences in the extent to which elderly participants utilized reward cues to prepare and perform more efficient antisaccades predicted structural connectivity of the striatum with cortical areas involved in reward anticipation and oculomotor control. These striatal connectivity profiles endow us with a network account for individual differences in motivated behavior among older adults. More generally, the data suggest that capturing individual differences may be crucial to better understand developmental trajectories in motivated behavior. PMID- 22436570 TI - Distinct linear and non-linear trajectories of reward and punishment reversal learning during development: relevance for dopamine's role in adolescent decision making. AB - Abnormalities in value-based decision making during adolescence have often been attributed to non-linear, inverted-U shaped development of reward-related processes. This hypothesis is strengthened by functional imaging work revealing an inverted-U shaped relationship between age and reward-related activity in the striatum. However, behavioural studies have mostly reported linear rather than non-linear increases in reward-related performance. In the present study, we investigated the mechanisms underlying the development of reward- and punishment related processing across four age groups using a reversal learning task previously shown to depend on striatal dopamine. We demonstrate both linear and non-linear age effects on distinct components of reversal learning. Specifically, results revealed a linear shift with age in terms of valence-dependent reversal learning, with children exhibiting better punishment than reward reversal learning, adults exhibiting better reward than punishment reversal learning and adolescents exhibiting an intermediate performance pattern. In addition, we also observed a non-linear, inverted-U shaped relationship between age and valence independent reversal learning, which was due to aberrant ability of adolescents to update behaviour in response to negative performance feedback. These findings indicate that the (linear or nonlinear) nature of the relationship between age and reward learning depends on the type of reward learning under study. PMID- 22436571 TI - The effect of the OPRM1 and DRD4 polymorphisms on the relation between attentional bias and alcohol use in adolescence and young adulthood. AB - BACKGROUND: The incentive sensitization theory posits that in the transition from sporadic to problematic alcohol use, the incentive value of alcohol increases (wanting) while its hedonic effects (liking) do not change or decreases. The effect of the OPRM1 c.118A>G polymorphism, associated with liking and wanting, and the DRD4-VNTR polymorphism, related to wanting, on the relation between attentional bias and alcohol use was investigated. METHODS: A total of 195 young adolescents (Study 1) and 86 young adult male heavy drinkers (Study 2) completed a visual probe test. Saliva samples were collected to test both polymorphisms. RESULTS: In Study 1, attentional bias was positively associated with adolescent alcohol use only for OPRM1 G-allele carriers. In Study 2, attentional bias was positively associated with problem drinking for carriers of a DRD4 long allele. DISCUSSION: It is tentatively proposed that an attentional bias for alcohol is related most strongly to liking and wanting in early adolescents, while in young adults, an attentional bias may reflect wanting. In addition, individual differences associated with two both genetic markers should be taken into account when examining the relation between attentional bias and alcohol use. PMID- 22436572 TI - Serotonin, motivation, and playfulness in the juvenile rat. AB - The effects of the selective 5HT(1A) agonist 8-OH-DPAT were assessed on the play behavior of juvenile rats. When both rats of the test pair were comparably motivated to play, the only significant effect of 8-OH-DPAT was for play to be reduced at higher doses. When there was a baseline asymmetry in playful solicitation due to a differential motivation to play and only one rat of the pair was treated, low doses of 8-OH-DPAT resulted in a collapse of asymmetry in playful solicitations. It did not matter whether the rat that was treated initially accounted for more nape contacts or fewer nape contacts, the net effect of 8-OH-DPAT in this model was for low doses of 8-OH-DPAT to decrease a pre established asymmetry in play solicitation. It is concluded that selective stimulation of 5HT(1A) receptors changes the dynamic of a playful interaction between two participants that are differentially motivated to play. These results are discussed within a broader framework of serotonergic involvement in mammalian playfulness. PMID- 22436573 TI - Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma? AB - BACKGROUND: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce. METHODS: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS). RESULTS: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively). Similar results were obtained for DFS. CONCLUSIONS: RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes. PMID- 22436574 TI - Neuroprotective effects of racemic ketamine and (S)-ketamine on spinal cord injury in rat. AB - BACKGROUND: The aim of this study was to investigate and to compare the potential neuroprotective effects of racemic ketamine, (S)-ketamine and methylprednisolone after an experimental spinal cord injury model in rats. METHODS: Fifty-nine Wistar albino rats were divided into three main groups as acute stage (A), subacute stage (SA) and sham groups and then acute and subacute stage groups were divided into four groups regarding the used drug as control (CONT), racemic ketamine (RK), (S)-ketamine (SK) and methylprednisolone (MP) groups. A dorsal laminectomy was performed; and spinal cord injury was induced by using a temporary aneurysm clip. Four hours later from the clip compression, except those of the sham and control groups, the drugs (60 mg/kg racemic ketamine, 60 mg/kg (S)-ketamine or 30 mg/kg methylprednisolone) were administered intraperitoneally. At 72th h and 7th days of the study, the spinal cords of rats were removed from T8 level to the conus medullaris level. The specimens were and evaluated histopathologically, tissue lipid peroxidation (LPO) and myeloperoxidation (MPO) levels were measured and biochemically. RESULTS: The histopathological results were similar both in the acute and in the subacute stage groups. There was a statistically significant difference among all groups regarding the tissue LPO levels (p<0.001). There was a statistically significant difference between the CONT-A group and the MP-A, RK-A and SK-A groups (p=0.004, p<0.001 and p=0.007, respectively) in acute stage and between the CONT-SA group and SK-SA group (p=0.002) in subacute stage. There was a statistically significant difference among all groups regarding the tissue MPO levels (p=0.001). The median MPO levels were similar among acute stage groups (p=0.057), but there was a statistical difference among subacute stage groups (p=0.046). CONCLUSION: (S)-ketamine is more effective than methylprednisolone and racemic ketamine to reduce the LPO levels in subacute stage of spinal cord injury in rats. And, it is as effective as methylprednisolone in preventing secondary spinal cord injury histopathologically. PMID- 22436575 TI - Social integration in friendship networks: the synergy of network structure and peer influence in relation to cigarette smoking among high risk adolescents. AB - Using data from a study of high risk adolescents in Southern California, U.S.A. (N=851), this study examined synergy between social network measures of social integration and peer influence in relation to past month cigarette smoking. Using Hierarchical Linear Modeling, results indicated that being central in networks was significantly and positively related to past month cigarette smoking, across all study models. In addition, there is modest evidence that the number of reciprocated friendship ties was positively related to past month cigarette smoking. There is also some modest evidence that the relationship between having reciprocated friendships and past month cigarette smoking was moderated by a network peer influence process, smoking with those in youths' best friend networks. Findings indicate that being integrated within a social network context of peer influences favoring drug use relates to more smoking among these high risk youth. PMID- 22436576 TI - Effect of sub-lethal doses of Bacillus thuringiensis subsp. Aizawai and deltamethrin with regard to fertility and organ toxicity in pregnant albino rats. AB - Products with Bacillus thuringiensis (Bt) and synthetic insecticides have been widely used against important vectors of human diseases. However, few studies have addressed the application of these substances on the female reproduction apparatus during pregnancy at doses that do not cause clinical symptoms of intoxication. Seventy pregnant albino rats were analyzed with regard to fertility and histopathology of the kidneys, liver and lungs as well as the morphology of the neonates. The rats were submitted to three sub-lethal doses of the biological insecticide XenTari((r)) WG (B. thuringiensis subsp. Aizawai) and the synthetic insecticide deltamethrin (Decis((r)) 25CE). After the confirmation of copulation, the insecticides were administered orally for either seven days or during the entire pregnancy. The analysis revealed histopathological alterations in all organs analyzed in both treatments. No miscarriages occurred and the neonates did not exhibit signs of malformation of the head, limbs, thorax or abdomen. However, there were a smaller number of pups in the groups that received higher doses of the insecticides in comparison to the control group. Both insecticides produced similar lesions in the kidneys, liver and lungs and reduced the fertility of rats when administered at sub-lethal doses with no clinical signs of intoxication. Thus, this study suggests that sublethal doses of both insecticides can provide chronic toxicity in humans. PMID- 22436577 TI - The impact of environmental metals in young urbanites' brains. AB - Air pollution exposures are linked to cognitive and olfaction deficits, oxidative stress, neuroinflammation and neurodegeneration including frontal hyperphosphorylated tau and diffuse amyloid plaques in Mexico City children and young adults. Mexico City residents are chronically exposed to fine particulate matter (PM(2.5)) concentrations (containing toxic combustion and industrial metals) above the annual standard (15 MUg/m(3)) and to contaminated water and soil. Here, we sought to address the brain-region-specific effects of metals and key neuroinflammatory and DNA repair responses in two air pollution targets: frontal lobe and olfactory bulb from 12 controls vs. 47 Mexico City children and young adults average age 33.06+/-4.8 SE years. Inductively coupled plasma mass spectrometry (metal analysis) and real time PCR (for COX2, IL1beta and DNA repair genes) in target tissues. Mexico City residents had higher concentrations of metals associated with PM: manganese (p=0.003), nickel and chromium (p=0.02) along with higher frontal COX2 mRNA (p=0.008) and IL1beta (p=0.0002) and COX2 (p=0.005) olfactory bulb indicating neuroinflammation. Frontal metals correlated with olfactory bulb DNA repair genes and with frontal and hippocampal inflammatory genes. Frontal manganese, cobalt and selenium increased with age in exposed subjects. Together, these findings suggest PM-metal neurotoxicity causes brain damage in young urbanites, the olfactory bulb is a target of air pollution and participates in the neuroinflammatory response and since metal concentrations vary significantly in Mexico City urban sub-areas, place of residency has to be integrated with the risk for CNS detrimental effects particularly in children. PMID- 22436578 TI - Sex differences in behavioral decision-making and the modulation of shared neural circuits. AB - Animals prioritize behaviors according to their physiological needs and reproductive goals, selecting a single behavioral strategy from a repertoire of possible responses to any given stimulus. Biological sex influences this decision making process in significant ways, differentiating the responses animals choose when faced with stimuli ranging from food to conspecifics. We review here recent work in invertebrate models, including C. elegans, Drosophila, and a variety of insects, mollusks and crustaceans, that has begun to offer intriguing insights into the neural mechanisms underlying the sexual modulation of behavioral decision-making. These findings show that an animal's sex can modulate neural function in surprisingly diverse ways, much like internal physiological variables such as hunger or thirst. In the context of homeostatic behaviors such as feeding, an animal's sex and nutritional status may converge on a common physiological mechanism, the functional modulation of shared sensory circuitry, to influence decision-making. Similarly, considerable evidence suggests that decisions on whether to mate or fight with conspecifics are also mediated through sex-specific neuromodulatory control of nominally shared neural circuits. This work offers a new perspective on how sex differences in behavior emerge, in which the regulated function of shared neural circuitry plays a crucial role. Emerging evidence from vertebrates indicates that this paradigm is likely to extend to more complex nervous systems as well. As men and women differ in their susceptibility to a variety of neuropsychiatric disorders affecting shared behaviors, these findings may ultimately have important implications for human health. PMID- 22436579 TI - Human 8-oxoguanine-DNA glycosylase-1 is downregulated in human basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common type of skin cancer and is a major public health problem in many Western countries. It usually occurs as a consequence of exposure to ultraviolet radiation (UV) with sunlight. The DNA photolesion 8-oxo-7,8-dihydroguanine (8-oxo-dG) is caused by reactive oxygen species (ROS) produced in response to UVA, UVB, and oxidative metabolism. If this damaged DNA is not repaired prior to cell division, then gene mutations may persist in daughter cells. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) is the main enzyme that excises 8-oxo-dG from damaged DNA via the base-excision repair pathway. However, the role of hOGG1 in human skin cancer is unknown. In this study, using immunohistochemical staining, we found low hOGG1 protein expression in human BCC compared to overlying epidermis or normal epidermis. We also found higher levels of 8-oxo-dG within the BCC compared to the basal layers of epidermis overlying the BCC lesions (E-BCC). The results suggest that low expression of hOGG1 within BCC results in accumulation of ROS generated 8-oxo-dG due to low levels of DNA repair, thereby implicating hOGG1 in human BCC carcinogenesis. These ROS are likely to be produced by the cancer cells during metabolism, as the BCC nests are too deep for UV to reach. Our data suggests that procedures that increase expression of hOGG1 within BCC, or protect from ROS may be beneficial for reducing progression of BCC. PMID- 22436580 TI - Therapeutic chaperone effect of N-octyl 4-epi-beta-valienamine on murine G(M1) gangliosidosis. AB - Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-beta valienamine (NOEV) was studied in G(M1)-gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal excretion after oral administration. Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood brain barrier to induce high expression of the apparently deficient beta galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months. Survival time was significantly prolonged. This result suggests that NOEV chaperone therapy will be clinically effective for prevention of neuronal damage if started early in life hopefully also in human patients with G(M1) gangliosidosis. PMID- 22436581 TI - Effect of curcumin in a mouse model of Pelizaeus-Merzbacher disease. AB - PLP1 amino acid substitutions cause accumulation of misfolded protein and induce endoplasmic reticulum (ER) stress, causing Pelizaeus-Merzbacher disease (PMD), a hypomyelinating disorder of the central nerve system. Currently no effective therapy is available for PMD. Promoted by its curative effects in other genetic disease models caused by similar molecular mechanisms, we tested if curcumin, a dietary compound, can rescue the lethal phenotype of a PMD mouse model (myelin synthesis deficient, msd). Curcumin was administered orally to myelin synthesis deficit (msd) mice at 180 mg.kg(-1).day(-1) from the postnatal day 3. We evaluated general and motor status, changes in myelination and apoptosis of oligodendrocytes by neuropathological and biochemical examination, and transcription levels for ER-related molecules. We also examined the pharmacological effect of curcumin in cell culture system. Oral curcumin treatment resulted in 25% longer survival (p<0.01). In addition, oligodendrocytes undergoing apoptosis were reduced in number (p<0.05). However, no apparent improvement in motor function, neurological phenotype, and myelin formation was observed. Curcumin treatment did not change the expression of ER stress markers and subcellular localization of the mutant protein in vitro and/or in vivo. Curcumin partially mitigated the clinical and pathological phenotype of msd mice, although molecular mechanisms underlying this curative effect are yet undetermined. Nonetheless, curcumin may serve as a potential therapeutic compound for PMD caused by PLP1 point mutations. PMID- 22436582 TI - Young adults' medicine use for headache: the combined effect of socioeconomic position and perceived stress, and the contribution of sense of coherence. AB - BACKGROUND: Over-the-counter analgesic (OTCA) use is increasingly common and may have potential harmful side effects. The primary reason for using analgesics is headache symptoms. Whether OTCA use for headache is sensitive to psychosocial and social circumstances is an understudied topic. OBJECTIVES: The purpose of this study was to examine the combined effect of socioeconomic position (SEP) and perceived stress on OTCA use for headache. An additional objective was to determine whether sense of coherence (SOC) modifies the association. METHODS: Data derived from the cross-sectional "Danish Lifestyle and Medicine Use Study," 2009. The study population consisted of men and women ages 25-44 years (n = 955). The dependent variable was OTCA use for headache within the past 14 days. The independent variables were SEP, perceived stress, and SOC. Gender, headache prevalence, and response method were included as covariates. Associations were examined by means of logistic regression analyses, and reported as odds ratios (ORs) with 95% confidence intervals. RESULTS: The OR for OTCA use was 1.42 (0.94 2.14) (statistically nonsignificant) among participants with low SEP but no perceived stress (reference high SEP, no perceived stress), 2.09 (1.53-2.85) for participants with perceived stress and high SEP, and 2.65 (1.66-4.25) among participants with perceived stress and low SEP. In analysis, stratified by SOC associations were stronger among participants with low SOC than among those with high SOC. CONCLUSIONS: Individuals exposed to both low SEP and high perceived stress have high odds for using OTCA for headache, apparently higher than participants only exposed to 1 of these factors. SOC may act as a buffer against the harmful effects of perceived stress and low SEP on OTCA use. Health care professionals and policymakers need to be aware of the sensitivity of OTCA use to psychosocial and social circumstances. PMID- 22436583 TI - Contingent valuation and pharmacists' acceptable levels of compensation for medication therapy management services. AB - BACKGROUND: Pharmacists' acceptable level of compensation for medication therapy management (MTM) services needs to be determined using various economic evaluation techniques. OBJECTIVES: Using contingent valuation method, determine pharmacists' acceptable levels of compensation for MTM services. METHODS: A mailing survey was used to elicit Tennessee (U.S.) pharmacists' acceptable levels of compensation for a 30-minute MTM session for a new patient with 2 medical conditions, 8 medications, and an annual drug cost of $2000. Three versions of a series of double-bounded, closed-ended, binary discrete choice questions were asked of pharmacists for their willingness to accept (WTA) for an original monetary value ($30, $60, or $90) and then follow-up higher or lower value depending on their responses to the original value. A Kaplan-Meier approach was taken to analyze pharmacists' WTA, and Cox's proportional hazards model was used to examine the effects of pharmacist characteristics on their WTA. RESULTS: Three hundred and forty-eight pharmacists responded to the survey. Pharmacists' WTA for the given MTM session had a mean of $63.31 and median of $60. The proportions of pharmacists willing to accept $30, $60, and $90 for the given MTM session were 30.61%, 85.19%, and 91.01%, respectively. Pharmacists' characteristics had statistically significant association with their WTA rates. CONCLUSIONS: Pharmacists' WTA for the given MTM session is higher than current Medicare MTM programs' compensation levels of $15-$50 and patients' willingness to pay of less than $40. Besides advocating for higher MTM compensation levels by third-party payers, pharmacists also may need to charge patients to reach sufficient compensation levels for MTM services. PMID- 22436584 TI - Binary mixtures of azinphos-methyl oxon and chlorpyrifos oxon produce in vitro synergistic cholinesterase inhibition in Planorbarius corneus. AB - In this study, the cholinesterase (ChE) and carboxylesterase (CES) activities present in whole organism homogenates from Planorbarius corneus and their in vitro sensitivity to organophosphorous (OP) pesticides were studied. Firstly, a characterization of ChE and CES activities using different substrates and selective inhibitors was performed. Secondly, the effects of azinphos-methyl oxon (AZM-oxon) and chlorpyrifos oxon (CPF-oxon), the active oxygen analogs of the OP insecticides AZM and CPF, on ChE and CES activities were evaluated. Finally, it was analyzed whether binary mixtures of the pesticide oxons cause additive, antagonistic or synergistic ChE inhibition in P. corneus homogenates. The results showed that the extracts of P. corneus preferentially hydrolyzed acetylthiocholine (AcSCh) over propionylthiocholine (PrSCh) and butyrylthiocholine (BuSCh). Besides, AcSCh hydrolyzing activity was inhibited by low concentrations of BW284c51, a selective inhibitor of AChE activity, and also by high concentrations of substrate. These facts suggest the presence of a typical AChE activity in this species. However, the different dose-response curves observed with BW284c51 when using PrSCh or BuSCh instead of AcSCh suggest the presence of at least another ChE activity. This would probably correspond to an atypical BuChE. Regarding CES activity, the highest specific activity was obtained when using 2-naphthyl acetate (2-NA), followed by 1-naphthyl acetate (1 NA); p-nitrophenyl acetate (p-NPA), and p-nitrophenyl butyrate (p-NPB). The comparison of the IC(50) values revealed that, regardless of the substrate used, CES activity was approximately one order of magnitude more sensitive to AZM-oxon than ChE activity. Although ChE activity was very sensitive to CPF-oxon, CES activity measured with 1-NA, 2-NA, and p-NPA was poorly inhibited by this pesticide. In contrast, CES activity measured with p-NPB was equally sensitive to CPF-oxon than ChE activity. Several specific binary combinations of AZM-oxon and CPF-oxon caused a synergistic effect on the ChE inhibition in P. corneus homogenates. The degree of synergism tended to increase as the ratio of AZM-oxon to CPF-oxon decreased. These results suggest that synergism is likely to occur in P. corneus snails exposed in vivo to binary mixtures of the OPs AZM and CPF. PMID- 22436585 TI - Chronic toxicity of copper on embryo development in Chinese toad, Bufo gargarizans. AB - This study examined the effects of copper exposure on embryonic development of Chinese toad, Bufo gargarizans. Firstly, the LC(50) values from 24 to 96 h of exposure were 3.61*10(-6) M, by means of a 4 d toxicity test with B. gargarizans embryos. Secondly, Chinese toad embryos were exposed to 10(-9)-10(-6) M copper from mid gastrula stage to operculum completion stage. Measurements included mortality, tadpole weight, tadpole total length, growth retardation, duration of different embryo stages and malformation. Embryonic survival was not affected by copper. Relative to control tadpoles, significantly decreased weight and total length were found at 10(-9)-10(-6) M reduced percentage of the embryos in right operculum stage after 10 d exposure to copper and reduced percentage of embryos in operculum completion stage after 12 d exposure to copper were also observed. Moreover, the duration of embryonic development increased at neural, circulation and operculum development stage in copper-treated groups. For the scanning microscope and histological observation, the abnormalities were malformation of wavy dorsal fin, flexural tail, curvature body axis, yolk sac oedema and reduced pigmentation in the yolk sac. Histopathological changes in olfactory, retinal epithelium and skin were also observed. DNA strand breaks exposed to the copper were analyzed by DNA ladder. In conclusion, copper induced toxic effects on B. gargarizans embryos. The present study indicated chronic toxicity tests may provide more accurate way in formulating the "safe levels" of heavy metals to amphibian. PMID- 22436586 TI - Removal of H2S from gas stream using combined plasma photolysis technique at atmospheric pressure. AB - In this paper, H(2)S in gas stream was successfully decomposed at atmospheric pressure by dielectric barrier discharge plasma and VUV-UV radiation from a combined plasma photolysis reactor (CDBD). In comparison with DBD, CDBD enhanced H(2)S removal efficiency significantly at the same applied voltage, inlet H(2)S concentration and gas residence time. H(2)S removal efficiency was determined as a function of Kr pressure, applied voltage, inlet H(2)S concentration, and gas residence time. H(2)S removal efficiency could reach as high as 93% at inlet H(2)S concentration of 27.1 mg m(-3), residence time of 0.4 s, and applied voltage of 7.5 kV. The main products were discerned as H(2)O and SO(4)(2-) based on FTIR and IC analysis. PMID- 22436587 TI - Temporal evolution in PPCP removal from urban wastewater by constructed wetlands of different configuration: a medium-term study. AB - Pharmaceuticals and personal care products (PPCPs) are widely distributed in urban wastewaters and can be removed to some extent by constructed wetlands (CWs). The medium-term (3-5 years) behaviour of these systems regarding PPCP removal is still unknown. Seven mesocosm-scale (1 m(2)) CWs of different configurations were operated outdoors for 39 months under the same conditions to assess their PPCP removal ability and temporal evolution. CWs differed in some design parameters, namely plant presence, species chosen (Typha angustifolia vs Phragmites australis), flow configuration and presence/absence of gravel bed (floating macrophytes surface flow, FM-SF; free-water surface flow, FW-SF; free water subsurface flow, FW-SSF; or conventional horizontal subsurface flow, SSF). PPCP efficiencies decreased throughout time and performance differences among CWs disappeared with the systems aging. This could be due to a homogenization process in the systems caused by detrimental factors like saturation, clogging and shading. Winter efficiencies were lower than summer ones for salicylic acid, caffeine, methyl dihydrojasmonate, galaxolide and tonalide, and seasonal biological activities seem key factors to explain this fact. Maximal removal efficiencies were achieved in an unplanted-FW-SSF for ketoprofen (47-81%), naproxen (58-81%) and salicylic acid (76-98%); in an unplanted-SSF for caffeine (65-99%); in a Phragmites-FM-SF for ibuprofen (49-96%) and diclofenac (16-68%); in a Typha-FM-SF for carbamazepine (35-71%); and in a Typha-FW-SSF for methyl dihydrojasmonate (71-96%), galaxolide (67-82%) and tonalide (55-74%). Photodegradation could be involved in ketoprofen, naproxen, ibuprofen and diclofenac removal. Carbamazepine and diclofenac were moderately removed by the most efficient CWs studied. Carbamazepine might be eliminated by vegetal uptake. PMID- 22436588 TI - Histopathological changes and antioxidant response in brain and kidney of common carp exposed to atrazine and chlorpyrifos. AB - We investigated oxidative stress response and histopathological changes in the brain and kidney of the common carp after a 40-d exposure to CPF and ATR, alone or in combination, and a 20-d recovery. Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) content were measured using standard assays. Our results indicated that exposure to ATR, CPF or a combination of the two for 40 d induced significant changes in antioxidant enzyme (SOD, CAT and GSH-Px) activities and MDA content in the brain and kidney of the common carp. Pathological changes included tissue damage that was more severe with increased of exposure dose. To our knowledge, this is the first report to study oxidative stress and histopathological effects caused by subchronic exposure to ATR, CPF and ATR/CPF combination on common carp. The information presented in this study may be helpful to understanding the mechanisms of ATR-, CPF- and ATR/CPF combination-induced oxidative stress in fish. PMID- 22436589 TI - Damage to DNA caused by UV-B radiation in the desert cyanobacterium Scytonema javanicum and the effects of exogenous chemicals on the process. AB - Radiation with UV-B increased the damage to DNA in Scytonema javanicum, a desert dwelling soil microorganism, and the level of damage varied with the intensity of UV-B radiation and duration of exposure. Production of reactive oxygen species (ROS) also increased because of the radiation. Different exogenous chemicals (ascorbate acid, ASC; N-acetylcysteine, NAC; glyphosate, GPS; and 2-methyl-4 chlorophenoxyacetic acid, MCPA-Na) differed in their effect on the extent of DNA damage and ROS production: whereas NAC and ASC protected the DNA from damage and resulted in reduced ROS production, the herbicides (GPS and MCPA-Na) increased the extent of damage, lowered the rate of photosynthesis, and differed in their effect on ROS production. The chemicals probably have different mechanisms to exercise their effects: NAC and ASC probably function as antioxidant agents or as precursors of other antioxidant molecules that protect the DNA and photosynthetic apparatus directly from the ROS produced as a result of UV-B radiation, and GPS and MCPA-Na probably disrupt the normal metabolism in S. javanicum to induce the leaking of ROS into the photosynthetic electron transfer pathway following UV-B radiation, and thereby damage the DNA. Such mechanisms have serious implications for the use of environment-friendly herbicides, which, because they can destroy DNA, may prove harmful to soil microorganisms. PMID- 22436590 TI - Antifeedant, larvicidal and growth inhibitory effects of ononitol monohydrate isolated from Cassia tora L. against Helicoverpa armigera (Hub.) and Spodoptera litura (Fab.) (Lepidoptera: Noctuidae). AB - Ononitol monohydrate isolated from the ethyl acetate extract of Cassia tora L. using column chromatography was evaluated for its antifeedant, larvicidal and growth inhibitory activities against Helicoverpa armigera and Spodoptera litura at different concentrations of 125, 250, 500 and 1000 ppm. Leaf disc no-choice method was used for the bioassay. The compound showed significant antifeedant, larvicidal and pupicidal activities against H. armigera and S. litura. The compound also prolonged the larval-pupal duration of the insect at all the tested concentrations. The activities were concentration dependent for both the insects. Ononitol could be used as an agent to prepare botanical new pesticidal formulations. PMID- 22436591 TI - Effects of alcohol taxes on alcohol-related disease mortality in New York State from 1969 to 2006. AB - OBJECTIVE: The relationship of increased alcohol taxes to reductions in alcohol related harm is well established. Few studies, however, have examined the effects of sudden decreases in alcohol tax rates or effects of narrow tax changes limited to specific beverage types. In the current study, we: (1) examine whether tax increases on spirits have similar effects in reducing alcohol-related disease mortality as increasing taxes on all types of alcoholic beverages simultaneously, and (2) evaluate effects of beer-specific tax decreases in New York State on mortality. METHOD: We used a time-series, quasi-experimental research design, including non-alcohol deaths within New York State and other states' rates of alcohol-related disease mortality for comparison. The dataset included 456 monthly observations of mortality in New York State over a 38-year period (1969 2006). We used a random-effects approach and included several other important covariates. RESULTS: Alcohol-related disease mortality declined by 7.0% after a 1990 tax increase for spirits and beer. A spirits-only tax increase (in 1972) was not significantly associated with mortality but a data anomaly increased error in this effect estimate. Small tax decreases on beer between 1996 and 2006 had no measurable effect on mortality. Doubling the beer tax from $0.11 to $0.22 per gallon, a return to New York State's 1990 levels, would decrease deaths by an estimated 250 deaths per year. CONCLUSIONS: Excise tax increases on beer and spirits were associated with reductions in alcohol-related disease mortality. Modifying tax rates on a single beverage type does not appear to be as effective as doing so on multiple alcoholic beverages simultaneously. In New York, small decreases in beer taxes were not significantly associated with alcohol-related disease mortality. PMID- 22436593 TI - A tridimensional view of pituitary development and function. AB - Recent advances in tridimensional (3D) tissue imaging have considerably enriched our view of the pituitary gland and its development. Whereas traditional histology of the pituitary anterior lobe portrayed this tissue as a patchwork of cells, 3D imaging revealed that cells of each lineage form extensive and structured homotypic networks. In the adult gland these networks contribute to the robustness and coordination of the cell response to secretagogs. In addition, the network organization adapts to changes in endocrine environment, as revealed by the sexually dimorphic growth hormone (GH) cell network. Further work is required to establish better the molecular basis for homotypic and heterotypic interactions in the pituitary as well as the implications of these interactions for pituitary function and dysfunction in humans. PMID- 22436594 TI - Cotunneling current through a two-level quantum dot coupled to magnetic leads: the role of exchange interaction. AB - The cotunneling current through a two-level quantum dot weakly coupled to ferromagnetic leads is studied in the Coulomb blockade regime. The cotunneling current is calculated analytically under simple but realistic assumptions as follows: (i) the quantum dot is described by the universal Hamiltonian, (ii) it is doubly occupied, and (iii) it displays a fast spin relaxation. We find that the dependence of the differential conductance on the bias voltage is significantly affected by the exchange interaction on the quantum dot. In particular, for antiparallel magnetic configurations in the leads, the exchange interaction results in the appearance of interference-type contributions from the inelastic processes to the cotunneling current. Such dependence of the cotunneling current on the tunneling amplitude phases should also occur in multi level quantum dots weakly coupled to ferromagnetic leads near the mesoscopic Stoner instabilities. PMID- 22436595 TI - Treatment effects on insular and anterior cingulate cortex activation during classic and emotional Stroop interference in child abuse-related complex post traumatic stress disorder. AB - BACKGROUND: Functional neuroimaging studies have shown increased Stroop interference coupled with altered anterior cingulate cortex (ACC) and insula activation in post-traumatic stress disorder (PTSD). These brain areas are associated with error detection and emotional arousal. There is some evidence that treatment can normalize these activation patterns. METHOD: At baseline, we compared classic and emotional Stroop performance and blood oxygenation level dependent responses (functional magnetic resonance imaging) of 29 child abuse related complex PTSD patients with 22 non-trauma-exposed healthy controls. In 16 of these patients, we studied treatment effects of psycho-educational and cognitive behavioural stabilizing group treatment (experimental treatment; EXP) added to treatment as usual (TAU) versus TAU only, and correlations with clinical improvement. RESULTS: At baseline, complex PTSD patients showed a trend for increased left anterior insula and dorsal ACC activation in the classic Stroop task. Only EXP patients showed decreased dorsal ACC and left anterior insula activation after treatment. In the emotional Stroop contrasts, clinical improvement was associated with decreased dorsal ACC activation and decreased left anterior insula activation. CONCLUSIONS: We found further evidence that successful treatment in child abuse-related complex PTSD is associated with functional changes in the ACC and insula, which may be due to improved selective attention and lower emotional arousal, indicating greater cognitive control over PTSD symptoms. PMID- 22436596 TI - Effect of image compression and scaling on automated scoring of immunohistochemical stainings and segmentation of tumor epithelium. AB - BACKGROUND: Digital whole-slide scanning of tissue specimens produces large images demanding increasing storing capacity. To reduce the need of extensive data storage systems image files can be compressed and scaled down. The aim of this article is to study the effect of different levels of image compression and scaling on automated image analysis of immunohistochemical (IHC) stainings and automated tumor segmentation. METHODS: Two tissue microarray (TMA) slides containing 800 samples of breast cancer tissue immunostained against Ki-67 protein and two TMA slides containing 144 samples of colorectal cancer immunostained against EGFR were digitized with a whole-slide scanner. The TMA images were JPEG2000 wavelet compressed with four compression ratios: lossless, and 1:12, 1:25 and 1:50 lossy compression. Each of the compressed breast cancer images was furthermore scaled down either to 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64 or 1:128. Breast cancer images were analyzed using an algorithm that quantitates the extent of staining in Ki-67 immunostained images, and EGFR immunostained colorectal cancer images were analyzed with an automated tumor segmentation algorithm. The automated tools were validated by comparing the results from losslessly compressed and non-scaled images with results from conventional visual assessments. Percentage agreement and kappa statistics were calculated between results from compressed and scaled images and results from lossless and non scaled images. RESULTS: Both of the studied image analysis methods showed good agreement between visual and automated results. In the automated IHC quantification, an agreement of over 98% and a kappa value of over 0.96 was observed between losslessly compressed and non-scaled images and combined compression ratios up to 1:50 and scaling down to 1:8. In automated tumor segmentation, an agreement of over 97% and a kappa value of over 0.93 was observed between losslessly compressed images and compression ratios up to 1:25. CONCLUSIONS: The results of this study suggest that images stored for assessment of the extent of immunohistochemical staining can be compressed and scaled significantly, and images of tumors to be segmented can be compressed without compromising computer-assisted analysis results using studied methods. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2442925476534995. PMID- 22436597 TI - Developing an online learning community for mental health professionals and service users: a discursive analysis. AB - BACKGROUND: There is increasing interest in online collaborative learning tools in health education, to reduce costs, and to offer alternative communication opportunities. Patients and students often have extensive experience of using the Internet for health information and support, and many health organisations are increasingly trying out online tools, while many healthcare professionals are unused to, and have reservations about, online interaction. METHODS: We ran three week-long collaborative learning courses, in which 19 mental health professionals (MHPs) and 12 mental health service users (MHSUs) participated. Data were analysed using a discursive approach to consider the ways in which participants interacted, and how this contributed to the goal of online learning about using Internet technologies for mental health practice. RESULTS: MHSUs and MHPs were able to discuss issues together, listening to the views of the other stakeholders. Discussions on synchronous format encouraged participation by service users while the MHPs showed a preference for an asynchronous format with longer, reasoned postings. Although participants regularly drew on their MHP or MHSU status in discussions, and participants typically drew on either a medical expert discourse or a "lived experience" discourse, there was a blurred boundary as participants shifted between these positions. CONCLUSIONS: The anonymous format was successful in that it produced a "co-constructed asymmetry" which permitted the MHPs and MHSUs to discuss issues online, listening to the views of other stakeholders. Although anonymity was essential for this course to 'work' at all, the recourse to expert or lay discourses demonstrates that it did not eliminate the hierarchies between teacher and learner, or MHP and MHSU. The mix of synchronous and asynchronous formats helped MHSUs to contribute. Moderators might best facilitate service user experience by responding within an experiential discourse rather than an academic one. PMID- 22436598 TI - Harmonizing databases? Developing a quasi-experimental design to evaluate a public mental health re-entry program. AB - Our study is the first-ever initiative to merge administrative databases in Massachusetts to evaluate an important public mental health program. It examines post-incarceration outcomes of adults with serious mental illness (SMI) enrolled in the Massachusetts Department of Mental Health (DMH) Forensic Transition Team (FTT) program. The program began in 1998 with the goal of transitioning offenders with SMI released from state and local correctional facilities utilizing a core set of transition activities. In this study we evaluate the program's effectiveness using merged administrative data from various state agencies for the years 2007-2011, comparing FTT clients to released prisoners who, despite having serious mental health disorders, did not meet the criterion for DMH services. By systematically describing our original study design and the barriers we encountered, this report will inform future efforts to evaluate public programs using merged administrative databases and electronic health records. PMID- 22436599 TI - Sleep disturbance in relatives of palliative patients cared for at home. AB - OBJECTIVE: The aim of the present pilot study was to investigate insomnia, sleep quality, and daytime sleepiness in relatives of dying patients cared for at home. METHOD: The study has a descriptive, comparative, and cross-sectional design. The sample consisted of relatives of patients cared for through palliative home care in Uppsala County on 3 specific days. Relatives completed a questionnaire consisting of demographic questions, and items from the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale (ESS), and the Richard Campell Sleep Questionnaire (RCSQ). RESULTS: Seventy-five relatives answered the questionnaire. The average total ISI score was 9.6, with 23% reporting moderate or severe clinical insomnia. The mean sleep duration was 6.5 hours, the mean assessed need of sleep was 8 hours, and the mean discrepancy was 1 hour. The total mean ESS score was 5.6 and only 15% of respondents reported excessive daytime sleepiness. Four percent scored very poor sleep quality, whereas 39% scored very good sleep quality (RCSQ). Two general age- and gender-related patterns were observed. Negative correlations were found between age and sleep problems, with younger relatives reporting more insomnia problems and more daytime sleepiness than did older relatives. The other general pattern was that womens' sleep quality was significantly inferior to that of men. A significant positive correlation was found between ISI and ESS, but not between RCSQ and ESS. SIGNIFICANCE OF RESULTS: The picture of the relatives' sleep condition is fairly complex. A minority reported clinical insomnia problems or excessive daytime sleepiness, and 73% reported getting less sleep than they wanted. PMID- 22436600 TI - [The use of fibrolaryngoscopy in muscle tension dysphonia in telemarketers]. AB - INTRODUCTION: Muscle tension dysphonia (MTD) is a voice disorder in the absence of current organic laryngeal pathology, without obvious psychogenic or neurological aetiology. The laryngeal features of MTD include a posterior glottal gap and supraglottic hyperfunctional activities; however, it remains unclear if these features are specific to MTD. This report aims to compare the laryngeal features in telemarketer patients with MTD versus non-dysphonic control subjects. METHODS: We reported on an observational, analytic and transversal study. Fiberoptic nasal endoscopy was performed on 57 patients (28 telemarketers with MTD and 29 control subjects). These random-sequence videotapes were independently rated by an expert laryngologist according to the modified Morrison and Rammage classification. In addition, a questionnaire about vocal symptoms and other details was completed. RESULTS: The posterior glottal gap was the most common feature in telemarketers with MTD, while incomplete glottal gap was observed more frequently in non-dysphonic patients. More than 70% of the videotapes were rated as pathologic. There was no statistical difference in the prevalence of normal features or bowing glottal gap between patients and control subjects. Anterior posterior supraglottic contraction was more frequent in the control group. The major symptoms found were: voice gets tired quickly, increased vocal effort and neck tension. CONCLUSIONS: The heterogeneity in the laryngeal features in telemarketers with MTD seen under fibroscopy and their presence among the non dysphonic population suggest that they cannot determine by themselves the diagnosis of MTD. PMID- 22436601 TI - [Sedation and analgesia in emergency structure. How far is too far?]. PMID- 22436602 TI - [Sedation and analgesia in emergency structure. Which sedation and/or analgesia for the patient presenting neurological injury?]. PMID- 22436603 TI - [Sedation and analgesia in emergency structure. Which are the properties and the disadvantages of the products used?]. PMID- 22436604 TI - Evaluation of a training program for nurse supervisors who monitor nurses in an alternative-to-discipline program. AB - Nurse alternative-to-discipline programs aim to protect the public from the harm of impaired practice and to support nurses in early recovery from substance use disorders. Supervisor observation of work behavior is one key monitoring activity that protects the public. We evaluate a supervisory training called "Fit to Perform" for nurse managers to help them monitor and manage nurses enrolled in an alternative-to-discipline program. We observed significant mean changes in knowledge, training utility, self-efficacy, and substance abuse stigma. The results suggest that the training positively affects knowledge about substance use disorders, confidence to supervise nurses enrolled in an alternative-to discipline program, and reduces stigma, which may create a supportive workplace for nurses in recovery. PMID- 22436605 TI - Single polymorphism nucleotide rs1333049 on chromosome 9p21 is associated with carotid plaques but not with common carotid intima-media thickness in older adults. A combined analysis of the Three-City and the EVA studies. AB - OBJECTIVES: To address the relationship of rs1333049, the 9p21 variant showing the strongest association with coronary heart disease (CHD), with carotid plaques and plaque-free common carotid artery intima-media thickness (CCA-IMT) in older adults from 2 French population-based cohorts. METHODS: We genotyped for rs1333049, 4097 CHD-free participants including 3191 aged 65-86 years from the Three-City (3C) Study and 906 aged 59-71 years from the Vascular Aging Study (EVA). Plaque-free mean CCA-IMT and the presence of carotid plaques were assessed. RESULTS: In multivariate analysis, each C allele copy of rs1333049 was associated with baseline carotid plaques (odds ratio (OR)=1.24; 95% confidence interval (CI)=1.13-1.36; p<0.001) but not with baseline CCA-IMT (p=0.19). Among the EVA participants, the C allele was associated with 4-year plaques progression (p=0.04) but not with CCA-IMT progression. CONCLUSION: The chromosome 9p21 locus might influence CHD risk through carotid plaques development. PMID- 22436606 TI - High sodium intake adversely affects oxidative-inflammatory response, cardiac remodelling and mortality after myocardial infarction. AB - OBJECTIVE: Enhanced sodium intake increases volume overload, oxidative stress and production of proinflammatory cytokines. In animal models, increased sodium intake favours ventricular dysfunction after myocardial infarction (MI). The aim of this study was to investigate, in human subjects presenting with ST-segment elevation MI (STEMI), the impact of sodium intake prior the coronary event. METHODS: Consecutive patients (n=372) admitted within the first 24 h of STEMI were classified by a food intake questionnaire as having a chronic daily intake of sodium higher (HS) or lower (LS) than 1.2 g in the last 90 days before MI. Plasma levels of 8-isoprostane, interleucin-2 (IL-2), tumour necrosis factor type alpha (TNF-alpha), C-reactive protein (CRP) and brain natriuretic peptide (BNP) were measured at admission and at the fifth day. Magnetic resonance imaging was performed immediately after discharge. Total mortality and recurrence of acute coronary events were investigated over 4 years of follow-up. RESULTS: The decrease of 8-isoprostane was more prominent and the increase of IL-2, TNF-alpha and CRP less intense during the first 5 days in LS than in HS patients (p<0.05). Sodium intake correlated with change in plasma BNP between admission and fifth day (r=0.46; p<0.0001). End-diastolic volumes of left atrium and left ventricle were greater in HS than in LS patients (p<0.05). In the first 30 days after MI and up to 4 years afterwards, total mortality was higher in HS than in LS patients (p<0.05). CONCLUSION: Excessive sodium intake increases oxidative stress, inflammatory response, myocardial stretching and dilatation, and short and long-term mortality after STEMI. PMID- 22436607 TI - "... the cadaver can be placed at your disposition here." - Legal, administrative basis of the transfer of cadavers in the Third Reich, its traces in archival sources. AB - For more than 15 years, the memorial site "Roter Ochse (Red Ox)" in Halle/Saale, Germany, has studied documents of special and military courts in Mitteldeutschland (central Germany). Hundreds of death sentences have been executed during the last years of the war in the former state prison of Halle. The resulting dead bodies were used in biomedical research and teaching. The number of executions was marginal before 1933 but increased steadily after the Nazis seized power. The judiciary delivered an increasing number of death sentences against political opponents and persons who were to be eradicated from the "Volksgemeinschaft" (national community) according to racist ideology. However, the dead bodies were not distributed evenly to each of the anatomical institutes. The distribution depended on factors such as the distance of the institute to an execution place, the court responsible for the sentence, and whether the state or relatives had the right to dispose of the bodies. At the beginning of the year 1939, the Reichsjustizministerium (department of justice) issued a decree that changed the distribution process of dead bodies. As a rule, after the responsible ministry informed the anatomical institute of a pending execution, the institute confirmed the pick-up day of the body. Details of the actual delivery of bodies can be found in execution protocols, reports by execution overseers, receipts of body deliveries, body registers of the institutes, etc. This paper will review the historical progression of ministerial decisions and demonstrate how administrative documents can be used as a point of departure for current research projects. PMID- 22436608 TI - Synergistic degradation of methyl orange in an ultrasound intensified photocatalytic reactor. AB - An original ultrasound (US) directly intensified photocatalytic reactor was designed to degrade azo dye pollutant methyl orange (MeO) using Degussa TiO(2) as the photocatalyst. The sonolytic, photocatalytic and sonophotocatalytic degradation of MeO in the new reactor and the synergistic effect between sonolysis and photocatalysis were investigated. Effects of operation parameters i.e., US power, TiO(2) dosage, liquid circulation velocity and air flow rate on degradation efficiency were investigated and optimized. The results showed that all parameters have optimal values for the sonophotocatalytic degradation of MeO, and the optimum conditions for the new process are US power 600 W, TiO(2) dosage 3g/L, liquid circulation velocity 4.05*10(-2) m/s and air flow rate 0.2 L/min. Under the optimum conditions, 91.52% MeO had been degraded within 1h, and the combination of sonolysis and TiO(2) photocatalysis exhibited an obvious synergetic effect. PMID- 22436609 TI - KRAS rs61764370 is associated with HER2-overexpressed and poorly-differentiated breast cancer in hormone replacement therapy users: a case control study. AB - BACKGROUND: A single nucleotide polymorphism located in the 3'-untranslated region of the KRAS oncogene (KRAS variant; rs61764370) disrupts a let-7 miRNA binding and was recently reported to act as a genetic marker for increased risk of developing human cancers. We aimed to investigate an association of the KRAS variant with sporadic and familial breast cancer and breast tumor characteristics. METHODS: Genotyping was accomplished in 530 sporadic postmenopausal breast cancer cases, 165 familial breast cancer cases (including N = 29, who test positive for BRCA1/2 mutations) and 270 postmenopausal control women using the flurogenic 5' nuclease assay. Information on hormone replacement therapy (HRT) use and tumor characteristics in sporadic breast cancer cases was ascertained from a postal questionnaire and pathology reports, respectively. Associations between the KRAS genotype and breast cancer or breast tumor characteristics were assessed using chi-square test and logistic regression models. RESULTS: No evidence of association was observed between the KRAS variant and risk of sporadic and familial breast cancer - either among BRCA carriers or non-BRCA carriers. The KRAS variant was statistically significantly more often associated with human epidermal growth factor receptor 2 (HER2) - positive tumors and tumors of higher histopathologic grade. However, both associations were detected only in HRT users. CONCLUSION: Our data do not support the hypothesis that the KRAS variant rs61764370 is implicated in the aetiology of sporadic or of familial breast cancer. In postmenopausal women using HRT, the KRAS variant might lead to HER2 overexpressed and poorly-differentiated breast tumors, both indicators of a worse prognosis. PMID- 22436610 TI - The oncoprotein ErbB3 is endocytosed in the absence of added ligand in a clathrin dependent manner. AB - The oncoprotein ErbB3 is overexpressed in several human cancers, for example in pancreatic adenocarcinoma and in ovarian cancers, and ErbB3-containing heterodimers have been demonstrated to be potent signaling units in carcinogenesis. This especially applies to ErbB2-ErbB3 and epidermal growth factor receptor (EGFR)-ErbB3 heterodimers providing anti-apoptotic signaling. Relatively little is understood about the signaling of EGFR-ErbB3 heterodimers and especially about mechanisms involved in downregulation of ErbB3 from the plasma membrane. This is in contrast to EGFR homodimers, for which trafficking has been extensively characterized. In the present study, we have investigated mechanisms involved in endocytosis of ErbB3 in porcine aortic endothelial cells stably expressing either ErbB3 only or stably expressing ErbB3 and EGFR. Our data show that ErbB3 is endocytosed in the absence of added ligand, independently of its tyrosine phosphorylation state and in a clathrin-dependent manner. Functional EGFR-ErbB3 heterodimers were observed to be formed, and dimerization with ErbB3 was observed to negatively affect endocytosis of the EGFR. PMID- 22436611 TI - Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling. AB - Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj 8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions. PMID- 22436612 TI - Selenoproteins reduce susceptibility to DMBA-induced mammary carcinogenesis. AB - Selenium is an essential micronutrient in the diet of humans and other mammals. Based largely on animal studies and epidemiological evidence, selenium is purported to be a promising cancer chemopreventive agent. However, the biological mechanisms by which chemopreventive activity takes place are poorly understood. It remains unclear whether selenium acts in its elemental form, through incorporation into organic compounds, through selenoproteins or any combination of these. The purpose of this study was to determine whether selenoproteins mitigate the risk of developing chemically induced mammary cancer. Selenoprotein expression was ablated in mouse mammary epithelial cells through genetic deletion of the selenocysteine (Sec) tRNA gene (Trsp), whose product, designated selenocysteine tRNA, is required for selenoprotein translation. Trsp floxed and mouse mammary tumor virus (MMTV)-cre mice were crossed to achieve tissue-specific excision of Trsp in targeted mammary glands. Eight- to twelve-week-old second generation Trsp(fl/+);wt, Trsp(fl/+);MMTV-cre, Trsp(fl/fl);wt and Trsp(fl/fl);MMTV-cre female mice were administered standard doses of the carcinogen, 7,12-dimethylbenzylbenz[a]antracene. Our results revealed that heterozygous, Trsp(fl/+);MMTV-cre mice showed no difference in tumor incidence, tumor rate and survival compared with the Trsp(fl/+);wt mice. However, 54.8% of homozygous Trsp(fl/f)(l);MMTV-cre mice developed mammary tumors and exhibited significantly shorter survival than the corresponding Trsp(fl/fl);wt mice, where only 36.4% developed tumors. Loss of the homozygous Trsp alleles was associated with the reduction of selenoprotein expression. The results suggest that mice with reduced selenoprotein expression have increased susceptibility to developing carcinogen-induced mammary tumors and that a major protective mechanism against carcinogen-induced mammary cancer requires the expression of these selenoproteins. PMID- 22436613 TI - Hepatocyte growth factor activates Wnt pathway by transcriptional activation of LEF1 to facilitate tumor invasion. AB - Hepatocyte growth factor (HGF) is a secretory protein that plays important roles in cancer growth and metastasis. Lymphoid-enhancing factor 1 (LEF1) is a transcription factor mediating Wnt/beta-catenin signaling. Using microarray analysis, we found HGF induced expression of LEF1 in liver and breast cancer cell lines. HGF induced expression of LEF1 through phosphatidylinositol 3-kinase/Akt and nuclear factor-kappa B (NF-kappaB) signaling. Multiple NF-kappaB-binding sites were mapped within 3 kb upstream of LEF1 transcription initiation site. NF kappaB binding to a site 2 kb upstream of LEF1 transcription initiation site was confirmed by chromatin immunoprecipitation assay. Knockdown of LEF1 inhibited the expression of Slug and Zinc finger E-box-binding homeobox 2 (ZEB2) and markedly attenuated HGF-induced tumor migration and invasion. Using immunohistochemical staining, we found LEF1 was frequently expressed in multiple types of carcinoma but not in the non-tumorous epithelial cells. Our finding suggest that transcriptional activation of LEF1 is a mechanism of cross talk between HGF/c-Met and Wnt/beta-catenin pathways and is essential for HGF-induced tumor invasion. PMID- 22436614 TI - A randomized, placebo-controlled double-blinded comparative clinical study of five over-the-counter non-pharmacological topical analgesics for myofascial pain: single session findings. AB - OBJECTIVES: To investigate the effects of topical agents for the treatment of Myofascial Pain Syndrome (MPS) and Myofascial Trigger Point (MTRP). METHODS: Subjects with an identifiable trigger point in the trapezius muscle, age 18-80 were recruited for a single-session randomized, placebo-blinded clinical study. Baseline measurements of trapezius muscle pressure pain threshold (PPT: by pressure algometer) along with right and left cervical lateral flexion (rangiometer) were obtained by a blinded examiner. An assessor blinded to the outcomes assessments applied one of 6 topical formulations which had been placed in identical plastic containers. Five of these topicals were proposed active formulations; the control group was given a non-active formulation (PLA). Five minutes after the application of the formula the outcome measures were re-tested. Data were analyzed with a 5-way ANOVA and Holms-adjusted t-tests with an alpha level of 0.05. RESULTS: 120 subjects were entered into the study (63 females; ages 16-82); 20 subjects randomly allocated into each group. The pre- and post treatment results for pressure threshold did show significant intra-group increases for the Ben-Gay Ultra Strength Muscle Pain Ointment (BG), the Professional Therapy MuscleCare Roll-on (PTMC roll-on) and Motion Medicine Cream (MM) with an increased threshold of 0.5 kg/cm2 (+/-0.15), 0.72 kg/cm2 (+/-0.17) and 0.47 Kg/cm2 (+/-0.19) respectively. With respect to the inter-group comparisons, PTMC roll-on showed significant increases in pressure threshold compared with Placebo (PLA) (p = 0.002) and Icy Hot Extra Strength Cream (IH) (p = 0.006). In addition, BG demonstrated significant increases in pressure threshold compared with PLA (p = 0.0003). CONCLUSIONS: With regards to pressure threshold, PTMC roll-on, BG and MM showed significant increases in pain threshold tolerance after a short-term application on a trigger points located in the trapezius muscle. PTMC roll-on and BG were both shown to be superior vs placebo while PTMC was also shown to be superior to IH in patients with trigger points located in the trapezius muscle on a single application.CMCC Research Ethics Board Approval # 1012X01, 2011. PMID- 22436615 TI - Venous spasm during contrast-guided axillary vein puncture for pacemaker or defibrillator lead implantation. AB - AIMS: Contrast-guided axillary vein puncture is commonly used for pacemaker or defibrillator lead implantation. Venous spasm during contrast-guided axillary vein puncture has been reported rarely. We investigated the incidence of venous spasm during contrast-guided axillary vein puncture and the impact of venous spasm on axillary vein puncture. METHODS AND RESULTS: Seventy-four consecutive patients referred for contrast-guided axillary vein puncture for pacemaker or defibrillator implantation were included in the study. The puncture was guided by fluoroscopy and the venogram of axillary vein. After the success of puncture, the venography was taken again. When the puncture could not be successful up to 3 min, the second venography was taken and the puncture was guided by the second venogram. The degree of venous spasm was evaluated by the reduction in the lumen calibre of the axillary vein after puncture. Mild venous spasm and severe venous spasm were defined as a reduction in the lumen calibre of 50-90 and >= 90%, respectively. The success rate of axillary vein puncture within 3 min was 87.8%, and the total success rate was 95.9%. Mild venous spasm occurred in 22 patients (29.7%) and severe venous spasm occurred in 6 patients (8.1%). Severe venous spasm occurred in all the three patients with a failed puncture. Severe venous spasm was independently negatively correlated with both success rate within 3 min and total success rate. CONCLUSION: Venous spasm is not a rare phenomenon during the contrast-guided puncture of axillary vein and it has an important negative impact on the puncture. PMID- 22436616 TI - Effects of baseline P-wave duration and choice of atrial septal pacing site on shortening atrial activation time during pacing. AB - BACKGROUND: Atrial septal pacing (ASP) has been shown to shorten P-wave duration (PWD) and reduce recurrence of atrial fibrillation (AF) in patients with bradyarrhythmias. However, variability of interatrial connections and atrial conduction properties may explain ASP's modest clinical benefit. The aim of this study was to assess the effect of ASP site on the duration of the paced P wave. METHODS AND RESULTS: Atrial septal pacing at high atrial septum (HAS), posterior septum behind the fossa ovalis (PSFO), and coronary sinus ostium (CSo) was performed in 69 patients admitted for electrophysiological study (52 +/- 16 years, 41 men). Twelve-lead electrocardiogram was recorded at baseline and during pacing, signal-averaged for analysis of PWD and P-wave shortening achieved by ASP (DeltaPWD = paced PWD-baseline PWD). Baseline PWD was 128 +/- 15 ms. The shortest PWD during pacing was achieved at CSo (112 +/- 15 ms) followed by HAS (122 +/- 14 ms, P< 0.001 vs. CSo) and PSFO (124 +/- 21 ms, P< 0.001 vs. CSo). P wave was shortened during pacing in patients with baseline PWD of > 120 ms (n= 50), whereas those with PWD of <= 120 ms showed PWD lengthening (n= 19) when paced at HAS (8 +/- 17 vs. -12 +/- 15 ms, P< 0.001), PSFO (15 +/- 17 vs. -12 +/- 26 ms, P< 0.001) and CSo (6 +/- 16 vs. -25 +/- 18 ms, P< 0.001). CONCLUSION: Pacing at CSo is associated with the shortest PWD. P-wave shortening is greatest in patients with baseline PWD of > 120 ms regardless of the pacing site. The results may have implications on the selection of candidates for ASP and the placement of the atrial septal lead, and warrant further evaluation in cases of permanent pacing in patients with paroxysmal AF. PMID- 22436617 TI - Cerebellar dysfunction and cognitive impairments after stroke. PMID- 22436618 TI - Tinnitus as a consequence of the fight or flight response. PMID- 22436619 TI - Predictors of suicide attempts in patients with borderline personality disorder over 16 years of prospective follow-up. AB - BACKGROUND: It is clinically important to understand the factors that increase the likelihood of the frequent and recurrent suicide attempts seen in those with borderline personality disorder (BPD). Although several studies have examined this subject in a cross-sectional manner, the aim of this study was to determine the most clinically relevant baseline and time-varying predictors of suicide attempts over 16 years of prospective follow-up among patients with BPD. METHOD: Two-hundred and ninety in-patients meeting Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD were assessed during their index admission using a series of semistructured interviews and self-report measures. These subjects were then reassessed using the same instruments every 2 years. The generalized estimating equations (GEE) approach was used to model the odds of suicide attempts in longitudinal analyses, controlling for assessment period, yielding an odds ratio (OR) and 95% confidence interval (CI) for each predictor. RESULTS: Nineteen variables were found to be significant bivariate predictors of suicide attempts. Eight of these, seven of which were time-varying, remained significant in multivariate analyses: diagnosis of major depressive disorder (MDD), substance use disorder (SUD), post-traumatic stress disorder (PTSD), presence of self-harm, adult sexual assault, having a caretaker who has completed suicide, affective instability, and more severe dissociation. CONCLUSIONS: The results of this study suggest that prediction of suicide attempts among borderline patients is complex, involving co-occurring disorders, co-occurring symptoms of BPD (self-harm, affective reactivity and dissociation), adult adversity, and a family history of completed suicide. PMID- 22436620 TI - Comparison of HemoCue(r) hemoglobin-meter and automated hematology analyzer in measurement of hemoglobin levels in pregnant women at Khartoum hospital, Sudan. AB - BACKGROUND: Assessment of hemoglobin is one of the most reliable indicators for anemia, and is widely used to screen for anemia among pregnant women. The HemoCue(r) has been widely used for as a point-of-care device for hemoglobin estimation in health facilities. Previous studies showed contradictory results regarding the accuracy of HemoCue(r). METHODS: This was a hospital-based cross sectional study carried- out among pregnant women at Khartoum hospital in Sudan to find out whether the measurement of hemoglobin concentration by HemoCue(r) using venous or capillary samples was comparable to that of the automated hematology analyzer as standard. Bland and Altman method was used to compare the measurements with an acceptable difference of +/- 1.0 g/dl. RESULTS: Among the 108 subjects in this study the mean (SD) level of hemoglobin level using HemoCue(r) venous sample, HemoCue(r) capillary sample and automated hematology analyzer were 12.70 (1.77), 12.87 (2.04) and 11.53 (1.63) g/dl, respectively. Although the correlations between the measurements were all significant there was no agreement between HemoCue(r) and automated hematology analyzer. The bias + SD (limits of agreement) for HemoCue(r) venous versus hematology analyzer was 1.17 +/- 1.57 (-1.97, 4.31) g/dl, HemoCue(r) capillary versus hematology analyzer was 1.34 +/- 1.85 (-2.36, 5.04) g/dl, and HemoCue(r) venous versus HemoCue(r) capillary samples was 017 +/- 1.90 and (3.97-3.63) g/dl. CONCLUSION: Hemoglobin concentration assessment by HemoCue(r) using either venous or capillary blood samples has shown unacceptable agreement with automated hematology analyzer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8797022296725036. PMID- 22436621 TI - Origin of the nitrogen over- and understoichiometry in Ti(0.5)Al(0.5)N thin films. AB - To identify the origin of the experimentally observed nitrogen over- and understoichiometry in TiAlN thin films, various point defect configurations were studied by ab initio calculations in terms of formation energies, equilibrium volume and elastic moduli. From formation energies and comparison to existing experimental equilibrium volume and elasticity data, it is shown that nitrogen vacancies and metal vacancies are responsible for nitrogen understoichiometry and overstoichiometry, respectively. Irrespective of the type of vacancies, the bulk modulus is decreased by approximately 7% as the nitrogen concentration is increased or decreased by 3 at.%. PMID- 22436623 TI - Immune receptors and adhesion molecules in human pulmonary leptospirosis. AB - Pulmonary involvement in leptospirosis has been increasingly reported in the last 20 years, being related to the severity and mortality of the disease. The pathogenesis of pulmonary hemorrhage in leptospirosis is not understood. Lung endothelial cells have been proposed as targets in the pathogenesis of lung involvement in leptospirosis through the activation of Toll-like receptor 2 or the complement system, which stimulates the release of cytokines that lead to the activation of adhesion molecules. The aim of this study was to investigate the involvement of immune pathways and of the intercellular and vascular cell adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule, respectively) in the lungs of patients with pulmonary involvement of leptospirosis. We studied the lungs of 18 patients who died of leptospirosis and compared them with 2 groups of controls: normal and noninfectious hemorrhagic lungs. Using immunohistochemistry and image analysis, we quantified the expression of the C3a anaphylatoxin receptor, intercellular adhesion molecule, vascular cell adhesion molecule, and Toll-like receptor 2 in small pulmonary vessels and in the alveolar septa. There was an increased expression of intercellular adhesion molecule (P < .03) and C3a anaphylatoxin receptor (P < .008) in alveolar septa in the leptospirosis group compared with the normal and hemorrhagic controls. In the vessels of the leptospirosis group, there was an increased expression of intercellular adhesion molecule (P = .004), vascular cell adhesion molecule (P = .030), and Toll-like receptor 2 (P = .042) compared with the normal group. Vascular cell adhesion molecule expression in vessels was higher in the leptospirosis group compared with the hemorrhagic group (P = .015). Our results indicate that immune receptors and adhesion molecules participate in the phenomena leading to pulmonary hemorrhage in leptospirosis. PMID- 22436622 TI - Macrophages associated with the intrinsic and extrinsic autonomic innervation of the rat gastrointestinal tract. AB - Interactions between macrophages and the autonomic innervation of gastrointestinal (GI) tract smooth muscle have received little experimental attention. To better understand this relationship, immunohistochemistry was performed on GI whole mounts from rats at three ages. The phenotypes, morphologies, and distributions of gut macrophages are consistent with the cells performing extensive housekeeping functions in the smooth muscle layers. Specifically, a dense population of macrophages was located throughout the muscle wall where they were distributed among the muscle fibers and along the vasculature. Macrophages were also associated with ganglia and connectives of the myenteric plexus and with the sympathetic innervation. Additionally, these cells were in tight registration with the dendrites and axons of the myenteric neurons as well as the varicosities along the length of the sympathetic axons, suggestive of a contribution by the macrophages to the homeostasis of both synapses and contacts between the various elements of the enteric circuitry. Similarly, macrophages were involved in the presumed elimination of neuropathies as indicated by their association with dystrophic neurons and neurites which are located throughout the myenteric plexus and smooth muscle wall of aged rats. Importantly, the patterns of macrophage-neuron interactions in the gut paralleled the much more extensively characterized interactions of macrophages (i.e., microglia) and neurons in the CNS. The present observations in the PNS as well as extrapolations from homologous microglia in the CNS suggest that GI macrophages play significant roles in maintaining the nervous system of the gut in the face of wear and tear, disease, and aging. PMID- 22436624 TI - "Piling up" clear cells in mullerian-type mucinous and mixed cell-type borderline tumor do not represent concomitant clear cell neoplasms. AB - The nature of "piling up" proliferation of clear cells in mullerian mucinous/mixed borderline tumor has not been well characterized. The purpose of this study was to clarify whether or not such clear cells represent concomitant clear cell neoplasms. First, we carefully reviewed hematoxylin and eosin slides taken from 139 ovarian tumors diagnosed as clear cell carcinoma (112 cases) and mullerian mucinous/mixed borderline tumor (27 cases) to clarify (1) the frequency of piling-up clear cells in mullerian mucinous/mixed borderline tumor and (2) the frequency of the coexistence of typical clear cell carcinoma and mullerian mucinous/mixed borderline tumor. Second, we investigated the immunohistochemical expression of estrogen receptor, hepatocyte nuclear factor-1beta, and glypican-3 in proliferating clear cells in both tumors. We identified piling-up clear cells in 56% of mullerian mucinous/mixed borderline tumors. Such clear cells lacked the severe nuclear atypia, complex branching, and dense hyalinized cores of typical clear cell carcinoma. We did not find coexistence of typical clear cell carcinoma and mullerian mucinous/mixed borderline tumor in any tumors. Piling-up clear cells and endocervical-like mucinous cells were positive for estrogen receptor but negative for hepatocyte nuclear factor-1beta and glypican-3. Most clear cell carcinomas showed a hepatocyte nuclear factor-1beta-positive/estrogen receptor negative immunophenotype, and about half of them were glypican-3 positive. In conclusion, piling-up clear cells in mullerian mucinous/mixed borderline tumor do not represent concomitant clear cell neoplasms because clear cell carcinoma and mullerian mucinous/mixed borderline tumor hardly ever coexist and because such clear cells in both tumors are immunophenotypically distinct. PMID- 22436625 TI - Correlation between tumor suppressor inhibitor of growth family member 4 expression and microvessel density in breast cancer. AB - Suppression of cell spreading and migration by inhibitor of growth 4 suggests that its loss may induce metastasis. Inhibitor of growth 4 expression level in 60 breast cancer tissues, 30 normal adjacent tissues, and tissues from patients with benign hyperplasia was determined by real-time polymerase chain reaction, Western blot, and immunohistochemistry. The correlation between inhibitor of growth 4 expression and clinical stage, histologic grade, and microvessel density in breast cancer was analyzed. Inhibitor of growth 4 messenger RNA and protein expression in breast cancer was significantly lower than that observed in adjacent normal and hyperplastic breast tissues (P < .05). Inhibitor of growth 4 expression decreased with increasing clinical stage and histologic grade. Moreover, the presence of lymph node metastasis was correlated with decreased inhibitor of growth 4 messenger RNA expression (P < .01), and a negative correlation was noted between inhibitor of growth 4 protein expression and microvessel density in breast cancer. Inhibitor of growth 4 may represent an important biomarker for assessing the severity of breast cancer. Further studies are required to fully evaluate the diagnostic and possible prognostic value of determining inhibitor of growth 4 levels in breast cancer. PMID- 22436626 TI - Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies. AB - Hepatocellular carcinoma and intrahepatic cholangiocarcinoma account for 95% of primary liver cancer. For each of these malignancies, the outcome is dismal; incidence is rapidly increasing, and mechanistic understanding is limited. We observed abnormal proliferation of both biliary epithelium and hepatocytes in mice after genetic manipulation of Yes-associated protein, a transcription coactivator. Here, we comprehensively documented Yes-associated protein expression in the human liver and primary liver cancers. We showed that nuclear Yes-associated protein expression is significantly increased in human intrahepatic cholangiocarcinoma and hepatocellular carcinoma. We found that increased Yes-associated protein levels in hepatocellular carcinoma are due to multiple mechanisms including gene amplification and transcriptional and posttranscriptional regulation. Survivin, a member of the inhibitors-of-apoptosis protein family, has been reported as an independent prognostic factor for poor survival in both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. We found that nuclear Yes-associated protein expression correlates significantly with nuclear Survivin expression for both intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Furthermore, using mice engineered to conditionally overexpress Yes-associated protein in the liver, we found that Survivin messenger RNA expression depends upon Yes-associated protein levels. Our findings suggested that Yes-associated protein contributes to primary liver tumorigenesis and likely mediates its oncogenic effects through modulating Survivin expression. PMID- 22436627 TI - Clinical and biological relevance of enhancer of zeste homolog 2 in triple negative breast cancer. AB - The polycomb group protein, enhancer of zeste homolog 2, is a transcriptional repressor involved in cell cycle regulation and has been linked to aggressive breast cancer. We examined the clinical and biological significance of enhancer of zeste homolog 2 expression in triple-negative breast cancers. Tissue microarrays were constructed with invasive breast cancer cases and stained with the enhancer of zeste homolog 2, cytokeratin 5/6, epidermal growth factor receptor 1, and p53. The expression of these markers was correlated with clinicopathologic variables and patients' outcome. Furthermore, in vivo enhancer of zeste homolog 2 gene silencing was achieved using small interfering RNA incorporated into chitosan nanoparticles. Of 261 cases of invasive breast cancer, high expression of the enhancer of zeste homolog 2 was detected in 87 (33%) cases, and it was strongly associated with a triple-negative breast cancer phenotype (P < .001) compared with all other non-triple-negative breast cancers. Furthermore, high enhancer of zeste homolog 2 was significantly associated with high histologic grade (P = .01), estrogen receptor negativity (P < .001), progesterone receptor negativity (P < .001), epidermal growth factor receptor positivity (P = .04), and high p53 expression (P < .001). Survival analysis demonstrated that patients with high enhancer of zeste homolog 2 had a poorer overall survival compared with those with low enhancer of zeste homolog 2 (P = .03), and it retained its significance as an independent prognostic factor (P = .02). In addition, enhancer of zeste homolog 2 gene silencing resulted in a significant reduction in tumor growth (P < .01) in the orthotopic MB-231 mouse model of breast carcinoma. Our results show that high enhancer of zeste homolog 2 expression is significantly associated with triple-negative breast cancer and decreased survival. Enhancer of zeste homolog 2 may represent a potential therapeutic target for this aggressive disease, which warrants further investigation. PMID- 22436628 TI - The significance of plasma cell infiltrate in acute cellular rejection of liver allografts. AB - Acute cellular rejections of higher grades of histologic severity are associated with increased risk of graft failure and death after liver transplantation. Plasma cell-rich infiltrates are associated with adverse clinical outcomes in acute renal allograft rejection and in liver allografts without rejection, but there are limited data on plasma cell-rich infiltrates in acute liver allograft rejection. In this study, 59 biopsies of acute liver allograft rejection were confirmed histologically and clinically, independently graded, and the percentage of plasma cells in portal inflammatory infiltrate was objectively assessed using a standardized protocol. Plasma cell infiltrates were observed in 32 (54%) of the specimens, the mean percentage of plasma cells in the infiltrates being 2.97%. Infiltrates with any plasma cells were significantly more common in groups with higher histologic severity of rejection (75% and 100% versus 31% and 48%, P = .006). The mean percentage of plasma cells in the portal infiltrate was also significantly higher in groups with higher histologic severity of rejection (4.95% and 17.82% versus 0.37 and 0.82%, P = .0002). All the biopsies with more than 30% plasma cells in the infiltrate were found to have severe rejection, whereas all with more than 10% plasma cells had either moderate or severe rejection. The association of plasma cell-rich infiltrates with histologic severity of rejection suggests that plasma cell-rich infiltrates could potentially be useful as a marker of severe rejection. PMID- 22436629 TI - Carbonic anhydrase IX up-regulation is associated with adverse clinicopathologic and biologic factors in neuroblastomas. AB - The overexpression of carbonic anhydrase IX, a hypoxia-induced enzyme, is associated with an adverse prognosis in many cancers. However, carbonic anhydrase IX expression in neuroblastoma, the most common extracranial pediatric tumor, has not been reported. Membranous and/or strong cytoplasmic carbonic anhydrase IX expression, assessed by immunohistochemistry, was present in 21 (23%) of 91 neuroblastomas but was absent in ganglioneuromas (n = 9). The proportion of neuroblastomas showing membranous carbonic anhydrase IX expression was higher in neuroblastomas with 1p deletion and MYCN amplification. Nuclear carbonic anhydrase IX expression was seen in less than 10% of ganglion cells in all ganglioneuromas. Of 91 neuroblastomas, 16 (18%) showed nuclear carbonic anhydrase IX expression in 10% or more tumoral cells. The proportion of neuroblastomas showing nuclear carbonic anhydrase IX expression was significantly higher in patients with adverse clinical (increasing stage and high-risk group), pathologic (unfavorable group and high mitosis-karyorrhexis-index), and biologic (MYCN amplification and 1p deletion) factors. Carbonic anhydrase IX total protein levels, quantified by enzyme-linked immunosorbent assay, were higher in neuroblastomas (n = 49; geometric mean, 0.47 pg/ug; range, 0.0-6.52 pg/ug) than in ganglioneuromas (n = 6; geometric mean, 0.20 pg/ug; range, 0.09-0.47 pg/ug) and were significantly higher in MYCN-amplified neuroblastomas. Nuclear carbonic anhydrase IX expression was associated with a poorer overall survival (P = .003) and event-free survival (P = .004), although the relationships were no longer significant when adjusted for high-risk disease. There was no significant association of membranous carbonic anhydrase IX expression or higher-than-median total protein levels with overall survival or event-free survival. Carbonic anhydrase IX is expressed at significantly higher levels in neuroblastomas from patients with adverse clinicopathologic and biologic factors indicating that it is a biomarker of aggressive disease in neuroblastomas. PMID- 22436630 TI - [Percutaneous mitral commissurotomy associated to sinus venosus atrial septal defect and partially anomalous pulmonary venous connection: a case report]. AB - Lutembacher's syndrome refers to the rare combination of congenital atrial septal defect and acquired mitral stenosis. It is rarely associated to partial anomalous pulmonary venous connection. This condition is treated surgically by mitral commissurotomy or mitral valve operation with concomitant closure of the atrial septal defect with correction of the abnormal pulmonary venous connection. Percutaneous mitral commissurotomy before surgery can be a therapeutic alternative when mitral valve stenosis is severe and valve anatomy is favourable. The authors bring back the case of a 24 years old man having mitral stenosis in sinus rhythm associated to sinus venosus septal defect and partial anomalous pulmonary venous connection. The diagnosis was made for the age of 17 years old on the occasion of dyspnea. He benefited in February 2003 of rescue percutaneous mitral commissurotomy because of pulmonary oedema. Mitral valve area increased from 0.7 cm(2) to 1.6 cm(2). The patient was clinically approved, so that he refused surgery and was lost sight. Seven years later (August 2010) he was taken back for a second rescue percutaneous mitral commissurotomy because of a very severe mitral stenosis (mitral valve area was 0.8cm(2)), in pulmonary oedema with echocardiographic evaluated pulmonary hypertension at 68mmHg. The trans-septal complicated of a false road from the right atrium, towards the pericardic cavity. The patient was operated as the matter of urgency, and benefited from a mitral valve replacement by mechanical prosthesis, of closure of sinus venosus septal defect by PTFE patch and correction of abnormal pulmonary venous connection. Operating suites were simple, and the postoperative echocardiography concludes to a good prosthesis profile, the absence of residual shunt and a decrease of pulmonary artery blood pressure from 68 to 40mmHg. In conclusion, percutaneous mitral commissurotomy may be a waiting procedure for surgery of this disease or emergency treatment of it's valve anomaly, with regular monitoring while awaiting surgery faster and in better conditions. PMID- 22436631 TI - [Periaortic abscess and infective endocarditis: beware of this dangerous duo]. AB - OBJECTIVE: To determine clinical, echocardiographic features, management and outcomes of patients presenting peri aortic abscess complicating infective endocarditis (IE) and demonstrate the impact of periaortic abscess on morbidity and mortality of these patients. METHODS: We have analyzed clinical, microbiological, echocardiographic aspects, therapies and outcomes of patients with aortic abscess occurring during IE, and we compared these data with those of patients presenting IE without peri aortic abscess in the same period in the cardiology department of the University Hospital of Marrakech from January 2006 to January 2010. RESULTS: Above 56 cases of infective endocarditis, 16 patients had an aortic abscess. Mean age was 33 +/- 11 years with a clear male predominance in the group IE with abscess versus IE without abscess. Heart failure was noted in all patients in periaortic abscess group, and was more severe in this group compared to control. Streptococcus and staphylococcus predominated with no significant difference between the two groups. Transthoracic echocardiography coupled with transesophageal echocardiography made the diagnosis of aortic abscess witch was isolated in 11 cases and associated with other complications in five cases. In terms of complications, splenic infarction was more frequent in the group with abscess (25 versus 2.5%, P<0.05). There was not a significant difference between the two groups for the others complications. Surgery associated with a double antibiotic therapy was the standard treatment with a variable delay for surgery of four days to four weeks. Hospital mortality in the acute phase was higher in periaortic abscess group (37% versus 10%, P<0.05). The evolution of survivors at six months was favorable. CONCLUSION: Periaortic abscess complicating IE is associated with a high morbidity and mortality in spite of modern approach as well as on medical or surgical treatment. It requires therefore a strict monitoring of patients with infective endocarditis. PMID- 22436632 TI - [Valvular surgery for an exercise-induced functional mitral regurgitation in heart failure and preserved ejection fraction: a case study]. AB - We here report the case of a 67-year-old woman with moderate mitral regurgitation without significant structural abnormalities that get worse during severe recurrent heart failures and preserved ejection fraction with concomitant paroxysmal atrial fibrillation. Atrial fibrillation became permanent and despite a well-controlled cardiac frequency, new heart failure episodes occurred. Exercise doppler echocardiography showed that the mechanism of this mitral regurgitation was a two leaflet mitral tenting. We discuss here the different mechanisms that could induce these kinds of mitral regurgitation with excessive tenting. We emphasize the interest of early detection by exercise doppler echocardiography even when a triggering factor like atrial fibrillation seems to be involved. We also discuss the interest of mitral valve replacement for these patients. PMID- 22436633 TI - [Isolated left ventricular congenital diverticulum in adult: Report of cardiac imaging]. AB - Cardiac diverticulum is an infrequent congenital malformation, it's even more rare in adulthood. It's often associated with other thoraco-abdominal diverticulums, and rarely isolated. The diagnosis relies on echocardiography. By the way, the magnetic resonance imagery (MRI) allows a finer analysis of the diverticulum, its topography and its situation contributed to vascular and cardiac structures, it has largely replaced the ventriculography. We report in this article the case of a patient of 36 years whose diagnosis of the diverticulum was made by transthoracic echocardiography (TTE) at the time of an assessment of dyspnea, this exam also objectified a mitral insufficiency by deformation and dilatation of the mitral annulus. Radiological assessment was completed by a transoesophageal echocardiography (TOE) and magnetic resonance imagery (MRI). Surgical treatment consisted of surgical closing of the diverticulum and mitral annuloplasty. PMID- 22436635 TI - [Use of drug-eluting stents: impact of French recommendations on the rate of clinical restenosis at 2 years]. AB - AIMS: The drug-eluting stents (DES) reduce restenosis rate compared to bare metal stents. The clinical efficacy is greater in some subgroups of patients at high risk of restenosis. The aim of this study is to evaluate the use of drug-eluting stent based on the recommendations of the French Society of Cardiology and its impact on the restenosis rate at 2 years. METHODS: We included all patients who had coronary angioplasty with stenting in 2008. We evaluated the percentage of drug-eluting stent, the proportion of patients for which the French recommendations have been followed, and the rate of clinical restenosis at 2 years. RESULTS: Four hundred and seventy-nine angioplasties were performed in 2008. The percentage of drug-eluting stents was 21.8%. Acute coronary syndrome with or without elevation of the ST segment were the main indications of angioplasty (67.9%). For the 115 drug-eluting stents implanted in 2008, French recommendations were followed in 93% of cases (107 stents). For 89 patients who received DES, these recommendations were followed in 91% of cases (81 patients). The clinical restenosis rate at 2 years evaluated in 89% of patients was 5.6%. The rate of in-stent restenosis in bare metal and drug-eluting stents were 5.9 and 3.7%. CONCLUSION: The use of DES in our center is characterized by a small rate and a good compliance of the recommendations of the French Society of Cardiology. This strategy is associated with a low rate of restenosis at 2 years of follow-up. PMID- 22436634 TI - [Tamponade reveals an intra-pericardial hydatid cyst - a case report]. AB - INTRODUCTION: Hydatid disease is a parasitic infection caused by the development of the larval form of the Teania of Echinococcus granulosus. It is endemic in many regions of the world such as the Mediterranean basin. Location without pericardial cardiac involvement is extremely rare. In this case study, we will elaborate the case of an intra-pericardial hydatidosis disease without cardiac location revealed by a tamponade. OBSERVATION: AA is a 60-year-old man with no pathological history and who was admitted for a tamponade assessment. Indeed, the cardiovascular examination showed a muffling of the heart sound and signs of a right heart failure. Besides, the ECG shows a microvoltage, and the chest radiography shows cardiomegaly. Moreover, the transthoracic echocardiogram confirmed the presence of an abundant pericardial effusion along with signs of a tamponade. It also reifies the presence of, at the intra-pericardial level, a multiple vesicular formation giving a cluster of grapes highly suggestive of an intra-pericardial hydatid disease. An emergency surgical drainage allowed removing about two liters of suspicious fluid along with cysts and white membranous. The pathological examination of the membranous confirmed the diagnosis of a pericardial hydatid cyst. The performance of a chest CT and an abdominal ultrasound's scan to identify other locations shows no further anomalies. The patient was put under medical treatment (Albendazole((r))) and is showing a good clinical improvement. CONCLUSION: The intra-pericardial hydatid disease is another cause of tamponade not to fail despite its rareness, as it is endemic to North African countries. PMID- 22436636 TI - [Cardiogenic pulmonary edema following beta2 agonist infusion for acute, severe asthma]. AB - We report the case of a severe acute pulmonary edema secondary to the administration of salbutamol to a patient admitted for severe asthma. The diagnosis of acute pulmonary edema was suspected on the clinical examination, chest radiography, biological (plasmatic Pro-BNP rate) and echocardiographic findings. Rapid improvement under dobutamine and mechanical ventilation argue in favour of cardiogenic pulmonary edema. The young age of our patient, the absence of history of cardiovascular disease and the chronology of this complication onset regarded to salbutamol infusion could suggest beta2 agonist involvement in this event. The improvement of cardiac function on echocardiography and the normal results obtained with myocardial perfusion scintigraphy performed 35 days later show the left ventricular reversible dysfunction. PMID- 22436638 TI - Atherogenic effects of TNF-alpha and IL-6 via up-regulation of scavenger receptors. AB - Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) have a high risk of developing cardiovascular disease. We evaluated the effects of TNF-alpha and IL-6 on foam cell formation, a pivotal process in atherogenesis. Accumulation of intracellular oxidized LDL (oxLDL) was induced when THP 1/macrophages were stimulated with TNF-alpha or IL-6. TNF-alpha induced the expressions of scavenger receptors SR-A and LOX-1, and IL-6 induced SR-A expression. Inhibition of the NF-kappaB signaling markedly decreased TNF-alpha induced foam cell formation and SR-A expression. Serum from RA patients, but not healthy subjects, induced foam cell formation, which was partially reversed by either IL-6 or TNF-alpha blockade in conjunction with inhibiting the induction of scavenger receptors. The present study clearly showed that in patients with chronic inflammation mediated by TNF-alpha and IL-6, these cytokines are directly implicated in atherosclerotic plaque formation. PMID- 22436639 TI - Geometry strongly influences the response of numerical models of the lumbar spine -a probabilistic finite element analysis. AB - Typical FE models of the human lumbar spine consider a single, fixed geometry. Such models cannot account for potential effects of the natural variability of the spine's geometry. In this study, we performed a probabilistic uncertainty and sensitivity analysis of a fully parameterized, geometrically simplified model of the L3-L4 segment. We examined the impact of the uncertainty in all 40 geometry parameters, estimated lower and upper bounds for the required sample size and determined the most important geometry parameters. The natural variability of the spine's geometry indeed strongly affects intradiscal pressure, range of motion and facet joint contact forces. Deriving generalized statements from fixed geometry models as well as transferring those results to different cases thus can easily lead to wrong conclusions and should only be performed with extreme caution. We recommend a sample size of ~ 100 to obtain reasonable accurate point estimates and a sufficient overview of the remaining uncertainties. Yet, only few parameters, especially those determining the disc geometry (disc height, end plate width and depth) and the facets' position (intra-articular space, pedicle length, facet angles), proved to be truly important. Accurate measurement and modeling of those structures should therefore be prioritized. PMID- 22436640 TI - Impact of intestinal microbiota and gastrointestinal conditions on the in vitro survival and growth of Bacillus cereus. AB - Ingestion of B. cereus can result in diarrhea, if these bacteria survive gastrointestinal passage and achieve growth and enterotoxin production in the small intestine. The gastrointestinal survival of vegetative cells and spores of the diarrheal food poisoning strain B. cereus NVH 1230-88 was investigated during in vitro batch experiments simulating the stomach, duodenum and ileum using simulation media and competing intestinal microbiota. All spores and approx. 30% of the vegetative B. cereus cells survived the 2 h incubation in gastric medium with pH 4.0. Sterile intestinal medium induced germination of spores and enabled outgrowth of vegetative cells to approx. 7 log CFU/mL. The behavior of B. cereus in the intestinal environment with competing intestinal bacteria was determined by their relative concentrations. Besides the numbers of intestinal bacteria, the nutrition and composition of the intestinal community were also very important for the growth inhibition of B. cereus. PMID- 22436641 TI - Development and implementation of a palliative care consultation tool. AB - OBJECTIVE: Palliative care services are becoming more commonplace in hospitals and have the potential to reduce hospital costs through length of stay reduction and remediation of symptoms. However, there has been little systematic attempt to identify when a palliative care consultation should be triggered in a hospital, and there is some evidence that these services are under-utilized and not fully understood. METHOD: In an initial attempt to address when a consultation might be appropriate, we attempted to pilot test a novel palliative care screening tool to help guide clinician judgment in this regard. A one-page, face-valid instrument was developed using expert opinion. RESULTS: The sample comprised 33 men (44.6%) and 41 women (55.4%) with an average age of 63.4 years (SD = 13.8) and an average length of stay of 22.7 days (SD = 10.1). The most significant symptom was pain, indicated as moderate-to-severe in 23 patients (31%). This was followed by fatigue (n = 10, 13.5%) and nausea (n = 6, 8.1%). At unit entry, 20 patients (33%) had moderate or severe pain. Upon discharge, this number had been reduced to 12/60 (20%). Chi-Square analysis showed a significant decrease in pain rankings overall (chi2 = 36.3, p < 0.0001). The average total tool score was 7.5 (SD = 3.1). Using an initial threshold of 12 to trigger a palliative care referral, 64 patients (86.5%) would not have received a referral and 10 (13.5%) would have. Of these 10 patients, 2 (20%) did not receive a palliative care consultation while they were hospitalized. SIGNIFICANCE OF RESULTS: The tool we developed increased consultations over the time period in which it was used, compared with the same time period 1 year prior. Although the threshold developed for triggering referrals seemed artificially high, the implementation of the screening tool did increase referrals. PMID- 22436642 TI - Intermediate-term results of 505 consecutive minithoracotomy mitral valve procedures. AB - BACKGROUND: : Patient demand for less invasive surgery and interest in avoiding sternotomy has led to the increased use of the minithoracotomy for mitral valve surgery. Although the feasibility of this approach has been established, few data are available regarding intermediate-term results. METHODS: : A total of 505 consecutive minithoracotomy mitral valve procedures performed between 1996 and 2004 were analyzed. Procedures were mitral replacement (191/505, 38%) and repair (314/505, 62%). Concomitant cardiac procedures were performed in 78 cases (13%) (maze 36, tricuspid 29, atrial septal defect/patent foramen ovale 13) and reoperation in 92 cases (18%). Arterial cannulation was ascending aorta in 403 cases (80%), femoral in 101 cases (20%), and axillary in 1 case (<1%). An endoluminal aortic clamp was used in 406 cases (80%), an external clamp was used in 19 cases (4%), and 80 procedures (16%) were performed with ventricular fibrillation. Robotic assistance was used in 12 cases (2%). RESULTS: : Mean patient age was 58.7 years (range 18-90 years). Median follow-up was 3.1 years. Operative mortality was 4 of 505 cases (<1%). Major complications included stroke in 7 cases (1%) and reoperation for bleeding in 18 cases (4%); there were no cases of mediastinitis. Late complications included chronic aortic dissection in 1 case (<1%) and mitral reoperation in 13 cases (3%) (subacute bacterial endocarditis 6, failed repair 2, other 5). Five-year survival was (83% +/- 2%) and freedom from mitral reoperation was (96% +/- 1%). Follow-up echocardiograms were available in 246 of 314 cases (78%) mitral repairs and mean mitral regurgitation grade was 1 +/- 1. Mitral regurgitation was grade 3-4+ in 14 of 246 cases (6%) (subacute bacterial endocarditis 4, low ejection fraction 5, other 5). Five-year freedom from 3-4+ mitral regurgitation was 89% +/- 3%. CONCLUSIONS: : Mitral valve surgery via minithoracotomy can be performed safely with a low perioperative complication rate. A durable technical result and excellent long term survival can be expected. PMID- 22436643 TI - Midterm Follow-up of Robotic Biventricular Pacing Demonstrates Excellent Lead Stability and Improved Response Rates. AB - BACKGROUND: : Robotically assisted left ventricular (LV) lead placement is an effective minimally invasive rescue procedure for cardiac resynchronization in the setting of failed coronary sinus lead insertion. The long-term response rate and durability of this technique has not been reported. The authors evaluated the midterm outcome of biventricular pacing performed with robotically placed LV leads. METHODS: : Forty-two patients underwent implantation of LV epicardial leads using robotic assistance and the posterior approach. Half of the patients had prior cardiac surgery. All leads were placed in an optimal site along the posterolateral surface of the LV. The patients were prospectively followed up for clinical response, LV reverse remodeling, and LV lead stability over a mean period of 16.7 +/- 9.5 months (range, 3-34 months). A multivariate Cox proportional hazards model was used to determine predictors of response. RESULTS: : All patients had successful LV lead placement with no postoperative mortality. Statistically significant improvements in left ventricular ejection fraction, NYHA heart failure class, systolic left ventricular internal dimension index, and diastolic left ventricular internal dimension index. The 3-month clinical response rate was 81% and dropped to 71% at average maximal follow-up. Multivariate analysis of 9 variables revealed only LVEF greater than 15% and absence of pulmonary hypertension to be predictors of response. No difference in operative time, response rate, or LV lead stability was detected when primary versus reoperative cases were compared. CONCLUSIONS: : Robotic LV lead placement is a reliable technique for optimal lead placement with durable long-term results. PMID- 22436644 TI - Three-year experience with totally endoscopic robotic thymectomy. AB - BACKGROUND: : Robotic technology has facilitated the evaluation and treatment of anterior mediastinal pathology. We describe a 3-year experience using the da Vinci Robotic Surgical System to perform thymectomies for a range of diseases. METHODS: : From March 2002 to November 2004, 9 patients (3 myasthenia gravis, 3 mediastinal mass, 2 myasthenia gravis plus thymoma, 1 hyperparathyroidism) underwent totally endoscopic robotic thymectomy. Medical records and operative databases were reviewed. The cohort was divided into an early experience (group A) and a later experience (group B). Data were analyzed with the Fisher exact test and Mann-Whitney test. RESULTS: : Complete robotic resection of the thymus was accomplished in all 9 patients. The mean age for the entire cohort was 40 +/- 12 years (range 28-66 years) and 78% of the patients were women. No significant differences in age, gender, or operative conversions were detected between the groups. Patients in group A were more likely to have a bilateral approach. Group B demonstrated statistically significant reductions in operating room and operation time and a trend toward decreased chest tube days and length of stay. No morbidity or mortality associated with the procedure was noted in either group. CONCLUSIONS: : Robotic thymectomy is a safe and effective procedure. Its steep learning curve promises to allow more surgeons to adopt minimally invasive approaches to the mediastinum safely and efficiently. PMID- 22436645 TI - Robotic replacement of the descending thoracic aorta: an alternative to endovascular therapy? AB - BACKGROUND: : Replacement of the descending thoracic aorta is traditionally performed via a left thoracotomy. Endovascular treatment of descending thoracic aortic aneurysms has recently evolved as an alternative treatment for selected patients, yet no long-term results are available. The authors replaced the descending thoracic aorta in a group of pigs with an interposition Dacron graft using a closed-chest, totally robotic technique. METHODS: : Ten pigs, weighing 25 to 45 kg, underwent surgery using the DaVinci robotic surgical system. Under single-lung ventilation and CO2 insufflation, the descending thoracic aorta was completely mobilized. Proximal and distal cross-clamps were applied through separate accessory stab wounds. The mid-descending thoracic aorta was excised. An interposition Dacron graft was robotically sewn in an end-to-end fashion to the descending thoracic aorta using interrupted nitinol clips. RESULTS: : All animals survived the procedure. Mean aortic clamp time was 55 +/- 14 minutes. All anastomoses were completed without difficulty with a mean total anastomotic time of 42 +/- 11 minutes. The anastomoses were challenged for bleeding by administrating alpha1-adrenergic receptor agonists to a systolic blood pressure of 200 mm Hg with no evidence of leak. DISCUSSION: : Robotic replacement of the thoracic aorta is feasible and reproducible. This procedure provides the standard Dacron graft repair with its known long-term results. The added value of robotic technology to the therapeutic armamentarium in the treatment of thoracic aortic aneurysms may be worth the effort required for procedural development. Furthermore, it may serve as a valid alternative to endovascular treatment of thoracic aortic aneurysms. PMID- 22436646 TI - Clinical Application of an Original Flexible MK Stent-Graft For Nonruptured Thoracic Aortic Aneurysms: Early Experience. AB - OBJECTIVE: : To obtain early MK stent-grafting results for nonruptured thoracic aortic aneurysms and thoracoabdominal aortic aneurysms. METHODS: : The authors analyzed 47 patients who underwent treatment using MK stent-grafting. All patients (40 men and 7 women; mean age, 70.8 years) underwent elective procedures. Straight, curved, or tapered MK stents were constructed from a nitinol wire and covered with seamless, cylindrical woven polyester fabric grafts. The mean stent-graft diameter was 24 to 48 mm. In cases where the aneurysm had a short proximal neck (under 15 mm), supraaortic arch artery bypass surgery was planned to lengthen the neck. RESULTS: : Simple stent-grafting without bypass was performed in 26 patients, whereas stent-grafting with supraaortic arch artery bypass was performed in 21 patients. An 18 or 20 F sheath was used as the delivery system in 46 patients (96%). In all 47 patients, the stent-grafts were successfully deployed. Two patients died while in hospital, and another 2 patients suffered a stroke. No other perioperative complications were observed. Postoperative computed tomography after 3 months showed complete thrombus formation in 42 patients (93.3%; 42/45 patients). CONCLUSIONS: : Forty seven patients with thoracic aortic aneurysm were treated with our original flexible MK stent-graft system. Using a small sheath system, straight or curved M K stent-grafts could be deployed to adequately fit to the aorta as planned. Furthermore, simultaneous bypass surgery widened the application of stent grafting. However, careful long-term observation is necessary, and further studies are needed to assess such stent-grafting with bypass surgery. PMID- 22436647 TI - Endovascular treatment of a blunt thoracic aortic laceration due to thoracolumbar spine fracture. AB - A 36-year-old woman sustained an aortic laceration at the level of the diaphragmatic hiatus owing to a displaced thoracolumbar spine fracture (TLS). We herein report the first case of aortic trauma secondary to a TLS fracture treated with a thoracic stent-graft. PMID- 22436648 TI - A new multisuction cardiac positioner for multivessel off-pump coronary artery bypass grafting. AB - OBJECTIVE: : To accomplish successful multivessel off-pump coronary artery bypass grafting, safe, reproducible, and effective exposure of all coronary territories is essential. For this purpose, we developed a new, simple, multisuction cardiac positioner. METHODS: : This new cardiac positioner consists of 3 small independent suction cups and suction tubes made of silicone. Unlike an apical suction cardiac positioner, this positioner has no arm. The suction cups can be applied with negative pressure of 300 mm Hg to various surfaces of the ventricle, including not only the apex but also the lateral, inferior, and right ventricular walls, according to surgeon preference. We applied this positioner in 15 clinical multivessel off-pump coronary artery bypass procedures. RESULTS: : In all cases, all target vessels including those on the lateral or inferior wall were successfully exposed and grafted without hemodynamic compromise. Surgical exposure, especially on the lateral and inferior walls, was quite similar to that of conventional coronary artery bypass graft procedures performed during cardiopulmonary bypass. CONCLUSIONS: : The multisuction cardiac positioner provided reproducible and easy access in multivessel off-pump coronary artery bypass surgery. This simple, variable, and inexpensive cardiac positioner may be used as a new tool to aid in the performance of successful multivessel off-pump coronary artery bypass surgery. PMID- 22436649 TI - Dual-beam ultrasound versus transit-time flow meter for intraoperative graft flow measurement during coronary artery bypass grafting. AB - OBJECTIVE: : Assessment of graft flow during coronary artery bypass grafting (CABG) is increasingly practiced as a quality measure, particularly in patients undergoing minimally invasive or "off-pump" revascularization. Transit-time flow meters such as Transonic system (TS) are currently the most frequently used technology. The QuantixOR flow probe (QOR) is a novel technology comprised of dual-beam ultrasound transducer and a digital pulse-wave Doppler, allowing immediate, quantitative blood flow measurements. Excellent correlation between QOR and TS was observed in phantom and animal models. This study evaluated the QOR in patients undergoing CABG. METHODS: : Graft flow was measured in 75 patients undergoing CABG (203 grafts). Intraobserver (n = 169) and interobserver (n = 33) variability was assessed and the QOR was compared with the TS (n = 155). RESULTS: : An average of 2 probe sizes per case and "skeletonization" of a short segment of the vessel were required to measure flow in arterial conduits using TS. In contrast, measurements of flow with the QOR were achieved using a single probe without special vessel preparation for all types of conduits. Average intraobserver and interobserver variability using the QOR were 5 +/- 41% and 4 +/ 40%, respectively. Correlation was observed between 2 sets of measurements by the same observer (R = 0.746, P < 0.0001) and between 2 different observers (R = 0.667, P < 0.0001). Correlation was also observed between the QOR and TS (R = 0.542, P < 0.0001) with a variance of 12 +/- 21%. CONCLUSIONS: : The QOR technology provides a reliable quantitative graft flow assessment that is simpler to obtain compared with TS. Correlation between the QOR and TS is excellent. PMID- 22436650 TI - Integrating evidence into policy and sustainable disability services delivery in western New South Wales, Australia: the 'wobbly hub and double spokes' project. AB - BACKGROUND: Policy that supports rural allied health service delivery is important given the shortage of services outside of Australian metropolitan centres. The shortage of allied health professionals means that rural clinicians work long hours and have little peer or service support. Service delivery to rural and remote communities is further complicated because relatively small numbers of clients are dispersed over large geographic areas. The aim of this five-year multi-stage project is to generate evidence to confirm and develop evidence-based policies and to evaluate their implementation in procedures that allow a regional allied health workforce to more expeditiously respond to disability service need in regional New South Wales, Australia. METHODS/DESIGN: The project consists of four inter-related stages that together constitute a full policy cycle. It uses mixed quantitative and qualitative methods, guided by key policy concerns such as: access, complexity, cost, distribution of benefits, timeliness, effectiveness, equity, policy consistency, and community and political acceptability. Stage 1 adopts a policy analysis approach in which existing relevant policies and related documentation will be collected and reviewed. Policy-makers and senior managers within the region and in central offices will be interviewed about issues that influence policy development and implementation. Stage 2 uses a mixed methods approach to collecting information from allied health professionals, clients, and carers. Focus groups and interviews will explore issues related to providing and receiving allied health services. Discrete Choice Experiments will elicit staff and client/carer preferences. Stage 3 synthesises Stage 1 and 2 findings with reference to the key policy issues to develop and implement policies and procedures to establish several innovative regional workforce and service provision projects. Stage 4 uses mixed methods to monitor and evaluate the implementation and impact of new or adapted policies that arise from the preceding stages. DISCUSSION: The project will provide policy makers with research evidence to support consideration of the complex balance between: (i) the equitable allocation of scarce resources; (ii) the intent of current eligibility and prioritisation policies; (iii) workforce constraints (and strengths); and (iv) the most effective, evidence-based clinical practice. PMID- 22436651 TI - Altered expression of the clock gene machinery in kidney cancer patients. AB - BACKGROUND AND AIM: Kidney cancer is associated with alteration in the pathways regulated by von Hippel-Lindau protein and hypoxia inducible factor alpha. Tight interrelationships have been evidenced between hypoxia response pathways and circadian pathways. The dysregulation of the circadian clock circuitry is involved in carcinogenesis. The aim of our study was to evaluate the clock gene machinery in kidney cancer. METHODS: mRNA expression levels of the clock genes ARNTL1, ARNTL2, CLOCK, PER1, PER2, PER3, CRY1, CRY2, TIMELESS, TIPIN and CSNK1E and of the clock controlled gene SERPINE1 were evaluated by DNA microarray assays and by qRT-PCR in primary tumor and matched nontumorous tissue collected from a cohort of 11 consecutive kidney cancer patients. RESULTS: In kidney tumor tissue, we found down-regulation of PER2 (median=0.658, Q1-Q3=0.562-0.744, P<0.01), TIMELESS (median=0.705, Q1-Q3=0.299-1.330, P=0.04) and TIPIN (median=0.556, Q1 Q3=0.385-1.945, P=0.01), up-regulation of SERPINE1 (median=1.628, Q1-Q3=0.339 4.071, P=0.04), whereas the expression of ARNTL2 (median=0.605, Q1-Q3=0.318 1.738, P=0.74) and CSNK1E (median=0.927, Q1-Q3=0.612-2.321, P=0.33) did not differ. A statistically significant correlation was evidenced between mRNA levels of PER2 and CSNKIE (r=0.791, P<0.01), PER2 and TIPIN (r=0.729, P=0.01), PER2 and SERPINE1 (r=0.704, P=0.01), TIMELESS and TIPIN (r=0.605, P=0.04), TIMELESS and CSNKIE (r=0.637, P=0.03), TIPIN and CSNKIE (r=0.940, P<0.01). CONCLUSION: In kidney cancer, the circadian clock circuitry is deregulated and the altered expression of the clock genes might be involved in disease onset and progression. PMID- 22436652 TI - HDAC inhibitor M344 suppresses MCF-7 breast cancer cell proliferation. AB - Histone deacetylase (HDAC) inhibitors represent a novel class of drugs that selectively induce cell cycle arrest and apoptosis in transformed cells. This study examined, for the first time, the effects of the relatively new HDAC inhibitor, M344 [4-dimethylamino-N-(6-hydroxycarbamoylhexyl)-benzamide], on the proliferation of MCF-7 breast cancer cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] assays revealed significant concentration- and time dependent decreases in MCF-7 cell proliferation following treatment with M344 (1 100MUM). In contrast to the significant induction of p21(waf1/cip1) mRNA expression following treatment with M344 (10MUM) for 1 or 3 days, there was a significant decrease in p53 mRNA expression, although p53 protein levels were unchanged. Similar treatment with M344 also induced expression of the pro apoptotic genes, Puma and Bax, together with the morphological features of apoptosis, in MCF-7 cells. The results of this study reinforce previous findings indicating that HDAC inhibitors are an important group of oncostatic drugs, and show that M344 is a potent suppressor of breast cancer cell proliferation. PMID- 22436653 TI - Singing in groups for Parkinson's disease (SING-PD): a pilot study of group singing therapy for PD-related voice/speech disorders. AB - Parkinson's disease related speech and voice impairment have significant impact on quality of life measures. LSVT((r))LOUD voice and speech therapy (Lee Silverman Voice Therapy) has demonstrated scientific efficacy and clinical effectiveness, but musically based voice and speech therapy has been underexplored as a potentially useful method of rehabilitation. We undertook a pilot, open-label study of a group-based singing intervention, consisting of twelve 90-min weekly sessions led by a voice and speech therapist/singing instructor. The primary outcome measure of vocal loudness as measured by sound pressure level (SPL) at 50 cm during connected speech was not significantly different one week after the intervention or at 13 weeks after the intervention. A number of secondary measures reflecting pitch range, phonation time and maximum loudness also were unchanged. Voice related quality of life (VRQOL) and voice handicap index (VHI) also were unchanged. This study suggests that a group singing therapy intervention at this intensity and frequency does not result in significant improvement in objective and subject-rated measures of voice and speech impairment. PMID- 22436654 TI - Cortical involvement in a gait-related imagery task: comparison between Parkinson's disease and normal aging. AB - PURPOSE: We employed imaginary tasks to investigate the neurophysiology of gait in patients with Parkinson's disease (PD) using functional magnetic resonance imaging (fMRI). METHODS: Cortical activation of gait-related imagery was explored in 13 PD patients, 13 age-matched controls (Old), and 14 young volunteers (Young) using fMRI. The tasks included gait initiation, stepping over an obstacle and gait termination using an event-related design. Subjects watched a video clip showing an actor walking and imagined the walking process. RESULTS: At gait initiation, no significant difference could be found between PD and the Old controls. Activation in the visual related areas in the Old subjects was increased compared to the Young subjects. While imagining stepping over obstacles, the right dorsal premotor area (PMd), precentral, right inferior parietal lobule, and bilateral precuneus were more activated in PD compared to the Old. An extensive network of bilateral SMA, PMd, posterior parietal lobe and visual association areas was activated in the Old versus the Young subjects. At gait termination, visual related areas were noted when PD was compared to the Old. In contrast, increased activation in bilateral pre-SMA, PMd, ventral premotor area, precentral, posterior parietal lobes and visual association areas were activated in the Old when compared to the Young. CONCLUSIONS: Our study provides image based evidence for gait disturbance in PD patients and during normal aging. The compensatory cortical mechanism in the findings could be a background resource for further therapeutic interventions. PMID- 22436655 TI - The SNCA (A53T, A30P, E46K) and LRRK2 (G2019S) mutations are rare cause of Parkinson's disease in South Indian patients. PMID- 22436657 TI - Structural heart intervention. Beyond transcatheter valve therapy. PMID- 22436656 TI - The ARGA study with general practitioners: impact of medical education on asthma/rhinitis management. AB - AIM: To evaluate the impact of a medical education course (MEC) on the behaviour of general practitioners (GPs) to treat asthma and allergic rhinitis (AR). METHODS: Data on 1820 patients (mean age 41 yrs +/- 17 yrs) with asthma or AR were collected by 107 Italian GPs: 50% attended a MEC and 50% didn't (group B). The adherence for AR and asthma treatment was evaluated according to ARIA and GINA guidelines (GL). RESULTS: AR and asthma were diagnosed in 78% and 56% of patients; 34% had concomitant AR and asthma. Regardless of the MEC, the adherence to GL was significantly higher for AR than for asthma treatment (52 versus 19%). Group B GPs were more compliant to ARIA guidelines in the treatment of mild AR, whereas group A were more compliant in the treatment of moderate-severe AR; the adherence didn't differ between the groups for AR patients with comorbid asthma. Adherence to GINA GL for asthma treatment did not differ between GPs of groups A and B, independently from concomitant AR. Though insignificantly, group A were more compliant to GINA GL in the treatment of patients with only severe persistent asthma (63 versus 46%) as group B were for patients with severe persistent asthma and concomitant AR. CONCLUSIONS: GPs often tend to treat patients independently from GL. The impact of a single MEC did not improve adherence to GL in treating less severe AR and asthma patients, while there was a trend towards the opposite attitude in more severe AR patients without concomitant asthma. PMID- 22436658 TI - Meat texture and antioxidant status are improved when carnosic acid is included in the diet of fattening lambs. AB - Thirty-two Merino lambs fed barley straw and a concentrate alone (CONTROL group) or enriched with carnosic acid [0.6 g kg(-1) dry matter (DM), CARN006 group; 1.2 g kg(-1) DM, CARN012 group] or vitamin E (0.6 g kg(-1) DM, VITE006 group) were used to assess the effect of these antioxidant compounds on meat quality. After being fed the experimental diets for at least 5 weeks, the animals were slaughtered with the 25 kg intended body weight and the different muscles (longissimus lumborum; LL, gluteus medius; GM) were sliced and kept refrigerated under modified atmosphere packaging during 0, 7 and 14 days. The results indicate that carnosic acid seemed to be useful to delay lipid peroxidation in a medium colour-stable muscle such as GM, but this effect was lower than that observed when vitamin E was supplemented to fattening lambs. On the contrary, meat texture and protection against cholesterol oxidation were equally improved with both compounds. PMID- 22436659 TI - Meta-analysis of the comparison of the metabolic and contractile characteristics of two bovine muscles: longissimus thoracis and semitendinosus. AB - This study used the BIF-Beef data warehouse to determine whether semitendinosus (ST) was a muscle with a faster contraction speed and more glycolytic than longissimus thoracis (LT), regardless of the sex and breed of animals. With more than 500 animals from 7 breeds, we confirmed that LT was more oxidative than ST in males and females, but not in steers, and in all the breeds studied except Montbeliard. The LT had more slow oxidative (SO) and fewer fast oxido-glycolytic (FOG) and fast-glycolytic (FG) muscle fibres than the ST muscle, regardless of sex, in all breeds except Montbeliard and Holstein. SO proportion and the oxidative activity were negatively correlated to FG proportion and to the glycolytic activity. Similarly, FOG proportion was positively correlated to the glycolytic activity and negatively to FG proportion. However, these relationships are not consistent across sexes and breeds. In conclusion, differences in muscle types may be affected by sex or breed but to a moderate extent only. PMID- 22436660 TI - A human nose scoring system for boar taint and its relationship with androstenone and skatole. AB - A system for sensory evaluation of boar taint was used to evaluate boar taint in fat samples from 6574 entire males. The term "human nose scoring" has been used to describe this system. The samples from each boar were heated with a hot iron and three panelists assigned scores of 0 to 4. The reproducibility of HNS ranged from 0.19 to 0.32 reflecting natural variation in the ability of human beings to detect different odors. The correlations of HNS with androstenone ranged from 0.22 to 0.52, while those with skatole ranged from 0.31 to 0.89, suggesting that skatole is a better predictor of boar taint. Considering (1) the relationship of HNS with the boar taint compounds, (2) the ability of HNS to capture variation not accounted for by the boar taint compounds, (3) low estimation costs and (4) low time requirements, HNS can be used in large scale evaluations of boar taint. PMID- 22436661 TI - Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol. AB - BACKGROUND: The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. METHODS: ParvOryx01 is an open, non controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. DISCUSSION: This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01301430. PMID- 22436662 TI - Infant feeding practices among mildly wasted children: a retrospective study on Nias Island, Indonesia. AB - BACKGROUND: This study investigated the infant feeding practices of participating mothers who were recruited into a research project aimed at improving the nutritional status of mildly wasted children (< -1.0 to >= -1.5 Weight-for-Height Z-scores) aged >= 6 to < 60 months on Nias Island, Indonesia. METHODS: Cross sectional, questionnaire-based interview of mothers of the index children (n = 215) who were admitted to the community program for mildly wasted children in the study area. Four focus groups and twenty in-depth interviews were conducted to explore further information on infant feeding practices in the study area. RESULTS: Retrospective results indicated that 6% of the mothers never breastfed. Fifty two percent of mothers initiated breastfeeding within six hours of birth, but 17% discarded colostrum. Exclusive breastfeeding until 6 months of age was practiced by 12%. Seventy-four percent of the mothers offered supplementary liquids besides breast milk within the first 7 days of life, and 14% of infants received these supplementary liquids from 7 days onwards until 6 months of age. Moreover, 79% of the infants were given complementary foods (solid, semi-solid, or soft foods) before 6 months of age. About 9% of the children were breastfed at least two years. Less than one in five of the mildly wasted children (19%) were breastfed on admission to the community program. Qualitative assessments found that inappropriate infant feeding practices were strongly influenced by traditional beliefs of the mothers and paternal grandmothers in the study areas. CONCLUSION: Generally, suboptimal infant feeding was widely practiced among mothers of mildly wasted children in the study area on Nias Island, Indonesia. To promote breastfeeding practices among mothers on Nias Island, appropriate nutrition training for community workers and health-nutrition officers is needed to improve relevant counseling skills. In addition, encouraging public nutrition education that promotes breastfeeding, taking into account social-cultural factors such as the influence of paternal grandmothers on infant feeding practice, is needed. PMID- 22436663 TI - Children's ability to answer different types of questions. AB - Young children answer many questions every day. The extent to which they do this in an adult-like way - following Grice's Maxim of Quantity by providing the requested information, no more no less - has been studied very little. In an experiment, we found that two-, three- and four-year-old children are quite skilled at answering argument-focus questions and predicate-focus questions with intransitives in which their response requires only a single element. But predicate-focus questions for transitives - requiring both the predicate and the direct object - are difficult for children below four years of age. Even more difficult for children this young are sentence-focus questions such as "What's happening?", which give the child no anchor in given information around which to structure their answer. In addition, in a corpus study, we found that parents ask their children predicate-focus and sentence-focus questions very infrequently, thus giving children little experience with them. PMID- 22436664 TI - Processes controlling manganese distributions and associations in organic-rich freshwater aquatic systems: the example of Loch Bradan, Scotland. AB - Recent increases in manganese (Mn) concentrations in surface waters, including drinking water supplies, have triggered renewed interest in its geochemical behaviour in freshwater systems. This study, involving analysis of bottom sediments and ultrafiltered water (stream, loch and sediment porewater) samples, identified changes in aqueous phase speciation of Mn upon entering the loch waters and during its transit from the inflow to the outflow of Loch Bradan, a drinking water reservoir in SW Scotland. Diffusion out of the bottom sediments during calm periods or mixing of porewaters with loch water during resuspension events also released Mn into the overlying waters. Although 65% Mn was in colloidal form (3 kDa-0.2 MUm) in the main streamwater inflow at the western end, 57-66% was present in the <3 kDa fraction in the proximal loch waters, at least partly as a result of the release of Mn(2+) from the bottom sediments. Towards the outflow at the eastern end, however, the increase in the amount of Mn associated with large organic colloids (100 kDa-0.2 MUm) correlated with the speciation of Mn in the bottom water and the bottom sediment porewaters. While the inflow waters do have some impact upon Mn speciation at the western end of the loch, it appears that within-loch processes have a greater impact on Mn speciation near the outflow. These findings emphasise the importance of understanding the geochemical controls on Mn behaviour in aquatic systems: it is clear that although Mn may be present as truly dissolved Mn(2+) in some parts of the loch, it can also be associated to a significant extent (35-47%) with large organic colloids. These findings are important not only with respect to water treatment but also in terms of understanding the likely consequences of climatic change which may exacerbate losses of Mn from the bottom sediments. PMID- 22436665 TI - Good and bad fever. AB - Fever is considered a key actor of innate immunity aimed to fight infection. A new investigation reports an association of the use of antipyretic drugs with poorer outcome among patients with sepsis. In contrast, high temperature in non infectious intensive care patients is associated with higher mortality. PMID- 22436666 TI - CHROM2--a method to enhance the dynamic binding capacity, yield and productivity of a chromatographic column. AB - Therapeutic proteins are biotechnological products with a fast-growing market. Despite the rapid development of available process technologies, a bottleneck in production capacities is still present due to limitations in the associated downstream process, particularly within chromatographic purification steps. Membrane chromatography has been introduced as a promising alternative for conventional chromatography because it allows for higher throughputs but it does not deliver comparable dynamic binding capacities. To combine the strengths of the two technologies, the so-called "CHROM(2) concepts" are introduced, which merge conventional chromatography with membrane adsorption. The serial connection of a large conventional chromatographic column followed by a small membrane chromatography unit enables to combine the strength of both the individual technologies. The larger column delivers the required high binding capacity, whereas the rapid binding kinetics of membrane chromatography sharpens the breakthrough curve. Furthermore applied higher velocities do not result in poor breakthrough performance since the membrane chromatography is able to compensate for the poor column breakthrough performance. In comparison to column chromatography, the CHROM(2) setup exploits the full column capacity and delivers higher productivities and yields. PMID- 22436667 TI - Ion-exchange centrifugal partition chromatography: a methodological approach for peptide separation. AB - This article presents the scope and optimization strategies employed in ion exchange centrifugal partition chromatography (IXCPC). Both the weak and the strong modes were used to separate the constituents of a model mixture of dipeptides. Thus, the combined use of the quaternary biphasic solvent system, methyl-tert-butylether/acetonitrile/n-butanol/water (2:1:2:5, v/v) in the descending mode, of the lipophilic di(2-ethylhexyl)phosphoric acid (DEHPA) cation exchanger, and of two displacers: calcium chloride and hydrochloric acid, has proven to be efficient for the preparative separation of the model mixture of five dipeptides (GG, GY, AY, LV and LY, in the order they were collected). The separation was optimized by splitting the stationary phase into two sections that differed by their triethylamine concentration. Moreover, the chemical nature of the exchanger/analyte entities that were involved in the chromatographic process was determined by (31)P and (1)H DOSY NMR experiments. PMID- 22436668 TI - Simultaneous determination of fluoxetine and norfluoxetine enantiomers using isotope discrimination mass spectroscopy solution method and its application in the CYP2C9-mediated stereoselective interactions. AB - In this study, we developed an LC-MS/MS method based on an isotope discrimination mass spectroscopy solution (IDMSS) technology to simultaneously quantify enantiomers of fluoxetine (FLX) and norfluoxetine (NFLX) in a CYP2C9 incubation mixture. S-FLX and S-NFLX were labeled to form S-FLX-d5 and S-NFLX-d5. The method has several advantages over conventional chiral separation methods, in terms of the analysis period, resolution, and lower limit of quantification. The primary advantage of the method is that the two enantiomers can always be simultaneously determined by mass spectroscopy regardless if they are separated on column or not, owing to which it has high throughput and high sensitivity. The lower limit of quantification (amount on column) is 12.5 and 1.25 pg for FLX and NFLX, respectively. The retention time of FLX, NFLX, and the internal standard is only 1.9 min. The calibration curves were linear over the concentration range of 0.1 100 ng/ml for NFLX and 1-1000 ng/ml for FLX with an accepted reproducible (RSD<10%) and accurate (CV<10%). No significant kinetic isotope effect was found in the metabolism of S-FLX-d5 catalyzed by CYP2C9*1 and CYP2C9*2. The half maximal inhibitory concentration values between R-FLX and S-FLX catalyzed by CYP2C9*1 and CYP2C9*2 were determined in this study. The inhibitory effects of R- to S-FLX were stronger than those of S- to R-FLX in both CYP2C9*1 and CYP2C9*2. The IDMSS technology is useful for stereoselective study of chiral compound in vitro. PMID- 22436669 TI - One step solvent bar microextraction and derivatization followed by gas chromatography-mass spectrometry for the determination of pharmaceutically active compounds in drain water samples. AB - For the first time, a simple and novel one-step combined solvent bar microextraction with derivatization with GC-MS analysis, was developed for the determination of pharmaceutically active compounds (PhACs) in water samples. In the procedure, the derivatization reagent was added in the extraction solvent (solvent bar), so that the analytes could be extracted from the aqueous sample and simultaneously derivatized in the solvent bar to enhance their volatility and improve chromatographic performance. After extraction, the derivatized analytes in the extract were directly injected into a GC-MS system for analysis. Six PhACs including naproxen, ibuprofen, ketoprofen, propranolol, diclofenac, and alprenolol were used here to develop and evaluate the method. The parameters affecting the derivatization and extraction efficiency including derivatization time and temperature, the proportion of derivatization reagent, the type of organic solvent, extraction time, extraction temperature, pH of sample solution, effect of ionic strength, and sample agitation speed, were investigated in detail. Under the most favorable conditions, the method provided good limits of detection ranging from 0.006 to 0.022 MUg/L, linearity (from 0.1-50 to 0.2-50 MUg/L, depending on analytes) and repeatability of extractions (RSDs below 9.5%, n=5). The proposed method was compared to hollow fiber protected liquid-phase microextraction and solid-phase microextraction, and showed higher extraction efficiency and/or shorter extraction time. The proposed method was applied to the determination of six PhACs in drain water, and was demonstrated to be simple, fast and efficient. PMID- 22436670 TI - The National Adult Inpatient Survey conducted in the English National Health Service from 2002 to 2009: how have the data been used and what do we know as a result? AB - BACKGROUND: When it was initiated in 2001, England's national patient survey programme was one of the first in the world and has now been widely emulated in other healthcare systems. The aim of the survey programme was to make the National Health Service (NHS) more "patient centred" and more responsive to patient feedback. The national inpatient survey has now been running in England annually since 2002 gathering data from over 600,000 patients. The aim of this study is to investigate how the data have been used and to summarise what has been learned about patients' evaluation of care as a result. METHODS: Two independent researchers systematically gathered all research that included analyses of the English national adult inpatient survey data. Journals, databases and relevant websites were searched. Publications prior to 2002 were excluded. Articles were also identified following consultation with experts. All documents were then critically appraised by two co-authors both of whom have a background in statistical analysis. RESULTS: We found that the majority of the studies identified were reports produced by organisations contracted to gather the data or co-ordinate the data collection and used mainly descriptive statistics. A few articles used the survey data for evidence based reporting or linked the survey to other healthcare data. The patient's socio-demographic characteristics appeared to influence their evaluation of their care but characteristics of the workforce and the. At a national level, the results of the survey have been remarkably stable over time. Only in those areas where there have been co ordinated government-led campaigns, targets and incentives, have improvements been shown. The main findings of the review are that while the survey data have been used for different purposes they seem to have incited little academic interest. CONCLUSIONS: The national inpatient survey has been a useful resource for many authors and organisations but the full potential inherent in this large, longitudinal publicly available dataset about patients' experiences has not as yet been fully exploited.This review suggests that the presence of survey results alone is not enough to improve patients' experiences and further research is required to understand whether and how the survey can be best used to improve standards of care in the NHS. PMID- 22436671 TI - Temperature-dependent ideal strength and stacking fault energy of fcc Ni: a first principles study of shear deformation. AB - Variations of energy, stress, and magnetic moment of fcc Ni as a response to shear deformation and the associated ideal shear strength (tau(IS)), intrinsic (gamma(SF)) and unstable (gamma(US)) stacking fault energies have been studied in terms of first-principles calculations under both the alias and affine shear regimes within the {111} slip plane along the <112> and <110> directions. It is found that (i) the intrinsic stacking fault energy gamma(SF) is nearly independent of the shear deformation regimes used, albeit a slightly smaller value is predicted by pure shear (with relaxation) compared to the one from simple shear (without relaxation); (ii) the minimum ideal shear strength tau(IS) is obtained by pure alias shear of {111}<112>; and (iii) the dissociation of the 1/2[110] dislocation into two partial Shockley dislocations (1/6[211] + 1/6[121]) is observed under pure alias shear of {111}<110>. Based on the quasiharmonic approach from first-principles phonon calculations, the predicted gamma(SF) has been extended to finite temperatures. In particular, using a proposed quasistatic approach on the basis of the predicted volume versus temperature relation, the temperature dependence of tau(IS) is also obtained. Both the gamma(SF) and the tau(IS) of fcc Ni decrease with increasing temperature. The computed ideal shear strengths as well as the intrinsic and unstable stacking fault energies are in favorable accord with experiments and other predictions in the literature. PMID- 22436672 TI - What do we have against operations that lack mechanistic gratification? PMID- 22436673 TI - Proposal for a novel concept of a hybrid, minimally invasive cardiovascular surgical practice. AB - BACKGROUND: : Due to the increase in new Interventional cardiovascular technologies, traditional lines of division between the interventional and surgical aspects are expected to blur, with these procedures modified and adopted into cardiovascular surgical practice. This proposal introduces new concepts and visions for such new devices and procedures. METHODS: : I-Precision PlanningII Examples of Proposed DevicesIII-Examples of Proposed Procedures RESULTS: : Over the past few years there has been a growing sense of anxiety about new interventional devices in the cardiovascular surgical community. As physicians, our main task is to formulate simpler, more effective and safer solutions to clinical problems; and as surgeons, we "devise mechanical solutions to clinical problems." CONCLUSIONS: : Nowadays, there is an urgent need for the cardiovascular surgical community to rediscover and reinvent itself. We should see these new innovations as exciting new ideas and tools that we can "modify, simplify and apply" to revitalize our own practice. PMID- 22436674 TI - Adjunctive atrial fibrillation therapy with off-pump coronary artery bypass grafting: standard of care? AB - OBJECTIVES: : To validate the safety and applicability of a previously unreported innovative technique: bipolar epicardial radiofrequency pulmonary vein ablation for the treatment of atrial fibrillation (AF) in conjunction with off-pump coronary artery bypass surgery. METHODS: : After the completion of off-pump coronary artery bypass grafting (OPCAB) via sternotomy, patients underwent epicardial pulmonary vein ablation using a bipolar radiofrequency clamp placed on the left atrial cuff. The left atrial appendage was removed or excluded in all patients. RESULTS: : Fifteen patients (aged 59-81 years) were treated and reviewed. An average of 2.8 +/- 1 grafts were performed per patient; all patients received left internal mammary artery grafts. All sets of pulmonary veins were encircled successfully and ablated. Four patients had additional lesions placed. No patient had pulmonary vein injury. There were no reoperations for bleeding and no mortality. Preoperatively, AF was continuous in 4 patients and intermittent in 11; 10 patients were taking Coumadin preoperatively and 11 were taking antiarrhythmic drugs (AAD). At the follow-up evaluation (7.6 +/- 4.4 months; range 1-16 months), 12 patients (80%) are in sinus rhythm (100% in the intermittent AF group, 25% in the continuous AF group); Coumadin has been discontinued in 5 of 10 patients (50% reduction) and AAD have been discontinued in 7 of 11 patients (74% reduction). CONCLUSIONS: : Bipolar radiofrequency epicardial pulmonary vein ablation can be safely and reproducibly used for the treatment of AF in conjunction with OPCAB. Patients with intermittent AF should be strongly considered for adjunctive treatment at the time of OPCAB. PMID- 22436675 TI - Concomitant beating-heart mitral valve surgery and coronary artery bypass in patients with compromised ventricular function. AB - BACKGROUND: : Surgical repair of mitral valve disease and concomitant coronary artery occlusive disease has high operative risk. Myocardial protection for protracted, complicated procedures is seminal to the overall operative outcome; specifically, preservation of left ventricular function. METHODS: The authors conducted a retrospective review of 25 patients undergoing combined mitral valve repair/replacement (MVR) and coronary artery bypass surgery (CABG) using the beating-heart technique at the Miller/University of Miami School of Medicine. The CABG was performed without cardiopulmonary bypass support. During the mitral valve surgery the perfusion pressure was maintained at 80-90 mm Hg and the systemic temperature at 35-36oC. The aorta was not cross-clamped. RESULTS: : Twenty-five patients underwent MVR/CABG, including 7 patients with acute myocardial infarction. Preoperative echocardiograms revealed a mean ejection fraction (EF) of 41 +/- 4.5%. One patient required a preoperative intraarterial balloon pump. An average of 2.12 +/- 0.9 grafts and a total of 10 mitral valve repairs were performed. The average length of stay in the intensive care unit was 14 +/- 1.8 days, and average hospitalization time was 23 +/- 3. The mean postoperative EF was 41 +/- 4.5%. The mortality in this patient group was 12 % (3/25) with a morbidity rate of 52% (13/25). CONCLUSIONS: : The data suggest that the technique is safe and reproducible, and that it potentially has a short-term benefit on left ventricular function. Therefore, this particular technique may be efficacious in patients with compromised left ventricular function requiring a combined MVR/CABG. PMID- 22436676 TI - External reshaping of the left ventricle in off-pump surgery. AB - BACKGROUND: : Dyskinetic areas of the lateral and inferior left ventricular (LV) wall are frequently encountered in patients with coronary artery disease. In clinical practice, all of the techniques described for the restoration of shape and function of the LV require cardiopulmonary bypass. A new technique of LV external reshaping that aims to obtain a near-normal ventricular conical shape is described. This technique is performed during an off-pump coronary artery bypass graft (CABG) operation. It is used mainly on the inferior and lateral walls of the ventricle, but also on the anterolateral wall when warranted. This technique can be considered an alternative to classic aneurysmectomy in high-risk cases. METHODS: : All patients underwent total arterial revascularization without aortic manipulation. Intraoperative transesophageal echocardiography was used in all cases to define the dilated akinetic/dyskinetic area. This area was effectively plicated using interrupted mattress sutures reinforced with Teflon felt or pericardial strips. This technique allows near normalization of the geometry of the ventricle and LV end-diastolic volume reduction. In cases of preexisting mitral regurgitation (MR), a reduction of the MR was observed after lateral wall restoration. From September 2002 to April 2005, the external reshaping technique was applied on 56 cases among 949 off-pump CABG cases (5.9%). A detailed transthoracic echocardiogram was obtained preoperatively. The mean ejection fraction of all enrolled patients was 31.2 +/- 7%. The location of the plication was: lateral wall in 22, inferior wall in 16, and anterolateral wall in 18. The average number of coronary anastomoses was 2.6. Twelve patients were found to have 2-3+ MR. All patients were followed up during a period of 35 months. RESULTS: : One patient died due to severe right ventricular dysfunction. Seven patients developed atrial fibrillation, and one had ventricular tachycardia. During the follow-up period, we observed a reduction of left ventricular end diastolic diameter and a parallel augmentation of ejection fraction (mean 42.2 +/ 4%). The ventricular cavity's architecture was normalized. Among the 12 patients with MR, an improvement of regurgitation was noted in 10 (from 2-3+ to 1-2+). One patient died during the follow-up period, and 1 patient required reoperation due to persistent severe MR. CONCLUSIONS: : The external reshaping of the LV during beating heart surgery is technically feasible, has promising results, and can be performed without major complications. PMID- 22436677 TI - Aortic valve replacement through a mini lateral thoracotomy with high thoracic epidural anesthesia. AB - BACKGROUND: : Minimally invasive aortic valve surgery is usually performed through a right parasternal incision or a modification of partial sternotomy. We explored the feasibility of using a video-assisted small right lateral thoracotomy (RLT) to approach the aortic valve. METHODS: : From August 2003 to December 2004, 12 patients with aortic stenosis (9) or regurgitation (3) underwent an aortic valve replacement through an 8 cm RLT in the 4th intercostal space. There were 4 men and 8 women with a mean age of 61 years (range 30-79 years). Nine mechanical and 3 biologic prostheses were implanted. Endotracheal narcosis was combined with high thoracic epidural anesthesia. Transesophageal echocardiographic monitoring was performed in all cases. Cannulation was done via the right femoral artery and vein and right jugular vein. The video-assisted operation was performed in moderate hypothermia (30 degrees C) and in cardioplegic arrest. Transthoracic aortic clamping was used in all cases. RESULTS: : Mean operation, perfusion, and clamping times were 223 minutes, 132 minutes, and 73 minutes, respectively. There was no mortality. One patient required conversion to sternotomy due to discovery of a calcium fragment entrapped in a mechanical prosthesis. One patient developed a groin seroma that was treated surgically. All patients, except one were extubated in the operative room and transferred to the intermediate care unit after 6 hours; all had an uneventful recovery. CONCLUSIONS: : Aortic valve replacement through an RLT is feasible and safe. Operative time, perfusion, and cross-clamping times are only marginally longer than a conventional operation, and recovery is rapid. PMID- 22436678 TI - Single venous return for mitral valve operations. AB - OBJECTIVE: : Most cardiac surgeons routinely perform bicaval venous cannulation for mitral valve operations. We describe the technique and advantage of a single venous cannulation strategy. METHODS/RESULTS: : Single venous cannulation with a 29-French small-bore cannula (facilitated by vacuum-assisted venous drainage) yields reliable decompression of the right heart and affords outstanding exposure of the mitral valve. CONCLUSIONS: : We recommend and use this technique for all mitral valve operations not requiring opening the right atrium. PMID- 22436679 TI - Extraanatomic Bypass for Recurrent Aortic Coarctation Involving the Arch and Replacement of the Ascending Aorta via Sternotomy. AB - A suction device, currently used to lift the heart in off-pump coronary surgery, was used to facilitate an extraanatomic bypass grafting procedure in a patient with recoarctation of the aorta, hypoplasia of the aortic arch, and dilatation of the ascending aorta. PMID- 22436680 TI - Thoracoscopic lobectomy with the da vinci surgical system. AB - Thoracoscopic upper lobectomy has been performed with the da Vinci surgical system in human cadavers. A minithoracotomy and two additional thoraco ports provided access to the thoracic cavity. An auxiliary port was used for both retraction of the lung and suction. The pulmonary vessels were ligated by robotic instruments, and the bronchi were divided after suturing robotically or with automatic staplers. A standard lymph node dissection was performed. The current da Vinci surgical system provided superior optics and enhanced dexterity. The application of the system for minimally invasive lobectomy may add benefits for both surgeon and patients. PMID- 22436681 TI - Video-assisted thoracoscopic splanchnicectomy for pain control in chronic pancreatitis. AB - BACKGROUND: : Management of pain in patients with chronic pancreatitis can be frustrating. The authors retrospectively evaluated their experience with video assisted thoracoscopic surgery (VATS) for pain secondary to chronic pancreatitis. METHODS: : From September 1999 to August 2004, 16 patients underwent VATS for pain associated with chronic pancreatitis. Data were collected retrospectively. RESULTS: : Eight patients were female and 8 were male. Their ages ranged from 17 to 81 years, with a mean age of 40 years. There were 22 VATS splanchnicectomies performed: 7 right, 10 left, and 5 bilateral. The average operative time was 75 minutes for right VATS splanchnicectomy, 86 minutes for left VATS splanchnicectomy, and 88 minutes for bilateral VATS splanchnicectomies. The average length of stay (LOS) was 2.6 days after right VATS splanchnicectomy, 2.2 days after left VATS splanchnicectomy, and 1 day after bilateral VATS splanchnicectomies. Two cases were nonelective and not included in the determination of LOS. No postoperative complications occurred in any of the patients admitted for elective operations. Postoperative mortality was zero. Complete resolution of pain occurred in 4 patients (25%): 1 right splanchnicectomy, 1 left splanchnicectomy, and 2 bilateral splanchnicectomies. Total pancreatectomy with islet cell transplant was subsequently performed in 5 patients (31%), who improved but then had recurrent pain. Continued chronic pain managed with nonsteroidal antiinflammatory drugs and narcotic analgesics was the result in 7 patients (44%) CONCLUSIONS: : Video-assisted thoracoscopic splanchnicectomy surgery may alleviate pain in patients with chronic pancreatitis. It can be performed with minimal morbidity and mortality, and has been safe and useful in the workup, evaluation, and management of pain associated with chronic pancreatitis. PMID- 22436682 TI - International society for minimally invasive cardiothoracic surgery consensus statements: definitions and terms of reference. PMID- 22436683 TI - Program Outline: Subject to change, Updated 4/24/2006. PMID- 22436684 TI - The advanced cancer patient experience of undertaking meaning and purpose (MaP) therapy. AB - OBJECTIVE: The objective of this study was to describe the experience of undertaking meaning and purpose (MaP) therapy for patients with advanced cancer, with an aim of refining therapeutic processes involved prior to pilot testing. Specifically, we were interested in examining the themes arising from participation in the intervention in relation to our therapeutic goals, and how acceptable both the number of sessions and processes used were. METHOD: A convenience sample of people living with advanced cancer was recruited to participate in this process, resulting in 24 therapy sessions for analysis. RESULTS: A thematic analysis of each session illustrated that the process of MaP therapy is one that encourages reflection, offers insights, and can be confrontational, but can also allow participants to "shift" their perspective and focus onto meaningful goals. Results illustrate how the therapist creates a therapeutic frame that holds up a poignant portrayal of the meaning of life lived, and mirrors this to the patient, such that they grasp its rich texture. Participants' descriptions showed how they were buoyed forward as a result, with renewed vigor and enthusiasm, despite their illness and any physical restrictions that it imposed. SIGNIFICANCE OF RESULTS: A planned pilot test of this intervention will enable us to determine potential effect sizes of this therapy in reducing distress and increasing meaning prior to a full randomized controlled trial. Understanding the processes involved and the experiences of participation in meaning-based therapies is crucial to the future strength of this area of psychotherapy. PMID- 22436685 TI - [An herpes zoster with behavior disorder]. PMID- 22436686 TI - Biofunctionalization of nanoparticle assisted mass spectrometry as biosensors for rapid detection of plant associated bacteria. AB - This study is based on the application of matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) as biosensor to detect the plant associated bacteria (PAB) isolates from rhizospheric soil and root. The rapid bacterial detection via on particle ionization/enrichment technique using IgG functionalized Pt NPs (IgG-Pt NPs) assisted MALDI-TOF MS was successfully used to explore two PAB isolates, namely, Bacillus thuringiensis and B. subtilis from rhizospheric soil and roots of carrot plant. When these bacteria are used as bioformulations in agricultural as well as biotechnological applications, the plant growth promotion of economic crops was observed especially when the crops grow in less fertilize soil regions. This study proved that even at low concentrations, bacteria can also be directly detected without morphological, molecular and biochemical test. The current applied technique is simple, rapid and highly sensitive. Besides, it could be widely used for the detection of beneficially important PAB isolates in environmental samples. PMID- 22436687 TI - Self-stacked submersible microbial fuel cell (SSMFC) for improved remote power generation from lake sediments. AB - Electric energy can be harvested from aquatic sediments by utilizing microbial fuel cells (MFCs). A main challenge of this application is the limited voltage output. In this study, an innovative self-stacked submersible MFC (SSMFC) was developed to improve the voltage generation from lake sediments. The SSMFC successfully produced a maximum power density of 294 mW/m(2) and had an open circuit voltage (OCV) of 1.12 V. However, voltage reversal was observed in one cell at high current density. Investigation on the cause for voltage reversal revealed that voltage reversal was occurring only when low external resistance (<= 400Omega in this study) was applied. In addition, the internal resistance and OCV were the most important parameters for predicting which cell unit had the highest probability to undergo voltage reversal. Use of a capacitor was found to be an effective way to prevent voltage reversal and at the same time store power. These results provide new insight into the development of effective MFC system, capable of extracting energy and promoting bioremediation of organic pollutants from sediments. PMID- 22436688 TI - Comparing lower lumbar kinematics in cyclists with low back pain (flexion pattern) versus asymptomatic controls--field study using a wireless posture monitoring system. AB - The aim of this study was to examine lower lumbar kinematics in cyclists with and without non-specific chronic low back pain (NS-CLBP) during a cross-sectional cycling field study. Although LBP is a common problem among cyclists, studies investigating the causes of LBP during cycling are scarce and are mainly focussed on geometric bike-related variables. Until now no cycling field studies have investigated the relationship between maladaptive lumbar kinematics and LBP during cycling. Eight cyclists with NS-CLBP classified as having a 'Flexion Pattern' (FP) disorder and nine age- and gender-matched asymptomatic cyclists were tested. Subjects performed a 2 h outdoor cycling task on their personal race bike. Lower lumbar kinematics was measured with the BodyGuardTM monitoring system. Pain intensity during and after cycling was measured using a numerical pain rating scale. The NS-CLBP (FP) subjects were significantly more flexed at the lower lumbar spine during cycling compared to healthy controls (p = 0.018), and reported a significant increase in pain over the 2 h of cycling (p < 0.001). One-way repeated measures ANOVA revealed a significant main effect for group (p = 0.035, F = 5.546) which remained just significant when adding saddle angle as a covariate (p = 0.05, F = 4.747). The difference in posture between groups did not change over time. These findings suggest that a subgroup of cyclists with NS-CLBP (FP) demonstrate an underlying maladaptive motor control pattern resulting in greater lower lumbar flexion during cycling which is related to a significant increase in pain. PMID- 22436689 TI - Calcific aortic valve stenosis: Immunohistochemical analysis of inflammatory infiltrate. AB - Calcific aortic valve disease is considered a form of atherosclerosis and, like the latter, possibly of inflammatory origin. The aim of our work was to study the pattern of cellular infiltrate in calcific aortic valve stenosis (CAS). Fifteen operatively excised calcified aortic valves were examined by histology and immunohistochemistry (CD20, CD79alpha, CD3, CD4, CD8, CD68, CD138, CD117, BJK, BJL, IgA, IgD, IgG, IgG4 and IgM). The findings revealed that in CAS, there were chronic inflammatory features with infiltrates comprising lymphocytes, polyclonal plasma cells, histiocytes and mast cells. In T-lymphocytes, CD4 prevailed over CD8. In B-lymphocytes, there was a slight preponderance of CD20 over CD79alpha. The BJL (lambda)-positive plasma cells prevailed over the BJK (kappa) ones. The CD138-positive plasma cells comprised 24% IgA-, 20% IgD-, 41% IgG- (including 11% of IgG4-) and 15% IgM-positive cells. CAS did not fulfill the criteria of the recently described clinicopathological entity IgG4-related sclerosing systemic disease. The inflammatory process was the same in both subsets of CAS - those with trileaflet (normally formed) valves and those with congenitally bicuspid valves. PMID- 22436690 TI - Temperature-dependent structures of proton-conducting Ba(Zr(0.8 x)Ce(x)Y(0.2))O(2.9) ceramics by Raman scattering and x-ray diffraction. AB - In situ temperature-dependent micro-Raman scattering and x-ray diffraction have been performed to study atomic vibration, lattice parameter and structural transition of proton-conducting Ba(Zr(0.8-x)Ce(x)Y(0.2))O(2.9) (BZCY) ceramics (x = 0.0-0.8) synthesized by the glycine-nitrate combustion process. The Raman vibrations have been identified and their frequencies increase with decreasing x as the heavier Ce(4+) ions are replaced by Zr(4+) ions. The main Raman vibrations of Ba(Ce(0.8)Y (0.2))O(2.9) appear near 305, 332, 352, 440 and 635 cm(-1). The X O ( X=Ce, Zr, Y) stretching modes are sensitive to the variation of Ce/Zr ratio. A rhombohedral-cubic structural transition was observed for x = 0.5-0.8, in which the transition shifts toward higher temperature as cerium increases, except for Ba(Ce(0.8)Y(0.2))O(2.9). A minor monoclinic phase possibly coexists in the rhombohedral matrix for x = 0.5-0.8. The lower-cerium BZCYs (x = 0.0-0.4) ceramics do not exhibit any transition in the region of 20-900 degrees C, indicating a cubic phase at and above room temperature. PMID- 22436691 TI - The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes. AB - BACKGROUND: The SR proteins comprise a family of essential, structurally related RNA binding proteins. The complexity of their RNA targets and specificity of RNA recognition in vivo is not well understood. Here we use iCLIP to globally analyze and compare the RNA binding properties of two SR proteins, SRSF3 and SRSF4, in murine cells. RESULTS: SRSF3 and SRSF4 binding sites mapped to largely non overlapping target genes, and in vivo consensus binding motifs were distinct. Interactions with intronless and intron-containing mRNAs as well as non-coding RNAs were detected. Surprisingly, both SR proteins bound to the 3' ends of the majority of intronless histone transcripts, implicating SRSF3 and SRSF4 in histone mRNA metabolism. In contrast, SRSF3 but not SRSF4 specifically bound transcripts encoding numerous RNA binding proteins. Remarkably, SRSF3 was shown to modulate alternative splicing of its own as well as three other transcripts encoding SR proteins. These SRSF3-mediated splicing events led to downregulation of heterologous SR proteins via nonsense-mediated decay. CONCLUSIONS: SRSF3 and SRSF4 display unique RNA binding properties underlying diverse cellular regulatory mechanisms, with shared as well as unique coding and non-coding targets. Importantly, CLIP analysis led to the discovery that SRSF3 cross regulates the expression of other SR protein family members. PMID- 22436692 TI - The farming population in Ireland: mortality trends during the 'Celtic Tiger' years. AB - BACKGROUND: Although the Irish farming population is a significant occupational group, analysis of their mortality patterns is limited. This study compared mortality trends with other occupational groups and assessed the impact of socio economic factors. METHODS: Population and mortality data (2000-06) were obtained to calculate standardized mortality ratios (SMRs) by cause of death and matched with socio-economic data. The extent to which variation in mortality was explained by variations in the socio-economic data was determined using multiple regression. RESULTS: Farmers and agricultural workers experienced the highest levels of mortality for all causes of death (2000-06). Farmers are 5.14 times more likely and agricultural workers are 7.35 times more likely to die from any cause of death than the lowest risk group. Circulatory disease is a significant cause of mortality among farmers [SMR = 215.91, 95% confidence interval (CI) = 201.83-229.98]. Other significant causes include cancers (SMR = 156.60, CI = 146.73-166.48) and injuries and poisonings (SMR = 149.69, CI = 135.44-163.93). Agricultural workers have similar mortality trends: circulatory disease (SMR = 226.27; CI = 192.45-260.08), cancers (SMR = 221.44; CI = 193.88-249.00), and injuries and poisonings (SMR = 353.90; CI = 302.48-405.32). From 2000 to 2006, SMRs increased incrementally. Multiple regression identified farm size and income poverty risk as predictors of mortality. CONCLUSION: Irish farmers and agricultural workers have experienced a reversal of mortality trends compared to the 1980s and 1990 s. Policies should target them as a high-risk group. PMID- 22436693 TI - Developmental programming of neonatal pancreatic beta-cells by a maternal low protein diet in rats involves a switch from proliferation to differentiation. AB - Maternal low-protein diets (LP) impair pancreatic beta-cell development, resulting in later-life failure and susceptibility to type 2 diabetes (T2D). We hypothesized that intrauterine and/or postnatal developmental programming seen in this situation involve altered beta-cell structure and relative time course of expression of genes critical to beta-cell differentiation and growth. Pregnant Wistar rats were fed either control (C) 20% or restricted (R) 6% protein diets during pregnancy (1st letter) and/or lactation (2nd letter) in four groups: CC, RR, RC, and CR. At postnatal days 7 and 21, we measured male offspring beta-cell fraction, mass, proliferation, aggregate number, and size as well as mRNA level for 13 key genes regulating beta-cell development and function in isolated islets. Compared with CC, pre- and postnatal LP (RR) decreased beta-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Isl1, Rfx6, and Slc2a2 mRNA levels. LP only in pregnancy (RC) also decreased beta-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Rfx6, and Ins mRNA levels. Postnatal LP offspring (CR) showed decreased beta-cell mass but increased beta-cell fraction, aggregate number, and Hnf1a, Hnf4a, Rfx6, and Slc2a2 mRNA levels. We conclude that LP in pregnancy sets the trajectory of postnatal beta-cell growth and differentiation, whereas LP in lactation has smaller effects. We propose that LP promotes differentiation through upregulation of transcription factors that stimulate differentiation at the expense of proliferation. This results in a decreased beta cell reserve, which can contribute to later-life predisposition to T2D. PMID- 22436694 TI - Fine-tuning metabolism--how products of contraction regulate skeletal muscle adaptation. PMID- 22436695 TI - Coordinate regulation of heterogeneous nuclear ribonucleoprotein dynamics by steroid hormones in the human fallopian tube and endometrium in vivo and in vitro. AB - Heterogeneous nuclear ribonucleoproteins (hnRNPs), which are chromatin-associated RNA-binding proteins, participate in mRNA stability, transport, intracellular localization, and translation by acting as transacting factors. Several studies have shown that steroid hormones can regulate hnRNP expression. However, to date, the regulation of hnRNPs and their interactions with steroid hormone signaling in fallopian tubes and endometrium are not fully elucidated. In the present study, we determined whether hnRNP expression is regulated during the menstrual cycle and correlates with estrogen receptor (ER) and progesterone receptor (PR) levels in human fallopian tubes in vivo. Because of the limited availability of human tubal tissues for the research, we also explored the mechanisms of hnRNP regulation in human endometrium in vitro. Fallopian tissue was obtained from patients in the early, late, and postovulatory phases and the midsecretory phase and endometrial tissue from premenopausal and postmenopausal women undergoing hysterectomy. We measured expression of hnRNPs and assessed their intracellular localization and interactions with ERs and PRs. We also determined the effects of human chorionic gonadotropin, 17beta-estradiol (E(2)), and progesterone (P(4)) on hnRNP expression. In fallopian tubes, mRNA and protein levels of hnRNP A1, AB, D, G, H, and U changed dynamically during ovulation and in the midsecretory phase. In coimmunolocation and coimmunoprecipitation experiments, hnRNPs interacted with each other and with ERs and PRs in fallopian tubes. After treatment with E(2) and/or P(4) to activate ERs and PRs, hnRNP A1, AB, D, G, and U proteins displayed overlapping but distinct patterns of regulation in the endometrium in vitro. Our findings expand the physiological repertoire of hnRNPs in human fallopian tubes and endometrium and suggest that steroid hormones regulate different hnRNPs directly by interacting with ERs and/or PRs or indirectly by binding other hnRNPs. Both actions may contribute to regulation of gene transcription. PMID- 22436697 TI - Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARgamma in 3T3-L1 cells. AB - Here, we show that Elovl3 (elongation of very long-chain fatty acids 3) was involved in the regulation of the progression of adipogenesis through activation of peroxisome proliferator-activated receptor (PPAR)gamma in mouse adipocytic 3T3 L1 cells. The expression of the Elovl3 gene increased during adipogenesis, the expression pattern of which was similar to that of the PPARgamma gene. Troglitazone, a PPARgamma agonist, enhanced Elovl3 expression in adipocytes, as it did that of other PPARgamma target genes. Promoter-reporter analysis demonstrated that three PPAR-responsive elements in the Elovl3 gene promoter had the potential to activate its expression in 3T3-L1 cells. Moreover, a chromatin immunoprecipitation assay revealed that PPARgamma bound these PPAR-responsive elements of the Elovl3 promoter. When the Elovl3 mRNA level was suppressed by its siRNAs, the level of intracellular triglycerides was significantly decreased, and the expression levels of adipogenic, lipolytic, and lipogenic genes were also repressed. In a mammalian two-hybrid assay, C18:1 and C20:1 very long-chain fatty acids (VLCFAs), which are the products of Elovl3 and activated PPARgamma function. In addition, these same VLCFAs could prevent the Elovl3 siRNA-mediated suppression of adipogenesis by enhancing the expression of adipogenic, lipolytic, and lipogenic genes in adipocytes. Moreover, this VLCFAs-mediated activation was repressed by a PPARgamma antagonist. These results indicate that the expression of the Elovl3 gene was activated by PPARgamma during adipogenesis. Elovl3 produced C18:1 and C20:1 VLCFAs acted as agonists of PPARgamma in 3T3-L1 cells. Thus, the Elovl3-PPARgamma cascade is a novel regulatory circuit for the regulation of adipogenesis through improvement of PPARgamma function in adipocytes. PMID- 22436696 TI - NAD(+)/NADH and skeletal muscle mitochondrial adaptations to exercise. AB - The pyridine nucleotides, NAD(+) and NADH, are coenzymes that provide oxidoreductive power for the generation of ATP by mitochondria. In skeletal muscle, exercise perturbs the levels of NAD(+), NADH, and consequently, the NAD(+)/NADH ratio, and initial research in this area focused on the contribution of redox control to ATP production. More recently, numerous signaling pathways that are sensitive to perturbations in NAD(+)(H) have come to the fore, as has an appreciation for the potential importance of compartmentation of NAD(+)(H) metabolism and its subsequent effects on various signaling pathways. These pathways, which include the sirtuin (SIRT) proteins SIRT1 and SIRT3, the poly(ADP ribose) polymerase (PARP) proteins PARP1 and PARP2, and COOH-terminal binding protein (CtBP), are of particular interest because they potentially link changes in cellular redox state to both immediate, metabolic-related changes and transcriptional adaptations to exercise. In this review, we discuss what is known, and not known, about the contribution of NAD(+)(H) metabolism and these aforementioned proteins to mitochondrial adaptations to acute and chronic endurance exercise. PMID- 22436698 TI - Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons. AB - Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K(+) currents. A potential K(+) current is the M-current, a noninactivating, subthreshold outward K(+) current. Previously, we found that M current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond to energy states, we hypothesized that fasting may alter the M-current and/or its modulation by serotonergic input to POMC neurons. Using visualized-patch recording in neurons from fed male enhanced green fluorescent protein-POMC transgenic mice, we established that POMC neurons expressed a robust M-current (102.1 +/- 6.7 pA) that was antagonized by the selective KCNQ channel blocker XE-991 (40 MUM). However, the XE-991-sensitive current in POMC neurons did not differ between fed and fasted states. To determine if serotonin suppresses the M-current via the 5-HT(2C) receptor, we examined the effects of the 5-HT(2A)/5-HT(2C) receptor agonist 2,5-dimethoxy-4 iodoamphetamine (DOI) on the M-current. Indeed, DOI attenuated the M-current by 34.5 +/- 6.9% and 42.0 +/- 5.3% in POMC neurons from fed and fasted male mice, respectively. In addition, the 5-HT(1B)/5-HT(2C) receptor agonist m chlorophenylpiperazine attenuated the M-current by 42.4 +/- 5.4% in POMC neurons from fed male mice. Moreover, the selective 5-HT(2C) receptor antagonist RS 102221 abrogated the actions of DOI in suppressing the M-current. Collectively, these data suggest that although M-current expression does not differ between fed and fasted states in POMC neurons, serotonin inhibits the M-current via activation of 5-HT(2C) receptors to increase POMC neuronal excitability and, subsequently, reduce food intake. PMID- 22436699 TI - Chronic high-carbohydrate, high-fat feeding in rats induces reversible metabolic, cardiovascular, and liver changes. AB - Age-related physiological changes develop at the same time as the increase in metabolic syndrome in humans after young adulthood. There is a paucity of data in models mimicking chronic diet-induced changes in human middle age and interventions to reverse these changes. This study measured the changes during chronic consumption of a high-carbohydrate (as cornstarch), low-fat (C) diet and a high-carbohydrate (as fructose and sucrose), high-fat (H) diet in rats for 32 wk. C diet feeding induced changes without metabolic syndrome, such as disproportionate increases in total body lean and fat mass, reduced bone mineral content, cardiovascular remodeling with increased systolic blood pressure, left ventricular and arterial stiffness, and increased plasma markers of liver injury. H diet feeding induced visceral adiposity with reduced lean mass, increased lipid infiltration in the skeletal muscle, impaired glucose and insulin tolerance, cardiovascular remodeling, hepatic steatosis, and increased infiltration of inflammatory cells in the heart and the liver. Chia seed supplementation for 24 wk attenuated most structural and functional modifications induced by age or H diet, including increased whole body lean mass and lipid redistribution from the abdominal area, and normalized the chronic low-grade inflammation induced by H diet feeding; these effects may be mediated by increased metabolism of anti inflammatory n-3 fatty acids from chia seed. These results suggest that chronic H diet feeding for 32 wk mimics the diet-induced cardiovascular and metabolic changes in middle age and that chia seed may serve as an alternative dietary strategy in the management of these changes. PMID- 22436700 TI - Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. AB - Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml.day(-1).rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFalpha, osteoclast marker receptor activator of nuclear factor-kappaB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss. PMID- 22436701 TI - A role for aberrant protein palmitoylation in FFA-induced ER stress and beta-cell death. AB - Exposure of insulin-producing cells to elevated levels of the free fatty acid (FFA) palmitate results in the loss of beta-cell function and induction of apoptosis. The induction of endoplasmic reticulum (ER) stress is one mechanism proposed to be responsible for the loss of beta-cell viability in response to palmitate treatment; however, the pathways responsible for the induction of ER stress by palmitate have yet to be determined. Protein palmitoylation is a major posttranslational modification that regulates protein localization, stability, and activity. Defects in, or dysregulation of, protein palmitoylation could be one mechanism by which palmitate may induce ER stress in beta-cells. The purpose of this study was to evaluate the hypothesis that palmitate-induced ER stress and beta-cell toxicity are mediated by excess or aberrant protein palmitoylation. In a concentration-dependent fashion, palmitate treatment of RINm5F cells results in a loss of viability. Similar to palmitate, stearate also induces a concentration related loss of RINm5F cell viability, while the monounsaturated fatty acids, such as palmoleate and oleate, are not toxic to RINm5F cells. 2-Bromopalmitate (2BrP), a classical inhibitor of protein palmitoylation that has been extensively used as an inhibitor of G protein-coupled receptor signaling, attenuates palmitate-induced RINm5F cell death in a concentration-dependent manner. The protective effects of 2BrP are associated with the inhibition of [(3)H]palmitate incorporation into RINm5F cell protein. Furthermore, 2BrP does not inhibit, but appears to enhance, the oxidation of palmitate. The induction of ER stress in response to palmitate treatment and the activation of caspase activity are attenuated by 2BrP. Consistent with protective effects on insulinoma cells, 2BrP also attenuates the inhibitory actions of prolonged palmitate treatment on insulin secretion by isolated rat islets. These studies support a role for aberrant protein palmitoylation as a mechanism by which palmitate enhances ER stress activation and causes the loss of insulinoma cell viability. PMID- 22436703 TI - Surgical innovation in the information age: the heavy burden of great potential. PMID- 22436702 TI - Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells. AB - BACKGROUND: The leading cause of death for patients suffering from diabetes is macrovascular disease. Endothelial dysfunction is often observed in type 2 diabetic patients and it is considered to be an important early event in the pathogenesis of atherogenesis and cardiovascular disease. Many drugs are clinically applied to treat diabetic patients. However, little is known whether these agents directly interfere with endothelial cell proliferation and apoptosis. This study therefore aimed to investigate how anti-diabetic and cardioprotective agents affect human coronary artery endothelial cells (HCAECs). METHODS: The effect of anti-diabetic and cardioprotective agents on HCAEC viability, proliferation and apoptosis was studied. Viability was assessed using Trypan blue exclusion; proliferation in 5 mM and 11 mM of glucose was analyzed using [3H]thymidine incorporation. Lipoapoptosis of the cells was investigated by determining caspase-3 activity and the subsequent DNA fragmentation after incubation with the free fatty acid palmitate, mimicking diabetic lipotoxicity. RESULTS: Our data show that insulin, metformin, BLX-1002, and rosuvastatin improved HCAEC viability and they could also significantly increase cell proliferation in low glucose. The proliferative effect of insulin and BLX-1002 was also evident at 11 mM of glucose. In addition, insulin, metformin, BLX-1002, pioglitazone, and candesartan significantly decreased the caspase-3 activity and the subsequent DNA fragmentation evoked by palmitate, suggesting a protective effect of the drugs against lipoapoptosis. CONCLUSION: Our results suggest that the anti-diabetic and cardioprotective agents mentioned above have direct and beneficial effects on endothelial cell viability, regeneration and apoptosis. This may add yet another valuable property to their therapeutic effect, increasing their clinical utility in type 2 diabetic patients in whom endothelial dysfunction is a prominent feature that adversely affect their survival. PMID- 22436704 TI - Clinical advances in diaphragm pacing. AB - Diaphragmatic pacing is a valuable tool that can significantly benefit certain patients with respiratory insufficiency provided they have an intact phrenic nerve and a functional diaphragm. Careful patient selection is critical to successful long-term results. The main populations that derive benefit from pacing include those with congenital or acquired central hypoventilation syndrome and more commonly those with a high cervical spinal cord injury, where the phrenic nerves remain intact. The pacing electrode of most phrenic nerve pacemakers is implanted directly on the phrenic nerve. A newer device relies on intramuscular implantation of the electrode on the diaphragm at the phrenic nerve motor point. Most patients can be successfully weaned from mechanical ventilation for a substantial time each day, if not completely. This has significant impact on quality of life and implications for healthcare costs. The potential exists for application of this technology to patients with other types of respiratory failure as investigative experience emerges. These include the chronic progressive disease, amyotrophic lateral sclerosis, or temporary scenarios in difficult-to-wean intensive care unit patients. This enabling technology should hold a place in the thoracic surgeon's armamentarium. PMID- 22436705 TI - The off-pump implantation of an apicoaortic valved graft is safe and has no negative impact on coronary flow and hemodynamics. AB - OBJECTIVE: : To determine the hemodynamic effect of an off-pump apicoaortic valved graft (AAVG) implantation, we performed a quantitative coronary flow analysis in a swine model of severe aortic stenosis. METHODS: : In 10 swine, cardiac output, coronary flow, right common carotid artery flow, and internal mammary artery flow were measured along with left and right ventricular pressures and aortic and pulmonary artery pressures. A novel AAVG was implanted off-pump on the left ventricular (LV) apex using a specially designed implantation tool and anastomosed to the descending thoracic aorta. Aortic flow was measured proximally and distally of the AAVG-to-descending thoracic aorta anastomosis. After AAVG implantation, epicardial echo confirmed occlusion of the LV outflow tract by a valvuloplasty balloon. Baseline simultaneous measurements of all parameters were repeated after AAVG implantation and intravenous Dobutamine administration. RESULTS: : The AAVG was implanted without any blood loss. After AAVG implantation and LV outflow tract occlusion, the aortic flow proximal to the AAVG-to descending thoracic aorta anastomosis changed from antegrade (1508 +/- 435 mL/min) to retrograde (-529 +/- 241 mL/min, P < 0.001). All other measured parameters remained unchanged compared with baseline. After intravenous Dobutamine administration, LV pressure increased from 88 +/- 20 to 184 +/- 36 mm Hg (+209%, P < 0.0001) and coronary flow increased from 75 +/- 34 to 193 +/- 90 mL/min (+257%, P = 0.001). CONCLUSIONS: : The off-pump implantation of an AAVG is bloodless, safe, reproducible and has no negative impact on coronary flow and hemodynamics. In addition, to the best of our knowledge, this is the first study where blood flow in all coronary arteries was measured simultaneously during an AAVG implantation. PMID- 22436706 TI - Comparison of the early robot-assisted lobectomy experience to video-assisted thoracic surgery lobectomy for lung cancer: a single-institution case series matching study. AB - OBJECTIVE: : Robotic surgery has evolved in urology, gynecology, and general surgery and seems to be an oncologically sound surgical approach. Robotic surgery has been infrequently reported for pulmonary lobectomy. The aim of this study is to compare the outcomes of our early experience in performing robot-assisted lobectomy (RAL) with video-assisted thoracic surgery (VATS) for the treatment of non-small cell lung cancer. METHODS: : Between February and October 2009, 40 patients underwent RAL for resectable non-small cell lung cancer. The dissection and anatomic isolation of the hilar structures were performed using two arms of the da Vinci S system. A retrospective comparison with two VATS groups was performed, our initial 40 VATS patients (between January 2006 and February 2007) and our most recent 40 VATS patients (between June 2008 and September 2009). The entire experience with VATS lobectomy is 163 cases. RESULTS: : In the RAL group, the mean age was 64 years, and there were 23 male patients. Adenocarcinoma was diagnosed in 29 patients with a mean tumor size of 3.5 cm. There were no conversions to open thoracotomy. Among the patients in our initial and recent VATS lobectomy groups, the conversion rate was 3 (8%) and 2 (5%) patients, respectively. The operative time for the RAL (240 +/- 62 minutes) and the initial VATS lobectomy groups (257 +/- 57 minutes) were similar but was longer than the recent VATS lobectomy group (161 +/- 39 minutes, P < 0.001). However, the rate of postoperative complications in the RAL group (n = 4, 10%) was significantly lower than that of the initial VATS group (n = 13, 32.5%, P = 0.027) and similar to that of the recent VATS group (n = 7, 17.5%, P = 0.755). Intraoperative bleeding was reduced in the RAL group compared with the initial VATS group (219 mL vs 374 mL P = 0.017), and the median length of postoperative stay was significantly shorter for the RAL group compared with the initial VATS group (6 vs 9 days, P < 0.001). CONCLUSIONS: : The outcomes of our early RAL experience was comparable to the our outcomes achieved with VATS lobectomy, whether performed early or late. PMID- 22436707 TI - Revival of continuous suture technique in aortic valve replacement in patient with aortic valve stenosis: a novel modified technique. AB - OBJECTIVE: : The continuous suture technique has numerous advantages as simple, quick, and effective for aortic valve replacement; however, it is technically difficult. We have modified the continuous suture technique and evaluated our new technique in patients with aortic stenosis. METHODS: : Between July 2007 and May 2010, 86 patients with aortic valve stenosis underwent aortic valve replacement alone or with other concomitant cardiac procedures including mitral valve surgery in our hospital. The patients were randomly divided into two groups: group A (n = 43) in which the continuous suture technique with some modifications was used and group B (n = 43) in which the conventional interrupted suture technique was used. There were no statistical differences between two groups in age, sex, body surface area, concomitant cardiac procedures, blood loss, and postoperative extubation time. RESULTS: : The aortic cross-clamp time, cardiopulmonary bypass time, operation time, and hospital stay were significantly shorter in group A than that in group B, and the valve size was significantly larger in group A. No perivalvular leak was detected in postoperative echocardiograms. All patients recovered satisfactorily without complications associated with suture technique or prosthesis. During follow-up of 4 to 38 months, there were no clinically significant complications in group A, while one patient in group B developed perivalvular leakage requiring reoperation 3 months after surgery. CONCLUSIONS: : Our modified continuous suture method is useful for aortic valve replacement in patients with aortic stenosis and beneficial for the patients because the procedure is less invasive and a larger valve can be implanted. PMID- 22436708 TI - Single-institution experience on robot-assisted thoracoscopic operations for mediastinal diseases. AB - OBJECTIVE: : After the introduction of video-assisted thoracoscopic surgery 20 years ago, the minimally invasive techniques in thoracic surgery have found a growing application. The recent introduction of robotic technology has increased the potentiality of thoracoscopic technique leading to an expansion of indications and applications, particularly for the management of mediastinal diseases. We reviewed our experience in robot-assisted thoracoscopic resection of benign and malignant mediastinal diseases. METHODS: : Between 2002 and 2010, 108 patients (79 women and 29 men; median age 38 y) underwent robot-assisted thoracoscopy using the "da Vinci" robotic system for several mediastinal diseases. There were 100 thymectomies, 3 resections of paravertebral tumors, 1 thymic cyst, 1 ectopic goitre, 1 ectopic mediastinal parathyroidectomy, 1 thymic carcinoid, and 1 foregut cyst. Ninety-five (87.9%) patients were affected by myasthenia gravis. RESULTS: : All procedures were completed successfully using the da Vinci robot; no open conversions were required, but in three (2.8%) cases, a fourth access was added. There was no surgical mortality; four (3.6%) patients had postoperative complications (two hemothorax, one chylothorax, and one fever) treated conservatively. Median operation time was 120 (range 60-300) minutes and median hospitalization was 3 (range 2-14) days. Global benefit rate for patients with myasthenia gravis reached the value of 93.4% with progressive improvement over years. CONCLUSIONS: : Several mediastinal operations may be feasible by using a robot-aided thoracoscopic approach. The technical innovations offered by robotic instrumentation make all procedures safer and easier when compared with standard thoracoscopic approach, with particular reference for application in mediastinal field. PMID- 22436709 TI - Investigating perioperative heart migration during robot-assisted coronary artery bypass grafting interventions. AB - OBJECTIVE: : For robot-assisted coronary artery bypass graft interventions, surgeons typically use a preoperative thoracic computed tomography scan of the patient to plan the procedure. However, the cardiac anatomy is prone to changes induced perioperatively in the effort to access the heart and surgical targets, which, in turn, may invalidate the initial plan. This article presents a method to estimate the perioperative heart migration, information which can be further exploited to refine the preoperative surgical plan. METHODS: : Tracked transesophageal ultrasound images of four patients' hearts were acquired at each stage in the procedure: before lung deflation, after lung deflation, and after both lung deflation and CO2 thoracic insufflation. Anatomic features of interest the mitral and aortic valves-were identified from each dataset, and their movement between the different procedure stages was recorded and used to estimate the global heart displacement. Moreover, the local morphology of the features of interest was investigated to provide insight on the extent of the deformation the heart has undergone during the workflow. RESULTS: : The study suggested that the heart does undergo substantial displacement-on the order of 10 to 15 mm in each direction (axial, coronal, and sagittal) after lung deflation and CO2 thoracic insufflation. However, no significant differences (P > 0.1) were observed in the morphologic characteristics of the features of interest across the multiple workflow stages, suggesting that local deformations occur at a much smaller scale compared with the global migration. CONCLUSIONS: : The quantification of the perioperatively induced changes is critical to track the displacement of the heart and surgical targets. The recorded migration patterns should not be ignored but rather be used to update the surgical plan to better suit the intraoperative environment. PMID- 22436710 TI - Minimally invasive ivor lewis esophagectomy after induction therapy yields similar early outcomes to surgery alone. AB - OBJECTIVE: : Although considered an integral part of treatment for regionally advanced esophageal cancer, there is conflicting literature regarding the effect of neoadjuvant chemoradiotherapy on esophagectomy. The objectives of this study are to examine the effect of neoadjuvant therapy in regard to perioperative parameters, morbidity, and short-term mortality in patients undergoing a minimally invasive Ivor Lewis esophagectomy (MIE). METHODS: : This is a retrospective review of 39 patients undergoing MIE for esophageal cancer during 2007-2010. RESULTS: : Of the 39 patients, 14 (36%) did not receive neoadjuvant therapy (NCR) and 25 (64%) did receive either chemoradiotherapy or chemotherapy (CR). On comparing NCR vs CR, there was no difference in operative time (361 vs 362 minutes; P = 0.94) or estimated blood loss (233 vs 190 mL; P = 0.06). All patients underwent an R0 resection, and there was no difference in the mean number of lymph nodes harvested (NCR 21.5 vs CR 21.6; P = 0.95). Both groups had mean intensive care unit stay of 1 day (P = 0.7), and there was no difference in length of stay (NCR 7.4 vs CR 8.2 days; P = 0.38). There were no deaths or anastomotic leaks in either group. The incidence of complications in the NCR group was 21% (3/14) while in the CR group was 48% (12/25). Complications were not associated with neoadjuvant therapy [CR vs NCR: odds ratio = 3.44 (0.72 16.38); P = 0.121], even after adjusting for comorbidities and age. CONCLUSIONS: : MIE can be performed safely following neoadjuvant therapy with similar perioperative results, morbidity, and short-term mortality when compared with MIE alone. Longer follow-up is required for oncologic validity. PMID- 22436711 TI - Ultrasound-guided, video-assisted transdiaphragmatic radiofrequency ablation for primary liver malignancy or metastatic nodules. AB - OBJECTIVE: : Percutaneous radiofrequency ablation (RFA) is among the best options in the treatment of primary liver malignancy and metastases because it is a highly effective and minimally invasive alternative to resection in small, nonresectable tumors or in poor surgical candidates and is associated with low morbidity and mortality. We evaluated the clinical feasibility and safety of thoracoscopic, ultrasound (US)-guided RFA of subdiaphragmatic liver malignancies in advanced cirrhotic patients awaiting transplantation. METHODS: : Two patients (one female and one male) with end-stage cirrhosis who developed hepatocellular carcinoma were treated thoracoscopically by US-guided RFA. An endoscopic US probe was inserted into the right pleural space through a 10-mm working channel. An RF operating needle applicator was inserted through a second 10-mm working port after identification of the lesion, penetrating the diaphragm toward the lesion. The procedure duration, applied energy, and generator output were recorded during the intervention. The treatment result and procedure-related complications were analyzed. RESULTS: : The procedure duration was 74 and 92 minutes, respectively. A mean energy deposition of 353 joules resulted in a mean coagulation volume of 115 cm. Tumor ablation was achieved as determined by the postinterventional lack of contrast enhancement in the target region at the follow-up computed tomographic scans performed after 4 months. CONCLUSIONS: : RFA offers definite possibilities in the management of small-sized tumors. Thoracoscopic, US-guided transdiaphragmatic RFA has proven to be clinically feasible and safe and can be an effective modality for treating subdiaphragmatic liver lesions. Its minimally invasive nature is the most important advantage compared with surgical resection, especially for patients with high operative risk. PMID- 22436712 TI - Video-Assisted Implantation of a Left Ventricular Lead and Intrathoracic Tunneling to a Right-Sided CRT-D Device. AB - We describe two cases in which a biventricular implantable cardioverter defibrillator for cardiac resynchronization therapy had to be placed on the right side due to unsuitability of the left subclavian vein. Endocardial implantation of a left ventricular lead through the coronary sinus was previously attempted but was unsuccessful. Implantation of the epicardial left ventricular pacing lead was performed through video-assisted thoracic surgery on the left side. The connector end of the left ventricular pacing lead was tunnelized through the anterior mediastinum into the right pleural space. The right-sided pocket was then opened. A tunnel was created from the pocket to the thoracic wall, and the pleural space was entered over the second rib. The lead was retrieved from the right pleural space and connected with the Cardiac resynchronization therapy device (CRT-D). Both procedures and postoperative periods were uneventful. Intrathoracic left-to-right tunneling of an epicardial left ventricular lead by video-assisted thoracic surgery is feasible and safe. It provides an alternative to subcutaneous tunneling. PMID- 22436713 TI - Rapid novel aortic arch replacement for thoracic aortic aneurysm using three continuous sutures and a felt cylindrical collar. AB - This report describes the novel parachute technique of open distal anastomosis at the aortic arch replacement. Two Teflon felt cylindrical collars were initially placed on the anastomotic site of the descending aorta. All four to five outer loops of the stitches used in the parachute technique were tracked by the gathering suture. The anastomotic sutures and three gathering sutures were finally pulled simultaneously. The prosthetic graft and the aortic stump with Teflon felt were safely and completely anastomosed. Surgical or hospital death and serious complications were not found. The mean anastomotic duration (circulatory arrest duration) in 16 patients was 23 minutes. Our novel technique using a Teflon felt cylindrical collar and modified continuous suturing was not only safe but also reduced the duration of anastomosis and minimized blood loss. This technique is simple and can be applied to aortic valve replacement. PMID- 22436714 TI - How does successful off-pump pulmonary vein isolation for paroxysmal atrial fibrillation influence heart rate variability and autonomic activity? AB - OBJECTIVE: : Surgical pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) blocks trigger stimulation from PVs and partially disconnects the atria from sympathetic and parasympathetic neural stimulation. This study describes long-term changes in heart rate variability (HRV) and autonomic activity (AA) after successful bipolar radiofrequency PVI. METHODS: : Twenty seven patients who underwent coronary artery bypass grafting and successful (defined as stable sinus rhythm for 1 year) off-pump bipolar radiofrequency PVI for PAF were prospectively followed 3, 6, and 12 months after surgery including 24 hours Holter electrocardiogram. The following HRV and AA parameters were calculated: mean NN-interval, SD of NN-intervals, SD of averaged NN-intervals, root mean square of successive differences, low frequency (LF) power (0.04-0.15 Hz; a parameter specific for sympathetic activity), high frequency (HF) power (0.15-0.4 Hz; a parameter specific for parasympathetic activity), and the LF:HF ratio. RESULTS: : Preoperatively, high HRV and AA parameters were recorded. In 3 , 6-, and 12-month time, a progressive reduction of HRV and AA was observed, reaching significance after 12 months. Respective rates before surgery and 12 months after it were: for SD of averaged NN-intervals (122.4 +/- 113; 80.5 +/- 42 milliseconds; P = 0.046), for root mean square of successive differences (79.2 +/ 93; 45 +/- 20 milliseconds; P = 0.04). The LF:HF ratios were 1.22 and 0.73 before and 12 months after surgery, respectively. The statistically significant continuous reduction in LF:HF ratio (P = 0.02) is suggestive of a progressive parasympathetic dominance 12 months after surgery. CONCLUSIONS: : Successful PVI for PAF results in HRV and sympathetic activity reduction with preoperative sympathetic dominance and oncoming vagal dominance after 1 year from surgery. Despite preoperative sympathetic dominance, successful PVI for PAF results in HRV and a reduction in sympathetic activity with emerging parasympathetic dominance 12 months after surgery. PMID- 22436715 TI - "Spot" ECGs Underestimate Atrial Fibrillation Recurrence After Surgical Ablation. AB - OBJECTIVE: : Historically, success of surgical treatment of atrial fibrillation (AF) has been measured by electrocardiograms (ECGs) at various intervals. However, continuous monitoring of cardiac rhythms by "autocapture" devices has recently become more available and convenient. The concordance of measurements of freedom from AF by these two techniques has not been reported after surgical ablation. METHODS: : Between August 2005 and May 2006, 47 patients at a single academic center underwent surgical ablation procedures for AF and had recurrence of AF assessed by both "spot" 12-lead ECG and autocapture event monitoring. Forty one ablation procedures were concomitant with other cardiac surgery and six were stand alone, nonsternotomy procedures. Agreement between these diagnostic modes was measured using the kappa statistic at 3, 6, and 12 months (kappa of 1 is perfect agreement, 0 is no agreement). McNemar test was employed to determine whether agreement significantly changed from 3 to 12 months. RESULTS: : At 3 months follow-up, spot ECGs suggested that 81% (38 of 47) of surgical patients were free of any AF, whereas 1-week event recordings found only 70% (31 of 44) of patients were free of any AF. At 6 months, spot ECGs estimated that 87% (40 of 46) of surgical patients were free of AF; 1-week event recordings found only 74% (34 of 46) of patients were free of AF. At 12 months, spot ECGs estimated that 84% (26 of 31) of surgical patients were free of AF compared with only 68% (19 of 28) as measured by the 1-week event recorder. The kappa measures (with 95% confidence interval) at 3, 6, and 12 months were 0.52 (0.24-0.80), 0.60 (0.32 0.87), and 0.63 (0.32-0.94) respectively, showing only moderate agreement. McNemar test showed no significant shift in agreement from 3 to 6 months (P = 0.7055), 3 to 12 months (P = 1.000), or 6 to 12 months (P = 1.000). There were no deaths or strokes, but one myocardial infarction among these 47 patients during 12 months follow-up. CONCLUSIONS: : "Spot" ECGs underestimate the incidence of recurrent AF after surgical ablation for AF and show poor agreement with the more reliable 1-week autocapture event recordings. PMID- 22436716 TI - Robotic mitral valve repairs requiring reoperations. AB - OBJECTIVE: : Robotic mitral valve (MV) repairs are performed at many institutions. Repair failures have been attributed to the challenging technology and potentially to the use of annuloplasty band anchoring U-clips. The purpose of this study was to characterize causes of robotic MV repair failure. METHODS: : A total of 300 patients underwent a da Vinci robotic MV repair between May 2000 and November 2006 by a single operating console surgeon. Standard repair techniques and a Cosgrove annuloplasty band were used in every case. Clinical data in patients requiring a reoperation, as well as videos of their original operation, were reviewed. MV pathology, repair methods, and findings at reoperation were determined. RESULTS: : Sixteen (5.3%) patients required reoperation. Seven (7%) failures occurred in the first 100 cases and 9 (4.5%) in the last 200 cases. Initial MV pathology included isolated anterior (n = 4) or posterior leaflet prolapse (n = 6), bileaflet prolapse (n = 3), and annular dilation (n = 3). Reoperations after their initial operation were required early (<6 months) in 8 patients and later in 8 patients. Reasons for reoperation included CHF (n = 9), hemolysis (n = 4), systolic anterior leaflet motion (n = 2), and endocarditis (n = 1). At reoperation, 7 patients had partial dehiscence of the annuloplasty band. The incidence of band dehiscence was not associated with the use of U-clips and decreased with experience. CONCLUSIONS: : Reoperative rates seemed to decrease with increased case volume and surgeon's experience. Repair results using robotic techniques are similar to conventional techniques. The use of U-clips is not associated with a higher reoperation rate. PMID- 22436717 TI - The use of the mini-cardiopulmonary bypass circuit in robotic mitral valve surgery. AB - BACKGROUND: : Computer enabled robotic mitral valve repair cases have longer cross-clamp and perfusion times because of the more technically difficult procedure. To modify some of the well-documented side effects of standard cardiopulmonary bypass (CPB), we used a new mini-circuit on three robotic mitral cases. METHODS: : Three patients having mitral valve repair (triangular resection of P2 and annuloplasty ring) using the daVinci Robot (Intuitive Surgical, Sunnyvale, CA) had circulatory support using a modified Resting Heart System (Medtronic, Inc., Fridley, MN), a vertically oriented space saving CPB configuration incorporating a high efficiency miniaturized oxygenator, centrifugal pump, shortened heparin coated tubing and an air evacuation system with a closed circuit. RESULTS: : All patients had successful mitral repair (echo = 0 to trace residual leakage) under a cross-clamp time of 161 +/- 54 minutes and perfusion time of 229 +/- 31 minutes. No blood was given during CPB and 0.7 +/- 1.2 red cell units after the CPB run and 0.7 +/- 1.2 units during the postoperative course. CONCLUSION: : Miniaturized bypass circuit reducing the level of necessary anticoagulation, hemodilation, and blood trauma can be used despite the increased perfusion time necessary for robotic mitral surgery. PMID- 22436718 TI - Propensity-score analysis of early outcomes after bilateral versus single internal thoracic artery grafting. AB - OBJECTIVE: : The use of bilateral internal thoracic arteries (BITAs) during coronary artery bypass grafting (CABG) improves long-term and event-free survival compared with single internal thoracic artery (SITA) grafting. It is controversial whether BITA grafting alters in-hospital adverse events after CABG. METHODS: : Isolated CABG cases using BITA or SITA at a single US academic center between January 1, 1997 and June 30, 2006 were retrospectively reviewed. A propensity score was used as a covariate to balance the treatment groups (BITA and SITA) with respect to 44 preoperative risk factors. A multivariable logistic regression model tested whether treatment type was significantly associated with in-hospital death, deep sternal wound infection (DSWI), or hospital length of stay (LOS). RESULTS: : There were 599 BITA and 10,212 SITA cases performed. Overall for all BITA versus SITA cases, adjusted mortality (0.8% vs. 1.7%, P = 0.85) was not different between the groups. However, adjusted incidence of DSWI (2.0% vs. 1.2%, P = 0.036) and LOS (6.7 vs. 6.1, P = 0.025) were significantly higher in BITA patients. Subsets analyses of obese patients and diabetic patients revealed no statistical differences for any of the outcomes between BITA and SITA. CONCLUSIONS: : The long-term benefits of BITA grafting do not come at the cost of increased adjusted risk of in-hospital death. BITA grafting was associated with an increased risk of DSWI and a longer adjusted LOS. Neither obesity, nor diabetes significantly increased the risk of poor outcomes after BITA. PMID- 22436719 TI - Intraoperative in situ radial artery conduit flow assessment. AB - A technique is described for simple flow assessment of the in situ radial artery conduit during coronary bypass via a small incision. This technique allows morphologic and physiologic direct intraoperative assessment of radial artery quality and expands the use of radial artery during coronary artery surgery. PMID- 22436720 TI - Percutaneous aortic valve replacement: endovascular sealing studies in situ. AB - OBJECTIVE: : To improve the outcome of percutaneous valve replacement in aortic stenosis endovascular resection of calcified aortic valves will be necessary. In this study different sealing methods were evaluated. The focus of this research was feasibility and mechanical functionality in human anatomy. METHODS: : The aortic valve isolation chamber (AVIC) is a catheter-based system to seal the aortic valve during resection, and was installed antegrade and retrograde. Firstly, AVIC was inserted antegrade via the cardiac apex in human postmortem models (n = 2), and secondly in porcine in vivo models under extra corporeal circulation (n = 5). Endoscopic inspection of the valve was recorded. AVIC was installed via a port system through the descending aorta. Micro- and macropathologies were performed. RESULTS: : AVIC transapical deployment in the two human models took 3 and 4 minutes respectively and 2.2 +/- 1.3 minutes in average in the porcine model. From the descending aorta, the deployment took 9.3 +/- 5.5 minutes. Fluoroscopy and macroscopy demonstrated sealed chambers. Microscopic and histologic analysis demonstrated no profound damages of the surrounding tissue. CONCLUSION: : This study demonstrates the feasibility of transapical and retrograde endovascular sealing of the aortic valve in vitro and in vivo in nonbeating hearts. PMID- 22436721 TI - Tension measurement of artificial chordae tendinae implanted between the anterior mitral valve leaflet and the left ventricular apex: an in vitro study. AB - OBJECTIVE: : A newly developed surgical technique allows implantation of artificial chordae tendinae between a mitral valve leaflet and the left ventricular (LV) apex in a closed-chest, off-pump mitral valve repair operation. However, this orientation causes tension vectors on the mitral valve leaflet in a different direction than those of native chordae. The purpose of this study was to investigate the relationship between systolic LV pressure and the tension of artificial chordae secured at the ventricular apex to assess if the altered tension vectors on the mitral leaflet resulted in excessive stress on the chordae/leaflet system. METHODS: : Freshly harvested porcine mitral valves were suspended in a mechanical LV simulator. Two 5-0 Gore-Tex sutures were secured to the free edge of the middle scallop of the anterior leaflet adjacent to the insertion point of two major native chordae. The native chordae were then cut. A simulator pump was activated at different pressure levels, and the tension of the artificial chordae was measured with a digital tensiometer during several cardiac cycles. RESULTS: : The numerical relationship between chordal tension (in Newtons, N) and LV pressure (in mm Hg/100) averaged at 0.8 (range 0.6-1.05). This tension/pressure relationship was similar in order of magnitude and range to that measured in native chordae in previously published studies. CONCLUSIONS: : In this in vitro model, orienting artificial chordae in a direction mimicking implantation between the valve and the LV apex does not result in excessive tension stress on either the chordae or the mitral leaflet. PMID- 22436722 TI - Efficacy of intramyocardial injection of angiogenic cell precursors for ischemic cardiomyopathy: a case match study. AB - INTRODUCTION: : The objective of this study is to determine the efficacy of intramyocardial angiogenic cell precursors (ACPs) injection in ischemic cardiomyopathy (ICM). METHODS: : Twenty-five ICM patients (cell group) underwent intramyocardial ACPs injection. Seventeen ICM patients (control group) treated by medical means were matched with cell group. There was no statistically significant difference between cell and control groups in relation to left ventricular ejection fraction (LVEF) and comorbidities. In the cell group, mean age was 58.4 +/- 13.7 years. Mean LVEF was 26.1% +/- 7.4%. New York Heart Association (NYHA) class was 2.9 +/- 0.6. The ACPs were derived and expanded from autologous blood. The number of cells before injection was 27.4 +/- 18.8 million cells. The cells were injected into the nonviable myocardium and hypokinetic segments in the cell group. RESULTS: : There was no new ventricular arrhythmia. NYHA was improved by 0.9 +/- 1.0 (P < 0.001) at 229.9 +/- 98.8 days. Six-minute walk test and quality of life assessed by short form-36 improved in the cell group. LVEF was improved in 72% of patients (18 of 25). LVEF improved by 6.4 +/- 9.9 points % (P = 0.003) at 290.4 +/- 210.3 days. The percentage of infarction area decreased 21.9 +/- 17.4 points % at 159 +/- 54 days postoperatively. There was no significant improvement of NYHA and LVEF in the control group. CONCLUSIONS: : For this efficacy study, the NYHA class, quality of life, and six minute walk test were improved after cell transplantation. The LVEF was also significantly improved in the cell treated group. PMID- 22436723 TI - Results of antibiotic susceptibility testing do not influence clinical outcome in children with cystic fibrosis. AB - INTRODUCTION: Patients with CF experience pulmonary exacerbations. These are often initially empirically treated with intravenous antibiotics, with antibiotic choice refined after susceptibility testing. METHODS: We completed a 5-year retrospective review of children attending the Paediatric CF Unit, Nottingham. The respiratory sampling, antibiotic prescribing and susceptibility testing guidance were audited. Episodes were classified according to the concordance between the antibiotics prescribed and antibiotic susceptibility testing. RESULTS: Of 52 patients who had previously isolated Pseudomonas aeruginosa, 103 antibiotic courses were commenced that coincided with an isolation of P. aeruginosa. P. aeruginosa was fully susceptible, partially susceptible or fully resistant on 33%, 44.7% or 16.5% of occasions respectively. The antibiotic prescriptions were never changed following antibiotic susceptibility testing. We found no association between change in FEV(1) (p=0.54), change in BMI (p=0.12) or time to next exacerbation (p=0.66) and concordance between antibiotic susceptibility and the antibiotics administered. CONCLUSION: This study contributes to mounting evidence questioning the utility of routine antibiotic susceptibility testing. PMID- 22436724 TI - Diverse norovirus genotypes identified in sewage-polluted river water in South Africa. AB - This study aimed to assess norovirus (NoV) contamination and genotype diversity in surface water in Gauteng, South Africa. Between January 2008 and December 2010, three rivers, namely Klip, Suikerbosrant, and Rietspruit were monitored for NoV genogroup (G)I and GII. Viruses were recovered using the glass wool adsorption-elution technique and detected by real-time reverse transcription polymerase chain reaction. From 2008 to 2010, NoVs were detected in 66% (70/106) of Klip river samples. The Rietspruit and Suikerbosrant rivers were contaminated with NoV in 95% (20/21) and 21% (5/24) of samples, respectively. NoV-positive samples comprised of 33% GI, 29% GII and 38% of both GI and GII strains. Based on partial capsid gene analysis (region C), 16 NoV genotypes (6 GI, 10 GII) were identified. The major genotypes detected were GI.4, GI.5 and GII.4. These rivers could be a potential source of NoV infection for communities using the water for domestic or recreational purposes. PMID- 22436725 TI - Using particle tracking to probe the local dynamics of barley beta-glucan solutions upon gelation. AB - The sol-gel transition of aqueous barley beta-glucan solutions which undergo gelation with ageing has been studied by conventional bulk rheology, phase contrast microscopy and particle tracking microrheology. Characterisation of the primary structure of the beta-glucan isolate was carried out by enzymic methods and HPLC. The Brownian diffusion of fluorescent microspheres (0.75 MUm diameter, carboxylate-coated particles) was used to probe the spatial mechanical properties of the gelling systems at the scale of microns; the potential use of passive particle tracking to study biopolymer gelling systems that present spatial heterogeneities is thus explored. For the beta-glucan gels cured at 25 degrees C both microrheology and bulk rheology revealed that with increasing the polysaccharide concentration the gelation time decreased, while the gelation rate and gel strength of the barley beta-glucan gels increased. The particle tracking method had higher sensitivity and could map molecular ordering and structural heterogeneities in the evolving polysaccharide network at a micro-level. That is, different size pores were generated upon ageing with regions of depleted or less amount of beta-glucan molecules. Furthermore, this method could detect changes in the fine structure of the system before such events can be registered by bulk rheological measurements; i.e. microheterogeneity and aggregation of beta-glucan chains were revealed by particle tracking at earlier temporal stages of the experiment. PMID- 22436726 TI - Fabrication of small-sized silver NPs/graphene sheets for high-quality surface enhanced Raman scattering. AB - In this paper, small-sized and highly dispersed Ag nanoparticles (NPs) supported on graphene nanosheets are fabricated via a strategy for etching a copper template with Ag(+). Firstly, big-sized Cu NPs are supported on graphene, and then the small-sized and highly dispersed Ag NPs are supported on graphene by replacement reaction, mainly making use of graphene passing electrons between Cu and Ag(+). The graphene used in the experiment is prepared by in situ self generating template and has good dispersion, excellent crystallinity and little defects. Thus, in the process of Ag/graphene synthesis, there is no any intervention of surfactant, which ensures that SERS activity sites have not been passivated. And, the little defects of graphene benefit the excellent conductivity of graphene and ensured the replacement reaction between Cu and Ag(+). The obtained material exhibits significant high-quality and distinctive SERS activity. Especially, a serial new peak of p-aminothiophenol (PATP) is observed, this is suggested two reasons: one is "surface geometry" of the PATP on small-sized Ag NPs and another is the charge-transfer between Ag and graphene. PMID- 22436727 TI - Synthesis of hollow ellipsoidal silica nanostructures using a wet-chemical etching approach. AB - We have utilized wet-chemical etching of ellipsoidal silica nanoparticles (ESNs) to form silica nanoshells of a range of elliptical morphologies, with the thicknesses of the ellipsoidal silica nanoshells (ESSs) controlled through variation of synthesis conditions. A mechanism has been proposed to explain how the nanoshells are formed, and we demonstrate that the porosity of the silica ellipsoid plays a role in generating silica shells. Our self-templated, wet etching approach is an attractive alternate procedure to the approaches presently in existence for the following reasons: (i) it is a facile, one-step process that directly produces ellipsoidal silica nanoshells, while overcoming barriers (such as requirement of removing a solid-core template seed) utilized in many reported chemical etching studies; (ii) it results in ellipsoidal silica nanostructures with dimension less than 100 nm; (iii) with an appropriate etchant, the roughness of the silica shells can be well-controlled; and (iv) it results in tunable, uniform size particles with controllable shell thicknesses. Moreover, the silica materials with the unique structures might be adjusted to meet practical application requirements. PMID- 22436728 TI - MicroRNA-34a upregulation during seizure-induced neuronal death. AB - MicroRNAs (miRNAs) are short, noncoding RNAs that function as posttranscriptional regulators of gene expression by controlling translation of mRNAs. A subset of miRNAs may be critical for the control of cell death, including the p53-regulated miRNA, miR-34a. Because seizures activate p53, and p53-deficient mice are reportedly resistant to damage caused by prolonged seizures, we investigated the role of miR-34a in seizure-induced neuronal death in vivo. Status epilepticus was induced by intra-amygdala microinjection of kainic acid in mice. This led to an early (2 h) multifold upregulation of miR-34a in the CA3 and CA1 hippocampal subfields and lower protein levels of mitogen-activated kinase kinase kinase 9, a validated miR-34a target. Immunoprecipitation of the RNA-induced silencing complex component, Argonaute-2, eluted significantly higher levels of miR-34a after seizures. Injection of mice with pifithrin-alpha, a putative p53 inhibitor, prevented miR-34a upregulation after seizures. Intracerebroventricular injection of antagomirs targeting miR-34a reduced hippocampal miR-34a levels and had a small modulatory effect on apoptosis-associated signaling, but did not prevent hippocampal neuronal death in models of either severe or moderate severity status epilepticus. Thus, prolonged seizures cause subfield-specific, temporally restricted upregulation of miR-34a, which may be p53 dependent, but miR-34a is probably not important for seizure-induced neuronal death in this model. PMID- 22436730 TI - Reduced lung diffusion capacity in type 2 diabetes is independent of heart failure. AB - In a case-control analysis comparing 303 patients with diabetes and 303 without (matched on age, race, sex and height), diabetics had reduced lung diffusion (DLCO) independent of smoking, obesity, clinical heart failure, asymptomatic left ventricular systolic and diastolic dysfunction: DLCO (mean+/-SE: 15.5+/-0.9 vs. 16.4 +/-0.9, p=0.01). PMID- 22436731 TI - Can faith-based correctional programs work? An outcome evaluation of the innerchange freedom initiative in Minnesota. AB - This study evaluated the effectiveness of the InnerChange Freedom Initiative (InnerChange), a faith-based prisoner reentry program, by examining recidivism outcomes among 732 offenders released from Minnesota prisons between 2003 and 2009. Results from the Cox regression analyses revealed that participating in InnerChange significantly reduced reoffending (rearrest, reconviction, and new offense reincarceration), although it did not have a significant impact on reincarceration for a technical violation revocation. The findings further suggest that the beneficial recidivism outcomes for InnerChange participants may have been due, in part, to the continuum of mentoring support some offenders received in the institution and the community. The results imply that faith-based correctional programs can reduce recidivism, but only if they apply evidence based practices that focus on providing a behavioral intervention within a therapeutic community, addressing the criminogenic needs of participants and delivering a continuum of care from the institution to the community. Given that InnerChange relies heavily on volunteers and program costs are privately funded, the program exacts no additional costs to the State of Minnesota. Yet, because InnerChange lowers recidivism, which includes reduced reincarceration and victimization costs, the program may be especially advantageous from a cost benefit perspective. PMID- 22436732 TI - International immigration, internal migration, and homicide in Canadian provinces. AB - The relationship between immigration and crime is politically charged and often fueled by the presence (or lack) of xenophobia. Many theoretical and empirical assessments of this relationship indicate that immigration does indeed lead to increased crime, but more recent (and very early) research investigating homicide calls this finding into question. The current analysis investigates the relationship between immigration and homicide using multiple measures of migration and Canadian provinces as the unit of analysis. It is found that the link between immigration and homicide is complex and dependent on the measure of migration used. Generally speaking, the results presented here are consistent with the more recent and very early research. Immigration, in and of itself, does not increase homicide. Rather it is the increase in the most criminogenic subpopulation that matters, that is young males. PMID- 22436733 TI - Treatment or else: coerced treatment for drug-involved California parolees. AB - This study evaluated a community-based correctional program in California, in which parolees tested positive on illicit drugs were given the option of going into a treatment program or having their parole revoked and returned to prison in California. Two comparison groups were constructed to assess the treatment effect a propensity-based comparison group extracted from the general parolee population and program dropouts. Although implicitly coercive, some parolees who finished the program were less likely to be reincarcerated 12 months following release than both comparison groups. However, the observed treatment advantage quickly eroded in the second observation year. Savings realized from the incarcerations avoided were more than enough to pay for the program. Findings from this study suggest that boosting participation in reentry services through coercive measures may yield currently unrealized individual and societal benefits. However, systemic efforts are needed to extend the short-term treatment effects. Design and data limitations in the study weaken the persuasiveness of these findings. Methodological implications and policy issues about coerced treatment are discussed. PMID- 22436734 TI - Cultural processes and homicide across nations. AB - This article is concerned with the macro-level propositions of Nisbett and Cohen's culture of honor thesis. The results suggest that the culture of honor proxy has a strong positive influence on homicide across nations. In fact, culture of honor exhibited larger effect sizes than all of the important social structural controls. These results suggest that consideration of cultural processes is important for understanding macro-level variation in violence. PMID- 22436735 TI - Sexual sadism in the context of rape and sexual homicide: an examination of crime scene indicators. AB - This study investigates the convergent and predictive validity of behavioral crime scene indicators of sexual sadism in the context of rape and sexual homicide. The study is based on a sample of 268 adult males sentenced to a federal penitentiary in Canada. Information regarding crime scene behaviors was gathered from police records, a clinical interview with a psychologist, and a semistructured interview with the offender. A series of logistic regressions were performed to determine whether behavioral crime scene indicators of sexual sadism were associated with an official diagnosis of sexual sadism and were able to distinguish between sexual aggressors against women and sexual murderers. Findings suggest that several crime scene behaviors overlap with an official diagnosis of sexual sadism as well as being able to distinguish between sexual aggressors of women and sexual murderers. Importantly, the majority of crime scene behaviors associated with a clinical diagnosis of sexual sadism are not the same as those associated with sexual homicide. PMID- 22436736 TI - Factors that affect college students' perceptions of rape: what is the role of gender and other situational factors? AB - Prior research has shown that various situational factors and behaviors can affect one's perception of whether a rape has occurred. Moreover, some hold false beliefs about rape. This can also affect one's perception of ambiguous situations. This study included the administration of a survey to 584 college students; the survey examined the prevalence of rape myths and responses to vignettes of potential rape scenarios. It was found that although the majority of this sample did not support rape myths, male students were significantly more likely than female students to support rape myths. Furthermore, approximately 20% of students did support one subscale of the rape myth scale: He didn't mean to [commit rape]. The results also revealed an interaction effect between the observer's sex and the victim's sex, suggesting a complex gender relationship. PMID- 22436737 TI - [Pacemaker lead-induced tricuspid stenosis: a report of two cases]. AB - Tricuspid stenosis (TS) is an uncommon complication of transvenous ventricular pacemaker implantation, with few cases reported in the literature. The mechanisms described are obstruction of right ventricular inflow by tricuspid vegetations (endocarditis), multiple pacemaker leads and tricuspid valve (TV) fibrosis secondary to perforation or laceration of the TV leaflets, or adherence between redundant portions of the lead and valvular and subvalvular tissue. We report two cases of severe TS, with different etiologies and management: one caused by leaflet perforation, resolved surgically, and the other secondary to fusion between a loop of the pacemaker lead and the subvalvular apparatus, which was treated medically. PMID- 22436739 TI - Telomeres: The perils of peripheral damage. PMID- 22436742 TI - Cell cycle: Finding space in the APC/C. PMID- 22436743 TI - Development: Leading a programmed death. PMID- 22436747 TI - MicroRNAs in metabolism and metabolic disorders. AB - MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b have a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element binding protein (SREBP) transcription factors. Other metabolic miRNAs, such as miR-103 and miR-107, regulate insulin and glucose homeostasis, whereas miRNAs such as miR-34a are emerging as key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders. PMID- 22436748 TI - AMPK: a nutrient and energy sensor that maintains energy homeostasis. AB - AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability. PMID- 22436750 TI - Percutaneous subxiphoid access to the epicardium using a miniature crawling robotic device. AB - BACKGROUND: : To expand minimally invasive beating-heart surgery, we have developed a miniature 2-footed crawling robot (HeartLander) that navigates on the epicardium. This paradigm obviates mechanical stabilization and lung deflation, and avoids the access limitations of current approaches. We tested the locomotion of the device on a beating porcine heart accessed through a closed-chest subxiphoid approach. METHODS: : HeartLander consists of 2 modules that are connected by an extensible midsection. It adheres to the epicardium using suction pads. Locomotion and turning are accomplished by moving the 2 modules in an alternating fashion using wires that run through the midsection between them. After a preliminary test with a plastic beating-heart model, we performed a porcine study in vivo. The device was inserted into the pericardial space through a subxiphoid incision, while the test was observed using a left thoracoscopy. The blood pressure and electrocardiogram were monitored, and vacuum pressure and driving forces on the wires were recorded. RESULTS: : HeartLander traveled across the anterior and lateral surfaces of the beating heart without restriction, including locomotion forward, backward, and turning. The vacuum pressure was kept below 450 mm Hg at all times. The average maximum force during elongation was 1.86 +/- 0.97 N, and during retraction was 1.24 +/- 0.33 N. No adverse hemodynamic or electrophysiologic events were noted during the trial. No epicardial damage was found on the excised heart after the porcine trial. CONCLUSIONS: : The current HeartLander prototype demonstrated safe and successful locomotion on a beating porcine heart through a closed-chest subxiphoid approach. PMID- 22436749 TI - Innovation: Metabolomics: the apogee of the omics trilogy. AB - Metabolites, the chemical entities that are transformed during metabolism, provide a functional readout of cellular biochemistry. With emerging technologies in mass spectrometry, thousands of metabolites can now be quantitatively measured from minimal amounts of biological material, which has thereby enabled systems level analyses. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping our understanding of cell biology, physiology and medicine. PMID- 22436751 TI - Planned Simultaneous Beating-heart Totally Endoscopic Coronary Artery Bypass (TECAB) and Percutaneous Intervention in a Single Operative Setting. AB - BACKGROUND: : Staged hybrid revascularization integrated with minimally invasive coronary artery bypass grafting (CABG) and arrested heart totally endoscopic CABG has been reported. We report the first case of planned simultaneous hybrid coronary revascularization, integrating beating-heart TECAB, and percutaneous intervention (PCI) in the same operative setting. METHODS: : A 73-year-old woman with symptoms of angina and a history of diabetes was found to have 2-vessel coronary artery disease involving the left anterior descending (LAD) and the right coronary artery (RCA). Left internal thoracic artery (LITA) to the LAD grafting was done on a beating heart in a totally endoscopic manner using the da Vinci robotic system through 4 ports. Immediately after LITA to LAD TECAB, percutaneous angioplasty and stent placement was done through the right femoral artery using the OEC 9800 mobile C-arm in the operating room. RESULTS: : There was no stenosis noted in the RCA after the intervention. LITA angiography showed a completely patent anastomosis. The total operative time for both procedures was 165 minutes. Occlusion and anastomotic times were 14 and 8 minutes, respectively. Total PCI and fluoroscopy times were 10 and 3 minutes, respectively. The patient received clopidogrel (Plavix) and aspirin in the immediate postoperative period and was discharged home on the second postoperative day. CONCLUSION: : This planned hybrid approach involving a beating-heart single-vessel TECAB and simultaneous angioplasty-stent in a single operative setting achieved complete coronary artery revascularization in a less invasive way. PMID- 22436752 TI - Total Endoscopic Beating-Heart Coronary Artery Bypass Grafting Using A New 3D Imaging System. AB - OBJECTIVE: : Since 1999, the authors of this study have performed total endoscopic beating-heart coronary artery bypass. They have developed a new three dimensional (3D) endoscopic imaging system and have used it successfully in three patients. METHODS: : From January 2004, a new 3D endoscopic imaging system was used. This device, composed of an optical high-resolution, 3D endoscope and two liquid crystal monitors, gives bright, natural, 3D imaging and enables quick, precise manipulation. After the 15-mm port for the 3D endoscope was inserted through fourth intercostal space (ICS) in the posterior axillary line, the left internal thoracic artery (LITA) was taken down endoscopically in semiskeletonized fashion, using two instrumental 5-mm ports (third and sixth anterior axillary ICS). The pericardium was then opened, and the left anterior descending artery was identified. Another 10-mm port for an endoscopic needle holder was inserted through fourth ICS in the midclavicular line. Three ports were placed in the fourth ICS in line for the anastomosis. An original suction stabilizer was inserted through the first instrumental port, and the left anterior descending artery was immobilized. A conventional end-to-side anastomosis was done with 8-0 Prolene running sutures. RESULTS: : The average LITA harvesting time was significantly shortened from 68 minutes with two-dimensional imaging to 36 minutes with new 3D imaging. The average anastomotic time was shortened from 34 minutes with two-dimensional imaging and 27 minutes with former 3D imaging to 17 minutes with new 3D imaging. There were no complications and no operative deaths. CONCLUSIONS: : This new 3D endoscopic imaging system facilitates quick, precise anastomosis and is a useful device for endoscopic coronary bypass surgery. PMID- 22436753 TI - Initial experience with robotic epicardial off-pump pulmonary vein isolation for paroxysmal atrial fibrillation. AB - OBJECTIVE: : To evaluate the feasibility and results of isolated endoscopic pulmonary vein isolation for paroxysmal atrial fibrillation using robotics. METHODS: : Between November 2004 and December 2005, 13 patients (38.5% female) underwent robotic pulmonary vein isolation at our institution. Mean age was 46.8 +/- 8.4 years and mean preoperative duration of atrial fibrillation was 52.7 +/- 31.5 months. Indication for surgery was symptomatic drug-refractory paroxysmal atrial fibrillation or recurrence after percutaneous treatment (n = 3). Mean preoperative left atrial dimension was 38.5 +/- 6.9 mm. The surgical procedure was performed off-pump as an isolated right chest approach. All procedures were performed using the Flex 10 microwave ablator (Guidant, Indianapolis, IN), which was positioned from the right side through the transverse sinus and around the 4 pulmonary veins. Postoperative drug regimen included sotalol and Coumadin. Mean follow-up was 8.5 +/- 3.4 months. RESULTS: : The procedure was successful in 11 patients. One patient needed conversion to median sternotomy for right pulmonary artery bleeding and a second patient had severe transverse sinus adhesions requiring conversion to a bilateral video-assisted small thoracotomy approach. No other morbidity occurred. Mean procedure time in successful cases was 2.7 +/- 0.8 hours (range 1.7 to 4 hours). Permanent sinus rhythm was successfully restored in 10 of 13 patients (76.9% beyond 6 months). Nonsuccessful patients had markedly reduced symptoms and frequency of events. One patient required a left and another a right atrial flutter ablation during follow-up. CONCLUSIONS: : Robotic pulmonary vein isolation is a feasible procedure that has the potential to become a valid option in the treatment of paroxysmal atrial fibrillation. PMID- 22436754 TI - Skeletonized Radial Artery Graft Prepared With Phosphodiesterase-III Inhibitors Indicates Favorable Results Compared With Pedicled Radial Artery Graft in Angiographic Studies. AB - OBJECTIVES: : The technique used to harvest the radial artery was modified, with improved results. Skeletonized radial artery conduits prepared with phosphodiesterase-III inhibitor were compared with pedicled conduits by angiography. METHODS: : Isolated coronary artery bypass graft surgery that used the radial artery for conduits was performed on 83 consecutive occasions from March 2003 to February 2004. The mean age of the patients was 68 +/- 7 years; 65% were male. The radial arteries were harvested randomly for skeletonized (group SPD and group SPa) or pedicled (group PPD). A phosphodiesterase-III inhibitor, olprinone hydrochloride, was used as an antispastic agent during harvesting of the radial artery for both in groups SPD and PPD. Papaverine was used in group SPa. Postoperative angiograms were performed within 1 month. Diameters of the radial artery were scaled at proximal, mid, and distal sections and averaged. Optical stenosis was measured as a percent stenosis value. RESULTS: : There were no significant differences among groups SPD, SPa, and PPD in morbidity or mortality rates. Graft patency rates were 97.4% in group SPD, 98.6% in group SPa, and 95.4% in group PPD (P = 0.67). Diameters of the radial artery conduits were significantly wider in group SPD compared with group PPD (P < 0.001). Spasm and stenosis were less frequent in group PPD (P < 0.05). CONCLUSIONS: : Skeletonized radial artery grafting prepared with a phosphodiesterase-III inhibitor indicated favorable results in angiographic studies. PMID- 22436755 TI - Patency outcomes of aortic connectors. AB - OBJECTIVE: : Controlled outcome analysis of mechanical aortic connectors for proximal saphenous vein bypass graft anastomosis is lacking. We report the clinical and angiographic outcome of patients receiving the Symmetry aortic connector (St. Jude Medical, Inc St. Paul, MN, US) within a multicenter, prospective, randomized study. METHODS: : Twenty-five patients at 3 study sites received aortic connectors at the time of coronary artery bypass surgery. Protocol-defined angiographic follow-up was completed in 19 of 25 patients (76%) at time-points up to 14 months postoperatively; 32 connector anastomoses were evaluated in these 19 patients. Beating heart surgery was performed in 17 patients, and 2 were performed with cardiopulmonary bypass. Age was 69.7 +/- 8.1 year; all patients were males. RESULTS: : The connector anastomosis patency rate was 15.6% (5/32). There were no deaths during the follow-up period. Four patients (21%) suffered myocardial infarction and 2 additional patients (10.5%) required percutaneous coronary interventions; one of who required 3 percutaneous coronary interventions, the other received one percutaneous coronary intervention. CONCLUSIONS: : In this nonrandomized cohort of patients, occlusion rate with Symmetry connectors was significantly greater than anticipated. Patients who have received these connectors during coronary artery bypass surgery may require closer follow-up and evaluation. While the manufacturer has stopped producing this device, there has been no recall of the product, clinical support remains ongoing, and next generation connectors have now been marketed. Consideration should be given to discontinuation of the clinical use of Symmetry connectors. PMID- 22436756 TI - Feasibility of intravascular near-infrared spectroscopy in off-pump myocardial revascularization. AB - OBJECTIVES: : The intravascular application of near-infrared spectroscopy was previously evaluated in acute ischemia-reperfusion studies in animal experiments. The objective of our study was to assess the technical feasibility and clinical reliability of an online myocardial ischemia monitoring by using intravascular near-infrared spectroscopy during off-pump coronary bypass surgery. METHODS: : Intravascular near-infrared spectroscopy of coronary sinus blood was performed in 10 elective patients selected for off-pump coronary bypass surgery. Light signals were transferred through a fiberoptic catheter for emission and collection from the coronary sinus blood. Spectrometric analyses were performed before and after revascularization with internal thoracic artery and saphenous vein grafts. Changes in spectroscopic data were compared with hemodynamic parameters and electrocardiographic, transesophageal echocardiographic, and laboratory findings. RESULTS: : All of the operations were finished as off-pump procedures. No remarkable intraoperative myocardial ischemia was observed in the patient group, as indicated by electrocardiography and transesophageal echocardiography. Reproducible absorption spectra of coronary sinus blood were obtained at every defined step of the surgical procedure. Clear ischemia-related changes were detected in none of the patients. CONCLUSIONS: : Our initial results showed that intravascular near-infrared spectroscopic ischemia monitoring is technically feasible. However, the method must be further evaluated and standardized under varying conditions to determine the role of near-infrared spectroscopy as an ischemia monitoring tool in off-pump coronary bypass surgery. PMID- 22436757 TI - Thoracoscopic approach to epicardial lead implantation in adult patients with previous congenital cardiac surgery. AB - BACKGROUND: : Substantial technical challenges exist in placing transvenous pacing leads in the heterogeneous adult congenital heart disease patient population. Anatomical issues including occlusion of central veins, single ventricle physiology, and lack of transvenous access to systemic right ventricles, often require thoracotomy for epicardial lead placement. METHODS: : We assessed the feasibility of performing a totally thoracoscopic approach to epicardial pacing lead implantation in 10 adult patients (mean age 32.5 years) with congenital heart disease. The underlying cardiac anatomy consisted of transposition of the great arteries, status post (s/p) Mustard procedure (3); tricuspid atresia, s/p Fontan procedure (3); congenitally corrected transposition (1); Ebstein's anomaly, s/p tricuspid valve replacement (1); AV canal, s/p repair (1); and hypertrophic cardiomyopathy, s/p myomectomy (1). Twenty-six previous cardiac operations (mean 2.8 per patient) had been performed in this group. RESULTS: : Indications for thoracoscopic lead insertion included primary rhythm disturbances, progressive heart failure with a QRS>120 milliseconds, and an unapproachable coronary sinus or failed transvenous lead insertion. All patients underwent thoracoscopic implantation of 2 epicardial leads to the systemic ventricle and generator insertion. Intraoperative transesophageal echocardiography (TEE) was used in all cases, which facilitated port placement. Measurements at operation showed mean threshold of 2.0V (95% CI 0.9-3.1V at 0.5 milliseconds) and a mean impedance of 1259 Ohms (95% CI 418-2100). There were no procedural related complications and no patient required conversion to an open procedure. Seventy percent of patients were extubated immediately after the procedure and were discharged from the intensive care unit within 24 hours. There was 1 noncardiac death due to gastrointestinal ischemia. CONCLUSION: : Adults with congenital heart disease present significant challenges to pacing lead implantation including variability of the location of the systemic ventricle, coronary sinus anatomy, right-sided valve replacement, a small thoracic cavity, limited vascular access, and adhesions from prior cardiac procedures. Additionally, thoracoscopy has been previously considered a contraindication in this subgroup of patients. However, we have demonstrated that with careful preoperative planning and the assistance of TEE, a totally thoracoscopic approach to epicardial lead implantation is both feasible and safe. PMID- 22436758 TI - Simple amiodarone protocol reduces postoperative atrial fibrillation. AB - BACKGROUND: : Incorporating amiodarone into an existing postoperative atrial fibrillation (AF) prevention pathway may reduce postoperative AF and length of stay (LOS). METHODS: : From July 2002 through December 2002, 476 consecutive cardiac surgical patients were managed with an AF prevention protocol using aggressive potassium replacement, intraoperative/postoperative magnesium supplementation, and postoperative resumption of beta-blockers. From January 2003 through June 2003, 592 additional patients were subjected to the same protocol except amiodarone was initiated intraoperatively (150 mg intravenously) and continued postoperatively until discharge (200 mg orally three times daily). Incidence of AF, postoperative LOS, and AF risk factors were collected prospectively and compared using regression models with propensity scores to adjust for dissimilarities between groups. RESULTS: : Incorporating amiodarone into an existing AF protocol resulted in a 45% reduction in postoperative AF (29% [136/476] versus 16% [94/592], P < 0.0001). After adjustment for covariates and propensity score, the relative risk reduction with amiodarone in this protocol remained significant (P = 0.001, RR 0.65, 95% CI 0.5-0.8). Multivariate risks for postoperative AF included no amiodarone (P = 0.0001), age (P < 0.0001), ejection fraction <40% (P = 0.0005), ventilator support >24 hours (P = 0.002), no postoperative beta-blocker (P = 0.002), and mitral valve procedure (P = 0.03). When postoperative AF did occur, risk adjusted LOS was less in patients on the amiodarone protocol (mean 9.4 days versus 13.1 days, P = 0.06). Readmission after discharge for any reason (10% [49/476] versus 8% [45/592], P = 0.1) or for AF (1.1% [5/476] versus 0.7% [4/592], P = 0.5) was similar between groups. CONCLUSION: : Amiodarone initiated intraoperatively followed by oral dosing significantly reduces postoperative AF and tends to reduce LOS if AF occurs. PMID- 22436759 TI - Use of the navigator probe after radiotracer injection to identify nonpalpable rib lesions requiring surgical resection. AB - BACKGROUND: : Patients with nonpalpable rib lesions (NPRL) requiring biopsy present a challenging problem for the thoracic surgeon. Ideally, a small incision directly over the NPRL should be performed to minimize morbidity, particularly if the lesion is benign. The Navigator probe is routinely used after lymphoscintigraphy by surgical oncologists to isolate sentinel lymph nodes requiring removal, but can also be used to guide resection of nonpalpable focal rib lesions demonstrating increased technetium-99m hydroxymethylene diphosphonate (Tc-99m HDP) uptake. This report describes our initial experience with this technique. METHODS: : Over a 5-month period, 3 patients with focal NPRL underwent rib resection. All patients had solitary lesions demonstrated on recently performed Tc-99m HDP bone scanning. Prior cancers were reported in 2 patients, and pain in 2 patients. Before surgery, all patients underwent intravenous injection of 20 to 25 mCi Tc-99m HDP at least 2 hours before the Navigator probe guided procedure. RESULTS: : The Navigator probe identified all 3 lesions, allowing a single 4 cm or smaller incision in all cases. Histology included metastatic breast cancer (1), pathologic fracture secondary to metastatic palatal cancer (1), and eosinophilic granuloma (1). No patient required further resection. CONCLUSIONS: : Intraoperative localization of NPRL that are positive on Tc-99m HDP bone scanning using the Navigator probe is feasible and was 100% successful in our initial experience. This technique allows a minimally invasive approach, which is beneficial for those patients who do not require further resection. PMID- 22436760 TI - Complex Bileaflet Mitral Valve Repair (Barlow's) Using the da Vinci Robotic Surgical System. AB - Robotic mitral valve repair (RMVR) is less invasive and potentially more precise. However, RMVR lengthens both cardiopulmonary bypass and arrested heart times. In our initial experience, only posterior leaflet repair and/or annuloplasty were performed. With increasing experience, we have performed more complex bileaflet RMVR. A 50-year-old man presented with severe mitral regurgitation. Transesophageal echocardiography (TEE) demonstrated a complex bileaflet prolapse and preserved left ventricular function. Through a 4 cm working port and with the da Vinci Robotic Surgical System (Intuitive Surgical, Sunnyvale, CA) RMVR was performed. Details of the technique and patient's hospital course are described. The repair comprised closure of clefts between A3 and P3, quadrangular resection of P2, transfer of multiple chords from P2 to A2/A3 and a #38 Cosgrove-Edwards (Edwards Lifesciences, Irvine, CA) band annuloplasty. Nitinol U-Clips (Medtronic, Minneapolis, MN) were used to complete the annuloplasty. Postoperative TEE showed no mitral regurgitation. The patient was discharged on the third postoperative day. Cardiopulmonary bypass and arrested heart times were 3 hours and 29 minutes and 2 hours and 59 minutes, respectively. Complex bileaflet repair of mitral valve with Barlow's disease can be successfully performed with the da Vinci Robotic Surgical System. Long-term follow-up is needed to assess the durability of repair. PMID- 22436761 TI - Image-guided surgical ligation of the supreme branch of left internal mammary artery: a case report. PMID- 22436762 TI - Complete repair of a total defect type aortopulmonary window in an extremely low birth weight neonate. AB - The authors performed a complete repair for a total defect type aortopulmonary window (APW) in an extremely low birth weight neonate weighing 1.1 kg. The APW was repaired using an autologous pericardial patch. A novel cardiopulmonary bypass system with low priming volume allowed a safe surgery for the premature patient. PMID- 22436763 TI - Off-pump Coronary Artery Bypass Leads to a Regional Hypercoagulable State Not Detectable Using Systemic Markers. PMID- 22436764 TI - An oscillatory mechanism for prioritizing salient unattended stimuli. AB - To survive in a complex world, it is important that unattended, but salient, input can still draw one's attention. In this article, we suggest that posterior alpha oscillations (8-13Hz) provide a mechanism for prioritizing and ordering unattended visual input according to 'relevance'. Gamma oscillations (30-100Hz) that are phase-locked to the alpha oscillations keep competing unattended representations apart in time, thus creating a sequence of perceptual cycles. As inhibition gradually lowers within an alpha cycle, the ordered sequence of competing input is activated, producing a temporal phase code for saliency. The proposed mechanism is based on recent experiments indicating that the phase of alpha activity modulates perception and that alpha oscillations are produced by periodic pulses of inhibition. PMID- 22436765 TI - Histopathological evaluation of a novel radiofrequency surgical ablation system. AB - PURPOSE: : Using a porcine model, this feasibility study was undertaken to evaluate the histopathological characteristics of lesions created in the proximity of the pulmonary veins after ablation with a new endoscopic-guided radiofrequency device. METHODS: : Five adult female swine underwent endoscopic surgical ablation on the epicardial surface of the beating heart. Histologic sections taken from around the pulmonary vein pedicle, representing 10 separate anatomic sites, underwent independent qualitative histopathological evaluation as well as quantitative histomorphometric measurement of lesion depth and section thickness. RESULTS: : Sections from all five animals had histologically identical lesions, with the majority of ablation foci having pronounced thermal injury characterized by deep and extensive zones of acute myocardial necrosis in the absence of tissue charring. Fifty-seven percent (13 of 23) of the lesions were completely transmural and 91% (21 of 23) of the sections demonstrated >=70% transmurality. No collateral injuries were noted. CONCLUSIONS: : This irrigated, suction-stabilized unipolar radiofrequency device can produce histologically transmural lesions around the pulmonary veins and is amenable to endoscopic guided application on the beating heart. PMID- 22436766 TI - Robotically Assisted Beating Heart Totally Endoscopic Coronary Artery Bypass (TECAB). Is There a Future? AB - OBJECTIVE: : Since the introduction of beating heart totally endoscopic coronary artery bypass (TECAB), approximately 400 patients have undergone the procedure worldwide. Despite satisfactory results and reduced morbidity, the procedure has not gained wide acceptance. This report describes the authors' experience of beating heart TECAB with robotic assistance and the potential adoption of this technique for the future. METHODS: : Between July 2004 and December 2005, 93 patients underwent successful for beating heart TECAB (47 males and 46 females). Mean age was 67.4 + 12.3 years. Fifteen (13.8%) were excluded or converted intraoperatively to thoracotomy for completion of procedure. The procedure was performed through port incisions for the robotic arms and the endostabilizer. Single or bilateral internal thoracic arteries were used as conduits. Anastomoses were done using surgical U-clips. Eighteen (19.4%) patients underwent planned hybrid revascularization. Eighty-four (90.3%) patients underwent computed tomography or conventional angiography. RESULTS: : Details of 93 completed revascularization cases are summarized in the tables. No in-hospital mortality, myocardial infarction, or CVA was noted. Mean operative time was 272.6 + 128.9 minutes (median, 270 minutes). Mean anastomotic time was 13.8 + 3.7 minutes. Mean length of hospital stay was 3.4 + 2.0 days (median, 3 days). At the time of study, 122 of 122 (100%) grafts were found to be patent. CONCLUSIONS: : Single- and multivessel beating heart TECAB with or without hybrid revascularization may offer a less invasive approach in a selected group of patients. PMID- 22436767 TI - Highly efficient disulfide bridging polymers for bioconjugates from radical compatible dithiophenol maleimides. AB - The direct synthesis of dithiophenol maleimide functional polymers by living radical polymerisation is described without the need for protecting group chemistry. The synthesised polymers have been successfully employed as disulfide bridging agents for salmon calcitonin when used in equimolar quantities, negating the requirement for complex purification strategies, traditionally associated with peptide bioconjugation. PMID- 22436768 TI - Techniques of aortic valve repair. AB - Similar to mitral repair, newer methods of aortic valve reconstruction are achieving excellent outcomes with an 85% to 90% freedom from valve-related complications at 10 years. The goal of this review is to illustrate these newer and more stable techniques of aortic valve repair. Most patients with aortic insufficiency from either trileaflet or bicuspid aortic valves are candidates for repair, in addition to selected patients with mixed aortic stenosis/insufficiency and aortic root aneurysms. Initially, aggressive commissural annuloplasty is performed to reduce measured valve diameter to 19 to 21 mm. Leaflet prolapse is corrected with plication stitches placed in the free edge of each leaflet adjacent to the Nodulus Arantius. In this regard, the leaflet free edge functions as the chorda tendinea of the aortic valve, and shortening with plication stitches raises the leaflet to a proper "effective height." Leaflet defects are augmented with gluteraldehyde-fixed autologous pericardium, and mild-to-moderate strategically placed spicules of calcium are removed with the cavitron ultrasonic surgical aspirator. Using these methods, most insufficient aortic valves, and many with mixed lesions, can be satisfactorily repaired. Six cases are illustrated in this review, spanning the spectrum of pathologies from annular dilatation without leaflet defects, to standard congenital bicuspid valve with prolapse, to trileaflet prolapse, to unusual bicuspid pathology with calcification, to a moderately calcified trileaflet valve with mixed lesions, and to aortic root aneurysms with severe aortic insufficiency. All valves were repaired using the techniques described above with trivial residual leak and minimal gradients. All repairs have been followed with yearly echocardiography, and valve reconstruction with these methods is now quite stable with excellent late outcomes. Most insufficient aortic valves now can undergo stable repair with minimal late valve-related complications. Greater application of aortic valve repair seems indicated. PMID- 22436769 TI - Experience with robotic lobectomy for lung cancer. AB - OBJECTIVE: In this study, we analyze our experience so far with robotic pulmonary lobectomy, compare it with published data, and suggest a learning curve for the operation. METHODS: Ninety-one patients with suspected or proven clinical stage I III lung cancer underwent robotic lobectomy. Selection criteria included lesion <5 cm and normal respiratory function. One surgeon performed the operations using the da Vinci system with three ports and a 3-cm utility thoracotomy. RESULTS: Median duration of operation was 239 (range 85-411) minutes, 260 minutes in the first 18 patients and 221 minutes in the remaining 73 cases (P=0.01). Median hospitalization declined from 6 days in the first 18 cases to 5 days in the remaining cases (P=0.002). Conversion rate and number of complications reduced nonsignificantly from the initial to later series. Major complications occurred in 11% of the first 18 cases and 4% of the later cases. The number of lymph nodes removed did not change over the two series. There was no 30-day postoperative mortality. After a median follow-up of 24 months, 80 of 91 patients were alive with no sign of disease. CONCLUSIONS: Our data suggest that about 20 operations are required to achieve surgical competence. Robotic lobectomy appears safe, oncologically radical, and associated with shorter postoperative hospitalization than open surgery. PMID- 22436770 TI - Transaxillary approach: short- and mid-term results in a single-center experience. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) is increasingly accepted as an alternative procedure in patients with severe, symptomatic aortic stenosis and high risk for surgical aortic valve replacement. Transfemoral (TF) approach is the first option when feasible, but in case of peripheral vascular disease this approach is precluded. In our institution, for this kind of patients we considered transaxillary (TAx) approach as second choice and transapical (TAp) or transaortic (TAa) as last routes. This study describes short- and mid-term morbidity and mortality for TAx approach. METHODS: From November 2007 to March 2011, 284 patients underwent TAVI at our site; 229 treated by TF approach, 22 TAp, 2 TAa, and 31 TAx. Four patients were treated with an Edwards Sapien valve (Edwards Lifesciences, Inc., Irvine, CA USA) with TAx approach and 27 with CoreValve Revalving System (Medtronic Inc., Minneapolis, MN USA). TAx TAVI was performed in cath-laboratory with local anesthesia and mild sedation by a multispeciality valve team. We analyzed major adverse cardiac and cerebrovascular events, major adverse valve-related events, vascular complications, and 30 days and 6 months mortality. RESULTS: The procedural success rate (successful implantation of the device without intraprocedural mortality or need to conversion to open heart surgery) was 96.8% (30/31). Major adverse valve-related events were 12.9% (4/31). 30-day mortality was 6.4% (2/31) and actuarial survival at 6 months was 82.95% +/- 7.96%. In one patient, procedure was converted to a TF CoreValve in emergency for hemodynamic instability after valvuloplasty due to severe difficulty to introduce the Edwards valve in the subclavian artery. CONCLUSIONS: TAx approach is a feasible and technically simple procedure with encouraging results considering morbidity and mortality at short- and mid-term follow-up. TAx is a valid solution in patients with contraindications to TF approach and it is an alternative approach potentially less invasive than TAp or TAa. PMID- 22436771 TI - Hybrid repair of thoracic and thoracoabdominal aortic aneurysms (mega aortic syndrome) with lupiae technique. AB - OBJECTIVE: Several techniques have been described for the treatment of thoracic and thoracoabdominal aneurysms in patients with mega aortic syndrome (MAS), but the incidence of stroke, spinal cord injury, and endoleaks remains high. We present the midterm results of a new hybrid, multistep technique to treat patients with MAS. METHODS: From November 2005 to January 2011, 80 patients with MAS underwent hybrid repair of thoracic and thoracoabdominal aneurysms with the Lupiae technique. Forty-six patients presented with chronic aortic aneurysms, and 34 patients who had undergone aortic arch debranching with the Lupiae graft for acute aortic dissection presented with an expanding false lumen into the residual aorta. Sixty patients underwent ascending aorta and arch replacement with a Gelweave Lupiae prosthesis plus epiaortic vessel debranching (thoracic Lupiae procedure). Fourteen patients underwent a thoracic Lupiae procedure plus partial visceral debranching (celiac trunk and superior mesenteric artery) through a mini laparotomy. Six patients underwent a thoracic Lupiae procedure plus a complete visceral debranching (celiac trunk, superior mesenteric artery, and renal arteries) with the implant of a second Lupiae prosthesis to replace the abdominal aorta. After the surgical steps, all the surviving patients underwent an endovascular procedure to implant multiple stent grafts to exclude the residual segment of diseased aorta. RESULTS: In-hospital mortality was 8.4%, and the incidence of temporary renal failure was 5.2%. None of the patients had a stroke or a spinal cord injury, and none of the patients presented endoleaks immediately following the procedure or during the follow-up computed tomography scans. No deaths occurred during the 6-year follow-up after the hybrid procedure. CONCLUSIONS: These preliminary results showed that the Lupiae technique is a safe and effective option for the treatment of patients with MAS. Indeed, the Lupiae technique achieves complete exclusion of thoracic and thoracoabdominal aneurysms with a low risk of paraplegia and endoleaks. PMID- 22436772 TI - Surgical treatment for isolated atrial fibrillation: minimally invasive vs. classic cut and sew maze. AB - OBJECTIVE: We sought to compare outcomes after two surgical approaches for the treatment of atrial fibrillation (AF): a minimally invasive, staged hybrid approach combining surgery with catheter ablation, [Hybrid Maze (HM)] and the classic cut and sew Maze (CM). METHODS: From April 2004 to March 2010, 63 stand alone AF procedures were performed by two surgeons at a single center and followed up for >=6 months. CM was offered to all patients. After July 2007, patients were also prospectively offered a two-stage HM: stage 1 = a beating heart bipolar radiofrequency pulmonary vein isolation and left atrial appendage ligation; stage 2 = transvenous catheter ablation connecting the pulmonary veins to each other and the mitral annulus when AF was present after stage 1. Outcomes were compared between 25 HM and 38 CM using chi or Fisher exact test analysis. RESULTS: Postoperatively, there was no difference in 30-day mortality (0%), complications (4% HM vs. 18% CM), or median length of stay (5 days). At last follow-up, 88% of HM and 95% of CM were free from AF; 80% of HM and 90% of CM were free from AF and antiarrhythmic medication (P >= 0.3). Twenty-nine percent of HM required a subsequent catheter ablation (stage 2) when compared with 8% of the CM patients (P = 0.04). Freedom from AF and antiarrhythmic medication at 1 year was 52% for the HM and 87.5% for the CM (P = 0.004). CONCLUSIONS: In AF patients reluctant to undergo a CM but willing to undergo subsequent catheter ablation, a minimally invasive approach is a reasonable strategy. Because pulmonary vein isolation alone may be sufficient in two-thirds of patients and delayed reconnection is common, an interval two-stage hybrid approach may prove preferable over a one-stage combined hybrid approach; however, successful sinus restoration may take longer with this approach. PMID- 22436773 TI - Perceval sutureless aortic valve prosthesis: easy, fast, and safe. AB - OBJECTIVE: There is an increase of old patients needing aortic valve surgery. Especially in this age group, a lot of new less-invasive strategies are proposed. Our goal was to study whether a sutureless aortic valve, which is implanted surgically after removal of the native valve, could be an alternative for a subgroup of patients. METHODS: The Sorin Perceval S is a biologic pericardial aortic valve assembled in a metal super elastic alloy stent and implanted in the aortic root without the need of suturing. As part of a premarketing multicenter study (Cavalier trial), 34 patients were screened for Perceval S implantation. All patients underwent cardiopulmonary bypass and mini-invasive approach (partial upper sternotomy). RESULTS: Fourteen patients were excluded due to standardized criteria. Twenty patients received a 21-mm valve (2 patients), 23-mm valve (6 patients), or 25-mm valve (12 patients). X-clamp time was 20.6 +/- 7.6 minutes, and implantation time was 8.6 +/- 3.1 minutes. Intra- and postoperative echocardiography showed no paravalvular leakage, low gradients (max 16.3 +/- 5, mean 9.8 +/- 4.2), and two patients with an intraprosthesis reflux (one patient with 1/4+, one patient with 2/4+). All patients were discharged without major in hospital complications (intensive care unit stay 1.4 +/- 0.5 days, hospital stay 7 +/- 0.7 days). CONCLUSIONS: The sutureless Perceval S aortic valve is hemodynamically excellent and a safe prosthesis in selected patients. Due to a simple and fast implantation technique, this valve could guarantee a shorter operation time in combination with a mini-invasive approach. PMID- 22436774 TI - Pilot study of sternal plating for primary closure of the sternum in cardiac surgical patients. AB - OBJECTIVE: Postoperative sternal wound complications are a significant problem in high-risk patients. In addition to closure with conventional wires, several systems involving rigid fixation with metal plates are currently available. The rapid sternal closure system (Talon) is approved for stabilization and fixation of the anterior chest wall. Anecdotal evidence suggests that use of the Talon may result in improved postoperative recovery. METHODS: Fifty-one cardiac surgical patients at higher risk for sternal wound complications were enrolled at two sites. Subjects were randomized to insertion of Talons (n = 28) or wires only (control, n = 23) for sternal closure. The primary endpoint was a comparison between study groups of the percent of baseline incentive spirometry volume through postoperative day 7. Secondary endpoints included other measures of quality of recovery, sternal wound infection, and nonunion. RESULTS: The percentage of preoperative incentive spirometry volume achieved was higher in the Talon arm (67% +/- 32%) versus control (58% +/- 24%); however, this was not statistically significant (P = 0.41). Use of the Talon was associated with decreased use of opiates (21.3 +/- 11.8 vs. 25.4 +/- 21.6 mg, P = 0.44), increased ability to ambulate 1000 ft on postoperative day 5 (25% vs. 13%, P = 0.28), and decreased duration of mechanical ventilation (median 0.5 vs 1.0 days, P = 0.24) and hospital length of stay (4.5 +/- 3.2 vs. 5.3 +/- 4.0 days, P = 0.40). One superficial sternal wound infection was observed in each study arm. There were no cases of nonunion. CONCLUSIONS: In this pilot study, the primary endpoint was not statistically different between the treatment groups. Use of the Talon was associated with trends toward benefit in endpoints consistent with enhanced postoperative recovery, highlighting a need for additional data from larger randomized trials. PMID- 22436775 TI - Concomitant transapical transcatheter aortic valve implantation and minimally invasive direct coronary artery bypass. AB - We represent a successful minimally invasive combined off-pump procedure consisting of a transapical aortic valve implantation and a direct coronary artery bypass grafting in a woman with a severe aortic stenosis and a critical coronary artery disease. Due to her comorbidities, she was classified as a high risk patient qualifying for a transcatheter procedure. We performed this combined procedure in a hybrid operation room, starting with the coronary bypass to maintain a coronary blood flow during the transapical valve implantation. The operation processed without any complications and she was discharged at the seventh postoperative day into the allocating hospital. PMID- 22436776 TI - Robotically assisted coronary endarterectomy. AB - Robotic assistance has enabled coronary artery bypass surgery to be performed safely in a completely endoscopic fashion, but diffusely diseased target vessels may pose a technical challenge. We present a case in which coronary endarterectomy was performed on the left anterior descending coronary artery during a two-vessel totally endoscopic coronary artery bypass procedure. A 52 year-old woman presented with intermittent substernal pain. Preoperative studies showed diffuse disease in the left coronary artery system. Bilateral internal mammary arteries were harvested robotically using a skeletonized technique in a completely endoscopic fashion. Cardiopulmonary bypass was achieved via peripheral cannulation, and the heart was arrested with intermittent cold antegrade hyperkalemic blood cardioplegia delivered via an ascending aortic occlusion balloon catheter. The first obtuse marginal anastomosis was performed. The left anterior descending coronary artery was diffusely diseased and heavily calcified. An end-to-side anastomosis was attempted to the right internal mammary artery with unsatisfactory results. A localized coronary endarterectomy was performed, and an extended anastomosis was completed using the right internal mammary artery. The patient recovered uneventfully and was discharged home on postoperative day 6. Diffuse coronary artery disease was once thought to be a prohibitive challenge for minimally invasive coronary bypass procedures. This case demonstrates that local coronary endarterectomy is feasible and safe in robotic totally endoscopic coronary artery bypass surgery. PMID- 22436777 TI - Transcatheter aortic valve implantation and hybrid coronary artery revascularization: time to combine them. AB - We report on simultaneous off-pump coronary artery bypass grafting to the left anterior descending artery, modified transapical aortic valve implantation, and stenting of the circumflex and right coronary arteries in an 84-year-old patient. The poly-morbid patient with a logistic EuroSCORE of 85% experienced recent myocardial infarction; the left ventricular ejection fraction was reduced to 20%. Postoperative recovery was fast and short. The strategy described is the next logical step in broadening the indication for transcatheter aortic valve interventions. PMID- 22436778 TI - Chest wall resection and reconstruction: a true thoracoscopic approach. AB - We set out to perform resection of a chest wall mass with subsequent reconstruction using a pure thoracoscopic approach. Using video-assisted thoracic surgery via a three-incision approach, we successfully removed an 8.5 * 3.5-cm specimen en bloc. We then reconstructed the chest wall with 2-mm polytetrafluoroethylene. A total thoracoscopic approach to chest wall resection and reconstruction represent an additional option in this area of thoracic surgery. This approach avoids some of the drawbacks of more invasive procedures. This report outlines a totally thoracoscopic approach that we feel represents a safe and viable option for patients requiring chest wall resection and reconstruction. PMID- 22436779 TI - Wire network behavior in superconducting Nb films with diluted triangular arrays of holes. AB - We present results of transport measurements on superconducting Nb films with diluted triangular arrays (honeycomb and kagome) of holes. The patterned films have large disk-shaped interstitial regions even when the edge-to-edge separations between nearest neighboring holes are comparable to the coherence length. Changes in the field interval of two consecutive minima in the field dependent resistance R(H) curves are observed. In the low field region, fine structures in the R(H) and T(c)(H) curves are identified in both arrays. Comparison of experimental data with calculation results reveals that these structures observed in honeycomb and kagome hole arrays resemble those in wire networks with triangular and T(3) symmetries, respectively. The findings suggest that even in these specified periodic hole arrays with very large interstitial regions, the low field fine structures are determined by the connectivity of the nanostructures. PMID- 22436780 TI - Determination of microcystin-LR in waters in the subnanomolar range by sol-gel imprinted polymers on solid contact electrodes. AB - The present work reports new sensors for the direct determination of Microcystin LR (MC-LR) in environmental waters. Both selective membrane and solid contact were optimized to ensure suitable analytical features in potentiometric transduction. The sensing layer consisted of Imprinted Sol-Gel (ISG) materials capable of establishing surface interactions with MC-LR. Non-Imprinted Sol-Gel (NISG) membranes were used as negative control. The effects of an ionic lipophilic additive, time of sol-gel polymerization, time of extraction of MC-LR from the sensitive layer, and pH were also studied. The solid contact was made of carbon, aluminium, titanium, copper or nickel/chromium alloys (80 : 20 or 90 : 10). The best ISG sensor had a carbon solid contact and displayed average slopes of 211.3 mV per decade, with detection limits of 7.3 * 10(-10) M, corresponding to 0.75 MUg L(-1). It showed linear responses in the range of 7.7 * 10(-10) to 1.9 * 10(-9) M of MC-LR (corresponding to 0.77-2.00 MUg L(-1)), thus including the limiting value for MC-LR in waters (1.0 MUg L(-1)). The potentiometric selectivity coefficients were assessed by the matched potential method for ionic species regularly found in waters up to their limiting levels. Chloride (Cl(-)) showed limited interference while aluminium (Al(3+)), ammonium (NH(4)(+)), magnesium (Mg(2+)), manganese (Mn(2+)), sodium (Na(+)), and sulfate (SO(4)(2-)) were unable to cause the required potential change. Spiked solutions were tested with the proposed sensor. The relative errors and standard deviation obtained confirmed the accuracy and precision of the method. It also offered the advantages of low cost, portability, easy operation and suitability for adaptation to flow methods. PMID- 22436781 TI - Dose--volume effects on patient-reported acute gastrointestinal symptoms during chemoradiation therapy for rectal cancer. AB - PURPOSE: Research on patient-reported outcomes (PROs) in rectal cancer is limited. We examined whether dose-volume parameters of the small bowel and large bowel were associated with patient-reported gastrointestinal (GI) symptoms during 5-fluorouracil (5-FU)-based chemoradiation treatment for rectal cancer. METHODS AND MATERIALS: 66 patients treated at the Brigham & Women's Hospital or Massachusetts General Hospital between 2006 and 2008 were included. Weekly during treatment, patients completed a questionnaire assessing severity of diarrhea, urgency, pain, cramping, mucus, and tenesmus. The association between dosimetric parameters and changes in overall GI symptoms from baseline through treatment was examined by using Spearman's correlation. Potential associations between these parameters and individual GI symptoms were also explored. RESULTS: The amount of small bowel receiving at least 15 Gy (V15) was significantly associated with acute symptoms (p = 0.01), and other dosimetric parameters ranging from V5 to V45 also trended toward association. For the large bowel, correlations between dosimetric parameters and overall GI symptoms at the higher dose levels from V25 to V45 did not reach statistical significance (p = 0.1), and a significant association was seen with rectal pain from V15 to V45 (p < 0.01). Other individual symptoms did not correlate with small bowel or large bowel dosimetric parameters. CONCLUSIONS: The results of this study using PROs are consistent with prior studies with physician-assessed acute toxicity, and they identify small bowel V15 as an important predictor of acute GI symptoms during 5-FU-based chemoradiation treatment. A better understanding of the relationship between radiation dosimetric parameters and PROs may allow physicians to improve radiation planning to optimize patient outcomes. PMID- 22436782 TI - Dose--volume metrics associated with radiation pneumonitis after stereotactic body radiation therapy for lung cancer. AB - PURPOSE: To identify dose-volume factors associated with radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for lung cancer. METHODS AND MATERIALS: This study analyzed 74 patients who underwent SBRT for primary lung cancer. The prescribed dose for SBRT was uniformly 48 Gy in four fractions at the isocenter. RP was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.3. Symptomatic RP was defined as grade 2 or worse. Optimal cut-offs dividing the patient population into two subgroups based on the incidence of symptomatic RP were sought using the following dose-volume metrics: PTV volume (ml), mean lung dose (Gy), and V5, V10, V15, V20, V25, V30, V35, and V40 (%) of both lungs excluding the PTV. RESULTS: With a median follow-up duration of 31.4 months, symptomatic RP was observed in 15 patients (20.3%), including 1 patient with grade 3. Optimal cut-offs for pulmonary dose-volume metrics were V25 and V20. These two factors were highly correlated with each other, and V25 was more significant. Symptomatic RP was observed in 14.8% of the patients with V25 <4.2%, and the rate was 46.2% in the remainder (p = 0.019). PTV volume was another significant factor. The symptomatic RP rate was significantly lower in the group with PTV <37.7 ml compared with the larger PTV group (11.1% vs. 34.5%, p = 0.020). The patients were divided into three subgroups (patients with PTV <37.7 ml; patients with, PTV >=37.7 ml and V25 <4.2%; and patients with PTV >=37.7 ml and V25 >=4.2%); the incidence of RP grade 2 or worse was 11.1%, 23.5%, and 50.0%, respectively (p = 0.013). CONCLUSIONS: Lung V25 and PTV volume were significant factors associated with RP after SBRT. PMID- 22436783 TI - Dosimetric and clinical outcomes of involved-field intensity-modulated radiotherapy after chemotherapy for early-stage Hodgkin's lymphoma with mediastinal involvement. AB - PURPOSE: To evaluate the dosimetric and clinical outcomes of involved-field intensity-modulated radiotherapy (IF-IMRT) for patients with early-stage Hodgkin's lymphoma (HL) with mediastinal involvement. METHODS AND MATERIALS: Fifty-two patients with early-stage HL that involved the mediastinum were reviewed. Eight patients had Stage I disease, and 44 patients had Stage II disease. Twenty-three patients (44%) presented with a bulky mediastinum, whereas 42 patients (81%) had involvement of both the mediastinum and either cervical or axillary nodes. All patients received combination chemotherapy followed by IF IMRT. The prescribed radiation dose was 30-40 Gy. The dose-volume histograms of the target volume and critical normal structures were evaluated. RESULTS: The median mean dose to the primary involved regions (planning target volume, PTV1) and boost area (PTV2) was 37.5 Gy and 42.1 Gy, respectively. Only 0.4% and 1.3% of the PTV1 and 0.1% and 0.5% of the PTV2 received less than 90% and 95% of the prescribed dose, indicating excellent PTV coverage. The median mean lung dose and V20 to the lungs were 13.8 Gy and 25.9%, respectively. The 3-year overall survival, local control, and progression-free survival rates were 100%, 97.9%, and 96%, respectively. No Grade 4 or 5 acute or late toxicities were reported. CONCLUSIONS: Despite the large target volume, IF-IMRT gave excellent dose coverage and a favorable prognosis, with mild toxicity in patients with early stage mediastinal HL. PMID- 22436784 TI - Four-dimensional measurement of the displacement of internal fiducial and skin markers during 320-multislice computed tomography scanning of breast cancer. AB - PURPOSE: To study the three-dimensional movement of internal tumor bed fiducial and breast skin markers, using 320-multislice computed tomography (CT); and to analyze intrafractional errors for breast cancer patients undergoing breast irradiation. METHODS AND MATERIALS: This study examined 280 markers on the skin of the breast (200 markers) and on the primary tumor bed (80 markers) of 20 patients treated by external-beam photon radiotherapy. Motion assessment was analyzed in 41 respiratory phases during 20 s of cine CT in the radiotherapy position. To assess intrafractional errors resulting from respiratory motion, four-dimensional CT scans were acquired for 20 patients. RESULTS: Motion in the anterior-posterior (A/P) and superior-inferior (S/I) directions showed a strong correlation (|r| > 0.7) with the respiratory curve for most markers (79% and 70%, respectively). The average marker displacements between maximum and minimum value during 20 s for the 200 breast skin metal markers were 1.1 +/- 0.3 mm, 2.1 +/- 0.6 mm, and 1.6 +/- 0.4 mm in the left-right, A/P, and S/I directions, respectively. For the 80 tumor bed clips, displacements were 0.9 +/- 0.2 mm in left-right, 1.7 +/- 0.5 mm in A/P, and 1.1 +/- 0.3 mm in S/I. There was no significant difference in the motion between breast quadrant regions or between the primary site and the other regions. CONCLUSIONS: Motion in primary breast tumors was evaluated with 320-multislice CT. Very little change was detected during individual radiation treatment fractions. PMID- 22436785 TI - Characterization and management of interfractional anatomic changes for pancreatic cancer radiotherapy. AB - PURPOSE: To quantitatively characterize interfractional anatomic variations in pancreatic cancer radiotherapy (RT) and to study dosimetric advantages for using an online adaptive replanning scheme to account for these variations. METHODS AND MATERIALS: Targets and organs at risk (OAR) were delineated by autosegmentation based on daily computed tomography (CT) images acquired using a respiration-gated in-room CT during daily image-guided RT (IGRT) for 10 pancreatic cancer patients. Various parameters, including the maximum overlap ratio (MOR) between the volumes based on planning and daily CTs for a structure, while the overlapping volumes were maximized, were used to quantify the interfractional organ deformation with the intrafractional variations largely excluded. An online adaptive RT (ART) was applied to these daily CTs. To evaluate the dosimetric benefits of ART, the dose distributions from the online ART were compared to those from the repositioning in the current standard IGRT practice. RESULTS: The interfractional anatomic variations, particularly the organ deformation, are significant during pancreas irradiation. For the patients studied, the average MORs of all daily CTs were 80.2%, 61.7%, and 72.2% for pancreatic head, duodenum, and stomach, respectively. The online ART leads to improved dosimetric plan with better target coverage and/or OAR sparing than IGRT repositioning. For the patients studied, the mean V(50.4 Gy) (volume covered by 50.4 Gy) for the duodenum was reduced from 43.4% for IGRT to 15.6% for the online ART scheme. CONCLUSIONS: The online adaptive RT scheme can effectively account for the significant interfractional anatomic variations observed in pancreas irradiation. The dosimetric advantages with the online ART may enable safe dose escalation in radiation therapy for pancreatic cancer. PMID- 22436786 TI - Kilovoltage rotational external beam radiotherapy on a breast computed tomography platform: a feasibility study. AB - PURPOSE: To demonstrate the feasibility of a dedicated breast computed tomography (bCT) platform to deliver rotational kilovoltage (kV) external beam radiotherapy (RT) for partial breast irradiation, whole breast irradiation, and dose painting. METHODS AND MATERIALS: Rotational kV-external beam RT using the geometry of a prototype bCT platform was evaluated using a Monte Carlo simulator. A point source emitting 178 keV photons (approximating a 320-kVp spectrum with 4-mm copper filtration) was rotated around a 14-cm voxelized polyethylene disk (0.1 cm tall) or cylinder (9 cm tall) to simulate primary and primary plus scattered photon interactions, respectively. Simulations were also performed using voxelized bCT patient images. Beam collimation was varied in the x-y plane (1-14 cm) and in the z-direction (0.1-10 cm). Dose painting for multiple foci, line, and ring distributions was demonstrated using multiple rotations with varying beam collimation. Simulations using the scanner's native hardware (120 kVp filtered by 0.2-mm copper) were validated experimentally. RESULTS: As the x-y collimator was narrowed, the two-dimensional dose profiles shifted from a cupped profile with a high edge dose to an increasingly peaked central dose distribution with a sharp dose falloff. Using a 1-cm beam, the cylinder edge dose was <7% of the dose deposition at the cylinder center. Simulations using 120-kVp X-rays showed distributions similar to the experimental measurements. A homogeneous dose distribution (<2.5% dose fluctuation) with a 20% decrease in dose deposition at the cylinder edge (i.e., skin sparing) was demonstrated by weighted summation of four dose profiles using different collimation widths. Simulations using patient bCT images demonstrated the potential for treatment planning and image-guided RT. CONCLUSIONS: Rotational kV-external beam RT for partial breast irradiation, dose painting, and whole breast irradiation with skin sparing is feasible on a bCT platform with the potential for high-resolution image-guided RT. PMID- 22436787 TI - Radiotherapy treatment planning for testicular seminoma. AB - Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 * 1-2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior-posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior-posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e.g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy). PMID- 22436788 TI - Impact of heterogeneity-based dose calculation using a deterministic grid-based Boltzmann equation solver for intracavitary brachytherapy. AB - PURPOSE: To investigate the dosimetric impact of the heterogeneity dose calculation Acuros (Transpire Inc., Gig Harbor, WA), a grid-based Boltzmann equation solver (GBBS), for brachytherapy in a cohort of cervical cancer patients. METHODS AND MATERIALS: The impact of heterogeneities was retrospectively assessed in treatment plans for 26 patients who had previously received (192)Ir intracavitary brachytherapy for cervical cancer with computed tomography (CT)/magnetic resonance-compatible tandems and unshielded colpostats. The GBBS models sources, patient boundaries, applicators, and tissue heterogeneities. Multiple GBBS calculations were performed with and without solid model applicator, with and without overriding the patient contour to 1 g/cm(3) muscle, and with and without overriding contrast materials to muscle or 2.25 g/cm(3) bone. Impact of source and boundary modeling, applicator, tissue heterogeneities, and sensitivity of CT-to-material mapping of contrast were derived from the multiple calculations. American Association of Physicists in Medicine Task Group 43 (TG-43) guidelines and the GBBS were compared for the following clinical dosimetric parameters: Manchester points A and B, International Commission on Radiation Units and Measurements (ICRU) report 38 rectal and bladder points, three and nine o'clock, and (D2cm3) to the bladder, rectum, and sigmoid. RESULTS: Points A and B, D(2) cm(3) bladder, ICRU bladder, and three and nine o'clock were within 5% of TG-43 for all GBBS calculations. The source and boundary and applicator account for most of the differences between the GBBS and TG-43 guidelines. The D(2cm3) rectum (n = 3), D(2cm3) sigmoid (n = 1), and ICRU rectum (n = 6) had differences of >5% from TG-43 for the worst case incorrect mapping of contrast to bone. Clinical dosimetric parameters were within 5% of TG-43 when rectal and balloon contrast were mapped to bone and radiopaque packing was not overridden. CONCLUSIONS: The GBBS has minimal impact on clinical parameters for this cohort of patients with unshielded applicators. The incorrect mapping of rectal and balloon contrast does not have a significant impact on clinical parameters. Rectal parameters may be sensitive to the mapping of radiopaque packing. PMID- 22436789 TI - Locally advanced prostate cancer: three-dimensional magnetic resonance spectroscopy to monitor prostate response to therapy. AB - PURPOSE: To correlate results of three-dimensional magnetic resonance spectroscopic imaging (MRSI) with prostate-specific antigen (PSA) levels and time since external beam irradiation (EBRT) in patients treated with long-term hormone therapy (HT) and EBRT for locally advanced disease to verify successful treatment by documenting the achievement of metabolic atrophy (MA). METHODS AND MATERIALS: Between 2006 and 2008, 109 patients were consecutively enrolled. MA was assessed by choline and citrate peak area-to-noise-ratio <5:1. Cancerous metabolism (CM) was defined by choline-to-creatine ratio >1.5:1 or choline signal-to-noise-ratio >5:1. To test the strength of association between MRSI results and the time elapsed since EBRT (TEFRT), PSA levels, Gleason score (GS), and stage, logistic regression (LR) was performed. p value <0.05 was statistically significant. The patients' outcomes were verified in 2011. RESULTS: MRSI documented MA in 84 of 109 and CM in 25 of 109 cases. LR showed that age, GS, stage, and initial and recent PSA had no significant impact on MRSI results which were significantly related to PSA values at the time of MRSI and to TEFRT. Patients were divided into three groups according to TEFRT: <1 year, 1-2 years, and >2 years. MA was detected in 54.1% of patients of group 1, 88.9% of group 2, and in 94.5% of group 3 (100% when PSA nadir was reached). CM was detected in 50% of patients with reached PSA nadir in group 1. Local relapse was found in 3 patients previously showing CM at long TEFRT. CONCLUSION: MA detection, indicative of successful treatment because growth of normal or abnormal cells cannot occur without metabolism, increases with decreasing PSA levels and increasing time on HT after EBRT. This supports long-term HT in advanced prostate cancer. Larger study series are needed to assess whether MRSI could predict local relapse by detecting CM at long TEFRT. PMID- 22436790 TI - A research agenda for radiation oncology: results of the radiation oncology institute's comprehensive research needs assessment. AB - PURPOSE: To promote the rational use of scarce research funding, scholars have developed methods for the systematic identification and prioritization of health research needs. The Radiation Oncology Institute commissioned an independent, comprehensive assessment of research needs for the advancement of radiation oncology care. METHODS AND MATERIALS: The research needs assessment used a mixed method, qualitative and quantitative social scientific approach, including structured interviews with diverse stakeholders, focus groups, surveys of American Society for Radiation Oncology (ASTRO) members, and a prioritization exercise using a modified Delphi technique. RESULTS: Six co-equal priorities were identified: (1) Identify and develop communication strategies to help patients and others better understand radiation therapy; (2) Establish a set of quality indicators for major radiation oncology procedures and evaluate their use in radiation oncology delivery; (3) Identify best practices for the management of radiation toxicity and issues in cancer survivorship; (4) Conduct comparative effectiveness studies related to radiation therapy that consider clinical benefit, toxicity (including quality of life), and other outcomes; (5) Assess the value of radiation therapy; and (6) Develop a radiation oncology registry. CONCLUSIONS: To our knowledge, this prioritization exercise is the only comprehensive and methodologically rigorous assessment of research needs in the field of radiation oncology. Broad dissemination of these findings is critical to maximally leverage the impact of this work, particularly because grant funding decisions are often made by committees on which highly specialized disciplines such as radiation oncology are not well represented. PMID- 22436791 TI - Chemoradiotherapy of anal carcinoma: survival and recurrence in an unselected national cohort. AB - PURPOSE: To evaluate treatment results, elucidate whether national guidelines were followed, and identify areas demanding further treatment optimization. METHODS AND MATERIAL: Between July 2000 and June 2007, 328 patients were treated with curatively intended chemoradiotherapy (CRT) for nonmetastatic squamous cell carcinoma of the anal region, according to national treatment guidelines based on tumor stage. RESULTS: Complete response after CRT was obtained in 87% of patients, rising to 93% after salvage surgery. Chemotherapy, elective irradiation of the groin and salvage surgery were performed to a lesser extent in elderly patients, mainly because of frailty and comorbidity. Recurrence occurred in 24% of the patients, resulting in a 3- and 5-year recurrence-free survival (RFS) of 79% and 74%, respectively. Locoregional recurrences dominated, most commonly in the primary tumor site. Recurrence was treated with curative intent in 45% of the cases. The 3- and 5-year overall survival were 79% and 66%, and cancer-specific survival (CSS) were 84% and 75%, respectively. The risk of adverse outcome increased significantly with more locally advanced tumors and for male gender in multivariable analyses for RFS and CSS. CONCLUSIONS: The treatment results are in accordance with similar cohorts. The primary treatment control rate was high, but there was a significant risk of locoregional recurrence in advanced tumors. The loyalty to national guidelines was broad, although individual adjustments occurred. However, caution to avoid toxicity must not lead to inadequate treatment. Male gender seems to have inferior outcome. PMID- 22436792 TI - Frequency and clinical significance of previously undetected incidental findings detected on computed tomography simulation scans for breast cancer patients. AB - PURPOSE: To determine the frequency and clinical significance of previously undetected incidental findings found on computed tomography (CT) simulation images for breast cancer patients. METHODS AND MATERIALS: All CT simulation images were first interpreted prospectively by radiation oncologists and then double-checked by diagnostic radiologists. The official reports of CT simulation images for 881 consecutive postoperative breast cancer patients from 2009 to 2010 were retrospectively reviewed. Potentially important incidental findings (PIIFs) were defined as any previously undetected benign or malignancy-related findings requiring further medical follow-up or investigation. For all patients in whom a PIIF was detected, we reviewed the clinical records to determine the clinical significance of the PIIF. If the findings from the additional studies prompted by a PIIF required a change in management, the PIIF was also recorded as a clinically important incidental finding (CIIF). RESULTS: There were a total of 57 (6%) PIIFs. The 57 patients in whom a PIIF was detected were followed for a median of 17 months (range, 3-26). Six cases of CIIFs (0.7% of total) were detected. Of the six CIIFs, three (50%) cases had not been noted by the radiation oncologist until the diagnostic radiologist detected the finding. On multivariate analysis, previous CT examination was an independent predictor for PIIF (p = 0.04). Patients who had not previously received chest CT examinations within 1 year had a statistically significantly higher risk of PIIF than those who had received CT examinations within 6 months (odds ratio, 3.54; 95% confidence interval, 1.32-9.50; p = 0.01). CONCLUSIONS: The rate of incidental findings prompting a change in management was low. However, radiation oncologists appear to have some difficulty in detecting incidental findings that require a change in management. Considering cost, it may be reasonable that routine interpretations are given to those who have not received previous chest CT examinations within 1 year. PMID- 22436793 TI - Celiac node failure patterns after definitive chemoradiation for esophageal cancer in the modern era. AB - PURPOSE: The celiac lymph node axis acts as a gateway for metastatic systemic spread. The need for prophylactic celiac nodal coverage in chemoradiation therapy for esophageal cancer is controversial. Given the improved ability to evaluate lymph node status before treatment via positron emission tomography (PET) and endoscopic ultrasound, we hypothesized that prophylactic celiac node irradiation may not be needed for patients with localized esophageal carcinoma. METHODS AND MATERIALS: We reviewed the radiation treatment volumes for 131 patients who underwent definitive chemoradiation for esophageal cancer. Patients with celiac lymph node involvement at baseline were excluded. Median radiation dose was 50.4 Gy. The location of all celiac node failures was compared with the radiation treatment plan to determine whether the failures occurred within or outside the radiation treatment field. RESULTS: At a median follow-up time of 52.6 months (95% CI 46.1-56.7 months), 6 of 60 patients (10%) without celiac node coverage had celiac nodal failure; in 5 of these patients, the failures represented the first site of recurrence. Of the 71 patients who had celiac coverage, only 5 patients (7%) had celiac region relapse. In multivariate analyses, having a pretreatment-to-post-treatment change in standardized uptake value on PET >52% (odds ratio [OR] 0.198, p = 0.0327) and having failure in the clinical target volume (OR 10.72, p = 0.001) were associated with risk of celiac region relapse. Of those without celiac coverage, the 6 patients that later developed celiac failure had a worse median overall survival time compared with the other 54 patients who did not fail (median overall survival time: 16.5 months vs. 31.5 months, p = 0.041). Acute and late toxicities were similar in both groups. CONCLUSIONS: Although celiac lymph node failures occur in approximately 1 of 10 patients, the lack of effective salvage treatments and subsequent low morbidity may justify prophylactic treatment in distal esophageal cancer patients. PMID- 22436794 TI - A three-isocenter jagged-junction IMRT approach for craniospinal irradiation without beam edge matching for field junctions. AB - PURPOSE: Traditionally craniospinal irradiation treats the central nervous system using two or three adjacent field sets. We propose a technique using a three isocenter intensity-modulated radiotherapy (IMRT) plan (jagged-junction IMRT) which overcomes problems associated with field junctions and beam edge matching and improves planning and treatment setup efficiencies with homogenous target dose distribution. METHODS AND MATERIALS: Treatments for 3 patients with a prescription of 36 Gy in 20 fractions were retrospectively planned with jagged junction IMRT and compared to conventional treatment plans. Planning target volume (PTV) included the whole brain and spinal canal to the S3 vertebral level. The plan used three field sets, each with a unique isocenter. One field set with seven fields treated the cranium. Two field sets treated the spine, each set using three fields. Fields from adjacent sets were overlapped, and the optimization process smoothly integrated the dose inside the overlapped junction. RESULTS: For jagged-junction IMRT plans vs. conventional technique, the average homogeneity index equaled 0.08 +/- 0.01 vs. 0.12 +/- 0.02, respectively, and conformity number equaled 0.79 +/- 0.01 vs. 0.47 +/- 0.12, respectively. The 95% isodose surface covered (99.5 +/- 0.3)% of the PTV vs. (98.1 +/- 2.0)%, respectively. Both jagged-junction IMRT plans and the conventional plans had good sparing of organs at risk. CONCLUSIONS: Jagged-junction IMRT planning provided good dose homogeneity and conformity to the target while maintaining a low dose to organs at risk. Results from jagged-junction IMRT plans were better than or equivalent to those from the conventional technique. Jagged-junction IMRT optimization smoothly distributed dose in the junction between field sets. Because there was no beam matching, this treatment technique is less likely to produce hot or cold spots at the junction, in contrast to conventional techniques. The planning process is also simplified as only one IMRT plan is required for the entire target volume. PMID- 22436795 TI - Impact of triple-negative phenotype on prognosis of patients with breast cancer brain metastases. AB - PURPOSE: To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. RESULTS: The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. CONCLUSION: The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor. PMID- 22436796 TI - Optimizing normal tissue sparing in ion therapy using calculated isoeffective dose for ion selection. AB - PURPOSE: To investigate how the selection of ion type affects the calculated isoeffective dose to the surrounding normal tissue as a function of both normal tissue and target tissue alpha/beta ratios. METHODS AND MATERIALS: A microdosimetric biologic dose model was incorporated into a Geant4 simulation of parallel opposed beams of protons, helium, lithium, beryllium, carbon, and neon ions. The beams were constructed to give a homogeneous isoeffective dose to a volume in the center of a water phantom for target tissues covering a range of cobalt equivalent alpha/beta ratios of 1-20 Gy. Concomitant normal tissue isoeffective doses in the plateau of the ion beam were then compared for different ions across the range of normal tissue and target tissue radiosensitivities for a fixed isoeffective dose to the target tissue. RESULTS: The ion type yielding the optimal normal tissue sparing was highly dependent on the alpha/beta ratio of both the normal and the target tissue. For carbon ions, the calculated isoeffective dose to normal tissue at a 5-cm depth varied by almost a factor of 5, depending on the alpha/beta ratios of the normal and target tissue. This ranges from a factor of 2 less than the isoeffective dose of a similar proton treatment to a factor of 2 greater. CONCLUSIONS: No single ion is optimal for all treatment scenarios. The heavier ions are superior in cases in which the alpha/beta ratio of the target tissue is low and the alpha/beta ratio of normal tissue is high, and protons are superior in the opposite circumstances. Lithium and beryllium appear to offer dose advantages similar to carbon, with a considerably lower normal tissue dose when the alpha/beta ratio in the target tissue is high and the alpha/beta ratio in the normal tissue is low. PMID- 22436797 TI - Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: a randomized trial. AB - BACKGROUND: The aim of this randomized, parallel-arm trial was to study the effect of treating subsyndromal delirium with risperidone on the incidence of clinical delirium in elderly patients who underwent on-pump cardiac surgery. METHODS: One hundred one patients aged 65 yr or older who experienced subsyndromal delirium after on-pump cardiac surgery were randomized using a computer-generated list to receive 0.5 mg risperidone (n = 51) or placebo (n = 50) every 12 h by mouth. Patients were assessed at 8 h by a blinded observer using the Intensive Care Delirium Screening Checklist, and those scoring more than 3 were evaluated by a blinded psychiatrist to confirm delirium. Patients in either group who experienced delirium were treated according to the same algorithm. Initially, risperidone was administered and if symptoms were not controlled, haloperidol was administered. The primary outcome was the proportion of patients who experienced delirium in either group. RESULTS: Seven (13.7%) patients in the risperidone group experienced delirium versus 17 (34%) in the placebo group (P = 0.031) Competing-risks regression analysis showed that failure to treat subsyndromal delirium with risperidone was an independent risk factor for delirium (subhazard ratio, 3.83; 95% CI, 1.63-8.98; P = 0.002). Two (3.9%) patients in the risperidone group experienced extrapyramidal manifestations versus one (2%) in the placebo group (P = 1.0). CONCLUSION: Administration of risperidone to elderly patients who experienced subsyndromal delirium after on pump cardiac surgery was associated with significantly lower incidence of delirium. Larger studies are required to determine whether early administration of risperidone during the subsyndromal phase of delirium would influence the clinical course of such patients. PMID- 22436798 TI - In vivo biocompatibility and biodegradation of 3D-printed porous scaffolds based on a hydroxyl-functionalized poly(epsilon-caprolactone). AB - The aim of this study was to evaluate the in vivo biodegradation and biocompatibility of three-dimensional (3D) scaffolds based on a hydroxyl functionalized polyester (poly(hydroxymethylglycolide-co-epsilon-caprolactone), PHMGCL), which has enhanced hydrophilicity, increased degradation rate, and improved cell-material interactions as compared to its counterpart poly(epsilon caprolactone), PCL. In this study, 3D scaffolds based on this polymer (PHMGCL, HMG:CL 8:92) were prepared by means of fiber deposition (melt-plotting). The biodegradation and tissue biocompatibility of PHMGCL and PCL scaffolds after subcutaneous implantation in Balb/c mice were investigated. At 4 and 12 weeks post implantation, the scaffolds were retrieved and evaluated for extent of degradation by measuring the residual weight of the scaffolds, thermal properties (DSC), and morphology (SEM) whereas the polymer was analyzed for both its composition ((1)H NMR) and molecular weight (GPC). The scaffolds with infiltrated tissues were harvested, fixed, stained and histologically analyzed. The in vitro enzymatic degradation of these scaffolds was also investigated in lipase solutions. It was shown that PHMGCL 3D-scaffolds lost more than 60% of their weight within 3 months of implantation while PCL scaffolds showed no weight loss in this time frame. The molecular weight (M(w)) of PHMGCL decreased from 46.9 kDa before implantation to 23.2 kDa after 3 months of implantation, while the molecular weight of PCL was unchanged in this period. (1)H NMR analysis showed that the degradation of PHMGCL was characterized by a loss of HMG units. In vitro enzymatic degradation showed that PHMGCL scaffolds were degraded within 50 h, while the degradation time for PCL scaffolds of similar structure was 72 h. A normal foreign body response to both scaffold types characterized by the presence of macrophages, lymphocytes, and fibrosis was observed with a more rapid onset in PHMGCL scaffolds. The extent of tissue-scaffold interactions as well as vascularization was shown to be higher for PHMGCL scaffolds compared to PCL ones. Therefore, the fast degradable PHMGCL which showed good biocompatibility is a promising biomaterial for tissue engineering applications. PMID- 22436799 TI - The functional properties of nephronectin: an adhesion molecule for cardiac tissue engineering. AB - Despite significant advances in preventive cardiovascular medicine and therapy for acute and chronic heart failure, cardiovascular diseases remain among the leading causes of death worldwide. In recent years cardiac tissue engineering has been established as a possible future treatment option for cardiac disease. However, the quality of engineered myocardial tissues remains poor. In tissue engineering it is important that the scaffold allows cells to attach, spread, maintain their differentiation status or differentiate into functional cells in order to exhibit their physiological function. Here, we have investigated the suitability of the natural cardiac extracellular matrix component nephronectin as an adhesive material for cardiac tissue engineering. Primary neonatal rat cardiomyocytes were seeded on collagen-, fibronectin- or nephronectin-coated glass coverslips and analyzed for cell adhesion, cellular metabolic activity, response to extracellular stimuli, cell-to-cell communication, differentiation and contractility. Our data demonstrate that most neonatal cardiomyocytes attached in an RGD domain-dependent manner within 18 h to nephronectin. The cells exhibited high metabolic activity, responded to growth factor stimuli and maintained their differentiation status. Moreover, nephronectin promoted sarcomere maturation and alignment, cell-to-cell communication and synchronous contractions. In conclusion, our findings demonstrate that nephronectin has excellent properties for cardiomyocyte adhesion and function and thus has the potential to improve current cardiac tissue engineering approaches. PMID- 22436800 TI - A mPEG-PLGA-b-PLL copolymer carrier for adriamycin and siRNA delivery. AB - A amphiphilic block copolymer composed of conventional monomethoxy (polyethylene glycol)-poly (d,l-lactide-co-glycolide)-poly (l-lysine) (mPEG-PLGA-b-PLL) was synthesized. The chemical structure of this copolymer and its precursors was confirmed by Fourier Transform Infrared Spectroscopy (FTIR), (1)H Nuclear Magnetic Resonance ((1)H NMR) and Gel Permeation Chromatography (GPC). The copolymer was used to prepare nanoparticles (NPs) that were then loaded with either the anti-cancer drug adriamycin or small interfering RNA-negative (siRNA) using a double emulsion method. MTT assays used to study the in vitro cytotoxicity of mPEG-PLGA-b-PLL NPs showed that these particles were not toxic in huh-7 hepatic carcinoma cells. Confocal laser scanning microscopy (CLSM) and flow cytometer analysis results demonstrated efficient mPEG-PLGA-b-PLL NPs-mediated delivery of both adriamycin and siRNA into the cells. In vivo the targeting delivery of adriamycin or siRNA mediated by mPEG-PLGA-b-PLL NPs in the huh-7 hepatic carcinoma-bearing mice was evaluated using a fluorescence imaging system. The targeting delivery results and froze section analysis confirmed that drug or siRNA is deliver to tumor more efficiently by mPEG-PLGA-b-PLL NPs than free drug or LipofectamineTM2000. The high efficiency delivery of mPEG-PLGA-b-PLL NPs mainly due to the enhancement of cellular uptake. These results imply that mPEG PLGA-b-PLL NPs have a great potential to be used as an effective carriers for adriamycin or siRNA. PMID- 22436801 TI - The effect of TNFalpha secreted from macrophages activated by titanium particles on osteogenic activity regulated by WNT/BMP signaling in osteoprogenitor cells. AB - Wear particles are the major cause of osteolysis associated with failure of implant following total joint replacement. During this pathologic process, activated macrophages mediate inflammatory responses to increase osteoclastogenesis, leading to enhanced bone resorption. In osteolysis caused by wear particles, osteoprogenitors present along with macrophages at the implant interface may play significant roles in bone regeneration and implant osteointegration. Although the direct effects of wear particles on osteoblasts have been addressed recently, the role of activated macrophages in regulation of osteogenic activity of osteoblasts has scarcely been studied. In the present study, we examined the molecular communication between macrophages and osteoprogenitor cells that may explain the effect of wear particles on impaired bone forming activity in inflammatory bone diseases. It has been demonstrated that conditioned medium of macrophages challenged with titanium particles (Ti CM) suppresses early and late differentiation markers of osteoprogenitors, including alkaline phosphatase (ALP) activity, collagen synthesis, matrix mineralization and expression of osteocalcin and Runx2. Moreover, bone forming signals such as WNT and BMP signaling pathways were inhibited by Ti CM. Interestingly, TNFalpha was identified as a predominant factor in Ti CM to suppress osteogenic activity as well as WNT and BMP signaling activity. Furthermore, Ti CM or TNFalpha induces the expression of sclerostin (SOST) which is able to inhibit WNT and BMP signaling pathways. It was determined that over-expression of SOST suppressed ALP activity, whereas the inhibition of SOST by siRNA partially restored the effect of Ti CM on ALP activity. This study highlights the role of activated macrophages in regulation of impaired osteogenic activity seen in inflammatory conditions and provides a potential mechanism for autocrine regulation of WNT and BMP signaling mediated by TNFalpha via induction of SOST in osteprogenitor cells. PMID- 22436802 TI - The role of well-defined patterned substrata on the regeneration of DRG neuron pathfinding and integrin expression dynamics using chondroitin sulfate proteoglycans. AB - Injured neurons intrinsically adapt to and partially overcome inhibitory proteoglycan expression in the central nervous system by upregulating integrin expression. It remains unclear however, to what extent varying proteoglycan concentrations influence the strength of this response, how rapidly neurons adapt to proteoglycans, and how pathfinding dynamics are altered over time as integrin expression is modulated in response to proteoglycan signals. To investigate these quandaries, we created well-defined substrata in which postnatal DRG neuron pathfinding dynamics and growth cone integrin expression were interrogated as a function of proteoglycan substrata density. DRGs responded by upregulating integrin expression in a proteoglycan dose dependent fashion and exhibited robust outgrowth over all proteoglycan densities at initial time frames. However, after prolonged proteoglycan exposure, neurons exhibited decreasing velocities associated with increasing proteoglycan densities, while neurons growing on low proteoglycan levels exhibited robust outgrowth at all time points. Additionally, DRG outgrowth over proteoglycan density step boundaries, and a brief beta1 integrin functional block proved that regeneration was integrin dependent and that DRGs exhibit delayed slowing and loss in persistence after even transient encounters with dense proteoglycan boundaries. These findings demonstrate the complexity of proteoglycan regulation on integrin expression and regenerative pathfinding. PMID- 22436803 TI - Reconstitution of laminin-111 biological activity using multiple peptide coupled to chitosan scaffolds. AB - Laminin-111, a multifunctional matrix protein, has diverse biological functions. Previously, we have identified various biologically active sequences in laminin 111 by a systematic peptide screening. We also demonstrated that peptide conjugated chitosan matrices enhance the biological functions of the active sequences and are useful as a scaffold. Here, we conjugated sixty biologically active laminin-111 peptides onto chitosan matrices. The twenty-nine peptide chitosan matrices promoted various biological activities, including cell attachment, spreading, and neurite outgrowth. The biological activities of peptide-chitosan matrices depend on the peptide. These peptide-chitosan matrices are categorized into six groups depending on their biological activities. Next, we conjugated five active peptides, which showed strong cell attachment activity in the each group, onto a single chitosan matrix to mimic the multiple activities of laminin-111. The mixed peptides-chitosan matrix significantly promoted cell attachment and cell spreading over that observed with the individual peptides. We also demonstrated that a mixed peptides-chitosan matrix, using four neurite outgrowth-promoting peptides each from a different group, enhanced the activity. These data suggest that the mixed peptides synergistically induce laminin-like biological activities on a chitosan matrix. The active peptides-chitosan matrices described here have potential for use as biomaterial for tissue engineering and regeneration. PMID- 22436804 TI - GDC learning outcomes for the undergraduate dental curriculum. PMID- 22436805 TI - Weak, unreliable evidence suggests flossing plus toothbrushing may be associated with a small reduction in plaque. PMID- 22436806 TI - Weak evidence of caries reduction using xylitol-based lozenges in two of three selected studies. PMID- 22436807 TI - Pit and fissure sealant retention. PMID- 22436808 TI - MTA or calcium hydroxide treatment for immature permanent teeth? PMID- 22436809 TI - Periodontitis associated with obesity although the magnitude of association unclear. PMID- 22436810 TI - Nutrients and periodontal disease. PMID- 22436811 TI - No strong evidence that any topical treatment is effective for relieving the sensation of dry mouth. PMID- 22436812 TI - Mate intake and risk of oral and pharyngeal cancers. PMID- 22436813 TI - Super-EBA and IRM for retrograde root filing. PMID- 22436814 TI - Topical preventive measures to avoid or reverse white spot lesions in orthodontic patients. PMID- 22436816 TI - No difference in effectiveness of Hawley and vacuum-formed retainers at 12 months. PMID- 22436815 TI - Limited evidence of a small effect on mandibular growth using functional appliances. PMID- 22436817 TI - Limited evidence for interceptive extraction of deciduous canines to prevent permanent canine impaction. PMID- 22436818 TI - Some evidence for the management temporomandibular joint disorders. PMID- 22436819 TI - Understanding statistics 6. PMID- 22436821 TI - Enrichment and purification of gardenia yellow from Gardenia jasminoides var. radicans Makino by column chromatography technique. AB - In present study, the performance and separation characteristics of nine macroporous resins for the enrichment and purification of gardenia yellow from Gardenia jasminoides var. radicans Makino have been evaluated. The adsorption and desorption properties of crude gardenia yellow solution on macroporous resins including HPD722, HPD100, HPD100A, HPD400, HPD400A, D101, AB-8, XAD-16, and NKA-9 have been compared. Then, HPD722 was chosen to purify gardenia yellow because of its strong adsorption and desorption abilities as well as high selectivity. Column packed with HPD722 resin was used to perform dynamic adsorption and desorption tests to optimize the separation process of gardenia yellow. The optimal conditions were as follows: The crude gardenia yellow solution with concentration of 15 mg/mL was loaded in column packed with HPD722 resin at the flow rate of 1.0 mL/min, and the adsorbate-laden column was washed with 800 mL water, 600 mL 15% ethanol water solution respectively at the speed of 2.5 mL/min, then desorbed with 200 mL 80% ethanol water solution at the speed of 3.5 mL/min. The colority of the product obtained were up to 300. The method developed in this study provides a new approach for scale-up separation and purification of gardenia yellow from G. jasminoides var. radicans Makino. PMID- 22436822 TI - Hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometry for the quantification of deferasirox, an oral iron chelator, in human plasma. AB - A rapid hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometric assay (HILIC/ESI-MS) was developed, validated and applied to the determination of deferasirox, in human plasma. The sample preparation process involved liquid-liquid extraction of 50 MUL plasma sample using ethyl acetate as an extraction solvent. Chromatographic separation was performed on an XBridge HILIC analytical column (150.0 mm * 2.1 mm i.d., particle size 3.5 MUm, 135 A) under isocratic elution. The mobile phase was composed of a 10% 8.0 mM ammonium acetate water solution pH=5.0, adjusted with formic acid, in a binary mixture of acetonitrile/methanol (50:50, v/v) and pumped at a flow rate of 0.20 mL/min. Quantitation of deferasirox was performed with selected ion monitoring (SIM) in positive ionization mode using electrospray ionization interface. The assay was found to be linear in the concentration range of 0.20-120.0 MUg/mL for deferasirox. Intermediate precision was found less than 3.9% over the tested concentration ranges. A run time of less than 6.0 min for each sample made it possible to analyze a large number of human plasma samples per day. The method can be used to support a wide range of clinical studies concerning deferasirox monitoring and it was applied to the analysis of human plasma samples obtained from patients with beta-thalassemia major. PMID- 22436823 TI - Separation and purification of phosvitin phosphopeptides using immobilized metal affinity nanoparticles. AB - Monodispersed and functional immobilized metal affinity magnetic chondroitin sodium sulfate nanoparticles (short as IMAN @ Fe (III)) were prepared and employed in extracting of Phosvitin Phosphopeptides (short as PPPs) from egg yolk. It was found that the diameter of the magnetic CS nanoparticles was about 20 nm, and they could easily be aggregated by a magnet when suspending in the aqueous solution. The adsorption equilibrium of PPPs onto the obtained nanocarriers fitted well with the Langmuir model. The adsorption capacity of PPPs onto the superparamagnetic nanoparticles was influenced by pH and the initial concentration of the peptides solution. The final nitrogen/phosphorus molar ratios (short as N/P) of PPPs from crude egg yolk peptides and phosvitin peptides were low to 5.78 and 5.23, respectively. Compared with traditional methods, the need for preparation of phosvitin before purification is obviated and the higher purity of PPPs were obtained. In conclusion, this type of IMAN @ Fe (III) would bring advantages to the conventional separation techniques of PPPs from chicken egg yolk. PMID- 22436824 TI - A new HPLC UV validated method for therapeutic monitoring of deferasirox in thalassaemic patients. AB - We describe a new high performance liquid chromatography coupled with ultraviolet detection method for the quantification of plasma concentration of oral iron chelating agent deferasirox. A simple protein precipitation extraction procedure was applied on 500 MUl of plasma aliquots. Chromatographic separation was achieved on a C18 reverse phase column and eluate was monitored at 295 nm, with 8 min of analytical run. This method has been validated following Food and Drug Administration procedures: mean intra and inter day variability was 4.64 and 10.55%; mean accuracy was 6.27%; mean extraction recovery 91.66%. Calibration curves ranged from 0.078125 to 40 MUg/ml. Limit of quantification was set at 0.15625 while limit of detection at 0.078125 MUg/ml. We applied methodology developed on plasma samples of thalassaemic patients treated with deferasirox, finding correlation between deferasirox plasma concentrations and serum ferritin levels. This methodology allowed a specific, sensitive and reliable determination of deferasirox, that could be useful to perform its therapeutic monitoring and pharmacokinetic studies in patients plasma. PMID- 22436825 TI - Rapid and efficient purification of chrysophanol in Rheum Palmatum LINN by supercritical fluid extraction coupled with preparative liquid chromatography in tandem. AB - Chrysophanol has high pharmaceutical values. However, it was difficult to use the traditional extraction method to extract high-concentration chrysophanol. Therefore, the purpose of this study is to purify and separate chrysophanol in traditional herb, Rheum Palmatum LINN, by using supercritical fluid extraction (SFE) and preparative high-performance liquid chromatography (P-HPLC) for rapid and large-scale isolation. The method is efficient for selective extraction of chrysophanol from the herbs, which have complex compositions. The extraction efficiency of chrysophanol with SFE is 25 * higher than that of boiled water extraction under the same extraction time. The optimal conditions for SFE were 210 atm and 85 degrees C for 30 min; for P-HPLC, a C18 column was used with a gradient elution of methanol and 1% acetic acid at a flow rate of 10 mL/min. According to (1)H NMR and LC-MS analyses, the purity of the isolated chrysophanol was as high as 99%. The recovery for chrysophanol in Rheum after SPE/PHPLC processing was in the range of 88-91.5%. Compared with other extraction and purification methods, the sequential system (SFE/P-HPLC) achieved the highest amount of extracted chrysophanol from Rheum Palmatum LINN (0.38 mg/g) and the shortest run time (3h). Hence, this rapid and environmentally friendly method can separate compounds based on polarity with high efficiencies and, coupled with P HPLC, it may be applicable in the large-scale production of foods and medicines in the future. PMID- 22436826 TI - The effect of syllable repetition rate on vocal characteristics. AB - This study examined whether mean vocal fundamental frequency (F(0)) or speech sound pressure level (SPL) varies with changes in syllable repetition rate. Twenty-four young adults (12 M and 12 F) repeated the syllables/p?/,/p?te/, and/p?teke/at a modeled "slow" rate of approximately one syllable per second, at a self-selected "comfortable" rate, and at their maximum rate. For both male and female subjects there was a significant increase in F(0), but not SPL, between the "slow" and "maximal" and between the "comfortable" and "maximal" repetition rates. Conversely, there was no significant difference in mean F(0) associated with syllable type, whereas significant SPL differences were most likely due to differences in plosive aspiration, syllable stress, and juncture between the mono , bi-, and tri-syllabic sequences. These results suggest that there is a laryngeal adjustment that attends an increase in speech rate, lending additional support for speech and voice treatment strategies that employ rate modification techniques. LEARNING OUTCOMES: The reader will be able to: (1) outline the advantages and disadvantages of using a syllable-repetition task to evaluate speech rate; (2) describe how vocal F(0) and speech SPL are affected by changes in speech rate; and (3) describe the clinical and theoretical implications of the results from this study. PMID- 22436827 TI - The effects of duration and frequency of occurrence of voiceless fricatives on listeners' perceptions of sound prolongations. AB - The present study examined listeners' identification and rating of words in passages as stuttered when the duration and frequency of occurrence of sound prolongations were manipulated. Thirty-six participants listened to a 219-word passage containing voiceless fricatives digitally increased from their normal durations to 200, 300, and 420ms. Listeners heard one of three passages that contained 5%, 10% or 15% altered stimuli within the passage. In Condition 1, listeners identified words considered stuttered. In Condition 2, listeners rated specifically selected words in the passage relative to the extent they considered the words stuttered. The results showed that (1) both the duration and the frequency of occurrence of the altered phonemes within the paragraph length material had an impact on listeners' perception of words identified as a sound prolongation; (2) listeners gave significantly higher ratings in Condition 2 than Condition 1 when determining if a word was stuttered or produced fluently. The implications of these results are discussed. LEARNING OUTCOMES: After reading this article, the reader will be able to: (1) Describe the past literature on listener perceptions of stuttering. (2) Differentiate between listener's perceptions of sound prolongations that are altered in duration and frequency of occurrence. (3) Describe how paragraph-length speech material compares to past research that has used isolated utterances. PMID- 22436828 TI - The Future of Surgery and ISMICS. PMID- 22436829 TI - A Cardiothoracic Resident's Perspective on the Future. PMID- 22436830 TI - Transmyocardial laser revascularization: a meta-analysis and systematic review of controlled trials. PMID- 22436831 TI - Transmyocardial Laser Revascularization: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2006. PMID- 22436832 TI - Incidence of residual clot strands in saphenous vein grafts after endoscopic harvest. AB - OBJECTIVE: : Strands of clot are frequently flushed out of saphenous vein grafts (SVG) during preparation for grafting, particularly those that are endoscopically harvested. However, saline distention at uncontrolled pressures increases graft thrombogenicity and the risk of early failure after coronary artery bypass grafting. The purpose of this prospective investigation was to define the incidence of intraluminal clot within endoscopically harvested SVG and the effect of attempted removal by saline distention. METHODS: : Endoscopically harvested SVG were intraoperatively prepared for grafting by using saline distention at uncontrolled pressure (n = 24) or without distension (n = 20). Optical coherence tomography, a catheter-based infrared imaging system, was used to identify and characterize intraluminal clot strands in surplus SVG segments (average length for analysis, 4.9 +/- 2.6 cm). These segments were also assessed for luminal tissue factor activity and percent endothelial integrity by CD31-directed immunohistochemistry. RESULTS: : Clot strands were observed in 45.4% (20 of 44) of imaged SVG segments (severity of observed clots: 54%, mild; 32%, moderate; 14%, severe). Compared with grafts distended with saline, vein segments that were not distended displayed significantly higher endothelial integrity (60.1% +/- 27.2% versus 24.7% +/- 24.1%, P < 0.05) and lower tissue factor activity (1.28 +/ 0.95 versus12.3 +/- 5.5 U/cm, P < 0.001) despite having a higher incidence of clot stands (65.0% versus 29.1%, P < 0.02, Fisher exact test). Static flow was observed in veins during endoscopic harvest. CONCLUSIONS: : Clot strands of varying severity are a common finding after endoscopic vein harvest. Saline distention is not completely effective in removing clot strands and increases overall graft thrombogenicity. Therefore, prevention of clot or less traumatic methods of removing clot are indicated. PMID- 22436833 TI - Computer-mediated power stapling for anatomical lung resection: experience in 100 consecutive cases. AB - OBJECTIVES: : Mechanical stapling is widely used for lung resection. Complications related to the stapling are few but not infrequent. This varies from complete disruption of the staples to incomplete sealing of vascular structures. A stapling platform that has a strong clamping force with precise and consistent staple formation suitable for thickness of tissue is likely to be an advance in existing devices and may reduce the complication rate. A new, computer mediated power stapling is currently available for lung resections, with three types of digital loading units (DLU). Clinical data on its use are limited. We report our experience with this stapling platform (SurgASSIST) in our first 100 patients undergoing anatomic lung resection. METHODS: : Fifty-four men and forty six women (mean age, 64 +/- 7 years) underwent anatomic lung resections, using a lateral, muscle-sparing mini-thoracotomy, during 2004 to 2005, with the SurgASSIST platform. Three types of DLUs were used for lung resection: a linear cutter, a right-angled vascular cutter, and a right-angled bronchial cutter. Observational data were collected prospectively on the operative procedure, type of staples used, duration of operation, chest tube drainage, and hospital length of stay. RESULTS: : There were 83 lobectomies, 5 bilobectomies, 5 segmental resections, and 7 pneumonectomies. A total of 502 DLUs (mean, 5 per patient; 102 vascular, 91 bronchial, and 309 linear cutters) were used in this series. There were no major operative complications. The mean operating time was 136 +/- 41 minutes. One bronchial dehiscence and one incomplete sealing of the pulmonary vein in the staple line were observed. In one patient, the linear cutter could not be opened in the automatic setting. There were 15% misreads by the computer on the DLU or their inserts. There was one hospital death unrelated to the stapling. Twenty additional complications included prolonged chest tube drainage (n = 8), reoperations (n = 2), atrial fibrillation (n = 5), hemothorax (n = 1), chylothorax (n = 1), C-dif colitis (n = 1), myocardial ischemia (n = 1), and incarcerated ventral hernia (n = 1). The median hospital length of stay was 5 days (range, 3 to 26 days) and the median length of chest tube drainage was 3 days (1 to 22 days). CONCLUSIONS: : Our experience shows that the computer mediated power stapling of lung parenchyma and hilar structures during anatomic resection is safe and reproducible. PMID- 22436834 TI - Videothoracoscopic resection of benign neurogenic tumors of the posterior mediastinum. AB - OBJECTIVE: : Videothoracoscopy is becoming the preferred approach for the removal of neurogenic mediastinal tumors. Tumors extending into the spinal canal (dumbbell type) require a combined neurosurgical approach. The aim of the study was to evaluate the feasibility of videothoracoscopic resection of benign neurogenic tumors (BNT) of the posterior mediastinum, including dumbbell-type tumors, through a retrospective review of our experience. METHODS: : Between January 1993 and November 2005, 30 patients underwent resection of a BNT of the posterior mediastinum at our institution. Twenty-five tumors developed in the costovertebral sulcus, and five were dumbbell type. Preoperative assessment included chest CT scan, nuclear magnetic resonance for dumbbell-type tumors, and spinal angiography when the tumor was located in the vicinity of the Adamkiewicz artery. RESULTS: : Mean tumor size was 5.6 +/- 1.4 cm (range, 4 to 11). Videothoracoscopic resection was possible in 26 patients, 5 of whom had dumbbell type tumors requiring a combined neurosurgical approach. Reasons for conversion to thoracotomy were pleural adhesions in one case and bleeding in three. Mean operative time was 215 +/- 42 minutes (range, 180 to 280) for the patients with dumbbell-type tumors and 140 +/- 55 minutes (range, 95 to 230) for those without. There were no operative and/or postoperative complications. Histology showed 25 schwannomas, 4 ganglioneuromas, and 1 neurofibroma. Mean postoperative stay was longer for the patients with dumbbell-type tumors (6.5 +/- 1 versus 4 +/- 1 day). CONCLUSIONS: : BNT of the posterior mediastinum, including dumbbell-type tumors, can be safely resected thoracoscopically. The feasibility of a videothoracoscopic approach should be assessed on the basis of the preoperative evaluation. Pleural adhesions and bleeding may determine conversion to thoracotomy. PMID- 22436835 TI - Changes in the prescription of psychotropic drugs in the palliative care of advanced cancer patients over a seven-year period. AB - CONTEXT: Psychiatric disorders are frequently underdiagnosed and undertreated in advanced cancer patients. OBJECTIVES: To assess changes in the prescription of psychotropic drugs in terminally ill patients. METHODS: All patients with advanced disease receiving palliative care between 2002 and 2009 were eligible. The consumption of benzodiazepines, antipsychotics, and antidepressants for the years 2002, 2006, and 2009 was compared. Data on the percentage and profile of psychotropic drugs prescribed were collected. RESULTS: The study population included 840 patients (241 in 2002, 274 in 2006, and 325 in 2009). The percentage of patients treated with psychotropic drugs increased from 82.2% in 2002 to 90.2% in 2009 (P = 0.006) and the mean number of drugs per patient from 1.66 in 2002 to 2.16 in 2006 (P = 0.003), and to 2.35 in 2009 (P<0.001). Benzodiazepines were prescribed to 72.6% of patients in 2002 and 84% in 2009 (P = 0.001), with lorazepam and midazolam as the most frequently used medications. The use of antipsychotics increased from 26.1% in 2002 to 37.2% in 2006 (P = 0.007) and to 40% in 2009 (P = 0.001), with haloperidol and risperidone as the most commonly prescribed. Antidepressants were prescribed to 17.8% in 2002, 28.1% in 2006 (P = 0.006), and 27.1% in 2009 (P = 0.010), with mirtazapine, citalopram, escitalopram, and duloxetine as the most frequent. CONCLUSION: Between 2002 and 2009, there was a significant increase in the use of psychotropic drugs and a change in the profile of drugs prescribed. PMID- 22436836 TI - Comparisons of exercise dose and symptom severity between exercisers and nonexercisers in women during and after cancer treatment. AB - CONTEXT: Although numerous studies of the efficacy of exercise are reported, few studies have evaluated changes in characteristics of exercise dose in women with cancer both during and after cancer treatment. OBJECTIVES: To describe the characteristics of exercise dose (i.e., frequency, duration, and intensity) and evaluate for differences in symptom severity (i.e., fatigue, sleep disturbance, depression, and pain) between women who did and did not exercise during and after cancer treatment. METHODS: In a sample of 119 women, two groups were classified: exercisers and nonexercisers. Exercisers were defined as women who met specific criteria for frequency (three times per week), duration (20 minutes/session), intensity (moderate), and mode (aerobic). Nonexercisers were defined as women who did not meet all these criteria. Evaluation of exercise dose was completed at baseline (T1: the week before chemotherapy cycle 2), at the end of cancer treatment (T2), and at the end of the study (T3: approximately one year after the T1 assessment) using self-report exercise questionnaires. RESULTS: Approximately 50% of the participants exercised during treatment and 70% exercised after treatment. At T1, exercisers had lower total fatigue, lower behavioral and sensory subscale fatigue scores, and lower depression scores (P = 0.038) than nonexercisers. No significant differences in sleep disturbance or pain were found between groups. At T2, exercisers had lower cognitive/mood subscale fatigue and depression scores than nonexercisers (P = 0.047). At T3, no significant differences were found between groups in any symptom severity scores. CONCLUSION: Both during and after cancer treatment, achieving or maintaining exercise guideline levels were met by most patients. Further study is needed to examine the link between exercise dose and symptom severity. PMID- 22436837 TI - Integrated model for assessing the cost and CO2 emission (IMACC) for sustainable structural design in ready-mix concrete. AB - Cost has traditionally been considered the most important factor in the decision making process. Recently, along with the consistent interest in environmental problems, environmental impact has also become a key factor. Accordingly, there is a need to develop a method that simultaneously reflects the cost and environmental impact in the decision-making process. This study proposed an integrated model for assessing the cost and CO(2) emission (IMACC) at the same time. IMACC is a model that assesses the cost and CO(2) emission of the various structural-design alternatives proposed in the structural-design process. To develop the IMACC, a standard on assessing the cost and CO(2) emission generated in the construction stage was proposed, along with the CO(2) emission factors in the structural materials, based on such materials' strengths. Moreover, using the economic and environmental scores that signify the cost and CO(2) emission reduction ratios, respectively, a method of selecting the best design alternative was proposed. To verify the applicability of IMACC, practical application was carried out. Structural designs were assessed, each of which used 21, 24, 27, and 30 MPa ready-mix concrete (RMC). The use of IMACC makes it easy to verify what the best design is. Results show the one that used 27 MPa RMC was the best design. Therefore, the proposed IMACC can be used as a tool for supporting the decision-making process in selecting the best design alternative. PMID- 22436838 TI - The demand incidence of symptomatic ankle osteoarthritis presenting to foot & ankle surgeons in the United Kingdom. AB - BACKGROUND: Ankle arthritis is a cause of major disability; however reports in the literature on the incidence of ankle osteoarthritis are rare. OBJECTIVES: To explore the methodological challenges in obtaining an incidence of ankle osteoarthritis and to estimate the incidence of symptomatic osteoarthritis presenting to Foot & Ankle specialists in the UK. METHODS: We searched available national diagnosis databases and also sent out a questionnaire-based survey to all Consultant members of the British Orthopaedic Foot & Ankle Society (n=180). RESULTS: 123 completed survey questionnaires were returned (68%) with each surgeon seeing on average 160 cases of symptomatic ankle arthritis and performing on average 20 definitive procedures for end-stage ankle osteoarthritis per year. There are no internationally agreed diagnostic or treatment codes specific for ankle osteoarthritis. CONCLUSION: There are an estimated 29,000 cases of symptomatic ankle osteoarthritis being referred to specialists in the UK, representing a demand incidence of 47.7 per 100,000. 3000 definitive operations to treat end stage ankle osteoarthritis take place in the UK annually. We recommend that specific codes pertaining to ankle arthritis and its treatment be included in any future revisions of the WHO International Classification of Diseases (ICD) and operative procedure coding systems. PMID- 22436839 TI - Trunk muscle activation during stabilization exercises with single and double leg support. AB - The aim of this study was to analyze trunk muscle activity during bridge style stabilization exercises, when combined with single and double leg support strategies. Twenty-nine healthy volunteers performed bridge exercises in 3 different positions (back, front and side bridges), with and without an elevated leg, and a quadruped exercise with contralateral arm and leg raise ("bird-dog"). Surface EMG was bilaterally recorded from rectus abdominis (RA), external and internal oblique (EO, IO), and erector spinae (ES). Back, front and side bridges primarily activated the ES (approximately 17% MVC), RA (approximately 30% MVC) and muscles required to support the lateral moment (mostly obliques), respectively. Compared with conventional bridge exercises, single leg support produced higher levels of trunk activation, predominantly in the oblique muscles. The bird-dog exercise produced greatest activity in IO on the side of the elevated arm and in the contralateral ES. In conclusion, during a common bridge with double leg support, the antigravity muscles were the most active. When performed with an elevated leg, however, rotation torques increased the activation of the trunk rotators, especially IO. This information may be useful for clinicians and rehabilitation specialists in determining appropriate exercise progression for the trunk stabilizers. PMID- 22436840 TI - Associations between eating frequency, adiposity, diet, and activity in 9-10 year old healthy-weight and centrally obese children. AB - The rising prevalence of childhood obesity is a key public health issue worldwide. Increased eating frequency (EF) is one aspect of diet that has been beneficially associated with obesity, although the mechanisms are unclear. The aims of the current study were to determine whether increased EF was associated with improved adiposity in children, and if this was due to differences in dietary and activity behaviors. Cross-sectional data from 1,700 children aged 9 10 year were analyzed to examine the associations between EF, as estimated from diet diaries, measures of adiposity, and activity measured by accelerometer. Analyses were stratified by obesity status using waist-to-height ratio to define obesity as it has been shown to be a good predictor of adverse health outcomes. Mean EF was 4.3 occasions/day and after adjustment for underreporting, energy intake (EI), and activity significant relative mean differences of -2.4% for body weight (P = 0.001), -1.0% for BMI (P = 0.020), -33% for BMI z-score (P = 0.014), and -0.6% for waist circumference (P = 0.031) per increase in eating occasion were found in healthy-weight but not centrally obese children. Differences between the extreme quartiles of EF were observed for total fat intake at breakfast (-18%, P < 0.001), fruit and vegetables from snacks (201% healthy weight and 209% centrally obese children, P < 0.01), and for healthy-weight children, vigorous activity (4%, P = 0.003). Increased EF was favorably associated with adiposity, diet quality, and activity behaviors in healthy-weight but not centrally obese children. Future obesity interventions should consider the mediating role of diet quality and activity in the relationship between EF and adiposity in children. PMID- 22436841 TI - Endurance training per se increases metabolic health in young, moderately overweight men. AB - Health benefits of physical activity may depend on a concomitant weight loss. In a randomized, controlled trial, we compared the effects of endurance training with or without weight loss to the effect of weight loss induced by an energy reduced diet in 48 sedentary, moderately overweight men who completed a 12-week intervention program of training (T), energy-reduced diet (D), training and increased diet (T-iD), or control (C). An energy deficit of 600 kcal/day was induced by endurance training or diet in T and D and a similar training regimen plus an increased dietary intake of 600 kcal/day defined the T-iD group. Primary end point was insulin sensitivity as evaluated by HOMA-IR (mainly reflecting hepatic insulin sensitivity) and hyperinsulinemic, isoglycemic clamps (primarily reflecting peripheral insulin sensitivity). Body mass decreased in T and D by 5.9 +/- 0.7 and 5.3 +/- 0.7 kg, respectively, whereas T-iD and C remained weight stable. Total and abdominal fat mass were reduced in an additive manner in the T iD, D, and T groups by 1.9 +/- 0.3/0.2 +/- 0.1, 4.4 +/- 0.7/0.5 +/- 0.1, and 7.7 +/- 0.8/0.9 +/- 0.1 kg, respectively. HOMA-IR was improved in T, D, and T-iD, whereas insulin-stimulated glucose clearance and suppression of plasma nonesterified fatty acids (NEFAs) were increased only in the two training groups. Thus, loss of fat mass (diet or training induced) improves hepatic insulin sensitivity, whereas peripheral insulin sensitivity in skeletal muscle and adipose tissue is increased by endurance training only. This demonstrates that endurance training per se increases various metabolic health parameters and that endurance training should preferably always be included in any intervention regimen for improving metabolic health in moderately overweight men. PMID- 22436843 TI - Preparation of quinazolino[3,2-a]quinazolines via a palladium-catalyzed three component reaction of carbodiimide, isocyanide, and amine. AB - A palladium-catalyzed three-component reaction of bis-(2-iodoaryl)carbodiimide, isocyanide, and amine gives rise to quinazolino[3,2-a]quinazolines and related compounds in good yields. Multi-bonds are formed in one pot through nucleophilic attack, isocyanide insertion, and C-N coupling during the reaction process. PMID- 22436842 TI - Misuse of odds ratios in obesity literature: an empirical analysis of published studies. AB - Odds ratios (ORs) are widely used in scientific research to demonstrate the associations between outcome variables and covariates (risk factors) of interest, and are often described in language suitable for risks or probabilities, but odds and probabilities are related, not equivalent. In situations where the outcome is not rare (e.g., obesity), ORs no longer approximate the relative risk ratio (RR) and may be misinterpreted. Our study examines the extent of misinterpretation of ORs in Obesity and International Journal of Obesity. We reviewed all 2010 issues of these journals to identify all articles that presented ORs. Included articles were then primarily reviewed for correct presentation and interpretation of ORs; and secondarily reviewed for article characteristics that may have been associated with how ORs are presented and interpreted. Of the 855 articles examined, 62 (7.3%) presented ORs. ORs were presented incorrectly in 23.2% of these articles. Clinical articles were more likely to present ORs correctly than social science or basic science articles. Studies with outcome variables that had higher relative prevalence were less likely to present ORs correctly. Overall, almost one-quarter of the studies presenting ORs in two leading journals on obesity misinterpreted them. Furthermore, even when researchers present ORs correctly, the lay media may misinterpret them as relative RRs. Therefore, we suggest that when the magnitude of associations is of interest, researchers should carefully and accurately present interpretable measures of association- including RRs and risk differences--to minimize confusion and misrepresentation of research results. PMID- 22436844 TI - Regulatory role of periodontal ligament fibroblasts for innate immune cell function and differentiation. AB - Innate immunity is crucial for an effective host defense against pathogenic microorganisms in periodontal tissues. As periodontal ligament (PDL) cells synthesize immunomodulatory cytokines, the aim of this in vitro study was to investigate whether these cells can interact with innate immune cells. Resting and inflammatory primed (IL-1beta, TNF-alpha, HMGB1) human PDL cells were co cultured with human monocyte-derived dendritic cells or macrophages. Migration, phenotypic maturation and modulation of phagocytosis of Porphyromonas gingivalis by immune cells were investigated upon co-culture with PDL cells and/or their released soluble factors. PDL cells interacted with immune cells under both non inflammatory and inflammatory conditions. Immune cell migration was significantly enhanced by co-culture with PDL cells, which also affected their phenotypic maturation both through cell-cell contact and through released soluble mediators. The dendritic cell maturation markers CD83 and CD86 were upregulated as much as both 'alternatively activated' M2 macrophage maturation markers CD23 and CD163. In contrast, the 'classically activated' M1 macrophage maturation marker CD64 was downregulated. Finally, PDL cells significantly enhanced the phagocytosis of Porphyromonas gingivalis by immune cells. Our experiments revealed that PDL cells are not only structural elements of the periodontium, but actively influence immune responses by interaction with innate immune cells. PMID- 22436845 TI - EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. PMID- 22436846 TI - Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. AB - AIMS: During reperfusion of the ischaemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain depressed. Direct stimulation of glucose oxidation via activation of pyruvate dehydrogenase (PDH), or secondary to an inhibition of malonyl CoA decarboxylase (MCD), improves cardiac functional recovery during reperfusion following ischaemia. However, the effects of such interventions on the evolution of myocardial infarction are unknown. The purpose of this study was to determine whether infarct size is decreased in response to increased glucose oxidation. METHODS AND RESULTS: In vivo, direct stimulation of PDH in mice with the PDH kinase (PDHK) inhibitor, dichloroacetate, significantly decreased infarct size following temporary ligation of the left anterior descending coronary artery. These results were recapitulated in PDHK 4-deficient (PDHK4-/-) mice, which have enhanced myocardial PDH activity. These interventions also protected against ischaemia/reperfusion injury in the working heart, and dichloroacetate failed to protect in PDHK4-/- mice. In addition, there was a dramatic reduction in the infarct size in malonyl CoA decarboxylase-deficient (MCD-/-) mice, in which glucose oxidation rates are enhanced (secondary to an inhibition of fatty acid oxidation) relative to their wild-type littermates (10.8 +/- 3.8 vs. 39.5 +/- 4.7%). This cardioprotective effect in MCD-/- mice was associated with increased PDH activity in the ischaemic area at risk (1.89 +/- 0.18 vs. 1.52 +/- 0.05 MUmol/g wet weight/min). CONCLUSION: These findings demonstrate that stimulating glucose oxidation via targeting either PDH or MCD decreases the infarct size, validating the concept that optimizing myocardial metabolism is a novel therapy for ischaemic heart disease. PMID- 22436847 TI - Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study. AB - AIMS: Vascular cartilaginous metaplasia and calcification are common in patients with atherosclerosis. However, sources of cells contributing to the development of this complication are currently unknown. In this study, we ascertained the origin of cells that give rise to cartilaginous and bony elements in atherosclerotic vessels. METHODS AND RESULTS: We utilized genetic fate mapping strategies to trace cells of smooth muscle (SM) origin via SM22alpha-Cre recombinase and Rosa26-LacZ Cre reporter alleles. In animals expressing both transgenes, co-existence within a single cell of beta-galactosidase [marking cells originally derived from SM cells (SMCs)] with osteochondrogenic (Runx2/Cbfa1) or chondrocytic (Sox9, type II collagen) markers, along with simultaneous loss of SM lineage proteins, provides a strong evidence supporting reprogramming of SMCs towards osteochondrogenic or chondrocytic differentiation. Using this technique, we found that vascular SMCs accounted for ~80% of Runx2/Cbfa1-positive cells and almost all of type II collagen-positive cells (~98%) in atherosclerotic vessels of LDLr-/- and ApoE-/- mice. We also assessed contribution from bone marrow (BM)-derived cells via analysing vessels dissected from chimerical ApoE-/- mice transplanted with green fluorescence protein expressing BM. Marrow-derived cells were found to account for ~20% of Runx2/Cbfa1 positive cells in calcified atherosclerotic vessels of ApoE-/- mice. CONCLUSION: Our results are the first to definitively identify cell sources attributable to atherosclerotic intimal calcification. SMCs were found to be a major contributor that reprogrammed its lineage towards osteochondrogenesis. Marrow-derived cells from the circulation also contributed significantly to the early osteochondrogenic differentiation in atherosclerotic vessels. PMID- 22436848 TI - In vitro biocompatibility assessment of multipurpose contact lens solutions: effects on human corneal epithelial viability and barrier function. AB - PURPOSE: To explore the in vitro effects of multipurpose contact lens solutions (MPSs) on corneal epithelial barrier function and viability. METHODS: Human corneal epithelial cells (HCEpiC) were exposed to 50% MPSs A-G. Viability was determined using metabolic activity, protease release and caspase assays. Barrier function was evaluated using immunostaining for the tight junction protein zonnula occludens-1 (ZO-1) and resistance measurements. RESULTS: MPS A and G did not affect HCEpiC monolayer viability after 2 h, while MPSs B-F significantly decreased viability. There was a significant decrease in stratified HCEpiC viability after exposure to MPSs B-E for 2 h, while there was no effect of MPS A. After exposure of HCEpiC monolayers to MPS A, F or G for 30 min, ZO-1 staining appeared similar to control. HCEpiC exposed to MPSs B and C demonstrated tight junction breakdown. There was no significant change in HCEpiC monolayer resistance after exposure to MPS A or F for 2 h, while MPSs B-E and G reduced resistance. After exposure to MPS A-E, stratified HCEpiC resistance was significantly decreased after 2 or 4 h. The decrease in resistance was significantly less with MPS A as compared to the other MPSs. CONCLUSIONS: MPSs caused varying modifications to cell viability and barrier function in monolayer and stratified HCEpiC. MPS A did not alter monolayer HCEpiC viability or barrier function, while MPSs B-G caused significant decreases of at least one parameter. Furthermore, MPS A had significantly less effect than MPSs B-E on viability and barrier function of stratified HCEpiC. PMID- 22436849 TI - Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase. AB - We investigated the effects of synthetic cannabinoids, WIN55,212-2 and HU210, on LPS-injected rat substantia nigra in vivo. Intranigral injection of LPS resulted in a significant loss of nigral dopaminergic (DA) neurons, as determined by Nissl staining and TH immunohistochemistry. LPS-induced neurotoxicity was accompanied by microglial activation, as demonstrated by OX-42 immunohistochemistry. In parallel, Western blot analysis, ELISA assay and hydroethidine histochemistry revealed activation of NADPH oxidase, as demonstrated by increased translocation of the cytosolic proteins p47(phox) and p67(phox), generation of reactive oxygen species (ROS) and increased level of proinflammatory cytokines (TNF-alpha and IL 1beta), where degeneration of nigral DA neurons was evident. Interestingly, WIN55,212-2 and HU210 increased the survival of nigral DA neurons at 7days post LPS treatment. Consistent with these results, cannabinoids inhibited activation of NADPH oxidase, ROS production and production of proinflammatory cytokines in the rat SN. The present data suggest that cannabinoids may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with microglial activation. PMID- 22436851 TI - The declining interest in a career in thoracic surgery. PMID- 22436850 TI - Caspase activation contributes to astrogliosis. AB - Caspases, a family of cysteine proteases, are widely activated in neurons and glia in the injured brain, a response thought to induce apoptosis. However, caspase activation in astrocytes following injury is not strongly associated with apoptosis. The present study investigates the potential role of caspase activation in astrocytes with another characteristic response to neural injury, astrogliosis. Caspase activity and morphological and biochemical indices of astrogliosis and apoptosis were assessed in (i) cultured neonatal rat astrocytes treated with astrogliosis-inducing stimuli (dibutryl cAMP, beta-amyloid peptide), and (ii) cultures of adult rat hippocampal astrocytes generated from control and kainate-lesioned rats. The effects of broad spectrum and specific pharmacological caspase inhibitors were assessed on indicators of astrogliosis, including stellate morphology and expression of glutamine synthetase and fibroblast growth factor-2. Reactive neonatal and adult astrocytes demonstrated an increase in total caspase activity with a corresponding increase in the expression of active caspase-3 in the absence of cell death. Broad spectrum caspase inhibition with zVAD significantly attenuated increases in glutamine synthetase and fibroblast growth factor-2 in the reactive astrocytes. In the reactive neonatal astrocyte cultures, specific inhibition of caspases-3 and -11 also attenuated glutamine synthetase and fibroblast growth factor-2 expression, but did not reverse the morphological reactive phenotype. Astrogliosis is observed in all forms of brain injury and despite extensive study, its molecular triggers remain largely unknown. While previous studies have demonstrated active caspases in astrocytes following acute brain injury, here we present evidence functionally implicating the caspases in astrogliosis. PMID- 22436852 TI - Rationale for minimally invasive pulmonary vein isolation and partial autonomic denervation for surgical treatment of atrial fibrillation. AB - We seek to demonstrate the rationale of a minimally invasive surgical approach to the treatment of atrial fibrillation which combines pulmonary vein antral isolation with targeted partial autonomic denervation. The literature supporting the rationale of this approach is reviewed. There is evidence-based literature that supports both pulmonary vein electrical isolation and targeted partial autonomic denervation in the treatment of atrial fibrillation. These techniques can be combined in a minimally invasive surgical approach. PMID- 22436853 TI - Hemodynamic assessment using apical suction versus pericardial retraction in beating heart surgery. AB - OBJECTIVE: : Aim of this study was to evaluate the perioperative hemodynamic function using an apical suction device (Xpose = XS) versus standard pericardial retraction sutures (PS) during off-pump myocardial revascularization. METHODS: : Twenty-seven consecutive patients (four female) with three-vessel disease receiving off-pump myocardial revascularization were prospectively evaluated. Mean age was 70 +/- 8 years and mean ejection fraction was 55 +/- 18%. Pulscontour continuous cardiac output, Swan Ganz catheter, and transesophageal echo measurements were performed. All patients received left internal mammary artery (LIMA)-left anterior descending grafting first. The XS or PS technique for marginal or right coronary artery branch exposure was used and after hemodynamic recovery the same measurements were performed using the other technique, thus each patient served as an intraindividual control. Finally, the anastomosis was performed in the respective territory. RESULTS: : All procedures were completed as off-pump coronary artery bypass without perioperative complications. The mean confidence interval (L/min/m)/mean arterial pressure (mm Hg) was 2.8 +/- 0.5/87 +/- 11 after opening the pericardium and 2.4 +/- 0.4/75 +/- 12 during left anterior descending exposure. During lateral wall exposure, it was 1.8 +/- 0.6/67 +/- 12 using XS and 1.9 +/- 0.6/68 +/- 12 using PS (P = ns). During inferior wall exposure, it was 2.1 +/- 0.4/69 +/- 12 using XS and 1.9 +/- 0.4/68 +/- 13 using PS (P = ns). No significant differences were seen comparing other parameters (cardiac output (CO), heart rate (HR), intrathoracic blood volume index) as well. CONCLUSIONS: : The lateral and inferior coronary arteries can be safely exposed on the beating heart with PS or XS technique. In individual patients, either XS or PS exposure yielded a better preservation of cardiac index and blood pressure compared with baseline. PMID- 22436854 TI - Preoperative hemoglobin a1c predicts sternal wound infection after coronary artery bypass surgery with bilateral versus single internal thoracic artery grafts. AB - OBJECTIVE: : Bilateral internal thoracic artery (BITA) grafting during coronary artery bypass (CABG) improves long-term and event-free survival but may carry a higher risk of wound complications. It is unknown whether preoperative hemoglobin A1c (HbA1c), a measure of long-term glucose control, predicts deep sternal wound infection (DSWI) after BITA grafting. METHODS: : Of 6356 consecutive patients who underwent isolated CABG between January 1, 2002 and March 30, 2007 and received at least one internal thoracic artery graft, 5199 (81.8%) had preoperative HbA1c levels obtained. BITA grafting was performed in 622 (9.8%) patients. A propensity score measured each patient's probability of having BITA versus single ITA based on 52 risk factors. The primary endpoint was DSWI. Multivariable logistic models with adjusted odds ratios (AOR) examined the effect of HbA1c, BITA grafting, and their interaction on outcomes, adjusted for the propensity score and postoperative glucose levels. RESULTS: : Patients undergoing BITA grafting with HbA1c >=7% had a higher incidence of DSWI compared with patients with HbA1c <7% (5.0% vs. 1.4%, P = 0.014). After multivariable adjustment, BITA was associated with an increased risk of DSWI (AOR = 2.84, 95% confidence interval 1.41-5.74) in all patients (P = 0.004). For each unit increase in HbA1c, there was a 31% increased risk of DSWI (AOR = 1.31, 95% CI 1.16-1.49, P < 0.001). Patients with HbA1c >=7% had 2.88-fold increase in DSWI compared with patients with HbA1c <7%. CONCLUSIONS: : Elevated preoperative HbA1c and BITA grafting were significant predictors of DSWI after CABG. Elevated HbA1c level should be considered in the risk/benefit analysis when selecting patients for BITA grafting. PMID- 22436855 TI - Robotic technology-probably a safe tool for development of completely endoscopic coronary revascularization procedures. AB - BACKGROUND: : Totally endoscopic coronary artery bypass grafting (TECAB) requires telemanipulation technologies because attempts using conventional thoracoscopic instrumentation have completely failed. These complex operations require individual and team learning curves and necessitate a stepwise approach. The aim of this study is to assess risk adjusted outcome in robotically assisted coronary artery bypass grafting (CABG) after the first 6 years of application. METHODS: : From 2001 to 2007, 177 CABG procedures were performed using the da Vinci system. A low risk patient population [age 59 (31-76) years, EuroSCORE 1 (0-7)] was treated. The following procedures were carried out: endoscopic internal mammary artery takedown in minimally invasive direct coronary artery bypass, Off-pump coronary artery bypass, and CABG (n = 26); robotic suturing of left internal mammary artery to left anterior descending artery anastomoses through sternotomy (n = 32); TECAB on the arrested heart (n = 108); TECAB on the beating heart (n = 11). RESULTS: : There was no hospital mortality, and cumulative risk adjusted mortality plots showed that 2.76 predicted events did not occur. Given 177 event free procedures Clopper Pearson estimations revealed a 95% confidence interval between 0.0% and 2.3% for perioperative mortality. CONCLUSIONS: : Introduction of robotic TECAB grafting appears to meet current CABG safety standards. Initial application in low risk patients and a stepwise approach towards completely endoscopic versions of the operation are worthwhile. Despite a high grade of innovation and despite learning curves, perioperative mortality may be lower than predicted. PMID- 22436856 TI - Can the Left Subclavian Artery be Safely Covered During Endovascular Repair of the Descending Thoracic Aorta? AB - OBJECTIVE: : Routine preoperative carotid-subclavian bypass or transposition is frequently recommended in patients undergoing endovascular repair of the descending thoracic aorta (DTA). We reviewed our comprehensive thoracic endografting experience with regards to coverage of the left subclavian artery (LSA) to assess whether mandatory preoperative carotid-subclavian bypass or transposition is necessary. METHODS: : Between February 2000 and November 2005, 255 patients were successfully treated with an endoluminal graft (ELG) to the DTA. Indications for intervention included atherosclerotic aneurysms (109/255, 42.7%), acute and chronic dissections (75/255, 29.4%), miscellaneous (41/255, 16.1%), and penetrating aortic ulcers (30/255, 11.8%). There were 151 males (151/255, 59.2%) and 104 females (104/255, 40.8%) with a mean age of 71 years (range, 23-91 years). RESULTS: : The LSA was completely covered with an ELG in 71 patients (71/255, 27.8%) and partially covered in 47 patients (47/255, 18.4%). In patients who had complete coverage of the LSA, 30 patients (30/71, 42.3%) had acute or chronic Type B dissections, 26 patients (26/71, 36.6%) had aneurysms, 11 patients (11/71, 15.5%) had miscellaneous aortic pathologies, and 4 patients (4/71, 5.6%) had pseudoaneurysms associated with prior coarctation repair. Fifteen patients (15/255, 5.9%) underwent preoperative carotid-subclavian bypass or transposition and subsequently underwent complete coverage of the LSA with an ELG. One patient (1/56, 1.8%) with complete coverage of the LSA required elective postoperative carotid-subclavian bypass secondary to left arm claudication. CONCLUSIONS: : Routine preoperative carotid-subclavian bypass is not necessary, except in select patients with a patent left internal mammary artery to the left anterior descending artery bypass graft or contralateral vertebral artery disease. PMID- 22436857 TI - Surgical feasibility of the injection of fibrin sealant in cardiac fat pads to reduce the incidence of postoperative atrial fibrillation after coronary artery bypass grafting or valve surgery: a pilot study. AB - OBJECTIVE: : Atrial fibrillation (AF) is the most common complication following coronary artery bypass grafting or valve surgery.The autonomic nervous system is an important determinant in the development of AF. We have assessed the role of injection of fibrin sealant (FS) as a method to modify conduction in the fad pads, to mimic temporary denervation and to reduce the incidence of postoperative AF in patients undergoing coronary artery bypass grafting or valve surgery. PATIENTS AND METHODS: : Twenty eligible patients who underwent coronary bypass grafting or aortic valve surgery in our Institution were included in this pilot - study.Detection of AF after surgical intervention was based on patient symptomatology and on daily electrocardiograms obtained on all patients. Telemetry was used in all patients for the entire hospitalization period. RESULTS: : 20% of the studied population (n = 4) developed postoperative AF. At the time of discharge one patient (5%) had persistent AF.Postoperative mortality was 5% (n = 1) and not cardiac related. None of the patients required permanent pacemaker implantation. CONCLUSIONS: : This first human study of FS injected into the anterior fad pads following low to moderate risk open heart surgery shows, that this procedure is safe and feasible. Moreover, CM -1 injection appears to reduce the need for postoperative intervention and/or treatment of AF by diminishing its incidence. PMID- 22436858 TI - SPY Imaging Assessment Correlates With Transesophageal Echocardiogram Assessment of Ventricular Function During Off-Pump Coronary Artery Bypass Grafting. AB - Intraoperative assessment of graft anastomoses is commonly performed after off pump coronary artery bypass grafting (OPCAB). The SPY imaging system allows intraoperative graft assessment. We document correlation between intraoperative SPY images and wall motion abnormality by transesophageal echocardiogram (TEE) during OPCAB. A 79-year-old female underwent OPCAB. Intraoperative graft patency assessment was performed with the SPY and left ventricular wall motion was assessed by TEE. SPY imaging demonstrated poor flow trough the distal vein graft anastomosis to the posterior descending artery, which correlated with a new posterior wall motion hypokinesis. After graft revision, SPY imaging demonstrated good distal flow and the TEE demonstrated normalization of the left ventricular posterior wall motion. SPY technology allows the surgeon to accurately assess graft patency intraoperatively and allows immediate correction of a technical problem. PMID- 22436859 TI - Hybrid thoracic stent graft repair of a complex type B aortic dissection in a patient who presented three weeks after repair of a type a aortic dissection. AB - Long-term management after repair of a type A aortic dissection includes aggressive medical therapy and routine surveillance with serial imaging to ensure thrombosis of the false lumen. Retained patency of the false lumen can lead to either the development of a false lumen aneurysm with a subsequent rupture or extension of dissection. Typically such events occur late, usually months after repair, and are treated with either a conventional one-stage open thoracoabdominal repair or a two-stage "elephant trunk" procedure. However, most patients who undergo such procedures experience major complications and the procedure-related mortality rate is high. We present a unique case of a 61-year old woman who presented with a ruptured type B aortic dissection 3 weeks after repair of a type A aortic dissection. She underwent an emergent thoracotomy and primary repair of the ruptured aorta followed by concomitant arch debranching and thoracic stent graft placement. Simultaneous surgical debranching with a median sternotomy and endovascular repair with stent grafts is an attractive hybrid approach in patients who present with an acute rupture of a false lumen aneurysm soon after initial repair of an aortic dissection, a situation in which a conventional repair is not feasible. This report emphasizes that hybrid thoracic stent graft repair should be considered for such high-risk patients in the near future as it offers them relatively lower morbidity and mortality compared with what is seen with conventional repairs. PMID- 22436860 TI - Safe and complete exclusion of the left atrial appendage: a simple epicardial approach. AB - A standardized technique to permanently exclude the left atrial appendage during cardiac surgical procedures to potentially prevent stroke has never been established. We describe a simplified technique using a combination of endoloop occlusion with direct purse-string suturing supported with multiple teflon pledgets placed epicardially at the base of the appendage. The left atrial appendage is subsequently opened and decompressed to facilitate contraction and scarring, reducing or eliminating the possibility of recannalization. The technique was used successfully in 195 off-pump coronary bypass grafting patients with long-term echocardiographic follow-up. PMID- 22436861 TI - Altered quantities and in vivo activities of cholinesterase from Daphnia magna in sub-lethal exposure to organophosphorus insecticides. AB - For investigating relationship between activity of cholinesterase (ChE) and ambient concentration of anticholinesterases, Daphnia magna had been exposed for 21 day to sub-lethal concentrations, i.e. 1/6 EC(50), 1/36 EC(50), and 1/216 EC(50), of either triazophos or chlorpyrifos. Samples were taken at different points of time for measuring total activity and immunoreactive content of ChE and actual concentrations of the anticholinesterases. A type of antigen formerly developed by immunizing mice with purified ChE was utilized in this study to establish an indirect non-competitive ELISA for measuring immunoreactive content of ChE in Daphnia. Studies showed that for apparent activity, i.e. activity that was scaled with total protein, the insecticides caused 5.2-6.9 percent inhibition and 17.0-17.7 percent inductions during the 21 d exposure, whereas for inherent activity, i.e. activity that was scaled with immunoreactive protein, no induction was detected during the exposure. Accompanied by up to 65.9 percent and 68.0 percent promotion in terms of the immunoreactive content, up to 42.8 percent and 44.6 percent inhibition in terms of the inherent activity was indicated, respectively, for triazophos and chlopyrifos. Judged by measured concentrations, the inherent activity recovered faster than the rate of dissipation of the anticholinesterases. Result of the study suggested that the inherent activity was more sensitive than the apparent one in predicting sub-lethal and/or long-term stress of anticholinesterases. It also suggested that apart from promotion in terms of content of the ChE, the Daphnia developed capacities to block bio concentration of anticholinesterases, and these capacities would make it liable to underestimate ambient concentration of anticholinesterases along with the time of exposure. PMID- 22436862 TI - [Fertility and pregnancy outcome following invasive management of severe postpartum hemorrhage]. AB - OBJECTIVE: Ligation of the internal iliac arteries and embolization of the uterine arteries are two techniques routinely used in the management of postpartum hemorrhage. The objective of this study was to examine the long-term consequences of these techniques on women's subsequent reproductive outcome and subsequent delivery morbidity. METHODS: Retrospective study including women who underwent ligation and those who underwent embolization, for the treatment of postpartum hemorrhage. We analyzed resumption of menses, fertility, pregnancy and delivery outcome after each treatment. RESULTS: The study included 85 women who underwent ligation and 90 who had embolization to treat postpartum hemorrhage. No adverse event related to menses, fertility, or pregnancy outcome followed either treatment. However, the rate of recurrent hemorrhage was high: 26% after ligation and 39% after embolization. All recurrences were treated medically in the ligation group, but in the embolization group, 42% (five of 12 patients) required invasive treatment and 33% (four patients) transfusions. CONCLUSION: From the perspective of subsequent menses, fertility and pregnancy outcome, both ligation and embolization are safe procedures for the management of postpartum hemorrhage. However, our results showed a high risk of recurrent postpartum hemorrhage after both treatments. Recurrences seemed more serious after the latter. PMID- 22436863 TI - Poly-lactic-glycolic-acid surface nanotopographies selectively decrease breast adenocarcinoma cell functions. AB - The ability of poly(lactic-co-glycolic acid) (PLGA, 50:50 PLG/PGA, wt%) nanotopographies to decrease lung epithelial carcinoma cell functions (including adhesion, proliferation, apoptosis and vascular endothelial growth factor (VEGF) secretion) has been previously reported. Specifically, results demonstrated decreased lung epithelial carcinoma cell VEGF synthesis on 23 nm surface-featured PLGA compared to traditional nanosmooth PLGA. However, clearly, different cell lines could have different behaviors on similar biomaterials. Thus, to investigate the universality of nanopatterned PLGA substrates to inhibit numerous cancer cell functions, here, breast epithelial adenocarcinoma cell (MCF-7) adhesion, proliferation, apoptosis and VEGF secretion were determined on different PLGA nanometer surface topographies. To isolate surface nanotopographical effects from all other surface properties, PLGA surfaces with various nanotopographies but similar chemistry and hydrophobicity were fabricated here. Atomic force microscopy (AFM) verified the varied nanotopographies on the PLGA surfaces prepared in this study. Importantly, results demonstrated for the first time significantly decreased breast adenocarcinoma cell functions (including decreased proliferation rate, increased apoptosis and decreased VEGF synthesis) on 23 nm featured PLGA surfaces compared to all other PLGA surface topographies fabricated (specifically, nanosmooth, 300 and 400 nm surface featured PLGA surfaces). In contrast, healthy breast epithelial cells proliferated more (24%) on the 23 nm featured PLGA surfaces compared to all other PLGA samples. In summary, these results provided further insights into understanding the role PLGA surface nanotopographies can have on cancer cell functions and, more importantly, open the possibility of using polymer nanotopographies for a wide range of anticancer regenerative medicine applications (without resorting to the use of chemotherapeutics). PMID- 22436864 TI - Increased oxidative stress and toxicity in ADH and CYP2E1 overexpressing human hepatoma VL-17A cells exposed to high glucose. AB - High glucose mediated oxidative stress and cell death is a well documented phenomenon. Using VL-17A cells which are HepG2 cells over-expressing alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) and control HepG2 cells, the association of ADH and CYP2E1 with high glucose mediated oxidative stress and toxicity in liver cells was investigated. Cell viability was measured and apoptosis or necrosis was determined through caspase-3 activity, Annexin V propidium iodide staining and detecting decreases in mitochondrial membrane potential. Reactive oxygen species, lipid peroxidation and the formation of advanced glycated-end products were assessed. The levels of several antioxidants which included glutathione, glutathione peroxidase, catalase and superoxide dismutase were altered in high glucose treated VL-17A cells. Greater toxicity was observed in VL-17A cells exposed to high glucose when compared to HepG2 cells. Oxidative stress parameters were greatly increased in high glucose exposed VL-17A cells and apoptotic cell death was observed. Inhibition of CYP2E1 or caspase 3 or addition of the antioxidant trolox led to significant decreases in high glucose mediated oxidative stress and toxicity. Thus, the over-expression of ADH and CYP2E1 in liver cells is associated with increased high glucose mediated oxidative stress and toxicity. PMID- 22436865 TI - Nanoparticles for treating brain tumors: unlimited possibilities. PMID- 22436866 TI - Surgery, a prognostic marker for progression-free survival? PMID- 22436868 TI - Comparison of central corneal thickness using optical low-coherence reflectometry and spectral-domain optical coherence tomography. AB - PURPOSE: To assess intraobserver and interobserver reliability of central corneal thickness (CCT) measurements using optical low-coherence reflectometry (OLCR) technology and its agreement with spectral-domain optical coherence tomography (SD-OCT). SETTING: Rio Hortega University Hospital, Valladolid, Spain. DESIGN: Evaluation of diagnostic technology. METHODS: To analyze OLCR intraobserver repeatability, 1 examiner obtained 4 successive measurements. To study interobserver reproducibility, a different examiner obtained another CCT measurement. To determine agreement with SD-OCT, the first examiner also obtained CCTs. Intraobserver and interobserver within-subject standard deviation (S(w)), coefficient of variation (CV(w)), and limits of agreement (LoA) were obtained for OLCR reliability analysis; for study agreement, data were analyzed using the paired-sample t test and the LoA were calculated. RESULTS: For OLCR intraobserver repeatability, the S(w) and precision (1.96*S(w)) were 2.33 and 4.56 MUm, respectively. The intraobserver CV(w) was 0.42%. For interobserver reproducibility, the S(w) and precision were 11.59 and 22.71 MUm, respectively; the CV(w) was 2.10%. The mean difference between observers was -1.35 MUm (95% confidence interval [CI], -3.97 to 1.26). The width of the LoA was 45.27 MUm. The mean CCT difference between OLCR and SD-OCT was 5.68+/-11.46 MUm (95% CI, 8.29 3.08 MUm; P=.0001), and the width of the LoA was 44.93 MUm. CONCLUSIONS: Optical low-coherence reflectometry technology provided reliable intraobserver and interobserver CCT measurements. Although OLCR underestimated the pachymetry by less than 6 MUm compared with SD-OCT, its interchangeability fell within the range of interobserver reproducibility. Both noncontact pachymetry measurements seem to be clinically useful and may be used interchangeably with minimum calibration adjustment. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22436869 TI - Can surgeons do complete revascularization in diabetic patients using the off pump technique? AB - BACKGROUND: : The arguments are discussed as to whether or not to proceed with multivessel percutaneous coronary intervention, with or without a drug-eluting stent, in patients with diabetes mellitus (DM), including (1) surgeons unable to complete revascularization because of smaller native arteries; and (2) diabetic patients being sicker and having higher operative mortality rates than nondiabetic patients (non-DM), particularly with the conventional coronary artery bypass surgery (on-pump) technique. To support or dispute the claims, a retrospective review of 480 consecutive patients at a single institution (195 DM and 285 non-DM) was carried out. Observations were made to see whether diabetes is a predictor of poor outcomes. MATERIALS AND METHODS: : The preoperative comorbidity, intraoperative measurement of the size of the artery at the site of anastomosis with different gauged probes, and the number of grafts per patient were recorded. Intraoperative and postoperative variables between two groups were compared. The observed number of grafts (O) after surgery was compared with the number of grafts predicted (P) before surgery. The O/P ratio or "completion index" of >=1 signifies complete revascularization. Logistic regression analysis was used to test the possibility that diabetes is a predictor of poor outcomes. RESULTS: : Diabetic patients were older, with more comorbidity (congestive heart failure, peripheral vascular diseases, dialysis-dependent). The number of grafts per patient was 4.2 +/- 1.3 (DM) and 4.2 +/- 1.3 (non-DM). The size of 742 DM and 949 non-DM arteries were gauged. There was no statistical difference in size between DM and non-DM (in millimeters) at each artery. All ratios ranged from 0.9 to 1.2, indicating similarity between DM and non-DM. The only significant risk factor for operative death was low left ventricular ejection fraction (P = 0.001). CONCLUSIONS: : Patients with DM were sicker but tolerated off-pump coronary artery bypass grafting as well as non-DM patients. The number of grafts per patient and O/P ratio signify the ability to perform complete revascularization. We are able to bypass the small target vessels, as anticipated. Diabetes is not a predictor of the outcomes. PMID- 22436870 TI - Autonomic ganglionated plexi: characterization and effect of epicardial microwave ablation in a canine model of vagally induced acute atrial fibrillation. AB - OBJECTIVE: : Autonomic ganglionated plexi (GP) in fat pads near the pulmonary veins may contribute to initiation and maintenance atrial fibrillation (AF). We attempted to localize these plexi in a canine model, and evaluate the efficacy of microwave ablation in eliminating their vagal reflexes. METHODS: : 8 Mongrel dogs (25-31 kg), underwent cervical vagal trunk stimulation to produce AV nodal block and sustained AF. Sternotomy was performed and the epicardial fat on the posterior left atrium and pulmonary veins was locally stimulated at high frequency (20 Hz, 3-5 mA). Locations that produced a vagal response were identified and in 7 dogs ablated using the Flex 4 epicardial microwave ablation probe (Guidant Corp) at 65 watts/90 sec. One animal was a control and not ablated. Vagal responses were retested with local stimulation as well as stimulation of the cervical vagal trunks. The presence of AV block and duration of sustained AF was recorded. RESULTS: : Baseline cervical vagal stimulation produced AV block and AF in all the animals. Local high-frequency stimulation (HFS) elicited vagal responses at the junction of the inferior vena cava and the middle pulmonary vein (IVC-MPV) in 8 animals, the base of the left pulmonary veins/ligament of Marshall (LoM) in 5 animals, and between the upper and lower right pulmonary veins (RPV) in 2 animals. Microwave ablation at the IVC-MPV eliminated the vagal response upon local fat pad HFS. Cervical vagal trunk stimulation yielded less AV block (n = 2) or no AV block (n = 5) after microwave ablation of the IVC-MPV alone (n = 4) or in conjunction with LoM area ablation (n = 3). The average duration of AF during cervical vagal stimulation decreased significantly from baseline (52.7 +/- 27.0 sec) versus after fat pad ablation (13.8 +/- 20.3 sec, p = 0.004). CONCLUSIONS: : In a canine model we found the primary epicardial autonomic ganglionated plexi to be at the junction of the IVC MPV. Epicardial microwave ablation of this GP eliminated the vagal response during local fat pad stimulation; and attenuated or eliminated AV block and induction of sustained AF during cervical vagal trunk stimulation. Epicardial microwave ablation of the ganglionated plexi in epicardial fat pads is feasible and can eliminate vagal reflexes that maybe important in atrial fibrillation. PMID- 22436871 TI - Displacement of the beating heart with a low-profile suction-based apical positioning device in a closed chest. AB - BACKGROUND: : Off-pump, multivessel, endoscopic coronary artery bypass requires cardiac displacement within an intact chest. The current study evaluated right ventricular performance and systemic hemodynamics while exposing the posterior surface of the heart using a novel, low-profile, apical suction-based cardiac positioner in a closed-chest, beating-heart model. METHODS: : Six pigs underwent instrumentation with continuous monitoring of arterial pressure by fluid-filled transducer and cardiac output and coronary blood flow by ultrasound transit time flow probe. Right ventricular (RV) pressure-volume loops were generated by an impedance catheter. Heart rate was maintained between 80 and 100 beats per minute pharmacologically. The cardiac positioner displaced the heart endoscopically through a port. Data were obtained in 5 sequential phases: (1) baseline/free beating, (2) positioner coaptation, (3) addition of Trendelenburg, (4) cardiac displacement with Trendelenburg, and (5) cardiac displacement without Trendelenburg. RESULTS: : Cardiac displacement without Trendelenburg (Phase 5) resulted in a significant (P < 0.05) decrease in cardiac output, coronary blood flow, RV systolic pressure (RVSP), mean arterial pressure, RV end-diastolic volume (RVEDV), and RV end-systolic volume (RVESV) compared with baseline (Phase 1). With Trendelenburg added to cardiac displacement (Phase 4), all parameters improved, but only RVSP, mean arterial pressure, and RVEDV were comparable to baseline (Phase 1). There were no local complications from device coaptation. CONCLUSIONS: : The low-profile endoscopic cardiac positioner is safe and effective in the closed-chest, beating-heart porcine model. Nevertheless, cardiac displacement in a closed chest does cause impairment in ventricular performance that can be ameliorated by the addition of Trendelenburg and further technological progress. PMID- 22436872 TI - StarfishTM heart positioner maintains right ventricular function during lateral wall displacement. AB - BACKGROUND: : The authors examined parameters of cardiovascular function using Starfish and deep pericardial sutures (DPS) in a beating heart porcine model and to clarify toleration of right ventricular function with Starfish in lateral wall displacement. METHODS: : Eight healthy pigs were used. In addition to normal pressure monitor catheters, a Swan-Ganz continuous cardiac output (CO) and end diastolic volume thermodilution catheter was used for precise and quantitative monitoring of the right ventricular function. RESULTS: : Lateral displacement of the heart with DPS resulted in a significant hemodynamic compromise. Cardiac output and right ventricular ejection fraction (RVEF) decreased from 3.0 +/- 0.9 to 2.6 +/- 1.0 L/min (P = 0.014) and from 27.9 +/- 3.0% to 23.3 +/- 4.8% (P = 0.019). With StarfishTM, CO and RVEF were maintained from 3.0 +/- 0.9 to 3.0 +/- 0.9 L/min (P = 0.743) and from 27.9 +/- 3.0% to 28.3 +/- 3.8% (P = 0.476). CONCLUSION: : StarfishTM contributed to the stability of hemodynamics by maintaining the right ventricular function. Lateral displacement with PDS resulted in significant hemodynamic compromised compared with StarfishTM and baseline neutral position. PMID- 22436873 TI - Technical innovations in the minimally invasive approach for treating pectus excavatum: a paradigm shift through six years' experience with 630 patients. AB - OBJECTIVE: : The multiple-momentum (MM) based multitarget (MT) approach has been developed through a single surgeon's experience to overcome the limits of the conventional Nuss procedure, which is the single target-single momentum approach that corrects only symmetric pectus excavatum (PE). The new techniques that have been devised on a morphologic basis, according to the Terrain Contour Matching (TERCOM) system, have made this approach a comprehensive one that can cover all types of pectus deformity. The aim of this study was to elucidate the difference between the conventional technique and the new approach. METHODS: : The data of 630 PE patients who received the modified Nuss procedure, based on the MM-MT TERCOM approach, between 1999 and 2005, were retrospectively studied. The conceptual differences between the new approach and the conventional one were determined. The techniques according to a new paradigm, for treating asymmetry, adults, and complex morphology, as well as the bar fixation technique, were analyzed. The results of the repair were assessed with a new CT index, the Asymmetry Index (AI). RESULTS: : According to the morphologic classification, 269 patients were asymmetric (42.7%): 138 were eccentric (53 Grand Canyon type), 88 were unbalanced, and 36 were combined. On the basis of the MM-MT-TERCOM concept for repairing complex morphology, multiple targets were selected in 224 patients (35.6%). To correct targets simultaneously, positive momentum (630 patients, 100%) and negative momentum (124 patients, 19.7%) were applied as appropriate. The techniques used were an asymmetric bar (250 patients, 39.7%), a seagull bar (107 patients, 17%), a complex bar via TERCOM (126 patients, 20%), the crest compression technique (59 patients, 9.4%), and a compound bar (84 patients, 13.3%). The postoperative changes of the AI were from 1.03 +/- 0.06 to 1.02 +/- 0.13 (P = 0.117) in the symmetric group and they were from 1.1 +/- 0.05 to 1.02 +/- 0.02 (P < 0.001) in the asymmetric group. CONCLUSIONS: : Refinement of techniques in accordance with the morphology and cause-effect basis of the bar action provided reproducible results for achieving postrepair symmetry for treating complex PE. Therefore, the new approach with techniques that use multiple momentums (MM-MT-TERCOM) supports the new paradigm of the Nuss procedure is effective in repair of all morphologic types of PE. PMID- 22436874 TI - Outcomes after off-pump reoperative coronary artery bypass grafting. AB - OBJECTIVE: : Application of off-pump techniques to reoperative coronary artery bypass (redo CABG) has been limited by technical difficulty and potential for embolism of atheromatous debris from diseased grafts, resulting in myocardial infarction and rapid hemodynamic deterioration. We compared outcomes after off pump (OPCAB) and on-pump (ONCAB) in redo CABG. METHODS: : A retrospective chart review was performed for patients who underwent redo CABG at a single academic institution between January 1997 and December 2004. Outcomes were compared between groups based on intention to treat. Propensity scores were calculated for each patient using 23 preoperative risk factors. Logistic regression was applied for each end point as a function of group and propensity score. RESULTS: : A total of 771 consecutive patients had redo CABG (639 ONCAB and 132 OPCAB); 22 patients (16.7%) were converted from OPCAB to ONCAB for hemodynamic in stability, severe adhesions, or graft injury; 7 patients (1.1%) were converted from ONCAB to OPCAB for severe aortic calcification. Propensity-matched comparison of outcomes after OPCAB versus ONCAB for redo CABG showed that OPCAB was associated with a reduction in postoperative complications, transfusion, atrial fibrillation, and length of stay. OPCAB patients received fewer grafts with similar use of left internal mammary artery conduit; conversion from OPCAB to ONCAB did not reduce the benefit of OPCAB. CONCLUSIONS: : OPCAB can be safely and effectively applied to reoperative CABG in selected cases. PMID- 22436875 TI - Use of peripheral ultrafiltration in the postoperative cardiac surgery patient. AB - BACKGROUND: : After cardiac surgery, most patients have development of third space fluid retention, commonly treated with diuretics. In some patients diuretics are ineffective. In this subset, a simplified system for ultrafiltration was used for fluid extraction. METHODS: : After obtaining permission from the institutional review board, the hospital charts of the first 30 patients having ultrafiltration were retrospectively reviewed to abstract data on fluid extraction and patient outcomes. Data are expressed as mean +/- standard deviation. RESULTS: : From April 2004 through January 2006, 30 patients were selected for ultrafiltration. In one patient, adequate intravenous access could not be obtained. There were 11 female and 18 male (age, 69 +/- 12 years) postoperative cardiac surgery patients. The mean ultrafiltration run was 10.5 +/- 9 hours, resulting in fluid extraction of 3528 +/- 2111 mL per run and 5596 +/- 3870 mL per patient (11 patients had more than 1 run). Hospital stay was 9.4 +/- 4.4 days. Three patients died unrelated to ultrafiltration. CONCLUSIONS: : Ultrafiltration as an alternative means of fluid extraction in postoperative cardiac surgery patients was effective and well tolerated. PMID- 22436876 TI - Hemostatic control of coronary arteries with poloxamer 407 reverse-thermal polymer during off-pump coronary artery bypass surgery in a pig model. AB - OBJECTIVE: : To evaluate a new material, poloxamer 407 reverse-thermal polymer, which may be of value in controlling bleeding during off-pump coronary anastomoses. METHODS: : Poloxamer 407 reverse-thermal polymer is a clear, nontoxic compound that is a viscous liquid at room temperature but instantly changes to a firm, water-soluble gel when warmed to body temperature. Six pigs underwent off-pump coronary artery bypass with the left internal mammary artery to the left anterior descending coronary artery. Blood loss from the arteriotomy was measured over a 15-minute period before and after injection of 500 MUL intracoronary polymer. After completion of the anastomosis, 10 mL of cold saline was poured along the left anterior descending artery to facilitate dissolution of the polymer. The heart was allowed to beat 2 additional hours with blood flowing through the left internal mammary to left anterior descending graft, after which a completion angiogram was obtained to evaluate graft patency and to look for gross angiographic evidence of coronary branch occlusion or intraluminal filling defects. The animals were then humanely euthanized, and myocardium from the area subtended by the left anterior descending was harvested for histologic evaluation. RESULTS: : All animals successfully underwent the surgical procedure and survived until study termination without any complications. The amount of bleeding from coronary arteriotomy was significantly higher before intracoronary injection of the polymer (5.25 +/- 1.65 mL/min versus 0.54 +/- 0.53 mL/min, P = 0.0004). Angiography demonstrated that the graft was patent, and there was no evidence of intraluminal foreign bodies. Myocardial samples from the subtended bed showed no evidence of intraarterial polymer or myonecrosis. CONCLUSIONS: : Poloxamer 407 reverse-thermal polymer may be a valuable tool in performing coronary anastomoses off-pump. Completion angiograms showed total dissolution of the material with no residual intraarterial polymer visible on tissue samples. PMID- 22436877 TI - Minimally invasive surgical cardiac resynchronization therapy: an intermediate term follow-up study. AB - BACKGROUND: : Cardiac resynchronization therapy (CRT) improves symptoms, quality of life, and ejection fraction in selected patients with congestive heart failure (CHF) and interventricular conduction delay. Transvenous insertion of left ventricular (LV) pacing leads via the coronary sinus is unsuccessful in 8-10% of patients. This study describes intermediate-term follow up of minimally invasive surgical techniques for CRT as a viable alternative after failed transvenous lead insertion. METHODS: : From March 2001 to October 2005, fifty-four patients with NYHA Class III-IV symptoms, QRS duration 181 +/- 40 milliseconds, and LV ejection fraction 19.7 +/- 8.0% underwent a total of 56 minimally invasive LV lead placements via thoracoscopic video assistance (n = 38) or minithoracotomy (n = 17). One patient required full thoracotomy after a previous video-assisted thoracoscopic procedure. Intraoperative transesophageal echocardiography was used to assess changes in LV function. RESULTS: : Acute thresholds for the active lead measured 1.10 +/- 0.62 V, with R-wave amplitude of 12.3 +/- 6.6 mV and impedance of 631 +/- 185 Ohm. Thirty-day mortality was 5%. There were no perioperative myocardial infarctions or strokes. Five patients required transfusion, 3 had exacerbation of prior renal insufficiency, 5 had pulmonary complications, and 8 required inotropic support for more than 48 hours. Intermediate-term follow up (mean 20 +/- 16 months, range 11 days to 55 months) revealed 3 patients with lead failure requiring additional surgical intervention. Hospitalization due to worsening CHF occurred in 5 patients, and 2 of these patients required intravenous inotropic support. QRS duration decreased to 146 +/- 36 milliseconds postoperatively (P < 0.001). CONCLUSION: : Minimally invasive surgical lead placement safely and effectively accomplishes cardiac resynchronization using either thoracoscopic or minithoracotomy techniques. PMID- 22436878 TI - Management of a right aberrant subclavian artery during complex hybrid stent graft procedures: a rare and complex issue. AB - A 76-year-old man with an ascending arch and proximal descending aortic aneurysm underwent a complex aortic replacement through a sternotomy with ligation of a right aberrant subclavian artery (RASA) distal to the right vertebral artery. The second-stage procedure was performed with a stent-graft deployed within the elephant trunk. At 6- and 12-month follow-up, the RASA was opacified by the patent right vertebral artery. Under ultrasound guidance, the patient's RASA stump was occluded by coils. Management of an RASA during complex hybrid stent graft procedures is discussed. PMID- 22436879 TI - The independent effect of tumor size in predicting ovarian malignancy. PMID- 22436880 TI - [Should thyroxine treatment be discontinued for four weeks before I(131) thyroid ablation?]. AB - BACKGROUND: It is a usual practice to discontinue thyroxine treatment for four weeks before (131)I ablation. Symptoms of hypothyroidism usually occur during this time. Use of rhTSH is a helpful alternative in some cases, but problems of availability of this agent during 2012 will limit its use. PATIENTS AND METHODS: Plasma TSH and FT4 levels were measured on days 7, 14, 21, and 28 after total thyroidectomy (12 patients) or discontinuation of thyroxine treatment (20 patients). A Mann-Whitney U test was used to compare quantitative variables, and a Chi-square test was used for nominal variables. RESULTS: On day 14, TSH levels were 30MUIU/mL of higher in 71% of patients (66% in the thyroidectomy group and 75% in the group discontinued thyroxine treatment). On day 21, almost all patients from both groups (91% in the thyroidectomy group and 100% in the group discontinued thyroxine treatment) had TSH levels of 30MUIU/mL or higher. On day 14, most patients in both groups had FT4 levels below the normal range. CONCLUSIONS: Discontinuation of thyroxine treatment for four weeks is not required. Fourteen days is an adequate time in most patients, and 21 days are sufficient in virtually all patients. PMID- 22436881 TI - A zinc(II) directed triple-stranded helicate incorporating a nine membered metallamacrocycle: supramolecular cylinders mimicking P1 nuclease. AB - We report herein the first small molecule based self-assembled fluorescent trinuclear Zn(II) supramolecular cylindrical motif as a structural and functional model of the active site of P1 nuclease. The DNA binding of the same was investigated through UV-Vis, fluorescence and circular dichroism studies. PMID- 22436882 TI - Managing incidental findings and research results in genomic research involving biobanks and archived data sets. AB - Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using "biobank" here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence. PMID- 22436883 TI - Association of periodontitis with the risk of oral leukoplakia. AB - BACKGROUND: Oral leukoplakia is an oral lesion suspected to be of premalignant character. Besides smoking and alcohol, the risk factors for the development of this oral lesion are still less identified. The purpose of this study was the search for a possible influence of periodontitis on the risk of leukoplakia. METHODS: We used data from 4233 subjects (2116 women and 2117 men) who were recruited for the population-based Study of Health in Pomerania (SHIP) and finished a standard medical and dental examination. One hundred two-three cases with oral leukoplakia were 1:2 age and sex-matched with 246 healthy control subjects. Measures of bleeding on probing and clinical attachment loss were related to oral leukoplakia. RESULTS: We found increased periodontal measures in subjects with leukoplakia. Adjusting for risk factors and possible confounders revealed a periodontitis-related dose-dependent increase in the probability of having oral leukoplakia. Odds ratios adjusted for socioeconomic factors and smoking computed for the second, third and fourth quartiles of clinical attachment loss were OR=1.7 (0.6-5.0), 3.3 (0.8-13.1) and 5.3 (1.2-22.7), respectively. For bleeding on probing the respective odds ratios were OR=2.0 (0.8 4.90), 2.9 (1.1-7.8) and 3.8 (1.5-9.8), respectively. Measures of systemic inflammation and of lipid metabolism were important cofactors attenuating these figures. While smoking is a risk factor of leukoplakia, oral hygiene is protective. In a follow-up survey, the leukoplakia subjects had lost more teeth than their counterparts (p=0.043). CONCLUSION: Periodontitis increases the risk of oral leukoplakia and, therefore, the risk of mucosal lesions predisposing to oral cancers. PMID- 22436884 TI - Comment on "Chole RH et al. Review of drug treatment of oral submucous fibrosis. Oral Oncol 2012; 48(5):393-398". PMID- 22436885 TI - Laryngeal edema after radiotherapy in patients with squamous cell carcinomas of the larynx and hypopharynx. AB - OBJECTIVES: Significant laryngeal edema (SLE) after radiotherapy for squamous cell carcinoma of the larynx and hypopharynx may be associated with upper airway obstruction or tumor recurrence. We assessed the risk factors predictive of SLE and those differentiating tumor recurrence from SLE. PATIENTS AND METHODS: We evaluated 127 patients with laryngohypopharyngeal squamous cell carcinomas who were primarily treated with radiotherapy with/without chemotherapy, had no previous major head and neck surgery, and underwent laryngoscopic examinations after radiotherapy. SLE was defined as RTOG grades >= 2 and patient characteristics and imaging, treatment and survival results were compared in patients with and without SLE. RESULTS: Of the 127 patients, 56 (44%) had SLE. Univariate analyses showed that tumor location, T and N classifications, overall stage, pathologic differentiation, and chemotherapy were significantly predictive of SLE (P<0.05). Multivariate analysis revealed that T classification remained an independent predictor of SLE (T1 vs. T2-4; odds ratio=5.070, 95% confidence interval=1.999-12.857; P=0.001). Twenty-seven (21%) patients had tumor recurrences, diagnosed by PET/CT (sensitivity 88%; specificity 92%) and CT (sensitivity 68%; specificity 88%). Twenty-seven patients with severe SLE were treated but only 9 (33%) had improvement. Tumor recurrence rate was higher (39% vs. 7%, P<0.001) and 3-year overall survival rate lower (54% vs. 87%, P<0.001) in patients with than without SLE. CONCLUSION: Patients with T2-4 laryngohypopharyngeal cancers are at higher risk of SLE development and tumor recurrence after radiotherapy that can be properly detected by (18)F-FDG PET/CT. PMID- 22436886 TI - Elective neck dissection: the gold standard for oral cavity carcinoma. PMID- 22436887 TI - Hypnotic ingroup-outgroup suggestion influences economic decision-making in an Ultimatum Game. AB - Studies in economic decision-making have demonstrated that individuals appreciate social values supporting equity and disapprove unfairness when distributing goods between two or more parties. However, this seems to critically depend on psychological mechanisms partly pertaining to the ingroup-outgroup distinction. Little is known as to what extent economic bargaining can be manipulated by means of psychological interventions such has hypnosis. Here we show that a hypnotic ingroup versus outgroup suggestion impacts the tolerance of unfairness in an Ultimatum Game. Specifically, the ingroup suggestion was associated with significantly greater acceptance rates of unfair offers than the outgroup suggestion, whereas hypnosis alone exerted only small effects on unfairness tolerance. These findings indicate that psychological interventions such as hypnotic suggestion can contribute to ingroup favoritism and outgroup rejection. PMID- 22436888 TI - Structural features of beta-(1->4)-D-galactomannans of plant origin as a probe for beta-(1->4)-mannanase polymeric substrate specificity. AB - Statistical modeling was applied for describing structural features of beta-(1 >4)-D-galactomannans. According to the model suggested theoretical ratios of limiting degrees of locust bean, tara gum and guar gum galactomannan conversions by two beta-(1->4)-mannanases of different origin (Myceliophthora thermophila and Trichoderma reesei) were calculated. Then the enzymes were tested for enzymatic hydrolysis of three considered galactomannans. Experimentally observed results were compared with theoretically calculated ones. It was shown that T. reesei beta-mannanase attacks sequences of four and more unsubstituted mannopyranosyl residues in a row, while M. thermophila beta-mannanase is a more specific enzyme and attacks sequences of five and more mannopyranosyl residues in a row. Considered statistical model and approach allows to characterize both galactomannan structures and enzyme requirements for regions of unsubstituted mannose residues for substrate hydrolysis. PMID- 22436889 TI - Photochemical generation of a new, highly fluorescent compound from non fluorescent resveratrol. AB - UV irradiation of trans-resveratrol leads to its photochemical transformation to a new, highly fluorescent compound, whose chemical structure was unambiguously identified. The new compound has large values of fluorescence quantum yield, Stokes' shift, and two-photon absorption cross section, which make it suitable for bio-imaging, multi-color labeling, and two-photon microscopy. PMID- 22436890 TI - Histology image analysis for carcinoma detection and grading. AB - This paper presents an overview of the image analysis techniques in the domain of histopathology, specifically, for the objective of automated carcinoma detection and classification. As in other biomedical imaging areas such as radiology, many computer assisted diagnosis (CAD) systems have been implemented to aid histopathologists and clinicians in cancer diagnosis and research, which have been attempted to significantly reduce the labor and subjectivity of traditional manual intervention with histology images. The task of automated histology image analysis is usually not simple due to the unique characteristics of histology imaging, including the variability in image preparation techniques, clinical interpretation protocols, and the complex structures and very large size of the images themselves. In this paper we discuss those characteristics, provide relevant background information about slide preparation and interpretation, and review the application of digital image processing techniques to the field of histology image analysis. In particular, emphasis is given to state-of-the-art image segmentation methods for feature extraction and disease classification. Four major carcinomas of cervix, prostate, breast, and lung are selected to illustrate the functions and capabilities of existing CAD systems. PMID- 22436891 TI - On the use of continuous glucose monitoring systems to design optimal clinical tests for the identification of type 1 diabetes models. AB - The identification of individual parameters of detailed physiological models of type 1 diabetes can be carried out by clinical tests designed optimally through model-based design of experiments (MBDoE) techniques. So far, MBDoE for diabetes models has been considered for discrete glucose measurement systems only. However, recent advances on sensor technology allowed for the development of continuous glucose monitoring systems (CGMSs), where glucose measurements can be collected with a frequency that is practically equivalent to continuous sampling. To specifically address the features of CGMSs, in this paper the optimal clinical test design problem is formulated and solved through a continuous, rather than discrete, approach. A simulated case study is used to assess the impact of CGMSs both in the optimal clinical test design problem and in the subsequent parameter estimation for the identification of a complex physiological model of glucose homeostasis. The results suggest that, although the optimal design of a clinical test is simpler if continuous glucose measurements are made available through a CGMS, the noise level and formulation may make continuous measurements less suitable for model identification than their discrete counterparts. PMID- 22436892 TI - Bats use a neuronally implemented computational acoustic model to form sonar images. AB - This paper reexamines neurophysiological results from echolocating big brown bats to propose a new perspective on FM biosonar processing in the auditory system. Individual auditory neurons are frequency-tuned and respond to brief, 2-10 ms FM sweeps with an average of one spike per sound to register their tuned frequencies, to detect echo arrival, or to register a local null in the echo spectrum. When initiated by the broadcast, these responses comprise a cascade of single spikes distributed across time in neurons tuned to different frequencies that persists for 30-50 ms, long after the sound has ended. Their progress mirrors the broadcast's propagation away from the bat and the return of echoes for distances out to 5-8 m. Each returning echo evokes a similar pattern of single spikes that coincide with ongoing responses to the broadcast to register the target's distance and shape. The hypothesis advanced here is that this flow of responses over time acts as an internal model of sonar acoustics that the bat executes using neuronal computations distributed across many neurons to accumulate a dynamic image of the bat's surroundings. PMID- 22436893 TI - The involvement of working memory in children's exact and approximate mental addition. AB - The involvement of working memory (WM) was examined in two types of mental calculation tasks: exact and approximate. Specifically, children attending Grades 3 and 4 of primary school were involved in three experiments that examined the role of verbal and visuospatial WM in solving addition problems presented in vertical or horizontal format. For Experiment 1, the children were required to solve addition problems with carrying. For Experiment 2, they were required to solve addition problems without carrying. Then, for Experiment 3, the children needed to solve approximate problems with and without carrying. Results confirmed that different WM components are involved in solving mental addition problems. In Experiment 1, horizontally presented addition problems were more impaired than vertically presented ones, according to a verbal WM load; conversely, vertically presented addition problems were more affected by a visuospatial WM load, especially when the children were required to perform approximate calculations. In Experiment 2, this pattern emerged in neither exact nor approximate calculations. Finally, in Experiment 3, the specific involvement of WM components was observed only in problems with carrying. Overall, these results reveal that both approximate calculation and carrying procedures demand particularly high WM resources that vary according to the task's constraints. PMID- 22436894 TI - Over-imitating preschoolers believe unnecessary actions are normative and enforce their performance by a third party. AB - Over-imitation, which is common in children, is the imitation of elements of an action sequence that are clearly unnecessary for reaching the final goal. A variety of cognitive mechanisms have been proposed to explain this phenomenon. Here, 48 3- and 5-year-olds together with a puppet observed an adult demonstrate instrumental tasks that included an unnecessary action. Failure of the puppet to perform the unnecessary action resulted in spontaneous protest by the majority of the children, with some using normative language. Children also protested in comparison tasks in which the puppet violated convention or instrumental rationality. Protest in response to the puppet's omission of unnecessary action occurred even after the puppet's successful achievement of the goal. This observation is not compatible with the hypothesis that the primary cause of over imitation is that children believe the unnecessary action causes the goal. There are multiple domains that children may believe determine the unnecessary action's normativity, two being social convention and instrumental rationality. Because the demonstration provides no information about which domains are relevant, children are capable of encoding apparently unnecessary action as normative without information as to which domain determines the unnecessary action's normativity. This study demonstrates an early link between two processes of fundamental importance for human culture: faithful imitation and the adherence to and enforcement of norms. PMID- 22436895 TI - INNOVATIONS-A New Editorial Team and a Renewed Commitment to Excellence. PMID- 22436896 TI - Whither or wither. PMID- 22436897 TI - The current status of anastomotic devices for coronary artery bypass surgery. AB - The purpose of this article is to briefly review the history of proximal and distal anastomotic devices and to discuss presently available devices. Clinical outcome data from the EPIC Trial of the Cardica PAS-Port Proximal Anastomosis System will also be presented. PMID- 22436898 TI - Intra-aortic Filtration in Cardiac Surgery: An Effective Method to Reduce Neurologic Injury in High-Risk Patients. AB - Cardiac surgery is associated with a significant risk of adverse outcomes, particularly neurologic and renal. Embolic events are the primary source of these deleterious consequences. Intraaortic filtration is the only current technology shown to effectively capture particulates released during cardiac procedures and decrease morbidity and mortality. Although most surgical candidates may potentially benefit from intraaortic filtration, some patients are more likely to experience improved outcomes. Based on the evidence reported in the literature and the extensive experience of the authors, the following opinion details the authors' rationale and recommendations for patient selection for intraaortic filtration during cardiac surgery. PMID- 22436899 TI - Off-pump atrial septal defect closure using the universal cardiac introducer(r): creation of models of atrial septal defects in the pig access and surgical technique. AB - OBJECTIVE: : Optimal atrial septal defect (ASD) closure should combine off-pump techniques with the effectiveness and versatility of open-heart techniques. We report our experience with off-pump ASD closure using the Universal Cardiac Introducer (UCI) in a porcine model. The goal was to create an ASD over the fossa ovale (FO) and position a patch over the ASD under ultrasound (US) imaging and augmented virtual reality guidance. METHODS: : An US probe (tracked with a magnetic tracking system) was positioned into the esophagus (transesophageal echocardiographic probe) for real-time image-guidance. The right atrium (RA) of six pigs was exposed via a right lateral thoracotomy or medial sternotomy. The UCI was attached to the RA wall. A punching tool was introduced via the UCI, navigated and positioned, under US guidance, to create an ASD into the FO. A patch with its holder and a stapling device were introduced into the RA via the UCI. The patch was positioned on the ASD. Occlusion of the ASD was determined using US and Doppler imaging. RESULTS: : The FO membrane was excised successfully in all animals. US image-guidance provided excellent visualization. The patch was positioned in all cases with complete occlusion of the ASD. The stapling device proved too bulky, impeding circumferential positioning. CONCLUSIONS: : Using the UCI, ASD closure was safe and feasible. US imaging, combined with virtual and augmented reality provided accurate navigating and positioning. This study also provided valuable information on the future design of anchoring devices for intracardiac procedures. PMID- 22436900 TI - Laparoscopic transdiaphragmatic access to the apex of the left ventricle of the heart. AB - OBJECTIVE: : Delivery of a collapsable aortic valve prosthesis via the left ventricular (LV) apex has proven problematic clinically. We describe our experience with a novel technique for a laparoscopic transdiaphragmatic approach to the LV outflow tract (LVOT). METHODS: : Laparoscopic transabdominal access to the left ventricle was achieved in four live swine and one human cadaver using three abdominal laparoscopic trocars. Pericardioscopy and cardioscopy were performed. A hemostatic purse-string suture was placed laparoscopically at the apex of the left ventricle in one pig, and an instrument passed through the purse string and into the LVOT. After the procedure, a thoracotomy was performed and the heart explanted for gross examination. RESULTS: : Transdiaphragmatic exposure of the LV apex was accomplished at a mean of 23 minutes. Hemodynamic stability was maintained in all animals and the pleural cavities were not violated. Pericardioscopy allowed visualization of both right and left pulmonary veins along with the left atrial appendage. In situ cardioscopy confirmed that access to the LVOT and the aortic annulus was possible from the LV apex entry site. CONCLUSIONS: : Laparoscopic transdiaphragmatic approach to the LVOT is a possible route for minimally invasive beating heart aortic valve implantation. This strategy permits a straight transapical line of access to the aortic valve; avoiding the potential for cardiac torsion via a thoracotomy. PMID- 22436901 TI - Endovascular thoracic aortic aneurysm repair without angiography. AB - OBJECTIVE: : Intravascular ultrasound (IVUS) generates high definition circumferential cross-sectional images and provides real-time readout of vascular dimensions, including visualization of vessel branches. We have used it as an alternative to angiography in the endovascular thoracic aneurysm repair work-up. METHODS: : Out of consecutive 203 patients with descending thoracic aortic aneurysm, 89 (43.8%) received endovascular treatment [mean age, 68 +/- 8 years; range, 29-82; male, 79 (88.7%); female, 10 (11.3%)] without using angiography during the endovascular procedure. IVUS (6 F, 12.5 MHz probe or 10 F 9 MHz) coupled with fluoroscopy for the placement of radiopaque markers was used for target site identification, landing zone measurement, device positioning, and assessment of endovascular repair. RESULTS: : Hospital mortality was 4/89 (4.5%). Number of devices implanted in each patient was 1.2 (range, 1-3). X-ray exposure time was 12 +/- 8 minutes. Median procedure time was 63 +/- 20 minutes. Conversion to open surgery was necessary in one patient (1.1%) because of aortic dissection. In nine patients (10.1%) left subclavian artery was covered because of a short neck. Two patients (2.2%) had vascular access lesions and required surgical repair. One patient developed paraplegia (1.1%). Early endoleak was observed in eight patients (8.9%) and 4 (4.5%) required additional procedures (proximal or distal extensions). Late conversion was necessary in one patient (1.1%). CONCLUSIONS: : IVUS provides all information necessary for device selection, target site identification as well as safe and correct deployment of thoracic endoprostheses and makes periprocedural angiography unnecessary, thus avoiding the risk of renal failure because of contrast medium. PMID- 22436902 TI - Thoracoscopic lobectomy with chest wall resection after neoadjuvant therapy. AB - Chest wall involvement from lung malignancy presents technical challenges for a minimally invasive surgical approach. Recently, new thoracoscopic rib cutting instrumentation has been developed and may offer a safe and efficient resection. Compared with thoracotomy, thoracoscopic lung and chest wall resection may potentially lower the morbidity associated with chest wall resection by thoracotomy. We present a case of thoracoscopic lobectomy with an en bloc chest wall resection. PMID- 22436903 TI - Right atrial tumor: a contraindication to minimally invasive surgery? AB - Cardiac tumors are rarely observed. The incidence of primary cardiac tumors in autopsy series ranges from 0.0017% to 0.19%. Surgical resection is the main therapy for the majority of the cardiac tumors. Surgical treatment of these tumors carries an operative mortality rate of 3% or less. In this article, we present our experience with a female patient, who had a right sided atrial tumor mimicking a myxoma. Port access surgery was performed through a small right sided "key-hole" working port in the fourth intercostal space. Extracorporeal circulation was conducted by femoro-femoral bypass and a kinetic assisted venous drainage system. Although, the safety and efficacy of port access approach have been well documented for resection of left atrial tumors in some series, use of this technique for right atrial tumor resection can be detrimental. PMID- 22436904 TI - Minimally invasive technique for iliac revascularization after large-bore sheath traumatic avulsion. AB - Percutaneous treatments of cardiac valvular and thoracic aortic diseases are rapidly progressing. To maintain an indispensable part of their treatment, cardiothoracic surgeons must evolve to be able to handle all complications related to the use of percutaneous devices. One of the most common complications is vascular access disruption. Presented here is a method for a combined surgical and endovascular treatment for minimally invasive repair of an iliac artery avulsion. PMID- 22436905 TI - Family history of venous thrombosis or sudden death as a risk factor for venous thromboembolism. PMID- 22436906 TI - Dentin-cement interfacial interaction: calcium silicates and polyalkenoates. AB - The interfacial properties of a new calcium-silicate-based coronal restorative material (BiodentineTM) and a glass-ionomer cement (GIC) with dentin have been studied by confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), micro-Raman spectroscopy, and two-photon auto-fluorescence and second-harmonic-generation (SHG) imaging. Results indicate the formation of tag like structures alongside an interfacial layer called the "mineral infiltration zone", where the alkaline caustic effect of the calcium silicate cement's hydration products degrades the collagenous component of the interfacial dentin. This degradation leads to the formation of a porous structure which facilitates the permeation of high concentrations of Ca(2+), OH(-), and CO(3) (2-) ions, leading to increased mineralization in this region. Comparison of the dentin restorative interfaces shows that there is a dentin-mineral infiltration with the Biodentine, whereas polyacrylic and tartaric acids and their salts characterize the penetration of the GIC. A new type of interfacial interaction, "the mineral infiltration zone", is suggested for these calcium-silicate-based cements. PMID- 22436907 TI - Incommensurate modulation of calcium barium niobate (CBN28 and Ce:CBN28). AB - The incommensurately modulated crystal structures of Ca(0.28)Ba(0.72)Nb(2)O(6) (CBN28) and Ce(0.02)Ca(0.25)Ba(0.72)Nb(2)O(6) (Ce:CBN28) were refined in the supercentred setting X4bm(AA0,-AA0) of the 3 + 2-dimensional superspace group P4bm(aa1/2,-aa1/2). Both compounds are isostructural with a tetragonal tungsten bronze-type structure. The modulation of CBN28 consists of a wavy distribution of Ba and Ca atoms as well as vacancies on the incompletely occupied Me2 site with 15-fold oxygen coordination. The occupational modulation is coupled with a modulation of the atomic displacement parameters and a very weak modulation of the positional parameters of Me2. The surrounding O atoms show strong displacive modulations with amplitudes up to ca 0.2 A owing to the cooperative tilting of the rigid NbO(6) octahedra. The Me1 site with 12-fold coordination and Nb atoms are hardly affected by the modulations. Only first-order satellites were observed and the modulations are described by first-order harmonics. In Ce:CBN28 cerium appears to be located on both the Me2 and Me1 sites. Wavevectors and structural modulations are only weakly modified upon substitutional incorporation of 0.02 cerium per formula unit of calcium. PMID- 22436908 TI - On the structural relations of malachite. I. The rosasite and ludwigite structure families. AB - The crystal structures of malachite Cu(2)(OH)(2)CO(3) and rosasite (Cu,Zn)(2)(OH)(2)CO(3), though not isotypic, are closely related. A previously proposed approach explaining this relation via a common hypothetical parent structure is elaborated upon on the basis of group-subgroup considerations, leading to the conclusion that the aristotype of malachite and rosasite should crystallize in the space group Pbam (No. 55). An ICSD database search for actual representatives of this aristotype leads to the interesting observation that the structure type of ludwigite (Mg,Fe)(2)FeO(2)BO(3), which is adopted by several natural and synthetic oxide orthoborates M(3)O(2)BO(3), is closely related to the proposed malachite-rosasite aristotype and thus to the malachite-rosasite family of hydroxide carbonates M(2)(OH)(2)CO(3) in general. Relations within both structure families and their analogies are summarized in a joint simplified Barnighausen tree. PMID- 22436909 TI - On the structural integrity of the spinel block in the beta"-alumina structure. AB - The beta''-alumina structure is examined in detail and an analysis is presented of the three-dimensional integrity of the lattice. The layer structure that is responsible for the very high sodium conduction rate is the specific focus. Rigid layers that are derived from the cubic spinel structure are interleaved by more open honeycomb pathways where rapid ion diffusion takes place. The three dimensional rigidity of the spinel block in this structure makes it possible to accurately quantify the conduction layer thickness based only on the hexagonal unit-cell dimensions, as suggested originally by Harbach [(1983), J. Mater. Sci. 18, 2437-2452]. His calculation is tested rigorously against the many single crystal structure determinations that have been made on the beta''-alumina family compounds and excellent correlation is found. PMID- 22436910 TI - Site occupancy and lattice parameters in sigma-phase Co-Cr alloys. AB - Neutron powder diffraction was used to study the distribution of Co and Cr atoms over different lattice sites as well as the lattice parameters of sigma-phase compounds Co(100 - x)Cr(x) with x = 57.0, 62.7 and 65.8. From the diffractograms recorded in the temperature range of 4.2-300 K it was found for the five crystallographically independent sites that A (2a) and D (8i) are predominantly occupied by Co atoms, while sites B (4f), C (8i) and E (8j) mainly accommodate Cr atoms. The lattice parameters a and c exhibit linear temperature dependencies, with different expansion coefficients in the temperature ranges of 4.2-100 and 100-300 K. PMID- 22436911 TI - Structures and phase transitions in a new ferroelectric -- pyridinium chlorochromate -- studied by X-ray diffraction, DSC and dielectric methods. AB - Pyridinium chlorochromate, [C(5)H(5)NH](+)[ClCrO(3)](-) (hereafter referred to as PyClCrO(3)), was studied by X-ray diffraction, differential scanning calorimetry (DSC) and dielectric methods. Studies reveal three reversible phase transitions at 346, 316 and 170 K with the following phase sequence: R 3m (I) -> R3m (II) -> Cm (III) -> Cc (IV), c' = 2c. PyClCrO(3) is the first pyridinium salt in which all four phases have been successfully characterized by a single-crystal X-ray diffraction method. Structural results together with dielectric and calorimetric studies allow the classification of the two intermediate phases (II) and (III) as ferroelectric with the Curie point at 346 K, and the lowest phase (IV) as most probably ferroelectric. The ferroelectric hysteresis loop was observed only in phase (III). The high ionic conductivity hindered its observation in phase (II). PMID- 22436912 TI - Rationalizing the molecular origins of Ru- and Fe-based dyes for dye-sensitized solar cells. AB - As part of an effort to design more efficient dyes for dye-sensitized solar cells (DSCs), structure-property relationships are established in the world's best performing chemical series of dyes: 2,2'-bipyridyl-4,4'-carboxylatoruthenium(II) complexes. Statistical analysis, based on crystallographic data from the Cambridge Structural Database, is used to determine common structural features and the effects of structural change to its salient molecular constituents. Also included is the report of two new crystal structures for tris(2,2' bipyridyl)dichlororuthenium(II)hexahydrate and tris(2,2' bipyridyl)iron(II)dithiocyanate; these add to this statistical enquiry. Results show that the metal (M) core exhibits a distorted octahedral environment with M-N pi-backbonding effects affording the propensity of the metal ion towards oxidation. The same characteristics are observed in iron-based analogues. The role of carboxylic groups in this series of dyes is assessed by comparing complexes which contain or are devoid of COOH groups. Space-group variation and large molecular conformational differences occur when COOH groups are present, while such structural features are very similar in their absence. The nature of the anion is also shown to influence the structure of COOH-containing complexes. These structural findings are corroborated by solution-based UV-vis absorption spectroscopy and DSC device performance tests. The presence of COOH groups in this series of compounds is shown to be mandatory for dye-uptake in TiO(2) in the DSC fabrication process. Throughout this study, results are compared with those of the world's most famous DSC dye, N3 (N719 in its fully protonated form): cis bis(isothiocyanato)bis(2,2'-bipyridyl-4,4'-dicarboxylato)ruthenium(II). Overall, the molecular origins of charge-transfer in these complexes are ascertained. The findings have important implications to the materials discovery of more efficient dyes for DSC technology. PMID- 22436913 TI - Detailed example of the identification and crystallographic analysis of a pseudo merohedrally twinned crystal. AB - A detailed description of the procedures utilized in the non-routine X-ray single crystal structural determination and refinement of a pseudo-merohedrally twinned crystal of an Fe/Ni organometallic complex is presented. It illustrates to the practitioners of crystallography how to properly handle such cases and describes the logic and concrete steps necessary to account for the twinning, pseudo symmetry and atomic positional disorder. PMID- 22436914 TI - Two novel Zn-MOFs: structures and characterization. AB - Two novel three-dimensional Zn-MOFs (zinc metal-organic frameworks), Zn(5)(MU(3) OH)(BTC)(3)(Phen)(4).5H(2)O (denoted as HUT-11) and Zn(4)(MU(4) O)(BTC)(2)(Phen)(2).4H(2)O (denoted as HUT-12), have been synthesized by metal ligand-directed assembly under hydrothermal conditions. Here, BTC and Phen are denoted as 1,3,5-benzenetricarboxylate and phenanthroline. HUT-11 contains two kinds of secondary building units (SBUs), Zn(3)(MU(3)-OH)(COO)(5) clusters and Zn(2)(COO)(4) clusters. This material exhibits a new three-dimensional (3,4,5) connected topology with the Schlafli symbol (4.6.8)(2)(4.8(2))(4.6(4).8(5))(4(2).6(2).8(2)). Two perpendicular planes cross at five coordinated Zn1-Zn3-Zn5 nodes, giving a new three-dimensional network. HUT-12 is composed of Zn(4)(MU(4)-O)(COO)(6) clusters as the secondary building units and displays a two-dimensional (3,6)-connected TiS(2) related net topology with the Schlafli symbol (4(2).6)(4(4).6(2).8(8).10). Both MOFs show blue light emission and a high thermal stability above 673 K. PMID- 22436915 TI - Structure of the inclusion complex of beta-cyclodextrin with lipoic acid from laboratory powder diffraction data. AB - The crystal structure of the inclusion complex of beta-cyclodextrin with lipoic acid was determined from laboratory powder diffraction data. Thermogravimetric data was used to estimate the number of water molecules in the crystal structure. Lipoic acid is included in beta-cyclodextrin through its primary face with the five-membered ring reaching the center plane of the cyclodextrin cavity and its fatty acid chain adopting a bent conformation. Lipoic acid and beta-cyclodextrin form a channel-like packing which is stabilized by guest-host hydrogen bonding and close contacts, host-host intermolecular interactions and hydrogen bonding involving the water molecules. PMID- 22436916 TI - Ab-initio crystal structure analysis and refinement approaches of oligo p benzamides based on electron diffraction data. AB - Ab-initio crystal structure analysis of organic materials from electron diffraction data is presented. The data were collected using the automated electron diffraction tomography (ADT) technique. The structure solution and refinement route is first validated on the basis of the known crystal structure of tri-p-benzamide. The same procedure is then applied to solve the previously unknown crystal structure of tetra-p-benzamide. In the crystal structure of tetra p-benzamide, an unusual hydrogen-bonding scheme is realised; the hydrogen-bonding scheme is, however, in perfect agreement with solid-state NMR data. PMID- 22436917 TI - Geometry and conformation of cyclopropane derivatives having sigma-acceptor and sigma-donor substituents: a theoretical and crystal structure database study. AB - The structures of cyclopropane rings which carry sigma-acceptor or sigma-donor substituents have been studied using density-functional theory (DFT), and mean bond lengths and conformational parameters retrieved from the Cambridge Structural Database. It is confirmed that sigma-acceptor substituents, e.g. halogens, generate positive ring bond-length asymmetry in which there is lengthening of the distal bond (opposite to the point of substitution), and shorterning of the two vicinal bonds. This is due to withdrawal of electron density from the cyclopropane 1e'' orbitals, which are bonding for the distal bond and antibonding for the vicinal bonds. For sigma-donor substituents such as SiH(3) or Si(CH(3))(3), the DFT and crystal structure data show negative ring bond-length asymmetry (distal bond shortened, vicinal bonds lengthened), owing to electron donation into the 4e' ring orbital, which are also bonding for the distal bond and antibonding for the vicinal bonds. The results also show that -OH substituents induce weak positive asymmetry, but that the effects of methyl or amino substituents are either non-existent or extremely small, certainly too small to measure using crystal structure information. PMID- 22436918 TI - Structural systematics and conformational analyses of a 3 * 3 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships. AB - An isomer grid of nine fluoro-N-(pyridyl)benzamides (Fxx) (x = para-/meta-/ortho ) has been examined to correlate structural relationships between the experimental crystal structure and ab initio calculations, based on the effect of fluorine (Fx) and pyridine N-atom (x) substitution patterns on molecular conformation. Eight isomers form N-H???N hydrogen bonds, and only one (Fom) aggregates via intermolecular N-H???O=C interactions exclusively. The Fpm and Fom isomers both crystallize as two polymorphs with Fpm_O (N-H???O=C chains, P-syn) and Fpm_N (N-H???N chains, P-anti) both in P2(1)/n (Z' = 1) differing by their meta-N atom locations (P-syn, P-anti; N(pyridine) referenced to N-H), whereas the disordered Fom_O is mostly P-syn (Z' = 6) compared with Fom_F (P-anti) (Z' = 1). In the Fxo triad twisted dimers form cyclic R(2)(2)(8) rings via N-H???N interactions. Computational modelling and conformational preferences of the isomer grid demonstrate that the solid-state conformations generally conform with the most stable calculated conformations except for the Fxm triad, while calculations of the Fox triad predict the intramolecular N-H???F interaction established by spectroscopic and crystallographic data. Comparisons of Fxx with related isomer grids reveal a high degree of similarity in solid-state aggregation and physicochemical properties, while correlation of the melting point behaviour indicates the significance of the substituent position on melting point behaviour rather than the nature of the substituent. PMID- 22436919 TI - Form, function and functionality of two dimeric toluene-2,4-diisocyanate polymorphs. AB - 2,4-Dioxo-1,3-diazetidine-1,3-bis(methyl-m-phenylene) diisocyanate (dimerized toluene-2,4-diisocyanate, TDI) is one of the most widely used aromatic diisocyanates in the polymer industry, and it crystallizes in at least two polymorphic forms (form A and form B) depending on reaction conditions. The crystal structures of the two forms were determined from high-resolution laboratory X-ray powder diffraction data using simulated annealing and Rietveld refinement. In spite of a marked structural similarity between them, significant discrepancies in the physical properties of the two forms prompted analysis of their partitioned energy terms in an effort to better our understanding of the driving force behind such differences in behaviour. PMID- 22436920 TI - Symmetry analysis of the structural and magnetic phase transitions in 122 iron arsenides. AB - It is evident from the literature that the 122 iron arsenides, XFe(2)As(2) with X = Ca, Sr, Ba or Eu, undergo one or more phase transitions from a higher temperature paramagnetic tetragonal structure in grey group I4/mmm1' to an antiferromagnetic structure with magnetic space group C(A)mca. Symmetry analysis is used to enumerate the possibilities for the transition (or transitions) between the higher- and lower-symmetry structures, and the results are used as a basis for comment on published experimental results. PMID- 22436921 TI - Sagrario Martinez-Carrera (1925-2011). PMID- 22436922 TI - Beating heart aortic valve replacement using real-time MRI guidance. AB - OBJECTIVE: : The principal limitations of percutaneous techniques to replace the aortic valve are detailed visualization and durable prostheses. We report the feasibility of using real-time magnetic resonance imaging (MRI) to provide precise anatomic detail and visual feedback to implant a proven bioprosthesis. METHODS: : Twelve domestic pigs were anesthetized, and, through a minimally invasive approach using real-time MRI guidance, underwent aortic valve replacement. This was accomplished on the beating heart by using a commercially available bioprosthesis. MRI was used to precisely identify the anatomic landmarks of the aortic annulus, coronary artery ostia, and the mitral valve leaflets. Additional intraoperative perfusion, flow velocity, and functional imaging were used to confirm adequacy of placement and function of the valve. RESULTS: : Under real-time MRI, multiple oblique planes were prescribed to delineate the anatomy of the native aortic valve and left ventricular outflow track. Enhanced by the use of an active marker wire, this imaging allowed correct placement and orientation of the valve. Through a transapical approach, a series of bioprosthetic aortic valves (21 to 25 mm) were inserted. The time to implantation after the placement of the trocar to deployment of the valve was less than 90 seconds. The average procedure duration was less than 40 minutes CONCLUSIONS: : Real-time MRI provides excellent anatomic detail and intraoperative assessment that permits placement of durable valve prostheses on the beating heart without the limitations of percutaneous approaches. PMID- 22436923 TI - Multicenter mitral valve study: a lateral approach using the da vinci surgical system. AB - OBJECTIVE: : The purpose of this study was to demonstrate the feasibility of simple to complex endoscopic robotic mitral valve repair, using a lateral approach. METHODS: : Data were retrospectively collected on 201 patients undergoing a lateral "ports only" endoscopic robotic mitral valve repair at three institutions. Techniques of aortic occlusion included the endoaortic balloon or a transthoracic clamp. The efficacy of the repair was measured intraoperatively by transesophageal echocardiogram. RESULTS: : Two hundred one patients with a mean age of 55.2 +/- 14.2 were intended to undergo elective robotic mitral valve surgery. One hundred eighty-six (92.5%) were scheduled for a repair procedure and 15 (7.5%) were scheduled for replacement. The repair was accomplished in 179 of 186 (96.2%) of patients. Eight patients (4.3%) required a conversion to sternotomy incision. Seven converted patients received a mitral valve repair and one received a replacement mitral valve. Mitral valve pathology included 10% isolated anterior leaflet involvement, 43% isolated posterior leaflet involvement, and 6% bileaflet pathology, and the remaining patients had dilated annulus, chordal rupture, or elongation. One hundred seventy-nine patients (96.2%) had regurgitation grade of 0 to 1 after repair. Two patients (1%) died. Other adverse events included reoperation for valve-related complications, 2 of 201 (1%); reoperation for cardiac-related complications, 3 of 201 (1.5%); and new onset of atrial fibrillation, 35 of 201 (17.4%). CONCLUSIONS: : A lateral endoscopic robotic approach to mitral valve repair is safe, feasible, and can be performed consistently with acceptable postoperative results. Further follow-up is required to determine the long-term efficacy of this approach to robotic mitral valve repair. PMID- 22436924 TI - Predictors of early postoperative atrial fibrillation after off-pump myocardial revascularization. AB - OBJECTIVE: : We determined the incidence and the predisposing factors of atrial fibrillation (AF) after aorta nontouch coronary artery bypass grafting without extracorporeal circulation. METHODS: : From February 2001 to November 2005, 1359 patients (1159 men, 85.3%) of mean (+/-SD) age 64.8 (+/-9.8) years, who underwent off-pump coronary artery bypass grafting (OP-CAB), were prospectively enrolled. Demographics, perioperative data, and comorbidities were recorded in all patients. A 24-hour rhythm monitoring was performed in all patients until hospital discharge. RESULTS: : Among 1359 patients, 273 (20.1%) had development of atrial fibrillation in the early postoperative period. Patients with AF had higher mean (+/-SD) age, 68.3 (+/-8.8) years, compared with control subjects [63.9 (+/-9.9)] (P <= 0.0005). Univariate analysis showed that apart from age, history of arterial hypertension (P <= 0.02), chronic obstructive pulmonary disease (P <= 0.02), and the use of bilateral internal mammary arteries (P <= 0.01) were predisposing factors for the development of AF. Logistic regression analysis showed that age, history of arterial hypertension, and the use of bilateral internal mammary arteries were predisposing factors for early postoperative AF after OP-CAB. CONCLUSIONS: : Atrial fibrillation occurred in approximately 20% of patients undergoing OP-CAB, mainly in older patients with arterial hypertension who received bilateral internal mammary artery grafts. PMID- 22436925 TI - Wide variations in energy delivery using an impedance-controlled algorithm in bipolar radiofrequency ablation: evidence against fixed time ablation. AB - OBJECTIVE: : Bipolar radiofrequency ablation recently has been used to replace many of the incisions of the Cox-Maze procedure in the surgical treatment of atrial fibrillation. The unique aspect of this technology is that it uses an algorithm based on changes in tissue conductance to determine the energy required to achieve a transmural lesion instead of relying on predetermined time and/or temperature criteria to determine ablation duration, as with most other ablation technologies. The purpose of this study was to determine variations in the different parameters of ablation needed to create transmural lesions in human atria. METHODS: : Initial impedance, total energy, temperature, and ablation time were measured in 38 patients undergoing surgery, using an impedance-controlled bipolar radiofrequency device (AtriCure Isolator, Cincinnati, OH). Lesions were categorized into the following groups: right atrial free wall, left atrial free wall, atrium up to mitral valve annulus, atrium up to tricuspid valve annulus, and right or left pulmonary veins. RESULTS: : There was a wide range of initial impedance (32.3 to 760.7 Ohms), and this correlated with total energy delivered (r = -0.31, P = 0.002). Ablation times varied widely (2.0 to 29.9 seconds) and were longer on left atrial structures than right (P < 0.005) and shortest near the tricuspid annulus (P < 0.001). Mean tissue temperature 1 mm from the electrode was only 45.7 +/- 7.8 degrees C (range, 23.7 degrees C to 69.3 degrees C). CONCLUSIONS: : Bipolar ablation of different atrial structures required widely different amounts of energy and ablation times, probably as the result of the inhomogeneity of atrial geometry and tissue impedance. These data cast doubt on the efficacy of any fixed-time or temperature ablations in the clinical setting. PMID- 22436926 TI - New instrument for robotic-enhanced skeletonized internal thoracic artery harvesting: triangular hook. AB - OBJECTIVE: : The introduction of robotic surgery has generated innovations in minimally invasive coronary surgery, including instrumentation. We have developed a small instrument, named by us the Triangular Hook, that expedites robotic skeletonization of the internal thoracic artery and makes the procedure safer. METHODS: : Bilateral skeletonized internal thoracic artery harvesting was performed in four dogs (weight, 22 to 36 kg), using the da Vinci surgical system (Intuitive Surgical, Inc, Sunnyvale, CA). One internal thoracic artery was harvested with the Triangular Hook; the other was harvested without it. Harvesting time was measured for each form of harvesting, with the data being reported as mean +/- SD. RESULTS: : All eight internal thoracic arteries were harvested successfully; they were patent at the end of harvesting. Significantly less time was required for the Triangular Hook (41.5 +/- 2.8 minutes) than for harvesting without it (47.5 +/- 3.9 minutes; P = 0.02). CONCLUSIONS: : The Triangular Hook is practicable and safe in robotic skeletonization of the internal thoracic artery. PMID- 22436927 TI - Minimally invasive anterior thoracotomy for routine lung cancer resection. AB - OBJECTIVES: : A 7-year experience with a minimally invasive approach to routine lung cancer resection is compared with standard lateral open thoracotomy. METHODS: : All patients undergoing lung resection with curative intent for primary lung cancer between July 1998 and November 2005 by a single surgical team were registered. Surgical access was obtained through a mini 5- to 6-cm anterior thoracotomy with video assistance; direct visualization was also used extensively. RESULTS: : Patients (n = 167) underwent major pulmonary resection for primary lung cancer. The minimally invasive group (MI), 137 patients, included 12 fully endoscopic or robotic approaches. The open lateral (OL) approach included 30 patients (18%). Both groups included pneumonectomies (8 MI, 3 OL), sleeve resections (3 MI, 2 OL), chest wall resections (2 MI, 5 OL), and pancoasts (3 MI, 0 OL) and had full lymph node resections. The Kaplan-Meier estimated overall mean survival was 64.5 months (95% CL, 58 to 71 months). Mean estimate survivals were stage 1a, 66%; stage 1b, 65%; stage 2a, 61%; stage 2b, 55%; stage 3a, 52%; stage 3b, 45%. Mean survival in the MI group was 64.3 months versus 59.3 with standard open access (OL) (Chi = 0.003 Mantel-Cox; significance, 0.959). In-hospital mortality rate was 2.2%; conversion from a mini to open procedure was 1.5%. Avoidance of rib spreading (soft tissue retractor) and small incisions appeared to have reduced pain and improved early recovery. CONCLUSIONS: : Kaplan-Meier survival for routine unselected lung cancer resection through a minimal access approach was not significantly different from the open approach and reflects published survival curves. PMID- 22436928 TI - Simultaneous off-pump coronary artery bypass grafting and ascending aortobifemoral bypass graft via ventral abdominal route. AB - Aortoiliac disease often coexists with coronary artery disease. It is not uncommon to subject a patient to two separate interventions. We report two cases in which in simultaneous off-pump coronary artery bypass grafting was done with an ascending aortobifemoral bypass graft through the ventral abdominal route without any additional morbidity. Combining a technically simple method of limb bypass with an off-pump cardiac surgery is a promising procedure for revascularization of myocardium and lower limbs. We discuss the merits of combining an off-pump coronary artery bypass grafting procedure with a limb bypass. PMID- 22436929 TI - Dacron Patch Aortoplasty of Thoracic Aortic Pseudoaneurysm due to Penetrating Atherosclerotic Ulcer. AB - We report the case of a patient with severe diffuse peripheral vascular disease, coronary artery disease, congestive heart failure, and gastrointestinal bleeding with a pseudoaneurysm of descending thoracic aorta who underwent successful Dacron patch aortoplasty. She was not a candidate for stent-graft repair because of poor access. Using a partial occluding clamp, the pseudoaneurysm was excised and the aorta repaired with a 3.5-cm Dacron patch. She was discharged home in 7 days and has successfully undergone stenting of the left subclavian artery and right and left carotid endarterectomy. PMID- 22436930 TI - Assisted transplant by suction. PMID- 22436931 TI - Video-assisted extended transcervical thymectomy. AB - OBJECTIVE: : The objective of this study was to demonstrate extended thymectomy via the transcervical route. METHODS: : With the use of the Rultract retractor (Rultract, Cleveland, OH), videothoracoscopy and single-lung ventilation allowed complete thymectomy. RESULTS: : This article demonstrates complete resection of all the thymus from the anterior and superior mediastinum. CONCLUSIONS: : In selected patients, the transcervical route can used to completely resect the thymus, avoiding the morbidity of sternotomy. PMID- 22436932 TI - ISMICS Winter Workshop 2006, Cairns, Australia. PMID- 22436933 TI - Make Plans to Attend ISMICS 10th Anniversary Annual Meeting in Rome: ISMICS Annual Meeting Preliminary Program (Subject To Change). PMID- 22436934 TI - 2007 POSTGRADUATE COURSE: Emerging AFIB Treatments: Wednesday, June 6, 2007 (Subject to Change). PMID- 22436935 TI - 2007 POSTGRADUATE COURSE: Endovascular Aortic Therapies: Wednesday, June 6, 2007 (Subject to Change). AB - OBJECTIVES: : As a result of attending this session attendees will understand current options for endovascular treatment of aortic aneurysms; be able to describe the typical pitfalls of endovascular stenting and outline the risks of stenting the dissected aorta. PMID- 22436936 TI - 2007 POSTGRADUATE COURSE: Percutaneous Valvular Therapies: Wednesday, June 6, 2007 (Subject to Change). AB - OBJECTIVES: : Attendees will be informed about the current state of the art of percutaneous aortic valve replacement, transapical aortic valve replacement, and percutaneous mitral valve repair, both edge to edge and coronary sinus-based annuloplasty, including numbers of procedures performed and results to date.Attendees will learn about the technical and anatomic hurdles associated with each procedure, and will gain an understanding of the tools and techniques required for successful implementation of each approach.Attendees will see which patients are currently being referred for each of these new technologies, and will gain an appreciation for where these procedures may be headed over the next 5-10 years. PMID- 22436937 TI - Highly efficient immobilization of beta-lactoglobulin in functionalized mesoporous nanoparticles: a simple and useful approach for enhancement of protein stability. AB - The immobilization of beta-lactoglobulin-B (BLG-B) onto the amine-functionalized KIT-6 [n-PrNH(2)-KIT-6], which has average pore diameter around 6.5 nm, was studied. [n-PrNH(2)-KIT-6] proved to be highly effective agent for BLG-B adsorption. UV-visible spectroscopy studies demonstrated that the immobilized BLG B was less prone to thermally induced aggregation than the free protein. Circular dichroism (CD) spectra of free and immobilized BLG-B were recorded and significant differences in both the backbone and aromatic regions of the spectra were observed upon thermic stress. The obtained results showed that structural elements of the immobilized BLG-B are kept strongly together, making the protein more resistant to heat denaturation. The melting temperatures of the free and immobilized BLG-B were measured by far-UV CD, which showed 19 degrees C higher heat resistance of the immobilized BLG-B compared with its free form. Acrylamide quenching of fluorescence of free and immobilized forms of BLG-B as a function of temperature revealed that the immobilized BLG-B was more resistant to Trp quenching. Therefore immobilization of BLG-B onto [n-PrNH(2)-KIT-6] is accompanied by favorable structural stability of BLG-B in the confined space. PMID- 22436938 TI - Stretching and distortion of a photosensitive polymer film by surface plasmon generated near fields in the vicinity of a nanometer sized metal pin hole. AB - Here we demonstrate how a surface plasmon (SP) generated near field pattern in the vicinity of a nano-scale pin hole can be used to generate reversible topography changes in a photosensitive polymer film above the opening. This can be achieved by simply changing the polarization state of the plasmon generating incoming light. In the case of linear polarization, the near field intensity pattern causes the film to laterally expand/contract according to the direction of the polarization. For circular polarization, two pronounced rims corresponding to maxima in the topography are observed. In all cases, the topographical variation is in close agreement with the SP intensity distribution computed from finite difference time domain simulation. Our results demonstrate the versatility of using SP near fields to imprint a variety of structures into photosensitive polymer films using only a single metallic mask. PMID- 22436939 TI - The cover. Lied aus der Ferne (Song from afar). PMID- 22436940 TI - Committee calls for framework to assess the safety of nanotechnology materials. PMID- 22436941 TI - Trials to address efficacy of midodrine 18 years after it gains FDA approval. PMID- 22436942 TI - Falls from taking multiple medications may be a risk for both young and old. PMID- 22436947 TI - Coronary heart disease risk factors and mortality. PMID- 22436948 TI - Coronary heart disease risk factors and mortality. PMID- 22436949 TI - Urinary sodium excretion and cardiovascular events. PMID- 22436950 TI - Response to etanercept in juvenile idiopathic arthritis. PMID- 22436951 TI - Physician violations of online professionalism and disciplinary actions: a national survey of state medical boards. PMID- 22436952 TI - Shortening medical training by 30%. PMID- 22436953 TI - Hearing loss in older adults: who's listening? PMID- 22436954 TI - A piece of my mind. A display of affection. PMID- 22436955 TI - Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. AB - CONTEXT: Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. OBJECTIVE: To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care. DESIGN, SETTING, AND PATIENTS: Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251). INTERVENTIONS: Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. MAIN OUTCOME MEASURES: For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223). RESULTS: Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001). CONCLUSIONS: Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00481312, NCT00479661. PMID- 22436956 TI - Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. AB - CONTEXT: Epinephrine is widely used in cardiopulmonary resuscitation for out-of hospital cardiac arrest (OHCA). However, the effectiveness of epinephrine use before hospital arrival has not been established. OBJECTIVE: To evaluate the association between epinephrine use before hospital arrival and short- and long term mortality in patients with cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nonrandomized, observational propensity analysis of data from 417 188 OHCAs occurring in 2005-2008 in Japan in which patients aged 18 years or older had an OHCA before arrival of emergency medical service (EMS) personnel, were treated by EMS personnel, and were transported to the hospital. MAIN OUTCOME MEASURES: Return of spontaneous circulation before hospital arrival, survival at 1 month after cardiac arrest, survival with good or moderate cerebral performance (Cerebral Performance Category [CPC] 1 or 2), and survival with no, mild, or moderate neurological disability (Overall Performance Category [OPC] 1 or 2). RESULTS: Return of spontaneous circulation before hospital arrival was observed in 2786 of 15,030 patients (18.5%) in the epinephrine group and 23,042 of 402,158 patients (5.7%) in the no-epinephrine group (P < .001); it was observed in 2446 (18.3%) and 1400 (10.5%) of 13,401 propensity-matched patients, respectively (P < .001). In the total sample, the numbers of patients with 1 month survival and survival with CPC 1 or 2 and OPC 1 or 2, respectively, were 805 (5.4%), 205 (1.4%), and 211 (1.4%) with epinephrine and 18,906 (4.7%), 8903 (2.2%), and 8831 (2.2%) without epinephrine (all P <.001). Corresponding numbers in propensity-matched patients were 687 (5.1%), 173 (1.3%), and 178 (1.3%) with epinephrine and 944 (7.0%), 413 (3.1%), and 410 (3.1%) without epinephrine (all P <.001). In all patients, a positive association was observed between prehospital epinephrine and return of spontaneous circulation before hospital arrival (adjusted odds ratio [OR], 2.36; 95% CI, 2.22-2.50; P < .001). In propensity matched patients, a positive association was also observed (adjusted OR, 2.51; 95% CI, 2.24-2.80; P < .001). In contrast, among all patients, negative associations were observed between prehospital epinephrine and long-term outcome measures (adjusted ORs: 1-month survival, 0.46 [95% CI, 0.42-0.51]; CPC 1-2, 0.31 [95% CI, 0.26-0.36]; and OPC 1-2, 0.32 [95% CI, 0.27-0.38]; all P < .001). Similar negative associations were observed among propensity-matched patients (adjusted ORs: 1-month survival, 0.54 [95% CI, 0.43-0.68]; CPC 1-2, 0.21 [95% CI, 0.10-0.44]; and OPC 1-2, 0.23 [95% CI, 0.11-0.45]; all P < .001). CONCLUSION: Among patients with OHCA in Japan, use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes 1 month after the event. PMID- 22436957 TI - Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. AB - CONTEXT: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. OBJECTIVE: To assess autologous MSCs as replacement of antibody induction for patients with end stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. DESIGN, SETTING, AND PATIENTS: One hundred fifty-nine patients were enrolled in this single-site, prospective, open label, randomized study from February 2008-May 2009, when recruitment was completed. INTERVENTION: Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. RESULTS: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) CONCLUSION: Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00658073. PMID- 22436958 TI - Utilization of anesthesia services during outpatient endoscopies and colonoscopies and associated spending in 2003-2009. AB - CONTEXT: The frequency with which anesthesiologists or nurse anesthetists provide sedation for gastrointestinal endoscopies, especially for low-risk patients, is poorly understood and controversial. OBJECTIVE: To quantify temporal comparisons and regional variation in the use of and payment for gastroenterology anesthesia services. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of claims data for a 5% representative sample of Medicare fee-for-service patients (1.1 million adults) and a sample of 5.5 million commercially insured patients between 2003 and 2009. MAIN OUTCOME MEASURES: Total number of upper gastrointestinal endoscopies and colonoscopies, proportion of gastroenterology procedures with associated anesthesia claims, payments for gastroenterology anesthesia services, and proportion of services and spending for gastroenterology anesthesia delivered to low-risk patients (American Society of Anesthesiologists physical status class 1 or 2). RESULTS: The number of gastroenterology procedures per million enrollees remained largely unchanged in Medicare patients (mean, 136,718 procedures), but increased more than 50% in commercially insured patients (from 33,599 in 2003 to 50,816 in 2009). In both populations, the proportion of procedures using anesthesia services increased from approximately 14% in 2003 to more than 30% in 2009, and more than two-thirds of anesthesia services were delivered to low-risk patients. There was substantial regional variation in the proportion of procedures using anesthesia services in both populations (ranging from 13% in the West to 59% in the Northeast). Payments for gastroenterology anesthesia services doubled in Medicare patients and quadrupled in commercially insured patients. CONCLUSIONS: Between 2003 and 2009, utilization of anesthesia services during gastroenterology procedures increased substantially. Anesthesia services are predominantly used in low-risk patients and show considerable regional variation. PMID- 22436959 TI - Hearing deficits in the older patient: "I didn't notice anything". AB - Hearing loss is common in older adults. Patients, clinicians, and health care staff often do not recognize hearing loss, particularly in its early stages, and it is undertreated. Age-related hearing loss or presbycusis, the most common type of hearing loss in older adults, is a multifactorial sensorineural loss that frequently includes a component of impaired speech discrimination. Simple office based screening and evaluation procedures can identify potential hearing disorders, which should prompt audiologic referral to confirm the diagnosis with audiometric testing. The mainstay of treatment is amplification. For many older adults, accepting the need for amplification, selecting and purchasing a hearing aid, and getting accustomed to its use is a daunting and often frustrating process. There are numerous barriers to hearing aid use, the most common of which is dissatisfaction with its performance across a range of sonic environments. Newer digital hearing aids have many features that improve performance, making them potentially more acceptable to users, but they are expensive and are not covered by Medicare. Hearing aids have been demonstrated to improve hearing function and hearing-related quality of life (QOL), but evidence is less robust for improving overall QOL. Depending upon the etiology of the hearing loss, other medical and surgical procedures, including cochlear implantation, may benefit older adults. Older adults with multiple morbidities and who are frail pose specific challenges for the management of hearing loss. These patients may require integration of hearing assessment and treatment as part of functional assessment in an interdisciplinary, team-based approach to care. PMID- 22436960 TI - Weighing the costs and benefits of a sedative. PMID- 22436961 TI - Questioning the use of epinephrine to treat cardiac arrest. PMID- 22436962 TI - Assessing the value of "discretionary" clinical care: the case of anesthesia services for endoscopy. PMID- 22436963 TI - JAMA patient page. Adult hearing loss. PMID- 22436966 TI - N-containing boronic esters as self-complementary building blocks for the assembly of 2D and 3D molecular networks. AB - The combination of two heteroaromatic boronic acids with pentaerythritol gave self-complementary tectons which were suitable for the generation of 2D and 3D molecular networks. PMID- 22436965 TI - Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells. AB - Achieving transgene integration into preselected genomic sites is currently one of the central tasks in stem cell gene therapy. A strategy to mediate such targeted integration involves site-specific endonucleases. Two genomic sites within the MBS85 and chemokine (C-C motif) receptor 5 (CCR5) genes (AAVS1 and CCR5 zinc-finger nuclease (CCR5-ZFN) sites, respectively) have recently been suggested as potential target regions for integration as their disruption has no functional consequence. We hypothesized that efficient transgene integration maybe affected by DNA accessibility of endonucleases and therefore studied the transcriptional and chromatin status of the AAVS1 and CCR5 sites in eight human induced pluripotent stem (iPS) cell lines and pooled CD34+ hematopoietic stem cells (HSCs). Matrix chromatin immunoprecipitation (ChIP) assays demonstrated that the CCR5 site and surrounding regions possessed a predominantly closed chromatin configuration consistent with its transcriptional inactivity in these cell types. In contrast, the AAVS1 site was located within a transcriptionally active region and exhibited an open chromatin configuration in both iPS cells and HSCs. To show that the AAVS1 site is readily amendable to genome modification, we expressed Rep78, an AAV2-derived protein with AAVS1-specific endonuclease activity, in iPS cells after adenoviral gene transfer. We showed that Rep78 efficiently associated with the AAVS1 site and triggered genome modifications within this site. On the other hand, binding to and modification of the CCR5-ZFN site by a ZFN was relatively inefficient. Our data suggest a critical influence of chromatin structure on efficacy of site-specific endonucleases used for genome editing. PMID- 22436967 TI - Cardiovascular implantable electronic device endocarditis treated with daptomycin with or without transvenous removal. AB - BACKGROUND AND METHODS: Nine patients with cardiovascular implantable electronic device (CIED) endocarditis were treated with daptomycin after the failure of previous treatment. The blood and CIED lead cultures of 1 patient were negative. In the other 8 patients, we observed 6 monomicrobic infections and 2 polymicrobic infections. Overall, 10 strains were isolated in these patients: 4 methicillin sensitive Staphylococcus aureus, 2 methicillin-sensitive Staphylococcus epidermidis, 1 methicillin-resistant Staphylococcus aureus, 1 methicillin resistant Staphylococcus epidermidis, 1 methicillin-sensitive Staphylococcus hominis, and 1 Propionibacterium acnes. The CIED was removed transvenously in 7 patients. Two patients were too sick for the removal of their CIED, and were cured with 6 mg/kg of daptomycin for 60 and 110 days, respectively, without adverse events. RESULTS: One patient died 4 days after the removal of his CIED because of a complicated abdominal aortic aneurysm. The other 8 patients were cured, with a mean follow-up of 17 +/- 8 months. The removed leads were negative, after daptomycin therapy, in 4 cases out of 7. The mean ratio between peak daptomycin concentration and minimal inhibitory concentration (MIC) of the causative strains was 38.3 +/- 18.5. For patients whose data were available, the ratio between peak daptomycin concentration and minimal bactericidal concentration (MBC) was 13.2 +/- 3.2. CONCLUSION: Daptomycin monotherapy may be a useful therapeutic tool in difficult-to-treat CIED endocarditis, resulting in a high rate of cures and sterilized leads removed. The ratio between peak daptomycin concentration and MIC or MBC may be useful as predictive tool for treatment success. PMID- 22436968 TI - Community trends in the use and characteristics of persons with acute myocardial infarction who are transported by emergency medical services. AB - OBJECTIVE: Limited data exist on recent trends in ambulance use and factors associated with ambulance use in patients hospitalized with acute myocardial infarction (AMI), particularly from the more generalizable perspective of a community-wide investigation. This population-based prospective epidemiologic study describes the decade-long trends (1997-2007) in the use of emergency medical services (EMS) by residents of the Worcester, Massachusetts, metropolitan area who are hospitalized for AMI and the characteristics of patients with AMI who are transported to the hospital by EMS (n = 3789) compared with those transported by other means (n = 1505). METHODS: The study population consisted of 5294 patients hospitalized for AMI at 11 greater Worcester medical centers in 5 annual periods between 1997 and 2007. Information on the use of EMS and the factors associated with EMS use was obtained through the review of hospital medical records. RESULTS: There was a progressive increase in the proportion of greater Worcester residents with AMI who were transported to central Massachusetts hospitals by ambulance over time (66.9% transported in 1997; 74.9% transported in 2007). Patients transported by EMS were older, more likely to be women, and more likely to have a greater prevalence of previously diagnosed comorbidities. CONCLUSION: Our findings provide encouragement for the use of EMS in residents of a large central New England community hospitalized with AMI. Despite increasing trends in ambulance use, more research is needed to explore the reasons why patients with AMI do not use EMS in the setting of an acute cardiac emergency. PMID- 22436969 TI - Facile synthesis of hybrid hollow mesoporous nanospheres with high content of interpenetrating polymers for size-selective peptides/proteins enrichment. AB - A facile synthesis of polymer-inorganic hybrid hollow mesoporous nanospheres was developed based on the entrapment of a dissolved polymer core template in the framework during the assembly process of the hybrid hollow nanospheres for efficient and size-selective enrichment of target peptides/proteins from complex biosamples. PMID- 22436970 TI - Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. AB - Prasugrel, through its active metabolite, reduces atherothrombosis and its clinical manifestations by inhibiting platelet activation and aggregation. Platelets also contribute to inflammation through interaction with different classes of leukocytes. We investigated whether the inhibitory effect of prasugrel on platelets also counteract inflammatory responses. The effect of prasugrel active metabolite, R-138727, was investigated on platelet P-selectin expression, platelet adhesion to polymorphonuclear leukocytes (PMN) and monocytes (MN) and Mac-1 expression in PMN and MN, in vitro, in human cells. The ex vivo effect of prasugrel administration on P-selectin, thromboxane (TXB)2 formation, platelet PMN conjugates and Mac-1 expression in PMN triggered by PAR-4 agonist peptide was examined in whole blood from healthy mice as well as from mice in which an acute inflammatory reaction was induced by treatment with endotoxin. The effect of prasugrel on inflammatory markers in endotoxin-treated animals was also tested in vivo. R-138727 inhibited agonist-stimulated expression of platelet P-selectin, platelet-PMN and platelet-MN adhesion and platelet-dependent Mac-1 expression in leukocytes. Addition of aspirin did not modify the inhibitory effect elicited by R-138727. Treatment of mice with prasugrel resulted in a profound inhibition of platelet P-selectin expression, TXB2 production, platelet-PMN adhesion and Mac-1 expression in PMN induced by ex vivo stimulation with PAR-4 agonist peptide of whole blood from healthy or endotoxin-treated mice. Measurement of markers revealed that prasugrel reduced TXB2 and tumour necrosis factor-alpha synthesis and increased nitric oxide metabolites in endotoxin-treated mice in vivo. In conclusion, prasugrel reduces platelet interactions with PMN and MN. Through these effects prasugrel may curb platelet-mediated inflammatory responses. PMID- 22436971 TI - Cost-effectiveness of integrating methadone maintenance and antiretroviral treatment for HIV-positive drug users in Vietnam's injection-driven HIV epidemics. AB - Drug use negatively affects adherence to and outcomes of antiretroviral treatment (ART). This study evaluated the cost-effectiveness of integrating methadone maintenance treatment (MMT) with ART for HIV-positive drug users (DUs) in Vietnam. A decision analytical model was developed to compare the costs and consequences of 3 HIV/AIDS treatment strategies for DUs: (1) only ART, (2) providing ART and MMT in separated sites (ART-MMT), and (3) integrating ART and MMT with direct administration (DAART-MMT). The model was parameterized using empirical data of costs and outcomes extracted from the MMT and ART cohort studies in Vietnam, and international published sources. Probabilistic sensitivity analysis was conducted to examine the model's robustness. The base case analysis showed that the cost-effectiveness ratio of ART, DAART-MMT, and ART MMT strategies was USD 1358.9, 1118.0 and 1327.1 per 1 Quality-Adjusted Life Year (QALY), equivalent to 1.22, 1.00, and 1.19 times Gross Domestic Product per capita (GDPpc). The incremental cost-effectiveness ratio for DAART-MMT and ART MMT versus ART strategy was 569.4 and 1227.8, approximately 0.51 and 1.10 times GDPpc/QALY. At the willingness to pay threshold of 3 times GDPpc, the probability of being cost-effective of DAART-MMT versus ART was 86.1%. These findings indicated that providing MMT along with ART for HIV-positive DUs is a cost effective intervention in Vietnam. Integrating MMT and ART services could facilitate the use of directly observed therapy that supports treatment adherence and brings about clinically important improvements in health outcomes. This approach is also incrementally cost-effective in this large injection-driven HIV epidemic. PMID- 22436972 TI - Spending trends on substance abuse treatment under private employer-sponsored insurance, 2001-2009. AB - BACKGROUND: From 1986 to 2003, substance abuse spending covered by private insurance fell in nominal dollars from $2444 million to $2239 million. The present study updated this literature to determine recent spending and utilization trends and provides a baseline for assessing the effects of recent health care policy changes. METHODS: We used insurance claims data from Thomson Reuters MarketScan Commercial Claims and Encounters Database to study approximately 100 large, self-insured employers and millions of enrollees. We examined patterns in substance abuse treatment utilization and spending from 2001 through 2009. RESULTS: The study revealed that substance abuse spending remained a relatively constant share of all health spending, comprising about 0.4% of all health spending in 2009. The share of substance abuse spending on medications increased from 1% to 14%, but remained a small share of all health spending at about $2.45 per-member per-year. CONCLUSIONS: The study has implications for anticipating the effects of the federal parity law, in that the low share of substance abuse treatment means that even large increases in substance abuse utilization and spending are unlikely to have a significant impact on total health care costs. PMID- 22436973 TI - Advice by the rheumatologist on quitting smoking: are we doing well with smokers? PMID- 22436974 TI - Elastofibroma dorsi: review of 4 cases. AB - Elastofibroma dorsi is a benign, uncommon fibroelastic tissue condition, more common in women after the fifth decade of life. It is usually located in the subscapular region, and can sometimes be bilateral. We present 4 patients, between 53 and 73 years of age, with this disease. It is often an asymptomatic lesion that can manifest, even at its apex, with mild pain when moving the scapula. All our patients had pain.The diagnosis is based on clinical findings and imaging studies, especially ultrasound, computed tomography, and nuclear magnetic resonance. The biopsy is reserved for patients who have no characteristic signs on imaging. In our series, surgical excision was necessary in one of the patients, and in the others, clinical and imaging studies allowed us to arrive at a definitive diagnosis. PMID- 22436975 TI - Repeated courses of antenatal corticosteroids have adverse effects on aspects of brain development in naturally delivered baboon infants. AB - INTRODUCTION: Repeated courses of antenatal steroids in women at risk of preterm delivery have beneficial effects on lung maturation, but concern exists about the effects on brain development. We aimed to determine whether repeated courses of corticosteroids increased the risk of neuropathology as compared with single courses or no treatment. METHODS: Single-course animals received a 6-mg dose of steroids at 123 and 124 d of gestation (dg; term, 185 dg; n = 6). Repeated-course animals received additional doses at 137 and 138 dg (n = 7). Controls received no steroids (n = 5). Baboons delivered naturally at term and necropsy was performed. Brains were assessed histologically for parameters of development and neuropathology. RESULTS: Body weights did not differ between the groups (P > 0.05); neither did brain/body weight ratio. Density of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes in white matter (WM) was increased in the single- (P < 0.05) and repeated-course (P < 0.01) groups as compared with controls. Density of myelin basic protein (MBP)-IR oligodendrocytes was reduced in the repeated-course animals as compared with both the control and single course groups (P < 0.05); oligodendrocyte transcription factor 2 (Olig2)-IR showed no difference between groups. DISCUSSION: Repeated courses of antenatal corticosteroids have effects on myelination in the developing nonhuman primate brain, which should be taken into account when determining a dosing regimen. PMID- 22436976 TI - From single cells to biology. PMID- 22436977 TI - Phosphorescent perylene imides. AB - Asymmetrically substituted perylene imide derivatives PIa and PIx display phosphorescence in glassy matrices at 77 K. The lifetime is 49.0 ms for PIa and 13.5 ms for PIx. The triplet energy is 1.79 eV for PIa and 1.68 eV for PIx as confirmed by sensitization experiments of the C(60) triplet. PMID- 22436979 TI - Progression free survival of first line vascular endothelial growth factor targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma. AB - PURPOSE: Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuable prognostic marker. We explored the duration of progression free survival (PFS) in first-line treatment and other variables as prognostic markers in mRCC. METHODS: Medical records from 119 mRCC patients receiving first line treatment with tyrosine kinase inhibitors (TKI) were retrieved retrospectively. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analysed clinical parameters for their prognostic relevance. RESULTS: The median PFS of first line treatment was 8.4 months (95% confidence interval 5.8-11) associated with a median OS of 28.2 months (95% CI 20.9-35.4). Second line therapy with another TKI or mTOR-inhibitor was applied to 81 patients (68%). PFS of any second line therapy was 5.1 and 3.7 months in first line treatment responders and non responders (p = 0.3), respectively. Univariate analyses revealed bone metastases, prior cytokine treatment, Memorial Sloan Kettering cancer centre (MSKCC) score, objective response rate, Eastern Cooperative Oncology Group (ECOG) performance status, first line PFS with 6 months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6 months (95% CI 0.154-0.641; HR 0.314), second line treatment (95% CI 0.162-0.657; HR 0.326), MSKCC score (95% CI 1.07-3.392; HR 1.905) and objective response rate (95% CI 0.358-0.989; HR 0.595) to be independent prognostic markers. CONCLUSIONS: The duration of first line PFS is an independent prognostic variable but not predictive for subsequent therapy. PMID- 22436980 TI - Predictive value of alpha-fetoprotein in the long-term risk of developing hepatocellular carcinoma in patients with hepatitis B virus infection--results from a clinic-based longitudinal cohort. AB - BACKGROUND: Although serum level of alpha-fetoprotein (AFP) has long been used to complement imaging tests in the screening and diagnosis of hepatocellular carcinoma (HCC), whether it can be used as a predictive marker of long-term risk for developing HCC in patients with hepatitis B virus (HBV) has not been extensively evaluated and thus remains controversial. METHODS: We retrospectively conducted a clinic-based longitudinal cohort study including 617 Korean American patients with HBV who had been followed for up to 22 years (median follow-up time, 6.2 years) to evaluate the association between baseline serum AFP level and the long-term risk of HCC. RESULTS: The median baseline AFP value of these patients was 3.8 ng/ml. Compared to patients with lower-than-median AFP value, those with higher-than-median baseline serum AFP had a significantly increased risk of developing HCC with a hazard ratio (HR) of 2.73 (95% confidence interval [CI] 1.25-5.99), independent of other major HCC risk factors. In addition, we calculated the cumulative incidence of HCC during different years of follow-up time by baseline serum AFP, and found that the cumulative incidence of HCC was significantly higher in HBV patients with high baseline serum AFP compared to those with low baseline serum AFP in each of the five follow-up time periods examined. CONCLUSIONS: Our results indicated that AFP was a strong independent prospective predictor of long-term HCC risk in high-risk HBV patients. More targeted prevention and early detection of HCC may be considered for these patients. PMID- 22436984 TI - A New Era for INNOVATIONS and for ISMICS-A Message from ISMICS President, John D. Puskas, MD. PMID- 22436985 TI - Stentless Versus Stented Bioprosthetic Aortic Valves: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2008. AB - OBJECTIVE: : The purpose of this consensus conference was to determine whether stentless bioprosthetic valves improve clinical and resource outcomes compared with stented valves in patients undergoing aortic valve replacement, and to outline evidence-based recommendations for the use of stentless and stented bioprosthetic valves in adult aortic valve replacement. METHODS: : Before the consensus conference, the best available evidence was reviewed in that systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. At the consensus conference, evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS AND RECOMMENDATIONS: : Seventeen randomized studies published in 23 articles involving 1317 patients, and 14 nonrandomized trial published in 18 articles involving 2485 patients were included in the meta analysis and consensus conference. All randomized trials inserted the stentless bioprosthetic valves in the subcoronary configuration. The consensus panel agreed upon the following statements and recommendations in patients undergoing aortic valve replacement:Because there were no randomized control trial comparing subcoronary stentless prosthetic valve and root replacement, the following recommendations are derived from expert opinion: PMID- 22436986 TI - Stentless versus stented bioprosthetic aortic valves: a systematic review and meta-analysis of controlled trials. AB - OBJECTIVE: : This meta-analysis sought to determine whether stentless bioprosthetic valves improve clinical and resource outcomes compared with stented valves in patients undergoing aortic valve replacement. METHODS: : A comprehensive search was undertaken to identify all randomized and nonrandomized controlled trials comparing stentless to stented bioprosthetic valves in patients undergoing aortic valve replacement available up to March 2008. The primary outcomes were clinical and resource outcomes in randomized controlled trial (RCT). Secondary outcomes clinical and resource outcomes in nonrandomized controlled trial (non-RCT). Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences and their 95% confidence intervals (CI) were analyzed as appropriate. RESULTS: : Seventeen RCTs published in 23 articles involving 1317 patients, and 14 non-RCTs published in 18 articles involving 2485 patients were included in the meta-analysis. For the primary analysis of randomized trials, mortality for stentless versus stented valve groups did not differ at 30 days (OR 1.36, 95% CI 0.68-2.72), 1 year (OR 1.01, 95% CI 0.55 1.85), or 2 to 10 years follow-up (OR 0.82, 95% CI 0.50-1.33). Aggregate event rates for all-cause mortality at 30 days were 3.7% versus 2.9%, at 1 year were 5.5% versus 5.9% and at 2 to 10 years were 17% versus 19% for stentless versus stented valve groups, respectively. Stroke or neurologic complications did not differ between stentless (3.6%) and stented (4.0%) valve groups. Risk of prosthesis-patient mismatch was numerically lower in the stentless group (11.0% vs. 31.3%, OR 0.30, 95% CI 0.05-1.66), but this parameter was reported in few trials and did not reach statistical significance. Effective orifice area index was significantly greater for stentless aortic valve compared with stented valves at 30 days (WMD 0.12 cm/m), at 2 to 6 months (WMD 0.15 cm/m), and at 1 year (WMD 0.26 cm/m). Mean gradient at 1 month was significantly lower in the stentless valve group (WMD -6 mm Hg), at 2 to 6 month follow-up (WMD -4 mm Hg,), at 1 year follow-up (WMD -3 mm Hg) and up to 3 year follow-up (WMD -3 mm Hg) compared with the stented valve group. Although the left ventricular mass index was generally lower in the stentless group versus the stented valve group, the aggregate estimates of mean difference did not reach significance during any time period of follow-up (1 month, 2-6 months, 1 year, and 8 years). CONCLUSIONS: : Evidence from randomized trials shows that subcoronary stentless aortic valves improve hemodynamic parameters of effective orifice area index, mean gradient, and peak gradient over the short and long term. These improvements have not led to proven impact on patient morbidity, mortality, and resource-related outcomes; however, few trials reported on clinical outcomes beyond 1 year and definitive conclusions are not possible until sufficient evidence addresses longer-term effects. PMID- 22436981 TI - Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer Consortium. AB - BACKGROUND AND METHODS: Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals. RESULTS: Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR) = 1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR = 1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR = 1.44, 95% CI: 1.07, 1.93), after adjustment. CONCLUSIONS: The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group. PMID- 22436987 TI - The use of rapid endovascular balloon occlusion in unstable patients with ruptured abdominal aortic aneurysm. AB - OBJECTIVE: : To present our results and demonstrate advantages of rapid endovascular balloon occlusion (REBO) of the juxtarenal aorta in unstable patients with ruptured abdominal aortic aneurysm (rAAA). METHODS: : Since 2006, all unstable patients with rAAA are immediately transferred to the operating room (OR). No computed tomography scan is performed once diagnosis is made on ultrasound examination. Instability is defined as systolic blood pressure less than 60 mm Hg, unconsciousness, cardiac ischemia, or intubation. Once arrived in the OR, a Reliant aortic balloon is introduced and inflated at the level of the renal arteries. Subsequently, an angiogram is made through the contralateral femoral artery in order to decide between open or endovascular repair (EVAR). RESULTS: : Twelve patients with rAAA were defined as unstable. REBO was installed within 10 minutes after arrival in the OR. Aortic occlusion resulted in immediate hemodynamic stability. Five patients were suitable for EVAR. Seven patients had open repair. For these abdominal dissection was more careful since no instability was encountered. All patients survived the procedure except one. Mean stay on intensive care unit was 19.7 days for open group and 8.4 for EVAR. CONCLUSIONS: : REBO of the juxtarenal abdominal aorta by pc technique in unstable patients with rAAA resulted in a 17% 30-day mortality and a 100% 1-year event-free follow-up for survivors. With this technique, EVAR exclusion is still a valuable treatment. Exposure and decision making for the open group is easier to perform with less risk for additional damaging to neighboring structures during dissection since urgent cross-clamping is not necessary. PMID- 22436988 TI - Off-Pump Coronary Artery Bypass Grafting is Associated With Reduced Operative Mortality and In-Hospital Adverse Events in Patients With Left Main Coronary Artery Disease. AB - OBJECTIVE: : Left main coronary artery disease (LMD) is a known risk factor for perioperative complications. This study compares off-pump coronary artery bypass (OPCAB) versus on-pump coronary artery bypass (ONCAB) grafting, CABG, with respect to in-hospital death, stroke, myocardial infarction, and major adverse cardiac events (MACE) in CABG patients with and without LMD. METHODS: : Among 13,108 consecutive isolated patients with CABG treated from 1997 to 2007, 2891 patients (22.1%) were preoperatively found to have LMD. Of 5917 patients with OPCAB, 1276 (21.6%) had LMD, whereas among patients with ONCAB, 1615 of 7191 (22.5%) had LMD. Surgery type, LMD, and their interaction were examined for their impact on operative mortality, stroke, myocardial infarction, and MACE via multiple logistic regression models and adjusted odds ratios (AOR). RESULTS: : Utilization of OPCAB for coronary revascularization in patients with LMD disease gradually increased from an initial low of 1.3% of patients in 1997 to a peak of 80.8% in 2007. OPCAB was associated with reduced incidence of stroke (AOR = 0.51, P < 0.001) and MACE (AOR = 0.66, P = 0.002), whereas LMD was associated with an increased incidence of MACE (AOR = 1.24, P = 0.038). No interactions between surgery type and LMD existed, meaning that the 2 conditions did not combine in any way to modify outcomes. CONCLUSIONS: : Patients with LMD are more likely to suffer a MACE event than those without LMD. Off-pump coronary artery bypass grafting is marginally associated with lesser risk of operative mortality and significantly associated with less stroke and overall MACE when compared with ONCAB. This benefit of OPCAB is similar for patients with and without LMD. PMID- 22436989 TI - Effects of ultrasonic skeletonization of the gastroepiploic artery on endothelial nitric oxide production. AB - OBJECTIVE: : The right gastroepiploic artery (GEA) is a reliable conduit for coronary artery bypass grafting. Recently, ultrasonic skeletonization in graft harvesting has attracted attention as an alternative technique to increase the length and caliber size of grafts. The influence of GEA skeletonization using an ultrasonically activated device with that using an electrosurgical unit was compared from the viewpoint of production of nitric oxide (NO). METHODS: : Fourteen pigs were used in this study. The GEA were harvested using an ultrasonically activated device (group ultrasonically activated device [USAD], n = 7) or electrocautery (group E, n = 7). Blood sampling was performed at the following three times from the distal end of the GEA: (1) preskeletonization, (2) pedicle, and (3) postskeletonization. Plasma NOx (NO metabolites) levels were measured by chemiluminescent assay. Moreover, in excised specimens, the expression of nitric oxide synthase was examined immunohistologically. RESULTS: : In group USAD, the preskeletonization basal level of plasma NOx in GEA was 25.7 +/- 10.9 MUmol/L, which then increased to 26.9 +/- 10.5 MUmol/L (pedicle) and 32.2 +/- 12.1 MUmol/L (postskeletonization). In group E, the preskeletonization basal plasma NOx level in GEA was 28.9 +/- 11.4 MUmol/L, which changed to 27.5 +/ 8.9 MUmol/L (pedicle) and 21.8 +/- 8.3 MUmol/L (postskeletonization). The results of multivariate analysis indicated that the patterns of changes in plasma NOx level were significantly different in both groups (P = 0.024). In group USAD, post hoc multiple comparison tests revealed a significant difference between preskeletonization and postskeletonization (P = 0.037). CONCLUSIONS: : Ultrasonically skeletonized GEA showed increased effective graft length, higher free flow capacity, and increased endothelial NO production than that prepared using an electrosurgical unit. PMID- 22436990 TI - Intraoperative epiaortic ultrasound scanning guides operative strategies and identifies patients at high risk during coronary artery bypass grafting. AB - OBJECTIVE: : Epiaortic ultrasound (EU) reliably reveals ascending aortic atherosclerosis (AAA), allowing strategies to minimize the risk of embolization or plaque disruption during coronary artery bypass grafting. Our objective was to delineate if EU-guided intervention improved outcomes. METHODS: : Patients undergoing coronary artery bypass grafting (2004-2007) were categorized by EU grade (grade 1-2 [mild] vs. 3-5 [moderate/severe]) and the use of an aortic clamp. A propensity score estimated probability of clamp use was based on 45 risk factors. Multiple logistic regression models measured the association between outcomes-death, stroke, myocardial infarction, and major adverse cardiac and cerebrovascular events (MACCE)-and the primary variables (grade and clamp use), adjusted for propensity score. RESULTS: : Grade was available in 4278 patients. Patients with grade 3 to 5 AAA had an increased risk of death (adjusted odds ratios (AOR) 3.11; P < 0.001), stroke (AOR 2.12; P < 0.001), and MACCE (AOR 2.58; P < 0.001). Aortic clamping (any clamp, all grades) led to a higher risk of stroke (AOR 2.77; P = 0.032). EU altered aortic manipulation in 530 patients (12.4%). In this group, patients with high grade aortas had similar rates of death, stroke or MACCE, when compared with patients with low-grade aortas. CONCLUSIONS: : EU alters surgical strategy. Patients with grade 3 to 5 AAA are at increased risk of death, stroke, and MACCE compared with patients with grade 1 to 2 AAA. Clamping the aorta (any grade) increases the risk for stroke. Aortic clamping should be avoided in patients with grade 3 to 5 AAA, but EU may minimize morbidity and mortality if a clamp must be used. PMID- 22436991 TI - Complex aortic valve surgery for endocarditis using the beating-heart technique. AB - OBJECTIVE: : Surgical outcomes of aortic valve surgery for endocarditis are poor. Postoperative deterioration of left ventricular (LV) function may contribute to this process. To enhance preservation of myocardial function during aortic valve surgery, we have used a beating-heart technique of myocardial protection without cardioplegic arrest. The aim of this article is to report our initial clinical experience with this technique. METHODS: : We identified 30 consecutive patients with endocarditis who underwent aortic valve repair (one patient) or replacement using either a mechanical prosthesis (four patients) or a biologic prosthesis (25 patients) with beating-heart technique. There were 22 men and eight women (mean age 52.8 +/- 16.1 years). There were one elective, 22 urgent/emergent, and seven "salvage" operations. Two patients had preoperative stroke, five respiratory failure, three renal failure, 12 congestive heart failure, eight septic shock, and one previous coronary artery bypass grafting. The etiology of the infection was identified in 15 patients (50%). Ten patients had severe, seven moderate, and four mild aortic insufficiency. All patients had vegetations, four had annular abscesses, and two had intracardiac fistulas. RESULTS: : Eight patients (26.6%) had redo procedures. Concomitant procedures included aortic and mitral valve procedure (14 patients), tricuspid valve procedure (two patients), and coronary artery bypass grafting (one patient). Aortic annular reconstruction was required in four patients (13.2%). Total CPB time was 125 +/- 67 minutes. Intra-aortic balloon pump was needed in one patient. Two patients (6.6%) had a stroke unrelated to air embolism. Mean follow-up was 7.9 +/- 12 months. Early mortality (30 days) was 13.3% (four patients), and late mortality was 10% (three patients). Total mortality was 18% in urgent/emergent cases, and 42% in salvage operations. There was no statistical difference between preoperative and postoperative echocardiographic values of LV function (ejection fraction and fractional shortening). LV end-diastolic dimension decreased postoperatively (P = 0.03), whereas LV end-systolic dimension and left atrial size were unchanged. CONCLUSIONS: : Our study did not show improved survival benefits of beating-heart aortic valve surgery compared with historical series in which conventional myocardial protection was used. However, our findings suggest that beating-heart technique is an alternative strategy of myocardial protection that may contribute to preservation of LV function in patients undergoing complex operations for aortic valve endocarditis. PMID- 22436992 TI - Simultaneous presentation of coarctation of the thoracic aorta and aneurysm of the superior mesenteric artery. AB - A 34-year-old woman presented with both coarctation of the thoracic aorta and aneurysm of the superior mesenteric artery. The former was managed by open surgical repair, the latter by stent-graft. This case illustrates the need for facility with both percutaneous and open approaches to diseases of the aorta and its branches. PMID- 22436993 TI - Tissue stabilizer reverse mounting in minimally invasive direct coronary artery bypass, a simple tool in difficult times. AB - The simple reverse mounting of an Octopus arm over a rib retractor can give more arm length by up to 5 cm inside the chest cavity which could prove to be very useful in patients with huge chest cavities, i.e. chronic obstructive pulmonary disease, high body mass index, allowing more flexibility and better maneuverability of the stabilizer arm during MIDCAB. PMID- 22436994 TI - Dual Pd and CuFe2O4 nanoparticles encapsulated in a core/shell silica microsphere for selective hydrogenation of arylacetylenes. AB - A dual catalyst containing Pd and CuFe(2)O(4) nanoparticles in a silica shell exhibits >98% conversion of arylacetylenes to related styrenes with selectivity greater than 98%, which are better than those obtained using a commercial Lindlar catalyst. The excellent synergy was likely a result of the proximal interaction between Pd and CuFe(2)O(4) nanoparticles. PMID- 22436995 TI - Experimental analysis of sources of error in evolutionary studies based on Roche/454 pyrosequencing of viral genomes. AB - Factors affecting the reliability of Roche/454 pyrosequencing for analyzing sequence polymorphism in within-host viral populations were assessed by two experiments: 1) sequencing four clonal simian immunodeficiency virus (SIV) stocks and 2) sequencing mixtures in different proportions of two SIV strains with known fixed nucleotide differences. Observed nucleotide diversity and frequency of undetermined nucleotides were increased at sites in homopolymer runs of four or more identical nucleotides, particularly at AT sites. However, in the mixed strain experiments, the effects on estimated nucleotide diversity of such errors were small in comparison to known strain differences. The results suggest that biologically meaningful variants present at a frequency of around 10% and possibly much lower are easily distinguished from artifacts of the sequencing process. Analysis of the clonal stocks revealed numerous rare variants that showed the signature of purifying selection and that elimination of variants at frequencies of less than 1% reduced estimates of nucleotide diversity by about an order of magnitude. Thus, using a 1% frequency cutoff for accepting a variant as real represents a conservative standard, which may be useful in studies that are focused on the discovery of specific mutations (such as those conferring immune escape or drug resistance). On the other hand, if the goal is to estimate nucleotide diversity, an optimal strategy might be to include all observed variants (even those at less than 1% frequency), while masking out homopolymer runs of four or more nucleotides. PMID- 22436996 TI - High expression hampers horizontal gene transfer. AB - Horizontal gene transfer (HGT), the movement of genetic material from one species to another, is a common phenomenon in prokaryotic evolution. Although the rate of HGT is known to vary among genes, our understanding of the cause of this variation, currently summarized by two rules, is far from complete. The first rule states that informational genes, which are involved in DNA replication, transcription, and translation, have lower transferabilities than operational genes. The second rule asserts that protein interactivity negatively impacts gene transferability. Here, we hypothesize that high expression hampers HGT, because the fitness cost of an HGT to the recipient, arising from the 1) energy expenditure in transcription and translation, 2) cytotoxic protein misfolding, 3) reduction in cellular translational efficiency, 4) detrimental protein misinteraction, and 5) disturbance of the optimal protein concentration or cell physiology, increases with the expression level of the transferred gene. To test this hypothesis, we examined laboratory and natural HGTs to Escherichia coli. We observed lower transferabilities of more highly expressed genes, even after controlling the confounding factors from the two established rules and the genic GC content. Furthermore, expression level predicts gene transferability better than all other factors examined. We also confirmed the significant negative impact of gene expression on the rate of HGTs to 127 of 133 genomes of eubacteria and archaebacteria. Together, these findings establish the gene expression level as a major determinant of horizontal gene transferability. They also suggest that most successful HGTs are initially slightly deleterious, fixed because of their negligibly low costs rather than high benefits to the recipient. PMID- 22436997 TI - Variation in base-substitution mutation in experimental and natural lineages of Caenorhabditis nematodes. AB - Variation among lineages in the mutation process has the potential to impact diverse biological processes ranging from susceptibilities to genetic disease to the mode and tempo of molecular evolution. The combination of high-throughput DNA sequencing (HTS) with mutation-accumulation (MA) experiments has provided a powerful approach to genome-wide mutation analysis, though insights into mutational variation have been limited by the vast evolutionary distances among the few species analyzed. We performed a HTS analysis of MA lines derived from four Caenorhabditis nematode natural genotypes: C. elegans N2 and PB306 and C. briggsae HK104 and PB800. Total mutation rates did not differ among the four sets of MA lines. A mutational bias toward G:C->A:T transitions and G:C->T:A transversions was observed in all four sets of MA lines. Chromosome-specific rates were mostly stable, though there was some evidence for a slightly elevated X chromosome mutation rate in PB306. Rates were homogeneous among functional coding sequence types and across autosomal cores, arms, and tips. Mutation spectra were similar among the four MA line sets but differed significantly when compared with patterns of natural base-substitution polymorphism for 13/14 comparisons performed. Our findings show that base-substitution mutation processes in these closely related animal lineages are mostly stable but differ from natural polymorphism patterns in these two species. PMID- 22436998 TI - The effect of variation in the effective population size on the rate of adaptive molecular evolution in eukaryotes. AB - The role of adaptation is a fundamental question in molecular evolution. Theory predicts that species with large effective population sizes should undergo a higher rate of adaptive evolution than species with low effective population sizes if adaptation is limited by the supply of mutations. Previous analyses have appeared to support this conjecture because estimates of the proportion of nonsynonymous substitutions fixed by adaptive evolution, alpha, tend to be higher in species with large N(e). However, alpha is a function of both the number of advantageous and effectively neutral substitutions, either of which might depend on N(e). Here, we investigate the relationship between N(e) and omega(a), the rate of adaptive evolution relative to the rate of neutral evolution, using nucleotide polymorphism and divergence data from 13 independent pairs of eukaryotic species. We find a highly significant positive correlation between omega(a) and N(e). We also find some evidence that the rate of adaptive evolution varies between groups of organisms for a given N(e). The correlation between omega(a) and N(e) does not appear to be an artifact of demographic change or selection on synonymous codon use. Our results suggest that adaptation is to some extent limited by the supply of mutations and that at least some adaptation depends on newly occurring mutations rather than on standing genetic variation. Finally, we show that the proportion of nearly neutral nonadaptive substitutions declines with increasing N(e). The low rate of adaptive evolution and the high proportion of effectively neutral substitution in species with small N(e) are expected to combine to make it difficult to detect adaptive molecular evolution in species with small N(e). PMID- 22437000 TI - Cardiac imaging: reclaiming a hunterian perspective. PMID- 22436999 TI - Synthesis, characterization and magnetic properties of polymer-Fe3O4 nanocomposite. AB - The chemical stability of magnetic particles is of great importance for their applications in medicine and biotechnology. The most challenging problem in physics of disordered systems of magnetic nanoparticles is the investigation of their dynamic properties. The chemical coprecipitation process was used to synthesize spherical magnetite nanoparticles of 14 nm. The as-prepared magnetite nanoparticles have been aged in the matrix. Magnetic properties and aging effect were studied by Mossbauer spectroscopy at temperatures ranging from 77 to 300 K, and X-ray diffraction. At room temperature, the Mossbauer spectrum showed superparamagnetic behavior of the particles, while well-defined sextets were observed at 77K, indicating a blocked regime. The superparamagnetic magnetite nanoparticles can be used as microbead biosensors. PMID- 22437001 TI - Thoracoscopic transmyocardial laser revascularization: is prior coronary artery bypass grafting a contraindication? AB - OBJECTIVE: : Recently, thoracoscopic techniques have been used to perform transmyocardial laser revascularization (TMR) in patients who are not suitable candidates for coronary artery bypass graft (CABG) surgery or percutaneous coronary interventions. Whether or not prior CABG contraindicates a port access only approach to TMR is unclear. This study compares patients with and without prior CABG who have undergone thoracoscopic TMR. METHODS: : Between May 2003 and October 2005, 23 consecutive patients (6 without prior CABG, group A; and 17 with prior CABG, group B) underwent thoracoscopic TMR, using a holmium:yttrium aluminum-garnet (Ho:YAG) laser system. Either 3 or 4 port incisions (each <=2 cm in length) were used, depending on the patient's anatomy. Procedural success was defined as the ability to create all intended channels without conversion to thoracotomy. RESULTS: : Patient demographics were not significantly different between group A and group B (mean age, 65.8 +/- 4.3 years versus 67.4 +/- 2.4 years, Canadian Cardiovascular Society angina class 3.7 +/- 0.2 versus 3.9 +/- 0.1, and Parsonnet score 12.0 +/- 3.2 versus 20.5 +/- 2.4). Fourteen (82.4%) group B patients had a prior left internal mammary artery to left anterior descending artery graft, of which 12 (85.7%) were patent. One patient in group A had an airway injury at intubation that led to an extended hospital stay of 30 days. One patient in group A (16.7%) and one patient in group B (5.9%) required a blood transfusion (P = NS). Adhesion lysis time in group B ranged from 0 to 68 minutes (mean, 27 +/- 5.6 minutes). Neither group had a conversion to thoracotomy or any deaths through a mean combined follow-up of 12 months. CONCLUSIONS: : A port access approach is safe and reproducible for patients who are candidates for sole therapy TMR. Prior CABG, including patent grafts, is not a contraindication to thoracoscopic TMR. PMID- 22437002 TI - Coronary artery bypass grafts assessment at one year by noninvasive multislice computed tomography and invasive coronary angiography. AB - OBJECTIVE: : The aim of this study was to evaluate and compare the postoperative graft patency by multislice computed tomography (MSCT) and invasive coronary angiography (ICA) in patients with multivessel coronary artery bypass grafting at 1 year of surgery. METHODS: : Patients (n = 114) who underwent isolated coronary artery bypass grafting at least 1 year (1.4 +/- 0.4 years) previously were subjected to both 16-slice CT angiography with cardiac gating and ICA, and their results were evaluated and compared. All patients were receiving beta-blockers; mean heart rate was 64 +/- 6 beats/min. RESULTS: : The mean age of the patients was 59.7 +/- 8.5 years. There was a total of 338 grafts (113 internal mammary artery grafts, 8 radial artery grafts, and 217 saphenous venous grafts). On MSCT angiography, all the left internal mammary arteries were visualized with 3D reconstruction. All internal mammary arteries were found to be patent. Twenty-one grafts were occluded or stenosed (21/338, 6.25%). One occluded graft was on the anterior wall (1/20, 0.83%), 11 occluded grafts were on the lateral wall of the heart (11/128, 8.59%), and 9 occluded grafts were on the inferior wall of the heart (9/90, 10.0%); MSCT resulted in no false-positive diagnosis of stenosis (specificity, 100%). However, 2 grafts that were found to be patent on MSCT angiography were blocked on ICA (MSCT sensitivity, 96.3%). CONCLUSIONS: : Postoperative assessment of coronary bypass grafts is possible with an excellent resolution by MSCT angiography. Patency of bypass grafts can be checked by MSCT angiography, and the assessment is comparable with ICA. PMID- 22437003 TI - Management of a catheter-induced pulmonary artery rupture: early presentation after off-pump coronary artery bypass surgery. AB - A frail, 79-year-old woman with small body habitus was admitted for elective coronary artery bypass surgery. She was known to have long-standing chronic stable angina with recent deterioration. Her only risk factor for coronary artery disease was that she was an ex-smoker of 6 years. PMID- 22437004 TI - Chordal tethering: a unique cause of structural mitral regurgitation in dilated cardiomyopathy. AB - Mitral regurgitation in dilated cardiomyopathy is usually considered "functional," and many such patients are treated medically. Surgery is often offered as a last resort in select patients who have failed medical therapy. We report a patient with dilated cardiomyopathy with ventricular tachycardia and ventricular dyssynchrony and "structural mitral regurgitation" due to chordal tethering, which was managed surgically using a minimally invasive approach. PMID- 22437005 TI - Fibrin formation by staphylothrombin facilitates Staphylococcus aureus-induced platelet aggregation. AB - Interactions of Staphylococcus aureus (S. aureus) and platelets play an important role in the pathogenesis of intravascular infections such as infective endocarditis (IE). A typical feature of S. aureus is the ability to generate thrombin activity through the secretion of two prothrombin activating molecules, staphylocoagulase and von Willebrand factor-binding protein (vWbp), which bind to human prothrombin to form the enzymatically active staphylothrombin complex. The role of staphylothrombin in the interaction between S. aureus and platelets has not yet been studied. We found that in contrast with thrombin, staphylothrombin did not directly activate human platelets. However, the staphylothrombin-mediated conversion of fibrinogen to fibrin initiated platelet aggregation and secondary activation and facilitated S. aureus-platelet interactions. Both the genetic absence of staphylocoagulase and vWbp and pharmacological inhibition of staphylothrombin increased the lag time to aggregation, and reduced platelet trapping by S. aureus in high shear stress conditions. The combined inhibition of staphylothrombin and immunoglobulin binding to platelets completely abolished the ability of S. aureus to aggregate platelets in vitro. In conclusion, although staphylothrombin did not directly activate platelets, the formation of a fibrin scaffold facilitated bacteria-platelet interaction, and the inhibition of staphylothrombin resulted in a reduced activation of platelets by S. aureus. PMID- 22437006 TI - IFN-gamma renders human intestinal epithelial cells responsive to lipopolysaccharide of Vibrio cholerae by down-regulation of DMBT1. AB - Although intestinal epithelial cells (IECs) are continuously exposed to high densities of enteric bacteria, they are not highly responsive to microbe associated molecular patterns (MAMPs). However, inflammatory cytokines such as interferon-gamma (IFN-gamma) are potentially capable of priming IECs to enhance responsiveness to MAMPs. In this study, we observed that heat-killed Vibrio cholerae (HKVC) and its lipopolysaccharide (LPS) poorly induced IL-8 production in a human IEC line, HT-29. However, both HKVC and the LPS showed a substantial induction of IL-8 production in IFN-gamma-primed HT-29 cells. LPS-induced IL-8 production was proportional to the IFN-gamma-priming period and LPS could not induce IL-8 production in the presence of polymyxin B. Moreover, LPS-induced IL-8 production in the IFN-gamma-primed HT-29 cells was mediated through signaling pathways requiring p38 kinase and ERK, but not the JNK/SAPK pathway. Since deleted in malignant brain tumor 1 (DMBT1) is known to interact with and antagonize the action of LPS, we hypothesized that IFN-gamma enhanced the responsiveness to LPS in HT-29 through down-regulation of DMBT1. We found that IFN-gamma indeed attenuated DMBT1 expression at both the mRNA and protein levels in HT-29 cells. Conversely, when the cells were transfected with small interfering RNA to specifically silence DMBT1, IL-8 expression was augmented even in the absence of IFN-gamma and the augmentation was further enhanced by treatment with V. cholerae LPS. Since IFN-gamma is known to increase IFN-beta expression in the IECs, we examined if IFN-beta functioned similar to IFN-gamma. Although IFN-beta alone was able to induce IL-8 expression, it failed to render HT-29 cells responsive to V. cholerae LPS. In conclusion, our study suggests that IFN-gamma primes IECs to become responsive to V. cholerae and its LPS by suppressing the expression of DMBT1. PMID- 22437007 TI - High-performance supercapacitors based on vertically aligned carbon nanotubes and nonaqueous electrolytes. AB - We demonstrate the high performance of supercapacitors fabricated with vertically aligned carbon nanotubes and nonaqueous electrolytes such as ionic liquids and conventional organic electrolytes. Specific capacitance, maximum power and energy density of the supercapacitor measured in ionic liquid were ~75 F g(-1), ~987 kW kg(-1) and ~27 W h kg(-1), respectively. The high power performance was consistently indicated by a fast relaxation time constant of 0.2 s. In addition, electrochemical oxidation of the carbon nanotubes improved the specific capacitance (~158 F g(-1)) and energy density (~53 W h kg(-1)). Both high power and energy density could be attributed to the fast ion transport realized by the alignment of carbon nanotubes and the wide operational voltage defined by the ionic liquid. The demonstrated carbon-nanotube- and nonaqueous-electrolyte-based supercapacitors show great potential for the development of high-performance energy storage devices. PMID- 22437008 TI - Validation of an open-formula, diagnostic real-time PCR method for 20-h detection of Salmonella in animal feeds. AB - A comparative study of a 20-h, non-commercial, open-formula PCR method and the standard culture-based method NMKL 187, for detection of Salmonella, was performed according to the validation protocol from the Nordic organisation for validation of alternative microbiological methods (NordVal) on 81 artificially or naturally contaminated animal feed samples. The PCR method is based on culture enrichment in buffered peptone water for 16 +/- 2 h followed by a magnetic beads based semi automated DNA extraction and real-time PCR analysis, including an internal amplification control. The limit of detection (LOD50) was found to be 7.19 and 7.24 CFU/sample for the PCR method and NMKL187, respectively. A very good correlation between results obtained by the two methods was found (Cohen's kappa=0.92). The relative accuracy, relative sensitivity and relative specificity were found to be 97.5%, 102.0% and 96.6%, respectively. This method is the fastest open PCR based analysis protocol for detection of Salmonella in feed samples. Implementing rapid methods such as the one validated in this study can speed up Salmonella testing of feed for food-producing animals. PMID- 22437009 TI - Evidence for the porcine origin of equine rotavirus strain H-1. AB - Equine group A rotavirus (RVA) strain H-1 (RVA/Horse-tc/GBR/H-1/1975/G5P9[7]) was found to have VP4, VP6-7, NSP1 and NSP4 genes of porcine origin. In order to obtain conclusive information on the exact origin and evolution of this unusual equine strain, the remaining six genes (VP1-3, NSP2-3 and NSP5 genes) of strain H 1 were analyzed in the present study. By whole genomic analysis, strain H-1 exhibited a porcine RVA-like genotype constellation (G5-P[7]-I5-R1-C1-M1-A8-N1-T1 E1-H1), different from those of typical equine RVA strains. The VP2-3 and NSP2-3 genes of strain H-1 were found to originate from porcine RVAs. On the other hand, it was difficult to pinpoint the exact origin of the VP1 and NSP5 genes of strain H-1, though phylogenetically, these genes appeared to be possibly derived from porcine or Wa-like human strains. Taken together, at least nine (VP2-4, VP6-7 and NSP1-4 genes) of the 11 gene segments of strain H-1 were found to be of porcine origin, revealing a porcine RVA-like genetic backbone. Therefore, strain H-1 is likely a porcine RVA strain that was transmitted to horses. PMID- 22437010 TI - Variability in nitrogen content of submerged aquatic vegetation: utility as an indicator of N dynamics within and among lakes. AB - Submerged aquatic vegetation (SAV) may serve as an integrative proxy of spatial and temporal nitrogen (N) availability in aquatic ecosystems as plants are physiologically capable of storing variable amounts of N. However, it is important to understand whether plant species behave similarly or differently within and among systems. We sampled different SAV species along a nutrient gradient at multiple sites within several lakes to determine variability in C:N ratios and % N content among species, among plants of the same species at a single site, among sites and among lakes. Species respond differently suggesting that not all plant types can be used universally as nutrient proxies. The greatest variability in % N and C:N ratios for Valliseneria americana was observed among lakes whereas for Elodea canadensis it was among sites within a lake and among plants within a site. This suggests that V. americana could be a particularly useful indicator of N availability at larger spatial scales (regional and within a large fluvial lake) but that E. canadensis was not a particularly useful proxy. PMID- 22437011 TI - Removal of organic impurities in waste glycerol from biodiesel production process through the acidification and coagulation processes. AB - Treatment of waste glycerol, a by-product of the biodiesel production process, can reduce water pollution and bring significant economic benefits for biodiesel facilities. In the present study, hydrochloric acid (HCl) was used as acidification to convert soaps into salts and free fatty acids which were recovered after treatment. The pH value, dosages of polyaluminum chloride (PACl) and dosage of polyacrylamide (PAM) were considered to be the factors that can influence coagulation efficiency. The pH value of waste glycerol was adjusted to a pH range of 3-9. The PACl and PAM added were in the range of 1-6 g/L and 0.005 0.07 g/L. The results showed best coagulation efficiency occurs at pH 4 when dosage of PACl and PAM were 2 and 0.01 g/L. The removal of chemical oxygen demand (COD), biochemical oxygen demand (BOD(5)), total suspended solids (TSS) and soaps were 80, 68, 97 and 100%, respectively. The compositions of organic matters in the treated waste glycerol were glycerol (288 g/L), methanol (3.8 g/L), and other impurities (0.3 g/L). PMID- 22437012 TI - Hydroponic system for the treatment of anaerobic liquid. AB - The effluent from anaerobic digestion process has high concentrations of nutrients, particularly nitrogen, essential for plant growth but is not suitable for direct disposal or application due to high chemical oxygen demand (COD), low dissolved oxygen (DO), odour issues and is potentially phytotoxic. This research explored the optimum conditions of anaerobic effluent for application and dilutions of the effluent required to obtain better plant growth. A small-scale hydroponic system was constructed in a glasshouse to test different concentrations of anaerobic effluent against a commercial hydroponic medium as the control for the growth of silverbeet. It was found that the survival of silverbeet was negatively affected at 50% concentration due to low DO and NH(4) toxicity. The concentration of 20% anaerobic liquid was found to be the most efficient with highest foliage yield and plant growth. The hydroponic system with 20% concentrated effluent had better utilisation of nutrients for plant growth and a COD reduction of 95% was achieved during the 50-day growth period. This preliminary evaluation revealed that the growth and development of silverbeet was significantly lower in anaerobic effluent compared with a commercial hydroponic plant growth solution. The nutrient quality of anaerobic effluent could be highly variable with the process and the waste material used and dilution may depend on the nutrient content of the effluent. It is recommended that, a pre-treatment of the effluent to increase DO and reduce ammonium content is required before plant application, and simple dilution by itself is not suitable for optimum plant growth in a hydroponic system. PMID- 22437013 TI - A calibration protocol of a one-dimensional moving bed bioreactor (MBBR) dynamic model for nitrogen removal. AB - This work suggests a procedure to correctly calibrate the parameters of a one dimensional MBBR dynamic model in nitrification treatment. The study deals with the MBBR configuration with two reactors in series, one for carbon treatment and the other for nitrogen treatment. Because of the influence of the first reactor on the second one, the approach needs a specific calibration strategy. Firstly, a comparison between measured values and simulated ones obtained with default parameters has been carried out. Simulated values of filtered COD, NH(4)-N and dissolved oxygen are underestimated and nitrates are overestimated compared with observed data. Thus, nitrifying rate and oxygen transfer into the biofilm are overvalued. Secondly, a sensitivity analysis was carried out for parameters and for COD fractionation. It revealed three classes of sensitive parameters: physical, diffusional and kinetic. Then a calibration protocol of the MBBR dynamic model was proposed. It was successfully tested on data recorded at a pilot-scale plant and a calibrated set of values was obtained for four parameters: the maximum biofilm thickness, the detachment rate, the maximum autotrophic growth rate and the oxygen transfer rate. PMID- 22437014 TI - Occurrence and fate of relevant substances in wastewater treatment plants regarding Water Framework Directive and future legislations. AB - The next challenge of wastewater treatment is to reliably remove micropollutants at the microgram per litre range. During the present work more than 100 substances were analysed through on-site mass balances over 19 municipal wastewater treatment lines. The most relevant substances according to their occurrence in raw wastewater, in treated wastewater and in sludge were identified, and their fate in wastewater treatment processes was assessed. About half of priority substances of WFD were found at concentrations higher than 0.1 MUg/L in wastewater. For 26 substances, potential non-compliance with Environmental Quality Standard of Water Framework Directive has been identified in treated wastewater, depending on river flow. Main concerns are for Cd, DEHP, diuron, alkylphenols, and chloroform. Emerging substances of particular concern are by-products, organic chemicals (e.g. triclosan, benzothiazole) and pharmaceuticals (e.g. ketoprofen, diclofenac, sulfamethoxazole, carbamazepine). About 80% of the load of micropollutants was removed by conventional activated sludge plants, but about two-thirds of removed substances were mainly transferred to sludge. PMID- 22437015 TI - Research and application of in-situ control technology for sediment rehabilitation in eutrophic water bodies. AB - Phosphorus (P) is often the limiting nutrient for algal growth, and P in sediments can be released under suitable conditions. To control P release, in situ control technology with lanthanum (La) modified bentonite clay (Phoslock((r))) was proposed and its effectiveness was tested and evaluated both in laboratory and field trials. The results of static and dynamic simulation experiments under different environmental conditions showed that with the application rate of Phoslock((r)) at 0.5 kg/m(2), the orthophosphate (PO(4)-P) concentration of the overlying water decreased to a low level (<=0.02 mg/L) within 10 days. Even under anaerobic and high pH (pH = 9.0) conditions, the phosphate release suppression efficiency reached 98.3%, and the P-release rate was -8.20 mg/m(2) d (negative value indicates P adsorption by Phoslock((r))). The monitoring data of the field sediments rehabilitation project were consistent with the results achieved in laboratory experiments, thus showing that the application of Phoslock((r)) could inhibit the internal P release effectively. PMID- 22437016 TI - Mandatory urban rainwater harvesting: learning from experience. AB - Rainwater harvesting is effectively mandated in several urban areas of New Zealand. To understand the costs and benefits of rainwater harvesting from an end user perspective, semistructured interviews were conducted with 14 homeowners in northern Auckland affected by these regulations. Residents report differences in four aspects of urban rainwater infrastructure - security of supply, water quality, the learning process and financial costs - that could represent key values for public acceptance. When responses are examined from the perspective of experience that has built empirical knowledge, participants explained how their satisfaction with rainwater harvesting increased over time. We hypothesise that for those lacking experience, urban rainwater consumption is a function of empirical knowledge and has initially rising marginal utility. Regulation that recognises the costs of social learning is likely to be a more effective pathway towards maximising the social benefits associated with integrated urban water management. PMID- 22437017 TI - Multi-walled carbon nanotubes as electrode material for microbial fuel cells. AB - The microbial fuel cell (MFC) is a novel and innovative technology that could allow direct harvesting of energy from wastewater through microbial activity with simultaneous oxidation of organic matter in wastewater. Among all MFC parts, electrode materials play a crucial role in electricity generation. A variety of electrode materials have been used, including plain graphite, carbon paper and carbon cloth. However, these electrode materials generated only limited electricity or power. Recently, many research studies have been conducted on carbon nanotubes (CNTs) because of their unique physical and chemical properties that include high conductivity, high surface area, corrosion resistance, and electrochemical stability. These properties make them extremely attractive for fabricating electrodes and catalyst supports. In this study, CNT-based electrodes had been developed to improve MFC performance in terms of electricity generation and treatment efficiency. Multi-walled carbon nanotubes (MWCNTs) with carboxyl groups have been employed to fabricate electrodes for single-chamber air-cathode MFCs. The quality of the prepared MWCNTs-based electrodes was evaluated by morphology, electrical conductivity and specific surface area using a field emission scanning electron microscope, four-probe method and Brunauer-Emmerr Teller method, respectively. The performance of MFCs equipped with MWCNT-based electrodes was evaluated by chemical analysis and electrical monitoring and calculation. In addition, the performance of these MFCs, using MWCNTs as electrodes, was compared against that using commercial carbon cloth. PMID- 22437018 TI - GIS-based applications of sensitivity analysis for sewer models. AB - Sensitivity analysis (SA) evaluates the impact of changes in model parameters on model predictions. Such an analysis is commonly used when developing or applying environmental models to improve the understanding of underlying system behaviours and the impact and interactions of model parameters. The novelty of this paper is a geo-referenced visualization of sensitivity indices for model parameters in a combined sewer model using geographic information system (GIS) software. The result is a collection of maps for each analysis, where sensitivity indices (calculated for model parameters of interest) are illustrated according to a predefined symbology. In this paper, four types of maps (an uncertainty map, calibration map, vulnerability map, and design map) are created for an example case study. This article highlights the advantages and limitations of GIS-based SA of sewer models. The conclusion shows that for all analyzed applications, GIS based SA is useful for analyzing, discussing and interpreting the model parameter sensitivity and its spatial dimension. The method can lead to a comprehensive view of the sewer system. PMID- 22437019 TI - Microbial fuel-cell-based toxicity sensor for fast monitoring of acidic toxicity. AB - Wastewater may contain various potential toxicants. A microbial fuel cell (MFC) is a device in which bacteria convert the chemical energy into electricity. If a toxic event occurs, microbial activity is inhibited and thus the power output of the MFC decreases. Therefore, an MFC could serve as an early toxicity warning device. A real-time biomonitoring system was developed using MFCs to detect the inflow of toxic substances into wastewater treatment systems. After the MFCs reached steady state, a toxic incident was created by adding HCl into the wastewater to alter its pH. Consequently, a rapid decrease in voltage was observed immediately, followed by a subsequent recovery. The optimal MFC design was a single-chamber air cathode MFC, where the anode and cathode were separated by a Selemion proton exchange membrane. Under an external resistance of 5 Omega, the maximum power averaged 0.23 +/- 0.023 mW with domestic wastewater. The optimized MFC showed high sensitivity and fast recovery when exposed to the acidic toxic event. When the hydraulic retention time was decreased from 22 to 3.5 min, sensitivity of the MFC increased substantially. Finally, the extent of inhibition observed was found to be related to the toxicity level, suggesting that a dosage-response relationship exists. PMID- 22437020 TI - Methane and hydrogen sulfide emissions in UASB reactors treating domestic wastewater. AB - The release of CH(4) and H(2)S in UASB reactors was evaluated with the aim to quantify the emissions from the liquid surfaces (three-phase separator and settler compartment) and also from the reactor's discharge hydraulic structures. The studies were carried out in two pilot- (360 L) and one demo-scale (14 m(3)) UASB reactors treating domestic wastewater. As expected, the release rates were much higher across the gas/liquid interfaces of the three-phase separators (5.4 9.7 kg CH(4) m(-2) d(-1) and 23.0-35.8 g S m(-2) d(-1)) as compared with the quiescent settler surfaces (11.0-17.8 g CH(4) m(-2) d(-1) and 0.21 to 0.37 g S m( 2) d(-1)). The decrease of dissolved methane and dissolved hydrogen sulfide was very large in the discharging hydraulic structures very close to the reactor (>60 and >80%, respectively), largely due to the loss to the atmosphere, indicating that the concentration of these compounds will probably fall to values close to zero in the near downstream structures. The emission factors due to the release of dissolved methane in the discharge structure amounted to around 0.040 g CH(4) g COD(infl)(-1) and 0.060 g CH(4) g COD(rem)(-1), representing around 60% of the methane collected in the three-phase separator. PMID- 22437021 TI - Denitrification with corncob as carbon source and biofilm carriers. AB - In this research the agricultural by-product corncob was investigated as a carbon source as well as a biofilm carrier to remove organic matter, expressed as chemical oxygen demand (COD) and nitrate nitrogen (nitrate-N), from wastewater in a batch laboratory reactor. The performance of a reactor with corncob as the carbon source and the biofilm carrier was compared with a control batch reactor with suspended plastic carriers and glucose as the sole carbon source. With 60 vol% of corncob carriers inside the reactor, a soluble COD/N ratio of 4.2 g COD g N(-1) was enough for total denitrification, nearly half of the control reactor (9.5 g COD g N(-1)), at 23 h reaction time. The specific denitrification rate decreased with increasing soluble COD consumption for both reactors. Nitrate and COD removal efficiencies decreased with shorter retention times, with accentuated effects in the reactor. This study suggested corncob as a feasible carbon source and that reaction time was a limiting factor with corncob used as the carbon source for denitrification. PMID- 22437022 TI - Removal of cyanobacterial metabolites through wastewater treatment plant filters. AB - Wastewaters have the potential to proliferate excessive numbers of cyanobacteria due to high nutrient levels. This could translate to the production of metabolites, such as the saxitoxins, geosmin and 2-methylisoborneol (MIB), which can impair the quality of wastewater destined for re-use. Biological sand filtration was assessed for its ability to remove these metabolites from a wastewater. Results indicated that the sand filter was incapable of effectively removing the saxitoxins and in some instances, the effluent of the sand filter displayed greater toxicity than the influent. Conversely, the sand filter was able to effectively remove geosmin and MIB, with removal attributed to biodegradation. Granular activated carbon was employed as an alternative filter medium to remove the saxitoxins. Results showed similar removals to previous drinking water studies, where efficient removals were initially observed, followed by a decrease in the removal; a consequence of the presence of competing organics which reduced adsorption of the saxitoxins. PMID- 22437023 TI - Comparison of methane production by co-digesting fruit and vegetable waste with first stage and second stage anaerobic digester sludge from a two stage digester. AB - Fruit and vegetable waste (FVW) was co-digested with first stage (FSS) and second stage anaerobic digester sludge (SSS) separately, over the course of 10 days, in batch reactors. Addition of FVW significantly increased the methane production in both sludges. After 10 days of digestion FSS + FVW produced 514 +/- 57 L CH(4) kg VS(-1)(added) compared with 392 +/- 16 L CH(4) for the SSS + FVW. The increased methane yield was most likely due to the higher inoculum substrate ratio of the FSS. The final VS and COD contents of the sewer sludge and FVW mixtures were not significantly different from the control values suggesting that all of the FVW added was degraded within 10 days. It is recommended that FVW be added to the first stage of the anaerobic digester in order to maximize methane generation. PMID- 22437024 TI - Considerations on methodological challenges for water footprint calculations. AB - We have investigated how different approaches for water footprint (WF) calculations lead to different results, taking sugar beet production and sugar refining as examples. To a large extent, results obtained from any WF calculation are reflective of the method used and the assumptions made. Real irrigation data for 59 European sugar beet growing areas showed inadequate estimation of irrigation water when a widely used simple approach was used. The method resulted in an overestimation of blue water and an underestimation of green water usage. Dependent on the chosen (available) water quality standard, the final grey WF can differ up to a factor of 10 and more. We conclude that further development and standardisation of the WF is needed to reach comparable and reliable results. A special focus should be on standardisation of the grey WF methodology based on receiving water quality standards. PMID- 22437025 TI - Treatment of paper mill effluent using an anaerobic/aerobic hybrid side-stream membrane bioreactor. AB - This paper presents the design and operational performance data of an anaerobic/aerobic hybrid side-stream Membrane Bioreactor (MBR) process for treating paper mill effluent operated over a 6 month period. The paper mill effluent stream was characterized by a chemical oxygen demand (COD) range of between 1,600 and 4,400 mg/L and an average BOD of 2,400 mg/L. Despite large fluctuations in COD feed concentration, stable process performance was achieved. The anaerobic Expanded Granular Sludge Bed (EGSB) pre-treatment step effectively lowered the organic loading by 65 to 85%, thus lowering the MBR COD feed concentration to consistently below 750 mg/L. The overall MBR COD removal was consistent at an average of 96%, regardless of the effluent COD or changes in the hydraulic retention time (HRT) and organic loading rate (OLR). Combining a high rate anaerobic pre-treatment EGSB with a Modified Ludzack-Ettinger (MLE) MBR process configuration produced a high quality permeate. Preliminary NF and RO results indicated an overall COD removal of around 97 and 98%, respectively. PMID- 22437026 TI - Nine steps towards a better water meter management. AB - The paper provides a comprehensive perspective of the critical aspects to be taken into account when planning the long-term management of water meters in a utility. In order to facilitate their quick understanding and practical implementation, they have been structured into nine steps. Ranging from an initial audit up to the final periodic meter replacement planning, these steps cover three aspects of the problem - field work, laboratory work and management tasks; and each one is developed in detail paying attention to the particular data needed and noting the practical outcome it will yield. PMID- 22437027 TI - Online estimation of VFA, alkalinity and bicarbonate concentrations by electrical conductivity measurement during anaerobic fermentation. AB - This paper describes the use of electrical conductivity for measurement of volatile fatty acids (VFA), alkalinity and bicarbonate concentrations, during the anaerobic fermentation process. Two anaerobic continuous processes were studied: the first was a laboratory reactor for hydrogen production from molasses and the second was a pilot process for anaerobic digestion (AD) of vinasses producing methane. In the hydrogen production process, the total VFA concentration, but not bicarbonate concentration, was well estimated from the on-line electrical conductivity measurements with a simple linear regression model. In the methane production process, the bicarbonate concentration and the VFA concentration were well estimated from the simultaneous on-line measurements of pH and electrical conductivity by means of non-linear regression with neural network models. Moreover, the total alkalinity concentration was well estimated from electrical conductivity measurements with a simple linear regression model. This demonstrates the use of electrical conductivity for monitoring the AD processes. PMID- 22437028 TI - Upgrading Vienna's wastewater treatment plant - linking point source emissions to Environmental Quality Standards. AB - The new water quality protection approach of the EU combines the control of emissions with instream Environmental Quality Standards (=EQS). Since 1 April 2006 and actually relevant in the version of 2010 in Austria, priority substances from list A of the EUROPEAN DIERECTIVE 76/464 and further EQS of relevant chemical substances (list B), identified by a national risk assessment, have to be reached to achieve a good ecological state in the surface water (Edict for Water Quality Standards, 2006; changes to the Edict for Water Quality Standards 2010). The practical assessment of these substances after point source emissions is prescribed in the Edict, but rarely carried out. In this paper, two substances, namely: (1) ammonium (list B); and (2) nonylphenol, an endocrine disrupting compound (list A) are presented to discuss: (i) the improvement of treatment efficiency due to the upgrade of a large Waste Water Treatment Plant (=WWTP); (ii) the relevance of mixing processes and modelling as a method to control EQS after point source emissions; and (iii) the improvement of water quality in the ambient surface waters. It is shown that the improved treatment in the case of nonylphenol leads to emission values which fall below the EQS, making an assessment unnecessary. In the case of ammonium emission, values are significantly reduced and violation of EQS is avoided, while mixing modelling is shown to be a suitable instrument to address the resulting instream concentrations at different border conditions. PMID- 22437029 TI - Effects of silver nanoparticles on biological nitrogen removal processes. AB - The effects of silver (Ag) nanoparticles (NPs) on activated sludge in a biological nitrogen removal (BNR) process were investigated under aerobic and anoxic conditions. We show that nitrification was more vulnerable to Ag NPs exposure than denitrification at the same Ag NPs concentration. In continuous operation of the BNR process, a higher inhibitory effect on nitrification was attributed to a smaller size of Ag NPs. About 70-90% of the Ag NPs supplied were embedded in the sludge matrix but 10-30% of the Ag NPs remained in the supernatant. This indicates that significant amounts of Ag NPs could be discharged from wastewater treatment plants and potentially impact on aquatic ecosystems. PMID- 22437030 TI - Performance indicators for wastewater treatment plants. AB - The Swedish Water & Wastewater Association has operated a web-based system, VASS, for the collection and compilation of key data from the Swedish water utilities since 2003. The VASS system will now be expanded to include data on operation of individual wastewater treatment plants (WWTP). The objective is to provide performance indicators (PIs) for performance and economy and the use of resources such as energy, chemicals and manpower. A set of PIs has been developed that also includes explanatory factors to compensate for differences in the condition of operation between plants. This paper discusses the data required for the calculation of PI but also for explanatory factors, quality checks and for plant operation context. The discussion is based on the experiences from a test round with the participation of 24 WWTP. PMID- 22437031 TI - The correlation of sorption coefficients with nonlinearity of sorption isotherms in contaminated nearshore sediments in Bohai Bay (China). AB - Phenanthrene sorption to seven nearshore sediments (Bohai Bay, China) collected under similar environments were investigated. Based upon well-fitted Freundlich models, the calculated organic carbon-normalized sorption coefficients at aqueous concentrations of 1 and 5,900 MUg/L (PHE supercooled liquid solubility) showed positive and negative correlation with the nonlinearity of sorption isotherms, respectively, and the latter has not previously been reported. The present observations highlighted the viewpoint that PHE at low concentrations is primarily adsorbed to low quantity but highly adsorptive black carbon (BC) whereas partitioning to soft carbon may take over for high concentrations. Therefore, BC should be taken into account when modelling PHE (and analogues) sorption in contaminated sediments, and the correlation approach provides a promising diagnostic tool to this end. PMID- 22437032 TI - Saving phosphorus removal at the Henderson NV plant. AB - While the mechanism of biological phosphorus removal (BPR) and the need for volatile fatty acids (VFA) have been well researched and documented to the point where it is now possible to design a plant with a very reliable phosphorus removal process using formal flow sheets, BPR is still observed in a number of plants that have no designated anaerobic zone, which was considered essential for phosphorus removal. Some examples are given in this paper. A theory is proposed and then applied to solve problems with a shortage of VFA in the influent of the Henderson NV plant. Mixed liquor was fermented in the anaerobic zone, which resulted in phosphorus removal to very low levels. This paper will discuss some of the background, and some case histories and applications, and present a simple postulation as to the mechanism and efforts at modelling the results. PMID- 22437033 TI - A PCR-DGGE approach to evaluate the impact of wastewater source on the antibiotic resistance diversity in treated wastewater effluent. AB - Increased incidence of antibiotics in human-affected environments is raising concerns about increase in acquired antibiotic resistance by environmental bacteria. Wastewater collection and treatment systems are likely significant anthropogenic sinks and vectors for antibiotics and associated antibiotic resistance. Typical municipal treatment plants collect wastewaters of various sources, including well-established antibiotic resistance reservoirs such as hospitals, intensive care units and nursing homes, and integrate them with sources not commonly identified as major sources of antibiotic resistance, such as residential or industrial sources. A comprehensive PCR-DGGE diversity analysis of wastewater antibiotic-resistant bacteria was performed to evaluate the role of various wastewater sources in the discharge of antibiotic resistance by a municipal treatment plant. Wastewater sources are clearly inducing resistance in the final effluent but the role of each source type is highly variable, likely as a function of variable environmental conditions or water use patterns. Comparisons between primary treatment and secondary treatment stages indicate a strong role of the intensity of the wastewater treatment in the diversity profiles of antibiotic-resistant bacteria. While pervasiveness of antibiotic resistance in the system impedes clear discrimination between sources in the tested system, there are indications of specific source type related impacts. PMID- 22437034 TI - Spatio-temporal variation of flood vulnerability at the Poyang Lake Ecological Economic Zone, Jiangxi Province, China. AB - For a long time areas of Poyang Lake have been threatened by floods. It is therefore important to assess flood vulnerability in this area. A composite flood vulnerability index was developed using an indicator approach to detect spatial distribution and temporal variation of flood vulnerability in the Poyang Lake Ecological Economic Zone (abbreviated to PLEEZ). Thematic maps of flood vulnerability showed a spatially ring-shaped distribution. The flood vulnerability ranking of one unit negatively correlated with the distance between the unit and the lake. Although flood vulnerability in PLEEZ declined significantly, the spatial distribution hardly changed from 1997 to 2006. The degree of flood vulnerability is highly related to exposure; variations in flood vulnerability are influenced by sensitivity and adaptive capacity. Based on correlation analysis, three proxies were identified as determinants of flood vulnerability variation over the past 10 years. This approach could provide policymakers with important flood risk information and entry points for flood management. PMID- 22437035 TI - The mitogenome of Gammarus duebeni (Crustacea Amphipoda): A new gene order and non-neutral sequence evolution of tandem repeats in the control region. AB - We determined the complete mitogenome sequence of Gammarus duebeni (Peracarida, Amphipoda). The mitogenome is circular and has a length of 15,651bp. The content corresponds to typical mitogenomes of metazoans. The gene order and transcriptional polarity of the protein-coding genes is identical to the pancrustacean ground pattern. Six tRNA genes are rearranged, making the gene order unique. Thus it will bring forward the understanding of mitogenome evolution within the Peracarida, for which much more derived gene orders are known. We postulate that the gene string trnA-trnS1 (AGN)-trnN-trnE-trnR constitutes an apomorphic character for the Amphipoda. In contrast to the relatively large genome size, we found two extremely truncated rRNA genes. The rrnL gene is the shortest (986bp) reported up until now for crustaceans. A six time imperfect tandem repeat was observed within the control region. The inferred deterministic pattern of variation between the repeat units makes it likely, that functional constraints play an important role in the evolutionary dynamics and extant appearance of the repeat array. PMID- 22437036 TI - The Momedemameter: An Affordable Preeclampsia Detector For Low Resource Environments. AB - BACKGROUND: Preeclampsia, a pregnancy-specific disorder, is the third leading cause of maternal morbidity and mortality worldwide. METHOD OF APPROACH: To develop a device to detect preeclampsia in pregnant women living in low resource environments, a method was needed that had to be very low cost and, preferably, easily monitored by the woman herself. Due to the high cost and expertise involved in monitoring the two diagnostic criteria of preeclampsia (elevated blood pressure and proteinuria), edema, an indicator of preeclampsia was chosen instead. RESULTS: The general principle of the method is to have each pregnant woman, early in pregnancy, fitted, on either her wrist or ankle, with a detection band, which is set to a preset expansion limit (e.g., expansion by 5%). When edema causes that body part to swell to the limit, the pregnant mother knows that she should seek medical assistance. CONCLUSIONS: The resulting prototype device and calibration method requires little knowledge, and is very durable, cost effective and portable. PMID- 22437038 TI - Blood pressure changes during pregnancy. PMID- 22437039 TI - And in the end--Telmisartan directly binds to PPARgamma. PMID- 22437040 TI - Walking nanothermometers: spatiotemporal temperature measurement of transported acidic organelles in single living cells. AB - We fabricated fluorescent nanoparticles which monitor temperature changes without sensitivity to pH (4-10) and ionic strength (0-500 mM). The nanothermometers spontaneously enter living HeLa cells via endocytosis, enclosed in acidic organelles, i.e., endosome/lysosome, and then transported along microtubules in a temperature-dependent manner, working as "walking nanothermometers". PMID- 22437041 TI - Metal centre effects on HNO binding in porphyrins and the electronic origin: metal's electronic configuration, position in the periodic table, and oxidation state. AB - HNO binds to many different metals in organometallic and bioinorganic chemistry. To help understand experimentally observed metal centre effects, a quantum chemical investigation was performed, revealing clear general binding trends with respect to metal centre characteristics and the electronic origin for the first time. PMID- 22437042 TI - Emphysema detected on computed tomography and risk of lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Studies exploring the association between emphysema detected on chest computed tomography (CT) and lung cancer have yielded mixed results. Our objective was to systematically review the evidence for this association. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library for the terms "lung cancer", "emphysema" and "computed tomography" without language restriction. Bibliographies were also reviewed and authors contacted for additional information. Human studies in which CTs were performed and assessed for emphysema and in which subjects were evaluated systematically for lung cancer were included. Qualitative synthesis of evidence was performed followed by pooling of effect estimates using a random-effects model. RESULTS: Of 187 citations, 7 were included in the qualitative synthesis and 5 in the meta-analysis. Three studies assessing emphysema visually observed an association with lung cancer, independent of smoking history and airflow obstruction. Three studies using densitometry to detect emphysema found no association with lung cancer. Another study directly comparing automated and visual emphysema detection techniques found only the latter to associate with lung cancer. Among 7368 subjects included in the meta-analysis, 2809 had emphysema on CT and 870 were diagnosed with lung cancer. The pooled adjusted odds ratio for lung cancer in the presence of emphysema on CT was 2.11 (95% CI 1.10-4.04); stratification by detection method yielded OR of 3.50 (95% CI 2.71-4.51) with visually detected emphysema and 1.16 (95% CI 0.48-2.81) with densitometric emphysema. CONCLUSION: Systematic literature review shows emphysema detected visually on CT to be independently associated with increased odds of lung cancer. This association did not hold with automated emphysema detection. PMID- 22437043 TI - Message from the editor. PMID- 22437044 TI - Message from the president. PMID- 22437045 TI - ISMICS 2009 Scientific Program. PMID- 22437046 TI - Analysis of reasons for decline of bioleaching efficiency of spent Zn-Mn batteries at high pulp densities and exploration measure for improving performance. AB - The reasons for decline of bioleaching efficiency of Zn and Mn from spent batteries at high pulp densities were analyzed; the measures for improving bioleaching efficiency were investigated. The results showed that extraction efficiency of Zn dropped from 100% at 1% of pulp density to 29.9% at 8% of pulp density, with Mn from 94% to only 2.5%. It was almost the linear reduction of the activity of the sulfur-oxidizing bacteria with increase of pulp density that witnessed declined bioleaching efficiency of Zn; it was the complete inactivation of the iron-oxidizing bacteria at 2% of pulp density or higher that witnessed declined bioleaching dose of Mn. By means of reducing initial pH value of leaching media, increasing concentration of energy matters and exogenous acid adjustment of media during bioleaching, the maximum extraction efficiency of almost 100% for Zn and 89% for Mn at 4% of pulp density was attained, respectively. PMID- 22437047 TI - Mass balance and transformation of corn stover by pretreatment with different dilute organic acids. AB - Previous studies indicated high xylose yield could be achieved after pretreatment using organic acids, but it is necessary to systematically investigate the effects of different parameters during organic acid pretreatments. Corn stover was pretreated with sulfuric, oxalic, citric, tartaric and acetic acid at 50 and 90 mM from 130 to 190 degrees C. The xylan balance for each different acid was distinct, but all balances were very close to 100% by determining xylan recovery, xylooligomer yield, xylose yield and furfural yield. The effects of combined severity on the recovery or yields of these components were also studied. The acid pK(a) value affected the proportion of xylan degradation products. The maximum value of xylose and xylooligomer yield for specific acid pretreatment was also determined by pK(a) value. The maximum xylose yield was obtained after pretreatment with sulfuric and oxalic acid, but more xylooligomers were obtained after pretreatment with weaker acids. PMID- 22437048 TI - Investigating the structure-effect relationships of various natural phenols used as laccase mediators in the biobleaching of kenaf and sisal pulps. AB - Nine phenol derivatives, p-coumaric acid (PC), vanillin (V), acetovanillone (AV), acetosyringone (AS), syringaldehyde (SA), coniferaldehyde (CLD), ferulic acid (FRC), sinapic acid (SNC), and sinapyl aldehyde (SLD) were assayed as laccase redox mediators in the biobleaching of kenaf and sisal pulps. As a general behaviour, the phenolic mediators increased the kappa number (KN) and reduced the brightness of pulps. In particular, these changes were found to depend in a linear manner on the energy of the highest occupied molecular orbital (E(HOMO)) of the mediators. The phenolic mediator with the lowest E(HOMO) (PC) led to the highest increase of KN and the lowest reduction of brightness. On the contrary, syringyl derivatives (i.e. SA) with high E(HOMO) values caused small KN increases and significant losses of brightness. This behaviour was explained on the basis of a competition between grafting and polymerisation processes. The former basically affects KN, whereas the latter affects pulp brightness. PMID- 22437049 TI - Synthesis of oxygenated fuel additives via the solventless etherification of glycerol. AB - The synthesis of oxygenated fuel additives via solvent freebase-catalyzed etherification of glycerol is reported. The products of glycerol etherification arediglycerol (DG) and triglycerol (TG) with DG being the favorable one. The catalytic activity of different homogeneous alkali catalysts (LiOH, NaOH, KOH and Na(2)CO(3)) was investigated during the glycerol etherification process. LiOH exhibited an excellent catalytic activity during this reaction, indicated by the complete glycerol conversion with a corresponding selectivity of 33% toward DG. The best reaction conditions were a reaction temperature of 240 degrees C, a catalyst/glycerol mass ratio of 0.02 and a reaction time of 6h. The influences of various reaction variables such as nature of the catalyst, catalyst loading, reaction time and reaction temperature on glycerol etherification were elucidated. Industrially, the findings attained in this study might contribute towards promoting the biodiesel industry through utilization of its by-products. PMID- 22437050 TI - Effect of aeration rate, C/N ratio and moisture content on the stability and maturity of compost. AB - To estimate the order of importance of factors affecting the stability and maturation of compost, pig feces and corn stalks were co-composted at different aeration rates (AR: 0.24, 0.48, 0.72 L kg(-1)dry matter (DM)min(-1)), C/N ratios (15, 18, 21), and moisture contents (MC: 65%, 70%, 75%). The thermophilic phase with all treatments was long enough to meet sanitation requirements. The oxygen content and N losses increased with increasing AR, but no significant differences were observed between the moderate and high treatments. The compost with the lowest initial C/N ratio was significantly different from the other treatments and had the lowest germination index (53-66%). AR was the main factor influencing compost stability, while the C/N ratio mainly contributed to compost maturity, and the MC had an insignificant effect on the compost quality. The recommended parameters for composting are an AR of 0.48 L kg(-1) DM min(-1) and a C/N ratio of 18 with MCs of 65-75%. PMID- 22437051 TI - Reduced coagulation at high altitude identified by thromboelastography. AB - The impact of hypoxaemia on blood coagulation remains unclear despite use of a variety of measures to address the issue. We report the first use of thromboelastography (TEG) at high altitude to describe the dynamics of clot formation in whole blood samples. Seventeen healthy volunteers ascended to 5,300 m following an identical ascent profile; TEG measurements at 4,250 m and 5,300 m were compared with those from sea level. Peripheral oxygen saturation (SpO2) and haematocrit were also measured. Ascent resulted in a decline in SpO2 from 97.8 (+/- 1.2) % at sea level to 86.9 (+/- 3.3) % at 4,250 m and 79.5 (+/- 5.8) % at 5,300 m (p<0.001); haematocrit rose from 43.7 (+/- 2.8) % at sea level, to 46.7 (+/- 3.9) % and 52.6 (+/- 3.2) % at 4,250 m and 5,300 m, respectively (p<0.01). TEG reaction (R)-time and kinetic (K)-time were both increased at 5,300 m compared to sea level, 8.95 (+/- 1.37) minutes (min) to 11.69 (+/- 2.91) min (p=0.016) and 2.40 (+/- 0.66) min to 4.99 (+/- 1.67) min (p<0.001), respectively. Additionally the alpha (alpha)-angle was decreased from 57.7 (+/- 8.2) to 51.6 (+/- 6.4) (p<0.001). There was no change in maximum amplitude (MA) on ascent to altitude. These changes are consistent with an overall pattern of slowed coagulation at high altitude. PMID- 22437052 TI - Processing noncanonical sentences in broca's region: reflections of movement distance and type. AB - Various noncanonical sentence constructions are derived from basic sentence structures by a phrase displacement called Movement. The moved phrase (filler) leaves a silent copy at the extracted position (gap) and is reactivated when the hearer/reader passes over the gap. Consequently, memory operations are assumed to occur to establish the filler-gap link. For languages that have a relatively free word order like German, a distinct linguistic operation called Scrambling is proposed. Although Movement and Scrambling are assumed to be different linguistic operations, they both involve memory prone filler-gap processes. To clarify whether filler-gap memory processes in Scrambling and Movement differ neuroanatomically, we designed a functional magnetic resonance imaging study and compared the effect of memory load parameterized by filler-gap distance in the 2 sentence types. Here, we show that processing of the 2 sentence types commonly relies on a left hemispheric network consisting of the inferior frontal gyrus, middle part of the middle temporal gyrus, and intraparietal sulcus. However, we found differences for the 2 sentence types in the linearity of filler-gap distance effect. Thus, the present results suggest that the same neural substrate supports the memory processes of sentences constructed by Movement and Scrambling, although differentially modulated by memory load. PMID- 22437053 TI - Decoding the role of the insula in human cognition: functional parcellation and large-scale reverse inference. AB - Recent work has indicated that the insula may be involved in goal-directed cognition, switching between networks, and the conscious awareness of affect and somatosensation. However, these findings have been limited by the insula's remarkably high base rate of activation and considerable functional heterogeneity. The present study used a relatively unbiased data-driven approach combining resting-state connectivity-based parcellation of the insula with large scale meta-analysis to understand how the insula is anatomically organized based on functional connectivity patterns as well as the consistency and specificity of the associated cognitive functions. Our findings support a tripartite subdivision of the insula and reveal that the patterns of functional connectivity in the resting-state analysis appear to be relatively conserved across tasks in the meta analytic coactivation analysis. The function of the networks was meta analytically "decoded" using the Neurosynth framework and revealed that while the dorsoanterior insula is more consistently involved in human cognition than ventroanterior and posterior networks, each parcellated network is specifically associated with a distinct function. Collectively, this work suggests that the insula is instrumental in integrating disparate functional systems involved in processing affect, sensory-motor processing, and general cognition and is well suited to provide an interface between feelings, cognition, and action. PMID- 22437054 TI - Frequency and multiplicity of human papillomavirus infection in HIV-1 positive women in Italy. AB - BACKGROUND: Natural history of HPV infection is altered in HIV positive women, with increased risk of cervical dysplasia. Limited data are available about the influence of HPV genotypes and HPV multiple infections on cervical disease in HIV positive women. OBJECTIVES: We determined HPV genotype prevalence in cervical samples from 553 HIV-infected women attending the gynaecological service at "L. Spallanzani" Hospital. Association of HPV multiple infections with cervical abnormalities was investigated. STUDY DESIGN: MY09/MY11 consensus primers were used to detect HPV-DNA; HPV typing was performed by RFLP. A commercial array based kit was used to define unresolved RFLP patterns. RESULTS: HPV was detected in 244/553 (44.1%) patients, correlating with low CD4 counts (p<0.001) and age (p=0.001). Multiple HPV types were observed in 44.4% of cases, more frequently involving HR than LR HPV (OR=12.8, p<0.00001). Multiple HPV infections were associated with low CD4 counts (OR=3.8 in CD4<200 vs CD4>=500 cells/mm(3)). Dyskaryosis was associated with decreased CD4 counts (>=500 vs 200-499 vs <200 cells/mm(3), chi(2) for trend, p=0.001) and with HPV types multiplicity (1 vs 2-3 vs >=4, chi(2) for trend, p<0.00001). Notably, in 3 H-SIL cases only LR types were detected (HPV62, n=2; HPV81, n=1). CONCLUSIONS: Multiple HPV infections, often involving HR types, are frequent in HIV-infected women. Association between multiple HPV infection, low CD4 count and cytological abnormalities supports the interplay of virological and immunological factors in cervical cancer pathogenesis. Assessment of multiple HPV infections might gain importance in cervical cancer screening, particularly in patients with predisposing factors like immuno-suppression. PMID- 22437055 TI - Impact of Preoperative 64-Slice CT Scanning on Mini-Maze Atrial Fibrillation Surgery. AB - BACKGROUND: : Multidetector computed tomography (MDCT) is emerging as a powerful noninvasive diagnostic tool. The appropriate role of this technique in the preoperative evaluation of cardiovascular disease has yet to be fully defined. Atrial fibrillation is the most common sustained cardiac arrhythmia, and novel minimally invasive surgical techniques have been developed to treat this condition by electrically isolating the pulmonary veins. The ideal methodology to preoperatively evaluate these patients remains debatable. We hypothesized that 64 slice CT could significantly affect perioperative planning. METHODS: : Thirty-six consecutive patients who consented to undergo minimally invasive pulmonary vein isolation at our institution underwent a preoperative 64-slice cardiac CT scan. All cardiac and noncardiac abnormalities were recorded, and modifications to the initial surgical plan were documented. RESULTS: : The mean patient age was 64.4 +/- 11.9 years [26 men (72.2%), 17 with known coronary artery disease (47.2%)]. Preoperative CT scanning detected 12 patients with abnormal pulmonary venous anatomy (33.3%), 3 with left atrial thrombus (8.3%), and 17 with significant coronary artery disease (47.2%). Furthermore, 20 studies (55.6%) detected pulmonary abnormalities (including 11 nodules). Preoperative scanning significantly altered surgical planning in 10 cases (27.8%). Alterations in patient treatment included preoperative invasive angiography, conversion of the mini-maze to an open chest procedure, alteration of surgical approach, and postponement/cancellation. CONCLUSIONS: : Sixty-four-slice CT scanning is a safe, rapid, and accurate procedure with important ramifications for surgical planning. This methodology could become an alternative approach to screen preoperative cardiac surgical patients. PMID- 22437056 TI - Platelet function changes in different cardiac surgery subgroups as evaluated with an innovative technology. AB - OBJECTIVES: : During cardiac surgery, platelets undergo substantial changes. The purpose of this study was to assess platelet function and compare these changes between different cardiac operations using an innovative technology. METHODS: : Perioperative platelet function was evaluated by the Impact test [cone and plate(let) analyzer (CPA)]. The Impact test yields 2 parameters for platelet function: average size (AS, the mean size of the platelet aggregates) and surface coverage (SC, the percentage of the surface covered by the platelet aggregates), which correspond to platelet aggregation and adhesion. The study groups were compared for platelet function results in various surgery stages and correlation with bleeding. RESULTS: : A significant decrease in surface coverage was detected on establishment of cardiopulmonary bypass, with an increase up to preoperative values at the end of the surgery in all groups. In contrast to operations performed on bypass, in patients operated without cardiopulmonary bypass, the postoperative AS and SC were higher than the preoperative values, 30.4 +/- 8.1 MUmol versus 23.3 +/- 6.9 MUmol, P = 0.02 in AS, and 7.6 +/- 3.6% versus 5.2 +/- 1.8%, P = 0.04 in SC. Preoperative AS and SC were the only parameters significantly (P = 0.01) and linearly (r = 0.6) related to postoperative bleeding. CONCLUSIONS: : Preoperative platelet function, as evaluated by the CPA, is an independent risk factor determining postoperative bleeding. The off-pump patients presented an increased platelet function at the end of surgery, a finding that can imply a higher risk of thrombosis. The impact test appears to be a useful tool to determine perioperative platelet function and help in prediction of postoperative bleeding. PMID- 22437057 TI - Thoracic aortic stent grafting in patients with connective tissue disorders: a word of caution. AB - OBJECTIVE: : Use of thoracic Stent-graft in patients with connective tissue disorders (CTD) remains limited. We herein report 3 patients with CTD who underwent stent grafting. METHODS AND RESULTS: : Case 1; A male Marfan patient was operated for thoraco-abdominal aneurysm. On computed tomography (CT), large false aneurysm at the proximal anastomosis was documented which was excluded with a 30 mm Talent stent-graft with 10-15% oversize. Case 2; A female with Ehlers Danlos syndrome had undergone resection of descending aortic thoracic aneurysm presented with an enlarging aneurysm distal to the graft. Three Talent stent grafts (15% oversize) were deployed with balloon dilatation to exclude the aneurysm. The immediate postoperative period was complicated by an extensive intramural hematoma of the descending aorta with hemothorax, managed conservatively. Case 3; A female Marfan patient had undergone Bentall procedure and mitral repair followed with resection of the proximal descending aorta. Three months later a false aneurysm at the distal anastomosis was treated with a 24 mm Valiant stent-graft (30% oversize). Aortic dissection distal to stent was documented on the early postoperative CT. The dissected aneurysm enlarged significantly with a type I distal endoleak during follow-up. Concomitantly, the patient presented a class III dyspnea owing to a severe mitral regurgitation. The patient underwent a successful MVR and stent-graft explantation with replacement of the descending aorta. CONCLUSION: : Significant complications supervened when stent-grafts were deployed in native aorta. We thus recommend that deploying a stent-graft in a CTD diseased aorta should be considered a relative contraindication. In cases with prohibitive or high risk surgery, use of a stent graft with minimal radial force and minimal oversizing without balloon dilatation should be considered. PMID- 22437058 TI - Beating heart direct left atrial access balloon cryoablation: safety and efficacy of pulmonary vein isolation in an ovine model. AB - OBJECTIVE: : Clinical experience with endocardial cryoablation for the surgical treatment of atrial fibrillation has demonstrated safety and efficacy. Direct access to the left atrium via a thoracoscopic or pericardial approach with a balloon-tipped cryoablation catheter might facilitate endocardial cryoablation on the beating heart. We investigated the ability of a novel cryoballoon to produce endocardial pulmonary vein ostial cryolesions on the beating heart in a large animal model. METHODS: : Six sheep underwent small left thoracotomy. A 10.5F catheter with a 23-mm cryoballoon was inserted directly into the left atrium under fluoroscopic and intracardiac echo (ICE) guidance. Cryoablation of the pulmonary vein ostia was performed. Animals were killed at 14 days. Pulmonary venous electrical isolation was assessed immediately before the animals were killed. RESULTS: : All animals survived balloon cryoablation with no periprocedural complications. Balloon occlusion was well tolerated hemodynamically, with minimal change in blood pressure (-4 +/- 6 mm Hg systolic BP) and no change in heart rate. ICE demonstrated an absence of intracardiac air or ice embolization during ablation. Mean balloon temperature was -67 +/- 8 degrees C. All animals were neurologically intact after the procedure. Five of 6 (83%) veins exhibited circumferential exit block. Phrenic nerve function was intact in all animals. On gross inspection, all lesions were circumferential and continuous without evidence of endocardial thrombus. Pathology confirmed circumferential transmurality in all treated veins. CONCLUSIONS: : Direct left atrial access cryoballoon ablation was effective for isolating pulmonary veins. This technology may be an important component of a minimally invasive beating heart CryoMaze procedure for the treatment of atrial fibrillation. PMID- 22437059 TI - Renal outcome in off-pump coronary artery bypass grafting: predictors for renal impairment with multivariate analysis. AB - OBJECTIVE: : Recent studies on the efficacy of off-pump coronary artery bypass grafting (OPCABG) have reported encouraging results on postoperative renal function, but improvements can still be made. METHODS: : A total of 368 patients, none needing chronic dialysis, underwent isolated OPCABG at our institution between January 1999 and March 2005. They were divided into 3 groups according to renal function as indicated by the serum creatinine levels: group N (n = 332) with normal function, group M (n = 30) with mild to moderate renal dysfunction, and group S (n = 6), with severe renal dysfunction. Creatinine ratio and early outcomes were compared among the groups. Predictors for renal impairment were determined by multiple regression analysis. RESULTS: : In-hospital mortality rate was similar (group N, 0.6%; group M, 0%; group S, 0%). The percentage of patients with a creatinine ratio greater than 1.6 was significantly larger in group S (group N, 13%; group M, 13%; group S, 50%; P < 0.05). Postoperative hemodialysis, which was temporary, was required more frequently in group S (group N, 0.3%; group M, 3%; group S, 67%; P < 0.05). In group N, 38 patients (11%) had new renal impairment after OPCABG. Preoperative serum creatinine levels >=2.5 mg/dL, ejection fraction <0.4, amount of blood transfusion, and more than 4 bypasses were potent predictors for postoperative renal impairment. CONCLUSIONS: : Clinical results of OPCABG on renal function were satisfactory regardless of preoperative renal function. However, perioperative renal function should be closely monitored in patients with known risk factors, even when OPCABG is performed. PMID- 22437060 TI - Hand-Sewn Proximal Anastomoses in Off-Pump Coronary Artery Bypass Without the Need for Partial Occlusion Clamping: Experience With the Heartstring II Proximal Seal System. AB - OBJECTIVE: : To evaluate the use of the Heartstring II Proximal Seal System (HPSS) in saphenous vein to aorta anastomoses in off-pump coronary artery bypass (OPCAB). METHODS: : The HPSS consists of an aortic cutter and a proximal seal system. A prospective study was done using the HPSS to facilitate proximal hand sewn anastomoses in OPCAB without partial occlusion clamping. Intraoperative observations, including technical success and post operative clinical data, were recorded. RESULTS: : Using the HPSS, 84 hand-sewn proximal saphenous vein-to aorta anastomoses were done in 50 patients. In no case was conversion to partial occlusion clamping required. After deployment of the HPSS, operator evaluation showed acceptable hemostasis in 83 of the grafts. One graft required redeployment of a second HPSS. Each bypass graft was evaluated using the Medtronic Medistem Flow Probe. Acceptable flow probe values were present in all grafts, and no revisions were required. The mean length of time for completion of the proximal anastomosis was 5 minutes (range, 4 to 14 minutes). Postoperative clinical evaluation showed no adverse events attributed to the use of the HPSS. CONCLUSIONS: : The use of HPSS is a safe and effective method to avoid partial occlusion clamping in hand-sewn proximal anastomoses with OPCAB. PMID- 22437061 TI - Use of the Purified Poloxamer 407 for Temporary Coronary Occlusion in Off-Pump CABG Does Not Cause Myocardial Injury. AB - OBJECTIVE: : The new poloxamer 407 (LeGoo), a thermoreversible gel, previously showed efficiency in temporarily occluding coronary arteries and preserving endothelial function. However, its long-term effect on the myocardium after dissolution in bloodstream is uncertain. METHODS: : Two groups of pigs (12 total) were compared after being submitted to a 10-minute coronary occlusion either with silastic loops (snare group) or with poloxamer 407 injection (P407 group). Reflow was procured by snare removal or P407 dissolution with topical cooling. Animals were kept alive for 3 days with creatine kinase-MB and troponin T (TnT) plasmatic measurement at 3 hours and 3 days after surgery, when they were killed for myocardial histopathologic study. RESULTS: : Each animal survived during the study. Baseline plasmatic levels of cardiac enzymes were similar between both groups. No variation in creatine kinase-MB level throughout the study was seen in either group. A significant rise in TnT from baseline was noted 3 hours after reperfusion in both groups, with a peak level significantly lower in the P407 group (P < 0.05). TnT plasmatic levels returned to baseline level in both groups on the day the animals were killed (3 days). Histopathologic examinations of the stained myocardial samples showed no evidence of myocardial infarction either in the snare group or in the P407 group. CONCLUSIONS: : Poloxamer 407 does not cause myocardial damage after elimination in the bloodstream. The safety of this hemostatic device is now established, and application for FDA approval for human clinical studies is under way. PMID- 22437062 TI - A new and safe device for minimally invasive saphenous vein harvesting: results after 100 cases. AB - PURPOSE: : The saphenous vein is the most commonly used bypass conduit for coronary surgery. Endoscopic harvesting techniques are associated with significant reduction of wound complications but are time-consuming and expensive. The authors developed a device to perform minimally invasive harvesting of the saphenous vein-rapidly, inexpensively, and safely. DESCRIPTION: : Patients hospitalized for isolated CABG (n = 134) participated in the study. Each vein had been harvested through the use of our minimally invasive system. EVALUATION: : The veins were harvested in 130 cases; 378 vein samples were collected for pathology study, with complete integrity of the vein as the result of the "no touch" technique with the device. This integrity could be very important for the long-term patency of the vein graft. After surgery, there were no wound dehiscences, infections, or major hematomas. There was 1 case (0.76%) of superficial hematoma and 3 cases (2.30%) of lymphoceles. CONCLUSIONS: : Although commercial disposable systems are now available to allow minimally invasive harvesting of the saphenous vein, the authors think that harvesting the greater saphenous vein with the cylinder steel device is easy to learn can be used safely and at much-reduced costs. PMID- 22437063 TI - Self-sealing antegrade cardioplegia system for video-assisted cardiac surgery: preliminary results. PMID- 22437065 TI - Letter to the editor. PMID- 22437064 TI - Traumatic suprahepatic inferior vena cava injury: surgical management. AB - SUMMARY: : Suprahepatic inferior vena caval (IVC) injuries are rare but carry nearly a 100% mortality rate. The main problem with its surgical management is the technical difficulty in draining the IVC during cardiopulmonary bypass. In this report, an efficient method of IVC drainage for repair of the IVC on cardiopulmonary bypass is described. PMID- 22437066 TI - Atypical fibroxanthoma and malignant fibrous histiocytoma: what the plastic surgeon should know. PMID- 22437068 TI - Influence of aspirin therapy in the ulcer associated with chronic venous insufficiency. AB - BACKGROUND: To determine the effect of aspirin on ulcer healing rate in patients with chronic venous insufficiency, and to establish prognostic factors that influence ulcer evolution. METHODS: Between 2001 and 2005, 78 patients with ulcerated lesions of diameter >2 cm and associated with chronic venous insufficiency were evaluated in our hospital. Of these, 51 patients (22 men, 29 women) with mean age of 60 years (range: 36-86) were included in a prospective randomized trial with a parallel control group. The treatment group received 300 mg of aspirin and the control group received no drug treatment; in both groups, healing was associated with standard compression therapy. During follow-up, held weekly in a blinded fashion, there was ulcer healing as well as cases of recurrence. Results were analyzed by intention-to-treat approach. Cure rate was estimated using Kaplan-Meier survival analysis, and the influence of prognostic factors was analyzed by applying the Cox proportional hazards model. RESULTS: In the presence of gradual compression therapy, healing occurred more rapidly in patients receiving aspirin versus the control subjects (12 weeks in the treated group vs. 22 weeks in the control group), with a 46% reduction in healing time. The main prognostic factor was estimated initial area of injury (P = 0.032). Age, sex, systemic therapy, and infection showed little relevance to evolution. CONCLUSIONS: The administration of aspirin daily dose of 300 mg shortens the healing time of ulcerated lesions in the chronic venous insufficiency (CVI). The main prognostic factor for healing of venous ulcerated lesions is the initial surface area of the ulcer. PMID- 22437069 TI - Selective use of percutaneous endovascular aneurysm repair in women leads to fewer groin complications. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) in women is often technically limited by smaller access vessel anatomy, particularly at the femoral and iliac artery levels. Percutaneous femoral artery access and closure using the "Preclose" technique (PERC) is a less invasive alternative to open surgical femoral arterial exposure and has been reported to be technically feasible, particularly in male cohorts. The purpose of this study was to evaluate the efficacy and access-related outcomes of PERC in women undergoing EVAR. METHODS: We identified female patients in a prospectively maintained EVAR database from 2000 to 2009. An all-percutaneous approach was adopted in 2007 if technically feasible, based on preoperative computed tomography angiogram criteria including a femoral diameter >7 mm, <25% posterior plaque and lack of circumferential calcification/disease. All percutaneous EVAR procedures were performed using two Perclose Proglide devices in a standardized manner for sheath sizes ranging between 12F and 26F. RESULTS: In period 1 (2000-2006), most cases were performed with open femoral exposure. In period 2 (2007-2009), our group adopted a percutaneous-first approach. Of 736 EVARs performed during the study period, 120 (16.3%) were in women, leading to 178 femoral arteries requiring large sheath access. Period 1 included 90 women and period 2 included 30 women who were evaluated for percutaneous access. During period 2, of the 47 eligible femoral arteries for possible PERC, 24 (51%) met appropriate criteria, and the Preclose technique was employed. The remaining 23 femoral arteries during period 2 were accessed with surgical exposure (OPEN). Technical success rate of PERC in period 2 was 96%, with one device pulling through a thin anterior arterial wall requiring open femoral conversion. During period 2, the OPEN cohort had a higher rate of total wound complications compared with PERC (34.8% vs. 8.3%, P = 0.02), including hematomas (8.7% vs. 0%), wound breakdowns (8.7% vs. 0%), and pseudoaneurysms (4.3% vs. 0%). There were two cases of femoral artery thrombosis in the PERC group requiring repair in the immediate postoperative period; however, this was not significantly different compared with the OPEN group (8.7% vs. 8.3%). CONCLUSIONS: Selective percutaneous access of the femoral arteries for EVAR is safe and effective in the female population, with fewer wound complications than open exposure. Approximately one-half of femoral arteries in women are eligible for PERC access, and complications can be limited with careful selection based on preoperative imaging. PMID- 22437070 TI - Perforation of the aorta by a rib edge: an unusual complication after chest wall resection. AB - Thoracic aortic perforation in the context of a minor trauma is extremely rare. In this article, we describe a case of an 80-year-old man who presented with an aortic perforation after a fall from his height during his hospitalization. The patient had previously undergone a left superior lobectomy, a partial chest wall resection, and reconstruction for a locally invasive lung cancer. He was directly transferred to the operating room, as he presented with hemodynamic instability. A 4-mm laceration in the descending thoracic aorta was identified and repaired. The postoperative course was uneventful. This case illustrates the importance of applying a solid fixation to the rib stumps when performing a chest wall resection, irrespective of the size of the wall defect. PMID- 22437071 TI - Endovascular management of iliac vein rupture during percutaneous interventions for occlusive lesions. AB - Iatrogenic Iliac vein rupture is a rare and potentially lethal complication. We present herein two different clinical scenarios of iatrogenic iliac vein rupture that resulted from performing percutaneous endoluminal interventions to treat symptomatic veno-occlusive lesions. The first case was due to the presence of surgical clips from the patient's previous gynecologic surgery, which caused iliac vein compression and eventually led to acute deep vein thrombosis. The second case resulted from central venous outflow obstruction ipsilateral to a lower extremity arteriovenous dialysis access site. Both Iliac vein ruptures were the result of percutaneous attempts to correct the outflow lesion (delayed in the first case and acute in the second case). Hemorrhage was successfully controlled in both cases using a self-expandable Viabahn (W. L. Gore and Associates, Flagstaff, AZ) covered stent while maintaining vessel patency and resolving symptoms related to veno-occlusive disease. PMID- 22437072 TI - Practices and perspectives on building integrated data repositories: results from a 2010 CTSA survey. AB - Clinical integrated data repositories (IDRs) are poised to become a foundational element of biomedical and translational research by providing the coordinated data sources necessary to conduct retrospective analytic research and to identify and recruit prospective research subjects. The Clinical and Translational Science Award (CTSA) consortium's Informatics IDR Group conducted a survey of 2010 consortium members to evaluate recent trends in IDR implementation and use to support research between 2008 and 2010. A web-based survey based in part on a prior 2008 survey was developed and deployed to 46 national CTSA centers. A total of 35 separate organizations completed the survey (74%), representing 28 CTSAs and the National Institutes of Health Clinical Center. Survey results suggest that individual organizations are progressing in their approaches to the development, management, and use of IDRs as a means to support a broad array of research. We describe the major trends and emerging practices below. PMID- 22437073 TI - Automated extraction of ejection fraction for quality measurement using regular expressions in Unstructured Information Management Architecture (UIMA) for heart failure. AB - OBJECTIVES: Left ventricular ejection fraction (EF) is a key component of heart failure quality measures used within the Department of Veteran Affairs (VA). Our goals were to build a natural language processing system to extract the EF from free-text echocardiogram reports to automate measurement reporting and to validate the accuracy of the system using a comparison reference standard developed through human review. This project was a Translational Use Case Project within the VA Consortium for Healthcare Informatics. MATERIALS AND METHODS: We created a set of regular expressions and rules to capture the EF using a random sample of 765 echocardiograms from seven VA medical centers. The documents were randomly assigned to two sets: a set of 275 used for training and a second set of 490 used for testing and validation. To establish the reference standard, two independent reviewers annotated all documents in both sets; a third reviewer adjudicated disagreements. RESULTS: System test results for document-level classification of EF of <40% had a sensitivity (recall) of 98.41%, a specificity of 100%, a positive predictive value (precision) of 100%, and an F measure of 99.2%. System test results at the concept level had a sensitivity of 88.9% (95% CI 87.7% to 90.0%), a positive predictive value of 95% (95% CI 94.2% to 95.9%), and an F measure of 91.9% (95% CI 91.2% to 92.7%). DISCUSSION: An EF value of <40% can be accurately identified in VA echocardiogram reports. CONCLUSIONS: An automated information extraction system can be used to accurately extract EF for quality measurement. PMID- 22437074 TI - Intensive care unit nurses' information needs and recommendations for integrated displays to improve nurses' situation awareness. AB - OBJECTIVE: Fatal errors can occur in intensive care units (ICUs). Researchers claim that information integration at the bedside may improve nurses' situation awareness (SA) of patients and decrease errors. However, it is unclear which information should be integrated and in what form. Our research uses the theory of SA to analyze the type of tasks, and their associated information gaps. We aimed to provide recommendations for integrated, consolidated information displays to improve nurses' SA. MATERIALS AND METHODS: Systematic observations methods were used to follow 19 ICU nurses for 38 hours in 3 clinical practice settings. Storyboard methods and concept mapping helped to categorize the observed tasks, the associated information needs, and the information gaps of the most frequent tasks by SA level. Consensus and discussion of the research team was used to propose recommendations to improve information displays at the bedside based on information deficits. RESULTS: Nurses performed 46 different tasks at a rate of 23.4 tasks per hour. The information needed to perform the most common tasks was often inaccessible, difficult to see at a distance or located on multiple monitoring devices. Current devices at the ICU bedside do not adequately support a nurse's information-gathering activities. Medication management was the most frequent category of tasks. DISCUSSION: Information gaps were present at all levels of SA and across most of the tasks. Using a theoretical model to understand information gaps can aid in designing functional requirements. CONCLUSION: Integrated information that enhances nurses' Situation Awareness may decrease errors and improve patient safety in the future. PMID- 22437075 TI - Leveraging medical thesauri and physician feedback for improving medical literature retrieval for case queries. AB - OBJECTIVE: This paper presents a study of methods for medical literature retrieval for case queries, in which the goal is to retrieve literature articles similar to a given patient case. In particular, it focuses on analyzing the performance of state-of-the-art general retrieval methods and improving them by the use of medical thesauri and physician feedback. MATERIALS AND METHODS: The Kullback-Leibler divergence retrieval model with Dirichlet smoothing is used as the state-of-the-art general retrieval method. Pseudorelevance feedback and term weighing methods are proposed by leveraging MeSH and UMLS thesauri. Evaluation is performed on a test collection recently created for the ImageCLEF medical case retrieval challenge. RESULTS: Experimental results show that a well-tuned state of-the-art general retrieval model achieves a mean average precision of 0.2754, but the performance can be improved by over 40% to 0.3980, through the proposed methods. DISCUSSION: The results over the ImageCLEF test collection, which is currently the best collection available for the task, are encouraging. There are, however, limitations due to small evaluation set size. The analysis shows that further refinement of the methods is necessary before they can be really useful in a clinical setting. CONCLUSION: Medical case-based literature retrieval is a critical search application that presents a number of unique challenges. This analysis shows that the state-of-the-art general retrieval models are reasonably good for the task, but the performance can be significantly improved by developing new task-specific retrieval models that incorporate medical thesauri and physician feedback. PMID- 22437076 TI - Lymphotoxin-beta receptor activation on macrophages ameliorates acute DSS-induced intestinal inflammation in a TRIM30alpha-dependent manner. AB - Our previous studies indicated that LTbetaR activation mainly by T cell derived LTalpha1beta2 is crucial for the control and down-regulation of intestinal inflammation. In order to dissect the cellular and molecular role of LTbetaR activation in the experimental model of DSS-induced intestinal inflammation, we have generated cell type-specific LTbetaR-deficient mice with specific ablation of LTbetaR expression on macrophages/neutrophils (LTbetaR((flox/flox))*LysM-Cre). These mice develop an exacerbated intestinal inflammation in our experimental model indicating that LTbetaR expression on macrophages/neutrophils is responsible for the control and down-regulation of the inflammatory reaction. These results were verified by adoptive transfer experiments of BMDM from wild type and LTbetaR-deficient mice. Furthermore, transfer of activated CD4+ T cells derived from wild-type mice, but not from LTbetaR ligand-deficient mice attenuated the signs of intestinal inflammation. Finally, we demonstrate that LTbetaR activation on BMDM results in induction of TRIM30alpha, a negative regulator of NFkappaB activation. Concordantly, ablation of LTbetaR signaling results in the inability to induce TRIM30alpha expression concomitant with an increased expression of pro-inflammatory cytokines in our experimental model. Taken together, our data demonstrate that LTbetaR activation on macrophages by CD4+ T cell derived LTalphabeta controls the pro-inflammatory response by activation of a TRIM30alpha-dependent signaling pathway, crucial for the down regulation of the inflammatory response in this experimental model. PMID- 22437077 TI - Role of macrophage scavenger receptors in atherosclerosis. AB - Accumulating evidence indicates that atherosclerosis is a chronic inflammatory disease. The key innate immune cells that are involved in the pathogenesis of atherosclerosis are circulating monocytes and plaque macrophages. Complex interplay between immune and metabolic processes results in pathological activity of these cells. The best understood pathological process mediated by macrophages is their inability to process modified lipoproteins properly resulting in the formation of foamy cells, which are a dangerous component of atherosclerotic plaques. Key molecules involved in the recognition and processing of modified lipoproteins are scavenger receptors (SR). This is a large family of surface expressed structurally heterogeneous receptors with a broad spectrum of endogenous and exogenous ligands. The common functional feature of SR is internalisation of extracellular components and targeting them for lysosomal degradation. However, these relatively simple functions can have complex consequences, since they are linked to diverse specific signalling pathways and to other membrane transport pathways. Moreover, scavenger receptors can co operate with other types of receptors increasing the variability of the macrophage response to multiple extracellular ligands. At least some SRs respond to modified lipoproteins by amplification of inflammation and accumulation of macrophages in the plaque, while some SRs may support tolerogenic reactions. Outcome of different SR activities will be the decision of monocytes and macrophage to guard homeostatic balance, support atherosclerosis progression and plaque instability by inflammatory reactions, or support rapid fibrotic processes in the plaque that stabilise it. Despite the accumulating knowledge about the molecular mechanisms of scavenger receptor action, their role in the progression of atherosclerosis remains controversial. The activities of scavenger receptors that can contribute to each of these processes are a subject of current review. PMID- 22437078 TI - Preparation of highly oxidized nitrogen-doped carbon nanotubes. AB - A method for the preparation of highly oxidized nitrogen-doped carbon nanotubes (N-CNTs) from KMnO(4) + H(2)SO(4) solution is described. The atomic ratio of C/O in oxidized N-CNTs is as low as 1.2. The x-ray photoelectron spectroscopy results show that about 75% of the carbon atoms are oxidized and bound to oxygen containing functional groups. The oxidation reaction mainly occurs at the outer sidewalls, which destroys the graphene stack to an sp(3)-rich structure and helps to preserve the tubular structure of the inner N-CNTs. The oxidized N-CNTs show an energy gap of ~2.1 eV. PMID- 22437079 TI - Partograph as a tool for team work management of spontaneous labor. AB - It is presently being debated whether the partograph is a useful tool for labor supervision and, if useful, where should the action line be located between 2, 3 or 4 h to improve the fetomaternal outcome. This review adduces facts to show that this debate is because there is a poor understanding of the essence and purpose of the partograph. The partograph is a form on which labor observations are recorded to provide an overview of labor, aiming to alert midwives and obstetricians to deviations in labor progress as well as maternal and fetal wellbeing. When deviations in labor progress are recognized early and corrected, complications are prevented and normal labor and delivery can occur. The earliest deviation in labor progress is slow labor progress, for which the partograph alert line is a prompt for early recognition by the midwives and other non obstetric staff. The intervention to correct the deviation is at the action line by the staff with the requisite skill. In the circumstance in which the partogram was produced, the action to correct the deviation in labor progress was after 4 h, represented by the 4-h action line, but other workers have attempted with 2- and 3-h action lines and have had equally good results. However, in all these, the action at the action line was instituted by the staff with the appropriate skill, irrespective of whether the action line was 2, 3 or 4 h. As long as the action at the action line is by the staff with the requisite training, the deviation in labor progress will be corrected by either medical or surgical means irrespective of the action line location at 2, 3 or 4 h. In conclusion, the essence and purpose of the partograph is to ensure that labor progress is monitored to identify slow labor by the alert line but appropriate treatment must begin at the action line by the staff with the cognate skill, whether at 2, 3 or 4 h. The appropriateness of the intervention at the action line is the determinant of the outcome and not the delay. PMID- 22437080 TI - Review of hormonal treatment of breast cancer. AB - This critical review focuses on the role of steroid hormones and their receptors in the development and treatment of breast cancer, with special reference to estrogen receptors, as well as mechanisms of receptor-ligand interactions, response or resistance to hormonal therapy against breast cancer, in conjunction with other modalities like surgery and chemotherapy. Tamoxifen is used in hormonal treatment of breast cancer for up to five years, depending on the presentation. However, there have been recent developments in hormonal therapy of breast cancer in the last ten years, with the introduction of many different alternative therapies for this condition. A critical review of published articles in Pubmed/Medline, Athens, AJOL, NHS Evidence, Science Direct and Google, relating to hormonal treatment of breast cancer, was undertaken, in order to evaluate the mechanisms of estrogen receptor-ligand interactions, their involvement in the etio-pathogenesis of breast cancer, resistance of breast cancer cells to anti-hormonal agents, as well as ways of treating breast cancer using anti-hormone drugs like tamoxifen. Although tamoxifen is the established drug for hormonal treatment of breast cancer, cases of hormone resistance breast cancer have been described recently in the literature. This can happen from the beginning, or during treatment. Therefore, we aim to examine the causes of resistance to hormonal treatment with a view to understand the options of tackling this problem, and suggest other novel alternative hormonal therapies that can be tried, which may overtake tamoxifen in the future. We also seek to emphasize that hormonal therapy has a definite place in the treatment of breast cancer along with surgery, chemotherapy and radiotherapy, as the disease is often considered to be multi-systemic even from the beginning. PMID- 22437081 TI - Control to goal of cardiometabolic risk factors among Nigerians living with type 2 diabetes mellitus. AB - BACKGROUND: Cardiovascular risk factors contribute to morbidity and mortality among diabetic patients. National and international guidelines on management of diabetes therefore emphasize control to goals of blood glucose, blood pressure, dyslipidemia, and obesity so as to minimize the development of complications and enhance the patients' quality of life. OBJECTIVE: To evaluate the status of control to goals of cardiometabolic risk factors among the diabetic patients attending the Diabetes clinic of University of Nigeria Teaching Hospital, Enugu. MATERIALS AND METHODS: A survey of 233 type 2 diabetic patients recruited from the Diabetes clinic of our hospital was carried out. Standard procedures as described in the WHO STEP instrument were used to determine the waist circumference, weight, height, and systolic and diastolic blood pressure. Fasting blood glucose and lipid profiles were also assessed. Therapeutic goals used to define risk or poor control were values adopted by expert groups such as American diabetes association (ADA), National cholesterol education program (NCEP), American association of clinical endocrinologist (AACE) and International diabetes federation (IDF). RESULTS: There were 98 males and 135 females with mean (SD) duration of diabetes mellitus (DM) of 6.7 (6.3) years. Suboptimal glycemic, blood pressure control and dyslipidemia were observed in 65.7%, 51.9%, 97.1% of the subjects respectively while 60.1% of the subjects were found to be overweight/obese. Comparing the mean indices of risk factors with the recommended therapeutic goals, status of control was optimal for HDL-cholesterol, waist circumference and triglycerides. All the other risk factors were suboptimal. CONCLUSION: Control to goals of cardiovascular risk factors is poor among the patients. There is the need to identify and tackle the possible contributing factors so as to reduce the morbidity and mortality in these patients. PMID- 22437082 TI - Epidemiology of armed robbery-related gunshot injuries in Maiduguri, Nigeria. AB - BACKGROUND AND OBJECTIVES: Gunshot Injuries used to be rare in Nigeria until the civil war of 1967-1970. Unfortunately, it has become very rampant recently. The objective of this paper is to look at the epidemiology of armed robbery-related gunshot injuries as seen in the University of Maiduguri Teaching Hospital over a five-year period. MATERIALS AND METHODS: Data on patients that presented with gunshot injuries within the study period (January 2002 to December 2006) were collected and analyzed retrospectively. RESULTS: We studied 129 patients with gunshot injuries that were managed during the study period. This comprises of 117 males and 12 females (M:F=9.8:1). Eighty four (65.1%) were young males between 20 and 40 years. One hundred and fifteen (89.2%) of the 129 victims were shot by armed robbers, the remaining 14 (10.8%) were shot under other circumstances not related to armed robbery. Analysis of the time of attack revealed 72% of victims were attacked at night. Over 80% of victims were shot along the highway. The anatomical sites of gunshot entry wound show the extremities having the highest of 46.1%. Ninety one (79.1%) victims were treated operatively while 16 (13.9%) were treated nonoperatively. CONCLUSION: Armed robbery is the motive behind most gunshot injuries in Nigeria. Most of these attacks are preventable if the government would support and motivate the security apparatus responsible. There is also need for the government to support the victims by shouldering their treatment and subsequent rehabilitation. PMID- 22437083 TI - Relationships between hemoglobin A 1c and spot glucose measurements in Nigerians with type 2 diabetes mellitus. AB - BACKGROUND: Glycosylated hemoglobin, HbA 1c is the most acceptable measure of chronic glycemia. It is not widely available and/or affordable in Nigeria. The mean of the monthly fasting plasma glucose (MFPG) of the preceding 3 months is often used as surrogate for assessing chronic glycemia. OBJECTIVE: To determine the relationships among fasting plasma glucose (FPG), 2-hour post-prandial glucose (2-hPG), HbA1c, and MFPG. MATERIALS AND METHODS: Hospital records were used to derive the MFPGs of diabetic subjects from the mean of their monthly FPGs of the preceding three months. Other data extracted included the patient's age, sex, body mass index (BMI), waist circumference (WC), and duration of diabetes mellitus (DMDU). FPG, 2- hPG and HbA 1c were determined during this index consultation. RESULTS: Ninety five persons (65 males, 30 females) with type 2 were included in the study. Their mean age and DMDU were 54.7 +/- 8.9 years and 8.1 +/- 6.1 years, respectively. Their mean WC, BMI, FPG, 2-hPG, HbA1c, and MFPG were 100.2 +/- 11.0 cm, 24.2 +/- 4.3 kgm/2, 7.5 +/- 2.4 mmol/l, 10.4 +/- 4.1 mmol/l, 8.2 +/- 2.2%, and 5.9 +/- 2.2 mmol/l, respectively. The males were significantly older (57.5 +/- 8.4 vs 49.3 +/- 7.6, P<0.001) while the females had higher waist circumference and BMI than their male counterparts: 104.8 +/- 11.6 cm vs 92.8 +/- 10.1 cm, P<0.004; and 25.8 +/- 4.9 kg/m 2 vs 23.3 +/- 3.7 kg/m 2 , P<0.005, respectively. There were no significant differences in FPG, 2-hPG, MFPG and HbA1c levels between male and female subjects. There were significant positive correlations between FPG and HbA1c (r=0.45, P=0.05) and between 2-hPG and HbA1c (r=0.52, P=0.01), but there was no positive correlation between MFPG and HbA1c (r=-0.20, P=0.18). CONCLUSION: There is no positive correlation between MFPG and HbA 1c and thus MFPG may not be a good surrogate for HbA1c in assessment of chronic glycemia in our patients. PMID- 22437084 TI - Pattern of morphine prescription by doctors in a Nigeria tertiary hospital. AB - BACKGROUND: Morphine was reintroduced into Nigeria after a long period of absence due to technical problems relating to stock accounting. With this reintroduction, prescriber education was commenced in many centers including the University of Ibadan. AIMS AND OBJECTIVE: The aim of this study is to review the morphine prescription habits of the medical doctors practicing at the University College Hospital, Ibadan, and to assess the level of conformity with international guidelines. MATERIALS AND METHODS: All the prescriptions on oral morphine in the hospital's pharmacy records within a 6 months period were reviewed. RESULTS: The results showed that more than half (51.7%) of all morphine prescriptions were from the Radiation Oncology Department, while the newly created Day Care Hospice Unit accounted for 31.8% of the prescriptions. No prescriptions were seen from the Labor ward. Only 1.1% of all the prescriptions conformed to international guideline as contained in the "Blue Book." CONCLUSION: The results showed that there is a need for more education and advocacy programmes to increase awareness among doctors about morphine prescriptions. PMID- 22437085 TI - Serum antioxidant vitamins and the risk of oral cancer in patients seen at a tertiary institution in Nigeria. AB - OBJECTIVES: Tobacco and alcohol are major risk factors of oral cancer, but nutritional deficiency may also contribute to development of oral cancer. This study compared serum antioxidant vitamin levels in oral cancer patients and controls in order to validate the role of vitamin deficiencies in the etiology of oral cancer. MATERIALS AND METHODS: Serum vitamin A, C, and E levels of 33 oral cancer patients and 30 controls at University College Hospital, Ibadan, Nigeria, were determined using standard methods. The data obtained were analyzed using the Student t-test, odds ratio, and logistic regression. RESULTS: Mean vitamin A, C, and E levels were significantly lower in oral cancer patients (P=0.022, P=0.000, and P=0.013 respectively). Risk of oral cancer was 10.89, 11.35, and 5.6 times more in patients with low serum vitamins A, C, and E, respectively. However, on logistic regression analysis, only low serum vitamin E independently predicted occurrence of oral cancer. CONCLUSIONS: The lower serum vitamin A, C, and E levels in oral cancer patients could be either a cause or an effect of the oral cancer. Further studies using a larger sample size and cohort studies with long term follow-up of subjects are desirable. PMID- 22437086 TI - Complication rates of open transvesical prostatectomy according to the Clavien Dindo classification system. AB - BACKGROUND: Traditional open prostatectomies either transvesical or retropubic remains the reference standard for managing benign prostatic enlargement in some centers, especially in developing countries. The comparison of complication rates between the various types of open prostatectomies is usually a source of significant debate among urologists, most times with conflicting results. The Clavien-Dindo classification system is an excellent attempt at standardization of reporting complications associated with surgeries. MATERIALS AND METHODS: We reviewed retrospectively the records of patients who had open transvesical prostatectomy (TVP) in three specialist urology centers in Anambra state, Southeast Nigeria, over a period of 5 years (January 2004-December 2009), with the aim of documenting medical and surgical complications arising from open TVP. These complications were then categorized according to the Clavien-Dindo system. RESULTS: A total of 362 patients had open TVP over the period under review. Of this number, 145 had documented evidence of complications. The mean age of the patients was 66.3 years (SD 9.4 years; range 49-96 years). The mean follow-up period was 27.8 months (SD 12.6 months; range 6-33 months). The overall complication rate for open TVP in this study was 40.1% (145/362). Complication rates for grades i, id, ii, iiia, and iiib were 0.8%, 0.6%, 35.1%, 0.6%, and 3.0%, respectively. Most complications of open TVP occur in the early postoperative period. CONCLUSION: Open TVP still remains a valid surgical option in contemporary environment where advanced techniques for transurethral resection of the prostate and laparoscopic prostatectomy are unavailable. Most complications occur in the early postoperative period, with bleeding requiring several units of blood transfusion accounting for the commonest complication. This should be explained to patients during the preoperative counselling. PMID- 22437087 TI - Pattern and presentation of spine trauma in Gwagwalada-Abuja, Nigeria. AB - OBJECTIVE: The objective was to demonstrate the correlations and effects of age, gender, and cause of accident on the type of vertebral fracture as well as on the likelihood to sustain neurological deficit following trauma in Nigeria. BACKGROUND: Spinal column injury is a well-documented problem but literature has been mute on this problem in Nigeria unlike the many papers on spinal cord injury. MATERIALS AND METHODS: A retrospective review of spinal cord injured (SCI) patients was performed. Age, sex, cause and level of injury, fracture pattern and distribution, and neurologic presentation of SCI patients from 1997 to 2007 were studied from case notes. RESULTS: There were 202 patients with male preponderance and a mean age of 38.9 +/- 11.4 years over the 11-year period. The most common cause of spine injury was road traffic injury (79.7%). Cervical spine injury (10.4%) accounted for the highest number of cases with complete neurologic deficit. The majority of patients, 119 (58.9%) sustained a type A fracture, 37 (18.3%) a type B fracture, and 41(20.3%) patients experienced a type C fracture. All patients had neurologic deficits. Age (P=0.032) and road traffic injury (P=0.029) were independently associated with type of fracture after multivariate analysis. Age (P=0.038), road traffic injury (P=0.027), and cervical spine fracture (P=0.009) were also independently associated with neurologic deficit. CONCLUSION: These data showed the correlation between trauma mechanism and the type of fracture seen, and also the type of fracture and the incidence of neurologic deficit. The predictors of fracture types are age and road traffic injury while age, road traffic injury, and cervical spine fractures predict neurologic deficit. PMID- 22437088 TI - Therapeutic effect of a moderate intensity interval training program on the lipid profile in men with hypertension: a randomized controlled trial. AB - OBJECTIVE: Physical inactivity has been established as a major primary risk factor for the development of hypertension. Also, factors such as elevated total cholesterol (TC) and reduced high density lipoprotein cholesterol (HDL) have been implicated as risk factors for coronary events in hypertension. The purpose of the present study was to investigate the effect of interval training program on blood pressure and lipid profile of subjects with hypertension. MATERIALS AND METHODS: A total of 245 male patients with mild-to-moderate hypertension (systolic blood pressure [SBP] between 140 and 180 mmHg and diastolic blood pressure [DBP] between 90 and 109 mmHg) were age matched and grouped into interval and control groups. The interval (n=140; 58.90 +/- 7.35 years) group was involved in an 8-week interval training (60-79% HR max reserve) program of between 45 minutes and 60 minutes at a work/rest ratio of 1:1 of 6 minutes each, while the control hypertensive (n=105; 58.27 +/- 6.24 years) group remained sedentary during this period. Cardiovascular parameters (SBP and DBP), VO 2 max, TC, HDL, and artrogenic index (AI) were assessed. Student's t-test and Pearson correlation test were used in data analysis. RESULTS: Findings of the study revealed significant decreased effects of the interval training program on SBP, DBP, TC AI, and significant increased effects on VO 2 max and HDL level at P<0.05. There was also a significant correlation between changes VO 2 max and changes in AI. CONCLUSIONS: It was concluded that the interval training program is an effective adjunct nonpharmacological management of hypertension and a means of upregulation of HDL. PMID- 22437089 TI - Diagnosis of prostate cancer with needle biopsy: should all cases be biopsied before treatment? AB - BACKGROUND: The triad of digital rectal examination (DRE), serum prostate specific antigen, and transrectal ultrasound-guided prostate biopsy is used in the detection of prostate cancer (PCa). It is recommended that all cases of PCa should be diagnosed with needle biopsy before treatment. The exclusion criteria for those that may not be suitable have not yet been defined. MATERIALS AND METHODS: We reviewed all the patients diagnosed with PCa at the Nnamdi Azikiwe University Teaching Hospital Nnewi, Southeast, Nigeria, from January 2007 to December 2010. Relevant biodata and method of diagnosis of PCa before treatment were reviewed. RESULTS: A total of 133 patients had bilateral orchidectomy over the period. 120 (90.2%) had their diagnosis confirmed by needle biopsy before bilateral orchidectomy (category 1), while 13 (9.8%) had bilateral orchidectomy before diagnosis was confirmed. The method of diagnosis for category 1 patients was with lower urinary tract symptoms (LUTS), abnormal DRE findings, elevated prostate-specific antigen (PSA), and transrectal needle biopsy. For category 11 patients, diagnosis of PCa was suspected based on LUTS, abnormal DRE findings, and elevated PSA. Of this number, 11 (84.6%) had, in addition, sudden onset paraplegia at presentation, while 2 (15.4%) had severe uncontrolled hematuria at presentation. All the patients in both categories had needle biopsy confirmation of their disease. The sensitivity of PSA was 99.2%. CONCLUSION: Needle biopsy of the prostate is the preferred method for the diagnosis of PCa in most cases before treatment is undertaken. There are valid reasons why all PCas will not be diagnosed in this fashion. Elevated PSA when combined with an abnormal DRE finding increases the predictive value for cancer. In areas where pathologists are lacking, abnormal DRE and elevated PSA results can be a guide to proceed to treatment especially, where there is severe compromise of patients' quality of life due to symptoms of advanced PCa while awaiting confirmation. PMID- 22437090 TI - Some emerging issues in medical admission pattern in the tropics. AB - BACKGROUND: There is a changing pattern in terms of medical admissions worldwide with an alarming increase in the prevalence of noncommunicable diseases, especially in the tropics over the last decade. The aim of this study was to describe the pattern of medical admission and highlight emerging issues of noncommunicable diseases in a Nigerian University Teaching Hospital. MATERIALS AND METHODS: A retrospective review of medical admission at the Ladoke Akintola University of Technology Teaching Hospital, Osogbo, South Western Nigeria, over a 3 years period (January 2005 to December 2007). Data were retrieved from the medical records of all medical admission over the study period. RESULTS: During the study period, 1786 patients were admitted into the medical wards. This consisted of 1089 males (61.0%) and 697 females (39.0%). Their ages ranged from 14 to 96 years with mean ages of 51 +/- 16.89 years. Subjects >=60 years of age accounted for 27.3% and 29.8% of total males and female admissions which were the largest age group. Noncommunicable diseases were responsible for 47.99% of total medical admissions. The indications for admission in order of frequency include cerebrovascular accidents 239 (13.4%), diabetes mellitus 194 (10.9%), tuberculosis 151 (8.5%), and chronic kidney disease 116 (6.5%). Hypertension was the underlying risk factor in majority of patients with CVD and CKD. CONCLUSION: Noncommunicable disease accounted for a significant number of admissions over 3 year duration. The elderly accounted for a major age group admitted for medical diseases. Therefore, preventive strategies against noncommunicable disease and effective geriatric care are advocated. PMID- 22437091 TI - Antioxidant status of type 2 diabetic patients in Port Harcourt, Nigeria. AB - CONTEXT: Oxidative stress has been implicated in the pathogenesis of type 2 diabetes mellitus (T2DM) and its complications. AIMS: This study was conducted to determine and compare total antioxidant status (TAS), vitamin C and E levels in T2DM patients and healthy control subjects. SETTINGS AND DESIGN: Fifty-five previously diagnosed DM patients aged between 34 years and 70 years and 50 control subjects aged between 35 years and 69 years were consecutively recruited into this study. MATERIALS AND METHODS: Blood pressure (mmHg), body mass index (kg/m 2 ), concentrations of plasma glucose (mmol/l), lipid profile (mmol/l), TAS (mmol/l), vitamins C (MUmol/l), and E (MUmol/l) were determined in all participants. STATISTICAL ANALYSIS USED: Statistical Package for Social Sciences (SPSS) version 11.0 was used for statistical analysis. RESULTS: The mean plasma TAS (1.18 +/- 0.27 mmol/l), vitamin C (26.59 +/- 7.39 MUmol/L) and vitamin E (15.33 +/- 4.05 MUmol/l) of T2DM patients were significantly lower (P=0.0001 for all) than those of controls (1.58 +/- 0.28 mmol/l, 43.56 +/- 6.86 MUmol/l, 31.22 +/- 6.20 MUmol/l respectively). TAS had a positive correlation with vitamin E (r=0.588; P=0.013) but no correlation with vitamin C (r=-0.387; P=0.139) among diabetics. CONCLUSIONS: TAS, vitamin C and E levels are reduced in T2DM patients compared with those of controls. PMID- 22437092 TI - Utilization of health care services by depressed patients attending the general out-patients department of the Jos University Teaching Hospital, Jos, Nigeria. AB - BACKGROUND: Depression is a common psychiatric disorder in primary health care throughout the world with increasing incidence and prevalence. It is often under treated and under-diagnosed. Consequently, several studies have revealed that patients with depression are high utilizers of medical services. OBJECTIVES: The study was aimed at determining the frequency of consultation and the utilization of investigative procedures by the depressed and non-depressed patients in the last 12 months. MATERIALS AND METHODS: This was a cross-sectional descriptive study among 200 consecutive patients attending the General Out-Patient Department of the Jos University Teaching Hospital between November 2006 and March 2007. A semi-structured questionnaire was used to collect socio-demographic data and health services utilization indices. Structured Clinical Interview for DSM-IV axis-1 Disorders (SCID) was used for diagnosis of depression. RESULTS: The study found that 51(25.5%) of the respondents met DSM-IV criteria for the diagnosis of major depression while 149 (74.5%) did not. Depressed patients significantly had more number of consultations with their doctors (P=0.000), had consulted more number of hospitals (P=0.000), stayed longer on admission (P=0.000) and had consumed more types of medicine (P=0.005) in the last 12 months compared with the non-depressed. The depressed patients also had significantly higher mean of different types of investigations compared with non-depressed; urinalysis (1.69 vs 0.55, P=0.000), chest X-ray (0.57 vs 0.21, P=0.000) and Widal test (1.92 vs 0.39, P=0.000). Others are HIV screening (0.39vs0.11, P=0.000) urine mcs (0.94 vs 0.18, P=0.000), stool mcs (1.24 vs 0.20, P=0.000). CONCLUSION: The study demonstrated that patients who suffer from depression are higher utilizers of health care resources compared with the non-depressed. Therefore, it is recommended that general practitioners and other health workers need to be better equipped to deal with the diagnosis and management of depression. PMID- 22437093 TI - Period of onset and lack of clinical manifestation of hepatotoxicity after commencing highly active antiretroviral therapy. AB - AIM: The period of onset of hepatotoxicity varies between cohorts as do their clinical manifestations. Clinical manifestations of hepatotoxicity that have been previously reported include fatal portal hypertension, dress syndrome, and lipodystrophy syndrome. The aim of this study was to determine the period of onset and clinical manifestation of hepatotoxicity after commencing HAART. MATERIALS AND METHODS: This study was carried out on patients with HIV on HAART attending infectious disease clinic, gastroenterology clinic or admitted into the medical wards of University of Benin Teaching Hospital. Patients with HIV but not on HAART were used as controls. A clinical evaluation and relevant laboratory investigations were done. Hepatotoxicity was defined using a standardized toxicity grade scale. RESULTS: A total of 84 cases and 42 controls were studied. The mean ages were 35.2 +/- 9.9 years and 35.5 +/- 9.0 years for the cases and the controls respectively. Over 70% of the study population and controls were females. The overall incidence of hepatotoxicity was 17.85% and severe hepatotoxicity occurred in 10.71% of the patients. Over 80% of liver enzyme elevations occurred within 3 months, most of which were asymptomatic. CONCLUSION: This study shows that over 80% of enzyme elevations occurred within 3 months and were mostly asymptomatic. There is a need for regular monitoring of liver function tests at short intervals in HIV patients starting HAART since most of the cases of hepatotoxicity found in this study occurred early and were asymptomatic. PMID- 22437094 TI - The differential impact of two anesthetic techniques on cortisol levels in Nigerian surgical patients. AB - BACKGROUND: Surgical procedures are associated with a complexity of stress response characterized by neurohumoral, immunologic, and metabolic alterations. AIM: The aim was to compare the effects on the stress response by isoflurane based intratracheal general anesthesia (ITGA) and bupivacaine-based epidural anesthesia (EA), using cortisol as a biochemical marker. MATERIALS AND METHODS: Following the approval of the Hospital Ethical Board, informed written consent from patients recruited into this study was obtained. One group received general anesthesia with relaxant technique (group A) while the other group had bupicaine epidural anesthesia with catheter placement for top-ups (group B) for their surgeries. Both groups were assessed for plasma cortisol levels - baseline, 30 minutes after skin the start of surgery and at skin closure. RESULTS: There was no statistically significant difference in the baseline mean heart rate, mean arterial pressure (mean MAP) and the mean duration of surgery between the two groups; the baseline mean plasma cortisol level was 88.70 +/- 3.85 ng/ml for group A and 85.55 +/- 2.29 ng/ml for group B, P=0.148. At 30 minutes after the start of surgery the plasma cortisol level in the GA group was 361.60 +/- 31.27 ng/ml while it was 147.45 +/- 22.36 ng/ml in the EA group, showing a significant difference, P=0.001. At skin closure the mean plasma cortisol value of 384.65 +/- 48.04 ng/ml recorded in the GA group was found to be significantly higher than the value of 140.20 +/- 10.74 ng/ml in the GA group, P<0.002. CONCLUSION: Using plasma cortisol as a measure, bupivacaine-based epidural anesthesia significantly reduces the stress response to surgical stimuli when compared with isoflurane based tracheal general anesthesia. PMID- 22437095 TI - Anesthetic equipment, facilities and services available for pediatric anesthesia in Nigeria. AB - BACKGROUND: Facilities and equipment are known to contribute to improved patient care and outcome. Hospitals for sub-specialized pediatric anesthetic service are routinely available worldwide. In Nigeria, such hospitals now exist. It is therefore relevant to study the facilities and equipment available for pediatric anesthetic service to measure the quality of care in a health institution. MATERIALS AND METHODS: A prospective study of the anesthetic equipment, facilities and services available for pediatric anesthesia was carried out in Nigerian hospitals using anonymously administered questionnaires from October, 2008 to October, 2009, after relevant ethics approval. RESULT: Ten of the 30 hospitals studied had intensive care unit facilities (33.3%) and only three of them had organized ambulatory anesthesia units for pediatric patients (10%). Facilities available for pediatric anesthetic care were service delivery oriented and not information technology based (automated anesthesia information management services - AIMS). A quarter of the hospitals studied (7) had their facilities and equipment updated recently. Also, there were no reception rooms nor post anesthetic care units specifically designed for pediatric patients. Equipment for acute pain service such as infusion pumps and patient controlled analgesia pumps (PCA pumps) and for capnography were found in only two hospitals (6.6%) at the time of the study. The anesthetic equipment used did not conform to the same standards (98%) even in the same hospital. Also, the use of disposable anesthetic equipment was low. CONCLUSION: We conclude that anesthetic services for pediatric patients should be based on the use of automated anesthesia information technology service. Anesthetic equipment should conform to the same standards and should be computerized. Disposable anesthetic equipment should also be used where applicable to minimize the incidence of nosocomial infections. This would result in improved peri-operative care in pediatric patients. PMID- 22437096 TI - Perceptions of female sexual health and sexual dysfunction in a cohort of urban professional women in Abuja, Nigeria. AB - CONTEXT: Data on sexual health behaviors, and the prevalence and risk factors for female sexual dysfunction (FSD) are rare, particularly from sub-Saharan Africa. AIMS: This study was to briefly investigate the perceptions of a cohort of adult urban female professionals about female sexual health and sexual dysfunction awareness. PATIENTS AND METHODS: Fifty female hospital staff attending an introductory seminar on FSD participated in this study by completing a 15-item questionnaire on some aspects of female sexual health. Questions asked ranged from sexual activity in the preceding 6 months, menopausal status, if they thought they had sexual dysfunction to their willingness to discuss an FSD with a sexual health physician if they had access to one. RESULTS: Over 50% (n=28) of the respondents had an idea about what FSD was before the survey. These respondents further defined FSD as either the inability of a female to respond to sex, a lack of urge to engage in sexual activities, or inability to attain orgasm. About half of the respondents (n=21) did not know that FSD could be managed; however, 70% of them felt comfortable with discussing FSD symptoms with a sexual health practitioner.76.9% of the respondents who thought they had symptoms of FSD in this series (n=10) were willing to see a sexual health expert if they had access to one. CONCLUSIONS: This study provides a brief insight into FSD awareness amongst apparently healthy female workers of a health care facility and the need for further community-based studies on female sexual health issues in our society. Furthermore, it highlights the appropriateness of a comprehensive sexual medicine service in tertiary health care facilities in Nigeria for adequate screening and diagnosis of patients before appropriate treatment of FSD. PMID- 22437097 TI - Psychiatric morbidity in hypertensives attending a cardiology outpatient clinic in West Africa. AB - OBJECTIVES: To determine kinds of psychiatric morbidity among a sample of stable hypertensive outpatients in a teaching hospital. MATERIALS AND METHODS: A cross sectional study of 260 enrolled outpatients. Psychiatric morbidity was assessed using a 2-stage evaluation method with the General Health Questionnaire Version 12 (GHQ-12) and Structured Clinical Interview for DSM-IV (SCID) to assess for psychiatric diagnosis. RESULTS: 28 (10.8%) of the 260 patients endorsed some psychological distress, with a mean GHQ-12 score of >= 2. At the second stage, 16.1% (N=13 of 81) interviewed had one or more psychiatric disorder on the SCID. The commonest psychiatric diagnosis made were mood disorders, with current major depressive disorder occurring at a rate of 6.2%. Other disorders found were past major depressive episode (2.5%), organic mood syndrome (3.7%), and somatoform disorder (3.7%). CONCLUSION: The relationship between hypertension and mood disorders should inform a higher index of suspicion among physicians and general practitioners in order to give patients appropriate treatments or referrals where necessary. It is recommended that collaboration with mental health service providers be encouraged. PMID- 22437098 TI - Squamous papillomas of the conjunctiva: a retrospective clinicopathological study. AB - BACKGROUND: There is very limited literature on squamous papillomas of the conjunctiva from Nigeria and sub-Saharan Africa. In an attempt to contribute to the literature on the subject, we studied the clinicopathological characteristics of patients histologically diagnosed with squamous papilloma of the conjunctiva in Ibadan, Nigeria. MATERIALS AND METHODS: Clinical and pathological records of patients with histological diagnosis of squamous papilloma of the conjunctiva made in the Department of Pathology, University College Hospital, Ibadan, between January 1985 and December 2004, were reviewed. RESULTS: There were totally 26 cases. Patients' ages ranged from 2 to 58 years with a mean age of 32 years. Male to female ratio was 1.4:1. Size of tumors ranged from 2 to 10 mm. Duration of presenting complaints was from 2 months to 10 years. The lesions in 10 cases were located in the medial canthus, at or close to the limbus in another 10 cases, and in the tarsal conjunctiva in a single case. Five cases had no documentation of location. Sixteen cases (61.5%) had multiple papillomas. Four cases had a history of chemical injury (alkaline based - hair relaxer in a single case, acid based - wet cell car battery fluid in two cases, and unknown chemical in a single case) preceding the lesion by at least 6 weeks. Fourteen cases had koilocytosis on histology suggestive of Human Papilloma Virus (HPV) etiology. HIV screening test was negative in the three patients who had the screening done. Preoperative clinical diagnosis was squamous papilloma in 16 cases, pterygium in 6 cases and squamous cell carcinoma in 2 cases. CONCLUSION: In the environment where we practice, conjunctival squamous papilloma occurs most commonly in the fourth decade of life. Only very few cases are submitted for histological diagnosis. HPV infection and chemical injury are the main etiology. We strongly advocate that all excisions of the conjunctiva, irrespective of the clinical impression, should be submitted routinely for histological assessment. PMID- 22437099 TI - Scorpion sting pain: which way to treat? AB - The objective of reporting this case is to highlight the clinical usefulness of chloroquine in the management of scorpion sting pain with the hope of stimulating interest and research, especially in areas where local anesthetic agents may not be available. In this case reported here, lidocaine failed to provide sustained analgesia for pain relief following scorpion sting. Two milliliters of parenteral chloroquine was injected intradermally around the bite site. Chloroquine provided immediate pain relief within 3 minutes of injection. The pain relief was sustained beyond 24 hours. The use of local anesthetic agents should be continued while other agents such as chloroquine, which may also have relevant clinical usefulness, should be considered. PMID- 22437100 TI - Ocular complications of malaria treatment. AB - Malaria is endemic in Nigeria. With the emergence of chloroquine resistance various modes of treatment including parenteral quinine are employed with consequent untoward effects. This article reports two cases of severe ocular toxicity, including mimicry of intracranial space-occupying lesion, from treatment of malaria with various drugs including quinine. Medical practitioners are advised to exhaust other less toxic modes of therapy before using drugs with great potential for severe untoward effects such as quinine. PMID- 22437101 TI - Hypohidrotic (anhidrotic) ectodermal dysplasia in female twins. AB - Autosomal recessive hereditary ectodermal dysplasia (HED) has not been described in sub-Saharan Africa. It is acknowledged to be rarer than the occasionally reported x-linked and autosomal dominant variants. We report a pair of Nigerian female twins with family history and clinical features suggestive of recessive HED, thereby showing the existence of this rare form in sub-Saharan Africa. PMID- 22437102 TI - Angiodysplasia of the colon: a report of two cases and review of literature. AB - Angiodysplasias of the colon are enlarged and fragile blood vessels in the colon result in occasional loss of blood from the lower gastrointestinal tract. It may be observed incidentally at colonoscopy or patients may present with lower gastrointestinal bleeding. The objective of this case report is to highlight two cases of colonic vascular ectasia seen using a Pentax video colonoscope at the Endoscopy unit of Crescent hospital, Ilorin. The first patient is an 85-year-old man, who presented with constipation, left-sided abdominal pain, and weight loss of two weeks duration. There was no anorexia, abdominal swelling, diarrhea, or hematochezia. Abdomino-pelvic ultrasonography showed normal findings. Colonoscopy done, reaching the ileo-cecal valve and caecum, showed an area of dilated tortuous blood vessel (vascular ectasia) in the wall of the descending colon approximately 45 cm from the anal verge, with no features of bleeding. No ulcers or mass lesion was seen. Colonoscopy showed angiodysplasia of the colon. The second patient is a 30-year-old female trader who presented with two days history of massive hematochezia of about 7 episodes prior to presentation with an estimated blood loss per episode of about 300 ml. There were clinical features of shock. Packed cell volume at presentation was 14%. She was transfused with 4 units of fresh whole blood. Post stabilization, colonoscopy was done 5 days after bleeding had stopped, which revealed an area of erosion with mucosal blood clot about 27 cm from the anal verge. An area of angiodysplasia was seen. No hemorrhoids or mass lesion was seen anywhere in the colon. Angiodysplasia is an uncommon finding in Ilorin. These are the first reported cases of angiodysplasia of the colon from Ilorin, Nigeria. PMID- 22437103 TI - Bilateral post-traumatic acute extradural hematomas: a report of four cases and review of literature. AB - Bilateral extradural hematomas are rare and follow significant trauma. The mortality is higher than with unilateral single extradural hematomas and postoperative outcome depends on preoperative neurological status. PMID- 22437104 TI - Esthetics with prosthetics in case of maxillary canine transposition: a clinical report. AB - Transposition is a dental anomaly manifested by a positional interchange of two permanent teeth. The maxillary permanent canine usually transposes with the first premolar and occasionally with the lateral incisor. These are mainly genetically governed and are treated orthodontically if complete segment of tooth is present; in case of missing teeth, participation of cosmetic dentist is must. The present case report describes a situation where left canine to lateral incisor complete transposition was present along with a missing left central incisor. Esthetic rehabilitation of the "smile zone" was the major concern. Scrupulous treatment planning to esthetically contour transposed teeth according to their normal positions, i.e., transposed left canine to lateral incisor and transposed left lateral incisor to canine with replacement of missing tooth, was a challenge. PMID- 22437105 TI - A clinical case report of Hashimoto's thyroiditis and its impact on the treatment of chronic periodontitis. AB - Periodontitis is a multifactorial disease with microbial dental plaque as the initiator of periodontal disease. However, the manifestation and progression of the disease is influenced by a wide variety of determinants and factors. The strongest type of causal relationship is the association of systemic and periodontal disease. Hashimoto's thyroiditis has also been considered as one of the causes of periodontal disease. This clinical case report highlights the impact of Hashimoto's thyroiditis on the outcome of periodontal therapy. PMID- 22437106 TI - Simple hepatic cyst. PMID- 22437107 TI - Is penile atherosclerosis the link between erectile dysfunction and cardiovascular risk? An autopsy study. AB - Erectile dysfunction (ED) is increasingly linked to coronary heart disease risk. Aim of this study was to test the hypothesis whether this association is due to penile atherosclerosis. We evaluated the prevalence and severity of penile atherosclerosis in relation to coronary and peripheral atherosclerosis. Between January and June 2010, a consecutive series of 31 men underwent an autopsy at the Department of Pathology at the Medical University Vienna. Atherosclerosis at the following localizations were histologically classified: right coronary artery, left coronary artery, left circumflex artery, internal iliac artery, dorsal penile artery and deep penile artery (bilateral). Coronary and peripheral atherosclerosis was present in 87.1 and 77.4% of cases. Atherosclerosis of penile arteries was detectable in only 4 men (12.9%). The only factor linked to penile atherosclerosis was diabetes (P=0.03). All other parameters as assessed according to medical history, general finding from autopsy or histological results regarding arterial lesions in general were not correlated to penile arterial lesions. In contrast to the high prevalence of atherosclerosis in general, penile arterial lesions are rarely present. PMID- 22437108 TI - Looking toward the future.... PMID- 22437109 TI - 2-anilino-4-aryl-8H-purine derivatives as inhibitors of PDK1. AB - A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serine-threonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub micromolar cell proliferation activity and 65% oral bioavailability in mice. PMID- 22437110 TI - Synthesis of new bergenin derivatives as potent inhibitors of inflammatory mediators NO and TNF-alpha. AB - Bergenin is an isocoumarin natural product which aides in fat loss, healthy weight maintenance, enhancing the lipolytic effects of norepinephrine, inhibiting the formation of interleukin 1alpha and cyclooxygenases-2. Here we describe the anti-inflammatory activity of new bergenin derivatives 1-15 in the respiratory burst assay. Bergenin was isolated from the crude extract of Mallotus philippenensis after repeated column chromatography and was then subjected to chemical derivatization. The structures of all compounds were elucidated by NMR and mass spectroscopic techniques. Compound 2 was also studied using single crystal X-ray diffraction. Compounds 4, (54.5+/-2.2%) 5 (47.5+/-0.5%) 5, and 15 (86.8+/-1.9%) showed significant (P<=0.005) NO inhibitory activities whereas 6, 7, 11, 12 and 13 displayed moderate inhibitory activities that ranges between 16% and 31%. Furthermore compounds 4 and 15, were discovered as significant (P<=0.005) TNF-alpha inhibitors with 98% and 96% inhibition, respectively, while compounds 3, 5, 7, 8, 11, and 12 showed low level of TNF-alpha inhibition (0.4 28%). Compounds 8, 13 and 15 exhibited moderate anti-inflammatory IC(50) activities with 212, 222, and 253 MUM, respectively, compared to the standard anti-inflammatory drug indomethacin as well as the parent bergenin compound. No cytotoxic effects could be detected when the compounds were tested on 3T3 cells up to concentrations of 100 MUM. PMID- 22437111 TI - CB 1/2 dual agonists with 3-carbamoyl 2-pyridone derivatives as antipruritics: reduction of CNS side effects by introducing polar functional groups. AB - Our lead compound 1 showed high affinity for both CB1 and CB2 receptors, suggesting the possibility of inducing psychoactive side effects through the CB1 receptor in the brain. To solve this issue, polar functional groups were introduced at the 3-position of the pyridone core of compound 1 to find CB1/2 dual agonists such as 17 and 20 which did not show any CNS side effects. PMID- 22437112 TI - Synthesis and biological activity of bi/tricyclic azasugars fused thiazolidin-4 one and thiazinan-4-one by microwave-assisted tandem Staudinger/aza Wittig/cyclization. AB - A convenient synthesis of novel bi/tricyclic azasugars fused thiazolidin-4-one and thiazinan-4-one by the one-pot tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation was demonstrated. The reactions were carried out with the azidosugar 1 and mercaptan acids via a key intermediate Schiff base and stereoselectively afforded the titled bi/tricyclic azasugars in good yield. All the dominant products were in the 1,2-trans form and the reaction stereoselectivity mainly depended upon the steric hindrance of the neighboring rigid cyclic isopropylidene groups on C-2, 3 which favors the exo-attack of the sulfur atom (in mercaptan acids) to the intermediate imine. The preliminary biological evaluation of the compounds 10-17 showed that compounds 10b, 11a, 12b, 14b, 16b, 17a, and 17b were found to active the natural killer (NK) cells significantly (immunopotentiating activity) and compounds 10a, 10b, 12a, 16b, and 17b exhibited weak inhibitory activity against beta-glucosidase. Yet none of these tested compounds have obvious effects on T cell proliferation, or show inhibition against alpha-amylase and alpha-glucosidase. PMID- 22437113 TI - Design and synthesis of naphthoquinone derivatives as antiproliferative agents and 20S proteasome inhibitors. AB - Fourteen naphthoquinone derivatives (1-14) were designed based on a putative proteasome inhibitor PI-083. These compounds were synthesized and evaluated against A549, DU145, KB, and KBvin tumor cell lines. Six compounds (2, 4, 8, 9, 10, and 13) showed antiproliferative activities comparable to that of PI-083. Among them, compound 8 was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings endorse further optimization efforts based on this structural phenotype to develop potential anticancer drug candidates. PMID- 22437114 TI - New triazole derivatives as antifungal agents: synthesis via click reaction, in vitro evaluation and molecular docking studies. AB - A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2 propanols (5a-5y) which are analogues of fluconazole, have been designed and synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition on the basis of computational docking experiments to the active site of the cytochrome P450 14alpha-demethylase (CYP51). The in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi. Compound 5l showed the best antifungal activities. PMID- 22437115 TI - Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). AB - A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model. PMID- 22437116 TI - Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group. AB - A series of dihydropyrimidine derivatives were synthesized by utilizing Biginelli reaction and evaluated for their in vitro anticancer activity against MCF-7 human breast cancer (HBC) cell line using sulforhodamine B (SRB) assay and antitubercular activity against Mycobacterium tuberculosis (MTB) H(37)Rv using Microplate Alamar Blue Assay (MABA). Compounds 13p, 13t were exhibited 70.6% and 63.7% of HBC cell growth inhibition at 10 MUM concentration. Interestingly compound 13p was also found to be the most potent in the series against MTB H(37)Rv with MIC value of 0.125 MUg/mL. PMID- 22437117 TI - Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation. AB - Synthesis and preliminary SAR of the N1 substituent of a novel series of indazole sulfonamide chemokine receptor 4 (CCR4) antagonist is reported. Compound 7r was identified for further development. PMID- 22437118 TI - Erectile dysfunction and its association with metabolic syndrome and endothelial function among patients with type 2 diabetes mellitus. AB - CONTEXT: Evidence suggests that numerous comorbid conditions contribute to erectile dysfunction (ED) among patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To review the relationship and mechanism between diabetes, metabolic syndrome, cardiovascular disease (CVD), and ED. METHODS: A manual review of authoritative literature from peer-reviewed publications from January 2001 through July 2010 was performed. These publications were further mined to consider the impact of metabolic syndrome as a comorbid condition. Publications from key references were also consulted. RESULTS: The associations between obesity, dyslipidemia, metabolic syndrome, T2DM, CVD, and depression with sexual dysfunction suggest that sexual dysfunction, particularly ED, is a precursor to CVD. Because these conditions share important risk factors with CVD, identifying them and their relationships with the pathogenesis of ED is likely to be critical to the manner in which primary care physicians screen for and manage this condition. CONCLUSIONS: Primary care physicians ought to establish trusting relationships with their patients, providing opportunities for them to probe such sensitive issues as sexual activities, as a means of addressing the possibility of ED. When making the new diagnosis of sexual dysfunction in the absence of metabolic disease or CVD, physicians ought to consider the risk for T2DM and CVD. Associations between metabolic disease, heart disease, and sexual dysfunction further suggest that all patients who are obese and have dyslipidemia, T2DM, and/or depression should be further screened for ED. PMID- 22437119 TI - Transcatheter aortic valve implantation: is perception reality? PMID- 22437120 TI - Transcatheter aortic valve implantation. AB - There has been significant improvement in device designs, operative techniques, and early clinical outcomes in <5 years. Presently, there are two catheter-based bioprostheses (balloon expandable or self-expandable), which have been widely used in humans and are undergoing clinical investigations. Three approaches, including transvenous, transarterial, and transapical have been used for delivery of the catheter-based bioprostheses, and transarterial and transapical approaches have been adopted by cardiologists and cardiac surgeons worldwide. The most recent clinical results have been very encouraging and promising. With experience, 30-day operative mortality with either balloon-expandable or self expandable bioprosthesis was reduced significantly to approximately 10% in high risk patients. In vivo long-term durability of catheter-based bioprostheses remains unknown, and presently transcatheter procedure is limited to the cohort of high-risk patients. Expanding this new technology to low-risk patients should be done with extreme caution because conventional aortic valve replacement still provides the best long-term outcome with minimal operative mortality and morbidity in low-risk patients. Ongoing clinical trials will address many unanswered questions, such as patient selection, long-term in vivo durability, preoperative assessment, and the role of the procedures in management of valvular diseases. PMID- 22437121 TI - Thymopericardial augmented encasement for coronary artery bypass graft surgery: a report of 245 cases. AB - OBJECTIVE: : A pedicled prepericardial fat flap was created to augment the pericardial cavity and applied for patients undergoing coronary artery bypass grafting. The efficacy and durability of this method were investigated. METHODS: : Between July 2005 and November 2008, the present technique was applied for consecutive 245 patients (165 men and 80 women, aged 67 +/- 8.3 years) undergoing isolated coronary artery bypass grafting in which 240 (98.0%) were off-pump cases. The left and/or right internal thoracic artery and the gastroepiploic artery were used in 244 and 160 patients, respectively, and the saphenous vein and the radial artery were used in 51 and 10 patients, respectively. Ninety-seven (40.0%) patients had been diabetic, 18 (7.3%) had had chronic renal failure, and three were redo cases. The prepericardial soft tissue, involving the pedicled thymic gland, was dissected en bloc and sewn with pericardiotomies to wrap the heart and the grafts. Angiography or three-dimensional computed tomography was used to assess the intrapericardial pathways of each graft and a long-term durability of the fat pad. RESULTS: : Early angiography or three-dimensional computed tomography proved that the graft pathways were unaffected by the encasements. Resternotomies in two patients and sternal treatments for infectious dehiscence in two patients were safely achievable. Five-year postoperative computed tomography showed the intact fat pad in the retrosternal space. CONCLUSIONS: : The present technique can encase the heart not the least jeopardizing each pathway of the grafts, and the durable fat pad functions protectively when the sternotomy is either reopened or infected. PMID- 22437122 TI - The effect of the cryosurgical cox-maze procedure on pulmonary veins diameter and left atrial size: computed tomography angiographic assessment. AB - OBJECTIVE: : The Cox-Maze procedure using cryoablation results in transmural lesions, which follow the lesion pattern of the cut-and-sew Cox-Maze procedure. The purpose of our study was to evaluate the effect of the Cox-Maze procedure on left atrial and pulmonary vein size using computed tomography angiogram (CTA). An additional aim was to evaluate pulmonary vein anatomic variability. METHODS: : Six patients (four women and two men; ages 39-63 years, mean age 54.3) underwent chest CTA 1 day before and 38 to 104 days (mean 62.6 days) after the cryosurgical Cox-Maze procedure. Measurements of pulmonary vein ostia and left atrial cranio caudal, left-to-right and anterior-posterior diameters were derived by consensus. The change in diameters after therapy was compared using the Wilcoxon nonparametric test for paired measurements. Four patients (1 woman and 3 men; age 57-73 years; mean age 59) were evaluated with postoperative CTA alone 296-530 days (mean 447) after surgery, for the development of postoperative pulmonary vein stenosis. A single patient underwent preoperative CTA, but surgery was not performed. Pulmonary venous anatomy was recorded in all 11 patients. RESULTS: : Sinus rhythm was restored in all operated patients. No focal ostial stenosis of the pulmonary veins was observed. The quantitative assessment in the six patients with preoperative and postoperative studies disclosed only slight changes in pulmonary vein diameter with either reduction or dilatation of no more than 20% from baseline (P > 0.05). There was a consistent trend toward decrease in left atrial dimensions, which did not reach statistical significance. Six patients (55%) had standard pulmonary venous anatomy and five patients (45%) had at least one variation in their pulmonary vein anatomy. CONCLUSIONS: : In this study, we found that a very intensive cryoablation protocol around the pulmonary veins did not result in pulmonary vein stenosis. In addition, a relatively high incidence of anatomic variations of the pulmonary veins was documented. PMID- 22437123 TI - Fast track minimally invasive transmyocardial revascularization. AB - OBJECTIVE: : We evaluated the initial results of a fast-track discharge protocol for patients undergoing minimally invasive transmyocardial revascularization (MiTMR). METHODS: : Fifteen male patients, aged 64.5 +/- 9.2 years, with an ejection fraction of 46.8% +/- 9.9%, underwent MiTMR through a mini-left anterior thoracotomy aided by robotic-controlled thoracoscopic assistance. A postoperative management protocol included immediate extubation, early chest tube and pulmonary artery catheter removal, and mobilization within 12 hours. RESULTS: : There were no operative arrhythmias or in-hospital mortalities. Three of 15 patients developed left lower lobe atelectasis, delaying discharge between 2 and 5 days. Overall hospital length of stay was 1.4 +/- 1.2 days, although 12 of 15 patients (80%) were discharged to home in 23 hours. Mild-moderate cardiomyopathy (ejection fraction 30%-50%) was not associated with prolonged length of stay. Mean hospital profit margin was $1882.50. One 30-day readmission occurred on day 23 for rapid atrial fibrillation, and one death occurred on day 11. CONCLUSIONS: : Despite these high-risk patients having end-staged, ischemic coronary artery disease, most MiTMR patients can be discharged to home in less than 24 hours. Perioperative morbidity and mortality rates are relatively low, and hospital profit margins are modest. PMID- 22437124 TI - Minimally Invasive Mitral Valve Replacement Using the Valve-in-valve Technique. AB - A 90-year-old woman with two previous mitral valve replacements, presented with pulmonary edema due to mitral regurgitation from degeneration of her bioprosthetic mitral valve. A minimally invasive approach was used to replace the bioprosthetic mitral valve. During surgery, the bioprosthetic valve was noted to be too adherent to the endocardium of the left atrium, making removal of the prosthesis not only difficult, but also potentially harmful. The new bioprosthetic valve was instead placed using a valve-in-valve approach. PMID- 22437125 TI - A novel robot-assisted technique for excision of a posterior mediastinal thyroid goiter: a combined cervico-mediastinal approach. AB - OBJECTIVE: : Intrathoracic thyroid goiter is an uncommon condition. Most goiters are found in the superior and anterior mediastinum, which can be removed either through a cervical approach or through a combined cervicotomy and sternotomy approach. Extension of the goiter into the posterior mediastinum is even less common. Transcervival approach to thyroid goiters in the posterior mediastinum can be difficult, necessitating a thoracotomy, with its associated morbidity. METHODS: : A 69-year-old patient underwent robotic assisted minimally invasive procedure, with the daVinci surgical robotic system to excise a thyroid goiter that extended into the posterior mediastinum. The blood supply of the mediastinal portion of the goiter originated from the right internal thoracic artery. The thoracic and mediastinal portion of the goiter was approached with robot-assisted minimally invasive surgical techniques. Small incisions were used to gain access to the posterior mediastinum via the right pleural cavity, obviating the need for thoracotomy. Using precise movements of the robotic arm, the mediastinal part of the goiter was dissected off vital structures, from within the posterior mediastinum. Total thyroidectomy was then completed using the cervical approach. RESULTS: : The patient tolerated the procedure well, with minimal intraoperative blood loss. The patient was discharged home after a short hospital stay. DISCUSSION: : Robotic surgical techniques for removal of a substernal goiter and other thyroid masses with mediastinal extension, in combination with cervical incision, are effective. Robotic-assisted techniques can complement video assisted thoracic surgical techniques and broaden the indications for minimally invasive surgery. PMID- 22437126 TI - Robotic artificial chordal replacement for repair of mitral valve prolapse. AB - Artificial chordal replacement (ACR) has emerged as a superior method of mitral valve repair with excellent early and late efficacy. It is also ideal to combine with robotic techniques for correction of mitral prolapse, and this article presents a current method of robotic Gore-Tex ACR. Patients with isolated posterior leaflet prolapse are approached with the fourth-generation DaVinci robotic system and endoaortic balloon occlusion. A pledgetted anchor stitch is placed in a papillary muscle, and a 2-o Gore-Tex suture is passed through the anchor pledget. After full annuloplasty ring placement, the Gore-Tex suture is woven into the prolapsing segment and positioned temporarily with robotic forceps. Chordal length is then "adjusted" by lengthening or shortening the temporary knot over 1-cm increments as the valve is tested by injection of cold saline into the ventricle. After achieving good leaflet position and valve competence, the chord is tied permanently. The "adjustable" ACR procedure preserves leaflet surface area and produces a competent valve in the majority of patients. Postoperative transesophageal echo shows a large surface area of coaptation. Patient recovery is facilitated by the minimally invasive approach, while long-term stability of similar open ACR techniques have been excellent with a 2% to 3% failure rate over 10 years of follow-up. Robotic Gore-Tex ACR without leaflet resection is a reproducible procedure that simplifies mitral repair for prolapse. The outcomes observed in early robotic applications have been excellent. It is suggested that most patients with simple prolapse might validly be approached in this manner. PMID- 22437127 TI - Paracardioscopy provides endoscopic visualization of the heart. AB - Paracardioscopy provides totally endoscopic access to the heart via a transabdominal, transdiaphragmatic approach. Structures such as the pulmonary veins, inferior vena cava, left and right atrial appendage, and posterior left atrium can be visualized. Epicardial cardiac procedures, such as ablation procedures for atrial fibrillation, can be successfully performed using this development. This report describes paracardioscopy. PMID- 22437128 TI - Left ventricular pseudoaneurysm demonstrated by 64-multislice computed tomography. AB - A 50-year-old man with a history of left ventricular aneurysmectomy was evaluated with a 64-multislice computed tomogram, which demonstrated left ventricular enlargement and a pseudoaneurysm at the apicolateral side. The images were critical to our management. We resected the pseudoaneurysm with an excellent outcome. PMID- 22437129 TI - Will the new target-specific oral anticoagulants improve the treatment of venous thromboembolism? PMID- 22437130 TI - Influence of Prior Coronary Stenting on the Immediate and Mid-term Outcome of Isolated Coronary Artery Bypass Surgery. AB - BACKGROUND: : There has been little emphasis on the possible consequences of prior stent placement on the outcome of coronary bypass surgery (CABG). We compared the results of isolated CABG patients who had prior stents with those who had not with respect to preoperative status, operative procedure, and postoperative immediate and long-term outcome. METHODS: : Records of 1471 patients undergoing isolated CABG at our institution between January 1, 2000, and March 31, 2005, were reviewed. Patients were divided into three groups. Group I had no stents (n = 1317). Group II had one to three stents (n = 137). Group III had more than three stents (n = 17). Groups were compared with respect to preoperative risk factors, operative procedures, and postoperative results. Long term survival data were obtained on 97.6% of patients with a mean follow-up, 4.1 +/- 2.3 years. RESULTS: : Stented patients were younger (66.1 +/- 10.8 vs. 69.1 +/- 10.8 years, P = 0.006), had more unstable angina (68.2% vs. 58.9%, P = 0.02), hypercholesterolemia (83.8% vs. 61.2%, P = 0.00), chronic obstructive pulmonary disease (13.6% vs. 8.4%, P = 0.03), peripheral vascular disease (15.2% vs. 8.4%, P = 0.00), and previous CABG (10.1% vs. 4.2%, P = 0.00), fewer low ejection fractions (1.3% vs. 5.2%, P = 0.02), left main disease (25.3% vs. 32.6%, P = 0.04), diabetes (31.2% vs. 40.8%, P = 0.01), or diffuse disease (19.5 +/- 10.5 vs. 22.5 +/- 10.9, P = 0.00), had more off pump procedures (53.2% vs. 45.3%, P = 0.03), fewer internal thoracic artery grafts (80.5% vs. 86.6%, P = 0.03), fewer grafts placed (>3: 52.6% vs. 61.8%, P = 0.02), more complications (76.5% vs. 42.6%, P = 0.005), atrial fibrillation (47.1% vs. 19.7%, P = 0.011), longer hospital stays (12.2 vs. 8.3 days, P = 0.019). Percentage survival for groups I, II, and III at 60 months was 82.1%, 84.7%, and 72.6%, respectively. CONCLUSIONS: : Stents placed before surgery in isolated CABG patients may be associated with higher preoperative risk, altered operative procedures, more postoperative complications, longer hospitalizations, and more readmissions. Overall, stented patients experienced more preoperative hospitalizations, catheterizations, and percutaneous coronary interventions (PCIs) than nonstented patients. Survival for those with more than three stents may be diminished. PMID- 22437131 TI - Transmyocardial Laser Revascularization Enhances Blood Flow within Bypass Grafts. AB - OBJECTIVE: : Early benefits from transmyocardial laser revascularization (TMR) may be related to acute sympathetic denervation. This study hypothesized that TMR as an adjunct to off-pump coronary artery bypass (OPCAB) would improve myocardial runoff in the TMR-treated regions and increase graft flow. METHODS: : Graft blood flow was measured in 145 consecutive OPCAB patients. In patients with graft flow <40 mL/min (n = 25), the myocardial region served by the graft was treated with TMR. Blood flow was reassessed 10 minutes after TMR and compared with graft flow in the nontreated regions. Postoperative outcomes, transcardiac thrombin production, coagulation activation, myocardial, and inflammatory markers were assessed. A control group not treated with TMR (n = 14) was selected with similar graft flows and other baseline characteristics. RESULTS: : Risk factors, comorbidities, and preoperative medications were similar in all groups. TMR led to a 48% increase in bypass graft flow in 12 patients, but no significant change in flow in the remainder (n = 13). The control group also showed no change in graft flow measured during the same time-points. Compared with those that did not respond to TMR, responders showed a greater drop in pH during warm ischemia caused by distal anastomoses during OPCAB and significantly higher transcardiac gradients of F1.2, IL-8, TNFalpha, and VCAM. CONCLUSIONS: : TMR acutely improves venous bypass graft flow in regions with more severe myocardial acidosis and inflammation during and after OPCAB. Acute sympathetic denervation after TMR may provide mechanistic insight into the early clinical benefits of TMR as an adjunct to OPCAB. PMID- 22437132 TI - The effect of different topical negative pressures on microvascular blood flow in reperfused myocardium during hypothermia. AB - OBJECTIVE: : Hypothermia is known to limit the extent of myocardial infarction. The earlier hypothermia is applied to an ischemic myocardium, the more tissue can be salvaged. Topical negative pressure (TNP) is known to increase blood flow and stimulate angiogenesis in subcutaneous tissue and skeletal muscle. We have previously shown that a myocardial TNP of -50 mm Hg significantly increases microvascular blood flow in the underlying myocardium in ischemic and reperfused porcine myocardium. The present study was designed to elucidate the effect of different TNP levels on microvascular blood flow in reperfused myocardium during hypothermia. METHODS: : Seven pigs underwent median sternotomy. The microvascular blood flow in the myocardium was recorded before and after the application of 50, -75, -100, -125, and -150 mm Hg using laser Doppler velocimetry. Analysis was performed in the epicardium and at a depth of 6 to 8 mm in the myocardium after 40 minutes of occlusion of the left anterior descending artery followed by cooling to 31 degrees C, and reperfusion for another 20 minutes. RESULTS: : A TNP of -50 mm Hg significantly increased blood the flow in the epicardium, from 116.7 +/- 10.0 PU to 244.5 +/- 52.6 PU (*P < 0.05) at 31 degrees C. A TNP of -50 mm Hg significantly increased microvascular blood flow in the myocardium, from 155.0 +/ 8.4 PU to 236.7 +/- 61.5 PU (*P < 0.05). CONCLUSIONS: : Only a TNP of -50 mm Hg, applied over the left anterior descending artery region in reperfused hypothermic myocardium significantly increased the microvascular blood flow in the epicardium and in the myocardium. PMID- 22437133 TI - Quantitative description of mitral valve geometry using real-time three dimensional echocardiography. AB - OBJECTIVES: : Leaflet and annular geometry are important determinants of mitral valve (MV) stress. Repair techniques which optimize valvular geometry will reduce stress and potentially increase repair durability. The development of such procedures will require image processing methodologies that provide a quantitative description of three-dimensional valvular geometry. Using three dimensional echocardiography in conjunction with novel geometric modeling and rendering techniques, we have developed a high-resolution, quantitative, three dimensional methodology for imaging the human MV. METHODS: : Five normal adults underwent MV imaging using real-time three-dimensional echocardiography. Using specially designed image analysis software, multiple valvular geometric parameters, including the magnitude and orientation of leaflet curvature, leaflet surface area, annular height, intercommissural width, septolateral annular diameter, and annular area were determined for each subject. Image rendering techniques that allow for the clear and concise presentation of this detailed information are also presented. RESULTS: : Although three-dimensional annular and leaflet geometry were found to be highly conserved among normal human subjects, substantial regional variation in leaflet geometry was observed. Interestingly, leaflet geometric heterogeneity was most pronounced in the midposterior leaflet, the region most commonly involved in leaflet flail in subjects with myxomatous disease. CONCLUSIONS: : The image processing and graphical rendering techniques that we have developed can be used to provide a complete description of three dimensional MV geometry in human subjects. Widespread application of these techniques to normal subjects and patients with MV disease will provide insight into the geometric basis of both valvular pathology and repair durability. PMID- 22437134 TI - Prospective evaluation of patency and early experience utilizing an automated distal anastomosis device (C-port). AB - BACKGROUND: : In November 2005, a new automated distal anastomotic device (C Port) for coronary artery bypass grafting (CABG) was cleared by the FDA for use in the United States. This study represents a prospective evaluation of our early experience using the device with graft patency assessment determined by 64 slice multidetector row computed tomography angiography (64CT). MATERIALS AND METHODS: : Patients undergoing coronary artery bypass were evaluated preoperatively by cine angiography for possible use of the C-Port system. A final decision for its use was made clinically at operation based on target vessel and vein graft specifications. Patency of the grafts was evaluated at 1 to 7 months (average 91 days) by 64CT with IRB approval and signed informed consent. RESULTS: : The C Port device was used to form 69 distal anastomoses in 50 patients (46 CABG were performed off pump). There were eight misfires with no adverse effects for an immediate success rate of 88.4%. Thirty-five of 41 patients were available postoperatively for evaluation by 64CT (85.4% follow-up). There was one postoperative death. Seventeen sequential anastomoses were excluded because of inability to reliably evaluate patency by 64CT. Four 64CT scans were uninterpretable. For the remaining 31 patients, 64CT scans were used to evaluate for graft patency. The overall patency rate for all anastomoses was 94.5% (86/91) with selected patency for internal mammary artery of 100% (28/28), for C-Port connectors of 93.3% (42/45), and for hand-sewn venous end-to-side anastomosis of 88.9% (16/18). The difference in patency between C-Port anastomoses and hand sewn was not statistically significant (P = 0.62). CONCLUSIONS: : The C-Port system provides reliable and reproducible compliant automated distal venous anastomoses, which results in acceptable patency at intermediate follow-up. With proper training, the learning curve for using this connector system is relatively short and the need to abandon the procedure is low. 64CT is an excellent noninvasive method for cardiac surgeons and their institutions to accurately evaluate their actual surgical results. PMID- 22437135 TI - Robotic-assisted excision of a left ventricular thrombus. AB - OBJECTIVE: : Left ventricular thrombus is a rare entity usually associated with myocardial infarction. The daVinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, Calif) offers excellent visualization of the mitral subvalvular apparatus and should provide an effective means to excise a left ventricular mass. METHODS: : A 34-year-old man presented to an outside institution with fever of unknown origin and ulcerative colitis. As part of this workup, he underwent a transthoracic echocardiogram and subsequently a transesophageal echocardiogram that showed a 2-cm left ventricular apical pedunculated mass. He was referred to our institution for excision of this ventricular mass. Because of the pedunculated nature of the mass, he was deemed a candidate for a robotic-assisted minimally invasive approach. RESULTS: : The patient underwent successful robotic assisted excision of a left ventricular mass. Total robotic time was 15 minutes. Pathology revealed that the mass was a left ventricular thrombus. The patient experienced an uneventful recovery and was discharged home in 4 days. CONCLUSIONS: : Left ventricular mass excision can be safely performed with the daVinci Surgical System. The daVinci Surgical System offers excellent visualization of the entire left ventricular cavity. PMID- 22437136 TI - Robotic-assisted lung resection for malignant disease. AB - OBJECTIVE: : There have been few reports of the use of robotic surgery to resect lung malignancies. Feasibility and safety of robotic lung resection for malignant lung lesions will be assessed by performing a retrospective analysis. METHODS: : Between September 2004 and November 2006, 21 patients (11 male and 10 female patients) underwent robotic lung resection. Twenty resections were performed for primary nonsmall cell lung cancer and two for metastatic lesions. One patient had bilateral resections for two primary tumors. Fourteen lobectomies, five segementectomies, one wedge resection, and two bilobectomies were performed. Seventy-two percent of operative procedures included mediastinoscopy and/or bronchoscopy at the time of resection. RESULTS: : Thirty-day mortality and conversion rate was 0%. The median operating room time and estimated blood loss was 3.6 hours and 100 mL, respectively. The median intensive care unit and total length of hospital stays were 2 and 4 days, respectively. Chest tubes were removed after a median of 2.0 days. The complication rate was 27%, which included atrial fibrillation, need for postoperative bronchoscopy, and pneumonia. The median tumor size and number of lymph nodes harvested was 2.3 cm and 16, respectively. All resection margins were negative. Median follow-up time was 9.8 months, with no local recurrences at this time. CONCLUSION: : Robotic lung resection appears safe and feasible and allows for significant lymph node retrieval, offers short hospital stays and low morbidity for patients undergoing surgical resection of lung malignancies. Future studies are needed to define the role of robotic surgery in lung cancer treatment. PMID- 22437137 TI - Grasping scissors for minimally invasive surgery. PMID- 22437138 TI - Effects of replacement therapy on sleep architecture in children with growth hormone deficiency. AB - OBJECTIVE: Children with GH deficiency (GHD) show a general decrease in electroencephalographic (EEG) arousability represented by a significant global decrease in Cyclic Alternating Pattern (CAP). The aim of the present study was to evaluate if sleep structure is influenced by GH substitutive therapy by analyzing the classical sleep architecture parameters and sleep microstructure by means of CAP. SUBJECTS AND METHODS: Laboratory polysomnographic sleep recordings were obtained from five children affected by GHD (two girls and three boys; mean age: 4.6 +/- 3.1 years), at baseline and after GH therapy, and from 10 normal healthy children (four girls and six boys, mean age: 5.6 +/- 2.2 years). RESULTS: Compared to controls, GHD subjects showed a reduced total sleep time with increased wakefulness and a consequent decrease in sleep efficiency; GH therapy was associated with an increase of the awakenings/hour and a large effect size was evident for sleep latency, sleep efficiency, and stage N3, which were decreased, and for stage W, which was increased. CAP appeared to be globally reduced and all phase A subtypes and CAP cycle showed a longer duration in GHD children vs. controls. GH substitutive treatment was followed by an increase in CAP rate (total, in N2, and in N3); additionally, A1 index was also significantly increased, especially during stage N3, with a very large effect size. On the other hand, A2 and A3 index and CAP cycle mean duration were reduced. CONCLUSION: Sleep stage architecture seems to be influenced by the GH status, but the analysis of sleep microstructure by means of CAP reveals an enhancement of EEG slow oscillations in GHD patients (demonstrated by an increase in CAP rate and A1 index during N3) after the start of GH replacement therapy. These findings deserve to be verified in a larger trial. PMID- 22437139 TI - Impact of continuous positive airway pressure treatment on right ventricle performance in patients with obstructive sleep apnoea, assessed by three dimensional echocardiography. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is a predictor of right ventricle (RV) impairment. However, there is scant information on the effect of OSA treatment on RV performance. We sought to evaluate the impact of OSA treatment with a continuous positive airway pressure (CPAP) device on RV volume and function, as well as on variables related to pulmonary vascular haemodynamics. METHODS: Fifty six OSA patients and 50 controls were studied. All individuals underwent three dimensional echocardiogram (3DE) to estimate RV volumes, function, pulmonary vascular resistance, and tricuspid regurgitation velocity. A total of 30 patients with apnoea-hypopnoea index greater than 20 were randomly selected to receive placebo (n=15) or effective CPAP (n=15) for 24 weeks. They underwent 3DE examination on three different occasions: at baseline, after 12 weeks, and after 24 weeks of CPAP or placebo. RESULTS: Higher pulmonary vascular resistance (2.1 Wood's +/- 0.5 vs. 1.8 Wood's +/- 0.4), larger end-diastolic RV volume index (52.2 mL/m(2) +/- 7.3 vs. 49.9 mL/m(2) +/- 6.0), larger end-systolic RV volume index (18.7 mL/m(2) +/- 4.3 vs. 15.4 mL/m(2) +/- 3.6), and lower RV ejection fraction (64.3% +/- 6.8 vs. 68.4% +/- 5.9) were observed in the OSA group compared to non-OSA controls (P<0.05, all). In the effective CPAP group we observed the following changes from the baseline to the 24-week echo evaluation: (A) reduction in pulmonary vascular resistance (2.2 Wood's +/- 0.3 to 1.8 Wood's +/- 0.3); (B) reduction in the RV end-systolic volume index (20.3 mL/m(2) +/- 4.5 to 16 mL/m(2) +/- 2.1); and (C) increase in RV ejection fraction (63.0% +/- 7.2 to 70.8% +/- 0.9) (P<0.05 for all). CONCLUSION: Twenty-four-week treatment with CPAP improved RV performance but did not change RV structural variables. PMID- 22437140 TI - The gating role of the thalamus to protect sleep: an f-MRI report. PMID- 22437141 TI - Full recovery of agrypnia associated with anti-Lgi1 antibodies encephalitis under immunomodulatory treatment: a case report with sequential polysomnographic assessment. PMID- 22437142 TI - The discrepancy between actigraphic and sleep diary measures of sleep in adolescents. AB - OBJECTIVE: To explore the discrepancy between sleep diary and actigraphic measures of sleep in adolescents and to ascertain whether these discrepancies may vary according to characteristics of the participant. METHODS: Participants were 385 adolescents aged 13-18years (X=15.6, standard deviation [SD]=0.95; 60% male) from eight high schools in South Australia. Adolescents completed the School Sleep Habits Survey and Pediatric Daytime Sleepiness Scale during class time, followed by an 8-day sleep diary and wrist actigraphy. The Flinders Fatigue Scale was completed on the final day of the study. Parents completed a sleep, medical, education, and family history survey. RESULTS: Actigraphic estimates of wake after sleep onset (WASO) were substantially greater than sleep diary estimates (74min actigraphy vs. 7min sleep diary) and actigraphic estimates of total sleep time were substantially less than sleep diary and parent report (6h 51min actigraphy vs. 8h 16min sleep diary vs. 8h 51 parent report). Actigraphy displayed no significant relationship with daytime functioning and weak relationships with concomitantly recorded sleep diary variables. Sex and puberty related differences in actigraphic scoring were found, with more WASO and less sleep scored in boys compared to girls and more WASO scored amongst pubertally mature boys than boys of less advanced pubertal development. CONCLUSIONS: There may be differences in the sleep of adolescents that result in less actigraphic total sleep scored than perceived, particularly in boys, possibly because of increased sleep motor activity in adolescents that actigraphic algorithms score as wake. This is a significant concern that requires further examination with polysomnography. PMID- 22437143 TI - Disturbed sleep and COPD outcomes: cart meets horse. PMID- 22437144 TI - HHT based cardiopulmonary coupling analysis for sleep apnea detection. AB - STUDY OBJECTIVES: To validate the feasibility of the Hilbert-Huang transform (HHT) based cardiopulmonary coupling (CPC) technique in respiratory events detection and estimation of the severity of apnea/hypopnea. METHODS: The HHT-CPC sleep spectrogram technique was applied to a total of 69 single-lead ECG signals downloaded from the Physionet Sleep Apnea Database. Sleep spectrograms generated by both the original and the improved CPC method were compared on the structure distribution and time-frequency resolution. The performance of respiratory events detection by using the power of low frequency coupling (pLFC) in the new method was estimated by receiver operating characteristic analysis. Furthermore, correlation between HHT-CPC index (temporal Variability of Dominant Frequency, TVDF) and conventional OSAHS scoring was computed. RESULTS: The HHT-CPC spectrum provides much finer temporal resolution and frequency resolution (8 s and 0.001 Hz) compared with the original CPC (8.5 min and 0.004 Hz). The area under the ROC curve of pLFC was 0.79 in distinguishing respiratory events from normal breathing. Significant differences were found in TVDF among groups with different severities of OSAHS (normal, mild, moderate, and severe, p<0.001). TVDF has a strong negative correlation with the apnea/hypopnea index (AHI, correlation coefficient -0.71). CONCLUSIONS: The HHT-CPC spectrum could exhibit more detailed temporal-frequency information about cardiopulmonary coupling during sleep. As two spectrographic markers, pLFC and TVDF can be used to identify respiratory events and represent the disruption extent of sleep architecture in patients with sleep apnea/hypopnea, respectively. The proposed technique might serve as a complementary approach to enhance diagnostic efforts. PMID- 22437145 TI - Targeting the leukocyte activation cascade: getting to the site of inflammation using microfabricated assays. AB - This paper describes the use of microfabricated devices to study the leukocyte activation cascade (LAC). The devices consist of microchannels fabricated in polydimethylsiloxane using soft lithography. Microfluidics, used to generate physiologically relevant levels of shear flow, was achieved by the simple attachment of a syringe pump. Microchannel surfaces were modified by self assembled monolayer (SAM) chemistries. The devices were adapted to standard 96 well tissue culture format with microchannels that could accommodate either a monolayer of endothelial cells or a SAM with immobilized chemokines. Chemotaxis was performed using linear gradients of chemokine set in a 3D matrix. Using this approach, we demonstrated robust chemotaxis of primary human leukocytes (PHLs) in response to a gradient of the chemokine CCL2. Rolling and adhesion assays performed under shear flow demonstrated that leukocyte recruitment to the substrate was highly sensitive to both biological and physical forces. CCL2 and CXCL12 treatment of PHLs dose dependently increased activation and adhesion. These actions could be inhibited by the use of peptide or small molecule antagonists. These devices provide a robust platform to perform LAC assays under in vivo-like conditions. PMID- 22437146 TI - Enhancement of the differentiation of protocorm-like bodies of Dendrobium officinale to shoots by ultrasound treatment. AB - An efficient micropropagation protocol has been developed for Dendrobium officinale, through protocorm-like bodies (PLBs). A correlation between enhanced differentiation of PLBs of D. officinale by ultrasound and changes in the levels of endogenous hormones and the antioxidant enzyme activities was described. Ultrasound treatments improved the conversion of PLBs of D. officinale to shoots. The highest conversion frequency of PLBs to shoots was obtained following the ultrasound treatment at 300 W for 5 min. Compared to the control, the enhanced conversion of PLBs to shoots following the ultrasound treatment was accompanied by an increase in the ratio of total cytokinins (CTKs) to indole-3-acetic acid (IAA), which was due to a decrease in the endogenous level of IAA and an increase in the endogenous level of total CTKs. Analysis of enzyme activities indicated that the increased endogenous level of total CTKs driven by ultrasound was associated with the inhibition of CTK decomposition by CTK oxidase (EC 1.4.3.6), while the decreased endogenous level of IAA was associated with the promotion of IAA decomposition by IAA oxidase (EC 1.10.3.3). In addition, ultrasound treatment increased the activities of superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6) and peroxidase (EC 1.11.1.7) in the conversion process of PLBs to shoots. PMID- 22437147 TI - Methylglyoxal-induced stomatal closure accompanied by peroxidase-mediated ROS production in Arabidopsis. AB - Methylglyoxal (MG) is an oxygenated short aldehyde and a glycolytic intermediate that accumulates in plants under environmental stresses. Being a reactive alpha oxoaldehyde, MG may act as a signaling molecule in plants during stresses. We investigated whether MG induces stomatal closure, reactive oxygen species (ROS) production, and cytosolic free calcium concentration ([Ca2+](cyt)) to clarify roles of MG in Arabidopsis guard cells. MG induced production of ROS and [Ca2+](cyt) oscillations, leading to stomatal closure. The MG-induced stomatal closure and ROS production were completely inhibited by a peroxidase inhibitor, salicylhydroxamic acid (SHAM), but were not affected by an NAD(P)H oxidase mutation, atrbohD atrbohF. Furthermore, the MG-elicited [Ca2+](cyt) oscillations were significantly suppressed by SHAM but not by the atrbohD atrbohF mutation. Neither endogenous abscisic acid nor endogenous methyl jasmonate was involved in MG-induced stomatal closure. These results suggest that intrinsic metabolite MG can induce stomatal closure in Arabidopsis accompanied by extracellular ROS production mediated by SHAM-sensitive peroxidases, intracellular ROS accumulation, and [Ca2+](cyt) oscillations. PMID- 22437148 TI - Evaluation of DNA fragmentation in llama (Lama glama) sperm using the sperm chromatin dispersion test. AB - The integrity of sperm chromatin is now viewed as an important factor in male fertility and in early embryonic development. The objectives of this study were: (1) adapt the simple and inexpensive sperm chromatin dispersion (SCD) test to evaluate DNA fragmentation in llama sperm and establish the halo patterns observed in this species, (2) determine an effective and reliable positive control for this technique and (3) evaluate correlation between the SCD test and the toluidine blue (TB) stain. To adapt the SCD test, three different mercaptoethanol (ME) concentrations were assayed (2.5%, 5% and 10% ME). To determine an effective positive control, three treatments (incubation at 100 degrees C for 30 min, incubation with 0.3 M NaOH for 30 min at room temperature and exposure to UV light for 2h) were assayed. The concentration selected to use in the SCD test was 5% ME, because it produced the largest halo while still conserving the structure of the core. Four DNA dispersion patterns were clearly observed: (I) nuclei with large DNA dispersion halos; (II) nuclei with medium halos; (III) nuclei with very small halos and (IV) nuclei with no halo. All treatments used as positive controls were effective in producing DNA fragmentation. A high correlation (r=0.84, P=0.03) was observed between spermatozoa without halos and TB positive cells. To conclude, SCD patterns in llama sperm have been established as well as a repeatable positive control for the assay. The SCD test and TB stain are simple and inexpensive techniques that can be used to evaluate DNA damage in llama sperm. PMID- 22437150 TI - Trends in lower respiratory tract infection hospitalizations among American Indian/Alaska Native children and the general US child population. AB - OBJECTIVE: To describe trends in the rate of hospitalization for lower respiratory tract infection (LRTI) among American Indian/Alaska Native (AI/AN) children and the general US population of children aged <5 years. STUDY DESIGN: This was a retrospective analysis of trends and hospitalization rates for LRTI associated hospitalizations in 1998-2008 among AI/AN children aged <5 years using the Indian Health Service direct/contract inpatient data, and also among the general population of US children aged <5 years using the Nationwide Inpatient Sample. RESULTS: The 2006-2008 LRTI-associated hospitalization rate for AI/AN children aged <5 years (21.8 per 1000/year) was 32% lower than the 1998-1999 rate, and 1.6-fold higher than the general US children rate (13.8 per 1000/year; 95% CI, 12.8-14.8). Higher rates were seen in AI/AN children aged <5 years in the Alaska and the Southwest regions of the United States (41.2 and 28.0 per 1000/year, respectively). In infants, these rates were 136.4 and 82.4 per 1000/year, respectively, exceeding the rate in the general US infant population (37.1 per 1000/year; 95% CI, 34.3-40.0). The greatest disparity in the LRTI associated hospitalization rate between AI/AN infants and the general US infant population was seen for pneumonia, with a 3-fold higher rate in AI/AN infants (36.2 per 1000/year vs 12.7 per 1000/year; 95% CI, 11.8-13.6). CONCLUSION: The LRTI-associated hospitalization rate is higher in AI/AN children, particularly infants from Alaska and the American Southwest, compared with the general US child population. Closing this gap will require addressing housing and sanitation inequities and ensuring high immunization rates and access to care. PMID- 22437151 TI - Self-assembled ferromagnetic cobalt/yttria-stabilized zirconia nanocomposites for ultrahigh density storage applications. AB - We report on a low-cost, innovative approach for synthesizing prepatterned, magnetic nanostructures, the shapes and dimensions of which can be easily tuned to meet requirements for next-generation data storage technology. The magnetic nanostructures consist of self-assembled Co nanodots and nanowires embedded in yttria-stabilized zirconia (YSZ) matrices. The controllable size and aspect ratio of the nanostructures allows the selection of morphologies ranging from nanodots to nanowires. Co nanowires show strong shape anisotropy and large remanence at 300 K. In contrast, Co nanodots display minimal effects of magnetocrystalline anisotropy and superparamagnetic relaxation above the blocking temperature. These prepatterned magnetic nanostructures are very promising candidates for data storage technology with an ultrahigh density of 1 terabit in(-2) or higher. PMID- 22437152 TI - Multimodality imaging training curriculum--parts II and III. PMID- 22437153 TI - Training for multimodality imaging. PMID- 22437154 TI - Monitoring new oral anticoagulants, managing thrombosis, or both? PMID- 22437155 TI - Under the microscope: foot and ankle fellowships. PMID- 22437156 TI - Microbes inside--from diversity to function: the case of Akkermansia. AB - The human intestinal tract is colonized by a myriad of microbes that have developed intimate interactions with the host. In healthy individuals, this complex ecosystem remains stable and resilient to stressors. There is significant attention on the understanding of the composition and function of this intestinal microbiota in health and disease. Current developments in metaomics and systems biology approaches allow to probe the functional potential and activity of the intestinal microbiota. However, all these approaches inherently suffer from the fact that the information on macromolecules (DNA, RNA and protein) is collected at the ecosystem level. Similarly, all physiological and other information collected from isolated strains relates to pure cultures grown in vitro or in gnotobiotic systems. It is essential to integrate these two worlds of predominantly chemistry and biology by linking the molecules to the cells. Here, we will address the integration of omics- and culture-based approaches with the complexity of the human intestinal microbiota in mind and the mucus-degrading bacteria Akkermansia spp. as a paradigm. PMID- 22437157 TI - Changes in coral microbial communities in response to a natural pH gradient. AB - Surface seawater pH is currently 0.1 units lower than pre-industrial values and is projected to decrease by up to 0.4 units by the end of the century. This acidification has the potential to cause significant perturbations to the physiology of ocean organisms, particularly those such as corals that build their skeletons/shells from calcium carbonate. Reduced ocean pH could also have an impact on the coral microbial community, and thus may affect coral physiology and health. Most of the studies to date have examined the impact of ocean acidification on corals and/or associated microbiota under controlled laboratory conditions. Here we report the first study that examines the changes in coral microbial communities in response to a natural pH gradient (mean pH(T) 7.3-8.1) caused by volcanic CO(2) vents off Ischia, Gulf of Naples, Italy. Two Mediterranean coral species, Balanophyllia europaea and Cladocora caespitosa, were examined. The microbial community diversity and the physiological parameters of the endosymbiotic dinoflagellates (Symbiodinium spp.) were monitored. We found that pH did not have a significant impact on the composition of associated microbial communities in both coral species. In contrast to some earlier studies, we found that corals present at the lower pH sites exhibited only minor physiological changes and no microbial pathogens were detected. Together, these results provide new insights into the impact of ocean acidification on the coral holobiont. PMID- 22437158 TI - A highly enantioselective approach towards 2-substituted 3-bromopyrrolidines. AB - A facile and highly enantioselective approach towards 2-substituted 3 bromopyrrolidines has been developed. The process involves an amino-thiocarbamate catalyzed bromoaminocyclization of 1,2-disubstituted olefinic amides. The pyrrolidine products could readily be converted into other useful building blocks including a dihydropyrrole and a 2-substituted pyrrolidine. PMID- 22437159 TI - Structural approaches to probing metal interaction with proteins. AB - In this mini-review we focus on metal interactions with proteins with a particular emphasis on the evident synergism between different biophysical approaches toward understanding metallobiology. We highlight three recent examples from our own laboratory. Firstly, we describe metallodrug interactions with glutathione S-transferases, an enzyme family known to attack commonly used anti-cancer drugs. We then describe a protein target for memory enhancing drugs called insulin-regulated aminopeptidase in which zinc plays a role in catalysis and regulation. Finally we describe our studies on a protein, amyloid precursor protein, that appears to play a central role in Alzheimer's disease. Copper ions have been implicated in playing both beneficial and detrimental roles in the disease by binding to different regions of this protein. PMID- 22437161 TI - New feature for innovations: industry corner. PMID- 22437160 TI - Structures of asymmetric complexes of human neuron specific enolase with resolved substrate and product and an analogous complex with two inhibitors indicate subunit interaction and inhibitor cooperativity. AB - In the presence of magnesium, enolase catalyzes the dehydration of 2-phospho-d glycerate (PGA) to phosphoenolpyruvate (PEP) in glycolysis and the reverse reaction in gluconeogensis at comparable rates. The structure of human neuron specific enolase (hNSE) crystals soaked in PGA showed that the enzyme is active in the crystals and produced PEP; conversely soaking in PEP produced PGA. Moreover, the hNSE dimer contains PGA bound in one subunit and PEP or a mixture of PEP and PGA in the other. Crystals soaked in a mixture of competitive inhibitors tartronate semialdehyde phosphate (TSP) and lactic acid phosphate (LAP) showed asymmetry with TSP binding in the same site as PGA and LAP in the PEP site. Kinetic studies showed that the inhibition of NSE by mixtures of TSP and LAP is stronger than predicted for independently acting inhibitors. This indicates that in some cases inhibition of homodimeric enzymes by mixtures of inhibitors ("heteroinhibition") may offer advantages over single inhibitors. PMID- 22437163 TI - Presidential Address, 2009: ISMICS Means Innovation. PMID- 22437162 TI - The Surgical Treatment for Atrial Fibrillation: Should the Maze be Modified? PMID- 22437164 TI - Early Results of Edge-to-Edge Alfieri Mitral Repair Via Right Mini-Thoracotomy in 68 Consecutive Patients. AB - OBJECTIVE: : To examine early outcomes of mitral valve repair using Alfieri repair via a right mini-thoracotomy approach. METHODS: : Records were examined in 68 consecutive patients undergoing Alfieri mitral repair via 6 cm right mini thoracotomy. Most repairs were performed under cardioplegic arrest, using percutaneous femoral cannulation and direct aortic cannulation through the right first intercostal space. All patients without hypertrophic cardiomyopathy received rigid ring annuloplasty. The indications for Alfieri repair were extensive prolapse with ring size at least 30 mm. RESULTS: : Mean age was 56 +/- 13 (range, 20-80). Mitral disease etiology was Barlow disease in 17 of 68 (25%) patients and myxomatous disease in 47 of 68 (69%). Concurrent procedures were performed in 29 of 68 (43%) patients. Median ring size was 34 mm. Despite extensive leaflet disease, 59 of 68 (87%) patients were repaired without leaflet resection. Chord pairs were inserted on the posterior leaflet in 18 of 68 (26%) patients and anterior leaflet in four patients. There were no 30-day or late deaths. Residual intraoperative mitral regurgitation was absent in 54 of 68 (79%) patients and trace in the remainder. Local echocardiography follow-up at a mean of 99 days showed median residual regurgitation to be trace. Only two patients developed moderate regurgitation. Mean mitral gradient at follow-up was 4 +/- 2 mm Hg. Local follow-up showed 28 of 39 (72%) patients to be New York Heart Association class I. CONCLUSIONS: : An edge-to-edge Alfieri repair via mini thoracotomy can provide excellent short-term results in selected patients with complex myxomatous mitral disease when minimizing the need for leaflet resection. PMID- 22437165 TI - A comparison of endovascular repair versus open repair of abdominal aortic aneurysms in a community setting. AB - OBJECTIVE: : To compare outcomes between endovascular versus surgical repair of abdominal aortic aneurysms (AAA) in a community hospital setting. METHODS: : A retrospective analysis of all patients undergoing repair of AAA during 2007. Inclusion criteria included stability and anatomic suitability for endovascular repair (EVAR). Data analyzed included comorbidity, length of stay, complications, and cost to the hospital. RESULTS: : Thirty-one endovascular and 12 open cases fit criteria. There were no significant differences in mortality risk, size of aneurysm, or age between the groups (endovascular 71.6 +/- 8 years vs. open 66.7 +/- 9 years, P = 0.07). The endovascular group included three patients with contained retroperitoneal rupture, one of whom died secondary to visceral embolization and thrombosis (the only mortality). EVAR was performed with local anesthesia in three and spinal in three cases. Twenty-three cases were performed completely percutaneously. There were no deaths in the surgical group, but four patients experienced major complications. There was no difference between groups in terms of "contribution" costs, but EVAR had significantly greater cost/benefit when measuring "fully loaded" costs (endovascular 4436 +/- 7418$ vs. open -1418 +/- 6756$, P = 0.02). Endovascular was associated with significantly shorter intensive care unit stay (1.3 +/- 0.7 days vs. 2.8 +/- 2.1 days, P = 0.001) and overall stay (2.5 +/- 2.1 days vs. 7.2 +/- 1.6 days, P = 0.001). CONCLUSIONS: : Endovascular of AAA seems to be at least equivalent to open repair in terms of acute outcomes, with much improved cost/benefit predominantly linked to reduced length of stay. PMID- 22437166 TI - The effect of combined clopidogrel and aspirin therapy after off-pump coronary surgery: a pilot study. AB - OBJECTIVE: : The purpose of this randomized study was to evaluate the effect on graft patency by adding clopidogrel to aspirin in off-pump coronary artery bypass (OPCAB) grafting and the possible side effects of such therapy. METHODS: : Twenty patients who underwent standard OPCAB through median sternotomy were randomized immediately after surgery in two groups. Patients in group A (n = 10) received 100 mg of aspirin starting preoperatively, continuing indefinitely. Patients in group B received 100 mg of aspirin and, in addition, 75 mg of clopidogrel starting immediately after the operation and for 3 months. Postoperative bleeding and other perioperative parameters were compared. Angiography was repeated 3 months after surgery to determine the patency and quality of grafts. RESULTS: : Preoperative risk factors were similar in the two groups. There was no significant difference in average number of distal anastomosis (P = 0.572), operation time (P = 0.686), postoperative bleeding (P = 0.256), ventilation time (P = 0.635), and intensive care unit stay (P = 0.065). Length of stay was shorter in group B (P = 0.024). There was no postoperative complication in either groups. Eight of 27 grafts in group A and 2 of 29 grafts in group B (P = 0.037) were occluded at the time of control angiography. CONCLUSIONS: : Early administration of a combined regimen of clopidogrel and aspirin after OPCAB grafting is not associated with increased postoperative bleeding or other major complications. Despite the small number of patients in this study and small number of examined grafts, the results suggest that the addition of clopidogrel may increase graft patency after OPCAB grafting. PMID- 22437167 TI - Off-pump positioning of a conventional aortic valve prosthesis through the left ventricular apex with the universal cardiac introducer under sole ultrasound guidance, in the pig. AB - OBJECTIVE: : To test an alternative to catheter and open-heart techniques, by documenting the feasibility of implanting an unmodified mechanical aortic valve (AoV) in the off pump, beating heart using the universal cardiac introducer (UCI) attached to the left ventricular (LV) apex. METHODS: : In six pigs, the LV apex was exposed by a median sternotomy. The UCI was attached to the apex. A 12-mm punching tool (punch), introduced through the UCI, was used to create a cylindrical opening through the apex. Then, the AoV, secured to a holder, was introduced into the LV, using transesophageal echocardiographic, guided through the apical LV opening, navigated into the LV outflow tract, and positioned within the aortic annulus. Transesophageal echocardiographic guidance was useful for navigation and positioning by superimposing the aortic annulus and prosthetic ring while Doppler imaging verified preserved prosthetic function and absence of perivalvular leaks. The valve function and hemodynamics were observed before termination for macroscopic evaluation. RESULTS: : The punch produced a clean opening without fragmentation or myocardial embolization. During advancement of the mechanical AoV, there were no arrhythmias, mitral valve dysfunctions, evidence of myocardial ischemia, or hemodynamic instability. The AoVs were well seated over the annulus, without obstructing the coronaries or contact with the conduction system. The ring of AoVs was well circumscribed by the aortic annulus. CONCLUSIONS: : This study documented the feasibility of positioning a mechanical AoV on the closed, beating heart. These results should encourage the development of adjunct technologies to deliver current tissue or mechanical AoV with minimal side effects. PMID- 22437168 TI - Right inframammary mini-thoracotomy approach to the mitral valve in women with breast implants. AB - OBJECTIVE: : Minimally invasive cardiac surgery in patients with breast implants is challenging. Obtaining access to cardiac structures without injuring the prosthesis and at the same time maintaining cosmesis is of particular concern in these patients. Mitral valve surgery can be performed using a right mini inframammary thoracotomy in female patients with breast implants. We describe our experience with this approach to preserve the cosmetic results of previous breast augmentation. METHODS: : Six female patients with previous breast implantation presented for isolated mitral valve surgery for degenerative disease. Surgery was performed through an inframammary incision, in most cases using the previous surgical incision from breast implantation. Peripheral cannulation was used for cardiopulmonary bypass. The breast prosthesis was explanted through a 6-cm skin incision, and then the mitral valve was approached through a right mini anterior thoracotomy. At the end of mitral surgery, the implant was replaced. RESULTS: : All patients had satisfactory outcomes. The mitral valve was repaired in five patients and replaced in one patient. Average length of stay was 5.3 days (range, 4-8 days). There were no conversions to median sternotomy. There were no bleeding complications. There were no wound complications or implant infections. Cosmesis was preserved. CONCLUSIONS: : Our experience with this approach has allowed both mitral valve repair and replacement at the same time preserving cosmetic results. This minimally invasive technique may also have applications in performing atrial septal defect closure, Maze procedures for atrial fibrillation, and tricuspid valve surgery in patients with breast implants. PMID- 22437169 TI - The role of thromboelastography in directing blood product usage in infant open heart surgery. AB - OBJECTIVE: : Thromboelastography (TEG) measures the dynamics of clot formation in whole blood and provides data that can guide specific blood component therapy. This study analyzed whether the implementation of TEG affected blood product utilization and overall hemostasis in infants (6 months and younger) undergoing open heart surgery. METHODS: : TEG values measured include R (time to fibrin formation), angle (fibrinogen formation), and MA (platelet function). Blood product usage, TEG values, and operative parameters were collected during surgery on 112 consecutive infants (66 acyanotic) undergoing open heart surgery within the first 6 months of life. Controls consisted of chart data on 70 consecutive patients (57 acyanotic) undergoing the same surgical procedures before implementation of TEG (pre-TEG). RESULTS: : Using TEG, the pattern of blood product utilization changed. Compared with the pre-TEG era, TEG era patients demonstrated a significant increase in fresh frozen plasma usage intraoperatively (4.74 vs. 1.83 mL/kg; P < 0.001) and reduced postoperative use of platelets (1.69 vs. 3.74 mL/kg; P = 0.006) and cryoprecipitate (0.89 vs. 1.95 mL/kg; P = 0.149). Chest tube drainage was significantly reduced at 1, 2, and 24 hours in the TEG group.TEG angle and MA measurements suggest that fibrinogen and platelets of cyanotic patients are more sensitive to hemodilution than the acyanotic patients. CONCLUSIONS: : TEG allows for proactive, goal-directed blood component therapy with improved postoperative hemostasis in infants undergoing cardiopulmonary bypass. PMID- 22437170 TI - Improvement in the severity of mitral regurgitation after direct intramyocardial injection of angiogenic cell precursor. AB - We reported a case of dilated cardiomyopathy and moderate-severe mitral regurgitation (MR) who we treated by surgical direct intramyocardial angiogenic cell precursors injection. The patient was a New York Heart Association functional class III-IV, 56 year old man, who presented with end-stage congestive heart failure, moderate/severe mitral regurgitation, and myocardial fibrosis with the left ventricular ejection fraction of 13%. After he underwent direct surgical intramyocardial cell implantation, the myocardial fibrosis was resolved at 3 months follow-up. The severity of MR reduced to moderate and mild at 3 and 9 months, respectively. The left ventricular function gradually improved up to 53% at 19 months. To our knowledge, this is one of the only reports of successful direct surgical intramyocardial peripheral blood stem cell implantation to treat MR in dilated cardiomyopathy patient. PMID- 22437171 TI - Irrigated radiofrequency-biophysics and application to surgical ablation. AB - Surgical ablation has become a routine procedure in many institutions and is a nearing standard of care for certain conditions. A variety of energy sources are available to the surgeon to induce cell death and create a line of conduction block. This article provides a brief review of the biophysics of irrigated radiofrequency and its application to monopolar and bipolar ablation. PMID- 22437172 TI - Dystroglycan and dystroglycanopathies: report of the 187th ENMC Workshop 11-13 November 2011, Naarden, The Netherlands. PMID- 22437173 TI - Naturalists, natural history, and the nature of biological diversity. AB - Abstract In this essay, I argue that natural history--observing the natural world and deciphering its patterns--is as essential today as it was during Darwin's lifetime to the continuing development of ecology and evolutionary biology. This tradition, which I illustrate through the example of E. O. Wilson's discovery of the taxon cycle 50 years ago, is still very much alive, but there is a growing tendency for observation to serve theory rather provide new insight or to test the predictions of theory. This tendency manifests itself in the failure of ideas about the diversity, distribution, and abundance of species to be informed by patterns in nature that are readily apparent. On the one hand, supporters of neutral theory have sidestepped the unrealistically slow dynamics of random processes in large metacommunities, and they have failed to note global correlations in species numbers and population sizes within taxa. On the other hand, proponents of niche theory have disregarded the implications of variation in distribution and abundance among close relatives, which implies population regulation largely by species-specific agents, such as pathogens. Nor has community niche theory addressed the independence of distribution and abundance with respect to number of close relatives (and presumed competitors). The diversity, abundances, and distributions of species represent the unfolding of many processes over a historically and geographically contingent landscape, for which experimental methods of scientific inquiry are poorly suited. To interpret patterns of diversity, we must continue to depend on inductive reasoning inspired by the data of natural history. PMID- 22437175 TI - Genetic versus census estimators of the opportunity for sexual selection in the wild. AB - Abstract The existence of a direct link between intensity of sexual selection and mating-system type is widely accepted. However, the quantification of sexual selection has proven problematic. Several measures of sexual selection have been proposed, including the operational sex ratio (OSR), the breeding sex ratio (BSR), and the opportunity for sexual selection (I(mates)). For a wild population of pronghorn (Antilocapra americana), we calculated OSR and BSR. We estimated I(mates) from census data on the spatial and temporal distribution of receptive females in rut and from a multigenerational genetic pedigree. OSR and BSR indicated weak sexual selection on males, but census and pedigree I(mates) suggested stronger sexual selection on males than on females. OSR and BSR correlated with census but not pedigree estimates of I(mates), and census I(mates) did not correlate with pedigree estimates. This suggests that the behavioral mating system, as deduced from the spatial and temporal distribution of females, does not predict the genetic mating system of pronghorn. The differences we observed between estimators were primarily due to female mate sampling and choice and to the sex ratio. For most species, behavioral data are not perfectly accurate and therefore will be an insufficient alternative to using multigenerational pedigrees to quantify sexual selection. PMID- 22437174 TI - Detecting the molecular signature of social conflict: theory and a test with bacterial quorum sensing genes. AB - Extending social evolution theory to the molecular level opens the door to an unparalleled abundance of data and statistical tools for testing alternative hypotheses about the long-term evolutionary dynamics of cooperation and conflict. To this end, we take a collection of known sociality genes (bacterial quorum sensing [QS] genes), model their evolution in terms of patterns that are detectable using gene sequence data, and then test model predictions using available genetic data sets. Specifically, we test two alternative hypotheses of social conflict: (1) the "adaptive" hypothesis that cheaters are maintained in natural populations by frequency-dependent balancing selection as an evolutionarily stable strategy and (2) the "evolutionary null" hypothesis that cheaters are opposed by purifying kin selection yet exist transiently because of their recurrent introduction into populations by mutation (i.e., kin selection mutation balance). We find that QS genes have elevated within- and among-species sequence variation, nonsignificant signatures of natural selection, and putatively small effect sizes of mutant alleles, all patterns predicted by our evolutionary null model but not by the stable cheater hypothesis. These empirical findings support our theoretical prediction that QS genes experience relaxed selection due to nonclonality of social groups, conditional expression, and the individual-level advantage enjoyed by cheaters. Furthermore, cheaters are evolutionarily transient, persisting in populations because of their recurrent introduction by mutation and not because they enjoy a frequency-dependent fitness advantage. PMID- 22437176 TI - Effects of territory competition and climate change on timing of arrival to breeding grounds: a game-theory approach. AB - Phenology is an important part of life history that is gaining increased attention because of recent climate change. We use game theory to model phenological adaptation in migratory birds that compete for territories at their breeding grounds. We investigate how the evolutionarily stable strategy (ESS) for the timing of arrival is affected by changes in the onset of spring, the timing of the resource peak, and the season length. We compare the ESS mean arrival date with the environmental optimum, that is, the mean arrival date that maximizes fitness in the absence of competition. When competition is strong, the ESS mean arrival date responds less than the environmental optimum to shifts in the resource peak but more to changes in the onset of spring. Increased season length may not necessarily affect the environmental optimum but can still advance the ESS mean arrival date. Conversely, shifting a narrow resource distribution may change the environmental optimum without affecting the ESS mean arrival date. The ESS mean arrival date and the environmental optimum may even shift in different directions. Hence, treating phenology as an evolutionary game rather than an optimization problem fundamentally changes what we predict to be an adaptive response to environmental changes. PMID- 22437177 TI - Generalized movement strategies for constrained consumers: ignoring fitness can be adaptive. AB - Abstract Movements made by real organisms--such as movements involved in dispersal, migration, and habitat selection--are expected to occasionally be suboptimal because of realistic constraints imposed by incomplete information, perceptual limitations, and stochasticity. Previous theory considering such constraints has shown that movements appropriately conditioned on habitat or resource characteristics can balance out suboptimal components of movement and thereby lead organisms to ideal free distributions and fitness maxima, whereas movements conditioned on fitness differentials cannot. These findings suggest a somewhat paradoxical hypothesis: even if organisms have information about their fitness, movement strategies that maximize fitness may be conditioned on something other than fitness per se. We test this hypothesis by investigating the evolutionary stability of generalized, conditional movement strategies that vary in their use of information on fitness versus information on habitat characteristics. We show that when costs of sensory machinery are included, natural selection should favor movement strategies that completely ignore fitness information. Finally, we synthesize previous work by showing how several previous important theoretical results for adaptive movement strategies are united under our one general model. PMID- 22437178 TI - Rapid adaptive evolution of photoperiodic response during invasion and range expansion across a climatic gradient. AB - Abstract Understanding the mechanisms of adaptation to spatiotemporal environmental variation is a fundamental goal of evolutionary biology. This issue also has important implications for anticipating biological responses to contemporary climate warming and determining the processes by which invasive species are able to spread rapidly across broad geographic ranges. Here, we compare data from a historical study of latitudinal variation in photoperiodic response among Japanese and U.S. populations of the invasive Asian tiger mosquito Aedes albopictus with contemporary data obtained using comparable methods. Our results demonstrated rapid adaptive evolution of the photoperiodic response during invasion and range expansion across ~15 degrees of latitude in the United States. In contrast to the photoperiodic response, size-based morphological traits implicated in climatic adaptation in a wide range of other insects did not show evidence of adaptive variation in Ae. albopictus across either the U.S. (invasive) or Japanese (native) range. These results show that photoperiodism has been an important adaptation to climatic variation across the U.S. range of Ae. albopictus and, in conjunction with previous studies, strongly implicate the photoperiodic control of seasonal development as a critical evolutionary response to ongoing contemporary climate change. These results also emphasize that photoperiodism warrants increased attention in studies of the evolution of invasive species. PMID- 22437179 TI - Phylogenetic signal in module composition and species connectivity in compartmentalized host-parasite networks. AB - Abstract Across different taxa, networks of mutualistic or antagonistic interactions show consistent architecture. Most networks are modular, with modules being distinct species subsets connected mainly with each other and having few connections to other modules. We investigate the phylogenetic relatedness of species within modules and whether a phylogenetic signal is detectable in the within- and among-module connectivity of species using 27 mammal-flea networks from the Palaearctic. In the 24 networks that were modular, closely related hosts co-occurred in the same module more often than expected by chance; in contrast, this was rarely the case for parasites. The within- and among-module connectivity of the same host or parasite species varied geographically. However, among-module but not within-module connectivity of host and parasites was somewhat phylogenetically constrained. These findings suggest that the establishment of host-parasite networks results from the interplay between phylogenetic influences acting mostly on hosts and local factors acting on parasites, to create an asymmetrically constrained pattern of geographic variation in modular structure. Modularity in host-parasite networks seems to result from the shared evolutionary history of hosts and by trait convergence among unrelated parasites. This suggests profound differences between hosts and parasites in the establishment and functioning of bipartite antagonistic networks. PMID- 22437180 TI - Regional pools and environmental controls of vertebrate richness. AB - Abstract The species richness of local communities depends on the richness of the regional pool and the filtering processes that preclude some regional species from occurring locally. These filters may include absolute attributes of the local environment and also how representative the local environment is of the surrounding region. The latter is consistent with a species-sorting perspective, in which regional species only occupy the local habitats to which they are adapted. Here we evaluate the relative effects of local environmental conditions, environmental representativeness, and environment-independent processes on the probability of local species occurrence, given their regional presence, of birds, mammals, and amphibians worldwide. In multipredictor models, environmental representativeness is a strong independent predictor of local species occurrence probability, with a relative contribution greater than that of absolute local environmental conditions. Furthermore, we find that local occurrence probability diminishes with increased regional richness independent of the local environment. This is consistent with reduced local occupancy in richer regions, which is a pattern that could stem from a largely neutral community assembly process. Our results support the importance of both environment-independent and species sorting processes and suggest that regional richness and environmental representativeness should be jointly used for understanding richness gradients across scales. PMID- 22437181 TI - Causality and persistence in ecological systems: a nonparametric spectral granger causality approach. AB - Abstract Directionality in coupling, defined as the linkage relating causes to their effects at a later time, can be used to explain the core dynamics of ecological systems by untangling direct and feedback relationships between the different components of the systems. Inferring causality from measured ecological variables sampled through time remains a formidable challenge further made difficult by the action of periodic drivers overlapping the natural dynamics of the system. Periodicity in the drivers can often mask the self-sustained oscillations originating from the autonomous dynamics. While linear and direct causal relationships are commonly addressed in the time domain, using the well established machinery of Granger causality (G-causality), the presence of periodic forcing requires frequency-based statistics (e.g., the Fourier transform), able to distinguish coupling induced by oscillations in external drivers from genuine endogenous interactions. Recent nonparametric spectral extensions of G-causality to the frequency domain pave the way for the scale-by scale decomposition of causality, which can improve our ability to link oscillatory behaviors of ecological networks to causal mechanisms. The performance of both spectral G-causality and its conditional extension for multivariate systems is explored in quantifying causal interactions within ecological networks. Through two case studies involving synthetic and actual time series, it is demonstrated that conditional G-causality outperforms standard G causality in identifying causal links and their concomitant timescales. PMID- 22437182 TI - Within-season synchrony of a masting conifer enhances seed escape. AB - Predator satiation resulting from interannual reproductive synchrony has been widely documented in masting plants, but how reproductive synchrony within a year influences seed escape is poorly understood. We evaluated whether the intra annual reproductive synchrony of individual white spruce trees (Picea glauca) increased seed escape from their primary predispersal seed predator, North American red squirrels (Tamiasciurus hudsonicus). Trees with cones that matured synchronously relative to those of other trees within red squirrel territories were significantly more likely to escape squirrel predation in years with both low and superabundant levels of cone production, generating a significantly positive linear selection differential for increasing intra-annual reproductive synchrony. Thus, this masting plant escapes seed predation in numbers through interannual synchrony in seed production and in time through intra-annual synchrony of seed availability. PMID- 22437183 TI - Classification tree methods provide a multifactorial approach to predicting insular body size evolution in rodents. AB - Many hypotheses have been proposed to explain size changes in insular mammals, but no single variable suffices to explain the diversity of responses, particularly within Rodentia. Here in a data set on insular rodents, we observe strong consistency in the direction of size change within islands and within species but (outside of Heteromyidae) little consistency at broader taxonomic scales. Using traits of islands and of species in a classification tree analysis, we find the most important factor predicting direction of change to be mainland body mass (large rodents decrease, small ones increase); other variables (island climate, number of rodent species, and area) were significant, although their roles as revealed by the classification tree were context dependent. Ecological interactions appear relatively uninformative, and on any given island, the largest and smallest rodent species converged or diverged in size with equal frequency. Our approach provides a promising framework for continuing examination of insular body size evolution. PMID- 22437185 TI - The role of physical barriers in the location of avian suture zones in the Guiana Shield, northern Amazonia. AB - Suture zones represent natural forums in which to examine the role of geography and ecology in the speciation process. Here, we conduct a comparative analysis designed to investigate the location of avian phylogeographic breaks and contact zones in the Guiana Shield, northern Amazonia. We use distributional and genetic data from 78 pairs of avian taxa to address whether phylogeographic breaks and contact zones are associated with contemporary landscape features. Using spatially explicit statistical models, we found that phylogeographic breaks and contact zones are not randomly distributed throughout the landscape. In general, geographic breaks cluster along physical barriers (rivers, nonforested habitats, and small mountain ranges), whereas contact zones aggregate where these barriers either break down or are easier to overcome, such as around rivers' headwaters. Our results indicate that although major Amazonian rivers are often key determinants of taxon boundaries, the "riverine barrier effect" is a synergistic consequence of the wide lower reaches of some rivers, coupled with nonriverine landscape features at the headwaters. Our data suggest that ancestral refugia are not necessary to explain current distribution patterns and that pairs of codistributed taxa do not seem to be the result of simultaneous diversification processes. PMID- 22437186 TI - Genetic analysis of life-history constraint and evolution in a wild ungulate population. AB - Trade-offs among life-history traits are central to evolutionary theory. In quantitative genetic terms, trade-offs may be manifested as negative genetic covariances relative to the direction of selection on phenotypic traits. Although the expression and selection of ecologically important phenotypic variation are fundamentally multivariate phenomena, the in situ quantification of genetic covariances is challenging. Even for life-history traits, where well-developed theory exists with which to relate phenotypic variation to fitness variation, little evidence exists from in situ studies that negative genetic covariances are an important aspect of the genetic architecture of life-history traits. In fact, the majority of reported estimates of genetic covariances among life-history traits are positive. Here we apply theory of the genetics and selection of life histories in organisms with complex life cycles to provide a framework for quantifying the contribution of multivariate genetically based relationships among traits to evolutionary constraint. We use a Bayesian framework to link pedigree-based inference of the genetic basis of variation in life-history traits to evolutionary demography theory regarding how life histories are selected. Our results suggest that genetic covariances may be acting to constrain the evolution of female life-history traits in a wild population of red deer Cervus elaphus: genetic covariances are estimated to reduce the rate of adaptation by about 40%, relative to predicted evolutionary change in the absence of genetic covariances. Furthermore, multivariate phenotypic (rather than genetic) relationships among female life-history traits do not reveal this constraint. PMID- 22437187 TI - Parental incarceration and gender-based risks for increased body mass index: evidence from the National Longitudinal Study of Adolescent Health in the United States. AB - Although recent studies suggest that 13% of young adults, including at least one fourth of African Americans, experience parental incarceration, little research has examined links between parental incarceration and physical health. Using data from the National Longitudinal Study of Adolescent Health (1994-2008) and gender based theories of stress, the authors examined whether parental incarceration is associated with increased body mass index among women but not men. Panel analysis spanning adolescence and adulthood, controlling for stressful life events, internalizing behaviors, and a range of individual, familial, and neighborhood characteristics, reveals that body mass index for women who have experienced parental incarceration is 0.49 units (P < 0.004) higher than that for women whose parents have never been incarcerated. This association is not evident among men. Similarly, in change score models between waves II and IV, women experiencing parental incarceration have a 0.92-unit increase in body mass index (P < 0.026) relative to women who did not have a parent undergo incarceration. In supplemental analysis examining if gender differences in incarceration stress response (externalizing vs. internalizing) explain these findings, the authors found that obesity status moderates the relation between depression and parental incarceration. Results suggest a stress internalization process that, for the first time, links parental incarceration with obesity among women. PMID- 22437188 TI - Risk factors for neonatal brachial plexus paralysis. AB - PURPOSE: The study was aimed to identify risk factors for neonatal brachial plexus paralysis. METHODS: A retrospective case-control study was designed. A comparison was performed between cases of brachial plexus paralysis, with all consecutive deliveries during the same 5 months period, without brachial plexus paralysis. Statistical analysis was performed using the SPSS package. RESULTS: The prevalence of brachial plexus paralysis was 1.62/1,000 (9/5,525) vaginal births. Independent risk factors for brachial plexus paralysis were shoulder dystocia (OR = 525; 95% CI 51-4,977, P < 0.001), vacuum delivery (OR = 16.4; 95% CI 3.7-70.5, P < 0.001), macrosomia (birth weight >4,000 g; OR = 16.3; 95% CI 3.7 70.2, P < 0.001), prolonged second stage (OR = 40.8; 95% CI 7.9-188.2, P < 0.001) and vaginal breech delivery (OR = 36.1; 95% CI 4.5-262.5, P = 0.032). CONCLUSIONS: In our population, shoulder dystocia, macrosomia, labor dystocia, vacuum delivery and vaginal breech deliveries were significant risk factors for neonatal brachial plexus paralysis, while maternal characteristics such as obesity and diabetes were not. Despite our growing knowledge concerning the risk factors associated with brachial plexus paralysis, unfortunately, this condition cannot be predicted or prevented. PMID- 22437189 TI - Obstetricians' perspective towards cesarean section delivery based on professional level: experience from Egypt. AB - OBJECTIVES: (1) To investigate Egyptian obstetricians' views towards cesarean delivery on maternal request, (2) to investigate Egyptian obstetricians' views towards some of the "potentially neglected" or controversial obstetrical skills or maneuvers as external cephalic version (ECV), fetal scalp pH measurement or tubal ligation during CS and (3) to examine the effect of professional level on the above factors. STUDY DESIGN: This is a descriptive study performed at the 8th annual Obstetrics and Gynecology conference of Suez Canal University held at Ismailia city in Egypt in June 2011 via a structured self administered questionnaire. Questionnaire was distributed to 223 conference attendants from the three professional levels (consultants, specialists and registrars) working at the two major institutions in Egypt: University and Ministry of Health. The structured questionnaire was based on informed opinion and professional guidelines. In total, 167 (75%) completed the questionnaire. RESULTS: Cesarean delivery on maternal request was accepted by 66% of the studied group and acceptance was significantly higher among consultants. There was no difference in all physicians' practices of cesarean section in both private and public settings. Limited access to medical equipment such as cardiotocogram (CTG) was shown in consultant group reflecting improper private sector preparations. The study revealed that 59% of obstetricians accepted vaginal breech delivery, and only 14% would consider ECV. Fetal scalp pH taking in cases of abnormal CTG was accepted by only 16.3% and 49% rejected the practice of instrumental delivery. There were significant differences among the three professional and the two institutional groups regarding these attitudes. There were different views regarding tubal sterilization during CS. CONCLUSIONS: Lack of knowledge, the need to improve some clinical skills and some professional attitudes may shed light on rising CS rates in Egypt. PMID- 22437190 TI - The association of prenatal attachment and perinatal factors with pre- and postpartum depression in first-time mothers. AB - PURPOSE: This prospective study investigated associations between prenatal attachment of adult first-time mothers to the unborn child, perinatal factors and levels of depression before and up to 18 months after delivery. METHOD: Primiparas (N = 161) without specific risk factors answered the following questionnaires during the last term of pregnancy (t1): Edinburgh Postnatal Depression Scale (EPDS), Maternal Antenatal Attachment Scale (MAAS), questionnaire on the schema of the unborn child, and a questionnaire about the pregnancy. Perinatal data were taken from the patients' files. The EPDS was answered 3 weeks (t2, N = 157), 6 months (t3, N = 159), and 18 months (t4, N = 132) postpartum. RESULTS: During pregnancy, 16.9 % of the women indicated mild depressive symptoms, and 7.5 %, medium to severe symptoms of depression. Mild symptoms of depression were found in 25.5 % at t2, 10.1 % at t3, and 12.2 % at t4; medium to severe symptoms were reported by 7.6, 1.9 and 5.6 %, respectively. Women with low control during delivery (emergency Caesarean) showed a tendency for higher levels (p = 0.067) of depression at t3 than women with elective Caesarean did. The quality of prenatal attachment to the unborn child correlated negatively with depressive symptoms at t1-t4. CONCLUSIONS: The closer the prenatal attachment of a mother to her unborn child, the less symptoms of depression she reports during the last term of pregnancy and postpartum. Therefore, promoting good mother-child attachment during pregnancy might influence the level of postpartum depression. PMID- 22437191 TI - Normal vaginal flora, disorders and application of probiotics in pregnancy. AB - PURPOSE: To assess the effectiveness of vaginal administration of the probiotic Lactobacillus rhamnosus BMX 54 in preventing the occurrence of abnormal vaginal flora and the alteration of parameters relevant to the progression of pregnancy. METHODS: Sixty pregnant women were assigned randomly to the untreated arm of the study (n = 30) or received (n = 30) vaginal application of one tablet containing Lactobacillus rhamnosus BMX 54, once a week for 12 weeks. Every 4 weeks (T0-T3), vaginal and cervical swabs were collected and pH, and quantity and quality of vaginal discharge measured as well as consistency, length and dilatation of cervix, and level of the presenting part of the foetus relative to interspinous diameter. RESULTS: In untreated women, there was a significant trend towards increase in the presence of pathogenic microorganisms in the vaginal and/or cervical swabs (p < 0.05), and in average pH values (p < 0.05), amount (p < 0.05) and "whiff test" positivity (p < 0.05) of vaginal discharge. Significant trend was also found for decrease in length (p < 0.0001) and increase in dilatation (p < 0.05) of cervix, as well as for lower position of the foetus (p < 0.0001). In the group treated with Lactobacillus rhamnosus BMX 54, none of these values significantly changed throughout the observation period, with the exception of cervical length that was significantly decreased at T3 (p < 0.01). CONCLUSIONS: During pregnancy, vaginal administration of Lactobacillus rhamnosus BMX 54 is effective in preventing the development of abnormal vaginal microflora, lowering of the presenting part of the foetus and modifying cervical parameters that could represent risk factors of vulnerability to preterm delivery. PMID- 22437193 TI - [Clinically relevant pharmacokinetic drug interactions in the intensive care unit: an overview]. AB - Critically ill patients in the intensive care unit (ICU) are predisposed to pharmacokinetic drug interactions because of the complexity of the drug regimens received in the intensive care setting. Drugs may affect the absorption, distribution, metabolism and/or elimination of an object drug and consequently alter the intended pharmacologic response and potentially lead to an adverse event. The paper presents an overview of pharmacokinetic drug-drug interactions which can occur with commonly used drugs in the ICU and outlines the underlying types and mechanisms. PMID- 22437194 TI - [Acute kidney injury]. AB - Acute kidney injury plays a pivotal role in intensive care medicine and exerts crucial adverse effects on the course of the disease and overall prognosis of the critically ill patient. Intensive renal support, including initiation of earlier dialysis or maximal uremic toxin removal by higher dosage and frequency of renal replacement therapy, and individualized selection of modality were not able to decrease excessive mortality in this population. Systemic acute inflammation, mediated, at least in part, by cytokines, and not secondary uremic side effects, seems to have a major impact on nonrenal organ damage. Assessment of short-term outcome in critically ill patients who develop acute kidney injury may underestimate the true burden of disease. The overall survival at 5 years in patients discharged alive after severe acute kidney injury necessitating renal replacement therapy is only 20-30%, comparable to cancer patients. In addition, acute renal damage was identified as an independent risk factor for progression of chronic renal insufficiency. Current research focuses on strategies for the prevention of acute kidney injury and on the establishment of effective biomarkers for the early recognition and accurate diagnosis of subclinical renal damage. PMID- 22437196 TI - Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials. AB - OBJECTIVES: : This meta-analysis sought to determine whether video-assisted thoracic surgery (VATS) improves clinical and resource outcomes compared with thoracotomy (OPEN) in adults undergoing lobectomy for nonsmall cell lung cancer. METHODS: : A comprehensive search was undertaken to identify all randomized (RCT) and nonrandomized (non-RCT) controlled trials comparing VATS with OPEN thoracotomy available up to April 2007. The primary outcome was survival. Secondary outcomes included any other reported clinical outcome and resource utilization. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences (SMD), and their 95% confidence intervals (95% CI) were analyzed as appropriate. RESULTS: : Baseline prognosis was more favorable for VATS (more females, smaller tumor size, less advanced stage, histology associated with peripheral location and with more indolent disease) than for OPEN in non-RCTs, but not RCT. Postoperative complications were significantly reduced in the VATS group compared with OPEN surgery when both RCT and non-RCT were considered in aggregate (OR 0.48, 95% CI 0.32-0.70). Although overall blood loss was significantly reduced with VATS compared with OPEN (-80 mL, 95% CI -110 to -50 mL), the incidence of excessive blood loss (generally defined as >500 mL) and incidence of re-exploration for bleeding was not significantly reduced. Pain measured via visual analog scales (10-point VAS) was significantly reduced by <1 point on day 1, by >2 points at 1 week, and by <1 point at week 2 to 4. Similarly, analgesia requirements were significantly reduced in the VATS group. Postoperative vital capacity was significantly improved (WMD 20, 95% CI 15-25), and at 1 year was significantly greater for VATS versus OPEN surgery (WMD 7, 95% CI 2-12). The incidence of patients reporting limited activity at 3 months was reduced (OR 0.04, 95% CI 0.00-0.82), and time to full activity was significantly reduced in the VATS versus OPEN surgery (WMD -1.5, 95% CI -2.1 to -0.9). Overall patient-reported physical function scores did not differ between groups at 3 years follow-up. Hospital length of stay was significantly reduced by 2.6 days despite increased 16 minutes of operating time for VATS versus OPEN. The incidence of cancer recurrence (local or distal) was not significantly different, but chemotherapy delays were significantly reduced for VATS versus OPEN (OR 0.15, 95% CI 0.06-0.38). The need for chemotherapy reduction was also decreased (OR 0.37, 95% CI 0.16-0.87), and the number of patients who did not receive at least 75% of their planned chemotherapy without delays were reduced (OR 0.41, 95% CI 0.18-0.93). The risk of death was not significantly reduced when RCTs were considered alone; however, when non-RCTs (n = 18) were included, the risk of death at 1 to 5 years was significantly reduced (OR 0.72, 95% CI 0.55-0.94; P = 0.02) for VATS versus OPEN. Stage-specific survival to 5 years was not significantly different between groups. CONCLUSIONS: : This meta-analysis suggests that there may be some short term, and possibly even long-term, advantages to performing lung resections with VATS techniques rather than through conventional thoracotomy. Overall, VATS for lobectomy may reduce acute and chronic pain, perioperative morbidity, and improve delivery of adjuvant therapies, without a decrease in stage specific long-term survival. However, the results are largely dependent on non-RCTs, and future adequately powered randomized trials with long-term follow-up are encouraged. PMID- 22437197 TI - Video-Assisted Thoracic Surgery for Lung Cancer Resection: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2007. AB - OBJECTIVE: : The purpose of this consensus conference was to determine whether video-assisted thoracic surgery (VATS) improves clinical and resource outcomes compared with conventional thoracotomy (OPEN) in adults undergoing lobectomy for lung cancer, and to outline evidence-based recommendations for the use of VATS in performing lobectomy for lung cancer. METHODS: : Before the consensus conference, the best available evidence was reviewed in that systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. At the consensus conference, evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS AND RECOMMENDATIONS: : The consensus panel agreed upon the following statements and recommendations in patients with clinical stage I nonsmall cell lung cancer undergoing lung lobectomy: PMID- 22437198 TI - How do Surgeons Randomize Between Different Levels of Surgical Trauma?: Commentary on: Video-Assisted Thoracic Surgery in Lung Cancer Resection-A Meta Analysis and Systematic Review of Controlled Trials. PMID- 22437200 TI - Prognostic value of a positive-to-negative change in hormone receptor status after neoadjuvant chemotherapy in patients with hormone receptor-positive breast cancer. AB - BACKGROUND: To investigate the prognostic value of positive-to-negative changes in hormone receptor (HR) status after neoadjuvant chemotherapy (NCT) in patients with HR-positive breast cancer. METHODS: Data from 224 stage II-III breast cancer patients with positive HR status before NCT who had residual disease in the breast after NCT were collected. HR status of the residual tumors was retested after NCT. A survival analysis was performed in 214 patients with adjuvant endocrine therapy regardless of post-NCT HR status. The survival analysis also examined other clinical and pathologic variables. RESULTS: In total, 15.2 % of patients had a positive-to-negative change in HR status after NCT, and this change was observed more frequently in HER-2-positive tumors than HER-2-negative tumors (P = 0.001). In 214 patients who had been treated with adjuvant endocrine therapy regardless of post-NCT HR status, the alteration in HR status was an independent factor for the prediction of a poorer disease-free survival (P = 0.026) and overall survival (P < 0.001) in the adjuvant endocrine therapy patients. The 5-year disease-free survival and overall survival rates were 43.5 % and 59.8 %, respectively, in patients with HR status conversion and 67.8 % and 82.5 %, respectively, in patients whose HR status remained positive (log rank test P = 0.003 and P = 0.001). CONCLUSIONS: The switch of HR status after NCT is remarkable for HR-positive tumors. An HR-negative switch may identify patients who would benefit from alternative systemic therapies. PMID- 22437199 TI - Thyroid hormone's role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes. AB - Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism. Here we review potential mechanisms for such regulation. Importantly, TH imbalance is often encountered in combination with metabolic disorders such as diabetes, and may cause additional metabolic dysregulation and hence worsening of disease states. TH's potential as a regulator of brain glucose metabolism is heightened by interactions with insulin signaling, but there have been relatively few studies on this topic or on the actions of TH in a mature brain. This review discusses evidence for mechanistic links between TH, insulin, cognitive function, and brain glucose metabolism, and reaches the conclusion that TH may modulate memory processes, likely at least in part by modulation of central insulin signaling and glucose metabolism. PMID- 22437201 TI - Primary hyperparathyroidism and negative Tc99 sestamibi imaging: to operate or not? AB - BACKGROUND: The indications for surgery in primary hyperparathyroidism (1HPT) are the same for patients with and without localization on imaging. However, patients with negative imaging may not be referred for surgery or the surgeon may be reluctant to operate. We compare outcomes in patients with negative imaging to those with localization. METHODS: A review of patients who underwent primary operation for 1HPT with a preoperative Tc99 sestamibi I-123 (MIBI) scan was conducted. Imaging, laboratory, operative findings, pathologic findings, and outcomes were used to compare patients with negative scans to those with localization. RESULTS: A total of 2,681 patients had an operation for 1HPT with preoperative MIBI. MIBI imaging was negative in 136 (5.7 %). The negative MIBI group had a lower calcium (10.9 vs. 11.0 mg/ml, P=0.02), phosphorus (2.9 vs. 3.1 mg/dl, P<0.001), and urinary calcium (251 vs. 287 mg/ml, P=0.02) and no difference in parathyroid hormone, 25-OH vitamin D, or bone loss. Multigland resection was higher with a negative scan (32 vs. 13 %, P<0.001). A curative operation was performed in 90.4 % with a negative MIBI compared to 97.5 % with localization (P<0.001). Patients who underwent successful surgery despite a negative MIBI scan had lower calcium (10.8 vs. 11.1 mg/ml, P=0.04) and parathyroid hormone (98 vs. 196 pg/ml, P=0.03) than those not cured. Patients with both a negative ultrasound result and negative MIBI had a cure rate of 89 %. CONCLUSIONS: A curative operation is performed at an acceptably lower rate with negative MIBI imaging. A decision for surgery with a negative MIBI finding should consider lower cure rates and symptom severity. PMID- 22437202 TI - Patient and caregiver perceptions of the social impact of advanced Parkinson's disease and dyskinesias. AB - Parkinson's disease (PD) exacts a physical and emotional toll on both patients and family. The aim of this study was to compare patient and caregiver perceptions of the social consequences of basic symptoms of PD and levodopa induced dyskinesias. Forty patients with PD and dyskinesias and 35 of their caregivers completed a self-report questionnaire on the impact of PD and dyskinesias on their feelings of security and embarrassment and participation in family/social events, and indicated their preference for the "on" (with dyskinesias) or the "off" (without dyskinesias) state. The patients scored significantly higher than the caregivers did on the negative social impact of the disease in general (p = 0.002) and of the dyskinesias in particular (p = 0.03). Nevertheless, the patients expressed a significantly greater preference for the "on" state (83 %) than the caregivers (59 %) (p = 0.03). Preferences turned to be reverse in direction among spouse-caregivers who significantly preferred the "off" state (54 %) than the patients (25 %) (p = 0.04). Although patients have a worse perception of the effects of PD than their caregivers do, they prefer the more independent "on" state, whereas their caregivers prefer the "off" state. PMID- 22437203 TI - Should the commonly accepted definition of "unprovoked venous thrombembolism" be revisited? PMID- 22437204 TI - Personality and reduced incidence of walking limitation in late life: findings from the Health, Aging, and Body Composition Study. AB - OBJECTIVES: To examine the association between openness to experience and conscientiousness and incident reported walking limitation. METHOD: The study population consisted of 786 men and women aged 71-81 years (M = 75 years, SD = 2.7) participating in the Health, Aging, and Body Composition-Cognitive Vitality Substudy. RESULTS: Nearly 20% of participants (155/786) developed walking limitation during 6 years of follow-up. High openness was associated with a reduced risk of walking limitation (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.69-0.98), independent of sociodemographic factors, health conditions, and conscientiousness. This association was not mediated by lifestyle factors and was not substantially modified by other risk factors for functional disability. Conscientiousness was not associated with risk of walking limitation (HR = 0.91, 95% CI = 0.77-1.07). DISCUSSION: Findings suggest that personality dimensions, specifically higher openness to experience, may contribute to functional resilience in late life. PMID- 22437205 TI - Unraveling the concentration-dependent metabolic response of Pseudomonas sp. HF-1 to nicotine stress by 1H NMR-based metabolomics. AB - Nicotine can cause oxidative damage to organisms; however, some bacteria, for example Pseudomonas sp. HF-1, are resistant to such oxidative stress. In the present study, we analyzed the concentration-dependent metabolic response of Pseudomonas sp. HF-1 to nicotine stress using 1H NMR spectroscopy coupled with multivariate data analysis. We found that the dominant metabolites in Pseudomonas sp. HF-1 were eight aliphatic organic acids, six amino acids, three sugars and 11 nucleotides. After 18 h of cultivation, 1 g/L nicotine caused significant elevation of sugar (glucose, trehalose and maltose), succinate and nucleic acid metabolites (cytidine, 5'-CMP, guanine 2',3'-cyclic phosphate and adenosine 2',3' cyclic phosphate), but decrease of glutamate, putrescine, pyrimidine, 2-propanol, diethyl ether and acetamide levels. Similar metabolomic changes were induced by 2 g/L nicotine, except that no significant change in trehalose, 5'-UMP levels and diethyl ether were found. However, 3 g/L nicotine led to a significant elevation in the two sugars (trehalose and maltose) levels and decrease in the levels of glutamate, putrescine, pyrimidine and 2-propanol. Our findings indicated that nicotine resulted in the enhanced nucleotide biosynthesis, decreased glucose catabolism, elevated succinate accumulation, severe disturbance in osmoregulation and complex antioxidant strategy. And a further increase of nicotine level was a critical threshold value that triggered the change of metabolic flow in Pseudomonas sp. HF-1. These findings revealed the comprehensive insights into the metabolic response of nicotine-degrading bacteria to nicotine-induced oxidative toxicity. PMID- 22437206 TI - Kabuki syndrome revisited. AB - Kabuki syndrome (KS) is a congenital syndrome with an estimated prevalence of 1 in 32 000. Individuals with the syndrome have multiple malformations, but remain identifiable by the presence of the distinctive craniofacial anomalies associated with the condition. Discovered in 1981 by two independent groups of Japanese scientists, spearheaded by Yoshikazu Kuroki and Norio Niikawa, much ambiguity relating to the syndrome persisted for over 30 years after it was initially discovered, with no definitive conclusions about its etiology having ever been established. Recently, mutations within the MLL2 gene have been identified as potentially implicative. Mutations within the MLL2 gene in KS patients have been promising not only because of their relatively high presence in affected individuals, but also because of pre-existing information in the literature having validated mutant MLL2 genes in KS as a highly significant finding. Although found to be present in the majority of cases, the absence of MLL2 mutations in all patients with the syndrome is suggestive that the condition may still display a degree of genetic heterogeneity, and further still, present with more complex inter genomic interactions than initially proposed. PMID- 22437207 TI - Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome. AB - Congenital central hypoventilation syndrome (CCHS; MIM 209880) is caused mostly by dominant alanine expansion (most prevalent is 7-alanine expansion) mutations in PHOX2B. More than 90% of the alanine expansion mutations had been considered to be de novo due to unequal crossover during gametogenesis. However, a recent report stated that 25% of patients inherited the alanine-expanded allele from their parents with somatic mosaicism or constitutive mutation. We studied inheritance in 45 unrelated families, and found that one patient (2%) inherited 5 alanine expansion mutation from a parent with late-onset central hypoventilation syndrome and nine patients (20%) inherited 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. Analysis using a sensitive method would be recommended to all parents of CCHS proband due to high incidence of somatic mosaicism. The absence of an alanine-contracted allele (expected counterpart allele in unequal crossover) and the highest prevalence of 6-alanine expansion mutation in somatic mosaicism suggest that the somatic mosaicism is likely caused by a mechanism other than an unequal crossover, such as a replication mechanism. PMID- 22437208 TI - Revisiting the role of the Himalayas in peopling Nepal: insights from mitochondrial genomes. AB - Himalayas was believed to be a formidably geographical barrier between South and East Asia. The observed high frequency of the East Eurasian paternal lineages in Nepal led some researchers to suggest that these lineages were introduced into Nepal from Tibet directly; however, it is also possible that the East Eurasian genetic components might trace their origins to northeast India where abundant East Eurasian maternal lineages have been detected. To trace the origin of the Nepalese maternal genetic components, especially those of East Eurasian ancestry, and then to better understand the role of the Himalayas in peopling Nepal, we have studied the matenal genetic composition extensively, especially the East Eurasian lineages, in Nepalese and its surrounding populations. Our results revealed the closer affinity between the Nepalese and the Tibetans, specifically, the Nepalese lineages of the East Eurasian ancestry generally are phylogenetically closer with the ones from Tibet, albeit a few mitochondrial DNA haplotypes, likely resulted from recent gene flow, were shared between the Nepalese and northeast Indians. It seems that Tibet was most likely to be the homeland for most of the East Eurasian in the Nepalese. Taking into account the previous observation on Y chromosome, now it is convincing that bearer of the East Eurasian genetic components had entered Nepal across the Himalayas around 6 kilo years ago (kya), a scenario in good agreement with the previous results from linguistics and archeology. PMID- 22437209 TI - Genetic variants on chromosome 6p21.1 and 6p22.3 are associated with type 2 diabetes risk: a case-control study in Han Chinese. AB - Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) on chromosome 6p21.1 and 6p22.3 as type 2 diabetes (T2D) susceptibility loci in the European and Japanese populations. However, these SNPs have not been well evaluated in Chinese population. Here, we performed a case control study with 2925 T2D cases and 3281 controls in a Chinese population. We used TaqMan OpenArray and Sequenom MassARRAY to genotype the four SNPs (rs4712523, rs7756992, rs4712524 and rs6931514) in CDKAL1 (cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1) at 6p22.3 and one SNP (rs9472138) near vascular endothelial growth factor A (VEGFA) at 6p21.1. All the five SNPs were significantly associated with T2D risk with overall effects (odds ratio, OR) from 1.19 to 1.29 in the additive genetic model (rs6931514: OR=1.29, 95% confidence intervals (95% CI)=1.19-1.39, P=5.6 * 10(-10); rs7756992: OR=1.23, 95% CI=1.15-1.32, P=1.2 * 10(-8); rs4712523: OR=1.25, 95% CI=1.15-1.35, P=3.8 * 10(-8); rs4712524: OR=1.24, 95% CI=1.15-1.35, P=6.8 * 10(-8); rs9472138: OR=1.19, 95% CI=1.05-1.34, P=006). Conditional analysis identified two independent signals (rs6931514 at 6p22.3 and rs9472138 at 6p21.1) that were significantly associated with T2D. Compared with the wild homozygote of rs6931514 and rs9472138, subjects with variant alleles of the two SNPs had increased risk for T2D susceptibility in a dose-response manner (P(trend)=7.4 * 10(-12)). Our findings indicated that genetic variants of CDKAL1 and VEGFA on chromosome 6 may contribute to T2D risk in Chinese population, especially for rs9472138 at 6p21.1 identified for the first time to significantly increase the T2D risk in Chinese individuals. PMID- 22437210 TI - Elastomeric microposts integrated into microfluidics for flow-mediated endothelial mechanotransduction analysis. AB - Mechanotransduction is known as the cellular mechanism converting insoluble biophysical signals in the local cellular microenvironment (e.g. matrix rigidity, external mechanical forces, and fluid shear) into intracellular signalling to regulate cellular behaviours. While microfluidic technologies support a precise and independent control of soluble factors in the cellular microenvironment (e.g. growth factors, nutrients, and dissolved gases), the regulation of insoluble biophysical signals in microfluidics, especially matrix rigidity and adhesive pattern, has not yet been achieved. Here we reported an integrated soft lithography-compatible microfluidic methodology that could enable independent controls and modulations of fluid shear, substrate rigidity, and adhesive pattern in a microfluidic environment, by integrating micromolded elastomeric micropost arrays and microcontact printing with microfluidics. The geometry of the elastomeric micropost array could be regulated to mediate substrate rigidity and adhesive pattern, and further the elastomeric microposts could be utilized as force sensors to map live-cell subcellular contractile forces. To illustrate the general application of our methodology, we investigated the flow-mediated endothelial mechanotransduction process and examined specifically the involvement of subcellular contractile forces in the morphological realignment process of endothelial cells under a sustained directional fluid shear. Our results showed that the cytoskeletal contractile forces of endothelial cells were spatiotemporally regulated and coordinated to facilitate their morphology elongation process along the direction of flow. Together, our study provided an integrated microfluidic strategy to modulate the in vitro cellular microenvironment with both defined soluble and insoluble signals, and we demonstrated its application to investigate quantitatively the involvement of cytoskeletal contractile forces in the flow-mediated mechanotransduction process of endothelial cells. PMID- 22437211 TI - Vasodilating versus first-generation beta-blockers for cardiovascular protection. AB - The utility of beta-blockers in the treatment of hypertension has created much speculation as to their efficacy in patients with comorbid conditions, and there are concerns regarding their adverse metabolic effects. It is important to note that these findings were observed with traditional beta-blockers, such as atenolol and metoprolol. The newer generation of beta-blockers, namely carvedilol and nebivolol, is changing the manner in which beta-blockers are viewed in hypertension management. Their ability to inhibit A1 adrenoreceptors and influence nitric oxide leads to vasodilation, which traditional beta-blockers fail to do. These agents have been shown to have favorable metabolic effects while maintaining the beneficial cardiovascular effects of this drug class in post-myocardial infarction patients and the heart failure population. PMID- 22437212 TI - Acute coronary syndromes: identifying the appropriate patient for prasugrel. AB - Acute coronary syndrome (ACS) remains the leading cause of morbidity and mortality. More than half of patients presenting with ACS will experience a recurrent ischemic event; thus, preventing recurrent events is essential to reduce morbidity and mortality associated with ACS. While dual antiplatelet therapy with aspirin and clopidogrel has been the foundation of management for patients presenting with ACS, clopidogrel is limited by delayed antiplatelet effect and a variable patient response. Prasugrel is more potent, has a more rapid and consistent antiplatelet effect, and has been associated with improved outcomes compared with clopidogrel in select patients with ACS. Although prasugrel reduces the risk of recurrent cardiovascular events, it also increases the risk of major bleeding. Careful patient selection will improve the likelihood that patients treated with prasugrel will experience the benefit of this antiplatelet agent with the lowest possible risk of an adverse event. This article reviews the data supporting the use of prasugrel in ACS with an emphasis on characteristics that will help identify the most appropriate patient for this therapy. PMID- 22437213 TI - Hyponatremia, heart failure, and the role of tolvaptan. AB - Hyponatremia-usually defined by serum sodium < 135 mEq/L-is common in heart failure (HF); it remains unclear whether it worsens HF or is merely a marker of more severe disease. Hyponatremia may develop from causes besides HF and symptoms may be mistakenly attributed to HF. Hyponatremia correction may be required for optimal HF management in some cases, and it can prevent neurologic complications. Symptoms, volume status, and onset timing determine treatment, which should correct serum sodium in a controlled manner. Arginine vasopressin is elevated in hypervolemic/euvolemic hyponatremia, favoring water reabsorption despite low serum osmolality. The oral selective V(2)-receptor antagonist tolvaptan blocks arginine vasopressin effects in the renal collecting ducts, promoting aquaresis without increasing sodium/potassium excretion. In clinical trials, tolvaptan significantly increased serum sodium in patients with euvolemic/hypervolemic hyponatremia, including HF. When added to conventional HF treatment, tolvaptan produced early symptomatic benefit, without long-term improvement in an HF population consisting primarily of normonatremic patients. Tolvaptan is approved for treatment of clinically significant hypervolemic/euvolemic hyponatremia (serum sodium < 125 mEq/L or less marked symptomatic hyponatremia that has resisted correction with fluid restriction), but not HF without hyponatremia. PMID- 22437214 TI - The role of ARBs alone or with HCTZ in the treatment of hypertension and prevention of cardiovascular and renal complications. AB - BACKGROUND: Hypertension (HTN) management guidelines stress the importance of effective blood pressure (BP) control to prevent progression to adverse cardiovascular (CV) and renal outcomes. OBJECTIVE: To review the efficacy of different angiotensin II receptor blocking agents (ARBs) as monotherapy or in combination therapy as antihypertensive agents and their effects on renal and CV outcomes beyond BP control. METHODS: The emerging use of ARBs was reviewed from the current literature (1997-2010). RESULTS: Evidence from clinical trials indicates that most patients will need > 1 agent to achieve their BP goal. First line combination therapy is becoming increasingly accepted as standard, especially in patients with moderate to severe HTN, as combination therapy not only allows patients to benefit from additive or synergistic properties of drugs with complementary mechanisms of action, but also improves patient compliance and offers better tolerability. Furthermore, because HTN is a key risk factor for vascular disease, it is becoming clear that additional beneficial effects, such as cardio- and renoprotection, should also be considered when choosing antihypertensive agents, or combinations, for treatment. Angiotensin receptor blockers as a class of antihypertensive agents are noted for their efficacy and good tolerability in combination with other agents, especially diuretics. Irbesartan/hydrochlorothiazide (HCTZ) treatment resulted in a reduction of 27.1 and 14.6 mm Hg in systolic BP (SBP) and diastolic BP (DBP), respectively. Combination treatment of losartan, olmesartan, telmisartan, valsartan, and HCTZ all achieved significant reductions in SBP/DBP compared with monotherapy regimens. CONCLUSIONS: Early use of ARB/HCTZ combination therapy achieves critical decrease in BP and is an effective treatment for patients with moderate to severe HTN. Angiotensin receptor blockers also have renal- and CV-protective properties in conjunction with their antihypertensive effects, providing additional benefit to patients who at risk of vascular disease. PMID- 22437215 TI - Investigation of end-digit preference in blood pressure records of hospitalized chinese patients and analysis of risk factors. AB - OBJECTIVE: End-digit preference is common in blood pressure (BP) measurement, but there are no data available on end-digit preference in China. The purpose of this study was to investigate the frequency of end-digit preference in Chinese hospitalized patients and to explore its risk factors. METHODS: We used systematic sampling to investigate the BP values and related characteristics in records from Chinese patients hospitalized at a university-affiliated hospital in Shanghai, China. Data were collected from January to December 2010. Logistic regression models were created to analyze the relationship between potential risk factors and zero end digit in recorded BP values. RESULTS: Of all 4511 patient records, 57.1% of patients were male. The mean age was 55.1 years (standard deviation [SD], 15.4 years). When admitted, the mean BP values were 124.6 mm Hg (SD, 14.3 mm Hg) for systolic blood pressure (SBP) and 77.5 mm Hg (SD, 8.6 mm Hg) for diastolic blood pressure (DBP). 81.8% and 81.2% of SBP and DBP values had an end digit of zero. 7.7% and 9.6% of SBP and DBP values had an end digit of "5." In the logistic regression analyses, female sex (odds ratio [OR], 1.34 for SBP, 1.24 for DBP), admission to a surgical department (OR, 2.04 for SBP, 1.88 for DBP), admission heart rate of >= 80 bpm (OR, 1.41 for SBP, 1.61 for DBP), and not having a history of hypertension (OR, 1.41 for SBP, 1.33 for DBP) were related to a high risk of having SBP and DBP values with a zero end digit. Patients with SBP values of >= 140 mm Hg had a high risk of having a zero end digit in SBP values (OR, 1.33) and a low risk of having a zero end digit in DBP values (OR, 0.67). Patients whose DBP values were >= 90 mm Hg had a high risk of having a zero end digit in DBP values (OR, 2.49). CONCLUSION: The zero end-digit preference in recorded BP values of hospitalized patients in China was strong. Patients' sex, admission to a surgical department, admission heart rate, history of hypertension, and SBP and DBP values were risk factors that influenced the preference for zero as the end-digit BP value. PMID- 22437216 TI - Different treatment interventions affect plasma NT-ProBNP levels and early exercise tolerance in patients with acute ST-segment elevation myocardial infarction. AB - OBJECTIVE: The aim of this study was to investigate the effect of different treatment interventions on plasma N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) levels and early exercise tolerance in patients with acute ST-segment elevation myocardial infarction. METHODS: 146 consecutive patients with ST-segment elevation myocardial infarction who received emergency percutaneous coronary intervention (PCI) (n = 55), elective PCI (n = 47), or drug treatment (n = 44) were included. Plasma NT-proBNP levels and left ventricular ejection fractions (LVEFs) were measured before the treatment intervention and at 1 week and 1 month afterward. An exercise stress test was performed 1 month after the intervention, and the occurrences of major adverse cardiac events (MACE) were recorded at the 1-month follow-up. RESULTS: Compared with the elective PCI and drug treatment groups, at 1 week and 1 month after the intervention, the emergency PCI group's plasma NT-proBNP levels were significantly lower, and the group's LVEFs were significantly higher (all P < 0.05). There was a significantly negative correlation between plasma NT-proBNP levels and LVEFs in each group (all P < 0.05). The positive exercise stress testing rates were 13.0%, 32.6%, and 38.6% in the emergency PCI, elective PCI, and drug treatment groups, respectively (P < 0.05). The occurrences of MACE in the emergency PCI, elective PCI, and drug treatment groups were 34.5%, 59.5%, and 65.9%, respectively (P < 0.05). CONCLUSION: Emergency PCI resulted in lower plasma NT-proBNP levels, lower MACE incidence, higher LVEFs, and better early exercise tolerance compared with elective PCI or drug treatment, indicating that lower plasma NT-proBNP levels predicted a better prognosis. PMID- 22437217 TI - Managing diabetes with integrated teams: maximizing your efforts with limited time. AB - The importance of glycemic control has been well established. In response, the American Diabetes Association has established goals for glycemic control and other cardiovascular parameters, including blood pressure and low-density and high-density lipoprotein cholesterol. However, the National Health and Nutrition Examination Survey has shown that only about half (57%) of patients with diabetes meet a glycated hemoglobin A(1c) (HbA(1c)) goal of < 7%, approximately 45% meet blood pressure and total cholesterol goals, and only 12% achieve all 3 treatment goals. While treating hyperglycemia remains the primary treatment goal, careful selection of pharmacotherapies that do not adversely affect cardiovascular risk factors or long-term glycemic control is an important consideration for patients with type 2 diabetes mellitus. During the past 5 years, the number of treatment options and the complexity of treatment guidelines for diabetes have increased markedly, which makes treatment decisions more complicated and time-consuming, and greatly impacts the workload of the primary care physicians who deliver care to the majority of this population. To provide optimal diabetes care when time and resources are limited, primary care physicians may want to enlist the support of other providers, such as nurse practitioners, physician assistants, diabetes educators, dietitians, and social and case workers. The use of team care, coupled with appropriately chosen pharmacologic therapy and patient education that fosters the development of critical thinking skills and the ability to make self management decisions, have been shown to improve glycemic control and cardiovascular outcomes. PMID- 22437218 TI - Health care utilization and costs in type 2 diabetes mellitus and their association with renal impairment. AB - OBJECTIVE: To evaluate the health economic burden of renal impairment (RI) in patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective analysis used medical and pharmacy claims and outpatient laboratory data from a large US health care plan (January 1, 2004 to December 31, 2008). Patients with T2DM aged >= 18 years with continuous enrollment for >= 12 months pre- and post index date (defined as date of first evidence of T2DM) who had >= 1 serum creatinine (SCr) laboratory test in pre- and post-index periods were included. Renal impairment prevalence was determined by laboratory data and compared with prevalence of RI identified from claims (physician-diagnosed). Renal impairment stages were categorized using estimated glomerular filtration rate. Multivariate analyses were conducted to examine association between pre-index RI status and post-index total diabetes-related health care costs. RESULTS: Of 82 263 patients with T2DM with post-index SCr laboratory values, 34.4% had RI as evidenced by laboratory data, while 11.9% had RI using claims-based criteria. The prevalence as determined from laboratory data was roughly 3 times higher than the prevalence determined from claims data, probably due to under-recognition and under diagnosis by providers. Compared with patients without pre-index RI, patients with RI were more likely to incur >= 1 diabetes-related ambulatory visit (88.8% vs 85.2%; P < 0.001), emergency room visit (7.2% vs 4.5%; P < 0.001), and inpatient stay (13.8% vs 6.6%; P < 0.001) during the 12-month post-index evaluation period. Patients with pre-index RI incurred 41.8% higher post-index total diabetes-related health care costs compared with no RI (odds ratio, 1.42 [CI, 1.29-1.56]; P < 0.001). Compared with no RI, insulin-related health care costs were independently associated with increases of 37.4% (mild RI), 166.8% (moderate RI), 408.3% (severe RI), and 343.8% (end-stage RI). CONCLUSION: Renal impairment in T2DM is associated with high health care utilization and costs. PMID- 22437219 TI - Tumor lysis syndrome: a systematic review of case series and case reports. AB - Tumor lysis syndrome (TLS) is a clinical condition that is caused by a massive lysis of tumor cells that accumulate very rapidly and disturb hemodynamics. This oncologic emergency requires immediate intervention. Tumor lysis syndrome was first described in the 19th century. Since then, it has become a well-known disease with improved management measures. Tumor lysis syndrome can occur after any type of neoplasm. It is highly associated with rapidly proliferating tumors compared with those that are well demarcated, such as acute lymphoblastic leukemia and high-grade non-Hodgkin lymphoma. Initiation of chemotherapy, radiotherapy, or steroid treatment may trigger TLS, or it may develop spontaneously. The release of massive quantities of intracellular contents may produce hyperkalemia, hyperphosphatemia, secondary hypocalcemia, hyperuricemia, and acute renal failure. Prevention and treatment measures include intravenous hydration, use of allopurinol and rasburicase, management of TLS-associated electrolyte abnormalities, and renal replacement therapy; the use of urine alkalinization remains controversial. In this article, we summarize the findings of case series and case reports published over the past 6 years in an effort to help familiarize clinicians better recognize and manage TLS. PMID- 22437220 TI - Medical management of diabetic foot infections. AB - Diabetic foot infections (DFIs) are a commonly encountered medical problem. They are associated with an increased frequency and length of hospitalization and risk for lower-extremity amputation. Furthermore, they have substantial economic consequences. Patients with diabetes mellitus are particularly susceptible to foot infections because of neuropathy, vascular insufficiency, and diminished neutrophil function. The approach to managing DFIs starts with determining if an infection exists. If an infection exists, then the type, severity, extent of infection, and risk factors for resistant organisms should be determined through history, physical examination, and additional laboratory and radiological testing. Optimal management requires surgical debridement, pressure offloading, effective antibiotic therapy, wound care and moisture, maintaining good vascular supply, and correction of metabolic abnormalities, such as hyperglycemia, through a multidisciplinary team. Empiric antibiotics for DFIs vary based on the severity of the infection, but must include anti-staphylococcal coverage. PMID- 22437224 TI - Minimally Invasive Ivor-Lewis Esophagectomy: Use of the OrVIL Device for the EEA Intrathoracic Anastomosis. PMID- 22437221 TI - Tolerability of concomitant use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors and oxymorphone extended release. AB - BACKGROUND: Opioids and antidepressants are frequently prescribed for chronic low back pain (cLBP). This post hoc analysis was conducted to assess the tolerability of oxymorphone extended release (ER) for cLBP in patients taking selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) compared with patients not taking SSRIs/SNRIs. METHODS: Patients in 2 clinical trials (NCT00225797, November 22, 2004 to July 18, 2005; NCT00226421, October 13, 2004 to August 19, 2005) aged >= 18 years with moderate to severe cLBP were titrated to a stabilized dose of oxymorphone ER during an open-label titration phase and then randomized to treatment with this dose or placebo every 12 hours for 12 weeks. In a post hoc analysis, adverse events (AEs) were compared between patients taking versus not taking SSRIs/SNRIs. Treatment efficacy was assessed as change from baseline in average daily pain intensity on a 100-mm visual analog scale. RESULTS: Of 575 patients enrolled, 45 of 89 (50.6%) taking SSRIs/SNRIs and 303 of 486 (62.3%) not taking SSRIs/SNRIs successfully titrated to oxymorphone ER. The frequency of any AE did not differ significantly between the 2 subpopulations. During the titration phase, serious AEs occurred more frequently in patients taking SSRIs/SNRIs (3/89; 3.4%) compared with those not taking SSRIs/SNRIs (4/486; 0.8%; P = 0.04); however, during the double-blind treatment phase, there was no significant difference in the frequency of serious AEs in patients treated with oxymorphone ER taking (1/29; 3.4%) versus those not taking (3/146; 2.0%) SSRIs/SNRIs. Visual analog scale scores were similar in patients taking versus those not taking SSRIs/SNRIs throughout the study. CONCLUSION: The concomitant use of oxymorphone ER with SSRIs or SNRIs was well tolerated in patients with cLBP. PMID- 22437225 TI - Clinical outcomes after hybrid coronary revascularization versus off-pump coronary artery bypass: a prospective evaluation. AB - OBJECTIVE: : Hybrid coronary revascularization is offered as an alternative strategy for patients with multivessel coronary artery disease (CAD). We present our experience and provide a comparative analysis to off-pump coronary artery bypass grafting (OPCAB). METHODS: : Ninety-one patients with multivessel CAD underwent minimally invasive left internal mammary artery to left anterior descending grafting in combination with percutaneous coronary intervention of nonleft anterior descending targets (HYBRID). The primary end point of this study was major adverse cardiac and cerebrovascular events (MACCE), defined as death, stroke, and nonfatal myocardial infarction. MACCE in the HYBRID group were compared with 4175 contemporaneously performed OPCAB operations by logistic (30 day outcomes) and Cox proportional hazards (long-term survival) regression methods. Propensity scoring was used to adjust for potential selection bias. RESULTS: : The 30-day MACCE (death/stroke/nonfatal myocardial infarction) rate was 1.1% for the HYBRID group (0%/0%/1.1%) and 3.0% for the OPCAB group (1.8%/1.1%/0.5%) (odds ratio = 0.47, P = 0.48). Angiographic left internal mammary artery evaluation was obtained in 95.6% of patients (87 of 91) revealing FitzGibbon A patency in 98.0% (96 of 98). The reintervention rate at 1 year for the HYBRID group was 5.5% (5 of 91) and was limited to repeat percutaneous coronary intervention. Three-year survival was statistically similar for the two groups (hazard ratio = 0.44, P = 0.18, see Kaplan-Meier figure). CONCLUSIONS: : Hybrid coronary revascularization may be noninferior to OPCAB with respect to early MACCE and 3-year survival in the treatment of multivessel CAD. PMID- 22437226 TI - How Informed is "Informed Consent" for Robotic Cardiothoracic Surgery? AB - OBJECTIVE: : The education of patients in the informed consent process remains a challenge for many surgeons. In cardiothoracic surgery, emerging minimally invasive techniques including robotics add another level of complexity to the patient education process. We sought to evaluate our patients' perceptions and informed knowledge after robotic-assisted cardiothoracic surgery. METHODS: : A survey containing questions designed to elicit patients' perceptions about robotic cardiothoracic surgery was given postoperatively by telephone 1 month to 12 months after surgery. The survey included questions about the type of procedure, function of the organ operated on, purpose of the operation, primary "surgeon" (robot vs. human), patients' opinion about robotic-assisted surgery, educational level, and socioeconomic background. Continuous variables are reported as mean +/- SD. Continuous and categorical variables were compared using the Student t test and Pearson chi test, respectively. Ordinal variables were compared using the Mann-Whitney U test. P values of <0.05 were considered significant. RESULTS: : Between 2002 and 2007, 198 patients underwent robotic cardiothoracic surgery. One hundred fifty patients (76%) were contacted and 89 (45%) fully completed the survey. Of the respondents, there were 31 coronary artery bypasses, 33 pacemaker lead implantations, esophageal resections, 8 thymectomies, and 9 others. The mean age of the patients was 61.1 +/- 15 years (range, 23-87) and there were 52 men (58.4%). A total of 96.6% of patients were satisfied with the information provided by the surgeon and 92.1% felt that they understood the information. The diagnosis, target organ, and procedure were correctly identified by 81 (91.0%), 83 (93.3%), and 76 (85.4%) of the patients, respectively. A total of 80 (89.9%) knew a robot was involved and 73.8% understood the role of the robot in the surgery. These results were independent of age, income, and education level achieved. CONCLUSIONS: : Overall, patients demonstrated an understanding of the role of the robot in their cardiothoracic surgery. Despite the increasing complexity of robotics, preoperative patient education can result in patients who are both satisfied and well educated about their cardiothoracic surgery procedures. PMID- 22437227 TI - Clinical results of minimally invasive mitral valve surgery: endoaortic clamp versus external aortic clamp techniques. AB - OBJECTIVE: : This study was carried out with the aim of presenting our experience with minimally invasive mitral surgery and compare the endoaortic clamp with the external aortic clamp (EAC) techniques. METHODS: : Between December 2002 and May 2009, 139 patients (75 men, aged 63 +/- 11 years) underwent video-assisted mitral valve surgery through right thoracotomy. Twelve (9%) patients were operated without clamping the aorta, 32 (23%) patients (group A) were operated on by using the endoaortic clamp, and 95 (68%) patients were operated on by using the EAC (group B). There was no significant difference between groups A and B regarding preoperative variables. RESULTS: : Intraoperative procedure-associated problems were experienced in three group A patients (9.3%, two aortic dissections with conversion to sternotomy; one conversion due to bad exposure) and in two group B patients (2%, one conversion to sternotomy for bleeding and one for ascending aorta hematoma). At a mean follow-up of 32 months, 121 patients (97%) were in New York Heart Association class I-II, with satisfactory echocardiographic results. There was one in-hospital and six late deaths (three noncardiac, two cardiac, and one valve related). Five-year actuarial survival was 88% +/- 8%. There were three reoperations, one early (<30 days) after complex mitral valve repair, with a 5 year freedom from reoperation of 97% +/- 2%. Postoperative levels of myocardial cytonecrosis enzymes as well as the extracorporeal circulation time were significantly lower in group B patients (P < 0.05). CONCLUSIONS: : Intraoperative procedure-associated complications with endoclamping combined with an apparently better myocardial protection forced us to change our practice to the more simple and economic EAC technique. PMID- 22437228 TI - Minimally Invasive Esophagectomy: Esophagogastric Anastomosis Using the Transoral Orvil for the End-to-Side Ivor-Lewis Technique. AB - OBJECTIVE: : Minimally invasive esophagectomy (MIE) can be performed a variety of ways using different techniques for the anastomosis. End-to-end anastomosis (EEA) transoral circular staplers have traditionally been used in gastric bypass surgery with good success. An evaluation of the safety and utility of the EEA transoral circular stapler for esophageal anastomoses in MIE is reviewed. METHODS: : A retrospective chart review of all patients who underwent transthoracic MIE with EEA-stapled transoral anastomoses between January 2008 and May 2009 was performed. Patient demographics, indication for esophagectomy, perioperative treatments, intraoperative data, postoperative complications, hospital length of stay, and in-hospital mortality were evaluated. RESULTS: : Twenty-six consecutive patients underwent MIE with EEA circular-stapled transthoracic anastomoses. Twenty-three were male with a mean age of 64 years (32 88). Indications for esophagectomy included esophageal cancer (24), high-grade dysplasia (1), and refractory stricture (1). Fifteen patients (63%) had neoadjuvant chemotherapy and radiation. There were no conversions to open thoracotomy or laparotomy. Mean operative time was 6.0 hours. Eight patients (31%) suffered postoperative complications; including leak from the gastric conduit staple line requiring operative intervention (1), postoperative bleeding requiring multiple transfusions (1), aspiration pneumonia (1), acute respiratory distress syndrome (1), myocardial infarction (1), chylothorax (1), and anastomotic stricture (2). Median hospital length of stay was 9 days (range 6 43). There were no in-hospital mortalities. CONCLUSIONS: : In our series, the EEA circular stapler seems technically feasible and relatively safe for an intrathoracic anastomosis in MIE. PMID- 22437229 TI - Butterfly-needle video-assisted thoracoscopic segmentectomy: a retrospective review and technique in detail. AB - OBJECTIVE: : A pulmonary segmentectomy is requires the identification of the segmental planes, making it technically more difficult than a lobectomy. Therefore, we present a new method that uses a butterfly needle to distinguish the intersegmental plane under video-assisted thoracoscopic surgery (VATS). METHODS: : From May 2005 to August 2008, 15 patients underwent anatomic segmentectomy using VATS. In this approach, a working port 4 to 7 cm in length was made in the fifth intercostal space. Additional 1.2-cm thoracic ports were made in the seventh intercostal space on the anterior axillary line and the ninth intercostal space on the posterior axillary line. Each segment was selectively isolated, and the targeted bronchovascular pedicle was divided. For the segmentectomy, the lung was deflated, and the pulmonary artery and vein to the involved segment were divided. The segmental bronchus was divided using a stapling device. Using a butterfly needle, oxygen/air (1-2 L) was used to inflate the involved segment, and the involved segment was severed and removed using electrocautery or a stapling device. The raw surface was covered with an absorbable sealing material such as polyglycolic acid to prevent air leaks. RESULTS: : Using this method, apical segment of the right upper lobe (S1), apical posterior segment of the left upper lobe (S1 + 2), upper division, and posterior segment of the right upper lobe (S2), superior segment of the right or left lower lobe (S6), and basal segmentectomies could be performed with VATS. However, the technique did not work in one patient with severe emphysematous changes, because the plane was not readily identifiable. CONCLUSIONS: : Butterfly-needle video assisted segmentectomy is a useful technique. Selective segmental inflation allows the intersegmental plane to be identified completely under the surgeon's control, eliminating the need for an anesthesiologist to pass a bronchoscope or insufflate the lung in a particular manner. PMID- 22437230 TI - Robotic right gastroepiploic artery harvesting. AB - OBJECTIVE: : Robotic surgery promises to extend the capabilities of the minimally invasive surgeon, and many surgical specialties are applying this new technology. However, there is no report of robotic harvesting of the right gastroepiploic artery (rGEA). We evaluated the possibility of video-endoscopic dissection of the rGEA using the da Vinci surgical system for use in minimally invasive coronary artery bypass surgery. METHODS: : The procedure was performed on a porcine rGEA harvesting model using the Tuebingen MIS-Trainer and a pig model. In the pig model, a pneumoperitoneum (maximal pressure, 12 mm Hg) was established after the insertion of a 12-mm trocar (camera) using the open method. The surgical cart was positioned at the head of the pig. A 30-degree three-dimensional camera, using two parallel-arranged three-chip cameras, was inserted and mounted on the middle 12-mm trocar. Under direct visualization, the two lateral surgical arm trocars were then placed at both sides of the camera port. We mounted a permanent cautery hook and Cadiere forceps on the right and left surgical arm, respectively. RESULTS: : We performed harvesting of the rGEA with the permanent cautery hook and Cadiere forceps mounted on the surgical arms. The rGEA were easily visualized and dissection with complete mobilization was achieved without injury in both models. The bleeding from the branch of the rGEA was prevented by use of the permanent cautery hook in the pig model. CONCLUSIONS: : We have preliminarily established, in pig, the feasibility of robotic rGEA harvesting without laparotomy, avoiding the risks of abdominal complications and expanding its use for all patients. However, further studies need to be undertaken to prove its practical feasibility in humans using the da Vinci surgical system to make it an effective operation. PMID- 22437231 TI - Impact of Previous PCI on Hospital Mortality After Off-Pump Coronary Artery Bypass Grafting in Diabetic Patients With Multivessel Disease. AB - OBJECTIVE: : Because percutaneous coronary intervention (PCI) has been performed excessively, many patients initially managed with PCI are being referred for coronary artery bypass grafting (CABG). The purpose of this study was to assess the impact of previous PCI on surgical mortality after off-pump CABG in diabetic patients with multivessel disease. METHODS: : Between January 2002 and April 2008, 595 consecutive patients (99.8% off-pump) had isolated CABG by one single surgeon. Of these, 274 patients with diabetes mellitus and multivessel disease were retrospectively analyzed. Patients with previous PCI (n = 79) were compared with patients with no previous PCI (n = 196), and risk-adjusted impact of previous PCI on surgical mortality after CABG was determined using multivariate and propensity score analyses. RESULTS: : All patients underwent off-pump CABG without conversion to cardiopulmonary bypass during operation. Patients with previous PCI had a significantly higher prevalence of history of myocardial infarction, renal dysfunction, and hemodialysis. Rates of surgical mortality were higher in patients with previous PCI (7.6% versus 1.0%, P = 0.008). After multivariate logistic regression analysis including all potential univariate predictors, previous PCI remained a strong predictor of surgical mortality [odds ratio (OR), 6.9; 95% confidence interval (CI), 1.2 to 42.1; P = 0.035]. After matching and regression adjustment by propensity score, the impact of previous PCI on surgical mortality was similar in direction (matching OR, 6.5; 95% CI, 0.8 to 55.0; P = 0.088; regression adjustment OR, 6.3; 95% CI, 1.2 to 33.6; P = 0.031). CONCLUSIONS: : Previous PCI increases the risk of surgical mortality after off-pump CABG in diabetic patients with multivessel disease. PMID- 22437232 TI - Comparison of minimally invasive direct coronary artery bypass surgery with implantation of drug-eluting stentsin patients with left anterior descending coronary artery disease. AB - OBJECTIVE: : Bypass surgery and percutaneous coronary interventions improve the clinical status of patients with left anterior descending coronary artery disease. However, these techniques differ in invasiveness and in the need for subsequent reinterventions. The development of minimally invasive direct coronary artery bypass (MIDCAB) surgery and of drug-eluting stents (DES) offers perspectives to close this gap. METHODS: : We compared the long-term clinical outcome of 308 patients after revascularization for isolated left anterior descending coronary artery disease. One hundred fifty-four patients were treated with MIDCAB and 154 with percutaneous coronary interventions and DES implantation. RESULTS: : Both groups were similar in age (63 +/- 13 and 62 +/- 10 years), Euroscore (3.3 +/- 2.8 and 3.4 +/- 2.6), and mean duration of follow-up (30 +/- 17 and 24 +/- 10 months). Two-year survival was similar after MIDCAB and after DES (97.4% and 94.8%). During follow-up, four patients (2.6%) of the MIDCAB group and 21 patients (13.6%) of the DES group needed subsequent revascularization of the target vessel (P = 0.001). Revascularization of a nontarget vessel was needed in 11 patients (7%) of the MIDCAB group and in 17 patients (11%) of the DES group (NS). Neurologic complications included two transient ischemic accidents and two strokes in the MIDCAB group but three fatal cerebral hemorrhages and one stroke in the DES group. Major adverse coronary and cerebrovascular events rates were 14% in the MIDCAB and 31% in the DES group. CONCLUSIONS: : MIDCAB and DES implantation showed similar rates of mortality but a higher reintervention rate after DES. Anticoagulation implications remain critical for the future of DES. PMID- 22437233 TI - Tactile mapping system: a novel imaging technology for surface topography and elasticity of tissues or organs. AB - OBJECTIVE: : We demonstrated that the tactile mapping system (TMS) has a high degree of spatial precision in the distribution mapping of surface elasticity of tissues or organs. METHODS: : Samples used were a circumferential section of a small-caliber porcine artery (diameter: ~3 mm) and an elasticity test pattern with a line and space configuration for the distribution mapping of elasticity, prepared by regional micropatterning of a 14-MUm thick gelatin hydrogel coating on a polyurethane sheet. Surface topography and elasticity in normal saline were simultaneously investigated by TMS using a probe with a diameter of 5 or 12 MUm, a spatial interval of 1 to 5 MUm, and an indentation depth of 4 MUm. RESULTS: : In the test pattern, a spatial resolution in TMS of <5 MUm was acquired under water with a minimal probe diameter and spatial interval of the probe movement. TMS was used for the distribution mapping of surface elasticity in a flat, circumferential section (thickness: ~0.5 mm) of a porcine artery, and the concentric layers of the vascular wall, including the collagen-rich and elastin rich layers, could be clearly differentiated in terms of surface elasticity at the spatial resolution of <2 MUm. CONCLUSIONS: : TMS is a simple and inexpensive technique for the distribution mapping of the surface elasticity in vascular tissues at the spatial resolution <2 MUm. TMS has the ability to analyze a complex structure of the tissue samples under normal saline. PMID- 22437234 TI - Left atrial myxoma: extraction by robotic and vacuum assistance. AB - We report a single case of left atrial giant myxoma excision using the da Vinci S surgical system in a 47-year-old woman. A vacuum extractor device was designed to avoid tumor fragmentation or embolization. The myxoma was entirely removed under aspiration through the extractor device, achieving all the surgical tenets of myxoma excision. PMID- 22437235 TI - Robotic fourth-arm enucleation of an esophageal leiomyoma and review of literature. AB - Esophageal leiomyomas are resected in symptomatic and/or malignancy-suspicious cases. Traditionally, they have been removed by laparotomy or thoracotomy and more recently by thoracoscopy and laparoscopy. Mucosal injury is reported as high as 7% of cases but may be higher in unreported general practice. Robotic technology seems to offer advantages. We describe a robotic approach that seems to minimize mobilization of the esophagus, potentially decreasing the likelihood of mucosal injury and postoperative recovery time. We review the literature to evaluate the reports of mucosal injury with the open, minimally invasive, and robotic techniques and describe our own method. To improve efficiency, we use a four-arm technique. PMID- 22437236 TI - High-dose daptomycin for cardiac implantable electronic device-related infective endocarditis caused by staphylococcal small-colony variants. PMID- 22437237 TI - Nomenclature for immune correlates of protection after vaccination. AB - Identification of immune correlates of protection after vaccination is an important part of vaccinology for both theoretical and practical reasons. The terminology and definition of correlates have been confusing, because different authors have used variable terms and concepts. Here, we attempt to give precision to the field by defining 3 terms: correlate of protection (CoP), mechanistic correlate of protection (mCoP), and nonmechanistic correlate of protection (nCoP). A CoP is a marker of immune function that statistically correlates with protection after vaccination that may be either an mCoP, which is a mechanistic cause of protection, or an nCoP, which does not cause protection but nevertheless predicts protection through its (partial) correlation with another immune response(s) that mechanistically protects. PMID- 22437238 TI - Pharmacokinetic and pharmacodynamic issues for antimicrobial therapy in patients with cancer. AB - In patients battling cancer, many aspects of antimicrobial treatment become more complex, and standard antimicrobial regimens may be inadequate. Various pathophysiological changes in critically ill patients with cancer significantly affect the pharmacokinetics (PK) of antimicrobials. In an unacceptably high percentage of these patients, variability of relevant PK parameters results in inadequate antimicrobial drug exposure across all drug classes. The pathogen, with its susceptibility to an antibacterial agent (ie, pharmacodynamics [PD]), is a given; however, drug exposure (ie, PK) can be influenced by adjusting the dosage regimen. Dosage optimization strategies to improve the probability of attaining the PK/PD target and, thus, achieve clinical success are a key area of current translational research. An intensified focus on dosage regimens targeted at bacterial killing of both the fully susceptible bacterial population and resistant mutants may prevent emergence of resistance while also better meeting the needs of this substantial patient population. PMID- 22437239 TI - Influenza-associated pneumonia among hospitalized patients with 2009 pandemic influenza A (H1N1) virus--United States, 2009. AB - BACKGROUND: Pneumonia was a common complication among hospitalized patients with 2009 pandemic influenza A H1N1 [pH1N1] in the United States in 2009. METHODS: Through 2 national case series conducted during spring and fall of 2009, medical records were reviewed. A pneumonia case was defined as a hospitalized person with laboratory-confirmed pH1N1 virus and a chest radiographic report consistent with pneumonia based on agreement among 3 physicians. RESULTS: Of 451 patients with chest radiographs performed, 195 (43%) had pneumonia (spring, 106 of 237 [45%]; fall, 89 of 214 [42%]). Compared with 256 patients without pneumonia, these 195 patients with pneumonia were more likely to be admitted to the intensive care unit (52% vs 16%), have acute respiratory distress syndrome (ARDS; 26% vs 2%), have sepsis (18% vs 3%), and die (17% vs 2%; P < .0001). One hundred eighteen (61%) of the patients with pneumonia had >=1 underlying condition. Bacterial infections were reported in 13 patients with pneumonia and 2 patients without pneumonia. Patients with pneumonia, when compared with patients without pneumonia, were equally likely to receive influenza antiviral agents (78% vs 79%) but less likely to receive antiviral agents within <=2 days of illness onset (28% vs 50%; P < .0001). CONCLUSIONS: Hospitalized patients with pH1N1 and pneumonia were at risk for severe outcomes including ARDS, sepsis, and death; antiviral treatment was often delayed. In the absence of accurate pneumonia diagnostics, patients hospitalized with suspected influenza and lung infiltrates on chest radiography should receive early and aggressive treatment with antibiotics and influenza antiviral agents. PMID- 22437240 TI - Electrophoretic Mobility of Lipoprotein Nanoparticle Mimics. AB - Lipoprotein particles (LPPs) are biological nanoparticles whose physiological roles are greatly influenced by their sizes. The four major classes of LP are: very low density lipoprotein, intermediate density lipoprotein, low density lipoprotein (LDL) and high density lipoprotein. Since the predominance of small, dense LDLs is associated with increased risk of coronary artery disease (CAD) and diabetes mellitus, LPP profiling can be used to predict metabolic risk factors. Highly tunable LPP mimics can be synthesized using nanoparticles to carefully control for size, lipid composition and surface charge to facilitate the study LPPs in CAD. Here, we engineered LPP mimics using gold nanoparticles between 10 50 nm in diameters. We measured the mobility and zeta potential of these LPP mimics and showed that each mimics have distinct electrokinetic properties and are electrostatically stable. PMID- 22437241 TI - Menthol inhibits the proliferation and motility of prostate cancer DU145 cells. AB - In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer. We have found that forced overexpression of TRPM8 in PC-3 cells can inhibit the cell proliferation and motility probably through the TRPM8 activation. In this study, we aimed to investigate whether activating the TRPM8 channel by its selective agonist menthol can inhibit the proliferation and motility of androgen-independent prostate cancer (AIPC) with remarkable expression of TRPM8. Menthol is a naturally occurring compound, which has been widely used in cosmetics and pharmaceutical products, and also as flavoring in food. DU145 cells are androgen-independent but have a remarkable expression of TRPM8. The demonstration of the existence of TRPM8 and the absence of TRPA1 in DU145 cells provided the foundation for the following experiments, because both TRPM8 and TRPA1 are molecular targets of menthol. The outcome of MTT assay indicated that menthol inhibited the cell growth (p < 0.01). Cell cycle distribution and scratch assay analysis revealed that menthol induced cell cycle arrest at the G(0)/G(1) phase (p < 0.01). Furthermore, menthol inhibited the migration of DU145 cells by downregulating the focal-adhesion kinase. So it suggests that the activation of the existing TRPM8 channels may serve as a potential and pragmatic treatment for those AIPC with remarkable expression of TRPM8, and menthol is a useful compound for future development as an anticancer agent. PMID- 22437244 TI - Triterpene glycosides from Astragalus angustifolius. AB - Six new cycloartane-type (1- 6) and four new oleanane-type (7- 10) triterpene glycosides were isolated from Astragalus angustifolius Lam., together with five known triterpene glycosides. Their structures were established by the extensive use of 1D and 2D-NMR experiments along with ESIMS and HRMS analysis. Compounds 1- 3 are glycosides of cycloastragenol, while compounds 4- 6 show the C-24 epimer of cycloastragenol as aglycone, encountered for the first time in nature. All compounds were evaluated for their antiproliferative activity in Hela, H-446, HT 29, and U937 cell lines. Only compound 8 displayed a weak activity with IC (50) values of 36 and 50 uM against Hela and HT-29 cell lines, respectively. PMID- 22437245 TI - Drimane-type sesquiterpenes with a dioxabicyclooctane skeleton from the fruiting bodies of Nigrofomes melanoporus and their cytotoxicity. AB - Two new drimane-type compounds, nigrofomins A ( 1) and B ( 2), possessing a rare dioxabicyclooctane moiety, were purified from the fruiting bodies of Nigrofomes melanoporus. Their structures were determined using 1D-, 2D-NMR and HR-ESI-MS spectroscopic analyses. In addition, 1 was established by X-ray crystallographic studies. Both nigrofomins A ( 1) and B ( 2) exhibited cytotoxicity on acute T cell leukemia (Jurkat), human nasopharyngeal carcinoma (NPC-TW01), and lung cancer (NCI-H661) cells with IC (50) values in the range of 99.44-246.32 uM. Furthermore, the effects of 1 and 2 on cell-cycle progression of Jurkat cells displayed a concentration-dependent accumulation in the G (0)/G (1) phase. PMID- 22437246 TI - A highly versatile microscope imaging technology platform for the multiplex real time detection of biomolecules and autoimmune antibodies. AB - The analysis of different biomolecules is of prime importance for life science research and medical diagnostics. Due to the discovery of new molecules and new emerging bioanalytical problems, there is an ongoing demand for a technology platform that provides a broad range of assays with a user-friendly flexibility and rapid adaptability to new applications. Here we describe a highly versatile microscopy platform, VideoScan, for the rapid and simultaneous analysis of various assay formats based on fluorescence microscopic detection. The technological design is equally suitable for assays in solution, microbead-based assays and cell pattern recognition. The multiplex real-time capability for tracking of changes under dynamic heating conditions makes it a useful tool for PCR applications and nucleic acid hybridization, enabling kinetic data acquisition impossible to obtain by other technologies using endpoint detection. The paper discusses the technological principle of the platform regarding data acquisition and processing. Microbead-based and solution applications for the detection of diverse biomolecules, including antigens, antibodies, peptides, oligonucleotides and amplicons in small reaction volumes, are presented together with a high-content detection of autoimmune antibodies using a HEp-2 cell assay. Its adaptiveness and versatility gives VideoScan a competitive edge over other bioanalytical technologies. PMID- 22437247 TI - Can enhanced recovery programmes be further improved by the addition of omega three fatty acids? AB - AIMS: The term "enhanced recovery programme (ERP)" means applying defined protocols to augment the recovery of patients following surgery. Inflammation is body's response to insults such as infection, injury and surgical procedures. Inflammatory mediators whose function is initially protective may cause undesirable consequences, if the response is unnecessarily prolonged. The principle effects of ERP result from the reduction of the profound stress which results following major surgical procedures. METHODS: A Pubmed literature search was undertaken using the keywords enhanced recovery, surgery and omega-3. The primary endpoint was whether the addition of omega-3 to ERP improved morbidity and mortality. RESULTS: Nine randomised trials examining the effect of omega-3 enriched diets following surgery were analysed. Inclusion of omega-3 helps in maintaining a positive nitrogen balance, overcome immune dysfunction, lower the incidence of post-operative infections with the consequence of reduced morbidity and mortality. CONCLUSIONS: The provision of early or continuous nutrition is one of the cornerstones of an ERP. A theoretically ideal regimen would provide an energy substrate and protein and contain a component which would limit inappropriate inflammation. The beneficial role of omega-3 results from a number of effects which limit the inflammatory response, principally by influencing the production of eicosanoids and modulating cytokines. They also enhance cell mediated immunity and preserve immune function better than standard dietary formulations. Although ERPs have already produced significant progress, there is sufficient evidence to suggest that the provision of omega-3 fatty acids may result in further improvements. PMID- 22437248 TI - Developing a standardized tool to improve nurse communication during shift report. AB - Standardization of communication has been suggested as an effective approach to improve communication during patient handoffs such as shift report. Using the clinical microsystem framework, unit leaders and nursing staff developed and pilot tested the medical intensive care unit communication tool. Findings from the pilot study indicated that perceived communication among nurses in general and communication specific to shift report improved significantly following implementation of the tool. PMID- 22437249 TI - Standardized discharge planning assessments: impact on patient outcomes. AB - The purpose of the study was to determine whether a difference exists in patient reported problems and unmet needs after discharge when a standardized discharge planning assessment is added to usual care by staff nurses. Two groups of 130 adult patients were enrolled while hospitalized. The intervention group patients reported fewer unmet needs (P = .01) and had fewer problems complying with their discharge instructions (P = .04). Standardizing discharge planning assessments by staff nurses may improve identification of continuing care needs. PMID- 22437250 TI - The interdepartmental ticket (IT) factor: enhancing communication to improve quality. AB - This article presents the implementation and 1-year evaluation of a staff nurse driven initiative addressing a Joint Commission patient safety imperative to improve the consistency of handoff communication. An interdepartmental ticket was developed and implemented through a planned process. The interdepartmental ticket serves as a requisite passport for providing key communication of critical information to facilitate a safe transition between medical-surgical and progressive care nursing units and specific ancillary departments. PMID- 22437251 TI - Management and outcome of salivary duct carcinoma in major salivary glands. AB - Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with poor prognosis. Its histomorphology is distinctly reminiscent of the ductal carcinoma of the breast. We reviewed the treatment and outcome of SDCs at a single tertiary care centre. Twenty-five cases of SDC of major salivary gland origin, diagnosed and treated at the Department of Otolaryngology, Head and Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland, during a 14-year period from 1997 to 2011, were reviewed retrospectively. Survival outcome was analyzed for 18 patients with a minimum follow-up of 24 months. There were 16 male (64 %) and 9 female (36 %) patients with a median age of 61 years (range 36-82 years). The majority of the cases occurred in the parotid gland (n = 21, 84 %) followed by the submandibular gland (n = 4, 16 %). The primary treatment consisted of surgical resection in all cases and 17 (68 %) patients also underwent neck dissection. Most of the patients (n = 18, 72 %) were treated with postoperative radiotherapy. Seven patients (28 %) had a disease recurrence within a median follow-up time of 15 months (range 3-27 months). In the group (n = 18) with a minimum follow-up time of 24 months, the 2- and 5-year overall and disease specific survival rates were 66, 41 % and 75, 55 %, respectively. These results confirm the aggressive nature of SDCs in major salivary glands. Diagnostics and management of these tumours need to be centralized in experienced surgical Head and Neck Oncology Centres, and new treatment strategies should be investigated. PMID- 22437252 TI - Current treatment options for recurrent/metastatic head and neck cancer: a post ASCO 2011 update and review of last year's literature. AB - The majority of patients with a squamous cell carcinoma of the head and neck present with locally advanced tumors. The first-line treatment of locally advanced tumor stages consists of a combined modality management. Despite these aggressive protocols, many patients develop locoregional recurrences or metastasis and place particularly high demands on the interdisciplinary treatment team. Treatment with a curative intent must be differentiated from a palliative one. In addition to prior treatment, resectability, age and performance status, patient wishes must be taken into consideration in treatment planning, especially considering that most therapies offer little to no overall survival benefit. Salvage surgery, chemo- and target therapies, and reirradiation are head and neck surgeon's and radiooncologist's weapons in the fight against these strong opponents. This review focuses on publications and meeting news from last year and reviews the current status of the clinical application of each treatment modality in recurrent or metastatic head and neck cancer. PMID- 22437253 TI - Identification of three new type-specific antigen epitopes in the capsid protein of porcine circovirus type 1. AB - Porcine circovirus type 1 (PCV1) has been identified as a contaminant of porcine kidney cell line (PK-15). Serological evidence and genetic studies have suggested that PCV1 is widespread in domestic pigs. In this study, monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) were generated against a recombinant PCV1 Cap protein (PCV1-Cap), which was expressed using the baculovirus system. PEPSCAN analysis was used to identify epitopes on the PCV1-Cap with mAbs and pAbs. Three linear B-cell epitopes, including residues (85)GGTNPLP(91), (162)FTPKPELDKTIDWFHPNNK(180) and (219)YVQFREFILKDPLNK(233), specific for PCV1 Cap, were finely defined. These results will facilitate future investigations into antigenic differences and differential diagnosis between PCV1 and PCV2. PMID- 22437254 TI - Spatial and temporal diversity of begomoviral complexes in papayas with leaf curl disease. AB - Old World, monopartite begomoviruses associated with satellite DNA beta were observed in papaya showing symptoms of leaf curl disease sampled randomly over five years from within a radius of 250 km in north-central India. Three groups of DNA A sequences were evident. One group resembled chili leaf curl virus infecting tomatoes (ChiLCuV). Another group resembled tomato leaf curl New Delhi virus (ToLCuNDV). The third group was novel (tentatively named papaya leaf crumple virus, PaLCrV), with less than 89% identity to known begomovirus sequences in the GenBank database. At least seven DNA A sequences were putative recombinants. The AC4-encoding regions exhibited highest numbers of non-synonymous substitutions. Most DNA beta sequences resembled tomato leaf curl virus-associated DNA betas. A few DNA beta sequences were similar to that of croton yellow vein mosaic virus associated DNA beta (CroYVMVbeta). One DNA beta sequence was novel and showed <65% similarity to its counterparts. Mixed infections and sequence diversity among 25 cloned av1 genes indicated that papayas grown in plantations, kitchen gardens and feral patches in the region are vulnerable to disease outbreak. No geographic or temporal patterns were discernable in the distribution of these viruses. PMID- 22437255 TI - The movement protein of barley yellow dwarf virus-GAV self-interacts and forms homodimers in vitro and in vivo. AB - The 17-kDa movement protein (MP) of the GAV strain of barley yellow dwarf virus (BYDV-GAV) can bind the viral RNA and target to the nucleus. However, much less is known about the active form of the MP in planta. In this study, the ability of the MP to self-interact was analyzed by yeast two-hybrid assay and bimolecular fluorescence complementation. The BYDV-GAV MP has a strong potential to self interact in vitro and in vivo, and self-interaction was mediated by the N terminal domain spanning the second alpha-helix (residues 17-39). Chemical cross linking and heterologous MP expression from a pea early browning virus (PEBV) vector further showed that MP self-interacts to form homodimers in vitro and in planta. Interestingly, the N-terminal domain necessary for MP self-interaction has previously been identified as important for nuclear targeting. Based on these findings, a functional link between MP self-interaction and nuclear targeting is discussed. PMID- 22437256 TI - Plasma sodium and blood pressure in individuals on haemodialysis. AB - To study the relationship between pre-dialysis plasma sodium and blood pressure (BP), we performed an audit of patients who were on stable haemodialysis at St Bartholomew's and The Royal London Hospital from 1 June 2009 to 15 June 2010. There were 651 patients with 7445 dialysis sessions where both plasma biochemistry and BP were measured before haemodialysis. We found a significant association between plasma sodium and both systolic and diastolic BP. A 1 mmol l( 1) increase in plasma sodium was related to 0.65/0.36 mm Hg increase in BP (P<0.001 for both systolic and diastolic BP) after adjusting for potential confounding factors, including weight gain between dialyses and plasma albumin, both of which are crude indices of extracellular fluid volume. A separate analysis excluding individuals who were on BP treatment showed a similar relationship, with a 1-mmol l(-1) increase in plasma sodium associated with 0.82/0.56 mm Hg increase in BP (P<0.001 for both, N=177). These results provide further support for the accumulating evidence that plasma sodium has an important role in regulating BP, which may be independent of extracellular volume. Our findings in conjunction with other evidence suggest that small changes in plasma sodium could be an important mechanism for the beneficial effects of lower dialysate sodium and lower salt intake on BP in haemodialysis patients. PMID- 22437257 TI - Chiral uranium phosphonates constructed from achiral units with three-dimensional frameworks. AB - Two chiral, porous uranium methylenediphosphonates, [C(2)H(10)N(2)]{UO(2)[CH(2)(PO(3))(2)]}.H(2)O (UC1P2N-1) and [N(C(2)H(5))(4)]K{(UO(2))(3)[CH(2)(PO(3))(2)](2)(H(2)O)(2)}.1.5H(2)O (KUC1P2-1), have been synthesized without chiral starting materials. Both compounds display channels ~1 * 1 nm that are large enough for these materials to conduct ion exchange with coordination complexes such as [Co(en)(3)](3+). PMID- 22437261 TI - Zygomycosis caused by Rhizopus microsporus and Rhizopus oryzae in Madhya Pradesh (M.P.) Central India: a report of two cases. AB - Zygomycosis encompasses infections due to two distinct orders of fungi, Mucorales and Entomophthorales. With rare exception, Entomophthorales are restricted to tropical areas. By contrast, mucorales are ubiquitous opportunistic fungi, which play a crucial part in the natural decay process. In human pathology, they may be opportunistic agents and be responsible for rare infection called (Mucormycosis) zygomycosis. We report two cases of zygomycosis from Madhya Pradesh, Central India, one caused by Rhizopus oryzae in a diabetic patient and another caused by Rhizopus microsporus in an apparently healthy patient. The cases were diagnosed by direct microscopy, histopathological examination and culture. Both the patients were successfully treated with liposomal amphotericin B. Rhizopus microsporus is, for the first time reported from Madhya Pradesh, India, causing rhino-maxillary orbital zygomycosis. PMID- 22437262 TI - Practical guidelines for adaptive seamless phase II/III clinical trials that use Bayesian methods. AB - Hommel (Biometrical Journal; 45:581-589) proposed a flexible testing procedure for seamless phase II/III clinical trials. Schmidli et al. (Statistics in Medicine; 26:4925-4938), Kimani et al. (Statistics in Medicine; 28:917-936) and Brannath et al. (Statistics in Medicine; 28:1445-1463) exploited the flexible testing of Hommel to propose adaptation in seamless phase II/III clinical trials that incorporate prior knowledge by using Bayesian methods. In this paper, we show that adaptation incorporating prior knowledge may lead to higher power. Other important issues to consider in such adaptive designs are the gain in power (or saving in patients) over traditional testing and how utility values used to make the adaptation may be used to stop a trial early. In contrast to the aforementioned authors, we discuss these issues in detail and propose a unified approach to address them so that implementing the aforementioned designs and proposing similar designs is clearer. PMID- 22437263 TI - Venous thromboembolism risk factors in breast cancer patients undergoing deep inferior epigastric perforator flap reconstruction. PMID- 22437265 TI - Predicting discharge location of hip fracture patients; the new discharge of hip fracture patients score. AB - PURPOSE: This paper reports on the development and validity of a new instrument, called the discharge of hip fracture patients score (DHP), that predicts at admission the discharge location in patients living in their own home prior to hip fracture surgery. METHODS: A total of 310 patients aged 50 years and above were included. Risk factors for discharge to an alternative location (DAL) were analysed with a multivariable regression analysis taking the admission variables into account with different weights based on the estimates. The score ranged from 0-100 points. The cut-off point for DAL was calculated using a ROC analysis. Reliability of the DHP was evaluated. RESULTS: Risk factors for DAL were higher age, female gender, dementia, absence of a partner and a limited level of mobility. The cut-off point was set at 30 points, with a sensitivity of 83.8%, a specificity of 64.7% and positive predictive value of 79.2%. CONCLUSION: The DHP is a valid, simple and short instrument to be used at admission to predict discharge location of hip fracture patients. PMID- 22437266 TI - P2Y(4) nucleotide receptor: a novel actor in post-natal cardiac development. AB - Communication between endothelial cells and cardiomyocytes is critical for cardiac development and regeneration. However the mechanisms involved in these endothelial-cardiomyocyte interactions remain poorly understood. Nucleotides are released within the heart, especially under ischemia or pressure overload. The function of P2Y nucleotide receptors in cardiac development has never been investigated. Here we show that adult P2Y(4)-null mice display microcardia. P2Y(4) nucleotide receptor is expressed in cardiac endothelial cells but not in cardiomyocytes. Loss of P2Y(4) in cardiac endothelial cells strongly inhibits their growth, migration and PDGF-B secretion in response to UTP. Proliferation of microvessels and cardiomyocytes is reduced in P2Y(4)-null hearts early after birth, resulting in reduced heart growth. Our study uncovers mouse P2Y(4) receptor as an essential regulator of cardiac endothelial cell function, and illustrates the involvement of endothelial-cardiomyocyte interactions in post natal heart development. We also detected P2Y(4) expression in human cardiac microvessels. P2Y(4) receptor could constitute a therapeutic target to regulate cardiac remodelling and post-ischemic revascularisation. PMID- 22437267 TI - Off pump coronary artery bypass: a valuable technique but not for everyone. PMID- 22437268 TI - Comparison of Minithoracotomy versus Sternotomy in 304 Consecutive Tricuspid Valve Operations. AB - OBJECTIVE: : The relative outcomes of sternotomy versus thoracotomy for tricuspid valve operation were examined over a 22-year period. METHODS: : Three hundred four consecutive patients undergoing tricuspid valve operation using right minithoracotomy (THORC group; n = 124) versus median sternotomy (STERN group; n = 180) between 1985 and 2007 were retrospectively analyzed. Minithoracotomy used a 6-cm incision with femoral venous cannulation and augmented venous return. Sternotomy patients undergoing aortic valve, coronary bypass, or other procedure not feasible through a right minithoracotomy were excluded. RESULTS: : Both groups were similar except that STERN patients had an earlier operative year. Combined mitral and tricuspid valve operation was performed in 70% (214/304) of patients. The tricuspid valve was repaired in 59% (180/304) of patients. Previous sternotomy was present in 56% (171/304) of patients. The mean cardiopulmonary bypass times were longer in the THORC group (216 vs. 167 minutes, P < 0.0001). THORC was associated with a lower 30-day mortality (2% vs. 11%, P = 0.007), less atrial fibrillation (18% vs. 34%, P = 0.0025), less renal failure (3% vs. 11%, P = 0.016), and shorter length of stay (11 vs. 15 days, P = 0.012), although these differences were less apparent in more recent years. Stroke (3% vs. 2%, P = 0.72), respiratory failure (7% vs. 31%, P = 0.06), and infection rates (11% vs. 16%, P = 0.25) were similar. Five-year survival was also similar (63% vs. 64%, P = 0.84). CONCLUSIONS: : Given the limitations of a large, retrospective experience, minithoracotomy versus sternotomy is associated with low short-term morbidity and mortality, with advantages of avoiding sternotomy and minimizing mediastinal dissection in an otherwise high-risk group of patients. PMID- 22437269 TI - Cerebral Emboli Generation During Off-Pump Coronary Artery Bypass Grafting With a Clampless Device versus Partial Clamping of the Ascending Aorta. AB - OBJECTIVE: : It is not known whether use of a clampless facilitating device during proximal graft anastamosis decreases intraoperative cerebral emboli in patients with mild atherosclerotic ascending aorta (AAA) having off-pump coronary artery bypass. METHODS: : After intraoperative epiaortic ultrasound showed no more than mild (grade I-II) atherosclerotic ascending aorta, 20 patients were randomized to receive either partial clamping (PC, n = 10) or the HEARTSTRING clampless device (HS, n = 9) for proximal graft construction on the ascending aorta. Continuous transcranial Doppler monitoring, with capability to discern gaseous from solid particulates, was used intraoperatively to monitor high intensity transient signals (HITS) in the middle cerebral arteries. Postoperative diffusion-weighted brain magnetic resonance imaging documented old and new ischemic brain lesions. RESULTS: : There were no significant differences between the groups in the number of proximals (P = 0.14), distals (P = 0.4), or intraoperative cell saver transfusions (P = 0.69). The total number of HITS was not significantly different between the PC and HS groups (P = 0.2). However, the number of solid HITS was significantly lower in the HS than in the PC group (2.7 +/- 2.6 versus 14.0 +/- 8.1; P < 0.001). The number of gaseous emboli in the HS group was fourfold greater when a mister-blower rather than a suction device was used to clear blood away from the HS site. Postoperatively, there were no deaths, myocardial infarctions, or clinical strokes observed in either group. Diffusion weighted cerebral magnetic resonance imaging revealed no statistical difference between groups for new infarct lesions. CONCLUSIONS: : Use of the HS device during off-pump coronary artery bypass was associated with significantly fewer intraoperative solid emboli in the middle cerebral artery than PC of the ascending aorta. PMID- 22437270 TI - Sutureless Aortic Valve Replacement via Partial Sternotomy. AB - OBJECTIVE: : For elderly patients with symptomatic aortic valve stenosis, aortic valve replacement with tissue valves is still the treatment of choice. Stentless valves were introduced to clinical practice for better hemodynamic features as compared with stented tissue valves. However, the implantation is more complex and time demanding, especially in minimal invasive aortic valve replacement. We present our clinical data on 22 patients having received a sutureless ATS 3f Enable aortic bioprosthesis via partial upper sternotomy. METHODS: : The procedure was performed using CPB with cardioplegic arrest. After resection of the stenotic aortic valve and debridement of the annulus, the valve was inserted and released. Mean age was 79 years, and mean logistic Euroscore was 13. Subvalvular myectomy was performed in two patients. Prosthetic valve sizes were 19 mm (n = 1), 21 mm (n = 7), 23 mm (n = 6), 25 mm (n = 6), and 27 mm (n = 2). RESULTS: : Implantation of the valve required 10 +/- 6 minutes. Cardiopulmonary bypass and aortic crossclamp time were 87 +/- 16 and 55 +/- 11 minutes, respectively. Early mortality (<90 days) was 9% (2 patients). No paravalvular leakage was detected intraoperatively or in follow-up echocardiography. The mean transvalvular gradients were 9 +/- 6 mm Hg at discharge and 8 +/- 2 mm Hg at 1 year follow-up. CONCLUSIONS: : Sutureless valve implantation via partial sternotomy is feasible and safe with the ATS 3f Enable bioprosthesis. Reduction of cardiopulmonary bypass and aortic crossclamp time seems possible with increasing experience. Hemodynamic data are very promising with low gradients at discharge and after 12 month. Sutureless valve implantation via minimal invasive access may be an alternative treatment option for elderly patients with high comorbidity. PMID- 22437271 TI - Resizable ventricular patch plasty in the porcine left ventricle: a pilot study. AB - OBJECTIVE: : Endoventricular circular patch plasty is a method used to reconstruct the ventricular cavity in patients with (post) ischemic left ventricular aneurysm or global dilatation. However, late redilatation with mitral regurgitation has been reported, in which postoperative apex shape seems to play an important role. We studied the feasibility of ventricular volume downsizing with a variably shaped patch in porcine hearts. METHODS: : In five in vitro and two acute animal experiments, a dyskinetic aneurysm was simulated with a pericardial insert. Reducing patch surface by changing patch shape diminished end diastolic volume. In vitro, static end-diastolic volume was determined for each patch shape using volumetry and echocardiography. In the acute animal experiments, preliminary observations of patch behavior in live material were made, and pressure/time relationship, dPdTmax, was registered. RESULTS: : In vitro, bringing the convex patch into a flat plane reduced LV volume from 66 +/- 7 mL (aneurysm) to 49 +/- 5 mL. Four of 5 patch shapes further reduced volume to a mean of 38 +/- 7 mL (P = 0.03). The in vitro echocardiographic measurements correlated with volumetry findings (r = 0.81). In the acute animal experiments, dPdTmax varied with patch shape, independent of volume changes. CONCLUSIONS: : In this pilot study, in vitro shape configuration of the resizable ventricular patch resulted in a calibrated end-diastolic volume reduction. The data of the two in vivo pilot experiments clearly indicate that change in patch configuration in the situation of more or less unchanged end-diastolic volume had impact on cardiac performance. Future studies must substantiate the results of this observation. PMID- 22437272 TI - Minimally invasive direct coronary artery bypass as a primary strategy for reoperative myocardial revascularization. AB - OBJECTIVE: : Conventional reoperative coronary artery bypass grafting is associated with risk of sternal re-entry, injury to patent grafts, and embolization from diseased grafts. Sternal sparing minimally invasive direct coronary artery bypass (MIDCAB) avoids such risks in cases where it is technically feasible. We sought to examine in-hospital outcomes of reoperative MIDCAB surgery. METHODS: : We recorded prospective standardized data from the New York Cardiac Surgical Reporting System database of 369 reoperative MIDCAB cases from 1996 to 2006 and compared with 822 primary MIDCAB patients in the same time period. We compared the preoperative risk profile and postoperative in-hospital outcomes and length of stay for both groups. RESULTS: : There was a significantly higher risk profile typical of the reoperative patient population (P < 0.001 for stroke, peripheral/cerebrovascular disease, extensive aortic calcification, renal failure, and left ventricular ejection fraction <40%) compared with the primary MIDCAB group. Despite this fact, there was no difference in the in-hospital outcomes and length of hospital stay between the two groups. CONCLUSIONS: : Reoperative MIDCAB provides targeted coronary revascularization and avoids hazards of sternal re-entry, graft injury and manipulation, and deleterious effects of cardiopulmonary bypass. This hastens recovery and provides excellent early outcomes equivalent to primary MIDCAB procedures. PMID- 22437273 TI - Acute feasibility study of a novel device for the treatment of mitral regurgitation in a normal canine model. AB - OBJECTIVE: : The purpose of this study was to evaluate the implantability of a novel epicardial mitral annuloplasty device and its ability to reduce the septal lateral (S-L) dimension of the mitral annulus. METHODS: : The devices were implanted on the beating heart in 2 healthy dogs (the 24-mm long device in dog A and the 27-mm and 24-mm standard devices in dog B) by sliding the anterior arm onto the floor of the transverse sinus and positioning the posterior arm just apical to the atrioventricular groove on the left ventricular posterolateral wall. The devices were secured with titanium helical tacks driven through the device into the ventricular wall. Two-dimensional epicardial echocardiograms were performed before and after device implantation to evaluate the degree of mitral regurgitation (MR) and the S-L dimension. RESULTS: : Device implantation was uneventful, taking only ~30 seconds to deploy. MR (1+) in both dogs at baseline was reduced to zero after implant. The reductions in S-L dimension in systole for the 24-mm device were 7.5% in dog A and 30.5% in dog B. For the 27-mm device in dog B, S-L reduction in systole was 29.9%. The leaflet coaptation length was increased in both cases. CONCLUSIONS: : The new device was effective in reducing S-L dimension and 1+ MR without requiring the use of cardiopulmonary bypass. We are currently evaluating this device for the treatment of MR in a rapid-pacing canine heart failure model. PMID- 22437274 TI - Off-pump Coronary Bypass Surgery in Patients With Low Ejection Fraction: Is There a Long-Term Survival Advantage? AB - OBJECTIVE: : Long-term survival after off-pump surgery in patients with low ejection fraction was investigated. METHODS: : Three hundred forty-six patients with ejection fraction 30% or less with isolated off-pump coronary artery bypass surgery (OPCAB) were compared with a propensity matched historical group operated on-pump (ONCAB) and with data from literature after percutaneous coronary intervention and OPCAB surgery. RESULTS: : The lower invasiveness of OPCAB contributed to a significantly better 30-day survival, shorter postoperative length of stay, and fewer in-hospital complications. Incomplete revascularization of the posterior and lateral territories of the heart correlated with higher 1 year mortality. The probability of survival for 8 years after OPCAB was 50.1% (n = 76) versus 49.7% (n = 82) for ONCAB without comparable data from literature for OPCAB or percutaneous coronary intervention in these high-risk patients. CONCLUSIONS: : OPCAB surgery in patients with low ejection fraction is a viable alternative but so far without demonstrable long-term survival advantage to ONCAB. PMID- 22437275 TI - The active tube clearance system: a novel bedside chest-tube clearance device. AB - OBJECTIVE: : Chest-tube clogging can lead to complications after heart and lung surgery. Surgeons often choose large-diameter chest tubes or place more than one chest tube when concerned about the potential for clogging. The purpose of this report is to describe the design and function of a proprietary active tube clearance system, a novel device that clears clots and debris from chest tubes. DEVICE DESCRIPTION:: The active tube clearance system is a novel chest tube clearance apparatus developed to maintain chest tube patency. Chest tube clearance is achieved by advancing the specially designed clearance member back and forth within the chest tube under sterile conditions, breaking down and pulling clots back toward the drainage receptacle, thereby leaving the inner portion of the chest tube clear of any obstructing material. CONCLUSIONS: : By maintaining chest tube patency, chest tube drainage can be performed more safely, and this apparatus may possibly lead to the use of smaller chest tubes and less invasive insertion techniques. PMID- 22437276 TI - Successful intracardiac robotic surgery: initial results from Japan. AB - OBJECTIVE: : The purpose of this study is to report our 2-year experience of performing endoscopic intracardiac procedures using the da Vinci Surgical System. Our teams at Kanazawa University and Tokyo Medical University groups began using the da Vinci Surgical System (Intuitive Surgical, Inc, Sunnyvale, CA) in 2005. This series represents the first Japanese application of robotic technology for totally endoscopic open-heart surgery. METHODS: : From January 2008 to February 2009, 10 patients (mean age: 46.8 +/- 16.3 years, 70% women) underwent endoscopic atrial septal defect closure and resection of the left atrial myxoma using the da Vinci Surgical System and peripheral cardiopulmonary bypass technique. Of the 10 patients, nine were classified as New York Heart Association class II and 1 patient exhibited atrial arrhythmias. In addition, two patients required mitral valve plasty (n = 2) and tricuspid annuloplasty (n = 1). RESULTS: : Mean da Vinci Surgical System working time was 140.7 +/- 57.4 minutes. Mean cardiopulmonary bypass and aortic cross clamp times were 103.1 +/- 37.1 and 30.0 +/- 16.9 minutes, respectively. There were no conversions to sternotomy or small thoracotomy. There were no hospital deaths. Mean intensive care unit and hospital stays were 1 day and 3.1 +/- 0.3 days, respectively. All patients appreciated the cosmetic result and fast recovery. CONCLUSIONS: : Closed-chest atrial septal defect closure and myxoma resection performed using robotic techniques achieved excellent results and rapid postoperative recovery and provided an attractive cosmetic advantage over median sternotomy. PMID- 22437277 TI - Percutaneous aortic valve replacement: emerging tractability for sufficient intracardiac resection of the aortic valve. AB - OBJECTIVE: : The feasibility of endovascular resection of highly calcified aortic valves has already been demonstrated by our group. Different endovascular and intracardiac tractability methods were applied. In this study, these technologies were analyzed comparing the tractability, the resection time, and the lesions in the surrounding tissue. METHODS: : All aortic valve resections (seven human hearts and 21 porcine hearts) were performed using a Thulium:YAG laser (continuous wave, wavelength of 2.01 MUm, 20 watts power rating). In the first resection system, the laser fiber was controlled by a free in-lying flexible endoscope (O 2.5 mm, length of 600 mm). The distal part of the endoscope (40 mm) was moved in one plane by proximal manual control (three degrees of freedom). The resection system was separated into defined rooms assigning one room for one tool. The fiber was controlled by the above-mentioned endoscope (*) (three degrees of freedom). The third resection system was a mechanical microactuator carrying the laser fiber (three degrees of freedom). The fourth resection system contains a rotatable inlay with defined rooms and a newly designed nitinol (NiTi) microactuator that controlled the laser fiber (four degrees of freedom). The resection time per leaflet was measured in minutes. Gross anatomy and histology in the surrounding tissue were evaluated. RESULTS: : The resection time in approaches 1, 2, 3, and 4 was 5.5 +/- 2.3 minutes, 7.4 +/- 2.7 minutes, +/- 6.6 minutes, and2.3 +/- 1.2 minutes, respectively. The gross anatomy and histology of collateral damages revealed only superficial lesions of the surrounding tissue. The amount of lesions and the resection time were lower in the fourth approach with four degrees of freedom. CONCLUSIONS: : This analysis demonstrated that a precise tractability with four degrees of freedom is necessary for a faster and safer endovascular resection of the aortic valve. The analysis will help to optimize the ongoing development of the endovascular and intracardiac resection technology. PMID- 22437278 TI - Use of a novel acellular xenograft as a patch for aortic annular enlargement during aortic valve replacement. AB - A patient with a history of aortic valve endocarditis and surgical debridement presented with acute congestive heart failure because of severe aortic stenosis. During valve replacement surgery, an aortic annular enlargement was required to overcome a potential patient-prosthesis mismatch. We describe the use of a novel, bioresorbable, acellular xenograft for the enlargement patch. This material is expected to remodel into native patient tissue over time. This case offers an alternative implant for left heart reconstruction using a regenerative patch. PMID- 22437279 TI - Novel techniques in mitral repair: extended and rotational chordal transfer. AB - Mitral valve repair is preferable to mitral valve replacement because of low rate of thromboembolism, resistance to endocarditis, excellent late durability, and no need for anticoagulation in the majority of patients. This article describes 2 novel techniques for repairing the anterior mitral leaflet prolapse. The extended chordal transfer is achieved by transferring an extended segment of posterior mitral leaflet and, rotational chordal transfer, by rotating the transferred segment either vertical or horizontal. Both techniques are simple and reproducible. It uses patient's own natural chorda and eliminates the problem of knotting and determination of appropriate chordal length faced with other techniques. PMID- 22437280 TI - Fluidic low pass filter for hydrodynamic flow stabilization in microfluidic environments. AB - Fluctuations in flow rate invariably occur in microfluidic devices. This fluidic instability results in a deteriorating performance and the suspension of their unique functions occasionally. In this study, a fluidic-LPF (low pass filter), which is composed of an ACU (air compliance unit) and a FCSP (fluidic channel with high fluidic resistance for sufficient preload), has been proposed for providing the stabilization of hydrodynamic flow in microfluidic devices. To investigate the characteristics of various fluidic networks including our fluidic LPF, we used a parametric identification method to estimate the time constants via a transient response that was based on a discrete parameter model. In addition, we propose the use of a pulsation index (PI) to quantify the fluctuations in flow rate. We verified the formula for PI derived herein by varying individually both the periods and the air compliance volumes in the ACU, both theoretically and experimentally. We found that the PI depended strongly on either the time constants or the periods of the flow rates at the inlet. Additionally, the normalized differences between the experimental results and the theoretical estimations were less than 6%, which shows that the proposed formula for PI can provide an accurate quantification of the fluctuations in flow, and estimate the parametric effects. Finally, we have successfully demonstrated that our fluidic-LPF can regulate fluctuations in the flow at extremely low flow rates (~ 10 MUL h(-1)) and can also control severe fluidic fluctuations (PI = 0.67) with excessively long periods (100 s) via a microfluidic viscometer. We therefore believe that the stabilization of hydrodynamic flow using a fluidic-LPF could be used easily and extensively with a range of microfluidic platforms that require constant flow rates. PMID- 22437281 TI - Arthroscopic inferior capsular shift: long-term follow-up. AB - BACKGROUND: Neer and Foster's open inferior capsular shift to treat acquired cases of anteroinferior shoulder instability due to an overstretched and redundant capsule is described with good results. Recently, new arthroscopic techniques were described to manage this problem. PURPOSE: To assess the results of a new arthroscopic reinforced inferior capsular shift technique based on Neer and Foster's open inferior capsular shift. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This new technique of arthroscopic inferior capsular shift was used to treat 108 patients with anteroinferior shoulder instability due to capsular redundancy as confirmed clinically and during arthroscopy. It reduces the size of the redundant capsular pouch and reinforces the thinned-out capsule. Intraoperatively, patients with associated labral tears (n = 25) and patients with open rotator intervals (n = 8) were excluded, and only 75 patients with pure capsular redundancy were included in this study. RESULTS: Patients were followed for a minimum of 7 years. All 75 patients had patulous and redundant capsules. Three patients (4.0%) had a redislocation after a significant trauma. The range of motion preoperatively was 168.1 degrees +/- 7.5 degrees in forward elevation, 64.7 degrees +/- 7.9 degrees in external rotation, and T5.0 +/- T0.8 in internal rotation. Postoperatively, it was 167.2 degrees +/- 5.8 degrees in forward elevation, 59.95 degrees +/- 4.9 degrees in external rotation, and T7.1 +/- T1.0 in internal rotation. The American Shoulder and Elbow Surgeons (ASES) (70.76 to 97.53; P < .001), Constant (90.02 to 99.24; P < .001), and University of California, Los Angeles (UCLA) (21.97 to 33.84; P < .001) scores demonstrated significant improvement postoperatively. CONCLUSION: This novel technique of arthroscopic capsular shift addresses the problem of capsular redundancy present in many cases of anteroinferior shoulder instability. It tries to achieve a capsular shift based on the principles of Neer. The long-term results are very good. PMID- 22437282 TI - The role of medial retinaculum plication versus medial patellofemoral ligament reconstruction in combined procedures for recurrent patellar instability in adults. AB - BACKGROUND: The comparative clinical outcome of medial retinaculum plication (MRP) versus medial patellofemoral ligament reconstruction (MPFLR) for recurrent patellar instability in adults is unknown. HYPOTHESIS: Arthroscopic MRP can yield similar results to MPFLR for recurrent patellar instability in adults. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: One hundred patients with recurrent patellar instability were randomly divided into 2 groups receiving either arthroscopic MRP or MPFLR. Lateral release and anteromedial or distal tibial tubercle transfers were also performed as indicated. Follow-ups were performed at 12, 24, and 60 months postoperatively, and computed tomography (CT) was performed immediately after the operation and at follow-up. The passive patella glide test was performed before surgery and at each follow-up point. The degree of knee function was evaluated preoperatively and at 2 and 5 years postoperatively using the International Knee Documentation Committee (IKDC), Lysholm, and Kujala rating scales. Survival analysis was performed, and redislocation or multiple episodes of patellar instability were considered as indicating failure. RESULTS: Forty-three patients in the MRP group and 45 patients in the MPFLR group were followed for 5 years and received complete evaluations. The correction of the static patellar position deteriorated over time in both groups, but significantly better results were observed for the MPFLR group. The results of the passive patella glide test indicated more stable patellae in the MPFLR group at each follow-up point. Functional evaluations at 2 and 5 years (final Lysholm score, 69.3 +/- 6.9 vs 86.9 +/- 6.1; Kujala score, 73.8 +/- 5.5 vs 87.4 +/- 5.7) revealed statistically significant superior results in the MPFLR group. Finally, 4 patients (9.3%) in the MRP group and 1 (2.2%) in the MPFLR group experienced episodes of redislocation, and 7 patients (16.3%) in the MRP group and 3 (6.7%) in the MPFLR group experienced multiple episodes of patellar instability (P = .037). Kaplan-Meier survival analysis and a log-rank test indicated better results and a significantly higher survival rate (P = .006) in the MPFLR group. CONCLUSION: MPFLR results in better static patellar position and functional outcome than MRP in the treatment of recurrent patellar dislocation in adults. PMID- 22437283 TI - The enigma of genetics etiology of atherosclerosis in the post-GWAS era. AB - Coronary atherosclerosis is a complex heritable trait with an enigmatic genetic etiology. Genome-wide association studies (GWAS) have successfully led to identification of over 100 different loci for susceptibility to coronary atherosclerosis. Most identified single nucleotide polymorphisms (SNP)s and genes have not been previously implicated in the pathogenesis of atherosclerosis and hence, have modest biological plausibility. The novel discoveries, however, might provide the opportunity for identification of new pathways and consequently novel preventive and therapeutic targets. A notable outcome of GWAS is relatively modest effect sizes of the associated SNPs. Collectively, the identified SNPs account for a relatively small fraction of heritability of coronary atherosclerosis, which raises the question of "missing heritability". Because GWAS test the common disease-comment variant hypothesis, a plausible explanation might be the presence of uncommon and rare variants in the genome that are untested in GWAS but that might exert large effect sizes on the risk of atherosclerosis. The latter, however, remains an empiric question pending validation through experimentation. Alternative mechanisms, such as transgenerational epigenetics including microRNAs, might in part account for the heritability of coronary atherosclerosis. Collectively, the recent findings are indicative of the etiological complexity of coronary atherosclerosis. Hence, it is expected that genetic etiology of coronary atherosclerosis will remain enigmatic in the foreseeable future. PMID- 22437284 TI - [Preoperative alpha-receptor block in patients with pheochromocytoma? Against]. AB - Perioperative mortality regarding the resection of catecholamine-producing tumors has been markedly improved. This improvement has been attributed to the preoperative treatment with alpha-receptor blocking agents. An alpha-receptor block is still recommended prior to the resection of pheochromocytoma or paraganglioma. However, the effect has never been tested in a randomized clinical trial. Despite an assumed effective alpha-receptor block, many centers report systolic blood pressure increases beyond 200 mmHg. Out of 200 consecutive resections of catecholamine-producing tumors, 73 patients without an alpha receptor blockade were treated. There was no significant difference in the maximum systolic blood pressure or in the incidence of hypertensive episodes. There was no correlation between the individual dose of phenoxybenzamine and the maximum blood pressure. Overall it can be concluded that with the improvement of surgical techniques, diagnostic tools and highly effective short acting substances to control hemodynamics intraoperatively, the question must be raised whether a time-consuming, unreliable pretreatment burdened with significant side effects is still required. PMID- 22437285 TI - Surgical treatment of glioblastoma multiforme localized in the motor area of the brain using the technique of cortical electrostimulation. AB - AIM: Glioblastoma multiforme in the motor area is the surgical challenge because of the need for more radical resection in order to extend the life of the patient, and the risk that radicalism could lead to additional neurological deficit. MATERIAL AND METHODS: We present series of 26 patients with glioblastoma multiforme localized in and around the motor area, who were hospitalized from October 2004 to February 2009. During all operations, we conducted electrostimulation display area of the brain, to the anatomical location of M1 segment of the motor cortex. RESULTS: Distance of the central sulcus in relation to the coronary suture, measured by magnetic resonance imaging (MRI) was 18.38 mm +/- 9.564 mm. The volume of electricity required for a motor response was mean 8.79 +/- 1.484 mA, with increasing distance from the coronary suture the amperage required to explicit motor responses decreased. The difference (mm) between the distance from the coronary suture measured using MRI and distances measured electrostimulation smaller and power consumption was less (F = 13.285, p < 0.01). CONCLUSION: The method of cortical cerebral cortex electrostimulation is simple and safe method and a binding protocol to the patient safe operation glioblastoma multiforme localized in the motor area of the brain. PMID- 22437286 TI - Endovascular treatments for distal posterior cerebral artery aneurysms. AB - AIM: The purpose of the current study was to evaluate the methods and results of endovascular treatments for distal posterior cerebral artery (PCA) aneurysms. MATERIAL AND METHODS: We studied 10 patients admitted to our hospital, of which 6 had aneurysms at the P2 segment (2 were saccular, 2 were fusiform, 2 were dissecting), 1 had a dissecting aneurysm at the P2-P3 junction and 3 had dissecting aneurysms at the P3 segment. Coil embolization was used for saccular aneurysms to retain parent arteries, stent was used for fusiform aneurysm to reconstruct the parent arteries, coil embolization in combination with parent artery occlusion was used for dissecting aneurysms at P2 segment or P2-P3 junction, aneurysm embolization in combination with parent artery occlusion by Glubran glue was used for dissenting aneurysms at the P3 segment. RESULTS: Nine patients got a score of 5, one patient got a score of 4. DSA follow up in nine accepted the review (one patient with fusiform aneurysm at the P2 segment was lost). No reoccurrence was found. CONCLUSION: The results of this study suggested that to achieve a satisfying prognosis, the types and locations of the aneurysms should be considered when performing the endovascular treatment for distal PCA aneurysms. PMID- 22437287 TI - Anaesthetic considerations and perioperative features of endoscopic third ventriculostomy in infants: analysis of 57 cases. AB - AIM: Endoscopic third ventriculostomy (ETV) is currently considered the best alternative to shunt systems in the treatment of triventricular hydrocephalus. However, there has been very few published data about the anaesthetic management and the complications of ETV procedure in infants. In this report, we detail our experience with 57 infants, who underwent ETV as an initial treatment for obstructive triventricular hydrocephalus between 2003 and 2010. MATERIAL AND METHODS: Anesthesia chart-records were retrospectively investigated and perioperative data were classified according to the stages of the procedure. RESULTS: In this series, mean heart rate values showed a statistically significant difference in the period concerning the balloon dilatation of ventriculostomy orifice. An episode of bradycardia occurred in 2 patients during balloon dilatation. After the deflation of the balloon, bradycardia resolved immediately without administration of any medication. Video recordings of those two patients revealed that one of them had a narrow and opaque tuber cinereum, and the other had a shallow interpeduncular cistern. CONCLUSION: During ETV procedure in infants, bradycardia may be a serious complication especially when performing balloon dilatation of the ventriculostomy orifice. We believe that close communication between the surgeon and the anaesthetist is extremely essential in this stage of the procedure. PMID- 22437288 TI - Anterior lumbar interbody fusion combined with percutaneous pedicle screw fixation for degenerative lumbar instability: minimum four-year follow-up. AB - AIM: Our goal was to investigate the long-term results of anterior lumbar interbody fusion combined with percutaneous pedicle screw fixation for degenerative lumbar instability. MATERIAL AND METHODS: Forty-seven patients that had undergone anterior lumbar interbody fusion combined with percutaneous pedicle screw fixation for degenerative lumbar instability at Tianjin Hospital between May 2003 and January 2007 were reviewed retrospectively. Radiographic results including the fusion rate, disc space height, segmental lordosis and whole lumbar lordosis were analyzed, and clinical outcomes were assessed using the Japanese Orthopaedic Association score. RESULTS: In 47 patients, no surgery-related neurological deficit or wound breakdown was observed and 45 patients obtained a solid fusion. The mean JOA score increased significantly (p < 0.05) from 9.4 before surgery to 24.6 six months after surgery and 26.1 at final follow-up. The disc space height, segmental lordosis and whole lumbar lordosis increased significantly from pre-operative values to both six months postoperatively (p < 0.05) and at the final follow up (p < 0.05). Radiographic evidence of adjacent segmental degeneration was found in 14 patients (29.8%) and symptomatic adjacent segmental disease developed in 1 patient (2.1%). CONCLUSION: Anterior lumbar interbody fusion combined with percutaneous pedicle screws fixation in patients with degenerative lumbar instability results in good clinical and radiographic outcomes at long-term follow-up. PMID- 22437289 TI - Application of a crescent-shaped PMMA strut in anterior spinal reconstruction of thoracolumbar and lumbar burst fractures: a new technique. AB - AIM: Our aim was to evaluate the safety and efficacy of the novel crescent-shaped PMMA strut for anterior spinal reconstruction and fusion in patients with thoracolumbar bust fractures. The surgical results using this technique are reviewed. MATERIAL AND METHODS: Six patients suffering thoracolumbar and lumbar fracture using a crescent-shaped PMMA strut combined with fixation for reconstruction of the anterior spinal column. Postoperative radiographic, included plain x-ray and 3-D computed tomography (CT) imaging, evaluated fusion status postoperatively. Pain relief and neurological status was assessed by comparing Frankel Score and Vision Analogue Score (VAS) pre- and postoperatively. RESULTS: All six patients achieved immediate stabilization. No patient needs additional posterior instrumentation stabilization due to loss of sagittal alignment and kyphosis deformity. All patients achieved significant relief of back pain, improvement of neurological function, correction of preoperative deformity and excellent bone fusion results documented on plain x-rays and 3-D CT reconstruction imaging. There were no complications of neurological worsening, wound infection, subsidence and dislodgement of PMMA strut, or anterior instrumentation failure during the follow-up. CONCLUSION: The crescent-shaped PMMA strut is an alternative for anterior spinal reconstruction and fusion in patients with thoracolumbar burst fracture. However, the long-term clinical effects and possible complications need further evaluation. PMID- 22437290 TI - The effects of low-dose radiation in the treatment of sciatic nerve injury in rats. AB - AIM: Peripheral nerve regeneration is often blocked by scar formation and misdirection of axon sprouts. The aim of this study is to evaluate electrophysiological and histopathological effects of low-dose radiation therapy on the prevention of intraneural scar formation in peripheral nerve injury. MATERIAL AND METHODS: In this experimental study, twenty rats were randomly divided into two groups. Left sciatic nerves were exposed and clipped by temporary aneurysm clip for 5 minutes in both groups. In all animals, electrophysiological recordings were performed between 22-24 hours after sciatic nerve injury. The control group was not given any treatment. In the experimental group, 700 cGy low-dose radiation was administered on the left sciatic nerves 24 hours after clipping. Six weeks after injury, electrophysiological recordings were performed in both groups and animals were sacrificed to evaluate the injured nerves histopathologically. RESULTS: We observed that low-dose radiotherapy increased the amplitude and improved latency measurements in electrophysiological examinations. Histopathologically, more axonal degeneration and vacuolization was observed in the control group comparing with the experimental group. Endoneural space increased slightly more in the control group than the experimental group. CONCLUSION: It was observed that low-dose radiotherapy may prevent intraneural scar formation and may improve electrophysiological recovery in sciatic nerve injury performed in rats. PMID- 22437291 TI - Unilateral frontal interhemispheric transfalcial approaches for the removal of olfactory groove meninjiomas. AB - AIM: A unilateral subfrontal interhemispheric transfalcial approach for the removal of olfactory groove meningiomas (OGM) was evaluated in terms of surgical technique, complications, clinical outcomes, and recurrence rate. MATERIAL AND METHODS: Twenty-four females and eighteen males with a mean age of 59 years were operated on for OGM within a 12- year (1996-2008) period. The pre- and post operative Mini-Mental Test (MMT) scores, visual impairment scores (VIS), pre operative clinical symptoms (headache, epileptic seizure and anosmia), Karnofsky performance scores (KPS), tumor size and tumor extensions were evaluated. The effects of the pre-operative parameters on post-operative MMT, VIS and KPS were investigated. RESULTS: Tumor size and pre-operative MMT significantly affected pre-operative KPS. Mean tumor diameter was 5.6+/-0.8 cm. Total excision was achieved in 97.6% of all cases. No peri-operative mortality was seen. Ten patients (23.8%) experienced surgery-related complications. The mean follow-up period of cases was 52 months, and the rate of residual tumor re-growth was 2.3%. No parameter showed any effect on post-operative KPS, as no significant difference was seen between pre- and post-operative KPS. A significant positive difference was detected between pre- and post-operative MMT and VIS. CONCLUSION: A unilateral subfrontal interhemispheric transfalcial approach can be the preferred modality for treating OGM. PMID- 22437292 TI - Transforaminal epidural steroid injection via a preganglionic approach for the treatment of lumbar radicular pain. AB - AIM: To evaluate the effectiveness of transforaminal epidural steroid injection (TFESI) for lumbar radiculopathy with respect to effect of injection levels, gender, and age group. MATERIAL AND METHODS: Hundred-fifty-three consecutive patients who underwent to lumbar TFESI were enrolled. The outcomes were measured by using a visual numeric scale (VNS), NASS and EQ-5D. The relationship between possible outcome predictors and the therapeutic effect were evaluated. RESULTS: All the patients completed the 2nd year follow-up visits. Significant differences were observed between the pre-procedure and post-procedure VNSs, NASS patients' satisfactions scores and EQ-5D (P < 0.01) except 1st and 2nd year follow-up (P=0.12, P=0.27and P=0.19 respectively). Gender (higher in female patients) showed significant effect to pre-procedure VNS (P=0.04). An increase in the level number was significantly associated with an increase in the 6th month (P=0.005, P=0.004 respectively) and the 1st year (P=0.05, P=0.029 respectively) NASS and EQ 5D. No complication was occurred except discitis in two chronic renal failure patients. CONCLUSION: Especially in the patients with severe co-morbidities TFESI is an option to provide higher life quality. The clinical course of the success of the TFESI decreases in one year and becomes stable thereafter. In the patients with immune deficiency, the practitioners should always be aware for an infectious complication. PMID- 22437293 TI - Effect of curcumin on lipid peroxidation, early ultrastructural findings and neurological recovery after experimental spinal cord contusion injury in rats. AB - AIM: After acute spinal cord injury (SCI), a large number of axons are lost by a cascade of pathophysiological events known as a secondary injury. The main aim of the current study was to investigate the potential neuroprotective effects of curcumin on lipid peroxidation (LPO), neurological function, and ultrastructural findings after SCI. MATERIAL AND METHODS: Forty adult Wistar albino rats were randomized into five groups: control, SCI alone (50 g/cm weight drop), methylprednisolone sodium succinate (MPSS) (30 mg/kg), curcumin + dimethyl sulfoxide (DMSO) (300 mg/kg), and DMSO alone (0.1 mg/kg). RESULTS: Administration of curcumin significantly decreased LPO in first 24 hours. However, there were no differences in the neurological scores of injured rats between the medication groups and the control group. Curcumin was more effective than DMSO and MPSS in reducing LPO, whereas DMSO was more effective than curcumin and MPSS in minimizing ultrastuctural changes. The results of this study indicate that curcumin exerts a beneficial effect by decreasing LPO and may reduce tissue damage. CONCLUSION: Since ultrastructural and neurological findings does not support biochemical finding, our findings do not exclude the possibility that curcumin has a protective effect on the spinal cord ultrastructure and neurological recovery after SCI. A combination of curcumin with other vehicle may also have a considerable synergy in protecting spinal cord. PMID- 22437294 TI - Results of single burr hole drainage for acute subdural hematoma with non reactive pupil. AB - AIM: To investigate the effects of emergency burr hole drainage for acute subdural hematoma (ASDH) with bilateral non-reactive pupils. MATERIAL AND METHODS: A retrospective study was conducted by reviewing medical records from 1998 to 2007. Patients meeting the following criteria were included: 1) head injury with unconsciousness (Glasgow Coma Scale score 8); 2) bilateral non reactive pupils on arrival; 3) ASDH with disappearance of basal cistern on computed tomography (CT); and 4) performance of emergency single burr hole drainage. Subjects were divided into survival and non-survival groups. RESULTS: Pupil size on the small side was significantly smaller in the survival group than in the non-survival group. All pupils on the small side in the survival group were 4 mm. CONCLUSION: Emergency burr hole drainage should still be considered in patients with ASDH showing bilateral non-reactive pupils and one pupil 4 mm. PMID- 22437295 TI - Comparison of effectiveness of facet joint injection and radiofrequency denervation in chronic low back pain. AB - AIM: The study was conducted to compare the clinical effectiveness of FJ injections (FJI) and FJ radiofrequency (FJRF) denervation in patients with chronic low back pain. MATERIAL AND METHODS: This study included 100 patients; 50 in FJI 50 in FJRF group. VNS, NASS and EQ-5D were used to evaluate the outcomes. All outcome assessments were performed at baseline, 3 months, 6 months and 12 months. RESULTS: FJI in early post-op but FJRF in 1st, 6th and 12th month VNS showed better results (p < 0.001). There was no significant difference in the 1st (p=1) and 6th month (p=0.13) but in 12th month (p=0.04) in NASS. Increase in level number showed positive effect in NASS in FJRF group (p=0.018) but no effect in FJI group (p=0.823) in the 12th month follow-up. There was no significant difference with respect to 1st month (p=0.17), 6th month (p=0.22) and 12th month (p=0.11) post-procedure follow-ups in EQ-5D. At the short term FJI was more effective than FJRF however in midterm follow-up FJRF had more satisfying results than FJRF. CONCLUSION: To our knowledge, the first choice should be the FJI and if pain reoccurs after a period of time or injection is not effective, RF procedure should be used for the treatment of chronic lumbar pain. PMID- 22437296 TI - Reduction of lesion in injured rat spinal cord and partial functional recovery of motility after bone marrow derived mesenchymal stem cell transplantation. AB - AIM: This study aimed to analyze the effect of rat bone marrow-mesenchymal stem cells (rBM-MSCs) delivery on lesion site after spinal cord injury, and to observe the functional recovery after transplantation. MATERIAL AND METHODS: MSCs were isolated from rat femurs and tibias. The experimental rat population was divided into four groups: only laminectomy (1); laminectomy+trauma (2); laminectomy+trauma+PBS (3); laminectomy+trauma+MSCs (4). Their motility were scored regularly. After 4-weeks, rats were sacrificed, and their spinal cords were examined for GFP labeled rBM-MSCs by immunostainings. RESULTS: In the early posttraumatic period, the ultrastructures of spinal cord tissue were preserved in Group 4. The majority of cells forming the ependymal region around the central canal were found to be MSCs. The gray-and-white-matter around the ependymal region were composed of Nestin+/GFAP+ cells, with astrocytic-like appearance. The scores showed significant motor recovery in Group 4, especially in hind limb functions. However, no obvious change was observed in other groups. CONCLUSION: The increase Nestin+/GFAP+ cells in the gray-and-white-matter around the ependymal region could indicate the potential to self-renew and plasticity. Thus, transplantation of rBM-MSCs might be an effective strategy to improve functional recovery following spinal cord trauma. In conclusion, molecular factors in cell fate decisions could be manipulated to enhance reparative potential of cell-based therapy. PMID- 22437297 TI - Use of an ultra-low field intraoperative MRI system for pediatric brain tumor cases: initial experience with 'PoleStar N20'. AB - AIM: Use of intraoperative MRI (iMRI) is the highest contemporary supportive means for brain tumor surgery. In this article we describe the issues related to iMRI use in pediatric cranial operations. MATERIAL AND METHODS: Pediatric cases operated with the aid of Polestar N20 iMRI system are defined and the pros and cons of the system are emphasized. RESULTS: Patient positioning is easier and the obtained images are better in pediatric cases, particularly for posterior fossa tumors. CONCLUSION: iMRI should be used in all pediatric brain tumor operations when possible. PMID- 22437298 TI - Giant cerebral cavernous hemangiomas: a report of two cases and review of the literature. AB - Giant cerebral cavernous malformations (GCM) are rare vascular anomalies. They occur predominantly as solitary lesions in the supratentorial compartment. They are usually not associated with any other vascular malformations. Clinical Presentation GCM are common in the second decade, affecting females predominantly, and occur without familial association. They are all symptomatic due to their giant size and location. The GCM mimic neoplastic lesions because of their size and need to be considered in the differential diagnosis. A complete surgical extirpation is the treatment of choice. Use of intraoperative neuronavigation, diffusion tensor imaging (DTI) of fiber tracts and electrophysiological monitoring assist in safe and total excision of the lesions. A complete surgical excision of GCM is possible without significant surgical morbidity and results in long term cure. PMID- 22437299 TI - Recurrent chemical meningitis in craniopharyngioma without reduction in size of cyst: case report of two cases and review of the literature. AB - Chemical meningitis is a rare phenomenon due to rupture of a craniopharyngioma cyst; it develops because of presence of cholesterol crystals in cyst fluid secreted by the squamous epithelium lining of the cyst. Spontaneous rupture of the cyst may present with or without meningitis, depending upon the cholesterol contents of cystic fluid of tumor. A decrease in the size of cyst may or may not be noted. Here we report two cases of craniopharyngioma, one which had a recurrent episode of chemical meningitis after surgery due to leak from residual component of the craniopharyngioma without evidence of recurrence of lesion, or decrease in the size of the cyst. Another case presented with initial symptoms and signs of meningitis, with no change in the size of the lesion after the second episode of chemical meningitis. PMID- 22437300 TI - Programmable valve shunts: are they really better? AB - Programmable valve shunts allows selection of opening pressure of shunt valve. In the presented article, a unique complication pertaining to programmable shunts has been discussed. A 5-year-old boy who had tectal plate low grade glioma with obstructive hydrocephalus was managed with Codman programmable ventriculoperitoneal shunt. There was a spontaneous change in the opening pressure of the shunt valve leading to shunt malfunction. Routinely used household appliances produce a magnetic field strong enough to cause change in the setting of shunt valve pressure and may lead to valve malfunction. Other causes of programmable valve malfunction also discussed. PMID- 22437301 TI - Incidental traumatic pseudoaneurysm of the middle meningeal artery: case report and literature review. AB - Traumatic pseudoaneurysm of the middle meningeal artery is rare and is associated with high mortality. Skull fracture is usually an associated feature of this entity. An elderly male was brought to our hospital in a stage of coma. The details of ictus were not known. The Glasgow coma scale score was 9/15. Examination revealed a pseudo-aneurysm arising from the posterior branch of the left middle meningeal artery which was excised. The case is presented for its rarity and its characteristic radiology. Traumatic pseudoaneurysm of middle meningeal artery is rare. It is important to recognize this treatable entity. PMID- 22437302 TI - Transcranial approach for spontaneous CSF rhinorrhea due to Sternberg's canal intrasphenoidal meningoencephalocele: case report and review of the literature. AB - One type of congenital intrasphenoidal meningoencephalocele is remnant of lateral craniopharyngeal (Sternberg's) canal. We present a case of a 23-year girl with 10-month history of right side CSF rhinorrhea. CT scan, MRI revealed congenital meningoencephalocele and CSF leak from middle fossa to right side of sphenoid sinus, and there were bony defects at the floor of the anterior aspect of the right middle fossa. Transcranial repair was performed with right side pterional craniotomy. Careful preoperative evaluation and localization of the sphenoid defect are essential for selection of the best possible surgical approach and skull base reconstruction for repair of sphenoid sinus CSF leaks and meningoencephaloceles. In this case, an endoscopic technique was not successful so, transcranial repair was performed with right side pterional craniotomy. PMID- 22437303 TI - Optochiasmatic tuberculomas: a vision-threatening paradoxical response in tuberculous meningitis. AB - The single main cause of death from infectious diseases worldwide is tuberculosis, which is more prevalent in developing countries. Tuberculous meningitis (TBM) is a severe form of TB in which morbidity and mortality depend upon the stage of presentation. Intracranial brain parenchymal tuberculomas may form paradoxically, days to months after starting antituberculous drug therapy. Tuberculomas may develop in and around he optic chiasm and optic nerves after institution of antituberculous treatment as a quite rare occurrence in TBM; this may lead to severe visual loss if not treated properly. We describe a 56-year-old man with documented TBM being treated with first line antituberculous drugs who developed visual impairment 2 months after starting the treatment. MRI after gadolinium administration revealed multiple perichiasmatic and a few parenchymal ring enhancing lesions due to tuberculomas. The patient was treated with corticosteroids and antituberculous therapy was continued after which he recovered his vision gradually. Visual impairment developing in a patient on treatment with antituberculous drugs should give rise to a suspicion of rare optochiasmatic tuberculomas; this necessitates urgent contrast-enhanced MRI of the brain and prompt treatment with steroids. PMID- 22437304 TI - Holocord ependymoma. AB - Intramedullary tumors affecting the entire cord from the cervicomedullary junction to the conus are termed "holocord tumors". Ependymomas are the most frequent intramedullary tumor in adults. Holocord ependymoma is an exceedingly rare condition. An extensive review of the literature revealed that only five other cases have been reported. We report the sixth case of holocord ependymoma. In this article, we present a case of holocord ependymoma in a 19-year-old girl which was totally resected in a two-stage approach. A two-staged operation is recommended for the aim of total resection for this disease. Besides, cysts are common feature of all spinal ependymomas. There was a solid mass not accompanied by a cyst a any level in our patient's tumor. To the authors' best knowledge, a pure solid mass not accompanied by a cyst has not been previously reported with holocord ependymoma cases. PMID- 22437305 TI - Malignant peripheral nerve sheath tumour of scalp with extradural extension: case report. AB - Malignant peripheral nerve sheath tumours are uncommon aggressive soft tissue sarcomas that originate from peripheral nerves or cells associated with the nerve sheath. Scalp malignant peripheral nerve sheath tumours are extremely rare and the role of multimodality management is unclear. We report a 43-year-old female with scalp swelling and rapid growth. Imaging demonstrated an aggressive lesion with extradural extension. A wide excision with negative margins was achieved and he defect reconstructed by rotational flap. The patient was given adjuvant radiation. A follow-up scan done one year post radiation did not show any recurrence. Malignant peripheral nerve sheath tumours of the scalp are extremely rare and such an extradural extension has not been described earlier. PMID- 22437306 TI - Vertex epidural hematoma with bilateral abducent nerve palsy: case report and literature review. AB - Epidural hematomas which are located at the vertex are rarely seen and form a small percentage of total epidural hematomas. Tearing in the superior sagittal sinus is the usual cause of an epidural hematoma located in the vertex. The clinical features of this entity are non-specific; hence, localization of the lesion is difficult. We report an adult who was hit by a motorcycle and was initially discharged from the hospital as a case of concussional head injury. He returned back with raised intracranial pressure symptoms, so a CT scan was done but was misinterpreted, and he reported one week later with bilateral abducent nerve palsy. Magnetic resonance imaging confirmed vertex EDH for which he was operated.These hematomas are seen rarely and can be interpreted as an artifact. Its recognition is important because it has an excellent prognosis. We concluded that all head injury patients should get high axial cuts on the CT scan, and any degree of suspicion should prompt a neurosurgeon to investigate further with coronal CT scan or MRI. PMID- 22437307 TI - An unusual ventriculoperitoneal shunt complication: spontaneous knot formation. AB - This article aims to describe an extraordinary complication of a ventriculoperitoneal shunt system that formed a knot spontaneously and lead to a shunt malfunction. A 3-year-old male patient was operated due to posttraumatic hydrocephalus. After an uneventful follow-up period of 34 months, he presented with shunt malfunction. During the shunt revision surgery, the peritoneal catheter was found to form a loop over itself. There are various complications of ventriculoperitoneal shunt systems. Migration to body cavities is among the most interesting ones. This is the fifth report describing this rare complication. Hydrocephalic patients should be closely followed up after shunt surgery for various extraordinary complications. PMID- 22437308 TI - Neuroendoscopic foraminoplasty for bilateral idiopathic occlusion of foramina of Monro. AB - We report the safety and efficacy of bilateral foraminoplasty of Monro in a patient with partial occlusion of right Monro and complete occlusion of the left one. A 38-year-old man who underwent a ventriculoperitoneal shunt three years ago, and shunt revision surgery twice, presented with hydrocephalus, and was referred to us because of continuing complaints of headaches, nausea and vomiting. The primary surgical treatment of the patient was bilateral endoscopic Monro foraminoplasty. Then, the patient did not need a ventriculoperitoneal shunt, and hydrocephalus was resolved. Bilateral monroplasty in a single-session surgery can be the treatment of choice, instead of microsurgically open reconstruction of the foramen of Monro. The procedure can be less invasive, and it avoids ventriculoperitoneal shunting. PMID- 22437309 TI - Role of integrins in regulating proteases to mediate extracellular matrix remodeling. AB - The extracellular matrix (ECM) is an extracellular scaffold composed of complex mixtures of proteins that plays a pivotal role in tumor progression. ECM remodeling is crucial for tumor migration and invasion during the process of metastasis. ECM can be remodeled by several processes including synthesis, contraction and proteolytic degradation. In order to cross through the ECM barriers, malignant cells produce a spectrum of extracellular proteinases including matrix metalloproteinases (MMPs), serine proteases (mainly the urokinase plasminogen activator (uPA) system) and cysteine proteases to degrade ECM components. As major adhesion molecules to support cell attachment to ECM, integrins play critical roles in tumor progression by enhancing tumor cell survival, migration and invasion. Previous studies have shown that integrins can regulate the expression and activity of these proteases through different pathways. This review summarizes the roles of MMPs and uPA system in ECM remodeling and discusses the regulatory functions of integrins on these proteases in invasive tumors. PMID- 22437310 TI - Estrogen depletion results in nanoscale morphology changes in dermal collagen. AB - Tissue cryo-sectioning combined with atomic force microscopy imaging reveals that the nanoscale morphology of dermal collagen fibrils, quantified using the metric of D-periodic spacing, changes under the condition of estrogen depletion. Specifically, a new subpopulation of fibrils with D-spacings in the region between 56 and 59 nm is present 2 years following ovariectomy in ovine dermal samples. In addition, the overall width of the distribution, both values above and below the mean, was found to be increased. The change in width due to an increase in lower values of D-spacings was previously reported for ovine bone; however, this report demonstrates that the effect is also present in non mineralized collagen fibrils. A nonparametric Kolmogorov-Smirnov test of the cumulative density function indicates a statistical difference in the sham and OVX D-spacing distributions (P<0.01). PMID- 22437311 TI - In vivo evidence for a bridging role of a collagen V subtype at the epidermis dermis interface. AB - Collagen V is the defective product in most cases of classical Ehlers-Danlos syndrome (EDS), a connective tissue disorder typically characterized by skin fragility and abnormal wound healing. Collagen V assembles into diverse molecular forms. The predominant alpha1(V)(2)alpha2(V) heterotrimer controls fibrillogenesis in skin and other tissues. The alpha1(V)(3) minor form is thought to occur in skin, but its function is unknown. To elucidate its role, we generated transgenic mice that overexpress the human alpha1(V)(3) homotrimer in the epidermis. The transgene-derived product is deposited as thin unstriated fibrillar material in the basement membrane zone of embryonic and perinatal epidermis and hair follicles. Accumulation of alpha1(V)(3)-containing fibrils leads to ultrastructural modifications at the epidermis-dermis interface and provokes changes in biomechanical properties, although not statistically significant. Using superparamagnetic immunobeads to isolate authentic suprastructures and protein-binding assays, we demonstrate that the homotrimer is part of a protein network containing collagen IV, laminin-111, and the dermal collagen VI. Our data show that the homotrimer serves as a bridging molecule that contributes to the stabilization of the epidermal-dermal interface. This finding strongly suggests that collagen V may be expressed in skin as different subtypes with important but distinct roles in matrix organization and stability. PMID- 22437312 TI - Melanocortin receptors 1 and 5 might mediate inhibitory effects of alpha melanocyte-stimulating hormone on antigen-induced chronic allergic skin inflammation in IgE transgenic mice. PMID- 22437313 TI - Long-term faithful recapitulation of transglutaminase 1-deficient lamellar ichthyosis in a skin-humanized mouse model, and insights from proteomic studies. PMID- 22437314 TI - Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. AB - Aberrant activation of the BRAF kinase occurs in ~60% of melanomas, and although BRAF inhibitors have shown significant early clinical success, acquired resistance occurs in most patients. Resistance to chronic BRAF inhibition often involves reactivation of mitogen-activated protein kinase (MAPK) signaling, and the combined targeting of BRAF and its downstream target MAPK/ERK kinase (MEK) may delay or overcome resistance. To investigate the efficacy of combination BRAF and MEK inhibition, we generated melanoma cell clones resistant to the BRAF inhibitor GSK2118436. These BRAF inhibitor-resistant sublines acquired resistance through several distinct mechanisms, including the acquisition of activating N RAS mutations and increased accumulation of COT1. These alterations uniformly promoted MAPK reactivation and most conferred resistance to MEK inhibition and to the concurrent inhibition of BRAF and MEK. These data indicate that melanoma tumors are likely to develop heterogeneous mechanisms of resistance, many of which will confer resistance to multiple MAPK inhibitory therapies. PMID- 22437315 TI - Type 1 segmental Galli-Galli disease resulting from a previously unreported keratin 5 mutation. PMID- 22437316 TI - Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris. AB - Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by anti epithelial antibodies, leading to disruption of cell-cell adhesion. Although the disease is exceedingly rare worldwide, it is known to be relatively prevalent in Jewish populations. The low prevalence of the disease represents a significant obstacle to a genome-wide approach to the mapping of susceptibility genes. We reasoned that the study of a genetically homogeneous cohort characterized by a high prevalence of PV may help exposing associated signals while reducing spurious results due to population sub-structure. We performed a genome-wide association study using 300K single-nucleotide polymorphisms (SNPs) in a case control study of 100 PV patients of Jewish descent and 397 matched control individuals, followed by replication of significantly associated SNPs in three additional cohorts of Jewish, Egyptian, and German origin. In addition to the major histocompatibility complex locus, a genomic segment on 8q11.23 that spans the ST18 gene was also found to be significantly associated with PV. This association was confirmed in the Jewish and Egyptian replication sets but not in the German sample, suggesting that ST18-associated variants may predispose to PV in a population-specific manner. ST18 regulates apoptosis and inflammation, two processes of direct relevance to the pathogenesis of PV. Further supporting the relevance of ST18 to PV, we found this gene to be overexpressed in the skin of PV patients as compared with healthy individuals. PMID- 22437317 TI - Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility. AB - Previous genetic and functional studies have implicated the human endogenous retrovirus K (HERV-K) dUTPase located within the PSORS1 locus in the major histocompatibility complex region as a candidate psoriasis gene. Here, we describe a variant discovery and case-control association study of HERV-K dUTPase variants in 708 psoriasis cases and 349 healthy controls. Five common HERV-K dUTPase variants were found to be highly associated with psoriasis, with the strongest association occurring at the missense single-nucleotide polymorphism (SNP) rs3134774 (K158R, P=3.28 * 10(-15), odds ratio =2.36 (95% confidence interval: 1.91-2.92)). After adjusting the association of the HERV-K dUTPase variants for the potential confounding effects of HLA alleles associated with psoriasis, the HERV-K SNPs rs9264082 and rs3134774 remained significantly associated. Haplotype analysis revealed that HERV-K haplotypes containing the non risk alleles for rs3134774 and rs9264082 significantly reduced the risk of psoriasis. Functional testing showed higher antibody responses against recombinant HERV-K dUTPase in psoriasis patients compared with controls (P<0.05), as well as higher T-cell responses against a single HERV-K dUTPase peptide (P<0.05). Our data support an independent role for the HERV-K dUTPase on psoriasis susceptibility, and suggest the need for additional studies to clarify the role of this dUTPase in the pathogenesis of psoriasis. PMID- 22437318 TI - TGFbeta/Smad3 signal pathway is not required for epidermal Langerhans cell development. PMID- 22437319 TI - The mutation profiles of common oncogenes involved in melanoma in southern China. PMID- 22437320 TI - C/EBPgamma regulates wound repair and EGF receptor signaling. AB - We aimed at identifying novel regulators of skin wound healing (WH), in an epidermal scratch WH assay, by a small interfering RNA (siRNA) silencing approach. Several transcription factors have been previously reported to affect wound repair. We here show that gene silencing of the transcription factor CAAT enhancer-binding protein gamma (C/EBPgamma), STAT3, REL, RELA, RELB, SP1, and NFkB impaired WH in vitro, in keratinocytes, whereas E2F and CREBBP silencing accelerated the WH process. We further characterized C/EBPgamma, as its silencing yielded the maximal impairment (52.2 +/- 12.5%) of scratch wounding (SW). We found that C/EBPgamma silencing inhibited both EGF- and serum-induced keratinocyte migration, whereas C/EBPgamma overexpression enhanced cell migration to EGF and to serum via the EGFR. Further, C/EBPgamma silencing impaired scratch induced Y1068 and Y1173 EGFR phosphorylation, as well as Y118 paxillin phosphorylation, key molecules regulating cell migration and epidermal WH. Moreover, C/EBPgamma levels were induced in keratinocytes, following both SW and EGF stimulation. C/EBPgamma siRNA silencing in vivo impaired WH at 3, 5, 7, and 14 days following excisional wounding in mice inhibited both re-epithelialization and granulation tissue formation, and induced a decrease of arteriole number. In conclusion, we here report that C/EBPgamma positively regulates wound repair both in vitro and in vivo, at least in part, by affecting EGFR signaling. PMID- 22437321 TI - Antisaccade performance in patients with obsessive-compulsive disorder and unaffected relatives: further evidence for impaired response inhibition as a candidate endophenotype. AB - Cognitive dysfunctions such as inhibitory deficits and visuospatial abnormalities are often found in patients with obsessive-compulsive disorder (OCD). Recent findings in unaffected relatives indicate that response inhibition and other neuropsychological functions may also constitute endophenotypes of OCD. In the present study, 30 OCD patients, 30 first-degree relatives, and 30 healthy control subjects were assessed using a comprehensive neuropsychological test battery. A subsample of 21 subjects of each group also performed an antisaccade task. The samples were matched according to age, gender, education, and verbal intelligence. The OCD patients and the unaffected OCD relatives showed increased antisaccade error rates compared with the healthy control group (p = 0.003, p = 0.028, respectively). Significantly prolonged antisaccade latencies as compared to prosaccade latencies were only found in the OCD patients compared with the healthy control group (p = 0.019). Only OCD patients but not the unaffected OCD relatives were impaired with regard to visuospatial functions, problem-solving, and processing speed. Antisaccade errors did not correlate with severity of OCD or depressive symptoms. This study confirms inhibitory deficits, as indicated by increased antisaccade error rates, as a candidate endophenotype of OCD. In agreement with previous findings from imaging studies, our data suggest that functional abnormalities in frontostriatal and parietal cortical regions form part of the vulnerability for OCD. PMID- 22437322 TI - A systematic indoor air quality audit approach for public buildings. AB - Good indoor air quality (IAQ) in buildings provides a comfortable and healthy environment for the occupants to work, learn, study, etc. Therefore, it is important to ascertain the IAQ status in the buildings. This study is aimed to establish and demonstrate the comprehensive IAQ audit approach for public buildings, based on Portugal national laws. Four public buildings in Portugal are used to demonstrate the IAQ audit application. The systematic approach involves the measurement of physical parameters (temperature, relative humidity, and concentration of the suspended particulate matter), monitoring of the concentrations of selected chemical indicators [carbon dioxide (CO(2)), carbon monoxide, formaldehyde, ozone, and total volatile organic compounds], and the measurements of biological indicators (bacteria and fungi). In addition, air exchange rates are measured by the concentration decay method using metabolic CO(2) as the tracer gas. The comprehensive audits indicated some situations of common IAQ problems in buildings, namely: (1) insufficient ventilation rate, (2) too high particle concentration; and (3) poor filtration effectiveness and hygienic conditions in most of the air handling units. Accordingly, a set of recommendations for the improvement of IAQ conditions were advised to the building owner/managers. PMID- 22437323 TI - Calculating of river water quality sampling frequency by the analytic hierarchy process (AHP). AB - River water quality sampling frequency is an important aspect of the river water quality monitoring network. A suitable sampling frequency for each station as well as for the whole network will provide a measure of the real water quality status for the water quality managers as well as the decision makers. The analytic hierarchy process (AHP) is an effective method for decision analysis and calculation of weighting factors based on multiple criteria to solve complicated problems. This study introduces a new procedure to design river water quality sampling frequency by applying the AHP. We introduce and combine weighting factors of variables with the relative weights of stations to select the sampling frequency for each station, monthly and yearly. The new procedure was applied for Jingmei and Xindian rivers, Taipei, Taiwan. The results showed that sampling frequency should be increased at high weighted stations while decreased at low weighted stations. In addition, a detailed monitoring plan for each station and each month could be scheduled from the output results. Finally, the study showed that the AHP is a suitable method to design a system for sampling frequency as it could combine multiple weights and multiple levels for stations and variables to calculate a final weight for stations, variables, and months. PMID- 22437324 TI - Residues and ecological risks of organochlorine pesticides in Lake Small Baiyangdian, North China. AB - The levels of hexachlorocyclohexane (HCH) and dichloro-diphenyl-trichloroethane (DDT) in the water, suspended particulate matter (SPM), and sediments from Lake Small Baiyangdian were measured by gas chromatograph with a (63)Ni microelectron capture detector. The residual levels of the total HCHs in the water, SPM, and sediments were 1.59 +/- 2.24 ng L(-1), 25.42 +/- 1.72 ng g(-1) dw (dry weight), and 0.86 +/- 1.44 ng g(-1) dw, respectively. DDTs were not detected in the water samples. The concentrations of total DDTs were 158.79 +/- 1.67 ng g(-1) dw in SPM and 0.46 +/- 1.97 ng g(-1) dw in the sediments. Compared to other areas in China and abroad, the levels of residual HCH and DDT were relatively low in the water and sediments, but they were moderate to high in the SPM. Organic carbon partition coefficient values for HCH in this study were higher than previously published values and may reflect new input in this area. The residual HCHs in this area could be derived from a mixture of technical HCH and lindane because ongoing lindane use may be occurring. DDT in the majority of the study area was primarily attributed to historical discharge, but some regions may be receiving new input. The ecological risks of gamma-HCH in the water were very low according to species sensitivity distribution models. The concentrations of HCH and DDT in the sediments from the study area did not exceed the sediment quality guidelines, which indicate little risk for benthic organisms. PMID- 22437325 TI - Silica-porphyrin hybrid nanotubes for in vivo cell tracking by near-infrared fluorescence imaging. AB - Near-infrared fluorescent silica-porphyrin hybrid nanotubes (HNTs) were successfully synthesized by pi-pi stacking, electrostatic interaction and a sol gel reaction. The HNTs-labeled macrophages were detected in vivo, and the minimum detectable number of cells was 200. Furthermore, the biodistribution of HNTs labeled macrophages was tracked by fluorescence imaging. PMID- 22437326 TI - Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors. AB - Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulation of TLRs and NOD2 in 67 CLL cases assigned to different subgroups on the basis of immunoglobulin heavy variable (IGHV ) gene usage, IGHV gene mutational status or B-cell receptor (BcR) stereotypy. Differences in the induction of costimulatory molecules and/or apoptosis were observed in mutated versus unmutated CLL. Different responses were also identified in subsets with stereotyped BcRs, underscoring the idea that "subset biased" innate immunity responses may occur independently of mutational status. Additionally, differential modulation of kinase activities was induced by TLR stimulation of different CLL subgroups, revealing a TLR7-tolerant state for cases belonging to stereotyped subset #4. The distinct patterns of TLR/NOD2 functional activity in cells from CLL subgroups defined by the molecular features of the clonotypic BcRs might prove relevant for elucidating the immune mechanisms underlying CLL natural history and for defining subgroups of patients who might benefit from treatment with specific TLR ligands. PMID- 22437327 TI - Fabry disease: incidence of the common later-onset alpha-galactosidase A IVS4+919G->A mutation in Taiwanese newborns--superiority of DNA-based to enzyme based newborn screening for common mutations. AB - Fabry disease is a panethnic, X-linked, inborn error of glycosphingolipid metabolism resulting from mutations in the alpha-galactosidase A gene (GLA) that lead to the deficient activity of the lysosomal enzyme, alpha-galactosidase A (alpha-Gal A). Affected males with no alpha-Gal A activity have the early-onset classic phenotype, whereas those with residual activity present with the later onset subtype. Recently, we reported that newborn enzyme-based screening using dried blood spots (DBS) in Taiwan revealed a high incidence of newborn males who had the GLA c.936+919G->A (IVS4+919G->A) mutation. This lesion causes cryptic splicing, markedly reducing the amount of wild-type GLA mRNA, and has been found in males with the later-onset Fabry phenotype, manifesting as cardiac, renal and/or cerebrovascular disease. To more accurately determine the incidence of the IVS4+919G->A mutation, 20,063 consecutive newborns were screened by a deoxyribonucleic acid (DNA)-based assay. Of the 10,499 males, 12 (1/875) and 24 of the 9,564 females (1/399) had the mutation. On the basis of these frequencies, the previous newborn enzyme-based DBS screening (cutoff: <30% of the normal mean) only identified 67% and 17% of mutation-positive males and females, respectively. The mean DBS alpha-Gal A activities in the mutation-positive males and females were 23% (1.54 U) and 55% (3.63 U) of normal mean male/female values, respectively. These studies confirm the high incidence of the IVS4+919G->A mutation in the Taiwanese population and indicate that its detectability by enzyme-based DBS screening is unreliable, especially in females. These studies emphasize the superiority of DNA-based newborn screening for common mutations, particularly for X-linked diseases. PMID- 22437329 TI - Risk factors of falls in community-dwelling older adults: logistic regression tree analysis. AB - PURPOSE OF THE STUDY: A novel logistic regression tree-based method was applied to identify fall risk factors and possible interaction effects of those risk factors. DESIGN AND METHODS: A nationally representative sample of American older adults aged 65 years and older (N = 9,592) in the Health and Retirement Study 2004 and 2006 modules was used. Logistic Tree with Unbiased Selection, a computer algorithm for tree-based modeling, recursively split the entire group in the data set into mutually exclusive subgroups and fit a logistic regression model in each subgroup to generate an easily interpreted tree diagram. RESULTS: A subgroup of older adults with a fall history and either no activities of daily living (ADL) limitation and at least one instrumental activity of daily living or at least one ADL limitation was classified as at high risk of falling. Additionally, within each identified subgroup, the best predictor of falls varied over subgroups and was also evaluated. IMPLICATIONS: Application of tree-based methods may provide useful information for intervention program design and resource allocation planning targeting subpopulations of older adults at risk of falls. PMID- 22437330 TI - The BRIGHTEN program: implementation and evaluation of a program to bridge resources of an interdisciplinary geriatric health team via electronic networking. AB - PURPOSE: To demonstrate the feasibility of the BRIGHTEN Program (Bridging Resources of an Interdisciplinary Geriatric Health Team via Electronic Networking), an interdisciplinary team intervention for assessing and treating older adults for depression in outpatient primary and specialty medical clinics. The BRIGHTEN team collaborates "virtually" to review patient assessment results, develop a treatment plan, and refer to appropriate team members for follow-up care. DESIGN AND METHODS: Older adults in 9 academic medical center clinics and 2 community-based clinics completed screening forms for symptoms of depression and anxiety. Those with positive screens engaged in comprehensive assessment with the BRIGHTEN Program Coordinator; the BRIGHTEN virtual team provided treatment recommendations based on the results of assessment. A collaborative treatment plan was developed with each participant, who was then connected to appropriate services. RESULTS: Two thousand four hundred twenty-two older adults were screened in participating clinics over a 40-month period. Eight hundred fifty nine older adults screened positive, and 150 elected to enroll in BRIGHTEN. From baseline to 6 months, significant improvements were found in depression symptoms (Geriatric Depression Scale, p < .01) and general mental health (SF-12 Mental Component, p < .01). IMPLICATIONS: The BRIGHTEN Program demonstrated that an interdisciplinary virtual team linked with outpatient medical clinics can be an effective, nonthreatening, and seamless approach to enable older adults to access treatment for depression. PMID- 22437331 TI - A pilot feasibility study for immediate relief of referred knee pain by hip traction in hip osteoarthritis. PMID- 22437332 TI - Nondura-based clear cell meningioma of the cauda equina in an adult. PMID- 22437333 TI - Adverse results with PMMA fillers. AB - BACKGROUND: Various alloplastic materials have been used for filling depressions and for body contouring. Among them, polymethylmethacrylate (PMMA) has provoked many clinical compilations in both the acute and chronic phases. This study shows the correlation between the clinical application of PMMA and the physiopathology of the acute and late complications. METHODS: Histological studies were performed on biopsy samples from patients who presented with side effects and acute and late complications after PMMA injections given at other health-care centers or aesthetic services. RESULTS: The histological findings of the samples that were harvested from patients who developed clinical complications or side effects caused by injection of PMMA disclosed not only normal tissues from the implanted areas but also development of capsules that involved individual microspheres of PMMA, and when the capsules were close together they formed concentric capsular groups involving various sets of microspheres and their capsules. CONCLUSIONS: The injection of PMMA within the tissues can cause severe complications and side effects in both acute and chronic phases. Initially, the complications are related to vascular compromise, but at the late phase they are a consequence of capsular contracture that involves particles of PMMA. The contracture causes local tissue hardening and clinical nodulation of the implanted areas, ending with extrusion of the filler material. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22437334 TI - France prohibits the use of macrolane in aesthetic breast augmentation for reasons similar to criticisms of autologous fat grafting to the breast. PMID- 22437335 TI - Two-Z-epicanthoplasty in a three-dimensional model of Asian eyelids. AB - BACKGROUND: Epicanthoplasty is a procedure currently available for medial epicanthus correction. However, potential problems such as difficult designs, undercorrection, and unpleasant scarring in the medial canthus area make patients hesitant about undergoing epicanthoplasty. These barriers are challenges to surgeons. METHODS: From January 2007 to May 2010, epicanthoplasty was performed for 23 patients using two-Z-plasty in a three-dimensional surgery model. A total of 20 patients underwent a simultaneous double-eyelid operation when required. The medial canthal distance was measured preoperatively and 12 months postoperatively. The extent of postoperative scarring and improvement of the epicanthal fold were evaluated after surgery. RESULTS: The average intercanthal length decreased significantly from a mean of 37.0+/-2.1 mm preoperatively to 31.4+/-1.9 mm 12 months postoperatively (p<0.01, paired t test). Epicanthoplasty yielded excellent aesthetic results in terms of an open medial canthus without definite relapse, hypertrophic scarring, and injury of the lacrimal apparatus during the 12-month follow-up period. CONCLUSIONS: Two-Z-epicanthoplasty can be reproduced easily in a three-dimensional surgery model. This procedure is very effective for correction of the epicanthal fold, resulting in a pleasant appearing, inconspicuous scar and a long-lasting outcome. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 22437338 TI - Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. AB - The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer's Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on "probable" and "possible" AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies. PMID- 22437339 TI - Cerebral white matter oxidation and nitrosylation in young rodents with kaolin induced hydrocephalus. AB - Hydrocephalus is associated with reduced blood flow in periventricular white matter. To investigate hypoxic and oxidative damage in the brains of rats with hydrocephalus, kaolin was injected into the cisterna magna of newborn 7- and 21 day-old Sprague-Dawley rats, and ventricle size was assessed by magnetic resonance imaging at 7, 21, and 42 days of age. In-situ evidence of hypoxia in periventricular capillaries and glial cells was shown by pimonidazole hydrochloride binding. Biochemical assay of thiobarbituric acid reaction and immunohistochemical detection of malondialdehyde and 4-hydroxy-2-nonenal indicated the presence of lipid peroxidation in white matter. Biochemical assay of nitrite indicated increased nitric oxide production. Nitrotyrosine immunohistochemistry showed nitrosylated proteins in white matter reactive microglia and astrocytes. Activities of the antioxidant enzymes catalase and glutathione peroxidase were not increased, and altered hypoxia-inducible factor 1alpha was not detected by quantitative reverse transcription-polymerase chain reaction. Cerebral vascular endothelial growth factor expression determined by quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay was not changed, but vascular endothelial growth factor immunoreactivity was increased in reactive astrocytes of hydrocephalic white matter. To determine if nitric oxide synthase is involved in the pathogenesis, we induced hydrocephalus in 7-day-old wild-type and neuronal nitric oxide synthase deficient mice. At 7 days, the wild-type and mutant mice exhibited equally severe ventriculomegaly and no behavioral differences, although increased glial fibrillary acidic protein was less in the mutant mice. We conclude that hypoxia, via peroxidation and nitrosylation, contributes to brain changes in young rodents with hydrocephalus and that compensatory mechanisms are negligible. PMID- 22437340 TI - Altered balance of proteolytic isoforms of pro-brain-derived neurotrophic factor in autism. AB - Defects in synaptic development and plasticity may lead to autism. Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptogenesis and synaptic plasticity. BDNF is synthesized as a precursor, pro-BDNF, which can be processed into either a truncated form or into mature BDNF. Previous studies reported increased BDNF-immunoreactive protein in autism, but the mechanism of this increase has not been investigated. We examined BDNF mRNA by real-time reverse transcription-polymerase chain reaction and BDNF protein by Western blotting and enzyme-linked immunosorbent assay in postmortem fusiform gyrus tissue from 11 patients with autism and 14 controls. BDNF mRNA levels were not different in the autism versus control samples, but total BDNF-like immunoreactive protein, measured by enzyme-linked immunosorbent assay, was greater in autism than in controls. Western blotting revealed greater pro-BDNF and less truncated BDNF in autism compared with controls. These data demonstrate that increased levels of BDNF-immunoreactive protein in autism are not transcriptionally driven. Increased pro-BDNF and reduced truncated BDNF are consistent with defective processing of pro-BDNF to its truncated form. Distortion of the balance among the 3 BDNF isoforms, each of which may exhibit different biological activities, could lead to changes in connectivity and synaptic plasticity and, hence, behavior. Thus, imbalance in proteolytic isoforms is a possible new mechanism for altered synaptic plasticity leading to autism. PMID- 22437341 TI - The collapsin response mediator protein 5 onconeural protein is expressed in Schwann cells under axonal signals and regulates axon-Schwann cell interactions. AB - Collapsin response mediator protein 5 (CRMP5) is one of the rare peripheral nerve antigens that is a target of autoantibodies in a paraneoplastic peripheral neuropathy. The pattern of axonal and myelin alterations suggests that CRMP5 is involved in axon-Schwann cell interaction. We examined CRMP5 expression and function in primary cultures of Schwann cells and neurons and at various developmental and regenerating stages of rat sciatic nerve and in CRMP5-deficient mice in vivo. Collapsin response mediator protein 5 was strongly expressed during postnatal development and regeneration and decreased with myelination. It was mainly expressed by immature Schwann cells and persisted in Remak cells in the adult; however, a subpopulation of Schwann cells that were induced to myelinate also expressed CRMP5. We identified 2 axonal molecular cues regulating CRMP5 expression: human neuregulin type 1, which induces CRMP5 expression in immature and premyelinating Schwann cells, and cyclic adenosine monophosphate, which inhibits CRMP5 expression when Schwann cells begin myelination. Collapsin response mediator protein 5-deficient mice showed abnormal Schwann process extension resulting in abnormal cell-axon segregation, indicating that CRMP5 is involved in the morphologic adaptation of Schwann cells to surround axons. These results demonstrate the importance of CRMP5 in axon-Schwann cell cooperation during development and regeneration. PMID- 22437342 TI - Somatostatin and neuropeptide Y neurons undergo different plasticity in parahippocampal regions in kainic acid-induced epilepsy. AB - Parahippocampal brain areas including the subiculum, presubiculum and parasubiculum, and entorhinal cortex give rise to major input and output neurons of the hippocampus and exert increased excitability in animal models and human temporal lobe epilepsy. Using immunohistochemistry and in situ hybridization for somatostatin and neuropeptide Y, we investigated plastic morphologic and neurochemical changes in parahippocampal neurons in the kainic acid (KA) model of temporal lobe epilepsy. Although constitutively contained in similar subclasses of gamma-aminobutyric acid (GABA)-ergic neurons, both neuropeptide systems undergo distinctly different changes in their expression. Somatostatin messenger RNA (mRNA) is rapidly but transiently expressed de novo in pyramidal neurons of the subiculum and entorhinal cortex 24 hours after KA. Surviving somatostatin interneurons display increased mRNA levels at late intervals (3 months) after KA and increased labeling of their terminals in the outer molecular layer of the subiculum; the labeling correlates with the number of spontaneous seizures, suggesting that the seizures may trigger somatostatin expression. In contrast, neuropeptide Y mRNA is consistently expressed in principal neurons of the proximal subiculum and the lateral entorhinal cortex and labeling for the peptide persistently increased in virtually all major excitatory pathways of the hippocampal formation. The pronounced plastic changes differentially involving both neuropeptide systems indicate marked rearrangement of parahippocampal areas, presumably aiming at endogenous seizure protection. Their receptors may be targets for anticonvulsive drug therapy. PMID- 22437343 TI - Hypoxia-induced activation of N-methyl-D-aspartate receptors causes retinal ganglion cell death in the neonatal retina. AB - It is well established that hypoxia causes excess accumulation of glutamate in developing neural tissues. This study aimed to elucidate the mechanism by which glutamate can cause retinal ganglion cell (RGC) death through the N-methyl-D aspartate (NMDA) receptors (NR) in the developing retina. One-day-old Wistar rats were exposed to hypoxia for 2 hours and then killed at different time points. Normal age-matched rats were used as controls. NR1, NR2A-D, and NR3A messenger RNA and protein expression showed significant increases over control values, notably at early time points (3 hours to 7 days) after the hypoxic exposure, and immunoexpression of NR1, NR2A-D and NR3A on retinal ganglion cells (RGCs) was enhanced in hypoxic rats and this was confirmed in cultured hypoxic RGCs. Ca(2+) influx in cultured RGCs was increased after hypoxic exposure, and the intracellular Ca(2+) concentration was suppressed by MK-801. Mitochondrial permeability transition pore opening, mitochondrial/cytosolic cytochrome c, and cytosolic caspase-3 expression levels were significantly increased in the hypoxic RGCs. These increases were reversed by MK-801, suggesting that the NMDA receptor subunits in the retina respond rapidly to the hypoxia-induced glutamate overload that leads to the cascade of events that result in RGC death. PMID- 22437344 TI - Moderate traumatic brain injury triggers rapid necrotic death of immature neurons in the hippocampus. AB - Traumatic brain injury (TBI) causes cell death predominantly in the cerebral cortex, but there is additional secondary cell death in the hippocampus. We previously found that most of the dying cells in the mouse hippocampus are newborn immature granular neurons in a mouse model of lateral controlled cortical impact (CCI) injury with a moderate level of impact. It is not known how long this selective cell death in the hippocampal dentate gyrus lasts, and how it is induced. Using Fluoro-Jade B and immunohistochemistry, we show that most of the neuron death in the hippocampus occurs within 24 hours after TBI and that cell death continues at low level for at least another 2 weeks in this lateral CCI model. Most of the dying immature granular neurons did not exhibit morphologic characteristics of apoptosis, and only a small subpopulation of the dying cells was positive for apoptotic markers. In contrast, most of the dying cells coexpressed the receptor-interacting protein 1, a marker of necrosis, suggesting that immature neurons mainly died of necrosis. These results indicate that moderate TBI mainly triggers rapid necrotic death of immature neurons in the hippocampus in a mouse CCI model. PMID- 22437345 TI - Lab-in-a-tube: ultracompact components for on-chip capture and detection of individual micro-/nanoorganisms. AB - A review of present and future on-chip rolled-up devices, which can be used to develop lab-in-a-tube total analysis systems, is presented. Lab-in-a-tube is the integration of numerous rolled-up components into a single device constituting a microsystem of hundreds/thousands of independent units on a chip, each individually capable of sorting, detecting and analyzing singular organisms. Such a system allows for a scale-down of biosensing systems, while at the same time increasing the data collection through a large, smart array of individual biosensors. A close look at these ultracompact components which have been developed over the past decade is given. Methods for the capture of biomaterial are laid out and progress of cell culturing in three-dimensional scaffolding is detailed. Rolled-up optical sensors based on photoluminescence, optomechanics, optofluidics and metamaterials are presented. Magnetic sensors are introduced as well as electrical components including heating, energy storage and resistor devices. PMID- 22437346 TI - Stereotactic radiosurgery for patients with recurrent intracranial ependymomas. AB - The objective of the study is to define the tumor control rate and complications associated with stereotactic radiosurgery (SRS) for patients with recurrent intracranial ependymoma. Retrospective review of 26 patients (49 tumors) having SRS between 1990 and 2008. Twenty-five patients (96 %) had undergone one or more craniotomies; one patient underwent SRS for a metastatic tumor after resection of a spinal ependymoma. Nineteen patients (73 %) had received cranial external beam radiotherapy (median dose, 54 Gy). Eight patients (31 %) were less than 18 years old. The median target volume was 2.2 cm(3) (range, 0.3-66.6); the median tumor margin dose was 18 Gy (range, 12-24). The median follow-up after SRS was 3.1 years (range, 3 months-13.1 years). The median overall survival after SRS was 5.5 years. The 1-year and 3-year survival rates were 96 and 69 %, respectively. Local tumor control (LC) was achieved in 33 of 49 lesions (67 %) with a median time to progression of 14.7 months (range, 2.9 months-11.2 years). The 1-year and 3-year progression-free survival rates were 80 and 66 %, respectively. The 1-year and 3 year LC rate was 85 and 72 %, respectively. On univariate analysis, higher tumor grade was associated with worse OS (grade 3-4, 27 % vs grade 2, 82 %, p = 0.04). Seven patients (27 %) had distant tumor progression and two patients (8 %) had symptomatic radiation necrosis after SRS. SRS for recurrent intracranial ependymoma provided good LC and may improve survival for patients with limited recurrent disease after prior treatment. PMID- 22437347 TI - Racial discrimination, social support, and sexual HIV risk among Black heterosexual men. AB - Numerous studies document the adverse impact of racial discrimination on African Americans' health outcomes, but few have focused on HIV risk. We examined the relationship between racial discrimination and sexual risk in a sample of 526 Black heterosexual men and tested the hypothesis that social support would moderate this relationship. Participants in the predominantly low-income urban sample ranged in age from 18 to 45. High social support had a buffering impact on the relationship between racial discrimination and sexual risk. Among men reporting high racial discrimination, those with more social support reported less sexual risk than men with low social support. Men who reported high racial discrimination and low social support reported more sexual risk than men in any of the other groups. The study highlights social support as an important but understudied protective factor that may reduce sexual risk for Black heterosexual men who report high levels of racial discrimination. PMID- 22437348 TI - Enhanced catalytic decomposition of a phosphate triester by modularly accessible bimetallic porphyrin dyads and dimers. AB - A series of metalloporphyrin dimers were modularly prepared and shown to catalyze the methanolysis of a phosphate triester, yielding rates that are large compared to the rate of the uncatalyzed reaction. Up to 1300-fold rate acceleration can be achieved via a combination of cavity-localized Lewis-acid activation and methoxide-induced methanolysis. PMID- 22437349 TI - Evaluation and prognostic significance of human tissue kallikrein-related peptidase 10 (KLK10) in colorectal cancer. AB - The prognosis of patients with colorectal cancer (CRC) is assessed through conventional clinicopathological parameters, which are not always accurate. Members of the human kallikrein-related peptidases gene family represent potential cancer biomarkers. The aim of this study was to investigate the expression of human tissue kallikrein-related peptidase 10 (KLK10) by immunohistochemistry in CRC, to correlate this expression with various histopathological and clinical variables, and to evaluate its significance as a predictor of disease outcome. KLK10 expression was evaluated by immunohistochemistry and a combined expression score was calculated for each case based on intensity and percentage of positivity. A statistically significant positive association was observed between KLK10 and tumor stage and liver metastases (p = 0.015 and p = 0.035, respectively). Paradoxically, a negative association was observed between KLK10 and tumor grade (p = 0.009). Kaplan-Meier survival curves and univariate analysis showed that both KLK10 expression and stage had statistically significant correlations with disease-free survival (DFS) (p = 0.030 and p < 0.001, respectively) and overall survival (p = 0.010 and p = 0.001, respectively). Cox multivariate analysis showed that both KLK10 expression and stage were independent predictors of unfavorable DFS (p = 0.057 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.001, respectively). In conclusion, KLK10 immunostaining is an independent prognostic marker in patients with CRC. PMID- 22437350 TI - Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors. AB - The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates. PMID- 22437351 TI - OPCAB versus On-Pump Surgery: The Beat Goes On. PMID- 22437352 TI - Endoscopic vein-graft harvesting: balancing the risk and benefits. PMID- 22437353 TI - Surgical Ablation for Atrial Fibrillation in Cardiac Surgery: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2009. AB - OBJECTIVE: : This purpose of this consensus conference was to determine whether surgical atrial fibrillation (AF) ablation during cardiac surgery improves clinical and resource outcomes compared with cardiac surgery alone in adults undergoing cardiac surgery for valve or coronary artery bypass grafting. METHODS: : Before the consensus conference, the consensus panel reviewed the best available evidence, whereby systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. Evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS: : The consensus panel agreed on the following statements in patients with AF undergoing cardiac surgery concomitant surgical ablation: CONCLUSIONS: : Given these evidence-based statements, the consensus panel stated that, in patients with persistent and permanent AF undergoing cardiac surgery, concomitant surgical ablation is recommended to increase incidence of sinus rhythm at short- and long-term follow up (class 1, level A); to reduce the risk of stroke and thromboembolic events (class 2a, level B); to improve EF (class 2a, level A); and to exercise tolerance (class 2a, level A) and long-term survival (class 2a, level B). PMID- 22437354 TI - Surgical ablation for atrial fibrillation in cardiac surgery: a meta-analysis and systematic review. AB - OBJECTIVES: : This meta-analysis sought to determine whether surgical ablation improves clinical outcomes and resource utilization compared with no ablation in adult patients with persistent and permanent atrial fibrillation (AF) undergoing cardiac surgery. METHODS: : A comprehensive search was undertaken to identify all randomized (RCT) and nonrandomized (non-RCT) controlled trials of surgical ablation versus no ablation in patients with AF undergoing cardiac surgery up to April 2009. The primary outcome was sinus rhythm. Secondary outcomes included survival and any other reported clinically relevant outcome or indicator of resource utilization. Odds ratios (OR) and weighted mean differences (WMD) and their 95% confidence intervals (95% CI) were analyzed as appropriate using the random effects model. Heterogeneity was measured using the I statistic. Meta regression was performed to explore the relationship between the benefit from surgical AF and duration of follow-up. RESULTS: : Thirty-three studies met the inclusion criteria (10 RCTs and 23 non-RCTs) for a total of 4647 patients. The number of patients in sinus rhythm was significantly improved at discharge in the surgical AF ablation group versus (68.6%) the surgery alone group (23.0%) in RCTs (OR 10.1, 95% CI 4.5-22.5) and non-RCTs (OR 7.15, 95% CI 3.42-14.95). This effect on sinus rhythm (74.6% vs. 18.4%) remained at follow-up of 1 to 5 years (OR 6.7, 95% CI 2.8-15.7 for RCT, and OR 15.5, 95% CI 6.6-36.7 for non-RCT). The risk of all-cause mortality at 30 days was not different between the groups in RCT (OR 1.20, 95% CI 0.52-3.16) or non-RCT studies (OR 0.99, 95% CI 0.52-1.87). In studies reporting all-cause mortality at 1 year or more (up to 5 years), mortality did not differ in RCT studies (OR 1.21, 95% CI 0.59-2.51) but was significantly reduced in non-RCT studies (OR 0.54, 95% CI 0.31-0.96). Stroke incidence was not reduced significantly; however, in meta-regression, the risk of stroke decreased significantly with longer follow-up. Other clinical outcomes were similar between groups. Operation time was significantly increased with surgical AF ablation; however, overall impact on length of stay was variable. CONCLUSIONS: : In patients with persistent or permanent AF who present for cardiac surgery, the addition of surgical AF ablation led to a significantly higher rate of sinus rhythm in RCT and non-RCT studies compared with cardiac surgery alone, and this effect remains robust over the longer term (1-5 years). Although non-RCT studies suggest the possibility of reduced risk of stroke and death, this remains to be proven in prospective RCTs with adequate power and follow-up. PMID- 22437355 TI - Early outcomes after bilateral thoracoscopy versus median sternotomy for lung volume reduction. AB - OBJECTIVE: : A National Emphysema Treatment Trial subanalysis, although finally describing outcomes as "comparable," suggested that bilateral lung volume reduction surgery (LVRS) by video-assisted thoracoscopic surgery (VATS) may be slightly less morbid than by median sternotomy (MS). We report a single surgeon experience using both the MS and VATS approaches to provide additional information on this issue in a setting of uniform patient selection and perioperative management. Our hypothesis was that a VATS approach would provide equivalent or less morbidity than MS despite being applied to a group of patients subjectively selected to be higher risk than those undergoing MS. METHODS: : Consecutive patients over a 9-year period underwent LVRS by one surgeon by either MS or VATS in a nonrandomized fashion. Thoracoscopy was selected over MS primarily when the surgeon estimated a greater overall risk profile and thus a greater chance of morbidity/mortality in a particular patient. RESULTS: : There were 15 patients in the VATS group and 35 in the MS group. In terms of measures of risk profile, there were no differences between the groups that met statistical significance, but several values trended toward higher risk within the VATS group (eg, age, 63 VATS vs. 59 MS, P = 0.08; moderate pulmonary hypertension, 38% VATS vs. 14% MS, P = 0.11; and residual volume, 241% VATS vs. 226% MS, P = 0.32). With regard to outcomes, operative time was significantly longer in the VATS group (VATS = 155 minutes vs. MS=129 minutes, P = 0.01). All other outcomes, including the incidence of major complications (13.3% VATS vs. 17.1% MS, P = 0.39), were similar between the groups. There was a single death within 90 days (1.9% of entire series; 2.9% of MS group). CONCLUSIONS: : In this series, although patients undergoing LVRS by VATS tended to have a higher risk profile, their outcomes were no worse than in those undergoing LVRS by MS. This suggests that the VATS approach to bilateral LVRS may incur slightly less morbidity and thus may be the best option in the most compromised patients who is nonetheless felt will benefit from LVRS. PMID- 22437356 TI - Long-Term Outcomes After CABG With Concomitant CO2 Transmyocardial Revascularization in Comparison With CABG Alone. AB - OBJECTIVES: : Transmyocardial revascularization (TMR) has been used as an isolated or adjunctive revascularization therapy in patients presumed to have nonbypassable coronary artery disease. The purpose of this study is to evaluate the short- and midterm mortality for patients with complete revascularization using TMR and coronary artery bypass grafting (CABG) compared with those patients with incomplete CABG revascularization and to document long-term follow-up in patients receiving TMR + CABG. METHODS: : Seventy TMR + CABG patients were cohort matched with 70 patients undergoing isolated CABG with circumflex coronary artery disease, but with no bypassable distal targets, from 1999 to 2005 at Emory University Hospital. The data were retrospectively reviewed from a database after being prospectively entered. Results are presented in mean +/- standard deviation, and Kaplan-Meier curves were created for long-term all-cause mortality. RESULTS: : The TMR + CABG patients had a similar incidences to the CABG only group for preoperative ejection fraction (50.9 +/- 11.2% vs. 50.7 +/- 10.3%, P = 0.93), number of grafts (2.6 +/- 1.1 vs. 2.5 +/- 1.3, P = 0.5), and number of diseased vessels (2.8 +/- 0.3 vs. 2.9 +/- 0.4, P = 0.26). Off-pump surgery was used more often in the CABG alone group versus the TMR combined with CABG group (74.3% vs. 41.4%, P < 0.001). Postoperatively, there was no statistical difference among the TMR + CABG and the CABG alone groups for intensive care unit length of stay (4.3 +/- 7.8 days vs. 2.6 +/- 3.4 days, P = 0.026), postsurgical length of stay (7.6 +/- 6.1 days vs. 6.8 +/- 4.5 days, P = 0.31), stroke events (1.4% vs. 1.4%, P = 1.00), myocardial infarction (4.3% vs. 2.9%, P = 0.65), and 30-day mortality (5.7% vs. 4.3%, P = 0.70). Long-term survival rate was not statistically significant. In addition, 4-year follow-up in the TMR + CABG group had symptom improvement with reduction in New York Heart Association classification for class III/IV (P < 0.0001, baseline vs. 4-year follow-up). CONCLUSIONS: : The combination of TMR and CABG for complete revascularization is safe and carries no further risk to patients compared with CABG only. CABG + TMR patients tend to have increased resource utilization. Long term follow-up shows similar survival between the groups. TMR can be a useful adjunct to CABG for complete revascularization. PMID- 22437357 TI - Early patency evaluation of new distal anastomotic device in internal mammary artery grafts using computed tomography angiography. AB - INTRODUCTION: : Traditional coronary artery bypass grafting is performed using a hand sewn technique. The C-Port xA and Flex A anastomotic stapling devices (Cardica Inc., Redwood City, CA) were cleared by the Food and Drug Administration for use in distal coronary anastomoses in November 2006 and April 2007, respectively. They provide the ability to create a compliant, consistently reproducible, and automated anastomosis. Multidetector computed tomography (CT) has been shown to be effective in evaluating coronary artery bypass graft patency. METHODS: : The first 24 patients to undergo internal mammary artery (IMA) anastomosis using the automated device in our practice were included in the study. Twenty-five IMA grafts (24 left IMA and 1 right IMA) were created using the C-Port xA or Flex A anastomotic device as part of multivessel off-pump coronary revascularization by sternotomy. Graft patency was evaluated at 30 days in the first 10 grafts and at 90 days in the next 15 grafts using multidetector (64 slice) CT. RESULTS: : There were no device failures. There were no perioperative strokes, myocardial infarctions, or deaths. All 10 IMA grafts evaluated at 30 days were patent using multidetector CT. One of the 15 IMA grafts studied at 90 days was occluded using multidetector computed tomography. CONCLUSIONS: : The C-Port xA and Flex A distal anastomotic devices provided a safe and effective means to create a left IMA-left anterior descending artery anastomoses in coronary bypass surgery with excellent short to midterm patency in this early experience. Long-term follow-up is warranted. These findings will have important implications for future sternal sparing coronary bypass surgery. PMID- 22437358 TI - Medtentia double helix mitral annuloplasty system evaluated in a porcine experimental model. AB - OBJECTIVE: : To further develop and improve minimally invasive surgical procedures, dedicated appropriate surgical devices are mandatory. In this study, the safety and feasibility of implanting the novel Medtentia double helix mitral annuloplasty ring, which uses the key-ring principle to potentially allow faster and sutureless implantation, was assessed using both minimally invasive and conventional surgical techniques. Because of ethical concerns, a human compatible porcine experimental model of mitral valve surgery was used. METHODS: : Twelve 50 kg pigs were allocated to implantation of the Medtentia double helix annuloplasty ring using conventional midline sternotomy including cardioplegic arrest or a minimally invasive approach using peripheral cannulation and left ventricular fibrillation. Ten weeks after surgery, echocardiography was performed to assess mitral valve function. Animals were then killed, and gross mitral valve anatomy was examined ex vivo. RESULTS: : All animals survived 10 weeks without developing mitral regurgitation, structural leaflet damage, ring dehiscence, or endocarditis. In the minimally invasive compared with the midline sternotomy group (mean +/- SD), significantly reduced recovery time (80 +/- 16 vs. 327 +/- 23 minutes, P < 0.01) and a tendency toward increased operating time (199 +/- 33 vs. 168 +/- 15 minutes, P > 0.05) and cardiopulmonary bypass time (98 +/- 12 vs. 91 +/- 11 minutes, P > 0.05) were observed. CONCLUSIONS: : By using a both minimally invasive and conventional midline sternotomy implantation techniques, the Medtentia double helix annuloplasty ring showed no mitral valve dysfunction or tissue damage 10 weeks postoperatively. PMID- 22437359 TI - "Beyond beating heart surgery": heartstring device protects against perioperative neurological events. AB - OBJECTIVE: : There is a growing body of evidence favoring off-pump coronary artery bypass surgery (OPCAB) over traditional coronary artery bypass surgery (CABG) with cardiopulmonary bypass as a method for reducing perioperative neurologic events. Aortic manipulation, whether with OPCAB or coronary artery bypass surgery with cardiopulmonary bypass, is strongly linked with adverse neurologic outcomes. Although the aortic "no-touch" technique has merit, most cardiac surgeons are reluctant to base entire myocardial revascularization exclusively on mammary pedicles. The purpose of this study was to analyze our experience with OPCAB combined with the use of a Heartstring proximal anastomotic device, as a strategy for reducing clinically evident cerebrovascular accidents. METHODS: : Two hundred twenty-seven consecutive isolated OPCAB were performed without the use of a side-biting aortic clamp. In all these operations, a Heartstring device was used, permitting clampless hand-sutured proximal anastomoses. All patients were managed in this fashion regardless of the status of their ascending aorta. A mean of 3.4 bypasses were performed during each operation, with one or two mammary arteries harvested routinely. In 98% of patients, a single proximal anastomosis was performed; there was liberal use of sequential bypass grafts. RESULTS: : Mean age was 69.3 years, with 17% octogenarians. Preexisting cerebrovascular disease was present in 22.4% of patients. There were no clinically evident perioperative neurologic events in any patients. There were no operative deaths. CONCLUSIONS: : This series suggests that OPCAB performed with a single, clampless, proximal aortic anastomosis, and with a Heartstring device may protect against perioperative strokes. PMID- 22437360 TI - Thermosensitive polymer use for shunt sealing in off-pump coronary artery bypass. AB - OBJECTIVE: : To check the efficacy of a reverse thermosensitive gel (poloxamer P407) for intracoronary shunt sealing in off-pump coronary artery bypass surgery to stop residual bleeding from the shunt and avoid the use of blowers. METHODS: : Nineteen coronary anastomoses were performed on five patients who underwent off pump coronary artery bypass surgery. Intracoronary shunting was adopted in all procedures. All the shunts were sealed into the coronary lumen with the injection of a reverse thermosensitive gel. Before tying the sutures, a piece of ice was applied on the anastomotic sites to dissolve the gel. Bleeding from the coronary lumen was always checked after shunt removal. RESULTS: : Bleeding was stopped or reduced and anastomoses performed without blower use. In one case, bleeding started again after shunt manipulation, and the shunt sealing procedure needed to be repeated. No intraoperative surface electrocardiogram and regional motion changes were detected. All patients showed normal creatine kinase-MB (CK-MB) levels in the postoperative period. All patients were free from adverse cardiovascular events at 4 months from operation. CONCLUSIONS: : The use of a thermosensitive polymer for intracoronary shunt sealing was effective in controlling bleeding, eliminated the necessity for blower use, and was not associated to operative complications. PMID- 22437361 TI - Tangential triangular resection: an option to treat the giant left atrium. AB - A 21-year-old woman presented with congestive heart failure caused by congenital mitral and tricuspid insufficiency, associated with great left atrium enlargement. Transthoracic echocardiogram revealed heart dextroversion associated with mitral and tricuspid severe insufficiency and left atrium enlargement (14 cm), confirmed by magnetic resonance study. The left atrium was reduced by a tangential triangular resection of the posterior wall, between the pulmonary veins, suturing the edges of the left atrium with bovine pericardium strip reinforcement. Mitral and tricuspid valves were repaired. The postoperative course was uneventful, and the patient was discharged in the 15th postoperative day. A control magnetic resonance study revealed a 50% reduction in left atrium size. Evolution of left atrium resection is excellent, with low recurrence of arrhythmias, embolism, or heart failure. PMID- 22437362 TI - Precise Stent Placement Using the New Siemens Artis Zeego 3D Rotation Angiography in a Stenosis of a Shelhigh Pulmonary Conduit. AB - Stenting of the Shelhigh pulmonary conduit was performed 2 years after a Ross procedure because of a stenosis of the distal segment. We used the new Siemens Artis Zeego technology. A precise placement of the stent to release the stenosis within the distal segment simultaneously retaining a competent valve was possible by using the Dyna-computed tomography technology. The early onset of a stenosis of the Shelhigh xenograft in the pulmonary position is alarming, thus, its use can not be recommended for a replacement of the pulmonary valve. PMID- 22437363 TI - Traumatic aneurysm in persistent sciatic artery. AB - A 59-year-old male patient admitted to our hospital with a pulsatile right gluteal mass with history of formation after blunt trauma. Persistent sciatic artery and its traumatic aneurysm was diagnosed after medical examination followed by peripheric digital substraction angiography. Surgery was performed under general anesthesia, and the patient was discharged from the hospital on postoperative day 7 without any problems. The sciatic artery, a continuation of the internal iliac artery into the popliteal-tibial vessels, represents the major blood supply to the lower limb in early embryologic development. Its persistence is very rare, and the aneurysmatic dilatation is the most common pathology diagnosed. Here, we present a rare case of persistent sciatic artery presenting with a traumatic aneurysm treated by iliopopliteal bypass surgery and ligation of the internal iliac artery proximal to the aneurysm. PMID- 22437364 TI - Tetraplegia after coronary artery bypass surgery in a patient with cervical herniation. AB - Tetraplegia is a rare complication after coronary artery bypass surgery. The authors present a case of tetraplegia after uncomplicated coronary artery bypass surgery because of cervical disc herniation. No distinct abnormality was found in the preoperative neurologic examination although the postoperative cervical magnetic resonance imaging revealed a huge hernia at C5-C6 level presenting with tetraplegia. Surgical decompression was performed on the second postoperative day of bypass surgery, and neurologic deficits gradually improved. PMID- 22437365 TI - "Ring pledget": a new concept for secure apex closure during transapical aortic valve implantation. AB - Transapical aortic valve implantation requires puncture of the left ventricle apex and insertion of a 32-French delivery sheath. A critical step in the procedure consists of secure closure of the ventricular apex. We describe 2 cases of apical rupture of 42 transapical aortic valve implantations. Furthermore, we describe the use of a newly designed single circular Teflon pledget that can help to avoid this complication. This pledget provides a more secure and uniform shrinkage of the entire apex to close the defect left by the delivery sheath. PMID- 22437366 TI - Technological advances in minimally invasive radiofrequency ablation of cardiac tissues. AB - Ablative techniques have been sought in many circumstances as alternatives to surgical resection/incision. Besides being minimally invasive, potential benefits of ablation include greater speed and improved access to target tissue compared with other surgical techniques. There is a wide variety of ablation technologies currently in use for medical treatment. These include but are not limited to tissue heating by radiofrequency (RF) current, microwaves, laser, and high intensity ultrasound. RF is among the most heavily used because of its relatively low complexity and cost. Ablative techniques have proven to be viable alternatives to surgical resection/incision of tissue. Although there are other means of tissue heating besides RF, RF is the most commonly used technique in operating rooms because of the reliability of transmural lesions and the low complexity of the system. Optimal systems account for the heterogeneous nature of tissue and variations in tissue property through the ablation cycle. It is important to monitor and assure adequate energy delivery by selecting the appropriate configuration of devices. Energy delivery varies between the various generators and systems, some more responsive than others with relative to changes in tissue impedance that will affect the end results of the operation. PMID- 22437367 TI - A convenient and mild chromatography-free method for the purification of the products of Wittig and Appel reactions. AB - A mild method for the facile removal of phosphine oxide from the crude products of Wittig and Appel reactions is described. Work-up with oxalyl chloride to generate insoluble chlorophosphonium salt (CPS) yields phosphorus-free products for a wide variety of these reactions. The CPS product can be further converted into phosphine. PMID- 22437368 TI - Dietary amino acid L-tryptophan requirement of fingerling Indian catfish, Heteropneustes fossilis (Bloch), estimated by growth and haemato-biochemical parameters. AB - An 8-week feeding trial was conducted to determine the dietary tryptophan requirement of fingerling Indian catfish, Heteropneustes fossilis (6.10 +/- 1.15 cm, 4.44 +/- 0.50 g). Six isonitrogenous (40 g 100 g-1) and isoenergetic (17.90 kJ g-1) amino acid test diets were formulated with gradation of 0.1 g 100 g-1 containing graded levels of L-tryptophan (0.04-0.54 g 100 g-1, dry diet). Fish were stocked in triplicate groups, in 75-L circular trough with flow-through system and fed experimental diets at 4% BW/day twice daily. Maximum live weight gain (258%), best feed conversion ratio (FCR) (1.54) and protein efficiency ratio (PER) (1.62) were obtained in fish fed diet containing 0.34 g 100 g-1 tryptophan. However, quadratic regression analysis of weight gain, FCR, PER and body protein deposition (BPD) data indicated requirements for dietary tryptophan at 0.37, 0.33, 0.32 and 0.33 g 100 g-1 of dry diet, respectively. Significantly (P < 0.05) higher body protein, minimum moisture and intermediate fat contents were recorded at 0.34 g 100 g-1 dietary tryptophan diet. Ash content was not significantly different (P > 0.05) among treatments except for diets 0.04 and 0.14 g 100 g-1. Excellent somatic and haematological indices values were obtained at the requirement level. Based on above results, it is recommended that the diet for H. fossilis should contain tryptophan at 0.32 g 100 g-1, dry diet, corresponding to 0.80 g 100 g-1 dietary protein for optimum growth and efficient feed utilization. PMID- 22437369 TI - Oogenesis and lipids in gonad and liver of daubed shanny (Leptoclinus maculatus) females from Svalbard waters. AB - Oocyte and liver histomorphology of the daubed shanny (Leptoclinus maculatus) from Isfjorden and Kongsfjorden in Svalbard were investigated during three Arctic seasons: summer (July), autumn (October) and winter (April). Three oocyte developmental phases were observed: primary growth phase, secondary growth phase and maturation phase. We observed four different developmental stages: (1) perinucleolus stage with cortical alveolus formation, (2) lipid droplets formation, (3) vitellogenesis stage and (4) maturation. Late maturation stage of oocytes in the ovaries was from the autumn season. Females accumulated lipids in liver (up to 35.2 % dw) and deposited large amounts of lipids into gonads (up to 52.2 % dw) during maturation. Lipid classes in female gonads changed seasonally, with relative increase in cholesterol during summer and depletion of storage lipids (triacylglycerols and wax esters/cholesterol esters) during the winter. Lipid composition in liver changed during oocyte development and spawning, as neutral lipids were transferred to developing oocytes during summer to autumn. During winter, storage lipids were depleted during starvation. Based on the increase in gonadosomatic index (GSI) with length and observed maturation stages, females seem to mature at a length of about 125-130 mm. The GSI and hepatosomatic index of large females sampled in autumn (September-October) were significantly higher than for females in late winter (April) and spring (May). These results indicate that spawning takes place during winter in Isfjorden and that energy reserves stored in the liver are utilized by females during gonadal development and reproduction. PMID- 22437370 TI - Effect of yeast polysaccharide on some hematologic parameter and gut morphology in channel catfish (Ictalurus punctatus). AB - A study was conducted to investigate the effect of dietary yeast polysaccharides on some hematologic parameters and intestinal morphology of channel catfish. Channel catfish were fed diets containing yeast polysaccharides at 0 (control), 0.1, 0.2, or 0.3 % for 7 weeks. Each diet was provided to 10 channel catfish specimens (5.82 +/- 0.13 g initial weight) replicated 3 times in individual 250 L fiberglass tanks. Some hematologic parameters, leukocyte phagocytic activity, and intestinal morphology were monitored. After 7 weeks of trial, 0.2 % yeast polysaccharides resulted in significantly higher (P < 0.05) monocyte numbers. Furthermore, fish fed 0.2 % yeast polysaccharide diet had higher (P < 0.05) phagocytic rate of leukocyte. And 0.3 % yeast polysaccharide enhanced (P < 0.05) phagocytic index of leukocyte. Histological evaluation showed yeast polysaccharide supplementation increased the height of intestine fold (0.1, 0.2 and 0.3 %) and the thick of muscular layers (0.2 %) in intestine (P < 0.05). In addition, 0.1 and 0.3 % yeast polysaccharide supplementation improved the number of goblet cells (P < 0.05). The results of this trial indicate that yeast polysaccharides supplementation could affect blood monocytes, improve leukocytes phagocytic activity, and the development of intestine in channel catfish. PMID- 22437371 TI - Aortic atherosclerosis and embolic events. AB - Aortic plaques are a manifestation of the general process of atherosclerosis in which there is a progressive accumulation of cholesterol and other lipids in the intimal-medial layer of the aorta with secondary inflammation, repetitive fibrous tissue deposition, and eventually luminal surface erosions and appearance of often mobile thrombi protruding into the lumen of the aorta. Aortic plaques may give rise to two types of emboli: thromboemboli and atheroemboli (cholesterol crystal emboli). Thromboemboli are relatively large, tend to occlude medium to large arteries, and cause strokes, transient ischemic attacks, and renal infarcts and other forms of peripheral thromboembolism. Cholesterol crystal emboli are relatively minute, tend to occlude small arteries and arterioles, and may cause the blue toe syndrome, new or worsening renal insufficiency, gut ischemia, etc. Transesophageal echocardiography remains the gold standard for visualization of aortic plaques in the thoracic aorta. There are no proven therapies for aortic embolism per se; general atherosclerosis management strategies are recommended. PMID- 22437372 TI - Myocardial contrast echocardiography after myocardial infarction. AB - Myocardial contrast echocardiography (MCE) enables direct assessment of the degree and adequacy of microvascular perfusion as well as the presence of wall motion abnormalities. MCE has the following benefits in patients with acute myocardial infarction (MI): 1) rapid and definite diagnosis of acute MI; 2) identification of patients who may benefit from prompt reperfusion therapy; 3) assessment of the efficacy of mechanical or pharmacologic intervention for an open infarct-related artery; 4) estimation of MI size early after reperfusion and residual myocardial viability; 5) identification of being at high risk for post MI complications and left ventricular remodeling; and 6) assessment of myocardial viability and ischemia prior to hospital discharge. Therefore, MCE is an ideal tool for correct triaging of patients to revascularization and has both prognostic and therapeutic implications in patients with acute MI. PMID- 22437373 TI - Is myocardial recovery possible and how do you measure it? AB - Medical and device therapies that reduce heart failure morbidity and mortality also lead to decreased left ventricular volume and mass, and a more normal elliptical shape of the ventricle. These are due to changes in myocyte size, structure, and organization that have been referred to collectively as "reverse remodeling." Moreover, there are subsets of patients whose hearts have undergone reverse remodeling following mechanical circulatory support with a ventricular assist device (VAD), who are able to be weaned from their VADs, which has been referred to as "myocardial recovery." Although the term myocardial recovery has been used to describe the reversal of various aspects of the heart failure phenotype following medical and device therapy, there is no consensus with regard to what constitutes myocardial recovery; moreover, the methodology for identifying myocardial recovery in patients is unclear. These topics will be discussed in the current review. PMID- 22437374 TI - Role of self-care in the patient with heart failure. AB - Optimal outcomes and quality of life for patients with heart failure depend on engagement in effective self-care activities. Self-care is a complex set of activities and most clinicians are not adequately prepared to assist their patients to engage in effective self-care. In this paper, we provide an overview of self-care that includes definitions, the importance of self-care to outcomes, the physiologic basis for better outcomes with good self-care, cultural perspectives of self-care, and recommendations for the improvement of self-care. Promotion of effective self-care by all clinicians could substantially reduce the economic and personal burden of repeated rehospitalizations among patients with heart failure. PMID- 22437375 TI - An efficient alternative to the stratified Cox model analysis. AB - Consider a typical two-treatment randomized clinical trial involving a time-to event endpoint, with randomization stratified by a categorical prognostic factor (for example gender). At the design stage, it is often assumed that the treatment hazard ratio (HR) is constant across the strata, and the data are commonly analyzed using the stratified Cox proportional hazards model. We caution that this ubiquitous approach is needlessly risky because departures from the assumption of the HR being the same for all the strata can result in a notably biased and/or less powerful analysis. An alternative approach is proposed in which first the [log] HR is estimated separately for each stratum using an unstratified Cox model, and then the stratum-specific estimates are combined for overall inference using either sample size or 'minimum risk' stratum weights. The advantages of the proposed two-step analysis versus the common one-step stratified Cox model analysis are illustrated using simulations that were conducted to support the design of a vaccine clinical trial. PMID- 22437376 TI - [Avulsion fracture of the lesser trochanter]. AB - An avulsion fracture of the lesser trochanter is a very rare injury often misdiagnosed as a muscle lesion or hip distortion. This report concerns the avulsion fracture of the lesser trochanter of a 13-year-old boy, suffered on a runway preparing for a long jump. Conservative treatment without weight-bearing was indicated for 6 weeks. Twelve weeks after the injury the patient resumed his normal sport activities. PMID- 22437377 TI - Halitosis and tongue coating in patients with erosive gastroesophageal reflux disease versus nonerosive gastroesophageal reflux disease. AB - OBJECTIVE: The aim of this study was to investigate whether patients with diagnosed erosive gastroesophageal reflux disease (ERD) have an increased probability of halitosis and tongue coating compared to patients with nonerosive gastroesophageal reflux disease (NERD). MATERIALS AND METHODS: Sixty-six patients (33 males and 33 females) were recruited for the study and received an upper gastrointestinal endoscopy. The presence of ERD (n = 31) and NERD (n = 35) was classified based on the Los Angeles classification for erosive changes in the esophagus. Additionally, the patients filled in a questionnaire regarding their subjective assessment of halitosis, and an organoleptic assessment of halitosis, a measurement of oral volatile sulfur compounds (VSC) with the Halimeter, and a tongue coating index were performed. ERD and NERD subjects were compared with regard to Halitosis-related clinical and anamnestic findings. RESULTS: No statistically significant difference could be found between ERD and NERD patients regarding tongue coating index, organoleptic scores, and VSC values as well as self-perceived bad taste, tongue coating, and bad breath. CONCLUSIONS: These data suggest that halitosis is not typically associated with erosive gastroesophageal reflux disease and the presence of esophageal mucosal damage (ERD patients). CLINICAL RELEVANCE: The data of this investigation support the findings of interdisciplinary bad breath clinics that gastroesophageal reflux disease is not a leading cause for halitosis. PMID- 22437379 TI - Zooplankton community resilience and aquatic environmental stability on aquaculture practices: a study using net cages. AB - Fish farming in net cages causes changes in environmental conditions. We evaluated the resilience of zooplankton concerning this activity in Rosana Reservoir (Paranapanema River, PR-SP). Samples were taken near the net cages installed at distances upstream and downstream, before and after net cage installation. The resilience was estimated by the decrease in the groups' abundance after installing the net cages. The zooplankton community was represented by 106 species. The most abundant species were Synchaeta pectinata, S. oblonga, Conochilus coenobasis, Polyarthra dolichoptera and C. unicornis (Rotifera), Ceriodaphnia cornuta, Moina minuta, Bosmina hagmanni and C. silvestrii (Cladocera) and Notodiaptomus amazonicus (Copepoda). The resilience of microcrustaceans was affected in the growing points as this activity left the production environment for longer, delaying the natural ability of community responses. Microcrustaceans groups, mainly calanoid and cyclopoid copepods, had a different return rate. The net cage installation acted as a stress factor on the zooplankton community. Management strategies that cause fewer risks to the organisms and maximize energy flow may help in maintaining system stability. PMID- 22437380 TI - Composition and abundance of zooplankton community of an impacted estuarine lagoon in Northeast Brazil. AB - Guarairas Lagoon is a shallow coastal lagoon subject to intense human impacts, including shrimp aquaculture, urban expansion and agricultural activities, and is therefore vulnerable to eutrophication. With the aim of detecting the effects of human-mediated disturbance and environmental change in the lagoon, a spatial temporal study was conducted in order to assess the actual ecological status of the lagoon and the species composition and density of the mesozooplankton, highlighting copepod assemblages. Algal biomass (chlorophyll-a) and total phosphorus concentration indicated that the lagoon is a meso-eutrophic coastal system in the inner part, and is oligotrophic in the areas influenced by the marine waters. High salinities were recorded in the lagoon, characterizing the lagoon as a coastal-marine ecosystem, rather than true estuarine. Mesozooplankton abundance fluctuated widely and showed marked spatial heterogeneity. The copepod assemblage was characterized by a coastal/estuarine group dominated by Oithona spp., Acartia lilljeborgi and Parvocalanus crassirostris in the inner areas of the lagoon, and a marine group characterized by the copepods Paracalanus quasimodo, Calanopia americana, Corycaeus (C.) speciosus and Monstrilloida in the area of marine influence. Thus, the spatial variability in the distribution of mesozooplankton species can be ascribed to the presence of a horizontal gradient of salinity and trophic conditions. Overall, the results showed that spatial variation in the water physicochemical characteristics of Guarairas Lagoon have significant effects on the structure and repartition of the mesozooplankton assemblages, which may potentially affect the functioning and biodiversity of this coastal ecosystem. PMID- 22437381 TI - Frugivory and seed dispersal of Miconia theaezans (Bonpl.) Cogniaux (Melastomataceae) by birds in a transition palm swamp: gallery forest in Central Brazil. AB - The objective of this study was to evaluate potential avian dispersers of Miconia theaezans by dietary habits in the Cerrado of Central Brazil. Forty-two hours and 40 minutes of focal tree observation were conducted between 7:00 AM and 5:00 PM. For each bird species that consumed the fruit, we registered: the time they remained on the plant, the total amount of fruit they consumed, foraging tactics and strategies to consume the fruit. Five-hundred and fifty-nine units of fruit were consumed in 47 visits by seven bird species. Thraupidae was the most frequent and representative family and Tangara cayana was the main consumer. The Tachyphonus rufus had the highest rate of intake of the entire fruit, however the rates were not significantly different among the visitors. The most-used foraging tactic by all species was to consume the fruit while "perched" (95.74% of the visits). The most commonly-used consumption strategy was to mandibulate the fruit and swallow all the contents (65.12%). Omnivores were the predominant visitors (71.43%) and made most of the visits (89.36%). All visiting species could act as potential dispersers of M. theaezans, which demonstrates the low selectiveness of this pioneer plant towards its frugivorous. PMID- 22437382 TI - Grazing impacts of the invasive bivalve Limnoperna fortunei (Dunker, 1857) on single-celled, colonial and filamentous cyanobacteria. AB - Feeding behavior of the invasive bivalve Limnoperna fortunei in the presence of single-celled, colonial, and filamentous cyanobacteria was tested in laboratory experiments to evaluate the effects of size and shape on mussel feeding. The first hypothesis holds that golden mussel filters more efficiently smaller particles, such as single cells of Microcystis, which could be more easily assimilated by its filtering apparatus. The second hypothesis sustains that L. fortunei filters more efficiently rounded colonies, such as Microcystis, which would be more easily ingested than lengthy filamentous, such as Planktothrix. Filtration rates of golden mussel in the presence of single-celled, colonial and filamentous cyanobacteria were similar. Nevertheless, there was a great difference in the ingestion and pseudofeces production rates. Single cells were widely accepted as food, while filamentous and colonial cyanobacteria were massively expelled as pseudofeces. The results confirmed the first hypothesis that golden mussel prefers to ingest smaller particles. The second hypothesis was rejected since filamentous were preferentially ingested than colonial cyanobacteria. Golden mussel has the potential to remove toxic cells (Microcystis), however this potential would be reduced in cyanobacteria blooms, where colonial forms which are preferentially rejected by L. fortunei, are predominant. In this case, the presence of this invasive bivalve could also enhance the occurrence of blooms by rejecting colonial and filamentous cyanobacteria in pseudofeces. PMID- 22437383 TI - Feeding behavior of the invasive bivalve Limnoperna fortunei (Dunker, 1857) under exposure to toxic cyanobacteria Microcystis aeruginosa. AB - The aim of this study was to test the effects of cyanobacteria toxicity on feeding behavior of the golden mussel Limnoperna fortunei. First, it was tested the hypothesis that L. fortunei preferentially graze on non-toxic phytoplankton and reject toxic cyanobacteria. Second, it was tested the hypothesis that toxic cyanobacteria negatively affect feeding and survival of L. fortunei. The present study is the first to evaluate the effects of toxic cyanobacteria on L. fortunei feeding and survival. In the short-term grazing, golden mussel filtration rates were evaluated in the presence of toxic and non-toxic strains of cyanobacteria Microcystis aeruginosa, and non-toxic phytoplankton Nitzschia palea. Highest filtration rates were registered when mussels fed on Nitzschia. Despite that, golden mussel expelled Nitzschia cells in large quantities and preferentially ingested Microcystis cells, both toxic and non-toxic strains. In the long-term grazing, mussels were exposed to toxic and non-toxic strains of Microcystis during 5 days. Filtration rates were not significantly different for toxic and non-toxic Microcystis throughout exposure period. The results have demonstrated cyanobacteria toxicity is not the main factor influencing L. fortunei feeding behavior. Survival of L. fortunei feeding on toxic cyanobacteria shows the potential of this invasive bivalve as a vector to the transference of cyanotoxins to higher trophic levels. PMID- 22437384 TI - The community of hummingbirds (Aves: Trochilidae) and the assemblage of flowers in a Caatinga vegetation. AB - We studied hummingbirds and their food plants in an area of caatinga vegetation. We specifically examined their seasonal use of this habitat, migratory and non migratory status, their foraging strategies and community roles The study was conducted in an area of arboreal-shrub caatinga, located in the Serra do Para, municipality of Santa Cruz do Capibaribe, state of Pernambuco in northeastern Brazil. Field work was undertaken during 12 expeditions on a monthly basis between June, 2007 and May, 2008. Five species of hummingbirds were recorded visiting flowers in the community studied. Three were considered residents: Chlorostilbon lucidus (Shaw, 1812), Eupetomena macroura (Gmelin, 1788), and Heliomaster squamosus (Temminck, 1823). Hummingbirds visited 31 species of plants, of which only five presented attributes related to ornithophily. C. lucidus visited 29 plant species, including all ornithophilous species, and it was the most aggressive, defending territories. Among hummingbirds, C. lucidus may be considered the principal pollinator. Hummingbirds may also be acting as pollen vectors for some of the plant species not identified as ornithophilous. The hummingbird guilds varied among the plant species used as floral resources, as well as in their frequency of visits. Differences in plant species abundance, hummingbird preference, competitive exclusion or flowering seasonality are factors likely to influence those variations. PMID- 22437385 TI - Breeding and trade of wildlife in Santa Catarina state, Brazil. AB - The wildlife trade is becoming increasingly more relevant in discussions concerning conservation biology and the sustainable management of natural resources. The aim of this study was to document the trade and breeding of wildlife in Santa Catarina state, in southern Brazil. Data was collected from annual reports (1996-2008) of wildlife breeders which were sent to IBAMA. By the end of 2008, there were 79 wildlife breeders and 11 wildlife traders distributed in Santa Catarina. Commercial breeding accounted for the highest number of breeders (51%). In total, there are 213 species of wild animals bred in the state: 177 birds, 19 mammals and 17 reptiles. Of these, 48% are native to Santa Catarina, 32% occur in other Brazilian states and 20% are exotic to Brazil. Nine percent of the species bred are vulnerable or endangered. It was observed that some breeders reported breeding unauthorized species. Altogether, 93 species are bred illegally by 19 breeders. Of these species, 48 are native to Santa Catarina and three are classified as vulnerable or in danger of extinction. We hope the data presented in this paper contributes to the development of conservation strategies and conscious use of wildlife resources in Brazil. PMID- 22437386 TI - Population structure of Uncancylus concentricus (d'Orbigny, 1835) (Ancylidae, Pulmonata, Basommatophora) in the Multiple Use Reserve Martin Garcia Island, Upper Rio de la Plata, Argentina. AB - The present work analyzes the population dynamics of Uncancylus concentricus in natural conditions in the northeastern coastal area of the Multiple Use Natural Reserve Isla Martin Garcia (Beach of Basural), Buenos Aires, Argentina. Martin Garcia Island is located in the Upper Rio de La Plata, to the south of the mouth of the Uruguay River (34 degrees 11' 25" S and 58 degrees 15'38" W). Monthly collections were made from August 2005 to December 2006. The size frequency of the U. concentricus population throughout the sampling period ranges from 1.2 to 8.3 m. The changes in the size frequencies throughout the months surveyed indicate a variable distribution pattern because of the increase and decrease in water flow, but we observed a peak in the frequency of individuals within the size range 3.5 to 4.5 mm in the population. It can be concluded that this species lives for at least a year in the wild since the juveniles are highly abundant in spring and summer. PMID- 22437387 TI - The use of Salvinia auriculata as a bioindicator in aquatic ecosystems: biomass and structure dependent on the cadmium concentration. AB - This study shows, in a multiple-level approach, the responses of Salvinia auriculata to Cd pollution in aquatic ecosystems. S. auriculata ramets were cultivated in nutrient solution and subjected to five treatments with Cd for ten days. At the end of the experiment, the number of new ramets and the dry biomass were determined. For ultrastructural observations, the leaves of S. auriculata were analyzed using a scanning electron microscope and transmission electron microscope. At the end of the experiment, the plants exposed to Cd showed damage in the leaves including necrosis and chlorosis, stomate deformations and damaged trichomes. We observed a decrease in the number of new ramets and dry biomass of S. auriculata following the increase in Cd concentration in the solution. At the ultrastructural level, leaves exposed to Cd presented chloroplast deformations and deterioration in the cell wall. All the symptoms of toxicity were directly proportionate to the concentration of Cd in the solution. The results suggests that S. auriculata shows good potential for use as a bioindicator and it can be used in the biomonitoring of aquatic ecosystems contaminated by Cd. PMID- 22437388 TI - Environmental factors affecting the distribution of land snails in the Atlantic Rain Forest of Ilha Grande, Angra dos Reis, RJ, Brazil. AB - The distribution and abundance of terrestrial molluscs are affected by environmental factors, but data are lacking for Brazilian land snails. The aim of this study was to understand the relationship between measured environmental factors and the land-snail species composition of two hillsides covered with Atlantic Rain Forest on Ilha Grande. On each hillside, five plots located at 100 m intervals between 100 to 500 m asl were chosen. Each plot was sampled by carrying out timed searches and collecting and sorting litter samples from ten quadrats of 25 * 75 cm. A range of environmental data was measured for each of the quadrats in a plot. A Cluster Analysis was carried out for the richness and abundance data. The environmental variables were analysed using a Pearson Correlation Matrix and Discriminant Analysis. Our results show that the two mountains are similar in species richness, but species composition and abundance are different, probably reflecting observed differences in environmental conditions. The environmental factors associated with compositional variation between the two mountains were: atmospheric temperature, soil temperature, litter depth, and relative air humidity. Distinct luminosity and canopy closure conditions were related to the composition of the land-snail community of one hillside. PMID- 22437389 TI - Composition and structure of fish assemblage from Passa Cinco stream, Corumbatai river sub-basin, SP, Brazil. AB - The aim of this work was to determine the composition of the fish assemblage of Passa Cinco stream and verify changes in their structure on the altitudinal gradient. Six samples were performed at five different sites in Passa Cinco stream (from the headwater, at order two, to its mouth, at order six), using an electric fishery equipment and gill nets in May, July, September and November of 2005 and January and March of 2006. The indices of Shannon's diversity, Pielou's evenness and Margalef's richness were quantified separately considering the different fishery equipment (nets versus electric fishery equipment). An ANOVA was used to compare samples collected in relation to values of abundance, diversity, evenness and richness. The representativeness of the species was summarised by their average values of abundance and weight. We captured 5082 individuals distributed into 61 species. We observed a trend of increasing diversity, richness and evenness of species from site 1 to 3, with further decrease in sites 4 and 5. The values found for habitat diversity also followed this pattern. Significant differences were found for all three indices considering the electric fishery samples. For individuals caught with nets, only the richness index showed a significant difference. Characidium aff. zebra was an important species in the headwater and transition sites and Hypostomus strigaticeps in middle-lower course sites. Despite the small extension of the Passa Cinco stream, environments structurally well defined were evidenced by the species distribution and assemblage composition along the gradient. PMID- 22437390 TI - Changes in phytoplankton composition in response to tides, wind-induced mixing conditions, and freshwater outflows in an urbanised estuarine complex. AB - Recent reports have shown an increase in potentially harmful phytoplankton in Santos bay (Southeastern Brazilian Coast), located in a highly urbanised estuarine complex. Prediction of blooms is, thus, essential but the phytoplankton community structure in very dynamic regions is difficult to determine. In the present work, we discriminate bloom forming microphytoplankton dominance and their relationship to physical and meteorological variables to look for patterns observed in different tides and seasons. Comparing 8 distinct situations, we found five scenarios of dominance that could be related to winds, tides and rainfall: i) Surfers, diatoms occurring during high surf zone energies; ii) Sinkers, represented by larger celled diatoms during spring tide, after periods of high precipitation rates; iii) Opportunistic mixers, composed of chain forming diatoms with small or elongate cells occurring during neap tides; iv) Local mixers, microplanktonic diatoms and dinoflagellates which occurred throughout the 298 sampling stations; and v) Mixotrophic dinoflagellates, after intense estuarine discharges. Results suggest alterations in the temporal patterns for some bloom-forming species, while others appeared in abundances above safe limits for public health. This approach can also illustrate possible impacts of changes in freshwater discharge in highly urbanised estuaries. PMID- 22437391 TI - Ichthyofauna diversity of Taperoa II reservoir, semi-arid region of Paraiba, Brazil. AB - To determine the fish species present in Taperoa II Reservoir, and their relevance to the local economy, this research aimed to evaluate the composition, abundance, degree of dominance and constancy of species, along with diversity, richness, evenness and similarity indices in a tropical semi-arid fish assemblage, during one year. Six 24 hour-long samplings were carried out between October 2005 and October 2006 using cast, seine and gillnets. The 889 collected individuals belonged to 11 species from 9 families. Temporal variation was observed in the capture frequency of different species, and a significant negative correlation between precipitation and number of individuals was also observed. Among the recorded families, Characidae showed a higher frequency of occurrence (38.4%), mostly due to Astyanax bimaculatus (Linnaeus, 1758) and A. fasciatus (Cuvier, 1819). Eight species were categorised as constant, two as accessory and one as accidental. Diversity index values were intermediate with low fluctuation throughout the study period, and no correlation with precipitation or water volume. However, the greatest diversity value was recorded in March 2006, when the peak of the precipitation was recorded. Evenness values showed a similar trend to the diversity index. PMID- 22437392 TI - Mollusks (Gastropoda and Bivalvia) of the Multiple-Use Reserve Martin Garcia Island, Rio de la Plata River: biodiversity and ecology. AB - The Island of Martin Garcia is located in the Upper Rio de la Plata, to the south of mouth the Uruguay River. The aim of the present study was to analyse the biodiversity of the island freshwater mollusks and their relationships to environmental variables. Twelve sampling sites were selected, five were along the littoral section of the island and seven were Inland ponds. Seven major environmental variables were measured: water and air temperature, percentage of oxygen saturation, dissolved oxygen, electrical conductivity, total dissolved solids and pH. Twenty-seven mollusk species were found, Antillorbis nordestensis, Biomphalaria tenagophila tenagophila , B. t. guaibensis, B. straminea, B. peregrina, Drepanotrema kermatoides, D. cimex, D. depressissimum, Chilina fluminea, C. rushii, C. megastoma, Uncancylus concentricus, Hebetancylus moricandi, Stenophysa marmorata, Heleobia piscium, H. parchappii, Potamolithus agapetus, P. buschii, P. lapidum, Pomacea canaliculata, P. megastoma, Asolene platae, Corbicula fluminea, Eupera platensis, Pisidium sterkianum, P. taraguyense and Limnoperna fortunei. UPGMA clustering of species based on their occurrence in different ecological conditions revealed two main species groups. The Canonical Correspondence Analysis suggests that the species distribution is related to the physico-chemical condition of water. Axis two of the ordination diagram displayed the approximately 95.6% of the correlation between species and environmental variables. Dissolved oxygen, conductivity, water temperature and pH showed the highest fluctuations during the sampling period. The species richness (S) showed relationships mainly with water temperature and conductivity. The biodiversity of the gastropods and bivalves from Martin Garcia Island amounts to up to 26 species. Among the Gastropoda, the Planorbidae family made the most sizeable contribution. The Lithogliphidae P. agapetus (26.28%) and P. buschii (9.50%) showed the highest relative frequencies of occurrence within the littoral environments, while the Planorbidae D. cimex (23.83%) and D. kermatoides (11.59%) likewise did so in the inland ponds. PMID- 22437393 TI - Histopathological alterations observed in the liver of Poecilia vivipara (Cyprinodontiformes: Poeciliidae) as a tool for the environmental quality assessment of the Cachoeira River, BA. AB - Histopathological alterations in liver have been widely used as a tool in studies for monitoring environmental quality. To evaluate the environmental quality in the Cachoeira river, five spots were monitored between the municipal districts of Itape and Ilheus, using liver histological analysis. The species chosen for analysis was Poecilia vivipara due to the fact that it is one of the most abundant in the sampling. The routine technique of inclusion and impregnation in paraffin was used, and the cuts were stained with Hematoxylin and Eosin (H & E). Histopathological alterations in the liver were evaluated semi-quantitatively and based on the severity of the lesions. The results of the histopathological alteration frequency together with the average taken from the Histopathological Alteration Index from points 1 (Vila de Itape) and 2 (Fazenda Santa Amelia) showed that in this area the environment is more threatened because of some stressor agent, possibly contaminants that seem to be acting in the environment and endangering the health of fish. The statistic results demonstrated that there were no significant differences among points 1, 2 and 4, which means they are very similar to one another, and are ecologically endangered. PMID- 22437394 TI - Toxicity of herbicides on Escherichia coli growth. AB - Agriculture uses a huge variety and quantity of chemicals. If, on one hand, the goal is to increase productivity, on the other hand these products contaminate aquatic environments. Among these products, herbicides deserve greater attention in relation to contamination of aquatic environments due to their extensive use to weed control. This study was carried out because the effects of these molecules on aquatic microorganisms such as Escherichia coli, is still unclear. Using microdilution plate assays, Escherichia coli were exposed to various commercial formulations of herbicides widely used in Brazil. The herbicide paraquat was the only one able to prevent the growth of Escherichia coli and is characterized as bacteriostatic. PMID- 22437395 TI - Triploidy in the hematology of jundia juveniles (Siluriformes: Heptapteridae). AB - This study compared the hematological characteristics of diploid and triploid of jundia, Rhamdia quelen juveniles, an important freshwater fish cultured in south Brazil. Hematological morphometry of erythrocytes were determined in blood smears under a light microscope. The blood was used to measure the number of red blood cells (RBC) with a hemocytometer Neubauer chamber, and the numbers of white blood cells (WBC) and thrombocytes that were obtained using an indirect method. The results showed that triploidy increased (p < 0.01) the size and volume of the erythrocytes. Nevertheless, as expected, triploidy decreased (p < 0.01) the number of circulating erythrocytes, leucocytes and trombocytes in the blood of jundia. Moreover differential cell counts were different in diploids and triploids, suggesting that triploidy affects the number of cells and their proportion in blood. Lymphocytes were the most predominant cells in the differential counting of diploid fish (62.5%) while monocytes were predominant in triploid fish (49.6%). These results suggest performance differences between ploidies of jundia, and require future studies to evaluate the potential of triploid jundia in the culture conditions and resistance to infection. PMID- 22437396 TI - Morphological variations and sexual dimorphism in Chelonoidis carbonaria (Spix, 1824) and Chelonoidis denticulata (Linnaeus, 1766) (Testudinidae). AB - Chelonoidis Dcarbonaria and C. denticulata are two tortoises which are widely distributed Brazil. Although they occur sympatrically in different areas, C. carbonaria prefers open areas, while C. denticulata chooses forest areas. Significant morphological variations can be observed in these species due to the fact that they occupy a vast and environmentally diverse area. Data on shell shape of captive individuals reveal important differences between the two species, mainly in the plastron scutes, carapace width, and head length. Variation in shape is greater in C. carbonaria than in C. denticulata, which may be associated to a more elaborate and complex mating ritual. The shell shape in C. denticulata is more elongated than in C. carbonaria due to ecological habits. These aspects lead to a greater restriction in shape, limiting variation and dimorphism. In C. carbonaria, the shell opening is larger than in C. denticulata, which affords greater variation in shape. A more elongated shell facilitates movements of C. denticulata in densely forested areas. Yet, this characteristic reduces shell opening, lessening the possibilities of variation in form. PMID- 22437397 TI - Structural variations among monocot emergent and amphibious species from lakes of the semi-arid region of Bahia, Brazil. AB - Temporary lakes are common in the semi-arid region of the State of Bahia and form water mirrors in the rainy season. In this period, various vegetal species appear having different life forms adapted to the seasonality conditions of the rainfall regime. This work surveyed the adaptive anatomical structures of some emergent and amphibious monocot species occurring in these lakes. We studied the anatomy of roots, rhizomes, leaves and scapes of Cyperus odoratus, Oxycaryum cubense, Pycreus macrostachyos (Cyperaceae) - amphibious species; and of Echinodorus grandiflorus (Alismataceae), Eichhornia paniculata (Pontederiaceae) and Habenaria repens (Orchidaceae) - emergent species. The anatomical features of the dermal, fundamental and vascular systems confirming the tendency of the adaptive convergence of these plants to temporary lacustrine the environment include: single layered epidermal cells with a thin cuticle layer in the aerial organs; the presence of air canals in all the organs; few or no supporting tissues; and less numerous conducting elements and thinner cell walls in the xylem. The reduction of the supporting tissues, the number of stomata, which can even be absent, and the number of conducting elements and the degree of cell wall lignification in the xylem of the emergent species is more accentuated than that of the amphibious species. The pattern of distribution of aerenchyma in the roots of the studied species was considered important to distinguish between amphibious and emergent life forms. PMID- 22437398 TI - Reproduction of Phylloderma stenops in captivity (Chiroptera, Phyllostomidae). AB - A reproductive colony of Phylloderma stenops was established in captivity. The bats were maintained in 1/2" wired screen cages sized 90 * 60 * 80 cm in a room with cycles of 13 hours of light and 11 hours of dark and with temperature and humidity ranging from 27 to 31 degrees C and 75 to 90% respectively. Bats were fed with a semi-liquid diet composed of chopped fruits, raw eggs, bovine meat, dog food, honey, dehydrated shrimp, salt and a vitamin and mineral complex offered daily. In the first two years of confinement the diet was complemented with laboratory-raised cockroaches, mealworms, young mice and seasonal fruits. Nine births occurred from three wild caught females 770-1050 days after capture and two captive-born females. Births occurred in September, February and November December. The neonate measured 15.0 g of weight and present 34.1 mm of forearm length. Two captive-born females gave birth for the first time at 402-445 days of age. Phylloderma stenops species presents postpartum oestrus, gestation of 5.5 months, lactation of 3.3 months and sexual maturity at 8.0-8.5 months. Fetuses are palpable around two months before birth and females may present synchronisation of births. PMID- 22437399 TI - Growth and survival of the pearl oyster Pteria hirundo (L.,1758) in an intermediate stage of culture in Santa Catarina, Brazil. AB - There are no records in Brazil for the culture of Pteridae family oysters, genus Pteria and Pinctada. The intermediate culture can be considered one of the critical stages during the oyster farming. The changes in life conditions from a semi-closed environment provided by the collector to the structures utilized for the growth represents a considerable stress factor to which the animals are subjected. The goal of the present study was to evaluate the growth and survival of the pearl oyster Pteria hirundo (Linnaeus, 1758) kept in intermediate lanterns. Seeds of P. hirundo, obtained through larviculture carried out at the Marine Molluscs Laboratory (UFSC), southern Brazil were detached from the collectors, transferred and kept in an intermediate culture system (oyster lantern). During 6 months, growth (dorso-ventral height - DVH in mm) and survival (%) were evaluated. Two size classes were tested: medium (M), between 3.4 and 4.4 mm, and large (L), bigger than 4.5 mm. The density of occupation in each floor of the lantern was 50%. At the end of the experiment, the survivals observed were 90 and 94% for the sizes M and L, respectively. Medium juveniles of Pteria hirundo had an average (Std) increase of 16.1 (+/-4.38) mm in the dorso-ventral height, and large juveniles an average increase of 11.4 (+/-3.77) mm after six months of experiment. The results observed during the intermediate stage of cultivation indicate that Pteria hirundo presents survival and growth similar to other species of pearl oysters traditionally used in the pearl industry in several countries. PMID- 22437400 TI - Energy reserves of Artibeus lituratus (Chiroptera: Phyllostomidae) in two areas with different degrees of conservation in Minas Gerais, Brazil. AB - Forest fragmentation associated with the expansion of human development is a phenomenon that occurs worldwide. Studies reveal that there have been both a decline in species diversity and a decrease in Neotropical bat population size because of habitat loss. The aim of this study was to investigate whether human action has been affecting the food availability to wildlife species, which could impact the storage of body energy reserves. For this purpose, fruit-eating bats (Artibeus lituratus) were collected in two areas in Minas Gerais state, Brazil. The concentrations of plasma glucose, as well as glycogen, lipids and protein in liver in muscles were performed, in addition to adipose tissue weight and carcass fatty acids. Our results indicate that fat reserves were significantly lower in most tested tissues (muscle of the hindlimbs, breast muscles, adipose tissue and carcass) in animals collected in the region with a higher degree of human disturbance. The other parameters showed no significant differences in the groups collected at different locations. In conclusion, we suggest that human action on the environment may be affecting the storage of body fat energy reserves of this species during the autumn, particularly in metropolitan region areas of Belo Horizonte, MG - Brazil, requiring special attention to the species conservation. PMID- 22437401 TI - An update in the structure, function, and regulation of V-ATPases: the role of the C subunit. AB - Vacuolar ATPases (V-ATPases) are present in specialized proton secretory cells in which they pump protons across the membranes of various intracellular organelles and across the plasma membrane. The proton transport mechanism is electrogenic and establishes an acidic pH and a positive transmembrane potential in these intracellular and extracellular compartments. V-ATPases have been found to be practically identical in terms of the composition of their subunits in all eukaryotic cells. They have two distinct structures: a peripheral catalytic sector (V1) and a hydrophobic membrane sector (V0) responsible for driving protons. V-ATPase activity is regulated by three different mechanisms, which control pump density, association/dissociation of the V1 and V0 domains, and secretory activity. The C subunit is a 40-kDa protein located in the V1 domain of V-ATPase. The protein is encoded by the ATP6V1C gene and is located at position 22 of the long arm of chromosome 8 (8q22.3). The C subunit has very important functions in terms of controlling the regulation of the reversible dissociation of V-ATPases. PMID- 22437402 TI - Reproductive indices in natural nests of giant Amazon river turtles Podocnemis expansa (Schweigger, 1812) (Testudines, Podocnemididae) in the Environmental Protection Area Meanders of the Araguaia River. AB - A count was made of unhatched eggs and hatchling live and dead Podocnemis expansa turtles in 327 natural nests located on the beaches of the Environmental Protection Area (EPA) Meanders of the Araguaia River, to determine the percentage of hatching (94.63%), non-hatching (5.37%), survival (94.24%) and hatchling mortality (5.76%), and the average percentage of dead hatchlings during the 15 days in the nursery (0.97%). The mean number of hatchlings per nest was determined from the sum of the number of live and dead hatchlings divided by the total number of nests, while the mean number of eggs per nest was determined from the sum of live and dead hatchlings and unhatched eggs divided by the number of nests. These calculations yielded the following mean values: live hatchlings (88.98 +/- 23.94), dead hatchlings (0.37 +/- 0.93), unhatched eggs (5.07 +/- 9.57), and total number of eggs (94.42 +/- 21.30). The reproductive efficiency of the wild population of P. expansa can be affected by many environmental factors such as temperature, humidity and rainfall. In addition, man-made factors like the presence of chemicals in the water and the potential for infectious disease also have significant impact. The reproductive indices data obtained from this study are indispensable for future investigations of hatching anomalies. PMID- 22437403 TI - Comparative analysis of the leaf anatomy in two Parodiolyra species (Poaceae: Olyreae) occurring on forests in Eastern Brazil. AB - Parodiolyra is a member of Olyreae, a tribe of herbaceous bamboo species within the Poaceae. The genus has five species, four of which were previously regarded as belonging to Olyra L. Parodiolyra has a Neotropical distribution and only two species occur on forests in Eastern Brazil: P. micrantha (Kunth) Zuloaga & Davidse and P. ramosissima (Trin.) Soderstr. & Zuloaga, the first widely distributed in the Neotropics while the second is endemic to the state of Bahia. Leaf anatomy of the two species was analysed with the aid of an optical microscope. The objective was to describe the microscopic characters and evaluate if they can be useful for the taxonomy of the genus. The observed anatomical structures did not differ from other genera of herbaceous bamboos, however some characters, both from the mesophyll and the epidermis, were useful to delimit the two species. PMID- 22437404 TI - Natural history of interaction between Meteorus sp. Haliday, 1835 (Hymenoptera: Braconidae) and its hyperparasitoid Toxeumella albipes Girault, 1913 (Hymenoptera: Pteromalidae). AB - Some parasitoids build a cocoon mass that hangs in the host body until the adults emergence, which is an advantage against attack by predators who troll the vegetation in search of prey. However, such behaviour is not effective against the hyperparasitoid attacks. This study reports the interaction between the caterpillar Manduca sexta Linnaeus, 1763 (Lepidoptera, Sphingidae) parasitised by Meteorus sp. (Hymenoptera, Braconidae) larvae and its hyperparasitoid Toxeumella albipes (Hymenoptera, Pteromalidae). This is the first description of the attack and oviposition of T. albipes. PMID- 22437405 TI - Occurrence and biology of Dinocampus coccinellae (Schrank, 1802) (Hymenoptera; Braconidae: Euphorinae) parasitising different species of Coccinellidae (Coleoptera) in Neotropical region. AB - Surveys on Coccinellidae (Coleoptera) in Sete Lagoas city, Minas Gerais state, Brazil, indicated the parasitism of adults of the species Coleomegilla maculata De Geer, 1775, Eriopis connexa (Germar, 1824) and Olla v-nigrum (Mulsant, 1866), by Dinocampus coccinellae (Schrank, 1802) (Hymenoptera; Braconidae: Euphorinae). Since then, the parasitoid have been maintained in its original hosts at the Insect Rearing Laboratory - LACRI of the Brazilian Agricultural Research Institution - Embrapa Milho e Sorgo. Besides the citation of occurrence in Brazil, this work also indicates the parasitoid preference for C. maculata (70% of parasitism), followed by O. v-nigrum (43.3% of parasitism) and E. connexa (36.7% of parasitism). Total life cycle of D. coccinellae was longer on C. maculata (32.4 +/- 0.48 days), compared to O. v-nigrum (29.5 +/- 0.49 days) and E. connexa (27.8 +/- 0.4 days). Due to the relatively high percentage of field parasitism, D. coccinellae can reduce the efficiency of biological pest control by Coccinellidae predators especially in the case of C. maculata. PMID- 22437406 TI - Parasitism on Araneus venatrix (Koch, 1838) (Araneae: Araneidae) by Hymenoepimecis silvanae Loffredo and Penteado-Dias, 2009 (Ichneumonidae, Pimplinae) with description of male of the wasp. AB - The wasp Hymenoepimecis silvanae Loffredo and Penteado-Dias, 2009, was recorded parasitising females of Araneus venatrix. The male of H. silvanae is described and illustrated. Specimens were collected in the Parque Estadual de Intervales and Reserva Biologica Serra do Japi, both located in the state of Sao Paulo, Brazil. PMID- 22437407 TI - New altitudinal records of the endemic species Cycloramphus brasiliensis (Anura, Cycloramphidae) from the Atlantic Rainforest in the state of Rio de Janeiro, southeastern Brazil. PMID- 22437408 TI - New host of Anastrepha parishi Stone (Diptera: Tephritidae) reported in Brazil. PMID- 22437409 TI - Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease. AB - Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed. PMID- 22437410 TI - Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. AB - Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world, and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI, which concurrently target various kidney cell types including epithelial, endothelial, and inflammatory cells. Here, we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin (DT) receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of DT, a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The DT-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme-derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation, leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at 1-week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis, and glomerulosclerosis, which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction, and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD. PMID- 22437411 TI - The health-related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial. AB - The Normal Hematocrit Trial (NHT) was the largest trial of epoetin randomizing 1265 hemodialysis patients with cardiac disease to lower (9-11 g/dl) or higher (13-15 g/dl) hemoglobin (Hgb), hypothesizing that higher Hgb would reduce mortality, and improve survival and quality of life. The trial was terminated early, and a 1998 publication reported that targeting higher hematocrit levels led to an insignificant increase in the primary end points (death or myocardial infarct), or risk ratio 1.3, 95% confidence interval (CI), 0.9-1.90, but the P value was not given, and all-cause death risk was not reported. A higher target reportedly did not increase hospitalization rates, but did significantly improve the 'physical function' domain of quality of life. Comparing the 1996 Food and Drug Administration (FDA)-filed clinical trial report to the 1998 publication, however, found several discrepancies. Among these, the 1998 article reported interim trial results with only the adjusted CI but did not state that the unadjusted CIs were 99.912th percentile, and despite being a secondary end point, reported only the association of achieved Hgb with higher quality of life score. Randomization to the higher target had actually increased the risk for the primary end point (risk ratio 1.28, 95% CI=1.06-1.56; P=0.0112; 99.92% CI=0.92 1.78), the risk of death (risk ratio 1.27, 95% CI=1.04-1.54), non-access thrombotic events (P=0.041), and hospitalization rate (P=0.04), while 'physical function' did not improve (P=0.88). Hence, disclosure of these results in the 1998 publication or access to the FDA-filed report on the NHT in the late 1990s would likely have led to earlier concerns about epoetin safety and greater doubts about its benefits. PMID- 22437412 TI - Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. AB - Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy. PMID- 22437413 TI - Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity. AB - Apoptosis, necrosis, and inflammation are hallmarks of cisplatin nephrotoxicity; however, the role and mechanisms of necrosis and inflammation remains undefined. As poly(ADP-ribose) polymerase 1 (PARP1) inhibition or its gene deletion is renoprotective in several renal disease models, we tested whether its activation may be involved in cisplatin nephrotoxicity. Parp1 deficiency was found to reduce cisplatin-induced kidney dysfunction, oxidative stress, and tubular necrosis, but not apoptosis. Moreover, neutrophil infiltration, activation of nuclear factor kappaB, c-Jun N-terminal kinases, p38 mitogen-activated protein kinase, and upregulation of proinflammatory genes were all abrogated by Parp1 deficiency. Using proximal tubule epithelial cells isolated from Parp1-deficient and wild type mice and pharmacological inhibitors, we found evidence for a PARP1/Toll-like receptor 4/p38/tumor necrosis factor-alpha axis following cisplatin injury. Furthermore, pharmacological inhibition of PARP1 protected against cisplatin induced kidney structural/functional damage and inflammation. Thus, our findings suggest that PARP1 activation is a primary signal and its inhibition/loss protects against cisplatin-induced nephrotoxicity. Targeting PARP1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity. PMID- 22437414 TI - Reprogramming the kidney: a novel approach for regeneration. AB - Nuclear reprogramming has reshaped stem cell science and created new avenues for cell-based therapies. The ability to bestow any given phenotype upon adult cells regardless of their origin is an exciting possibility. How can this powerful tool be harnessed for the treatment of kidney disease? Many approaches, including induced pluripotent stem cell (iPSC) production, direct lineage conversion, and reprogramming to a kidney progenitor, are now possible. Indeed, the generation of iPSC lines from adult kidney-derived cells has been successfully achieved. This, however, is just the beginning of the challenge. This review will discuss the fundamental concepts of transcription factor-based reprogramming in its various forms, highlighting recent advances in the field and how these are applicable to the kidney. The relative merits of each approach will be discussed in the context of what is a realistic and feasible strategy for kidney regeneration via reprogramming. PMID- 22437415 TI - Reporting of the estimated glomerular filtration rate was associated with increased use of angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers in CKD. AB - Many guidelines suggest that angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists (collectively referred to as renin, angiotensin, aldosterone system blockers (RAAS blockers)) are the preferred treatment for hypertension in most patients with chronic kidney disease (CKD). Improving the recognition of CKD with the introduction of eGFR reporting was intended to have more patients recognized with and treated for this disease. To quantify this, we examined trends in RAAS-blocker use over an 88-month period before and after routine eGFR reporting in southwestern Ontario, Canada. An intervention analysis with seasonal time-series modeling on linked health administrative data for 45,361 ambulatory residents with CKD (eGFR stages 3-5) older than 65 years was performed with a primary outcome of RAAS-blocker usage. The reporting of eGFR was associated with a significant increase in the use of RAAS blockers, as the prescription rate was 571 per 1000 patients with CKD prior to reporting but improved to 607 per 1000 after reporting. There was a significant increase in RAAS-blocker use attributable to eGFR reporting of 19 per 1000 CKD patients. Since about 8% of the adult population has CKD, this equates to about 15,200 new patients receiving RAAS-blocker treatment by 1 year after the introduction of eGFR reporting in community laboratories. Thus, eGFR reporting contributes to improved, guideline-appropriate care of older patients with CKD. PMID- 22437416 TI - The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli. AB - Aging is both a natural and inevitable biological process. With advancing age, the kidneys undergo anatomical and physiological changes that are not only the consequences of normal organ senescence but also of specific diseases (such as atherosclerosis or diabetes) that occur with greater frequency in older individuals. Disentangling these two processes, one pathologic and the other physiologic, is difficult. In this review we concentrate on the glomerular structural and functional alterations that accompany natural aging. We also analyze how these changes affect the identification of individuals of advancing age as having chronic kidney disease (CKD) and how these changes can influence prognosis for adverse outcomes, including all-cause mortality, end-stage renal disease, cardiovascular events and mortality, and acute kidney injury. This review describes important shortcomings and deficiencies with our current approach and understanding of CKD in the older and elderly adult. PMID- 22437417 TI - Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney. AB - Severe sepsis is often accompanied by acute renal failure with renal tubular dysfunction. Albuminuria is a common finding in septic patients and we studied whether it was due to an impairment of proximal tubular endocytosis of filtered albumin. We studied the regulation of megalin and cubilin, the two critical multiligand receptors responsible for albumin absorption, during severe experimental endotoxemia. Lipopolysaccharide (LPS) caused a time- and dose dependent suppression of megalin and cubilin expression that was paralleled by a decrease in plasma albumin levels and an increase in the urine concentration of albumin in mice. Incubation of rat renal cortical slices with LPS also reduced the mRNA expression of megalin and cubilin. Further, LPS suppressed megalin and cubilin mRNA expression in murine primary proximal tubule cells and decreased the uptake of FITC albumin in these cells. In addition, the increase in urine levels of albumin in response to ischemia/reperfusion-induced acute renal failure was paralleled by a decrease in the expression of megalin and cubilin. Thus, our data indicate that the expression of megalin and cubilin is decreased during experimental endotoxemia and in response to renal ischemia/reperfusion injury. This downregulation may contribute, in part, to an increase in urine levels of albumin during acute renal failure. PMID- 22437418 TI - Characterization of the renal CD4+ T-cell response in experimental autoimmune glomerulonephritis. AB - Autoimmunity against the Goodpasture antigen alpha3IV-NC1 results in antiglomerular basement membrane glomerulonephritis. Although antibodies are central to the pathogenesis, there is good evidence for the participation of T cells in this disease. To define the contribution of T cells, we used the model of experimental autoimmune glomerulonephritis. Immunization of DBA/1 mice with alpha3IV-NC1 resulted in proteinuria, a biphasic course of the disease, and an eventual loss of kidney function. In the initial phase, the mice developed an alpha3IV-NC1-specific IgG response, had IgG deposition along the glomerular basement membrane, and steadily increased proteinuria, but only marginal signs of inflammation with limited leukocyte infiltration. After 9-13 weeks, mice proceeded to develop crescentic glomerulonephritis, extensive tubulointerstitial damage, and massive macrophage infiltration. T-cell infiltration was less pronounced, mostly confined to the interstitium, and T cells displayed an activated phenotype with a significant fraction of Th1 or Th17 CD4(+) T cells. Close examination revealed the presence of autoreactive T cells producing IFNgamma upon restimulation with alpha3IV-NC1. Thus, our results suggest that accumulation of effector T cells, including autoreactive T cells, represents a critical step in the progression from mild glomerulonephritis, with limited glomerular damage, to severe crescentic glomerulonephritis accompanied by tubulointerstitial inflammation and loss of kidney function. PMID- 22437419 TI - Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting ankylosis protein homolog expression. AB - Vascular calcification is a major risk factor of cardiovascular mortality, particularly for patients with end-stage renal disease and diabetes. Although chronic inflammation is one of the etiologic factors, the underlying mechanism is not fully understood. To clarify this, we studied how nuclear factor-kappa B (NF kappaB) induction, a mediator of inflammation, might promote vascular calcification. Activation of NF-kappaB by tumor necrosis factor (TNF) promoted inorganic phosphate-induced calcification in human aortic smooth muscle cells. Pyrophosphate (an inhibitor of calcification) efflux to the extracellular matrix was suppressed along with the decreased expression of ankylosis protein homolog (ANKH), a transmembrane protein that controls pyrophosphate efflux of cells. The restoration of ANKH expression in these cells overcame the decreased pyrophosphate efflux and calcification. Tristetraprolin, a downstream product of NF-kappaB activation, may mediate destabilization of ANKH mRNA as its knockdown by shRNA increased ANKH expression and decreased calcification. Furthermore, a rat chronic renal failure model, with increased serum TNF levels, activated NF kappaB and decreased ANKH levels. In contrast, the inhibition of NF-kappaB maintained ANKH expression and attenuated vascular calcification both in vivo and in vitro. Both human calcified atherosclerotic lesions and arteries from patients with chronic kidney disease had activated NF-kappaB and decreased ANKH expression. Thus, TNF-activated NF-kappaB promotes inflammation-accelerated vascular calcification by inhibiting ankylosis protein homolog expression and consequent pyrophosphate secretion. PMID- 22437420 TI - The effects of locked and unlocked neutralization plates on load bearing of fractures fixed with a lag screw. AB - OBJECTIVES: Because locked plates as a neutralization device for lag screw fracture fixation have different biomechanics than that of unlocked plates, we investigated how this would affect lag screw load at the fracture site. The purpose of this study was to assess the load at a fracture site compressed with a lag screw when both locked and unlocked plates are used as neutralization devices. MATERIALS AND METHODS: Nine cadaver femurs had a mid-shaft oblique fracture created and were fixed with a lag screw, incorporating load transducers at the fracture site and lag screw. Three neutralization plate constructs (a standard plate, a locked plate, and an offset locked plate) were sequentially applied and loaded. Loads at the fracture site and the lag screw were measured after sequential application of axial loads. RESULTS: Plate application to the lag screw fixations did not significantly change (P > 0.26) the load at the fracture site or on the lag screw that were approximately 200 N. The unlocked, locked, and offset locked plates behaved similarly. The addition of a load to the specimens did not change the lag screw loads but increased the average fracture loads by approximately 20% of the applied load. CONCLUSIONS: Unlocked and locked neutralization plates do not affect the initial compressive load across a fracture fixed by a lag screw, and both behave similarly in transferring the load when the fracture was loaded. For a well-fixed stable fracture fixed with a lag screw, there is no advantage in using a more expensive locked plate over a standard plate for neutralization purposes if adequate screw purchase can be achieved. PMID- 22437421 TI - Determination of sagittal alignment measurements in distal femurs. AB - OBJECTIVE: Open reduction and internal fixation is presently the treatment of choice for distal femur fractures. Anatomic reconstruction of the articular surface and restoration of biomechanical relations to the diaphysis are desired. A method to determine sagittal alignment on plain radiographs is warranted. METHODS: Consecutive adult, normal, distal femur/knee, plain lateral radiographs and scanned and digitalized cadaveric distal femurs were analyzed. Measurement of 7 different angles was performed. RESULTS: Ninety-four adults [39 men (41.5%) and 55 women (58.5%)] with a mean age of 54 years (range, 18-92 years) and body mass index (BMI) of 29.7 kg/m(2) (range, 16.6-47.2 kg/m(2)), as well and 35 cadaveric femora [24 men (68.6%) and 11 women (31.4%)] with a mean age of 53 years (25-85 years) and BMI of 29.8 kg/m(2) (17.7-53.3 kg/m(2)) were studied. Twenty-two of the patients (23.4%) had radiographic findings of arthrosis. If arthrosis was diagnosed, measurements including the proximal rim of the articular surface were significantly greater (P = 0.001). Two angles were significantly smaller in women (P < 0.05). No significant differences in any measurement for age or BMI were recorded. CONCLUSIONS: The necessity for reliability and quality of intraoperative and postoperative radiographic controls of the obtained fracture reduction, implant insertion, and final healed fracture increases with popularity of less invasive indirect reduction and stabilization methods. The ability to obtain exact sagittal alignment measurements has been problematic with other studies. Two different and reliable methods of measuring sagittal plane anatomy and measurements independent of implants were confirmed using plain radiographic images. PMID- 22437422 TI - Fate of combat nerve injury. AB - OBJECTIVE: Assess a cohort of combat-related type III open tibia fractures with peripheral nerve injury to determine the injury mechanism and likelihood for recovery or improvement in nerve function. DESIGN: Retrospective study. SETTING: Three military medical centers. PATIENTS AND PARTICIPANTS: Out of a study cohort of 213 type III open tibia fractures, 32 fractures (in 32 patients) with a total of 43 peripheral nerve injuries (peroneal or tibial) distal to the popliteal fossa met inclusion criteria and were available for follow-up at an average of 20 months (range, 2-48 months). MAIN OUTCOME MEASUREMENTS: Clinical assessment of motor and sensory nerve improvement. RESULTS: There was a 22% incidence of peripheral nerve injury in the study cohort. At an average follow-up of 20 months (range, 2-48 months), 89% of injured motor nerves were functional, whereas the injured sensory nerves had function in 93%. Fifty percent and 27% of motor and sensory injuries demonstrated improvement, respectively (P = 0.043). With the numbers available, there was no difference in motor or sensory improvement based on mechanism of injury, fracture severity or location, soft tissue injury, or specific nerve injured. In the subset of patients with an initially impaired sensory examination, full improvement was related to fracture location (P = 0.0164). CONCLUSIONS: Type III open tibia fractures sustained in combat are associated with a 22% incidence of peripheral nerve injury, and the majority are due to multiple projectile penetrating injury. Despite the severe nature of these injuries, the vast majority of patients had a functional nerve status by an average of 2-year follow-up. Based on these findings, discussions regarding limb salvage and amputation should not be overly influenced by the patient's peripheral nerve status. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22437423 TI - Lag screw fixation of medial malleolar fractures: a biomechanical, radiographic, and clinical comparison of unicortical partially threaded lag screws and bicortical fully threaded lag screws. AB - OBJECTIVES: Bicortical fully threaded (FT) lag screw fixation (lag by method) is a technique for medial malleolar fixation that may provide advantages to partially threaded (PT) cancellous lag screws (lag by screw design). A direct comparison of the biomechanical properties and the clinical outcomes of these 2 methods of medial malleolar lag screw fixation were undertaken. The null hypotheses were that unicortical PT lag screws and bicortical FT lag screws had similar biomechanical and clinical outcomes. DESIGN: Biomechanics--Human cadaver biomechanical investigation. Clinical-Retrospective cohort series with control. Settings-Level-1 trauma center. PATIENTS: One hundred forty-one consecutive patients with closed medial malleolar fractures (OTA 44) treated with lag screw fixation were identified from a prospective orthopaedic trauma database. Thirty nine were lost to follow-up and 12 were treated with a single screw leaving 46 in the PT group and 46 in the FT group all treated with 2 screws for their medial malleolar fracture. INTERVENTION: Biomechanics--Human cadavers (n = 3) had bilateral oblique medial malleolar fractures (n = 6) created with an osteotome to simulate a typical medial malleolar fracture amenable to lag screw fixation. Fixation of each side was randomly allocated to either two 4.0-mm PT lag screws (length 45 mm) or two 3.5-mm FT threaded screws [length determined by depth gauge after near cortex overdrilled and far cortex (distal lateral tibia) drilled based on core diameter (2.7 mm)]. Clinical-Either 2 traditional PT (n = 46) or 2 FT screws (n = 46) were used for fixation of medial malleolus fractures. MAIN OUTCOME MEASUREMENTS: Biomechanics--Peak insertion torque generated during screw insertion. Clinical: Radiographic evidence of screw loosening, clinical non union, and reoperation. RESULTS: Biomechanics--The FT lag screw group (n = 6 screws) showed an average maximum torque of 14.4 in-lbf (range 8.0-20.1, SD = 4.4) before screw stripping. This was over 3 times greater than that seen with the PT lag screws (n = 6) (average maximum torque generation = 4.0 in-lbf, range 2.5-6.6, SD = 1.4), P < 0.0002. Clinical-Radiographic screw loosening was evident in one of the 46 patients (2%) in the FT cohort and in 11 of the 46 patients (24%) in the PT cohort, P < 0.003. Two of the patients with screw loosening in the PT cohort required reoperation for removal of symptomatic hardware, whereas no patient from the LT screw group required removal. All patients in the LT cohort healed after the index procedure although 2 in the PT cohort had nonunions. CONCLUSIONS: Screws placed with the lag by method technique that engaged the distal lateral tibial cortex have superior biomechanical, radiographic, and clinical outcomes compared to traditional PT screws for the fixation of medial malleolar fractures. PMID- 22437424 TI - Financial implications of nonoperative fracture care at an academic trauma center. AB - OBJECTIVE: To determine if nonoperative fracture Current Procedural Technology codes generate a significant portion of annual revenues in an academic practice. DESIGN: Retrospective review of an orthopaedic trauma practice billings during fiscal year 2008. SETTING: An urban level-1 trauma center. PATIENTS: Outpatient clinic, and all consults, to the orthopaedic trauma service in the emergency room and hospital wards staffed by an attending traumatologist. MAIN OUTCOME MEASUREMENTS: An analysis was made of relative value units (RVUs) generated by operative and nonoperative care, separating the later into clinic, consults, and closed (nonoperative) fracture treatment. RESULTS: A total of 19,815 RVUs were generated by the trauma service during the 2008 fiscal year. Emergency department and ward consults generated 2176 (11%) of RVUs, whereas outpatient clinic generated an additional 1313 (7%) of RVUs. Nonoperative (closed) fracture care generated 2725 (14%) RVUs, whereas surgical procedures were responsible for the remaining 13,490 (68%) of RVUs. In terms of overall financial reimbursement, nonoperative management, consults, and office visits generated 31% of income for the trauma service. CONCLUSIONS: Although the largest financial contribution to a busy surgical practice is operative procedures, 1 must not overlook the important impact of nonoperative fracture care and consults. In our academic center, nearly one-third of all income was generated from nonsurgical procedures. In the current medical/financial climate, 1 must be diligent in optimizing the finances of trauma care to sustain an economically viable practice. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22437426 TI - Problems, tricks, and pearls in intramedullary nailing of proximal third tibial fractures. AB - Proximal third tibial shaft fractures have been notoriously difficult to treat. Early reports resulting in high rates of malunion and fixation failure trended surgeons to move away from intramedullary nailing as definitive treatment. However, with the advent of a deepened understanding of the surround anatomy, several techniques have been developed to help maintain proper alignment without early failure or malunion. This review provides a concise update on the tips, tricks, and pearls available in achieving a stable well-aligned construct when definitively treating proximal third tibial shaft fractures via intramedullary nail. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 22437427 TI - Exploring the reactivity of flavonoid compounds with metal-associated amyloid beta species. AB - Metal ions associated with amyloid-beta (Abeta) peptides have been suggested to be involved in the development of Alzheimer's disease (AD), but this remains unclear and controversial. Some attempts to rationally design or select small molecules with structural moieties for metal chelation and Abeta interaction (i.e., bifunctionality) have been made to gain a better understanding of the hypothesis. In order to contribute to these efforts, four synthetic flavonoid derivatives FL1-FL4 were rationally selected according to the principles of bifunctionality and their abilities to chelate metal ions, interact with Abeta, inhibit metal-induced Abeta aggregation, scavenge radicals, and regulate the formation of reactive oxygen species (ROS) were studied using physical methods and biological assays. The compounds FL1-FL3 were able to chelate metal ions, but showed limited solubility in aqueous buffered solutions. In the case of FL4, which was most compatible with aqueous conditions, its binding affinities for Cu(2+) and Zn(2+) (nM and MUM, respectively) were obtained through solution speciation studies. The direct interaction between FL4 and Abeta monomer was weak, which was monitored by NMR spectroscopy and mass spectrometry. Employing FL1-FL4, no noticeable inhibitory effect on metal-mediated Abeta aggregation was observed. Among FL1-FL4, FL3, having 3-OH, 4-oxo, and 4'-N(CH(3))(2) groups, exhibited similar antioxidant activity to the vitamin E analogue, Trolox, and ca. 60% reduction in the amount of hydrogen peroxide (H(2)O(2)) generated by Cu(2+) Abeta in the presence of dioxygen (O(2)) and a reducing agent. Overall, the studies here suggest that although four flavonoid molecules were selected based on expected bifunctionality, their properties and metal-Abeta reactivity were varied depending on the structure differences, demonstrating that bifunctionality must be well tuned to afford desirable reactivity. PMID- 22437428 TI - Genetic studies in chronic kidney disease: basic concepts. AB - In spite of extensive research resulting in major advances in renal care including technological improvements of dialysis, the poor outcome of chronic kidney disease patients has only marginally been improved since the 1980s. It has thus become clear that new strategies are needed to move forward. There are now great expectations that increased knowledge about genetic characteristics combined with other biological markers will identify pathophysiological pathways involved in the initiation and progression of renal damage and that this in turn will help define tools for early disease intervention and personalized treatment strategies. Already, new methodologies have made it possible to study the heritable component of many kidney diseases, and it is probable that DNA-based diagnostics will be performed on a regular basis for many conditions in the near future. This article discusses basic genetic concepts and highlights some of the novel approaches available for genome-wide genetic analyses. We hope that it may serve as an introduction to the research field of what we call "nephrogenetics." A second article in this series will focus on the interpretation and evaluation of genetic association studies and how to make use of this information to improve patient care and outcomes. PMID- 22437429 TI - Comment on the article: "cost comparison of online haemodiafiltration with high flux haemodialysis" by Oates et al. PMID- 22437431 TI - Managing United States public lands in response to climate change: a view from the ground up. AB - Federal land managers are faced with the task of balancing multiple uses and goals when making decisions about land use and the activities that occur on public lands. Though climate change is now well recognized by federal agencies and their local land and resource managers, it is not yet clear how issues related to climate change will be incorporated into on-the-ground decision making within the framework of multiple use objectives. We conducted a case study of a federal land management agency field office, the San Juan Public Lands Center in Durango, CO, U.S.A., to understand from their perspective how decisions are currently made, and how climate change and carbon management are being factored into decision making. We evaluated three major management sectors in which climate change or carbon management may intersect other use goals: forests, biofuels, and grazing. While land managers are aware of climate change and eager to understand more about how it might affect land resources, the incorporation of climate change considerations into everyday decision making is currently quite limited. Climate change is therefore on the radar screen, but remains a lower priority than other issues. To assist the office in making decisions that are based on sound scientific information, further research is needed into how management activities influence carbon storage and resilience of the landscape under climate change. PMID- 22437432 TI - Section 404 permitting in coastal Texas: a longitudinal analysis of the relationship between peak streamflow and wetland alteration. AB - As early as the passage of the 1972 Federal Water Pollution Control Act the U.S. government has sought to protect the nation's water resources through regulatory tools. While there has been a large amount of research on wetlands and wetland mitigation, very little is known about the impact of Section 404 permitting on water quantity. This research examines the impact of Section 404 permit types on peak annual streamflow in Coastal Texas from 1996 to 2003. Results of cross sectional time-series regression analyses indicate that all four permit types have positive and significant effects on peak streamflow. These effects also vary by permit type, with Individual permits having the highest per-permit impact on peak annual flow. PMID- 22437433 TI - The premises and promises of trolls in Norwegian biodiversity preservation: on the boundaries between bureaucracy and science. AB - This paper examines the perception and implementation of scientific knowledge among Norwegian environmental bureaucrats in the process of preserving biodiversity. Based on interviews with environmental officials and scientists, and document studies, the data reveal a mismatch between the ideal administrative world presented by environmental managers, and the empirical reality of biodiversity vulnerability and preservation. The environmental officials depict a process where their mandate is merely instrumental, where science provides objective descriptions of biodiversity value, and where the spheres of science, policy and administration are strictly separated. Instead of a transparent strategy for handling scientific ambiguities inherent in biodiversity value assessments (such as complexity and uncertainty), and administrative judgments, the paper argues that these boundary objects and areas are perceived as 'trolls' that are ignored and hidden by environmental officials. This strategy appears intuitive and guided by a linear decision making paradigm where boundary objects are considered illegitimate. As a solution to possible obstacles stemming from this institutional vacuum, the article finally discusses the potential of adapting or assimilating the trolls to better meet the challenges of biodiversity preservation. A viable first step might be cross-disciplinary characterisation of complexities and uncertainties of biodiversity assessments. This might help to articulate the binary ontology of value assessments and to better address the critical administrative, political and scientific intersections. These boundary areas must be re-institutionalised by environmental agencies, and cognizant strategies must be devised and implemented for making professional judgment and discretion. Finally, it may amount to a more honest stance on conservation, where the inherent complexities to biodiversity preservation may be managed as complexities, and not as trolls. PMID- 22437434 TI - In vivo electroporation of a new gene vaccine encoding ten repeats of Abeta3-10 prevents brain Abeta deposition and delays cognitive impairment in young Tg APPswe/PSEN1dE9 mice. AB - Active immunization holds great promise for the treatment of Alzheimer's disease but the infiltration of T-lymphocytes and associated meningoencephalitis observed in clinical trials needs to be overcome. To avoid this toxicity, previous studies have used synthetic truncated derivatives of Abeta to promote humoral immunity. In this study, we developed a novel vaccine [p(Abeta3-10)10-MT] that expresses ten repeats of Abeta3-10 with melatonin (MT) as an adjuvant, and administered it intramuscularly in three-month-old Tg-APPswe/PSEN1dE9 (Tg) mice by in vivo electroporation. The p(Abeta3-10)10-MT vaccine induced high titers of anti-Abeta antibodies, which in turn reduced Abeta deposits in the mouse brains and decreased cognitive impairment. Immunoglobulin isotyping revealed a predominantly IgG1 response, indicating a Th2 anti-inflammatory response. Ex vivo cultured splenocytes exhibited a low IFN-gamma and high IL-4 response. Immunohistochemical analysis revealed that glial cell activation was also attenuated. These results indicate that p(Abeta3-10)10-MT may potentially be an effective vaccine to reduce accumulated Abeta and attenuate cognitive deficits. PMID- 22437435 TI - Long-term methionine exposure induces memory impairment on inhibitory avoidance task and alters acetylcholinesterase activity and expression in zebrafish (Danio rerio). AB - Hypermethioninemic patients exhibit a variable degree of neurological dysfunction. However, the mechanisms involved in these alterations have not been completely clarified. Cholinergic system has been implicated in many physiological processes, including cognitive performances, as learning, and memory. Parameters of cholinergic signaling have already been characterized in zebrafish brain. Since zebrafish is a small freshwater teleost which is a vertebrate model for modeling behavioral and functional parameters related to human pathogenesis and for clinical treatment screenings, in the present study we investigated the effects of short- and long-term methionine exposure on cognitive impairment, AChE activity and gene expression in zebrafish. For the studies, animals were exposed at two methionine concentrations (1.5 and 3.0 mM) during 1 h or 7 days (short- or long-term treatments, respectively). We observed a significant increase in AChE activity of zebrafish brain membranes after long term methionine exposure at 3.0 mM. However, AChE gene expression decreased significantly in both concentrations tested after 7 days of treatment, suggesting that post-translational events are involved in the enhancement of AChE activity. Methionine treatment induces memory deficit in zebrafish after long-term exposure to this amino acid, which could be related, at least in part, with cognitive impairment observed in hypermethioninemia. Therefore, the results here presented raise a new perspective to use the zebrafish as a complementary vertebrate model for studying inborn errors of metabolism, which may help to better understand the pathophysiology of this disease. PMID- 22437436 TI - Levels of amyloid beta-42, interleukin-6 and tumor necrosis factor-alpha in Alzheimer's disease and vascular dementia. AB - Amyloid beta42 (Abeta42) and proinflammatory cytokines such as interleukin-6 (IL 6) and tumor necrosis factor-alpha (TNF-alpha) have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). Our aim was to examine whether the changes in these parameters would be able to discriminate the patients with AD from those with VaD and from healthy individuals. We have analyzed the levels of Abeta42, IL-6 and TNF-alpha in the serum of newly diagnosed 28 AD patients, 16 VaD patients and 26 healthy non demented controls. We also investigated whether there is an association between Abeta42, IL-6 and TNF-alpha levels and mini-mental state examination (MMSE) scores and body mass indexes (BMI) of patients. Our data showed a significant decrease in serum Abeta-42 levels in AD patients compared to VaD patients and controls. Levels of IL-6 and TNF-alpha were not different between AD patients, VaD patients and controls. We observed a correlation between Abeta-42 levels and MMSE scores and BMI levels in both AD and VaD patients. However, Abeta-42 levels were not correlated with IL-6 and TNF-alpha levels. Significantly lower levels of Abeta42 found in the serum of AD patients than that of VaD patients and controls suggests that it can be a specific biochemical marker for AD. PMID- 22437437 TI - Ultrafast rotary PCR system for multiple influenza viral RNA detection. AB - We presented a novel platform for an ultrafast PCR system, called the Rotary PCR Genetic Analyzer, which incorporates a thermal block and resistive temperature detector (RTD) for thermal cycling control, a disposable PCR microchip, and a stepper motor. The influenza viral RNAs from H3N2, H5N1, and H1N1 were simultaneously identified with high sensitivity and speed. PMID- 22437438 TI - Message from the editor. PMID- 22437440 TI - Ismics 2010 scientific program. PMID- 22437439 TI - Message from the president. PMID- 22437441 TI - Shewanella seohaensis sp. nov., isolated from a tidal flat sediment. AB - A Gram-negative, motile and rod-shaped bacterial strain, designated S7-3(T), was isolated from a tidal flat sediment at Saemankum on the western coast of Korea. Phylogenetic analyses based on 16S rRNA gene and gyrB sequences showed that strain S7-3(T) belonged to the genus Shewanella, clustering with Shewanella decolorationis S12(T). Strain S7-3(T) exhibited 98.8 % 16S rRNA gene sequence similarity and 96.8 % gyrB sequence similarity to S. decolorationis S12(T), respectively. The 16S rRNA gene sequence similarity values between strain S7-3(T) and other members of the genus Shewanella were in the range of 93.0-98.0 %. Strain S7-3(T) contained simultaneously both menaquinones (MK) and ubiquinones (Q); the predominant menaquinone was MK-7 and the predominant ubiquinones were Q 7 and Q-8. The fatty acid profiles of strain S7-3(T) and S. decolorationis JCM 21555(T) were similar; major components were C(17:1) omega8c, iso-C(15:0) and iso C(15:0) 2-OH and/or C(16:1) omega7c. The DNA G+C content of strain S7-3(T) was 51.8 mol% and its mean DNA-DNA relatedness value with S. decolorationis JCM 21555(T) was 43 %. Differential phenotypic properties of strain S7-3(T), together with the phylogenetic and genetic distinctiveness, revealed that this strain is distinguishable from recognized Shewanella species. On the basis of the data presented, strain S7-3(T) is considered to represent a novel Shewanella species, for which the name Shewanella seohaensis sp. nov. is proposed. The type strain is S7-3(T) (=KCTC 23556(T) = CCUG 60900(T)). PMID- 22437442 TI - Pragmatic abilities in children with congenital visual impairment: an exploration of non-literal language and advanced theory of mind understanding. AB - Children with congenital visual impairment have been reported to be delayed in theory of mind development. So far, research focused on first-order theory of mind, and included mainly blind children, whereas the majority of visually impaired children is not totally blind. The present study set out to explore whether children with a broader range of congenital visual impairments have a delay in more advanced theory of mind understanding, in particular second-order theory of mind (i.e. awareness that other people have beliefs about beliefs) and non-literal language (e.g. irony or figure of speech). Twenty-four children with congenital visual impairment and 24 typically developing sighted children aged between 6 and 13 were included. All children were presented with a series of stories involving understanding of theory of mind and non-literal language. When compared with sighted children of similar age and verbal intelligence, performance of children with congenital visual impairment on advanced theory of mind and non-literal stories was alike. The ability to understand the motivations behind non-literal language was associated with age, verbal intelligence and theory of mind skills, but was not associated with visual ability. PMID- 22437444 TI - Effects of water and polymer content on covalent amide-linked adduct formation in peptide-containing amorphous lyophiles. AB - Deamidation of asparagine-containing proteins and peptides results in the formation of hydrolysis products via a reactive succinimide intermediate. In amorphous lyophile formulations at low water content, nucleophilic amine groups in neighboring molecules can effectively compete with water for reaction with the succinimide intermediate resulting in the formation of a variety of covalent amide-linked adducts. This study examines the effects of changes in percentage of a polymeric excipient [hypromellose (HPMC)] and water content on the degradants formed from a model asparaginyl peptide (Gly-Phe-L-Asn-Gly) in amorphous solids also containing an excess of Gly-Val and carbonate buffer and stored at 40 degrees C. Degradation of Gly-Phe-L-Asn-Gly and formation of succinimide intermediates, aspartyl peptides, and covalent amide-linked adducts were monitored by high-performance liquid chromatography. In all formulations and storage conditions, the formation kinetics of aspartyl hydrolysis products and covalent adducts could be described by a mechanism-based model that assigned a central role to the succinimide intermediate. Increasing the percentage of HPMC (i.e., reactant dilution) favored the formation of hydrolysis products over covalent amide-linked adducts, consistent with the bimolecular nature of covalent adduct formation. Increases in water content as relative humidity (RH) was varied from 33% to 75% produced orders-of-magnitude increases in the rate constants for succinimide formation and hydrolysis with both becoming nearly constant at high water contents. A bell-shaped profile for the dependence of the rate of covalent adduct formation on water content was observed, a result that may be indicative of phase separation at higher RHs. PMID- 22437443 TI - Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab CHOP Consortium Program Study. AB - Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy. PMID- 22437445 TI - [19th annual conference of the working group on kidney transplantation of the academy of german urologists : mainz, 10-12 november 2011]. AB - The 19th Annual Conference of the Working Group on Kidney Transplantation (KTX) of the Academy of German Urologists took place on 10-12 November 2011 in Mainz. The main topics at the meeting were surgical and technical aspects, immunosuppressive therapy, transplant rejection, pregnancy, sexuality, and psychological conflicts of kidney transplant recipients. The speakers documented the pertinence of interdisciplinarity for KTX and were not only from the field of urology but also from anesthesiology, gynecology, surgery, dermatology, nephrology, radiology, and psychosomatic medicine. The Bernd Schonberger Prize was awarded at the end of the event. PMID- 22437446 TI - [Foundation of the german network renal cell tumors association]. PMID- 22437447 TI - Nonhuman primate models of stroke for translational neuroprotection research. AB - Despite the discovery of several promising neuroprotective therapies in rodent models of stroke, no therapy other than the fibrinolytics has been found to be effective in human clinical trials. To address potential discrepancies between rodent and human studies, the Stroke Therapy Academic Industry Roundtable (STAIR) committee suggested that nonhuman primates (NHPs) be used for preclinical, translational stroke studies. Due to the paucity of stroke studies in NHPs, few experimental models have been described. Critical factors in designing NHP stroke models include the choice of species, the method of inducing the stroke and the choice of outcome measures. In this review, we describe established NHP models of stroke and discuss factors that may influence model development with a focus on models that may be useful in preclinical studies for neuroprotective drug screening prior to clinical trials. PMID- 22437449 TI - Pharmacokinetics of lacosamide in healthy korean male volunteers. AB - AIM: The aim of this study was to evaluate the pharmacokinetics (PK) of single and repeated doses of lacosamide in healthy male Korean volunteers and to compare the PK profile of lacosamide in Korean and Caucasian populations. METHODS: In a double-blind, placebo-controlled, parallel-group, dose-escalation trial, 16 volunteers received a single dose (50 mg) of lacosamide or placebo, and 32 volunteers were administered single/repeated twice-daily doses (100 or 200 mg) of lacosamide or placebo. RESULTS: For multiple doses of 100 and 200 mg twice daily, the geometric means C(max,ss) were 6.23 (15.0) and 13.13 (8.9) MUg/ml respectively, and AUC(tau)(,s)(s) values were 52.10 (17.0) and 112.35 (13.0) MUg.h/ml, respectively. Values for both parameters were relatively higher than those seen in Caucasians. To further describe ethnic differences, population PK analysis was assessed. A one-compartment model with first-order absorption and elimination was selected and effects of CL(creatinine) on CL/F and body surface area on V/F were included in the final model. CONCLUSION: There were no other ethnic differences in the PK profile of lacosamide between Koreans and Caucasians based on the population PK analysis, except for the demographic differences. PMID- 22437450 TI - Two strings to choose from: do ravens pull the easier one? AB - There are simple co-occurrences as well as functional relationships between events. One may assume that animals detect and use causation rather than mere co variation. However, understanding causation often requires concepts of hidden forces. In string pulling, obstacles may hamper the access to food. Here, I studied whether ravens have an abstract concept of effort. First, in a competitive situation, ravens (Corvus corax) could choose one out of two strings. The strings differed in whether they were baited with meat and in how far away the meat was. Ravens pulled mainly the string containing meat and where the meat was nearer to the perch, respectively. Second, ravens could choose between two strings that had either a functional obstacle or a non-functional obstacle. Optimal performance required the integration of at least two cues: object and height. In 5 ravens, the model that best matched behaviour took into account only that meat was on a string, ignoring the obstacle. However, 2 ravens' performance was best explained by a model that took into account both an object's identity (meat or wood) and its height on the string. Third, one string out of two was loaded with a heavy meat piece. In this overloaded string condition, 5 out of 7 ravens did not try to pull the heavy meat piece but went straight for pulling the smaller piece. The pattern of results indicated that ravens can judge the effort required to pull a string. PMID- 22437451 TI - Confidence intervals and statistical testing for ratio measures of percent change. AB - In public health and medical research, ratio measures of percent change relative to baseline are often used to express a change in disease incidence. Estimating variance becomes more complex when the comparison is to an expectation based on previous data (E), rather than to an observed value (O). In 2009, the decline in reported tuberculosis (TB) cases was the largest single-year decrease since national TB surveillance began in 1953. To investigate the 2009 TB decline compared with expected counts, we analyzed TB cases reported to the Center for Disease Control and Prevention's National Tuberculosis Surveillance System. We log-transformed case counts for 2000-2008, and performed linear regression stratified by patient and clinical characteristics. We calculated relative declines from expectation as (O - E) / E for patient subgroups, and constructed 95% confidence intervals for TB declines. We then formulated a Z-score test statistic comparing declines across patient subgroups under the null hypothesis that the difference of the two ratio measures was zero. We illustrate our methods by comparing 2009 declines from expectation for US-born versus foreign-born patients. Predicted values and confidence intervals assessed the magnitude of unexpected TB declines within patient groups, while statistical tests comparing ratio measures evaluated relative TB declines across groups. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID- 22437452 TI - Relation between chronic obstructive pulmonary disease and antibiotics. AB - Chronic obstructive pulmonary disease (COPD) constitutes a major health problem. Recurrent acute exacerbations are characteristic of the course of COPD (AECOPD) associated with significant healthcare costs and contribute to the progress of the disease. Given that almost half of AECOPD is caused by bacteria, administration of antibacterial agents is recommended for patients with severe exacerbations or severe underlying COPD. Optimal antibiotic selection for exacerbations has therefore incorporated quantifying the risk for a poor outcome of the exacerbation and choosing antibiotics differently for low risk and high risk patients. It is unclear whether antibiotics should be provided as prophylactic agents in COPD patients although ongoing trials are reexamining the question of whether the antiinflammatory action of antibiotics such as macrolides can be useful in preventing exacerbations. In addition, nowadays, the occurrence of pneumonia in COPD has received considerable recent attention as it appears to be increased by the use of inhaled corticosteroids. PMID- 22437453 TI - "Innovations has a New Affiliation". PMID- 22437454 TI - Third-generation continuous flow left ventricular assist devices. AB - Tremendous advances have been made in the treatment of end-stage heart failure patients with left ventricular assist devices (LVADs). An important factor playing a role in the improved clinical outcomes is the development of continuous flow, rotary LVADs. New technology using magnetic levitation and hydrodynamic suspension to eliminate contact bearings offers the potential of more durable and efficacious mechanical circulatory blood pumps. Clinical trials evaluating these novel "third-generation" LVADs are in progress. PMID- 22437455 TI - Long-term monitoring for patients after surgical ablation of atrial fibrillation: are all devices the same? AB - In recent years, the nonmedical management of atrial fibrillation (AF) has rapidly evolved, with more options available to address the arrhythmia. Determining the successful return of sinus rhythm and the medical management after ablation requires the selection of the correct diagnostic method. In May 2007, the Heart Rhythm Society in conjunction with the Society for Thoracic Surgeons, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society identified the need for programs to adopt a consistent method of follow-up and monitoring. Choosing the right monitor for the determination of the success, postsurgical ablation that meets the Heart Rhythm Society guidelines for monitoring especially for asymptomatic patients is imperative. Therefore, we reviewed the current devices available to assist practitioners in determining which monitor best meets their needs The criteria selected to perform the review include (1) ease of use for patients (compliance), (2) ability of the monitor to perform internal analysis, (3) the monitor has >24 hours of storage capability, and (4) external support. Our selection criteria revealed six cardiac rhythm monitors currently available for use. This review compared the different arrhythmia monitors from an established monitoring program perspective to assist practitioners in choosing a monitor that meets their practice needs for determining the return to sinus rhythm postsurgical ablation. PMID- 22437456 TI - Endoscopic radial artery harvest produces equivalent and excellent midterm patency compared with open harvest. AB - OBJECTIVE: A recent multicenter study reported reduced patency of aortocoronary bypass grafts when the saphenous vein was harvested by endoscopic technique compared with patency of vein grafted after harvest by the traditional "open" approach. Our aim was to compare the patency rates of radial artery graft (RAG) harvested endoscopically with those harvested using an open technique. METHODS: Two cohorts were identified: from January 1995 to January 2000, 724 consecutive patients had one or both radial arteries harvested through an open technique, and from February 2000 to January 2008, 727 consecutive patients had endoscopic radial artery (RA) harvest. All patients who underwent symptom-indicated angiography in our institution at any time after coronary artery bypass grafting (CABG) surgery were identified. RESULTS: Two hundred two patients had angiograms for symptoms: 90 of these patients (119 RAG) had open RA harvest and were studied 78.3 +/- 40 months (range, 1-156 months) after CABG. The other 112 patients (148 RAG) had endoscopic RA harvest and underwent angiography 36 +/- 24 months (range, 1-96 months) after CABG. The two groups had identical demographics and risk profiles. Overall patency of the "open" RAG was 78.9% versus 83.7% for the endoscopic group (P = 0.3). Patency increased to 90% in both groups when the RAG was anastomosed to a native coronary vessel with stenosis >80%. CONCLUSIONS: Endoscopic and open RA harvesting techniques have equivalent and excellent midterm and long-term patency rates in CABG patients studied by angiography for recurrent symptoms of myocardial ischemia. The degree of stenosis of the target vessel strongly influences the patency rate independent of the harvesting technique. PMID- 22437457 TI - Prospective, randomized study comparing two different minimized versus conventional cardiopulmonary bypass systems. AB - OBJECTIVE: Conventional cardiopulmonary bypass (CCPB) is a major trigger of inflammatory response. We aimed to assess the impact of two different minimized cardiopulmonary bypass systems (mini-CPB) with and without Bioline-coating compared with CCPB regarding organ function, inflammatory response, and early clinical outcome. METHODS: In a prospective, randomized study, 120 patients underwent elective coronary artery bypass grafting and were randomized into three groups: mini-CPB using a Bioline-coated (group A, n = 40) or an uncoated (group B, n = 40) circuit, or CCPB (group C, n = 40). Cytokines (interleukin-6, interleukin-8, and tumor necrosis factor-alpha), myocardial markers (creatine kinase [CK], CK-MB, and troponin-T), hematocrit, and platelet counts were measured up to 48 hours postoperatively. Early clinical outcome was assessed at 3 months postoperatively. RESULTS: Demographics, number of distal anastomoses, ventilation time, blood loss, intensive care unit, and hospital stay were comparable (P = not significant). Extracorporeal circulation and cross-clamp time were significantly longer in group A and B versus C (P < 0.005). No significant differences could be found in the release of interleukin-6, interleukin-8, and tumor necrosis factor-alpha among groups. Myocardial markers were significantly reduced in group A and B versus group C (P < 0.001). Hematocrit and platelet counts did not differ among the groups. No differences could be found in early clinical outcome up to 3 months. CONCLUSIONS: This study showed significant better myocardial preservation with lower CK-MB and troponin-T levels in both mini-CPB groups. No significant differences could be found in terms of inflammation, hematologic effects, and early clinical outcome. PMID- 22437458 TI - Totally endoscopic robotic ventricular septal defect repair. AB - OBJECTIVE: Recent advances in robotic instrumentation have facilitated totally endoscopic intracardiac procedures. However, totally endoscopic robotic ventricular septal defect (VSD) repair has not been reported in the literatures to our knowledge. We report our first three cases of closed chest VSD repair using da Vinci S Surgical System. METHODS: Three female patients underwent totally endoscopic robotic VSD repair. Echocardiography demonstrated that the perimembranous VSD sizes in three patients were 6, 8, and 8 mm, respectively, and a patent foramen ovale in one patient. RESULTS: All the VSD repair and right atrial closure were completed with the da Vinci robot. Mean cardiopulmonary bypass and mean cross-clamp times were 70 and 22 minutes, respectively. No blood transfusions were received. Postoperative transesophagel echocardiogram (TEE) demonstrated intact ventricular septum. The mean hospital stay was 5 days. The patients returned to normal function without any complications. CONCLUSIONS: With a limited number of cases, the study showed that totally endoscopic robotic VSD repair in adult patients is feasible and safe. PMID- 22437459 TI - Neochordae implantation made easy with an adjustable device: early report of acute and chronic animal experiments. AB - OBJECTIVE: Neochordae implantation is a well-established surgical solution for the treatment of mitral valve prolapse. The main limitation to wide usage of the technique has been the difficulty associated with accurate determination of neochordal length. We describe a system specifically designed to facilitate rapid, uncomplicated implantation and off-pump, beating heart adjustment of neochordae. METHODS: Five swine underwent implantation of the adjustable neochordal system (V-Chordal; Valtech Cardio LTD, Israel) while on cardiopulmonary bypass after cutting native chordae to create a significant lesion. Neochordae length was adjusted with millimeter-level resolution, off-pump after discontinuation from bypass. RESULTS: In all animals, the implant was successful. Under echocardiographic monitoring, flail lesions were corrected in all cases, using the anatomic landmarks or the degree of mitral regurgitation for real-time guidance. At postmortem gross examination, the implant and the neochordae were completely healed with evidence of tissue ingrowth. CONCLUSIONS: Preliminary animal experience suggests that the V-Chordal-adjustable neochordae system can be safely and effectively implanted, with accurate and precise adjustment of chordal length. The design of the device is suitable for a minimally invasive environment because of the long, flexible shafted design of the delivery system. PMID- 22437460 TI - Anesthesia management for robotically assisted endoscopic coronary artery bypass grafting on beating heart. AB - OBJECTIVE: To outline the initial anesthetic experience for robotically assisted coronary artery bypass grafting surgery on beating heart using the da Vinci surgical system. METHODS: Between February 2007 and September 2009, 76 patients received the surgery with the da Vinci S Surgical System. The crucial issue of anesthesia for the surgery is to deal with the hemodynamic compromise, hypoxia and hypercarbia relevant to one-lung ventilation (OLV), and intrathoracic insufflation of CO2 with positive pressure (CO2 pneumothorax). RESULTS: After initiation of OLV and CO2 pneumothorax, PaO2 and mixed venous saturation showed a significant decrease. Meanwhile, the SpO2 decreased to 92% in 14 of the 76 patients. In these patients, application of continuous positive airway pressure setting 5 to 15 cm H2O to the collapsed lung resulted in an increase in PaO2 from 59 +/- 12 to 115 +/- 23 mm Hg (P < 0.05). Moreover, at the beginning of CO2 pneumothorax, the most dramatic fall in mean arterial pressure and cardiac index was showed with an increase in mean pulmonary artery pressure and heart rate. The hemodynamic compromise was counteracted by transfusion and inotropes/vasopressors. Postoperatively, the average extubation time was 7.5 +/- 3.1 hours, and median intensive care unit length of stay was 21 hours. One patient remained in the intensive care unit for 3 days for treatment of a postoperative pneumonia. There were two cases of new onset postoperative atrial fibrillation. All patients were discharged home 4 to 7 days after surgery. CONCLUSIONS: Anesthetic management for the procedures requires detailed knowledge of OLV and CO2 pneumothorax in addition to expertise required in conventional cardiac surgery. PMID- 22437461 TI - Robot-assisted mitral valve repair: a single institution review. AB - OBJECTIVE: Mitral valve repair (MVR) is the definitive therapy for mitral myxomatous degeneration. Median sternotomy has been the traditional approach to repair until the advent of the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA). Minimally invasive surgical approaches for mitral repair have been slow to gain acceptance in cardiac surgery. We review the MVR results from our single-institution academic robotic program. METHODS: From August 2004 through April 2008, patients who underwent a robotic-assisted (RA) MVR were identified. RA technique included a 4-cm right minithoracotomy, femoral cardiopulmonary bypass with transthoracic aortic occlusion, and RA-MVR. Repair types were combinations of quadrangular/triangular leaflet resection, sliding plasty, chordal transfer/replacement, and edge-to-edge approximation, with band annuloplasty in all cases. Postrepair echocardiography and morbidity follow-ups were completed in all patients. Our primary outcome was adequacy of repair, and secondary outcome was major complications. RESULTS: There were 43 patients (29 male and 14 female) who underwent RA-MVR for severe (4+) mitral regurgitation during the 4-year review. Average operative time was 272.26 minutes. Only one patient had mild postoperative mitral regurgitation, whereas 20 had trace and 22 had no regurgitation after repair. Mean ventilator time was 32.1 hours, and length of stay was 5.7 days. One third of the patients (33%) received postoperative-packed red blood cell transfusions (average: 2.4 units per patient). Twenty-eight percent of patients developed atrial fibrillation after repair. Most of the patients (95.3%) were discharged home. There were no 30-day mortalities. CONCLUSIONS: Based on our small single-institution experience, RA MVR provides an effective treatment for severe mitral valve regurgitation. Although procedure durability is slowly being established, preliminary results are promising. Careful programmatic advances with an integrated team approach can facilitate acceptable postoperative outcomes and excellent MVR. PMID- 22437462 TI - Lung hernia after video-assisted thoracoscopic lobectomy. AB - Lung hernias are rare and are most commonly secondary to blunt or penetrating trauma. Few cases have been reported after video-assisted thoracoscopic surgery and only one case after video-assisted thoracoscopic surgery lobectomy. We report a case of lung hernia after video-assisted, thoracoscopic, right upper lobectomy. The hernia was demonstrated by computerized tomography and repaired by minimally invasive techniques. We believe that the combination of removal of a large lung specimen and the presence of emphysema may predispose to lung herniation after thoracoscopic lobectomy. Thoracic surgeons should be aware of this possible complication. PMID- 22437463 TI - Left ventricular giant pseudoaneurysm. AB - Left ventricular (LV) pseudoaneurysm is a rare complication of myocardial infarction. It may also occur as a complication of mitral valve surgery, chest trauma, and bacterial endocarditis. It forms when a cardiac rupture contains adherent pericardium or scar tissue and is typically located on the posterior or inferior LV wall. Pseudoaneurysms have a propensity to spontaneous rupture; hence, immediate surgical intervention is the treatment of choice for LV pseudoaneurysms diagnosed in the first months after myocardial infarction. The management of chronic LV pseudoaneurysms is still a subject of debate. PMID- 22437464 TI - Advantages of sutureless aortic valve in a patient with unsuspected pheochromocytoma. AB - We describe a 60-year-old man who underwent elective aortic valve replacement and concurrent single graft coronary artery bypass surgery with acute intraoperative hypertension. The early suspicion of a pheochromocytoma and immediate aggressive pharmacologic intervention are discussed. Expeditious surgery contributed to the good outcome. It is possible that the short implant time of the sutureless valve may have been beneficial, but this is speculative. The management of an undiagnosed pheochromocytoma presenting during general anesthesia is reviewed. PMID- 22437465 TI - A completely detachable aortic clamping instrument for minimally invasive cardiac surgery. AB - A minimally invasive cardiac surgery is becoming more popular and is still undergoing a refinement of surgical techniques and dedicated instrumentarium as well. New specifically designed instruments are quintessence of safe surgery with improving operative outcomes and comfortable operator-oriented working conditions. In this article, we attempt to present our early clinical experience with a new aortic clamping instrument specifically developed for limited single access minimally invasive valve surgery. PMID- 22437466 TI - Surgical removal of duct occluder device under mild hypothermia without cardiopulmonary bypass. AB - Because the use of percutaneous intervention is increasing for the closure of the patent ductus arteriosus, the procedure-related complications are also on rise, with migration of the device being most common. The routine practice is to remove the migrated duct occluder device under cardiopulmonary bypass. Amplatzer duct occluder used in a 4-month-old infant dislodged into the descending thoracic aorta. It was removed by the posterolateral thoracotomy under mild hypothermia through juxtaductal aortotomy between the aortic cross-clamps. The use of cardiopulmonary bypass is thus avoided. PMID- 22437467 TI - Quantitative and qualitative bone analysis in the maxillary lateral region. AB - PURPOSES: The present study was conducted to assess the amount of bone present between root apices and the maxillary sinus floor in the maxillary lateral region, to compare the evaluations on cone beam computed tomography (CBCT) and orthopantomography (OPG), and to evaluate the bone density of the same region using three-dimensional images on CBCT. METHODS: Fifty-one dental patients were recruited for the study. All subjects were partially edentulous. The distances from the maxillary premolars and molars apices to the maxillary sinus floor were assessed using CBCT and OPG. Color codes were assigned to the bone density of edentulous loci. Parametric and non-parametric tests were used for statistical analyses. A p value <0.05 was considered statistically significant. RESULTS: The maxillary first and second molars recorded the shortest mean distances to the sinus floor, in contrast to the maxillary first premolar. The bone density of the maxillary lateral area increased from the maxillary first premolar to the second molar. No statistical significant differences were found between the evaluated sites. CONCLUSIONS: Our results provide estimates of the minimal and maximal distances between teeth and sinus, as well as the average bone density in the maxillary lateral region. It is important that evaluation of a specific patient be performed during the preoperative planning of implants. PMID- 22437468 TI - Quality of life in patients postcolectomy for pediatric-onset ulcerative colitis. AB - BACKGROUND: Ulcerative colitis in children can have a negative effect on quality of life (QOL). METHODS: We included 16 of 31 patients who underwent colectomy for ulcerative colitis before 20 years of age between 1980 and 2005 at University of California in San Francisco Benioff Children's Hospital. A disease-specific QOL questionnaire (Inflammatory Bowel Disease Questionnaire-32), validated for adults, was used to determine QOL and an additional questionnaire addressing bowel function and reproductive health in long-term follow-up of these patients. RESULTS: Median age at the time of survey was 20.3 years (17.9-25.3), and time postcolectomy was 6.9 years (4.8-9.0). Mean total score was 159.7 +/- 43.3 (58 210). Two patients (12.5%) had scores of >= 200, 12 (75.0%) had 101 to 199, and 2 (12.5%) had <= 100. Patients ages 18 years or younger at the time of survey showed higher QOL, particularly in emotional health (P=0.020), social function (P=0.014), and overall QOL (P=0.009). Social function scored highest of all of the systems (median 7; interquartile range 4-7). Patients with scores <= 100 had repeated episodes of pouchitis (16-30) compared with the other 14 patients (0-3). Children who were diagnosed ages 12 years or younger tended to have higher QOL (p=0.072). Years postcolectomy did not correlate to QOL. Eleven patients were sexually active. Two males had feelings of impotence and decreased libido, and 6 females experienced dyspareunia. Three women tried unsuccessfully to conceive after colectomy. One woman became pregnant 4 times, each leading to miscarriage. CONCLUSIONS: Younger age at time of colectomy, diagnosis, and survey show higher QOL. Highest satisfaction was found in ability to attend school, work, and social engagements. Pouchitis continued to be an issue for a small number of the patients, with 2 patients having recurring episodes that severely affected QOL. Patients reported decreased sexual activity and fertility at the time of survey due to colectomy, especially for females. PMID- 22437469 TI - Total and abdominal obesity are risk factors for gastroesophageal reflux symptoms in children. AB - OBJECTIVES: The association between GERD and obesity has been frequently reported in adults. Data in children are scarce and inconclusive, evaluating only general obesity. Central adiposity has never been investigated in children as a possible risk factor for GERD. The aims of the present study were to evaluate the prevalence of gastroesophageal reflux disease (GERD) symptoms in overweight and obese children in comparison with a general normal-weight population and whether the GERD symptoms are associated with waist circumference (WC). METHODS: The study population consisted of 153 healthy children. A detailed clinical history and a physical examination were obtained from each patient. A questionnaire on reflux symptoms was completed by caregivers. RESULTS: The reflux symptomatic score resulted significantly higher in obese than in normal-weight children and in children with WC >90th percentile compared with those with WC <75th percentile. CONCLUSIONS: These preliminary data show that both total and abdominal obesity are risk factors for the development of GERD symptoms in children. The risk of GERD symptoms rises progressively with the increase in both body mass index and waist circumference, even in normal-weight children. PMID- 22437470 TI - Severity scores in children with acute pancreatitis. AB - Severity scores are used to predict the outcome of acute pancreatitis (AP). Several scores are used in adult patients, but none has been thoroughly validated for specific use in paediatric patients. We retrospectively collected data from 48 children with AP (13 severe and 35 mild). The main causes were trauma (23%), idiopathic (23%), lithiasis (12.5%), and virus (10.5%). We evaluated 3 clinical scores (Ranson, Glasgow modified, and DeBanto) and Balthazar computed tomography severity index. The clinical scores had a good specificity (approximately 85%) but a low sensitivity (approximately 55%) in predicting the severity of paediatric AP. The radiological score is better (sensitivity 80%, specificity 86%). The area under the receiver operator characteristic curve was 0.699 (95% CI 0.508%-0.891%, P = 0.054) for the DeBanto score, 0.846 (95% CI 0.69%-1%, P = 0.001) for the Ranson score, and 0.774 (95% CI 0.584%-0.964%, P = 0.008) for the Glasgow and 0.898 (95% CI 0.73%-1%, P = 0.011) for the Balthazar computed tomography severity index score. In our paediatric cohort, the severity of AP was best predicted by Balthazar computed tomography-based scoring scale. Our results confirm previously reported low sensitivity of adult-based clinical scoring scales. PMID- 22437471 TI - Rectal lipoma in a pediatric patient with inflammatory bowel disease. PMID- 22437472 TI - Effect of added calcium, phosphorus, and infant formula on calcium and phosphorus dialyzability in preterm donor human milk. AB - OBJECTIVES: We studied the effect of preparing donor human milk (DHM) with commonly used nutritional additives on the dialyzability of calcium and phosphate. We hypothesized that the additives to DHM would decrease the dialyzability of calcium and phosphate when prepared according to hospital protocols. METHODS: An in vitro system simulating premature infant digestion was developed to measure dialyzability of calcium and phosphate in DHM. Dialyzable calcium and phosphate were measured after in vitro digestion in DHM before and after preparation of DHM with the following additives according to hospital protocols: calcium glubionate, sodium potassium phosphate, calcium glubionate and sodium potassium phosphate added together, Similac human milk fortifier, Similac NeoSure, or Enfamil Enfacare. RESULTS: The percentage of dialyzable calcium in DHM with added calcium and calcium and phosphate together was greater than the percentage of dialyzable calcium in DHM with added powdered infant formulas (P<0.0001). Dialyzable calcium was greater in DHM with added calcium and with added calcium and phosphate than in all other treatment groups (P<0.0001). Dialyzable calcium in DHM without additives was not different from dialyzable calcium in DHM with added phosphate or with added powdered infant formulas. Dialyzable phosphate did not differ between the treatment groups. CONCLUSIONS: The addition of calcium alone or calcium and phosphate together increased calcium dialyzability in DHM significantly, whereas the addition of powdered human milk fortifier or formulas did not. The addition of calcium or calcium with phosphate together to DHM may provide the most dialyzable calcium. PMID- 22437473 TI - Omeprazole-induced myositis in a child receiving triple therapy for Helicobacter pylori infection. PMID- 22437474 TI - Paediatric Helicobacter pylori practice in the United Kingdom: a BSPGHAN survey. PMID- 22437475 TI - Acute febrile cholestatic jaundice in children: keep in mind Kawasaki disease. AB - Kawasaki disease (KD) is characterized by persistent fever in addition to 4 of 5 signs of mucocutaneous inflammation. Although gastrointestinal involvement does not belong to the classic diagnostic criteria, it has been often associated with KD onset. We reviewed patients who were admitted for febrile cholestatic jaundice between 2003 and 2010 in 2 tertiary pediatric care centers. KD was the second most frequent cause (21%) after viral infections. Considering the relative high frequency of this condition, a high index of suspicion of KD should be maintained in patients presenting with febrile cholestatic jaundice. PMID- 22437476 TI - Impaired gastric emptying and small bowel transit in children with mitochondrial disorders. AB - OBJECTIVES: The primary aim of our study was to evaluate gastric emptying (GE) and intestinal transit time (ITT) in children with mitochondrial disorders (MD), and secondarily to evaluate the effect of prokinetics in those with prolonged GE. METHODS: We enrolled subjects 3 to 18 years with MD and having any of the following gastrointestinal (GI) symptoms: abdominal pain, vomiting, constipation, diarrhea, or gastroesophageal reflux. Abdominal pain was scored by visual analog pain scale (1-10). Age-appropriate diet was labeled with radioactive technetium 99 sulfur colloid and its movement tracked along the GI tract. Delayed GE based on our institutional standards was defined as half emptying time >90 minutes for a solid and >60 minutes for a semisolid meal. Prolonged ITT was defined as >4 hours for the tracer to pass from mouth to cecum. A prokinetic was instituted to those with delayed GE, and the study was repeated if possible in 4 to 8 weeks. RESULTS: Of the 26 subjects, 18 (69%) had delayed GE (median GE 99 minutes) and 12 (46%) had prolonged ITT. The study was repeated in 9 subjects after administering a prokinetic for >1 month. GE normalized in only 3 subjects (median GE on treatment 128 minutes). Mean abdominal pain score, which was 4.8 (max 10) in the 9 subjects, did not improve (5.6 after prokinetic therapy). CONCLUSIONS: A high prevalence of delayed GE and prolonged ITT was seen in children with MD having GI symptoms, and these abnormalities were poorly responsive to prokinetic therapy. PMID- 22437477 TI - Reliability and validity of child/adolescent food frequency questionnaires that assess foods and/or food groups. AB - OBJECTIVE: Summarize the validity and reliability of child/adolescent food frequency questionnaires (FFQs) that assess food and/or food groups. METHODS: We performed a systematic review of child/adolescent (6-18 years) FFQ studies published between January 2001 and December 2010 using MEDLINE, Cochrane Library, PsycINFO, and Google Scholar. Main inclusion criteria were peer reviewed, written in English, and reported reliability or validity of questionnaires that assessed intake of food/food groups. Studies were excluded that focused on diseased people or used a combined dietary assessment method. Two authors independently selected the articles and extracted questionnaire characteristics such as number of items, portion size information, time span, category intake frequencies, and method of administration. Validity and reliability coefficients were extracted and reported for food categories and averaged across food categories for each study. RESULTS: Twenty-one studies were selected from 873, 18 included validity data, and 14 included test-retest reliability data. Publications were from the United States, Europe, Africa, Brazil, and the south Pacific. Validity correlations ranged from 0.01 to 0.80, and reliability correlations ranged from 0.05 to 0.88. The highest average validity correlations were obtained when the questionnaire did not assess portion size, measured a shorter time span (ie, previous day/week), was of medium length (ie, ~ 20-60 items), and was not administered to the child's parents. CONCLUSIONS: There are design and administration features of child/adolescent FFQs that should be considered to obtain reliable and valid estimates of dietary intake in this population. PMID- 22437478 TI - Weight and reflux: what is the relation? PMID- 22437479 TI - Microfluidic approaches for cancer cell detection, characterization, and separation. AB - This article reviews the recent developments in microfluidic technologies for in vitro cancer diagnosis. We summarize the working principles and experimental results of key microfluidic platforms for cancer cell detection, characterization, and separation based on cell-affinity micro-chromatography, magnetic activated micro-sorting, and cellular biophysics (e.g., cell size and mechanical and electrical properties). We examine the advantages and limitations of each technique and discuss future research opportunities for improving device throughput and purity, and for enabling on-chip analysis of captured cancer cells. PMID- 22437480 TI - Selective formation of a polar incomplete coordination cage induced by remote ligand substituents. AB - Instead of highly symmetrical T-symmetry cages common in self-assembly, the p NMe(2)-substituted triphosphine CH(3)C{CH(2)P(4-C(6)H(4)NMe(2))(3) gives open, polar C(3) symmetry cages [Ag(6)(triphos)(4)X(3)](3+) which lack one of the expected face-capping anions; despite its subtlety this difference occurs selectively in solution and two examples have been crystallographically characterised. PMID- 22437481 TI - Chi-square analysis of the reduction of ATP levels in L-02 hepatocytes by hexavalent chromium. AB - This study explored the reduction of adenosine triphosphate (ATP) levels in L-02 hepatocytes by hexavalent chromium (Cr(VI)) using chi-square analysis. Cells were treated with 2, 4, 8, 16, or 32 MUM Cr(VI) for 12, 24, or 36 h. Methyl thiazolyl tetrazolium (MTT) experiments and measurements of intracellular ATP levels were performed by spectrophotometry or bioluminescence assays following Cr(VI) treatment. The chi-square test was used to determine the difference between cell survival rate and ATP levels. For the chi-square analysis, the results of the MTT or ATP experiments were transformed into a relative ratio with respect to the control (%). The relative ATP levels increased at 12 h, decreased at 24 h, and increased slightly again at 36 h following 4, 8, 16, 32 MUM Cr(VI) treatment, corresponding to a "V-shaped" curve. Furthermore, the results of the chi-square analysis demonstrated a significant difference of the ATP level in the 32-MUM Cr(VI) group (P < 0.05). The results suggest that the chi-square test can be applied to analyze the interference effects of Cr(VI) on ATP levels in L-02 hepatocytes. The decreased ATP levels at 24 h indicated disruption of mitochondrial energy metabolism and the slight increase of ATP levels at 36 h indicated partial recovery of mitochondrial function or activated glycolysis in L 02 hepatocytes. PMID- 22437482 TI - Protection against neurotoxicity by an autophagic mechanism. AB - The objective of the present study was to investigate the effects of 3-n butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP+)-induced cellular model of Parkinson's disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of alpha-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of alpha-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy mediated alpha-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD. PMID- 22437483 TI - On the relationships between ultrasonic calling and anxiety-related behavior in rats. AB - In the present review, the phenomenon of ultrasonic vocalization in rats will be outlined, including the three classes of vocalizations, namely 40-kHz calls of pups, and 22- and 50-kHz calls of juvenile and adult rats, their general relevance to behavioral neuroscience, and their special relevance to research on anxiety, fear, and defense mechanisms. Here, the emphasis will be placed on 40- and 22-kHz calls, since they are typical for various situations with aversive properties. Among other topics, we will discuss whether such behavioral signals can index a certain affective state, and how these signals can be used in social neuroscience, especially with respect to communication. Furthermore, we will address the phenomenon of inter-individual variability in ultrasonic calling and what we currently know about the mechanisms, which may determine such variability. Finally, we will address the current knowledge on the neural and pharmacological mechanisms underlying 22-kHz ultrasonic vocalization, which show a substantial overlap with mechanisms known from other research on fear and anxiety, such as those involving the periaqueductal gray or the amygdala. PMID- 22437484 TI - Panic-like defensive behavior but not fear-induced antinociception is differently organized by dorsomedial and posterior hypothalamic nuclei of Rattus norvegicus (Rodentia, Muridae). AB - The hypothalamus is a forebrain structure critically involved in the organization of defensive responses to aversive stimuli. Gamma-aminobutyric acid (GABA)ergic dysfunction in dorsomedial and posterior hypothalamic nuclei is implicated in the origin of panic-like defensive behavior, as well as in pain modulation. The present study was conducted to test the difference between these two hypothalamic nuclei regarding defensive and antinociceptive mechanisms. Thus, the GABA(A) antagonist bicuculline (40 ng/0.2 uL) or saline (0.9% NaCl) was microinjected into the dorsomedial or posterior hypothalamus in independent groups. Innate fear induced responses characterized by defensive attention, defensive immobility and elaborate escape behavior were evoked by hypothalamic blockade of GABA(A) receptors. Fear-induced defensive behavior organized by the posterior hypothalamus was more intense than that organized by dorsomedial hypothalamic nuclei. Escape behavior elicited by GABA(A) receptor blockade in both the dorsomedial and posterior hypothalamus was followed by an increase in nociceptive threshold. Interestingly, there was no difference in the intensity or in the duration of fear-induced antinociception shown by each hypothalamic division presently investigated. The present study showed that GABAergic dysfunction in nuclei of both the dorsomedial and posterior hypothalamus elicit panic attack like defensive responses followed by fear-induced antinociception, although the innate fear-induced behavior originates differently in the posterior hypothalamus in comparison to the activity of medial hypothalamic subdivisions. PMID- 22437485 TI - New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray. AB - Panic disorder patients are vulnerable to recurrent panic attacks. Two neurochemical hypotheses have been proposed to explain this susceptibility. The first assumes that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organize defensive reactions to cope with proximal threats and of sympathomotor control areas of the rostral ventrolateral medulla that generate most of the neurovegetative symptoms of the panic attack. The second suggests that endogenous opioids buffer normal subjects from the behavioral and physiological manifestations of the panic attack, and their deficit brings about heightened suffocation sensitivity and separation anxiety in panic patients, making them more vulnerable to panic attacks. Experimental results obtained in rats performing one-way escape in the elevated T-maze, an animal model of panic, indicate that the inhibitory action of serotonin on defense is connected with activation of endogenous opioids in the periaqueductal gray. This allows reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology, the periaqueductal gray being the fulcrum of serotonin-opioid interaction. PMID- 22437486 TI - Long-term changes in endothelial cell counts after early phacoemulsification versus laser peripheral iridotomy using sequential argon:YAG laser technique in acute primary angle closure. AB - OBJECTIVE: To compare the change in endothelial cell counts (ECC) after early phacoemulsification and laser peripheral iridotomy (LPI) using sequential argon:yttrium-aluminum-garnet (YAG) laser technique for the treatment of acute primary angle closure (APAC). METHODS: This was a retrospective chart review, case-control study; 86 APAC patients were enrolled. Sixteen patients who underwent early phacoemulsification with intraocular lens implantation and 32 patients who underwent LPI were matched by propensity score analysis. All subjects underwent a complete ophthalmic examination, including intraocular pressure (IOP) measurements, optic disc examinations, and gonioscopy. ECC were acquired at the center of the cornea with a noncontact specular microscope before treatment, and at 1, 6, 12, and 24 months following phacoemulsification or LPI. RESULTS: The mean follow-up was 26.1 +/- 4.7 months in the phacoemulsification group and 26.3 +/- 4.5 months in the LPI group. After intervention, the changes in anterior chamber depth and Shaffer grading by gonioscopy were significantly different between groups. ECC were not different before treatment; however, after phacoemulsification or LPI at 12 months (2280 +/- 320 vs 1993 +/- 380 cells/mm(2)) and 24 months (2113 +/- 333 vs 1880 +/- 422 cells/mm(2)), there was a significant difference between the two groups (P = 0.040 and P = 0.032 respectively). Regression analysis showed that anterior chamber depth at baseline (P = 0.041) and intervention modality (phacoemulsification vs LPI; P < 0.001) were significantly related to the change in ECC. CONCLUSIONS: Early phacoemulsification showed lower endothelial cell loss than did LPI in the treatment of APAC after a 2-year follow-up. In terms of ECC, early phacoemulsification could be a better intervention modality for APAC. PMID- 22437487 TI - Pharmacokinetic-pharmacodynamic modeling of the D2 and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats. AB - PURPOSE: A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D2 and serotonin 5 HT(2A) receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats. METHODS: A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D2 and 5-HT(2A) RO data. A previously published physiology- and mechanism based (PBPKPD) model describing brain concentrations and D2 receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT(2A) receptors in the frontal cortex. RESULTS: A two compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D2 and 5-HT(2A) RO well. Inclusion of binding to 5-HT(2A) receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern. CONCLUSION: Binding to both D2 and 5-HT(2A) receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D2 and 5 HT(2A) receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs. PMID- 22437488 TI - Amorphous-state characterization of efavirenz--polymer hot-melt extrusion systems for dissolution enhancement. AB - The aim of this study was to improve the dissolution rate of efavirenz (EFV) by formulating a physically stable dispersion in polymers. Hot-melt extrusion (HME) was used to prepare solid solutions of EFV with Eudragit EPO (a low-glass transition polymer) or Plasdone S-630 (a high-glass transition polymer). The drug polymer blends were characterized for their thermal and rheological properties as a function of drug concentration to understand their miscibility and processability by HME. The solid-state stability of extrudates was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and dissolution studies. Thermal and rheological studies revealed that the drug is miscible with both polymers, and a decrease in melt viscosity was observed as the drug concentration increased. XRD and DSC studies confirmed the existence of amorphous state of EFV in the extrudates during storage. The dissolution rate of EFV from the extrudates was substantially higher than the crystalline drug. FTIR studies revealed an interaction between the EFV and Plasdone S-630, which reduced the molecular mobility and prevented crystallization upon storage. EFV and Eudragit EPO systems lack specific interactions, but are less susceptible to crystallization due to the antiplasticization effect of the polymer. PMID- 22437489 TI - 2D coordination polymers of macrocyclic oxamide with polycarboxylates: syntheses, crystal structures and magnetic properties. AB - Five new 2D coordination polymers, [Co(nip)(CuL)(H(2)O)].CH(3)OH (1), [Mn(ip)(NiL)].0.63H(2)O (2), [Cu(ip)(CuL)] (3), [Mn(6)(CuL)(6)(btc)(4)(H(2)O)(4)].7H(2)O (4), and [Cu(CuL)(Hbtc)(H(2)O)] (5)(ML, H(2)L = 2,3-dioxo-5,6,14,15-dibenzo-1,4,8,12-tetraazacyclo-pentadeca-7,13-diene; H(2)nip = 5-nitroisophthalic acid; H(2)ip = m-isophthalic acid; H(3)btc = 1,3,5 benzenetricarboxylic acid) have been synthesized by a solvothermal method and characterized by single-crystal X-ray diffraction. Complexes 1-5 exhibit different 2D layered structures formed by Co(2)Cu(2) (1), Mn(2)Ni(2) (2), Cu(4) (3), Mn(3)Ni(3) (4), Cu(4) (5) units, respectively, via the oxamide and diverse carboxylic acid bridges. Compounds 1, 2, 3 and 5 are uninodal 4-connected (4, 4) grids topology, while complex 4 possesses a 2D network with (3, 4)-connected (4(2).8)(4)(4(3).6(2).8)(3) topology. The results of magnetic determination show pronounced antiferromagnetic interactions in 1-4. PMID- 22437490 TI - Genetic structure and linkage disequilibrium pattern of a rapeseed (Brassica napus L.) association mapping panel revealed by microsatellites. AB - Understanding the population structure and linkage disequilibrium (LD) is a prerequisite for association mapping of complex traits in a target population. In this study, we assessed the genetic diversity, population structure and the extent of LD in a panel of 192 inbred lines of Brassica napus from all over the world using 451 single-locus microsatellite markers. The inbred lines could be divided into P1 and P2 groups by a model-based population structure analysis. Out of the 142 inbred lines in the P1 group, 126 lines were from China and Japan, and the remaining 16 lines were from Europe, Canada and Australia. In the P2 group, 33 out of the 50 lines were from Europe, Canada, and Australia, and the remaining 17 lines were from China. Structure analysis further divided each group into two subgroups. AMOVA, pairwise F (ST) and neutrality analyses confirmed the differentiation between groups and subgroups. More than 80 % of the pairwise kinship estimates between inbred lines were <0.05, indicating that relative kinship is weak in our panel. Only 6 % linked marker pairs showed LD, suggesting the low level of LD in this association panel. The LD decayed within 0.5-1 cM at the genome level, and varied considerably across each group and subgroup, due to the population size, genetic background and genetic drift. The characterization of the population structure and LD patterns would be useful for performing association studies for complex agronomic traits in rapeseed. PMID- 22437491 TI - Bayesian mapping of multiple traits in maize: the importance of pleiotropic effects in studying the inheritance of quantitative traits. AB - Pleiotropy has played an important role in understanding quantitative traits. However, the extensiveness of this effect in the genome and its consequences for plant improvement have not been fully elucidated. The aim of this study was to identify pleiotropic quantitative trait loci (QTLs) in maize using Bayesian multiple interval mapping. Additionally, we sought to obtain a better understanding of the inheritance, extent and distribution of pleiotropic effects of several components in maize production. The design III procedure was used from a population derived from the cross of the inbred lines L-14-04B and L-08-05F. Two hundred and fifty plants were genotyped with 177 microsatellite markers and backcrossed to both parents giving rise to 500 backcrossed progenies, which were evaluated in six environments for grain yield and its components. The results of this study suggest that mapping isolated traits limits our understanding of the genetic architecture of quantitative traits. This architecture can be better understood by using pleiotropic networks that facilitate the visualization of the complexity of quantitative inheritance, and this characterization will help to develop new selection strategies. It was also possible to confront the idea that it is feasible to identify QTLs for complex traits such as grain yield, as pleiotropy acts prominently on its subtraits and as this "trait" can be broken down and predicted almost completely by the QTLs of its components. Additionally, pleiotropic QTLs do not necessarily signify pleiotropy of allelic interactions, and this indicates that the pervasive pleiotropy does not limit the genetic adaptability of plants. PMID- 22437492 TI - QTLs for agronomic and cell wall traits in a maize RIL progeny derived from a cross between an old Minnesota13 line and a modern Iodent line. AB - In order to contribute to the inventory of genomic areas involved in maize cell wall lignification and degradability, QTL analyses were investigated in a RIL progeny between an old Minnesota13 dent line (WM13) and a modern Iodent line (RIo). Significant variation for agronomic- and cell wall-related traits was observed for the RIL per se (plants without ears) and topcross (whole plants) experiments after crossing with both old (Ia153) and modern tester (RFl) lines. Three QTLs for stover (plant without ear) yield were observed in per se experiments, with alleles increasing yield originating from RIo in two genomic locations with the highest effects. However, no QTL for whole plant yield was detected in topcross experiments, despite the fact that two QTLs for starch content were shown with increasing alleles originating from the modern RIo line. Fifteen lignin QTLs were shown, including a QTL for Klason lignins in per se experiments, located in bin 2.04, which explained 43 % of the observed genetic variation. Thirteen QTLs for p-hydroxycinnamic acid contents and nine QTLs related to the monomeric composition of lignin were shown in per se experiments, with syringaldehyde and diferulate QTLs explaining nearly 25 % of trait variations. Nine and seven QTLs for cell wall digestibility were mapped in per se and topcross experiments, respectively. Five of the per se QTLs explained more than 15 % of the variation, up to nearly 25 %. QTL positions in bins 2.06, 5.04, 5.08 and 8.02 for ADL/NDF, IVNDFD, lignin structure and/or p-hydroxycinnamic acid contents have not been previously shown and were thus first identified in the RIo * WM13 progeny. Based on QTL colocalizations, differences in cell wall degradability between RIo and WM13 were less often related to acid detergent lignin (ADL) content than in previous RIL investigations. QTL colocalizations then highlighted the probable importance of ferulate cross linkages in variation for cell wall digestibility. No colocalizations of QTL for cell wall phenolic related traits were shown with genes involved in monolignol biosynthesis or polymerization. In contrast, colocalizations were most often shown with MYB and NAC transcription factors, including orthologs of master genes involved in Arabidopsis secondary wall assembly. QTL colocalizations also strengthened the probable involvement of members of the CoA-dependent acyltransferase PF02458 family in the feruloylation of arabinoxylan chains. PMID- 22437493 TI - Therapeutic effect of SN50, an inhibitor of nuclear factor-kappaB, in treatment of TBI in mice. AB - NF-kappaB upregulation has been demonstrated in neurons and glial cells in response to experimental injury and neuropathological disorders, where it has been related to both neurodegenerative and neuroprotective activities. It has been generally recognized that NF-kappaB plays important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. However, the regulatory mechanism of NF-kappaB in apoptosis remained to be determined. The present study sought to first investigate the effect of a NF-kappaB inhibitor SN50, which inhibits NF-kappaB nuclear translocation, on cell death and behavioral deficits in our mice traumatic brain injury (TBI) models. Additionally, we tried to elucidate the possible mechanisms of the therapeutic effect of SN50 through NF-kappaB regulating apoptotic and inflammatory pathway in vivo. Encouragingly, the results showed that pretreatment with SN50 remarkably attenuated TBI-induced cell death (detected by PI labeling), cumulative loss of cells (detected by lesion volume), and motor and cognitive dysfunction (detected by motor test and Morris water maze). To analyze the mechanism of SN50 on cell apoptotic and inflammatory signaling pathway, we thus assessed expression levels of TNF-alpha, cathepsin B and caspase-3, Bid cleavage and cytochrome c release in SN50-pretreated groups compared with those in saline vehicle groups. The results imply that through NF-kappaB/TNF-alpha/cathepsin networks SN50 may contribute to TBI-induced extrinsic and intrinsic apoptosis, and inflammatory pathways, which partly determined the fate of injured cells in our TBI model. PMID- 22437494 TI - Successful subthalamic stimulation, but levodopa-induced dystonia, in a genetic Parkinson's disease. AB - Recently, it is under scrutiny the possibility to anticipate the stereotactic implantation of the subthalamic nucleus (STN) even in relatively mild Parkinson's disease (PD) patients with an unsatisfying response to drugs. In addition, it is debated whether levodopa (LD) and deep brain stimulation (DBS) are congruent or, instead, mutually exclusive. A 56-year-old LRRK2-positive PD patient, with 7 years of disease history, dominated by severe left resting tremor, was submitted to bilateral implantation of the subthalamic nucleus (STN). Before surgery, the combination of LD and dopamine agonists failed to handle tremor unless administered at doses, which induced undesirable adverse events. STN deep brain stimulation (DBS) abolished tremor but did not provide satisfying control of hypokinetic-rigid symptoms. The condition STIM-ON plus LD, albeit transiently beneficial, installed a painful dystonia developing slowly after 24-36 h. Only a chronic therapy combining rotigotine plus STN-DBS proved effective without side effects. This case report, based upon the surprising difference between the therapeutic response to the combination of LD and dopamine agonist (before surgery) and the combination of DBS and agonist after surgery, emphasizes how STIM and LD target different motor domains through mechanisms with differential plasticity and confirms the efficacy of STN-DBS in LRKK2 patients. PMID- 22437495 TI - Nutraceutical preparations in childhood migraine prophylaxis: effects on headache outcomes including disability and behaviour. AB - Migraine is common in children, but few specific drugs are available. We performed an open-label comparison of effects of two nutraceutical preparations (ginkgolide B vs. Griffonia simplicifolia extract) on outcomes in 374 school-age children (mean 10.7 years) with migraine without aura. Half of them received ginkgolide B; and half, Griffonia simplicifolia. Both preparations were given orally twice a day for 6 months. Patients kept a headache diary. Outcomes at the beginning and end of treatment were compared. Both preparations reduced all outcome measures after 6 months of treatment. However, reductions in headache frequency, duration and intensity, PedMIDAS score and behavioural reactions to headache were significantly greater in the ginkgolide B group. Both nutraceutical treatments appear promising in paediatric migraine without aura, particularly because of their lack of side effects. However, the ginkgolide B preparation was significantly more effective in the medium-term (6 months). PMID- 22437496 TI - Clinical and biomarker profile of trauma-induced secondary cardiac injury. AB - BACKGROUND: Secondary cardiac injury has been demonstrated in critical illness and is associated with worse outcomes. The aim of this study was to establish the existence of trauma-induced secondary cardiac injury, and investigate its impact on outcomes in injured patients. METHODS: Injured adult patients eligible for enrolment in the Activation of Coagulation and Inflammation in Trauma 2 study, and admitted to the intensive care unit between January 2008 and January 2010, were selected retrospectively for the study. Markers of cardiac injury (brain natriuretic peptide (BNP), heart-type fatty acid binding protein (H-FABP) and troponin I) were measured on admission, and after 24 and 72 h in blood samples from injured patients. Individual records were reviewed for adverse cardiac events and death. RESULTS: During the study period, 135 patients were enrolled (106 male, 78.5 per cent) with a median age of 40 (range 16-89) years. Eighteen patients (13.3 per cent) had an adverse cardiac event during admission and these events were not associated with direct thoracic injury. The in-hospital mortality rate was higher among the adverse cardiac event cohort: 44 per cent (8 of 18) versus 17.1 per cent (20 of 117) (P = 0.008). Raised levels of H-FABP and BNP at 0, 24 and 72 h, and troponin I at 24 and 72 h, were associated with increased adverse cardiac events. BNP levels were higher in non-survivors on admission (median 550 versus 403 fmol/ml; P = 0.022), after 24 h (794 versus 567 fmol/ml; P = 0.033) and after 72 h (1043 versus 753 fmol/ml; P = 0.036), as were admission troponin I levels. CONCLUSION: Clinical and cardiac biomarker characteristics support the existence of trauma-induced secondary cardiac injury, which is associated with death, and unrelated to direct thoracic injury. PMID- 22437497 TI - Transcription factor PIF4 controls the thermosensory activation of flowering. AB - Plant growth and development are strongly affected by small differences in temperature. Current climate change has already altered global plant phenology and distribution, and projected increases in temperature pose a significant challenge to agriculture. Despite the important role of temperature on plant development, the underlying pathways are unknown. It has previously been shown that thermal acceleration of flowering is dependent on the florigen, FLOWERING LOCUS T (FT). How this occurs is, however, not understood, because the major pathway known to upregulate FT, the photoperiod pathway, is not required for thermal acceleration of flowering. Here we demonstrate a direct mechanism by which increasing temperature causes the bHLH transcription factor PHYTOCHROME INTERACTING FACTOR4 (PIF4) to activate FT. Our findings provide a new understanding of how plants control their timing of reproduction in response to temperature. Flowering time is an important trait in crops as well as affecting the life cycles of pollinator species. A molecular understanding of how temperature affects flowering will be important for mitigating the effects of climate change. PMID- 22437498 TI - Spontaneous coherence in a cold exciton gas. AB - If bosonic particles are cooled down below the temperature of quantum degeneracy, they can spontaneously form a coherent state in which individual matter waves synchronize and combine. Spontaneous coherence of matter waves forms the basis of a number of fundamental phenomena in physics, including superconductivity, superfluidity and Bose-Einstein condensation. Spontaneous coherence is the key characteristic of condensation in momentum space. Excitons--bound pairs of electrons and holes--form a model system to explore the quantum physics of cold bosons in solids. Cold exciton gases can be realized in a system of indirect excitons, which can cool down below the temperature of quantum degeneracy owing to their long lifetimes. Here we report measurements of spontaneous coherence in a gas of indirect excitons. We found that spontaneous coherence of excitons emerges in the region of the macroscopically ordered exciton state and in the region of vortices of linear polarization. The coherence length in these regions is much larger than in a classical gas, indicating a coherent state with a much narrower than classical exciton distribution in momentum space, characteristic of a condensate. A pattern of extended spontaneous coherence is correlated with a pattern of spontaneous polarization, revealing the properties of a multicomponent coherent state. We also observed phase singularities in the coherent exciton gas. All these phenomena emerge when the exciton gas is cooled below a few kelvin. PMID- 22437499 TI - Structure of the mitotic checkpoint complex. AB - In mitosis, the spindle assembly checkpoint (SAC) ensures genome stability by delaying chromosome segregation until all sister chromatids have achieved bipolar attachment to the mitotic spindle. The SAC is imposed by the mitotic checkpoint complex (MCC), whose assembly is catalysed by unattached chromosomes and which binds and inhibits the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome segregation. Here, using the crystal structure of Schizosaccharomyces pombe MCC (a complex of mitotic spindle assembly checkpoint proteins Mad2, Mad3 and APC/C co-activator protein Cdc20), we reveal the molecular basis of MCC-mediated APC/C inhibition and the regulation of MCC assembly. The MCC inhibits the APC/C by obstructing degron recognition sites on Cdc20 (the substrate recruitment subunit of the APC/C) and displacing Cdc20 to disrupt formation of a bipartite D-box receptor with the APC/C subunit Apc10. Mad2, in the closed conformation (C-Mad2), stabilizes the complex by optimally positioning the Mad3 KEN-box degron to bind Cdc20. Mad3 and p31(comet) (also known as MAD2L1-binding protein) compete for the same C-Mad2 interface, which explains how p31(comet) disrupts MCC assembly to antagonize the SAC. This study shows how APC/C inhibition is coupled to degron recognition by co-activators. PMID- 22437500 TI - Quantum optics: An entangled walk of photons. PMID- 22437501 TI - A new understanding of the decoding principle on the ribosome. AB - During protein synthesis, the ribosome accurately selects transfer RNAs (tRNAs) in accordance with the messenger RNA (mRNA) triplet in the decoding centre. tRNA selection is initiated by elongation factor Tu, which delivers tRNA to the aminoacyl tRNA-binding site (A site) and hydrolyses GTP upon establishing codon anticodon interactions in the decoding centre. At the following proofreading step the ribosome re-examines the tRNA and rejects it if it does not match the A codon. It was suggested that universally conserved G530, A1492 and A1493 of 16S ribosomal RNA, critical for tRNA binding in the A site, actively monitor cognate tRNA, and that recognition of the correct codon-anticodon duplex induces an overall ribosome conformational change (domain closure). Here we propose an integrated mechanism for decoding based on six X-ray structures of the 70S ribosome determined at 3.1-3.4 A resolution, modelling cognate or near-cognate states of the decoding centre at the proofreading step. We show that the 30S subunit undergoes an identical domain closure upon binding of either cognate or near-cognate tRNA. This conformational change of the 30S subunit forms a decoding centre that constrains the mRNA in such a way that the first two nucleotides of the A codon are limited to form Watson-Crick base pairs. When U.G and G.U mismatches, generally considered to form wobble base pairs, are at the first or second codon-anticodon position, the decoding centre forces this pair to adopt the geometry close to that of a canonical C.G pair. This by itself, or with distortions in the codon-anticodon mini-helix and the anticodon loop, causes the near-cognate tRNA to dissociate from the ribosome. PMID- 22437502 TI - Crystal structure of the u-opioid receptor bound to a morphinan antagonist. AB - Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein coupled u-opioid receptor (u-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse u-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the u-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction. PMID- 22437503 TI - Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. AB - In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia. PMID- 22437505 TI - Government officials' representation of nurses and migration in the Philippines. AB - During the past few decades, the nursing workforce has been in crisis in the United States and around the world. Many health care organizations in developed countries recruit nurses from other countries to maintain acceptable staffing levels. The Philippines is the centre of a large, mostly private nursing education sector and an important supplier of nurses worldwide, despite its weak domestic health system and uneven distribution of health workers. This situation suggests a dilemma faced by developing countries that train health professionals for overseas markets: how do government officials balance competing interests in overseas health professionals' remittances and the need for well-qualified health professional workforces in domestic health systems? This study uses case studies of two recent controversies in nursing education and migration to examine how Philippine government officials represent nurses when nurse migration is the subject of debate. The study finds that Philippine government officials cast nurses as global rather than domestic providers of health care, implicating them in development more as sources of remittance income than for their potential contributions to the country's health care system. This orientation is motivated not simply by the desire for remittance revenues, but also as a way to cope with overproduction and lack of domestic opportunities for nurses in the Philippines. PMID- 22437504 TI - Structure of the human kappa-opioid receptor in complex with JDTic. AB - Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of kappa-opioid receptor (kappa-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human kappa-OR. Modelling of other important kappa-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5' guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR. PMID- 22437506 TI - Increase in facility-based deliveries associated with a maternal health voucher programme in informal settlements in Nairobi, Kenya. AB - OBJECTIVE: To measure whether there was an association between the introduction of an output-based voucher programme and the odds of a facility-based delivery in two Nairobi informal settlements. DATA SOURCES: Nairobi Urban Health and Demographic Surveillance System (NUHDSS) and two cross-sectional household surveys in Korogocho and Viwandani informal settlements in 2004-05 and 2006-08. METHODS: Odds of facility-based delivery were estimated before and after introduction of an output-based voucher. Supporting NUHDSS data were used to determine whether any trend in maternal health care was coincident with immunizations, a non-voucher outpatient service. As part of NUHDSS, households in Korogocho and Viwandani reported place of delivery and the presence of a skilled birth attendant (2003-10) and vaccination coverage (2003-09). A detailed maternal and child health (MCH) tool was added to NUHDSS (September 2006-10). Prospective enrolment in NUHDSS-MCH was conditional on having a newborn after September 2006. In addition to recording mother's place of delivery, NUHDSS-MCH recorded the use of the voucher. FINDINGS: There were significantly greater odds of a facility based delivery among respondents during the voucher programme compared with similar respondents prior to voucher launch. Testing whether unrelated outpatient care also increased, a falsification exercise found no significant increase in immunizations for children 12-23 months of age in the same period. Although the proportion completing any antenatal care (ANC) visit remained above 95% of all reported pregnancies and there was a significant increase in facility-based deliveries, the proportion of women completing 4+ ANC visits was significantly lower during the voucher programme. CONCLUSIONS: A positive association was observed between vouchers and facility-based deliveries in Nairobi. Although there is a need for higher quality evidence and validation in future studies, this statistically significant and policy relevant finding suggests that increases in facility-based deliveries can be achieved through output-based finance models that target subsidies to underserved populations. PMID- 22437507 TI - Temozolomide dosing regimens for glioma patients. AB - Even in modern times of high-precision brain surgery and irradiation, malignant gliomas belong to the deadliest types of cancer. Due to a marked primary and presumably also acquired resistance, the beneficial effects of cytotoxic chemotherapy are limited. Only one randomized clinical trial demonstrated a significant impact on overall survival with temozolomide. Ever since, there have been attempts to improve the efficacy of alkylating chemotherapy by modulating the distribution of dose in time aiming at a better treatment success. Apart from higher cumulative doses per cycle, better efficacy by depletion of the anti alkylating O6-methylguanine-DNA methyltransferase (MGMT) protein has been a major goal of these regimens. After promising results of single-arm pilot studies, however, randomized studies have been disappointing so far. In this overview, the different strategies of dose-dense temozolomide regimen are highlighted and results of clinical trials put into perspective. PMID- 22437508 TI - Inefficiency of randomization methods that balance on stratum margins and improvements with permuted blocks and a sequential method. AB - Stratified permuted blocks randomization is commonly applied in clinical trials, but other randomization methods that attempt to balance treatment counts marginally for the stratification variables are able to accommodate more stratification variables. When the analysis stratifies on the cells formed by crossing the stratification variables, these other randomization methods yield treatment effect estimates with larger variance than does stratified permuted blocks. When it is truly necessary to balance the randomization on many stratification variables, it is shown how this inefficiency can be improved by using a sequential randomization method where the first level balances on the crossing of the strata used in the analysis and further stratification variables fall lower in the sequential hierarchy. PMID- 22437509 TI - Partial anomalous pulmonary venous return through a left subaortic vein. AB - We present an unusual case of partial anomalous pulmonary venous return draining a subsegmental area of the left upper lobe into the superior vena cava. To our knowledge, this type of partial anomalous pulmonary venous return has not been described previously. We briefly describe embryologic considerations that we believe could help explain the origin of this rare anomaly. PMID- 22437510 TI - Contralateral decubitus positioning enhances computed tomographic angiographic evaluation of pulmonary vasculature in a patient with a pulmonary arteriovenous malformation. AB - Computed tomographic pulmonary angiography has become the diagnostic procedure of choice in patients suspected of having a pulmonary embolus. However, intrapulmonary shunting of blood in a variety of pathologic conditions can cause suboptimal opacification of the pulmonary arterial circulation and result in a suboptimal or even nondiagnostic study. Radiologists should be aware of these conditions and be familiar with positioning techniques to minimize such shunting. We report a patient suspected of having pulmonary embolism, in whom a preexisting unilateral arteriovenous malformation prevented adequate evaluation of the pulmonary circulation. Positioning the patient in the contralateral decubitus position significantly enhanced image quality. PMID- 22437511 TI - MorePower 6.0 for ANOVA with relational confidence intervals and Bayesian analysis. AB - MorePower 6.0 is a flexible freeware statistical calculator that computes sample size, effect size, and power statistics for factorial ANOVA designs. It also calculates relational confidence intervals for ANOVA effects based on formulas from Jarmasz and Hollands (Canadian Journal of Experimental Psychology 63:124 138, 2009), as well as Bayesian posterior probabilities for the null and alternative hypotheses based on formulas in Masson (Behavior Research Methods 43:679-690, 2011). The program is unique in affording direct comparison of these three approaches to the interpretation of ANOVA tests. Its high numerical precision and ability to work with complex ANOVA designs could facilitate researchers' attention to issues of statistical power, Bayesian analysis, and the use of confidence intervals for data interpretation. MorePower 6.0 is available at https://wiki.usask.ca/pages/viewpageattachments.action?pageId=420413544 . PMID- 22437512 TI - The Vienna comparative cognition technology (VCCT): an innovative operant conditioning system for various species and experimental procedures. AB - This article describes a laboratory system for running learning experiments in operant chambers with various species. It is based on a modern version of a classical learning chamber for operant conditioning, the so-called "Skinner box". Rather than constituting a stand-alone unit, as is usually the case, it is an integrated part of a comprehensive technical solution, thereby eliminating a number of practical problems that are frequently encountered in research on animal learning and behavior. The Vienna comparative cognition technology combines modern computer, stimulus presentation, and reinforcement technology with flexibility and user-friendliness, which allows for efficient, widely automatized across-species experimentation, and thus makes the system appropriate for use in a broad range of learning tasks. PMID- 22437513 TI - Our origin, our passion, and our responsibility. PMID- 22437514 TI - Early antiplatelet therapy in coronary artery bypass grafting: a calculated benefit. AB - Studies have demonstrated that antagonists of platelet activity, including aspirin and clopidogrel, reduce the risk of major adverse events in patients with acute coronary syndromes. Although antiplatelet agents also convey an increased risk of bleeding, particularly in patients proceeding to coronary artery bypass graft surgery, in most cases, the benefits of early initiation of antiplatelet therapy outweigh the risks. The purpose of this review is to distinguish perceived and actual risk versus the benefit associated with early antiplatelet therapy to help clinicians make informed decisions on using these agents in an acute setting where patients may require coronary artery bypass grafting. PMID- 22437515 TI - Aortic valve replacement through right minithoracotomy in 306 consecutive patients. AB - OBJECTIVE: To define the role and early results of aortic valve surgery through a right minithoracotomy. METHODS: A retrospective analysis was performed on 306 consecutive patients undergoing aortic valve replacement through an 8-cm right minithoracotomy in the second intercostal space. The initial experience was included. The right second and third ribs were detached from the sternum in most cases and repaired at the end of each case. Most operations were performed using anterograde and retrograde cardioplegic arrest with percutaneous femoral venous cannulation and direct aortic cannulation through the incision. Standard instruments were used with direct digital knot tying. RESULTS: Mean age was 65 +/ 14 (range, 20-90) years. Aortic valve disease cause was calcific disease in 160 of 306 (52%) patients, bicuspid disease in 95 of 306 (31%) patients, and endocarditis in 9 of 306 (3%) patients. Previous cardiac surgery was present in 13 of 306 (4%) patients. Biologic prostheses were used in 240 of 306 (78%) patients. Median valve size was 23 mm. Mean clamp times and pump times were 103 +/- 26 and 158 +/- 35 minutes, respectively. Median postoperative length of stay was 5 days. Thirty-day mortality was found in 4 of 306 (1%) cases. There were no deep wound infections or mediastinitis. Stroke occurred in 5 of 306 (1.6%) patients, and new pacemaker required in 11 of 306 (4%) patients. Reoperation for bleeding occurred in 2 of 306 (1%) patients. Conversion to median sternotomy occurred in 15 of 306 (5%) patients caused by chest wall anatomy (n = 7), bleeding (n = 3), coronary disease (n = 2), or aortic disease (n = 3). Patients were allowed to return to driving or preoperative activity in 2 weeks. With a mean follow-up of 2.8 +/- 2.2 years, one patient required reoperation for aortic root disease. CONCLUSIONS: Right minithoracotomy is a safe but limited alternative to sternotomy in isolated aortic valve replacement. This approach may be particularly valuable in some higher risk, elderly patients and opens options for a hybrid approach combined with percutaneous coronary angioplasty. PMID- 22437516 TI - Predischarge angiographical evaluation of radial artery graft harvested by endoscopic harvesting system. AB - OBJECTIVE: Endoscopic radial artery harvesting (ERAH) has superior cosmetic advantages over conventional harvesting methods. With instrumental advancements, these techniques have become easier to adopt and require less time to learn. In most reported cases, the quality of harvested conduits is discussed based on macroscopic and histologic examinations and clinical outcomes. However, predischarge angiography gives a straightforward answer regarding quality of harvested conduit. The aim of this study is to assess the quality of endoscopically harvested radial artery by predischarge angiographic evaluation. METHODS: Endoscopic procedure using VasoView 4 system was performed in 87 patients between September 2004 and December 2007, and 78 predischarge angiographical evaluations were completed and reviewed. Mean age of the patients was 66 +/- 10 years and 18% were women. After ERAH was performed, accompanying veins were dissected by ultrasound scalpel. All conduits were as aortocoronary bypass under cardiopulmonary bypass. RESULTS: Mean arm ischemic time was 32 +/- 13 minutes and length of harvested conduit was 17.8 +/- 1.3 cm. Predischarge angiography demonstrated two occlusions at the proximal anastomosis in the 51st and 71st cases, although intraoperative flow study showed normal flow patterns in both cases. Stenosis in the conduits was observed in the first, sixth, and seventh cases. No further angiographical problems were found in the remaining conduits. CONCLUSIONS: Based on the angiographical results, problems with the harvested conduits occurred only in initial period. ERAH with VasoView system provides satisfactory angiographical quality after initial learning curve. PMID- 22437517 TI - Preoperative evaluation of patient anatomy to increase success of robotics assisted bypass surgery. AB - OBJECTIVE: Robotics-assisted endoscopic atraumatic coronary artery bypass has been shown to be effective in reducing surgical morbidity and length of hospital stay. Unfortunately, the criteria for selecting eligible patients for this procedure are still primitive. This has motivated the use of preoperative computed tomography scans to establish patient eligibility. The objective of this study is to establish which image measurements can be correlated to procedure success. METHODS: A retrospective study was performed in 144 patients who underwent robotics-assisted coronary bypass surgery. After an initial set of 55 patients, preoperative computed tomography scans of the other patients were used to obtain patient specific measurements: the lateral distance between the midline of the sternum to the left anterior descending coronary artery and its depth from the skin surface, anteroposterior diameter of the thoracic cavity, and the transverse diameter of the thoracic cavity. The procedures were rated as successful if completed in a minimally invasive manner. Different combinations of the variables were evaluated and correlated with success. RESULTS: A strong correlation was found between success rate and the ratio of the lateral distance to the transverse diameter in the female patients only (0.532, P = 0.006). A ratio of less than 0.20 significantly increased the occurrence of conversion during this procedure in female cases. CONCLUSIONS: The lateral distance of the left anterior descending coronary artery from the midline divided by the transverse thoracic width of a female patient shows a significant correlation with procedure success. No significant correlations were found for male patients. PMID- 22437518 TI - Peripheral insertion techniques for the Impella 5.0 circulatory support system. AB - OBJECTIVE: The Impella 5.0 is a peripherally inserted short-term left ventricular assist device. It is typically inserted through a large peripheral artery such as the common femoral artery. We describe both a graft technique and a purse-string technique in detail. METHODS: In the course of introducing this technology to our hospital, we independently developed two techniques for the insertion of the device. These novel insertion techniques are different from those described by the manufacturer. RESULTS: The techniques described have distinct advantages that may be helpful to physicians inserting the device. Common areas of difficulty with insertion of the device and solutions to these problems are also described. CONCLUSIONS: Insertion techniques for the Impella 5.0 are described in detail. PMID- 22437519 TI - Minimally invasive video-assisted epicardial lead cardiac resynchronization therapy for the dilated cardiomyopathy heart failure cases. AB - OBJECTIVE: Cardiac resynchronization therapy (CRT) with biventricular pacing has demonstrated cardiac function improvement in treating congestive heart failure. Traditional CRT through coronary sinus lead method is difficult to perform. Minimally invasive video-assisted epicardial lead (Epi-lead) CRT for the dilated cardiomyopathy heart failure cases was explored. METHODS: From April 2007 to June 2009, a total of 12 patients (age, 63 +/- 9 years) with depressed systolic left ventricular (LV) function (ejection fraction, <35%), left bundle branch block (mean QRS [Q wave, R wave, S wave], 158 +/- 15 milliseconds), and congestive heart failure of New York Heart Association class III/IV were enrolled. The patients received minimally invasive video-assisted epicardial steroid-eluting LV lead implantation for the CRT. The right atrial and right ventricle leads were implanted, guided by x-ray. The mean follow-up time was 13.7 months (range, 7-27 months). RESULTS: All patients received LV lead implantation at the most late activated site. The mean QRS duration decreased significantly from 158 +/- 15 to 124 +/- 11 milliseconds (P < 0.05). There was no surgical or hospital mortality in the entire series. The mean procedure duration (skin to skin) of the LV lead implantation was 52.4 +/- 15.8 minutes. The mean postoperative stay was 7.1 +/- 2.7 days. During the follow-up, cardiac function improved significantly in 11 patients. Threshold capture of the Epi-leads remained stable at 1.12 +/- 0.3 V/0.5 ms during the follow-up. None died during the follow-up. CONCLUSIONS: Surgical Epi-lead placement for the resynchronization therapy is a safe and reliable technique and should be considered as an equal alternative. PMID- 22437520 TI - Selective beta-1 receptor blockade further reduces the mechanically stabilized target coronary artery motion during beating heart surgery. AB - OBJECTIVE: Adequate stabilization of anastomosis sites during off-pump coronary artery bypass is essential to obtain excellent graft patency. We examined the effect of beta-1 adrenergic receptor blockade on the target coronary artery motion by three-dimensional (3D) digital motion capture and reconstruction technology. METHODS: Eight pigs underwent a sternotomy. Reflection markers were attached to the surface coronary arteries, followed by a mechanical stabilizer application. Two high-speed digital cameras captured two-dimensional (2D) motion of the markers from different angles. These 2D data were reconstructed into 3D data points, representing the motion of each coronary artery. Landiolol hydrochloride, a novel selective beta-1 receptor blocker, was infused intravenously after acquisition of control data. RESULTS: Beta-1 receptor blockade decreased heart rate (105 +/- 16 vs. 90 +/- 9 beat/min; P = 0.007) without decreasing arterial blood pressure. The 3D distance moved (millimeter) during one cardiac cycle was significantly reduced on the left anterior descending (9.6 +/- 2.8 vs. 6.6 +/- 1.9 mm; P = 0.003), left circumflex (10.5 +/- 6.3 vs. 6.4 +/- 2.6 mm; P = 0.038), and right coronary (8.3 +/- 3.6 vs. 6.5 +/- 2.1 mm; P = 0.028) arteries. Reduction in the maximal velocity, maximal acceleration, and maximal deceleration of the anastomosis site in all coronary arteries was also found in a quantitative fashion. CONCLUSIONS: Selective beta-1 receptor blockade significantly reduces the 3D motion at anastomosis sites on the beating heart, with stable systemic blood pressure. Further quantitative investigations of pharmacological stabilization are warranted to achieve better outcome of the patients undergoing off-pump coronary artery bypass surgery. PMID- 22437521 TI - Integrated cerebral protection: combined antegrade and retrograde cerebral perfusion during deep hypothermic circulatory arrest. AB - OBJECTIVE: Aortic arch surgery requires temporary interruption of cerebral perfusion. Hypothermic circulatory arrest (HCA) is an established method of central nervous system protection for limited periods of absent cerebral blood flow. Adjuncts to increase the safe duration of circulatory arrest include either retrograde cerebral perfusion (RCP) or antegrade cerebral perfusion (ACP), with most complex aortic operations now performed using HCA with ACP. We reasoned that optimal cerebral protection might be achieved with a combination of ACP and RCP (integrated brain protection) and present an early clinical experience that supports this approach. METHODS: The integrated brain protection strategy included sequential overlapping periods of RCP, ACP, and RCP during HCA. Moderate systemic hypothermia (25 degrees C) was used. Patient data were gathered through retrospective chart review. RESULTS: Between 2008 and 2009, six consecutive patients underwent ascending aortic graft replacement for acute type A dissection using HCA and integrated brain protection. The mean minimum systemic temperature was 22.9 +/- 1.8 degrees C, the mean total HCA time was 34 +/- 5 minutes, and the mean duration of ACP and RCP was 22 +/- 6 and 7 +/- 5 minutes, respectively. Patients were awake and followed commands 10.1 +/- 3.4 (range, 5-13) hours after operation, and there was no evidence of temporary neurologic dysfunction. There was no operative mortality. CONCLUSIONS: Integrated brain protection using both RCP and ACP during HCA is a promising approach for the safe performance of complex aortic surgery and is worthy of evaluation in larger clinical series. PMID- 22437522 TI - Histologic evaluation of stapled right atrial appendages with fabric buttressing. AB - OBJECTIVE: The aim of this study was to histologically evaluate the importance of using buttressing materials in stapling the atrial appendages. METHODS: We stapled the right atrial appendage with a commercial apparatus in 11 mongrel dogs. To evaluate the efficiency of using a buttressing material as an adjunct to stapling, we conducted 30-day studies without (group A: n = 2) or with buttressing material (group B: n = 3) and 90-day studies without (group C: n = 3) or with buttressing material (group D: n = 3) and thereafter made assessments using Doppler echocardiography and performed histologic analyses on all stapled appendages. RESULTS: During surgery, blood oozing from the stapling sites was observed in four of five cases of groups A and C; with buttressing, there was no oozing in groups B and D. In groups A and B, we observed the myocardium of the appendage being focally replaced with fibrous tissue. Myocardium in group C was infiltrated diffusely with loose fibrous tissue and in group D had been almost completely replaced with fibrous tissue. CONCLUSIONS: The buttressing material was useful not only in preventing oozing but also likely promoting the growth of fibrous tissue in the right atrial appendage. PMID- 22437523 TI - A novel surgical approach to cardiac autotransplantation in complex cardiac sarcoma resection. AB - A 28-year-old woman was admitted to our institution, reporting progressive dyspnea, cough, and weight loss of 14 kg. Two-dimensional echocardiography revealed a left atrial mass, and cardiac magnetic resonance imaging showed localized involvement of the mass with adjacent structures. These clinical signs and radiographic images were highly suggestive of cardiac sarcoma. The patient underwent emergent mediastinal exploration, and an incisional biopsy of the mass showed high-grade sarcoma. Removing the tumor required radical en bloc resection of the left atrium, including the mitral valve, the left pulmonary vein, and the left lower lobe of the lung. Autotransplantation was necessary for the resection and reconstruction. We report a unique method of handling the right atrium to avoid the potential complications associated with bicaval anastomoses after autotransplantation. PMID- 22437524 TI - The use of the Impella RD as a bridge to recovery for right ventricular dysfunction after cardiac transplantation. AB - Right ventricular failure after orthotopic heart transplantation is associated with significant mortality and morbidity. We report the use of a paracardiac microaxial pump, the Impella RD, as a bridge to recovery in a patient with right ventricular infarction after orthotopic heart transplantation. PMID- 22437525 TI - Combined treatment of traumatic aortic transection and Kommerell diverticulum. AB - We present the case of a 41-year-old male trauma patient admitted to the emergency department after being struck in a pedestrian versus a motor vehicle accident. Computed tomography revealed a traumatic transaction of the descending aorta with pseudoaneurysm and an aberrant right subclavian artery with Kommerell diverticulum. Surgical correction was accomplished with bilateral subclavian carotid bypass, with occlusion of both subclavian arteries followed by the placement of endovascular stent grafts to repair the aortic injury. PMID- 22437526 TI - Simultaneous robotic-assisted mitral valve repair and percutaneous coronary intervention. AB - We present a case report of a robotic-assisted mitral valve repair with simultaneous percutaneous coronary intervention. A 58-year-old man presented with New York Heart Association class III symptoms from severe mitral regurgitation and significant stenosis of the right coronary artery. In a hybrid operating theater, the patient underwent placement of a bare metal stent in the right coronary artery followed immediately by robotic-assisted mitral valve repair. Both procedures were successful and occurred in a timely fashion. The patient experienced no immediate postoperative complications and was discharged home on postoperative day 5. At 2-week follow-up, he had returned to his normal activities of daily living and at 1 year remained asymptomatic. This case report demonstrates the benefits of minimally invasive robotic mitral valve repair in allowing for successful repair, early postoperative return to activity, minimal incision pain, and high patient satisfaction. It further highlights the potential benefit of a hybrid operating theater in allowing surgical and percutaneous coronary intervention procedures to be delivered in a safe and efficient manner. PMID- 22437527 TI - Stentless aortic valve implantation through an upper manubrium-limited V-type ministernotomy. AB - In this piece of work, we attempt to highlight our approach and early experience with minimally invasive aortic valve replacement with aortic Freedom Solo stentless bioprosthesis performed through an upper manubrium-limited ministernotomy in the second intercostal space. The novel suturing technique is required for stentless aortic bioprosthesis implantation, and this, in its turn, will predetermine and influence the surgeon's choice for operative access. In our department, the feasibility of the approach was first assessed; aortic valve was replaced by stentless bioprosthesis in a total of 23 patients (mean age 57 +/- 12 years). In all cases, a cardiopulmonary bypass was established by a central ascending aorta cannulation and peripheral percutaneous venous cannula insertion. This approach was found to be technically reproducible and safe. The surgical technique used is described in this article. PMID- 22437528 TI - A novel technology for large vessel recanalization. AB - Large vessels recanalization is a challenge for mechanical atherectomy devices, where the lumen debulked is close in diameter to the device crossing profile, which may be only 25% to 30% of the original lumen size; so, the procedure can restore only a fraction of the original blood flow. Moreover, small diameter lumens are prone to be repeatedly occluded after a relatively short period of time. In this article, we present a novel technology of recanalization, using a catheter-based microjet system to deliver a flux of biocompatible abrasive particles to the lesion site, resulting in microchipping of the plaque, while minimizing trauma to the vessel wall. Plaque debris is removed from the blood flow, and blood flow is restored. In contrast to rotating mechanical devices, plaque debulking can be performed up to diameters that are substantially larger than the device crossing profile, supporting superior long-term patency. As a case study, we evaluated the technology for use in the superficial femoral artery where the lesions tend to be very long and heavily calcified with high restenosis rates. PMID- 22437529 TI - Fast neutron irradiation deteriorates hippocampus-related memory ability in adult mice. AB - Object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice exposed to cranial fast neutron irradiation (0.8 Gy) were examined to evaluate hippocampus-related behavioral dysfunction following acute exposure to relatively low doses of fast neutrons. In addition, hippocampal neurogenesis changes in adult murine brain after cranial irradiation were analyzed using the neurogenesis immunohistochemical markers Ki-67 and doublecortin (DCX). In the object recognition memory test and contextual fear conditioning, mice trained 1 and 7 days after irradiation displayed significant memory deficits compared to the sham-irradiated controls. The number of Ki-67- and DCX-positive cells decreased significantly 24 h post-irradiation. These results indicate that acute exposure of the adult mouse brain to a relatively low dose of fast neutrons interrupts hippocampal functions, including learning and memory, possibly by inhibiting neurogenesis. PMID- 22437530 TI - Elm tree bark extract inhibits HepG2 hepatic cancer cell growth via pro-apoptotic activity. AB - Control of inflammation is widely accepted as an important strategy for cancer chemoprevention. Anti-inflammatory effects of bark extracts of elm tree (BEE) have been amply reported. Therefore, BEE may be a good candidate cancer chemopreventive agent. Considering the high incidence of hepatic cancer and limited therapeutic approaches for treating this disease, it is important to develop liver cancer-specific chemopreventive agents. To evaluate the chemopreventive potential of BEE, we investigated the growth inhibition effect of BEE on the HepG2 human hepatocellular carcinoma cell line. We performed a cell counting kit-8 assay to determine cell viability, and 4,6-diamino-2-phenylindole staining and flow cytometry to measure apoptotic cell death. Finally, the expression levels of pro- and anti-apoptotic proteins were measured. BEE inhibited the growth of HepG2 cells and induced apoptosis in a dose-dependent manner. Pro-apoptotic activity was promoted via the mitochondrial pathway of apoptosis, as demonstrated by the activation of pro-apoptotic proteins Bax, caspase-9, caspase-3, and poly (ADP-ribose) polymerase as well as the down regulation of the anti-apoptotic protein Bcl-2. These results suggest that BEE may have potential use in hepatic cancer chemoprevention by suppressing cancer cell growth via pro-apoptotic activity. PMID- 22437531 TI - Prevalence and molecular characterization of Cryptosporidium spp. in dairy cattle from farms in China. AB - Fecal samples of 2,056 dairy cattle from 14 farms were collected in three geographical regions of China and stained using a modified acid-fast staining technique to identify Cryptosporidium oocysts. A total of 387 (18.82%) positive samples were identified and further analyzed by polymerase chain reaction (PCR) using primers designed to amplify DNA fragments from the small subunit ribosomal RNA. The PCR products were sequenced and the sequences were deposited in the GenBank database under accession numbers EU369377-84 and GU070730-33. Phylogenetic analysis was performed and a distances matrix generated from these sequences confirmed the existence of Cryptosporidium (C.) parvum 'mouse' genotype, C. bovis, C. andersoni, C. hominis, and C. serpentis in cattle. These results represent the first report on the prevalence and genetic identification of Cryptosporidium species, and may contribute to a better understanding of the epidemiology of Cryptosporidium in cattle in China. PMID- 22437532 TI - Immunomodulatory effects of human amniotic membrane-derived mesenchymal stem cells. AB - Human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) are capable of differentiating into several lineages and possess immunomodulatory properties. In this study, we investigated the soluble factor-mediated immunomodulatory effects of hAM-MSCs. Mitogen-induced peripheral blood mononuclear cell (PBMC) proliferation was suppressed by hAM-MSCs in a dose-dependent manner as well as hAM-MSC culture supernatant. Moreover, interferon-gamma and interleukin (IL)-17 production significantly decreased from PBMC, whereas IL-10 from PBMCs and transforming growth factor beta (TGF-beta) production from hAM-MSCs significantly increased in co-cultures of hAM-MSCs and PBMCs. Production of several MSC factors, including hepatocyte growth factor (HGF), TGF-beta, prostaglandin E2 (PGE2), and indoleamine 2, 3 dioxygenase (IDO), increased significantly in hAM MSCs co-cultured with PBMCs. These results indicate that the immunomodulatory effects of hAM-MSCs may be associated with soluble factors (TGF-beta, HGF, PGE2, and IDO), suggesting that hAM-MSCs may have potential clinical use in regenerative medicine. PMID- 22437533 TI - The effect of conglutinin on production of reactive oxygen species in bovine granulocytes. AB - Conglutinin is a high molecular-weight lectin originally detected in bovine serum. It belongs to the family of collectins that bind sugar residues in a Ca(2+)-dependent manner and are effector molecules in innate immunity. Conglutinin appears to play an important role in immune defense mechanisms, showing antiviral and antibacterial activities when tested in vivo and in vitro. The present study evaluated the effect of conglutinin on the respiratory bursts in bovine peripheral phagocytes. Using nitroblue tetrazolium and hydrogen peroxide assays, we showed that sugar ligand-bound conglutinin stimulated the production of superoxide and H2O2 in granulocytes whereas the non-sugar-bound form of conglutinin inhibited these processes. These results indicate that both forms of conglutinin are able to interact with surface leukocyte receptors but have opposite effects on phagocytic activity. Our findings suggest that conglutinin bound to sugar residues on microbial surfaces can induce oxygen burst in phagocytes, and thereby mediates the elimination of pathogens and prevents the spread of infection. PMID- 22437534 TI - Alpha basic crystallin expression in canine mammary tumors. AB - The aim of this study was to evaluate prognostic and/or diagnostic factors of canine mammary tumors by immunohistochemically analyzing the expression of alpha basic crystallin (alphaB-c). For this, formalin-fixed, paraffin-embedded blocks of 51 naturally-occurring canine mammary tumors (11 benign and 40 malignant) were used. Tissue from eight normal canine mammary glands were served as a control. Immunohistochemically, in the control mammary tissues, a few luminal epithelial cells were alphaB-c positive but myoepithelial cells were negative. In benign or simple type malignant tumors, alphaB-c expression was observed in luminal epithelial cells while the myoepithelial basal cells were negative. In benign or complex type malign tumors, positive staining was predominantly found in the cytoplasm of epithelial cells. Immunoreactivity of alphaB-c was also observed in neoplastic myoepithelial cells. Statistically, the number of cells immunolabeled with alphaB-c was found to be significantly different among tissues from normal canine mammary glands, benign lesions, and malignant tumors (p < 0.05). alphaB-c immunoreactivity was higher in malignant tumors than the control mammary tissues (p < 0.001). Data obtained in the current study revealed a strong association between high expression levels of alphaB-c and primary mammary gland tumors in canines. PMID- 22437535 TI - Comparison of four diagnostic methods for detecting rabies viruses circulating in Korea. AB - It is essential to rapidly and precisely diagnose rabies. In this study, we evaluated four diagnostic methods, indirect fluorescent antibody test (FAT), virus isolation (VI), reverse transcriptase polymerase chain reaction (RT-PCR), and rapid immunodiagnostic assay (RIDA), to detect rabies in animal brain homogenates. Out of the 110 animal brain samples tested, 20 (18.2%) were positive for rabies according to the FAT. Compared to the FAT, the sensitivities of VI, RT PCR, and RIDA were 100, 100, and 95%, respectively. The specificities of VI, RT PCR and RIDA were found to be 100, 100, and 98.9%, respectively. Rabies viruses circulating in Korea were isolated and propagated in murine neuroblastoma (NG108 15) cells with titers ranging from 10(1.5) to 10(4.5) TCID(50)/mL. Although the RIDA findings did not completely coincide with results obtained from FAT, VI, and RT-PCR, RIDA appears to be a fast and reliable assay that can be used to analyze brain samples. In summary, the results from our study showed that VI, RT-PCR, and RIDA can be used as supplementary diagnostic tools for detecting rabies viruses in both laboratory and field settings. PMID- 22437536 TI - Cloning and characterization of a selenium-independent glutathione peroxidase (HC29) from adult Haemonchus contortus. AB - The complete coding sequence of Haemonchus (H.) contortus HC29 cDNA was generated by rapid amplification of cDNA ends in combination with PCR using primers targeting the 5'- and 3'-ends of the partial mRNA sequence. The cloned HC29 cDNA was shown to be 1,113 bp in size with an open reading frame of 507 bp, encoding a protein of 168 amino acid with a calculated molecular mass of 18.9 kDa. Amino acid sequence analysis revealed that the cloned HC29 cDNA contained the conserved catalytic triad and dimer interface of selenium-independent glutathione peroxidase (GPX). Alignment of the predicted amino acid sequences demonstrated that the protein shared 44.7~80.4% similarity with GPX homologues in the thioredoxin-like family. Phylogenetic analysis revealed close evolutionary proximity of the GPX sequence to the counterpart sequences. These results suggest that HC29 cDNA is a GPX, a member of the thioredoxin-like family. Alignment of the nucleic acid and amino acid sequences of HC29 with those of the reported selenium-independent GPX of H. contortus showed that HC29 contained different types of spliced leader sequences as well as dimer interface sites, although the active sites of both were identical. Enzymatic analysis of recombinant prokaryotic HC29 protein showed activity for the hydrolysis of H(2)O(2). These findings indicate that HC29 is a selenium-independent GPX of H. contortus. PMID- 22437537 TI - Induction of humoral responses to BHV-1 glycoprotein D expressed by HSV-1 amplicon vectors. AB - Herpes simplex virus type-1 (HSV-1) amplicon vectors are versatile and useful tools for transferring genes into cells that are capable of stimulating a specific immune response to their expressed antigens. In this work, two HSV-1 derived amplicon vectors were generated. One of these expressed the full-length glycoprotein D (gD) of bovine herpesvirus 1 while the second expressed the truncated form of gD (gDtr) which lacked the trans-membrane region. After evaluating gD expression in the infected cells, the ability of both vectors to induce a specific gD immune response was tested in BALB/c mice that were intramuscularly immunized. Specific serum antibody responses were detected in mice inoculated with both vectors, and the response against truncated gD was higher than the response against full-length gD. These results reinforce previous findings that HSV-1 amplicon vectors can potentially deliver antigens to animals and highlight the prospective use of these vectors for treating infectious bovine rhinotracheitis disease. PMID- 22437538 TI - Effect of oxytocin infusion on luteal blood flow and progesterone secretion in dairy cattle. AB - The objective of this study was to investigate the effects of oxytocin infusion on corpus luteum (CL) function during early to mid-diestrus by measuring luteal size (LS) and luteal blood flow (LBF) along with plasma levels of progesterone (P4) and prostaglandin metabolites (13,14-dihydro-15-keto-prostaglandin F(2alpha), PGFM). On day (D) 7 of the estrus cycle (D1 = ovulation), seven cows received 100 IU of oxytocin (OXY) or placebo (PL) following a Latin square design. LS and LBF increased in both groups over time and no differences were observed between the groups. PGFM did not differ either within the groups over time or between the groups at any time point. P4 of the OXY group was higher compared to that of the the PL group 360 min after the infusion (p = 0.01) and tended to be higher at the time points 450 min, 48 h, and 72 h (all p = 0.08). Results from this study support the hypothesis that OXY is not directly involved in the mechanism(s) governing blood flow of the CL and has no remarkable effects either on luteal size or P4 and PGFM plasma levels. Further investigation is needed to elucidate the role of OXY in CL blood flow during early and late luteal phases. PMID- 22437539 TI - Development and characterization of a potential diagnostic monoclonal antibody against capsid protein VP1 of the chicken anemia virus. AB - Chicken anemia virus (CAV) is an important viral pathogen that causes anemia and severe immunodeficiency syndrome in chickens worldwide. In this study, a potential diagnostic monoclonal antibody against the CAV VP1 protein was developed which can precisely recognize the CAV antigen for diagnostic and virus recovery purposes. The VP1 gene of CAV encoding the N-terminus-deleted VP1 protein, VP1Nd129, was cloned into an Escherichia (E.) coli expression vector. After isopropyl-beta-D-thiogalactopyronoside induction, VP1Nd129 protein was shown to be successfully expressed in the E. coli. By performing an enzyme-linked immunoabsorbent assay using two coating antigens, purified VP1Nd129 and CAV infected liver tissue lysate, E3 monoclonal antibody (mAb) was found to have higher reactivity against VP1 protein than the other positive clones according to the result of limiting dilution method from 64 clones. Using immunohistochemistry, the presence of the VP1-specific mAb, E3, was confirmed using CAV-infected liver and thymus tissues as positive-infected samples. Additionally, CAV particle purification was also performed using an immunoaffinity column containing E3 mAb. The monoclonal E3 mAb developed in this study will not only be very useful for detecting CAV infection and performing histopathology studies of infected chickens, but may also be used to purify CAV particles in the future. PMID- 22437540 TI - Establishment and characterization of an infectious cDNA clone of a classical swine fever virus LOM strain. AB - Classical swine fever virus (CSFV) causes a highly contagious disease among swine that has an important economic impact worldwide. CSFV strain LOM is an attenuated virus of low virulent strain of Miyagi isolated from Japan in 1956. Eight DNA fragments representing the genome of the CSFV strain LOM were obtained by RT-PCR. These were used to determine the complete nucleotide sequence and construct a full-length cDNA clone which was called Flc-LOM. Sequence analysis of the recombinant clone (Flc-LOM) revealed the presence of eight mutations, resulting in two amino acid substitutions, when compared to the parental sequence. RNA transcripts of both LOM and Flc-LOM were directly infectious in PK-15 cells. The rescued Flc-LOM virus grew more slowly than the parental virus, LOM, in the cells. Intramuscular immunization with Flc-LOM was safe and highly immunogenic in pigs; no clinical signs or virus transmission to sentinel animals were observed after 35 days. CSFV-specific neutralizing antibodies were detected 14 days post infection. After challenge with the virulent CSFV strain SW03, pigs immunized with Flc-LOM were shown to be fully protected. Thus, our newly established infectious clone of CSFV, Flc-LOM, could serve as a vaccine candidate. PMID- 22437541 TI - Biceps femoris muscle transposition for treatment of cranial cruciate ligament rupture in small breed dogs. AB - The purpose of this study was to evaluate a new extracapsular surgical technique for the treatment of cranial cruciate ligament rupture in small breed dogs. Nine small breed dogs (seven females and two males) weighing <= 15 kg were treated with biceps femoris muscle transposition (BFT). The duration of the BFT procedure was 20 min. Each patient underwent a standard clinical protocol and a questionnaire for the owners. Follow-up (at 1, 3, and 12 months postoperative) confirmed significant improvement in all patients, especially at 1 month postoperatively (p < 0.01) and again after complete stifle joint assessment at 3 months postoperatively. After 12 months, only two patients showed a slight increase in osteoarthritis. According to our results, BFT is a simple extracapsular surgical technique that can be used for the treatment of cranial cruciate ligament rupture in small breed dogs. PMID- 22437542 TI - Evaluation and comparison of native and recombinant LipL21 protein-based ELISAs for diagnosis of bovine leptospirosis. AB - A 21-kDa leptospiral lipoprotein (LipL21) was evaluated for its diagnostic potential to detect bovine leptospirosis by ELISA. Both native LipL21 (nLipL21) and recombinant LipL21 (rLipL21) proteins were tested and compared regarding diagnostic efficiency, and no statistically significant difference was observed. The sensitivity of rLipL21 ELISA for 62 microscopic agglutination test (MAT) positive sera was 100% and the specificity with 378 MAT negative sera was 97.09%. Thus, rLipL21 protein-based ELISA could be used as an alternative to MAT for the diagnosis of bovine leptospirosis. PMID- 22437543 TI - Prevalence and antibiotic resistance of mastitis pathogens isolated from dairy herds transitioning to organic management. AB - Changes in udder health and antibiotic resistance of mastitis pathogens isolated from dairies upon conversion from conventional to organic management over a 3 year period was studied. Coagulase-negative staphylococci (CNS) were the most prevalent mastitis pathogens isolated. CNS were significantly less resistant to beta-lactam antibiotics when isolated from milk after the herd transitioned to organic management. Cessation of the use of antimicrobial therapies in dairies in combination with organic management could lead to a reduction in the antimicrobial resistance of mastitis pathogens. PMID- 22437544 TI - Histopathological and biochemical findings of congenital copper deficiency: are these similar to those of caprine arthritis-encephalitis? AB - This study was done after identifying animals with a twisted carpal joint in goat herd. These included a kid goat walking on its articulus carpii and a newborn goat with a stiff leg. Necropsies of the diseased goats revealed swollen carpal joints that were twisted backwards. Arthritis was observed during microscopic examination of the carpal joints. Very low levels of eosinophil, leucocyte, and lymphocyte cell infiltration were found in the central nervous system and meninges. Serum copper levels were significantly decreased in most of the animals. All of these results led us to diagnose the animals with swayback disease. PMID- 22437545 TI - Superatomic orbitals in sixteen-coordinate M@Li16 bonded by metallic bonds. AB - Based on density-functional calculation and genetic algorithm structure search, we propose a series of 16-coordinate core-shell clusters: M@Li(16)(M = Ca, Sr, Ba, Ti, Zr, Hf). A tetrahedral (T(d)) structure with an outer shell of 16 lithium atoms and one enclosed heavy atom is found to be the global minimum in the structural exploration of BaLi(16) based on genetic algorithm. This structure also has lower energy compared to the other isomers we employed in all the MLi(16) clusters. In this structure, the atoms are bonded together by metallic bonds with alkali (IA) and alkaline-earth (IIA) metal atoms. Their corresponding first electronic shells are closed with significant energy gaps because their total numbers of valence electrons fulfil the 18-electron rule. Such a combination could be extended to 20-electron systems by enclosing IVB elements. With simple valence electrons and highly symmetric structures, superatomic molecular orbitals are identified in all of the T(d) clusters. PMID- 22437546 TI - Impact of emotional and behavioral symptoms on quality of life in children and adolescents. AB - PURPOSE: To evaluate how levels of anxiety, depressive and behavioral symptoms influence self-perceived quality of life (QOL) in general population of children and adolescents. METHOD: A total of 237 children and adolescents aged 8-18 years participated in the study. The Screen for Child Anxiety Related Emotional Disorders Questionnaire (SCARED), Short Mood and Feeling Questionnaire (SMFQ) and Strengths and Difficulties Questionnaire (SDQ) were used to assess levels of anxiety, depressive and behavioral symptoms, respectively. The Pediatric Quality of Life Inventory (PedsQL) was used for QOL assessments. In a regression model, the PedsQL score was the dependent variable, while anxiety, depressive and behavioral symptoms were the QOL predictors. RESULTS: In children, the SCARED and SMFQ scores together with age and gender explained 30 % of the variance in the PedsQL scores (F = 12.31, p < 0.001), while in adolescents, the same set of variables was responsible for 36 % of the variance (F = 15.77, p < 0.001). The SCARED was a more significant predictor than the SMFQ. The SDQ scores did not emerge as the PedsQL predictors. CONCLUSION: Levels of anxiety and depressive symptoms, but not behavioral ones, significantly affect self-reported QOL in general population of children and adolescents. PMID- 22437547 TI - Water soluble polyperoxides from 2-(2-methoxyethoxy)ethyl methacrylate: influence of molecular oxygen on thermoresponsive properties and thermal degradation. AB - The 2-(2-methoxyethoxy)ethyl methacrylate and molecular oxygen react at 50 degrees C under high pressure in the presence of a radical initiator to give water soluble, thermoresponsive poly(2-(2-methoxyethoxy)ethyl methacrylate) peroxide (PMEO(2)MAP), which degrades highly exothermically. The polymer structure has been confirmed by spectroscopy, elemental analysis, calorimetry and mass spectrometry. PMID- 22437548 TI - Does the contact time of alginate with plaster cast influence its properties? AB - The aim of this study was to verify the influence of the time of contact between alginate and gypsum after the modeling procedure on the properties of the plaster cast, such as surface detail, dimensional stability and microhardness. Thirty cylindrical specimens of orthodontic gypsum Type III were made by means of impressions of a stainless steel master model which had five reference lines in the upper surface. The samples were divided into two groups: Group 1 (G1) - with time of contact of 1 hour; and Group 2 (G2) - 12 hours of contact. All the specimens were stored up to 48 hours until they underwent laboratory testing. Surface detail and dimensional stability were tested by one calibrated examiner using a visual analysis and a profilometer (Profile Projector Nikon model 6C, Nikon Corporation, Tokyo, Japan), respectively, to evaluate the quality of reproduction of the lines and the distances between them. The microhardness was determined for each sample by making six indentations with a Vickers diamond pyramid indenter (Buehler, Lake Bluff, USA) under a load of 100 gF for 15 s. The results showed significant difference (P <= 0.05) between groups in two of the three properties examined: surface detail and microhardness, which decreased as the time of contact rose. The 12-hour time of contact between alginate and the plaster cast is not recommended because it influences the quality of the plaster cast. PMID- 22437549 TI - Fracture resistance of teeth restored with different resin-based restorative systems. AB - The aim of the present study was to evaluate the fracture resistance of teeth restored with resin composite. Forty-eight maxillary premolar teeth were chosen and randomly divided to six groups: G1 (control): sound teeth; G2: MOD preparation, unrestored; G3: MOD + Adper Single Bond 2/P60; G4: MOD + Adper Easy One/P60; G5: MOD + P90 restorative system; G6: MOD + Adper Easy One/P90 Bond/P90. Specimens were subjected to compressive axial loading (0.5 mm/min). Flexural strength and the modulus of elasticity were also tested (n = 7). The only statistical equivalence with sound teeth was noted for G3 (p < 0.05). Flexural strength and the modulus of elasticity varied among the composites tested (n = 10). The reestablishment of the resistance to fracture in premolars subjected to Class II MOD preparations is restorative-system-dependent. The silorane restorative system is not able to recover the resistance to fracture. PMID- 22437550 TI - Determination of segregation tendency of granules using surface imaging. AB - In this study, powder surface imaging was utilized in evaluation of particle size related segregation behavior of granules during vibration and tableting processes. Altogether, eight granule batches were manufactured using a fluidized bed granulator. The particle size distribution of each batch was measured with sieve and image analysis. Segregation tendency of the batches was studied by a vibrational measurement setup. In addition, segregation during tableting was studied by taking samples during the tableting process. Image analysis was utilized to analyze the segregation in both cases. Roughness parameters (Ra) were calculated from images taken during simulation of segregation. In addition, weight variation of tablets was calculated. Finally, principal component analysis was used to visualize the effect of specific particle size fractions on segregation tendency of granules. According to the results, a broad particle size distribution and large particle size can inflict problems during tableting. Surface imaging was an efficient method to monitor the segregation tendency of granules during vibration and tableting. In addition, the segregation tendency of a granular material can be directly linked to weight variation of tablets during tableting and thus be used in a predictive manner. PMID- 22437551 TI - Fluctuating asymmetry and masculinity/femininity in humans: a meta-analysis. AB - Theory predicts that if particular morphological features correlate with "genetic" quality--i.e., mating with individuals bearing those characteristics increases fitness--selection favors preferences for these features. Both developmental instability (DI)--which emerges morphologically as small random deviations from perfect symmetry, i.e., fluctuating asymmetry (FA)--and sexually dimorphic traits due to variation in sex hormones, like facial masculinity and digit ratios, may reflect mate quality and/or relate to attractiveness. Therefore, FA and morphological expressions of sex hormones may represent interrelated measures/signals of individual quality. This article presents a meta analysis of these associations, including 44 effect sizes from 16 studies. Mean effect size (Pearson correlation) was nearly zero (r = .04, SE = 0.05). Largest effect sizes occurred for the few studies measuring sex hormone levels directly. This result was, however, unexpected since there is little evidence that hormone levels determined at a single time point would accurately reflect masculinity/femininity. Facial masculinity/femininity, which contains information on the functioning of the endocrine system, did not relate to DI (average effect size: r = .01, SE = 0.04). In spite of a substantial body of literature, there is little evidence for a robust association between DI and sexual dimorphism. Nevertheless, estimates of average effect sizes in DI showed wide confidence intervals. It is, therefore, premature to draw general conclusions in any direction. Further research is clearly required both to study associations between DI and sexual dimorphic morphological traits and the link between these dimorphic traits and levels of reproductive hormones. PMID- 22437552 TI - Analysis of the local structure of phosphorus-substituted LAMOX oxide ion conductors. AB - The effect of partial substitution of molybdenum by phosphorus on the global and local structural arrangement of the fast oxide-ion conductor La(2)Mo(2)O(9) (LAMOX) has been studied by X-ray powder diffraction as well as (139)La and (31)P solid state NMR. The diffraction patterns show that La(2)Mo(2-y)P(y)O(9-y/2) forms a solid solution at low phosphorus concentrations, and that there is a structural phase transition upon increasing phosphorus concentration. This phase transition is also reflected in (139)La and (31)P NMR spectra. The possibility to excite (31)P multiple-quantum coherences of one of the (31)P NMR signals gives evidence of an accumulation of phosphorus atoms on neighbouring Mo-type sites already before formation of three-dimensional precipitates. On the basis of our X ray and NMR results we propose a possible structural arrangement of the compound La(2)Mo(2-y)P(y)O(9-y/2) that explains the experimental observations by crystal twinning. PMID- 22437553 TI - Alkylresorcinol metabolite concentrations in spot urine samples correlated with whole grain and cereal fiber intake but showed low to modest reproducibility over one to three years in U.S. women. AB - Two alkylresorcinol (AR) metabolites, 3, 5-dihydroxybenzoic acid (DHBA) and 3 (3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), in urine have been suggested as biomarkers of whole grain (WG) and cereal fiber intake but the long-term reproducibility and correlation with habitual intake has not been determined. Therefore, we evaluated the long-term reproducibility of AR metabolites in spot urine samples and investigated their correlation with habitual WG and cereal fiber intake in U.S. women. AR metabolites were analyzed in 104 women participating in the Nurses' Health Study II and WG and fiber intakes were assessed using a FFQ. Long-term reproducibility was assessed by calculating the intra-class correlation coefficients (ICC) using samples taken 1-3 y (mean 1.8 y) apart. The observed Spearman correlation coefficients (r(s)) and r(s) adjusted for within-participant variation in the biomarker were calculated between WG and fiber intake and biomarkers. The long-term reproducibility was poor for DHBA [ICC = 0.17 (95% CI: 0.05, 0.43)] and modest for DHPPA [ICC = 0.31 (95% CI: 0.17, 0.51)]. The correlation between WG intake in 1995 and DHPPA measured 2 y later was 0.37 (P < 0.0001); the adjusted correlation was 0.60 (95% CI: 0.37, 0.76). Cereal fiber and WG intake were similarly correlated to the biomarkers. DHPPA in spot urine samples reflected WG intake despite relatively low intake of food sources of AR. The poor to modest reproducibility may limit the use of single measurements of these biomarkers in cohort studies in the US, where WG intake is relatively low and has changed over time. But DHPPA in repeated samples may be useful for validating WG intake and assessing compliance in WG intervention studies. PMID- 22437554 TI - Genome-wide association study identifies three common variants associated with serologic response to vitamin E supplementation in men. AB - Vitamin E inhibits lipid peroxidation in cell membranes, prevents oxidative damage to DNA by scavenging free radicals, and reduces carcinogen production. No study to our knowledge, however, has examined the association between genetic variants and response to long-term vitamin E supplementation. We conducted a genome-wide association study (GWAS) of common variants associated with circulating alpha-tocopherol concentrations following 3 y of controlled supplementation. The study population included 2112 middle-aged, male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort who received a trial supplementation of alpha-tocopherol (50 mg/d) and had fasting serum alpha tocopherol concentrations measured after 3 y. Serum concentrations were log transformed for statistical analysis and general linear models adjusted for age, BMI, serum total cholesterol, and cancer case status. Associations with serum response to alpha-tocopherol supplementation achieved genome-wide significance for 2 single nucleotide polymorphisms (SNP): rs964184 on 11q23.3 (P = 2.6 * 10( 12)) and rs2108622 on 19pter-p13.11 (P = 2.2 * 10(-7)), and approached genome wide significance for one SNP, rs7834588 on 8q12.3 (P = 6.2 * 10(-7)). Combined, these SNP explain 3.4% of the residual variance in serum alpha-tocopherol concentrations during controlled vitamin E supplementation. A GWAS has identified 3 genetic variants at different loci that appear associated with serum concentrations after vitamin E supplementation in men. Identifying genetic variants that influence serum nutrient biochemical status (e.g., alpha tocopherol) under supplementation conditions improves our understanding of the biological determinants of these nutritional exposures and their associations with cancer etiology. PMID- 22437555 TI - Supplemental dietary folic acid has no effect on chromosome damage in erythrocyte progenitor cells of mice. AB - Folate deficiency can cause chromosome damage, which could result from reduced de novo thymidylate synthesis or DNA hypomethylation. High folic acid intake has been hypothesized to inhibit folate-dependent one-carbon metabolism, which could also lead to DNA damage. A large proportion of the general population may have high folic acid intakes. In this study, 2 experiments were conducted to examine the effects of folate on chromosome damage. First, male mice were fed folic acid deficient (D) (0 mg folic acid/kg diet), control (C) (2 mg/kg), or folic acid supplemented (S) (6 mg folic acid/kg diet) diets from weaning to maturity. Second, female mice were fed the D, C, or S diet throughout pregnancy, lactation, and breeding for 3 generations; male mice from the F3 generation were fed the same diet as their mothers from weaning, producing D, C, and S F3 male mice. RBC micronucleus frequencies, a measure of chromosome damage or aneuploidy, were determined for both experimental groups. In mice fed diets from weaning to maturity, erythrocyte micronucleus frequency was 24% greater in D compared with C mice. F3 mice fed diet D had 260% and 174% greater reticulocyte and erythrocyte micronucleus frequencies compared with F3 C mice, respectively. The S diets did not affect micronucleus frequency, suggesting that excess folic acid at this level does not promote or protect against chromosome damage. The results suggest that chronic exposure to folic acid at the levels similar to those achieved through fortification is unlikely to be clastogenic or aneugenic. PMID- 22437556 TI - Multiple micronutrient-fortified rice affects physical performance and plasma vitamin B-12 and homocysteine concentrations of Indian school children. AB - Fortifying rice with multiple micronutrients could be a promising strategy for combat micronutrient deficiencies in developing countries. We determined the efficacy of extruded rice grains fortified with multiple micronutrients on the prevalence of anemia, micronutrient status, and physical and cognitive performance in 6- to 12-y-old, low-income school children in Bangalore, India. In a randomized, double-blind, controlled trial, 258 children were assigned to 1 of 3 intervention groups to receive rice-based lunch meals fortified with multiple micronutrients with either low-iron (6.25 mg) or high-iron (12.5 mg) concentrations or identical meals with unfortified rice. The meals were provided 6 d/wk for 6 mo. Anthropometric, biochemical, physical performance, and cognitive assessments were taken at baseline and endpoint. At baseline, study groups were comparable, with 61% of the children being anemic. However, only <10% were deficient in iron, vitamin A, and zinc. After 6 mo, plasma vitamin B-12 and homocysteine concentrations (both P < 0.001) as well as physical performance (P < 0.05) significantly improved in the intervention arms. No between-group differences were observed in hemoglobin concentration, anemia, and deficiencies of other micronutrients or cognitive function after 6 mo, but paired analyses revealed a small reduction in anemia prevalence in children in the low-iron group. The fortified rice was efficacious in improving vitamin B-12 status and physical performance in Indian school children. PMID- 22437557 TI - Changes in measurement procedure from a radioassay to a microbiologic assay necessitate adjustment of serum and RBC folate concentrations in the U.S. population from the NHANES 1988-2010. AB - The NHANES measured serum and RBC folate concentrations by using a radioassay during prefortification (1988-1994) and postfortification (1999-2006) periods followed by the use of a microbiologic assay (MBA) from 2007-2010. The MBA produces higher concentrations than does the radioassay and is considered to be more accurate. To allow for accurate long-term trending (1988-2010), we evaluated different regression models (linear, piecewise linear, and fractional polynomial) to assay-adjust the radioassay results to be comparable to the MBA results. The data used to derive the regression models originated from 2 crossover studies in which the 2 assays were applied to a set of 325 serum and 171 whole-blood samples. Fractional polynomial regression of logarithmically transformed data provided the best fit for serum folate. Linear regression of logarithmically transformed whole-blood data provided an equally good fit compared with the other models and was the simplest to apply for RBC folate. Prefortification serum and RBC folate geometric mean concentrations increased after adjustment from 13.0 to 16.7 nmol/L and from 403 to 747 nmol/L, respectively. Postfortification serum folate concentrations increased from ~30 to ~43 nmol/L, and RBC folate concentrations increased from ~600 to ~1100 nmol/L after adjustment, with some variation across survey cycles. The presented regression equations allow the estimation of more accurate prevalence estimates and long-term trends in blood folate concentrations in the U.S. population by using results that are equivalent to the MBA. This information will be useful to public health officials in the United States who are dealing with folic acid fortification issues. PMID- 22437558 TI - Age group and sex do not influence responses of vitamin K biomarkers to changes in dietary vitamin K. AB - Inadequate vitamin K intake has been associated with abnormal soft tissue calcification. Older adults may have insufficient intakes of vitamin K and respond less to vitamin K supplementation compared with younger adults. However, little is known about the determinants that influence the response to vitamin K supplementation. Our primary objective was to assess dietary and nondietary determinants of vitamin K status in healthy younger and older adults. In a nonrandomized, nonmasked study, 21 younger (18-40 y) and 21 older (55-80 y) men and women consumed a baseline diet (200 MUg phylloquinone/d) for 5 d, a phylloquinone-restricted diet (10 MUg phylloquinone/d) for 28 d, and a phylloquinone-supplemented diet (500 MUg phylloquinone/d) for 28 d. Changes in vitamin K status markers in response to vitamin K depletion and repletion were studied and the influences of BMI, body fat, and circulating TG were assessed by including them as covariates in the model. Despite baseline differences in measures of vitamin K status, plasma phylloquinone tended to increase (P = 0.07) and the percentage of uncarboxylated osteocalcin and uncarboxylated prothrombin both improved with phylloquinone supplementation (P < 0.007), regardless of age group or sex. Only the excretion of urinary menadione, a vitamin K metabolite, was greater among younger adults in response to depletion than in older adults (P = 0.012), regardless of sex. Adiposity measures and circulating TG did not predict response of any measures. In conclusion, poor vitamin K status can be similarly improved with vitamin K supplementation, regardless of age group or sex. PMID- 22437559 TI - Deuterium-labeled phylloquinone has tissue-specific conversion to menaquinone-4 among Fischer 344 male rats. AB - Phylloquinone (PK) is converted into menaquinone-4 (MK-4) via side chain removal addition. Stable isotope use is an effective approach to identify the tissue location of this conversion, which is currently unknown. Following a 14-d PK deficient diet, male Fischer 344 rats (8 mo; n = 15) were fed 1.6 mg deuterium labeled PK (L-PK) per kg diet for 0 (control), 1 d (PK-1d), and 7 d (PK-7d). Both L-PK and deuterium-labeled MK-4 (L-MK-4) were detected in tissues in PK-1d and PK 7d, although the results varied. Whereas some tissues had an overall increase in MK-4 in response to L-PK, total brain, testes, and fat MK-4 concentrations did not. In contrast, L-MK-4 concentrations increased in all 3 tissues. The deuterium label was found only on the L-MK-4 naphthoquinone ring, confirming the need for side chain removal for the formation of MK-4. Labeled menadione (MD) was detected in urine and serum in PK-1d and PK-7d, confirming its role as an intermediate. A Caco-2 cell monolayer model was used to study the role of the enterocytes in the conversion process. Neither MK-4 nor MD was detected in Caco-2 cells treated with PK. However, when Caco-2 cells were treated with MD, MK-4 was formed. Similarly, MK-4 was formed in response to MD-treated 293T kidney cells, but not HuH7 liver cells. These data demonstrate that MK-4 is the predominant form of vitamin K in multiple tissues, but there appears to be a tissue-specific regulation for the conversion of PK to MK-4. PMID- 22437560 TI - Central adiposity and protein intake are associated with arterial stiffness in overweight children. AB - Being overweight is associated with vascular abnormalities, which are important in the development of atherosclerosis. However, little is known about dietary and lifestyle determinants of vascular function in overweight children. In adults, dietary protein and milk intake are associated with reduced blood pressure and reduced risk of metabolic syndrome. This study examined the associations between dietary protein, milk intake, physical activity, and adiposity on arterial stiffness in overweight children. In a cross-sectional study, overweight children with habitual milk intakes <= 250 mL/d were examined by DXA scans, pedometer counts, anthropometry, and metabolic variables. Dietary intake was registered for 4 d. The outcomes were arterial stiffness measured by pulse wave velocity (PWV) (n = 182) and augmentation index (Aix) (n = 183). The PWV (mean +/- SD) was 4.78 +/- 0.72 m/s and the Aix was -0.77 +/- 9.44%. In multivariate models, the android fat:gynoid fat and android fat:body fat ratios were positively associated with PWV (beta = 1.49 and beta = 10.3, both P < 0.05) and Aix (beta = 28.3, P < 0.01 and beta = 153, P < 0.05), whereas the gynoid fat:body fat ratio was negatively associated with the Aix (beta = -134; P < 0.001). Protein intake (percentage energy) was positively associated with PWV (beta = 0.05; P < 0.01). Milk intake (L/d) tended to be negatively associated with PWV (beta = -0.64; P = 0.05). Pedometer counts were negatively associated with the Aix; however, the association became nonsignificant after controlling for HOMA, which was positively associated with the Aix (beta = 0.95; P < 0.01). In conclusion, central adiposity and protein intake are associated with increased arterial stiffness measured as PWV in overweight children independent of blood pressure and heart rate. The effect of protein intake may be caused by meat, because the milk intake was low. PMID- 22437561 TI - Serum retinol is associated with stage of pregnancy and the acute phase response in pregnant women in Guinea-Bissau. AB - Vitamin A deficiencies in pregnancy may impair the health of the mother and the growth, development, and later health of her offspring. However, the understanding of the variability of micronutrient status markers during pregnancy is limited. We measured serum retinol and beta-carotene and the acute phase proteins C-reactive protein (CRP) and alpha(1)-antichymotrypsin (ACT) in 738 pregnant women in a cross-sectional study in Guinea-Bissau, West Africa. Gestational age ranged from 7 to 42 wk (mean +/- SD = 23 +/- 7 wk). The serum retinol concentration was 1.03 +/- 0.33 MUmol/L (mean +/- SD) whereas serum beta carotene was 1.40 (0.85, 2.13) MUmol/L [median (25, 75 percentile)]. Vitamin A deficiency (serum retinol <0.70 MUmol/L) was observed in 13.8% of individuals. Serum CRP was elevated (>3 mg/L) in 51.6% of individuals and ACT (>0.3 g/L) in 66.3%. Gestational age >20 wk (beta = -0.11; P < 0.001) as well as elevated serum CRP (beta = -0.16; P < 0.001) and ACT (beta = -0.80; P = 0.004) were associated with lower serum retinol. Based on this large cross-sectional study, we suggest that serum retinol and its conventional cutoff may be underestimating the vitamin A status in late pregnancy and in populations with high prevalence of infections. However, prospective cohort studies measuring the serum concentration of retinol during and after pregnancy and inflammation are needed to describe the physiological behavior of serum retinol and thereby to improve the assessment of vitamin A status. PMID- 22437562 TI - Nutritional repletion of children with severe acute malnutrition does not affect VLDL apolipoprotein B-100 synthesis rate. AB - VLDL apo B-100 is essential for the secretion of liver fat. It is thought that synthesis of this lipoprotein is impaired in childhood severe acute malnutrition (SAM), especially in the edematous syndromes, and that this contributes to the common occurrence of hepatic steatosis in this condition. However, to our knowledge, it has not been confirmed that VLDL apo B-100 synthesis is slower in edematous compared with nonedematous SAM and that it is impaired in the malnourished compared with the well-nourished state. Therefore, VLDL apo B-100 kinetics were measured in 2 groups of children with SAM (15 edematous and 7 nonedematous), aged 4-20 mo, at 3 stages during treatment. Measurements were done at 4 +/- 1 d postadmission, mid- catch-up growth in weight, and at recovery (normal weight-for-length). VLDL apo B-100 synthesis was determined using stable isotope methodology to measure the rate of incorporation of (2)H(3)-leucine into its apoprotein moiety. The fractional and absolute synthesis of VLDL apo B-100 did not differ between the groups or from the initial malnourished stage to the recovery stage. Concentrations of VLDL apo B-100 were greater in the edematous than in the nonedematous group (P < 0.04) and did not differ from the initial stage to recovery. The data indicate that VLDL apo B-100 synthesis is not reduced when children develop either edematous or nonedematous SAM. PMID- 22437563 TI - Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. AB - The NHANES has monitored folate status of the U.S. population from prefortification (1988-1994) to postfortification (1999-2010) by measuring serum and RBC folate concentrations. The Bio-Rad radioassay (BR) was used from 1988 to 2006, and the microbiologic assay (MBA) was used from 2007 to 2010. The MBA produces higher concentrations than the BR and is considered to be more accurate. Thus, to bridge assay differences and to examine folate trends over time, we adjusted the BR results to be comparable to the MBA results. Postfortification, assay-adjusted serum and RBC folate concentrations were 2.5 times and 1.5 times prefortification concentrations, respectively, and showed a significant linear trend (P < 0.001) to slightly lower concentrations during 1999-2010. The postfortification prevalence of low serum (<10 nmol/L) or RBC (<340 nmol/L) folate concentrations was <= 1%, regardless of demographic subgroup, compared with 24% for serum folate and 3.5% for RBC folate prefortification, with substantial variation among demographic subgroups. The central 95% reference intervals for serum and RBC folate varied by demographic subgroup during both pre and postfortification periods. Age and dietary supplement use had the greatest effects on prevalence estimates of low folate concentrations during the prefortification period. In summary, the MBA-equivalent blood folate concentrations in the U.S. population showed first a sharp increase from pre- to postfortification, then showed a slight decrease (17% for serum and 12% for RBC folate) during the 12-y postfortification period. The MBA-equivalent pre- and postfortification reference concentrations will inform countries that plan folic acid fortification or that need to evaluate its impact. PMID- 22437564 TI - Dietary cholecalciferol and calcium levels in a Western-style defined rodent diet alter energy metabolism and inflammatory responses in mice. AB - Male and female C57Bl6 mice were fed a control AIN76A diet, a new Western-style diet (NWD1) reflecting dietary patterns linked to elevated colon cancer incidence (higher fat, lower cholecalciferol, calcium, methyl donors, fiber), or NWD1 with elevated cholecalciferol and calcium (NWD2) from weaning. After 24 wk, serum 25 hydroxyvitamin D [25(OH)D] decreased by >80% in the NWD1 group compared with controls, but with no alteration in serum calcium or bone mineral density. The decreased serum 25(OH)D was prevented in the NWD2 group. After 32 wk, the NWD1 group compared with controls reduced overall energy expenditure by 15% without altering food consumption or physical activity and induced glucose intolerance, phenotypes associated with metabolic syndrome. These responses were unexpectedly exacerbated in the NWD2 group, further shifting mice toward greater fatty acid storage rather than oxidation compared with both control and NWD1 groups, but there was no change in physical activity, causing significant weight gain due to increased fat mass. The NWD1 group also exhibited inflammatory responses compared with controls, including macrophage-associated crown-like structures in epididymal adipose tissue and increased serum concentrations of the proinflammatory cytokine IL-1beta, and of its targets, MCP-1 and Rantes, which were prevented or greatly mitigated in the NWD2 group. However, there was also elevated lipid storage in the liver and steatosis not seen in the control and NWD1 groups. Thus, elevating cholecalciferol and calcium in a Western-style diet can reduce inflammation associated with risk for colon tumor development, but interaction of nutrients in this diet can compromise liver function when fed long term. PMID- 22437565 TI - Are Mexican agricultural farmlands PCDD/F soil reservoirs? AB - Our aim was to identify polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzo-p-furans (PCDFs) in agricultural farmland soils in the Northwest of Mexico. We obtained ~50 g of soil in five Yaqui Valley (VY) agricultural fields in the north-western Mexican State of Sonora and in five Culiacan Valley (VC) agricultural fields in the north-western Mexican State of Sinaloa. Fields with minimal tillage, with ferti-irrigation, and those with intensive aerial and manual tillage were included. All soil samples were subjected to the chemical activated luciferase gene expression (CALUX((r))) test to determine PCDD/F. On average, samples contained 4.2 +/- 1.2 PCDD/F ppt TEQ; VY soil samples contained 4.72 +/- 1.23 PCDD/F ppt TEQ, while VC soil samples showed 3.6 +/- 1.1 PCDD/F ppt TEQ (p = 0.47). On considering tillage-type, in agricultural fields catalogued as intensive tillage, PCDD/F concentrations were 4.40 +/- 0.43 in agricultural fields catalogued as intensive tillage, while in farmlands of another tillage-type these concentrations were slightly higher (5.53 +/- 0.8). PMID- 22437566 TI - Dissipation study of Quinalphos (25 EC) in/on brinjal and soil. AB - A field experiment was conducted at Agricultural Research Station, Durgapura, Jaipur during kharif 2008 to study the dissipation of Quinalphos (25 EC) in/on brinjal and soil, when sprayed at its recommended dose (375 g a.i. ha(-1)) and double of the recommended dose (750 g a.i. ha(-1)). The residue data revealed the magnitude of dissipation and persistence by calculating safety parameters like RL(50) and T(tol). The initial deposit of Quinalphos in brinjal at 375 and 750 g a.i. ha(-1) were recorded as 0.0866 and 0.1517 mg kg(-1), respectively which reached to below detectable level (0.01 mg kg(-1)) in 7 and 10 days at recommended (375 g a.i. ha(-1)) and double of the recommended dose (750 g a.i. ha(-1)), respectively. The residues, however, had a half life value (RL(50)) of 2 days for lower dose and 3 days for higher dose. Hence 6 and 9 days waiting period was suggested for recommended and double of the recommended dose, respectively. No residues were detected in soil in treated plots at both the treatment levels 30 days after the spray of insecticide to the crop. PMID- 22437567 TI - A Bayesian compressed-sensing approach for reconstructing neural connectivity from subsampled anatomical data. AB - In recent years, the problem of reconstructing the connectivity in large neural circuits ("connectomics") has re-emerged as one of the main objectives of neuroscience. Classically, reconstructions of neural connectivity have been approached anatomically, using electron or light microscopy and histological tracing methods. This paper describes a statistical approach for connectivity reconstruction that relies on relatively easy-to-obtain measurements using fluorescent probes such as synaptic markers, cytoplasmic dyes, transsynaptic tracers, or activity-dependent dyes. We describe the possible design of these experiments and develop a Bayesian framework for extracting synaptic neural connectivity from such data. We show that the statistical reconstruction problem can be formulated naturally as a tractable L1-regularized quadratic optimization. As a concrete example, we consider a realistic hypothetical connectivity reconstruction experiment in C. elegans, a popular neuroscience model where a complete wiring diagram has been previously obtained based on long-term electron microscopy work. We show that the new statistical approach could lead to an orders of magnitude reduction in experimental effort in reconstructing the connectivity in this circuit. We further demonstrate that the spatial heterogeneity and biological variability in the connectivity matrix--not just the "average" connectivity--can also be estimated using the same method. PMID- 22437568 TI - Presurgical planning for arteriovenous malformations using multidetector row CT. AB - Microsurgical resection remains an important treatment for cerebral arteriovenous malformations (AVMs). We developed an accurate method for planning AVM resections using multidetector row CT (MDCT). Between January 2007 and January 2011, 21 consecutive patients with AVMs were enrolled in this study. Sixteen patients were symptomatic, and of these, 15 had a hemorrhagic onset. Preoperative CT angiography (CTA) was performed using an MDCT scanner (GE Lightspeed VCT; GE Healthcare, Milwaukee, WI, USA). In total, 1 to 1.2 mL/kg of iopamidol, a low osmolar iodinated contrast material, was administered intravenously with the bolus tracking method. In all cases, three-dimensional CTA imaging demonstrated critical arterial feeders and their specific geometric associations with the nidus. Accurate visualization of the architecture of AVMs and surgical trajectory was possible with the volume rendering method, especially when using transparency imaging. Additionally, employing feeder extraction imaging with segmentation post processing, clear preoperative identification of the feeding arteries around the surrounding structures allowed for not only intraoperative orientation but also planning for presurgical embolization. Moreover, the precise anatomical structures of the brain surface were obtained using fusion imaging with MRI. While it is difficult to scientifically assign a value to a technology, we sought to objectively assess the utility of the currently available CTA. The significant benefits of this modality for presurgical planning include enhanced surgeon confidence and optimization of the sequence of surgical procedures. PMID- 22437569 TI - Incidental benefits. PMID- 22437570 TI - Flight risk. PMID- 22437571 TI - Mass appeal. PMID- 22437572 TI - Change the approach to sustainable development. PMID- 22437583 TI - Activists ground primate flights. PMID- 22437584 TI - Opioid receptors revealed. PMID- 22437585 TI - Indian budget disappoints. PMID- 22437586 TI - Clashing nations back SESAME. PMID- 22437587 TI - DNA donor rights affirmed. PMID- 22437588 TI - Photonic chips made easier. PMID- 22437589 TI - Mice guide human drug trial. PMID- 22437590 TI - Prehistoric proteins: Raising the dead. PMID- 22437591 TI - Neuroscience: Making connections. PMID- 22437592 TI - Neuroscience: Observatories of the mind. PMID- 22437593 TI - Biodiversity: Think big for marine conservation. PMID- 22437594 TI - Physics: A century of cosmic rays. PMID- 22437599 TI - Conservation: Work together to crack wildlife trade. PMID- 22437600 TI - China: A cultural shift for science. PMID- 22437601 TI - China: Philosophers sparked good science. PMID- 22437602 TI - Free press: Mixed media policies of US federal agencies. PMID- 22437603 TI - Fracking: Colorado methane study not clear-cut. PMID- 22437605 TI - Renato Dulbecco (1914-2012). PMID- 22437606 TI - Evolutionary biology: Life imperfectly imitates life. PMID- 22437607 TI - Biological physics: Swarming microtubules. PMID- 22437608 TI - Molecular biology: How to duplicate a DNA package. PMID- 22437609 TI - Geochemistry: Bubbles from the deep. PMID- 22437610 TI - Microscopy: Plasmons go quantum. PMID- 22437611 TI - Quantum plasmon resonances of individual metallic nanoparticles. AB - The plasmon resonances of metallic nanoparticles have received considerable attention for their applications in nanophotonics, biology, sensing, spectroscopy and solar energy harvesting. Although thoroughly characterized for spheres larger than ten nanometres in diameter, the plasmonic properties of particles in the quantum size regime have been historically difficult to describe owing to weak optical scattering, metal-ligand interactions, and inhomogeneity in ensemble measurements. Such difficulties have precluded probing and controlling the plasmonic properties of quantum-sized particles in many natural and engineered processes, notably catalysis. Here we investigate the plasmon resonances of individual ligand-free silver nanoparticles using aberration-corrected transmission electron microscope (TEM) imaging and monochromated scanning TEM electron energy-loss spectroscopy (EELS). This technique allows direct correlation between a particle's geometry and its plasmon resonance. As the nanoparticle diameter decreases from 20 nanometres to less than two nanometres, the plasmon resonance shifts to higher energy by 0.5 electronvolts, a substantial deviation from classical predictions. We present an analytical quantum mechanical model that describes this shift due to a change in particle permittivity. Our results highlight the quantum plasmonic properties of small metallic nanospheres, with direct application to understanding and exploiting catalytically active and biologically relevant nanoparticles. PMID- 22437612 TI - Electron tomography at 2.4-angstrom resolution. AB - Transmission electron microscopy is a powerful imaging tool that has found broad application in materials science, nanoscience and biology. With the introduction of aberration-corrected electron lenses, both the spatial resolution and the image quality in transmission electron microscopy have been significantly improved and resolution below 0.5 angstroms has been demonstrated. To reveal the three-dimensional (3D) structure of thin samples, electron tomography is the method of choice, with cubic-nanometre resolution currently achievable. Discrete tomography has recently been used to generate a 3D atomic reconstruction of a silver nanoparticle two to three nanometres in diameter, but this statistical method assumes prior knowledge of the particle's lattice structure and requires that the atoms fit rigidly on that lattice. Here we report the experimental demonstration of a general electron tomography method that achieves atomic-scale resolution without initial assumptions about the sample structure. By combining a novel projection alignment and tomographic reconstruction method with scanning transmission electron microscopy, we have determined the 3D structure of an approximately ten-nanometre gold nanoparticle at 2.4-angstrom resolution. Although we cannot definitively locate all of the atoms inside the nanoparticle, individual atoms are observed in some regions of the particle and several grains are identified in three dimensions. The 3D surface morphology and internal lattice structure revealed are consistent with a distorted icosahedral multiply twinned particle. We anticipate that this general method can be applied not only to determine the 3D structure of nanomaterials at atomic-scale resolution, but also to improve the spatial resolution and image quality in other tomography fields. PMID- 22437613 TI - Large-scale vortex lattice emerging from collectively moving microtubules. AB - Spontaneous collective motion, as in some flocks of bird and schools of fish, is an example of an emergent phenomenon. Such phenomena are at present of great interest and physicists have put forward a number of theoretical results that so far lack experimental verification. In animal behaviour studies, large-scale data collection is now technologically possible, but data are still scarce and arise from observations rather than controlled experiments. Multicellular biological systems, such as bacterial colonies or tissues, allow more control, but may have many hidden variables and interactions, hindering proper tests of theoretical ideas. However, in systems on the subcellular scale such tests may be possible, particularly in in vitro experiments with only few purified components. Motility assays, in which protein filaments are driven by molecular motors grafted to a substrate in the presence of ATP, can show collective motion for high densities of motors and attached filaments. This was demonstrated recently for the actomyosin system, but a complete understanding of the mechanisms at work is still lacking. Here we report experiments in which microtubules are propelled by surface-bound dyneins. In this system it is possible to study the local interaction: we find that colliding microtubules align with each other with high probability. At high densities, this alignment results in self-organization of the microtubules, which are on average 15 um long, into vortices with diameters of around 400 um. Inside the vortices, the microtubules circulate both clockwise and anticlockwise. On longer timescales, the vortices form a lattice structure. The emergence of these structures, as verified by a mathematical model, is the result of the smooth, reptation-like motion of single microtubules in combination with local interactions (the nematic alignment due to collisions)--there is no need for long-range interactions. Apart from its potential relevance to cortical arrays in plant cells and other biological situations, our study provides evidence for the existence of previously unsuspected universality classes of collective motion phenomena. PMID- 22437614 TI - A comparative analysis of the evolution of imperfect mimicry. AB - Although exceptional examples of adaptation are frequently celebrated, some outcomes of natural selection seem far from perfect. For example, many hoverflies (Diptera: Syrphidae) are harmless (Batesian) mimics of stinging Hymenoptera. However, although some hoverfly species are considered excellent mimics, other species bear only a superficial resemblance to their models and it is unclear why this is so. To evaluate hypotheses that have been put forward to explain interspecific variation in the mimetic fidelity of Palearctic Syrphidae we use a comparative approach. We show that the most plausible explanation is that predators impose less selection for mimetic fidelity on smaller hoverfly species because they are less profitable prey items. In particular, our findings, in combination with previous results, allow us to reject several key hypotheses for imperfect mimicry: first, human ratings of mimetic fidelity are positively correlated with both morphometric measures and avian rankings, indicating that variation in mimetic fidelity is not simply an illusion based on human perception; second, no species of syrphid maps out in multidimensional space as being intermediate in appearance between several different hymenopteran model species, as the multimodel hypothesis requires; and third, we find no evidence for a negative relationship between mimetic fidelity and abundance, which calls into question the kin-selection hypothesis. By contrast, a strong positive relationship between mimetic fidelity and body size supports the relaxed selection hypothesis, suggesting that reduced predation pressure on less profitable prey species limits the selection for mimetic perfection. PMID- 22437616 TI - Outcomes of simultaneous pancreas-kidney transplantation from brain-dead and controlled circulatory death donors. AB - BACKGROUND: Organ scarcity has prompted increased use of organs from donation after circulatory death (DCD) donors. An early single-centre experience of simultaneous pancreas-kidney (SPK) transplantation from controlled DCD donors is described here. METHODS: Outcomes of SPK transplants from DCD and donation after brain death (DBD) donors between August 2008 and January 2011 were reviewed retrospectively. RESULTS: SPK transplants from 20 DCD and 40 DBD donors were carried out. Donor and recipient characteristics were similar for both groups, although pancreas cold ischaemia times were shorter in DCD recipients: median (range) 8.2 (5.9-10.5) versus 9.5 (3.8-12.5) h respectively (P = 0.004). Median time from treatment withdrawal to cold perfusion was 24 (range 16-110) min for DCD donors. There were no episodes of delayed pancreatic graft function in either group; the graft thrombosis rates were both 5 per cent. Similarly, there were no differences in haemoglobin A1c level at 12 months: median (range) 5.4 (4.9-7.7) per cent in DCD group versus 5.4 (4.1-6.2) per cent in DBD group (P = 0.910). Pancreas graft survival rates were not significantly different, with Kaplan-Meier 1-year survival estimates of 84 and 95 per cent respectively (P = 0.181). CONCLUSION: DCD SPK grafts had comparable short-term outcomes to DBD grafts, even when procured from selected donors with a prolonged agonal phase. PMID- 22437617 TI - Validation of a neighborhood SES index in a managed care organization. AB - BACKGROUND/OBJECTIVE: Neighborhood socioeconomic status (SES), beyond individual SES, has been associated with health behaviors and outcomes. We constructed a neighborhood SES index using readily available US Census variables and studied associations of the index with self-reported education, formal education, and neighborhood residential characteristics among adult enrollees of a managed care organization (MCO). METHODS: A neighborhood SES index was constructed for MCO enrollees using a principal components analysis of 7 Census measures of their residential tracts or block groups. Quartiles of resulting neighborhood SES scores were matched with self-reported education, household income, and neighborhood residential characteristics obtained on 3 surveys of MCO adults ranging in age from 18 to 99. Cross-tabulations of neighborhood SES with self reported measures were used to assess concordance. RESULTS: Consistent with other non-MCO populations, distributions of the neighborhood SES index and self reported education, household income, and other neighborhood residential characteristics were concordant. The presence of high SES MCO enrollees in low SES neighborhoods and low SES MCO enrollees in high SES neighborhoods was, however, common. MCO enrollees living in low SES neighborhoods also reported neighborhood problems (crime, unattended dogs) known to affect walkability more frequently than those living in high SES neighborhoods. CONCLUSIONS: A simple, valid neighborhood SES index can be constructed for MCO populations using readily available US Census variables. Although individual and neighborhood SES are on average concordant, discrepancies between individual and neighborhood SES suggest that other factors may influence how area-based SES contributes to health behaviors and outcomes in an MCO population. PMID- 22437618 TI - Reducing costs of acute care for ambulatory care-sensitive medical conditions: the central roles of comorbid mental illness. AB - BACKGROUND: New patient-centered models of ambulatory care aim to substitute better primary care for preventable acute care within existing primary care practices. This study aims to identify whether mental illness and other characteristics of primary care patients are related to risk for an acute event for an ambulatory care-sensitive condition (ACSC). METHODS: We conducted a 2 year, longitudinal analysis comparing ambulatory care-sensitive admissions and emergency department (ED) visits for a cohort of 18,526 primary care patients followed in 5 veterans affairs (VA) primary care sites. We compared rates, risks, and costs of ACSC-related acute events during a follow-up year for patients with and without mental illness seen during the previous year in primary care. RESULTS: The 12-month rate of ACSC admissions was 31.7 admissions per 1000 patients with mental health diagnoses compared with 21.0 admissions per 1000 patients without (P=0.0009). The ACSC-associated ED visit rate was also significantly higher (P<0.0001). In adjusted analyses controlling for demographics, chronic disease, illness severity, and prior ambulatory care, those with depression or drug use disorders had higher odds of receiving ACSC-related acute care (odds ratio=1.10, 95% confidence interval: 1.03, 1.17 for depression; odds ratio=1.48, 95% confidence interval: 1.05, 1.99 for drug use disorders). Costs per admission and ED visit were similar across patient groups. Higher medication use and lower medication regimen complexity were significantly associated with decreased risk for ACSC events. CONCLUSIONS: Prior mental health diagnoses and medication use were independent risk factors for ACSC-related acute care. These risk factors require focused attention if the full benefits of new primary care models are to be achieved. PMID- 22437619 TI - Determination of colonoscopy indication from administrative claims data. AB - BACKGROUND: Colonoscopy outcomes, such as polyp detection or complication rates, may differ by procedure indication. OBJECTIVES: To develop methods to classify colonoscopy indications from administrative data, facilitating study of colonoscopy quality and outcomes. RESEARCH DESIGN: We linked 14,844 colonoscopy reports from the Clinical Outcomes Research Initiative, a national repository of endoscopic reports, to the corresponding Medicare Carrier and Outpatient File claims. Colonoscopy indication was determined from the procedure reports. We developed algorithms using classification and regression trees and linear discriminant analysis (LDA) to classify colonoscopy indication. Predictor variables included ICD-9CM and CPT/HCPCS codes present on the colonoscopy claim or in the 12 months prior, patient demographics, and site of colonoscopy service. Algorithms were developed on a training set of 7515 procedures, then validated using a test set of 7329 procedures. RESULTS: Sensitivity was lowest for identifying average-risk screening colonoscopies, varying between 55% and 86% for the different algorithms, but specificity for this indication was consistently over 95%. Sensitivity for diagnostic colonoscopy varied between 77% and 89%, with specificity between 55% and 87%. Algorithms with classification and regression trees with 7 variables or LDA with 10 variables had similar overall accuracy, and generally lower accuracy than the algorithm using LDA with 30 variables. CONCLUSIONS: Algorithms using Medicare claims data have moderate sensitivity and specificity for colonoscopy indication, and will be useful for studying colonoscopy quality in this population. Further validation may be needed before use in alternative populations. PMID- 22437620 TI - Impact of bariatric surgery on health care utilization and costs among patients with diabetes. PMID- 22437621 TI - Very low birth weight hospital volume and mortality: an instrumental variables approach. AB - BACKGROUND: Previous studies of very low birth weight (VLBW) hospital volume effects on in-hospital mortality have used standard risk-adjusted models that only account for observable confounders but not for self-selection bias due to unobservable confounders. OBJECTIVE: To assess the effects of hospital volume of VLBW infants on in-hospital mortality while explicitly accounting for unobservable confounders and self-selection bias using an instrumental variables (IV) model. METHODS: The sample includes 4553 VLBW infants born in 63 hospitals in 2000-2004 in New Jersey. We use IV analysis with the differences between the patient's distances to the nearest low (<50 VLBW infants annually), moderate (51 100 infants annually), and high (>100 VLBW infants annually)-volume hospitals as instruments. We evaluate several volume measures and adjusted for observable infant and hospital characteristics. RESULTS: We find beneficial volume effects on survival that are significantly underestimated in classic risk-adjusted models, under which low and moderate volumes compared with high volumes increase mortality odds by 1.8 and 1.88 times, respectively (risk ratios of 1.4 and 1.5, respectively). However, using the IV approach, we find that low and moderate volumes increase mortality odds by 5.42 and 3.51 times, respectively (risk ratios of 2.76 and 2.21, respectively). These findings suggest unobservable confounders that increase the selection of infants at a greater mortality risk into higher volume hospitals. CONCLUSIONS: Accounting for unobserved self-selection bias reveals large survival benefits from delivering and treating VLBW infants at high volume hospitals. This supports policies regionalizing the delivery and care for pregnancies at risk for VLBW at high-volume hospitals. PMID- 22437623 TI - Area-level variations in cancer care and outcomes. AB - BACKGROUND: : Substantial regional variations in health-care spending exist across the United States; yet, care and outcomes are not better in higher spending areas. Most studies have focused on care in fee-for-service Medicare; whether spillover effects exist in settings without financial incentives for more care is unknown. OBJECTIVE: : We studied care for cancer patients in fee-for service Medicare and the Veterans Health Administration (VA) to understand whether processes and outcomes of care vary with area-level Medicare spending. DESIGN: : An observational study using logistic regression to assess care by area level measures of Medicare spending. SUBJECTS: : Patients with lung, colorectal, or prostate cancers diagnosed during 2001-2004 in Surveillance, Epidemiology, and End Results (SEER) areas or the VA. The SEER cohort included fee-for-service Medicare patients aged older than 65 years. MEASURES: : Recommended and preference-sensitive cancer care and mortality. RESULTS: : In fee-for-service Medicare, higher-spending areas had higher rates of recommended care (curative surgery and adjuvant chemotherapy for early-stage non-small-cell lung cancer and chemotherapy for stage III colon cancer) and preference-sensitive care (chemotherapy for stage IV lung and colon cancer and primary treatment of local/regional prostate cancer) and had lower lung cancer mortality. In the VA, we observed minimal variation in care by area-level Medicare spending. DISCUSSION: : Our findings suggest that intensity of care for Medicare beneficiaries is not driving variations in VA care, despite some overlap in physician networks. Although the Dartmouth Atlas work has been of unprecedented importance in demonstrating variations in Medicare spending, new measures may be needed to better understand variations in other populations. PMID- 22437624 TI - Translating research into practice: the role of provider-based research networks in the diffusion of an evidence-based colon cancer treatment innovation. AB - BACKGROUND: Provider-based research networks (PBRNs)--collaborative research partnerships between academic centers and community-based practitioners--are a promising model for accelerating the translation of research into practice; however, empirical evidence of accelerated translation is limited. Oxaliplatin in adjuvant combination chemotherapy is an innovation with clinical trial-proven survival benefit compared with prior therapies. The goal of this study is to examine the diffusion of oxaliplatin into community practice, and whether affiliation with the National Cancer Institute's (NCI's) Community Clinical Oncology Program (CCOP)--a nationwide cancer-focused PBRN--is associated with accelerated innovation adoption. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational study used linked Surveillance, Epidemiology, and End Results-Medicare and NCI CCOP data to examine Medicare participants with stage III colon cancer initiating treatment in 2003 through 2006, the years surrounding oxaliplatin's Food and Drug Administration approval. A fixed-effects analysis examined chemotherapy use among patients treated outside academic centers at CCOP affiliated practices compared with non-CCOP practices. Two-group modeling controlled for multiple levels of clustering, year of chemotherapy initiation, tumor characteristics, patient age, race, comorbidity, Medicaid dual-eligibility status, and education. RESULTS: Of 4055 community patients, 35% received 5 fluoruracil, 20% received oxaliplatin, 7% received another chemotherapy, and 38% received no chemotherapy. Twenty-five percent of CCOP patients received oxaliplatin, compared with 19% of non-CCOP patients. In multivariable analysis, CCOP exposure was associated with higher odds of receiving guideline-concordant treatment in general, and oxaliplatin specifically. CONCLUSIONS: These findings contribute to a growing set of evidence linking PBRNs with a greater probability of receiving treatment innovations and high-quality cancer care, with implications for clinical and research policy. PMID- 22437625 TI - Psychometric evaluation of a cultural competency assessment instrument for health professionals. AB - BACKGROUND: Few valid and reliable measures exist for health care professionals interested in determining their levels of cultural and linguistic competence. OBJECTIVE: To evaluate the measurement properties of the Cultural Competence Health Practitioner Assessment (CCHPA-129). METHODS: The CCHPA-129 is a 129-item web-based instrument, developed by the National Center for Cultural Competence. Responses on the CCHPA -129 were examined using factor analysis; Rasch modeling; and differential item functioning across race, ethnicity, sex, and profession. SUBJECTS: A total of 2504 practitioners, including 1864 nurses (RN/LPN/BSN); 341 clinicians (PA/NP); and 299 physicians (MD/DO), who completed the CCHPA-129 online between 2005 and 2008. RESULTS: Three factors representing domains of Knowledge, Adapting Practice, and Promoting Health for culturally and linguistically diverse populations accounted for 46% of the variance. Among Knowledge factor items, 53% (23/43) fit the Rasch model, item difficulties ranged from -1.01 logits (least difficult) to +1.11 logits (most difficult), separation index (SI) 13.82, and Cronbach's alpha 0.92. Forty-seven percent (21/44) Adapting Practice factor items fit the model, item difficulties -0.07 to +1.11 logits, SI 11.59, Cronbach's alpha 0.88; and 58% (23/39). Promoting Health factor items fit the model, item difficulties -1.01 to +1.38 logits, SI 22.64, Cronbach's alpha 0.92. Early evidence of validity was established by known groups having statistically different scores. CONCLUSIONS: The 67-item CCHPA-67 is psychometrically sound. This shorted instrument can be used to establish associations between practitioners' cultural and linguistic competence and health outcomes as well as to evaluate interventions to increase practitioners' cultural and linguistic competence. PMID- 22437626 TI - Family interventions in Schizophrenia: promise and pitfalls over 30 years. AB - The stress of living with unpredictable, disturbing schizophrenic symptoms can erode interpersonal relationships. Stressful family interactions are associated with poorer prognosis. Several investigators have developed educational or more intensive skills-based family programs to increase illness knowledge and improve prognosis in schizophrenia. An extensive body of research supports the benefits of participating in family-based treatments for schizophrenia, especially those of longer duration and emphasizing skill development, in reducing relapse rates. In spite of the data, these programs are underimplemented and underutilized. Barriers to their use likely arise from patients, relatives, and mental health professionals. Newer programs, which include novel engagement strategies, target subpopulations with poor prognoses, or use innovative technologies, may make these programs more accessible to a wider range of families. Engaging individuals with schizophrenia and their loved ones in a collaborative effort to design new, more consumer-driven family interventions is warranted. PMID- 22437627 TI - Pediatric trichotillomania. AB - Trichotillomania (TTM) is an impulse control disorder characterized by chronic hair-pulling, distress, and impairment. Although the negative effects of TTM are documented and often readily evident, there remains a paucity of psychopathology and treatment research on this disorder, particularly in pediatric populations. In an effort to improve assessment of pediatric TTM, several TTM-specific instruments for youth have now been developed to reliably identify symptoms and examine related phenomenology. Instrument development has now yielded instruments to evaluate TTM and related symptoms in the context of clinical trials of youth, and the first randomized controlled trial of any treatment for pediatric TTM was recently published. Using the initial pediatric TTM studies as building blocks, future research is now needed to create a stronger body of knowledge about the relative and combined efficacy of potential interventions for TTM in youth, as well as to examine the effects of TTM phenomenology and comorbidity on treatment outcome. Dissemination efforts must also be heightened for this knowledge to best reach these vulnerable populations. PMID- 22437628 TI - Zoledronic acid improves bone mineral density in pediatric spinal cord injury. AB - Spinal cord injury (SCI) is associated with rapid and sustained bone loss and increase risk of fracture. Disuse is the primary cause for bone loss, although neural and hormonal changes may also contribute via different mechanisms. Bisphosphonates are used widely to treat osteoporosis in adults and are used increasingly for primary and secondary osteoporosis in children. Current data are insufficient to recommend routine use of bisphosphonates for fracture prevention in adult patients post-SCI and there are no available data in pediatric SCI. We report a 12-year-old boy with non-traumatic SCI who was treated with six monthly zoledronic acid (0.05 mg/kg/dose) for 18 months. The patient (AA) was diagnosed with transverse myelitis at 8.1 years of age, resulting in ventilator-dependent incomplete C3 tetraplegia. Following a fragility fracture to the surgical neck of the right humerus at 9.5 years of age, he was started on zoledronic acid. Bone turnover decreased and bone densitometry data (dual-energy X-ray absorptiometry [DXA] and peripheral quantitative computed tomography [pQCT]) showed improvement in metaphyseal and diaphyseal bone mineral content (BMC), volumetric bone mineral density (vBMD), and size, after 18 months of treatment. In the growing skeleton post-SCI, zoledronic acid potentially increases vertebral and long-bone strength by preserving trabecular bone (increased BMC and vBMD) and increasing cortical vBMD and cross-sectional area (CSA). PMID- 22437629 TI - A smoothing expectation and substitution algorithm for the semiparametric accelerated failure time frailty model. AB - This paper proposes an estimation procedure for the semiparametric accelerated failure time frailty model that combines smoothing with an Expectation and Maximization-like algorithm for estimating equations. The resulting algorithm permits simultaneous estimation of the regression parameter, the baseline cumulative hazard, and the parameter indexing a general frailty distribution. We develop novel moment-based estimators for the frailty parameter, including a generalized method of moments estimator. Standard error estimates for all parameters are easily obtained using a randomly weighted bootstrap procedure. For the commonly used gamma frailty distribution, the proposed algorithm is very easy to implement using widely available numerical methods. Simulation results demonstrate that the algorithm performs very well in this setting. We re-analyz several previously analyzed data sets for illustrative purposes. PMID- 22437630 TI - Approaches to dog health education programs in Australian rural and remote Indigenous communities: four case studies. AB - Dog health in rural and remote Australian Indigenous communities is below urban averages in numerous respects. Many Indigenous communities have called for knowledge sharing in this area. However, dog health education programs are in their infancy, and lack data on effective practices. Without this core knowledge, health promotion efforts cannot progress effectively. This paper discusses a strategy that draws from successful approaches in human health and indigenous education, such as dadirri, and culturally respectful community engagement and development. Negotiating an appropriate education program is explored in its practical application through four case studies. Though each case was unique, the comparison of the four illustrated the importance of listening (community consultation), developing and maintaining relationships, community involvement and employment. The most successful case studies were those that could fully implement all four areas. Outcomes included improved local dog health capacity, local employment and engagement with the program and significantly improved dog health. PMID- 22437631 TI - Galectin-3 increases the motility of mouse melanoma cells by regulating matrix metalloproteinase-1 expression. AB - Although mounting evidence indicates the involvement of galectin-3 in cancer progression and metastasis, the underlying molecular mechanisms remain largely unknown. In this study, we investigated the effect and possible mechanism of galectin-3 on the migration and invasion of B16F10, a metastatic melanoma cell line, in which galectin-3 and matrix metalloproteinase- 1 (MMP-1) were both found to be highly expressed. Knockdown of galectin-3 with specific siRNA reduced migration and invasion, which was associated with reduced expression of MMP-1. To further investigate the underlying mechanism, we examined the effect of galectin 3 knockdown on the activity of AP-1, a transcriptional factor regulating MMP-1 expression. We found that galectin-3 directly interacted with AP-1 and facilitated the binding of this complex to the MMP-1 promoter that drives MMP-1 transcription. Moreover, silencing of galectin-3 inhibited binding of fra-1 and c Jun to promoter sites of MMP-1 gene. Consistent with these in vitro findings, our in vivo study demonstrated that galectin-3 shRNA treatment significantly reduced the total number of mouse lung metastatic nodules. Taken together, galectin- 3 facilitates cell migration and invasion in melanoma in vitro and can induce metastasis in vivo, in part through, regulating the transcription activity of AP 1 and thereby up-regulating MMP-1 expression. PMID- 22437632 TI - The new era of cardiac surgery: hybrid therapy for cardiovascular disease. AB - Surgical therapy for cardiovascular disease carries excellent long-term outcomes but it is relatively invasive. With the development of new devices and techniques, modern cardiovascular surgery is trending toward less invasive approaches, especially for patients at high risk for traditional open heart surgery. A hybrid strategy combines traditional surgical treatments performed in the operating room with treatments traditionally available only in the catheterization laboratory with the goal of offering patients the best available therapy for any set of cardiovascular diseases. Examples of hybrid procedures include hybrid coronary artery bypass grafting, hybrid valve surgery and percutaneous coronary intervention, hybrid endocardial and epicardial atrial fibrillation procedures, and hybrid coronary artery bypass grafting/carotid artery stenting. This multidisciplinary approach requires strong collaboration between cardiac surgeons, vascular surgeons, and interventional cardiologists to obtain optimal patient outcomes. PMID- 22437633 TI - Transaortic endoclamp for mitral valve operation through right minithoracotomy in 369 patients. AB - OBJECTIVE: : The effects and benefits of a transaortic endoclamp for mitral valve operation through right minithoracotomy have not been established. METHODS: : The records were examined in 671 patients undergoing mitral valve operation using aortic cannulation through a 6-cm right minithoracotomy in the fourth intercostal space. The ascending aorta was cannulated with a 24-Fr cannula through a 12-mm port in the first intercostal space. The experience from 1998 to 2006 with aortic endoclamping (group A, N = 436) was compared with the experience from 2006 to 2009 with external aortic clamping (group B, N = 235). Aortic endoclamping was achieved with a 30 mL endoclamp introduced through the aortic cannula into the ascending aorta to provide aortic endoclamping, anterograde cardioplegia, and root venting. Percutaneous femoral venous cannulation was used. RESULTS: : Group A and group B had similar demographics. Endoclamp availability (group A) resulted in significantly less fibrillatory arrest (no clamping) in 67 of 436 (15%) versus 104 of 235 (44%) patients in group B (P = 0.001). In patients with aortic clamping, endoclamp (group A) versus external clamp (group B) was not a determinant of clamp time or pump time. Hospital and late outcomes were not different between groups. No patient complications could be attributed to the endoclamp. CONCLUSIONS: : Aortic endoclamping requires no more clamp or pump time than external clamping and can provide a more bloodless field than ventricular fibrillation without obstructing hardware. Aortic endoclamping is a safe alternative for mitral surgery through right minithoracotomy. PMID- 22437634 TI - Long-Term Survival After Minimal Invasive Direct Coronary Artery Bypass (MIDCAB) Surgery in Patients With Low Ejection Fraction. AB - OBJECTIVE: : The long-term survival after minimal invasive direct coronary artery bypass (MIDCAB) surgery to any coronary territory in patients with ejection fraction of <=30% was investigated for the first time in literature. METHODS: : Seventy-three patients with primary MIDCAB and 89 patients with reoperative MIDCAB were studied including preoperative risk factors, operative details, early postoperative complications, and survival up to 10 years postoperatively. RESULTS: : Despite the high-risk profile of the patients, the MIDCAB approach for targeted revascularization resulted in excellent short-term results. Ventricular arrhythmia contributed to four of six early deaths. Survival at 5 years postoperatively was 62.5% for primary MIDCAB and 43.2% for reoperative MIDCAB and at 10 years was 36.9% and 29.5%, respectively. Functionally complete vascularization correlates with significantly better long-term survival particularly in primary MIDCAB procedures. CONCLUSIONS: : MIDCAB is a valuable option for targeted revascularization in high-risk patients with low ejection fraction and reoperation. PMID- 22437635 TI - Performance of four risk algorithms in predicting intermediate survival in patients undergoing aortic valve replacement. AB - OBJECTIVE: : Several risk models exist to predict operative outcomes after cardiac surgery and are used in selecting patients for alternative procedures such as transcatheter valve implantation. We sought to evaluate the performance of the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) model in accurately identifying patients at high risk for aortic valve replacement (AVR). METHODS: : Three hundred and ninety four consecutive patients who underwent isolated AVR from January 1, 2001, to July 1, 2007, at a tertiary care center were analyzed using the STS database. Patients were stratified into tertiles according to operative surgical risk calculated by the four models [STS PROM, European system for cardiac operative risk evaluation (EuroSCORE), Ambler, and Providence]. Vital status at 1 year was determined using the National Death Index and Social Security Death Index. RESULTS: : There were 310 low-risk patients, 56 intermediate-risk patients, and 28 high-risk patients with respect to the STS-PROM. The predicted risk of death for the low-risk, intermediate-risk, and high-risk groups were 2.4% +/- 1.1%, 6.9% +/- 1.4%, 15.8% +/- 7.6% (P < 0.001) with respect to the STS-PROM model. Actual operative mortality for each respective group was 1.94%, 5.36%, 14.29% (P < 0.001) and 1-year mortality was 3.23%, 12.50%, 21.43% (P < 0.001), respectively. CONCLUSIONS: : High-risk patients have significantly high mortality after AVR. The STS-PROM accurately predicts operative mortality and can be used to predict 1-year survival as well. This risk model may be preferentially used instead of the EuroSCORE. PMID- 22437636 TI - Video-assisted minimally invasive mitral valve surgery: external aortic clamp versus endoclamp techniques. AB - OBJECTIVE: : Video-assisted minimally invasive mitral valve surgery can be performed through different approaches. The aim of the study was to report our early results and compare the external transthoracic aortic clamping with the endoaortic balloon occlusion techniques according to our experience. METHODS: : Between January 2000 and March 2010, 138 patients (103 women, aged 58.4 +/- 10.2 years) underwent video-assisted mitral valve surgery through a right thoracotomy. Cardiopulmonary bypass was instituted by femoral arterial and bicaval cannulation with active venous drainage and normothermia; cardioplegic arrest achieved with intermittent blood cardioplegia. In group A (93 patients, 68 women, aged 58.8 +/- 7.8 years, 72 MV replacement, 21 MV repair), aortic clamping was achieved using the external transthoracic aortic clamp. In group B (45 patients, 35 women, aged 58.1 +/- 11.4 years, 33 MV replacement, 12 MV repair), aortic clamping was achieved with endoaortic balloon occlusion. RESULTS: : Intraoperative procedure associated problems were experienced in one patient (0.7%) in group A (one conversion to sternotomy for pleural adhesions and bad exposure). At a mean follow-up of 36 +/- 18 months, 135 patients (97.8%) were in New York Heart Association class I to II, with satisfactory echocardiographic follow-up. In group A, two patients had noncardiac-related deaths. No perioperative deaths were observed in both groups. There were four (2.8%) transient ischemic attacks and one (0.7%) peripheral ischemic event (group A) during the early postoperative period. Mitral valve repair patients had a 5-year freedom from reoperation of 100% in both groups. There was no significant difference between the two groups regarding preoperative variables, such as age, sex, New York Heart Association class, and left ventricular ejection fraction (P > 0.05). Postoperative levels of myocardial cytonecrosis enzymes (MB fraction, creatine kinase, and troponine I) as well as operative time, extracorporeal circulation, and aortic cross-clamping times or ventilation and intensive care unit times were not significantly different between the two groups (P > 0.05). More microembolic events were observed in group A than in group B (total 143.4 +/- 30.6 per patient vs 78.9 +/- 28.6 per patient) by means of continuous automated intraoperative transcranial Doppler evaluations (P < 0.05) applied to part of population. CONCLUSIONS: : Both techniques proved safe and comparable with low risk of morbidity and mortality. Patients undergoing endoclamp technique resulted to be less subject to embolism. PMID- 22437637 TI - Robot-assisted aortic valve replacement using a novel sutureless bovine pericardial prosthesis: proof of concept as an alternative to percutaneous implantation. AB - OBJECTIVE: : Percutaneous aortic valve implantation within native valve calcium has progressed to clinical use despite the absence of data proving equivalence to complete surgical excision and prosthetic valve replacement. A novel self expanding sutureless bovine pericardial prosthesis (Sorin Perceval) derived from a proven stented valve has been successfully used in humans recently through an open transaortic approach. We sought to develop a minimally invasive technique for native aortic valve excision and sutureless prosthetic aortic valve replacement using robot assistance. METHODS: : The da Vinci S-HD system was used to open and suspend the pericardium anterior to the phrenic nerve in cadavers. A transthoracic cross-clamp was placed across the midascending aorta, following which a transverse aortotomy was made. The native aortic valve cusps were excised, and annular calcium was removed with robotic instruments. After placement of three guide sutures, the Perceval self-expanding pericardial prosthesis mounted on a flexible delivery system was inserted through a working port and lowered into the aortic annulus. RESULTS: : Successful implantation of all valves was possible using a 3-cm right second intercostal space working port, along with two additional 1-cm instrument ports. A standard transverse aortotomy was sufficient for examination/debridement of the native aortic valve cusps, sizing of the annulus, and deployment of the nitinol-stented, bovine pericardial prosthesis. Delivery, seating, and stability of the device were easily confirmed above and below the aortic valve annulus using the robotic camera. CONCLUSIONS: : Complete excision of diseased native aortic valve cusps with robot assistance facilitates accurate and reproducible aortic valve replacement using a novel self expanding sutureless version of a proven bovine pericardial prosthesis. This approach is comparable to the current surgical gold standard and is ready for clinical use as an alternative to percutaneous aortic valve implantation. PMID- 22437638 TI - Thromboembolic events in patients on extracorporeal membrane oxygenation without anticoagulation. AB - OBJECTIVE: : Heparinization is thought to be mandatory to avoid thromboembolic complications during venoarterial extracorporeal membrane oxygenation (VA-ECMO). However, bleeding complications are common. We report our experience of VA-ECMO without systemic anticoagulation. METHODS: : A prospectively assembled database describing all ECMO cases from 2000 to 2008 was analyzed. A heparin coated circuit (Medtronic, Inc., Minneapolis, MN USA) and membrane oxygenator (Quadrox D Bioline oxygenator; MAQUET, Rastatt, Germany) were used in all cases. After the initiation of VA-ECMO support, all coagulation parameters were corrected. No further systemic maintenance anticoagulant was given, except at the time of weaning. RESULTS: : Thirty-two patients received VA-ECMO support; 20 patients (62.5%) were males with a median age of 52.5 years (interquartile range, 40.4 61.1 years). Central and peripheral cannulations were 53% and 47%, respectively. Etiologies of cardiogenic shock were postcardiotomy (75%, n = 24) and as a support to cardiopulmonary resuscitation in 25% of cases (n = 8). Thirty-day mortality was 43.8%. Median duration of ECMO support was 46.3 hours (interquartile range, 26.8-87.8 hours). The median number of packed red blood cell transfusions was 18 +/- 25. Complications include five patients (16%) with limb ischemia requiring intervention, 15 patients (46.9%) had acute renal failure, two patients had deep vein thrombosis, and two patients had intracardiac clots detected on echocardiograms. No patient had a cerebrovascular event. Incidence of membrane oxygenator failure was low, requiring replacement in three patients; no adverse event occurred during replacement. Fourteen patients (43.8%) were reexplored for bleeding. Fourteen patients (44%) were discharged home and were long-term survivors. CONCLUSIONS: : VA-ECMO support without systemic anticoagulation may reduce bleeding complications and transfusion requirement, without increasing the risk of thromboembolism. PMID- 22437639 TI - Augmented reality image guidance during off-pump mitral valve replacement through the guiraudon universal cardiac introducer. AB - OBJECTIVE: : We report our experience with ultrasound augmented reality (US-AR) guidance for mitral valve prosthesis (MVP) implantation in the pig using off pump, closed, beating intracardiac access through the Guiraudon Universal Cardiac Introducer attached to the left atrial appendage. METHODS: : Before testing US-AR guidance, a feasibility pilot study on nine pigs was performed using US alone. US AR guidance, tested on a heart phantom, was subsequently used in three pigs (~65 kg) using a tracked transesophageal echocardiography probe, augmented with registration of a 3D computed tomography scan, and virtual representation of the MVP and clip-delivering tool (Clipper); three pigs were used to test feature based registration. RESULTS: : Navigation of the MVP was facilitated by the 3D anatomic display. AR displayed the MVP and the Clipper within the Atamai Viewer, with excellent accuracy for tool placement. Positioning the Clipper was hampered by the design of the MVP holder and Clipper. These limitations were well displayed by AR, which provided guidance for improved design of tools. CONCLUSIONS: : US-AR provided informative image guidance. It documented the flaws of the current implantation technology. This information could not be obtained by any other method of evaluation. These evaluations provided guidance for designing an integrated tool: combining an unobtrusive valve holder that allows the MVP to function properly as soon as positioned, and an anchoring system, with clips that can be released one at a time, and retracted if necessary, for optimal results. The portability of Real-time US-AR may prove to be the ideal practical image guidance system for all closed intracardiac interventions. PMID- 22437640 TI - Treatment of mechanical aortic valve thrombosis: fibrinolytic treatment versus surgical intervention: result of eight cases. AB - OBJECTIVE: : Thrombosis of mechanical heart valve prosthesis is a rare fatal complication after heart valve replacement. Although surgical intervention is the suggested treatment in many series, fibrinolytic treatment offers a good alternative. We describe eight cases with mechanical aortic valve thrombosis and compare their results after fibrinolytic treatment or redo aortic valve replacement. METHODS: : Between February 2008 and March 2009, eight patients with previous mechanical prosthetic aortic valve replacement history were admitted to our center with mechanical aortic valve thrombosis. Four patients were operated, and the remaining four patients received low-dose fibrinolytic treatment. All patients' data were collected prospectively. RESULTS: : Two of the four operated patients died. In the fibrinolytic group, all patients totally recovered, and there was no mortality or morbidity during the follow-up period. CONCLUSIONS: : We thought that fibrinolytic treatment is a feasible and effective method for thrombosed mechanical aortic valve. However, much more populated patient groups are needed for the vigorous inference. PMID- 22437641 TI - Activation of coagulation and fibrinolysis after off-pump coronary artery bypass grafting with or without endotracheal general anesthesia. AB - OBJECTIVE: : In this study, we measured the activity of coagulation and fibrinolysis and clarified the presence of certain differences between off-pump coronary artery bypass grafting (OPCAB) cases and awake off-pump coronary artery bypass grafting (AOCAB) cases to evaluate whether AOCAB is actually safe from the viewpoint of coagulability. METHODS: : 8 underwent OPCAB and 6 underwent AOCAB. The following factors inducing coagulation and fibrinolysis were measured for upto 5 days after the operation: platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin degeneration products, d-dimer, thrombin-antithrombin III complex (TAT), alpha2-plasmin inhibitor-plasmin complex, prothrombin fragment 1, 2 (F1+2), thrombomodulin, beta-thromboglobulin (beta-TG), and platelet factor-4. RESULTS: : At 5 days after the operation, fibrin degeneration products, d-dimer, alpha2-plasmin inhibitor-plasmin complex, and F1+2 levels of the OPCAB group were significantly higher compared with their baseline values and those of the AOCAB group. At 5 days after the operation, thrombin-antithrombin III complex levels of the OPCAB group were significantly higher than those of the AOCAB group. Fibrinogen levels of the OPCAB group were significantly higher than their baseline values at 3 days after the operation (POD3) and 5 days after the operation (POD5). CONCLUSIONS: : In this study, the hypercoagulable state at POD5 was suggested in the patients in the OPCAB group, but not in those in the AOCAB group. Further study is necessary to confirm these results, and future studies would evaluate the potential benefit of AOCAB procedure from the viewpoint of perioperative coagulability. PMID- 22437642 TI - Neointimal hyperplasia associated with the use of u-clip. AB - The U-Clip (Coalescent Surgical, Sunnydale, CA USA) allows the surgeon to create an interrupted anastomosis in the same amount of time that is required for a continuous anastomosis with the elimination of knotting. Its use is indicated especially in minimally invasive surgery. We describe a case of a patient in which the proximal anastomosis was performed by interrupted suture with Coalescent U-Clip anastomotic device. Six months later, he presented with stenosis of the anastomosis, and intravascular ultrasound showed anastomotic neointimal hyperplasia. PMID- 22437643 TI - Quadricuspid aortic valve: intraoperative transesophageal echocardiograph image. AB - Quadricuspid aortic valve is an extremely rare congenital anomaly. In Quadricuspid aortic valve, the aortic valve has four distinct leaflets. The most common type A variant has four equal cusps. The most common presentation is aortic insufficiency. A 70-year-old woman and a 32-year-old man presented to our practice in a 3-month time span were described here. PMID- 22437644 TI - Mitral re-repair and right coronary fistula closure: advantage of minimally invasive approach. AB - A 51-year-old man developed severe mitral regurgitation 10 years after previous mitral valve repair; the echocardiographic images showed a remarkable eccentric jet toward posterior wall of left atrium associated with a high degree of pulmonary vein retrograde flow. The coronary arteriography pointed out no pathologic lesions but a coronary fistula from the proximal right coronary to the right atrium. The standard approach was avoided, and a right anterolateral minithoracotomy was chosen, providing an excellent view. Under cardiopulmonary bypass and mild hypothermia, the mitral valve was re-repaired, and a new ring was implanted. After aortic cross-clamp release, the right coronary fistula was closed through the right atrium. The postoperative course was uneventful, and the patient was discharged on the fourth postoperative day. In such a high-risk reintervention and concomitant procedure, we think that this different approach may represent a feasible and reliable alternative. PMID- 22437645 TI - Intraoperative 3D Echocardiographic Image of Bileaflet Aortic and Mitral Valve Replacement and Amplatz Occluder. PMID- 22437646 TI - Ectopic expression of VpALDH2B4, a novel aldehyde dehydrogenase gene from Chinese wild grapevine (Vitis pseudoreticulata), enhances resistance to mildew pathogens and salt stress in Arabidopsis. AB - Aldehyde dehydrogenases (ALDHs) catalyze the irreversible oxidation of a broad spectrum of reactive aldehydes to their corresponding carboxylic acids. Although the proteins have been studied from various organisms and at different growth stages in plants, their potential roles in pathogen infection have not been examined. Here we isolated and functionally characterized a pathogen-inducible ALDH gene (VpALDH2B4) from Chinese wild grapevine Vitis pseudoreticulata accession Baihe-35-1. When transiently expressed in Arabidopsis leaves, VpALDH2B4 was found to be localized in mitochondria. Escherichia coli expressed GST VpALDH2B4 exhibited ALDH activity in vitro and was capable of utilizing malondialdehyde (MDA), acetaldehyde and glyceraldehydes as its substrate. Over expression of VpALDH2B4 in Arabidopsis resulted in hypersensitive response-like cell death, enhanced resistance to downy mildew and powdery mildew presumably via the SA-signaling pathway. The same Arabidopsis transgenic plants also showed enhanced tolerance to salt stress, which is accompanied by less MDA accumulation and upregulation of the stress-responsive superoxide dismutase activity. Taken together, our results suggest that VpALDH2B4 and perhaps its orthologous genes may be involved in responses of plants to stresses imposed by both biotrophic pathogens and high salinity conditions. PMID- 22437647 TI - Light response, oxidative stress management and nucleic acid stability in closely related Linderniaceae species differing in desiccation tolerance. AB - In the present study, three closely related Linderniaceae species which differ in their sensitivity to desiccation are compared in response to light and oxidative stress defence. Lindernia brevidens, a desiccation-tolerant plant, displayed intense purple pigmentation in leaves under long-day conditions in contrast to Craterostigma plantagineum (desiccation tolerant) and Lindernia subracemosa (desiccation sensitive). The intense pigmentation in leaves does not affect the desiccation tolerance behaviour but seems to be related to oxidative stress protection. Green leaves of short-day and purple leaves of long-day plants provided suitable material for comparing basic photosynthetic parameters. An increase in non-photochemical quenching in purple leaves appears to prevent photoinhibition. Treatment with methyl viologen decreased the photochemical activities in both long-day and short-day plants but long-day plants which accumulate anthocyanins maintained a higher non-photochemical quenching than short-day plants. No differences were seen in the expression of desiccation induced proteins and proteins involved in carbohydrate metabolism in short-day and long-day grown plants, whereas differences were observed in the expression of transcripts encoding chloroplast-localised stress proteins and transcripts encoding antioxidant enzymes. While the expression of genes encoding antioxidant enzymes were either constitutive or up-regulated during desiccation in C. plantagineum, the expression was down-regulated in L. subracemosa. RNA expression analysis indicated degradation of mRNA during desiccation in L. subracemosa but not in desiccation tolerant species. These results indicate that a better oxidative stress management and mRNA stability are correlated with desiccation tolerance. PMID- 22437648 TI - Syntheses, crystal structures and SHG properties of a series of polar alkali metal molybdenum(VI) selenites based on strandberg-type [Mo5O15(SeO3)2]4- polyanion. AB - Four new quaternary molybdenum selenites, namely, HRb(3)(Mo(5)O(15))(SeO(3))(2)(H(2)O)(2)1, alpha Rb(4)Mo(5)O(15)(SeO(3))(2)(H(2)O)(2)2, beta-Rb(4)Mo(5)O(15)(SeO(3))(2)(H(2)O)(2)3 and K(4)Mo(5)O(15)(SeO(3))(2)(H(2)O)(2)4 were synthesized by hydrothermal reactions. All of the four compounds feature a zero-dimensional (0D) [(Mo(5)O(15))(SeO(3))(2)](4-) anionic unit composed of a five-member MoO(6) octahedral ring capped by two SeO(3)(2-) trigonal pyramids, with the Rb(+)/K(+) or/and H(+) cations and water molecules acting as spacers and keeping charge balance. Although these compounds exhibit similar chemical formula, their structures are slightly different. HRb(3)(Mo(5)O(15))(SeO(3))(2)(H(2)O)(2)1 crystallizes in a polar space group (Pca2(1)). alpha Rb(4)Mo(5)O(15)(SeO(3))(2)(H(2)O)(2)2 crystallizes in a centrosymmetric (CS) space group (P2(1)/n) whereas beta-Rb(4)Mo(5)O(15)(SeO(3))(2)(H(2)O)(2)3 and K(4)Mo(5)O(15)(SeO(3))(2)(H(2)O)(2)4 are isomorphous, crystallize in a chiral space group (C2). The chiral structures of 3 and 4 contain two similar polyanions of [Mo(5)O(15)(SeO(3))(2)](4-) with opposite handedness. Second-harmonic generation (SHG) measurements indicate that 1, 3 and 4 are all SHG-active. Compound 1 displays a weak SHG response of about 20% of that of KDP (KH(2)PO(4)) and is phase-matchable whereas the SHG responses of 3 and 4 are very weak (less than 5% of that of KDP). Thermal analyses and optical property measurements have also been performed. PMID- 22437650 TI - Heparin from bovine intestinal mucosa: glycans with multiple sulfation patterns and anticoagulant effects. AB - Pharmaceutical grade heparins from porcine intestine and bovine lung consist mainly of repeating tri-sulfated units, of the disaccharide ->4-alpha-IdoA2S-1->4 alpha-GlcNS6S-1->. Heparin preparations from bovine intestine, in contrast, are more heterogeneous. Nuclear magnetic resonance (NMR) and disaccharide analysis after heparinase digestions show that heparin from bovine intestine contains alpha-glucosamine with significant substitutive variations: 64% are 6-O-sulfated and N -sulfated, as in porcine intestinal heparin while 36% are 6-desulfated. Desulfated alpha-iduronic acid units are contained in slightly lower proportions in bovine than in porcine heparin. NMR data also indicate N-, 3- and 6 trisulfated alpha-glucosamine (lower proportions) and alpha-GlcNS-1->4-alpha-GlcA and alpha-IdoA2S-1->4-alpha-GlcNAc (higher amounts) in bovine than in porcine heparin. Porcine and bovine heparins can be fractionated by anion exchange chromatography into three fractions containing different substitutions on the alpha-glucosamine units. Each individual fraction shows close disaccharide composition and anticoagulant activity, regardless of their origin (bovine or porcine intestine). However, these two heparins differ markedly in the proportions of the three fractions. Interestingly, fractions with the typical heparin disaccharides of porcine intestine are present in bovine intestinal heparin. These fractions contain high in vitro anticoagulant activity, reduced antithrombotic effect and high bleeding tendency. These observations indicate that the prediction of haemostatic effects of heparin preparations cannot rely exclusively on structural analysis and anticoagulant assays in vitro . Minor structural components may account for variations on in vivo effects. In conclusion, we suggest that pharmaceutical grade bovine intestinal heparin, even after purification procedures, is not an equivalent drug to porcine intestinal heparin. PMID- 22437651 TI - Synthesis of silver nanoparticle necklaces without explicit addition of reducing or templating agents. AB - Here we report that silver nanoparticle necklaces can be readily formed by treatment of colloidal silica with ammoniacal silver complex solution followed by washing, deposition and ageing. We investigate the morphology of the produced materials and elucidate the key variables that influence this promising new approach to one-dimensional nanostructuring. PMID- 22437652 TI - Transient elevation of serum cystatin C concentrations during perioperative cisplatin-based chemotherapy in esophageal cancer patients. AB - PURPOSE: In the present study, the time-concentration profile of platinum (Pt) in plasma was compared to that of serum cystatin C (Cys C) in Japanese esophageal cancer patients receiving perioperative cisplatin-based chemotherapy. METHODS: Five male and one female patients receiving 2 successive cycles of cisplatin based chemotherapy combined with 5-fluorouracil, the treatment for esophageal squamous cell carcinoma, participated in this study. The pharmacokinetic parameters in each patient were calculated from the individual plasma Pt concentration-time curve after intravenous infusion of cisplatin using the one compartment model. RESULTS: Within a week of starting the first cycle of chemotherapy, serum Cys C concentrations increased in all patients from 122.6 to 143.0%, subsequently returning to baseline levels in approximately 10 days. A similar increase in serum Cys C levels also occurred during the second treatment cycle. However, no increase in serum creatinine levels was observed during either treatment cycle. In addition, the concentration of plasma Pt 2 days after treatment in the first and second cycles did not correlate with those of either serum Cys C or creatinine. Finally, the half-life of Pt in plasma during the first treatment cycle was not significantly different from that in the second cycle. CONCLUSIONS: These findings suggest that concentration fluctuations in serum Cys C are unlikely to correlate with Pt elimination from the plasma and that renal function estimates based on serum Cys C concentration might be underestimated during perioperative cisplatin-based chemotherapy for esophageal cancer. PMID- 22437653 TI - Lupus anticoagulant and ANCA associated thrombotic vasculopathy due to cocaine contaminated with levamisole: a case report and review of the literature. AB - A 2010 US report recently detected the presence of levamisole in greater than 77 % of seized cocaine samples. A syndrome of retiform purpura, often involving ears and flanks, with vasculopathy or vasculitis on biopsy, associated with anti nuclear cytoplasmic antibodies as well as antiphospholipid antibodies, previously associated with therapeutic use of levamisole has now re-emerged, and is associated with cocaine adulterated with levamisole. Patients with this unusual constellation of signs and laboratory findings should be questioned about exposure to cocaine. PMID- 22437654 TI - Economic evaluation of the use of point-of-care devices in patients with long term oral anticoagulation. AB - To examine the cost and cost-effectiveness of the use of point-of-care (POC) devices by the general practitioner (GP), in anticoagulation clinic or by the patient in self-testing (PST) and self-management (PSM), compared with standard laboratory testing to realize international normalized ratio tests for patients on long term anticoagulation therapy. An economic evaluation was performed from the Belgian health care payer's perspective using a Markov model. Outcomes data were derived from a meta-analysis and cost data were derived from claims databases. Several scenarios were tested based on number of tests and GP's contacts and probabilistic sensitivity analysis was used to handle uncertainty. Evidence on the impact of POC on mortality was only found for PSM. Therefore, a cost-effectiveness analysis was performed for PSM and for other strategies, only a cost comparison was done. With an unchanged number of tests, POC is cost-saving compared to laboratory testing (probability > 70%). In scenarios where POC induces more tests, results were different: with 52 tests/year, only PSM kept a probability of remaining cost-saving superior to 50%. Except in the case of 100% of GP consultations maintained and 52 tests/year performed, PSM resulted in significantly more "life years gained" (LYG) than usual care and was on average cost-saving. The organisation of long term oral anticoagulation monitoring should be directed towards PSM and, to a lesser extent, PST for selected and trained patients. PMID- 22437655 TI - Clinical evidence of particle beam therapy. PMID- 22437656 TI - The limits of precision in conventionally instrumented computer-navigated total knee arthroplasty. AB - PURPOSE: Computer-navigated total knee arthroplasty (TKA) improves the accuracy of component implantation. However, the final implant alignment may not match planned alignment. The hypothesis of this study is that although computer navigation improves alignment, imprecision may not be completely eliminated. The aim of the study was to establish the incidence and sources of imprecision during TKA using computer navigation to measure deviations from planned alignment. METHODS: Computer navigation was used to quantify changes in planned alignment at four steps during 136 TKA's: application of cutting blocks, addition of definitive pin fixation, bone cuts and after prosthesis application. Mean changes in alignment deviation at each step in each plane were measured and the number of significant outliers (>3 degrees from the planned resection plane) were assessed in each plane. RESULTS: Overall changes in planned alignment were small and non cumulative between steps but the incidence of outliers (cuts measured as >3 degrees from planned alignment at each step) increased through the steps, with 21.3 % (n = 29) of final implants outlying in the tibial sagittal plane, which was the least precise plane. The highest number of outliers occurred after bone resection and the addition of pins to cutting blocks was also identified as a source of imprecision. CONCLUSION: Despite improved accuracy of bone resection with computer-navigated TKA, the precision of bone cuts may be affected at several steps of the procedure. Cutting block application, bone resection and prosthesis application may all affect accuracy. Bone cuts should be made with meticulous care, whether navigated or not, and navigated cuts should be checked and corrected, particularly in the tibial sagittal plane. LEVEL OF EVIDENCE: IV. PMID- 22437657 TI - Lessons learned from the last 20 years of ACL-related in vivo-biomechanics research of the knee joint. AB - PURPOSE: Technological advances in recent years have allowed the easy and accurate assessment of knee motion during athletic activities. Subsequently, thousands of studies have been published that greatly improved our understanding of the aetiology, surgical reconstruction techniques and prevention of anterior cruciate ligament (ACL) injuries. The purpose of this review is to summarize the evidence from biomechanical studies on ACL-related research. METHODS: High-impact articles that enhanced understanding of ACL injury aetiology, rehabilitation, prevention and adaptations after reconstruction were selected. RESULTS: The importance of restoring internal tibial rotation after ACL reconstruction has emerged in several studies. Criteria-based, individualized rehabilitation protocols have replaced the traditional time-based protocols. Excessive knee valgus, poor trunk control, excessive quadriceps forces and leg asymmetries have been identified as potential high risk biomechanical factors for ACL tear. Injury prevention programmes have emerged as low cost and effective means of preventing ACL injuries, particularly in female athletes. CONCLUSION: As a result of biomechanical research, clinicians have a better understanding of ACL injury aetiology, prevention and rehabilitation. Athletes exhibiting neuromuscular deficits predisposing them to ACL injury can be identified and enrolled into prevention programmes. Clinicians should assess ACL-reconstructed patients for excessive internal tibial rotation that may lead to poor outcomes. PMID- 22437658 TI - Anterior crucial ligament rupture: self-healing through dynamic intraligamentary stabilization technique. AB - PURPOSE: Surgery involving arthroscopic reconstruction of the injured ligament is the gold standard treatment for torn anterior cruciate ligament (ACL). Recent studies support the hypothesis of biological self-healing of ruptured ACL. The aim of the study is to evaluate, in an animal model, the efficacy of a new technique, dynamic intraligamentary stabilization that utilizes biological self healing for repair of acute ACL ruptures. METHODS: The ACL in 11 adult female white alpine sheep was transected and in 8 sheep reconstructed by dynamic intraligamentary stabilization. To enhance the healing potential, microfracturing and collagen were used in all animals. The contralateral, non-operated knees served as controls. At 3 months postkilling, all animals were submitted to magnetic resonance imaging and biomechanical and histological evaluation. RESULTS: No surgery-related complications were observed. Postoperatively, all animals regularly used the operated leg with full weight bearing and no lameness. At the time of killing, all animals exhibited radiological and histological healing of the transacted ACL. Biomechanical tests confirmed successful restoration of anteroposterior translation in the dynamic intraligamentary stabilization knees. Histological examination revealed dense scar tissue at the ends of the transected ligaments exhibiting hypercellularity and hypervascularization. CONCLUSION: The dynamic intraligamentary stabilization technique successfully induced self-healing of ruptured ACL in a sheep model. Knee joints remained stable during the healing period allowing free range of motion and full weight bearing, and no signs of osteoarthritis or other intraarticular damage in the follow up were observed. PMID- 22437659 TI - Is arthroscopic surgery beneficial in treating non-traumatic, degenerative medial meniscal tears? A five year follow-up. AB - PURPOSE: The aim of this prospective randomized intervention study was to evaluate the outcome at a 2 and 5 year follow-up whether combined arthroscopic surgery followed by exercise therapy was superior to the same exercise therapy alone when treating non-traumatic, degenerative medial meniscal tears. METHODS: Ninety-six middle-aged patients with MRI-verified degenerative medial meniscus tear and radiographic osteoarthritis grade <=1 (Ahlback) participated in the study. Radiographic examination was done before randomization and after 5 years. The patients were randomly assigned to either arthroscopic treatment followed by exercise therapy for 2 months or to the same exercise therapy alone. At the start of the study and at the follow-ups at 24 and 60 months the patients answered three questionnaires KOOS, Lysholm Knee Scoring Scale and Tegner Activity Scale and made pain ratings on the Visual Analogue Scale (VAS). RESULTS: Both groups showed highly significant clinical improvements from baseline to the follow-ups at 24 and 60 months on all subscales of KOOS, Lysholm Knee Scoring Scale and VAS (p < 0.0001). No group differences were found at any of the testing occasions. One third of the patients that were treated with exercise therapy alone did not feel better after the treatment but were improved after arthroscopic surgery. According to radiographic findings two patients from each group had a slight progression of their osteoarthritis after 5 years. CONCLUSION: The findings indicate that arthroscopic surgery followed by exercise therapy was not superior to the same exercise therapy alone for this type of patients. Consequently, exercise therapy can be recommended as initial treatment. However, one third of the patients from the exercise group still had disabling knee symptoms after exercise therapy but improved to the same level as the rest of the patients after arthroscopic surgery with partial meniscectomy. LEVEL OF EVIDENCE: I. PMID- 22437660 TI - The effect of tunnel placement on rotational stability after ACL reconstruction: evaluation with use of triaxial accelerometry in a porcine model. AB - PURPOSE: Conventional transtibial technique fails to restore the rotational knee stability in spite of successful anterior laxity, while anatomic anterior cruciate ligament reconstruction using the anteromedial portal technique has been developed expecting better rotational kinematics because of closer reproduction of the native anterior cruciate ligament anatomy. However, the rotational instability after those two procedures has not been fully examined especially in terms of dynamic component of the rotational stability. The purpose was to assess the effect of anatomic versus non-anatomic tunnel placement on rotational knee stability after anterior cruciate ligament reconstruction using triaxial accelerometry. METHODS: Sixteen porcine knees underwent a manual pivot-shift test at four different conditions: (1) anterior cruciate ligament intact, (2) anterior cruciate ligament deficient, (3) non-anatomic transtibial reconstruction, and (4) anatomic anteromedial portal reconstruction. The three-dimensional acceleration of knee motion during the pivot-shift test was recorded using a triaxial accelerometer. RESULTS: Both anterior cruciate ligament reconstructions decreased significantly the acceleration of the pivot-shift test from the increased level in the anterior cruciate ligament-deficient condition. However, the transtibial technique fails to reach the intact level of acceleration, while the anteromedial portal technique reduced the acceleration to even less than the intact level. CONCLUSION: The transtibial anterior cruciate ligament reconstruction could not restore the dynamic rotational stability of the intact knee, whereas the anteromedial portal technique restored the dynamic rotational stability closer to the intact level. LEVEL OF EVIDENCE: III. PMID- 22437661 TI - Agenesis of the posterolateral bundle of anterior cruciate ligament. AB - The objective of this article is to report an anterior cruciate ligament variation that has not been previously described, in which the posterolateral bundle of anterior cruciate ligament is congenitally not developed. The clinical picture and the magnetic resonance images are presented, and the arthroscopic appearance is described. PMID- 22437662 TI - Foliar aphid feeding recruits rhizosphere bacteria and primes plant immunity against pathogenic and non-pathogenic bacteria in pepper. AB - BACKGROUND AND AIMS: Plants modulate defence signalling networks in response to different biotic stresses. The present study evaluated the effect of a phloem sucking aphid on plant defence mechanisms in pepper (Capsicum annuum) during subsequent pathogen attacks on leaves and rhizosphere bacteria on roots. METHODS: Plants were pretreated with aphids and/or the chemical trigger benzothiadiazol (BTH) 7 d before being challenged with two pathogenic bacteria, Xanthomonas axonopodis pv. vesicatoria (Xav) as a compatible pathogen and X. axonopodis pv. glycines (Xag) as an incompatible (non-host) pathogen. KEY RESULTS: Disease severity was noticeably lower in aphid- and BTH + aphid-treated plants than in controls. Although treatment with BTH or aphids alone did not affect the hypersensitive response (HR) against Xag strain 8ra, the combination treatment had a synergistic effect on the HR. The aphid population was reduced by BTH pretreatment and by combination treatment with BTH and bacterial pathogens in a synergistic manner. Analysis of the expression of the defence-related genes Capsicum annum pathogenesis-related gene 9 (CaPR9), chitinase 2 (CaCHI2), SAR8.2 and Lipoxygenase1 (CaLOX1) revealed that aphid infestation resulted in the priming of the systemic defence responses against compatible and incompatible pathogens. Conversely, pre-challenge with the compatible pathogen Xav on pepper leaves significantly reduced aphid numbers. Aphid infestation increased the population of the beneficial Bacillus subtilis GB03 but reduced that of the pathogenic Ralstonia solanacearum SL1931. The expression of defence-related genes in the root and leaf after aphid feeding indicated that the above-ground aphid infestation elicited salicylic acid and jasmonic acid signalling throughout the whole plant. CONCLUSIONS: The findings of this study show that aphid feeding elicits plant resistance responses and attracts beneficial bacterial populations to help the plant cope with subsequent pathogen attacks. PMID- 22437663 TI - Tall or short? Slender or thick? A plant strategy for regulating elongation growth of roots by low concentrations of gibberellin. AB - BACKGROUND: Since the plant hormone gibberellin (GA) was discovered as a fungal toxin that caused abnormal elongation of rice shoots, the physiological function of GA has mainly been investigated in relation to the regulation of plant height. However, an indispensable role for GA in root growth has been elucidated by using severely GA-depleted plants, either with a gene mutation in GA biosynthesis or which have been treated by an inhibitor of GA biosynthesis. The molecular sequence of GA signalling has also been studied to understand GA functions in root growth. SCOPE: This review addresses research progress on the physiological functions of GA in root growth. Concentration-dependent stimulation of elongation growth by GA is important for the regulation of plant height and root length. Thus the endogenous level of GA and/or the GA sensitivity of shoots and roots plays a role in determining the shoot-to-root ratio of the plant body. Since the shoot-to-root ratio is an important parameter for agricultural production, control of GA production and GA sensitivity may provide a strategy for improving agricultural productivity. The sequence of GA signal transduction has recently been unveiled, and some component molecules are suggested as candidate in planta regulatory sites and as points for the artificial manipulation of GA-mediated growth control. CONCLUSIONS: This paper reviews: (1) the breakthrough dose response experiments that show that root growth is regulated by GA in a lower concentration range than is required for shoot growth; (2) research on the regulation of GA biosynthesis pathways that are known predominantly to control shoot growth; and (3) recent research on GA signalling pathways, including GA receptors, which have been suggested to participate in GA-mediated growth regulation. This provides useful information to suggest a possible strategy for the selective control of shoot and root growth, and to explain how GA plays a role in rosette and liana plants with tall or short, and slender or thick axial organs. PMID- 22437664 TI - The proteome of Populus nigra woody root: response to bending. AB - BACKGROUND AND AIMS: Morphological and biomechanical alterations occurring in woody roots of many plant species in response to mechanical stresses are well documented; however, little is known about the molecular mechanisms regulating these important alterations. The first forest tree genome to be decoded is that of Populus, thereby providing a tool with which to investigate the mechanisms controlling adaptation of woody roots to changing environments. The aim of this study was to use a proteomic approach to investigate the response of Populus nigra woody taproot to mechanical stress. METHODS: To simulate mechanical perturbations, the taproots of 30 one-year-old seedlings were bent to an angle of 90 degrees using a steel net. A spatial and temporal two-dimensional proteome map of the taproot axis was obtained. We compared the events occurring in the above-bending, central bending and below-bending sectors of the taproot. KEY RESULTS: The first poplar woody taproot proteome map is reported here; a total of 207 proteins were identified. Spatial and temporal proteomic analysis revealed that factors involved in plant defence, metabolism, reaction wood formation and lateral root development were differentially expressed in the various sectors of bent vs. control roots, seemingly in relation to the distribution of mechanical forces along the stressed woody taproots. A complex interplay among different signal transduction pathways involving reactive oxygen species appears to modulate these responses. CONCLUSIONS: Poplar woody root uses different temporal and spatial mechanisms to respond to mechanical stress. Long-term bending treatment seem to reinforce the defence machinery, thereby enabling the taproot to better overcome winter and to be ready to resume growth earlier than controls. PMID- 22437665 TI - Temporal changes in population genetic diversity and structure in red and white clover grown in three contrasting environments in northern Europe. AB - BACKGOUND AND AIMS: Extending the cultivation of forage legume species into regions where they are close to the margin of their natural distribution requires knowledge of population responses to environmental stresses. This study was conducted at three north European sites (Iceland, Sweden and the UK) using AFLP markers to analyse changes in genetic structure over time in two population types of red and white clover (Trifolium pratense and T. repens, respectively): (1) standard commercial varieties; (2) wide genetic base (WGB) composite populations constructed from many commercial varieties plus unselected material obtained from germplasm collections. METHODS: At each site populations were grown in field plots, then randomly sampled after 3-5 years to obtain survivor populations. AFLP markers were used to calculate genetic differentiation within and between original and survivor populations. KEY RESULTS: No consistent changes in average genetic diversity were observed between original and survivor populations. In both species the original varieties were always genetically distinct from each other. Significant genetic shift was observed in the white clover 'Ramona' grown in Sweden. The WGB original populations were more genetically similar. However, genetic differentiation occurred between original and survivor WGB germplasm in both species, particularly in Sweden. Regression of climatic data with genetic differentiation showed that low autumn temperature was the best predictor. Within the set of cold sites the highest level of genetic shift in populations was observed in Sweden. CONCLUSIONS: The results suggest that changes in population structure can occur within a short time span in forage legumes, resulting in the rapid formation of distinct survivor populations in environmentally challenging sites. PMID- 22437666 TI - Lunisolar tidal force and the growth of plant roots, and some other of its effects on plant movements. AB - BACKGROUND: Correlative evidence has often suggested that the lunisolar tidal force, to which the Sun contributes 30 % and the Moon 60 % of the combined gravitational acceleration, regulates a number of features of plant growth upon Earth. The time scales of the effects studied have ranged from the lunar day, with a period of approx. 24.8 h, to longer, monthly or seasonal variations. SCOPE: We review evidence for a lunar involvement with plant growth. In particular, we describe experimental observations which indicate a putative lunar based relationship with the rate of elongation of roots of Arabidopsis thaliana maintained in constant light. The evidence suggests that there may be continuous modulation of root elongation growth by the lunisolar tidal force. In order to provide further supportive evidence for a more general hypothesis of a lunisolar regulation of growth, we highlight similarly suggestive evidence from the time courses of (a) bean leaf movements obtained from kymographic observations; (b) dilatation cycles of tree stems obtained from dendrograms; and (c) the diurnal changes of wood-water relationships in a living tree obtained by reflectometry. CONCLUSIONS: At present, the evidence for a lunar or a lunisolar influence on root growth or, indeed, on any other plant system, is correlative, and therefore circumstantial. Although it is not possible to alter the lunisolar gravitational force experienced by living organisms on Earth, it is possible to predict how this putative lunisolar influence will vary at times in the near future. This may offer ways of testing predictions about possible Moon-plant relationships. As for a hypothesis about how the three-body system of Earth-Sun-Moon could interact with biological systems to produce a specific growth response, this remains a challenge for the future. Plant growth responses are mainly brought about by differential movement of water across protoplasmic membranes in conjunction with water movement in the super-symplasm. It may be in this realm of water movements, or even in the physical forms which water adopts within cells, that the lunisolar tidal force has an impact upon living growth systems. PMID- 22437667 TI - Intraoperative detection and removal of microscopic residual sarcoma using wide field imaging. AB - BACKGROUND: The goal of limb-sparing surgery for a soft tissue sarcoma of the extremity is to remove all malignant cells while preserving limb function. After initial surgery, microscopic residual disease in the tumor bed will cause a local recurrence in approximately 33% of patients with sarcoma. To help identify these patients, the authors developed an in vivo imaging system to investigate the suitability of molecular imaging for intraoperative visualization. METHODS: A primary mouse model of soft tissue sarcoma and a wide field-of-view imaging device were used to investigate a series of exogenously administered, near infrared (NIR) fluorescent probes activated by cathepsin proteases for real-time intraoperative imaging. RESULTS: The authors demonstrated that exogenously administered cathepsin-activated probes can be used for image-guided surgery to identify microscopic residual NIR fluorescence in the tumor beds of mice. The presence of residual NIR fluorescence was correlated with microscopic residual sarcoma and local recurrence. The removal of residual NIR fluorescence improved local control. CONCLUSIONS: The authors concluded that their technique has the potential to be used for intraoperative image-guided surgery to identify microscopic residual disease in patients with cancer. PMID- 22437668 TI - Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel. AB - OBJECTIVE: The clinical use of paclitaxel is limited by variable responses and the potential for significant toxicity. To date, studies of associations between variants in candidate genes and paclitaxel effects have yielded conflicting results. We aimed to evaluate the relationships between global gene expression and paclitaxel sensitivity. METHODS: We utilized well-genotyped lymphoblastoid cell lines derived from the International HapMap Project to evaluate the relationships between cellular susceptibility to paclitaxel and global gene expression. Cells were exposed to varying concentrations of paclitaxel to evaluate paclitaxel-induced cytotoxicity and apoptosis. Among the top genes, we identified solute carrier (SLC) genes associated with paclitaxel sensitivity and narrowed down the list to those that had single nucleotide polymorphisms associated with both the expression level of the SLC gene and also with paclitaxel sensitivity. We performed an independent validation in an independent set of cell lines and also conducted functional studies using RNA interference. RESULTS: Of all genes associated with paclitaxel-induced cytotoxicity at P less than 0.05 (1713 genes), there was a significant enrichment in SLC genes (31 genes). A subset of SLC genes, namely SLC31A2, SLC43A1, SLC35A5, and SLC41A2, was associated with paclitaxel sensitivity and had regulating single nucleotide polymorphisms that were also associated with paclitaxel-induced cytotoxicity. Multivariate modeling demonstrated that those four SLC genes together explained 20% of the observed variability in paclitaxel susceptibility. Using RNA interference, we demonstrated increased paclitaxel susceptibility with knockdown of three SLC genes, SLC31A2, SLC35A5, and SLC41A2. CONCLUSION: Our findings are novel and lend further support to the role of transporters, specifically solute carriers, in mediating cellular susceptibility to paclitaxel. PMID- 22437669 TI - Improved insulin sensitivity after treatment with PPARgamma and PPARalpha ligands is mediated by genetically modulated transcripts. AB - OBJECTIVES: We aimed to define the effects of peroxisomal proliferator-activated receptor gamma (PPARgamma) and PPARalpha agonist mono and combination therapy on adipose tissue and skeletal muscle gene expression in relation to insulin sensitivity. We further investigated the role of genetic polymorphisms in PPAR ligand-modulated genes in transcriptional regulation and glucose homeostasis. MATERIALS AND METHODS: Genome-wide transcript profiles of subcutaneous adipose and skeletal muscle and metabolic phenotypes were assessed before and after 10 weeks of pioglitazone and fenofibrate mono or combination therapy in 26 patients with impaired glucose tolerance. To establish the functional role of single nucleotide polymorphisms (SNPs) in genes modulated by pioglitazone alone or in combination with fenofibrate, we examined genome-wide association data of continuous glycemic phenotypes from the Meta-Analyses of Glucose and Insulin Related Traits Consortium study and adipose eQTL data from the Multi Tissue Human Expression Resource study. RESULTS: PPARgamma, alone or in combination with PPARalpha agonists, mediated upregulation of genes involved in the TCA cycle, branched-chain amino acid (BCAA) metabolism, fatty acid metabolism, PPAR signaling, AMPK and cAMP signaling, and insulin signaling pathways, and downregulation of genes in antigen processing and presentation, and immune and inflammatory response in adipose tissue. Remarkably few changes were found in muscle. Strong enrichment of genes involved in propanoate metabolism, fatty acid elongation in the mitochondria, and acetyl-CoA metabolic process were observed only in adipose tissue of the combined pioglitazone and fenofibrate treatment group. After examining Meta-Analyses of Glucose and Insulin-Related Traits Consortium data, SNPs in 22 genes modulated by PPAR ligands were associated with fasting plasma glucose and the expression of 28 transcripts modulated by PPAR ligands was under control of local genetic regulators (cis-eQTLs) in adipose tissue of Multi Tissue Human Expression Resource study twins. CONCLUSION: We found differences in transcriptional mechanisms that may describe the insulin sensitizing effects of PPARgamma agonist monotherapy or in combination with a PPARalpha agonist. The regulatory and glucose homeostasis trait-associated SNPs in PPAR agonist-modulated genes are important candidates for future studies that may explain the interindividual variability in response to thiazolidinedione and fenofibrate treatment. PMID- 22437670 TI - Influence of periodontal therapy on C-reactive protein level: a systematic review and meta-analysis. AB - The influence of oral infections, especially periodontal disease, on systemic diseases has been extensively discussed in the literature. Because periodontal disease is a persistent infection, it promotes an inflammatory response. C reactive protein is a marker for inflammatory reactions that is frequently studied, since elevated levels of this protein are related to coronary events. OBJECTIVE: The aim of this study was to investigate the effect of periodontal therapy on reducing the serum levels of C-reactive protein, by means of a systematic review of the literature and meta-analysis. MATERIAL AND METHODS: A systematic review of the English-language literature was conducted in the PUBMED MEDLINE database, using the key words "periodontal disease", "C-reactive protein", "periodontal therapy" and "periodontal treatment", in accordance with the terms for Medical Subject Headings (MeSH), to evaluate the effect of periodontal therapy on C-reactive protein levels. A qualitative analysis of studies of randomized clinical trial design was performed using CONSORT, with subsequent meta-analysis. RESULTS: The literature search initially retrieved 46 potentially relevant studies available in the databases. From these, in accordance with the inclusion criteria, only 11 were selected, of which only 4 fulfilled the criteria of randomized clinical trial design. According to CONSORT, the studies evaluated generally presented good quality with regard to the criteria analyzed. Through meta-analysis, the reduction in mean levels of C reactive protein (-0.231; p=0.000) after introducing periodontal treatment was estimated. The result was statistically significant, without evidence of heterogeneity between the studies (p=0.311). CONCLUSIONS: The findings indicated that non-surgical periodontal treatment had a positive effect with regard to reduction of the serum levels of C-reactive protein. PMID- 22437671 TI - Rehabilitative treatment of cleft lip and palate: experience of the Hospital for Rehabilitation of Craniofacial Anomalies/USP (HRAC/USP)--Part 1: overall aspects. AB - Cleft lip and palate is the most common among craniofacial malformations and causes several esthetic and functional implications that require rehabilitation. This paper aims to generally describe the several aspects related to this complex pathology and the treatment protocol used by the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo (HRAC-USP) along 40 years of experience in the treatment of individuals with cleft lip and palate. PMID- 22437672 TI - Diametral tensile strength and film thickness of an experimental dental luting agent derived from castor oil. AB - The need to develop new dental luting agents in order to improve the success of treatments has greatly motivated research. OBJECTIVE: The aim of this study was to evaluate the diametral tensile strength (DTS) and film thickness (FT) of an experimental dental luting agent derived from castor oil (COP) with or without addition of different quantities of filler (calcium carbonate - CaCO3). MATERIAL AND METHODS: Eighty specimens were manufactured (DTS N=40; FT N=40) and divided into 4 groups: Pure COP; COP 10%; COP 50% and zinc phosphate (control). The cements were mixed according to the manufacturers' recommendations and submitted to the tests. The DTS test was performed in the MTS 810 testing machine (10 KN, 0.5 mm/min). For FT test, the cements were sandwiched between two glass plates (2 cm2) and a load of 15 kg was applied vertically on the top of the specimen for 10 min. The data were analyzed by means of one-way ANOVA and Tukey's test (alpha=0.05). RESULTS: The values of DTS (MPa) were: Pure COP- 10.94 +/- 1.30; COP 10%- 30.06 +/- 0.64; COP 50%- 29.87 +/- 0.27; zinc phosphate- 4.88 +/- 0.96. The values of FT (um) were: Pure COP- 31.09 +/- 3.16; COP 10%- 17.05 +/- 4.83; COP 50%- 13.03 +/- 4.83; Zinc Phosphate- 20.00 +/- 0.12. One-way ANOVA showed statistically significant differences among the groups (DTS - p=1.01E-40; FT - p=2.4E-10). CONCLUSION: The experimental dental luting agent with 50% of filler showed the best diametral tensile strength and film thickness. PMID- 22437673 TI - A comparative evaluation of the efficacy of manual, magnetostrictive and piezoelectric ultrasonic instruments--an in vitro profilometric and SEM study. AB - OBJECTIVES: The debridement of diseased root surface is usually performed by mechanical scaling and root planing using manual and power driven instruments. Many new designs in ultrasonic powered scaling tips have been developed. However, their effectiveness as compared to manual curettes has always been debatable. Thus, the objective of this in vitro study was to comparatively evaluate the efficacy of manual, magnetostrictive and piezoelectric ultrasonic instrumentation on periodontally involved extracted teeth using profilometer and scanning electron microscope (SEM). MATERIAL AND METHODS: 30 periodontally involved extracted human teeth were divided into 3 groups. The teeth were instrumented with hand and ultrasonic instruments resembling clinical application. In Group A all teeth were scaled with a new universal hand curette (Hu Friedy Gracey After Five Vision curette; Hu Friedy, Chicago, USA). In Group B CavitronTM FSI - SLI TM ultrasonic device with focused spray slimline inserts (Dentsply International Inc., York, PA, USA) were used. In Group C teeth were scaled with an EMS piezoelectric ultrasonic device with prototype modified PS inserts. The surfaces were analyzed by a Precision profilometer to measure the surface roughness (Ra value in um) consecutively before and after the instrumentation. The samples were examined under SEM at magnifications ranging from 17x to 300x and 600x. RESULTS: The mean Ra values (um) before and after instrumentation in all the three groups A, B and C were tabulated. After statistically analyzing the data, no significant difference was observed in the three experimental groups. Though there was a decrease in the percentage reduction of Ra values consecutively from group A to C. CONCLUSION: Within the limits of the present study, given that the manual, magnetostrictive and piezoelectric ultrasonic instruments produce the same surface roughness, it can be concluded that their efficacy for creating a biologically compatible surface of periodontally diseased teeth is similar. PMID- 22437674 TI - Fluoride and aluminum release from restorative materials using ion chromatography. AB - OBJECTIVE: The aim of this study was to determine the amounts of fluoride and aluminum released from different restorative materials stored in artificial saliva and double-distilled water. MATERIAL AND METHODS: Cylindrical specimens (10 x 1 mm) were prepared from 4 different restorative materials (Kavitan Plus, Vitremer, Dyract Extra, and Surefil). For each material, 20 specimens were prepared, 10 of which were stored in 5 mL artificial saliva and 10 of which were stored in 5 mL of double-distilled water. Concentrations of fluoride and aluminum in the solutions were measured using ion chromatography. Measurements were taken daily for one week and then weekly for two additional weeks. Data were analyzed using two-way ANOVA and Duncan's multiple range tests (p<0.05). RESULTS: The highest amounts of both fluoride and aluminum were released by the resin-modified glass ionomer cement Vitremer in double-distilled water (p<0.05). All materials released significantly more fluoride in double-distilled water than in artificial saliva (p<0.05). In artificial saliva, none of the materials were observed to release aluminum. CONCLUSION: It was concluded that storage media and method of analysis should be taken into account when the fluoride and aluminum release from dental materials is assessed. PMID- 22437675 TI - Antimicrobial capacity of Aloe vera and propolis dentifrice against Streptococcus mutans strains in toothbrushes: an in vitro study. AB - OBJECTIVES: This study evaluated in vitro the efficiency of Aloe vera and propolis dentifrice on reducing the contamination of toothbrush bristles by a standard strain of Streptococcus mutans (ATCC 25175; SM), after toothbrushing. MATERIAL AND METHODS: Fifteen sterile toothbrushes were randomly divided into 5 toothbrushing groups: I (negative control): without dentifrice; II: with fluoridated dentifrice; III: with triclosan and gantrez dentifrice; IV (positive control): without dentifrice and irrigation with 10 mL of 0.12% chlorhexidine gluconate; V: with Aloe vera and propolis dentifrice. In each group, 1 sterile bovine tooth was brushed for 1 min, where the toothbrush bristles were contaminated with 25 uL of SM. After toothbrushing, the bristles were stored in individual test tubes with 3 mL of BHI under anaerobiosis of 37 degrees C for 48 h. Then, they were seeded with sterile swab in triplicate in the Mitis salivarius - Bacitracin culture medium. The samples were kept under anaerobiosis of 37 degrees C for 48 h. Scores were used to count the number of colony forming units (cfu). The results were submitted to the Mann-Whitney statistical test at 5% significance level. RESULTS: There was statistically significant difference (p<0.05) for the reduction of bristle contamination comparing groups II, III, IV and V to group I. CONCLUSIONS: It may be stated that after toothbrushing, the Aloe vera and propolis dentifrice reduced the contamination of toothbrush bristles by SM, without differentiation from the other chemical agents used. PMID- 22437676 TI - Relation between oral health and nutritional condition in the elderly. AB - Oral health is a prerequisite for a good chewing function, which may have an impact on food choices and nutritional well-being. OBJECTIVE: This study was designed to evaluate the relationship between oral health status and nutritional status in the elderly. MATERIAL AND METHODS: In this cross-sectional study, 33 elderly people from the Group for the Elderly Interdisciplinary Geriatrics and Gerontology Program, at Fluminense Federal University, Niteroi, RJ, Brazil, completed a questionnaire to collect information on socioeconomic status, eating habits, physical activity and health habits, undertook a clinical oral examination, blood test, and anthropometric measurements, and were allocated into groups according to age. The oral health status was assessed using the index for decayed, missing and filled teeth (DMFT). The nutritional status was assessed using hemoglobin, hematocrit and albumin concentrations in blood, anthropometric values and the body mass index. RESULTS: Tooth loss was the biggest nuisance to the elderly subjects (57.6%), followed by the use of dentures (30.3%) and ill fitting dentures (33.3%). 66.6% of patients had difficulty in chewing, and 54.5% reported this to be due to prostheses and 13.6% to the absence of teeth. A significant correlation was found between DMFT and the value of suprailiac skinfold thickness (rho=0.380, p=0.029). CONCLUSION: The results support the temporal association between tooth loss and detrimental changes in anthropometry, which could contribute to increased risk of developing chronic diseases. PMID- 22437677 TI - Effect of antibacterial agents on the surface hardness of a conventional glass ionomer cement. AB - In atraumatic restorative treatment (ART), caries removal with hand excavation instruments is not as efficient as that with rotary burs in eliminating bacteria under the glass ionomer cements (GICs). Thus, different antibacterial agents have been used in recent studies to enhance the antibacterial properties of the GICs, without jeopardizing their basic physical properties. OBJECTIVE: The objective of this study was to evaluate the effect of antibacterial agents on the surface hardness of a conventional GIC (Fuji IX) using Vickers microhardness [Vickers hardness number (VHN)] test. MATERIAL AND METHODS: Cetrimide (CT), cetylpyridinium chloride (CPC) and chlorhexidine (CHX) were added to the powder and benzalkonium chloride (BC) was added to the liquid of Fuji IX in concentrations of 1% and 2%, and served as the experimental groups. A control group containing no additive was also prepared. After the completion of setting reaction, VHN measurements were recorded at 1, 7, 15, 30, 60, and 90 days after storage in 37 degrees C distilled water. A one-way ANOVA was performed followed by a Dunnett t test and Tamhane T2 tests and also repeated measurements ANOVA was used for multiple comparisons in 95% confidence interval. RESULTS: VHN results showed significant differences between the control and the experimental groups at all time periods (p<0.05 for all). Significant differences were observed between all study periods for individual groups (p<0.05). After 7 days, VHNs were decreased in all experimental groups while they continued to increase in the control group. BC and CHX groups demonstrated the least whereas CT and CPC groups exhibited most adverse effect on the hardness of set cements. CONCLUSIONS: Despite the decreased microhardness values in all experimental groups compared to the controls after 7 up to 90 days, incorporating certain antibacterial agents into Fuji IX GIC showed tolerable microhardness alterations within the limitations of this in vitro study. PMID- 22437678 TI - Histopathological analysis of corticosteroid-antibiotic preparation and propolis paste formulation as intracanal medication after pulpectomy: an in vivo study. AB - Intracanal medication in pulpectomy therapy is used between appointments with the objective of reducing pain and inflammatory processes in pulp and periapical tissues. Propolis has been known as a natural antibiotic and has been subject of medical and dental research due to its therapeutic properties such as antibiotic, analgesic and anti-inflammatory effects. OBJECTIVE: The aim was to carry out an in vivo evaluation of the periapical tissue response to propolis paste when used as an intracanal medication in the teeth of dogs after pulpectomy. MATERIAL AND METHODS: 72 dog's incisors were selected for the experiment. After biomechanical preparation the root canal was filled with a corticosteroid-antibiotic preparation, experimental propolis paste, non-medicament (negative control) or non-pulpectomy at all (positive control). The medications were left inside the root canal for 7, 14 or 28 days. At the end of the experimental period histological sections were prepared and all laboratories processes for Harris hematoxylin and eosin staining was proceeded followed by the analysis using an optical microscope. Sections were classified according to a score representing the inflammatory events observed: the presence of polymorphonuclear neutrophils, polymorphonuclear eosinophils, lymphocytes and plasma cells, macrophages and/or giant cells, fibrous condensation and abscesses. RESULTS: There were statistically significant differences between the tissue reactions caused by the two substances being tested, after different experimental periods, with the periapical tissue that was in contact with propolis paste exhibiting fewer inflammatory reactions in comparison to corticosteroid-antibiotic preparation. CONCLUSIONS: The low tissue responses from propolis paste suggest that this material could be considered as an option for root canal medication after pulpectomy. PMID- 22437679 TI - Analysis of kinematic, kinetic and electromyographic patterns during root canal preparation with rotary and manual instruments. AB - OBJECTIVE: This study assessed the muscular activity during root canal preparation through kinematics, kinetics, and electromyography (EMG). MATERIAL AND METHODS: The operators prepared one canal with RaCe rotary instruments and another with Flexo-files. The kinematics of the major joints was reconstructed using an optoelectronic system and electromyographic responses of the flexor carpi radialis, extensor carpi radialis, brachioradialis, biceps brachii, triceps brachii, middle deltoid, and upper trapezius were recorded. The joint torques of the shoulder, elbow and wrist were calculated using inverse dynamics. In the kinematic analysis, angular movements of the wrist and elbow were classified as low risk factors for work-related musculoskeletal disorders. With respect to the shoulder, the classification was medium-risk. RESULTS: There was no significant difference revealed by the kinetic reports. The EMG results showed that for the middle deltoid and upper trapezius the rotary instrumentation elicited higher values. The flexor carpi radialis and extensor carpi radialis, as well as the brachioradialis showed a higher value with the manual method. CONCLUSION: The muscular recruitment for accomplishment of articular movements for root canal preparation with either the rotary or manual techniques is distinct. Nevertheless, the rotary instrument presented less difficulty in the generation of the joint torque in each articulation, thus, presenting a greater uniformity of joint torques. PMID- 22437680 TI - Standard of disocclusion in complete dentures supported by implants without free distal ends: analysis by the finite elements method. AB - OBJECTIVE: The occlusal patterns are key requirements for the clinical success of oral rehabilitation supported by implants. This study compared the stresses generated by the disocclusion in the canine guide occlusion (CGO) and bilateral balanced occlusion (BBO) on the implants and metallic infrastructure of a complete Branemark protocol-type denture modified with the inclusion of one posterior short implant on each side. MATERIAL AND METHODS: A three-dimensional model simulated a mandible with seven titanium implants as pillars, five of them installed between the mental foramen and the two posterior implants, located at the midpoint of the occlusal surface of the first molar. A load of 15 N with an angle of 45 degrees was applied to a tooth or distributed across three teeth to simulate the CGO or BBO, respectively. The commercial program ABAQUS(r) was used for the model development, before and after the processing of the data. The results were based on a linear static analysis and were used to compare the magnitude of the equivalent stress for each of the simulations. RESULTS: The results showed that the disocclusion in CGO generated higher stresses concentrated on the working side in the region of the short implant. In BBO, the stresses were less intense and more evenly distributed on the prosthesis. The maximum stress found in the simulation of the disocclusion in CGO was two times higher than that found in the simulation of the BBO. The point of maximum stress was located in the neck of the short implant on the working side. CONCLUSIONS: Under the conditions of this study, it was concluded that the BBO pattern was more suitable than CGO for the lower complete denture supported by implants without free distal ends. PMID- 22437681 TI - Multi-species biofilm of Candida albicans and non-Candida albicans Candida species on acrylic substrate. AB - OBJECTIVE: In polymicrobial biofilms bacteria extensively interact with Candida species, but the interaction among the different species of the Candida is yet to be completely evaluated. In the present study, the difference in biofilm formation ability of clinical isolates of four species of Candida in both single species and multi-species combinations on the surface of dental acrylic resin strips was evaluated. MATERIAL AND METHODS: The species of Candida, isolated from multiple species oral candidiasis of the neutropenic patients, were used for the experiment. Organisms were cultured on Sabouraud dextrose broth with 8% glucose (SDB). Biofilm production on the acrylic resins strips was determined by crystal violet assay. Student's t-test and ANOVA were used to compare in vitro biofilm formation for the individual species of Candida and its different multi-species combinations. RESULTS: In the present study, differences between the mean values of the biofilm-forming ability of individual species (C. glabrata>C. krusei>C. tropicalis>C. albicans) and in its multi-species' combinations (the highest for C. albicans with C. glabrata and the lowest for all the four species combination) were reported. CONCLUSIONS: The findings of this study showed that biofilm forming ability was found greater for non-Candida albicans Candida species (NCAC) than for C. albicans species with intra-species variation. Presence of C. albicans in multi-species biofilms increased, whereas; C. tropicalis decreased the biofilm production with all other NCAC species. PMID- 22437682 TI - Morphometric study of the root anatomy in furcation area of mandibular first molars. AB - Furcation involvement in periodontal disease has been a challenge for the dentist. OBJECTIVE: The aim of this study was to investigate root dimensions in the furcation area of 233 mandibular first molars. MATERIAL AND METHODS: Digital photomicrographs were used to obtain the following measurements on the buccal and lingual surfaces of each tooth: root trunk height (RT), horizontal interadicular distance obtained 1 mm (D1) and 2 mm (D2) below the fornix and interadicular angle (IA). RESULTS: Mean +/- standard deviation of buccal and lingual furcation measurements were, respectively, 1.37 +/- 0.78 mm and 2.04 +/- 0.89 mm for RT; 0.86 +/- 0.39 mm and 0.71 +/- 0.42 mm for D1; 1.50 +/- 0.48 mm and 1.38 +/- 0.48 mm for D2; 41.68 +/- 13.20 degrees and 37.78 +/- 13.18 degrees for IA. Statistically significant differences were found between all measured parameters for buccal and lingual sides (p<0.05, paired t test). CONCLUSIONS: In conclusion, the lingual furcation of mandibular first molars presented narrower entrance and longer root trunk than the buccal furcation, suggesting more limitation for instrumentation and worse prognosis to lingual furcation involvements in comparison to buccal lesions. PMID- 22437683 TI - Quality of cellular attachment to various root-end filling materials. AB - OBJECTIVES: This study investigated cellular attachment to 6 root-end filling materials as a measure of the biocompatibility of the materials. MATERIAL AND METHODS: Class I retrograde cavities were prepared in root slices and these cavities were filled with the test materials, and incubated with Balb/C 3T3 fibroblasts for 24 h. Root slices with the cavities left empty served as the controls. The root slices were then processed for scanning electron microscopy, and were viewed to assess the quality of cellular attachment by observing the shape of cells, spread, and membrane outline. RESULTS: The best cellular attachment was observed at MTA and Geristore surfaces: cells exhibited characteristic elongated fibroblastic morphology, with projections of lamellipodia, filopodia, blebs, and microvilli from their surfaces, reflecting good attachment to the material. Fibroblasts attached poorly to the surfaces of IRM, Super EBA, KetacFil and Retroplast. Furthermore, the cells did not attach well to the tooth structure next to IRM and Super EBA. CONCLUSIONS: The present study demonstrated a variation in cellular attachment to different root-end filling materials with the best cellular attachment to the surfaces of MTA and Geristore. IRM and Super EBA, KetacFil and Retroplast rendered poor attachment. PMID- 22437684 TI - Blood contamination effect on shear bond strength of an orthodontic hydrophilic resin. AB - OBJECTIVE: The aim of this study was to assess the impact of blood contamination on shear bond strength (SBS) and bond failure pattern of metallic brackets bonded using a new hydrophilic resin. MATERIAL AND METHODS: Eighty human premolars were randomly allocated into 4 groups (n=20) according to the bonding material and contamination pattern. GI: brackets bonded with the Transbond XT conventional system without contamination; GII: brackets bonded with the Transbond XT conventional system with blood contamination; GIII: brackets bonded with the Transbond Self Etching Primer and Transbond Plus Color without contamination; GIV: brackets bonded with the Transbond Self Etching Primer and Transbond Plus Color with blood contamination. The specimens were stored in distilled water at 37 degrees C for 24 h and then submitted to SBS test at a crosshead speed of 0.5 mm/min. After bond failure, the enamel surfaces were observed under an optical microscope at 40x magnification. RESULTS: Blood contamination decreased (P<0.05) shear bond strength when both the hydrophobic (GII) and the hydrophilic resin (GIV) were used. However, the bond strength of Transbond Color Change group was significantly higher (P<0.05) than that of the Transbond XT conventional system group under blood contamination condition. Under dry conditions no difference was observed between the hydrophobic and hydrophilic resin groups. Regarding the bond failure pattern, when blood contaminated the enamel, the adhesive remnant index (ARI) showed predominance of scores 0 and 1, which indicates low adhesion to enamel. CONCLUSIONS: Although there was a significant decrease in the shear bond strength for both adhesive systems under blood contamination, the hydrophilic system showed significantly higher bond strength than the hydrophobic resin adhesive. Therefore, it is advisable to use the hydrophilic resin under risk of blood contamination. PMID- 22437685 TI - Anticaries effect of dentifrices with calcium citrate and sodium trimetaphosphate. AB - Because of the growing concerns regarding fluoride ingestion by young children and dental fluorosis, it is necessary to develop new dentifrices. OBJECTIVE: The aim of this study was to evaluate the effect of dentifrices with calcium citrate (Cacit) and sodium trimetaphosphate (TMP) on enamel demineralization. MATERIAL AND METHODS: Enamel blocks (n=70), previously selected through surface hardness analysis, were submitted to daily treatment with dentifrices diluted in artificial saliva and to a pH-cycling model. The fluoride concentration in dentifrices was 0, 250, 450, 550, 1,000 and 1,100 ug F/g. CrestTM was used as a positive control (1,100 mg F/g). Cacit (0.25%) and TMP (0.25%) were added to dentifrices with 450 and 1,000 ug F/g. Surface hardness was measured again and integrated loss of subsurface hardness and fluoride concentration in enamel were calculated. Parametric and correlation tests were used to determine difference (p<0.05) and dose-response relationship between treatments. RESULTS: The addition of Cacit and TMP did not provide a higher fluoride concentration in enamel, however it reduced (p<0.05) mineral loss when compared to other dentifrices; the dentifrice with Cacit and TMP and a low fluoride concentration presented similar results when compared to a dentifrice with 1,100 mg F/g (p>0.05). CONCLUSIONS: Dentifrices with 450 and 1,000 ug F/g, Cacit and TMP were as effective as a gold standard one. PMID- 22437686 TI - Reliability and accuracy of a radiographic analysis method for posterior maxillary mini-implant location. AB - OBJECTIVE: The purpose of this study was to evaluate the reliability and accuracy of a radiographic analysis method for the location of mini-implants inserted in the posterior region of the maxilla. MATERIAL AND METHODS: Two self-drilling mini implants were installed between the second premolar and the first molar on the right side and left side in three dry skulls. Three operators performed three occlusal radiographs, using an occlusal x-ray film holder, at three different times in each of the three skulls. RESULTS: The interclass correlation coefficient showed a significantly high, positive correlation (p<0.05), indicating an excellent reliability between operators. The analysis of variance showed no significant differences in time and among the operators. CONCLUSION: Based of these findings, it may be concluded that this methodology can be used by several operators in longitudinal clinical studies on orthodontic mini-implants at the anterior-posterior and lateral-medial locations or longitudinal displacement. PMID- 22437687 TI - Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study. AB - OBJECTIVE: This study investigated the role of periodontal disease in the development of stroke or cerebral infarction in patients by evaluating the clinical periodontal conditions and the subgingival levels of periodontopathogens. MATERIAL AND METHODS: Twenty patients with ischemic (I-CVA) or hemorrhagic (H-CVA) cerebrovascular episodes (test group) and 60 systemically healthy patients (control group) were evaluated for: probing depth, clinical attachment level, bleeding on probing and plaque index. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were both identified and quantified in subgingival plaque samples by conventional and real-time PCR, respectively. RESULTS: The test group showed a significant increase in each of the following parameters: pocket depth, clinical attachment loss, bleeding on probing, plaque index and number of missing teeth when compared to control values (p<0.05, unpaired t-test). Likewise, the test group had increased numbers of sites that were contaminated with P. gingivalis (60%x10%; p<0.001; chi-squared test) and displayed greater prevalence of periodontal disease, with an odds ratio of 48.06 (95% CI: 5.96-387.72; p<0.001). Notably, a positive correlation between probing depth and the levels of P. gingivalis in ischemic stroke was found (r=0.60; p=0.03; Spearman's rank correlation coefficient test). A. actinomycetemcomitans DNA was not detected in any of the groups by conventional or real-time PCR. CONCLUSIONS: Stroke patients had deeper pockets, more severe attachment loss, increased bleeding on probing, increased plaque indexes, and in their pockets harbored increased levels of P. gingivalis. These findings suggest that periodontal disease is a risk factor for the development of cerebral hemorrhage or infarction. Early treatment of periodontitis may counteract the development of cerebrovascular episodes. PMID- 22437688 TI - Non-inflammatory destructive periodontal disease: a clinical, microbiological, immunological and genetic investigation. AB - Periodontitis comprises a group of multifactorial diseases in which periodontopathogens accumulate in dental plaque and trigger host chronic inflammatory and immune responses against periodontal structures, which are determinant to the disease outcome. Although unusual cases of non-inflammatory destructive periodontal disease (NIDPD) are described, their pathogenesis remains unknown. A unique NIDPD case was investigated by clinical, microbiological, immunological and genetic tools. The patient, a non-smoking dental surgeon with excessive oral hygiene practice, presented a generalized bone resorption and tooth mobility, but not gingival inflammation or occlusion problems. No hematological, immunological or endocrine alterations were found. No periodontopathogens (A. actinomycetemcomitans, P. gingivalis, F. nucleatum and T. denticola) or viruses (HCMV, EBV-1 and HSV-1) were detected, along with levels of IL-1beta and TNF-a in GCF compatible with healthy tissues. Conversely ALP, ACP and RANKL GCF levels were similar to diseased periodontal sites. Genetic investigation demonstrated that the patient carried some SNPs, as well HLA-DR4 (*0404) and HLA-B27 alleles, considered risk factors for bone loss. Then, a less vigorous and diminished frequency of toothbrushing was recommended to the patient, resulting in the arrest of alveolar bone loss, associated with the return of ALP, ACP and RANKL in GCF to normality levels. In conclusion, the unusual case presented here is compatible with the previous description of NIDPD, and the results that a possible combination of excessive force and frequency of mechanical stimulation with a potentially bone loss prone genotype could result in the alveolar bone loss seen in NIDPD. PMID- 22437689 TI - Cleft lip and palate: recommendations for dental anesthetic procedure based on anatomic evidences. AB - Patients with cleft lip and palate usually present dental anomalies of number, shape, structure and position in the cleft area and the general dentist is frequently asked to restore or extract those teeth. Considering that several anatomic variations are expected in teeth adjacent to cleft areas and that knowledge of these variations by general dentists is required for optimal treatment, the objectives of this paper are: 1) to describe changes in the innervation pattern of anterior teeth and soft tissue caused by the presence of a cleft, 2) to describe a local anesthetic procedure in unilateral and bilateral clefts, and 3) to provide recommendations to improve anesthetic procedures in patients with cleft lip and palate. The cases of 2 patients are presented: one with complete unilateral cleft lip and palate, and the other with complete bilateral cleft lip and palate. The patients underwent local anesthesia in the cleft area in order to extract teeth with poor bone support. The modified anesthetic procedure, respecting the altered course of nerves in the cleft maxilla and soft tissue alterations at the cleft site, was accomplished successfully and the tooth extraction was performed with no pain to the patients. General dentists should be aware of the anatomic variations in nerve courses in the cleft area to offer high quality treatment to patients with cleft lip and palate. PMID- 22437691 TI - Biodegradable polylactide/hydroxyapatite nanocomposite foam scaffolds for bone tissue engineering applications. AB - Supercritical carbon dioxide processing of poly-L-lactide (PLLA)/hydroxyapatite (nHA) nanocomposites was investigated as a means to prepare foams suitable as scaffolds in bone tissue engineering applications. For given foaming parameters, addition of nHA to the PLLA gave reduced cell sizes and improved homogeneity in the size distribution, but did not significantly affect the degree of crystallinity, which remained of the order of 50 wt% in all the foams. The compressive modulus and strength were primarily influenced by the porosity and there was no significant reinforcement of the matrix by the nHA. The mechanical properties of the foams were nevertheless comparable with those of trabecular bone, and by adjusting the saturation pressure and depressurization rate it was possible to generate porosities of about 85 %, an interconnected morphology and cell diameters in the range 200-400 MUm from PLLA containing 4.17 vol% nHA, satisfying established geometrical requirements for bone replacement scaffolds. PMID- 22437692 TI - Nanoscale investigation of the electrical properties in semiconductor polymer carbon nanotube hybrid materials. AB - The morphology and electrical properties of hybrids of a semiconducting polymer (namely poly(3-hexylthiophene) P3HT) and carbon nanotubes are investigated at the nanoscale with a combination of Scanning Probe Microscopy techniques, i.e., Conductive Atomic Force Microscopy (C-AFM) and time-resolved Current Sensing Force Spectroscopy Atomic Force Microscopy (CSFS-AFM, or PeakForce TUNATM). This allows us to probe the electrical properties of the 15 nm wide P3HT nanofibers as well as the interface between the polymer and single carbon nanotubes. This is achieved by applying controlled, low forces on the tip during imaging, which allows a direct comparison between the morphology and the electrical properties at the nanometre scale. PMID- 22437693 TI - Chemical intuition or chemical institution? PMID- 22437699 TI - Blogroll: Scary chemicals. PMID- 22437695 TI - A chronicler of chemistry. Interview by Stuart Cantrill. PMID- 22437702 TI - Two-dimensional materials: Polymers stripped down. PMID- 22437703 TI - Ion dynamics: Wired-up water. PMID- 22437704 TI - Polymer vesicles: Autonomous propulsion. PMID- 22437705 TI - Protein labelling: Playing tag with proteins. PMID- 22437706 TI - Zeolite nanosystems: Imagination has no limits. PMID- 22437707 TI - Transparent conducting materials: Flexibility with a metallic skin. PMID- 22437708 TI - Catalysis: Temporary intramolecularity. PMID- 22437709 TI - Electron-transfer processes in dendrimers and their implication in biology, catalysis, sensing and nanotechnology. AB - The extraordinary development of the design and synthesis of dendrimers has allowed scientists to locate redox sites at precise positions (core, focal points, branching points, termini, cavities) of these perfectly defined macromolecules, which have generation-controlled sizes and topologies matching those of biomolecules. Redox-dendrimer engineering has led to fine modelling studies of electron-transfer metalloproteins, in which the branches of the dendrimers hinder access to the active site in a manner reminiscent of that of the protein. It has also enabled the construction of remarkable catalysts, sensors and printboards, including by sophisticated design of the interface between redox dendrimers and solid-state devices - for example by functionalizing electrodes and other surfaces. Electron-transfer processes between dendrimers and a variety of other molecules hold promising applications in diverse areas that range from bio-engineering to sensing, catalysis and energy materials. PMID- 22437710 TI - Autonomous movement of platinum-loaded stomatocytes. AB - Polymer stomatocytes are bowl-shaped structures of nanosize dimensions formed by the controlled deformation of polymer vesicles. The stable nanocavity and strict control of the opening are ideal for the physical entrapment of nanoparticles which, when catalytically active, can turn the stomatocyte morphology into a nanoreactor. Herein we report an approach to generate autonomous movement of the polymer stomatocytes by selectively entrapping catalytically active platinum nanoparticles within their nanocavities and subsequently using catalysis as a driving force for movement. Hydrogen peroxide is free to access the inner stomatocyte cavity, where it is decomposed by the active catalyst (the entrapped platinum nanoparticles) into oxygen and water. This generates a rapid discharge, which induces thrust and directional movement. The design of the platinum-loaded stomatocytes resembles a miniature monopropellant rocket engine, in which the controlled opening of the stomatocytes directs the expulsion of the decomposition products away from the reaction chamber (inner stomatocyte cavity). PMID- 22437711 TI - Diamidocarbenes as versatile and reversible [2 + 1] cycloaddition reagents. AB - We describe the synthesis of a variety of cyclopropanes and epoxides by combining a readily accessible and isolable N,N'-diamidocarbene with a range of structurally and electronically diverse olefins and aldehydes, including electron rich derivatives. Surprisingly, the cyclopropanation and epoxidation reactions were discovered to be rapid and thermally reversible at relatively low temperatures, two features often desired for applications that utilize dynamic covalent chemistry. In addition, a diamidocyclopropane derivative prepared via this method was hydrolysed successfully to form the corresponding linear carboxylic acid in a metal- and carbon monoxide-free hydrocarboxylation reaction. As such, diamidocarbenes are expected to find utility in the synthesis of cyclopropanes, epoxides and their derivatives, as well as in dynamic covalent chemistry applications. PMID- 22437712 TI - Topological insulator nanostructures for near-infrared transparent flexible electrodes. AB - Topological insulators are an intriguing class of materials with an insulating bulk state and gapless Dirac-type edge/surface states. Recent theoretical work predicts that few-layer topological insulators are promising candidates for broadband and high-performance optoelectronic devices due to their spin-momentum locked massless Dirac edge/surface states, which are topologically protected against all time-reversal-invariant perturbations. Here, we present the first experimental demonstration of near-infrared transparent flexible electrodes based on few-layer topological-insulator Bi(2)Se(3) nanostructures epitaxially grown on mica substrates by means of van der Waals epitaxy. The large, continuous, Bi(2)Se(3)-nanosheet transparent electrodes have single Dirac cone surface states, and exhibit sheet resistances as low as ~330 Omega per square, with a transparency of more than 70% over a wide range of wavelengths. Furthermore, Bi(2)Se(3)-nanosheet transparent electrodes show high chemical and thermal stabilities as well as excellent mechanical durability, which may lead to novel optoelectronic devices with unique properties. PMID- 22437713 TI - A two-dimensional polymer prepared by organic synthesis. AB - Synthetic polymers are widely used materials, as attested by a production of more than 200 millions of tons per year, and are typically composed of linear repeat units. They may also be branched or irregularly crosslinked. Here, we introduce a two-dimensional polymer with internal periodicity composed of areal repeat units. This is an extension of Staudinger's polymerization concept (to form macromolecules by covalently linking repeat units together), but in two dimensions. A well-known example of such a two-dimensional polymer is graphene, but its thermolytic synthesis precludes molecular design on demand. Here, we have rationally synthesized an ordered, non-equilibrium two-dimensional polymer far beyond molecular dimensions. The procedure includes the crystallization of a specifically designed photoreactive monomer into a layered structure, a photo polymerization step within the crystal and a solvent-induced delamination step that isolates individual two-dimensional polymers as free-standing, monolayered molecular sheets. PMID- 22437714 TI - Evidence that a 'dynamic knockout' in Escherichia coli dihydrofolate reductase does not affect the chemical step of catalysis. AB - The question of whether protein motions play a role in the chemical step of enzymatic catalysis has generated much controversy in recent years. Debate has recently reignited over possible dynamic contributions to catalysis in dihydrofolate reductase, following conflicting conclusions from studies of the N23PP/S148A variant of the Escherichia coli enzyme. By investigating the temperature dependence of kinetic isotope effects, we present evidence that the reduction in the hydride transfer rate constants in this variant is not a direct result of impairment of conformational fluctuations. Instead, the conformational state of the enzyme immediately before hydride transfer, which determines the electrostatic environment of the active site, affects the rate constant for the reaction. Although protein motions are clearly important for binding and release of substrates and products, there appears to be no detectable dynamic coupling of protein motions to the hydride transfer step itself. PMID- 22437715 TI - Genetically encoded norbornene directs site-specific cellular protein labelling via a rapid bioorthogonal reaction. AB - The site-specific incorporation of bioorthogonal groups via genetic code expansion provides a powerful general strategy for site-specifically labelling proteins with any probe. However, the slow reactivity of the bioorthogonal functional groups that can be encoded genetically limits the utility of this strategy. We demonstrate the genetic encoding of a norbornene amino acid using the pyrrolysyl tRNA synthetase/tRNA(CUA) pair in Escherichia coli and mammalian cells. We developed a series of tetrazine-based probes that exhibit 'turn-on' fluorescence on their rapid reaction with norbornenes. We demonstrate that the labelling of an encoded norbornene is specific with respect to the entire soluble E. coli proteome and thousands of times faster than established encodable bioorthogonal reactions. We show explicitly the advantages of this approach over state-of-the-art bioorthogonal reactions for protein labelling in vitro and on mammalian cells, and demonstrate the rapid bioorthogonal site-specific labelling of a protein on the mammalian cell surface. PMID- 22437716 TI - Chemically homogeneous and thermally reversible oxidation of epitaxial graphene. AB - With its exceptional charge mobility, graphene holds great promise for applications in next-generation electronics. In an effort to tailor its properties and interfacial characteristics, the chemical functionalization of graphene is being actively pursued. The oxidation of graphene via the Hummers method is most widely used in current studies, although the chemical inhomogeneity and irreversibility of the resulting graphene oxide compromises its use in high-performance devices. Here, we present an alternative approach for oxidizing epitaxial graphene using atomic oxygen in ultrahigh vacuum. Atomic resolution characterization with scanning tunnelling microscopy is quantitatively compared to density functional theory, showing that ultrahigh-vacuum oxidization results in uniform epoxy functionalization. Furthermore, this oxidation is shown to be fully reversible at temperatures as low as 260 degrees C using scanning tunnelling microscopy and spectroscopic techniques. In this manner, ultrahigh vacuum oxidation overcomes the limitations of Hummers-method graphene oxide, thus creating new opportunities for the study and application of chemically functionalized graphene. PMID- 22437717 TI - Imparting functionality to a metal-organic framework material by controlled nanoparticle encapsulation. AB - Microporous metal-organic frameworks (MOFs) that display permanent porosity show great promise for a myriad of purposes. The potential applications of MOFs can be developed further and extended by encapsulating various functional species (for example, nanoparticles) within the frameworks. However, despite increasing numbers of reports of nanoparticle/MOF composites, simultaneously to control the size, composition, dispersed nature, spatial distribution and confinement of the incorporated nanoparticles within MOF matrices remains a significant challenge. Here, we report a controlled encapsulation strategy that enables surfactant capped nanostructured objects of various sizes, shapes and compositions to be enshrouded by a zeolitic imidazolate framework (ZIF-8). The incorporated nanoparticles are well dispersed and fully confined within the ZIF-8 crystals. This strategy also allows the controlled incorporation of multiple nanoparticles within each ZIF-8 crystallite. The as-prepared nanoparticle/ZIF-8 composites exhibit active (catalytic, magnetic and optical) properties that derive from the nanoparticles as well as molecular sieving and orientation effects that originate from the framework material. PMID- 22437718 TI - Self-assembly of the oxy-tyrosinase core and the fundamental components of phenolic hydroxylation. AB - The enzyme tyrosinase contains two Cu(I) centres, trigonally coordinated by imidazole nitrogens of six conserved histidine residues. The enzyme activates O(2) to form a u-eta(2):eta(2)-peroxo-dicopper(II) core, which hydroxylates tyrosine to a catechol in the first committed step of melanin biosynthesis. Here, we report a family of synthetic peroxo complexes, with spectroscopic and chemical features consistent with those of oxygenated tyrosinase, formed through the self assembly of monodentate imidazole ligands, Cu(I) and O(2) at -125 degrees C. An extensively studied complex reproduces the enzymatic electrophilic oxidation of exogenous phenolic substrates to catechols in good stoichiometric yields. The self-assembly and subsequent reactivity support the intrinsic stability of the Cu(2)O(2) core with imidazole ligation, in the absence of a polypeptide framework, and the innate capacity to effect hydroxylation of phenolic substrates. These observations suggest that a foundational role of the protein matrix is to facilitate expression of properties native to the core by bearing the entropic costs of assembly and precluding undesired oxidative degradation pathways. PMID- 22437719 TI - Ionization of dimethyluracil dimers leads to facile proton transfer in the absence of hydrogen bonds. AB - Proton transfer is ubiquitous in chemistry and biology, occurring, for example, in proteins, enzyme reactions and across proton channels and pumps. However, it has always been described in the context of hydrogen-bonding networks ('proton wires') acting as proton conduits. Here, we report efficient intramolecular ionization-induced proton transfer across a 1,3-dimethyluracil dimer, a model pi stacked system with no hydrogen bonds. Upon photoionization by tunable vacuum ultraviolet synchrotron radiation, the dimethyluracil dimer undergoes proton transfer and dissociates to produce a protonated monomer. Deuterated dimethyluracil experiments confirm that proton transfer occurs from the methyl groups and not from the aromatic C-H sites. Calculations reveal qualitative differences between the proton transfer reaction coordinate in the pi-stacked and hydrogen-bonded base pairs, and that proton transfer in methylated dimers involves significant rearrangements of the two fragments, facilitating a relatively low potential energy barrier of only 0.6 eV in the ionized dimer. PMID- 22437720 TI - An M18L24 stellated cuboctahedron through post-stellation of an M12L24 core. AB - Platonic and Archimedean polyhedra, well-known to mathematicians, have been recently constructed by chemists at a molecular scale by defining the vertices and the edges with metal ions (M) and organic ligands (L), respectively. Here, we report the first synthesis of a concave-surface 'stellated polyhedron', constructed by extending the faces of its precursor polyhedron until they intersect, forming additional nodes. Our approach involves the formation of an M(12)L(24) cuboctahedron core, the linkers of which each bear a pendant ligand site that is subsequently able to bind an additional metal centre to form the stellated M(18)L(24) cuboctahedron. During this post-stellation process, the square faces of the M(12)L(24) core are closed by coordination of the pendant moieties to the additional metal centres, but they are re-opened on removing these metals ions from the vertices. This behaviour is reminiscent of the analogous metal-triggered gate opening-closing switches found in spherical virus capsids. PMID- 22437721 TI - Counting on copper. PMID- 22437722 TI - Assessment of skewed exposure in case-control studies with pooling. AB - Pooling-based strategies that combine samples from multiple participants for laboratory assays have been proposed for epidemiologic investigations of biomarkers to address issues including cost, efficiency, detection, and when minimal sample volume is available. A modification of the standard logistic regression model has been previously described to allow use with pooled data; however, this model makes assumptions regarding exposure distribution and logit linearity of risk (i.e., constant odds ratio) that can be violated in practice. We were motivated by a nested case-control study of miscarriage and inflammatory factors with highly skewed distributions to develop a more flexible model for analysis of pooled data. Using characteristics of the gamma distribution and the relation between models of binary outcome conditional on exposure and of exposure conditional on outcome, we use a modified logistic regression to accommodate nonlinearity because of unequal shape parameters in gamma distributed exposure for cases and controls. Using simulations, we compare our approach with existing methods for logistic regression for pooled data considering: (1) constant and dose-dependent effects; (2) gamma and log-normal distributed exposure; (3) effect size; and (4) the proportions of biospecimens pooled. We show that our approach allows estimation of odds ratios that vary with exposure level, yet has minimal loss of efficiency compared with existing approaches when exposure effects are dose-invariant. Our model performed similarly to a maximum likelihood estimation approach in terms of bias and efficiency, and provides an easily implemented approach for estimation with pooled biomarker data when effects may not be constant across exposure. PMID- 22437723 TI - Enhanced biodecolorization of reactive dyes by basidiomycetes under static conditions. AB - This study presents the biodecolorization potential of basidiomycete fungi Trametes hirsuta, Pycnoporus sp., and Irpex sp. for different reactive dyes viz. Reactive Red 120, Remazol Brilliant Blue R (RBBR), Reactive Orange G, and Reactive Orange 16 under static and shaking conditions. The screening trials revealed that T. hirsuta exhibited maximum potential (83.75 %) for biodecolorization of RBBR dye under static conditions after the fifth day of incubation. However, the rate of biodecolorization of RBBR dye by Pycnoporus sp. was much slow and reached maximum (81.25 %) after 15 days of incubation under shaking conditions. By process optimization, enhanced decolorization (91.2 %) of RBBR by T. hirsuta was achieved at pH 5.5 within 24 h using a defined salt medium amended with p-coumaric acid under static conditions. pH was found to be an important parameter for the enzymatic system involved in RBBR dye decolorization by T. hirsuta and Pycnoporus sp. Biodecolorization of RBBR dye was determined by a reduction in optical density at the wavelength of maximum absorbance (lambda, 578 nm) by UV-vis spectrophotometer. The shift in maximum wavelength toward shorter/longer wavelength in UV-vis scanning spectrum revealed the degradation of RBBR dye into different transformation products. PMID- 22437724 TI - [Pediatric asthma: novel examinations and tools useful for diagnosis]. PMID- 22437725 TI - [Allergic rhinitis]. PMID- 22437726 TI - [Japanese guideline for care of contact dermatitis: the guess and identification of the allergens]. PMID- 22437727 TI - [Allergic diseases and pregnancy-drug use in pregnancy and lactation-]. PMID- 22437728 TI - [Use of forced oscillation technique to detect airflow limitations in adult Japanese asthmatics]. AB - BACKGROUND: The forced oscillation technique (FOT) is a noninvasive method that is used to measure respiratory mechanics, including respiratory resistance and reactance at multiple frequencies. The advantage of FOT over spirometry is that FOT does not require forced expiratory maneuvers. Moreover, a new FOT machine called MostGraph (Chest Co. Ltd., Tokyo, Japan), has been developed in Japan, and can be used clinically to diagnose and monitor asthma. The purpose of this study is to show the standard of FOT measured with MostGraph in adult Japanese asthmatics. METHODS: From our outpatient clinic, we recruited 151 stable asthmatics who were being treated with inhaled corticosteroids at the time of the study. For each subject, we measured the fraction of exhaled nitric oxide (FeNO) by using a chemiluminescent nitric oxide analyzer (Sievers280, GE, Boulder, Co); we determined the levels of forced expiratory volume in 1s (%FEV1) and maximum mid-expiratory flow rate (%MMF) by using spirometory; and we measured resistance at 5 Hz(R5), resistance at 20 Hz(R20), R5-R20, reactance at 5 Hz(X5), frequency of resonance (Fres), and low-frequency reactance area (ALX), by using a MostGraph FOT machine. RESULTS: Each of the FOT parameters measured by using the MostGraph machine was significantly correlated with %FEV1 and %MMF (p<0.001), with Fres showing the strongest association. Three of the FOT parameters, X5, Fres, and ALX, were significantly associated with the subject's age (p=0.01, p<0.001, p<0.001, respectively), and all FOT parameters were significantly associated with the subject's body mass index (BMI) (p<0.001 to p=0.018). The results of multiple regression analyses between FOT parameters and FEV1, age, BMI, and FeNO, showed that Fres was significantly associated with FEV1(p<0.001) and BMI (p<0.001). From the results of the simple linear regression between Fres and FEV1, we estimated that Fres values of 17.5 Hz corresponded to %FEV1 values of 60%; Fres values of 11.3 Hz corresponded to %FEV1 values of 80%; and Fres values of 4.94 Hz corresponded to %FEV1 values of 100%. CONCLUSION: FOT parameters measured by using a MostGraph machine can be used successfully to assess the level of airflow limitation in adult stable asthmatics. PMID- 22437729 TI - [Effects of educational guidance on airway inflammation of patients with severe persistent asthma]. AB - BACKGROUND: Airway inflammation is a fundamental feature of bronchial asthma. We examined whether educational guidance using a text on pathophysiology and management of asthma modify airway inflammation of severe asthma. METHODS: Eighteen severe persistent asthmatics were enrolled in this study. Evaluation on asthma control using Asthma Control Test (ACT), Asthma Health Questionnaire (AHQ) Japan), FEV1, percentages of eosinophils and neutrophils in induced sputum were analyzed before and 4 weeks after patient education process. RESULTS: Following educational guidance, ACT and FEV1 did not improve, but AHQ score significantly improved. Furthermore, percentage of eosinophils in sputum significantly reduced. On the contrary, the percentage of neutrophils in sputum was not changed. In accordance with this lack of the change in neutrophil numbers, neutrophil chemoattractants including IL-8 or CXCR3 in the induced sputum did not change before and after patient guidance. CONCLUSION: Educational guidance using a text on pathophysiology and management of asthma provides some effects on quality of life in asthmatic patients and eosinophilic inflammation, however, this procedure does not modify the control status of asthma and neutrophilic inflammation seen with severe asthma. PMID- 22437730 TI - [Treatment of facial lesion in infantile and childhood atopic dermatitis]. AB - BACKGROUND: Treatment of infantile and childhood atopic dermatitis needs special consideration compared to adult's counterpart. Repeated exposure to irritation by slaver or rubbing makes facial lesions difficult to treat in infants and children. We considered the deterioration factor and the treatment that we performed. METHODS: We considered 6 infantile and childhood atopic dermatitis who had severe condition on their face. RESULT: All the patients needed enough application of topical steroids. Exacerbation of atopic dermatitis masked concomitant skin infection such as impetigo or Kaposi's varicelliform eruption. Guardian usually hesitated periorbital and perioral application of topical steroids and tacrolimus. In order to obtain the guardian's understanding and cooperation, it was very important to establish a good doctor/guardian relationship by educational approach including an enough explanation about treatment policy. CONCLUSION: It was important for the treatment of infantile and childhood atopic dermatitis to identify and eliminate triggering factors. And we need to obtain the guardian's understanding and cooperation for our treatment policy. PMID- 22437731 TI - [A case of severe asthma and peach allergy that improved with omalizumab therapy: a case report]. AB - A 30-year-old woman had refractory asthma. She had also experienced twice severe anaphylaxis episodes after ingesting peaches. The patient was extremely wary about reoccurrence of anaphylaxis and avoided ingesting any fruits, including peaches. She visited our hospital for testing and treatment for asthma and the peach allergy. Skin and serologic testing showed that she had a severe allergy to house dust, mites, and peaches. The food challenge test results showed that ingesting 6.5 g of the peach fruit induced dyspnea in the patient. Her asthma could not be controlled despite treatment involving a leukotriene receptor antagonist and combination inhalation of high-dose salmeterol xinafoate/fluticasone propionate. We advised the patient to keep strict avoidance ingesting peaches because of her food allergy. However, she hoped to overcome her food restrictions, especially those for fruits. We initiated treatment involving the recombinant humanized monoclonal anti-IgE antibody omalizumab (150 mg, once a month) to ensure that the asthma was controlled well and to improve the patient's diet. The asthmatic symptoms ameliorated, and the peak expiratory flow increased in a short time. We gradually reduced the restriction on peach consumption. This was achieved by rechallenging the patient with increasing doses of 290 mg of the peach fruit and was initiated at 28 weeks after starting omalizumab therapy. The restriction on peach consumption was lifted eventually, and the patient did not experience any allergic symptoms subsequently on ingesting peaches. Thus, for our patient, omalizumab therapy was highly effective in achieving remission from both asthma and peach allergy. PMID- 22437732 TI - Claudin 18 is a novel negative regulator of bone resorption and osteoclast differentiation. AB - Claudin 18 (Cldn-18) belongs to a large family of transmembrane proteins that are important components of tight junction strands. Although several claudin members are expressed in bone, the functional role for any claudin member in bone is unknown. Here we demonstrate that disruption of Cldn-18 in mice markedly decreased total body bone mineral density, trabecular bone volume, and cortical thickness in Cldn-18(-/-) mice. Histomorphometric studies revealed that bone resorption parameters were increased significantly in Cldn-18(-/-) mice without changes in bone formation. Serum levels of tartrate-resistant acid phosphatase 5b (TRAP5b) and mRNA expression levels of osteoclast specific markers and signaling molecules were also increased. Loss of Cldn-18 further exacerbated calcium deficiency induced bone loss by influencing bone resorption, thereby resulting in mechanically weaker bone. In vitro studies with bone marrow macrophages revealed Cldn-18 disruption markedly enhanced receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation but not macrophage colony-stimulating factor (MCSF)-induced bone marrow macrophage (BMM) proliferation. Consistent with a direct role for Cldn-18 in regulating osteoclast differentiation, overexpression of wild type but not PDZ binding motif deleted Cldn-18 inhibited RANKL-induced osteoclast differentiation. Furthermore, our findings indicate that Cldn-18 interacts with Zonula occludens 2 (ZO-2) to modulate RANKL signaling in osteoclasts. In conclusion, we demonstrate that Cldn-18 is a novel negative regulator of bone resorption and osteoclast differentiation. PMID- 22437733 TI - Prion potency in stem cells biology. AB - Prion protein (PrP) can be considered a pivotal molecule because it interacts with several partners to perform a diverse range of critical biological functions that might differ in embryonic and adult cells. In recent years, there have been major advances in elucidating the putative role of PrP in the basic biology of stem cells in many different systems. Here, we review the evidence indicating that PrP is a key molecule involved in driving different aspects of the potency of embryonic and tissue-specific stem cells in self-perpetuation and differentiation in many cell types. It has been shown that PrP is involved in stem cell self-renewal, controlling pluripotency gene expression, proliferation, and neural and cardiomyocyte differentiation. PrP also has essential roles in distinct processes that regulate tissue-specific stem cell biology in nervous and hematopoietic systems and during muscle regeneration. Results from our own investigations have shown that PrP is able to modulate self-renewal and proliferation in neural stem cells, processes that are enhanced by PrP interactions with stress inducible protein 1 (STI1). Thus, the available data reveal the influence of PrP in acting upon the maintenance of pluripotent status or the differentiation of stem cells from the early embryogenesis through adulthood. PMID- 22437734 TI - The end of the road. PMID- 22437735 TI - Unraveling the neuroprotective mechanisms of PrP (C) in excitotoxicity. AB - Knowledge of the natural roles of cellular prion protein (PrP (C) ) is essential to an understanding of the molecular basis of prion pathologies. This GPI anchored protein has been described in synaptic contacts, and loss of its synaptic function in complex systems may contribute to the synaptic loss and neuronal degeneration observed in prionopathy. In addition, Prnp knockout mice show enhanced susceptibility to several excitotoxic insults, GABAA receptor mediated fast inhibition was weakened, LTP was modified and cellular stress increased. Although little is known about how PrP (C) exerts its function at the synapse or the downstream events leading to PrP (C) -mediated neuroprotection against excitotoxic insults, PrP (C) has recently been reported to interact with two glutamate receptor subunits (NR2D and GluR6/7). In both cases the presence of PrP (C) blocks the neurotoxicity induced by NMDA and Kainate respectively. Furthermore, signals for seizure and neuronal cell death in response to Kainate in Prnp knockout mouse are associated with JNK3 activity, through enhancing the interaction of GluR6 with PSD-95. In combination with previous data, these results shed light on the molecular mechanisms behind the role of PrP (C) in excitotoxicity. Future experimental approaches are suggested and discussed. PMID- 22437736 TI - Phenotypic characterization of cells participating in transport of prion protein aggregates across the intestinal mucosa of sheep. AB - The oral route is considered to be the main entry site of several transmissible spongiform encephalopathies or prion diseases of animals and man. Following natural and experimental oral exposure to scrapie, sheep first accumulate disease associated prion protein (PrP (d) ) in Peyer's patch (PP) lymphoid follicles. In this study, recombinant ovine prion protein (rPrP) was inoculated into gut loops of young lambs and the transportation across the intestinal wall studied. In particular, the immunohistochemical phenotypes of cells bearing the inoculated prion protein were investigated. The rPrP was shown to be transported across the villi of the gut, into the lacteals and submucosal lymphatics, mimicking the transport route of PrP (d) from scrapie brain inoculum observed in a previous intestinal loop experiment. The cells bearing the inoculated rPrP were mainly mononuclear cells, and multicolor immunofluorescence procedures were used to show that the rPrP bearing cells were professional antigen presenting cells expressing Major histocompatibility complex II (MHCII). In addition, the rPrP bearing cells labeled with CD205, CD11b and the macrophage marker CD68, and not with the dendritic cell markers CD11c and CD209. Others have reported that cells expressing CD205 and CD11b in the absence of CD11c have been shown to induce T cell tolerance or regulatory T cells. Based on this association, it was speculated that the rPrP and by extension PrP (d) and scrapie infective material may exploit the physiological process of macromolecular uptake across the gut, and that this route of entry may have implications for immune surveillance. PMID- 22437737 TI - Domain swapping and amyloid fibril conformation. AB - For several different proteins an apparent correlation has been observed between the propensity for dimerization by domain-swapping and the ability to aggregate into amyloid-like fibrils. Examples include the disease-related proteins beta 2 microglobulin and transthyretin. This has led to proposals that the amyloid formation pathway may feature extensive domain swapping. One possible consequence of such an aggregation pathway is that the resulting fibrils would incorporate structural elements that resemble the domain-swapped forms of the protein and, thus, reflect certain native-like structures or domain-interactions. In magic angle spinning solid-state NMR-based and other structural studies of such amyloid fibrils, it appears that many of these proteins form fibrils that are not native like. Several fibrils, instead, have an in-register, parallel conformation, which is a common amyloid structural motif and is seen, for instance, in various prion fibrils. Such a lack of native structure in the fibrils suggests that the apparent connection between domain-swapping ability and amyloid-formation may be more subtle or complex than may be presumed at first glance. PMID- 22437739 TI - Relationship between rates of respiratory proton extrusion and ATP synthesis in obligately alkaliphilic Bacillus clarkii DSM 8720(T). AB - To elucidate the energy production mechanism of alkaliphiles, the relationship between the rate of proton extrusion via the respiratory chain and the corresponding ATP synthesis rate was examined in obligately alkaliphilic Bacillus clarkii DSM 8720(T) and neutralophilic Bacillus subtilis IAM 1026. The oxygen consumption rate of B. subtilis IAM 1026 cells at pH 7 was approximately 2.5 times higher than that of B. clarkii DSM 8720(T) cells at pH 10. The H+/O ratio of B. clarkii DSM 8720(T) cells was approximately 1.8 times higher than that of B. subtilis IAM 1026 cells. On the basis of oxygen consumption rate and H+/O ratio, the rate of proton translocation via the respiratory chain in B. subtilis IAM 1026 is expected to be approximately 1.4 times higher than that in B. clarkii DSM 8720(T). Conversely, the rate of ATP synthesis in B. clarkii DSM 8720(T) at pH 10 was approximately 7.5 times higher than that in B. subtilis IAM 1026 at pH 7. It can be predicted that the difference in rate of ATP synthesis is due to the effect of transmembrane electrical potential (Deltapsi) on protons translocated via the respiratory chain. The Deltapsi values of B. clarkii DSM 8720(T) and B. subtilis IAM 1026 were estimated as -192 mV (pH 10) and -122 mV (pH 7), respectively. It is considered that the discrepancy between the rates of proton translocation and ATP synthesis between the strains used in this study is due to the difference in ATP production efficiency per translocated proton between the two strains caused by the difference in Deltapsi. PMID- 22437738 TI - Resveratrol and diabetic cardiac function: focus on recent in vitro and in vivo studies. AB - Resveratrol, a natural phytoalexin found in wine has the potential to impact a variety of human diseases. Resveratrol like other polyphenols activates many of the same intracellular pathways as those activated by caloric restriction. It can quench reactive oxidative species, ROS and induce eNOS and iNOS expression. Resveratrol also can activate SIRT1, a NAD+-dependent deacetylase, that leads an improved in mitochondrial function, and then this procedure turns to activate the transcription factor Nrf2 that coordinates expression of key antioxidant mechanisms by binding to the antioxidant response elements. Resveratrol provides cardioprotection by triggering preconditioning and inducing autophagy. It also presents chemical similarities with estrogen and was reported to activate both nuclear and extranuclear estrogen receptors. Resveratrol treatment alleviated diabetes-induced cardiovascular system disorders via different endogeneous signaling pathways including oxidative stress/antioxidant defense system, glucose/insulin metabolism, overexpression of iNOS/nitrotyrosine, and preconditioning. Resveratrol treatment significantly reduced the blood glucose level in STZ-treated type 1 diabetic animals through insulin-dependent and insulin-independent pathways. Resveratrol triggers some of the similar intracellular insulin signalling components in myocardium such as eNOS, AKT through the AMPK pathway, and plays an essential role in Glut-4 translocation and glucose uptake in STZ-induced diabetic myocardium. However, resveratrol can exhibit hormetic action expressing health benefits at lower doses whereas being detrimental at higher doses. It might also exert antidiabetic effects by activating SIRT1 directly in the brain. This review includes a summary of the role of resveratrol and diabetic cardiac function including a brief discussion on in vitro and in vivo studies as well as our original observations in diabetic rats. PMID- 22437740 TI - The endocannabinoid 2-arachidonoylglicerol decreases calcium induced cytochrome c release from liver mitochondria. AB - 2-Arachidonoylglicerol (2-AG) is an endocannabinoid that mimics the pharmacological effects of Delta9 tetrahydrocannabinol, the psychoactive component of the plant Cannabis sativa. It is present in many mammalian tissues, such as brain, liver, spleen, heart and kidney, where it exerts different biological effects either receptor mediated or independently of receptor activation. This work analyzes the effects of 2-AG on liver mitochondrial functions. It is shown that 2-AG causes a relevant decrease of calcium induced cyclosporine A sensitive cytochrome c release from mitochondria, a process representing an early event of the apoptotic program. Cyclosporin sensitive matrix swelling and ROS production measured under the same conditions are, on the contrary, almost unaffected or even enhanced, respectively, by 2-AG. Furthemore, 2-AG is found to stimulate resting state succinate oxidase activity and to inhibit oligomycin sensitive F0F1 ATP synthase activity. All these effects are apparently associated with 2-AG dependent alteration in the fluidity of the mitochondrial membranes, which was measured as generalized polarization of laurdan fluorescence. PMID- 22437741 TI - Comparison of four immunohistochemical tests and FISH for measuring HER2 expression in gastric carcinomas. AB - AIM: : Accurate testing for HER2 is essential to identify patients who are likely to benefit from trastuzumab therapy. Although comparative studies on the performance of commercially available immunohistochemistry (IHC) antibodies for HER2 have been performed in breast cancer, similar studies have not been done in gastric carcinoma (GC) thus far. METHODS: : Quadruplicate tissue microarrays (TMAs) of 289 advanced GCs were immunostained with HercepTest, A0485, 4B5 and CB11, and the results were compared to those of gene amplification by fluorescence in situ hybridisation (FISH). RESULTS: : HER2 was amplified by FISH in 38 (13.2%) GCs. HER2 overexpression (2+ or 3+) was observed in 40 (13.8%) cases by HercepTest, 46 (15.9%) by A0485, 40 (13.8%) by 4B5 and 27 (9.3%) by CB11. The sensitivity and specificity of IHC compared to FISH was 78.9%/96% for HercepTest, 86.5%/94.4% for A0485, 76.3%/95.6% for 4B5 and 60.5%/98.4% for CB11. Focal HER2 gene amplification was more common in GCs with no (0 and 1+) or low (2+) HER2 expression. Discordant IHC results were seen in 23 cases (8.0%) with the four antibodies. All HER2 3+ cases (n = 22) by HercepTest were positive with A0485 and 4B5, while one was negative with CB11. CB11 was found to be negative in 10 HercepTest 2+ and FISH+ cases. CONCLUSION: : Focal HER2 gene amplification is more common in GCs with no or low expression of HER2. Although the specificity and positive predictive value of CB11 for FISH is highest, it lacks sufficient sensitivity to be used as a first line screening test to assess HER2 status in GCs. PMID- 22437742 TI - Peritoneal melanosis associated with metastatic melanoma involving the omentum. PMID- 22437743 TI - Bilateral dysgerminoma associated with gonadoblastoma and sex-cord stromal tumour with annular tubules in a 28-year-old fertile woman with normal karyotype. PMID- 22437744 TI - Aggressive gastrointestinal stromal tumour of the oesophagus with homozygous KIT exon 11 deletion mutation. PMID- 22437745 TI - Malignant gastric glomus tumour mimicking GIST. PMID- 22437746 TI - Cytomegalovirus colitis presenting as a polypoid nodular lesion. PMID- 22437747 TI - Malignant peripheral nerve sheath tumour of the liver. PMID- 22437748 TI - The prevalence and importance of clefts in cutaneous neoplasms. PMID- 22437749 TI - Glioblastoma with primitive neuroectodermal tumour-like components. PMID- 22437750 TI - Neuroendocrine ductal carcinoma in situ, comedo type, of the breast detected by screening mammography: a potentially pre-invasive counterpart of high grade neuroendocrine tumours. PMID- 22437751 TI - Kimura's disease in two Caucasians, one with multiple recurrences associated with prominent IgG4 production. PMID- 22437752 TI - Biotin interference on TSH and free thyroid hormone measurement. PMID- 22437753 TI - A novel ALDH5A1 mutation in a patient with succinic semialdehyde dehydrogenase deficiency. PMID- 22437754 TI - A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuroendocrine tumors. AB - BACKGROUND: Neuroendocrine tumor (NET) cell lines frequently express both insulin like growth factor (IGF) ligand and the cognate IGF-1 receptor (IGF-1R) and, as such, potentially depend on the activation of IGF-1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF-1-dependent signaling, suggesting that IGF 1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK-0646, a fully human monoclonal antibody (MoAb) that binds to the IGF-1R, as monotherapy in patients with metastatic, well-differentiated NETs. METHODS: A phase 2 study was performed in which patients received intravenous MK-0646 10 mg/kg once weekly over 1 hour. Archived pretreatment tumor tissue was obtained and genotyped for v Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-3 kinase, catalytic, alpha polypeptide (PIK3CA); and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, and immunohistochemistry was performed to measure the expression IGF-1R. RESULTS: Twenty-five patients received treatment (40% women; median age, 61 years; age range, 37-83 years), including 15 patients with carcinoid tumors and 10 patients with pancreatic NETs. No partial or complete responses were observed. The median progression-free survival was 4.2 months in the pancreatic NET cohort (range, 0.7-6.7 months) and 2.7 months in the carcinoid cohort (range, 2-3 months). Serious adverse events that were potentially related to MK-0646 included grade 3/4 hyperglycemia in 8 of 25 patients (32%), grade 2 hypersensitivity reaction in 1 of 24 patients (4%), and grade 3 lipase elevation in 1 of 25 patients (4%). CONCLUSIONS: Despite a compelling preclinical rationale, MK-0646 was inactive as a single agent in well differentiated NETs. Further studies of MK-0646 as a monotherapy in unselected NETs are unwarranted. PMID- 22437755 TI - Health-related quality of life. The effect of pelvic floor muscle training and midurethral sling surgery: a systematic review. AB - Stress urinary incontinence (SUI) is a bothersome condition affecting health related quality of life (HRQoL) to a great extent in women. From a patient's perspective, improving HRQoL is probably equally important as objective cure of SUI. Our objective was to assess the effect of pelvic floor muscle training (PFMT) and midurethral sling surgery on condition-specific HRQoL in women with SUI. A systematic literature search was conducted in the PubMed, Embase, and Cochrane databases. Studies reporting on HRQoL after intervention for SUI or mixed incontinence with a predominant SUI component were selected. Retrieved articles were appraised by all authors regarding participant entry criteria, study design, intervention, questionnaire, objective cure, and HRQoL presentation. There were three articles reporting HRQoL after PFMT and 11 after midurethral sling surgery. Improvement in HRQoL seemed higher after midurethral sling surgery compared with PFMT. However, methods of HRQoL assessment varied widely, limiting the possibility of comparison and interpretation between studies. PMID- 22437756 TI - Novel syntheses and properties of meso-tetraaryl-octabromo tetranaphtho[2,3]porphyrins (Ar4Br8TNPs). AB - o-Quinodimethane (o-QDM) generated from benzosultine was used to extend the pyrrole system for the preparation of octabromo-tetranaphtho[2,3]porphyrins via oxidative aromatization. The properties of these bromoporphyrins were presented and chemical transformation via Pd-catalyzed Suzuki reaction was also effectively achieved. PMID- 22437757 TI - Recognition of copper and hydrogen sulfide in vitro using a fluorescein derivative indicator. AB - We report the development of a fluorescein-based chemosensor (L1) for monitoring ions or micromolecules (H(2)S). Copper ions are known to be toxic at high concentrations and hydrogen sulfide induces various problems. Herein we develop a simple method for detecting Cu(II) and H(2)S with high selectivity and sensitivity. The chemosensor L1 displays on-off-on type fluorescence change with alternately added Cu(II) and H(2)S to the media along with reversible forming separating of the complex. The potential biomedical relevance of the chemical mechanisms involved in the detection of L1 is described. PMID- 22437758 TI - Bayesian nonparametric inference on quantile residual life function: Application to breast cancer data. AB - There is often an interest in estimating a residual life function as a summary measure of survival data. For ease in presentation of the potential therapeutic effect of a new drug, investigators may summarize survival data in terms of the remaining life years of patients. Under heavy right censoring, however, some reasonably high quantiles (e.g., median) of a residual lifetime distribution cannot be always estimated via a popular nonparametric approach on the basis of the Kaplan-Meier estimator. To overcome the difficulties in dealing with heavily censored survival data, this paper develops a Bayesian nonparametric approach that takes advantage of a fully model-based but highly flexible probabilistic framework. We use a Dirichlet process mixture of Weibull distributions to avoid strong parametric assumptions on the unknown failure time distribution, making it possible to estimate any quantile residual life function under heavy censoring. Posterior computation through Markov chain Monte Carlo is straightforward and efficient because of conjugacy properties and partial collapse. We illustrate the proposed methods by using both simulated data and heavily censored survival data from a recent breast cancer clinical trial conducted by the National Surgical Adjuvant Breast and Bowel Project. PMID- 22437759 TI - Role of transglutaminase 2 in celiac disease pathogenesis. AB - A number of lines of evidence suggest that transglutaminase 2 (TG2) may be one of the earliest disease-relevant proteins to encounter immunotoxic gluten in the celiac gut. These and other investigations also suggest that the reaction catalyzed by TG2 on dietary gluten peptides is essential for the pathogenesis of celiac disease. If so, several questions are of critical significance. How is TG2 activated in the celiac gut? What are the disease-specific and general consequences of activating TG2? Can local inhibition of TG2 in the celiac intestine suppress gluten induced pathogenesis in a dose-responsive manner? And what are the long-term consequences of suppressing TG2 activity in the small intestinal mucosa? Answers to these questions will depend upon the development of judicious models and chemical tools. They also have the potential of yielding powerful next-generation drug candidates for treating this widespread but overlooked chronic disease. PMID- 22437761 TI - [Syphilis and pregnancy...the story continues!]. PMID- 22437760 TI - The role of sialic acid as a modulator of the anti-inflammatory activity of IgG. AB - Immunoglobulin G (IgG) molecules can have two completely opposing activities. They can be very potent pro-inflammatory mediators on the one hand, directing the effector functions of the innate immune system towards infected cells, tumor cells or healthy tissues in the case of autoimmune diseases. On the other hand, a mixture of IgG molecules purified from the blood of ten thousands of healthy donors is used as an anti-inflammatory treatment for many autoimmune diseases since several decades. It has become evident only recently that certain residues in the sugar moiety attached to the IgG constant fragment can dramatically alter the pro- and anti-inflammatory activities of IgG. This review will focus on sialic acid residues as a modulator of the anti-inflammatory activity and provide an overview of situations where serum IgG glycosylation and sialylation is altered and which molecular and cellular pathways may be involved in this immunomodulatory pathway. PMID- 22437762 TI - [Syphilis during pregnancy and fetal death: back to the future]. PMID- 22437763 TI - [Pregnancies complicated by maternal syphilis and fetal death]. AB - PURPOSE: To describe the characteristics of pregnancies complicated by maternal syphilis and fetal death. METHODS: Retrospective descriptive study performed by reviewing the medical records of 48 pregnant women with maternal syphilis and fetal death outcome admitted to Hospital Geral de Nova Iguacu, Baixada Fluminense, State of Rio de Janeiro, during the period from 2005 to 2008. Birth weight >500 g and fetal death documented by Death Certificate were the inclusion criteria. The following aspects were analyzed: sociodemographic factors, reproductive history, aspects of the current pregnancy, prenatal care, Venereal Disease Research Laboratory (VDRL) testing, and other gestational conditions, in addition to syphilis. The fetal deaths were classified as maternal, placental or fetal. Percentage, mean, standard deviation (SD), maximum and minimum values were reported. RESULTS: The mean maternal age was 22.7 years (SD=0.9 years), and at least 50% of the patients had low educational level. At hospital admission, 68.8% of the subjects were in the third trimester, with a mean gestational age of 29.2 weeks (SD=0.5), and more than 50% were in labor. The vast majority of fetal deaths (93%) occurred before maternal hospitalization. Among the patients who received prenatal care (54.2%), 30.8% had no VDRL test, 30.8 and 15.4% had a reactive and non-reactive result, respectively, and none had more than one prenatal VDRL test. At the time of childbirth, most of the mothers (95.8%) carried out VDRL testing. Overall, the VDRL titers varied from 1:1 to 1:512, with predominant values >1:4 (91.7%). In 23% of cases other clinical conditions related to fetal death, in addition to syphilis, were found. CONCLUSIONS: The infection was the main clinically identified cause of fetal death in this patient series. Fetal death occurred during the preterm period and in the presence of high titers of maternal infection, suggesting recent syphilis infection. PMID- 22437764 TI - [Seroepidemiology of toxoplasmosis in pregnant women since the implementation of the Surveillance Program of Toxoplasmosis Acquired in Pregnancy and Congenital in the western region of Parana, Brazil]. AB - PURPOSE: To evaluate the susceptibility to toxoplasmosis in pregnant women in the public health service from two cities in the western region of Parana, Brazil. METHODS: Four thousand twenty-two pregnant women were evaluated for anti Toxoplasma gondii IgG and IgM by ELISA and MEIA. Seronegative pregnant women repeated the serology in the second and third trimester of pregnancy. Neonatal screening of 27 newborns was also performed in one of the cities to detect IgM anti- Toxoplasma gondii by fluorometry. All pregnant women answered an epidemiological questionnaire to analyze the factors associated with the risk of infection by Toxoplasma gondii. For statistical analysis, the presence of IgG anti-Toxoplasma gondii was considered as the dependent variable and the variables contained in the epidemiological questionnaire as the independent ones. RESULTS: The prevalence of anti-Toxoplasma gondii IgG in pregnant women was 59.8 and 60.6%. In one of the cities, the variables associated with the presence of IgG antibodies were low educational level and more than one pregnancy. There was no association with other factors studied such as consumption of raw or undercooked meat, consumption of raw vegetables, consumption of colonial salami, handling soil or sand, the presence of a home vegetable garden and cats in the household. In the other city there was no statistical association with the variables studied. No case of acute infection and no seroconversion were confirmed in either city. None of the infants evaluated were positive for toxoplasmosis. CONCLUSION: Toxoplasmosis is common in pregnant women attended by the public health service in the region studied and 40% of them are susceptible to the infection. These data reinforce the need to keep the screening program in these cities. PMID- 22437765 TI - [Perception influence of professionals regarding unsafe in attention to women's health]. AB - PURPOSE: To identify the knowledge and awareness of health professionals regarding the Brazilian legislation on induced abortion. METHODS: Unidentified sealed envelopes containing the questionnaires were sent to all professionals (n=149) working in the Obstetrics Department of a university hospital and public hospital at the periphery of Sao Paulo (SP), Brazil. A total of 119 professionals responded to the questionnaire. The 0.05 confidence interval and the Fisher exact test and chi2 test were used for data analysis. RESULTS: Of the respondents, 48.7% were physicians, 33.6% were nursing professionals and 17.6% were professionals from other fields (psychologists, nutritionists, physiotherapists, laboratory technicians and administrators). There was a significant difference (p=0.01) in the proportion of professionals who believe that abortion for non lethal fetal malformation and due to unplanned pregnancies should be included in the Brazilian legislation. It was observed that the knowledge about the law and the description of the circumstances allowed by law on abortion was significantly different when comparing health professionals (p=0.01). When asked about the situations in which Brazilian law allows abortion, 32.7% of physicians, 97.5% of nursing professionals and 90.5% of other professionals were unaware of the law. CONCLUSION: This study demonstrated the lack of of knowledge of Brazilian law among health professionals, to a lesser extent among obstetricians and a to a greater extent among nursing professionals. Attitudes of discrimination and prejudice were observed regarding the care provided to women who induce an abortion. PMID- 22437766 TI - [Insulin resistance in women with polycystic ovary syndrome: relationship with anthropometric and biochemical variables]. AB - PURPOSE: To analyze the prevalence of insulin resistance, according to different biochemical and anthropometric measurements in women with polycystic ovary syndrome. METHODS: A total of 189 patients with polycystic ovary syndrome were retrospectively analyzed. Insulin resistance diagnosis was performed using fasting insulin, HOMA-IR, QUICKI, insulin sensibility index and glucose/fasting insulin ratio. Body mass index and lipid accumulation product were used. Data were analyzed statistically by descriptive statistics, ANOVA, Tukey post-test, and Pearson's correlation. RESULTS: The polycystic ovary syndrome patients had a mean age of 24.9 +/- 5.2 and a mean body mass index of 31.8 +/- 7.6. The percentage of obese patients was 57.14%. Among the methods of insulin resistance investigation, the insulin sensibility index was the technique that most detected (56.4%) the presence of insulin resistance in women with polycystic ovary syndrome. The insulin resistance was detected in 87% of obese patients. The fasting glucose/fasting insulin ratio and insulin sensibility index were strongly correlated with lipid accumulation product. CONCLUSION: The prevalence of insulin resistance varied according to the method used, and it was greater the higher the body mass index. Lipid accumulation product was also related to insulin resistance. PMID- 22437767 TI - [Results of hysteroscopic endometrial ablation after five-year follow-up]. AB - PURPOSE: To evaluate the clinical outcomes after a minimum period of 5 years of follow-up of patients with abnormal uterine bleeding of benign etiology who underwent endometrial ablation, analyzing the success rate of treatment defined as patient satisfaction and improvement in uterine abnormal bleeding, as well as late complications and factors associated with recurrence of symptoms. METHODS: A cross-sectional survey was conducted after a minimum period of 5 years after surgery in patients who underwent the procedure between 1999 and 2004. We analyzed the following data: age at the time of surgery, immediate and late complications and associated factors. Logistic regression with Odds Ratio (OR) calculation was performed to evaluate possible associations between the success rate of surgery and the analyzed variables. RESULTS: A total of 114 patients underwent endometrial ablation between March 1999 and April 2004. The median follow-up was 82 months. The logistic regression model allowed the correct prediction of the success of endometrial ablation in 80.6% of cases. Age was directly related to the success of the procedure (OR=1.2; p=0.003) and previous tubal ligation showed a negative association with the success of endometrial ablation (OR=0.3; p=0.049). Among the patients with treatment failure, 21 (72.4%) underwent hysterectomy. In one of the hysterectomy cases, hydro/hematosalpinx was confirmed by the anatomopathological exam, characterizing the postablation-tubal sterilization syndrome. CONCLUSION: Endometrial ablation has proven to be a worthwhile treatment option, maintaining high rates of patient satisfaction, even over long-term follow-up. The age at endometrial ablation influenced the therapeutic success. Further studies are needed to evaluate the factors that may influence the future indication for the procedure in selected cases. PMID- 22437768 TI - [Evaluation of a strategy adopted to expand adherence to breast cancer screening in Brazilian Northeast]. AB - PURPOSE: To evaluate the actions of the "Um Beijo Pela Vida" Program developed in a Brazilian Northeast city to increase adherence to breast cancer screening by women registered by the Brazilian Family Health Strategy for breast cancer screening. METHODS: A quantitative approach was used to evaluate the coverage of screening actions for aged 40 years-old or more. Community workers from the nine Family Health Teams of the town carried out an active search. The percentage of eligible women who were screened for breast cancer by clinical breast examination or mammography, mammogram classification according to BI-RADS(r), women screened who were referred for further testing and treatment, and the number of breast cancers detected were collected by means of a structured questionnaire, analyzed with the EPI-INFO TM software and compared to previously defined patterns. RESULTS: 3,608 women were included, corresponding to 68.4% of the target population registered in the Brazilian Family Health Strategy. Coverage rates of clinical breast examination for women aged 40 to 49 years-old and of mammograms for women aged 50 to 69 years-old were 58.9 and 56.7%, respectively. All women with highly suspicious mammographic lesions were submitted to fine needle aspiration or core biopsy (100%). Six new cases of cancer were detected and 80% of the standards established for this evaluation were carried out. CONCLUSIONS: The evaluation of the actions of the Program suggests its adequacy considering the degree of fulfillment of the previously defined requirements. PMID- 22437769 TI - [Macroprolactinemia and intermediate hyperprolactinemia: clinical manifestations and image]. AB - PURPOSE: To characterize patients with indeterminate values of hyperprolactinemia (PEG test for the identification of macroprolactinemias with recovery between 30 and 65%) (PRLi) or macroprolactinemia (PRLm), in relation to clinical characteristics, such as the presence or absence of symptoms, as well as their intensity and variation, and the presence or absence of central nervous system tumors. METHODS: This is a cross-sectional retrospective survey of records of 24 patients with hyperprolactinemia, in reproductive ages, with prolactin >25 ng/dL. Eleven women with PRLm and 13 with PRLi were included. Records from the two groups were extracted for analysis: age, parity, body mass index, presence of galactorrhea, infertility, and central nervous system tumor. Anthropometrics data were expressed as mean and standard deviation. To compare groups regarding the presence of central nervous system tumor, galactorrhea, as well as infertility we used the Student's t-test. RESULTS: Galactorrhea was more prevalent in patients with PRLi (p=0.01). Seventy percent of women with PRLi presented pituitary tumor (microprolactinoma), whereas this finding was evident in 17% of the PRLm Group (p=0.04). Among the patients with and PRLm PRLi, nine were not investigated with the image of the central nervous system because they have low levels of prolactin (five carriers and four PRLm PRLi). There were no significant differences regarding the occurrence of infertility or irregular menstrual cycles between groups. DISCUSSION: Women with intermediate hyperprolactinemia present more galactorrhea symptoms as well as central nervous system tumors than women with macroprolactinemia. PMID- 22437770 TI - Cep70 contributes to angiogenesis by modulating microtubule rearrangement and stimulating cell polarization and migration. AB - Centrosomal proteins intricately regulate diverse microtubule-mediated cellular activities, including cell polarization and migration. However, the direct participation of these proteins in angiogenesis, which involves vascular endothelial cell migration from preexisting blood vessels, remains elusive. Here we show that the centrosomal protein Cep70 is necessary for angiogenic response in mice. This protein is also required for tube formation and capillary sprouting in vitro from vascular endothelial cells. Wound healing and transwell assays reveal that Cep70 plays a significant role in endothelial cell migration. Depletion of Cep70 results in severe defects in membrane ruffling and centrosome reorientation, indicating a requirement for this protein in cell polarization. In addition, Cep70 is critically involved in microtubule rearrangement in response to the migratory stimulus. Our data further demonstrate that Cep70 is important for Cdc42 and Rac1 activation to promote angiogenesis. These findings thus establish Cep70 as a crucial regulator of the angiogenic process and emphasize the significance of microtubule rearrangement and cell polarization and migration in angiogenesis. PMID- 22437771 TI - The scientific marketplace. PMID- 22437772 TI - A photoferroelectric material is more than the sum of its parts. PMID- 22437774 TI - The m word. Interview by Christian Martin. PMID- 22437773 TI - One-click science marketing. PMID- 22437780 TI - Polymer glasses: From gas to nanoglobular glass. PMID- 22437781 TI - siRNA delivery: Loaded-up microsponges. PMID- 22437782 TI - Phase-change materials: Fast transformers. PMID- 22437783 TI - Material witness: Why leaves have stones. PMID- 22437784 TI - Light-matter interactions: Ultrastrong routes to new chemistry. PMID- 22437785 TI - Spider webs: Damage control. PMID- 22437786 TI - Metallic glasses: Family traits. PMID- 22437787 TI - DNA origami: Nanorobots grab cellular control. PMID- 22437788 TI - Conflict of interest: a long way ahead. PMID- 22437791 TI - Highly efficient photoelectrochemical water splitting using a thin film photoanode of BiVO4/SnO2/WO3 multi-composite in a carbonate electrolyte. AB - The solar energy conversion efficiency considering the energy loss by the external bias for water splitting reached ca. 0.9 or 1.35% using single- or double-stacked photoanodes, respectively, of BiVO(4)/SnO(2)/WO(3) multilayers in a highly concentrated carbonate electrolyte aqueous solution. PMID- 22437790 TI - Therapeutic immunization with radio-attenuated Leishmania parasites through i.m. route revealed protection against the experimental murine visceral leishmaniasis. AB - After our promising results from prophylactic and therapeutic study (i.p. route) with the radio-attenuated Leishmania donovani parasites against experimental murine visceral leishmaniasis, we prompted to check their therapeutic efficacy through i.m route. BALB/c mice were infected with highly virulent L. donovani parasites. After 75 days, mice were treated with gamma (gamma)-irradiated parasites. A second therapeutic immunization was given after 15 days of first immunization. The protection against kala-azar was estimated with the reduction of Leishman-Donovan unit from spleen and liver that scored up to 80% and 93%, respectively, while a twofold increase in nitric oxide (NO) and reactive oxygen species (ROS) productions has been observed in the immunized groups of animals. These groups of mice also showed disease regression by skewing Th2 cytokines (IL 10) towards Th1 cytokine (IFN-gamma) bias along with the increased generation of NO and ROS, while the infected control group of mice without such treatment surrendered to the disease. Establishment of Th1 ambience in the treated groups has also been supported from the measured antileishmanial antibody IgG subsets (IgG2a and IgG1) with higher anti-soluble Leishmania antigen-specific IgG2a titer. As seen in our previous studies, doses of attenuation by gamma-radiation should be taken into serious consideration. Attenuation of parasites at 50 Gy of absorbed dose of gamma rays has not worked well. Thus, therapeutic use of L. donovani parasites radio-attenuated at particular doses can be exploited as a promising vaccine agent. Absence of any adjuvant may increase its acceptability as vaccine candidate further. PMID- 22437792 TI - A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial. AB - The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (>=1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean +/- SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% +/- 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% +/- 2.9%) or placebo (0.5% +/- 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. PMID- 22437793 TI - A simple, high sensitivity mutation screening using Ampligase mediated T7 endonuclease I and Surveyor nuclease with microfluidic capillary electrophoresis. AB - Mutation and polymorphism detection is of increasing importance for a variety of medical applications, including identification of cancer biomarkers and genotyping for inherited genetic disorders. Among various mutation-screening technologies, enzyme mismatch cleavage (EMC) represents a great potential as an ideal scanning method for its simplicity and high efficiency, where the heteroduplex DNAs are recognized and cleaved into DNA fragments by mismatch recognizing nucleases. Thereby, the enzymatic cleavage activities of the resolving nucleases play a critical role for the EMC sensitivity. In this study, we utilized the unique features of microfluidic capillary electrophoresis and de novo gene synthesis to explore the enzymatic properties of T7 endonuclease I and Surveyor nuclease for EMC. Homoduplex and HE DNAs with specific mismatches at desired positions were synthesized using PCR (polymerase chain reaction) gene synthesis. The effects of nonspecific cleavage, preference of mismatches, exonuclease activity, incubation time, and DNA loading capability were systematically examined. In addition, the utilization of a thermostable DNA ligase for real-time ligase mediation was investigated. Analysis of the experimental results has led to new insights into the enzymatic cleavage activities of T7 endonuclease I and Surveyor nuclease, and aided in optimizing EMC conditions, which enhance the sensitivity and efficiency in screening of unknown DNA variations. PMID- 22437794 TI - Regional lung chemotherapy techniques. AB - Selective delivery of chemotherapy to an affected organ or region of the body promises improved drug efficacy for the targeted area while minimizing the systemic exposure and toxicity. Several intravascular surgical techniques to achieve targeted regional lung chemotherapy have been developed. Investigations have been carried out to determine the feasibility, safety, and efficacy of these techniques in the primary or adjuvant setting with the intent to palliate or cure. This overview describes the history, rationale, technical aspects, and clinical experience of four regional lung chemotherapy techniques delivered by vascular manipulations including bronchial artery infusion, pulmonary artery chemoembolization, isolated lung perfusion, and lung suffusion. PMID- 22437795 TI - Is transthoracic minimally invasive aortic valve replacement too time-consuming for the busy cardiac surgeon? AB - OBJECTIVE: : Transthoracic minimally invasive aortic valve replacement (TMI-AVR) is gaining popularity despite criticism that time from incision to the initiation of cardiopulmonary bypass (exposure time, ET), cardiopulmonary bypass time (CPBT), and cross-clamp time (XCT) is excessive. Database analysis was used to characterize these parameters and their associated learning curves. METHODS: : From 2004 to 2008, 101 patients underwent TMI-AVR at a single institution. Of them, 54 were men (53%) and 47 were women (47%). Mean age was 70 years (range, 24 90 years). ET includes 6-cm incision, second intercostals anterior thoracotomy, medial transection of the third rib, opening pericardial sac, retracing pericardium with stay sutures, placing aortic arterial, and right arterial venous bypass cannulae. ET, CPBT, XCT, and operating room times were calculated. Logarithmic trend analysis established associated learning curves. RESULTS: : ET steadily improved over time. ET decreased from an average of 51 minutes for the first 25 patients to 39 minutes for the most recent 25 patients. When surgeon experience reached 10 procedures, the ET trend line began to decline steadily and plateaued by 55 cases. Cross-clamp (55 +/- 21 minutes), cardiopulmonary bypass (77 +/- 31 minutes), and operating room times (304 +/- 67 minutes) all remained constant. There were no early deaths or conversions to sternotomy. CONCLUSIONS: : ET learning curve for TMI-AVR was reflected after 10 procedures with continued gradual improvement. Reliability of TMI-AVR was observed in the absence of a learning curve for XCT, CPBT, and operating room times. A sternal-sparing transthoracic approach for AVR can be performed safely, with expected operative times equivalent to sternotomy. PMID- 22437796 TI - Long-term follow-up of patients operated with the symmetry proximal connector device. AB - OBJECTIVE: : The Symmetry proximal connector device was introduced as a facilitator for construction of proximal anastomosis in coronary bypass surgery. Use of the connector made it unnecessary to clamp the ascending aorta. Early results were promising, but a controlled study performed in our center demonstrated poor angiographic patency of saphenous veins attached with the connector. The objective of this study was to investigate long-term clinical results in patients operated with connector or traditional suture technique. METHODS: : At a minimum of 5 years after surgery, medical records of 46 patients who had undergone off-pump coronary bypass with Symmetry (n = 23) or traditional suture (n = 23) were examined, and the patients were interviewed personally by phone. Patients were asked about the presence of angina pectoris, hospital admission for cardiac conditions, or the need for new interventions. The Norwegian population registry was used to document survival status. RESULTS: : Two control patients and five Symmetry patients died during the observation period (P = 0.414). Seven Symmetry and one control patient required reintervention (P = 0.015). Of the patients who were interviewed, 8 of 19 Symmetry patients suffered from angina and none of 20 control patients (P = 0.003). CONCLUSIONS: : Patients who were operated with the Symmetry connector device have a high chance of having cardiac ischemia in the intermediate to long term after surgery, despite of relatively frequent reintervention. Patients operated with this connector requires close clinical follow-up. PMID- 22437797 TI - Performance of a novel dual-electrode bipolar radiofrequency ablation device: a chronic porcine study. AB - OBJECTIVE: : Over recent years, a variety of energy sources, including bipolar radiofrequency, have been used to replace the traditional incisions of the Cox Maze procedure for the surgical treatment of atrial fibrillation (AF). The purpose of this study was to evaluate the safety and efficacy of a novel dual electrode bipolar radiofrequency ablation device Synergy (Atricure, Inc., Cincinnati, OH USA) for AF in a chronic porcine model. METHODS: : Six domestic pigs underwent a modified Cox-Maze IV procedure without cardiopulmonary bypass using the Synergy device. Animals survived for 30 days. Each pig then underwent induction of AF and was killed to remove the heart en bloc for histologic assessment. Each ablation line was dissected perpendicularly at 5-mm intervals to assess the lesion width, depth, and transmurality. RESULTS: : All animals survived the operation. Electrical isolation of the left atrial appendage and the pulmonary veins were documented by pacing acutely and at 30 days after the operation in all six animals. All animals failed to be induced in AF at 30 days. There was no gross evidence of intra-atrial thrombus formation or stricture of the pulmonary veins. All ablations (n = 209) examined were discrete, linear, and transmural, with a mean lesion width of 3.0 +/- 0.7 mm and a mean lesion depth of 5.4 +/- 3.3 mm. The mean ablation time was 16.3 +/- 4.4 seconds, with a mean total energy delivery of 238 +/- 170 J. CONCLUSIONS: : The Atricure Synergy was able to create reliable chronic transmural lesions of the modified Cox-Maze IV procedure on a porcine beating heart without cardiopulmonary bypass. The ablation lines were significantly wider when compared with its predecessor, the Isolator II. PMID- 22437798 TI - Multivessel awake off-pump coronary bypass grafting using median approach: technical considerations. AB - OBJECTIVE: : Several reports of awake off-pump coronary artery bypass grafting (AOCAB) under high thoracic epidural anesthesia (TEA) for single-vessel grafts have been published, but few have described its application in multiple bypass procedures. We report the procedures and safety of AOCAB for multivessel disease. METHODS: : Fifty-five multivessel AOCAB (52 men, 3 women; aged 68 +/- 9.5 years) were performed at our hospital between 2003 and 2010. A medium sternotomy was made after TEA was established. During coronary artery anastomosis, a stabilizer and an apical suction device were used, and a coronary artery active perfusion system was used to maintain flow distal to the anastomosis. Pneumothorax due to pleural opening, when occurred, was repaired using Neoveil sheet and drainage tube. RESULTS: : There was no operative death and no cerebral ischemia, cardiac arrhythmia, and chronic obstructive pulmonary disease. Operating time was 177 +/- 35 minutes. Left internal thoracic artery was used in 55 anastomoses, right internal thoracic artery in 7, gastroepiploic artery in 17, radial artery in 48, and saphenous vein in 24. Time of anastomosis was 4.93 +/- 0.92 minutes for left anterior descending coronary artery, 4.75 +/- 1.21 minutes for circumflex artery, and 4.98 +/- 1.02 minutes for right coronary artery. Intraprocedural pneumothorax occurred in 17 cases; 14 were repaired and nonintubated AOCAB was accomplished, 1 was intubated, and 2 had temporary assisted ventilation and laryngeal mask. Time to discharge was 15.5 +/- 8.4 days. CONCLUSIONS: : Multivessel AOCAB under TEA is not only feasible but also safe. Multiple grafts can be harvested under TEA, and complete vascularization is possible under constant monitoring of blood pressure and consciousness. PMID- 22437799 TI - Short-term outcomes after thoracoscopic lobectomy in elderly compared to younger patients. AB - OBJECTIVE: : As the population continues to age, more benign and malignant lung lesions requiring surgical intervention are being identified in elderly patients. Historically, advanced age has been used to justify performing wedge resection rather than a lobectomy in elderly patients. The introduction of thoracoscopic surgery has resulted in improved short-term outcomes compared with thoracotomy. The objective of this study is to compare short-term outcomes of thoracoscopic lung resection in elderly patients to that in younger patients. METHODS: : A retrospective review was performed of all patients undergoing thoracoscopic anatomic lobectomy without previous chemotherapy or radiation between April 2006 and April 2009. Patient charts were reviewed to determine risk factors, perioperative complications, and length of stay. Student's t test was used for comparison between groups. RESULTS: : Over the period studied, 86 patients underwent thoracoscopic lobectomy. Forty of them were 70 years or older. Baseline pulmonary function testing showed an average FEV1 of 85% predicted (81% younger vs 90% older, P = nonsignificant). Median chest tube duration was 3 days and median length of stay was 4 days in both groups. The overall incidence of perioperative complications was 21% and was not different in the two groups (20% younger vs 22% older). CONCLUSIONS: : Elderly patients with good baseline pulmonary function tolerate thoracoscopic lobectomy as well as younger patients. Advanced age alone should not be considered a contraindication to lobectomy in the era of thoracoscopy. Elderly patients should be offered lobectomy rather than wedge resection on the basis of the same criteria used in younger patients. PMID- 22437800 TI - Performance of bioprosthetic valves after glycerol dehydration, ethylene oxide sterilization, and rehydration. AB - OBJECTIVE: : Most commercially available bioprosthetic valves are stored in an aldehyde solution. We report a new alternative method: Self-expanding valves composed of dehydrated tissues with a high glycerin:water ratio can be collapsed into specially designed sheaths prior to sterilization for ease of delivery and storage. MATERIALS AND METHODS: : Changes in tissue dimension of five samples of bovine pericardium were evaluated from baseline after glycerol treatment, air drying, ethylene oxide (EtO) sterilization, and rehydration with water. Three valves fabricated from glutaraldehyde cross-linked tissues, including porcine pericardial tissue, bovine pericardial tissue, and porcine aortic valve, were dehydrated through a proprietary glycerin-based process, collapsed, placed within a catheter, EtO sterilized, stored for up to 212 days, and rehydrated with water. These valves were characterized in a mock circulation by mounting them at the inlet portion of a pneumatic pump before dehydration and after rehydration to evaluate the effects of dehydration and rehydration on the valve performance. RESULTS: : Tissues treated with glycerol solution showed no significant changes in dimension from baseline after glycerol treatment, air-drying, EtO sterilization, and rehydration with water. In all the valves, pump flows reached the maximum output capacity of the pneumatic pump after rehydration without an increase in filling pressures as compared with those before dehydration. CONCLUSIONS: : This method for storing collapsible bioprosthetic valves using a proprietary glycerin-based process demonstrated excellent valve performance. PMID- 22437801 TI - Fluid Dynamic Investigation of the ATS 3F Enable Sutureless Heart Valve. AB - OBJECTIVE: : Currently, sutureless heart valves (SHV) reveal good clinical results during aortic valve replacement. The aim of this study was to evaluate the fluid dynamics of the ATS 3F Enable SHV in the ascending aorta and their influence on the aortic wall in an in vitro setup. METHODS: : A two-dimensional particle image velocimetry study with an image rate of 15 Hz was conducted to evaluate the fluid dynamics of the SHV in the aortic flow field. The prosthesis (diameter, 23 mm) was placed inside a silicone mock aorta under pulsatile flow conditions. Velocities, vorticity, and strain rate were obtained and calculated with a fixed frequency (70 Hz) at constant stroke volume (70 mL). RESULTS: : 3F Enable showed a jet flow type profile with a maximum velocity of 1.01 +/- 0.13 m/s during peak flow phase (PFP). The jet flow was surrounded by ambilateral vortices with a slightly higher percentage of clockwise than counterclockwise vorticity (377 +/- 57/s vs 389 +/- 76/s), strain rate (370 +/- 79/s for elongation vs -370 +/- 102/s for contraction) was nearly similar. The point-of interest analysis revealed a higher velocity for bottom compared with upper aortic wall (0.28 +/- 0.07 m/s vs 0.31 +/- 0.06 m/s, P = 0.024). All values were lower during acceleration and deceleration phase compared with PFP. CONCLUSIONS: : The peak flow of the 3F Enable SHV seems to be little higher compared with native aortic valves, thus simulating nearly physiologic conditions. Vorticity and strain rate are high during PFP and low during other phases and might have an influence on the aortic wall as well. PMID- 22437802 TI - Uni-incisional video-assisted thoracoscopic left lower lobectomy in a patient with an incomplete fissure. AB - Video-assisted thoracoscopic surgery (VATS) was introduced nearly two decades ago. Since then, there has been a rapid development in minimal invasive techniques for lung cancer treatment. The common approach is the one performed through three incisions, including a utility incision of ~3 to 5 cm. However, lobectomy can be performed by using only two incisions (one camera port and working incision). A few clinics perform this approach. We began the two-incision technique in our institution in February 2009. After performing 95 cases with this technique, we observed that for lower lobes the second incision could be eliminated, and we performed the surgery by using only the 4-cm utility incision. This article describes a case report of a 57-year-old woman operated by this uni incisional approach for a lower lobe video-assisted thoracoscopic surgery lobectomy. PMID- 22437803 TI - Successful Intraoperative Reversal of Heparin With Factor VII in a Patient With Protamine Reaction. AB - Factor VII has been utilized to treat post-operative bleeding after cardiac surgery refractory to other intervention. We report the case of a patient who developed intractable bleeding after a severe protamine reaction following emergency repair of type A aortic dissection and was successfully treated with factor VII. PMID- 22437804 TI - Ten-year follow-up after endovascular repair of traumatic abdominal aortic rupture. AB - Blunt abdominal aortic injury is often associated with bowel injury that precludes operative repair because of the risk of graft infection. Endovascular repair has been reported but with limited follow-up. We present a case of a 15 year-old boy who underwent endovascular repair of blunt abdominal aortic rupture and whom we were able to follow up over a decade. Our experience with this case and three others, as well as the experience reported in the literature, suggests that endovascular repair is a reasonable option in the setting of concomitant bowel injury. The risk of over sizing, collapse, and migration may be less than that described for thoracic aortic injuries because there is no need to deploy the endograft across an angle. PMID- 22437805 TI - A novel design of posterior leaflet butterfly resection for mitral valve repair. AB - A new design for posterior leaflet resection, "butterfly resection," is proposed. It is a combination of two triangular resections in the prolapsing posterior leaflet segment. This method minimizes resection in the target segment, and it prevents systolic anterior motion by reducing the height of the posterior leaflet according to the amount of excess tissue. We have used this technique for 60.4% (29 of 48) of posterior leaflet prolapse cases with zero hospital mortality and no morbidity. Postbypass transesophageal echocardiography identified no more than mild regurgitation and no sign of systolic anterior motion. During 13.1 +/- 6.8 months of follow-up, patients neither died nor needed reoperation. PMID- 22437806 TI - The techniques of endobronchial ultrasound-guided transbronchial needle aspiration. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive modality for mediastinal lymph node staging in lung cancer patients as well as for the diagnosis of mediastinal and hilar adenopathy. The high diagnostic yield of EBUS-TBNA for lymph node staging has been shown in systematic reviews and meta-analysis. It has attracted physicians and surgeons as an alternative modality to surgical biopsy for the assessment of patients with enlarged mediastinal and/or hilar lymph nodes. Cell blocks obtained by EBUS-TBNA can be applicable not only for pathologic diagnosis but also for further investigations such as immunohistochemistry and fluorescence in situ hybridization. In addition, samples obtained by EBUS-TBNA can also be used for molecular analysis. Unlike regular bronchoscopy, EBUS-TBNA uses the convex probe EBUS with an ultrasound probe on the tip of a flexible bronchoscope. It is important for the bronchoscopist to fully understand the mediastinal anatomy and be able to correlate it with the ultrasound images for a successful EBUS-TBNA. The dedicated transbronchial needle used for EBUS-TBNA is somewhat different from an ordinary transbronchial biopsy forceps. Training is mandatory for achieving high diagnostic yield without complications. The learning curve of EBUS-TBNA is different from each physician, and continuous training program will be needed for impartiality. This article explains the detailed techniques of EBUS-TBNA to master this innovative procedure. PMID- 22437807 TI - Serum calcitonin and endothelial dysfunction in chronic kidney disease: a novel risk factor? AB - BACKGROUND: Endothelial dysfunction (ED) is highly prevalent in patients with CKD. The relationship between ED and calcitonin has not been demonstrated before in CKD patients. METHODS: The study included non-diabetic CKD patients not on dialysis. Demographic data (age, gender, comorbidities, current drug therapy, smoking status, weight, and height) were collected from the individual charts in the hospital's electronic database. After overnight fasting, laboratory measurements including serum calcitonin levels were performed in all patients. A single observer who was blinded to the results of the study assessed ED by measurement of flow-mediated dilatation (FMD). RESULTS: In total, 84 CKD patients (41 men, age 45.1 +/- 13.3 years) were included. Thirty-seven patients had stage 3 and 47 patients had stage 4 CKD. Patients with calcitonin levels above the median had lower FMD (6.87 +/- 0.58 vs. 7.23 +/- 0.66, P = 0.008) when compared with patients with calcitonin levels below the median. None of the other demographic, laboratory and clinical parameters was different between the two groups. In multivariate regression analysis, serum calcitonin (P = 0.01), fetuin A (P < 0.001), high-sensitive C-reactive protein (P < 0.001), and hemoglobin (P = 0.004) were independently associated with FMD. CONCLUSION: Our present study demonstrated for the first time that serum calcitonin is independently related with ED. This finding deserves further experimental and clinical exploration, in order to elucidate whether calcitonin is an innocent bystander or has a pathophysiologic relationship with ED in patients with CKD. PMID- 22437808 TI - Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review. AB - Inflammation and venous thrombosis are intertwined. Only in the recent 15 years clinical epidemiological studies have focussed on inflammatory or infectious diseases as risk factors for venous thrombosis. Although a few reviews and many case reports or studies on these topic has been written, a review reporting relative or absolute risks for venous thrombosis has not been published yet. We performed a systematic review using Medline, Pubmed and Embase and found 31 eligible articles. Inflammatory bowel disease, ANCA-associated vasculitis, infections in general and more specifically, human immunodeficiency virus, pneumonia and urinary tract infections are associated with an increased risk of venous thrombosis. PMID- 22437809 TI - Current developments in cell culture technology. AB - The ideal features of a cell culture system for in vitro investigation depend on what questions the system is to address. However, in general, highly valuable systems will replicate the characteristics and more specifically, the responses, of normal human tissues. Systems that can faithfully replicate different tissue types provide tremendous potential value for in vitro research and have been the subject of much research effort in this area over many years. Furthermore, a range of such systems that could mimic key genetic variations or diseases would have special value for toxicology and drug discovery. In the pursuit of such model systems, there are a number of significant practical issues to consider for their application, which includes ability to deliver with ease, the required quantities of cells at the time needed. In addition any cell culture assay will need to be robust and reliable and provide readily interpreted and quantified endpoints. Other general criteria for cell culture systems include scalability to provide the very large cell numbers that may be required for high throughput systems, with a high degree of reliability and reproducibility. The amenability of the cell culture for down-scaling may also be important, to permit the use of very small test samples (e.g., in 96-well arrays), even down to the level of single cell analysis. This chapter explores the range of new cell culture systems for scaling up cell cultures that will be needed for high throughput toxicology and drug discovery assays. It also reviews the increasing range of novel systems that enable high content analysis from small cell numbers or even single cells. The hopes and challenges for the use of human stem cell lines are also investigated in comparison with the range of eukaryotic cells types currently in use in toxicology. PMID- 22437810 TI - Embryonic stem cells in safety pharmacology and toxicology. AB - Embryonic stem (ES) cells undergo self-renewal and are pluripotent, i.e., they can give rise to all the types of specialised cells in the body. Scientific knowledge on ES cells is increasing rapidly, leading to opportunities for establishment of ES cell-based in vitro tests for drug discovery, preclinical safety pharmacology and toxicology. The main properties of ES cells making them useful in in vitro assays are that they have a normal diploid karyotype and can provide a large number of cells for high-throughput assays. Human ES cells additionally have the potential to provide solutions to problems related to interspecies differences and methods for screening for human polymorphisms, thus supporting robust human hazard identification and optimised drug discovery strategies. Importantly, ES cell based assays could be potential tools to reduce and perhaps replace, animal experiments. This chapter will describe ongoing research in the use of ES cells in toxicology and safety pharmacology, focusing on the major areas of progress, namely, embryotoxicology, cardiotoxicology and hepatoxicology. PMID- 22437811 TI - Trends in cell culture technology. AB - Dynamic macroscale bioreactor systems are the most recent breakthrough in cell culture technology. This major achievement, at the beginning of the 21st century, fortunately coincided with an embarrassing gap in the measures to predict the safety and modes of action of chemicals, cosmetics, air particles and pharmaceuticals. The major hurdles to the translation of these breakthrough achievements of cell culture technology into meaningful solutions for predictive high throughput substance testing remain miniaturization from the milliliter to the microliter scale and the supply of relevant amounts of standardized human tissue. This chapter provides insights into the latest developments in this area, illustrates an original multi-micro-organ bioreactor concept and identifies highways for closing the gap. PMID- 22437812 TI - Tissue engineering in the development of replacement technologies. AB - The field of tissue engineering is generating new scaffolds, bioreactors and methods for stimulating cells within complex cultures, with the aim of recreating the conditions under which cells form functional tissues. Hitherto, the primary focus of this field has been on clinical applications. However, there are many methods of in vitro tissue engineering that represent new opportunities in 3D cell culture and could be the basis for new replacement methods that either replace the use of a tissue isolated from an animal or the use of a living animal. This chapter presents an overview of tissue engineering and provides tissue-specific examples of recent advances. PMID- 22437813 TI - Toxicity testing of nanomaterials. AB - The large-scale production and consumer exposure to a variety of nanotechnology innovations has stirred interest concerning the health consequences of human exposure to nanomaterials. In order to investigate these questions, in vitro systems are used to rapidly and inexpensively predict the effects of nanomaterials at the cellular level. Recent advances in the toxicity testing of nanomaterials are beginning to shed light on the characteristics, uptake and mechanisms of their toxicity in a variety of cell types. Once the nanomaterials have been satisfactorily characterized, the evaluation of their interactions with cells can be studied with microscopy and biochemical assays. The combination of viability testing, observation of morphology and the generation of oxidative stress provide clues to the mechanisms of nanomaterial toxicity. The results of these studies are used to better understand how the size, chemical composition, shape and functionalization may contribute to their toxicity. This chapter will introduce the reader to the impact of nanomaterials in the workplace and marketplace with an emphasis on carbon-based and metal-based nanomaterials, which are most commonly encountered. While most purified carbon nanomaterials were nontoxic to many cell lines, many metal nanoparticles (e.g., silver or manganese) were more toxic. Other side- effects of nanoparticle interactions with cells can also occur, such as increased branching and dopamine depletion. Further investigation into the characteristics, uptake and mechanisms of nanomaterial toxicity will continue to elucidate this fascinating and rapidly growing area of science. PMID- 22437814 TI - Physiologically-based pharmacokinetic (PBPK) models in toxicity testing and risk assessment. AB - Physiologically-based pharmacokinetic (PBPK) modeling offers a scientifically sound framework for integrating mechanistic data on absorption, distribution, metabolism and elimination to predict the time-course of parent chemical, metabolite(s) or biomarkers in the exposed organism. A major advantage of PBPK models is their ability to forecast the impact of specific mechanistic processes and determinants on the tissue dose. In this regard, they facilitate integration of data obtained with in vitro and in silico methods, for making predictions of the tissue dosimetry in the whole animal, thus reducing and/or refining the use of animals in pharmacokinetic and toxicity studies. This chapter presents the principles and practice of PBPK modeling, as well as the application of these models in toxicity testing and health risk assessments. PMID- 22437815 TI - In silico methods for toxicity prediction. AB - The principles and uses of (Q)SAR models and expert systems for predicting toxicity and the biotransformation of foreign chemicals (xenobiotics) are described and illustrated for some key toxicity endpoints, with examples from the published literature. The advantages and disadvantages of the methods and issues concerned with their validation, acceptance and use by regulatory bodies are also discussed. In addition, consideration is given to the potential application of these techniques in regulatory toxicity testing, both individually and as part of a chemically-based read-across approach, particularly for the risk assessment of chemicals within intelligent, integrated decision-tree testing schemes. It is concluded that, while there has been great progress in recent years in the development and application of in silico approaches, there is still much that has to be achieved to enable them to fulfill their potential for regulatory toxicity testing. In particular, there is a need for the wider availability of appropriate biological data and international agreement on how the systems should be validated. In addition, it is important that correlations between activity and physicochemical properties are based on a mechanistic basis to maximize the predictivity of models for novel chemicals. PMID- 22437816 TI - Luminescent quantum dots for molecular toxicology. AB - Recent developments in nanotechnology have made available a host of new approaches for the improved quantitative detection of biomarkers due to the enhanced sensitivity of nanoparticle-based assays. The majority of molecular toxicology studies revolve around sensitive measurement of cell-death (apoptosis) and cell-health biomarkers present in living cells or formalin-fixed and paraffin embedded (FFPE) tissue samples. In this regard, semi-conductor quantum dots (QDs) which exhibit high brightness, photo-stability and degree of multiplexing, are predicted to have a significant impact on research in molecular toxicology. Due to these superior photophysical properties of QDs as compared to traditional fluorophores and the unsurpassed versatility of QDs as enabling components for new assays, these nanoparticles promise to facilitate new discoveries in molecular toxicology. Indeed, multiplexed QD-based assays have been incorporated into cell imaging, flow cytometry and other homogenized sample-based assays for detecting multiple biomarkers including those associated with cell injury and apoptosis. PMID- 22437817 TI - Engineering Quasi-Vivo in vitro organ models. AB - Cell culture is the workhorse of biologists, toxicologists, tissue engineers and a whole host of research fields in both academia and industry. Having explored individual molecular mechanisms inside cells for decades using traditional cell culture techniques, researchers have only just begun to appreciate that the intricate interconnectivity between cells and cellular networks as well as with the external environment is far more important to cellular orchestration than are single molecular events inside the cell. For example many questions regarding cell, tissue, organ and system response to drugs, environmental toxins, stress and nutrients cannot possibly be answered by concentrating on the minutiae of what goes on in the deepest recesses of single cells. New models are required to investigate cellular cross-talk between different cell types and to construct complex in-vitro models to properly study tissue, organ and system interaction without resorting to animal experiments. This chapter describes how tissue and organ models can be developed using the Quasi-Vivo system and discusses how they may be used in drug toxicity studies. PMID- 22437818 TI - ECVAM and new technologies for toxicity testing. AB - The development of alternative empirical (testing) and non-empirical (non testing) methods to traditional toxicological tests for complex human health effects is a tremendous task. Toxicants may potentially interfere with a vast number of physiological mechanisms thereby causing disturbances on various levels of complexity of human physiology. Only a limited number of mechanisms relevant for toxicity ('pathways' of toxicity) have been identified with certainty so far and, presumably, many more mechanisms by which toxicants cause adverse effects remain to be identified. Recapitulating in empirical model systems (i.e., in vitro test systems) all those relevant physiological mechanisms prone to be disturbed by toxicants and relevant for causing the toxicity effect in question poses an enormous challenge. First, the mechanism(s) of action of toxicants in relation to the most relevant adverse effects of a specific human health endpoint need to be identified. Subsequently, these mechanisms need to be modeled in reductionist test systems that allow assessing whether an unknown substance may operate via a specific (array of) mechanism(s). Ideally, such test systems should be relevant for the species of interest, i.e., based on human cells or modeling mechanisms present in humans. Since much of our understanding about toxicity mechanisms is based on studies using animal model systems (i.e., experimental animals or animal-derived cells), designing test systems that model mechanisms relevant for the human situation may be limited by the lack of relevant information from basic research. New technologies from molecular biology and cell biology, as well as progress in tissue engineering, imaging techniques and automated testing platforms hold the promise to alleviate some of the traditional difficulties associated with improving toxicity testing for complex endpoints. Such new technologies are expected (1) to accelerate the identification of toxicity pathways with human relevance that need to be modeled in test methods for toxicity testing (2) to enable the reconstruction of reductionist test systems modeling at a reduced level of complexity the target system/organ of interest (e.g., through tissue engineering, use of human-derived cell lines and stem cells etc.), (3) to allow the measurement of specific mechanisms relevant for a given health endpoint in such test methods (e.g., through gene and protein expression, changes in metabolites, receptor activation, changes in neural activity etc.), (4) to allow to measure toxicity mechanisms at higher throughput rates through the use of automated testing. In this chapter, we discuss the potential impact of new technologies on the development, optimization and use of empirical testing methods, grouped according to important toxicological endpoints. We highlight, from an ECVAM perspective, the areas of topical toxicity, skin absorption, reproductive and developmental toxicity, carcinogenicity/genotoxicity, sensitization, hematopoeisis and toxicokinetics and discuss strategic developments including ECVAM's database service on alternative methods. Neither the areas of toxicity discussed nor the highlighted new technologies represent comprehensive listings which would be an impossible endeavor in the context of a book chapter. However, we feel that these areas are of utmost importance and we predict that new technologies are likely to contribute significantly to test development in these fields. We summarize which new technologies are expected to contribute to the development of new alternative testing methods over the next few years and point out current and planned ECVAM projects for each of these areas. PMID- 22437819 TI - Medium to high throughput screening: microfabrication and chip-based technology. AB - Medium to high throughput screening for toxicity testing can provide a wealth of information with significant time and cost savings. New technologies, such as microfabrication, microfluidics and chip-based technology, combined with advanced cell culture and detection techniques, open up new opportunities in toxicity testing. In this chapter, fundamentals of microfabrication and microfluidics are discussed with a focus on the broad and novel applications on toxicity studies enabled by these technologies. Emphasis is placed on microscale cell and tissue culture models for medium and high throughput systemic toxicity studies in vitro. PMID- 22437820 TI - The use of genomics in model in vitro systems. AB - Traditional toxicological tests generally provide descriptive information regarding the potential toxicity of chemicals, drugs and physical agents and are limited in their ability to assess risk to humans because they use model systems that are nonhuman in origin. Upon completion of the sequencing of the human genome, new tools were established that identify early biomarkers of toxicity and disease not only in model organisms but also in man. Gene expression profiling led to the development of a new subdiscipline of toxicology termed toxicogenomics. This new subdiscipline combines the emerging technologies of genomics, proteomics and bioinformatics to identify and characterize mechanisms of action of known and suspected toxicants. This chapter describes some advances in the area of toxicogenomics and discusses several models to study chemical induced liver injury. PMID- 22437821 TI - The use of integrated and intelligent testing strategies in the prediction of toxic hazard and in risk assessment. AB - There is increasing concern that insurmountable differences between humans and laboratory animals limit the relevance and reliability for hazard identification and risk assessment purposes of animal data produced by traditional toxicity test procedures. A way forward is offered by the emerging new technologies, which can be directly applied to human material or even to human beings themselves. This promises to revolutionise the evaluation of the safety of chemicals and chemical products of various kinds and, in particular, pharmaceuticals. The available and developing technologies are summarised and it is emphasised that they will need to be used selectively, in integrated and intelligent testing strategies, which, in addition to being scientifically sound, must be manageable and affordable. Examples are given of proposed testing strategies for general chemicals, cosmetic ingredients, candidate pharmaceuticals, inhaled substances, nanoparticles and neurotoxicity. PMID- 22437822 TI - A novel STAT1 mutation associated with disseminated mycobacterial disease. AB - STAT1 is a key component of Interferon (IFN)-gamma and IFN-alpha signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-gamma driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-gamma driven GAS-luciferase activity, and expression of IFN-gamma target genes are reduced. IFN-alpha driven ISRE response, but not IFN alpha driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-gamma related immunity and is recessive for IFN-alpha induced immune function. PMID- 22437823 TI - Analyses of the PRF1 gene in individuals with hemophagocytic lymphohystiocytosis reveal the common haplotype R54C/A91V in Colombian unrelated families associated with late onset disease. AB - Familial hemophagocytic lymphohistiocytosis (FHL), is a rare autosomal recessive disorder characterized by an impairment of cytotoxic cells and uncontrolled activation of macrophages. This study presents the first description of four patients with FHL type 2 in Latin America. Patient 1 fulfilled the disease diagnostic criteria since 2 months of age, whereas patients 2, 3 and 4 exhibited the typical manifestations of the disease only later in their childhood. The PRF1 genetic analysis in these patients revealed two previously reported mutations: L17fsx50 and R54C. Interestingly, seven out of the 8 alleles evaluated here in patients carried the haplotype R54C/A91V, suggesting that this is a highly frequent FHL type 2 allele in Colombia. This haplotype confers residual cytotoxic function leading to late onset disease. Therefore, this report highlights the remarkable complexity of FHL diagnostic, emphasizing the importance of the genetic characterization of the disease. PMID- 22437824 TI - Clinical and histopathologic characteristics of rash in cancer patients treated with mammalian target of rapamycin inhibitors. AB - BACKGROUND: Dermatologic adverse events stemming from anticancer therapies have become an increasingly frequent clinical problem. Inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, have been associated with a high rate of skin eruptions, but their clinical and histopathologic characteristics have not been explored. METHODS: A retrospective analysis of patients who were referred to the Dermatology Service for diagnosis and management of rash in the setting of therapy with the mTOR inhibitors everolimus and temsirolimus was performed. The parameters that were studied included the time to onset, clinical presentation at the time of dermatologic evaluation, associated symptoms, evolution, results of microbiologic studies, concomitant medications, the need for dose reduction and/or treatment interruption because of rash, and routine histopathology. RESULTS: In total, 13 patients were analyzed. Most rashes were mild (grade 1; 31%) and moderate (grade 2; 54%) in severity, and grade 3 rashes were observed only in 2 patients (15%). The trunk was the most frequently affected region (77%), with the scalp (23%), face (38%), neck (54%), and extremities (69%) also commonly involved. Erythematous papules and pustules constituted the predominant primary lesion morphology (62%). No unique or uniform histopathologic reaction pattern was observed. The most common reaction pattern was that of a mixed, spongiotic interface and perivascular dermatitis, which was observed in 7 of 11 patients (63%). CONCLUSIONS: Although mTOR inhibitors may commonly induce erythematous papules and pustules, they are associated with a spectrum of lesion morphologies and a variety of histopathologic findings. Further clinicohistologic correlation studies are needed. PMID- 22437825 TI - An unconventional hexacoordinated flavohemoglobin from Mycobacterium tuberculosis. AB - Being an obligate aerobe, Mycobacterium tuberculosis faces a number of energetic challenges when it encounters hypoxia and environmental stress during intracellular infection. Consequently, it has evolved innovative strategies to cope with these unfavorable conditions. Here, we report a novel flavohemoglobin (MtbFHb) from M. tuberculosis that exhibits unique features within its heme and reductase domains distinct from conventional FHbs, including the absence of the characteristic hydrogen bonding interactions within the proximal heme pocket and mutations in the FAD and NADH binding regions of the reductase domain. In contrast to conventional FHbs, it has a hexacoordinate low-spin heme with a proximal histidine ligand lacking imidazolate character and a distal heme pocket with a relatively low electrostatic potential. Additionally, MtbFHb carries a new FAD binding site in its reductase domain similar to that of D-lactate dehydrogenase (D-LDH). When overexpressed in Escherichia coli or Mycobacterium smegmatis, MtbFHb remained associated with the cell membrane and exhibited D lactate:phenazine methosulfate reductase activity and oxidized D-lactate into pyruvate by converting the heme iron from Fe(3+) to Fe(2+) in a FAD-dependent manner, indicating electron transfer from D-lactate to the heme via FAD cofactor. Under oxidative stress, MtbFHb-expressing cells exhibited growth advantage with reduced levels of lipid peroxidation. Given the fact that D-lactate is a byproduct of lipid peroxidation and that M. tuberculosis lacks the gene encoding D-LDH, we propose that the novel D-lactate metabolizing activity of MtbFHb uniquely equips M. tuberculosis to balance the stress level by protecting the cell membrane from oxidative damage via cycling between the Fe(3+)/Fe(2+) redox states. PMID- 22437826 TI - Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons. AB - Wnt signaling plays critical roles during synaptic development and plasticity. However, the mechanisms by which Wnts are released and travel to target cells are unresolved. During synaptic development, the secretion of Drosophila Wnt1, Wingless, requires the function of Evenness Interrupted (Evi)/Wls, a Wingless binding protein that is secreted along with Wingless at the neuromuscular junction. Given that Evi is a transmembrane protein, these studies suggested the presence of a novel vesicular mechanism of trans-synaptic communication, potentially in the form of exosomes. To establish the mechanisms for the release of Evi vesicles, we used a dsRNA assay in cultured cells to screen for genes that when down-regulated prevent the release of Evi vesicles. We identified two proteins, Rab11 and Syntaxin 1A (Syx1A), that were required for Evi vesicle release. To determine whether the same mechanisms were used in vivo at the neuromuscular junction, we altered the activity of Rab11 and Syx1A in motoneurons and determined the impact on Evi release. We found that Syx1A, Rab11, and its effector Myosin5 were required for proper Evi vesicle release. Furthermore, ultrastructural analysis of synaptic boutons demonstrated the presence of multivesicular bodies, organelles involved in the production and release of exosomes, and these multivesicular bodies contained Evi. We also used mass spectrometry, electron microscopy, and biochemical techniques to characterize the exosome fraction from cultured cells. Our studies revealed that secreted Evi vesicles show remarkable conservation with exosomes in other systems. In summary, our observations unravel some of the in vivo mechanisms required for Evi vesicle release. PMID- 22437827 TI - Cell-penetrating peptides split into two groups based on modulation of intracellular calcium concentration. AB - Cell-penetrating peptides (CPPs) promote the uptake of different cargo molecules, e.g. therapeutic compounds, making the harnessing of CPPs a promising strategy for drug design and delivery. However, the internalization mechanisms of CPPs are still under discussion, and it is not clear how cells compensate the disturbances induced by peptides in the plasma membrane. In this study, we demonstrate that the uptake of various CPPs enhances the intracellular Ca(2+) levels in Jurkat and HeLa cells. The elevated Ca(2+) concentration in turn triggers plasma membrane blebbing, lysosomal exocytosis, and membrane repair response. Our results indicate that CPPs split into two major classes: (i) amphipathic CPPs that modulate the plasma membrane integrity inducing influx of Ca(2+) and activating downstream responses starting from low concentrations; (ii) non-amphipathic CPPs that do not evoke changes at relevant concentrations. Triggering of the membrane repair response may help cells to replace distorted plasma membrane regions and cells can recover from the influx of Ca(2+) if its level is not drastically elevated. PMID- 22437828 TI - Structural characterization of closely related O-antigen lipopolysaccharide (LPS) chain length regulators. AB - The surface O-antigen polymers of gram-negative bacteria exhibit a modal length distribution that depends on dedicated chain length regulator periplasmic proteins (polysaccharide co-polymerases, PCPs) anchored in the inner membrane by two transmembrane helices. In an attempt to determine whether structural changes underlie the O-antigen modal length specification, we have determined the crystal structures of several closely related PCPs, namely two chimeric PCP-1 family members solved at 1.6 and 2.8 A and a wild-type PCP-1 from Shigella flexneri solved at 2.8 A. The chimeric proteins form circular octamers, whereas the wild type WzzB from S. flexneri was found to be an open trimer. We also present the structure of a Wzz(FepE) mutant, which exhibits severe attenuation in its ability to produce very long O-antigen polymers. Our findings suggest that the differences in the modal length distribution depend primarily on the surface exposed amino acids in specific regions rather than on the differences in the oligomeric state of the PCP protomers. PMID- 22437829 TI - Substrate selectivity of YgfU, a uric acid transporter from Escherichia coli. AB - The ubiquitous nucleobase-ascorbate transporter (NAT/NCS2) family includes more than 2,000 members, but only 15 have been characterized experimentally. Escherichia coli has 10 members, of which the uracil permease UraA and the xanthine permeases XanQ and XanP are functionally known. Of the remaining members, YgfU is closely related in sequence and genomic locus with XanQ. We analyzed YgfU and showed that it is a proton-gradient dependent, low-affinity (K(m) 0.5 mM), and high-capacity transporter for uric acid. It also shows a low capacity for transport of xanthine at 37 degrees C but not at 25 degrees C. Based on the set of positions delineated as important from our previous Cys scanning analysis of permease XanQ, we subjected YgfU to rationally designed site directed mutagenesis. The results show that the conserved His-37 (TM1), Glu-270 (TM8), Asp-298 (TM9), and Gln-318 and Asn-319 (TM10) are functionally irreplaceable, and Thr-100 (TM3) is essential for the uric acid selectivity because its replacement with Ala allows efficient uptake of xanthine. The key role of these residues is corroborated by the conservation pattern and homology modeling on the recently described x-ray structure of permease UraA. In addition, site-specific replacements at TM8 (S271A, M274D, V282S) impair expression in the membrane, and V320N (TM10) inactivates the permease, whereas R327G (TM10) or S426N (TM14) reduces the affinity for uric acid (4-fold increased K(m)). Our study shows that comprehensive analysis of structure-function relationships in a newly characterized transporter can be accomplished with relatively few site directed replacements, based on the knowledge available from Cys-scanning mutagenesis of a prototypic homolog. PMID- 22437830 TI - Selective inhibition of biotin protein ligase from Staphylococcus aureus. AB - There is a well documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes immune to current resistance mechanisms that inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3-triazole analogues using click chemistry yielded our most potent structure (K(i) 90 nM) with a >1100 fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus but not cultured mammalian cells. The biotin 1,2,3-triazole provides a novel pharmacophore for future medicinal chemistry programs to develop this new antibiotic class. PMID- 22437831 TI - Tra2beta protein is required for tissue-specific splicing of a smooth muscle myosin phosphatase targeting subunit alternative exon. AB - Alternative splicing of the smooth muscle myosin phosphatase targeting subunit (Mypt1) exon 23 (E23) is tissue-specific and developmentally regulated and, thus, an attractive model for the study of smooth muscle phenotypic specification. We have proposed that Tra2beta functions as a tissue-specific activator of Mypt1 E23 splicing on the basis of concordant expression patterns and Tra2beta activation of Mypt1 E23 mini-gene splicing in vitro. In this study we examined the relationship between Tra2beta and Mypt1 E23 splicing in vivo in the mouse. Tra2beta was 2- to 5-fold more abundant in phasic smooth muscle tissues, such as the portal vein, small intestine, and small mesenteric artery, in which Mypt1 E23 is predominately included as compared with the tonic smooth muscle tissues, such as the aorta and inferior vena cava, in which Mypt1 E23 is predominately skipped. Tra2beta was up-regulated in the small intestine postnatally, concordant with a switch to Mypt1 E23 splicing. Targeting of Tra2beta in smooth muscle cells using SM22alpha-Cre caused a substantial reduction in Mypt1 E23 inclusion specifically in the intestinal smooth muscle of heterozygotes, indicating sensitivity to Tra2beta gene dosage. The switch to the Mypt1 E23 skipped isoform coding for the C-terminal leucine zipper motif caused increased sensitivity of the muscle to the relaxant effects of 8-Br-cyclic guanosine monophosphate (cGMP). We conclude that Tra2beta is necessary for the tissue-specific splicing of Mypt1 E23 in the phasic intestinal smooth muscle. Tra2beta, by regulating the splicing of Mypt1 E23, sets the sensitivity of smooth muscle to cGMP-mediated relaxation. PMID- 22437832 TI - Calmodulin bound to the first IQ motif is responsible for calcium-dependent regulation of myosin 5a. AB - Myosin 5a is as yet the best-characterized unconventional myosin motor involved in transport of organelles along actin filaments. It is well-established that myosin 5a is regulated by its tail in a Ca(2+)-dependent manner. The fact that the actin-activated ATPase activity of myosin 5a is stimulated by micromolar concentrations of Ca(2+) and that calmodulin (CaM) binds to IQ motifs of the myosin 5a heavy chain indicates that Ca(2+) regulates myosin 5a function via bound CaM. However, it is not known which IQ motif and bound CaM are responsible for the Ca(2+)-dependent regulation and how the head-tail interaction is affected by Ca(2+). Here, we found that the CaM in the first IQ motif (IQ1) is responsible for Ca(2+) regulation of myosin 5a. In addition, we demonstrate that the C-lobe fragment of CaM in IQ1 is necessary for mediating Ca(2+) regulation of myosin 5a, suggesting that the C-lobe fragment of CaM in IQ1 participates in the interaction between the head and the tail. We propose that Ca(2+) induces a conformational change of the C-lobe of CaM in IQ1 and prevents interaction between the head and the tail, thus activating motor function. PMID- 22437833 TI - Deciphering modern glucocorticoid cross-pharmacology using ancestral corticosteroid receptors. AB - Steroid receptors (SRs) are the largest family of metazoan transcription factors and control genes involved in development, endocrine signaling, reproduction, immunity, and cancer. The entire hormone receptor system is driven by a molecular switch triggered by the binding of small lipophilic ligands. This makes the SRs ideal pharmaceutical targets, yet even the best clinically approved synthetic steroidal agonists are prone to cross-reactivity and off-target pharmacology. The mechanism underlying this promiscuity is derived from the fact that SRs share common structural features derived from their evolutionary relationship. More often than not, rational attempts to probe SR drug selectivity via mutagenesis fail even when high quality structural and functional data are available due to the fact that important mutations often result in nonfunctional receptors. This highlights the fact that SRs suffer from instability, preventing in-depth mutational analysis and hampering crystallization of key receptor-ligand complexes. We have taken a unique approach to address this problem by using a resurrected ancestral protein to determine the structure of a previously intractable complex and identified the structural mechanisms that confer activation and selectivity for a widely used glucocorticoid, mometasone furoate. Moreover, we have identified a single residue located outside of the ligand binding pocket that controls mometasone furoate antagonism versus agonism in the human mineralocorticoid receptor. PMID- 22437834 TI - Reciprocal regulation of syndecan-2 and Notch signaling in vascular smooth muscle cells. AB - Vascular cell interactions mediated through cell surface receptors play a critical role in the assembly and maintenance of blood vessels. These signaling interactions transmit important information that alters cell function through changes in protein dynamics and gene expression. Here, we identify syndecan-2 (SDC2) as a gene whose expression is induced in smooth muscle cells upon physical contact with endothelial cells. Syndecan-2 is a heparan sulfate proteoglycan that is known to be important for developmental processes, including angiogenesis. Our results show that endothelial cells induce mRNA expression of syndecan-2 in smooth muscle cells by activating Notch receptor signaling. Both NOTCH2 and NOTCH3 contribute to the increased expression of syndecan-2 and are themselves sufficient to promote its expression independent of endothelial cells. Syndecan family members serve as coreceptors for signaling molecules, and interestingly, our data show that syndecan-2 regulates Notch signaling and physically interacts with NOTCH3. Notch activity is attenuated in smooth muscle cells made deficient in syndecan-2, and this specifically prevents expression of the differentiation marker smooth muscle alpha-actin. These results show a novel mechanism in which Notch receptors control their own activity by inducing the expression of syndecan 2, which then acts to propagate Notch signaling by direct receptor interaction. PMID- 22437835 TI - Lignin-degrading peroxidases from genome of selective ligninolytic fungus Ceriporiopsis subvermispora. AB - The white-rot fungus Ceriporiopsis subvermispora delignifies lignocellulose with high selectivity, but until now it has appeared to lack the specialized peroxidases, termed lignin peroxidases (LiPs) and versatile peroxidases (VPs), that are generally thought important for ligninolysis. We screened the recently sequenced C. subvermispora genome for genes that encode peroxidases with a potential ligninolytic role. A total of 26 peroxidase genes was apparent after a structural-functional classification based on homology modeling and a search for diagnostic catalytic amino acid residues. In addition to revealing the presence of nine heme-thiolate peroxidase superfamily members and the unexpected absence of the dye-decolorizing peroxidase superfamily, the search showed that the C. subvermispora genome encodes 16 class II enzymes in the plant-fungal-bacterial peroxidase superfamily, where LiPs and VPs are classified. The 16 encoded enzymes include 13 putative manganese peroxidases and one generic peroxidase but most notably two peroxidases containing the catalytic tryptophan characteristic of LiPs and VPs. We expressed these two enzymes in Escherichia coli and determined their substrate specificities on typical LiP/VP substrates, including nonphenolic lignin model monomers and dimers, as well as synthetic lignin. The results show that the two newly discovered C. subvermispora peroxidases are functionally competent LiPs and also suggest that they are phylogenetically and catalytically intermediate between classical LiPs and VPs. These results offer new insight into selective lignin degradation by C. subvermispora. PMID- 22437836 TI - Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. AB - The multifunctional HIV-1 enzyme integrase interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the integrase-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here, we show that this class of compounds impairs both integrase-LEDGF binding and LEDGF independent integrase catalytic activities with similar IC(50) values, defining them as bona fide allosteric inhibitors of integrase function. Furthermore, we show that 2-(quinolin-3-yl) acetic acid derivatives block the formation of the stable synaptic complex between integrase and viral DNA by allosterically stabilizing an inactive multimeric form of integrase. In addition, these compounds inhibit LEDGF binding to the stable synaptic complex. This multimode mechanism of action concordantly results in cooperative inhibition of the concerted integration of viral DNA ends in vitro and HIV-1 replication in cell culture. Our findings, coupled with the fact that high cooperativity of antiviral inhibitors correlates with their increased instantaneous inhibitory potential, an important clinical parameter, argue strongly that improved 2-(quinolin-3-yl) acetic acid derivatives could exhibit desirable clinical properties. PMID- 22437837 TI - Loop diuretic and ion-binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of Na-K-Cl cotransporter (NKCC1). AB - The Na-K-Cl cotransporter (NKCC) plays central roles in cellular chloride homeostasis and in epithelial salt transport, but to date little is known about the mechanism by which the transporter moves ions across the membrane. We examined the functional role of transmembrane helix 3 (TM3) in NKCC1 using cysteine- and tryptophan-scanning mutagenesis and analyzed our results in the context of a structural homology model based on an alignment of NKCC1 with other amino acid polyamine organocation superfamily members, AdiC and ApcT. Mutations of residues along one face of TM3 (Tyr-383, Met-382, Ala-379, Asn-376, Ala-375, Phe-372, Gly-369, and Ile-368) had large effects on translocation rate, apparent ion affinities, and loop diuretic affinity, consistent with a proposed role of TM3 in the translocation pathway. The prediction that Met-382 is part of an extracellular gate that closes to form an occluded state is strongly supported by conformational sensitivity of this residue to 2-(trimethylammonium)ethyl methanethiosulfonate, and the bumetanide insensitivity of M382W is consistent with tryptophan blocking entry of bumetanide into the cavity. Substitution effects on residues at the intracellular end of TM3 suggest that this region is also involved in ion coordination and may be part of the translocation pathway in an inward-open conformation. Mutations of predicted pore residues had large effects on binding of bumetanide and furosemide, consistent with the hypothesis that loop diuretic drugs bind within the translocation cavity. The results presented here strongly support predictions of homology models of NKCC1 and demonstrate important roles for TM3 residues in ion translocation and loop diuretic inhibition. PMID- 22437838 TI - Structure of the novel C-terminal domain of vacuolar protein sorting 30/autophagy related protein 6 and its specific role in autophagy. AB - Vacuolar protein sorting 30 (Vps30)/autophagy-related protein 6 (Atg6) is a common component of two distinct phosphatidylinositol 3-kinase complexes. In complex I, Atg14 links Vps30 to Vps34 lipid kinase and exerts its specific role in autophagy, whereas in complex II, Vps38 links Vps30 to Vps34 and plays a crucial role in vacuolar protein sorting. However, the molecular role of Vps30 in each pathway remains unclear. Here, we report the crystal structure of the carboxyl-terminal domain of Vps30. The structure is a novel globular fold comprised of three beta-sheet-alpha-helix repeats. Truncation analyses showed that the domain is dispensable for the construction of both complexes, but is specifically required for autophagy through the targeting of complex I to the pre autophagosomal structure. Thus, the domain is named the beta-alpha repeated, autophagy-specific (BARA) domain. On the other hand, the N-terminal region of Vps30 was shown to be specifically required for vacuolar protein sorting. These structural and functional investigations of Vps30 domains, which are also conserved in the mammalian ortholog, Beclin 1, will form the basis for studying the molecular functions of this protein family in various biological processes. PMID- 22437839 TI - Conversion of human steroid 5beta-reductase (AKR1D1) into 3beta-hydroxysteroid dehydrogenase by single point mutation E120H: example of perfect enzyme engineering. AB - Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5beta reduction of Delta(4)-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4 pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His(120) (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5beta-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5alpha-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3beta-HSD as opposed to a 3alpha-HSD. The catalytic efficiency achieved for 3beta-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5beta-dihydrotestosterone, and Delta(4)-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the Delta(4)-double bond and confers 3beta-HSD activity on the 5beta-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its alpha-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference. PMID- 22437840 TI - Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1. AB - An unresolved issue about many neurodegenerative diseases is why neurons are particularly sensitive to defects in ubiquitous cellular processes. One example is Niemann Pick type C1, caused by defects in cholesterol trafficking in all cells, but where neurons are preferentially damaged. Understanding this selective failure is limited by the difficulty in obtaining live human neurons from affected patients. To solve this problem, we generated neurons with decreased function of NPC1 from human embryonic stem cells and used them to test the hypothesis that defective cholesterol handling leads to enhanced pathological phenotypes in neurons. We found that human NPC1 neurons have strong spontaneous activation of autophagy, and, contrary to previous reports in patient fibroblasts, a block of autophagic progression leading to defective mitochondrial clearance. Mitochondrial fragmentation is an exceptionally severe phenotype in NPC1 neurons compared with fibroblasts, causing abnormal accumulation of mitochondrial proteins. Contrary to expectation, these abnormal phenotypes were rescued by treatment with the autophagy inhibitor 3-methyladenine and by treatment with the potential therapeutic cyclodextrin, which mobilizes cholesterol from the lysosomal compartment. Our findings suggest that neurons are especially sensitive to lysosomal cholesterol accumulation because of autophagy disruption and accumulation of fragmented mitochondria, thus defining a new route to effective drug development for NPC1 disease. PMID- 22437841 TI - Expression of calmodulin in germ cells is associated with fenvalerate-induced male reproductive toxicity. AB - Exposure to fenvalerate was demonstrated to be toxic to the male reproductive system. Our previous data revealed that intracellular calcium plays an important role in regulating the above toxicity, through actions on both T-type calcium channels and endoplasmic reticulum calcium signals. The present study explored the effects of fenvalerate on the expression of calmodulin in mouse testis and GC 2spd(ts) cells, and its association with fenvalerate-induced male reproductive toxicity. Male mice were subjected to different doses (3.71, 18.56, 37.12, 92.81 mg/kg bw) of fenvalerate or vehicle control for 4 weeks. Expression of calmodulin was determined by real-time polymerase chain reaction (PCR) and Western blot analysis in mouse testis. Similar approaches were utilized in GC-2spd(ts) cells cultured with 5 MUM fenvalerate at different time points. In the in vivo study, all mice survived through the entire 4 weeks. Administration of fenvalerate resulted in a dose-dependent reduction in testis weight/body weight, sperm motility, and increased head abnormality rate. By histological staining, mice treated with fenvalerate at higher doses showed dilated seminiferous tubules and disturbed arrangement of spermatogenic cells. Meanwhile, both mRNA and protein expression of calmodulin were significantly increased in the testes of mice exposed to fenvalerate compared to control mice. Moreover, in the in vitro study, 5 MUM fenvalerate significantly increased the expression of calmodulin at the mRNA and protein levels in GC-2spd(ts) cells after 8 h of incubation and sustained these levels for at least 24 h. Collectively, these data suggested that enhanced expression of calmodulin correlates with male reproductive damage induced by fenvalerate. PMID- 22437842 TI - Reactivation kinetics of a homologous series of bispyridinium bis-oximes with nerve agent-inhibited human acetylcholinesterase. AB - The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-oximes bearing a (E)-but-2-ene linker with tabun-, sarin-, and cyclosarin inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested oximes was equally effective against all used OPs. In addition, the data indicate that a (E)-but-2-ene linker decreased in most cases the reactivating potency in comparison to oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs. PMID- 22437843 TI - Biomimetic synthesis, antibacterial activity and structure-activity properties of the pyroglutamate core of oxazolomycin. AB - Biomimetic intramolecular aldol reactions on oxazolidine templates derived from serine may be used to generate densely functionalised pyroglutamates, which are simpler mimics of the right hand side of oxazolomycin. Some of the compounds from this sequence exhibit in vivo activity against S. aureus and E. coli, suggesting that pyroglutamate scaffolds may be useful templates for the development of novel antibacterials, and cheminformatic analysis has been used to provide some structure-activity data. PMID- 22437844 TI - The bHLH Rac Immunity1 (RAI1) Is Activated by OsRac1 via OsMAPK3 and OsMAPK6 in Rice Immunity. AB - The Rac/Rop GTPase OsRac1 plays an essential role in rice immunity. However, the regulatory genes acting downstream of OsRac1 are largely unknown. We focused on the RAI1 gene, which is up-regulated in suspension cells expressing a constitutively active form of OsRac1. RAI1 encodes a putative basic helix-loop helix transcription factor. A microarray analysis of cells transformed with an inducible RAI1 construct showed increased expression of PAL1 and OsWRKY19 genes after induction, suggesting that these genes are regulated by RAI1. This was confirmed using RAI1 T-DNA activation-tagged and RNA interference lines. The PAL1 and OsWRKY19 genes were also up-regulated by sphingolipid and chitin elicitors, and the RAI1 activation-tagged plants had increased resistance to a rice blast fungus. These results indicated that RAI1 is involved in defense responses in rice. RAI1 interacted with OsMAPK3 and OsMAPK6 proteins in vivo and in vitro. Also, RAI1 was phosphorylated by OsMAPK3/6 and OsMKK4-dd in vitro. Overexpression of OsMAPK6 and/or OsMAPK3 together with OsMKK4-dd increased PAL1 and OsWRKY19 expression in rice protoplasts. Therefore, the regulation of PAL1 and OsWRKY19 expression by RAI1 could be controlled via an OsMKK4-OsMAPK3/6 cascade. Co immunoprecipitation assays indicated that OsMAPK3 and OsRac1 occur in the same complex as OsMAPK6. Taken together, our results indicate that RAI1 could be regulated by OsRac1 through an OsMAPK3/6 cascade. In this study, we have identified RAI1 as the first transcription factor acting downstream of OsRac1. This work will help us to understand the immune system regulated by OsRac1 in rice and its orthologs in other plant species. PMID- 22437845 TI - An Arabidopsis T-DNA insertion mutant for galactokinase (AtGALK, At3g06580) hyperaccumulates free galactose and is insensitive to exogenous galactose. AB - Galactokinase (GALK, EC 2.7.1.6) is a cytosolic enzyme with a wide occurrence across the taxonomic kingdoms. It catalyzes the phosphorylation of alpha-d galactose (Gal) to alpha-d-Gal-1-P. The cytotoxicity of free (unphosphorylated) Gal is well documented in plants and causes marked defects. An Arabidopsis GALK (AtGALK, At3g06580) was previously identified, cloned and functionally characterized in Escherichia coli and was suggested to occur as a single copy gene in Arabidopsis. We identified an AtGALK T-DNA insertion mutant (atgalk) that (i) is AtGALK transcript deficient; (ii) displays no GALK activity in vegetative tissues; and (iii) accumulates Gal up to 6.8 mg g(-1) FW in vegetative tissues, in contrast to wild-type plants. By constitutively overexpressing the AtGALK cDNA, atgalk was functionally rescued. Three independent transformed lines showed restored AtGALK transcripts and GALK activity and had low leaf Gal concentrations comparable with those observed in wild-type plants. Surprisingly, in vitro grown atgalk plants were largely insensitive to the exogenous application of up to 100 mM free Gal, while wild-type plants exhibited sensitivity to low Gal concentrations (10 mM). Furthermore, atgalk seedlings retained the capacity for uptake of exogenously supplied Gal (100 mM), accumulating up to 57 mg g(-1) FW in leaves. Leaves from soil-grown atgalk plants that exhibited no growth or morphological defects were used to demonstrate that the accumulating Gal occurred exclusively in the vacuoles of mesophyll protoplasts. Collectively, these findings suggest a novel Gal detoxification pathway that targets free Gal to the vacuole and is active in the atgalk mutant background. PMID- 22437846 TI - High-throughput cryopreservation of plant cell cultures for functional genomics. AB - Suspension-cultured cell lines from plant species are useful for genetic engineering. However, maintenance of these lines is laborious, involves routine subculturing and hampers wider use of transgenic lines, especially when many lines are required for a high-throughput functional genomics application. Cryopreservation of these lines may reduce the need for subculturing. Here, we established a simple protocol for cryopreservation of cell lines from five commonly used plant species, Arabidopsis thaliana, Daucus carota, Lotus japonicus, Nicotiana tabacum and Oryza sativa. The LSP solution (2 M glycerol, 0.4 M sucrose and 86.9 mM proline) protected cells from damage during freezing and was only mildly toxic to cells kept at room temperature for at least 2 h. More than 100 samples were processed for freezing simultaneously. Initially, we determined the conditions for cryopreservation using a programmable freezer; we then developed a modified simple protocol that did not require a programmable freezer. In the simple protocol, a thick expanded polystyrene (EPS) container containing the vials with the cell-LSP solution mixtures was kept at -30 degrees C for 6 h to cool the cells slowly (pre-freezing); samples from the EPS containers were then plunged into liquid nitrogen before long-term storage. Transgenic Arabidopsis cells were subjected to cryopreservation, thawed and then re-grown in culture; transcriptome and metabolome analyses indicated that there was no significant difference in gene expression or metabolism between cryopreserved cells and control cells. The simplicity of the protocol will accelerate the pace of research in functional plant genomics. PMID- 22437847 TI - Role of T-cell-specific nuclear factor kappaB in islet allograft rejection. AB - BACKGROUND: Pancreatic islet transplantation has the potential to cure type 1 diabetes, a chronic lifelong disease, but its clinical applicability is limited by allograft rejection. Nuclear factor kappaB (NF-kappaB) is a transcription factor important for survival and differentiation of T cells. In this study, we tested whether NF-kappaB in T cells is required for the rejection of islet allografts. METHODS: Mice expressing a superrepressor form of NF-kappaB selectively in T cells (IkappaBalphaDeltaN-Tg mice) with or without the antiapoptotic factor Bcl-xL, or mice with impaired T-cell receptor (TCR)- and B cell receptor-driven NF-kappaB activity (CARMA1-KO mice) were rendered diabetic and transplanted with islet allografts. Secondary skin transplantation in long term acceptors of islet allografts was used to test for the development of donor specific tolerance. Immune infiltration of the transplanted islets was examined by immunofluorescence. TCR-transgenic CD4 T cells were used to follow T-cell priming and differentiation. RESULTS: Islet allograft survival was prolonged in IkappaBalphaDeltaN-Tg mice, although the animals did not develop donor-specific tolerance. Reduced NF-kappaB activity did not prevent T-cell priming or differentiation but reduced survival of activated T cells, as transgenic expression of Bcl-xL restored islet allograft rejection in IkappaBalphaDeltaN-Tg mice. Abolishing TCR- and B cell receptor-driven activation of NF-kappaB selectively by CARMA1 deficiency prevented T-cell priming and islet allograft rejection. CONCLUSIONS: Our data suggest that T cell-NF-kappaB plays an important role in the rejection of islet allografts. Targeting NF-kappaB selectively in lymphocytes seems a promising approach to facilitate acceptance of transplanted islets. PMID- 22437848 TI - Epigenetics: time to translate into transplantation. AB - Substantial progress has been made in identifying genetic loci associated with multifactorial disorders, including variants that seem to impact outcomes following solid organ transplantation. Despite these advances, much of the heritability and susceptibility to chronic disease processes remains unexplained. Epigenetic modifications may exert their effect independently or complementary to genetic variants. Epigenetic modifications can change gene expression without altering the DNA sequence. These modifications are dynamic, potentially heritable, and can be induced by environmental stimuli or drugs. The impact of epigenetic phenomena on the outcomes of organ transplantation is currently poorly understood. Epigenetic modifications can occur during periods of illness; these may persist and potentially influence allograft outcomes. Epigenetic mechanisms influence the activation, proliferation, and differentiation of the immune cells involved in allograft rejection. The donor's epigenome may also impact transplant survival, and initial research has demonstrated that peritransplant conditions induce rapid epigenetic modification within the allograft. Further research will help to define the importance of epigenetic modifications in transplantation. This will potentially lead to the identification of useful biomarkers and the development of novel pharmacotherapies. This review explores the nature of epigenetic modification in disease and the emerging evidence for epigenetic influences on allograft survival. PMID- 22437849 TI - Molybdenum-catalyzed reduction of molecular dinitrogen under mild reaction conditions. AB - Quite recently we have found two nitrogen fixation systems catalyzed by molybdenum-dinitrogen complexes under mild reaction conditions; one is the transformation of molecular dinitrogen into its synthetic equivalent of ammonia and the other is that into ammonia. A molybdenum-dinitrogen complex bearing two ferrocenyl diphosphines works as a good catalyst in the transformation of molecular dinitrogen into silylamine, where up to 226 equiv are produced based on the catalyst. A dinitrogen-bridged dimolybdenum complex bearing a PNP-type pincer ligand works as a good catalyst in the direct transformation of molecular dinitrogen into ammonia, where up to 23 equiv are produced based on the catalyst. We believe that both systems provide a new aspect in the development of novel nitrogen fixation. PMID- 22437850 TI - Fast stochastic algorithm for simulating evolutionary population dynamics. AB - MOTIVATION: Many important aspects of evolutionary dynamics can only be addressed through simulations. However, accurate simulations of realistically large populations over long periods of time needed for evolution to proceed are computationally expensive. Mutants can be present in very small numbers and yet (if they are more fit than others) be the key part of the evolutionary process. This leads to significant stochasticity that needs to be accounted for. Different evolutionary events occur at very different time scales: mutations are typically much rarer than reproduction and deaths. RESULTS: We introduce a new exact algorithm for fast fully stochastic simulations of evolutionary dynamics that include birth, death and mutation events. It produces a significant speedup compared to direct stochastic simulations in a typical case when the population size is large and the mutation rates are much smaller than birth and death rates. The algorithm performance is illustrated by several examples that include evolution on a smooth and rugged fitness landscape. We also show how this algorithm can be adapted for approximate simulations of more complex evolutionary problems and illustrate it by simulations of a stochastic competitive growth model. PMID- 22437851 TI - MDWeb and MDMoby: an integrated web-based platform for molecular dynamics simulations. AB - SUMMARY: MDWeb and MDMoby constitute a web-based platform to help access to molecular dynamics (MD) in the standard and high-throughput regime. The platform provides tools to prepare systems from PDB structures mimicking the procedures followed by human experts. It provides inputs and can send simulations for three of the most popular MD packages (Amber, NAMD and Gromacs). Tools for analysis of trajectories, either provided by the user or retrieved from our MoDEL database (http://mmb.pcb.ub.es/MoDEL) are also incorporated. The platform has two ways of access, a set of web-services based on the BioMoby framework (MDMoby), programmatically accessible and a web portal (MDWeb). AVAILABILITY: http://mmb.irbbarcelona.org/MDWeb; additional information and methodology details can be found at the web site ( http://mmb.irbbarcelona.org/MDWeb/help.php) PMID- 22437852 TI - Identification of valine- or leucine-containing glycopeptidolipids from Mycobacterium avium-intracellulare complex. AB - Mycobacterium avium-intracellulare complex is a species of acid-fast microorganisms that cause opportunistic infections in immuno-compromised hosts. The cell wall of this microbe is rich in glycopeptidolipids (GPLs), which are composed of a fatty acyl moiety, several sugar moieties and a tripeptide-amino alcohol, D-Phe-D-alloThr-D-Ala-L-Alaninol. GPLs have molecular diversity in the hydrocarbon chain variety of the acyl moiety, and methyl and acetyl modifications of the sugar moiety, but there has been no report of any variety in the tripeptide-amino alcohol component. In this study, we showed two atypical GPL ions of 34 or 48 Da less than the dominant ions of GPLs by mass spectrometry. These ions could not be explained as resulting from conventional molecular diversity. To investigate the reasons why these ions appeared, we made a preparation of the lipopeptide component from intact GPLs and structurally analyzed the molecules. The results suggested that these atypical ions differed from the typical ions in amino acid composition. We further determined its composition by amino acid analysis, and the results showed that the tripeptide portion of the two atypical ions is composed of the Val-alloThr-Ala or the Leu alloThr-Ala amino acid sequence. In this study, we present novel variations in the tripeptide portion of GPL molecules. PMID- 22437853 TI - Expression of a biologically active GFP-alpha(S1)-casein fusion protein in Lactococcus lactis. AB - In this study, we successfully developed a recombinant strain of Lactococcus lactis NZ9000 (NZ9000) that produced green fluorescent protein fused to alpha(S1) casein (GFP-alpha(S1)Cas). A modified lactic acid bacterial vector (pNZ8148#2) was constructed by inserting genes for GFP and alpha(S1)-casein, a major cow's milk allergen, and the resulting vector, pNZ8148#2-GFP-alpha(S1)Cas, was applied to the expression of recombinant GFP-alpha(S1)Cas protein (rGFP-alpha(S1)Cas) in NZ9000. After inducing expression with nisin, the production of rGFP-alpha(S1)Cas was confirmed by confocal laser microscopic analysis, and the expression conditions were optimized based on fluorescent analysis and western blotting results. Moreover, the in vitro treatment of splenocytes isolated from alpha casein (>=70 % alpha(S)-casein)-immunized mice with rGFP-alpha(S1)Cas resulted in increased IL-13 mRNA expression. The observed allergic activity is indicative of the Th2-cell mediated immune response and is similar to the effects induced by exposure to alpha-casein. Our results suggest that the expression of rGFP alpha(S1)Cas in NZ9000 may facilitate in vivo applications of this system aimed at improving the specificity of immunological responses to specific milk allergen. PMID- 22437854 TI - Social inequalities in access to dental care. PMID- 22437855 TI - Environmental lead poisoning among children in Porto Alegre state, Southern Brazil. AB - OBJECTIVE: To estimate the prevalence of lead poisoning in children and to identify associated factors, as well as possible local sources of contamination. METHODS: A cross-sectional prevalence study conducted in 2006 with a random sample of 97 children age zero to five years from a neighborhood in Porto Alegre, Southern Brazil. Blood lead levels were measured and a questionnaire administered to collect information on sociodemographics, recycling and dwelling. A preliminary environmental evaluation was carried out with direct analysis of soil and indirect analysis of air pollution with bioindicators to identify possible sources of contamination. To analyze lead concentrations from the different collection sites, for each type of material studied, ANOVA was performed with a Brown-Forsythe adjustment for heteroscedasticity and with Dunnett's T3 procedure for multiple comparisons of unequal variances. RESULTS: Blood lead levels > 10.0 ug/dL was found in 16.5% of children. Recycling of waste at home, low father's education level, and increased age of children were associated with increase blood lead levels. High lead levels were found in soil, and there was little indication of lead air pollution. CONCLUSIONS: A high prevalence of lead poisoning was identified, and the potential sources of contamination in this community appear related to waste recylcing activities. Studies should be conducted with other populations of Brazilian children and evaluate potential sources of local and general contamination, to accurately characterize this issue in Brazil. PMID- 22437856 TI - Reduction of social inequalities in utilization of dental care in Brazil from 1998 to 2008. AB - OBJECTIVE: To analyze access to and utilization of dental care services in Brazil. METHODS: We used data from the 2003 and 2008 Brazilian National Household Surveys, which we compared to data from the 1998 survey. We investigated access and utilization variables at ages three, six, nine, 12, 15, and 19 years in the first (Q1) and fifth (Q5) quintiles of per capita family income. All analyses took into account the complex sampling strategy. RESULTS: The proportion of subjects that had never seen a dentist decreased during the period (18.7% in 1998, 15.9% in 2003 and 11.7% in 2008). There was an important reduction in the absolute difference in failure to use dental care services after age nine years between Q1 and Q5 from 1998 to 2008, which decreased to about half its value at 15 (30.3 percentage points - pp to 16.1 pp) and 19 years (20.4 pp to 9.9 pp). Q5/Q1 ratios for recent dental appointments fell across all age groups, especially between zero and six years (Q5/Q1 from 3.2 to 2.6); utilization of the National Health Care System for dental care increased in Q1 and Q5, with a reduction in the Q1/Q5 ratio of approximately 20%. Use of the National Health Care System for dental care increased by approximately 8% in Q1 and 35% in Q5 between 2003 and 2008. CONCLUSIONS: There have been considerable advances in terms of reducing inequalities in access to, and increasing the utilization of, dental care services in Brazil between 1998 and 2008. However, inequality between social groups remains substantial. PMID- 22437857 TI - Explicit discrimination and health: development and psychometric properties of an assessment instrument. AB - OBJECTIVE: To develop an instrument to assess discrimination effects on health outcomes and behaviors, capable of distinguishing harmful differential treatment effects from their interpretation as discriminatory events. METHODS: Successive versions of an instrument were developed based on a systematic review of instruments assessing racial discrimination, focus groups and review by a panel comprising seven experts. The instrument was refined using cognitive interviews and pilot-testing. The final version of the instrument was administered to 424 undergraduate college students in the city of Rio de Janeiro, Southeastern Brazil, in 2010. Structural dimensionality, two types of reliability and construct validity were analyzed. RESULTS: Exploratory factor analysis corroborated the hypothesis of the instrument's unidimensionality, and seven experts verified its face and content validity. The internal consistency was 0.8, and test-retest reliability was higher than 0.5 for 14 out of 18 items. The overall score was higher among socially disadvantaged individuals and correlated with adverse health behaviors/conditions, particularly when differential treatments were attributed to discrimination. CONCLUSIONS: These findings indicate the validity and reliability of the instrument developed. The proposed instrument enables the investigation of novel aspects of the relationship between discrimination and health. PMID- 22437858 TI - Trends in suicide mortality among Brazilian adults and elderly, 1980 - 2006. AB - OBJECTIVE: To describe mortality from suicide in Brazil, with emphasis on the older adult population. METHODS: Temporal analysis and trend analysis by polynomial regression were conducted on suicide in the population above 10 years old in Brazil and the State of Rio de Janeiro (Southeastern Brazil) from 1980 2006. The data were extracted from the Mortality Information System, and the rates calculated by gender and age per 100,000 inhabitants, considering the resident population provided by DATASUS. For the period between 1980 and 1995, the ninth revision of International Statistical Classification of Diseases and Related Health Problems was used, and for 1996 to 2006, the tenth revision. RESULTS: Suicide rates significantly increased in Brazil and in Rio de Janeiro (respectively reaching 5.7 and 3.1 deaths per 100,000 inhabitants in 2006). The change was caused by the increase in suicides among the male population at all ages. The increase occurred especially among men over 60 years. In Rio de Janeiro, the increase was not statistically significant among men, while there was a decrease among women. The principal means utilized for suicide by men were hanging, suffocation, strangulation and firearms. For women, death by hanging also ranks first, followed by ingestion of solids or liquids, smoke or fire, and jumping from heights. The high rate of suicide by unspecified means reveals problems with data quality. CONCLUSIONS: Suicides are important events in the male population, especially among older men over time. In Rio de Janeiro, the suicide rate is also higher in men, although the difference is not statistically significant. According to the World Health Organization and the Ministry of Health, suicide is preventable, and established interventions exist for each age group. PMID- 22437859 TI - Self-perceived health status in older adults: regional and sociodemographic inequalities in Spain. AB - OBJECTIVE: To assess regional and sociodemographic differences in self-perceived health status among older adults. METHODS: A face-to-face quality of life survey was conducted in a representative sample of the Spanish population comprising 1,106 non-institutionalized elderly aged 60 or more in 2008. Logistic regression models were used to explain self-perceived health status according to the EuroQol Group Visual Analogue Scale (EQ-VAS). Independent variables included sociodemographic and health characteristics as well as the nomenclature of territorial units for statistics level 1 (NUTS1: group of autonomous regions) and level 2 (NUTS 2: autonomous regions). RESULTS: Younger and better off respondents were more likely to have a positive self-perceived health status. Having no chronic conditions, independence in performing daily living activities and lower level of depression were also associated with positive self-perceived health status. People living in the south of Spain showed a more negative self-perceived health status than those living in other regions. CONCLUSION: The study results point to health inequality among Spanish older adults of lower socioeconomic condition and living in the south of Spain. The analysis by geographic units allows for international cross-regional comparisons. PMID- 22437860 TI - Perspectives on access to in vitro fertilization in Portugal. AB - OBJECTIVE: To analyze users' reasons for choosing in vitro fertilization treatment in public or private services and to identify their suggestions for improving fertility treatment. METHODS: A qualitative study using an interpretative approach was conducted. Fifteen semi-structured interviews were conducted with patients undergoing in vitro fertilization treatment (nine women, one man and five couples) at home or at their workplace in the districts of Viana do Castelo, Braga, Porto and Lisbon, Portugal, between July 2005 and February 2006. RESULTS: Users evaluated access to in vitro fertilization treatment in public and private services based mainly on their individual experiences and called for more access to less costly, faster and friendlier care with suitable facilities, appropriate time management and caring medical providers. These perceptions were also associated with views on the need for fighting stigmatization of infertility, protecting children's rights and guaranteeing sustainability of health care system. Interviewees sought to balance reduced waiting time and more attentive care with costs involved. The choice of services depended on the users' purchase power and place of residence and availability of attentive care. CONCLUSIONS: Current national policies on in vitro fertilization treatment meet user's demands of promoting access to, and quality, availability and affordability of in vitro fertilization treatment. However, their focus on legal regulation and technical-scientific aspects contrasts with the users' emphasis on reimbursement, insurance coverage and focus on emotional aspects of the treatment. The study showed these policies should ensure insurance coverage, participation of user representatives in the National Council for Assisted Reproductive Technology, promotion of infertility research and certification of fertility laboratories. PMID- 22437861 TI - [Legal proceedings to ensure supply of medicines in Brazil: a process that needs streamlining]. PMID- 22437862 TI - [Doing science in qualitative research: an evaluation exercise]. PMID- 22437863 TI - [Off label use: a mistake or a need?]. PMID- 22437864 TI - [Sanitary surveillance of tobacco in the state os Sao Paulo, Brazil]. PMID- 22437866 TI - Tumour immunogenicity: editorial selection demystified. PMID- 22437867 TI - Tumour immunology: suppressing tumorigenic inflammation. PMID- 22437868 TI - Immunotherapy: Combinations that work. PMID- 22437869 TI - Combining immunotherapy and targeted therapies in cancer treatment. AB - During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes. PMID- 22437870 TI - The blockade of immune checkpoints in cancer immunotherapy. AB - Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses. PMID- 22437872 TI - Antibody therapy of cancer. AB - The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody-drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials. PMID- 22437871 TI - Cancer immunotherapy via dendritic cells. AB - Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer. PMID- 22437873 TI - Regulation of gene expression during early neuronal differentiation: evidence for patterns conserved across neuron populations and vertebrate classes. AB - Analysis of transcription factor function during neurogenesis has provided a huge amount of data on the generation and specification of diverse neuron populations in the central and peripheral nervous systems of vertebrates. However, an understanding of the induction of key neuron functions including electrical information processing and synaptic transmission lags seriously behind. Whereas pan-neuronal markers such as neurofilaments, neuron-specific tubulin and RNA binding proteins have often been included in developmental analysis, the molecular players underlying electrical activity and transmitter release have been neglected in studies addressing gene expression during neuronal induction. Here, I summarize the evidence for a distinct accumulation pattern of mRNAs for synaptic proteins, a pattern that is delayed compared with pan-neuronal gene expression during neurogenesis. The conservation of this pattern across diverse avian and mammalian neuron populations suggests a common mechanism for the regulation of various sets of neuronal genes during initial neuronal differentiation. The co-regulation of genes coding for synaptic proteins from embryonic to postnatal development indicates that the expression of the players required for synaptic transmission shares common regulatory features. For the ion channels involved in neuronal electrical activity, such as voltage-gated sodium channels, the situation is less clear because of the lack of comparative studies early during neurogenesis. Transcription factors have been characterized that regulate the expression of synaptic proteins in vitro and in vivo. They currently do not explain the co-regulation of these genes across different neuron populations. The neuron-restrictive silencing factor NRSF/REST targets a large gene set, but not all of the genes coding for pan-neuronal, synaptic and ion channel proteins. The discrepancy between NRSF/REST loss-of-function and silencer to-activator-switch studies leaves the full functional implications of this factor open. Together with microRNAs, splicing regulators, chromatin remodellers and an increasing list of transcriptional regulators, the factor is embedded in feedback circuits with the potential to orchestrate neuronal differentiation. The precise regulation of the coordinated expression of proteins underlying key neuronal functions by these circuits during neuronal induction is a major emerging topic. PMID- 22437874 TI - The perineuronal net and the control of CNS plasticity. AB - Perineuronal nets (PNNs) are reticular structures that surround the cell body of many neurones, and extend along their dendrites. They are considered to be a specialized extracellular matrix in the central nervous system (CNS). PNN formation is first detected relatively late in development, as the mature synaptic circuitry of the CNS is established and stabilized. Its unique distribution in different CNS regions, the timing of its establishment, and the changes it undergoes after injury all point toward diverse and important functions that it may be performing. The involvement of PNNs in neuronal plasticity has been extensively studied over recent years, with developmental, behavioural, and functional correlations. In this review, we will first briefly detail the structure and organization of PNNs, before focusing our discussion on their unique roles in neuronal development and plasticity. The PNN is an important regulator of CNS plasticity, both during development and into adulthood. Production of critical PNN components is often triggered by appropriate sensory experiences during early postnatal development. PNN deposition around neurones helps to stabilize the established neuronal connections, and to restrict the plastic changes due to future experiences within the CNS. Disruption of PNNs can reactivate plasticity in many CNSs, allowing activity-dependent changes to once again modify neuronal connections. The mechanisms through which PNNs restrict CNS plasticity remain unclear, although recent advances promise to shed additional light on this important subject. PMID- 22437875 TI - Effects of VEGF and FGF-2 on proliferation and differentiation of human periodontal ligament stem cells. AB - Human periodontal ligament stem cells (PDLSCs) from extracted third molar teeth are a type of adult stem cell originating from dental tissue. PDLSCs are known to have a self-renewal capacity and multi-lineage differentiation potential. Vascular endothelial growth factor (VEGF), an angiogenic/vasculogenic factor, has been shown to stimulate endothelial cell mitogenesis and cell migration. Another growth factor, fibroblast growth factor-2 (FGF-2), a mitogenic factor, enhances osteogenesis in mesenchymal stem cells (MSCs). This study examines the effects of VEGF and FGF-2 on PDLSCs in vitro and in vivo compared with those on bone marrow stem cells (BMSCs) as a positive control. Treatment of PDLSCs with VEGF increases the accumulation of calcium nodules, alkaline phosphatase (ALP) activity and the formation of hard tissue and up-regulates the mRNA level of runt-related transcription factor 2 (Runx2). In contrast, FGF-2 enhances the proliferation of PDLSCs in vitro in cell culture, where it significantly decreases calcium accumulation and ALP activity and down-regulates the expression of osteogenic gene markers (i.e., Runx2, ALP, type I collagen) involved in osteogenic induction. We have also transplanted PDLSCs with hydroxyapatite/tricalcium phosphate particles (HA/TCP) as carriers for each factor (VEGF, FGF-2) into nude mice and, after 8 weeks, observed the in vivo formation of hard tissue at the dorsal surface. Based on our results, we suggest that VEGF has positive effects on odonto-/osteogenic differentiation in vitro and on the formation of mineralized structure in vivo. FGF-2 might be a powerful promoter of the proliferation of progenitor cells in hard tissue regeneration but exogenous FGF-2 might inhibit terminal differentiation. PMID- 22437876 TI - A longitudinal, genetically informative, study of associations between anxiety sensitivity, anxiety and depression. AB - The current study sought to examine the direction of influences on longitudinal associations between anxiety sensitivity, anxiety and depression. The continuity of genetic and environmental influences on these traits over adolescence was also investigated. Self reports of anxiety sensitivity, anxiety and depression were collected from approximately 1,300 twin and sibling pairs, on two occasions (mean ages 15 and 17). The direction and etiology of the associations between these traits were examined using longitudinal genetic cross-lagged models. All traits were stable over time and this stability accounted for the largest proportion of variance at time 2. There was, however, also evidence of reciprocal associations between variables over time. Genetic effects were fairly stable across time, although new genetic influences were evident at the second time point. Environmental effects tended to be more time specific. This study adds to our understanding of the direction of effects between anxiety sensitivity, anxiety and depression in adolescence, and the risks underlying their associations. PMID- 22437877 TI - A new GLUT-1 mutation in a family with glucose transporter 1 deficiency syndrome. PMID- 22437878 TI - Lack of genomic imprinting of DNA primase, polypeptide 2 (PRIM2) in human term placenta and white blood cells. AB - PRIM2, encoding a subunit of primase involved in DNA replication and transcription, is expressed in the placenta and is crucial for mammalian development and growth. Its role in placental function is not well understood. Recently, PRIM2 was reported as imprinted in human white blood cells (WBC). We report here our failure to confirm imprinting of the PRIM2 locus in human placenta or WBC. The discordance between our results and those of others are likely due to an incorrectly annotated PRIM2 pseudogene found in the human genome database. PMID- 22437879 TI - Quantitative analysis and parametric imaging of 18F-labeled monomeric and dimeric RGD peptides using compartment model. AB - PURPOSE: Non-invasive PET imaging with radiolabeled RGD peptides for alpha(v)beta(3) integrin targeting has become an important tool for tumor diagnosis and treatment monitoring in both pre-clinical and clinical studies. To better understand the molecular process and tracer pharmacokinetics, we introduced kinetic modeling in the investigation of (18)F-labeled RGD peptide monomer (18)F-FP-c(RGDyK) (denoted as (18)F-FPRGD) and dimer (18)F-FP-PEG3 E[c(RGDyK)](2) (denoted as (18)F-FPPRGD2). PROCEDURES: MDA-MB-435 tumor-bearing mice underwent 60 min dynamic PET scans following the injection of either (18)F FPRGD or (18)F-FPPRGD2. Blocking studies with pre-injection of a blocking mass dose were performed for both monomeric and dimeric RGD groups. (18)F-FPRAD (RAD) was used as a negative control. Kinetic parameters (K(1), k(2), k(3), k(4)) of a three-compartment model were fitted to the dynamic data to allow quantitative comparisons between the monomeric and dimeric RGD peptides. RESULTS: Dimeric RGD peptide tracer showed significantly higher binding potential (Bp(ND) = k(3)/k(4), 5.87 +/- 0.31) than that of the monomeric analog (2.75 +/- 0.48, p = 0.0022, n = 4/group). The Bp(ND) values showed a significantly greater ratio (dimer/monomer ~2.1) than the difference in %ID/g uptake measured from static images (dimer/monomer ~1.5, p = 0.0045). Significant decrease in Bp(ND) was found in the blocked groups compared with the unblocked ones (dimer p = 0.00024, monomer p = 0.005, n = 4/group). Similarly, the RAD control group showed the lowest Bp(ND) value among all the test groups, as the RAD peptide does not bind to integrin alpha(v)beta(3). Volume of distribution (V(T) = K(1)/k (2)(1 + k (3)/k (4))) could be separated into non-specific (V (ND) = K (1)/k (2)) and specific (V (S) = K (1) k (3)/(k (2) k (4))) components. Specific distribution volume (V(S)) was the dominant component of V(T) in the unblocked groups and decreased in the blocked groups. Unblocked RGD dimer also showed higher V(S) than that of the monomer (dimer V(S) = 2.38 +/- 0.15, monomer V(S) = 0.90 +/- 0.17, p = 0.0013, n = 4/group), well correlated with Bp(ND) calculations. Little difference in V(ND) was found among all groups. Moreover, parametric maps allowed quantitative analysis at voxel level and provided higher tumor-to-background contrast for Bp(ND) maps than the static images. Tumor heterogeneity in kinetic parameters was found in parametric images, which could not be clearly identified in static intensity images. CONCLUSIONS: The pharmacokinetics of both monomeric and dimeric RGD peptide tracers was compared, and the RGD dimers showed significantly higher binding affinity than the monomeric analogs. Kinetic parameters were demonstrated to be valuable for separating specific and non-specific binding and may allow more sensitive and detailed quantification than simple standardized uptake value analysis. PMID- 22437880 TI - Influence of immobilized biomolecules on magnetic bead plug formation and retention in capillary electrophoresis. AB - Significant changes in the formation and retention of magnetic bead plugs in a capillary during electrophoresis were studied, and it was demonstrated that these effects were due to the type of biological molecule immobilized on the surface of these beads. Three biological molecules, an antibody, an oligonucleotide, and alkaline phosphatase (AP), were attached to otherwise identical streptavidin coated magnetic beads through biotin-avidin binding in order to isolate differences in bead immobilization in a magnetic field resulting from the type of biological molecule immobilized on the bead surface. AP was also attached to the magnetic beads using epoxy groups on the bead surfaces (instead of avidin-biotin binding) to study the impact of immobilization chemistry. The formation and retention of magnetic bead plugs were studied quantitatively using light scattering detection of magnetic particles eluting from the bead plugs and qualitatively using microscopy. Both the types of biomolecule immobilized on the magnetic bead surface and the chemistry used to link the biomolecule to the magnetic bead impacted the formation and retention of the bead plugs. PMID- 22437881 TI - The future of nursing and school nursing. PMID- 22437882 TI - Impact of high electromagnetic field levels on childhood leukemia incidence. AB - The increasing exposure to electromagnetic fields (EMFs) has raised concern, as increased exposure may result in an increased risk of childhood leukemia (CL). Besides a short introduction of CL and EMF, our article gives an evaluation of the evidence of a causal relation between EMF and CL by critically appraising the epidemiological and biological evidence. The potential impact is also estimated by the population attributable risk. The etiology of CL is largely unknown, but is probably multifactorial. EMF may be one of the environmental exposures involved. Three pooled analyses of case-control studies showed a 1.4- to 1.7-fold increased CL risk for extremely low-frequency EMF (ELF-EMF) exposure levels above 0.3 MUT. Several biases may have played a role in these studies, but are unlikely to fully explain the increased risk. For effects of radiofrequency ELF evidence is lacking. None of the proposed biological mechanisms by which ELF-EMF might cause CL have been confirmed. The estimated overall population attributable risk was 1.9%, with the highest estimates in Northern America and Brazil (4.2% and 4.1%, respectively). The potential impact of EMF exposure on public health is probably limited, although in some countries exposure might be relatively high and thus might have a more substantial impact. We recommend nationwide surveys to gain more insight into the contemporary exposure levels among children. Reducing exposure from power lines near densely populated areas and schools is advised. Future epidemiological studies should focus on limiting bias. PMID- 22437883 TI - Increased serum levels of ischemia-modified albumin and C-reactive protein in type 1 diabetes patients with ketoacidosis. AB - Ischemia-modified albumin (IMA) levels have been advocated as a biomarker for evaluating the oxidative stress status. No data are showed on the potential role of IMA in type 1 diabetes (T1D). We aimed to establish the correlation among serum levels of IMA, C-reactive protein (CRP), and diabetic ketoacidosis (DKA) in patients with T1D. Fifty-seven patients with T1D, 27 patients with DKA, and 40 controls were enrolled. Serum IMA and CRP levels were measured and evaluated to distinguish from DKA. CRP and IMA levels were significantly elevated in patients with DKA at admission to the hospital compared to non-DKA and control subjects. CRP and IMA levels were higher in non-DKA patients than in controls. CRP, plasma glucose, and IMA levels were reduced after insulin treatment. Serum IMA levels were an independent risk marker for DKA (OR = 1.225, p = 0.002, 95 % CI: 1.076 1.394). Receiver operating characteristic curve analyses showed no difference in the areas under curve for serum IMA and CRP values. This study indicates that IMA and CRP levels were significantly correlated with DKA diagnosis. IMA can act as a biomarker that reflects the presence of DKA. PMID- 22437884 TI - From system to organ to cell: oxygenation and perfusion measurement in anesthesia and critical care. AB - Maintenance or restoration of adequate tissue oxygenation is a main goal of anesthesiologic and intensive care patient management. Pathophysiological disturbances which interfere with aerobic metabolism may occur at any stage in the oxygen cascade from atmospheric gas to the mitochondria, and there is no single monitoring modality that allows comprehensive determination of "the oxygenation". To facilitate early detection of tissue hypoxia (or hyperoxia) and to allow a goal directed therapy targeted at the underlying problem, the anesthesiologist and intensive care physician require a thorough understanding of the numerous determinants that influence cellular oxygenation. This article reviews the basic physiology of oxygen uptake and delivery to tissues as well as the options to monitor determinants of oxygenation at different stages from the alveolus to the cell. PMID- 22437885 TI - LMA Pro SealTM: not for MRI brain. PMID- 22437886 TI - Comparison of free and anonymous testing for HIV and sexually transmitted infections between the University Hospital and Health Center. AB - We gathered data regarding age, sex, and positivity rates for human immunodeficiency virus (HIV), syphilis, gonococcus, and chlamydia from individuals who underwent free and anonymous sexually transmitted infection (STI) testing conducted at the Jikei University School of Medicine Hospital (our hospital). These data were compared to results of subjects who underwent similar testing at the Minato Health Center and several private facilities of urologists and gynecologists belonging to the Minato Ward Medical Association. The positivity rate of chlamydia was found to be high in female subjects, particularly at the Minato Health Center, with 15 of 194 subjects (7.73 %) testing positive. In our hospital, we only detected 3 of 133 subjects (2.26 %) who were gonococcus positive. On the other hand, at the doctor's facilities, 10 of 188 male subjects (5.32 %) were syphilis positive, and 8 of 185 male subjects (4.32 %) were chlamydia positive, thus showing high positivity rates for both infections. At our hospital, 1 of 231 subjects was positive for gonococcus and 4 of 230 subjects (1.74 %) were positive for chlamydia, thus showing lower positivity rates for both infections. HIV-positive subjects were, however, only confirmed at our hospital, with 2 of 243 subjects (0.82 %) being positive. We were able to diagnose infected patients using free and anonymous STI testing at hospitals, and the same as at doctors' facilities. This result suggests that the hospitals that have many opportunities to diagnose HIV patients may become potential candidates for the development of new consultation facilities, establishment of testing facilities, and enhancement of consultation processes that include STI prevention. PMID- 22437887 TI - Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3 kinase inhibition. AB - Tissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-alpha or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-alpha induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor kappaB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-alpha. In conclusion, caffeine enhances TNF-alpha-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects. PMID- 22437888 TI - Minimal traumatic aortic injuries: meaning and natural history. AB - OBJECTIVE Minimal aortic injuries (MAIs) are being recognized more frequently due to the increasing use of high-resolution diagnostic techniques. The objective of this case series review was to report the clinical and radiological characteristics and outcomes of a series of patients with MAI. METHODS From January 2000 to December 2011, 54 major blunt trauma patients were admitted to our institution with traumatic aortic injuries. Nine of them presented with MAI, whereas the remaining 45 patients suffered a significant aortic injury (SAI). RESULTS MAIs accounted for 17% of the overall traumatic aortic injuries in our series. Major trauma patients with MAI and SAI were similar regarding the presence of severe associated non-aortic injuries and the expected mortality calculated by injury severity score, revised trauma score and trauma injury severity score. There were no statistically significant differences in in hospital mortality between MAI (22.2%) and SAI (30.2%). No death in the MAI group was aortic related, whereas five deaths in the SAI group were caused by an aortic complication. The survival of MAI patients was 77.8% at 1 and 5 years. There was no late mortality among MAI patients. The survival of SAI patients was 69.7% at 1 year and 63.6% at 5 and 10 years. None of the seven surviving patients with MAI presented a progression of the aortic injury. In six patients, the intimal tear completely healed in imaging controls, whereas one patient developed a small saccular pseudoaneurysm. CONCLUSIONS Blunt traumas presenting MAI are as severe as traumas that associate SAI and present similar in-hospital mortality. In contrast to SAI traumas, in-hospital mortality due to MAI is not usually related to the aortic injury, so these injuries are more amenable to a conservative management. It is mandatory to perform a close imaging surveillance to detect early any potential adverse evolution of an MAI. Nevertheless, a balance must be struck between a close serial imaging surveillance and the potentially detrimental effects of obtaining high-resolution additional images. PMID- 22437889 TI - What is Innovation? PMID- 22437890 TI - Minimally invasive versus open mitral valve surgery: a consensus statement of the international society of minimally invasive coronary surgery (ISMICS) 2010. AB - OBJECTIVE: : The purpose of this consensus conference was to deliberate the evidence regarding whether minimally invasive mitral valve surgery via thoracotomy improves clinical and resource outcomes compared with conventional open mitral valve surgery via median sternotomy in adults who require surgical intervention for mitral valve disease. METHODS: : Before the consensus conference, the consensus panel reviewed the best available evidence up to March 2010, whereby systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. The accompanying meta-analysis article in this issue of the Journal provides the systematic review of the evidence. Based on this systematic review, evidence-based statements were created for prespecified clinical questions, and consensus processes were used to derive recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. RESULTS AND CONCLUSIONS: : Considering the underlying level of evidence, and notwithstanding the limitations of the evidence base (retrospective studies with important differences in baseline patient characteristics, which may produce bias in results of the evidence syntheses), the consensus panel provided the following evidence-based statements and overall recommendation:In patients with mitral valve disease, minimally invasive surgery may be an alternative to conventional mitral valve surgery (Class IIb), given that there was comparable short-term and long-term mortality (level B), comparable in-hospital morbidity (renal, pulmonary, cardiac complications, pain perception, and readmissions) (level B), reduced sternal complications, transfusions, postoperative atrial fibrillation, duration of ventilation, and intensive care unit and hospital length of stay (level B). However, this should be considered against the increased risk of stroke (2.1% vs 1.2%) (level B), aortic dissection (0.2% vs 0%) (level B), phrenic nerve palsy (3% vs 0%) (level B), groin infections/complications (2% vs 0%) (level B), and, prolonged cross-clamp time, cardiopulmonary bypass time, and procedure time (level B). The available evidence consists almost entirely of observational studies and must not be considered definitive until future adequately controlled randomized trials further address the risk of stroke, aortic complications, phrenic nerve complications, pain, long term survival, need for reintervention, quality of life, and cost-effectiveness. PMID- 22437891 TI - Bilateral internal thoracic artery grafting: current state of the art. AB - The purpose of this article is to review the key literature and assess the current status of bilateral internal thoracic artery grafting. Numerous retrospective studies have demonstrated a benefit of bilateral internal thoracic artery grafting over single internal thoracic artery grafting in terms of the long-term risk of all-cause death, cardiac-related death, and cardiac events. The survival benefit of bilateral internal thoracic artery grafting manifests relatively early after operation for high-risk patients. The skeletonization technique reduces the risk of sternal wound complications in all patients and particularly in those with diabetes. Both the left and right internal thoracic arteries have better patency when grated to the left coronary territory than saphenous vein. However, the right internal thoracic artery does not always have good patency when grafted to the right coronary artery. Bilateral internal thoracic artery grafting using the skeletonization technique is recommended for revascularization of the left coronary territory. PMID- 22437892 TI - Minimally invasive versus conventional open mitral valve surgery: a meta-analysis and systematic review. AB - OBJECTIVE: : This meta-analysis sought to determine whether minimally invasive mitral valve surgery (mini-MVS) improves clinical outcomes and resource utilization compared with conventional open mitral valve surgery (conv-MVS) in patients undergoing mitral valve repair or replacement. METHODS: : A comprehensive search of MEDLINE, Cochrane Library, EMBASE, CTSnet, and databases of abstracts was undertaken to identify all randomized and nonrandomized studies up to March 2010 of mini-MVS through thoracotomy versus conv-MVS through median sternotomy for mitral valve repair or replacement. Outcomes of interest included death, stroke, myocardial infarction, aortic dissection, need for reintervention, and any other reported clinically relevant outcomes or indicator of resource utilization. Relative risk and weighted mean differences and their 95% confidence intervals were analyzed as appropriate using the random effects model. Heterogeneity was measured using the I statistic. RESULTS: : Thirty-five studies met the inclusion criteria (two randomized controlled trials and 33 nonrandomized studies). The mortality rate after mini-MVS versus conv-MVS was similar at 30 days (1.2% vs 1.5%), 1 year (0.9% vs 1.3%), 3 years (0.5% vs 0.5%), and 9 years (0% vs 3.7%). A number of clinical outcomes were significantly improved with mini MVS versus conv-MVS including atrial fibrillation (18% vs 22%), chest tube drainage (578 vs 871 mL), transfusions, sternal infection (0.04% vs 0.27%), time to return to normal activity, and patient scar satisfaction. However, the 30-day risk of stroke (2.1% vs 1.2%), aortic dissection/injury (0.2% vs 0%), groin infection (2% vs 0%), and phrenic nerve palsy (3% vs 0%) were significantly increased for mini-MVS versus conv-MVS. Other clinical outcomes were similar between groups. Cross-clamp time, cardiopulmonary bypass time, and procedure time were significantly increased with mini-MVS; however, ventilation time and length of stay in intensive care unit and hospital were reduced. CONCLUSIONS: : Current evidence suggests that mini-MVS maybe associated with decreased bleeding, blood product transfusion, atrial fibrillation, sternal wound infection, scar dissatisfaction, ventilation time, intensive care unit stay, hospital length of stay, and reduced time to return to normal activity, without detected adverse impact on long-term need for valvular reintervention and survival beyond 1 year. However, these potential benefits for mini-MVS may come with an increased risk of stroke, aortic dissection or aortic injury, phrenic nerve palsy, groin infections/complications, and increased cross-clamp, cardiopulmonary bypass, and procedure time. Available evidence is largely limited to retrospective comparisons of small cohorts comparing mini-MVS versus conv-MVS that provide only short-term outcomes. Given these limitations, randomized controlled trials with adequate power and duration of follow-up to measure clinically relevant outcomes are recommended to determine the balance of benefits and risks. PMID- 22437893 TI - VATS thymectomy for nonthymomatous myasthenia gravis: standardized outcome assessment using the myasthenia gravis foundation of America clinical classification. AB - OBJECTIVE: : Video-assisted thoracoscopic (VATS) thymectomy has been practiced in Australia for nearly two decades. Our aim was to assess the complete stable remission and asymptomatic disease rates after VATS thymectomy in nonthymomatous myasthenia gravis. There remains doubt that minimally invasive techniques achieve equal remission rates to open maximal operations. Therefore, we report our outcomes using the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification and Kaplan-Meier analysis and compare the results to the literature. METHODS: : A retrospective analysis of 78 consecutive patients undergoing right VATS thymectomy between April 1994 and March 2007 at two Thoracic Surgery Units in Melbourne, Australia, was undertaken. Patients with thymoma were excluded. Therefore, 57 patients were followed-up for a minimum of 12 months to apply the MGFA Clinical Classification. VATS thymectomy was performed by a three-port right side technique. RESULTS: : The complete stable remission rate was 15% at 3 years and 28% at 5 years. The asymptomatic disease rate was 59% at 5 years. Median follow-up was 32 months. No prognostic factors for remission were identified. The overall morbidity rate was 14% (8/57). CONCLUSIONS: : Right VATS thymectomy achieves comparable remission and asymptomatic disease rates to other minimally invasive and open techniques when compared with studies using either MGFA or older criteria. PMID- 22437894 TI - Short- and long-term outcomes in octogenarian patients undergoing off-pump coronary artery bypass grafting compared with on-pump coronary artery bypass grafting. AB - OBJECTIVE: : Coronary artery bypass grafting (CAB) on elderly patients presenting with multivessel coronary artery disease has become routine in modern day operating rooms. The aim of our study was to compare short- and long-term outcomes in octogenarian patients undergoing off-pump CAB (OPCAB) versus on-pump CAB (ONCAB). METHODS: : A propensity-adjusted, retrospective review of patients older than 80 years who underwent primary CAB from January 1996 to September 2008 at our institution's hospitals was performed. Nine hundred thirty-seven patients were divided into two groups: OPCAB (n = 540) or ONCAB (n = 397). A propensity score was calculated based on 29 preoperative risk factors to adjust for selection bias when comparing the groups for differences in death, stroke, myocardial infarction incidence, and their composite (major adverse cardiac events). Long-term survival status was determined by cross-referencing patient records with the Social Security Death Index. Logistic regression analysis and Cox proportional hazards analysis were used to determine group differences in short- and long-term survival, respectively, adjusted for the propensity score. Kaplan-Meier curves were fit to estimate 10-year survival. RESULTS: : The mean age (OPCAB: 82.9 +/- 2.8 years vs ONCAB: 82.3 +/- 2.4, P = 0.003) and male sex (OPCAB: 292/540, 54.1% vs ONCAB: 220/397, 55.4%, P = 0.68) were clinically similar between groups. Although the ejection fraction (OPCAB: 52.1 +/- 12.5% vs ONCAB: 50.6 +/- 13.1, P = 0.10) were similar between groups, the mean number of distal anastomoses [OPCAB: 2.7 +/- 1.0 (median 3) vs ONCAB: 3.4 +/- 0.9 (median 3), P < 0.001] were less in the OPCAB group. The median postoperative length of stay was 7 days for OPCAB group and 6 for the ONCAB group (P = 0.31). The Society of Thoracic Surgery predicted risk of in-hospital mortality was similar for OPCAB (5.4%) and ONCAB (5.3%) patients (P = 0.81). However, observed in-hospital mortality was improved for patients in the OPCAB group (OPCAB: 15/540, 2.8% vs ONCAB: 37/397, 9.3%, P = 0.007). Ten-year survival was similar between groups (OPCAB: 28.8% vs ONCAB: 26.3%, P = 0.22). CONCLUSIONS: : In this series, OPCAB reduced the incidence of in-hospital mortality compared with ONCAB. Long-term mortality was similar between groups. PMID- 22437895 TI - Sternum sparing thoracotomy incisions in lung transplantation surgery: a superior technique to the clamshell approach. AB - OBJECTIVE: : Bilateral anterior transsternal thoracotomy incision (clamshell technique) is the standard approach used for bilateral sequential lung transplantation (LTX). The morbidity and wound complications of this large incision can be considerable and costly. Muscle sparing anterior thoracotomies without division of the sternum may lead to decreasing the sequelae of wound complications. The objective of this study was to determine the rate of wound complications in the nonsternal incising lung transplant patients. METHODS: : We used the single-institution-based transplant data bank, phone questionnaire, and ambulatory care unit follow-up data to investigate retrospectively the incidence of wound healing complications following muscle and sternum sparing and mammary artery protecting limited access small submammary anterior thoracotomy incisions (AT) for LTX surgery. In the need for cardiopulmonary bypass, the femoral artery and vein were cannulated. RESULTS: : After exclusion of seven clamshell operations for LTX combined with cardiac surgery, 91 recipients (65% male), aged 19 to 68 years (mean, 54 +/- 8 years), underwent 84 AT and 48 lateral thoracotomies (LT) for idiopathic pulmonary fibrosis (IPF) (48%), obstructive disease (40%), cystic fibrosis (CF) (5%), and pulmonary arterial hypertension (PAH) (7%). AT ranged from 5.5 to 26 cm (mean, 20.3 +/- 4.8 cm) and LT from 12 to 25 cm (mean, 19.8 +/- 2.4 cm) and was not significantly different (P = 0.37). Warm ischemic times ranged from 30 to 92 minutes (mean, 56 +/- 11 minutes). Four patients required rethoracotomy for bleeding/hematoma formation. Cardiopulmonary bypass/intraop extracorporeal membrane oxygenation (ECMO) was used in 64%. Superficial wound infection and subsequent drainage/care was needed in four LTX incisions. Reoperation for lung herniation using patch repair technique for thoracic wall stabilization was required in two AT and three LT. CONCLUSIONS: : Sternum sparing and mammary artery protecting limited access submammary anterior and lateral thoracotomy incisions for LTX surgery are safe and effective. This approach avoids complications related to sternal transaction and may minimize the development of severe wound complications following LTX surgery. PMID- 22437896 TI - Direct endoscopy-guided mitral valve repair in the beating heart: an acute animal study. AB - OBJECTIVE: : The purpose of this study was to develop a new method for minimally invasive mitral valve repair under direct endoscopic visualization in the beating heart. METHODS: : Fiberoptic cardioscopy of the left heart was conducted in 12 calves. Systemic perfusion was maintained by cardiopulmonary bypass through a median sternotomy. A clear solution (Ringer's lactate) was temporarily administered via the pulmonary artery to flush out the pulmonary vasculature, and additional perfusion of the left heart chambers enhanced visualization of the intracardiac anatomy. The endoscope, with an open-ended transparent flexible outer sheath, was inserted through the left ventricular apex, and an endoscopic clip was used for edge-to-edge mitral valve repair. Hemodilution was avoided by the drainage of irrigation fluid via a left ventricular cannula. RESULTS: : Direct endoscopic visualization of the mitral valve in an in vivo beating heart was obtained clearly, avoiding systemic hemodilution. In the last experiment, edge-to-edge repair using an endoscopic clip was successfully performed. Use of an effective intracardiac irrigation method was important for successful image acquisition and achievement of repair procedures. CONCLUSIONS: : This acute animal study showed the technical feasibility of beating-heart mitral valve surgery under direct endoscopic imaging. Although this study was performed under open-chest conditions, our successful experiment is a first step toward closed chest intracardiac surgery with direct endoscopic visualization. PMID- 22437897 TI - Robotic-assisted cryosurgical treatment of atrioventricular node reentrant tachycardia. AB - Atrioventricular nodal reentrant tachycardias typically arise from the existence of variable refractoriness in fast and slow conduction pathways within the triangle of Koch, which provide input to the atrioventricular node. Standard therapy includes medical management and catheter-based ablation procedures. Robotic-assisted, minimally invasive cryosurgical modification of the atrioventricular node can provide definitive therapy for patients who fail traditional therapy. A 65-year-old man presented with a several-year history of recurrent atrioventricular nodal reentrant tachycardia. Despite medical management and attempted percutaneous ablation, the patient remained symptomatic with weekly episodes. Access was via a 4-cm right anterolateral thoracotomy and peripheral perfusion. The da Vinci S robotic system was used to manipulate the cryoprobe (CryoMaze Probe; ATS Medical, Plymouth, MN USA). A series of spot freezes (tip 60 degrees C) were made along the boundaries of the triangle of Koch until transient complete heart block was achieved and nodal rhythm was recovered. At follow-up 3 weeks postoperatively, the patient was asymptomatic in first degree heart block. Robotic-assisted cryosurgical atrioventricular node ablation is an effective, minimally invasive treatment for patients with atrioventricular nodal reentrant tachycardia. PMID- 22437898 TI - Chylopericardial tamponade masquerading as hemopericardium: an uncommon complication of cardiac surgery. AB - Chylopericardial tamponade occurs very rarely after heart surgery. It may be the result of lymphatic duct interruption during mammary artery harvest, division of a large thymic remnant, or thrombosis of the subclavian or internal jugular vein by an indwelling central line. Although relatively straightforward when the pericardial aspirate has the usual milky appearance, the correct diagnosis can easily be overlooked particularly early after surgery when the patient is still fasting. We present a case report that illustrates the importance of sending all aspirates for chemical analysis irrespective of their color to arrive at the correct diagnosis and institute the appropriate medical management of this rare condition. PMID- 22437899 TI - Suggested immobilization test for diagnosis of restless legs syndrome in Parkinson's disease. AB - Diagnosis of restless leg syndrome (RLS) in Parkinson's disease (PD) is difficult because of clinical confounds. The suggested immobilization test (SIT) is validated for diagnosis of primary RLS. This study evaluated the usefulness of the SIT for diagnosis of RLS in PD. We compared SIT scores, as well as polysomnography measures in 50 patients with PD (25 with RLS, 25 without), 25 patients with primary RLS, and 25 age/sex matched controls. Mean leg discomfort score was increased in patients with PD and RLS compared to PD without RLS, and also in patients with primary RLS compared to controls. Leg discomfort was significantly higher at the end of the test in patients with RLS compared to patients without RLS. Intensity of leg discomfort was similar between patients with RLS, with or without PD. Using a mean leg discomfort cutoff of 11, we showed sensitivity of 91% and specificity of 72% for RLS diagnosis in PD during symptomatic time intervals. Periodic leg movements index during the SIT did not differ between groups. Periodic leg movements index during sleep and wakefulness was increased in patients with primary RLS compared to controls, but did not differ between patients with PD, with and without RLS. The sensory SIT is a simple test that may help diagnose RLS in patients with PD. PMID- 22437900 TI - Diagnosis, clinical features and treatment outcome of microsporidial keratoconjunctivitis. AB - AIM: To report the clinical and microbiological profile of patients with microsporidial keratoconjunctivitis in a tertiary eye care centre in India. METHODS: A retrospective analysis of medical records of all cases of microbiologically confirmed microsporidial keratoconjunctivitis, who presented between March 2007 and October 2010, was done. In a single-centre, institutional setting, 278 eyes of 277 apparently healthy patients were analysed. RESULTS: The mean age was 36 +/- 14 years (range 6-80). The mean duration of symptoms was 7.7 +/- 6.2 days (range 1-60). Keratic precipitates were present in 20.1% patients. A superficial scar was present in 39.2% patients. Majority (26.6%) of the patients reported in the month of August. Microscopic examination of corneal scraping, using potassium hydroxide with calcofluor white and Gram stain, demonstrated microsporidial spores in 98.9% and 89.7% cases, respectively. Patients received either topical 0.02% polyhexamethylene biguanide or lubricants. The mean time for resolution was 6.0 +/- 2.9 days (range 2-18). Final visual acuity was >= 20/30 in 75.1% cases. CONCLUSIONS: Microsporidial keratoconjunctivitis is common in India. It is seasonal, can occur in healthy individuals and can be diagnosed using simple microbiological methods. Treatment outcome is generally satisfactory. PMID- 22437901 TI - Two-step method for constructing Arabidopsis artificial microRNA vectors. AB - Artificial microRNA (amiRNA) technology is used for gene silencing in Arabidopsis. We describe a method for constructing amiRNA vectors that requires only one PCR and one ligation reaction. Vectors produced by this method are the same as those from the method of Schwab et al. (Plant Cell 2006, 18:1121-1133). Transgenic plants created by this method can therefore be tested in the same way or compared with existing transgenic material without the risk of alteration to the amiRNA skeleton. With optimized parameters, 36-42 % colonies had the insertion in the expected orientation and 85-95 % of these had the correct sequence. Using this method, a transient gene knock-down analysis in Arabidopsis could be completed in 4-5 days. PMID- 22437902 TI - [The role of Prison Health Care in preventing and treating the consumption of illegal drugs]. PMID- 22437903 TI - [Evaluation of needle exchange program at Pereiro de Aguiar prison (Ourense, Spain): ten years of experience]. AB - OBJECTIVES: To evaluate the effectiveness of NEPs in prison to reduce the prevalence of infections associated with intravenous drug use and to know more about acceptance of the program by inmates and staff. MATERIAL AND METHODS: cross sectional observational study at baseline, 6 and 12 months and 10 years of program development. Interviews were conducted with program users, as well as random sample surveys of officials at the various cuts, and a random sample of inmates from the centre after10 years. Activity indicators of the program were recorded continuously, and the prevalence of HIV, HBV and HCV at baseline and after 10 years was evaluated. For the statistical analysis, the chi-square test was used with the Yates correction when necessary. RESULTS: In ten years we have supplied a total of 15,962 syringes to 429 users, (average 20.2 users/month), and 11,327 (70.9%) were returned. The prevalence of HIV infection decreased from 21% in 1999 to 8.5% in 2009, HCV prevalence from 40% to 26.1% (p <0.01), finding no significant differences in the prevalence of HBsAg +. Most of the inmates and civil servants believe that the program did not increase intravenous drug use and improves hygienic living conditions in prison. CONCLUSIONS: After ten years of development of the NEP, there was a significant decrease in the prevalence of HIV and HCV in the prison population at the centre, and the program is accepted as beneficial by most of the inmates and staff participating in the survey. PMID- 22437904 TI - [Prevalence of latent tuberculosis infection amongst immigrants entering prison]. AB - OBJECTIVE: To study the prevalence of latent tuberculosis infection (LTBI) and the predictive factors amongst immigrants entering prison. METHODS: prospective study conducted in May and June of 2009. The tuberculin skin test (TST) was performed, with induration of >= 10 mm being regarded as positive. Variables collected were: age, origin, number of incarcerations, length of time living in Spain, heroin and cocaine consumption, intravenous drug use and HIV infection. The rate of LTBI was calculated and the overall infection rate (ITL and history of TB). To study predictable factors, a bivariant and multivariant analysis were carried out using logistic regression. RESULTS: 152 male immigrants. Average age: 31.9 years +/- 7.8; 37.2% of them with heroin or cocaine consumption and 7.5% IDU. 12 patients were previously TST positive and 6 patients had history of TB. TST was performed on 134 people, 63 with positive results and 71 with negative ones. ITL rate: 49.3. Overall infection rate: 53.3%. Bivariate associated with LTBI: more than one incarceration (67.4% vs. 36.4% in primary, p=0.001), age (76% >= 40 vs. 40.4% under this age and heroin and cocaine consumption (60% consumers vs. 39.3% non consumers; p=0.02. Multivariate analysis only confirmed the association with age (p=0.001; OR: 2.34, IC=1.39-3.94). CONCLUSIONS: The LTBI rate amongst immigrants entering prison is very high. A complete study is recommended for all of them, with special attention being paid to the most vulnerable ones, such as older people. PMID- 22437905 TI - [Multi-centre study of the prevalence of infection from HIV and associated factors in Spanish prisons]. AB - OBJECTIVE: To determine the prevalence and associated factors of HIV infection amongst inmates in Spain. MATERIAL AND METHODS: Observational and transversal study (June 2008). For 62,000 inmates an "n" of 364 was determined (5% variability, error correction alpha 5% and 10% missing). 18 prisons were randomly selected and 21 inmates/prison. Frequency measurement: prevalence. Magnitude of the association: odds ratio of prevalence (ORP) with 95%. Statistical significance p<0.05. RESULTS: 371 prisoners were studied (91.6% male, 66.9% <= 40 years, 60.6% Spanish, 23.5% IDU and 71.2% incarcerated <5 years). HIV prevalence was 10.8% (CI: 7.5 to 14). 85% were co-infected with HCV, 12.5% with HBV and HCV and 63.2% with M. tuberculosis. This represents a proportion to the prison population of 9.2%, 1.3% and 6.7% respectively. HIV infection was associated with: a) > 40 years (p <0.01), b) imprisoned> 5 years (p <0.001), c) non-Arab (p <0.01), d) Spanish nationality (p <0.001), e) IDUs (p <0.001), f) co-infected with HCV (p <0.001), and g) co-infected with HBV (p <0.001]. Multivariate analysis confirmed the association: a) >= 40 years [OR = 2.66 (CI : 1.16-6.07), b) IDU [OR = 28.08 (IC-9.61-81.99), c) infected with HCV [OR = 6.96 (CI :1.90 25.39)], and d) infected with HBV [OR = 13.52 (CI = 1.76-103.82). CONCLUSION: The prevalence of HIV infection among prisoners in Spain is 10.8%. Those that are infected are usually IDUs and over 40 years. 85% are co-infected with HCV and 12.5% with HBV and HCV. PMID- 22437906 TI - [Delay in diagnosis of HIV infection]. AB - Late presentation of HIV is common. It has been associated with greater risk of AIDS, death, lower immunological response, greater toxicity and a higher probability of transmission. In this study we review the impact of different definitions in terms of mortality and morbidity, associated factors, economic implications, as well as strategies for increasing diagnosis. PMID- 22437907 TI - [Voluntary swallowing of a nail clipper: follow up via plain x-ray of abdomen]. PMID- 22437908 TI - Phenotypic and genetic differentiation among yellow monkeyflower populations from thermal and non-thermal soils in Yellowstone National Park. AB - In flowering plants, soil heterogeneity can generate divergent natural selection over fine spatial scales, and thus promote local adaptation in the absence of geographic barriers to gene flow. Here, we investigate phenotypic and genetic differentiation in one of the few flowering plants that thrives in both geothermal and non-thermal soils in Yellowstone National Park (YNP). Yellow monkeyflowers (Mimulus guttatus) growing at two geothermal ("thermal") sites in YNP were distinct in growth form and phenology from paired populations growing nearby (<500 m distant) in non-thermal soils. In simulated thermal and non thermal environments, thermal plants remained significantly divergent from non thermal plants in vegetative, floral, mating system, and phenological traits. Plants from both thermal populations flowered closer to the ground, allocated relatively more to sexual reproduction, were more likely to initiate flowering under short daylengths, and made smaller flowers that could efficiently self fertilize without pollinators. These shared differences are consistent with local adaptation to life in the ephemeral window for growth and reproduction created by winter and spring snowmelt on hot soils. In contrast, habitat type (thermal vs. non-thermal) explained little of the genetic variation at neutral markers. Instead, we found that one thermal population (Agrostis Headquarters; AHQ-T) was strongly differentiated from all other populations (all F (ST) > 0.34), which were only weakly differentiated from each other (all F (ST) < 0.07). Phenotypic differentiation of thermal M. guttatus, but little population genetic evidence of long-term ecotypic divergence, encourages further investigations of the potential for fine-scale adaptation and reproductive isolation across the geothermal gradient in Yellowstone. PMID- 22437909 TI - Spatial and temporal predictions of moose winter distribution. AB - Herbivores are usually distributed unevenly across the landscape often because of variation in resource availability. We used zero-inflated generalised additive models (to account for data with a high number of zeros) that include georeferences to predict winter distribution of a large herbivore (moose Alces alces). Moose distribution was analysed in relation to forage availability and distance to neighbouring sites. Our results showed that the ability to explain moose distribution indexed by pellet count data at a local scale increased when spatial information (longitude and latitude) was added to the model compared to the model only including food availability. By using the relationship between moose and forage distribution, and the spatial information, we predicted patch choice by moose reasonably well in 2 out of 4 years. However, the distribution of moose was also influenced by weather conditions, as it was most clumped in the year with most snow. In conclusion, our study lends support for a non-linear approach using georeferences for a comprehensive understanding of herbivore distribution at a small scale. This result also indicates that the use of a certain patch by moose not only depends on the selected patch itself but is also influenced by the neighbouring patch and factors at a larger spatial scale, such as moose management influencing the density above moose home range level. The relatively high proportion of unexplained variation suggests that the use of a certain patch is also influenced by other factors such as topography, predation, competition, weather conditions, and wildlife management strategies. PMID- 22437910 TI - Levels of thioredoxin are related to the severity of obstructive sleep apnea: based on oxidative stress concept. AB - BACKGROUND: Oxidative stress is a typical feature of obstructive sleep apnea (OSA). Thioredoxin (TRX), as one of the oxidative stress biomarkers, is a potent protein disulfide reductase in antioxidant defense. Our study is designed to test whether thioredoxin could assess the severity of OSA. METHODS: Sixty-three adults suspected of having OSA were included in this study and were divided into four groups based on the results of polysomnography (PSG): control, mild, moderate, and severe. Subjects with chronic medical diseases (with the exception of essential hypertension) or taking any antioxidant medication were excluded. Blood samples were obtained within an hour after the overnight PSG test. Plasma TRX levels were detected by enzyme-linked immunosorbent assay. RESULTS: The plasma TRX level in severe group was obviously increased (8.62 +/- 2.14, 13.33 +/- 5.60, 14.71 +/- 5.53, and 16.10 +/- 7.34 ng/ml; p < 0.05). The TRX positively related to AHI (r = 0.313; p < 0.05), while negatively related to the lowest O(2) saturation (r = 0.266; p < 0.037). The OSA patients associated with hypertension showed elevated TRX level (17.70 +/- 6.98 vs. 13.43 +/- 5.83 ng/ml; t = 2.434, p < 0.018). The cutoff value of TRX for identifying OSA was 9.39 ng/ml (sensitivity 91 %, specificity 78 %), and its cutoff value for differentiating moderate-severe OSA from mild OSA was 11.79 ng/ml (sensitivity 75 %, specificity 65 %). CONCLUSION: These results suggest that plasma TRX level is associated with the severity of OSA. Therefore, TRX may be used as a severity indicator of OSA. PMID- 22437911 TI - Trends in tuberculosis - United States, 2011. AB - In 2011, a total of 10,521 new tuberculosis (TB) cases were reported in the United States, an incidence of 3.4 cases per 100,000 population, which is 6.4% lower than the rate in 2010. This is the lowest rate recorded since national reporting began in 1953. The percentage decline is greater than the average 3.8% decline per year observed from 2000 to 2008 but not as large as the record decline of 11.4% from 2008 to 2009. This report summarizes 2011 TB surveillance data reported to CDC's National Tuberculosis Surveillance System. Although TB cases and rates decreased among foreign-born and U.S.-born persons, foreign-born persons and racial/ethnic minorities continue to be affected disproportionately. The rate of incident TB cases (representing new infection and reactivation of latent infection) among foreign-born persons in the United States was 12 times greater than among U.S.-born persons. For the first time since the current reporting system began in 1993, non-Hispanic Asians surpassed persons of Hispanic ethnicity as the largest racial/ethnic group among TB patients in 2011. Compared with non-Hispanic whites, the TB rate among non-Hispanic Asians was 25 times greater, and rates among non-Hispanic blacks and Hispanics were eight and seven times greater, respectively. Among U.S.-born racial and ethnic groups, the greatest racial disparity in TB rates occurred among non-Hispanic blacks, whose rate was six times the rate for non-Hispanic whites. The need for continued awareness and surveillance of TB persists despite the continued decline in U.S. TB cases and rates. Initiatives to improve awareness, testing, and treatment of latent infection and TB disease in minorities and foreign-born populations might facilitate progress toward the elimination of TB in the United States. PMID- 22437912 TI - Tuberculosis outbreak associated with a homeless shelter - Kane County, Illinois, 2007-2011. AB - Despite the overall decline in tuberculosis (TB) incidence in the United States to a record low, outbreaks of TB among homeless persons continue to challenge TB control efforts. In January 2010, public health officials recognized an outbreak of TB after three overnight guests at a homeless shelter in Illinois received diagnoses of TB disease caused by Mycobacterium tuberculosis isolates with matching genotype patterns. As of September 2011, a total of 28 outbreak associated cases involving shelter guests, dating back to 2007, had been recognized, indicating ongoing M. tuberculosis transmission. The subsequent investigation found that all patients were homeless and had been overnight shelter guests. Excess alcohol use was common (82%), and two bars emerged as additional sites of potential transmission. Patients with outbreak-associated TB were treated successfully for TB disease. To prevent future cases of TB, public health officials are implementing a program to offer 12 once-weekly doses of isoniazid and rifapentine under direct observation for treatment of latent tuberculosis infection (LTBI) in this high-risk population. Although the United States has made progress toward TB elimination, this outbreak demonstrates the vulnerability of homeless persons to outbreaks of TB, highlighting the need for aggressive and sustained TB control efforts. PMID- 22437913 TI - Progress toward Global Polio Eradication - Africa, 2011. AB - By January 2012, 23 years after the Global Polio Eradication Initiative (GPEI) was begun, indigenous wild poliovirus (WPV) transmission had been interrupted in all countries except Afghanistan, Pakistan, and Nigeria. However, importation of WPV into 29 previously polio-free African countries during 2003-2011 led to reestablished WPV transmission (i.e., lasting >12 months) in Angola, Chad, Democratic Republic of the Congo (DRC), and Sudan (although the last confirmed case in Sudan occurred in 2009). This report summarizes progress toward polio eradication in Africa. In 2011, 350 WPV cases were reported by 12 African countries, a 47% decrease from the 657 cases reported in 2010. From 2010 to 2011, the number of cases decreased in Angola (from 33 to five) and DRC (from 100 to 93) and increased in Nigeria (from 21 to 62) and Chad (from 26 to 132). New WPV outbreaks were reported in 2011 in eight African countries, and transmission subsequently was interrupted in six of those countries. Ongoing endemic transmission in Nigeria poses a major threat to the success of GPEI. Vigilant surveillance and high population immunity levels must be maintained in all African countries to prevent and limit new outbreaks. PMID- 22437914 TI - Notes from the field: multistate outbreak of Salmonella Altona and Johannesburg infections linked to chicks and ducklings from a mail-order hatchery - United States, February-October 2011. AB - Salmonella infections from contact with live poultry (chickens, ducks, turkeys, and geese) continue to be a public health problem. In summer 2011, two clusters of human Salmonella infections were identified through PulseNet, a molecular subtyping network for foodborne disease surveillance. Standard outbreak and traceback investigations were conducted. From February 25 to October 10, 2011, a cluster of 68 cases caused by Salmonella serotype Altona and a cluster of 28 cases caused by Salmonella Johannesburg were identified in 24 states. Among persons infected, 32% of those with Salmonella Altona and 75% of those with Salmonella Johannesburg were aged <=5 years. Forty-two of 57 (74%) Salmonella Altona patients and 17 of 24 (71%) of Salmonella Johannesburg patients had contact with live poultry in the week preceding illness. Most patients or their parents reported purchasing chicks or ducklings from multiple locations of an agricultural feed store chain that was supplied by a single mail-order hatchery. Live poultry were purchased for either backyard flocks or as pets. PMID- 22437915 TI - Myosin II is a negative regulator of oligodendrocyte morphological differentiation. AB - During their development as myelinating cells, oligodendrocyte progenitors (OPC) undergo dramatic changes in the organization of their cytoskeleton. These changes involve an increase in cell branching and in lamella extension, which is important for the ability of oligodendrocytes to myelinate multiple axons in the CNS. We have previously shown that the levels of the actin-associated motor protein nonmuscle myosin II (NMII) decrease as oligodendrocyte differentiate and that inhibition of NMII activity increases branching and myelination, suggesting that NMII is a negative regulator of oligodendrocyte differentiation. In agreement with this interpretation, we have found that overexpression of NMII prevents oligodendrocyte branching and differentiation and that OPC maturation is accelerated in NMII knockout mice as shown by a significant increase in the percentage of mature MBP(+) cells. Although several pathways have been implicated in oligodendrocyte morphogenesis, their specific contribution to the regulation of NMII activity has not been directly examined. We tested the hypothesis that the activity of NMII in OPC is controlled by Fyn kinase via downregulation of RhoA-ROCK-NMII phosphorylation. We found that treatment with PP2 or knockdown of Fyn using siRNA prevents the decrease in myosin phosphorylation normally observed during OPC differentiation and that the inhibition of branching induced by overexpression of constitutively active RhoA can be reversed by treatment with Y27632 or blebbistatin. Taken together, our results demonstrate that Fyn kinase downregulates NMII activity, thus promoting oligodendrocyte morphological differentiation. PMID- 22437916 TI - Vanadate complexes bearing an imidazolidine-bridged bis(aryloxido) ligand: synthesis and solid state and solution structure. AB - A new imidazolidine-bridged bis(aryloxido) ligand precursor (H(2)L) [H(2)L = 2,2' (imidazolidine-1,3-diylbis(methylene))bis(4-(1,1,3,3-tetramethylbutyl-2 yl)phenol)] was prepared in a relatively high yield (~60%) via a single-step Mannich condensation of 4-(1,1,3,3-tetramethylbutyl)phenol, ethylenediamine and paraformaldehyde at 2:1:3 molar ratio and characterized by chemical and physical techniques including X-ray crystallography. Reactions of H(2)L with [VO(OEt)(3)] at 1:1 and 1:2 molar ratios in toluene afforded [V(L-kappa(3)O,N,N,O)(O)(OEt)] (1) and [V(2)(MU-L-kappa(4)O,N,N,O)(MU-OEt)(2)(O)(2)(OEt)(2)] (2), respectively. Alcoholysis of 1 with EtOH enables elimination of one molecule of H(2)L and the formation of 2. Compounds 1 and 2 were characterized by IR and NMR spectroscopy as well as ES-MS experiments. The definitive molecular structure of 2 was provided by a single-crystal analysis and revealed its dinuclear nature, featuring two octahedral vanadium centres bridged by both OEt groups and the L ligand. The (51)V, (1)H and (13)C NMR spectra as well as ES-MS showed that 2 does not stay intact in solution and undergoes dissociation to give 1 and [VO(OEt)(3)]. PMID- 22437917 TI - Pancreatic neuroendocrine tumors: a comprehensive review. AB - Pancreatic neuroendocrine tumors (NETs) are a heterogeneous group of tumors. Despite being relatively rare, representing just 1-2% of all pancreatic neoplasms, the incidence of pancreatic NET has increased over the past two decades. Although the primary treatment for localized NET is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pancreatic NET. Recently, the targeted agents sunitinib malate (SUTENT(r), Pfizer Inc, NYC) and everolimus (AFINITOR(r), Novartis, Basel, Switzerland)-both with different mechanisms of action-received United States Food and Drug Administration approval for the treatment of progressive, well differentiated, pancreatic NET in patients with unresectable, locally advanced or metastatic disease. SUTENT(r) also received approval for this indication by the European Commission in 2010. Our article presents an overview of pancreatic NET, with a focus on their diagnostic work-up, clinical presentation and treatment options. Topics for further investigation of targeted therapy are also discussed. PMID- 22437918 TI - Fibrinogen residue gammaAla341 is necessary for calcium binding and 'A-a' interactions. AB - The fibrinogen gamma-module has several important sites relating to fibrinogen function, which include the high affinity calcium binding site, hole 'a' that binds with knob 'A', and the D:D interface. Residue gammaAla341, which is located in the vicinity of these sites, is altered in three variant fibrinogens: fibrinogen Seoul (gammaAla341Asp), Tolaga Bay (gammaAla341Val), and Lyon III (gammaAla341Thr). In order to investigate the impaired polymerisation of fibrinogens gammaAla341Asp and gammaAla341Val to understand the role of gammaAla341 in fibrin polymerisation and fibrinogen synthesis, we have expressed gammaAla341Asp and gammaAla341Val in Chinese hamster ovary (CHO) cells, purified these fibrinogens from the culture media and performed biochemical tests to elucidate their function. Expression in CHO cells was similar for these variants. For both variants the kinetics of thrombin-catalysed FpA release was not different from normal fibrinogen, while FpB release was slower than that of normal. Thrombin-catalysed polymerisation of both variants was dependent on the calcium concentration. At physiologic calcium (1 mM) the variants showed impaired polymerisation with a longer lag period and a slower Vmax than normal fibrinogen. Scanning electron micrographs showed the clots were less organised than normal, having thicker and more twisted fibers, and larger pores. Analysis by SDS-PAGE showed that factor XIIIa-catalysed gamma and alpha chain cross-linking was delayed, and plasmin-catalysed lysis was not reduced by the presence of 5 mM calcium or 5 mM GPRP (Gly-Pro-Arg-Pro). Our data indicate that fibrinogen residue gammaAla341 is important for the proper conformation of the gamma-module, maintaining calcium-binding site and 'A-a' interactions. PMID- 22437920 TI - Cystic versus predominantly cystic thyroid nodules: efficacy of ethanol ablation and analysis of related factors. AB - OBJECTIVES: To compare the efficacy of ethanol ablation (EA) of cystic and predominantly cystic thyroid nodules, and to evaluate factors affecting efficacy. METHODS: From October 2008 to December 2010, a total of 217 thyroid nodules were treated with EA. Nodule volumes, symptoms and cosmetic scores were evaluated before and after EA. EA efficacy in treating cystic and predominantly cystic nodules was compared; and factors related to EA efficacy in each type, including initial volume, solid component, vascularity, fluid nature, ethanol retention time and number of EA sessions, were evaluated. RESULTS: Mean nodule volume decreased from 15.7 +/- 18.1 ml to 3.0 +/- 7.9 ml (mean volume reduction, 85.2 +/ 16.1%) and the therapeutic success rate was 90.3% at last follow-up. EA was significantly more effective in cystic than predominantly cystic nodules. Independent predictors of EA efficacy for all nodules included initial volume, solid component and vascularity. Initial volume and vascularity were independent predictors of EA efficacy in predominantly cystic nodules, but no factor was independently related to efficacy in cystic nodules. CONCLUSIONS: EA is effective in both cystic and predominantly cystic nodules, especially the former. EA is less effective in large or vascular predominantly cystic nodules, but is effective in cystic nodules regardless of related factors. KEY POINTS: * Ethanol ablation under ultrasound guidance is increasingly used for cystic thyroid nodules. * EA seems effective for cystic and predominantly cystic nodules, especially cystic nodules. * The effectiveness of EA was reduced in large or vascular predominantly cystic nodules. PMID- 22437921 TI - Appearance of hepatocellular adenomas on gadoxetic acid-enhanced MRI. AB - OBJECTIVE: The purpose of this study was to evaluate enhancement characteristics of hepatocellular adenomas (HCAs) using gadoxetic acid as a hepatocyte-specific MR contrast agent. METHODS: Twenty-four patients with histopathologically proven HCAs were retrospectively identified. MRI consisted of T1- and T2-weighted (w) sequences with and without fat saturation (fs), multiphase dynamic T1-w images, and fs T1-w images during the hepatobiliary phase. Standard of reference was surgical resection (n = 19) or biopsy (n = 5). Images were analysed for morphology and contrast behaviour including signal intensity (SI) measurement on T1-w images normalised to the pre-contrast base line. RESULTS: In total 34 HCAs were evaluated. All HCAs showed enhancement in the arterial phase; 38 % of HCAs showed reduced contrast enhancement ("wash-out") in the venous phase. All HCAs showed enhancement (SI increase, 56 +/- 53 %; P <0.001) in the hepatobiliary phase, although liver uptake was stronger (96 +/- 58 %). Thus, 31 of all HCAs (91 %) appeared hypointense to the surrounding liver in the hepatobiliary phase, while 3 out of 34 lesions were iso-/hyperintense. CONCLUSIONS: Gadoxetic acid accumulates in HCAs in the hepatobiliary phase, although significantly less than in surrounding liver. Thus, HCA appears in the vast majority of cases as a hypointense lesion on hepatobiliary phase images. KEY POINTS: * Magnetic resonance-specific contrast agents are now available for hepatic imaging. * Hepatocellular adenomas enhance with gadoxetic acid as in previous CT/MRI experience. * Enhancement during the hepatobiliary phase is less in HCAs than in liver. * Typical HCAs appear as hypointense lesions on T1-w hepatobiliary phase images. * True hyperintense HCA enhancement can occasionally occur during the hepatobiliary phase. PMID- 22437922 TI - Central skeletal sarcoidosis: a case report with sustained remission only on methotrexate, and a literature review on the imaging approach, treatment, and assessment of disease activity. AB - We report a case of multifocal involvement of the central skeleton in a patient with long-term stage I pulmonary sarcoidosis who experienced sustained clinical remission of musculoskeletal symptoms while on methotrexate (MTX) alone. Concomitant normalization of laboratory tests [inflammatory markers and angiotensin-converting enzyme (ACE) levels] was observed, and improvements were seen in follow-up magnetic resonance imaging (MRI) of the lumbar spine and bone scintigraphy. To date, there are no specific tools for the assessment of skeletal disease activity in sarcoidosis. Our case suggests that inflammatory markers and ACE levels, when initially elevated, bone scintigraphy, and-in the case of vertebral involvement-MRI could serve as such tools. A literature review on the imaging approach, treatment, and disease activity monitoring of skeletal sarcoidosis is also provided. PMID- 22437923 TI - Quadracyclic adenine: a non-perturbing fluorescent adenine analogue. AB - Fluorescent-base analogues (FBAs) comprise a group of increasingly important molecules for the investigation of nucleic acid structure and dynamics as well as of interactions between nucleic acids and other molecules. Here, we report on the synthesis, detailed spectroscopic characterisation and base-pairing properties of a new environment-sensitive fluorescent adenine analogue, quadracyclic adenine (qA). After developing an efficient route of synthesis for the phosphoramidite of qA it was incorporated into DNA in high yield by using standard solid-phase synthesis procedures. In DNA qA serves as an adenine analogue that preserves the B-form and, in contrast to most currently available FBAs, maintains or even increases the stability of the duplex. We demonstrate that, unlike fluorescent adenine analogues, such as the most commonly used one, 2-aminopurine, and the recently developed triazole adenine, qA shows highly specific base-pairing with thymine. Moreover, qA has an absorption band outside the absorption of the natural nucleobases (>300 nm) and can thus be selectively excited. Upon excitation the qA monomer displays a fluorescence quantum yield of 6.8 % with an emission maximum at 456 nm. More importantly, upon incorporation into DNA the fluorescence of qA is significantly less quenched than most FBAs. This results in quantum yields that in some sequences reach values that are up to fourfold higher than maximum values reported for 2-aminopurine. To facilitate future utilisation of qA in biochemical and biophysical studies we investigated its fluorescence properties in greater detail and resolved its absorption band outside the DNA absorption region into distinct transition dipole moments. In conclusion, the unique combination of properties of qA make it a promising alternative to current fluorescent adenine analogues for future detailed studies of nucleic acid containing systems. PMID- 22437925 TI - Message from the President. PMID- 22437927 TI - B cells: An innate talent uncovered. PMID- 22437928 TI - Autoimmunity: Fortune tellers. PMID- 22437929 TI - T cell memory: Skin-deep memory. PMID- 22437936 TI - Tumour immunology: Editorial selection demystified. PMID- 22437937 TI - Targeting natural killer cells and natural killer T cells in cancer. AB - Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans. PMID- 22437940 TI - Pleiotropic functions of the CXC-type chemokine CXCL14 in mammals. AB - CXCL14 is a member of the CXC chemokine family. CXCL14 possesses chemoattractive activity for activated macrophages, immature dendritic cells and natural killer cells. CXCL14-deficient mice do not exhibit clear immune system abnormalities, suggesting that the function of CXCL14 can be compensated for by other chemokines. However, CXCL14 does appear to have unique biological roles. It suppresses the in vivo growth of lung and head-and-neck carcinoma cells, whereas the invasiveness of breast and prostate cancer cells appears to be promoted by CXCL14. Moreover, recent evidence revealed that CXCL14 participates in glucose metabolism, feeding behaviour-associated neuronal circuits, and anti-microbial defense. Based on the expression patterns of CXCL14 and CXCL12 during embryonic development and in the perinatal brain in mice, the functions of these two chemokines may be opposite or interactive. Although CXCL14 receptors have not yet been identified, the intracellular activity of CXCL14 in breast cancer cells suggests that the CXCL14 receptor(s) and signal transduction pathway(s) may be different from those of conventional CXC-type chemokines. PMID- 22437939 TI - Adoptive immunotherapy for cancer: harnessing the T cell response. AB - Immunotherapy based on the adoptive transfer of naturally occurring or gene engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we discuss progress in the use of adoptively transferred T cells, focusing on how they can mediate tumour cell eradication. Recent advances include more accurate targeting of antigens expressed by tumours and the associated vasculature, and the successful use of gene engineering to re-target T cells before their transfer into the patient. We also describe how new research has helped to identify the particular T cell subsets that can most effectively promote tumour eradication. PMID- 22437938 TI - Coordinated regulation of myeloid cells by tumours. AB - Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The three groups of terminally differentiated myeloid cells - macrophages, dendritic cells and granulocytes - are essential for the normal function of both the innate and adaptive immune systems. Mounting evidence indicates that the tumour microenvironment alters myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider myeloid cells as an intricately connected, complex, single system and we focus on how tumours manipulate the myeloid system to evade the host immune response. PMID- 22437941 TI - Identification of the P-body component PATL1 as a novel ALG-2-interacting protein by in silico and far-Western screening of proline-rich proteins. AB - ALG-2 (also named PDCD6) is a 22-kDa Ca(2+)-binding protein that belongs to the penta-EF-hand family including calpain small subunit and interacts with various proteins such as ALIX and Sec31A at their specific sites containing an ALG-2 binding motif (ABM) present in their respective Pro-rich region (PRR). In this study, to search for novel ALG-2-interacting proteins, we first performed in silico screening of ABM-containing PRRs in a human protein database. After selecting 17 sequences, we expressed the PRR or full-length proteins fused with green fluorescent protein (GFP) in HEK293T cells and analysed their abilities to bind to ALG-2 by Far-Western blotting using biotinylated ALG-2 as a probe. As a result, we found 10 positive new ALG-2-binding candidates with different degrees of binding ability. For further investigation, we selected PATL1 (alternatively designated Pat1b), a component of the P-body, which is a cytoplasmic non membranous granule composed of translation-inactive mRNAs and proteins involved in mRNA decay. Interactions between endogenous PATL1 and ALG-2 proteins were demonstrated by a co-immunoprecipitation assay using their specific antibodies. Furthermore, in immunofluorescence microscopic analyses, PATL1 as well as DCP1A, a well-known P-body marker, co-localized with a subset of ALG-2. This is the first report showing interaction of ALG-2 with a P-body component. PMID- 22437942 TI - Phosphorylation in the activation loop as the finishing touch in c-Kit activation. AB - Receptor tyrosine kinases are a group of transmembrane proteins that transmit signals in response to stimulation by ligands including growth factors and cytokines. They share a common mechanism of activation through receptor dimerization or oligomerization, but subsequent routes to their full activation appear to be various. A recent paper published by DiNitto et al. (Function of activation loop tyrosine phosphorylation in the mechanism of c-Kit autoactivation and its implication in sunitinib resistance. J. Biochem. 2010;147:601-609) analysed a process of c-Kit autoactivation in detail. They revealed that phosphorylation in the activation loop, which is crucial for activation of many types of tyrosine kinases, is dispensable for c-Kit activation. However, the phosphorylation affects the sensitivity of c-Kit to kinase inhibitors, thus representing the finishing touch in c-Kit activation. PMID- 22437943 TI - Toward a mechanistic understanding of how variability in neurobiology shapes individual differences in behavior. AB - Research has begun to identify how variability in brain function contributes to individual differences in complex behavioral traits. Examining variability in molecular signaling pathways with emerging and established methodologies such as pharmacologic fMRI, multimodal PET/fMRI, and hormonal assays are beginning to provide a mechanistic understanding of how individual differences in brain function arise. Against this background, functional genetic polymorphisms are being utilized to understand the origins of variability in signaling pathways as well as to efficiently model how such emergent variability impacts behaviorally relevant brain function and health outcomes. This chapter provides an overview of a research strategy that integrates these complimentary levels of analysis; existing empirical data is used to illustrate the effectiveness of this approach in illuminating the mechanistic neurobiology of individual differences in complex behavioral traits. This chapter also discusses how such efforts can contribute to the identification of predictive risk markers that interact with unique environmental factors to precipitate psychopathology. PMID- 22437944 TI - Psychosocial functioning in children and adolescents with extreme obesity. AB - The aim of this study was to investigate the psychosocial differences among obese pediatric patients, particularly those who are "extremely obese" as compared to "obese." Information was collected for 249 subjects at a multidisciplinary treatment clinic for obese youth. A battery of measures was administered and demographic data and height/weight was obtained. The results showed positive correlations between degree of obesity, psychosocial functioning, and quality of life. Specifically, the "extremely obese" were significantly more depressed, more socially anxious, and had poorer quality of life than the "obese" group. Girls and Caucasians were more socially anxious than boys and African Americans, respectively. There is mounting evidence that children and adolescents who are extremely obese are most at risk for psychiatric and medical disorders. Thus, targeting this group for assessment and/or designing treatment options specific for "extremely obese" youth is critical for the successful management of this population. PMID- 22437945 TI - Preparing psychologists in academic health centers for the rapidly changing health care environment. AB - The Association of Psychologists in Academic Health Centers (APAHC) convened its 5th National APAHC Conference in Boston March 3-5 2011. The conference and its theme, "Preparing Psychologists for a Rapidly Changing Health Care Environment," brought psychologists from academic health centers together to examine how psychology can adapt to and help lead health care efforts in the face of health care reform. This paper reports on the conference and introduces the special issue of JCPMS that is dedicated to the conference. The conference theme is framed in the historical context of the four national conferences that preceded it. In examining the focus and topics of the preceding conferences, recurrent themes are identified and progress in certain areas is highlighted. PMID- 22437946 TI - Factors associated with adherence to the recommended postpolypectomy surveillance interval. AB - BACKGROUND: Appropriate surveillance intervals are important to ensure that the benefits of surveillance are not offset by harm. This study aimed to determine the factors associated with nonadherence to recommended colonoscopic surveillance intervals. METHODS: The study enrolled 296 patients who underwent screening colonoscopy. The colonoscopies were performed by four endoscopists in the first or second year of fellowship. After each procedure, the endoscopists responded to a questionnaire that elicited information on the degree of concern for missed polyps (using a visual analog scale [VAS]), colonoscopic technical factors, and surveillance intervals. RESULTS: Of the 296 patients, 105 (36%) were adherent and 191 (64%) and were nonadherent to the guidelines. There were no differences in insertion time, withdrawal time, or polyp detection rate between the adherence and nonadherence groups. The endoscopy at cecal intubation was longer in the nonadherence group than in the adherence group (P = 0.013). The proportion of patients with poor bowel preparation was higher in the nonadherence group than in the adherence group (P = 0.011). The endoscopist's concern for missed polyps was greater in the nonadherence group than in the adherence group (P < 0.001). Based on multivariate analysis, only the endoscopist's concern was an independent factor associated with adherence to guidelines (P = 0.008). Poor bowel preparation, loop formation, and colonoscopy experience were independent factors associated with a high concern for missed polyps. CONCLUSIONS: Nonadherence to the recommended guidelines was associated with the endoscopist's concern for missed polyps. Improving colonoscopic skills and bowel preparation may decrease nonadherence to the recommended postpolypectomy surveillance interval. PMID- 22437947 TI - Laparoscopic robotic-assisted pancreaticoduodenectomy: a case-matched comparison with open resection. AB - BACKGROUND: Minimally invasive procedures have expanded recently to include pancreaticoduodenectomy (PD), but the efficacy of a laparoscopic robotic-assisted approach has not been demonstrated. A case-matched comparison was undertaken to study outcomes between laparoscopic robotic approach (LRPD) and the conventional open counterpart (OPD). METHODS: From March 2009 through December 2010, 30 LRPD were performed by two pancreaticobiliary surgeons at the Cleveland Clinic. Thirty OPD patients operated by four pancreaticobiliary surgeons during this same period were matched by demographics, and postoperative outcomes were compared from review of a prospectively collected database. RESULTS: Mean age was 62 years for LRPD versus 61 years for OPD (p = 0.43). Mean body mass index was 24.8 versus 25.6 kg/m(2) (p = 0.49). Surgical indications included adenocarcinoma in 14 patients from each group (46%), intraductal papillary mucinous neoplasm in 4 (14%), and other in 12 (40%). There was one preoperative death in the LRPD group and none following OPD. Morbidity occurred in nine patients (30%) following LRPD versus 13 (44%) in the OPD group (p = 0.14). Intraoperative factors assessed included blood loss (485.8 vs 775 ml, p = 0.13) and operative time (476.2 vs 366.4 min, p = 0.0005). Conversion from LRPD to open occurred in three patients (12%) due to bleeding. Reoperation was performed in two patients (6%) following LRPD versus seven (24%) following OPD (p = 0.17). Length of hospital stay was 9.79 days for LRPD versus 13.26 days in the OPD group (p = 0.043). CONCLUSIONS: This is the first comparison of a novel laparoscopic robotic-assisted PD with the open PD in a case-matched fashion. Our data demonstrate a significant increase in operative time but decreased length of stay for LRPD. The favorable morbidity following LRPD makes it a reasonable surgical approach for selected patients requiring PD. PMID- 22437948 TI - Technical notes: a self-designed, simple, secure, and safe six-loop intracorporeal Pringle's maneuver for laparoscopic liver resection. AB - BACKGROUND: The aim of this study is to design a simple, secure, and safe technique of intracorporeal Pringle's maneuver to facilitate safer laparoscopic liver resection. METHODS: A self-designed six-loop catheter was made using 20 French T-tube and 10-French nelaton urethral catheter. The cross head and stem of the T-tube were trimmed to 1 cm, respectively. The nelaton was shortened to 12-cm long tube from the round tip, and the cut end was inserted and sutured to the stem of the T-tube. After establishment of pneumoperitoneum, the T-tube with nelaton was placed into the abdomen. The round end of the nelaton was inserted into the lesser sac and pulled through the foramen of Winslow, and the end of nelaton was then inserted into one end of the T-tube and pulled through the other end, forming a six-loop. The nelaton was pulled to occlude the hepatic inflow and temporarily fixed with 1-0 Vicryl on a curved round needle on the other end of the T-tube. The protocol of Pringle's maneuver was 15-min clamp and 5-min release periods. The liver parenchymal transection was performed using Harmonic scalpel. RESULTS: From November 2009 to August 2011, 20 patients received laparoscopic liver resection using the six-loop Pringle's maneuver. During operation, 17 patients were positioned supine, 2 patients in left decubitus, and 1 patient in supine followed by left decubitus position. There were 9 anatomical resections and 11 nonanatomical resections (18 patients for single lesion, 1 for two lesions, and 1 for three lesions). The average times of liver resection and Pringle's maneuver were 33.1 and 36.2 min, respectively. Mean blood loss was 102.5 ml. The postoperative course was uneventful, and average hospital stay was 4.4 days. CONCLUSION: Our self-designed six-loop intracorporeal Pringle's maneuver can facilitate safer laparoscopic liver resection. PMID- 22437949 TI - Development and evaluation of a laparoscopic common bile duct exploration simulator and procedural rating scale. AB - INTRODUCTION: Laparoscopic common bile duct exploration (LCBDE) is an effective, single-stage treatment for choledocholithiasis. However, LCBDE requires specific cognitive and technical skills, is infrequently performed by residents, and currently lacks suitable training and assessment modalities outside of the operating room. To address this gap in training, a simulator model for transcystic and transcholedochal LCBDE was developed and evaluated. METHODS: A procedure algorithm incorporating essential cognitive and technical steps of LCBDE was developed, along with a physical model to allow performance of a simulated procedure. Modified Objective Structured Assessment of Technical Skills (OSATS) rating scales were developed to assess performance on the model. Construct validity was assessed by comparing the performance of novices (residents and surgeons without LCBDE experience) versus experienced subjects (surgeons with previous LCBDE experience). Concurrent validity was assessed by comparing scores from the LCBDE scales to those from the standard OSATS scale. Internal consistency and interrater reliability were assessed by comparing performance scores assigned by three independent raters. RESULTS: Sixteen novices and five experienced subjects performed simulated procedures, with novices scoring lower than experienced subjects on both transcystic (20 +/- 3 vs. 33 +/- 2 [possible score range, 0-45], p < 0.001) and transcholedochal (25 +/- 8 vs. 42 +/- 3 [possible score range, 0-53], p < 0.001) rating scales. Scores on the rating scales correlated significantly with scores from the standard OSATS scale. Internal consistency and interrater reliability of the LCBDE rating scales were favorable. CONCLUSIONS: The LCBDE simulator is a low-cost yet realistic physical model that allows performance and evaluation of technical skills required for LCBDE. The LCBDE rating scales show evidence of construct validity, concurrent validity, internal consistency, and interrater reliability. Use of the LCBDE model and associated rating scales allows procedure-specific feedback for trainees and could be used to improve current training. PMID- 22437950 TI - Robot-assisted total mesorectal excision: is there a learning curve? AB - BACKGROUND: Laparoscopic total mesorectal excision (TME) is associated with a steep learning curve, but the learning curve for robotic TME is unknown. This study aimed to evaluate the learning curve for robotic TME. METHODS: Between November 2004 and April 2009, 80 patients underwent robotic TME performed by a single surgeon. The operative experience was divided into two groups: group 1 (the first 40 cases) and group 2 (the subsequent 40 cases). Patient demographics, operative characteristics, and morbidities were compared. RESULTS: The two patient populations selected did not differ statistically in age, body mass index (BMI), preoperative risk assessment, stage, preoperative chemoradiotherapy, or tumor location. The mean operative times in group 1 (310 min) and group 2 (297 min) were similar (p = 0.55), and the mean robotic TME time did not differ between the two groups (60 vs. 64 min; p = 0.65). In addition, the operative times did not improve during the course of the study. There were no differences in EBL, margin status, or number of lymph nodes harvested. Furthermore, there were no differences in conversion rate, time to resumption of diet, length of hospital stay, or postoperative complications. CONCLUSION: Robot-assisted TME may attenuate the learning curve for laparoscopic rectal cancer resection. Further studies are necessary to establish the role of robotic surgery in minimally invasive rectal operations. PMID- 22437951 TI - Flexible versus rigid single-port peritoneoscopy: a randomized controlled trial in a live porcine model followed by initial experience in human cadavers. AB - INTRODUCTION: We compared single incision laparoscopic surgery with flexible endoscope ("flexible SILS") and with rigid optic ("rigid SILS") for access to 11 elective sites of peritoneal carcinomatosis. MATERIALS AND METHODS: Back-to-back flexible and rigid SILS peritoneoscopy were performed in ten live pigs. SILS peritoneoscopy was performed using a flexible endoscope or a rigid optic, in random order, together with two rigid 5-mm laparoscopic forceps. Primary endpoint was access success rate to 11 elective sites of peritoneal carcinomatosis. Findings for the most favorable option were then assessed in four human cadavers. RESULTS: In the porcine model, the overall rate of access to targets was 98% with flexible SILS and 87% with rigid SILS (p < 0.001). Both flexible and rigid SILS allowed a 100% access rate to diaphragmatic domes, paracolic gutters, splenic and hepatic hilum, pelvic floor, and trigonal bladder. The rates of access to other sites by flexible versus rigid SILS, respectively, were: root of the mesentery (90 vs. 50%), origin of the inferior mesenteric vein (90 vs. 50%), inferior vena cava (100 vs. 90%), and cul-de-sac of Douglas (100 vs. 50%). No complications were observed. Procedures were performed in mean time of 26 and 24 min, respectively. These findings were confirmed for flexible SILS in four human cadavers. CONCLUSIONS: Flexible SILS is superior to rigid SILS to evaluate the peritoneal cavity in a timely manner. This suggests a need for flexible instrumentation or other technical solutions to perform thorough minimally invasive surgical evaluation of peritoneal carcinomatosis. PMID- 22437952 TI - Randomized double-blind placebo-controlled study of the efficacy of continuous infusion of local anesthetic to the diaphragm closure following laparoscopic hiatal hernia repair. AB - BACKGROUND: Laparoscopic repair of hiatal hernia can result in significant postoperative pain requiring use of narcotics and patient dissatisfaction. A catheter-based delivery method that has demonstrated effectiveness and safety in other laparoscopic and open procedures (ON-Q, I Flow Corporation) was used to deliver pain medicine. This randomized double-blind, placebo-controlled study evaluated the efficacy of continuous infusion of local anesthetic to the diaphragm closure post laparoscopic hiatal hernia repair. METHODS: After obtaining Institutional Review Board approval, qualifying patients undergoing laparoscopic repair of hiatal hernia voluntarily consented to the study protocol. Standard techniques for routine closure of hiatal hernia repair were used. The ON Q pain pump catheter was placed adjacent to the sutures used to repair the hiatal hernia, so that it rested between the diaphragm and the collagen patch used to reinforce the hernia repair. The pump infused either bupivacaine 0.5% or NaCl 0.9% at 2 cc/h for 5 days postoperatively. Patients kept a daily diary for pain scores, number of narcotic pain pills taken, and number of nausea pills taken. RESULTS: Of the 46 patients enrolled in the study, seven were dropped for adverse events or noncompliance; 20 were given placebo (0.9% NaCl) and 19 were given 0.5% bupivacaine. CONCLUSION: This randomized double-blind, placebo-controlled trial showed no advantage in using the ON-Q pain pump in terms of providing measurable reduction of pain or concomitant narcotic or nausea medication use. Further studies are indicated to determine alternatives for reducing postoperative pain after laparoscopic hiatal hernia repair. PMID- 22437953 TI - The relationship between percutaneous endoscopic gastrostomy and gastro oesophageal reflux disease in children: a systematic review. AB - BACKGROUND: The relationship between percutaneous endoscopic gastrostomy (PEG) insertion and gastro-oesophageal reflux disease (GERD) is widely disputed in the current literature. The aim of this systematic review is to examine the available evidence documenting the association between PEG and GERD. METHODS: The following databases were searched: MEDLINE (1950 to week 2, January 2011), PubMed, ISI Web of Knowledge (1898 to week 2, January, 2011), EMBASE (1980 to week 2, January 2011) and The Cochrane Central Register of Controlled Trials (CENTRAL) using the terms "gastroesophageal reflux", "gastroesophageal disease", "GERD", "GERD", "GER", "GER" and "percutaneous endoscopic gastrostomy", "PEG", "gastrostomy". In addition, the reference lists of all included studies were reviewed for relevant citations. Studies examining children pre and post insertion of PEG for GERD and written in English language were included. Data extraction was performed by two authors, and the methodology and statistical analysis of each study were assessed. RESULTS: Eight studies were included in this systematic review. Two reported increased incidence of GERD after PEG. However, neither was of high methodological quality. The remaining six reported no change or decreased GERD. Nonetheless, few demonstrated rigorous methodology. CONCLUSIONS: The current evidence examining the effect of PEG insertion on GERD has been inconsistent and is not of high quality and therefore is unconvincing, preventing a definitive conclusion. Overall, the available literature on this topic does not demonstrate a causal effect of PEG insertion on GERD. PMID- 22437954 TI - Ergonomic and geometric tricks of laparoendoscopic single-site surgery (LESS) by using conventional laparoscopic instruments. AB - BACKGROUND: The aim of this study was to explore the feasibility and safety of performing laparoendoscopic single-site surgery (LESS) with conventional laparoscopic instruments. METHODS: We retrospectively reviewed our data from 175 patients who underwent various urological LESS procedures via the same ergonomic and geometric principles between 2008 and 2011. LESS procedures performed included adrenalectomy (N = 23), radical nephrectomy (N = 5), radical nephroureterectomy with bladder cuff resection (N = 5), varicocelectomy (N = 12), nephropexy (N = 4), lumbar sympathectomy (N = 4), orchiectomy for intra-abdominal testis (N = 1), pyeloureterostomy (N = 1), dismembered pyeloplasty (N = 1), and adult inguinal hernia mesh repair (N = 119). RESULTS: All procedures were completed successfully without the use of ancillary ports or articulating instruments except two cases that required laparoscopic conversion. The mean patient age was 48.9 years. Mean operative time was 99.7 min, mean estimated blood loss was 17.3 ml, and mean hospital stay was 2.1 days. There were no intraoperative complications. CONCLUSION: According to our ergonomic and geometric principles, use of conventional laparoscopic instruments is feasible and safe in LESS procedures. PMID- 22437955 TI - Evidence to support the use of laparoscopic over open appendicectomy for obese individuals: a meta-analysis. AB - BACKGROUND: Laparoscopic appendicectomy (LA) in the obese population has been controversial. A recent SAGES guideline and a Cochrane Review have suggested a benefit for LA over the open approach but did not provide supporting data. This study is the first systematic review and meta-analysis to compare the LA with open surgery in the obese population to provide a quantitative estimate of the relative benefits. METHODS: A comprehensive search of the online databases identified seven retrospective and prospective randomized studies that contained sufficient data on obese patients. Analysis was based on intention-to-treat. We calculated pooled odds ratios (ORs) and 95 % confidence intervals using a random effects model. RESULTS: The LA group contained more females (43 vs. 32 %, p < 0.001), had fewer perforations (18 vs. 23 %; p < 0.001), and fewer overall complications (OR: 0.49; 95 % CI: 0.37-0.63), including fewer wound infections (OR: 0.34; 95 % CI: 0.18-0.66). There was no difference in the intra-abdominal abscess rate between the groups (OR: 0.99; 95 % CI: 0.29-3.37). The LA group had a shorter length of stay (2.46 vs. 3.63 days; p < 0.001) but a longer operation time (96 vs. 78 min, p < 0.001). There was no heterogeneity between the studies. CONCLUSIONS: This meta-analysis of the current published data establishes the laparoscopic approach to appendicectomy as the preferred technique for the obese population, delivering a 50 % reduction in morbidity, with a 66 % reduction in wound infections and a significantly shorter inpatient hospital stay without increasing the intra-abdominal abscess rate. PMID- 22437956 TI - Reply to: doi:10.1007/s0046-4-010-1485-0: Re: Evaluation of factors affecting the difficulty of laparoscopic anterior resection for rectal cancer: "narrow pelvis" is not a contraindication (Surg Endosc 2011 Jan;25:1907-1912): What factors should be considered in the preoperative planning of laparoscopic rectal cancer surgery? PMID- 22437957 TI - Totally laparoscopic strategies for the management of colorectal cancer with synchronous liver metastasis. AB - INTRODUCTION: Laparoscopy is an accepted treatment for colorectal cancer and liver metastases, but there is no consensus for its use in the management of synchronous liver metastases (SCRLM). The purpose of this study was to evaluate totally laparoscopic strategies in the management of colorectal cancer with synchronous liver metastases. METHODS: Patients presenting to Ninewells Hospital between July 2007 and August 2010, with adenocarcinoma of the colon and rectum with synchronous liver metastases were considered. Patients underwent simultaneous laparoscopic liver and colon cancer resection, a staged laparoscopic resection of SCRLM and colon cancer, or simultaneous colon resection and radiofrequency ablation (RFA) of SCRLM. Primary endpoints were in-hospital morbidity and mortality, total hospital stay, intraoperative blood loss, duration of surgery, and resection margin status. RESULTS: Twenty-eight patients presented with synchronous colorectal liver metastases. Thirteen patients underwent a simultaneous laparoscopic liver and colon resection (median operating time, 370 (range, 190-540) min; median hospital stay, 7 (range, 3-54) days), seven patients had a staged laparoscopic resection of SCRLM and primary colon cancer (median operating time, 530 (range, 360-980) min; median hospital stay 14, (range, 6-51) days), and eight patients underwent laparoscopic colon resection and RFA of SCRLM (median operating time, 310 (range, 240-425) min; median hospital stay, 8 (range, 6-13) days). There were no conversions to an open procedure. Overall in-hospital morbidity and mortality was 28 and 0 % respectively. An R0 resection margin was achieved in 91 % of the resection group. At a median follow-up of 26 (range, 18 55) months, 19 (90 %) patients remain disease-free. CONCLUSIONS: Totally laparoscopic strategies for the radical treatment of stage IV colorectal cancer are feasible with low morbidity and favorable outcomes. A laparoscopic approach for the simultaneous management of SCRLM and primary colon cancer is associated with reduced surgical access trauma, postoperative morbidity, and hospital stay with no compromise in short-term oncological outcome. PMID- 22437958 TI - Intraoperative cholangiography in the laparoscopic cholecystectomy era: why are we still debating? AB - Laparoscopic cholecystectomy is now one of the most frequently performed abdominal surgical procedures in the world. The most common major complication is bile duct injury, which can have catastrophic repercussions for patients and it has been suggested that intraoperative cholangiography may reduce the rate of bile duct injury. Whether this procedure should be performed routinely is still an active subject of debate. We discuss the available evidence and likely implications for the future. PMID- 22437959 TI - Re: bilateral total extraperitoneal inguinal hernia repair (TEP) has outcomes similar to those for unilateral TEP: population-based analysis of prospective data of 6,505 patients. PMID- 22437960 TI - Endoscopic surgeons' preferences for inguinal hernia repair: TEP, TAPP, or OPEN. AB - INTRODUCTION: The use of endoscopic inguinal hernia repair has slowly increased in the past years, but the indications have remained vague. Some surgeons perform a tailored approach depending on patient or hernia characteristics, whereas others perform the same approach and technique for all hernias. METHODS: Based on these principles, a survey of 19 questions was conducted during the 18th Congress of the European Association of Endoscopic Surgeons, which took place in Geneva, Switzerland, in 2010, to determine surgeons' preference depending on the hernia and the patient. RESULTS: All surgeons who attended the session (N = 100) responded to all questions. Eighty two percent of surgeons preferred a tailored approach, whereas 18 % used the same technique in all cases. Endoscopic techniques are used more frequently than the open approach in bilateral (7 vs. 93 %) and recurrent hernias (19 vs. 81 %), whereas in primary unilateral hernias all three techniques were used with almost similar frequency (32 % open, 39 % TAPP vs. 29 % TEP). TAPP was used more frequently than TEP, and even those surgeons who are expert in TEP preferred to perform a TAPP in difficult hernias, such as in obese patients and large scrotal hernias. Based on the age of patients, the open approach is preferred in patients younger than 18 years and older than 70 years, whereas the endoscopic approach is preferred in young active males and females, with a trend to use TAPP (44 %) more frequently than TEP (40 %) in females. Surgeons tended to use the open (vs. endoscopic) approach in patients with hematologic disorders (58 % open vs. 42 % endoscopic), previous laparotomy (59 % open vs. 41 % endoscopic) or emergency surgery (66 vs. 33 % in incarcerated hernias and 74 vs. 26 % in strangulated hernia). CONCLUSIONS: This survey showed that most surgeons who perform an endoscopic approach for inguinal hernia as the first option are convinced that not all hernias are good indications for this approach. On the other hand, most surgeons think that it is better to be able to offer patients an endoscopic technique or an open approach depending on the case. PMID- 22437961 TI - Hand shaping using hapsis resembles visually guided hand shaping. AB - The reach-to-grasp movement is composed of a number of movement elements including hand transport, hand shaping, and grasping. These movement elements are featured in grasping when it is guided by vision, when it is guided by haptic input from the non-reaching hand or other body parts, and when it is guided by off-line perceptual (remembered) knowledge. An unanswered question is how is the reach-to-grasp movement achieved when all information about the target must be acquired by the grasping hand? The answer to this question was obtained by asking participants to reach for three randomly presented food items that varied in size: an orange slice, a small round donut ball, or a blueberry. In order to constrain the grasping pattern, participants were asked to pick up an item with the intention of placing it in the mouth. Thus, in the unsighted condition, participants did not know which item they were reaching for until they made haptic contact with it. Hand transport, shaping, and grasping were examined using frame-by-frame video analysis and linear kinematics. These measures showed that in unsighted reaching, hand transport first served to establish haptic contact between either the second or third digit and the target. After haptic identification of the target, the hand and/or grasping digits adjusted their trajectory, reshaped, and reoriented for grasping. A comparison of haptically guided grasping and visually guided grasping indicated that the two were very similar. This similarity is discussed in relation to contemporary ideas concerning the neural mechanisms that guide hand use. PMID- 22437962 TI - Event coding and motor priming: how attentional modulation may influence binding across action properties. AB - When we perceive an action it is internally transformed into a motor representation akin to the execution of that same action. Motor priming studies show that action observation facilitates the execution of physically similar actions, but interferes with the performance of dissimilar actions. Some evidence suggests, however, that once a specific motor plan is formed, perceiving an action with partially overlapping features (e.g. a congruent grip-type but and incongruent end-goal) can result in interference. In two experiments we investigate how modulating attention towards observed actions influences the binding that occurs between action features, and therefore the amount of partial overlap interference to participants' performance. In the first study we directed attention towards a salient action feature (the grip-type). We found that perceiving partially overlapping (i.e. partially congruent) actions slowed participants' responses compared with observation of completely congruent or incongruent actions. In the second experiment attentional resources were taxed through the use of a secondary task. This resulted in the elimination of the partial-overlap interference effect. We discuss results in relation to feature binding and event codes. PMID- 22437963 TI - A novel Cre/loxP system for mosaic gene expression in the Drosophila embryo. AB - BACKGROUND: Mosaic analysis is used to assess gene function and cell autonomy in a subset of cells in an organism, and has been extensively applied in Drosophila studies. However, it is difficult to generate mosaic cells in Drosophila embryonic tissues using existing methods. Therefore, we developed a new method for generating genetic mosaic embryos using a modified Cre/loxP system. In this report, we also characterized the capabilities and limitations of this novel method. RESULTS: We first constructed a novel cassette combining loxP with the Actin 5C enhancer and Gal4 cDNA, and generated a transgenic fly carrying this construct (Aloxg-Gal4). In Aloxg-Gal4, the activation of Gal4 expression is suppressed by the gypsy insulator. Once the gypsy insulator is removed, however, Gal4 is expressed when site-specific recombination between loxP sites is induced by Cre recombinase. This system allowed the mosaic expression of Gal4 in Drosophila embryonic tissues (epidermis, amnioserosa, tracheal system, malpighian tubules, foregut, hindgut, midgut, and neuron), leading to the Gal4-dependent activation of arbitrary genes under the control of the upstream activation sequence (UAS). CONCLUSIONS: This practical method can be used to generate mosaic cells in Drosophila embryonic tissues and can be applied to any gene without specialized equipment. PMID- 22437964 TI - Motor signs in the prodromal phase of Parkinson's disease. AB - Relatively subtle deterioration of the motor system likely occurs well before the patient meets established motor criteria for a clinical diagnosis of Parkinson's disease; ie, the occurrence of at least 2 of the cardinal motor deficits: bradykinesia, rigidity, tremor, and/or postural instability. Powerful compensatory mechanisms may mask these clinical symptoms and make them difficult to identify and evaluate in the earliest stages of the illness. This review summarizes our current knowledge of motor signs that are thought to occur in the prodromal phase of Parkinson's disease and suggests how motor assessment batteries could be designed to detect these subclinical motor deficits with a high degree of accuracy and sensitivity. PMID- 22437965 TI - Core-modified hexaphyrin: synthesis and characterization of 31,34 disilahexaphyrinoid. AB - Condensation of 16-silatripyrrane with pentafluorobenzaldehyde under catalytic conditions followed by DDQ oxidation leads to 31,34-disilahexaphyrinoid--a four times reduced derivative of 31,34-disilahexaphyrin which contains two built-in silole units flanked by four tetrahedrally hybridized meso carbons. In the preferred folded macrocyclic conformation the silole rings remain perpendicular to each other. The steric hindrance of bulky substituents at silicon atoms and beta-positions of siloles prevented aromatization. Only one meso diastereomer (5S, 15S, 20R, 30R) has been isolated and subsequently identified by 1D and 2D NMR techniques. The density functional theory (DFT) has been applied to model the molecular structure of 31,34-disilahexaphyrinoid consistent with constraints imposed by NOE experiments. The total energies calculated at the B3LYP/6 31G**//B3LYP/6-31G** level for four feasible meso diastereomers clearly demonstrated the energetic preference for the meso diastereomer (5S, 15S, 20R, 30R). PMID- 22437966 TI - Molecular characterization of Wilms' tumor from a resource-constrained region of sub-Saharan Africa. AB - Sub-Saharan African children have an increased incidence of Wilms' tumor (WT) and experience alarmingly poor outcomes. Although these outcomes are largely due to inadequate therapy, we hypothesized that WT from this region exhibits features of biological aggressiveness that may warrant broader implementation of high-risk therapeutic protocols. We evaluated 15 Kenyan WT (KWT) for features of aggressive disease (blastemal predominance and Ki67/cellular proliferation) and treatment resistance (anaplasia and p53 immunopositivity). To explore the additional biological features of KWT, we determined the mutational status of the CTNNB1/beta-catenin and WT1 genes and performed immunostaining for markers of Wnt pathway activation (beta-catenin) and nephronic progenitor cell self-renewal (WT1, CITED1 and SIX2). We characterized the proteome of KWT using imaging mass spectrometry (IMS). The results were compared to histology- and age-matched North American WT (NAWT) controls. For patients with KWT, blastemal predominance was noted in 53.3% and anaplasia in 13%. We detected increased loss to follow-up (p = 0.028), disease relapse (p = 0.044), mortality (p = 0.001) and nuclear unrest (p = 0.001) in patients with KWT compared to controls. KWT and NAWT showed similar Ki67/cellular proliferation. We detected an increased proportion of epithelial nuclear beta-catenin in KWT (p = 0.013). All 15 KWT specimens were found to harbor wild-type CTNNB1/beta-catenin, and one contained a WT1 nonsense mutation. WT1 was detected by immunostaining in 100% of KWT, CITED1 in 80% and SIX2 in 80%. IMS revealed a molecular signature unique to KWT that was distinct from NAWT. The African WT specimens appear to express markers of adverse clinical behavior and treatment resistance and may require alternative therapies or implementation of high-risk treatment protocols. PMID- 22437967 TI - Low fluence-high repetition rate diode laser hair removal 12-month evaluation: reducing pain and risks while keeping clinical efficacy. AB - BACKGROUND AND OBJECTIVE: High fluence diode lasers with contact cooling have emerged as the mainstay modality for hair removal. However, the use of these devices is associated with pain and side effects, especially in patients with dark or tanned skin. A novel concept of depilation at low fluence using 810 nm diode laser has been introduced as a solution to these shortcomings. The purpose of this study was to evaluate the lasting efficacy and safety of low-level fluence 810 nm (15 J/cm(2) ) and high repetition rate (5 Hz) F1 Diode LaserTM therapy on hair reduction in patients with various skin types. STUDY DESIGN/MATERIALS AND METHODS: This randomised, controlled, bilaterally paired within-patient, double-blind study compared low level fluence 810 nm (15 Joules/cm(2) ) laser diode therapy to nontreated shaved control areas on long term hair reduction. Seventeen patients with skin type II-V were treated four times at 1 month intervals. Hair count was assessed monthly over 10 months using an objective computerised method. Safety and tolerability were assessed by adverse reactions monitoring. RESULTS: Statistically significant differences in hair count between treated and control sites were observed at each follow-up visit. The majority of patients reported a slight but bearable sensation of heat during the laser treatment, and transient erythema post-treatment. CONCLUSIONS: This study showed that laser hair removal with the F1 Diode LaserTM system was generally well tolerated, safe, and efficacious in this small sample study of patients with various skin types. After just four treatments, permanent hair reduction following one complete hair cycle has been shown. Controlled studies on larger groups of patients within each skin phototype are needed to confirm these promising results. PMID- 22437968 TI - Biological decolorization of xanthene dyes by anaerobic granular biomass. AB - Biodegradation of a xanthene dyes was investigated for the first time using anaerobic granular sludge. On a first screening, biomass was able to decolorize, at different extents, six azo dye solutions: acid orange 7, direct black 19, direct blue 71, mordant yellow 10, reactive red 2 and reactive red 120 and two xanthene dyes--Erythrosine B and Eosin Y. Biomass concentration, type of electron donor, induction of biomass with dye and mediation with activated carbon (AC) were variables studied for Erythrosine B (Ery) as model dye. Maximum color removal efficiency was achieved with 4.71 g VSS L-1, while the process rates were independent of the biomass concentration above 1.89 g VSS L-1. No considerable effects were observed when different substrates were used as electron donors (VFA, glucose or lactose). Addition of Ery in the incubation period of biomass led to a fivefold increase of the decolorization rate. The rate of Ery decolorization almost duplicated in the presence of commercial AC (0.1 g L-1 AC0). Using different modified AC samples (from the treatment of AC0), a threefold higher rate was obtained with the most basic one, AC(H2), as compared with non-mediated reaction. Higher rates were obtained at pH 6.0. Chemical reduction using Na2S confirmed the recalcitrant nature of this dye. The results attest that decolorization of Ery is essentially due to enzymatic and adsorption phenomena. PMID- 22437969 TI - Effect of hypercapnia on spleen-related haemoglobin increase during apnea. AB - BACKGROUND: Splenic contraction associated with apnea causes increased haemoglobin concentration and haematocrit (Hct), an effect that may promote prolonged breath-holding. Hypoxia has been shown to augment this effect, but hypercapnic influences have not been investigated previously. METHODS: Eight non divers performed three series of apneas on separate days after inspiration of oxygen with different carbon dioxide (CO2) levels. Each series consisted of three apneas 2 minutes apart: one with pre-breathing of 5% CO2 in oxygen (O2, 'Hypercapnia'); one with pre-breathing of 100% O2 ('Normocapnia'); and one with hyperventilation of 100% O2 ('Hypocapnia'). The apnea durations were repeated identically in all trials, determined from the maximum duration attained in the CO2 trial. A fourth trial, breathing 5% CO2 in O2 for the same duration as these apneas was also performed ('Eupneic hypercapnia'). In three subjects, spleen size was measured using ultrasonic imaging. RESULTS: Haemoglobin increased by 4% after apneas in the 'Hypercapnia' trial (P = 0.002) and by 3% in the 'Normocapnia' trial (P = 0.011), while the 'Hypocapnia' and 'Eupneic hypercapnia' trials showed no changes. The 'easy' phase of apnea, i.e., the period without involuntary breathing movements, was longest in the 'Hypocapnia' trial and shortest in the 'Hypercapnia' trial. A decrease in spleen size was evident in the hypercapnic trial, whereas in the hypocapnia trial spleen size increased, while only minor changes occurred in the other trials. No differences were observed between trials in the cardiovascular diving response. CONCLUSION: There appears to be a dose response effect of CO2 on triggering splenic contraction during apnea in the absence of hypoxia. PMID- 22437970 TI - The effect of intravenous perfluorocarbon emulsions on whole-body oxygenation after severe decompression sickness. AB - INTRODUCTION: Decompression sickness (DCS) results from a decrease in ambient pressure leading to supersaturation of tissues with inert gas and bubble formation. Perfluorocarbons (PFCs) are able to dissolve vast amounts of non-polar gases. Intravenous (IV) PFC emulsions reduce both morbidity and mortality associated with DCS, but the mechanism of this protective effect has not yet been demonstrated. METHODS: Juvenile Dorper-cross sheep (n = 31) were anaesthetised and instrumented for physiological monitoring, IV fluid administration and blood sampling. Animals were compressed in air in a hyperbaric chamber to 608 kPa for 30 minutes and then rapidly decompressed. Upon decompression, animals were randomly assigned to receive 6 mmol per L of PFC or saline over 10 minutes beginning immediately after chamber exit. Arterial and mixed venous bloods were drawn at 5, 10, 15, 30, 60 and 90 minutes to examine pH, partial pressures of oxygen and carbon dioxide, oxygen saturation and electrolytes. RESULTS: Compared to saline, PFC administration increased arterial oxygen content (16.33 +/- 0.28 vs. 14.68 +/- 0.26 ml per dL, P < 0.0001), mixed venous oxygen content (12.56 +/- 0.28 vs. 11.62 +/- 0.26 ml per dL, P = 0.0167), oxygen delivery (14.83 +/- 0.28 vs. 13.39 +/- 0.26 mmol per L kg, P = 0.0003) and tissue oxygen consumption (3.30 +/- 0.15 vs. 2.78 +/- 0.13 mmol per L kg, P = 0.0149) but did not increase extraction ratio (0.22 +/- 0.012 vs. 0.21 +/- 0.011, P = 0.5343). CONCLUSIONS: It is likely that the improved oxygenation explains, at least in part, the previously-observed therapeutic effects of PFCs in DCS. PMID- 22437971 TI - Diver Health Survey score and probability of decompression sickness among occupational dive guides and instructors. AB - INTRODUCTION: This study attempted to correlate self-reported post-dive Diver Health Survey (DHS) scores with computed daily probability of decompression sickness (pDCS) values as a measure of decompression stress in occupational divers in the recreational diving industry. METHODS: Divers completed the DHS form and their dive profiles were recorded electronically. The pDCS for each dive was calculated using the LE1 probabilistic model. Data were analysed using a mixed effects model. RESULTS: DHS was not significantly associated with pDCS. Mean DHS on non-diving days was 1.6 and increased by 0.8 for each dive made during any day. Mean number of daily dives was 1.9 and mean DHS on diving days was 3.1. CONCLUSION: Utility of the DHS for monitoring daily decompression stress among occupational divers working in the recreational diving industry in New Zealand remains unproven. PMID- 22437972 TI - Postal survey of fitness-to-dive opinions of diving doctors and general practitioners. AB - AIM: To determine the consensus and concordance with published standards and expert opinion among New Zealand's designated diving doctors (DDDs) and general practitioners (GPs) regarding medical fitness-to-dive. METHODS: A postal survey canvassed doctors' opinions regarding fitness-to-dive of 20 'real-life' applicants with potentially relevant medical conditions. In 17 cases, a 'desired response' was identified as expert opinion and the relevant published Standard concurred; the remaining three cases were excluded from analysis. Consensus was measured between the groups of doctors, and concordance measured against the 'desired response'. The performance of the DDDs was also correlated with both the number of diver medical assessments conducted annually and time since completing a diving medicine course. RESULTS: Seventy-seven of 98 DDDs (79%) and 75 of 200 GPs (38%) responded to the questionnaire. The mean concordance was 60% and 50% for DDDs and GPs respectively. Consensus between DDDs and GPs was generally high, but was low between these groups and the 'desired response'. DDD's concordance was negatively correlated (r = -0.3) with time since undertaking a diving medicine course, but was positively correlated (r = 0.2) with their annual number of dive medical assessments. Both groups were more likely to differ from the 'desired response' by considering an 'unfit' diver as 'fit' than the converse. CONCLUSIONS: There is poor concordance between doctors assessing fitness to dive and both published recommendations and expert opinion when there is a relevant medical condition. This supports the current New Zealand practice of centralised audit of occupational diver medical fitness prior to certification. PMID- 22437973 TI - Rapid ascent and buoyancy problems among Western Australian certified recreational divers. AB - INTRODUCTION: We investigated risk factors associated with ascending rapidly and/or losing buoyancy control among recreational divers. METHODS: Dive and diver information were collected and depth/time loggers attached to recreational divers. Case dives recording an ascent > 18 m per min were compared with control dives made at the same dive site and time by divers recording ascents <= 18 m per min. In a second analysis, case dives with reported buoyancy problems were compared with control dives during which no problems were reported. Conditional logistic regression identified factors significantly associated with ascending faster than 18 m per min or reporting a buoyancy problem. RESULTS: In total, 1,032 dive profiles were collected. Case dives (n = 71) recording an ascent > 18 m per min were compared with 282 control dives. The main risk factor for making a rapid ascent was a loss of buoyancy control. Case dives were also shorter. Dives resulting in reported buoyancy problems (n = 68 cases) were compared with 320 control dives. The three main risk factors for buoyancy problems were an inability to describe how to check for neutral buoyancy, reportedly not being in control during the final ascent and maximum ascent rates that were a mean of 20% faster than during control dives. CONCLUSIONS: Further research is necessary to identify if ascending rapidly is the result of a loss of buoyancy control, a lack of ascent rate reference or a failure to appreciate the potential consequences of ascending rapidly. The inability of many divers to describe how to check for neutral buoyancy also deserves attention. PMID- 22437974 TI - Ultrasound in diving and hyperbaric medicine. AB - Ultrasound is a safe and effective imaging modality, the use of which is increasing exponentially in many areas of clinical medicine. In this article, we present what is, to our knowledge, the first in-chamber use of an ultrasound machine. We discuss the challenges this presented, how they were addressed and explore the possible clinical applications that in-chamber ultrasound may deliver in hyperbaric medicine. PMID- 22437975 TI - Scuba divers' pulmonary oedema: recurrences and fatalities. AB - Scuba divers' pulmonary oedema (SDPE) is an increasingly recognised disorder in divers. We report three fatal cases of SDPE, demonstrating its potential serious nature even in the absence of underlying cardiac disease demonstrable clinically or at autopsy. This, together with the frequency of recurrences, has implications on assessing fitness for subsequent diving, snorkelling and swimming. The differential diagnosis of this disorder is also considered, as is its possible inducement by salt water aspiration and its relationship to drowning. PMID- 22437977 TI - Endoscopic vein harvesting: just a promised land? PMID- 22437976 TI - Role of new anticoagulants for the prevention of venous thromboembolism after major orthopaedic surgery and in hospitalised acutely ill medical patients. AB - Anticoagulation therapy for the prevention of venous thromboembolic events is indicated in patients after major orthopaedic surgery and in hospitalised acutely ill medical patients, who have a high or moderate risk of venous thromboembolism (VTE), respectively. Clinical trials have clearly demonstrated that short-term anticoagulation reduces the risk of VTE in these patient groups and that longer term anticoagulation is beneficial for some indications. Evidence-based guidelines for thromboprophylaxis have been developed based on these studies. However, despite these guidelines, thromboprophylaxis is still underused, or used suboptimally, in many patients. This is, in part, because of the limitations of traditional anticoagulants such as unfractionated heparin, low- molecular-weight heparin, synthetic pentasaccharides, and vitamin K antagonists. Newer oral anticoagulants, such as rivaroxaban, apixaban, and dabigatran etexilate, have certain advantages over traditional agents. They can be administered orally at a fixed dose without routine coagulation monitoring and have minimal food and drug interactions. These characteristics may result in better adherence to guidelines and improved patient outcomes. This review provides an overview of phase III clinical trial data for these newer anticoagulants in major orthopaedic surgery and in hospitalised acutely ill medical patients, and discusses their potential for extended use in the post-hospital discharge setting. All three newer oral anticoagulants are approved in many countries for the prevention of VTE after hip replacement or knee replacement surgery in adult patients, and it is likely that these drugs will contribute considerably towards reducing the substantial healthcare burden associated with VTE. PMID- 22437978 TI - Increasing mitral valve repair rates with nonresectional techniques. AB - In every common mitral pathology studied to date, repairing the patient's own diseased valve to adequate function has yielded superior long-term results as compared with prosthetic valve replacement with either tissue or mechanical devices. Thus, increasing rates of mitral repair across all valve pathologies would seem to be a logical clinical goal. Techniques for mitral valve repair have undergone continual evolution over the past 50 years. Recently, emphasis has been placed on preserving leaflet surface area and avoiding tissue resection, by combining the methods of Gore-Tex artificial chordal replacement, autologous pericardial leaflet augmentation, and full ring annuloplasty. Using combinations of these three techniques appropriate to the given valve pathology, acute mitral repair rates now are approximating 98% for all common mitral disease etiologies. Simultaneously, operative mortalities for mitral repair have fallen significantly and now are negligible, whereas long-term outcomes using these methods have been increasingly more stable. As a result of innovations from multiple sources, mitral valve surgery has been converted from a higher risk procedure to one of the safest operations in most centers. This review will detail the technical application of "nonresectional" mitral repair approaches to a broad range of mitral disease pathologies. PMID- 22437979 TI - A novel biodegradable septal defect occluder: the "Chinese Lantern" design, proof of concept. AB - OBJECTIVE: Atrial septal defect (ASD) is a general term used to describe an opening in the atrial septum that divides the two atria; unless the hole is occluded, it can give rise to serious complications. Given the need for percutaneous deployment for ASD or patent foramen ovale (PFO) occluders, all currently available devices are made of metals (specifically nitinol) and synthetic fabric. However, their permanent presence in the human body is not desirable due to the risks of long-term allergy, toxicity, and complications such as thrombus formation, device arm fracture, and nickel allergy. Once the hole is covered by a newly regenerated tissue, the device is no longer needed; thus it is ideal if the device is fully absorbed by the body when healing is completed. METHODS: The "Chinese Lantern" device is made of fully biodegradable polymers featured with a unique pull-fold mechanism. The device was inserted across the ASD/PFO model created on Yorkshire swines through a short sheath by hybrid open surgery. X-ray imaging, echocardiography, and postmortem histopathology were obtained during the 1-month follow-up study period. RESULTS: X-ray imaging showed that the devices were in satisfactory position and stable. Echocardiography showed that there is no shunting from the right atrium to the left atrium, indicating excellent sealing. The in vitro degradation study and postmortem explantation study confirmed that the devices have good integrity during the 1 month trial. Furthermore, the devices appeared to be completely endothelialized after 1 month. CONCLUSIONS: This work proves the feasibility of interventional closure of ASD or PFO with an innovative biodegradable device, which we call the "Chinese Lantern" for its symbolic design. PMID- 22437980 TI - Image-guided transapical aortic valve implantation: sensorless tracking of stenotic valve landmarks in live fluoroscopic images. AB - OBJECTIVE: Aortic valve stenosis is one of the most frequently acquired valvular heart diseases, accounting for almost 70% of valvular cardiac surgery. Transapical transcatheter aortic valve implantation has recently become a suitable minimally invasive technique for high-risk and elderly patients with severe aortic stenosis. In this article, we aim to automatically define a target area of valve implantation, namely, the area between the coronary ostia and the lowest points of two aortic valve cusps. Therefore, we present a new image-based tracking method of these aortic landmarks to assist in the placement of aortic valve prosthesis under live 2D fluoroscopy guidance. METHODS: We propose a rigid intensity-based image registration technique for tracking valve landmarks in 2D fluoroscopic image sequences, based on a real-time alignment of a contrast image including the initialized manual valve landmarks to each image of sequence. The contrast image is automatically detected to visualize aortic valve features when the aortic root is filled with a contrast agent. RESULTS: Our registration-based tracking method has been retrospectively applied to 10 fluoroscopic image sequences from routine transapical aortic valve implantation procedures. Most of all tested fluoroscopic images showed a successful tracking of valve landmarks, especially for the images without contrast agent injections. CONCLUSIONS: A new intraoperative image-based method has been developed for tracking aortic valve landmarks in live 2D fluoroscopic images to assist transapical aortic valve implantations and to increase the overall safety of surgery as well. PMID- 22437981 TI - Early experience with robotic-assisted lung resection. AB - OBJECTIVE: Robotic-assisted surgery is not widely accepted for general thoracic surgical procedures, and the technical advantages, cost effectiveness, and patient benefit are in question. Few reports have been published to date regarding clinical experience with this technology. We describe our first consecutive case experience with robotic-assisted lung resection. METHODS: A total of 23 robotic-assisted lung resections were performed from December 1, 2008, to September 30, 2010. Patients were selected on the basis of being candidates for a minimally invasive approach to their lung resection, including criteria such as known or suspected early-stage nonsmall-cell lung cancer, no prior thoracotomy, no neoadjuvant therapy, and a body mass index (BMI) less than 40 kg/cm2. Data on patient characteristics and perioperative results were collected retrospectively. RESULTS: Overall 90-day mortality was 0%. The total postoperative complication rate was 39%. Conversion of the robotic-assisted procedure to a video-assisted procedure was necessary in four patients (17%), and to a thoracotomy in one patient (4%). We assessed operative time, chest tube duration, and length of hospital stay. Comparison to published outcomes from the Society of Thoracic Surgeons database demonstrated comparable outcomes to standard approaches. CONCLUSIONS: Robotic-assisted lung resection is safe and feasible, with comparable short-term outcomes to published results from video assisted or open approaches. PMID- 22437982 TI - Simultaneous catheter and epicardial ablations enable a comprehensive atrial fibrillation procedure. AB - OBJECTIVE: Transmural and contiguous ablations and a comprehensive lesion pattern are difficult to create from the surface of a beating heart but are critical to the successful treatment of persistent, isolated atrial fibrillation. A codisciplinary simultaneous epicardial (surgical) and endocardial (catheter) procedure (Convergent procedure) addresses these issues. METHODS: Patients with symptomatic atrial fibrillation who failed medical treatment were evaluated. Using only pericardioscopy, the surgeon performed near-complete epicardial isolation of the pulmonary veins and a "box" lesion on the posterior left atrium using unipolar radiofrequency ablation. Simultaneous endocardial catheter radiofrequency ablation completed pulmonary vein isolation, performed a mitral annular and cavotricuspid isthmus line of block, and debulked the coronary sinus. Twelve-month results for the Convergent procedure were compared with 12-month results for concomitant and pericardioscopic (stand-alone transdiaphragmatic/thoracoscopic) atrial fibrillation procedures using unipolar radiofrequency ablation. RESULTS: Sixty-five patients underwent the Convergent procedure (mean age, 62 y; mean body surface area, 2.17 m2; mean atrial fibrillation duration, 4.8 y; mean left atrial size, 5.2 cm). Ninety-two percent were in persistent or long-standing persistent atrial fibrillation. At 12 months, evaluation with 24-hour Holter monitors found 82% of patients in sinus rhythm, while only 47% of pericardioscopic and 77% of concomitant patients treated with unipolar radiofrequency ablation were in sinus rhythm. CONCLUSIONS: Simultaneous epicardial and endocardial ablation improves outcomes for patients with persistent or longstanding persistent atrial fibrillation. This successful collaboration between cardiac surgeon and electrophysiologist is an important treatment option for patients with large left atriums and chronic atrial fibrillation. PMID- 22437983 TI - An audit of pain control pathways following video-assisted thoracoscopic surgery. AB - OBJECTIVE: To compare different modes of pain management following video-assisted thoracoscopic surgery (VATS) to our national standard. METHODS: This is an audit based on patient's experiences. One hundred consecutive patients who underwent VATS with or without pleurodesis were managed by one of the following pain relief pathways: (A) thoracic paravertebral block + morphine patient-controlled analgesia (PCA), (B) percutaneous thoracic paravertebral catheter +/- morphine PCA, (C) thoracic epidural +/- morphine PCA, (D) morphine PCA alone, and (E) intravenous or subcutaneous morphine as required. Pain score was documented up to four times per day for each patient. The incidence of severe pain was defined as visual analog scale >= 7. The results were compared with the standard set by the audit commission for postoperative pain relief in the UK. The mean daily pain scores were calculated retrospectively for all patients. RESULTS: There were no statistically significant differences in mean daily pain scores irrespective of having a pleurodesis. The percentage of patients experiencing severe pain was 34% [mean visual analog scale = 8 (standard deviation = 1.0)]. This was almost seven times the standard. Among these pathways, B had the least percentage incidence of severe pain (16.7%) followed by A (25.0%) D (33.3%), C (35.7%), and E (52.4%). CONCLUSIONS: We are not compliant with the standards set by the audit commission. Pain management in theater recovery needs to be targeted. In the light of these results, we recommend the use of percutaneous thoracic paravertebral catheter +/- morphine PCA for postoperative VATS pain relief. PMID- 22437984 TI - Edwards EndoVent as a pacing catheter for minimally invasive aortic valve surgery: a novel approach. AB - OBJECTIVE: The placement of epicardial pacing wires before weaning from bypass during port-access heart surgery can be difficult or impossible. Sometimes, it is necessary to pacing the patient to wean from bypass, and it is problematic to exchange the Edwards pulmonary vent (EndoVent) for a pace catheter under the drapes. Our objective was to devise an effective means of pacing the patient using the pulmonary vent catheter. METHODS: All patients having aortic valve minimally invasive port-access surgery have a pacing wire deployed through the Edwards EndoVent catheter. We did a retrospective chart analysis of these cases. RESULTS: After reviewing the anesthesia records, we determined that we were able to reliably convert the pulmonary vent catheter, which is beneficial for the surgery, into a pacing catheter before weaning from bypass 100% of the time. The mean pacing threshold current was 1.60 mA with the wire in the right ventricular apex. CONCLUSIONS: We found that in all 25 patients we were able to rapidly convert the vent catheter into a reliable pacing catheter without any complications. PMID- 22437985 TI - Handheld office-based spirometry versus laboratory spirometry in low-risk patients undergoing lung resection. AB - OBJECTIVE: To compare handheld office spirometry with laboratory spirometry in evaluation of low-risk patients undergoing pulmonary resection. METHODS: Low-risk patients evaluated for lung resection were enrolled in a prospective study and underwent office and laboratory spirometry. Standard laboratory spirometry values were considered the gold standard. Values of forced expiratory volume in 1 second (FEV1) <1.5 L or FEV1% <60% were determined in advance to signal high risk. RESULTS: Thirty patients with mean age 64 +/- 12 years and median Karnofsky performance status 100 (80-100) were evaluated. The mean FEV1-office spirometry and mean FEV1-laboratory spirometry were comparable (2.14 L vs 2.36 L) as were the mean FEV1%-office spirometry and FEV1%-laboratory spirometry (78% vs 85%). The differences were within limits established a priori. Laboratory spirometry identified 3 of 30 (10%) patients as high risk and office spirometry identified 5 of 30 (16%) patients as high risk, including the 3 patients identified by laboratory spirometry. The sensitivity of office spirometry for detecting high risk was 100% (3/3) and specificity was 93% (25/27). The negative predictive value of office spirometry was 100% (25/25). Office spirometry added a median of 1 minute to the office visit, whereas laboratory spirometry added 42 minutes. Eventually, 25 of 30 (83%) patients underwent lung resection. There were 12 lobar and 13 sublobar resections. One patient developed postoperative respiratory morbidity. This patient was high risk by office spirometry but not by laboratory spirometry. This patient was discharged on home oxygen. CONCLUSIONS: Office spirometry FEV1 and FEV1% are clinically comparable to formal laboratory spirometry values. Office Spirometry saves time and possibly expense in the preoperative workup of patients evaluated for lung resection. PMID- 22437986 TI - Mediastinal parathyroidectomy with the da Vinci robot. AB - Mediastinal parathyroid glands are often located in a position which is inaccessible through a cervical approach. Because of the significant morbidity of open surgery, the need for minimal invasive approaches is high. More recently, robotic systems have been introduced to refine the dissection and optimize the view in the mediastinal region. We present two cases. The first case is a 34-year old woman who was diagnosed with primary hyperparathyroidism. Because a bilateral neck dissection disclosed no parathyroid adenoma, we performed a parathyroid sestamibi scan and computed tomographic scan of neck and mediastinum to look for aberrant parathyroid glands. Both showed a parathyroid adenoma in the mediastinum on the left side. The second case is a 66-year-old man. A sestamibi scan showed a parathyroid adenoma of 3 cm in the superior mediastinum which was confirmed by and computed tomographic scan. In both cases, we performed a parathyroidectomy with the da Vinci robotic system through a left-sided approach. Three thoracoports were inserted around the mammary gland for the robot and a fourth auxiliary port was positioned in between. Single-lung ventilation was installed, and the mediastinum was entered by opening the parietal pleura along the left phrenic nerve. The upper margin for dissection was the left brachiocephalic vein that was followed until the right pleura. All the tissue in front of the pericardium was dissected en bloc. The sinking test of the nodule and a preoperative frozen section analysis confirmed the diagnosis of parathyroid adenoma, which was also proven by rapid parathyroid hormone analysis. The resection of a parathyroid adenoma from the aortopulmonary window represents an ideal case for robotic surgery. PMID- 22437987 TI - Insertion of the Impella 5.0 left ventricular assist device via right anterior mini-thoracotomy: a novel practical approach. AB - The Impella 5.0 microaxial pump is a miniaturized left ventricular assist device commonly used for circulatory support in acute cardiogenic shock. The catheter based pump is designed to be inserted either into a peripheral artery or directly into the ascending aorta. We report the first case in which the Impella 5.0 device was placed directly into the ascending aorta via a small right anterior thoracotomy in a patient following acute myocardial infarction complicated by cardiogenic shock. PMID- 22437988 TI - Embolization with Onyx in iatrogenic bleeding of the gluteal region. AB - We report a unique method using transcatheter Onyx embolization in a bleeding due to morphine injection in the gluteal region. A 47-year-old man with a rare blood type presented a painful gluteal hematoma due to iatrogenic injury. A computed tomographic angiography verified bleeding from a suspected branch of the deep femoral artery. Because of the unbearable pain, the hematoma was evacuated by means of computed tomography (CT)-guided puncture and the insertion of a pigtail catheter combined with the injection of a human plasminogen activation agent (t PA). The initial result was positive. To stop the bleeding, angiographic embolization with Onyx was successfully used. Onyx can be used in small vessel bleedings and might offer the advantage of selective embolization in cases where the access to the bleeding vessel is challenging or time-consuming. PMID- 22437989 TI - Use of navigation bronchoscopy for biopsy and endobronchial fiducial placement. AB - Electromagnetic navigation bronchoscopy (ENB) is a technique that can be used to biopsy pulmonary lesions beyond areas that are traditionally accessible by bronchoscopy. It can also guide biopsies of peribronchial lymph nodes and guide the placement of fiducial markers for stereotactic radiosurgery. With ENB, the patient is placed in a magnetic field and their anatomy is merged with a 3D reconstructed chest cat scan (CCT). A locatable, steerable probe is used to guide a working channel to the target, usually a peripheral tumor. Biopsies can be taken, and markers can be placed. The accuracy of this system depends largely on a small bronchus leading toward to target. The diagnostic yield is similar to CT guided biopsies, with a false-negative rate of about 30%, although results may be improved with combined ENB and radial endoscopic ultrasound (EUS). The incidence of pneumothorax is 5% to 8% with ENB-directed biopsies compared with approximately 30% with CT-guided transthoracic biopsy. PMID- 22437990 TI - Tissue temperature feedback control of power: the key to successful ablation. AB - Multiple ablation technologies are used to treat atrial fibrillation during cardiac operations. All such ablation technologies use locally induced temperature extremes (>50 degrees C or <-20 degrees C) to kill tissue and create a lesion pattern in the atria which blocks activation pathways that initiate and sustain atrial fibrillation. The technologies used to heat tissue have included radiofrequency (RF), microwave, high-intensity focused ultrasound, and infrared laser. RF accounts for more than 95% of the heating-based ablation technology used by cardiac surgeons. Energy delivery with RF is easier to control than with some other technologies, the heating produced by the energy source is well understood, and manufacturing costs are not excessive. Whichever heating technology is used, control of energy delivery is required to ensure both safe and effective heating of the targeted tissue. All targeted tissue needs to be heated above 50 degrees C to achieve cell death. However, the targeted tissue should not be heated above 100 degrees C, as this can cause perforation due to a steam pop. In addition, adjacent noncardiac tissues must not be damaged during the ablation procedure. The best method to achieve this control uses direct measurement of tissue temperature, because the tissue temperature defines both the safe and effective limits for the ablative process. PMID- 22437991 TI - Accelerating the multifunctionalization of therapeutic nanoparticles by using a multicomponent reaction. AB - Simpler and faster! Multifunctionalized nanoparticles are crucial for nanobiomedical applications, but their syntheses are tedious and time-consuming. A multicomponent reaction on nanostructures is an excellent way to prepare such nanomaterials. The gold nanosystem illustrated in the scheme was built and shown to enhance cancer cell targeting and killing by combining the effects of a therapeutic drug with X-ray radiation. PMID- 22437992 TI - The connection-set algebra--a novel formalism for the representation of connectivity structure in neuronal network models. AB - The connection-set algebra (CSA) is a novel and general formalism for the description of connectivity in neuronal network models, from small-scale to large scale structure. The algebra provides operators to form more complex sets of connections from simpler ones and also provides parameterization of such sets. CSA is expressive enough to describe a wide range of connection patterns, including multiple types of random and/or geometrically dependent connectivity, and can serve as a concise notation for network structure in scientific writing. CSA implementations allow for scalable and efficient representation of connectivity in parallel neuronal network simulators and could even allow for avoiding explicit representation of connections in computer memory. The expressiveness of CSA makes prototyping of network structure easy. A C+ + version of the algebra has been implemented and used in a large-scale neuronal network simulation (Djurfeldt et al., IBM J Res Dev 52(1/2):31-42, 2008b) and an implementation in Python has been publicly released. PMID- 22437993 TI - Sulfolobus tokodaii RadA paralog, stRadC2, is involved in DNA recombination via interaction with RadA and Hjc. AB - Rad51/RadA paralogs found in eukaryotes and euryarchaea play important roles during recombination and repair, and mutations in one of the human Rad51 paralogs, Rad51C, are associated with breast and ovarian cancers. The hyperthermophilic crenarchaeon Sulfolobus tokodaii encodes four putative RadA paralogs and studies on these proteins may assist in understanding the functions of human Rad51 paralogs. Here, we report the biochemical characterization of stRadC2, a S. tokodaii RadA paralog. Pull-down assays revealed that the protein was able to interact with the recombinase, RadA, and the Holliday junction endonuclease, Hjc. stRadC2 inhibited the strand exchange activity of RadA and facilitated Hjc-mediated Holliday junction DNA cleavage in vitro. RT-PCR analysis revealed that stRadC2 transcription was immediately reduced after UV irradiation, but was restored to normal levels at the late stages of DNA repair. Our results suggest that stRadC2 may act as an anti-recombination factor in DNA recombinational repair in S. tokodaii. PMID- 22437994 TI - Dynamic change of Numbl expression after sciatic nerve crush and its role in Schwann cell differentiation. AB - Numbl, as a conserved homolog of Drosophila Numb, has been implicated in early development of the nervous system, but its expression and roles in nervous system lesion and repair remained unknown. Here, we performed an acute sciatic nerve injury model in adult rats and studied the dynamic changes of Numbl expression in the sciatic nerve. Temporally, Numbl expression was sharply decreased after sciatic nerve crush and reached a valley at day 7. Spatially, Numbl was widely expressed in the normal sciatic nerve, including axons and Schwann cells, whereas, after injury, Numbl expression was decreased predominantly in Schwann cells. In vitro, we induced Schwann cell differentiation with cAMP and found that Numbl expression was decreased in the differentiated process. Depletion of Numbl could promote Schwann cell differentiation. In addition, we demonstrated that in vitro myelination was suppressed by overexpression of Numbl in Schwann cells. Collectively, we hypothesized peripheral nerve injury induced a downregulation of Numbl in the sciatic nerve, which was associated with Schwann cell differentiation. PMID- 22437995 TI - Sensitive immunoassay detection of multiple environmental chemicals on protein microarrays using DNA/dye conjugate as a fluorescent label. AB - Indirect competitive immunoassays were developed on protein microarrays for the sensitive and simultaneous detection of multiple environmental chemicals in one sample. In this assay, a DNA/SYTOX Orange conjugate was employed as an antibody label to increase the fluorescence signal and sensitivity of the immunoassays. Epoxy-modified glass slides were selected as the substrate for the production of 4 * 4 coating antigen microarrays. With this signal-enhancing system, competition curves for 17beta-estradiol (E2), benzo[a]pyrene (BaP) and 2,2',4,4' tetrabromodiphenyl ether (BDE-47) were obtained individually on the protein microarray. The IC(50) and calculated limit of detection (LOD) are 0.32 MUg L(-1) and 0.022 MUg L(-1) for E2, 37.2 MUg L(-1) and 24.5 MUg L(-1) for BaP, and 31.6 MUg L(-1) and 2.8 MUg L(-1) for BDE-47, respectively. LOD of E2 is 14-fold lower than the value reported in a previous study using Cy3 labeled antibody (Du et al., Clin. Chem, 2005, 51, 368-375). The results of the microarray immunoassay were within 15% of chromatographic analysis for all three pollutants in spiked river water samples, thus verifying the immunoassay. Simultaneous detection of E2, BaP and BDE-47 in one sample was demonstrated. There was no cross-reaction in the immunoassay between these three environmental chemicals. These results suggest that microarray-based immunoassays with DNA/dye conjugate labels are useful tools for the rapid, sensitive, and high throughput screening of multiple environmental contaminants. PMID- 22437996 TI - Randomized clinical trial of rotating-platform and fixed-bearing total knee arthroplasty: no clinically detectable differences at five years. AB - BACKGROUND: For some surgeons, rotating-platform total knee designs are an intellectually appealing option to use for total knee arthroplasty because of the contention that they can self-align and accommodate small mismatches in the rotational position of the tibial and femoral components. We carried out a randomized clinical trial to determine if a posterior-stabilized, rotating platform knee design provided better maximum knee flexion, better function, or better durability at five years of follow-up when compared with a fixed-bearing design. METHODS: This randomized clinical trial of 240 primary total knee arthroplasties involved a single type of distal femoral implant (posterior stabilized) and three different types of tibial implant (all-polyethylene fixed bearing, modular-metal-backed fixed-bearing, and rotating-platform). The three tibial implant groups were balanced dynamically with a computerized randomization process that accounted for patient age, sex, and body mass index; surgeon; and implant type. Patients returned for examination and radiographs at three months, one year, two years, and five years postoperatively. RESULTS: Knee range of motion was not significantly different among the all-polyethylene, modular-metal backed, and rotating-platform tibial component groups at two years (mean, 111 degrees , 111 degrees , and 110 degrees , respectively) or five years (mean, 110 degrees , 109 degrees , and 109 degrees , respectively). Function, as measured with Knee Society scores, was not significantly different among the all polyethylene, modular-metal-backed, and rotating-platform groups at two years (mean, 90, 91, and 91 points, respectively) or five years (mean, 88, 89, and 88 points, respectively). Stair-climbing scores were not significantly different among the three groups at two years (mean, 39, 40, and 39 points, respectively) or five years (mean, 37, 40, and 36 points, respectively). There were four revisions: one in the all-polyethylene group (patellar fracture), two in the modular-metal-backed group (aseptic loosening), and one in the rotating-platform group (deep infection). CONCLUSIONS: In this randomized clinical trial, the rotating-platform total knee design was reliable and durable but did not provide better maximum knee flexion, better function, or better durability at five years postoperatively when compared with a posterior-stabilized, fixed-bearing design incorporating either an all-polyethylene or a modular-metal-backed tibial component. PMID- 22437997 TI - Efficacy of surgical preparation solutions in lumbar spine surgery. AB - BACKGROUND: Postoperative spinal wound infections are relatively common and are often associated with increased morbidity and poor long-term patient outcomes. The purposes of this study were to identify the common bacterial flora on the skin overlying the lumbar spine and evaluate the efficacy of readily available skin-preparation solutions in the elimination of bacterial pathogens from the surgical site following skin preparation. METHODS: A prospective randomized study was undertaken to evaluate 100 consecutive patients undergoing elective lumbar spine surgery. At the time of surgery, the patients were randomized to be treated with one of two widely used, and Food and Drug Administration (FDA)-approved, surgical skin-preparation solutions: ChloraPrep (2% chlorhexidine gluconate and 70% isopropyl alcohol) or DuraPrep (0.7% available iodine and 74% isopropyl alcohol). Specimens for aerobic and anaerobic cultures were obtained prior to skin preparation (pre-preparation), after skin preparation (post-preparation), and after wound closure (post-closure). A validated neutralization solution was used for each culture to ensure that the antimicrobial activity was stopped immediately after the sample was taken. Positive cultures and specific bacterial pathogens were recorded. RESULTS: Coagulase-negative Staphylococcus, Propionibacterium acnes, and Corynebacterium were the most commonly isolated organisms prior to skin preparation. The overall rate of positive cultures prior to skin preparation was 82%. The overall rate of positive cultures after skin preparation was 0% (zero of fifty) in the ChloraPrep group and 6% (three of fifty) in the DuraPrep group (p = 0.24, 95% confidence interval [CI] = 0.006 to 0.085). There was an increase in positive cultures after wound closure, but there was no difference between the ChloraPrep group (34%, seventeen of fifty) and the DuraPrep group (32%, sixteen of fifty) (p = 0.22, 95% CI = 0.284 to 0.483). Body mass index (BMI), duration of surgery, and estimated blood loss did not a show significant association with post-closure positive culture results. CONCLUSIONS: ChloraPrep and DuraPrep are equally effective skin-preparation solutions for eradication of common bacterial pathogens on the skin overlying the lumbar spine. PMID- 22437998 TI - The incidence of thromboembolic events in surgically treated ankle fracture. AB - BACKGROUND: Thromboembolic events occur following musculoskeletal injury, and some have serious sequelae, including death. The purpose of this study was to determine the incidence of thromboembolic events and its relationship with risk factors in ambulatory patients with ankle fracture requiring open reduction and internal fixation. METHODS: We conducted a retrospective chart review of 2478 patients who underwent open reduction and internal fixation of an ankle fracture at any one of three university hospitals between January 1, 1997, and April 30, 2005. One thousand five hundred and forty patients meeting the inclusion criteria and with complete records (minimum follow-up, six months) were identified. The median age of the patients at the time of surgery was forty-six years, and there was an equal proportion of male and female patients. Fracture types included 45% unimalleolar fractures, 31% bimalleolar, and 24% trimalleolar. Charts were reviewed to identify thromboembolic events, risk factors (neoplasia, hormone use, pregnancy, blood dyscrasia, history of a previous thromboembolic event, a current history of smoking, obesity, dyslipidemia, atherosclerotic vascular disease, or paralysis), and use of thromboprophylactic agents. A thromboembolic event was defined as symptomatic when deep venous thrombosis was confirmed with use of Doppler ultrasonography or when pulmonary embolism was confirmed with use of ventilation and perfusion scintigraphy or helical computed tomography. RESULTS: The incidence of thromboembolic events was 2.99% (forty-six patients), with 2.66% (forty-one patients) involving a deep venous thrombosis and 0.32% (five patients) involving a nonfatal pulmonary embolism. There were no fatal pulmonary emboli recorded. The incidence did not differ among hospitals. Of the 1540 patients, 16.43% received thromboprophylaxis during their hospital stay and for six weeks (for the 10.78% taking low-molecular-weight heparin) or three months (for the 5.65% taking warfarin) after discharge without significantly modifying the incidence of thromboembolic events (2.56% vs. 2.37%, relative risk = 0.91). However patients with one or more risk factors had a greater risk of a thromboembolic event than did patients with no risk factors (3.59% vs. 2.38%, respectively; relative risk = 0.66). The use of thromboprophylaxis had no apparent impact on the occurrence of thromboembolic events in patients who did or did not have risk factors (3.68% vs. 3.55%, respectively; relative risk = 0.96). No significant correlation could be identified between the occurrence of thromboembolic events and fracture types, age, or sex. CONCLUSIONS: Clinically detectable thromboembolic events after surgical treatment of ankle fractures are uncommon and do not appear to be influenced by the use of thromboprophylaxis. Patients with risk factors appear to be at higher risk for these events, but there is a need for prospective studies to determine the efficacy of thromboprophylaxis after surgical treatment of ankle fractures. PMID- 22437999 TI - Comparative effect of orthosis design on functional performance. AB - BACKGROUND: High-energy extremity trauma is common in combat. Orthotic options for patients whose lower extremities have been salvaged are limited. A custom energy-storing ankle-foot orthosis, the Intrepid Dynamic Exoskeletal Orthosis (IDEO), was created and used with high-intensity rehabilitation as part of the Return to Run clinical pathway. We hypothesized that the IDEO would improve functional performance compared with a non-custom carbon fiber orthosis (BlueRocker), a posterior leaf spring orthosis, and no brace. METHODS: Eighteen subjects with unilateral dorsiflexion and/or plantar flexion weakness were evaluated with six functional tests while they were wearing the IDEO, BlueRocker, posterior leaf spring, or no brace. The brace order was randomized, and five trials were completed for each of the functional measures, which included a four square step test, a sit-to-stand five times test, tests of self-selected walking velocity over level and rocky terrain, and a timed stair ascent. They also completed one trial of a forty-yard (37-m) dash, filled out a satisfaction questionnaire, and indicated whether they had ever considered an amputation and, if so, whether they still intended to proceed with it. RESULTS: Performance was significantly better with the IDEO with respect to all functional measures compared with all other bracing conditions (p < 0.004), with the exception of the sit-to-stand five times test, in which there was a significant improvement only as compared with the BlueRocker (p = 0.014). The forty-yard dash improved by approximately 35% over the values for the posterior leaf spring and no-brace conditions, and by 28% over the BlueRocker. The BlueRocker demonstrated a significant improvement in the forty-yard dash compared with no brace (p = 0.033), and a significant improvement in self-selected walking velocity on level terrain compared with no brace and the posterior leaf spring orthosis (p < 0.028). However, no significant difference was found among the posterior leaf spring, BlueRocker, and no-brace conditions with respect to any other functional measure. Thirteen patients initially considered amputation, but after completion of the clinical pathway, eight desired limb salvage, two were undecided, and three still desired amputation. CONCLUSIONS: Use of the IDEO significantly improves performance on validated tests of agility, power, and speed. The majority of subjects initially considering amputation favored limb salvage after this noninvasive intervention. PMID- 22438000 TI - Revision posterior cruciate ligament reconstruction using a modified tibial-inlay double-bundle technique. AB - BACKGROUND: Revision of an unsuccessful posterior cruciate ligament (PCL) reconstruction is a complicated clinical procedure with an outcome that may be less satisfactory than that after a typical primary PCL reconstruction. The purpose of this study was to evaluate the reasons for failure of primary PCL reconstructions and to determine the clinical outcomes of revision PCL reconstruction after a minimum of two years of follow-up. METHODS: Twenty-eight revision PCL reconstructions were performed by a single surgeon. Four cases that involved diverse operative procedures and two cases with a duration of follow-up of less than twenty-four months were excluded; the outcomes of the remaining twenty-two reconstructions were analyzed at the time of the latest follow-up (at least twenty-four months postoperatively). A technique involving a double femoral tunnel, a modified tibial inlay, and Achilles tendon allograft was used in all twenty-two of these revision reconstructions. Seventeen patients (77%) underwent concomitant reconstruction of posterolateral corner structures. Knee stability was measured with use of posterior stress radiography as well as with a maximum manual displacement test utilizing a KT1000 arthrometer. The subjective International Knee Documentation Committee (IKDC) and objective Orthopadische Arbeitsgruppe Knie (OAK) scoring systems were used to evaluate the clinical outcome. RESULTS: Nine (41%) of the primary PCL reconstructions most likely failed because of a single factor and thirteen (59%) most likely failed because of multiple factors. The most common probable causes of failure were posterolateral rotatory instability (seventeen knees, 77%) and improper graft tunnel placement (nine knees, 41%). Side-to-side differences during posterior stress radiography improved from 9.9 +/- 2.8 mm preoperatively to 2.8 +/- 1.8 mm at the time of the latest follow-up (p < 0.001). The subjective and objective clinical scores at the latest follow-up evaluation were significantly better than the preoperative scores (p < 0.001). CONCLUSIONS: Arthroscopic revision PCL reconstruction with use of the modified tibial-inlay double-bundle technique improved knee stability, as measured with posterior stress radiography and clinically, and outcomes. Associated posterolateral rotatory instability should be surgically corrected during PCL reconstruction to prevent graft failure resulting from abnormal opening of the lateral aspect of the tibiofemoral joint. PMID- 22438001 TI - Disability, impairment, and physical therapy utilization after arthroscopic partial meniscectomy in patients receiving workers' compensation. AB - BACKGROUND: The treatment of meniscal tears in injured workers is associated with less favorable outcomes and higher utilization of clinical services. It was hypothesized that patients receiving Workers' Compensation who undergo arthroscopic meniscectomy can have excellent outcomes with physical therapy utilization below the national best-practices benchmarks. METHODS: The records of 155 injured workers who had undergone 164 primary arthroscopic meniscectomies were reviewed at least one year following claim closure. The time to release to unrestricted full work duty and the number of postoperative physical therapy visits were compared between the study group (managed with a protocol-driven, independent exercise program) and the control group (managed with traditional outpatient physical therapy). The traditional therapy regimen was implemented by means of a written referral stating general goals (knee range of motion, strength, and function) and recommending a range or a maximum number of visits to be attended. Patients in the study group received a written referral specifying the exact number of visits that were approved, a kit containing exercise equipment with a booklet illustrating twenty-five exercises, and a prescribed rehabilitation protocol outlining the philosophy, expected subjective and functional outcomes, and specific objective weekly goals. RESULTS: The median number of physical therapy visits per patient was 40% lower in the study group than in the control group (six compared with ten; p < 0.001). There was no difference between the study group and the control group with regard to the permanent partial disability rate (0% compared with 4.3%; p = 0.076). Following arthroscopic meniscectomy, there was no significant difference between the study group and the control group in terms of the time to release to light duty, the time to release to full duty, the time to claim closure, or the rate of impairment. CONCLUSIONS: The implementation of a structured, independent exercise protocol appears promising as a method to reduce physical therapy utilization to levels below the national best-practices benchmarks without negatively impacting impairment and disability rates for patients receiving Workers' Compensation who undergo arthroscopic meniscectomy. PMID- 22438002 TI - Outcome of revision anterior cruciate ligament reconstruction: a systematic review. AB - BACKGROUND: Revision anterior cruciate ligament (ACL) reconstruction is believed to have an inferior outcome compared with primary ACL reconstruction. The available literature on the outcome of revision ACL reconstruction is sparse compared with that for primary reconstruction. The purpose of this systematic review was to test the hypothesis that the outcome of revision ACL reconstruction compares unfavorably with the historical outcome of primary ACL reconstruction. METHODS: A systematic review of studies evaluating the outcome of revision ACL reconstructions with a minimum of two years of follow-up was performed. Pooled data were collected when appropriate and a mixed-effect-model meta-analysis was performed for important outcome measures that were reported in several studies (objective graft failure, Lysholm score, International Knee Documentation Committee [IKDC] subjective score, and IKDC objective score). Objective failure was defined as repeat revision, a side-to-side difference of >5 mm measured with use of a KT1000 arthrometer, or a pivot-shift grade of 2+ or 3+. RESULTS: Twenty one studies were included, and 863 of the 1004 patients in these studies had a minimum of two years of follow-up and were analyzed. The pooled mean age of the patients at the time of the revision procedure was 30.6 years, and 66% were male. Objective failure occurred in 13.7% +/- 2.7% of the patients (95% confidence interval, 8.0% to 19.4%). The mean Lysholm score in 491 patients was 82.1 +/- 3.3 (95% confidence interval, 74.6 to 89.5) according to a mixed-model meta-analysis. The mean IKDC subjective score in 202 patients was 74.8 +/- 4.4 (95% confidence interval, 62.5 to 87.0). CONCLUSIONS: Revision ACL reconstruction resulted in a worse outcome compared with primary ACL reconstruction. Patient-reported outcome scores were inferior to previously published results of primary ACL reconstruction, but these differences may not be clinically important. A dramatically elevated failure rate was noted after revision ACL reconstruction; this rate was nearly three to four times the failure rate in prospective series of primary ACL reconstructions. PMID- 22438003 TI - Outcome of lower-limb preservation with an expandable endoprosthesis after bone tumor resection in children. AB - BACKGROUND: The optimal treatment of malignant pediatric lower-extremity bone tumors is controversial. Expandable endoprostheses allow limb preservation, but the revision rate and limited function are considered barriers to their use. This study investigated the functional, emotional, and oncologic outcomes of thirty eight patients treated with an expandable endoprosthesis. METHODS: A retrospective chart review was performed, and surviving patients were asked to complete the Musculoskeletal Tumor Society (MSTS) outcomes instrument and the Pediatric Outcomes Data Collection Instrument (PODCI). Additional data including the range of hip and knee motion, limb-length discrepancy, and total lengthening were also obtained. RESULTS: Thirty-eight patients were treated with an expandable endoprosthesis, and twenty-six of these patients were alive at the time of the study. The mean global MSTS score was 26.1, and the mean global PODCI score was 85.8. The mean emotional acceptance and happiness subscores were high. The mean sagittal-plane hip motion in patients who had undergone replacement of the proximal aspect of the femur was 103 degrees . The mean knee motion in patients who had undergone replacement of the proximal aspect of the femur, the distal aspect of the femur, or the proximal aspect of the tibia was 127 degrees , 97 degrees , and 107 degrees , respectively. The mean lengthening at the time of skeletal maturity was 4.5 cm, and the mean limb-length discrepancy was 0.7 cm. Forty-two percent of the patients experienced complications, with ten patients requiring prosthesis revision and two of these patients requiring amputation. CONCLUSIONS: Current technology does not offer a single best reconstruction option for children. Previous studies and the present series have indicated that physical and emotional functioning in patients treated with an expandable endoprosthesis are good but that complication rates remain high. Amputation and rotationplasty are alternative treatments if patients and their families are amenable to these procedures. The literature supports no single superior treatment among these three options with regard to physical or emotional health. PMID- 22438004 TI - Outcomes following distal humeral fracture fixation with an extensor mechanism-on approach. AB - BACKGROUND: Distal humeral fractures have traditionally been managed with surgical approaches that disrupt the extensor mechanism. We hypothesized that an extensor mechanism-on approach for operative fixation of distal humeral fractures with parallel or orthogonal plate constructs would allow excellent healing, a motion arc of the elbow exceeding 100 degrees , and maintenance of extensor mechanism strength. METHODS: Distal humeral open reduction and internal fixation (ORIF) was performed with either orthogonal or parallel plate constructs in seventy-nine elbows. Thirty-seven elbows were fixed via an extensor mechanism-on surgical approach, and twenty-four of them were available for additional evaluation. Radiographs as well as MEPI (Mayo Elbow Performance Index), DASH (Disabilities of the Arm, Shoulder and Hand), and SF-36 (Short Form-36) scores were obtained. RESULTS: All thirty-seven fractures healed primarily. Three elbows underwent later release because of stiffness. The median arc of elbow motion was 126 degrees (range, 60 degrees to 141 degrees ). The mean MEPI was 91.5 points and the mean DASH score was 15.9 points, indicating excellent scores with mild impairment. The median percent loss of triceps strength was 10% (range, 0% to 49%) compared with the contralateral, normal elbow. CONCLUSIONS: Open treatment of distal humeral fractures with an extensor mechanism-on approach results in excellent healing, a mean elbow flexion-extension arc exceeding 100 degrees , and maintenance of 90% of elbow extension strength compared with that of the contralateral, normal elbow. PMID- 22438005 TI - Distal humeral fractures: role of internal fixation and elbow arthroplasty. PMID- 22438006 TI - What's new in hand surgery. PMID- 22438007 TI - Rotator cuff tear arthropathy: evaluation, diagnosis, and treatment: AAOS exhibit selection. AB - Rotator cuff tear arthropathy encompasses a broad spectrum of pathology, but it involves at least three critical features: rotator cuff insufficiency, degenerative changes of the glenohumeral joint, and superior migration of the humeral head. Although many patients possess altered biomechanics of the glenohumeral joint secondary to rotator cuff pathology, not all patients develop rotator cuff tear arthropathy, and thus the exact etiology of rotator cuff tear arthropathy remains unclear. The objectives of this manuscript are to (1) review the biomechanical properties of the rotator cuff and the glenohumeral joint, (2) discuss the proposed causes of rotator cuff tear arthropathy, (3) provide a brief review of the historically used surgical options to treat rotator cuff tear arthropathy, and (4) present a treatment algorithm for rotator cuff tear arthropathy based on a patient's clinical presentation, functional goals, and anatomic integrity. PMID- 22438008 TI - Clinical trials in orthopaedics research. Part III. Overcoming operational challenges in the design and conduct of randomized clinical trials in orthopaedic surgery. PMID- 22438009 TI - Assessment of musculoskeletal physical examination skills and attitudes of orthopaedic residents. AB - BACKGROUND: Although the musculoskeletal physical examination is an essential part of patient encounters, we believe that it is underemphasized in residency education and that residents' physical examination skills may be lacking. We sought to assess attitudes regarding teaching of the physical examination in orthopaedic residencies, to assess physical examination knowledge and skills among residents, and to develop a method to track the skill level of residents in order to improve our physical examination curriculum. METHODS: We created a thirty-question multiple-choice musculoskeletal physical examination test and administered it to our residents. We created a five-question survey assessing attitudes toward physical examination teaching in orthopaedic residencies and distributed it to U.S. orthopaedic department chairs We developed an Objective Structured Clinical Examination (OSCE), in which standardized patients enact four clinical scenarios, to observe and assess physical examination skills. RESULTS: The mean score on the multiple-choice physical examination test was 76% despite the fact that our residents consistently scored above 90% on the Orthopaedic In Training Examination. Department chairs and residents agreed that, although learning to perform the physical examination is important, there is not enough time in the clinical setting to observe and critique a resident's patient examination. The overall score of our residents on the OSCE was 66%. CONCLUSIONS: We have exposed a deficiency in the physical examination knowledge and skills of our residents. Although the musculoskeletal physical examination is a vital practice component, our data indicate that it is likely underemphasized in training. Clinic time alone is likely insufficient for the teaching and learning of the musculoskeletal physical examination. PMID- 22438010 TI - Are we wasting money on rehabilitation for patients receiving workers' compensation? Commentary on an article by John Di Paola, MD: "Disability, impairment, and physical therapy utilization after arthroscopic partial meniscectomy in patients receiving workers' compensation". PMID- 22438011 TI - Lower-limb preservation with an expandable endoprosthesis after tumor resection in children: is the cup half full or half empty? Commentary on an article by Eric R. Henderson, MD, et al.: "Outcome of lower-limb preservation with an expandable endoprosthesis after bone tumor resection in children". PMID- 22438012 TI - QTL on mouse chromosomes 1 and 4 causing sperm-head morphological abnormality and male subfertility. AB - The B10.M mouse strain represents a model for male subfertility as it produces a significantly low number of offspring. The only known male reproductive phenotype of this strain is its high frequency of sperm-head morphological abnormalities (44.7 +/- 2.4 %). We previously reported that this phenotype was the product of two recessive loci. In this study we mapped the loci causing the high frequency of sperm-head morphological abnormalities in this strain using F2 animals produced by crossing B10.M and C3H mice. Quantitative trait loci (QTL) analysis (n = 178) identified two recessive genes, one on Chromosome (Chr) 1 (LOD score = 30.585) and one on Chr 4 (LOD score = 4.532). Further analysis (n = 854) mapped the locus on Chr 1 between Ercc5 (23.55 cM) and D1Mit528 (25.95 cM) and the locus on Chr 4 between D4Mit148 (69.48 cM) and D4Mit170 (70.47 cM). It was also found that the effects of these two loci were not independent. The major locus on Chr 1 determines the expression of sperm-head abnormalities, while the locus on Chr 4 enhances the frequency of abnormalities only when the genotype of the Chr 1 locus is homozygous for the B10.M allele. The major locus on Chr 1 was named sperm-head morphology 1 (Shm1), while the modifier locus on Chr 4 was named sperm-head morphology 2 (Shm2). PMID- 22438013 TI - Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations ameliorate reduction in infarct heart function through cardiomyocyte-mediated neovascularization. AB - Although stem cell therapy is a promising strategy for cardiac restoration, the heterogeneity of transplanted cells has been hampering the precise understanding of the cellular and molecular mechanisms. Previously, we established a cardiovascular cell differentiation system from mouse pluripotent stem cells, in which cardiomyocytes (CMs), endothelial cells (ECs), and mural cells (MCs) can be systematically induced and purified. Combining this with cell sheet technology, we generated cardiac tissue sheets reassembled with defined cardiovascular populations. Here, we show the potentials and mechanisms of cardiac tissue sheet transplantation in cardiac function after myocardial infarction (MI). Transplantation of the cardiac tissue sheet to a rat MI model showed significant and sustained improvement of systolic function accompanied by neovascularization. Reduction of the infarct wall thinning and fibrotic length indicated the attenuation of left ventricular remodeling. Cell tracing with species-specific fluorescent in situ hybridization after transplantation revealed a relatively early loss of transplanted cells and an increase in endogenous neovascularization in the proximity of the graft, suggesting an indirect angiogenic effect of cardiac tissue sheets rather than direct CM contributions. We prospectively dissected the functional mechanisms with cell type-controlled sheet analyses. Sheet CMs were the main source of vascular endothelial growth factor. Transplantation of sheets lacking CMs resulted in the disappearance of neovascularization and subsequent functional improvement, indicating that the beneficial effects of the sheet were achieved by sheet CMs. ECs and MCs enhanced the sheet functions and structural integration. Supplying CMs to ischemic regions with cellular interaction could be a strategic key in future cardiac cell therapy. PMID- 22438014 TI - Isolation and identification of host cues from mango, Mangifera indica, that attract gravid female oriental fruit fly, Bactrocera dorsalis. AB - The oriental fruit fly, Bactrocera dorsalis, is an economically damaging, polyphagous pest of fruit crops in South-East Asia and Hawaii, and a quarantine pest in other parts of the world. The objective of our study was to identify new attractants for B. dorsalis from overripe mango fruits. Headspace samples of volatiles were collected from two cultivars of mango, 'Alphonso' and 'Chausa', and a strong positive behavioral response was observed when female B. dorsalis were exposed to these volatiles in olfactometer bioassays. Coupled GC-EAG with female B. dorsalis revealed 7 compounds from 'Alphonso' headspace and 15 compounds from 'Chausa' headspace that elicited an EAG response. The EAG-active compounds, from 'Alphonso', were identified, using GC-MS, as heptane, myrcene, (Z)-ocimene, (E)-ocimene, allo-ocimene, (Z)-myroxide, and gamma-octalactone, with the two ocimene isomers being the dominant compounds. The EAG-active compounds from 'Chausa' were 3-hydroxy-2-butanone, 3-methyl-1-butanol, ethyl butanoate, ethyl methacrylate, ethyl crotonate, ethyl tiglate, 1-octen-3-ol, ethyl hexanoate, 3-carene, p-cymene, ethyl sorbate, alpha-terpinolene, phenyl ethyl alcohol, ethyl octanoate, and benzothiazole. Individual compounds were significantly attractive when a standard dose (1 MUg on filter paper) was tested in the olfactometer. Furthermore, synthetic blends with the same concentration and ratio of compounds as in the natural headspace samples were highly attractive (P < 0.001), and in a choice test, fruit flies did not show any preference for the natural samples over the synthetic blends. Results are discussed in relation to developing a lure for female B. dorsalis to bait traps with. PMID- 22438015 TI - Host suitability affects odor association in Cotesia marginiventris: implications in generalist parasitoid host-finding. AB - Insect herbivores often induce plant volatile compounds that can attract natural enemies. Cotesia marginiventris (Hymenoptera: Braconidae) is a generalist parasitoid wasp of noctuid caterpillars and is highly attracted to Spodoptera exigua-induced plant volatiles. The plasticity of C. marginiventris associative learning to volatile blends of various stimuli, such as host presence, also has been shown, but little is known about how this generalist parasitoid distinguishes between host species of varying suitability. Spodoptera exigua is an excellent host that yields high parasitoid emergence, while Trichoplusia ni serves as a sub-optimal host species due to high pre-imaginal wasp mortality. We have found that S. exigua and T. ni induce different volatile blends while feeding on cotton. Here, wind tunnel flight assays were used to determine the importance of differentially induced volatiles in host-finding by C. marginiventris. We found that, while this generalist parasitoid wasp can distinguish between the two discrete volatile blends when presented concurrently, a positive oviposition experience on the preferred host species (S. exigua) is more important than host-specific volatile cues in eliciting flight behavior towards plants damaged by either host species. Furthermore, wasps with oviposition experience on both host species did not exhibit a deterioration in positive flight behavior, suggesting that oviposition in the sub-optimal host species (T. ni) does not cause aversive odor association. PMID- 22438016 TI - Late complications after Takeuchi repair of anomalous left coronary artery from the pulmonary artery: case series and review of literature. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart lesion that if left untreated, results in high mortality. Surgical treatment options include reimplantation of the anomalous coronary ostia, use of extracardiac arterial blood supply, or the Takeuchi procedure. The Takeuchi procedure involves creation of an aortopulmonary window and an intrapulmonary tunnel that baffles the aorta to the ostium of the anomalous left coronary artery. The incidence of late complications following the Takeuchi repair is unknown. The goal of our study was to determine the long-term outcome after palliation of ALCAPA using the Takeuchi Procedure. A total of 9 patients with a history of ALCAPA palliated with the Takeuchi procedure were identified from our surgical database. Chart review was performed. The mean age at time of Takeuchi procedure was 49.6 months (range 5 weeks-14.6 years). There was one late death, of unknown cause. Of the remaining 8 patients, the mean length of follow-up after surgery was 15.9 years (13.5-19.7 years). All 8 survivors had some degree of main pulmonary artery stenosis in the area of the intrapulmonary baffle, with moderate stenosis in 2 and severe stenosis in 1. Three late survivors (38 %) had a baffle leak. Two patients (25 %) had decreased left ventricular systolic function and 3 (38 %) had developed at least moderate mitral valve regurgitation. Three of the 8 late survivors (38 %) required a reoperation for repair of mitral valve regurgitation, baffle leak, and main pulmonary artery (MPA) stenosis. Review of literature demonstrated similar complication rates and need for reoperation following the Takeuchi procedure. Compared with patients after direct reimplantation for ALCAPA at our institution, there was no significant difference in late survival or freedom from reoperation. The Takeuchi procedure is a method to establish a two-coronary repair for ALCAPA. Late complications are common, necessitating lifelong care in a center experienced with caring for adults with congenital heart disease. PMID- 22438017 TI - Pulmonary stenosis is a predictor of unfavorable outcome after surgery for supravalvular aortic stenosis. AB - We sought to evaluate whether the presence of pulmonary stenosis (PS), amongst other factors, influences the mortality and the rate of reoperations in the long term follow-up of patients with supravalvular aortic stenosis (SVAS). We identified all patients with SVAS from our surgical database. The patients with multi-level aortic stenosis or concomitant cardiac procedures were excluded from this study. Follow-up (100 %) was conducted between 2008 and 2010. Twenty-six patients underwent surgery for SVAS between 1974 and 2006. Seventeen patients (65 %) were diagnosed with Williams-Beuren-Syndrome, six (17 %) had a diffuse form of SVAS and 10 (39 %) had PS. No patient had a surgical or interventional procedure for PS at the initial operation or during follow-up. There was no statistically significant association between PS and WBS (p = 0.30) or diffuse form of SVAS (p = 0.13). Patients with PS were operated at younger age (p = 0.028). Median follow up time was 14.6 years. Overall mortality was 11.5 %. One patient with preoperatively severely decreased LV-function died 27 days postoperatively. Two late deaths occurred 7 and 10 years after the initial operation. Reoperations were required in 4 patients (15 %), 4-19 years after the original operation, due to aortic arch stenosis, supravalvular restenosis or poststenotic aortic dilatation. PS was found to be a risk factor for reoperation (p = 0.005) and for the combined reoperation/death end-point (p = 0.003). PS in patients with SVAS is a risk factor for reoperations in the aortic region and might be considered an indicator of the severity of the arterial disease and a predictor of an unfavourable outcome. PMID- 22438018 TI - Cell proliferation and apoptosis in gill filaments of the lucinid Codakia orbiculata (Montagu, 1808) (Mollusca: Bivalvia) during bacterial decolonization and recolonization. AB - The shallow-water bivalve Codakia orbiculata which harbors gill-endosymbiotic sulfur-oxidizing gamma-proteobacteria can lose and acquire its endosymbionts throughout its life. Long-term starvation and recolonization experiments led to changes in the organization of cells in the lateral zone of gill filaments. This plasticity is linked to the presence or absence of gill-endosymbionts. Herein, we propose that this reorganization can be explained by three hypotheses: (a) a variation in the number of bacteriocytes and granule cells due to proliferation or apoptosis processes, (b) a variation of the volume of these two cell types without modification in the number, and (c) a combination of both number and cell volume variation. To test these hypotheses, we analyzed cell reorganization in terms of proliferation and apoptosis in adults submitted to starvation and returned to the field using catalyzed reporter deposition fluorescence in situ hybridization, immunohistochemistry, and structural analyses. We observed that cell and tissue reorganization in gills filaments is due to a variation in cell relative abundance that maybe associated with a variation in cell apparent volume and depends on the environment. In fact, bacteriocytes mostly multiply in freshly collected and newly recolonized individuals, and excess bacteriocytes are eliminated in later recolonization stages. We highlight that host tissue regeneration in gill filaments of this symbiotic bivalve can occur by both replication of existing cells and division of undifferentiated cells localized in tissular bridges, which might be a tissue-specific multipotent stem cell zone. PMID- 22438019 TI - Carnitine supplementation improves cardiac strain rate in children on chronic hemodialysis. AB - BACKGROUND: Carnitine plays a key role in energy production in the myocardium. Carnitine deficiency commonly occurs in patients on chronic hemodialysis (HD) and may contribute to cardiomyopathy. METHODS: Carnitine levels and cardiac function of nine children on HD were assessed before and after 6 months of intravenous levocarnitine supplementation. Standard echocardiographic (ECHO) measures of left ventricular (LV) function as well as strain and strain rate analysis using novel speckle-tracking echocardiography were performed and the results compared to those of a control group of children on chronic HD. RESULTS: Following carnitine supplementation, total (49.0 +/- 1.67 vs. 298.0 +/- 31.8 MUmol/L) and free carnitine (29.0 +/- 1.20 vs. 180.4 +/- 19.2 MUmol/L) increased (p < 0.0001), and the acyl:free (A:F) carnitine ratio improved (0.73 +/- 0.04 vs. 0.65 +/- 0.05; p = 0.02). There were no changes in standard ECHO measures of LV function, including end diastolic dimension, mass index, ejection fraction, and fractional shortening. There was significant (p = 0.017) improvement in the longitudinal strain rate (-1.48 +/- 0.11 vs -1.91 +/- 0.12) after carnitine supplementation in the study group. No improvements in LV function, strain, or strain rate occurred in controls. CONCLUSIONS: Levocarnitine supplementation improved carnitine levels, the A:F ratio, and longitudinal strain rate in children on HD. PMID- 22438020 TI - Boosting crop yields with plant steroids. AB - Plant sterols and steroid hormones, the brassinosteroids (BRs), are compounds that exert a wide range of biological activities. They are essential for plant growth, reproduction, and responses to various abiotic and biotic stresses. Given the importance of sterols and BRs in these processes, engineering their biosynthetic and signaling pathways offers exciting potentials for enhancing crop yield. In this review, we focus on how alterations in components of sterol and BR metabolism and signaling or application of exogenous steroids and steroid inhibitors affect traits of agronomic importance. We also discuss areas for future research and identify the fine-tuning modulation of endogenous BR content as a promising strategy for crop improvement. PMID- 22438021 TI - Ion exchangers NHX1 and NHX2 mediate active potassium uptake into vacuoles to regulate cell turgor and stomatal function in Arabidopsis. AB - Intracellular NHX proteins are Na(+),K(+)/H(+) antiporters involved in K(+) homeostasis, endosomal pH regulation, and salt tolerance. Proteins NHX1 and NHX2 are the two major tonoplast-localized NHX isoforms. Here, we show that NHX1 and NHX2 have similar expression patterns and identical biochemical activity, and together they account for a significant amount of the Na(+),K(+)/H(+) antiport activity in tonoplast vesicles. Reverse genetics showed functional redundancy of NHX1 and NHX2 genes. Growth of the double mutant nhx1 nhx2 was severely impaired, and plants were extremely sensitive to external K(+). By contrast, nhx1 nhx2 mutants showed similar sensitivity to salinity stress and even greater rates of Na(+) sequestration than the wild type. Double mutants had reduced ability to create the vacuolar K(+) pool, which in turn provoked greater K(+) retention in the cytosol, impaired osmoregulation, and compromised turgor generation for cell expansion. Genes NHX1 and NHX2 were highly expressed in guard cells, and stomatal function was defective in mutant plants, further compromising their ability to regulate water relations. Together, these results show that tonoplast-localized NHX proteins are essential for active K(+) uptake at the tonoplast, for turgor regulation, and for stomatal function. PMID- 22438022 TI - Gain and loss of photosynthetic membranes during plastid differentiation in the shoot apex of Arabidopsis. AB - Chloroplasts of higher plants develop from proplastids, which are undifferentiated plastids that lack photosynthetic (thylakoid) membranes. In flowering plants, the proplastid-chloroplast transition takes place at the shoot apex, which consists of the shoot apical meristem (SAM) and the flanking leaf primordia. It has been believed that the SAM contains only proplastids and that these become chloroplasts only in the primordial leaves. Here, we show that plastids of the SAM are neither homogeneous nor necessarily null. Rather, their developmental state varies with the specific region and/or layer of the SAM in which they are found. Plastids throughout the L1 and L3 layers of the SAM possess fairly developed thylakoid networks. However, many of these plastids eventually lose their thylakoids during leaf maturation. By contrast, plastids at the central, stem cell-harboring region of the L2 layer of the SAM lack thylakoid membranes; these appear only at the periphery, near the leaf primordia. Thus, plastids in the SAM undergo distinct differentiation processes that, depending on their lineage and position, lead to either development or loss of thylakoid membranes. These processes continue along the course of leaf maturation. PMID- 22438023 TI - Genome-wide analysis of DNA methylation and gene expression changes in two Arabidopsis ecotypes and their reciprocal hybrids. AB - Heterosis is a fundamental biological phenomenon characterized by the superior performance of a hybrid over its parents in many traits, but the underlying molecular basis remains elusive. To investigate whether DNA methylation plays a role in heterosis, we compared at single-base-pair resolution the DNA methylomes of Arabidopsis thaliana Landsberg erecta and C24 parental lines and their reciprocal F1 hybrids that exhibited heterosis. Both hybrids displayed increased DNA methylation across their entire genomes, especially in transposable elements. Interestingly, increased methylation of the hybrid genomes predominantly occurred in regions that were differentially methylated in the two parents and covered by small RNAs, implying that the RNA-directed DNA methylation (RdDM) pathway may direct DNA methylation in hybrids. In addition, we found that 77 genes sensitive to methylome remodeling were transcriptionally repressed in both reciprocal hybrids, including genes involved in flavonoid biosynthesis and two circadian oscillator genes circadian clock associated1 and late elongated hypocotyl. Moreover, growth vigor of F1 hybrids was compromised by treatment with an agent that demethylates DNA and by abolishing production of functional small RNAs due to mutations in Arabidopsis RNA methyltransferase HUA enhancer1. Together, our data suggest that genome-wide remodeling of DNA methylation directed by the RdDM pathway may play a role in heterosis. PMID- 22438024 TI - Tuberous sclerosis and epilepsy: role of astrocytes. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is among the most common genetic causes of epilepsy. Focal brain lesions in TSC, known as cortical tubers, have been implicated in promoting epileptogenesis in TSC. Histological, cellular, and molecular abnormalities in astrocytes are characteristic features of tubers and perituberal cortex, suggesting that astrocyte dysfunction may contribute to the pathophysiology of epilepsy in TSC. Numerous astrocytes can be seen histologically in tubers expressing glial fibrillary acidic and S100 proteins. In some analyses, astrocytes exhibit enhanced activation of the mammalian target of rapamycin suggesting a link between TSC1 and TSC2 mutations and astrocytic proliferation. Astrocytic proliferation in subependymal giant cell astrocytoma is associated with progressive growth and compression of surrounding brain structures by these lesions. Increased numbers of enlarged astrocytes has been observed in several TSC mouse models and may be intimately linked to epileptogenesis. Impairment of astrocytic buffering mechanisms for glutamate and potassium has been identified in TSC animal models and human tuber tissue and likely promotes neuronal excitability and seizures in TSC. Targeting these defects in astrocytes may represent a novel therapeutic strategy for epilepsy in patients with TSC. PMID- 22438025 TI - Disposable electrochemical immunosensor by using carbon sphere/gold nanoparticle composites as labels for signal amplification. AB - This work designed a simple, sensitive, and low-cost immunosensor for the detection of protein marker by using a carbon sphere/gold nanoparticle (CNS/AuNP) composite as an electrochemical label. The nanoscale carbon spheres, prepared with a hydrothermal method by using glucose as raw material, were used to load AuNPs for labeling antibody by electrostatic interaction, which provided a feasible pathway for electron transfer due to the remarkable conductivity. The disposable immunosensor was constructed by coating a polyethylene glycol (PEG) film on a screen-printed carbon-working electrode and then immobilizing capture antibody on the film. With a sandwich-type immunoassay format, the analyte and then the CNS/AuNP-labeled antibody were successively bound to the immunosensor. The bound AuNPs were finally electro-oxidized in 0.1 M HCl to produce AuCl(4)(-) for differential pulse voltammetric (DPV) detection. The high-loading capability of AuNPs on CNS for the sandwich-type immunorecognition led to obvious signal amplification. By using human immunoglobulin G (IgG) as model target, the DPV signal of AuNPs after electro-oxidized at optimal potential of +1.40 V for 40 s showed a wide linear dependence on the logarithm of target concentration ranging from 10 pg mL(-1) to 10 ng mL(-1). The detection limit was around 9 pg mL(-1). The immunosensor showed excellent analytical performance with cost effectivity, good fabrication reproducibility, and acceptable precision and accuracy, providing significant potential application in clinical analysis. PMID- 22438026 TI - Fertility preservation methods in young women with systemic lupus erythematosus prior to cytotoxic therapy: experiences from the FertiPROTEKT network. AB - OBJECTIVES: Despite new treatment options, some patients with systemic lupus erythematosus (SLE) need to be treated with the cytotoxic agent cyclophosphamide (CYC). Unlike malignant disease, there are no recommendations for ovarian protection in SLE. The clinical experience of the FertiPROTEKT network as well as recommendations after literature review will be presented in this paper. METHODS: Retrospective analyses of counselling and treatment data from the FertiPROTEKT register with special respect to SLE patients under 40 years prior to planned CYC treatment. RESULTS: A total of 2836 patients were advised prior to cytotoxic treatment in one of the FertiPROTEKT centres during January 2007 to November 2011. Of those, 68 patients (mean age 25 +/- 6.07 years) were counselled for severe SLE. Only five women did not make use of a fertility preservation method. Sixty-three patients (92.6%) decided in favour of a fertility preservation method. The largest proportion (91.2%) opted for treatment with a GnRH analogue. Ovarian tissue removal for cryoconservation was performed in 16 patients (25%). Stimulation therapy for cryoconservation of fertilized egg cells was performed in three patients (4.4%). CONCLUSIONS: When counselling patients with SLE for fertility preservation one has to be aware of the disease-specific risks. According to the literature, a safe and effective option in SLE up to now has been the use of a GnRH analogue. Cryoconservation of ovarian tissue must still be seen as an experimental treatment, but as data on removal, cryoconservation, retransplantation and pregnancies are steadily rising, this presents a promising option for young SLE patients. Cryoconservation of oocytes must be very critically evaluated due to the need for a stimulation therapy and should only be performed after particular consideration of the individual risks. PMID- 22438027 TI - Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. AB - AIM: The optimal maintenance therapy for active diffuse lupus nephritis remains to be established. In this study, we explored the efficacy and safety of tacrolimus for maintaining remission of active lupus nephritis compared to that of azathioprine. METHODS: Seventy patients with biopsy-proven lupus nephritis who achieved remission were enrolled in nine nephrology centers in China from 2006 to 2008. Patients were randomized either to tacrolimus plus prednisone (n = 34) or azathioprine plus prednisone (n = 36) for six months. Tacrolimus was titrated to achieve a trough blood concentration of 4-6 ng/mL, and the dosage of azathioprine was 2 mg/kg/d. Prednisone was administered at a dose of 10 mg/d to both groups. The primary outcome was incidence of relapse. Response, clinical parameters and adverse effects were secondary endpoints. RESULTS: After six months of therapy, two of the azathioprine-treated patients developed renal relapse compared to none of the tacrolimus-treated patients (p = 0.49; odds ratio, 1.06; 95% CI (0.98, 1.15)). Leucopenia (defined as < 2000 cells per cubic millimeter) was significantly more frequent in the azathioprine group than the tacrolimus group (47% vs. 9%, p < .001). CONCLUSION: In conjunction with prednisone, maintenance therapy with tacrolimus and azathioprine has a similar low rate of renal relapse, and the tacrolimus regimen has a more favorable safety profile, with less leucopenia. However, since our study lacked sufficient power, longer follow-up is needed to draw final conclusions. PMID- 22438028 TI - Response to ustekinumab in a patient with both severe psoriasis and hypertrophic cutaneous lupus. AB - Psoriasis is an autoimmune inflammatory disease that has recently been treated with a novel treatment, ustekinumab, a human monoclonal antibody that targets the Th17 pathway. Discoid lupus is a subset of chronic cutaneous lupus erythematosus. Recent studies have suggested the Th17 pathway may be involved in cutaneous lupus. We present a case of a 41-year-old man with both severe psoriasis and hypertrophic discoid lupus treated with ustekinumab. After three doses of 45 mg subcutaneous injections at day 1, week 4, and week 16, his psoriasis plaques cleared and his hypertrophic discoid lupus plaques showed moderate improvement. Following a fourth dose of 90 mg his lupus plaques showed marked improvement. Ustekinumab may be a promising therapy for this and other forms of cutaneous lupus. PMID- 22438029 TI - A case of multiple sclerosis improvement following removal of heavy metal intoxication: lessons learnt from Matteo's case. AB - Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system (CNS) provoking disability and neurological symptoms. The exact causes of SM are unknown, even if it is characterized by focal inflammatory lesions in CNS accompanied by autoimmune reaction against myelin. Indeed, many drugs able to modulate the immune response of patients have been used to treat MS. More recently, toxic metals have been proposed as possible causes of neurodegenerative diseases. The objective of this study is to investigate in vivo the impact of heavy metal intoxication in MS progression. We studied the case of a patient affected by MS, who has been unsuccessfully treated for some years with current therapies. We examined his levels of toxic heavy metals in the urine, following intravenous "challenge" with the chelating agent calcium disodium ethylene diamine tetraacetic acid (EDTA).The patient displayed elevated levels of aluminium, lead and mercury in the urine. Indeed, he was subjected to treatment with EDTA twice a month. Under treatment, the patient revealed in time improved symptoms suggestive of MS remission. The clinical data correlated with the reduction of heavy metal levels in the urine to normal range values. Our case report suggests that levels of toxic metals can be tested in patients affected by neurodegenerative diseases as MS. PMID- 22438030 TI - Full dates (day, month, year) should be used in population-based cancer survival studies. AB - Accurate survival estimates are essential for monitoring cancer survival trends, for health care planning and for resource allocation. To obtain precise estimates of survival, full dates (day, month and year) rather than partial dates (month and year) are required. In some jurisdictions, however, cancer registries are constrained from providing full dates on the grounds of confidentiality. The bias resulting from the use of partial dates in the estimation and comparison of survival makes it impossible to determine precisely the differences in the risk of death from cancer between population groups or in successive calendar periods. Important operational arguments also exist against the use of incomplete dates for survival analysis, including increased workload for cancer registry staff and the introduction of avoidable complexity for quality control of survival data. Cancer survival is one of the most widely known outputs produced by population based cancer registries, and it is a crucial metric for the comparative effectiveness of health services. The bodies that set data access guidelines must take a more balanced view of the risks and benefits of using full dates for the estimation of cancer survival. PMID- 22438031 TI - Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. AB - Due to low bioavailability and high inter-individual variability, monitoring of dabigatran may be required in specific situations to prevent the risk of bleedings or thrombosis. The aim of the study was to determine which coagulation assay(s) could be used to assess the impact of dabigatran on secondary haemostasis. Dabigatran was spiked at concentrations ranging from 4.7 ng/ml to 943.0 ng/ml in pooled citrated human platelet-poor plasma. The following clotting assays were performed: prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); ecarin clotting time (ECT); ecarin chromogenic assay (ECA); prothrombinase-induced clotting time (PiCT); activated clotting time (ACT); Hemoclot Thrombin Inhibitor (HTI) and thrombin generation assay (TGA). A concentration-dependent prolongation of PT, dPT, and aPTT was observed with aPTT being the more sensitive test. The results varied mostly due to the clotting reagent. HTI, ECT and TGA were the most sensitive tests but are not available 24 hours a day. In addition, HTI showed a linear correlation with a good reproducibility. Dabigatran induced a concentration-dependent delay and inhibition of tissue factor-induced TGA. Cut-offs related with higher risk of bleedings or thrombosis were defined for each reagent of aPTT and HTI. In conclusion, aPTT could be used for the monitoring of dabigatran and as screening test for the risk of overdose. However, because of its higher sensitivity, good reproducibility, excellent linear correlation at all doses, its simplicity of use, and possibilities of automation, HTI should be considered as the gold standard. PMID- 22438032 TI - CCR5 plays an important role in resolving an inflammatory response to single walled carbon nanotubes. AB - Owing to the development of new materials and technology, the pollutants in the environment are becoming more varied and complex over time. In our previous study using ICR mice, we suggested that a single intratracheal instillation of single walled carbon nanotubes (SWCNTs) induced early lung fibrosis and subchronic tissue damage. In the present study, to investigate the role of CCR5 in inflammatory responses to the uptake of SWCNTs, we compared BAL (Bronchoalveolar lavage) cell composition, cell cycles, cytokines, cell phenotypes, inflammatory response-related proteins, cell surface receptors and histopathology using CCR5 knockout (KO) and wild-type mice. Results showed that the distribution of neutrophils in BAL fluid significantly decreased in KO mice. The expression of apoptosis-related proteins including caspase-3, p53, phospho-p53, p21 and cleaved PARP, TGF betal and mesothelin markedly increased in KO mice compared with wild type mice. Histopathological lesions were also more frequently noted in KO mice. Moreover, the secretion of IL-13 and IL-17 with IL-6 significantly increased in KO mice compared with wild-type mice, whereas that of IL-12 significantly decreased in comparison to wild-type mice. The distribution of B cells and CD8+ T cells was predominant in the inflammatory responses in KO mice, whereas that of T cells and CD4+ T cells was predominant in the inflammatory responses in wild-type mice. Furthermore, the expression of CCR4 and CCR7 significantly increased in KO mice. Based on these results, we suggest that the absence of CCR5 delays the resolution of inflammatory responses triggered by SWCNTs inflowing into the lungs and shifts inflammatory response for SWCNTs clearance from Th1-type to Th2-type. PMID- 22438033 TI - The most stable protein-ligand complex: applications for one-step affinity purification and identification of protein assemblies. PMID- 22438034 TI - Vasohibin-1 and vasohibin-2 expression in gastric cancer cells and TAMs. AB - Accumulating evidence suggests that TAMs contribute to tumor progression. Recently, vasohibin-1 and vasohibin-2 were detected in endothelial cells and considered as intrinsic angiogenesis inhibitors. However, it is not known whether they are also expressed in cancer cells or tumor-associated macrophages (TAMs). Realtime RT-PCR was used to investigate the vasohibin-1 and vasohibin-2 expression in four gastric cancer cell lines, including a non-metastatic cell line AGS, and metastatic cell lines HGC-27, Hs-746T and NCI-N87, co-cultured with or without TAMs. The effect of hypoxic conditions on vasohibin expression was evaluated as well, and the correlation between vasohibin-1, vasohibin-2 and VEGF A expression under different culture conditions was analyzed. We found that both vasohibin-1 and vasohibin-2 were expressed in the four gastric cancer cell lines and in TAMs. Under normal conditions, vasohibin-1 and vasohibin-2 expressions were significantly upregulated by TAMs in all the gastric cancer cell lines. Under hypoxia, both vasohibin-1 and vasohibin-2 expressions were significantly decreased in the distant metastasis cancer cell line Hs-746T, cultured with or without TAMs (P<0.001). After induction by TAMs or hypoxia, the vasohibin-1 and vasohibin-2 expressions correlated with that of VEGF-A. In addition, TAMs, when co-cultured with the metastatic cancer cell lines, showed hypoxia-induced vasohibin-1 upregulation (P<0.05). In conclusion, both vasohibin-1 and vasohibin 2 mRNA are expressed in gastric cancer cells and in TAMs, and their expressions are altered by hypoxia. PMID- 22438036 TI - Repeated measures design: a methodological issue of conducting research on patients with chronic pain. PMID- 22438037 TI - Rational design of a NIR-emitting Pd(II) sensor via oxidative cyclization to form a benzoxazole ring. AB - By using the substituent effect to tune the palladium(II)-involved reactivity, a new probe is found to respond quantitatively to Pd(II). Unexpectedly, the probe gave an emission band in the desirable near-infrared (NIR) region (780 nm), thus providing the first NIR sensor for palladium detection. PMID- 22438035 TI - The role of gap junction channels during physiologic and pathologic conditions of the human central nervous system. AB - Gap junctions (GJs) are expressed in most cell types of the nervous system, including neuronal stem cells, neurons, astrocytes, oligodendrocytes, cells of the blood brain barrier (endothelial cells and astrocytes) and under inflammatory conditions in microglia/macrophages. GJs connect cells by the docking of two hemichannels, one from each cell with each hemichannel being formed by 6 proteins named connexins (Cx). Unapposed hemichannels (uHC) also can be open on the surface of the cells allowing the release of different intracellular factors to the extracellular space. GJs provide a mechanism of cell-to-cell communication between adjacent cells that enables the direct exchange of intracellular messengers, such as calcium, nucleotides, IP(3), and diverse metabolites, as well as electrical signals that ultimately coordinate tissue homeostasis, proliferation, differentiation, metabolism, cell survival and death. Despite their essential functions in physiological conditions, relatively little is known about the role of GJs and uHC in human diseases, especially within the nervous system. The focus of this review is to summarize recent findings related to the role of GJs and uHC in physiologic and pathologic conditions of the central nervous system. PMID- 22438038 TI - Endocrine disrupting chemicals in New Orleans surface waters and Mississippi Sound sediments. AB - Endocrine disrupting compounds (EDCs), represented by steroid hormones, organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and bisphenol A have been determined in four sediment cores from the Gulf of Mexico, from New Orleans surface water (Lake Pontchartrain and Mississippi River), and from the influent and effluent of a New Orleans municipal sewage treatment plant. During the five-month monitoring of selected EDCs in the Mississippi River (MR) and Lake Pontchartrain (LP) in 2008, 21 of 29 OCPs in MR and 17 of 29 OCPs in LP were detected; bisphenol A was detected in all of the samples. Steroid hormones (estrone, 17beta-estradiol and 17alpha-ethinylestradiol) were detected occasionally. Total EDC (OCPs + PCBs + steroid hormones + bisphenol A) concentrations in the two surface water samples were found to vary from 148 to 1112 ng L(-1). Strong correlation of the distribution of total OCPs, total PCBs and total EDCs between solid and water phases was found in LP, while moderate or no correlation existed in MR. OCPs, PCBs, steroid hormones, and bisphenol A were all detected in the ocean sediments, and total EDCs were measured in the range of 77 to 1796 ng g(-1) dry sediment weight. The EDCs were also found in untreated and treated municipal sewage samples with a removal efficiency of 83% for OCPs but no removal efficiency for 17alpha-ethinylestradiol. PMID- 22438039 TI - Distribution of mycosporine-like amino acids along a surface water meridional transect of the Atlantic. AB - The composition and abundance of mycosporine-like amino acids (MAAs) were investigated in the surface waters along a 13,000-km meridional transect (52 degrees N to 45 degrees S) in the Atlantic Ocean (Atlantic Meridional Transect programme: Cruise AMT 18: 4/10/2008-10/11/2008). MAAs were ubiquitous along the transect, although the composition of the MAAs was variable. Highest concentrations were in the far south (below 40 degrees S; MAA >1 MUg L(-1)) and in north subtropical equatorial region (NER: 0-25 degrees N; MAA up to 0.8 MUg L(-1)). Highest MAA relative to chlorophyll-a occurred in the NER (MAA/chl-a ratio between 2 and 5). MAA/chl-a significantly correlated with the preceding month's mean daily UV dose and with UV-B/UV-A. In the far south, high MAA concentrations coincided with high phytoplankton biomass, high nutrients and a deep mixed layer associated with the austral spring. Here, the phytoplankton community was dominated by micro- and nano-eukaryotes. At the NER, the high MAA/chl-a coincided with low nutrient concentrations, a shallow mixed layer depth (20-70 m) and to a lesser extent to a shallow nitracline (40-90 m). Here, the phytoplankton consisted primarily of picophytoplankton (0-0.2 MUm), dominated by the pico-cyanobacteria Synechococcus sp. and Prochlorococcus sp. and by the nitrogen fixing filamentous cyanobacterium Trichodesmium. The low nitrate concentrations (<0.1 MUmol L(-1)) at the NER suggest that nitrogen fixation was required for MAA production. Specific MAAs could not easily be assigned to particular groups of phytoplankton and we could not rule out the possibility that MAAs were associated with symbiotic cyanobacteria contained within heterotrophic dinoflagellates or diatoms. PMID- 22438040 TI - New insights into the ecological interaction between grape berry microorganisms and Drosophila flies during the development of sour rot. AB - In this work, we studied the ecological interactions between grape berry microorganisms and Drosophila sp. flies involved in sour rot disease during grape ripening. After veraison the total microbial counts of grape berries affected by sour rot increased from about 2 log CFU/g of berries to more than 7 log CFU/g. Berry damage provoked a clear shift in yeast diversity from basidiomycetes to ascomycetous fermentative species. The latter were mostly Pichia terricola, Hanseniaspora uvarum, Candida zemplinina, and Zygoascus hellenicus. However, these species were not able to produce the metabolites characteristic of sour rot (gluconic and acetic acids) in inoculated berries. On the contrary, the acetic acid bacteria Gluconacetobacter saccharivorans produced high levels of these acids, mainly when berries were incubated in the presence of the insect Drosophila sp. Sour rot was not observed when grape bunches were physically separated from insects, even when berries were artificially injured. The wounds made in berry skin healed in the absence of insects, thus preventing the development of sour rot. Therefore, in the vineyard, the induction of sour rot depends on the contamination of wounded berries by a microbial consortium--yeasts and acetic acid bacteria--transported by drosophilid insects which disseminate sour rot among damaged berries. In the absence of these insects, plant defense mechanisms are effective and lead to skin healing, preventing disease spread. Thus, we showed that Drosophila sp. act as a vector for microorganisms associated with grape sour rot disease. PMID- 22438041 TI - Simulation of the electrification of wind-blown sand. AB - The triboelectric charging of collision particles is essential to understand sand electrification in wind-blown sand fluxes. The physical model of electron trapped in high-energy states has been proposed to explain the triboelectric charging between identical insulating granular materials. In this study we propose an improved triboelectric charging model which combines the soft sphere model and the trapped electron model to calculate the net charge transfer during particles' collisions. Based on our charging model, we investigate the sand electrification of wind-blown sand, such as the charge flux varying with height, the charge-to mass ratio of wind-blown sand, and the equilibrium time that the charge takes to approach a stable state. Numerical simulation results of the averaged charge-to mass ratio in wind-blown sand fluxes are in good agreement with the experimental data. PMID- 22438042 TI - Reduced stress concentration and enhanced fracture toughness by yielding rehardening combination. AB - A range of tough materials (e.g., metals and polymer solids) exhibit a characteristic mechanical behavior, that is, a combination of yielding and subsequent rehardening. We numerically investigate how the combination of these mechanical behaviors enhances resistance to crack propagation.Our system has a 2 dimensional square lattice structure where pairs of adjacent lattice points are connected by "special" bonds. An isolated bond behaves as a linear spring for small deformations, but yields at a threshold force to produce a plateau in its force-deformation curve, and then shows rehardening on further loading up to a critical force of bond-breaking; on unloading from above the yielding point, the force rapidly decreases with deformation (hysteresis). We simulate crack propagation in the entire system (the square lattice structure) from an initial crack driven by boundary loading. The threshold force for bond-yielding is varied as a simulation parameter, while the critical force for bond-breaking in the rehardening regime is fixed to 1. In other words, the substantial simulation parameter is the ratio between the yielding and breaking forces. We find that the fracture behavior drastically changes depending on the ratio: when the ratio is low, the bond-breaking energy (of a single bond) is low, but more work is required to fracture the entire system via the crack propagation. The opposite tendency between the bond-breaking energy and the fracture work is due to formation of a well-developed yielding zone around the crack tip. PMID- 22438043 TI - Ethynyl benziodoxolones for the direct alkynylation of heterocycles: structural requirement, improved procedure for pyrroles, and insights into the mechanism. AB - This report describes a full study of the gold-catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3- and 6-position of triisopropylsilylethynyl-1,2 benziodoxol-3(1H)-one (TIPS-EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2-pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a pi activation or an oxidative mechanism are most probable for the alkynylation reaction. PMID- 22438045 TI - Management of lymphadenitis due to non-tuberculous mycobacterial infection in children. AB - PURPOSE: Non-tuberculous mycobacterial (NTM) infection is an important cause of cervico-facial lymph node enlargement in young children. The optimal treatment is thought to be early complete excision without chemotherapy. We compared management of patients referred to our centre to this "gold standard" and determined clinical outcomes by type of primary surgical intervention (complete excision vs. incomplete excision). METHODS: Retrospective study of management and clinical outcomes of all children (<12 years) with NTM lymphadenitis referred to a single UK centre between May 1998 and May 2008. RESULTS: We identified 43 children. Median time from onset of swelling to operation was 6 weeks. Management was: no operation (n = 1, 2 %), complete excision (n = 20, 47 %), incision and drainage (n = 17, 40 %) and fine needle aspirate (n = 5, 12 %). Children not treated by primary complete excision were more likely to have: re-operation (91 vs. 30 %; chi(2) = 16.48; p < 0.0001); persistent lymphadenitis (77 vs. 30 %; chi(2) = 9.45; p = 0.002); sinus formation (26 vs. 5 %; chi2 = 3.74; p = 0.05). CONCLUSION: Failure to undertake primary complete excision leads to further morbidity. A high index of suspicion is required for timely appropriate management to avoid unnecessary morbidity and further intervention. PMID- 22438044 TI - Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Abeta by microglia. AB - Complement components and their receptors are found within and around amyloid beta (Abeta) cerebral plaques in Alzheimer's disease (AD). Microglia defend against pathogens through phagocytosis via complement component C3 and/or engagement of C3 cleavage product iC3b with complement receptor type 3 (CR3, Mac 1). Here, we provide direct evidence that C3 and Mac-1 mediate, in part, phagocytosis and clearance of fibrillar amyloid-beta (fAbeta) by murine microglia in vitro and in vivo. Microglia took up not only synthetic fAbeta(42) but also amyloid cores from patients with AD, transporting them to lysosomes in vitro. Fibrillar Abeta(42) uptake was significantly attenuated by the deficiency or knockdown of C3 or Mac-1 and scavenger receptor class A ligands. In addition, C3 or Mac-1 knockdown combined with a scavenger receptor ligand, fucoidan, further attenuated fibrillar Abeta(42) uptake by N9 microglia. Fluorescent fibrillar Abeta(42) microinjected cortically was significantly higher in C3 and Mac-1 knockout mice compared with wild-type mice 5 days after surgery, indicating reduced clearance in vivo. Together, these results demonstrate that C3 and Mac-1 are involved in phagocytosis and clearance of fAbeta by microglia, providing support for a potential beneficial role for microglia and the complement system in AD pathogenesis. (c) 2012 Wiley Periodicals, Inc. PMID- 22438047 TI - Non-invasive quantification of tumor vascular architecture during docetaxel chemotherapy. AB - New ultrasound parameters, potentially predictive of tumor response to chemotherapy, were sought after analyzing details of vascular architecture of mammary tumors during chemotherapy. Tumor-bearing rats were separated into untreated or docetaxel-treated group (6 mg/kg/week). Power Doppler Index and vascular contrast-enhanced ultrasound (CEUS) reference endpoints (Peak, area under the curve (AUC), blood flow) were evaluated at the beginning (W (0)), and after 2 and 6 weeks of docetaxel treatment (W (+2) and W (+6)). An improved CEUS image analysis, taking advantage of individual pixel intensity, was developed to quantify large, medium, and small vessels of tumors. Standard immunohistochemistry validated this new methodology analyzing tumor vascular architecture. In rats, there was an enrichment of vascularization with large vessels during tumor growth indicative of a vascular adjustment to tumor size. Docetaxel stopped tumor growth, and showed a sequential effect on vascular parameters. After an initial enrichment in larger vessels (by threefold) at W (+2), docetaxel led to a diminution of vascular parameters at W (+6) (-46 % for peak, -55 % for AUC -31 % compared to W (0)) and a vascular remodeling in favor of small vessels. One of the CEUS parameters measured before chemotherapy, the so called global contrast-enhanced pixels density, was predictive of rat tumor response to treatment (r = 0.80; p < 0.01). The method was then applied in a clinical setting to detect changes of vascular architecture during chemotherapy of human breast carcinoma. The docetaxel chemotherapy of breast carcinomas induced a similar sequential effect, with vessel enlargement after two cycles of docetaxel treatment and an antiangiogenic effect after six cycles. Such vascular remodeling was not noticed when patients were treated with 5-fluorouracil epirubicin-cyclophosphamide. Taken together, the sharpened analysis of CEUS pixel intensity presented here strengthened the monitoring of breast tumor vasculature with the potential to improve the prediction of docetaxel efficacy. PMID- 22438048 TI - Introduction to special issue translational goals of neoadjuvant therapy. PMID- 22438049 TI - Accuracy of BRCA1/2 mutation prediction models in Korean breast cancer patients. AB - BRCAPRO and Myriad II are widely used models for predicting BRCA1/2 mutation probability before genetic testing. However, the accuracy of these models in Koreans is not known. This study was performed to evaluate the accuracy of the BRCAPRO and Myriad II models. Two hundred thirty-six women with breast cancer who underwent comprehensive BRCA1/2 genetic testing at our hospital between 2003 and 2010 were included in this study. We evaluated the performance of each model by comparing the numbers of observed versus predicted mutation carriers. We calculated sensitivity, specificity, and predictive values at 10 % estimated probability. Forty-six individuals were identified to carry a deleterious BRCA mutation. The prevalence of BRCA mutation (19.5 %) was significantly higher than that predicted by BRCAPRO (9.0 %, p = 0.001) and Myriad (5.6 %, p < 0.001). In familial breast cancer patients, BRCA mutation rate (observed 22.7 %) was underestimated by both BRCAPRO (expected 11.4 %, p = 0.006) and Myriad II (expected 6.4 %, p < 0.001). Subgroup analyses showed that both models underestimated the risk of BRCA mutation in patients with a family history of breast cancer (probands' age at breast cancer diagnosis >50 years), with only one relative with breast cancer, and with non-familial early-onset breast cancer or bilateral breast cancer. Using a 10 % cut-off, the sensitivities were 47.8 % (BRCAPRO) and 50.0 % (Myriad), and positive predictive values were 44.9 % (BRCAPRO) and 43.4 % (Myriad). Both BRCAPRO and Myriad II underestimated the risk of BRCA1/2 mutation in Koreans. Our findings suggest that these models are less sensitive in Korean women, and therefore a new BRCA mutation prediction model based on Korean data is needed for proper genetic counseling. PMID- 22438050 TI - The fibroblast growth factor receptor 1 (FGFR1), a marker of response to chemoradiotherapy in breast cancer? AB - The goal of the present study was to evaluate the role of the tyrosine kinase receptor fibroblast growth factor-1 (FGFR1) and its ligand, the fibroblast growth factor 2 (FGF2) in determining the response to chemoradiotherapy of breast cancers. S14 was a phase II neoadjuvant study carried out at the Institut Curie that recruited 59 patients between November 2001 and September 2003. This prospective study aimed to assess the pathological response after preoperative radiochemotherapy (5FU-Navelbine-radiotherapy) for large breast cancers. The expression of FGFR1 and FGF2 in tumor cells were assessed by immunohistochemistry. Tumors in which no staining was seen, were considered as negative for that protein. We used the Khi-2 test or the Fisher test to compare the qualitative variables and the Student t test or the non-parametric Wilcoxon test for the quantitative variables. We included in the present study all the 32 patients from the S14 cohort for whom the tissue blocks from the biopsy specimens were available with sufficient tumoral tissue. FGFR1 and FGF2 staining were observed respectively in 17 (56%) and 22 (68%) of the 32 tumoral biopsies. The expression of FGFR1 was associated with the hormone receptor positive status (p=0.0191). Only 11% (1/9) of the high grade tumors failed to respond to chemoradiotherapy compared to 68 % resistant tumors (15/22) among the low/intermediate grade tumors (p=0.0199). Among the low/intermediate grade tumors, FGFR1 negative tumors did not respond to chemoradiotherapy (0/9), compared with tumors expressing FGFR1 among which, almost one half had a good response (6/13) (p=0.0167). Among the low and intermediate grade breast cancers, the FGFR1 negative tumors were resistant to chemoradiotherapy. The expression of FGFR1 in patients' biopsies may serve as a marker of response to chemoradiotherapy. PMID- 22438051 TI - Using neoadjuvant therapy for breast cancer in clinical practice: when and how? PMID- 22438052 TI - Climate change in Europe and effects on thermal resources for crops. AB - Atmospheric variables play a fundamental role in driving man-managed ecosystems and more specifically in agro-ecosystems, determining the quantity and quality of crop production. On the other hand, climate variability can be seen as the superimposition of gradual and abrupt changes. This paper is focused on European surface air temperature in the period 1951-2010. Analysis of this dataset identified breakpoints that define two homogeneous sub-periods: 1951-1987 and 1988-2010. Thermal resources for crops were analyzed adopting a "normal heat hours" approach. Computation highlighted a general increase in thermal resources in the European continent for crop groups II and III (C3 and C4 plants adapted to high or moderate temperatures), while a decline of thermal resources for crop group I (cold adapted C3) was highlighted in the Mediterranean area. The climate variability justifies a change in the potential latitudinal limits of different groups of crops, representing a fundamental step for crop adaptation to climate change. PMID- 22438053 TI - A respiratory alert model for the Shenandoah Valley, Virginia, USA. AB - Respiratory morbidity (particularly COPD and asthma) can be influenced by short term weather fluctuations that affect air quality and lung function. We developed a model to evaluate meteorological conditions associated with respiratory hospital admissions in the Shenandoah Valley of Virginia, USA. We generated ensembles of classification trees based on six years of respiratory-related hospital admissions (64,620 cases) and a suite of 83 potential environmental predictor variables. As our goal was to identify short-term weather linkages to high admission periods, the dependent variable was formulated as a binary classification of five-day moving average respiratory admission departures from the seasonal mean value. Accounting for seasonality removed the long-term apparent inverse relationship between temperature and admissions. We generated eight total models specific to the northern and southern portions of the valley for each season. All eight models demonstrate predictive skill (mean odds ratio = 3.635) when evaluated using a randomization procedure. The predictor variables selected by the ensembling algorithm vary across models, and both meteorological and air quality variables are included. In general, the models indicate complex linkages between respiratory health and environmental conditions that may be difficult to identify using more traditional approaches. PMID- 22438054 TI - The proto-oncogene Myc is essential for mammary stem cell function. AB - The mammary epithelium comprises two major cell lineages: basal and luminal. Basal cells (BCs) isolated from the mammary epithelium and transplanted into the mouse mammary fat pad cleared from the endogenous epithelium regenerate the mammary gland, strongly suggesting that the basal epithelial compartment harbors a long-lived cell population with multipotent stem cell potential. The luminal cell layer is devoid of the regenerative potential, but it contains cells with clonogenic capacity, the luminal progenitors. Mammary BCs and luminal progenitors express high levels of the transcription factor Myc. Here, we show that deletion of Myc from mammary basal epithelial cells led to impaired stem cell self-renewal as evaluated by limiting dilution and serial transplantation assays. Luminal progenitor population was significantly diminished in mutant epithelium suggesting control by the BC layer. Colony formation assay performed with isolated BCs showed that clonogenic capacity was abolished by Myc deletion. Moreover, transplanted BCs depleted of Myc failed to produce epithelial outgrowths. Stimulation with ovarian hormones estrogen (E) and progesterone (P) partially rescued the repopulation capacity of Myc-depleted BCs; however, the Myc deficient mammary epithelium developed in response to E/P treatment lacked stem and progenitor cells. This study provides the first evidence that in the mammary gland, Myc has an essential nonredundant function in the maintenance of the self renewing multipotent stem cell population responsible for the regenerative capacity of the mammary epithelium and is required downstream from ovarian hormones, for the control of mammary stem and progenitor cell functions. PMID- 22438055 TI - Meat consumption, heterocyclic amines and colorectal cancer risk: the Multiethnic Cohort Study. AB - Greater consumption of red and processed meat has been associated with an increased risk of colorectal cancer in several recent meta-analyses. Heterocyclic amines (HCAs) have been hypothesized to underlie this association. In this prospective analysis conducted within the Multiethnic Cohort Study, we examined whether greater consumption of total, red or processed meat was associated with the risk of colorectal cancer among 165,717 participants who completed a detailed food frequency questionnaire at baseline. In addition, we examined whether greater estimated intake of HCAs was associated with the risk of colorectal cancer among 131,763 participants who completed a follow-up questionnaire that included a meat-cooking module. A total of 3,404 and 1,757 invasive colorectal cancers were identified from baseline to the end of follow-up and from the date of administration of the meat-cooking module to the end of follow-up, respectively. Proportional hazard models were used to estimate basic and multivariable-adjusted relative risks (RRs) and 95% confidence intervals for colorectal cancer associated with dietary exposures. In multivariable models, no association with the risk of colorectal cancer was detected for density-adjusted total meat (RR(Q5 vs. Q1) = 0.93 [0.83-1.05]), red meat (RR = 1.02 [0.91-1.16]) or processed meat intake (RR = 1.06 [0.94-1.19]) or for total (RR = 0.90 [0.76 1.05]) or specific HCA intake whether comparing quintiles of dietary exposure or using continuous variables. Although our results do not support a role for meat or for HCAs from meat in the etiology of colorectal cancer, we cannot rule out the possibility of a modest effect. PMID- 22438056 TI - Synthetic bio-nanoreactor: mechanical and chemical control of polymersome membrane permeability. PMID- 22438058 TI - Severe haematological complications during treatment with natalizumab. AB - The safety profile of natalizumab has been widely discussed due to several cases of progressive multifocal leukoencephalopathy, reported worldwide. Since the launch of natalizumab, 32 patients have been treated at our centre. In this context, we describe two cases (6.25%), one of immune-mediated acute haemolytic anaemia (IAHA) and another of immune thrombocytopenic purpura during treatment with natalizumab. The temporal relationship between drug administration and the nature of the haematological complications, confirmed with the serological findings in the case of the IAHA, suggests that natalizumab is the most probable cause for these adverse events. Although very uncommon, the haematological complications are severe enough to justify a close and careful monitoring for all patients with multiple sclerosis treated with an immunosuppressant treatment. PMID- 22438059 TI - CADM1 isoforms differentially regulate human mast cell survival and homotypic adhesion. AB - Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (~80% of clones), as well as SP1 (exons 7/8/9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1(L), but not Blc-2 or Bcl-X(L), and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases. PMID- 22438060 TI - Robotic assistance may reduce conversion to open in rectal carcinoma laparoscopic surgery: systematic review and meta-analysis. AB - BACKGROUND: We hypothesized that robotic assistance (RARS) could provide better intraoperative and short-term outcomes than a traditional laparoscopic approach (LARS) to rectal cancer surgery. METHODS: Systematic review of the literature, including electronic searches and communications to international robotic meetings. INCLUSION CRITERIA: studies involving rectal cancer patients and comparing outcomes of robotic surgery vs laparoscopic surgery. Primary end points: conversion and postoperative short-term complications. Meta-analysis performed using Review Manager 5.0 software. RESULTS: Five case-control studies involving 486 patients (203 RARS-283 LARS) were finally included. Conversion to open rate (RR = 0.31; 95% CI 0.12,0.78) was lower for RARS. No differences were found in oncological outcomes, hospital stay or anastomotic leakage. CONCLUSIONS: This meta-analysis of available non-randomized studies suggests that conversion to open rate may be reduced when using RARS instead of LARS for rectal cancer. PMID- 22438061 TI - Biochemical and proteomic characterization of a novel extracellular beta glucosidase from Trichoderma citrinoviride. AB - beta-Glucosidases are of pivotal importance in bioconversion of carbonic biomass into fermentable and other useful metabolites, food industry, biotransformation, glyco-trimming of metabolome, etc. Trichoderma citrinoviride when grown on delignified Lantana camara produced a beta-glucosidase and secreted it out in the medium. The extracellularly secreted beta-glucosidase of T. citrinoviride was homogeneity purified and then characterized for its kinetic properties and proteomic characteristics. The 90 kDa enzyme was monomeric in nature, optimally active at pH 5.5 and the catalytic reaction rate was highest at 55 degrees C. Uniquely, the enzyme was insensitive to inhibition by glucose (up to 5 mM). It also possessed catalytic ability of transglycosylation, as it could catalyze conversion of geraniol into its glucoside. MALDI-TOF assisted proteomic analysis revealed its high degree of sequence similarity with family 3 glycoside hydrolases. PMID- 22438062 TI - Quantitative phosphoproteome profiling of iron-deficient Arabidopsis roots. AB - Iron (Fe) is an essential mineral nutrient for plants, but often it is not available in sufficient quantities to sustain optimal growth. To gain insights into adaptive processes to low Fe availability at the posttranslational level, we conducted a quantitative analysis of Fe deficiency-induced changes in the phosphoproteome profile of Arabidopsis (Arabidopsis thaliana) roots. Isobaric tags for relative and absolute quantitation-labeled phosphopeptides were analyzed by liquid chromatography-tandem mass spectrometry on an LTQ-Orbitrap with collision-induced dissociation and high-energy collision dissociation capabilities. Using a combination of titanium dioxide and immobilized metal affinity chromatography to enrich phosphopeptides, we extracted 849 uniquely identified phosphopeptides corresponding to 425 proteins and identified several not previously described phosphorylation motifs. A subset of 45 phosphoproteins was defined as being significantly changed in abundance upon Fe deficiency. Kinase motifs in Fe-responsive proteins matched to protein kinase A/calcium calmodulin-dependent kinase II, casein kinase II, and proline-directed kinase, indicating a possible critical function of these kinase classes in Fe homeostasis. To validate our analysis, we conducted site-directed mutagenesis on IAA-CONJUGATE-RESISTANT4 (IAR4), a protein putatively functioning in auxin homeostasis. iar4 mutants showed compromised root hair formation and developed shorter primary roots. Changing serine-296 in IAR4 to alanine resulted in a phenotype intermediate between mutant and wild type, whereas acidic substitution to aspartate to mimic phosphorylation was either lethal or caused an extreme dwarf phenotype, supporting the critical importance of this residue in Fe homeostasis. Our analyses further disclose substantial changes in the abundance of phosphoproteins involved in primary carbohydrate metabolism upon Fe deficiency, complementing the picture derived from previous proteomic and transcriptomic profiling studies. PMID- 22438063 TI - The Arabidopsis thaliana SET-domain-containing protein ASHH1/SDG26 interacts with itself and with distinct histone lysine methyltransferases. AB - Polycomb group (PcG) and trithorax group (trxG) proteins are key regulators of homeotic genes and have central roles in cell proliferation, growth and development. In animals, PcG and trxG proteins form higher order protein complexes that contain SET domain proteins with histone methyltransferase activity, and are responsible for the different types of lysine methylation at the N-terminal tails of the core histone proteins. However, whether H3K4 methyltransferase complexes exist in Arabidopsis thaliana remains unknown. Here, we make use of the yeast two-hybrid system and the bimolecular fluorescence complementation assay to provide evidence for the self-association of the Arabidopsis thaliana SET-domain-containing protein SET DOMAIN GROUP 26 (SDG26), also known as ABSENT, SMALL, OR HOMEOTIC DISCS 1 HOMOLOG 1 (ASHH1). In addition, we show that the ASHH1 protein associates with SET-domain-containing sequences from two distinct histone lysine methyltransferases, the ARABIDOPSIS HOMOLOG OF TRITHORAX-1 (ATX1) and ASHH2 proteins. Furthermore, after screening a cDNA library we found that ASHH1 interacts with two proteins from the heat shock protein 40 kDa (Hsp40/DnaJ) superfamily, thus connecting the epigenetic network with a system sensing external cues. Our findings suggest that trxG complexes in Arabidopsis thaliana could involve different sets of histone lysine methyltransferases, and that these complexes may be engaged in multiple developmental processes in Arabidopsis. PMID- 22438064 TI - Distribution quantification on dermoscopy images for computer-assisted diagnosis of cutaneous melanomas. AB - Computerised analysis on skin lesion images has been reported to be helpful in achieving objective and reproducible diagnosis of melanoma. In particular, asymmetry in shape, colour and structure reflects the irregular growth of melanin under the skin and is of great importance for diagnosing the malignancy of skin lesions. This paper proposes a novel asymmetry analysis based on a newly developed pigmentation elevation model and the global point signatures (GPSs). Specifically, the pigmentation elevation model was first constructed by computer based analysis of dermoscopy images, for the identification of melanin and haemoglobin. Asymmetry of skin lesions was then assessed through quantifying distributions of the pigmentation elevation model using the GPSs, derived from a Laplace-Beltrami operator. This new approach allows quantifying the shape and pigmentation distributions of cutaneous lesions simultaneously. Algorithm performance was tested on 351 dermoscopy images, including 88 malignant melanomas and 263 benign naevi, employing a support vector machine (SVM) with tenfold cross validation strategy. Competitive diagnostic results were achieved using the proposed asymmetry descriptor only, presenting 86.36 % sensitivity, 82.13 % specificity and overall 83.43 % accuracy, respectively. In addition, the proposed GPS-based asymmetry analysis enables working on dermoscopy images from different databases and is approved to be inherently robust to the external imaging variations. These advantages suggested that the proposed method has good potential for follow-up treatment. PMID- 22438065 TI - Engineering axially vascularized bone in the sheep arteriovenous-loop model. AB - Treatment of complex bone defects in which vascular supply is insufficient is still a challenge. To overcome the limitations from autologous grafts, a sheep model has been established recently, which is characterized by the development of an independent axial vascularization of a bioartificial construct, permitting microsurgical transplantation. To engineer independently axially vascularized bone tissue in the sheep arteriovenous (AV)-loop model, mesenchymal stem cells (MSCs), without and in combination with recombinant human bone morphogenetic protein-2 (rhBMP-2), were harvested and directly autotransplanted in combination with beta-tricalcium phosphate-hydroxyapatite (beta-TCP-HA) granules into sheep in this study. After explantation after 12 weeks, histological and immunohistochemical evaluation revealed newly formed bone in both groups. An increased amount of bone area was obtained using directly autotransplanted MSCs with rhBMP-2 stimulation. Osteoblastic and osteoclastic cells were detected adjacent to the newly formed bone, revealing an active bone remodelling process. Directly autotransplanted MSCs can be found close to the beta-TCP-HA granules and are contributing to bone formation. Over time, magnetic resonance imaging (MRI) and micro-computed tomography (MUCT) imaging confirmed the dense vascularization arising from the AV-loop. This study shows de novo engineering of independently axially vascularized transplantable bone tissue in clinically significant amounts, using directly autotransplanted MSCs and rhBMP-2 stimulation in about 12 weeks in the sheep AV-loop model. This strategy of engineering vascularized transplantable bone tissue could be possibly transferred to the clinic in the future in order to augment current reconstructive strategies. PMID- 22438066 TI - Spatially distinct mitochondrial populations exhibit different mitofilin levels. AB - Subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria exhibit unique biochemical and functional properties; however, their association with structural membrane proteins that control mitochondrial morphology and functionality in striated muscle tissue was never reported. In IMF and SS mitochondria isolated from rat heart and gastrocnemius muscle, we analysed the expression levels of mitofilin, a mitochondria-associated protein involved in organelle structure maintenance. The statistically significant higher amounts of mitofilin detected in IMF compared with SS mitochondria, 37-fold in cardiac tissue and 3.8-fold in gastrocnemius, together with the specific energetic requirements of these mitochondrial populations highlight the importance of mitofilin in oxidative phosphorylation functionality and in mitochondrial plasticity in striated muscle. The differential expression levels of mitofilin between IMF and SS also suggest that this protein can be used as a specific molecular marker to comparatively discriminate spatially distant mitochondrial populations. PMID- 22438067 TI - Quercetin increased bioavailability and decreased methylation of green tea polyphenols in vitro and in vivo. AB - The extensive methylation of green tea polyphenols (GTPs) in vivo may limit their chemopreventive potential. We investigated whether quercetin, a natural inhibitor of catechol-O-methyltransferase (COMT) and multidrug resistance proteins (MRPs), will differentially increase the intracellular concentration and decrease the methylation of GTPs in different cancer cell lines. Intrinsic COMT activity was lowest in lung cancer A549 cells, intermediate in kidney 786-O cells and highest in liver HepG2 cells. Quercetin increased the cellular absorption of epigallocatechin gallate (EGCG) four-fold in A549 cells with a decreased methylation rate from 63 to 19%, 2-fold in 786-O cells with a decreased methylation from 97% to 56%, while no significant effect was observed in HepG2 cells. The combination significantly decreased the activity and protein expression of COMT and decreased the protein expression of MRP1 compared to individual treatments. The combination exhibited the strongest increase in antiproliferation in A549 cells, an intermediate effect in 786-O cells and lowest effect in HepG2 cells. The effect of quercetin on bioavailability and metabolism of GTPs was confirmed in vivo. Severe combined immunodeficiency (SCID) mice were administered brewed green tea (GT) and a diet supplemented with 0.4% quercetin alone or in combination for 2 weeks. We observed a 2- to 3-fold increase of total and non-methylated EGCG in lung and kidney and an increasing trend in liver. In summary, combining quercetin with GT provides a promising approach to enhance the chemoprevention of GT. Responses of different cancers to the combination may vary by tissue depending on the intrinsic COMT and MRP activity. PMID- 22438068 TI - Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma. AB - BACKGROUND: Genomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas (CRCs) compared to normal tissue. Some of these genes were linked to epithelial-mesenchymal transition. We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data. METHODS: Tissue microarrays of 402 R0-resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers. Furthermore, mRNA expression of desmocollins was evaluated in eight colon cancer cell lines. Demethylation test was performed by treatment with 5-aza-2'-deoxycytide in five colon cancer cell lines. RESULTS: On protein level, high expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2%. Reduced expression of DSC1-3 was statistically linked to higher grading and DSC2, E-cadherin and CDX2 with shorter survival in high-grade carcinomas. Multivariate analysis showed that pathological stage and low PITX1 expression were statistically associated with shorter patients survival. On mRNA level, seven out of eight cell lines exhibited no expression of DSC1, and four out of seven restored DSC1 expression after demethylation test. CONCLUSIONS: Reduced expression of PITX1 was independently correlated to shorter patients survival and could serve as a prognostic marker. Decreased expression of DSC1-3 is significantly correlated with higher tumor grading. Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells. PMID- 22438069 TI - Light-driven plasmonic color filters by overlaying photoresponsive liquid crystals on gold annular aperture arrays. PMID- 22438070 TI - Self-supported chiral titanium cluster (SCTC) as a robust catalyst for the asymmetric cyanation of imines under batch and continuous flow at room temperature. AB - A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine-cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self-supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium-alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98 % enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed-bed reactor to carry out the cyanation under continuous flow. Up to 97 % ee and quantitative conversion with a throughput of 45 mg h(-1) were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three-component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98 %. Synthetically useful ee values were also obtained for challenging alpha-branched aliphatic aldehyde by using the three-component continuous Strecker reaction. PMID- 22438071 TI - Physiological, pathophysiological and therapeutic impact of the enteric serotonergic system. AB - Serotonin (5-hydroxytryptamine, 5-HT) induces various effects in the central nervous system, cardiovascular system and gastrointestinal tract. The response depends primarily on the nature of the 5-HT receptors involved. In the light of the current knowledge about the anatomy and physiology of the serotonergic system and the distribution of the various 5-HT receptors in the gut, the established and potential therapeutic impact of 5-HT receptor ligands are discussed. In particular, selective 5-HT receptor ligands influencing intestinal motility and pain perception such as the 5-HT4 receptor agonist prucalopride appear promising for the treatment of irritable bowel syndrome. PMID- 22438072 TI - Phase IV study comparing diurnal glycemic profile following the administration of 2 NPH plus regular human DNA recombinant insulin regimens in type 1 diabetes mellitus (T1DM) adult patients. AB - Intensive insulin therapy (IIT) based on multiple daily injections of long plus rapid-acting insulin has been demonstrated to reduce mortality and morbidity associated with chronic hyperglycemia in T1DM patients. The objective of this study was to assess and compare the postprandial glycemic profile over a diurnal 12 h-period produced by the administration of a new NPH plus regular human DNA recombinant IIT (test regimen) relative to the reference IIT in T1DM patients. A phase IV, single-center, open-label, randomized, multiple-dose, balanced, cross over study in 12 T1DM patients was conducted. Patients were assigned to receive either the test (Densulin(r) N (NPH) plus Densulin(r) R (regular),100 UI/ml, Denver Farma, Argentina) followed by the reference (InsulatardHM(r) (NPH) plus ActrapidHM(r),100 UI/ml, Novo Nordisk Pharma Argentina) regimens or viceversa, according to a random sequence. Each treatment regimen consisted of 2 phases of an ambulatory run-in period of 7 days followed by 12 h confinement period. Blood glucose levels were measured. Glycemic profile was evaluated through glycemic plasma-concentration time curves, area under the time-concentration glycemic curves from basal to 2 h (GlyAUC0-2) and to 12 h (GlyAUC0-12) postprandial, and maximum glycemic postprandial concentration (GlyCmax). 12 hour glycemic concentration-time curves were similar for both test and reference regimens. Geometric least square means ratios Test/ref regimens and their 90% confidence interval for GlyAUC0-2, GlyAUC0-12 and GlyCmax were 94.33 (81.13-125.09), 107.75 (94.05-123.45) and 105 (92.89-118.68), respectively. Both regimens presented similar safety profile. This study demonstrated that the new human DNA recombinant NPH and regular insulin is equally effective to the reference regimen for postprandial diurnal glycemic profile. PMID- 22438073 TI - Mammographic breast density and breast cancer risk by menopausal status, postmenopausal hormone use and a family history of breast cancer. AB - PURPOSE: Few studies have investigated the association between breast density and breast cancer by a family history of breast cancer, menopausal status, and postmenopausal hormone use (PMH). We investigated if associations of breast density and breast cancer differ according to the status of these risk factors. METHODS: This study included 1,481 incident breast cancer cases diagnosed within the Nurses' Health Study I and II cohorts and 2,779 matched controls. Breast density was measured from digitized film images with computerized techniques. Information on breast cancer risk factors was obtained prospectively from the biennial questionnaires before the date of the cancer diagnosis for cancer cases and their matched controls. The data were analyzed with logistic regression. RESULTS: Breast cancer risk increased with increasing percent breast density in all strata (p for trend in all subsets <0.0001). The density-related risk of breast cancer was similar in women with and without a family history (OR = 4.00 [95 % CI 2.01-7.94] vs. 3.71 [95 % CI 2.79-4.94] for density >=50 % vs. <10 %, p for interaction = 0.53). The magnitude of the association between density and breast cancer risk, however, appeared to be stronger in premenopausal women than in postmenopausal women without PMH history (OR = 5.49 [95 % CI 2.44-12.39] vs. 3.02 [95 % CI 1.62-5.63] for density >=50 % vs. <10 %, p-heterogeneity = 0.17) and appeared to be stronger in postmenopausal women currently using hormones compared with postmenopausal women who never used PMH (OR = 4.50 [95 % CI 2.99 6.78] vs. 3.02, p-heterogeneity = 0.20) or with past hormone use (OR = 4.50 vs. 3.71 [95 % CI 1.90-7.23], p-heterogeneity = 0.23). CONCLUSIONS: Findings on associations by menopausal status/hormone use are suggestive and should be examined in additional larger studies. PMID- 22438074 TI - Ethnic differences in smoking rate, nicotine dependence, and cessation-related variables among adult smokers in Hawaii. AB - This study tests hypotheses concerning ethnic disparities in daily cigarette smoking rates, nicotine dependence, cessation motivation, and knowledge and past use of cessation methods (e.g., counseling) and products (e.g., nicotine patch) in a multiethnic sample of smokers in Hawaii. Previous research has revealed significant differences in smoking prevalence among Native Hawaiians, Filipinos, Japanese, and Caucasians in Hawaii. However, no study has examined differences in dependence and cessation-related knowledge and practices among smokers representing these ethnic groups. Participants were recruited through newspaper advertisement as part of a larger smoking cessation intervention study. Participants (N = 919; M age = 45.6, SD = 12.7; 48 % women) eligible to participate provided self-report data through mail and telephone. Participants included 271 self-identified Native Hawaiians, 63 Filipinos, 316 Caucasians, 145 "East Asians" (e.g., Japanese, Chinese), and 124 "other" (e.g., Hispanic, African American). Pair-wise comparisons of means, controlling for age, gender, income, education, and marital status, indicated that Native Hawaiian smokers reported significantly higher daily smoking rates and higher levels of nicotine dependence compared to East Asians. Native Hawaiian smokers reported significantly lower motivation to quit smoking than Caucasians. Further, Filipino and Native Hawaiian smokers reported lesser knowledge of cessation methods and products, and less frequent use of these methods and products than Caucasians. The results suggest that Native Hawaiian and Filipino smokers could be underserved with regard to receiving cessation-related advice, and may lack adequate access to smoking cessation products and services. In addition, cessation interventions tailored for Native Hawaiian smokers could benefit from a motivational enhancement component. PMID- 22438075 TI - Dietary intake of iron, heme-iron and magnesium and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort. AB - Several studies support a protective effect of dietary magnesium against type 2 diabetes, but a harmful effect for iron. As diabetes has been linked to pancreatic cancer, intake of these nutrients may be also associated with this cancer. We examined the association between dietary intake of magnesium, total iron and heme-iron and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In total, 142,203 men and 334,999 women, recruited between 1992 and 2000, were included. After an average follow-up of 11.3 years, 396 men and 469 women developed exocrine pancreatic cancer. Hazard ratios and 95% confidence intervals (CIs) were obtained using Cox regression stratified by age and center, and adjusted for energy intake, smoking status, height, weight, and self-reported diabetes status. Neither intake of magnesium, total iron nor heme-iron was associated with pancreatic cancer risk. In stratified analyses, a borderline inverse association was observed among overweight men (body mass index, >= 25 kg/m(2) ) with magnesium (HR(per 100 mg/day increase) = 0.79, 95% CI = 0.63-1.01) although this was less apparent using calibrated intake. In female smokers, a higher intake of heme-iron was associated with a higher pancreatic cancer risk (HR (per 1 mg/day increase) = 1.38, 95% CI = 1.10-1.74). After calibration, this risk increased significantly to 2.5-fold (95% CI = 1.22-5.28). Overall, dietary magnesium, total iron and heme iron were not associated with pancreatic cancer risk during the follow-up period. Our observation that heme-iron was associated with increased pancreatic cancer risk in female smokers warrants replication in additional study populations. PMID- 22438076 TI - X-ray-visible microcapsules containing mesenchymal stem cells improve hind limb perfusion in a rabbit model of peripheral arterial disease. AB - The therapeutic goal in peripheral arterial disease (PAD) patients is to restore blood flow to ischemic tissue. Stem cell transplantation offers a new avenue to enhance arteriogenesis and angiogenesis. Two major problems with cell therapies are poor cell survival and the lack of visualization of cell delivery and distribution. To address these therapeutic barriers, allogeneic bone marrow derived mesenchymal stem cells (MSCs) were encapsulated in alginate impregnated with a radiopaque contrast agent (MSC-Xcaps). In vitro MSC-Xcap viability by a fluorometric assay was high (96.9% +/- 2.7% at 30 days postencapsulation) and as few as 10 Xcaps were visible on clinical x-ray fluoroscopic systems. Using an endovascular PAD model, rabbits (n = 21) were randomized to receive MSC-Xcaps (n = 6), empty Xcaps (n = 5), unencapsulated MSCs (n = 5), or sham intramuscular injections (n = 5) in the ischemic thigh 24 hours postocclusion. Immediately after MSC transplantation and 14 days later, digital radiographs acquired on a clinical angiographic system demonstrated persistent visualization of the Xcap injection sites with retained contrast-to-noise. Using a modified TIMI frame count, quantitative angiography demonstrated a 65% improvement in hind limb perfusion or arteriogenesis in MSC-Xcap-treated animals versus empty Xcaps. Post mortem immunohistopathology of vessel density by anti-CD31 staining demonstrated an 87% enhancement in angiogenesis in Xcap-MSC-treated animals versus empty Xcaps. MSC-Xcaps represent the first x-ray-visible cellular therapeutic with enhanced efficacy for PAD treatment. PMID- 22438077 TI - Cosmetics and pharmaceutics: new trends in biophysical approaches. Preface. PMID- 22438078 TI - Characterization of callase (beta-1,3-D-glucanase) activity during microsporogenesis in the sterile anthers of Allium sativum L. and the fertile anthers of A. atropurpureum. AB - We examined callase activity in anthers of sterile Allium sativum (garlic) and fertile Allium atropurpureum. In A. sativum, a species that produces sterile pollen and propagates only vegetatively, callase was extracted from the thick walls of A. sativum microspore tetrads exhibited maximum activity at pH 4.8, and the corresponding in vivo values ranged from 4.5 to 5.0. Once microspores were released, in vitro callase activity peaked at three distinct pH values, reflecting the presence of three callase isoforms. One isoform, which was previously identified in the tetrad stage, displayed maximum activity at pH 4.8, and the remaining two isoforms, which were novel, were most active at pH 6.0 and 7.3. The corresponding in vivo values ranged from pH 4.75 to 6.0. In contrast, in A. atropurpureum, a sexually propagating species, three callase isoforms, active at pH 4.8-5.2, 6.1, and 7.3, were identified in samples of microsporangia that had released their microspores. The corresponding in vivo value for this plant was 5.9. The callose wall persists around A. sativum meiotic cells, whereas only one callase isoform, with an optimum activity of pH 4.8, is active in the acidic environment of the microsporangium. However, this isoform is degraded when the pH rises to 6.0 and two other callase isoforms, maximally active at pH 6.0 and 7.3, appear. Thus, factors that alter the pH of the microsporangium may indirectly affect the male gametophyte development by modulating the activity of callase and thereby regulating the degradation of the callose wall. PMID- 22438079 TI - First-principles design of highly active and selective catalysts for phosgene free synthesis of aromatic polyurethanes. PMID- 22438080 TI - High-efficiency si/polymer hybrid solar cells based on synergistic surface texturing of Si nanowires on pyramids. AB - An efficient Si/PEDOT:PSS hybrid solar cell using synergistic surface texturing of Si nanowires (SiNWs) on pyramids is demonstrated. A power conversion efficiency (PCE) of 9.9% is achieved from the cells using the SiNW/pyramid binary structure, which is much higher than similar cells based on planar Si, pyramid textured Si, and SiNWs. The PCE is the highest reported to-date for hybrid cells based on Si nanostructures and PEDOT. PMID- 22438082 TI - Context by treatment interactions as the primary object of study in cluster randomized controlled trials of population health interventions. AB - Cluster randomized controlled trials are increasingly used in population health intervention research. Through randomization, researchers attempt to isolate the treatment effect and remove all other effects, including any effects of social context. In many cases, the constant effect assumption cannot be satisfied in cluster randomized controlled trials. We argue that when studying population health interventions, the effective mechanism of intervention lies in the interaction between the treatment and social context. Researchers should be cognizant that attempts to remove the effect of social context using CRTC may fail. The interaction between the treatment and social context should be the primary object of study in population health intervention research. PMID- 22438081 TI - TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid beta deposition in APP/PS1 mice. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-beta (Abeta) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Abeta. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Abeta deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Abeta production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of gamma-secretase activity. Consequently, a significant decrease in Abeta(1-40) and Abeta(1-42) levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Abeta production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD. PMID- 22438083 TI - Joint trajectories of multiple health-related behaviors among the elderly. AB - OBJECTIVES: The main goal of this study was to identify the multiple trajectories of the following four health behaviors among the elderly by gender: smoking, drinking alcohol, getting regular exercise, and having a health checkup METHODS: Data were from a longitudinal survey conducted among the elderly from 1996 to 2007 in Taiwan. In total, 5,880 respondents were included in the analysis RESULTS: The trajectories of health-related behaviors differed between males and females. Five groups of male elderly were identified: smoking, inactive, healthy lifestyle, smoking and drinking, and quitting. Three groups of female elderly were identified: smoking and drinking, inactive, and healthy lifestyle. Age, education, self-rated health, depressive symptoms, and economic satisfaction at baseline were associated with the health behavior trajectories CONCLUSION: The nature of healthy behaviors and risky behaviors may differ. Thus, multiple trajectories can exhibit patterns that differ from those of single behavior trajectories. Strategies designed to promote health need to consider both gender and behavior patterns which may change over time. PMID- 22438084 TI - A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy. AB - TGF-beta is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF beta inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-beta and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-beta concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-beta treatment, vaccine treatment, and combined anti-TGF-beta vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy. PMID- 22438085 TI - Thyrotoxicosis after parathyroidectomy mimicking myocardial infarction: a case report and review of the literature. PMID- 22438086 TI - Effect of the application of a casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste and adhesive systems on bond durability of a fissure sealant. AB - This study aimed to evaluate the effect of the previous application of a casein phosphopeptide-amorphous calcium phosphate paste (MI Paste, MI) and adhesive systems on the bond durability of a fissure sealant. Ninety-eight enamel blocks were obtained from proximal surfaces of erupted third molars. Specimens were divided into 14 groups (n = 7) according to the previous application of MI (with and without) and the adhesive systems used (no adhesive system; hydrophobic resin of a three-step etch-and-rinse adhesive system; etch-and-rinse single-bottle adhesive system; all-in-one adhesive system; two-step self-etching adhesive system; additional phosphoric acid conditioning and all-in-one adhesive system; additional phosphoric acid conditioning and two-step self-etching adhesive system). A fissure sealant (Fluroshield) was applied and photoactivated for 20 s. Beams (~0.7 mm(2)) were prepared for the microtensile bond strength test, which was executed after 24 h or 6 months of water storage. Fractured specimens were analyzed by scanning electronic microscopy. Data were analyzed by two-way ANOVA with repeated measures/Tukey's test (P < 0.05). Groups that received MI application and adhesive systems presented higher means than those groups where MI was not applied. Higher frequency of cohesive failures was observed for groups with MI. Applying a CPP-ACP containing paste on enamel before adhesive systems was an effective method to increase bond durability of the sealant tested. PMID- 22438087 TI - Teratoma formation of human embryonic stem cells in three-dimensional perfusion culture bioreactors. AB - Teratoma formation in mice is today the most stringent test for pluripotency that is available for human pluripotent cells, as chimera formation and tetraploid complementation cannot be performed with human cells. The teratoma assay could also be applied for assessing the safety of human pluripotent cell-derived cell populations intended for therapeutic applications. In our study we examined the spontaneous differentiation behaviour of human embryonic stem cells (hESCs) in a perfused 3D multi-compartment bioreactor system and compared it with differentiation of hESCs and human induced pluripotent cells (hiPSCs) cultured in vitro as embryoid bodies and in vivo in an experimental mouse model of teratoma formation. Results from biochemical, histological/immunohistological and ultrastuctural analyses revealed that hESCs cultured in bioreactors formed tissue like structures containing derivatives of all three germ layers. Comparison with embryoid bodies and the teratomas revealed a high degree of similarity of the tissues formed in the bioreactor to these in the teratomas at the histological as well as transcriptional level, as detected by comparative whole-genome RNA expression profiling. The 3D culture system represents a novel in vitro model that permits stable long-term cultivation, spontaneous multi-lineage differentiation and tissue formation of pluripotent cells that is comparable to in vivo differentiation. Such a model is of interest, e.g. for the development of novel cell differentiation strategies. In addition, the 3D in vitro model could be used for teratoma studies and pluripotency assays in a fully defined, controlled environment, alternatively to in vivo mouse models. PMID- 22438088 TI - Successful retrograde arterial inflow through a muscular branch in a free anterolateral thigh chimeric flap transfer. AB - In this report, we present a case in which a free anterolateral thigh (ALT) flap was transferred for head and neck reconstruction after oropharyngeal cancer ablation, and a retrograde arterial inflow was used to salvage the flap when the main arterial pedicle showed usual repeated spasms. The flap was raised as a chimera flap comprising a fasciocutaneous flap and a vastus lateralis muscle flap. After reperfusion, the pedicle artery exhibited spasms repeatedly and vascular flow was unstable. Therefore, we performed arterial supercharge. In the distal portion of the muscle flap, a small arterial branch was dissected as a reverse-flow arterial pedicle. The recipient artery was also a retrograde limb of the superior thyroid artery. The flap survived; however, postoperative ultrasonographic echo evaluation revealed that the spastic descending branch of the lateral circumflex femoral artery was obstructed and that the reverse-flow muscular perforator alone nourished the whole flap. In free ALT flap transfer, a small perforator level artery was able to nourish a flap, even in a retrograde manner. Moreover, when the vasculature of the free flap is unstable, retrograde arterial supply to a small perforator can be an option to save the flap transfer. PMID- 22438089 TI - Coronary artery spasm and ventricular arrhythmias. AB - Coronary artery spasm (CAS) is characterised by chest pain at rest and transient ST segment elevation on the ECG. The natural history of variant angina is not fully understood. Patients with CAS are younger, mostly female subjects and usually do not have traditional cardiovascular risk factors other than cigarette smoking. Cardiac arrhythmias are known to be associated with CAS. Ventricular arrhythmia is a well-recognised complication and sudden cardiac death has also been documented. The most important diagnostic tool in CAS is coronary angiography. 24 h ECG Holter monitoring can be very useful in the diagnosis of ventricular arrhythmias caused by CAS. The mainstay therapy for CAS is calcium channel blockers and nitrates. The use of beta-blockers, especially the non selective group, can promote attacks or prolong vasospastic state. The indication for implantable cardioverter defibrillator (ICD) implantation in a patient with CAS is still not clearly established. The role of primary prevention with the use of ICD is controversial; however, ICD implantation should be considered in high risk patients despite optimal medical treatment. PMID- 22438090 TI - Cooperate concept of metastasis: site-specific requirement of activated differentiation and dynamic deterioration. AB - Cancer metastasis results from positive and negative cellular events such as constitutive activation of oncogenes (cOA) or genetic losses (GL) being modulated by downstream signals of epithelial-mesenchymal or mesenchymal-epithelial transition, thus constituting master programs of metastatic phenotype and site specificity. To address the complex nature of these programs, we introduced clinical and phenotypic markers like tumor size, grade, cellular shape, or expression of E-cadherin in 27 colon cancer (CC) patients (cOA and GL), and 41 patients with gastrointestinal stromal tumors (GIST, cOA) to produce scores of cOA and GL. Scores of cOA were highest in case of hepatic and lower in case of an isolated peritoneal spread (GIST), or (CC) of both, cOA and GL, highest in case of a combined hepatic and peritoneal spread and lower in case of an isolated peritoneal spread; but in case of an isolated hepatic spread, scores of cOA were high and low of GL. This indicates a differential contribution of cellular dissociation and recognition in site-specific metastasis, of cOA predominantly in production of hepatic and in the case of GL of serosal spread. PMID- 22438091 TI - Effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes. AB - Sinensetin is a rare polymethoxylated flavone found in certain citrus fruits. In this study, we investigated the effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes. Sinensetin decreased the expression of sterol regulatory element-binding protein 1c (SREBP1c), suggesting its antiadipogeneic property via downreguation of SREBP1c. Also, sinensetin increased the phosphorylation of protein kinase A and hormone-sensitive lipase, indicating its lipolytic property via a cAMP-mediated signaling pathway. Moreover, sinensetin inhibited insulin-stimulated glucose uptake by decreasing the phosphorylation of insulin receptor substrate and Akt. Furthermore, sinensetin increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. It also upregulated mRNA expression of carnitine palmitoyltransferase-1a, suggesting that sinensetin enhances fatty acid beta oxidation through the AMPK pathway. Taken together, these results suggest that sinensetin may have potential as a natural agent for prevention/improvement of obesity. PMID- 22438092 TI - State of the art of carbon nanotube fibers: opportunities and challenges. AB - The superb mechanical and physical properties of individual carbon nanotubes (CNTs) have provided the impetus for researchers in developing high-performance continuous fibers based upon CNTs. The reported high specific strength, specific stiffness and electrical conductivity of CNT fibers demonstrate the potential of their wide application in many fields. In this review paper, we assess the state of the art advances in CNT-based continuous fibers in terms of their fabrication methods, characterization and modeling of mechanical and physical properties, and applications. The opportunities and challenges in CNT fiber research are also discussed. PMID- 22438093 TI - The face in congenital melanocytic nevus syndrome. AB - Congenital melanocytic nevi (CMN) are known to be associated with neurological abnormalities and melanoma, but have not been considered to be part of a developmental syndrome. The objective of this study was to test our clinical observation that children with CMN show more facial similarities than might be expected by coincidence. We selected facial photographs of 95 white Caucasian children with CMN from our database only on the basis of good neutral views, allowing careful evaluation of facial morphology. These were scored independently by two clinical geneticists using standardized categories and definitions for facial morphology. Prevalence of age-independent features was compared to established norms in a large population, and associations with cutaneous phenotype were investigated. CMN were found to be associated with characteristic facies, and 74% of children in this series had at least three typical features. The characteristic features were: wide or prominent forehead, apparent hypertelorism, eyebrow variants, periorbital fullness, small/short nose, narrow nasal ridge, broad nasal tip, broad or round face, full cheeks, prominent pre maxilla, prominent/long philtrum, and everted lower lip. No association was found with the severity of cutaneous phenotype. We conclude that children with CMN often have a characteristic face. We propose the term "congenital melanocytic nevus syndrome" to describe this association. PMID- 22438094 TI - Family-based early intervention for anorexia nervosa. AB - OBJECTIVE: This study explores whether potential risk factors for anorexia nervosa (AN) can be modified by a family-based Internet-facilitated intervention and examines the feasibility, acceptability, and short-term efficacy of the Parents Act Now programme in the USA and Germany. METHOD: Forty-six girls aged 11 17 were studied during a 12-month period and evaluated at screening, baseline, and post-intervention. Parents participated in the six-week intervention. RESULTS: Twenty-four per cent of girls (n = 791) screened met the risk criteria for AN. Parents accessed the majority of the online sessions and rated the programme favourably. At post-assessment, 16 of 19 participants evidenced reduced risk status. Participants remained stable or increased in ideal body weight and reported decreased eating disorder attitudes and behaviours. DISCUSSION: Results suggest that an easily disseminated, brief, online programme with minimal therapist support is feasible, accepted favourably by parents, and may be beneficial for prevention of exacerbation of AN pathology. PMID- 22438095 TI - Chronic pancreatitis presenting with pseudocyst of pancreas and pseudo-aneurysm of hepatic artery. AB - A 2-y-old girl presented with recurrent abdominal pain and hematemesis. The patient was diagnosed to have chronic calcific pancreatitis complicated by pseudocyst of the head of pancreas and pseudo-aneurysm of the common hepatic artery. Diagnosis was made using abdominal ultrasonography and CT angiography. The rarity of the presentation of pseudocyst with pseudo-aneurysm formation in a pediatric patient is noted. The pseudo-aneurysm was treated by embolization of the artery and the pain being refractory to analgesics was managed by celiac plexus blockade. PMID- 22438096 TI - Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus. AB - BACKGROUND: Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients. METHODS: A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared. RESULTS: TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r (2) = 0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p = 0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p < 0.001). CONCLUSIONS: Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes. PMID- 22438097 TI - Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma. AB - BACKGROUND: In Japan, sorafenib is now the first-line therapy for individuals with advanced hepatocellular carcinoma (HCC), but no other treatment is available for such patients. The aim of this study was to assess the efficacy and safety of combination therapy with systemic continuous intravenous infusion of 5 fluorouracil (5-FU) and subcutaneous peginterferon alfa-2a, which was used before sorafenib was introduced to Japan. METHODS: Two hundred and twenty-three HCC patients, who were not amenable to curative surgery, percutaneous ablation, or transarterial chemoembolization (TACE), and for whom intraarterial chemotherapy was not indicated because of the presence of extrahepatic metastasis or stenosis of the common hepatic artery, received peginterferon alfa-2a (90 MUg subcutaneously on days 1, 8, 15, and 22) and 5-FU (500 mg/day intravenously given continuously on days 1-5 and 8-12). We assessed their response to treatment and survival, and treatment safety. RESULTS: The response rate was 9.4 % (including six patients with complete response) and the disease-control rate was 32.7 %. The median time to progression was 2.0 months. The overall median survival time was 6.5 months (Child-Pugh class A: 9.2 months vs. Child-Pugh class B: 2.8 months). In a multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status >0, Child-Pugh class B, and the presence of macroscopic vascular invasion were independent predictors of poor prognosis. The major grade 3-4 adverse events were leucopenia (13.9 %) and thrombocytopenia (5.8 %). No treatment-related deaths occurred. CONCLUSIONS: This combination therapy was well tolerated and showed promising efficacy. Further studies are needed to establish the usefulness of this treatment. PMID- 22438098 TI - Genetic polymorphism of pri-microRNA 325, targeting SLC6A4 3'-UTR, is closely associated with the risk of functional dyspepsia in Japan. AB - BACKGROUND: The role of genetics in the susceptibility to functional dyspepsia (FD) remains unclear. We attempted to clarify the association between FD and polymorphisms in SLC6A4. In addition, rs5981521 (C>T) in the pri-microRNA 325 (pri-miR-325) coding region was also investigated. METHODS: The study was performed in 395 subjects (172 with no upper abdominal symptoms and 223 with FD, including medication-resistant FD). We employed a polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method to detect gene polymorphisms. RESULTS: Neither SLC6A4 -185 A>C nor *463 G>T was associated with susceptibility to FD. The number of rs5981521 T alleles was significantly correlated with an increased risk for FD (odds ratio [OR] 1.45, 95 % confidence interval [CI] 1.05-1.98; p = 0.022) and the TT homozygote was more closely associated with the risk for FD (OR 3.01, 95 % CI 1.41-6.42; p = 0.0043). The TT homozygote also had significantly increased risks for both the epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) subtypes of FD (OR 3.04, 95 % CI 1.25-7.42; p = 0.014 and OR 3.05, 95 % CI 1.14-8.13; p = 0.026, respectively). In addition, Helicobacter pylori-negative TT homozygotes had a greater risk for FD (OR 8.37, 95 % CI 1.78-39.5; p = 0.0072). In subjects with the SLC6A4 5'-untranslated region (UTR) wild homozygote, the number of rs5981521 T alleles was significantly correlated to an increased risk for FD (OR 1.45, 95 % CI 1.03-2.04, p = 0.033). Of note, in subjects who were SLC6A4 3'-UTR mutant carriers, the number of rs5981521 T alleles was also significantly correlated with an increased risk for FD (OR 2.07, 95 % CI 1.08-3.98; p = 0.029). CONCLUSIONS: Our results suggest that the genetic polymorphism pri-miR-325 is associated with FD and interacts with SLC6A4 polymorphisms in increasing susceptibility to FD in Japanese. PMID- 22438099 TI - [Administrative expenditures in health care: how does the bureaucracy avoid them?]. PMID- 22438100 TI - Validation of the Swedish version of the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM). AB - The purpose of this study was to perform an initial validation of a Swedish translation of the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE OM). The CORE-OM is a broad self-report instrument of psychological problems, designed as an outcome measure for evaluating the effects of psychological therapy. Participants included a non-clinical group of 229 university students and a clinical group of 619 persons from four primary care sites. The Swedish CORE-OM showed excellent acceptability, high internal consistency and test-retest reliability, as well as acceptable convergent validity. There was strong differentiation of the clinical and non-clinical samples, with the clinical group scoring significantly more psychological problems than the non-clinical group. Sensitivity to change was demonstrated in psychological treatments in primary care. Overall, the psychometric characteristics of the Swedish CORE-OM were very similar to the original UK data. Nevertheless, the validity of the Swedish version needs to be examined more in detail, in larger and more diverse samples. Our results so far, however, provide support for using the Swedish CORE-OM as a psychological problems measure. To our knowledge, there are few other relatively short measures in Swedish that are free to reprint that meet the demands for psychometric properties and utility in primary care settings in which patients typically present a broad range of psychological problems. KEY PRACTITIONER MESSAGE: The Swedish version of the CORE-OM is a valid questionnaire for assessing the severity of a broad range of psychological problems. PMID- 22438101 TI - Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro. AB - Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-kappaB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors. PMID- 22438102 TI - Monitoring, control and diagnostics using RFID infrastructure. AB - This work demonstrates the developed application for disinfection control by the sensing of chemical agents. The objective was to develop an Automatic Disinfectant Tracker (ADT) that would verify the disinfection of the hands of nurses, doctors, staff, patients, and visitors in hospitals within a required time frame. We have successfully investigated the development of hand disinfection control mechanisms and demonstrated two approaches, both based on the wireless Ultra-High-Frequency-based Radio-Frequency Identification (UHF-RFID) technology. The 100 % efficacy of detecting propanol and ethanol concentration was achieved by using the static disinfectant control (SDC-ADT) method. The time domain response provides an accurate determination of their performance in practice simply by measuring the applied disinfectant concentration and the duration of application. The present paper resulted from the measurements of a capacitive chemical sensor fabricated in the Laboratory for Microelectronics, (LMFE) and on measurements, based on a commercially available resistive type of sensor. A graphic user interface (IDS-GUI) is designed to successfully set the logger parameters and display the results. PMID- 22438103 TI - The marine alga Gelidium amansii promotes the development and complexity of neuronal cytoarchitecture. AB - Neurotrophic factors are vital not only to support neuronal development but also to protect mature neurons from atrophy in neurodegenerative diseases. As an effort to explore natural sources that possess neurotrophic activity, we screened common marine algae for their neuritogenic activity in the developing rat hippocampal neurons in culture. Of the 22 seaweed species examined, ethanol extracts of Gelidium amansii (GAE) exhibited potent neuritogenic activity, followed by Undaria pinnatifida and Sargassum fulvellum extracts. The effects of GAE were dose dependent with an optimum concentration of 15 ug/mL. The GAE significantly promoted the initial neuronal differentiation from the stage I into the stage II and increased the indices of axonal and dendritic development such as the length, the numbers of primary processes, and branching frequencies by a minimum of twofold compared with the vehicle control. These results show that marine algae are promising candidates for neurotrophic potentials. PMID- 22438104 TI - A laminin-2-derived peptide promotes early-stage peripheral nerve regeneration in a dual-component artificial nerve graft. AB - The DLTIDDSYWYRI motif (Ln2-P3) of human laminin-2 has been reported to promote PC12 cell attachment through syndecan-1; however, the in vivo effects of Ln2-P3 have not been studied. In Schwann cells differentiated from skin-derived precursors, the peptide was effective in promoting cell attachment and spreading in vitro. To examine the effects of Ln2-P3 in peripheral nerve regeneration in vivo, we developed a dual-component poly(p-dioxanone) (PPD)/poly(lactic-co glycolic acid) (PLGA) artificial nerve graft. The novel graft was coated with scrambled peptide or Ln2-P3 and used to bridge a 10 mm defect in rat sciatic nerves. The dual-component nerve grafts provided tensile strength comparable to that of a real rat nerve trunk. The Ln2-P3-treated grafts promoted early-stage peripheral nerve regeneration by enhancing the nerve regeneration rate and significantly increased the myelinated fibre density compared with scrambled peptide-treated controls. These findings indicate that Ln2-P3, combined with tissue-engineering scaffolds, has potential biomedical applications in peripheral nerve injury repair. PMID- 22438105 TI - Extensive loss of connexins in Balo's disease: evidence for an auto-antibody independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction. AB - Extensive aquaporin-4 (AQP4) loss without perivascular deposition of either activated complement or immunoglobulins is a characteristic of Balo's disease. Our aim in this study was to investigate the relationship between astrocytopathy and demyelination in Balo's disease, focusing on connexins (Cx), which form gap junctions among glial cells and myelin. Autopsied specimens from four cases that provided seven actively demyelinating concentric lesions infiltrated with numerous CD68(+) macrophages were immunohistochemically examined for the astrocyte markers glial fibrillary acidic protein (GFAP), AQP4, Cx43, Cx30 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1). Specimens were also stained for oligodendrocyte/myelin markers, namely Cx32, Cx47, myelin associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP) and Nogo-A. Serum samples from six patients that had undergone magnetic resonance imaging, confirming a diagnosis of Balo's disease, were assayed for the presence of anti-Cx43, -Cx32 and -AQP4 antibodies. Despite the presence of numerous GFAP- and MLC1-positive astrocytes, there was a marked decrease in the levels of Cx43, Cx32 and Cx47. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, MLC1, Cx32, Cx47, MOG, MAG, and OSP immunoreactivity. Of the six Balo's disease patients, none were positive for anti-Cxs or -AQP4 antibodies. Balo's disease is characterized by extensive loss of Cxs and AQP4, and a lack of auto-antibodies to Cxs and AQP4. Loss of Cx43 and AQP4 in the presence of other oligodendrocyte/myelin proteins at the leading edges suggests the possibility that auto-antibody-independent astrocytopathy may contribute to disease pathology via the disruption of astrocyte-oligodendrocyte/myelin interactions. PMID- 22438106 TI - Evidence based clinical assessment of child and adolescent social phobia: a critical review of rating scales. AB - Investigating the empirical support of various assessment instruments, the evidence based assessment approach expands the scientific basis of psychotherapy. Starting from Hunsley and Mash's evaluative framework, we critically reviewed the rating scales designed to measure social anxiety or phobia in youth. Thirteen of the most researched social anxiety scales for children and adolescents were identified. An overview about the scientific support accumulated by these scales is offered. Our main results are consistent with recent reviews that consider the Social Phobia and Anxiety Scale for Children (SPAI-C) and the Social Anxiety Scale for Adolescents (SAS-A) among the most pertinent and empirically supported measures of social anxiety for youngsters. However, after considering the existing evidence, we highly recommend another couple of scales that proved to be empirically supported (i.e., the Social Phobia Inventory-SPIN, and the Liebowitz Social Anxiety Scale for Children and Adolescents-LSAS-CA). PMID- 22438107 TI - Rapid magnetophoretic separation of microalgae. AB - Magnetic collection of the microalgae Chlorella sp. from culture media facilitated by low-gradient magnetophoretic separation is achieved in real time. A removal efficiency as high as 99% is accomplished by binding of iron oxide nanoparticles (NPs) to microalgal cells in the presence of the cationic polyelectrolyte poly(diallyldimethylammonium chloride) (PDDA) as a binder and subsequently subjecting the mixture to a NdFeB permanent magnet with surface magnetic field ~6000 G and magnetic field gradient <80 T m(-1) . Surface functionalization of magnetic NPs with PDDA before exposure to Chlorella sp. is proven to be more effective in promoting higher magnetophoretic removal efficiency than the conventional procedure, in which premixing of microalgal cells with binder is carried out before the addition of NPs. Rodlike NPs are a superior candidate for enhancing the magnetophoretic separation compared to spherical NPs due to their stable magnetic moment that originates from shape anisotropy and the tendency to form large NP aggregates. Cell chaining is observed for nanorod-tagged Chlorella sp. which eventually fosters the formation of elongated cell clusters. PMID- 22438108 TI - Biobank participation and returning research results: perspectives from a deliberative engagement in South Side Chicago. AB - To be respectful of the public, biobank guiding principles and operations should be responsive to and inclusive of the values and beliefs of their participants. In an effort to increase knowledge and inform institutional policies, we conducted a deliberative engagement of individuals from two healthcare facilities in South Side Chicago that serve different socioeconomic communities to consider biobank policies regarding return of research results. We recruited primary caregivers of children receiving care at either a Federally Qualified Health Center or a university-based practice to attend two full-day deliberative engagement sessions, which included four educational presentations followed by focus group discussions. Surveys were administered to assess attitudes before and after the engagement, and an evaluation was conducted to assess the deliberative engagement process. All 45 participants self-identified as African-American. Focus group themes included: (1) overall interest in biobank participation, broad consent, and recontact; (2) root causes of distrust and potential biobank strategies to facilitate trust; (3) perceived positive and negative aspects of receiving research results; and (4) strong interest in receiving and managing their children's research results. Survey data indicated the same degree of interest in receiving results about themselves as about their children. Pre- and post-session findings showed mainly non-significant attitudinal changes in level of interest in biobank participation and return of research results, although there was a decrease in level of concern regarding identification from research data. Our findings reveal shared community insights important in facilitating relationships and policy discussions between biobank researchers and research participants. PMID- 22438109 TI - Metabolic flexibility of D-ribose producer strain of Bacillus pumilus under environmental perturbations. AB - The metabolic reaction rate vector is a bridge that links gene and protein expression alterations to the phenotypic endpoint. We present a simple approach for the estimation of flux distribution at key branch points in the metabolic network by using substrate uptake, metabolite secretion rate, and biomass growth rate for transketolase (tkt) deficient Bacillus pumilus ATCC 21951. We find that the glucose-6-phosphate (G6P) and pseudo catabolic/anabolic branch points are flexible in the D: -ribose-producing tkt deficient strain of B. pumilus. The normalized flux through the pentose phosphate pathway (PPP) varied from 1.5 to 86 % under different growth conditions, thereby enabling substantial extracellular accumulation of D: -ribose under certain conditions. Interestingly, the flux through PPP was affected by the extracellular phosphate concentration and dissolved oxygen concentration. This metabolic flexibility may have been the underlying reason for this strain being selected from thousands of others in a screening for D: -ribose producers conducted in the 1970s. PMID- 22438110 TI - Purification and characterization of an organic-solvent-tolerant cellulase from a halotolerant isolate, Bacillus sp. L1. AB - A halotolerant isolate Bacillus sp. L1 producing extracellular cellulase was isolated from Yuncheng, China. Production of the enzyme started from mid exponential phase of bacterial growth and reached a maximum level during the post stationary phase. The cellulase was purified to homogeneity with molecular mass of 45 kDa. Substrate specificity test indicated that it was an endoglucanase for soluble cellulose. Optimal enzyme activity was found to be at 60 degrees C, pH 8.0, and 7.5 % NaCl. Furthermore, it was highly active and stable over broad ranges of temperature (30-80 degrees C), pH (7.0-9.0), and NaCl concentration (2.5-15 %), thus showing its excellent thermostable, alkali-stable, and halotolerant nature. The cellulase activity was greatly inhibited by ethylenediaminetetraacetic acid, indicating that it was a metalloenzyme. Significant inhibition by phenylmethylsulfonyl fluoride and phenylarsine oxide revealed that serine and cysteine residues were essential for the enzyme catalysis. Moreover, the cellulase was highly active in the presence of surfactants, and it showed high stability in the presence of water-insoluble organic solvents with log P (ow)at least 0.88. Results from this study indicate that the purified cellulase from isolate L1 may have considerable potential for industrial application owing to its useful properties. PMID- 22438111 TI - Degree of bile-duct dilatation in liver-transplanted patients with biliary stricture: a magnetic resonance cholangiography-based study. AB - PURPOSE: This study assessed whether the degree of bile-duct dilatation in liver transplanted patients is correlated with the time from intervention and the type of underlying biliary stricture. METHODS AND MATERIALS: Fifty-seven 3D magnetic resonance cholangiograms (MRCs) performed on 42 liver-transplanted patients were retrospectively evaluated. Diameter was measured at the level of the extrahepatic bile duct (EBD), right hepatic duct (RHD), left hepatic duct (LHD), anterior and posterior right hepatic ducts (aRHD, pRHD) and left lateral and medial ducts (LLD, LMD). Data were stratified according to the type of biliary stricture (all types, anastomotic, ischaemic-like, mixed) and compared, on a per-examination basis: (a) between two groups based on time from transplantation using a 1-year threshold (nonlongitudinal analysis); (b) among 26 repeated examinations on 11 patients (longitudinal analysis); (c) among different stricture groups. RESULTS: The biliary tree was slightly dilated within 1 year from transplantation (2.9+/ 1.3 to 6.1+/-3.2 mm). In general, nonlongitudinal analysis showed minimally larger duct size after 1 year (mean +1.4+/-0.5 mm) despite significant differences at most sites of measurement considering all types of strictures (p<0.01; Mann-Whitney U test). Longitudinal analysis showed diameter increase over time, although without statistically significant differences (p>0.01; Kruskal-Wallis test). No significant difference in bile-duct size was observed when comparing types of stricture (p>0.01; Kruskal-Wallis test). CONCLUSIONS: Biliary dilatation after liver transplantation is mild and develops slowly regardless of the underlying type of stricture, possibly in relation to graft properties. MRC has a potential role as first-line imaging modality for a reliable assessment of biliary dilatation and the presence of a stricture. PMID- 22438112 TI - Carboxyethynyl anchoring ligands: a means to improving the efficiency of phthalocyanine-sensitized solar cells. PMID- 22438113 TI - Total scalp reconstruction with bilateral anterolateral thigh flaps. AB - Large scalp defects can require complicated options for reconstruction, often only achieved with free flaps. In some cases, even a single free flap may not suffice. We review the literature for options in the coverage of all reported large scalp defects, and report a unique case in which total scalp reconstruction was required. In this case, two anterolateral thigh (ALT) flaps were used to resurface a large scalp and defect, covering a total of 743 cm(2). The defect occurred after resection and radiotherapy for desmoplastic melanoma, with several failed skin grafts and local flaps and osteoradionecrosis involving both inner and outer tables of the skull. The reconstruction was achieved as a single-stage reconstruction and involved wide resection of cranium and overlying soft-tissues and reconstruction with calcium phosphate bone graft substitute, titanium mesh, and two large ALT flaps. The reconstruction was successfully achieved, with minor postoperative complications including tip necrosis of one of the flaps and wound breakdown at one of the donor sites. This is the first reported case of two large ALT flaps for scalp resurfacing and may be the largest reported scalp defect to be completely resurfaced by free flaps. The use of bilateral ALT flaps can be a viable option for the reconstruction of large and/or complicated scalp defects. PMID- 22438114 TI - Solution processed polymer tandem solar cell using efficient small and wide bandgap polymer:fullerene blends. AB - Solution processed polymer tandem solar cells that combine wide and small bandgap absorber layers reach a power conversion efficiency of 7% in a series configuration. This represents a 20% increase compared to the best single junction cells made with the individual active layers and shows that the tandem configuration reduces transmission and thermalization losses in converting sunlight. PMID- 22438115 TI - Complete disappearance of uptake of FDG in the multifocal liver hemangioendothelioma after radioembolization therapy using yttrium-90 microspheres. AB - Hemangioendothelioma (HE) is an intermediate grade tumor that originates from vascular endothelium. It is rarely encountered in the liver as multifocal lesions. In the treatment of the hepatic HE, surgical resection, chemotherapy, interferon-alpha 2 therapy and liver transplantation have been described in the literature. Intra-arterial radioembolization therapy with yttrium-90 microsphere is an advanced and promising technique in the treatment of hepatic multifocal HEs. In this report, we aimed to present pre- and post-treatment radio-nuclear imaging features and to discuss radioembolization technique in a 56-year-old patient with multifocal liver HE. PMID- 22438116 TI - [Cancer nanotherapy]. PMID- 22438117 TI - [Multiple myeloma]. PMID- 22438119 TI - [Paraneoplastic syndromes]. PMID- 22438120 TI - [Exercise and cancer]. PMID- 22438121 TI - [Long-term side effects of childhood cancer]. PMID- 22438122 TI - Retinotopic mapping of the peripheral visual field to human visual cortex by functional magnetic resonance imaging. AB - Retinotopic mapping is a key property of organization in the human occipital cortex. The retinotopic organization of the central visual field of visual areas V1, V2, and V3 has been well established. We used fMRI to measure the retinotopic map of the peripheral visual field (eccentricity up to 60 degrees ). We estimated the sizes of the visual areas between 0 degrees and 60 degrees and obtained results consistent with anatomical studies. We also estimated the cortical distances and magnification factors for reconstruction of the retinotopic map using the peripheral wedge dipole model. By comparing the retinotopic map with the flattened surface, we analyzed the datasets used to reconstruct the map. We found that: (1) the percentage of the striate cortex devoted to peripheral vision in humans is significantly larger than that in the macaque, (2) the estimate of the scaling factor in linear magnification is larger than that found in previous studies focusing on central vision, and (3) the estimate of the peripheral factor in the dipolar model is too large to make the curve direction of the dipolar map in the periphery equivalent to that in the center. On the basis of our results, we revised the dipolar map to fit our conditions. The revised map in humans has a similar elliptical shape to that of macaques, and the central parts of the two species are the same. The different parts of the map are the peripheral regions, for which the peripheral wedge dipole model in humans is reversed compared to that of macaques. PMID- 22438123 TI - Prediction of optimal endotracheal tube cuff volume from tracheal diameter and from patient height and age: a prospective cohort trial. AB - PURPOSE: Endotracheal tube intra-cuff pressure should be maintained between 20 and 30 cmH(2)O to prevent damage to the tracheal wall. However, cuff pressure is rarely measured, and clinicians estimate cuff pressure poorly. The goal of the present study was to predict the cuff volume that produces optimal cuff pressure either from tracheal diameter or from patient height and age. METHODS: In the development phase, initial cuff pressure and cuff volume were measured in 240 patients. Optimal cuff volume, defined as the volume halfway between the volumes required to produce cuff pressures of 20 and 30 cmH(2)O, was determined in each patient. Then, regression equations relating optimal cuff volume to tracheal diameter on chest X-ray, and between optimal cuff volume and a combination of height and age, were calculated. The primary outcome was the proportion of patients in a validation set (n = 104) who achieved a cuff pressure of 20-30 cmH(2)O when cuff volume was selected by each regression formula. RESULTS: Only 28% of the cuffs were optimally inflated using clinical criteria during the development phase. There was good correlation between optimal cuff volume and tracheal diameter and moderate correlation between optimal cuff volume and both height and age. Predicted cuff volume was more likely to provide optimal cuff pressure when based on tracheal diameter (65% of patients) than when based on both height and age (45% of patients). CONCLUSIONS: Optimal cuff volume was better estimated from tracheal diameter and patient height and age than from the manual palpation method. PMID- 22438124 TI - Delta-tocotrienol suppresses Notch-1 pathway by upregulating miR-34a in nonsmall cell lung cancer cells. AB - MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by delta-tocotrienol, correlated with upregulation of miR 34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR 34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that delta-tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents. PMID- 22438125 TI - Inhalation study of polymethyl methacrylate following radiologist exposure during percutaneous vertebroplasty. AB - OBJECTIVE: To assess the atmospheric concentrations of methyl methacrylate (MMA) vapors during percutaneous vertebroplasty for the interventional radiologist and the other operating room staff. MATERIALS AND METHODS: During percutaneous vertebroplasty, a polymethyl methacrylate (PMMA) mixture (about 20 mL) was prepared with a mixing system in a normally ventilated room. Atmospheric concentrations of MMA vapors were measured by a gas absorbent badge for individual exposure (GABIE) passive sampler attached to the surgical gowns of the interventional radiologist and the other operating room staff over a period of 460 min. Active sampling was performed over 15 min with an individual pump placed near the breathing zone of the radiologist. MMA vapor concentrations were then measured using gas chromatography and activated charcoal tubes. RESULTS: Mean MMA vapor concentrations measured by the GABIEs over the period of 460 min were 0.51 parts per million (ppm) for the radiologist and 0.22 ppm for the other operating room staff. The emission peaks measured by using charcoal tubes over 15 min were 3.7 ppm. CONCLUSION: MMA vapor concentrations during percutaneous vertebroplasty were well below the recommended maximum exposure of 100 ppm over the course of an 8-h workday. PMID- 22438126 TI - Intra-articular extraskeletal myxoid chondrosarcoma of the ankle. AB - We describe an extremely rare case of an intra-articular extraskeletal myxoid chondrosarcoma causing devastating destruction to the ankle joint in a 71-year old woman, which had been originally excised as a ganglion cyst. Histological analysis of the lesion revealed an extraskeletal myxoid chondrosarcoma. The patient proceeded to curative surgery with a below-the-knee amputation. PMID- 22438127 TI - The psychometric properties of an Iranian translation of the Work Ability Index (WAI) questionnaire. AB - BACKGROUND: This study was carried out to evaluate the psychometric properties of an Iranian translation of the Work Ability Index (WAI) questionnaire. METHODS: In this methodological study, nurses and healthcare workers aged 40 years and older who worked in educational hospitals in Ahvaz (236 workers) in 2010, completed the questionnaire and 60 of the workers filled out the WAI questionnaire for the second time to ensure test-retest reliability. Forward-backward method was applied to translate the questionnaire from English into Persian. The psychometric properties of the Iranian translation of the WAI were assessed using the fallowing tests: Internal consistency (to test reliability), test-retest analysis, exploratory factor analysis (construct validity), discriminate validity by comparing the mean WAI score in two groups of the employees that had different levels of sick leave, criterion validity by determining the correlation between the Persian version of short form health survey (SF-36) and WAI score. RESULTS: Cronbach's alpha coefficient was estimated to be 0.79 and it was concluded that the internal consistency was high enough. The intraclass correlation coefficient was recognized to be 0.92. Factor analysis indicated three factors in the structure of the work ability including self-perceived work ability (24.5% of the variance), mental resources (22.23% of the variance), and presence of disease and health related limitation (18.55% of the variance). Statistical tests showed that this questionnaire was capable of discriminating two groups of employees who had different levels of sick leave. Criterion validity analysis showed that this instrument and all dimensions of the Iranian version of SF-36 were correlated significantly. Item correlation corrective for overlap showed the items tests had a good correlation except for one. CONCLUSION: The finding of the study showed that the Iranian version of the WAI is a reliable and valid measure of work ability and can be used both in research and practical activities. PMID- 22438128 TI - 7-year follow-up after open reduction and internal screw fixation in Bennett fractures. AB - BACKGROUND: Bennett fractures are unstable, and, with inadequate treatment, lead to osteoarthritis, weakness and loss of function of the first carpometacarpal joint. This study focuses on long-term functional and radiological outcomes after open reduction and internal fixation. METHODS: Between June 1997 and December 2005, 24 patients with Bennett fractures were treated with open reduction and internal fixation with screws at our center. Radiological and functional assessments including range of motion of the thumb and pinch and grip strength were performed 4 months post-procedure and at the long-term follow-up, on average 83 months after surgery. RESULTS: Reduction of the Bennett fracture was maintained as it was at the time of the procedure in 96 % of the cases when fixation with two lag screws was performed. At the 4-month follow-up, mean pinch and grip strength reached 92 +/- 3 and 89 +/- 4 % of the contralateral side, respectively. Long-term follow-up demonstrated no correlation between the accuracy of the fracture reduction and the development of post-traumatic arthritis. CONCLUSION: Good clinical results could be observed, if successful reduction of the fracture was achieved and maintained. However, there was no correlation between the accuracy of the fracture reduction considering a gap and step <2 mm and the development of arthritis. PMID- 22438129 TI - Bayesian semiparametric regression models for evaluating pathway effects on continuous and binary clinical outcomes. AB - Many statistical methods for microarray data analysis consider one gene at a time, and they may miss subtle changes at the single gene level. This limitation may be overcome by considering a set of genes simultaneously where the gene sets are derived from prior biological knowledge. Limited work has been carried out in the regression setting to study the effects of clinical covariates and expression levels of genes in a pathway either on a continuous or on a binary clinical outcome. Hence, we propose a Bayesian approach for identifying pathways related to both types of outcomes. We compare our Bayesian approaches with a likelihood based approach that was developed by relating a least squares kernel machine for nonparametric pathway effect with a restricted maximum likelihood for variance components. Unlike the likelihood-based approach, the Bayesian approach allows us to directly estimate all parameters and pathway effects. It can incorporate prior knowledge into Bayesian hierarchical model formulation and makes inference by using the posterior samples without asymptotic theory. We consider several kernels (Gaussian, polynomial, and neural network kernels) to characterize gene expression effects in a pathway on clinical outcomes. Our simulation results suggest that the Bayesian approach has more accurate coverage probability than the likelihood-based approach, and this is especially so when the sample size is small compared with the number of genes being studied in a pathway. We demonstrate the usefulness of our approaches through its applications to a type II diabetes mellitus data set. Our approaches can also be applied to other settings where a large number of strongly correlated predictors are present. PMID- 22438130 TI - Chrysanthemum indicum L. extract induces apoptosis through suppression of constitutive STAT3 activation in human prostate cancer DU145 cells. AB - Chrysanthemum indicum L. has been shown to possess antiinflammatory and anticancer activities, but its molecular targets/pathways are not yet fully understood in tumor cells. In the present study, the potential effects of C. indicum on signal transducer and activator of transcription 3 (STAT3) signaling pathway in different tumor cells were examined. The solvent fractions (hexane, CH2Cl2, EtOAc, and BuOH,) were obtained from a crude extract (80% EOH extract) of C. indicum. The methylene chloride fraction of C. indicum (MCI) exhibited strong cytotoxic activity as compared with the other fractions and clearly suppressed constitutive STAT3 activation against both DU145 and U266 cells, but not MDA-MB 231 cells. The suppression of constitutive STAT3 activation by MCI is associated with blocking upstream JAK1 and JAK2, but not Src. MCI downregulated the expression of STAT3-regulated gene products; this is correlated with the accumulation of the cell cycle at sub-G1 phase, the induction of caspase-3 activation, and apoptosis. Moreover, the major components of the MCI were bioactive compounds such as sudachitin, hesperetin, chrysoeriol, and acacetin. Sudachitin, chrysoeriol, and acacetin also exerted significantly cytotoxicity, clearly suppressed constitutive STAT3 activation, and induced apoptosis, although hesperetin did not show any significant effect in DU145 cells. Overall, our results demonstrate that MCI could induce apoptosis through inhibition of the JAK1/2 and STAT3 signaling pathways. PMID- 22438132 TI - Cytogenetic and epidemiological findings in Down syndrome: England and Wales 1989 2009. AB - This study describes the characteristics of karyotypes leading to phenotypic Down syndrome (trisomy 21) in 29,256 cases diagnosed between 1989 and 2009 in England and Wales included in the National Down Syndrome Cytogenetic Register (NDSCR). The frequency of occurrence of the different karyotypes, proportions diagnosed prenatally, sex ratios, mean maternal age, and proportions of mothers with recurrences were analyzed. Nearly 97% of all cases were free trisomy 21; 2.9% contributory trisomy 21, 0.3% double or triple aneuploidies; 1% of all were mosaics. Mean maternal age of free trisomy 21 cases was 35 years, 54% were male, and 1% of mothers had recurrences. Free trisomy 21 mosaics had a lower mean maternal age (33 years), a lower proportion of males (39.5%), and 2.5% of mothers had recurrences. The majority of contributory translocations were Robertsonian or rea (21;21). Their mothers were younger, particularly those of Robertsonian translocations (28 years). Of the Robertsonian der (14;21) translocations of known parental origin, 54% were de novo, 41% maternal and 5% paternal and 15.8% of mothers of those of maternal origin had recurrences. Multiple aneuploidies have the highest proportion of males (67%), highest proportion of mosaics (40%), a mean maternal age of 37 years, and no mothers had a recurrence. The size of this national register allowed the frequency of occurrence of the rarer karyotypes of Down syndrome to be estimated and their epidemiology described. PMID- 22438133 TI - Expression and quantification of Oct-4 gene in blastocyst and embryonic stem cells derived from in vitro produced buffalo embryos. AB - The POU-domain transcription factor Pou5f1 (Oct-4) is involved in transcriptional regulation during early embryonic development and cell differentiation. Despite highly conserved genomic organization of Oct-4 gene in mammals, expression pattern of Oct-4 is highly variable in different species. In the present study, expression pattern of Oct-4 in buffalo blastocyst, trophoectoderm (TE), and embryonic stem cells (ESCs) was investigated. For the derivation and characterization of buffalo ESCs, inner cell masses (ICMs) were isolated from 18 hatched and 21 expanded in vitro produced buffalo blastocyst and cultured over mitomycin-C-treated buffalo fetal fibroblast feeder layer. Alkaline phosphatase (AP) activity, SSEA-1 and 4, TRA 1-60 and 1-81, and Oct-4 proteins were localized in ICM, TE, and ESCs. Quantification of Oct-4 was done by amplifying a transcript of 125 base pairs by real-time polymerase chain reaction. Primary cell colony formation was higher (P < 0.05) in hatched blastocyst (83.33%, 15/18) compared to mechanically isolated ICMs from expanded blastocyst (52.38%, 11/21). Undifferentiated buffalo ESCs were positive for AP and expressed Oct-4, SSEA-1 and 4, TRA-1-60, and TRA-1-81 proteins. Oct-4 transcripts and proteins were detected in the ICM, TE cells and were invariably present in ESCs; however, expression level of Oct-4 transcript were significantly higher in ICM and ESCs as compared to TE cells. In conclusion, expression of Oct-4 is not only restricted to the ICM and ESCs but its expression was also detected in TE cells suggesting that instead of using Oct-4 as a single marker, it is better to have other flanking molecular markers for the identification of buffalo pluripotent embryonic stem cells. PMID- 22438134 TI - Flaxseed sprouts induce apoptosis and inhibit growth in MCF-7 and MDA-MB-231 human breast cancer cells. AB - Flaxseeds have been shown to play a role in the prevention of cancer and heart disease, and it is believed that their more favorable fatty acid composition is responsible. Sprouting is a natural method to modify nutritional components and to decrease cyanide poisoning of raw flaxseeds. Here, we investigated the in vitro effects of flaxseed sprouts on cell growth and apoptosis of human breast cancer cells. In a series of in vitro experiments, estrogen-receptor-positive (MCF-7) and estrogen-receptor-negative (MDA-MB-231) cells were cultured and treated with flaxseed sprouts, and then cell proliferation, apoptosis, and gene expression were measured. Flaxseed sprouts significantly reduced the growth of both of MCF-7 and MDA-MB-231 cells and also increased apoptosis. However, flaxseed sprouts did not affect the growth of MCF-10A mammary epithelial cells. In gene transcription analysis using quantitative real-time polymerase chain reaction, flaxseed sprout treatment significantly upregulated p53 mRNA in both cell cancer lines. These results suggest that flaxseed sprouts induce apoptosis and inhibit cancer cell growth, thereby demonstrating their anti-proliferative effects in breast cancer cells. This study may provide important information for devising dietary strategies to reduce breast cancer risk. PMID- 22438135 TI - High-performance non-volatile organic ferroelectric memory on banknotes. AB - High-performance non-volatile polymer ferroelectric memory are fabricated on banknotes using poly(vinylidene fluoride trifluoroethylene). The devices show excellent performance with high remnant polarization, low operating voltages, low leakage, high mobility, and long retention times. PMID- 22438136 TI - Preparation and functional evaluation of cell aggregates incorporating gelatin microspheres with different degradabilities. AB - The objective of this study was to investigate the viability and biological functions of cells in their aggregates incorporating gelatin microspheres with different degradabilities. After being prepared by a water-in-oil emulsion procedure, the gelatin microspheres were dehydrothermally crosslinked at 140 degrees C for various time periods. In vitro degradation tests showed that the gelatin microspheres were slowly degraded slowly with an increase in the crosslinking time. When MC3T3-E1 cells were cultured with the gelatin hydrogel microspheres in the round U-bottom wells of 96-well microplates which had been coated with poly(vinyl alcohol), cell aggregates with homogeneously distributed gelatin microspheres were formed. A large amount of slowly degraded gelatin microspheres remained in the cell aggregates for long time periods, while a higher proliferation of MC3T3-E1 cells was observed. When evaluated as a measure of aerobic glycolysis, the ratio of l-lactic acid production:glucose consumption of MC3T3-E1 cells was lower for MC3T3-E1 cells in the cell aggregates incorporating slowly degraded gelatin microspheres than for aggregates incorporating rapidly degraded ones. The alkaline phosphatase activity and calcium content of MC3T3-E1 cells were higher for cell aggregates incorporating slowly degraded gelatin microspheres. It is possible that the incorporation of gelatin hydrogel microspheres with slow degradability enabled the permeation of oxygen and nutrients into the cell aggregates for longer time periods, resulting in better culture conditions for the survival, proliferation and differentiation of the cells. PMID- 22438137 TI - Anisotropy spectra of amino acids. PMID- 22438138 TI - The outcome of prostaglandin-E1 and dextran-40 compared to no antithrombotic therapy in head and neck free tissue transfer: analysis of 1,351 cases in a single center. AB - Free tissue transfer has become a popular technique for soft tissue defect reconstruction in head and neck cancer ablation. Although high success rates and good reliability of free flaps are proven, microvascular thrombosis is still the most critical issue for microsurgeons. Pharmacological antithrombotic agents are widely used but their efficacy is still debated. In this study, we analyzed whether prostaglandin-E1 (PGE1) and dextran-40 can improve the outcomes compared to no antithrombotic therapy at all. We retrospectively reviewed 1,351 free flaps performed for head and neck reconstruction after cancer ablation. Three groups defined were 232 flaps received PGE1, 283 flaps received dextran-40, and 836 received no antithrombotic therapy. The demographics of these three groups indicated no statistical differences. The results showed that flap survival revealed no significant difference among PGE1, dextran-40, and control group (P = 0.734). There was a tendency to hematomas in PGE1 group (P = 0.056) when compared with other two groups. Dextran-40 significantly increased flap failure rate in high-risk patients with diabetes mellitus (P = 0.006) or hypertension (P = 0.003), when compared with PGE1 and control group. These results revealed antithrombotic therapy with PGE1 and dextran-40 do not determine a significant improvement in flap survival. PMID- 22438139 TI - Synthetic peptides derived from an N-terminal domain of the E2 protein of GB virus C in the study of GBV-C/HIV-1 co-infection. AB - Synthetic peptides derived from GB virus C (GBV-C) have previously been studied in our group for the development of new systems capable of diagnosing diseases caused by this humanotropic virus. We also recently described specific peptide domains of the E2 envelop protein of GBV-C that have the capacity to interfere with the HIV-1 fusion peptide, produce a notable decrease in cellular membrane fusion, and perturb HIV-1 infectivity in a dose-dependent manner. The present work discloses the design and synthesis of both linear and cyclic branched peptides based on a previously reported N-terminal sequence of the GBV-C E2 protein. Immunoassays and cell-cell fusion assays were performed to evaluate their diagnostic value to detect anti-GBV-C antibodies in HIV-1 patients, as well as their putative anti-HIV-1 activity as entry inhibitors. Our results showed that chemical modifications of the selected E2(7-26) linear peptide to afford cyclic architecture do not result in an enhanced inhibition of gp41 HIV-1 mediated cell-cell fusion nor improved sensitivity in the detection of GBV-C antibodies in HIV-1 co-infected patients. Thus, the ELISA data reinforce the potential utility of linear versions of the E2(7-26) region for the development of new peptide-based immunosensor devices for the detection of anti-GBV-C antibodies in HIV-1 co-infected patients. PMID- 22438140 TI - A meta-analysis of spurious associations between type D personality and cardiovascular disease endpoints. PMID- 22438141 TI - Recovery-oriented services for individuals with mental illness and case managers' experience of professional burnout. AB - Present cross-sectional study examined perceptions of recovery-oriented services and reports of professional burnout and job satisfaction in a sample of 114 case managers working in community mental health centers across Ohio. The research examined the relative contribution of demographic characteristics, the structure of case management services, and case managers' beliefs about recovery-oriented services in describing their reports of professional burnout and job satisfaction. Regardless of individual characteristics of case managers and reports of the structure of their jobs, case managers who perceived their agency to offer higher levels of recovery-oriented services also reported lower levels of depersonalization and emotional exhaustion at work, and higher levels of professional accomplishment and job satisfaction. Directions for future research in the area are discussed. PMID- 22438142 TI - The association of tattooing/body piercing and psychopathology in adolescents: a community based study from Istanbul. AB - We aimed to investigate the association of psychopathology with tattooing and body piercing among adolescents in Istanbul by means of self-report questionnaires. Tenth, eleventh and twelfth grade students from 2 high schools in Istanbul with a total number of 607 participated in the study. The Youth Self Report, Children's Depression Inventory and a detailed semi-structured inquiry assessing tattooing, body piercing and some psychiatric and psychosocial variables were administered to the students. The prevalence of tattooing and body piercing were 4.8 and 7 %, respectively. The adolescents with tattooing and body piercing were found to have a higher frequency of alcohol and drug use, smoking, going to bars/night clubs and lower school grades when compared to those without tattooing and body piercing. Externalizing problems, mainly delinquent and aggressive behaviours were more prominent in the adolescents with tattooing and body piercing. Tattooing and body piercing in adolescents may be indicative of mental health risks. PMID- 22438143 TI - Acute obscure-overt gastrointestinal bleeding: capsule endoscopy first? PMID- 22438144 TI - Transesophageal pulmonary lobectomy with single transthoracic port assistance: study with survival assessment in a porcine model. AB - BACKGROUND AND STUDY AIMS: Thoracoscopic pulmonary lobectomy is being performed in an increasing number of patients. The aims of the current study were to assess natural orifice transluminal endoscopic surgery (NOTES) as an alternative to transthoracic endoscopic surgery, and to test the feasibility of peroral transesophageal right upper pulmonary lobectomy with the assistance of a single transthoracic trocar. METHODS: In 10 acute and 4 survival pigs, right upper pulmonary lobectomy was performed using a forward-viewing double-channel gastroscope and an operative thoracoscope with a 5-mm working channel inserted through a single transthoracic 12-mm) port. Time, safety, and feasibility of the following steps were recorded in all animals: esophagotomy, hilar dissection, individual ligation of the hilum elements, pulmonary lobectomy, and specimen retrieval. In the survival experiments, esophagotomy was closed using a reticulated laparoscopy suture device and an esophageal stent was placed. These animals were kept alive and monitored for 2 weeks. RESULTS: Esophagotomy was performed safely in all animals (mean procedure duration 5.4 +/- 1.7 minutes). Dissection of the right upper lobe hilum elements (bronchus, arteries, and veins) was carried out without adverse events. Individual ligation of the hilum elements was performed in all but two cases (time for dissection and ligation 44.2 +/- 14.8 minutes). Lobectomy and specimen retrieval were completed in all animals (9.5 +/- 3.1 minutes). Esophagotomy closure and stent placement were carried out in 20.0 +/- 2.8 minutes in the survival animals. These animals fed normally and gained weight postoperatively without signs of disease. Endoscopic examination before necropsy revealed a pseudo-diverticulum in one animal, and wound dehiscence with confined collection/recess in the remaining animals. CONCLUSIONS: Transesophageal right upper pulmonary lobectomy using single transthoracic trocar assistance is feasible and may represent a step towards scar-free pulmonary lobectomy. PMID- 22438145 TI - Gastrointestinal bleeding: a peep into the future with stiffness, sprays, and sensors. PMID- 22438146 TI - Upper gastrointestinal tumors. PMID- 22438147 TI - Colonoscopy and tumors. PMID- 22438148 TI - Biliary endoscopic retrograde cholangiopancreatography. PMID- 22438149 TI - Pancreatic endoscopic retrograde cholangiopancreatography (ERCP). PMID- 22438150 TI - Natural orifice transluminal endoscopic surgery (NOTES). PMID- 22438151 TI - Preparation, sedation, and monitoring. PMID- 22438152 TI - Radiation protection in digestive endoscopy: European Society of Digestive Endoscopy (ESGE) guideline. AB - This article expresses the current view of the European Society of Gastrointestinal Endoscopy (ESGE) about radiation protection for endoscopic procedures, in particular endoscopic retrograde cholangiopancreatography (ERCP). Particular cases, including pregnant women and pediatric patients, are also discussed. This Guideline was developed by a group of endoscopists and medical physicists to ensure that all aspects of radiation protection are adequately dealt with. A two-page executive summary of evidence statements and recommendations is provided. The target readership for this Guideline mostly includes endoscopists, anesthesiologists, and endoscopy assistants who may be exposed to X-rays during endoscopic procedures. PMID- 22438153 TI - Biodegradable stents: another big step in the field of non-surgical therapy for fibrostenotic Crohn's disease. PMID- 22438155 TI - The physical basics of magnetic-guided capsule endoscopy of the stomach and results of a feasibility study in the porcine stomach. PMID- 22438156 TI - Endoscopic ultrasound-guided fine-needle aspiration can differentiate between tuberculosis and sarcoidosis. PMID- 22438159 TI - Clinical practice guidelines: quality of colonoscopy in colorectal cancer screening. PMID- 22438160 TI - Evidence for policy and regulation: a model to address development of unqualified faculty. AB - Nurses often do not become faculty through deliberate intention; rather they enter the role because of circumstance. While they may be expert practitioners, they are often not prepared for faculty roles. Unlike traditional preparation for nursing practice, which requires clinical education, the role of nurse teacher often has no systematic preparation. The purpose of the Nurse Faculty Intern (NFI) Pilot Study was to investigate the role development of nurse educators and the mechanism by which graduate students gain competencies related to pedagogy through practical experience and a relationship with mentors. Results from the study revealed need for intentional role development for the NFI. Even though NFI's had many years of nursing experience, they expressed the need for orientation to teaching pedagogy to better use their nursing knowledge when working with students. This article will present the findings and recommendations from the study. PMID- 22438161 TI - Public policy analysis to redress urban environmental health inequities. AB - Public policies may not have been designed to disadvantage certain populations, but the effects of some policies create unintended health inequities. The nature of community health nurses' daily work provides a privileged position to witness the lived experiences and effects of policy-produced social and health inequities. This privileged position requires policy competence including analytical skills to connect lived experiences to public policy. The purpose of this article is to present an example of an urban ethnography that explicates inequity-producing effects of public policy and is intended to inform necessary policy changes. This study sheds light on how issues of childcare, housing, nutrition, and urban infrastructure in the context of poverty are fundamental to the larger issues of environmental health. This policy analysis documents how the Day Care Act of Nova Scotia, Canada explicates patriarchal and neoliberal gender and class assumptions that have implications for mothers' health decisions. PMID- 22438162 TI - Interdisciplinary research and nursing knowledge development. PMID- 22438163 TI - Addressing disparities in access to care: lessons from the Kercheval Street clinic in the 1960s. AB - Health disparities for racial and ethnic minorities have been present in the United States and persist today. NMHCs (Nurse-Managed Health Center), which can serve as "Medical Homes," are one mechanism by which nurses can attempt to overcome these disparities within communities. In the mid-1960s, Nancy Milio developed and found funding for a NMHC to address disparities in Detroit, Michigan. History shows that the center was so valued by community members that it remained untouched during the Detroit riot of 1967, despite all buildings surrounding it having been burned down or destroyed. This article uses traditional historic methods to describe the establishment of the center in inner city Detroit in the 1960s in historical context and analyze factors that led to Milio's success. To address disparities via NMHCs, nurses must be persistent in acquiring funding and should involve a racially and culturally diverse group representative of community members in the development, planning, and ongoing operation of the enterprise. PMID- 22438164 TI - Linear and curvilinear correlations of brain white matter volume, fractional anisotropy, and mean diffusivity with age using voxel-based and region-of interest analyses in 246 healthy children. AB - In this study, we examined linear and curvilinear correlations of fractional anisotropy (FA), mean diffusivity (MD), and white matter volume with age by using brain structural and diffusion-tensor magnetic resonance imaging (MRI) in a large number of healthy children and voxel-based morphometry (VBM) and region-of interest (ROI) analyses. We collected data by brain structural MRI in 246 healthy children, aged 5-18 years. FA and MD images were normalized using the normalization parameter of the corresponding structural MRI. Next, we analyzed the correlations between FA and age and between MD and age by estimating linear and logarithmic functions. We also analyzed the correlation between white matter volume and age by linear, quadratic, and cubic functions. Correlations between FA and age and between MD and age showed exponential trajectories in most ROIs in boys and girls, except for several fibers, such as the corpus callosum connecting the bilateral rectal gyri in boys. The correlation between white matter volume and age showed significant positive linear trajectories in most ROIs in boys and girls, except for a few fibers, such as the bilateral uncinate fasciculus. Additionally, maturational rates differed among major fibers, and in girls, the left superior longitudinal fasciculus, which connects the frontal and temporal lobes, showed a slower rate of maturation than other fibers. Our results may help to clarify the mechanisms of normal brain maturation from the viewpoint of brain white matter. PMID- 22438165 TI - Loss of apical vertebral derotation in adolescent idiopathic scoliosis: 2-year follow-up using multi-planar reconstruction computed tomography. AB - PURPOSE: The objective of this study was to evaluate 2 years post-surgical loss of three-dimensional correction in adolescent idiopathic scoliosis (AIS) patients using multi-planar reconstruction computed tomography (CT). METHODS: Twenty-seven AIS patients treated by segmental pedicle screw (PS) constructs were included in this study. Correction in the axial plane was evaluated using the "relative apical vertebral rotation angle" (rAVR), defined as the difference between the axial rotation angles of the upper instrumented vertebra and the apical vertebra on reconstructed axial CT images. The Cobb angle of the main curve and apical vertebral translation was measured to evaluate the coronal correction. Thoracic kyphosis was also measured for the evaluation of sagittal profile. Measurements were performed before surgery, and 1 week and 2 years after surgery. The relationships between the correction losses and skeletal maturity, and variety of spinal constructs were also evaluated. RESULTS: The mean preoperative Cobb angle of the major curve was 59.1 degrees +/- 11.2 degrees before and 13.0 degrees +/- 7.2 degrees immediately after surgery. Two years later, the mean Cobb angle had increased significantly, to 15.5 degrees +/- 7.8 degrees , with a mean correction loss of 2.5 degrees +/- 1.5 degrees (p < 0.001). The mean preoperative rAVR of 28.5 degrees +/- 8.4 degrees was corrected to 15.8 degrees +/- 7.8 degrees after surgery. It had increased significantly to 18.5 +/- 8.4 by 2 years after surgery, with a mean correction loss of 2.7 degrees +/- 1.0 degrees (p < 0.001). The mean correction losses for both the Cobb angle and rAVR were significantly greater in the skeletally immature patients. The significant correlations were recognized between the correction losses and the proportion of multi-axial screws, and the materials of constructs. CONCLUSIONS: Statistically significant loss of correction in the Cobb angle and apical vertebral axial rotation angle (AVR) were recognized 2 years after surgery using PS constructs. The correction losses, especially AVR, were more evident in the skeletally immature patients, and in patients treated with more multi-axial screws and with titanium constructs rather than with stainless constructs. PMID- 22438166 TI - Rise in dermal CD11c+ dendritic cells associates with early-stage development of psoriatic lesions. AB - There is limited information available regarding the phenotype and function of leukocytes involved in the earliest stages of psoriatic lesion development. In this study, we examined the presence of different types of leukocytes in psoriatic point lesions collected at three 1-week interval time points from a recent and simultaneously formed group of point lesions. The cells were quantified and compared with K16 expression and epidermal thickness, both typically increased in this disease and considered as hallmarks. We found a significant correlation between K16(+) cell increment and the increase in epidermal thickness in the timeframe of 14 days. The change in CD3(+), CD4(+), and CD8(+) T-cell numbers in the dermis showed a significant association with these two features from d7 to d14, whereas in the epidermis only CD8(+) T cells demonstrated a significant correlation. Remarkably, the relationship between T cells and disease progression was preceded by a significant correlation of CD11c(+) dendritic cells (DCs) with K16 expression and epidermal thickness from baseline onwards. Interestingly, there was also a numeric correlation of CD11c(+) DCs with the CD3(+) T-cell shifts from d7 to d14. A significant correlation was also found between dermal CD14(+) cells and K16 expression from d7 to d14. BDCA 2(+) plasmacytoid DCs were absent in non-lesional skin, but found at low numbers in most lesions. The change in plasmacytoid DC or neutrophil numbers did not correlate with lesion development. In conclusion, our study suggests a relevant role for T cells, and in particular dermal CD11c(+) DCs, in the earliest stage of psoriatic lesion development. PMID- 22438169 TI - Inhibiting the color formation by gradient temperature-elevating Maillard reaction of soybean peptide-xylose system based on interaction of l-cysteine and Amadori compounds. AB - Light color and savory flavor enhancer are attractive for consumers and food producers. The effect of addition time of l-cysteine on inhibiting color formation was investigated in soybean peptide-xylose system, and the possible pathway was explored. Once dicarbonyl compounds were formed during the Maillard reaction, the addition of l-cysteine had no color-inhibiting effect; if l cysteine was added immediately after the Amadori compound was formed, the extraordinary color-inhibiting effect was observed. Therefore, an improved way to inhibit color formation was proposed on the basis of the interaction of l cysteine and Amadori compounds by controlling the addition time of l-cysteine through gradient temperature-elevating Maillard reaction. The system was heated at 80 degrees C for 60 min to form Amadori compounds, followed by the addition of L-cysteine, and the temperature was raised to 120 degrees C and held for 110 min. Compared with traditional products, the lightest color product was found desirable by GC/MS analysis and sensory evaluation. The novel method proposed can be a guide for the industrial preparation of light-colored products. PMID- 22438170 TI - Ratio of geometric means to analyze continuous outcomes in meta-analysis: comparison to mean differences and ratio of arithmetic means using empiric data and simulation. AB - Meta-analyses pooling continuous outcomes can use mean differences (MD), standardized MD (MD in pooled standard deviation units, SMD), or ratio of arithmetic means (RoM). Recently, ratio of geometric means using ad hoc (RoGM (ad hoc) ) or Taylor series (RoGM (Taylor) ) methods for estimating variances have been proposed as alternative effect measures for skewed continuous data. Skewed data are suggested for summary measures of clinical parameters restricted to positive values which have large coefficients of variation (CV). Our objective was to compare performance characteristics of RoGM (ad hoc) and RoGM (Taylor) to MD, SMD, and RoM. We used empiric data from systematic reviews reporting continuous outcomes and selected from each the meta-analysis with the most and at least 5 trials (Cochrane Database [2008, Issue 1]). We supplemented this with simulations conducted with representative parameters. Pooled results were calculated using each effect measure. Of the reviews, 232/5053 met the inclusion criteria. Empiric data and simulation showed that RoGM (ad hoc) exhibits more extreme treatment effects and greater heterogeneity than all other effect measures. Compared with MD, SMD, and RoM, RoGM (Taylor) exhibits similar treatment effects, more heterogeneity when CV <=0.7, and less heterogeneity when CV > 0.7. In conclusion, RoGM (Taylor) may be considered for pooling continuous outcomes in meta-analysis when data are skewed, but RoGM (ad hoc) should not be used. However, clinicians' lack of familiarity with geometric means combined with acceptable performance characteristics of RoM in most situations suggests that RoM may be the preferable ratio method for pooling continuous outcomes in meta analysis. PMID- 22438171 TI - Pinching spine: A potential treatment for depression. AB - OBJECTIVE: To investigate whether pinching spine (PS, i.e. , a traditional Chinese manipulative therapy) is beneficial to ameliorating the depressive state (including behavioral deficit, retardative weight gain and decreased sucrose consumption) in a rat model of depression induced by chronic unpredictable stress (CUS) and to explore the candidate mechanism of action. METHODS: PS was performed on rats' spine once daily for 1 week after exposure to CUS. The open-field test, body weight measuring, and sucrose intake test were applied on different dates: before stress (d0), at the end of stress (d21) and after PS treatment (d28), respectively. Then the rats' hippocampuses were performed genome-wide microarray analysis, and the expression levels of several genes were evaluated by real-time polymerase chain reaction (PCR). RESULTS: Exposure to CUS resulted in decreases of behavioral activity and sucrose consumption, which were reversed significantly after PS treatment. The expression of several genes relevant to energy metabolism, anti-oxidation, and olfactory receptor, etc., were down-regulated, while the expression of those relevant to hemostasis, immunity-inflammation, and restriction of activities and ingestion, etc., were up-regulated in hippocampuses of rats exposed to CUS. PS treatment significantly inverted these changes. Furthermore, increase or decrease in gene expression evaluated by realtime PCR was concordant with up-regulated or down-regulated expression evaluated by microarray analysis. CONCLUSION: PS showed a potential antidepressant-like effect, of which the action mechanism might be due to gene expression regulation in hippocampus. PMID- 22438172 TI - Pay attention to the study on active antiliver fibrosis components of Chinese herbal medicine. AB - In this review, the researches on Chinese herb components with anti-hepatic fibrosis activity in China in the recent 20 years were generalized. Almost thirty active herb components attracted author's attention, especially, salvianolic acid B and oxymatrine which were investigated comprehensively. Moreover, the author considered that, in view of the complex pathogenesis and the multi-pathway and multi-target superiority of Chinese medicine formula, the effective components formula investigations deserve more attention and probably prompt a potential researching direction. PMID- 22438173 TI - Fuzheng huayu capsule in the treatment of liver fibrosis: clinical evidence and mechanism of action. AB - Liver fibrosis represents the wound healing response to liver injury from a wide variety of etiologies. Remarkable progresses have been shown in the field of liver fibrosis in a range of areas in the past years. In particular, the reversibility of liver fibrosis has been well documented in both patients and animal models. Great progresses have been made in the treatment of liver fibrosis with Chinese medicine. This review summarizes the effects of fuzheng huayu capsule (FZHYC) in treating liver fibrosis and inflammation induced by chronic hepatitis B in clinical trials and the mechanism of action of FZHYC in reversing liver fibrosis in vivo and in vitro experiments. PMID- 22438174 TI - Uhwang Chungsim Won decreases blood oxygen level-dependent fMRI signal response to a motor stimulation task. AB - OBJECTIVES: To evaluate the effect of Uhwang Chungsim Won [UC, Niuhuang Qingxin Pill ()] on the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal response to a motor stimulation task using a hand grasping paradigm. METHODS: Ten healthy right-handed male volunteers were recruited. Their BOLD fMRI signal characteristics during hand grasping were determined before and 1 h after consuming UC. RESULTS: With the administration of UC, BOLD responses to the right hand motor task showed a decrease in both hemispheres including the right cerebellar culmen, right and left medial frontal gyrus, right parahippocampal gyrus, right and left sublobar insula, right and left posterior cingulate, left precuneus, and right precentral gyrus. Decreased BOLD responses to the left hand motor task were shown in the right lingual gyrus, right cerebellar culmen, left superior temporal gyrus, right and left middle frontal gyrus, and right precentral gyrus after UC administration. Increased BOLD responses to the left hand motor task were shown in the left and right posterior cingulate, while there was no increased response to the right hand motor task after UC administration. CONCLUSIONS: UC administration significantly decreased fMRI BOLD signal responses to hand grasping in most of the brain areas including the primary motor cortex, but it is not clear whether these decreased responses were caused by a decrease in neuronal activities or by an increase in cerebral blood flow due to the cerebral vasodilatory effects of UC. Further studies using positron emission tomography or single photon emission computed tomography are needed to fully elucidate these findings. PMID- 22438175 TI - Reconstructive indications of simultaneous double free flaps in the head and neck: a case series and literature review. AB - Extensive and complex defects of the head and neck involving multiple anatomical and functional subunits are a reconstructive challenge. The purpose of this study is to elucidate the reconstructive indications of the use of simultaneous double free flaps in head and neck oncological surgery. This is a retrospective review of 21 consecutive cases of head and neck malignancies treated surgically with resection and reconstruction with simultaneous use of double free flaps. Nineteen of 21 patients had T4 primary tumor stage. Eleven patients had prior history of radiotherapy or chemo-radiotherapy. Forty-two free flaps were used in these patients. The predominant combination was that of free fibula osteo-cutaneous flap with free anterolateral thigh (ALT) fascio-cutaneous flap. The indications of the simultaneous use of double free flaps can be broadly classified as: (a) large oro-mandibular bone and soft tissue defects (n = 13), (b) large oro mandibular soft tissue defects (n = 4), (c) complex skull-base defects (n = 2), and (d) dynamic total tongue reconstruction (n = 2). Flap survival rate was 95%. Median follow-up period was 11 months. Twelve patients were alive and free of disease at the end of the follow-up. Eighteen of 19 patients with oro-mandibular and glossectomy defects were able to resume an oral diet within two months while one patient remained gastrostomy dependant till his death due to disease not related to cancer. This patient had a combination of free fibula flap with free ALT flap, for an extensive oro-mandibular defect. The associated large defect involving the tongue accounted for the swallowing difficulty. Simultaneous use of double free flap aided the reconstruction in certain large complex defects after head and neck oncologic resections. Such combination permits better complex multiaxial subunit reconstruction. An algorithm for choice of flap combination for the appropriate indications is proposed. PMID- 22438176 TI - The use of acoustic force capture to ultra-purify lymphocyte subpopulations from human adult whole blood. AB - Pre-analytical enrichment of cell populations prior to therapeutic delivery is of paramount interest throughout the fields of regenerative medicine and clinical interventional therapies. Enrichment of a cell population typically involves two aspects: (a) the increase in concentration of particular subpopulation of the total cell fraction by means of removal of other cells of no interest to the particular interrogation; and (b) improvement of resolution of signal by removal of 'noise' mostly arising from cellular debris in the treated sample. In this research, leukocyte populations were obtained from erythrocyte-depleted primary whole blood from human adults and subjected to flow through acoustic fields within the ultrasound range to remove cellular debris. It was possible to demonstrate aggregation and holding of leukocytes by using ultrasound within the frequency range 11.448-11.483 MHz, which facilitated removal of cellular debris by washing under continuous perfusion. The T-lymphocyte population were phenotypically characterized using CD4/CD8 (T(h)/T(c)) immunocytochemistry by flow cytometry and demonstrated a significant decrease in 'false-positive' events during cellular analysis, due to the efficient eradication of non-specifically reactive cells and tissue debris from the cell populations of interest. Therefore, it was possible to conclude that flow through an ultrasonic acoustic system was capable of providing a non-destructive method for the hyper purification of primary derived cell populations, with potential exploitations throughout the fields of cellular research, medical diagnostics and clinical therapies. PMID- 22438177 TI - Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease. AB - In this special issue about biofactors causing cognitive impairment, we present evidence for and discuss two such biofactors. One is excess copper, causing neuronal toxicity. The other is zinc deficiency, causing neuronal damage. We present evidence that Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years. This leads to the conclusion that something in the developed environment is a major risk factor for AD. We hypothesize that the factor is inorganic copper, leached from the copper plumbing, the use of which coincides with the AD epidemic. We present a web of evidence supporting this hypothesis. Regarding zinc, we have shown that patients with AD are zinc deficient when compared with age-matched controls. Zinc has critical functions in the brain, and lack of zinc can cause neuronal death. A nonblinded study about 20 years ago showed considerable improvement in AD with zinc therapy, and a mouse AD model study also showed significant cognitive benefit from zinc supplementation. In a small blinded study we carried out, post hoc analysis revealed that 6 months of zinc therapy resulted in significant benefit relative to placebo controls in two cognitive measuring systems. These two factors may be linked in that zinc therapy significantly reduced free copper levels. Thus, zinc may act by lowering copper toxicity or by direct benefit on neuronal health, or both. PMID- 22438178 TI - Creativity and dementia: a review. AB - In these last years, creativity was found to play an important role for dementia patients in terms of diagnosis and rehabilitation strategies. This led us to explore the relationships between dementia and creativity. At the aim, artistic creativity and divergent thinking are considered both in non-artists and artists affected by different types of dementia. In general, artistic creativity can be expressed in exceptional cases both in Alzheimer's disease and Frontotemporal dementia, whereas divergent thinking decreases in dementia. The creation of paintings or music is anyway important for expressing emotions and well-being. Yet, creativity seems to emerge when the right prefrontal cortex, posterior temporal, and parietal areas are relatively intact, whereas it declines when these areas are damaged. However, enhanced creativity in dementia is not confirmed by controlled studies conducted in non-artists, and whether artists with dementia can show creativity has to be fully addressed. Future research directions are suggested. PMID- 22438179 TI - A genetically encoded norbornene amino acid for the mild and selective modification of proteins in a copper-free click reaction. PMID- 22438180 TI - Smith-Lemli-Opitz syndrome: Objective assessment of facial phenotype. AB - Smith-Lemli-Opitz syndrome (SLOS), is an autosomal recessive condition caused by cholesterol synthesis deficiency which results in a wide phenotypic spectrum which includes multiple malformations, distinctive facial appearance, and intellectual disability. This anthropometric and observational study was carried out to define the key facial characteristics of individuals with SLOS and to evaluate evolution of the facial phenotype with age. Clinical photographs were obtained on 51 subjects with SLOS and standardized facial anthropometry was performed on 42; the ages ranged from 6 months to 20 years. For each individual, 22 standardized cranial and facial measurements were obtained and compared to published age- and sex-matched controls. Craniofacial pattern profiles were compared between sexes, various age groups, plasma cholesterol concentration at the time of diagnosis, and physical severity score. Mean-Z, a measurement of overall facial size, and craniofacial variability index (CVI), a summary anthropometric measure of craniofacial deviation from the norm, were calculated and compared according to methods published previously. A characteristic craniofacial pattern profile was universally present: narrow forehead, brachycephaly, short palpebral fissures, short nasal ridge, anteverted nares, flat face, normal jaw width, and retrognathia. The facial measurements of subjects with SLOS had higher deviations from the norm with mean CVI of 2.11; SD = 0.47 (controls: Mean = 0.76, SD = 0.19; <0.0001) than age- and sex-matched controls. Their faces were also smaller than controls: 70% of subjects had mean-Z values 2 SD below the mean for controls; average Z-score was -1.64; SD = 0.85 (controls: mean = 0, SD = 0.64; <0.0001). There were no significant differences in the craniofacial pattern profile between the sexes or clinical severity as measured by either plasma cholesterol level at the time of diagnosis or the physical severity score. Patients with a lower weight at the time of assessment and patients with higher physical severity score had higher CVI measures (P < 0.001 and P < 0.002, respectively), suggesting that the degree of deviation from craniofacial norms is a function of the overall physical severity. PMID- 22438181 TI - Culture conditions for bovine embryonic stem cell-like cells isolated from blastocysts after external fertilization. AB - Although isolation and characterization of embryonic stem cells have been successful in cattle, maintenance of bovine embryonic stem cells in culture remains difficult. In this study, we compared different methods of cell passaging, feeder cell layers and medium conditions for bovine embryonic stem cell-like cells. We found that a murine embryonic fibroblast feeder layer is more suitable for embryonic stem cell-like cells than bovine embryonic fibroblasts. When murine embryonic fibroblasts were used, a mechanical method of passaging led to better cell growth than passaging by trypsin digestion. We also found that exogenous supplementation with leukemia inhibitory factor maintained the embryonic stem cell-like cells in an undifferentiated state, whereas addition of stem cell factor resulted in their differentiation. Our findings provide an experimental basis for the establishment of an effective culture system for bovine embryonic stem cells. PMID- 22438182 TI - Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. AB - Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43-87 years. Whole-brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol-associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular-related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults. PMID- 22438183 TI - Health beliefs and practices in an isolated polygamist community of southern Utah. AB - Short Creek is a largely closed and isolated community on the border between Utah and Arizona, made up of the sister towns of Hildale, Utah, and Colorado City, Arizona. Beginning from childhood, the 6,000 or so members of the Fundamentalist Church of Jesus Christ of Latter-Day Saints (FLDS) are brought up in a lifestyle of plural marriage, meaning a marriage among one man and more than one woman, and are surrounded by their peers in "the covenant." A lifestyle of plural marriage is likely to affect the health of community members, but its effects have not been studied because of the community's isolation and distrust of outsiders. This paper addresses several questions that arise in contemplating the health of the Short Creek community: What are the health beliefs in this community, and what are their historical bases? Where do families seek medical care, and for what or at what threshold of illness or injury? What is the attitude of care providers serving this community, and how are the providers viewed by the community? More broadly, this paper examines the ways in which polygamy configures health. In order to meet this objective, this paper aims first to provide a brief account of this community's history and demographic profile, followed by a discussion of health care in this community and how it is affected by the practice of plural marriage, with the data comprised of qualitative interviews with health care providers to the community. The goals of this project are to gain a rich, historically nuanced understanding of the health of community members, and to identify directions for further academic and policy research. Our findings indicate that health in this community is shaped by limited resources, an attitude of health fatalism, and a profound insularity and corresponding isolation from the outside world. PMID- 22438184 TI - Screening for co-existence of alpha-thalassemia in beta-thalassemia and in HbE heterozygotes via an enzyme-linked immunosorbent assay for Hb Bart's and embryonic zeta-globin chain. AB - We sought to demonstrate the ability of levels of Hb Bart's and zeta-globin chain quantified by enzyme-linked immunosorbent assay (ELISA) in detecting alpha thalassemia in beta-thalassemia and HbE heterozygotes. We developed an in-house sandwich ELISA method using monoclonal antibodies (mAbs) to Hb Bart's and zeta globin chain, and quantified levels of Hb Bart's and zeta-globin chain in 172 and 223 anonymous blood samples of beta-thalassemia and HbE heterozygotes, respectively. Genotypes of alpha-thalassemia 1, beta-thalassemia were identified, and HbE allele was confirmed using a newly developed multiplex allele-specific PCR. The in-house sandwich ELISA method detected Hb Bart's in 6.4% of beta thalassemia heterozygotes, of which 5.2% showed detectable amounts of the zeta globin chain. 15.2% of individuals heterozygous for HbE showed a detectable amount of Hb Bart's, and the zeta-globin chain was detected in 11.2% of this cohort. All samples having detectable amounts of Hb Bart's and the zeta-globin chain were verified to be SEA-type alpha-thalassemia 1. ELISA-quantified Hb Bart's and zeta-globin chain levels can be used to detect double heterozygosity of alpha- and beta-thalassemia and of alpha-thalassemia and HbE. This strategy may be useful in screening for co-existence of alpha-thalassemia in beta thalassemia and in HbE heterozygotes, particularly in countries where alpha-, beta-thalassemia and HbE are endemic. PMID- 22438185 TI - Ex vivo expansion of umbilical cord blood: where are we? AB - Since the first successful clinical use of umbilical cord blood (UCB) in 1988, UCB grafts have been used for over 20,000 patients with both malignant and non malignant diseases. UCB has several practical advantages over other transplantable graft sources. For example, the ease of procurement, the absence of donor risks, the reduced risk of transmissible infections, and the availability for immediate use make UCB an appealing graft choice. However, UCB grafts suffer from a few limitations related to the limited cell dose available for transplantation in each UCB unit and to defects in UCB stem cell homing. These limitations lead to increased post-transplant complications. In this review, we focus on the issue of limited cell dose in UCB units and discuss the possible approaches to overcome this limitation. We also summarize the various cellular pathways that have been explored to expand UCB units. PMID- 22438186 TI - A SNP in G6PC2 predicts insulin secretion in type 1 diabetes. AB - We investigated whether single nucleotide polymorphisms in genes related to glucose metabolism correlate with insulin secretion in type 1 diabetes patients. A cohort of 49 type 1 diabetes patients underwent serial mixed meal tolerance tests to assess insulin secretion. Patients were genotyped for SNPs related to glucose metabolism: CDKAL1 rs7754840, G6PC2 rs560887, HHEX rs1111875, KCNJ11 rs5215. Recently diagnosed patients (<100 days) homozygous for the G allele of G6PC2 had higher area under the curve C-peptide on mixed meal tolerance tests compared to non-homozygous patients (344.8 +/- 203.2 vs. 167.9 +/- 131.5, p = 0.04). Other SNPs did not correlate with insulin secretion in the new onset period. In a longitudinal survival analysis, homozygosity for the minor allele (A) in G6PC2 predicted more rapid loss of insulin secretion over time. A SNP in the beta cell gene G6PC2 may correlate with preserved insulin secretion in type 1 diabetes. PMID- 22438188 TI - MedJet--a new CO2-based disposable cleaning device allows safe and effective bowel cleansing during colonoscopy: a pilot study. AB - BACKGROUND AND STUDY AIMS: Complete bowel cleansing is mandatory for effective colon cancer screening and surveillance. The aim of the current pilot study, which was conducted in humans, was to test the safety and efficiency of a newly developed disposable cleaning device, the MedJet, for intraprocedural bowel cleansing. PATIENTS AND METHODS: Patients with screening or surveillance colonoscopy after previous polypectomy were included. The colonoscope was first inserted to the cecum and the overall cleansing was assessed according to the Ottawa scale. The MedJet device was used if colon cleansing had been incomplete. The MedJet catheter was passed over the working channel of the colonoscope and the colon was cleaned during withdrawal. The MedJet device delivered controlled jets comprising compressed CO2 and minimal amounts of sterile water, which allowed disintegration and removal of residual stool. The efficiency of cleaning was assessed according to the Boston scale. RESULTS: A total of 32 patients (16 female; mean age 61 years) were treated with the device. No device-related adverse or serious adverse events were noted. MedJet application during withdrawal provided effective and significant improvement in bowel cleansing (P = 0.005). Furthermore, 18 adenomas and 1 colon cancer, which were hidden behind stool remnants, could be identified in 11 patients following use of the MedJet device. However, the withdrawal times were prolonged (11.4+/-6.0 minutes) due to the additional cleaning procedure. All patients tolerated the procedure well. CONCLUSIONS: The new MedJet device enabled highly effective and safe bowel cleansing during colonoscopy. The catheter-based system was easy to use and CO2 was applied for cleansing. The procedure was well tolerated by patients. PMID- 22438190 TI - Designing a pilot sequential multiple assignment randomized trial for developing an adaptive treatment strategy. AB - There is growing interest in how best to adapt and readapt treatments to individuals to maximize clinical benefit. In response, adaptive treatment strategies (ATS), which operationalize adaptive, sequential clinical decision making, have been developed. From a patient's perspective an ATS is a sequence of treatments, each individualized to the patient's evolving health status. From a clinician's perspective, an ATS is a sequence of decision rules that input the patient's current health status and output the next recommended treatment. Sequential multiple assignment randomized trials (SMART) have been developed to address the sequencing questions that arise in the development of ATSs, but SMARTs are relatively new in clinical research. This article provides an introduction to ATSs and SMART designs. This article also discusses the design of SMART pilot studies to address feasibility concerns, and to prepare investigators for a full-scale SMART. We consider an example SMART for the development of an ATS in the treatment of pediatric generalized anxiety disorders. Using the example SMART, we identify and discuss design issues unique to SMARTs that are best addressed in an external pilot study prior to the full-scale SMART. We also address the question of how many participants are needed in a SMART pilot study. A properly executed pilot study can be used to effectively address concerns about acceptability and feasibility in preparation for (that is, prior to) executing a full-scale SMART. PMID- 22438193 TI - Microsurgical training model for lymphaticovenous anastomosis in rat. PMID- 22438191 TI - A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30 % of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the "miserable minority," the cognitive and physical symptoms do not resolve following the first 3 months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both posttraumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI. The challenge is thus to use neuroimaging tools that are sensitive to DAI/TAI, such as diffusion tensor imaging (DTI), in order to detect brain injuries in mTBI. Of note here, recent advances in neuroimaging techniques, such as DTI, make it possible to characterize better extant brain abnormalities in mTBI. These advances may lead to the development of biomarkers of injury, as well as to staging of reorganization and reversal of white matter changes following injury, and to the ability to track and to characterize changes in brain injury over time. Such tools will likely be used in future research to evaluate treatment efficacy, given their enhanced sensitivity to alterations in the brain. In this article we review the incidence of mTBI and the importance of characterizing this patient population using objective radiological measures. Evidence is presented for detecting brain abnormalities in mTBI based on studies that use advanced neuroimaging techniques. Taken together, these findings suggest that more sensitive neuroimaging tools improve the detection of brain abnormalities (i.e., diagnosis) in mTBI. These tools will likely also provide important information relevant to outcome (prognosis), as well as play an important role in longitudinal studies that are needed to understand the dynamic nature of brain injury in mTBI. Additionally, summary tables of MRI and DTI findings are included. We believe that the enhanced sensitivity of newer and more advanced neuroimaging techniques for identifying areas of brain damage in mTBI will be important for documenting the biological basis of postconcussive symptoms, which are likely associated with subtle brain alterations, alterations that have heretofore gone undetected due to the lack of sensitivity of earlier neuroimaging techniques. Nonetheless, it is noteworthy to point out that detecting brain abnormalities in mTBI does not mean that other disorders of a more psychogenic origin are not co-morbid with mTBI and equally important to treat. They arguably are. The controversy of psychogenic versus physiogenic, however, is not productive because the psychogenic view does not carefully consider the limitations of conventional neuroimaging techniques in detecting subtle brain injuries in mTBI, and the physiogenic view does not carefully consider the fact that PTSD and depression, and other co-morbid conditions, may be present in those suffering from mTBI. Finally, we end with a discussion of future directions in research that will lead to the improved care of patients diagnosed with mTBI. PMID- 22438194 TI - Synthesis and optoelectronic properties of hexahydroxylated 10-O-R-substituted anthracenes via a new modification of the Friedel-Crafts reaction using O protected ortho-acetal diarylmethanols. AB - A new modification of the Friedel-Crafts type intramolecular cyclization involving O-protected ortho-acetal diarylmethanols as a new type of reactant, was carried out for the first time in a medium containing a large amount of water at room temperature and enabled synthesis of a series of electron-rich, hexahydroxylated 10-O-R-substituted anthracenes, where R is an alkyl (Me, nBu, n C(16)H(33)) or arylalkyl group (CH(2)Ph, CH(2)-2-Napht, CH(2)C(6)H(4)CH(2)OAr) and also evaluation of their electronic and optoelectronic properties in solution, crystal, and solid thin film. In this transformation, a central 10-O-R substituted benzene ring was formed, fused to rings originating from two independent aromatic aldehydes. The reaction proceeded via two identified mechanisms involving acetal and/or free aldehyde groups. The acid sensitive acetal and dibenzyl alkoxy functions have never been used together in the intramolecular Friedel-Crafts type cyclization. The new compounds revealed deep blue fluorescence and quantum yields in solution around 0.3. The electrical properties investigated for thin films obtained by vacuum deposition on glass were 10-O-R-substituent dependent and showed much faster transient current decay in the case of the 10-O-CH(2)Ph derivative than for the material with a 10-O-Me substituent (the lifetime of charge carriers was 25 times shorter in this case). The AFM images of thin films, Stokes shifts, and X-ray analysis of pi-stacking interactions in crystals of the new materials have been also obtained. PMID- 22438195 TI - Enhanced depth imaging spectral-domain optical coherence tomography of subfoveal choroidal thickness in normal Japanese eyes. AB - PURPOSE: To investigate the subfoveal choroidal thickness of healthy Japanese subjects using enhanced depth imaging optical coherence tomography and to evaluate the association between subfoveal choroidal thickness and age in a group of subjects with a wide age range. SUBJECTS AND METHODS: A total of 145 eyes of 145 healthy volunteers (85 women, 60 men, age range 5-88 years, mean age 45.7 years) with no ophthalmic or systemic symptoms were evaluated; 23 subjects were under the age of 20 years. Exclusion criteria included high myopia (greater than 6 D) of spherical equivalent refractive error. RESULTS: The mean subfoveal choroidal thickness was 265.5 +/- 82.4 um. Although the subfoveal choroidal thickness showed a negative correlation with age (p < 0.05), subfoveal choroidal thickness in those subjects younger than 10 years old was significantly thicker than that in each of the other age groups. The subfoveal choroidal thickness remained unchanged from the age groups in the 10s to 20s, and it gradually decreased after the 30s. The subfoveal choroidal thickness tended to have a negative correlation with refractive error. Age and refractive error were statistically significant factors associated with subfoveal choroidal thickness (p < 0.01). The multiple regression formula was subfoveal choroidal thickness = 365.1 - 2.0 * age + 7.9 * refractive error. CONCLUSION: The subfoveal choroidal thickness in healthy Japanese subjects decreased in thickness by 20 um every 10 years. The subfoveal choroidal thickness in subjects younger than 10 years was significantly thicker than in other age groups. The subfoveal choroidal thickness also depended on the refractive error. PMID- 22438196 TI - Histopathologic analysis of the internal limiting membrane surgically peeled from eyes with diffuse diabetic macular edema. AB - PURPOSE: To investigate the pathogenesis of diffuse diabetic maculae edema (DME). METHODS: Internal limiting membrane (ILM) specimens were surgically peeled from 16 eyes of 15 patients with diffuse DME (diabetic retinopathy (DR) group) and from 12 eyes of 12 patients without diabetes (non-DR group). The specimens were then examined by light microscopy (LM), transmission electron microscopy (TEM), and immunohistochemistry. RESULTS: Examination by LM revealed numerous cells on the inner surface of the ILM specimens in the DR-group, among which five different cell types (glial cell, fibroblast-like cell, macrophages, neutrophils, and lymphocytes) were confirmed. Examination by TEM revealed that the thickness of the peeled ILMs in the DR group was significantly greater, and four types of cellular element (glial, fibroblast-like, macrophages, and lymphocytes) were confirmed on the surface of the vitreous side of the specimens. The existence of glial cells and macrophages was confirmed by immunohistochemistry. CONCLUSIONS: In diffuse DME, the ILM is thickened and a variety of cellular elements, especially numerous kinds of inflammatory cell, adhere to the inner surface of the ILM. To attenuate diffuse DME, vitrectomy combined with ILM peeling to remove the inflammatory cells and the physical barrier might be effective. PMID- 22438197 TI - Neuroendocrinology-based therapy for Alzheimer's disease. AB - The nervous system interacts directly with the endocrine system to control a plethora of central nervous system (CNS) functions. Metabolic and reproductive hormones are known to be important in the maintenance of neuronal health and their fluctuations are important for CNS aspects ranging from sleep and appetite regulation to cognitive function. This review will summarize and critically evaluate how age-related changes in sex and metabolic hormones modulate affect cognitive function and the implications of targeting the neuroendocrinological system as a therapeutic strategy in Alzheimer's disease. PMID- 22438198 TI - Cell bricks-enriched platelet-rich plasma gel for injectable cartilage engineering - an in vivo experiment in nude mice. AB - Clinical application of platelet-rich plasma (PRP)-based injectable tissue engineering is limited by weak mechanical properties and a rapid fibrinolytic rate. We proposed a new strategy, a cell bricks-stabilized PRP injectable system, to engineer and regenerate cartilage with stable morphology and structure in vivo. Chondrocytes from the auricular cartilage of rabbits were isolated and cultured to form cell bricks (fragmented cell sheet) or cell expansions. Fifteen nude mice were divided evenly (n = 5) into cells-PRP (C-P), cell bricks-PRP (CB P) and cell bricks-cells-PRP (CB-C-P) groups. Cells, cell bricks or a cell bricks/cells mixture were suspended in PRP and were injected subcutaneously in animals. After 8 weeks, all the constructs were replaced by white resilient tissue; however, specimens from the CB-P and CB-C-P groups were well maintained in shape, while the C-P group appeared distorted, with a compressed outline. Histologically, all groups presented lacuna-like structures, glycosaminoglycan enriched matrices and positive immunostaining of collagen type II. Different from the uniform structure presented in CB-C-P samples, CB-P presented interrupted, island-like chondrogenesis and contracted structure; fibrous interruption was shown in the C-P group. The highest percentage of matrix was presented in CB-C-P samples. Collagen and sGAG quantification confirmed that the CB-C-P constructs had statistically higher amounts than the C-P and CB-P groups; statistical differences were also found among the groups in terms of biomechanical properties and gene expression. We concluded that cell bricks-enriched PRP gel sufficiently enhanced the morphological stability of the constructs, maintained chondrocyte phenotypes and favoured chondrogenesis in vivo, which suggests that such an injectable, completely biological system is a suitable cell carrier for cell based cartilage repair. PMID- 22438199 TI - Brain activity during sympathetic response in anticipation and experience of pain. AB - Pain is a multidimensional phenomenon with sensory, affective, and autonomic components. Here, we used parametric functional magnetic resonance imaging (fMRI) to correlate regional brain activity with autonomic responses to (i) painful stimuli and to (ii) anticipation of pain. The autonomic parameters used for correlation were (i) skin blood flow (SBF) and (ii) skin conductance response (SCR). During (i) experience of pain and (ii) anticipation of pain, activity in the insular cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), posterior parietal cortex (PPC), secondary somatosensory cortex (S2), thalamus, and midbrain correlated with sympathetic outflow. A conjunction analysis revealed a common central sympathetic network for (i) pain experience and (ii) pain anticipation with similar correlations between brain activity and sympathetic parameters in the anterior insula, prefrontal cortex, thalamus, midbrain, and temporoparietal junction. Therefore, we here describe shared central neural networks involved in the central autonomic processing of the experience and anticipation of pain. PMID- 22438200 TI - Application of kernel principal component analysis for single-lead-ECG-derived respiration. AB - Recent studies show that principal component analysis (PCA) of heartbeats is a well-performing method to derive a respiratory signal from ECGs. In this study, an improved ECG-derived respiration (EDR) algorithm based on kernel PCA (kPCA) is presented. KPCA can be seen as a generalization of PCA where nonlinearities in the data are taken into account by nonlinear mapping of the data, using a kernel function, into a higher dimensional space in which PCA is carried out. The comparison of several kernels suggests that a radial basis function (RBF) kernel performs the best when deriving EDR signals. Further improvement is carried out by tuning the parameter sigma(2) that represents the variance of the RBF kernel. The performance of kPCA is assessed by comparing the EDR signals to a reference respiratory signal, using the correlation and the magnitude squared coherence coefficients. When comparing the coefficients of the tuned EDR signals using kPCA to EDR signals obtained using PCA and the algorithm based on the R peak amplitude, statistically significant differences are found in the correlation and coherence coefficients (both p<0.0001), showing that kPCA outperforms PCA and R peak amplitude in the extraction of a respiratory signal from single-lead ECGs. PMID- 22438201 TI - Ameliorative effect of tamarind leaf on fluoride-induced metabolic alterations. AB - OBJECTIVES: Fluoride is a serious health hazard across several nations, and chronic intake of fluoride deranges the carbohydrate, lipid and antioxidant metabolism in general. As there are limited remedial measures to prevent fluorosis, we investigated the role of tamarind leaf as a food supplement in restoration of carbohydrate, lipid and antioxidant metabolism in fluoride-exposed albino rats. METHODS: Albino rats were exposed to fluoride (100 ppm sodium fluoride) through drinking water and fed diet supplemented with tamarind leaf powder (2.5, 5 and 10 g %) for 4 weeks. Carbohydrate, lipid and antioxidant profiles were investigated in both controls and fluoride-exposed animals. RESULTS: While 4-week exposure to fluoride elevated plasma glucose and lipid profiles, simulating diabetic and hyperlipidaemic conditions, the antioxidant defence mechanisms of fluoride-exposed rats were compromised, with elevation and decline in lipid peroxidation and high-density lipoprotein (HDL)-cholesterol, respectively. When the diet was supplemented with tender tamarind leaves (used in southern India as a replacement for tamarind or other sour food ingredients), significant improvements in carbohydrate and lipid profiles occurred as evidenced by decreased plasma glucose and lipid levels, lipid peroxidation, increased hepatic glycogen content, hexokinase activity and cholesterol excretion, with simultaneous improvement in antioxidant profiles of both hepatic and renal tissues. CONCLUSIONS: These findings are significant in view of the need for cost effective approaches to tackle fluorosis as an environmental hazard and use of food supplements as ameliorative measures. PMID- 22438202 TI - Group-averaged anatomical connectivity mapping for improved human white matter pathway visualisation. AB - Anatomical connectivity mapping (ACM) is a measure of anatomical connectivity obtained by initiating streamline diffusion tractography from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. ACM highlights WM structures that present multiple connections to the rest of the brain but not necessarily strong microstructural orientation coherence. In this study, ACM was used to develop an atlas of the human brain. The ACM template was constructed from 3 T diffusion-weighted data from 19 healthy adults. To account for multiple diffusion directions in a voxel, a high angular resolution diffusion imaging (HARDI) technique, namely Q-ball, was used to model diffusion. To bring data from different subjects into a common space, an algorithm for rotating and averaging the principal directions was implemented, which can be generalized to any application requiring algebraic operations on principal directions derived from any HARDI method. ACM from the average dataset was computed and several white matter connections of interest were identified and highlighted. Fractional anisotropy (FA) from standard diffusion tensor modelling was also derived and FA-modulated colour coded images obtained from the mean tensor were also shown for comparison, highlighting differences and similarities. The ACM template can serve for educational purposes and as future reference for studies based on the evaluation of ACM in subjects affected by neurological and psychiatric disorders. PMID- 22438203 TI - Antioxidant SMe1EC2 may attenuate the disbalance of sodium homeostasis in the organism induced by higher intake of cholesterol. AB - The study was focused to the influence of higher intake of cholesterol on properties of the renal Na,K-ATPase, a key system in maintaining the homeostasis of sodium in the organism. Feeding for 4 weeks with cholesterol-enriched food for rats afflicted with hereditary hypertriglyceridemia by itself enhanced the activity of Na,K-ATPase, probably as a consequence of higher number of active enzyme molecules as suggested by 32 % increase of V (max) value. This may be hypothesized as a reason for the increased retention of sodium. Three-week lasting treatment of animals kept on high cholesterol diet with antioxidant SMe1EC2 in a dose of 10 mg kg(-1) day(-1) normalized the function of renal Na,K ATPase to the level comparable in hypertriglyceridemic rats fed with the standard diet. Therefore, our results suggest that the antioxidant SMe1EC2 in the applied dose seems to be effective in the attenuation of cholesterol-induced retention of sodium. Treatment for 3 weeks with Fenofibrate in a dose of 100 mg kg(-1) day(-1) reversed the function of renal Na,K-ATPase only slightly. PMID- 22438204 TI - Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion. AB - Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (K(v) ) generates an outward, 'delayed rectifier' potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several K(v) channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk S1), which selectively blocks K(v) 1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing K(v) 1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that K(v) 1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell K(v) current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes. PMID- 22438205 TI - Treating diet-induced obesity: a new role for vagal afferents? PMID- 22438206 TI - Reactivity of atmospherically relevant small radicals at the air-water interface. PMID- 22438207 TI - A facile way to rejuvenate Ag3PO4 as a recyclable highly efficient photocatalyst. AB - Recycling awarded the silver: Ag(3)PO(4), a highly efficient photocatalyst, decomposes to the weak photocatalyst Ag during consecutive photocatalytic cycles. A facile and very mild wet chemical oxidation method was proposed, which involves the cooperation of H(2)O(2) with Na(2)HPO(4), to rejuvenate Ag(3)PO(4) from Ag as a recyclable highly efficient photocatalyst. PMID- 22438208 TI - Testing superiority at interim analyses in a non-inferiority trial. AB - Shift in research and development strategy from developing follow-on or 'me-too' drugs to differentiated medical products with potentially better efficacy than the standard of care (e.g., first-in-class, best-in-class, and bio-betters) highlights the scientific and commercial interests in establishing superiority even when a non-inferiority design, adequately powered for a pre-specified non inferiority margin, is appropriate for various reasons. In this paper, we propose a group sequential design to test superiority at interim analyses in a non inferiority trial. We will test superiority at the interim analyses using conventional group sequential methods, and we may stop the study because of better efficacy. If the study fails to establish superior efficacy at the interim and final analyses, we will test the primary non-inferiority hypothesis at the final analysis at the nominal level without alpha adjustment. Whereas superiority/non-inferiority testing no longer has the hierarchical structure in which the rejection region for testing superiority is a subset of that for testing non-inferiority, the impact of repeated superiority tests on the false positive rate and statistical power for the primary non-inferiority test at the final analysis is essentially ignorable. For the commonly used O'Brien-Fleming type alpha-spending function, we show that the impact is extremely small based upon Brownian motion boundary-crossing properties. Numerical evaluation further supports the conclusion for other alpha-spending functions with a substantial amount of alpha being spent on the interim superiority tests. We use a clinical trial example to illustrate the proposed design. PMID- 22438209 TI - The extended diep flap: extending the possibilities for breast reconstruction with tissue from the lower abdomen. AB - BACKGROUND: The classical DIEP-flap is considered state-of-the-art in microsurgical autologous breast reconstruction. Some patients may require additional volume to match the contralateral breast. This quality control study prospectively evaluates the feasibility and outcome of a surgical technique, which pursues the volumetric augmentation of the DIEP-flap by harvesting of additional subscarpal fat tissue cranial to the classical flap border. PATIENTS AND METHODS: For radiologically based estimation of volumetric flap-gain potential, abdominal CT-scans of 10 Patients were randomly selected and used for computerized volumetric estimates. Surgical evaluation of the technique was prospectively performed between 09/2009 and 09/2010 in 10 patients undergoing breast reconstruction with extended DIEP-flap at two institutions. The outcome regarding size, volume, and symmetry was evaluated. RESULTS: Radiologically, the mean computed volume gain of an extended DIEP was 16.7%, when compared with the infraumbilical unilateral flap volume. Clinically, the intraoperatively measured mean volume gain was of 98.6 g (range: 75-121 g), representing 13.8% of the flap volume. All 10 flaps survived without revision surgery. In three flaps, minor fat necrosis occurred in zone III and was treated conservatively. No fat necrosis was observed in the extended flap area. CONCLUSIONS: In this first prospective series, the extended DIEP-flap proved to be feasible, reliable and safe for its use in breast reconstruction. Both radiological estimation and intraoperative measurements demonstrated a statistically significant volume gain with no complications in the extended area. The technique is of benefit in selected patients requiring additional reconstructive volume than the one achieved with the classical DIEP-flap. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 22438210 TI - Genetic screening for von Hippel-Lindau gene mutations in non-syndromic pheochromocytoma: low prevalence and false-positives or misdiagnosis indicate a need for caution. AB - Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs. PMID- 22438211 TI - Early exposure to a high-fat diet has more drastic consequences on metabolism compared with exposure during adulthood in rats. AB - The aim of this study was determine whether the introduction of a high-fat diet during the peripubertal phase induces significant changes in body weight control, glucose homeostasis and the parasympathetic tonus compared with the administration of this diet to adult rats. High-fat diet was offered to male Wistar rats at weaning or during adulthood. A group of rats received high-fat diet for 60 days, from weaning to 81-day-old (HF81) or from 60 to 120-day-old (HF120), whereas 2 other groups received a normal-fat diet (i. e., NF81 and NF120). We analyzed adiposity, glucose homeostasis, insulin sensitivity, and vagal nerve activity. High-fat diet increased the accumulation of adipose tissue in all of the rats, but the difference was greater in the rats that were fed the high-fat diet since weaning (p<0.001). The HF rats showed glucose intolerance with high levels of insulin secretion during the glucose tolerance test (p<0.01). Rats that were fed the high-fat diet presented severe insulin resistance, indicated by a low K itt (p<0.01). Interestingly, the HF81 rats exhibited greater insulin resistance compared with the HF120 rats (p<0.05). The recordings of vagus nerve activity showed that the HF rats had higher parasympathetic activity than the NF rats irrespective of age (p<0.01). Our results show that a high-fat diet offered to rats just after weaning or in adulthood both cause impairment of glycemic homeostasis and imbalance in parasympathetic activity. Importantly, the consumption of high-fat diet immediately after weaning has more drastic consequences compared with the consumption of the same diet during adulthood. PMID- 22438212 TI - Hormonal regulation of female reproduction. AB - Reproduction is an event that requires the coordination of peripheral organs with the nervous system to ensure that the internal and external environments are optimal for successful procreation of the species. This is accomplished by the hypothalamic-pituitary-gonadal axis that coordinates reproductive behavior with ovulation. The primary signal from the central nervous system is gonadotropin releasing hormone (GnRH), which modulates the activity of anterior pituitary gonadotropes regulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) release. As ovarian follicles develop they release estradiol, which negatively regulates further release of GnRH and FSH. As estradiol concentrations peak they trigger the surge release of GnRH, which leads to LH release inducing ovulation. Release of GnRH within the central nervous system helps modulate reproductive behaviors providing a node at which control of reproduction is regulated. To address these issues, this review focuses on several critical questions. How is the HPG axis regulated in species with different reproductive strategies? What internal and external conditions modulate the synthesis and release of GnRH? How does GnRH modulate reproductive behavior within the hypothalamus? How does disease shift the activity of the HPG axis? PMID- 22438213 TI - Weight loss due to a very low calorie diet differentially affects insulin sensitivity and interleukin-6 serum levels in nondiabetic obese human subjects. AB - Inflammatory mechanisms are involved in the pathogenesis of type 2 diabetes with interleukin (IL)-6 being particularly important. While long term exercise has been shown to be associated with reduction in IL-6 serum levels in several reports, the discussion on the effect of dietary intervention on IL-6 serum levels is controversial. In the present study, we aimed to investigate the effect of weight loss due to a very low calorie diet (VLCD) on insulin sensitivity and IL-6 serum levels in nondiabetic obese human individuals. 10 patients with obesity were examined during 12 weeks of a VLCD (800 kcal/d). Body composition was measured by impedance analysis. Blood samples were taken before, during, and after the dietary intervention. Leptin, adiponectin, and IL-6 serum levels were measured by ELISA. The body weight decreased significantly from 123.9+/-6.2 103.5+/-5.6 kg with a significant reduction in body fat content (43.2+/-2.3 36.1+/-3.1%). Leptin levels exhibited a significant decrease from 56.8+/-5.6 27.9+/-5.6 ng/ml while adiponectin levels increased significantly from 7.5+/-0.9 10.6+/-1.1 MUg/ml. Thereby the leptin-to-adiponectin ratio, a novel marker for insulin sensitivity, significantly improved. Mean IL-6 serum concentrations were within the normal range (3.2+/-0.8 pg/ml) before the study and were not significantly altered by the nutritional therapy. Despite improvement of insulin sensitivity, IL-6 serum levels did not change throughout the study period, suggesting that in nondiabetic obese human subjects IL-6 might have only a minor role in the impairment of insulin sensitivity. PMID- 22438214 TI - Circadian rhythm and response to an acute stressor of urinary corticosterone, testosterone, and creatinine in adult male mice. AB - In small laboratory species, steroid measures can be obtained more frequently and less invasively from urine than blood. Insofar as urinary levels reflect systemic levels, they could provide advantages particularly for measurement of glucocorticoids, whose blood levels react rapidly to handling and stress. In Experiment 1, urinary samples were collected from male mice every second hour over a 14:10 h light:dark cycle. Samples were analyzed via enzyme immunoassay for corticosterone, testosterone, and creatinine. Corticosterone had peak concentrations 1 h after light offset and a trough 1 h after light onset. Testosterone showed peak concentrations 5-7 h after light onset and lowest concentrations during the dark phase of the cycle. Creatinine showed some variation over the light-dark cycle, but steroid measures showed similar trends with and without adjustment for creatinine. In Experiment 2, mice were stressed via an injection at times close to the determined peak and trough levels of corticosterone. In urinary samples taken 90 min after injection, corticosterone was significantly higher in injected animals at both times relative to levels in control animals, but testosterone was unaffected by injection stress. In Experiment 3, serum and urine samples were collected from mice every sixth hour across the diurnal cycle. Corticosterone peaked in urine and serum immediately after light offset, and urinary measures predicted those in serum. These data indicate that urinary corticosterone reflects systemic levels in mice, document circadian variation in urinary testosterone, and indicate that circadian variation in creatinine is minimal, but potentially relevant in stressed animals. PMID- 22438215 TI - Differential roles of inferior frontal and inferior parietal cortex in task switching: evidence from stimulus-categorization switching and response-modality switching. AB - We used fMRI to investigate both common and differential neural mechanisms underlying two distinct types of switching requirements, namely switching between stimulus categorizations (color vs. form) and switching between response modalities (hand vs. foot responses). Both types of switching induced similar behavioral shift costs. However, at the neural level, switching between stimulus categorizations led to left-hemispheric activations including the inferior frontal gyrus as well as the intraparietal sulcus extending to the superior parietal gyrus and the supramarginal gyrus. In contrast, switching between response modalities was associated mainly with left-hemispheric activation of the intraparietal sulcus and the supramarginal gyrus. A conjunction analysis indicated common activation of the left intraparietal sulcus and the supramarginal gyrus for both types of switching. Together, these results qualify previous claims about a general role of the left prefrontal cortex in task control by suggesting that the left inferior frontal gyrus is specifically involved in switching between stimulus categorizations, whereas parietal cortex is more generally implicated in the selection of action rules. PMID- 22438216 TI - Blockade of beta1-, beta2- and beta3-adrenoceptors in the temporomandibular joint induces antinociception especially in female rats. AB - BACKGROUND: Temporomandibular joint (TMJ) receives rich sympathetic innervations that may contribute to TMJ pain through the local release of sympathomimetic amines. The aim of this study was to determine whether blockade of beta adrenoceptors in the TMJ of male and female rats reduces formalin-induced TMJ nociceptive behaviour. METHODS: We co-administrated each one of the selective beta(1) -, beta(2) - and beta(3) -adrenoceptors antagonists, atenolol, ICI 118.551 and SR59230A, respectively, with formalin in the TMJ of male and proestrus and dioestrus female rats. Because intra-temporomandibular joint formalin induces significantly different concentration-dependent responses among the three groups, with dioestrus females showing greater responses than males or proestrus females, equi-nociceptive formalin concentrations were used to test the effects of the beta-adrenoceptor antagonists. RESULTS: We found that atenolol, ICI 118.551 and SR59230A significantly reduced formalin-induced TMJ nociception in a dose response fashion in both males and females. However, a lower dose of each beta-adrenoceptor antagonist was sufficient to significantly reduce nociceptive responses in females than in males. Administration of the highest doses of each beta-adrenoceptor antagonist in the TMJ contralateral to that receiving formalin did not affect formalin-induced nociception in males and females, confirming the local action of the beta-adrenoceptor antagonists. CONCLUSIONS: We conclude that blockade of beta-adrenoceptors in the temporomandibular joint suppresses formalin-induced TMJ nociceptive behaviour in both males and females but females are more responsive. These findings suggest that the use of beta-blockers in the treatment of TMJ pain might be of benefit, especially in females. PMID- 22438217 TI - Tissue-engineered constructs: the effect of scaffold architecture in osteochondral repair. AB - Cartilage has a poor regenerative capacity. Tissue-engineering approaches using porous scaffolds seeded with chondrocytes may improve cartilage repair. The aim of this study was to examine the effect of pore size and pore interconnectivity on cartilage repair in osteochondral defects treated with different scaffolds seeded with allogenic chondrocytes. Scaffolds consisting of 55 wt% poly(ethylene oxide terephthalate) and 45 wt% poly(butylene terephthalate) (PEOT/PBT) with different pore sizes and interconnectivities were made, using a compression moulding (CM) and a three-dimensional fibre (3DF) deposition technique. In these scaffolds, allogenic chondrocytes were seeded, cultured for 3 weeks and implanted in osteochondral defects of skeletally mature rabbits. At 3 weeks no difference in cartilage repair between an empty osteochondral defect, CM or 3DF scaffolds was found. Three months post-implantation, cartilage repair was significantly improved after implantation of a 3DF scaffold compared to a CM scaffold. Although not significant, Mankin scores for osteoarthritis (OA) indicated less OA in the 3DF scaffold group compared to empty defects and CM-treated defects. It is concluded that scaffold pore size and pore interconnectivity influences osteochondral repair and a decreased pore interconnectivity seems to impair osteochondral repair. PMID- 22438218 TI - Classification and management of leaks after gastric bypass for patients with morbid obesity: a prospective study of 60 patients. AB - The most important and frequent major complication after gastric bypass is the appearance of a leak, which can result in death of a patient. The purpose of this prospective study was to determine the incidence of a postoperative leak, to propose a classification and to evaluate the results of conservative or surgical treatment. All patients submitted to gastric bypass either laparotomic or laparoscopic were included in a prospective protocol. In all radiological evaluation at 4(th) day after surgery was performed. The presence of a leak was evaluated according to the day of appearance, its location and its severity. Results of medical or surgical treatment were analyzed. From 1764 patients submitted to Roux-en-Y gastric bypass, 60 had a postoperative leak (3.4%). This leak appeared early after surgery (before 4 days) in 20%. It was a localized subclinical leak in 20% and clinical - septic in 80%. There were 7 possible anatomic location of a leak, being the gastrojejunal anastomosis the most frequent location (53%) followed by gastric pouch. The highest mortality was associated to the jejuno-jejunal anastomosis. Conservative treatment was employed in near 65% of the patients: The mean time of closure of a leak was 34 days. The appearance of a postoperative leak is a major and serious complication. It can be classified according to the day of appearance, its severity and its location. Conservative or surgical treatment can be employed properly if these 3 parameters are carefully evaluated. PMID- 22438219 TI - Laparoscopic sleeve gastrectomy as a stand-alone procedure for morbid obesity: report of 1,000 cases and 3-year follow-up. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an emerging surgical technique with encouraging results. The objective of this study is to report surgical results after 1,000 consecutive LSG cases as a stand-alone procedure for morbid obesity during a 3-year follow-up. METHODS: Data were obtained by review of our prospectively maintained database, patients' clinical charts, and phone interview of all patients who underwent LSG in our institution from December 2005 to February 2010. RESULTS: There were 773 (77.3%) women whose preoperative age and BMI was 36.9 +/- 11.5 years and 37.4 +/- 4.0 kg/m(2), respectively. The most common co-morbid conditions were insulin resistance 55.1%, dyslipidemia 45.5%, arterial hypertension 23.1%, hypothyroidism 15.4% and non-alcoholic fatty liver disease 12%. Excess weight loss was as follows: 1 year 86.6%, 2 years 84.1%, and 3 years 84.5%. Early and late complications occurred in 34 (3.4%) and 20 (2.0%) patients, respectively. Reoperation was required in seven (0.7%) patients. There was no mortality during follow-up. CONCLUSIONS: LSG seems to be a safe and effective surgical technique for morbid obesity as a stand-alone procedure. PMID- 22438220 TI - A review of unmet needs in obesity management. AB - The prevalence of obesity continues to escalate in the USA; however, there is no consensus regarding the optimal therapy for obesity. For the vast majority of severely obese patients, conventional medical therapies (i.e., diet, exercise, behavioral counseling) often fail over the long term. Existing pharmacotherapy adjunctive to behavioral therapy has limited effectiveness and an imperfect safety record. In contrast, bariatric surgery has a high degree of weight loss efficacy, yet only a small fraction of the qualifying obese population undergoes these procedures because of the associated perioperative risks and potential late complications. In addition, the role of bariatric surgery is unclear in certain patient populations, such as patients with lower body mass index (BMI, 30-35 kg/m(2)), the high-risk super-super obese patients (BMI > 60), the morbidly obese adolescent, and obese patients requiring weight reduction in preparation for other procedures, such as orthopedic, transplant, or vascular surgeries. In these circumstances, there is a need for an effective but less invasive treatment to bridge the gap between medical and surgical therapy. This review examines current treatment outcomes, identifies prominent areas of unmet clinical needs, and provides an overview of two minimally invasive "temporary procedures for weight loss" that may eventually address some of the unmet needs in obesity management. PMID- 22438221 TI - Prolonged use of extracorporeal membrane oxygenation combined with prone positioning in patients with acute respiratory distress syndrome and invasive Aspergillosis. AB - Extracorporeal membrane oxygenation (ECMO) is increasingly being used in patients with severe acute respiratory distress syndrome. In two large cohorts of such patients, the median duration of treatment with ECMO was 9 and 10 days. We describe two patients, both with H1N1 pneumonia complicated by invasive Aspergillosis, who required ECMO support significantly longer at 45 and 52 days, but eventually made a full recovery. In both patients, prone positioning was used during ECMO treatment. PMID- 22438222 TI - The effect of tepid amino acid-enriched induction cardioplegia on the outcome of infants undergoing cardiac surgery. AB - BACKGROUND: Despite promising experimental results, no information has been published on the clinical effects of amino acid-enriched induction cardioplegic solution on outcome in children undergoing cardiac surgery. METHODS: This is a retrospective study of 185 consecutive patients younger than 12 months with one of the following defects undergoing open heart surgery: atrioventricular septal defect, transposition of the great arteries, tetralogy of Fallot or ventricular septal defect. Patients were divided into two groups according to the following myocardial protection approaches: tepid substrate-enriched induction cardioplegia followed by cold blood cardioplegia (n=113) or only cold blood induction cardioplegia (n=72). Patient allocation was determined by the anesthesiologist in charge of cardiopulmonary bypass (CPB). The primary outcome measure was postoperative myocardial injury assessed by troponin T level and inotrope score. RESULTS: Demographic data were similar for both groups. Cardioplegic induction had no overall effect for inotrope score (16.3 +/- 9.2 vs.17.9 +/- 10.0, p=0.276) or lactate release (1.8 +/- 1.3 vs. 1.6 +/- 0.8, p=0.110) on arrival to the paediatric intensive care unit. On the first postoperative day, there were no significant differences between the cardioplegia groups for inotrope score (13.7 +/- 8.7 vs.14.3 +/- 9.1, p=0.657), troponin T (2.4 +/- 1.6 vs. 2.8 +/- 2.7 MUg/L, p=0.267), lactate (1.5 +/- 2.0 vs. 1.5 +/- 0.8, p=0.972), or any of the other clinical outcome measures. CONCLUSIONS: Compared to cold cardioplegia alone, the administration of tepid induction cardioplegia had no effect on the clinical outcome of infants who underwent cardiac surgery. PMID- 22438223 TI - 'Don't be so over-protective!'. PMID- 22438224 TI - Is age a risk factor for hypothyroidism in pregnancy? An analysis of 5223 pregnant women. AB - CONTEXT: The guidelines of American Thyroid Association from 2011 include age over 30 as one of the risk factors for hypothyroidism in pregnancy. OBJECTIVE: Our objective was to verify whether age increases the risk of autoimmune thyroid disease in pregnancy. DESIGN: We performed a cross-sectional study in 2006-2008 with laboratory assessment in a single center using primary care gynecological ambulances in cooperation with a referral center. PATIENTS: The study included 5223 consecutive pregnant women in gestational wk 9-12. MAIN OUTCOME MEASURE: We assessed the occurrence of pathological serum concentrations of TSH and/or antibodies against thyroperoxidase (TPOAb) with regard to age. Reference interval for TSH was 0.06-3.67 mU/liter; the upper cutoff value for TPOAb was 143 kU/liter. RESULTS: Overall, 857 women (16.4%) were positively screened. Of these, 294 (5.63%) had TSH elevation, 146 (2.79%) had TSH suppression, 561 (10.74%) were TPOAb positive, and 417 (7.98%) were euthyroid and TPOAb positive. The average age of women was 31.1 yr. The prevalence of hypothyroidism was 5.5 and 5.8% in women aged 30 or older and those under 30 yr, respectively (P value nonsignificant). Using a logistic regression model, we didn't find any significant association between age and serum TSH suppression, TSH elevation, or TPOAb positivity (P = 0.553, P = 0.680, and P = 0.056, respectively) or between age and TSH elevation with TPOAb positivity (P = 0.967). In a subgroup analysis of risk factors for hypothyroidism in 132 hypothyroid women, addition of age 30 or older increased the proportion of women identified in a case-finding screening strategy from 55.3 to 85.6%. CONCLUSIONS: Prevalence of autoimmune thyroid disease does not increase with age in pregnant women; however, addition of age 30 or over to the case-finding screening strategy may substantially improve its efficiency due to a larger number of women screened. PMID- 22438225 TI - Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. AB - CONTEXT: Fibroblast growth factor 21 (FGF-21), a potent activator of glucose uptake, has been proposed to be related to insulin resistance, metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), and weight status. OBJECTIVE: Our objective was to study the relationships between FGF-21, parameters of MetS, and NAFLD before and after weight loss in obese children. DESIGN AND SETTING: This was a cross-sectional comparison between obese and normal-weight children and longitudinal 1-yr follow-up study in obese children participating in a lifestyle intervention in a primary care setting. PATIENTS: Patients included 60 obese and 40 lean children of same age, gender, and pubertal stage. INTERVENTION: The outpatient 1-yr intervention program was based on exercise, behavior, and nutrition therapy. MAIN OUTCOMES MEASURES: We evaluated fasting serum FGF-21, weight status [body mass index (BMI) expressed as sd score (SDS)], body fat, insulin resistance index (homeostasis model assessment), leptin, transaminases, free fatty acids (FFA), waist circumference, blood pressure, and lipids. RESULTS: Compared with the normal-weight children, obese children demonstrated significantly (P < 0.001) increased FGF-21, leptin, and homeostasis model assessment levels. FGF-21 was significantly (P < 0.05) correlated to BMI, SDS BMI, FFA, and leptin both in cross-sectional and longitudinal analyses but not to any additional analyzed parameter. Children with and without MetS or NAFLD did not differ significantly with respect to their FGF-21 concentrations. A decrease of SDS-BMI was associated with a significant (P = 0.038) decrease of FGF-21 levels (mean -34%). CONCLUSIONS: FGF-21 concentrations are reversibly increased in obese children and are related to leptin and FFA. However, our data do not support a significant relationship between FGF-21, insulin resistance, and features of MetS or NAFLD in children. PMID- 22438226 TI - Plasma lipoproteins and preeclampsia in women with type 1 diabetes: a prospective study. AB - CONTEXT: In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown. OBJECTIVES: The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM. DESIGN AND SETTINGS: We conducted a multicenter prospective study in T1DM pregnancy. PATIENTS: We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 +/- 1.9, 21.6 +/- 1.5, and 31.5 +/- 1.7 wk gestation (means +/- SD)] and at term (37.6 +/- 2.0 wk). Nondiabetic normotensive pregnant women (n = 21) were included for reference. MAIN OUTCOME MEASURES: Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE. RESULTS: In women with vs. without subsequent PE, at the first and/or second study visits: low-density lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P < 0.05); peripheral lipoprotein lipolysis was decreased (P < 0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset. CONCLUSIONS: Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk. PMID- 22438227 TI - Functional variations in the ATM gene and susceptibility to differentiated thyroid carcinoma. AB - CONTEXT: ATM is critical in response to ionizing radiation-induced DNA damage. OBJECTIVE: Variations in ATM are hypothesized to affect individual susceptibility to thyroid cancer. Our objective was to evaluate the association between ATM polymorphisms and thyroid cancer risk. DESIGN, PARTICIPANTS, AND METHODS: Six ATM single nucleotide polymorphisms (SNP) were genotyped in two independent case control series including 592 patients with differentiated thyroid carcinoma (DTC) and 885 healthy individuals. An unconditional logistic regression model was applied to calculate odds ratios (OR) and 95% confidence intervals (CI) for each SNP with respect to risk of DTC and the combination effect of SNP on cancer risk. RESULTS: The risk-allele frequencies of all the SNP were similar in the two case control populations. Under a dominant model of inheritance, the G allele of ATM rs189037 exhibited a protective effect against DTC (adjusted OR = 0.8; 95% CI, 0.6-1.0; P = 0.04), and the G allele of rs1800057 was associated with increased risk of DTC (adjusted OR = 1.9; 95% CI, 1.1-3.1; P = 0.02). A protective haplotype (A-G-C-T-C-A) was associated with decreased risk of DTC in non-Hispanic whites (adjusted OR = 0.2; 95% CI, 0.0-0.8; P = 0.03). A significant dose response relationship was observed between the total number of risk alleles of ATM and DTC risk (P = 0.01). Carriers of a combination of six to seven and eight to 10 risk alleles were at 30% (adjusted OR = 1.3; 95% CI, 1.0-1.7) and 50% (adjusted OR = 1.5; 95% CI, 1.1-2.1) increased risk of DTC, respectively. CONCLUSION: Individual susceptibility to DTC may be attributable to polymorphisms of ATM, and the associations warrant confirmation in independent studies. PMID- 22438228 TI - Adiponectin as an independent predictor of the presence and degree of hepatic steatosis in the Dallas Heart Study. AB - CONTEXT: Previous small case-control studies have suggested an inverse relationship between adiponectin and hepatic steatosis, but whether this finding is independent of insulin sensitivity and other intraabdominal fat depots is unclear. OBJECTIVES AND MAIN OUTCOME MEASURES: The objective of this study was to establish whether an independent relationship exists between serum adiponectin concentrations and liver fat. DESIGN, SETTING, AND PATIENTS: Adiponectin levels were compared with hepatic triglyceride content (HTGC) as assessed by proton magnetic resonance spectroscopy in 2215 participants from the Dallas Heart Study. Multivariate modeling was performed to control for the effects of intraabdominal fat, insulin sensitivity, and other baseline factors. RESULTS: In unadjusted analysis, adiponectin levels displayed inverse correlations with the amount of intraabdominal fat and HTGC. After multivariate adjustment, including individual intraabdominal fat depots and homeostasis model assessment of insulin resistance, HTGC remained significantly associated with adiponectin levels (beta = -1.46, P < 0.0001 for women; beta = -1.81, P < 0.0001 for men). Race- and gender-specific models demonstrated that this association was consistent across groups, except for Hispanic men. The adjusted odds ratio for hepatic steatosis (HTGC > 5.5%) per 1-sd increase in adiponectin concentrations was 0.64 (95% confidence interval = 0.52-0.78) for women and 0.61 (95% confidence interval = 0.51-0.74) for men. CONCLUSION: Data from a large, multiethnic population-based cohort show adiponectin levels are inversely associated with hepatic steatosis even after controlling for measures of insulin sensitivity, extrahepatic abdominal adiposity, and ethnicity. The mechanistic underpinnings of this association warrant further exploration. PMID- 22438229 TI - Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. AB - BACKGROUND: Lipoprotein lipase-deficient (LPLD) individuals display marked chylomicronemia and hypertriglyceridemia associated with increased pancreatitis risk. The aim of this study was to determine the effect of i.m. administration of an adeno-associated viral vector (AAV1) for expression of LPL(S447X) in muscle (alipogene tiparvovec, AAV1-LPL(S447X)) on postprandial chylomicron metabolism and on nonesterified fatty acid (NEFA) and glycerol metabolism in LPLD individuals. METHODOLOGY: In an open-label clinical trial (CT-AMT-011-02), LPLD subjects were administered alipogene tiparvovec at a dose of 1 * 10(12) genome copies per kilogram. Two weeks before and 14 wk after administration, chylomicron metabolism and plasma palmitate and glycerol appearance rates were determined after ingestion of a low-fat meal containing (3)H-palmitate, combined with (continuous) iv infusion of [U-(13)C]palmitate and [1,1,2,3,3-(2)H]glycerol. PRINCIPAL FINDINGS: After administration of alipogene tiparvovec, the triglyceride (TG) content of the chylomicron fraction and the chylomicron TG/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron (3)H level and chylomicron (3)H area under the curve were greatly reduced (by 79 and 93%, 6 and 24 h after the test meal, respectively). There were no significant changes in plasma NEFA and glycerol appearance rates. Plasma glucose, insulin, and C-peptide also did not change. CONCLUSIONS/SIGNIFICANCE: Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover. PMID- 22438230 TI - Preeclampsia up-regulates angiogenesis-associated microRNA (i.e., miR-17, -20a, and -20b) that target ephrin-B2 and EPHB4 in human placenta. AB - CONTEXT: Placental angiogenesis contributes to the pathogenesis of preeclampsia (PE) that affects 5-8% of all human pregnancies. MicroRNA (miRNA) are a class of noncoding 21- to 25-nucleotide RNA that negatively regulate gene expression posttranscriptionly. OBJECTIVE: The aim of this study was to test the hypothesis that miRNA are differentially expressed in healthy term and PE placentas and a subclass of angiogenesis-associated miRNA are increased by PE. DESIGN: Total miRNA were extracted from villous placental tissues from healthy term and severe preeclamptic pregnancies. Differential miRNA expression was analyzed by microarray and real-time quantitative PCR. Angiogenesis-associated miRNA were analyzed by target prediction databases. In situ hybridization was used to localize miRNA. Target verification was performed by transfection of miRNA precursors or antagomirs into endothelial and BeWo cells and luciferase reporter assays. RESULTS: Three highly expressed miRNA (miR-17, -20a, and -20b) were found significantly increased in PE compared with healthy term placentas (n = 10 per group). They target on the same group of genes important for angiogenesis. miR 20b was expressed primarily in villous syncytiotrophoblasts in term placenta. Overexpression or inhibition of miR-20b differentially regulated mRNA expression of those genes in endothelial vs. trophoblast cells. Luciferase reporter assay showed that miR-20b targets EPHB4 and ephrin-B2 that have been shown to be critical for early human placental development. Placental ephrin-B2 mRNA was significantly down-regulated in PE compared with normotensive pregnancies. CONCLUSION: miR-17, miR-20a, and miR-20b are differentially regulated in human placentas by PE. They regulate EPHB4 and ephrin-B2 expression in trophoblast and endothelial cells via the same "seed" sequence, suggesting their roles in early placental development. PMID- 22438231 TI - PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves' ophthalmopathy patients. AB - PURPOSE: Thyroid-stimulating hormone receptor (TSHR) stimulating autoantibodies are associated with Graves' ophthalmopathy (GO), the orbital manifestation of Graves' disease (GD). TSHR autoantibody levels and orbital TSHR expression levels correlate positively with GO disease activity. Platelet-derived growth factors (PDGF) are increased in GO and potently activate orbital fibroblast effector functions. We investigated the possible relationship between PDGF and TSHR expression on orbital fibroblasts and how that influences the immunopathological effects of TSHR autoantibodies on orbital fibroblast activity. METHODS: Orbital fibroblasts were stimulated with PDGF-AA, PDGF-AB, and PDGF-BB, and TSHR expression was determined by flow cytometry. Stimulatory effects of bovine TSH and GD immunoglobulins on orbital fibroblasts (with or without PDGF-BB preincubation) were determined by IL-6, IL-8, chemokine (C-C motif) ligand (CCL) 2, CCL5, CCL7, and hyaluronan ELISA. The TSHR blocking antibody K1-70 and the cAMP inhibitor H89 were used to determine involvement of TSHR signaling. RESULTS: PDGF-AB and PDGF-BB stimulation increased TSHR expression on orbital fibroblasts, whereas PDGF-AA did not. Furthermore, stimulation with bovine TSH and immunoglobulins from GD patients induced IL-6, IL-8, CCL2, and hyaluronan production by orbital fibroblasts, and PDGF-BB preincubation enhanced this response of orbital fibroblasts. Blocking studies with a TSHR blocking antibody and a cAMP inhibitor inhibited these effects, indicating the involvement of TSHR signaling and thus of TSHR stimulating autoantibodies herein. CONCLUSIONS: These findings indicate that PDGF-B containing PDGF isoforms amplify the immunopathological effects of TSHR-stimulating autoantibodies in GO patients by stimulating TSHR expression on orbital fibroblasts. PMID- 22438232 TI - Prospective follow-up of novel markers of bone turnover in persistent asthmatics exposed to low and high doses of inhaled ciclesonide over 12 months. AB - CONTEXT: In asthmatic patients receiving long-term inhaled corticosteroid therapy, there are concerns regarding the potential for developing systemic adverse effects on bone metabolism, possibly even in the absence of adrenal suppression. OBJECTIVE: The aim of this study was to investigate whether exposure to inhaled ciclesonide at high vs. low doses over 1 yr causes any significant systemic adverse effect on sensitive biomarkers of bone turnover in asthmatic patients. DESIGN: Post hoc analysis of stored samples was performed in a subgroup of patients from a prospective, randomized parallel group trial with 1 yr follow up. SETTING: We conducted a primary care study in Tayside, Scotland. PARTICIPANTS: A total of 164 mild-moderate persistent asthmatics aged 18-65 yr with evidence of airway hyperresponsiveness using mannitol bronchial challenge were enrolled into the original study. Of the 119 completed patients per protocol, 100 participants had bone marker samples available for analysis. INTERVENTIONS: Ciclesonide was titrated to control persistent asthma against either mannitol bronchial challenge [airway hyperresponsiveness (AHR) strategy] or a control group (based on symptoms, reliever use, and pulmonary function) over 1 yr. OUTCOME MEASURES: We measured markers of bone formation [amino-terminal propeptide of type I collagen (PINP), amino-terminal propeptide of type III collagen (PIIINP)], resorption [carboxy-terminal telopeptide of type I collagen (ICTP), type I collagen cross-linked C-telopeptide (CTx)], and adrenal suppression (overnight urinary cortisol/creatinine ratio) at 0 and 12 months. RESULTS: Mean ciclesonide doses after 12 months were: AHR, 507 MUg/d (n = 50); and controls, 202 MUg/d (n = 50) (P < 0.00001). There were no significant differences between AHR and control groups either at baseline or after 12 months in PINP, PIIINP, ICTP, or CTx; or in ratios of bone turnover as PINP/ICTP, PIIINP/CTx, or overnight urinary cortisol/creatinine ratio. CONCLUSION: Higher doses of inhaled ciclesonide do not adversely affect sensitive markers of bone turnover in persistent asthmatics over 12 months. PMID- 22438233 TI - The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. AB - CONTEXT: Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time. OBJECTIVE: We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex. DESIGN, SETTING, AND PARTICIPANTS: Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication. MAIN OUTCOME MEASURE: Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex. RESULTS: Persistence of subclinical hypothyroidism was 56% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10% with TSH 7-9.9 mU/liter and 7% with TSH >=10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions. CONCLUSIONS: Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes. PMID- 22438234 TI - Chemerin as a mediator between obesity and vascular inflammation in children. AB - CONTEXT: The chemoattractant protein chemerin has recently been shown to be expressed in adipose tissue. OBJECTIVE: We aimed to evaluate the association of chemerin with obesity and early-onset metabolic and vascular sequelae in children. DESIGN: We quantified chemerin serum levels in 69 lean and 105 obese children and assessed associations with metabolic and cardiovascular parameters. In addition, a potential direct effect of chemerin on the expression of endothelial adhesion molecules and cell viability was assessed in human coronary artery endothelial cells in vitro. RESULTS: Chemerin concentrations were significantly higher in obese compared to lean children and correlated with obesity-related parameters such as body mass index sd score, leptin, and skinfold thickness. Moreover, we identified significant associations with the measures of inflammation high-sensitivity C-reactive protein and white blood cell count, as well as with the markers of endothelial activation intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Multiple regression analyses confirmed chemerin as the strongest predictor of ICAM-1 and E-selectin independent of body mass index sd score. Likewise, on the cellular level, chemerin induced ICAM-1 and E-selectin expression in endothelial cells in vitro, whereas VCAM-1 and eNOS expression and endothelial cell viability were unaffected. CONCLUSION: Our results suggest an association of chemerin with obesity and inflammatory and endothelial activation markers and support a role for chemerin as a molecular link between increasing fat mass and an early atherogenic risk profile in obese children. PMID- 22438235 TI - Cafe-au-lait macules and intertriginous freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and Legius syndrome. AB - Piebaldism is an autosomal dominant disorder characterized by congenital hypopigmented patches of skin and hair and has been found to be associated with mutations in the KIT or SLUG genes. Cafe-au-lait macules (CALM) may occasionally be seen in piebaldism. There are four reports describing six patients who were said to have both piebaldism and neurofibromatosis type 1 (NF1) due to the presence of multiple CALM and intertriginous freckling, but none of these patients had undergone comprehensive NF1 mutation analysis. We describe a large family with piebaldism in which two members meet diagnostic criteria for NF1 based on the presence of >5 CALM and intertriginous freckling. Interestingly, only these two family members are of mixed race, which could be of importance. A novel complex mutation in the KIT gene was identified in several family members affected with piebaldism; the proband meeting diagnostic criteria for NF1 also underwent comprehensive NF1 and SPRED1 testing with no mutations detected. These findings suggest that piebaldism may occasionally include CALM and intertriginous freckling, which may create diagnostic confusion especially in the absence of a family history of piebaldism. However, careful clinical evaluation and molecular testing if necessary should distinguish these two disorders. PMID- 22438236 TI - [Activity report 2010 of the Section Tissue Transplantation and Biotechnology in the German Society for Ophthalmology]. PMID- 22438237 TI - Pregnancy-induced analgesia: a combined psychophysical and neurophysiological study. AB - BACKGROUND: To investigate changes in heat pain threshold and modifications in heat pain processing during pregnancy and labour, seventy-six nulliparous pregnant women were enrolled in two studies. METHODS: In the first study (psychophysical), 60 pregnant women underwent a quantitative sensory testing (QST) investigating heat perception in two body areas (right forearm and T10 dermatome) according to these groups: 32-33 gestational weeks (GW), 39-40 GW, early stage of active labour and 24 h after the delivery. In the other study (neurophysiological), contact heat-evoked potentials (CHEPs) were recorded in other 16 women at the 32nd GW and in 11 of these also at the 40th GW. RESULTS: The psychophysical study showed that heat pain threshold was significantly increased at the forearm at 32-33 GW (median +/- IQR: 39.6 +/- 0.7 degrees C), at 39-40 GW (40.6 +/- 1.1 degrees C) and at early stage of active labour (40.8 +/- 1.5 degrees C) as compared to 20 non-pregnant controls (p < 0.001). Heat pain threshold tested at T10 level was significantly increased at 32-33 GW (41.0 +/- 1.6 degrees C), at 39-40 GW (42.1 +/- 1.8 degrees C), and at early stage of active labour (42.3 +/- 1.3 degrees C) as compared to the non-pregnant women (p < 0.001). The N2-P2 CHEP amplitude (main negative N2 and positive P2 components of the vertex biphasic potential) recorded from the pregnant women was significantly lower at the 40th than at the 32nd GW, after stimulation of both the forearm (p < 0.001) and the abdomen (p < 0.001). CONCLUSIONS: In pregnant women, there is a progressive increase of heat pain threshold and a reduction of the CHEP amplitude, suggesting that a general inhibitory mechanism may be involved. PMID- 22438238 TI - The origins of dramatic axial ligand effects: closed-shell Mn(V)O complexes use exchange-enhanced open-shell States to mediate efficient H abstraction reactions. PMID- 22438239 TI - Comparison of reconstruction plate and double flap for reconstruction of an extensive mandibular defect. AB - Functional reconstruction of the anterior mandibular defect in combination with a significant glossectomy is a challenging problem for reconstructive micro surgeons. In this retrospective study, clinical results were compared between mandibular reconstruction plate (MRP) procedures and double flap transfers. The subjects were 23 patients who underwent immediate reconstruction, after an anterior segmental mandibulectomy in combination with a significant glossectomy, from 1993 to 2009. The patients were divided into two groups based on the reconstructive methods used: MRP and soft tissue free flap transfer (MRP group: 12 patients) or double free flap transfer (double flap group: 11 patients). Operative stress, postoperative complications and oral intake ability were compared between the groups. The rate of recipient-site complication in the double flap group tended to be lower than that in the MRP group. The most frequent complications in the MRP group included infection and orocutaneous fistula. Operative stresses (operation time and blood loss) were significantly less in the MRP group than in the double flap group. Overall, 19 patients (82.6%) were able to tolerate an oral diet without the need for tube feeding. This study demonstrates that laryngeal preservation is possible in more than 80% of patients even after such an extensive ablation. Double flap transfer provides a more stable wound closure than MRP and should be the preferred reconstructive procedure if the patients can tolerate the associated operative stresses. PMID- 22438240 TI - Armitage lecture 2010: Understanding treatment effects: the value of integrating longitudinal data and survival analysis. AB - There is a single-minded focus on events in survival analysis, and we often ignore longitudinal data that are collected together with the event data. This is due to a lack of methodology but also a result of the artificial distinction between survival and longitudinal data analyses. Understanding the dynamics of such processes is important but has been hampered by a lack of appreciation of the difference between confirmatory and exploratory causal inferences. The latter represents an attempt at elucidating mechanisms by applying mediation analysis to statistical data and will usually be of a more tentative character than a confirmatory analysis. The concept of local independence and the associated graphs are useful. This is related to Granger causality, an important method from econometrics that is generally undervalued by statisticians. This causality concept is different from the counterfactual one since it lacks lacks the intervention aspect. The notion that one can intervene at will in naturally occurring processes, which seems to underly much of modern causal inference, is problematic when studying mediation and mechanisms. It is natural to assume a stochastic process point of view when analyzing dynamic relationships. We present some examples to illustrate this. It is not clear how survival analysis must be developed to handle the complex life-history data that are increasingly being collected today. We give some suggestions. PMID- 22438241 TI - Stromal vascular fraction isolated from lipo-aspirates using an automated processing system: bench and bed analysis. AB - The heterogeneous stromal vascular fraction (SVF), containing adipose-derived stem/progenitor cells (ASCs), can be easily isolated through enzymatic digestion of aspirated adipose tissue. In clinical settings, however, strict control of technical procedures according to standard operating procedures and validation of cell-processing conditions are required. Therefore, we evaluated the efficiency and reliability of an automated system for SVF isolation from adipose tissue. SVF cells, freshly isolated using the automated procedure, showed comparable number and viability to those from manual isolation. Flow cytometric analysis confirmed an SVF cell composition profile similar to that after manual isolation. In addition, the ASC yield after 1 week in culture was also not significantly different between the two groups. Our clinical study, in which SVF cells isolated with the automated system were transplanted with aspirated fat tissue for soft tissue augmentation/reconstruction in 42 patients, showed satisfactory outcomes with no serious side-effects. Taken together, our results suggested that the automated isolation system is as reliable a method as manual isolation and may also be useful in clinical settings. Automated isolation is expected to enable cell-based clinical trials in small facilities with an aseptic room, without the necessity of a good manufacturing practice-level cell processing area. PMID- 22438242 TI - The structural correlates of functional deficits in early huntington's disease. AB - Neuropathological studies in Huntington disease (HD) have demonstrated neuronal loss in the striatum, as well as in other brain regions including the cortex. With diffusion tensor MRI we evaluated the hypothesis that the clinical dysfunction in HD is related to regionally specific lesions of circuit-specific cortico-basal ganglia networks rather than to the striatum only. We included 27 HD and 24 controls from the TRACK-HD Paris cohort. The following assessments were used: self-paced tapping tasks, trail B making test (TMT), University of Pennsylvania smell identification test (UPSIT), and apathy scores from the problem behaviors assessment. Group comparisons of fractional anisotropy and mean diffusivity and correlations were performed using voxel-based analysis. In the cortex, HD patients showed significant correlations between: (i) self paced tapping and mean diffusivity in the parietal lobe at 1.8 Hz and prefrontal areas at 3 Hz, (ii) UPSIT and mean diffusivity in the parietal, and median temporal lobes, the cingulum and the insula, and fractional anisotropy in the insula and the external capsule, (iii) TMT B and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal and post central areas, and (iv) apathy and fractional anisotropy in the white matter of the rectus gyrus. In the basal ganglia, we found correlations between the self paced tapping, UPSIT, TMT tests, and mean diffusivity in the anterior part of the putamen and the caudate nucleus. In conclusion, disruption of motor, associative and limbic cortico-striatal circuits differentially contribute to the clinical signs of the disease. PMID- 22438243 TI - Contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines. AB - Vaccines are instrumental in controlling the burden of influenza virus infection in humans and animals. Antibodies raised against both major viral surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), can contribute to protective immunity. Vaccine-induced HA antibodies have been characterized extensively, and they generally confer protection by blocking the attachment and fusion of a homologous virus onto host cells. Although not as well characterized, some functions of NA antibodies in influenza vaccine-mediated immunity have been recognized for many years. In this review, we summarize the case for NA antibodies in influenza vaccine-mediated immunity. In the absence of well-matched HA antibodies, NA antibodies can provide varying degrees of protection against disease. NA proteins of seasonal influenza vaccines have been shown in some instances to elicit serum antibodies with cross-reactivity to avian-origin and swine-origin influenza strains, in addition to HA drift variants. NA-mediated immunity has been linked to (i) conserved NA epitopes amongst otherwise antigenically distinct strains, partly attributable to the segmented influenza viral genome; (ii) inhibition of NA enzymatic activity; and (iii) the NA content in vaccine formulations. There is a potential to enhance the effectiveness of existing and future influenza vaccines by focusing greater attention on the antigenic characteristics and potency of the NA protein. PMID- 22438244 TI - Selective killing of p53-deficient cancer cells by SP600125. AB - The genetic or functional inactivation of p53 is highly prevalent in human cancers. Using high-content videomicroscopy based on fluorescent TP53(+/+) and TP53(-/-) human colon carcinoma cells, we discovered that SP600125, a broad spectrum serine/threonine kinase inhibitor, kills p53-deficient cells more efficiently than their p53-proficient counterparts, in vitro. Similar observations were obtained in vivo, in mice carrying p53-deficient and proficient human xenografts. Such a preferential cytotoxicity could be attributed to the failure of p53-deficient cells to undergo cell cycle arrest in response to SP600125. TP53(-/-) (but not TP53(+/+) ) cells treated with SP600125 became polyploid upon mitotic abortion and progressively succumbed to mitochondrial apoptosis. The expression of an SP600125-resistant variant of the mitotic kinase MPS1 in TP53(-/-) cells reduced SP600125-induced polyploidization. Thus, by targeting MPS1, SP600125 triggers a polyploidization program that cannot be sustained by TP53(-/-) cells, resulting in the activation of mitotic catastrophe, an oncosuppressive mechanism for the eradication of mitosis incompetent cells. PMID- 22438245 TI - A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome. AB - It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf-Hirschhorn critical regions 1 or 2 (WHSCR 1 2). Here, we identify a 432 kb deletion located 600 kb proximal to both WHSCR1-2 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2. The clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Our results suggest that the WHSCR1-2 flanking sequence contributes directly or indirectly to the severity of WHS. Sequencing the Wolf-Hirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations. Long range position effects of the deletion that could influence gene expression within the WHSCR were excluded in EBV cell lines derived from patient lymphoblasts. We hypothesize that either (1) this locus harbors regulatory sequences which affect gene expression in the WHSCR1-2 in a defined temporal and spatial developmental window or (2) that this locus is additive to deletions of WHSCR1-2 increasing the phenotypic expression. PMID- 22438246 TI - Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection. AB - Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4(+) T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4(+) T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim 3 interactions to induce resistance of activated CD4(+) T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection. PMID- 22438247 TI - 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand. AB - Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G(2)/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS-re expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through "FAS-re-expression" and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined. PMID- 22438248 TI - MHC I-associated peptides preferentially derive from transcripts bearing miRNA response elements. AB - MHC I-associated peptides (MIPs) play an essential role in normal homeostasis and diverse pathologic conditions. MIPs derive mainly from defective ribosomal products (DRiPs), a subset of nascent proteins that fail to achieve a proper conformation and the physical nature of which remains elusive. In the present study, we used high-throughput proteomic and transcriptomic methods to unravel the structure and biogenesis of MIPs presented by HLA-A and HLA-B molecules on human EBV-infected B lymphocytes from 4 patients. We found that although HLA different subjects present distinctive MIPs derived from different proteins, these MIPs originate from proteins that are functionally interconnected and implicated in similar biologic pathways. Secondly, the MIP repertoire of human B cells showed no bias toward conserved versus polymorphic genomic sequences, were derived preferentially from abundant transcripts, and conveyed to the cell surface a cell-type-specific signature. Finally, we discovered that MIPs derive preferentially from transcripts bearing miRNA response elements. Furthermore, whereas MIPs of HLA-disparate subjects are coded by different sets of transcripts, these transcripts are regulated by mostly similar miRNAs. Our data support an emerging model in which the generation of MIPs by a transcript depends on its abundance and DRiP rate, which is regulated to a large extent by miRNAs. PMID- 22438249 TI - Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells. AB - Efficient in vitro generation of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) holds great promise for cell-based therapies to treat hematologic diseases. To date, HoxB4 remains the most effective transcription factor (TF) the overexpression of which in ESCs confers long-term repopulating ability to ESC-derived HSCs. Despite its importance, the components and dynamics of the HoxB4 transcriptional regulatory network is poorly understood, hindering efforts to develop more efficient protocols for in vitro derivation of HSCs. In the present study, we performed global gene-expression profiling and ChIP coupled with deep sequencing at 4 stages of the HoxB4-mediated ESC differentiation toward HSCs. Joint analyses of ChIP/deep sequencing and gene-expression profiling unveiled several global features of the HoxB4 regulatory network. First, it is highly dynamic and gradually expands during the differentiation process. Second, HoxB4 functions as a master regulator of hematopoiesis by regulating multiple hematopoietic TFs and chromatin-modification enzymes. Third, HoxB4 acts in different combinations with 4 other hematopoietic TFs (Fli1, Meis1, Runx1, and Scl) to regulate distinct sets of pathways. Finally, the results of our study suggest that down-regulation of mitochondria and lysosomal genes by HoxB4 plays a role in the impaired lymphoid lineage development from ESC-derived HSCs. PMID- 22438250 TI - Blood consult: therapeutic strategy and complications in the adolescent and young adult with acute lymphoblastic leukemia. PMID- 22438251 TI - Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. AB - FOXP3+ regulatory T (Treg) cells are a broadly acting and potent anti inflammatory population of CD4+ T cells essential for maintaining immune homeostasis and preventing debilitating autoimmunity. Based on chemokine receptor expression, we identified distinct populations of Treg cells in human blood expected to colocalize with different Th cell subsets. Although each population was functionally suppressive, they displayed unique patterns of pro- and anti inflammatory cytokine production, differentially expressed lineage-specifying transcription factors, and responded differently to antigens associated with Th1 and Th17 responses. These results highlight a previously unappreciated degree of phenotypic and functional diversity in human Treg cells that allows subsets with unique specificities and immunomodulatory functions to be targeted to defined immune environments during different types of inflammatory responses. PMID- 22438252 TI - Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia. AB - The protein tyrosine phosphatase CD45, encoded by the PTPRC gene, is well known as a regulator of B- and T-cell receptor signaling. In addition, CD45 negatively regulates JAK family kinases downstream of cytokine receptors. Here, we report the presence of CD45 inactivating mutations in T-cell acute lymphoblastic leukemia. Loss-of-function mutations of CD45 were detected in combination with activating mutations in IL-7R, JAK1, or LCK, and down-regulation of CD45 expression caused increased signaling downstream of these oncoproteins. Furthermore, we demonstrate that down-regulation of CD45 expression sensitizes T cells to cytokine stimulation, as observed by increased JAK/STAT signaling, whereas overexpression of CD45 decreases cytokine-induced signaling. Taken together, our data identify a tumor suppressor role for CD45 in T-cell acute lymphoblastic leukemia. PMID- 22438253 TI - Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice. AB - Desensitization controls G protein-dependent signaling of chemokine receptors. We investigate the physiologic implication of this process for CXCR4 in a mouse model harboring a heterozygous mutation of the Cxcr4 gene, which engenders a desensitization-resistant receptor. Such anomaly is linked to the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, a human rare combined immunodeficiency. Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients. Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia. Strikingly, neutropenia occurs in a context of normal bone marrow architecture and granulocyte lineage maturation, indicating a minor role for Cxcr4-dependent signaling in those processes. In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia. Concomitantly, mature T and B cells are abnormally compartmentalized in the periphery, with a reduction of primary follicles in the spleen and their absence in lymph nodes mirrored by an unfurling of the T-cell zone. These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function. PMID- 22438254 TI - The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells. AB - In response to antigens and cytokines, mouse B cells undergo class-switch recombination (CSR) and differentiate into Ig-secreting cells. T-bet, a T-box transcription factor that is up-regulated in lymphocytes by IFN-gamma or IL-27, was shown to regulate CSR to IgG2a after T cell-independent B-cell stimulations. However, the molecular mechanisms controlling this process remain unclear. In the present study, we show that inactivation of the Ets-1 transcription factor results in a severe decrease in IgG2a secretion in vivo and in vitro. No T-bet expression was observed in Ets-1-deficient (Ets-1(-/-)) B cells stimulated with IFN-gamma and lipopolysaccharide, and forced expression of T-bet in these cells rescued IgG2a secretion. Furthermore, we identified a transcriptional enhancer in the T-bet locus with an activity in B cells that relies on ETS-binding sites. After IFN-gamma stimulation of Ets-1(-/-) B cells, activated Stat1, which forms a complex with Ets-1 in wild-type cells, no longer binds to the T-bet enhancer or promotes histone modifications at this site. These results demonstrate that Ets-1 is critical for IgG2a CSR and acts as an essential cofactor for Stat1 in the regulation of T-bet expression in B cells. PMID- 22438255 TI - Cotargeting signaling pathways driving survival and cell cycle circumvents resistance to Kit inhibitors in leukemia. AB - Oncogenic mutations leading to persistent kinase activities are associated with malignancies. Therefore, deciphering the signaling networks downstream of these oncogenic stimuli remains a challenge to gather insights into targeted therapy. To elucidate the biochemical networks connecting the Kit mutant to leukemogenesis, in the present study, we performed a global profiling of tyrosine phosphorylated proteins from mutant Kit-driven murine leukemia proerythroblasts and identified Shp2 and Stat5 as proximal effectors of Kit. Shp2 or Stat5 gene depletion by sh-RNA, combined with pharmacologic inhibition of PI3kinase or Mek/Erk activities, revealed 2 distinct and independent signaling pathways contributing to malignancy. We demonstrate that cell survival is driven by the Kit/Shp2/Ras/Mek/Erk1/2 pathway, whereas the G(1)/S transition during the cell cycle is accelerated by both the Kit/Stat5 and Kit/PI3K/Akt pathways. The combined use of the clinically relevant drugs NVP-BEZ235, which targets the cell cycle, and Obatoclax, which targets survival, demonstrated synergistic effects to inhibit leukemia cell growth. This synergy was confirmed with a human mast leukemia cell line (HMC-1.2) that expresses mutant Kit. The results of the present study using liquid chromatography/tandem mass spectrometry analysis have elucidated signaling networks downstream of an oncogenic kinase, providing a molecular rationale for pathway-targeted therapy to treat cancer cells refractory to tyrosine kinase inhibitors. PMID- 22438256 TI - A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. AB - This phase 1 study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of obinutuzumab (GA101), a glycoengineered type II anti-CD20 monoclonal antibody administered as induction followed by 2 years of maintenance. Cohorts of 3 to 6 patients received obinutuzumab (200-2000 mg) intravenously weekly for 4 weeks. Patients with a complete or partial response (or stable disease and clinical benefit) continued to receive obinutuzumab every 3 months, for a maximum of 8 doses. Twenty-two patients with relapsed CD20-positive non Hodgkin lymphoma or chronic lymphocytic leukemia with an indication for treatment and no therapy of higher priority were enrolled. Patients received a median of 4 prior regimens; 86% had received at least 1 rituximab-containing regimen. No dose limiting or unexpected AEs were observed. Infusion-related reactions were most common (all grades, 73%; grade 3/4, 18%), followed by infection (32%), pyrexia (23%), neutropenia (23%), headache (18%), and nausea (18%). At end of induction, 5 (23%) patients achieved partial responses and 12 (54%) had stable disease. Eight patients received maintenance; best overall response was 32% (6 partial responses/1 complete response). Obinutuzumab induction and maintenance therapy was well tolerated with promising efficacy in this heterogeneous, highly pretreated population and warrants further investigation. This study was registered at www.clinicaltrials.gov (identifier NCT00576758). PMID- 22438257 TI - Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ. AB - Signal transduction of FMS-like tyrosine kinase 3 (FLT3) is regulated by protein tyrosine phosphatases (PTPs). We recently identified the PTP DEP-1/CD148/PTPRJ as a novel negative regulator of FLT3. This study addressed the role of DEP-1 for regulation of the acute myeloid leukemia (AML)-related mutant FLT3 internal tandem duplication (ITD) protein. Our experiments revealed that DEP-1 was expressed but dysfunctional in cells transformed by FLT3 ITD. This was caused by enzymatic inactivation of DEP-1 through oxidation of the DEP-1 catalytic cysteine. In intact cells, including primary AML cells, FLT3 ITD kinase inhibition reactivated DEP-1. DEP-1 reactivation was also achieved by counteracting the high levels of reactive oxygen species (ROS) production detected in FLT3 ITD-expressing cell lines by inhibition of reduced NAD phosphate (NADPH)-oxidases, or by overexpression of catalase or peroxiredoxin-1 (Prx-1). Interference with ROS production in 32D cells inhibited cell transformation by FLT3 ITD in a DEP-1-dependent manner, because RNAi-mediated depletion of DEP-1 partially abrogated the inhibitory effect of ROS quenching. Reactivation of DEP-1 by stable overexpression of Prx-1 extended survival of mice in the 32D cell/C3H/HeJ mouse model of FLT3 ITD-driven myeloproliferative disease. The study thus uncovered DEP-1 oxidation as a novel event contributing to cell transformation by FLT3 ITD. PMID- 22438258 TI - The tyrosine phosphatase SHP-1 dampens murine Th17 development. AB - Th17 cells represent a subset of CD4+ T helper cells that secrete the proinflammatory cytokine IL-17. Th17 cells have been ascribed both a beneficial role in promoting clearance of pathogenic fungi and bacteria, and a pathogenic role in autoimmune diseases. Here we identify the tyrosine phosphatase SHP-1 as a critical regulator of Th17 development, using 3 complementary approaches. Impaired SHP-1 activity through genetic deletion of SHP-1, transgenic expression of an inducible dominant negative SHP-1, or pharmacologic inhibition of SHP-1 strongly promotes the development of Th17. Ex vivo Th17 skewing assays demonstrate that genetic or pharmacologic disruption of SHP-1 activity in T cells results in a hyper-response to stimulation via IL-6 and IL-21, 2 cytokines that promote Th17 development. Mechanistically, we find that SHP-1 decreases the overall cytokine-induced phosphorylation of STAT3 in primary CD4+ T cells. These data identify SHP-1 as a key modifier of IL-6-and IL-21-driven Th17 development via regulation of STAT3 signaling and suggest SHP-1 as a potential new therapeutic target for manipulating Th17 differentiation in vivo. PMID- 22438259 TI - Inkpots for histopathology. PMID- 22438260 TI - Cationic microparticle [poly(D,L-lactide-co-glycolide)]-coated DNA vaccination induces a long-term immune response against foot and mouth disease in guinea pigs. AB - BACKGROUND: Foot and mouth disease (FMD) can be controlled by regular vaccination and restriction of the movement of infected animals in the endemic countries. Although presently used, tissue culture inactivated vaccine gives protection, it has several limitations, including a short duration of immunity. DNA vaccine delivered through microparticles could comprise an alternative approach to conventional vaccine when aiming to circumvent these limitations. METHODS: We constructed the expression plasmid (pVAC-1D) containing 1D gene FMD virus serotype Asia 1. Poly(D,L-lactide-co-glycolide) (PLG) microparticles were prepared and coated with the pVAC-1D plasmid. Guinea pigs were vaccinated with PLG-coated and naked DNA vaccine constructs intramuscularly. The humoral response was measured by an enzyme-linked immunosorbent assay (ELISA) and the serum neutralization test (SNT). Analysis of the persistence and the expression of pVAC 1D plasmid construct was carried out by quantitative polymerase chain reaction (qPCR). RESULTS: The humoral response lasted for 1 year, as measured by ELISA and SNT. Analysis of the persistence and the expression of pVAC-1D plasmid construct by qPCR has shown that pVAC-1D expression was seen for a longer duration compared to the naked DNA vaccine. Microparticles coated plasmid DNA-injected guinea pigs were protected when challenged with FMD virus. CONCLUSIONS: The present study has shown that the delivery of plasmid coated on cationic PLG microparticles enhance the duration of immunity of the DNA vaccine constructs. PMID- 22438261 TI - Engineering functional bladder tissues. AB - PURPOSE: End stage bladder disease can seriously affect patient quality of life and often requires surgical reconstruction with bowel tissue, which is associated with numerous complications. Bioengineering of functional bladder tissue using tissue-engineering techniques could provide new functional tissues for reconstruction. In this review, we discuss the current state of this field and address different approaches to enable physiologic voiding in engineered bladder tissues in the near future. MATERIALS AND METHODS: In a collaborative effort, we gathered researchers from four institutions to discuss the current state of functional bladder engineering. A MEDLINE(r) and PubMed(r) search was conducted for articles related to tissue engineering of the bladder, with special focus on the cells and biomaterials employed as well as the microenvironment, vascularisation and innervation strategies used. RESULTS: Over the last decade, advances in tissue engineering technology have laid the groundwork for the development of a biological substitute for bladder tissue that can support storage of urine and restore physiologic voiding. Although many researchers have been able to demonstrate the formation of engineered tissue with a structure similar to that of native bladder tissue, restoration of physiologic voiding using these constructs has never been demonstrated. The main issues hindering the development of larger contractile tissues that allow physiologic voiding include the development of correct muscle alignment, proper innervation and vascularization. CONCLUSION: Tissue engineering of a construct that will support the contractile properties that allow physiologic voiding is a complex process. The combination of smart scaffolds with controlled topography, the ability to deliver multiple trophic factors and an optimal cell source will allow for the engineering of functional bladder tissues in the near future. PMID- 22438262 TI - Selective excitation of concomitant electrochemiluminophores: tuning emission color by electrode potential. PMID- 22438263 TI - Sparse current source estimation for MEG using loose orientation constraints. AB - Spatially focal source estimates for magnetoencephalography (MEG) and electroencephalography (EEG) data can be obtained by imposing a minimum l(1) norm constraint on the distribution of the source currents. Anatomical information about the expected locations and orientations of the sources can be included in the source models. In particular, the sources can be assumed to be oriented perpendicular to the cortical surface. We introduce a minimum l(1) -norm estimation source modeling approach with loose orientation constraints (l(1) LOC), which integrates the estimation of the orientation, location, and strength of the source currents into a cost function to jointly model the residual error and the l(1) -norm of the source estimates. Evaluation with simulated MEG data indicated that the l(1) LOC method can provide low spatial dispersion, high localization accuracy, and high source detection rates. Application to somatosensory and auditory MEG data resulted in physiologically reasonable source distributions. The proposed l(1) LOC method appears useful for incorporating anatomical information about the source orientations into sparse source estimation of MEG data. PMID- 22438264 TI - Targeted approaches to the treatment of pulmonary hypertension. AB - Pulmonary arterial hypertension is a progressive and incurable disease. Over the past two decades, significant advances have been made in understanding and thus managing this disease. Multiple therapeutic options are currently available and optimizing the treatment of pulmonary arterial hypertension has become complex. Patients who meet the American College of Chest Physicians criteria for vasoresponsiveness can be safely and effectively treated with high-dose calcium channel blockers but require close follow up to assure durability of response. Patients with World Health Organization (WHO) functional class IV status and those with determinants of high risk for progression and death should be treated with an infused prostanoid agent without delay. These patients should also be referred early after stabilization for transplant evaluation. Patients with WHO functional class II status benefit from early initiation of oral therapies. Those with WHO functional class III status and lower determinants of risk for progression may receive treatment with one or more oral or inhaled agents, though many experts would advise early use of infused prostanoids for these patients as well. PMID- 22438265 TI - The role of immunotherapy in the management of childhood asthma. AB - Subcutaneous immunotherapy (SCIT) is still questioned as a safe and efficacious way of treating allergic asthma in children. In a Cochrane review published in 2010 it was, however, concluded that SCIT has significant and beneficial effects on symptoms and medication use in both children and adults with mostly mild asthma. Only a few studies have been performed to specifically study if SCIT in children with moderate asthma reduces the need for inhaled corticosteroids. There are conflicting results that illustrate the problem of the heterogeneity of the asthma disease and the fact that allergies may play different roles on the severity and symptoms of the disease. Furthermore, children with severe allergic asthma are often sensitized to multiple allergens, which makes SCIT both complicated and less safe to administer. On the other hand, if the child suffers from asthmatic symptoms despite adherence to pharmacotherapy, omalizumab or a combination of omalizumab and allergen immunotherapy might be useful. There is a need for more studies on this combination before it can be considered as an additional therapy in children with asthma and severe allergies. Sublingual immunotherapy (SLIT) has also been shown to improve asthma symptoms and medication use. SLIT is safe although its efficacy compared with SCIT has been studied very little. Another approach is to try to prevent asthma by treating children with SCIT for allergic rhinoconjunctivitis before asthma has developed. The most attractive prospect, however, is to find ways of preventing asthma by vaccination against the most common viruses, particularly rhinovirus. There is evidence that there are children at high risk of developing asthma in whom a viral infection can also enhance the risk of allergen sensitization. So far this vaccination has not been achievable although research is in progress. PMID- 22438266 TI - Exploring complexity. PMID- 22438271 TI - Adeno-associated virus-delivered polycistronic microRNA-clusters for knockdown of vascular endothelial growth factor in vivo. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that plays a critical role in several diseases, including cancer, rheumatoid arthritis and diseases of the eye. Persistent regulation of VEGF by expression of small interfering RNAs targeting VEGF represents a potential future strategy for treatment of such diseases. As a step toward this goal, the present study combines the potency of VEGF-targeted miRNA mimics, produced from a miRNA cluster, with delivery by adeno-associated virus (AAV)-based vectors. METHODS: Nine different engineered tri-cistronic miRNA clusters encoding anti-VEGF effectors were generated and tested in adult human retinal pigment epithelial (ARPE-19) cells using Renilla luciferase screening, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting and immunostaining analysis. In vivo efficacy was tested by the injection of scAAV2/8 vectors expressing the most effective miRNA cluster into murine hindlimb muscles, followed by quantitative RT-PCR. RESULTS: Plasmids containing anti-VEGF miRNA clusters showed efficient silencing of VEGF and demonstrated a combined gene silencing effect for miRNA clusters composed of multiple miRNA-mimicked RNA interference effectors. The most potent molecule, miR-5,10,7, resulted in a knockdown of VEGF by approximately 75%. Injection of scAAV2/8 vectors expressing miR-5,10,7 into murine hindlimb muscles, resulted in a 44% reduction of endogenous VEGF. CONCLUSIONS: We have developed miRNA clusters encoding anti-VEGF effectors and shown, in a mouse model, that VEGF is efficiently down-regulated by scAAV2/8-delivered miRNA clusters, allowing potent attenuation of VEGF. These findings may contribute to the development of gene therapy based on AAV-mediated delivery of miRNA clusters. PMID- 22438272 TI - Triple bioorthogonal ligation strategy for simultaneous labeling of multiple enzymatic activities. PMID- 22438273 TI - Proposed outcome measures for prospective clinical trials in juvenile idiopathic arthritis-associated uveitis: a consensus effort from the multinational interdisciplinary working group for uveitis in childhood. AB - OBJECTIVE: To develop a set of core outcome measures for use in randomized controlled trials (RCTs) and longitudinal observational studies in juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: The literature relating to outcome measures used in studies of uveitis in childhood and adolescence was reviewed. A set of core outcomes and domains was established using the Delphi process. This was reviewed by a representative multinational interdisciplinary working group. Nominal group technique consensus was reached on face and content validity of the range and content of the domains. The outcomes and the appropriate instruments for uveitis trials were adapted to the age ranges of patients with JIA-associated uveitis. RESULTS: Consensus was reached that data should be reported at defined time points in longitudinal studies with patients stratified by prognostic markers. Visual acuity testing should be age appropriate. The severity of uveitis (measured as anterior chamber cell grade) and duration of active inflammation should be documented. Visually significant structural complications should be recorded and quantified with standard measures. The responses to treatment and corticosteroid-sparing effects of treatment should be documented. Patient-reported disease activity and age specific uveitis-related quality of life should be reported using appropriate questionnaires. CONCLUSION: The proposed outcome measures in JIA-associated uveitis should aid in the standardization and comparison of future RCTs of the treatment regimens for this disease. The proposed outcome measures will be verified in a prospective validation study. PMID- 22438274 TI - The importance of the trans-enamine intermediate as a beta-lactamase inhibition strategy probed in inhibitor-resistant SHV beta-lactamase variants. AB - The ability of bacteria to express inhibitor-resistant (IR) beta-lactamases is stimulating the development of novel inhibitors of these enzymes. The 2'beta glutaroxypenicillinate sulfone, SA2-13, was previously designed to enhance the stabilization of the deacylation-refractory, trans-enamine inhibitory intermediate. To test whether this mode of inhibition can overcome different IR mutations, we determined the binding mode of SA2-13 through X-ray crystallography, obtaining co-crystals of the inhibitor-protein complex by soaking crystals of the IR sulfhydryl variable (SHV) beta-lactamase variants S130G and M69V with the inhibitor. The 1.45 A crystal structure of the S130G SHV:SA2-13 complex reveals that SA2-13 is still able to form the stable trans enamine intermediate similar to the wild-type complex structure, yet with its carboxyl linker shifted deeper into the active site in the space vacated by the S130G mutation. In contrast, data from crystals of the M69V SHV:SA2-13 complex at 1.3 A did not reveal clear inhibitor density indicating that this IR variant disfavors the trans-enamine conformation, likely due to a subtle shift in A237. PMID- 22438275 TI - Resting-state networks show dynamic functional connectivity in awake humans and anesthetized macaques. AB - Characterization of large-scale brain networks using blood-oxygenation-level dependent functional magnetic resonance imaging is typically based on the assumption of network stationarity across the duration of scan. Recent studies in humans have questioned this assumption by showing that within-network functional connectivity fluctuates on the order of seconds to minutes. Time-varying profiles of resting-state networks (RSNs) may relate to spontaneously shifting, electrophysiological network states and are thus mechanistically of particular importance. However, because these studies acquired data from awake subjects, the fluctuating connectivity could reflect various forms of conscious brain processing such as passive mind wandering, active monitoring, memory formation, or changes in attention and arousal during image acquisition. Here, we characterize RSN dynamics of anesthetized macaques that control for these accounts, and compare them to awake human subjects. We find that functional connectivity among nodes comprising the "oculomotor (OCM) network" strongly fluctuated over time during awake as well as anaesthetized states. For time dependent analysis with short windows (<60 s), periods of positive functional correlations alternated with prominent anticorrelations that were missed when assessed with longer time windows. Similarly, the analysis identified network nodes that transiently link to the OCM network and did not emerge in average RSN analysis. Furthermore, time-dependent analysis reliably revealed transient states of large-scale synchronization that spanned all seeds. The results illustrate that resting-state functional connectivity is not static and that RSNs can exhibit nonstationary, spontaneous relationships irrespective of conscious, cognitive processing. The findings imply that mechanistically important network information can be missed when using average functional connectivity as the single network measure. PMID- 22438276 TI - Review of the use of defined daily dose concept in drug utilisation research in China. AB - PURPOSE: This study aimed to understand the characteristics of drug utilisation researches (DURs) using concepts of defined daily dose in China and to provide further suggestion for future DURs in China. METHODS: DURs using concepts of defined daily dose published in China were identified from China Journal Full text Database, and in-depth data analysis was conducted for DURs published in every even-numbered year. RESULTS: In total, 2,911 DURs published between 1989 and 2009 were identified, of which 1,268 were included for further data analysis. All studies were hospital-based. Types of drugs commonly assessed in DURs were Anti-infectives for systemic use (34.1%), drugs for Nervous system (25.5%) and drugs for Alimentary tract and metabolism (14.3%). In addition, 63 DURs published in even-numbered year focusing on Chinese Herbal Medicine (CHM) were identified. Commonly used sources of defined dose were Xin Bian Yao Wu Xue/New Materia Medica (83.9%), drug information leaflets (66.8%) and Chinese Pharmacopoeia (52.0%). Common indicators used in DURs include defined daily doses (DDDs), drug utilisation index (DUI) and daily dose cost (DDC). CONCLUSION: DUR is a popular method to explore the use of both pharmaceutical drugs and CHM in China. The definition of defined daily dose and its related indicators presented in the DURs were highly varied. From this, it follows that DURs with more consistent methodology are highly needed for a thorough understanding of drug utilisation in China. Apart from DURs focusing on the hospital setting, more DURs from other health settings are needed. PMID- 22438277 TI - Atom tunneling in organic transformations. AB - There and gone: atoms, such as hydrogen or deuterium, commonly disappear and reappear at different locations in molecular structures. For example, carboxylic acids and hydroxycarbenes isomerize through atom tunneling events. It could happen in your reaction! PMID- 22438278 TI - Enhancement of DNA vaccine efficacy by targeting the xenogeneic human chorionic gonadotropin, survivin and vascular endothelial growth factor receptor 2 combined tumor antigen to the major histocompatibility complex class II pathway. AB - BACKGROUND: A number of strategies have been used to improve the efficacy of the DNA vaccine for the treatment of tumors. These strategies, ranging from activating CD4+ T cell, manipulating antigen presentation and/or processing to anti-angiogenesis, focus on one certain aspect in the functioning of the vaccine. Therefore, their combination is necessary for rational DNA vaccines design by synergizing different regimens and overcoming the limitations of each strategy. METHODS: A DNA fragment (HSV) encoding the C terminal 37 amino acids of human chorionic gonadotropin beta chain (hCGbeta), 5 different HLA-restricted cytotoxic T lymphocyte epitopes from human survivin and the third and fourth extracellular domains of vascular endothelial growth factor receptor 2 (VEGFR2) was inserted into the sequence between the luminal and transmembrane domain of human lysosome associated membrane protein-1 cDNA for the construction of a novel DNA vaccine. RESULTS: This novel vaccine, named p-L/HSV, has a potent antitumor effect on the LL/2 lung carcinoma model in syngeneic C57BL/6 mice. The immunologic mechanism involved in the antitumor effect referred to the activation of both cellular and humoral immune response. In addition, the tumor vasculature was abrogated as observed by immunohistochemistry in p-L/HSV immunized mice. Furthermore, the immunized mice received an additional boost with p-L/HSV 6 months later and showed a strong immune recall response. CONCLUSIONS: The present study indicates that the strategies of combining antitumor with antiangiogenesis and targeting the tumor antigen to the major histocompatibility complex class II pathway cooperate well. Such a study may shed new light on designing vaccine for cancer in the future. PMID- 22438279 TI - Characterization of Plasmodium liver stage inhibition by halofuginone. AB - Malaria is a devastating parasitic disease that afflicts one-third of the world's population. Antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. Most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the Plasmodium parasite's life cycle within the human host. The identification of inhibitors active against liver-stage malaria would benefit the development of chemical probes to elucidate the poorly understood biology of this phase of the parasite life cycle and could provide agents to prevent and eliminate the disease. Herein we report the development of a live-cell parasite traversal assay in 384-well format amenable to high throughput screening that exploits the wounding of liver cells by the parasite. This method identifies small molecules that may inhibit the parasite's actin myosin motor system. The traversal assay, in addition to established methods, was used to evaluate the activity of halofuginone, a synthetic halogenated derivative of the natural alkaloid febrifugine, against liver-stage Plasmodium berghei parasites. Halofuginone was found to inhibit P. berghei sporozoite load in HepG2 cells with an IC(50) value of 17 nM. While the compound does not affect parasite traversal through human liver cells, an inhibition time course assay indicates that it affects essential processes in both early- and late-stage parasite development. PMID- 22438280 TI - The right inhibition? Callosal correlates of hand performance in healthy children and adolescents callosal correlates of hand performance. AB - Numerous studies suggest that interhemispheric inhibition-relayed via the corpus callosum-plays an important role in unilateral hand motions. Interestingly, transcallosal inhibition appears to be indicative of a strong laterality effect, where generally the dominant hemisphere exerts inhibition on the nondominant one. These effects have been largely identified through functional studies in adult populations, but links between motor performance and callosal structure (especially during sensitive periods of neurodevelopment) remain largely unknown. We therefore investigated correlations between Purdue Pegboard performance (a test of motor function) and local callosal thickness in 170 right-handed children and adolescents (mean age: 11.5 +/- 3.4 years; range, 6-17 years). Better task performance with the right (dominant) hand was associated with greater callosal thickness in isthmus and posterior midbody. Task performance using both hands yielded smaller and less significant correlations in the same regions, while task performance using the left (nondominant) hand showed no significant correlations with callosal thickness. There were no significant interactions with age and sex. These links between motor performance and callosal structure may constitute the neural correlate of interhemispheric inhibition, which is thought to be necessary for fast and complex unilateral motions and to be biased towards the dominant hand. PMID- 22438281 TI - Influence of somatic symptoms on Patient Health Questionnaire-9 depression scores among patients with systemic sclerosis compared to a healthy general population sample. AB - OBJECTIVE: Depression symptom measures that include somatic symptoms may inflate severity estimates among medically ill patients, including patients with systemic sclerosis (SSc; scleroderma). The 9-item Patient Health Questionnaire (PHQ-9) is increasingly used to assess depressive symptoms in medical settings, but it is not known whether PHQ-9 scores are influenced by somatic symptoms common in medical illness. The objective was to assess whether SSc patients had higher somatic symptom scores on the PHQ-9 than non-medically ill respondents from the general population matched on cognitive/affective scores. METHODS: SSc patients from the Canadian Scleroderma Research Group Registry were matched with respondents from a random population survey of Alberta, Canada residents who were without chronic disease on total PHQ-9 cognitive/affective scores (5 items), sex, and, as close as possible, age. PHQ-9 somatic scores (4 items) were compared between SSc patients and healthy Alberta survey respondents using t-tests for unadjusted analyses and analysis of covariance to adjust for age differences that remained after matching. RESULTS: Somatic symptoms accounted for 64% of the total PHQ-9 scores for 762 matched SSc patients (n = 837 total) compared to 56% for 762 matched Alberta population survey respondents (n = 3,304 total), a mean difference of 1.0 point, or 19% of the total scores for the SSc patients (Hedges's g = 0.38). After adjusting for age, the mean difference increased to 1.4 points, reflecting 25% of the SSc patients' total scores (Hedges's g = 0.55). CONCLUSION: PHQ-9 scores among patients with SSc may include a small to moderate amount of variance from somatic symptoms that are not necessarily related to depression. PMID- 22438282 TI - Does access to improved sanitation reduce childhood diarrhea in rural India? AB - Almost nine million children under 5 years of age die every year. Diarrhea is considered to be the second leading cause of under-five mortality in developing countries. About one out of five deaths is caused by diarrhea. In this paper, we use the newly available data set District Level Household Survey 3 to quantify the impact of access to improved sanitation on diarrheal morbidity for children less than 5 years of age in India. Using propensity score matching, we find that access to improved sanitation reduces the risk of contracting diarrhea by 2.2 percentage points. There is considerable heterogeneity in the impacts of improved sanitation. We find statistically insignificant treatment effects for children in low or middle socioeconomic status households and for girls; however, boys and children in high socioeconomic status households experienced economically significant treatment effects. The magnitude of the treatment effect differs largely by hygiene behavior. PMID- 22438283 TI - Association between spirituality and depression in adults with type 2 diabetes. AB - PURPOSE: The purpose of the study was to examine the association between spirituality and depression among patients with type 2 diabetes. METHODS: This study included 201 adult participants with diabetes from an indigent clinic of an academic medical center. Participants completed validated surveys on spirituality and depression. The Daily Spiritual Experience (DSE) Scale measured a person's perception of the transcendent (God, the divine) in daily life. The Center for Epidemiologic Studies-Depression scale assessed depression. Linear regression analyses examined the association of spirituality as the predictor with depression as the outcome, adjusted for confounding variables. RESULTS: Greater spirituality was reported among females, non-Hispanic blacks, those with lower educational levels, and those with lower income. The unadjusted regression model showed greater spirituality was associated with less depression. This association was mildly diminished but still significant in the final adjusted model. Depression scores also increased (greater depression risk) with females and those who were unemployed but decreased with older age and non-Hispanic black race/ethnicity. CONCLUSIONS: Treatment of depression symptoms may be facilitated by incorporating the spiritual values and beliefs of patients with diabetes. Therefore, faith-based diabetes education is likely to improve self-care behaviors and glycemic control. PMID- 22438284 TI - Assessment of health-related family role functioning in systemic lupus erythematosus: preliminary validation of a new measure. AB - OBJECTIVE: Individuals with systemic lupus erythematosus (SLE) often experience symptoms that affect family relationships, which are important components of quality of life. To assess the impact of SLE on family role functioning, we developed a 6-domain (Fatigue, Activity participation, Mental health, Isolation, Love and intimacy, and You/fulfilling family roles [FAMILY]) measure. The objectives of this study were to pilot test and achieve preliminary validation for the SLE-FAMILY questionnaire. METHODS: This was a 3-phase study. In phase 1 (development), domains were identified and items were generated for evaluation. During phase 2 (pilot test), a pilot test was conducted to assess the performance of candidate items. In phase 3 (initial validation), 52 individuals with SLE completed questionnaires, including the 6-item SLE-FAMILY. Data were analyzed for internal consistency reliability, and validity was assessed using correlations between the SLE-FAMILY questionnaire and well-validated measures. RESULTS: The SLE-FAMILY had good test-retest reliability (0.82) and internal consistency (0.67). Reliability analysis of individual items revealed weakness in the performance of item 5. We reviewed raw data and determined that 9 individuals likely overlooked the reverse scoring of item 5, thus explaining its poor reliability. When these 9 individuals were excluded from analysis, Cronbach's alpha increased to 0.71, while test-retest reliability remained acceptable (0.75). Spearman's rho correlations supported the validity of the SLE-FAMILY measure. A pilot test of the SLE-FAMILY questionnaire without the reverse-scored item was conducted; results suggested that the modified version is superior to the initial form. CONCLUSION: The SLE-FAMILY questionnaire is a promising new instrument for robust measurement of family role functioning. PMID- 22438285 TI - Reversible electron transfer in a linear {Fe2Co} trinuclear complex induced by thermal treatment and photoirraditaion. PMID- 22438286 TI - Regulation of gene expression in retrovirus vectors by X-ray and proton beam radiation with artificially constructed promoters. AB - BACKGROUND: We previously obtained an X-ray responsive promoter from 11 promoters that we constructed. In the present study, we aimed to determine the efficiency of our promoter construction method. In addition, the reactivity of the promoter to X-rays in vivo is also investigated. METHODS: Promoters constructed by linking the TATA box to randomly combined binding sequences of transcription factors activated by radiation were cloned to prepare a promoter library. Combinations of promoters and various genes were stably-transfected into HeLa cells to establish recombinant cell lines, which were then exposed to X-rays or a proton beam to observe gene expression enhancement with or without anti-oxidants. Tumors of luciferase-expressing recombinant cells on mice were exposed to X-rays and promoter activation was evaluated by detecting bioluminescence. As a model for in vitro suicide gene therapy, fcy::fur-expressing recombinant cells were exposed to X-rays before incubation with 5-fluorocytosin. Cell viability was determined with WST-8. RESULTS: Twenty-five of the 62 promoters in the library enhanced luciferase activity over five-fold, 6 h after receiving 10 Gy of X-ray irradiation, suggesting the effectiveness of our method. Luciferase activity in recombinant cells was enhanced by X-rays and, to a lesser extent, by a proton beam. Anti-oxidants attenuated the enhancement, suggesting the involvement of oxidative stress. Promoters were less reactive to X-rays in tumors on mice. In our suicide gene therapy model, survival of post-irradiated cells decreased dose dependently with 5-fluorocytosin. CONCLUSIONS: Our method was efficient in generating radiation responsive promoters. Furthermore, we have successfully shown a potential therapeutic use for one of these promoters. PMID- 22438287 TI - Antibacterial activities of tellurium nanomaterials. AB - We prepared four differently shaped Te nanomaterials (NMs) as antibacterial reagents against Escherichia coli. By controlling the concentrations of hydrazine (N(2)H(4)) as reducing agent, NaCl, and temperature, we prepared Te nanowires, nanopencils, nanorices, and nanocubes. These four Te NMs resulted in a live/dead ratio of E. coli cells of less than 0.1, which is smaller than that of Ag nanoparticles. The order of antibacterial activity against E. coli is nanocubes ~ nanorices > nanopencils ~ nanowires. This is in good agreement with the concentration order of tellurite (TeO(3)(2-)) ions released from Te NMs in E. coli cells, revealing that TeO(3)(2-) ions account for the antibacterial activity of the four Te NMs. We found that spherical Te nanoparticles (32 nm in diameter) with TeO(3)(2-) ions were formed in the E. coli cells. Compared to Ag nanoparticles that are commonly used as antibacterial reagents, Te NMs have higher antibacterial activity and lower toxicity. Thus, Te NMs hold great practical potential as a new and efficient antibacterial agent. PMID- 22438288 TI - Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function. AB - The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. PMID- 22438289 TI - Mind matters in cancer survival. AB - OBJECTIVE: The very name "psycho-oncology" implies interaction between brain and body. One of the most intriguing scientific questions for the field is whether or not living better may also mean living longer. METHODS: Randomized intervention trials examining this question will be reviewed. RESULTS: The majority show a survival advantage for patients randomized to psychologically effective interventions for individuals with a variety of cancers, including breast, melanoma, gastrointestinal, lymphoma, and lung cancers. Importantly, for breast and other cancers, when aggressive anti-tumor treatments are less effective, supportive approaches appear to become more useful. This is highlighted by a recent randomized clinical trial of palliative care for non-small cell lung cancer patients.There is growing evidence that disruption of circadian rhythms, including rest-activity patterns and hypothalamic-pituitary-adrenal (HPA) axis function, affects cancer risk and progression. Women with metastatic breast cancer have flatter diurnal cortisol patterns than normal, and the degree of loss of daily variation in cortisol predicts earlier mortality. Mechanisms by which abnormal cortisol patterns affect metabolism, gene expression, and immune function are reviewed. The HPA hyperactivity associated with depression can produce elevated levels of cytokines that affect the brain. Tumor cells can, in turn, co-opt certain mediators of inflammation such as NFkB, interleukin-6, and angiogenic factors to promote metastasis. Also, exposure to elevated levels of norepinephrine triggers release of vascular endothelial growth factor, which facilitates tumor growth. CONCLUSIONS: Therefore, the stress of advancing cancer and management of it is associated with endocrine, immune, and autonomic dysfunction that has consequences for host resistance to cancer progression. PMID- 22438290 TI - Association between socioeconomic status, learned helplessness, and disease outcome in patients with inflammatory polyarthritis. AB - OBJECTIVE: Independent investigations have shown that socioeconomic status (SES) and learned helplessness (LH) are associated with poor disease outcome in patients with rheumatoid arthritis (RA). Our aim was to investigate the cross sectional relationship between SES, LH, and disease outcome in patients with recent-onset inflammatory polyarthritis (IP), the broader group of conditions of which RA is the major constituent. METHODS: SES was measured using the Index of Multiple Deprivation 2007 for 553 patients consecutively recruited to the Norfolk Arthritis Register. Patients also completed the Rheumatology Attitudes Index, a measure of LH. SES and LH were investigated as predictors of disease outcome (functional disability [Health Assessment Questionnaire (HAQ)] and disease activity [Disease Activity Score in 28 joints]) in a regression analysis, adjusted for age, sex, and symptom duration. The role of LH in the relationship between SES and disease outcome was then investigated. RESULTS: Compared to patients of the highest SES, those of the lowest SES had a significantly worse outcome (median difference in HAQ score 0.42; 95% confidence interval [95% CI] 0.08, 0.75). Compared to patients with normal LH, patients with low LH had a significantly better outcome and patients with high LH had a significantly worse outcome (median difference in HAQ score 1.12; 95% CI 0.82, 1.41). There was a significant likelihood that LH mediated the association between SES and disease outcome (P = 0.04). CONCLUSION: LH is robustly associated with cross-sectional disease outcome in patients with IP, and appears to mediate the relationship between SES and disease outcome. As LH is potentially modifiable, these findings have potential clinical implications. PMID- 22438291 TI - Dissociating anticipation from perception: Acute pain activates default mode network. AB - Few studies have explored the effect of acute pain on attentional networks and on the default mode network. Moreover, these studies convey conflicting results, seemingly caused by design. To reassess this issue, we studied 20 healthy subjects with functional magnetic resonance imaging while delivering painful electric shocks. The design was purposely constructed to separate rest, anticipation, and pain perception. We found that default mode network activity in response to pain was biphasic. It deactivated during anticipation when the dorsal attentional network was activated. During pain perception, the default mode network was activated, as were attentional networks. The left posterior fusiform gyrus showed the same dynamics as the default mode network, and its activity was negatively correlated to the subject's pain intensity rating. The associative pregenual anterior cingulate cortex seemed to play a key role in these coactivations. These results concur with data from the literature showing that enhanced pain perception results in greater default mode network activity and that the anticorrelation between the default mode network and the dorsal attentional network disappears in chronic pain patients. PMID- 22438292 TI - An expeditious and atom-economical synthesis of a new generation of substituted [4.6.4.6]fenestradienes. PMID- 22438293 TI - Photoinduced electron transfer from the inorganic core to the organic shell of hybrid core-shell nanoparticles: impedance spectroscopy. AB - In hybrid core-shell nanoparticles with inorganic nanocrystals in the core and organic molecules in the shell, photoinduced electron transfer occurs from the core to the shell. This leads to exciton dissociation through an ultrafast electron-transfer process that results in charge separation and finally photocurrent in the external circuit in devices based on such core-shell nanoparticles. In this work, we have fabricated and characterized sandwiched devices based on a series of core-shell systems. From impedance spectroscopy, we have observed that photoinduced charge separation in core-shell systems is associated with a decrease in the device resistance and an increase in the dielectric constant of the active material. In the series of core-shell systems, we have observed a one-to-one correlation between the photoinduced electron transfer process and the changes in resistive and dielectric parameters upon illumination. PMID- 22438294 TI - HSP70 immune reactivity and TUNEL positivity in the liver of toluene-inhaled and melatonin-treated rats. AB - Toluene is a clear, colorless and volatile hydrocarbon that is metabolized in liver, produced free oxygen radicals and can mediate cellular damage. Melatonin which is a pineal gland hormone is a very potent antioxidant. It can make the cellular membrane more durable against oxidative attacks and protect nuclear DNA from oxidative damage. This study aimed to investigate heat shock protein (HSP)70 immune reactivity and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positivity (apoptotic activity) in the liver of toluene inhaled and melatonin-treated rats. A total of 21 adult male Wistar albino rats were divided at random into 3 equal groups. Animals in group I were designated as control. The rats in group II were exposed to toluene (3000 ppm/1 h/day) for 30 days, while the rats in group III were treated with melatonin (10 mg/kg/day, intraperitoneally) plus toluene inhalation. At the end of the 30-day experimental period, all rats were killed by decapitation. Then the liver tissues of rats were removed and tissue specimens were embedded in paraffin blocks. The specimens were stained with periodic acid-schiff (PAS) following routine histological procedures. Sections obtained from paraffin blocks were used for immune detection of TUNEL and HSP70. In light microscopic observations of tissues from toluene inhaled rats, massive hepatocyte degeneration, ballooning degeneration and decreased PAS positivity were observed. Increased TUNEL positivity and HSP70 immune reactivity were determined in toluene-inhaled group and melatonin treatment decreased all these adverse effects. PMID- 22438295 TI - Biosynthesis of xyrrolin, a new cytotoxic hybrid polyketide/non-ribosomal peptide pyrroline with anticancer potential, in Xylaria sp. BCC 1067. AB - A gene from Xylaria sp. BCC 1067, pks3, that encodes a putative 3660-residue hybrid polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) was characterised by targeted gene disruption in combination with comprehensive product identification. Studies of the features of a corresponding mutant, YA3, allowed us to demonstrate that pks3 is responsible for the synthesis of a new pyrroline compound, named xyrrolin, in the wild-type Xylaria sp. BCC 1067. The structure of xyrrolin was established by extensive spectroscopic and spectrometric analyses, including low- and high-resolution MS, IR, (1)H NMR, (13)C NMR, (13)C NMR with Dept135, HMQC 2D NMR, HMBC 2D NMR and COSY 2D NMR. On the basis of the Pks3 domain organisation and the chemical structure of xyrrolin, we proposed that biosynthesis of this compound requires the condensation of a tetraketide and an L-serine unit, followed by Dieckmann or reductive cyclisation and enzymatic removal of ketone residue(s). Bioassays of the pure xyrrolin further displayed cytotoxicity against an oral cavity (KB) cancer cell line. PMID- 22438296 TI - Breaking the myth of the recalcitrant chemisorbed hydrogens on boron niride nanotubes: a theoretical perspective. PMID- 22438297 TI - Project onward: an innovative e-health intervention for cancer survivors. AB - OBJECTIVE: This study examined the feasibility and acceptability of an Individual Internet Intervention (III) embedded and integrated into an Internet Support Group (ISG) with the ultimate goal of enhancing adherence and learning, compared with an individual internet invention alone. METHOD: Thirty-one posttreatment cancer survivors were randomized in groups of seven to nine to either the 8-week III + ISG intervention or the 8-week III condition. Seventeen participants met the Hospital Anxiety and Depression Scale (HADS) criteria for depressive symptoms (HADS >= 8). RESULTS: Among all participants, the mean number of logins over 8 weeks was 20.8 +/- 17.7 logins for the III + ISG compared with 12.5 +/- 12.5 in III-only (p = 0.15). Two participants in the III + ISG dropped out, compared with five in III (p = 0.39). Among the 17 participants with depressive symptoms at baseline, both the Onward and the III-only condition showed large reductions in the depression scale of HADS (d = 1.27 and 0.89, respectively). Improvement over time and time x treatment effects only reached trend significance levels (ps = 0.07 & 0.12) as this pilot was not powered to detect these differences. CONCLUSION: Both the III + ISG and III-only demonstrated pre-post reductions in depressive symptoms and high rates of utilization compared with other web-based treatments for depression. Although it is premature to make any determination as to the efficacy of the interventions tested in this feasibility study, these results indicate that pursuing the III + ISG model, as well as standard IIIs, may be fruitful areas of future research. PMID- 22438298 TI - Using exercise training to counterbalance chronotropic incompetence and delayed heart rate recovery in systemic lupus erythematosus: a randomized trial. AB - OBJECTIVE: To evaluate the efficacy of a 3-month exercise training program in counteracting the chronotropic incompetence and delayed heart rate recovery in patients with systemic lupus erythematosus (SLE). METHODS: A 12-week randomized trial was conducted. Twenty-four inactive SLE patients were randomly assigned into 2 groups: trained (T; n = 15, 3-month exercise program) and nontrained (NT; n = 13). A sex-, body mass index-, and age-matched healthy control (C) group (n = 8) also underwent the exercise program. Subjects were assessed at baseline and at 12 weeks after training. Main measurements included the chronotropic reserve (CR) and the heart rate (HR) recovery (DeltaHRR) as defined by the difference between HR at peak exercise and at both the first (DeltaHRR1) and second (DeltaHRR2) minutes after the exercise test. RESULTS: Neither the NT SLE patients nor the C group presented any change in the CR or in DeltaHRR1 and DeltaHRR2 (P > 0.05). The exercise training program was effective in promoting significant increases in CR (P = 0.007, effect size [ES] 1.15) and in DeltaHRR1 and DeltaHRR2 (P = 0.009, ES 1.12 and P = 0.002, ES 1.11, respectively) in the SLE T group when compared with the NT group. Moreover, the HR response in SLE patients after training achieved parameters comparable to the C group, as evidenced by the analysis of variance and by the Z score analysis (P > 0.05, T versus C). Systemic Lupus Erythematosus Disease Activity Index scores remained stable throughout the study. CONCLUSION: A 3-month exercise training program was safe and capable of reducing the chronotropic incompetence and the delayed DeltaHRR observed in physically inactive SLE patients. PMID- 22438299 TI - A longitudinal study of age- and gender-related annual rate of volume changes in regional gray matter in healthy adults. AB - The aim of this study was to analyze correlations among the annual rate of gray matter volume change, age, gender, and cerebrovascular risk factors in 381 healthy community-dwelling subjects with a large age range by applying a longitudinal design over 6 years using brain magnetic resonance images (MRIs). Brain MRI data were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. The annual rate of regional gray matter volume change showed significant positive correlations with age in several regions, including the bilateral temporal pole, caudate nucleus, ventral and dorsolateral prefrontal cortices, insula, hippocampus, and temporoparietal cortex, whereas significant negative correlations with age were observed in several regions including the bilateral cingulate gyri and anterior lobe of the cerebellum. Additionally, a significant age-by-gender interaction was found for the annual rate of regional gray matter volume change in the bilateral hippocampus. No significant correlations were observed between the annual rate of regional gray matter volume change and body mass index or systolic blood pressure. A significant positive correlation between the annual rate of gray matter volume change and age indicates that the region shows not linear but accelerated gray matter loss with age. Therefore, evaluating the annual rate of the gray matter volume change with age in healthy subjects is important in understanding how gray matter volume changes with aging in each brain region and in anticipating what cognitive functions are likely to show accelerated decline with aging. PMID- 22438300 TI - A ternary charge-transfer complex composed of cyclotriveratrylene (CTV) and a polyoxometalate (POM) with quinone as an electronic modulator. PMID- 22438301 TI - The enhancement of cyclic electron flow around photosystem I improves the recovery of severely desiccated Porphyra yezoensis (Bangiales, Rhodophyta). AB - Porphyra yezoensis, a representative species of intertidal macro-algae, is able to withstand periodic desiccation at low tide but is submerged in seawater at high tide. In this study, changes in photosynthetic electron flow in P. yezoensis during desiccation and re-hydration were investigated. The results suggested that the cyclic electron flow around photosystem I (PSI) increased significantly during desiccation, continued to operate at times of severe desiccation, and showed greater tolerance to desiccation than the electron flow around PSII. In addition, PSI activity in desiccated blades recovered faster than PSII activity during re-hydration. Even though linear electron flow was suppressed by DCMU [3 (3',4'-dichlorophenyl)-1,1-dimethylurea], cyclic electron flow could still be restored. This process was insensitive to antimycin A and could be suppressed by dibromothymoquinone (DBMIB). The prolonged dark treatment of blades reduced the speed in which the cyclic electron flow around PSI recovered, suggesting that stromal reductants, including NAD(P)H, played an important role in the donation of electrons to PSI and were the main cause of the rapid recovery of cyclic electron flow in desiccated blades during re-hydration. These results suggested that cyclic electron flow in P. yezoensis played a significant physiological role during desiccation and re-hydration and may be one of the most important factors allowing P. yezoensis blades to adapt to intertidal environments. PMID- 22438302 TI - Effect of elevated CO2 and high temperature on seed-set and grain quality of rice. AB - Hybrid vigour may help overcome the negative effects of climate change in rice. A popular rice hybrid (IR75217H), a heat-tolerant check (N22), and a mega-variety (IR64) were tested for tolerance of seed-set and grain quality to high temperature stress at anthesis at ambient and elevated [CO(2)]. Under an ambient air temperature of 29 degrees C (tissue temperature 28.3 degrees C), elevated [CO(2)] increased vegetative and reproductive growth, including seed yield in all three genotypes. Seed-set was reduced by high temperature in all three genotypes, with the hybrid and IR64 equally affected and twice as sensitive as the tolerant cultivar N22. No interaction occurred between temperature and [CO(2)] for seed set. The hybrid had significantly more anthesed spikelets at all temperatures than IR64 and at 29 degrees C this resulted in a large yield advantage. At 35 degrees C (tissue temperature 32.9 degrees C) the hybrid had a higher seed yield than IR64 due to the higher spikelet number, but at 38 degrees C (tissue temperature 34-35 degrees C) there was no yield advantage. Grain gel consistency in the hybrid and IR64 was reduced by high temperatures only at elevated [CO(2)], while the percentage of broken grains increased from 10% at 29 degrees C to 35% at 38 degrees C in the hybrid. It is concluded that seed-set of hybrids is susceptible to short episodes of high temperature during anthesis, but that at intermediate tissue temperatures of 32.9 degrees C higher spikelet number (yield potential) of the hybrid can compensate to some extent. If the heat tolerance from N22 or other tolerant donors could be transferred into hybrids, yield could be maintained under the higher temperatures predicted with climate change. PMID- 22438303 TI - Three different mechanisms of energy dissipation of a desiccation-tolerant moss serve one common purpose: to protect reaction centres against photo-oxidation. AB - Three different types of non-photochemical de-excitation of absorbed light energy protect photosystem II of the sun- and desiccation-tolerant moss Rhytidium rugosum against photo-oxidation. The first mechanism, which is light-induced in hydrated thalli, is sensitive to inhibition by dithiothreitol. It is controlled by the protonation of a thylakoid protein. Other mechanisms are activated by desiccation. One of them permits exciton migration towards a far-red band in the antenna pigments where fast thermal deactivation takes place. This mechanism appears to be similar to a mechanism detected before in desiccated lichens. A third mechanism is based on the reversible photo-accumulation of a radical that acts as a quencher of excitation energy in reaction centres of photosystem II. On the basis of absorption changes around 800 nm, the quencher is suggested to be an oxidized chlorophyll. The data show that desiccated moss is better protected against photo-oxidative damage than hydrated moss. Slow drying of moss thalli in the light increases photo-protection more than slow drying in darkness. PMID- 22438304 TI - Auxin transport at cellular level: new insights supported by mathematical modelling. AB - The molecular basis of cellular auxin transport is still not fully understood. Although a number of carriers have been identified and proved to be involved in auxin transport, their regulation and possible activity of as yet unknown transporters remain unclear. Nevertheless, using single-cell-based systems it is possible to track the course of auxin accumulation inside cells and to specify and quantify some auxin transport parameters. The synthetic auxins 2,4 dichlorophenoxyacetic acid (2,4-D) and naphthalene-1-acetic acid (NAA) are generally considered to be suitable tools for auxin transport studies because they are transported specifically via either auxin influx or efflux carriers, respectively. Our results indicate that NAA can be metabolized rapidly in tobacco BY-2 cells. The predominant metabolite has been identified as NAA glucosyl ester and it is shown that all NAA metabolites were retained inside the cells. This implies that the transport efficiency of auxin efflux transporters is higher than previously assumed. By contrast, the metabolism of 2,4-D remained fairly weak. Moreover, using data on the accumulation of 2,4-D measured in the presence of auxin transport inhibitors, it is shown that 2,4-D is also transported by efflux carriers. These results suggest that 2,4-D is a promising tool for determining both auxin influx and efflux activities. Based on the accumulation data, a mathematical model of 2,4-D transport at a single-cell level is proposed. Optimization of the model provides estimates of crucial transport parameters and, together with its validation by successfully predicting the course of 2,4-D accumulation, it confirms the consistency of the present concept of cellular auxin transport. PMID- 22438305 TI - Biosynthesis and spectroscopic characterization of 2-TM fragments encompassing the sequence of a human GPCR, the Y4 receptor. AB - This paper presents a divide-and-conquer approach towards obtaining solution structures of G protein-coupled receptors. The human Y4 receptor was dissected into two to three transmembrane helix fragments, which were individually studied by solution NMR. We systematically compared various biosynthetic routes for the expression of the fragments in Escherichia coli and discuss purification strategies. In particular, we have compared the production of transmembrane (TM) fragments as inclusion bodies by using the DeltaTrp leader sequence, with membrane-directed expression by using Mistic as the fusion partner, and developed methods for enzymatic cleavage. In addition, direct expression of two-TM fragments into inclusion bodies is a successful route in some cases. With the exception of TM13, we could produce all fragments in isotope-labeled form in quantities sufficient for NMR studies. Almost complete backbone resonance assignment was obtained for the first two helices, as well as for helices 5 and 7, and a high degree was obtained for TM6, while conformational exchange processes resulted in the disappearance of many signals from TM4. In addition, complete assignments were obtained for all residues of the N-terminal domain, as well as the extracellular and cytosolic loops (with the exception of an undecapeptide segment in the second extracellular loop, EC2) and for the complete cytosolic C-terminal tail. In total, backbone resonances of 78 % of all residues were assigned for the Y4 receptor. Predictions of secondary structure based on backbone chemical shifts indicate that most residues from the TM regions adopt helical conformations, with exception of those around polar residues or prolines. However, the domain boundaries differ slightly from those predicted for homology models. We suggest that the obtained chemical shifts might be useful in assigning the full-length receptor. PMID- 22438306 TI - Reliability of the novel 7-joint ultrasound score: results from an inter- and intraobserver study performed by rheumatologists. AB - OBJECTIVE: To assess the inter- and intraobserver reliability of 26 rheumatologists when performing the 7-joint ultrasound score (US7). METHODS: Six patients with rheumatoid arthritis were examined by 26 sonographers in 12 rater groups who performed the US7 score. The US7 score includes the clinically dominant wrist, the second and third metacarpophalangeal (MCP) and proximal interphalangeal joints, and the second and fifth metatarsophalangeal (MTP) joints, which were evaluated for synovitis, tenosynovitis/paratenonitis, and erosions from the dorsal side and palmar/plantar aspects by gray-scale and power Doppler (PD) ultrasound. Additional lateral scans were performed at the MCP2 and MTP5 joints. All of the groups repeated the examination in 4 patients in order to calculate the intraobserver reliability. The results of one group that included 2 expert sonographers were considered as the reference standard. Kappa values, median agreement rates (interobserver), and P values (intraobserver evaluation) were calculated. RESULTS: The median overall kappa value for detecting synovitis was 0.51, for tenosynovitis/paratenonitis was 0.57, and for erosions was 0.45. In detail, the best interobserver results were found for the detection of erosions in the MTP2 joint from the plantar aspect (kappa = 1; median agreement rate 89.4%) and for PD signal detection in the palmar wrist region (kappa = 0.79; median agreement rate 78.8%). Good agreement was found for detecting erosions in the MCP2 joint from the radial side (kappa = 0.67; median agreement rate 77.3%). CONCLUSION: The inter- and intraobserver reliability of the US7 score shows moderate to substantial kappa values and good agreements. Therefore, this ultrasound score has the potential to be an important imaging tool, including multicenter analysis to assess structural changes. PMID- 22438307 TI - Ruthenium/C5 Me5/bisphosphine- or bisphosphite-based catalysts for normal selective hydroformylation. PMID- 22438308 TI - Accuracy of measures of medication adherence in a cholesterol-lowering regimen. AB - This study examined the concordance between multiple measures of adherence, as well as sensitivity to detection of poor adherers, specificity, and predictive validity using a daily cholesterol-lowering regimen. Participants (N = 180) aged 24 to 60 years participated in an adherence ancillary study in a clinical trial. Males constituted 53.9% of this well-educated, community sample. Data on adherence were collected over a 6-month period, using electronic monitoring, self report, specific recall, and pill counts. Electronically monitored (odds ratio [OR] = 5.348) and Shea self-report (OR = 2.678) predicted cholesterol lowering. Days (78.9%) and intervals (84.2%) adherent and the Shea (73.7%) were sensitive to the detection of poor adherers. Moderate associations were found between measures of the same type. Low correlations were found otherwise. The electronic monitor was the most accurate and informative measure. The Shea self-report was the most accurate brief, global estimate of adherence. Other measures were not associated with clinical outcome or sensitive to poor adherence. PMID- 22438309 TI - New frontiers in cell competition. AB - Cellular communication is at the heart of animal development, and guides the specification of cell fates, the movement of cells within and between tissues, and the coordinated arrangement of different body parts. During organ and tissue growth, cell-cell communication plays a critical role in decisions that determine whether cells survive to contribute to the organism. In this review, we discuss recent insights into cell competition, a social cellular phenomenon that selects the fittest cells in a tissue, and as such potentially contributes to the regulation of its growth and final size. The field of cell competition has seen a huge explosion in its study in the last several years, facilitated by the increasingly sophisticated genetic and molecular technology available in Drosophila and driven by its relevance to stem cell biology and human cancer. PMID- 22438310 TI - Correlation between high-sensitivity C-reactive protein and brain gray matter volume in healthy elderly subjects. AB - Although elevated serum high-sensitivity C-reactive protein (hsCRP) is related to atherosclerosis, brain infarction, and cognitive decline, it has not been clarified whether increased hsCRP is associated with the decline in brain gray matter volume. Therefore, the purpose of this study was to determine the relationship between hsCRP levels and brain regional gray matter volume using brain magnetic resonance imaging (MRI) data from 109 community-dwelling healthy elderly subjects. Brain MRIs were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra (DARTEL) procedure. We found a significant negative correlation between regional gray matter volume of the posterior and lateral aspects of the left temporal cortex and hsCRP level after adjusting for age, gender, and intracranial volume. Our results suggest that subjects who have mild inflammation related to arteriosclerosis have decreased regional gray matter volume in the posterior and lateral aspects of the left temporal cortex. Thus, preventing the progression of arteriosclerosis may be important for preventing a decrease in gray matter volume in healthy elderly subjects. PMID- 22438311 TI - Asymmetric calcium catalysis: highly enantioselective carbonyl-ene and Friedel Crafts reactions for the synthesis of quaternary alpha-hydroxy esters bearing a trifluoromethyl group. PMID- 22438312 TI - A caged ligand for a telomeric G-quadruplex. PMID- 22438313 TI - OMIP-005: Quality and phenotype of antigen-responsive rhesus macaque T cells. PMID- 22438314 TI - Cluster cytometry for high-capacity bioanalysis. AB - Flow cytometry specializes in high-content measurements of cells and particles in suspension. Having long excelled in analytical throughput of single cells and particles, only recently with the advent of HyperCyt sampling technology, flow cytometry's multiexperiment throughput has begun to approach the point of practicality for efficiently analyzing hundreds-of-thousands of samples, the realm of high-throughput screening (HTS). To extend performance and automation compatibility, we built a HyperCyt-linked Cluster Cytometer platform, a network of flow cytometers for analyzing samples displayed in high-density, 1,536-well plate format. To assess the performance, we used cell- and microsphere-based HTS assays that had been well characterized in the previous studies. Experiments addressed important technical issues: challenges of small wells (assay volumes 10 MUL or less, reagent mixing, cell and particle suspension), detecting and correcting for differences in performance of individual flow cytometers, and the ability to reanalyze a plate in the event of problems encountered during the primary analysis. Boosting sample throughput an additional fourfold, this platform is uniquely positioned to synergize with expanding suspension array and cell barcoding technologies in which as many as 100 experiments are performed in a single well or sample. As high-performance flow cytometers shrink in cost and size, cluster cytometry promises to become a practical, productive approach for HTS, and other large-scale investigations of biological complexity. PMID- 22438315 TI - Rational design of a tetrameric protein to enhance interactions between self assembled fibers gives molecular hydrogels. PMID- 22438316 TI - Gap junctional coupling with cardiomyocytes is necessary but not sufficient for cardiomyogenic differentiation of cocultured human mesenchymal stem cells. AB - Gap junctional coupling is important for functional integration of transplanted cells with host myocardium. However, the role of gap junctions in cardiomyogenic differentiation of transplanted cells has not been directly investigated. The objective of this work is to study the role of connexin43 (Cx43) in cardiomyogenic differentiation of human mesenchymal stem cells (hMSCs). Knockdown of Cx43 gene expression (Cx43?) was established in naturally Cx43-rich fetal amniotic membrane (AM) hMSCs, while Cx43 was overexpressed (Cx43?) in inherently Cx43-poor adult adipose tissue (AT) hMSCs. The hMSCs were exposed to cardiomyogenic stimuli by coincubation with neonatal rat ventricular cardiomyocytes (nrCMCs) for 10 days. Differentiation was assessed by immunostaining and whole-cell current clamping. To establish whether the effects of Cx43 knockdown could be rescued, Cx45 was overexpressed in Cx43? fetal AM hMSCs. Ten days after coincubation, not a single Cx43? fetal AM hMSC, control adult AT MSC, or Cx43? adult AT mesenchymal stem cell (MSC) expressed alpha actinin, while control fetal AM hMSCs did (2.2% +/- 0.4%, n = 5,000). Moreover, functional cardiomyogenic differentiation, based on action potential recordings, occurred only in control fetal AM hMSCs. Of interest, Cx45 overexpression in Cx43? fetal AM hMSCs restored their ability to undergo cardiomyogenesis (1.6% +/- 0.4%, n = 2,500) in coculture with nrCMCs. Gap junctional coupling is required for differentiation of fetal AM hMSCs into functional CMCs after coincubation with nrCMCs. Heterocellular gap junctional coupling thus plays an important role in the transfer of cardiomyogenic signals from nrCMCs to fetal hMSCs but is not sufficient to induce cardiomyogenic differentiation in adult AT hMSCs. PMID- 22438317 TI - Photoluminescent biocompatible silicon nanoparticles for cancer theranostic applications. AB - Silicon nanoparticles (SiNPs) obtained by mechanical grinding of porous silicon have been used for visualization of living cells in vitro. It was found that SiNPs could penetrate into the cells without any cytotoxic effect up to the concentration of 100 MUg/ml. The cell cytoplasm was observed to be filled by SiNPs, which exhibited bright photoluminescence at 1.6 eV. SiNPs could also act as photosensitizers of the singlet oxygen generation, which could be used in the photodynamic therapy of cancer. These properties of SiNPs are discussed in view of possible applications in theranostics (both in therapy and in diagnostics). PMID- 22438318 TI - A simple multicolor flow cytometry protocol for detection and molecular characterization of circulating tumor cells in epithelial cancers. AB - Circulating tumor cells (CTCs) might not only serve as prognostic marker but could also be useful for monitoring treatment efficacy. A multicolor flow cytometry protocol for their detection and molecular characterization in peripheral blood was developed which consisted of erythrocyte lysis followed by staining of cells with fluorochrome-labeled antibodies against CD45 and the epithelial markers EpCam and cytokeratin 7/8. For reducing the number of events acquired by flow cytometry, an electronic threshold for the fluorescent signals from the epithelial markers was applied. After establishment of the protocol by using spiking experiments, its suitability to determine the absolute number of CTCs as well as their expression of epidermal growth factor receptor (EGFR) and its phosphorylated form (phospho-EGFR) in blood samples from patients with squamous cell carcinoma of the head and neck (SCCHN) was validated. Spiking experiments demonstrated an excellent recovery (mean 85%) and a linear performance (R(2) = 0.98) of the protocol. Sensitivity and specificity were comparable to our former protocol using immunomagnetic CTC pre-enrichment. The analysis of 33 SCCHN patient samples revealed the presence of CTCs in 33.3% of cases with a mean +/- SD of 1.5 +/- 0.5 CTCs per 3.75 ml blood. EGFR was expressed in 100% and phospho-EGFR in 36.4% of the CTC+ cases. We have established a simple and sensitive multicolor flow cytometry protocol for detection of CTCs in patients with epithelial cancers including SCCHN which will allow their detailed molecular characterization. PMID- 22438319 TI - Hunting the chameleon: structural conformations of the intrinsically disordered protein alpha-synuclein. PMID- 22438320 TI - Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. AB - Castration is the standard therapy for advanced prostate cancer (PC). Although this treatment is initially effective, tumors invariably relapse as incurable, castration-resistant PC (CRPC). Adaptation of androgen-dependent PC cells to an androgen-depleted environment or selection of pre-existing, CRPC cells have been proposed as mechanisms of CRPC development. Stem cell (SC)-like PC cells have been implicated not only as tumor initiating/maintaining in PC but also as tumor reinitiating cells in CRPC. Recently, castration-resistant cells expressing the NK3 homeobox 1 (Nkx3-1) (CARNs), the other luminal markers cytokeratin 18 (CK18) and androgen receptor (AR), and possessing SC properties, have been found in castrated mouse prostate and proposed as the cell-of-origin of CRPC. However, the human counterpart of CARNs has not been identified yet. Here, we demonstrate that in the human PC xenograft BM18, pre-existing SC-like and neuroendocrine (NE) PC cells are selected by castration and survive as totally quiescent. SC-like BM18 cells, displaying the SC markers aldehyde dehydrogenase 1A1 or NANOG, coexpress the luminal markers NKX3-1, CK18, and a low level of AR (AR(low)) but not basal or NE markers. These CR luminal SC-like cells, but not NE cells, reinitiate BM18 tumor growth after androgen replacement. The AR(low) seems to mediate directly both castration survival and tumor reinitiation. This study identifies for the first time in human PC SC-/CARN-like cells that may represent the cell-of-origin of tumor reinitiation as CRPC. This finding will be fundamental for refining the hierarchy among human PC cancer cells and may have important clinical implications. PMID- 22438321 TI - Fast non-negative temporal deconvolution for laser scanning microscopy. AB - Laser scanning microscopy (LSM) is a common technique for high resolution fluorescent imaging. Here we describe a fast algorithm for non-negative deconvolution and apply it to readout of LSM detector photocurrents. By broadening photon impulses and deconvolving sampled photocurrent, effective quantum efficiency of the imaging system is increased. Using simulation and imaging with a custom-built two-photon microscope, we demonstrate improved fidelity of images acquired at short dwell times over a wide range of photon rates. Images formed show increased correlation-to-sample equivalent to a 25% increase in photon rate, lower noise, and reduced bleed-through compared to conventional image generation. PMID- 22438322 TI - OMIP-009: Characterization of antigen-specific human T-cells. PMID- 22438323 TI - Protein subunits released by surface collisions of noncovalent complexes: nativelike compact structures revealed by ion mobility mass spectrometry. PMID- 22438324 TI - Evaluation for West Nile Virus (WNV) RNA in urine of patients within 5 months of WNV infection. PMID- 22438325 TI - Transmission of GB virus type C via transfusion in a cohort of HIV-infected patients. AB - BACKGROUND: GB virus C (GBV-C) infection is transmitted by blood exposure and associated with lower human immunodeficiency virus (HIV) load and slower HIV disease progression. Few studies describe predictors of acute GBV-C infection following transfusion in HIV-infected patients. METHODS: We used a limited-access database from the National Heart Lung and Blood Institute's Viral Activation Transfusion Study, a randomized controlled trial of leukoreduced versus nonleukoreduced transfusions received by HIV-infected, transfusion-naive patients. Blood samples from 489 subjects were tested for GBV-C markers in pretransfusion and posttransfusion samples. We estimated the risk of acquiring GBV-C RNA and predictors of GBV-C acquisition, using pooled logistic regression. RESULTS: GBV-C RNA was detected <=120 days following the first transfusion in 22 (7.5%) of 294 subjects who were GBV-C negative before transfusion. The risk of GBV-C RNA acquisition increased with each unit transfused (odds ratio, 1.09; 95% confidence interval, 1.06-1.11). Lower baseline HIV load and use of antiretroviral therapy were associated with subsequent GBV-C RNA acquisition, after control for units of blood transfused. Leukoreduced status of transfused units was not associated with GBV-C transmission. CONCLUSIONS: Blood transfusion is associated with a significant risk of GBV-C acquisition among HIV-infected patients. Transmission of GBV-C by blood transfusion was inversely related to HIV load. PMID- 22438326 TI - Modulation of proteasome machinery by natural and synthetic analogues of the marine bioactive compound petrosaspongiolide M. AB - Natural or synthetic? Several petrosaspongiolide M natural and synthetic analogues have been tested as proteasome inhibitors and apoptosis modulators. The natural petrosaspongiolide M congeners gave a consistent decrease in activity. Among the synthetic analogues, the introduction of the benzothiophene ring resulted in a bioequivalent alternative of the petrosaspongiolide M terpenoid system. PMID- 22438327 TI - Using quality improvement to accelerate highly active antiretroviral treatment coverage in South Africa. AB - INTRODUCTION: The authors report on a health systems strengthening intervention using quality improvement (QI) methods at the subdistrict level to accelerate highly active antiretroviral treatment (HAART) initiation in South Africa. METHODS: Using a phased scale-up design between August 2006 and November 2009, 14 primary healthcare clinics, one community health centre, one district hospital and one tertiary hospital in a subdistrict were recruited into a 'learning network' using QI methods to facilitate cross-facility learning/mentorship/support. Clinic teams consisting of nurses, counsellors, clerks and/or doctors set collective and individual performance targets, analysed their care systems using 'real-time' data feedback, and designed/implemented a set of simple changes to improve HIV testing and HAART initiation rates across the region. DATA ANALYSIS: Primary clinic data were used to measure HAART initiation rates (primary outcome) and HIV testing (secondary outcome). We analysed data variation/trends using an interrupted time series design. Logistic regression analysis was applied to examine trends in HAART initiation during the intervention phases. RESULTS: Clinics in the learning network increased HIV testing by 301.8% from 891/month (SD=94.2) to 3580/month (SD=327.7) (p<0.0001). Monthly HAART initiations increased by 185.5% from 179/month (SD=17.22) to 511/month (SD=44.93) (p<0.0001). During the pilot (phase I), the monthly rate of HAART initiations increased by 3.6 patients. In the prototype collaborative (phase II), there was no acceleration in the rate of increase (3.3/month, p=0.92). Significant acceleration was observed in the rate of increase during the QI scale up (phase III) (10.1/month, p<0.001). The proportion of estimated need for HAART met in the region increased from 35.8% to 72.4% at a time of rapid population growth. CONCLUSION: A QI approach, using learning networks to teach simple data-driven methods for addressing system failures, with increased training and resource inputs, can assist districts to quickly reach universal coverage targets. PMID- 22438328 TI - Depolymerization and hydrodeoxygenation of switchgrass lignin with formic acid. AB - Organosolv switchgrass lignin is depolymerized and hydrodeoxygenated with a formic acid hydrogen source, 20 wt % Pt/C catalyst, and ethanol solvent. The combination of formic acid and Pt/C is found to promote production of higher fractions of lower molecular weight compounds in the liquid products. After 4 h of reaction, all of the switchgrass lignin is solubilized and 21 wt % of the biomass is shown to be converted into seven prominent molecular species that are identified and quantified. Reaction time is shown to be an important variable in affecting changes in product distributions and bulk liquid product properties. At 20 h of reaction, the lignin is significantly depolymerized to form liquid products with a 76 % reduction in the weighted average molecular weight. Elemental analysis also shows that the resultant liquid products have a 50 % reduction in O/C and 10 % increase in H/C molar ratios compared to the switchgrass lignin after 20 h. PMID- 22438329 TI - Synthesis of antimony-based nanowires using the simple vapor deposition method. AB - III-V nanowires have attracted plenty of attention because of their potential outstanding performance in a wide range of applications. However, compared to other III-V nanowires, the synthesis of high quality Sb-based nanowires is less developed, which obstructs the progress towards further applications. In this study we report high quality GaSb and InSb nanowires synthesized by a simple vapor deposition method. Epitaxial growth of nanowires on growth substrates is demonstrated. Te doped GaSb nanowires are achieved through in situ doping during the vapor deposition process. Electrical measurements of nanowire field-effect transistors show high performance of the synthesized InSb nanowires. PMID- 22438330 TI - Gaps: an elusive source of phylogenetic information. PMID- 22438331 TI - The pipid root. AB - The estimation of phylogenetic relationships is an essential component of understanding evolution. Accurate phylogenetic estimation is difficult, however, when internodes are short and old, when genealogical discordance is common due to large ancestral effective population sizes or ancestral population structure, and when homoplasy is prevalent. Inference of divergence times is also hampered by unknown and uneven rates of evolution, the incomplete fossil record, uncertainty in relationships between fossil and extant lineages, and uncertainty in the age of fossils. Ideally, these challenges can be overcome by developing large "phylogenomic" data sets and by analyzing them with methods that accommodate features of the evolutionary process, such as genealogical discordance, recurrent substitution, recombination, ancestral population structure, gene flow after speciation among sampled and unsampled taxa, and variation in evolutionary rates. In some phylogenetic problems, it is possible to use information that is independent of fossils, such as the geological record, to identify putative triggers for diversification whose associated estimated divergence times can then be compared a posteriori with estimated relationships and ages of fossils. The history of diversification of pipid frog genera Pipa, Hymenochirus, Silurana, and Xenopus, for instance, is characterized by many of these evolutionary and analytical challenges. These frogs diversified dozens of millions of years ago, they have a relatively rich fossil record, their distributions span continental plates with a well characterized geological record of ancient connectivity, and there is considerable disagreement across studies in estimated evolutionary relationships. We used high throughput sequencing and public databases to generate a large phylogenomic data set with which we estimated evolutionary relationships using multilocus coalescence methods. We collected sequence data from Pipa, Hymenochirus, Silurana, and Xenopus and the outgroup taxon Rhinophrynus dorsalis from coding sequence of 113 autosomal regions, averaging ~300 bp in length (range: 102-1695 bp) and also a portion of the mitochondrial genome. Analysis of these data using multiple approaches recovers strong support for the ((Xenopus, Silurana)(Pipa, Hymenochirus)) topology, and geologically calibrated divergence time estimates that are consistent with estimated ages and phylogenetic affinities of many fossils. These results provide new insights into the biogeography and chronology of pipid diversification during the breakup of Gondwanaland and illustrate how phylogenomic data may be necessary to tackle tough problems in molecular systematics. [Coalescence; gene tree; high-throughout sequencing; lineage sorting; pipid; species tree; Xenopus.]. PMID- 22438332 TI - Development of polylactide and polyethylene vinyl acetate blends for the manufacture of vaginal rings. AB - Vaginal rings are currently being investigated for delivery of HIV microbicides. However, vaginal rings are currently manufactured form hydrophobic polymers such as silicone elastomer and polyethylene vinyl acetate (PEVA), which do not permit release of hydrophilic microbicides such as the nucleotide reverse transcriptase inhibitor tenofovir. Biodegradable polymers such as polylactide (PLA) may help increase release rates by controlling polymer degradation rather than diffusion of the drug through the polymer. However, biodegradable polymers have limited flexibility making them unsuitable for use in the manufacture of vaginal rings. This study demonstrates that by blending PLA and PEVA together it is possible to achieve a blend that has flexibility similar to native PEVA but also allows for the release of tenofovir. PMID- 22438333 TI - A programmable laboratory testbed in support of evaluation of functional brain activation and connectivity. AB - An important determinant of the value of quantitative neuroimaging studies is the reliability of the derived information, which is a function of the data collection conditions. Near infrared spectroscopy (NIRS) and electroencelphalography are independent sensing domains that are well suited to explore principal elements of the brain's response to neuroactivation, and whose integration supports development of compact, even wearable, systems suitable for use in open environments. In an effort to maximize the translatability and utility of such resources, we have established an experimental laboratory testbed that supports measures and analysis of simulated macroscopic bioelectric and hemodynamic responses of the brain. Principal elements of the testbed include 1) a programmable anthropomorphic head phantom containing a multisignal source array embedded within a matrix that approximates the background optical and bioelectric properties of the brain, 2) integrated translatable headgear that support multimodal studies, and 3) an integrated data analysis environment that supports anatomically based mapping of experiment-derived measures that are directly and not directly observable. Here, we present a description of system components and fabrication, an overview of the analysis environment, and findings from a representative study that document the ability to experimentally validate effective connectivity models based on NIRS tomography. PMID- 22438334 TI - A nonlinear model for hippocampal cognitive prosthesis: memory facilitation by hippocampal ensemble stimulation. AB - Collaborative investigations have characterized how multineuron hippocampal ensembles encode memory necessary for subsequent successful performance by rodents in a delayed nonmatch to sample (DNMS) task and utilized that information to provide the basis for a memory prosthesis to enhance performance. By employing a unique nonlinear dynamic multi-input/multi-output (MIMO) model, developed and adapted to hippocampal neural ensemble firing patterns derived from simultaneous recorded CA1 and CA3 activity, it was possible to extract information encoded in the sample phase necessary for successful performance in the nonmatch phase of the task. The extension of this MIMO model to online delivery of electrical stimulation delivered to the same recording loci that mimicked successful CA1 firing patterns, provided the means to increase levels of performance on a trial by-trial basis. Inclusion of several control procedures provides evidence for the specificity of effective MIMO model generated patterns of electrical stimulation. Increased utility of the MIMO model as a prosthesis device was exhibited by the demonstration of cumulative increases in DNMS task performance with repeated MIMO stimulation over many sessions on both stimulation and nonstimulation trials, suggesting overall system modification with continued exposure. Results reported here are compatible with and extend prior demonstrations and further support the candidacy of the MIMO model as an effective cortical prosthesis. PMID- 22438335 TI - A hippocampal cognitive prosthesis: multi-input, multi-output nonlinear modeling and VLSI implementation. AB - This paper describes the development of a cognitive prosthesis designed to restore the ability to form new long-term memories typically lost after damage to the hippocampus. The animal model used is delayed nonmatch-to-sample (DNMS) behavior in the rat, and the "core" of the prosthesis is a biomimetic multi input/multi-output (MIMO) nonlinear model that provides the capability for predicting spatio-temporal spike train output of hippocampus (CA1) based on spatio-temporal spike train inputs recorded presynaptically to CA1 (e.g., CA3). We demonstrate the capability of the MIMO model for highly accurate predictions of CA1 coded memories that can be made on a single-trial basis and in real-time. When hippocampal CA1 function is blocked and long-term memory formation is lost, successful DNMS behavior also is abolished. However, when MIMO model predictions are used to reinstate CA1 memory-related activity by driving spatio-temporal electrical stimulation of hippocampal output to mimic the patterns of activity observed in control conditions, successful DNMS behavior is restored. We also outline the design in very-large-scale integration for a hardware implementation of a 16-input, 16-output MIMO model, along with spike sorting, amplification, and other functions necessary for a total system, when coupled together with electrode arrays to record extracellularly from populations of hippocampal neurons, that can serve as a cognitive prosthesis in behaving animals. PMID- 22438336 TI - Decoding intra-limb and inter-limb kinematics during treadmill walking from scalp electroencephalographic (EEG) signals. AB - Brain-machine interface (BMI) research has largely been focused on the upper limb. Although restoration of gait function has been a long-standing focus of rehabilitation research, surprisingly very little has been done to decode the cortical neural networks involved in the guidance and control of bipedal locomotion. A notable exception is the work by Nicolelis' group at Duke University that decoded gait kinematics from chronic recordings from ensembles of neurons in primary sensorimotor areas in rhesus monkeys. Recently, we showed that gait kinematics from the ankle, knee, and hip joints during human treadmill walking can be inferred from the electroencephalogram (EEG) with decoding accuracies comparable to those using intracortical recordings. Here we show that both intra- and inter-limb kinematics from human treadmill walking can be achieved with high accuracy from as few as 12 electrodes using scalp EEG. Interestingly, forward and backward predictors from EEG signals lagging or leading the kinematics, respectively, showed different spatial distributions suggesting distinct neural networks for feedforward and feedback control of gait. Of interest is that average decoding accuracy across subjects and decoding modes was ~0.68+/-0.08, supporting the feasibility of EEG-based BMI systems for restoration of walking in patients with paralysis. PMID- 22438337 TI - Ureteropelvic duplication as focus of recurrent infection. PMID- 22438338 TI - A method for screening the potential of MOFs as CO2 adsorbents in pressure swing adsorption processes. AB - This work reports the adsorption and coadsorption data of CO(2)/CH(4)/CO mixtures on several metal-organic frameworks [MOFs; MIL-100(Cr), MIL-47(V), MIL-140(Zr)-A, Cu-btc, and MIL-53(Cr)] and compares them with reference adsorbents, that is, zeolite NaX and an activated carbon material, AC35. We also evaluate the effect of H(2)O on CO(2) adsorption and on the stability of the structures. Based on the experimental adsorption data, the performance potential of MOFs in several pressure swing adsorption processes is estimated by making a ranking of working capacities and separation factors. We discuss the separation of biogas, the purification of H(2) produced by steam reforming of methane, and the removal of CO(2) from synthesis gas in IGCC (integrated gasification combined cycle) systems. Some MOFs are very well placed in the ranking of (isothermal) working capacity vs. selectivity. Yet, performance is not the only criterion for the selection of MOFs. Ease and cost of synthesis and long-term stability are other important aspects that have to be taken into account. PMID- 22438339 TI - Synthesis and characterization of wool keratin/hydroxyapatite nanocomposite. AB - Taking the inspiration from the biomineral, the wool keratin was selected to modulate the assembly of nanosized hydroxyapatite (HA) crystals via a coprecipitation method. A series of keratin/HA nanocomposite with different ratios were synthesized by adjusting the concentrations of keratin solutions and calcium phosphate and their final components were detected by thermogravimetric analysis (TGA). The transmission electron microscopy (TEM) and X-ray diffraction (XRD) confirmed that keratin in the composite decreased the crystallinity of HA. Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) were used to examine the chemical and surface structure of the composites. In vitro biocompatibility results revealed that cells showed better viability on keratin/HA composites which have a ratio of organics and inorganics similar to that of natural bones. PMID- 22438340 TI - Electrospun bio-composite P(LLA-CL)/collagen I/collagen III scaffolds for nerve tissue engineering. AB - One of the biggest challenges in peripheral nerve tissue engineering is to create an artificial nerve graft that could mimic the extracellular matrix (ECM) and assist in nerve regeneration. Bio-composite nanofibrous scaffolds made from synthetic and natural polymeric blends provide suitable substrate for tissue engineering and it can be used as nerve guides eliminating the need of autologous nerve grafts. Nanotopography or orientation of the fibers within the scaffolds greatly influences the nerve cell morphology and outgrowth, and the alignment of the fibers ensures better contact guidance of the cells. In this study, poly (L lactic acid)-co-poly(epsilon-caprolactone) or P(LLA-CL), collagen I and collagen III are utilized for the fabrication of nanofibers of different compositions and orientations (random and aligned) by electrospinning. The morphology, mechanical, physical, and chemical properties of the electrospun scaffolds along with their biocompatibility using C17.2 nerve stem cells are studied to identify the suitable material compositions and topography of the electrospun scaffolds required for peripheral nerve regeneration. Aligned P(LLA-CL)/collagen I/collagen III nanofibrous scaffolds with average diameter of 253 +/- 102 nm were fabricated and characterized with a tensile strength of 11.59 +/- 1.68 MPa. Cell proliferation studies showed 22% increase in cell proliferation on aligned P(LLA CL)/collagen I/collagen III scaffolds compared with aligned pure P(LLA-CL) scaffolds. Results of our in vitro cell proliferation, cell-scaffold interaction, and neurofilament protein expression studies demonstrated that the electrospun aligned P(LLA-CL)/collagen I/collagen III nanofibrous scaffolds mimic more closely towards the ECM of nerve and have great potential as a substrate for accelerated regeneration of the nerve. PMID- 22438343 TI - Prevalence of methicillin-resistant staphylococcus aureus as an etiology of community-acquired pneumonia. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of skin infections. Recent case series describe severe community-acquired pneumonia (CAP) caused by MRSA, but the prevalence and risk factors are unknown. METHODS: We prospectively enrolled adults hospitalized with CAP from 12 university-affiliated emergency departments during the winter-spring of 2006 and 2007. Clinical information and culture results were collected, and factors associated with MRSA were assessed. RESULTS: Of 627 patients, 595 (95%) had respiratory (50%) and/or blood cultures (92%) performed. A pathogen was identified in 102 (17%); MRSA was identified in 14 (2.4%; range by site, 0%-5%) patients and in 5% of patients admitted to the intensive care unit. Two (14%) MRSA pneumonia patients died. All 9 MRSA isolates tested were pulsed-field type USA300. Features significantly associated with isolation of MRSA (as compared with any other or no pathogen) included patient history of MRSA; nursing home admission in the previous year; close contact in the previous month with someone with a skin infection; multiple infiltrates or cavities on chest radiograph; and comatose state, intubation, receipt of pressors, or death in the emergency department. CONCLUSIONS: Methicillin-resistant Staphylococcus aureus remains an uncommon cause of CAP. Detection of MRSA was associated with more severe clinical presentation. PMID- 22438344 TI - Methicillin-resistant staphylococcus aureus and community-acquired pneumonia: an evolving relationship. PMID- 22438345 TI - Novel approaches to the treatment of systemic anthrax. AB - Anthrax continues to generate concern as an agent of bioterrorism and as a natural cause of sporadic disease outbreaks. Despite the use of appropriate antimicrobial agents and advanced supportive care, the mortality associated with the systemic disease remains high. This is primarily due to the pathogenic exotoxins produced by Bacillus anthracis as well as other virulence factors of the organism. For this reason, new therapeutic strategies that target events in the pathogenesis of anthrax and may potentially augment antimicrobials are being investigated. These include anti-toxin approaches, such as passive immune-based therapies; non-antimicrobial drugs with activity against anthrax toxin components; and agents that inhibit binding, processing, or assembly of toxins. Adjunct therapies that target spore germination or downstream events in anthrax intoxication are also under investigation. In combination, these modalities may enhance the management of systemic anthrax. PMID- 22438346 TI - Chronic cervical adenitis in an infant born to a woman with discoid lupus. PMID- 22438347 TI - HIV infection is associated with decreased thrombin generation. AB - BACKGROUND: Excess risk of cardiovascular disease occurs in effectively treated individuals with human immunodeficiency virus (HIV) infection. Although elevated plasma D-dimer levels are associated with increased morbidity and mortality, the impact of HIV infection on coagulation in vivo has not been well studied. METHODS: We measured D-dimers, antithrombin, endogenous thrombin potential (ETP; a functional measure of thrombin generation in vitro), thrombin/antithrombin complexes (TAT; a measure of thrombin generation in vivo), tissue factor, prothrombin fragment 1 + 2 (F1+2), and normalized APC sensitivity ratio (nAPCsr) in 199 HIV-positive men who were receiving antiretroviral therapy and had an undetectable HIV RNA level, in 79 HIV-positive untreated men, and in 39 uninfected controls. RESULTS: Median antithrombin levels were higher while the ETP was lower among HIV-infected adults (treated and untreated), compared with controls. There were few differences between coagulation markers in the 2 HIV groups. Compared with controls, the nAPCsr was lower in treated men and the TAT level was lower in untreated individuals. We observed little difference among measured levels of D-dimer, tissue factor, or F1+2 between HIV-infected individuals and controls. Antiretroviral therapy exposure was associated with a lower antithrombin level, a lower nAPCsr, and a lower ETP, while history of opportunistic infection was associated with a higher nAPCsr. CONCLUSIONS: HIV infection is associated with decreased thrombin generation, as measured by the ETP, and an increased antithrombin level. These data suggest that HIV infection may not be associated with increased propensity toward clotting, as has been suggested on the basis of isolated measures of D-dimer levels. PMID- 22438350 TI - IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. AB - Evidence-based guidelines for the diagnosis and initial management of suspected acute bacterial rhinosinusitis in adults and children were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America comprising clinicians and investigators representing internal medicine, pediatrics, emergency medicine, otolaryngology, public health, epidemiology, and adult and pediatric infectious disease specialties. Recommendations for diagnosis, laboratory investigation, and empiric antimicrobial and adjunctive therapy were developed. PMID- 22438359 TI - Advanced-stage hepatocellular carcinoma: transarterial chemoembolization versus sorafenib. AB - PURPOSE: To compare the efficacies of transarterial chemoembolization (TACE) and sorafenib in patients with advanced-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The retrospective analysis of the data was approved by the institutional review board; the requirement to obtain informed consent was waived. Three hundred seventy-two patients with HCC were treated between January 1999 and December 2009. Patients with advanced HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Child-Pugh class A or B, Eastern Cooperative Oncology Group performance status of 1-2, and/or macrovascular invasion or extrahepatic metastasis) were included in the study (n = 97). Thirty-four patients underwent conventional TACE with doxorubicin plus lipiodol or TACE with drug-eluting beads; 63 patients were treated with sorafenib. RESULTS: The median duration of sorafenib treatment was 4.6 months (95% confidence interval [CI]: 3.2, 6.0 months). The median number of TACE sessions per patient was 3 +/- 2. Side effects of TACE and sorafenib were comparable to those reported in the literature. The median time to progression was similar between the two treatment groups (P = .737). The median overall survival was 9.2 months (95% CI: 6.1, 12.3 months) for patients treated with TACE and 7.4 months (95% CI: 5.6, 9.2 months) for those treated with sorafenib (P = .377). Only Child-Pugh class was associated with a better overall survival at uni and multivariate analysis. CONCLUSION: TACE achieved a promising outcome in select patients with advanced HCC (BCLC stage C). PMID- 22438360 TI - Symptomatic benign thyroid nodules: efficacy of additional radiofrequency ablation treatment session--prospective randomized study. AB - PURPOSE: To prospectively evaluate the efficacy of additional radiofrequency (RF) ablation by comparing the results of one and two sessions. MATERIALS AND METHODS: All patients gave written informed consent to participate in this institutional review board-approved prospective study. From September 2007 to February 2008, 30 patients with benign predominantly solid thyroid nodules causing pressure symptoms and/or cosmetic problems were randomly assigned to undergo single session (group 1, n = 15) or two-session (group 2, n = 15) RF ablation. RF ablation was performed by using an 18-gauge internally cooled electrode with ultrasonographic guidance. Nodule volume and cosmetic and symptom scores were evaluated before ablation and at 1, 3, and 6 months after initial ablation, and quantitative comparisons of these were performed by using the Mann-Whitney and Wilcoxon signed rank tests; the Spearman rank test was used for correlation between nodule volume reduction and applied energy. RESULTS: At 6-month follow up, there was significant nodule volume reduction, from 13.3 mL +/- 12.9 (standard deviation) to 3.8 mL +/- 4.4 in group 1 (P = .001), and from 13.0 mL +/ 6.8 to 3.0 mL +/- 2.2 in group 2 (P = .001). Each group showed significant improvement in cosmetic (P < .0001) and symptom (P = .001) scores. However, there was no significant difference in volume reduction, cosmetic score, and symptom score between two groups (P = .078, P > .99, and P = .259, respectively). In group 1, three of four patients who had a pretreatment nodule volume larger than 20 mL underwent additional RF ablation because of unresolved clinical problems after the first session. CONCLUSION: Single-session RF ablation showed significant volume reduction and satisfactory clinical response in most patients. Therefore, additional RF ablation should be limited to patients with a large nodule (>20 mL) or unresolved clinical problems. PMID- 22438361 TI - Reproducibility of 2D and 3D fractal analysis techniques for the assessment of spatial heterogeneity of regional blood flow in rectal cancer. AB - PURPOSE: To characterize the two-dimensional (2D) and three-dimensional (3D) fractal properties of rectal cancer regional blood flow assessed by using volumetric helical perfusion computed tomography (CT) and to determine its reproducibility. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Ten prospective patients (eight men, two women; mean age, 72.3 years) with rectal adenocarcinoma underwent two repeated volumetric helical perfusion CT studies (four-dimensional adaptive spiral mode, 11.4-cm z-axis coverage) without intervening treatment within 24 hours, with regional blood flow derived by using deconvolution analysis. Two-dimensional and 3D fractal analyses of the rectal tumor were performed, after segmentation from surrounding structures by using thresholding, to derive fractal dimension and fractal abundance. Reproducibility was quantitatively assessed by using Bland Altman statistics. Two-dimensional and 3D lacunarity plots were also generated, allowing qualitative assessment of reproducibility. Statistical significance was at 5%. RESULTS: Mean blood flow was 63.50 mL/min/100 mL +/- 8.95 (standard deviation). Good agreement was noted between the repeated studies for fractal dimension; mean difference was -0.024 (95% limits of agreement: -0.212, 0.372) for 2D fractal analysis and -0.024 (95% limits of agreement: -0.307, 0.355) for 3D fractal analysis. Mean difference for fractal abundance was -0.355 (95% limits of agreement: -0.869, 1.579) for 2D fractal analysis and -0.043 (95% limits of agreement: -1.154, 1.239) for 3D fractal analysis. The 95% limits of agreement were narrower for 3D than 2D analysis. Lacunarity plots also visually confirmed close agreement between repeat studies. CONCLUSION: Regional blood flow in rectal cancer exhibits fractal properties. Good reproducibility was achieved between repeated studies with 2D and 3D fractal analysis. PMID- 22438362 TI - US-guided percutaneous microwave coagulation of small breast cancers: a clinical study. AB - PURPOSE: To determine the feasibility of percutaneous microwave coagulation (PMC) for the treatment of small solitary breast cancers. MATERIALS AND METHODS: With approval of the institutional ethics committee and written informed consent, 41 patients with core-needle-biopsy-proved breast cancers 3.0 cm or less in diameter accessed by using ultrasonography (US) were recruited. US-guided PMC was performed with general anesthesia, followed immediately by mastectomy. Histochemical staining with alpha-nicotinamide adenine dinucleotide, reduced (NADH)-diaphorase was used to determine cell viability and the extent of PMC lesions. RESULTS: The mean tumor volume was 5.26 cm(3) +/- 3.80 (standard deviation), with a range from 0.09 to 14.14 cm(3). PMC was successfully performed in all cases, with complete tumor ablation as assessed by using US. The mean time to reach complete ablation was 4.48 minutes, ranging from 3 to 10 minutes. With microscopic examination, 37 of 41 cases (90%; 95% confidence interval [CI]: 76.9%, 97.3%) showed complete tumor coagulation, as observed by using alpha-NADH diaphorase staining. Of 38 cases diagnosed with invasive ductal carcinoma, 36 cases (95%; 95% CI: 82.3%, 99.4%) showed complete tumor coagulation. Slight thermal injuries to the skin and pectoralis major muscle, which proved reversible, were found in three cases. CONCLUSION: US-guided PMC of small solitary breast cancers is feasible. Nevertheless, larger-scale clinical trials are still needed to validate PMC for adoption into a standard clinical practice. PMID- 22438363 TI - Extraspinal findings at lumbar spine CT examinations: prevalence and clinical importance. AB - PURPOSE: To prospectively determine the prevalence and clinical importance of extraspinal abnormalities in adult outpatients undergoing computed tomography (CT) of the lumbar spine. MATERIALS AND METHODS: Institutional review board approval was obtained for this prospective study. Informed consent was obtained from 400 consecutive adult outpatients (mean age, 49 years; 212 male and 188 female patients) undergoing lumbar spine CT for low back pain and/or radiculopathy. Those with known malignancy were excluded. Dedicated spinal and abdominal full-field-of-view (FOV) images for each patient were reviewed by at least one neuroradiologist and two body radiologists. Extraspinal abnormalities were classified according to the CT Colonography Reporting and Data System (C RADS). The electronic medical record of the patients with C-RADS E3 and E4 extraspinal findings were reviewed to assess how many of these findings were previously unknown, and the patients were followed up 24-36 months after the initial CT to determine their work-up and outcome. RESULTS: Extraspinal findings were present on images in 162 (40.5%) of 400 lumbar spine CT examinations; 59 (14.8%) patients had indeterminate or clinically important findings requiring clinical correlation or further evaluation. After review of the electronic medical record, the prevalence of clinically important findings was 4.3%, comprising an early-stage renal cell carcinoma and transitional cell carcinoma, chronic lymphocytic leukemia, sarcoidosis, and 13 abdominal aortic aneurysms. Excluding anatomic variants, the full FOV was required to best visualize extraspinal abnormalities in 127 (79.4%) of 160 patients. CONCLUSION: Reviewing the full-FOV images from lumbar spine CT examinations will result in the detection of a small number of substantial extraspinal pathologic findings in addition to many benign incidental findings. PMID- 22438364 TI - MR volumetric measurement of low rectal cancer helps predict tumor response and outcome after combined chemotherapy and radiation therapy. AB - PURPOSE: To retrospectively determine whether magnetic resonance (MR) volumetry of rectal cancer is a reproducible method for predicting disease-free survival (DFS) in patients with locally advanced low or midrectal tumors who undergo combined chemotherapy and radiation therapy (CRT) before total mesorectal excision. MATERIALS AND METHODS: The institutional review board does not require approval for the use of patient data obtained for an observational retrospective study. Fifty-eight patients were included in the study; 42 patients had low-lying tumors. Two radiologists independently measured tumor volumes before and after CRT with use of semiautomated software. The radiologists were blinded to the clinical information for each patient. The tumor volume reduction ratio, circumferential resection margin, T stage, and occurrence of downstaging were compared with the histopathologic response and DFS. The threshold of tumor volume reduction for predicting DFS was assessed with receiver operating characteristic curve analysis. DFS was estimated with the Kaplan-Meier method and compared between groups with the log-rank test. RESULTS: The interobserver correlation coefficient between the two radiologists was 0.87 (95% confidence interval [CI]: 0.76, 0.93) for pre-CRT volumetry and 0.81 (95% CI: 0.74, 0.90) for post-CRT volumetry. A tumor volume reduction of at least 70% was significantly associated with good histologic regression (tumor regression grade [TRG], 3 or 4) (P <.0001) compared with a volume reduction rate of less than 70%. DFS was studied in 51 patients. The mean follow-up of survivors at the time of analysis was 52 months +/- 20 (standard deviation). Patients with a volume reduction ratio of at least 70% had a higher DFS (P <.0001). Tumor volume reduction was an independent prognostic parameter in multivariate analysis for DFS (P = .003; 95% CI: 0.01, 0.4). CONCLUSION: The results demonstrate that volumetric measurements are reliable markers of rectal cancer prognosis, enabling the prediction of DFS and TRG. The cutoff of 70% is an easy parameter to use as a surrogate for clinical response to predict both TRG and outcome. PMID- 22438365 TI - Demyelinating diseases: myeloperoxidase as an imaging biomarker and therapeutic target. AB - PURPOSE: To evaluate myeloperoxidase (MPO) as a newer therapeutic target and bis 5-hydroxytryptamide-diethylenetriaminepentaacetate-gadolinium (Gd) (MPO-Gd) as an imaging biomarker for demyelinating diseases such as multiple sclerosis (MS) by using experimental autoimmune encephalomyelitis (EAE), a murine model of MS. MATERIALS AND METHODS: Animal experiments were approved by the institutional animal care committee. EAE was induced in SJL mice by using proteolipid protein (PLP), and mice were treated with either 4-aminobenzoic acid hydrazide (ABAH), 40 mg/kg injected intraperitoneally, an irreversible inhibitor of MPO, or saline as control, and followed up to day 40 after induction. In another group of SJL mice, induction was performed without PLP as shams. The mice were imaged by using MPO Gd to track changes in MPO activity noninvasively. Imaging results were corroborated by enzymatic assays, flow cytometry, and histopathologic analyses. Significance was computed by using the t test or Mann-Whitney U test. RESULTS: There was a 2.5-fold increase in myeloid cell infiltration in the brain (P = .026), with a concomitant increase in brain MPO level (P = .0087). Inhibiting MPO activity with ABAH resulted in decrease in MPO-Gd-positive lesion volume (P = .012), number (P = .009), and enhancement intensity (P = .03) at MR imaging, reflecting lower local MPO activity (P = .03), compared with controls. MPO inhibition was accompanied by decreased demyelination (P = .01) and lower inflammatory cell recruitment in the brain (P < .0001), suggesting a central MPO role in inflammatory demyelination. Clinically, MPO inhibition significantly reduced the severity of clinical symptoms (P = .0001) and improved survival (P = .0051) in mice with EAE. CONCLUSION: MPO may be a key mediator of myeloid inflammation and tissue damage in EAE. Therefore, MPO could represent a promising therapeutic target, as well as an imaging biomarker, for demyelinating diseases and potentially for other diseases in which MPO is implicated. PMID- 22438367 TI - Effect of implementation of Integrated Management of Neonatal and Childhood Illness (IMNCI) programme on neonatal and infant mortality: cluster randomised controlled trial. AB - OBJECTIVE: To evaluate the Indian Integrated Management of Neonatal and Childhood Illness (IMNCI) programme, which integrates improved treatment of illness for children with home visits for newborn care, to inform its scale-up. DESIGN: Cluster randomised trial. SETTING: 18 clusters (population 1.1 million) in Haryana, India. PARTICIPANTS: 29,667 births in intervention clusters and 30,813 in control clusters. INTERVENTION: Community health workers were trained to conduct postnatal home visits and women's group meetings; physicians, nurses, and community health workers were trained to treat or refer sick newborns and children; supply of drugs and supervision were strengthened. MAIN OUTCOME MEASURES: Neonatal and infant mortality; newborn care practices. RESULTS: The infant mortality rate (adjusted hazard ratio 0.85, 95% confidence interval 0.77 to 0.94) and the neonatal mortality rate beyond the first 24 hours (adjusted hazard ratio 0.86, 0.79 to 0.95) were significantly lower in the intervention clusters than in control clusters. The adjusted hazard ratio for neonatal mortality rate was 0.91 (0.80 to 1.03). A significant interaction was found between the place of birth and the effect of the intervention for all mortality outcomes except post-neonatal mortality rate. The neonatal mortality rate was significantly lower in the intervention clusters in the subgroup born at home (adjusted hazard ratio 0.80, 0.68 to 0.93) but not in the subgroup born in a health facility (1.06, 0.91 to 1.23) (P value for interaction = 0.001). Optimal newborn care practices were significantly more common in the intervention clusters. CONCLUSIONS: Implementation of the IMNCI resulted in substantial improvement in infant survival and in neonatal survival in those born at home. The IMNCI should be a part of India's strategy to achieve the millennium development goal on child survival. TRIAL REGISTRATION: Clinical trials NCT00474981; ICMR Clinical Trial Registry CTRI/2009/091/000715. PMID- 22438368 TI - How the Taliban undermined community healthcare in Swat, Pakistan. PMID- 22438366 TI - Patient acceptability and psychologic consequences of CT colonography compared with those of colonoscopy: results from a multicenter randomized controlled trial of symptomatic patients. AB - PURPOSE: To use a randomized design to compare patients' short- and longer-term experiences after computed tomographic (CT) colonography or colonoscopy. MATERIALS AND METHODS: After ethical approval, the trial was registered. Patients gave written informed consent. Five hundred forty-seven patients with symptoms suggestive of colorectal cancer who had been randomly assigned at a ratio of 2:1 to undergo either colonoscopy (n = 362) or CT colonography (n = 185) received a validated questionnaire to assess immediate test experience (including satisfaction, worry, discomfort, adverse effects) and a 3-month questionnaire to assess psychologic outcomes (including satisfaction with result dissemination and reassurance). Data were analyzed by using Mann-Whitney U, Kruskal-Wallis, and chi(2) test statistics. RESULTS: Patients undergoing colonoscopy were less satisfied than those undergoing CT colonography (median score of 61 and interquartile range [IQR] of 55-67 vs median score of 64 and IQR of 58-70, respectively; P = .008) and significantly more worried (median score of 16 [IQR, 12-21] vs 15 [IQR, 9-19], P = .007); they also experienced more physical discomfort (median score of 39 [IQR, 29-51] vs 35 [IQR, 24-44]) and more adverse events (82 of 246 vs 28 of 122 reported feeling faint or dizzy, P = .039). However, at 3 months, they were more satisfied with how results were received (median score of 4 [IQR, 3-4] vs 3 [IQR, 3-3], P < .0005) and less likely to require follow-up colonic investigations (17 of 230 vs 37 of 107, P < .0005). No differences were observed between the tests regarding 3-month psychologic consequences of the diagnostic episode, except for a trend toward a difference (P = .050) in negative affect (unpleasant emotions such as distress), with patients undergoing CT colonography reporting less intense negative affect. CONCLUSION: CT colonography has superior patient acceptability compared with colonoscopy in the short term, but colonoscopy offers some benefits to patients that become apparent after longer-term follow-up. The respective advantages of each test should be balanced when referring symptomatic patients. PMID- 22438369 TI - Regulation is appropriate for this diverse range of products. PMID- 22438370 TI - We must not forget the benefits of these devices. PMID- 22438371 TI - Clinical governance requirements are needed now. PMID- 22438372 TI - Patients need to be informed about the evidence. PMID- 22438373 TI - Roadside drug testing would not be much of a deterrent. PMID- 22438374 TI - Cannabis and the DVLA. PMID- 22438375 TI - Guidance for prescribing in frail adults is now available. PMID- 22438376 TI - Trials must enrol people with multiple problems. PMID- 22438377 TI - See the person in the patient. PMID- 22438378 TI - More guidance is needed on how to communicate about DCIS. PMID- 22438379 TI - Should H pylori always be eradicated? PMID- 22438380 TI - In defence of Atos. PMID- 22438381 TI - Patient safety: where nothing is unavoidable. PMID- 22438382 TI - Baby boomers go bust. PMID- 22438383 TI - Are other companies prepared? PMID- 22438384 TI - UK regulator asks cardiologists to report adverse effects of heart device. PMID- 22438385 TI - Reducing neonatal mortality in resource poor settings. PMID- 22438386 TI - NHS reforms pass final hurdle in House of Lords. PMID- 22438387 TI - The world on tilt. PMID- 22438388 TI - CLOSURE 1 seen through the MIST. PMID- 22438389 TI - Government faces "steep climb" to implement health bill amid professional opposition. PMID- 22438391 TI - No laughing matter. PMID- 22438392 TI - Whose data are they anyway? PMID- 22438393 TI - NHS needs to do more to meet UK targets on greenhouse gases. PMID- 22438394 TI - More reasons to reexamine the definition of viral blip during antiretroviral therapy. PMID- 22438395 TI - Aspergillus terreus: how inoculum size and host characteristics affect its virulence. PMID- 22438397 TI - Murine infection models for Aspergillus terreus pulmonary aspergillosis reveal long-term persistence of conidia and liver degeneration. AB - Aspergillus terreus is emerging as a causative agent of life-threatening invasive aspergillosis. Prognosis for affected patients is often worse than for A. fumigatus infections. To study A. terreus-mediated disease, we developed 3 infection models. In embryonated hen's eggs and leucopenic mice, the outcome of invasive aspergillosis was similar to that described for A. fumigatus. However, 10(2)- and 10(3)-fold higher conidia concentrations were required for 100% lethality. In corticosteroid-treated mice, only 50% mortality was observed, although bioluminescence imaging revealed transient disease in all infected animals. In surviving animals, we observed persistence of ungerminated but viable conidia. Cytokine levels in these mice were comparable to uninfected controls. In contrast to A. fumigatus infections, all mice infected with A. terreus developed fatty liver degeneration, suggesting the production of toxic secondary metabolites. Thus, at least in mice, persistence and subclinical liver damage are unique features of A. terreus infections. PMID- 22438396 TI - Magnitude of virologic blips is associated with a higher risk for virologic rebound in HIV-infected individuals: a recurrent events analysis. AB - BACKGROUND: The importance of human immunodeficiency virus (HIV) blip magnitude on virologic rebound has been raised in clinical guidelines relating to viral load assays. METHODS: Antiretroviral-naive individuals initiating combination antiretroviral therapy (cART) after 1 January 2000 and achieving virologic suppression were studied. Negative binomial models were used to identify blip correlates. Recurrent event models were used to determine the association between blips and rebound by incorporating multiple periods of virologic suppression per individual. RESULTS: 3550 participants (82% male; median age, 40 years) were included. In a multivariable negative binomial regression model, the Amplicor assay was associated with a lower blip rate than branched DNA (rate ratio, 0.69; P < .01), controlling for age, sex, region, baseline HIV-1 RNA and CD4 count, AIDS-defining illnesses, year of cART initiation, cART type, and HIV-1 RNA testing frequency. In a multivariable recurrent event model controlling for age, sex, intravenous drug use, cART start year, cART type, assay type, and HIV-1 RNA testing frequency, blips of 500-999 copies/mL were associated with virologic rebound (hazard ratio, 2.70; P = .002), whereas blips of 50-499 were not. CONCLUSIONS: HIV-1 RNA assay was an important determinant of blip rates and should be considered in clinical guidelines. Blips >=500 copies/mL were associated with increased rebound risk. PMID- 22438405 TI - Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma. AB - OBJECTIVE: To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease. METHODS: Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus. RESULTS: Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months. CONCLUSIONS: Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance. PMID- 22438406 TI - The long-term results with delayed-combined androgen blockade therapy in local or locally advanced prostate cancer. AB - OBJECTIVE: To evaluate long-term clinical outcomes in cT1c-T3a prostate cancer patients following delayed-combined androgen blockade therapy. METHODS: From January 2001 to December 2004, 92 cT1c-T3a prostate cancer cases were enrolled. Medical castration and anti-androgen treatment were used sequentially as delayed combined androgen blockade therapy. Time to prostate-specific antigen biochemical failure was estimated, and risk factors for prostate-specific antigen biochemical failure were evaluated. RESULTS: The average patient age was 76.4 years (range, 59-91 years), the median observation period was 52.8 months (range, 26-106.6 months) and the median pre-treatment prostate-specific antigen level was 14 ng/ml (range, 3.68-492 ng/ml). The TNM classification distribution was as follows: T1c, n= 27; T2a, n = 39; T2b, n = 20; and T3a, n = 6. In the multivariate analysis, Gleason's score >=8 (P < 0.05; hazard ratio, 3.02), prostate-specific antigen nadir >1.4 ng/ml (P = 0.001; hazard ratio, 8.76) and a half-life of the prostate specific antigen level >1.2 months (P < 0.005; hazard ratio, 6.3) during the initial 6 months of luteinizing hormone-releasing hormone agonist monotherapy were significant independent risk factors for prostate-specific antigen biochemical failure with luteinizing hormone-releasing hormone agonist monotherapy. The high-risk group, which had at least one of these three risk factors, had a shorter time to prostate-specific antigen biochemical failure than the low-risk group, during luteinizing hormone-releasing hormone agonist monotherapy (P < 0.0001). For the total delayed-combined androgen blockade therapy observation period, the free-prostate-specific antigen biochemical failure rate was 88.3% at 5 years. Only a maintenance period following luteinizing hormone-releasing hormone agonist monotherapy (P < 0.005; hazard ratio, 16.8) was revealed to be a significant independent risk factor for prostate-specific antigen biochemical failure with total delayed-combined androgen blockade. CONCLUSIONS: The free-prostate-specific antigen biochemical failure rate of delayed-combined androgen blockade therapy in our study was as valuable as those in other androgen deprivation therapy of previous reports. PMID- 22438407 TI - Development of invasive colon cancer with microsatellite instability in a patient with hyperplastic polyposis syndrome. AB - The serrated pathway has recently been proposed as a route for the development of colorectal cancer with microsatellite instability. Hyperplastic polyposis syndrome is a rare syndrome defined by the presence of numerous serrated polyps, with a high risk of developing into colorectal cancer. We present here a case of hyperplastic polyposis syndrome developing into colorectal cancer with microsatellite instability from a serrated polyp. BRAF mutation and the loss of MLH1 protein were observed in the colorectal cancer, but not in the other serrated polyps around the colorectal cancer, suggesting that colorectal cancer with microsatellite instability develops rapidly from a specific serrated polyp with distinct molecular properties. PMID- 22438408 TI - eComment. thromboendarterectomy and aortic occlusion: the good, the bad and the ugly. PMID- 22438409 TI - eComment. transcatheter aortic valve implantation: need for continuing experimental research. PMID- 22438410 TI - eComment: do gentamicin-collagen sponges decrease the risk of mediastinitis? PMID- 22438411 TI - eComment. post-pneumonectomy bronchopleural fistula: covered metallic stent or Amplatzer occluder? PMID- 22438412 TI - eComment. post-pneumonectomy bronchopleural fistula. PMID- 22438413 TI - eComment. post-pneumonectomy empyema with bronchopleural fistula. PMID- 22438415 TI - eComment. platelet transfusion after aortic valve replacement by the Freedom Solo bioprosthesis. PMID- 22438416 TI - eComment. atrial fibrillation ablation - are we approaching an equivalent standard of cure? PMID- 22438417 TI - eComment. hybrid treatment of lone-standing atrial fibrillation. PMID- 22438418 TI - eComment. authors experience and recommendations. PMID- 22438419 TI - eComment. gastrointestinal stromal tumours. PMID- 22438420 TI - High reproducible ADCC analysis revealed a competitive relation between ADCC and CDC and differences between FcgammaRllla polymorphism. AB - The anti-CD20 chimeric monoclonal antibody rituximab mediates cytotoxicity in malignant B cells via multiple mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and direct induction of apoptosis. To optimize treatment of non-Hodgkin's lymphoma, a fuller understanding of these mechanisms and their relative contributions to clinical efficacy is required. Here, we report the characteristics of the mutual impact between ADCC and CDC, the two major effector functions through the Fc receptors. To compare ADCC induced under various conditions, we developed a highly reproducible method of estimating ADCC activity using immortalized effector cells. The set of the effector cells that we established was able to calculate net ADCC with high reproducibility by comparing the cytotoxicity of effector cells expressing exogeneous FcgammaRIIIa to those of mock effector cells. In addition, the different property of effector cells of two FcgammaRIIIa single nucleotide polymorphisms (SNP) could be also evaluated in exactly identical background. ADCC assessment in the presence of human serum directly provided the evidence of the competitive interaction of ADCC and CDC. The inhibition of ADCC of effector cells having low affinity SNP of FcgammaRIIIa by active complement was more potent than those having high-affinity SNP at the rituximab concentration comparable to the serum level obtained in patients. These findings could have a profound impact on optimization of the regimen of therapeutic antibodies and on the development of antibodies that will enhance effector function. PMID- 22438421 TI - Pursuing the "Holy Grail". PMID- 22438422 TI - In vivo clinical measures of intermediary metabolism are inadequate: can a new magnetic resonance spectroscopy technology do better? PMID- 22438423 TI - Quantification of systemic-to-pulmonary artery collateral flow: challenges and opportunities. PMID- 22438424 TI - Does imaging-guided selection of patients with ischemic heart failure for high risk revascularization improve identification of those with the highest clinical benefit?: Imaging-guided selection of patients with ischemic heart failure for high-risk revascularization improves identification of those with the highest clinical benefit. PMID- 22438425 TI - Does imaging-guided selection of patients with ischemic heart failure for high risk revascularization improve identification of those with the highest clinical benefit?: Myocardial imaging should not exclude patients with ischemic heart failure from coronary revascularization. PMID- 22438426 TI - Get closer to the diagnosis in a flash. PMID- 22438428 TI - Measuring socio-economic position for epidemiological studies in low- and middle income countries: a methods of measurement in epidemiology paper. AB - Much has been written about the measurement of socio-economic position (SEP) in high-income countries (HIC). Less has been written for an epidemiology, health systems and public health audience about the measurement of SEP in low- and middle-income countries (LMIC). The social stratification processes in many LMIC and therefore the appropriate measurement tools-differ considerably from those in HIC. Many measures of SEP have been utilized in epidemiological studies; the aspects of SEP captured by these measures and the pathways through which they may affect health are likely to be slightly different but overlapping. No single measure of SEP will be ideal for all studies and contexts; the strengths and limitations of a given indicator are likely to vary according to the specific research question. Understanding the general properties of different indicators, however, is essential for all those involved in the design or interpretation of epidemiological studies. In this article, we describe the measures of SEP used in LMIC. We concentrate on measures of individual or household-level SEP rather than area-based or ecological measures such as gross domestic product. We describe each indicator in terms of its theoretical basis, interpretation, measurement, strengths and limitations. We also provide brief comparisons between LMIC and HIC for each measure. PMID- 22438429 TI - Long-term follow-up of attenuated plaques in patients with acute myocardial infarction: an intravascular ultrasound substudy of the HORIZONS-AMI trial. AB - BACKGROUND: Intravascular ultrasound (IVUS)-attenuated plaque is characterized by absence of ultrasound signal behind hypoehcoic plaque and is seen almost exclusively in acute coronary syndromes. METHODS AND RESULTS: We analyzed poststenting and 13-month follow-up IVUS in 186 patients (195 lesions) with acute myocardial infarction who underwent primary percutaneous coronary intervention. The primary prespecified IVUS end point was the in-stent percent net volume obstruction at follow-up. Overall, 70.3% of lesions contained attenuated plaques at baseline. During follow-up, attenuation scores decreased significantly, behind paclitaxel-eluting stents (PES) (14.1 [11.9, 16.3] to 7.7 [5.4, 9.9], P<0.0001), behind bare metal stents (BMS) (18.5 [13.2, 23.8] to 12.0 [6.7, 17.3], P<0.0001), and within distal references (3.1 [1.1, 5.1] to 2.2 [0.2, 4.1], P=0.02). There was a greater calcium increase in attenuated than nonattenuated plaques in both PES (Deltacalcium score of 4.4 [3.3, 5.5] versus 1.6 [0.9, 2.3], P<0.0001) and BMS (Deltacalcium score of 4.1[2.3, 5.9] versus 1.0 [0.3, 1.7], P=0.001). PES implantation into attenuated plaques was particularly associated with late acquired stent malapposition (36.8% versus 15.4% compared with nonattenuated plaques treated with PES, P=0.03). Changes in attenuation scores correlated with changes in calcium scores both in PES (Pearson correlation coefficient=-0.456, P<0.0001] and BMS sites (Pearson correlation coefficient=-0.450, P=0.0006). In 3 years of follow-up, target lesion revascularization was significantly less in patients with attenuated plaque at baseline (6.0% versus 17.4% in patient without attenuated plaques, P=0.019). CONCLUSIONS: Attenuated plaques evolved into calcified plaques after stent implantation. Attenuated plaque is associated with late acquired stent malapposition and related less target lesion revascularization (consistent with less neointimal hyperplasia), especially after PES implantation in patients with acute myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966. PMID- 22438430 TI - Periprocedural myocardial infarction in a randomized trial of everolimus-eluting and Paclitaxel-eluting coronary stents: frequency and impact on mortality according to historic versus universal definitions. AB - BACKGROUND: A consensus definition for periprocedural myocardial infarction (MI) in coronary stent trials has not been established. Differences between a historic definition, based on modified World Health Organization (WHO) criteria, and a proposed universal definition have not been compared in a prospective clinical trial. METHODS AND RESULTS: We randomly assigned 3687 patients with stable coronary artery disease to undergo stenting with either everolimus-eluting stents (2458 patients) or paclitaxel-eluting stents (1229 patients). Serial creatine kinase (CK) and CKMB or troponin measurements were obtained before and after stenting. MI was classified by protocol according to the WHO definition (total CK >2* normal with elevated CKMB) and post hoc according to the Universal/Academic Research Consortium (ARC) definition (CKMB or troponin >3* normal). Protocol MI was determined in 58 (1.6%) and universal/ARC MI in 287 (7.8%) patients within 48 hours post index procedure. There were substantial differences in frequency of universal/ARC MI if only CKMB (5.4%) or troponin (18.7%) data were included for evaluation. Total stent length was a strong predictor of both protocol and universal/ARC MI. Mortality at 2 years was low (2.3%) and was not different for either MI definition. The mortality rates did not increase with elevations of CKMB or troponin to >10* normal. CONCLUSIONS: There was a marked difference in periprocedural MI rates according to protocol or universal/ARC MI definitions. No association was present between periprocedural MI and mortality up to 2 years by either definition. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00307047. PMID- 22438431 TI - Sources of hospital variation in short-term readmission rates after percutaneous coronary intervention. AB - BACKGROUND: Risk-standardized all-cause 30-day readmission rates (RSRRs) after percutaneous coronary intervention (PCI) have been endorsed as a national measure of hospital quality. Little is known about variation in the performance of hospitals on this measure, and whether high hospital rates of readmission after PCI are due to modifiable deficiencies in quality of care has not been assessed. METHODS AND RESULTS: We estimated 30-day, all-cause RSRRs for all nonfederal PCI performing hospitals in Massachusetts, adjusted for clinical and angiographic variables, between 2005 and 2008. We assessed if differences in race, insurance type, and PCI and post-PCI characteristics, including procedural complications and discharge characteristics, could explain variation between hospitals using nested hierarchical logistic regression models. Of 36 060 patients undergoing PCI at 24 hospitals and surviving to discharge, 4469 (12.4%) were readmitted within 30 days of discharge. Hospital RSRRs ranged from 9.5% to 17.9%, with 8 of 24 hospitals being identified as outliers (4 lower than expected and 4 higher than expected). Differences in race, insurance, PCI, and post-PCI factors accounted for 10.4% of the between-hospital variance in RSRRs. CONCLUSIONS: We observed wide variation in hospital 30-day all-cause RSRRs after PCI, most of which could not be explained by identifiable differences in procedural and postprocedural factors. A better understanding of etiologies of hospital variation is necessary to determine whether this measure is an actionable assessment of hospital quality, and, if so, how hospitals might improve their performance. PMID- 22438432 TI - Prediction of optimal deployment projection for transcatheter aortic valve replacement: angiographic 3-dimensional reconstruction of the aortic root versus multidetector computed tomography. AB - BACKGROUND: Identifying the optimal fluoroscopic projection of the aortic valve is important for successful transcatheter aortic valve replacement (TAVR). Various imaging modalities, including multidetector computed tomography (MDCT), have been proposed for prediction of the optimal deployment projection. We evaluated a method that provides 3-dimensional angiographic reconstructions (3DA) of the aortic root for prediction of the optimal deployment angle and compared it with MDCT. METHODS AND RESULTS: Forty patients undergoing transfemoral TAVR at St Paul's Hospital, Vancouver, Canada, were evaluated. All underwent preimplant 3DA and 68% underwent preimplant MDCT. Three-dimensional angiographic reconstructions were generated from images of a C-arm rotational aortic root angiogram during breath-hold, rapid ventricular pacing, and injection of 32 mL contrast medium at 8 mL/s. Two independent operators prospectively predicted perpendicular valve projections. The implant angle was chosen at the discretion of the physician performing TAVR. The angles from 3DA, from MDCT, the implant angle, and the postdeployment perpendicular prosthesis view were compared. The shortest distance from the postdeployment perpendicular prosthesis projection to the regression line of predicted perpendicular projections was calculated. All but 1 patient had adequate image quality for reproducible angle predictions. There was a significant correlation between 3DA and MDCT for prediction of perpendicular valve projections (r=0.682, P<0.001). Deviation from the regression line of predicted angles to the postdeployment prosthesis view was 5.1+/-4.6 degrees for 3DA and 7.9+/-4.9 degrees for MDCT (P=0.01). CONCLUSIONS: Three-dimensional angiographic reconstructions and MDCT are safe, practical, and accurate imaging modalities for identifying the optimal perpendicular valve deployment projection during TAVR. PMID- 22438433 TI - Antimicrobial prescribing in residential homes. AB - OBJECTIVES: Research in residential homes has been limited to date and the extent of systemic and topical antimicrobial prescribing is largely unknown. The aim of this study was to investigate antimicrobial prescribing in residential homes in Northern Ireland (NI). METHODS: Point prevalence studies (PPSs) were completed in November 2010 (PPS1) and April 2011 (PPS2) in 30 residential homes. Data were obtained from care plans, medication administration records and staff in relation to antimicrobial prescribing and facility and resident characteristics, and analysed descriptively. RESULTS: The point prevalence of systemic antimicrobial prescribing was 9.4% in PPS1 and 9.2% in PPS2 (range 0.0%-33.3% during both PPSs). Trimethoprim was the most commonly prescribed systemic antimicrobial and the main indication was the prevention of urinary tract infections. Almost 25% of systemic antimicrobials were prescribed at inappropriate doses. The point prevalence of topical antimicrobial prescribing was 6.4% (range 0.0%-22.2%) in PPS1 and 5.9% (range 0.0%-21.1%) in PPS2. The most commonly prescribed topical antimicrobials were chloramphenicol eye preparations in PPS1 and fusidic acid skin preparations in PPS2; treatment with these topical antimicrobials was generally prolonged. More than 25% of all systemic and 55% of all topical antimicrobials were initiated following telephone consultations as opposed to face-to-face consultations. CONCLUSIONS: The prevalence of systemic antimicrobial prescribing in residential homes in NI is relatively high compared with care homes (particularly nursing homes) in other countries. Systemic and topical antimicrobial prescribing is not always appropriate in terms of the doses prescribed and the duration of use. It is apparent that current strategies employed in NI are insufficient to ensure prudent antimicrobial prescribing within this environment. PMID- 22438434 TI - Prevalence of the oqxAB gene complex in Klebsiella pneumoniae and Escherichia coli clinical isolates. AB - OBJECTIVES: To investigate the epidemiology and genetic elements of the efflux pump gene, oqxAB, in clinical isolates of Escherichia coli and Klebsiella pneumoniae. METHODS: The prevalence of the oqxAB gene in a total of 308 consecutive clinical isolates of E. coli, K. pneumoniae and other Klebsiella spp. was investigated by PCR amplification. The full-length oqxAB gene was sequenced. Conjugation experiments were carried out in oqxAB-positive E. coli strains. RESULTS: Of 136 E. coli strains, 71.3% and 70.6% were non-susceptible to ciprofloxacin and levofloxacin, respectively, while 66.9% and 50.7% of the 154 K. pneumoniae were non-susceptible to these two quinolones. oqxA and oqxB were present in 6.6% of E. coli and in all K. pneumoniae strains. The oqxA and oqxB sequences of E. coli and randomly selected K. pneumoniae strains showed high similarity to the original oqxAB sequence of pOLA52. One or two amino acid substitutions were detected in the OqxA or OqxB sequences from two E. coli strains and were designated oqxA2, oqxB2 and oqxB3. oqxAB was transferred in seven of nine oqxAB-positive E. coli strains, and transconjugants showed 2- to 256-fold increases in ciprofloxacin and levofloxacin MICs relative to that for the recipient. CONCLUSIONS: Variants of the oqxAB gene, oqxA2, oqxB2 and oqxB3, were identified in two E. coli strains. The oqxAB gene was present in all K. pneumoniae strains studied and is likely located on the chromosome, thus identifying the genome of K. pneumoniae as a possible reservoir of oqxAB. PMID- 22438435 TI - Emergence of NDM-1-producing Enterobacteriaceae in China. PMID- 22438436 TI - Reduced expression of PBP-2A by neonatal mecA-positive coagulase-negative staphylococci (CoNS) blood isolates: beta-lactams are useful first-line agents for the treatment of neonatal CoNS sepsis, restricting the use of vancomycin. AB - OBJECTIVES: Vancomycin use for neonatal coagulase-negative staphylococci (CoNS) sepsis is based on a high CoNS carriage rate of mecA, encoding penicillin-binding protein (PBP)-2a, with low affinity for, and associated with resistance to, beta lactam antibiotics. The relationship between mecA gene carriage, phenotypic expression of the gene by PBP-2a production and in vitro resistance to the beta lactam antibiotics oxacillin, cefazolin and amoxicillin/clavulanate was determined for 85 CoNS blood isolates randomly obtained from our collection of isolates from neonates with CoNS sepsis. METHODS: The relationship between mecA gene carriage, phenotypic expression of the gene by PBP-2a production and in vitro resistance to the beta-lactam antibiotics oxacillin, cefazolin and amoxicillin/clavulanate was determined for randomly obtained CoNS blood isolates from our collection of isolates from neonates with CoNS sepsis. The mecA gene was detected using multiplex PCR, and PBP-2a expression was determined using a latex agglutination (LA) test (Oxoid). beta-Lactam susceptibility was determined using the Phoenix automated system and, in addition, by Etest with interpretation of MIC values according to the reference MIC breakpoints adopted from the CLSI guidelines M100-S20, InfobaseTM. RESULTS: Among 85 CoNS blood isolates, 73 (86%) were mecA positive and 12 (14%) were mecA negative. None of the mecA-negative isolates expressed PBP-2a and all were beta-lactam susceptible. All mecA-positive CoNS isolates were oxacillin resistant, although most oxacillin MICs were not very high, ranging from 2 to 8 mg/L for the majority of isolates. Only 8/73 (11%) mecA-positive CoNS isolates had oxacillin MICs >=32 mg/L (range 32 to >256 mg/L). mecA-positive CoNS blood isolates, although fully resistant to oxacillin, were almost universally susceptible to cefazolin and amoxicillin/clavulanate, which was associated with a low expression rate of PBP-2a. CONCLUSIONS: beta-Lactam antibiotics are useful for the treatment of neonatal CoNS sepsis, reserving vancomycin for selected cases. PMID- 22438437 TI - Increasing incidence of Escherichia coli bacteraemia is driven by an increase in antibiotic-resistant isolates: electronic database study in Oxfordshire 1999 2011. AB - OBJECTIVES: To investigate trends in Escherichia coli resistance, bacteraemia rates and post-bacteraemia outcomes over time. METHODS: Trends in E. coli bacteraemia incidence were monitored from January 1999 to June 2011 using an infection surveillance database including microbiological, clinical risk factor, infection severity and outcome data in Oxfordshire, UK, with imported temperature/rainfall data. RESULTS: A total of 2240 E. coli (from 2080 patients) were studied, of which 1728 (77%) were susceptible to co-amoxiclav, cefotaxime, ciprofloxacin and gentamicin. E. coli bacteraemia incidence increased from 3.4/10,000 bedstays in 1999 to 5.7/10,000 bedstays in 2011. The increase was fastest around 2006, and was essentially confined to organisms resistant to ciprofloxacin, co-amoxiclav, cefotaxime and/or aminoglycosides. Resistant E. coli isolation rates increased similarly in those with and without recent hospital contact. The sharp increase also occurred in urinary isolates, with similar timing. In addition to these long-term trends, increases in ambient temperature, but not rainfall, were associated with increased E. coli bacteraemia rates. It is unclear whether resistant E. coli bacteraemia rates are currently still increasing [incidence rate ratio = 1.07 per annum (95% CI = 0.99-1.16), P = 0.07], whereas current susceptible E. coli bacteraemia rates are not changing significantly [incidence rate ratio = 1.01 (95% CI = 0.99-1.02)]. However, neither mortality nor biomarkers associated with mortality (blood creatinine, urea/albumin concentrations, neutrophil counts) changed during the study. CONCLUSIONS: E. coli bacteraemia rates have risen due to rising rates of resistant organisms; little change occurred in susceptible E. coli. Although the severity of resistant infections, and their outcome, appear similar to susceptible E. coli in the setting studied, the increasing burden of highly resistant organisms is alarming and merits on-going surveillance. PMID- 22438438 TI - Science to practice: imaging of cellular microparticles--magic dust or just dirt? PMID- 22438440 TI - Diffusion-weighted MR imaging in the head and neck. AB - Extracranial applications of diffusion-weighted (DW) magnetic resonance (MR) imaging are gaining increasing importance, including in head and neck radiology. The main indications for performing DW imaging in this relatively small but challenging region of the body are tissue characterization, nodal staging, therapy monitoring, and early detection of treatment failure by differentiating recurrence from posttherapeutic changes. Lower apparent diffusion coefficients (ADCs) have been reported in the head and neck region of adults and children for most malignant lesions, as compared with ADCs of benign lesions. For nodal staging, DW imaging has shown promise in helping detect lymph node metastases, even in small (subcentimeter) nodes with lower ADCs, as compared with normal or reactive nodes. Follow-up of early response to treatment is reflected in an ADC increase in the primary tumor and nodal metastases; whereas nonresponding lesions tend to reveal only a slight increase or even a decrease in ADC during follow-up. Optimization and standardization of DW imaging technical parameters, comparison of DW images with morphologic images, and increasing experience, however, are prerequisites for successful application of this challenging technique in the evaluation of various head and neck pathologic conditions. PMID- 22438439 TI - Osteoporosis imaging: state of the art and advanced imaging. AB - Osteoporosis is becoming an increasingly important public health issue, and effective treatments to prevent fragility fractures are available. Osteoporosis imaging is of critical importance in identifying individuals at risk for fractures who would require pharmacotherapy to reduce fracture risk and also in monitoring response to treatment. Dual x-ray absorptiometry is currently the state-of-the-art technique to measure bone mineral density and to diagnose osteoporosis according to the World Health Organization guidelines. Motivated by a 2000 National Institutes of Health consensus conference, substantial research efforts have focused on assessing bone quality by using advanced imaging techniques. Among these techniques aimed at better characterizing fracture risk and treatment effects, high-resolution peripheral quantitative computed tomography (CT) currently plays a central role, and a large number of recent studies have used this technique to study trabecular and cortical bone architecture. Other techniques to analyze bone quality include multidetector CT, magnetic resonance imaging, and quantitative ultrasonography. In addition to quantitative imaging techniques measuring bone density and quality, imaging needs to be used to diagnose prevalent osteoporotic fractures, such as spine fractures on chest radiographs and sagittal multidetector CT reconstructions. Radiologists need to be sensitized to the fact that the presence of fragility fractures will alter patient care, and these fractures need to be described in the report. This review article covers state-of-the-art imaging techniques to measure bone mineral density, describes novel techniques to study bone quality, and focuses on how standard imaging techniques should be used to diagnose prevalent osteoporotic fractures. PMID- 22438441 TI - Neoadjuvant chemotherapy in breast cancer: prediction of pathologic response with PET/CT and dynamic contrast-enhanced MR imaging--prospective assessment. AB - PURPOSE: To clarify whether fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging performed after two cycles of neoadjuvant chemotherapy (NAC) can be used to predict pathologic response in breast cancer. MATERIALS AND METHODS: Institutional human research committee approval and written informed consent were obtained. Accuracy after two cycles of NAC for predicting pathologic complete response (pCR) was examined in 142 women (mean age, 57 years: range, 43-72 years) with histologically proved breast cancer between December 2005 and February 2009. Quantitative PET/CT and DCE MR imaging were performed at baseline and after two cycles of NAC. Parameters of PET/CT and of blood flow and microvascular permeability at DCE MR were compared with pathologic response. Patients were also evaluated after NAC by using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on DCE MR measurements and European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in Solid Tumors (PERCIST) 1.0 based on PET/CT measurements. Multiple logistic regression analyses were performed to examine continuous variables at PET/CT and DCE MR to predict pCR, and diagnostic accuracies were compared with the McNemar test. RESULTS: Significant decrease from baseline of all parameters at PET/CT and DCE MR was observed after NAC. Therapeutic response was obtained in 24 patients (17%) with pCR and 118 (83%) without pCR. Sensitivity, specificity, and accuracy to predict pCR were 45.5%, 85.5%, and 82.4%, respectively, with RECIST and 70.4%, 95.7%, and 90.8%, respectively, with EORTC and PERCIST. Multiple logistic regression revealed three significant independent predictors of pCR: percentage maximum standardized uptake value (%SUV(max)) (odds ratio [OR], 1.22; 95% confidence interval [CI]: 1.11, 1.34; P < .0001), percentage rate constant (%k(ep)) (OR, 1.07; CI: 1.03, 1.12; P = .002), and percentage area under the time-intensity curve over 90 seconds (%AUC(90)) (OR, 1.04; CI: 1.01, 1.07; P = .048). When diagnostic accuracies are compared, PET/CT is superior to DCE MR for the prediction of pCR (%SUV(max) [90.1%] vs %kappa(ep) [83.8%] or %AUC(90) [76.8%]; P < .05). CONCLUSION: The sensitivities of %SUV(max) (66.7%), %k(ep) (51.7%), and %AUC(90) (50.0%) at (18)F-FDG PET/CT and DCE MR after two cycles of NAC are not acceptable, but the specificities (96.4%, 92.0%, and 95.2%, respectively) are high for stratification of pCR cases in breast cancer. PMID- 22438442 TI - Readout-segmented echo-planar imaging improves the diagnostic performance of diffusion-weighted MR breast examinations at 3.0 T. AB - PURPOSE: To qualitatively and quantitatively compare the diagnostic value of diffusion-weighted (DW) magnetic resonance (MR) imaging based on standard single shot echo-planar imaging and readout-segmented echo-planar imaging in patients with breast cancer at 3.0 T. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Forty-seven patients with 49 histopathologically verified lesions were included in this study. In all patients, DW imaging, with single-shot echo-planar imaging and readout-segmented echo-planar imaging with comparable imaging parameters, was performed with a 3.0 T MR imager. Two independent readers visually assessed image quality and lesion conspicuity, and image properties (ie, signal-to-noise ratio, contrast, geometric distortions) were quantified. Regions of interest were drawn in all lesions (28 malignant, 21 benign) and in the normal breast parenchyma to investigate differences in apparent diffusion coefficient (ADC). Diagnostic accuracy was calculated on the basis of an ADC threshold of 1.25 * 10(-3) mm(2)/sec. RESULTS: Each reader found a higher diagnostic accuracy for readout-segmented (96%) than for single-shot (90%) echo-planar imaging. The area under the curve for readout segmented echo-planar imaging (0.981) was significantly larger than for single shot echo-planar imaging (0.867) (P = .026). There was no significant difference in the ADC obtained by using either DW imaging method. Lesion conspicuity and image quality of readout-segmented echo-planar imaging were rated superior to those of single-shot echo-planar imaging (P < .001). Readout-segmented echo planar imaging reduced geometric distortions by a factor of three. CONCLUSION: DW imaging based on readout-segmented echo-planar imaging provided significantly higher image quality and lesion conspicuity than single-shot echo-planar imaging by reducing geometric distortions, image blurring, and artifact level with a clinical high-field-strength MR imager. Thereby, readout-segmented echo-planar imaging reached a higher diagnostic accuracy for the differentiation of benign and malignant breast lesions. PMID- 22438443 TI - Independent radiologic review in metastatic colorectal cancer: systematic review and meta-analysis. AB - PURPOSE: To perform a meta-analysis addressing evaluation bias in local radiologic assessment (LRA) of lesions when compared with independent radiologic review (IRR) in randomized controlled trials (RCTs) testing chemotherapy for metastatic colorectal cancer (CRC). MATERIALS AND METHODS: MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library, and Web sites for major medical meetings were searched for RCTs of chemotherapy for metastatic CRC that reported response evaluation by both LRA and IRR. The risk ratios (RRs) of response in the experimental (RR(exp)) and control (RR(cont)) arms were calculated (response rate in LRA divided by response rate in IRR) for each selected study. The ratio of RR of response was calculated (RR of response of LRA divided by RR of response of IRR). The random-effects model was applied. Meta-regression was used to examine the effect of study characteristics on outcomes. RESULTS: LRA and IRR results were concordant (13 studies; 7742 patients; ratio of RR of response = 0.97; 95% confidence interval [95% CI]: 0.90, 1.04; P = .35). However, LRA overestimated tumor response independently of therapy allocation (interaction test, P = .81) both in control (RR(cont), 1.163; 95% CI: 1.086, 1.246; P < .001) and experimental (RR(exp), 1.156; 95% CI: 1.093, 1.222; P < .001) therapies. Meta regression did not show any effect of trial characteristics on effects. CONCLUSION: LRA yields higher response rates in RCTs testing chemotherapy for metastatic CRC, although there was no sign of bias toward experimental therapy. The need for IRR to control evaluation bias must be reappraised. PMID- 22438444 TI - Hyperthermia in bone generated with MR imaging-controlled focused ultrasound: control strategies and drug delivery. AB - PURPOSE: To evaluate the feasibility of achieving image-guided drug delivery in bone by using magnetic resonance (MR) imaging-controlled focused ultrasound hyperthermia and temperature-sensitive liposomes. MATERIALS AND METHODS: Experiments were approved by the institutional animal care committee. Hyperthermia (43 degrees C, 20 minutes) was generated in 10-mm-diameter regions at a muscle-bone interface in nine rabbit thighs by using focused ultrasound under closed-loop temperature control with MR thermometry. Thermosensitive liposomal doxorubicin was administered systemically during heating. Heating uniformity and drug delivery were evaluated for control strategies with the temperature control image centered 10 mm (four rabbits) or 0 mm (five rabbits) from the bone. Simulations estimated temperature elevations in bone. Drug delivery was quantified by using the fluorescence of doxorubicin extracted from bone marrow and muscle and was compared between treated and untreated thighs by using the one-sided Wilcoxon signed rank test. RESULTS: With ultrasound focus and MR temperature control plane 0 mm and 10 mm from the bone interface, average target region temperatures were 43.1 degrees C and 43.3 degrees C, respectively; numerically estimated bone temperatures were 46.8 degrees C and 78.1 degrees C. The 10-mm offset resulted in thermal ablation; numerically estimated muscle temperature was 66.1 degrees C at the bone interface. Significant increases in doxorubicin concentration occurred in heated versus unheated marrow (8.2-fold, P = .002) and muscle (16.8-fold, P = .002). Enhancement occurred for 0- and 10-mm offsets, which suggests localized drug delivery in bone is possible with both hyperthermia and thermal ablation. CONCLUSION: MR imaging-controlled focused ultrasound can achieve localized hyperthermia in bone for image-guided drug delivery in bone with temperature-sensitive drug carriers. PMID- 22438445 TI - Detection of osteophytes and subchondral cysts in the knee with use of tomosynthesis. AB - PURPOSE: To evaluate the diagnostic performance of tomosynthesis in depicting osteophytes and subchondral cysts, with use of magnetic resonance (MR) imaging as the reference, and to test whether the lesions detected at radiography and tomosynthesis are associated with pain. MATERIALS AND METHODS: The study was approved by local institutional review board, and all subjects gave written informed consent. Forty subjects (80 knees) older than 40 years were recruited irrespective of knee pain or radiographic osteoarthritis. Knees were imaged with radiography, tomosynthesis, and MR imaging. Presence of osteophytes and subchondral cysts in four locations of tibiofemoral joint (medial and lateral femur and tibia) was recorded. Knee pain was assessed by using the Western Ontario and McMaster University pain subscale. RESULTS: MR imaging depicted 171 osteophytes and 51 subchondral cysts. Tomosynthesis had a higher sensitivity for osteophyte detection in left and right lateral femur (0.96 vs 0.75, P = .025, and 1.00 vs 0.71, P = .008, respectively), right medial femur (0.94 vs 0.72, P = .046), and right lateral tibia (1.00 vs 0.83, P = .046). For subchondral cyst detection, the sensitivity of tomosynthesis was 0.14-1.00 and that of radiography was 0.00-0.56. Both modalities had similar specificity for both lesions. Subjects with tomosynthesis-depicted osteophytes (odds ratio, 4.2-6.4; P = .001-.011) and medially located subchondral cysts (odds ratio, 6.7-17.8; P = .004-.03) were more likely to feel pain than those without. However, radiography-depicted osteophytes were more strongly associated with pain than were tomosynthesis-depicted osteophytes. CONCLUSION: Tomosynthesis depicted more osteophytes and subchondral cysts than did radiography. Subjects with tomosynthesis-depicted osteophytes and subchondral cysts were more likely to feel pain than those without such lesions. PMID- 22438446 TI - The role of demyelination in neuromyelitis optica damage: diffusion-tensor MR imaging study. AB - PURPOSE: To test the hypothesis that white matter damage in neuromyelitis optica (NMO) is more extensive than previously described and likely includes involvement of normal-appearing white matter and to explore by using diffusion-tensor (DT) imaging whether white matter lesions are not only related to wallerian degeneration but are also caused by demyelination. MATERIALS AND METHODS: Seventeen patients with NMO (mean age, 45 years; 14 women) were compared with 17 sex- and age-matched control subjects. The institutional review board approved the study, and all subjects gave written informed consent. In addition to conventional magnetic resonance imaging sequences, DT imaging was performed along 30 noncollinear directions by using a 1.5-T imager. For tract-based spatial statistics (TBSS) analysis, the white matter skeleton was created, and a permutation-based inference with 5000 permutations with a threshold of P less than .05 to enable the identification of abnormalities in fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) was used. Partial correlation was applied to identify whether the number of clinical relapses and disease duration were correlated with all TBSS parameters. RESULTS: TBSS showed multiple areas with significant FA decrease in patients with NMO, mainly located in the corona radiata, uncinate fasciculus, corpus callosum, optic radiation, internal and external capsules, and cerebral peduncles. The mean FA, RD, and AD in the abnormal voxels located on the corpus callosum were, respectively, 0.69 +/ 0.03 (standard deviation), 0.39 * 10(23) mm(2)/sec +/- 0.04, and 1.53 * 10(23) mm(2)/sec +/- 0.04 in patients with NMO compared with 0.75 +/- 0.02, 0.33 * 10(23) mm(2)/sec +/- 0.03, and 1.57 * 10(23) mm(2)/sec +/- 0.04 in control subjects (P < .0001, P < .0001, and P = .007, respectively). There was a highly significant inverse correlation between FA and RD (r = 20.976, P < .0001). CONCLUSION: The use of TBSS allowed the identification of extensive white matter damage in patients with NMO. Multiple white matter tracts were involved, including the pyramidal tract, optic radiation, and corpus callosum, likely related to both demyelination and wallerian degeneration. PMID- 22438447 TI - Radiology's value chain. AB - A diagnostic radiology value chain is constructed to define its main components, all of which are vulnerable to change, because digitization has caused disaggregation of the chain. Some components afford opportunities to improve productivity, some add value, while some face outsourcing to lower labor cost and to information technology substitutes, raising commoditization risks. Digital image information, because it can be competitive at smaller economies of scale, allows faster, differential rates of technological innovation of components, initiating a centralization-to-decentralization technology trend. Digitization, having triggered disaggregation of radiology's professional service model, may soon usher in an information business model. This means moving from a mind-set of "reading images" to an orientation of creating and organizing information for greater accuracy, faster speed, and lower cost in medical decision making. Information businesses view value chain investments differently than do small professional services. In the former model, producing a better business product will extend image interpretation beyond a radiologist's personal fund of knowledge to encompass expanding external imaging databases. A follow-on expansion with integration of image and molecular information into a report will offer new value in medical decision making. Improved interpretation plus new integration will enrich and diversify radiology's key service products, the report and consultation. A more robust, information-rich report derived from a "systems" and "computational" radiology approach will be facilitated by a transition from a professional service to an information business. Under health care reform, radiology will transition its emphasis from volume to greater value. Radiology's future brightens with the adoption of a philosophy of offering information rather than "reads" for decision making. Staunchly defending the status quo via turf wars is unlikely to constitute a forward-looking, competitive strategy. PMID- 22438448 TI - MR imaging of pulmonary embolism: diagnostic accuracy of contrast-enhanced 3D MR pulmonary angiography, contrast-enhanced low-flip angle 3D GRE, and nonenhanced free-induction FISP sequences. AB - PURPOSE: To evaluate relative detection of pulmonary embolism (PE) with standard bolus-triggered contrast-enhanced breath-hold magnetic resonance (MR) pulmonary angiography, contrast-enhanced recirculation-phase breath-hold low-flip angle three-dimensional (3D) gradient-echo (GRE), and nonenhanced free-induction cardiac- and respiratory-triggered true fast imaging with steady-state precession (FISP) MR sequences. MATERIALS AND METHODS: The study was HIPAA compliant and institutional review board approved. Twenty-two patients with a computed tomographic (CT) angiography diagnosis of PE underwent MR imaging within 48 hours of CT. MR included three complementary techniques: MR pulmonary angiography, 3D GRE, and triggered true FISP. Each sequence was analyzed separately by two independent reviewers who recorded presence of emboli in categorized pulmonary artery anatomic territories. CT angiography results were analyzed by a third independent reviewer, who retrospectively recorded presence of emboli using the same format; these results served as the reference standard. Sensitivity, specificity, and positive and negative predictive values for PE detection were calculated for each MR technique on a per-embolus basis, and 95% confidence intervals were calculated according to the efficient-score method. A two-sample t test was used to compare values among MR techniques. RESULTS: Sensitivities for PE detection were 55% for MR pulmonary angiography, 67% for triggered true FISP, and 73% for 3D GRE MR imaging. Combining all three MR sequences improved overall sensitivity to 84%. Specificity was 100% for all detection methods except for MR pulmonary angiography (one false-positive). Agreement between readers was high (kappa = 0.87). Embolus detection rates were lowest in the lingula branch for all MR sequences compared with remainder of the vascular territories (P = .07). CONCLUSION: There are complementary benefits to combining standard MR pulmonary angiography, 3D GRE, and triggered true FISP MR examinations for evaluation of PE. PMID- 22438449 TI - Internal growth of nonsolid lung nodules: radiologic-pathologic correlation. AB - PURPOSE: To determine whether computed tomographic (CT) attenuation values correlate with the histologic measurements of a lung cancer manifesting as a nonsolid nodule and to quantify the extent to which the tumor replaces the airspace within the nodule. MATERIALS AND METHODS: Informed consent was obtained to analyze images from CT and pathologic examination under an institutional review board-approved protocol. Fifteen patients who had undergone resection of nonsolid lung cancer were evaluated. On the basis of the CT attenuation values of nonsolid nodules, nonneoplastic lung, soft tissue, and air, the overall proportion of soft tissue in the nodule and nonneoplastic lung and the difference between these two measures were calculated. The analogous measures were obtained from a representative digitized histologic slide. The area of each nodule and the proportion of air within it were measured, and the proportion of soft tissue in the nodule and nonneoplastic lung and the difference between the two were calculated. The difference between the two proportions at CT and histologic examination are the proportions attributable to the cancer on the basis of CT and histologic examinations, respectively. Linear regression was performed to assess the relationship between these measures. RESULTS: The average proportions of soft tissue in the nodule at CT and histologic examination were 48% and 69%, respectively, and they showed significant correlation with each other (P = .02); in addition, each showed significant correlation with the attenuation of the nodule (P < .0001 and P = .02, respectively). The difference between the proportions of soft tissue in nodule and nonneoplastic lung at CT and histologic examination were 37% and 30%, respectively, and both were independent of the tumor diameter (P = .26 and P = .41). CONCLUSION: The proportion of soft tissue within a nonsolid nodule is correlated with attenuation at CT. This allows for measurement of change within the nodule. An increase of 100 HU in nodule attenuation represents an approximately 10% increase in tumor volume. PMID- 22438451 TI - Case 180: thoracic duct cyst. PMID- 22438452 TI - A possible anatomic explanation for inaccuracies in the derivation of pulmonary artery pressure, with thin-section CT, in interstitial lung fibrosis. PMID- 22438453 TI - The older, the better. PMID- 22438454 TI - Swedish two-county trial: total mortality data are needed. PMID- 22438455 TI - Hepatic artery stenosis after liver transplantation. PMID- 22438456 TI - Uncertainties in the measurement of lumbar spinal stenosis at MR imaging: are they clinically relevant? PMID- 22438457 TI - Diffusion-weighted MR volumetry for assessing the response of rectal cancer to combined radiation therapy with chemotherapy. PMID- 22438458 TI - The influence of measurement location on reliability of quantitative nailfold videocapillaroscopy in patients with SSc. AB - OBJECTIVES: Nailfold videocapillaroscopy is being increasingly used as a marker of SSc-related microvascular disease, including in response to treatment. However, it requires further validation. Our aim was to assess the inter observer, intra-observer and test-retest variability of semi-automated measurement of capillary features as well as of a manual density measurement. METHODS: All capillary apexes in images from 58 patients with SSc were marked up independently by two trained observers (inter-observer variability). The first observer then re-marked the images (intra-observer variability), and finally, the first observer marked up a second image of the same nailfold (test-retest). Mark up of capillaries was carried out on cropped mosaic images (cropped independently by the observers to a fixed width, to allow the same length of nail bed to be studied for each patient) and on whole mosaic images (examining the whole nail bed). RESULTS: Reproducibility of independently cropped mosaic images was poor and was due to the variation in the positioning of the cropped area. However, quantification of whole mosaic images was highly reproducible, e.g. for inter capillary distance, the intra-class correlation coefficient for inter-observer, intra-observer and test-retest reliability was 0.95, 0.98 and 0.90 (compared with 0.88, 0.79 and 0.89 for cropped mosaic images), respectively. Intra-observer limits of agreement for whole mosaic images were better than inter-observer reproducibility. CONCLUSION: Quantitative assessment of SSc-related change in nailfold capillaries is unreliable if examination of the same set of capillaries cannot be guaranteed. Conversely a wide-field, high-magnification system that allows visualization of the whole nail bed offers a highly reproducible approach for quantitative assessment and therefore has potential as an outcome measure. PMID- 22438459 TI - Open science and data sharing in clinical research: basing informed decisions on the totality of the evidence. PMID- 22438460 TI - The double-edged sword of open access to research data. PMID- 22438461 TI - Glucose, blood pressure, and cardiovascular risk. PMID- 22438462 TI - Hospital value-based purchasing: will Medicare's new policy exacerbate disparities? PMID- 22438463 TI - Observational comparative effectiveness research: comparative effectiveness and caveat emptor. PMID- 22438464 TI - Strengthening and opening up health research by sharing our raw data. PMID- 22438465 TI - The importance of clinical trial data sharing: toward more open science. PMID- 22438466 TI - Most important papers in health costs, cost-effectiveness, and resource utilization. AB - The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts (as selected by the Editor) that have published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, and general cardiology audience. The studies included in this article represent the most significant research in the area of health costs, cost-effectiveness, and resource utilization. PMID- 22438467 TI - Crowding follows the binding of relative position and orientation. AB - Crowding--the deleterious influence of clutter on object recognition--disrupts the identification of visual features as diverse as orientation, motion, and color. It is unclear whether this occurs via independent feature-specific crowding processes (preceding the feature binding process) or via a singular (late) mechanism tuned for combined features. To examine the relationship between feature binding and crowding, we measured interactions between the crowding of relative position and orientation. Stimuli were a target cross and two flanker crosses (each composed of two near-orthogonal lines), 15 degrees in the periphery. Observers judged either the orientation (clockwise/counterclockwise) of the near-horizontal target line, its position (up/down relative to the stimulus center), or both. For single-feature judgments, crowding affected position and orientation similarly: thresholds were elevated and responses biased in a manner suggesting that the target appeared more like the flankers. These effects were tuned for orientation, with near-orthogonal elements producing little crowding. This tuning allowed us to separate the predictions of independent (feature specific) and combined (singular) models: for an independent model, reduced crowding for one feature has no effect on crowding for other features, whereas a combined process affects either all features or none. When observers made conjoint judgments, a reduction of orientation crowding (by increasing target-flanker orientation differences) increased the rate of correct responses for both position and orientation, as predicted by our combined model. In contrast, our independent model incorrectly predicted a high rate of position errors, since the probability of positional crowding would be unaffected by changes in orientation. Thus, at least for these features, crowding is a singular process that affects bound position and orientation values in an all-or-none fashion. PMID- 22438468 TI - A common signal detection model accounts for both perception and discrimination of the watercolor effect. AB - Establishing the relation between perception and discrimination is a fundamental objective in psychophysics, with the goal of characterizing the neural mechanisms mediating perception. Here, we show that a procedure for estimating a perceptual scale based on a signal detection model also predicts discrimination performance. We use a recently developed procedure, Maximum Likelihood Difference Scaling (MLDS), to measure the perceptual strength of a long-range, color, filling-in phenomenon, the Watercolor Effect (WCE), as a function of the luminance ratio between the two components of its generating contour. MLDS is based on an equal variance, gaussian, signal detection model and yields a perceptual scale with interval properties. The strength of the fill-in percept increased 10-15 times the estimate of the internal noise level for a 3-fold increase in the luminance ratio. Each observer's estimated scale predicted discrimination performance in a subsequent paired-comparison task. A common signal detection model accounts for both the appearance and discrimination data. Since signal detection theory provides a common metric for relating discrimination performance and neural response, the results have implications for comparing perceptual and neural response functions. PMID- 22438469 TI - Genetic and environmental contributions to stability and change of sleep problems in toddlerhood. AB - OBJECTIVE: To examine genetic and environmental contributions to stability and change in sleep problems (SP) in early childhood. METHODS: The sample comprised over 300 twin pairs assessed at ages 2 and 3 years. Parents rated SP on the Sleep Problems subscale of the Child Behavior Checklist for ages 1.5-5 years. RESULTS: Longitudinal quantitative genetic analyses indicated that SP were genetically influenced at both ages. The stability of SP from ages 2 to 3 years was largely due to genetic factors common to both ages. Nonshared environmental influences displayed modest continuity across age. New genetic and nonshared environmental factors emerged at age 3 years. CONCLUSIONS: Genetic factors contribute to the stability in SP, whereas change is due to both genetic and nonshared environmental influences. Early interventions on SP and individualized treatments based on children's unique environmental experiences may be fruitful. PMID- 22438470 TI - Heat shock protein 25-enriched plasma transfusion preconditions the heart against doxorubicin-induced dilated cardiomyopathy in mice. AB - Extracellular heat shock proteins (eHsps) in the circulation have recently been found to activate both apoptotic and protective signaling in the heart. However, the role of eHsps in doxorubicin (Dox)-induced heart failure has not yet been studied. The objective of the present study was to determine how Dox affects circulating eHsp25 in blood plasma and how eHsp25 affects Dox-induced dilated cardiomyopathy. Wild-type mice [HSF-1(+/+)] were pretreated with 100 MUl of heterozygous heat shock factor-1 [HSF-1(+/-)] mouse plasma (which contained 4 fold higher eHsp25 compared with wild-type mice), HSF-1(+/+) plasma, or saline, before treatment with Dox (6 mg/kg). After 4 weeks of this treatment protocol, HSF-1(+/-) plasma-pretreated mice showed increased eHsp25 in plasma and improved cardiac function (percentage of fractional shortening 37.3 +/- 2.1 versus 26.4 +/ 4.0) and better life span (31 +/- 2 versus 22 +/- 3 days) compared with the HSF 1(+/+) plasma or saline-pretreated mice. Preincubation of isolated adult cardiomyocytes with HSF-1(+/-) plasma or recombinant human Hsp27 (rhHsp27) significantly reduced Dox-induced activation of nuclear factor-kappaB and cytokine release and delayed cardiomyocyte death. Moreover, when cardiomyocytes were incubated with fluorescence-tagged rhHsp27, a saturation in binding was observed, suggesting that eHsp25 can bind to surface receptors. Competitive assays with a Toll-like receptor 2 (TLR2) antibody reduced the rhHSP27 binding, indicating that Hsp25 interacts with TLR2. In conclusion, transfusion of Hsp25 enriched blood plasma protected the heart from Dox-induced cardiotoxicity. Hsp25 antagonized Dox binding to the TLR2 receptor on cardiomyocytes. PMID- 22438471 TI - Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys. AB - This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the alpha4beta2 receptor-selective antagonist dihydro-beta-erythroidine (DHbetaE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHbetaE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHbetaE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHbetaE sensitive receptors (i.e., alpha4beta2) is unclear. The current nicotine discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has over behavior. PMID- 22438472 TI - Contribution of the extracellular cAMP-adenosine pathway to dual coupling of beta2-adrenoceptors to Gs and Gi proteins in mouse skeletal muscle. AB - beta(2)-Adrenoceptor (beta(2)-AR) agonists increase skeletal muscle contractile force via activation of G(s) protein/adenylyl cyclases (AC) and increased generation of cAMP. Herein, we evaluated the possible dual coupling of beta(2)-AR to G(s) and G(i) proteins and the influence of the beta(2)-AR/G(s)-G(i)/cAMP signaling cascade on skeletal muscle contraction. Assuming that the increment of intracellular cAMP is followed by cAMP efflux and extracellular generation of adenosine, the contribution of the extracellular cAMP-adenosine pathway on the beta(2)-AR inotropic response was also addressed. The effects of clenbuterol/fenoterol (beta(2)-AR agonists), forskolin (AC activator), cAMP/8 bromo-cAMP, and adenosine were evaluated on isometric contractility of mouse diaphragm muscle induced by supramaximal direct electrical stimulation (0.1 Hz, 2 ms duration). Clenbuterol/fenoterol (10-1000 MUM), 1 MUM forskolin, and 20 MUM rolipram induced transient positive inotropic effects that peaked 30 min after stimulation onset, declining to 10 to 20% of peak levels in 30 min. The late descending phase of the beta(2)-AR agonist inotropic effect was mimicked by either cAMP or adenosine and abolished by preincubation of diaphragm with pertussis toxin (PTX) (G(i) signaling inhibitor) or the organic anion transporter inhibitor probenecid, indicating a delayed coupling of beta(2)-AR to G(i) protein which depends on cAMP efflux. Remarkably, the PTX-sensitive beta(2)-AR inotropic effect was inhibited by the A(1) adenosine receptor antagonist 8-cyclopentyl-1,3 dipropylxanthine and ecto-5'-phosphodiesterase inhibitor alpha,beta methyleneadenosine 5'-diphosphate sodium salt, indicating that beta(2)-AR coupling to G(i) is indirect and dependent on A(1) receptor activation. The involvement of the extracellular cAMP-adenosine pathway in beta(2)-AR signaling would provide a negative feedback loop that may limit stimulatory G protein coupled receptor positive inotropism and potential deleterious effects of excessive contractile response. PMID- 22438489 TI - Social learning of a communicative signal in captive chimpanzees. AB - The acquisition of linguistic competency from more experienced social partners is a fundamental aspect of human language. However, there is little evidence that non-human primates learn to use their vocalizations from social partners. Captive chimpanzees (Pan troglodytes) produce idiosyncratic vocal signals that are used intentionally to capture the attention of a human experimenter. Interestingly, not all apes produce these sounds, and it is unclear what factors explain this difference. We tested the hypothesis that these attention-getting (AG) sounds are socially learned via transmission between mothers and their offspring. We assessed 158 chimpanzees to determine if they produced AG sounds. A significant association was found between mother and offspring sound production. This association was attributable to individuals who were raised by their biological mother-as opposed to those raised by humans in a nursery environment. These data support the hypothesis that social learning plays a role in the acquisition and use of communicative vocal signals in chimpanzees. PMID- 22438490 TI - Dynamics of angiogenesis during murine retinal development: a coupled in vivo and in silico study. AB - The manner in which the superficial retinal vascular plexus (RVP) develops in neonatal wild-type mice is relatively well documented and poses an interesting challenge to the mathematical modelling community. Prior to birth, astrocyte sprouting and proliferation begin around the edge of the optic nerve head, and subsequent astrocyte migration in response to a chemotactic gradient of platelet derived growth factor (PDGF)-A results in the formation of a dense scaffold on the surface of the inner retina. Astrocytes express a variety of chemotactic and haptotactic proteins that subsequently induce endothelial cell sprouting and modulate growth of the RVP. An experimentally informed, two-dimensional hybrid partial differential equation-discrete model is derived to track the outward migration of individual astrocyte and endothelial tip cells in response to the appropriate biochemical cues. Blood perfusion is included throughout the development of the plexus, and the evolving retinal trees are allowed to adapt and remodel by means of several biological stimuli. The resulting wild-type in silico RVP structures are compared with corresponding experimental whole mounts taken at various stages of development, and agreement between the respective vascular morphologies is found to be excellent. Subsequent numerical predictions help elucidate some of the key biological processes underlying retinal development and demonstrate the potential of the virtual retina for the investigation of various vascular-related diseases of the eye. PMID- 22438491 TI - Planar covariation of limb elevation angles during bipedal walking in the Japanese macaque. AB - We investigated the planar covariation of lower limb segment elevation angles during bipedal walking in macaques to elucidate the mechanisms underlying the origin and evolution of the planar law in human walking. Two Japanese macaques and four adult humans walking on a treadmill were recorded, and the time course of the elevation angles at the thigh, shank and foot segments relative to the vertical axis were calculated. Our analyses indicated that the planar law also applies to macaque bipedal walking. However, planarity was much lower in macaques, and orientations of the plane differed between the two species because of differences in the foot elevation angle. The human foot is rigidly structured to form a longitudinal arch, whereas the macaque's foot is more flexible and bends at the midtarsal region in the stance phase. This difference in midfoot flexibility between the two species studied was the main source of the difference in the planar law. Thus, the evolution of a stable midfoot in early hominins may have preceded the acquisition of the strong planar intersegmental coordination and possibly facilitated the subsequent emergence of habitual bipedal walking in the human lineage. PMID- 22438492 TI - The benefit of being a social butterfly: communal roosting deters predation. AB - Aposematic passion-vine butterflies from the genus Heliconius form communal roosts on a nightly basis. This behaviour has been hypothesized to be beneficial in terms of information sharing and/or anti-predator defence. To better understand the adaptive value of communal roosting, we tested these two hypotheses in field studies. The information-sharing hypothesis was addressed by examining following behaviour of butterflies departing from natural roosts. We found no evidence of roost mates following one another to resources, thus providing no support for this hypothesis. The anti-predator defence hypothesis was tested using avian-indiscriminable Heliconius erato models placed singly and in aggregations at field sites. A significantly higher number of predation attempts were observed on solitary models versus aggregations of models. This relationship between aggregation size and attack rate suggests that communally roosting butterflies enjoy the benefits of both overall decreased attack frequency as well as a prey dilution effect. Communal roosts probably deter predators through collective aposematism in which aggregations of conspicuous, unpalatable prey communicate a more effective repel signal to predators. On the basis of our results, we propose that predation by birds is a key selective pressure maintaining Heliconius communal roosting behaviour. PMID- 22438493 TI - When should cuckolded males care for extra-pair offspring? AB - In socially monogamous species with bi-parental care, males suffer reduced reproductive success if their mate engages in extra-pair copulations (EPCs). One might therefore expect that males should refuse to care for a brood if they can detect that an EPC has occurred. Here, we use a game-theory model to study male brood care in the face of EPCs in a cooperatively breeding species in which offspring help to raise their (half-) siblings in their parents' next breeding attempt. We show that under certain conditions males are selected to care even for broods completely unrelated to themselves. This counterintuitive result arises through a form of pseudo-reciprocity, whereby surviving extra-pair offspring, when helping to rear their younger half-siblings, can more than compensate for the cost incurred by the male that raised them. We argue that similar effects may not be limited to cooperative breeders, but may arise in various contexts in which cooperation between (half-) siblings occurs. PMID- 22438494 TI - Specialization for underwater hearing by the tympanic middle ear of the turtle, Trachemys scripta elegans. AB - Turtles, like other amphibious animals, face a trade-off between terrestrial and aquatic hearing. We used laser vibrometry and auditory brainstem responses to measure their sensitivity to vibration stimuli and to airborne versus underwater sound. Turtles are most sensitive to sound underwater, and their sensitivity depends on the large middle ear, which has a compliant tympanic disc attached to the columella. Behind the disc, the middle ear is a large air-filled cavity with a volume of approximately 0.5 ml and a resonance frequency of approximately 500 Hz underwater. Laser vibrometry measurements underwater showed peak vibrations at 500-600 Hz with a maximum of 300 um s(-1) Pa(-1), approximately 100 times more than the surrounding water. In air, the auditory brainstem response audiogram showed a best sensitivity to sound of 300-500 Hz. Audiograms before and after removing the skin covering reveal that the cartilaginous tympanic disc shows unchanged sensitivity, indicating that the tympanic disc, and not the overlying skin, is the key sound receiver. If air and water thresholds are compared in terms of sound intensity, thresholds in water are approximately 20-30 dB lower than in air. Therefore, this tympanic ear is specialized for underwater hearing, most probably because sound-induced pulsations of the air in the middle ear cavity drive the tympanic disc. PMID- 22438495 TI - Assessing the potential for egg chemoattractants to mediate sexual selection in a broadcast spawning marine invertebrate. AB - In numerous species, egg chemoattractants play a critical role in guiding sperm towards unfertilized eggs (sperm chemotaxis). Until now, the known functions of sperm chemotaxis include increasing the effective target size of eggs, thereby promoting sperm-egg encounters, and facilitating species recognition. Here, we report that in the broadcast spawning mussel, Mytilus galloprovincialis, egg chemoattractants may play an unforeseen role in sexual selection by enabling sperm to effectively 'choose' between the eggs of different conspecific females. In an initial experiment, we confirmed that sperm chemotaxis occurs in M. galloprovincialis by showing that sperm are attracted towards unfertilized eggs when given the choice of eggs or no eggs in a dichotomous chamber. We then conducted two cross-classified mating experiments, each comprising the same individual males and females crossed in identical male * female combinations, but under experimental conditions that offered sperm 'no-choice' (each fertilization trial took place in a Petri dish and involved a single male and female) or a 'choice' of a female's eggs (sperm were placed in the centre of a dichotomous choice chamber and allowed to choose eggs from different females). We show that male-by-female interactions characterized fertilization rates in both experiments, and that there was remarkable consistency between patterns of sperm migration in the egg-choice experiment and fertilization rates in the no-choice experiment. Thus, sperm appear to exploit chemical cues to preferentially swim towards eggs with which they are most compatible during direct sperm-to-egg encounters. These results reveal that sperm differentially select eggs on the basis of chemical cues, thus exposing the potential for egg chemoattractants to mediate mate choice for genetically compatible partners. Given the prevalence of sperm chemotaxis across diverse taxa, our findings may have broad implications for sexual selection in other mating systems. PMID- 22438496 TI - Plankton reach new heights in effort to avoid predators. AB - The marine environment associated with the air-water interface (neuston) provides an important food source to pelagic organisms where subsurface prey is limited. However, studies on predator-prey interactions within this environment are lacking. Copepods are known to produce strong escape jumps in response to predators, but must contend with a low-Reynolds-number environment where viscous forces limit escape distance. All previous work on copepod interaction with predators has focused on a liquid environment. Here, we describe a novel anti predator behaviour in two neustonic copepod species, where individuals frequently exit the water surface and travel many times their own body length through air to avoid predators. Using both field recordings with natural predators and high speed laboratory recordings, we obtain detailed kinematics of this behaviour, and estimate energetic cost associated with this behaviour. We demonstrate that despite losing up to 88 per cent of their initial kinetic energy, copepods that break the water surface travel significantly further than those escaping underwater and successfully exit the perceptive field of the predator. This behaviour provides an effective defence mechanism against subsurface-feeding visual predators and the results provide insight into trophic interactions within the neustonic environment. PMID- 22438497 TI - Bioeconomic synergy between tactics for insect eradication in the presence of Allee effects. AB - Preventing the establishment of invading pest species can be beneficial with respect to averting future environmental and economic impacts and also in preventing the accumulation of control costs. Allee effects play an important role in the dynamics of newly established, low-density populations by driving small populations into self-extinction, making Allee effects critical in influencing outcomes of eradication efforts. We consider interactions between management tactics in the presence of Allee effects to determine cost-effective and time-efficient combinations to achieve eradication by developing a model that considers pesticide application, predator augmentation and mating disruption as control tactics, using the gypsy moth as a case study. Our findings indicate that given a range of constant expenditure levels, applying moderate levels of pesticides in conjunction with mating disruption increases the Allee threshold which simultaneously substantially decreases the time to eradication relative to either tactic alone. In contrast, increasing predation in conjunction with other tactics requires larger economic expenditures to achieve similar outcomes for the use of pesticide application or mating disruption alone. These results demonstrate the beneficial synergy that may arise from nonlinearities associated with the simultaneous application of multiple eradication tactics and offer new prospects for preventing the establishment of damaging non-native species. PMID- 22438498 TI - How do antigenically varying pathogens avoid cross-reactive responses to invariant antigens? AB - Pathogens such as trypanosomes and malaria use antigenic variation to evade immune responses and prolong the duration of infections. As pathogens typically express more than one antigen, even relatively rare conserved antigens might be expected to trigger cross-reactive immune responses capable of clearing the infection. We use simple mathematical models that explicitly consider the dynamic interplay between the replicating pathogen, immune responses to different antigens and immune exhaustion to explore how pathogens can escape the responses to both variable and invariant (conserved) antigens. Our results suggest two hypotheses. In the first, limited quantities of invariant antigens on each pathogen may lead to saturation in killing by cross-reactive responses. In the second, antigenic variation of the dominant antigens prolongs the duration of infection sufficiently to allow for exhaustion of the cross-reactive responses to subdominant, invariant epitopes prior to their being able to control the infection. These hypotheses make distinct predictions: the former predicts that cross-reactive responses will always be ineffective while the latter predicts that appropriately timed treatment could, by preventing exhaustion, lead to the generation of long-lasting protective cross-reactive immunity and thus act similarly to a vaccine. PMID- 22438499 TI - Perceived pattern regularity computed as a summary statistic: implications for camouflage. AB - Why do the equally spaced dots in figure 1 appear regularly spaced? The answer 'because they are' is naive and ignores the existence of sensory noise, which is known to limit the accuracy of positional localization. Actually, all the dots in figure 1 have been physically perturbed, but in the case of the apparently regular patterns to an extent that is below threshold for reliable detection. Only when retinal pathology causes severe distortions do regular grids appear perturbed. Here, we present evidence that low-level sensory noise does indeed corrupt the encoding of relative spatial position, and limits the accuracy with which observers can detect real distortions. The noise is equivalent to a Gaussian random variable with a standard deviation of approximately 5 per cent of the inter-element spacing. The just-noticeable difference in positional distortion between two patterns is smallest when neither of them is perfectly regular. The computation of variance is statistically inefficient, typically using only five or six of the available dots. PMID- 22438500 TI - A small cohort of Island Southeast Asian women founded Madagascar. AB - The settlement of Madagascar is one of the most unusual, and least understood, episodes in human prehistory. Madagascar was one of the last landmasses to be reached by people, and despite the island's location just off the east coast of Africa, evidence from genetics, language and culture all attests that it was settled jointly by Africans, and more surprisingly, Indonesians. Nevertheless, extremely little is known about the settlement process itself. Here, we report broad geographical screening of Malagasy and Indonesian genetic variation, from which we infer a statistically robust coalescent model of the island's initial settlement. Maximum-likelihood estimates favour a scenario in which Madagascar was settled approximately 1200 years ago by a very small group of women (approx. 30), most of Indonesian descent (approx. 93%). This highly restricted founding population raises the possibility that Madagascar was settled not as a large scale planned colonization event from Indonesia, but rather through a small, perhaps even unintended, transoceanic crossing. PMID- 22438501 TI - Individual plastic responses by males to rivals reveal mismatches between behaviour and fitness outcomes. AB - Plasticity in behaviour is of fundamental significance when environments are variable. Such plasticity is particularly important in the context of rapid changes in the socio-sexual environment. Males can exhibit adaptive plastic responses to variation in the overall level of reproductive competition. However, the extent of behavioural flexibility within individuals, and the degree to which rapidly changing plastic responses map onto fitness are unknown. We addressed this by determining the behaviour and fitness profiles of individual Drosophila melanogaster males subjected to up to three episodes of exposure to rivals or no rivals, in all combinations. Behaviour (mating duration) was remarkably sensitive to the level of competition and fully reversible, suggesting that substantial costs arise from the incorrect expression of even highly flexible behaviour. However, changes in mating duration matched fitness outcomes (offspring number) only in scenarios in which males experienced zero then high competition. Following the removal of competition, mating duration, but not offspring production, decreased to below control levels. This indicates that the benefit of increasing reproductive investment when encountering rivals may exceed that of decreasing investment when rivals disappear. Such asymmetric fitness benefits and mismatches with behavioural responses are expected to exert strong selection on the evolution of plasticity. PMID- 22438502 TI - Negotiation may lead selfish individuals to cooperate: the example of the collective vigilance game. AB - Game-theoretical models have been highly influential in behavioural ecology. However, these models generally assume that animals choose their action before observing the behaviour of their opponents while, in many natural situations, individuals in fact continuously react to the actions of others. A negotiation process then takes place and this may fundamentally influence the individual attitudes and the tendency to cooperate. Here, I use the classical model system of vigilance behaviour to demonstrate the consequences of such behavioural negotiation among selfish individuals, by predicting patterns of vigilance in a pair of animals foraging under threat of predation. I show that the game played by the animals and the resulting vigilance strategies take radically different forms, according to the way predation risk is shared in the pair. In particular, if predators choose their target at random, the prey respond by displaying moderate vigilance and taking turns scanning. By contrast, if the individual that takes flight later in an attack endures a higher risk of being targeted, vigilance increases and there is always at least one sentinel in the pair. Finally, when lagging behind its companion in fleeing from an attacker becomes extremely risky, vigilance decreases again and the animals scan simultaneously. PMID- 22438503 TI - Arrested embryonic development: a review of strategies to delay hatching in egg laying reptiles. AB - Arrested embryonic development involves the downregulation or cessation of active cell division and metabolic activity, and the capability of an animal to arrest embryonic development results in temporal plasticity of the duration of embryonic period. Arrested embryonic development is an important reproductive strategy for egg-laying animals that provide no parental care after oviposition. In this review, we discuss each type of embryonic developmental arrest used by oviparous reptiles. Environmental pressures that might have directed the evolution of arrest are addressed and we present previously undiscussed environmentally dependent physiological processes that may occur in the egg to bring about arrest. Areas for future research are proposed to clarify how ecology affects the phenotype of developing embryos. We hypothesize that oviparous reptilian mothers are capable of providing their embryos with a level of phenotypic adaptation to local environmental conditions by incorporating maternal factors into the internal environment of the egg that result in different levels of developmental sensitivity to environmental conditions after they are laid. PMID- 22438504 TI - Noise pollution alters ecological services: enhanced pollination and disrupted seed dispersal. AB - Noise pollution is a novel, widespread environmental force that has recently been shown to alter the behaviour and distribution of birds and other vertebrates, yet whether noise has cumulative, community-level consequences by changing critical ecological services is unknown. Herein, we examined the effects of noise pollution on pollination and seed dispersal and seedling establishment within a study system that isolated the effects of noise from confounding stimuli common to human-altered landscapes. Using observations, vegetation surveys and pollen transfer and seed removal experiments, we found that effects of noise pollution can reverberate through communities by disrupting or enhancing these ecological services. Specifically, noise pollution indirectly increased artificial flower pollination by hummingbirds, but altered the community of animals that prey upon and disperse Pinus edulis seeds, potentially explaining reduced P. edulis seedling recruitment in noisy areas. Despite evidence that some ecological services, such as pollination, may benefit indirectly owing to noise, declines in seedling recruitment for key-dominant species such as P. edulis may have dramatic long-term effects on ecosystem structure and diversity. Because the extent of noise pollution is growing, this study emphasizes that investigators should evaluate the ecological consequences of noise alongside other human-induced environmental changes that are reshaping human-altered landscapes worldwide. PMID- 22438505 TI - Influence of false-positive mammography results on subsequent screening: do physician recommendations buffer negative effects? AB - OBJECTIVE: Cancer screening guidelines often include discussion about the unintended negative consequences of routine screening. This prospective study examined effects of false-positive mammography results on women's adherence to subsequent breast cancer screening and psychological well-being. We also assessed whether barriers to screening exacerbated the effects of false-positive results. METHODS: We conducted secondary analyses of data from telephone interviews and medical claims records for 2406 insured women. The primary outcome was adherence to screening guidelines, defined as adherent (10-14 months), delayed (15-34 months), or no subsequent mammogram on record. RESULTS: About 8% of women reported that their most recent screening mammograms produced false-positive results. In the absence of self-reported advice from their physicians to be screened, women were more likely to have no subsequent mammograms on record if they received false-positive results than if they received normal results (18% vs. 7%, OR = 3.17, 95% CI = 1.30, 7.70). Receipt of false-positive results was not associated with this outcome for women who said their physicians had advised regular screening in the past year (7% vs. 10%, OR = 0.74, 95% CI = 0.38, 1.45). False-positive results were associated with greater breast cancer worry (P < .01), thinking more about the benefits of screening (P < .001), and belief that abnormal test results do not mean women have cancer (P < .01), regardless of physicians' screening recommendations. CONCLUSION: False-positive mammography results, coupled with reports that women's physicians did not advise regular screening, could lead to non-adherence to future screening. Abnormal mammograms that do not result in cancer diagnoses are opportunities for physicians to stress the importance of regular screening. PMID- 22438506 TI - Dry self-sampling versus provider-sampling of cervicovaginal specimens for human papillomavirus detection in the Inuit population of Nunavik, Quebec. AB - OBJECTIVE: To assess the comparability of self-collected cervicovaginal samples and provider-collected cervical samples for the detection of human papillomavirus (HPV) DNA among Inuit women in Nunavik, Quebec, avoiding the use of liquid-based storage and transport of the self-collected samples. METHODS: Ninety-three women aged 18-69 years were recruited from a previously formed cohort on the natural history of HPV to this cross-sectional measurement study. This study utilized HPV DNA test results from 89 paired specimens collected by study participant and health provider with Dacron swabs. Samples were tested for 36 HPV types with the PGMY-primer PCR protocol and genotyping with the linear array method. Unweighted kappa statistics and McNemar tests were used to measure the agreement between sampling techniques. RESULTS: In the self-collected samples, 30 different HPV types were found, compared with 29 types found in the provider-collected samples. The prevalence of high-risk (HR) HPV was 38.2% in the self-collected samples and 28.1% in the provider-collected samples. The agreement between collection methods for the detection of HR-HPV DNA (85.4%) was good. HR-HPV and type-specific HPV 16/18 were as likely to be detected in the self-collected samples compared with the provider-obtained samples. CONCLUSIONS: Women in this population were easily able to collect adequate cervicovaginal specimens for HPV testing. As self sampling has a high recovery of HR-HPV and is comparable with provider-sampling, we conclude that self-sampling with dry storage and transport could be a good cervical cancer screening alternative for Inuit women in Nunavik who have traditionally avoided speculum examination. PMID- 22438507 TI - Postpartum maternal death associated with undiagnosed Hodgkin's lymphoma. AB - The authors describe the case of a 28-year-old patient who died from an extensive intracerebral haemorrhage due to disseminated intravascular coagulation (DIC) which occurred a few days after delivery. Access to an emergency department of gynaecology on three separate occasions in the three days preceding hospitalization made judicial evaluation of the case necessary. The case was studied with a methodological approach based on the following steps: (1) examination of clinical records; (2) autopsy; (3) study of the placenta; (4) anatomo-histopathological observations concerning particular organs and structures potentially involved in postpartum maternal death; and (5) evaluation of physicians' behaviour, in the light of necroscopic findings and a review of the literature. The causes of death most frequently described in the postpartum period were excluded; a mediastinal nodular sclerosing Hodgkin's lymphoma with transdiaphragmatic diffusion, not diagnosed in life, was demonstrated. The cause of death was identified as intracerebral haemorrhage following DIC, Hodgkin's disease and recent delivery by caesarean section. Analysis of the physicians' conduct, together with a review of the literature, revealed a medical error. However, no causal relationship between the error and the death of the patient was considered to exist. The interest of the case lies in the unusual cause of DIC discussed in relation to a hypothesis of obstetric-gynaecological liability. PMID- 22438508 TI - A discriminative model of motion and cross ratio for view-invariant action recognition. AB - Action recognition is very important for many applications such as video surveillance, human-computer interaction, and so on; view-invariant action recognition is hot and difficult as well in this field. In this paper, a new discriminative model is proposed for video-based view-invariant action recognition. In the discriminative model, motion pattern and view invariants are perfectly fused together to make a better combination of invariance and distinctiveness. We address a series of issues, including interest point detection in image sequence, motion feature extraction and description, and view invariant calculation. First, motion detection is used to extract motion information from videos, which is much more efficient than traditional background modeling and tracking-based methods. Second, as for feature representation, we exact variety of statistical information from motion and view-invariant feature based on cross ratio. Last, in the action modeling, we apply a discriminative probabilistic model-hidden conditional random field to model motion patterns and view invariants, by which we could fuse the statistics of motion and projective invariability of cross ratio in one framework. Experimental results demonstrate that our method can improve the ability to distinguish different categories of actions with high robustness to view change in real circumstances. PMID- 22438509 TI - Gravity field and internal structure of Mercury from MESSENGER. AB - Radio tracking of the MESSENGER spacecraft has provided a model of Mercury's gravity field. In the northern hemisphere, several large gravity anomalies, including candidate mass concentrations (mascons), exceed 100 milli-Galileos (mgal). Mercury's northern hemisphere crust is thicker at low latitudes and thinner in the polar region and shows evidence for thinning beneath some impact basins. The low-degree gravity field, combined with planetary spin parameters, yields the moment of inertia C/MR(2) = 0.353 +/- 0.017, where M and R are Mercury's mass and radius, and a ratio of the moment of inertia of Mercury's solid outer shell to that of the planet of C(m)/C = 0.452 +/- 0.035. A model for Mercury's radial density distribution consistent with these results includes a solid silicate crust and mantle overlying a solid iron-sulfide layer and an iron rich liquid outer core and perhaps a solid inner core. PMID- 22438510 TI - Topography of the northern hemisphere of Mercury from MESSENGER laser altimetry. AB - Laser altimetry by the MESSENGER spacecraft has yielded a topographic model of the northern hemisphere of Mercury. The dynamic range of elevations is considerably smaller than those of Mars or the Moon. The most prominent feature is an extensive lowland at high northern latitudes that hosts the volcanic northern plains. Within this lowland is a broad topographic rise that experienced uplift after plains emplacement. The interior of the 1500-km-diameter Caloris impact basin has been modified so that part of the basin floor now stands higher than the rim. The elevated portion of the floor of Caloris appears to be part of a quasi-linear rise that extends for approximately half the planetary circumference at mid-latitudes. Collectively, these features imply that long wavelength changes to Mercury's topography occurred after the earliest phases of the planet's geological history. PMID- 22438511 TI - A sign-component-based framework for Chinese sign language recognition using accelerometer and sEMG data. AB - Identification of constituent components of each sign gesture can be beneficial to the improved performance of sign language recognition (SLR), especially for large-vocabulary SLR systems. Aiming at developing such a system using portable accelerometer (ACC) and surface electromyographic (sEMG) sensors, we propose a framework for automatic Chinese SLR at the component level. In the proposed framework, data segmentation, as an important preprocessing operation, is performed to divide a continuous sign language sentence into subword segments. Based on the features extracted from ACC and sEMG data, three basic components of sign subwords, namely the hand shape, orientation, and movement, are further modeled and the corresponding component classifiers are learned. At the decision level, a sequence of subwords can be recognized by fusing the likelihoods at the component level. The overall classification accuracy of 96.5% for a vocabulary of 120 signs and 86.7% for 200 sentences demonstrate the feasibility of interpreting sign components from ACC and sEMG data and clearly show the superior recognition performance of the proposed method when compared with the previous SLR method at the subword level. The proposed method seems promising for implementing large vocabulary portable SLR systems. PMID- 22438512 TI - Regression-based cardiac motion prediction from single-phase CTA. AB - State of the art cardiac computed tomography (CT) enables the acquisition of imaging data of the heart over the entire cardiac cycle at concurrent high spatial and temporal resolution. However, in clinical practice, acquisition is increasingly limited to 3-D images. Estimating the shape of the cardiac structures throughout the entire cardiac cycle from a 3-D image is therefore useful in applications such as the alignment of preoperative computed tomography angiography (CTA) to intra-operative X-ray images for improved guidance in coronary interventions. We hypothesize that the motion of the heart is partially explained by its shape and therefore investigate the use of three regression methods for motion estimation from single-phase shape information. Quantitative evaluation on 150 4-D CTA images showed a small, but statistically significant, increase in the accuracy of the predicted shape sequences when using any of the regression methods, compared to shape-independent motion prediction by application of the mean motion. The best results were achieved using principal component regression resulting in point-to-point errors of 2.3+/-0.5 mm, compared to values of 2.7+/-0.6 mm for shape-independent motion estimation. Finally, we showed that this significant difference withstands small variations in important parameter settings of the landmarking procedure. PMID- 22438513 TI - Formulating spatially varying performance in the statistical fusion framework. AB - To date, label fusion methods have primarily relied either on global [e.g., simultaneous truth and performance level estimation (STAPLE), globally weighted vote] or voxelwise (e.g., locally weighted vote) performance models. Optimality of the statistical fusion framework hinges upon the validity of the stochastic model of how a rater errs (i.e., the labeling process model). Hitherto, approaches have tended to focus on the extremes of potential models. Herein, we propose an extension to the STAPLE approach to seamlessly account for spatially varying performance by extending the performance level parameters to account for a smooth, voxelwise performance level field that is unique to each rater. This approach, Spatial STAPLE, provides significant improvements over state-of-the-art label fusion algorithms in both simulated and empirical data sets. PMID- 22438514 TI - Multiclass Imbalance Problems: Analysis and Potential Solutions. AB - Class imbalance problems have drawn growing interest recently because of their classification difficulty caused by the imbalanced class distributions. In particular, many ensemble methods have been proposed to deal with such imbalance. However, most efforts so far are only focused on two-class imbalance problems. There are unsolved issues in multiclass imbalance problems, which exist in real world applications. This paper studies the challenges posed by the multiclass imbalance problems and investigates the generalization ability of some ensemble solutions, including our recently proposed algorithm AdaBoost.NC, with the aim of handling multiclass and imbalance effectively and directly. We first study the impact of multiminority and multimajority on the performance of two basic resampling techniques. They both present strong negative effects. "Multimajority" tends to be more harmful to the generalization performance. Motivated by the results, we then apply AdaBoost.NC to several real-world multiclass imbalance tasks and compare it to other popular ensemble methods. AdaBoost.NC is shown to be better at recognizing minority class examples and balancing the performance among classes in terms of G-mean without using any class decomposition. PMID- 22438515 TI - A Comparison Study of Validity Indices on Swarm-Intelligence-Based Clustering. AB - Swarm intelligence has emerged as a worthwhile class of clustering methods due to its convenient implementation, parallel capability, ability to avoid local minima, and other advantages. In such applications, clustering validity indices usually operate as fitness functions to evaluate the qualities of the obtained clusters. However, as the validity indices are usually data dependent and are designed to address certain types of data, the selection of different indices as the fitness functions may critically affect cluster quality. Here, we compare the performances of eight well-known and widely used clustering validity indices, namely, the Calinski-Harabasz index, the CS index, the Davies-Bouldin index, the Dunn index with two of its generalized versions, the I index, and the silhouette statistic index, on both synthetic and real data sets in the framework of differential-evolution-particle-swarm-optimization (DEPSO)-based clustering. DEPSO is a hybrid evolutionary algorithm of the stochastic optimization approach (differential evolution) and the swarm intelligence method (particle swarm optimization) that further increases the search capability and achieves higher flexibility in exploring the problem space. According to the experimental results, we find that the silhouette statistic index stands out in most of the data sets that we examined. Meanwhile, we suggest that users reach their conclusions not just based on only one index, but after considering the results of several indices to achieve reliable clustering structures. PMID- 22438516 TI - Effect of particle size of hydroxyapatite nanoparticles on its biocompatibility. AB - Nano-particulate biomaterials have been used in clinical diagnosis and treatment, as drug carrier or in cosmetics because of their excellent performance properties. The toxicity and biocompatibility of nanoparticles (NPs), however, are always a focused concern for a doctor or a scientist. At present, there is almost no systemic evaluation standard or testing methods of safety for nanoparticles. In this study, two kinds of hydroxylapatite, (HAP) NPs with different particle sizes were selected. A number of biocompatibility tests in vivo or in vitro were conducted. They were cytotoxicity (MTT assay), genotoxicity (Ames, Mouse Lymphoma Mutagenesis Assay), and systemic toxicity (Acute and Subacute). The results indicated that, under the concentration of 100 mg/L, both HAP NPs could cause significant inhibition of cell growth. The size of NPs might have close tie with cell response. The mutagenic test in vitro was negative in this study. Histopathological findings showed that both kinds of HAP NPs could induce pseudotubercles in lung. Moreover, smaller size of nanoparticles resulted in a vacuolar degeneration of nephric tubule epithelium at 7 days post intraveneous injection. The results implied that the size of NPs might play an important role in the biocompatibility of the materials. The kidney might be the main organ of discharge of nanoparticles from body. PMID- 22438517 TI - Using and misusing statistics: what do we know about the effects of race on the impact of beta-blockers? PMID- 22438518 TI - Still at the drawing board: improving quality of life in heart failure. PMID- 22438519 TI - Heart allocation in the United States: intended and unintended consequences. PMID- 22438520 TI - Vitamin E supplementation and the risk of heart failure in women. AB - BACKGROUND: Oxidative stress may contribute to the development of heart failure (HF); however, an increased risk of HF has been observed with antioxidant therapy in secondary prevention trials. No large clinical trials have addressed the role of antioxidant therapy in the primary prevention of HF. METHODS AND RESULTS: We examined the effect of vitamin E and HF risk in 39 815 initially healthy women, aged at least 45 years at baseline, who were enrolled in the Women's Health Study, a randomized, double-blind, placebo-controlled trial of vitamin E (600 IU every other day). Over a median follow-up of 10.2 years, there were 220 incident HF events. In proportional hazards models, adjusting for age and randomized aspirin and beta carotene treatment, vitamin E assignment did not significantly affect HF risk (hazards ratio [HR], 0.93; 95% CI, 0.71-1.21; P=0.59). These results did not change with multivariate adjustment for other risk factors, including interim myocardial infarction. In a prespecified subgroup analysis, vitamin E was inversely related to developing HF with normal ejection fraction (>=50%) with HR 0.59 (95% CI, 0.38-0.92; P=0.02), but there was no statistically significant effect on the risk of developing systolic HF (HR, 1.26; 95% CI, 0.84 1.89; P=0.26). CONCLUSIONS: In this population of apparently healthy women, vitamin E did not affect the overall risk of HF. The possible benefit on diastolic HF requires confirmation in larger populations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479. PMID- 22438522 TI - When to stop a clinical trial early for benefit: lessons learned and future approaches. PMID- 22438521 TI - Frailty and the selection of patients for destination therapy left ventricular assist device. PMID- 22438523 TI - Myocarditis associated with campylobacter enteritis: report of three cases. PMID- 22438524 TI - Constrictive pericarditis presenting as a late complication of epicardial ventricular tachycardia ablation. PMID- 22438525 TI - Acute heart failure from lyme carditis. PMID- 22438526 TI - Utilization of cardiac computed tomography angiography for the diagnosis of left ventricular assist device thrombosis. PMID- 22438527 TI - Constrictive pericarditis caused by immunoglobulin G4-related disease. PMID- 22438529 TI - Letter by moreno regarding article, "cost-effectiveness analysis of continuous flow left ventricular assist devices as destination therapy". PMID- 22438530 TI - Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. AB - BACKGROUND: The optimal duration of dual-antiplatelet therapy and the risk benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration-approved drug-eluting or bare metal stents. METHODS AND RESULTS: We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74-1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24 month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. CONCLUSIONS: A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286. PMID- 22438531 TI - Grabbing the horns of a dilemma: the duration of dual antiplatelet therapy after stent implantation. PMID- 22438532 TI - The second receptor binding site of the globular head of the Newcastle disease virus hemagglutinin-neuraminidase activates the stalk of multiple paramyxovirus receptor binding proteins to trigger fusion. AB - The hemagglutinin-neuraminidase (HN) protein of paramyxoviruses carries out three distinct activities contributing to the ability of HN to promote viral fusion and entry: receptor binding, receptor cleavage (neuraminidase), and activation of the fusion protein. The relationship between receptor binding and fusion triggering functions of HN are not fully understood. For Newcastle disease virus (NDV), one bifunctional site (site I) on HN's globular head can mediate both receptor binding and neuraminidase activities, and a second site (site II) in the globular head is also capable of mediating receptor binding. The receptor analog, zanamivir, blocks receptor binding and cleavage activities of NDV HN's site I while activating receptor binding by site II. Comparison of chimeric proteins in which the globular head of NDV HN is connected to the stalk region of either human parainfluenza virus type 3 (HPIV3) or Nipah virus receptor binding proteins indicates that receptor binding to NDV HN site II not only can activate its own fusion (F) protein but can also activate the heterotypic fusion proteins. We suggest a general model for paramyxovirus fusion activation in which receptor engagement at site II plays an active role in F activation. PMID- 22438533 TI - HIV-1 and HIV-2 reverse transcriptases: different mechanisms of resistance to nucleoside reverse transcriptase inhibitors. AB - As anti-HIV therapy becomes more widely available in developing nations, it is clear that drug resistance will continue to be a major problem. The related viruses HIV-1 and HIV-2 share many of the same resistance pathways to nucleoside reverse transcriptase inhibitors (NRTIs). However, clinical data suggest that while HIV-1 reverse transcriptase (RT) usually uses an ATP-dependent excision pathway to develop resistance to the nucleoside analog zidovudine (AZT), HIV-2 RT does not appear to use this pathway. We previously described data that suggested that wild-type (WT) HIV-2 RT has a much lower ability to excise AZT monophosphate (AZTMP) than does WT HIV-1 RT and suggested that this is the reason that HIV-2 RT more readily adopts an exclusion pathway against AZT triphosphate (AZTTP), while HIV-1 RT is better able to exploit the ATP-dependent pyrophosphorolysis mechanism. However, we have now done additional experiments, which show that while HIV-1 RT can adopt either an exclusion- or excision-based resistance mechanism against AZT, HIV-2 RT can use only the exclusion mechanism. All of our attempts to make HIV-2 RT excision competent did not produce an AZT-resistant RT but instead yielded RTs that were less able to polymerize than the WT. This suggests that the exclusion pathway is the only pathway available to HIV-2. PMID- 22438534 TI - Targeting of dicer-2 and RNA by a viral RNA silencing suppressor in Drosophila cells. AB - RNA interference (RNAi) is a eukaryotic gene-silencing mechanism that functions in antiviral immunity in diverse organisms. To combat RNAi-mediated immunity, viruses encode viral suppressors of RNA silencing (VSRs) that target RNA and protein components in the RNAi machinery. Although the endonuclease Dicer plays key roles in RNAi immunity, little is known about how VSRs target Dicer. Here, we show that the B2 protein from Wuhan nodavirus (WhNV), the counterpart of Flock House virus (FHV), suppresses Drosophila melanogaster RNAi by directly interacting with Dicer-2 (Dcr-2) and sequestering double-stranded RNA (dsRNA) and small interfering RNA (siRNA). Further investigations reveal that WhNV B2 binds to the RNase III and Piwi-Argonaut-Zwille (PAZ) domains of Dcr-2 via its C terminal region, thereby blocking the activities of Dcr-2 in processing dsRNA and incorporating siRNA into the RNA-induced silencing complex (RISC). Moreover, we uncover an interrelationship among diverse activities of WhNV B2, showing that RNA binding enhances the B2-Dcr-2 interaction by promoting B2 homodimerization. Taken together, our findings establish a model of suppression of Drosophila RNAi by WhNV B2 targeting both Dcr-2 and RNA and provide evidence that an interrelationship exists among diverse activities of VSRs to antagonize RNAi. PMID- 22438535 TI - Computational reconstruction of Bole1a, a representative synthetic hepatitis C virus subtype 1a genome. AB - Hepatitis C virus (HCV) research is hampered by the use of arbitrary representative isolates in cell culture and immunology. The most replicative isolate in vitro is a subtype 2a virus (JFH-1); however, genotype 1 is more prevalent worldwide and represents about 70% of infections in the United States, and genotypes differ from one another by 31% to 33% at the nucleotide level. For phylogenetic and immunologic analyses, viruses H77 and HCV-1 (both subtype 1a) are commonly used based on their historic importance. In an effort to rationally design a representative subtype 1a virus (Bole1a), we used Bayesian phylogenetics, ancestral sequence reconstruction, and covariance analysis on a curated set of 390 full-length human HCV 1a sequences from GenBank. By design, Bole1a contains variations present in widely circulating strains and matches more epitope-sized peptides in a full-genome comparison to subtype 1a isolates than any other sequence studied. Parallel analyses confirm that selected epitopes from the Bole1a genome were able to elicit a robust T cell response. In a proof of concept for infectivity, the envelope genes (E1 and E2) of Bole1a were expressed in an HIV pseudoparticle system containing HCV envelope genes and HIV nonenvelope genes with luciferase expression. The resulting Bole1a pseudoparticle robustly infected Hep3B cells. In this study, we demonstrate that a rationally designed, fully synthetic HCV genome contains representative epitopes and envelope genes that assemble properly and mediate entry into target cells. PMID- 22438536 TI - Hepatitis E virus replication requires an active ubiquitin-proteasome system. AB - The mechanism of hepatitis E virus (HEV) replication remains largely unknown. Here we demonstrate that HEV replication requires an active ubiquitin-proteasome system and that proteasome inhibitors affect HEV replication, possibly by inhibition of viral transcription or/and translation without a significant effect on cellular translation. Overexpression of ubiquitin in inhibitor-treated cells partially reverses the inhibitor effect on HEV replication. The results suggest that HEV replication requires interactions with proteasome machinery, which could be a potential therapeutic target against HEV. PMID- 22438537 TI - Suppression of injuries caused by a lytic RNA virus (mengovirus) and their uncoupling from viral reproduction by mutual cell/virus disarmament. AB - Viruses often elicit cell injury (cytopathic effect [CPE]), a major cause of viral diseases. CPE is usually considered to be a prerequisite for and/or consequence of efficient viral growth. Recently, we proposed that viral CPE may largely be due to host defensive and viral antidefensive activities. This study aimed to check the validity of this proposal by using as a model HeLa cells infected with mengovirus (MV). As we showed previously, infection of these cells with wild-type MV resulted in necrosis, whereas a mutant with incapacitated antidefensive ("security") viral leader (L) protein induced apoptosis. Here, we showed that several major morphological and biochemical signs of CPE (e.g., alterations in cellular and nuclear shape, plasma membrane, cytoskeleton, chromatin, and metabolic activity) in cells infected with L(-) mutants in the presence of an apoptosis inhibitor were strongly suppressed or delayed for long after completion of viral reproduction. These facts demonstrate that the efficient reproduction of a lytic virus may not directly require development of at least some pathological alterations normally accompanying infection. They also imply that L protein is involved in the control of many apparently unrelated functions. The results also suggest that the virus-activated program with competing necrotic and apoptotic branches is host encoded, with the choice between apoptosis and necrosis depending on a variety of intrinsic and extrinsic conditions. Implementation of this defensive suicidal program could be uncoupled from the viral reproduction. The possibility of such uncoupling has significant implications for the pathogenesis and treatment of viral diseases. PMID- 22438538 TI - Accumulation of autophagosomes in Semliki Forest virus-infected cells is dependent on expression of the viral glycoproteins. AB - Autophagy is a cellular process that sequesters cargo in double-membraned vesicles termed autophagosomes and delivers this cargo to lysosomes to be degraded. It is enhanced during nutrient starvation to increase the rate of amino acid turnover. Diverse roles for autophagy have been reported for viral infections, including the assembly of viral replication complexes on autophagic membranes and protection of host cells from cell death. Here, we show that autophagosomes accumulate in Semliki Forest virus (SFV)-infected cells. Despite this, disruption of autophagy had no effect on the viral replication rate or formation of viral replication complexes. Also, viral proteins rarely colocalized with autophagosome markers, suggesting that SFV did not utilize autophagic membranes for its replication. Further, we found that SFV infection, unlike nutrient starvation, did not inactivate the constitutive negative regulator of autophagosome formation, mammalian target of rapamycin, suggesting that SFV dependent accumulation of autophagosomes was not a result of enhanced autophagosome formation. In starved cells, addition of NH(4)Cl, an inhibitor of lysosomal acidification, caused a dramatic accumulation of starvation-induced autophagosomes, while in SFV-infected cells, NH(4)Cl did not further increase levels of autophagosomes. These results suggest that accumulation of autophagosomes in SFV-infected cells is due to an inhibition of autophagosome degradation rather than enhanced rates of autophagosome formation. Finally, we show that the accumulation of autophagosomes in SFV-infected cells is dependent on the expression of the viral glycoprotein spike complex. PMID- 22438539 TI - Evaluation of pneumonia virus of mice as a possible human pathogen. AB - Pneumonia virus of mice (PVM), a relative of human respiratory syncytial virus (RSV), causes respiratory disease in mice. There is serologic evidence suggesting widespread exposure of humans to PVM. To investigate replication in primates, African green monkeys (AGM) and rhesus macaques (n = 4) were inoculated with PVM by the respiratory route. Virus was shed intermittently at low levels by a subset of animals, suggesting poor permissiveness. PVM efficiently replicated in cultured human cells and inhibited the type I interferon (IFN) response in these cells. This suggests that poor replication in nonhuman primates was not due to a general nonpermissiveness of primate cells or poor control of the IFN response. Seroprevalence in humans was examined by screening sera from 30 adults and 17 young children for PVM-neutralizing activity. Sera from a single child (6%) and 40% of adults had low neutralizing activity against PVM, which could be consistent with increasing incidence of exposure following early childhood. There was no cross-reaction of human or AGM sera between RSV and PVM and no cross protection in the mouse model. In native Western blots, human sera reacted with RSV but not PVM proteins under conditions in which AGM immune sera reacted strongly. Serum reactivity was further evaluated by flow cytometry using unfixed Vero cells infected with PVM or RSV expressing green fluorescent protein (GFP) as a measure of viral gene expression. The reactivity of human sera against RSV infected cells correlated with GFP expression, whereas reactivity against PVM infected cells was low and uncorrelated with GFP expression. Thus, PVM specificity was not evident. Our results indicate that the PVM-neutralizing activity of human sera is not due to RSV- or PVM-specific antibodies but may be due to low-affinity, polyreactive natural antibodies of the IgG subclass. The absence of PVM-specific antibodies and restriction in nonhuman primates makes PVM unlikely to be a human pathogen. PMID- 22438540 TI - The PSAP motif within the ORF3 protein of an avian strain of the hepatitis E virus is not critical for viral infectivity in vivo but plays a role in virus release. AB - The ORF3 protein of hepatitis E virus (HEV) is a multifunctional protein important for virus replication. The ORF3 proteins from human, swine, and avian strains of HEV contain a conserved PXXP amino acid motif, resembling either Src homology 3 (SH3) cell signaling interaction motifs or "late domains" involved in host cell interactions aiding in particle release. Using an avian strain of HEV, we determined the roles of the conserved prolines within the PREPSAPP motif in HEV replication and infectivity in Leghorn male hepatoma (LMH) chicken liver cells and in chickens. Each proline was changed to alanine to produce 8 avian HEV mutants containing single mutations (P64, P67, P70, and P71 to A), double mutations (P64/67A, P64/70A, and P67/70A), and triple mutations (P64/67/70A). The results showed that avian HEV mutants are replication competent in vitro, and none of the prolines in the PXXPXXPP motif are essential for infectivity in vivo; however, the second and third prolines appear to aid in fecal virus shedding, suggesting that the PSAP motif, but not the PREP motif, is involved in virus release. We also showed that the PSAP motif interacts with the host protein tumor suppressor gene 101 (TSG101) and that altering any proline within the PSAP motif disrupts this interaction. However, we showed that the ORF2 protein expressed in LMH cells is efficiently released from the cells in the absence of ORF3 and that coexpression of ORF2 and ORF3 did not act synergistically in this release, suggesting that another factor(s) such as ORF1 or viral genomic RNA may be necessary for proper particle release. PMID- 22438541 TI - Cold-adapted pandemic 2009 H1N1 influenza virus live vaccine elicits cross reactive immune responses against seasonal and H5 influenza A viruses. AB - The rapid transmission of the pandemic 2009 H1N1 influenza virus (pH1N1) among humans has raised the concern of a potential emergence of reassortment between pH1N1 and highly pathogenic influenza strains, especially the avian H5N1 influenza virus. Here, we report that the cold-adapted pH1N1 live attenuated vaccine (CApH1N1) elicits cross-reactive immunity to seasonal and H5 influenza A viruses in the mouse model. Immunization with CApH1N1 induced both systemic and mucosal antibodies with broad reactivity to seasonal and H5 strains, including HAPI H5N1 and the avian H5N2 virus, providing complete protection against heterologous and heterosubtypic lethal challenges. Our results not only accentuate the merit of using live attenuated influenza virus vaccines in view of cross-reactivity but also represent the potential of CApH1N1 live vaccine for mitigating the clinical severity of infections that arise from reassortments between pH1N1 and highly pathogenic H5 subtype viruses. PMID- 22438542 TI - Visualizing coronavirus RNA synthesis in time by using click chemistry. AB - Coronaviruses induce in infected cells the formation of replicative structures, consisting of double-membrane vesicles (DMVs) and convoluted membranes, where viral RNA synthesis supposedly takes place and to which the nonstructural proteins (nsp's) localize. Double-stranded RNA (dsRNA), the presumed intermediate in RNA synthesis, is localized to the DMV interior. However, as pores connecting the DMV interior with the cytoplasm have not been detected, it is unclear whether RNA synthesis occurs at these same sites. Here, we studied coronavirus RNA synthesis by feeding cells with a uridine analogue, after which nascent RNAs were detected using click chemistry. Early in infection, nascent viral RNA and nsp's colocalized with or occurred adjacent to dsRNA foci. Late in infection, the correlation between dsRNA dots, then found dispersed throughout the cytoplasm, and nsp's and nascent RNAs was less obvious. However, foci of nascent RNAs were always found to colocalize with the nsp12-encoded RNA-dependent RNA polymerase. These results demonstrate the feasibility of detecting viral RNA synthesis by using click chemistry and indicate that dsRNA dots do not necessarily correspond with sites of active viral RNA synthesis. Rather, late in infection many DMVs may harbor dsRNA molecules that are no longer functioning as intermediates in RNA synthesis. PMID- 22438543 TI - Formation of orthopoxvirus cytoplasmic A-type inclusion bodies and embedding of virions are dynamic processes requiring microtubules. AB - In cells infected with some orthopoxviruses, numerous mature virions (MVs) become embedded within large, cytoplasmic A-type inclusions (ATIs) that can protect infectivity after cell lysis. ATIs are composed of an abundant viral protein called ATIp, which is truncated in orthopoxviruses such as vaccinia virus (VACV) that do not form ATIs. To study ATI formation and occlusion of MVs within ATIs, we used recombinant VACVs that express the cowpox full-length ATIp or we transfected plasmids encoding ATIp into cells infected with VACV, enabling ATI formation. ATI enlargement and MV embedment required continued protein synthesis and an intact microtubular network. For live imaging of ATIs and MVs, plasmids expressing mCherry fluorescent protein fused to ATIp were transfected into cells infected with VACV expressing the viral core protein A4 fused to yellow fluorescent protein. ATIs appeared as dynamic, mobile bodies that enlarged by multiple coalescence events, which could be prevented by disrupting microtubules. Coalescence of ATIs was confirmed in cells infected with cowpox virus. MVs were predominantly at the periphery of ATIs early in infection. We determined that coalescence contributed to the distribution of MVs within ATIs and that microtubule-disrupting drugs abrogated coalescence-mediated MV embedment. In addition, MVs were shown to move from viral factories at speeds consistent with microtubular transport to the peripheries of ATIs, whereas disruption of microtubules prevented such trafficking. The data indicate an important role for microtubules in the coalescence of ATIs into larger structures, transport of MVs to ATIs, and embedment of MVs within the ATI matrix. PMID- 22438544 TI - Murine noroviruses bind glycolipid and glycoprotein attachment receptors in a strain-dependent manner. AB - Human norovirus infections are the most common cause of acute nonbacterial gastroenteritis in humans worldwide, and glycan binding plays an important role in the susceptibility to these infections. However, due to the lack of an efficient cell culture system or small animal model for human noroviruses, little is known about the biological role of glycan binding during infection. Murine noroviruses (MNV) are also enteric viruses that bind to cell surface glycans, but in contrast to their human counterparts, they can be grown in tissue culture and a small animal host. In this study, we determined glycan-binding specificities of the MNV strains MNV-1 and CR3 in vitro, identified molecular determinants of glycan binding, and analyzed infection in vivo. We showed that unlike MNV-1, CR3 binding to murine macrophages was resistant to neuraminidase treatment and glycosphingolipid depletion. Both strains depended on N-linked glycoproteins for binding, while only MNV-1 attachment to macrophages was sensitive to O-linked glycoprotein depletion. In vivo, CR3 showed differences in tissue tropism compared to MNV-1 by replicating in the large intestine. Mapping of a glycan binding site in the MNV-1 capsid by reverse genetics identified a region topologically similar to the histo-blood group antigen (HBGA)-binding sites of the human norovirus strain VA387. The recombinant virus showed distinct changes in tissue tropism compared to wild-type virus. Taken together, our data demonstrate that MNV strains evolved multiple strategies to bind different glycan receptors on the surface of murine macrophages and that glycan binding contributes to tissue tropism in vivo. PMID- 22438545 TI - RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions. AB - Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts (UL55-57) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics. PMID- 22438546 TI - Human SCARB2-dependent infection by coxsackievirus A7, A14, and A16 and enterovirus 71. AB - Human enterovirus species A (HEV-A) consists of at least 16 members of different serotypes that are known to be the causative agents of hand, foot, and mouth disease (HFMD), herpangina, and other diseases, such as respiratory disease and polio-like flaccid paralysis. Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of HFMD. CVA5, CVA6, CVA10, and CVA12 mainly cause herpangina or are occasionally involved with sporadic cases of HFMD. We have previously shown that human scavenger receptor class B, member 2 (SCARB2) is a cellular receptor for EV71 and CVA16. Using a large number of clinical isolates of HEV-A, we explored whether all clinical isolates of EV71 and other serotypes of HEV-A infected cells via SCARB2. We tested this possibility by infecting L-SCARB2 cells, which are L929 cells expressing human SCARB2, by infecting human RD cells that had been treated with small interfering RNAs for SCARB2 and by directly binding the viruses to a soluble SCARB2 protein. We showed that all 162 clinical isolates of EV71 propagated in L-SCARB2 cells, suggesting that SCARB2 is the critical receptor common to all EV71 strains. In addition, CVA7, CVA14, and CVA16, which are most closely related to each other, also utilized SCARB2 for infection. EV71, CVA14, and CVA16 are highly associated with HFMD, and EV71 and CVA7 are occasionally associated with neurological diseases, suggesting that SCARB2 plays important roles in the development of these diseases. In contrast, another group of viruses, such as CVA2, CVA3, CVA4, CVA5, CVA6, CVA8, CVA10, and CVA12, which are relatively distant from the EV71 group, is associated mainly with herpangina. None of these clinical isolates infected via the SCARB2-dependent pathway. HEV-A viruses can be divided into at least two groups depending on the use of SCARB2, and the receptor usage plays an important role in developing the specific diseases for each group. PMID- 22438547 TI - Recombinant monoclonal antibody recognizes a unique epitope on varicella-zoster virus immediate-early 63 protein. AB - We previously constructed a recombinant monoclonal antibody (rec-MAb 63P4) that detects immediate-early protein IE63 encoded by varicella-zoster virus (VZV) in the cytoplasm of productively infected cells. Here, we used ORF63 truncation mutants to map the rec-MAb 63P4 binding epitope to amino acids 141 to 150 of VZV IE63, a region not shared with other widely used anti-IE63 antibodies, and found that the recombinant antibody does not bind to the simian IE63 counterpart. PMID- 22438548 TI - The double-stranded RNA bluetongue virus induces type I interferon in plasmacytoid dendritic cells via a MYD88-dependent TLR7/8-independent signaling pathway. AB - Dendritic cells (DCs), especially plasmacytoid DCs (pDCs), produce large amounts of alpha/beta interferon (IFN-alpha/beta) upon infection with DNA or RNA viruses, which has impacts on the physiopathology of the viral infections and on the quality of the adaptive immunity. However, little is known about the IFN alpha/beta production by DCs during infections by double-stranded RNA (dsRNA) viruses. We present here novel information about the production of IFN-alpha/beta induced by bluetongue virus (BTV), a vector-borne dsRNA Orbivirus of ruminants, in sheep primary DCs. We found that BTV induced IFN-alpha/beta in skin lymph and in blood in vivo. Although BTV replicated in a substantial fraction of the conventional DCs (cDCs) and pDCs in vitro, only pDCs responded to BTV by producing a significant amount of IFN-alpha/beta. BTV replication in pDCs was not mandatory for IFN-alpha/beta production since it was still induced by UV inactivated BTV (UV-BTV). Other inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-12p40, were also induced by UV-BTV in primary pDCs. The induction of IFN-alpha/beta required endo /lysosomal acidification and maturation. However, despite being an RNA virus, UV BTV did not signal through Toll-like receptor 7 (TLR7) for IFN-alpha/beta induction. In contrast, pathways involving the MyD88 adaptor and kinases dsRNA activated protein kinase (PKR) and stress-activated protein kinase (SAPK)/Jun N terminal protein kinase (JNK) were implicated. This work highlights the importance of pDCs for the production of innate immunity cytokines induced by a dsRNA virus, and it shows that a dsRNA virus can induce IFN-alpha/beta in pDCs via a novel TLR-independent and Myd88-dependent pathway. These findings have implications for the design of efficient vaccines against dsRNA viruses. PMID- 22438549 TI - Identification of I137M and other mutations that modulate incubation periods for two human prion strains. AB - We report here the transmission of human prions to 18 new transgenic (Tg) mouse lines expressing 8 unique chimeric human/mouse prion proteins (PrP). Extracts from brains of two patients, who died of sporadic Creutzfeldt-Jakob disease (sCJD), contained either sCJD(MM1) or sCJD(VV2) prion strains and were used for inocula. Mice expressing chimeric PrP showed a direct correlation between expression level and incubation period for sCJD(MM1) prions irrespective of whether the transgene encoded methionine (M) or valine (V) at polymorphic residue 129. Tg mice expressing chimeric transgenes encoding V129 were unexpectedly resistant to infection with sCJD(VV2) prions, and when transmission did occur, it was accompanied by a change in strain type. The transmission of sCJD(MM1) prions was modulated by single amino acid reversions of each human PrP residue in the chimeric sequence. Reverting human residue 137 in the chimeric transgene from I to M prolonged the incubation time for sCJD(MM1) prions by more than 100 days; structural analyses suggest a profound change in the orientation of amino acid side chains with the I->M mutation. These findings argue that changing the surface charge in this region of PrP greatly altered the interaction between PrP isoforms during prion replication. Our studies contend that strain-specified replication of prions is modulated by PrP sequence-specific interactions between the prion precursor PrP(C) and the infectious product PrP(Sc). PMID- 22438550 TI - Evidence for ACE2-utilizing coronaviruses (CoVs) related to severe acute respiratory syndrome CoV in bats. AB - In 2002, severe acute respiratory syndrome (SARS)-coronavirus (CoV) appeared as a novel human virus with high similarity to bat coronaviruses. However, while SARS CoV uses the human angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry, no coronavirus isolated from bats appears to use ACE2. Here we show that signatures of recurrent positive selection in the bat ACE2 gene map almost perfectly to known SARS-CoV interaction surfaces. Our data indicate that ACE2 utilization preceded the emergence of SARS-CoV-like viruses from bats. PMID- 22438551 TI - Effects of manipulating apoptosis on Sindbis virus infection of Aedes aegypti mosquitoes. AB - Improved control of vector-borne diseases requires an understanding of the molecular factors that determine vector competence. Apoptosis has been shown to play a role in defense against viruses in insects and mammals. Although some observations suggest a correlation between apoptosis and resistance to arboviruses in mosquitoes, there is no direct evidence tying apoptosis to arbovirus vector competence. To determine whether apoptosis can influence arbovirus replication in mosquitoes, we manipulated apoptosis in Aedes aegypti mosquitoes by silencing the expression of genes that either positively or negatively regulate apoptosis. Silencing of the A. aegypti anti-apoptotic gene iap1 (Aeiap1) caused apoptosis in midgut epithelium, alterations in midgut morphology, and 60 to 70% mosquito mortality. Mortality induced by Aeiap1 silencing was rescued by cosilencing the initiator caspase gene Aedronc, indicating that the mortality was due to apoptosis. When mosquitoes which had been injected with Aeiap1 double-stranded RNA (dsRNA) were orally infected with Sindbis virus (SINV), increased midgut infection and virus dissemination to other organs were observed. This increase in virus infection may have been due to the effects of widespread apoptosis on infection barriers or innate immunity. In contrast, silencing the expression of Aedronc, which would be expected to inhibit apoptosis, reduced SINV midgut infection and virus dissemination. Thus, our data suggest that some level of caspase activity and/or apoptosis may be necessary for efficient virus replication and dissemination in mosquitoes. This is the first study to directly test the roles of apoptosis and caspases in determining mosquito vector competence for arboviruses. PMID- 22438552 TI - A physical interaction between viral replicase and capsid protein is required for genome-packaging specificity in an RNA virus. AB - Genome packaging is functionally coupled to replication in RNA viruses pathogenic to humans (Poliovirus), insects (Flock house virus [FHV]), and plants (Brome mosaic virus [BMV]). However, the underlying mechanism is not fully understood. We have observed previously that in FHV and BMV, unlike ectopically expressed capsid protein (CP), packaging specificity results from RNA encapsidation by CP that has been translated from mRNA produced from replicating genomic RNA. Consequently, we hypothesize that a physical interaction with replicase increases the CP specificity for packaging viral RNAs. We tested this hypothesis by evaluating the molecular interaction between replicase protein and CP using a FHV Nicotiana benthamiana system. Bimolecular fluorescence complementation in conjunction with fluorescent cellular protein markers and coimmunoprecipitation assays demonstrated that FHV replicase (protein A) and CP physically interact at the mitochondrial site of replication and that this interaction requires the N proximal region from either amino acids 1 to 31 or amino acids 32 to 50 of the CP. In contrast to the mitochondrial localization of CP derived from FHV replication, ectopic expression displayed a characteristic punctate pattern on the endoplasmic reticulum (ER). This pattern was altered to relocalize the CP throughout the cytoplasm when the C-proximal hydrophobic domain was deleted. Analysis of the packaging phenotypes of the CP mutants defective either in protein A-CP interactions or ER localization suggested that synchronization between protein A-CP interaction and its subcellular localization is imperative to confer packaging specificity. PMID- 22438553 TI - Virus-derived gene expression and RNA interference vector for grapevine. AB - The improvement of the agricultural and wine-making qualities of the grapevine (Vitis vinifera) is hampered by adherence to traditional varieties, the recalcitrance of this plant to genetic modifications, and public resistance to genetically modified organism (GMO) technologies. To address these challenges, we developed an RNA virus-based vector for the introduction of desired traits into grapevine without heritable modifications to the genome. This vector expresses recombinant proteins in the phloem tissue that is involved in sugar transport throughout the plant, from leaves to roots to berries. Furthermore, the vector provides a powerful RNA interference (RNAi) capability of regulating the expression of endogenous genes via virus-induced gene-silencing (VIGS) technology. Additional advantages of this vector include superb genetic capacity and stability, as well as the swiftness of technology implementation. The most significant applications of the viral vector include functional genomics of the grapevine and disease control via RNAi-enabled vaccination against pathogens or invertebrate pests. PMID- 22438554 TI - Molecular characterization of feline infectious peritonitis virus strain DF-2 and studies of the role of ORF3abc in viral cell tropism. AB - The full-length genome of the highly lethal feline infectious peritonitis virus (FIPV) strain DF-2 was sequenced and cloned into a bacterial artificial chromosome (BAC) to study the role of ORF3abc in the FIPV-feline enteric coronavirus (FECV) transition. The reverse genetic system allowed the replacement of the truncated ORF3abc of the original FIPV DF-2 genome with the intact ORF3abc of the canine coronavirus (CCoV) reference strain Elmo/02. The in vitro replication kinetics of these two viruses was studied in CrFK and FCWF-4 cell lines, as well as in feline peripheral blood monocytes. Both viruses showed similar replication kinetics in established cell lines. However, the strain with a full-length ORF3 showed markedly lower replication of more than 2 log(10) titers in feline peripheral blood monocytes. Our results suggest that the truncated ORF3abc plays an important role in the efficient macrophage/monocyte tropism of type II FIPV. PMID- 22438555 TI - Functional characterization of residues required for the herpes simplex virus 1 E3 ubiquitin ligase ICP0 to interact with the cellular E2 ubiquitin-conjugating enzyme UBE2D1 (UbcH5a). AB - The viral ubiquitin ligase ICP0 is required for efficient initiation of herpes simplex virus 1 (HSV-1) lytic infection and productive reactivation of viral genomes from latency. ICP0 has been shown to target a number of specific cellular proteins for proteasome-dependent degradation during lytic infection, including the promyelocytic leukemia protein (PML) and its small ubiquitin-like modified (SUMO) isoforms. We have shown previously that ICP0 can catalyze the formation of unanchored polyubiquitin chains and mediate the ubiquitination of specific substrate proteins in vitro in the presence of two E2 ubiquitin-conjugating enzymes, namely, UBE2D1 (UbcH5a) and UBE2E1 (UbcH6), in a RING finger-dependent manner. Using homology modeling in conjunction with site-directed mutagenesis, we identify specific residues required for the interaction between the RING finger domain of ICP0 and UBE2D1, and we report that point mutations at these residues compromise the ability of ICP0 to induce the colocalization of conjugated ubiquitin and the degradation of PML and its SUMO-modified isoforms. Furthermore, we show that RING finger mutants that are unable to interact with UBE2D1 fail not only to complement the plaque-forming defect of an ICP0-null mutant virus but also to mediate the derepression of quiescent HSV-1 genomes in cell culture. These data demonstrate that the ability of ICP0 to interact with cellular E2 ubiquitin-conjugating enzymes is fundamentally important for its biological functions during HSV-1 infection. PMID- 22438556 TI - Molecular genetic and biochemical characterization of the vaccinia virus I3 protein, the replicative single-stranded DNA binding protein. AB - Vaccinia virus, the prototypic poxvirus, efficiently and faithfully replicates its ~200-kb DNA genome within the cytoplasm of infected cells. This intracellular localization dictates that vaccinia virus encodes most, if not all, of its own DNA replication machinery. Included in the repertoire of viral replication proteins is the I3 protein, which binds to single-stranded DNA (ssDNA) with great specificity and stability and has been presumed to be the replicative ssDNA binding protein (SSB). We substantiate here that I3 colocalizes with bromodeoxyuridine (BrdU)-labeled nascent viral genomes and that these genomes accumulate in cytoplasmic factories that are delimited by membranes derived from the endoplasmic reticulum. Moreover, we report on a structure/function analysis of I3 involving the isolation and characterization of 10 clustered charge-to alanine mutants. These mutants were analyzed for their biochemical properties (self-interaction and DNA binding) and biological competence. Three of the mutant proteins, encoded by the I3 alleles I3-4, -5, and -7, were deficient in self interaction and unable to support virus viability, strongly suggesting that the multimerization of I3 is biologically significant. Mutant I3-5 was also deficient in DNA binding. Additionally, we demonstrate that small interfering RNA (siRNA) mediated depletion of I3 causes a significant decrease in the accumulation of progeny genomes and that this reduction diminishes the yield of infectious virus. PMID- 22438557 TI - Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with multifunctional angiogenin to utilize its antiapoptotic functions. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with the angioproliferative Kaposi's sarcoma (KS). KSHV infection and the expression of latency-associated nuclear antigen (LANA-1) upregulates the angiogenic multifunctional 123-amino-acid, 14-kDa protein angiogenin (ANG), which is detected in KS lesions and in KSHV-associated primary effusion lymphoma (PEL) cells. ANG knockdown or the inhibition of ANG's nuclear translocation resulted in decreased LANA-1 gene expression and reduced KSHV-infected endothelial and PEL cell survival (Sadagopan et al., J. Virol. 83:3342-3364, 2009). Further studies here demonstrate that LANA-1 and ANG colocalize and coimmunoprecipitate in de novo infected endothelial cells and in latently infected PEL (BCBL-1 and BC-3) cells. LANA-1 and ANG interaction occurred in the absence of the KSHV genome and other viral proteins. In gel filtration chromatography analyses of BC-3 cell lysates, ANG coeluted with LANA-1, p53, and Mdm2 in high-molecular-weight fractions, and LANA-1, p53, and Mdm2 also coimmunoprecipitated with ANG. LANA-1, ANG, and p53 colocalized in KSHV-infected cells, and colocalization between ANG and p53 was also observed in LANA-1-negative cells. The deletion constructs of ANG suggested that the C-terminal region of amino acids 104 to 123 is involved in LANA-1 and p53 interactions. Silencing ANG or inhibiting its nuclear translocation resulted in decreased nuclear LANA-1 and ANG levels, decreased interactions between ANG-LANA-1, ANG-p53, and LANA-1-p53, the induction of p53, p21, and Bax proteins, the increased cytoplasmic localization of p53, the downregulation of Bcl-2, the increased cleavage of caspase-3, and the apoptosis of cells. No such effects were observed in KSHV-negative BJAB cells. The phosphorylation of p53 at serine 15, which is essential for p53 stabilization and for p53's apoptotic and cell cycle regulation functions, was increased in BCBL-1 cells transduced with short hairpin RNA targeting ANG. Together, these studies suggest that the antiapoptosis observed in KSHV-infected cells and the suppression of p53 functions are mediated in part by ANG, and KSHV has probably evolved to utilize angiogenin's multiple functions for the maintenance of its latency and cell survival. Thus, targeting ANG to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV infection and associated malignancies. PMID- 22438559 TI - Temporal- and strain-specific host microRNA molecular signatures associated with swine-origin H1N1 and avian-origin H7N7 influenza A virus infection. AB - MicroRNAs (miRNAs) repress the expression levels of genes by binding to mRNA transcripts, acting as master regulators of cellular processes. Differential expression of miRNAs has been linked to virus-associated diseases involving members of the Hepacivirus, Herpesvirus, and Retrovirus families. In contrast, limited biological and molecular information has been reported on the potential role of cellular miRNAs in the life cycle of influenza A viruses (infA). In this study, we hypothesize that elucidating the miRNA expression signatures induced by low-pathogenicity swine-origin infA (S-OIV) pandemic H1N1 (2009) and highly pathogenic avian-origin infA (A-OIV) H7N7 (2003) infections could reveal temporal and strain-specific miRNA fingerprints during the viral life cycle, shedding important insights into the potential role of cellular miRNAs in host-infA interactions. Using a microfluidic microarray platform, we profiled cellular miRNA expression in human A549 cells infected with S- and A-OIVs at multiple time points during the viral life cycle, including global gene expression profiling during S-OIV infection. Using target prediction and pathway enrichment analyses, we identified the key cellular pathways associated with the differentially expressed miRNAs and predicted mRNA targets during infA infection, including the immune system, cell proliferation, apoptosis, cell cycle, and DNA replication and repair. By identifying the specific and dynamic molecular phenotypic changes (microRNAome) triggered by S- and A-OIV infection in human cells, we provide experimental evidence demonstrating a series of temporal and strain-specific host molecular responses involving different combinatorial contributions of multiple cellular miRNAs. Our results also identify novel potential exosomal miRNA biomarkers associated with pandemic S-OIV and deadly A-OIV-host infection. PMID- 22438560 TI - The mycovirus CHV1 disrupts secretion of a developmentally regulated protein in Cryphonectria parasitica. AB - Infection of the chestnut blight fungus Cryphonectria parasitica with Cryphonectria hypovirus 1 (CHV1) causes disruption of virulence, pigmentation, and sporulation. Transcriptional downregulation of key developmentally regulated fungal genes occurs during infection, but vegetative growth is unaffected. Previous studies showed that CHV1 utilizes trans-Golgi network (TGN) secretory vesicles for replication. In this study, the fungal cell surface hydrophobin cryparin was chosen as a marker to follow secretion in virally infected and noninfected strains. Subcellular fractionation, cryparin-green fluorescent protein (GFP) fusion, and Western blot studies confirmed that vesicles containing cryparin copurify with the same fractions previously shown to contain elements of the viral replication complex and the TGN resident endoprotease Kex2. This vesicle fraction accumulated to a much greater concentration in the CHV1-infected strains than in noninfected strains. Pulse-chase analysis showed that the rates and amount of cryparin being secreted by the CHV1 containing strains was much lower than in noninfected strains, and the dwell time of cryparin within the cell after labeling was significantly greater in the CHV1-infected strains than in the noninfected ones. These results suggest that the virus perturbs a specific late TGN secretory pathway resulting in buildup of a key protein important for fungal development. PMID- 22438558 TI - Establishment and lineage replacement of H6 influenza viruses in domestic ducks in southern China. AB - Domestic ducks in southern China act as an important reservoir for influenza viruses and have also facilitated the establishment of multiple H6 influenza virus lineages. To understand the continuing evolution of these established lineages, 297 H6 viruses isolated from domestic ducks during 2006 and 2007 were genetically and antigenically analyzed. Phylogenetic analyses showed that group II duck H6 viruses had replaced the previously predominant group I lineage and extended their geographic distribution from coastal to inland regions. Group II H6 virus showed that the genesis and development of multiple types of deletions in the neuraminidase (NA) stalk region could occur in the influenza viruses from domestic ducks. A gradual replacement of the N2 NA subtype with N6 was observed. Significant antigenic changes occurred within group II H6 viruses so that they became antigenically distinguishable from group I and gene pool viruses. Gene exchange between group II H6 viruses and the established H5N1, H9N2, or H6N1 virus lineages in poultry in the region was very limited. These findings suggest that domestic ducks can facilitate significant genetic and antigenic changes in viruses established in this host and highlight gaps in our knowledge of influenza virus ecology and even the evolutionary behavior of this virus family in its aquatic avian reservoirs. PMID- 22438561 TI - Dissection of the role of the stable signal peptide of the arenavirus envelope glycoprotein in membrane fusion. AB - The arenavirus envelope glycoprotein (GPC) retains a stable signal peptide (SSP) as an essential subunit in the mature complex. The 58-amino-acid residue SSP comprises two membrane-spanning hydrophobic regions separated by a short ectodomain loop that interacts with the G2 fusion subunit to promote pH-dependent membrane fusion. Small-molecule compounds that target this unique SSP-G2 interaction prevent arenavirus entry and infection. The interaction between SSP and G2 is sensitive to the phylogenetic distance between New World (Junin) and Old World (Lassa) arenaviruses. For example, heterotypic GPC complexes are unable to support virion entry. In this report, we demonstrate that the hybrid GPC complexes are properly assembled, proteolytically cleaved, and transported to the cell surface but are specifically defective in their membrane fusion activity. Chimeric SSP constructs reveal that this incompatibility is localized to the first transmembrane segment of SSP (TM1). Genetic changes in TM1 also affect sensitivity to small-molecule fusion inhibitors, generating resistance in some cases and inhibitor dependence in others. Our studies suggest that interactions of SSP TM1 with the transmembrane domain of G2 may be important for GPC-mediated membrane fusion and its inhibition. PMID- 22438562 TI - Increased protection from vaccinia virus infection in mice genetically prone to lymphoproliferative disorders. AB - Mutations in the genes that encode Fas or Fas ligand (FasL) can result in poor restraints on lymphocyte activation and in increased susceptibility to autoimmune disorders. Because these mutations portend a continuously activated immune state, we hypothesized that they might in some cases confer resistance to infection. To examine this possibility, the immune response to, morbidity caused by, and clearance of vaccinia virus (VACV) Western Reserve was examined in 5- to 7-week old Fas mutant (lpr) mice, before an overt lymphoproliferative disorder was observable. On day 6 after VACV infection, C57BL/6-lpr (B6-lpr) mice had decreased morbidity, decreased viral titers, and an increased percentage and number of CD4(+) and CD8(+) T cells. As early as day 2 after infection, B6-lpr mice had decreased liver and spleen viral titers and increased numbers of and increased gamma interferon (IFN-gamma) production by several different effector cell populations. Depletion of individual effector cell subsets did not inhibit the resistance of B6-lpr mice. Uninfected B6-lpr mice also had increased numbers of NK cells, gammadelta(+) T cells, and CD44(+) CD4(+) and CD44(+) CD8(+) T cells compared to uninfected B6 mice. Antibody to IFN-gamma resulted in increased virus load in both B6 and B6-lpr mice and eliminated the differences in viral titers between them. These results suggest that IFN-gamma produced by multiple activated leukocyte populations in Fas-deficient hosts enhances resistance to some viral infections. PMID- 22438563 TI - Nuclear egress of pseudorabies virus capsids is enhanced by a subspecies of the large tegument protein that is lost upon cytoplasmic maturation. AB - Herpesviruses morphogenesis occurs stepwise both temporally and spatially, beginning in the nucleus and concluding with the emergence of an extracellular virion. The mechanisms by which these viruses interact with and penetrate the nuclear envelope and subsequent compartments of the secretory pathway remain poorly defined. In this report, a conserved viral protein (VP1/2; pUL36) that directs cytoplasmic stages of egress is identified to have multiple isoforms. Of these, a novel truncated VP1/2 species translocates to the nucleus and assists the transfer of DNA-containing capsids to the cytoplasm. The capsids are handed off to full-length VP1/2, which replaces the nuclear isoform on the capsids and is required for the final cytoplasmic stages of viral particle maturation. These results document that distinct VP1/2 protein species serve as effectors of nuclear and cytoplasmic egress. PMID- 22438564 TI - Use of proteinase K nonspecific digestion for selective and comprehensive identification of interpeptide cross-links: application to prion proteins. AB - Chemical cross-linking combined with mass spectrometry is a rapidly developing technique for structural proteomics. Cross-linked proteins are usually digested with trypsin to generate cross-linked peptides, which are then analyzed by mass spectrometry. The most informative cross-links, the interpeptide cross-links, are often large in size, because they consist of two peptides that are connected by a cross-linker. In addition, trypsin targets the same residues as amino-reactive cross-linkers, and cleavage will not occur at these cross-linker-modified residues. This produces high molecular weight cross-linked peptides, which complicates their mass spectrometric analysis and identification. In this paper, we examine a nonspecific protease, proteinase K, as an alternative to trypsin for cross-linking studies. Initial tests on a model peptide that was digested by proteinase K resulted in a "family" of related cross-linked peptides, all of which contained the same cross-linking sites, thus providing additional verification of the cross-linking results, as was previously noted for other post translational modification studies. The procedure was next applied to the native (PrP(C)) and oligomeric form of prion protein (PrPbeta). Using proteinase K, the affinity-purifiable CID-cleavable and isotopically coded cross-linker cyanurbiotindipropionylsuccinimide and MALDI-MS cross-links were found for all of the possible cross-linking sites. After digestion with proteinase K, we obtained a mass distribution of the cross-linked peptides that is very suitable for MALDI MS analysis. Using this new method, we were able to detect over 60 interpeptide cross-links in the native PrP(C) and PrPbeta prion protein. The set of cross links for the native form was used as distance constraints in developing a model of the native prion protein structure, which includes the 90-124-amino acid N terminal portion of the protein. Several cross-links were unique to each form of the prion protein, including a Lys(185)-Lys(220) cross-link, which is unique to the PrPbeta and thus may be indicative of the conformational change involved in the formation of prion protein oligomers. PMID- 22438565 TI - Gender influences the class III and V beta-tubulin ability to predict poor outcome in colorectal cancer. AB - PURPOSE: Colorectal cancer is one of the deadliest diseases in Western countries. To predict the outcome of therapy, we assessed the role of class III (TUBB3) and class V beta-tubulin (TUBB6) as predictive biomarkers. EXPERIMENTAL DESIGN: Using immunohistochemistry and nanofluidics, the expression of TUBB3 and TUBB6 was assessed in two cohorts of 180 and 134 patients, respectively. The CYP17A1 RS743572 was genotyped to identify GG carriers with enhanced androgen levels. TUBB3 and TUBB6 were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation, the latter serving as activator of this prosurvival pathway. To ascertain the role of androgen receptor (AR) in such regulation, we silenced AR and checked TUBB3 and TUBB6 expression and sensitivity to chemotherapy. RESULTS: There was a link between poor survival, the expression of TUBB3/TUBB6, and AR only in females. Conversely, only in males carriers of the GG phenotype exhibited the worst outcome. Importantly, male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activated by androgens. In female cells this phenomenon was absent. In both genders, AR was the main driver of TUBB3/TUBB6 expression, as constitutive silencing of AR was associated with downregulation of TUBB3/TUBB6 expression and increased sensitivity to oxaliplatin and SN-38. CONCLUSIONS: The involvement of androgens in the TUBB3 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients. PMID- 22438566 TI - Wnt signaling in cancer. AB - Aberrant regulation of the Wnt signaling pathway is a prevalent theme in cancer biology. From the earliest observation that Wnt overexpression could lead to malignant transformation of mouse mammary tissue to the most recent genetic discoveries gleaned from tumor genome sequencing, the Wnt pathway continues to evolve as a central mechanism in cancer biology. This article summarizes the evidence supporting a role for Wnt signaling in human cancer. This includes a review of the genetic mutations affecting Wnt pathway components, as well as some of epigenetic mechanisms that alter expression of genes relevant to Wnt. I also highlight some research on the cooperativity of Wnt with other signaling pathways in cancer. Finally, some emphasis is placed on laboratory research that provides a proof of concept for the therapeutic inhibition of Wnt signaling in cancer. PMID- 22438567 TI - How to link ontologies and protein-protein interactions to literature: text mining approaches and the BioCreative experience. AB - There is an increasing interest in developing ontologies and controlled vocabularies to improve the efficiency and consistency of manual literature curation, to enable more formal biocuration workflow results and ultimately to improve analysis of biological data. Two ontologies that have been successfully used for this purpose are the Gene Ontology (GO) for annotating aspects of gene products and the Molecular Interaction ontology (PSI-MI) used by databases that archive protein-protein interactions. The examination of protein interactions has proven to be extremely promising for the understanding of cellular processes. Manual mapping of information from the biomedical literature to bio-ontology terms is one of the most challenging components in the curation pipeline. It requires that expert curators interpret the natural language descriptions contained in articles and infer their semantic equivalents in the ontology (controlled vocabulary). Since manual curation is a time-consuming process, there is strong motivation to implement text-mining techniques to automatically extract annotations from free text. A range of text mining strategies has been devised to assist in the automated extraction of biological data. These strategies either recognize technical terms used recurrently in the literature and propose them as candidates for inclusion in ontologies, or retrieve passages that serve as evidential support for annotating an ontology term, e.g. from the PSI-MI or GO controlled vocabularies. Here, we provide a general overview of current text mining methods to automatically extract annotations of GO and PSI-MI ontology terms in the context of the BioCreative (Critical Assessment of Information Extraction Systems in Biology) challenge. Special emphasis is given to protein protein interaction data and PSI-MI terms referring to interaction detection methods. PMID- 22438568 TI - Axial patterning interactions in the sea urchin embryo: suppression of nodal by Wnt1 signaling. AB - Wnt and Nodal signaling pathways are required for initial patterning of cell fates along anterior-posterior (AP) and dorsal-ventral (DV) axes, respectively, of sea urchin embryos during cleavage and early blastula stages. These mechanisms are connected because expression of nodal depends on early Wnt/beta-catenin signaling. Here, we show that an important subsequent function of Wnt signaling is to control the shape of the nodal expression domain and maintain correct specification of different cell types along the axes of the embryo. In the absence of Wnt1, the posterior-ventral region of the embryo is severely altered during early gastrulation. Strikingly, at this time, nodal and its downstream target genes gsc and bra are expressed ectopically, extending posteriorly to the blastopore. They override the initial specification of posterior-ventral ectoderm and endoderm fates, eliminating the ventral contribution to the gut and displacing the ciliary band dorsally towards, and occasionally beyond, the blastopore. Consequently, in Wnt1 morphants, the blastopore is located at the border of the re-specified posterior-ventral oral ectoderm and by larval stages it is in the same plane near the stomodeum on the ventral side. In normal embryos, a Nodal-dependent process downregulates wnt1 expression in dorsal posterior cells during early gastrulation, focusing Wnt1 signaling to the posterior-ventral region where it suppresses nodal expression. These subsequent interactions between Wnt and Nodal signaling are thus mutually antagonistic, each limiting the range of the other's activity, in order to maintain and stabilize the body plan initially established by those same signaling pathways in the early embryo. PMID- 22438569 TI - Germ cell pluripotency, premature differentiation and susceptibility to testicular teratomas in mice. AB - Testicular teratomas result from anomalies in germ cell development during embryogenesis. In the 129 family of inbred strains of mice, teratomas initiate around embryonic day (E) 13.5 during the same developmental period in which female germ cells initiate meiosis and male germ cells enter mitotic arrest. Here, we report that three germ cell developmental abnormalities, namely continued proliferation, retention of pluripotency, and premature induction of differentiation, associate with teratoma susceptibility. Using mouse strains with low versus high teratoma incidence (129 versus 129-Chr19(MOLF/Ei)), and resistant to teratoma formation (FVB), we found that germ cell proliferation and expression of the pluripotency factor Nanog at a specific time point, E15.5, were directly related with increased tumor risk. Additionally, we discovered that genes expressed in pre-meiotic embryonic female and adult male germ cells, including cyclin D1 (Ccnd1) and stimulated by retinoic acid 8 (Stra8), were prematurely expressed in teratoma-susceptible germ cells and, in rare instances, induced entry into meiosis. As with Nanog, expression of differentiation-associated factors at a specific time point, E15.5, increased with tumor risk. Furthermore, Nanog and Ccnd1, genes with known roles in testicular cancer risk and tumorigenesis, respectively, were co-expressed in teratoma-susceptible germ cells and tumor stem cells, suggesting that retention of pluripotency and premature germ cell differentiation both contribute to tumorigenesis. Importantly, Stra8 deficient mice had an 88% decrease in teratoma incidence, providing direct evidence that premature initiation of the meiotic program contributes to tumorigenesis. These results show that deregulation of the mitotic-meiotic switch in XY germ cells contributes to teratoma initiation. PMID- 22438570 TI - A TGFbeta-Smad4-Fgf6 signaling cascade controls myogenic differentiation and myoblast fusion during tongue development. AB - The tongue is a muscular organ and plays a crucial role in speech, deglutition and taste. Despite the important physiological functions of the tongue, little is known about the regulatory mechanisms of tongue muscle development. TGFbeta family members play important roles in regulating myogenesis, but the functional significance of Smad-dependent TGFbeta signaling in regulating tongue skeletal muscle development remains unclear. In this study, we have investigated Smad4 mediated TGFbeta signaling in the development of occipital somite-derived myogenic progenitors during tongue morphogenesis through tissue-specific inactivation of Smad4 (using Myf5-Cre;Smad4(flox/flox) mice). During the initiation of tongue development, cranial neural crest (CNC) cells occupy the tongue buds before myogenic progenitors migrate into the tongue primordium, suggesting that CNC cells play an instructive role in guiding tongue muscle development. Moreover, ablation of Smad4 results in defects in myogenic terminal differentiation and myoblast fusion. Despite compromised muscle differentiation, tendon formation appears unaffected in the tongue of Myf5-Cre;Smad4(flox/flox) mice, suggesting that the differentiation and maintenance of CNC-derived tendon cells are independent of Smad4-mediated signaling in myogenic cells in the tongue. Furthermore, loss of Smad4 results in a significant reduction in expression of several members of the FGF family, including Fgf6 and Fgfr4. Exogenous Fgf6 partially rescues the tongue myoblast fusion defect of Myf5 Cre;Smad4(flox/flox) mice. Taken together, our study demonstrates that a TGFbeta Smad4-Fgf6 signaling cascade plays a crucial role in myogenic cell fate determination and lineage progression during tongue myogenesis. PMID- 22438571 TI - Mei-P26 regulates the maintenance of ovarian germline stem cells by promoting BMP signaling. AB - In the Drosophila ovary, bone morphogenetic protein (BMP) ligands maintain germline stem cells (GSCs) in an undifferentiated state. The activation of the BMP pathway within GSCs results in the transcriptional repression of the differentiation factor bag of marbles (bam). The Nanos-Pumilio translational repressor complex and the miRNA pathway also help to promote GSC self-renewal. How the activities of different transcriptional and translational regulators are coordinated to keep the GSC in an undifferentiated state remains uncertain. Data presented here show that Mei-P26 cell-autonomously regulates GSC maintenance in addition to its previously described role of promoting germline cyst development. Within undifferentiated germ cells, Mei-P26 associates with miRNA pathway components and represses the translation of a shared target mRNA, suggesting that Mei-P26 can enhance miRNA-mediated silencing in specific contexts. In addition, disruption of mei-P26 compromises BMP signaling, resulting in the inappropriate expression of bam in germ cells immediately adjacent to the cap cell niche. Loss of mei-P26 results in premature translation of the BMP antagonist Brat in germline stem cells. These data suggest that Mei-P26 has distinct functions in the ovary and participates in regulating the fates of both GSCs and their differentiating daughters. PMID- 22438572 TI - Integration of an abdominal Hox complex with Pax2 yields cell-specific EGF secretion from Drosophila sensory precursor cells. AB - Cis-regulatory modules (CRMs) ensure specific developmental outcomes by mediating both proper spatiotemporal gene expression patterns and appropriate transcriptional levels. In Drosophila, the precise transcriptional control of the serine protease rhomboid regulates EGF signaling to specify distinct cell types. Recently, we identified a CRM that activates rhomboid expression and thereby EGF secretion from a subset of abdominal sensory organ precursor cells (SOPs) to induce an appropriate number of lipid-processing cells called oenocytes. Here, we use scanning mutagenesis coupled with reporter assays, biochemistry and genetics to dissect the transcriptional mechanisms regulating SOP-specific rhomboid activation. Our results show that proper spatial activity of the rhomboid CRM is dependent upon direct integration of the abdomen-specific Hox factor Abdominal-A and the SOP-restricted Pax2 factor. In addition, we show that the Extradenticle and Homothorax Hox co-factors are differentially integrated on the rhomboid CRM by abdominal versus thoracic Hox proteins in the presence of Pax2. Last, we show that Abdominal-A uses both Pax2-dependent and Pax2-independent mechanisms to stimulate rhomboid CRM activity to induce proper oenocyte numbers. Thus, these data demonstrate how a CRM integrates Hox and neural transcriptional inputs to regulate the appropriate spatial pattern and levels of EGF secretion to specify an essential cell fate. PMID- 22438573 TI - Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos. AB - How divergent genetic systems regulate a common pathway during the development of two serial structures, forelimbs and hindlimbs, is not well understood. Specifically, HAND2 has been shown to regulate Shh directly to initiate its expression in the posterior margin of the limb mesenchyme. Although the Hand2-Shh morphoregulatory system operates in both the forelimb and hindlimb bud, a recent analysis suggested that its upstream regulation is different in the forelimb and hindlimb bud. A combination of all four Hox9 genes is required for Hand2 expression in the forelimb-forming region; however, it remains elusive what genetic system regulates the Hand2-Shh pathway in the hindlimb-forming region. By conditional inactivation of Islet1 in the hindlimb-forming region using the Hoxb6Cre transgene, we show that Islet1 is required for establishing the posterior hindlimb field, but not the forelimb field, upstream of the Hand2-Shh pathway. Inactivation of Islet1 caused the loss of posterior structures in the distal and proximal regions, specifically in the hindlimb. We found that Hand2 expression was downregulated in the hindlimb field and that Shh expression was severely impaired in the hindlimb bud. In the Hoxb6Cre; Islet1 mutant pelvis, the proximal element that is formed in a Shh-independent manner, displayed complementary defects in comparison with Pitx1(-/-) hindlimbs. This suggests that Islet1 and Pitx1 function in parallel during girdle development in hindlimbs, which is in contrast with the known requirement for Tbx5 in girdle development in forelimbs. Our studies have identified a role for Islet1 in hindlimb-specific development and have revealed Islet1 functions in two distinct processes: regulation upstream of the Hand2-Shh pathway and contributions to girdle development. PMID- 22438574 TI - Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes. AB - Estrogen sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of estrogens, plays an important role in estrogen homeostasis. In this study, we showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone-, and high-fat diet-induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased estrogen deprivation and increased estrogenic activity in the liver, whereas such benefit was abolished in ovariectomized mice. Interestingly, the effect of Est was sex-specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet beta-cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of beta-cell mass in ob/ob males deficient in Est was associated with increased macrophage infiltration and inflammation in white adipose tissue. Our results revealed an essential role of EST in energy metabolism and the pathogenesis of type 2 diabetes. Inhibition of EST, at least in females, may represent a novel approach to manage type 2 diabetes. PMID- 22438575 TI - Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables. AB - Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA(+): n = 49) and without (MA(-): n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA(-) patients showed increased connectivity in networks involved in motor and visual processes, whereas MA(+) patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy. PMID- 22438576 TI - Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. AB - Vascular endothelial growth factor (VEGF)-induced breakdown of the blood-retinal barrier requires protein kinase C (PKC)beta activation. However, the molecular mechanisms related to this process remain poorly understood. In this study, the role of occludin phosphorylation and ubiquitination downstream of PKCbeta activation in tight junction (TJ) trafficking and endothelial permeability was investigated. Treatment of bovine retinal endothelial cells and intravitreal injection of PKCbeta inhibitors as well as expression of dominant-negative kinase was used to determine the contribution of PKCbeta to endothelial permeability and occludin phosphorylation at Ser490 detected with a site-specific antibody. In vitro kinase assay was used to demonstrate direct occludin phosphorylation by PKCbeta. Ubiquitination was measured by immunoblotting after occludin immunoprecipitation. Confocal microscopy revealed organization of TJ proteins. The results reveal that inhibition of VEGF-induced PKCbeta activation blocks occludin Ser490 phosphorylation, ubiquitination, and TJ trafficking in retinal vascular endothelial cells both in vitro and in vivo and prevents VEGF-stimulated vascular permeability. Occludin Ser490 is a direct target of PKCbeta, and mutating Ser490 to Ala (S490A) blocks permeability downstream of PKCbeta. Therefore, PKCbeta activation phosphorylates occludin on Ser490, leading to ubiquitination required for VEGF-induced permeability. These data demonstrate a novel mechanism for PKCbeta targeted inhibitors in regulating vascular permeability. PMID- 22438578 TI - Psychiatric ethics and the methodological virtues of bioethics. PMID- 22438579 TI - When four principles are too many: a commentary. AB - This commentary briefly argues that the four prima facie principles of beneficence, non-maleficence, respect for autonomy and justice enable a clinician (and anybody else) to make ethical sense of the author's proposed reliance on professional guidance and rules, on law, on professional integrity and on best interests, and to subject them all to ethical analysis and criticism based on widely acceptable basic prima facie moral obligations; and also to confront new situations in the light of those acceptable principles. PMID- 22438580 TI - Characterizing the roles of Met31 and Met32 in coordinating Met4-activated transcription in the absence of Met30. AB - Yeast sulfur metabolism is transcriptionally regulated by the activator Met4. Met4 lacks DNA-binding ability and relies on interactions with Met31 and Met32, paralogous proteins that bind the same cis-regulatory element, to activate its targets. Although Met31 and Met32 are redundant for growth in the absence of methionine, studies indicate that Met32 has a prominent role over Met31 when Met30, a negative regulator of Met4 and Met32, is inactive. To characterize different roles of Met31 and Met32 in coordinating Met4-activated transcription, we examined transcription in strains lacking either Met31 or Met32 upon Met4 induction in the absence of Met30. Microarray analysis revealed that transcripts involved in sulfate assimilation and sulfonate metabolism were dramatically decreased in met32Delta cells compared to its wild-type and met31Delta counterparts. Despite this difference, both met31Delta and met32Delta cells used inorganic sulfur compounds and sulfonates as sole sulfur sources in minimal media when Met30 was present. This discrepancy may be explained by differential binding of Met31 to Cbf1-dependent promoters between these two conditions. In the absence of Met30, genome-wide chromatin immunoprecipitation analyses found that Met32 bound all Met4-bound targets, supporting Met32 as the main platform for Met4 recruitment. Finally, Met31 and Met32 levels were differentially regulated, with Met32 levels mimicking the profile for active Met4. These different properties of Met32 likely contribute to its prominent role in Met4-activated transcription when Met30 is absent. PMID- 22438581 TI - Vesicular trafficking through cortical actin during exocytosis is regulated by the Rab27a effector JFC1/Slp1 and the RhoA-GTPase-activating protein Gem interacting protein. AB - Cytoskeleton remodeling is important for the regulation of vesicular transport associated with exocytosis, but a direct association between granular secretory proteins and actin-remodeling molecules has not been shown, and this mechanism remains obscure. Using a proteomic approach, we identified the RhoA-GTPase activating protein Gem-interacting protein (GMIP) as a factor that associates with the Rab27a effector JFC1 and modulates vesicular transport and exocytosis. GMIP down-regulation induced RhoA activation and actin polymerization. Importantly, GMIP-down-regulated cells showed impaired vesicular transport and exocytosis, while inhibition of the RhoA-signaling pathway induced actin depolymerization and facilitated exocytosis. We show that RhoA activity polarizes around JFC1-containing secretory granules, suggesting that it may control directionality of granule movement. Using quantitative live-cell microscopy, we show that JFC1-containing secretory organelles move in areas near the plasma membrane deprived of polymerized actin and that dynamic vesicles maintain an actin-free environment in their surroundings. Supporting a role for JFC1 in RhoA inactivation and actin remodeling during exocytosis, JFC1 knockout neutrophils showed increased RhoA activity, and azurophilic granules were unable to traverse cortical actin in cells lacking JFC1. We propose that during exocytosis, actin depolymerization commences near the secretory organelle, not the plasma membrane, and that secretory granules use a JFC1- and GMIP-dependent molecular mechanism to traverse cortical actin. PMID- 22438582 TI - Spindle pole body components are reorganized during fission yeast meiosis. AB - During meiosis, the centrosome/spindle pole body (SPB) must be regulated in a manner distinct from that of mitosis to achieve a specialized cell division that will produce gametes. In this paper, we demonstrate that several SPB components are localized to SPBs in a meiosis-specific manner in the fission yeast Schizosaccharomyces pombe. SPB components, such as Cut12, Pcp1, and Spo15, which stay on the SPB during the mitotic cell cycle, disassociate from the SPB during meiotic prophase and then return to the SPB immediately before the onset of meiosis I. Interestingly, the polo kinase Plo1, which normally localizes to the SPB during mitosis, is excluded from them in meiotic prophase, when meiosis specific, horse-tail nuclear movement occurs. We found that exclusion of Plo1 during this period was essential to properly remodel SPBs, because artificial targeting of Plo1 to SPBs resulted in an overduplication of SPBs. We also found that the centrin Cdc31 was required for meiotic SPB remodeling. Thus Plo1 and a centrin play central roles in the meiotic SPB remodeling, which is essential for generating the proper number of meiotic SPBs and, thereby provide unique characteristics to meiotic divisions. PMID- 22438583 TI - Gcn5p-dependent acetylation induces degradation of the meiotic transcriptional repressor Ume6p. AB - Ume6p represses early meiotic gene transcription in Saccharomyces cerevisiae by recruiting the Rpd3p histone deacetylase and chromatin-remodeling proteins. Ume6p repression is relieved in a two-step destruction process mediated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase. The first step induces partial Ume6p degradation when vegetative cells shift from glucose- to acetate based medium. Complete proteolysis happens only upon meiotic entry. Here we demonstrate that the first step in Ume6p destruction is controlled by its acetylation and deacetylation by the Gcn5p acetyltransferase and Rpd3p, respectively. Ume6p acetylation occurs in medium lacking dextrose and results in a partial destruction of the repressor. Preventing acetylation delays Ume6p meiotic destruction and retards both the transient transcription program and execution of the meiotic nuclear divisions. Conversely, mimicking acetylation induces partial destruction of Ume6p in dextrose medium and accelerates meiotic degradation by the APC/C. These studies reveal a new mechanism by which acetyltransferase activity induces gene expression through targeted destruction of a transcriptional repressor. These findings also demonstrate an important role for nonhistone acetylation in the transition between mitotic and meiotic cell division. PMID- 22438584 TI - Cell surface annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin. AB - A disintegrin and metalloproteinase (ADAM) is a family of enzymes involved in ectodomain shedding of various membrane proteins. However, the molecular mechanism underlying substrate recognition by ADAMs remains unknown. In this study, we successfully captured and analyzed cell surface transient assemblies between the transmembrane amphiregulin precursor (proAREG) and ADAM17 during an early shedding phase, which enabled the identification of cell surface annexins as components of their shedding complex. Annexin family members annexin A2 (ANXA2), A8, and A9 interacted with proAREG and ADAM17 on the cell surface. Shedding of proAREG was increased when ANXA2 was knocked down but decreased with ANXA8 and A9 knockdown, because of enhanced and impaired association with ADAM17, respectively. Knockdown of ANXA2 and A8 in primary keratinocytes altered wound induced cell migration and ultraviolet B-induced phosphorylation of epidermal growth factor receptor (EGFR), suggesting that annexins play an essential role in the ADAM-mediated ectodomain shedding of EGFR ligands. On the basis of these data, we propose that annexins on the cell surface function as "shedding platform" proteins to determine the substrate selectivity of ADAM17, with possible therapeutic potential in ADAM-related diseases. PMID- 22438585 TI - Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking. AB - The reggie/flotillin proteins are implicated in membrane trafficking and, together with the cellular prion protein (PrP), in the recruitment of E-cadherin to cell contact sites. Here, we demonstrate that reggies, as well as PrP down regulation, in epithelial A431 cells cause overlapping processes and abnormal formation of adherens junctions (AJs). This defect in cell adhesion results from reggie effects on Src tyrosine kinases and epidermal growth factor receptor (EGFR): loss of reggies reduces Src activation and EGFR phosphorylation at residues targeted by Src and c-cbl and leads to increased surface exposure of EGFR by blocking its internalization. The prolonged EGFR signaling at the plasma membrane enhances cell motility and macropinocytosis, by which junction associated E-cadherin is internalized and recycled back to AJs. Accordingly, blockage of EGFR signaling or macropinocytosis in reggie-deficient cells restores normal AJ formation. Thus, by promoting EGFR internalization, reggies restrict the EGFR signaling involved in E-cadherin macropinocytosis and recycling and regulate AJ formation and dynamics and thereby cell adhesion. PMID- 22438586 TI - Antiproliferative factor regulates connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells. AB - Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis (IC)-a chronic, painful bladder disease of unknown etiology. APF inhibits the proliferation of normal bladder epithelial and T24 bladder carcinoma cells in vitro by binding to cytoskeleton-associated protein 4 (CKAP4) and altering the transcription of genes involved in proliferation, cellular adhesion, and tumorigenesis; however, specific molecular mechanisms and effector genes that control APF's antiproliferative effects are unknown. In this study, we found that there was a 7.5-fold up-regulation of connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells treated with APF. Western blot revealed a dose-dependent increase in CCN2 protein levels, with secretion into the culture medium after APF treatment. CCN2 overexpression enhanced APF's antiproliferative activity, whereas CCN2 knockdown diminished APF-induced p53 expression. Using a luciferase reporter construct, we found that APF treatment resulted in fivefold activation of the CCN2 proximal promoter and, of importance, that small interfering RNA-mediated knockdown of CKAP4 inhibited CCN2 upregulation. In addition, we demonstrate that CKAP4 translocates to the nucleus and binds to the CCN2 proximal promoter in an APF dependent manner, providing evidence that CCN2 regulation by APF involves CKAP4 nuclear translocation and binding to the CCN2 promoter. PMID- 22438587 TI - Mechanistic mathematical model of polarity in yeast. AB - The establishment of cell polarity involves positive-feedback mechanisms that concentrate polarity regulators, including the conserved GTPase Cdc42p, at the "front" of the polarized cell. Previous studies in yeast suggested the presence of two parallel positive-feedback loops, one operating as a diffusion-based system, and the other involving actin-directed trafficking of Cdc42p on vesicles. F-actin (and hence directed vesicle traffic) speeds fluorescence recovery of Cdc42p after photobleaching, suggesting that vesicle traffic of Cdc42p contributes to polarization. We present a mathematical modeling framework that combines previously developed mechanistic reaction-diffusion and vesicle trafficking models. Surprisingly, the combined model recapitulated the observed effect of vesicle traffic on Cdc42p dynamics even when the vesicles did not carry significant amounts of Cdc42p. Vesicle traffic reduced the concentration of Cdc42p at the front, so that fluorescence recovery mediated by Cdc42p flux from the cytoplasm took less time to replenish the bleached pool. Simulations in which Cdc42p was concentrated into vesicles or depleted from vesicles yielded almost identical predictions, because Cdc42p flux from the cytoplasm was dominant. These findings indicate that vesicle-mediated delivery of Cdc42p is not required to explain the observed Cdc42p dynamics, and raise the question of whether such Cdc42p traffic actually contributes to polarity establishment. PMID- 22438588 TI - Rewiring of posttranscriptional RNA regulons: Puf4p in fungi as an example. AB - It has been increasingly clear that changes in gene regulation play important roles in physiological and phenotypic evolution. Rewiring gene-regulatory networks, i.e., alteration of the gene-regulation system for different biological functions, has been demonstrated in various species. Posttranscriptional regulons have prominent roles in coordinating gene expression in a variety of eukaryotes. In this study, using Puf4p in fungi as an example, we demonstrate that posttranscriptional regulatory networks can also be rewired during evolution. Although Puf4p is highly conserved in fungi, targets of the posttranscriptional regulon are functionally diverse among known fungal species. In the Saccharomycotina subdivision, target genes of Puf4p mostly conduct function in the nucleolus; however, in the Pezizomycotina subdivision, they are enriched in the mitochondria. Furthermore, we demonstrate different regulation efficiencies of mitochondrial function by PUF proteins in different fungal clades. Our results indicate that rewiring of posttranscription regulatory networks may be an important way of generating genetic novelties in gene regulation during evolution. PMID- 22438589 TI - Philip D. Lawley (1927-2011). PMID- 22438590 TI - Much more than just an interview. PMID- 22438591 TI - Integration as a paramount educational strategy in academic pharmacy. PMID- 22438592 TI - University-based continuing education for pharmacists. AB - University-based continuing education (CE) fulfills an important role to support the professional development of pharmacists, advance the practice of pharmacy, and contribute to societal needs for research and healthcare services. Opportunities for pharmacists to engage in new models of patient care are numerous worldwide, particularly as pharmacists' scope of practice has expanded. Approaches to CE have changed to address the changing needs of pharmacists and now include a variety of approaches to support development of knowledge and skills. There is emphasis on the learning process as well as the knowledge, with the introduction of the concept of continuing professional development (CPD).As institutions of research and education, universities are uniquely positioned to bridge the gap between academic and practice environments, providing opportunities for translation of knowledge to practice. The Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta is a provider of CE in Alberta, Canada, where an expanded scope of pharmacy practice includes prescribing, administering injections, accessing electronic patient records, and ordering laboratory tests. In this paper, the Faculty offers views about future directions for CE, including the integration of CE with core faculty activities, expanding the audience for CE, areas of focus for learning, and partnerships. Finally, we hope to ignite dialogue with others in the profession about the role and function of university-based CE. PMID- 22438593 TI - Pakistani pharmacy students' perception about complementary and alternative medicine. AB - OBJECTIVES: To assess Pakistani pharmacy students' perceptions of complementary and alternative medicine (CAM), the frequency with which they use CAM, and barriers to use of CAM. METHOD: A CAM health belief questionnaire was administered to 595 students enrolled in a 5-year doctor of pharmacy program (PharmD) in Pakistan. RESULTS: Attitudes of students towards CAM were positive. Lack of evidence supporting CAM practices was considered to be the major barrier toward more students using CAM. A majority of students (79%) agreed that clinical care should integrate conventional medicine and CAM practices. Many CAM-based therapies, such as dietary supplements, massage, herbal medicines, and homoeopathic medicines were used by the students. Significant gender differences in attitude were observed, with male students having more conservative attitudes toward CAM use. A high percentage of students desired more training in CAM. CONCLUSIONS: Pakistani students exhibited positive attitudes about the value of CAM and most felt that CAM should be included in the PharmD curriculum. PMID- 22438594 TI - Evaluation of an interview process for admission into a school of pharmacy. AB - OBJECTIVE: To evaluate the doctor of pharmacy (PharmD) admissions interview process at North Dakota State University (NDSU). METHODS: Faculty pairs interviewed candidates using a standardized grading rubric to evaluate qualitative parameters or attributes such as ethics, relevant life and work experience, emotional maturity, commitment to patient care, leadership, and understanding of the pharmacy profession. Total interview scores, individual attribute domain scores, and the consistency and reliability of the interviewers were assessed. RESULTS: The total mean interview score for the candidate pool was 17.4 of 25 points. Mean scores for individual domains ranged from 2.3 to 3.0 on a Likert-scale of 0-4. Nine of the 11 faculty pairs showed no mean differences from their interview partner in total interview scores given. Evaluations by 8 of the 11 faculty pairs produced high interrater reliability. CONCLUSIONS: The current interview process is generally consistent and reliable; however, future improvements such as additional interviewer training and adoption of a multiple mini-interview format could be made. PMID- 22438595 TI - Individualized education and competency development of Croatian community pharmacists using the general level framework. AB - OBJECTIVES: To measure Croatian community pharmacists' progress in competency development using the General Level Framework (GLF) as an educational tool in a longitudinal study. METHODS: Patient care competencies of 100 community pharmacists were evaluated twice, in 2009 and in 2010 in a prospective cohort study. During this 12-month period, tailored educational programs based on the GLF were organized and conducted, new services and standard operating procedures were implemented, and documentation of contributions to patient care in the pharmacist's portfolio became mandatory. RESULTS: Pharmacists' development of all GLF patient care competencies was significant with the greatest improvements seen in the following competencies: patient consultation, monitoring drug therapy, medicine information and patient education, and evaluation of outcomes. CONCLUSIONS: This study, which retested the effectiveness of an evidence-based competency framework, confirmed that GLF is a valid educational tool for pharmacist development. PMID- 22438596 TI - Empathy levels in first- and third-year students in health and non-health disciplines. AB - OBJECTIVE: To compare empathy scores between health professions students (pharmacy and nursing) and non-health professions (law) students and between first- and third-year students. METHODS: The Jefferson Scale of Physician Empathy Student Version was completed by 282 students. RESULTS: Nursing and pharmacy students had significantly more empathy than did law students. Third-year pharmacy students scored higher on empathy than did first-year pharmacy students, whereas the converse was true for nurses. There was no significant difference in empathy between first- and third-year law students. Across the study years, empathy increased among pharmacy students, decreased among nurses, and remained the same among law students. Women scored higher on empathy than did males. CONCLUSIONS: Empathy scores among university students vary depending on discipline and year of study. PMID- 22438597 TI - A pilot common reading experience to integrate basic and clinical sciences in pharmacy education. AB - OBJECTIVE: To use a common reading experience that engages students in academic discourse both before and during a PharmD degree program and introduces students to basic science and ethical foundations in health care. DESIGN: First-year (P1) pharmacy students were assigned a nonfiction text to read during the summer prior to admission to be followed by facilitated discussions. Activities using the text were integrated into the first-year curriculum. Pre-experience and post experience student and faculty survey instruments were administered. ASSESSMENT: Students and faculty members reported that 3 first-year courses used the text. Students noted that the text's historical perspective enhanced their understanding of both healthcare delivery and clinical research. Most students (78%) recommended continuation of the common reading experience activity. CONCLUSION: Students and participating faculty members found the common reading experience, which provided a hub for discussion around issues such as health literacy and ethical treatment of patients, to be a positive addition to the curriculum. Future intentions for this project include expansion across all healthcare colleges at the university. PMID- 22438598 TI - The impact of elective active-learning courses in pregnancy/lactation and pediatric pharmacotherapy. AB - OBJECTIVE: To implement and evaluate the impact of 2 elective courses, Pregnancy & Lactation and Pediatrics on student acquisition of knowledge and development of lifelong learning skills related to these special populations. DESIGN: Two 3 credit elective courses were implemented using various student-driven learning techniques, such as case-based exercises, group presentations, pro-con debates, and pharmacist "grab bag" questions. Strong emphasis was placed on medication literature retrieval and analysis, and a wiki was used to create an electronic resource for longitudinal use. ASSESSMENT: Pre- and post-course tests showed significant improvement in knowledge related to pregnancy, lactation, and pediatrics. Pre- and post-course confidence and ratings on satisfaction survey tools also revealed significant improvement in several domains relating to lifelong-learning skills, knowledge related to medication use within these special populations, use of technology to enhance learning, and overall course design. CONCLUSION: The combination of student-directed learning techniques used in 2 pediatric-concentration courses is an effective teaching model. PMID- 22438599 TI - Teaching cultural competency through a pharmacy skills and applications course series. AB - OBJECTIVE: To incorporate cultural competency in a Pharmacy Skills and Application course series and assess the level of cultural competency in students who did and did not complete the courses. DESIGN: The course series focused on cultural competency throughout the PharmD curriculum and included such activities as self-reflection, lecture, diversity service-learning, case studies, and discussion. ASSESSMENT: The Inventory for Assessing the Process of Cultural Competence Among Healthcare Professionals-Revised (IAPCC-R) was used to measure cultural competence in 2 cohorts: the last class preceding implementation of the new course series and the first class after its implementation. Overall scores between the 2 cohorts were not significantly different; however, 2 subscale scores were significantly higher among students who completed the course series: cultural skills (p = 0.021) and cultural encounters (p = 0.048). CONCLUSIONS: The Pharmacy Skills and Application course series appears to improve some aspects of cultural competence in pharmacy students, but may not be sufficient to elicit change in all areas. PMID- 22438600 TI - Comparison of active-learning strategies for motivational interviewing skills, knowledge, and confidence in first-year pharmacy students. AB - OBJECTIVE: To compare 3 strategies for pharmacy student learning of motivational interviewing skills, knowledge of motivational interviewing principles, and confidence in and attitudes toward their application. DESIGN: Following a motivational interviewing lecture, first-year students were randomized to perform practice activities (written dialogue, peer role-play, or mock-patient counseling activities). Motivational interviewing skills, knowledge, confidence, and attitudes were measured. ASSESSMENT: All students demonstrated improvement in skills, knowledge, and confidence. Students in the mock-patient counseling group demonstrated significantly better motivational interviewing skills during practice and trended toward higher scores on the summative evaluation. They also demonstrated a significant improvement in knowledge compared with that of the written dialogue group during practice. Feedback at the end was generally positive, with students expressing recognition for the value of motivational interviewing. CONCLUSIONS: Students demonstrated their best performance of motivational interviewing during assessments using interactions with mock or standardized patients. PMID- 22438601 TI - A continuous professional development process for first-year pharmacy students. AB - OBJECTIVES: To develop, pilot test, and evaluate a continuous professional development (CPD) process for first-year pharmacy (P1) students. DESIGN: Students and faculty members were introduced to the important elements of the CPD process via a live training program. Students completed the year-long 4-step CPD cycle by identifying a learning objective, creating a plan, completing the learning activity, evaluating their learning outcome, documenting each step, and meeting with their faculty advisor for feedback and advice. ASSESSMENT: Seventy-five first-year students (100%) successfully completed the CPD process during the 2009 2010 academic year. The students spent an average of 7 hours (range 2 to 20 hours) on the CPD process. The majority of faculty members (83%) completing the survey instrument found the process valuable for the students and would like to see the program continued. CONCLUSION: Integrating a CPD requirement for students in a college or school of pharmacy is feasible and valuable to students' developing life-long learning skills. Effective and frequent training of faculty members and students is a key element in the CPD process. PMID- 22438602 TI - An elective course to promote academic pharmacy as a career. AB - OBJECTIVE: To implement and assess an elective course that engages pharmacy students' interest in and directs them toward a career in academia. DESIGN: A blended-design elective that included online and face-to-face components was offered to first through third-year pharmacy students. ASSESSMENT: Students' knowledge, skills, and attitudes toward academic pharmacy were measured by pre- and post-course assessments, online quizzes, personal journal entries, course assignments, and exit interviews. The elective course promoting academic pharmacy as a profession was successful and provided students with an awareness about another career avenue to consider upon graduation. The students demonstrated mastery of the course content. CONCLUSIONS: Students agreed that the elective course on pharmacy teaching and learning was valuable and that they would recommend it to their peers. Forty percent responded that after completing the course, they were considering academic pharmacy as a career. PMID- 22438603 TI - The impact of team-based learning on a foundational pharmacokinetics course. AB - OBJECTIVE: To assess the impact of team-based learning (TBL) in a foundational pharmacokinetics course. DESIGN: The course was arranged into 5 modules based on the TBL format. Each module contained preclass preparation; readiness-assurance process; and in-class, clinical cases. Survey instruments on professionalism and attitudes of team learning were administered pre- and post-course. ASSESSMENT: Examination grades focused at the evaluation/creation level were significantly higher in the TBL format compared with the previous year. Professionalism scores increased over the course of the semester, particularly in altruism and honesty. Other measures of team-learning attitudes significantly increased over time, although there was no change in major subscales. End-of-semester course evaluations showed improvements in active engagement and in various areas of skill development. CONCLUSION: The TBL format can be used successfully in a foundational pharmacokinetics course to increase higher levels of learning, team learning skills, and professionalism in pharmacy students. PMID- 22438604 TI - Using Facebook to facilitate course-related discussion between students and faculty members. AB - OBJECTIVES: To use Facebook to facilitate online discussion of the content of a Comprehensive Disease Management course and to evaluate student use and perceptions of this exercise. DESIGN: A Facebook page was created and coordinators encouraged students to "like" the page and to post and view study tips, links, or questions. At the end of the course, students' use and perceptions were evaluated using an anonymous survey tool. ASSESSMENT: At the end of week 1, there were 81 followers, 5 wall posts, and 474 visits to the course Facebook page. At peak use, the page had 117 followers, 18 wall posts, and 1,326 visits. One hundred nineteen students (97% of the class) completed the survey tool. Twenty-six percent of students contributed posts compared to 11% who posted on the course discussion board on Blackboard. Students were more likely to post and be exposed to posts on Facebook than on Blackboard. Students found Facebook helpful and 57% said they would miss Facebook if use was not continued in subsequent courses. CONCLUSIONS: Students in a Comprehensive Disease Management course found the addition of a Facebook page a valuable study tool and thought most posts added to their learning. PMID- 22438605 TI - A multi-instructor, team-based, active-learning exercise to integrate basic and clinical sciences content. AB - OBJECTIVES: To introduce a multiple-instructor, team-based, active-learning exercise to promote the integration of basic sciences (pathophysiology, pharmacology, and medicinal chemistry) and clinical sciences in a doctor of pharmacy curriculum. DESIGN: A team-based learning activity that involved pre class reading assignments, individual-and team-answered multiple-choice questions, and evaluation and discussion of a clinical case, was designed, implemented, and moderated by 3 faculty members from the pharmaceutical sciences and pharmacy practice departments. ASSESSMENT: Student performance was assessed using a multiple-choice examination, an individual readiness assurance test (IRAT), a team readiness assurance test (TRAT), and a subjective, objective, assessment, and plan (SOAP) note. Student attitudes were assessed using a pre- and post-exercise survey instrument. Students' understanding of possible correct treatment strategies for depression improved. Students were appreciative of this true integration of basic sciences knowledge in a pharmacotherapy course and to have faculty members from both disciplines present to answer questions. Mean student score on the on depression module for the examination was 80.4%, indicating mastery of the content. CONCLUSIONS: An exercise led by multiple instructors improved student perceptions of the importance of team-based teaching. Integrated teaching and learning may be achieved when instructors from multiple disciplines work together in the classroom using proven team-based, active-learning exercises. PMID- 22438606 TI - Impact of pharmacists' participation in a pharmacotherapy follow-up program. AB - OBJECTIVE: To evaluate the impact of a continuing pharmacy education (CPE) course on Spanish community pharmacists' participation in a pharmacotherapy follow-up program. DESIGN: Participation in a CPE course offered 4 times over a 4-year period via satellite teleconferencing was monitored and the data analyzed to determine the course's impact on community pharmacists' participation in a pharmacotherapy follow-up program. ASSESSMENT: Community pharmacists' participation in the pharmaceutical care CPE course had a slightly positive impact on their participation in the pharmacotherapy follow-up program. In the best profiles, there was a probability of 7.3% that participants would participate in the pharmacotherapy follow-up program. CONCLUSIONS: Completion of pharmaceutical care CPE courses did not have a significant impact on pharmacists' participation in a pharmacotherapy follow-up program. PMID- 22438607 TI - The Hispanic Americans Baseline Alcohol Survey (HABLAS): Acculturation, Birthplace and Alcohol-Related Social Problems Across Hispanic National Groups. AB - OBJECTIVE: To examine the association between acculturation, birthplace, and alcohol-related social problems across Hispanic national groups. METHOD: 5,224 Hispanic adults (18+ years) were interviewed using a multistage cluster sample design in Miami, New York, Philadelphia, Houston, and Los Angeles. RESULTS: Multivariate analysis shows no association between acculturation and problems among men or women. Birthplace is a risk factor for social problems among both genders. Among men, Mexican Americans, Puerto Ricans, and South/Central Americans are more likely to report social problems than Cuban Americans. Other risk factors for men are unemployment, a higher volume of drinking, and a higher frequency of binge drinking. Among women, Mexican American origin and binge drinking are also risk factors for reporting problems. CONCLUSIONS: U.S.-born Hispanics may experience stress and other detrimental effects to health because of their minority status, which may increase the likelihood of more drinking and the development of alcohol-related problems. PMID- 22438608 TI - Cytogenetic biomonitoring in petrol station attendants: A micronucleus study. AB - BACKGROUND: Benzene, which is a major organic product, on chronic exposure can result in many malignant disorders, and therefore exposure to gasoline vapors is classified by the International Agency for Research of Cancer as possible carcinogenic to humans. Petrol station attendants are chronically exposed to petroleum derivatives through inhalation of petrol during vehicle refuelling. AIM: This study is aimed to investigate cytogenotoxic damage in exfoliated buccal cells obtained from petrol station workers and control subjects using micronucleus (MN) test. MATERIALS AND METHODS: This study was carried out on 30 petrol station attendants working at different petrol stations located in Indore. The control group consisted of 30 healthy subjects who were not exposed to benzene. Buccal cell samples were collected at the end of the work shift. Slides were stained and were evaluated to determine the MN frequencies. Exposure monitoring was performed by the detection of phenol excreted in the urine. Urinary phenol measurements were performed following the colorimetric quantitative determination method of Yamaguchi and Hayashi. RESULTS: Variations in MN frequencies were seen in control and petrol bunk attendants. CONCLUSION: The MN test in exfoliated epithelial cells seems to be a useful biomarker of occupational exposure to genotoxic chemicals. Phenol is the principal metabolite of benzene. Therefore, phenol concentration in the urine of exposed workers can be used as a biomarker of external exposure. PMID- 22438609 TI - Evaluation of precision of guidance techniques in image guided fine needle aspiration cytology of thoracic mass lesions. AB - BACKGROUND: Transthoracic fine needle aspiration cytology (FNAC) is an established and safe technique for diagnosis of thoracic mass lesions. Computed tomography (CT) scan depicts clear anatomical details and provides access to any area of the body. It is, however, expensive and the needle is not passed in real time. Ultrasound is cheaper, radiation free, and allows real time monitoring. Its limitations are obscurement of lesions by aerated lung, smaller, deep seated, and cavitary lesions. AIMS: This study aims to compare sensitivity and specificity of CT scan and ultrasonography (USG) in thoracic FNAC. MATERIALS AND METHODS: The study was conducted on patients who presented with thoracic mass lesions in lungs, mediastinum, hilar lymph nodes, thoracic vertebrae, paraspinal soft tissue, and pleura. One hundred and twenty patients were studied. Only those cases in which sonographic guidance was not possible were taken up for CT guided FNAC. The lesions were assigned to benign and malignant categories and into specific diagnoses where possible. Biopsy correlation was available in 113 cases. Patients were lost to follow-up in five lung and two mediastinal masses. STATISTICAL ANALYSIS: Statistical tests applied included diagnostic tests for sensitivity and specificity. RESULTS: An accuracy of 70.8% was found for image guided FNACs with a sensitivity and specificity of 92.2% and 100%, respectively. CT had a sensitivity of 93.2% and specificity of 100%. For USG guidance, the same was 91.3% and 100%, respectively. CONCLUSIONS: Precision of USG and CT scan is comparable for guidance in FNAC from thoracic mass lesions. PMID- 22438610 TI - Diagnostic utility of the cell block method versus the conventional smear study in pleural fluid cytology. AB - BACKGROUND: The cytological examinations of serous effusions have been well accepted, and a positive diagnosis is often considered as a definitive diagnosis. It helps in staging, prognosis and management of the patients in malignancies and also gives information about various inflammatory and non-inflammatory lesions. Diagnostic problems arise in everyday practice to differentiate reactive atypical mesothelial cells and malignant cells by the routine conventional smear (CS) method. AIMS: To compare the morphological features of the CS method with those of the cell block (CB) method and also to assess the utility and sensitivity of the CB method in the cytodiagnosis of pleural effusions. MATERIALS AND METHODS: The study was conducted in the cytology section of the Department of Pathology. Sixty pleural fluid samples were subjected to diagnostic evaluation for over a period of 20 months. Along with the conventional smears, cell blocks were prepared by using 10% alcohol-formalin as a fixative agent. Statistical analysis with the 'z test' was performed to identify the cellularity, using the CS and CB methods. Mc. Naemer's chi(2)test was used to identify the additional yield for malignancy by the CB method. RESULTS: Cellularity and additional yield for malignancy was 15% more by the CB method. CONCLUSIONS: The CB method provides high cellularity, better architectural patterns, morphological features and an additional yield of malignant cells, and thereby, increases the sensitivity of the cytodiagnosis when compared with the CS method. PMID- 22438611 TI - Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India. AB - BACKGROUND: Regardless of the availability of newer and more sophisticated modalities of investigation, urinary tract cytology still remains the most commonly used non-invasive test for the diagnosis of bladder cancer. AIMS: As hematuria is the commonest presenting symptom in patients with malignancy of urinary tract, we undertook this study to know the usefulness of urine cytology in evaluation of the hematuric patients for malignancy. MATERIALS AND METHODS: A total of 21,557 fresh voided urine samples received at our tertiary care referral centre over a period of three years were included in the study. Of these, 1428 cases had hematuria, criteria of either gross or microscopic. RESULTS: Among these hematuric cases included in the study, 32.5% (464 cases) were found to have positive finding of atypical cells. In these cases with atypia, 9.5% (136 cases) were proved to have malignancy both with the histopathological biopsy and cystoscopic findings. Other cases of atypia were found to be of reactive origin, either due to instrumentation or foreign body. A large number of hematuric cases, that is, 964 cases (67.5%) were negative for atypical cells. CONCLUSIONS: The limited ability of urine cytology to detect low grade bladder tumors, its subjectivity and lack of uniformity in reporting, all render urine cytology a less than perfect tool. With added collaboration between clinician and cytopathologist, urine cytology can be used an adjunct tool in evaluation of patients with hematuria. PMID- 22438612 TI - Clinicopathological importance of Papanicolaou smears for the diagnosis of premalignant and malignant lesions of the cervix. AB - BACKGROUND: Premalignant and malignant lesions are not uncommon in Pakistani women, especially in the older age-groups AIM: This study was conducted to determine the clinicopathological importance of conventional Papanicolaou (Pap) smears for the diagnosis of premalignant and malignant lesions of the cervix. MATERIALS AND METHODS: Pap smears of 1000 women were examined from January 2007 to June 2009. Only cases with neoplastic cytology were included. RESULTS: The overall frequency of normal, inadequate, neoplastic, and infective smears was 50%, 1.8%, 10.2%, and 38.3%, respectively. Most of the patients (67%) were in the postmenopausal age-group, with the mean age being 44.7+/-15.63 years. The commonest clinical signs/symptoms seen among the 102 patients with neoplastic gynecological lesions were vaginal discharge and abnormal bleeding (93/102;(91.2% and 62/102;60.7%). Of the 102 cases with neoplastic lesions 46 patients (45%) had low-grade squamous cell intraepithelial lesions (LSILs), 22 (21.5%) had high grade squamous cell intraepithelial lesions (HSILs), 14 (13.7%) had squamous cell carcinoma, and 6 (5.8%) showed features of adenocarcinoma. Ten (9.8%) cases showed cytology of atypical squamous cells of undetermined significance (ASCUS) and four (3.9%) cases had atypical glandular cells of undetermined significance (AGUS). CONCLUSION: We conclude that cervical smear examination is well suited for diagnosing neoplastic disease. It is clear that cervical neoplastic lesions are becoming a problem in Pakistan. PMID- 22438613 TI - Clinicopathologic study of parapharyngeal tumors. AB - BACKGROUND: Parapharyngeal space (PPS) tumors are rare. Three main groups are identified, namely those of salivary origin, neurogenic tumors and paragangliomas. Early pathological classification of PPS tumors is important for pin point diagnosis and timely management. AIMS: The PPS is a complex anatomical potential space and poses high risk of per and postoperative complication. This study was done to perform optimum preoperative evaluation by clinicoradiologic correlation and guided fine needle aspiration cytology (FNAC) which is essential to minimize intraoperative risk. MATERIALS AND METHODS: Guided FNAC was carried out to diagnose parapharyngeal tumors in 48 patients from January 2008 to January 2010. The inflammatory lesions were excluded in the present study. Correlation with histopathology was done in all the cases. RESULTS: The mean age for all the patients was 38.2 years. There were 23 male and 25 female subjects. Seventy nine percent of the lesions were benign with pleomorphic salivary adenoma being the commonest, while only 20.8% of the lesions were malignant. All the patients presented with neck swelling. No complication was encountered in the present study. CONCLUSION: FNAC can replace incisional biopsy which may be hazardous in this area. Immediate treatment can be planned based on the FNAC report. PMID- 22438614 TI - Study of computed tomography-guided fine needle aspiration cytology of thoracic lesions. AB - BACKGROUND: Thoracic lesions include a variety of benign and malignant lesions of lung, pleura, chest wall and mediastinum. Transthoracic fine needle aspiration cytology (TFNAC) is a well established technique for work up of thoracic lesions. Computed tomography (CT) has extended the use of FNAC, because it is accurate for localization, needle puncture and above all it permits evaluation of lesions less than 1 cm. This diagnostic modality has a high sensitivity, specificity and is of relatively low cost. AIMS: To assess the role of CT-guided FNAC in the diagnosis of thoracic lesions. MATERIALS AND METHODS: Eighty three patients with various thoracic lesions were evaluated by CT guided FNAC. The cytologic findings were compared with cell blocks whenever available. RESULTS: Conclusive opinion was offered on cytology smears in 80 patients. Lesions of the lung were the most common. Neoplastic lesions in our study accounted for 65% of cases. The sensitivity and specificity of the study were 93.33% and 100%, respectively. CONCLUSION: CT-guided TFNAC is a low cost, safe, minimally invasive and accurate diagnostic procedure with high sensitivity and specificity and when interpreted in conjunction with clinical and radiological data can prevent some of the pitfalls in diagnosis. PMID- 22438615 TI - Urothelial cells in smears from cervix uteri. AB - OBJECTIVES: To establish the cytological criteria to identify the urothelial cells in cervical smears in order to avoid mistakes in the cytological diagnosis. MATERIALS AND METHODS: Cervical smears from 34 post menopausal women with vesicovaginal fistulas, advanced bladder prolapse and genital erosive lichen planes (vulvar kraurosis) (Group 1) and transitional cell metaplasia of the cervix (TCM, Group 2) were stained with Papanicolaou technique. The cervical samples were taken during the routine annual examination for prevention of the uterine cancer. RESULTS: The smears of cervix from Group 1 showed urothelial cells from the three layers of the transitional epithelium. The umbrella cells are the bigger ones with relatively large nuclei. Frequently, they are multinucleated with single or multiple nucleoli and a typical "frothy" cytoplasm (cytoplasmic vacuoles). The cells of the Group 2 showed nuclei with oval to spindled shapes, some tapered ends, less cytoplasm than squamous metaplastic cells, powdery chromatin, small nucleoli and nuclear grooves. CONCLUSIONS: The umbrella cells may be mistaken for dysplastic cells originating in low grade squamous intraepithelial lesions lesions (LSILs) due to their nuclear and cytoplasm sizes. Therefore, it is important to know the possibility of their appearance in the cervical smears, especially in post menopausal patients in order to avoid a false diagnosis of an intraepithelial lesion. It is unlikely that deeper cells of urothelium would be confused with high grade squamous intraepithelial lesion (HSIL) cells. However, their presence might be a reason of mistake in the diagnosis. TCM is an under-recognized metaplastic phenomenon of the cervix and vagina, which is a mimicker of high-grade squamous intraepithelial lesion. The differential characteristic between umbrella cells, cells from TCM and the deeper urothelial cells, and LSIL and HSIL are detailed in the present paper. PMID- 22438616 TI - Detection of abnormal cervical cytology in Papanicolaou smears. AB - BACKGROUND: Cervical cytology by Papanicolaou (Pap) smears is an effective means of screening for cervical premalignant and malignant conditions. Cervical intra epithelial neoplasia (CIN) and cervical cancer remain important health problems for women worldwide. AIM: To study the role of Pap smear in detecting premalignant and malignant lesions of cervix; and to determine the prevalence of various lesions. MATERIALS AND METHODS: This study is based on 300 patients who attended the out-patient Department of Obstetrics and Gynaecology. Pap smears were prepared from patients presenting with complaints like vaginal discharge, post-coital bleeding, inter-menstrual bleeding, dyspareunia, and pain lower abdomen. After fixation and staining, each smear was carefully examined. RESULTS: Epithelial cell abnormalities were found in 5% smears, atypical squamous cells of undetermined significance (ASCUS) in 0.3%, squamous intraepithelial lesion (SIL) in 3.4% which includes low grade squamous intraepithelial lesion (LSIL) (2.7%) and high grade squamous intraepithelial lesion (HSIL) 0.7%. Invasive carcinoma was seen in 1.3% cases. Mean age of the patients with diagnosis of LSIL was 32.3 years and for HSIL, it was 40.5 years. The mean age of the patients with invasive carcinoma was 57 years. CONCLUSION: Premalignant and malignant lesions of cervix are not uncommon in our set up and can be diagnosed early by Pap smears. PMID- 22438617 TI - Cytomorphological spectrum of hydatidosis with eosinophilia, clinically mimicking a malignancy: An uncommon presentation. PMID- 22438618 TI - Aggressive giant cell tumor of the anterior arc of the rib. AB - Giant cell tumor of bone also known as osteoclastoma is a distinct clinical, roentgenographic and pathologic entity with specific characteristics. It is a benign but locally aggressive neoplasm, classically seen as a purely lytic lesion of the epiphyseal or metaphyseal-epiphyseal region of long tubular bones extending to the articular surface. It usually occurs after skeletal maturation and is one of the rare bone tumors that more frequently affects women. Even though rarely it can occur in ribs, it usually occurs in the posterior aspect. We report here a case of giant cell tumor originating from the anterior arc of the rib diagnosed on fine needle aspiration cytology. PMID- 22438619 TI - Fine needle aspiration cytology of unilesional mycosis fungoides d'emblee. AB - Primary cutaneous T-cell lymphoma is a rare lymphoproliferative disorder accounting for 2% of all lymphomas. Mycosis fungoides (MF) is a rare, albeit commonest form of primary cutaneous T cell lymphoma. MF d'emblee is an uncommon variant which is easily mistaken clinically for epithelial malignancy. Diagnosis at cytology is challenging due to low degree of suspicion, rare occurrence and diverse morphology. We report a case of 51-year-old male presenting with a solitary nodulo-ulcerative lesion over right thigh. Smear showed atypical lymphocytes with hyper-convoluted cerebriform nuclei along with few mature lymphocytes consistent with MF. To our knowledge, this is the first report of unilesional MF d'emblee diagnosed at fine needle aspiration cytology (FNAC). Our case emphasizes that FNAC is an accurate method for early diagnosis and clinical staging of patients with MF. PMID- 22438620 TI - Multicentric synchronous recurrent aggressive fibromatosis. AB - Extra-abdominal desmoid tumors are known as aggressive fibromatosis (AFM). Synchronous and metachronous multicentric aggressive fibromatosis are rare lesions and pose dilemma in diagnosis and management. A rare and interesting case of recurrent multicentric, synchronous AFM is presented which to the best of our knowledge has not been reported earlier. A young male presented with well defined, hard, fixed swelling on the thigh. Resected tumor mass on histopathology was diagnosed as an extra abdominal fibromatosis. He presented again after two months with swelling at the same site; and two more swellings on the foot. Fine needle aspiration cytology (FNAC) from all three sites was performed; and was suggestive of benign spindle cell lesion of fibrogenic origin with the possibility of multicentric synchronous recurrent aggressive fibromatosis. PMID- 22438621 TI - Granular cell tumor in inguinal region: A case of mistaken identity on cytology. AB - A 63-year-old male presented with sudden increase in size of a right inguinal swelling which was present for the past 10 years. Clinical diagnosis of inguinal soft tissue mass/lymph node enlargement was made and patient was investigated further for a conclusive diagnosis. Ultrasound examination suggested it to be a lymph node and guided fine needle aspiration cytology was performed. Cytology was suggestive of a reactive lymph node. Subsequently, an excision biopsy was performed that revealed a granular cell tumor with many lymphoid aggregates. On reviewing the cytosmears, we realised that the granular neoplastic cells were mistaken for histiocytes; and the lymphoid background and bare nuclei mislead us to consider it a reactive lymph node. Since granular cell tumor can occur almost anywhere, a careful examination of cytosmears and knowledge of its distinctive cyto-morphological features would be helpful in providing an accurate diagnosis on cytology. PMID- 22438622 TI - Cytodiagnosis of secretory carcinoma of the breast. AB - Secretory carcinoma is a rare form of breast carcinoma which has a predilection for juveniles and young adults (usually less than 30 years of age), becoming progressively less common with advancing age. It is a low grade breast carcinoma which shows distinct features at histology. Diagnosis of this carcinoma on fine needle aspiration cytology (FNAC) is difficult. We report a case of a 62-year-old woman diagnosed to have secretory carcinoma of breast on FNAC. Histopathological examination confirmed the diagnosis. The recognition of secretory carcinoma is important because the cytological findings can be confused with those of lactating breast. Preoperative diagnosis is essential for appropriate surgical therapy. Secretory carcinoma is reported to have good prognosis, but surgical therapy with an axillary node dissection is recommended, since axillary metastases have been found in approximately 30% of the recorded cases. PMID- 22438623 TI - Fine needle aspiration cytology in fibromatosis. AB - Fibromatosis form a spectrum of clinicopathologic entities characterized by the infiltrative proliferation of fibroblasts that lack malignant cytologic features. The fibromatosis can be localized or infiltrative and multicentric and can involve internal tissues and organs as the mesentery, retroperitoneum, breast, and almost every organ and region of the body, including the bones, the meninges and the central nervous system. We report a case of 37-year-old male who presented with a right supraclavicular mass with superficial infiltrative type of fibromatosis and fine needle aspiration cytology (FNAC) was performed. We report this case because of limited literature of FNAC in fibromatosis and quick role of FNAC in the diagnosis of fibromatosis. PMID- 22438624 TI - Oncocytic carcinoma of lip: A rare neoplasm of minor salivary gland. AB - Oncocytic carcinoma is an extremely rare neoplasm of the salivary gland, with only a few cases reported in literature till date. We report the occurrence of this rare lesion in lip in a 43-year-old female presenting with a progressively increasing swelling for which excision was done. Fine needle aspiration was done and the smears revealed tumor cells with well-defined cell borders, round to oval, central to eccentrically located moderately pleomorphic nuclei with fine chromatin, prominent nucleoli and abundant eosinophilic granular cytoplasm. Microscopic examination of the resected tumor showed solid sheets, nests, islands and cords of oncocytic cells diffusely infiltrating the surrounding tissues. After 5 months, the patient again presented with bilateral submandibular and right axillary lymphadenopathy revealing metastatic deposits from oncocytic carcinoma. We report this case of oncocytic carcinoma because of its unusual location, the minor salivary gland of lip being a rare site for the tumor. PMID- 22438625 TI - Mucinous carcinoma of the male breast with axillary lymph node metastasis: Report of a case based on fine needle aspiration cytology. AB - Pure mucinous carcinoma of the male breast is an uncommon malignant breast neoplasm and extremely rare is its metastasis in axillary lymph nodes. Most of these cases have been diagnosed after surgical resection with only a few cases diagnosed on fine needle aspiration cytology (FNAC). Although FNAC is well established in the evaluation of breast masses in females there are few reports in males. We are presenting a case of pure mucinous carcinoma of the male breast with metastasis in axillary lymph nodes in a 75-year-old male diagnosed by FNAC and confirmed on histopathology. PMID- 22438626 TI - Sebaceous carcinoma of the eyelid diagnosed on fine needle aspiration cytology. AB - Sebaceous carcinoma of the ocular adnexa is a malignant neoplasm which has aggressive local behavior and can metastasize to regional lymph nodes and distant organs. It is a malignant neoplasm known to masquerade as other benign and less malignant lesions, resulting in delay in diagnosis and relatively high morbidity and mortality. Aspiration cytological features of this neoplasm have not been well characterized in the literature. We report a case of this tumor diagnosed on fine needle aspiration. Clinically, a diagnosis of chalazion was made and fine needle aspiration cytology (FNAC) was performed. Cytological diagnosis of a malignant tumor with closest resemblance to sebaceous carcinoma was suggested which was confirmed on histopathology. Eyelid reconstruction was done after histopathological confirmation of tumor-free margins. The article highlights the role of FNAC in early diagnosis and subsequent appropriate surgical management of eyelid sebaceous gland carcinoma to prevent recurrence and metastasis. PMID- 22438627 TI - Detection of lupus erythematosus cells in pleural effusion: An unusual presentation of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory disease typically diagnosed by a combination of physical findings and clinical laboratory testing. Several decades ago, the diagnosis of lupus included the lupus erythematosus (LE) cell assay. SLE is associated with pleuropulmonary manifestations in well over 50% of cases. Although pleural effusion is common but very rarely is the initial manifestation of disease. There are very few reports of SLE diagnosed in a cytopathology laboratory. We report an unusual case of SLE in a 16-year-old female who presented with acute shortness of breath, fever and cough. Her chest radiograph showed bilateral pleural effusion. This effusion was tapped and sent to the cytopathology laboratory. The cytological examination of the pleural fluid revealed numerous LE cells and led to the diagnosis of SLE. Autoimmune serology techniques such as anti-nuclear antibody staining have replaced the LE cell assay. However, as presented in this report and found in a review of the literature, the in vivo finding of LE cells by cytopathology can provide an important clue to the diagnosis of SLE, especially when associated with an uncommon presentation. PMID- 22438628 TI - Oncocytic lesion of parotid gland: A dilemma for cytopathologists. AB - Oncocytes are epithelial cells with abundant, granular, eosinophilic cytoplasm due to presence of numerous large mitochondria of varied sizes. The presence of oncocytes in salivary glands can occur in a variety of conditions. Here, we present a rare case of a 68 year old male patient who presented with a 6 cm diameter swelling in the right parotid region. A fine needle aspiration cytology done from the lesion showed a cellular oncocytic lesion. A possibility of oncocytoma was entertained. Histopathology of the mass showed a rare entity called diffuse hyperplastic oncocytosis. Originally believed to be a metaplastic process, oncocytes can occur in various lesions ranging from hyperplastic conditions to malignant neoplasms. However, diagnosis on cytological smears can be very challenging for the cytopathologist. PMID- 22438629 TI - Fine needle aspiration diagnosis of Rosai-Dorfman Disease involving thyroid. AB - Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy is a rare disease involving the lymph nodes. Extranodal RDD involving the thyroid is extremely rare. So far, six cases of RDD involving thyroid have been reported in the literature; all have occurred in females with a mean age of 56.3 years. Clinically, radiologically and cytologically, all the cases were initially diagnosed as thyroid malignancies with lymph nodal metastasis. The final diagnosis was made histologically only after total thyroidectomy. We herein, present a seventh case of RDD involving the thyroid in a 15-year-old female, diagnosed first on fine needle aspiration cytology (FNAC). We conclude that FNAC is a useful diagnostic procedure for RDD involving thyroid; it can avoid an unnecessary thyroidectomy. PMID- 22438630 TI - Cytological diagnosis of tuberculous cervicitis: A case report with review of literature. AB - Tuberculosis of cervix is a rare disease. Tuberculosis usually affects women of childbearing age, indicating hormone dependence of infection. The patient presents with menstrual irregularities, infertility or vaginal discharge. Cervical lesions presents as papillary/vegetative growth or ulceration mimicking cervical cancer. Cervical Papanicolaou (Pap) smear plays an important role in diagnosing the disease by non-invasive technique in which the presence of epithelioid cells and Langhan's type of giant cells is diagnostic. However, other causes of granulomatous cervicitis should be considered and ruled out. Ziehl Neelsen (ZN) stain for acid fast bacilli, fluorescent technique, biopsy and culture help in confirming the disease. We present the case of a 45-year-old female, who presented with vaginal discharge, dysfunctional uterine bleeding, first degree uterine descent with grade II cystocele and rectocele and cervical ulcer. Pap smear revealed epithelioid cells and Langhan's type of giant cells, confirmed by ZN stain of cervical smear, fluorescent technique and culture. PMID- 22438631 TI - Hemangioendothelioma of soft tissue: Cytological dilemma in two cases at unusual sites. AB - Hemangioendothelioma is a rare vascular tumor of intermediate malignancy. Cytologically, it can simulate a non-vascular malignant tumor. We report two cases of this tumor, which were misdiagnosed at cytology. In the first case, a 27 year-old man presented with an anterior abdominal wall tumor. Fine needle aspiration cytology (FNAC) of the tumor showed polygonal cells with vacuolated cytoplasm in clusters having moderate nuclear atypia in a background of necrosis. A diagnosis of metastatic carcinoma was made. The histological examination showed features of epithelioid hemangioendothelioma. In the second case, a 13-year-old female child presented with unilateral enlargement of the right tonsil. At ultrasound-guided FNAC, a diagnosis of, 'small round cell tumor, could be consistent with alveolar rhabdomyosarcoma,' was made. The histological examination showed features of papillary intralymphatic angioendothelioma (Dabska's tumor). We conclude that epithelioid hemangioendothelioma should be considered in the differential diagnosis of metastatic carcinoma and small round cell tumor even at unusual sites. PMID- 22438632 TI - Isolated intrathyroidal metastasis revealing an occult lung adenocarcinoma. AB - Thyroid gland is an uncommon site of tumor metastasis inspite of rich vascular supply. Most of the cases are picked up after the diagnosis or during the work up for the primary. Unexpected involvement of thyroid gland as the first presenting sign in a primary lung adenocarcinoma is an extremely rare, however, clinically significant finding, upstaging the disease. Fine needle aspiration cytology as a primary tool for detecting metastasis in thyroid is a rapid procedure, associated with high accuracy and low morbidity. PMID- 22438633 TI - Eggs containing larvae of Enterobius vermicularis in vaginal smear. AB - Enterobius vermicularis also known commonly as pinworm is the most common intestinal parasite. It is a nematode that inhabits the human terminal ileum, colon and appendix. The fertilized female migrates to the perianal area where eggs are deposited but occasionally introduces itself into adjacent orifices, most commonly the female genitourinary tract. Thus the eggs can be seen in the vaginal smear as a result of contamination. We report a case wherein the patient presented with signs and symptoms of vulvovaginitis. In her vaginal smear there were eggs of Enterobius vermicularis which showed a coiled larva within it. In the background there were plenty of acute inflammatory cells. This patient responded favorably to antihelminthics. We report this case to highlight the morphology of the parasite and also to emphasize that such findings should not be neglected. Timely reporting and appropriate treatment of such cases will prevent further complications of this parasite including endometritis, salphingitis and peritonitis. PMID- 22438634 TI - Poorly differentiated (insular) thyroid carcinoma arising in a long-standing colloid goitre: A cytological dilemma. AB - Poorly differentiated (insular) thyroid carcinoma (PDITC) is an uncommon thyroglobulin producing neoplasm intermediate in aggressiveness between well differentiated carcinomas of follicular cell origin and undifferentiated anaplastic carcinoma. Its cytomorphological recognition is essential for planning surgery and subsequent management as it is known for its aggressive behavior, advanced stage at presentation, local recurrences and rapid dissemination. We report a case of PDITC arising in a long-standing goiter, in which presence of microfollicular structures and minimal necrosis resulted in difficulty in distinguishing it from a follicular neoplasm of thyroid. PMID- 22438635 TI - Response to "CT-guided fine needle aspiration cytology diagnosis of extra-adrenal pheochromocytoma". PMID- 22438636 TI - Readership survey 2011. PMID- 22438637 TI - Autofluorescence spectroscopy of betel quid chewers and oral submucous fibrosis: A pilot study. AB - CONTEXT: Oral lesions related to the use of commercially available tobacco (gutkha) is going to pose a major challenge for health care providers in India. Therefore, techniques that are useful for mass screening of the public for early identification of pre-cancerous lesions and conditions are necessary to overcome this challenge. AIMS: To identify the differences in autofluorescence spectra of normal oral mucosa, mucosa of betel quid chewers, and mucosa of oral sub mucous fibrosis. MATERIALS AND METHODS: Group I consist of 15 individuals with clinical diagnosis of oral submucous fibrosis, Group II consists of 18 individuals without oral submucous fibrosis, having the habit of betel quid (gutkha) chewing and Group III consists of 18 normal individuals without the habit of betel quid chewing. Both males and females were included in the study with their age ranging from 18 to 53 years. In vivo fluorescence spectra were obtained using an optical fibre probe attached to Fluoromax-2 spectrofluorometer in the Department of Medical Physics, Anna University, Chennai, India. STATISTICAL ANALYSIS USED: Fisher's Chi square test was used for statistical analysis. Probability value (P value) was also obtained to discriminate the statistical differences between the three groups. RESULTS: The averaged emission and excitation spectra of oral submucous fibrosis was significantly less compared to normal mucosa and betel quid chewers. The statistical findings showed significant differences (P<0.001) between oral submucous fibrosis and the other two groups. CONCLUSIONS: Fluorescence spectroscopy can be used effectively for diagnosing the individuals affected by OSMF. However, this technique was unable to discriminate the betel chewers mucosa from normal individuals. PMID- 22438638 TI - Establishment of field change by expression of cytokeratins 8/18, 19, and MMP-9 in an apparently normal oral mucosa adjacent to squamous cell carcinoma: A immunohistochemical study. AB - BACKGROUND: Squamous cell carcinoma is the most frequent malignancy of the oral cavity. The survival rate of this malignancy has not improved from past two decades. The major factors responsible for this could be due to loco regional and distant metastatic spread. However, the other important prognostic factor is concomitant occurrence and recurrence of multiple primary carcinomas in the head and neck region, which is explained as the concept of field cancerization. The evidence to support the field change in normal mucosa of Oral squamous cell carcinoma (OSCC) through biological markers using immunohistochemistry has always been challenging. AIM: Hence, the aim of the present research is to identify changes in the expression of CK 8/18, 19, and MMP-9 to visualize field changes in the clinically normal mucosa adjacent to OSCC and compare with non neoplastic normal oral mucosa. MATERIALS AND METHODS: 20 cases of OSCC with radical resection specimens were included in the study. Lesional tissue and adjacent normal looking mucosa were taken during grossing. Ten cases of non-neoplastic normal oral mucosa are also included in the study. Markers such as CK 8/18, CK 19, and MMP-9 are used by the immunohistochemical method in this present study. RESULT AND CONCLUSION: The enhance expression of CK 8/18 (80%), CK 19 (70%), and MMP 9 (90%) in ANM was noted and furthermore in six ANM showing severe dysplasia with enhance expression of CK 8/18, CK 19, and MMP 9 in the apparently normal oral mucosa can suggest a field cancerization. PMID- 22438639 TI - Pediatric jaw tumors: Our experience. AB - BACKGROUND: Reports of series of central jaw tumours in children are rare hence predicting their biological behaviour as well as treatment, prognosis have not been documented from this part of the world. AIM: To study retrospectively, the paediatric central jaw tumours, reported to our institute with relation to site of occurrence, presentation and biological behaviour. MATERIALS AND METHODS: All consecutive patients (<18 years), between 2004-2010, histologically diagnosed as having an intraosseous tumour or tumour-like lesions formed the study population. Patients fulfilling the inclusion criteria were only considered for further study. The entire study material was analyzed and grouped into various categories for logical conclusions. The data accumulated were grouped, entered and analyzed. RESULTS: Sixty-one cases fulfilled the criteria. Gender distribution was equal, with mandible predominance (2.2:1) and a predominance of non-odontogenic lesions (2:1). There were 4 malignant and 57 benign conditions. Anterior jaw lesions were 23 while 38 were present in the posterior region of jaws (1:1:6). CONCLUSIONS: The pattern of central jaw tumours presentation in children from this part of India has been documented. In this study, paediatric jaw tumours are less common compared to those in adults with non-odontogenic tumours being common. The finding of the present study indicates that an impacted tooth, beyond the eruption time deserves more attention for the reason of associated pathologies in children. PMID- 22438640 TI - Oropharyngeal candidosis relative frequency in radiotherapy patient for head and neck cancer. AB - BACKGROUND: Radiation given during treatment of oral and pharyngeal malignancy frequently causes alteration of the oral environment predisposing to the colonization of the oral mucosa by yeast species most frequently Candida. OBJECTIVE: Thus, this study was undertaken in 107 patients to find out association between radiation therapy and frequency of oropharyngeal candidosis, to quantitate colony forming units (CFUs) to identify Candida at species level and to check the incidence of serotype A and B in C. albicans. MATERIALS AND METHODS: The study was done on patients suffering from oropharyngeal cancer who were advised radiotherapy. The oral rinse collection method was used to collect the sample. Sabourauds Dextrose Agar (SDA) was used as primary culture media and subsequently speciation was done using standard techniques. The strains of C. albicans were serotyped employing the method described by Hansclever and Mitchell (1961, J Bacteriol 1961;82:570-3). RESULTS: 26.16% patients were mycologically positive for candida before radiotherapy with CFUs 100. 14 +/- 59.11 that increased to 60.74% patients during radiotherapy with an increase in CFUs to 490.15 +/- 207.97. Clinically, grading of mucositis was done and also individual signs and symptoms were noted in each patient. The occurrence of erythmatous lesions, ulceration, and xerostomia were found to be statistically significant (P<0.05). C. albicans was the most frequently encountered species with higher prevalence of serotype A suggesting higher virulent species. CONCLUSION: It is proposed that in such patients taking radiotherapy prophylactic antifungal treatment should be given specially in patients showing development of oral mucosal lesions such as erythmatous lesions, ulcerations, and complaining about dryness of mouth, that is, xerostomia irrespective of presence or absence of clinical oral candidosis. PMID- 22438641 TI - Isolation, identification, and carriage of candidal species in PHLAs and their correlation with immunological status in cases with and without HAART. AB - AIMS AND OBJECTIVES: To know the prevalence of Candidal colonization, and to isolate and know the Candidal species prevalent in the oral cavity from the oral rinse samples collected from the individuals attending to the Voluntary Counseling and Confidential Testing Center (VCCTC) and the antiretro-viral therapy (ART) Center at Government General Hospital, Guntur, Andhra Pradesh, South India. MATERIALS AND METHODS: The study group consisted of 50 HIV negative asymptomatic individuals (Group I); 50 HIV positive individuals (people living with HIV AIDS [PLWHA's]), who are naive to antiretro-viral therapy (direct walk in clients of VCCTC) (Group II); and 50 HIV positive individuals with CD4+ count less than 250 and who are started on highly active anti retroviral therapy (HAART) (Group III). Routine mycological tests for the isolation of pure cultures of Candida and also the speciation procedures were done. RESULTS: In the study group, 53 (Group I=11; Group II=23; Group III=19) were culture positive. The prevalence of Candida was comparatively high in the age range between 41-50 years in Group II; 51-60 years, in Group III. A male predominance was observed in the Group I (M:F=16:6) and Group III (M:F=20:18), with a slight female predominance in the Group II (F:M=24:22). The overall culture positivity was 35.3%. Candida albicans was the highest prevalent species (47.17% of the isolates). A comparison of the culture positivity with the CD(4) counts of the study subjects was statistically highly significant. A pair wise comparison of the culture positivity with that of the colony forming units/mL from the subjects showed a high significance between Group I and Group II, and between Group I and Group III. CONCLUSION: Candidal infections in immuno compromised patients are often severe, rapidly progressive, and difficult to treat and such patients have a definitive risk of developing oral candidiasis wherein, even the members of the normal oral flora may become pathogenic. Candida albicans is the common isolate. Nonalbicans species are also emerging as opportunistic pathogens. In view of this changing pattern, it is strongly recommended that species identification can help in much better treatment strategies, and thus, gain a good control over the disease. The findings of this study would be helpful in any further studies which, if done prospectively on a larger cohort, can be confirmatory. PMID- 22438642 TI - Role of angiogenesis in the pathogenesis of oral lichen planus. AB - BACKGROUND: The etiology of oral lichen planus (OLP) is not fully understood. It is generally considered to be a T-cell mediated chronic inflammatory oral mucosal disease. There is increasing evidence that chronic inflammation is linked to the diseases associated with endothelial dysfunction and is involved in the induction of aberrant angiogenesis. AIM: Our aim was to evaluate the role of angiogenesis in the pathogenesis of OLP by immunohistochemistry, using the CD34 antibody. MATERIALS AND METHODS: Forty tissue sections (7 of erosive lichen planus, 18 of reticular oral lichen planus, and 15 of normal oral mucosa), were assessed for microvessel density (MVD) in five selected areas of high inflammatory infiltrate by immunohistochemistry for the expression of CD34 antibody. RESULTS AND CONCLUSION: The mean MVD was 44.47 in the control group (normal oral mucosa) and 97.24 in the OLP group, showing that there is increased angiogenesis in the latter. Reticular OLP had mean MVD of 84.61 and erosive OLP had mean MVD of 129.71, showing relatively greater angiogenesis in erosive OLP as compared to reticular OLP. Thus, angiogenesis can be considered to play a role in both the etiopathogenesis and the progression of OLP. PMID- 22438643 TI - Determination of levels of salivary IgA subclasses in patients with minor recurrent aphthous ulcer. AB - CONTEXT: Recurrent Aphthous Ulcer (RAU) is an inflammatory disease characterized by recurrent, painful oral ulcers. It is of multifactorial etiology. Salivary immunoglobulins have important role in the protection of mucosal surfaces. AIM: The aim of this study was to determine salivary immunoglobulin A1 (IgA1) and IgA2 in acute and remission phases of the disease. MATERIALS AND METHODS: Thirty clinically confirmed cases of RAU and 30 age-and sex-matched controls were included in the study. After detailed case history and thorough clinical examination, 2 mL of saliva was collected in both acute and remission phases of the disease. The obtained saliva samples were subjected to quantification of IgA1 and IgA2 levels using RID kit. RESULTS: The mean IgA2 level was significantly higher (P<.001) in both acute and remission phase of the study group. The mean IgA1 level also showed a significant increase in the acute phase compared to remission as well as controls (P<.05). Females exhibited a higher level in acute phase for IgA1 and in both phases for IgA2 (P<.05). CONCLUSION: The results associated with clinical observations suggest that acute phase is characterized with increase in IgA2 that might reflect increased immune response as a possible result of the microbial stimulation seen in the acute phase in comparison to the remission period. IgA plays an important role in the pathogenesis of RAU and it can be used as a parameter to assess the mucosal immune status. PMID- 22438644 TI - Assessment of the alkaline phosphatase level in gingival crevicular fluid, as a biomarker to evaluate the effect of scaling and root planing on chronic periodontitis: An in vivo study. AB - CONTEXT: Clinical evaluation of gingivitis and/or periodontitis does not predict the progression or remission of the disease. Due to this diagnostic constraint, clinicians assume that the pathology has an increased risk of progression and plan treatments, despite the knowledge that all inflamed sites are not necessarily progressing. Extensive research has been carried out on gingival crevicular fluid (GCF) components that might serve as potential diagnostic markers for periodontitis. Among them alkaline phosphatase (ALP) levels in GCF has shown promise as a diagnostic marker. AIM: This study compares the levels of GCF alkaline phosphatase in patients with chronic periodontitis before and after scaling and root planing. MATERIALS AND METHODS: This study is an in vivo longitudinal study conducted on twenty patients with localized periodontitis. The GCF was collected from the affected site prior to scaling and root planing and ALP level estimated. The probing depth and plaque index at the site were also measured for correlation. Patients were recalled after 7, 30, and 60 days for reassessment. RESULTS: The GCF ALP values showed a sustained, statistically significant decrease after treatment. There was a positive correlation with probing depth but not with plaque index measured at each interval. CONCLUSION: The assessment of level of periodontal disease and effect of mechanical plaque control on the progression and regression of the disease can be evaluated precisely by the corresponding GCF ALP levels. Thus, alkaline phosphatase level is not only a biomarker for the pathology but also an indicator of prognosis of periodontitis. PMID- 22438645 TI - A comprehensive review of the genetic basis of cleft lip and palate. AB - Cleft lip and palate (CLP) are birth defects that affect the upper lip and the roof of the mouth. CLP has a multifactorial etiology, comprising both genetic and environmental factors. In this review we discuss the recent data on the etiology of cleft lip and palate. We conducted a search of the MEDLINE database (Entrez PubMed) from January 1986 to December 2010 using the key words: 'cleft lip,' 'cleft palate,' 'etiology,' and 'genetics.' The etiology of CLP seems complex, with genetics playing a major role. Several genes causing syndromic CLP have been discovered. Three of them-T-box transcription factor-22 (TBX22), poliovirus receptor-like-1 (PVRL1), and interferon regulatory factor-6 (IRF6)-are responsible for causing X-linked cleft palate, cleft lip/palate-ectodermal dysplasia syndrome, and Van der Woude and popliteal pterygium syndromes, respectively; they are also implicated in nonsyndromic CLP. The nature and functions of these genes vary widely, illustrating the high vulnerability within the craniofacial developmental pathways. The etiological complexity of nonsyndromic cleft lip and palate is also exemplified by the large number of candidate genes and loci. To conclude, although the etiology of nonsyndromic CLP is still largely unknown, mutations in candidate genes have been identified in a small proportion of cases. Determining the relative risk of CLP on the basis of genetic background and environmental influence (including smoking, alcohol use, and dietary factors) will be useful for genetic counseling and the development of future preventive measures. PMID- 22438646 TI - Potential role of septins in oral carcinogenesis: An update and avenues for future research. AB - Septins belong to the GTPase superclass of conserved proteins and have been identified to play a role in diverse aspects of cell biology, from cytokinesis to the maintenance of cellular morphology. At least 14 septins have been identified in humans. With their complex patterns in gene expressions and interaction, it has been reported that alterations in septin expression are observed in human diseases. Although much is not known about the role of human septins in oral carcinogenesis, circumstantial evidence does indicate that it may play a major role. This review intends to summarize the basis of septin biology, with the focus being on the evidence for septin involvement in human oral cancer. PMID- 22438647 TI - Rare occurrence of intraosseous schwannoma in a young child, its review and its pathogenesis. AB - Schwannoma is a benign, encapsulated, perineural tumor that arises from the Schwann cells. Approximately 25% of the reported cases originate from the head and neck region. Of these, approximately 1-12% occurs intraorally. The intrabony lesion accounts for less than 1% of the central neoplasms. We report a rare case of intraosseous schwannoma in an 8-year-old male patient characteristically originating from the mental nerve. Radiographic examination followed by histopathological evaluation was further confirmed by immunohistochemical markers, S-100 protein, and GFAP that stained intensely positive for the tumor. Thus, confirming the diagnosis of intraosseous schwannoma. PMID- 22438648 TI - Primary B-cell MALT lymphoma of the palate: A case report and distinction from benign lymphoid hyperplasia (pseudolymphoma). AB - Diagnosis of palatal swellings is a challenge. Benign and malignant tumors may be misinterpreted as lesions of inflammatory origin. We present a case of B-cell non Hodgkin lymphoma on the palate of a 40-year-old male. A number of factors can make the diagnosis of oral lymphoma difficult. Many lymphomas are extranodal, there is usually a prominent superimposed nonspecific inflammatory response and thus they mimic benign lymphoid hyperplasia. It is important for the pathologist to be familiar with features that distinguish benign from malignant lymphoid proliferations. PMID- 22438649 TI - Non-infiltrating angiolipoma of the upper lip: A rare entity. AB - Angiolipoma is a variant of lipoma with a prominent vascular component. It is the most common tumor of the forearm followed by trunk and extremities of young individuals. It's occurrence in head and neck region is rare. In this report, we present clinical and histopathologic features of non-infiltrating angiolipoma occurring on the upper lip in a 9-year-old female. Toluidine blue stain is used to demonstrate increased mast cell density around blood vessels, speculating its role in vasculogenesis. PMID- 22438650 TI - Squamous odontogenic tumor: A case report and review of literature. AB - The squamous odontogenic tumor (SOT) is a rare, benign, locally infiltrative neoplasm of the jaws that appears to originate from the rests of Malassez, gingival surface epithelium or from remnants of the dental lamina. SOT was first described by Pullon et al. (1975). Since then there has been paucity in the number of reported cases, especially in the Indian subcontinent. The tumor is often asymptomatic, although it can present with symptoms of pain and tooth mobility. The characteristic radiographic appearance is that of a triangular shaped unilocular radiolucency associated with the roots of erupted, vital teeth and has a predilection for the anterior maxilla and the posterior mandible. Histologically, the tumor is characterized by the formation of variably sized nests and cords of uniform, benign-appearing, squamous epithelium with occasional vacuolization and keratinization. We report a case of SOT occurring in a 58-year old male in the anterior mandible with unusual localization and appearance. PMID- 22438651 TI - Adenomatoid odontogenic tumor: A unique report with histological diversity. AB - Odontogenic tumors are a group of heterogeneous lesions, features of which have been catalogued for several decades. Adenomatoid odontogenic tumor (AOT) is a relatively rare and distinct odontogenic tumor that is exclusively odontogenic epithelium in origin. Although considerable number of reports is available with regard to the clinical and histological spectrum of AOT, very few have highlighted its varied histological presentations. Therefore, this article focuses on the assorted histoarchitectural patterns of AOT. PMID- 22438652 TI - Idiopathic multiple impacted unerupted teeth: Case report and discussion. AB - Multiple impacted permanent teeth are usually related to syndromes, metabolic and hormonal disorders. However, in some cases, impaction of multiple teeth is not associated with any syndrome. In this report, we present a case of 17-year-old male patient with missing teeth. Radiographs revealed multiple impacted permanent teeth, though medical and family history along with physical examination was not suggestive of any syndromes. If other investigations are negative, an idiopathic case of multiple impacted teeth is suggested to be the possible diagnosis. The objective of this report is to increase awareness of such cases especially in the absence of hereditary/genetic/metabolic factors usually inherent in such scenarios. The patient management in such cases needs to be planned specifically from a multidisciplinary standpoint. PMID- 22438653 TI - Clear cell variant of intraosseous mucoepidermoid carcinoma: Report of a rare entity. AB - Intraosseous mucoepidermoid carcinoma of jaw bones is a rare lesion. Abundance of clear cells in an intraosseous mucoepidermoid carcinoma may complicate its histopathologic diagnosis. It becomes extremely important to distinguish this lesion from other clear cell lesions of jaw region. Here, we report a case of clear cell variant of intraosseous mucoepidermoid carcinoma in the mandible. PMID- 22438654 TI - Hyalohyphomycosis of maxillary antrum. AB - Fungal infection of the paranasal sinuses is an increasingly recognized entity, both in normal and immunocompromised individuals. The recent increase in mycotic nasal and paranasal infections is due to both improved diagnostic research and an increase in the conditions that favor fungal infection. Although fungal infections of the paranasal sinus are uncommon, 3-5% of incidence is reported. Aspergillus, Candida, and Mucor species are the most common causative agents of fungal sinusitis, but infection with lesser known species have been reported across the world infrequently. This article reviews and presents a case report of chronic fungal sinusitis in an immunocompetent adult male infected with two species of Hyalohyphomycosis group namely, Paecilomyces and Scopulariopsis which are opportunistic soil saprophytes, uncommon to humans. PMID- 22438655 TI - 2012 - Another successful new year for Pharmacogn Mag. PMID- 22438656 TI - Application of deoxyribonucleic acid barcoding in Lauraceae plants. AB - BACKGROUND: This study aims to determine the candidate markers that can be used as DNA barcode in the Lauraceae family. MATERIAL AND METHODS: Polymerase chain reaction amplification, sequencing efficiency, differential intra- and interspecific divergences, DNA barcoding gap, and identification efficiency were used to evaluate the four different DNA sequences of psbA-trnH, matK, rbcL, and ITS2. We tested the discrimination ability of psbA-trnH in 68 plant samples belonging to 42 species from 11 distinct genera and found that the rate of successful identification with the psbA-trnH was 82.4% at the species level. However, the correct identification of matK and rbcL were only 30.9% and 25.0%, respectively, using BLAST1. The PCR amplification efficiency of the ITS2 region was poor; thus, ITS2 was not included in subsequent experiments. To verify the capacity of the identification of psbA-trnH in more samples, 175 samples belonging to 117 species from the experimental data and from the GenBank database of the Lauraceae family were tested. RESULTS: Using the BLAST1 method, the identification efficiency were 84.0% and 92.3% at the species and genus level, respectively. CONCLUSION: Therefore, psbA-trnH is confirmed as a useful marker for differentiating closely related species within Lauraceae. PMID- 22438657 TI - A new flavonol glycoside from the Abelmoschus esculentus Linn. AB - BACKGROUND: Abelmoschus esculentus L. belonging to the family Malvaceae is a kind of one year herbage plant, which is one of the most important vegetables widely grown in Nigeria for its tender fruits and young leaves. It's easy to be cultivated and grows well in both tropical and temperate zones, that is, it is widely planted from Africa to Asia, South European to America. A new flavonol glycoside characterized as 5,7,3',4'-tetrahydroxy-4''-O-methyl flavonol -3-O-beta D- glucopyranoside (1) has been isolated from the fruit of A. esculentus together with one known compound 5,7,3',4'-tetrahydroxy flavonol -3-O-[beta-D glucopyranosyl-(1->6)]-beta-D-glucopyranoside (2). The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass (MS) spectra. The antioxidant activities of the isolated compounds 1 and 2 were evaluated by 2 assays, the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and ferric reducing antioxidant power (FRAP). The present work deals with the isolation, identification and antioxidant activity of the two compounds. MATERIALS AND METHODS: The compounds were isolated by Diaion HP-20, Sephedex LH-20 column chromatography methods, their structures were identified by physicochemical properties and spectroscopic analysis. The antioxidant activities of the isolated compounds 1 and 2 were evaluated by two assays, e.g., DPPH and FRAP. RESULTS: Two flavonol glycosides have been isolated from the fruit of Abelmoschus esculentus L. for the first time, and the compound 1 was a new compound, the compound 2 was isolated from the plant for the first time. CONCLUSION: The results show that the two flavonol glycosides have strong ability for scavenging DPPH and FRAP free radical by the experiment of antioxidant activities, so A. esculentus may be a natural antioxidants resource. PMID- 22438658 TI - Phytochemical characterization of several hawthorn (Crataegus spp.) species sampled from the Eastern Mediterranean region of Turkey. AB - BACKGROUND: We evaluated the total phenolic content, antioxidant capacity as well as antioxidant activity of five Crataegus species (A1, A2, Y1, Y2, Y4 accessions of Crataegus aronia var. aronia; B2, B3, B5, B6, B7, B9, Y5 accessions of C. aronia var. dentata; B10 accession of C. aronia var. minuta; Y3 accession of Crataegus orientalis var. orientalis and A3 accession of Crataegus monogyna subsp. azarella). MATERIALS AND METHODS: Antioxidant activity and total phenolic content of fruits were determined by beta-carotene bleaching and Folin-Ciocalteu assays. Antioxidant capacity was determined by using 2,2-diphenyl-1 picrylhydrazyl (DPPH) assay. RESULTS: C. monogyna subsp. azarella had the highest total phenol, antioxidant activity and antioxidant capacity of 55.2 mg gallic acid equivalents (GAE)/g dry weight (DW), 81.9% and 31.2%, respectively. C. aronia var. aronia was found to have the lowest total phenolic content (35.7 mg GAE/g DW). The antioxidant activities of fruit extracts increased in the order of C. orientalis var. orientalis < C. aronia var. minuta < C. aronia var. dentata < C. aronia var. aronia < C. monogyna subsp. azarella according to beta carotene/linoleic acid assay. In recent years, C. aronia var. dentata has gained importance as a commercial species in this region. B3 and B7 accessions had fruit weight more than 14 g, and considerable total phenol content, antioxidant activity and antioxidant capacity. CONCLUSION: This investigation shows the potential value of hawthorn fruit species as a good source of natural antioxidants and that consumption of hawthorn fruit or its products may contribute substantial amounts of antioxidants to the diet. PMID- 22438659 TI - Isolation and characterization of a bactericidal withanolide from Physalis virginiana. AB - BACKGROUND: Physalis virginiana (Virginia Groundcherry) is a member of the family Solenaceae. Several species of the Physalis genus have been used traditionally by American Indians as medicinal treatments. MATERIALS AND METHODS: This study investigated the antibacterial activity of chemicals extracted from P. virginiana through antibacterial disc and cytotoxicity assays. Isolation and purification of an antimicrobial compound was achieved through flash chromatography and preparative HPLC. Finally, identification of chemical structure was determined from (1)H and (13)C NMR and MS. RESULTS: Disc assays showed that crude ethanol extracts were effective antibacterial agents against one gram-negative and seven gram-positive bacterial strains. Cytotoxicity assays indicated that it is less toxic than gentamicin controls. Isolation of the active component showed it to be a relatively polar compound. (1)H and (13)C NMR chemical shifts together with HRMS indicated a similar structure to withanolides previously identified from Physalis angulata. HRMS analysis showed a molecular mass of 472.2857 which corresponds to a molecular formula C(28)H(40)O(6). CONCLUSION: An antibacterial withanolide was isolated from P. virginiana using flash chromatography and HPLC separations. The chemical structure was determined by NMR and MS to be the withanolide physagulin V. PMID- 22438660 TI - Species identification of Rhododendron (Ericaceae) using the chloroplast deoxyribonucleic acid PsbA-trnH genetic marker. AB - BACKGROUND: Rhododendron is a group of famous landscape plants with high medicinal value. However, there is no simple or universal manner to discriminate the various species of this group. Deoxyribonucleic acid (DNA) barcoding technique is a new biological tool that can accurately and objectively identify species by using short and standard DNA regions. OBJECTIVE: To choose a suitable DNA marker to authenticate the Rhododendron species. MATERIALS AND METHODS: Four candidate DNA barcodes (rbcL, matK, psbAtrnH, and ITS2 intergenic spacer) were tested on 68 samples of 38 species. RESULTS: The psbAtrnH candidate barcode yielded 86.8% sequencing efficiency. The highest interspecific divergence was provided by the psbA-trnH intergenic spacer, based on six parameters, and the Wilcoxon signed rank tests. Although there was not a clear barcoding gap, the Wilcoxon Two sample tests indicated that the interspecific divergence of the psbA trnH intergenic spacer was significantly higher than the relevant intraspecific variation. The psbA-trnH DNA barcode possessed the highest species identification efficiency at 100% by the BLAST1 method. The present results showed that the psbA trnH intergenic spacer was the most promising one of the four markers for barcoding the Rhododendron species. To further evaluate the ability of the psbA trnH marker, to discriminate the closely related species, the samples were expanded to 94 samples of 53 species in the genus, and the rate of successful identification was 93.6%. The psbA-trnH region would be useful even for unidentified samples, as it could significantly narrow their possible taxa to a small area. CONCLUSION: The psbA-trnH intergenic region is a valuable DNA marker for identifying the Rhododendron species. PMID- 22438661 TI - Comparative study of rosmarinic acid content in some plants of Labiatae family. AB - BACKGROUND: Plants of Labiatae are used in traditional medicine and phytotherapy. Rosmarinic acid (RA) is a phenolic compound which is found in many genus of Labiatae and exhibits important biological activities. MATERIALS AND METHODS: In this investigation, RA contents of 29 species of Labiatae named Salvia officinalis, Salvia limbata, Salvia virgata, Salvia hypoleuca, Salvia macrosiphon, Salvia choloroleuca, Melissa officinalis, Origanum vulgare, Lavandula angustifolia, Rosmarinus officinalis, Thymus daenensis, Thymus citriodorous, Thymus pubescens, Thymus vulgaris, Zataria multiflora, Mentha piperita, Mentha pulegium, Mentha longifolia, Mentha spicata, Mentha aquatica, Mentha crispa, Perovskia artemisoides, Zhumeria majdae, Satureja hortensis, Satureja khuzistanica, Satureja bachtiarica, Satureja atropatana, Satureja mutica and Satureja macrantha were determined by using high-performance liquid chromatographic method. RESULTS: The results showed that RA content in different species of Labiatae was 0.0-58.5 mg g(-1) of dried plants. The highest amount of RA was found in Mentha species especially M. spicata. CONCLUSION: M. spicata can be considered as a new source of rosmarinic acid . PMID- 22438662 TI - A novel high-performance liquid chromatography fingerprint approach to discriminate Phyllostachys pubescens from China. AB - BACKGROUND: A high-performance liquid chromatography fingerprint of different variants of Phyllostachys pubescens was developed for the source discrimination and quality control of Phyllostachys pubescens medicines produced in Zhejiang Province, China. MATERIALS AND METHODS: Samples of Phyllostachys pubescens collected from nine cultivars in Zhejiang Province were used to establish the fingerprint. Taking the chromatographic peak (isoorientin) as the reference peak, the chromatographic column was Sunfire C(18) ODS (250 mm*4.6 mm, 5 MUm) at a column temperature of 25 degrees C. The mobile phase was acetonitrile 0.8% acetic acid water solution (in a gradient elution mode) at a flow rate of 1 ml/min. The detection wavelength was 330 nm. RESULTS: 20 common peaks were established in the chromatographic fingerprints of Phyllostachys pubescens. And then by comparing the UV and standard substance with those of the authentic standards and literature, eight main peaks in the fingerprints were identified. Data of nine cultivars were evaluated statistically using similarity analysis, hierarchical cluster analysis (HCA) in order to establish a similarity standard of fingerprint for quality control of Phyllostachys pubescens, then to classify the samples. The similarity indexes were all above 0.95 between reference chromatogram and each sample's chromatogram. CONCLUSION: in this study, the methods established are reliable, and could be used to evaluate the quality and to identify the species of Phyllostachys pubescens in the future. PMID- 22438663 TI - Validated reversed phase-high performance liquid chromatography-diode array detector method for the quantitation of Rutin, a natural immunostimulant for improving survival in aquaculture practice, in toonea sinensis folium. AB - BACKGROUND: Rutin is a bioflavonoid of strong immunostimulating activity from the Toonea Sinensis Folium, which has shown a significant ability to increase the survival rate of white shrimp with bacterial infection. However, no method for the quantitation of this active ingredient in the herb has been reported to date. MATERIALS AND METHODS: A reversed phase-high performance liquid chromatography diode array detector (RP-HPLC-DAD) method was developed to quantify Rutin in the Toonea Sinensis Folium, with the HPLC conditions optimized, followed by validation for linearity, accuracy, precision, limit of detection (LOD), repeatability, and stability. Then, the established method was used to determine the content of Rutin in two samples. RESULTS: The separation was performed on a Waters XBridge Shield RP18 column (150 mm * 4.6 mm, 5 MUm) kept at 25 degrees C, and acetonitrile and water containing 0.1% acetate acid (18:82, v / v)-composed mobile phase was constantly driven at 1.0 mL / minute during the analysis. Twenty microliters of sample solution or standard solution were injected into the HPLC system and 254 nm was selected to monitor the separation. A strong linear relationship between the peak area and concentration of Rutin was observed within the range of 0.01044 - 0.2610 mg / mL (r(2) = 1.0000). The LOD was 0.03915 MUg / mL, and recovery of Rutin was from 97.6 to 99.6%. In addition, the method was also validated to be repeatable, stable, precise, and accurate. CONCLUSIONS: An efficient and reliable RP-HPLC-DAD method was established, which could be used for routine analysis of Rutin in Toonea Sinensis Folium and to assist in the quality control of this herb. PMID- 22438664 TI - Effects of H(2)O(2), paraquat, and ethephon on herbal drug quality of Schiandra chinensis based on reactive oxygen species system. AB - BACKGROUND: Nowadays, more and more herbal drugs of traditional Chinese medicine (TCM) rely on cultivation rather than natural resources because of overexploitation, and the study on quality of cultivated herbal medicines has become a hotspot in the research field of ecology of TCM resources. Though some of molecular biology techniques could improve the contents of secondary metabolites, those chemical compositions may differ from what we require from natural products, resulting in different treatment efficacy. OBJECTIVE: To explore ways and means of improving TCM quality by means of regulating secondary metabolism from the perspective of natural physiological ecology. MATERIALS AND METHODS: H(2)O(2) and paraquat as carriers of ROS, propyl gallate as a ROS scavenger, and ethephon as a ROS inductive agent were sprayed on Schisandra chinensis (Turcz.) Baill. RESULTS: The hypo-concentration ROS could enhance the activities of POD, PPO, as well as CAT, and propyl gallate acted on the opposite side, but they all failed to break the homeostasis between ROS and oxidase activity and to exert any effect on the contents of the schisandrin, deoxyschizandrin, and schisandrin B. The hypso-concentration ROS could break the homeostasis, reduce the activities of POD, PPO, as well as CAT, and improve the quality of S. chinensis fruit. The ethephon could effectively improve the quality of S. chinensis without the limitation of metabolic regulation. CONCLUSION: The conclusions accord with the hypothesis that ROS regulates secondary metabolism. PMID- 22438665 TI - Cytotoxicity of fucosterol containing fraction of marine algae against breast and colon carcinoma cell line. AB - CONTEXT: Marine algae produce different secondary metabolites with a wide range of biological activities. Many studies have been achieved on the screening of biological effects of marine organisms and a lot of active compounds were isolated and characterized. AIMS: In an attempt to find cytotoxic compound of hexane fraction, isolation, identification, and cytotoxicity of active compound of this fraction were performed. MATERIALS AND METHODS: In this study, total methanolic (70%) extract and partition fractions of hexane, chloroform (CHCl(3)), ethyl acetate (EtOAc), and MeOH-H(2)O of Sargassum angustifolium, Chondria dasyphylla, and Ulva flexuosa, collected from coastlines of the Persian Gulf in south of Iran, were studied against colon carcinoma (HT-29), colorectal adenocarcinoma (Caco-2), breast ductal carcinoma (T47D), and Swiss mouse embryo fibroblast (NIH 3T3) cell lines by MTT assay. STATISTICAL ANALYSIS USED: IC(50) (median growth inhibitory concentration) values were calculated by Sigmaplot (10) software. RESULTS: Hexane fraction of Chondria dasyphylla (IC(50) 82.26 +/- 4.09 MUg/ml) and MeOH-H(2)O fraction of Ulva flexuosa (IC(50) 116.92 +/- 8.58 MUg/ml) showed cytotoxic activity against proliferation of T47D cells. Hexane fraction of Sargassum angustifolium was also observed for cytotoxicity against T47D and HT-29 cell lines (IC(50) 166.42 +/- 26.7 and 190.24 +/- 52.8 MUg/ml), respectively. An investigation of a component from the hexane fraction of Sargassum angustifolium yielded a steroidal metabolite, fucosterol, with cytotoxicity in T47D and HT29 (IC(50) 27.94 +/- 9.3 and 70.41 +/- 7.5 MUg/ml). CONCLUSIONS: These results indicated that fucosterol, the most abundant phytosterol in brown algae, is responsible for cytotoxic effect of this extract against breast and colon carcinoma cell lines. PMID- 22438666 TI - Antihyperglycemic and antihyperlipidemic effects of guar gum on streptozotocin induced diabetes in male rats. AB - BACKGROUND: Herbal medicine is widely used in the treatment of diseases like diabetes mellitus. We investigated the effects of guar gum in diabetic rats for the reduction of the risk of diabetes and cardiovascular disease. Dietary pattern emphasizing foods high in complex carbohydrates and fiber are associated with low blood glucose and cholesterol levels. MATERIALS AND METHODS: Diet containing 0%, 5%, 10% and 20% (w/w) guar gum was fed to diabetic rats for 28 days. Blood serum glucose, triglycerides, cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol levels, atherogenic index levels, body weights and food intake were monitored at 0, 7.14 and 28 days after induction of diabetes. RESULTS: In spite of the fact that diabetes elevated blood lipids in all rats after 14 days, the guar gum diet significantly decreased the serum concentration of cholesterol, triacylglicerols and LDL-C and atherogenic index. The most significant result in this study was the reduction of blood glucose in diabetic rats treated with the guar gum diet after 28 days versus non- and glibenclamide-treated rats. The gum promoted a general improvement in the condition of the diabetic rats in body weight and food intake in comparison with nontreated rats. CONCLUSION: The results of this research suggest that guar gum was significantly effective in comparison with glibenclamide in the treatment of hyperlipidemia and hyperglycemia in diabetes rats. Therefore, it may be suggested as a reliable fiber in diabetic regimes in diabetic patients. PMID- 22438667 TI - Inorganic ions in the medium modify tropane alkaloids and riboflavin output in Hyoscyamus niger root cultures. AB - CONTEXT: Hyoscyamus niger L. (Solanaceae) roots are rich of tropane alkaloids, such as hyoscyamine and scopolamine are used as the source of raw material for the pharmaceutical industry. AIMS: The aim of the present study was to investigate the effect of calcium, magnesium, and iron ions on the production of tropane alkaloids and excretion of riboflavin in H. niger root cultures. MATERIALS AND METHODS: The calcium, magnesium, or iron enriched/deprived Murashige and Skoog (MS) growth medium were used for culture of H. niger root tissues. The secondary metabolites were quantified using high performance liquid chromatography with ultraviolet detector (HPLC-UV) and fluorimetry techniques. RESULTS: An increased calcium content in the medium unidirectionally reduced hyoscyamine, while increasing scopolamine production with only a moderate impact on riboflavin excretion. Manipulations with magnesium and iron contents in the medium resulted in divergent changes in hyoscyamine, scopolamine, and riboflavin concentrations. CONCLUSIONS: Our results show that increased calcium ion content in the Murashige and Skoog medium may be used for the intensification of the scopolamine production in H. niger root cultures. PMID- 22438668 TI - Clonal propagation of Phyllanthus amarus: A hepatoprotector. AB - BACKGROUND: The micropropagation protocol for Phyllanthus amarus, an important medicinal herb used widely for the treatment of hepatitis in ethnomedicinal systems, was standardized with shoot tip and single node explants. MATERIALS AND METHODS: The micropropagation was carried out for the hyperproducing ecotype (phyllanthin content 463.828 ppm; hypophyllanthin content: 75.469 ppm) collected from Aanaikatti, Coimbatore, and grown in mist chamber, CPMB, TNAU. For micropropagation studies, the leaves were trimmed off and the shoot tips (6 mm long) and nodal segments (single node) were used for initiation. RESULTS: Shoot tips and single node explants gave a maximum of 6.00 and 7.00 multiple shoots per explant with Benzyl Amino Purine (BAP) (1.0mg/L mg/L). Upon subculturing, a shoot length of around 7 cm with an average of eight internodes per shoot was observed after 20 days in the elongation medium supplemented with BAP (0.2 mg/Lmg/L) and Indole Acetic Acid (IAA) (2.0 mg/L). Seven to ten adventitious roots developed when the elongated microshoots were cultured in half strength MS medium with Indole Butyric Acid (IBA) (2.0 mg/Lmg/L) and NAA (1.0 mg/L mg/L) in 15-20 days after transfer. The rooted shoots acclimatized successfully to field conditions. CONCLUSION: A method for successful micropropagation of the valuable medicinal plant was established which will provide a better source for continuous supply of plants for manufacturing drugs. PMID- 22438669 TI - Efficacy and tolerability of lapatinib in the management of breast cancer. AB - Approximately 20%-25% of all breast cancers over express a key cell surface growth factor receptor known as HER2. HER2 plays a key role in cell growth and proliferation and is linked to worse clinical outcomes, making it a logical therapeutic target. The first HER2 targeted drug to be approved by the FDA, was the humanized monoclonal antibody trastuzumab, after it showed improvements in survival in the adjuvant setting, and delayed time to progression in the metastatic setting. Although highly effective, for reasons that are not clear, some patients display resistance to trastuzumab. Lapatinib is an oral, small molecule tyrosine kinase inhibitor, that inhibits both the HER1 ahd HER2 receptors and may be able to overcome trastuzumab resistance. Lapatinib is approved in the second line setting for use in combination with capecitabine or with letrozole. In this review, we will discuss the indications, concerns or any issues with regards to the drug. PMID- 22438670 TI - Environmental health funding challenges during difficult budget times. PMID- 22438671 TI - Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. AB - Because of the pathological role of IL-6 in rheumatoid arthritis (RA), tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, was expected to improve inflammation and joint destruction of RA. Indeed, randomized clinical trials demonstrated the clinical efficacy of TCZ as monotherapy or combined with methotrexate (MTX) for RA patients with inadequate responses to disease-modifying antirheumatic drugs, MTX or tumor necrosis factor (TNF) inhibitors. Although long-term tolerability for TCZ is superior to that for TNF inhibitors, information regarding the potency of drug free remission of TCZ is limited at present. In terms of its safety profile, the general risk of infection when using TCZ is comparable to that of TNF inhibitors. TCZ has some advantage in RA patients who can not use MTX and are non-responders to TNF inhibitors. In conclusion, TCZ is one of the most prospective next generation biologics for the treatment of RA. PMID- 22438672 TI - Assessment of ventricular pacing in the setting of an institutional improvement program: insights into physiological pacing. AB - BACKGROUND: Excessive ventricular pacing is known to be detrimental. The purpose of this study was to assess ventricular pacing in the setting of an institutional improvement program in order to decrease unnecessary pacing. METHOD: This cross sectional single-center study performed in a university hospital assessed 80 consecutive patients attending for a cardiac electronic device (pacemaker or cardioverter defibrillator) check. Forty percent of ventricular pacing was set as the cutoff level beyond which pacing was considered excessive. RESULTS: Three patients were excluded. Forty-six (59.7%) patients (group 1) had more than 40% ventricular pacing and 31 (40.3%) patients (group 2) showed ventricular pacing less than 41%. In group 1, corrective action was successful in 27 (58.7%) patients, but 19 (41.3%) continued to have ventricular pacing over 40% and were discussed accordingly. An improvement program was established at the institution in order to decrease unnecessary ventricular pacing. CONCLUSION: Unnecessary ventricular pacing was encountered in many of the patients in this study, corrective actions were performed, and an institutional improvement project was set up as a consequence. PMID- 22438673 TI - Neuronal autophagy: a housekeeper or a fighter in neuronal cell survival? AB - Neurons have highly dynamic cellular processes for their proper functions such as cell growth, synaptic formation, or synaptic plasticity by regulating protein synthesis and degradation. Therefore, the quality control of proteins in neurons is essential for their physiology and pathology. Autophagy is a cellular degradation pathway by which cytosolic components are sequestered in autophagosomes and degraded upon their fusion with lysosomal components. Thus, the autophagic pathway may play important roles in neuronal cell survival and neuronal function under physiological condition and pathological conditions. Recent several findings suggest that the loss of basal autophagy or imbalance of autophagic flux leads to neurodegeneration. Autophagosomes accumulate abnormally in affected neurons of several neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), or Frontotemporal dementia (FTD). Thus, the understanding how autophagy is associated with several neurological diseases would be the first step for new therapeutic intervention in neurological disorders. In this review, I will discuss the molecular mechanism of autophagy in neurons and autophagy-associated neurodegenerative diseases. PMID- 22438674 TI - Neuronal Functions of ESCRTs. AB - The endosomal sorting complexes required for transport (ESCRTs) regulate protein trafficking from endosomes to lysosomes. Recent studies have shown that ESCRTs are involved in various cellular processes, including membrane scission, microRNA function, viral budding, and the autophagy pathway in many tissues, including the nervous system. Indeed, dysfunctional ESCRTs are associated with neurodegeneration. However, it remains largely elusive how ESCRTs act in post mitotic neurons, a highly specialized cell type that requires dynamic changes in neuronal structures and signaling for proper function. This review focuses on our current understandings of the functions of ESCRTs in neuronal morphology, synaptic plasticity, and neurodegenerative diseases. PMID- 22438675 TI - Repeated Short-term (2h*14d) Emotional Stress Induces Lasting Depression-like Behavior in Mice. AB - Chronic behavioral stress is a risk factor for depression. To understand chronic stress effects and the mechanism underlying stress-induced emotional changes, various animals model have been developed. We recently reported that mice treated with restraints for 2 h daily for 14 consecutive days (2h-14d or 2h*14d) show lasting depression-like behavior. Restraint provokes emotional stress in the body, but the nature of stress induced by restraints is presumably more complex than emotional stress. So a question remains unsolved whether a similar procedure with "emotional" stress is sufficient to cause depression-like behavior. To address this, we examined whether "emotional" constraints in mice treated for 2h*14d by enforcing them to individually stand on a small stepping platform placed in a water bucket with a quarter full of water, and the stress evoked by this procedure was termed "water-bucket stress". The water-bucket stress activated the hypothalamus-pituitary-adrenal gland (HPA) system in a manner similar to restraint as evidenced by elevation of serum glucocorticoids. After the 2h*14d water-bucket stress, mice showed behavioral changes that were attributed to depression-like behavior, which was stably detected >3 weeks after last water-bucket stress endorsement. Administration of the anti-depressant, imipramine, for 20 days from time after the last emotional constraint completely reversed the stress-induced depression-like behavior. These results suggest that emotional stress evokes for 2h*14d in mice stably induces depression-like behavior in mice, as does the 2h*14d restraint. PMID- 22438676 TI - Inactivation of the medial prefrontal cortex interferes with the expression but not the acquisition of differential fear conditioning in rats. AB - The medial prefrontal cortex (mPFC) has been implicated in the processing of emotionally significant stimuli, particularly the inhibition of inappropriate responses. We examined the role of the mPFC in regulation of fear responses using a differential fear conditioning procedure in which the excitatory conditioned stimulus (CS+) was paired with an aversive footshock and intermixed with the inhibitory conditioned stimulus (CS-). In the first experiment, using rats as subjects, muscimol, a gamma-amino-butyric acid type A (GABAA) receptor agonist, or artificial cerebrospinal fluid (aCSF) was infused intracranially into the mPFC across three conditioning sessions. Twenty-four hours after the last conditioning session, freezing response of the rats was tested in a drug-free state. Neither the muscimol nor the aCSF infusion had any effect on differential responding. In the second experiment, the same experimental procedure was used except that the infusion was made before the testing session rather than the conditioning sessions. The results showed that muscimol infusion impaired differential responding: the level of freezing to CS- was indiscriminable from that to CS+. Taken together, these results suggest that the mPFC is responsible for the regulation of fear response by inhibiting inappropriate fear expressions. PMID- 22438677 TI - Effects of polychlorinated biphenyls on the development of neuronal cells in growth period; structure-activity relationship. AB - Polychlorinated biphenyls (PCBs) are accumulated in our body through food chain and cause a variety of adverse health effects including neurotoxicities such as cognitive deficits and motor dysfunction. In particular, neonates are considered as a high risk group for the neurotoxicity of PCBs exposure. The present study attempted to analyze the structure-activity relationship among PCB congeners and the mechanism of PCBs-induced neurotoxicity. We measured total protein kinase C (PKC) activities, PKC isoforms, reactive oxygen species (ROS), and induction of neurogranin (RC-3) and growth associated protein-43 (GAP-43) mRNA in cerebellar granule cells of neonatal rats with phorbol 12, 13-dibutyrate ([(3)H]PDBu) binding assay, western blot, ROS assay, and reverse transcription PCR (RT-PCR) analysis respectively following the different structural PCBs exposure. Only non coplanar PCBs showed a significant increase of total PKC-alpha and betaII activity as measured with [(3)H]PDBu binding assay. ROS were more increased with non-coplanar PCBs than coplanar PCBs. The mRNA levels of RC-3 and GAP-43 were more induced with non-coplanar PCBs than coplanar PCBs, indicating that these factors may be useful biomarkers for differentiating non-coplanar PCBs from coplanar PCBs. Non-coplanar PCBs may be more potent neurotoxic congeners than coplanar PCBs. This study provides evidences that non-coplanar PCBs, which have been neglected in the risk assessment processes, should be added in the future to improve the quality and accuracy of risk assessment on the neuroendocrinal adverse effects of PCBs exposures. PMID- 22438678 TI - Radiofrequency ablation of benign thyroid nodules and recurrent thyroid cancers: consensus statement and recommendations. AB - Thermal ablation using radiofrequency is a new, minimally invasive modality employed as an alternative to surgery in patients with benign thyroid nodules and recurrent thyroid cancers. The Task Force Committee of the Korean Society of Thyroid Radiology has developed recommendations for the optimal use of radiofrequency ablation for thyroid nodules. These recommendations are based on a comprehensive analysis of the current literature, the results of multicenter studies, and expert consensus. PMID- 22438679 TI - New statistical method to analyze three-dimensional landmark configurations obtained with cone-beam CT: basic features and clinical application for rapid maxillary expansion. AB - OBJECTIVE: To describe a statistical method of three-dimensional landmark configuration data and apply it to an orthodontic data set comparing two types of rapid maxillary expansion (RME) treatments. MATERIALS AND METHODS: Landmark configurations obtained from cone beam CT scans were used to represent patients in two types (please describe what were two types) of RME groups and a control group over four time points. A method using tools from persistent homology and dimensionality reduction is presented and used to identify variability between the subjects. RESULTS: The analysis was in agreement with previous results using conventional methods, which found significant differences between treatment groups and the control, but no distinction between the types of treatment. Additionally, it was found that second molar eruption varied considerably between the subjects, and this has not been evaluated in previous analyses. CONCLUSION: This method of analysis allows entire configurations to be considered as a whole, and does not require specific inter-landmark distances or angles to be selected. Sources of variability present themselves, without having to be individually sought after. This method is suggested as an additional tool for the analysis of landmark configuration data. PMID- 22438680 TI - Digital tomosynthesis for PNS evaluation: comparisons of patient exposure and image quality with plain radiography. AB - OBJECTIVE: We investigated low dose digital tomosynthesis (DT) for the evaluation of the paranasal sinus (PNS), and compared its diagnostic accuracy with a PNS radiography series (XR). MATERIALS AND METHODS: We enrolled 43 patients for whom XR, PNS DT, and OMU CT were performed. We measured effective doses (EDs) of XR, DT, and OMU CT using Monte Carlo simulation software. Two radiologists performed independent observation of both XR and DT. For seven PNSs, they scored anatomic conspicuity of sinuses and confidence on the presence of sinusitis using nine point scales. OMU CT was observed by the third radiologist and the findings were regarded as reference standard. We compared scores for conspicuity and sinusitis confidence between XR and DT. RESULTS: Mean EDs were 29 +/- 6 uSv, 48 +/- 10 uSv, and 980 +/- 250 uSv, respectively, for XR, DT, and CT. Mean scores for conspicuity were 6.3 and 7.4, respectively, for XR and DT. Sensitivity per patient basis for sinusitis detection were 52% and 96%, respectively, for XR and DT in observer 1 (p = 0.001) and 80% and 92% for observer 2 (p = 0.25). Specificities for sinusitis exclusion were 100% for both XR and DT for observer 1 and 89% and 100% for observer 2 (p = 0.50). Accuracies for sinusitis diagnosis were 72% and 98%, respectively, for XR and DT for observer 1 (p = 0.001) and 84% and 95% for observer 2 (p = 0.125). CONCLUSION: Patient radiation dose from low dose DT is comparable with that of PNS XR. Diagnostic sensitivity of DT for sinusitis was superior to PNS XR. PMID- 22438681 TI - Cumulative radiation exposure during follow-up after curative surgery for gastric cancer. AB - OBJECTIVE: To quantify the cumulative effective dose (cED) of radiation due to repeated CT and PET/CT examinations after curative resection of gastric cancer and to assess the lifetime attributable risk (LAR) estimates based on Biological Effects of Ionizing Radiation VII models. SUBJECTS AND METHODS: Patients who underwent a curative resection for gastric cancer between January 2006 and December 2006 and were followed-up until May 2010 were included in this study. The cED was calculated by using the dose-length product values and conversion factors for quantitative risk assessment of radiation exposure. cED and LAR were compared between early and advanced gastric cancer patients and among American Joint Committee on Cancer TNM stage groups (stage I, II, and III). The nonparametric Mann-Whitney U and Kruskal-Wallis tests, followed by a post-hoc analysis with Bonferroni adjustment, were employed as part of the statistical analysis. RESULTS: The overall median cED was 57.8 mSv (interquartile range [IQR], 43.9-74.7). The cED was significantly higher in the advanced (median, 67.0; IQR, 49.1-102.3) than in the early gastric cancer group (median, 52.3; IQR, 41.5-67.9) (p < 0.001), and increased as the TNM stage increased. For radiation exposure, 62% of all patients received an estimated cED of over 50 mSv, while 11% of patients received over 100 mSv. The median LAR of cancer incidence was 0.28% (IQR, 0.20-0.40) and there were significant differences between the early gastric cancer and advanced gastric cancer group (p < 0.001) as well as among the three TNM stage groups (p = 0.015). The LAR of cancer incidence exceeded 1% in 2.4% of the patients. CONCLUSION: The cED increases proportionally along with tumor stage and, even in early gastric cancer or stage I patients, cED is much higher than that found among the general population. Considering the very good prognosis of early gastric cancer after curative surgery, the cED should be considered when designing a postoperative follow-up CT protocol. PMID- 22438682 TI - 80-kVp CT using Iterative Reconstruction in Image Space algorithm for the detection of hypervascular hepatocellular carcinoma: phantom and initial clinical experience. AB - OBJECTIVE: To investigate whether the low-tube-voltage (80-kVp), intermediate tube-current (340-mAs) MDCT using the Iterative Reconstruction in Image Space (IRIS) algorithm improves lesion-to-liver contrast at reduced radiation dosage while maintaining acceptable image noise in the detection of hepatocellular carcinomas (HCC) in thin (mean body mass index, 24 +/- 0.4 kg/m(2)) adults. SUBJECTS AND METHODS: A phantom simulating the liver with HCC was scanned at 50 400 mAs for 80, 100, 120 and 140-kVp. In addition, fifty patients with HCC who underwent multiphasic liver CT using dual-energy (80-kVp and 140-kVp) arterial scans were enrolled. Virtual 120-kVP scans (protocol A) and 80-kVp scans (protocol B) of the late arterial phase were reconstructed with filtered back projection (FBP), while corresponding 80-kVp scans were reconstructed with IRIS (protocol C). Contrast-to-noise ratio (CNR) of HCCs and abdominal organs were assessed quantitatively, whereas lesion conspicuity, image noise, and overall image quality were assessed qualitatively. RESULTS: IRIS effectively reduced image noise, and yielded 29% higher CNR than the FBP at equivalent tube voltage and current in the phantom study. In the quantitative patient study, protocol C helped improve CNR by 51% and 172% than protocols A and B (p < 0.001), respectively, at equivalent radiation dosage. In the qualitative study, protocol C acquired the highest score for lesion conspicuity albeit with an inferior score to protocol A for overall image quality (p < 0.001). Mean effective dose was 2.63 mSv with protocol A and 1.12-mSv with protocols B and C. CONCLUSION: CT using the low-tube-voltage, intermediate-tube-current and IRIS help improve lesion-to-liver CNR of HCC in thin adults during the arterial phase at a lower radiation dose when compared with the standard technique using 120-kVp and FBP. PMID- 22438683 TI - Evaluation of ultra-low dose CT in the diagnosis of pediatric-like fractures using an experimental animal study. AB - OBJECTIVE: The aim of this prospective study was to evaluate the performance of ultra-low dose CT for the diagnosis of pediatric-like fractures and ascertain the lowest dose level sufficient for diagnostics. MATERIALS AND METHODS: Fifty-one bones of young pig cadavers were artificially fractured and subsequently examined by using a 64 multi-detector CT with 36 various dose levels down to a dose comparable with that of X-rays. Two pediatric radiologists analysed the CT scans according to the presence or absence of a fracture, determination of the fracture type and the displacement as well as the diagnostic certainty. For each dose protocol, a success rate for the correct determination of the above-mentioned CT analyses was calculated. A success rate of at least 95% was considered sufficient for diagnostics. RESULTS: All but the lowest dose levels were sufficient to identify the fracture. Only the two lowest dose levels were insufficient to detect the fracture type. All dose levels were adequate for the identification of the displacement. The lowest dose level sufficient for diagnostics was 120 kVp, 11 mAs, and pitch 1.5, with a CTDIvol of 10% of a standard dose and an effective dose three times as large as that of X-rays. CONCLUSION: Ultra-low dose CT provides the feasibility of a significant dose reduction, still allowing sufficient diagnostics of pediatric-like fractures. PMID- 22438684 TI - Incidence and management of bleeding complications following percutaneous radiologic gastrostomy. AB - OBJECTIVE: Upper gastrointestinal (GI) bleeding is a serious complication that sometimes occurs after percutaneous radiologic gastrostomy (PRG). We evaluated the incidence of bleeding complications after a PRG and its management including transcatheter arterial embolization (TAE). MATERIALS AND METHODS: We retrospectively reviewed 574 patients who underwent PRG in our institution between 2000 and 2010. Eight patients (1.4%) had symptoms or signs of upper GI bleeding after PRG. RESULTS: The initial presentation was hematemesis (n = 3), melena (n = 2), hematochezia (n = 2) and bloody drainage through the gastrostomy tube (n = 1). The time interval between PRG placement and detection of bleeding ranged from immediately after to 3 days later (mean: 28 hours). The mean decrease in hemoglobin concentration was 3.69 g/dL (range, 0.9 to 6.8 g/dL). In three patients, bleeding was controlled by transfusion (n = 2) or compression of the gastrostomy site (n = 1). The remaining five patients underwent an angiography because bleeding could not be controlled by transfusion only. In one patient, the bleeding focus was not evident on angiography or endoscopy, and wedge resection including the tube insertion site was performed for hemostasis. The other four patients underwent prophylactic (n = 1) or therapeutic (n = 3) TAEs. In three patients, successful hemostasis was achieved by TAE, whereas the remaining one patient underwent exploration due to persistent bleeding despite TAE. CONCLUSION: We observed an incidence of upper GI bleeding complicating the PRG of 1.4%. TAE following conservative management appears to be safe and effective for hemostasis. PMID- 22438685 TI - Fluoroscopically guided three-tube insertion for the treatment of postoperative gastroesophageal anastomotic leakage. AB - OBJECTIVE: To retrospectively evaluate the feasibility and effectiveness of three tube insertion for the treatment of postoperative gastroesophageal anastomotic leakage (GEAL). MATERIALS AND METHODS: From January 2007 to January 2011, 28 cases of postoperative GEAL after an esophagectomy with intrathoracic esophagogastric anastomotic procedures for esophageal and cardiac carcinoma were treated by the insertion of three tubes under fluoroscopic guidance. The three tubes consisted of a drainage tube through the leak, a nasogastric decompression tube, and a nasojejunum feeding tube. The study population consisted of 28 patients (18 males, 10 females) ranging in their ages from 36 to 72 years (mean: 59 years). We evaluated the feasibility of three-tube insertion to facilitate leakage site closure, and the patients' nutritional benefit by checking their serum albumin levels between pre- and post-enteral feeding via the feeding tube. RESULTS: The three tubes were successfully placed under fluoroscopic guidance in all twenty-eight patients (100%). The procedure times for the three tube insertion ranged from 30 to 70 minutes (mean time: 45 minutes). In 27 of 28 patients (96%), leakage site closure after three-tube insertion was achieved, while it was not attained in one patient who received stent implantation as a substitute. All patients showed good tolerance of the three-tube insertion in the nasal cavity. The mean time needed for leakage treatment was 21 +/- 3.5 days. The serum albumin level change was significant, increasing from pre-enteral feeding (2.5 +/- 0.40 g/dL) to post-enteral feeding (3.7 +/- 0.51 g/dL) via the feeding tube (p < 0.001). The duration of follow-up ranged from 7 to 60 months (mean: 28 months). CONCLUSION: Based on the results of this study, the insertion of three tubes under fluoroscopic guidance is safe, and also provides effective relief from postesophagectomy GEAL. Moreover, our findings suggest that three-tube insertion may be used as the primary procedure to treat postoperative GEAL. PMID- 22438686 TI - Alternative techniques for cannulation of biliary strictures resistant to the 0.035" system following living donor liver transplantation. AB - OBJECTIVE: To assess the clinical efficacy of alternative techniques for biliary stricture cannulation in patients undergoing living donor liver transplantation (LDLT), after cannulation failure with a conventional (0.035-inch guidewire) technique. SUBJECTS AND METHODS: Of 293 patients with biliary strictures after LDLT, 19 (6%) patients, 11 men and 8 women of mean age 48.5 years, had the failed cannulation of the stricture by conventional techniques. Recannulation was attempted by using two alternative methods, namely a micro-catheter set via percutaneous access and a snare (rendezvous) technique using percutaneous and endoscopic approaches. RESULTS: Strictures were successfully cannulated in 16 (84%) of the 19 patients. A microcatheter set was used in 12 and a snare technique in four patients. Stricture cannulation failed in the remaining three patients, who finally underwent surgical revision. CONCLUSION: Most technical failures using a conventional technique for biliary stricture cannulation after LDLT can be overcome by using a microcatheter set or a snare (rendezvous) technique. PMID- 22438687 TI - Effects of arsenic trioxide on radiofrequency ablation of VX2 liver tumor: intraarterial versus intravenous administration. AB - OBJECTIVE: Arsenic trioxide (As(2)O(3)) can be used as a possible pharmaceutical alternative that augments radiofrequency (RF) ablation by reducing tumor blood flow. The aim of this study was to assess the effect of intraarterial and intravenous administration of As(2)O(3) on RF-induced ablation in an experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in the livers of 30 rabbits. As(2)O(3) (1 mg/kg) was administered through the hepatic artery (n = 10, group A) or ear vein (n = 10, group B), 30 minutes before RF ablation (125 mA +/- 35; 90 +/- 5C). As a control group, 10 rabbits were treated with RF ablation alone (group C). RF was intentionally applied to the peripheral margin of the tumor so that ablation can cover the tumor and adjacent hepatic parenchyma. Ablation areas of the tumor and adjacent parenchymal changes among three groups were compared by the Kruskal-Wallis and Mann-Whitney U test. RESULTS: The overall ablation areas were 156 +/- 28.9 mm(2) (group A), 119 +/- 31.7 (group B), and 92 +/- 17.4 (group C, p < 0.04). The ablation area of the tumor was significantly larger in group A (73 +/- 19.7 mm(2)) than both group B (50 +/- 19.4, p = 0.02) and group C (28 +/- 2.2, p < 0.01). The ratios of the tumoral ablation area to the overall ablation area were larger in group A (47 +/- 10.5%) than that of the other groups (42 +/- 7.3% in group B and 32 +/- 5.6% in group C) (p < 0.03). CONCLUSION: Radiofrequency-induced ablation area can be increased with intraarterial or intravenous administration of As(2)O(3). The intraarterial administration of As(2)O(3) seems to be helpful for the selective ablation of the tumor. PMID- 22438688 TI - Radiology residents' awareness about ionizing radiation doses in imaging studies and their cancer risk during radiological examinations. AB - OBJECTIVE: Imaging methods that use ionizing radiation have been more frequent in various medical fields with advances in imaging technology. The aim of our study was to make residents be aware of the radiation dose they are subjected to when they conduct radiological imaging methods, and of cancer risk. MATERIALS AND METHODS: A total of 364 residents participated in this descriptive study which was conducted during the period between October, 2008 and January, 2009. The questionnaires were completed under strict control on a one-to-one basis from each department. A chi(2)-test was used for the evaluation of data obtained. RESULTS: Only 7% of residents correctly answered to the question about the ionizing radiation dose of a posteroanterior (PA) chest X-ray. The question asking about the equivalent number of PA chest X-rays to the ionizing dose of a brain CT was answered correctly by 24% of residents; the same question regarding abdominal CT was answered correctly by 16% of residents, thorax CT by 16%, thyroid scintigraphy by 15%, intravenous pyelography by 9%, and lumbar spine radiography by 2%. The risk of developing a cancer throughout lifetime by a brain and abdominal CT were 33% and 28%, respectively. CONCLUSION: Radiologic residents should have updated knowledge about radiation dose content and attendant cancer risks of various radiological imaging methods during both basic medical training period and following practice period. PMID- 22438689 TI - CT-guided percutaneous biopsy of intrathoracic lesions. AB - Percutaneous CT-guided needle biopsy of mediastinal and pulmonary lesions is a minimally invasive approach for obtaining tissue for histopathological examination. Although it is a widely accepted procedure with relatively few complications, precise planning and detailed knowledge of various aspects of the biopsy procedure is mandatory to avert complications. In this pictorial review, we reviewed important anatomical approaches, technical aspects of the procedure, and its associated complications. PMID- 22438690 TI - Successful treatment of malignant superior vena cava syndrome using a stent graft. AB - We report successful outcomes after endovascular placement of a stent graft in a 74- and a 77-year-old men, both of whom had malignant superior vena cava syndrome caused by squamous cell carcinoma. In each patient, successful palliation of the malignant superior vena cava syndrome was achieved by placement of a stent graft. No procedure-related complications were observed. The patients were asymptomatic until their deaths, seven and 14 months after stent graft placement, respectively. PMID- 22438691 TI - Percutaneous treatment of a primary pancreatic hydatid cyst using a catheterization technique. AB - Primary pancreatic hydatid cysts are rare and its percutaneous treatment and catheterization technique has, to the best of our knowledge, not been published in literature. A 33-year-old male patient who presented with abdominal pain was evaluated by ultrasonography (US) and computed tomography examinations. Both examinations revealed a cyst in the neck of the pancreas. After the administration of albendazole chemoprophylaxis, the patient underwent diagnostic puncture showing high pressure spring water which harbored the scoleces and was treated percutaneously by the catheterization technique. In this technique, first the cyst was punctured, the fluid content aspirated, the radiocontrast material injected to see possible fistulisation, and then re-aspirated. The 20% hypertonic saline solution was injected and re-aspiration was performed to the best of our abilities, followed by the insertion of a catheter for drainage of the remaining non-aspiratable fluid content. At follow-up examination, the cyst was not visible on US after 6 months. There was no evidence of cyst recurrence or dissemination after 18 months at serologic and imaging follow-up. PMID- 22438692 TI - Diffusion MR imaging of postoperative bilateral acute ischemic optic neuropathy. AB - A 57-year-old woman experienced bilateral acute ischemic optic neuropathy after spine surgery. Routine MR imaging sequence, T2-weighted image, showed subtle high signal intensity on bilateral optic nerves. A contrast-enhanced T1 weighted image showed enhancement along the bilateral optic nerve sheath. Moreover, diffusion weighted image (DWI) and an apparent diffusion coefficient map showed markedly restricted diffusion on bilateral optic nerves. Although MR findings of T2 weighted and contrast enhanced T1-weighted images may be nonspecific, the DWI finding of cytotoxic edema of bilateral optic nerves will be helpful for the diagnosis of acute ischemic optic neuropathy after spine surgery. PMID- 22438693 TI - Intracranial extramedullary hematopoiesis in beta-thalassemia. AB - Extramedullary hematopoiesis (EMH) represents tumor-like proliferation of hemopoietic tissue which complicates chronic hemoglobinopathy. Intracranial EMH is an extremely rare occurrence. Magnetic resonance imaging (MRI) offers a precise diagnosis. It is essential to distinguish EMH from other extradural central nervous system tumors, because treatment and prognosis are totally different. Herein, we report the imaging findings of beta-thalassemia in a 13 year-old boy complaining of weakness of left side of the body and gait disturbance; CT and MRI revealed an extradural mass in the right temporoparietal region. PMID- 22438694 TI - Isolated non-compaction of the left ventricle in a patient with new-onset heart failure: morphologic and functional evaluation with cardiac multidetector computed tomography. AB - We describe a case of new-onset heart failure in a patient in whom cardiac CT enabled the non-invasive diagnosis of isolated non-compaction and associated functional abnormalities of the left ventricle with the concomitant evaluation of coronary arteries. This case highlights the utility of cardiac CT for the morphological and functional evaluation of the heart as a single imaging modality. PMID- 22438695 TI - Micropapillary lung cancer with breast metastasis simulating primary breast cancer due to architectural distortion on images. AB - A 47-year-old Korean woman with right middle lobe lung adenocarcinoma, malignant pleural effusion, and multiple lymph node and bone metastases, after three months of lung cancer diagnosis, presented with a palpable right breast mass. Images of the right breast demonstrated architectural distortion that strongly suggested primary breast cancer. Breast biopsy revealed metastatic lung cancer with a negative result for estrogen receptor (ER), progesterone receptor (PR) and mammaglobin, and a positive result for thyroid transcription factor-1 (TTF-1). We present a case of breast metastasis from a case of lung cancer with an extensive micropapillary component, which was initially misinterpreted as a primary breast cancer due to unusual image findings with architectural distortion. PMID- 22438696 TI - RE: few comments on: "musculoskeletal applications of elastography: a pictorial essay of our initial experience". PMID- 22438698 TI - Anemia and Related Factors in Preschool Children in the Southern Rural Lao People's Democratic Republic. AB - Anemia is a severe public health problem in the Lao People's Democratic Republic (PDR). Consequently, a new control strategy to reduce the burden of anemia has been introduced for preschool children (aged 6-52 months). The objective of this study was to assess the current prevalence of anemia and related factors in preschool children in southern rural Lao PDR. A population-based cross-sectional study was carried out in six communities in Songkhone district, Savannakheth province, in February 2009. As a result, the prevalence of anemia was found to be 48.9% (95% confidence interval (CI), 43.5-54.3), although most cases were mild. A multiple logistic regression analysis indicated that there was no protective effect of breastfeeding against anemia. The anemia prevalence was higher in 1) children aged 6-23 months (Odds Ratio (OR) = 1.73, 95% CI, 1.02-2.90) than in older children, 2) children in large families (6 or more members) (OR = 1.96, 95% CI, 1.17-3.29), and 3) children in three remote villages with relatively difficult access to markets (OR = 3.01, 95% CI, 1.25-7.47).In Lao PDR, improvement of food practices and home-fortified food supplementation interventions are essential. High-risk groups should be targeted and a long-term health education program that aims to modify food habits implemented. Furthermore, in settings where iron deficiency is not the only cause of anemia, combining an iron supplement with other measures is necessary. PMID- 22438699 TI - Evaluation of the NOW Malaria Immunochromatographic Test for Quantitative Diagnosis of Falciparum and Vivax Malaria Parasite Density. AB - The NOW(r) Malaria Test, an immunochromatographic test (ICT), was evaluated to determine its ability to quantitatively detect malaria parasites using 100 blood samples from Thailand, including 50 Plasmodium falciparum (Pf) infections and 50 P. vivax (Pv) infections. Intensities of the thickness of the visible bands of the positive ICT were compared with the parasite densities. In cases of Pf infection, the intensities of both HRP-2 bands (T1 bands: Pf specific bands) and aldolase bands (T2 bands: pan-Plasmodium bands) correlated with the parasite densities. The intensities of T2 bands in Pf positive samples showed better correlation with the parasite densities than the T1 bands. In the cases of Pv infection, the intensities of T2 bands were also well correlated with parasite density. These results suggest that the ICT is useful not only for rapid detection of malaria parasites but also for estimating parasite density. PMID- 22438700 TI - Knowledge, attitudes and practices relevant to malaria control in remote island populations of manus, papua new Guinea. AB - A community-based cross-sectional survey of 262 participants in four island communities of Manus, Papua New Guinea was conducted using a structured questionnaire to examine possible factors of malaria prevalence, including education experiences, knowledge, attitudes, and preventive behaviors, in relation to antimalarial antibody titers. Bivariate and multivariate analyses revealed that micro-environmental conditions caused inter-community differences in malaria prevalence. Ninety-nine percent of the subject villagers recognized mosquito bites as a cause of malaria transmission, which explains the high possession rate of bednets. There was a significant correlation between malaria education experience at schools and knowledge (p < 0.01) and between knowledge and bednet use (p < 0.05). However, regular bednet users were only 35% of the total, due primarily to feelings of discomfort, heat, and stuffiness inside the bednet. Villagers' behavior of consulting an aid post orderly (APO) in case of high fever significantly lowered the titer level (p < 0.05), while their bednet use did not. This unexpected result was attributable to inappropriate bednet use and to daily living patterns, including both subsistence and social activities. We conclude that information regarding lifestyles and attitudes toward bednet use as well as malaria education experience at schools are particularly important for practical malaria prevention. PMID- 22438701 TI - Effect of Inducers, Incubation Time and Heme Concentration on IC(50) Value Variation in Anti-heme Crystallization Assay. AB - Heme detoxification through crystallization into hemozoin has been suggested as a good target for the development of screening assays for new antimalarials. However, comparisons among the data obtained from different experiments are difficult, and the IC(50) values (the concentrations of drug that are required to inhibit 50% of hemozoin formation) for the same drug vary widely. We studied the effects of changes in heme concentration (precursor of beta-hematin), incubation time and three inducers (SDS, Tween 20 and linoleic acid) on the IC(50) of some antimalarials (chloroquine, quinine, amodiaquine, and clotrimazole). The results showed that increasing both inducer concentration and incubation time raised the IC(50) of selected antimalarials. Any change in those factors caused the IC(50) value to vary. Standardization of assay conditions is, therefore, necessary to increase reproducibility and reduce discrepancies in assay performance. Considering all of the variables, the best choice of inducers is in the order of SDS > Tween 20 > linoleic acid. PMID- 22438702 TI - Uncommon sources and some unsual manifestations of lead poisoning in a tropical developing country. AB - Lead-containing cooking utensils, sometimes used in South Indian homes, and indigenous medications, widely used in India and increasingly in developed countries, may be responsible for lead intoxication in adults. We report chronic lead poisoning in five adult patients. Not all patients had abdominal colic, while dramatic weight loss, depression and encephalopathy were seen. Once recognized, lead poisoning is treatable and sometimes preventable. Response to chelation therapy with agents such as calcium ethylenediaminetetraacetate (CaEDTA) is impressive, although several courses of therapy may be necessary. PMID- 22438703 TI - Hand motion classification using a multi-channel surface electromyography sensor. AB - The human hand has multiple degrees of freedom (DOF) for achieving high-dexterity motions. Identifying and replicating human hand motions are necessary to perform precise and delicate operations in many applications, such as haptic applications. Surface electromyography (sEMG) sensors are a low-cost method for identifying hand motions, in addition to the conventional methods that use data gloves and vision detection. The identification of multiple hand motions is challenging because the error rate typically increases significantly with the addition of more hand motions. Thus, the current study proposes two new methods for feature extraction to solve the problem above. The first method is the extraction of the energy ratio features in the time-domain, which are robust and invariant to motion forces and speeds for the same gesture. The second method is the extraction of the concordance correlation features that describe the relationship between every two channels of the multi-channel sEMG sensor system. The concordance correlation features of a multi-channel sEMG sensor system were shown to provide a vast amount of useful information for identification. Furthermore, a new cascaded-structure classifier is also proposed, in which 11 types of hand gestures can be identified accurately using the newly defined features. Experimental results show that the success rate for the identification of the 11 gestures is significantly high. PMID- 22438704 TI - Complete vision-based traffic sign recognition supported by an I2V communication system. AB - This paper presents a complete traffic sign recognition system based on vision sensor onboard a moving vehicle which detects and recognizes up to one hundred of the most important road signs, including circular and triangular signs. A restricted Hough transform is used as detection method from the information extracted in contour images, while the proposed recognition system is based on Support Vector Machines (SVM). A novel solution to the problem of discarding detected signs that do not pertain to the host road is proposed. For that purpose infrastructure-to-vehicle (I2V) communication and a stereo vision sensor are used. Furthermore, the outputs provided by the vision sensor and the data supplied by the CAN Bus and a GPS sensor are combined to obtain the global position of the detected traffic signs, which is used to identify a traffic sign in the I2V communication. This paper presents plenty of tests in real driving conditions, both day and night, in which an average detection rate over 95% and an average recognition rate around 93% were obtained with an average runtime of 35 ms that allows real-time performance. PMID- 22438705 TI - The electromechanical behavior of a micro-ring driven by traveling electrostatic force. AB - There is no literature mentioning the electromechanical behavior of micro structures driven by traveling electrostatic forces. This article is thus the first to present the dynamics and stabilities of a micro-ring subjected to a traveling electrostatic force. The traveling electrostatic force may be induced by sequentially actuated electrodes which are arranged around the flexible micro ring. The analysis is based on a linearized distributed model considering the electromechanical coupling effects between electrostatic force and structure. The micro-ring will resonate when the traveling speeds of the electrostatic force approach some critical speeds. The critical speeds are equal to the ratio of the natural frequencies to the wave number of the correlative natural mode of the ring. Apart from resonance, the ring may be unstable at some unstable traveling speeds. The unstable regions appear not only near the critical speeds, but also near some fractions of some critical speeds differences. Furthermore the unstable regions expand with increasing driving voltage. This article may lead to a new research branch on electrostatic-driven micro devices. PMID- 22438706 TI - Applications of aptasensors in clinical diagnostics. AB - Aptamers are artificial oligonucleotides (DNA or RNA) selected in vitro that bind a broad range of targets with high affinity and specificity; a sensitive yet simple method to utilize aptamers as recognition elements for the development of biosensors (aptasensors) is to transduce the signal electrochemically. So far, aptasensors have been applied to clinical diagnostics and several technologies are in development. Aptasensors will extend the limits of current clinical diagnostics. Although the potential diagnostic applications are unlimited, the most current applications are foreseen in the areas of biomarker detection, cancer clinical testing, detection of infectious microorganisms and viruses. This review attempts to list examples of the research progresses of aptamers in biosensor platforms that have been published in recent years; in particular, we display cases of aptasensors that are already incorporated in clinical diagnostics or have potential applications in clinical diagnostics. PMID- 22438707 TI - Enhancing the reliability of head nodes in underwater sensor networks. AB - Underwater environments are quite different from terrestrial environments in terms of the communication media and operating conditions associated with those environments. In underwater sensor networks, the probability of node failure is high because sensor nodes are deployed in harsher environments than ground-based networks. The sensor nodes are surrounded by salt water and moved around by waves and currents. Many studies have focused on underwater communication environments in an effort to improve the data transmission throughput. In this paper, we present a checkpointing scheme for the head nodes to quickly recover from a head node failure. Experimental results show that the proposed scheme enhances the reliability of the networks and makes them more efficient in terms of energy consumption and the recovery latency compared to the previous scheme without checkpointing. PMID- 22438709 TI - Enhanced responsivity of photodetectors realized via impact ionization. AB - To increase the responsivity is one of the vital issues for a photodetector. By employing ZnO as a representative material of ultraviolet photodetectors and Si as a representative material of visible photodetectors, an impact ionization process, in which additional carriers can be generated in an insulating layer at a relatively large electric field, has been employed to increase the responsivity of a semiconductor photodetector. It is found that the responsivity of the photodetectors can be enhanced by tens of times via this impact ionization process. The results reported in this paper provide a general route to enhance the responsivity of a photodetector, thus may represent a step towards high performance photodetectors. PMID- 22438710 TI - A compact inductive position sensor made by inkjet printing technology on a flexible substrate. AB - This paper describes the design, simulation and fabrication of an inductive angular position sensor on a flexible substrate. The sensor is composed of meandering silver coils printed on a flexible substrate (Kapton film) using inkjet technology. The flexibility enables that after printing in the plane, the coils could be rolled and put inside each other. By changing the angular position of the internal coil (rotor) related to the external one (stator), the mutual inductance is changed and consequently the impedance. It is possible to determine the angular position from the measured real and imaginary part of the impedance, in our case in the frequency range from 1 MHz to 10 MHz. Experimental results were compared with simulation results obtained by in-house developed software tool, and very good agreement has been achieved. Thanks to the simple design and fabrication, smaller package space requirements and weight, the presented sensor represents a cost-effective alternative to the other sensors currently used in series production applications. PMID- 22438708 TI - Brain computer interfaces, a review. AB - A brain-computer interface (BCI) is a hardware and software communications system that permits cerebral activity alone to control computers or external devices. The immediate goal of BCI research is to provide communications capabilities to severely disabled people who are totally paralyzed or 'locked in' by neurological neuromuscular disorders, such as amyotrophic lateral sclerosis, brain stem stroke, or spinal cord injury. Here, we review the state-of-the-art of BCIs, looking at the different steps that form a standard BCI: signal acquisition, preprocessing or signal enhancement, feature extraction, classification and the control interface. We discuss their advantages, drawbacks, and latest advances, and we survey the numerous technologies reported in the scientific literature to design each step of a BCI. First, the review examines the neuroimaging modalities used in the signal acquisition step, each of which monitors a different functional brain activity such as electrical, magnetic or metabolic activity. Second, the review discusses different electrophysiological control signals that determine user intentions, which can be detected in brain activity. Third, the review includes some techniques used in the signal enhancement step to deal with the artifacts in the control signals and improve the performance. Fourth, the review studies some mathematic algorithms used in the feature extraction and classification steps which translate the information in the control signals into commands that operate a computer or other device. Finally, the review provides an overview of various BCI applications that control a range of devices. PMID- 22438711 TI - Development of a low-cost airborne ultrasound sensor for the detection of brick joints behind a wall painting. AB - Non-destructive methods are of great interest for the analysis of cultural heritage. Among the different possible techniques, this paper presents a low cost prototype based on the emission and reception of airborne ultrasound without direct contact with the test specimen. We successfully performed a method test for the detection of brick joints under a XV th century Renaissance fresco of the Metropolitan Cathedral of the city of Valencia (Spain). Both laboratory and in situ results are in agreement. Using this prototype system, an early moisture detection system has been installed in the dome that supports the fresco. The result is encouraging and opens interesting prospects for future research. PMID- 22438712 TI - Underwater Wireless Sensor Networks: how do acoustic propagation models impact the performance of higher-level protocols? AB - Several Medium Access Control (MAC) and routing protocols have been developed in the last years for Underwater Wireless Sensor Networks (UWSNs). One of the main difficulties to compare and validate the performance of different proposals is the lack of a common standard to model the acoustic propagation in the underwater environment. In this paper we analyze the evolution of underwater acoustic prediction models from a simple approach to more detailed and accurate models. Then, different high layer network protocols are tested with different acoustic propagation models in order to determine the influence of environmental parameters on the obtained results. After several experiments, we can conclude that higher-level protocols are sensitive to both: (a) physical layer parameters related to the network scenario and (b) the acoustic propagation model. Conditions like ocean surface activity, scenario location, bathymetry or floor sediment composition, may change the signal propagation behavior. So, when designing network architectures for UWSNs, the role of the physical layer should be seriously taken into account in order to assert that the obtained simulation results will be close to the ones obtained in real network scenarios. PMID- 22438713 TI - A radar-enabled collaborative sensor network integrating COTS technology for surveillance and tracking. AB - The feasibility of using Commercial Off-The-Shelf (COTS) sensor nodes is studied in a distributed network, aiming at dynamic surveillance and tracking of ground targets. Data acquisition by low-cost (<$50 US) miniature low-power radar through a wireless mote is described. We demonstrate the detection, ranging and velocity estimation, classification and tracking capabilities of the mini-radar, and compare results to simulations and manual measurements. Furthermore, we supplement the radar output with other sensor modalities, such as acoustic and vibration sensors. This method provides innovative solutions for detecting, identifying, and tracking vehicles and dismounts over a wide area in noisy conditions. This study presents a step towards distributed intelligent decision support and demonstrates effectiveness of small cheap sensors, which can complement advanced technologies in certain real-life scenarios. PMID- 22438714 TI - On the feasibility of interoperable schemes in hand biometrics. AB - Personal recognition through hand-based biometrics has attracted the interest of many researchers in the last twenty years. A significant number of proposals based on different procedures and acquisition devices have been published in the literature. However, comparisons between devices and their interoperability have not been thoroughly studied. This paper tries to fill this gap by proposing procedures to improve the interoperability among different hand biometric schemes. The experiments were conducted on a database made up of 8,320 hand images acquired from six different hand biometric schemes, including a flat scanner, webcams at different wavelengths, high quality cameras, and contactless devices. Acquisitions on both sides of the hand were included. Our experiment includes four feature extraction methods which determine the best performance among the different scenarios for two of the most popular hand biometrics: hand shape and palm print. We propose smoothing techniques at the image and feature levels to reduce interdevice variability. Results suggest that comparative hand shape offers better performance in terms of interoperability than palm prints, but palm prints can be more effective when using similar sensors. PMID- 22438715 TI - Multi-sensor arrays for online monitoring of cell dynamics in in vitro studies with choroid plexus epithelial cells. AB - Sensors and multi-sensor arrays are the basis of new technologies for the non label monitoring of cell activity. In this paper we show that choroid plexus cells can be cultured on silicon chips and that sensors register in real time changes in their activity, constituting an interesting experimental paradigm for cell biology and medical research. To validate the signals recorded (metabolism = peri-cellular acidification, oxygen consumption = respiration; impedance = adhesion, cell shape and motility) we performed experiments with compounds that act in a well-known way on cells, influencing these parameters. Our in vitro model demonstrates the advantages of multi-sensor arrays in assessment and experimental characterization of dynamic cellular events--in this case in choroid plexus functions, however with applicability to other cell types as well. PMID- 22438716 TI - Use of a real-time remote monitoring network (RTRM) to characterize the Guadalquivir estuary (Spain). AB - The temporal variability of hydrological variables in the Guadalquivir estuary was examined during three years through a real-time remote monitoring network (RTRM). The network was developed with the aim of studying the influence of hydrodynamical and hydrological features within the estuary on the functioning of the pelagic ecosystem. Completing this data-gathering network, monthly cruises were performed in order to measure biogeochemical variables that are indicative of the trophic status of the aquatic environment. The results showed that several sources of physical forcing, such as wind, tide-associated currents and river discharge were responsible for the spatio-temporal patterns of dissolved oxygen, salinity and turbidity in the estuary. The analysis was conducted under tidal and flood regime, which allowed us to identify river discharge as the main forcing agent of the hydrology inside the estuary. In particular, episodes of elevated turbidity detected by the network, together with episodes of low salinity and dissolved oxygen were closely related to the increase in water supply from a dam located upstream. The network installed provided accurate data that can be rapidly used for research or educational applications and by policy-makers or agencies in charge of the management of the coastal area. PMID- 22438717 TI - An electronic nose based on coated piezoelectric quartz crystals to certify ewes' cheese and to discriminate between cheese varieties. AB - An electronic nose based on coated piezoelectric quartz crystals was used to distinguish cheese made from ewes' milk, and to distinguish cheese varieties. Two sensors coated with Nafion and Carbowax could certify half the ewes' cheese samples, exclude 32 cheeses made from cow's milk and to classify half of the ewes' cheese samples as possibly authentic. Two other sensors, coated with polyvinylpyrrolidone and triethanolamine clearly distinguished between Flamengo, Brie, Gruyere and Mozzarella cheeses. Brie cheeses were further separated according to their origin, and Mozzarella grated cheese also appeared clearly separated from non-grated Mozzarella. PMID- 22438718 TI - Accuracy and resolution of Kinect depth data for indoor mapping applications. AB - Consumer-grade range cameras such as the Kinect sensor have the potential to be used in mapping applications where accuracy requirements are less strict. To realize this potential insight into the geometric quality of the data acquired by the sensor is essential. In this paper we discuss the calibration of the Kinect sensor, and provide an analysis of the accuracy and resolution of its depth data. Based on a mathematical model of depth measurement from disparity a theoretical error analysis is presented, which provides an insight into the factors influencing the accuracy of the data. Experimental results show that the random error of depth measurement increases with increasing distance to the sensor, and ranges from a few millimeters up to about 4 cm at the maximum range of the sensor. The quality of the data is also found to be influenced by the low resolution of the depth measurements. PMID- 22438719 TI - An aluminum microfluidic chip fabrication using a convenient micromilling process for fluorescent poly(DL-lactide-co-glycolide) microparticle generation. AB - This study presents the development of a robust aluminum-based microfluidic chip fabricated by conventional mechanical micromachining (computer numerical control based micro-milling process). It applied the aluminum-based microfluidic chip to form poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulating CdSe/ZnS quantum dots (QDs). A cross-flow design and flow-focusing system were employed to control the oil-in-water (o/w) emulsification to ensure the generation of uniformly-sized droplets. The size of the droplets could be tuned by adjusting the flow rates of the water and oil phases. The proposed microfluidic platform is easy to fabricate, set up, organize as well as program, and is valuable for further applications under harsh reaction conditions (high temperature and/or strong organic solvent systems). The proposed method has the advantages of actively controlling the droplet diameter, with a narrow size distribution, good sphericity, as well as being a simple process with a high throughput. In addition to the fluorescent PLGA microparticles in this study, this approach can also be applied to many applications in the pharmaceutical and biomedical area. PMID- 22438720 TI - Performance study of the application of Artificial Neural Networks to the completion and prediction of data retrieved by underwater sensors. AB - This paper presents a proposal for an Artificial Neural Network (ANN)-based architecture for completion and prediction of data retrieved by underwater sensors. Due to the specific conditions under which these sensors operate, it is not uncommon for them to fail, and maintenance operations are difficult and costly. Therefore, completion and prediction of the missing data can greatly improve the quality of the underwater datasets. A performance study using real data is presented to validate the approach, concluding that the proposed architecture is able to provide very low errors. The numbers show as well that the solution is especially suitable for cases where large portions of data are missing, while in situations where the missing values are isolated the improvement over other simple interpolation methods is limited. PMID- 22438721 TI - Embedded palmprint recognition system using OMAP 3530. AB - We have proposed in this paper an embedded palmprint recognition system using the dual-core OMAP 3530 platform. An improved algorithm based on palm code was proposed first. In this method, a Gabor wavelet is first convolved with the palmprint image to produce a response image, where local binary patterns are then applied to code the relation among the magnitude of wavelet response at the central pixel with that of its neighbors. The method is fully tested using the public PolyU palmprint database. While palm code achieves only about 89% accuracy, over 96% accuracy is achieved by the proposed G-LBP approach. The proposed algorithm was then deployed to the DSP processor of OMAP 3530 and work together with the ARM processor for feature extraction. When complicated algorithms run on the DSP processor, the ARM processor can focus on image capture, user interface and peripheral control. Integrated with an image sensing module and central processing board, the designed device can achieve accurate and real time performance. PMID- 22438722 TI - Miniaturized protein microarray with internal calibration as point-of-care device for diagnosis of neonatal sepsis. AB - Neonatal sepsis is still a leading cause of death among newborns. Therefore a protein-microarray for point-of-care testing that simultaneously quantifies the sepsis associated serum proteins IL-6, IL-8, IL-10, TNF alpha, S-100, PCT, E Selectin, CRP and Neopterin has been developed. The chip works with only a 4 MUL patient serum sample and hence minimizes excessive blood withdrawal from newborns. The 4 MUL patient samples are diluted with 36 MUL assay buffer and distributed to four slides for repetitive measurements. Streptavidin coated magnetic particles that act as distinct stirring detection components are added, not only to stir the sample, but also to detect antibody antigen binding events. We demonstrate that the test is complete within 2.5 h using a single step assay. S-100 conjugated to BSA is spotted in increasing concentrations to create an internal calibration. The presented low volume protein-chip fulfills the requirements of point-of-care testing for accurate and repeatable (CV < 14%) quantification of serum proteins for the diagnosis of neonatal sepsis. PMID- 22438723 TI - Video sensor architecture for surveillance applications. AB - This paper introduces a flexible hardware and software architecture for a smart video sensor. This sensor has been applied in a video surveillance application where some of these video sensors are deployed, constituting the sensory nodes of a distributed surveillance system. In this system, a video sensor node processes images locally in order to extract objects of interest, and classify them. The sensor node reports the processing results to other nodes in the cloud (a user or higher level software) in the form of an XML description. The hardware architecture of each sensor node has been developed using two DSP processors and an FPGA that controls, in a flexible way, the interconnection among processors and the image data flow. The developed node software is based on pluggable components and runs on a provided execution run-time. Some basic and application specific software components have been developed, in particular: acquisition, segmentation, labeling, tracking, classification and feature extraction. Preliminary results demonstrate that the system can achieve up to 7.5 frames per second in the worst case, and the true positive rates in the classification of objects are better than 80%. PMID- 22438724 TI - An LDPC decoder architecture for wireless sensor network applications. AB - The pervasive use of wireless sensors in a growing spectrum of human activities reinforces the need for devices with low energy dissipation. In this work, coded communication between a couple of wireless sensor devices is considered as a method to reduce the dissipated energy per transmitted bit with respect to uncoded communication. Different Low Density Parity Check (LDPC) codes are considered to this purpose and post layout results are shown for a low-area low energy decoder, which offers percentage energy savings with respect to the uncoded solution in the range of 40%-80%, depending on considered environment, distance and bit error rate. PMID- 22438725 TI - Pseudomonas fluorescens HK44: lessons learned from a model whole-cell bioreporter with a broad application history. AB - Initially described in 1990, Pseudomonas fluorescens HK44 served as the first whole-cell bioreporter genetically endowed with a bioluminescent (luxCDABE) phenotype directly linked to a catabolic (naphthalene degradative) pathway. HK44 was the first genetically engineered microorganism to be released in the field to monitor bioremediation potential. Subsequent to that release, strain HK44 had been introduced into other solids (soils, sands), liquid (water, wastewater), and volatile environments. In these matrices, it has functioned as one of the best characterized chemically-responsive environmental bioreporters and as a model organism for understanding bacterial colonization and transport, cell immobilization strategies, and the kinetics of cellular bioluminescent emission. This review summarizes the characteristics of P. fluorescens HK44 and the extensive range of its applications with special focus on the monitoring of bioremediation processes and biosensing of environmental pollution. PMID- 22438726 TI - Method for reading sensors and controlling actuators using audio interfaces of mobile devices. AB - This article presents a novel closed loop control architecture based on audio channels of several types of computing devices, such as mobile phones and tablet computers, but not restricted to them. The communication is based on an audio interface that relies on the exchange of audio tones, allowing sensors to be read and actuators to be controlled. As an application example, the presented technique is used to build a low cost mobile robot, but the system can also be used in a variety of mechatronics applications and sensor networks, where smartphones are the basic building blocks. PMID- 22438727 TI - Gait analysis using floor markers and inertial sensors. AB - In this paper, a gait analysis system which estimates step length and foot angles is proposed. A measurement unit, which consists of a camera and inertial sensors, is installed on a shoe. When the foot touches the floor, markers are recognized by the camera to obtain the current position and attitude. A simple planar marker with 4,096 different codes is used. These markers printed on paper are placed on the floor. When the foot is moving off the floor, the position and attitude are estimated using an inertial navigation algorithm. For accurate estimation, a smoother is proposed, where vision information and inertial sensor data are combined. Through experiments, it is shown that the proposed system can both track foot motion and estimate step length. PMID- 22438728 TI - Fast decision algorithms in low-power embedded processors for quality-of-service based connectivity of mobile sensors in heterogeneous wireless sensor networks. AB - When a mobile wireless sensor is moving along heterogeneous wireless sensor networks, it can be under the coverage of more than one network many times. In these situations, the Vertical Handoff process can happen, where the mobile sensor decides to change its connection from a network to the best network among the available ones according to their quality of service characteristics. A fitness function is used for the handoff decision, being desirable to minimize it. This is an optimization problem which consists of the adjustment of a set of weights for the quality of service. Solving this problem efficiently is relevant to heterogeneous wireless sensor networks in many advanced applications. Numerous works can be found in the literature dealing with the vertical handoff decision, although they all suffer from the same shortfall: a non-comparable efficiency. Therefore, the aim of this work is twofold: first, to develop a fast decision algorithm that explores the entire space of possible combinations of weights, searching that one that minimizes the fitness function; and second, to design and implement a system on chip architecture based on reconfigurable hardware and embedded processors to achieve several goals necessary for competitive mobile terminals: good performance, low power consumption, low economic cost, and small area integration. PMID- 22438729 TI - E-SAP: efficient-strong authentication protocol for healthcare applications using wireless medical sensor networks. AB - A wireless medical sensor network (WMSN) can sense humans' physiological signs without sacrificing patient comfort and transmit patient vital signs to health professionals' hand-held devices. The patient physiological data are highly sensitive and WMSNs are extremely vulnerable to many attacks. Therefore, it must be ensured that patients' medical signs are not exposed to unauthorized users. Consequently, strong user authentication is the main concern for the success and large scale deployment of WMSNs. In this regard, this paper presents an efficient, strong authentication protocol, named E-SAP, for healthcare application using WMSNs. The proposed E-SAP includes: (1) a two-factor (i.e., password and smartcard) professional authentication; (2) mutual authentication between the professional and the medical sensor; (3) symmetric encryption/decryption for providing message confidentiality; (4) establishment of a secure session key at the end of authentication; and (5) professionals can change their password. Further, the proposed protocol requires three message exchanges between the professional, medical sensor node and gateway node, and achieves efficiency (i.e., low computation and communication cost). Through the formal analysis, security analysis and performance analysis, we demonstrate that E-SAP is more secure against many practical attacks, and allows a tradeoff between the security and the performance cost for healthcare application using WMSNs. PMID- 22438730 TI - Protein reporter bioassay systems for the phenotypic screening of candidate drugs: a mouse platform for anti-aging drug screening. AB - Recent drug discovery efforts have utilized high throughput screening (HTS) of large chemical libraries to identify compounds that modify the activity of discrete molecular targets. The molecular target approach to drug screening is widely used in the pharmaceutical and biotechnology industries, because of the amount of knowledge now available regarding protein structure that has been obtained by computer simulation. The molecular target approach requires that the structure of target molecules, and an understanding of their physiological functions, is known. This approach to drug discovery may, however, limit the identification of novel drugs. As an alternative, the phenotypic- or pathway screening approach to drug discovery is gaining popularity, particularly in the academic sector. This approach not only provides the opportunity to identify promising drug candidates, but also enables novel information regarding biological pathways to be unveiled. Reporter assays are a powerful tool for the phenotypic screening of compound libraries. Of the various reporter genes that can be used in such assays, those encoding secreted proteins enable the screening of hit molecules in both living cells and animals. Cell- and animal-based screens enable simultaneous evaluation of drug metabolism or toxicity with biological activity. Therefore, drug candidates identified in these screens may have increased biological efficacy and a lower risk of side effects in humans. In this article, we review the reporter bioassay systems available for phenotypic drug discovery. PMID- 22438732 TI - A Web Service-based framework model for people-centric sensing applications applied to social networking. AB - As the Internet evolved, social networks (such as Facebook) have bloomed and brought together an astonishing number of users. Mashing up mobile phones and sensors with these social environments enables the creation of people-centric sensing systems which have great potential for expanding our current social networking usage. However, such systems also have many associated technical challenges, such as privacy concerns, activity detection mechanisms or intermittent connectivity, as well as limitations due to the heterogeneity of sensor nodes and networks. Considering the openness of the Web 2.0, good technical solutions for these cases consist of frameworks that expose sensing data and functionalities as common Web-Services. This paper presents our RESTful Web Service-based model for people-centric sensing frameworks, which uses sensors and mobile phones to detect users' activities and locations, sharing this information amongst the user's friends within a social networking site. We also present some screenshot results of our experimental prototype. PMID- 22438731 TI - Noble metal nanoparticles for biosensing applications. AB - In the last decade the use of nanomaterials has been having a great impact in biosensing. In particular, the unique properties of noble metal nanoparticles have allowed for the development of new biosensing platforms with enhanced capabilities in the specific detection of bioanalytes. Noble metal nanoparticles show unique physicochemical properties (such as ease of functionalization via simple chemistry and high surface-to-volume ratios) that allied with their unique spectral and optical properties have prompted the development of a plethora of biosensing platforms. Additionally, they also provide an additional or enhanced layer of application for commonly used techniques, such as fluorescence, infrared and Raman spectroscopy. Herein we review the use of noble metal nanoparticles for biosensing strategies--from synthesis and functionalization to integration in molecular diagnostics platforms, with special focus on those that have made their way into the diagnostics laboratory. PMID- 22438733 TI - Social network extraction and analysis based on multimodal dyadic interaction. AB - Social interactions are a very important component in people's lives. Social network analysis has become a common technique used to model and quantify the properties of social interactions. In this paper, we propose an integrated framework to explore the characteristics of a social network extracted from multimodal dyadic interactions. For our study, we used a set of videos belonging to New York Times' Blogging Heads opinion blog. The Social Network is represented as an oriented graph, whose directed links are determined by the Influence Model. The links' weights are a measure of the "influence" a person has over the other. The states of the Influence Model encode automatically extracted audio/visual features from our videos using state-of-the art algorithms. Our results are reported in terms of accuracy of audio/visual data fusion for speaker segmentation and centrality measures used to characterize the extracted social network. PMID- 22438734 TI - Signal processing of MEMS gyroscope arrays to improve accuracy using a 1st order Markov for rate signal modeling. AB - This paper presents a signal processing technique to improve angular rate accuracy of the gyroscope by combining the outputs of an array of MEMS gyroscope. A mathematical model for the accuracy improvement was described and a Kalman filter (KF) was designed to obtain optimal rate estimates. Especially, the rate signal was modeled by a first-order Markov process instead of a random walk to improve overall performance. The accuracy of the combined rate signal and affecting factors were analyzed using a steady-state covariance. A system comprising a six-gyroscope array was developed to test the presented KF. Experimental tests proved that the presented model was effective at improving the gyroscope accuracy. The experimental results indicated that six identical gyroscopes with an ARW noise of 6.2 degrees /?h and a bias drift of 54.14 degrees /h could be combined into a rate signal with an ARW noise of 1.8 degrees /?h and a bias drift of 16.3 degrees /h, while the estimated rate signal by the random walk model has an ARW noise of 2.4 degrees /?h and a bias drift of 20.6 degrees /h. It revealed that both models could improve the angular rate accuracy and have a similar performance in static condition. In dynamic condition, the test results showed that the first-order Markov process model could reduce the dynamic errors 20% more than the random walk model. PMID- 22438735 TI - Finger vein recognition based on a personalized best bit map. AB - Finger vein patterns have recently been recognized as an effective biometric identifier. In this paper, we propose a finger vein recognition method based on a personalized best bit map (PBBM). Our method is rooted in a local binary pattern based method and then inclined to use the best bits only for matching. We first present the concept of PBBM and the generating algorithm. Then we propose the finger vein recognition framework, which consists of preprocessing, feature extraction, and matching. Finally, we design extensive experiments to evaluate the effectiveness of our proposal. Experimental results show that PBBM achieves not only better performance, but also high robustness and reliability. In addition, PBBM can be used as a general framework for binary pattern based recognition. PMID- 22438736 TI - Comparison between conduction and convection effects on self-heating in doped microcantilevers. AB - The present study investigates the effects of thermal conduction and convection on self-heating temperatures and bimetallic deflections produced in doped microcantilever sensors. These cantilevers are commonly used as sensors and actuators in microsystems. The cantilever is a monolith, multi-layer structure with a thin U-shaped element inside. The cantilever substrate is made of silicon and silicon dioxide, respectively, and the element is p-doped silicon. A numerical analysis package (ANSYS) is used to study the effect of cantilever substrate material, element width, applied voltage and the operating environments on cantilever characteristics. The numerical results for temperature are compared against their analytical models. Results indicate the numerical results are accurate within 6% of analytical, and Si/Si cantilevers are more suitable for biosensors and AFM, whereas, Si/SiO(2) are for hotplates and actuators applications. PMID- 22438737 TI - Vector disparity sensor with vergence control for active vision systems. AB - This paper presents an architecture for computing vector disparity for active vision systems as used on robotics applications. The control of the vergence angle of a binocular system allows us to efficiently explore dynamic environments, but requires a generalization of the disparity computation with respect to a static camera setup, where the disparity is strictly 1-D after the image rectification. The interaction between vision and motor control allows us to develop an active sensor that achieves high accuracy of the disparity computation around the fixation point, and fast reaction time for the vergence control. In this contribution, we address the development of a real-time architecture for vector disparity computation using an FPGA device. We implement the disparity unit and the control module for vergence, version, and tilt to determine the fixation point. In addition, two on-chip different alternatives for the vector disparity engines are discussed based on the luminance (gradient based) and phase information of the binocular images. The multiscale versions of these engines are able to estimate the vector disparity up to 32 fps on VGA resolution images with very good accuracy as shown using benchmark sequences with known ground-truth. The performances in terms of frame-rate, resource utilization, and accuracy of the presented approaches are discussed. On the basis of these results, our study indicates that the gradient-based approach leads to the best trade-off choice for the integration with the active vision system. PMID- 22438738 TI - A platform for combined DNA and protein microarrays based on total internal reflection fluorescence. AB - We have developed a novel microarray technology based on total internal reflection fluorescence (TIRF) in combination with DNA and protein bioassays immobilized at the TIRF surface. Unlike conventional microarrays that exhibit reduced signal-to-background ratio, require several stages of incubation, rinsing and stringency control, and measure only end-point results, our TIRF microarray technology provides several orders of magnitude better signal-to-background ratio, performs analysis rapidly in one step, and measures the entire course of association and dissociation kinetics between target DNA and protein molecules and the bioassays. In many practical cases detection of only DNA or protein markers alone does not provide the necessary accuracy for diagnosing a disease or detecting a pathogen. Here we describe TIRF microarrays that detect DNA and protein markers simultaneously, which reduces the probabilities of false responses. Supersensitive and multiplexed TIRF DNA and protein microarray technology may provide a platform for accurate diagnosis or enhanced research studies. Our TIRF microarray system can be mounted on upright or inverted microscopes or interfaced directly with CCD cameras equipped with a single objective, facilitating the development of portable devices. As proof-of-concept we applied TIRF microarrays for detecting molecular markers from Bacillus anthracis, the pathogen responsible for anthrax. PMID- 22438739 TI - Evaluation of electrical and optical plethysmography sensors for noninvasive monitoring of hemoglobin concentration. AB - Completely noninvasive monitoring of hemoglobin concentration has not yet been fully realized in the clinical setting. This study investigates the viability of measuring hemoglobin concentration noninvasively by evaluating the performance of two types of sensor using a tissue phantom perfused with a blood substitute. An electrical sensor designed to measure blood volume changes during the cardiac cycle was used together with an infrared optical sensor for detection of erythrocyte-bound hemoglobin. Both sensors demonstrated sensitivity to changes in pulse volume (plethysmography). The electrical sensor produced a signal referred to as capacitance plethysmograph (CPG) a quantity which was invariant to the concentration of an infrared absorbing dye present in the blood substitute. The optical sensor signal (photoplethysmograph) increased in amplitude with increasing absorber concentration. The ratio PPG:CPG is invariant to pulse pressure. This quantity is discussed as a possible index of in vivo hemoglobin concentration. PMID- 22438740 TI - AURP: an AUV-aided underwater routing protocol for underwater acoustic sensor networks. AB - Deploying a multi-hop underwater acoustic sensor network (UASN) in a large area brings about new challenges in reliable data transmissions and survivability of network due to the limited underwater communication range/bandwidth and the limited energy of underwater sensor nodes. In order to address those challenges and achieve the objectives of maximization of data delivery ratio and minimization of energy consumption of underwater sensor nodes, this paper proposes a new underwater routing scheme, namely AURP (AUV-aided underwater routing protocol), which uses not only heterogeneous acoustic communication channels but also controlled mobility of multiple autonomous underwater vehicles (AUVs). In AURP, the total data transmissions are minimized by using AUVs as relay nodes, which collect sensed data from gateway nodes and then forward to the sink. Moreover, controlled mobility of AUVs makes it possible to apply a short range high data rate underwater channel for transmissions of a large amount of data. To the best to our knowledge, this work is the first attempt to employ multiple AUVs as relay nodes in a multi-hop UASN to improve the network performance in terms of data delivery ratio and energy consumption. Simulations, which are incorporated with a realistic underwater acoustic communication channel model, are carried out to evaluate the performance of the proposed scheme, and the results indicate that a high delivery ratio and low energy consumption can be achieved. PMID- 22438741 TI - Extraction and analysis of impervious surfaces based on a spectral un-mixing method using Pearl River Delta of China Landsat TM/ETM+ imagery from 1998 to 2008. AB - Impervious surface area (ISA) is considered as an indicator of environment change and is regarded as an important input parameter for hydrological cycle simulation, water management and area pollution assessment. The Pearl River Delta (PRD), the 3rd most important economic district of China, is chosen in this paper to extract the ISA information based on Landsat images of 1998, 2003 and 2008 by using a linear spectral un-mixing method and to monitor impervious surface change by analyzing the multi-temporal Landsat-derived fractional impervious surface. Results of this study were as follows: (1) the area of ISA in the PRD increased 79.09% from 1998 to 2003 and 26.88% from 2003 to 2008 separately; (2) the spatial distribution of ISA was described according to the 1998/2003 percentage respectively. Most of middle and high percentage ISA was located in northwestern and southeastern of the whole delta, and middle percentage ISA was mainly located in the city interior, high percentage ISA was mainly located in the suburban around the city accordingly; (3) the expanding direction and trend of high percentage ISA was discussed in order to understand the change of urban in this delta; High percentage ISA moved from inner city to edge of urban area during 1998-2003 and moved to the suburban area that far from the urban area mixed with jumpily and gradually during 2003-2008. According to the discussion of high percentage ISA spatial expanded direction, it could be found out that high percentage ISA moved outward from the centre line of Pearl River of the whole delta while a high ISA percentage in both shores of the Pearl River Estuary moved toward the Pearl River; (4) combining the change of ISA with social conditions, the driving relationship was analyzed in detail. It was evident that ISA percentage change had a deep relationship with the economic development of this region in the past ten years. Contemporaneous major sport events (16th Asia Games of Guangzhou, 26th Summer Universidad of Shenzhen) and the government policies also promoted the development of the ISA. Meanwhile, topographical features like the National Nature Reserve of China restricted and affected the expansion of the ISA. Above all, this paper attempted to extract ISA in a major region of the PRD; the temporal and spatial analyses to PRD ISA demonstrated the drastic changes in developed areas of China. These results were important and valuable for land use management, ecological protection and policy establishment. PMID- 22438742 TI - Parametric dense stereovision implementation on a system-on chip (SoC). AB - This paper proposes a novel hardware implementation of a dense recovery of stereovision 3D measurements. Traditionally 3D stereo systems have imposed the maximum number of stereo correspondences, introducing a large restriction on artificial vision algorithms. The proposed system-on-chip (SoC) provides great performance and efficiency, with a scalable architecture available for many different situations, addressing real time processing of stereo image flow. Using double buffering techniques properly combined with pipelined processing, the use of reconfigurable hardware achieves a parametrisable SoC which gives the designer the opportunity to decide its right dimension and features. The proposed architecture does not need any external memory because the processing is done as image flow arrives. Our SoC provides 3D data directly without the storage of whole stereo images. Our goal is to obtain high processing speed while maintaining the accuracy of 3D data using minimum resources. Configurable parameters may be controlled by later/parallel stages of the vision algorithm executed on an embedded processor. Considering hardware FPGA clock of 100 MHz, image flows up to 50 frames per second (fps) of dense stereo maps of more than 30,000 depth points could be obtained considering 2 Mpix images, with a minimum initial latency. The implementation of computer vision algorithms on reconfigurable hardware, explicitly low level processing, opens up the prospect of its use in autonomous systems, and they can act as a coprocessor to reconstruct 3D images with high density information in real time. PMID- 22438743 TI - Gen-2 hand-held optical imager towards cancer imaging: reflectance and transillumination phantom studies. AB - Hand-held near-infrared (NIR) optical imagers are developed by various researchers towards non-invasive clinical breast imaging. Unlike these existing imagers that can perform only reflectance imaging, a generation-2 (Gen-2) hand held optical imager has been recently developed to perform both reflectance and transillumination imaging. The unique forked design of the hand-held probe head(s) allows for reflectance imaging (as in ultrasound) and transillumination or compressed imaging (as in X-ray mammography). Phantom studies were performed to demonstrate two-dimensional (2D) target detection via reflectance and transillumination imaging at various target depths (1-5 cm deep) and using simultaneous multiple point illumination approach. It was observed that 0.45 cc targets were detected up to 5 cm deep during transillumination, but limited to 2.5 cm deep during reflectance imaging. Additionally, implementing appropriate data post-processing techniques along with a polynomial fitting approach, to plot 2D surface contours of the detected signal, yields distinct target detectability and localization. The ability of the gen-2 imager to perform both reflectance and transillumination imaging allows its direct comparison to ultrasound and X-ray mammography results, respectively, in future clinical breast imaging studies. PMID- 22438744 TI - Fiber Bragg grating sensors for harsh environments. AB - Because of their small size, passive nature, immunity to electromagnetic interference, and capability to directly measure physical parameters such as temperature and strain, fiber Bragg grating sensors have developed beyond a laboratory curiosity and are becoming a mainstream sensing technology. Recently, high temperature stable gratings based on regeneration techniques and femtosecond infrared laser processing have shown promise for use in extreme environments such as high temperature, pressure or ionizing radiation. Such gratings are ideally suited for energy production applications where there is a requirement for advanced energy system instrumentation and controls that are operable in harsh environments. This paper will present a review of some of the more recent developments. PMID- 22438745 TI - The effect of direction on cursor moving kinematics. AB - There have been only few studies to substantiate the kinematic characteristics of cursor movement. In this study, a quantitative experimental research method was used to explore the effect of moving direction on the kinematics of cursor movement in 24 typical young persons using our previously developed computerized measuring program. The results of multiple one way repeated measures ANOVAs and post hoc LSD tests demonstrated that the moving direction had effects on average velocity, movement time, movement unit and peak velocity. Moving leftward showed better efficiency than moving rightward, upward and downward from the kinematic evidences such as velocity, movement unit and time. Moreover, the unique pattern of the power spectral density (PSD) of velocity (strategy for power application) explained why the smoothness was still maintained while moving leftward even under an unstable situation with larger momentum. Moreover, the information from this cursor moving study can guide us to relocate the toolbars and icons in the window interface, especially for individuals with physical disabilities whose performances are easily interrupted while controlling the cursor in specific directions. PMID- 22438746 TI - Sunlight intensity based global positioning system for near-surface underwater sensors. AB - Water monitoring is important in domains including documenting climate change, weather prediction and fishing. This paper presents a simple and energy efficient localization strategy for near surface buoy based sensors. Sensors can be dropped randomly in the ocean and thus self-calibrate in terms of geographic location such that geo-tagged observations of water quality can be made without the need for costly and energy consuming GPS-hardware. The strategy is based on nodes with an accurate clock and light sensors that can regularly sample the level of light intensity. The measurements are fitted into a celestial model of the earth motion around the sun. By identifying the trajectory of the sun across the skies one can accurately determine sunrise and sunset times, and thus extract the longitude and latitude of the sensor. Unlike previous localization techniques for underwater sensors, the current approach does not rely on stationary or mobile reference points. PMID- 22438747 TI - Electrical model of a carbon-polymer composite (CPC) collision detector. AB - We present a study of an electrical model of electromechanically active carbon polymer composite (CPC) with carbide-derived carbon (CDC) electrodes. The major focus is on investigation of surface electrode behavior upon external bending of the material. We show that electrical impedance measured from the surface of the CDC-based CPC can be used to determine the curvature of the material and, hence, the tip displacement of a CPC laminate in a cantilever configuration. It is also shown that by measuring surface signals in the process of an actuator's work cycle, we obtain a self-sensing collision-detecting CPC actuator that can be considered as a counterpart of biomimetic vibrissae. PMID- 22438748 TI - Secure cooperation of autonomous mobile sensors using an underwater acoustic network. AB - Methodologies and algorithms are presented for the secure cooperation of a team of autonomous mobile underwater sensors, connected through an acoustic communication network, within surveillance and patrolling applications. In particular, the work proposes a cooperative algorithm in which the mobile underwater sensors (installed on Autonomous Underwater Vehicles-AUVs) respond to simple local rules based on the available information to perform the mission and maintain the communication link with the network (behavioral approach). The algorithm is intrinsically robust: with loss of communication among the vehicles the coverage performance (i.e., the mission goal) is degraded but not lost. The ensuing form of graceful degradation provides also a reactive measure against Denial of Service. The cooperative algorithm relies on the fact that the available information from the other sensors, though not necessarily complete, is trustworthy. To ensure trustworthiness, a security suite has been designed, specifically oriented to the underwater scenario, and in particular with the goal of reducing the communication overhead introduced by security in terms of number and size of messages. The paper gives implementation details on the integration between the security suite and the cooperative algorithm and provides statistics on the performance of the system as collected during the UAN project sea trial held in Trondheim, Norway, in May 2011. PMID- 22438749 TI - Robust kernel-based tracking with multiple subtemplates in vision guidance system. AB - The mean shift algorithm has achieved considerable success in target tracking due to its simplicity and robustness. However, the lack of spatial information may result in its failure to get high tracking precision. This might be even worse when the target is scale variant and the sequences are gray-levels. This paper presents a novel multiple subtemplates based tracking algorithm for the terminal guidance application. By applying a separate tracker to each subtemplate, it can handle more complicated situations such as rotation, scaling, and partial coverage of the target. The innovations include: (1) an optimal subtemplates selection algorithm is designed, which ensures that the selected subtemplates maximally represent the information of the entire template while having the least mutual redundancy; (2) based on the serial tracking results and the spatial constraint prior to those subtemplates, a Gaussian weighted voting method is proposed to locate the target center; (3) the optimal scale factor is determined by maximizing the voting results among the scale searching layers, which avoids the complicated threshold setting problem. Experiments on some videos with static scenes show that the proposed method greatly improves the tracking accuracy compared to the original mean shift algorithm. PMID- 22438750 TI - A method based on multi-sensor data fusion for fault detection of planetary gearboxes. AB - Studies on fault detection and diagnosis of planetary gearboxes are quite limited compared with those of fixed-axis gearboxes. Different from fixed-axis gearboxes, planetary gearboxes exhibit unique behaviors, which invalidate fault diagnosis methods that work well for fixed-axis gearboxes. It is a fact that for systems as complex as planetary gearboxes, multiple sensors mounted on different locations provide complementary information on the health condition of the systems. On this basis, a fault detection method based on multi-sensor data fusion is introduced in this paper. In this method, two features developed for planetary gearboxes are used to characterize the gear health conditions, and an adaptive neuro-fuzzy inference system (ANFIS) is utilized to fuse all features from different sensors. In order to demonstrate the effectiveness of the proposed method, experiments are carried out on a planetary gearbox test rig, on which multiple accelerometers are mounted for data collection. The comparisons between the proposed method and the methods based on individual sensors show that the former achieves much higher accuracies in detecting planetary gearbox faults. PMID- 22438751 TI - Highly sensitive detection of naphthalene in solvent vapor using a functionalized PBG refractive index sensor. AB - We report an optical refractive index sensor system based on a planar Bragg grating which is functionalized by substituted gamma-cyclodextrin to determine low concentrations of naphthalene in solvent vapor. The sensor system exhibits a quasi-instantaneous shift of the Bragg wavelength and is therefore capable for online detection. The overall shift of the Bragg wavelength reveals a linear relationship to the analyte concentration with a gradient of 12.5 +/- 1.5 pm/ppm. Due to the spectral resolution and repeatability of the interrogation system, this corresponds to acquisition steps of 80 ppb. Taking into account the experimentally detected signal noise a minimum detection limit of 0.48 +/- 0.05 ppm is deduced. PMID- 22438752 TI - Localization algorithms of Underwater Wireless Sensor Networks: a survey. AB - In Underwater Wireless Sensor Networks (UWSNs), localization is one of most important technologies since it plays a critical role in many applications. Motivated by widespread adoption of localization, in this paper, we present a comprehensive survey of localization algorithms. First, we classify localization algorithms into three categories based on sensor nodes' mobility: stationary localization algorithms, mobile localization algorithms and hybrid localization algorithms. Moreover, we compare the localization algorithms in detail and analyze future research directions of localization algorithms in UWSNs. PMID- 22438753 TI - Architecture and protocol of a semantic system designed for video tagging with sensor data in mobile devices. AB - Current mobile phones come with several sensors and powerful video cameras. These video cameras can be used to capture good quality scenes, which can be complemented with the information gathered by the sensors also embedded in the phones. For example, the surroundings of a beach recorded by the camera of the mobile phone, jointly with the temperature of the site can let users know via the Internet if the weather is nice enough to swim. In this paper, we present a system that tags the video frames of the video recorded from mobile phones with the data collected by the embedded sensors. The tagged video is uploaded to a video server, which is placed on the Internet and is accessible by any user. The proposed system uses a semantic approach with the stored information in order to make easy and efficient video searches. Our experimental results show that it is possible to tag video frames in real time and send the tagged video to the server with very low packet delay variations. As far as we know there is not any other application developed as the one presented in this paper. PMID- 22438754 TI - Investigation of the transient behavior of a cantilever beam using PVDF sensors. AB - In this paper, a PVDF film sensor was used to measure the transient responses of a cantilever beam subjected to an impact loading. The measurement capability of a PVDF sensor is affected by the area of the PVDF film sensor and the signal conditioner (charge amplifier). The influences of these effects on the experimental measurements were investigated. The transient responses for the dynamic strain of the beam were measured simultaneously by the PVDF sensor and a conventional strain gauge. The resonant frequencies of the beam were determined by applying the Fast Fourier Transform on transient results in the time domain of the PVDF sensor and the strain gauge. The experimentally measured resonant frequencies from the PVDF sensor and the strain gauge were compared with those predicted from theoretical and FEM numerical calculations. Based on the comparison of the results measured for these two sensors, the PVDF film sensor proved capable of measuring transient responses for dynamic strain, and its sensitivity is better than that of the strain gauge. Furthermore, almost all the resonant frequencies can be obtained from the results of transient responses for PVDF film. PMID- 22438755 TI - Experimental assessment of different receiver structures for underwater acoustic communications over multipath channels. AB - Underwater communication channels are often complicated, and in particular multipath propagation may cause intersymbol interference (ISI). This paper addresses how to remove ISI, and evaluates the performance of three different receiver structures and their implementations. Using real data collected in a high-frequency (10-14 kHz) field experiment, the receiver structures are evaluated by off-line data processing. The three structures are multichannel decision feedback equalizer (DFE), passive time reversal receiver (passive-phase conjugation (PPC) with a single channel DFE), and the joint PPC with multichannel DFE. In sparse channels, dominant arrivals represent the channel information, and the matching pursuit (MP) algorithm which exploits the channel sparseness has been investigated for PPC processing. In the assessment, it is found that: (1) it is advantageous to obtain spatial gain using the adaptive multichannel combining scheme; and (2) the MP algorithm improves the performance of communications using PPC processing. PMID- 22438756 TI - Waveguide-mode sensors as aptasensors. AB - Aptamers are artificial nucleic acid ligands that can be generated by in vitro selection through partition and amplification. Aptamers can be generated against a wide range of biomolecules through the formation of versatile stem-loop structures. Because aptamers are potential substitutes for antibodies and drugs, the development of an aptamer-based sensor (aptasensor) is mandatory for diagnosis. We previously reported that waveguide-mode sensors are useful in the analysis of a wide range of biomolecular interactions, including aptamers. The advantages of the waveguide-mode sensor that we developed include physical and chemical stability and that higher sensitivity can be achieved with ease by perforating the waveguide layer or using colored materials such as dyes or metal nanoparticles as labels. Herein, we provide an overview of the strategies and applications for aptamer-based analyses using waveguide-mode sensors. PMID- 22438757 TI - Objective display and discrimination of floral odors from Amorphophallus titanum, bloomed on different dates and at different locations, using an electronic nose. AB - As olfactory perceptions vary from person to person, it is difficult to describe smells objectively. In contrast, electronic noses also detect smells with their sensors, but in addition describe those using electronic signals. Here we showed a virtual connection method between a human nose perceptions and electronic nose responses with the smell of standard gases. In this method, Amorphophallus titanum flowers, which emit a strong carrion smell, could objectively be described using an electronic nose, in a way resembling the skill of sommeliers. We could describe the flower smell to be close to that of a mixture of methyl mercaptan and propionic acid, by calculation of the dilution index from electronic resistances. In other words, the smell resembled that of "decayed cabbage, garlic and pungent sour" with possible descriptors. Additionally, we compared the smells of flowers which bloomed on different dates and at different locations and showed the similarity of odor intensities visually, in standard gas categories. We anticipate our assay to be a starting point for a perceptive connection between our noses and electronic noses. PMID- 22438758 TI - A highly sensitive CMOS digital Hall sensor for low magnetic field applications. AB - Integrated CMOS Hall sensors have been widely used to measure magnetic fields. However, they are difficult to work with in a low magnetic field environment due to their low sensitivity and large offset. This paper describes a highly sensitive digital Hall sensor fabricated in 0.18 MUm high voltage CMOS technology for low field applications. The sensor consists of a switched cross-shaped Hall plate and a novel signal conditioner. It effectively eliminates offset and low frequency 1/f noise by applying a dynamic quadrature offset cancellation technique. The measured results show the optimal Hall plate achieves a high current related sensitivity of about 310 V/AT. The whole sensor has a remarkable ability to measure a minimum +/- 2 mT magnetic field and output a digital Hall signal in a wide temperature range from -40 degrees C to 120 degrees C. PMID- 22438759 TI - A survey on virtualization of Wireless Sensor Networks. AB - Wireless Sensor Networks (WSNs) are gaining tremendous importance thanks to their broad range of commercial applications such as in smart home automation, health care and industrial automation. In these applications multi-vendor and heterogeneous sensor nodes are deployed. Due to strict administrative control over the specific WSN domains, communication barriers, conflicting goals and the economic interests of different WSN sensor node vendors, it is difficult to introduce a large scale federated WSN. By allowing heterogeneous sensor nodes in WSNs to coexist on a shared physical sensor substrate, virtualization in sensor network may provide flexibility, cost effective solutions, promote diversity, ensure security and increase manageability. This paper surveys the novel approach of using the large scale federated WSN resources in a sensor virtualization environment. Our focus in this paper is to introduce a few design goals, the challenges and opportunities of research in the field of sensor network virtualization as well as to illustrate a current status of research in this field. This paper also presents a wide array of state-of-the art projects related to sensor network virtualization. PMID- 22438760 TI - Near infrared characterization of hetero-core optical fiber SPR sensors coated with Ta2O5 film and their applications. AB - This paper describes the characteristics of optical fiber sensors with surface plasmon resonance (SPR) at 1,310 nm in which the scattering loss of silica optical fiber is low. SPR operation in the infrared wavelength range is achieved by coating a thin tantalum pentaoxide (Ta(2)O(5)) film. The novelty of this paper lies in the verification of how the hetero-core scheme could be operated as a commercial base candidate in the sense of easy fabrication, sufficient mechanical strength, and significant sensitivity as a liquid detector under the basis of a low loss transmission network in the near infrared wavelength region. The effect of Ta(2)O(5) layer thickness has been experimentally revealed in the wavelength region extending to 1,800 nm by using the hetero-core structured optical fiber. SPR characterizations have been made in the wavelength region 1,000-1,300 nm, showing the feasible operation at the near infrared wavelength and the possible practical applications. In addition, the technique developed in this work has been interestingly applied to a multi-point water-detection and a water-level gauge in which tandem-connected SPR sensors system using hetero-core structured fibers were incorporated. The detailed performance characteristics are also shown on these applications. PMID- 22438761 TI - Improving planetary rover attitude estimation via MEMS sensor characterization. AB - Micro Electro-Mechanical Systems (MEMS) are currently being considered in the space sector due to its suitable level of performance for spacecrafts in terms of mechanical robustness with low power consumption, small mass and size, and significant advantage in system design and accommodation. However, there is still a lack of understanding regarding the performance and testing of these new sensors, especially in planetary robotics. This paper presents what is missing in the field: a complete methodology regarding the characterization and modeling of MEMS sensors with direct application. A reproducible and complete approach including all the intermediate steps, tools and laboratory equipment is described. The process of sensor error characterization and modeling through to the final integration in the sensor fusion scheme is explained with detail. Although the concept of fusion is relatively easy to comprehend, carefully characterizing and filtering sensor information is not an easy task and is essential for good performance. The strength of the approach has been verified with representative tests of novel high-grade MEMS inertia sensors and exemplary planetary rover platforms with promising results. PMID- 22438762 TI - Respiratory physiology and the impact of different modes of ventilation on the photoplethysmographic waveform. AB - The photoplethysmographic waveform sits at the core of the most used, and arguably the most important, clinical monitor, the pulse oximeter. Interestingly, the pulse oximeter was discovered while examining an artifact during the development of a noninvasive cardiac output monitor. This article will explore the response of the pulse oximeter waveform to various modes of ventilation. Modern digital signal processing is allowing for a re-examination of this ubiquitous signal. The effect of ventilation on the photoplethysmographic waveform has long been thought of as a source of artifact. The primary goal of this article is to improve the understanding of the underlying physiology responsible for the observed phenomena, thereby encouraging the utilization of this understanding to develop new methods of patient monitoring. The reader will be presented with a review of respiratory physiology followed by numerous examples of the impact of ventilation on the photoplethysmographic waveform. PMID- 22438763 TI - Gait analysis using wearable sensors. AB - Gait analysis using wearable sensors is an inexpensive, convenient, and efficient manner of providing useful information for multiple health-related applications. As a clinical tool applied in the rehabilitation and diagnosis of medical conditions and sport activities, gait analysis using wearable sensors shows great prospects. The current paper reviews available wearable sensors and ambulatory gait analysis methods based on the various wearable sensors. After an introduction of the gait phases, the principles and features of wearable sensors used in gait analysis are provided. The gait analysis methods based on wearable sensors is divided into gait kinematics, gait kinetics, and electromyography. Studies on the current methods are reviewed, and applications in sports, rehabilitation, and clinical diagnosis are summarized separately. With the development of sensor technology and the analysis method, gait analysis using wearable sensors is expected to play an increasingly important role in clinical applications. PMID- 22438764 TI - Biomarker discovery by novel sensors based on nanoproteomics approaches. AB - During the last years, proteomics has facilitated biomarker discovery by coupling high-throughput techniques with novel nanosensors. In the present review, we focus on the study of label-based and label-free detection systems, as well as nanotechnology approaches, indicating their advantages and applications in biomarker discovery. In addition, several disease biomarkers are shown in order to display the clinical importance of the improvement of sensitivity and selectivity by using nanoproteomics approaches as novel sensors. PMID- 22438765 TI - Design and implementation of an omni-directional underwater acoustic micro-modem based on a low-power micro-controller unit. AB - For decades, underwater acoustic communication has been restricted to the point to-point long distance applications such as deep sea probes and offshore oil fields. For this reason, previous acoustic modems were typically characterized by high data rates and long working ranges at the expense of large size and high power consumption. Recently, as the need for underwater wireless sensor networks (UWSNs) has increased, the research and development of compact and low-power consuming communication devices has become the focus. From the consideration that the requisites of acoustic modems for UWSNs are low power consumption, omni directional beam pattern, low cost and so on, in this paper, we design and implement an omni-directional underwater acoustic micro-modem satisfying these requirements. In order to execute fast digital domain signal processing and support flexible interfaces with other peripherals, an ARM Cortex-M3 is embedded in the micro-modem. Also, for the realization of small and omni-directional properties, a spherical transducer having a resonant frequency of 70 kHz and a diameter of 34 mm is utilized for the implementation. Physical layer frame format and symbol structure for efficient packet-based underwater communication systems are also investigated. The developed acoustic micro-modem is verified analytically and experimentally in indoor and outdoor environments in terms of functionality and performance. Since the modem satisfies the requirements for use in UWSNs, it could be deployed in a wide range of applications requiring underwater acoustic communication. PMID- 22438766 TI - A bioanalytical platform for simultaneous detection and quantification of biological toxins. AB - Prevalent incidents support the notion that toxins, produced by bacteria, fungi, plants or animals are increasingly responsible for food poisoning or intoxication. Owing to their high toxicity some toxins are also regarded as potential biological warfare agents. Accordingly, control, detection and neutralization of toxic substances are a considerable economic burden to food safety, health care and military biodefense. The present contribution describes a new versatile instrument and related procedures for array-based simultaneous detection of bacterial and plant toxins using a bioanalytical platform which combines the specificity of covalently immobilized capture probes with a dedicated instrumentation and immuno-based microarray analytics. The bioanalytical platform consists of a microstructured polymer slide serving both as support of printed arrays and as incubation chamber. The platform further includes an easy-to-operate instrument for simultaneous slide processing at selectable assay temperature. Cy5 coupled streptavidin is used as unifying fluorescent tracer. Fluorescence image analysis and signal quantitation allow determination of the toxin's identity and concentration. The system's performance has been investigated by immunological detection of Botulinum Neurotoxin type A (BoNT/A), Staphylococcal enterotoxin B (SEB), and the plant toxin ricin. Toxins were detectable at levels as low as 0.5-1 ng . mL(-1) in buffer or in raw milk. PMID- 22438767 TI - NIR monitoring of ammonia in anaerobic digesters using a diffuse reflectance probe. AB - The feasibility of using a diffuse reflectance probe attached to a near infrared spectrometer to monitor the total ammonia nitrogen (TAN) content in an anaerobic digester run on cattle manure was investigated; as a previous study has indicated that this probe can be easily attached to an anaerobic digester. Multivariate modelling techniques such as partial least squares regression and interval partial least squares methods were used to build models. Various data pre treatments were applied to improve the models. The TAN concentrations measured were in the range of 1.5 to 5.5 g/L. An R(2) of 0.91 with an RMSEP of 0.32 was obtained implying that the probe could be used for monitoring and screening purposes. PMID- 22438768 TI - "The Lower Threshold" phenomenon in tumor cells toward endogenous digitalis-like compounds: Responsible for tumorigenesis? AB - Since their first discovery as potential anti-cancer drugs decades ago, there is increasing evidence that digitalis-like compounds (DLC) have anti-tumor effects. Less is known about endogenous DLC (EDLC) metabolism and regulation. As stress hormones synthesized in and secreted from the adrenal gland, they likely take part in the hypothalamo-pituitary-adrenal (HPA) axis. In a previous study, we revealed reduced EDLC concentrations in plasma and organs from immune-compromised animals and proposed that a similar situation of a deregulated HPA axis with "adrenal EDLF exhaustion" may contribute to tumorigenesis in chronic stress situations. Here, we put forward the hypothesis that a lowered EDLC response threshold of tumor cells as compared with normal cells increases the risk of tumorigenesis, especially in those individuals with reduced EDLC plasma concentrations after chronic stress exposure. We will evaluate this hypothesis by (a) summarizing the effects of different DLC concentrations on tumor as compared with normal cells and (b) reviewing some essential differences in the Na/K-ATPase of tumor as compared with normal cells (isoform pattern, pump activity, mutations of other signalosome receptors). We will conclude that (1) tumor cells, indeed, seem to have their individual "physiologic" EDLC response range that already starts at pmolar levels and (2) that individuals with markedly reduced (pmolar) EDLC plasma levels are predisposed to cancer because these EDLC concentrations will predominantly stimulate the proliferation of tumor cells. Finally, we will summarize preliminary results from our department supporting this hypothesis. PMID- 22438769 TI - The cellular functions of RASSF1A and its inactivation in prostate cancer. AB - Epigenetic events significantly impact the transcriptome of cells and often contribute to the onset and progression of human cancers. RASSF1A (Ras association domain family 1 isoform A), a well-known tumor suppressor gene, is frequently silenced by epigenetic mechanisms such as promoter hypermethylation in a wide range of cancers. In the past decade a vast body of literature has emerged describing the silencing of RASSF1A expression in various cancers and demonstrating its ability to reverse the cancerous phenotype when re-expressed in cancer cells. However, the mechanisms by which RASSF1A exerts its tumor suppressive properties have not been entirely defined. RASSF1A appears to mediate three important cellular processes: microtubule stability, cell cycle progression, and the induction of apoptosis through specific molecular interactions with key factors involved in these processes. Loss of function of RASSF1A leads to accelerated cell cycle progression and resistance to apoptotic signals, resulting in increased cell proliferation. In this review, we attempt to summarize the current understanding of the biological functions of RASSF1A and provide insight that the development of targeted drugs to restore RASSF1A function holds promise for the treatment of prostate cancer. PMID- 22438771 TI - From the Editor's Desk. PMID- 22438770 TI - Oncogenic activation in prostate cancer progression and metastasis: Molecular insights and future challenges. AB - Prostate cancer is a leading cause of death among men in the United States, and currently early diagnosis and appropriate treatment remain key approaches for patient care. Molecularly prostate cancer cells carry multiple perturbations that generate malignant phenotype capable of uncontrolled growth, survival, and invasion-metastasis to other organs. These alterations are acquired both by genetic and epigenetic changes in tumor cells resulting in the activation of growth factor receptors, signaling proteins, kinases, transcription factors and coregulators, and multiple proteases required for the progression of the disease. Recent advances provide novel insights into the molecular functions of these oncogenic activators, implicating potential therapeutic targeting opportunities for the treatment of prostate cancer. PMID- 22438772 TI - Bioethics in practice: a quarterly column about medical ethics - the value of bioethics consults. PMID- 22438773 TI - The Last Nail in Hydrochlorothiazide's Coffin? PMID- 22438774 TI - The importance of colorectal cancer screening. PMID- 22438775 TI - Huey P. Long's Last Operation: When Medicine and Politics Don't Mix. AB - Ochsner has a rich historical heritage in the Gulf South, Louisiana, and New Orleans. It is therefore not surprising that connections exist between Ochsner and one of the most important events in Louisiana history in the 20th century. This article examines the medical care Huey P. Long received after a gunshot wound in 1935 and the circumstances that may have ultimately led to his demise, as well as the important questions of whether the care he received was consistent with standards of the time and whether the best available surgical team participated in his care. Politics and medicine were intertwined in this incident, and the Ochsner connections are worth examination in this context. PMID- 22438776 TI - Smoking cessation in pain patients. AB - BACKGROUND: Chronic pain patients often have comorbidities, including social habits such as tobacco abuse, they use to cope with pain states. This study tested the hypothesis that physician activism, communication, and interest in smoking cessation can reduce or eliminate tobacco use. METHODS: We developed a survey to evaluate patients' smoking habits and to determine if active physician participation changed these habits. RESULTS: We surveyed a total of 112 patients. Of the 56 smokers, 59% reported they had previously tried to stop. Smokers initially reported smoking 25.5 cigarettes per day for an average of 18.4 years. After receiving monthly physician messages regarding smoking, 51 of the smokers (91%) reported a reduction. These patients reported an average of 7.2 cigarettes smoked per day. Of the smoking patients, 79% indicated that they were influenced to reduce or stop smoking at the clinic, and 86% recalled that they heard specific statements from their doctor in the clinic. After reducing the number of cigarettes smoked, patients reported breathing better (68%), feeling better (66%), and experiencing less pain (34%). CONCLUSION: Physician influence correlated with smoking reduction in this study. PMID- 22438777 TI - Collateral benefits of improving glycemic control on lipids in a diabetic population. AB - BACKGROUND: Diabetes is an illness with multiple quality indicators. This retrospective cohort study sought to determine if interventions directed at physicians to target improvements in hemoglobin A1c (HgA1c) quality indicators had collateral benefits on similarly measured low-density lipoprotein (LDL) indicators. METHODS: We initially analyzed the primary care diabetic patient electronic databases from 2008 (N = 16,503) and 2010 (N = 23,040). We then identified and selected for the study the cohort of patients who appeared in both databases (N = 11,288) and analyzed various measures of process and outcomes. RESULTS: Mean HgA1c decreased from 7.34% to 7.21% (P < .0001). Mean LDL level also improved from 100.2 mg/dL to 95.6 mg/dL (P < .0001). The proportion of patients with poor glycemic control and poor lipid control decreased from 10.3% to 8.42% (P < .0001) and from 38.2% to 32.1% (P < .0001), respectively. CONCLUSIONS: Sustained interventions directed at the glycemic control of a large population of diabetic patients were associated with significant improvement in their glycemic control and had collateral benefits for indicators of their lipid control. Targeted interventions to improve HgA1c levels may have further benefits in improving other quality measures of diabetic care. PMID- 22438778 TI - Presence of anesthesia resident trainees in day surgery unit has mixed effects on operating room efficiency measures. AB - BACKGROUND: Three competing goals at academic medical centers are to increase efficiency, to optimize clinical care, and to train residents. The goal of this project was to compare day surgery operating room (OR) efficiency measures for anesthesiologists working alone, working with residents, and working with certified nurse anesthetists in a tertiary multisubspecialty teaching hospital to determine if trainees significantly impact OR efficiency. METHODS: We retrospectively evaluated operating room times data for 2,427 day surgery cases, comparing first case on-time starts, anesthesia-controlled times, induction times, emergence times, and turnover times for the 3 anesthesiologist groups. RESULTS: Compared to the solo anesthesiologist group, anesthesiologists working with residents had significantly longer induction, emergence, and total anesthesia-controlled times (20.2 +/- 8.0 vs 18.4 +/- 7.0 minutes). However, the anesthesiologists working with residents had more on-time starts (65% vs 53%) and lower turnover times 47.3 +/- 13.6 vs 50.8 +/- 14.5 minutes) than the solo anesthesiologist group. CONCLUSION: The pairing of anesthesiology residents with anesthesia staff has mixed effects on OR efficiency measures in a day surgery unit. PMID- 22438779 TI - Anesthetic management for Wingspan stent. AB - BACKGROUND: The bare metal self-expanding Wingspan stent (Boston Scientific, Natick, MA) was approved by the Food and Drug Administration under the Humanitarian Device Exemption in August 2005 for patients with intracranial atherosclerotic disease (ICAD) who are refractory to medical therapy. Relatively low rates of periprocedural morbidity and mortality have been reported. METHODS: After receiving institutional review board approval, we conducted a retrospective chart review to examine the anesthetic management and perioperative mortality and morbidity for all Wingspan stent insertions performed at our institution from 2005 to 2007. RESULTS: A total of 72 patients with a history of intracranial stenosis had angioplasty and Wingspan stent insertion: 34 male and 38 female, with an average age of 64 +/- 11.6 years. Preoperative systolic blood pressure was 200 +/- 45 mmHg, and diastolic blood pressure was 100 +/- 23 mmHg. All patients received general anesthesia for stent insertion. Five patients died (6.9%), 4 had perioperative stroke (5.5%), and 9 had recurrent stenosis (12.5%). CONCLUSIONS: Anesthetic management for Wingspan stent insertion for ICAD is challenging. Maintenance of hemodynamic stability with optimum brain perfusion during the stent deployment is crucial to patient safety. A prospective study is warranted to assess the optimal anesthetic choice during Wingspan stent insertion. PMID- 22438780 TI - Prevalence, associations, and risk factors for orthostatic hypotension in medical, surgical, and trauma inpatients: an observational cohort study. AB - BACKGROUND: Orthostatic hypotension (OH) is prevalent in hospitalized elderly patients. It is defined as a reduction in systolic blood pressure (SBP) of at least 20 mmHg and/or diastolic blood pressure (DBP) of at least 10 mmHg within 3 minutes of standing from a lying position. This observational cohort study describes the prevalence, association with symptoms, and risk factors for OH in medical, surgical, and trauma wards in a tertiary hospital and the differences in hemodynamic behaviors between OH-positive (OHP) and OH-negative (OHN) patients. METHODS: All 76 patients who were hemodynamically stable and able to stand from 4 hospital wards had noninvasive supine and orthostatic blood pressures (BPs) and pulse rates (PRs) measured over 4 days. RESULTS: Mean age of the 76 patients included in the study was 67.8 +/- 19.6 years. Overall prevalence of OH was 23.7% (95% CI: 14.7%-34.8%) with 21.2% (95% CI: 9.0%-38.9%) in medical, 31.8% (95% CI: 13.9%-54.9%) in surgical, and 19.0% (95% CI: 5.4%-41.9%) in trauma wards. OH had no association with symptoms (P = .53). We found no differences in age, number of comorbidities, and medication use between the OHN and OHP groups. The two groups displayed very different hemodynamic responses. The OHN group demonstrated a statistically significant compensatory rise in BP and PR over time to orthostatic challenge, while the OHP group displayed the opposite effect with BP. There was no statistically significant compensatory increase in PR over time to standing in the OHP group. CONCLUSIONS: OH is common and mostly asymptomatic. Routine measurements are recommended to detect cases in the hospital setting. Our study did not identify any significant risk factors for OH but rather confirmed the previous finding that underlying impairment in autonomic responses in individuals may have instead contributed to the development of OH. PMID- 22438781 TI - Bariatric surgery significantly improves body proportion. AB - BACKGROUND: It is well known that bariatric surgery provides excellent weight loss and resolution of comorbid conditions. We propose an additional benefit: Because body proportion is an independent predictor of diabetes and cardiovascular risk, we hypothesize that bariatric surgery results in improved body proportion and may thus improve health risk independent of overall weight loss and resolution of comorbid conditions. METHODS: A total of 168 patients underwent laparoscopic bariatric surgery at our institution from December 2006 to September 2009. Prospective data gathered preoperatively and at 3, 6, and 12 months postoperatively included body mass index (BMI); excess weight loss (EWL); waist-hip ratio (WHR); and discontinuation of hypertensive, hyperlipidemic, and diabetic medications. RESULTS: Of the 168 patients, 122 underwent Roux-en-Y gastric bypass, 40 gastric band, and 6 gastric sleeve procedures. Mean preoperative BMI was 48.6 kg/m(2) (SD = 7.8 kg/m(2)). Mean EWL was 33.7 lbs (SD = 11.9 lbs) at 3 months, 46.35 lbs (SD = 15.58 lbs) at 6 months, and 52.48 lbs (SD = 24.19 lbs) at 1 year. Mean WHR was 0.91 (SD = 0.1) preoperatively, 0.87 (SD = 0.1) at 3 months (P < .0001), 0.87 (SD = 0.09) at 6 months (P < .0001), and 0.86 (SD = 0.1) at 1 year (P = .0006). At 1-year follow-up, 52% of patients had discontinued hypertensive medications, 64% had discontinued diabetic medications, and 56% had discontinued hyperlipidemic medications. CONCLUSIONS: Along with well-known improvements in overall weight and comorbid conditions, bariatric surgery significantly improves body proportion, which may decrease health risk. Continued follow-up will determine if this change is long term or if patients will revert to preoperative WHRs. Future studies with sufficient power to study individual bariatric procedures will determine which procedures, if any, provide patients with the greatest improvement in WHR and if inferior WHR results are associated with cardiovascular events. PMID- 22438782 TI - Use and acceptance of complementary and alternative medicine among the general population and medical personnel: a systematic review. AB - BACKGROUND: The interest in complementary and alternative medicine (CAM) has increased during the past decade and the attitude of the general public is mainly positive, but the debate about the clinical effectiveness of these therapies remains controversial among many medical professionals. METHODS: We conducted a systematic search of the existing literature utilizing different databases, including PubMed/Medline, PSYNDEX, and PsycLit, to research the use and acceptance of CAM among the general population and medical personnel. A special focus on CAM-referring literature was set by limiting the PubMed search to "Complementary Medicine" and adding two other search engines: CAMbase (www.cambase.de) and CAMRESEARCH (www.camresearch.net). These engines were used to reveal publications that at the time of the review were not indexed in PubMed. RESULTS: A total of 16 papers met the scope criteria. Prevalence rates of CAM in each of the included studies were between 5% and 74.8%. We found a higher utilization of homeopathy and acupuncture in German-speaking countries. Excluding any form of spiritual prayer, the data demonstrate that chiropractic manipulation, herbal medicine, massage, and homeopathy were the therapies most commonly used by the general population. We identified sex, age, and education as predictors of CAM utilization: More users were women, middle aged, and more educated. The ailments most often associated with CAM utilization included back pain or pathology, depression, insomnia, severe headache or migraine, and stomach or intestinal illnesses. Medical students were the most critical toward CAM. Compared to students of other professions (ie, nursing students: 44.7%, pharmacy students: 18.2%), medical students reported the least consultation with a CAM practitioner (10%). CONCLUSIONS: The present data demonstrate an increase of CAM usage from 1990 through 2006 in all countries investigated. We found geographical differences, as well as differences between the general population and medical personnel. PMID- 22438783 TI - The heart of the matter of opinion and evidence: the value of evidence-based medicine. AB - Evidence-based medicine is an important aspect of continuing medical education. This article reviews previous and current examples of conflicting topics that evidence-based medicine has clarified to allow us to provide the best possible patient care. PMID- 22438784 TI - Preanesthetic Assessment of the Jehovah's Witness Patient. AB - The Jehovah's Witnesses, a religious group of 7 million people in more than 200 countries, teaches its followers to not accept blood, resulting in potentially challenging and ethical dilemmas for anesthesiologists. In recent years, Jehovah's Witnesses changed certain elements of their approach to blood transfusion practice, including accepting autologous transfusions in certain circumstances. We examine mechanisms to resolve ethical conflicts, such as additional medical consultations with other involved physicians, surgeons, and anesthesiologists; short-term counseling or psychiatric consultation for patient and family; case management conferences; consultation with individuals trained in clinical ethics or a hospital-based ethics committee; and discussions with hospital administration. We also discuss treatment options, including certain blood products, anesthetic techniques, and pharmacological interventions. PMID- 22438785 TI - Mesothelioma: a review. AB - Mesothelioma is an insidious disease with long latency after asbestos exposure. New cases are continually diagnosed, although levels are declining with recognition of the asbestos risk and efforts to remove asbestos from the workplace. Treatment for early stage disease with surgery and radiation is potentially curative, but many patients either are too ill to undergo aggressive surgery or present with advanced disease. Chemotherapy with cisplatin and pemetrexed is considered standard, although relapse is common. Second-line therapy is disappointing. New targeted therapies may pose promise and are being addressed in various clinical trial settings. Palliative care remains an important component of the management of this devastating illness. PMID- 22438786 TI - Lumbar incisional hernia repair after iliac crest bone graft. AB - The iliac crest is a common donor site for autogenous bone grafts. Among the reported complications, lumbar hernias occur infrequently with a reported incidence of 5% to 9%. Surgical repair is advocated secondary to the risk of incarceration or strangulation. Computed tomography is the diagnostic study of choice. Various transabdominal, retroperitoneal, and laparoscopic approaches have been described for the repair of lumbar hernias. We describe a case of successful lumbar incisional hernia repair after iliac crest bone graft harvesting that used prosthetic mesh. PMID- 22438788 TI - Letters to the editor. PMID- 22438787 TI - Male urethral diverticulum after placement of an artificial urinary sphincter. AB - Urethral diverticula are sac-like dilatations of the urethra that communicate with the true urethral lumen. Because the condition is rare in men, no consensus exists regarding the management of male diverticula. Excision with primary repair of the urethra, urethroplasty (both one- and two-stage), and even endoscopic techniques have been used. We report a case of an acquired urethral diverticulum in a male following placement of an artificial urinary sphincter (AUS). Urethral diverticula arising after placement of an AUS have been described in the literature, but those cases occurred after erosion of the AUS. To our knowledge, our case is the first reported in a patient with a functioning AUS. PMID- 22438789 TI - CME Upcoming Events. PMID- 22438790 TI - CME Test/CME Application Form. PMID- 22438791 TI - Post-translational modifications of nuclear receptors and human disease. AB - Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor alpha (ERalpha), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor gamma (PPARgamma). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERalpha phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERalpha acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARgamma phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARgamma is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments. PMID- 22438792 TI - Use of differential scanning fluorimetry as a high-throughput assay to identify nuclear receptor ligands. AB - Identification of ligands that interact with nuclear receptors is both a major biological problem and an important initial step in drug discovery. Several in vitro and in vivo techniques are commonly used to screen ligand candidates against nuclear receptors; however, none of the current assays allow screening without modification of either the protein and/or the ligand in a high-throughput fashion. Differential scanning fluorimetry (DSF) allows unmodified potential ligands to be screened as 10uL reactions in 96-well format against partially purified protein, revealing specific interactors. As a proof of principle, we used a commercially-available nuclear receptor ligand candidate chemical library to identify interactors of the human estrogen receptor alpha ligand binding domain (ERalpha LBD). Compounds that interact specifically with ERalpha LBD stabilize the protein and result in an elevation of the thermal denaturation point, as monitored by the environmentally-sensitive dye SYPRO orange. We successfully identified all three compounds in the library that have previously been identified to interact with ERalpha, with no false positive results. PMID- 22438793 TI - EMBO Retinoids 2011: Mechanisms, biology and pathology of signaling by retinoic acid and retinoic acid receptors. AB - Retinoic acid (RA) is one of the principal active metabolites of vitamin A (retinol) which mediates a spectrum of critical physiological and developmental processes. Transcriptional regulation by RA is mediated primarily by members of the retinoic acid receptor (RAR) subfamily of the nuclear receptor (NR) superfamily of transcription factors. NRs bind specific genomic DNA sequence motifs and engage coregulators and components of the basal transcription machinery to effect transcriptional regulation at target gene promoters. Disruption of signaling by retinoic acid is thought to underlie the etiology of a number of inflammatory and neoplastic diseases including breast cancer and haematological malignancies. A meeting of international researchers in retinoid signaling was convened in Strasbourg in September 2011 under the auspices of the European Molecular Biology Organization (EMBO). Retinoids 2011 encompassed myriad mechanistic, biological and pathological aspects of these hormones and their cognate receptors, as well as setting these advances in the context of wider current questions on signaling by members of the NR superfamily. PMID- 22438794 TI - Cell shape dynamics: from waves to migration. AB - We observe and quantify wave-like characteristics of amoeboid migration. Using the amoeba Dictyostelium discoideum, a model system for the study of chemotaxis, we demonstrate that cell shape changes in a wave-like manner. Cells have regions of high boundary curvature that propagate from the leading edge toward the back, usually along alternating sides of the cell. Curvature waves are easily seen in cells that do not adhere to a surface, such as cells that are electrostatically repelled from surfaces or cells that extend over the edge of micro-fabricated cliffs. Without surface contact, curvature waves travel from the leading edge to the back of a cell at -35 um/min. Non-adherent myosin II null cells do not exhibit these curvature waves. At the leading edge of adherent cells, curvature waves are associated with protrusive activity. Like regions of high curvature, protrusive activity travels along the boundary in a wave-like manner. Upon contact with a surface, the protrusions stop moving relative to the surface, and the boundary shape thus reflects the history of protrusive motion. The wave-like character of protrusions provides a plausible mechanism for the zig-zagging of pseudopods and for the ability of cells both to swim in viscous fluids and to navigate complex three dimensional topography. PMID- 22438795 TI - AutoClickChem: click chemistry in silico. AB - Academic researchers and many in industry often lack the financial resources available to scientists working in "big pharma." High costs include those associated with high-throughput screening and chemical synthesis. In order to address these challenges, many researchers have in part turned to alternate methodologies. Virtual screening, for example, often substitutes for high throughput screening, and click chemistry ensures that chemical synthesis is fast, cheap, and comparatively easy. Though both in silico screening and click chemistry seek to make drug discovery more feasible, it is not yet routine to couple these two methodologies. We here present a novel computer algorithm, called AutoClickChem, capable of performing many click-chemistry reactions in silico. AutoClickChem can be used to produce large combinatorial libraries of compound models for use in virtual screens. As the compounds of these libraries are constructed according to the reactions of click chemistry, they can be easily synthesized for subsequent testing in biochemical assays. Additionally, in silico modeling of click-chemistry products may prove useful in rational drug design and drug optimization. AutoClickChem is based on the pymolecule toolbox, a framework that may facilitate the development of future python-based programs that require the manipulation of molecular models. Both the pymolecule toolbox and AutoClickChem are released under the GNU General Public License version 3 and are available for download from http://autoclickchem.ucsd.edu. PMID- 22438796 TI - Network evolution: rewiring and signatures of conservation in signaling. AB - The analysis of network evolution has been hampered by limited availability of protein interaction data for different organisms. In this study, we investigate evolutionary mechanisms in Src Homology 3 (SH3) domain and kinase interaction networks using high-resolution specificity profiles. We constructed and examined networks for 23 fungal species ranging from Saccharomyces cerevisiae to Schizosaccharomyces pombe. We quantify rates of different rewiring mechanisms and show that interaction change through binding site evolution is faster than through gene gain or loss. We found that SH3 interactions evolve swiftly, at rates similar to those found in phosphoregulation evolution. Importantly, we show that interaction changes are sufficiently rapid to exhibit saturation phenomena at the observed timescales. Finally, focusing on the SH3 interaction network, we observe extensive clustering of binding sites on target proteins by SH3 domains and a strong correlation between the number of domains that bind a target protein (target in-degree) and interaction conservation. The relationship between in degree and interaction conservation is driven by two different effects, namely the number of clusters that correspond to interaction interfaces and the number of domains that bind to each cluster leads to sequence specific conservation, which in turn results in interaction conservation. In summary, we uncover several network evolution mechanisms likely to generalize across peptide recognition modules. PMID- 22438797 TI - Highly sensitive and specific detection of rare variants in mixed viral populations from massively parallel sequence data. AB - Viruses diversify over time within hosts, often undercutting the effectiveness of host defenses and therapeutic interventions. To design successful vaccines and therapeutics, it is critical to better understand viral diversification, including comprehensively characterizing the genetic variants in viral intra-host populations and modeling changes from transmission through the course of infection. Massively parallel sequencing technologies can overcome the cost constraints of older sequencing methods and obtain the high sequence coverage needed to detect rare genetic variants (< 1%) within an infected host, and to assay variants without prior knowledge. Critical to interpreting deep sequence data sets is the ability to distinguish biological variants from process errors with high sensitivity and specificity. To address this challenge, we describe V Phaser, an algorithm able to recognize rare biological variants in mixed populations. V-Phaser uses covariation (i.e. phasing) between observed variants to increase sensitivity and an expectation maximization algorithm that iteratively recalibrates base quality scores to increase specificity. Overall, V Phaser achieved > 97% sensitivity and > 97% specificity on control read sets. On data derived from a patient after four years of HIV-1 infection, V-Phaser detected 2,015 variants across the -10 kb genome, including 603 rare variants (< 1% frequency) detected only using phase information. V-Phaser identified variants at frequencies down to 0.2%, comparable to the detection threshold of allele specific PCR, a method that requires prior knowledge of the variants. The high sensitivity and specificity of V-Phaser enables identifying and tracking changes in low frequency variants in mixed populations such as RNA viruses. PMID- 22438798 TI - Conformational control of the binding of the transactivation domain of the MLL protein and c-Myb to the KIX domain of CREB. AB - The KIX domain of CBP is a transcriptional coactivator. Concomitant binding to the activation domain of proto-oncogene protein c-Myb and the transactivation domain of the trithorax group protein mixed lineage leukemia (MLL) transcription factor lead to the biologically active ternary MLL?KIX?c-Myb complex which plays a role in Pol II-mediated transcription. The binding of the activation domain of MLL to KIX enhances c-Myb binding. Here we carried out molecular dynamics (MD) simulations for the MLL?KIX?c-Myb ternary complex, its binary components and KIX with the goal of providing a mechanistic explanation for the experimental observations. The dynamic behavior revealed that the MLL binding site is allosterically coupled to the c-Myb binding site. MLL binding redistributes the conformational ensemble of KIX, leading to higher populations of states which favor c-Myb binding. The key element in the allosteric communication pathways is the KIX loop, which acts as a control mechanism to enhance subsequent binding events. We tested this conclusion by in silico mutations of loop residues in the KIX?MLL complex and by comparing wild type and mutant dynamics through MD simulations. The loop assumed MLL binding conformation similar to that observed in the KIX?c-Myb state which disfavors the allosteric network. The coupling with c-Myb binding site faded, abolishing the positive cooperativity observed in the presence of MLL. Our major conclusion is that by eliciting a loop-mediated allosteric switch between the different states following the binding events, transcriptional activation can be regulated. The KIX system presents an example how nature makes use of conformational control in higher level regulation of transcriptional activity and thus cellular events. PMID- 22438799 TI - Gradients and modulation of K(+) channels optimize temporal accuracy in networks of auditory neurons. AB - Accurate timing of action potentials is required for neurons in auditory brainstem nuclei to encode the frequency and phase of incoming sound stimuli. Many such neurons express "high threshold" Kv3-family channels that are required for firing at high rates (> -200 Hz). Kv3 channels are expressed in gradients along the medial-lateral tonotopic axis of the nuclei. Numerical simulations of auditory brainstem neurons were used to calculate the input-output relations of ensembles of 1-50 neurons, stimulated at rates between 100-1500 Hz. Individual neurons with different levels of potassium currents differ in their ability to follow specific rates of stimulation but all perform poorly when the stimulus rate is greater than the maximal firing rate of the neurons. The temporal accuracy of the combined synaptic output of an ensemble is, however, enhanced by the presence of gradients in Kv3 channel levels over that measured when neurons express uniform levels of channels. Surprisingly, at high rates of stimulation, temporal accuracy is also enhanced by the occurrence of random spontaneous activity, such as is normally observed in the absence of sound stimulation. For any pattern of stimulation, however, greatest accuracy is observed when, in the presence of spontaneous activity, the levels of potassium conductance in all of the neurons is adjusted to that found in the subset of neurons that respond better than their neighbors. This optimization of response by adjusting the K(+) conductance occurs for stimulus patterns containing either single and or multiple frequencies in the phase-locking range. The findings suggest that gradients of channel expression are required for normal auditory processing and that changes in levels of potassium currents across the nuclei, by mechanisms such as protein phosphorylation and rapid changes in channel synthesis, adapt the nuclei to the ongoing auditory environment. PMID- 22438800 TI - The impact of oxygen on metabolic evolution: a chemoinformatic investigation. AB - The appearance of planetary oxygen likely transformed the chemical and biochemical makeup of life and probably triggered episodes of organismal diversification. Here we use chemoinformatic methods to explore the impact of the rise of oxygen on metabolic evolution. We undertake a comprehensive comparative analysis of structures, chemical properties and chemical reactions of anaerobic and aerobic metabolites. The results indicate that aerobic metabolism has expanded the structural and chemical space of metabolites considerably, including the appearance of 130 novel molecular scaffolds. The molecular functions of these metabolites are mainly associated with derived aspects of cellular life, such as signal transfer, defense against biotic factors, and protection of organisms from oxidation. Moreover, aerobic metabolites are more hydrophobic and rigid than anaerobic compounds, suggesting they are better fit to modulate membrane functions and to serve as transmembrane signaling factors. Since higher organisms depend largely on sophisticated membrane-enabled functions and intercellular signaling systems, the metabolic developments brought about by oxygen benefit the diversity of cellular makeup and the complexity of cellular organization as well. These findings enhance our understanding of the molecular link between oxygen and evolution. They also show the significance of chemoinformatics in addressing basic biological questions. PMID- 22438801 TI - Entropic tension in crowded membranes. AB - Unlike their model membrane counterparts, biological membranes are richly decorated with a heterogeneous assembly of membrane proteins. These proteins are so tightly packed that their excluded area interactions can alter the free energy landscape controlling the conformational transitions suffered by such proteins. For membrane channels, this effect can alter the critical membrane tension at which they undergo a transition from a closed to an open state, and therefore influence protein function in vivo. Despite their obvious importance, crowding phenomena in membranes are much less well studied than in the cytoplasm. Using statistical mechanics results for hard disk liquids, we show that crowding induces an entropic tension in the membrane, which influences transitions that alter the projected area and circumference of a membrane protein. As a specific case study in this effect, we consider the impact of crowding on the gating properties of bacterial mechanosensitive membrane channels, which are thought to confer osmoprotection when these cells are subjected to osmotic shock. We find that crowding can alter the gating energies by more than [Formula: see text] in physiological conditions, a substantial fraction of the total gating energies in some cases. Given the ubiquity of membrane crowding, the nonspecific nature of excluded volume interactions, and the fact that the function of many membrane proteins involve significant conformational changes, this specific case study highlights a general aspect in the function of membrane proteins. PMID- 22438803 TI - New insights into Blastocystis spp.: a potential link with irritable bowel syndrome. PMID- 22438804 TI - A peptidoglycan fragment triggers beta-lactam resistance in Bacillus licheniformis. AB - To resist to beta-lactam antibiotics Eubacteria either constitutively synthesize a beta-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence of antibiotic outside the cell. In Bacillus licheniformis and Staphylococcus aureus, a membrane-bound penicillin receptor (BlaR/MecR) detects the presence of beta-lactam and launches a cytoplasmic signal leading to the inactivation of BlaI/MecI repressor, and the synthesis of a beta-lactamase or a low affinity target. We identified a dipeptide, resulting from the peptidoglycan turnover and present in bacterial cytoplasm, which is able to directly bind to the BlaI/MecI repressor and to destabilize the BlaI/MecI-DNA complex. We propose a general model, in which the acylation of BlaR/MecR receptor and the cellular stress induced by the antibiotic, are both necessary to generate a cell wall-derived coactivator responsible for the expression of an inducible beta-lactam-resistance factor. The new model proposed confirms and emphasizes the role of peptidoglycan degradation fragments in bacterial cell regulation. PMID- 22438805 TI - E2F1 mediated apoptosis induced by the DNA damage response is blocked by EBV nuclear antigen 3C in lymphoblastoid cells. AB - EBV latent antigen EBNA3C is indispensible for in vitro B-cell immortalization resulting in continuously proliferating lymphoblastoid cell lines (LCLs). EBNA3C was previously shown to target pRb for ubiquitin-proteasome mediated degradation, which facilitates G1 to S transition controlled by the major transcriptional activator E2F1. E2F1 also plays a pivotal role in regulating DNA damage induced apoptosis through both p53-dependent and -independent pathways. In this study, we demonstrate that in response to DNA damage LCLs knocked down for EBNA3C undergo a drastic induction of apoptosis, as a possible consequence of both p53- and E2F1 mediated activities. Importantly, EBNA3C was previously shown to suppress p53 induced apoptosis. Now, we also show that EBNA3C efficiently blocks E2F1-mediated apoptosis, as well as its anti-proliferative effects in a p53-independent manner, in response to DNA damage. The N- and C-terminal domains of EBNA3C form a stable pRb independent complex with the N-terminal DNA-binding region of E2F1 responsible for inducing apoptosis. Mechanistically, we show that EBNA3C represses E2F1 transcriptional activity via blocking its DNA-binding activity at the responsive promoters of p73 and Apaf-1 apoptosis induced genes, and also facilitates E2F1 degradation in an ubiquitin-proteasome dependent fashion. Moreover, in response to DNA damage, E2F1 knockdown LCLs exhibited a significant reduction in apoptosis with higher cell-viability. In the presence of normal mitogenic stimuli the growth rate of LCLs knockdown for E2F1 was markedly impaired; indicating that E2F1 plays a dual role in EBV positive cells and that active engagement of the EBNA3C-E2F1 complex is crucial for inhibition of DNA damage induced E2F1-mediated apoptosis. This study offers novel insights into our current understanding of EBV biology and enhances the potential for development of effective therapies against EBV associated B-cell lymphomas. PMID- 22438806 TI - Stage specific assessment of Candida albicans phagocytosis by macrophages identifies cell wall composition and morphogenesis as key determinants. AB - Candida albicans is a major life-threatening human fungal pathogen. Host defence against systemic Candida infection relies mainly on phagocytosis of fungal cells by cells of the innate immune system. In this study, we have employed video microscopy, coupled with sophisticated image analysis tools, to assess the contribution of distinct C. albicans cell wall components and yeast-hypha morphogenesis to specific stages of phagocytosis by macrophages. We show that macrophage migration towards C. albicans was dependent on the glycosylation status of the fungal cell wall, but not cell viability or morphogenic switching from yeast to hyphal forms. This was not a consequence of differences in maximal macrophage track velocity, but stems from a greater percentage of macrophages pursuing glycosylation deficient C. albicans during the first hour of the phagocytosis assay. The rate of engulfment of C. albicans attached to the macrophage surface was significantly delayed for glycosylation and yeast-locked morphogenetic mutant strains, but enhanced for non-viable cells. Hyphal cells were engulfed at a slower rate than yeast cells, especially those with hyphae in excess of 20 um, but there was no correlation between hyphal length and the rate of engulfment below this threshold. We show that spatial orientation of the hypha and whether hyphal C. albicans attached to the macrophage via the yeast or hyphal end were also important determinants of the rate of engulfment. Breaking down the overall phagocytic process into its individual components revealed novel insights into what determines the speed and effectiveness of C. albicans phagocytosis by macrophages. PMID- 22438807 TI - HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children. AB - Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)(n) repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1 expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)(n) repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients. PMID- 22438808 TI - Preferential entry of botulinum neurotoxin A Hc domain through intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine. AB - Botulism, characterized by flaccid paralysis, commonly results from botulinum neurotoxin (BoNT) absorption across the epithelial barrier from the digestive tract and then dissemination through the blood circulation to target autonomic and motor nerve terminals. The trafficking pathway of BoNT/A passage through the intestinal barrier is not yet fully understood. We report that intralumenal administration of purified BoNT/A into mouse ileum segment impaired spontaneous muscle contractions and abolished the smooth muscle contractions evoked by electric field stimulation. Entry of BoNT/A into the mouse upper small intestine was monitored with fluorescent HcA (half C-terminal domain of heavy chain) which interacts with cell surface receptor(s). We show that HcA preferentially recognizes a subset of neuroendocrine intestinal crypt cells, which probably represent the entry site of the toxin through the intestinal barrier, then targets specific neurons in the submucosa and later (90-120 min) in the musculosa. HcA mainly binds to certain cholinergic neurons of both submucosal and myenteric plexuses, but also recognizes, although to a lower extent, other neuronal cells including glutamatergic and serotoninergic neurons in the submucosa. Intestinal cholinergic neuron targeting by HcA could account for the inhibition of intestinal peristaltism and secretion observed in botulism, but the consequences of the targeting to non-cholinergic neurons remains to be determined. PMID- 22438809 TI - Nasal Acai polysaccharides potentiate innate immunity to protect against pulmonary Francisella tularensis and Burkholderia pseudomallei Infections. AB - Pulmonary Francisella tularensis and Burkholderia pseudomallei infections are highly lethal in untreated patients, and current antibiotic regimens are not always effective. Activating the innate immune system provides an alternative means of treating infection and can also complement antibiotic therapies. Several natural agonists were screened for their ability to enhance host resistance to infection, and polysaccharides derived from the Acai berry (Acai PS) were found to have potent abilities as an immunotherapeutic to treat F. tularensis and B. pseudomallei infections. In vitro, Acai PS impaired replication of Francisella in primary human macrophages co-cultured with autologous NK cells via augmentation of NK cell IFN-gamma. Furthermore, Acai PS administered nasally before or after infection protected mice against type A F. tularensis aerosol challenge with survival rates up to 80%, and protection was still observed, albeit reduced, when mice were treated two days post-infection. Nasal Acai PS administration augmented intracellular expression of IFN-gamma by NK cells in the lungs of F. tularensis infected mice, and neutralization of IFN-gamma ablated the protective effect of Acai PS. Likewise, nasal Acai PS treatment conferred protection against pulmonary infection with B. pseudomallei strain 1026b. Acai PS dramatically reduced the replication of B. pseudomallei in the lung and blocked bacterial dissemination to the spleen and liver. Nasal administration of Acai PS enhanced IFN-gamma responses by NK and gammadelta T cells in the lungs, while neutralization of IFN gamma totally abrogated the protective effect of Acai PS against pulmonary B. pseudomallei infection. Collectively, these results demonstrate Acai PS is a potent innate immune agonist that can resolve F. tularensis and B. pseudomallei infections, suggesting this innate immune agonist has broad-spectrum activity against virulent intracellular pathogens. PMID- 22438810 TI - The novel Candida albicans transporter Dur31 Is a multi-stage pathogenicity factor. AB - Candida albicans is the most frequent cause of oral fungal infections. However, the exact pathogenicity mechanisms that this fungus employs are largely unknown and many of the genes expressed during oral infection are uncharacterized. In this study we sought to functionally characterize 12 previously unknown function genes associated with oral candidiasis. We generated homozygous knockout mutants for all 12 genes and analyzed their interaction with human oral epithelium in vitro. Eleven mutants caused significantly less epithelial damage and, of these, deletion of orf19.6656 (DUR31) elicited the strongest reduction in pathogenicity. Interestingly, DUR31 was not only involved in oral epithelial damage, but in multiple stages of candidiasis, including surviving attack by human neutrophils, endothelial damage and virulence in vivo. In silico analysis indicated that DUR31 encodes a sodium/substrate symporter with 13 transmembrane domains and no human homologue. We provide evidence that Dur31 transports histatin 5. This is one of the very first examples of microbial driven import of this highly cytotoxic antimicrobial peptide. Also, in contrast to wild type C. albicans, dur31Delta/Delta was unable to actively increase local environmental pH, suggesting that Dur31 lies in the extracellular alkalinization hyphal auto induction pathway; and, indeed, DUR31 was required for morphogenesis. In agreement with this observation, dur31Delta/Delta was unable to assimilate the polyamine spermidine. PMID- 22438811 TI - Inflammation and disintegration of intestinal villi in an experimental model for Vibrio parahaemolyticus-induced diarrhea. AB - Vibrio parahaemolyticus is a leading cause of seafood-borne gastroenteritis in many parts of the world, but there is limited knowledge of the pathogenesis of V. parahaemolyticus-induced diarrhea. The absence of an oral infection-based small animal model to study V. parahaemolyticus intestinal colonization and disease has constrained analyses of the course of infection and the factors that mediate it. Here, we demonstrate that infant rabbits oro-gastrically inoculated with V. parahaemolyticus develop severe diarrhea and enteritis, the main clinical and pathologic manifestations of disease in infected individuals. The pathogen principally colonizes the distal small intestine, and this colonization is dependent upon type III secretion system 2. The distal small intestine is also the major site of V. parahaemolyticus-induced tissue damage, reduced epithelial barrier function, and inflammation, suggesting that disease in this region of the gastrointestinal tract accounts for most of the diarrhea that accompanies V. parahaemolyticus infection. Infection appears to proceed through a characteristic sequence of steps that includes remarkable elongation of microvilli and the formation of V. parahaemolyticus-filled cavities within the epithelial surface, and culminates in villus disruption. Both depletion of epithelial cell cytoplasm and epithelial cell extrusion contribute to formation of the cavities in the epithelial surface. V. parahaemolyticus also induces proliferation of epithelial cells and recruitment of inflammatory cells, both of which occur before wide spread damage to the epithelium is evident. Collectively, our findings suggest that V. parahaemolyticus damages the host intestine and elicits disease via previously undescribed processes and mechanisms. PMID- 22438812 TI - TGF-beta1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. AB - The mechanism underlying persistent hepatitis B virus (HBV) infection remains unclear. We investigated the role of innate immune responses to persistent HBV infection in 154 HBV-infected patients and 95 healthy controls. The expression of NKG2D- and 2B4-activating receptors on NK cells was significantly decreased, and moreover, the expression of DAP10 and SAP, the intracellular adaptor proteins of NKG2D and 2B4 (respectively), were lower, which then impaired NK cell-mediated cytotoxic capacity and interferon-gamma production. Higher concentrations of transforming growth factor-beta 1 (TGF-beta1) were found in sera from persistently infected HBV patients. TGF-beta1 down-regulated the expression of NKG2D and 2B4 on NK cells in our in vitro study, leading to an impairment of their effector functions. Anti-TGF-beta1 antibodies could restore the expression of NKG2D and 2B4 on NK cells in vitro. Furthermore, TGF-beta1 induced cell-cycle arrest in NK cells by up-regulating the expression of p15 and p21 in NK cells from immunotolerant (IT) patients. We conclude that TGF-beta1 may reduce the expression of NKG2D/DAP10 and 2B4/SAP, and those IT patients who are deficient in these double-activating signals have impaired NK cell function, which is correlated with persistent HBV infection. PMID- 22438813 TI - Molecular determinants of resistance activation and suppression by Phytophthora infestans effector IPI-O. AB - Despite intensive breeding efforts, potato late blight, caused by the oomycete pathogen Phytophthora infestans, remains a threat to potato production worldwide because newly evolved pathogen strains have consistently overcome major resistance genes. The potato RB gene, derived from the wild species Solanum bulbocastanum, confers resistance to most P. infestans strains through recognition of members of the pathogen effector family IPI-O. While the majority of IPI-O proteins are recognized by RB to elicit resistance (e.g. IPI-O1, IPI O2), some family members are able to elude detection (e.g. IPI-O4). In addition, IPI-O4 blocks recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death. Here, we report results that elucidate molecular mechanisms governing resistance elicitation or suppression of RB by IPI-O. Our data indicate self-association of the RB coiled coil (CC) domain as well as a physical interaction between this domain and the effectors IPI-O4 and IPI-O1. We identified four amino acids within IPI-O that are critical for interaction with the RB CC domain and one of these amino acids, at position 129, determines hypersensitive response (HR) elicitation in planta. IPI-O1 mutant L129P fails to induce HR in presence of RB while IPI-O4 P129L gains the ability to induce an HR. Like IPI-O4, IPI-O1 L129P is also able to suppress the HR mediated by RB, indicating a critical step in the evolution of this gene family. Our results point to a model in which IPI-O effectors can affect RB function through interaction with the RB CC domain. PMID- 22438814 TI - An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity. AB - The individual risk for common diseases not only depends on genetic but also on epigenetic polymorphisms. To assess the role of epigenetic variations in the individual risk for obesity, we have determined the methylation status of two CpG islands at the POMC locus in obese and normal-weight children. We found a hypermethylation variant targeting individual CpGs at the intron 2-exon 3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity. POMC exon 3 hypermethylation interferes with binding of the transcription enhancer P300 and reduces expression of the POMC transcript. Since intron 2 contains Alu elements that are known to influence methylation in their genomic vicinity, the exon 3 methylation variant seems to result from an Alu element-triggered default state of methylation boundary definition. Exon 3 hypermethylation in the POMC locus represents the first identified DNA methylation variant that is associated with the individual risk for obesity. PMID- 22438815 TI - Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database. AB - More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 * 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3 * 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies. PMID- 22438816 TI - Mitochondrial oxidative stress alters a pathway in Caenorhabditis elegans strongly resembling that of bile acid biosynthesis and secretion in vertebrates. AB - Mammalian bile acids (BAs) are oxidized metabolites of cholesterol whose amphiphilic properties serve in lipid and cholesterol uptake. BAs also act as hormone-like substances that regulate metabolism. The Caenorhabditis elegans clk 1 mutants sustain elevated mitochondrial oxidative stress and display a slow defecation phenotype that is sensitive to the level of dietary cholesterol. We found that: 1) The defecation phenotype of clk-1 mutants is suppressed by mutations in tat-2 identified in a previous unbiased screen for suppressors of clk-1. TAT-2 is homologous to ATP8B1, a flippase required for normal BA secretion in mammals. 2) The phenotype is suppressed by cholestyramine, a resin that binds BAs. 3) The phenotype is suppressed by the knock-down of C. elegans homologues of BA-biosynthetic enzymes. 4) The phenotype is enhanced by treatment with BAs. 5) Lipid extracts from C. elegans contain an activity that mimics the effect of BAs on clk-1, and the activity is more abundant in clk-1 extracts. 6) clk-1 and clk 1;tat-2 double mutants show altered cholesterol content. 7) The clk-1 phenotype is enhanced by high dietary cholesterol and this requires TAT-2. 8) Suppression of clk-1 by tat-2 is rescued by BAs, and this requires dietary cholesterol. 9) The clk-1 phenotype, including the level of activity in lipid extracts, is suppressed by antioxidants and enhanced by depletion of mitochondrial superoxide dismutases. These observations suggest that C. elegans synthesizes and secretes molecules with properties and functions resembling those of BAs. These molecules act in cholesterol uptake, and their level of synthesis is up-regulated by mitochondrial oxidative stress. Future investigations should reveal whether these molecules are in fact BAs, which would suggest the unexplored possibility that the elevated oxidative stress that characterizes the metabolic syndrome might participate in disease processes by affecting the regulation of metabolism by BAs. PMID- 22438817 TI - Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry. AB - The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with -10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time. PMID- 22438818 TI - Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure. AB - Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance. PMID- 22438819 TI - Autoregulation of the Drosophila Noncoding roX1 RNA Gene. AB - Most genes along the male single X chromosome in Drosophila are hypertranscribed about two-fold relative to each of the two female X chromosomes. This is accomplished by the MSL (male-specific lethal) complex that acetylates histone H4 at lysine 16. The MSL complex contains two large noncoding RNAs, roX1 (RNA on X) and roX2, that help target chromatin modifying enzymes to the X. The roX RNAs are functionally redundant but differ in size, sequence, and transcriptional control. We wanted to find out how roX1 production is regulated. Ectopic DC can be induced in wild-type (roX1(+) roX2(+)) females if we provide a heterologous source of MSL2. However, in the absence of roX2, we found that roX1 expression failed to come on reliably. Using an in situ hybridization probe that is specific only to endogenous roX1, we found that expression was restored if we introduced either roX2 or a truncated but functional version of roX1. This shows that pre-existing roX RNA is required to positively autoregulate roX1 expression. We also observed massive cis spreading of the MSL complex from the site of roX1 transcription at its endogenous location on the X chromosome. We propose that retention of newly assembled MSL complex around the roX gene is needed to drive sustained transcription and that spreading into flanking chromatin contributes to the X chromosome targeting specificity. Finally, we found that the gene encoding the key male-limited protein subunit, msl2, is transcribed predominantly during DNA replication. This suggests that new MSL complex is made as the chromatin template doubles. We offer a model describing how the production of roX1 and msl2, two key components of the MSL complex, are coordinated to meet the dosage compensation demands of the male cell. PMID- 22438820 TI - The nucleoside diphosphate kinase gene Nme3 acts as quantitative trait locus promoting non-Mendelian inheritance. AB - The t-haplotype, a variant form of the t-complex region on mouse chromosome 17, acts as selfish genetic element and is transmitted at high frequencies (> 95%) from heterozygous (t/+) males to their offspring. This phenotype is termed transmission ratio distortion (TRD) and is caused by the interaction of the t complex responder (Tcr) with several quantitative trait loci (QTL), the t-complex distorters (Tcd1 to Tcd4), all located within the t-haplotype region. Current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder, whereas (+)-sperm remains partially dysfunctional. Recently we have identified two distorters as regulators of RHO small G proteins. Here we show that the nucleoside diphosphate kinase gene Nme3 acts as a QTL on TRD. Reduction of the Nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t haplotype and phenocopied distorter function. Genetic and biochemical analysis showed that the t-allele of Nme3 harbors a mutation (P89S) that compromises enzymatic activity of the protein and genetically acts as a hypomorph. Transgenic overexpression of the Nme3 t-allele reduced t-haplotype transmission, proving it to be a distorter. We propose that the NME3 protein interacts with RHO signaling cascades to impair sperm motility through hyperactivation of SMOK, the wild-type form of the responder. This deleterious effect of the distorters is counter balanced by the responder, SMOK(Tcr), a dominant-negative protein kinase exclusively expressed in t-sperm, thus permitting selfish behaviour and preferential transmission of the t-haplotype. In addition, the previously reported association of NME family members with RHO signaling in somatic cell motility and metastasis, in conjunction with our data involving RHO signaling in sperm motility, suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa. PMID- 22438821 TI - Neurobeachin, a regulator of synaptic protein targeting, is associated with body fat mass and feeding behavior in mice and body-mass index in humans. AB - Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/- mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity. PMID- 22438822 TI - Genetic architecture of highly complex chemical resistance traits across four yeast strains. AB - Many questions about the genetic basis of complex traits remain unanswered. This is in part due to the low statistical power of traditional genetic mapping studies. We used a statistically powerful approach, extreme QTL mapping (X-QTL), to identify the genetic basis of resistance to 13 chemicals in all 6 pairwise crosses of four ecologically and genetically diverse yeast strains, and we detected a total of more than 800 loci. We found that the number of loci detected in each experiment was primarily a function of the trait (explaining 46% of the variance) rather than the cross (11%), suggesting that the level of genetic complexity is a consistent property of a trait across different genetic backgrounds. Further, we observed that most loci had trait-specific effects, although a small number of loci with effects in many conditions were identified. We used the patterns of resistance and susceptibility alleles in the four parent strains to make inferences about the allele frequency spectrum of functional variants. We also observed evidence of more complex allelic series at a number of loci, as well as strain-specific signatures of selection. These results improve our understanding of complex traits in yeast and have implications for study design in other organisms. PMID- 22438823 TI - Transcriptional control in cardiac progenitors: Tbx1 interacts with the BAF chromatin remodeling complex and regulates Wnt5a. AB - Mutations of the Wnt5a gene, encoding a ligand of the non-canonical Wnt pathway, and the Ror2 gene, encoding its receptor, have been found in patients with cardiac outflow tract defects. We found that Wnt5a is expressed in the second heart field (SHF), a population of cardiac progenitor cells destined to populate the cardiac outflow tract and the right ventricle. Because of cardiac phenotype similarities between Wnt5a and Tbx1 mutant mice, we tested potential interactions between the two genes. We found a strong genetic interaction in vivo and determined that the loss of both genes caused severe hypoplasia of SHF-dependent segments of the heart. We demonstrated that Wnt5a is a transcriptional target of Tbx1 and explored the mechanisms of gene regulation. Tbx1 occupies T-box binding elements within the Wnt5a gene and interacts with the Baf60a/Smarcd1 subunit of a chromatin remodeling complex. It also interacts with the Setd7 histone H3K4 monomethyltransferase. Tbx1 enhances Baf60a occupation at the Wnt5a gene and enhances its H3K4 monomethylation status. Finally, we show that Baf60a is required for Tbx1-driven regulation of target genes. These data suggest a model in which Tbx1 interacts with, and probably recruits a specific subunit of, the BAF complex as well as histone methylases to activate or enhance transcription. We speculate that this may be a general mechanism of T-box function and that Baf60a is a key component of the transcriptional control in cardiac progenitors. PMID- 22438824 TI - Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/-) mice by deregulation of Gap43-dependent granule cell precursor migration. AB - Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression. PMID- 22438825 TI - Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis. AB - c-Myc (hereafter called Myc) belongs to a family of transcription factors that regulates cell growth, cell proliferation, and differentiation. Myc initiates the transcription of a large cast of genes involved in cell growth by stimulating metabolism and protein synthesis. Some of these, like those involved in glycolysis, may be part of the Warburg effect, which is defined as increased glucose uptake and lactate production in the presence of adequate oxygen supply. In this study, we have taken a mouse-genetics approach to challenge the role of select Myc-regulated metabolic enzymes in tumorigenesis in vivo. By breeding lambda-Myc transgenic mice, Apc(Min) mice, and p53 knockout mice with mouse models carrying inactivating alleles of Lactate dehydrogenase A (Ldha), 3 Phosphoglycerate dehydrogenase (Phgdh) and Serine hydroxymethyltransferase 1 (Shmt1), we obtained offspring that were monitored for tumor development. Very surprisingly, we found that these genes are dispensable for tumorigenesis in these genetic settings. However, experiments in fibroblasts and colon carcinoma cells expressing oncogenic Ras show that these cells are sensitive to Ldha knockdown. Our genetic models reveal cell context dependency and a remarkable ability of tumor cells to adapt to alterations in critical metabolic pathways. Thus, to achieve clinical success, it will be of importance to correctly stratify patients and to find synthetic lethal combinations of inhibitors targeting metabolic enzymes. PMID- 22438826 TI - Temporal transcriptional profiling of somatic and germ cells reveals biased lineage priming of sexual fate in the fetal mouse gonad. AB - The divergence of distinct cell populations from multipotent progenitors is poorly understood, particularly in vivo. The gonad is an ideal place to study this process, because it originates as a bipotential primordium where multiple distinct lineages acquire sex-specific fates as the organ differentiates as a testis or an ovary. To gain a more detailed understanding of the process of gonadal differentiation at the level of the individual cell populations, we conducted microarrays on sorted cells from XX and XY mouse gonads at three time points spanning the period when the gonadal cells transition from sexually undifferentiated progenitors to their respective sex-specific fates. We analyzed supporting cells, interstitial/stromal cells, germ cells, and endothelial cells. This work identified genes specifically depleted and enriched in each lineage as it underwent sex-specific differentiation. We determined that the sexually undifferentiated germ cell and supporting cell progenitors showed lineage priming. We found that germ cell progenitors were primed with a bias toward the male fate. In contrast, supporting cells were primed with a female bias, indicative of the robust repression program involved in the commitment to XY supporting cell fate. This study provides a molecular explanation reconciling the female default and balanced models of sex determination and represents a rich resource for the field. More importantly, it yields new insights into the mechanisms by which different cell types in a single organ adopt their respective fates. PMID- 22438827 TI - Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal. AB - Polycomb repressive complex 2 (PRC2) trimethylates lysine 27 of histone H3 (H3K27me3) to regulate gene expression during diverse biological transitions in development, embryonic stem cell (ESC) differentiation, and cancer. Here, we show that Polycomb-like 3 (Pcl3) is a component of PRC2 that promotes ESC self renewal. Using mass spectrometry, we identified Pcl3 as a Suz12 binding partner and confirmed Pcl3 interactions with core PRC2 components by co immunoprecipitation. Knockdown of Pcl3 in ESCs increases spontaneous differentiation, yet does not affect early differentiation decisions as assessed in teratomas and embryoid bodies, indicating that Pcl3 has a specific role in regulating ESC self-renewal. Consistent with Pcl3 promoting PRC2 function, decreasing Pcl3 levels reduces H3K27me3 levels while overexpressing Pcl3 increases H3K27me3 levels. Furthermore, chromatin immunoprecipitation and sequencing (ChIP-seq) reveal that Pcl3 co-localizes with PRC2 core component, Suz12, and depletion of Pcl3 decreases Suz12 binding at over 60% of PRC2 targets. Mutation of conserved residues within the Pcl3 Tudor domain, a domain implicated in recognizing methylated histones, compromises H3K27me3 formation, suggesting that the Tudor domain of Pcl3 is essential for function. We also show that Pcl3 and its paralog, Pcl2, exist in different PRC2 complexes but bind many of the same PRC2 targets, particularly CpG islands regulated by Pcl3. Thus, Pcl3 is a component of PRC2 critical for ESC self-renewal, histone methylation, and recruitment of PRC2 to a subset of its genomic sites. PMID- 22438828 TI - Promoter nucleosome organization shapes the evolution of gene expression. AB - Understanding why genes evolve at different rates is fundamental to evolutionary thinking. In species of the budding yeast, the rate at which genes diverge in expression correlates with the organization of their promoter nucleosomes: genes lacking a nucleosome-free region (denoted OPN for "Occupied Proximal Nucleosomes") vary widely between the species, while the expression of those containing NFR (denoted DPN for "Depleted Proximal Nucleosomes") remains largely conserved. To examine if early evolutionary dynamics contributes to this difference in divergence, we artificially selected for high expression of GFP fused proteins. Surprisingly, selection was equally successful for OPN and DPN genes, with -80% of genes in each group stably increasing in expression by a similar amount. Notably, the two groups adapted by distinct mechanisms: DPN selected strains duplicated large genomic regions, while OPN-selected strains favored trans mutations not involving duplications. When selection was removed, DPN (but not OPN) genes reverted rapidly to wild-type expression levels, consistent with their lower diversity between species. Our results suggest that promoter organization constrains the early evolutionary dynamics and in this way biases the path of long-term evolution. PMID- 22438829 TI - Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis. AB - Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5' to and within the MSRA gene were associated with MI (P = 1.99 * 10( 5) to 1.08 * 10(-6); Bonferroni P = 0.057 to 3.1 * 10(-3)). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53-0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2 * 10(-4)). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr(-/-) and Cftr(-/-)Msra(-/-) mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function. PMID- 22438830 TI - A splice site variant in the bovine RNF11 gene compromises growth and regulation of the inflammatory response. AB - We report association mapping of a locus on bovine chromosome 3 that underlies a Mendelian form of stunted growth in Belgian Blue Cattle (BBC). By resequencing positional candidates, we identify the causative c124-2A>G splice variant in intron 1 of the RNF11 gene, for which all affected animals are homozygous. We make the remarkable observation that 26% of healthy Belgian Blue animals carry the corresponding variant. We demonstrate in a prospective study design that approximately one third of homozygous mutants die prematurely with major inflammatory lesions, hence explaining the rarity of growth-stunted animals despite the high frequency of carriers. We provide preliminary evidence that heterozygous advantage for an as of yet unidentified phenotype may have caused a selective sweep accounting for the high frequency of the RNF11 c124-2A>G mutation in Belgian Blue Cattle. PMID- 22438831 TI - Antagonistic regulation of apoptosis and differentiation by the Cut transcription factor represents a tumor-suppressing mechanism in Drosophila. AB - Apoptosis is essential to prevent oncogenic transformation by triggering self destruction of harmful cells, including those unable to differentiate. However, the mechanisms linking impaired cell differentiation and apoptosis during development and disease are not well understood. Here we report that the Drosophila transcription factor Cut coordinately controls differentiation and repression of apoptosis via direct regulation of the pro-apoptotic gene reaper. We also demonstrate that this regulatory circuit acts in diverse cell lineages to remove uncommitted precursor cells in status nascendi and thereby interferes with their potential to develop into cancer cells. Consistent with the role of Cut homologues in controlling cell death in vertebrates, we find repression of apoptosis regulators by Cux1 in human cancer cells. Finally, we present evidence that suggests that other lineage-restricted specification factors employ a similar mechanism to put the brakes on the oncogenic process. PMID- 22438832 TI - The yeast forkhead transcription factors fkh1 and fkh2 regulate lifespan and stress response together with the anaphase-promoting complex. AB - Forkhead box O (FOXO) transcription factors have a conserved function in regulating metazoan lifespan. A key function in this process involves the regulation of the cell cycle and stress responses including free radical scavenging. We employed yeast chronological and replicative lifespan assays, as well as oxidative stress assays, to explore the potential evolutionary conservation of function between the FOXOs and the yeast forkhead box transcription factors FKH1 and FKH2. We report that the deletion of both FKH genes impedes normal lifespan and stress resistance, particularly in stationary phase cells, which are non-responsive to caloric restriction. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress response. Here we show the Anaphase-Promoting Complex (APC) genetically interacts with the Fkh pathway, likely working in a linear pathway under normal conditions, as fkh1Delta fkh2Delta post-mitotic survival is epistatic to that observed in apc5(CA) mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5(CA) fkh1Delta fkh2Delta, while increased expression of either FKH rescues APC mutant growth defects. This study establishes the FKHs role as evolutionarily conserved regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism under certain conditions, likely through combined regulation of stress response, genomic stability, and cell cycle regulation. PMID- 22438833 TI - ppk23-Dependent chemosensory functions contribute to courtship behavior in Drosophila melanogaster. AB - Insects utilize diverse families of ion channels to respond to environmental cues and control mating, feeding, and the response to threats. Although degenerin/epithelial sodium channels (DEG/ENaC) represent one of the largest families of ion channels in Drosophila melanogaster, the physiological functions of these proteins are still poorly understood. We found that the DEG/ENaC channel ppk23 is expressed in a subpopulation of sexually dimorphic gustatory-like chemosensory bristles that are distinct from those expressing feeding-related gustatory receptors. Disrupting ppk23 or inhibiting activity of ppk23-expressing neurons did not alter gustatory responses. Instead, blocking ppk23-positive neurons or mutating the ppk23 gene delayed the initiation and reduced the intensity of male courtship. Furthermore, mutations in ppk23 altered the behavioral response of males to the female-specific aphrodisiac pheromone 7(Z), 11(Z)-Heptacosadiene. Together, these data indicate that ppk23 and the cells expressing it play an important role in the peripheral sensory system that determines sexual behavior in Drosophila. PMID- 22438834 TI - A genome-wide association study identifies variants underlying the Arabidopsis thaliana shade avoidance response. AB - Shade avoidance is an ecologically and molecularly well-understood set of plant developmental responses that occur when the ratio of red to far-red light (R:FR) is reduced as a result of foliar shade. Here, a genome-wide association study (GWAS) in Arabidopsis thaliana was used to identify variants underlying one of these responses: increased hypocotyl elongation. Four hypocotyl phenotypes were included in the study, including height in high R:FR conditions (simulated sun), height in low R:FR conditions (simulated shade), and two different indices of the response of height to low R:FR. GWAS results showed that variation in these traits is controlled by many loci of small to moderate effect. A known PHYC variant contributing to hypocotyl height variation was identified and lists of significantly associated genes were enriched in a priori candidates, suggesting that this GWAS was capable of generating meaningful results. Using metadata such as expression data, GO terms, and other annotation, we were also able to identify variants in candidate de novo genes. Patterns of significance among our four phenotypes allowed us to categorize associations into three groups: those that affected hypocotyl height without influencing shade avoidance, those that affected shade avoidance in a height-dependent fashion, and those that exerted specific control over shade avoidance. This grouping allowed for the development of explicit hypotheses about the genetics underlying shade avoidance variation. Additionally, the response to shade did not exhibit any marked geographic distribution, suggesting that variation in low R:FR-induced hypocotyl elongation may represent a response to local conditions. PMID- 22438835 TI - A systematic analysis of cell cycle regulators in yeast reveals that most factors act independently of cell size to control initiation of division. AB - Upstream events that trigger initiation of cell division, at a point called START in yeast, determine the overall rates of cell proliferation. The identity and complete sequence of those events remain unknown. Previous studies relied mainly on cell size changes to identify systematically genes required for the timely completion of START. Here, we evaluated panels of non-essential single gene deletion strains for altered DNA content by flow cytometry. This analysis revealed that most gene deletions that altered cell cycle progression did not change cell size. Our results highlight a strong requirement for ribosomal biogenesis and protein synthesis for initiation of cell division. We also identified numerous factors that have not been previously implicated in cell cycle control mechanisms. We found that CBS, which catalyzes the synthesis of cystathionine from serine and homocysteine, advances START in two ways: by promoting cell growth, which requires CBS's catalytic activity, and by a separate function, which does not require CBS's catalytic activity. CBS defects cause disease in humans, and in animals CBS has vital, non-catalytic, unknown roles. Hence, our results may be relevant for human biology. Taken together, these findings significantly expand the range of factors required for the timely initiation of cell division. The systematic identification of non-essential regulators of cell division we describe will be a valuable resource for analysis of cell cycle progression in yeast and other organisms. PMID- 22438836 TI - Bioinformatics Tools for Mass Spectroscopy-Based Metabolomic Data Processing and Analysis. AB - Biological systems are increasingly being studied in a holistic manner, using omics approaches, to provide quantitative and qualitative descriptions of the diverse collection of cellular components. Among the omics approaches, metabolomics, which deals with the quantitative global profiling of small molecules or metabolites, is being used extensively to explore the dynamic response of living systems, such as organelles, cells, tissues, organs and whole organisms, under diverse physiological and pathological conditions. This technology is now used routinely in a number of applications, including basic and clinical research, agriculture, microbiology, food science, nutrition, pharmaceutical research, environmental science and the development of biofuels. Of the multiple analytical platforms available to perform such analyses, nuclear magnetic resonance and mass spectrometry have come to dominate, owing to the high resolution and large datasets that can be generated with these techniques. The large multidimensional datasets that result from such studies must be processed and analyzed to render this data meaningful. Thus, bioinformatics tools are essential for the efficient processing of huge datasets, the characterization of the detected signals, and to align multiple datasets and their features. This paper provides a state-of-the-art overview of the data processing tools available, and reviews a collection of recent reports on the topic. Data conversion, pre-processing, alignment, normalization and statistical analysis are introduced, with their advantages and disadvantages, and comparisons are made to guide the reader. PMID- 22438837 TI - Presynaptic Active Zone Density during Development and Synaptic Plasticity. AB - Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density) during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs), the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS), active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and beta adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated. PMID- 22438838 TI - Input dependent cell assembly dynamics in a model of the striatal medium spiny neuron network. AB - The striatal medium spiny neuron (MSN) network is sparsely connected with fairly weak GABAergic collaterals receiving an excitatory glutamatergic cortical projection. Peri-stimulus time histograms (PSTH) of MSN population response investigated in various experimental studies display strong firing rate modulations distributed throughout behavioral task epochs. In previous work we have shown by numerical simulation that sparse random networks of inhibitory spiking neurons with characteristics appropriate for UP state MSNs form cell assemblies which fire together coherently in sequences on long behaviorally relevant timescales when the network receives a fixed pattern of constant input excitation. Here we first extend that model to the case where cortical excitation is composed of many independent noisy Poisson processes and demonstrate that cell assembly dynamics is still observed when the input is sufficiently weak. However if cortical excitation strength is increased more regularly firing and completely quiescent cells are found, which depend on the cortical stimulation. Subsequently we further extend previous work to consider what happens when the excitatory input varies as it would when the animal is engaged in behavior. We investigate how sudden switches in excitation interact with network generated patterned activity. We show that sequences of cell assembly activations can be locked to the excitatory input sequence and outline the range of parameters where this behavior is shown. Model cell population PSTH display both stimulus and temporal specificity, with large population firing rate modulations locked to elapsed time from task events. Thus the random network can generate a large diversity of temporally evolving stimulus dependent responses even though the input is fixed between switches. We suggest the MSN network is well suited to the generation of such slow coherent task dependent response which could be utilized by the animal in behavior. PMID- 22438839 TI - Time and number sense develop in tandem? PMID- 22438840 TI - Extinction procedure induces pruning of dendritic spines in CA1 hippocampal field depending on strength of training in rats. AB - Numerous reports indicate that learning and memory of conditioned responses are accompanied by genesis of dendritic spines in the hippocampus, although there is a conspicuous lack of information regarding spine modifications after behavioral extinction. There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training. PMID- 22438841 TI - Episodic memory function is associated with multiple measures of white matter integrity in cognitive aging. AB - Previous neuroimaging research indicates that white matter injury and integrity, measured respectively by white matter hyperintensities (WMH) and fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI), differ with aging and cerebrovascular disease (CVD) and are associated with episodic memory deficits in cognitively normal older adults. However, knowledge about tract specific relationships between WMH, FA, and episodic memory in aging remains limited. We hypothesized that white matter connections between frontal cortex and subcortical structures as well as connections between frontal and temporo parietal cortex would be most affected. In the current study, we examined relationships between WMH, FA and episodic memory in 15 young adults, 13 elders with minimal WMH and 15 elders with extensive WMH, using an episodic recognition memory test for object-color associations. Voxel-based statistics were used to identify voxel clusters where white matter measures were specifically associated with variations in episodic memory performance, and white matter tracts intersecting these clusters were analyzed to examine white matter-memory relationships. White matter injury and integrity measures were significantly associated with episodic memory in extensive regions of white matter, located predominantly in frontal, parietal, and subcortical regions. Template based tractography indicated that white matter injury, as measured by WMH, in the uncinate and inferior longitudinal fasciculi were significantly negatively associated with episodic memory performance. Other tracts such as thalamo-frontal projections, superior longitudinal fasciculus, and dorsal cingulum bundle demonstrated strong negative associations as well. The results suggest that white matter injury to multiple pathways, including connections of frontal and temporal cortex and frontal-subcortical white matter tracts, plays a critical role in memory differences seen in older individuals. PMID- 22438842 TI - Neuromantic - from semi-manual to semi-automatic reconstruction of neuron morphology. AB - The ability to create accurate geometric models of neuronal morphology is important for understanding the role of shape in information processing. Despite a significant amount of research on automating neuron reconstructions from image stacks obtained via microscopy, in practice most data are still collected manually. This paper describes Neuromantic, an open source system for three dimensional digital tracing of neurites. Neuromantic reconstructions are comparable in quality to those of existing commercial and freeware systems while balancing speed and accuracy of manual reconstruction. The combination of semi automatic tracing, intuitive editing, and ability of visualizing large image stacks on standard computing platforms provides a versatile tool that can help address the reconstructions availability bottleneck. Practical considerations for reducing the computational time and space requirements of the extended algorithm are also discussed. PMID- 22438843 TI - Direct Antioxidant Properties of Bilirubin and Biliverdin. Is there a Role for Biliverdin Reductase? AB - Reactive oxygen species (ROS) and signaling events are involved in the pathogenesis of endothelial dysfunction and represent a major contribution to vascular regulation. Molecular signaling is highly dependent on ROS. But depending on the amount of ROS production it might have toxic or protective effects. Despite a large number of negative outcomes in large clinical trials (e.g., HOPE, HOPE-TOO), antioxidant molecules and agents are important players to influence the critical balance between production and elimination of reactive oxygen and nitrogen species. However, chronic systemic antioxidant therapy lacks clinical efficacy, probably by interfering with important physiological redox signaling pathways. Therefore, it may be a much more promising attempt to induce intrinsic antioxidant pathways in order to increase the antioxidants not systemically but at the place of oxidative stress and complications. Among others, heme oxygenase (HO) has been shown to be important for attenuating the overall production of ROS in a broad range of disease states through its ability to degrade heme and to produce carbon monoxide and biliverdin/bilirubin. With the present review we would like to highlight the important antioxidant role of the HO system and especially discuss the contribution of the biliverdin, bilirubin, and biliverdin reductase (BVR) to these beneficial effects. The BVR was reported to confer an antioxidant redox amplification cycle by which low, physiological bilirubin concentrations confer potent antioxidant protection via recycling of biliverdin from oxidized bilirubin by the BVR, linking this sink for oxidants to the NADPH pool. To date the existence and role of this antioxidant redox cycle is still under debate and we present and discuss the pros and cons as well as our own findings on this topic. PMID- 22438844 TI - Go green: the anti-inflammatory effects of biliverdin reductase. AB - Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule. Conversion of BV to bilirubin (BR) is catalyzed by biliverdin reductase (BVR) and is required for the downstream signaling and nuclear localization of BVR. Recent data by others and us make clear that BVR is a critical regulator of innate immune responses resulting from acute insult and injury and moreover, that a lack of BVR results in an enhanced proinflammatory phenotype. In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL 10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter. In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator. PMID- 22438845 TI - Cooperation-induced topological complexity: a promising road to fault tolerance and hebbian learning. AB - According to an increasing number of researchers intelligence emerges from criticality as a consequence of locality breakdown and long-range correlation, well known properties of phase transition processes. We study a model of interacting units, as an idealization of real cooperative systems such as the brain or a flock of birds, for the purpose of discussing the emergence of long range correlation from the coupling of any unit with its nearest neighbors. We focus on the critical condition that has been recently shown to maximize information transport and we study the topological structure of the network of dynamically linked nodes. Although the topology of this network depends on the arbitrary choice of correlation threshold, namely the correlation intensity selected to establish a link between two nodes; the numerical calculations of this paper afford some important indications on the dynamically induced topology. The first important property is the emergence of a perception length as large as the flock size, thanks to some nodes with a large number of links, thus playing the leadership role. All the units are equivalent and leadership moves in time from one to another set of nodes, thereby insuring fault tolerance. Then we focus on the correlation threshold generating a scale-free topology with power index nu ~ 1 and we find that if this topological structure is selected to establish consensus through the linked nodes, the control parameter necessary to generate criticality is close to the critical value corresponding to the all-to-all coupling condition. We find that criticality in this case generates also a third state, corresponding to a total lack of consensus. However, we make a numerical analysis of the dynamically induced network, and we find that it consists of two almost independent structures, each of which is equivalent to a network in the all-to-all coupling condition. This observation confirms that cooperation makes the system evolve toward favoring consensus topological structures. We argue that these results are compatible with both Hebbian learning and fault tolerance. PMID- 22438846 TI - Inhibitory control and l2 proficiency modulate bilingual language production: evidence from spontaneous monologue and dialogue speech. AB - Bilingual language production requires that speakers recruit inhibitory control (IC) to optimally balance the activation of more than one linguistic system when they produce speech. Moreover, the amount of IC necessary to maintain an optimal balance is likely to vary across individuals as a function of second language (L2) proficiency and inhibitory capacity, as well as the demands of a particular communicative situation. Here, we investigate how these factors relate to bilingual language production across monologue and dialogue spontaneous speech. In these tasks, 42 English-French and French-English bilinguals produced spontaneous speech in their first language (L1) and their L2, with and without a conversational partner. Participants also completed a separate battery that assessed L2 proficiency and inhibitory capacity. The results showed that L2 vs. L1 production was generally more effortful, as was dialogue vs. monologue speech production although the clarity of what was produced was higher for dialogues vs. monologues. As well, language production effort significantly varied as a function of individual differences in L2 proficiency and inhibitory capacity. Taken together, the overall pattern of findings suggests that both increased L2 proficiency and inhibitory capacity relate to efficient language production during spontaneous monologue and dialogue speech. PMID- 22438847 TI - Ten steps to effective teaching as a non-physician educator. PMID- 22438848 TI - Partial recovery of alcohol dependence-related deficits in sleep evoked potentials following 12 months of abstinence. AB - Stimuli presented during sleep can produce an evoked EEG delta wave referred to as a K-complex. These responses occur when large numbers of cortical cells burst fire in a synchronized manner. Large amplitude synchronized scalp responses require that the CNS contain large numbers of healthy neurons that are interconnected with highly functional white matter pathways. The P2, N550, and P900 components of the evoked K-complex are sensitive measures of normal healthy brain aging, showing a decrease in amplitude with age. N550 and P900 amplitudes are also reduced in recently detoxified alcoholics, most dramatically over frontal scalp regions. The present study tested the hypothesis that the amplitude of K-complex related evoked potential components would increase with prolonged abstinence. Fifteen alcoholics (12 men) were studied twice, separated by a 12 month period, during which time they were followed with monthly phone calls. Subjects were aged between 38 and 60 years at their first study. They had on average a 29.3 +/- 6.7 year drinking history and had been abstinent for between 54 and 405 days at initial testing. Evoked K-complexes were identified in the EEG and averaged to enable measurement of the P2, N550 and P900 peaks. Data were collected from seven scalp sites (FP1, FP2, Fz, FCz, Cz, CPz, and Pz). N550 and P900 amplitudes were significantly higher after 12 months of abstinence and an improvement of at least 5 MUV occurred in 12 of the 15 subjects. N550 and P900 also showed highly significant site by night interactions with the largest increases occurring over prefrontal and frontal sites. The data indicate that the sleep evoked response may provide a sensitive marker of brain recovery with abstinence from alcohol. PMID- 22438849 TI - Disruption of Transitional Stages in 24-h Blood Pressure Recording in Renal Transplant Recipients. AB - Patients with kidney replacement exhibit disrupted circadian rhythms. Most studies measuring blood pressure use the dipper/non-dipper classification, which does not consider analysis of transitional stages between low and high blood pressure, confidence intervals nor shifts in the time of peak, while assuming subjective onsets of night and day phases. In order to better understand the nature of daily variation of blood pressure in these patients, we analyzed 24 h recordings from 41 renal transplant recipients using the non-symmetrical double logistic fitting assessment which does not assume abruptness nor symmetry in ascending and descending stages of the blood pressure profile, and a cosine best fitting regression method (Cosinor). Compared with matched controls, double logistic fitting showed that the times for most transitional stages (ascending systolic and descending systolic, diastolic, and mean arterial pressure) had a wider distribution along the 24-h. The proportion of individuals without daily blood pressure rhythm in the transplanted group was larger only for systolic arterial pressure, and the amplitude showed no significant difference. Furthermore, the transplant recipient group had a less pronounced slope in descending systolic and ascending mean blood pressure. Cosinor analysis confirmed this phase-related changes, showing a wider distribution of times of peak (acrophases). We conclude that daily disruptions in renal transplant recipients can be explained not necessarily by an absence in diurnal variation, but also by changes in waveform-related parameters of the rhythm, and that alterations in the phase of the rhythm are the most consistent finding in these patients. PMID- 22438850 TI - Dynamism in Activity of the Neural Networks in Brain is the Basis of Sleep Wakefulness Oscillations. PMID- 22438851 TI - Specificity of Salt Marsh Diazotrophs for Vegetation Zones and Plant Hosts: Results from a North American marsh. AB - Salt marshes located on the east coast of temperate North America are highly productive, typically nitrogen-limited, and support diverse assemblages of free living nitrogen fixing (diazotrophic) bacteria. This article reviews and analyzes data from North Inlet estuary (SC, USA), addressing diazotroph assemblage structure and the influence of plant host and environmental conditions on the assemblage. The North Inlet estuary is a salt marsh ecosystem in which anthropogenic influences are minimal and the distributions of diazotrophs are governed by the natural biota and dynamics of the system. Denaturing gradient gel electrophoresis fingerprinting and phylogenetic analyses of recovered sequences demonstrated that the distributions of some diazotrophs reflect plant host specificity and that diazotroph assemblages distributed across marsh gradients are also heavily influenced by edaphic conditions. Broadly distributed diazotrophs that are capable of maintaining populations under all environmental conditions spanning such gradients are also present in these assemblages. Statistical analyses indicate that the structures of diazotroph assemblages in different vegetation zones are significantly (p < 0.01) different. New data presented here demonstrate the heterogeneity of salt marsh rhizosphere microenvironments, and corroborate previous findings from different plant hosts growing at several locations within this estuary. The data from these collected works support the hypothesis that the biogeography of microorganisms is non random and these biogeographic patterns are predictable. PMID- 22438852 TI - Targeting the oxidative stress response system of fungi with redox-potent chemosensitizing agents. AB - The cellular antioxidant system is a target in the antifungal action of amphotericin B (AMB) and itraconazole (ITZ), in filamentous fungi. The sakADelta mutant of Aspergillus fumigatus, a mitogen-activated protein kinase (MAPK) gene deletion mutant in the antioxidant system, was found to be more sensitive to AMB or ITZ than other A. fumigatus strains, a wild type and a mpkCDelta mutant (a MAPK gene deletion mutant in the polyalcohol sugar utilization system). Complete fungal kill (>=99.9%) by ITZ or AMB was also achieved by much lower dosages for the sakADelta mutant than for the other strains. It appears msnA, an Aspergillus ortholog to Saccharomyces cerevisiaeMSN2 (encoding a stress-responsive C(2)H(2) type zinc-finger regulator) and sakA and/or mpkC (upstream MAPKs) are in the same stress response network under tert-butyl hydroperoxide (t-BuOOH)-, hydrogen peroxide (H(2)O(2))- or AMB-triggered toxicity. Of note is that ITZ-sensitive yeast pathogens were also sensitive to t-BuOOH, showing a connection between ITZ sensitivity and antioxidant capacity of fungi. Enhanced antifungal activity of AMB or ITZ was achieved when these drugs were co-applied with redox-potent natural compounds, 2,3-dihydroxybenzaldehyde, thymol or salicylaldehyde, as chemosensitizing agents. We concluded that redox-potent compounds, which target the antioxidant system in fungi, possess a chemosensitizing capacity to enhance efficacy of conventional drugs. PMID- 22438853 TI - Redox Transformations of Iron at Extremely Low pH: Fundamental and Applied Aspects. AB - Many different species of acidophilic prokaryotes, widely distributed within the domains Bacteria and Archaea, can catalyze the dissimilatory oxidation of ferrous iron or reduction of ferric iron, or can do both. Microbially mediated cycling of iron in extremely acidic environments (pH < 3) is strongly influenced by the enhanced chemical stability of ferrous iron and far greater solubility of ferric iron under such conditions. Cycling of iron has been demonstrated in vitro using both pure and mixed cultures of acidophiles, and there is considerable evidence that active cycling of iron occurs in acid mine drainage streams, pit lakes, and iron-rich acidic rivers, such as the Rio Tinto. Measurements of specific rates of iron oxidation and reduction by acidophilic microorganisms show that different species vary in their capacities for iron oxido-reduction, and that this is influenced by the electron donor provided and growth conditions used. These measurements, and comparison with corresponding data for oxidation of reduced sulfur compounds, also help explain why ferrous iron is usually used preferentially as an electron donor by acidophiles that can oxidize both iron and sulfur, even though the energy yield from oxidizing iron is much smaller than that available from sulfur oxidation. Iron-oxidizing acidophiles have been used in biomining (a technology that harness their abilities to accelerate the oxidative dissolution of sulfidic minerals and thereby facilitate the extraction of precious and base metals) for several decades. More recently they have also been used to simultaneously remediate iron-contaminated surface and ground waters and produce a useful mineral by-product (schwertmannite). Bioprocessing of oxidized mineral ores using acidophiles that catalyze the reductive dissolution of ferric iron minerals such as goethite has also recently been demonstrated, and new biomining technologies based on this approach are being developed. PMID- 22438854 TI - ACE2 and Angiotensin-(1-7) in Hypertensive Renal Disease. AB - The recently discovered angiotensin-converting enzyme-related carboxypeptidase 2 (ACE2)-[Angiotensin-(1-7)(Ang-(1-7)]-Mas receptor axis has an opposing function to that of the ACE-Angiotensin II (Ang II)-Angiotensin type 1 (AT1) receptor axis. Ang-(1-7) is present in the kidneys at concentrations comparable to those of Ang II and is associated with vasodilation, modulation of sodium and water transport, and stimulation of nitric oxide (NO) synthase. Ang-(1-7) also acts as a physiological antagonist of Ang II by counterbalancing the Ang II-mediated intracellular signaling pathway. In a hypertensive model, increased ACE and decreased ACE2 along with a higher ACE/ACE2 ratio in hypertensive kidneys appeared to favor Ang II generation, leading to hypertensive renal damage. In addition, the administration of a selective Ang-(1-7) receptor blocker or an ACE2 inhibitor was associated with worsening of hypertension and renal function. Ang (1-7)-mediated increases in renal blood flow were abolished by blockade of the Mas receptor and by inhibition of prostaglandin release and NO in spontaneously hypertensive rats and in Wistar-Kyoto controls. Further research on the function of the ACE2-Ang-(1-7)-Mas receptor axis could lead to a novel target for inhibiting kidney disease progression. PMID- 22438855 TI - Mechanisms of the effects of acidosis and hypokalemia on renal ammonia metabolism. AB - Renal ammonia metabolism is the predominant component of net acid excretion and new bicarbonate generation. Renal ammonia metabolism is regulated by acid-base balance. Both acute and chronic acid loads enhance ammonia production in the proximal tubule and secretion into the urine. In contrast, alkalosis reduces ammoniagenesis. Hypokalemia is a common electrolyte disorder that significantly increases renal ammonia production and excretion, despite causing metabolic alkalosis. Although the net effects of hypokalemia are similar to metabolic acidosis, molecular mechanisms of renal ammonia production and transport have not been well understood. This mini review summarizes recent findings regarding renal ammonia metabolism in response to chronic hypokalemia. PMID- 22438856 TI - V2 receptor antagonist; tolvaptan. AB - Hyponatremia is the most common electrolyte disorder in hospitalized patients. Many studies documented that it was related to increased morbidity and mortality in patients with congestive heart failure, liver cirrhosis, and neurologic diseases. Although knowledge of hyponatremia has been cumulated, the optimal management of hyponatremia remains incompletely established in clinical practice because of the diversity of underlying disease states, and its multiple causes with differing pathophysiologic mechanisms. Since vasopressin receptor antagonists have unique aquaretic effect to selectively increase electrolytes free water excretion, clinicians could apply a more effective method to treat hyponatremia. Tolvaptan has significant evidence that it improves serum sodium levels in patients with euvolemic or hypervolemic hyponatremia related with heart failure, cirrhosis or syndrome of inappropriate anti-diuretic hormone. Tolvaptan has acceptable safety and tolerability for long-term usage in chronic hyponatremia, and the beneficial effects on serum Na(+) occurred in patients with both mild and marked hyponatremia. PMID- 22438857 TI - Effects of dietary salt restriction on puromycin aminonucleoside nephrosis: preliminary data. AB - Proteinuria is a major promoter that induces tubulointerstitial injury in glomerulopathy. Dietary salt restriction may reduce proteinuria, although the mechanism is not clear. We investigated the effects of dietary salt restriction on rat kidneys in an animal model of glomerular proteinuria. Male Sprague-Dawley rats were used and divided into 3 groups: vehicle-treated normal-salt controls, puromycin aminonucleoside (PA)-treated normal-salt rats, and PA-treated low-salt rats. PA was given at a dose of 150 mg/kg BW at time 0, followed by 50 mg/kg BW on days 28, 35, and 42. Sodium-deficient rodent diet with and without additional NaCl (0.5%) were provided for normal-salt rats and low-salt rats, respectively. On day 63, kidneys were harvested for histopathologic examination and immunohistochemistry. PA treatment produced overt proteinuria and renal damage. Dietary salt restriction insignificantly reduced proteinuria in PA-treated rats, and PA-treated low-salt rats had lower urine output and lower creatinine clearance than vehicle-treated normal-salt controls. When tubulointerstitial injury was semiquantitatively evaluated, it had a positive correlation with proteinuria. The tubulointerstitial injury score was significantly increased by PA treatment and relieved by low-salt diet. ED1-positive infiltrating cells and immunostaining for interstitial collagen III were significantly increased by PA treatment. These changes appeared to be less common in PA-treated low-salt rats, although the differences in PA-treated normal-salt versus low-salt rats did not reach statistical significance. Our results suggest that renal histopathology in PA nephrosis may potentially be improved by dietary salt restriction. Non hemodynamic mechanisms induced by low-sodium diet might contribute to renoprotection. PMID- 22438858 TI - Volume control by using the body composition monitor in a puerperal patient on hemodialysis. AB - Accurate measurement of the volume status in hemodialysis patients is important as it can affect mortality. However, no studies have been conducted regarding volume management in cases where a sudden change of body fluid occurs, such as during puerperium in hemodialysis patients. This report presents a case in which the patient was monitored for her body composition and her volume status was controlled using a body composition monitor (BCM) during the puerperal period. This case suggests that using a BCM for volume management may help maintain hemodynamic stability in patients with a rapidly changing volume status for a short term period, such as during puerperium. PMID- 22438859 TI - Two smalls in one: Coincident small cell carcinoma and small lymphocytic lymphoma in a lymph node diagnosed by fine-needle aspiration biopsy. AB - BACKGROUND: B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) is one of the most common lymphoproliferative disorders in western countries. Patients with SLL / CLL are at increased risk of site-specific secondary cancers. We present a unique case of a 71-year-old male, with a history of SLL / CLL, who presented with pulmonary symptoms and a mediastinal mass. Fine needle aspiration (FNA) of the mediastinal lymph node revealed synchronous SLL / CLL and small cell carcinoma (SCC). MATERIALS AND METHODS: The patient underwent a computed tomography (CT) scan of the chest and endobronchial ultrasound-guided transbronchial fine needle aspiration of the mediastinal lymph node (4R). The sample was submitted for cytopathology, immunohistochemical stains, and flow cytometry evaluation. RESULTS: Fine needle aspiration of the mediastinal lymph node revealed neoplastic cells, in clusters and singly, with cytological features suggestive of small cell carcinoma. The immunohistochemistry results confirmed this diagnosis. Small-to-medium, mature-appearing lymphocytes were also present in the background. Flow cytometry analysis revealed that these lymphocytes possessed an immunophenotype consistent with CLL / SLL. CONCLUSIONS: This case illustrates the importance of a pathologist's awareness of the possibility of concurrent lymphoma and metastatic carcinoma in a lymph node. When evaluating lymph nodes, pathologists must strive to identify both foreign cells and subtle lymphoid changes. As demonstrated by our case, ancillary techniques (such as immunohistochemistry and flow cytometry) can be critical to making a complete and accurate diagnosis. The diagnosis of small cell carcinoma in the enlarged lymph node, primarily harboring CLL / SLL, is of critical importance for decision making and treatment purposes, in addition to having a significant adverse impact on the overall survival. PMID- 22438860 TI - Fine-needle aspiration cytology of eccrine hidrocystoma. PMID- 22438861 TI - Location of zeros of Wiener and distance polynomials. AB - The geometry of polynomials explores geometrical relationships between the zeros and the coefficients of a polynomial. A classical problem in this theory is to locate the zeros of a given polynomial by determining disks in the complex plane in which all its zeros are situated. In this paper, we infer bounds for general polynomials and apply classical and new results to graph polynomials namely Wiener and distance polynomials whose zeros have not been yet investigated. Also, we examine the quality of such bounds by considering four graph classes and interpret the results. PMID- 22438862 TI - Cryptic diversity in Indo-Pacific coral-reef fishes revealed by DNA-barcoding provides new support to the centre-of-overlap hypothesis. AB - Diversity in coral reef fishes is not evenly distributed and tends to accumulate in the Indo-Malay-Philippines Archipelago (IMPA). The comprehension of the mechanisms that initiated this pattern is in its infancy despite its importance for the conservation of coral reefs. Considering the IMPA either as an area of overlap or a cradle of marine biodiversity, the hypotheses proposed to account for this pattern rely on extant knowledge about taxonomy and species range distribution. The recent large-scale use of standard molecular data (DNA barcoding), however, has revealed the importance of taking into account cryptic diversity when assessing tropical biodiversity. We DNA barcoded 2276 specimens belonging to 668 coral reef fish species through a collaborative effort conducted concomitantly in both Indian and Pacific oceans to appraise the importance of cryptic diversity in species with an Indo-Pacific distribution range. Of the 141 species sampled on each side of the IMPA, 62 presented no spatial structure whereas 67 exhibited divergent lineages on each side of the IMPA with K2P distances ranging between 1% and 12%, and 12 presented several lineages with K2P distances ranging between 3% and 22%. Thus, from this initial pool of 141 nominal species with Indo-Pacific distribution, 79 dissolved into 165 biological units among which 162 were found in a single ocean. This result is consistent with the view that the IMPA accumulates diversity as a consequence of its geological history, its location on the junction between the two main tropical oceans and the presence of a land bridge during glacial times in the IMPA that fostered allopatric divergence and secondary contacts between the Indian and Pacific oceans. PMID- 22438863 TI - Amyloid-like fibril formation by polyQ proteins: a critical balance between the polyQ length and the constraints imposed by the host protein. AB - Nine neurodegenerative disorders, called polyglutamine (polyQ) diseases, are characterized by the formation of intranuclear amyloid-like aggregates by nine proteins containing a polyQ tract above a threshold length. These insoluble aggregates and/or some of their soluble precursors are thought to play a role in the pathogenesis. The mechanism by which polyQ expansions trigger the aggregation of the relevant proteins remains, however, unclear. In this work, polyQ tracts of different lengths were inserted into a solvent-exposed loop of the beta-lactamase BlaP and the effects of these insertions on the properties of BlaP were investigated by a range of biophysical techniques. The insertion of up to 79 glutamines does not modify the structure of BlaP; it does, however, significantly destabilize the enzyme. The extent of destabilization is largely independent of the polyQ length, allowing us to study independently the effects intrinsic to the polyQ length and those related to the structural integrity of BlaP on the aggregating properties of the chimeras. Only chimeras with 55Q and 79Q readily form amyloid-like fibrils; therefore, similarly to the proteins associated with diseases, there is a threshold number of glutamines above which the chimeras aggregate into amyloid-like fibrils. Most importantly, the chimera containing 79Q forms amyloid-like fibrils at the same rate whether BlaP is folded or not, whereas the 55Q chimera aggregates into amyloid-like fibrils only if BlaP is unfolded. The threshold value for amyloid-like fibril formation depends, therefore, on the structural integrity of the beta-lactamase moiety and thus on the steric and/or conformational constraints applied to the polyQ tract. These constraints have, however, no significant effect on the propensity of the 79Q tract to trigger fibril formation. These results suggest that the influence of the protein context on the aggregating properties of polyQ disease-associated proteins could be negligible when the latter contain particularly long polyQ tracts. PMID- 22438864 TI - Species shifts in the Anopheles gambiae complex: do LLINs successfully control Anopheles arabiensis? AB - INTRODUCTION: High coverage of conventional and long-lasting insecticide treated nets (ITNs and LLINs) in parts of E Africa are associated with reductions in local malaria burdens. Shifts in malaria vector species ratio have coincided with the scale-up suggesting that some species are being controlled by ITNs/LLINs better than others. METHODS: Between 2005-2006 six experimental hut trials of ITNs and LLINs were conducted in parallel at two field stations in northeastern Tanzania; the first station was in Lower Moshi Rice Irrigation Zone, an area where An. arabiensis predominates, and the second was in coastal Muheza, where An. gambiae and An. funestus predominate. Five pyrethroids and one carbamate insecticide were evaluated on nets in terms of insecticide-induced mortality, blood-feeding inhibition and exiting rates. RESULTS: In the experimental hut trials mortality of An. arabiensis was consistently lower than that of An. gambiae and An. funestus. The mortality rates in trials with pyrethroid-treated nets ranged from 25-52% for An. arabiensis, 63-88% for An. gambiae s.s. and 53 78% for An. funestus. All pyrethroid-treated nets provided considerable protection for the occupants, despite being deliberately holed, with blood feeding inhibition (percentage reduction in biting rates) being consistent between species. Veranda exiting rates did not differ between species. Percentage mortality of mosquitoes tested in cone bioassays on netting was similar for An. gambiae and An. arabiensis. CONCLUSIONS: LLINs and ITNs treated with pyrethroids were more effective at killing An. gambiae and An. funestus than An. arabiensis. This could be a major contributing factor to the species shifts observed in East Africa following scale up of LLINs. With continued expansion of LLIN coverage in Africa An. arabiensis is likely to remain responsible for residual malaria transmission, and species shifts might be reported over larger areas. Supplementary control measures to LLINs may be necessary to control this vector species. PMID- 22438865 TI - Identification of vascular and hematopoietic genes downstream of etsrp by deep sequencing in zebrafish. AB - The transcription factor etsrp/Er71/Etv2 is a master control gene for vasculogenesis in all species studied to date. It is also required for hematopoiesis in zebrafish and mice. Several novel genes expressed in vasculature have been identified through transcriptional profiling of zebrafish embryos overexpressing etsrp by microarrays. Here we re-examined this transcriptional profile by Illumina RNA-sequencing technology, revealing a substantially increased number of candidate genes regulated by etsrp. Expression studies of 50 selected candidate genes from this dataset resulted in the identification of 39 new genes that are expressed in vascular cells. Regulation of these genes by etsrp was confirmed by their ectopic induction in etsrp overexpressing and decreased expression in etsrp deficient embryos. Our studies demonstrate the effectiveness of the RNA-sequencing technology to identify biologically relevant genes in zebrfish and produced a comprehensive profile of genes previously unexplored in vascular endothelial cell biology. PMID- 22438866 TI - Characterization of OxyR as a negative transcriptional regulator that represses catalase production in Corynebacterium diphtheriae. AB - Corynebacterium diphtheriae and Corynebacterium glutamicum each have one gene (cat) encoding catalase. In-frame Deltacat mutants of C. diphtheriae and C. glutamicum were hyper-sensitive to growth inhibition and killing by H(2)O(2). In C. diphtheriae C7(beta), both catalase activity and cat transcription decreased ~2-fold during transition from exponential growth to early stationary phase. Prototypic OxyR in Escherichia coli senses oxidative stress and it activates katG transcription and catalase production in response to H(2)O(2). In contrast, exposure of C. diphtheriae C7(beta) to H(2)O(2) did not stimulate transcription of cat. OxyR from C. diphtheriae and C. glutamicum have 52% similarity with E. coli OxyR and contain homologs of the two cysteine residues involved in H(2)O(2) sensing by E. coli OxyR. In-frame DeltaoxyR deletion mutants of C. diphtheriae C7(beta), C. diphtheriae NCTC13129, and C. glutamicum were much more resistant than their parental wild type strains to growth inhibition by H(2)O(2). In the C. diphtheriae C7(beta) DeltaoxyR mutant, cat transcripts were about 8-fold more abundant and catalase activity was about 20-fold greater than in the C7(beta) wild type strain. The oxyR gene from C. diphtheriae or C. glutamicum, but not from E. coli, complemented the defect in DeltaoxyR mutants of C. diphtheriae and C. glutamicum and decreased their H(2)O(2) resistance to the level of their parental strains. Gel-mobility shift, DNaseI footprint, and primer extension assays showed that purified OxyR from C. diphtheriae C7(beta) bound, in the presence or absence of DTT, to a sequence in the cat promoter region that extends from nucleotide position -55 to -10 with respect to the +1 nucleotide in the cat ORF. These results demonstrate that OxyR from C. diphtheriae or C. glutamicum functions as a transcriptional repressor of the cat gene by a mechanism that is independent of oxidative stress induced by H(2)O(2). PMID- 22438867 TI - The Cryptosporidium parvum transcriptome during in vitro development. AB - Cryptosporidiosis is caused by an obligate intracellular parasite that has eluded global transcriptional or proteomic analysis of the intracellular developmental stages. The transcript abundance for 3,302 genes (87%) of the Cryptosporidium parvum protein coding genome was elucidated over a 72 hr infection within HCT8 cells using Real Time-PCR. The parasite had detectable transcription of all genes in vitro within at least one time point tested, and adjacent genes were not co regulated. Five genes were not detected within the first 24 hr of infection, one containing two AP2 domains. The fewest genes detected were at 2 hr post infection, while 30% (985) of the genes have their highest expression at 48 and/or 72 hr. Nine expression clusters were formed over the entire 72 hr time course and indicate patterns of transcriptional increases at each of the 7 time points collected except 36 hr, including genes paralleling parasite 18S rRNA transcript levels. Clustering within only the first 24 hr of infection indicates spikes in expression at each of the 4 time points, a group paralleling 18S rRNA transcript levels, and a cluster with peaks at both 6 and 24 hr. All genes were classified into 18 functional categories, which were unequally distributed across clusters. Expression of metabolic, ribosomal and proteasome proteins did not parallel 18S rRNA levels indicating distinct biochemical profiles during developmental stage progression. Proteins involved in translation are over represented at 6 hr, while structural proteins are over-represented at 12 hr. Standardization methods identified 107 genes with <80% at a single of its total expression at a single time point over 72 hr. This comprehensive transcriptome of the intracellular stages of C. parvum provides insight for understanding its complex development following parasitization of intestinal epithelial cells. PMID- 22438868 TI - Genetic divergence between freshwater and marine morphs of alewife (Alosa pseudoharengus): a 'next-generation' sequencing analysis. AB - Alewife Alosa pseudoharengus, a small clupeid fish native to Atlantic Ocean, has recently (~150 years ago) invaded the North American Great Lakes and despite challenges of freshwater environment its populations exploded and disrupted local food web structures. This range expansion has been accompanied by dramatic changes at all levels of organization. Growth rates, size at maturation, or fecundity are only a few of the most distinct morphological and life history traits that contrast the two alewife morphs. A question arises to what extent these rapidly evolving differences between marine and freshwater varieties result from regulatory (including phenotypic plasticity) or structural mutations. To gain insights into expression changes and sequence divergence between marine and freshwater alewives, we sequenced transcriptomes of individuals from Lake Michigan and Atlantic Ocean. Population specific single nucleotide polymorphisms were rare but interestingly occurred in sequences of genes that also tended to show large differences in expression. Our results show that the striking phenotypic divergence between anadromous and lake alewives can be attributed to massive regulatory modifications rather than coding changes. PMID- 22438869 TI - High diversity, low disparity and small body size in plesiosaurs (Reptilia, Sauropterygia) from the Triassic-Jurassic boundary. AB - Invasion of the open ocean by tetrapods represents a major evolutionary transition that occurred independently in cetaceans, mosasauroids, chelonioids (sea turtles), ichthyosaurs and plesiosaurs. Plesiosaurian reptiles invaded pelagic ocean environments immediately following the Late Triassic extinctions. This diversification is recorded by three intensively-sampled European fossil faunas, spanning 20 million years (Ma). These provide an unparalleled opportunity to document changes in key macroevolutionary parameters associated with secondary adaptation to pelagic life in tetrapods. A comprehensive assessment focuses on the oldest fauna, from the Blue Lias Formation of Street, and nearby localities, in Somerset, UK (Earliest Jurassic: 200 Ma), identifying three new species representing two small-bodied rhomaleosaurids (Stratesaurus taylori gen et sp. nov.; Avalonnectes arturi gen. et sp. nov) and the most basal plesiosauroid, Eoplesiosaurus antiquior gen. et sp. nov. The initial radiation of plesiosaurs was characterised by high, but short-lived, diversity of an archaic clade, Rhomaleosauridae. Representatives of this initial radiation were replaced by derived, neoplesiosaurian plesiosaurs at small-medium body sizes during a more gradual accumulation of morphological disparity. This gradualistic modality suggests that adaptive radiations within tetrapod subclades are not always characterised by the initially high levels of disparity observed in the Paleozoic origins of major metazoan body plans, or in the origin of tetrapods. High rhomaleosaurid diversity immediately following the Triassic-Jurassic boundary supports the gradual model of Late Triassic extinctions, mostly predating the boundary itself. Increase in both maximum and minimum body length early in plesiosaurian history suggests a driven evolutionary trend. However, Maximum likelihood models suggest only passive expansion into higher body size categories. PMID- 22438870 TI - Selection of reliable reference genes in Caenorhabditis elegans for analysis of nanotoxicity. AB - Despite rapid development and application of a wide range of manufactured metal oxide nanoparticles (NPs), the understanding of potential risks of using NPs is less completed, especially at the molecular level. The nematode Caenorhabditis elegans (C.elegans) has been emerging as an environmental model to study the molecular mechanism of environmental contaminations, using standard genetic tools such as the real-time quantitative PCR (RT-qPCR). The most important factor that may affect the accuracy of RT-qPCR is to choose appropriate genes for normalization. In this study, we selected 13 reference gene candidates (act-1, cdc-42, pmp-3, eif-3.C, actin, act-2, csq-1, Y45F10D.4, tba-1, mdh-1, ama-1, F35G12.2, and rbd-1) to test their expression stability under different doses of nano-copper oxide (CuO 0, 1, 10, and 50 ug/mL) using RT-qPCR. Four algorithms, geNorm, NormFinder, BestKeeper, and the comparative DeltaCt method, were employed to evaluate these 13 candidates expressions. As a result, tba-1, Y45F10D.4 and pmp-3 were the most reliable, which may be used as reference genes in future study of nanoparticle-induced genetic response using C.elegans. PMID- 22438871 TI - Identification and pathway analysis of microRNAs with no previous involvement in breast cancer. AB - microRNA expression signatures can differentiate normal and breast cancer tissues and can define specific clinico-pathological phenotypes in breast tumors. In order to further evaluate the microRNA expression profile in breast cancer, we analyzed the expression of 667 microRNAs in 29 tumors and 21 adjacent normal tissues using TaqMan Low-density arrays. 130 miRNAs showed significant differential expression (adjusted P value = 0.05, Fold Change = 2) in breast tumors compared to the normal adjacent tissue. Importantly, the role of 43 of these microRNAs has not been previously reported in breast cancer, including several evolutionary conserved microRNA*, showing similar expression rates to that of their corresponding leading strand. The expression of 14 microRNAs was replicated in an independent set of 55 tumors. Bioinformatic analysis of mRNA targets of the altered miRNAs, identified oncogenes like ERBB2, YY1, several MAP kinases, and known tumor-suppressors like FOXA1 and SMAD4. Pathway analysis identified that some biological process which are important in breast carcinogenesis are affected by the altered microRNA expression, including signaling through MAP kinases and TP53 pathways, as well as biological processes like cell death and communication, focal adhesion and ERBB2-ERBB3 signaling. Our data identified the altered expression of several microRNAs whose aberrant expression might have an important impact on cancer-related cellular pathways and whose role in breast cancer has not been previously described. PMID- 22438872 TI - Full genome sequencing and genetic characterization of Eubenangee viruses identify Pata virus as a distinct species within the genus Orbivirus. AB - Eubenangee virus has previously been identified as the cause of Tammar sudden death syndrome (TSDS). Eubenangee virus (EUBV), Tilligery virus (TILV), Pata virus (PATAV) and Ngoupe virus (NGOV) are currently all classified within the Eubenangee virus species of the genus Orbivirus, family Reoviridae. Full genome sequencing confirmed that EUBV and TILV (both of which are from Australia) show high levels of aa sequence identity (>92%) in the conserved polymerase VP1(Pol), sub-core VP3(T2) and outer core VP7(T13) proteins, and are therefore appropriately classified within the same virus species. However, they show much lower amino acid (aa) identity levels in their larger outer-capsid protein VP2 (<53%), consistent with membership of two different serotypes - EUBV-1 and EUBV-2 (respectively). In contrast PATAV showed significantly lower levels of aa sequence identity with either EUBV or TILV (with <71% in VP1(Pol) and VP3(T2), and <57% aa identity in VP7(T13)) consistent with membership of a distinct virus species. A proposal has therefore been sent to the Reoviridae Study Group of ICTV to recognise 'Pata virus' as a new Orbivirus species, with the PATAV isolate as serotype 1 (PATAV-1). Amongst the other orbiviruses, PATAV shows closest relationships to Epizootic Haemorrhagic Disease virus (EHDV), with 80.7%, 72.4% and 66.9% aa identity in VP3(T2), VP1(Pol), and VP7(T13) respectively. Although Ngoupe virus was not available for these studies, like PATAV it was isolated in Central Africa, and therefore seems likely to also belong to the new species, possibly as a distinct 'type'. The data presented will facilitate diagnostic assay design and the identification of additional isolates of these viruses. PMID- 22438873 TI - A coupled discrete/continuum model for describing cancer-therapeutic transport in the lung. AB - We propose a computational simulation framework for describing cancer-therapeutic transport in the lung. A discrete vascular graph model (VGM) is coupled to a double-continuum model (DCM) to determine the amount of administered therapeutic agent that will reach the cancer cells. An alveolar cell carcinoma is considered. The processes in the bigger blood vessels (arteries, arterioles, venules and veins) are described by the VGM. The processes in the alveolar capillaries and the surrounding tissue are represented by a continuum approach for porous media. The system of equations of the coupled discrete/continuum model contains terms that account for degradation processes of the therapeutic agent, the reduction of the number of drug molecules by the lymphatic system and the interaction of the drug with the tissue cells. The functionality of the coupled discrete/continuum model is demonstrated in example simulations using simplified pulmonary vascular networks, which are designed to show-off the capabilities of the model rather than being physiologically accurate. PMID- 22438874 TI - Combining nitrous oxide with carbon dioxide decreases the time to loss of consciousness during euthanasia in mice--refinement of animal welfare? AB - Carbon dioxide (CO(2)) is the most commonly used euthanasia agent for rodents despite potentially causing pain and distress. Nitrous oxide is used in man to speed induction of anaesthesia with volatile anaesthetics, via a mechanism referred to as the "second gas" effect. We therefore evaluated the addition of Nitrous Oxide (N(2)O) to a rising CO(2) concentration could be used as a welfare refinement of the euthanasia process in mice, by shortening the duration of conscious exposure to CO2. Firstly, to assess the effect of N(2)O on the induction of anaesthesia in mice, 12 female C57Bl/6 mice were anaesthetized in a crossover protocol with the following combinations: Isoflurane (5%)+O(2) (95%); Isoflurane (5%)+N(2)O (75%)+O(2) (25%) and N(2)O (75%)+O(2) (25%) with a total flow rate of 3 l/min (into a 7 l induction chamber). The addition of N(2)O to isoflurane reduced the time to loss of the righting reflex by 17.6%. Secondly, 18 C57Bl/6 and 18 CD1 mice were individually euthanized by gradually filling the induction chamber with either: CO(2) (20% of the chamber volume.min-1); CO(2)+N(2)O (20 and 60% of the chamber volume.min(-1) respectively); or CO(2)+Nitrogen (N(2)) (20 and 60% of the chamber volume.min-1). Arterial partial pressure (P(a)) of O(2) and CO(2) were measured as well as blood pH and lactate. When compared to the gradually rising CO(2) euthanasia, addition of a high concentration of N(2)O to CO(2) lowered the time to loss of righting reflex by 10.3% (P<0.001), lead to a lower P(a)O(2) (12.55 +/- 3.67 mmHg, P<0.001), a higher lactataemia (4.64 +/- 1.04 mmol.l(-1), P = 0.026), without any behaviour indicative of distress. Nitrous oxide reduces the time of conscious exposure to gradually rising CO(2) during euthanasia and hence may reduce the duration of any stress or distress to which mice are exposed during euthanasia. PMID- 22438875 TI - The MPI facial expression database--a validated database of emotional and conversational facial expressions. AB - The ability to communicate is one of the core aspects of human life. For this, we use not only verbal but also nonverbal signals of remarkable complexity. Among the latter, facial expressions belong to the most important information channels. Despite the large variety of facial expressions we use in daily life, research on facial expressions has so far mostly focused on the emotional aspect. Consequently, most databases of facial expressions available to the research community also include only emotional expressions, neglecting the largely unexplored aspect of conversational expressions. To fill this gap, we present the MPI facial expression database, which contains a large variety of natural emotional and conversational expressions. The database contains 55 different facial expressions performed by 19 German participants. Expressions were elicited with the help of a method-acting protocol, which guarantees both well-defined and natural facial expressions. The method-acting protocol was based on every-day scenarios, which are used to define the necessary context information for each expression. All facial expressions are available in three repetitions, in two intensities, as well as from three different camera angles. A detailed frame annotation is provided, from which a dynamic and a static version of the database have been created. In addition to describing the database in detail, we also present the results of an experiment with two conditions that serve to validate the context scenarios as well as the naturalness and recognizability of the video sequences. Our results provide clear evidence that conversational expressions can be recognized surprisingly well from visual information alone. The MPI facial expression database will enable researchers from different research fields (including the perceptual and cognitive sciences, but also affective computing, as well as computer vision) to investigate the processing of a wider range of natural facial expressions. PMID- 22438876 TI - Oligomeric status and nucleotide binding properties of the plastid ATP/ADP transporter 1: toward a molecular understanding of the transport mechanism. AB - BACKGROUND: Chloroplast ATP/ADP transporters are essential to energy homeostasis in plant cells. However, their molecular mechanism remains poorly understood, primarily due to the difficulty of producing and purifying functional recombinant forms of these transporters. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we describe an expression and purification protocol providing good yields and efficient solubilization of NTT1 protein from Arabidopsis thaliana. By biochemical and biophysical analyses, we identified the best detergent for solubilization and purification of functional proteins, LAPAO. Purified NTT1 was found to accumulate as two independent pools of well folded, stable monomers and dimers. ATP and ADP binding properties were determined, and Pi, a co-substrate of ADP, was confirmed to be essential for nucleotide steady-state transport. Nucleotide binding studies and analysis of NTT1 mutants lead us to suggest the existence of two distinct and probably inter-dependent binding sites. Finally, fusion and deletion experiments demonstrated that the C-terminus of NTT1 is not essential for multimerization, but probably plays a regulatory role, controlling the nucleotide exchange rate. CONCLUSIONS/SIGNIFICANCE: Taken together, these data provide a comprehensive molecular characterization of a chloroplast ATP/ADP transporter. PMID- 22438877 TI - A novel dynamic impact approach (DIA) for functional analysis of time-course omics studies: validation using the bovine mammary transcriptome. AB - The overrepresented approach (ORA) is the most widely-accepted method for functional analysis of microarray datasets. The ORA is computationally-efficient and robust; however, it suffers from the inability of comparing results from multiple gene lists particularly with time-course experiments or those involving multiple treatments. To overcome such limitation a novel method termed Dynamic Impact Approach (DIA) is proposed. The DIA provides an estimate of the biological impact of the experimental conditions and the direction of the impact. The impact is obtained by combining the proportion of differentially expressed genes (DEG) with the log2 mean fold change and mean -log P-value of genes associated with the biological term. The direction of the impact is calculated as the difference of the impact of up-regulated DEG and down-regulated DEG associated with the biological term. The DIA was validated using microarray data from a time-course experiment of bovine mammary gland across the lactation cycle. Several annotation databases were analyzed with DIA and compared to the same analysis performed by the ORA. The DIA highlighted that during lactation both BTA6 and BTA14 were the most impacted chromosomes; among Uniprot tissues those related with lactating mammary gland were the most positively-impacted; within KEGG pathways 'Galactose metabolism' and several metabolism categories related to lipid synthesis were among the most impacted and induced; within Gene Ontology "lactose biosynthesis" among Biological processes and "Lactose synthase activity" and "Stearoyl-CoA 9 desaturase activity" among Molecular processes were the most impacted and induced. With the exception of the terms 'Milk', 'Milk protein' and 'Mammary gland' among Uniprot tissues and SP_PIR_Keyword, the use of ORA failed to capture as significantly-enriched (i.e., biologically relevant) any term known to be associated with lactating mammary gland. Results indicate the DIA is a biologically-sound approach for analysis of time-course experiments. This tool represents an alternative to ORA for functional analysis. PMID- 22438878 TI - When two become one: the limits of causality analysis of brain dynamics. AB - Biological systems often consist of multiple interacting subsystems, the brain being a prominent example. To understand the functions of such systems it is important to analyze if and how the subsystems interact and to describe the effect of these interactions. In this work we investigate the extent to which the cause-and-effect framework is applicable to such interacting subsystems. We base our work on a standard notion of causal effects and define a new concept called natural causal effect. This new concept takes into account that when studying interactions in biological systems, one is often not interested in the effect of perturbations that alter the dynamics. The interest is instead in how the causal connections participate in the generation of the observed natural dynamics. We identify the constraints on the structure of the causal connections that determine the existence of natural causal effects. In particular, we show that the influence of the causal connections on the natural dynamics of the system often cannot be analyzed in terms of the causal effect of one subsystem on another. Only when the causing subsystem is autonomous with respect to the rest can this interpretation be made. We note that subsystems in the brain are often bidirectionally connected, which means that interactions rarely should be quantified in terms of cause-and-effect. We furthermore introduce a framework for how natural causal effects can be characterized when they exist. Our work also has important consequences for the interpretation of other approaches commonly applied to study causality in the brain. Specifically, we discuss how the notion of natural causal effects can be combined with Granger causality and Dynamic Causal Modeling (DCM). Our results are generic and the concept of natural causal effects is relevant in all areas where the effects of interactions between subsystems are of interest. PMID- 22438879 TI - Ethnic differences in tissue creatine kinase activity: an observational study. AB - BACKGROUND: Serum creatine kinase (CK) levels are reported to be around 70% higher in healthy black people, as compared to white people (median value 88 IU/L in white vs 149 IU/L in black people). As serum CK in healthy people is thought to occur from a proportional leak from normal tissues, we hypothesized that the black population subgroup has a generalized higher CK activity in tissues. METHODOLOGY/PRINCIPAL FINDINGS: We compared CK activity spectrophotometrically in tissues with high and fluctuating energy demands including cerebrum, cerebellum, heart, renal artery, and skeletal muscle, obtained post-mortem in black and white men. Based on serum values, we conservatively estimated to find a 50% greater CK activity in black people compared with white people, and calculated a need for 10 subjects of one gender in each group to detect this difference. We used mixed linear regression models to assess the possible influence of ethnicity on CK activity in different tissues, with ethnicity as a fixed categorical subject factor, and CK of different tissues clustered within one person as the repeated effect response variable. We collected post-mortem tissue samples from 17 white and 10 black males, mean age 62 y (SE 4). Mean tissue CK activity was 76% higher in tissues from black people (estimated marginal means 107.2 [95% CI, 76.7 to 137.7] mU/mg protein in white, versus 188.6 [148.8 to 228.4] in black people, p = 0.002). CONCLUSION: We found evidence that black people have higher CK activity in all tissues with high and fluctuating energy demands studied. This finding may help explain the higher serum CK levels found in this population subgroup. Furthermore, our data imply that there are differences in CK-dependent ATP buffer capacity in tissue between the black and the white population subgroup, which may become apparent with high energy demands. PMID- 22438880 TI - Direct matrix-assisted laser desorption ionization time-of-flight mass spectrometry improves appropriateness of antibiotic treatment of bacteremia. AB - Matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) allows the identification of microorganisms directly from positive blood culture broths. Use of the MALDI-TOF MS for rapid identification of microorganisms from blood culture broths can reduce the turnaround time to identification and may lead to earlier appropriate treatment of bacteremia. During February and April 2010, direct MALDI-TOF MS was routinely performed on all positive blood cultures. During December 2009 and March 2010 no direct MALDI TOF MS was used. Information on antibiotic therapy was collected from the hospital and intensive care units' information systems from all positive blood cultures during the study period. In total, 253 episodes of bacteremia were included of which 89 during the intervention period and 164 during the control period. Direct performance of MALDI-TOF MS on positive blood culture broths reduced the time till species identification by 28.8-h and was associated with an 11.3% increase in the proportion of patients receiving appropriate antibiotic treatment 24 hours after blood culture positivity (64.0% in the control period versus 75.3% in the intervention period (p0.01)). Routine implementation of this technique increased the proportion of patients on adequate antimicrobial treatment within 24 hours. PMID- 22438881 TI - Increased migration of monocytes in essential hypertension is associated with increased transient receptor potential channel canonical type 3 channels. AB - Increased transient receptor potential canonical type 3 (TRPC3) channels have been observed in patients with essential hypertension. In the present study we tested the hypothesis that increased monocyte migration is associated with increased TRPC3 expression. Monocyte migration assay was performed in a microchemotaxis chamber using chemoattractants formylated peptide Met-Leu-Phe (fMLP) and tumor necrosis factor-alpha (TNF-alpha). Proteins were identified by immunoblotting and quantitative in-cell Western assay. The effects of TRP channel inhibitor 2-aminoethoxydiphenylborane (2-APB) and small interfering RNA knockdown of TRPC3 were investigated. We observed an increased fMLP-induced migration of monocytes from hypertensive patients compared with normotensive control subjects (246 +/- 14% vs 151 +/- 10%). The TNF-alpha-induced migration of monocytes in patients with essential hypertension was also significantly increased compared to normotensive control subjects (221 +/- 20% vs 138 +/- 18%). In the presence of 2 APB or after siRNA knockdown of TRPC3 the fMLP-induced monocyte migration was significantly blocked. The fMLP-induced changes of cytosolic calcium were significantly increased in monocytes from hypertensive patients compared to normotensive control subjects. The fMLP-induced monocyte migration was significantly reduced in the presence of inhibitors of tyrosine kinase and phosphoinositide 3-kinase. We conclude that increased monocyte migration in patients with essential hypertension is associated with increased TRPC3 channels. PMID- 22438882 TI - The 3' untranslated regions of influenza genomic sequences are 5'PPP-independent ligands for RIG-I. AB - Retinoic acid inducible gene-I (RIG-I) is a key regulator of antiviral immunity. RIG-I is generally thought to be activated by ssRNA species containing a 5' triphosphate (PPP) group or by unphosphorylated dsRNA up to ~300 bp in length. However, it is not yet clear how changes in the length, nucleotide sequence, secondary structure, and 5' end modification affect the abilities of these ligands to bind and activate RIG-I. To further investigate these parameters in the context of naturally occurring ligands, we examined RNA sequences derived from the 5' and 3' untranslated regions (UTR) of the influenza virus NS1 gene segment. As expected, RIG-I-dependent interferon-beta (IFN-beta) induction by sequences from the 5' UTR of the influenza cRNA or its complement (26 nt in length) required the presence of a 5'PPP group. In contrast, activation of RIG-I by the 3' UTR cRNA sequence or its complement (172 nt) exhibited only a partial 5'PPP-dependence, as capping the 5' end or treatment with CIP showed a modest reduction in RIG-I activation. Furthermore, induction of IFN-beta by a smaller, U/A-rich region within the 3' UTR was completely 5'PPP-independent. Our findings demonstrated that RNA sequence, length, and secondary structure all contributed to whether or not the 5'PPP moiety is needed for interferon induction by RIG-I. PMID- 22438883 TI - Integrated sequence-structure motifs suffice to identify microRNA precursors. AB - BACKGROUND: Upwards of 1200 miRNA loci have hitherto been annotated in the human genome. The specific features defining a miRNA precursor and deciding its recognition and subsequent processing are not yet exhaustively described and miRNA loci can thus not be computationally identified with sufficient confidence. RESULTS: We rendered pre-miRNA and non-pre-miRNA hairpins as strings of integrated sequence-structure information, and used the software Teiresias to identify sequence-structure motifs (ss-motifs) of variable length in these data sets. Using only ss-motifs as features in a Support Vector Machine (SVM) algorithm for pre-miRNA identification achieved 99.2% specificity and 97.6% sensitivity on a human test data set, which is comparable to previously published algorithms employing combinations of sequence-structure and additional features. Further analysis of the ss-motif information contents revealed strongly significant deviations from those of the respective training sets, revealing important potential clues as to how the sequence and structural information of RNA hairpins are utilized by the miRNA processing apparatus. CONCLUSION: Integrated sequence-structure motifs of variable length apparently capture nearly all information required to distinguish miRNA precursors from other stem-loop structures. PMID- 22438884 TI - African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three U.S. population cohorts. AB - The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13-1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6 * 10(-6)). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk. PMID- 22438885 TI - Identification of XMRV infection-associated microRNAs in four cell types in culture. AB - INTRODUCTION: XMRV is a gammaretrovirus that was thought to be associated with prostate cancer (PC) and chronic fatigue syndrome (CFS) in humans until recently. The virus is culturable in various cells of human origin like the lymphocytes, NK cells, neuronal cells, and prostate cell lines. MicroRNAs (miRNA), which regulate gene expression, were so far not identified in cells infected with XMRV in culture. METHODS: Two prostate cell lines (LNCaP and DU145) and two primary cells, Peripheral Blood Lymphocytes [PBL] and Monocyte-derived Macrophages [MDM] were infected with XMRV. Total mRNA was extracted from mock- and virus-infected cells at 6, 24 and 48 hours post infection and evaluated for microRNA profile in a microarray. RESULTS: MicroRNA expression profiles of XMRV-infected continuous prostate cancer cell lines differ from that of virus-infected primary cells (PBL and MDMs). miR-193a-3p and miRPlus-E1245 observed to be specific to XMRV infection in all 4 cell types. While miR-193a-3p levels were down regulated miRPlus-E1245 on the other hand exhibited varied expression profile between the 4 cell types. DISCUSSION: The present study clearly demonstrates that cellular microRNAs are expressed during XMRV infection of human cells and this is the first report demonstrating the regulation of miR193a-3p and miRPlus-E1245 during XMRV infection in four different human cell types. PMID- 22438886 TI - Melt analysis of mismatch amplification mutation assays (Melt-MAMA): a functional study of a cost-effective SNP genotyping assay in bacterial models. AB - Single nucleotide polymorphisms (SNPs) are abundant in genomes of all species and biologically informative markers extensively used across broad scientific disciplines. Newly identified SNP markers are publicly available at an ever increasing rate due to advancements in sequencing technologies. Efficient, cost effective SNP genotyping methods to screen sample populations are in great demand in well-equipped laboratories, but also in developing world situations. Dual Probe TaqMan assays are robust but can be cost-prohibitive and require specialized equipment. The Mismatch Amplification Mutation Assay, coupled with melt analysis (Melt-MAMA), is flexible, efficient and cost-effective. However, Melt-MAMA traditionally suffers from high rates of assay design failures and knowledge gaps on assay robustness and sensitivity. In this study, we identified strategies that improved the success of Melt-MAMA. We examined the performance of 185 Melt-MAMAs across eight different pathogens using various optimization parameters. We evaluated the effects of genome size and %GC content on assay development. When used collectively, specific strategies markedly improved the rate of successful assays at the first design attempt from ~50% to ~80%. We observed that Melt-MAMA accurately genotypes across a broad DNA range (~100 ng to ~0.1 pg). Genomic size and %GC content influence the rate of successful assay design in an independent manner. Finally, we demonstrated the versatility of these assays by the creation of a duplex Melt-MAMA real-time PCR (two SNPs) and conversion to a size-based genotyping system, which uses agarose gel electrophoresis. Melt-MAMA is comparable to Dual Probe TaqMan assays in terms of design success rate and accuracy. Although sensitivity is less robust than Dual Probe TaqMan assays, Melt-MAMA is superior in terms of cost-effectiveness, speed of development and versatility. We detail the parameters most important for the successful application of Melt-MAMA, which should prove useful to the wider scientific community. PMID- 22438887 TI - Amiloride enhances antigen specific CTL by faciliting HBV DNA vaccine entry into cells. AB - The induction of relatively weak immunity by DNA vaccines in humans can be largely attributed to the low efficiency of transduction of somatic cells. Although formulation with liposomes has been shown to enhance DNA transduction of cultured cells, little, if any, effect is observed on the transduction of somatic tissues and cells. To improve the rate of transduction, DNA vaccine delivery by gene gun and the recently developed electroporation techniques have been employed. We report here that to circumvent requirement for such equipment, amiloride, a drug that is prescribed for hypertension treatment, can accelerate plasmid entry into antigen presenting cells (APCs) both in vitro and in vivo. The combination induced APCs more dramatically in both maturation and cytokine secretion. Amiloride enhanced development of full CD8 cytolytic function including induction of high levels of antigen specific CTL and expression of IFN gamma+perforin+granzymeB+ in CD8+ T cells. Thus, amiloride is a facilitator for DNA transduction into host cells which in turn enhances the efficiency of the immune responses. PMID- 22438888 TI - Neuropathological similarities and differences between schizophrenia and bipolar disorder: a flow cytometric postmortem brain study. AB - Recent studies suggest that schizophrenia (SCH) and bipolar disorder (BPD) may share a similar etiopathology. However, their precise neuropathological natures have rarely been characterized in a comprehensive and quantitative fashion. We have recently developed a rapid, quantitative cell-counting method for frozen unfixed postmortem brains using a flow cytometer. In the present study, we not only counted stained nuclei, but also measured their sizes in the gray matter of frontopolar cortices (FPCs) and inferior temporal cortices (ITCs) from patients with SCH or BPD, as well as in that from normal controls. In terms of NeuN(+) neuronal nuclei size, particularly in the reduced densities of small NeuN(+) nuclei, we found abnormal distributions present in the ITC gray matter of both patient groups. These same abnormalities were also found in the FPCs of SCH patients, whereas in the FPCs of BPD patients, a reduction in oligodendrocyte lineage (olig2(+)) cells was much more common. Surprisingly, in the SCH FPC, normal left-greater-than-right asymmetry in neural nuclei densities was almost completely reversed. In the BPD FPC, this asymmetry, though not obvious, differed significantly from that in the SCH FPC. These findings indicate that while similar neuropathological abnormalities are shared by patients with SCH or BPD, differences also exist, mainly in the FPC, which may at least partially explain the differences observed in many aspects in these disorders. PMID- 22438889 TI - Gene expression profiling in gastric mucosa from Helicobacter pylori-infected and uninfected patients undergoing chronic superficial gastritis. AB - Helicobacter pylori infection reprograms host gene expression and influences various cellular processes, which have been investigated by cDNA microarray using in vitro culture cells and in vivo gastric biopsies from patients of the Chronic Abdominal Complaint. To further explore the effects of H. pylori infection on host gene expression, we have collected the gastric antral mucosa samples from 6 untreated patients with gastroscopic and pathologic confirmation of chronic superficial gastritis. Among them three patients were infected by H. pylori and the other three patients were not. These samples were analyzed by a microarray chip which contains 14,112 cloned cDNAs, and microarray data were analyzed via BRB ArrayTools software and Ingenuity Pathways Analysis (IPA) website. The results showed 34 genes of 38 differentially expressed genes regulated by H. pylori infection had been annotated. The annotated genes were involved in protein metabolism, inflammatory and immunological reaction, signal transduction, gene transcription, trace element metabolism, and so on. The 82% of these genes (28/34) were categorized in three molecular interaction networks involved in gene expression, cancer progress, antigen presentation and inflammatory response. The expression data of the array hybridization was confirmed by quantitative real time PCR assays. Taken together, these data indicated that H. pylori infection could alter cellular gene expression processes, escape host defense mechanism, increase inflammatory and immune responses, activate NF-kappaB and Wnt/beta catenin signaling pathway, disturb metal ion homeostasis, and induce carcinogenesis. All of these might help to explain H. pylori pathogenic mechanism and the gastroduodenal pathogenesis induced by H. pylori infection. PMID- 22438890 TI - Plant diversity changes during the postglacial in East Asia: insights from Forest Refugia on Halla Volcano, Jeju Island. AB - Understanding how past climate changes affected biodiversity is a key issue in contemporary ecology and conservation biology. These diversity changes are, however, difficult to reconstruct from paleoecological sources alone, because macrofossil and pollen records do not provide complete information about species assemblages. Ecologists therefore use information from modern analogues of past communities in order to get a better understanding of past diversity changes. Here we compare plant diversity, species traits and environment between late glacial Abies, early-Holocene Quercus, and mid-Holocene warm-temperate Carpinus forest refugia on Jeju Island, Korea in order to provide insights into postglacial changes associated with their replacement. Based on detailed study of relict communities, we propose that the late-glacial open-canopy conifer forests in southern part of Korean Peninsula were rich in vascular plants, in particular of heliophilous herbs, whose dramatic decline was caused by the early Holocene invasion of dwarf bamboo into the understory of Quercus forests, followed by mid Holocene expansion of strongly shading trees such as maple and hornbeam. This diversity loss was partly compensated in the Carpinus forests by an increase in shade-tolerant evergreen trees, shrubs and lianas. However, the pool of these species is much smaller than that of light-demanding herbs, and hence the total species richness is lower, both locally and in the whole area of the Carpinus and Quercus forests. The strongly shading tree species dominating in the hornbeam forests have higher leaf tissue N and P concentrations and smaller leaf dry matter content, which enhances litter decomposition and nutrient cycling and in turn favored the selection of highly competitive species in the shrub layer. This further reduced available light and caused almost complete disappearance of understory herbs, including dwarf bamboo. PMID- 22438891 TI - Maize (Zea mays L.) genome diversity as revealed by RNA-sequencing. AB - Maize is rich in genetic and phenotypic diversity. Understanding the sequence, structural, and expression variation that contributes to phenotypic diversity would facilitate more efficient varietal improvement. RNA based sequencing (RNA seq) is a powerful approach for transcriptional analysis, assessing sequence variation, and identifying novel transcript sequences, particularly in large, complex, repetitive genomes such as maize. In this study, we sequenced RNA from whole seedlings of 21 maize inbred lines representing diverse North American and exotic germplasm. Single nucleotide polymorphism (SNP) detection identified 351,710 polymorphic loci distributed throughout the genome covering 22,830 annotated genes. Tight clustering of two distinct heterotic groups and exotic lines was evident using these SNPs as genetic markers. Transcript abundance analysis revealed minimal variation in the total number of genes expressed across these 21 lines (57.1% to 66.0%). However, the transcribed gene set among the 21 lines varied, with 48.7% expressed in all of the lines, 27.9% expressed in one to 20 lines, and 23.4% expressed in none of the lines. De novo assembly of RNA-seq reads that did not map to the reference B73 genome sequence revealed 1,321 high confidence novel transcripts, of which, 564 loci were present in all 21 lines, including B73, and 757 loci were restricted to a subset of the lines. RT-PCR validation demonstrated 87.5% concordance with the computational prediction of these expressed novel transcripts. Intriguingly, 145 of the novel de novo assembled loci were present in lines from only one of the two heterotic groups consistent with the hypothesis that, in addition to sequence polymorphisms and transcript abundance, transcript presence/absence variation is present and, thereby, may be a mechanism contributing to the genetic basis of heterosis. PMID- 22438892 TI - Incremental effects of endocrine and metabolic biomarkers and abdominal obesity on cardiovascular mortality prediction. AB - BACKGROUND: Biomarkers may help clinicians predict cardiovascular risk. We aimed to determine if the addition of endocrine, metabolic, and obesity-associated biomarkers to conventional risk factors improves the prediction of cardiovascular and all-cause mortality. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based cohort study (the Study of Health in Pomerania) of 3,967 subjects (age 20-80 years) free of cardiovascular disease with a median follow-up of 10.0 years (38,638 person-years), we assessed the predictive value of conventional cardiovascular risk factors and the biomarkers thyrotropin; testosterone (in men only); insulin-like growth factor-1 (IGF-1); hemoglobin A1c (HbA1c); creatinine; high-sensitive C-reactive protein (hsCRP); fibrinogen; urinary albumin-to creatinine ratio; and waist-to-height ratio (WHtR) on cardiovascular and all cause death. During follow-up, we observed 339 all-cause including 103 cardiovascular deaths. In Cox regression models with conventional risk factors, the following biomarkers were retained as significant predictors of cardiovascular death after backward elimination: HbA1c, IGF-1, and hsCRP. IGF-1 and hsCRP were retained as significant predictors of all-cause death. For cardiovascular death, adding these biomarkers to the conventional risk factors changed the C-statistic from 0.898 to 0.910 (p = 0.02). The net reclassification improvement was 10.6%. For all-cause death, the C-statistic changed from 0.849 to 0.853 (P = 0.09). CONCLUSIONS/SIGNIFICANCE: HbA1c, IGF-1, and hsCRP predict cardiovascular death independently of conventional cardiovascular risk factors. These easily assessed endocrine and metabolic biomarkers might improve the ability to predict cardiovascular death. PMID- 22438893 TI - Global analysis of dynamical decision-making models through local computation around the hidden saddle. AB - Bistable dynamical switches are frequently encountered in mathematical modeling of biological systems because binary decisions are at the core of many cellular processes. Bistable switches present two stable steady-states, each of them corresponding to a distinct decision. In response to a transient signal, the system can flip back and forth between these two stable steady-states, switching between both decisions. Understanding which parameters and states affect this switch between stable states may shed light on the mechanisms underlying the decision-making process. Yet, answering such a question involves analyzing the global dynamical (i.e., transient) behavior of a nonlinear, possibly high dimensional model. In this paper, we show how a local analysis at a particular equilibrium point of bistable systems is highly relevant to understand the global properties of the switching system. The local analysis is performed at the saddle point, an often disregarded equilibrium point of bistable models but which is shown to be a key ruler of the decision-making process. Results are illustrated on three previously published models of biological switches: two models of apoptosis, the programmed cell death and one model of long-term potentiation, a phenomenon underlying synaptic plasticity. PMID- 22438894 TI - 'Visual' acuity of the congenitally blind using visual-to-auditory sensory substitution. AB - Sensory Substitution Devices (SSDs) convey visual information through sounds or touch, thus theoretically enabling a form of visual rehabilitation in the blind. However, for clinical use, these devices must provide fine-detailed visual information which was not yet shown for this or other means of visual restoration. To test the possible functional acuity conveyed by such devices, we used the Snellen acuity test conveyed through a high-resolution visual-to auditory SSD (The vOICe). We show that congenitally fully blind adults can exceed the World Health Organization (WHO) blindness acuity threshold using SSDs, reaching the highest acuity reported yet with any visual rehabilitation approach. This demonstrates the potential capacity of SSDs as inexpensive, non-invasive visual rehabilitation aids, alone or when supplementing visual prostheses. PMID- 22438895 TI - A unique modification of the eukaryotic initiation factor 5A shows the presence of the complete hypusine pathway in Leishmania donovani. AB - Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post translational synthesis of an unusual amino acid hypusine (N(?)-(4-amino-2 hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5A (eIF5A). We present here the molecular and structural basis of the function of DOHH from the protozoan parasite, Leishmania donovani, which causes visceral leishmaniasis. The L. donovani DOHH gene is 981 bp and encodes a putative polypeptide of 326 amino acids. DOHH is a HEAT-repeat protein with eight tandem repeats of alpha-helical pairs. Four conserved histidine-glutamate sequences have been identified that may act as metal coordination sites. A ~42 kDa recombinant protein with a His-tag was obtained by heterologous expression of DOHH in Escherichia coli. Purified recombinant DOHH effectively catalyzed the hydroxylation of the intermediate, eIF5A-deoxyhypusine (eIF5A-Dhp), in vitro. L. donovani DOHH (LdDOHH) showed ~40.6% sequence identity with its human homolog. The alignment of L. donovani DOHH with the human homolog shows that there are two significant insertions in the former, corresponding to the alignment positions 159-162 (four amino acid residues) and 174-183 (ten amino acid residues) which are present in the variable loop connecting the N- and C-terminal halves of the protein, the latter being present near the substrate binding site. Deletion of the ten-amino-acid-long insertion decreased LdDOHH activity to 14% of the wild type recombinant LdDOHH. Metal chelators like ciclopirox olamine (CPX) and mimosine significantly inhibited the growth of L. donovani and DOHH activity in vitro. These inhibitors were more effective against the parasite enzyme than the human enzyme. This report, for the first time, confirms the presence of a complete hypusine pathway in a kinetoplastid unlike eubacteria and archaea. The structural differences between the L. donovani DOHH and the human homolog may be exploited for structure based design of selective inhibitors against the parasite. PMID- 22438896 TI - Bone turnover in wild type and pleiotrophin-transgenic mice housed for three months in the International Space Station (ISS). AB - Bone is a complex dynamic tissue undergoing a continuous remodeling process. Gravity is a physical force playing a role in the remodeling and contributing to the maintenance of bone integrity. This article reports an investigation on the alterations of the bone microarchitecture that occurred in wild type (Wt) and pleiotrophin-transgenic (PTN-Tg) mice exposed to a near-zero gravity on the International Space Station (ISS) during the Mice Drawer System (MDS) mission, to date, the longest mice permanence (91 days) in space. The transgenic mouse strain over-expressing pleiotrophin (PTN) in bone was selected because of the PTN positive effects on bone turnover. Wt and PTN-Tg control animals were maintained on Earth either in a MDS payload or in a standard vivarium cage. This study revealed a bone loss during spaceflight in the weight-bearing bones of both strains. For both Tg and Wt a decrease of the trabecular number as well as an increase of the mean trabecular separation was observed after flight, whereas trabecular thickness did not show any significant change. Non weight-bearing bones were not affected. The PTN-Tg mice exposed to normal gravity presented a poorer trabecular organization than Wt mice, but interestingly, the expression of the PTN transgene during the flight resulted in some protection against microgravity's negative effects. Moreover, osteocytes of the Wt mice, but not of Tg mice, acquired a round shape, thus showing for the first time osteocyte space related morphological alterations in vivo. The analysis of specific bone formation and resorption marker expression suggested that the microgravity induced bone loss was due to both an increased bone resorption and a decreased bone deposition. Apparently, the PTN transgene protection was the result of a higher osteoblast activity in the flight mice. PMID- 22438898 TI - Preimaginal stages of the emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae): an invasive pest on ash trees (Fraxinus). AB - This study provides the most detailed description of the immature stages of Agrilus planipennis Fairmaire to date and illustrates suites of larval characters useful in distinguishing among Agrilus Curtis species and instars. Immature stages of eight species of Agrilus were examined and imaged using light and scanning electron microscopy. For A. planipennis all preimaginal stages (egg, instars I-IV, prepupa and pupa) were described. A combination of 14 character states were identified that serve to identify larvae of A. planipennis. Our results support the segregation of Agrilus larvae into two informal assemblages based on characters of the mouthparts, prothorax, and abdomen: the A. viridis and A. ater assemblages, with A. planipennis being more similar to the former. Additional evidence is provided in favor of excluding A. planipennis from the subgenus Uragrilus. PMID- 22438897 TI - The role of host genetics in susceptibility to influenza: a systematic review. AB - BACKGROUND: The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380). METHODS AND FINDINGS: PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven. CONCLUSION: The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies. PMID- 22438899 TI - Concomitant active tuberculosis prolongs survival in non-small cell lung cancer: a study in a tuberculosis-endemic country. AB - BACKGROUND: Adjuvant tumor cell vaccine with chemotherapy against non-small cell lung cancer (NSCLC) shows limited clinical response. Whether it provokes effective cellular immunity in tumor microenvironment is questionable. Concomitant active tuberculosis in NSCLC (TBLC) resembles locoregional immunotherapy of tumor cell vaccine; thus, maximally enriches effective anti tumor immunity. This study compares the survival and immunological cell profile in TBLC over NSCLC alone. METHODS: Retrospective review of NSCLC patients within 1-year-period of 2007 and follow-up till 2010. RESULTS: A total 276 NSCLC patients were included. The median survival of TBLC is longer than those of NSCLC alone (11.6 vs. 8.8 month, p<0.01). Active tuberculosis is an independent predictor of better survival with HR of 0.68 (95% CI, 0.48 ~ 0.97). Squamous cell carcinoma (SCC) (55.8 vs. 31.7%, p<0.01) is a significant risk factor for NSCLC with active TB. The median survival of SCC with active tuberculosis is significantly longer than adenocarcinoma or undetermined NSCLC with TB (14.2 vs. 6.6 and 2.8 months, p<0.05). Active tuberculosis in SCC increases the expression of CD3 (46.4 +/- 24.8 vs. 24.0 +/- 16.0, p<0.05), CXCR3 (35.1 +/- 16.4 vs. 19.2 +/- 13.3, p<0.01) and IP-10 (63.5 +/- 21.9 vs. 35.5 +/- 21.0, p<0.01), while expression of FOXP3 is decreased (3.5 +/- 0.5 vs. 13.3 +/- 3.7 p<0.05, p<0.05). Survival of SCC with high expression of CD3 (12.1 vs. 3.6 month, p<0.05) and CXCR3 (12.1 vs. 4.4 month, p<0.05) is longer than that with low expression. CONCLUSIONS: Active tuberculosis in NSCLC shows better survival outcome. The effective T lymphocyte infiltration in tumor possibly underlies the mechanism. Locoregional immunotherapy of tumor cell vaccine may deserve further researches. PMID- 22438900 TI - Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions--a meta-analysis. AB - BACKGROUND: Numerous observational studies suggest that preventable adverse drug reactions are a significant burden in healthcare, but no meta-analysis using a standardised definition for adverse drug reactions exists. The aim of the study was to estimate the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions in adult outpatients and inpatients. METHODS: Studies were identified through searching Cochrane, CINAHL, EMBASE, IPA, Medline, PsycINFO and Web of Science in September 2010, and by hand searching the reference lists of identified papers. Original peer reviewed research articles in English that defined adverse drug reactions according to WHO's or similar definition and assessed preventability were included. Disease or treatment specific studies were excluded. Meta-analysis on the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions was conducted. RESULTS: Data were analysed from 16 original studies on outpatients with 48797 emergency visits or hospital admissions and from 8 studies involving 24128 inpatients. No studies in primary care were identified. Among adult outpatients, 2.0% (95% confidence interval (CI): 1.2-3.2%) had preventable adverse drug reactions and 52% (95% CI: 42-62%) of adverse drug reactions were preventable. Among inpatients, 1.6% (95% CI: 0.1-51%) had preventable adverse drug reactions and 45% (95% CI: 33-58%) of adverse drug reactions were preventable. CONCLUSIONS: This meta-analysis corroborates that preventable adverse drug reactions are a significant burden to healthcare among adult outpatients. Among both outpatients and inpatients, approximately half of adverse drug reactions are preventable, demonstrating that further evidence on prevention strategies is required. The percentage of patients with preventable adverse drug reactions among inpatients and in primary care is largely unknown and should be investigated in future research. PMID- 22438901 TI - MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo. AB - PURPOSE: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or "wet" Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. METHODS: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with "wet" AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8(+/-) mice expressing beta-galactosidase. Aged Mfge8(+/-) and Mfge8(-/-) mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser induced CNV. RESULTS: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8(-/-) mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8(-/-) mice as compared to controls. CONCLUSIONS: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8(-/-) mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD. PMID- 22438902 TI - Effects of frugivore preferences and habitat heterogeneity on seed rain: a multi scale analysis. AB - Seed rain mediated by frugivores is influenced by (1) the seed-deposition distances following fruit ingestion, (2) the disperser activity, as determined by its behaviour and habitat preferences, and (3) the structure of the habitat within the landscape. Here, we evaluated such components using the fleshy-fruited shrub Ephedra fragilis and the frugivorous Balearic lizard Podarcis lilfordi. We estimated seed-deposition patterns based on the displacements and habitat preferences of lizards, derived from visual surveys and telemetry data. The influence of variables potentially determining lizard habitat preference (i.e., height, slope, four measures of habitat abundance and four measures of habitat fragmentation) was evaluated at three spatial scales: 'home-range' (c. 2.5 10*10(3) m(2); telemetry data), 'within home-range' (c. 100 m(2); telemetry data) and 'microhabitat' (<100 m(2); visual survey). Cumulative lizard displacement (from each telemetric location to the initial capture point) saturated before the peak of seed defecation (seed-retention time), indicating that lizard home-range size and habitat preferences were the main determinants of the spread and shape of seed shadows. Shrub cover was positively correlated with habitat preference at the three scales of analysis, whereas slope was negatively correlated at the home range scale. Model scenarios indicated that spatially-aggregated seed rain emerged when we incorporated the joint effect of habitat preference at the two largest (home-range and within home-range) scales. We conclude that, in order to predict seed rain in animal dispersed plants, it is important to consider the multi-scale effects of habitat preference by frugivores. PMID- 22438903 TI - Differential mechanical response of mesenchymal stem cells and fibroblasts to tumor-secreted soluble factors. AB - The progression of neoplastic malignancies is a complex process resulting not only from the accumulation of mutations within tumor cells, but also modulation of the tumor microenvironment. Recent advances have shown that the recruitment and subsequent heterotypic interactions of stromal cells--including fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs)--are crucial for carcinogenesis. Though extensive work has been done analyzing the signals that recruit these cells, the governing mechanical properties have not been fully investigated. Here, we report that despite their initial similarities, MSCs respond not only faster but also more dramatically to pro-migratory tumor secreted soluble factors. Utilizing multiple particle tracking microrheology to probe the cytoskeletal mechanical properties, we show that MSCs stiffen completely within one hour, three times faster than fibroblasts. In addition, unlike fibroblasts, MSCs exposed to tumor-secreted soluble factors display a functionally different phenotype characterized by morphological elongation, decreased actin stress fiber density, and decreased adhesion. Quantitative real time PCR indicates these phenomena occur based on differential expression of small GTPases RhoA and Cdc42, but not Rac1. These findings demonstrate a fundamental difference in the recruitment of fibroblasts and MSCs. PMID- 22438904 TI - Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus. AB - Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape. PMID- 22438905 TI - Bleomycin sensitivity in Escherichia coli is medium-dependent. AB - Bleomycin (BLM) is a glycopeptide antibiotic and anti-tumor agent that targets primarily the furanose rings of DNA and in the presence of ferrous ions produces oxidative damage and DNA strand breaks. Escherichia coli cells growing in broth medium and exposed to low concentrations of BLM contain double-strand breaks and require homologous recombination to survive. To a lesser extent, the cells also require the abasic (AP) endonucleases associated with base excision repair, presumably to repair oxidative damage. As expected, there is strong induction of the SOS system in treated cells. In contrast, E. coli cells growing in glucose or glycerol minimal medium are resistant to the lethal action of BLM and do not require either homologous recombination functions or AP-endonucleases for survival. DNA ligase activity, however, is needed for cells growing in minimal medium to resist the lethal effects of BLM. There is weak SOS induction in such treated cells. PMID- 22438906 TI - Jellyfish support high energy intake of leatherback sea turtles (Dermochelys coriacea): video evidence from animal-borne cameras. AB - The endangered leatherback turtle is a large, highly migratory marine predator that inexplicably relies upon a diet of low-energy gelatinous zooplankton. The location of these prey may be predictable at large oceanographic scales, given that leatherback turtles perform long distance migrations (1000s of km) from nesting beaches to high latitude foraging grounds. However, little is known about the profitability of this migration and foraging strategy. We used GPS location data and video from animal-borne cameras to examine how prey characteristics (i.e., prey size, prey type, prey encounter rate) correlate with the daytime foraging behavior of leatherbacks (n = 19) in shelf waters off Cape Breton Island, NS, Canada, during August and September. Video was recorded continuously, averaged 1:53 h per turtle (range 0:08-3:38 h), and documented a total of 601 prey captures. Lion's mane jellyfish (Cyanea capillata) was the dominant prey (83 100%), but moon jellyfish (Aurelia aurita) were also consumed. Turtles approached and attacked most jellyfish within the camera's field of view and appeared to consume prey completely. There was no significant relationship between encounter rate and dive duration (p = 0.74, linear mixed-effects models). Handling time increased with prey size regardless of prey species (p = 0.0001). Estimates of energy intake averaged 66,018 kJ * d(-1) but were as high as 167,797 kJ * d(-1) corresponding to turtles consuming an average of 330 kg wet mass * d(-1) (up to 840 kg * d(-1)) or approximately 261 (up to 664) jellyfish * d(-1). Assuming our turtles averaged 455 kg body mass, they consumed an average of 73% of their body mass * d(-1) equating to an average energy intake of 3-7 times their daily metabolic requirements, depending on estimates used. This study provides evidence that feeding tactics used by leatherbacks in Atlantic Canadian waters are highly profitable and our results are consistent with estimates of mass gain prior to southward migration. PMID- 22438907 TI - The diversification of the LIM superclass at the base of the metazoa increased subcellular complexity and promoted multicellular specialization. AB - BACKGROUND: Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass. RESULTS: We have identified and characterized all known LIM domain-containing proteins in six metazoans and three non-metazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineage-specific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study. CONCLUSION: Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity. PMID- 22438908 TI - CCL21/CCR7 prevents apoptosis via the ERK pathway in human non-small cell lung cancer cells. AB - Previously, we confirmed that C-C chemokine receptor 7 (CCR7) promotes cell proliferation via the extracellular signal-regulated kinase (ERK) pathway, but its role in apoptosis of non-small cell lung cancer (NSCLC) cell lines remains unknown. A549 and H460 cells of NSCLC were used to examine the effect of CCL21/CCR7 on apoptosis using flow cytometry. The results showed that activation of CCR7 by its specific ligand, exogenous chemokine ligand 21 (CCL21), was associated with a significant decline in the percent of apoptosis. Western blot and real-time PCR assays indicated that activation of CCR7 significantly caused upregulation of anti-apoptotic bcl-2 and downregulation of pro-apoptotic bax and caspase-3, but not p53, at both protein and mRNA levels. CCR7 small interfering RNA significantly attenuated these effects of exogenous CCL21. Besides, PD98059, a selective inhibitor of MEK that disrupts the activation of downstream ERK, significantly abolished these effects of CCL21/CCR7. Coimmunoprecipitation further confirmed that there was an interaction between p-ERK and bcl-2, bax, or caspase-3, particularly in the presence of CCL21. These results strongly suggest that CCL21/CCR7 prevents apoptosis by upregulating the expression of bcl-2 and by downregulating the expression of bax and caspase-3 potentially via the ERK pathway in A549 and H460 cells of NSCLC. PMID- 22438909 TI - Blimp1 activation by AP-1 in human lung cancer cells promotes a migratory phenotype and is inhibited by the lysyl oxidase propeptide. AB - B lymphocyte-induced maturation protein 1 (Blimp1) is a master regulator of B cell differentiation, and controls migration of primordial germ cells. Recently we observed aberrant Blimp1 expression in breast cancer cells resulting from an NF-kappaB RelB to Ras signaling pathway. In order to address the question of whether the unexpected expression of Blimp1 is seen in other epithelial-derived tumors, we selected lung cancers as they are frequently driven by Ras signaling. Blimp1 was detected in all five lung cancer cell lines examined and shown to promote lung cancer cell migration and invasion. Interrogation of microarray datasets demonstrated elevated BLIMP1 RNA expression in lung adenocarcinoma, pancreatic ductal carcinomas, head and neck tumors as well as in glioblastomas. Involvement of Ras and its downstream kinase c-Raf was confirmed using mutant and siRNA strategies. We next addressed the issue of mechanism of Blimp1 activation in lung cancer. Using knockdown and ectopic expression, the role of the Activator Protein (AP)-1 family of transcription factors was demonstrated. Further, chromatin immunoprecipitation assays confirmed binding to identified AP-1 elements in the BLIMP1 promoter of ectopically expressed c-Jun and of endogenous AP-1 subunits following serum stimulation. The propeptide domain of lysyl oxidase (LOX-PP) was identified as a tumor suppressor, with ability to reduce Ras signaling in lung cancer cells. LOX-PP reduced expression of Blimp1 by binding to c-Raf and inhibiting activation of AP-1, thereby attenuating the migratory phenotype of lung cancer cells. Thus, Blimp1 is a mediator of Ras/Raf/AP-1 signaling that promotes cell migration, and is repressed by LOX-PP in lung cancer. PMID- 22438910 TI - Llama antibody fragments recognizing various epitopes of the CD4bs neutralize a broad range of HIV-1 subtypes A, B and C. AB - Many of the neutralising antibodies, isolated to date, display limited activities against the globally most prevalent HIV-1 subtypes A and C. Therefore, those subtypes are considered to be an important target for antibody-based therapy. Variable domains of llama heavy chain antibodies (VHH) have some superior properties compared with classical antibodies. Therefore we describe the application of trimeric forms of envelope proteins (Env), derived from HIV-1 of subtype A and B/C, for a prolonged immunization of two llamas. A panel of VHH, which interfere with CD4 binding to HIV-1 Env were selected with use of panning. The results of binding and competition assays to various Env, including a variant with a stabilized CD4-binding state (gp120(Ds2)), cross-competition experiments, maturation analysis and neutralisation assays, enabled us to classify the selected VHH into three groups. The VHH of group I were efficient mainly against viruses of subtype A, C and B'/C. The VHH of group II resemble the broadly neutralising antibody (bnmAb) b12, neutralizing mainly subtype B and C viruses, however some had a broader neutralisation profile. A representative of the third group, 2E7, had an even higher neutralization breadth, neutralizing 21 out of the 26 tested strains belonging to the A, A/G, B, B/C and C subtypes. To evaluate the contribution of certain amino acids to the potency of the VHH a small set of the mutants were constructed. Surprisingly this yielded one mutant with slightly improved neutralisation potency against 92UG37.A9 (subtype A) and 96ZM651.02 (subtype C). These findings and the well-known stability of VHH indicate the potential application of these VHH as anti-HIV-1 microbicides. PMID- 22438911 TI - Elevated mercury concentrations in humans of Madre de Dios, Peru. AB - The enormous increase in practically unregulated mining in Madre de Dios Peru is leading to massive release of liquid elemental mercury to the environment. Rapidly increasing global prices for gold are causing a massive upsurge in artisanal mining in the Peruvian Amazon, considered to be one of the most biodiverse places on the planet. This study identifies the current levels of mercury in the human population, through identifying levels of total mercury in human hair in mining zones of Madre de Dios Department and in the nearby city of Puerto Maldonado. A regression analysis reveals that fish consumption, gender, and location of residence were significant indicators of mercury levels; while duration of residence and age had no significant relationship to mercury levels. Increased fish consumption levels were the strongest indicators of increased total mercury levels across the entire population. The levels of total mercury in hair was significantly (alpha = 0.05) higher in mining zones, than Puerto Maldonado. In both areas men had significantly higher levels than women, likely due to a difference in metabolism or varying levels of direct involvement in gold mining- a male predominated industry. This is the first study to show the health threat that mercury poses to this region, however further research needs to be done to gain a more refined understanding of the predominant routes of exposure in this population. PMID- 22438912 TI - A computational mechanism for unified gain and timing control in the cerebellum. AB - Precise gain and timing control is the goal of cerebellar motor learning. Because the basic neural circuitry of the cerebellum is homogeneous throughout the cerebellar cortex, a single computational mechanism may be used for simultaneous gain and timing control. Although many computational models of the cerebellum have been proposed for either gain or timing control, few models have aimed to unify them. In this paper, we hypothesize that gain and timing control can be unified by learning of the complete waveform of the desired movement profile instructed by climbing fiber signals. To justify our hypothesis, we adopted a large-scale spiking network model of the cerebellum, which was originally developed for cerebellar timing mechanisms to explain the experimental data of Pavlovian delay eyeblink conditioning, to the gain adaptation of optokinetic response (OKR) eye movements. By conducting large-scale computer simulations, we could reproduce some features of OKR adaptation, such as the learning-related change of simple spike firing of model Purkinje cells and vestibular nuclear neurons, simulated gain increase, and frequency-dependent gain increase. These results suggest that the cerebellum may use a single computational mechanism to control gain and timing simultaneously. PMID- 22438913 TI - Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody. AB - BACKGROUND: Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity. CONCLUSION AND SIGNIFICANCE: The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells. PMID- 22438914 TI - Therapeutic effects of autologous tumor-derived nanovesicles on melanoma growth and metastasis. AB - Cancer vaccines with optimal tumor-associated antigens show promise for anti tumor immunotherapy. Recently, nano-sized vesicles, such as exosomes derived from tumors, were suggested as potential antigen candidates, although the total yield of exosomes is not sufficient for clinical applications. In the present study, we developed a new vaccine strategy based on nano-sized vesicles derived from primary autologous tumors. Through homogenization and sonication of tumor tissues, we achieved high yields of vesicle-bound antigens. These nanovesicles were enriched with antigenic membrane targets but lacked nuclear autoantigens. Furthermore, these nanovesicles together with adjuvant activated dendritic cells in vitro, and induced effective anti-tumor immune responses in both primary and metastatic melanoma mouse models. Therefore, autologous tumor-derived nanovesicles may represent a novel source of antigens with high-level immunogenicity for use in acellular vaccines without compromising safety. Our strategy is cost-effective and can be applied to patient-specific cancer therapeutic vaccination. PMID- 22438915 TI - Regulation of synaptic vesicle docking by different classes of macromolecules in active zone material. AB - The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission. Dense networks of macromolecules, called active zone material, (AZM) are attached to the presynaptic membrane next to docked vesicles. Electron tomography has shown that some AZM macromolecules are connected to docked vesicles, leading to the suggestion that AZM is somehow involved in the docking process. We used electron tomography on the simply arranged active zones at frog neuromuscular junctions to characterize the connections of AZM to docked synaptic vesicles and to search for the establishment of such connections during vesicle docking. We show that each docked vesicle is connected to 10-15 AZM macromolecules, which fall into four classes based on several criteria including their position relative to the presynaptic membrane. In activated axon terminals fixed during replacement of docked vesicles by previously undocked vesicles, undocked vesicles near vacated docking sites on the presynaptic membrane have connections to the same classes of AZM macromolecules that are connected to docked vesicles in resting terminals. The number of classes and the total number of macromolecules to which the undocked vesicles are connected are inversely proportional to the vesicles' distance from the presynaptic membrane. We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane. Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry. PMID- 22438916 TI - Ape conservation physiology: fecal glucocorticoid responses in wild Pongo pygmaeus morio following human visitation. AB - Nature-based tourism can generate important revenue to support conservation of biodiversity. However, constant exposure to tourists and subsequent chronic activation of stress responses can produce pathological effects, including impaired cognition, growth, reproduction, and immunity in the same animals we are interested in protecting. Utilizing fecal samples (N = 53) from 2 wild habituated orangutans (Pongo pygmaeus morio) (in addition to 26 fecal samples from 4 wild unhabituated orangutans) in the Lower Kinabatangan Wildlife Sanctuary of Sabah, Malaysian Borneo, we predicted that i) fecal glucocorticoid metabolite concentrations would be elevated on the day after tourist visitation (indicative of normal stress response to exposure to tourists on the previous day) compared to samples taken before or during tourist visitation in wild, habituated orangutans, and ii) that samples collected from habituated animals would have lower fecal glucocorticoid metabolites than unhabituated animals not used for tourism. Among the habituated animals used for tourism, fecal glucocorticoid metabolite levels were significantly elevated in samples collected the day after tourist visitation (indicative of elevated cortisol production on the previous day during tourist visitation). Fecal glucocorticoid metabolite levels were also lower in the habituated animals compared to their age-matched unhabituated counterparts. We conclude that the habituated animals used for this singular ecotourism project are not chronically stressed, unlike other species/populations with documented permanent alterations in stress responses. Animal temperament, species, the presence of coping/escape mechanisms, social confounders, and variation in amount of tourism may explain differences among previous experiments. Acute alterations in glucocorticoid measures in wildlife exposed to tourism must be interpreted conservatively. While permanently altered stress responses can be detrimental, preliminary results in these wild habituated orangutans suggest that low levels of predictable disturbance can likely result in low physiological impact on these animals. PMID- 22438917 TI - Saccharomyces cerevisiae possesses a stress-inducible glycyl-tRNA synthetase gene. AB - Aminoacyl-tRNA synthetases are a large family of housekeeping enzymes that are pivotal in protein translation and other vital cellular processes. Saccharomyces cerevisiae possesses two distinct nuclear glycyl-tRNA synthetase (GlyRS) genes, GRS1 and GRS2. GRS1 encodes both cytoplasmic and mitochondrial activities, while GRS2 is essentially silent and dispensable under normal conditions. We herein present evidence that expression of GRS2 was drastically induced upon heat shock, ethanol or hydrogen peroxide addition, and high pH, while expression of GRS1 was somewhat repressed under those conditions. In addition, GlyRS2 (the enzyme encoded by GRS2) had a higher protein stability and a lower K(M) value for yeast tRNA(Gly) under heat shock conditions than under normal conditions. Moreover, GRS2 rescued the growth defect of a GRS1 knockout strain when highly expressed by a strong promoter at 37 degrees C, but not at the optimal temperature of 30 degrees C. These results suggest that GRS2 is actually an inducible gene that may function to rescue the activity of GRS1 under stress conditions. PMID- 22438918 TI - Visualisation and identification of the interaction between STIM1s in resting cells. AB - Store-operated Ca(2+) channels are a major Ca(2+) entry pathway in nonexcitable cells, which drive various essential cellular functions. Recently, STIM1 and Orai proteins have been identified as the major molecular components of the Ca(2+) release-activated Ca(2+) (CRAC) channel. As the key subunit of the CRAC channel, STIM1 is the ER Ca(2+) sensor and is essential for the recruitment and activation of Orai1. However, the mechanisms in transmission of information of STIM1 to Orai1 still need further investigation. Bimolecular fluorescence complementation (BiFC) is one of the most advanced and powerful tools for studying and visualising protein-protein interactions in living cells. We utilised BiFC and acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments to visualise and determine the state of STIM1 in the living cells in resting state. Our results demonstrate that STIM1 exists in an oligomeric form in resting cells and that rather than the SAM motif, it is the C-terminus (residues 233-474) of STIM1 that is the key domain for the interaction between STIM1s. The STIM1 oligomers (BiFC-STIM1) and wild-type STIM1 colocalised and had a fibrillar distribution in resting conditions. Depletion of ER Ca(2+) stores induced BiFC STIM1 distribution to become punctate, an effect that could be prevented or reversed by 2-APB. After depletion of the Ca(2+) stores, BiFC-STIM1 has the ability to form puncta that colocalise with wild-type STIM1 or Orai1 near the plasma membrane. Our data also indicate that the function of BiFC-STIM1 was not altered compared with that of wild-type STIM1. PMID- 22438919 TI - GlmS and NagB regulate amino sugar metabolism in opposing directions and affect Streptococcus mutans virulence. AB - Streptococcus mutans is a cariogenic pathogen that produces an extracellular polysaccharide (glucan) from dietary sugars, which allows it to establish a reproductive niche and secrete acids that degrade tooth enamel. While two enzymes (GlmS and NagB) are known to be key factors affecting the entrance of amino sugars into glycolysis and cell wall synthesis in several other bacteria, their roles in S. mutans remain unclear. Therefore, we investigated the roles of GlmS and NagB in S. mutans sugar metabolism and determined whether they have an effect on virulence. NagB expression increased in the presence of GlcNAc while GlmS expression decreased, suggesting that the regulation of these enzymes, which functionally oppose one another, is dependent on the concentration of environmental GlcNAc. A glmS-inactivated mutant could not grow in the absence of GlcNAc, while nagB-inactivated mutant growth was decreased in the presence of GlcNAc. Also, nagB inactivation was found to decrease the expression of virulence factors, including cell-surface protein antigen and glucosyltransferase, and to decrease biofilm formation and saliva-induced S. mutans aggregation, while glmS inactivation had the opposite effects on virulence factor expression and bacterial aggregation. Our results suggest that GlmS and NagB function in sugar metabolism in opposing directions, increasing and decreasing S. mutans virulence, respectively. PMID- 22438920 TI - Mutations in polymerase genes enhanced the virulence of 2009 pandemic H1N1 influenza virus in mice. AB - Influenza A virus can infect a wide variety of animal species with illness ranging from mild to severe, and is a continual cause for concern. Genetic mutations that occur either naturally or during viral adaptation in a poorly susceptible host are key mechanisms underlying the evolution and virulence of influenza A virus. Here, the variants containing PA-A36T or PB2-H357N observed in the mouse-adapted descendants of 2009 pandemic H1N1 virus (pH1N1), A/Sichuan/1/2009 (SC), were characterized. Both mutations enhanced polymerase activity in mammalian cells. These effects were confirmed using recombinant SC virus containing polymerase genes with wild type (WT) or mutant PA or PB2. The PA A36T mutant showed enhanced growth property compared to the WT in both human A549 cells and porcine PK15 cells in vitro, without significant effect on viral propagation in murine LA-4 cells and pathogenicity in mice; however, it did enhance the lung virus titer. PB2-H357N variant demonstrated growth ability comparable to the WT in A549 cells, but replicated well in PK15, LA-4 cells and in mice with an enhanced pathogenic phenotype. Despite such mutations are rare in nature, they could be observed in avian H5 and H7 subtype viruses which were currently recognized to pose potential threat to human. Our findings indicated that pH1N1 may adapt well in mammals when acquiring these mutations. Therefore, future molecular epidemiological surveillance should include scrutiny of both markers because of their potential impact on pathogenesis. PMID- 22438921 TI - Nicotinic acetylcholine receptor variants are related to smoking habits, but not directly to COPD. AB - Genome-wide association studies identified single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptors (nAChRs) cluster as a risk factor for nicotine dependency and COPD. We investigated whether SNPs in the nAChR cluster are associated with smoking habits and lung function decline, and if these potential associations are independent of each other. The SNPs rs569207, rs1051730 and rs8034191 in the nAChR cluster were analyzed in the Vlagtwedde Vlaardingen cohort (n = 1,390) that was followed for 25 years. We used GEE and LME models to analyze the associations of the SNPs with quitting or restarting smoking and with the annual FEV(1) decline respectively. Individuals homozygote (CC) for rs569207 were more likely to quit smoking (OR (95%CI) = 1.58 (1.05 2.38)) compared to wild-type (TT) individuals. Individuals homozygote (TT) for rs1051730 were less likely to quit smoking (0.64 (0.42; 0.97)) compared to wild type (CC) individuals. None of the SNPs was significantly associated with the annual FEV(1) decline in smokers and ex-smokers. We show that SNPs in the nAChR region are associated with smoking habits such as quitting smoking, but have no significant effect on the annual FEV(1) decline in smokers and ex-smokers, suggesting a potential role of these SNPs in COPD development via smoking habits rather than via direct effects on lung function. PMID- 22438922 TI - A novel high-throughput vaccinia virus neutralization assay and preexisting immunity in populations from different geographic regions in China. AB - BACKGROUND: Pre-existing immunity to Vaccinia Tian Tan virus (VTT) resulting from a large vaccination campaign against smallpox prior to the early 1980s in China, has been a major issue for application of VTT-vector based vaccines. It is essential to establish a sensitive and high-throughput neutralization assay to understand the epidemiology of Vaccinia-specific immunity in current populations in China. METHODOLOGY/PRINCIPAL FINDINGS: A new anti-Vaccinia virus (VACV) neutralization assay that used the attenuated replication-competent VTT carrying the firefly luciferase gene of Photinus pyralis (rTV-Fluc) was established and standardized for critical parameters that included the choice of cell line, viral infection dose, and the infection time. The current study evaluated the maintenance of virus-specific immunity after smallpox vaccination by conducting a non-randomized, cross-sectional analysis of antiviral antibody-mediated immune responses in volunteers examined 30-55 years after vaccination. The rTV-Fluc neutralization assay was able to detect neutralizing antibodies (NAbs) against Vaccinia virus without the ability to differentiate strains of Vaccinia virus. We showed that the neutralizing titers measured by our assay were similar to those obtained by the traditional plaque reduction neutralization test (PRNT). Using this assay, we found a low prevalence of NAb to VTT (7.6%) in individuals born before 1980 from Beijing and Anhui provinces in China, and when present, anti-VTT NAb titers were low. No NAbs were detected in all 222 samples from individuals born after 1980. There was no significant difference observed for titer or prevalence by gender, age range and geographic origin. CONCLUSION: A simplified, sensitive, standardized, reproducible, and high-throughput assay was developed for the quantitation of NAbs against different Vaccinia strains. The current study provides useful insights for the future development of VTT-based vaccination in Beijing and Anhui provinces of China. PMID- 22438923 TI - MiRNA-mediated control of HLA-G expression and function. AB - HLA-G is a non-classical HLA class-Ib molecule expressed mainly by the extravillous cytotrophoblasts (EVT) of the placenta. The expression of HLA-G on these fetal cells protects the EVT cells from immune rejection and is therefore important for a healthy pregnancy. The mechanisms controlling HLA-G expression are largely unknown. Here we demonstrate that miR-148a and miR-152 down-regulate HLA-G expression by binding its 3'UTR and that this down-regulation of HLA-G affects LILRB1 recognition and consequently, abolishes the LILRB1-mediated inhibition of NK cell killing. We further demonstrate that the C/G polymorphism at position +3142 of HLA-G 3'UTR has no effect on the miRNA targeting of HLA-G. We show that in the placenta both miR-148a and miR-152 miRNAs are expressed at relatively low levels, compared to other healthy tissues, and that the mRNA levels of HLA-G are particularly high and we therefore suggest that this might enable the tissue specific expression of HLA-G. PMID- 22438924 TI - Effects of blood products on inflammatory response in endothelial cells in vitro. AB - BACKGROUND: Transfusing blood products may induce inflammatory reactions within the vascular compartment potentially leading to a systemic inflammatory response. Experiments were designed to assess the inflammatory potential of different blood products in an endothelial cell-based in vitro model and to compare baseline levels of potentially activating substances in transfusion products. METHODS: The inflammatory response from pre-activated (endotoxin-stimulated) and non-activated endothelial cells as well as neutrophil endothelial transmigration in response to packed red blood cells (PRBC), platelet concentrates (PC) and fresh frozen plasma (FFP) was determined. Baseline inflammatory mediator and lipid concentrations in blood products were evaluated. RESULTS: Following incubation with all blood products, an increased inflammatory mediator release from endothelial cells was observed. Platelet concentrates, and to a lesser extent also FFP, caused the most pronounced response, which was accentuated in already pre-stimulated endothelial cells. Inflammatory response of endothelial cells as well as blood product induced migration of neutrophils through the endothelium was in good agreement with the lipid content of the according blood product. CONCLUSION: Within the group of different blood transfusion products both PC and FFP have a high inflammatory potential with regard to activation of endothelial cells. Inflammation upon blood product exposure is strongly accentuated when endothelial cells are pre-injured. High lipid contents in the respective blood products goes along with an accentuated inflammatory reaction from endothelial cells. PMID- 22438925 TI - KREX2 is not essential for either procyclic or bloodstream form Trypanosoma brucei. AB - BACKGROUND: Most mitochondrial mRNAs in Trypanosoma brucei require RNA editing for maturation and translation. The edited RNAs primarily encode proteins of the oxidative phosphorylation system. These parasites undergo extensive changes in energy metabolism between the insect and bloodstream stages which are mirrored by alterations in RNA editing. Two U-specific exonucleases, KREX1 and KREX2, are both present in protein complexes (editosomes) that catalyze RNA editing but the relative roles of each protein are not known. METHODOLOGY/PRINCIPAL FINDINGS: The requirement for KREX2 for RNA editing in vivo was assessed in both procyclic (insect) and bloodstream form parasites by methods that use homologous recombination for gene elimination. These studies resulted in null mutant cells in which both alleles were eliminated. The viability of these cells demonstrates that KREX2 is not essential in either life cycle stage, despite certain defects in RNA editing in vivo. Furthermore, editosomes isolated from KREX2 null cells require KREX1 for in vitro U-specific exonuclease activity. CONCLUSIONS: KREX2 is a U-specific exonuclease that is dispensable for RNA editing in vivo in T. brucei BFs and PFs. This result suggests that the U deletion activity, which is required for RNA editing, is primarily mediated in vivo by KREX1 which is normally found associated with only one type of editosome. The retention of the KREX2 gene implies a non-essential role or a role that is essential in other life cycle stages or conditions. PMID- 22438926 TI - Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice. AB - Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impact on progress of the ALS studies. Recently, it has been recognized that genetic background and gender affect many physiological and pathological phenotypes. However, no systematic studies focusing on such effects using ALS models other than SOD1(G93A) mice have been conducted. To clarify the effects of genetic background and gender on gross phenotypes among different ALS models, we here conducted a comparative analysis of growth curves and lifespans using congenic lines of SOD1(G93A) and SOD1(H46R) mice on two different genetic backgrounds; C57BL/6N (B6) and FVB/N (FVB). Copy number of the transgene and their expression between SOD1(G93A) and SOD1(H46R) lines were comparable. B6 congenic mutant SOD1 transgenic lines irrespective of their mutation and gender differences lived longer than corresponding FVB lines. Notably, the G93A mutation caused severer disease phenotypes than did the H46R mutation, where SOD1(G93A) mice, particularly on a FVB background, showed more extensive body weight loss and earlier death. Gender effect on survival also solely emerged in FVB congenic SOD1(G93A) mice. Conversely, consistent with our previous study using B6 lines, lack of Als2, a murine homolog for the recessive juvenile ALS causative gene, in FVB congenic SOD1(H46R), but not SOD1(G93A), mice resulted in an earlier death, implying a genetic background-independent but mutation-dependent phenotypic modification. These results indicate that SOD1(G93A)- and SOD1(H46R)-mediated toxicity and their associated pathogenic pathways are not identical. Further, distinctive injurious effects resulted from different SOD1 mutations, which are associated with genetic background and/or gender, suggests the presence of several genetic modifiers of disease expression in the mouse genome. PMID- 22438927 TI - A single-stranded DNA aptamer that selectively binds to Staphylococcus aureus enterotoxin B. AB - The bacterium Staphylococcus aureus is a common foodborne pathogen capable of secreting a cocktail of small, stable, and strain-specific, staphylococcal enterotoxins (SEs). Staphylococcal food poisoning (SFP) results when improperly handled food contaminated with SEs is consumed. Gastrointestinal symptoms of SFP include emesis, diarrhea and severe abdominal pain, which manifest within hours of ingesting contaminated food. Immuno-affinity based methods directly detect, identify, and quantify several SEs within a food or clinical sample. However, the success of these assays depends upon the availability of a monoclonal antibody, the development of which is non-trivial and costly. The current scope of the available immuno-affinity based methods is limited to the classical SEs and does not encompass all of the known or emergent SEs. In contrast to antibodies, aptamers are short nucleic acids that exhibit high affinity and specificity for their targets without the high-costs and ethical concerns of animal husbandry. Further, researchers may choose to freely distribute aptamers and develop assays without the proprietary issues that increase the per-sample cost of immuno affinity assays. This study describes a novel aptamer, selected in vitro, with affinity to staphylococcal enterotoxin B (SEB) that may be used in lieu of antibodies in SE detection assays. The aptamer, designated APT(SEB1), successfully isolates SEB from a complex mixture of SEs with extremely high discrimination. This work sets the foundation for future aptamer and assay development towards the entire family of SEs. The rapid, robust, and low-cost identification and quantification of all of the SEs in S. aureus contaminated food is essential for food safety and epidemiological efforts. An in vitro generated library of SE aptamers could potentially allow for the comprehensive and cost-effective analysis of food samples that immuno-affinity assays currently cannot provide. PMID- 22438928 TI - The brain-specific Beta4 subunit downregulates BK channel cell surface expression. AB - The large-conductance K(+) channel (BK channel) can control neural excitability, and enhanced channel currents facilitate high firing rates in cortical neurons. The brain-specific auxiliary subunit beta4 alters channel Ca(++)- and voltage sensitivity, and beta4 knock-out animals exhibit spontaneous seizures. Here we investigate beta4's effect on BK channel trafficking to the plasma membrane. Using a novel genetic tag to track the cellular location of the pore-forming BKalpha subunit in living cells, we find that beta4 expression profoundly reduces surface localization of BK channels via a C-terminal ER retention sequence. In hippocampal CA3 neurons from C57BL/6 mice with endogenously high beta4 expression, whole-cell BK channel currents display none of the characteristic properties of BKalpha+beta4 channels observed in heterologous cells. Finally, beta4 knock-out animals exhibit a 2.5-fold increase in whole-cell BK channel current, indicating that beta4 also regulates current magnitude in vivo. Thus, we propose that a major function of the brain-specific beta4 subunit in CA3 neurons is control of surface trafficking. PMID- 22438929 TI - Modeling effective dosages in hormetic dose-response studies. AB - BACKGROUND: Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. METHODOLOGY/PRINCIPAL FINDINGS: The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0-1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0-26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. CONCLUSIONS/SIGNIFICANCE: The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy. PMID- 22438930 TI - Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex. AB - Analysis of global methylation in cells has revealed correlations between overall DNA methylation status and some biological states. Recent studies suggest that epigenetic regulation through DNA methylation could be responsible for neuroadaptations induced by addictive drugs. However, there is no investigation to determine global DNA methylation status following repeated exposure to addictive drugs. Using mice conditioned place preference (CPP) procedure, we measured global DNA methylation level in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) associated with drug rewarding effects. We found that cocaine-, but not morphine- or food-CPP training decreased global DNA methylation in the PFC. Chronic treatment with methionine, a methyl donor, for 25 consecutive days prior to and during CPP training inhibited the establishment of cocaine, but not morphine or food CPP. We also found that both mRNA and protein level of DNMT (DNA methytransferase) 3b in the PFC were downregulated following the establishment of cocaine CPP, and the downregulation could be reversed by repeated administration of methionine. Our study indicates a crucial role of global PFC DNA hypomethylation in the rewarding effects of cocaine. Reversal of global DNA hypomethylation could significantly attenuate the rewarding effects induced by cocaine. Our results suggest that methionine may have become a potential therapeutic target to treat cocaine addiction. PMID- 22438931 TI - Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. AB - BACKGROUND: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. METHODS AND RESULTS: We developed a model of IL-1beta-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1beta 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL . kg(-1) . min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). CONCLUSIONS: These findings suggest that IL-1beta activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1beta blockade as a novel strategy for pharmacologic intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01300650. PMID- 22438932 TI - Gut bacterial communities in the giant land snail Achatina fulica and their modification by sugarcane-based diet. AB - The invasive land snail Achatina fulica is one of the most damaging agricultural pests worldwide representing a potentially serious threat to natural ecosystems and human health. This species is known to carry parasites and harbors a dense and metabolically active microbial community; however, little is known about its diversity and composition. Here, we assessed for the first time the complexity of bacterial communities occurring in the digestive tracts of field-collected snails (FC) by using culture-independent molecular analysis. Crop and intestinal bacteria in FC were then compared to those from groups of snails that were reared in the laboratory (RL) on a sugarcane-based diet. Most of the sequences recovered were novel and related to those reported for herbivorous gut. Changes in the relative abundance of Bacteroidetes and Firmicutes were observed when the snails were fed a high-sugar diet, suggesting that the snail gut microbiota can influence the energy balance equation. Furthermore, this study represents a first step in gaining a better understanding of land snail gut microbiota and shows that this is a complex holobiont system containing diverse, abundant and active microbial communities. PMID- 22438933 TI - Risk of subsequent coronary heart disease in patients hospitalized for immune mediated diseases: a nationwide follow-up study from Sweden. AB - BACKGROUND: Certain immune-mediated diseases (IMDs), such as rheumatoid arthritis and systemic lupus erythematosus, have been linked to cardiovascular disorders. We examined whether there is an association between 32 different IMDs and risk of subsequent hospitalization for coronary heart disease (CHD) related to coronary atherosclerosis in a nationwide follow up study in Sweden. METHODS AND FINDINGS: All individuals in Sweden hospitalized with a main diagnosis of an IMD (n = 336,479) without previous or coexisting CHD, between January 1, 1964 and December 31 2008, were followed for first hospitalization for CHD. The reference population was the total population of Sweden. Standardized incidence ratios (SIRs) for CHD were calculated. Overall risk of CHD during the first year after hospitalization for an IMD was 2.92 (95% CI 2.84-2.99). Twenty-seven of the 32 IMDs studied were associated with an increased risk of CHD during the first year after hospitalization. The overall risk of CHD decreased over time, from 1.75 after 1-5 years (95% CI 1.73-1.78), to 1.43 after 5-10 years (95% CI 1.41-1.46) and 1.28 after 10+ years (95% CI 1.26-1.30). Females generally had higher SIRs than males. The IMDs for which the SIRs of CDH were highest during the first year after hospitalization included chorea minor 6.98 (95% CI 1.32-20.65), systemic lupus erythematosus 4.94 (95% CI 4.15-5.83), rheumatic fever 4.65 (95% CI 3.53 6.01), Hashimoto's thyroiditis 4.30 (95% CI 3.87-4.75), polymyositis/dermatomyositis 3.81 (95% CI 2.62-5.35), polyarteritis nodosa 3.81 (95% CI 2.72-5.19), rheumatoid arthritis 3.72 (95% CI 3.56-3.88), systemic sclerosis 3.44 (95% CI 2.86-4.09), primary biliary cirrhosis 3.32 (95% CI 2.34 4.58), and autoimmune hemolytic anemia 3.17 (95% CI 2.16-4.47). CONCLUSIONS: Most IMDs are associated with increased risk of CHD in the first year after hospital admission. Our findings suggest that many hospitalized IMDs are tightly linked to coronary atherosclerosis. PMID- 22438934 TI - Immaturity of the oculomotor saccade and vergence interaction in dyslexic children: evidence from a reading and visual search study. AB - Studies comparing binocular eye movements during reading and visual search in dyslexic children are, at our knowledge, inexistent. In the present study we examined ocular motor characteristics in dyslexic children versus two groups of non dyslexic children with chronological/reading age-matched. Binocular eye movements were recorded by an infrared system (mobileEBT(r), e(ye)BRAIN) in twelve dyslexic children (mean age 11 years old) and a group of chronological age matched (N = 9) and reading age-matched (N = 10) non dyslexic children. Two visual tasks were used: text reading and visual search. Independently of the task, the ocular motor behavior in dyslexic children is similar to those reported in reading age-matched non dyslexic children: many and longer fixations as well as poor quality of binocular coordination during and after the saccades. In contrast, chronological age-matched non dyslexic children showed a small number of fixations and short duration of fixations in reading task with respect to visual search task; furthermore their saccades were well yoked in both tasks. The atypical eye movement's patterns observed in dyslexic children suggest a deficiency in the visual attentional processing as well as an immaturity of the ocular motor saccade and vergence systems interaction. PMID- 22438935 TI - The phrenic component of acute schizophrenia--a name and its physiological reality. AB - Decreased heart rate variability (HRV) was shown for unmedicated patients with schizophrenia and their first-degree relatives, implying genetic associations. This is known to be an important risk factor for increased cardiac mortality in other diseases. The interaction of cardio-respiratory function and respiratory physiology has never been investigated in the disease although it might be closely related to the pattern of autonomic dysfunction. We hypothesized that increased breathing rates and reduced cardio-respiratory coupling in patients with acute schizophrenia would be associated with low vagal function. We assessed variability of breathing rates and depth, HRV and cardio-respiratory coupling in patients, their first-degree relatives and controls at rest. Control subjects were investigated a second time by means of a stress task to identify stress related changes of cardio-respiratory function. A total of 73 subjects were investigated, consisting of 23 unmedicated patients, 20 healthy, first-degree relatives and 30 control subjects matched for age, gender, smoking and physical fitness. The LifeShirt(r), a multi-function ambulatory device, was used for data recording (30 minutes). Patients breathe significantly faster (p<.001) and shallower (p<.001) than controls most pronouncedly during exhalation. Patients' breathing is characterized by a significantly increased amount of middle- (p<.001), high- (p<.001), and very high frequency fluctuations (p<.001). These measures correlated positively with positive symptoms as assessed by the PANSS scale (e.g., middle frequency: r = 521; p<.01). Cardio-respiratory coupling was reduced in patients only, while HRV was decreased in patients and healthy relatives in comparison to controls. Respiratory alterations might reflect arousal in acutely ill patients, which is supported by comparable physiological changes in healthy subjects during stress. Future research needs to further investigate these findings with respect to their physiological consequences for patients. These results are invaluable for researchers studying changes of biological signals prone to the influence of breathing rate and rhythm (e.g., functional imaging). PMID- 22438936 TI - A selective emotional decision-making bias elicited by facial expressions. AB - Emotional and social information can sway otherwise rational decisions. For example, when participants decide between two faces that are probabilistically rewarded, they make biased choices that favor smiling relative to angry faces. This bias may arise because facial expressions evoke positive and negative emotional responses, which in turn may motivate social approach and avoidance. We tested a wide range of pictures that evoke emotions or convey social information, including animals, words, foods, a variety of scenes, and faces differing in trustworthiness or attractiveness, but we found only facial expressions biased decisions. Our results extend brain imaging and pharmacological findings, which suggest that a brain mechanism supporting social interaction may be involved. Facial expressions appear to exert special influence over this social interaction mechanism, one capable of biasing otherwise rational choices. These results illustrate that only specific types of emotional experiences can best sway our choices. PMID- 22438937 TI - Social determinants of health and tobacco use in thirteen low and middle income countries: evidence from Global Adult Tobacco Survey. AB - BACKGROUND: Tobacco use has been identified as the single biggest cause of inequality in morbidity. The objective of this study is to examine the role of social determinants on current tobacco use in thirteen low-and-middle income countries. METHODOLOGY/PRINCIPAL FINDINGS: We used nationally representative data from the Global Adult Tobacco Survey (GATS) conducted during 2008-2010 in 13 low and-middle income countries: Bangladesh, China, Egypt, India, Mexico, Philippines, Poland, Russian Federation, Thailand, Turkey, Ukraine, Uruguay, and Viet Nam. These surveys provided information on 209,027 respondent's aged 15 years and above and the country datasets were analyzed individually for estimating current tobacco use across various socio-demographic factors (gender, age, place of residence, education, wealth index, and knowledge on harmful effects of smoking). Multiple logistic regression analysis was used to predict the impact of these determinants on current tobacco use status. Current tobacco use was defined as current smoking or use of smokeless tobacco, either daily or occasionally. Former smokers were excluded from the analysis. Adjusted odds ratios for current tobacco use after controlling other cofactors, was significantly higher for males across all countries and for urban areas in eight of the 13 countries. For educational level, the trend was significant in Bangladesh, Egypt, India, Philippines and Thailand demonstrating decreasing prevalence of tobacco use with increasing levels of education. For wealth index, the trend of decreasing prevalence of tobacco use with increasing wealth was significant for Bangladesh, India, Philippines, Thailand, Turkey, Ukraine, Uruguay and Viet Nam. The trend of decreasing prevalence with increasing levels of knowledge on harmful effects of smoking was significant in China, India, Philippines, Poland, Russian Federation, Thailand, Ukraine and Viet Nam. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate a significant but varied role of social determinants on current tobacco use within and across countries. PMID- 22438938 TI - Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor induced-fit mechanism. AB - Shikimate kinase (SK), which catalyzes the specific phosphorylation of the 3 hydroxyl group of shikimic acid in the presence of ATP, is the enzyme in the fifth step of the shikimate pathway for biosynthesis of aromatic amino acids. This pathway is present in bacteria, fungi, and plants but absent in mammals and therefore represents an attractive target pathway for the development of new antimicrobial agents, herbicides, and antiparasitic agents. Here we investigated the detailed structure-activity relationship of SK from Helicobacter pylori (HpSK). Site-directed mutagenesis and isothermal titration calorimetry studies revealed critical conserved residues (D33, F48, R57, R116, and R132) that interact with shikimate and are therefore involved in catalysis. Crystal structures of HpSK.SO(4), R57A, and HpSK*shikimate-3-phosphate * ADP show a characteristic three-layer architecture and a conformationally elastic region consisting of F48, R57, R116, and R132, occupied by shikimate. The structure of the inhibitor complex, E114A * 162535, was also determined, which revealed a dramatic shift in the elastic LID region and resulted in conformational locking into a distinctive form. These results reveal considerable insight into the active-site chemistry of SKs and a selective inhibitor-induced-fit mechanism. PMID- 22438939 TI - Jack of all trades, master of all: a positive association between habitat niche breadth and foraging performance in pit-building antlion larvae. AB - Species utilizing a wide range of resources are intuitively expected to be less efficient in exploiting each resource type compared to species which have developed an optimal phenotype for utilizing only one or a few resources. We report here the results of an empirical study whose aim was to test for a negative association between habitat niche breadth and foraging performance. As a model system to address this question, we used two highly abundant species of pit building antlions varying in their habitat niche breadth: the habitat generalist Myrmeleon hyalinus, which inhabits a variety of soil types but occurs mainly in sandy soils, and the habitat specialist Cueta lineosa, which is restricted to light soils such as loess. Both species were able to discriminate between the two soils, with each showing a distinct and higher preference to the soil type providing higher prey capture success and characterizing its primary habitat-of origin. As expected, only small differences in the foraging performances of the habitat generalist were evident between the two soils, while the performance of the habitat specialist was markedly reduced in the alternative sandy soil. Remarkably, in both soil types, the habitat generalist constructed pits and responded to prey faster than the habitat specialist, at least under the temperature range of this study. Furthermore, prey capture success of the habitat generalist was higher than that of the habitat specialist irrespective of the soil type or prey ant species encountered, implying a positive association between habitat niche-breadth and foraging performance. Alternatively, C. lineosa specialization to light soils does not necessarily confer upon its superiority in utilizing such habitats. We thus suggest that habitat specialization in C. lineosa is either an evolutionary dead-end, or, more likely, that this species' superiority in light soils can only be evident when considering additional niche axes. PMID- 22438940 TI - Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking. AB - Several genome-wide association and candidate gene studies have linked chromosome 15q24-q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.2840 assessing oocyte yields, stratified for better (anti-Mullerian hormone, AMH >1.05 ng/mL) or poorer (AMH <= 1.05 ng/mL) functional reserve (FOR)). Mean age was 42.4 +/- 2.0 years, mean AMH 0.76 +/- 0.92 ng/mL and mean oocyte yield 5.3 +/- 5.4. Overall, and in women with better FOR, FMR1 did not affect oocyte yields. With poorer FOR (AMH <= 1.05 ng/mL) women with het norm/high, however, demonstrated higher oocyte yields (5.0 +/- 3.8) than those with het-norm/low sub-genotype 3.1 +/- 2.5; P = 0.03), confirmed after log conversion. Known associated with low FOR at young age, het-norm/high, thus, appears to preserve FOR into older age, and both het sub-genotypes appear to expand female reproductive lifespan into opposite directions. PMID- 22438972 TI - Evaluation of an antimicrobial L-amino acid oxidase and peptide derivatives from Bothropoides mattogrosensis pitviper venom. AB - Healthcare-associated infections (HAIs) are causes of mortality and morbidity worldwide. The prevalence of bacterial resistance to common antibiotics has increased in recent years, highlighting the need to develop novel alternatives for controlling these pathogens. Pitviper venoms are composed of a multifaceted mixture of peptides, proteins and inorganic components. L-amino oxidase (LAO) is a multifunctional enzyme that is able to develop different activities including antibacterial activity. In this study a novel LAO from Bothrops mattogrosensis (BmLAO) was isolated and biochemically characterized. Partial enzyme sequence showed full identity to Bothrops pauloensis LAO. Moreover, LAO here isolated showed remarkable antibacterial activity against Gram-positive and -negative bacteria, clearly suggesting a secondary protective function. Otherwise, no cytotoxic activities against macrophages and erythrocytes were observed. Finally, some LAO fragments (BmLAO-f1, BmLAO-f2 and BmLAO-f3) were synthesized and further evaluated, also showing enhanced antimicrobial activity. Peptide fragments, which are the key residues involved in antimicrobial activity, were also structurally studied by using theoretical models. The fragments reported here may be promising candidates in the rational design of new antibiotics that could be used to control resistant microorganisms. PMID- 22438973 TI - Comparison of promoter hypermethylation pattern in salivary rinses collected with and without an exfoliating brush from patients with HNSCC. AB - BACKGROUND: Salivary rinses have been recently proposed as a valuable resource for the development of epigenetic biomarkers for detection and monitoring of head and neck squamous cell carcinoma (HNSCC). Both salivary rinses collected with and without an exfoliating brush from patients with HNSCC are used in detection of promoter hypermethylation, yet their correlation of promoter hypermethylation has not been evaluated. This study was to evaluate the concordance of promoter hypermethylation between salivary rinses collected with and without an exfoliating brush from patients with HNSCC. METHODOLGY: 57 paired salivary rinses collected with or without an exfoliating brush from identical HNSCC patients were evaluated for promoter hypermethylation status using Quantitative Methylation Specific PCR. Target tumor suppressor gene promoter regions were selected based on our previous studies describing a panel for HNSCC screening and surveillance, including P16, CCNA1, DCC, TIMP3, MGMT, DAPK and MINT31. PRINCIPAL FINDINGS: In salivary rinses collected with and without brush, frequent methylation was detected in P16 (8.8% vs. 5.2%), CCNA1 (26.3% vs. 22.8%), DCC (33.3% vs. 29.8%), TIMP3 (31.6% vs. 36.8%), MGMT (29.8% vs. 38.6%), DAPK (14.0% vs. 19.2%), and MINT31 (10.5% vs. 8.8%). Spearman's rank correlation coefficient showed a positive correlation between salivary rinses collected with and without brush for P16 (rho = 0.79), CCNA1 (rho = 0.61), DCC (rho = 0.58), TIMP3 (rho = 0.10), MGMT (rho = 0.70), DAPK (rho = 0.51) and MINT31 (rho = 0.72) (P<0.01). The percent agreement of promoter methylation between salivary rinses with brush and without brush were 96.5% for P16, 82.5% for CCNA1, 78.9% for DCC, 59.7% for TIMP3, 84.2% for MGMT, 84.2% for DAPK, and 94.7% for MINT31. CONCLUSIONS: Our study demonstrated strong correlations of gene promoter hypermethylation between salivary rinses collected with and without an exfoliating brush. Salivary rinse collection without using an exfoliating brush may offer a cost effective, rapid, non-invasive, and reliable means for development of epigenetic salivary rinse biomarkers. PMID- 22438974 TI - Genome physical mapping of polyploids: a BIBAC physical map of cultivated tetraploid cotton, Gossypium hirsutum L. AB - Polyploids account for approximately 70% of flowering plants, including many field, horticulture and forage crops. Cottons are a world-leading fiber and important oilseed crop, and a model species for study of plant polyploidization, cellulose biosynthesis and cell wall biogenesis. This study has addressed the concerns of physical mapping of polyploids with BACs and/or BIBACs by constructing a physical map of the tetraploid cotton, Gossypium hirsutum L. The physical map consists of 3,450 BIBAC contigs with an N50 contig size of 863 kb, collectively spanning 2,244 Mb. We sorted the map contigs according to their origin of subgenome, showing that we assembled physical maps for the A- and D subgenomes of the tetraploid cotton, separately. We also identified the BIBACs in the map minimal tilling path, which consists of 15,277 clones. Moreover, we have marked the physical map with nearly 10,000 BIBAC ends (BESs), making one BES in approximately 250 kb. This physical map provides a line of evidence and a strategy for physical mapping of polyploids, and a platform for advanced research of the tetraploid cotton genome, particularly fine mapping and cloning the cotton agronomic genes and QTLs, and sequencing and assembling the cotton genome using the modern next-generation sequencing technology. PMID- 22438975 TI - Immediate, but not delayed, microsurgical skull reconstruction exacerbates brain damage in experimental traumatic brain injury model. AB - Moderate to severe traumatic brain injury (TBI) often results in malformations to the skull. Aesthetic surgical maneuvers may offer normalized skull structure, but inconsistent surgical closure of the skull area accompanies TBI. We examined whether wound closure by replacement of skull flap and bone wax would allow aesthetic reconstruction of the TBI-induced skull damage without causing any detrimental effects to the cortical tissue. Adult male Sprague-Dawley rats were subjected to TBI using the controlled cortical impact (CCI) injury model. Immediately after the TBI surgery, animals were randomly assigned to skull flap replacement with or without bone wax or no bone reconstruction, then were euthanized at five days post-TBI for pathological analyses. The skull reconstruction provided normalized gross bone architecture, but 2,3,5 triphenyltetrazolium chloride and hematoxylin and eosin staining results revealed larger cortical damage in these animals compared to those that underwent no surgical maneuver at all. Brain swelling accompanied TBI, especially the severe model, that could have relieved the intracranial pressure in those animals with no skull reconstruction. In contrast, the immediate skull reconstruction produced an upregulation of the edema marker aquaporin-4 staining, which likely prevented the therapeutic benefits of brain swelling and resulted in larger cortical infarcts. Interestingly, TBI animals introduced to a delay in skull reconstruction (i.e., 2 days post-TBI) showed significantly reduced edema and infarcts compared to those exposed to immediate skull reconstruction. That immediate, but not delayed, skull reconstruction may exacerbate TBI-induced cortical tissue damage warrants a careful consideration of aesthetic repair of the skull in TBI. PMID- 22438976 TI - Motion extrapolation in the central fovea. AB - Neural transmission latency would introduce a spatial lag when an object moves across the visual field, if the latency was not compensated. A visual predictive mechanism has been proposed, which overcomes such spatial lag by extrapolating the position of the moving object forward. However, a forward position shift is often absent if the object abruptly stops moving (motion-termination). A recent "correction-for-extrapolation" hypothesis suggests that the absence of forward shifts is caused by sensory signals representing 'failed' predictions. Thus far, this hypothesis has been tested only for extra-foveal retinal locations. We tested this hypothesis using two foveal scotomas: scotoma to dim light and scotoma to blue light. We found that the perceived position of a dim dot is extrapolated into the fovea during motion-termination. Next, we compared the perceived position shifts of a blue versus a green moving dot. As predicted the extrapolation at motion-termination was only found with the blue moving dot. The results provide new evidence for the correction-for-extrapolation hypothesis for the region with highest spatial acuity, the fovea. PMID- 22438977 TI - High accordance in prognosis prediction of colorectal cancer across independent datasets by multi-gene module expression profiles. AB - A considerable portion of patients with colorectal cancer have a high risk of disease recurrence after surgery. These patients can be identified by analyzing the expression profiles of signature genes in tumors. But there is no consensus on which genes should be used and the performance of specific set of signature genes varies greatly with different datasets, impeding their implementation in the routine clinical application. Instead of using individual genes, here we identified functional multi-gene modules with significant expression changes between recurrent and recurrence-free tumors, used them as the signatures for predicting colorectal cancer recurrence in multiple datasets that were collected independently and profiled on different microarray platforms. The multi-gene modules we identified have a significant enrichment of known genes and biological processes relevant to cancer development, including genes from the chemokine pathway. Most strikingly, they recruited a significant enrichment of somatic mutations found in colorectal cancer. These results confirmed the functional relevance of these modules for colorectal cancer development. Further, these functional modules from different datasets overlapped significantly. Finally, we demonstrated that, leveraging above information of these modules, our module based classifier avoided arbitrary fitting the classifier function and screening the signatures using the training data, and achieved more consistency in prognosis prediction across three independent datasets, which holds even using very small training sets of tumors. PMID- 22438978 TI - HIV-1 Vpr triggers mitochondrial destruction by impairing Mfn2-mediated ER mitochondria interaction. AB - Human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) has been shown to induce host cell death by increasing the permeability of mitochondrial outer membrane (MOM). The mechanism underlying the damage to the mitochondria by Vpr, however, is not clearly illustrated. In this study, Vpr that is introduced, via transient transfection or lentivirus infection, into the human embryonic kidney cell line HEK293, human CD4(+) T lymphoblast cell line SupT1, or human primary CD4(+) T cells serves as the model system to study the molecular mechanism of Vpr mediated HIV-1 pathogenesis. The results show that Vpr injures MOM and causes a loss in membrane potential (MMP) by posttranscriptionally reducing the expression of mitofusin 2 (Mfn2) via VprBP-DDB1-CUL4A ubiquitin ligase complex, gradually weakening MOM, and increasing mitochondrial deformation. Vpr also markedly decreases cytoplasmic levels of dynamin-related protein 1 (DRP1) and increases bulging in mitochondria-associated membranes (MAM), the specific regions of endoplasmic reticulum (ER) which form physical contacts with the mitochondria. Overexpression of Mfn2 and DRP1 significantly decreased the loss of MMP and apoptotic cell death caused by Vpr. Furthermore, by employing time-lapse confocal fluorescence microscopy, we identify the transport of Vpr protein from the ER, via MAM to the mitochondria. Taken together, our results suggest that Vpr mediated cellular damage may occur on an alternative protein transport pathway from the ER, via MAM to the mitochondria, which are modulated by Mfn2 and DRP1. PMID- 22438979 TI - The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration. AB - BACKGROUND: Myelinating Schwann cells (mSCs) form myelin in the peripheral nervous system. Because of the works by us and others, matrix metalloproteinase-9 (MMP-9) has recently emerged as an essential component of the Schwann cell signaling network during sciatic nerve regeneration. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, using the genome-wide transcriptional profiling of normal and injured sciatic nerves in mice followed by extensive bioinformatics analyses of the data, we determined that an endogenous, specific MMP-9 inhibitor [tissue inhibitor of metalloproteinases (TIMP)-1] was a top up-regulated gene in the injured nerve. MMP-9 capture followed by gelatin zymography and Western blotting of the isolated samples revealed the presence of the MMP-9/TIMP-1 heterodimers and the activated MMP-9 enzyme in the injured nerve within the first 24 h post-injury. MMP-9 and TIMP-1 co-localized in mSCs. Knockout of the MMP-9 gene in mice resulted in elevated numbers of de-differentiated/immature mSCs in the damaged nerve. Our comparative studies using MMP-9 knockout and wild-type mice documented an aberrantly enhanced proliferative activity and, accordingly, an increased number of post-mitotic Schwann cells, short internodes and additional nodal abnormalities in remyelinated nerves of MMP-9 knockout mice. These data imply that during the first days post-injury MMP-9 exhibits a functionally important anti-mitogenic activity in the wild-type mice. Pharmacological inhibition of MMP activity suppressed the expression of Na(v)1.7/1.8 channels in the crushed nerves. CONCLUSION/SIGNIFICANCE: Collectively, our data established an essential role of the MMP-9/TIMP-1 axis in guiding the mSC differentiation and the molecular assembly of myelin domains in the course of the nerve repair process. Our findings of the MMP-dependent regulation of Na(v) channels, which we document here for the first time, provide a basis for therapeutic intervention in sensorimotor pathologies and pain. PMID- 22438980 TI - Alteration of striatal dopaminergic neurotransmission in a mouse model of DYT11 myoclonus-dystonia. AB - BACKGROUND: DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding epsilon sarcoglycan (epsilon-SG); the mouse homolog of this gene is Sgce. Paternally inherited Sgce heterozygous knockout (Sgce KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of Sgce KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. METHODOLOGY/PRINCIPAL FINDINGS: The protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in Sgce KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in Sgce KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in Sgce KO mice without altering DAT and D1R. Sgce KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates. CONCLUSION/SIGNIFICANCE: The results suggest epsilon-SG may have a role in the regulation of D2R expression. The loss of epsilon-SG results in decreased striatal D2R, and subsequently leads to increased discharge of dopamine which could contribute to the behavioral impairment observed in DYT11 dystonia patients and in Sgce KO mice. The results suggest that reduction of striatal D2R and enhanced striatal dopamine release may contribute to the pathophysiology of DYT11 M-D patients. PMID- 22438981 TI - Modulation of beta-catenin signaling by glucagon receptor activation. AB - The glucagon receptor (GCGR) is a member of the class B G protein-coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA) pathway, activation of GCGR also induced beta-catenin stabilization and activated beta-catenin-mediated transcription. Activation of beta-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R) and glucagon-like peptide 1 (GLP-1R) receptors. Since low-density-lipoprotein receptor-related protein 5 (Lrp5) is an essential co-receptor required for Wnt protein mediated beta-catenin signaling, we examined the role of Lrp5 in glucagon induced beta-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon induced beta-catenin stabilization and TCF promoter-mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1) or by expression of the Lrp5 extracellular domain blocked glucagon-induced beta-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and beta catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations. PMID- 22438982 TI - The database for aggregate analysis of ClinicalTrials.gov (AACT) and subsequent regrouping by clinical specialty. AB - BACKGROUND: The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. METHODS/PRINCIPAL RESULTS: The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. CONCLUSIONS/SIGNIFICANCE: The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups. PMID- 22438983 TI - Seawater acidification and elevated temperature affect gene expression patterns of the pearl oyster Pinctada fucata. AB - Oceanic uptake of anthropogenic carbon dioxide results in decrease in seawater pH and increase in temperature. In this study, we demonstrated the synergistic effects of elevated seawater temperature and declined seawater pH on gene expression patterns of aspein, calmodulin, nacrein, she-7-F10 and hsp70 in the pearl oyster Pinctada fucata. Under 'business-as-usual' scenarios, four treatments were examined: (1) ambient pH (8.10) and ambient temperature (27 degrees C) (control condition), (2) ambient pH and elevated temperature (+3 degrees C), (3) declined pH (7.70) and ambient temperature, (4) declined pH and elevated temperature. The results showed that under warming and acidic seawater conditions, expression of aspein and calmodulin showed no significant differences among different time point in condition 8.10 T. But the levels of aspein and calmodulin in conditions 8.10 T+3, 7.70 T and 7.70 T+3, and levels of nacrein, she-7-F10 in all the four treatments changed significantly. Low pH and pH * temperature interaction influenced the expression of aspein and calmodulin significantly after hours 48 and 96. Significant effects of low pH and pH * temperature interaction on the expression of nacrein were observed at hour 96. The expression level of she-7-F10 was affected significantly by pH after hours 48 and 96. The expression of hsp70 was significantly affected by temperature, pH, temperature * pH interaction at hour 6, and by temperature * pH interaction at hour 24. This study suggested that declined pH and pH * temperature interaction induced down regulation of calcification related genes, and the interaction between declined seawater pH and elevated temperature caused up regulation of hsp70 in P. facata. These results demonstrate that the declined seawater pH and elevated temperature will impact the physiological process, and potentially the adaptability of P. fucata to future warming and acidified ocean. PMID- 22438984 TI - Research on the stability of a rabbit dry eye model induced by topical application of the preservative benzalkonium chloride. AB - BACKGROUND: Dry eye is a common disease worldwide, and animal models are critical for the study of it. At present, there is no research about the stability of the extant animal models, which may have negative implications for previous dry eye studies. In this study, we observed the stability of a rabbit dry eye model induced by the topical benzalkonium chloride (BAC) and determined the valid time of this model. METHODS AND FINDINGS: Eighty white rabbits were randomly divided into four groups. One eye from each rabbit was randomly chosen to receive topical 0.1% BAC twice daily for 2 weeks (Group BAC-W2), 3 weeks (Group BAC-W3), 4 weeks (Group BAC-W4), or 5 weeks (Group BAC-W5). Fluorescein staining, Schirmer's tests, and conjunctival impression cytology were performed before BAC treatment (normal) and on days 0, 7, 14 and 21 after BAC removal. The eyeballs were collected at these time points for immunofluorescence staining, hematoxylin and eosin (HE) staining, and electron microscopy. After removing BAC, the signs of dry eye in Group BAC-W2 lasted one week. Compared with normal, there were still significant differences in the results of Schirmer's tests and fluorescein staining in Groups BAC-W3 and BAC-W4 on day 7 (P<0.05) and in Group BAC-W5 on day 14 (P<0.05). Decreases in goblet cell density remained stable in the three experimental groups at all time points (P<0.001). Decreased levels of mucin-5 subtype AC (MUC5AC), along with histopathological and ultrastructural disorders of the cornea and conjunctiva could be observed in Group BAC-W4 and particularly in Group BAC-W5 until day 21. CONCLUSIONS: A stable rabbit dry eye model was induced by topical 0.1% BAC for 5 weeks, and after BAC removal, the signs of dry eye were sustained for 2 weeks (for the mixed type of dry eye) or for at least 3 weeks (for mucin-deficient dry eye). PMID- 22438985 TI - Escherichia coli frameshift mutation rate depends on the chromosomal context but not on the GATC content near the mutation site. AB - Different studies have suggested that mutation rate varies at different positions in the genome. In this work we analyzed if the chromosomal context and/or the presence of GATC sites can affect the frameshift mutation rate in the Escherichia coli genome. We show that in a mismatch repair deficient background, a condition where the mutation rate reflects the fidelity of the DNA polymerization process, the frameshift mutation rate could vary up to four times among different chromosomal contexts. Furthermore, the mismatch repair efficiency could vary up to eight times when compared at different chromosomal locations, indicating that detection and/or repair of frameshift events also depends on the chromosomal context. Also, GATC sequences have been proved to be essential for the correct functioning of the E. coli mismatch repair system. Using bacteriophage heteroduplexes molecules it has been shown that GATC influence the mismatch repair efficiency in a distance- and number-dependent manner, being almost nonfunctional when GATC sequences are located at 1 kb or more from the mutation site. Interestingly, we found that in E. coli genomic DNA the mismatch repair system can efficiently function even if the nearest GATC sequence is located more than 2 kb away from the mutation site. The results presented in this work show that even though frameshift mutations can be efficiently generated and/or repaired anywhere in the genome, these processes can be modulated by the chromosomal context that surrounds the mutation site. PMID- 22438986 TI - Hiwi mediated tumorigenesis is associated with DNA hypermethylation. AB - Expression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis. PMID- 22438987 TI - Systemic and mucosal immune responses to sublingual or intramuscular human papilloma virus antigens in healthy female volunteers. AB - The sublingual route has been proposed as a needle-free option to induce systemic and mucosal immune protection against viral infections. In a translational study of systemic and mucosal humoral immune responses to sublingual or systemically administered viral antigens, eighteen healthy female volunteers aged 19-31 years received three immunizations with a quadravalent Human Papilloma Virus vaccine at 0, 4 and 16 weeks as sublingual drops (SL, n = 12) or intramuscular injection (IM, n = 6). IM antigen delivery induced or boosted HPV-specific serum IgG and pseudovirus-neutralizing antibodies, HPV-specific cervical and vaginal IgG, and elicited circulating IgG and IgA antibody secreting cells. SL antigens induced ~38-fold lower serum and ~2-fold lower cervical/vaginal IgG than IM delivery, and induced or boosted serum virus neutralizing antibody in only 3/12 subjects. Neither route reproducibly induced HPV-specific mucosal IgA. Alternative delivery systems and adjuvants will be required to enhance and evaluate immune responses following sublingual immunization in humans. TRIAL REGISTRATION: ClinicalTrials.govNCT00949572. PMID- 22438988 TI - Control of dendritic morphogenesis by Trio in Drosophila melanogaster. AB - Abl tyrosine kinase and its effectors among the Rho family of GTPases each act to control dendritic morphogenesis in Drosophila. It has not been established, however, which of the many GTPase regulators in the cell link these signaling molecules in the dendrite. In axons, the bifunctional guanine exchange factor, Trio, is an essential link between the Abl tyrosine kinase signaling pathway and Rho GTPases, particularly Rac, allowing these systems to act coordinately to control actin organization. In dendritic morphogenesis, however, Abl and Rac have contrary rather than reinforcing effects, raising the question of whether Trio is involved, and if so, whether it acts through Rac, Rho or both. We now find that Trio is expressed in sensory neurons of the Drosophila embryo and regulates their dendritic arborization. trio mutants display a reduction in dendritic branching and increase in average branch length, whereas over-expression of trio has the opposite effect. We further show that it is the Rac GEF domain of Trio, and not its Rho GEF domain that is primarily responsible for the dendritic function of Trio. Thus, Trio shapes the complexity of dendritic arbors and does so in a way that mimics the effects of its target, Rac. PMID- 22438989 TI - Bi-directional exchange of membrane components occurs during co-culture of mesenchymal stem cells and nucleus pulposus cells. AB - Mesenchymal stem cell (MSC)-based therapies have been proposed as novel treatments for intervertebral disc (IVD) degeneration. We have previously demonstrated that when MSCs are co-cultured with nucleus pulposus (NP) cells with direct cell-cell contact, they differentiate along the NP lineage and simultaneously stimulate the degenerate NP cell population to regain a normal (non-degenerate) phenotype, an effect which requires cell-cell communication. However, the mechanisms by which NP cells and MSCs interact in this system are currently unclear. Thus, in this study we investigated a range of potential mechanisms for exchange of cellular components or information that may direct these changes, including cell fusion, gap-junctional communication and exchange of membrane components by direct transfer or via microvesicle formation. Flow cytometry of fluorescently labeled MSCs and NP cells revealed evidence of some cell fusion and formation of gapjunctions, although at the three timepoints studied these phenomena were detectable only in a small proportion of cells. While these mechanisms may play a role in cell-cell communication, the data suggests they are not the predominant mechanism of interaction. However, flow cytometry of fluorescently dual-labeled cells showed that extensive bi directional transfer of membrane components is operational during direct co culture of MSCs and NP cells. Furthermore, there was also evidence for secretion and internalization of membrane-bound microvesicles by both cell types. Thus, this study highlights bi-directional intercellular transfer of membrane components as a possible mechanism of cellular communication between MSC and NP cells. PMID- 22438990 TI - Novel binding mode of a potent and selective tankyrase inhibitor. AB - Tankyrases (TNKS1 and TNKS2) are key regulators of cellular processes such as telomere pathway and Wnt signaling. IWRs (inhibitors of Wnt response) have recently been identified as potent and selective inhibitors of tankyrases. However, it is not clear how these IWRs interact with tankyrases. Here we report the crystal structure of the catalytic domain of human TNKS1 in complex with IWR2, which reveals a novel binding site for tankyrase inhibitors. The TNKS1/IWR2 complex provides a molecular basis for their strong and specific interactions and suggests clues for further development of tankyrase inhibitors. PMID- 22438991 TI - Developmental regulation and spatiotemporal redistribution of the sumoylation machinery in the rat central nervous system. AB - BACKGROUND: Small Ubiquitin-like MOdifier protein (SUMO) is a key regulator of nuclear functions but little is known regarding the role of the post translational modification sumoylation outside of the nucleus, particularly in the Central Nervous System (CNS). METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that the expression levels of SUMO-modified substrates as well as the components of the sumoylation machinery are temporally and spatially regulated in the developing rat brain. Interestingly, while the overall sumoylation is decreasing during brain development, there are progressively more SUMO substrates localized at synapses. This increase is correlated with a differential redistribution of the sumoylation machinery into dendritic spines during neuronal maturation. CONCLUSIONS/SIGNIFICANCE: Overall, our data clearly demonstrate that the sumoylation process is developmentally regulated in the brain with high levels of nuclear sumoylation early in the development suggesting a role for this post translational modification during the synaptogenesis period and a redistribution of the SUMO system towards dendritic spines at a later developmental stage to modulate synaptic protein function. PMID- 22438992 TI - Downregulation of six microRNAs is associated with advanced stage, lymph node metastasis and poor prognosis in small cell carcinoma of the cervix. AB - BACKGROUND: Small cell carcinoma of the cervix (SCCC) is very rare, and due to the long time period required to recruit sufficient numbers of patients, there is a paucity of information regarding the prognostic factors associated with survival. MicroRNAs (miRNAs) have been used as cancer-related biomarkers in a variety of tumor types, and the objective of this study was to determine whether microRNA expression profiles can predict clinical outcome in SCCC. METHODOLOGY/PRINCIPAL FINDINGS: Forty-four patients with SCCC who underwent radical hysterectomy between January 2000 and October 2009 were enrolled. Using the GeneCopoeia All-in-OneTM Customized Human qPCR Primer Array, the expression profiles of 30 miRNAs associated with tumor metastasis was obtained from the formalin-fixed paraffin embedded samples of all 44 patients. Seven miRNAs, has let-7c, has-miR-10b, has-miR-100, has-miR-125b, has-miR-143, has-miR-145 and has miR-199a-5p were significantly down-regulated in advanced stage SCCC patients (FIGO IB2-IV) compared to early stage SCCC patients (FIGOIB1). Among, downregulation of six miRNAs, has-let-7c, has-miR-100, has-miR-125b, has-miR-143, has-miR-145 and has-miR-199a-5p were significantly associated with lymph node metastasis and reduced survival in SCCC. Kaplan-Meier survival analyses revealed that SCCC patients with low expression of has-miR-100 (P = 0.019) and has-miR 125b (P = 0.020) projected a significant tendency towards poorer prognosis. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that downregulation of 7 miRNA associated with advanced stage, 6 miRNAs with metastasis and 2 with poor prognosis in SCCC. Functional analysis of these miRNAs may enhance our understanding of SCCC, as altered expression of specific miRNAs may regulate the metastatic pathway and provide novel targets for therapy. PMID- 22438993 TI - Inhibition of miR-29 by TGF-beta-Smad3 signaling through dual mechanisms promotes transdifferentiation of mouse myoblasts into myofibroblasts. AB - MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression in post transcriptional fashion, and emerging studies support their importance in regulating many biological processes, including myogenic differentiation and muscle development. miR-29 is a promoting factor during myogenesis but its full spectrum of impact on muscle cells has yet to be explored. Here we describe an analysis of miR-29 affected transcriptome in C2C12 muscle cells using a high throughput RNA-sequencing platform. The results reveal that miR-29 not only functions to promote myogenic differentiation but also suppresses the transdifferentiation of myoblasts into myofibroblasts. miR-29 inhibits the fibrogenic differentiation through down-regulating both extracellular matrix genes and cell adhesion genes. We further demonstrate that miR-29 is under negative regulation by TGF-beta (TGF-beta)-Smad3 signaling via dual mechanisms of both inhibiting MyoD binding and enhancing Yin Yang 1 (YY1)-recruited Polycomb association. Together, these results identify miR-29 as a pleiotropic molecule in both myogenic and fibrogenic differentiation of muscle cells. PMID- 22438994 TI - Dopaminergic polymorphisms associated with time-on-task declines and fatigue in the Psychomotor Vigilance Test. AB - Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary. PMID- 22438995 TI - Changes in the heart rate variability in patients with obstructive sleep apnea and its response to acute CPAP treatment. AB - INTRODUCTION: Obstructive Sleep Apnea (OSA) is a major risk factor for cardiovascular disease. The goal of this study was to demonstrate whether the use of CPAP produces significant changes in the heart rate or in the heart rate variability of patients with OSA in the first night of treatment and whether gender and obesity play a role in these differences. METHODS: Single-center transversal study including patients with severe OSA corrected with CPAP. Only patients with total correction after CPAP were included. Patients underwent two sleep studies on consecutive nights: the first night a basal study, and the second with CPAP. We also analyzed the heart rate changes and their relationship with CPAP treatment, sleep stages, sex and body mass index. Twenty-minute segments of the ECG were selected from the sleep periods of REM, no-REM and awake. Heart rate (HR) and heart rate variability (HRV) were studied by comparing the R-R interval in the different conditions. We also compared samples from the basal study and CPAP nights. RESULTS: 39 patients (15 females, 24 males) were studied. The mean age was 50.67 years old, the mean AHI was 48.54, and mean body mass index was 33.41 kg/m(2) (31.83 males, 35.95 females). Our results showed that HRV (SDNN) decreased after the use of CPAP during the first night of treatment, especially in non-REM sleep. Gender and obesity did not have any influence on our results. CONCLUSIONS: These findings support that cardiac variability improves as an acute effect, independently of gender or weight, in the first night of CPAP use in severe OSA patients, supporting the idea of continuous use and emphasizing that noncompliance of CPAP treatment should be avoided even if it is just once. PMID- 22438996 TI - RhoA of the Rho family small GTPases is essential for B lymphocyte development. AB - RhoA is a member of the Rho family small GTPases that are implicated in various cell functions including proliferation and survival. However, the physiological role of RhoA in vivo remains largely unknown. Here, we deleted RhoA in the B cell and hematopoietic stem cell (HSC) populations in RhoA(flox/flox) mice with CD19 and Mx promoter-driven Cre expression, respectively. Deletion of RhoA by CD19(Cre/+) significantly blocked B cell development in spleen, leading to a marked reduction in the number of transitional, marginal zone, and follicular B cells. Surprisingly, neither B cell proliferation in response to either LPS or B cell receptor (BCR) engagement nor B cell survival rate in vivo was affected by RhoA deletion. Furthermore, RhoA(-/-) B cells, like control cells, were rescued from apoptosis by BCR crosslinking in vitro. In contrast, RhoA deficiency led to a defect in B cell activating factor (BAFF)-mediated B cell survival that was associated with a dampened expression of BAFF receptor and a loss of BAFF mediated Akt activation. Finally, HSC deletion of RhoA by Mx-Cre severely reduced proB/preB and immature B cell populations in bone marrow while common lymphoid progenitors were increased, indicating that RhoA is also required for B cell progenitor/precursor differentiation. Taken together, our results uncover an important role for RhoA at multiple stages of B cell development. PMID- 22438997 TI - Plasmodium falciparum-infected erythrocytes induce granzyme B by NK cells through expression of host-Hsp70. AB - In the early immune response to Plasmodium falciparum-infected erythrocytes (iRBC), Natural Killer (NK) cells are activated, which suggests an important role in innate anti-parasitic immunity. However, it is not well understood whether NK cells directly recognize iRBC or whether stimulation of NK cells depends mainly on activating signals from accessory cells through cell-to-cell contact or soluble factors. In the present study, we investigated the influence of membrane bound host Heat shock protein (Hsp) 70 in triggering cytotoxicity of NK cells from malaria-naive donors or the cell line NK92 against iRBC. Hsp70 and HLA-E membrane expression on iRBC and potential activatory NK cell receptors (NKG2C, CD94) were assessed by flow cytometry and immunoblot. Upon contact with iRBC, Granzyme B (GzmB) production and release was initiated by unstimulated and Hsp70 peptide (TKD) pre-stimulated NK cells, as determined by Western blot, RT-PCR and ELISPOT analysis. Eryptosis of iRBC was determined by Annexin V-staining. Our results suggest that presence of Hsp70 and absence of HLA-E on the membrane of iRBC prompt the infected host cells to become targets for NK cell-mediated cytotoxicity, as evidenced by impaired parasite development. Contact of iRBC with NK cells induced release of GzmB. We propose that following GzmB uptake, iRBC undergo eryptosis via a perforin-independent, GzmB-mediated mechanism. Since NK activity toward iRBC could be specifically enhanced by TKD peptide and abrogated to baseline levels by blocking Hsp70 exposure, we propose TKD as an innovative immunostimulatory agent to be tested as an adjunct to anti-parasitic treatments in vivo. PMID- 22438998 TI - Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation. AB - BACKGROUND: Asthma is a respiratory tract disorder characterized by airway hyper reactivity and chronic inflammation. Allergic asthma is associated with the production of allergen-specific IgE and expansion of allergen-specific T-cell populations. Progression of allergic inflammation is driven by T-helper type 2 (Th2) mediators and is associated with alterations in the levels of lipid mediators. OBJECTIVES: Responses of the respiratory system to birch allergen provocation in allergic asthmatics were investigated. Eicosanoids and other oxylipins were quantified in the bronchoalveolar lumen to provide a measure of shifts in lipid mediators associated with allergen challenge in allergic asthmatics. METHODS: Eighty-seven lipid mediators representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS following off-line extraction of bronchoalveolar lavage fluid (BALF). Multivariate statistics using OPLS were employed to interrogate acquired oxylipin data in combination with immunological markers. RESULTS: Thirty two oxylipins were quantified, with baseline asthmatics possessing a different oxylipin profile relative to healthy individuals that became more distinct following allergen provocation. The most prominent differences included 15-LOX derived omega-3 and omega-6 oxylipins. Shared-and-Unique-Structures (SUS)-plot modeling showed a correlation (R(2) = 0.7) between OPLS models for baseline asthmatics (R(2)Y[cum] = 0.87, Q(2)[cum] = 0.51) and allergen-provoked asthmatics (R(2)Y[cum] = 0.95, Q(2)[cum] = 0.73), with the majority of quantified lipid mediators and cytokines contributing equally to both groups. Unique structures for allergen provocation included leukotrienes (LTB(4) and 6-trans-LTB(4)), CYP derivatives of linoleic acid (epoxides/diols), and IL-10. CONCLUSIONS: Differences in asthmatic relative to healthy profiles suggest a role for 15-LOX products of both omega-6 and omega-3 origin in allergic inflammation. Prominent differences at baseline levels indicate that non-symptomatic asthmatics are subject to an underlying inflammatory condition not observed with other traditional mediators. Results suggest that oxylipin profiling may provide a sensitive means of characterizing low-level inflammation and that even individuals with mild disease display distinct phenotypic profiles, which may have clinical ramifications for disease. PMID- 22438999 TI - Host genetics and Chlamydia disease: prediction and validation of disease severity mechanisms. AB - Genetic mapping studies may provide association between sequence variants and disease susceptibility that can, with further experimental and computational analysis, lead to discovery of causal mechanisms and effective intervention. We have previously demonstrated that polymorphisms in immunity-related GTPases (IRG) confer a significant difference in susceptibility to Chlamydia psittaci infection in BXD recombinant mice. Here we combine genetic mapping and network modeling to identify causal pathways underlying this association. We infected a large panel of BXD strains with C. psittaci and assessed host genotype, IRG protein polymorphisms, pathogen load, expression of 32 cytokines, inflammatory cell populations, and weight change. Proinflammatory cytokines correlated with each other and were controlled by a novel genetic locus on chromosome 1, but did not affect disease status, as quantified by weight change 6 days after infection In contrast, weight change correlated strongly with levels of inflammatory cell populations and pathogen load that were controlled by an IRG encoding genetic locus (Ctrq3) on chromosome 11. These data provided content to generate a predictive model of infection using a Bayesian framework incorporating genotypes, immune system parameters, and weight change as a measure of disease severity. Two predictions derived from the model were tested and confirmed in a second round of experiments. First, strains with the susceptible IRG haplotype lost weight as a function of pathogen load whereas strains with the resistant haplotype were almost completely unaffected over a very wide range of pathogen load. Second, we predicted that macrophage activation by Ctrq3 would be central in conferring pathogen tolerance. We demonstrated that macrophage depletion in strains with the resistant haplotype led to neutrophil influx and greater weight loss despite a lower pathogen burden. Our results show that genetic mapping and network modeling can be combined to identify causal pathways underlying chlamydial disease susceptibility. PMID- 22439000 TI - Rapid susceptibility testing and microcolony analysis of Candida spp. cultured and imaged on porous aluminum oxide. AB - BACKGROUND: Acquired resistance to antifungal agents now supports the introduction of susceptibility testing for species-drug combinations for which this was previously thought unnecessary. For pathogenic yeasts, conventional phenotypic testing needs at least 24 h. Culture on a porous aluminum oxide (PAO) support combined with microscopy offers a route to more rapid results. METHODS: Microcolonies of Candida species grown on PAO were stained with the fluorogenic dyes Fun-1 and Calcofluor White and then imaged by fluorescence microscopy. Images were captured by a charge-coupled device camera and processed by publicly available software. By this method, the growth of yeasts could be detected and quantified within 2 h. Microcolony imaging was then used to assess the susceptibility of the yeasts to amphotericin B, anidulafungin and caspofungin (3.5 h culture), and voriconazole and itraconazole (7 h culture). SIGNIFICANCE: Overall, the results showed good agreement with EUCAST (86.5% agreement; n = 170) and E-test (85.9% agreement; n = 170). The closest agreement to standard tests was found when testing susceptibility to amphotericin B and echinocandins (88.2 to 91.2%) and the least good for the triazoles (79.4 to 82.4%). Furthermore, large datasets on population variation could be rapidly obtained. An analysis of microcolonies revealed subtle effects of antimycotics on resistant strains and below the MIC of sensitive strains, particularly an increase in population heterogeneity and cell density-dependent effects of triazoles. Additionally, the method could be adapted to strain identification via germ tube extension. We suggest PAO culture is a rapid and versatile method that may be usefully adapted to clinical mycology and has research applications. PMID- 22439001 TI - High resolution genetic mapping by genome sequencing reveals genome duplication and tetraploid genetic structure of the diploid Miscanthus sinensis. AB - We have created a high-resolution linkage map of Miscanthus sinensis, using genotyping-by-sequencing (GBS), identifying all 19 linkage groups for the first time. The result is technically significant since Miscanthus has a very large and highly heterozygous genome, but has no or limited genomics information to date. The composite linkage map containing markers from both parental linkage maps is composed of 3,745 SNP markers spanning 2,396 cM on 19 linkage groups with a 0.64 cM average resolution. Comparative genomics analyses of the M. sinensis composite linkage map to the genomes of sorghum, maize, rice, and Brachypodium distachyon indicate that sorghum has the closest syntenic relationship to Miscanthus compared to other species. The comparative results revealed that each pair of the 19 M. sinensis linkages aligned to one sorghum chromosome, except for LG8, which mapped to two sorghum chromosomes (4 and 7), presumably due to a chromosome fusion event after genome duplication. The data also revealed several other chromosome rearrangements relative to sorghum, including two telomere-centromere inversions of the sorghum syntenic chromosome 7 in LG8 of M. sinensis and two paracentric inversions of sorghum syntenic chromosome 4 in LG7 and LG8 of M. sinensis. The results clearly demonstrate, for the first time, that the diploid M. sinensis is tetraploid origin consisting of two sub-genomes. This complete and high resolution composite linkage map will not only serve as a useful resource for novel QTL discoveries, but also enable informed deployment of the wealth of existing genomics resources of other species to the improvement of Miscanthus as a high biomass energy crop. In addition, it has utility as a reference for genome sequence assembly for the forthcoming whole genome sequencing of the Miscanthus genus. PMID- 22439002 TI - Expression and characterization of Drosophila signal peptide peptidase-like (sppL), a gene that encodes an intramembrane protease. AB - Intramembrane proteases of the Signal Peptide Peptidase (SPP) family play important roles in developmental, metabolic and signaling pathways. Although vertebrates have one SPP and four SPP-like (SPPL) genes, we found that insect genomes encode one Spp and one SppL. Characterization of the Drosophila sppL gene revealed that the predicted SppL protein is a highly conserved structural homolog of the vertebrate SPPL3 proteases, with a predicted nine-transmembrane topology, an active site containing aspartyl residues within a transmembrane region, and a carboxy-terminal PAL domain. SppL protein localized to both the Golgi and ER. Whereas spp is an essential gene that is required during early larval stages and whereas spp loss-of-function reduced the unfolded protein response (UPR), sppL loss of function had no apparent phenotype. This was unexpected given that genetic knockdown phenotypes in other organisms suggested significant roles for Spp-related proteases. PMID- 22439003 TI - Prediction of promiscuous p-glycoprotein inhibition using a novel machine learning scheme. AB - BACKGROUND: P-glycoprotein (P-gp) is an ATP-dependent membrane transporter that plays a pivotal role in eliminating xenobiotics by active extrusion of xenobiotics from the cell. Multidrug resistance (MDR) is highly associated with the over-expression of P-gp by cells, resulting in increased efflux of chemotherapeutical agents and reduction of intracellular drug accumulation. It is of clinical importance to develop a P-gp inhibition predictive model in the process of drug discovery and development. METHODOLOGY/PRINCIPAL FINDINGS: An in silico model was derived to predict the inhibition of P-gp using the newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme based on the data compiled from the literature. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those structurally diverse molecules in the training set (n = 31, r(2) = 0.89, q(2) = 0.86, RMSE = 0.40, s = 0.28), the test set (n = 88, r(2) = 0.87, RMSE = 0.39, s = 0.25) and the outlier set (n = 11, r(2) = 0.96, RMSE = 0.10, s = 0.05). The generated PhE/SVM model also showed high accuracy when subjected to those validation criteria generally adopted to gauge the predictivity of a theoretical model. CONCLUSIONS/SIGNIFICANCE: This accurate, fast and robust PhE/SVM model that can take into account the promiscuous nature of P-gp can be applied to predict the P gp inhibition of structurally diverse compounds that otherwise cannot be done by any other methods in a high-throughput fashion to facilitate drug discovery and development by designing drug candidates with better metabolism profile. PMID- 22439004 TI - GsAPK, an ABA-activated and calcium-independent SnRK2-type kinase from G. soja, mediates the regulation of plant tolerance to salinity and ABA stress. AB - Plant Snf1 (sucrose non-fermenting-1) related protein kinase (SnRK), a subfamily of serine/threonine kinases, has been implicated as a crucial upstream regulator of ABA and osmotic signaling as in many other signaling cascades. In this paper, we have isolated a novel plant specific ABA activated calcium independent protein kinase (GsAPK) from a highly salt tolerant plant, Glycine soja (50109), which is a member of the SnRK2 family. Subcellular localization studies using GFP fusion protein indicated that GsAPK is localized in the plasma membrane. We found that autophosphorylation and Myelin Basis Protein phosphorylation activity of GsAPK is only activated by ABA and the kinase activity also was observed when calcium was replaced by EGTA, suggesting its independence of calcium in enzyme activity. We also found that cold, salinity, drought, and ABA stress alter GsAPK gene transcripts and heterogonous overexpression of GsAPK in Arabidopsis alters plant tolerance to high salinity and ABA stress. In summary, we demonstrated that GsAPK is a Glycine soja ABA activated calcium independent SnRK-type kinase presumably involved in ABA mediated stress signal transduction. PMID- 22439005 TI - Stability of strong species interactions resist the synergistic effects of local and global pollution in kelp forests. AB - Foundation species, such as kelp, exert disproportionately strong community effects and persist, in part, by dominating taxa that inhibit their regeneration. Human activities which benefit their competitors, however, may reduce stability of communities, increasing the probability of phase-shifts. We tested whether a foundation species (kelp) would continue to inhibit a key competitor (turf forming algae) under moderately increased local (nutrient) and near-future forecasted global pollution (CO(2)). Our results reveal that in the absence of kelp, local and global pollutants combined to cause the greatest cover and mass of turfs, a synergistic response whereby turfs increased more than would be predicted by adding the independent effects of treatments (kelp absence, elevated nutrients, forecasted CO(2)). The positive effects of nutrient and CO(2) enrichment on turfs were, however, inhibited by the presence of kelp, indicating the competitive effect of kelp was stronger than synergistic effects of moderate enrichment of local and global pollutants. Quantification of physicochemical parameters within experimental mesocosms suggests turf inhibition was likely due to an effect of kelp on physical (i.e. shading) rather than chemical conditions. Such results indicate that while forecasted climates may increase the probability of phase-shifts, maintenance of intact populations of foundation species could enable the continued strength of interactions and persistence of communities. PMID- 22439006 TI - Lettuce cultivar mediates both phyllosphere and rhizosphere activity of Escherichia coli O157:H7. AB - Plant roots and leaves can be colonized by human pathogenic bacteria, and accordingly some of the largest outbreaks of foodborne illness have been associated with salad leaves contaminated by E. coli O157. Integrated disease management strategies often exploit cultivar resistance to provide a level of protection from economically important plant pathogens; however, there is limited evidence of whether the genotype of the plant can also influence the extent of E. coli O157 colonization. To determine cultivar-specific effects on colonization by E. coli O157, we used 12 different cultivars of lettuce inoculated with a chromosomally lux-marked strain of E. coli O157:H7. Lettuce seedlings grown gnotobiotically in vitro did exhibit a differential cultivar-specific response to E. coli O157 colonization, although importantly there was no relationship between metabolic activity (measured as bioluminescence) and cell numbers. Metabolic activity was highest and lowest on the cultivars Vaila-winter gem and Dazzle respectively, and much higher in endophytic and tightly bound cells than in epiphytic and loosely bound cells. The cultivar effect was also evident in the rhizosphere of plants grown in compost, which suggests that cultivar-specific root exudate influences E. coli O157 activity. However, the influence of cultivar in the rhizosphere was the opposite to that in the phyllosphere, and the higher number and activity of E. coli O157 cells in the rhizosphere may be a consequence of them not being able to gain entry to the plant as effectively. If metabolic activity in the phyllosphere corresponds to a more prepared state of infectivity during human consumption, leaf internalization of E. coli O157 may pose more of a public health risk than leaf surface contamination alone. PMID- 22439007 TI - Inhibition of ERbeta induces resistance to cisplatin by enhancing Rad51-mediated DNA repair in human medulloblastoma cell lines. AB - Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERbeta, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERbeta considered as a supplemental anticancer therapy, has been found to interfere with cisplatin-induced cytotoxicity in human medulloblastoma cell lines. PMID- 22439008 TI - Quantification of hepatic iron concentration in chronic viral hepatitis: usefulness of T2-weighted single-shot spin-echo echo-planar MR imaging. AB - OBJECTIVE: To investigate the usefulness of single-shot spin-echo echo-planar imaging (SSEPI) sequence for quantifying mild degree of hepatic iron stores in patients with viral hepatitis. METHODS: This retrospective study included 34 patients with chronic viral hepatitis/cirrhosis who had undergone histological investigation and magnetic resonance imaging with T2-weighted gradient-recalled echo sequence (T2-GRE) and diffusion-weighted SSEPI sequence with b-factors of 0 s/mm(2) (T2-EPI), 500 s/mm(2) (DW-EPI-500), and 1000 s/mm(2) (DW-EPI-1000). The correlation between the liver-to-muscle signal intensity ratio, which was generated by regions of interest placed in the liver and paraspinous muscles of each sequence image, and the hepatic iron concentration (umol/g dry liver), which was assessed by spectrophotometry, was analyzed by linear regression using a spline model. Akaike information criterion (AIC) was used to select the optimal model. RESULTS: Mean +/- standard deviation of the hepatic iron concentration quantified by spectrophotometry was 24.6 +/- 16.4 (range, 5.5 to 83.2) umol/g dry liver. DW-EPI correlated more closely with hepatic iron concentration than T2-GRE (R square values: 0.75 for T2-EPI, 0.69 for DW-EPI-500, 0.62 for DW-EPI-1000, and 0.61 for T2-GRE, respectively, all P<0.0001). Using the AIC, the regression model for T2-EPI generated by spline model was optimal because of lowest cross validation error. CONCLUSION: T2-EPI was sensitive to hepatic iron, and might be a more useful sequence for quantifying mild degree of hepatic iron stores in patients with chronic viral hepatitis. PMID- 22439009 TI - Recognition of tennis serve performed by a digital player: comparison among polygon, shadow, and stick-figure models. AB - The objective of this study was to assess the cognitive effect of human character models on the observer's ability to extract relevant information from computer graphics animation of tennis serve motions. Three digital human models (polygon, shadow, and stick-figure) were used to display the computationally simulated serve motions, which were perturbed at the racket-arm by modulating the speed (slower or faster) of one of the joint rotations (wrist, elbow, or shoulder). Twenty-one experienced tennis players and 21 novices made discrimination responses about the modulated joint and also specified the perceived swing speeds on a visual analogue scale. The result showed that the discrimination accuracies of the experienced players were both above and below chance level depending on the modulated joint whereas those of the novices mostly remained at chance or guessing levels. As far as the experienced players were concerned, the polygon model decreased the discrimination accuracy as compared with the stick-figure model. This suggests that the complicated pictorial information may have a distracting effect on the recognition of the observed action. On the other hand, the perceived swing speed of the perturbed motion relative to the control was lower for the stick-figure model than for the polygon model regardless of the skill level. This result suggests that the simplified visual information can bias the perception of the motion speed toward slower. It was also shown that the increasing the joint rotation speed increased the perceived swing speed, although the resulting racket velocity had little correlation with this speed sensation. Collectively, observer's recognition of the motion pattern and perception of the motion speed can be affected by the pictorial information of the human model as well as by the perturbation processing applied to the observed motion. PMID- 22439010 TI - Co-variations and clustering of chronic disease behavioral risk factors in China: China Chronic Disease and Risk Factor Surveillance, 2007. AB - BACKGROUND: Chronic diseases have become the leading causes of mortality in China and related behavioral risk factors (BRFs) changed dramatically in past decades. We aimed to examine the prevalence, co-variations, clustering and the independent correlates of five BRFs at the national level. METHODOLOGY/PRINCIPAL FINDINGS: We used data from the 2007 China Chronic Disease and Risk Factor Surveillance, in which multistage clustering sampling was adopted to collect a nationally representative sample of 49,247 Chinese aged 15 to 69 years. We estimated the prevalence and clustering (mean number of BRFs) of five BRFs: tobacco use, excessive alcohol drinking, insufficient intake of vegetable and fruit, physical inactivity, and overweight or obesity. We conducted binary logistic regression models to examine the co-variations among five BRFs with adjustment of demographic and socioeconomic factors, chronic conditions and other BRFs. Ordinal logistic regression was constructed to investigate the independent associations between each covariate and the clustering of BRFs within individuals. Overall, 57.0% of Chinese population had at least two BRFs and the mean number of BRFs is 1.80 (95% confidence interval: 1.78-1.83). Eight of the ten pairs of bivariate associations between the five BRFs were found statistically significant. Chinese with older age, being a male, living in rural areas, having lower education level and lower yearly household income experienced increased likelihood of having more BRFs. CONCLUSIONS/SIGNIFICANCE: Current BRFs place the majority of Chinese aged 15 to 69 years at risk for the future development of chronic disease, which calls for urgent public health programs to reduce these risk factors. Prominent correlations between BRFs imply that a combined package of interventions targeting multiple BRFs might be appropriate. These interventions should target elder population, men, and rural residents, especially those with lower SES. PMID- 22439011 TI - microPIR: an integrated database of microRNA target sites within human promoter sequences. AB - BACKGROUND: microRNAs are generally understood to regulate gene expression through binding to target sequences within 3'-UTRs of mRNAs. Therefore, computational prediction of target sites is usually restricted to these gene regions. Recent experimental studies though have suggested that microRNAs may alternatively modulate gene expression by interacting with promoters. A database of potential microRNA target sites in promoters would stimulate research in this field leading to more understanding of complex microRNA regulatory mechanism. METHODOLOGY: We developed a database hosting predicted microRNA target sites located within human promoter sequences and their associated genomic features, called microPIR (microRNA-Promoter Interaction Resource). microRNA seed sequences were used to identify perfect complementary matching sequences in the human promoters and the potential target sites were predicted using the RNAhybrid program. >15 million target sites were identified which are located within 5000 bp upstream of all human genes, on both sense and antisense strands. The experimentally confirmed argonaute (AGO) binding sites and EST expression data including the sequence conservation across vertebrate species of each predicted target are presented for researchers to appraise the quality of predicted target sites. The microPIR database integrates various annotated genomic sequence databases, e.g. repetitive elements, transcription factor binding sites, CpG islands, and SNPs, offering users the facility to extensively explore relationships among target sites and other genomic features. Furthermore, functional information of target genes including gene ontologies, KEGG pathways, and OMIM associations are provided. The built-in genome browser of microPIR provides a comprehensive view of multidimensional genomic data. Finally, microPIR incorporates a PCR primer design module to facilitate experimental validation. CONCLUSIONS: The proposed microPIR database is a useful integrated resource of microRNA-promoter target interactions for experimental microRNA researchers and computational biologists to study the microRNA regulation through gene promoter. The database can be freely accessed from: http://www4a.biotec.or.th/micropir. PMID- 22439012 TI - Additive pressures of elevated sea surface temperatures and herbicides on symbiont-bearing foraminifera. AB - Elevated ocean temperatures and agrochemical pollution individually threaten inshore coral reefs, but these pressures are likely to occur simultaneously. Experiments were conducted to evaluate the combined effects of elevated temperature and the photosystem II (PSII) inhibiting herbicide diuron on several types of symbiotic algae (diatom, dinoflagellate or rhodophyte) of benthic foraminifera in hospite. Diuron was shown to evoke a direct effect on photosynthetic efficiency (reduced effective PSII quantum yield DeltaF/F'(m)), while elevated temperatures (>30 degrees C, only 2 degrees C above current average summer temperatures) were observed to impact photosynthesis more indirectly by causing reductions in maximum PSII quantum yield (F(v)/F(m)), interpreted as photodamage. Additionally, elevated temperatures were shown to cause bleaching through loss of chlorophyll a in foraminifera hosting either diatoms or dinoflagellates. A significant linear correlation was found between reduced F(v)/F(m) and loss of chlorophyll a. In most cases, symbionts within foraminifera proved more sensitive to thermal stress in the presence of diuron (>= 1 ug L(-1)). The mixture toxicity model of Independent Action (IA) described the combined effects of temperature and diuron on the photosystem of species hosting diatoms or dinoflagellates convincingly and in agreement with probabilistic statistics, so a response additive joint action can be assumed. We thus demonstrate that improving water quality can improve resilience of symbiotic phototrophs to projected increases in ocean temperatures. As IA described the observed combined effects from elevated temperature and diuron stress it may therefore be employed for prediction of untested mixtures and for assessing the efficacy of management measures. PMID- 22439013 TI - Clinical impact of atrial fibrillation in patients with pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension (PH) is associated with progressive impairment of right ventricular function, reduced exercise capacity and a poor prognosis. Little is known about the prevalence, clinical manifestation and impact of atrial fibrillation (AF) on cardiac function in PH. METHODS: In a four year single centre retrospective analysis 225 patients with confirmed PH of various origins were enrolled to investigate the prevalence of AF, and to assess the clinical manifestation, 6-minute walk distance, NT-proBNP levels, echocardiographic parameters and hemodynamics obtained by right heart catheterization in PH with AF. RESULTS: AF was prevalent in 31.1%. In patients with PH and AF, parameters of clinical deterioration (NYHA/WHO functional class, 6-minute walk distance, NT proBNP levels) and renal function were significantly compromised compared to patients with PH and sinus rhythm (SR). In the total PH cohort and in PH not related to left heart disease occurrence of AF was associated with an increase of right atrial pressure (RAP) and right atrial dilatation. While no direct association was found between pulmonary artery pressure (PAP) and AF in these patients, right ventricular function was reduced in AF, indicating more advanced disease. In PH due to left heart failure the prevalence of AF was particularly high (57.7% vs. 23.1% in other forms of PH). In this subgroup, left atrial dilatation, increase of pulmonary capillary wedge pressure, PAP and RAP were more pronounced in AF than in SR, suggesting that more marked backward failure led to AF in this setting. CONCLUSION: PH is associated with increased prevalence of AF. Occurrence of AF in PH indicates clinical deterioration and more advanced disease. PMID- 22439014 TI - Speech spectrum's correlation with speakers' Eysenck personality traits. AB - The current study explored the correlation between speakers' Eysenck personality traits and speech spectrum parameters. Forty-six subjects completed the Eysenck Personality Questionnaire. They were instructed to verbally answer the questions shown on a computer screen and their responses were recorded by the computer. Spectrum parameters of /sh/ and /i/ were analyzed by Praat voice software. Formant frequencies of the consonant /sh/ in lying responses were significantly lower than that in truthful responses, whereas no difference existed on the vowel /i/ speech spectrum. The second formant bandwidth of the consonant /sh/ speech spectrum was significantly correlated with the personality traits of Psychoticism, Extraversion, and Neuroticism, and the correlation differed between truthful and lying responses, whereas the first formant frequency of the vowel /i/ speech spectrum was negatively correlated with Neuroticism in both response types. The results suggest that personality characteristics may be conveyed through the human voice, although the extent to which these effects are due to physiological differences in the organs associated with speech or to a general Pygmalion effect is yet unknown. PMID- 22439015 TI - CAXII Is a sero-diagnostic marker for lung cancer. AB - To develop sero-diagnostic markers for lung cancer, we generated monoclonal antibodies using pulmonary adenocarcinoma (AD)-derived A549 cells as antigens by employing the random immunization method. Hybridoma supernatants were immunohistochemically screened for antibodies with AMeX-fixed and paraffin embedded A549 cell preparations. Positive clones were monocloned twice through limiting dilutions. From the obtained monoclonal antibodies, we selected an antibody designated as KU-Lu-5 which showed intense membrane staining of A549 cells. Based on immunoprecipitation and MADLI TOF/TOF-MS analysis, this antibody was recognized as carbonic anhydrase XII (CAXII). To evaluate the utility of this antibody as a sero-diagnostic marker for lung cancer, we performed dot blot analysis with a training set consisting of sera from 70 lung cancer patients and 30 healthy controls. The CAXII expression levels were significantly higher in lung cancer patients than in healthy controls in the training set (P<0.0001), and the area under the curve of ROC was 0.794, with 70.0% specificity and 82.9% sensitivity. In lung cancers, expression levels of CAXII were significantly higher in patients with squamous cell carcinoma (SCC) than with AD (P = 0.035). Furthermore, CAXII was significantly higher in well- and moderately differentiated SCCs than in poorly differentiated ones (P = 0.027). To further confirm the utility of serum CAXII levels as a sero-diagnostic marker, an additional set consisting of sera from 26 lung cancer patients and 30 healthy controls was also investigated by dot blot analysis as a validation study. Serum CAXII levels were also significantly higher in lung cancer patients than in healthy controls in the validation set (P = 0.030). Thus, the serum CAXII levels should be applicable markers discriminating lung cancer patients from healthy controls. To our knowledge, this is the first report providing evidence that CAXII may be a novel sero-diagnostic marker for lung cancer. PMID- 22439017 TI - Cerebrovascular Casting of the Adult Mouse for 3D Imaging and Morphological Analysis. AB - Vascular imaging is crucial in the clinical diagnosis and management of cerebrovascular diseases, such as brain arteriovenous malformations (BAVMs). Animal models are necessary for studying the etiopathology and potential therapies of cerebrovascular diseases. Imaging the vasculature in large animals is relatively easy. However, developing vessel imaging methods of murine brain disease models is desirable due to the cost and availability of genetically modified mouse lines. Imaging the murine cerebral vascular tree is a challenge. In humans and larger animals, the gold standard for assessing the angioarchitecture at the macrovascular (conductance) level is x-ray catheter contrast-based angiography, a method not suited for small rodents. PMID- 22439016 TI - Reversal of the DeltadegP phenotypes by a novel rpoE allele of Escherichia coli. AB - RseA sequesters RpoE (sigma(E)) to the inner membrane of Escherichia coli when envelope stress is low. Elevated envelope stress triggers RseA cleavage by the sequential action of two membrane proteases, DegS and RseP, releasing sigma(E) to activate an envelope stress reducing pathway. Revertants of a DeltadegP DeltabamB strain, which fails to grow at 37 degrees C due to high envelope stress, harbored mutations in the rseA and rpoE genes. Null and missense rseA mutations constitutively hyper-activated the sigma(E) regulon and significantly reduced the major outer membrane protein (OMP) levels. In contrast, a novel rpoE allele, rpoE3, resulting from the partial duplication of the rpoE gene, increased sigma(E) levels greater than that seen in the rseA mutant background but did not reduce OMP levels. A sigma(E)-dependent RybB::LacZ construct showed only a weak activation of the sigma(E) pathway by rpoE3. Despite this, rpoE3 fully reversed the growth and envelope vesiculation phenotypes of DeltadegP. Interestingly, rpoE3 also brought down the modestly activated Cpx envelope stress pathway in the DeltadegP strain to the wild type level, showing the complementary nature of the sigma(E) and Cpx pathways. Through employing a labile mutant periplasmic protein, AcrA(L222Q), it was determined that the rpoE3 mutation overcomes the DeltadegP phenotypes, in part, by activating a sigma(E)-dependent proteolytic pathway. Our data suggest that a reduction in the OMP levels is not intrinsic to the sigma(E) mediated mechanism of lowering envelope stress. They also suggest that under extreme envelope stress, a tight homeostasis loop between RseA and sigma(E) may partly be responsible for cell death, and this loop can be broken by mutations that either lower RseA activity or increase sigma(E) levels. PMID- 22439018 TI - Fetal weight estimation for prediction of fetal macrosomia: does additional clinical and demographic data using pattern recognition algorithm improve detection? AB - OBJECTIVE: The aim of this study was to test whether pattern recognition classifiers with multiple clinical and sonographic variables could improve ultrasound prediction of fetal macrosomia over prediction which relies on the commonly used formulas for the sonographic estimation of fetal weight. METHODS: THE SVM ALGORITHM WAS USED FOR BINARY CLASSIFICATION BETWEEN TWO CATEGORIES OF WEIGHT ESTIMATION: >4000gr and <4000gr. Clinical and sononographic input variables of 100 pregnancies suspected of having LGA fetuses were tested. RESULTS: Thirteen out of 38 features were selected as contributing variables that distinguish birth weights of below 4000gr and of 4000gr and above. Considering 4000gr. as a cutoff weight the pattern recognition algorithm predicted macrosomia with a sensitivity of 81%, specificity of 73%, positive predictive value of 81% and negative predictive value of 73%. The comparative figures according to the combined criteria based on two commonly used formulas generated from regression analysis were 88.1%, 34%, 65.8%, 66.7%. CONCLUSIONS: The SVM algorithm provides a comparable prediction of LGA fetuses as other commonly used formulas generated from regression analysis. The better specificity and better positive predictive value suggest potential value for this method and further accumulation of data may improve the reliability of this approach. PMID- 22439019 TI - Prenatal screening of Cystic Fibrosis: a single centre experience. AB - OBJECTIVE: The gene responsible for the pathogenesis of cystic fibrosis has been known for over 15 years and represent the most common autosomal recessive disease in the european population. We aimed to investigate the incidence of this condition during fetal life. METHODS: In the past 10 years we examined in our centre 25393 fetuses of women underwent to amniocentesis. We carried out the examination of the most frequent mutations which enable, according to the literature data, the identification of almost 80% of the affected alleles. RESULT: We identified 922 heterozygous and 9 homozygous for the mutation. The frequency of heterozygousin the examined sample was 1/27,5 while that of the affected was 1/2821. CONCLUSION: We encourage new thoughts regarding the diagnostic validity of the most frequent panel of mutations among the italian population in order to exclude never encountered mutations and the insertion of other more significant mutations. PMID- 22439020 TI - Analysis of fetal biometric measurements in the last 30 years. AB - OBJECTIVES: To compare fetal biometric measurements with standard growth charts for ultrasound parameters existing from the last 30 years. STUDY DESIGN: A preliminary prospective study. SETTING: Artemisia Mean Centre of Perinatal Diagnosis, Rome,Italy. MATERIAL AND METHOD: A cross sectional study involving 1000 pregnant women with uncomplicated singleton pregnancy between 14(th) and 41(th) weeks of gestation from 1 January to 30 June 2008. All recruited pregnant women enrolled had an abdominal ultrasonography for fetal biometry. For each measurement, regression models were fitted to estimate the mean and SD. The results were compared with existing references from the last 30 years using Student's T distribution. Moreover, neonatal weights were obtained from 1977 to 2008 by ISTAT. RESULTS: One thousand normal fetuses from pregnant women, between 22(th) and 23(th) weeks, between 32(th) and 33(th) weeks and at 38(th) week, were thoroughly measured. THERE WERE SIGNIFICANT DIFFERENCES FROM THE COMPARISON WITH OUR DATA FOR EACH GESTATIONAL AGE: femur length and homer length, abdominal circumference, head circumference and occipitofrontal diameter were longer than all parameters of existing references from the last 30 years. The analysis of neonatal weights on ISTAT data from 1977 to 2007 demonstrated a significant increment through the years. CONCLUSION: Fetus is grown up across the years. It is necessary to modify the standard growth charts for ultrasound parameters existing from the last 30 years with actually fetal biometric measurements. It is helpful for a correct clinical approach and for an appropriate management mother fetus. PMID- 22439021 TI - Preterm delivery at low gestational age: risk factors for short latency. A multivariated analysis. AB - OBJECTIVE: The aim of this study is to identify the risk factors for a short latency in preterm delivery at low gestational ages (GA). STUDY DESIGN: A retrospective analysis involving, between January 2004 and May 2006, 204 singleton pregnancies with admission diagnosis of preterm labor and, in particular, 91 pregnant women admitted between 24+0 and 31+6 weeks' gestation. RESULTS: In pregnant women with a diagnosis of preterm labor at 24-31+6 weeks' gestation, at ROC curve, a value of considering WBC and cervical dilatation, combined in the following formula (75.237 - (2.290 * "WBC") - (10.787 * "cervical dilatation")) <=33.101 has a 74.2% Sensitivity and a 78.3% Specificity in predicting a latency =< 4 days (+LR 3.42 and -LR 0.33) and a 70% Sensitivity and a 84.3% Specificity in predicting GA at delivery at 24-31 weeks' gestation (+LR 4.46 and -LR 0.36). CONCLUSION: We suggest a more strictly monitoring and a more aggressive therapy in presence of prognostic parameters of shorter latency. PMID- 22439022 TI - History of colposcopy: a brief biography of Hinselmann. AB - OBJECTIVES: To consider all the historical reasons for the slow growth of colposcopy through a brief biography of Hinselmann. The history of colposcopy is beginning in March 1924. In the first experiments, colposcopic examination was almost impossible to perform because of the distance from the focus, that was no more than 80 mm. Hinselmann tried to solve this problem by pulling out the uterine cervix. The examined part is anemised by this procedure, which can prejudice the final result and a small amount of blood might leak as well. Beside that, a patient can feel pain if the portio is held by a thin forceps. The colposcopy, established in Germany, had spread throughout slowly its motherland, probably thanks to the many mistakes caused by Hinselmann himself: a technique proposed and almost exclusively intended for early discovery of cervical carcinoma;very authoritative imposition of terms, especially histological, which caused resistance by hystopathologists possibly induced by the fear of loosing their prestige who considered them too complex;his stubbornness in considering leukoplakia as precancerous lesion imposed him a lot of opponents;until the 1950's there had not yet been any adequate didactic material at the disposal of numerous gynaecologists;Hinselmann's temper, described by Wespi as a mixture of innocence and missionary eagerness, had not prepared him for dialogue and compromise. CONCLUSION: It might seem surprising that colposcopy, accurate in detecting all benign lesions and initial atypical transformations, and perfectly capable of pointing safe biopsy in cases of suspicious lesions, did not develop as it should have a method whose function is of great importance in the prevention and treatment of CIN. Despite the role and the importance of cytology in the realization of the population programme of cervical cancer detection, the colposcopy allows the precise diagnosis among women with abnormal pap smears. PMID- 22439023 TI - Severe, early onset hypertrophic cardiomyopathy in a family with LEOPARD syndrome. AB - OBJECTIVE: Leopard syndrome is an acronym (multiple Lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) describing an autosomal dominant disease due to mutations in the raS-MapK pathway. METHODS: Here, we describe a family (mother and daughter) with clinical and molecular diagnosis of Leopard syndrome 1 and HCM, and we report the prenatal diagnosis of HCM in a fetus at risk for Leopard syndrome. RESULTS: An echocardiography was conducted showing a significant hypertrophy of both ventricles (left and right ventricular wall thickness 9mm and 3 mm). After a multidisciplinary counseling the couple opted for the termination of pregnancy CONCLUSION: Further genotype-phenotype studies are warranted to fully elucidate the impact of the genotype on the natural history of patients with LS and LVH. PMID- 22439024 TI - Indication of prenatal diagnosis in pregnancies complicated by undetectable second-trimester maternal serum estriol levels. AB - OBJECTIVES: Undetectable maternal serum unconjugated estriol levels in the second trimester screening test have been associated with congenital pathology and an adverse pregnancy outcome. We reviewed outcomes of pregnancies with undetectable levels of estriol (<0.25 ng/ml) in the triple-marker screening test and assessed the clinical value of this finding. METHODS: We studied estriol values in 6,018 pregnant patients who underwent a triple-marker screening test during a seven year period. RESULTS: 26 women had estriol levels at or below the sensitivity of the assay. The most common explanations were dating errors, prematurity, growth restriction and X-linked ichthyosis. We also observed one fetal death at 16 weeks, one severe threatened fetal abortion, one case of multiple congenital anomalies and one case of isolated adrenocorticotropin hormone deficiency. There were 6 women remaining with unexplained undetectable estriol. CONCLUSION: Undetectable maternal estriol values may indicate a severe fetal pathology and should lead to further investigations. PMID- 22439025 TI - Two-dimensional fetal echocardiography: where we are. AB - Congenital Heart Disease (CHD) is the most common severe congenital abnormality in the newborn and the cause of over half the deaths from congenital anomalies in childhood. Prenatal diagnosis, possible as early as 15 weeks of gestation, allows physicians and families the greatest number of therapeutic options, and can improve the postnatal outcome. There are several potential indications for performing such examination. Evaluation of the heart in the setting of restricted fetal growth or fetal distress is often recommended. Whenever extracardiac anomalies are detected during fetal ultrasound examination or in presence of chromosomal abnormalities detected with amniocentesis, cardiac assessment is mandatory. The test should also be performed as part of the assessment of fetal arrhythmias. Finally, whenever congenital heart disease is suspected for other reasons, such as maternal exposure to teratogenic substances or a parental history of previous children with congenital lesions, the examination should be considered. The performance of a fetal echocardiogram requires experience and a systematic approach. Guidelines for training have been formulated, and only qualified individuals should perform this highly specialized examination. A description of the techniques of heart examination is presented below. PMID- 22439026 TI - Exploring SOD1 Gene for the Detection of Fetal Down Syndrome. AB - OBJECTIVE: Fetal cells and circulating cellfree fetal DNA increases in the maternal circulation in women carrying trisomy 21 fetus. METHODS: We attempted the use of superoxide dismutase (SOD-1) gene, which is located at the Down Syndrome Critical Region, to overcome this situation for the prenatal screening of Down syndrome. The prospective of the gene using real-time quantitative polymerase chain reaction was explored. RESULTS: The level of SOD-1 sequences is significantly elevated in the third trimester normal pregnancies (mean = 11728 copies/MUl) when compared to the second trimester (mean = 5705.6 copies/MUl), (p<0.005) and non pregnant normal women (mean = 3580.2 copies/MUl), (p<0.0001). Down syndrome pregnancies have the greatest elevation compared to all the three trimesters of normal singleton pregnancies and twin pregnancies, p<0.05. CONCLUSIONS: These data indicate that a quantitative analysis using a gene associated with a disorder could be used in screening for the prenatal diagnosis of fetal aneuploidies regardless of the sex of the fetus. PMID- 22439027 TI - Prevention of Neural Tube Defects and proper folate periconceptional supplementation. AB - "Patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community." (WHO, 1985).The WHO statement on the rationale use of medicines, and the reasons why medicines are often used irrationally should be carefully considered even in the present days, as physician must face lack of knowledge, limited economic resources, and a plethora of therapeutic suggestions. PMID- 22439028 TI - Prenatal third trimester sonographic behavior of a thanatophoric dwarfs. AB - OBJECTIVES: Thanatophoric dysplasia (TD), the most common of the congenital lethal skeletal dysplasias occurs sporadically in 1/64,000-100,000 live births. To the best of our knowledge, the in utero attitudes and behaviours of such babies with serial ultrasound scans have not been previously described. We present the in utero third trimester sonographic behaviors of TD in a 22-year-old primigravida diagnosed at '32weeks' gestational age along with the clinical and radiographic characteristics. METHODS: The same radiologists to observe the behavior of a thanatophoric dwarfs did three fortnights serial ultrasound scans. RESULTS: The baby was found to have short limbs that were constantly in rigid abduction, flexed at both elbows and knees, and demonstrated poverty of synchronous movements. The upper limbs were perpetually in embracing position during all scans. In addition, he was hyperactive, showing "yoyo" body movement and constantly hyper-extended neck. Postmortem radiograph was diagnostic of TD. CONCLUSION: Though he baby died intra partum, the observed attitudes and behaviors on serial prenatal ultrasonography, which provided us with sufficient information to counsel the family, managed the pregnancy, and direct the postnatal evaluation could possibly add to the in utero diagnostic sonographic features of TD. PMID- 22439029 TI - An isolated fetal cor triatriatum dexter during a targeted anatomic survey at 22 weeks' gestation. AB - OBJECTIVE: Cor triatriatum dexter is a rare cardiac malformation characterized by division of the right atrium into two compartments by a usually fenestrated membrane, whose degree of partitioning or septation is responsible for different clinical manifestations. METHODS: We report the first case of an isolated fetal cor triatriatum dexter that was diagnosed during ultrasound screening at 22 weeks of gestation. RESULTS: The sonographic examination of the fetal cardiac morphology revealed the presence of a membrane stretched between the medial and lateral walls of right atrium in the apical four-chamber view. Fetal morphology and biometric features were normal and appropriate for gestational age. CONCLUSION: This is the first report of an isolated fetal cor triatriatum dexter that was diagnosed during ultrasound screening at 22 weeks of gestation. PMID- 22439030 TI - Hypertensive disorders of pregnancy. AB - Hypertension is the most common medical problem encountered during pregnancy, complicating 2-3% of pregnancies. Hypertensive disorders during pregnancy are classified into 4 categories, as recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy: 1) chronic hypertension, 2) preeclampsia-eclampsia, 3) preeclampsia superimposed on chronic hypertension, and 4) gestational hypertension (transient hypertension of pregnancy or chronic hypertension identified in the latter half of pregnancy) (1). This terminology is preferred over the older but widely used term pregnancy induced hypertension (PIH) because it is more precise. PMID- 22439031 TI - Obstetric management of IUGR. AB - The intrauterine growth retardation (IUGR) takes second position after the premature births as a cause for neonate with smaller weight for it's gestational age. Perinatal morbidity of retard children is important, but perinatal mortality is about eight times higher then normal weighted neonates. It is very important to make the right diagnosis of IUGR, the cause of their illness, the therapy they need and when it's necessary to find the right time, place and way of birth. PMID- 22439032 TI - Case report: successful of a spontaneous quadruplet pregnancy. AB - OBJECTIVE: To report a rare case of successful pregnancy and delivery of two pair of monozygotic twins (quadruplets). METHODS: We reported a Case Report of a 32 year-old nulligravida, who had had a previous twin pregnancy and was herself a twin assisted hatching. Prophylactic cervical cerclage sec. McDonald in the 23st week of pregnancy, hospitalization, and intensive care of pregnancy were performed. RESULTS: Successful pregnancy and delivery of two male and two female twins in the 34th week of pregnancy. PMID- 22439033 TI - Fetal cystic lymphangioma of the neck: a case report. AB - OBJECTIVE: A case of fetal neck lymphangioma is reported METHODS: A 34-year-old primigravida presented with a fetus at 21+5 weeks' gestation with a neckl cystic mass. RESULTS: Diagnosis of neck lymphangioma was made; the couple opted for termination of pregnancy a 22 weeks; they refused fetal autopsy. CONCLUSION: Counseling in case of neck lynphangioma is still difficult. Prognosis in guarded as many patients decide for interruption of pregnancy. PMID- 22439034 TI - Management of molar pregnancy. AB - Gestational Trophoblastic Disease (GTD) originates from placental tissue and is among the rare human tumors that can be cured even in the presence of widespread metastases. GTD include a spectrum of interrelated tumors including complete and partial hydatidiform mole, invasive mole, choriocarcinoma, and placental site trophoblastic tumor, that have different propensities for local invasion and spread. Although most GTD develop after a mole, they can follow any antecedent pregnancy.Transvaginal ultrasound, routinary dosage of beta-hCG and current approaches to chemotherapy, let most women with malignant gestational trophoblastic disease to be cured and their reproductive function preserved. PMID- 22439035 TI - Prenatal diagnosis of limb abnormalities: role of fetal ultrasonography. AB - Fetal ultrasonografy is the most important tool to provide prenatal diagnosis of fetal anomalies. The detection of limb abnormalities may be a complex problem if the correct diagnostic approch is not established. A careful description of the abnormality using the rigth nomenclature is the first step. Looking for other associated abnormalities is the threshold to suspect chromosomal abnormalities or single gene disorder. According to the patogenic point of view, limb abnormalities may be the result of malformation, deformation, or disruption. The prenatal diagnosis and the management of limb abnormalities involve a multidisciplinary team of ostetrician, radiologist/sonologist, clinical geneticist, neonatologist, and orthopedic surgeons to provide the parents with the information regarding etiology of the disorder, prognosis, option related to the pregnancy and recurrence risk for future pregnancies.The aim of this review is to describe the importance of detailed fetal ultrasonography in prenatal diagnosis of limb abnormalities. PMID- 22439036 TI - Now you can! Reality & Future Applications of array CGH in prenatal diagnosis. PMID- 22439037 TI - Obstetric management in Rh alloimmunizated pregnancy. AB - Rh alloimmunization occurs when maternal immune system is sensitized to D(Rh) erythrocyte surface antigens.The most common causes of maternal Rh alloimmunisation are blood transfusion and antepartum or intrapartum fetomaternal hemorrhage (abdominal trauma, abortion, ectopic pregnancy, invasive obstetric procedures, placental abruption, external cephalic version).The risk of alloimmunization is affected by several factors, including the degree of fetomaternal hemorrhage and maternal immune respons.Although the introduction of anti D prophylaxis reduced dramatically the rate of alloimmunization in susceptible women, his prevention is not universal and about 0.3% of susceptible women still become Rh D alloimmunized.The aim of this article is to review the management of the Rh alloimmunizated pregnant. PMID- 22439038 TI - Fetal intracranial cysts: prenatal diagnosis and outcome. AB - Intracranial cysts are central nervous system malformations involving different brain regions, and commonly diagnosed during prenatal period by ultrasound scan (US). A malformative cyst is a nontumoral fluid-filled collection exerting a mass effect on the brain parenchyma and/or on the ventricles, regardless of its location within subarachnoid spaces, brain or ventricles, and of the nature of its limiting membrane, which is always unknown prenatally. Although a large number of case reports have been published, many uncertainties remain concerning their epidemiology, pathogenesis, and outcome. Most of these lesions, if not associated with other fetal anomalies, are benign in nature, remain clinically silent, do not evolve or even frequently regress spontaneously and do not impair physiologic neurodevelopment. The normality of the adjacent brain is the major argument in favour of a malformative lesion. The correct diagnosis is of crucial importance to exclude the presence of other rare lesions (e.g. cystic neoplasms or intracranial hemorrhage) that could negatively affect neurodevelopmental outcome of the child. To establish a correct prognosis all efforts must aim to precisely interpret the US images accurately analyzing the brain anatomy. PMID- 22439039 TI - Echotomography of craniosynostosis: review of literature. AB - Ultrasound examination of the foetal cranium can diagnose fetal cranial defects and abnormal skull shape and it's aim is to detect in prenatal age most various abnormalities of the skull, brain and foetal face. The changes of each of these components frequently determine the growth of the other two.The abnormalities of the foetal head frequently appear and can associate serious pathological sceneries of high foetal and perinatal morbidity and mortality.Anomalies of the head have been observed using ultrasound study during the early second trimester. To establish diagnosis and long term prognosis is particularly important and helpful correct detection of the nature of the malformation. PMID- 22439040 TI - The amniotic fluid-derived cells: the biomedical challenge for the third millennium. AB - Human amniotic fluid cells (H-AFC) have been used as a diagnostic tool for the prenatal diagnosis of fetal genetic anomalies for more than 50 years.In the early 1990s small nucleated cells, which were identified as he-matopoietic progenitors, were detected in the amniotic fluid. After this evidence several other scientific novelties as been brought out to the attention of the scientific community. In these brief history of the Human amniotic fluid cells (H-AFC) the last but not least evidence, provided in the last 5 years, suggests that they can also harbor a therapeutic potential for human diseases. PMID- 22439041 TI - Prenatal diagnosis of left isomerism with normal heart: a case report. AB - OBJECTIVE: Left isomerism, also called polysplenia, is a laterality disturbance associated with with paired leftsidedness viscera and multiple small spleens. Left isomerism, heart congenital abnormalities and gastrointestinal malformation are strongly associated. METHODS: We present a case of prenatal diagnosis of left isomerism in a fetus with a structurally normal heart. CONCLUSION: Left isomerism syndrone may coesist with a structurally normal heart. If prenatal left isomerism is suspected, even in presence of a normal heart, is mandatory to esclude sign of gastrointestinal abnormalities, as late poly hy dramnios, and cardiac rhytm disturbance during the pregnancy and neonatal age. PMID- 22439042 TI - Proteomic analysis for the study of amniotic fluid protein composition. AB - Amniotic fluid (AF), routinely used for prenatal diagnosis, contains large amounts of proteins produced by the amnion epithelial cells, fetal tissues, fetal excretions and placental tissuesAlthough many amniotic fluid proteins have been identified and are currently used to detect potential fetal anomalies, little is known about the functions of these proteins and how they interact with one another. Identification of changes in the protein content of amniotic fluid, therefore, may be used to detect a particular type of pathology, or to ascertain a specific genetic disorder. In the present work we used a proteomic approach, combining 2DE and MS, in order to study the protein composition of AFS. PMID- 22439043 TI - A prenatally diagnosed case of sirenomelia with dextrocardia and omphalocele. AB - OBJECTIVE: Sirenomelia (Mermaid syndrome) is a rare anomaly of caudal region of the body, presented with fusion of the lower limbs. Genito-urinary, gastro intestinal, neural tube and vertebral anomalies are found in most cases. METHODS: We present a case of sirenomelia diagnosed in the first tri-mester, associated with dextrocardia, and omphalocele CONCLUSION: First trimester diagnosis of sirenomielia is possible and early diagnosis gives the parents the option of early pregnancy termination. PMID- 22439044 TI - Abnormal skull findings in neural tube defects. AB - The human neural tube develops and closes during the third and fourth week after conception and is normally completed by 28 days post-conception. Malformations, knows as neural tube defects, occure, when the normal closure process fails. Several clinical types of neural tube defects are recognized, anencefaly and spina bifida being the most common. Such malformations are generally associated with cranial abnormlities. PMID- 22439045 TI - Fetal lung lesions diagnosis: the crucial role of ultrasonography. AB - Fetal lung lesions may cause significant effects of mass and may evolve into a non-immune hydrops and lead to the death of the fetus or the child. Treatment options for these severely affected infants are constantly evolving. The widespread use of ultrasound in prenatal diagnosis, in tertiary center like ours, allows us to identify the fetus, including lung lesions more 'small. Prenatal diagnosis and possible therapeutic intervention in the immediate prenatal or postnatal period has significantly changed the quality of life and the survival of fetuses and infants, especially those who were completely asymptomatic at birth.Object of our interest is the pulmonary sequestration and congenital pulmonary malformation is the second in order of frequency, with an incidence between 0.15% and 6.4% of cases. PMID- 22439046 TI - Addison's disease and pregnancy: case report. AB - OBJECTIVE: Addisonian crises, a rare but life-threatening event in pregnant women, may accompany stressful conditions such as labor, puerperium, infection, hyperemesis gravidarum or surgery. METHODS: A 36-year-old woman, primigravida, with Addison's disease, diagnosed when she was 10 year-old and treated with cortisone and fludrocortisone. The therapy was regulated to avoid adrenal crisis during pregnancy. RESULT: The woman underwent to caesarean section at 38th week and gave birth to a normal baby. CONCLUSION: The successful management of pregnant women with Addison's disease, regarding her state and that of the foetus, reassures those women that nowadays Addison's disease and pregnancy are not incompatible when proper monitoring and management is provided. PMID- 22439047 TI - Pregnancy outcome during haemodialysis: a case report. AB - OBJECTIVE: Successful pregnancy outcome is an uncommon occurrence in women requiring chronic dialysis treatment. METHODS: We reported the course and outcome of a case of pregnancy occurred in a woman affected by lupus erythematosus on chronic hemodialysis. RESULTS: At 33rd gestational week the woman underwent to caesarean section because of starting labour. The newborn, female, well-being baby of which weight was 1530 grams and APGAR score was 8/9 at 1st and 5th min. CONCLUSION: The pregnancy of an woman in chronic dialysis is at very high risk but it should reach a good outcome with a multidisciplinary management, by nephrologists, obstetricians and neonatologists. PMID- 22439048 TI - Post partum pelvic floor changes. AB - Pelvic-perineal dysfunctions, are the most common diseases in women after pregnancy. Urinary incontinence and genital prolapsy, often associated, are the most important consequences of childbirth and are determined by specific alterations in the structure of neurological and musculo-fascial pelvic support.Causation is difficult to prove because symptom occur remote from delivery.Furthermore it is unclear whether changes are secondary to the method of childbirth or to the pregnancy itself.This controversy fuels the debate about whether or not women should be offered the choice of elective caesarean delivery to avoid the development of subsequent pelvic floor disfunction.But it has been demonstrated that pregnancy itself, by means of mechanical changes of pelvic statics and changes in hormones, can be a significant risk factor for these diseases. Especially is the first child to be decisive for the stability of the pelvic floor.During pregnancy, the progressive increase in volume of the uterus subject perineal structures to a major overload. During delivery, the parties present and passes through the urogenital hiatus leading to growing pressure on the tissues causing the stretching of the pelvic floor with possible muscle damage, connective tissue and / or nervous.In this article we aim to describe genitourinary post partum changes with particular attention to the impact of pregnancy or childbirth on these changes. PMID- 22439049 TI - Ultrasound Scanning in Fetal Renal Pelvis Dilatation: not only Hydronephrosis. AB - Pelvic dilatation is the alteration of the urinary tractmost frequently detected by maternal-fetalultra-sound. Hydronephrosis is not a diagnosis; it is an imagefinding. The diagnosis is the cause that produces it. Since pelvic dilatation is relatively frequent in thenormal fetus, and the definition and diagnosis of hy-dronephrosis are difficult, once it is detected, adequate follow up is required. Therefore, it is important for the urologist and obstetrician to understanddifferential diagnosis and clinical implications in order to offer an accurate counselling to the parents. PMID- 22439050 TI - Reference interval for fetal biometry in Italian population. AB - OBJECTIVES: To validate new references charts and equations for fetal biometry in an Italian unselected population. METHODS: A cross-sectional study involving 4896 women with singleton viable pregnancies, at Artemisia Fetal Maternal Medical Centre between May 2009 and December 2009. Each woman was scanned only once, between 14+0 and 40+0 weeks of gestation. The fetal standard biometric measurements were recorded. For each parameter, regression models were fitted to estimate the percentile at each gestational age. In order to be compared to other reference equations, the fetal biometric measurements at each gestational age were expressed as Z-scores. RESULTS: New fetal charts and references equations for Italian population were developed according to the recommend multistep statistical procedure. CONCLUSION: To our knowledge this is the first Italian study with the largest sample size ever reported in the literature. In addiction, our newer charts of reference centiles for fetal biometric measurements are useful in the obstetrical clinical practice for the Italian population. PMID- 22439051 TI - Putative protective effects of cesarean section on pelvic floor disorders. AB - Pregnancy can affect the lower genitourinary tract through physiologic changes, or traumatic injury tissue stretching and tearing, besides neurologic and vascular compression and compromise, and muscle strain are inevitable during childbirth.The levator ani complex of the pubococcygeus, puborectalis, and iliococcygeus muscles must allow passage of the fetus. The perineal body and external anal sphincter may become injured, with or without episiotomy, but sometimes as a necessary maneuver to allow passage of the fetal head or shoulders. The traumatic insults may lead to permanent damage on pelvic floor and subsequent urinary or anal incontinence.In this article we aim to review the literature regarding the impact of pregnancy or childbirth on pelvic floor changes. PMID- 22439052 TI - Obesity and fetal-maternal outcomes. AB - In women Obesity has a significant impact on every aspect of female reproductive life both in terms of infertility and early pregnancy complications. It is linked to a number of adverse obstetric outcomes as well as increased maternal and neonatal morbidity and mortality. These complications include miscarriage, congenital abnormalities, pre-eclampsia, gestational diabetes mellitus, iatrogenic preterm delivery, post-dates pregangy with increased rates of induction of labour, caesarian section and complications during and following operative procedures, post-partum haemorrhage, shoulder dystocia, infection, venous thromboembolism and increased hospital day. It is important to consider obese pregnant women as a high risk group with a linear increase in risk of complications associated with their degree of obesity. PMID- 22439053 TI - Uterine rupture after prostaglandin analogues to induce midtrimester abortion. AB - Although prostaglandins are largely used and considered safe drugs to induce midtrimester abortion, the literature reports several cases of uterine rupture consequent to their administration. We report the second ever-described case of uterine rupture after administration of gemeprost and sulprostone for midtrimester abortion in a 45 years-old women with scarred uterus.She was admitted to our Unit for termination at 20 weeks' gestation because of trisomy 21 diagnosed by chromosomal analysis of amniotic liquid at 16 weeks' gestation. Five pessaries of gemeprost (one pessary, every 3 hours) were administered into the posterior vaginal fornix. Since the cervix remained closed and uneffaced, another cycle of 5 gemeprost administration was conducted. When the cervix changed in consistency and dilatation, we decided to administrate sulprostone. At the obstetric examination any visible fetus was evidenced. The abdominal ultrasonography showed an empty uterine cavity and the gestational sac with the dead fetus in abdomen. Emergency laparotomy was therefore undertaken. Primary suture of the ruptured uterus was initially attempted but in vain. Therefore, total abdominal hysterectomy was performed to control bleeding and eventual hypovolemic shock.Given the lack of strong evidence in literature and the fact that case reports are not an optimal method for assessing frequency of an event nor the overall risks of a procedure since they frequently report rare single events, other larger studies are needed to assess whether women with multiple risk factors (e.g. advanced age and previous uterine surgery), and administered with prostaglandins' association have a higher risk of uterine rupture. PMID- 22439054 TI - Antepartum haemorrhage. AB - OBJECTIVE: Antepartum haemorrhage (APH) defined as bleeding from the genital tract in the second half of pregnancy, remains a major cause of perinatal mortality and maternal morbidity in the developed world. RESULTS: In approximately half of all women presenting with APH, a diagnosis of placental abruption or placenta praevia will be made; no firm diagnosis will be made in the other half even after investigations. CONCLUSION: In cases presenting with APH, the evaluation consists of history, clinical signs and symptoms and once the mother is stabilized, a speculum examination and an ultrasound scan.A revision of the literature was mode only larger prospective tials or case-control study were taken into account. PMID- 22439055 TI - The value of the middle cerebral to umbilical artery Doppler ratio in the prediction of neonatal outcome in patient with preeclampsia and gestational hypertension. AB - OBJECTIVE: To investigate the diagnostic value of MCA/UA pulsatility index ratio for the prediction of adverse perinatal outcome in the fetuses with preeclampsia and gestational hypertension. MATERIALS AND METHODS: We included in the study 738 patients recovered in our Hospital with the diagnosis of preeclampsia and gestational hypertension, from January 2006 to December 2009. All the patients underwent accurate color Doppler velocimetry examination. The study population was divided into two groups depending on the normal or abnormal values of MCA/UA pulsatility index ratio.Outcome variables were intrauterine and early neo natal death, admission to the neonatal intensive care unit and the duration of treatment, Apgar score below 7 at 5 minutes,cesarean delivery for fetal distress, gestational age at delivery, neonatal birth weight, IUGR. RESULTS: We divided the study population into two groups depending on normal or abnormal value of MCA/UA pulsatility index ratio. In 314 patients we found abnormal values of MCA/UA pulsatility index ratio. Neonates of mothers with abnormal values of MCA/UA pulsatility index ratio had significantly lower gestational age at delivery (34.8 versus 38.4, P<0.0001), lower birth weight (2174.6 g versus 3215.0g, P<0.001), significantly greater risk for perinatal death (30.8% versus 0.23%, P<0.0001) significantly greater risk of admission to intensive care unit (77.8% versus 47.4%, P<0.0001), longer duration of treatment in NICU (10.6 days versus 6.5 days, P<0.0001), greater rate of cesarean delivery for fetal distress (76.7% versus 62.5%,P<0.0001), a great number of neonates with low Apgar score at 5 minute (61.9% versus 22.4%, P<0.0001) greater rate of cesarean delivery for fetal distress (71.9% versus 62.5%,P<0.0001), a great number of fetuses IUGR (7.18% versus 1.76%,P<0.0001). CONCLUSION: ACM/UA pulsatility index ratio is a very good predictor of adverse outcome in the fetuses of women with preeclampsia and gestational hypertension. PMID- 22439056 TI - Postpartum period: three distinct but continuous phases. AB - Postpartum period is distinct in three phases. The third phase is the delayed postpartum period, which can last up to 6 months. Some changes to the genitourinary system are much longer in resolving, and some may never fully revert to the prepregnant state. A burgeoning volume of literature on pelvic floor support implicates childbirth as the initiation of a whole host of conditions including stress urinary incontinence, incontinence of flatus or feces, uterine prolapse, cystocele, and rectocele. The duration and severity of these conditions affect many variables, including the patient's intrinsic collagen support, the size of the infant, the route of delivery, and the degree of perineal trauma occurring either naturally (lacerations) or iatrogenically (episiotomy). PMID- 22439057 TI - Prevalence of gestational trophoblastic disease in ectopic pregnancy. AB - OBJECTIVE: To describe the prevalence of gestational trophoblastic disease in ectopic pregnancy. STUDY DESIGN: Medical records of 105 patients from January 2007 to October 2009. We excluded of the study 5 cases (one case where the answer of the biopsy was not clear; 4 others with diagnosis of adhnexial mass where the pregnancy test had resulted positive but the answer of biopsy have been resulted ruptured ovary cyst and pyosalpingitis). So definitely the size of the sample was 100 patients. RESULTS: 79 patients with EP underwent surgery due to a (diagnosis of EP with hem peritoneum and enraptured ectopic pregnancy) and in 18 of them the answer of the biopsy was GTD. 4 of 75 cases admitted in our hospital with diagnosis of EP, (pregnancy test was used instead of estimation of the level of beta-hCG because our hospital couldn't offer estimation of the level of beta-hCG during 24 hours) have been not confirmed diagnosis of EP by biopsy, but ruptured ovary cyst with hem peritoneum, pyosalpingitis.31 cases with EP (enraptured EP) underwent medical treatment with methotroxate. In 10 cases last management was failed and surgical intervention was institutionalized and histological analysis revealed GTD in 6 of them (partial mole). beta-hCG level was detected in 31 cases with enraptured fallopian pregnancy; in all cases where treatment with methotroxate has been failed and GTD was confirmed, the level of beta-hCG was > 10.234 mUI/ml. 21 cases with enraptured fallopian pregnancy were successfully treated, and at this point we never learned the answer of biopsy. We registered one case with cervical pregnancy and one cornual (interstitial portion) pregnancy. CONCLUSION: we found 18 cases of GTD in EP /11.500 deliveries (1,56 per 1,000 deliveries), prevalence of the GTD in EP was about 18%. PMID- 22439058 TI - Ectopic pregnancy comparison of different treatments. AB - OBJECTIVES: We would like to determine the best treatment option depending of ectopic pregnancy situation.Methods. This is a retrospective cohort study that registered all women admitted in Obstetrics and Gynecologic "Queen Geraldine" Hospital June 2003 until 2008 dicember. There were admitted 228 women diagnosed with Ectopic Pregnancy that were treated in our Hospital. RESULTS: Unruptured ectopic pregnancy is diagnosed in 5,2 week of pregnancy and ruptured ectopic in an average of 6,4 weeks. Surgical intervention is registered in 170 patients and we did tubectomy. Success rate of Methotrexate application was more successful if beta-hCG level was lower. If the beta-hCG level is higher over 10 000 the success rate will decrease in 83 % and in beta-hCG levels over 15 000 the success rate will be until 50%. CONCLUSIONS: The treatment will be determined by combination of clinical symptoms, ultrasound examination and beta-hCG levels. MTX is recommended for all women without hemodinamic problems, unruptured pregnancy and low beta-hCG level (beta-hCG < 5000 mlU/mL). It is confirmed that the reduction of 15% of beta-hCG in the fourth day after application of MTX is a success guide. PMID- 22439059 TI - Shoulder dystocia: an Evidence-Based approach. AB - Shoulder Dystocia (SD) is the nightmare of obstetricians. Despite its low incidence, SD still represents a huge risk of morbidity for both the mother and fetus. Even though several studies showed the existence of both major and minor risk factors that may complicate a delivery, SD remains an unpreventable and unpredictable obstetric emergency. When it occurs, SD is difficult to manage due to the fact that there are not univocal algorithms for its management.Nevertheless, even if it is appropriately managed, SD is one of the most litigated cause in obstetrics, because it is frequently associated with permanent birth-related injuries and mother complications.All the physicians should be prepared to manage this obstetric emergency by attending periodic training, even if SD is difficult to teach for its rare occurrence and because in clinical practice it is often handled by experienced obstetricians.THE PURPOSE OF THIS STUDY IS TO REVIEW THE LITERATURE CONCERNING THE EVERLASTING PROBLEMS OF SD: identification of risk factors for the early detection of delivery at high risk of SD and a systematic management of this terrifying obstetric emergency in order to avoid the subsequent health, medico-legal and economic complications. PMID- 22439060 TI - Nonvisualization of fetal gallbladder: a case report and review of the literature. AB - Failure to visualize prenatally the gallbladder at ultrasound scan may indicate different fetal malformations with a highly variable prognosis, but also a simple anatomic variable. An adequate prenatal management could help in defining diagnosis and prognosis. PMID- 22439061 TI - The use of DHPLC (Denaturing High Performance Liquid Chromatography) in II level screening of the CFTR gene in Prenatal Diagnosis. AB - OBJECTIVE: The aim of the study is to evaluate the role of Denaturing High Performance Liquid Chromatography (DHPLC) in the second level screening of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. METHODS: A 9 month prospective study, between June 2008 and March 2009 at Artemisia Fetal Medical Centre, included 3829 samples of amniotic fluid collected from women undergoing mid-trimester amniocentesis.The genetic diagnosis of CF was based on research of the main mutations of the CFTR gene on fetal DNA extracted from the amniocytes, (first level screening) using different commercial diagnostic systems. A second level screening using DHPLC, on the amniotic fluid and on a blood sample from the couple, was offered in case of fetuses heterozygous at first level screening. RESULTS: Of 3829 fetuses, 134 were found to be positive, 129 heterozygous and 5 affected. Of the 129 couples, following appropriate genetic counselling, 53 requested a second level screening. Through the use of DHPLC, 44 couples were found to be negative, and in nine couples, nine rare mutations were identified. CONCLUSIONS: The first level screening can be useful to evidence up to 75% of the CF mutations. The second level screening can identify a further 10% of mutant alleles. DHPLC was found to be a reliable and specific method for the rapid identification of the rare CFTR mutations which were not revealed in initial first level screening. PMID- 22439062 TI - Comparison of maternal and neonatal outcomes in women with HELLP syndrome and women with severe preeclampsia without HELLP syndrome. AB - OBJECTIVE: To examine and to compare postpartum maternal and neonatal complications and morbidities in women with HELLP syndrome (HELLP group) and women with severe preeclampsia without HELLP syndrome (severe preeclamptic group). METHODS: In this retrospective study, 111 patients in the HELLP group were matched with 467 patients in the severe preeclamptic group according to maternal and neonatal complications and morbidities. RESULTS: The rate of transfusion of blood products and acute renal failure was significantly greater in women with HELLP syndrome. One maternal mortality (0.9 % ) was found in women withHELLP syndrome, and no maternal mortality in women in severe preeclamptic group a. There were significant differences between the HELLP group and the severe preeclamptic group in neonatal mortality and morbidity. It was found that HELLP syndrome cases had significantly lower gestational age and fetal bodyweight. The simultaneous presence of HELLP syndrome and preeclampsia, along with oliguria, ascites, thrombocytopenia, elevated liver enzymes and caesarean delivery, was associated with post-partum complications. CONCLUSION: This study shows that maternal and neonatal morbidity and mortality are increased in pregnancies complicated by severe preeclampsia with HELLP syndrome. Neonatal mortality and morbidity appear to be influenced primarily by gestational age at delivery. PMID- 22439063 TI - Uterine artery Doppler flow studies in obstetric practice. AB - In women who develop preeclampsia there is a pathological increase in placental vascular resistance should be detectable by abnormal Dopplerf low studies of the maternal uterine vessels. In women considered at low risk with abnormal early pregnancy uterine artery Doppler studies are needed. Until such time as these are available, routine uterine artery Doppler screening of women considered at low risk is not recommended. Uterine artery Doppler screening of high-risk women appears to identify those at substantially increased risk for adverse pregnancy outcomes and interventions that might improve clinical outcomes.Abnormal testing in these women could potentially lead to increased surveillance and interventions that might improve clinical outcomes. PMID- 22439064 TI - Parvovirus B19 during pregnancy: a review. AB - Several infections in adults warrant special consideration in pregnant women given the potential fetal consequences. Among these is parvovirus B19 deserves special attention since the harmful effects on the pregnant woman and fetus. It can then cause fetal anemia, non-immune fetal hydrops and fetal death. Among cases with fetal demise, B19 is foundin significant numbers, especially in the second andthird trimesters of pregnancy. There is no specific treatment or prophylaxis available against B19 infection, but counseling of non-immune mothers and active monitoring of confirmed maternal infections with intervention to correct fetal anemia is likely to decrease mortality. PMID- 22439065 TI - Update on systemic lupus erythematosus pregnancy. AB - Women with Systemic Lupus Erythematosus (SLE) still face significant risks when embarking on a pregnancy. Improvements in the field of pathophysiology, in diagnosis and a greater number of therapeutic options in the treatment of SLE, have made the medical community regard these patients with less trepidation. Despite these advances, however, the risk of significant morbidity to both the mother and the fetus still exists. THE INTERACTION OF LUPUS AND PREGNANCY IS VERY COMPLEX: the consensus is that pregnancy can worsen the lupus disease process, even if this is not predictable, and pregnancy can mimic the clinical manifestations of lupus, particularly preeclampsia/eclampsia. More specifically, pregnancy is associated in 50 to 60% of cases with a clinical flare manifesting as renalor hematological symptoms. Severe flares are uncommon (10%) and the risk of maternal death is now2 to 3%. The risk of the fetus remains high, however with increased risk of spontaneous fetal wastage and premature births, by 4.8 and 6.8 times, respectively. It is well documented that antiphospholipid syndrome and antiphospholipid antibodies are strongly associated with fetal wastage. Low-dose aspirin orheparin improves fetal outcome in these cases.Timing a pregnancy to coincide with a period of disease quiescence for at least 6 months strongly increases the chances for a healthy and uneventful pregnancy for both mother and baby. Close surveillance, with monitoring of blood pressure, proteinuria and placental blood flow by doppler studies helps the early diagnosis and treatment of complications such as preeclampsia andfoetal distress. Women with SLE frequently need treatment throughout pregnancy based on hydroxychloroquine, lowdose steroids and azathioprine. This update, based on previous available literature, should inform rheumatologists, obstetricians and neonatologists who guide patients in their reproductive decisions. PMID- 22439066 TI - Iniencephaly with mediastinal bronchogenic cyst: A case report. AB - OBJECTIVE: Iniencephaly is a rare neural tube defectwith consisting of a defect in the occipital bone,spina bifida of many vertebrae, and retroflexion of the head on the spine. In majorty of cases it is a le-?thal condition. METHODS: We present the first case of iniencephalywith large bronchogenic cyst diagnosed prenatally. RESULTS: At 19 week's gestation showed that fetalcardiac activity was present with normal placentaand amniotic fluid, fetus had occipital bone defect, anencephaly, retroflexion of the head, abnormally short cervicothoracic spine and posterior mediastinal unilocular anechoic cyst. Therapeutic abortion was induced. CONCLUSION: Iniencephaly is a rare condition during prenatal life. When diagnosed early in pregnancy amultidisciplinary approach is firmly suggested. PMID- 22439067 TI - Cytomegalovirus infection in pregnancy: review of the literature. AB - The aim of this review is to summarize the principles of cytomegalovirus (CMV) infection in pregnancy.In particular, the aim of this review is to evaluate:Incidence and mother-to-child transmissionThe value of screening of pregnant womenDiagnosis of CMV maternal infectionDiagnosis of fetal infection (evaluate the value of ultrasound examination and amniocentesis and evaluate whether the amniotic viral load of mothers with primary cytomegalovirus infection correlate with fetal or neonatal outcomes)Diagnosis of infection in newbornsTherapy in pregnancy, postnatal therapy and prevention. PMID- 22439068 TI - Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome? AB - "Soft markers" are considered variants of normal and should be considered distinct from fetal anatomic malformations. Hyperechogenicity of the fetal bowel, is one of the few soft markers that can also associated with a variety of other pathologic conditions. In this review we will focalise our attention on the significate of an increased echogenicity of fetal bowel and on management of fetuses with this condition. PMID- 22439069 TI - Current strategy for detection and diagnosis of hyperglycemic disorders in pregnancy. AB - Gestational diabetes mellitus (GDM) is a metabolic alteration frequently found in pregnant women. In women with GDM, failure of pancreatic beta-cells to adapt the production of insulin at the increased metabolic demand in pregnancy, results in a inadequate insulin response, with consequent hyperglycemia. The criteria currently used for the diagnosis of GDM are too restrictive as some author suggested that different degrees of hyperglycemia, even though not diagnostic for diabetes, increase the risks of adverse perinatal outcomes (large for gestational age (LGA), higher rate of cesarean section, neonatal hypo-glycemia, respiratory distress, perinatal mortality). The objective of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was to clarify the associations of levels of maternal glucose, lower than those diagnostic of diabetes, with perinatal outcome, defining a new overall strategy recommended for detection and diagnosis of hyperglycemic disorders in pregnancy. PMID- 22439070 TI - The impact of preeclampsia in pregnancy. AB - Objective. To observe the influence of preeclampsia during pregnancy. Materials and methods. 5711 patient's records of the year 2008 and 6188 patient's records of the year 2009 of Obstetric/Gynecologic hospital 'Queen Geraldina' have been consulted. The age of women that we studied in 2008 was between 23-35 and in 2009 was be-tween 25-34 years old. We have made a careful diagnose of inducted hypertension of pregnancy and preeclampsia. Results. The incidence of preeclampsia in the population was 4.1% (n =238) in 2008 and 3.1% (n=192) in 2009.The incidence of the cases that developed from preeclampsia to eclampsia were respectively 1.6% (n=4) and 1.5% (n=3) on 2009. Babies which have preeclamptic mothers were preterm in 13% (n=31) of cases, and 14.5% (n=28) of which have severe hypotrophia vs. 10% (n=24) and 11% (n=21) severe hypotrophia in 2009. Babies mortality on the preeclamptic population were respectively 8% (n=19) and 7.8% (n=15). Conclusions. From the survey resulted that patients diagnosed with preeclampsia manifested on a high rate hypertension and proteinuria. Prematurity, severe hypotrophy and baby's mortality were the major complications of preeclampsia. Women with preeclampsia were especially the youngest. PMID- 22439071 TI - Increased nuchal traslucency in normal karyotype fetuses. AB - Nuchal traslucency (NT) measurement between 11 and 14 weeks' gestation is a reliable marker for chromosomal abnormalities, including trisomy 21. However, even if conventional karyotyping is normal, increased NT is a predictive value of adverse pregnancy outcome, because it is associated with several fetal malformations, congenital heart defects, genetic syndromes, intrauterine death and miscarriages; the majority of these structural anomalies are undetectable before birth. The risk is proportional to the nuchal translucency thickness, in fact it statistically increases after measurement reaching 3.5 mm or more. However, when these chromosomally normal fetuses with an enlarged NT survive, even if a detailed ultrasound examination and echocardiography fail to reveal any abnormalities, their uneventful outcome and postnatal developmental delay will be not statistically increased when compared to the general population. These parents should be confidently reassured that the residual chance of structural anomalies and abnormal neurodevelopment may not be higher than in the general population. PMID- 22439072 TI - Maternal weight gain during pregnancy and neonatal birth weight: a review of the literature. AB - Obesity has become a serious global public health issue and has consequences for nearly all areas of medicine. Within obstetrics, obesity not only has direct implications for the health of a pregnancy but also impacts on the weight of the child in infancy and beyond. As such, maternal weight may influence the prevalence and severity of obesity in future generations. Pregnancy has been identified as a key time to target a weight control or weight loss strategy to help curb the rapidly growing obesity epidemic. This study reviews the current evidence for interventions to promote weight control or weight loss in women around the time of pregnancy. Studies have shown positive correlations between both maternal pre-pregnancy weight and gestational weight gain with the birth weight of the infant and associated health risks, so interventions have been put to clinical trials at both time points. Many women are concerned about the health of their babies during pregnancy and are in frequent contact with their healthcare providers, pregnancy may be an especially powerful "teachable moment" for the promotion of healthy eating and physical activity behaviors among women. PMID- 22439073 TI - Fetal growth restriction: current perspectives. AB - Intrauterine growth restriction is one of the most common and complex problems in modern obstetrics. The cut off value mainly used for defining an IUGR is at the 10th percentile. There are many evidence demonstrating that the adverse perinatal outcome are mainly confined to infants below the 5th or 3th percentile. The mains causes for the onset of IUGR can be divided into three categories: maternal, fetal and placental. Aim of this study is to obtain a review from which speculate useful indication in clinical practice. Evidence from randomized controlled trials finds few interventions beneficial in preventing or treating IUGR. PMID- 22439074 TI - Gestational weight gain, prepregnancy body mass index related to pregnancy outcomes in KAZERUN, FARS, IRAN. AB - OBJECTIVE: The aim of this study was to evaluate associations between pregnancy outcomes and prepregnancy body mass index and gestational weight gain among pregnant women who regularly attended health centers of Kazerun, Fars, Iran. METHODS: In this descriptive study records from 5172 pregnant women were considered in this study, based on the methodology criteria. Women were distributed across 4 prepregnancy categories according to the Institute of Medicine (IOM) (1990) classification of body mass index, and to 4 end-of pregnancy categories according to median weekly gestational weight gain. RESULTS: The risks for gestational diabetes, gestational hypertension, pre-eclampsia, and preterm premature rupture of membranes were higher for those who were overweight or obese before becoming pregnant (P < 0.05). Moreover, a gestational weight gain of 0.50 kg per week or greater was associated with a higher risk for gestational hypertension, preterm premature rupture of membranes, and fetal macrosomia (P < 0.05). Women in the highest quartile for weight gain (>= 0.59 kg per week) were at higher risk for pre-eclampsia (P < 0.05). DISCUSSION: The results seems to indicate that excessive gestational weight gain and high prepregnancy body mass index were associated with increased risks for adverse pregnancy outcomes. PMID- 22439075 TI - Antiphospholipid Syndrome during pregnancy: the state of the art. AB - Obstetric complications are the hallmark of antiphospholipid syndrome. Recurrent miscarriage, early delivery, oligohydramnios, prematurity, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, pre eclampsia/eclampsia, HELLP syndrome, arterial or venous thrombosis and placental insufficiency are the most severe APS-related complication for pregnant women. Antiphospholipid antibodies promote activation of endothelial cells, monocytes and platelets, causing an overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. These factors, associated with the typical changes in the hemostatic system during normal pregnancy, result in a hypercoagulable state. This is responsible of thrombosis that is presumed to provoke many of the pregnancy complications associated with APS. Obstetric care is based on combined medical-obstetric high-risk management and treatment with the association between aspirin and heparin. This review aims to deter- mine the current state of the art of APS by investigating the knowledge achievements of recent years, to provide the most appropriate diagnostic and therapeutic management for pregnant women suffering from this syndrome. PMID- 22439076 TI - The use of uterine artery doppler as a predictive tool for adverse gestational outcomes in pregnant patients with autoimmune and thrombophilic disease. AB - OBJECTIVES: To verify whether Doppler velocimetry on the uterine arteries can be used to single out abnormal hemodynamic adjustments in the uteroplacental district and to prognose adverse gestational outcomes in pregnant women with autoimmune and trombophilic disease. METHODS: The study included 67 patients divided into 3 groups selected by a developed pathology. Attention was given to the performance of the Resistance Index (RI) in Doppler velocimetry checks at 10th, 16th-18th, 21st and 28th weeks of gestation. RESULTS: A significant correlation between Doppler values at week 21st and development of preeclampsia was observed (p <0.05) in the three patient groups. High Doppler values at the 21st week were found to be strongly associated (p <0.01) with preterm delivery. We also observed a significant correlation (p <0.05) between high Doppler values at week 21st and low weight at birth. Doppler was found to have a predictive power for gestational adverse outcomes already at week 16th. CONCLUSION: RI values of more than 0.58 (taken as a cut-off) at 16/18th weeks allowed us to identify the category most at risk, if confirmed at 21 weeks. PMID- 22439077 TI - Fetal cardiac function during the first trimester of pregnancy. AB - Chromosomally normal first trimester fetuses with an increased nuchal translucency measurement have an elevated risk of congenital heart defect (CHD). so there is an increased demand for imaging the fetal heart during the first and early second trimesters of pregnancy.Echocardiographic and anatomical correlations in firsttrimester fetuses show that by 11 weeks' gestation, the position of the fetal heart within the chest is similar to that in later gestation, and the spatial relation of the great arteries and their relative sizes are similar to those on second-trimester scans by 12 weeks' gestation.In the first trimester during the heart analysis it's possible value: anatomic structure (size, rate), hemodynamic development through analysis of these waveforms and flow patterns (inflow and outflow waveforms of the diastolic filling and the systolic ejection) and modification during the first trimester. PMID- 22439078 TI - Treatment of gestational diabetes: oral hypoglycemic agents or insulin? AB - Our report aims to verify whether perinatal maternal glycemic control in gestational diabetes can only be achieved with insulin or with oral hypoglycaemic agents. Then we want to evaluate the efficacy and safety of oral hypoglycemic agents in the treatment of gestational diabetes and then to compare these results with those associated with the use of insulin. PMID- 22439079 TI - Is counselling for CCAM that difficult? Learning from parental experience. AB - OBJECTIVE: Cystic adenomatoid malformations (CCAM) are relatively rare developmental abnormalities of the lung. Despite outcome is usually benign, parents often exhibit high anxiety level. The purpose of the present study was to collect parents'subjective experience of communication of diagnosis when expecting a fetus with CCAM. METHODS: In the period ranging between 2004 to 2007 all couples referred to our hospital for prenatal suspicion of CCAM, were contacted to participate in the study by means of a questionnaire. RESULTS: Twenty-seven couples returned fully completed questionnaire and form the object of this study. 13/27 couples were recommended pregnancy termination.MAJOR RISKS PRESENTED WERE: fetal distress (27/27), intrauterine death (16/27), death at birth (12/27).THE MOST DISTRESSING MOMENTS WERE: communication of diagnosis and the time lag between communication of diagnosis and consultation with the surgeon. CONCLUSIONS: Despite CCAM carries a favourable prognosis, couples often appear to receive incomplete information with risk of fetal distress and demise prevailing over survival rate and long term outcome. To provide the couple with the most accurate information concerning the anomaly and the associated prognosis to make informed decision a referral to a tertiary pediatric surgery unit should be made as soon as possible. PMID- 22439080 TI - Biochemical markers for prediction of preclampsia: review of the literature. AB - Preeclampsia (PE) is one of the most common diseases worldwide, complicating ~5% of all pregnancies.Although no major progress has been achieved in the treatment of PE, our ability to identify women at highrisk has increased considerably during the past decade.The early identification of patients with an increased risk for preeclampsia is therefore one of the most important goals in obstetrics. Today, several markers may offer the potential to be used, most likely in a combinatory analysis, as predictors or diagnostic tools. We present here the current knowledge on the biology of preeclampsia and review several biochemical markers which may be used to monitor preeclampsia in a future, that, we hope, is not to distant from today. PMID- 22439081 TI - Missed diagnosis of syrinx. AB - STUDY DESIGN: Prospective, randomized, controlled human study. PURPOSE: We checked the proportion of missed syrinx diagnoses among the examinees of the Korean military conscription. OVERVIEW OF LITERATURE: A syrinx is a fluid-filled cavity within the spinal cord or brain stem and causes various neurological symptoms. A syrinx could easily be diagnosed by magnetic resonance image (MRI), but missed diagnoses seldom occur. METHODS: In this study, we reviewed 103 cases using cervical images, cervical MRI, or whole spine sagittal MRI, and syrinxes was observed in 18 of these cases. A review of medical certificates or interviews was conducted, and the proportion of syrinx diagnoses was calculated. RESULTS: The proportion of syrinx diagnoses was about 66.7% (12 cases among 18). Missed diagnoses were not the result of the length of the syrinx, but due to the type of image used for the initial diagnosis. CONCLUSIONS: The missed diagnosis proportion of the syrinx is relatively high, therefore, a more careful imaging review is recommended. PMID- 22439082 TI - Long-term Follow-up of Percutaneous Vertebroplasty in Osteoporotic Compression Fracture: Minimum of 5 Years Follow-up. AB - STUDY DESIGN: This was designed as a retrospective study. PURPOSE: We assessed the radiographic and clinical outcome of patients who underwent percutaneous vertebroplasty (PVP) in osteoporotic compression fractures with a minimum of 5 years follow-up. OVERVIEW OF LITERATURE: Percutaneous vertebroplasty is effective surgical method for treating osteoporotic compression fracture. METHODS: Between January 2000 and August 2005, 159 patients were treated with PVP for osteoporotic compression fracture at our department; 43 patients died during follow-up, and 69 patients (121 vertebras) were available for follow-up for over 5 years. We analyzed the clinical and radiologic outcome including cement feature. RESULTS: The mean follow-up period was 5.7 years. Clinical outcome by mean visual analogue scale (VAS) score revealed a decreased 4.9 points perioperatively. A decreased score was maintained over 5 years in 46% of patients. A new adjacent vertebral fracture was documented by 33 vertebral bodies in 22 patients. During the follow up period, 43 patients (38%) in 112 patients died. Anterior body heig ht in the last follow-up was improved about 0.3 mm compared with the preprocedural value, but was not statistically significant. Also, the focal kyphotic angle was reduced from 12.3 degrees at the preprocedural state to 11.7 degrees at the postprocedural state, but was not statistically significant (p > 0.05). CONCLUSIONS: PVP for osteoporotic compression fracture is an efficient procedure for pain relief by long term follow-up. The cement injected vertebrae showed stable radiologic progression without significant changes in vertebral height or kyphotic angle. PMID- 22439083 TI - Posterior lumbar interbody fusion using compressive bone graft with allograft and autograft in the pyogenic discitis. AB - STUDY DESIGN: This is a retrospective study. PURPOSE: To evaluate the advantages and effects of posterior lumbar interbody fusion (PLIF) using allograft and posterior instrumentation in the lumbar pyogenic discitis, which are resistant to antibiotics. OVERVIEW OF LITERATURE: To present preliminary results of PLIF using a compressive bone graft with allograft and pedicle screw fixation in the lumbar pyogenic discitis. METHODS: Fifteen patients who had lumbar pyogenic discitis were treated by posterior approach from May 2004 to July 2008. The mean follow-up duration was 27.2 +/- 18.68 months. The standing radiographs of the lumbar spine and clinical results were compared and analyzed in order to assess the bony union, the changes in the distance between the two vertebral bodies and the changes in the lordotic angle formed between the fused bodies immediately after surgery and at the final follow-up. RESULTS: Fifteen solid unions at an average of 15.2 +/- 3.5 weeks after operation. The mean preoperative lordotic angle of the affected segments was 14.3 +/- 15.1 degrees , compared to 20.3 +/- 12.3 degrees after surgery and 19.8 +/- 15.2 degrees at last follow-up. For the functional result according to the Kirkaldy-Willis criteria, the outcome was excellent in 9, good in 5, fair in 1, and there were no poor cases. The average visual analogue scale score was decreased from 7.4 before surgery to 3.4 at 2 weeks postoperative. CONCLUSIONS: The main advantage in the procedure of PLIF using compressive bone graft with allograft and post instrumentation is early ambulation. We believe that this is another good procedure for patients with poor general condition because a further autograft bone harvest is not required. PMID- 22439084 TI - Feasibility of FRAX for Prediction of Osteoporotic Vertebral Fractures in Korea. AB - STUDY DESIGN: Retrospective study. PURPOSE: To assess the feasibility and limitations of fracture risk assessment tool (FRAX) for osteoporotic vertebral fractures in the Korean population. OVERVIEW OF LITERATURE: The FRAX algorithm is country specific and uses clinical risk factor data to calculate an individual patient's 10-year probability of hip fracture and 10-year probability of major osteoporotic fracture. However, it has not been adequately investigated for Korean. METHODS: ONE HUNDRED NINETY FOUR PATIENTS WHO HAD ALL RISK FACTOR DATA FOR THE CALCULATION OF FRAX WERE DIVIDED INTO TWO GROUPS DEPENDING ON THE EXISTENCE OF VERTEBRAL FRACTURES: the fracture group was comprised of 88 patients and the non-facture group comprised of 105 patients. We analyzed prediction of the fracture by applying respectively the Korean, Japanese, USA and UK model, and compared their FRAX results by calculating lumbar bone mineral density (BMD) instead of femoral neck BMD. RESULTS: The prediction of vertebral fracture using FRAX was 10.9 +/- 6.2% in the fracture group, 9.5 +/- 5.5% of the non-fracture group in the Korean model (p = 0.108); 17.9 +/- 10.2% in the fracture group, 14.6 +/- 9.0% in the non-fracture group in the Japanese model (p = 0.017). Only the Japanese model exhibited significant difference in vertebral fracture risk. The prediction of vertebral fracture using lumbar BMD instead of femoral neck BMD was 19.5 +/- 12.1% in the fracture group, 16.0 +/- 10.3% in the non-fracture group in the Korean model (p = 0.029). All models had statistically significant differences for the prediction of osteoporotic vertebral fracture. CONCLUSIONS: The 10-year probability of osteoporotic vertebral fracture had underestimation of the risk considering treatment eligibility based on the National Osteoporosis Foundation guidelines. BMD that accurately reflects the contribution of each result to fracture risk should be preferred for the prediction of fracture using FRAX, when lumbar spine and hip BMD measurements are both performed for clinical purposes in Korean. PMID- 22439085 TI - Magnetic resonance imaging in cervical facet dislocation: a third world perspective. AB - STUDY DESIGN: Retrospective case series. PURPOSE: The objective of our study was to determine the change in management brought about by magnetic resonance imaging (MRI) of the cervical spine in alert and awake patients with facet dislocation and spinal cord injury presenting within 4 hours after injury. OVERVIEW OF LITERATURE: Spinal cord injury is a common clinical entity. The role of MRI is well established in evaluating spinal trauma. However, the time at which MRI should be used is still controversial. METHODS: Retrospective data from 2002-2010 was evaluated. All of the alert and awake patients with spinal cord injury, based on clinical examination with facet dislocation diagnosed on lateral cervical spine X-rays, were included. A questionnaire was also conducted, the data of which consisted of demographic details including age and sex, the mechanism of injury, clinical examination, X-ray findings, MRI findings, whether or not surgery was performed and the time elapsed since injury. Data was analyzed using SPSS ver. 17.0. Continuous variables such as age were expressed in terms of mean +/- standard deviation. Categorical variables such as change in management, X ray/MRI findings and neurological motor level were assessed in terms of percentage. RESULTS: Fifty patients participated in our study. All these patients had spinal cord injury with defined motor levels. The mean age was 35.5 +/- 8.95 years (range, 20 to 52 years). Fifty percent showed a motor level at C6 level. None of the patients required any change in management based on the MRI. CONCLUSIONS: MRI of the spine in awake patients within 4 hours after injury does not change the management of patients. However, we can hypothesize that such patients can proceed to traction without waiting for the MRI. PMID- 22439086 TI - Vertebroplasty Using Calcium Phosphate Cement for Osteoporotic Vertebral Fractures: Study of Outcomes at a Minimum Follow-up of Two Years. AB - STUDY DESIGN: A case-series study. PURPOSE: To assess the long-term clinical and radiographic outcomes after vertebroplasty using calcium phosphate cement (CPC) for treatment of osteoporotic vertebral fractures (OVF). OVERVIEW OF LITERATURE: Vertebroplasty has become common for the treatment of OVF. However, few studies have reported the clinical application of CPC to vertebroplasty. METHODS: We reviewed 86 consecutive patients undergoing 99 vertebroplasties using CPC. Following repositioning and curettage of the pathological soft tissue of the vertebral body (VB), vertebroplasty using CPC was performed in patients with osteoporotic burst fracture and pseudoarthrosis (procedure A). Vertebroplasty was also performed in patients with osteoporotic compression fractures (procedure B). Back pain and lower back pain were evaluated using the visual analogue scale (VAS). The VB deformity index was measured in a lateral radiograph as the ratio of the VB's height to its longitudinal diameter. RESULTS: The mean age at time of surgery was 77 years old. The mean duration of follow-up was forty-four months. All patients reported decreased pain according to the VAS immediately after vertebroplasty, and pain relief was maintained at the last follow-up in all patients without new OVFs. Complete bone union was observed in all cases by six months after surgery. The mean recovery rate of deformity index was 5.9% in procedure A and 0.02% in procedure B at the final follow-up visit. CONCLUSIONS: Vertebroplasty using CPC gave a satisfactory outcome and no delayed complications in elderly patients with osteoporotic vertebral fractures at follow-up times of at least two years. PMID- 22439087 TI - Management of Thoracal and Lumbar Schwannomas Using a Unilateral Approach without Instability: An Analysis of 15 Cases. AB - STUDY DESIGN: Retrospective case series. PURPOSE: The objectives of this study were to determine and discuss the surgical planning of patients who underwent operations following diagnoses of thoracal and lumbar spinal schwannomas. We also aimed to discuss the application of unilateral hemilaminectomy for the microsurgery of schwannomas. OVERVIEW OF LITERATURE: Schwannomas are located in different regions and sites. These differences require several surgical approaches. Unilateral laminectomy without stabilization of the spine provides a more minimally invasive removal of the tumor. METHODS: In this retrospective study, 15 patients with spinal schwannomas were evaluated with regards to age, sex, onset history, neurological findings, tumor locations, McCormick scale, surgical procedure, and operational results. The lateral approach provides exposure of intradural structures and posterior paraspinal regions. Extensions of tumors cause problem for the surgeon in terms of approach, resectability of the tumor, and stability of the spine. Gross total resection was achieved in all cases, and none of the patients necessary required a fusion procedure. RESULTS: Five patients were males and 10 were females. The age interval was 29-65 years. The tumor was located in the lumbar region in 9 patients, in the thoracic region in 2 patients, and in the thoracolumbar junction in 4 patients. The intradural lesions were removed by laminectomy and the extradural lesions were resected with hemilaminectomy. The paramedian route was used to explore the extraspinal part of the tumor. Costotransversectomy was for the thoracic region. Subtotal resection was performed in 1 patient. Patient symptoms recovered gradually in the postoperative period. CONCLUSIONS: Resection of giant schwannomas is challenging and usually requires a different approach. We describe the complete resection of complex dumbbell or paraspinal schwannomas of the thoracic and lumbar spine by unilateral hemilaminectomy. PMID- 22439088 TI - Is It Real False Negative Finding in Motor Evoked Potential Monitoring during Corrective Surgery of Ankylosing Spondylitis? A Case Report. AB - We performed L1 posterior vertebral columnar resection and posterior correction for Andersson's lesion and thoracolumbar kyphosis in an ankylosing spondylitis patient during motor evoked potential (MEP) monitoring. We checked MEP intra operatively, whenever a dangerous procedure for neural elements was performed, and no abnormal findings were seen during surgery. After the operation, we examined neurologic function in the recovery room; the patient showed a progressive neurologic deficit and no response to MEP. After emergency neural exploration and decompression surgery, the neurologic deficit was recovered. We questioned whether to acknowledge the results of this case as a false negative. We think the possible reason for this result may be delayed development of paralysis. So, we recommend that MEP monitoring should be performed not only after important operative steps but also after all steps, including skin suturing, for final confirmation. PMID- 22439089 TI - Unilateral paramedian transpedicular approach for repair of anterior transdural spinal cord herniation: report of a case and literature review. AB - Idiopathic spinal cord herniation is a rare but potentially treatable cause of thoracic myelopathy. The rarity and variable clinical presentation often results in missed diagnosis and delay in treatment. Posterior midline approach with laminectomy has been the most common approach performed for spinal cord herniation in cases described in the literature. A posterior approach is limited by the danger of retracting the spinal cord and difficulty visualizing the dural defect. Considering the anterior location of the dural defect, a posterolateral allows for a more ventral view without spinal cord manipulation. We report a rare case of idiopathic spinal cord herniation which was managed by unilateral paramedian transpedicular approach with an excellent clinical outcome. PMID- 22439090 TI - Posterior Fixation of a Cervical Fracture Using the RRS Loop Spine System and Polyethylene Tape in an Elderly Ankylosing Spondylitis Patient: A Case Report. AB - An 80-year-old woman presented with neck pain and paraparesis of Frankel C in her upper and lower extremities after falling. Imaging revealed an ankylosing cervical spine and a fracture line running obliquely from the anterior C3-4 to the posterior C4-5 level. Posterior fixation from the occi pit to T3 was performed using the RRS Loop Spine System and concomitant polyethylene tape fixation. This system is characterized by the uniqueness of how it screws to the occi pit and its use of a fixation rod with a larger diameter than in other instrumentation devices for use in the cervical region. Sublaminar banding using polyethylene tape was used to secure fixation. Her postoperative course was unremarkable, and her neck pain was relieved, although neurological improvement was minor. To our knowledge, this is the first report of an application of the RRS Loop Spine System to an ankylosing spondylitis patient with a cervical fracture. PMID- 22439091 TI - Myelopathy and Quadriparesis due to Spinal Cord Compression of C1 Laminar Osteochondroma. AB - The aim of this paper is to show that osteochondromas of the cervical vertebrae can cause myelopathy and neck pain.The reported etiology, diagnosis, treatment and differential diagnosis were reviewed. Osteochondromas may present as a solitary lesion with no genetic component or as multiple lesions as a part of a genetic disorder known as hereditary multiple exostosis. Osteochondromas of the spine are rarely encountered in clinical practice. These lesions are reported more commonly with neural compression in cases associated with hereditary multiple exostosis. The authors describe a unusual clinical manifestation of a solitary osteochondroma located in the right posterior arch of the atlas. Complete removal of the tumor was performed resulting in the relief of neck pain and spastic quadriparesis. Although unusual, osteochondromas of the cervical spine must be considered in patients with persistent neck pain and progressive symptoms of myelopathy. Computed tomography and magnetic resonance imaging in conjunction with plain radiograms is the neuroradiological modality of choice. The diagnosis and surgical excision of these tumors are important because they can cause spinal stenosis resulting in neural tissue compression and myelopathy. PMID- 22439092 TI - Metastatic spinal tumor. AB - In accordance with extending survival periods of cancer patients, number of consecutively developing metastatic spinal tumor is also increasing. There have been improvements in the treatment results of metastatic spine tumor by virtue of the developments in diagnostic radiology, chemotherapy, adjuvant treatment, operative device and technique, discrete preoperative plan, and standardized operation. Accordingly, surgical indication has also increased. Clinically, in case of metastatic spine tumor, treatment of tumor itself should be focused on pain relief, preservation of neurologic function, prevention of pathologic fracture, prevention of pathologic fracture, and correction of spinal instability for improving quality of life, rather than for extension of survival. Additionally, etiology of spinal tumor, correct diagnosis and subsequent treatment principles should be thoroughly understood before establishing treatment plans for effective treatments. PMID- 22439093 TI - The effect of different fiber reinforcements on flexural strength of provisional restorative resins: an in-vitro study. AB - PURPOSE: The aim of this study was to compare the flexural strength of polymethyl methacrylate (PMMA) and bis-acryl composite resin reinforced with polyethylene and glass fibers. MATERIALS AND METHODS: Three groups of rectangular test specimens (n = 15) of each of the two resin/fiber reinforcement were prepared for flexural strength test and unreinforced group served as the control. Specimens were loaded in a universal testing machine until fracture. The mean flexural strengths (MPa) was compared by one way ANOVA test, followed by Scheffe analysis, using a significance level of 0.05. Flexural strength between fiber-reinforced resin groups were compared by independent samples t-test. RESULTS: For control groups, the flexural strength for PMMA (215.53 MPa) was significantly lower than for bis-acryl composite resin (240.09 MPa). Glass fiber reinforcement produced significantly higher flexural strength for both PMMA (267.01 MPa) and bis-acryl composite resin (305.65 MPa), but the polyethylene fibers showed no significant difference (PMMA resin-218.55 MPa and bis-acryl composite resin-241.66 MPa). Among the reinforced groups, silane impregnated glass fibers showed highest flexural strength for bis-acryl composite resin (305.65 MPa). CONCLUSION: Of two fiber reinforcement methods evaluated, glass fiber reinforcement for the PMMA resin and bis-acryl composite resin materials produced highest flexural strength. CLINICAL IMPLICATIONS: On the basis of this in-vitro study, the use of glass and polyethylene fibers may be an effective way to reinforce provisional restorative resins. When esthetics and space are of concern, glass fiber seems to be the most appropriate method for reinforcing provisional restorative resins. PMID- 22439094 TI - Relationship between articulation paper mark size and percentage of force measured with computerized occlusal analysis. AB - PURPOSE: Articulation paper mark size is widely accepted as an indicator of forceful tooth contacts. However, mark size is indicative of contact location and surface area only, and does not quantify occlusal force. The purpose of this study is to determine if a relationship exists between the size of paper marks and the percentage of force applied to the same tooth. MATERIALS AND METHODS: Thirty dentate female subjects intercuspated into articulation paper strips to mark occlusal contacts on their maxillary posterior teeth, followed by taking photographs. Then each subject made a multi-bite digital occlusal force percentage recording. The surface area of the largest and darkest articulation paper mark (n = 240 marks) in each quadrant (n = 60 quadrants) was calculated in photographic pixels, and compared with the force percentage present on the same tooth. RESULTS: Regression analysis shows a bi-variant fit of force % on tooth (P<.05). The correlation coefficient between the mark area and the percentage of force indicated a low positive correlation. The coefficient of determination showed a low causative relationship between mark area and force (r(2) = 0.067). The largest paper mark in each quadrant was matched with the most forceful tooth in that same quadrant only 38.3% of time. Only 6 2/3% of mark surface area could be explained by applied occlusal force, while most of the mark area results from other factors unrelated to the applied occlusal force. CONCLUSION: The findings of this study indicate that size of articulation paper mark is an unreliable indicator of applied occlusal force, to guide treatment occlusal adjustments. PMID- 22439095 TI - A morphometric analysis of maxillary central incisor on the basis of facial appearance in Korea. AB - PURPOSE: We aimed to identify a more esthetic width-to-length ratio by analyzing maxillary central incisor of Korean adult population. Information regarding tooth ratio in the Korean population may be useful to clinicians when restoring anterior teeth. MATERIALS AND METHODS: A total of 40 men and 40 women were included in this study. The NON-MEDIA group included 40 non-celebrities, who were healthy and 25 to 39 years old, with normal dentofacial appearance. The MEDIA group consisted of 40 celebrities selected only on the basis of their soft-tissue facial appearance. The facial photographs of 40 celebrities were collected from the Internet websites. The width and length of the maxillary central incisor were measured using Adobe Photoshop(r) 7.0, a software for analysis, measurement and edition of photographs. Data were analyzed statistically using the Independent t test at 5% statistical significance level. RESULTS: The mean ratio for the MEDIA group was 0.77, whereas that of the NON-MEDIA group was 0.88. The difference between the two groups was statistically significant. No significant gender differences were found in the width-to-length ratio in MEDIA group. In NON-MEDIA group, however, there were significant differences between female and male. CONCLUSION: After analyzing maxillary anterior teeth of Korean adults, our results were in accordance with the general Western standards of esthetics. A dentist restoring the natural look and beauty of teeth will have to consider those standards. PMID- 22439096 TI - Effect of loading time on the survival rate of anodic oxidized implants: prospective multicenter study. AB - PURPOSE: The purpose of this prospective study was to evaluate the effect of early loading on survival rate or clinical parameter of anodic oxidized implants during the 12-month postloading period. MATERIALS AND METHODS: Total 69 implants were placed in 42 patients. Anodic oxidized implants (GS II, Osstem Cor., Busan, Korea) placed on the posterior mandibles were divided into two groups, according to their prosthetic loading times: test group (2 to 6 weeks), and control group (3 to 4 months). The implant survival rates were determined during one-year postloading period and analyzed by Kaplan-Meier method. The radiographic peri implant bone loss and periodontal parameters were also evaluated and statistically analyzed by unpaired t-test. RESULTS: Total 69 implants were placed in 42 patients. The cumulative postloading implant survival rates were 88.89% in test group, compared to 100% in control group (P<.05). Periimplant marginal bone loss (T: 0.27+/-0.54 mm, C: 0.40+/-0.55 mm) and periodontal parameters showed no significant difference between the groups (P>.05). CONCLUSION: Within the limitation of the present study, implant survival was affected by early loading on the anodic oxidized implants placed on posterior mandibles during one-year follow-up. Early implant loading did not influence peri-implant marginal bone loss, and periodontal parameters. PMID- 22439097 TI - Comparative evaluation of sodium hypochlorite and microwave disinfection on dimensional stability of denture bases. AB - PURPOSE: To compare the effect of sodium hypochlorite and microwave disinfection on the dimensional stability of denture bases without and with relining. MATERIALS AND METHODS: A brass die was prepared by simulating an edentulous maxillary arch. It was used to fabricate 1.5 mm and 3 mm of thickness denture bases (n = 40). The 1.5 mm of thickness-specimens (n = 20) were relined with 1.5 mm of autopolymerizing relining resin. Five holes were prepared over crest of ridge of brass die with intimately fitting stainless steel pins which were transferred to the intaglio surface of specimens during fabrication of denture bases. For calculation of dimensional changes in denture bases, differences between the baseline area before and after disinfection of the specimens were used. The denture bases without and with relining were divided into 2 groups (each n = 20). Data were analyzed using student paired 't' and unpaired 't' test. RESULTS: Microwave disinfection produces significant shrinkage in both denture bases without relining (t = 17.16; P<.001) and with relining (t = 14.9; P<.001). Denture bases without relining showed more shrinkage when compared with relined denture bases after microwave disinfection (t = 6.09; P<.001). The changes in dimensional stability after sodium hypochlorite disinfection were not significant for both denture bases without relining (t = 2.19; P=.056) and denture bases with relining (t = 2.17; P=.058). CONCLUSION: Microwave disinfection leads to increased shrinkage of denture bases without and with relining. Chemical disinfection with sodium hypochlorite seems to be a safer method of disinfection with regards to physical properties such as changes in dimensional stability. PMID- 22439098 TI - Effect of fiber reinforcement on impact strength of heat polymerized polymethyl methacrylate denture base resin: in vitro study and SEM analysis. AB - PURPOSE: The aim of this in-vitro investigation was to describe the effect of reinforcement with different fibers on impact strength of heat polymerized polymethyl methacrylate (PMMA) denture base resin and to analyze the effect of surface treatment of the fibers on the impact strength. MATERIALS AND METHODS: The specimens were fabricated from the dies formed as per standard ASTM D4812. 2% by weight of glass, polyethylene and polypropylene fibers were incorporated in the PMMA resin. The Izod impact testing was performed on the unnotched specimens and the values obtained were analyzed using appropriate one way ANOVA, followed by unpaired t-test. Fractured ends of the samples were subjected to the SEM analysis. RESULTS: The polypropylene fibers with plasma treatment showed the highest impact strength (9.229 * 10(2) J/m) followed by the plasma treated polyethylene fibers (9.096 * 10(2) J/m), untreated polypropylene fibers (8.697 * 10(2) J/m), untreated polyethylene fibers (7.580 * 10(2) J/m), silane treated glass fibers (6.448 * 10(2) J/m) and untreated glass fibers (5.764 * 10(2) J/m). Also the surface treatment of all the fibers has shown the significant improvement in impact strength. Findings of the SEM analysis justified the improvement in impact strength after surface treatment. CONCLUSION: Reinforcement with the fiber is an effective method to increase the impact strength of PMMA denture base resin. The surface treatment of fibers further increases the impact strength significantly. PMID- 22439099 TI - Influence of modification in core building procedure on fracture strength and failure patterns of premolars restored with fiber post and composite core. AB - PURPOSE: The influence of the modified process in the fiber-reinforced post and resin core foundation treatment on the fracture resistance and failure pattern of premolar was tested in this study. MATERIALS AND METHODS: Thirty-six human mandibular premolars were divided into 4 groups (n = 9). In group DCT, the quartz fibre post (D.T. Light-post) was cemented with resin cement (DUO-LINK) and a core foundation was formed with composite resin (LIGHT-CORE). In group DMO and DMT, resin cement (DUO-LINK) was used for post (D.T. Light-post) cementation and core foundation; in group DMO, these procedures were performed simultaneously in one step, while DMT group was accomplished in separated two steps. In group LCT, the glass fiber post (LuxaPost) cementation and core foundation was accomplished with composite resin (LuxaCore-Dual) in separated procedures. Tooth were prepared with 2 mm ferrule and restored with nickel-chromium crowns. A static loading test was carried out and loads were applied to the buccal surface of the buccal cusp at a 45 degree inclination to the long axis of the tooth until failure occurred. The data were analyzed with MANOVA (alpha = .05). The failure pattern was observed and classified as either favorable (allowing repair) or unfavorable (not allowing repair). RESULTS: The mean fracture strength was highest in group DCT followed in descending order by groups DMO, DMT, and LCT. However, there were no significant differences in fracture strength between the groups. A higher prevalence of favorable fractures was detected in group DMT but there were no significant differences between the groups. CONCLUSION: The change of post or core foundation method does not appear to influence the fracture strength and failure patterns. PMID- 22439100 TI - Effect of sociodemographic variables on complete denture satisfaction. AB - PURPOSE: The objective of this study was to evaluate the effect of sociodemographic factors on quality of satisfaction towards denture treatment. MATERIALS AND METHODS: One hundred subjects (filling inclusion criteria) who were wearing a denture for at least two months were enrolled and divided into five groups on the basis of sociodemographic variables (age, gender, literacy level, socio-economic and marital status). Questionnaires consisting of 38 questions (positive and negative attitude towards denture satisfaction) related to patients' perception of clinical outcome in different domains such as mastication, appearance, speech, comfort, health, denture care and social status were scored by the subjects. Questions reflecting positive attitude were scored as 2, 1, or 0 (yes, uncertain and no, respectively) and reversely for the negative questions. Statistical analysis was done by using Statistical Package for Social Sciences (alpha = .05). RESULTS: Level of denture satisfaction was higher in age subgroup belonging to 45 - 65 years of age in relation to comfort, health and denture care. Female and male showed significant priority for denture treatment because of esthetic and function respectively. Level of satisfaction was statistically significant with literacy level. Upper high income group showed significantly higher level of satisfaction only in case of social status. Married group showed significantly higher satisfaction level only with comfort. CONCLUSION: Patients' sociodemographic variables were influential factors on denture satisfaction. PMID- 22439101 TI - Immediate placement and functional loading of implants on canine with fixed partial denture for a patient having canine protected occlusion: a case report. AB - Conventional implant protocols required a load-free healing period of three to six months between placement and functional loading of the implants. Many efforts have been made to minimize the duration of treatment time. Several literatures have documented immediate function with provisional or definitive prosthesis within a week of the placement in response to these demands. In addition, immediate implant placement has advantages such as shortened treatment time and preservation of soft tissue architectures. This article presents immediate implant placement into fresh extraction sockets followed by functional immediate loading with provisional prosthesis on canine and premolars for a patient having canine protected occlusion. PMID- 22439102 TI - An implant-supported removable partial denture for a patient with post inflammatory scar contracture caused by burn complications: a clinical report. AB - The scars and contracture around the oral-facial region may cause difficulty in prosthodontic treatment to restore esthetics and function for the patients, who suffered severe burns. This article presents a technique that uses a fixed partial denture prepared with a conventional milling technique and an attachment to support anterior cantilever removable partial denture, thereby providing a more esthetically acceptable and functional result. PMID- 22439103 TI - Human behavior in Prisoner's Dilemma experiments suppresses network reciprocity. AB - During the last few years, much research has been devoted to strategic interactions on complex networks. In this context, the Prisoner's Dilemma has become a paradigmatic model, and it has been established that imitative evolutionary dynamics lead to very different outcomes depending on the details of the network. We here report that when one takes into account the real behavior of people observed in the experiments, both at the mean-field level and on utterly different networks, the observed level of cooperation is the same. We thus show that when human subjects interact in a heterogeneous mix including cooperators, defectors and moody conditional cooperators, the structure of the population does not promote or inhibit cooperation with respect to a well mixed population. PMID- 22439104 TI - Hierarchical CO(2)-protective shell for highly efficient oxygen reduction reaction. AB - The widespread application of intermediate-temperature solid oxide fuel cells is mainly being hurdled by the cathode's low efficiency on oxygen reduction reaction and poor resistance to carbon dioxide impurity. Here we report the fabrication of a hierarchical shell-covered porous cathode through infiltration followed by microwave plasma treatment. The hierarchical shell consists of a dense thin-film substrate with cones on the top of the substrate, leading to a three-dimensional (3D) heterostructured electrode. The shell allows the cathode working stably in CO(2)-containing air, and significantly improving the cathode's oxygen reduction reactivity with an area specific resistance of ~0.13 Omegacm(2) at 575 degrees C. The method is also suitable for fabricating functional shell on the irregularly shaped substrate in various applications. PMID- 22439105 TI - Scale-invariant structure of size fluctuations in plants. AB - A wide range of physical and biological systems exhibit complex behaviours characterised by a scale-invariant structure of the fluctuations in their output signals. In the context of plant populations, scaling relationships are typically allometric. In this study, we analysed spatial variation in the size of maize plants (Zea Mays L.) grown in agricultural plots at constant densities and found evidence of scaling in the size fluctuations of plants. The findings indicate that the scaling of the probability distribution of spatial size fluctuation exhibits non-Gaussian behaviour compatible with a Levy stable process. The scaling relationships were observed for spatial scales spanning three orders of magnitude. These findings should provide additional information for the selection and development of empirically accurate models of pattern formation in plant populations. PMID- 22439106 TI - Exposure of the sciatic nerve in the gluteal region without sectioning the gluteus maximus: Analysis of a series of 18 cases. AB - BACKGROUND: Dissecting through the gluteus maximus muscle by splitting its fibers, instead of complete sectioning of the muscle, is faster, involves less damage to tissues, and diminishes recovery time. The objective of the current paper is to present a clinical series of sciatic nerve lesions where the nerve was sufficiently exposed via the transgluteal approach. METHODS: We retrospectively selected 18 traumatic sciatic nerve lesions within the buttock, operated upon from January 2005 to December 2009, with a minimum follow-up of 2 years. In all patients, a transgluteal approach was employed to explore and reconstruct the nerve. RESULTS: Ten males and eight females, with a mean age of 39.7 years, were studied. The etiology of the nerve lesion was previous hip surgery (n = 7), stab wound (n = 4), gunshot wound (n = 3), injection (n = 3), and hip dislocation (n = 1). In 15 (83.3%) cases, a motor deficit was present; in 12 (66.6%) cases neuropathic pain and in 12 (66.6%) cases sensory alterations were present. In all cases, the transgluteal approach was adequate to expose the injury and treat it by neurolysis alone (10 cases), neurolysis and neurorrhaphy (4 cases), and reconstruction with grafts (4 cases; three of these paired with neurolysis). The mean pre- and postoperative grades for the tibial nerve (LSUHSC scale) were 1.6 and 3.6, respectively; meanwhile, for the peroneal division, preoperative grade was 1.2 and postoperative grade was 2.4. CONCLUSIONS: The transgluteal approach adequately exposes sciatic nerve injuries of traumatic origin in the buttock and allows for adequate nerve reconstruction without sectioning the gluteus maximus muscle. PMID- 22439108 TI - Diagnostic and surgical challenges in resection of cerebellar angle tumors and acoustic neuromas. AB - BACKGROUND: Cerebellopontine angle (CPA) lesions can mimic more common tumors through nonspecific symptoms and radiologic findings. METHODS: To increase the preoperative diagnostic accuracy for CPA pathologies, the authors review the full spectrum of reported CPA lesions. RESULTS: A wide spectrum of lesions mimics vestibular schwannoma (VS) in the space of the CPA. CONCLUSION: The presence of any suspicious clinical and radiographic finding uncharacteristic of VS makes it necessary to maintain a broad differential diagnosis list. Differentiation of CPA lesions, although challenging, may be best achieved by incorporating the clinical history, physical exam findings, audiometry results, and multi-modality imaging studies to construct a comprehensive preoperative knowledge of the lesion. This knowledge will allow improved operative execution and outcomes. PMID- 22439107 TI - Concussions: What a neurosurgeon should know about current scientific evidence and management strategies. AB - BACKGROUND: There has been a tremendous amount of interest focused on the topic of concussions over the past few decades. Neurosurgeons are frequently consulted to manage patients with mild traumatic brain injuries (mTBI) that have radiographic evidence of cerebral injury. These injuries share significant overlap with concussions, injuries that typically do not reveal radiographic evidence of structural injury, in the realms of epidemiology, pathophysiology, outcomes, and management. Further, neurosurgeons often manage patients with extracranial injuries that have concomitant concussions. In these cases, neurosurgeons are often the only "concussion experts" that patients encounter. RESULTS: The literature has been reviewed and data have been synthesized on the topic including sections on historical background, epidemiology, pathophysiology, diagnostic advances, clinical sequelae, and treatment suggestions, with neurosurgeons as the intended target audience. CONCLUSIONS: Neurosurgeons should have a fundamental knowledge of the scientific evidence that has developed regarding concussions and be prepared to guide patients with treatment plans. PMID- 22439109 TI - Progressive tentorial cavernous malformation. AB - BACKGROUND: Because extra-axial cavernous malformations (CMs) are rare, the common clinical course remains unclear. We report the case of a patient with progressive CM originating from the cerebellar tentorium. CASE DESCRIPTION: A 64 year-old woman was admitted to our hospital with the complaint of diplopia. Magnetic resonance (MR) imaging revealed a lesion attached to the left cerebellar tentorium, close to the cerebral peduncle. This well-demarcated lesion rapidly enlarged for 3 months and eroded into the midbrain. Cerebral angiography showed a branch of the middle meningeal artery supplying the lesion and pooling of the contrast medium in the venous phase. A dark reddish and mulberry-like mass of the tentorium was observed intraoperatively, allowing the diagnosis of a tentorial CM. The feeding artery was identified in the tentorium and was coagulated. Postoperative MR imaging showed remarkable mass reduction and central necrosis of the lesion. However, the lesion recurred in 3 months; consequently, gamma knife radiosurgery was performed. After an additional 2 months, the lesion shrank in response to the radiosurgery. CONCLUSIONS: We report an extremely rare case of tentorial CM which showed rapid growth in a short period. Coagulation of the feeding artery was not sufficient to control the lesion. Gamma knife radiosurgery may prove highly effective for recurrent lesions. PMID- 22439111 TI - Dynamic changes in blood flow of a bypassed superficial temporal artery with unstable internal carotid artery stenosis. AB - BACKGROUND: There are limited indications for superficial temporal artery to middle cerebral artery (STA-MCA) bypass in the treatment of cerebral atherosclerotic disease. However, recent reports emphasize that STA-MCA bypass may be beneficial for select patients. In this report, we describe a case in which a flow-dependent STA-MCA bypass was achieved in a patient with unstable internal carotid artery (ICA) stenosis. CASE DESCRIPTION: A 51-year-old woman presented with left ICA occlusion. A severely elongated mean transit time (MTT) indicated misery perfusion. STA-MCA bypass was performed immediately and blood flow through the graft appeared excellent on magnetic resonance angiography (MRA). Two weeks later, MRA revealed normal anterograde ICA blood flow and the bypass graft was not visible. Three years later, the left ICA stenosis again became severe and the patient developed contralateral hemiparesis. She underwent endovascular surgery and the ipsilateral MCA became occluded during the procedure. The STA-MCA bypass graft appeared immediately after the MCA occlusion and became a major provider of blood flow to the ipsilateral MCA area. She recovered with almost no deficit. CONCLUSION: This is a rare case which shows that dynamic flow changes through an STA-MCA bypass can occur with variable ICA blood flow. STA-MCA bypass can be beneficial for the treatment of unstable ICA stenosis. PMID- 22439112 TI - Basioccipital bone osteochondroma growing into the foramen magnum. AB - BACKGROUND: Osteochondroma is a common bone tumor and rarely affects the central nervous system. Although intraspinal osteochondromas are known to cause neurological deficits, intracranial osteochondromas with neurological compromise are very rare. CASE DESCRIPTION: The authors report an exceptional case of a quadriparetic 73-year-old patient with a basioccipital bone osteochondroma growing into the foramen magnum. The embryology, differential diagnoses, and optimal management strategies are discussed. CONCLUSION: Although extremely rare, osteochondromas should be included in the differential diagnoses of tumors within the foramen magnum. For the tumors originating from the basioccipital bone, a simple medial suboccipital approach might suffice, while for ventral tumors, a far lateral transcondylar approach is necessary to avoid any neurovascular complications. Despite potentially catastrophic presenting symptoms, these tumors are pathologically benign and complete excision often results in long-term cure. To the best of our knowledge, this is the first report of an osteochondroma arising from the basiocciput. PMID- 22439110 TI - Natural plant products and extracts that reduce immunoexcitotoxicity-associated neurodegeneration and promote repair within the central nervous system. AB - Our understanding of the pathophysiological and biochemical basis of a number of neurological disorders has increased enormously over the last three decades. Parallel with this growth of knowledge has been a clearer understanding of the mechanism by which a number of naturally occurring plant extracts, as well as whole plants, can affect these mechanisms so as to offer protection against injury and promote healing of neurological tissues. Curcumin, quercetin, green tea catechins, balcalein, and luteolin have been extensively studied, and they demonstrate important effects on cell signaling that go far beyond their antioxidant effects. Of particular interest is the effect of these compounds on immunoexcitotoxicity, which, the authors suggest, is a common mechanism in a number of neurological disorders. By suppressing or affecting microglial activation states as well as the excitotoxic cascade and inflammatory mediators, these compounds dramatically affect the pathophysiology of central nervous system disorders and promote the release and generation of neurotrophic factors essential for central nervous system healing. We discuss the various aspects of these processes and suggest future directions for study. PMID- 22439113 TI - Non-operative management is superior to surgical stabilization in spine injury patients with complete neurological deficits: Some additional perspectives. PMID- 22439114 TI - Duplication of the pituitary gland associated with multiple blastogenesis defects: Duplication of the pituitary gland (DPG)-plus syndrome. Case report and review of literature. AB - BACKGROUND: Duplication of the pituitary gland (DPG) is a rare craniofacial developmental anomaly occurring during blastogenesis with postulated etiology such as incomplete twinning, teratogens, median cleft face syndrome or splitting of the notochord. The complex craniocaudal spectrum of blastogenesis defects associated with DPG is examined with an illustrative case. CASE DESCRIPTION: We report for the first time in the medical literature some unique associations with DPG, such as a clival encephalocele, third cerebral peduncle, duplicate odontoid process and a double tongue with independent volitional control. This patient also has the previously reported common associations such as duplicated sella, cleft palate, hypertelorism, callosal agenesis, hypothalamic enlargement, nasopharyngeal teratoma, fenestrated basilar artery and supernumerary teeth. This study also reviews 37 cases of DPG identified through MEDLINE literature search from 1880 to 2011. It provides a detailed analysis of the current case through physical examination and imaging. CONCLUSION: The authors propose that the developmental deformities associated with duplication of pituitary gland (DPG) occur as part of a developmental continuum, not as chance associations. Considering the fact that DPG is uniquely and certainly present throughout the spectrum of these blastogenesis defects, we suggest the term DPG-plus syndrome. PMID- 22439115 TI - Acute hemorrhage in a colloid cyst of the third ventricle: A rare cause of sudden deterioration. AB - BACKGROUND: Acute neurological deterioration and death in a patient harboring a colloid cyst of the third ventricle remains a poorly understood phenomenon. Sudden neurological derangement caused by spontaneous bleeding within a colloid cyst is a rare and potentially fatal event, usually requiring immediate diagnosis and emergency surgical treatment. CASE DESCRIPTION: A 47-year-old male presented with acute right-sided hemiparesis and speech impediment, followed by rapid deterioration of consciousness. Neuroimaging studies showed a rounded mass at the roof of the anterior third ventricle, causing biventricular hydrocephalus along with a left-sided basal ganglia hematoma. The lesion showed scattered foci of a recent hemorrhage which extended into the left lateral ventricle. Surgical treatment involved emergency external ventricular drainage followed by the prompt elective total resection of the lesion via a transcallosal route. Pathological findings confirmed the diagnosis of a colloid cyst with focal areas of vascular congestion and blood extravasation within its wall. CONCLUSIONS: Spontaneous bleeding into a colloid cyst of the third ventricle may cause acute obstructive hydrocephalus and intracranial hypertension due to rapid enlargement of the lesion. This event may account for the sudden neurological deterioration and/or death observed in a previously asymptomatic patient. The diagnosis of hemorrhagic phenomena within a colloid cyst represents a challenge due to the variable signal usually displayed by these lesions on computed tomography (CT) and magnetic resonance imaging (MRI). Emergency ventricular drainage followed by elective tumoral removal constitutes a valid and safe treatment strategy. PMID- 22439116 TI - Complications in patients undergoing combined transforaminal lumbar interbody fusion and posterior instrumentation with deformity correction for degenerative scoliosis and spinal stenosis. AB - BACKGROUND: Utilization of the transforaminal lumbar interbody fusion (TLIF) approach for scoliosis offers the patients deformity correction and interbody fusion without the additional morbidity associated with more invasive reconstructive techniques. Published reports on complications associated with these surgical procedures are limited. The purpose of this study was to quantify the intra- and postoperative complications associated with the TLIF surgical approach in patients undergoing surgery for spinal stenosis and degenerative scoliosis correction. METHODS: This study included patients undergoing TLIF for degenerative scoliosis with neurogenic claudication and painful lumbar degenerative disc disease. The TLIF technique was performed along with posterior pedicle screw instrumentation. The average follow-up time was 30 months (range, 15-47). RESULTS: A total of 29 patients with an average age of 65.9 years (range, 49-83) were evaluated. TLIFs were performed at 2.2 levels on average (range, 1-4) in addition to 6.0 (range, 4-9) levels of posterolateral instrumented fusion. The preoperative mean lumbar lordosis was 37.6 degrees (range, 16 degrees -55 degrees ) compared to 40.5 degrees (range, 26 degrees -59.2 degrees ) postoperatively. The preoperative mean coronal Cobb angle was 32.3 degrees (range, 15 degrees -55 degrees ) compared to 15.4 degrees (range, 1 degrees -49 degrees ) postoperatively. The mean operative time was 528 min (range, 276-906), estimated blood loss was 1091.7 mL (range, 150-2500), and hospitalization time was 8.0 days (range, 3-28). A baseline mean Visual Analog Scale (VAS) score of 7.6 (range, 4-10) decreased to 3.6 (range, 0-8) postoperatively. There were a total of 14 (49%) hardware and/or surgical technique related complications, and 8 (28%) patients required additional surgeries. Five (17%) patients developed pseudoarthrosis. The systemic complications (31%) included death (1), cardiopulmonary arrest with resuscitation (1), myocardial infarction (1), pneumonia (5), and pulmonary embolism (1). CONCLUSION: This study suggests that although the TLIF approach is a feasible and effective method to treat degenerative adult scoliosis, it is associated with a high rate of intra- and postoperative complications and a long recovery process. PMID- 22439117 TI - Anesthetic management during Cesarean section in a woman with residual Arnold Chiari malformation Type I, cervical kyphosis, and syringomyelia. AB - BACKGROUND: Type I Arnold-Chiari malformation (ACM) has an adult onset and consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum. There is paucity of literature on the anesthetic management during pregnancy of residual ACM Type I, with cervical xyphosis and persistent syringomyelia. CASE DESCRIPTION: A 34-year-old woman with surgically corrected ACM Type I presented for Cesarean delivery. A recent MRI demonstrated worsening of cervical xyphosis after several laminectomies and residual syringomyelia besides syringopleural shunt. Awake fiberoptic intubation was performed under generous topical anesthesia to minimize head and neck movement during endotracheal intubation. We used a multimodal general anesthesia without neuromuscular blockade. The neck was maintained in a neutral position. Following delivery, the patient completely recovered in post-anesthesia care unit (PACU), with no headache and no exacerbation or worsening of neurological function. CONCLUSIONS: The present case demonstrates that patients with partially corrected ACM, syringomyelia, cervical kyphosis, and difficult intubation undergoing Cesarean delivery require an interdisciplinary team approach, diligent preparation, and skilled physicians. PMID- 22439118 TI - Changes in stroke research productivity: A global perspective. AB - BACKGROUND: While stroke is the second leading cause of death worldwide, little work has been done to quantify the growth and progress of stroke publications. The purpose of this study is to quantitatively analyze trends in the stroke literature over the past 12 years, specifically examining changes in worldwide productivity and study methodology. METHODS: The study was a retrospective bibliometric analysis of all stroke articles published between 1996 and 2008 indexed in MEDLINE. Country of origin, MEDLINE-defined methodology, specialty of the first author, and funding sources (for US articles) were recorded. Growth was analyzed by using linear and nonlinear regression. RESULTS: Total articles numbered 32,309 during the study period, with leading global contributors including the United States with 8795 (27.2%) articles, Japan with 2757 (8.5%) articles, and the United Kingdom with 2629 (8.1%) articles. Growth globally and in the United States followed a linear pattern at 209.9 and 56.2 articles per year, respectively (both P < 0.001). Review articles and clinical trials numbered 5932 (18.4%) and 2934 (9.1%), respectively. Clinical trials followed an exponential growth pattern of 7.7% per year (P < 0.001). Regarding specialty influence, pain management and rehabilitation had the largest proportional growth in clinical trials from 4 to 51 articles. CONCLUSIONS: Within the stroke literature, we observed continued growth worldwide, sustained growth in the United States, and a steady increase in the number of clinical trials, especially by pain management and rehabilitation. PMID- 22439119 TI - The Russian political turmoil (2012): An American perspective. PMID- 22439120 TI - Decompressive hemicraniectomy in supra-tentorial malignant infarcts. AB - BACKGROUND: Decompressive hemicraniectomy not only reduces the intracranial pressure but has been demonstrated to increase survival and decrease the morbidity in patients with supratentorial malignant brain infarcts (STMBI). The aim of this study was to assess the efficacy of surgical decompression to decrease the mortality and morbidity in patients with STMBI refractory to medical therapy and to compare the results with those of the medically managed patients. METHODS: All the 24 consecutive patients with clinical and radiological diagnosis of STMBI, refractory to medical management in 2 years, were included. Option of surgical decompression after explaining the outcome, risk and benefits of the procedure was given to the attendants/relatives of all patients who were fulfilling the inclusion criteria. The patient group, whose attendants/relatives were not willing to undergo surgery, were subjected to the same medical therapy and they were taken as the "control group." RESULTS: Supratentorial malignant infarcts were more common in the age group of 41-60 years. Mean age of presentation was 42.16 +/- 16.2 years and the mean GCS on admission was 7.83 +/- 2.1. Mortality was 16.7% in the surgically and 25.0% in the medically managed group. Patients operated early (<48 h), age <=60 years, midline shift <5 mm and size of infarct less than 2/3(rd) of the vascular territory involved showed good prognosis. The functional outcome revealed by modified Rankin Score (mRS) and Glasgow Outcome Score (GOS) was better in surgically managed patients. Results of the Zung Self-Rating Depression Score were better in surgically managed patients at 1 year. Barthal Index in the surgically managed group showed statistically significant results. CONCLUSIONS: Decompressive hemicraniectomy with duroplasty if performed early in STMBI not only decreases the mortality but also increases the functional outcome when compared with patients who were managed conservatively with medical therapy only. PMID- 22439121 TI - A pathologist-in-the-loop IHC antibody test selection using the entropy-based probabilistic method. AB - BACKGROUND: Immunohistochemistry (IHC) is an important tool to identify and quantify expression of certain proteins (antigens) to gain insights into the molecular processes in a diseased tissue. However, it is a challenge for pathologists to remember the discriminative characteristics of the growing number of such antigens across multiple diseases. The complexity of their expression patterns, fueled by continuous discoveries in molecular pathology, gives rise to a combinatorial explosion that places an unprecedented burden on a practicing pathologist and therefore increases cost and variability of IHC studies. MATERIALS AND METHODS: To tackle these issues, we have developed antibody test optimized selection method, a novel informatics tool to help pathologists in improving the IHC antibody selection process. The method uses extensions of Shannon's information entropies and Bayesian probabilities to dynamically build an efficient diagnostic tree. RESULTS: A comparative analysis of our method with the expert and World Health Organization classification guidelines showed that the proposed method brings threefold reduction in number of antibody tests required to reach a diagnostic conclusion. CONCLUSION: The developed method can significantly streamline the antibody test selection process, decrease associated costs and reduce inter- and intrapathologist variability in IHC decision-making. PMID- 22439122 TI - Virtual microscopy using whole-slide imaging as an enabler for teledermatopathology: A paired consultant validation study. AB - BACKGROUND: There is a need for telemedicine, particularly in countries with large geographical areas and widely scattered low-density communities as is the case of the Canadian system, particularly if equality of care is to be achieved or the difference gap is to be narrowed between urban centers and more peripheral communities. AIMS: 1. To validate teledermatopathology as a diagnostic tool in under-serviced areas; 2. To test its utilization in inflammatory and melanocytic lesions; 3. To compare the impact of 20* (0.5 MUm/pixel) and 40* (0.25 MUm/pixel) scans on the diagnostic accuracy. MATERIALS AND METHODS: A total of 103 dermatopathology cases divided into three arms were evaluated by two pathologists and results compared. The first arm consisted of 79 consecutive routine cases (n=79). The second arm consisted of 12 inflammatory skin biopsies (n=12) and the third arm consisted of 12 melanocytic lesions (n=12). Diagnosis concordance was used to evaluate the first arm. Whereas concordance of preset objective findings were used to evaluate the second and third arms. RESULTS: The diagnostic concordance rate for the first arm was 96%. The concordance rates of the objective findings for the second and third arms were 100%. The image quality was deemed superior to light microscopy for 40* scans. CONCLUSION: The current scanners produce high-resolution images that are adequate for evaluation of a variety of cases of different complexities. PMID- 22439123 TI - A novel strategy for evaluating the effects of an electronic test ordering alert message: Optimizing cardiac marker use. AB - BACKGROUND: Laboratory ordering functions within computerized provider order entry (CPOE) systems typically support the display of electronic alert messages to improve test utilization or implement new ordering policies. However, alert strategies have been shown to vary considerably in their success and the characteristics contributing to an alert's success are poorly understood. Improved methodologies are needed to evaluate alerts and their mechanisms of action. MATERIALS AND METHODS: Clinicians order inpatient and emergency department laboratory tests using our institutional CPOE system. We analyzed user interaction data captured by our CPOE system to evaluate how clinicians responded to an alert. We evaluated an alert designed to implement an institutional policy restricting the indications for ordering creatine kinase-MB (CKMB). RESULTS: Within 2 months of alert implementation, CKMB-associated searches declined by 79% with a corresponding decline in CKMB orders. Furthermore, while prior to alert implementation, clinicians searching for CKMB ultimately ordered this test 99% of the time, following implementation, only 60% of CKMB searches ultimately led to CKMB test orders. This difference presumably represents clinicians who reconsidered the need for CKMB in response to the alert, demonstrating the alert's just-in-time advisory capability. In addition, as clinicians repeatedly viewed the alert, there was a "dose-dependant" decrease in the fraction of searches without orders. This presumably reflects the alerting strategy's long term educational component, as clinicians aware of the new policy will not search for CKMB when not indicated. CONCLUSIONS: Our analytic approach provides insight into the mechanism of a CPOE alert and demonstrates that alerts may act through a combination of just-in-time advice and longer term education. Use of this approach when implementing alerts may prove useful to improve the success of a given alerting strategy. PMID- 22439124 TI - Full field optical coherence tomography can identify spermatogenesis in a rodent sertoli-cell only model. AB - BACKGROUND: Microdissection testicular sperm extraction (micro-TESE) has replaced conventional testis biopsies as a method of choice for obtaining sperm for in vitro fertilization for men with nonobstructive azoospermia. A technical challenge of micro-TESE is that the low magnification inspection of the tubules with a surgical microscope is insufficient to definitively identify sperm containing tubules, necessitating tissue removal and cytologic assessment. Full field optical coherence tomography (FFOCT) uses white light interference microscopy to generate quick high-resolution tomographic images of fresh (unprocessed and unstained) tissue. Furthermore, by using a nonlaser safe light source (150 W halogen lamp) for tissue illumination, it ensures that the sperm extracted for in vitro fertilization are not photo-damaged or mutagenized. MATERIALS AND METHODS: A focal Sertoli-cell only rodent model was created with busulfan injection in adult rats. Ex vivo testicular tissues from both normal and busulfan-treated rats were imaged with a commercial modified FFOCT system, Light CTTM, and the images were correlated with gold standard hematoxylin and eosin staining. RESULTS: Light-CTTM identified spermatogenesis within the seminiferous tubules in freshly excised testicular tissue, without the use of exogenous contrast or fixation. Normal adult rats exhibited tubules with uniform size and shape (diameter 328 +/-11 MUm). The busulfan-treated animals showed marked heterogeneity in tubular size and shape (diameter 178 +/- 35 MUm) and only 10% contained sperm within the lumen. CONCLUSION: FFOCT has the potential to facilitate real-time visualization of spermatogenesis in humans, and aid in micro TESE for men with infertility. PMID- 22439125 TI - How useful are delta checks in the 21 century? A stochastic-dynamic model of specimen mix-up and detection. AB - INTRODUCTION: Delta checks use two specimen test results taken in succession in order to detect test result changes greater than expected physiological variation. One of the most common and serious errors detected by delta checks is specimen mix-up errors. The positive and negative predictive values of delta checks for detecting specimen mix-up errors, however, are largely unknown. MATERIALS AND METHODS: We addressed this question by first constructing a stochastic dynamic model using repeat test values for five analytes from approximately 8000 inpatients in Calgary, Alberta, Canada. The analytes examined were sodium, potassium, chloride, bicarbonate, and creatinine. The model simulated specimen mix-up errors by randomly switching a set number of pairs of second test results. Sensitivities and specificities were then calculated for each analyte for six combinations of delta check equations and cut-off values from the published literature. RESULTS: Delta check specificities obtained from this model ranged from 50% to 99%; however the sensitivities were generally below 20% with the exception of creatinine for which the best performing delta check had a sensitivity of 82.8%. Within a plausible incidence range of specimen mix ups the positive predictive values of even the best performing delta check equation and analyte became negligible. CONCLUSION: This finding casts doubt on the ongoing clinical utility of delta checks in the setting of low rates of specimen mix-ups. PMID- 22439126 TI - All aboard: Cytotechnology student training in pathology informatics. PMID- 22439127 TI - Acute Concomitant Anterior Cruciate Ligament and Patellar Tendon Tears in a Non dislocated Knee. AB - Anterior cruciate ligament (ACL) tears are common and may occur in isolation or with other internal derangements of the joint. Tears of the patellar tendon (PT) occur less frequently and are rarely associated with intra-articular pathology. Acute combined tears of both the ACL and PT are known complications of high energy traumatic knee dislocations. We present a case of an acute concomitant ACL and PT tears in a low-energy non-dislocated knee. To our knowledge, this injury has only been described in a limited number of case reports in the orthopedic literature. We present the imaging findings of this combined injury and discuss the importance of magnetic resonance (MR) in diagnosis. PMID- 22439128 TI - An Unusual Case of Extraosseous Accumulation of Bone Scan Tracer in a Renal Calculus - Demonstration by SPECT-CT. AB - Extraosseous localization of radioisotope, used in bone scan, in a variety of physiological and pathological conditions is a well-known phenomenon. The causes of extraosseous accumulation of bone-seeking radiotracers should be kept in mind when bone-imaging studies are reviewed to avoid incorrect interpretations. We report an extremely rare occurrence of extraosseous accumulation of bone scintigraphy tracer in a renal calculus, in a patient with adenocarcinoma of prostate, that was demonstrated by Single Photon Emission Computed Tomography and Computed Tomography (SPECT-CT) fusion imaging. PMID- 22439129 TI - Fibrochondrogenesis, an antenatal and postnatal correlation. AB - Fibrochondrogenesis is a rare, neonatally lethal osteochondrodysplasia, with autosomal recessive inheritance. It differs from other lethal dwarfisms in that it leads to broad, long-bone metaphyses (dumb-bell shaped) and pear-shaped vertebral bodies. We report a case of fibrochondrogenesis with severe pear-shaped platyspondyly, suspected antenatally, and give a comprehensive pictorial review of the antenatal ultrasound and postnatal radiographic findings. Only few cases of fibrochondrogenesis are diagnosed before the termination of pregnancy. PMID- 22439130 TI - Krukenberg tumor: a rare cause of ovarian torsion. AB - Ovarian torsion is the fifth most common gynecological surgical emergency. Ovarian torsion is usually associated with a cyst or a tumor, which is typically benign. The most common is mature cystic teratoma. We report the case of a 43 year-old woman who came to the Emergency Department with rare acute presentation of bilateral Krukenberg tumors, due to unilateral ovarian torsion. In this case report, we highlight the specific computed tomography (CT) features of ovarian torsion and demonstrate the unique radiological findings on CT imaging. Metastasis to the ovary is not rare and 5 to 10% of all ovarian malignancies are metastatic. The stomach is the common primary site in most Krukenberg tumors (70%); an acute presentation of metastatic Krukenberg tumors with ovarian torsion is rare and not previously reported in radiology literature. PMID- 22439131 TI - Dedicated Cone-beam Breast Computed Tomography and Diagnostic Mammography: Comparison of Radiation Dose, Patient Comfort, And Qualitative Review of Imaging Findings in BI-RADS 4 and 5 Lesions. AB - OBJECTIVE: This pilot study was undertaken to compare radiation dose, relative visibility/conspicuity of biopsy-proven lesions, and relative patient comfort in diagnostic mammography and dedicated cone-beam breast computed tomography (CBBCT) in Breast Imaging-Reporting and Data System (BI-RADS)((r)) 4 or 5 lesions. MATERIALS AND METHODS: Thirty-six consecutive patients (37 breasts) with abnormal mammographic and/or ultrasound categorized as BI-RADS((r)) 4 or 5 lesions were evaluated with CBBCT prior to biopsy. Administered radiation dose was calculated for each modality. Mammograms and CBBCT images were compared side-by-side and lesion visibility/conspicuity was qualitatively scored. Histopathology of lesions was reviewed. Patients were administered a survey for qualitative evaluation of comfort between the two modalities. RESULTS: CBBCT dose was similar to or less than diagnostic mammography, with a mean dose of 9.4 mGy (+/-3.1 SD) for CBBCT vs. 16.9 mGy (+/-6.9 SD) for diagnostic mammography in a total of 37 imaged breasts (P<0.001). Thirty-three of 34 mammographic lesions were scored as equally or better visualized in CBBCT relative to diagnostic mammography. Characterization of high-risk lesions was excellent. Patients reported greater comfort in CBBCT imaging relative to mammography. CONCLUSION: Our experience of side-by-side comparison of CBBCT and diagnostic mammography in BI-RADS((r)) 4 and 5 breast lesions demonstrated a high degree of correlation between the two modalities across a variety of lesion types. Owing to favorable radiation dose profile, excellent visualization of lesions, and qualitative benefits including improved patient comfort, excellent field-of-view, and more anatomical evaluation of lesion margins, CBBCT offers a promising modality for diagnostic evaluation of breast lesions. PMID- 22439132 TI - Aggressive form of cherubism. AB - Cherubism is a rare non-neoplastic hereditary disease related to genetic mutations characterized by symmetrically swollen cheeks, particularly over the angles of the mandible, and an upward turning of the eyes. The affected mandible and maxilla begin to swell in early childhood, and gradually increase until the age of puberty. Apparently, surgical intervention is unnecessary unless significant functional, esthetic, or emotional disturbances develop. In the present paper, we report a case of cherubism, with classic features that was classified as grade 3, managed with surgery and followed up for 2-years after treatment. PMID- 22439133 TI - College-Bound Teens' Decisions about the Transition to Sex: Negotiating Competing Norms. AB - The normative influence of parents, close friends, and other peers on teens' sexual behavior has been well documented. Yet, we still know little about the processes through which these oftentimes competing norms impact teens' own sexual norms and behaviors. Drawing on qualitative data from 47 interviews conducted with college-bound teens, we investigate the processes through which perceived parental, close friend, and other peer norms about sex influenced teens' decisions about whether and when to have sex. Although virtually all teens perceived that most of their peers were having sex and that parents were almost universally against teen sex, some teens had sex and others did not. Our findings demonstrate that teens who remained virgins and those who were sexually active during high school often negotiated different sets of competing norms. Differences in understandings of age norms, in close friends' sexual norms and behaviors, and in communication about sex with parents, close friends and other peers were related to different levels of sexual behavior for teens who otherwise shared many similarities in social location (e.g.. class, race, and educational status). While virgins reported an individualized process of deciding whether they were ready for sex, we find that their behavior fits within a traditional understanding of an age norm because of the emphasis on avoiding negative sanctions. Sexually experienced teens, on the other hand, explicitly reported abiding by a group age norm that prescribed sex as normal during high school. Finally, parents' normative objections to teen sex - either moral or practical - and the ways they communicated with their teen about sex had important influence on teens' own sexual norms and behaviors during high school. PMID- 22439134 TI - [Sitagliptin in the treatment of type 2 diabetes: new data presented during the American Diabetes Association annual meeting (San Diego, California, June 2011)]. AB - In the context of a need for improved strategies to control glycemia in patients with type 2 diabetes, new information was discussed during the American Diabetes Association's annual meeting on the dipeptidyl peptidase 4 inhibitor sitagliptin. As reviewed below, clinical trials corroborated the feasibility of adding sitagliptin to ongoing metformin or pioglitazone therapy, without the risk for hypoglycemia or the negative impact on body weight observed after add-on sulfonylureas, although the neutral or beneficial effect of sitagliptin on body weight resulted from a complex interaction with baseline levels of hemoglobin A1c levels and the change brought about by treatment. New studies of sitagliptin presented during the meeting also indicated additional effects of the drug not mediated by inhibition of dipeptidyl peptidase-4, but through direct inhibition of endogenous glucose production and/or glucagon responses and improved beta-cell glucose sensitivity. PMID- 22439135 TI - Graphene oxide integrated sensor for electrochemical monitoring of mitomycin C DNA interaction. AB - We present a graphene oxide (GO) integrated disposable electrochemical sensor for the enhanced detection of nucleic acids and the sensitive monitoring of the surface-confined interactions between the anticancer drug mitomycin C (MC) and DNA. Interfacial interactions between immobilized calf thymus double-stranded (dsDNA) and anticancer drug MC were investigated using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) techniques. Based on three repetitive voltammetric measurements of 120 MUg mL(-1) DNA immobilized on GO-modified electrodes, the RSD % (n = 3) was calculated as 10.47% and the detection limit (DL) for dsDNA was found to be 9.06 MUg mL(-1). EIS studies revealed that the binding of the drug MC to dsDNA leads to a gradual decrease of its negative charge. As a consequence of this interaction, the negative redox species were allowed to approach the electrode, and thus increase the charge transfer kinetics. On the other hand, DPV studies exploited the decrease of the guanine signal due to drug binding as the basis for specifically probing the biointeraction process between MC and dsDNA. PMID- 22439136 TI - An indicator-displacement assay for naked-eye detection and quantification of histidine in human urine. AB - A simple and efficient colorimetric method for the naked-eye detection and quantification of histidine in biological fluids was developed based on an indicator-displacement assay (IDA) and the Ni(2+)-histidine affinity pair. In this IDA approach, a commercially available dye, murexide, was used as the indicator and the selective detection of histidine was achieved based on the competition between indicator and histidine for the binding with Ni(2+). The competition of histidine with murexide for Ni(2+) resulted in an obvious color change of the solution from yellow to purple, and the permitted naked-eye detection of trace histidine. The developed bioassay allows the rapid, sensitive and selective detection of histidine in urine samples, and does not need complicated sample pretreatment. The detection limit was 0.4 MUM with a linear range from 2 to 30 MUM. The relative standard deviation for 11 replicate detections of 8 MUM histidine was 2.0%. The developed sensor was successfully applied to the determination of histidine in human urine samples with recoveries from 97 to 105%. PMID- 22439137 TI - A sensitive and selective enzyme-linked immunosorbent assay for the analysis of Para red in foods. AB - Para red is a synthetic dye and a potential genotoxic carcinogen. A hapten mimicking Para red structure was synthesized by introducing a carboxyl to the naphthol part of Para red and coupled to carrier protein to form an immunogen for the production of specific antibodies. A sensitive and selective enzyme-linked immunosorbent assay (ELISA) was developed for the detection of Para red in food samples. The limit of detection and inhibition half-maximum concentrations of Para red in phosphate buffered saline with 10% methanol were 0.06 and 2.2 ng mL( 1), respectively. Cross-reactivity values of the ELISA with the tested compounds including Sudan red I, II, III, IV, and G, sunset yellow, 2-naphthol, and 4 nitroaniline were <=0.2%. This assay was used to determine Para red in tomato sauce, chilli sauce, chilli powder and sausage samples after ultrasonic extraction, cleanup and concentration steps. The average recoveries, repeatability (intraday extractions and analysis), and intra-laboratory reproducibility (interday extractions and analysis) were in the range 90-108%, 4 12% and 8-17%, respectively. This assay was compared to a high-performance liquid chromatographic method for 28 samples, displaying a good correlation (R(2) = 0.95). Para red residues in 53 real world samples determined by ELISA were below the limit of detection. PMID- 22439138 TI - Optimization of an efficient semi-solid culture protocol for sterilization and plant regeneration of Centella asiatica (L.) as a medicinal herb. AB - The present study investigates the effects of different concentrations, as well as type of plant growth regulators (PGRs) and medium (MS, Duchefa) on the growth and development of Centella asiatica in semi-solid culture. In addition, a protocol for successful sterilization of C.asiatica explants prepared from field grown plants highly exposed to fungal and bacterial contamination was determined. Results for sterilization treatments revealed that applying HgCl2 and Plant Preservative Mixture (PPM) with cetrimide, bavistin and trimethoprim which were included after washing with tap water, followed by the addition of PPM in the medium, produced a very satisfactory result (clean culture 90 +/- 1.33%) and TS5 (decon + cetrimide 1% + bavistin 150 mg/L + trimethoprim 50 mg/L + HgCl20.1% + PPM 2% soak and 2 mL/L in medium) was hence chosen as the best method of sterilization for C.asiatica. The synergistic combination of 6 benzylaminopurine (BAP) and 1-naphthaleneacetic acid (NAA) in concentrations of 2 mg/L and 0.1 mg/L, respectively, in Duchefa medium compared with MS induced the most optimal percentage of sprouted shoots (93 +/- 0.667), number of shoots (5.2 +/- 0.079) and nodes (4 +/- 0.067) per explant, leaf per explant (14 +/- 0.107) and shoot length (4.1 +/- 0.67 cm). Furthermore, optimum rooting frequency (95.2 +/- 0.81%), the number of roots/shoot (7.5 +/- 0.107) and the mean root length (4.5 +/- 0.133 cm) occurred for shoots that were cultured on full-strength MS medium containing 0.5 mg/L indole-3-butyric acid (IBA). In this study, the acclimatized plantlets were successfully established with almost 85% survival. The findings of this study have proven an efficient medium and PGR concentration for the mass propagation of C.asiatica. These findings would be useful in micropropagation and ex situ conservation of this plant. PMID- 22439139 TI - International disease monitoring, October to December 2011. PMID- 22439140 TI - Abstracts of the 19th International Congress of the European Association for Endoscopic Surgery (EAES). Torino, Italy. June 15-18, 2011. PMID- 22439141 TI - Abstracts of EURO-NOTES 2011, 5th Joint European Notes Workshop. Frankfurt am Main, Germany. September 22-24, 2011. PMID- 22439142 TI - Abstracts of the Association of Laparoscopic Surgeons of Great Britain and Ireland (ALS). Cardiff, United Kingdom. November 17-18, 2011. PMID- 22439143 TI - Abstracts of the 2012 Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). San Diego, California, USA. March 7-10, 2012. PMID- 22439144 TI - Bath salts: they are not what you think. AB - Psychoactive bath salts are a relatively new group of designer drugs sold as tablets, capsules, or powder and pur-chased in places such as tobacco and convenience stores, gas stations, head shops, and the Internet. Bath salts are stimulant agents that mimic cocaine,lysergic acid diethylamide, methamphetamine, or methylenedioxymethamphetamine (ecstasy). The most common bath salts are the cathinone derivatives 3,4-methylenedioxypyrovalerone(MDPV), 4 methylmethcathinone(mephedrone), and 3,4-methylenedioxy-N-methylcathinone (methylone). The drugs cause intense stimulation, eu-phoria, elevated mood, and a pleasurable "rush" Tachycardia, hypertension,peripheral constriction, chest pain, hallucinations, paranoia, erratic behavior,inattention, lack of memory of substance use, and psychosis have been observed in those who have used bath salts. The U.S. Drug Enforcement Administration recently exercised an emergency authority to name three key ingredients in bath salts as Schedule I, thereby making them illegal to possess or sell in the United States. Nursing implications related to both clinical and educational settings are discussed. PMID- 22439145 TI - Implementation of comfort rooms to reduce seclusion, restraint use, and acting out behaviors. AB - The use of seclusion and restraint as methods to control acting-out behaviors by individuals with mental illness continues, despite deaths and other negative outcomes to both the clients themselves and the staff members applying these techniques. Additionally, client-to-client and client-to-staff assaults and self injurious behaviors can lead to injury or possible fatalities to both parties.Thus, there is a need to find alternative approaches to mitigate or even eliminate some of these behaviors. The use of comfort rooms is one such approach. With the institution of comfort rooms, one small, rural, tertiary mental health hospital demonstrated a reduction in seclusion and restraint use and assaultive behaviors of clients. In addition, 92.9% of the clients who used these rooms found them to be helpful when they experienced increasing levels of distress. With the provision of an area for clients to go voluntarily to self-manage their distress,nurses play a role in promoting autonomy and person-centered care, while reducing environmental stress and potential negative outcomes. PMID- 22439146 TI - Psychiatric nursing emergency: a simulated experience of a wrist-cutting suicide attempt. AB - A simulated wrist-cutting suicide attempt scenario was developed and implemented, with the goal of integrating the concepts of psychiatric emergency care, contraband, environmental assessment, and personal safety. Faculty also wanted to convey and provide care and support for participants through-out the visually and emotionally stimulating activity. The under-lying premise was that providing readings and lecture material on these topics was insufficient to the level of learning and performance needed by nursing students and novice nurses. How-ever, actual student clinical episodes integrating these concepts were also infrequent, unpredictable, and often not conducive to student learning. Therefore, faculty implemented a simulation teaching modality to deliver the concepts in a vivid and memorable format. A standardized rating scale on perceived learning and care from faculty during the course of the simulation was administered immediately following participation in the activity. Participants were overwhelmingly positive in their assessment of the activity, reporting an enhanced appreciation for safety in the conduct of inpatient psychiatric nursing care.Further, the faculty member's observation and post-simulation processing of the activity noted cognitive, behavioral, and emotional responses at the individual and group levels related to communication, observation and assessment, decision making,and interpersonal support PMID- 22439147 TI - Malignant pleural mesothelioma: a therapeutic challenge. PMID- 22439148 TI - Genetic variants in the ADIPOQ gene and the risk of metabolic syndrome: a case control study of a Chinese Han population. AB - Our aim was to investigate whether the ADIPOQ gene polymorphisms are associated with the metabolic syndrome (MetS). Genotypes of MetS patients (n=1049) and normal controls (n= 1092) were analysed by TaqMan(r) assay, and serum adiponectin concentration was measured by ELISA. The variant genotypes rs266729CG; rs1063539GC, GC/CC; rs16861205AA and rs7649121AT, AT/TT (Adjusted P=0.037, 0.044, 0.025, 0.011, 0.019, 0.020, respectively) of the ADIPOQ gene were associated with MetS. Patients with rs266729CG, CG/GG genotypes (P=0.034, 0.035) and rs7649121AT, AT/TT genotypes (P=0.013, 0.022) had higher levels of serum adiponectin than those with the CC and AA genotypes respectively. Furthermore, the prevalence of haplotypes GGAAAATC and GGGTAACC was lower in cases (10.7% and 4.5%) than in controls (12.1% and 5.9%) [Adjusted ORs (95% CIs)=0.70 (0.54-0.91), 0.65 (0.46 0.92)]. The ADIPOQ gene variants associated with the risk of MetS in this study must be validated by further functional studies to reveal any potential effects on metabolism. PMID- 22439149 TI - A cardiologist's quick guide to lupus. AB - Accelerated atherosclerosis has emerged as an important complication in lupus patients. PMID- 22439150 TI - JACC, the Journal of the American College of Cardiology. AB - Anthony N. DeMaria discusses the journal's history, its focus,and innovative ideas for Internet reading. PMID- 22439151 TI - Virtual institution to boost German cardiology research. AB - The German government has promised many millions over the next 5 years for a "virtual" cardiology institution linking up researchers in seven major centres. Emma Wilkinson speaks to two of those involved in the project about what it hopes to achieve PMID- 22439152 TI - The effects of radiation exposure on interventional cardiologists. AB - Professional exposure of interventional cardiologist to low-dose radiation prompts cellular changes that may protect from harm. PMID- 22439153 TI - Foot strike patterns in runners. PMID- 22439154 TI - The legitimacy of leadership in international climate change negotiations. AB - Leadeship is an essential ingredient in reaching international agreements and overcoming the collective action problems associated with responding to climate change. In this study, we aim at answering two questions that are crucial for understanding the legitimacy of leadership in international climate change negotiations. Based on the responses of the three consecutive surveys distributed at COPs 14-16, we seek first to chart which actors are actually recognized as leaders by climate change negotiation participants. Second, we aim to explain what motivates COP participants to support different actors as leaders. Both these questions are indeed crucial for understanding the role, importance, and legitimacy of leadership in the international climate change regime. Our results show that the leadership landscape in this issue area is fragmented, with no one clear-cut leader, and strongly suggest that it is imperative for any actor seeking recognition as climate change leader to be perceived as being devoted to promoting the common good. PMID- 22439166 TI - [Abstracts of the XVIII Congress of the Ukrainian Physiological Society with international participation, May 20-22, 2010. Odessa, Ukraine]. PMID- 22439167 TI - Engagement and action. PMID- 22439168 TI - Global health curriculum in family medicine: resident perspective. PMID- 22439169 TI - Hypocalcemia: updates in diagnosis and management for primary care. AB - OBJECTIVE: To provide family physicians with an evidence-based approach to the diagnosis and management of hypocalcemia. Quality of evidence MEDLINE and EMBASE articles from 2000 to 2010 were searched, with a focus on the diagnosis and management of hypocalcemia. Levels of evidence (I to III) were cited where appropriate, with most studies providing level II or III evidence. References of pertinent papers were also searched for relevant articles. Main message Chronic hypocalcemia is commonly due to inadequate levels of parathyroid hormone or vitamin D, or due to resistance to these hormones. Treatment focuses on oral calcium and vitamin D supplements, as well as magnesium if deficiency is present. Treatment can be further intensified with thiazide diuretics, phosphate binders, and a low-salt and low-phosphorus diet when treating hypocalcemia secondary to hypoparathyroidism. Acute and life-threatening calcium deficit requires treatment with intravenous calcium.The current treatment recommendations are largely based on expert clinical opinion and published case reports,as adequately controlled clinical trial data are not currently available. Complications of current therapies for hypoparathyroidism include hypercalciuria, nephrocalcinosis, renal impairment, and soft tissue calcification. Current therapy is limited by serum calcium fluctuations. Although these complications are well recognized, the effects of therapy on overall well-being, mood, cognition, and quality of life, as well as the risk of complications,have not been adequately studied. CONCLUSION: Family physicians play a crucial role in educating patients about the long-term management and complications of hypocalcemia. Currently, management is suboptimal and marked by fluctuations in serum calcium and a lack of approved parathyroid hormone replacement therapy for hypoparathyroidism. PMID- 22439170 TI - [Abstracts of the 5th International Conference 'Biological Basis of Individual Sensitivity to Psychotropic Drugs", June 1-4, 2010, Russia]. PMID- 22439171 TI - Prevalence of anemia among Quebec Cree infants from 2002 to 2007 compared with 1995 to 2000. AB - OBJECTIVE: To determine if screening of infants for anemia at 9 months in the Cree region of Quebec should continue,by comparing the prevalence of anemia in the initial years of screening (1995 to 2000) with prevalence data from infants screened between 2002 and 2007. DESIGN: Comparison of anemia prevalence from 2 cross-sectional surveys. Nonoverlapping 95% CIs were used to determine if results were significantly different. SETTING: Nine Quebec Cree communities. Participants Infants screened for anemia between 1995 and 2000 (n = 716) or 2002 and 2007 (n = 1325). Main outcome measures Anemia was diagnosed based on hemoglobin concentration. An erythrocyte mean cell volume of less than 71 fL was used as a proxy for iron deficiency. RESULTS: Hemoglobin concentration among infants screened from 2002 to 2007 was, on average, 7 g/L greater than among infants screened from 1995 to 2000 (mean [standard deviation] 121 [11] g/L vs 114 [11] g/L). The prevalence of anemia (hemoglobin < 110 g/L) from 1995 to 2000 was 31.7% (95% CI 28.3% to 35.1%), but from 2002 to 2007 it was significantly lower at 12.5% (95% CI 10.7% to 14.2%). Using a hemoglobin concentration more specific to iron deficiency anemia (IDA) (hemoglobin < 100 g/L), from 1995 to 2000 7.5% (95% CI 5.6% to 9.4%) of infants had IDA, whereas from 2002 to 2007 only 2.0% (95% CI 1.2% to 2.8%) had IDA. The prevalence of iron deficiency based on mean cell volume declined from 18.3% (95% CI 15.5% to 21.1%) from 1995 to 2000 to 4.2% (95% CI 3.1% to 5.3%) from 2002 to 2007. CONCLUSION: The 12.5% prevalence of anemia (hemoglobin < 110 g/L) among Cree infants from 2002 to 2007 was much lower than the prevalence from 1995 to 2000 but somewhat higher than among nonaboriginal infants (8.0%). The low anemia prevalence among Quebec Cree infants after 2002 suggests that replacing universal screening with targeted screening of higher risk infants needs to be considered following studies to identify risk factors for anemia. PMID- 22439172 TI - Management of aboriginal and nonaboriginal people with chronic kidney disease in Quebec: quality-of-care indicators. AB - OBJECTIVE: To compare quality-of-care indicators for management of patients with chronic kidney disease (CKD) and type 2 diabetes among the James Bay Cree of Northern Quebec with those among residents of Montreal, Que. DESIGN: A cross sectional survey using medical records from patients seen between 2002 and 2008. SETTING: Predialysis clinics of the McGill University Health Centre in Montreal. PARTICIPANTS: Thirty Cree and 51 nonaboriginal patients older than 18 years of age with type 2 diabetes mellitus and estimated glomerular filtration rates of less than 60 mL/min/1.73 m2. MAIN OUTCOME MEASURES: Rates of anemia, iron deficiency, obesity, and renoprotective medication use among aboriginal and nonaboriginal patients. RESULTS: Overall, the Cree patients were younger (59 vs 68 years of age, P < .0035) and weighed more (101 vs 77 kg,P < .001). The 2 groups were prescribed medication to control blood pressure, lipids, and phosphate levels at similar rates, but the Cree patients were more likely to receive renoprotective agents (87% vs 65%, P = .04). Despite similar rates of erythropoietin supplementation, the Cree patients were at greater risk of anemia, with an adjusted risk ratio of 2.80 (95% CI 1.01 to 7.87). CONCLUSION: Cree patients with CKD were younger, weighed more, and were more likely to receive renoprotective agents. With the exception of the management of anemia, quality of CKD care was similar between the 2 groups.Anemia education for family physicians and continuous monitoring of quality indicators must be implemented in northern Quebec. PMID- 22439173 TI - Patterns of referral and knowledge of palliative radiotherapy in Alberta. AB - OBJECTIVE: To assess practitioners' referral patterns and knowledge of palliative radiotherapy (PRT). DESIGN: A 23-item questionnaire. SETTING: Northern Alberta and parts of British Columbia, Saskatchewan, the Northwest Territories, and Nunavut. PARTICIPANTS: A total of 1360 health practitioners, including primary care physicians and nurse clinicians in rural, remote, or far northern regions; FP-oncologists working in community cancer centres; palliative care (PC)specialists; and medical oncologists. MAIN OUTCOME MEASURES: Survey respondents rated how much certain factors influenced their decisions to refer patients for PRT and estimated their knowledge of PRT. Descriptive and summary statistics were compiled. RESULTS: The overall eligible response rate was 31.8% (412 of 1294); 85.4% of respondents were FPs, 65.3% were men, and 44.9% practised in rural settings. A total of 81.8% of respondents sometimes or often provided PC and 71.0% had referred patients for PRT. Main factors taken into account when referring patients were functional status (93.1%; 349 of 375), histology (75.4%; 285 of 378), and concern about side effects (75.3%; 281 of 373).Half of respondents considered wait times for PRT delivery important. Self-rated knowledge of PRT was poor for 74.0% of respondents, fair for 24.5%, and good for 1.5%. Actual knowledge scores were poor for 46.6% of respondents, fair for 36.7%, and good for 16.7%. Respondents who referred patients for PRT had been in practice longer, saw more cancer patients per month, provided PC more frequently, had higher self-rated PRT knowledge,and had better actual PRT knowledge. CONCLUSION: Disease- and patient-related factors outweighed concerns about wait times. Although referring practitioners are better informed than they believe themselves to be, further improvements in their knowledge could increase referrals of appropriate patients for PRT. PMID- 22439174 TI - Proceedings of the First International Workshop 'Mathematical Methods in System Biology', January 4-7, 2010, Tel Aviv, Israel. PMID- 22439175 TI - Structure of the protein subunits in the photosynthetic reaction centre of Rhodopseudomonas viridis at 3A resolution. AB - The molecular structure of the photosynthetic reaction centre from Rhodopseudomonas viridis has been elucidated using X-ray crystallographic analysis. The central part of the complex consists of two subunits, L and M, each of which forms five membrane-spanning helices. We present the first description of the high-resolution structure of an integral membrane protein. PMID- 22439176 TI - The next generation. PMID- 22439178 TI - Civil war and French Better Homes & Gardens. PMID- 22439179 TI - Cultivating the global garden. PMID- 22439181 TI - Domestic troubles: tragedy and the Northern Ireland conflict. PMID- 22439182 TI - Domesticity and beyond: Hindi women's journals in the early twentieth century. PMID- 22439185 TI - [Work - school - play: children's space in the 18th and 19th centuries]. PMID- 22439187 TI - [A sad lot? Single women in the 1950's]. PMID- 22439188 TI - [Family, slavery, and paid employment: children and work in Africa in the 19th and 20th centuries]. PMID- 22439189 TI - Primary care outreach in Markham, Ont. PMID- 22439190 TI - Abstracts of the IV Polish Meeting of Clinical Toxicologists, September 9-10, 2011, Cracow, Poland. PMID- 22439191 TI - Can ondansetron help children with vomiting due to gastroenteritis? PMID- 22439192 TI - [Women's work during the Cold War]. PMID- 22439193 TI - [Graves as places of remembrance: on the postwar phase of the Herero war]. PMID- 22439194 TI - [Children discover the world: playing and working. Examples and perspectives from the 1920's to the 1940's]. PMID- 22439195 TI - [Child labor among merchants in Leipzig? Pictorial and literary sources]. PMID- 22439196 TI - [Child labor and the economics of time in East Germany: an examination of how children's daily lives in East Germany were regulated]. PMID- 22439197 TI - [Marx and alienation: the merits and false promises of the critique of alienation]. PMID- 22439198 TI - [Marx and his delicate approach toward unsolved problems of morality: criticism, normality, and human rights]. PMID- 22439200 TI - [Between potato fields and football fields: the daily life of working-class boys in the Weser-Solling region during the 1950's]. PMID- 22439201 TI - Transplantation of uncultured omental adipose-derived stromal vascular fraction improves sciatic nerve regeneration and functional recovery through inside-out vein graft in rats. AB - BACKGROUND: Despite presence of various nerve coaptation materials and techniques, achievement of desired functional peripheral nerve regeneration is still inadequate. Effects of transplantation of uncultured and uncharacterized stromal vascular fraction (SVF) from omental adipose tissue on peripheral nerve regeneration were studied using a rat sciatic nerve transection model. METHODS: A 10-mm sciatic nerve defect was bridged using an inside-out vein graft (IOVG) filled with SVF. In control group, the vein was filled with phosphate-buffered saline alone. The regenerated nerve fibers were studied 4 weeks, 8 weeks, and 12 weeks after surgery. In sham-operated group, the sciatic nerve was only exposed and manipulated. RESULTS: Functional study confirmed faster recovery of regenerated axons in IOVG/SVF than in IOVG group (p < 0.05). Gastrocnemius muscle mass in IOVG/SVF is found to be significantly more than that in IOVG group. Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in IOVG/SVF than in control group.In immunohistochemistry, location of reactions to S-100 in IOVG/SVF was clearly more positive than that in IOVG group. CONCLUSIONS: SVF could be considered as a readily accessible source of stromal cells that improve functional recovery of sciatic nerve because of reduction in the interval from tissue collection until cell injection and simplicity of laboratory procedure, especially where atraumatic injury is dealt with. PMID- 22439202 TI - [The costly peace: extracts from the notes of a Hessian farmer after the Thirty Years War, 1648-51]. PMID- 22439203 TI - L-arginine infusion during resuscitation for hemorrhagic shock: impact and mechanism. AB - BACKGROUND: Our previous work showed a survival advantage with L-arginine (L-Arg) pretreatment in a swine model of severe hemorrhagic shock. This study was designed to evaluating whether the benefit is sustained when L-Arg is given during resuscitation and whether the mechanism is mediated by enzymatic activation of nitric oxide (NO) synthesis. METHODS: Adult rats (n = 30) underwent 40% blood volume loss and were resuscitated with saline (3 shed blood volume). Animals were divided into five treatment groups of six animals each: (1) Sham, (2) Control (resuscitation alone), (3) L-Arg (300 mg/kg)with resuscitation, (4) L Arg + L-nitroarginine methyl ester pretreatment, and (5) D-arginine (300 mg/kg) with resuscitation.Animals were observed for 240 minutes postresuscitation or until death. Hemodynamic, metabolic, histologic, and survival outcomes were measured. RESULTS: Administration of L-Arg after hemorrhage and before resuscitation significantly improved outcomes, relative to the control group.The L-Arg infusion improved terminal arterial pressures, lowered lactate, improved small bowel histologic signs of reperfusion injury, and increased survival (p < 0.05). Endpoints of the L-Arg group were similar to the Sham group. The benefits of L-Arg infusion were abolished or attenuated when animals were pretreated with L-nitro arginine methyl ester and potentiated with D-arginine, suggesting a NO specific mechanism of L-Arg. Finally, severe shock and resuscitation injury significantly elevated circulating asymmetric dimethylarginine levels, which are potent competitive inhibitors of NO synthetase. CONCLUSION: L-Arg infusion during resuscitation offers a significant functional, metabolic, and survival benefit after severe hemorrhagic shock.The mechanism seems to be by activation of NO synthesis with its attendant benefits to local perfusion and inflammation after global reperfusion. PMID- 22439204 TI - [Everyday life and uniqueness: Russian conservatives and the cult of home life in 1800-60's]. PMID- 22439205 TI - High circulating adrenaline levels at admission predict increased mortality after trauma. AB - BACKGROUND: Trauma-induced acute coagulopathy predicts a poor outcome. Although its pathophysiology is unclear, severe injury and shock(hypoperfusion) are proposed drivers. This study investigated the association between sympathoadrenal activation (circulating catecholamines) and biomarkers of coagulopathy. METHODS: Prospective study of 75 adult trauma patients admitted to a Level I trauma center directly from the scene of accident. Patients were selected blinded post hoc from three predefined Injury Severity Score groups (<16, 16-27, and >27) and had available blood samples on arrival. We measured activated partial thromboplastin time, international normalized ratio, hematology, biochemistry, circulating adrenaline and noradrenaline, 11 biomarkers of tissue and endothelial damage, glycocalyx degradation, natural anticoagulation and fibrinolysis (histone complexed DNA fragments, high-mobility group box 1, syndecan-1, von Willebrand factor, soluble thrombomodulin, protein C, tissue factor pathway inhibitor, antithrombin, tissue-type plasminogen activator, plasminogen activator inhibitor 1,D-dimer) and registered 30-day mortality. Biomarkers were compared between survivors and nonsurvivors. RESULTS: The adrenaline level was increased in nonsurvivors (p = 0.026), it was independently associated with increased activated partial thromboplastin time (p = 0.034) and syndecan-1 (p = 0.007), a marker of glycocalyx degradation, and it correlated with biomarkers of tissue and endothelial damage (histone-complexed DNA, high-mobility group box 1, soluble thrombomodulin) and hyperfibrinolysis (tissue-type plasminogen activator, D dimer). Furthermore, nonsurvivors had higher syndecan-1, tissue factor pathway inhibitor, and D-dimer levels (all p < 0.05). Circulating adrenaline was independently associated with 30-day mortality(OR, 5.92 [95% CI, 1.48 -23.73]; p = 0.012) together with age (p = 0.001) and severe head injury (Abbreviated Injury Scale head >3; p = 0.011). CONCLUSIONS: The trauma-induced catecholamine surge is closely associated with biomarkers of tissue and endothelial damage, glycocalyx degradation,coagulopathy including hyperfibrinolysis and independently predicts mortality. PMID- 22439207 TI - Hemorrhage after low-energy pelvic trauma. AB - BACKGROUND: Severe pelvic hemorrhage after low-energy trauma has been described in some reports of single cases only. However, it might not be as rare and unique as generally expected. The aim of this study was therefore to present a case series of 11 patients with severe pelvic hemorrhage after sustaining low-energy trauma and to discuss relevant considerations for the management of these patients. METHODS: A consecutive series of eleven patients with pelvic hemorrhage and the need for arterial embolization after sustaining low-energy pelvic trauma was identified. A contrast-enhanced computed tomography (CT) scan was performed in all patients, if pelvic hemorrhage was suspected due to a relevant hemoglobin (Hb) drop. After the CT scans showed active arterial bleeding, arterial embolization was immediately performed. RESULTS: All patients sustained low energy pelvic injuries after simple falls from standing height. The mean initial Hb level was 13.0 g/dL.Contrast-enhanced CT scans were performed after a mean of 14.3 hours after trauma and showed contrast medium extravasations in all patients. The mean Hb level at the time of CT scan was 9.0 g/dL. Embolization was successfully performed in all patients within a mean of 4.5 hours. CONCLUSIONS: Geriatric patients are prone to arterial hemorrhage after low-energy pelvic trauma. They should be admitted as an inpatient for observation with repeated control of the Hb level to diagnose hemorrhage at an early stage. Contrast enhanced CT scans is the preferred imaging method for the assessment of pelvic hemorrhage, whereas arterial embolization is highly successful in terms of hemostasis. PMID- 22439208 TI - The sensual and intellectual pleasures of rowing: Pierre de Coubertin's ideal for modern sport. PMID- 22439209 TI - Fitness innovation or sexual exploitation? Bob Hoffman and the women weightlifters of Muscletown USA. PMID- 22439210 TI - Primary blast survival and injury risk assessment for repeated blast exposures. AB - BACKGROUND: The widespread use of explosives by modern insurgents and terrorists has increased the potential frequency of blast exposure in soldiers and civilians. This growing threat highlights the importance of understanding and evaluating blast injury risk and the increase of injury risk from exposure to repeated blast effects. METHODS: Data from more than 3,250 large animal experiments were collected from studies focusing on the effects of blast exposure. The current study uses 2,349 experiments from the data collection for analysis of the primary blast injury and survival risk for both long- and short duration blasts, including the effects from repeated exposures. A piecewise linear logistic regression was performed on the data to develop survival and injury risk assessment curves. RESULTS: New injury risk assessment curves uniting long- and short-duration blasts were developed for incident and reflected pressure measures and were used to evaluate the risk of injury based on blast over pressure, positive-phase duration, and the number of repeated exposures. The risk assessments were derived for three levels of injury severity: nonauditory, pulmonary, and fatality. The analysis showed a marked initial decrease in injury tolerance with each subsequent blast exposure. This effect decreases with increasing number of blast exposures. CONCLUSIONS: The new injury risk functions showed good agreement with the existing experimental data and provided a simplified model for primary blast injury risk. This model can be used to predict blast injury or fatality risk for single exposure and repeated exposure cases and has application in modern combat scenarios or in setting occupational health limits. PMID- 22439211 TI - Impact of isolated acetabular and lower extremity fractures on long-term outcome. AB - BACKGROUND: The long-term clinical status of surviving patients with multiple injuries has not been well described. The aim of this study was to evaluate the long-term outcome of acetabular and lower limb injuries. METHODS: Patients treated at a Level I trauma center at least 10 years before participation in this study were invited for a follow-up physical examination. Six hundred thirty-seven patients were examined. Inclusion criteria are as follows: Injury Severity Score >=16 Points;treatment in a Level I trauma center; and injuries of the lower limb: fractures of the acetabulum, proximal femur, femoral shaft,knee joint, and tibial shaft. Exclusion criteria are as follows: incomplete follow-up examination, amputations, ankle and foot fractures, and patients older than 60 years and younger than 3 years. The follow-up examination included the following parameters:range of motion, pain, limping, successful rehabilitation, and outcome scores. RESULTS: Of 525 patients with fractures of the acetabulum and lower limb, 229 patients fulfilled the inclusion criteria. Mean age: 24.9 (range,3-60) years; Injury Severity Score: 19.66 (range, 16-43). The most frequent rates of ongoing local pain were stated by patients with fractures of the acetabulum (50%) and the proximal femur (45%). Moreover, the incidence of abnormal gait was significantly lower in patients with femoral shaft fractures when compared with the patients with fractures of the acetabulum (3.7% vs. 35%;p 0.0001), proximal femur (3.7% vs. 20%; p<= 0.006), and tibial shaft (3.7% vs. 14.7%; p = 0.023). CONCLUSIONS: Our results demonstrate a better long-term outcome in patients with femur shaft fractures, whereas patients with articular fractures and proximal femur fractures were associated with poorer outcomes. Fracture location is determining factor for long-term outcome PMID- 22439212 TI - Margot Polivy, legal costs, and the demise of the Association for Intercollegiate Athletics for Women. PMID- 22439214 TI - Sport, status, and style. PMID- 22439215 TI - "Stewards of ice hockey": a historical review of safety rules in Canadian amateur ice hockey. PMID- 22439216 TI - Wes Santee, the four-minute mile, and the Amateur Athletic Union of the United States. PMID- 22439219 TI - Change in plasma gelsolin level after traumatic brain injury. AB - BACKGROUND: Plasma gelsolin depletion has been associated with poor outcome of critically ill patients. However, there is a paucity of data available on circulating plasma gelsolin concentration in traumatic brain injury (TBI). Thus, we sought to investigate change in plasma gelsolin level after TBI and to evaluate its relation with disease outcome. METHODS: Fifty healthy controls and 94 patients with acute severe TBI were included. Plasma samples were obtained on admission and at days 1, 2, 3, 5, and 7. Its concentration was measured by enzyme linked immunosorbent assay. RESULTS: Twenty-six patients (27.7%) died from TBI in a month. After TBI, plasma gelsolin level in patients decreased during the 6-hour period immediately, was at the nadir in 24 hours, increased gradually thereafter, and was substantially lower than that in healthy controls during the 7-day period. A multivariate analysis showed plasma gelsolin level was an independent predictor for 1-month mortality (odds ratio, 0.941; 95% confidence interval, 0.895- 0.989; p = 0.017) and positively associated with Glasgow Coma Scale (GCS) score (t = 6.538, p 0.001). A receiver operating characteristic curve identified that a baseline plasma gelsolin level 52.7 mg/L predicted 1-month mortality with 88.5% sensitivity and 79.4% specificity (area under the curve, 0.869; 95%confidence interval, 0.783- 0.930). The predictive value of the gelsolin concentration was thus similar to that of GCS scores (p =0.185). However, gelsolin did not statistically significantly improve the area under the curve of GCS scores (p = 0.517). CONCLUSIONS: Decreased plasma gelsolin level is associated with GCS scores and an independent prognostic marker of mortality after TBI. Reversing plasma gelsolin deficiency may be an effective treatment for TBI. PMID- 22439220 TI - Cricket spectator disorder: myths and historical evidence. PMID- 22439221 TI - Impact of stress on resident performance in simulated trauma scenarios. AB - BACKGROUND: Training and practice in medicine are inherently stressful. The effects of stress on performance in clinical situations are poorly understood. The purpose of this study was to examine the stress responses and clinical performance of residents during low and high stress (HS) simulated trauma resuscitations. METHODS: Thirteen emergency medicine and general surgery residents were evaluated in HS and low stress (LS) trauma resuscitation simulations. Subjective and physiologic (heart rate, salivary cortisol) responses were measured at baseline and in response to the scenarios. Performance was assessed with global rating and checklist scores of technical performance, time to record critical information, and the Anesthesia Non-Technical Skills tool. Post-scenario recall was assessed with the completion of a standardized trauma history form. RESULTS: Post-scenario subjective stress and cortisol levels were higher in the HS scenario compared with the LS scenario (p < 0.05). Checklist performance scores and post-scenario recall were significantly lower in the HS compared with the LS condition (p < 0.05). CONCLUSION: In trainees, some aspects of performance and immediate recall appear to be impaired in complex clinical scenarios in which they exhibit elevated subjective and physiologic stress responses. The findings of this study highlight a potential threat to patient safety and demand further investigation. Future studies should strive to further elucidate the effects of stress on specific components of performance and investigate ways to reduce its negative impact. PMID- 22439222 TI - Patriotism or pleasure? The nineteenth century volunteer force as a vehicle for rural working-class male sport. PMID- 22439223 TI - Playing to the flag: a history of deaf football and deaf footballers in Britain. PMID- 22439224 TI - Physical effects of trauma and the psychological consequences of preexisting diseases account for a significant portion of the health-related quality of life patterns of former trauma patients. AB - BACKGROUND: Health-related quality of life (HRQoL) is known to be significantly affected in former trauma patients. However, the underlying factors that lead to this outcome are largely unknown. In former intensive care unit (ICU) patients, it has been recognized that preexisting disease is the most important factor for the long-term HRQoL. The aim of this study was to investigate HRQoL up to2 years after trauma and to examine the contribution of the trauma-specific, ICU-related, sociodemographic factors together with the effects of preexisting disease, and further to make a comparison with a large general population. METHODS: A prospective 2-year multicenter study in Sweden of 108 injured patients. By mailed questionnaires, HRQoL was assessed at 6 months,12 months, and 24 months after the stay in ICU by Short Form (SF)-36, and information of preexisting disease was collected from the national hospital database. ICU-related factors were obtained from the local ICU database. Comorbidity and HRQoL (SF-36) was also examined in the reference group, a random sample of 10,000 inhabitants in the uptake area of the hospitals. RESULTS: For the trauma patients, there was a marked and early decrease in the physical dimensions of the SF-36 (role limitations due to physical problems and bodily pain). This decrease improved rapidly and was almost normalized after 24 months. In parallel, there were extensive decreases in the psychologic dimensions (vitality, social functioning, role limitations due to emotional problems,and mental health) of the SF-36 when comparisons were made with the general reference population. CONCLUSIONS: The new and important finding in this study is that the trauma population seems to have a trauma-specific HRQoL outcome pattern.First, there is a large and significant decrease in the physical dimensions of the SF-36, which is due to musculoskeletal effects and pain secondary to the trauma. This normalizes within 2 years, whereas the overall decrease in HRQoL remains and most importantly it is seen mainly in the psychologic dimensions and it is due to preexisting diseases. PMID- 22439225 TI - Sport, nationalism and culture in Scotland. PMID- 22439226 TI - The cult of the Nordic superman: between the pre-modern and the modern. PMID- 22439227 TI - Health-related quality of life after burns: a prospective multicenter cohort study with 18 months follow-up. AB - BACKGROUND: Health-related quality of life (HRQOL) is an important parameter after medical treatments. Knowledge of (predictors of) diminished quality of life can help improve medical outcome. The aim of this study was to quantify health loss in patients with burns and to assess the contribution of injury extent, age, gender, and psychologic factors to HRQOL and speed of recovery. A multicenter prospective cohort design was used to address these aims. METHODS: Data were obtained from 260 adults with burns. Patients completed the EQ-5D at 3 weeks, 3, 6, 9, and 18 months after burn and psychologic questionnaires during hospitalization. Patients' scores were compared with an age- and gender-weighted normpopulation. RESULTS: Patients suffered from substantial health losses at short term, but after 18 months the majority reached a HRQOL comparable with the norm population with the exception of patients requiring two or more surgeries. The best predictor of long-term HRQOL and the speed of recovery was the number of surgeries, followed by psychologic problems. Both predicted baseline and trajectories of improvement. Symptoms of traumatic stress were most debilitating over time. CONCLUSIONS: Both injury severity and psychologic problems play a pivotal role in reduced HRQOL and the speed of recovery. The number of surgeries seems to give a practically useful indication of the expected recovery speed that could aid in decision making and provides adequate information for patients in the aftermath of their initial surgical treatment. Screening for traumatic stress is recommended. PMID- 22439228 TI - Readmission of trauma patients in a nonacademic Level II trauma center. AB - BACKGROUND: Readmission of trauma patients has been identified as a quality indicator for trauma care. Few if any studies on this topic can be found from a nonacademic trauma center. The objectives of the study were to determine the rate, cause, and preventability for readmission and to identify predictors of readmission in a nonacademic trauma center. METHODS: Cases registered from 2007 to 2009 were identified from trauma registry. A retrospective chart review of 98 readmission trauma patients was done to elicit the complications and outcomes. Criteria were selected to elicit preventability of readmissions.Predictors for readmission were identified by using a logistic regression analysis. RESULTS: Of 4,986 patients, 98 (1.96%) required readmission due to wound (23.47%), abdominal (16.33%), thromboembolic (4.08%),central nervous system (21.43%), hematoma (5.10%), and pulmonary (7.14%) complications. Among all readmission cases,surgery was performed in 38.78%, days to readmission was 19.44 +/- 8.80, and six patients experienced a readmission chain.Penetrating injury, Injury Severity Score 25, and hospital length of stay were predictors of readmission. 90.82% of the trauma readmissions were trauma related and 15% were potentially preventable readmissions. Fifty-three percent of the readmissions occurred before a follow-up appointment. CONCLUSIONS: The incidence of readmissions was similar to published data from academic trauma centers, but the reason for readmission and the need for surgery at readmission were very different. Potentially preventable readmissions have not been well addressed in literature. Therefore, further multicenter studies that include nonacademic trauma centers are needed to analyze this complicated problem. PMID- 22439229 TI - The floating shoulder--clinical and radiological results after intramedullary stabilization of the clavicle in cases with minor displacement of the scapular neck fracture. AB - BACKGROUND: The aim of this study was to compare the clinical and radiologic results of titanium elastic nail (TEN) and plate osteosynthesis for treatment of clavicle fractures in patients with a floating shoulder injury. PATIENTS AND METHODS: From 2000 to 2008, 16 patients with a floating shoulder injury (ipsilateral clavicle and minor displaced scapular neck fracture) were treated by isolated stabilization of the clavicle. The patients were treated with open reduction and plate osteosynthesis (group 1[G1]) or TEN osteosynthesis (group 2 [G2]). Both procedures were compared with regard to functional and radiologic outcome. RESULTS: Nine patients were treated with a plate osteosynthesis (G1) and seven with a TEN osteosynthesis (G2). The follow-up time was 35.7 months +/- 16 months. There was no difference in functional outcome with regard to the intraindividual Constant score 83.9(G1) versus 86.7 (G2) or the American Shoulder and Elbow Surgeons score 79.1 (G1) versus 85.7 (G2). No significant postoperative dislocation of the glenopolar angle appeared. In the TEN-treated group, a clavicle shortening of 2.4 mm was observed. Subgroup analysis revealed significant greater shortening in type B and C compared with type A (OTA) clavicle fractures(4.7 mm vs. 0.8 mm). No clavicle shortening in the plate treated group appeared. CONCLUSION: The treatment of floating shoulder injuries with TEN and plate osteosynthesis of the clavicle and nonoperative treatment of a minimally displaced glenoid neck fracture provide equal functional results. However, in type B and C (but not in type A) fractures of the clavicle, a shortening of 5 mm can be expected after titanium elastic nailing. PMID- 22439230 TI - Coracoid fractures: therapeutic strategy and surgical outcomes. AB - BACKGROUND: The majority of type I coracoid fractures set out in Ogawa's classification constitute double disruption of the superior shoulder suspensory complex (SSSC) as proposed by Goss, frequently resulting in healing delay and adverse functional consequences.However, there are few reports alluding to strategies or concrete treatment methods of such injuries. The purpose of this report is to introduce our surgical strategy for treating the type I coracoid fracture with concurrent injuries and to describe our treatment method with their outcomes. METHODS: Thirty-six patients, who had acute type I coracoid fractures surgically treated and were followed up for 1 year or longer, constituted the present study population. Reduction and stabilization were undertaken beginning with the most medial unstable injury of SSSC and proceeding to the lateral ones. The respective coracoid fractures were finally reduced and fixed. In the follow up, patients were directly examined and evaluated using the ratios of the Constant score for the injured side to that for the normal side. RESULTS: There were a total of 80 ipsilateral injuries of SSSC, including the coracoid fractures, and double disruption accounted for 94%of the patients. Of these, 62 injuries were surgically treated. No complications associated with surgery were observed. Bone union was achieved in all fractures; no patients required an additional operation. The Constant score ratio at the follow-up was 93% +/- 7.4% on average. CONCLUSION: Although the majority of cases with type I coracoid fractures suffered double disruptions of SSSC, satisfactory results have been obtained with surgical treatment focusing on the assured reconstruction of a firm scapuloclavicular union. PMID- 22439231 TI - Comparative functional outcome of AO/OTA type C distal humerus fractures: open injuries do worse than closed fractures. AB - BACKGROUND: Open distal humerus fractures present significant soft-tissue injury and bone devitalization that require prompt irrigation and debridement, temporization, and soft-tissue coverage. METHODS: This case-control comparison of open and closed AO type C fractures of the distal humerus tests the null hypothesis that there is no difference in the outcomes and prognosis of open versus closed distal humerus fractures treated operatively. Outcomes were determined clinically and radiographically and reported by the Short Musculoskeletal Function Assessment, the Short Form-36,and the Mayo Elbow Performance Index. RESULTS: Twenty-eight matched cohort patients treated by operative fixation were identified (14 open and 14 closed injuries), with average follow-up 98.9 weeks (range, 52-160 weeks). The average time to osseous healing after definitive treatment was 24.7 weeks for open fractures, when compared with 18.7 weeks for the closed group (p = 0.085). The average range of motion at final follow-up for open fractures was 82.5 degrees, versus 108.7 degrees for the closed group (p = 0.03). Short form-36 was significantly poorer(p = 0.002) in the open group (57.9) when compared with the closed group (79.0). CONCLUSIONS: When compared with closed fractures, open distal humerus fractures have worse functional outcome scores and decreased range of motion. Patients with open fractures also demonstrated a trend toward having higher complication rates, prolonged times to union, and higher rates of persistent nerve deficits requiring further surgery. PMID- 22439232 TI - Scaphoid fracture epidemiology. AB - BACKGROUND: The current available literature related to scaphoid fracture epidemiology is inconsistent. The aim of this study was to describe the epidemiology of true scaphoid fractures in a defined adult population. METHODS: Using a prospective database, we identified all patients who sustained a radiographically confirmed acute fracture of the scaphoid over a 1-year period. Age, gender, mechanism of injury, the Herbert fracture classification, and associated injuries were recorded and analyzed. RESULTS: There were 151 scaphoid fractures diagnosed giving an annual incidence of 29 per 100,000 (95% confidence interval, 25-34). The median age of males was significantly younger when compared with females (p = 0.002), with a male (n = 105) predominance seen (p 0.001). Low energy falls from a standing height were most common (40.4%), but with males being significantly more likely to sustain their fracture after a high-energy injury (p 0.001). The most common fracture was Herbert classification B2 (n =55, 36.4%), with unstable fractures more common in younger patients (p = 0.025) following a high-energy injury (p = 0.042). CONCLUSIONS: We have reported the epidemiology of true scaphoid fractures, with young males at risk of sustaining a fracture. Knowledge of the true incidence of scaphoid fractures and an understanding of the demographic risk factors are essential when assessing the suspected scaphoid fracture, particularly when considering further imaging modalities. PMID- 22439233 TI - Potential of polymethylmethacrylate cement-augmented helical proximal femoral nail antirotation blades to improve implant stability--a biomechanical investigation in human cadaveric femoral heads. AB - BACKGROUND: Cement augmentation may improve fixation stability and reduce cut-out rate in the treatment of intertrochanteric hip fractures. The aim of this study was to compare the number of cycles to failure of polymethylmethacrylate (PMMA) augmented helical blades with nonaugmented ones in human cadaveric femoral heads. METHODS: Six pairs of cadaveric femoral heads were instrumented with a perforated proximal femoral nail antirotation blade. Within each pair, one blade was augmented using 3 mL of PMMA. All specimens underwent cyclic axial loading under physiologic conditions.Starting at 1,000 N, the load was monotonically increased by 0.1 N/cycle until construct failure occurred. To monitor the migration of the blade, anteroposterior radiographs were taken at 250 cycle increments. Nonparametric test statistics were done to calculate correlations and identify differences between study groups. RESULTS: Inducing failure required a significantly higher number of cycles in the augmented group (p = 0.028). Bone mineral density was significantly related with the number of cycles to failure in nonaugmented specimens (p 0.001, R2 = 0.97), but not in the augmented group (p = 0.91, R2 = 0.34). CONCLUSION: Implant augmentation with small amounts of PMMA enhances the cut-out resistance in proximal femoral fractures. Especially in osteoporotic bone, the procedure may improve patient care. PMID- 22439234 TI - [Best practices in perinatology. Best practices of the Neonatal Czech Society]. PMID- 22439235 TI - A biomechanical comparison of static versus dynamic lag screw modes for cephalomedullary nails used to fix unstable peritrochanteric fractures. AB - BACKGROUND: The gamma nail has an option to statically lock its lag screw (static mode) or to allow its lag screw to move within the nail to compress the intertrochanteric fracture (dynamic mode). The purpose of this study was to compare the biomechanical stiffness of static and dynamic lag screw modes for a cephalomedullary nail used to fix an unstable peritrochanteric fracture. METHODS: Unstable four-part peritrochanteric fractures were created in 30 synthetic femurs and fixed with Long Gamma 3 Nails. Mechanical tests were conducted for axial, lateral, and torsional stiffness with intact femurs, femur-nail constructs with static lag screw mode,and femur-nail constructs with dynamic lag screw mode. A paired Student's t test was used for all statistical comparisons between test groups. RESULTS: Axial and torsional stiffness of intact femurs was significantly greater than femur-nail constructs (p < 0.01 all comparisons),whereas lateral stiffness was significantly less (p < 0.01 all comparisons). Axial stiffness of the femur-nail construct was significantly greater (p < 0.01) in static mode (484.3 N/mm 80.2 N/mm) than in dynamic mode (424.1 N/mm 78.0 N/mm).Lateral stiffness was significantly greater (p < 0.01) in static mode (113.9 N/mm 8.4 N/mm) than in dynamic mode (109.5N/mm 8.8 N/mm). Torsional stiffness was significantly greater (p = 0.02) in dynamic mode (114.5 N/mm 28.2 N/mm) than in static mode (111.7 N/mm 27.0 N/mm). DISCUSSION: There is a 60 N/mm (12.4%) reduction in axial stiffness when the lag screw is in dynamic mode. Given the statistically significant reduction in axial and lateral stiffness with use of the dynamic mode, static lag screw mode should be further explored clinically for treatment of unstable peritrochanteric fractures. PMID- 22439236 TI - Massive juxta-articular defects of the distal femur reconstructed by series connected double-strut free-vascularized fibular grafts. AB - BACKGROUND: We evaluate the clinical results of reconstructing massive juxta articular defects of the distal femur (mean, 16.4 cm) with series-connected double-strut free-vascularized fibular grafting (FVFG) and external fixator fixation. METHODS: We retrospectively reviewed a consecutive series of 19 patients, who underwent FVFG transfer because of massive juxta-articular defects of distal femur. Sixteen cases had complete records and included in this study. Five patients underwent double-strut FVFGand 11 patients underwent series connected double-strut FVFG. FVFG was performed from 2 months to 3 months after the clinica lsigns of the infection had subsided and erythrocyte sedimentation rates had returned to normal. Both fibulas (mean, 18.6 cm) were harvested to reconstruct the femoral defect, half-ring sulcated external fixator (Orthofix Srl, Italy), and K-wires were used to provide stabilization. RESULTS: Five fibular grafts (15.6%) had vascular complications on flap monitoring. Fifteen of the sixteen reconstructed femurs (93.8%)united primarily. Stress fracture occurred in one patient. The mean duration to achieve union was 7.1 month (range, 4-18 months).Full weight-bearing walking was allowed 3 months after the confirmation of bone union (mean, 10 months; range, 7-22 months).The external fixator was removed 12.2 months (range, 10-16 months) postoperatively. The K wires were removed 26.4 months(range, 23-30 months) postoperatively. There was no statistically significant difference of hypertrophic change between series connected grafts and conventional double-strut grafts (27.18 vs. 24.43%, p = 0.186) and also between the three levels of the grafted fibula. Within the series connected group, the difference of hypertrophic change between anterograde fibular grafts and retrograde fibular grafts was also not significant (25.24 vs. 29.12%, p = 0.178). The overall rate of knee stiffness (90 degree)was as high as 68.75% (11 of 16 patients). CONCLUSIONS: Massive juxta-articular defects of the distal femur are difficult and uncommon injuries. The results of this study indicate that the huge femoral defect reconstructed by series-connected double strut FVFG provide good results in achieving bone union, reducing stress fracture rate, and achieving leg length equality. PMID- 22439237 TI - [Laboratory medicine: innovational technologies in analytics, diagnosis, education, and organization. Abstracts of the 2008 National Days of Laboratory Medicine]. PMID- 22439238 TI - Judet quadricepsplasty in the treatment of posttraumatic knee rigidity: long-term outcomes of 45 cases. AB - BACKGROUND: Posttraumatic knee stiffness is a very debilitating condition. Judet's quadricepsplasty technique has been used for more than 50 years. However, few reports of quadricepsplasty results exist in the literature. METHODS: We report the results of 45 cases of posttraumatic arthrofibrosis of the knee treated with Judet's quadricepsplasty. The results of the procedure were analyzed by measuring the degrees of flexion of the operated knees at different time points (before, immediately after, and late postoperatively). RESULTS: The degree of flexion increased from 33.6 degrees (range, 5-80 degrees) preoperatively to 105 degrees (range, 45-160 degrees)immediately after surgery, followed by a slight fall in the range of motion (ROM) in the late postoperative period, which reached an average of 84.8 degrees. There was no significant correlation between knee strength and the patient's gender, but there was a slight trend of lower strength with age. Although Judet's quadricepsplasty technique dates from more than 50 years ago, it still provides good outcomes in the treatment of rigid knees of various etiologies. In general, all cases showed the same pattern of a small decrease in the ROM in the late postoperative period. CONCLUSION: Judet's quadricepsplasty can increase the ROM of rigid knees. The ROM obtained with the surgery persists long term. PMID- 22439239 TI - International Students' Conference on Medical Sciences, Cracow, 26-28 March 2009. PMID- 22439241 TI - [National Days of Laboratory Medicine of Russia, 2010. Abstracts from the 4th Congress of the Russian Scientific Society of Clinical Laboratory Diagnosis Specialists]. PMID- 22439240 TI - Percutaneous locking plates for fractures of the distal tibia: our experience and a review of the literature. AB - BACKGROUND: Distal tibial metaphyseal fractures pose many complexities. This study assessed the outcomes of distal tibial fractures treated with medial locking plates. METHODS: Eighteen patients were selected based on the fracture pattern and classified using the AO classification and stabilized with an AO medial tibial locking plate. Time to fracture union, complications, and outcomes were assessed with the American Orthopedic Foot and Ankle Society Ankle score at 12 months. RESULTS: Sixteen of the 18 patients achieved fracture union, with 1 patient lost to follow-up. Twelve fractures united within 24 weeks, with an average union time of 23.1 weeks. Three delayed unions, two at 28 weeks and one at 56 weeks. The average time to union was 32 weeks in the smokers and 15.3 weeks in the nonsmokers. Five of the 18 patients (27%) developed complications. One superficial wound infection, and one chronic wound infection, resulting in nonunion at 56 weeks, requiring revision. Two patients required plate removal, one after sustaining an open fracture at the proximal end of the plate 6 months after surgery (postfracture union)and the other for painful hardware. One patient had implant failure of three proximal diaphyseal locking screws at the screwhead/neck junction, but successful fracture union. The average American Orthopedic Foot and Ankle Society ankle score was 88.8 overall, and 92.1 in fractures that united within 24 weeks. CONCLUSIONS: Distal tibial locking plates have high fracture union rates, minimum soft tissue complications, and good functional outcomes. The literature shows similar fracture union and complication rates in locking and nonlocking plates. PMID- 22439242 TI - Reconstruction of radial bone defects using the reinforced tissue-engineered periosteum: an experimental study on rabbit weightbearing segment. AB - BACKGROUND: The objective of this study was to compare the osteogenic potential of reinforced and conventional tissue-engineered periosteum. METHODS: Adipose derived stromal cells of rabbits were induced into osteoblasts. Osteoinduced cells were seeded onto chitosan-tricalcium-phosphate-gelatin (Cs-TCP-Gel) and chitosan (Cs) scaffold, thus constructing the reinforced and conventional tissue engineered periostea, respectively. Alkaline phosphatase (ALP) and von Kossa staining protocols were used to assess osteoblast phenotype.We surgically created a 15-mm-long bone defect in the right radii of New Zealand rabbits. The defects were treated with reinforced biomimetic periosteum in group A (n = 30) and treated with conventional tissue-engineered periosteum in group B (n = 30).Group C (n = 30) received CS-TCP-Gel scaffold alone, and group D (n = 30) served as untreated side (sham group). Radiologic,histologic, immunohistochemical, and histomorphometric studies were used to analyze healing pattern. RESULTS: ALP was remarkably expressed in the osteoinduced cells, indicating that osteoblastic differentiation was stable. Extracellular matrix calcification with dark nodule was detected by von Kossa staining. Compared with groups B and C, histologic results demonstrated that de novo osteogenesis proliferated in group A at 4 weeks. This was further confirmed by radiographic findings, which displayed the segmental gap completely healed by mature bone at 12 weeks. Robust expression of bone morphogenetic protein-2 in group A was also evident, whereas group D displayed poor osteogenic performance. Furthermore, histomorphometric and biomechanical results in group A demonstrated statistical significance over those in other groups (p 0.05). CONCLUSIONS: Our findings show that the reinforced tissue-engineered periosteum is superior to conventional one as a better biomimetic tissue,further indicating that it can repair the weight-bearing defects. PMID- 22439243 TI - Early complications associated with cephalomedullary nail for intertrochanteric hip fractures. AB - BACKGROUND: Use of cephalomedullary devices for pertrochanteric fractures has been associated with complications of cutout, fracture distal to the tip of the implant, infection, and hardware failure. The goal of recent design changes (a trapezoidal shape of the proximal device, with interdigitation of the cephalocervical screws) in cephalomedullary nails was to improve fracture fixation and stability of pertrochanteric fractures. This is a retrospective review of the first 127 surgeries using this new cephalomedullary nail to review early complications seen with this device. METHODS: A review of early complications (cutout, infection, fracture distal to the tip, fracture collapse, and hardware failure) for 100 patients who met inclusion criteria was performed. RESULTS: Postoperative mechanical complications included six (6%) patients with significant collapse of the femoral neck, six (6%) fractures distal to the implant (short nail only, n = 75), one (1%) cutout, four (4%) infections, and one (1%) implant breakage. The implant breakage occurred at the screw-nail interface. CONCLUSION: In our study population, we found this newer cephalomedullary device had complications similar to those reported with devices in previous studies. PMID- 22439244 TI - A comparison of absorbable screws and metallic plates in treating calcaneal fractures: a prospective randomized trial. AB - BACKGROUND: Intra-articular calcaneal fractures are more likely to suffer consequences in terms of pain and disability. Many studies have suggested that operative treatment for these fractures may result in better outcomes than nonoperative treatment. The metallic screws and plates are among the most common alternatives to stabilize calcaneal fractures. However, the complications of plating of calcaneal fractures are not uncommon. Complications such as infection, poor wound healing, and soft tissue irritation exist. With the advent of bioabsorbable screws, many reports have demonstrated favorable results in treating intra-articular fractures with these screws. The comparative outcomes of operative treatment of calcaneal fractures stabilized with plates and absorbable screws are rarely reported. The purpose of this study is to compare the clinical outcomes and complications related to fracture stabilization with plates and absorbable screws. METHODS: Ninety-seven patients with intra-articular calcaneal fractures were managed at our institution between February 2007 and March 2009. In this prospective, randomized study, the plates were used in 52 cases (group A), and the absorbable screws were used in 47 cases (group B). There were 71 men and 26 women who had a mean age of 41 years (range, 19-67 years). The clinical outcome and complications were assessed and compared. The adjusted American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (subjective component only), Foot Function Index, and the calcaneal fracture scoring system were used to assess the results. RESULTS: The patients were followed up at an average of 23 months (range, 15-32 months). Radiographically, there were no nonunions in either group. One year after operation, in group A and B, the mean adjusted American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Score were 71.6 +/- 12.5 and 72.3 +/- 17.4, respectively (p > 0.05); the mean Foot Function Index score were 21.4 +/- 6.6 and 22.7 +/-5.2, respectively (p > 0.05); and the mean calcaneal fracture scoring system score were 73.5 +/- 8.3 and 75.1 +/- 6.9, respectively (p >0.05). In group A, there were six cases of poor wound healing, one case of deep infection, and four cases of peroneal tendon irritation.In group B, there was one case of superficial infection, and no deep infection and soft tissue irritation. CONCLUSIONS: In this report, the outcomes of operative treatment with absorbable screws are comparable with the outcomes of operative treatment with plates. Both plates and absorbable screws showed favorable results in the surgical treatment of calcaneal fractures. However,the metallic plates were associated with increased complications. The stabilizations of displaced intra-articular calcaneal fractures with bioabsorbable screws are reasonable with advantages of fewer complications and without the need for screw removal. PMID- 22439245 TI - Paying more for primary care: can it help bend the Medicare cost curve? AB - The health reform law boosted Medicare fees for primary care ambulatory visits by 10 percent for five years starting in 2011. Using a simulation model with real world parameters, we evaluate the effects of a permanent 10 percent increase in these fees. Our analysis shows the fee increase would increase primary care visits by 8.8 percent, and raise the overall cost of primary care visits by 17 percent. However, these increases would yield more than a sixfold annual return in lower Medicare costs for other services-mostly inpatient and postacute care once the full effects on treatment patterns are realized. The net result would be a drop in Medicare costs of nearly 2 percent. These findings suggest that, under reasonable assumptions, promoting primary care can help bend the Medicare cost curve. PMID- 22439246 TI - [To get low TB incidence]. PMID- 22439247 TI - Implementing the Affordable Care Act: state action on early market reforms. AB - The Affordable Care Act includes numerous consumer protections that took effect on September 23, 2010. This issue brief examines new state action on a subset of these "early market reforms." The analysis finds that 49 states and the District of Columbia have passed new legislation, issued a new regulation, issued new subregulatory guidance, or are actively reviewing insurer policy forms for compliance with these protections. These findings suggest that states have required or encouraged compliance with the early market reforms, and that efforts to understand how states are responding cannot focus on legislative action alone. The findings also raise important questions regarding how states may implement the Affordable Care Act's broader 2014 market reforms, and suggest the need for continued tracking of state action. PMID- 22439248 TI - [Outcome and challenge brought about by molecular epidemiology of tuberculous organisms]. PMID- 22439249 TI - [The East Japan Earthquake and tsunami disaster and tuberculosis]. PMID- 22439250 TI - [The present status and problems of tuberculosis proposed by the specialized fields]. PMID- 22439251 TI - [Tuberculous pleurisy]. PMID- 22439252 TI - [Cooperation of relevant organizations for tuberculosis control]. PMID- 22439253 TI - [New movement of IGRA]. PMID- 22439254 TI - The team: the restorative dentist-periodontist partnership. PMID- 22439255 TI - Health, beauty, prosperity and periodontics. PMID- 22439256 TI - Advances in regeneration: restoratively driven, periodontally enhanced. PMID- 22439257 TI - Interdisciplinary treatment of cervical lesions. AB - Soft tissue grafting is an integral part of treatment of cervical lesions due to the common lack of adequate attached gingiva and root exposure associated with these lesions. Complete root coverage is a predictable outcome for Miller Class I and II recession defects, and partial root coverage can be achieved in Miller Class III defects. In the esthetic zone, it is desirable to cover as much of the root as possible, and all sites require an adequate zone of attached gingiva, especially adjacent to a restoration. Restorations are required for cervical lesions with excessive depth and significant involvement of the enamel, but they should be avoided where the lesion is shallow and the enamel involvement is minimal. Of course, some sites will require both soft-tissue grafting and placement of a restoration. An interdisciplinary approach to treating cervical lesions will create the most biologically appropriate, stable, and esthetic outcome. Establishing the appropriate tooth form first in treatment planning and sequencing will determine the gingival level and extent of periodontal procedures necessary to achieve the desired outcome. PMID- 22439258 TI - Esthetic and functional issues with replacing a single missing anterior tooth with an osseointegrated dental implant. PMID- 22439259 TI - Implant-supported reconstruction in the esthetic zone. PMID- 22439260 TI - Interdisciplinary solutions for esthetic periodontal prosthodontic rehabilitation. PMID- 22439261 TI - Loving your liver: this busy organ is critical to health. PMID- 22439262 TI - 6 ways to take a bite out of heart disease. PMID- 22439263 TI - Indomitable snowman. Extreme diabetes: snowboarder Sean Busby carves a new line. PMID- 22439264 TI - Stopping diabetes before it starts: diabetes prevention works out at the Y. PMID- 22439265 TI - Build your best body: personal trainer and power lifter Ginger Vieira offers tips on getting stronger. PMID- 22439266 TI - Playing the virtual field: are video games an answer to better fitness? PMID- 22439267 TI - At the summit. Simon says: you, too, can reach the top. PMID- 22439268 TI - Nature bottled: Are dietary supplements and vitamins helpful for people with diabetes? PMID- 22439269 TI - Fruits of paradise. PMID- 22439270 TI - Editor's choice December 2011. PMID- 22439271 TI - Future for laboratory based research for leprosy. PMID- 22439272 TI - New insights and tools to combat leprosy nerve damage. PMID- 22439273 TI - Do we need laboratory based research any longer? PMID- 22439274 TI - Keep the faith--leprosy still needs new diagnostic tools and laboratory research. PMID- 22439275 TI - The role of Mycobacterium leprae phenolic glycolipid I (PGL-I) in serodiagnosis and in the pathogenesis of leprosy. AB - PGL-I (phenolic glycolipid I) emerged in the early 1980s on the one hand as part of intensive efforts to define the typing antigens of a host of Mycobacterium spp. and also from characterisation of the lipids of skin biopsies from highly bacillary positive lepromatous leprosy patients. PGL-I, despite its extreme lipophilicity due to its inherent phthiocerol dimycocerosyl component, is highly antigenic evoking high titre IgM antibodies in lepromatous leprosy patients, attributable largely to the unique 3,6-di-O-methyl-beta-D-glucosyl entity at the non-reducing terminus of its trisaccharide. PGL-I itself or in the form of semisynthetic neoglycoproteins containing the synthetic terminal disaccharide or the whole trisaccharide chemically conjugated to such as bovine or human serum albumin, has found its greatest utility in the serological diagnosis, confirmation and management of lepromatous leprosy. PGL-I has also been implicated in the tropism of M. leprae for Schwann cells, through specific binding to laminin, and to play an important role in downregulation of the inflammatory immune response and inhibition of dendritic cell maturation and activation, thereby facilitating the persistence of M. leprae/leprosy. PMID- 22439276 TI - Anti-PGL-I seroepidemiology in leprosy cases: household contacts and school children from a hyperendemic municipality of the Brazilian Amazon. AB - OBJECTIVE: We investigated the prevalence of antibodies against PGL-I in people affected by leprosy (PAL) who were diagnosed and treated between 2004 and 2010, their household contacts (HC) and school children (SC) from a hyperendemic municipality in the Brazilian Amazon, and determined the prevalence of previously undiagnosed leprosy (PPUL) among both the HC and SC. DESIGN: We conducted a cross sectional study involving 87 PAL, 302 HC and 188 SC. The subjects were clinically assessed, and their levels of anti-PGL-I antibodies were determined by ELISA. The subjects were also interviewed to determine their demographic and socio-economic characteristics. RESULTS: For PAL, a mean of 44 (SD = 21.8) months had passed since their initial diagnosis, and 34 (39%) of them remained seropositive. The level of anti-PGL-I antibodies was significantly higher in multibacillary (MB) than in paucibacillary (PB) cases (P < 0.05). Thirty-nine percent of HC were positive for anti-PGL-I, and we detected eight (2.6%) new cases among these individuals. One hundred and twenty-five SC (66.5%) were seropositive, and we detected nine (4.8%) new cases of leprosy (eight PB and one MB) in this group. When we visited the homes of SC affected by leprosy, 31 contacts were clinically examined, and three (10%) new cases were detected (one PB and two MB). The mean age of students with leprosy was 14.1 years (SD = 2.5; min = 10, max = 18). CONCLUSION: The seroepidemiology of anti-PGL-I and the PPUL among both HC and SC suggests that there are many active foci of infection and that Mycobacterium leprae is circulating among this population. PMID- 22439277 TI - Serum cytokine profile in leprosy and its correlation with clinico histopathological profile. AB - OBJECTIVES: To analyse the serum levels of cytokines in leprosy patients, to correlate them with clinico-histopathological profile, and to study the effect of standard multidrug therapy on serum cytokine levels. DESIGN: Serum immunoassays of TNF-alpha, IFN-gamma, IL-1 beta and IL-10 were performed by ELISA in 61 newly diagnosed cases of leprosy before starting therapy and during reactional episodes. Of these, cytokine assays could be performed in 17 cases after completion of therapy. RESULTS: Levels of all the studied cytokines were significantly raised in cases compared to controls (P < 0.05). Levels of TNF alpha and IFN-gamma were significantly raised in paucibacillary cases whereas all the studied cytokines were raised in multibacillary cases with rise in IL-1 beta and IL-10 being statistically significant (P < 0.001). No significant difference was however noted between TT and BT type; and BB, BL and LL types. All the studied cytokines were raised in reactional cases as compared to non-reactional cases. Comparing Type 2 reaction (T2R) and Type 1 reaction (T1R) cases, levels of IFN-gamma, IL-1 beta and IL-10 were higher in T2R cases but only IL-10 was found to be statistically significant (P = 0.05) while TNF-alpha was higher in T1R cases. Post therapy serum levels of all the studied cytokines were significantly lower than pretherapy levels (P < 0.05) and were comparable to controls. Among the paucibacillary cases, levels of all the cytokines were seen to decrease after 6 months of standard multidrug therapy. In the multibacillary cases, mean levels of the cytokines were found to decrease after 1 year of therapy except IFN-gamma. CONCLUSION: Serum cytokine estimation may have a significant role in classifying various forms of leprosy and can be used to monitor therapy. PMID- 22439278 TI - Serological detection of leprosy employing Mycobacterium leprae derived serine rich 45 kDa, ESAT-6, CFP-10 and PGL-I: a compilation of data from studies in Indian populations. AB - This article is a compilation of our findings recorded in the recent past where we have investigated the serological performance of Mycobacterium leprae antigens like-serine-rich 45 kDa protein (45 kD), early secretary antigenic target-6 (ESAT 6), culture filtrate protein-10 (CFP-10) and phenolic glycolipid-I (PGL-I) for detection (employing antibody detecting ELISA) of leprosy patients, particularly those belonging to the paucibacillary (PB) group. All of these antigens were capable of detecting, by themselves the majority (82-100%) of multibacillary (MB) patients. However, with respect to PB patients, only 18-47% (i.e. less than half) of the cases could be detected. Based on the results of serological assays for each of the four antigens separately a combinatorial approach was performed for these antigens, which increased the sensitivity for detection of PB patients to 73%, giving 36% improvement over conventional PGL-I based ELISA. Thus, the multi antigenic serological approach is worthwhile for its establishment for detection of leprosy patients. Since ESAT-6 and CFP-10 are secreted proteins by nature, antibodies against them are worth exploring for detection of early infections and for monitoring of treatment efficiency. Nevertheless, efforts towards identification of more new antigens with serological potential are still desirable in order to further improve the detection rate of leprosy. PMID- 22439279 TI - Comparison of three immunological tests for leprosy diagnosis and detection of subclinical infection. AB - OBJECTIVE: Our aim was to compare the performance of three serological assays in leprosy patients and their household contacts utilising two quantitative ELISA tests using native PGL-I (PGL-1 ELISA), synthetic ND-O-HSA (ND-O-HSA ELISA), and the semi-quantitative lateral flow test (ML Flow). METHODS: Comparisons among three immunological assays, PGL-I ELISA, ND-O-HSA ELISA, and ML Flow were performed in 154 leprosy patients, 191 household contacts and 52 health subjects. RESULTS: The sensitivity results of the PGL-1, ND-O-HSA, and ML Flow were 68.83%, 63.84%, and 60.65%, respectively, with specificity of 98% for both ELISA assays. The native and synthetic PGL-I ELISA assays detected antibodies in 22.73% and 31.82% of the paucibacillary (PB) patients, respectively and the ML Flow test did not detect antibodies in this group. The ML Flow test was able to discriminate patients into PB or multibacillary (MB) forms, while the native PGL-I and ND-O HSA was correlated with the bacillary load and the Ridley-Jopling clinical forms. In household contacts, the native PGL-I, ND-O-HSA, and ML Flow assays detected seropositivity of 25%, 17%, and 10%, respectively. CONCLUSIONS: The use of ELISA and ML Flow tests are thus recommended as additional tools in the diagnosis and classification of the clinical forms, aiding in prescribing the correct treatment regimen to prevent subsequent nerve damage and disability, and besides, the PGL-I ELISA may be used to detect subclinical infection in leprosy. PMID- 22439280 TI - Postgenomic Mycobacterium leprae antigens for cellular and serological diagnosis of M. leprae exposure, infection and leprosy disease. AB - Due to changes in leprosy control programs and the special expertise required for diagnosis, the need for simple rapid diagnostic tests that could be applied in non-expert settings may now be greater than ever before. Since the sequencing of the M. leprae genome, many research groups have investigated the potential of M. leprae antigens in either serologic or cell mediated assays. Here we provide an overview of the nearly 200 recombinant single proteins that were investigated during the last decade for their potential to be applied in field-friendly tests for the early diagnosis of leprosy. PMID- 22439281 TI - Cytokine responses to Mycobacterium leprae unique proteins differentiate between Mycobacterium leprae infected and naive armadillos. AB - New diagnostic tools for early detection of leprosy are necessary to help reduce its transmission and severity. M. leprae unique proteins have been used to assess differences in human T-cell responses in leprosy patients, household contacts and endemic controls. In this study, we examined the response of M. leprae-infected armadillos to a variety of M. leprae recombinant antigen candidates currently being examined for diagnostic efficacy in humans. Among recently M. leprae infected armadillos, IFN-gamma expression was enhanced after stimulation of PBMC with all M. leprae recombinant proteins except for ML2283 (mean: 2.65 Relative Quantification (RQ)). The group mean stimulation index for M. leprae proteins ML0009, ML1601, ML2478 and ML2531 averaged 35.2 RQ and was significantly higher (P < 0.05) than that measured among the non-infected, naive group (mean 6.2 RQ). Although ML0840 tended to enhance IFN-gamma levels, the mean IFN-gamma transcript levels of the currently experimentally inoculated group (20.1 RQ) was not significantly different statistically (P = 0.10) from the mean of the naive group (7.5 RQ). Also no statistically significant differences were observed in IFN gamma transcript levels between the resistant and currently experimentally inoculated group (P > 0.05) or between the resistant and the naive group (P > 0.05) after stimulation of PBMCs with all M. leprae recombinant proteins. Only low levels of TNF-alpha were observed across all groups after in vitro stimulation with all the antigens examined. These data suggest that armadillos can be used effectively to help identify M. leprae specific proteins that may be applied for monitoring T-cell responses in M. leprae infected hosts as their disease progresses as well as for the early diagnosis of leprosy. PMID- 22439282 TI - Development of a mouse food pad model for detection of sub clinical leprosy. AB - Early diagnosis of leprosy and a multi-drug therapy (MDT) regimen will block the trajectory of nerve damage, disability and deformity that are the hallmarks of this chronic disease. However, the diagnosis of leprosy is made solely by recognition of clinical signs and symptoms, requiring special expertise. These limitations also result in the under reporting of worldwide prevalence and incidence rates for leprosy. Sorely needed is an objective laboratory test for detecting early leprosy. As the antigenic burden of M. leprae can be virtually undetectable in early clinical leprosy, cell mediated immunity and antibody responses will likely be weak. So the sensitivity of new diagnostic tests is as important as specificity. Major efforts are underway employing recombinant M. leprae antigens and synthetic peptides, to develop diagnostic assays for early leprosy infection, using in vitro T cell reactivity or serological tests. We have used the initial phase of the mouse foot pad model as an 'early' model of leprosy infection to screen T cell responses against M. leprae specific antigens and synthetic peptides. Unlike human disease in animal models we can control infection progress and monitor bacillary growth relative to time course of development of T cell response to specific M. leprae antigens. The study employed splenic T cells instead of draining lymph node T cells to model the systemic response as opposed to a local one. We found that 10(5) live M. leprae is the minimum dose required for any meaningful and consistent in vitro splenic IFN gamma response against M. leprae antigens 3 months after foot pad inoculation. Using this model we found that several M. leprae recombinant proteins, ML0840, ML2028, ML2307, ML2346, ML2478, and ML2532, induced significant levels of IFN gamma secretion. By controlling for variables that can be confounding factors in the sensitivity of human testing, this mouse model provides an interface between M. leprae diagnostic antigen development and the screening of these antigens in humans under field conditions. PMID- 22439283 TI - Immunogenicity of Mycobacterium leprae unique antigens in leprosy endemic populations in Asia and Africa. AB - Ongoing transmission of leprosy is evident from the stable disease incidence in high burden areas. Tools for early detection of Mycobacterium leprae (M. leprae) infection, particularly in sub-clinically infected individuals, are urgently required to reduce transmission. Following the sequencing of the M. leprae genome, many M. leprae-unique candidate proteins have been identified, several of which have been tested for induction of M. leprae specific T cell responses in different leprosy endemic areas. In this study, 21 M. leprae-unique proteins and 10 peptide pools covering the complete sequence of five M. leprae-unique proteins (ML0576, ML1989, ML1990, ML2283, and ML2567) were evaluated in 160 individuals in Nepal and Ethiopia. These included: tuberculoid and borderline tuberculoid (TT/BT), borderline borderline and borderline lepromatous (BB/BL) leprosy patients; healthy household contacts (HHC); tuberculosis (TB) patients and endemic controls (EC). Immunogenicity of the proteins was determined by IFN-gamma secretion via stimulation of PBMC in 6 days lymphocyte stimulation tests (LST) or in whole blood assays (WBA). In LST, BB/BL patients (40%) responded to ML0573 and ML1601 whereas ML1604 was most immunogenic in TT/BT (35%) and HHC (36%). Additionally, significant numbers of EC displayed IFN-gamma production in response to ML0573 (54%), ML1601 (50%) and ML1604 (54%). TB patients on the other hand, hardly responded to any of the proteins except for ML1989. Comparison of IFN-gamma responses to ML0121, ML0141 and ML0188 for TT/BT patients showed specific increase in diluted 6 days WBA compared to the undiluted 24 hours WBA, whereas EC showed a reduced response in the diluted WBA, which may indicate detection of disease-specific responses in the 6 days WBA. In summary, identification of multiple M. leprae proteins inducing M. leprae-specific T cell responses in groups at high risk of developing leprosy may contribute to improve early detection for M. leprae infection. PMID- 22439284 TI - Realizing possibilities/OTs speaking up. PMID- 22439285 TI - Concussion in hockey: taking an occupational perspective on risk in sports. PMID- 22439286 TI - The meaning gap in occupational therapy: finding meaning in our own occupation. PMID- 22439287 TI - Canadian Occupational Performance Measure: impact of blinded parent-proxy ratings on outcome. AB - BACKGROUND: There is potential for unintended effects on intervention outcome when using the Canadian Occupational Performance Measure (COPM) in intervention studies. PURPOSE: To determine the effect of blinded parent-proxy ratings of the COPM on outcomes at later endpoints. METHODS: Data were drawn from a randomized trial of 50 children with hemiplegic cerebral palsy aged 19 months to seven years. Outcomes were measured at baseline, post-intervention, and six months. Parents of 36 children were randomly allocated to complete six-month COPM proxy ratings blinded or unblinded to previous ratings. A group of 32 parents rated the six-month COPM blinded and then re-rated it after access to previous ratings. FINDINGS: There was no statistically significant difference in ratings between those completing the COPM blinded compared to unblinded. IMPLICATIONS: The COPM should continue to be rated blinded at post-intervention endpoints in the absence of further research to the contrary. PMID- 22439288 TI - Figured world of eating disorders: occupations of illness. AB - BACKGROUND: The biomedical diagnosis of eating disorders signifies a mental illness with complex physical symptomology. The socio-cultural determinants and impact of eating disorders on daily occupations are not adequately addressed in this classification. PURPOSE: This paper introduces the concept of a figured world as a framework for how eating disorders exist in daily activity and social discourse. How occupations become ascribed with meaning generated by an eating disorder will be proposed through the voice of a composite character in the figured world. KEY ISSUES: Central elements to contextualizing figured worlds include positional identity, self-authoring, and semiotic mediation. The generation of meaning in illness arises from the integration of these elements into this specific figured world. IMPLICATIONS: The competing agendas of the biomedical model and figured world permit a new understanding of the challenges associated with recovery. For occupational therapists, these challenges require the reattribution of meaning of daily occupations. PMID- 22439289 TI - [The participation of seniors in volunteer activities: a systematic review]. AB - CONTEXT: Volunteer work can be a very significant form of social participation for seniors. It can also provide seniors with important physical and psychological health benefits. This explains why occupational therapists and other health care professionals, as well as community workers who are concerned with healthy aging, appeal to seniors to volunteer in health promotion and community support However, the recruitment and ongoing involvement of seniors as volunteers is often challenging. OBJECTIVE: A systematic review of the literature was undertaken to enlighten practitioners working in this domain. The objective was to identify factors that influence seniors' participation in volunteer work. METHOD: Six bibliographic databases were searched using key words. RESULTS: A total of 27 relevant papers were retrieved and allowed an identification of a series of factors that could influence seniors' participation in volunteer work, namely personal factors, environmental factors, and occupational factors. IMPLICATIONS: This analysis leads to practical guidelines for facilitating the recruitment and maintenance of seniors' engagement in volunteer work. PMID- 22439290 TI - Problem-solving strategies of women undergoing chemotherapy for breast cancer. AB - BACKGROUND: Many women undergoing chemotherapy for breast cancer experience side effects that make it difficult to perform daily occupations. PURPOSE: To summarize the types of challenges, goals, and adaptive strategies identified by women with stage 1-3 breast cancer participating in a pilot study of Problem solving Treatment-Occupational Therapy (PST-OT). METHODS: Content analysis of 80 PST-OT sessions. FINDINGS: Women addressed 11 types of challenging activities, with exercise and instrumental activities of daily living (IADL) being the most common. Most women set a goal to adapt a current activity, but also set goals to find a new activity, plan the steps of a current activity, or gather information about a possible activity change in the future. The adaptive strategies generated by the women were grouped into five types. Most often they found ways to add a new step to an activity, but they also brainstormed about when, how, where, and with whom they could do activities. IMPLICATIONS: The women were usually trying to adapt familiar activities but also were looking for ways to include new, healthy occupations into their routines. PMID- 22439291 TI - Partnering for change: an innovative school-based occupational therapy service delivery model for children with developmental coordination disorder. AB - BACKGROUND: Developmental coordination disorder (DCD) is a common, chronic health condition that is poorly recognized and understood in school settings. Without appropriate support, children with DCD are at increased risk of depression, decreased fitness, and obesity. Evidence shows that occupational therapy intervention needs to shift from remediation of impairment to chronic disease management. PURPOSE: This paper describes Partnering for Change (P4C), an innovative, empirically derived school health service delivery model for children with DCD. KEY ISSUES: The model emphasizes the partnership of the occupational therapist with educators and parents to change the life and daily environment of a child. The P4C partnership focuses on capacity building through collaboration and coaching in context. The model uses a tiered approach which includes whole class instruction, dynamic performance analysis, and monitoring response to intervention. IMPLICATIONS: P4C is a model that responds to the needs of this population, addresses issues identified in research, and provides a continuum of services designed to build capacity. PMID- 22439292 TI - "Support for everyone": Experiences of occupational therapists delivering a new model of school-based service. AB - BACKGROUND: Occupational therapists working in school health have recognized the need to move away from a one-to-one direct service delivery model towards a more collaborative, classroom-based approach. Partnering for Change (P4C) is an innovative service delivery model that may enhance school-based collaborative care. PURPOSE: To capture the experiences of occupational therapists implementing P4C and to elicit their perspectives about how this model differs from the direct service approach. METHODS: Semi-structured, face-to-face interviews were conducted with seven therapists who had delivered P4C in 10 Ontario schools. Thematic analysis was utilized with themes verified through member checking. FINDINGS: Five themes (a year of growth, becoming a community, the key ingredients of P4C, a balancing act, and providing services that make an impact) reflected therapists'personal and professional growth, aspects of the model they believed were key, challenges they encountered, and the impact they felt they had made. IMPLICATIONS: Partnering for Change has the potential to transform school based occupational therapy and overcome existing barriers to collaboration. This model also may better address the needs of children with motor coordination difficulties. PMID- 22439293 TI - Sensory processing and ADHD in children with fetal alcohol spectrum disorder. AB - BACKGROUND: Sensory processing problems are prevalent in children who have fetal alcohol spectrum disorder. It is unclear to what degree these problems are distinct from attention deficits as measured during the diagnostic process in these children. PURPOSE: To understand sensory processing in these children, which may assist with early identification and intervention. METHOD: The relationship between attention and sensory processing was studied in a retrospective sample of 26 Canadian children diagnosed with fetal alcohol spectrum disorder. FINDINGS: A very low correlation (r = .02) between Short Sensory Profile scores and the attention deficit hyperactivity index of the Conners' Parent Rating Scales was found for the five- to ten-year-old children. Sensory processing problems were found in 81% of the children, similar to other studies of children with fetal alcohol spectrum disorder. IMPLICATIONS: These findings can guide modifications of the environments, tasks, and approaches to children with fetal alcohol spectrum disorder. PMID- 22439294 TI - Brain-derived neurotrophic factor, adiponectin, and proinflammatory markers in various subtypes of depression in young men. AB - OBJECTIVES: We aimed to investigate levels of brain-derived neurotrophic factor (BDNF), adiponectin, and proinflammatory cytokines in various subtypes of depression in a cohort of young men. METHODS: Sixty-two men 18-30 years of age were recruited for the study. Forty-two were newly diagnosed with depression according to DSM-IV criteria and were divided into three subtypes: reactive depression (N = 13), major depression (N = 18), and bipolar depression (N = 10). Controls included 21 young men without significant clinical morbidity. Serum levels of BDNF, adiponectin, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured. RESULTS: Serum BDNF was significantly lower and TNF-alpha significantly higher than controls for all subtypes of depression. No statistically significant differences between subtypes were found for BDNF, adiponectin, hsCRP, TNF-alpha, or IL-6. Although established diagnosis of depression and level of TNF-alpha were found to independently affect BDNF level in depressed subjects, they executed inverse effects. No associations were found between BDNF and adiponectin, hsCRP, TNF-alpha, or IL-6 in any depressed subject, showing that decreased BDNF in depression is influenced by multiple factors and complex mechanisms, including environmental and genetic concerns. No influence of age on BDNF level was found in any depressive subtype. CONCLUSIONS: Our results lend support to the cytokine and neurotrophic hypotheses of depression by demonstrating significantly lower levels of BDNF in all subtypes of depression. The mechanism underlying this phenomenon is uncertain and assumed to be multifactorial. Development of novel antidepressant treatments will require a multidisciplinary approach. PMID- 22439296 TI - Religious, spiritual, and traditional beliefs and practices and the ethics of mental health research in less wealthy countries. AB - This discussion article contributes to ethics reform by introducing the contribution of religious, spiritual, and traditional beliefs and practices to both subject vulnerability and patient improvement. A growing body of evidence suggests that religious, spiritual, and traditional beliefs and practices may provide positive benefits, although in some cases mixed or negative consequences to mental and physical health. These beliefs and practices add a new level of complexity to ethical deliberations, in terms of what ignoring them may mean for both distributive justice and respect for persons. International ethical guidelines need to be created that are expansive enough to cover an array of social groups and circumstances. It is proposed that these guidelines incorporate the religious, spiritual, and/or traditional principles that characterize a local population. Providing effective mental healthcare requires respecting and understanding how differences, including ones that express a population's religious, spiritual, or traditional belief systems, play into the complex deliberations and negotiations that must be undertaken if researchers are to adhere to ethical imperatives in research and treatment. PMID- 22439295 TI - Medical treatment of alcohol dependence: a systematic review. AB - OBJECTIVE: To summarize published data on pharmacologic treatments for alcohol dependence alone and in combination with brief psychosocial therapies that may be feasible for primary care and specialty medical settings. METHODS: We conducted electronic searches of published original research articles and reviews in MEDLINE, SCOPUS, CINAHL, Embase, and PsychINFO. In addition, hand searches of reference lists of review articles, supplemental searches of internet references and contacts with experts in the field were conducted. Randomized controlled studies published between January 1960 and August 2010 that met our inclusion/exclusion criteria were included. RESULTS: A total of 85 studies, representing 18,937 subjects, met our criteria for inclusion. The evidence base for oral naltrexone (6% more days abstinent than placebo in the largest study) and topiramate (prescribed off-label) (e.g., 26.2% more days abstinent than placebo in a recent study) is positive but modest. Acamprosate shows modest efficacy with recently abstinent patients, with European studies showing better results than U.S. ones. The evidence-base for disulfiram is equivocal. Depot naltrexone shows efficacy (25% greater reduction in rate of heavy drinking vs. placebo, in one of the largest studies) in a limited number of studies. Some studies suggest that patients do better with extensive psychosocial treatments added to medications while others show that brief support can be equally effective. CONCLUSIONS: Although treatment effects are modest, medications for alcohol dependence, in conjunction with either brief support or more extensive psychosocial therapy, can be effective in primary and specialty care medical settings. PMID- 22439297 TI - When breast cancer survivors report cognitive problems at work. AB - OBJECTIVE: Breast cancer survivors (BCS) who wish to stay actively employed following primary treatment of cancer may experience cognitive problems at work. Management of these cognitive problems may need to focus on associated symptoms. The current study determined whether fatigue and depressive symptoms, which can co-occur with one another, are independently and/or interactively related to cognitive limitations at work. METHOD: A cross-sectional study was conducted. BCS (n = 133) and a non-cancer comparison group (NCCG; n = 122) completed measures of work-related cognitive limitations, fatigue, and depression. RESULTS: Three years post primary treatment, BCS reported higher levels of fatigue (p = 0.001), depressive symptoms (p = 0.001), and work related cognitive limitations (p = 0.001) than the NCCG. Fatigue and depressive symptoms were each independently associated with cognitive limitations in both those with and without a history of cancer. CONCLUSIONS: When BCS report problems with cognitive abilities at work along with fatigue and depressive symptoms, it is important to recognize that these symptoms can be independently related to cognitive limitations. This study also suggests that management of symptoms of fatigue and depression may benefit from different approaches when improvement in cognitive function at work is a desired outcome. PMID- 22439298 TI - Shared care between specialized psychiatric services and primary care: the experiences and expectations of consultant psychiatrists in Ireland. AB - BACKGROUND: Internationally, there has been a growing interest in the pursuit of collaborative forms of care for patients with enduring mental health difficulties. OBJECTIVE: The study aims to explore the views of consultant psychiatrists in Ireland on shared care between specialized psychiatric services and primary care for patients with mental health difficulties. METHOD: A self administered questionnaire was designed and posted to 470 consultant psychiatrists who are members of the College of Psychiatry of Ireland. Stamped self-addressed envelopes were included for the return of completed questionnaires. RESULTS: Overall, 213 questionnaires were returned, giving a response rate of 45%. Of the respondents, 194 (91%) reported that they would support a general policy on shared care between primary care and specialized psychiatric services for patients who are stable on their treatment. However, 181 (85%) reported that they foresaw difficulties for patients in implementing such a policy including: increased financial burden on some patients (141, 66%); some patients may lack confidence in GP care (100, 47%); primary care is not adequately resourced with allied health professionals to support provision of psychiatric care (128, 60%); primary care providers are not adequately trained to provide psychiatric care (111, 52%); and lack of adequate cooperation between primary care and specialized mental health services (96, 45%). CONCLUSION: The Irish government and the Colleges of General Practitioners and Psychiatrists in Ireland need to work together to remove the bottlenecks that hinder the active involvement of primary care in the management of patients with enduring mental health difficulties. Also, the health care systems need to be organized along a shared care model to facilitate effective collaboration between primary and specialized psychiatric services. PMID- 22439299 TI - A spirituality teaching program for depression: a randomized controlled trial. AB - OBJECTIVE: This randomized controlled trial assessed the efficacy of a Spirituality Teaching Program to treat unipolar major depression. METHOD: A randomized controlled, assessor blinded trial design was used. A total of 84 individuals aged 18 years or older with unipolar major depression of mild to moderate severity were recruited in Calgary, Canada and randomized to two study arms: 1) Spirituality Teaching Program Group (8 week, home-based Spirituality Teaching Program); and 2) Waitlist Control Group (no intervention followed by Spirituality Teaching Program starting at week 9). Outcome measures (depression severity, response rate, remission rate) were assessed at baseline, 8, 16, and 24 weeks using the Hamilton Depression Rating Scale (HAM-D). RESULTS: The two trial groups were similar in their demographic and disease characteristics at baseline. At the 8-week point, the change in depression severity was significantly different between the two groups (change in HAM-D score: 8.5 for the Spirituality Group and 2.3 for the Waitlist Control Group, p < 0.001). The Spirituality Teaching Program Group had significantly higher response (36% vs. 4.4%, p < 0.001) and remission rates (31% vs. 4.4%, p < 0.001) than the Waitlist Control Group. The benefits remained throughout the observation period for the Spirituality Teaching Program Group participants with response rates of 56.4% at 16 weeks and 58.9% at 24 weeks. CONCLUSION: The Spirituality Program significantly reduced depression severity and increased response and remission rates. This non-drug treatment program should be investigated further as a treatment option for depression. PMID- 22439300 TI - When non-epileptic seizures fool the experts. AB - Even when non-epileptic seizures are correctly diagnosed, appropriate treatment recommendations may not be fully or correctly implemented. We present a case of a 17-year-old girl with frequent non-epileptic seizures who presented for frequent trips to the emergency room (ER) and was admitted to an inpatient Child and Adolescent Psychiatric Facility. Despite being informed that episodes were non epileptic seizures, various staff and healthcare providers at the psychiatric hospital continued to send the patient to the ER to treat suspected epileptic seizures. We discuss possible reasons why this may have occurred, including psychosocial and emotional reactions of staff members to the episodes. This discussion may also help to explain the persistence of the patient's episodes. We also present options for minimizing the potential for future mismanagement of non epileptic seizures. PMID- 22439301 TI - Don't hold the salt when working up dermatoses of pregnancy. PMID- 22439302 TI - Contact allergy to dimethacrylate. AB - Contact allergy to methacrylates is uncommon. We present a 55-year-old woman with a 10-year history of persistent pruritus and burning sensation of the gums every time she wore her dentures. Initially she developed swelling and erythema of the face soon after the dentures were placed on the gums. These symptoms abated after a barrier liner was applied between her gums and the dentures. However, the burning sensation and pruritus of the gums progressively worsened and she started to develop blisters on the gums. The skin allergen patch test was 3+ positive with erythema, edema, papules, ulceration, and pruritus for the denture component dimethacrylate. The diagnosis was supported by the patient's medical history, notably positive patch test, and complete amelioration of the symptoms upon cessation of dimethacrylate denture usage. PMID- 22439303 TI - What is your diagnosis? Desmoplastic Spitz nevus. PMID- 22439304 TI - Cutaneous paraneoplastic syndrome presenting with wartylike oral lesions. PMID- 22439305 TI - Bullous systemic lupus erythematosus with lupus nephritis: a rare case of a subepidermal bullous disorder in a child. AB - Bullous systemic lupus erythematosus (BSLE) is a rare subset of systemic lupus erythematosus (SLE) with bullous lesions in a case fulfilling the American Rheumatism Association (Atlanta) criteria, histologically characterized by a neutrophil-predominant infiltrate in the upper dermis with immunoglobulin (IgG, IgA, IgM) and C3 deposition at the basement membrane zone (BMZ). It often is associated with autoimmunity to type VII collagen (NC1 [noncollagenous domain 1] domain), although occasionally other antigens such as laminin 5, laminin 6, and BP230 (bullous pemphigoid antigen) have been described. Bullous systemic lupus erythematosus is extremely rare in children. We report here a case of a 9-year old girl with BSLE as an initial presentation with lupus nephritis class III, a rare occurrence at such a young age. Despite the rarity, we suggest that BSLE should be considered in the differential diagnosis of subepidermal bullous diseases in children in view of associated potentially serious systemic manifestations. PMID- 22439306 TI - Giant syringomas: a case report. AB - We report a case of a 71-year-old man with multiple localized giant syringomas on the upper and lower eyelids. Few cases have been reported of syringomas with a diameter greater than 5 mm. PMID- 22439307 TI - Dermatologic care in the homeless and underserved populations: observations from the Venice Family Clinic. AB - Dermatologic care in the homeless and impoverished urban underserved populations is rarely described despite the wide prevalence of skin concerns in this population. Because the homeless population may be subject to increased sun exposure compared to the nonhomeless population, they also may be at increased risk for skin cancer. We sought to describe the spectrum of dermatologic diseases seen in a free clinic in Venice, California--the Venice Family Clinic (VFC)--as well as the differences in diagnoses between the homeless and nonhomeless patients seen at this clinic. A retrospective chart review was performed of dermatology patients (N = 82) seen at VFC throughout the 2006 calendar year. The homeless population (n = 22) was found to have more diagnoses of malignant/premalignant growths (25% [16/64] of all homeless diagnoses) compared to their nonhomeless (n = 60) counterparts (6.1% [8/132] of all nonhomeless diagnoses; P < .0001). This difference was sustained when ethnicity was controlled, with 29.6% [16/54] of diagnoses in the homeless white group consisting of malignant/ premalignant growths compared to 8.9% [4/45] of diagnoses in the nonhomeless white cohort (P < .005). Homeless patients may have a higher incidence of skin cancers and precancerous skin lesions due to increased sun exposure and/or limited access to dermatologic care. PMID- 22439308 TI - Leser-Trelat sign presenting in a patient with recurrent pre-B-cell acute lymphocytic leukemia. AB - The presence of multiple seborrheic keratoses appearing abruptly in association with an underlying malignancy is known as Leser-Trelat sign, a rare paraneoplastic cutaneous syndrome. Although this finding is most commonly associated with solid organ tumors, it also can be a clue for the presence of underlying hematologic malignancies. We present a unique case of Leser-Trelat sign in a 20-year-old man who experienced a relapse of pre-B-cell acute lymphocytic leukemia (ALL) that was previously treated with multiple courses of chemotherapy and external radiation therapy. The patient was admitted for a new cycle of chemotherapy with etoposide and cyclophosphamide and was noted to have an eruption of yellowish brown papules and plaques over his upper body. Biopsy of a representative lesion was consistent with seborrheic keratosis. A large number of rapidly appearing seborrheic keratoses is an uncommon finding in young patients and should be considered clinically suspicious as a potential indicator of Leser-Trelat sign. A thorough history and physical examination should be performed in patients presenting with this sign to rule out possible internal solid organ and hematologic malignancies. PMID- 22439309 TI - Multisegmental herpes zoster in an immunocompetent girl. AB - Children infrequently are afflicted with herpes zoster (HZ). Activation of latent varicella-zoster virus (VZV) in a partially immune host results in HZ. Herpes zoster in children can be benign or with varied severity, especially in cases associated with malignancy. Because of its rarity, we report widespread multisegmental HZ primarily presenting on the right side of the body and abdomen in a 6-year-old immunocompetent girl. PMID- 22439310 TI - Conjunctival papilloma. AB - Conjunctival papillomas are some of the most common tumors of the conjunctiva and are well-described in ophthalmology textbooks. However, they have not be well recognized by the dermatologic community. These lesions may be encountered by the dermatologist during a full skin examination or they may be the presenting concern of a patient. PMID- 22439311 TI - Necrobiotic xanthogranuloma of the extremities with paraproteinemia and without periorbital involvement at presentation. AB - We report a rare case of necrobiotic xanthogranuloma (NXG) of the extremities with paraproteinemia and without periorbital involvement at presentation in a 58 year-old white woman. A combination of oral cyclophosphamide and oral dexamethasone was attempted, but the patient then developed a left intraorbital lesion. Treatment was not successful in that the gammopathy did not improve and the patient continued to develop more lesions. PMID- 22439312 TI - Squamous cell carcinoma manifesting as cutaneous cystic lesions. AB - Squamous cell carcinoma (SCC), a malignancy of epidermal keratinocytes, is the second most common cause of skin cancer in the United States. Our case represents an unusual variant of this common tumor. We report a clinical presentation of a case of SCC occurring as cutaneous cystic lesions on the face of an 87-year-old white woman with a medical history of multiple SCCs. PMID- 22439313 TI - After the survey. PMID- 22439314 TI - A device for the collection of submandibular saliva. AB - The objective of this study was to describe the construction of a non-invasive device for the collection of submandibular saliva. Preliminary tests were carried out on saliva collected from a single donor in order to determine whether the rheological properties of submandibular saliva collected using the device were comparable to whole saliva collected using the expectoration (or 'spit') method. The device collected a lower quantity of saliva than that collected using the expectoration method. Stimulated saliva collected using the device had a pH close to that of unstimulated saliva because the sealed collection unit in the device minimised contamination. Saliva exhibited shear-thinning behaviour regardless of the method of collection, although that collected using the device was more viscous. The viscoelasticity of saliva collected using the two methods was different, probably as a result of differences in composition. This difference was greater with stimulated saliva. Despite the discrepancies between whole saliva and submandibular saliva, the device provides a non-invasive method for the collection of high-quality saliva over extended periods. PMID- 22439315 TI - Evaluation of mandibular growth using cone-beam computed tomography in a rabbit model: a pilot study. AB - OBJECTIVES: The aim of this pilot study was to describe three-dimensional (3D) changes during mandibular growth in a rabbit model using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: CBCT scans were taken of three growing New Zealand white rabbits at baseline and then fortnightly for eight weeks. Metallic tantalum 1-mm spheres were implanted as bone reference markers. 3D images were constructed, and mandibular growth was described by six measurements. RESULTS: The animals coped well with the experimental procedures. The use of CBCT to evaluate 3D mandibular growth appeared feasible in this rabbit model. Consistent mandibular growth (of 0.6 to 5.7 mm) was observed in all rabbits. Distances between the bone markers changed slightly (0.0 to 1.6 mm). CONCLUSION: During the observation period, vertical ramus growth in the rabbit mandible was more prominent than either sagittal or transverse growth. The mandibular molar region seemed to be the most stable area for radiographic superimposition in the rabbit model. 3D evaluation of mandibular growth in a rabbit model using CBCT represents a promising approach for the preclinical evaluation of proposed treatment intervention studies. PMID- 22439316 TI - Development of a dental model hardener. AB - The paper presents a novel method of strengthening dental gypsum materials by infiltrating with a low-viscosity autopolymerising monomer. Gypsum specimens were infiltrated with diluted butyl-cyanoacrylate monomer at different concentrations. Nanoindentation was employed to measure their hardness and elastic modulus. A standard single-edge-notched beam (SENB) method was used to measure fracture toughness. Biaxial strength was measured using a universal test machine with a piston-on-ring jig. Scanning Electron Microscopy (SEM) and affiliated energy dispersive X-ray spectroscopy (EDX) were used to observe the fracture topography and the depth of infiltration. Infiltration and autopolymerisation of the cyanoacrylate improved the biaxial strength and fracture toughness of the gypsum by around 39% and around 30%, respectively. The hardness and elastic modulus for the treated specimens were also higher, albeit slightly. The proposed method provides a convenient way to strengthen and repair dental gypsum models in situ. PMID- 22439317 TI - An exploratory study of the acceptability of delivering oral health information in community pharmacies. AB - OBJECTIVE: The community pharmacy is an accessible service which, with further training and support, could be used to deliver oral health messages. This is important especially for those with systemic diseases such as diabetes mellitus and cardiovascular disease, where the oral environment may have a negative impact. This qualitative study assessed the feasibility of pharmacists delivering oral health messages in community pharmacies. DESIGN AND METHODS: Semi-structured interviews were conducted with 49 pharmacists in Dunedin and Auckland, New Zealand, with a focus on the pharmacists' current knowledge, attitudes and possibilities for providing oral health information to patients with diabetes and cardiovascular disease. FINDINGS: There is potential for community pharmacists to provide oral health information to patients, dependent on the approach of the pharmacist and the patient response. The majority of pharmacists agreed that providing oral health advice was within their role; however, few did so proactively. They highlighted a lack of available resources relating to oral health and systemic disease. Further training relating to oral health and systemic disease would be necessary to provide the knowledge to support any resources. The preferred option by pharmacists for such training was an evening course or workshop. PMID- 22439318 TI - Coolant effectiveness in dental cutting with air-turbine handpieces. AB - OBJECTIVE: To establish a strategy for evaluating coolant effectiveness and to compare typical cooling conditions used in dental cutting. MATERIALS AND METHODS: A test system comprising a resistive heat source and an array of four type K thermocouples was used to compare the cooling effectiveness of air alone, water stream alone, and an air-water spray, as delivered by representative air-turbine handpieces. Mean temperature change at the four sites was recorded for a range of water flow rates in the range 10 to 90 mL min(-1), with and without air, and with and without the turbine running. The thermal resistance of the system, R, was calculated as the temperature change per watt (KW(-1)). RESULTS: For wet cooling (water stream and air-water spray), R was 5.1 to 11.5 KW(-1), whereas for air coolant alone the range was 18.5 to 30.7 KW(-1). R for air-water spray was lower than for water stream cooling at the same flow rate. CONCLUSIONS: The thermal resistivity approach is a viable means of comparative testing of cooling efficacy in simulated dental cutting. It may provide a reliable means of testing handpiece nozzle design, thus enabling the development of more efficient cooling. PMID- 22439319 TI - Re: A nine-year review of orthognathic surgery at the University of Otago. A L Patel et al, New Zealand Dental Journal 107, 4: 117-120, December 2011. PMID- 22439320 TI - Activity of superoxide dysmutase, catalase and glutathione peroxidase in rats exposed to chlorpyrifos and erofloxacin. AB - The aim of the study was to investigate the influence of administration of chlorpyrifos and/or enrofloxacin on the activity of chosen antioxidative enzymes i.e.: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in erythrocytes of rats. Chlorpyrifos was administered by stomach tube during 28 days at a dose of 3 mg/kg bw (0.02 LD50), and enrofloxacin was administered by stomach tube at a dose of 5 mg/kg bw during 3 subsequent days. It was stated that administration of enrofloxacin at applied dose did not cause any major changes in the activity of investigated antioxidative enzymes. The four-week exposure of rats to chlorpyrifos caused noticeable decrease in SOD and CAT activity in erythrocytes of rats at the beginning of the experiment (up to 24th hour) in comparison with the control group. The activity of GPx during all periods of the experiment was increased. In the group of animals in which both chlorpyrifos and enrofloxacin were applied, the profile of changes in activity of examined enzymes was similar to that one, which was observed after administration of chlorpyrifos exclusively, what may indicate lack of co-action between compounds used in the experiment. PMID- 22439321 TI - Immunohistochemical detection of Lawsonia intracellularis in tissue sections from pigs. AB - The aim of the present study was to develop an immunohistochemical method (IHC) for detection of Lawsonia intracellularis (L. intracellularis) in formalin-fixed, paraffin embedded sections of intestines from pigs and to implement this method in differential diagnosis of swine diseases with diarrhea in postweaning pigs. The study was conducted on 165 sections of intestines (ileum, caecum and colon) collected from 76 pigs, representing 42 Polish pig farms. The animals included in the analysis suffered from diarrhea, with bloody or grey to brown feces, and were suspected of porcine proliferative enteropathy (PPE). Sections of intestines were analyzed for the presence of L. intracellularis by polymerase chain reaction (PCR) and IHC. Among 165 intestinal samples from pigs with diarrhea, L. intracellularis DNA was detected by PCR in 33 (20.0%) samples. In this group, 30 samples (18.2% of all the samples tested) were also found positive in IHC, while only 3 (1.8%) were IHC-negative. One hundred thirty-two (80.0%) samples were negative in both tests. The PCR- and IHC-positive samples originated from 11 pigs, 4- to 20-week old, from 8 farms. L. intracellularis antigen was visualized by IHC mostly in intestinal crypts and/or in mononuclear cells of the lamina propria). The positive signal in epithelial cells was observed close to the luminal borders, creating typical specifically stained rims around the crypt lumina. The results of the present study further confirm the usefulness of IHC in the detection of L. intracellularis antigen in the intestinal tissues. PMID- 22439322 TI - Concentrations of oestrogens in blood plasma and seminal plasma of boars during the postpuberal period. AB - Concentrations of oestrogens in the blood plasma and seminal plasma of mature boars are high. However, little is known about their concentrations after reaching sexual maturity. The aim of this study was to determine the concentration of oestrogens in blood plasma and seminal plasma of boars during the postpuberal period. Free and conjugated oestrone and oestradiol-17beta were determined by radioimmunoassay in blood from the testicular vein and artery, and peripheral circulation as well as in seminal plasma collected from 18 Polish Landrace boars. The animals were divided into three groups (n = 6) according to age (8, 12 and 16 months, respectively). Oestrone was predominant free and conjugated oestrogen. The highest values of oestrogens were measured in the testicular vein (p < or = 0.05). The concentrations of oestrogens in seminal plasma did not differ from those found in the peripheral circulation. An age dependent increase in levels of all four oestrogens (p < or = 0.05) was observed. This can be associated with biochemical maturation of the reproductive system during the postpuberal period. PMID- 22439323 TI - Assessment of diclofenac LC50 reference values in juvenile and embryonic stages of the zebrafish (Danio rerio). AB - The aim of the study was to compare the acute toxicity of diclofenac to juvenile and embryonic stages of the zebrafish (Danio rerio). Acute toxicity tests were performed on the aquarium fish Danio rerio, which is one of the model organisms most commonly used in toxicity testing. The tests were performed using a semi static method according to OECD guideline No. 203 (Fish, acute toxicity test). Embryo toxicity tests were performed in zebrafish embryos (Danio rerio) in compliance with OECD No. 212 methodology (Fish, short-term toxicity test on embryo and sac-fry stages). The results were subjected to a probit analysis using the EKO-TOX 5.2 programme to determine 96hLC50 and 144hLC50 (median lethal concentration, 50% mortality after a 96 h or 144 h interval, respectively) values of diclofenac. The statistical significance of the difference between LC50 values in juvenile and embryonic stages of Danio rerio was tested using the Mann-Whitney non-parametric test implemented in the Unistat 5.1 programme. The LC50 mean value of diclofenac was 166.6 +/- 9.8 mg/L in juvenile Danio rerio, and 6.11 +/- 2.48 mg/L in embryonic stages of Danio rerio. The study demonstrated a statistically higher sensitivity to diclofenac (P < 0.05) in embryonic stages compared to the juvenile fish. PMID- 22439324 TI - NT-pro-BNP and troponin I as predictors of mortality in dogs with heart failure. AB - The purpose of this study was to develop prognostic models for heart failure in dogs with dilated cardiomyopathy (DCM). The prospective study included 26 dogs with DCM and 58 healthy dogs. The ervation time median was 250 days (1-600 days). All the dogs were clinically examined, had echocardiography, electrocardiography, and morphological and biochemical blood sampling. Twenty four deaths were found in the group of dogs with DCM and 1 demise in the healthy dog's group. There was a significant increase in the level of NT-pro-BNP and cTnI (p < 0.0005) in the group of dogs with DCM and a significant higher level of NT-pro-BNP and cTnI (p < 0.0005) in the dead dogs from group with DCM that died or were euthanized up to the 60th day of observation, compared to the animals that outlasted over 60 days of observation. The median level of NT-pro-BNP in the dogs which had short survival period (no more than 60 days) was 4865 pmol/L and the median level of cTnI in the same group of dogs was 0.63 ng/ml. The median level of NT-pro-BNP in the group of dogs with DCM, which lived longer than 60 days of observation was 978 pmol/l and the median level of cTnI in this group was 0.1 ng/ml. The level of NT-pro-BNP (r = 0.79) and cTnI (r = 0.4) correlated with the dogs' death. NT-pro BNP and cTnI measurements could be useful to evaluate the survival the dogs with DCM. Increased level of NT-pro-BNP and cTnI is a bad prognosis. In the performed analysis of the Cox hazard regression it was found that cTnI level has a significant impact of the survival of the dogs (HR = 8.54; Cl 1.1-46.6; p = 0.02). PMID- 22439325 TI - The effect of Linola and W92/72 transgenic flax seeds on the rabbit caecal fermentation--in vitro study. AB - The effect of W92/72 transgenic flax seeds taken from a variety of Linola on the production of SCFA, ammonia and methane by bacteria inhabiting rabbit caecum was studied. The in vitro method was used where caecal contents from rabbits was incubated with W92/72 transgenic or Linola flax seeds, or without any additives (control samples). The total concentration of SCFA was higher in samples with the addition of flax seeds than in the control samples. The increase in concentrations of acetic, propionic and butyric acids was the highest in samples with Linola seeds added. A higher percentage of propionic and butyric acids was observed in the contents incubated with addition of flax seeds as compared to the control samples. This increase was the result of a percentage decrease in acetic acid. No differences were observed in the concentration of ammonia between fermented samples. Moreover, the addition of flax seeds resulted in slight decrease of pH in incubated samples. In gas samples, the methane level was higher in samples with flax seeds added, although the highest level was found in samples with transgenic seeds. In addition, gas pressure was significantly higher in samples with flax seeds added as compared to control samples, and this may indicate a higher intensity of microbiological fermentation processes. These studies suggest that neither Linola nor W92/72 flax seeds have any unfavorable effect on the caecal microflora activity of rabbits. A beneficial influence of flax seeds on the microbiological fermentation process in rabbit caecum was observed, based on an increase in percentage ratio of propionic acid in samples with flax seeds added. PMID- 22439326 TI - A comparison of immunohistochemistry and in situ hybridization for the detection of porcine circovirus type 2 in pigs. AB - The aim of this study was to develop and to optimize an immunohistochemistry (IHC) method for PCV2 identification and to compare it with an in situ hybridization (ISH) technique. The results demonstrated that both ISH and IHC successfully detected PCV2 viral antigens or nucleic acid in the examined tissues. Most of the slides identified previously in ISH as PCV2-positive were also positive in IHC. In the case of nearly half of the slides the results of IHC examination revealed an increase in the intensity of staining. IHC presented higher sensitivity and specificity than ISH. No negative impact of the time of paraffin block storage on ISH detection results was observed. In addition, IHC results were easier to interpret due to better image quality after staining. Overall results confirmed IHC was a reliable and useful technique for PMWS diagnosis. PMID- 22439327 TI - The survey of wild birds for West Nile virus in Poland. AB - Two thousand one hundred and forty birds belonging to 39 different species from different locations in Poland were examined. The study has taken place from the early spring till late autumn 2007-2010 when the activity of the mosquitoes was the highest. The brain samples were taken from the birds and whole cellular RNA was isolated, then the RT-PCR and NRT-PCR were performed to detect the presence of West Nile virus (WNV). The obtained results were confirmed by the commercial WNV Kit. No genetic material of WNV was found in the examined samples. PMID- 22439328 TI - Serological survey for bovine immunodeficiency virus in dairy cattle from Poland. AB - A seroprevalence study of bovine immunodeficiency virus (BIV) was undertaken on 1,541 serum samples from Holstein cattle from 23 herds, located in different geographical regions of Poland. The analysis was performed using ELISA, with recombinant Gag protein of BIV as antigen. The average BIV prevalence was 4.9% in individual cattle, while the percentage of herds harboring at least one seropositive animal, was 82.6%. To demonstrate the correlation of BIV and bovine leukemia virus infection, all sera were analysed for BLV antibodies and there was only a slight association between both infections. Overall, these results show that BIV infection is present in dairy cattle in Poland at a prevalence rate found in other European countries. PMID- 22439329 TI - Influence of chronic caprine arthritis-encephalitis virus infection on the population of peripheral blood leukocytes. AB - The influence of caprine arthritis-encephalitis (CAE) virus infection on the population of peripheral blood leukocytes in goats was evaluated. For this purpose two groups of adult dairy female goats were formed. The experimental group consisted of 17 goats, which had been naturally infected for many years. The control group comprised 29 non-infected goats, which originated from CAE-free herd. All goats were clinically healthy. Whole blood was collected and tested in hematological analyzer and light microscope to assess the total number of leukocytes and the percentage of four leukocyte populations--neutrophils, eosinophils, monocytes and lymphocytes. Then, flow cytometry with monoclonal antibodies against several surface antigens (namely CD14, CD2, B-B2, CD4, CD8h, TCR-N6, WC1-N2 and WC1-N3) was performed to assess the proportion of lymphocyte subpopulations. Statistically significant differences (alpha < or = 0.01) were observed only in the subpopulations of T lymphocytes--percentage of all subpopulations were significantly higher in the group of seropositive goats. No statistically significant differences were revealed with respect to the total number of blood leukocytes, the average percentage of blood leukocyte populations and proportions of both T and B lymphocytes. PMID- 22439330 TI - Root surface temperature rise of mandibular first molar during root canal filling with high-temperature thermoplasticized Gutta-Percha in the dog. AB - This in vitro study evaluated the temperature rise on the outer root surface of the mandibular first molar following root canal filling using the high temperature, thermoplasticized, Gutta-Percha technique (HTTG) (BeeFill) in the dog. Twelve extracted dog mandibular first molars were used. After root canal preparation, the teeth were filled with thermoplasticized Gutta-Percha and root canal sealer. Temperature changes on the vestibular surfaces of the mesial and distal roots of mandibular first molars were measured using a thermal imaging camera. The results of this in vitro study showed that using HTTG to fill mandibular first molars in dogs produces a safe temperature rise on the root surface and, therefore, should not damage the periodontal ligament and/or surrounding tissues. PMID- 22439331 TI - The effect of silver nanoparticles on splenocyte activity and selected cytokine levels in the mouse serum at early stage of experimental endotoxemia. AB - The objective of this study was to determine the effect of a nonionic silver nanocolloid administered orally for 7 or 14 days at three concentration levels (25 ppm, 2.5 ppm, and 0.25 ppm) on the phagocytic activity and mitogenic response of splenocytes and selected cytokine serum levels (IL-1beta, IL-6, IL-10, IL-12 p70, TNF-alpha) in NMRI mice at the early stage of experimental endotoxemia induced with single 30 microg/mouse dose of bacterial LPS. Regardless of the period of administration, silver nanoparticles enhanced the production of proinflammatory cytokines and anti-inflammatory cytokine IL-10, and they inhibited IL-12 p70 levels in response to LPS challenge. The studied nanoparticles' effect on splenocyte activity was determined by the period of administration. After 7 days of use, silver nanoparticles enhanced the phagocytic activity, and doses of 2.5 ppm stimulated the mitogenic response of splenocytes. After 14 days of administration, silver nanoparticles lowered the phagocytic activity regardless of the dose applied. Although the results obtained are ambiguous, they suggest that silver nanoparticles administered via the alimentary tract are more likely to increase an inflammatory response of an organism than offer protection after LPS challenge. PMID- 22439332 TI - Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) mRNA levels in relation to the gastrointestinal tract (GIT) development in newborn calves. AB - The study was aimed at determining the age-depended changes in insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) mRNA levels in relation to the gastrointestinal tract (GIT) development in newborn calves. Twenty four male calves (5-day-old) were randomly allocated to 4 groups which were slaughtered at day 5, 12, 19 and 26 of their life, respectively. Tissue samples from the rumen, abomasum, duodenum, jejunum and liver were taken for analysis, and the level of IGF-1 and IGF-2 mRNA was determined using RT semi-quantitative PCR method. Both IGF-1 and IGF-2 mRNA level was the biggest on 5 day of life, significantly decreased up to day 12-19 in most of analyzed GIT parts, and started to increase thereafter. In the rumen the reduction in the amount of IGFs transcripts was associated with the reduction in papillae length and tunica muscularis thickness. The abomasum weight and tunica mucosa thickness increased from the 5 day up to 19 day of life, whereas abomasal IGF-1 mRNA level decreased together with calf's age up to 19 day of life, and the level of IGF-2 mRNA did not change. The reduction in IGFs mRNA level after 5 day of life in the duodenum (IGF-1 and IGF-2) and in the jejunum (IGF-1) was associated with reduction in villi length (duodenum and jejunum), and the increase of crypt depth (duodenum). PMID- 22439333 TI - Evaluation of commercial ELISA kits for the detection of antibodies against bluetongue virus. AB - The aim of this study was to estimate the diagnostic value of different commercially available ELISA kits for the detection of bluetongue virus (BTV) antibodies in infected and vaccinated animals. The relative specificity of ELISA kits was evaluated using a panel of sera originating from healthy cattle, never vaccinated nor exposed to BTV. All ELISA kits applied had a high relative specificity (99.3 - 100%). The relative sensitivity of ELISA kits assessed using a panel of sera collected from BTV infected cattle was also high and similar for all the kits (97.3 - 100%). However, the relative sensitivity evaluated on the basis of testing vaccinated animals was different: the highest sensitivity was found for Ingenasa, PrioCHECK and ID VET ELISAs (96.5 - 98.3%). Slightly lower sensitivity was calculated for Pourquier and LSI kits (82.8% and 85.4%, respectively) and much lower sensitivity was found for VMRD ELISA kit (69.5%). The repeatability of BTV ELISA kits was expressed as a coefficient of variation (CV) of results of sera tested 5 times in the same day and in different days by the period of 2 months, by the same person, in the same conditions, and by using the same equipment. The CVs of sera tested in all ELISA kits ranged from 6.1 to 9.8% and were below 10% threshold adopted as a maximum for the acceptable repeatability of the method. In conclusion, it can be stated that the applied ELISA kits can be a valuable diagnostic tool for the serological monitoring studies in the BTV contaminated premises. All the methods are very specific and sensitive when testing BTV infected animals. Nevertheless, the Ingenasa and PrioCHECK can be the most useful in sero-surveillance of livestock following vaccination. PMID- 22439334 TI - The penetration of topically applied ointment containing hyaluronic acid in rabbit tissues. AB - The properties of hyaluronic acid used for treatment of acute and chronic joint disease are known for many years and this compound is widely used both in humans and animals. To obtain a therapeutic effect of a certain drug, the appropriate concentration in the target organ or tissue is important. The application of labeled compounds is one of the frequently applied techniques to estimate drug penetration into the skin and other body tissues or organs. The aim of the study was to evaluate the penetration of hyaluronic acid labeled with I-131 through the skin and its distribution within the knee joint and other internal organs in rabbits after a topical application of an ointment containing hyaluronic acid. The experiment was performed on 22 albino rabbits divided into control and examined groups. Fifteen rabbits were exposed to the multicomponent ointment containing hyaluronic acid labeled with I-131. Time of exposure was 48 hours. Hyaluronate penetrated to a high degree into the examined tissues. No significant differences in terms of leg tissue activity were observed between a leg tissue exposed to labeled ointment and that unexposed, suggesting that after topical administration, the active component of the ointment is delivered to the joint via the blood stream. Hyaluronate applied topically penetrates through the skin into the rabbit tissues and organs and into the joint fluid of both legs (exposed and not exposed). This route of administration seems to be useful for this drug delivery and allows to avoid unnecessary side effects. PMID- 22439335 TI - The influence of alpha-tocopherol supplementation on plasma concentration of this vitamin and insulin in sedentary or physically trained rats. AB - Male young growing rats of Wistar strain (n = 54) were fed a vitamin E deficient diet for 3 days of adaptation period and then 10 days of experimental period. After adaptation half of the rats ran, once per a day, on a treadmill with a rate of 2.0 m/s for 15 minutes for the following 10 days. Animals were given orally 0, 0.5, 1.0 or 4.0 mg/d/rat of alpha-tocopherol. The aim of the study was to evaluate the influence of physical training on tocopherol and insulin concentrations in the blood plasma of rats treated with different doses of vitamin E. The concentrations of alpha-tocopherol (HPLC-UV method used) and insulin (rat insulin specific RIA method used) were estimated in the blood plasma. Lower concentration of vitamin E in physically trained animals was observed, which may suggest increased needs of organisms for antioxidants, as a result of increased free radical production. In trained rats a lower concentration of plasma insulin was also observed. This effect is probably related to improvement in insulin action observed in organisms under physical exercise. The most significant impact on plasma alpha-tocopherol was due to its supplementation level. The treatment of rats with different doses of alpha tocopherol was found to be not related to insulin concentration in plasma. A significant increase in feed conversion factor was noted in vitamin E treated animals. The obtained results suggest that the increased requirement of trained rats for antioxidants might be covered by alpha-tocopherol supplementation. PMID- 22439336 TI - Na+, K(+)-ATPase activity and ATP concentration in horses of the Wielkopolski breed in relation to age. AB - This study aimed at determining relationships between the age of the Wielkopolski horses, ATP in whole blood and in the erythrocytes, and between erythrocyte Na+, K(+)-ATPase activity, and serum concentrations of mineral components. ATP was measured in whole blood and in erythrocytes by HPLC method. Serum concentrations of Ca2+ and Mg2+ were measured spectrophotometrically, while Na+ and K+ by flame photometry. In horses aged from 4 to 48 months, a dynamic decrease in ATP activity was found. Erythrocyte Na+, K(+)-ATPase activity decreased proportionally with the decrease in ATP activity. The results of this study may enable planning physical effort of horses at optimum use of energetic efficiency of their erythrocytes and mineral components in relation to their age. PMID- 22439337 TI - The transcriptomic signature of myostatin inhibitory influence on the differentiation of mouse C2C12 myoblasts. AB - GDF8 (myostatin) is a unique cytokine strongly affecting the skeletal muscle phenotype in human and animals. The aim of the present study was to elucidate the molecular mechanism of myostatin influence on the differentiation of mouse C2C12 myoblasts, using the global-transcriptome analysis with the DNA microarray technique. Treatment with exogenous GDF8 strongly affected the growth and development of C2C12 mouse myoblasts. This was manifested by the inhibition of proliferation and differentiation as well as the impairment of cell fusion. DNA microarray analysis revealed 778 genes regulated by GDF8 in differentiating myoblasts (436 down-regulated and 235 up-regulated). Ontological analysis revealed their involvement in 17 types of biological processes, 10 types of molecular functions and 68 different signalling pathways. The effect of GDF8 was mainly mediated by the disruption of the cell cycle, calcium and insulin signalling pathways and expression of cytoskeletal and muscle specific proteins. The identified key-genes that could play a role as GDF8 targets in differentiating myoblasts are: Mef2, Hgf, Ilbl, Itgb1, Edn1, Ppargc1a. PMID- 22439338 TI - Phylogenetic analysis of bovine papillomavirus E5 detected in equine sarcoids in Poland. AB - The aim of the study was to analyse a part of the sequence of the E5 gene of bovine papillomaviruses (BPV) associated with equine sarcoids in Polish horses. Samples of 40 skin lesions obtained from 29 horses were collected for molecular examination. The PCR amplicons of BPV DNA were detected in 38 specimens. After phylogenetic analysis 37 specimens were recognized as BPV-1 and one as BPV-2. Phylogenetic analysis has allowed the classification of the amplicons into two phylogenetic groups (A1,) and four separate isolates (2, 10, 16, 17). PMID- 22439339 TI - Construction of a reporter system for Lactobacillus sp. using the gfpuv gene. AB - Lactobacilli are bacteria commonly associated with the gastrointestinal tract of animals and humans. They are able to produce antimicrobial substances such as bacteriocins, lactic acid and hydrogen peroxide, the factors which have been shown to be beneficial for controlling overgrowth of potentially pathogenic bacteria. For this reason lactobacilli are often applied in probiotics. The aim of present study was to construct a reporter strain based on the gfpuv expression system which can bee used as a strain with the ability to colonize the intestinal tract in future experiments. PMID- 22439340 TI - Autochthonous canine Dirofilaria repens in the vicinity of Warsaw. AB - In 2009 microfilaremia was recognized in ten dogs living in five distinct districts located near Warsaw, the capital of Poland. Based on PCR results, all the animals were found to be infected with Dirofilaria repens. Nine of the infected dogs have never travelled outside the country and it was assumed that the cases were native. Monitoring the infection in the European countries should be introduced to establish the actual geographic range of dirofilariosis. PMID- 22439341 TI - The influence of selected techniques of bovine leukocyte isolation on their viability and metabolism. AB - The aim of the study was to assess the effect of selected isolation methods on the viability and metabolism of bovine leukocytes. The cells were isolated using a Ficoll 1077, Histopaque 1083 gradient and osmotic shock method, and Ficoll or Histopaque with osmotic shock. Evaluation were made of the total number of cells, viability after isolation and in 24h culture on RPMI 1640 medium and metabolism with NBT reduction assay. Microscopic and cytometric evaluation of the leukocytes revealed that the isolation methods applied had an influence on their number and viability. Based on the results it can be concluded that isolation methods of cells in a Histopaque or Ficoll yield highly pure cell fractions with high viability. PMID- 22439342 TI - Porcine circovirus type 2 viremia and seroconversion in pigs from a farm affected by postweaning multisystemic wasting syndrome. AB - The aim of the study was to assess the usefulness of real-time PCR and serological methods as indicators of postweaning multisystemic wasting syndrome (PMWS) occurrence. Significantly higher level of porcine circovirus type 2 (PCV2) viral load in serum and significantly lower titre of specific antibodies in PMWS affected pigs indicated that combination of quantitative PCR and serological methods may support diagnosis of PMWS. PMID- 22439343 TI - Polymorphism in the promoter region of the tumor necrosis factor-alpha gene in cattle herds naturally infected and uninfected with the bovine leukemia virus. AB - The objective of this study was to describe and compare the genetic structure (TNF-alpha -position 824) of dairy cattle herds infected and not infected with the bovine leukemia virus (BLV). The results of the present study indicate that BLV-positive herds were characterized by similar genetic structure (TNF-alpha 824A/G). The genetic equilibrium in these herds was preserved, but a tendency to increased frequency of G/G homozygotes was found. The genetic structure of the healthy herd differed considerably from that of leukemic herds. PMID- 22439344 TI - A clinical evaluation of glass-fibre posts and restorative materials used for the reconstruction of fractured canines after one-step root canal treatment in cats. AB - This article describes a procedure for a one-step root canal treatment and the subsequent restoration of fractured canine teeth in cats. Standard glass fibre posts were used in the reconstruction of the teeth which were then divided into two groups and restored anatomically using two different composite materials. The procedures were successfully performed on six cats. The subject teeth were four upper and two lower canines. PMID- 22439345 TI - Real-time PCR detection of Mycoplasma felis in domestic cats suffering from chronic conjunctivitis (Poland). AB - Real-time PCR directed to intergenic spacer (IGS) noncoding region between 16S and 23S rRNA genes was used for species specific detection of Mycoplasma felis in conjunctival scrapings. Samples were collected from 57 cats suffering from chronic conjunctivitis in 2008-2010 (Wroclaw, Poland). Samples from 36 cats (63.2%) were shown to be positive for Mycoplasma felis. Our research gives a first insight in the occurrence of Mycoplasma felis among domestic cats in Poland suggesting that this pathogen may constitute an underestimated cause of chronic conjunctivitis. PMID- 22439346 TI - Sensitivity of skeletal muscle to pro-apoptotic factors. AB - In mononuclear cells, apoptosis leads to DNA fragmentation and cell destruction, regardless of the activated pathway. As regards multinuclear cells, e.g. skeletal muscle fibers, apoptosis rarely induces the death of the entire cell, and it generally affects single nuclei. This process, referred to as nuclear apoptosis, has a negative effect on the expression of genes in the myonuclear domain. Apoptosis may be initiated in muscle cells by external stimuli which activate cell membrane death receptors as well as by internal stimuli which stimulate the mitochondrial release of pro-apoptotic proteins. Reactive oxygen species also play an important role in the initiation of apoptosis. In muscle cells, ROS are produced in response to extracellular reactions or by cell mitochondria. It is, therefore, believed that mitochondria play a central role in apoptosis within skeletal muscle. Skeletal muscles have a well-developed system that protects them against oxidative damage. Myogenic stem cells are an integral part of multinucleated myofibers, and they are critically important for the maintenance of normal muscle mass, muscle growth, regeneration and hypertrophy. The latest research results indicate that myogenic cells are more sensitive to oxidative stress and pro-apoptotic factors than well-differentiated cells, such as myotubes. The complex structure and activity of skeletal muscle prompted research into the role of apoptosis and its intensity under various physiological and pathological conditions. This review summarizes the results of research investigating control mechanisms and the apoptosis process in skeletal muscle fibers, and indicates unresearched areas where further work is required. PMID- 22439347 TI - The effects of prenatal exposure to methylxanthines. AB - This review discusses epidemiology and laboratory studies on the effects of prenatal methylxanthine administration on some systems developing organisms. They are mainly absorbed from coffee, tea and cocoa products such as cola beverages and chocolate bars. Prenatal methylxanthine exposure can induce several unfavourables changes in the developing organism, which are persistent even in later phases of life. Based on results obtained from animal studies, the effect on embryogenesis is not only poorly understood but also controversial. It is therefore important to study interspecies differences as results may differ depending on animals used and administration methods. PMID- 22439348 TI - Retroviruses of wild and cultured fish. AB - Retroviruses comprise a large group of enveloped RNA viruses which have been found in a wide range of vertebrate species including fish. To date a number of fish retrovirus genomes have been partially or completely sequenced. Phylogenetic analysis and genome organization indicate a high diversity of fish retroviruses as well as some unique structural features that have not been found in any other retroviruses. Piscine retroviruses comprise both exogenous and endogenous viruses; most of them are associated with proliferative diseases. Because several of these proliferative diseases have a seasonal trend, they provide an excellent model for studying tumor development and regression. The aim of this work was to review the best-described fish retroviruses. PMID- 22439349 TI - Getting along. PMID- 22439350 TI - The red eye: information for ophthalmic nurses and technicians. PMID- 22439351 TI - The impact of vision loss from age-related macular degeneration: a review (Part 2). PMID- 22439352 TI - Usefulness of iris reactivity to light to determine the peak cycloplegia in hyperopic children. PMID- 22439353 TI - Corneal burns associated with phacoemulsification. AB - Corneal burns can have devastating surgical results. The surgical team in an ophthalmic operating room needs to be well trained on the phacoemulsification equipment and ophthalmic procedures. PMID- 22439354 TI - Vision screenings to identify eye issues in children and young adults. PMID- 22439355 TI - Chart smarts: benefit from better documentation. PMID- 22439356 TI - Tuberculosis. PMID- 22439357 TI - "Eyes of War" exhibit highlights ophthalmology's contributions during World War II. PMID- 22439358 TI - Bird watching. PMID- 22439359 TI - On-the-job ocular injuries. PMID- 22439360 TI - Targeting relevance: the challenges of interdisciplinary teaching and learning. PMID- 22439361 TI - Reporting of studies using animal and human subjects in APS journals: how the society protects authors from ethical minefields. PMID- 22439362 TI - IOM offers more guidelines for chimpanzee research; NIH to review its portfolio. PMID- 22439363 TI - NIH to adopt new guide January 1, 2012. PMID- 22439364 TI - APS comments on managing NIH resources. PMID- 22439365 TI - APS comments on the 21st century bioeconomy. PMID- 22439366 TI - Why in Oregon, and elsewhere, the AKF Premium Assistance Fund is needed. PMID- 22439367 TI - How APs can improve CKD education. PMID- 22439368 TI - Stories from the trenches: the first year experience with kidney disease education. PMID- 22439369 TI - Improving the fistula rate: the northwest renal network experience. AB - In November 2010, Northwest Renal Network was the first of the 18 ESRD Networks to reach the Fistula First goal of greater than 66% prevalent hemodialysis patients using an arteriovenous fistula (AVF). The network has sustained that goal over time and as of August 2011, has achieved an AVF rate of 67.7%. The Northwest Renal Network has been successfully motivating facilities to embrace change using thorough root cause analyses and targeted quality improvement projects throughout the Network's five-state region. PMID- 22439370 TI - This year's [political] forecast: rainy and sunny, hot and cold, windy and calm ... PMID- 22439371 TI - Medicare pilot program on bundled payments to health care providers could be the next PPS for dialysis. PMID- 22439372 TI - New focus for long term care accreditation program. PMID- 22439373 TI - Standards changes for ambulatory surgical centers that use deemed status. PMID- 22439375 TI - Errata: Reinstated decision rule for accreditation with follow-up survey in 2012. PMID- 22439374 TI - Clarification: Eligibility for advanced certification for palliative care. PMID- 22439377 TI - Making strides. Four ways to boost your walking workout. PMID- 22439376 TI - A rise at dawn. Why does blood glucose spike in the a.m.? PMID- 22439378 TI - Forward motion. The NBA's Gary Forbes scores on his dreams. PMID- 22439379 TI - Temptation strikes. What makes us crave foods--and how to fight back. PMID- 22439380 TI - From one to the next. Improvements in pancreas transplants offer new prospects. PMID- 22439381 TI - Spring greens. PMID- 22439382 TI - Kind-to- kidneys meal planning. Help damaged filters function at their best. PMID- 22439383 TI - Rapid responer. Volunteer is honored for his work after a tornado. PMID- 22439384 TI - Better care for PCOS. Studying women's genes to find out what works. PMID- 22439385 TI - Minding your financial house: a means to an end. PMID- 22439386 TI - Why each specialty needs its own coding audit form. PMID- 22439387 TI - How do you compensate nurse practitioners? PMID- 22439388 TI - The top 10 government issues for practice executives to watch in 2012. PMID- 22439389 TI - Getting ahead of the cost curve. PMID- 22439390 TI - Can bundling compensate physicians, align their interests and performance? PMID- 22439391 TI - Reach for the cloud: technology simplifies processes, manages finances. PMID- 22439392 TI - Physician scribes improve productivity. Oak Street Medical allows doctors to spend more face time with patients, improve job satisfaction. PMID- 22439393 TI - 5 steps to more timely payments. Patient counseling increases clinic collections by 40%. PMID- 22439394 TI - To 'EACH' its own incentive payment. New CCHIT program rewards groups with EHR systems. PMID- 22439395 TI - Reap what you sow. Group reaps millions in unpaid claims with claima dispute process. AB - Read the story of one group's efforts to recoup money owed from unpaid claims with a systematic approach. The partnership of emergency physicians, urgent care physicians and hospitalists recoups about $4 million annually from these efforts. PMID- 22439396 TI - Small-practice culture influences EHR success. Age of EHRs has not rendered post it notes extinct. AB - Reports indicate that physicians in small family practices have been slow to transition from paper records to EHRs, and case studies explain why. Learn from the experiences of three medical groups. PMID- 22439397 TI - Intellectual engagement stitch by stitch by stitch. PMID- 22439398 TI - Covariates of high-risk human papillomavirus (HPV) infections are distinct for incident CIN1, CIN2 and CIN3 as disclosed by competing-risks regression models. AB - BACKGROUND: In addition to the oncogenic human papillomavirus (HPV), several cofactors are needed in cervical carcinogenesis, but whether the HPV covariates associated with incident (i) CIN1 are different from those of incident (ii) CIN2 and (iii) CIN3 needs further assessment. OBJECTIVES: To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV covariates associated with incident CIN1, CIN2, and CIN3. STUDY DESIGN AND METHODS: HPV covariates associated with progression to CIN1, CIN2 and CIN3 were analysed in the combined cohort of the NIS (n = 3187) and LAMS study (n = 12,114), using competing-risks regression models (in panel data) for baseline HR HPV-positive women (n = 1105), who represent a sub-cohort of all 1865 women prospectively followed-up in these two studies. RESULTS: Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2, and CIN3, respectively. Among these baseline HR-HPV-positive women, the risk profiles of incident CIN1, CIN2 and CIN3 were unique in that completely different HPV covariates were associated with progression to CIN1, CIN2 and CIN3, irrespective which categories (non-progression, CIN1, CIN2, CIN3 or all) were used as competing-risks events in univariate and multivariate models. CONCLUSIONS: These data confirm our previous analysis based on multinomial regression models implicating that distinct covariates of HR-HPV are associated with progression to CIN1, CIN2 and CIN3. This emphasises true biological differences between the three grades of CIN, which revisits the concept of combining CIN2 with CIN3 or with CIN1 in histological classification or used as a common endpoint, e.g., in HPV vaccine trials. PMID- 22439399 TI - Expression of beclin 1, an autophagy-related protein, in human cervical carcinoma and its clinical significance. AB - PURPOSE: To investigate the impact of beclin 1 on prognosis of cervical cancer, we determined the expression of beclin 1 in cervical cancer, cervical intraepithelial neoplasia (CIN) and normal cervical tissues. METHODS: A total of 122 cases of cervical cancer, 35 cases with CIN and 31 cases with uterine fibroids were collected at the Cancer Center of Sun Yat University to determine the expression of beclin 1. RESULTS: Beclin 1 positive rate in normal cervical tissues, CIN tissues and cervical cancers was 83.9%, 74.3% and 53.3%, respectively, and it was significantly different between the three groups (p < 0.01). Beclin 1 expression was negatively correlated with cervical cancer differentiation, lymph node metastasis, recurrence and death (p < 0.05). The negative expression is the risk factor affecting overall survival (p < 0.05) and progression-free survival (PFS) (p < 0.05). Multivariate analysis showed that beclin 1 negative expression was an independent risk factor of PFS time. CONCLUSIONS: Beclin 1 may play a role in the occurrence and development of cervical cancer. Beclin 1 positive expression in patients indicates a better prognosis. PMID- 22439400 TI - Comparison of nerve content in removed parametrial tissue after classic radical hysterectomy and nerve-sparing radical hysterectomy--histologic evaluation. AB - PURPOSE OF INVESTIGATION: The aim of this study was to find whether nerve-sparing radical hysterectomy resulted in a lower amount of nerves in the removed parametrial tissue. METHODS: Histological specimens from nerve-sparing radical hysterectomy (28 cases) were compared with those obtained after classic radical hysterectomy (26 cases). Width of the parametria and vaginal cuff were measured. Using a point counting technique, nerve areal density was determined in cross sections of resected parametria at 0.5 cm (A), 1 cm (B), 1.5 cm (C) from the cervix. RESULTS: The width of the resected parametria was smaller in the study group (right side p < 0.013; left side; p < 0.011). The nerve areal density in the lateral part of the right parametrium was lower in the study group (p < 0.01) (Student's t-test). CCONCLUSION: Modified radical hysterectomy is less radical and is nerve-sparing. PMID- 22439401 TI - Comparison of tumor markers and clinicopathological features in serous and mucinous borderline ovarian tumors. AB - OBJECTIVE: The aim of this study was to assess tumor markers and clinicopathological findings of patients with serous and mucinous borderline ovarian tumor (BOT) features. METHODS: The study consisted of 50 patients that were diagnosed with and treated for BOT between 2005-2010 in three centers. CA125, CA19-9, and CA125+CA19-9 levels and clinicopathological features were compared in serous and mucinous histotypes. In serous and mucinous BOTs, correlations between tumor markers and demographics such as age, menopausal status, parity, clinical findings (stage, relapse, adjuvant chemotherapy, cytology, lymph node involvement and tumoral morphology (cystic-solid content, papilla, septation) were evaluated. RESULTS: There were no significant differences between serous and mucinous tumors in the clinicopathological features such as stage, tumor markers, age, menopausal status, or cytology. In serous BOTs we found a significant relation between elevated CA125+ CA19-9, CA19 9 and recurrence (p < 0.05). Also there was a significant relation between elevated CA125+ CA19-9, CA19-9 and cytology positivity (p < 0.05). We found a significant relation in serous BOTs between elevated CA125+CA19-9, adjuvant chemotherapy and lymph node metastases (p < 0.05). Also In mucinous BOTs with papilla formation we found a significant relation between elevated CA125 and CA125+ CA19-9 (p < 0.05). There was significant relation between cytology positivity and elevated CA19-9 in mucinous BOTs (p < 0.05). CONCLUSION: Serum tumor markers of serous and mucinous BOTs were different in relation to their clinicopathological features. This may reflect differences of serous and mucinous BOTs. PMID- 22439402 TI - Is magnetic resonance imaging useful in early evaluation of women on neoadjuvant chemotherapy for locally advanced cervical cancer? AB - OBJECTIVE: To evaluate the accuracy of magnetic resonance imaging (MRI) in staging cervical tumors after neoadjuvant chemotherapy (NACT). METHODS: 26 women, affected by locally advanced cervical cancer and triaged for surgery after NACT, were submitted to three cycles of neoadjuvant chemotherapy. All patients were submitted to MRI before and after NACT. We evaluated the MRI sensitivity and specificity in staging cervical tumors after chemotherapy, relating MRI findings after NACT with the pathological findings as the gold standard. RESULTS: In our series, MRI sensitivity was 58.8% and specificity was 66.7%. CONCLUSIONS: In our study MRI accuracy after NACT was lower than that of MRI used to stage patients with early cervical cancer scheduled for primary surgery, reported by the literature. MRI false negative cases are the major problem because of the delay in application of an effective therapy in non responders to NACT. PMID- 22439403 TI - 3D optical coherence tomography of cervical intraepithelial neoplasia--early experience and some pitfalls. AB - OBJECTIVES: To compare two different systems for optical coherence tomography for the diagnosis of cervical dysplasia and to assess potential benefits of three dimensional imaging. MATERIALS AND METHODS: OCT images were taken from unsuspicious and suspicious areas of fresh conisation specimens using two different imaging systems, one with the capability to produce three-dimensional images. All OCT images were separately evaluated by two blinded investigators based on a 6-grade classification (normal, inflammation, CIN 1, CIN 2, CIN 3, squamous carcinoma) and later compared to the corresponding histology. Sensitivity and specificity of OCT in detecting cervical dysplasia were determined. RESULTS: OCT images using both OCT systems were taken from 46 sites in ten conisation specimens and later compared to the corresponding histology. CIN lesions were diagnosed correctly by the two-dimensional OCT system with a sensitivity and specificity of 91% and 78% accordingly. Using the three dimensional system sensitivity and specificity were 82% and 86% accordingly. CONCLUSIONS: Both OCT systems used were highly sensitive in identifying cervical intraepithelial neoplasia. Despite technical problems experienced in the present series, we believe that three-dimensional imaging has the potential to further improve the accuracy of optical coherence tomography. PMID- 22439404 TI - Combination of fertility preservation strategies in young women with recently diagnosed cancer. AB - BACKGROUND/AIMS: The study describes clinical management and outcomes of currently available fertility preservation techniques in a set of 154 young female cancer patients. METHODS: Patients in reproductive age with newly diagnosed cancer were offered embryo or oocyte cryopreservation, ovarian tissue cryopreservation and the administration of GnRH analogues during chemotherapy. Particular attention was given to the technical aspects and clinical application of these fertility preservation techniques. RESULTS: During the study period (2004-2009), 154 young female cancer patients were offered fertility preservation counseling. Patient's average age was 29.4 years and average parity was 0.7 children. Administration of GnRH analogues (n = 123, 79.9%) and ovarian tissue cryopreservation (n = 15, 9.7%) were the most commonly used fertility preservation strategies. In 20 cases (16.1%), the combination of several fertility preservation techniques was offered to individually selected patients. CONCLUSIONS: Combination of fertility preservation techniques gives young cancer patients the best chance for future fertility and should be concentrated in specialized centers. PMID- 22439405 TI - Mammographic features in infertile women as a potential risk for breast cancer: a preliminary study. AB - The purpose of the present study was to evaluate breast mammographic features, particularly mammographic density in a selected population of infertile women and to assess if these women should be considered at higher risk for breast cancer. The prevalence of female infertility in Western countries is approximately 10-15% and since causes affecting the female are involved in 35-40%, concerns have developed about the future health of these women, specifically whether infertility could represent a risk factor for future cancer development. Moreover, infertility is now often treated with medication and procedures that could modify the hormonal environment and be cofactors in the cellular changes towards cancer development. Mammographic breast density is a useful marker for breast cancer risk and breast density is considered one of the strongest risk factors for breast cancer. Breast density is associated with known breast cancer risk factors such as reproductive and menstrual factors including serum estrogen and progesterone concentrations. In Italy the National Federation for Breast Cancer (FONCAM) guidelines suggest the usefulness of mammography from 35 years of age for women who undergo infertility hormone therapy (FONCAM Guidelines, 2005). According to this recommendation 294 women aged > or = 35, with primary infertility, sent to our breast service before joining an IVF program were recruited and then underwent clinical examination and X-ray mammography. Women were divided into two groups: dense breast (DB) and non-dense breast (NDB). Univariate analysis was employed to evaluate if there was an association between mammographic density and other risk factors. Evaluation of mammographic features showed the presence of BI-RADs C and D in the sample of 200 (68%) patients with DB and in 94 (32%) patients with NDB BI-RADS A and B. Univariate analysis showed that there were no statistically significant differences between the groups BD and NDB as regards age at mammography, age at menarche, BMI and family history for breast cancer, while ovulatory etiology of infertility was found to be associated with high mammographic density (p < 0.05). In conclusion, bearing in mind that 68% of our study sample had high breast density, we can assume that patients with primary infertility might represent a group at high risk for breast cancer, particularly if infertility is due to an ovulatory factor. We suggest breast screening from the age of 35 in infertile patients who undergo treatment with fertility drugs in accordance with FONCAM recommendations. This might allow the identification of higher risk patients who need more closely monitored breast examinations. PMID- 22439406 TI - Prognosis of primary peritoneal carcinoma: effect of cytoreductive surgery combined with neoadjuvant chemotherapy after laparoscopic diagnosis and evaluation: a multi-center trial. AB - OBJECTIVE: To evaluate the clinical outcome and prognosis of patients with primary peritoneal carcinoma (PPC) treated with cytoreductive surgery and neoadjuvant chemotherapy after laparoscopic diagnosis. MATERIAL AND METHODS: We retrospectively reviewed 29 patients with PPC, treated between March 2001 and June 2009 at three hospitals. All patients underwent laparoscopy to diagnose and evaluate whether they were good candidates for optimal cytoreductive surgery. After confirmed to be PPC histologically, the patients who were not suitable to undergo optimal cytoreductive surgery received chemotherapy for three to six cycles before operation, and then underwent cytoreductive surgery, followed with chemotherapy again for six cycles. The study included patient demographics, surgery procedures, surgery stage, pathologic findings, chemotherapy programs, and outcomes. RESULTS: The mean age of the 29 patients was 58.5 years. One patient was at Stage IIIB, 23 at Stage IIIC, and five at Stage IV. The rate of optimal cytoreductive surgery was 79.3%. At the time of this review, three patients had stable disease--two with progressive disease, eight were partial responders, and 16 were complete responders; 16 patients were alive without evidence of disease, seven were alive with disease, and six had died from disease. The mean and median overall survival time was 46 and 48 months. CONCLUSION: Combination of neoadjuvant chemotherapy and cytoreductive surgery after laparoscopic diagnosis and evaluation is effective in the treatment of patients with PPC. PMID- 22439407 TI - Could endometrial cytology be helpful in detecting endometrial malignancies? AB - This short communication assesses the concordance indexes between hysteroscopic biopsies and endometrial cytology for each endometrial pattern found in a sample of 37 women. Patients underwent endometrial cytology under sonographic guidance. The specimens were obtained with an endocervical brush and were fixed on slides (no liquid-based methods). After endometrial cytology, hysteroscopy with biopsy was performed. The best concordance index was found for endometrial malignancies, suggesting that endometrial cytology is able to detect cancers but not other endometrial diseases, as compared with endometrial hysteroscopic biopsies. Therefore, the overall concordance index suggests a fair concordance between histological and cytological findings. This leads us to conclude that usual endometrial cytology should not be recommended to screen endometrial diseases, but it may be used as an alternative diagnostic tool when hysteroscopic biopsies or other blinded procedures for endometrial sampling are unwanted, because it allows malignancies to be detected as well as hysteroscopic-guided biopsies. PMID- 22439408 TI - Evaluation of treatment results and prognostic factors in early-stage cervical carcinoma patients treated with postoperative radiotherapy or radiochemotherapy. AB - PURPOSE: To investigate the clinical features, prognostic factors, and treatment outcome in early-stage cervical carcinoma patients treated with postoperative radiotherapy (RT)/radiochemotherapy (RCT). METHODS: The records of 256 Stage IB and II cervical cancer patients treated with postoperative RT/RCT from 1992-2007 were retrospectively reviewed. Median age of the patients was 47 (range: 25-78). Two hundred one (78.6%) patients had squamous cell carcinoma and 29 (11.3%) had adenocarcinoma. One hundred and eighty-seven (73.0%) had FIGO Stage IB and 69 (27%) had Stage II disease. Concomitant cisplatin-based chemotherapy was administered to 47 (18.4%) patients. Metastatic lymph node ratio (MLNR), defined as number of metastatic lymph nodes divided by the number of dissected lymph nodes, was 0 in 142 (55.5%) patients, from 1% to 10% in 27 (10.5%) and > 10% in 31 (12.1%) patients. RESULTS: Median follow-up duration was 60.5 months (range: 6 202 months). Five-year locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS) rates were 90.8%, 83.4%, 91.2%, and 85%, respectively. In multivariate analysis; bulky tumor (> 4 cm) was shown as an important prognostic factor for LRC, DFS and DSS. Pretreatment hemoglobin level (< 10 g/dl) was associated with lower OS rate. Endometrial involvement was associated with lower LRC and DFS. Treatment break > 14 days showed significance for DFS and DSS. MLNR was found as a valuable prognostic factor for all endpoints (LRC, DFS, DSS and OS). The rate of grade 3-4 late toxicity was 3.6% and 2%, respectively. CONCLUSION: Postoperative RT/RCT is an effective treatment modality for early-stage cervical cancer patients with unfavorable features and provides satisfactory local control and survival rates with low morbidity. PMID- 22439409 TI - Small cell neuroendocrine carcinoma of the cervix: analysis of the prognosis and role of radiation therapy for 43 cases. AB - OBJECTIVE: To explore the outcomes and pattern of recurrence in patients with small cell neuroendocrine carcinoma of the cervix (SCNEC), and to determine the effects of adjuvant radiation therapy on survival in patients with early-stage disease. METHODS: A retrospective analysis of 43 patients with SCNEC was carried out at Zhejiang Provincial Tumor Hospital between January 1985 and August 2007. All pathological specimens were examined and definitively diagnosed by two independent pathologists. The radiotherapeutic efficacy and prognosis of SCNEC were explored. Patient survival status was analyzed with the Kaplan-Meier method and survival rate was compared with the log-rank test; p < 0.05 was considered statistically significant. RESULTS: Of 43 patients, 32 were early-stage and 11 were advance-stage. The median age was 45 years (range 25-85 years). There were 21 cases of metastasis or progression occurring in the lungs, retroperitoneal lymph node and brain within two years. In early-stage patients, distant metastasis or progression occurred in 13 cases within two years. The estimated 5 year survival rate for the entire group was 29%. Median overall survival for patients with early-stage disease was 89.6 months and 34.4 months for patients with advance-stage disease (p = 0.001). The 3-year survival for early-stage patients who received postoperative adjuvant chemotherapy was 57.1% compared with 56.4% for those who underwent adjuvant chemoradiotherapy, and their median survival periods were 84.7 and 89.1 months, respectively (p = 0.671). CONCLUSION: We confirmed the unfavorable prognosis related to early nodal and hematogenous metastasis in SCNEC, resulting in a relatively poor prognosis; clinical staging was an important prognostic factor. Chemoradiotherapy may be provided for advance stage patients. For early-stage patients, the efficacy and site of postoperative adjuvant radiotherapy need further evaluation. PMID- 22439410 TI - Possible effects of insulin-like growth factor-I, IGF-binding protein-3 and IGF 1/IGFBP-3 molar ratio on mammographic density: a cross-sectional study. AB - The purpose of this study was to examine the possible effects of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density and assess whether this relationship was similar in subgroups of pre- and postmenopausal women. A group of 341 Italian women of childbearing age or naturally postmenopausal who had performed mammographic examination at the section of radiology of our department a maximum three months prior to recruitment were enrolled. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio was calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). To assess the association between mammographic density and IGF-1, IGFBP-3 and Molar ratio Student's t-test was employed before and after stratified by menopausal status. The analysis of the relationship between mammographic density and plasma levels of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group whereas IGFBP-3 showed similar values in both groups (DB and NDB). After stratification of the study population by menopausal status, no association was found. Our study provides strong evidence of a crude association between breast density, and plasma levels of IGF-1 and molar ratio. IGF-1 and molar ratio might increase mammographic density and thus the risk of developing breast cancer. PMID- 22439411 TI - Alterations in the mortality and growth cycle of cervical cancer cells treated with electroporation at different electric strengths. AB - OBJECTIVE: To explore the biological effects of electric fields of various strengths on Hela cells. METHODS: Electroporation experiments were performed using Hela cells. Changes in cell mortality, cell vitality, cell cycle, and apoptosis status were examined. In addition, temperature changes in the surrounding tissue were measured. RESULTS: Cell proliferation was markedly inhibited after treatment with field strengths of 2-2.5 kV/cm. The expression of caspase-3 increased significantly in cells treated with field strengths of 1.5 2.5 kV/cm. Field strengths of 1.75-2.5 kV/cm produced complete cancer cell ablation. G2 phase frequency increased significantly after treatment with field strengths of 2-2.5 kV/cm. During this process, the maximum temperature increase in the pulsed electric field was 4.9 -/+ 1.17 degrees C under free air convection. CONCLUSIONS: IRE can be used alone for the treatment of cancer, and its thermal effect is negligible. Cell death was caused by the effects of IRE and apoptosis. The tumor cells must be destroyed completely, or the altered cell cycle may lead to tumor recurrence and accelerated growth. PMID- 22439412 TI - Retrospective study comparing irinotecan and pegylated liposomal doxorubicin in treatment of recurrent platinum-refractory/resistant epithelial ovarian cancer. AB - PURPOSE: The standard regimen for platinum-resistant/refractory recurrent epithelial ovarian cancer (EOC) remains to be determined. In this study, we retrospectively compared the effect of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in the treatment of platinum-resistant recurrent EOC. METHODS: Thirty patients who received salvage chemotherapy with CPT-11 or PLD were included in the study. CPT-11 (100 mg/m2) was administered intravenously on days 1, 8 and 15 every four weeks. PLD (50 mg/m2) was administered on day 1 every four weeks. Treatment was repeated, provided that no disease progression or intolerable toxicity occurred. RESULTS: Response rate in the CPT-11 group and PLD group showed no difference at 26.7% (p = 0.66) in both, while non-PD rate was 73.3% vs. 33.3% (p < 0.05), respectively. Progression-free survival after CPT-11 treatment and PLD treatment was 28.4 weeks and 16.8 weeks (p = 0.07), respectively. Hand-foot syndrome and mucositis were more common in the PLD group than in the CPT-11 group (p < 0.05). CONCLUSIONS: The results indicate that CPT 11 is a promising drug for the treatment of platinum-resistant recurrent EOC. PMID- 22439413 TI - Immunohistochemical evaluation of a new epithelial antigen, BER-EP4 in ovarian cancer: a propos of 62 cases. AB - OBJECTIVE: To assess the immunohistochemical expression of BerEP4, a new epithelial antigen in ovarian cancer. METHODS: We studied 62 cases of ovarian cancer in which BerEP4, CEA and CA-125 were investigated by an immunohistochemical method. We evaluated the correlations among immunohistochemical positivity and the grading, histotype and stage of disease. RESULTS: BerEP4 was positive in 45 out of 62 cases (72.58%), CA-125 in 36 out of 62 cases (58.06%) and CEA in ten out of 62 cases (16.13%). BerEP4 was present both in serous and in mucinous tumors (80.96% vs. 80.77%). CA-125 was mainly expressed in serous vs mucinous tumors (66.67% vs. 57.69%). CEA was more prevalent in mucinous vs. serous tumors. Ber-EP4 was mainly expressed in G1 (75%) and G2 (77.27%). CA-125 was more present in G1 and G3 (both 62.50%) than G2 (50%), whereas CEA showed positivity in G1: 12.50%, G2: 22.73% and G3: 12.50%. There were no differences among the three antigens studied with regard to clinical stage. CONCLUSIONS: In our study Ber-EP4 was positive in 45 out of 62 cases (72.58%) of primary epithelial ovarian cancers. The presence of this antigen seemed to be related to the histotype and grading but not to clinical stage. PMID- 22439414 TI - Outcomes of conservative surgery in early epithelial ovarian carcinoma. AB - OBJECTIVE: To investigate clinical outcomes and fertility status of conservative treatment for epithelial ovarian carcinoma. METHODS: The data of clinicopathological characteristics and follow-up were retrospectively collected and analyzed in 17 patients with early epithelial ovarian carcinoma who underwent conservative surgery. RESULTS: The tumor histologic types of 17 patients included 13 mucinous, one serous, one endometrioid, and two mixed mucinous and serous carcinomas. The FIGO stages were: ten Stage IA, six IC, and one IIIA disease. Tumor grades involved 15 grade 1 and two grade 2. Sixteen patients received adjuvant platinum-based combined chemotherapy. The medium duration of follow-up was 61 months (range 17-115 months). Only one patient recurred at 36 months after primary surgery. All of the 17 patients were alive at end of follow-up. Eight patients attempted pregnancy and five patients conceived naturally; there were six term pregnancies and one abortion. CONCLUSION: Conservative surgery can be considered for young patients with FIGO Stage I including grade 1 and grade 2 epithelial ovarian cancers who desire further childbearing. PMID- 22439415 TI - Desmoplastic small round cell tumor (DSRCT) arising in the ovary: report of a case diagnosed at an early stage and review of the literature. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma tumor affecting mainly young adult males. It rarely has an ovarian involvement. CASE: A 29-year-old woman presented to her gynecologist for amenorrhoea. The laboratory results demonstrated a menopausal status and the ultrasound revealed a large mass of the right ovary. The right ovary was completely removed by laparoscopy. Pathology, cytology and immunochemistry revealed a DSRCT. In January 2009 a left salpingo-oophorectomy and a right salpingectomy were performed via laparoscopy. After 35 months from diagnosis there was no clinical evidence of disease recurrence. CONCLUSION: DSRCT is a rare ovarian tumor in adolescence with a general poor outcome. Every ovarian mass regardless of age should be approached with caution. PMID- 22439416 TI - Peritoneal mesotheliomas mimicking adnexal tumors. Clinicopathological characteristics of four cases and a short literature review. AB - Three cases of peritoneal benign cystic mesotheliomas in women 32-34 years of age and one case of peritoneal malignant mesothelioma in a 47-year-old woman are reported. All cases presented with abdominal discomfort and/or pain and the physical and radiological diagnostic methods showed adnexal tumors. The cystic mesotheliomas developed in the cul-de-sac and the right pelvic sidewall, presented as multiple small cysts or large multilocular cystic mass. The malignant mesothelioma showed extensive infiltration of the omentum the intestinal loops and the surface of the uterus and adnexa, with bilateral hydrosalpinx and ascites. All cases presented histological and immunohistochemical characteristics consistent with tumors of mesothelial origin. No history of asbestos exposure was reported. The correct diagnostic and therapeutic approaches to these neoplasms are discussed. PMID- 22439417 TI - Perivascular epithelioid cell tumor (PEComa) of gynecologic origin: a clinicopathological study of three cases. AB - Perivascular epithelioid cell tumors (PEComas), occasionally associated with the tuberous sclerosis complex, are characterized by varying amounts of spindle and epithelioid cells with clear to eosinophilic cytoplasm that display immunoreactivity for melanocytic markers, most frequently HMB-45. Perivascular epithelioid cell tumor of gynecologic origin is very rare, and there have been only a few reported cases. This study describes the clinical, histological, and immunohistochemical features and prognoses of three cases of gynecologic origin. Two of the three tumors were confined to the uterus and one to the vagina. None of the patients had tuberous sclerosis complex. Immunohistochemistry indicated that all three cases expressed at least one melanocytic marker, and HMB45 was a positive marker for all of them. These markers can be found in both epithelial cells and spindle cells. Except for MiTF, which was located in the nucleus, all the other antibodies were located in the cytoplasm. The three cases have been followed up for 26, 22, and three months, respectively, with disease-free survival in all cases. We conclude that PEComas of gynecologic origin have morphological and immunohistochemical features of the PEComa family, which are rare and should be included in the differential diagnosis with other tumors. Until more cases of this rare tumor are evaluated with longer follow-up, firm criteria for malignancy remain uncertain. PMID- 22439418 TI - Primary gynaecological tumours mistaken for metastases: report of two cases with review of literature. AB - We describe two neoplasms of rare occurrence, one of ovarian and the other of uterine origin that were sent for consultation. Both lesions were diagnosed as metastatic carcinomas by pathologists with special interest in gynaecological pathology. The cases were referred for a second opinion because of subsequent failure to identify the primary source. We discuss the differential diagnoses, the need for generous sampling particularly in ovarian mucinous neoplasms and the value of including particular antibodies in the panel to aid the diagnostic process. Metastatic tumours mimicking primary tumours are always challenging. These two cases illustrate the need to be vigilant against the reverse scenario as well. PMID- 22439419 TI - Rare metastases of pancreatic tail carcinoma in female genital organs. AB - A case is presented of pancreatic tail carcinoma metastasizing to the uterus, right ovary and right sacrouterine ligament 2.5 years after the primary tumor had been detected and treated. During explorative laparotomy, performed after 3D color Doppler ultrasonographic visualization of a suspected finding in the right adnexal region, metastatic deposits in the uterus, right ovary, right sacrouterine ligament and right ureter originating from the primary adenocarcinoma of the tail of the pancreas were detected and surgically removed. PMID- 22439420 TI - Atypical polypoid adenomyoma of the uterus. A case report and a review of the literature. AB - Atypical polypoid adenomyoma (APA) is a rare, benign lesion. The tumor occurs in nulliparous women aged 22-48 years (average 33 years) and it has been suggested as being related to prolonged estrogenic stimulation. We describe a case of a 72 year-old woman who presented at our hospital with persistent, worsening urinary incontinence and pelvic pain. Physical examination and pelvic ultrasound disclosed uterine enlargement, a mass in the endometrial cavity and multiple small myomas. Total hysterectomy with bilateral salpingo-oophorectomy was performed. The histological diagnosis for the mass of the endometrial cavity was atypical polypoid adenomyoma. APA should be distinguished from endometrial carcinoma and other malignant uterine neoplasms such as adenofibroma, adenosarcoma and malignant mixed mullerian tumor. The immunohistochemical panel which usually includes alpha smooth muscle actin, desmin, Ki67 and recently CD10 is often helpful in establishing the diagnosis. The treatment may vary depending on the patient's age, her desire to preserve fertility, and the severity of her symptoms. PMID- 22439421 TI - Haematozoans from deep water fishes trawled off the Cape Verde Islands and over the Porcupine Seabight, with a revision of species within the genus Desseria (Adeleorina: Haemogregarinidae). AB - Archived blood smears from 32 of 113 fishes in 18 families and 12 orders, trawled from deep North Atlantic waters off the Cape Verde Islands in 1999 and over the Porcupine Seabight in 2001 were found to harbour haematozoans. These included four species of haemogregarines (Adeleorina, Haemogregarinidae) and a species of trypanosome (Trypanosomatina, Trypanosomatidae) located in Porcupine Seabight fishes. Also present were Haemohormidium-like structures of uncertain status found in samples from this location and from the Cape Verde Islands. Although material was limited, two of the haemogregarines were provisionally named Desseria harriottae sp. n. from Harriotta raleighana Goode et Bean (Chimaeriformes, Rhinochimaeridae), and Haemogregarina bathysauri sp. n. from Bathysaurus ferox Gunther (Aulopiformes, Bathysauridae). The two remaining haemogregarines were identified as Desseria marshalllairdi (Khan, Threlfall et Whitty, 1992) from Halosauropsis macrochir (Gunther) (Notacanthiformes, Halosauridae), and Haemogregarina michaeljohnstoni (Davies et Merrett, 2000) from Cataetyx laticeps Koefoed (Ophidiformes, Bythitidae). The name H. michaeljohnstoni was proposed to replace Haemogregarinajohnstoni Davies et Merrett, 2000 from C. laticeps and to avoid confusion with Hepatozoon johnstoni (Mackerras, 1961) Smith, 1996 from varanid lizards, originally named Haemogregarina johnstoni Mackerras, 1961. The trypanosome formed a mixed parasitaemia with D. harriottae in H. raleighana and was provisionally named Trypanosoma harriottae sp. n. No blood parasites had been described previously from cartilaginous fishes of the Holocephali, making the finds in H. raleighana unique. Haemohormidium-like structures were located in erythrocytes in one fish, Coryphaenoides armatus (Hector), among the Cape Verde Islands samples and in 12 species of fishes from the Porcupine Seabight; all these hosts were bony fishes. Finally, the haemogregarine species listed in the genus Desseria Siddall, 1995 were reassessed. Of the original list of 41 species, 30 were retained and 5 species added, including D. harriottae, so that the genus now contains 35 species. PMID- 22439422 TI - A new species of Choleoeimeria (apicomplexa: eimeriidae) from oustalet's chameleon, Furcifer oustaleti (Sauria: Chamaeleonidae). AB - One of three (33%) captive specimens of Oustalet's chameleon, Furcifer oustaleti (Mocquard) originally from Madagascar and housed at the Oklahoma City Zoological Park Herpetarium, Oklahoma County, Oklahoma, USA, was found to be passing an undescribed species of Choleoeimeria in its faeces. Oocysts of Choleoeimeria fischeri sp. n. were cylindroidal, 30.3 x 16.8 (28-34 x 15-18) microm, with a smooth, bilayered wall and a length/width ratio (L/W) of 1.8. A micropyle and oocyst residuum was absent but a fragmented polar granule was often present. Sporocysts were ovoidal, 9.6 x 8.0 (9-10 x 7-9) jm, with an L/W of 1.2. Stieda, sub-Stieda, and para-Stieda bodies were absent. The sporocyst residuum consists of large globules dispersed between sporozoites. Sporozoites were elongate, 8.6 x 2.9 (8-10 x 2-3) microm, with an elongate posterior refractile body. The new species represents the second coccidian described from this lizard. PMID- 22439423 TI - Genetic characterisation of Giardia duodenalis in dairy cattle in Brazil. AB - The intestinal protozoan parasite Giardia duodenalis (Lambl, 1859) Kofoid & Christiansen, 1915 [syn. Giardia intestinalis and Giardia lamblia] has emerged as a widespread enteric pathogen in humans and domestic animals. In recent years, G. duodenalis has been found in cattle worldwide and longitudinal studies have reported cumulative prevalence of 100% in some herds. In the present study, we determined the prevalence and genetic characterisation of G. duodenalis in 200 dairy cattle from 10 dairy farms in Sao Paulo state, Brazil. All faecal specimens were screened for the presence of G. duodenalis using microscopy examination, enzyme immunoassay (EIA) and polymerase chain reaction (PCR). DNA was extracted from faecal samples and G. duodenalis were identified by amplification of the small subunit ribosomal (SSU-rDNA) and glutamate dehydrogenase (GDH) genes followed by restriction fragment length polymorphism (RFLP) or sequencing analysis. Giardia was identified in eight farm locations (80% prevalence). Overall, 15/200 (7.5%) animals were positive for infection, only one of which was a cow. Giardia duodenalis genotype E was present in 14 of the animals tested. Zoonotic genotype AI was present in one positive sample. Genotype E and genotype A represented 93% and 7% of G. duodenalis infections, respectively. This study demonstrates that G. duodenalis infection was prevalent in dairy calves in Sao Paulo state and that the non-zoonotic genotype E predominates in cattle in this region. Nevertheless, calves naturally infected in Brazil can shed Giardia cysts that can potentially infect humans, and thus, they may represent a public health risk. PMID- 22439424 TI - Urine sample used for detection of toxoplasma gondii infection by loop-mediated isothermal amplification (LAMP). AB - In this study, a loop-mediated isothermal amplification (LAMP) assay was established to detect Toxoplasma gondii DNA in mice infected with T. gondii PRU strain. This LAMP assay was based on the sequence of highly repetitive B1 gene. The detection limit of T. gondii LAMP assay was 1 pg of T. gondii DNA, which was evaluated using 10-fold serially diluted DNA of cultured parasites. The LAMP assay was also highly specific for T. gondii and able to detect T. gondii DNA in urine of mice treated with dexamethasone at 90 day post infection (p.i.), although this assay could not detect the DNA in mice urine 2-6 days p.i. These results demonstrated that LAMP is effective for evaluation of therapy effectiveness for T. gondii infection. The established LAMP assay may represent a useful and practical tool for the routine diagnosis and therapeutic evaluation of human toxoplasmosis. PMID- 22439425 TI - Redescription of Eimeria dorcadis Mantovani, 1966 (Apicomplexa: Eimeriidae) from the dorcas gazelle (Gazella dorcas) in Saudi Arabia. AB - Eimeria dorcadis Mantovani, 1966 is redescribed from dorcas gazelle (Gazella dorcas (L.)) from Saudi Arabia. Oocysts were detected in 7 out of 22 faecal samples (32%) using floatation method. The sporulated oocysts are cylindrical, slightly flattened at the micropylar pole, measure in average 32 x 19 microm (27 36 x 16-24 microm), length/width ratio being 1.7 (1.5-2.1). Oocyst wall is 1.2 microm thick, smooth, double-layered; outer layer is slightly thicker, light blue in colour; inner layer brownish, with micropyle in the inner layer and apparently continual outer one, measures 2.2 microm, but lacks a micropylar cap. The sporocyst elongate-ellipsoidal, measures 14 x 8 microm (12-17 x 6-9 microm), length/width ratio being 1.8, with sporocyst residuum as circular compact, coarse, refractile granules. Stieda body is present, while substieda body is absent. Sporozoites banana-shaped, measure 11 x 2.5 microm, each with a large spheroidal refractile body at the wider pole. Sporulation time is 2-3 days at 25 +/- 2 degrees C. PMID- 22439426 TI - Spermiogenesis and spermatozoon of the liver fluke Mediogonimus jourdanei (Microphalloidea: Prosthogonimidae), a parasite of Myodes glareolus (Rodentia: Cricetidae). AB - Spermatological characters of the liver fluke Mediogonimus jourdanei Mas-Coma et Rocamora, 1978 were studied by means of transmission and scanning electron microscopy. Spermiogenesis begins with the formation of the differentiation zone containing two centrioles associated with striated rootlets and an intercentriolar body. These two centrioles originate two free flagella that undergo a 90 degrees rotation before fusing with the median cytoplasmic process. Both nuclear and mitochondrial migrations toward the median cytoplasmic process occur before the proximodistal fusion of flagella. Finally, the constriction of the ring of arched membranes gives rise to the young spermatozoon. The mature sperm of M. jourdanei measures about 260 microm and presents two axonemes of different lengths with the typical pattern of the Trepaxonemata, two bundles of parallel cortical microtubules, one mitochondrion, a nucleus and granules of glycogen. An analysis of all the microphalloidean species studied to date emphasised some differences in certain characters found in Maritrema linguilla Jagerskiold, 1908 and Ganeo tigrinum Mehra et Negi, 1928 in comparison to those in the remaining microphalloideans. The presence and variability of such ultrastructural characters according to family, superfamily or order have led several authors to propose their use in the analysis of trematode relationships and phylogeny. Therefore, apart from producing new data on the family Prosthogonimidae, the present study also compares the spermatological organization of M jourdanei with other available ultrastructural studies focusing on the Microphalloidea. PMID- 22439427 TI - Histochemical demonstration of five enzymes' activities in Macrogyrodactylus clarii (Monogenea: Gyrodactylidae) from the catfish Clarias gariepinus. AB - Histochemical techniques were applied to whole mounts, to study the distribution of the enzymes alkaline phosphatase, acid phosphatase, adenosine triphosphatase, 5'-nucleotidase and glucose-6-phosphatase in the organs and tissues of a viviparous monogenean, Macrogyrodactylus clarii Gussev, 1961, from the gills of the North African catfish Clarias gariepinus (Burchell) in Egypt. The following organs and tissues were studied: head region, anterior adhesive glands, mouth region, pharynx, intestine, testis, vesicula seminalis, male accessory gland, male accessory reservoir, copulatory organ, receptaculum seminis, egg-cell forming region, embryonic cells, excretory system, nerve cells, haptor, muscle fibres and subtegumental cell bodies (cytons). The enzymes showed marked differences in their activities among the studied organs and tissues. Alkaline phosphatase and acid phosphatase activities were detected in many organs and tissues, while the activities of adenosine triphosphatase, 5'-nucleotidase and glucose-6-phosphatase were restricted to a few organs. Although no positive reaction for any enzyme was observed in the anterior adhesive gland cells, a positive reaction for acid phosphatase was detected in the anterior adhesive areas. All enzymes showed marked activity in the digestive and excretory systems. The distribution of the enzymes in the tissues and organs of M clarii is compared with those of other monogeneans, including other gyrodactylids parasitizing the same host fish. Some possible functions of the enzymes are discussed. PMID- 22439428 TI - The microecology of dactylogyrids (Monogenea: Dactylogyridae) on the gills of wild spotted rose snapper Lutjanus guttatus (Lutjanidae) from Mazatlan Bay, Mexico. AB - The spatial distribution and coexistence of monogenean dactylogyrids was assessed on the gills of 63 specimens of wild spotted rose snapper, Lutjanus guttatus (Steindachner), caught in the Mazatlan Bay, Sinaloa, Mexico. Five species are reported: Euryhaliotrema perezponcei Garcia-Vargas, Fajer-Avila et Lamothe Argumedo, 2008, Euryhaliotrematoides sp., Haliotrematoides spinatus Kritsky et Mendoza-Franco, 2009, H. plectridium Kritsky et Mendoza-Franco, 2009, and H. guttati Garcia-Vargas, Fajer-Avila et Lamothe-Argumedo, 2008. All except E. perezponcei and H. guttati represent new geographical records for the Pacific coast. The most prevalent dactylogyrid species was E. perezponcei (100%), H. plectridium and H. spinatus had > 80% prevalence, and H. guttati and Euryhaliotrematoides sp. had the lowest prevalence. The mean abundance of H. plectridium and E. perezponcei was close to 60 parasites/fish, whereas Euryhaliotrematoides sp. and H. guttati had the lowest abundance. The dactylogyrid species exhibited a tendency for attachment to gill arch 2: 25% attachment occurring on gill arch 1, 30% on 2, 27% on 3 and 18% on 4, and showed a significant preference for the central sector of the gill (42%). Haliotrematoides plectridium had a preference for attachment to gill arches 2 and 3 and the central sector. Haliotrematoides spinatus tended to settle on the gill arches 2 and 3 and had a preference for the central sector. Euryhaliotrema perezponcei tended to settle on the gill arches 1 and 2 and the anterior gill sector. Euryhaliotrematoides sp. and H. guttati did not show a preference for any gill arch or sector. The intraspecific aggregation was stronger than the interspecific aggregation, indicating that all the dactylogyrid species on spotted rose snapper were aggregated, and there was no evidence of competition among the species. PMID- 22439429 TI - Two new species of protogyrodactylus (Monogenoidea: Dactylogyridae) from the gills of Gerres nigri (Teleostei: Gerreidae) from Senegal. AB - Protogyrodactylus ethiopicus sp. n. and P. kritskyi sp. n. are described from the gills of Gerres nigri Gunther (Gerreidae, Perciformes) captured from the estuary of the Sine-Saloum River (Senegal, West Africa). These new species differ from previously described species within the genus by a mid- or dextro-ventral vaginal opening (dextral in all other species). They are part of a morphological species group within Protogyrodactylus Johnston et Tiegs, 1922 that has the tip of the superficial root of the ventral anchor resembling a hook and two anterior projections on the anterior margin of the ventral bar. Protogyrodactylus ethiopicus differs from the remaining species in this group mainly by the morphology of the base of the male copulatory organ (MCO), which is disk-shaped, and the shape of the anterior projections of the ventral bar (round in the new species and relatively elongate in the other species of the group). The other new species, P. kritskyi, differs from all others in the same morphological group in having a MCO with a greatly expanded base that bears a heel-like subterminal sclerotization. PMID- 22439430 TI - A new species of Neoascarophis (Nematoda: Cystidicolidae) parasitic in Mullus argentinae (Perciformes: Mullidae) from the Atlantic coast of South America. AB - A new nematode species (Neoascarophis mariae n. sp.) is described based on specimens collected from the Argentine goatfish Mullus argentinae (Hubbs et Marini) from coastal waters off the state of Rio de Janeiro, Brazil. In the genus, the new species belongs to the group of species with females that have the vulva near the posterior end of the body. Only males of Neoascarophis longispicula Moravec et Klimpel, 2009 are known and can be distinguished from those of the new species by their larger body, developed and somewhat dorsoventrally expanded flat inner part of the pseudolabia, bifurcate deirids and larger spicules (the left one with a rounded tip) with a different length ratio. Other species with females that have the vulva near the equatorial region are N. yarihige Machida, 1976 and N. bathygadi Machida, 1976. Both males and females of N. yarihige are longer than those of the new species and have a shorter vestibule; males have shorter spicules with a different length ratio. Neoascarophis bathygadi is the only member of the genus that shares the presence of a cephalic vesicle with the new species, which, however, is shorter and arises at 40 microm from the anterior end instead from the deirids, as in the new species. Both males and females of N. bathygadi are also longer than those of the new species and have a shorter vestibule; males have a larger left spicule, but shorter right spicule and a different length ratio. Ascarophis upeneichthys Johnston et Mawson, 1945, a parasite ofa mullid host, is transferred to Neoascarophis Machida, 1976 and is distinguished from the new species by having a shorter vestibule in females and shorter spicules (left spicule with a pointed tip) with a different length ratio in males. PMID- 22439431 TI - Two species of philometrid nematodes (philometridae) from marine fishes off Japan, including Philometroides branchiostegi sp. n. from Branchiostegus japonicus (malacanthidae). AB - Gravid females of two species of philometrid nematodes (Philometridae) were collected from marine perciform fishes in Japanese waters, mainly from the southern Sea of Japan. Based on light microscopy and scanning electron microscopy examinations, the previously described but poorly known species Philometra cryptocentri Yamaguti, 1961 is redescribed from specimens recovered from the abdominal cavity of Acanthogobius flavimanus (Temminck et Schlegel), Pterogobius elapoides (Gunther) and P. zonoleucus Jordan et Snyder (all Gobiidae) (all new host records); the number (14) and arrangement of cephalic papillae in this species are described for the first time. The new species, Philometroides branchiostegi sp. n. from head tissues of Branchiostegus japonicus (Houttuyn) (Malacanthidae), based on a single specimen, is mainly characterized by the embossment of the entire body except for the cephalic end, presence of four submedian pairs of large cephalic papillae of external circle and two small lateral single papillae of internal circle, pair of large papilla-like caudal projections, the oesophagus with a distinct anterior inflation, by a markedly small body (length about 18 mm) and the larvae 306-465 microm long. PMID- 22439432 TI - Antiviral activity of crude extracts of Eugenia jambolana Lam. against highly pathogenic avian influenza (H5N1) virus. AB - Crude extracts of leaves and bark of E. jambolana were tested for antiviral activity against highly pathogenic avian influenza virus (H5N1) by CPE reduction assay in three different layouts to elucidate virucidal, post-exposure and preexposure antiviral activity of the extracts. The cold and hot aqueous extracts of bark and hot aqueous extract of leaves of E. jambolana showed significant virucidal activity (100% inhibition) which was further confirmed in virus yield reduction assay (-98 to 99% reduction) and by egg based in ovo assay. The selective index (CC50/EC50) of hot aqueous extract (248) and cold aqueous extract (43.5) of bark of E. jambolana showed their antiviral potential against H5N1 virus. The significant virucidal activity of leaves and bark of E. jambolana merits further investigation as it may provide alternative antiviral agent for managing avian influenza infections in poultry farms and potential avian-human transmission. PMID- 22439433 TI - Anti-tumor activity of rosmarinic acid in 7,12-dimethylbenz(a)anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. AB - Aim of the present study was to evaluate the anti-tumor effect of orally administered rosmarinic acid in 7,12-dimethylbenz(a)anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. Phase I and II detoxication agents, lipid peroxidation byproducts, antioxidants and apoptotic biomarkers were used to assess chemopreventive efficacy of rosmarinic acid in DMBA induced skin carcinogenesis. Skin squamous cell carcinoma was induced at the shaved back of mice by applying DMBA (20 microg in 0.1 mL acetone) twice weekly for 8 weeks. Tumor formation (100%) was observed within 15 weeks of treatment in DMBA alone. Marked alterations in the status of above mentioned biomarkers were observed in tumor bearing mice. Oral administration of rosmarinic acid completely prevented the formation of skin tumors during DMBA-induced mouse skin carcinogenesis. Also, oral administration of rosmarinic acid brought back the status of phase I and phase II detoxication agents, lipid peroxidation byproducts, antioxidants and apoptotic markers (p53, Bcl-2, caspase-3 and caspase-9) in DMBA treated mice. Results of the present study suggested that rosmarinic acid had potent anticancer, anti-lipid peroxidative and apoptotic effect in DMBA-induced skin carcinogenesis. PMID- 22439434 TI - Protective effect of triphala on radiation induced acute intestinal mucosal damage in Sprague Dawley rats. AB - Aim of the study was to determine protective effect of triphala on radiation induced rectal mucosal damage. Male Sprague Dawley rats (30) were divided into 5 groups. Rats in group A were sham irradiated and rats in group B underwent only irradiation. Rats in group C were administered triphala 1 g/kg/day orally for 5 consecutive days before irradiation. Rats in group D and E were administered triphala 1 and 1.5 g/kg/day orally for 10 consecutive days, respectively. Rectal mucosal damage was induced by a single fraction of 12.5Gy gamma irradiation (Ir 192) on 5th day. All the rats were autopsied on 11th day and histological changes in surface epithelium, glands, and lamina propria were assessed. Proctitis showed significant improvement in surface epithelium (P < 0.024), glands (P < 0.000) and lamina propria (P < 0.002) in group E compared to group B. Rats in group E showed significantly less change in glands (P < 0.000) compared to rats in group D, All histological variables (surface epithelium, P < 0.001; glands, P < 0.000; lamina propria, P < 0.003) compared to rats in group C. In a Tukey-b test, group E had a significantly recovered grade for glands (P < 0.000) compared to groups B, C and D. Results of the present study showed that high-dose triphala improved radiation induced damage of glands. PMID- 22439435 TI - Preventive and curative effects of Achyranthes aspera Linn. extract in experimentally induced nephrolithiasis. AB - The present study was undertaken to evaluate the efficacy of Achyranthes aspera in preventing and reducing the growth of calcium oxalate stones in ethylene glycol induced nephrolithiatic model. Hyperoxaluria was induced in rats using ethylene glycol (EG, 0.4%) and ammonium chloride (1%) for 15 days and was then replaced with EG (0.4%) only. Upon administration of cystone (750 mg/kg body wt.), aqueous extract of A. aspera (500 and 1000 mg/kg body wt.), levels of renal injury markers (lactate dehydrogenase and alkaline phosphatase) were normalized with a decrease in serum urea and serum creatinine. Concurrent treatment reduced changes in the architecture of renal tissue and also decreased the size of crystals thereby helping in quick expulsion of the crystals. The present results indicated that Achyranthes aspera had an ability to maintain renal functioning and reduced renal injury. PMID- 22439436 TI - Amelioration of ionizing radiation induced lipid peroxidation in mouse liver by Moringa oleifera Lam. leaf extract. AB - Protective effect of Moringa oleifera leaf extract (MoLE) against radiation induced lipid peroxidation has been investigated. Swiss albino mice, selected from an inbred colony, were administered with MoLE (300 mg/kg body wt) for 15 days before exposing to a single dose of 5 Gy 60Co-gamma radiation. After treatments, animals were necropsied at different post irradiation intervals (days 1, 7 and 15) and hepatic lipid peroxidation and reduced glutathione (GSH) contents were estimated to observe the relative changes due to irradiation and its possible amelioration by MoLE. It was observed that, MoLE treatment restored GSH in liver and prevented radiation induced augmentation in hepatic lipid peroxidation. Phytochemical analysis showed that MoLE possess various phytochemicals such as ascorbic acid, phenolics (catechin, epicatechin, ferulic acid, ellagic acid, myricetin) etc., which may play the key role in prevention of hepatic lipid peroxidation by scavenging radiation induced free radicals. PMID- 22439437 TI - Effect of rosuvastatin on obesity-induced cardiac oxidative stress in Wistar rats -a preliminary study. AB - The prevalence of obesity has been rising alarmingly and it has now become a global concern causing an enormous economic burden on the health care system. Obesity is generally linked to complications in lipid metabolism and oxidative stress. The aim of the present study was to investigate the effect of rosuvastatin (10 mg/kg, po) on obesity-induced oxidative stress in high fat-fed Wistar rats. Oral administration of rosuvastatin (10 mg/kg) for 21 days along with high fat diet brought about significant elevation in serum high density lipoprotein and cardiac antioxidant enzymes levels (superoxide dismutase, catalase, glutathione, glutathione peroxidase, glutathione peroxidase-, glutathione reductase- and glutathione-S-transferase) while decreasing in serum lactate dehydrogenase, apolipoprotein-B, lipids (triglycerides, total cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein cholesterol and atherogenic index) and cardiac thiobarbituric acid reactive substances levels. The results were comparable with orlistat, a standard antiobesity drug. These preliminary results for the first time demonstrate that administration of rosuvastatin can be beneficial for the suppression of obesity induced oxidative stress and dyslipidemia in high fat-fed Wistar rats. PMID- 22439438 TI - Effect of consumption of fatty acids, calcium, vitamin D and boron with regular physical activity on bone mechanical properties and corresponding metabolic hormones in rats. AB - The consumption of fatty acids, nutrients, and regular physical activity, individually influence bone mechanical properties in rats. To investigate their effects in combination, male rats were divided into the seven groups: G1: regular food and drinking water; G2: same as Gr.1 + physical activity (Whole body vibration; WBV); G3: same as Gr.2 + Calcium, Vit. D, Boron; G4: same as Gr.3 + canola oil; G5: same as Gr.3 + sunflower oil; G6: same as Gr.3 + mix of sunflower oil and canola oil; and G7: same as Gr.3 + coconut oil; and treated for 8 weeks. Analysis between the control with the groups 2 and 3 revealed that vibration in the G2 increased the body weight (P = 0.04), with no other major difference in plasma and bone indices. Comparison between the control with the G4-G7 (the oil groups) revealed that the rats in the G5 had a lower body weight (15 % less) and a significant increase in plasma levels of Estradiol in the G7 was noted. In addition, levels of Testosterone in the G4 and G7, and Free Testosterone in the G7 had a remarkable increase. Similar trend was observed for plasma levels of Vit. D in the G4 and G5. The stiffness and the breaking strength of the femur in the G7, and the breaking strength of the lumbar in the G7 compared to the control and the G4 and G5 was significantly higher and tended to increase in comparison to the G6. Better and stronger measurements observed for coconut oil is warranted to further study its effect on biomechanical properties of bones. PMID- 22439439 TI - Mortality and testicular derangements in red flour beetles, Tribolium castaneum (Herbst) exposed to hen's egg white proteins. AB - Red flour beetle (T. castaneum) is a major pest of stored grains and is known for its adaptability to all classes of insecticides. The present study was carried out to determine the insecticidal potential of egg white proteins to manage beetle population. Protein samples obtained through salt fractionation were lyophilized and were used separately and simultaneously in different concentrations by adding them to wheat flour and milk powder. The results indicated that the mortality rate of the adult beetles was dependent on the type of treatment, concentration of protein samples and duration of feeding. In multiple-choice feeding trials beetles showed their movement towards the control section as the concentration of treatment increases. Marked abnormalities were observed in appearance and dimensions of the testes which indicated that the egg white proteins caused considerable effect on the process of spermatogenesis and sperm functions. SEM study revealed the formation of deep wrinkles and folds on the testicular surface of the testes of beetles fed on treated diets, points towards the depletion of internal cellular material. The results suggest that egg white protein affects the survival and cause subsequent derangements in the testis of red flour beetle. PMID- 22439440 TI - Safety and immunogenicity of Brucella abortus strain RB51 vaccine in cross bred cattle calves in India. AB - Safety and immunogenicity of Brucella abortus RB51 vaccine has been evaluated in an organised dairy farm in India. All the cattle (r = 29) vaccinated with strain RB51 'responded' to the vaccine as demonstrated by iELISA using acetone killed strain RB51 antigen. The percentage responders at day 35, 60 and 90 post vaccination were 100%, 95% and 20%, respectively. Strain RB51 was able to elicit a good IFN-gamma response from vaccinated animals. The post-vaccination time point analysis indicated that the cumulative IFN-gamma response of whole blood from vaccinates stimulated with heat killed RB51 antigen was elicited in 80% of calves at 60 days post vaccination. Absence of strain RB51 in the secretions and excretion and lack of local or systemic reaction indicated the safety of the vaccine. PMID- 22439441 TI - The coalition is no friend to women. PMID- 22439442 TI - An update on children's and young people's health. PMID- 22439443 TI - Paediatric continence: taking political action to improve services. PMID- 22439444 TI - Where next for the care of older people? PMID- 22439445 TI - QNI Opening Doors project--improving health for homeless people and families. AB - This paper looks at homeless health issues and specifically the Opening Doors project being delivered by the Queens Nursing Institute. The paper starts by looking at the subject of homelessness generally, before moving onto the specific health issues and service provision. It then describes the Opening Doors project which is open to nurses and other health professionals working with homeless people and families with particular reference to substance misuse. The project aims to improve the healthcare of the client group by providing resources that practitioners can then apply to their daily work. The paper details the outline of the project, aims, achievements and outcomes to date, along with nurse's views on the issues of working with this client group and two case studies from services that are a part of the project to show the type of work that is being done. PMID- 22439446 TI - Juggling the dual role of practitioner and educator: practice teachers' perceptions. AB - This paper reports on a study exploring the role (caseload manager; practitioner; educator) of Specialist Community Public Health Nursing (SCPHN) Practice Teachers (PTs) and mentors for Specialist Practice Community (SPC) district nursing students. Methodological triangulation was used, comprising questionnaires completed by 15 PTs and mentors, followed by six semistructured interviews, to provide quantitative and qualitative data. The results of the study identify that post-registration students demanded considerable time due to their need to develop leadership and higher cognitive skills in practice. PTs and mentors identified feeling undervalued by the organisation and colleagues as they tried to maintain their dual role with limited time or resources allocated. Respondents reported that they often worked over their hours to maintain both roles which impacted on their work life balance. They reported that both peer and university support groups were valuable and suggested that increased contact from lecturers and greater flexibility in university courses would accommodate their continuing professional development. It is, therefore, concluded that further support is needed by both the organisation and the university to enable this dual role. PMID- 22439447 TI - An evaluation of a community-based basic parenting programme: a two-year follow up. AB - Behavioural difficulties in the early years and through primary school age present a challenge to community practitioners; and the long-term costs to society of untreated conduct disorder place a huge financial strain on services, as well as leading to a poor prognosis for the children affected. The aim of this study was to establish the long-term effects for participants attending a 12-week Basic Incredible Years Programme, two years post-completion. Fifty-seven participants were interviewed, representing 63% of the original sample, who parented children aged 1-12 years. Pre- and post-intervention and follow-up measures were the General Health Questionnaire (30) and Eyberg Child Behaviour Checklist. The most common theme reported was that it had helped to change their child's behaviour, and this was demonstrated quantitatively with mean average scores for the Eyberg Child Behaviour Inventory reducing to below clinical cut off post-group and at two years. This same pattern was seen for participants' mental health, with improvements largely maintained at two years. Of the one third of the children whose behaviour deteriorated two years after the course, two-thirds of these children had experienced adverse life events or had a secondary diagnosis. PMID- 22439448 TI - The NHS in 2012: what lies ahead? PMID- 22439449 TI - Preventing drug and alcohol use by school children. PMID- 22439450 TI - Epidemic proportions. PMID- 22439451 TI - School-based screening for scoliosis. PMID- 22439452 TI - Number needed to treat (NNT); number needed to harm (NNH). PMID- 22439453 TI - Contagion as a fiscal problem. PMID- 22439454 TI - Evaluation of possible inflammatory bowel disease: a survey of Rhode Island physicians. AB - BACKGROUND: Patients with undiagnosed inflammatory bowel disease (IBD) are often evaluated initially by primary care physicians (PCPs). Despite the frequency with which PCPs evaluate chronic abdominal pain and chronic diarrhea, little is known about how they approach these symptoms. OBJECTIVES: To determine the diagnostic practices and referral patterns of PCPs when confronting a patient with potential IBD. METHODS: We conducted a mail survey of PCPs practicing in Rhode Island. Clinical vignettes describing patients with chronic abdominal pain and chronic diarrhea were presented. Respondents were asked to indicate how they would evaluate these scenarios and when they would refer to a specialist. RESULTS: 432 PCPs were surveyed; 35.6% responded. Wide variation in PCPs' definitions of chronic abdominal pain and chronic diarrhea was found, with only 26% and 51% of physicians, respectively, defining these symptoms to be chronic per standard definitions. Laboratory testing was found to vary significantly with practice type (p < 0.01 for 2 patient groups). Patient age influenced the ordering of diagnostic imaging (p < 0.0001), while patient gender did not. CONCLUSIONS: There is significant variability among PCPs in the threshold after which common gastrointestinal symptoms become chronic as well as in their diagnostic evaluation of these symptoms. This variability may lead to a lag in the diagnosis of IBD and influence patient outcomes. PMID- 22439455 TI - State-wide support for physician-mothers who are breastfeeding. PMID- 22439456 TI - Case of malignant priapism and review of the literature. AB - Malignant priapism, or priapism secondary to locally invasive or metastatic cancer, is a rarely reported phenomenon with a very poor prognosis. We report on a case of malignant priapism secondary to metastasis of urothelial carcinoma of the bladder in a 73 year old gentleman who underwent a radical cystectomy with negative margins but positive nodal disease three months prior to presentation. The rapid progression of disease and resultant demise of this patient is unusual even when compared to the limited available literature. Rapid progression to muscle invasion despite intravesical immunotherapy, histologic involvement of the prostate and seminal vesicles with extensive lymphovascular invasion, and the rapid development of metastasis are all consistent with the aggressive nature of a cancer that has metastasized to the penis. Further, while conservative penile sparing therapy may be a goal in patients with limited life expectancy, ongoing pain and infectious concerns may force the physician to resort to a penectomy. PMID- 22439457 TI - Ascending colon ganglioneuroma. PMID- 22439458 TI - Drug-induced chronic pancreatitis. PMID- 22439459 TI - Spinal epidural abscess. PMID- 22439460 TI - The impact of Rhode Island's statewide smoke-free ordinance on hospital admissions and costs for acute myocardial infarction and asthma. PMID- 22439461 TI - The Rh words of medicine. PMID- 22439462 TI - Social networking through the ages. PMID- 22439463 TI - Nursing and Social media 101. PMID- 22439464 TI - Nurses & the use of social media. PMID- 22439465 TI - Building your business with social media and relationship marketing. PMID- 22439466 TI - Social networking: connecting holistic nurses globally. PMID- 22439467 TI - Social media, holistic nursing & holistic nursing education. PMID- 22439469 TI - Dental contracts 101. PMID- 22439468 TI - Health promotion for nurses: expanding consciousness and professional sustainability. PMID- 22439470 TI - Benefits byline. PMID- 22439471 TI - The inspiration of Mary Webster. PMID- 22439472 TI - Insuring your life with permanence--is it right for you? PMID- 22439473 TI - Do you take my insurance? PMID- 22439474 TI - It's an 'ugly weather pattern' for dentistry. PMID- 22439475 TI - 'Volunteerism is not a program'. PMID- 22439476 TI - The sounds of silence. PMID- 22439477 TI - Q&A with John Gerding, 2012 CDS President. PMID- 22439478 TI - We introduce you to a patient's perspective. PMID- 22439479 TI - FAQs about the Illinois Dental Practice Act. PMID- 22439480 TI - Dental Lifeline Network hits the road. PMID- 22439481 TI - Our struggle to be heard is not a new one. PMID- 22439482 TI - Bad breath. PMID- 22439483 TI - What does professionalism mean these days? PMID- 22439484 TI - The road to here. PMID- 22439485 TI - CDA takes important step for access. PMID- 22439486 TI - Customer service key to patients returning. PMID- 22439487 TI - CDA research. Introduction. PMID- 22439488 TI - California's state oral health infrastructure: opportunities for improvement and funding. AB - California has virtually no statewide dental public health infrastructure leaving the state without leadership, a surveillance program, an oral health plan, oral health promotion and disease prevention programs, and federal funding. Based on a literature review and interviews with 15 oral health officials nationally, the paper recommends hiring a state dental director with public health experience, developing a state oral health plan, and seeking federal and private funding to support an office of oral health. PMID- 22439489 TI - Advanced dental education programs: status and implications for access to care in California. AB - Primary care residencies in dentistry include general practice residency and advanced education in general dentistry--collectively known as postdoctoral general--dentistry and pediatric dentistry. These primary care programs are the most likely to serve underserved populations during the training experience. An expansion of primary care dental residency positions in California has the potential to positively impact access to care in California. However, there are significant political and financial barriers to realizing this potential. PMID- 22439490 TI - Economic feasibility of alternative practitioners for provision of dental care to the underserved. AB - This study assesses the viability of three alternative practitioner types for provision of dental care to the underserved. Key factors modeled include compensation, training and practice costs, productivity, and payer mix scenarios. Utilizing dental therapists or dental health aide therapists is cost-effective for enhancing access. However, to be sustainable, the practices will require a subsidy or a better reimbursement than modeled. Without tuition support, the debt burden will deter applicants mostlikely to treat the underserved. PMID- 22439492 TI - My dream: to sleep. PMID- 22439491 TI - Are procedures performed by dental auxiliaries safe and of comparable quality? A systematic review. AB - The objective of the current study was to systematically evaluate the existing evidence in relation to the safety, quality, productivity or cost-benefit, and patient satisfaction of the procedures performed by the different groups of dental providers. Due to the diversity of the procedures performed and the outcomes measured, it was not possible to create pooled estimates in a meaningful manner. Therefore, summary results of individual studies are presented and critically evaluated. PMID- 22439493 TI - A good row focuses the mind. PMID- 22439494 TI - Staff sign up to show their support for care campaign. PMID- 22439495 TI - Guidelines introduced to tackle group A streptococcal infections. PMID- 22439496 TI - Creating a positive workplace culture. AB - This article considers the link between emotional resilience and the mental and physical wellbeing of healthcare staff, and how this affects leadership and patient care. The authors outline six steps to building and sustaining emotional resilience. In two NHS surveys (Boorman 2009, Healthcare Commission 2010) staff reported that their physical health and emotional wellbeing affected their ability to undertake daily activities and their ability to care for patients. Some NHS trusts are addressing staff wellbeing through emotional resilience training. Guy's and St Thomas' NHS Foundation Trust, London, for example, includes it in its preceptorship programme, which supports transition from student to staff nurse. PMID- 22439497 TI - Graduate foundation scheme with a focus on dignity and older adults. AB - The care experiences of older people in Wales and the rest of the UK have risen to the top of the political agenda recently, and it is the role of nurse managers to find ways to meet the dignity agenda. A review by the Older People's Commissioner for Wales (Marks 2011) recommends that 'better knowledge of the needs of older people with dementia is needed, together with improved communication, training, support and standards of care'. In an effort to meet this recommendation, one healthcare organisation, Cwm Taf Health Board, has developed a graduate foundation programme that focuses on the dignity of older patients in various hospital settings. This article describes the development and implementation of the programme. PMID- 22439498 TI - Senior nurses' views about factors that lead to service failures. AB - Significant failures in nursing services have led to numerous recommendations for improvement, yet problems continue. This article reports the findings of a study carried out in Wales to explore the underlying causes of such failures. It also reports how the findings were used to support the development of a senior nurses' framework with the aim of achieving successful nursing services. PMID- 22439499 TI - Flexible learning to support safe, person-centred care. AB - Effective Practitioner is an educational initiative that supports nurses, midwives and allied health professionals to deliver person-centred, safe and effective care. It offers access to flexible work-based learning and development resources. This article describes the progress of the initiative and sets out the expected effects on service delivery, as well as exploring the Scottish context and the initiative's relevance to the rest of the UK and abroad. PMID- 22439500 TI - Leadership scheme to develop the careers of talented candidates. AB - The Top Leaders programme supports career development by identifying talented staff and equipping them with a range of management skills and approaches. The programme uses a diagnostic test to help candidates assess their strengths, leadership styles and development needs, and offers them 360 degrees feedback. This enables them to identify areas they need to develop to be effective and supportive leaders. Two case studies illustrate the programme in action. PMID- 22439501 TI - "Lansley's experiment with the NHS must never be repeated". PMID- 22439502 TI - Review to scrutinise NMC. PMID- 22439503 TI - "New forum must focus on the future and not look backwards". PMID- 22439504 TI - "We won't win brain of Britain as long as protocols deskill us". PMID- 22439505 TI - "Beware the implications for nurses of assisted dying law". PMID- 22439506 TI - Toilet privacy in hospital. AB - Good practice in toilet management and continence promotion can help hospital patients to maintain their dignity. This article reports on an audit that highlighted the issues important to patients and nurses in terms of improving privacy and dignity for inpatients using the toilet. PMID- 22439507 TI - Intermittent self-catheterisation in MS. AB - People with multiple sclerosis may experience complex bladder problems; intermittent self-catheterisation can be used in cases of incomplete bladder emptying. This literature review examines the qualitative research on the use of ISC in patients with MS, focusing on concordance, training and quality of life. PMID- 22439508 TI - Causes and strategies for moisture lesions. AB - Moisture lesions or incontinence-associated dermatitis are painful and distressing consequences of prolonged exposure to urine and faeces. They may adversely affect patients' physical and psychological wellbeing, so minimising damage is a vital part of the nurse's role. This article outlines their causes and strategies to prevent and treat them, as well as the causes of urinary and faecal incontinence and containment options. PMID- 22439509 TI - Leading change: 2--planning. AB - National initiatives have outlined the importance of involving frontline staff in service improvement, and the ability to influence and manage change has been identified as an essential skill for delivering new models of care. Nurses often have to take the lead in managing change in clinical practice. The second in a three-part series is designed to help nurses at all levels develop the knowledge and skills to function as change agents within their organisations. This article focuses on planning the change and dealing with resistance. PMID- 22439510 TI - Sharing ideas. PMID- 22439511 TI - Understand when to give praise. PMID- 22439512 TI - Water fluoridation: a target for budget cuts. PMID- 22439513 TI - Slip and fall liability. PMID- 22439514 TI - Accommodation requirements for nursing mothers. PMID- 22439515 TI - Why it's not ok to date your patients. PMID- 22439516 TI - Health plan provides accident insurance, wider entry age band. PMID- 22439517 TI - Determining and reporting your full fee. PMID- 22439519 TI - Simply controlling fluid intake can help solve incontinence. PMID- 22439518 TI - Competition in a contrary economy. PMID- 22439520 TI - A collective effort for children's dental health. PMID- 22439521 TI - Rubber dam isolation in pediatric patients: a review. AB - The rubber dam has been available to the dental profession for over 145 years and can serve as an invaluable tool to dental practitioners. Here we review the rubber dam and its application on children including advantages and disadvantages associated with its use and alternative isolation methods. PMID- 22439522 TI - Space maintenance in the primary and mixed dentitions. AB - Loss of space in the primary dentition is considered one of the main causes of malocclusion in the permanent dentition. The purpose of this paper is to review ond summarize the indications and use of space maintainers in primary and mixed dentitions as preventive measures of future malocclusion. Two main types of space maintainers are used to maintain the space in primary ond mixed dentitions: fixed and removable appliances. Band and loop is the appliance of choice when a primary maxillary or mandibular first molar is prematurely lost. With the premature loss of a second primary molar, Nance or transpalatal (TPA) appliances can be used on the maxillary arch and the lower lingual holding arch (LLHA) for the mandibular arch. PMID- 22439523 TI - Dental trauma: review of common dental injuries and their management in primary and permanent dentitions. AB - Management of dental trauma in children can be a challenging problem in dental practices. Knowledge of current trauma guidelines is vital in effectively managing dental trauma so that favorable outcomes are achieved. The purpose of this paper is to review the current guidelines and management strategies of dental trauma in primary and permanent dentitions. When planning emergency treatment for a primary tooth, it is important to consider the lifespan of the tooth, the potential damage to the permanent dentition, and the behavior of the child. After injury to permanent teeth, the treatment strategy is dictated by the concern for vitality of the periodontal ligament and pulp of the injured tooth. The emergency nature of dental trauma requires that the dentist be knowledgeable and readily available during and after office hours to provide care. PMID- 22439524 TI - "I'm grateful with all my heart". PMID- 22439525 TI - Opportunities of change. PMID- 22439526 TI - In the starting blocks for 2012. PMID- 22439527 TI - Haiti 2011. PMID- 22439528 TI - Perio causes everything? Perspectives on the association of oral health and systemic disease. PMID- 22439529 TI - The clinical significance of marginal fit. AB - Clinical evaluation of restoration acceptability includes marginal adaptation, restoration and preservation of anatomic form, color match, cavosurface discoloration, and presence of marginal caries. This paper will review what is known about marginal fit of all materials relative to their acceptable fit. Some explanation will be given of how material properties affect marginal fit, what the expected longevity of different materials is relative to marginal fit, and how marginal fit affects development of secondary or marginal caries. Marginal fit is assumed to affect restoration longevity by either encouraging or discouraging microleakage and development of secondary or marginal caries. Marginal fit and its effect on the health of the gingival tissues have been reviewed in an earlier paper on polishing and will not be reviewed here. Is there some correlation between marginal fit of the various materials used in restorative dentistry and this assumption? This paper will review the literature found on Medline and present the science behind the clinical significance of marginal fit utilizing in vitro studies where necessary and in vivo studies whenever possible. Numerous authors replicating these studies are used to improve reliability and replicability. PMID- 22439530 TI - The controversy over antibiotic prophylaxis for dental patients with prosthetic joints. PMID- 22439531 TI - Old friends. PMID- 22439532 TI - Becoming a master of your time. PMID- 22439533 TI - Every day we begin again. PMID- 22439534 TI - Part of the fabric. PMID- 22439535 TI - Collaborators, colleagues and friends. Key relationships with many organizations help ACHE serve its affiliates. PMID- 22439536 TI - Interview with ACHES's 2012-2013 chairman. Dale L. Capozzalo. Interview by Jessica D Squazzo. PMID- 22439537 TI - Reducing hospital readmissions. PMID- 22439538 TI - The pursuit of perfection: hospitals take heightened actions to reduce adverse events. PMID- 22439539 TI - Overcoming limiting behaviors and habits. PMID- 22439540 TI - Commanding a podium presence. PMID- 22439541 TI - Streamline your meetings. PMID- 22439542 TI - Ethics and advertising. Healthcare organizations must have an ethical framework in place for advertising. PMID- 22439543 TI - Consumer-centric Healthcare. Consumer-focused initiatives offer opportunities and challenges for providers. PMID- 22439544 TI - Overcoming barriers through community engagement. Pediatric asthma program succeeds through collaboration and commitment. PMID- 22439545 TI - A summary of CMS 2012 final rules. Five facility types are highlighted. PMID- 22439546 TI - Push vs. pull. Managing a job change in an uncertain market. PMID- 22439547 TI - Governing the physician enterprise for transparent clinical outcomes. It is the new reality in an era of pay for performance. PMID- 22439548 TI - Leadership for the triple aim. Three-pronged framework helps executives lead quality initiatives. PMID- 22439549 TI - ACOs: To prepare for the future, focus on the fundamentals. Quality, cost control and physician collaboration will position hospitals for success. PMID- 22439550 TI - Increasing diversity awareness. Chapter takes advantage of grant program to further diversity initiative. PMID- 22439551 TI - Healthcare executives' responsibility to their communities. PMID- 22439552 TI - Creating an ethical culture within the healthcare organization. PMID- 22439553 TI - Application of response surface methodology in the optimization of photocatalytic removal of environmental pollutants using nanocatalysts. AB - Response surface methodology is a widely used technique for modelling and optimization of the photocatalytic treatment processes of water and wastewater. This methodology not only estimates linear, interaction and quadratic effects of the factors on the response, but also provides a prediction model for the response at the range of the variables studied and the optimum conditions to achieve the highest performance. The present paper reviews the results of application of this innovative methodology in modelling and optimization of the photocatalytic treatment processes. Different experimental designs including 3k factorial, Doehlert, Box-Behnken and central composite designs have been developed to describe the treatment processes of dyeing effluents, pharmaceutical agents and hazardous phenolic compounds. The results showed that response surface methodology can describe the behaviour of complex reaction systems, such as photocatalytic processes, in the range of experimental conditions adopted. Optimization based on response surface methodology can also estimate the conditions of the photocatalytic processes to achieve the highest performance. PMID- 22439554 TI - A review of the impact and potential of intermittent aeration on continuous flow nitrifying activated sludge. AB - Intermittent aeration of activated sludge plants (ASPs) is a potential strategy that may help deliver reduced operational costs while providing an adequate effluent quality. This review paper critically assesses the implications of temporary turning aeration offin continuous flow nitrifying ASPs, including impact on dissolved oxygen concentrations, process biology and operational parameters. The potential savings and pitfalls of the approach are further illustrated through an example scenario. Findings from this review indicate rapid dissolved oxygen depletion times of 1-60 minutes and a significant reduction of nitrification rates from 0.12 to less than 0.04 g NH4-N/g VSS/d. Further negative impacts include a potential increase in nitrous oxide emissions from 0.07% to 27% N2O-N per mole of NH4-N oxidized; enhanced filamentous bacteria growth; a noticeable increase in effluent turbidity developing within one hour of air supply interruption; and, if no mechanical mixing is in place, risk of mixed liquor suspended solids settling in the bioreactor within short times (23-53 min). However, the potential savings in terms of aeration costs could amount to 33%-45% if instrumentation adequacy and impact on process biology and carbon equivalent emissions are excluded from the economic analysis. Further research on the areas of nitrous oxide emissions and the use of hybrid systems to provide resilience and robustness to the intermittent operation of continuous flow nitrifying ASPs is recommended. PMID- 22439555 TI - The 'bankability' of the new waste technologies: an econometric method for risk sharing in private finance waste contracts. AB - The identification of risk and its appropriate allocation to partners in project consortia is essential for minimizing overall project risks, ensuring timely delivery and maximizing benefit for money invested. Risk management guidance available from government bodies, especially in the UK, does not specify methodologies for quantitative risk assessment, nor does it offer a procedure for allocating risk among project partners. Here, a methodology to quantify project risk and potential approaches to allocating risk and their implications are discussed. Construction and operation of a waste management facility through a public-private finance contract are discussed. Public-private partnership contracts are special purpose vehicle (SPV) financing methods promoted by the UK government to boost private sector investment in facilities for public service enhancement. Our findings question the appropriateness of using standard deviation as a measure for project risk and confirm the concept of portfolio theory, suggesting the pooling of risk can reduce total risk and its impact. PMID- 22439556 TI - Pilot-scale UV/H2O2 advanced oxidation process for surface water treatment and downstream biological treatment: effects on natural organic matter characteristics and DBP formation potential. AB - The effects of the advanced oxidation process (AOP) of ultraviolet radiation in combination with hydrogen peroxide (UV/H2O2) on the structure and biodegradability of dissolved natural organic matter (NOM) and on the formation of disinfection by-products (DBPs) through the post-UV/H2O2 chlorination were investigated using UV reactors equipped with either low-pressure amalgam lamps or medium-pressure mercury vapour lamps. With electrical energy doses and H2O2 concentrations typically applied in full-scale UV systems for water remediation, the UV/H2O2 AOP partially oxidized NOM, reducing its degree of aromaticity and leading to an increase in the level of biodegradable species. Also, when combined with a downstream biological activated carbon (BAC) filter, UV/H2O2 AOP reduced the formation of DBPs by up to 60% for trihalomethanes and 75% for haloacetic acids. Biological activated carbon was also shown to effectively remove biodegradable by-products and residual H2O2. PMID- 22439557 TI - Adsorption of clofibric acid and ketoprofen onto powdered activated carbon: effect of natural organic matter. AB - The adsorption of two acidic pharmaceutically active compounds (PhACs), clofibric acid and ketoprofen, onto powdered activated carbon (PAC) was investigated with a particular focus on the influence of natural organic matter (NOM) on the adsorption of the PhACs. Suwannee River humic acids (SRHAs) were used as a substitute for NOM. Batch adsorption experiments were conducted to obtain adsorption kinetics and adsorption isotherms with and without SRHAs in the system. The adsorption isotherms and adsorption kinetics showed that the adsorption ofclofibric acid was not significantly affected by the presence of SRHAs at a concentration of 5 mg (as carbon) L(-1). An adsorption capacity of 70 to 140 mg g(-1) was observed and equilibrium was reached within 48 h. In contrast, the adsorption of ketoprofen was markedly decreased (from about 120 mg g(-1) to 70-100 mg g(-1)) in the presence of SRHAs. Higher initial concentrations of clofibric acid than ketoprofen during testing may explain the different behaviours that were observed. Also, the more hydrophobic ketoprofen molecules may have less affinity for PAC when humic acids (which are hydrophilic) are present. The possible intermolecular forces that could account for the different behaviour of clofibric acid and ketoprofen adsorption onto PAC are discussed. In particular, the relevance of electrostatic forces, electron donor-acceptor interaction, hydrogen bonding and London dispersion forces are discussed PMID- 22439558 TI - How to minimize iron loss while decontaminating converter dust from lead. AB - The purpose of this work was to decontaminate a converter flue dust from lead while minimizing the iron loss from the dust matrix. A physicochemical method based on a leaching cascade was applied to remove lead impurities with HCl. Finally, the lead-rich wastes generated at the end of the operations were further treated in order to meet the standards of waste disposal sites. The results show that lead could be removed from the dust with efficiencies of better than 90%. However, some iron was lost in these operations. It was noticed that under optimum conditions 8.5 g of iron would be lost as leachate per each gram of removed lead. It was also noticed that the lead-treated dust was more concentrated in iron and had less calcium. A number of parameters that could affect the amount of iron loss, such as acid dose, exposure time and temperature, were identified and the extent of the effects are presented. It was concluded that the lead content in the flue dust could practically be lowered to any level. It was also concluded that the difference between the solubility of lead chloride in cold and hot water, as well as the affinity of certain ligands such as Cl- and OH- to form stable complexes with lead ions, played a key role in this study. The lead-containing complexes in the leachate were identified to be predominantly PbCl3- and PbCl+. PMID- 22439559 TI - Simple and template-free method for preparation of (ZnO)1-x[Cd(OH)2]x nanoparticles in water and their photocatalytic activities. AB - A simple and template-free method was applied for preparation of (ZnO)1-x [Cd(OH)2]x nanoparticles (x = 0-1) in water by refluxing for 4h at about 95 degrees C. The nanoparticles were investigated by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and UV-Vis spectroscopy. XRD patterns show that the products are excellently crystallized in a hexagonal structure. The SEM images demonstrate that the nanoparticles are nearly spherical. The UV-Vis spectrum for the nanoparticles with x = 0.2 shows an absorption tail in the visible light region. Photocatalytic degradation of methylene blue (MB) on the nanoparticles was evaluated under visible light irradiation. Nanoparticles of (ZnO)0.8 [Cd(OH)2]0.2 exhibit the highest photocatalytic activity among the prepared samples. The nanoparticles prepared by refluxing for 4 h have the greatest photocatalytic activity. Increasing photocatalytic activity was attributed to the trapping of charge carriers and the existing absorption tail in the visible region for the nanoparticles with x = 0.2. PMID- 22439560 TI - Hydrocarbon degradation by a new Pseudomonas sp., strain RW-II, with polycationic surfactant to modify the cell hydrophobicity. AB - Pseudomonas putida RW-II isolated from petroleum refinery wastewater was tested for hydrocarbon degradation potential in the presence of polycationic surfactant, cetyl trimethylammonium bromide (CTAB). The effects of CTAB on growth profile, cell surface hydrophobicity, cell adhesion, zeta potential and hydrocarbon biodegradation were investigated. The addition of CTAB had a significant effect on the growth profile of RW-II and the growth was increased 1.11 times in hexadecane containing medium. In the presence of CTAB, the growth of Pseudomonas putida RW-II increased about 14.4%. The zeta potential of Pseudomonas putida RW II decreased significantly when CTAB was added to the medium. The addition of CTAB not only decreased the zeta potential of surface, but also significantly increased the hydrophobicity of the cell surface. The degradation rate of hexadecane, anthracene and naphthalene was observed as 64.8%, 46% and 56% at the end of 120 h, respectively. Biodegradation of hexadecane, anthracene and naphthalene was enhanced 1.16, 1.15 and 1.08 times at 40 mg/L CTAB addition, respectively. The increase in biodegradation resulted from improved interaction between the hydrocarbon and microorganism derived from the increased adhesion. Thus, the use of CTAB has been proposed to be a valuable effect to enhance the biodegradation of hydrocarbons. PMID- 22439561 TI - Trip time model for municipal solid waste collection applicable to developing countries. AB - Municipal authorities in developing countries are faced with how to effectively and efficiently collect solid wastes from service points to disposal sites. Options for economy of time and improvement in the efficiency of collection operation can best be evaluated by conducting a time and motion study on an existing system. This study presents the development of a simulation model that calculates the time required to accomplish a solid waste collection trip. In order to determine a collection trip time, the collection operation was separated into units and the time required to perform each of these unit operations was simulated from field data. Results from the studied collection vehicle showed that the average pickup time was 1.68 minutes/trip, the average drop-down rate was 1.8 minutes/trip, and the average at-site time was 1.38 minutes/trip. The average time spent at intersections and turns was approximately 0.38 minutes and 0.18 minutes respectively. The haul time to the disposal site represented 0.034 of the travel distance to the disposal site, while the haul time from the disposal site represented 0.030 of the travel distance from the disposal site. When the model was applied to municipal solid waste collection in Ilorin, Nigeria, the estimated trip times were approximately 84% of the observed trip times. The estimated trip times by the model can find practical application as a decision support tool for municipal solid waste managers in areas of trip assignments, route design, logistics management and costs and emission reduction strategies. PMID- 22439562 TI - Treatment of a slaughterhouse wastewater: effect of internal recycle rate on chemical oxygen demand, total Kjeldahl nitrogen and total phosphorus removal. AB - This study investigated the ability of an anaerobic/anoxic/oxic (A2/O) system to treat a slaughterhouse wastewater. The system employed two identical continuous flow reactors (101 total liquid volume each) running in parallel with the main operational variable, being the internal recycle (IR) rate. The chemical oxygen demand (COD), total Kjeldahl nitrogen (TKN) and total phosphorus (TP) performance was evaluated as the IR flowrate was increased from a Q of 151d(-1) to 4Q at a system hydraulic retention time of 16 h and a solids retention time of 10 d. The COD:TKN and COD:TP ratios were 8.2:1 and 54:1, which supported both nitrogen and phosphorus removal. For all IR multiples of Q, the COD removal was in excess of 90%. The TKN removal showed a modest improvement (a 4-5% increase, depending on the dissolved oxygen (DO)) as the IR doubled from Q to 2Q, but no further increase was observed at the 4Q IR rate. The TP removal reached its optimum (around 85%-89% (again depending on the DO)) at the 2Q rate. PMID- 22439563 TI - Degradation of nitrobenzene in simulated wastewater by iron-carbon micro electrolysis packing. AB - The reductive degradation of nitrobenzene (NB) by iron-carbon micro-electrolysis packing was investigated. The influence of initial NB concentration, pH value and packing amount on the removal rate of NB were studied. The results showed that the reaction with packing followed the pseudo-first-order reaction. The optimum pH was 3.0 for the degradation of NB in the tested pH ranges of 3-9 and the optimum packing amount was 40 g/200 ml. The flow-through column packed with packing was designed to remove NB from simulated wastewater for approximately 68 days. The removal rate was over 90% within initial periods. It could be seen that after running for 68 days, the packing still had good performance after the long term column experiment. In addition, the changes of the packing surfaces morphologies and matters before, during and after the column experiment were analysed by scanning electron microscopy in conjunction with energy-dispersion spectroscopy (EDS). PMID- 22439564 TI - Influence of the apparent molecular size of aquatic humic substances on colour removal by coagulation and filtration. AB - This study aims to verify the influence of the apparent molecular size of aquatic humic substances (AHSs) on the effectiveness of coagulation with aluminium sulphate and ferric chloride. Coagulation-filtration tests using the jar test and bench-scale sand filters were carried out with water samples having a true colour of approximately 100 Hazen units and prepared with AHSs of different molecular sizes. Stability diagrams are presented showing regions of > or = 90% and > or = 95% apparent colour removal delineated for each water sample using plots of total metal ion concentration (Al3+ and Fe3+) versus coagulation pH. To achieve the same degree of colour removal, the water samples with smaller apparent molecular sizes and a higher percentage of fulvic acids required higher dosages of both aluminium sulphate and ferric chloride. PMID- 22439565 TI - Microbial degradation of microcystin-LR by Ralstonia solanacearum. AB - A bacterial strain was isolated from Lake Dianchi (China) and its degradability and degradative pathways of the cyanobacterial toxin microcystin-LR (MC-LR) were studied. On the basis of morphological, physiological and biochemical tests, the strain was identified as Ralstonia solanacearum. The acute oral toxicity tests showed that Ralstonia solanacearum belongs to a non-toxic class. This bacterium degraded MC-LR at the rate of 9.4 mg/L per day, which was higher than those of the other bacterial strains reported in the literature. As for the degradative pathways, the results showed that the Adda-Arg peptide bond of MC-LR was initially hydrolysed by Ralstonia solanacearum to form a linear molecule as an intermediate. The intermediate product subsequently underwent a cyclisation reaction via dehydration to form a final product with a small peptide ring at one end of the molecule. These biodegradative pathways were different from those reported with other bacterial strains, suggesting that MC-LR may undergo different transformations, and different products were formed due to different compositions of bacteria present in natural lakes and reservoirs. These results suggest that there is a significant potential for Ralstonia solanacearum as a degrader for MC-LR removal from wastewater. PMID- 22439566 TI - Converting poultry litter to activated carbon: optimal carbonization conditions and product sorption for benzene. AB - To promote utilization of poultry litter as a source material for manufacturing low-cost activated carbon (AC) that can be used in wastewater treatment, this study investigated optimal production conditions and water-borne organic sorption potential of poultry litter-based AC. Pelletized broiler litter was carbonized at different temperatures for varied time periods and activated with steam at a range of flow rate and time. The AC products were examined for quality characteristics using standard methods and for organic sorption potentials using batch benzene sorption techniques. The study shows that the yield and quality of litter AC varied with production conditions. The optimal production conditions for poultry litter-based AC were carbonization at 700 degrees C for 45 min followed by activation with 2.5 ml min(-1) steam for another 45 min. The resulting AC possessed an iodine number of 454 mg g(-1) and a specific surface area of 403 m2 g(-1). It sorbed benzene in water following sigmoidal kinetic and isothermal patterns. The sorption capacity for benzene was 23.70 mg g(-1), lower than that of top-class commercial AC. The results, together with other reported research findings, suggest that poultry litter is a reasonable feedstock for low cost AC applicable to pre-treat wastewater contaminated by organic pollutants and heavy metals. PMID- 22439567 TI - Preparation of platinum- and silver-incorporated TiO2 coatings in thin-film photoreactor for the photocatalytic decomposition of o-cresol. AB - Platinum-incorporated TiO2 (Pt-TiO2) and silver-incorporated TiO2 (Ag-TiO2) coatings on sapphire tubes of a thin-film photoreactor were prepared using a photoreduction process. Results of X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) revealed that the Ag-TiO2 coatings consisted of a mixture of Ag2O, Ag and TiO2 particles, owing to the partial oxidization of silver particles on the TiO2 coatings, while the Pt-TiO2 coating contained a mixture of Pt and TiO2 particles. Diffuse reflectance UV-Vis spectra (DRS) showed that metal particles (Ag or Pt) incorporated into the TiO2 coatings promoted optical absorption in the visible region and made it possible for the coatings to be excited by visible light. Photoluminescence (PL) spectra showed that the PL intensity of the Pt-TiO2 coating was lower than that of the Ag-TiO2 and TiO2 coatings, indicating that the Pt-TiO2 coating had a higher efficiency of charge carrier trapping, immigration and transfer, which subsequently promoted the pseudo-first-order rate constants after the UV/TiO2 process. The Pt-TiO2 coatings for the photocatalytic decomposition of o-cresol under UV light irradiation corresponded to a higher pseudo-first-order rate constant (k) of 0.02 min(-1) when compared with the photocatalytic decomposition rates of pure TiO2 coatings (k = 0.0062 min(-1)) and Ag-TiO2 coatings (k = 0.01 min(-1)). The experimental results also indicated that the photodegradation rate of the Pt-TiO2 coating under visible light irradiation was significantly higher than the photodegradation rates of the Ag-TiO2 and pure TiO2 coatings. PMID- 22439568 TI - Retrospective study of metal contamination time trends in the French part of the Bay of Biscay. AB - Two cores were sampled in the Bay of Biscay: one a few miles off the Gironde estuary (pointe de la Coubre), the other near the Spanish border (Capbreton canyon) to study past variations in sediment contamination. Radiochronology (210Pb, 137Cs) and total metal determinations by ICP-MS allowed the study of time trends for metal concentrations in sediment. Off the Gironde, during the time interval recorded by the core (1958-1999), all metal concentrations remained less than OSPAR background values. Some variations occurred along the Cd and Zn profiles, which may correspond to a very attenuated signal from the Gironde outputs. This suggests that this area was not submitted to any significant anthropogenic input of metals between 1958 and 1999. In the canyon of Capbreton, the undisturbed part of the core recorded the influence of surface deposition between 1977 and 1999. From as early as 1977 high lead and mercury concentrations were noticed. Mercury concentrations increased until 1992, then decreased until 1999. This marks a drop of inputs in 1992, but the final concentration remained elevated. Lead had important concentrations (more than twice the OSPAR reference) all along the core and began to decrease only in the upper level of the unmixed layer. This shows a late (near 1998) drop of lead inputs. Other metals (Cd, Cu, Zn, Ni, Cr) stayed at a much lower level: less than the OSPAR reference for Cu, Cr and Ni or not far from the OSPAR reference for Cd and Zn. PMID- 22439569 TI - Investigating microbial activities during a starch-amended co-composting process at mesophilic and thermophilic temperatures. AB - The aim of this study was to assess the use of functional microbial ecological techniques in detailing processes during composting. Using starch as an amendment for a co-composting process, small-scale individual mesocosms were investigated at two temperatures, 30 degrees C and 60 degrees C, over a five-week period. In order to determine the more exact processes occurring during degradation, extracellular enzyme analysis (EEA) and community-level physiological profiling (CLPP) were used. The EEA demonstrated that, although assay temperature effects were present, no significant difference between the two in situ composting temperatures was observed for the two enzyme substrates, alpha- and beta glucosidase, used. The CLPP profiling was only performed on the 30 degrees C compost samples. These analyses indicated a dynamic, but broadly predictable, environment, suggesting that the use of this approach may be further applicable to these types of study. By investigating both total dry and organic weights, no difference in organic matter degradation between the two temperatures was observed. These results showed that either starch degradation acted independently of temperature or compensatory effects occurred. The former hypothesis was supported by a second experiment investigating starch degradation at both temperatures with appropriate negative controls. Trying to reconcile the EEA results with the changes in total matter was difficult without making speculative assumptions. The study highlights the need to further develop and evaluate these microbial ecological techniques to address such problems. PMID- 22439570 TI - Assessment of potential nutrient build-up around beef cattle production areas using electromagnetic induction. AB - Electromagnetic induction (EMI) has been used to map soil properties such as salinity and water content. The objective of this research is to use EMI to map the potential distribution of nutrients around beef cattle pens and to relate this distribution to major physiographic field features. Beef cattle farms in different physiographic locations were surveyed in Manitoba, Canada, using an EM 38 conductivity meter georeferenced with a GPS receiver. Samples were collected using a response surface design and analysed for electrical conductivity (ECe), which was used as a proxy for determining potential build-up of nutrients. Multiple linear regression models (MLR) were used for calibration of the EM readings. The results showed that areas 1 through 4 had ECe < or = 3.5 dSm(-1), but areas 5 and 6 exceeded this concentration and reached maximum values of 5.5 and 7.0 dS m(-1), respectively. Higher values in area 6 were probably due to the presence of a rocky layer at 0.3 m depth, leaving a thin soil layer to accumulate the nutrients. Micro-depressions played a major role in salt accumulation, with the depressions corresponding to higher values of ECe. The presence of features such as drainage ditches and compacted soils beneath roads strongly affected the direction of the plumes. Based on these results, the location of the pens on high elevations and the provision to collect the run-off from the pens were identified as good design criteria. Highly permeable soils may require a low permeability liner to capture the deep percolation and redirect it towards a collection area. PMID- 22439571 TI - Growth kinetic models for phenol biodegradation in a batch culture of Pseudomonas putida. AB - Biodegradation of phenol with pure culture of Pseudomonas putida was investigated. P. putida (PTCC 1694) was grown in facultative anaerobic condition at 27 degrees C and media pH value of 7. The effect of initial phenol concentration on the biodegradation rate was studied. The initial concentrations of phenol varied from 300 to 1000 mg/l. Experiments were performed for the duration of seven days while daily samples were withdrawn. The initial rate of biodegradation of phenol increased with initial concentration of 300-500 mg/l. Further increase in phenol concentration resulted in a slight decrease in the rate of biodegradation due to phenol inhibition. It was observed that by increasing the concentration of phenol, the lag phase was prolonged. Phenol is known to be an inhibitory substrate, thus Monod, Haldane and logistic kinetic models were applied to evaluate the growth kinetic parameters. The Monod model was unable to present the growth parameters over the defined concentration range. However, Haldane and logistic models perfectly fitted with the experimental data. The yield coefficients for the growth on phenol at concentrations of 300, 500, 700 and 1000 mg/l were 0.177, 0.062, 0.035 and 0.012 mg/mg, respectively. PMID- 22439572 TI - Estimating the removal efficiency of refractory dissolved organic matter in wastewater treatment plants using a fluorescence technique. AB - The spectroscopic characteristics and relative distribution of refractory dissolved organic matter (R-DOM) in sewage have been investigated using the influent and the effluent samples collected from 15 large-scale biological wastewater treatment plants (WWTPs). Correlation between the characteristics of the influent and the final removal efficiency was also examined. Enhancement of specific ultraviolet absorbance (SUVA) and a higher R-DOM distribution ratio were observed for the effluent DOM compared with the influent DOM. However, the use of conventional rather than advanced biological treatments did not appear to affect either the effluent DOM or the removal efficiency, and there was no statistical significant difference between the two. No consistent trend was observed in the changes in the synchronous fluorescence spectra of the DOM after biological treatment. Irrespective of the treatment option, the removal efficiency of DOM was greater when the influent DOM had a lower SUVA, reduced DOC-normalized humic substance-like fluorescence, and a lower R-DOM distribution. These results suggest that selected characteristics of the influent may provide an indication of DOM removal efficiency in WWTPs. For R-DOM removal efficiency, however, similar characteristics of the influent did not show a negative relationship, and even exhibited a slight positive correlation, suggesting that the presence of refractory organic carbon structures in the influent sewage may stimulate microbial activity and inhibit the production of R-DOM during biological treatment. PMID- 22439573 TI - Removal of nitrate and ammonium ions from livestock wastewater by hybrid systems composed of zero-valent iron and adsorbents. AB - The feasibility of hybrid systems for simultaneous removal of nitrate (NO3-) and ammonium ions (NH4+) from livestock wastewater was examined in batch experiments. As a part of efforts to remove nitrate and ammonium simultaneously, Fe0 and adsorbents including coconut-based granular activated carbon (GAC), sepiolite and filtralite were used. Various parameters such as adsorbent dosages and temperature were studied. Removal of NO3- increased with increase in temperature. Maximum NO3- removal (85.3%) was observed for the Fe0-filtralite hybrid system at 45 degrees C for a 24 h reaction time. Increase in GAC and sepiolite dosages had significant (P < 0.01) effect on the NH4+ removal efficiency, which was primarily due to the net negative surface charge of the adsorbents. The efficiency of hybrid systems for the removal of NO3- was in the order of filtralite > sepiolite > GAC, and the order of the removal of NH4+ was GAC > sepiolite > filtralite. The results of the present study suggest that the use of hybrid systems could be a promising innovative technology for achieving simultaneous removal of NO3- and NH4 from livestock wastewater. PMID- 22439574 TI - Enhanced treatment of wastewater from the vitamin C biosynthesis industry using a UASB reactor supplemented with zero-valent iron. AB - The effects of zero-valent iron (Fe0) on the performance of a mesophilic upflow anaerobic sludge blanket (UASB) reactor treating high-strength wastewater from the vitamin C biosynthesis industry (VCW) was investigated during a 200-day period. The results showed that the chemical oxygen demand (COD) removal efficiency, CH4 content in biogas, specific methanogenic activity of sludge, and phosphate removal efficiency were significantly improved up to 81.8-96.1%, 76.5 79.6%, 1.71-2.87 g CH4-COD g(-1) VSS d(-1) and 68.5-85.2%, respectively, at elevated organic loading rates (OLRs) in the Fe0-amended reactor (RFe). In contrast, the corresponding values of 65.3-83.4%, 69.1-70.8%, 1.12-1.95 g CH4-COD g(-1) VSS d(-1) and 1.4-1.6%, respectively, were recorded in the control (R0). Elevated ferrous concentration of nearly 400 mg L(-1) in sludge was detected in RFe, whereas in the effluent of both reactors it was low (< 1.0 mg L(-1)). Batch tests further showed that Fe0 significantly enhanced the biodegradability of the VCW as shown by an increase in BOD/COD ratio from 0.41 to 0.65, and could serve as the electron donor for methanogenesis by anaerobic sludge, which were responsible for the differences between RFe and R0. The results suggest this integrated Fe0-microbial system is promising in facilitating the anaerobic digestion of VCW in UASB reactors. PMID- 22439575 TI - Removal of coloured compounds from textile industry effluents by UV/H2O2 advanced oxidation and toxicity evaluation. AB - This study has investigated the reduction in coloured substances and toxic compounds present in textile industry effluent by the use of an advanced oxidation process using hydrogen peroxide (H2O2) as oxidant, activated by ultraviolet radiation. The investigation was carried out on industrial effluents, both raw and after biological treatment, using different concentrations of H2O2 in a photochemical reactor equipped with a 250 W high-pressure mercury vapour lamp. The results showed that after 60 minutes of ultraviolet irradiation a H2O2 concentration of 500 mg L(-1) was able to remove approximately 73% of the coloured compounds present in raw effluent and 96% of those present in biologically treated effluent. Additionally, post-treatment toxicity tests performed using the microcrustacean Daphnia magna showed a significant effective reduction in the acute toxicity of the raw effluent. In tests carried out with treatment at a concentration of 750 and 1000 mg L(-1) H2O2, analysis of the frequency ofmicronuclei in erythrocytes of Tilapia cf rendalli exposed to treated effluent samples confirmed that there were no mutagenic effects on the fish. Together, these results indicate that the oxidation process offers a good alternative for the removal of colour and toxicity from textile industry effluent. PMID- 22439576 TI - Sorption of endosulphan sulphate in soil organic matter. AB - Sorption of endosulphan sulphate in soil organic matter was investigated using Standard Elliot soil humic acid (HA) and soil fulvic acid (FA) at two ionic strengths (0.001 and 0.01). It was observed that divalent calcium ion and ionic strength affect the sorption of endosulphan sulphate in HA. All the experiments were carried out at pH 6.7 +/- 0.1. In the presence and absence of calcium (ionic strength 0.001), the solubility enhancement method was used to estimate the sorption coefficients of endosulphan sulphate in HA. For FA, the solubility enhancement method was used to estimate the sorption coefficients at an ionic strength of 0.001 (in the presence of calcium) and 0.01. The presence of calcium was found to significantly enhance (alpha = 0.01) the solubility of endosulphan sulphate in HA. Sorption coefficients at pH 6.7, obtained using the solubility enhancement method, were found to be 10-21 L/g in HA and 6 L/g in FA (in the presence of calcium). Increase in ionic strength from 0.001 to 0.01 decreased the sorption of endosulphan sulphate in HA. The effect of ionic strength and calcium on the sorption of endosulphan sulphate was most satisfactorily explained on the basis of the Donnan volume. PMID- 22439577 TI - Improvement of a three-step process for the treatment of aluminium hazardous wastes containing PAHs (benzo[b,j,k]fluoranthene and chrysene) and fluoride. AB - Hazardous wastes from a primary aluminium production plant could be decontaminated by a three-step process. First, the PAHs contained in these wastes were extracted with an amphoteric surfactant (0.25% or 0.50% w/w of cocamidopropylhydroxysultaine [CAS]) by cell or column flotation, depending on the particle size fraction (under or above 500 microm). Then, the fluorides were stabilized with lime (8% w/w) or a mixture of lime (4% w/w) and phosphoric acid (0.95% w/w). The decontaminated wastes satisfied the Quebec PAH norm, fixed at 1000 mg kg(-1), with values of 900 +/- 352 mg kg(-1) and 624 +/- 179 mg kg(-1) for benzo(b,j,k)fluoranthene (BJK) at laboratory and pilot scales, respectively. The fluoride stabilization in the treated wastes was characterized by TCLP values of 138 +/- 67 mg F- L(-1) and 29.5 +/- 7.6 mg F- L(-1) for laboratory and pilot experiments, which were under the Quebec norm (< 150 mg F- L(-1)). Finally, the metals in the process effluent were recovered by precipitation with sulphuric acid (10% v/v), and the final effluent and metallic residue obtained were recirculated without liquid fraction enrichment impact. The whole process was successfully tested at pilot scale. The preliminary economic study showed the potential of the process for the treatment of aluminium hazardous wastes. PMID- 22439578 TI - Isolation and characterization of catechol 2,3-dioxygenase genes from phenanthrene degraders Sphingomonas, sp. ZP1 and Pseudomonas sp. ZP2. AB - Two bacterial strains, Sphingomonas sp. ZP1 and Pseudomonas stutzeri sp ZP2, were identified as having phenanthrene-degrading ability and were characterized. The activity of catechol-2,3-dioxygenase (C230) of both strains was measured. With degradation of phenanthrene with an initial concentration of 250 ppm, the C230 activity of both strain ZP1 and ZP2 increased. The ZP1 strain consumed all phenanthrene at day 6, and strain ZP2 degraded 250 ppm of phenanthrene at around day 5; C230 activity in strain ZP1 reached its peak of 6.92 U at day 6, and C230 activity in strain ZP2 achieved 7.80 U as its peak at day 5. After all phenanthrene (250ppm) was consumed, C230 activity in both Sphingomonas sp. ZP1 and Pseudomonas stutzeri ZP2 decreased. Analysis of the C230 gene sequence indicated that gene PhnZP1 from strain ZP1 has close sequence similarity with the C230 gene from the nearest strain Sphingomonas. sp. KMG 425 (98% identity), 97% similarity with the C230 gene catA from S. paucimobilis sp. TZS-7, and 94% similar with catE gene from S. sp. HV3. The sequence of the C230 gene PhnZP2 of strain ZP2 has 98% similarity with the cmpE gene from strain S. sp., 92% similarity with the phnE gene from P. sp. DJ77 strain, and 90% similarity with all selected C230 genes from Pseudomonas genus strains. PMID- 22439579 TI - The effects of nickel(II) and chromium(VI) on oxygen demand, nitrogen and metal removal in a sequencing batch reactor. AB - The objective of this study was to evaluate the effects ofNi(II) and Cr(VI) individually and in combination on the simultaneous removal of chemical oxygen demand (COD), nitrogen and metals under a sequencing batch reactor (SBR) operation. Three identical laboratory-scale SBRs were operated with FILL, REACT, SETTLE, DRAW and IDLE periods in a ratio of 1:12:1:2:8 for a cycle time of 24 h until the steady state was achieved. Nickel(II) at increasing concentrations up to 35 mg/L was added to one of the reactors; Cr(VI) at increasing concentrations up to 25 mg/L was added to a second reactor; while a combination of Ni(II) and Cr(VI) in equal concentrations up to 10 mg/L was added to a third reactor. The results demonstrate that both Ni(II) and Cr(VI) exerted a more pronounced inhibitory effect on the removal of ammonia nitrogen (AN) than on COD removal. Synergistic and antagonistic inhibitory effects on the rates of COD and AN removal, respectively, were observed for the 50% Ni(II) and 50% Cr(VI) (w/w) mixture in the concentration range between 10 and 20 mg/L. The simultaneous presence of 50% Ni(II) and 50% Cr(VI) at a concentration of 20 mg/L resulted in system failure. PMID- 22439580 TI - Microemulsion-enhanced remediation of soils contaminated with organochlorine pesticides. AB - Soil contaminated by organic pollutants, especially chlorinated aromatic compounds such as DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane), is an environmental concern because of the strong sorption of organochlorine pesticide onto the soil matrix and persistence in the environment. The remediation of organochlorine pesticide contaminated soils through microemulsion is an innovative technology to expedite this process. The remediation efficiency was evaluated by batch experiments through studying the desorption of DDT and hexachlorocyclohexane (y-HCH) and sorption of microemulsion composed of Triton X 100, 1-pentanol and linseed oil in the soil-surfactant-water suspension system. The reduction of desorption efficiency caused by the sorption loss of microemulsion components onto the soil could be corrected by the appropriate adjustment of C/S (Cosurfactant/Surfactant) and O/S (Oil/Surfactant) ratio. The C/S and O/S ratios of 1:2 and 3:20 were suitable to desorb DDT and gamma-HCH from the studied soils because of the lower sorption of Triton X-100 onto the soil. Inorganic salts added in microemulsion increased the pesticides desorption efficiency of pesticides and calcium chloride has a stronger ability to enhance the desorption of DDT than sodium chloride. From the remediation perspective, the balance of surfactant or cosurfactant sorbed to soil and desorption efficiency should be taken into consideration to enhance the remediation of soils contaminated by organochlorine pesticides. PMID- 22439581 TI - Application of the International Water Association activated sludge models to describe aerobic sludge digestion. AB - Batch and semi-continuous flow aerobic digesters were used to stabilize thickened waste-activated sludge at different initial conditions and mean solids retention times. Under dynamic conditions, total suspended solids, volatile suspended solids (VSS) and total and particulate chemical oxygen demand (COD and PCOD) were monitored in the batch reactors and effluent from the semi-continuous flow reactors. Activated Sludge Model (ASM) no. 1 and ASM no. 3 were applied to measured data (calibration data set) to evaluate the consistency and performances of models at different flow regimes for digester COD and VSS modelling. The results indicated that both ASM1 and ASM3 predicted digester COD, VSS and PCOD concentrations well (R2, Ra2 > or = 0.93). Parameter estimation concluded that compared to ASM1, ASM3 parameters were more consistent across different batch and semi-continuous flow runs with different operating conditions. Model validation on a data set independent from the calibration data successfully predicted digester COD (R2 = 0.88) and VSS (R2 = 0.94) concentrations by ASM3, while ASM1 overestimated both reactor COD (R2 = 0.74) and VSS concentrations (R2 = 0.79) after 15 days of aerobic batch digestion. PMID- 22439582 TI - Treatment of aqueous and simulated wastewater of Luganil blue N dye--a new electrochemical approach. AB - Treatment of aqueous solution containing Luganil blue N (LBN) azo dye was performed by an electrochemical method under galvanostatic conditions using an undivided cell with platinum electrodes as working and auxiliary electrodes and standard calomel as the reference electrode. The aqueous solution of NaCl was used as the supporting electrolyte. Preliminary voltammetric studies were performed to establish the mode of degradation process. The effect of polarity of the electrode on degradation and decolouration rate was studied. The effect of the supporting electrolytes, concentration of NaCl, electrolysis time, solution pH and initial dye concentration on degradation rate were evaluated. The optimized operating conditions were used for the treatment of simulated wastewater containing LBN dye. The electrolysis process was monitored by an ultraviolet-visible spectrophotometer and measuring the chemical oxygen demand of the electrolysed solutions. The degradation products were identified using gas chromatograph/mass spectrometry studies, and a suitable mechanism for the LBN dye degradation was proposed. PMID- 22439583 TI - Characterization and optimization of Fe(II)Cit-No reduction by Pseudomonas sp. AB - Biological reduction of nitric oxide (NO), chelated by ferrous L (L: chelate reagent), to N2 is one of the core processes in a chemical absorption-biological reduction integrated technique for nitrogen oxide (NOx) removal from flue gases. In this study, a newly isolated strain, Pseudomonas sp., was used to reduce NO chelated by Fe(II)Cit (Cit: citrate) as Fe(II)Cit-NO, and some factors were investigated. The results showed that, at the NO concentration of 670 mg/m3, 65.9% of NO was totally reduced within 25 h under anaerobic conditions, and the optimal conditions for the bioreduction of NO were found. The strain of Pseudomonas sp. could efficiently use glucose as the carbon source for Fe(II)Cit NO reduction. Though each complex could be reduced by its own dedicated bacterial strain, Fe(III)Cit could also be reduced by the strain of Pseudomonas sp. The nitrite ion, NO2-, could inhibit cell growth and thus affect the Fe(III) reduction process. These findings provide some useful data for Fe(II)Cit-NO reduction, scrubber solution regeneration and NOx removal process design. PMID- 22439584 TI - Simulation of a membrane bioreactor pilot treating old landfill leachates with activated sludge model no. 1 and no. 3. AB - Activated sludge model No. 1 (ASM1) and activated sludge model No. 3 (ASM3) can simulate correctly the behaviour of a pilot membrane bioreactor treating old landfill leachates. Both models show similar results, which are consistent with measured data. In this work, a simplified calibration procedure is applied including hydrodynamic and oxygen transfer characterization. The wastewater characterisation was based on a physical-chemical method combined with a BOD analysis for the COD fractions and on standard analysis for nitrogen forms. Default parameters were used for both models; despite this, good simulations were obtained showing the flexibility and accuracy of the well-achieved ASM family models. The sensibility analysis performed allows identification of the most important kinetic, stoichiometric and operational parameters that should be measured to confirm or replace default values. In this specific case, the simulation is most sensitive to heterotrophic yield, particularly under anoxic conditions. PMID- 22439585 TI - Analysis and comparison of biotreatment of air polluted with ethanol using biofiltration and biotrickling filtration. AB - This study analyses the performance of ethanol biofiltration with percolation (biotrickling filtration, BTF) comparing to a conventional biofilter (biofiltration, BF). Two biofilters packed with clay balls were operated in a range of inlet concentrations of ethanol in the air varying from 0.47 to 2.36 g m(-3). For both the BF and BTF, the specific growth rate (mu) and the elimination capacity (EC) decreased with the ethanol inlet concentration, presenting a kinetic of substrate inhibition. A Haldane-type model was adjusted for both biofilters in order to model both EC and mu as a function of the ethanol inlet concentration in the gas. The maximum EC was similar for both biofilters, at around 46 g m(-3) h(-1), whereas the maximum mu was 0.0057 h(-1) for the BF and 0.0103 h(-1) for the BTF. The maximum of ethanol removed, occurred at the lowest inlet concentration of (0.47 gm(-3)), and reached 86% for the BF and 74% for the BTF. PMID- 22439586 TI - Application of fishmeal wastewater as a potential low-cost medium for lipid production by Lipomyces starkeyi HL. AB - Due to the high organic compounds and high salinity of fishmeal wastewater (FW), it was firstly used as a novel medium to produce microbial lipid in this paper. Fermentation of FW without any additives adding showed that the broth was appropriate for the growth of strain Lipomyces starkeyi HL; however, production of 5.34 g l(-1) of biomass containing 20.8% of lipid was not satisfied. In order to enhance the accumulation of lipid and cell growth, FW was supplemented with various concentrations of glucose; meanwhile, the influence of initial pH was investigated. Biomass and lipid yield on FW were markedly affected by glucose concentration and initial pH. The addition of 20 g l(-1) glucose at initial pH 4.0 got the best results: 17.6 g l(-1) of biomass, 2.7 g l(-1) of lipid yield, 91.2% of protein removal and 43.4% of the chemical oxygen demand removal. The variation of fatty acid composition upon time course in the cellular lipid on FW or a mixture of glucose and FW was further studied. PMID- 22439587 TI - Simultaneous removal of formaldehyde and benzene in indoor air with a combination of sorption- and decomposition-type air filters. AB - Urgent measures for indoor air pollution caused by volatile organic compounds are required in urban areas of China. Considering indoor air concentration levels and hazardous properties, formaldehyde and benzene should be given priority for pollution control in China. The authors proposed the use of air-cleaning devices, including stand-alone room air cleaners and in-duct devices. This study aimed to find the best combination of sorption and decomposition filters for the simultaneous removal of formaldehyde and benzene, employing four types of air filter units: an activated charcoal filter (ACF), an ACF impregnated with a trapping agent for acidic gases (ACID), a MnO2 filter (MDF) for oxidative decomposition of formaldehyde at room temperature and a photocatalyst filter (PHOTO) coupled with a parallel beam ultraviolet (UV) irradiation device. The performance of the combined systems under air flow rates of 35-165 m3 h(-1) was evaluated in a test chamber (2 m3) with a constant gas generation system. The experimental results and data analysis using a kinetic approach showed the combined system of ACF, PHOTO and MDF significantly reduced both concentrations of formaldehyde and benzene in air without any unpleasant odours caused by the UV induced photocatalytic reaction. The system was then evaluated in a full-size laboratory (22 m3). This test proved the practical performance of the system even at full scale, and also suggested that the filters should be arranged in the order of PHOTO/ACF/MDF from upstream to downstream. The proposed system has the potential of being used for improving indoor air quality of houses and buildings in China. PMID- 22439588 TI - Structural dynamics of a noncovalent charge transfer complex from femtosecond stimulated Raman spectroscopy. AB - Femtosecond stimulated Raman spectroscopy is used to examine the structural dynamics of photoinduced charge transfer within a noncovalent electron acceptor/donor complex of pyromellitic dianhydride (PMDA, electron acceptor) and hexamethylbenzene (HMB, electron donor) in ethylacetate and acetonitrile. The evolution of the vibrational spectrum reveals the ultrafast structural changes that occur during the charge separation (Franck-Condon excited state complex -> contact ion pair) and the subsequent charge recombination (contact ion pair -> ground state complex). The Franck-Condon excited state is shown to have significant charge-separated character because its vibrational spectrum is similar to that of the ion pair. The charge separation rate (2.5 ps in ethylacetate and ~0.5 ps in acetonitrile) is comparable to solvation dynamics and is unaffected by the perdeuteration of HMB, supporting the dominant role of solvent rearrangement in charge separation. On the other hand, the charge recombination slows by a factor of ~1.4 when using perdeuterated HMB, indicating that methyl hydrogen motions of HMB mediate the charge recombination process. Resonance Raman enhancement of the HMB vibrations in the complex reveals that the ring stretches of HMB, and especially the C-CH(3) deformations are the primary acceptor modes promoting charge recombination. PMID- 22439589 TI - Modeling nonspecific toxicity of organic compounds to the fathead minnow fish by means of chromatographic systems. AB - The performance of chromatographic systems to mimic aquatic toxicity to the fathead minnow fish is evaluated taking into account the factors that contribute to the variance of biological-chromatographic correlations. These factors are the precision to measure the fathead minnow toxicity, the precision of the surrogate chromatographic system, and the error from the dissimilarity between the fathead minnow and chromatographic systems. The precisions are estimated through the characterization of the systems by the solvation parameter model. Several chromatographic systems as well as the common reference octanol-water partition system have been selected to test their ability to model the nonspecific toxicity to the fathead minnow by means of the proposed approach. Predictions and experimental tests show that the micellar electrokinetic chromatography system of sodium taurocholate and chromatographic measurements using an immobilized artificial membrane column provide the most precise estimations of this biopartitioning property. The octanol-water partition system, the conventional C18 high-performance liquid chromatography systems, and the micellar electrokinetic chromatography system of sodium dodecylsulfate show worse performances. PMID- 22439590 TI - An exciton-coupled circular dichroism protocol for the determination of identity, chirality, and enantiomeric excess of chiral secondary alcohols. AB - Chiral mono-ols are among the most sought after targets in asymmetric synthesis, and therefore, their chemical characterization and associated enantiomeric excess (ee) values are commonly reported. A simple optical method for determining alcohol identity and ee could be widely used. Toward this end, an in situ generated multicomponent assembly that creates diastereomeric tris(pyridine) metal complexes incorporating chiral secondary alcohols was explored using exciton-coupled circular dichroism (ECCD). Qualitative models were proposed to predict the preferential diastereomer and its twist, and computational studies provided a rationalization of the CD spectra. Different ECCD spectra found for diastereomers formed in the self-assembled tris(pyridine) complexes were used to determine the absolute configurations of chiral mono-ols. Linear discriminant analysis was successfully employed to classify the alcohol analytes, thereby allowing identification of the alcohols. Conformational effects imparted by heteroatoms were also explored, further expanding the substrate scope. Finally, ee calibration curves allowed the determination of the ee of unknown samples of three chiral secondary alcohols with an average error of 3%. The assay described here is unique because no preparation of structurally elaborated chiral hosts is needed. PMID- 22439591 TI - Flacourtosides A-F, phenolic glycosides isolated from Flacourtia ramontchi. AB - In an effort to identify novel inhibitors of chikungunya (CHIKV) and dengue (DENV) virus replication, a systematic study with 820 ethyl acetate extracts of madagascan plants was performed in a virus-cell-based assay for CHIKV, and a DENV NS5 RNA-dependent RNA polymerase (RdRp) assay. The extract obtained from the stem bark of Flacourtia ramontchi was selected for its significant activity in both assays. Six new phenolic glycosides, named flacourtosides A-F (1-6), phenolic glycosides itoside H, xylosmin, scolochinenoside D, and poliothrysoside, and betulinic acid 3beta-caffeate were obtained using the bioassay-guided isolation process. Their structures were elucidated by comprehensive analyses of NMR spectroscopic and mass spectrometric data. Even though several extracts and fractions showed significant selective antiviral activity in the CHIKV virus-cell based assay, none of the purified compounds did. However, in the DENV RNA polymerase assay, significant inhibition was observed with betulinic acid 3beta caffeate (IC(50) = 0.85 +/- 0.1 MUM) and to a lesser extent for the flacourtosides A and E (1 and 5, respectively), and scolochinenoside D (IC(50) values ~10 MUM). PMID- 22439592 TI - Survival of neonates in rural Southern Tanzania: does place of delivery or continuum of care matter? AB - BACKGROUND: The concept of continuum of care has recently been highlighted as a core principle of maternal, newborn and child health initiatives, and as a means to save lives. However, evidence has consistently revealed that access to care during and post delivery (intra and postpartum) remains a challenge in the continuum of care framework. In places where skilled delivery assistance is exclusively available in health facilities, access to health facilities is critical to the survival of the mother and her newborn. However, little is known about the association of place of delivery and survival of neonates. This paper uses longitudinal data generated in a Health and Demographic Surveillance System in rural Southern Tanzania to assess associations of neonatal mortality and place of delivery. METHODS: Three cohorts of singleton births (born 2005, 2006 and 2007) were each followed up from birth to 28 days. Place of birth was classified as either "health facility" or "community". Neonatal mortality rates were produced for each year and by place of birth. Poisson regression was used to estimate crude relative risks of neonatal death by place of birth. Adjusted ratios were derived by controlling for maternal age, birth order, maternal schooling, sex of the child and wealth status of the maternal household. RESULTS: Neonatal mortality for health facility singleton deliveries in 2005 was 32.3 per 1000 live births while for those born in the community it was 29.7 per 1000 live births. In 2006, neonatal mortality rates were 28.9 and 26.9 per 1,000 live births for deliveries in health facilities and in the community respectively. In 2007 neonatal mortality rates were 33.2 and 27.0 per 1,000 live births for those born in health facilities and in the community respectively. Neonates born in a health facility had similar chances of dying as those born in the community in all the three years of study. Adjusted relative risks (ARR) for neonatal death born in a health facility in 2005, 2006 and 2007 were 0.99 (95% CI: 0.58 - 1.70), 0.98 (95% CI: 0.62 - 1.54) and 1.18 (95% CI: 0.76 - 1.85) respectively. CONCLUSIONS: We found no evidence to suggest that delivery in health facilities was associated with better survival chances of the neonates. PMID- 22439593 TI - Optimization of DNA hybridization efficiency by pH-driven nanomechanical bending. AB - The accessibility and binding affinity of DNA are two key parameters affecting the hybridization efficiency in surface-based biosensor technologies. Better accessibility will result in a higher hybridization efficiency. Often, mixed ssDNA and mercaptohexanol monolayers are used to increase the hybridization efficiency and accessibility of surface-bound oligonucleotides to complementary target DNA. Here, no mercaptohexanol monolayer was used. We demonstrate by differential microcantilever deflection measurements at different pH that the hybridization efficiency peaks between pH 7.5 and 8.5. At low pH 4.5, hydration and electrostatic forces led to tensile surface stress, implying the reduced accessibility of the bound ssDNA probe for hybridization. In contrast, at high pH 8.5, the steric interaction between neighboring ssDNA strands was decreased by higher electrostatic repulsive forces, bending the microcantilever away from the gold surface to provide more space for the target DNA. Cantilever deflection scales with pH-dependent surface hybridization efficiency because of high target DNA accessibility. Hence, by changing the pH, the hybridization efficiency is adjusted. PMID- 22439594 TI - Laboratory kinetic and mechanistic studies on the OH-initiated oxidation of acetone in aqueous solution. AB - The OH-initiated oxidation of acetone in aqueous solution is investigated because of its potential implications in atmospheric chemistry. The UV-spectrum of the transient acetonylperoxy radical was measured. Two characteristic absorption bands of the acetonylperoxy radical spectrum are found in the 220-400 nm wavelength region. The rate constant for the recombination reaction of the acetonylperoxy radical was determined as a function of temperature for the first time in aqueous solution with k(rec,298 K) = (7.3 +/- 1.3) * 10(8) M(-1) s(-1), E(A) = 4.5 +/- 3.3 kJ mol(-1), and A = (4.7 +/- 2.7) * 10(9) M(-1) s(-1). Furthermore, kinetic investigations of the OH-initiated oxidation of methylglyoxal and pyruvic acid were performed with the following results: for methylglyoxal, k(second) = (6.2 +/- 0.2) * 10(8) M(-1) s(-1), E(A) = 12 +/- 2 kJ mol(-1), and A = (7.8 +/- 0.2) * 10(9) M(-1) s(-1); for pyruvic acid (pH = 0), k(second) = (3.2 +/- 0.6) * 10(8) M(-1) s(-1), E(A) = 15 +/- 5 kJ mol(-1), and A = (1.1 +/- 0.1) * 10(11) M(-1) s(-1); for pyruvate (pH = 6), k(second) = (7.1 +/- 2.4) * 10(8) M(-1) s(-1), E(A) = 25 +/- 19 kJ mol(-1), and A = (1.5 +/- 0.4) * 10(13) M(-1) s(-1). Quantitative product studies were done as a function of the number of laser photolysis pulses for acetone and its oxidation products methylglyoxal, hydroxyacetone, pyruvic acid, acetic acid, and oxalic acid. After the recombination reaction of acetonylperoxy radicals, there are two possible decomposition reactions where the primary products methylglyoxal and hydroxyacetone are formed. From product analysis after a single photolysis laser shot, the ratio of the main product-forming reactions was determined as (A) 30% and (B) 56% for the methylglyoxal formation via channel A to yield two molecules of methylglyoxal and channel B to yield one molecule of methylglyoxal and one molecule of hydroxyacetone. The remaining product can be ascribed to channel C, the radical-retaining channel forming alkoxy radicals with a yield of 14%. Pyruvic acid and acetic acid were found to be the major intermediates estimated with concentrations in the same order of magnitude and a similar time profile, indicating that acetic acid is also a possible oxidation product of methylglyoxal. PMID- 22439595 TI - An unusual cause of fingernail dystrophy. PMID- 22439596 TI - Self-assembly and paclitaxel loading capacity of cellulose-graft-poly(lactide) nanomicelles. AB - A series of amiphiphilic cellulose-based graft copolymers (MCC-g-PLA) with various molecular factors were synthesized in ionic liquid BmimCl and characterized by FT-IR, (1)H NMR, (13)C NMR, XRD, and TGA. Their solubility in a variety of solvents was compared. The prepared MCC-g-PLA copolymers can self assemble into spherical nanomicelles (10-50 nm) in aqueous solution. The self assembly behaviors of the MCC-g-PLA copolymers were systematically investigated by fluorescence probe. Furthermore, the hydrophobic antitumor drug paclitaxel (PTX) was successfully encapsulated into the MCC-g-PLA micelles. The drug encapsulation efficiency and loading content were found to be as high as 89.30% (w/w) and 4.97%, respectively. Results in this study not only suggest a promising cellulose-based antitumor drug carrier but also provide information for property directed synthesis of the cellulose graft PLA copolymers. PMID- 22439597 TI - Independent 1D nanosized metal-organic tube: anion exchange, separation, and anion-responsive luminescence. AB - Three independent 1D metal-organic nanotubes AgL(2)X(2) [X = PF(6)(-) (1), ClO(4)(-) (2), and SbF(6)(-) (3)] with anion exchange, separation, and anion responsive photoluminescence are reported. PMID- 22439598 TI - Differential expression of moesin in breast cancers and its implication in epithelial-mesenchymal transition. AB - AIMS: Moesin belongs to the ERM (ezrin, radixin and moesin) family. Recent in vitro studies have shown the possible involvement of moesin in epithelial mesenchymal transition (EMT), but correlating in-vivo evidence is lacking. METHODS AND RESULTS: To study the biological significance of moesin, we used immunohistochemistry to investigate the in-situ expression profiles of moesin in 322 breast carcinomas of different subtypes, including 23 cases of metaplastic carcinoma (MCB) which is pathogenetically considered to involve EMT. Moesin was highly expressed in 95.7% of cases of MCB, and in 16% of cases of invasive ductal carcinoma (IDC), but was negative in all other subtypes of breast carcinomas. In IDCs, moesin expression correlated positively with a high histological grade (P < 0.001), basal-like phenotype (P < 0.001) and poor overall survival (P = 0.0263). Transfection of MCF7 cells with Snail, one of the key regulators of EMT, showed up-regulation of moesin at the transcriptional level. Finally, mRNA level of moesin correlated positively with Snail and EMT-related genes in a microarray data set using primary breast cancer samples. CONCLUSION: These results offer biological evidence of moesin as an EMT marker, support the association between moesin, Snail and EMT and suggest a role for moesin in breast cancer prognostication. PMID- 22439599 TI - Effects of bezafibrate on lipid and glucose metabolism in dyslipidemic patients with diabetes: the J-BENEFIT study. AB - BACKGROUND: The hypoglycemic effect of bezafibrate is well established, but administration to a large population of patients with diabetes has not been reported. We investigated glycemic control, relationship between lipid metabolism and HbA1c, and safety in diabetic patients treated with bezafibrate. METHODS: A prospective, observational analysis was conducted on 6,407 dyslipidemic patients suffering from diabetes or hyperglycemia who had not received bezafibrate previously. Subanalyses were performed on the concomitant use of diabetes drugs, diabetes duration, and baseline HbA1c levels. RESULTS: Bezafibrate significantly decreased HbA1c irrespective of concomitant use of other diabetes drugs in a baseline-HbA1c-dependent manner, with patients with a shorter diabetes duration showing a greater decrease in HbA1c than those with longer-term disease. The rate of change in triglyceride levels was significantly associated with that in HbA1c. Adverse drug reactions occurred in 306 patients (5.1%), of which reactions in 289 were not severe (94.4%). CONCLUSIONS: Bezafibrate significantly improved HbA1c in patients with diabetes given individualized treatment. Bezafibrate may offer clinicians an improved modality for the amelioration of disease course and improvement of outcome in these patients. PMID- 22439600 TI - A potential role of Escherichia coli pathobionts in the pathogenesis of pediatric inflammatory bowel disease. AB - Through genomic analysis of mucosa-associated Escherichia coli strains, we found a close genetic association among isolates from pediatric inflammatory bowel disease (IBD) patients. A specific E. coli pathovar, adherent-invasive E. coli (AIEC), was found in Crohn's disease (CD) adult patients - this pathovar has enhanced adhesive and invasive properties, mainly due to the mannose-bonding FimH protein. We aimed to characterize 52 mucosa-associated E. coli strains isolated from pediatric IBD and non-IBD patients. Eleven E. coli strains, showing a strong similarity in fimH gene sequence to that of E. coli AIEC LF82, were characterized for fimH gene sequence, genomic profiling, adhesive and invasive ability, and phylogrouping. The results were compared with E. coli strains AIEC LF82 and MG1655. The 11 E. coli isolates showed 82.4% +/- 1.4% fimH sequence similarity and 80.6% +/- 1.3% genomic similarity to strain AIEC LF82. All these strains harbored V27A and S78N FimH mutations, as found in LF82. Nine of them belonged to the more virulent B2 and D phylogroups. Neuraminidase treatment, mimicking inflamed mucosa, enhanced adhesion of all 11 strains by 3.5-fold, but none showed invasion ability. It could be argued that the 11 selected strains could be a branch of an E. coli subpopulation (pathobionts), that could take advantage in an inflamed context because of a suitable genomic and (or) genetic backdrop. PMID- 22439601 TI - HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses in fractionated gamma-irradiated mice by modulating the IL-12p70-STAT4 signaling pathway. AB - Whole body irradiated mice appear to experience a down-regulation of the helper T (Th)1-like immune response, and maintain a persistent immunological imbalance. In the current study, we evaluated the effect of HemoHIM (an herbal product made from Angelica Radix, Cnidium officinale , and Paeonia japonica cultivated in Korea) to ameliorate the immunological imbalance induce in fractionated gamma irradiated mice. The mice were exposed to gamma rays twice a week (0.5 Gy fractions) for a total dose of 5 Gy, and HemoHIM was administrated orally from 1 week before the first irradiation to 1 week before the final analysis. All experiments were performed 4 and 6 months after their first exposure. HemoHIM ameliorated the Th1- and Th2-related immune responses normally occur in irradiated mice with or without dinitrophenylated keyhole limpet hemocyanin immunization. HemoHIM also restored the natural killer cell activities without changing the percentage of natural killer cells in irradiated mice. Furthermore, the administration of HemoHIM prevented the reduction in levels of interleukin 12p70 in irradiated mice. Finally, we found that HemoHIM enhanced the phosphorylation of signal transducer and activator of transcription (STAT) 4 that was reduced in irradiated mice. Our findings suggest that HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses by modulating the IL 12p70/pSTAT4 signaling pathway. PMID- 22439602 TI - Intestinal microbiota as novel biomarkers of prior radiation exposure. AB - There is an urgent need for rapid, accurate, and sensitive diagnostic platforms to confirm exposure to radiation and estimate the dose absorbed by individuals subjected to acts of radiological terrorism, nuclear power plant accidents, or nuclear warfare. Clinical symptoms and physical dosimeters, even when available, do not provide adequate diagnostic information to triage and treat life threatening radiation injuries. We hypothesized that intestinal microbiota act as novel biomarkers of prior radiation exposure. Adult male Wistar rats (n = 5/group) received single or multiple fraction total-body irradiation of 10.0 Gy and 18.0 Gy, respectively. Fresh fecal pellets were obtained from each rat prior to (day 0) and at days 4, 11, and 21 post-irradiation. Fecal microbiota composition was determined using microarray and quantitative PCR (polymerase chain reaction) analyses. The radiation exposure biomarkers consisted of increased 16S rRNA levels of 12 members of the Bacteroidales, Lactobacillaceae, and Streptococcaceae after radiation exposure, unchanged levels of 98 Clostridiaceae and Peptostreptococcaceae, and decreased levels of 47 separate Clostridiaceae members; these biomarkers are present in human and rat feces. As a result of the ubiquity of these biomarkers, this biomarker technique is non invasive; microbiota provide a sustained level of reporting signals that are increased several-fold following exposure to radiation, and intestinal microbiota that are unaffected by radiation serve as internal controls. We conclude that intestinal microbiota serve as novel biomarkers of prior radiation exposure, and may be able to complement conventional chromosome aberrational analysis to significantly enhance biological dose assessments. PMID- 22439604 TI - Formation polarity dependent improved resistive switching memory characteristics using nanoscale (1.3 nm) core-shell IrOx nano-dots. AB - Improved resistive switching memory characteristics by controlling the formation polarity in an IrOx/Al2O3/IrOx-ND/Al2O3/WOx/W structure have been investigated. High density of 1 * 1013/cm2 and small size of 1.3 nm in diameter of the IrOx nano-dots (NDs) have been observed by high-resolution transmission electron microscopy. The IrOx-NDs, Al2O3, and WOx layers are confirmed by X-ray photo electron spectroscopy. Capacitance-voltage hysteresis characteristics show higher charge-trapping density in the IrOx-ND memory as compared to the pure Al2O3 devices. This suggests that the IrOx-ND device has more defect sites than that of the pure Al2O3 devices. Stable resistive switching characteristics under positive formation polarity on the IrOx electrode are observed, and the conducting filament is controlled by oxygen ion migration toward the Al2O3/IrOx top electrode interface. The switching mechanism is explained schematically based on our resistive switching parameters. The resistive switching random access memory (ReRAM) devices under positive formation polarity have an applicable resistance ratio of > 10 after extrapolation of 10 years data retention at 85 degrees C and a long read endurance of 105 cycles. A large memory size of > 60 Tbit/sq in. can be realized in future for ReRAM device application. This study is not only important for improving the resistive switching memory performance but also help design other nanoscale high-density nonvolatile memory in future. PMID- 22439605 TI - Increased composite maternal and neonatal morbidity associated with ultrasonographically suspected fetal macrosomia. AB - OBJECTIVE: To determine the composite risk of maternal and neonatal morbidity in pregnancies with suspected fetal macrosomia. METHODS: In a retrospective study of laboring women delivering singleton, term neonates, we defined 3 groups of patients by estimated fetal weight (EFW) in grams, using ultrasound: (1) <4000, (2) 4000-4499, and (3) 4500+, and tested them for association with a composite outcome using multivariable logistic regression models. The measure of composite morbidity included: shoulder dystocia, third/fourth degree perineal laceration, postpartum hemorrhage, maternal length of stay (LOS) >= 5 days, neonatal birth trauma, meconium aspiration syndrome, perinatal infection, and neonatal LOS >= 5 days. Because of potential interactions between diabetes and birthweight, women with maternal diabetes were examined separately. RESULTS: Of 8,843 deliveries, the proportion with composite morbidity by group was: (1): 26.2%, (2): 41.2%, and (3): 63.6% (p < 0.0001). The OR (95% CI) for groups (2) and (3) were: 1.9 (1.2 2.9) and 2.1 (0.6-7.2), for diabetics (9.7% of the final study population), and 2.3 (1.9-2.7) and 3.9 (2.2-6.9), for non-diabetics. CONCLUSIONS: Suspected fetal macrosomia appeared associated with increased risk for a composite measure of childbirth morbidity. PMID- 22439606 TI - Support for children identified with acute flaccid paralysis under the global polio eradication programme in Uttar Pradesh, India: a qualitative study. AB - BACKGROUND: Cases of polio in India declined after the implementation of the polio eradication programme especially in these recent years. The programme includes surveillance of acute flaccid paralysis (AFP) to detect and diagnose cases of polio at early stage. Under this surveillance, over 40,000 cases of AFP are reported annually since 2007 regardless of the number of actual polio cases. Yet, not much is known about these children. We conducted a qualitative research to explore care and support for children with AFP after their diagnosis. METHODS: The research was conducted in a district of western Uttar Pradesh classified as high-risk area for polio. In-depth interviews with parents of children with polio (17), with non-polio AFP (9), healthcare providers (40), and key informants from community including international and government officers, religious leaders, community leaders, journalists, and academics (21) were performed. RESULTS: Minimal medicine and attention were provided at government hospitals. Therefore, most parents preferred private-practice doctors for their children with AFP. Many were visited at homes to have stool samples collected by authorities. Some were visited repetitively following the sample collection, but had difficulty in understanding the reasons for these visits that pertained no treatment. Financial burden was a common concern among all families. Many parents expressed resentment for their children's disease, notably have been affected despite receiving multiple doses of polio vaccine. Both parents and healthcare providers lacked information and knowledge, furthermore poverty minimised the access to available healthcare services. Medicines, education, and transportation means were identified as foremost needs for children with AFP and residual paralysis. CONCLUSIONS: Despite the high number of children diagnosed with AFP as part of the global polio eradication programme, we found they were not provided with sufficient medical support following their diagnosis. Improvement in the quality and sufficiency of the healthcare system together with integration of AFP surveillance with other services in these underprivileged areas may serve as a key solution. PMID- 22439607 TI - Comparison of intensity modulated radiotherapy (IMRT) with intensity modulated particle therapy (IMPT) using fixed beams or an ion gantry for the treatment of patients with skull base meningiomas. AB - BACKGROUND: To examine the potential improvement in treatment planning for patients with skull base meningioma using IMRT compared to carbon ion or proton beams with and without a gantry. METHODS: Five patients originally treated with photon IMRT were selected for the study. Ion beams were chosen using a horizontal beam or an ion gantry. Intensity controlled raster scanning and the intensity modulated particle therapy mode were used for plan optimization. The evaluation included analysis of dose-volume histograms of the target volumes and organs at risk. RESULTS: In comparison with carbon and proton beams only with horizontal beams, carbon ion treatment plans could spare the OARs more and concentrated on the target volumes more than proton and photon IMRT treatment plans. Using only a horizontal fixed beam, satisfactory plans could be achieved for skull base tumors. CONCLUSION: The results of the case studies showed that using IMPT has the potential to overcome the lack of a gantry for skull base tumors. Carbon ion plans offered slightly better dose distributions than proton plans, but the differences were not clinically significant with established dose prescription concepts. PMID- 22439608 TI - Arena3D: visualizing time-driven phenotypic differences in biological systems. AB - BACKGROUND: Elucidating the genotype-phenotype connection is one of the big challenges of modern molecular biology. To fully understand this connection, it is necessary to consider the underlying networks and the time factor. In this context of data deluge and heterogeneous information, visualization plays an essential role in interpreting complex and dynamic topologies. Thus, software that is able to bring the network, phenotypic and temporal information together is needed. Arena3D has been previously introduced as a tool that facilitates link discovery between processes. It uses a layered display to separate different levels of information while emphasizing the connections between them. We present novel developments of the tool for the visualization and analysis of dynamic genotype-phenotype landscapes. RESULTS: Version 2.0 introduces novel features that allow handling time course data in a phenotypic context. Gene expression levels or other measures can be loaded and visualized at different time points and phenotypic comparison is facilitated through clustering and correlation display or highlighting of impacting changes through time. Similarity scoring allows the identification of global patterns in dynamic heterogeneous data. In this paper we demonstrate the utility of the tool on two distinct biological problems of different scales. First, we analyze a medium scale dataset that looks at perturbation effects of the pluripotency regulator Nanog in murine embryonic stem cells. Dynamic cluster analysis suggests alternative indirect links between Nanog and other proteins in the core stem cell network. Moreover, recurrent correlations from the epigenetic to the translational level are identified. Second, we investigate a large scale dataset consisting of genome-wide knockdown screens for human genes essential in the mitotic process. Here, a potential new role for the gene lsm14a in cytokinesis is suggested. We also show how phenotypic patterning allows for extensive comparison and identification of high impact knockdown targets. CONCLUSIONS: We present a new visualization approach for perturbation screens with multiple phenotypic outcomes. The novel functionality implemented in Arena3D enables effective understanding and comparison of temporal patterns within morphological layers, to help with the system-wide analysis of dynamic processes. Arena3D is available free of charge for academics as a downloadable standalone application from: http://arena3d.org/. PMID- 22439610 TI - A fiber-optic-based imaging system for nondestructive assessment of cell-seeded tissue-engineered scaffolds. AB - A major limitation in tissue engineering is the lack of nondestructive methods that assess the development of tissue scaffolds undergoing preconditioning in bioreactors. Due to significant optical scattering in most scaffolding materials, current microscope-based imaging methods cannot "see" through thick and optically opaque tissue constructs. To address this deficiency, we developed a fiber-optic based imaging method that is capable of nondestructive imaging of fluorescently labeled cells through a thick and optically opaque scaffold, contained in a bioreactor. This imaging modality is based on the local excitation of fluorescent cells, the acquisition of fluorescence through the scaffold, and fluorescence mapping based on the position of the excitation light. To evaluate the capability and accuracy of the imaging system, human endothelial cells (ECs), stably expressing green fluorescent protein (GFP), were imaged through a fibrous scaffold. Without sacrificing the scaffolds, we nondestructively visualized the distribution of GFP-labeled cells through a ~500 MUm thick scaffold with cell level resolution and distinct localization. These results were similar to control images obtained using an optical microscope with direct line-of-sight access. Through a detailed quantitative analysis, we demonstrated that this method achieved a resolution on the order of 20-30 MUm, with 10% or less deviation from standard optical microscopy. Furthermore, we demonstrated that the penetration depth of the imaging method exceeded that of confocal laser scanning microscopy by more than a factor of 2. Our imaging method also possesses a working distance (up to 8 cm) much longer than that of a standard confocal microscopy system, which can significantly facilitate bioreactor integration. This method will enable the nondestructive monitoring of ECs seeded on the lumen of a tissue engineered vascular graft during preconditioning in vitro, as well as for other tissue-engineered constructs in the future. PMID- 22439611 TI - Efficacy of acidic and basic electrolyzed water in eradicating Staphylococcus aureus biofilm. AB - Staphylococcus aureus is a major pathogen. It can form biofilm on the surfaces of medical devices and food equipment, which makes it more difficult to eradicate. To develop a novel method to eradicate S. aureus biofilm, the effects of electrolyzed water on removing and killing S. aureus biofilm were investigated in this study. By using a biofilm biomass assay with safranin staining and visualization of biofilm architecture with scanning electron microscopy, it was shown that basic electrolyzed water (BEW) could effectively remove established biofilm. The pH of electrolyzed water affected removal efficacy. Using a biofilm viability assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide staining, acidic electrolyzed water (AEW) efficiently killed biofilm-imbedded S. aureus. The available chlorine in AEW may be a main contributing factor for bactericidal activity. Additionally, BEW had a removal efficacy for S. aureus biofilm equivalent to 2% NaOH, and AEW had a bactericidal capability for S. aureus in biofilm equivalent to 2% HCl. These data suggested that AEW and BEW could be applied as a bactericide and removing agent for S. aureus in biofilm, respectively. PMID- 22439612 TI - Multiple effects of electroporation on the adhesive behaviour of breast cancer cells and fibroblasts. AB - BACKGROUND: Recently electroporation using biphasic pulses was successfully applied in clinical developments for treating tumours in humans and animals. We evaluated the effects of electrical treatment on cell adhesion behaviour of breast cancer cells and fibroblasts. By applying bipolar electrical pulses we studied short- and long-lived effects on cell adhesion and survival, actin cytoskeleton and cell adhesion contacts in adherent cancer cells and fibroblasts. METHODS: Two cancer cell lines (MDA-MB-231 and MCF-7) and one fibroblast cell line 3T3 were used. Cells were exposed to high field intensity (200 - 1000 V/cm). Cell adhesion and survival after electrical exposure were studied by crystal violet assay and MTS assay. Cytoskeleton rearrangement and cell adhesion contacts were visualized by actin staining and fluorescent microscope. RESULTS: The degree of electropermeabilization of the adherent cells elevated steadily with the increasing of the field intensity. Adhesion behaviour of fibroblasts and MCF-7 was not significantly affected by electrotreatment. Interestingly, treating the loosely adhesive cancer cell line MDA-MB-231 with 200 V/cm and 500 V/cm resulted in increased cell adhesion. Cell replication of both studied cancer cell lines was disturbed after electropermeabilization. Electroporation influenced the actin cytoskeleton in cancer cells and fibroblasts in different ways. Since it disturbed temporarily the actin cytoskeleton in 3T3 cells, in cancer cells treated with lower and middle field intensity actin cytoskeleton was well presented in stress fibers, filopodia and lamellipodia. The electrotreatment for cancer cells provoked preferentially cell-cell adhesion contacts for MCF-7 and cell-ECM contacts for MDA-MB- 231. CONCLUSIONS: Cell adhesion and survival as well as the type of cell adhesion (cell-ECM or cell-cell adhesion) induced by the electroporation process is cell specific. The application of suitable electric pulses can provoke changes in the cytoskeleton organization and cell adhesiveness, which could contribute to the restriction of tumour invasion and thus leads to the amplification of anti-tumour effect of electroporation-based tumour therapy. PMID- 22439613 TI - Experimental syringohydromyelia induced by adhesive arachnoiditis in the rabbit: changes in the blood-spinal cord barrier, neuroinflammatory foci, and syrinx formation. AB - There are many histological examinations of syringohydromyelia in the literature. However, there has been very little experimental work on blood permeability in the spinal cord vessels and ultrastructural changes. We prepared an animal model of spinal adhesive arachnoiditis by injecting kaolin into the subarachnoid space at the eighth thoracic vertebra of rabbits. The animals were evaluated 4 months later. Of the 30 rabbits given kaolin injection into the cerebrospinal fluid, 23 showed complete circumferential obstruction. In the 7 animals with partial obstruction of the subarachnoid space, intramedullary changes were not observed. However, among the 23 animals showing complete obstruction of the subarachnoid space, dilatation of the central canal (hydromyelia) occurred in 21, and intramedullary syrinx (syringomyelia) was observed in 11. In animals with complete obstruction, fluorescence microscopy revealed intramedullary edema around the central canal, extending to the posterior columns. Electron microscopy of hydromyelia revealed a marked reduction of villi on the ependymal cells, separation of the ependymal cells, and cavitation of the subependymal layer. The dilated perivascular spaces indicate alterations of fluid exchange between the subarachnoid and extracellular spaces. Syringomyelia revealed that nerve fibers and nerve cells were exposed on the surface of the syrinx, and necrotic tissue was removed by macrophages to leave a syrinx. Both pathologies differ in their mechanism of development: hydromyelia is attributed to disturbed reflux of cerebrospinal fluid, while tissue necrosis due to disturbed intramedullary blood flow is considered to be involved in formation of the syrinx in syringomyelia. PMID- 22439614 TI - Sports activity and the use of cigarettes and snus among young males in Finland in 1999-2010. AB - BACKGROUND: Studies of the relationship between sports activity and smoking among adolescents and young adults report contradictory results. We examined the association between sports activity (intensity and type of sport) and the current use of snus (Swedish snuff), cigarette smoking, and the combined use of cigarettes and snus (dual use) among young males in Finland. METHODS: Data were collected from 16,746 male conscripts who completed a survey during the first days of their conscription during the years 1999-2010 (median age 19 years, response rate 95%). Main outcome measures were self-reported daily/occasional use of snus, cigarette smoking, and dual use. The association between sports activity, type of sport, and several sociodemographic background variables was assessed using logistic regression analysis. RESULTS: Over the study period (1999 2010), the prevalence of cigarette smoking decreased from 42% to 34%, while snus use increased from 5% to 12%, and dual use increased from 7% to 13% (p < 0.001). Compared with no physical activity, regular competitive sports activity (defined as high-intensity sports activity) was positively associated with use of snus (odds ratio [OR] 10.2; 95% confidence interval [CI]: 7.8-13.5) and negatively with cigarette smoking (OR 0.2; 95% CI: 0.1-0.3). When stratified by type of sport in multivariate models, ice hockey was most strongly associated with snus use (OR 1.6; 95% CI: 1.4-1.9) and dual use (OR 2.0; 95% CI 1.8-2.3) compared with those not playing ice-hockey, followed by other team sports for snus use (OR 1.5; 95% CI: 1.3-1.8) and dual use (OR 1.8; 95% CI: 1.6-2.0) compared with those not participating in other team-sports. CONCLUSIONS: Our results show a clear association between snus use and intensity and type of training. Team sports were associated with increased use of snus and dual use compared with no participation in team sports. These findings should be acknowledged when planning and implementing preventive strategies. PMID- 22439615 TI - Halogen-enriched fragment libraries as leads for drug rescue of mutant p53. AB - The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent structure-guided design, we developed substituted 2-(aminomethyl)-4-ethynyl-6-iodophenols as p53-Y220C stabilizers. Crystal structures of their complexes highlight two key features: (i) a central scaffold with a robust binding mode anchored by halogen bonding of an iodine with a main-chain carbonyl and (ii) an acetylene linker, enabling the targeting of an additional subsite in the crevice. The best binders showed induction of apoptosis in a human cancer cell line with homozygous Y220C mutation. Our structural and biophysical data suggest a more widespread applicability of HEFLibs in drug discovery. PMID- 22439616 TI - From press release to news: mapping the framing of the 2009 H1N1 A influenza pandemic. AB - Pandemics challenge conventional assumptions about health promotion, message development, community engagement, and the role of news media. To understand the use of press releases in news coverage of pandemics, this study traces the development of framing devices from a government public health agency's press releases to news stories about the 2009 H1N1 A influenza pandemic. The communication management of the H1N1 pandemic, an international news event with local implications, by the Singapore government is a rich locus for understanding the dynamics of public relations, health communication, and journalism. A content analysis shows that the evolution of information from press release to news is marked by significant changes in media frames, including the expansion and diversification in dominant frames and emotion appeals, stronger thematic framing, more sources of information, conversion of loss frames into gain frames, and amplification of positive tone favoring the public health agency's position. Contrary to previous research that suggests that government information subsidies passed almost unchanged through media gatekeepers, the news coverage of the pandemic reflects journalists' selectivity in disseminating the government press releases and in mediating the information flow and frames from the press releases. PMID- 22439617 TI - Umbilical activin A concentration as an early marker of perinatal hypoxia. AB - OBJECTIVE: To evaluate activin A as a potential, early marker of perinatal hypoxia and to analyze factors, other than hypoxia, which influence on activin A concentration. METHODS: Umbilical cord blood samples were collected from 86 newborns with gestational age 30-41. Of the 86 newborns, 26 were regarded as hypoxic. Activin A concentrations were measured by means of specific two-site enzyme immunoassays. Activin A concentrations were correlated with newborns' gender, week gestation, mode of delivery and blood gas measurements. RESULTS: Activin A levels were significantly higher in hypoxic than nonhypoxic newborns (medians, minimum and maximum values: 1.516; 0.149 -1.974 versus 0.368; 0.054 - 1.041 ng/mL, p = 0.0452). Activin A concentration was significantly higher in male newborns (p = 0.0074). Activin A levels were lower in term than preterm babies but the differences were not statistically significant (p = 0.2368 in hypoxic, p = 0.2487 nonhypoxic). Mode of delivery did not influence on activin A concentration (p = 0.8293 hypoxic, p = 0.9458 nonhypoxic). The differences of occurrence of intraventricular hemorrhage (IVH) in both group was not statistically significant (p = 0.61). CONCLUSIONS: Umbilical artery activin A combined with other markers of hypoxia could be a useful marker of perinatal hypoxia. Concentration of activin A is significantly higher in male newborns. The mode and time of delivery have no influence on activin A concentration. PMID- 22439618 TI - Metabolism of anthocyanins by human gut microflora and their influence on gut bacterial growth. AB - Consumption of anthocyanins has been related with beneficial health effects. However, bioavailability studies have shown low concentration of anthocyanins in plasma and urine. In this study, we have investigated the bacterial-dependent metabolism of malvidin-3-glucoside, gallic acid and a mixture of anthocyanins using a pH-controlled, stirred, batch-culture fermentation system reflective of the distal human large intestine conditions. Most anthocyanins have disappeared after 5 h incubation while gallic acid remained constant through the first 5 h and was almost completely degraded following 24 h of fermentation. Incubation of malvidin-3-glucoside with fecal bacteria mainly resulted in the formation of syringic acid, while the mixture of anthocyanins resulted in formation of gallic, syringic and p-coumaric acids. All the anthocyanins tested enhanced significantly the growth of Bifidobacterium spp. and Lactobacillus-Enterococcus spp. These results suggest that anthocyanins and their metabolites may exert a positive modulation of the intestinal bacterial population. PMID- 22439619 TI - Effects of a feint on reactive agility performance. AB - This study compared reactive agility between higher-standard (n = 14) and lower standard (n = 14) Australian footballers using a reactive agility test incorporating a life-size video image of another player changing direction, including and excluding a feint. Mean agility time in the feint trials was 34% (509 +/- 243 ms; p < 0.001; effect size 3.06) longer than non-feint trials. In higher-standard players, agility time was shorter than for lower-standard players in both feint (114 +/- 140 ms; p = 0.18; effect size 0.52; likely beneficial) and non-feint (32 +/- 44 ms; p = 0.22; effect size 0.47; possibly beneficial) trials. Additionally, the inclusion of a feint resulted in movement time increasing over three times more in the lower-standard group (197 +/- 91 ms; p = 0.001; effect size 1.07; almost certainly detrimental) than the higher-standard group (62 +/- 86 ms; p = 0.23; effect size 0.66; likely detrimental). There were weak correlations between the feint and non-feint trials (r = -0.13-0.14; p > 0.05), suggesting that reactive agility involving a feint is a unique skill. Also, higher-standard players are more agile than their lower-standard peers, whose movement speed deteriorates more as task complexity increases with the inclusion of a feint. These results support the need for specific training in multi-turn reactive agility tasks. PMID- 22439620 TI - Phase networks of cross-beta peptide assemblies. AB - Recent evidence suggests that simple peptides can access diverse amphiphilic phases, and that these structures underlie the robust and widely distributed assemblies implicated in nearly 40 protein misfolding diseases. Here we exploit a minimal nucleating core of the Abeta peptide of Alzheimer's disease to map its morphologically accessible phases that include stable intermolecular molten particles, fibers, twisted and helical ribbons, and nanotubes. Analyses with both fluorescence lifetime imaging microscopy (FLIM) and transmission electron microscopy provide evidence for liquid-liquid phase separations, similar to the coexisting dilute and dense protein-rich liquid phases so critical for the liquid solid transition in protein crystallization. We show that the observed particles are critical for transitions to the more ordered cross-beta peptide phases, which are prevalent in all amyloid assemblies, and identify specific conditions that arrest assembly at the phase boundaries. We have identified a size dependence of the particles in order to transition to the para-crystalline phase and a width of the cross-beta assemblies that defines the transition between twisted fibers and helically coiled ribbons. These experimental results reveal an interconnected network of increasing molecularly ordered cross-beta transitions, greatly extending the initial computational models for cross-beta assemblies. PMID- 22439621 TI - New and emerging treatments for Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease and other dementias represent a significant and increasing clinical challenge. Dementia is also associated with a substantial economic cost and burden to health service provision. Existing treatments slow the progression of symptoms of the disease, but their efficacy does not extend to all patients and is not sustained beyond an average of 6 months. It is, therefore, critical to address the current lack of effective treatments to target the underlying pathology and disease process in Alzheimer's disease. AREAS COVERED: This review aims to highlight the main areas of new therapeutic development and discuss some of the main therapies currently being evaluated in clinical trials. Despite a number of promising rationales for therapeutic treatments in Alzheimer's disease, very few of these avenues have been developed beyond preclinical studies. The predominant focus of the current article is on treatments currently in Phase II and Phase III clinical trials, but some other promising areas of development are also discussed. There are currently only three therapeutics being investigated in Phase III clinical trials. This emphasizes the substantial caution and underinvestment in treatment development in this area. EXPERT OPINION: There is a distinct lack of novel approaches in the pipeline, and whether there is a new disease-modifying therapy for Alzheimer's disease in the next 5 years almost entirely depends on the success of currently ongoing immunotherapy studies. Importantly, there is potential benefit in exploring existing licensed treatments alongside novel drug development to increase the focus on novel targets within this time frame. PMID- 22439622 TI - Totopotensamides, polyketide-cyclic peptide hybrids from a mollusk-associated bacterium Streptomyces sp. AB - Two new compounds, the peptide-polyketide glycoside totopotensamide A (1) and its aglycone totopotensamide B (2), were isolated from a Streptomyces sp. cultivated from the gastropod mollusk Lienardia totopotens collected in the Philippines. The compounds contain a previously undescribed polyketide component, a novel 2,3 diaminobutyric acid-containing macrolactam, and a new amino acid, 4-chloro-5,7 dihydroxy-6-methylphenylglycine. The application of Marfey's method to phenylglycine derivatives was explored using quantum mechanical calculations and NMR. PMID- 22439623 TI - Detection of membrane-binding proteins by surface plasmon resonance with an all aqueous amplification scheme. AB - We report here a surface plasmon resonance (SPR) method for detection of cell membrane binding proteins with high degree signal amplification carried out in an all-aqueous condition. Ultrahigh detection sensitivity was achieved for a membrane-based biosensing interface through the use of functional gold nanoparticles (AuNP) in combination with in situ atom transfer radical polymerization (ATRP) reaction. Fusion of phosphatidylcholine vesicles on a calcinated SPR gold chip established a supported bilayer membrane in which cell receptor monosialoganglioside GM1 was embedded for capture of bacterial cholera toxin (CT). The surface-bound CT was recognized with biotinylated anti-CT, which was linked to the biotin-AuNP through an avidin bridge. The biotin-AuNP surface was functionalized with ATRP initiator that triggers localized growth of poly(hydroxyl-ethyl methacrylate) (PHEMA) brush, contributing to marked SPR signal enhancement and quantitative measurement of CT at very low concentrations. The resulting polymer film has been characterized by optical and atomic force microscopy. A calibration curve for CT detection has been obtained displaying a response range from 6.3 * 10(-16) to 6.3 * 10(-8) M with a detection limit of 160 aM (equivalent to ~9500 molecules in 100 MUL sample solution). Sensitive detection of biomolecules in complex medium has been conducted with CT-spiked serum, and the detection limit can be effectively improved by 6 orders of magnitude compared to direct measurement in serum. The combined AuNP/ATRP method reported here opens new avenues for ultrasensitive detection of proteins on delicate sensor interfaces constructed by lipid membranes or cell membrane mimics. PMID- 22439624 TI - Peritumoral vascular invasion and NHERF1 expression define an immunophenotype of grade 2 invasive breast cancer associated with poor prognosis. AB - BACKGROUND: Traditional determinants proven to be of prognostic importance in breast cancer include the TNM staging, histological grade, proliferative activity, hormone receptor status and HER2 overexpression. One of the limitations of the histological grading scheme is that a high percentage of breast cancers are still classified as grade 2, a category with ambiguous clinical significance. The aim of this study was to best characterize tumors scored as grade 2. METHODS: We investigated traditional prognostic factors and a panel of tumor markers not used in routine diagnosis, such as NHERF1, VEGFR1, HIF-1alpha and TWIST1, in 187 primary invasive breast cancers by immunohistochemistry, stratifying patients into good and poor prognostic groups by the Nottingham Prognostic Index. RESULTS: Grade 2 subgroup analysis showed that the PVI (p = 0.023) and the loss of membranous NHERF1 (p = 0.028) were adverse prognostic factors. Relevantly, 72% of grade 2 tumors were associated to PVI+/membranous NHERF1- expression phenotype, characterizing an adverse prognosis (p = 0.000). Multivariate logistic regression analysis in the whole series revealed poor prognosis correlated with PVI and MIB1 (p = 0.000 and p = 0.001, respectively). Furthermore, in the whole series of breast cancers we found cytoplasmic NHERF1 expression positively correlated to VEGFR1 (r = 0.382, p = 0.000), and in VEGFR1-overexpressing tumors the oncogenic receptor co-localized with NHERF1 at cytoplasmic level. CONCLUSIONS: The PVI+/membranous NHERF1- expression phenotype identifies a category of grade 2 tumors with the worst prognosis, including patient subgroup with a family history of breast cancer. These observations support the idea of the PVI+/membranous NHERF1- expression immunophenotype as a useful marker, which could improve the accuracy of predicting clinical outcome in grade 2 tumors. PMID- 22439625 TI - Real-time determination of intracellular oxygen in bacteria using a genetically encoded FRET-based biosensor. AB - BACKGROUND: Molecular oxygen (O2) is one of the key metabolites of all obligate and facultative aerobic pro- and eukaryotes. It plays a fundamental role in energy homeostasis whereas oxygen deprivation, in turn, broadly affects various physiological and pathophysiological processes. Therefore, real-time monitoring of cellular oxygen levels is basically a prerequisite for the analysis of hypoxia induced processes in living cells and tissues. RESULTS: We developed a genetically encoded Forster resonance energy transfer (FRET)-based biosensor allowing the observation of changing molecular oxygen concentrations inside living cells. This biosensor named FluBO (fluorescent protein-based biosensor for oxygen) consists of the yellow fluorescent protein (YFP) that is sensitive towards oxygen depletion and the hypoxia-tolerant flavin-binding fluorescent protein (FbFP). Since O2 is essential for the formation of the YFP chromophore, efficient FRET from the FbFP donor domain to the YFP acceptor domain only occurs in the presence but not in the absence of oxygen. The oxygen biosensor was used for continuous real-time monitoring of temporal changes of O2 levels in the cytoplasm of Escherichia coli cells during batch cultivation. CONCLUSIONS: FluBO represents a unique FRET-based oxygen biosensor which allows the non-invasive ratiometric readout of cellular oxygen. Thus, FluBO can serve as a novel and powerful probe for investigating the occurrence of hypoxia and its effects on a variety of (patho)physiological processes in living cells. PMID- 22439626 TI - Synthesis of a high-valent, four-coordinate manganese cubane cluster with a pendant Mn atom: photosystem II-inspired manganese-nitrogen clusters. AB - High-valent, four-coordinate manganese imido- and nitrido-bridged heterodicubane clusters have been prepared and characterized by single-crystal X-ray diffraction and spectroscopic techniques. The title compound, a corner-nitride-fused dicubane with the chemical formula [Mn(5)Li(3)(MU(6)-N)(N)(MU(3)-N(t)Bu)(6)(MU N(t)Bu)(3)(N(t)Bu)] (1), has been prepared as an adduct with a nearly isostructural tetramanganese cluster with one Mn atom replaced by Li. An important feature of the reported chemistry is the formation of nitride from tert butylamide, indicative of N-C bond cleavage facilitated by manganese. PMID- 22439627 TI - Pyoderma gangrenosum-like ulcer caused by Helicobacter cinaedi in a patient with x-linked agammaglobulinaemia. AB - Cutaneous lesions of the legs have been linked to Helicobacter species in a number of patients with X-linked agammaglobulinaemia (XLA), a primary immunodeficiency. We describe a 26-year-old patient with XLA, who was referred with an extensive skin ulcer that enlarged gradually over the course of 7 years. The ulcer resembled pyoderma gangrenosum (PG), and extended from below the knee to the ankle. The man (who has sex with men) was negative for human immunodeficiency virus. Helicobacter cinaedi was identified by 16S ribosomal (r)DNA PCR analysis from a biopsy of the lesion. This fastidious organism has been implicated previously in causing unexplained skin macules in one other patient with XLA. We suggest that early consideration of infection with Helicobacter species in immunocompromised patients who present with unexplained cutaneous lesions is important, as a prolonged antibiotic course can lead to clinical improvement. PMID- 22439628 TI - Economic evaluations of adult weight management interventions: a systematic literature review focusing on methods used for determining health impacts. AB - BACKGROUND: One of the challenges when undertaking economic evaluations of weight management interventions is to adequately assess future health impacts. Clinical trials commonly measure impacts using surrogate outcomes, such as reductions in body mass index, and investigators need to decide how these can best be used to predict future health effects. Since obesity is associated with an increased risk of numerous chronic diseases occurring at different future time points, modelling is needed for predictions. OBJECTIVE: To assess the methods used in economic evaluations to determine health impacts of weight management interventions and to investigate whether differences in methods affect the cost-effectiveness estimates. METHODS: Eight databases were systematically searched. Included studies were categorized according to a decision analytic approach and effect measures incorporated. RESULTS: A total of 44 articles were included; 21 evaluated behavioural interventions, 12 evaluated surgical procedures and 11 evaluated pharmacological compounds. Of the 27 papers that estimated future impacts, eleven used Markov modelling, seven used a decision tree, five used a mathematical application, two used patient-level simulation and the modelling method was unclear in two papers. The most common types of effects included were co-morbidity treatment costs, heath-related quality of life due to weight loss and gain in survival. Only 12 of the studies included heath-related quality of life gains due to reduced co-morbidities and only one study included productivity gains. Despite consensus that trial-based analysis on its own is inadequate in guiding resource allocation decisions, it was used in 39% of the studies. Several of the modelling papers used model structures not suitable for chronic diseases with changing health risks. Three studies concluded that the intervention dominated standard care; meaning that it generated more quality-adjusted life years (QALYs) for less cost. The incremental costs per QALY gained varied from $US235 to $US56,836 in the remaining studies using this outcome measure. An implicit hypothesis of the review was that studies including long-term health effects would illustrate greater cost effectiveness compared with trial-based studies. This hypothesis is partly confirmed with three studies arriving at dominating results, as these reach their conclusion from modelling future co morbidity treatment cost savings. However, for the remaining studies there is little indication that decision-analytic modelling disparities explain the differences. CONCLUSIONS: This is the first literature review comparing methods used in economic evaluations of weight management interventions, and it is the first time that observed differences in study results are addressed with a view to methodological explanations. We conclude that many studies have methodological deficiencies and we urge analysts to follow recommended practices and use models capable of depicting long-term health consequences. PMID- 22439629 TI - NMR evaluation of total statin content and HMG-CoA reductase inhibition in red yeast rice (Monascus spp.) food supplements. AB - BACKGROUND: Red yeast rice (i.e., rice fermented with Monascus spp.), as a food supplement, is claimed to be blood cholesterol-lowering. The red yeast rice constituent monacolin K, also known as lovastatin, is an inhibitor of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase. This article aims to develop a sensitive nuclear magnetic resonance (NMR) method to determine the total statin content of red yeast rice products. METHODS: The total statin content was determined by a 400 MHz 1H NMR spectroscopic method, based on the integration of the multiplet at delta 5.37-5.32 ppm of a hydrogen at the hexahydronaphthalene moiety in comparison to an external calibration with lovastatin. The activity of HMG-CoA reductase was measured by a commercial spectrophotometric assay kit. RESULTS: The NMR detection limit for total statins was 6 mg/L (equivalent to 0.3 mg/capsule, if two capsules are dissolved in 50 mL ethanol). The relative standard deviations were consistently lower than 11%. The total statin concentrations of five red yeast rice supplements were between 1.5 and 25.2 mg per specified daily dose. A dose-dependent inhibition of the HMG-CoA reductase enzyme activity by the red yeast rice products was demonstrated. CONCLUSION: A simple and direct NMR assay was developed to determine the total statin content in red yeast rice. The assay can be applied for the determination of statin content for the regulatory control of red yeast rice products. PMID- 22439630 TI - Layer-by-layer assembly of polyelectrolyte multilayers in three-dimensional inverse opal structured templates. AB - A novel means of layer-by-layer deposition (LbL) of polyelectrolyte multilayers on three-dimensionally porous inverse opal (3D-IO) structures is presented. The 3D-IO structures comprising UV-curable polymer are highly flexible and can be readily demonstrated as free-standing films with double-sided open porosity over a large scale. A conflict between the intrinsically hydrophobic polymeric structures and waterborne characteristics of the LbL deposition process is overcome by employing a mixed solvent system of water and alcohol. The deposition pH of the LbL assembly can strongly affect the charge density and the degree of entanglement of polyelectrolyte chains, resulting in contrastingly different film deposition and growth behaviors. Since this method utilizes a three-dimensionally structured surface as a deposition substrate, 3D-IO films with a thickness of tens of micrometers can be uniformly and completely deposited with polyelectrolyte multilayers using only several tens of bilayer depositions, which can offer a new pathway of fabricating functionalized polymeric films. Finally, the LbL treated 3D-IO films are applied to nanofiltration membranes for removing multivalent metallic cations. Due to the enhanced Donnan exclusion effect as a result of multiple interfaces formed inside the 3D-IO structures and the relatively large volumetric ratio of water-permeable polyelectrolyte complexes, outstanding membrane performance was observed. Specifically, a good rejection rate of metal ions was achieved even under highly diluted feed conditions without sacrificing the high permeation flux. PMID- 22439631 TI - Loss of nonsense mediated decay suppresses mutations in Saccharomyces cerevisiae TRA1. AB - BACKGROUND: Tra1 is an essential protein in Saccharomyces cerevisiae. It was first identified in the SAGA and NuA4 complexes, both with functions in multiple aspects of gene regulation and DNA repair, and recently found in the ASTRA complex. Tra1 belongs to the PIKK family of proteins with a C-terminal PI3K domain followed by a FATC domain. Previously we found that mutation of leucine to alanine at position 3733 in the FATC domain of Tra1 (tra1-L3733A) results in transcriptional changes and slow growth under conditions of stress. To further define the regulatory interactions of Tra1 we isolated extragenic suppressors of the tra1-L3733A allele. RESULTS: We screened for suppressors of the ethanol sensitivity caused by tra1-L3733A. Eleven extragenic recessive mutations, belonging to three complementation groups, were identified that partially suppressed a subset of the phenotypes caused by tra1-L3733A. Using whole genome sequencing we identified one of the mutations as an opal mutation at tryptophan 165 of UPF1/NAM7. Partial suppression of the transcriptional defect resulting from tra1-L3733A was observed at GAL10, but not at PHO5. Suppression was due to loss of nonsense mediated decay (NMD) since deletion of any one of the three NMD surveillance components (upf1/nam7, upf2/nmd2, or upf3) mediated the effect. Deletion of upf1 suppressed a second FATC domain mutation, tra1-F3744A, as well as a mutation to the PIK3 domain. In contrast, deletions of SAGA or NuA4 components were not suppressed. CONCLUSIONS: We have demonstrated a genetic interaction between TRA1 and genes of the NMD pathway. The suppression is specific for mutations in TRA1. Since NMD and Tra1 generally act reciprocally to control gene expression, and the FATC domain mutations do not directly affect NMD, we suggest that suppression occurs as the result of overlap and/or crosstalk in these two broad regulatory networks. PMID- 22439632 TI - Updated estimate of trans fat intake by the US population. AB - The dietary intake of industrially-produced trans fatty acids (IP-TFA) was estimated for the US population (aged 2 years or more), children (aged 2-5 years) and teenage boys (aged 13-18 years) using the 2003-2006 National Health and Nutrition Examination Survey (NHANES) food consumption database, market share information and trans fat levels based on label survey data and analytical data for packaged and in-store purchased foods. For fast foods, a Monte Carlo model was used to estimate IP-TFA intake. Further, the intake of trans fat was also estimated using trans fat levels reported in the US Department of Agriculture (USDA) National Nutrient Database for Standard Reference, Release 22 (SR 22, 2009) and the 2003-2006 NHANES food consumption database. The cumulative intake of IP-TFA was estimated to be 1.3 g per person per day (g/p/d) at the mean for the US population. Based on this estimate, the mean dietary intake of IP-TFA has decreased significantly from that cited in the 2003 US Food and Drug Administration (FDA) final rule that established labelling requirements for trans fat (4.6 g/p/d for adults). Although the overall intake of IP-TFA has decreased as a result of the implementation of labelling requirements, individuals with certain dietary habits may still consume high levels of IP-TFA if certain brands or types of food products are frequently chosen. PMID- 22439633 TI - Normative data for neuropsychological tests in a rural elderly Chinese cohort. AB - Normative information is important for appropriate interpretation of cognitive test scores as a critical component of dementia diagnosis in the elderly population. A cross-sectional evaluation of 1826 participants aged 65 years and older from four rural counties in China was conducted using six cognitive instruments including tests of global cognitive function (the Community Screening Instrument for Dementia), memory (Word List Learning and Recall tasks from the Consortium to Establish a Registry for Alzheimer's Disease, IU Story), language (Animal Fluency Test), and executive function (IU Token). Multiple regression models adjusting for demographic variables were used to provide standardized residuals z-scores and corresponding percentile ranking for each cognitive test. In all cognitive tests older age was associated with worse test performance while exposure to education was related to better cognitive test performance. We also detected a significant gender difference with men scoring better than women and a significant gender by education interaction on two tests. The interaction indicates that gender difference in test scores was much smaller in participants with more education than those who had less or no education. These demographically adjusted, regression-based norms can be a useful tool to clinicians involved with differential diagnosis of cognitive and memory disorders in older adults in rural China. PMID- 22439634 TI - Phylogenetic analysis of antimicrobial lactic acid bacteria from farmed seabass Dicentrarchus labrax. AB - The use of lactic acid bacteria (LAB) in the prevention or reduction of fish diseases is receiving increasing attention. In the present study, 47 LAB strains were isolated from farmed seabass ( Dicentrarchus labrax ) and were phenotypically and phylogenetically analysed by 16S rDNA and randomly amplified polymorphic DNA - polymerase chain reaction (RAPD-PCR). Their antimicrobial effect was tested in vitro against a wide variety of pathogenic and spoilage bacteria. Most of the strains isolated were enterococci belonging to the following species: Enterococcus faecium (59%), Enterococcus faecalis (21%), Enterococcus sanguinicola (4 strains), Enterococcus mundtii (1 strain), Enterococcus pseudoavium (1 strain), and Lactococcus lactis (1 strain). An Aerococcus viridans strain was also isolated. The survey of their antimicrobial susceptibility showed that all isolates were sensitive to vancomycin and exhibited resistance to between 4 and 10 other antibiotics relevant for therapy in human and animal medicine. Different patterns of resistance were noted for skin and intestines isolates. More than 69% (32 strains) of the isolates inhibited the growth of the majority of pathogenic and spoilage bacteria tested, including Listeria monocytogenes, Staphylococcus aureus, Aeromonas hydrophila, Aeromonas salmonicida, Vibrio anguillarum, and Carnobacterium sp. To our knowledge, this is the first report of bioactive enterococcal species isolated from seabass that could potentially inhibit the undesirable bacteria found in food systems. PMID- 22439635 TI - HIV prevalence among high school learners - opportunities for schools-based HIV testing programmes and sexual reproductive health services. AB - BACKGROUND: Young girls in sub Saharan Africa are reported to have higher rates of human immunodeficiency virus (HIV) infection compared to boys in the same age group. Knowledge of HIV status amongst high schools learners provides an important gateway to prevention and treatment services. This study aimed at determining the HIV prevalence and explored the feasibility of HIV testing among high school learners. METHODS: Between September 2010 and February 2011, a linked, anonymous cross-sectional survey was conducted in two public sector high schools in the rural KwaZulu-Natal midlands. Following written informed consent, dried blood spot samples (DBS) were collected and tested for HIV. The overall and age-specific HIV prevalence were compared with select demographic variables. RESULTS: The HIV prevalence in learners aged 12 to 25 in school A was 4.7% (95% CI 2.8-6.5) compared to 2.5% (95% CI 1.6-3.5) in school B, (p = 0.04). Whilst the HIV prevalence was similar for boys at 1.3% (95% CI 0-2.8) in school A and 1.7% (95% CI 0.5-2.8) in school B, the prevalence in girls was consistently higher and was 7.7% (95% CI 4.5-10.9) in school A and 3.2% (95% CI 1.8-4.6) in school B. The age-specific HIV prevalence in girls increased 1.5 to 2 fold for each two year age category, while for boys the prevalence was stable across all age groups. CONCLUSIONS: The high HIV prevalence in female learners underscores the importance of sexual reproductive health and schools-based HIV testing programs as an important gateway to prevention and treatment services. PMID- 22439636 TI - Correlating sterics parameters and diastereomeric ratio values for a multicomponent assembly to predict exciton-coupled circular dichroism intensity and thereby enantiomeric excess of chiral secondary alcohols. AB - Linear free energy relationship (LFER) substituent parameters are commonly employed for exploring reaction mechanisms and very recently have been used to guide the design of asymmetric catalysts, but their usage in dynamic covalent chemistry is rare. Herein, the properties of an in situ-generated dynamic multicomponent covalent assembly that creates tris(pyridine) metal complexes incorporating chiral secondary alcohols were explored using LFER-based steric parameters. The diastereomeric ratio (dr) of the assembly was correlated with the magnitude of the exciton-coupled circular dichroism (ECCD) induced by chiral alcohols. Charton steric parameters were successfully correlated with the dr values. Through the combination of these correlations, both the dr and CD intensity were predicted for test alcohols. These correlations were also employed to measure a few new Charton parameters. Finally, the prediction of enantiomeric excess (ee) of test samples with various alcohol structures was also successfully achieved. The prediction of spectral properties in advance by using well established steric parameters is shown to be useful for rapid ee screening because the need for calibration curves and enantiomerically enriched samples is avoided. PMID- 22439638 TI - The impact of witnessing athletic injury: a qualitative examination of vicarious trauma in artistic gymnastics. AB - We explored how athletes respond and cope after witnessing athletic injury in others participating in the same sport. Participants were eight competitive female artistic gymnasts aged 21-25 years. In the previous 3 years, participants had witnessed a serious athletic injury of another gymnast that had required hospital treatment. Participants took part in semi-structured interviews in which they were asked to discuss their experiences of witnessing injury, including descriptions of the injury's occurrence. Data were analysed using hierarchical content analysis. Following acute reactions to witnessing injury, participants reported experiencing intrusive cognitions and engaged in avoidance coping strategies. Participants reported gradually engaging in more approach coping strategies which served to lower their perceptions of vulnerability to injury. Despite the complex nature of trauma, suggestions may be made to assist applied sport psychologists working with athletes who have witnessed athletic injury. PMID- 22439637 TI - Differences in selective pressure on dhps and dhfr drug resistant mutations in western Kenya. AB - BACKGROUND: Understanding the origin and spread of mutations associated with drug resistance, especially in the context of combination therapy, will help guide strategies to halt and prevent the emergence of resistance. Unfortunately, studies have assessed these complex processes when resistance is already highly prevalent. Even further, information on the evolutionary dynamics leading to multidrug-resistant parasites is scattered and limited to areas with low or seasonal malaria transmission. This study describes the dynamics of strong selection for mutations conferring resistance against sulphadoxine-pyrimethamine (SP), a combination therapy, in western Kenya between 1992 and 1999, just before SP became first-line therapy (1999). Importantly, the study is based on longitudinal data, which allows for a comprehensive analysis that contrasts with previous cross-sectional studies carried out in other endemic regions. METHODS: This study used 236 blood samples collected between 1992 and 1999 in the Asembo Bay area of Kenya. Pyrosequencing was used to determine the alleles of dihydrofolate reductase (dhfr) and dihydropterote synthase (dhps) genes. Microsatellite alleles spanning 138 kb around dhfr and dhps, as well as, neutral markers spanning approximately 100 kb on chromosomes 2 and 3 were characterized. RESULTS: By 1992, the South-Asian dhfr triple mutant was already spreading, albeit in low frequency, in this holoendemic Kenyan population, prior to the use of SP as a first-line therapy. Additionally, dhfr triple mutant alleles that originated independently from the predominant Southeast Asian lineage were present in the sample set. Likewise, dhps double mutants were already present as early as 1992. There is evidence for soft selective sweeps of two dhfr mutant alleles and the possible emergence of a selective sweep of double mutant dhps alleles between 1992 and 1997. The longitudinal structure of the dataset allowed estimation of selection pressures on various dhfr and dhps mutants relative to each other based on a theoretical model tailored to P. falciparum. The data indicate that drug selection acted differently on the resistant alleles of dhfr and dhps, as evidenced by fitness differences. Thus a combination drug therapy such as SP, by itself, does not appear to select for "multidrug"-resistant parasites in areas with high recombination rate. CONCLUSIONS: The complexity of these observations emphasizes the importance of population-based studies to evaluate the effects of strong drug selection on Plasmodium falciparum populations. PMID- 22439639 TI - Building a bridge of trust: collaborative assessment with a person with serious mental illness. AB - Collaborative assessment utilizes psychological testing to help people make positive changes in their lives. Limited research has evaluated the utility of collaborative assessment for persons with serious mental illness. This case example uses the Personality Assessment Inventory to illustrate the usefulness of collaborative assessment with a person with serious mental illness. This approach informed not only diagnostic considerations but also revealed the client's current level of distress, contributed to enhanced therapeutic alliance, and directly pointed to psychiatric rehabilitation strategies. PMID- 22439640 TI - Defining optimal laser-fiber sweeping angle for effective tissue vaporization using 180 W 532 nm lithium triborate laser. AB - PURPOSE: The goal of this study is to identify the most efficient sweeping angle (SA) during photoselective vaporization of the prostate (PVP). MATERIALS AND METHODS: Experiments were conducted with GreenLight XPSTM laser at 120 and 180 W. Ten blocks of porcine kidney were used for each SA (0, 15, 30, 45, 60, 90, and 120 degrees). Vaporization efficiency was assessed by the amount of tissue removed per time. The coagulation zone (CZ) thickness was also measured. RESULTS: Maximal vaporization rate (VR) was achieved at SA 15 and 30 degrees. Irrespective of power, VR increased and CZ decreased linearly with decreasing SA from 120 to 30 degrees. The CZ was the thinnest at SA 30 degrees. CONCLUSIONS: Optimal vaporization occurred at a SA of 15 degrees and 30 degrees with the lowest CZ at 30 degrees. Contrary to a previous recommendation for a wider SA (60 degrees or greater), a narrower SA (30 degrees) achieved the maximal tissue vaporization efficiency. PMID- 22439641 TI - Competitive enzyme-linked immunoassay for sialoglycoprotein of edible bird's nest in food and cosmetics. AB - The proliferation of fake and inferior edible bird's nest (EBN) products has recently become an increasingly serious concern. To identify and classify EBN products, a competitive enzyme-linked immunoassay (ELISA) was developed to quantitate sialoglycoprotein in EBN used in food and cosmetic applications. The characteristic sialoglycoprotein in EBN was found, extracted, purified, and analyzed. Sialoglycoprotein, considered the main carrier of sialic acid in EBN, consisted of 106 and 128 kDa proteins. A monoclonal antibody that could recognize both proteins was prepared. The heat-treated process did not change the affinity of sialoglycoprotein with the antibody. An optimized ELISA method was established with a cross-reactivity of less than 0.1% and an IC(50) of 3.3 MUg/mL. On the basis of different food and cosmetic samples, the limits of detection (LOD) were 10-18 MUg/g. Recoveries of fortified samples at levels of 20 and 80 MUg/g ranged from 81.5 to 96.5%, respectively. The coefficients of variation were less than 8.0%. PMID- 22439642 TI - Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. AB - BACKGROUND: There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. RESULTS: To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17 demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)gamma inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease. CONCLUSIONS: We have established and validated a suite of highly reproducible tumor microplate three-dimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds. PMID- 22439643 TI - Model studies of methyl CoM reductase: methane formation via CH3-S bond cleavage of Ni(I) tetraazacyclic complexes having intramolecular methyl sulfide pendants. AB - The Ni(I) tetraazacycles [Ni(dmmtc)](+) and [Ni(mtc)](+), which have methylthioethyl pendants, were synthesized as models of the reduced state of the active site of methyl coenzyme M reductase (MCR), and their structures and redox properties were elucidated (dmmtc, 1,8-dimethyl-4,11-bis{(2-methylthio)ethyl} 1,4,8,11-tetraaza-1,4,8,11-cyclotetradecane; mtc, 1,8-{bis(2-methylthio)ethyl} 1,4,8,11-tetraaza-1,4,8,11-cyclotetradecane). The intramolecular CH(3)-S bond of the thioether pendant of [Ni(I)(dmmtc)](OTf) was cleaved in THF at 75 degrees C in the presence of the bulky thiol DmpSH, which acts as a proton source, and methane was formed in 31% yield and a Ni(II) thiolate complex was concomitantly obtained (Dmp = 2,6-dimesityphenyl). The CH(3)-S bond cleavage of [Ni(I)(mtc)](+) also proceeded similarly, but under milder conditions probably due to the lower potential of the [Ni(I)(mtc)](+) complex. These results indicate that the robust CH(3)-S bond can be homolytically cleaved by the Ni(I) center when they are properly arranged, which highlights the significance of the F430 Ni environment in the active site of the MCR protein. PMID- 22439644 TI - Stellettin A induces endoplasmic reticulum stress in murine B16 melanoma cells. AB - Isomalabaricanes are a small class of rearranged triterpenoids obtained from marine sponges. Most of these are cytotoxic to tumor cells, but the underlying mechanism is not clear. In this study, it was demonstrated that stellettin A (1), obtained from Geodia japonica, inhibited the growth of B16F10 murine melanoma cells by the induction of endoplasmic reticulum stress and accumulation of unfolded proteins. Immunoblotting analysis revealed abnormal glycosylation patterns of two melanoma marker proteins, tyrosinase and tyrosinase-related protein 1, and the retention of these proteins in the endoplasmic reticulum. Compound 1 induced the upregulation of the unfolded protein chaperone, glucose regulated protein 78, in a dose-dependent manner. Increase of autophagosome associated protein light chain 3 (LC3) in a membrane-bound form (LC3II) and its immunofluorescence co-localization with tyrosinase suggest the possible removal of deglycosylated and unfolded proteins by autophagy of the cells. There was no change in either the expression of the apoptosis marker protein Bcl-2 or the appearance of apoptotic nuclei in 1-treated cells. Taken together, 1 is an endoplasmic reticulum stressor that inhibits the growth of B16 melanoma cells by induction of abnormal protein glycosylation and autophagy. PMID- 22439645 TI - A pyrexial unwell child with a papular eruption. PMID- 22439646 TI - Tethered nanoparticle-polymer composites: phase stability and curvature. AB - Phase behavior of poly(ethylene glycol) (PEG) tethered silica nanoparticles dispersed in PEG hosts is investigated using small-angle X-ray scattering. Phase separation in dispersions of densely grafted nanoparticles is found to display strikingly different small-angle X-ray scattering signatures in comparison to phase-separated composites comprised of bare or sparsely grafted nanoparticles. A general diagram for the dispersion state and phase stability of polymer tethered nanoparticle-polymer composites incorporating results from this as well as various other contemporary studies is presented. We show that in the range of moderate to high grafting densities the dispersion state of nanoparticles in composites is largely insensitive to the grafting density of the tethered chains and chemistry of the polymer host. Instead, the ratio of the particle diameter to the size of the tethered chain and the ratio of the molecular weights of the host and tethered polymer chains (P/N) are shown to play a dominant role. Additionally, we find that well-functionalized nanoparticles form stable dispersions in their polymer host beyond the P/N limit that demarcates the wetting/dewetting transition in polymer brushes on flat substrates interacting with polymer melts. A general strategy for achieving uniform nanoparticle dispersion in polymers is proposed. PMID- 22439647 TI - The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. METHODS: We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes. RESULTS: One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). CONCLUSIONS: We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS. PMID- 22439648 TI - Carbonyl compounds indoors in a changing climate. AB - BACKGROUND: Formic acid, acetic acid and formaldehyde are important compounds in the indoor environment because of the potential for these acids to degrade calcareous materials (shells, eggs, tiles and geological specimens), paper and corrode or tarnish metals, especially copper and lead. Carbonyl sulfide tarnishes both silver and copper encouraging the formation of surface sulfides. RESULTS: Carbonyls are evolved more quickly at higher temperatures likely in the Cartoon Gallery at Knole, an important historic house near Sevenoaks in Kent, England where the study is focused. There is a potential for higher concentrations to accumulate. However, it may well be that in warmer climates they will be depleted more rapidly if ventilation increases. CONCLUSIONS: Carbonyls are likely to have a greater impact in the future. PMID- 22439649 TI - The relationship between drug clearance and body size: systematic review and meta analysis of the literature published from 2000 to 2007. AB - BACKGROUND: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. AIM: The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. METHODS: Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a 'nonlinear' relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting 'other' relationships (e.g. linear increase in CL with TBW, ideal body weight or height). RESULTS: A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)(2/3), or estimated exponent of 0.646, i.e. ~2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. CONCLUSIONS: To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ~2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size. PMID- 22439650 TI - Occurrence of aflatoxins in milk thistle herbal supplements. AB - Milk thistle (MT) dietary supplements are widely consumed due to their possible liver-health-promoting properties. As botanicals they can be contaminated with a variety of fungi and their secondary metabolites, mycotoxins. The aflatoxigenic fungus Aspergillus flavus has been previously isolated from these commodities. Currently, there is no published method for determining aflatoxins (AFs) in MT. Therefore, a liquid chromatography (LC) method validated for aflatoxin analysis in botanicals was evaluated and applied to MT. The method consisted of acetonitrile/water extraction, immunoaffinity column clean-up, LC separation, post-column photochemical reaction derivatisation and fluorescence detection. The average recoveries for AFs added to MT seeds, herb, oil-based liquid extract and alcohol-based liquid extract were 76% or higher. The mean relative standard deviation was <10%. The limit of detection (LOD) was 0.01 ug kg(-1) and the limit of quantification (LOQ) was 0.03 ug kg(-1). The method was used to conduct a small survey. A total of 83 MT samples from the US market were analysed. AFs were detected in 19% of the samples with levels ranging from 0.04 to 2.0 ug kg(-1). Additionally, an aflatoxigenic A. flavus strain from ATTC and an A. parasiticus strain isolated from MT herb powder were found to produce high amounts of aflatoxins (11,200 and 49,100 ug kg(-1), respectively) when cultured in MT seed powder. This is the first study reporting on aflatoxin contamination of MT botanical supplements and identifying methodology for AF analysis of these commodities. PMID- 22439651 TI - Abuse, not financial incentive, predicts non-credible cognitive performance in patients with psychogenic non-epileptic seizures. AB - Participants with psychogenic non-epileptic seizures (PNES) who fail symptom validity testing (SVT) perform worse on neuropsychological testing than those who do not, consistent with results found in participants with different clinical presentations (e.g., mild traumatic brain injury). However, little is known about how variables typically associated with SVT failure in other populations (e.g., the presence of financial incentives, exaggerated report of psychopathology) correlate with SVT failure in participants with PNES. Likewise the relationship between SVT failure and reported abuse, one of the most frequently described demographic characteristics of the PNES population, has not been examined. We found that failure on the Word Memory Test (WMT) in 91 participants with PNES was strongly associated with reported abuse but, contrary to expectations, was not associated with the presence of financial incentives or severity of reported psychopathology. These results indicate that the factors driving WMT failure may differ significantly in participants with PNES in ways that are potentially clinically relevant. PMID- 22439652 TI - Dexrazoxane provided moderate protection in a catecholamine model of severe cardiotoxicity. AB - Positive effects of dexrazoxane (DEX) in anthracycline cardiotoxicity have been mostly assumed to be associated with its iron-chelating properties. However, this explanation has been recently questioned. Iron plays also an important role in the catecholamine cardiotoxicity. Hence in this study, the influence of DEX on a catecholamine model of acute myocardial infarction (100 mg/kg of isoprenaline by subcutaneous injection) was assessed: (i) the effects of an intravenous dose of 20.4 mg/kg were analyzed after 24 h, (ii) the effects were monitored continuously during the first two hours after drug(s) administration to examine the mechanism(s) of cardioprotection. Additional in vitro experiments on iron chelation/reduction and influence on the Fenton chemistry were performed both with isoprenaline/DEX separately and in their combination. DEX partly decreased the mortality, reduced myocardial calcium overload, histological impairment, and peripheral haemodynamic disturbances 24 h after isoprenaline administration. Continuous 2 h experiments showed that DEX did not influence isoprenaline induced atrioventricular blocks and had little effect on the measured haemodynamic parameters. Its protective effects are probably mediated by inhibition of late myocardial impairment and ventricular fibrillation likely due to inhibition of myocardial calcium overload. Complementary in vitro experiments suggested that iron chelation properties of DEX apparently did not play the major role. PMID- 22439653 TI - The protocol for the Be Our Ally Beat Smoking (BOABS) study, a randomised controlled trial of an intensive smoking cessation intervention in a remote Aboriginal Australian health care setting. AB - BACKGROUND: Australian Aboriginal peoples and Torres Strait Islanders (Indigenous Australians) smoke at much higher rates than non-Indigenous people and smoking is an important contributor to increased disease, hospital admissions and deaths in Indigenous Australian populations. Smoking cessation programs in Australia have not had the same impact on Indigenous smokers as on non-Indigenous smokers. This paper describes the protocol for a study that aims to test the efficacy of a locally-tailored, intensive, multidimensional smoking cessation program. METHODS/DESIGN: This study is a parallel, randomised, controlled trial. Participants are Aboriginal and Torres Strait Islander smokers aged 16 years and over, who are randomly allocated to a 'control' or 'intervention' group in a 2:1 ratio. Those assigned to the 'intervention' group receive smoking cessation counselling at face-to-face visits, weekly for the first four weeks, monthly to six months and two monthly to 12 months. They are also encouraged to attend a monthly smoking cessation support group. The 'control' group receive 'usual care' (i.e. they do not receive the smoking cessation program). Aboriginal researchers deliver the intervention, the goal of which is to help Aboriginal peoples and Torres Strait Islanders quit smoking. Data collection occurs at baseline (when they enrol) and at six and 12 months after enrolling. The primary outcome is self reported smoking cessation with urinary cotinine confirmation at 12 months. DISCUSSION: Stopping smoking has been described as the single most important individual change Aboriginal and Torres Strait Islander smokers could make to improve their health. Smoking cessation programs are a major priority in Aboriginal and Torres Strait Islander health and evidence for effective approaches is essential for policy development and resourcing. A range of strategies have been used to encourage Aboriginal peoples and Torres Strait Islanders to quit smoking however there have been few good quality studies that show what approaches work best. More evidence of strategies that could work more widely in Indigenous primary health care settings is needed if effective policy is to be developed and implemented. Our project will make an important contribution in this area. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12608000604303). PMID- 22439654 TI - Evolutionary forces shaping genomic islands of population differentiation in humans. AB - BACKGROUND: Levels of differentiation among populations depend both on demographic and selective factors: genetic drift and local adaptation increase population differentiation, which is eroded by gene flow and balancing selection. We describe here the genomic distribution and the properties of genomic regions with unusually high and low levels of population differentiation in humans to assess the influence of selective and neutral processes on human genetic structure. METHODS: Individual SNPs of the Human Genome Diversity Panel (HGDP) showing significantly high or low levels of population differentiation were detected under a hierarchical-island model (HIM). A Hidden Markov Model allowed us to detect genomic regions or islands of high or low population differentiation. RESULTS: Under the HIM, only 1.5% of all SNPs are significant at the 1% level, but their genomic spatial distribution is significantly non-random. We find evidence that local adaptation shaped high-differentiation islands, as they are enriched for non-synonymous SNPs and overlap with previously identified candidate regions for positive selection. Moreover there is a negative relationship between the size of islands and recombination rate, which is stronger for islands overlapping with genes. Gene ontology analysis supports the role of diet as a major selective pressure in those highly differentiated islands. Low-differentiation islands are also enriched for non-synonymous SNPs, and contain an overly high proportion of genes belonging to the 'Oncogenesis' biological process. CONCLUSIONS: Even though selection seems to be acting in shaping islands of high population differentiation, neutral demographic processes might have promoted the appearance of some genomic islands since i) as much as 20% of islands are in non-genic regions ii) these non-genic islands are on average two times shorter than genic islands, suggesting a more rapid erosion by recombination, and iii) most loci are strongly differentiated between Africans and non-Africans, a result consistent with known human demographic history. PMID- 22439655 TI - A short measure of the need for affect. AB - Two studies are presented to introduce a 10-item short form of the Need for Affect Questionnaire (NAQ-S; cf. Maio & Esses, 2001 ). Study 1 was based on 4 independent samples (German or English language; N (total) = 2,151) and demonstrated the expected factorial structure of the NAQ-S; its measurement invariance with respect to gender, age, and education; and the predicted associations with relevant personality measures. A latent state-trait analysis conducted in Study 2 (N = 140) suggests that most of the reliable variance of the NAQ-S represents stable individual differences. PMID- 22439656 TI - Sufficient blood, safe blood: can we have both? AB - The decision in September 2011 in the UK to accept blood donations from non practicing men who have sex with men (MSM) has received significant public attention. Will this rule change substantially boost the number of blood donations or will it make our blood less safe? Clearly, most European countries have a blood procurement problem. Fewer young people are donating, while the population is aging and more invasive therapies are requiring more blood. Yet if that was the reason for allowing non-practicing MSM to donate, clearly re admission of some other, much larger populations that are currently deferred from donation should likewise be considered. As far as risks for blood safety are concerned, evidence has been provided that the current quality of infectious disease marker testing significantly mitigates against, although does not completely eradicate, risks associated with admission of donors with a high risk of carrying certain blood-transmissible agents. However, it could be argued that more effective recruitment of the non-donor pool, which is substantially larger than the group of currently ineligible donors, would be a better strategy. Recruitment of this group will benefit the availability of blood without jeopardizing the current excellent safety profile of blood. PMID- 22439657 TI - Enhanced expectancies improve movement efficiency in runners. AB - We followed up on recent findings demonstrating that enhancing performers' expectancies can improve their performance. Specifically, we examined whether providing experienced runners with positive feedback regarding their movement efficiency would increase running efficiency. Two groups of experienced runners ran on a treadmill at 75% of their maximum oxygen consumption (VO(2max)) for 10 min. One group (enhanced expectancy) was provided with (fabricated) feedback about the efficiency of their running style every 2 min. A control group was not given feedback. Oxygen consumption decreased in the enhanced expectancy group across measurement times (every 2 min for 10 min), but remained the same in the control group. In addition, performance perceptions changed only in the enhanced expectancy group, indicating a perception of greater ease of running and reduced fatigue when assessed after compared with before running. Finally, positive affect increased from a pre- to a post-test in the enhanced expectancy group, in contrast to the control group. Our findings show that enhanced expectancies can have a positive effect on movement efficiency and running experience. They add to the accumulating evidence for the social-cognitive-affective-motor nature of motor performance. PMID- 22439659 TI - Ellagic acid modulates antioxidant status, ornithine decarboxylase expression, and aberrant crypt foci progression in 1,2-dimethylhydrazine-instigated colon preneoplastic lesions in rats. AB - Chemoprevention offers a novel approach to control the incidence of colorectal cancer (CRC), which is a fatal cause of malignancies in both Western and Asia countries. Ornithine decarboxylase (ODC) functions as a cell transition factor by regulating the biosynthesis of polyamines, which, allied with aberrant crypt foci (ACF) proliferation, cause early lesions of CRC. This study exemplifies the chemopreventive efficacy of ellagic acid (EA) in 1,2-dimethylhydrazine (DMH) initiated CRC in rats. Subcutaneous injection of DMH (40 mg/kg body weight twice a week for 2 weeks) to the rats resulted in elevated expression of ODC, a genetic marker for CRC, and its transcription factor myelocytomatosis oncogene (c-myc). Furthermore, increased levels of lipid peroxidation and hydroperoxides with diminished levels of antioxidants including superoxide dismutase, catalase, and reduced glutathione were also observed in the tissues of DMH-intoxicated rats. Oral supplementation of EA significantly influences maintenance of antioxidant status and transcriptional inactivation of ODC expression, reducing ACF proliferation and/or progression, thus signifying the chemopreventive efficacy of EA against CRC. PMID- 22439658 TI - Genetic diversity in the block 2 region of the merozoite surface protein-1 of Plasmodium falciparum in central India. AB - BACKGROUND: Malaria continues to be a significant health problem in India. Several of the intended Plasmodium falciparum vaccine candidate antigens are highly polymorphic. The genetic diversity of P. falciparum merozoite surface protein-1 (MSP-1) has been extensively studied from various parts of the world. However, limited data are available from India. The aim of the present study was a molecular characterization of block 2 region of MSP-1 gene from the tribal dominated, forested region of Madhya Pradesh. METHODS: DNA sequencing analysis was carried out in 71 field isolates collected between July 2005 to November 2005 and in 98 field isolates collected from July 2009 to December 2009. Alleles identified by DNA sequencing were aligned with the strain 3D7 and polymorphism analysis was done by using Edit Sequence tool (DNASTAR). RESULTS: The malaria positivity was 26% in 2005, which rose to 29% in 2009 and P. falciparum prevalence was also increased from 72% in 2005 to 81% in 2009. The overall allelic prevalence was higher in K1 (51%) followed by MAD20 (28%) and RO33 (21%) in 2005 while in 2009, RO33 was highest (40%) followed by K1 (36%) and MAD20 (24%). CONCLUSIONS: The present study reports extensive genetic variations and dynamic evolution of block 2 region of MSP-1 in central India. Characterization of antigenic diversity in vaccine candidate antigens are valuable for future vaccine trials as well as understanding the population dynamics of P. falciparum parasites in this area. PMID- 22439660 TI - Germyl- and germylene-bridged complexes of Rh/Ir and subsequent chemistry of a bridging germylene group. AB - A series of neutral and cationic germylene-bridged complexes and a neutral germyl(germylene) complex have been synthesized and characterized by NMR spectroscopy and X-ray crystallography. Reaction of 1 equiv of primary germanes, RGeH(3) (R = Ph, (t)Bu), with [RhIr(CO)(3)(dppm)(2)] (1) at low-temperature yields [RhIr(GeH(2)R)(H)(CO)(3)(dppm)(2)] (R = Ph (3) or (t)Bu (4)), the products of single Ge-H bond activation, which upon warming transform to the germylene bridged dihydrides, [RhIr(H)(2)(CO)(2)(MU-GeHR)(dppm)(2)] (R = Ph (5) or (t)Bu (6)) by activation of a second Ge-H bond accompanied by CO loss. Both classes of compounds have the diphosphines folded back in a "cradle-shaped" geometry. Although compound 5 reacts with additional phenylgermane at -40 degrees C to give a germylene-bridged/germyl product, [RhIr(GeH(2)Ph)(H)(2)(CO)(2)(kappa(1) dppm)(MU-GeHPh)(MU-H)(dppm)] (7), warming results in decomposition. However, reaction of 5 with 1 equiv of diphenylgermane at ambient temperature results in a novel mixed bis(MU-germylene) complex, [RhIr(CO)(2)(MU-GeHPh)(MU GePh(2))(dppm)(2)] (8), containing both mono- and disubstituted germylene fragments. Reaction of 1 equiv of diphenylgermane with complex 1 produces a similar monogermylene-bridged product, [RhIr(H)(2)(CO)(2)(MU-GePh(2))(dppm)(2)] (9), while reaction of 1 with 2 equiv of diphenylgermane yields the germyl/germylene product [RhIr(H)(GeHPh(2))(CO)(3)(kappa(1)-dppm)(MU GePh(2))(dppm)] (10). The above reactions, incorporating first one and then a second equivalent of primary and secondary germanes, were studied by low temperature multinuclear NMR spectroscopy, revealing details about the stepwise activations of multiple Ge-H bonds. Reaction of diphenylgermane with the cationic complex [RhIr(CH(3))(CO)(2)(dppm)(2)][CF(3)SO(3)] (2) leads to a cationic A-frame type germylene- and hydride-bridged product, [RhIr(CO)(2)(MU-H)(MU GePh(2))(dppm)(2)][CF(3)SO(3)] (3), which reversibly activates H(2), yielding a germyl-bridged dihydride and reacts stoichiometrically with water, methanol, and HCl to yield the respective germanol, germamethoxy, and germylchloride products. PMID- 22439661 TI - Evaluation of WO2012003387, Gilead's ASK1 inhibitors. AB - A small number of novel N-(triazolylthiazol-2-yl) and N-(triazolylthienyl) benzamide and picolinamide derivatives are claimed. The compounds are ASK1 kinase inhibitors among which some have nanomolar potency and are potentially useful in the treatment of a diverse range of conditions. The claimed compounds define a pharmacophore, distinct from that described in the limited number of patent filings claiming ASK1 inhibitors. PMID- 22439662 TI - Differential response of normal human epidermal keratinocytes and HaCaT cells to hydrogen peroxide-induced oxidative stress. AB - BACKGROUND: Normal human epidermal keratinocytes (NHEKs) and HaCaT cells are the most common models used to study the effects of various factors on skin cells. These cell lines share some common characteristics, but little is known about their differences in handling hydrogen peroxide (H(2) O(2) )-induced oxidative stress. AIM: To investigate the differential response of NHEKs and HaCaT cells to H(2) O(2) -induced oxidative stress. METHODS: We examined differences in NHEKs and HaCaT cells after H(2) O(2) treatment, assessing changes in cell viability; levels of intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) and caspase-3/7; percentage of cells arrested in G1 phase; number of senescence-associated beta-galactosidase (SA-beta-Gal)-positive cells and; expression of senescence-related protein Klotho. RESULTS: The viability of NHEKs and HaCaT cells decreased in a concentration-dependent and time-dependent manner after exposure to H(2) O(2) . The inhibitory effect of 150 MUmol/L H(2) O(2) on cell viability was greater in HaCaT cells than in NHEKs (P<0.05). Levels of ROS and caspase-3/7, and the percentage of cells arrested in G1 phase, were higher in HaCaT cells than in NHEKs, whereas intracellular SOD was higher in NHEKs than in HaCaT cells after exposure to 150 MUmol/L H(2) O(2) (P < 0.05). SA-beta-Gal positive cells increased significantly in NHEKs after treatment with H(2) O(2) (P < 0.05). Klotho was significantly downregulated in both NHEKs and HaCaT cells after H(2) O(2) treatment, but no SA-beta-Gal-positive HaCaT cells were seen, even after treatment with H(2) O(2) . CONCLUSIONS: Normal human epidermal keratinocytes are more resistant than HaCaT cells to H(2) O(2) induced oxidative stress. HaCaT cells have senescence phenotypes, but do not express beta-Gal. PMID- 22439663 TI - Graphene nanoplatelet-induced strengthening of ultrahigh molecular weight polyethylene and biocompatibility in vitro. AB - Graphene nanoplatelets (GNPs) are added as reinforcement to ultrahigh molecular weight polyethylene (UHMWPE) with an intended application for orthopedic implants. Electrostatic spraying is established as a potential fabrication method for synthesizing large-scale UHMWPE-GNP composite films. At a low concentration of 0.1 wt % GNP, the composite film shows highest improvement in fracture toughness (54%) and tensile strength (71%) as compared to UHMWPE. Increased GNP content of 1 wt % leads to improvement in elastic modulus and yield strength but fracture toughness and tensile strength are reduced significantly at higher GNP content. The strengthening mechanisms of the UHMWPE-GNP system are highly influenced by the GNP concentration, which dictates its degree of dispersion and extent of polymer wrapping. The fraction of GNPs oriented along the tensile axis influences the elastic deformation, whereas the wrapping of polymer and GNP polymer interfacial strength determines the deformation behavior in the plastic regime. The cytotoxicity of GNP to osteoblast is dependent on its concentration and is also influenced by agglomeration of particles. Lowering the concentration of GNPs in UHMWPE improves the biocompatibility of the composite surface to bone cells. The survivability of osteoblasts deteriorates up to 86% on 1 wt % GNP containing surface, whereas much smaller (6-16%) reduction is observed for 0.1 wt % GNP over 5 days of incubation. PMID- 22439664 TI - Physicochemical characteristics of protein-NP bioconjugates: the role of particle curvature and solution conditions on human serum albumin conformation and fibrillogenesis inhibition. AB - Gold nanoparticles (Au NPs) from 5 to 100 nm in size synthesized with HAuCl(4) and sodium citrate were complexed with the plasma protein human serum albumin (HSA). Size, surface charge, and surface plasmon bands of the Au NPs are largely modified by the formation of a protein corona via electrostatic interactions and hydrogen bonding as revealed by thermodynamic data. Negative values of the entropy of binding suggested a restriction in the biomolecule mobility upon adsorption. The structure of the adsorbed protein molecules is slightly affected by the interaction with the metal surface, but this effect is enhanced as the NP curvature decreases. Also, it is observed that the protein molecules adsorbed onto the NP surface are more resistant to complete thermal denaturation than free protein ones as deduced from the increases in the melting temperature of the adsorbed protein. Differences in the conformations of the adsorbed protein molecules onto small (<40 nm) and large NPs were observed on the basis of zeta potential data and FTIR spectroscopy, also suggesting a better resistance of adsorbed protein molecules to thermal denaturing conditions. We think this enhanced protein stability is responsible for a reduced formation of HSA amyloid like fibrils in the presence of small Au NPs under HSA fibrillation conditions. PMID- 22439665 TI - Giant intradiploic epidermoid cyst with large osteolytic lesions of the skull: a case report. AB - INTRODUCTION: We report a case of tumor growth over a period of four decades, presenting with large multicentric lytic lesions of the skull and a profound mass effect, without neurological deficits. Clinical and radiological features of a patient with a giant intradiploic epidermoid and its impact on the choice of treatments are discussed. CASE PRESENTATION: An 81-year-old Caucasian man, who had first noticed a painless subcutaneous swelling over the left frontal scalp about 40 years ago, presented after a short episode of dizziness, which he experienced after treatment of focal retinal detachment. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations revealed an exceptionally large tumor involving major parts of the skull with extensive destruction of the bone and distinct deformation of the brain. Considering his age and the absence of neurological deficits or pain, the patient refused the option of tumor removal and cranioplasty, yet agreed to a biopsy, which confirmed the suspected diagnosis. CONCLUSIONS: The course of the disease demonstrates that even patients with large tumors, inducing distinct pathomorphological changes, do not necessarily experience significant impairment of their quality of life without surgery. This is an impressive example of the chance to lead a long and satisfying life without specific medical treatment, avoiding the inherent risks of these procedures. Yet, there is a clear indication for surgery of intradiploic epidermoids in most cases described in the literature. PMID- 22439666 TI - A phase II study for metabolic in vivo response monitoring with sequential 18FDG PET-CT during treatment with the EGFR-monoclonal-antibody cetuximab in metastatic colorectal cancer: the Heidelberg REMOTUX trial. AB - BACKGROUND: The epidermal growth factor receptor monoclonal antibody cetuximab has proven activity in metastatic colorectal cancer. To date, the mechanisms of action are not completely understood. Especially the impact on tumor glucose metabolism, or tumor vascularization remains largely unclear. The understanding of mechanisms such as early changes in tumor metabolism is of clinical importance since there may be a substantial influence on choice and sequence of drug combinations. Early signals of response to cetuximab may prove useful to identify patients having a relevant clinical treatment benefit. The objective of this trial is to evaluate the predictive relevance of the relative change in (18)F Fluorodeoxyglucose tumor uptake for early clinical response during short-term single agent treatment with cetuximab. Early clinical response will be routinely measured according to the response evaluation criteria in solid tumors. Accompanying research includes cytokine immune monitoring and analysis of tumor proteins and tumor genes. METHODS/DESIGN: The REMOTUX trial is an investigator initiated, prospective, open-label, single-arm, single-center early exploratory predictive study. The first (18)F-FDG PET-CT is conducted at baseline followed by the run-in phase with cetuximab at days 1 and 8. At day 14, the second (18)F-FDG PET-CT is performed. Subsequently, patients are treated according to the Folfiri cetuximab regimen as an active and approved first-line regimen for metastatic colorectal carcinoma. At day 56, clinical response is evaluated with a CT-scan compared to the baseline analysis. Tracer uptake is assessed using standardized uptake values (SUVs). The main hypothesis to be tested in the primary analysis is whether or not the relative change in the SUV from baseline to day 14 has any predictive relevance for early clinical response determined at day 56. Patients are followed until death from any cause or until 24 months after the last patient has ended trial treatment. DISCUSSION: The aim of this trial is to evaluate metabolic changes in metastatic colorectal cancer during short-term single agent treatment with cetuximab and to analyse their potential of predicting early clinical response. This could be helpful to answer the question if early identification of patients not responding to cetuximab is possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT200811021020; EudraCT 200901327923. PMID- 22439667 TI - Posterior scleritis presenting with angle closure glaucoma. AB - PURPOSE: To report a case of posterior scleritis associated with angle closure glaucoma and transient myopia. METHODS: A previously healthy 29-year-old male was referred for YAG laser iridotomy to treat angle closure glaucoma. He was suffering from severe pain and vision loss in his right eye. Findings on examination were hyperemia, proptosis, and myopia measuring approximately 6 diopters. Diagnosis of posterior scleritis was made due to presence of choroidal thickening, sub-Tenon effusion and the classical "T" sign observed on orbital ultrasonography. RESULTS: Treatment was initiated using oral prednisolone. After 8 days, the patient's symptoms regressed and visual acuity returned to 20/20. CONCLUSIONS: Posterior scleritis is an often misdiagnosed eye disease. Pain is the main symptom and may be accompanied by decrease in visual acuity. Early diagnosis and treatment is important to avoid permanent visual loss. PMID- 22439668 TI - Telaprevir: a review of its use in the management of genotype 1 chronic hepatitis C. AB - Telaprevir (Incivo(r), Incivek(r)), an orally administered inhibitor of the hepatitis C virus non-structural protein NS3-4A serine protease, is used in combination with pegylated interferon (peginterferon)-alpha and ribavirin in the treatment of adults with genotype 1 chronic hepatitis C virus (HCV) infection (chronic hepatitis C). This article reviews data on the clinical efficacy and tolerability of telaprevir in adults with genotype 1 chronic hepatitis C and provides a summary of its pharmacological properties. In in vitro studies, telaprevir shows good activity against genotype 1 HCV, including viral isolates from patients with chronic hepatitis C. Numerous resistant variants of HCV have been identified in clinical isolates from patients receiving treatment with telaprevir-based therapy. However, the clinical relevance of viral variants emerging during treatment requires further study. Telaprevir administered for 12 weeks in combination with peginterferon-alpha-2a and ribavirin for up to 48 weeks was effective in the treatment of previously untreated or previously treated adults with genotype 1 chronic hepatitis C in three major randomized phase III trials. Sustained virological response rates (i.e. percentages of patients with undetectable HCV RNA levels 24 weeks after the last planned dose of study medication: the primary endpoint) achieved with the telaprevir-based regimens were significantly higher than those produced with peginterferon-alpha-2a and ribavirin alone (the 'current standard of care'). In the largest trial (the ADVANCE trial) in previously untreated patients, 24 weeks after the last planned dose of study drug, recipients of 12 weeks' treatment with telaprevir in combination with peginterferon-alpha-2a and ribavirin followed by treatment with peginterferon-alpha-2a and ribavirin for a further 12 or 36 weeks experienced significantly (p < 0.001) higher sustained virological response rates than patients who received peginterferon-alpha-2a and ribavirin dual therapy for 48 weeks (75% vs 44%). Adverse events were reported more frequently with telaprevir based regimens than with peginterferon-alpha-2a and ribavirin dual therapy in the major trials. The most common adverse events included fatigue, rash, pruritus, anaemia and nausea. In conclusion, telaprevir in combination with peginterferon alpha and ribavirin is an effective treatment for treatment-naive and previously treated adults with genotype 1 chronic hepatitis C - patient groups in whom peginterferon-alpha and ribavirin dual therapy may not be successful. Thus, telaprevir is a valuable new treatment option for use in combination with peginterferon-alpha and ribavirin in treatment-naive or previously treated adults with genotype 1 chronic hepatitis C. PMID- 22439669 TI - Rasagiline: a review of its use in the treatment of idiopathic Parkinson's disease. AB - Rasagiline (Azilect(r)), a selective, irreversible, monoamine oxidase-B inhibitor, is available in the EU, the US and in several other countries worldwide, including Canada and Israel. It is indicated for the treatment of idiopathic Parkinson's disease as monotherapy or as adjunctive therapy to levodopa in patients [corrected]with end-of-dose fluctuations in the EU and for the treatment of adult patients with the signs and symptoms of idiopathic Parkinson's disease in the US. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of rasagiline as monotherapy or as adjunctive therapy to levodopa in patients with Parkinson's disease. Oral rasagiline as monotherapy or as adjunctive therapy to levodopa was effective in the symptomatic treatment of adult patients with Parkinson's disease participating in double-blind, placebo-controlled, multinational studies. In patients with early Parkinson's disease, monotherapy with rasagiline 1 mg/day (recommended dosage) significantly slowed the rate of worsening (i.e. an increase in the Unified Parkinson's Disease Rating Scale [UPDRS] score) in the ADAGIO and TEMPO studies, with the results from the ADAGIO study for rasagiline 1 mg/day suggesting a slowing of clinical progression. However, at the higher dosage of 2 mg/day, rasagiline met the primary endpoint in the TEMPO study and the first, but not the second, of three hierarchical primary endpoints in the ADAGIO study. Compared with delayed-start rasagiline monotherapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson's disease in the TEMPO study. As adjunctive therapy to levodopa in the LARGO and PRESTO studies, rasagiline 0.5 and/or 1 mg/day significantly reduced the total daily 'off' time (primary efficacy endpoint) and significantly improved the Clinical Global Impression score, the UPDRS activities of daily living subscale score during 'off' time and the UPDRS motor subscale score during 'on' time compared with placebo in patients with advanced Parkinson's disease. Although rasagiline showed neuroprotective properties both in vitro and in vivo, identifying its potential to slow clinical progression in the clinical setting has been elusive to date and was not definitively demonstrated in the studies discussed in this article. Additional rasagiline studies specifically designed to assess the clinical progression of Parkinson's disease while addressing the potentially confounding factors of the delayed-start study design would therefore be of interest. As monotherapy or as adjunctive therapy to levodopa, rasagiline was generally well tolerated, with the frequency and nature of treatment-emergent adverse events generally similar across clinical studies and between rasagiline and placebo groups. Therapy with rasagiline appears to be associated with a low incidence of cognitive and behavioural adverse events. Thus, oral rasagiline as monotherapy or as adjunctive therapy to levodopa provides a useful option in the treatment of adult patients with Parkinson's disease. PMID- 22439670 TI - Induction therapy in renal transplant recipients: how convincing is the current evidence? AB - The goal of organ transplantation is to provide durable organ function while minimizing risks such as infection and cancer. Induction therapy in renal transplantation provides improved short- and long-term graft outcomes compared with placebo. Three agents are currently available and widely used in the US; rabbit anti-thymocyte globulin (rATG), basiliximab and alemtuzumab. These agents are all clinically effective in transplantation. In patients at high risk of rejection, graft outcomes are improved with the use of depleting agents, such as rATG or alemtuzumab, rather than basiliximab. Depleting agents are associated with more complications, such as infection and malignancy. The risk-benefit analysis for low-risk patients indicates that basiliximab may be the preferred agent in this population. Use of induction therapy, particularly with rATG, may not only allow for but also mandate reduction of maintenance immunosuppression. The mechanisms by which induction agents lead to improved clinical outcomes have not been elucidated. rATG and alemtuzumab lead to prompt and durable lymphocyte depletion, but many other mechanisms contribute to their suppression of alloimmunity. For instance, rATG contains antibodies specific for multiple adhesion molecules and even human leukocyte antigen, while CD52 (the target of alemtuzumab) is present on many antigen-presenting cells as well as lymphocytes. The manner in which the immune system recovers after induction may also aid in establishment of immune tolerance, with proliferation of suppressor T lymphocytes seen with rATG use. The various contributions of these mechanisms in achieving the goal of allograft tolerance are currently being investigated. The currently available data are of generally low quality, based on many small and often retrospective studies. Definitions of 'high risk' vary between studies, as do induction and maintenance dosing regimens. Standardization of definitions and establishment of large, prospective, multicentre trials would lead to a better understanding of the currently available agents and their best use in renal transplantation induction therapy. PMID- 22439671 TI - Medical therapy of endometrial cancer: current status and promising novel treatments. AB - While early-stage endometrial cancer is often successfully treated with surgical intervention, treatment of advanced endometrial carcinoma can be difficult and prognosis poor, particularly in the context of metastatic or recurrent disease. Standard chemotherapy agents for both adjuvant first-line treatment (for selected patients deemed at high risk of relapse) and recurrent endometrial cancer include doxorubicin, platinum agents and paclitaxel. Investigational options currently being studied in phase II trials include both combined regimens of standard chemotherapeutic agents versus radiation as well as targeted treatments such as epothilones, mammalian target of rapamycin (mTOR) inhibitors and anti-angiogenic agents. Recent interest in the molecular pathways of carcinogenesis have lead to increased investigation of these novel agents and the hope that they will impact positively on the overall survival of women with endometrial cancer. PMID- 22439673 TI - Differences of prefrontal cortex activity between picture-based personality tests: a near-infrared spectroscopy study. AB - This study reports on brain activity induced by picture-based personality tests. Near-infrared spectroscopy is a newly developed, noninvasive technology in neuroimaging that can measure brain activity through blood volume changes. We measure the prefrontal cortex (Brodmann Area 10 [BA10]) activities of adolescents during the Rorschach (1921), the Rosenzweig Picture-Frustration Study (PFS; Hayashi, 1964), and Thematic Apperception Test (TAT; Murray, 1943). BA10 showed that the PFS was left-hemisphere dominant and significantly different from the Rorschach and TAT, which showed a tendency to be right-hemisphere dominant. We believe that this tendency reflects emotion and sociality. PMID- 22439674 TI - Cytotoxic alkaloids from Fusarium incarnatum associated with the mangrove tree Aegiceras corniculatum. AB - Several unusual alkaloids, N-2-methylpropyl-2-methylbutenamide (1), 2-acetyl 1,2,3,4-tetrahydro-beta-carboline (2), fusarine (3), fusamine (4), and 3-(1 aminoethylidene)-6-methyl-2H-pyran-2,4(3H)-dione (5), were isolated from the culture broth of Fusarium incarnatum (HKI0504), an endophytic fungus of the mangrove plant Aegiceras corniculatum. Compounds 2, 4, and 5 exhibit weak antiproliferative and cytotoxic activities against HUVEC, K-562, and HeLa human cell lines, respectively. PMID- 22439675 TI - Thiol-based photocycle of the blue and teal light-sensing cyanobacteriochrome Tlr1999. AB - Cyanobacteriochromes are a spectrally diverse photoreceptor family that binds a bilin chromophore. For some cyanobacteriochromes, in addition to the widely conserved cysteine to anchor the chromophore, its ligation with a second cysteine is responsible for a remarkable blue shift. Herein, we report a newly discovered cyanobacteriochrome Tlr1999 exhibiting reversible photoconversion between a blue absorbing form at 418 nm (P418) and a teal-absorbing form at 498 nm (P498). Acidic denaturation suggests that P418 harbors C15-Z phycoviolobilin, whereas P498 harbors C15-E phycoviolobilin. When treated with iodoacetamide, which irreversibly modifies thiol groups, P418 is slowly converted to a green-absorbing photoinactive form denoted P552. The absorption spectrum of P498 appears to be unaffected by iodoacetamide, but when iodoacetamide modified, it is photoconverted to P552. These results suggest that a covalent bond exists between the second Cys and the phycoviolobilin in P418 but not in P498. Subsequent treatment with dithiothreitol converts P552 into P418, whereas dithiothreitol reduces P498 to yield P420, a photoinactive form. Site-directed mutagenesis shows that the second Cys is essential for assembly of the photoactive holoprotein and that the photoactivity of this inert mutant is partially rescued by beta mercaptoethanol. These results suggest that the covalent attachment and detachment of a thiol, although not necessarily that of the second Cys, is critical for the reversible spectral blue shift and the complete photocycle. We propose a thiol-based photocycle, in which the thiol-modified P552 and P420 are intermediate-like forms. PMID- 22439676 TI - Characterization and differential expression of microRNAs elicited by sulfur deprivation in Chlamydomonas reinhardtii. AB - BACKGROUND: microRNAs (miRNAs) have been found to play an essential role in the modulation of numerous biological processes in eukaryotes. Chlamydomonas reinhardtii is an ideal model organism for the study of many metabolic processes including responses to sulfur-deprivation. We used a deep sequencing platform to extensively profile and identify changes in the miRNAs expression that occurred under sulfur-replete and sulfur-deprived conditions. The aim of our research was to characterize the differential expression of Chlamydomonas miRNAs under sulfur deprived conditions, and subsequently, the target genes of miRNA involved in sulfur-deprivation were further predicted and analyzed. RESULTS: By using high throughput sequencing, we characterized the microRNA transcriptomes under sulphur replete and sulfur-deprived conditions in Chlamydomonas reinhardtii. We predicted a total of 310 miRNAs which included 85 known miRNAs and 225 novel miRNAs. 13 miRNAs were the specific to the sulfur-deprived conditions. 47 miRNAs showed significantly differential expressions responding to sulfur-deprivation, and most were up-regulated in the small RNA libraries with sulfur-deprivation. Using a web based integrated system (Web MicroRNAs Designer 3) and combing the former information from a transcriptome of Chlamydomonas reinhardtii, 22 miRNAs and their targets involved in metabolism regulation with sulfur-deprivation were verified. CONCLUSIONS: Our results indicate that sulfur-deprivation may have a significant influence on small RNA expression patterns, and the differential expressions of miRNAs and interactions between miRNA and its targets might further reveal the molecular mechanism responding to sulfur-deprivation in Chlamydomonas reinhardtii. PMID- 22439677 TI - Targeting VEGF in lung cancer. AB - INTRODUCTION: VEGF promotes tumor angiogenesis and is an important target in various malignancies, including NSCLC. AREAS COVERED: Here, the authors review the data that led to the approval of bevacizumab, a monoclonal antibody against VEGF, in the treatment of lung cancer. The authors also review the key results from a number of Phase II and Phase III trials involving other anti-angiogenic agents being studied in NSCLC, including small-molecule tyrosine kinase inhibitors against the VEGF-receptor and vascular-disrupting agents (VDAs). EXPERT OPINION: Results from ongoing studies and the identification of reliable biomarkers remain critical goals in understanding the exact role of these anti angiogenic agents in the treatment paradigm of NSCLC. PMID- 22439678 TI - Triple signal amplification of graphene film, polybead carried gold nanoparticles as tracing tag and silver deposition for ultrasensitive electrochemical immunosensing. AB - A triple signal amplification strategy was designed for ultrasensitive immunosensing of cancer biomarker. This strategy was achieved using graphene to modify immunosensor surface for accelerating electron transfer, poly(styrene-co acrylic acid) microbead (PSA) carried gold nanoparticles (AuNPs) as tracing tag to label signal antibody (Ab(2)) and AuNPs induced silver deposition for anodic stripping analysis. The immunosensor was constructed by covalently immobilizing capture antibody on chitosan/electrochemically reduced graphene oxide film modified glass carbon electrode. The in situ synthesis of AuNPs led to the loading of numerous AuNPs on PSA surface and convenient labeling of the tag to Ab(2). With a sandwich-type immunoreaction, the AuNPs/PSA labeled Ab(2) was captured on the surface of an immunosensor to further induce a silver deposition process. The electrochemical stripping signal of the deposited silver nanoparticles in KCl was used to monitor the immunoreaction. The triple signal amplification greatly enhanced the sensitivity for biomarker detection. The proposed method could detect carcinoembryonic antigen with a linear range of 0.5 pg mL(-1) to 0.5 ng mL(-1) and a detection limit down to 0.12 pg mL(-1). The immunosensor exhibited good stability and acceptable reproducibility and accuracy, indicating potential applications in clinical diagnostics. PMID- 22439679 TI - Exercise training and impaired glucose tolerance in obese humans. AB - Individuals with impaired glucose tolerance (IGT) are at greater risk of developing diabetes than in normoglycaemia. The aim of this study was to examine the effects of 12-weeks exercise training in obese humans with IGT. Eleven participants (6 males and 5 females; 49+/-9 years; mean Body Mass Index (BMI) 32.4 kg . m(-2)), completed a 12-week brisk walking intervention (30 min per day, five days a week (d . wk(-1)), at 65% of age-predicted maximal heart rate (HR(max)). Anthropometric measurements, dietary intake, pulse wave velocity (PWV, to determine arterial stiffness) and blood pressure (BP) were examined at baseline and post intervention. Fasting blood glucose, glycosylated haemoglobin, insulin, blood lipids, indices of oxidative stress and inflammation (lipid hydroperoxides; superoxide dismutase; multimeric adiponectin concentration and high-sensitivity C-reactive protein) were also determined. Post intervention, PWV (9.08+/-1.27 m . s(-1) vs. 8.39+/-1.21 m . s(-1)), systolic BP (145.4+/-14.5 vs. 135.8+/-14.9 mmHg), triglycerides (1.52+/-0.53 mmol . L(-1) vs. 1.31+/-0.54 mmol . L(-1)), lipid hydroperoxides (1.20+/-0.47 MUM . L(-1) vs. 0.79+/-0.32 MUM . L( 1)) and anthropometric measures decreased significantly (P < 0.05). Moderate intensity exercise training improves upper limb vascular function in obese humans with IGT, possibly by improving triglyceride metabolism, which may subsequently reduce oxidative stress. These changes were independent of multimeric adiponectin modification and alterations in other blood biomarkers. PMID- 22439680 TI - Emv2, the only endogenous ecotropic murine leukemia virus of C57BL/6J mice. AB - With the proliferation of sequence data, great challenges are posed in the correct annotation of endogenous retroviruses, which together comprise up to ten per cent of the genomes of many organisms. It is therefore essential that all sources of information are carefully considered before drawing conclusions concerning the phylogeny, distribution and biological properties of endogenous retroviruses. We suggest that such due diligence has not been applied in the description of an endogenous ecotropic retrovirus that recently appeared in Retrovirology. PMID- 22439681 TI - An unusual cause of a pigmented lesion. PMID- 22439683 TI - [Gallium(III) protoporphyrin IX]2: a soluble diamagnetic model for malaria pigment. AB - Gallium(III) protoporphyrin IX forms a dimeric propionate-bridged dimer, 2, that is a soluble diamagnetic analogue of hematin anhydride. The single-crystal structure of 2 corresponds to a nondisordered inversion-symmetric dimer similar to malaria pigment but, unlike it, has a six-coordinate metal and an intraporphyrin rather than an interporphyrin hydrogen bond. NMR NOE correlations demonstrate the presence of the propionate linkage in solutions with pyridine. Taken together, this is the first single-crystal X-ray diffraction study of a propionate-linked dimer as found in malaria pigment and the first evidence for its presence in solution. PMID- 22439684 TI - Eating disorder features in indigenous Aboriginal and Torres Strait Islander Australian peoples. AB - BACKGROUND: Obesity and related cardiovascular and metabolic conditions are well recognized problems for Australian Aboriginal and Torres Strait Islander peoples. However, there is a dearth of research on relevant eating disorders (EDs) such as binge eating disorder in these groups. METHODS: Data were obtained from interviews of 3047 (in 2005) and 3034 (in 2008) adults who were participants in a randomly selected South Australian household survey of individuals' age > 15 years. The interviewed comprised a general health survey in which ED questions were embedded. Data were weighted according to national census results and comprised key features of ED symptoms. RESULTS: In 2005 there were 94 (85 weighted) First Australian respondents, and in 2008 65 (70 weighted). Controlling for secular differences, in 2005 rates of objective binge eating and levels of weight and shape influence on self-evaluation were significantly higher in indigenous compared to non-indigenous participants, but no significant differences were found in ED features in 2008. CONCLUSIONS: Whilst results on small numbers must be interpreted with caution, the main finding was consistent over the two samples. For First Australians ED symptoms are at least as frequent as for non-indigenous Australians. PMID- 22439685 TI - Impact of malaria morbidity on gross domestic product in Uganda. AB - BACKGROUND: The burden of malaria is a key challenge to both human and economic development in malaria endemic countries. The impact of malaria can be categorized from three dimensions, namely: health, social and economic. The objective of this study was to estimate the impact of malaria morbidity on gross domestic product (GDP) of Uganda. METHODS: The impact of malaria morbidity on GDP of Uganda was estimated using double-log econometric model. The 1997-2003 time series macro-data used in the analysis were for 28 quarters, i.e. 7 years times 4 quarters per year. It was obtained from national and international secondary sources. RESULTS: The slope coefficient for Malaria Index (M) was -0.00767; which indicates that when malaria morbidity increases by one unit, while holding all other explanatory variables constant, per capita GDP decreases by US$0.00767 per year. In 2003 Uganda lost US$ 49,825,003 of GDP due to malaria morbidity. Dividing the total loss of US$49.8 million by a population of 25,827,000 yields a loss in GDP of US$1.93 per person in Uganda in 2003. CONCLUSION: Malaria morbidity results in a substantive loss in GDP of Uganda. The high burden of malaria leads to decreased long-term economic growth, and works against poverty eradication efforts and socioeconomic development of the country. PMID- 22439686 TI - Charge-reversal lipids, peptide-based lipids, and nucleoside-based lipids for gene delivery. AB - Twenty years after gene therapy was introduced in the clinic, advances in the technique continue to garner headlines as successes pique the interest of clinicians, researchers, and the public. Gene therapy's appeal stems from its potential to revolutionize modern medical therapeutics by offering solutions to myriad diseases through treatments tailored to a specific individual's genetic code. Both viral and non-viral vectors have been used in the clinic, but the low transfection efficiencies when non-viral vectors are used have lead to an increased focus on engineering new gene delivery vectors. To address the challenges facing non-viral or synthetic vectors, specifically lipid-based carriers, we have focused on three main themes throughout our research: (1) The release of the nucleic acid from the carrier will increase gene transfection. (2) The use of biologically inspired designs, such as DNA binding proteins, to create lipids with peptide-based headgroups will improve delivery. (3) Mimicking the natural binding patterns observed within DNA, by using lipids having a nucleoside headgroup, will produce unique supramolecular assembles with high transfection efficiencies. The results presented in this Account demonstrate that engineering the chemical components of the lipid vectors to enhance nucleic acid binding and release kinetics can improve the cellular uptake and transfection efficacy of nucleic acids. Specifically, our research has shown that the incorporation of a charge-reversal moiety to initiate a shift of the lipid from positive to negative net charge improves transfection. In addition, by varying the composition of the spacer (rigid, flexible, short, long, or aromatic) between the cationic headgroup and the hydrophobic chains, we can tailor lipids to interact with different nucleic acids (DNA, RNA, siRNA) and accordingly affect delivery, uptake outcomes, and transfection efficiency. The introduction of a peptide headgroup into the lipid provides a mechanism to affect the binding of the lipid to the nucleic acid, to influence the supramolecular lipoplex structure, and to enhance gene transfection activity. Lastly, we discuss the in vitro successes that we have had when using lipids possessing a nucleoside headgroup to create unique self assembled structures and to deliver DNA to cells. In this Account, we state our hypotheses and design elements as well as describe the techniques that we have used in our research to provide readers with the tools to characterize and engineer new vectors. PMID- 22439687 TI - Green amorphous nanoplex as a new supersaturating drug delivery system. AB - The nanoscale formulation of amorphous drugs represents a highly viable supersaturating drug-delivery system for enhancing the bioavailability of poorly soluble drugs. Herein we present a new formulation of a nanoscale amorphous drug in the form of a drug-polyelectrolyte nanoparticle complex (or nanoplex), where the nanoplex is held together by the combination of a drug-polyelectrolyte electrostatic interaction and an interdrug hydrophobic interaction. The nanoplex is prepared by a truly simple, green process that involves the ambient mixing of drug and polyelectrolyte (PE) solutions in the presence of salt. Nanoplexes of poorly soluble acidic (i.e., ibuprofen and curcumin) and basic (i.e., ciprofloxacin) drugs are successfully prepared using biocompatible poly(allylamine hydrochloride) and dextran sulfate as the PE, respectively. The roles of salt, drug, and PE in nanoplex formation are examined from ternary phase diagrams of the drug-PE complex, from which the importance of the drug's charge density and hydrophobicity, as well as the PE ionization at different pH values, is recognized. Under the optimal conditions, the three nanoplexes exhibit high drug loadings of ~80-85% owing to the high drug complexation efficiency (~90 96%), which is achieved by keeping the feed charge ratio of the drug to PE below unity (i.e., excess PE). The nanoplex sizes are ~300-500 nm depending on the drug hydrophobicity. The nanoplex powders remain amorphous after 1 month of storage, indicating the high stability owed to the PE's high glass-transition temperature. FT-IR analysis shows that functional groups of the drug are conserved upon complexation. The nanoplexes are capable of generating prolonged supersaturation upon dissolution with precipitation inhibitors. The supersaturation level depends on the saturation solubility of the native drugs, where the lower the saturation solubility, the higher the supersaturation level. The solubility of curcumin as the least-soluble drug is magnified 9-fold upon its transformation to the nanoplex, and the supersaturated condition is maintained for 5 h. PMID- 22439688 TI - Patient and public involvement in developing patient-reported outcome measures: indispensable, desirable, challenging. PMID- 22439689 TI - Seeking what matters: patients as research partners. PMID- 22439690 TI - A look back and a look forward: the Journal of Health communication celebrates 100 issues. PMID- 22439691 TI - Health literate practices can facilitate state health insurance exchange communication. PMID- 22439692 TI - Effect of caloric intake on Western-style diet-induced intestinal tumors in a mouse model for hereditary colon cancer. AB - Increased caloric intake has been associated with increased risk for cancer of the large intestine. We studied caloric intake effect on tumor formation in Apc1638( N/+ ) mice, a preclinical model for human familial adenomatous polyposis. Mice were fed a controlled AIN-76A diet or a new Western-style diet (NWD). Intestinal tumor development was evaluated after 6 mo of feeding 1) AIN 76A diet (fed ad libitum) vs. AIN-76A (caloric intake reduced 30%); 2) NWD (fed ad libitum) vs. NWD (caloric intake reduced 30%); and 3) AIN-76A (fed ad libitum) vs. NWD (paired-fed with NWD providing equal caloric intakes to AIN-76A). Intestinal tumor incidences were 78-100% with intergroup variation P > 0.05; however, tumor multiplicity responded differently to dietary treatment: 1) Tumor multiplicity was unchanged after AIN-76A (caloric intake reduced 30% vs. mice fed AIN-76A ad libitum); 2) tumor multiplicity was unchanged after NWD (caloric intake reduced 30% vs. NWD ad libitum); and 3) tumor multiplicity increased 130% after NWD was paired-fed with the same caloric intake as mice fed AIN-76A ad libitum (P < 0.05). Body weights showed no association with tumor development. Findings indicated modified nutrients in NWD were mainly responsible for increased tumors in mice fed NWD vs. AIN-76A in this preclinical mouse model for human FAP. PMID- 22439693 TI - Impact of velvet complex on transcriptome and penicillin G production in glucose limited chemostat cultures of a beta-lactam high-producing Penicillium chrysogenum strain. AB - The multicomponent global regulator Velvet complex has been identified as a key regulator of secondary metabolite production in Aspergillus and Penicillium species. Previous work indicated a massive impact of PcvelA and PclaeA deletions on penicillin production in prolonged batch cultures of P. chrysogenum, as well as substantial changes in transcriptome. The present study investigated the impact of these mutations on product formation and genome-wide transcript profiles under glucose-limited aerobic conditions, relevant for industrial production of beta-lactams. Predicted amino acid sequences of PcVelA and PcLaeA in this strain were identical to those in its ancestor Wisconsin54-1255. Controls were performed to rule out transformation-associated loss of penicillin biosynthesis clusters. The correct PcvelA and PclaeA deletion strains revealed a small reduction of penicillin G productivity relative to the reference strain, which is a much smaller reduction than previously reported for prolonged batch cultures of similar P. chrysogenum mutants. Chemostat-based transcriptome analysis yielded only 23 genes with a consistent differential response in the PcvelADelta and PclaeADelta mutants when grown in the absence of the penicillin G side-chain precursor phenylacetic acid. Eleven of these genes belonged to two small gene clusters, one of which contained a gene with high homology to the aristolochene synthase. These results provide a clear caveat that the impact of the Velvet complex on secondary metabolism in filamentous fungi is strongly context dependent. PMID- 22439694 TI - Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. AB - BACKGROUND: Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). METHODS: OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs. RESULTS: Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p <= 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression.In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC. CONCLUSION: The downregulation of OCT1 is associated with tumor progression and a worse patient survival. PMID- 22439695 TI - Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso. AB - BACKGROUND: Patient immune status is thought to affect the efficacy of anti malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. METHODS: Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml) was obtained from each child to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. RESULTS: IgG levels to MSP3 were always higher in the successfully treated group than in the group with treatment failure. The same observation was made for GLURP but the reverse observation was noticed for MSP1-19. Cytophilic and non-cytophilic antibodies were significantly associated with protection against all three antigens, except for IgG4 to MSP1-19 and GLURP. CONCLUSION: Acquired anti-malarial antibodies may play an important role in the efficacy of anti-malarial drugs in younger children more susceptible to the disease. PMID- 22439696 TI - Coupled electron transfer and proton hopping in the final step of CYP19-catalyzed androgen aromatization. AB - Aromatase (CYP19) catalyzes the terminal step in estrogen biosynthesis, which requires three separate oxidation reactions, culminating in an enigmatic aromatization that converts an androgen to an estrogen. A stable ferric peroxo (Fe(3+)O(2)(2-)) intermediate is seen by electron paramagnetic resonance, but its role in this complex reaction remains controversial. Combining molecular dynamics simulation and hybrid quantum mechanics/molecular mechanics, we show that ferric peroxo addition to the 19-aldehyde initiates the reaction. Stepwise cleavage of the C10-C19 and O-O bonds of the peroxohemiacetal extrudes formate and yields Compound II, which in turn desaturates the steroid through successive abstraction of the 1beta-hydrogen atom and deprotonation of the 2beta-position. Throughout the transformation, a proton is cyclically relayed between D309 and the substrate to stabilize reaction intermediates. This mechanism invokes novel oxygen intermediates and provides a unifying interpretation of past experimental mechanistic studies. PMID- 22439698 TI - A surgical clue to an underlying gammopathy. PMID- 22439697 TI - Images of the self and self-esteem: do positive self-images improve self-esteem in social anxiety? AB - Negative self-images play an important role in maintaining social anxiety disorder. We propose that these images represent the working self in a Self Memory System that regulates retrieval of self-relevant information in particular situations. Self-esteem, one aspect of the working self, comprises explicit (conscious) and implicit (automatic) components. Implicit self-esteem reflects an automatic evaluative bias towards the self that is normally positive, but is reduced in socially anxious individuals. Forty-four high and 44 low socially anxious participants generated either a positive or a negative self-image and then completed measures of implicit and explicit self-esteem. Participants who held a negative self-image in mind reported lower implicit and explicit positive self-esteem, and higher explicit negative self-esteem than participants holding a positive image in mind, irrespective of social anxiety group. We then tested whether positive self-images protected high and low socially anxious individuals equally well against the threat to explicit self-esteem posed by social exclusion in a virtual ball toss game (Cyberball). We failed to find a predicted interaction between social anxiety and image condition. Instead, all participants holding positive self-images reported higher levels of explicit self-esteem after Cyberball than those holding negative self-images. Deliberate retrieval of positive self-images appears to facilitate access to a healthy positive implicit bias, as well as improving explicit self-esteem, whereas deliberate retrieval of negative self-images does the opposite. This is consistent with the idea that negative self-images may have a causal, as well as a maintaining, role in social anxiety disorder. PMID- 22439699 TI - Deciphering neo-sex and B chromosome evolution by the draft genome of Drosophila albomicans. AB - BACKGROUND: Drosophila albomicans is a unique model organism for studying both sex chromosome and B chromosome evolution. A pair of its autosomes comprising roughly 40% of the whole genome has fused to the ancient X and Y chromosomes only about 0.12 million years ago, thereby creating the youngest and most gene-rich neo-sex system reported to date. This species also possesses recently derived B chromosomes that show non-Mendelian inheritance and significantly influence fertility. METHODS: We sequenced male flies with B chromosomes at 124.5-fold genome coverage using next-generation sequencing. To characterize neo-Y specific changes and B chromosome sequences, we also sequenced inbred female flies derived from the same strain but without B's at 28.5-fold. RESULTS: We assembled a female genome and placed 53% of the sequence and 85% of the annotated proteins into specific chromosomes, by comparison with the 12 Drosophila genomes. Despite its very recent origin, the non-recombining neo-Y chromosome shows various signs of degeneration, including a significant enrichment of non-functional genes compared to the neo-X, and an excess of tandem duplications relative to other chromosomes. We also characterized a B-chromosome linked scaffold that contains an actively transcribed unit and shows sequence similarity to the subcentromeric regions of both the ancient X and the neo-X chromosome. CONCLUSIONS: Our results provide novel insights into the very early stages of sex chromosome evolution and B chromosome origination, and suggest an unprecedented connection between the births of these two systems in D. albomicans. PMID- 22439700 TI - Incretin-based therapies and cardiovascular risk. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors are currently used as glucose-lowering agents in type 2 diabetes, due to their effects on insulin and glucagon secretion. These agents, which are effective in improving glucose control, could also have a beneficial effect on the incidence of cardiovascular events. The analysis of major cardiovascular events reported during trials with metabolic endpoints shows a significant reduction of risk with both classes of drugs. Longer-term trials specifically designed to assess the effects of GLP-1 receptor agonists and DPP4 inhibitors on major cardiovascular events are currently ongoing. SCOPE: In order to elucidate potential mechanisms of cardiovascular protection with incretin based therapies, a Medline search (any date up to December 15th, 2011) was performed using the terms 'cardiovascular' and ('DPP-4' or 'GLP-1' or any single name of incretin-based drugs); papers which were considered relevant for the aim of this review were selected by the authors, on the basis of their judgment. FINDINGS: Incretin-based drugs have beneficial effects on cardiovascular risk factors, such as blood pressure and, to a lesser extent, cholesterol and triglyceride. GLP-1 receptor agonists also reduce body weight. A number of experimental studies has suggested that GLP-1 has direct, beneficial effects on myocardial and endothelial cells, but some of these actions could be mediated via GLP-1 receptor-independent pathways. Available experimental evidence, together with a few pilot studies in humans, shows that GLP-1 receptor agonists and DPP4 inhibitors are capable of ameliorating myocardial function and protect myocardiocytes from ischemic damage, independent of their glucose-lowering effects. Furthermore, both classes of drugs enhance endothelial function. In addition, DPP4 inhibitors increase the availability of endothelial progenitor cells, via a GLP-1 receptor-independent pathway. CONCLUSION: Taken together, available data suggest that incretin-based therapies could prevent cardiovascular disease via multiple mechanisms. PMID- 22439701 TI - Reply to Emv2, the only endogenous ecotropic murine leukemia virus of C57BL/6J mice. AB - This correspondence was written in response to the comments by Young et al. Following careful evaluation of the relevant dataset, each of the points brought up by Young et al. has been addressed in this response. We anticipate this will clarify our findings regarding ERVmch8, an ecotropic endogenous retrovirus that was shown to have cerebellum-specific and age-dependent expression patterns in C57BL/6J mice. PMID- 22439703 TI - Pseudomonas aeruginosa attachment on QCM-D sensors: the role of cell and surface hydrophobicities. AB - While biofilms are ubiquitous in nature, the mechanism by which they form is still poorly understood. This study investigated the process by which bacteria deposit and, shortly after, attach irreversibly to surfaces by reorienting to create a stronger interaction, which leads to biofilm formation. A model for attachment of Pseudomonas aeruginosa was developed using a quartz crystal microbalance with dissipation monitoring (QCM-D) technology, along with a fluorescent microscope and camera to monitor kinetics of adherence of the cells over time. In this model, the interaction differs depending on the force that dominates between the viscous, inertial, and elastic loads. P. aeruginosa, grown to the midexponential growth phase (hydrophilic) and stationary phase (hydrophobic) and two different surfaces, silica (SiO(2)) and polyvinylidene fluoride (PVDF), which are hydrophilic and hydrophobic, respectively, were used to test the model. The bacteria deposited on both of the sensor surfaces, though on the silica surface the cells reached a steady state where there was no net increase in deposition of bacteria, while the quantity of cells depositing on the PVDF surface continued to increase until the end of the experiments. The change in frequency and dissipation per cell were both positive for each overtone (n), except when the cells and surface are both hydrophilic. In the model three factors, specifically, viscous, inertial, and elastic loads, contribute to the change in frequency and dissipation at each overtone when a cell deposits on a sensor. On the basis of the model, hydrophobic cells were shown to form an elastic connection to either surface, with an increase of elasticity at higher overtones. At lower overtones, hydrophilic cells depositing on the hydrophobic surface were shown to also be elastic, but as the overtone increases the connection between the cells and sensor becomes more viscoelastic. In the case of hydrophilic cells interacting with the hydrophilic surface, the connection is viscous at each overtone measured. It could be inferred that the transformation of the viscoelasticity of the cell-surface connection is due to changes in the orientation of the cells to the surface, which allow the bacteria to attach irreversibly and begin biofilm formation. PMID- 22439702 TI - Click nucleic acid ligation: applications in biology and nanotechnology. AB - Biochemical strategies that use a combination of synthetic oligonucleotides, thermostable DNA polymerases, and DNA ligases can produce large DNA constructs up to 1 megabase in length. Although these ambitious targets are feasible biochemically, comparable technologies for the chemical synthesis of long DNA strands lag far behind. The best available chemical approach is the solid-phase phosphoramidite method, which can be used to assemble DNA strands up to 150 bases in length. Beyond this point, deficiencies in the chemistry make it impossible to produce pure DNA. A possible alternative approach to the chemical synthesis of large DNA strands is to join together carefully purified synthetic oligonucleotides by chemical methods. Click ligation by the copper-catalyzed azide-alkyne (CuAAC) reaction could facilitate this process. In this Account, we describe the synthesis, characterization, and applications of oligonucleotides prepared by click ligation. The alkyne and azide oligonucleotide strands can be prepared by standard protocols, and the ligation reaction is compatible with a wide range of chemical modifications to DNA and RNA. We have employed click ligation to synthesize DNA constructs up to 300 bases in length and much longer sequences are feasible. When the resulting triazole linkage is placed in a PCR template, various DNA polymerases correctly copy the entire base sequence. We have also successfully demonstrated both in vitro transcription and rolling circle amplification through the modified linkage. This linkage has shown in vivo biocompatibility: an antibiotic resistance gene containing triazole linkages functions in E. coli . Using click ligation, we have synthesized hairpin ribozymes up to 100 nucleotides in length and a hammerhead ribozyme with the triazole linkage located at the substrate cleavage site. At the opposite end of the length scale, click-ligated, cyclic mini-DNA duplexes have been used as models to study base pairing. Cyclic duplexes have potential therapeutic applications. They have extremely high thermodynamic stability, have increased resistance to enzymatic degradation, and have been investigated as decoys for regulatory proteins. For potential nanotechnology applications, we have synthesized double stranded DNA catenanes by click ligation. Other researchers have studied covalently fixed multistranded DNA constructs including triplexes and quadruplexes. PMID- 22439704 TI - The Health Care Quality Improvement Act of 1986 meets the era of health care reform: continuing themes and common threads. A symposium introduction and overview. PMID- 22439705 TI - Hospital-physician relations in a post-health care reform environment. PMID- 22439706 TI - From HCQIA to ACA. The 180 degrees arc of provider antitrust concerns in healthcare over 25 years. PMID- 22439707 TI - Historic and personal reflections on HCQIA. Perspectives of a former federal executive. PMID- 22439708 TI - From HCQIA to the ACA. The evolution of reporting as a quality improvement tool. PMID- 22439709 TI - State medical boards. Future challenges for regulation and quality enhancement of medical care. PMID- 22439710 TI - An ethical dilemma. Patents & profits v. access & affordability. PMID- 22439711 TI - It's in my patients' best interests, so what's the problem? The ethical, legal and professional implications of waiving patient co-payments. PMID- 22439712 TI - Home sweet home. A place to deliver, care for, and raise our children. PMID- 22439713 TI - The modern-day Nuremburg defense. The Federal Tort Claims Act, the Public Health Service Act, and immunity for those who violate the constitution. PMID- 22439714 TI - The good, the bad and the ugly. A 50-state survey exploring federal and state firearm regulations related to mental health. PMID- 22439716 TI - Analysis of genetic diversity in Brown Swiss, Jersey and Holstein populations using genome-wide single nucleotide polymorphism markers. AB - BACKGROUND: Studies of genetic diversity are essential in understanding the extent of differentiation between breeds, and in designing successful diversity conservation strategies. The objective of this study was to evaluate the level of genetic diversity within and between North American Brown Swiss (BS, n = 900), Jersey (JE, n = 2,922) and Holstein (HO, n = 3,535) cattle, using genotyped bulls. GENEPOP and FSTAT software were used to evaluate the level of genetic diversity within each breed and between each pair of the three breeds based on genome-wide SNP markers (n = 50,972). RESULTS: Hardy-Weinberg equilibrium (HWE) exact test within breeds showed a significant deviation from equilibrium within each population (P < 0.01), which could be a result of selection, genetic drift and inbreeding within each breed. Hardy-Weinberg test also confirmed significant heterozygote deficit in each breed over several loci. Moreover, results from population differentiation tests showed that the majority of loci have alleles or genotypes drawn from different distributions in each breed. Average gene diversity, expressed in terms of observed heterozygosity, over all loci in BS, JE and HO was 0.27, 0.26 and 0.31, respectively. The proportion of genetic diversity due to allele frequency differences among breeds (Fst) indicated that the combination of BS and HO in an ideally amalgamated population had higher genetic diversity than the other pairs of breeds. CONCLUSION: Results suggest that the three bull populations have substantially different gene pools. BS and HO show the largest gene differentiation and jointly the highest total expected gene diversity compared to when JE is considered. If the loss of genetic diversity within breeds worsens in the future, the use of crossbreeding might be an option to recover genetic diversity, especially for the breeds with small population size. PMID- 22439717 TI - Thinking outside the box: new strategies for antichlamydial control. PMID- 22439718 TI - Back to the future: host-targeted chemotherapeutics for drug-resistant TB. PMID- 22439720 TI - Endothelial cells and CMV dissemination. AB - Using the murine CMV animal model and the well-established model of Cre-lox-P mediated green-fluorescence tagging of endothelial cell (EC)-derived mouse CMV to quantify the role of infected ECs in transplantation-associated CMV dissemination (in mice expressing Cre recombinase under the control of either the Tie2 or the Tek promoter selectively expressed in vascular EC-Tie-Cre and Tek-Cre mice), it was shown that EC-derived virus contributed to 50% of the total viral load during primary infection, and there was no preference for dissemination of EC-derived viruses over viruses produced by other cell types. In addition, during secondary viremia, there was only a negligible contribution of EC-derived virus to dissemination to other organs. These results are novel in the methodology employed and are somewhat interesting. However, the data are limited to the mouse model with a short-term follow-up, and the immunodeficient host has not yet been studied. In humans, these conclusions must be taken with caution. First, in primary infection occurring through natural routes, epithelial cells are infected first, then ECs, unless primary infection occurs through blood transfusion, in which case endothelial vascular cells may become infected first. In both cases, the virus transport occurs through the intervention of leukocytes, namely monocytes and polymorphonuclear leukocytes. As monocytes differentiate to macrophages, they become highly susceptible to human CMV replication inside organ tissues, while polymorphonuclear leukocytes are active in virus capturing from infected endothelial vascular cells and transporting to distant sites. PMID- 22439721 TI - Flexicate molecules as a potential new class of antibiotics. AB - Helicates are alpha-helical, nonpeptide complexes that bind to DNA and exhibit antimicrobial activity. In the past, enthusiasm for the use of helicates in biological applications was limited, at least in part, by the presence of a racemic mixture of enantiomers or the formation of complexes that are insoluble in aqueous solutions. Recently, Howson et al. overcame the barriers associated with helicate synthesis by generating helicate-like complexes that are soluble and stable in water, optically pure and synthetically flexible. The mechanism synthesizes nonpeptide mimetic alpha-helical 'flexicates' that bind to DNA and show broad-spectrum antimicrobial activity against representative Gram-positive and Gram-negative bacterial pathogens. Although the application of flexicates as an antimicrobial therapy remains to be determined, this study provides important insight into flexicate activity and the prospective use of flexicates as microbicidal agents. PMID- 22439722 TI - Probing the cellular effects of bacterial effector proteins with the Yersinia toolbox. AB - The type 3 secretion system (T3SS) is a powerful bacterial nanomachine that is able to modify the host cellular immune defense in favor of the pathogen by injection of effector proteins. In this regard, cellular Rho GTPases such as Rac1, RhoA or Cdc42 are targeted by a large group of T3SS effectors by mimicking cellular guanine exchange factors or GTPase-activating proteins. However, functional analysis of one type of T3SS effector that is translocated by bacterial pathogens is challenging because the T3SS effector repertoire can comprise a large number of proteins with redundant or interfering functions. Therefore, we developed the Yersinia toolbox to either analyze singular effector proteins of Yersinia spp. or different bacterial species in the context of bacterial T3SS injection into cells. Here, we focus on the WxxxE guanine exchange factor mimetic proteins IpgB1, IpgB2 and Map, which activate Rac1, RhoA or Cdc42, respectively, as well as the Rho GTPase inactivators YopE (a GTPase-activating mimetic protein) and YopT (cysteine protease), to generate a toolbox module for Rho GTPase manipulation. PMID- 22439723 TI - Prevention of acute otitis media using currently available vaccines. AB - Acute otitis media (AOM) is common in infants and children. Although approximately two-thirds of cases are due to bacteria, almost all of the episodes are preceded by upper respiratory viral infection. Several viruses, among which respiratory syncytial virus is the most common, are involved in the determination of AOM. However, a significant number of AOM cases are associated with influenza infection, and influenza viruses are among the most frequently found respiratory viruses in the middle ear fluid during an acute episode of AOM. Consequently, influenza vaccination may have a favorable impact on the incidence and course of AOM. Moreover, as Streptococcus pneumoniae is one of the leading AOM bacterial pathogens and it is well known that influenza virus infection predisposes to pneumococcal infection, there is a further reason to suggest the use of influenza vaccine to reduce the risk of AOM. On the other hand, the administration of pneumococcal conjugate vaccine is considered per se a possible means of reducing the incidence of the disease. However, although a number of studies have measured the impact of both vaccines on AOM, it is still not known whether (and to what extent) they are really effective, nor what impact the more recently licensed vaccines may have. The aim of this review is to examine the clinical impact of vaccinations on AOM. PMID- 22439724 TI - Viral and host factors that contribute to pathogenicity of enterovirus 71. AB - The single-stranded RNA virus enterovirus 71 (EV71), which belongs to the Picornaviridae family, has caused epidemics worldwide, particularly in the Asia Pacific region. Most EV71 infections result in mild clinical symptoms, including herpangina and hand, foot and mouth disease. However, serious pathological complications have also been reported, especially for young children. The mechanisms of EV71 disease progression remain unclear. The pathogenesis of adverse clinical outcomes may relate to many factors, including cell tropism, cell death and host immune responses. This article reviews the recent advances in the identification of factors determining EV71 cell tropism, the associated mechanisms of viral infection-induced cell death and the interplay between EV71 and immunity. PMID- 22439725 TI - Human challenge studies: a review of adequacy of reporting methods and results. AB - Since the 1940s, researchers have purposefully infected healthy adult humans with pathogenic organisms to study how these pathogens cause disease and can be treated and prevented. 'Challenge studies' can be safe, ethical, extremely informative and an efficient use of resources during the clinical development of vaccines, but knowledge of this form of clinical research trial is not widespread. A review of the human challenge literature was performed to determine whether common elements of challenge studies can be identified in the articles published to date. The review demonstrated incomplete reporting of study characteristics deemed necessary for the correct interpretation and application of human challenge study results and for the accurate replication of study methodology. An unofficial extension of the Consolidated Standards of Reporting Trials (CONSORT) statement is proposed. PMID- 22439727 TI - How Mycobacterium tuberculosis goes to sleep: the dormancy survival regulator DosR a decade later. AB - With 2 million deaths per year, TB remains the most significant bacterial killer. The long duration of chemotherapy and the large pool of latently infected people represent challenges in disease control. To develop drugs that effectively eradicate latent infection and shorten treatment duration, the pathophysiology of the causative agent Mycobacterium tuberculosis needs to be understood. The discovery that the tubercle bacillus can develop a drug-tolerant dormant form and the identification of the underlying genetic program 10 years ago paved the way for a deeper understanding of the life of the parasite inside human lesions and for new approaches to antimycobacterial drug discovery. Here, we summarize what we have learnt since the discovery of the master regulator of dormancy, DosR, and the key gaps in our knowledge that remain. Furthermore, we discuss a possible wider clinical relevance of DosR for 'nontuberculous mycobacteria'. PMID- 22439726 TI - Oxidative stress resistance in Porphyromonas gingivalis. AB - Porphyromonas gingivalis, a black-pigmented, Gram-negative anaerobe, is an important etiologic agent of periodontal disease. The harsh inflammatory condition of the periodontal pocket implies that this organism has properties that will facilitate its ability to respond and adapt to oxidative stress. Because the stress response in the pathogen is a major determinant of its virulence, a comprehensive understanding of its oxidative stress resistance strategy is vital. We discuss multiple mechanisms and systems that clearly work in synergy to defend and protect P. gingivalis against oxidative damage caused by reactive oxygen species. The involvement of multiple hypothetical proteins and/or proteins of unknown function in this process may imply other unique mechanisms and potential therapeutic targets. PMID- 22439728 TI - Intravital models of infection lay the foundation for tissue microbiology. AB - In complex environments, such as those found in the human host, pathogenic bacteria constantly battle the unfavorable conditions imposed by the host response to their presence. During Escherichia coli-induced pyelonephritis, a cascade of events are shown in an intravital animal model to occur in a timely and sequential manner, representing the dynamic interplay between host and pathogen. Today, intravital techniques allow for observing infection in the living host. At resolutions almost on the single-cell level, improved detection methods offer a movie-like description of infection dynamics. Tissue microbiology involves monitoring host-pathogen interaction within the dynamic microecology of infectious sites in the live host. This new field holds great promise for insightful research into microbial disease intervention strategies. PMID- 22439729 TI - Identification by cDNA cloning of abundant sRNAs in a human-avirulent Yersinia pestis strain grown under five different growth conditions. AB - AIMS: sRNA regulation is supposedly involved in the stress response of a pathogen during infection. Yersinia pestis, the etiologic agent of plague, must encounter temperature and microenvironment changes, given its lifestyle. Here, we used the cDNA cloning approach to discover full-length sRNA candidates that are highly expressed in Y. pestis under five different growth conditions. MATERIALS & METHODS: The cDNA cloning approach was improved by combining the traditional cDNA library construction with the prevalent rapid amplification of cDNA ends and RNA size selection techniques. RESULTS: In total, 43 RNA species, including six previously annotated sRNAs, were identified. Of these, 25 sRNAs were encoded on the antisense strand of the annotated genes. Interestingly, two of these sRNAs were found on the complementary strand of noncoding RNAs. In addition, eight novel sRNAs encoded in the intergenic regions were also revealed. Ten sRNA candidates chosen for the northern blot analysis were successfully detected. Analysis of the expression patterns of 29 candidate sRNAs showed that 24 sRNAs are highly abundant in Y. pestis upon entry into the stationary growth phase. CONCLUSION: Our preliminary attempt at screening the novel sRNA candidates will lay the foundation for understanding the roles of sRNAs in Y. pestis physiology and pathogenesis. PMID- 22439731 TI - Relative risk of renal disease among people living with HIV: a systematic review and meta-analysis. AB - BACKGROUND: Antiretroviral therapy (ART) has substantially decreased mortality and HIV-related morbidity. However, other morbidities appear to be more common among PLHIV than in the general population. This study aimed to estimate the relative risk of renal disease among people living with HIV (PLHIV) compared to the HIV-uninfected population. METHODS: We conducted a systematic review and meta analysis of relative risks of renal disease among populations of PLHIV reported in studies from the peer-reviewed literature. We searched Medline for relevant journal articles published before September 2010, yielding papers published during or after 2002. We also searched conference proceedings of the International AIDS Society (IAS) and Conference on Retroviruses and Opportunistic Infections (CROI) prior to and including 2010. Eligible studies were observational studies reporting renal disease defined as acute or chronic reduced renal function with glomerular filtration rate less than or equal to 60 ml/min/1.73 m2 among HIV-positive adults. Pooled relative risks were calculated for various groupings, including class of ART drugs administered. RESULTS: The overall relative risk of renal disease was 3.87 (95% CI: 2.85-6.85) among HIV infected people compared to HIV-uninfected people. The relative risk of renal disease among people with late-stage HIV infection (AIDS) was 3.32 (1.86-5.93) compared to other PLHIV. The relative risk of renal disease among PLHIV who were receiving antiretroviral therapy (ART) was 0.54 (0.29-0.99) compared to treatment naive PLHIV; the relative risk of renal disease among PLHIV who were treated with tenofovir was 1.56 (0.83-2.93) compared to PLHIV who were treated with non tenofovir therapy. The risk of renal disease was also found to significantly increase with age. CONCLUSION: PLHIV are at increased risk of renal disease, with greater risk at later stages of infection and at older ages. ART prolongs survival and decreases the risk of renal disease. However, less reduction in renal disease risk occurs for Tenofovir-containing ART than for other regimens. PMID- 22439732 TI - Unfolding action of alcohols on a highly negatively charged state of cytochrome C. AB - It is well-known that hydrophobic effect play a major role in alcohol-protein interactions leading to structure unfolding. Studies with extremely alkaline cytochrome c (U(B) state, pH 13) in the presence of the first four alkyl alcohols suggests that the hydrophobic effect persistently overrides even though the protein carries a net charge of -17 under these conditions. Equilibrium unfolding of the U(B) state is accompanied by an unusual expansion of the chain involving an intermediate, I(alc), from which water is preferentially excluded, the extent of water exclusion being greater with the hydrocarbon content of the alcohol. The mobility and environmental averaging of side chains in the I(alc) state are generally constrained relative to those in the U(B) state. A few nuclear magnetic resonance-detected tertiary interactions are also found in the I(alc) state. The fact that the I(alc) state populates at low concentrations of methanol and ethanol and the fact that the extent of chain expansion in this state approaches that of the U(B) state indicate a definite influence of electrostatic repulsion severed by the low dielectric of the water/alcohol mixture. Interestingly, the U(B) ? I(alc) segment of the U(B) ? I(alc) ? U equilibrium, where U is the unfolded state, accounts for roughly 85% of the total number of water molecules preferentially excluded in unfolding. Stopped-flow refolding results report on a submillisecond hydrophobic collapse during which almost the entire buried surface area associated with the U(B) state is recovered, suggesting the overwhelming influence of hydrophobic interaction over electrostatic repulsions. PMID- 22439733 TI - The relationships between plasma and red cell vitamin B2 and B6 concentrations and the systemic and local inflammatory responses in patients with colorectal cancer. AB - B vitamins have been implicated in cancer pathogenesis. It is therefore of interest that plasma B6 falls as part of the systemic inflammatory response (SIR), whereas red cell concentrations do not. The modified Glasgow Prognostic Score (mGPS) is a validated inflammation-based prognostic score that consists of a combination of albumin and C-reactive protein concentrations. The aim of this study was to examine the relationships between the concentrations of plasma and red cell vitamin B concentrations, the local and systemic inflammatory response in patients with colorectal cancer. Preoperative venous blood of 108 patients with colorectal cancer were analyzed for C-reactive protein, albumin, flavin adenine dinucleotide (FAD), and pyridoxal phosphate (PLP), and lymphocyte counts. Pathological slides were retrieved for assessment of inflammatory cell infiltration. Increasing mGPS was associated with lower plasma PLP concentrations (P < 0.01) but not plasma and red cell FAD and red cell PLP concentrations. Increasing tumor stage was associated with the presence of venous invasion (P < 0.01) and low-grade inflammatory cell infiltrate (P < 0.05) but not the SIR, FAD, or PLP concentrations. A low-grade inflammatory cell infiltrate was not significantly associated with any other parameter. The presence of a SIR was associated with lower concentrations of plasma PLP but not red cell PLP concentrations in patients with colorectal cancer. Neither FAD and PLP were associated with the tumor inflammatory cell infiltrate. PMID- 22439734 TI - Cellular and humoral immune responses to pandemic influenza vaccine in healthy and in highly active antiretroviral therapy-treated HIV patients. AB - Influenza vaccination is recommended for HAART-treated HIV patients to prevent influenza illness and complications. Due to the known ability of T cells to mediate a broadly cross-reactive response, vaccination effectiveness in cell mediated immune (CMI) response induction is a main objective in new influenza vaccination strategies. Nevertheless, data on CMI responses after pandemic vaccination in HIV subjects are still missing. In the present study, the ability of a single dose of adjuvanted pandemic influenza vaccine to induce humoral and CMI responses was compared in HAART-treated HIV patients and in healthcare workers. Healthcare workers (HCW, n=65) and HAART-treated HIV patients (HIV, n=67) receiving pandemic vaccination were enrolled and analyzed before (t0) and after (t1) vaccination. The analysis of strain-specific humoral response was performed by HAI assay; CMI against pandemic (A/H1N1/Cal/09) and seasonal (A/H1N1/Brisb/07 and A/H3N2/Brisb/07) strains was analyzed by ELISpot and intracellular staining followed by flow cytometry. Pandemic vaccination was effective in inducing both humoral and cell-mediated responses in HAART-treated HIV patients as well as in HCWs. A large fraction of both HCWs and HIV-infected patients showed a T cell response to the pandemic strain before vaccination, suggesting possible previous exposure to A/H1N1/pdm/09 and/or cross-reactive T cells. Notably, pandemic vaccine was also able to boost cross-reactive immune responses to seasonal strains. Finally, a weaker boost of both strain-specific and cross-reactive T cell immunity was found in individuals showing a higher baseline response. These data show the effectiveness of adjuvanted pandemic vaccine to induce both humoral and cellular (strain-specific and cross-reactive) immune responses in HIV patients similar to HCWs. PMID- 22439735 TI - Scleroderma-like syndrome due to hydroxyurea. AB - Scleroderma-like cutaneous changes have been reported in association with several drugs, but not with hydroxyurea (HU), to our knowledge. We report the case of a 67-year-old man who was treated with HU (hydroxycarbamide) for 12 years for a myeloproliferative disorder, and presented a progressive pruritic woody induration, symmetrically affecting both legs. He also had Gottron-like papules on the back of the metacarpophalangeal joints, and a retroauricular undifferentiated squamous cell carcinoma. On histological examination of a skin biopsy taken from the leg, massive dermal fibrosis was seen, with thickening of collagen bundles throughout the entire dermis. Six months after HU withdrawal, the skin induration resolved without scarring. Scleroderma-like syndrome has not been previously considered one of the secondary effects of HU. The evolution of our patient's condition supports a causal relationship between the HU treatment and the sclerodermiform changes of the skin. PMID- 22439736 TI - Sample size requirements in trials using repeated measurements and the impact of trial design. AB - OBJECTIVE: Sample size calculations for clinical trials generally use expected changes between groups, and variances obtained from the literature. However, this approach neglects the impact of differences in trial design. We studied the effects of variations in trial design on the required sample size. METHODS: Data were used from the METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) trial in which carotid intima-media thickness (CIMT) measurements were performed twice at baseline, at 6, 12 and 18 months, and twice at the end of 2-year study treatment. A sample size formula for continuous outcome measures that incorporates between- and within-individual variance components was used to evaluate the impact of differences in the length of follow up, and the number of CIMT examinations. RESULTS: Trial designs with a shorter duration of follow-up have increased within-individual variance and require larger sample sizes to detect the same treatment effect. Reduction in the number of examinations within a trial with a given duration, i.e. by using single rather than duplicate baseline and end-of-study scans or by not performing intermediate scans, also increased the required sample size to maintain the same power. CONCLUSION: A longer trial duration and/or more frequent examinations within a trial which has repeated measures of an outcome variable substantially increase study power and reduce the required sample size. In situations where the costs of recruiting, retaining and examining individual participants are known, the sample size, study length and number of examinations can be balanced to optimize the trial design relative to costs or other study objectives. PMID- 22439737 TI - Evolution of the metabolic and regulatory networks associated with oxygen availability in two phytopathogenic enterobacteria. AB - BACKGROUND: Dickeya dadantii and Pectobacterium atrosepticum are phytopathogenic enterobacteria capable of facultative anaerobic growth in a wide range of O2 concentrations found in plant and natural environments. The transcriptional response to O2 remains under-explored for these and other phytopathogenic enterobacteria although it has been well characterized for animal-associated genera including Escherichia coli and Salmonella enterica. Knowledge of the extent of conservation of the transcriptional response across orthologous genes in more distantly related species is useful to identify rates and patterns of regulon evolution. Evolutionary events such as loss and acquisition of genes by lateral transfer events along each evolutionary branch results in lineage specific genes, some of which may have been subsequently incorporated into the O2 responsive stimulon. Here we present a comparison of transcriptional profiles measured using densely tiled oligonucleotide arrays for two phytopathogens, Dickeya dadantii 3937 and Pectobacterium atrosepticum SCRI1043, grown to mid-log phase in MOPS minimal medium (0.1% glucose) with and without O2. RESULTS: More than 7% of the genes of each phytopathogen are differentially expressed with greater than 3-fold changes under anaerobic conditions. In addition to anaerobic metabolism genes, the O2 responsive stimulon includes a variety of virulence and pathogenicity-genes. Few of these genes overlap with orthologous genes in the anaerobic stimulon of E. coli. We define these as the conserved core, in which the transcriptional pattern as well as genetic architecture are well preserved. This conserved core includes previously described anaerobic metabolic pathways such as fermentation. Other components of the anaerobic stimulon show variation in genetic content, genome architecture and regulation. Notably formate metabolism, nitrate/nitrite metabolism, and fermentative butanediol production, differ between E. coli and the phytopathogens. Surprisingly, the overlap of the anaerobic stimulon between the phytopathogens is also relatively small considering that they are closely related, occupy similar niches and employ similar strategies to cause disease. There are cases of interesting divergences in the pattern of transcription of genes between Dickeya and Pectobacterium for virulence-associated subsystems including the type VI secretion system (T6SS), suggesting that fine-tuning of the stimulon impacts interaction with plants or competing microbes. CONCLUSIONS: The small number of genes (an even smaller number if we consider operons) comprising the conserved core transcriptional response to O2 limitation demonstrates the extent of regulatory divergence prevalent in the Enterobacteriaceae. Our orthology-driven comparative transcriptomics approach indicates that the adaptive response in the eneterobacteria is a result of interaction of core (regulators) and lineage specific (structural and regulatory) genes. Our subsystems based approach reveals that similar phenotypic outcomes are sometimes achieved by each organism using different genes and regulatory strategies. PMID- 22439738 TI - Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma. AB - BACKGROUND: We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression. RESULTS: Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness. CONCLUSIONS: Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance. PMID- 22439739 TI - Viewpoint on Emv2, the onlhy endogenous ecotropic murine leukemia virus of C57BL/6 mice. AB - Here I comment on the articles by Lee and colleagues (Retrovirology 2011, 8:82) and Lee and Cho (Retrovirology 2012, 9:23) dealing with an endogenous ecotropic mouse leukemia virus found in C57BL mice. PMID- 22439740 TI - Bevacizumab based chemotherapy in first line treatment of HER2 negative metastatic breast cancer: results of a Moroccan observational institutional study. AB - BACKGROUND: In metastatic breast cancer (MBC) patients, randomised controlled trials evaluated Bevacizumab as first-line treatment showed improvements in tumour response rate and progression-free survival (PFS) when added to chemotherapy. In Morocco, we conducted an observational study to investigate clinical features, treatment and prognosis associated with Bevacizumab based chemotherapy in first line treatment of HER2 negative MBC. FINDINGS: Nineteen women were included in this study. All these women were diagnosed as having HER2 negative MBC at the National Institute of Oncology in Rabat, Morocco, between January 2009 and December 2010. The median age of patients was 48.1 years. Four patients (21%) had metastatic disease at diagnosis and 15 patients (79%) had received treatment for first metastatic relapse. Bone, liver and lung were the most frequent metastasis sites. Patients were followed up until April 2011. Most patients had objective response; 15.8% of complete response, 47.3% of partial response and 21.1% of stabilisation. Median PFS was estimated at 11.5 months. Sub groups analysis showed a statistically significant difference (Log-rank test: p = 0.01); PFS for patients receiving Bevacizumab - weekly Paclitaxel was estimated at 18.1 months, and at 9.1 months for patients receiving the combination Bevacizumab - Docetaxel. This benefit in PFS was associated with an acceptable safety profile. CONCLUSION: As demonstrated in this study, Bevacizumab based chemotherapy in first line treatment of HER2 negative MBC in Morocco and particularly in combination with Taxanes extends PFS, as confirmed in a recent meta-analysis of 3 randomised controlled phase III studies. PMID- 22439741 TI - Associations between psychological factors and nighttime/daytime symptomatology in insomnia. AB - PURPOSE: The aim of this study was to examine psychological factors in insomnia and the association between psychological mechanisms and nighttime and daytime symptoms. METHODS: A cross-sectional examination in the general population was used. The study sample consisted of 1890 participants from the general population. The participants completed a survey on nighttime and daytime symptoms, health outcomes, and psychological factors. RESULTS: Relative to poor and normal sleepers, the insomnia group had higher scores on worry, beliefs, physiologic arousal, monitoring/attentional bias, and safety behaviors than the other two groups, and the poor sleepers exhibited a similar pattern relative to the normal sleepers. High total wake time was associated with more worry, physiologic arousal, and safety behaviors (26.3% variance), low sleep restoration with more worry, unhelpful beliefs, and monitoring/attentional bias (28.2% variance), and low sleep quality with higher scores on all the psychological mechanisms (35.8% variance). Elevated daytime symptoms were related to more unhelpful beliefs and monitoring/attentional bias (44.3% variance). CONCLUSION: The findings indicate that psychological factors are linked to nighttime and daytime symptomatology in insomnia. PMID- 22439742 TI - Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial. AB - BACKGROUND: Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required. METHODS/DESIGN: This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 ((125)I BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with (125)I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during (125)I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non adaptive interval, and adverse events. DISCUSSION: To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa. TRIAL REGISTRATION: UMIN000003992. PMID- 22439743 TI - From stability to permeability of adhesive emulsion bilayers. AB - Water drops dispersed in chloroform and stabilized with phospholipids become adhesive if a bad solvent for lipids, such as silicone oil, is added to the continuous phase. In this way, two sticking drops are separated by a bilayer of phospholipids. By using microfluidic technologies, we probe the stability and properties of such membranes likewise encountered in foams or vesicles. We first establish the stability diagram of adhering drop pairs as a function of the continuous phase composition. We found two regimes of destabilization of the bilayer. The first one concerns a competition between the dynamics of adhesion and the transport of surfactants toward the interfaces that leads to a dilute surfactant coverage. The second one corresponds to a dense surface coverage where the lifetime distribution of the bilayer exponentially decreases as a signature of a nucleation process. In the stable regime, we observe the propagation of adhesion among a concentrated collection of drops. This is another remarkable illustration of the suction consequence when two close deformable objects are pulled apart. Moreover, the present experimental strategy offers a novel way to study the phase diagrams of bilayers from a single phospholipid to a mixture of phospholipids. Indeed, we detect phase transitions at a liquid-liquid interface that are ruled by the amount of bad solvent. Finally, we probe the transport of water molecules through the bilayer and show that its permeability is linked to the adhesion energy that reflects its fluidity. PMID- 22439747 TI - Comprehensive assessment of the quality of commercial cranberry products. Phenolic characterization and in vitro bioactivity. AB - Cranberry (Vaccinium macrocarpon) products have been widely recommended in traditional American medicine for the treatment of urinary tract infection (UTI). A total of 19 different commercial cranberry products from American and European markets have been analyzed by different global phenolic methods and by UPLC-DAD ESI-TQ MS. In addition, in vitro antioxidant capacity and uropathogenic bacterial antiadhesion activity tests have been performed. Results revealed that products found in the market widely differed in their phenolic content and distribution, including products completely devoid of flavan-3-ols to highly purified ones, either in A-type proanthocyanidins (PACs) or in anthocyanins. The product presentation form and polyphenolic profile widely affected the antiadhesion activity, ranging from a negative (nulel) effect to a MIC = 0.5 mg/mL for cranberry powders and a MIC=112 mg/mL for gel capsule samples. Only 4 of 19 products would provide the recommended dose of intake of 36 mg total PACs/day. Of most importance was the fact that this dose would actually provide as low as 0.00 and up to 205 MUg/g of procyanidin A2, indicating the lack of product standardization and incongruence between global and individual compound analysis. PMID- 22439748 TI - Role of electrostatic interactions in binding of thrombin to the fibrinogen gamma' chain. AB - Thrombin binds to the highly anionic fibrinogen gamma' chain through anion binding exosite II. This binding profoundly alters thrombin's ability to cleave substrates, including fibrinogen, factor VIII, and PAR1. However, it is unknown whether this interaction is due mainly to general electrostatic complementarity between the gamma' chain and exosite II or if there are critical charged gamma' chain residues involved. We therefore systematically determined the contribution of negatively charged amino acids in the gamma' chain, both individually and collectively, to thrombin binding affinity. Surface plasmon resonance binding experiments were performed using immobilized gamma' chain peptides with charged to-uncharged amino acid substitutions, i.e., Asp to Asn, Glu to Gln, and pTyr to Tyr. Individually, the substitution of uncharged for charged amino acids resulted in only minor changes in binding affinity, with a maximal change in K(d) from 0.440 to 0.705 MUM for the Asp419Asn substitution. However, substitution of all three charged amino acids in a conserved beta-turn that is predicted to contact thrombin, pTyr418Tyr, Asp419Asn, and pTyr422Tyr, resulted in the loss of measurable binding, as did substitution of all the flanking charged amino acids. In addition, the binding of the gamma' chain to thrombin was weakened in a dose dependent manner with increasing NaCl concentration, resulting in a net loss of three or four ion pairs between thrombin and the gamma' chain. Therefore, although each of the individual charges in the gamma' chain contributes only incrementally to the overall binding affinity, the ensemble of the combined charges plays a profound role in the thrombin-gamma' chain interactions. PMID- 22439749 TI - Feeding styles of caregivers of children 6-23 months of age in Derashe special district, Southern Ethiopia. AB - BACKGROUND: Apart from basic determinants, appropriate child care practices are important in prevention of growth faltering and undernutrition. Providing safe and appropriate quality complementary foods is crucial to child growth and development. However, some children in low-income communities grow normally mainly due to proper caregiver feeding behaviors. Hence, the objective of this study was to determine caregivers' feeding styles as well as to indentify predictors in Derashe special district, Southern Ethiopia. METHODS: A community based cross-sectional study design was employed in the seven randomly selected Kebeles (smallest administrative unit) of Derashe special district. A total of 826 caregivers provided data pertaining to socio-demographic variables. However, 764 caregivers had complete data for the outcome variable (caregiver feeding style). A multistage stratified sampling technique was used to identify study subjects. An adapted Caregiver's Feeding Styles Questionnaire (CFSQ) was used to gather information about caregivers' feeding styles. Multivariate multinomial logistic regression was employed to identify predictors of caregivers' feeding style. RESULTS: The majority (80.6%) of caregivers were biological mothers. Nearly seventy-six percent of the caregivers practiced a responsive feeding style. Caregivers other than the biological mother favoured a laissez-faire feeding style, while caregivers residing in rural Kebeles were more responsive. Caregivers with a breastfeeding frequency of more than eight times predicted both laissez-faire (RRR = 1.88; 95% CI = 1.03-3.41) and controlling (RRR = 1.7; 95% CI = 1.02-2.85) feeding styles as compared to responsive feeding. CONCLUSION: Responsive feeding was the commonest style practiced by the caregivers. Many of the caregivers who were rural residents and birth parents have been responsive in child feeding. The instruments needed to be validated in the Ethiopian context and an additional prospective study based on direct observation of caregiver child interactions is recommended. PMID- 22439750 TI - Quaternary structure, aggregation and cytotoxicity of transthyretin. AB - Transthyretin (TTR) with a Ser112-to-Ile mutation is known to cause amyloidosis with severe cardiomyopathy. We investigated the quaternary structure, aggregation and cytotoxicity of the S112I variant. This variant exists as a dimer at physiological pH, self-assembles into spherical aggregates and induces cell death in human neuroblastoma IMR-32 cells. In addition, we determined the neutron crystal structure of TTR at 2.0 A resolution. The neutron structure revealed that the hydrogen-bond network involving His88 is important for the stabilization of the dimer-dimer and monomer-monomer interfaces. PMID- 22439751 TI - A beta-cyclodextrin, polyethyleneimine and silk fibroin hydrogel containing Centella asiatica extract and hydrocortisone acetate: releasing properties and in vivo efficacy for healing of pressure sores. AB - BACKGROUND: Pressure sores are lesions caused by impaired blood flow. Conventional dressings can absorb exudates, but do not promote wound healing. A hydrogel composed of beta-cyclodextrin (beta-CD), polyethyleneimine (PEI) and silk fibroin (SF) was assessed for use in healing of pressure sores. METHODS: The hydrogel was prepared by crosslinking beta-CD-grafted PEI and SF using epichlorohydrin. The gel was then immersed in an aqueous solution of Centella asiatica extract (CAE) 0.7 mg/mL and/or hydrocortisone acetate (HCA) 0.5 mg/mL. The in vivo pressure sore-healing efficacy of the dry gel (with or without the drugs) was investigated in terms of the hyperplasia of epidermis and the number of neutrophils in the skin tissue. RESULTS: The specific loading of CAE was 0.0091 g/g of dry gel. The percentage of CAE released at 24 h at pH 3.0, 5.0 and 7.4 was approximately 63.9%, 55.0% and 44.4%, respectively. This pH-dependent release is possibly due to the degree of gel swelling, which decreased with increasing pH. The specific loading of HCA was 0.0050 g/g dry gel, and the percentage release of HCA at 24 h was around 20% at all three pH points. It is likely that HCA release is independent of pH. HCA is a hydrophobic compound, and therefore the release of HCA is affected by the partitioning of HCA between the beta-CD cavity and the bulk water phase, but not by the degree of swelling of the hydrogel. The pressure sores treated with the hydrogel healed in 6 days, compared with 10 days for controls. CONCLUSIONS: In this study, a beta-CD/PEI/SF hydrogel containing CAE and HCA reduced the healing time for pressure sores. PMID- 22439752 TI - Carpet-dust chemicals as measures of exposure: Implications of variability. AB - BACKGROUND: There is increasing interest in using chemicals measured in carpet dust as indicators of chemical exposures. However, investigators have rarely sampled dust repeatedly from the same households and therefore little is known about the variability of chemical levels that exist within and between households in dust samples. RESULTS: We analyzed 9 polycyclic aromatic hydrocarbons, 6 polychlorinated biphenyls, and nicotine in 68 carpet-dust samples from 21 households in agricultural communities of Fresno County, California collected from 2003-2005. Chemical concentrations (ng per g dust) ranged from < 2-3,609 for 9 polycyclic aromatic hydrocarbons, from < 1-150 for 6 polychlorinated biphenyls, and from < 20-7,776 for nicotine. We used random-effects models to estimate variance components for concentrations of each of these carpet-dust chemicals and calculated the variance ratio, lambda, defined as the ratio of the within household variance component to the between-household variance component. Subsequently, we used the variance ratios calculated from our data, to illustrate the potential effect of measurement error on the attenuation of odds ratios in hypothetical case-control studies. We found that the median value of the estimated variance ratios was 0.33 (range: 0.13-0.72). Correspondingly, in case control studies of associations between these carpet-dust chemicals and disease, given the collection of only one measurement per household and a hypothetical odds ratio of 1.5, we expect that the observed odds ratios would range from 1.27 to 1.43. Moreover, for each of the chemicals analyzed, the collection of three repeated dust samples would limit the expected magnitude of odds ratio attenuation to less than 20%. CONCLUSIONS: Our findings suggest that attenuation bias should be relatively modest when using these semi-volatile carpet-dust chemicals as exposure surrogates in epidemiologic studies. PMID- 22439753 TI - Dense two-dimensional silver single and double nanoparticle arrays with plasmonic response in wide spectral range. AB - We report the properties of plasmons in dense planar arrays of silver single and double nanostructures with various geometries fabricated by electron beam lithography (EBL) as a function of their size and spacing. We demonstrate a strong plasmon coupling mechanism due to near-field dipolar interactions between adjacent nanostructures, which produces a major red shift of the localized surface plasmon resonance (LSPR) in silver nanoparticles and leads to strong maximum electric field enhancements in a broad spectral range. The extinction spectra and maximum electric field enhancements are theoretically modeled by using the finite element method. Our modeling revealed that strong averaged electric field enhancements of up to 60 in visible range and up to 40 in mid infrared result from hybridization of multipolar resonances in such dense nanostructures; these are important for applications in surface enhanced spectroscopies. PMID- 22439754 TI - New sustained release of zidovudine matrix tablets - cytotoxicity toward Caco-2 cells. AB - OBJECTIVE: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones. METHODS: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit((r)) RS PO and Eudragit((r)) RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining. RESULTS: A specific formulation containing 5% of each excipient - HPMC K15M, HPMC K100M, Eudragit((r)) RS PO, and Eudragit((r)) RL PO - was found to yield the best release profile. Application of the Korsmeyer Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets' composition on the drug's cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0-15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48 h of incubation. Additionally, a high reversibility of the AZT effect was observed. CONCLUSIONS: The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one. PMID- 22439755 TI - Apoptosis in Buruli ulcer: a clinicopathological study of 45 cases. AB - AIMS: To investigate the presence and pathogenetic role of apoptosis in Buruli ulcer (BU), a highly destructive skin disease caused by Mycobacterium ulcerans. METHODS AND RESULTS: Forty-five skin biopsies obtained from 30 Beninese patients affected by BU, in different clinical and therapeutic periods, were analysed for the main histopathological features (inflammatory infiltration, necrosis, sclerosis, oedema, granulomas and nerve damage). Immunofluorescent detection of antigens (anti-Bax, anti-caspases-3 and -8), together with deoxyuridine, 5' triphosphate (dUTP) nick end labelling (TUNEL) assay, were also performed. A significant decrease in inflammatory infiltration (P = 0.0001) was detected between the beginning and end of antibiotic treatment. Neutrophils predominated in the first phase, while lymphocytes and plasma cells were increased at the end of the therapy. An inverse correlation between tissue necrosis and sclerosis was observed (P = 0.001). In 11 cases, inflammatory and regressive changes involved the nerve bundles with axonal degeneration and disruption of nerve fibres. TUNEL assay detected apoptotic bodies within nerve bundles, and these decreased from beginning to end of therapy. Bax, caspase-3 and -8 were down-regulated over the course of antibiotic therapy. CONCLUSIONS: In BU, apoptosis plays a role in promoting and sustaining the destructive changes and is implicated in the neural pathology that is associated with clinically detected anaesthesia. PMID- 22439756 TI - Combined analysis of mRNA expression of ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 to predict prognosis in patients with non-small cell lung cancer who received adjuvant chemotherapy. AB - BACKGROUND: The aim of this study was to investigate prognostic value of excision repair cross-complementing 1 (ERCC1), BCL2-associated athanogene (BAG-1), the breast and ovarian cancer susceptibility gene 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and class III beta-tubulin (TUBB3) in patients with non-small cell lung cancer (NSCLC) who received platinum- based adjuvant chemotherapy. METHODS: Messenger RNA expressions of these genes were examined in 85 tumor tissues and 34 adjacent tissue samples using semi-quantitative RT-PCR. The expressions of these five genes were analyzed in relation to chemotherapy and progression-free survival (PFS) and overall survival (OS). Seventy-four patients were enrolled into chemotherapy. RESULTS: Patients with ERCC1 or BAG-1 negative expression had a significantly longer PFS (P = 0.001 and P = 0.001) and OS (P = 0.001 and P = 0.001) than those with positive expression. Patients with negative ERCC1 and BAG-1 expression benefited more from platinum regimen (P = 0.001 and P = 0.002). Patients with BRCA1 negative expression might have a longer OS (P = 0.052), but not PFS (P = 0.088) than those with BRCA1 positive expression. A significant relationship was observed between the mRNA expression of ERCC1 and BAG-1 (P = 0.042). In multivariate analysis, ERCC1 and BAG-1 were significantly favorable factors for PFS (P = 0.018 and P = 0.017) and OS (P = 0.027 and P = 0.022). CONCLUSIONS: ERCC1 and BAG-1 are determinants of survival after surgical treatment of NSCLC, and its mRNA expression in tumor tissues could be used to predict the prognosis of NSCLC treated by platinum. PMID- 22439757 TI - miRNA-135a promotes breast cancer cell migration and invasion by targeting HOXA10. AB - BACKGROUND: miRNAs are a group of small RNA molecules regulating target genes by inducing mRNA degradation or translational repression. Aberrant expression of miRNAs correlates with various cancers. Although miR-135a has been implicated in several other cancers, its role in breast cancer is unknown. HOXA10 however, is associated with multiple cancer types and was recently shown to induce p53 expression in breast cancer cells and reduce their invasive ability. Because HOXA10 is a confirmed miR-135a target in more than one tissue, we examined miR 135a levels in relation to breast cancer phenotypes to determine if miR-135a plays role in this cancer type. METHODS: Expression levels of miR-135a in tissues and cells were determined by poly (A)-RT PCR. The effect of miR-135a on proliferation was evaluated by CCK8 assay, cell migration and invasion were evaluated by transwell migration and invasion assays, and target protein expression was determined by western blotting. GFP and luciferase reporter plasmids were constructed to confirm the action of miR-135a on downstream target genes including HOXA10. Results are reported as means +/- S.D. and differences were tested for significance using 2-sided Student"s t-test. RESULTS: Here we report that miR-135a was highly expressed in metastatic breast tumors. We found that the expression of miR-135a was required for the migration and invasion of breast cancer cells, but not their proliferation. HOXA10, which encodes a transcription factor required for embryonic development and is a metastasis suppressor in breast cancer, was shown to be a direct target of miR-135a in breast cancer cells. Our analysis showed that miR-135a suppressed the expression of HOXA10 both at the mRNA and protein level, and its ability to promote cellular migration and invasion was partially reversed by overexpression of HOXA10. CONCLUSIONS: In summary, our results indicate that miR-135a is an onco-miRNA that can promote breast cancer cell migration and invasion. HOXA10 is a target gene for miR-135a in breast cancer cells and overexpression of HOXA10 can partially reverse the miR-135a invasive phenotype. PMID- 22439758 TI - Use of uptake intrinsic clearance from attached rat hepatocytes to predict hepatic clearance for poorly permeable compounds. AB - We previously reported that the accuracy of clearance (CL) prediction could be differentiated by permeability. CL was drastically under-predicted by in vitro metabolic intrinsic clearance (CL(int)) for compounds with low permeability (<5 * 10(-6) cm/s). We determined apparent uptake CL(int) by measuring initial disappearance from medium using attached rat hepatocytes and metabolic CL(int) by measuring parent depletion in suspended rat hepatocytes (cells and medium). Uptake and metabolic CL(int) were comparable for highly permeable metabolic marker compounds. In contrast, uptake CL(int) was 3- to 40-fold higher than metabolic CL(int) for rosuvastatin, bosentan, and 15 proprietary compounds, which had low permeability, suggesting that uptake could be a rate-determining step in hepatic elimination for these poorly permeable compounds. The prediction of hepatic CL was improved significantly when using uptake CL(int) for the compounds with low permeability. The average fold error was 2.2 and 6, as opposed to >11 and >47 by metabolic CL(int), with and without applying a scaling factor of 4, respectively. Uptake CL(int) from attached hepatocytes can be used as an alternative approach to predict hepatic clearance and to understand the significance of hepatic uptake in elimination in an early drug discovery setting. PMID- 22439759 TI - Choline and/or folic acid deficiency is associated with genomic damage and cell death in human lymphocytes in vitro. AB - Choline and folate are interrelated methyl donors. Previous studies showed that folate prevents genomic damage in human lymphocytes in vitro; however, the association between choline and human genomic stability is uncertain. To explore the genotoxicity, cytotoxicity, and cytostatic effects and possible interactions of choline and/or folate deficiency on the human genome, lymphocytes from 6 volunteers were cultured in 18 combinations of choline (CC) and folic acid (FA) media for 9 days. The genotoxicity was evaluated by micronuclei, nucleoplasmic bridges, and nuclear buds in the binucleated cell; the cytotoxicity indices included apoptosis and necrosis, and the cytostatic effects were indicated by nuclear division index (NDI). Across all choline concentrations, the frequencies of all biomarkers except NDI were diminished when FA concentration was more than or equal to 120 nmol/L. The frequencies of micronuclei, buds, and necrosis were significantly higher at lower levels of CC (0-6 MUmol/L) compared with higher concentrations of CC (12-21.5 MUmol/L) while maintaining the same FA concentration. We concluded that both choline and folate significantly impact genomic stability and cell death, although effects of folate were 2.5- to 6.2 fold greater, depending on the biomarker and dose. A combination of 12 MUmol/L CC and 120 nmol/L FA appears to be optimal for genomic integrity in vitro. PMID- 22439760 TI - Antagonistic interactions peak at intermediate genetic distance in clinical and laboratory strains of Pseudomonas aeruginosa. AB - BACKGROUND: Bacteria excrete costly toxins to defend their ecological niche. The evolution of such antagonistic interactions between individuals is expected to depend on both the social environment and the strength of resource competition. Antagonism is expected to be weak among highly similar genotypes because most individuals are immune to antagonistic agents and among dissimilar genotypes because these are unlikely to be competing for the same resources and antagonism should not yield much benefit. The strength of antagonism is therefore expected to peak at intermediate genetic distance. RESULTS: We studied the ability of laboratory strains of Pseudomonas aeruginosa to prevent growth of 55 different clinical P. aeruginosa isolates derived from cystic fibrosis patients. Genetic distance was determined using genetic fingerprints. We found that the strength of antagonism was maximal among genotypes of intermediate genetic distance and we show that genetic distance and resource use are linked. CONCLUSIONS: Our results suggest that the importance of social interactions like antagonism may be modulated by the strength of resource competition. PMID- 22439761 TI - Quantifying carbon mitigation wedges in U.S. cities: near-term strategy analysis and critical review. AB - A case study of Denver, Colorado explores the roles of three social actors individual users, infrastructure designer-operators, and policy actors-in near term greenhouse gas (GHG) mitigation in U.S. cities. Energy efficiency, renewable energy, urban design, price- and behavioral-feedback strategies are evaluated across buildings-facilities, transportation, and materials/waste sectors in cities, comparing voluntary versus regulatory action configurations. GHG mitigation impact depends upon strategy effectiveness per unit, as well as societal participation rates in various action-configurations. Greatest impact occurs with regulations addressing the vast existing buildings stock in cities, followed by voluntary behavior change in electricity use/purchases, technology shifts (e.g., to teleconferencing), and green-energy purchases among individual users. A portfolio mix of voluntary and regulatory actions can yield a best-case maximum of ~1% GHG mitigation annually in buildings and transportation sectors, combined. Relying solely on voluntary actions reduces mitigation rates more than five-fold. A portfolio analysis of climate action plans in 55 U.S. cities reveals predominance of voluntary outreach programs that have low societal participation rates and hence low GHG impact, while innovative higher-impact behavioral, technological, and policy/regulatory strategies are under-utilized. Less than half the cities capitalize on cross-scale linkages with higher-impact state-scale policies. Interdisciplinary field research can help address the mis-match in plans, actions, and outcomes. PMID- 22439762 TI - A simulation model that predicts handling forces required to reposition surgical lights. AB - INTRODUCTION: High handling forces of surgical lighting systems limit their usability. To make improvements to the mechanical design of the system the behaviour of the system should be understood. Therefore, this study presents a model that predicts handling forces of surgical lighting systems. METHODS: Geometry and joint friction torques of a real lighting system were measured and implemented in a validated force model. Mean, standard deviation within the spatial region, minimum force and maximum force were computed for three different regions of the working area. RESULTS: The mean (standard deviation within the spatial region) forces were 129 (106) N in the centre region, and 61 (14) N and 60 (17) N in more offcentre regions. CONCLUSION: The simulation results showed high handling forces in the central region, explaining the observed repositioning patterns of the surgical light during surgery. The model can also be used to compare different lighting systems, or to evaluate the effect of design changes. PMID- 22439763 TI - Lung function decline in relation to diagnostic criteria for airflow obstruction in respiratory symptomatic subjects. AB - BACKGROUND: Current COPD guidelines advocate a fixed < 0.70 FEV1/FVC cutpoint to define airflow obstruction. We compared rate of lung function decline in respiratory symptomatic 40+ subjects who were 'obstructive' or 'non-obstructive' according to the fixed and/or age and gender specific lower limit of normal (LLN) FEV1/FVC cutpoints. METHODS: We studied 3,324 respiratory symptomatic subjects referred to primary care diagnostic centres for spirometry. The cohort was subdivided into four categories based on presence or absence of obstruction according to the fixed and LLN FEV1/FVC cutpoints. Postbronchodilator FEV1 decline served as primary outcome to compare subjects between the respective categories. RESULTS: 918 subjects were obstructive according to the fixed FEV1/FVC cutpoint; 389 (42%) of them were non-obstructive according to the LLN cutpoint. In smokers, postbronchodilator FEV1 decline was 21 (SE 3) ml/year in those non-obstructive according to both cutpoints, 21 (7) ml/year in those obstructive according to the fixed but not according to the LLN cutpoint, and 50 (5) ml/year in those obstructive according to both cutpoints (p = 0.004). CONCLUSION: This study showed that respiratory symptomatic 40+ smokers and non smokers who show FEV1/FVC values below the fixed 0.70 cutpoint but above their age/gender specific LLN value did not show accelerated FEV1 decline, in contrast with those showing FEV1/FVC values below their LLN cutpoint. PMID- 22439764 TI - Kupffer cells ameliorate hepatic insulin resistance induced by high-fat diet rich in monounsaturated fatty acids: the evidence for the involvement of alternatively activated macrophages. AB - BACKGROUND: Resident macrophages (Kupffer cells, KCs) in the liver can undergo both pro- or anti-inflammatory activation pathway and exert either beneficiary or detrimental effects on liver metabolism. Until now, their role in the metabolically dysfunctional state of steatosis remains enigmatic. Aim of our study was to characterize the role of KCs in relation to the onset of hepatic insulin resistance induced by a high-fat (HF) diet rich in monounsaturated fatty acids. METHODS: Male Wistar rats were fed either standard (SD) or high-fat (HF) diet for 4 weeks. Half of the animals were subjected to the acute GdCl3 treatment 24 and 72 hrs prior to the end of the experiment in order to induce the reduction of KCs population. We determined the effect of HF diet on activation status of liver macrophages and on the changes in hepatic insulin sensitivity and triacylglycerol metabolism imposed by acute KCs depletion by GdCl3. RESULTS: We found that a HF diet rich in MUFA itself triggers an alternative but not the classical activation program in KCs. In a steatotic, but not in normal liver, a reduction of the KCs population was associated with a decrease of alternative activation and with a shift towards the expression of pro-inflammatory activation markers, with the increased autophagy, elevated lysosomal lipolysis, increased formation of DAG, PKCepsilon activation and marked exacerbation of HF diet induced hepatic insulin resistance. CONCLUSIONS: We propose that in the presence of a high MUFA content the population of alternatively activated resident liver macrophages may mediate beneficial effects on liver insulin sensitivity and alleviate the metabolic disturbances imposed by HF diet feeding and steatosis. Our data indicate that macrophage polarization towards an alternative state might be a useful strategy for treating type 2 diabetes. PMID- 22439765 TI - An enzymatic pathway for the biosynthesis of the formylhydroxyornithine required for rhodochelin iron coordination. AB - Rhodochelin, a mixed catecholate-hydroxamate type siderophore isolated from Rhodococcus jostii RHA1, holds two L-delta-N-formyl-delta-N-hydroxyornithine (L fhOrn) moieties essential for proper iron coordination. Previously, bioinformatic and genetic analysis proposed rmo and rft as the genes required for the tailoring of the L-ornithine (L-Orn) precursor [Bosello, M. (2011) J. Am. Chem. Soc.133, 4587-4595]. In order to investigate if both Rmo and Rft constitute a pathway for L-fhOrn biosynthesis, the enzymes were heterologously produced and assayed in vitro. In the presence of molecular oxygen, NADPH and FAD, Rmo monooxygenase was able to convert L-Orn into L-delta-N-hydroxyornithine (L-hOrn). As confirmed in a coupled reaction assay, this hydroxylated intermediate serves as a substrate for the subsequent N(10)-formyl-tetrahydrofolate-dependent (N(10)-fH(4)F) Rtf catalyzed formylation reaction, establishing a route for the L-fhOrn biosynthesis, prior to its incorporation by the NRPS assembly line. It is of particular interest that a major improvement to this study has been reached with the use of an alternative approach to the chemoenzymatic FolD-dependent N(10) fH(4)F conversion, also rescuing the previously inactive CchA, the Rft-homologue in coelichelin assembly line [Buchenau, B. (2004) Arch. Microbiol.182, 313-325; Pohlmann, V. (2008) Org. Biomol. Chem.6, 1843-1848]. PMID- 22439766 TI - Influence of topical fluoride application on mechanical properties of orthodontic bonding materials under pH cycling. AB - OBJECTIVE: To evaluate in vitro the influence of topical fluoride application on the mechanical properties of orthodontic cements containing fluoride under pH cycling conditions. MATERIALS AND METHODS: Edgewise brackets for maxillary central incisors were bonded to 192 bovine incisors using Transbond XT (G1), Transbond Plus Color Change (G2), and Fuji Ortho LC (G3) (n = 64 for each group). The specimens of each group were subdivided (n = 16) into different subgroups. Subgroup A received no topical fluoride application during pH cycling, while the experimental subgroups received topical fluoride treatments as follows: B, application three times per day of fluoride dentifrice (1450 ppm F); C, application one time per day of fluoride mouth rinse (250 ppm F); and D, combination of fluoride dentifrice and fluoride mouth rinse. After 14 days of pH cycling, the shear bond strength and Adhesive Remnant Index were evaluated statistically. RESULTS: Polarized light microscopy showed that pH cycling induced mineral loss in all specimens. The topical application of fluoride did not have an influence on shear bond strength, although the association of fluoride dentifrice and mouth rinse increased the shear bond strength of the resinous cement without fluoride (P < .01). Regarding the Adhesive Remnant Index, no statistical differences were found within the groups G1 (P = .23), G2 (P = .47), and G3 (P = .74). CONCLUSION: Topical fluoride treatments improved the shear bond strength of resinous cement, regardless of the material's fluoride releasing capacity, and reached the adhesive fractures. PMID- 22439767 TI - Genetic expression of MMP-Matrix-mettalo-proteinases (MMP-1 and MMP-13) as a function of anterior mandibular repositioning appliance on the growth of mandibular condylar cartilage with and without administration of Insulin like growth factor (IGF-1) and Transforming growth factor-B (TGF-beta). AB - OBJECTIVE: To determine if the mandibular condylar cartilage (MCC) will grow with and without mandibular anterior repositioning appliances with the administration of insulin-like growth factor (IGF-1) and transforming growth factor-beta (TGF beta). MATERIALS AND METHODS: Twenty-four growing New Zealand rabbits were divided into three groups: a group with saline injection in the temporomandibular joint, a group that received anterior positioning appliance, and a group that received injection of growth factors as well as mandibular repositioning appliance. Real-time reverse transcription polymerase chain reaction technique was used to study gene expression supported by histomorphometry. RESULTS: Administration of growth factors along with mandibular repositioning appliances has induced 5.70-fold expression of matrix metalloproteinase-1 (MMP-1) (P < .0005) and 1.29-fold expression of MMP-13 (P < .0005). In contrast, administration of mandibular repositioning appliances only has induced 2.33-fold expression of MMP-1 (P < .0005) and 0.83-fold expression of MMP-13 (P < .0005). Histomorphometric analysis revealed increased proliferation of the condylar cartilage in the appliance and injection group as compared to the control group. CONCLUSION: The administration of growth factors along with the use of mandibular advancement appliance has increased genetic expression of MMP-1 and MMP-13 supported by histomorphometric evidence indicating growth of condylar cartilage. PMID- 22439768 TI - An unusual presentation of systemic AL amyloidosis: bullae, milia and nail dystrophy. PMID- 22439770 TI - Size-selective sliding of sessile drops on a slightly inclined plane using low frequency AC electrowetting. AB - When placed on an inclined solid plane, drops often stick to the solid surface due to pinning forces caused by contact angle hysteresis. When the drop size or the plane's incline angle is small, the drop is difficult to slide due to a decrease in gravitational force. Here we demonstrate that small drops (0.4-9 MUL) on a slightly inclined plane (~12 degrees , Teflon and parylene-C surface) can be mobilized through patterned electrodes by applying low-frequency ac electrowetting under 400 Hz (110-180 V(rms)), which has a mechanism different from that of the high-frequency ac method that induces sliding by reducing contact angle hysteresis. We attribute the sliding motion of our method to a combination of contact angle hysteresis and interfacial oscillation driven by ac electrowetting instead of the minimization of contact angle hysteresis at a high frequency. We investigated the effects of ac frequency on the sliding motion and terminal sliding of drops; the terminal sliding velocity is greatest at resonance frequency. Varying the electrowetting number (0.21-0.56) at a fixed frequency (40 Hz) for 5 MUL drops, we found an empirical relationship between the electrowetting number and the terminal sliding velocity. Using the relationship between the drop size and ac frequency, we can selectively slide drops of a specific size or merge two drops along an inclined plane. This simple method will help with constructing microfluidic platforms with sorting, merging, transporting, and mixing of drops without a programmable control of electrical signals. Also, this method has a potential in heat transfer applications because heat removal capacity can be enhanced significantly through drop oscillation. PMID- 22439769 TI - Novel approaches to flavivirus drug discovery. AB - INTRODUCTION: The members of the family Flaviviridae, including West Nile virus, yellow fever virus and dengue virus, are important human pathogens that are expanding their impact around the globe. The four serotypes of dengue infect 50 100 million people each year, yet the only clinical treatment is supportive care to reduce symptoms. Drugs that employ novel inhibition mechanisms and targets are urgently needed to combat the growing incidence of dengue worldwide. AREAS COVERED: The authors discuss recently discovered flavivirus inhibitors with a focus on antivirals targeting non-enzymatic proteins of the dengue virus lifecycle. Specifically, the authors discuss the flaviviruses, the need for novel inhibitors and the criteria for successful antiviral drug development. Current literature describing new advances in antiviral therapy at each stage of the flavivirus lifecycle (entry, endosomal escape, viral RNA processing and replication, assembly and immune evasion) are evaluated and summarized. EXPERT OPINION: Overall, the prognosis of flavivirus antiviral drug development is positive: new effective compounds have been discovered and studied. However, repurposing existing compounds and a greater translation to the clinical setting are recommended in order to combat the growing threat of flaviviruses. PMID- 22439771 TI - A palladium iodide-catalyzed carbonylative approach to functionalized pyrrole derivatives. AB - A novel and convenient approach to functionalized pyrroles is presented, based on Pd-catalyzed oxidative heterocyclization-alkoxycarbonylation of readily available N-Boc-1-amino-3-yn-2-ols. Reactions were carried out in alcoholic solvents at 80 100 degrees C and under 20 atm (at 25 degrees C) of a 4:1 mixture of CO-air, in the presence of the PdI(2)-KI catalytic system (2-5 mol % of PdI(2), KI/PdI(2) molar ratio = 10). In the case of N-Boc-1-amino-3-yn-2-ols 3, bearing alkyl or aryl substituents, the carbonylation reaction led to a mixture of Boc-protected and N-unsubstituted pyrrole-3-carboxylic esters 4 and 5, respectively. This mixture could be conveniently and quantitatively converted into deprotected pyrrole-3-carboxylic esters 5 by a simple basic treatment. In the case of diastereomeric (3RS,4RS)- and (3RS,4SR)-N-Boc-3-amino-2-methyldec-5-yn-4-ol (syn 3f and anti-3f, respectively, whose relative configuration was determined by X ray crystallographic analysis), no particular difference was observed in the reactivity of the two diastereomers between them and with respect to the diastereomeric mixture (3S,4S) + (3S,4R). Interestingly, N-Boc-2-alkynyl-1-amino 3-yn-2-ols 6, bearing an additional alkynyl substituent alpha to the hydroxyl group, spontaneously underwent N-deprotection under the reaction conditions and regioselective water addition to the alkynyl group at C-3 of the corresponding pyrrole-3-carboxylic ester derivative, thus directly affording highly functionalized pyrrole derivatives 7 in one step. In a similar manner, a novel functionalized dihydropyrrolizine derivative 9 was directly synthesized starting from (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8. PMID- 22439772 TI - Retinoic acid synthesis and functions in early embryonic development. AB - Retinoic acid (RA) is a morphogen derived from retinol (vitamin A) that plays important roles in cell growth, differentiation, and organogenesis. The production of RA from retinol requires two consecutive enzymatic reactions catalyzed by different sets of dehydrogenases. The retinol is first oxidized into retinal, which is then oxidized into RA. The RA interacts with retinoic acid receptor (RAR) and retinoic acid X receptor (RXR) which then regulate the target gene expression. In this review, we have discussed the metabolism of RA and the important components of RA signaling pathway, and highlighted current understanding of the functions of RA during early embryonic development. PMID- 22439774 TI - Characterization of the protein fraction of the temporary adhesive secreted by the tube feet of the sea star Asterias rubens. AB - Sea stars are able to make firm but temporary attachments to various substrata by secretions released by their tube feet. After tube foot detachment, the adhesive secretions remain on the substratum as a footprint. Proteins presumably play a key role in sea star adhesion, as evidenced by the removal of footprints from surfaces after a treatment with trypsin. However, until now, characterisation was hampered by their high insolubility. In this study, a non-hydrolytic method was used to render most of the proteins constituting the adhesive footprints soluble. After analysis by SDS-PAGE, the proteins separated into about 25 bands, which ranged from 25 to 450 kDa in apparent molecular weight. Using mass spectrometry and a homology-database search, it was shown that several of the proteins are known intracellular proteins, presumably resulting from contamination of footprint material with tube foot epidermal cells. However, 11 protein bands, comprising the most abundant proteins, were not identified and might correspond to novel adhesive proteins. They were named 'Sea star footprint proteins' (Sfps). Tandem mass spectrometry analysis of the protein bands yielded 43 de novo generated peptide sequences. Most of them were shared by several, if not all, Sfps. Polyclonal antibodies were raised against one of the peptides (HEASGEYYR from Sfp-115) and were used in immunoblotting. They specifically labelled Sfp-115 and other bands with lower apparent molecular weights. The different results suggest that all Sfps might belong to a single family of related proteins sharing similar motifs or, alternatively, they are the products of polymerization and/or degradation processes. PMID- 22439773 TI - Particular characteristics of allergic symptoms in tropical environments: follow up to 24 months in the FRAAT birth cohort study. AB - BACKGROUND: Early wheezing and asthma are relevant health problems in the tropics. Mite sensitization is an important risk factor, but the roles of others, inherent in poverty, are unknown. We designed a birth-cohort study in Cartagena (Colombia) to investigate genetic and environmental risk factors for asthma and atopy, considering as particular features perennial exposure to mites, parasite infections and poor living conditions. METHODS: Pregnant women representative of the low-income suburbs of the city were randomly screened for eligibility at delivery; 326 mother-infant pairs were included at baseline and biological samples were collected from birth to 24 months for immunological testing, molecular genetics and gene expression analysis. Pre and post-natal information was collected using questionnaires. RESULTS: 94% of families were from the poorest communes of the city, 40% lacked sewage and 11% tap-water. Intestinal parasites were found as early as 3 months; by the second year, 37.9% of children have had parasites and 5.22% detectable eggs of Ascaris lumbricoides in stools (Median 3458 epg, IQR 975-9256). The prevalence of "wheezing ever" was 17.5% at 6 months, 31.1% at 12 months and 38.3% at 24 months; and recurrent wheezing (3 or more episodes) 7.1% at 12 months and 14.2% at 24 months. Maternal rhinitis [aOR 3.03 (95%CI 1.60-5.74), p = 0.001] and male gender [aOR 2.09 (95%CI 1.09 - 4.01), p = 0.026], increased risk for wheezing at 6 months. At 24 months, maternal asthma was the main predisposing factor for wheezing [aOR 3.65 (95%CI 1.23-10.8), p = 0.01]. Clinical symptoms of milk/egg allergy or other food-induced allergies were scarce (1.8%) and no case of atopic eczema was observed. CONCLUSIONS: Wheezing is the most frequent phenotype during the first 24 months of life and is strongly associated with maternal asthma. At 24 months, the natural history of allergic symptoms is different to the "atopic march" described in some industrialized countries. This cohort is representative of socially deprived urban areas of underdeveloped tropical countries. The collection of biological samples, data on exposure and defined phenotypes, will contribute to understand the gene/environment interactions leading to allergy inception and evolution. PMID- 22439775 TI - Renal allograft tissue: its new role in patient management. PMID- 22439776 TI - Comparison of the human and bovine milk N-glycome via high-performance microfluidic chip liquid chromatography and tandem mass spectrometry. AB - The isolation of whey proteins from human and bovine milks followed by profiling of their entire N-glycan repertoire is described. Whey proteins resulting from centrifugation and ethanol precipitation of milk were treated with PNGase F to release protein-bound N-glycans. Once released, N-glycans were analyzed via nanoflow liquid chromatography coupled with quadrupole time-of-flight mass spectrometry following chromatographic separation on a porous graphitized carbon chip. In all, 38 N-glycan compositions were observed in the human milk sample while the bovine milk sample revealed 51 N-glycan compositions. These numbers translate to over a hundred compounds when isomers are considered and point to the complexity of the mixture. High mannose, neutral, and sialylated complex/hybrid glycans were observed in both milk sources. Although NeuAc sialylation was observed in both milk samples, the NeuGc residue was only observed in bovine milk and marks a major difference between human and bovine milks. To the best of our knowledge, this study is the first MS based confirmation of NeuGc in milk protein bound glycans as well as the first comprehensive N-glycan profile of bovine milk proteins. Tandem MS was necessary for resolving complications presented by the fact that (NeuGc:Fuc) corresponds to the exact mass of (NeuAc:Hex). Comparison of the relative distribution of the different glycan types in both milk sources was possible via their abundances. While the human milk analysis revealed a 6% high mannose, 57% sialylation, and 75% fucosylation distribution, a 10% high mannose, 68% sialylation, and 31% fucosylation distribution was observed in the bovine milk analysis. Comparison with the free milk oligosaccharides yielded low sialylation and high fucosylation in human, while high sialylation and low fucosylation are found in bovine. The results suggest that high fucosylation is a general trait in human, while high sialylation and low fucosylation are general features of glycosylation in bovine milk. PMID- 22439777 TI - Dietary patterns of adolescents in Germany--associations with nutrient intake and other health related lifestyle characteristics. AB - BACKGROUND: The aim of this study was to identify dietary patterns among a representative sample of German adolescents and their associations with energy and nutrient intake, socioeconomic and lifestyle characteristics, and overweight status. METHODS: In the analysis, data from the German Health Interview and Examination Survey for Children and Adolescents were used. The survey included a comprehensive dietary history interview conducted among 1272 adolescents aged 12 to 17 years. Dietary patterns were determined with principal component analysis (PCA) based on 48 food groups, for boys and girls separately. RESULTS: Three dietary patterns among boys and two among girls were identified. Among boys, high adherence to the 'western' pattern was associated with higher age, lower socioeconomic status (SES), and lower physical activity level (PA). High adherence to the 'healthy' pattern among boys, but not among girls, was associated with higher SES, and higher PA. Among boys, high adherence to the 'traditional' pattern was associated with higher age. Among girls, high adherence to the 'traditional and western' pattern was associated with lower age, lower SES and more hours watching TV per day. The nutrient density of several vitamins and minerals, particularly of B-vitamins and calcium, increased with increasing scores of the 'healthy' pattern among both sexes. Conversely, with increasing scores of the 'western' pattern among boys, most nutrient densities decreased, particularly of fibre, beta-carotene, vitamin D, biotin and calcium. Among girls with higher scores of the 'traditional and western' pattern, nutrient densities of vitamin A, C, E, K and folate decreased. Among boys, high adherence to the 'traditional' pattern was correlated with higher densities of vitamin B12 and vitamin D and lower densities of fibre, magnesium and iron. No significant associations between dietary patterns and overweight were found. CONCLUSIONS: Higher scores for dietary patterns characterized by higher consumption of take away food, meat, confectionary and soft drinks ('western' and 'traditional and western') were found particularly among 16- to 17-years old boys and among adolescents with lower SES. These patterns were also associated with higher energy density, higher percent of energy from unsaturated fatty acids and lower percent of energy from carbohydrates as well as lower nutrient densities of several vitamins and minerals. Therefore, nutritional interventions should try to focus more on adolescents with lower SES and boys in general. PMID- 22439778 TI - Streptococcus salivarius causing multiple liver abscesses in a patient with situs inversus. PMID- 22439779 TI - Chronic pelvic osteomyelitis. PMID- 22439780 TI - Lumbosacral spondylodiscitis after sacral colpopexy of a sigmoid neovagina in a patient with vaginal melanoma. PMID- 22439781 TI - Efficacy of tigecycline versus ceftriaxone plus metronidazole for the treatment of complicated intra-abdominal infections: results from a randomized, controlled trial. AB - BACKGROUND: This randomized, open-label, multi-center trial compared tigecycline (TGC), a broad-spectrum glycylcycline, with ceftriaxone-metronidazole (CTX/MET) for the treatment of complicated intra-abdominal infections (cIAI). METHODS: Eligible subjects were randomized to receive TGC 100 mg followed by 50 mg q 12 h or CTX 2 g qd plus MET 1-2 g daily for 4-14 days. Subjects were stratified by Acute Physiology and Chronic Health Evaluation (APACHE) II score <=10 or >10 and could not receive oral therapy. The primary endpoint was clinical response in the clinically evaluable (CE) population at the test of cure (TOC) assessment 8-44 days after the last drug dose. RESULTS: Clinical responses in the CE population were 81.8% (162/198) vs. 79.4% (150/189) for TGC and CTX/MET, respectively; a weighted estimate of the difference of 1.6 (95% confidence interval [CI] -6.4, 9.6). In the microbiologically evaluable (ME) population, microbiological eradication rates were 82.4% (98/119) for TGC vs. 79.6% (86/108) for CTX/MET: a difference of 2.7 (95% CI -7.9, 13.3). Common adverse events were nausea (21.6% TGC vs. 21.3% CTX/MET) and vomiting (17.7% TGC vs. 13.2% CTX/MET). Discontinuation rates because of adverse events were 7.8% for TGC and 6.4% for CTX/MET. CONCLUSIONS: Tigecycline was effective in the treatment of cIAI and was non-inferior to CTX/MET for the treatment of cIAI in hospitalized adults. Clinical Trials Identifier: NCT00230971. PMID- 22439782 TI - Cytomegalovirus enteritis manifesting as recurrent bowel obstruction and jejunal perforation in patient with acquired immunodeficiency syndrome: rare report of survival and review of the literature. AB - BACKGROUND: Cytomegalovirus (CMV) enteritis presenting with perforation in the setting of acquired immunodeficiency syndrome (AIDS) represents a particularly deadly combination. METHODS: Case report and review of the pertinent literature. CASE REPORT: The authors report a patient with AIDS and CMV enteritis presenting as recurrent small-bowel obstruction and leading to perforation of the jejunum with subsequent survival. CONCLUSION: This is believed to represent the second case in the English-language literature of survival after CMV-induced small intestinal perforation in a patient with AIDS. PMID- 22439783 TI - Timing of C-arm drape contamination. AB - BACKGROUND: Surgical site infection remains a concern in orthopedic surgery, and contamination of C-arm covers is a potentially modifiable risk factor. METHODS: A single-cohort study was conducted using 30 consecutive patients undergoing operative fracture fixation. Cultures were obtained from the C-arm cover after initial draping and every 20 min thereafter. The total number of persons in the operating room (person-hours/h of study time) and the number of door openings were recorded. The C-arm position changes and the time to contamination were monitored. RESULTS: The median time from the start of the operation to contamination was 20 min. There was a 17% contamination rate on initial draping, 50% at 20 min, 57% at 40 min, and 80% by 80 min. The C-arms in five cases were not contaminated during the surgery. Time to contamination correlated significantly with lateral position changes (correlation [r]=0.64; p=0.003) but was not related to C-arm position changes (r=0.22; p=0.34), number of door openings (r=0.20; p=0.39), or person-hours/h (r=0.04; p=0.85). CONCLUSIONS: Contamination of the C-arm drape occurs often and early during surgery for orthopedic fractures. We recommend minimal contact with the C-arm to avoid contamination of the surgical field. PMID- 22439784 TI - The association between baroreflex sensitivity and blood pressure in children. AB - Low baroreflex sensitivity (BRS) and heart rate variability (HRV) are associated with the pathogenesis of adult hypertension. However, limited information exists about the negative consequences of elevated childhood blood pressure (BP) and autonomic regulation. Additionally, there are developmental changes in autonomic regulation throughout puberty, yet studies have not appropriately accounted for this. The objective of this study was to investigate BRS and HRV in children with 2 different BP profiles, while controlling for the effects of maturation, age, sex, and body composition. A sample of 11- to 14-year-old participants were divided into 2 BP groups: high BP (HBP; >=95th percentile; n = 21) and normal BP (NBP; <90th percentile; n = 85). Automated BP was measured at 2 time points. In lab-based testing, 5 min of beat-to-beat BP (Finapres) and R-R interval (RRI) were recorded (standard electrocardiogram) after 15 min of supine rest. Spectral indices were computed using fast Fourier transform, and transfer function analysis was used to compute BRS. High frequency (HF) and low frequency (LF) power spectral areas were set to 0.15-0.4 Hz and 0.04-0.15 Hz, respectively, and BRS was determined for the LF area. After adjustment for age, sex, maturation, and body composition, BRS (p = 0.04), LF (p = 0.008), and HF (p = 0.01) RRI variability, and RRI total power (p = 0.005) were lower in the HBP than in the NBP participants. As well, the LF/HF systolic BP variability ratio was higher in the HBP than in the NBP group (p = 0.03). Despite their young age, these children with high, yet not clinically hypertensive BP, display reduced autonomic regulation. PMID- 22439785 TI - Increasing the success rate for Alzheimer's disease drug discovery and development. AB - This paper responds to the fact that over 200 Alzheimer's disease (AD) drug candidates have failed to date and draws on searches of the literature for studies of error effects in drug developments and the authors' published works. In the same period, basic knowledge of AD pathology has greatly expanded providing both potential therapeutic targets and rationales for modifications in strategies for testing AD drug candidates. Current opinion generally holds that AD drug candidates have failed because they address pathology that is already too advanced. Less attention is paid to numerous reported methodological weaknesses capable of biasing AD clinical trials and drug developments and thus invalidating conclusions to be reached about the drugs being tested. The costs of quality controls possibly needed to better insure validity in AD drug developments raises concerns that progress toward success in AD drug development may be hindered by the costs of intervening against current methodological barriers to the successful completions of AD drug developments. PMID- 22439786 TI - Vulval and perianal intraepithelial neoplasia: response to chemoradiotherapy in a woman with idiopathic CD4 lymphocytopenia. AB - Treatment of multicentric or multifocal anogenital intraepithelial neoplasia is challenging, especially if the patient has immunodeficiency. We report the case of a woman with idiopathic CD4 lymphocytopenia and vulval and perianal intraepithelial neoplasia with early invasive disease, who responded well to radiotherapy combined with chemotherapy. Chemoradiotherapy is often used in the primary treatment of anal carcinomas, but has rarely been reported as a treatment for premalignant anogenital conditions. PMID- 22439787 TI - Structure and activity of the Pseudomonas aeruginosa hotdog-fold thioesterases PA5202 and PA2801. AB - The hotdog fold is one of the basic protein folds widely present in bacteria, archaea and eukaryotes. Many of these proteins exhibit thioesterase activity against fatty acyl-CoAs and play important roles in lipid metabolism, cellular signalling and degradation of xenobiotics. The genome of the opportunistic pathogen Pseudomonas aeruginosa contains over 20 genes encoding predicted hotdog fold proteins, none of which have been experimentally characterized. We have found that two P. aeruginosa hotdog proteins display high thioesterase activity against 3-hydroxy-3-methylglutaryl-CoA and glutaryl-CoA (PA5202), and octanoyl CoA (PA2801). Crystal structures of these proteins were solved (at 1.70 and 1.75 A for PA5202 and PA2801 respectively) and revealed a hotdog fold with a potential catalytic carboxylate residue located on the long alpha-helix (Asp(57) in PA5202 and Glu(35) in PA2801). Alanine residue replacement mutagenesis of PA5202 identified four residues (Asn(42), Arg(43), Asp(57) and Thr(76)) that are critical for its activity and are located in the active site. A P. aeruginosa PA5202 deletion strain showed an increased secretion of the antimicrobial pigment pyocyanine and an increased expression of genes involved in pyocyanin biosynthesis, suggesting a functional link between PA5202 activity and pyocyanin production. Thus the P. aeruginosa hotdog thioesterases PA5202 and PA2801 have similar structures, but exhibit different substrate preferences and functions. PMID- 22439788 TI - Antistaphylococcal activity of bacteriophage derived chimeric protein P128. AB - BACKGROUND: Bacterial drug resistance is one of the most significant challenges to human health today. In particular, effective antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) are urgently needed. A causal relationship between nasal commensal S. aureus and infection has been reported. Accordingly, elimination of nasal S. aureus reduces the risk of infection. Enzymes that degrade bacterial cell walls show promise as antibacterial agents. Bacteriophage-encoded bacterial cell wall-degrading enzymes exhibit intrinsic bactericidal activity. P128 is a chimeric protein that combines the lethal activity of the phage tail-associated muralytic enzyme of Phage K and the staphylococcal cell wall targeting-domain (SH3b) of lysostaphin.Here we report results of in vitro studies evaluating the susceptibility of staphylococcal strains to this novel protein. RESULTS: Using the broth microdilution method adapted for lysostaphin, we found that P128 is effective against S. aureus clinical strains including MRSA, methicillin-sensitive S. aureus (MSSA), and a mupirocin-resistant S. aureus. Minimum bactericidal concentrations and minimum inhibitory concentrations of P128 (1-64 MUg/mL) were similar across the 32 S. aureus strains tested, demonstrating its bactericidal nature.In time-kill assays, P128 reduced colony-forming units by 99.99% within 1 h and inhibited growth up to 24 h.In an assay simulating topical application of P128 to skin or other biological surfaces, P128 hydrogel was efficacious when layered on cells seeded on solid media. P128 hydrogel was lethal to Staphylococci recovered from nares of healthy people and treated without any processing or culturing steps, indicating its in situ efficacy. This methodology used for in vitro assessment of P128 as an agent for eradicating nasal carriage is unique. CONCLUSIONS: The novel chimeric protein P128 is a staphylococcal cell wall-degrading enzyme under development for clearance of S. aureus nasal colonization and MRSA infection. The protein is active against globally prevalent antibiotic-resistant clinical isolates and other clinically significant staphylococcal species including S. epidermidis. The P128 hydrogel formulation was bactericidal against Staphylococci including S. aureus recovered from the nares of 31 healthy people, demonstrating its in situ efficacy. PMID- 22439789 TI - EEG phase synchronization during hypnosis induction. AB - Hypnosis is a mental state or set of attitudes usually induced by a procedure known as hypnotic induction. In order to provide the basic physiological conditions for potentially successful hypnosis treatment of medical and psychological problems, the determination of a subject's hypnotizability level is important. Currently, the hypnotizability level is determined using different standard subjective tests. To avoid the different drawbacks of these subjective clinical tests, a practical objective method based on the correlation between electroencephalograph (EEG) phase synchronization and hypnosis susceptibility levels is presented in this study. This method can be used by clinicians instead of the traditional subjective methods to classify hypnotizability level. Thirty two subjects with different hypnosis susceptibility levels contributed to this research. Using statistical analyses, it was concluded that, in highly hypnotizable people, the EEG phase synchronization between different paired channels, located on the frontal lobe, is significantly different from that in subjects with medium or low hypnotizability. PMID- 22439790 TI - Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. AB - BACKGROUND: Painful neuropathy is a common complication of diabetes. Previous studies have identified significant increases in the amount of voltage gated sodium channel isoforms Na(V)1.7 and Na(V)1.3 protein in the dorsal root ganglia (DRG) of rats with streptozotocin (STZ)-induced diabetes. We found that gene transfer-mediated release of the inhibitory neurotransmitters enkephalin or gamma amino butyric acid (GABA) from DRG neurons in diabetic animals reduced pain related behaviors coincident with a reduction in Na(V)1.7 protein levels in DRG in vivo. To further evaluate the role of Na(V)alpha subunit levels in DRG in the pathogenesis of pain in diabetic neuropathy, we constructed a non-replicating herpes simplex virus (HSV)-based vector expressing a microRNA (miRNA) against Na(V)alpha subunits. RESULTS: Subcutaneous inoculation of the miRNA-expressing HSV vector into the feet of diabetic rats to transduce DRG resulted in a reduction in Na(V)alpha subunit levels in DRG neurons, coincident with a reduction in cold allodynia, thermal hyperalgesia and mechanical hyperalgesia. CONCLUSIONS: These data support the role of increased Na(V)alpha protein in DRG in the pathogenesis of pain in diabetic neuropathy, and provide a proof-of principle demonstration for the development of a novel therapy that could be used to treat intractable pain in patients with diabetic neuropathy. PMID- 22439791 TI - Guidelines for chemical peeling in Japan (3rd edition). AB - Chemical peeling may be defined as the therapies, procedures and techniques used for the treatment of certain cutaneous diseases or conditions, and for aesthetic improvement. The procedures include the application of one or more chemical agents to the skin. Chemical peeling has been very popular in both medical and aesthetic fields. Because neither its scientific background is well understood nor a systematic approach established, medical and social problems have taken place. This prompted us to establish and distribute a standard guideline of care for chemical peeling. Previous guidelines such as the 2001 and 2004 versions included minimum standards of care such as indications, chemicals, applications, and any associated precautions, including post-peeling care. The principles in this updated version of chemical peeling are as follows: (i) chemical peeling should be performed under the strict technical control and responsibility of a physician; (ii) the physician should have sufficient knowledge of the structure and physiology of the skin and subcutaneous tissues, and understand the mechanisms of wound-healing induced by chemical peeling; (iii) the physician should be board-certified in an appropriate specialty such as dermatology; and (iv) the ultimate judgment regarding the appropriateness of any specific chemical peeling procedure must be made by the physician while considering all standard therapeutic protocols, which should be presented to each individual patient. Keeping these concepts in mind, this new version of the guidelines includes a more scientific and detailed approach from the viewpoint of evidence-based medicine. PMID- 22439792 TI - Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways. AB - BACKGROUND: Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs) and thromboxane A2 (TXA2). The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. METHODS: A trimellitic anhydride (TMA) sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2) after allergen challenge. RESULTS: Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187) induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5 lipoxygenase and cyclooxygenase pathways. CONCLUSIONS: The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells. PMID- 22439793 TI - Intussusception among Japanese children: an epidemiologic study using an administrative database. AB - BACKGROUND: The epidemiology of intussusception, including its incidence, can vary between different countries. The aim of this study was to describe the epidemiology of childhood intussusception in Japan using data from a nationwide inpatient database. METHODS: We screened the database for eligible cases <= 18 years of age, who were coded with a discharge diagnosis of intussusception (International Classification of Diseases, 10th revision: K-561) between July to December in 2007 and 2008. We then selected cases according to Level 1 of the diagnostic certainty criteria developed by the Brighton Collaboration Intussusception Working Group. We examined the demographics, management, and outcomes of cases, and estimated the incidence of intussusception. RESULTS: We identified 2,427 cases of intussusception. There were an estimated 2,000 cases of infantile intussusception annually in Japan, an incidence of 180-190 cases per 100,000 infants. The median age at diagnosis was 17 months, and two-thirds of the patients were male. Treatment with an enema was successful in 93.0% of cases (2255/2427). The remainder required surgery. Secondary cases accounted for 3.1% (76/2427). Median length of hospital stay was 3 days. Of the 2,427 cases, we found 2 fatal cases associated with intussusception. CONCLUSIONS: This is currently the largest survey of childhood intussusception in Asia using a standardized case definition. Our results provide an estimate of the baseline risk of intussusception in Japan, and it is higher than the risk observed in other countries. PMID- 22439794 TI - Multisubstituted furan formation from (Z)- or (E)-enynyl acetates: tandem reactions accelerated by electron-donating groups on aromatic rings. AB - Multisubstituted furans were readily prepared from (Z)- or (E)-conjugated enynyl acetates with NXS under metal-free conditions at room temperature via the same haloallenyl ketone intermediates. This tandem haloallenyl ketone formation-furan formation reaction sequence was accelerated by electron-donating groups on the aromatic rings. PMID- 22439795 TI - A theoretical investigation of xanthophyll-protein hydrogen bonding in the photosystem II antenna. AB - Photoprotective nonphotochemical quenching (NPQ) in higher plants is the result of the formation of energy-quenching traps in the light-harvesting antenna of photosystem II (PSII). The primary driving forces behind NPQ are the protonation of the thylakoid lumen and the de-epoxidation of the xanthophyll violaxanthin to zeaxanthin in the antenna. There is currently some disagreement over whether de epoxidation occurs only at the peripheral, V1, binding site of the major LHCII or also at the internal, L2, site of the minor antenna CP29 complex of PSII. We have used density functional theory (DFT) to study of hydrogen bonding between xanthophylls and the protein scaffold of LHCII and CP29. We argue that a lack of hydrogen bonding for violaxanthin in LHCII is consistent with it being weakly bound and accessible for de-epoxidation. Conversely, the strong violaxanthin protein hydrogen bonding at the L2 site of CP29 is consistent with evidence that it is not readily accessible for de-epoxidation and therefore quenching by zeaxanthin at the L2 of CP29 is an unlikely candidate for in vivo NPQ. PMID- 22439796 TI - A consumption-based GHG inventory for the U.S. state of Oregon. AB - Many U.S. states conduct greenhouse gas (GHG) inventories to inform their climate change planning efforts. These inventories usually follow a production-based method adapted from the Intergovernmental Panel on Climate Change. States could also take a consumption-based perspective, however, and estimate all emissions released to support consumption in their state, regardless of where the emissions occur. In what may be the first such comprehensive inventory conducted for a U.S. state, we find that consumption-based emissions for Oregon are 47% higher than those released in-state. This finding implies that Oregon's contribution to global greenhouse gas emissions (carbon footprint) is considerably higher than traditional production-based methods would suggest. Furthermore, the consumption based inventory helps highlight the role of goods and services (and associated purchasing behaviors) more so than do production-based methods. Accordingly, a consumption-based perspective opens new opportunities for many states and their local government partners to reduce GHG emissions, such as initiatives to advance lower-carbon public sector or household consumption, that are well within their sphere of influence. State and local governments should consider conducting consumption-based GHG inventories and adopting consumption-based emission reductions targets in order to broaden the reach and effectiveness of state and local actions in reducing global GHG emissions. Consumption-based frameworks should be viewed as a complement to, but not a substitute for, production-based (in-state) GHG emissions inventories and targets. PMID- 22439797 TI - Comparison of surgical and endoscopic sample collection for pancreatic cyst fluid biomarker identification. AB - Significant efforts are underway to develop new biomarkers from pancreatic cyst fluid. Previous research has made use of cyst fluid collected from surgically removed cysts, but the clinical implementation of biomarkers would use cyst fluid collected by endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA). The purpose of this study was to investigate the clinical applicability of cyst fluid research obtained using surgical specimens. Matched pairs of operating-room collected (OR) and EUS-FNA samples from 12 patients were evaluated for the levels of three previously described biomarkers, CA 19-9, CEA, and glycan levels detected by wheat germ agglutinin on MUC5AC (MUC5AC-WGA). CA 19-9 and MUC5AC-WGA correlated well between the sample types, although CEA was more variable between the sample types for certain patients. The variability was not due to the time delay between EUS-FNA and OR collection or differences in total protein concentrations but may be caused by contamination of the cyst fluid with blood proteins. The classification of each patient based on thresholds for each marker was perfectly consistent between sample types for CA 19-9 and MUC5AC-WGA and mostly consistent for CEA. Therefore, results obtained using OR-collected pancreatic cyst fluid samples should reliably transfer to the clinical setting using EUS-FNA samples. PMID- 22439798 TI - How quickly does a hole relax into an engineered defect state in CdSe quantum dots. AB - Intraband hole relaxation of colloidal Te-doped CdSe quantum dots is studied using state-selective transient absorption spectroscopy. The dots are excited at the band edge, and the defect band bleach caused by state filling of the hole is probed. Close to the defect energy, the hole relaxation is substantially slowed down, indicating a gap separating the defect state from the CdSe band edge. A clear dependence of the relaxation time with the QD's size is presented, implying that the hole relaxation is mediated by longitudinal optical (LO) phonon modes of the CdSe host. In addition, we find that overcoating the quantum dots by two monolayers of a ZnS shell extends the hole relaxation time by a factor of 2, suggesting a combined effect of LO phonons and surface effects governing intraband hole relaxation. PMID- 22439799 TI - The effect of hydrogel injection on cardiac function and myocardial mechanics in a computational post-infarction model. AB - An emerging therapy to limit adverse heart remodelling following myocardial infarction (MI) is the injection of polymers into the infarcted left ventricle (LV). In the few numerical studies carried out in this field, the definition and distribution of the hydrogel in the infarcted myocardium were simplified. In this computational study, a more realistic biomaterial distribution was simulated after which the effect on cardiac function and mechanics was studied. A validated finite element heart model was used in which an antero-apical infarct was defined. Four infarct models were created representing different temporal phases in the progression of a MI. Hydrogel layers were simulated in the infarcted myocardium in each model. Biomechanical and functional improvement of the LV was found after hydrogel inclusion in the ischaemic models representing the early phases of MI. In contrast, only functional but no mechanical restitution was shown in the scar model due to hydrogel presence. PMID- 22439800 TI - A new subfamily of agmatinases present in methanogenic Archaea is Fe(II) dependent. AB - Here we report that the Methanocaldococcus jannaschii enzyme derived from the MJ0309 gene is an Fe(II) dependent agmatinase (SpeB). This is the first report of an iron-dependent agmatinase. We demonstrate that aerobically isolated recombinant enzyme contains two disulfide bonds and only a trace amount of any metal and requires the presence of both dithiothreitol (DTT) and 4 equiv of Fe(II) for maximum activity. The DTT activation could be indicative of the presence of a redox system, which would regulate the activity of this as well as other enzymes in the methanogens. Site-directed mutagenesis of the four conserved cysteines C71, C136, C151, and C229 to alanine or serine showed that only the C71 and C151 mutants showed a significant drop in activity indicating that the disulfide bond responsible for regulating activity was likely between C136 and C229. We propose that the C71 and C151 cysteine thiols, produced by the DTT dependent reduction of their disulfide, are two additional metal binding ligands that alter the metal specificity of the M. jannaschii agmatinase from Mn(II) to Fe(II). PMID- 22439801 TI - Validity evidence for a modified version of the Orthotics and Prosthetics Users' Survey. AB - PURPOSE: To evaluate the validity of a modified version of the Orthotics and Prosthetics Users' Survey (OPUS) with persons using different prosthetic and orthotic (P&O) devices. METHOD: Two-hundred-and-eighty-two adults using prosthesis, orthosis, shoe insoles or orthopaedic shoes completed OPUS. OPUS comprises five modules - Lower and Upper Extremity Functional Status, respectively (LEFS and UEFS), Client Satisfaction with Device and Services, respectively (CSD and CSS), and, Health-Related Quality of Life (HRQoL). Eight new items were added to LEFS and six to UEFS. Rasch analysis was used for data analyses. RESULTS: Rating scales functioned satisfactory after some modifications. All modules demonstrated a ceiling effect. Unidimensionality was satisfactory after deleting some items and dividing HRQoL into two subscales, although somewhat weak on CSD and CSS. Item reliability was excellent for all modules and person reliability good for all but CSD and CSS. Some items demonstrated differential item functioning related to sex and age, but the impact on person measures was small. CONCLUSIONS: This study supports the validity of a modified version of OPUS for persons using different P&O devices, but also reveals limitations to be addressed in future studies. OPUS could be useful in clinical rehabilitation and research to evaluate P&O outcomes. PMID- 22439802 TI - Comparison of ultrasound and optical coherence tomography techniques for evaluation of integrity of spontaneously repaired horse cartilage. AB - The aim of this study was to compare sensitivity of ultrasound and optical coherence tomography (OCT) techniques for the evaluation of the integrity of spontaneously repaired horse cartilage. Articular surfaces of horse intercarpal joints, featuring both intact tissue and spontaneously healed chondral or osteochondral defects, were imaged ex vivo with arthroscopic ultrasound and laboratory OCT devices. Quantitative ultrasound (integrated reflection coefficient (IRC), apparent integrated backscattering coefficient (AIB) and ultrasound roughness index (URI)) and optical parameters (optical reflection coefficient (ORC), optical roughness index (ORI) and optical backscattering (OBS)) were determined and compared with histological integrity and mechanical properties of the tissue. Spontaneously healed tissue could be quantitatively discerned from the intact tissue with ultrasound and OCT techniques. Furthermore, several significant correlations (p < 0.05) were detected between ultrasound and OCT parameters. Superior resolution of OCT provided a more accurate measurement of cartilage surface roughness, while the ultrasound backscattering from the inner structures of the cartilage matched better with the histological findings. Since the techniques were found to be complementary to each other, dual modality imaging techniques could provide a useful tool for the arthroscopic evaluation of the integrity of articular cartilage. PMID- 22439805 TI - Musculoskeletal symptoms and computer use among Finnish adolescents--pain intensity and inconvenience to everyday life: a cross-sectional study. AB - BACKGROUND: Musculoskeletal symptoms among adolescents are related to the time spent using a computer, but little is known about the seriousness of the symptoms or how much they affect everyday life. The purpose of the present study was to examine the intensity of musculoskeletal pain and level of inconvenience to everyday life, in relation to time spent using a computer. METHODS: In a survey, 436 school children (12 to 13 and 15 to 16 years of age), answered a questionnaire on musculoskeletal and computer-associated musculoskeletal symptoms in neck-shoulder, low back, head, eyes, hands, and fingers or wrists. Pain intensity (computer-associated symptoms) and inconvenience to everyday life (musculoskeletal symptoms) were measured using a visual analogue scale. Based on the frequency and intensity, three categories were formed to classify pain at each anatomic site: none, mild, and moderate/severe. The association with time spent using the computer was analyzed by multinomial logistic regression. RESULTS: Moderate/severe pain intensity was most often reported in the neck shoulders (21%); head (20%); and eyes (14%); and moderate/severe inconvenience to everyday life was most often reported due to head (29%), neck-shoulders (21%), and low back (16%) pain. Compared with those using the computer less than 3.6 hours/week, computer use of >= 14 hours/week, was associated with moderate/severe increase in computer-associated musculoskeletal pain at all anatomic sites (odds ratio [OR] = 2.9-4.4), and moderate/severe inconvenience to everyday life due to low back (OR = 2.5) and head (OR = 2.0) pain. CONCLUSIONS: Musculoskeletal symptoms causing moderate/severe pain and inconvenience to everyday life are common among adolescent computer users. Daily computer use of 2 hours or more increases the risk for pain at most anatomic sites. PMID- 22439806 TI - Protection of cells from nitric oxide-mediated apoptotic death by glutathione C60 derivative. AB - The influence of the glutathione C60 derivative on the cytotoxicity of a highly reactive free radical NO (nitric oxide) has been investigated. Consistent with its cytoprotective abilities, the derivative scavenges ROS (reactive oxygen species) and RNS (reactive nitrogen species) both in vitro and under cell-free conditions. Moreover, the glutathione C60 derivative protected PC12 cells from the cytotoxic effect of the NO-releasing compound, SNP (sodium nitroprusside). Addition of glutathione C60 derivative alone did not induce apoptosis and necrosis. The results suggest that the glutathione C60 derivative has the potential to prevent NO-mediated cell death without evident toxicity. PMID- 22439807 TI - Effects of long-acting testosterone undecanoate on bone mineral density in middle aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. AB - We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 +/- 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 +/- 0.097 g/cm(2); femoral BMD= 0.847 +/- 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 +/- 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 +/- 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2) = 0.66, p < 0.0001) and femoral (r(2) =0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications. PMID- 22439808 TI - Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery. AB - INTRODUCTION: Nanoparticles are rapidly developing as drug carriers because of their size-dependent properties. Lipid nanoparticles (LNPs) are widely employed in drug delivery because of the biocompatibility of the lipid matrix. AREAS COVERED: Many different types of LNPs have been engineered in the last 20 years, the most important being solid lipid nanoparticles (SLNs), nanostrucured lipid carriers (NLCs), lipid-drug conjugates (LDCs) and lipid nanocapsules (LNCs). This review gives an overview of LNPs, including their physico-chemical properties and pharmacological uses. Moreover, it highlights the most important innovations in the preparation techniques of LNPs, aimed to encapsulate different molecules within the lipid matrix. Finally, it gives a short perspective on the challenges of drug delivery, which are a potential field of application for LNPs: cancer therapy, overcoming the blood-brain barrier and gene and protein delivery. EXPERT OPINION: LNPs are a safe and versatile vehicles for drug and active delivery, suitable for different administration routes. New technologies have been developed for LNP preparation and studies are currently underway in order to obtain the encapsulation of different drugs and to deliver the active molecule to the site of action. PMID- 22439809 TI - Bacterial genomics in infectious disease and the clinical pathology laboratory. AB - CONTEXT: Throughout history, technologic advancements have fueled the engine of innovation, which, in turn, has driven discovery. Accordingly, recent advancements in DNA sequencing technology are revolutionizing bacterial genomics. OBJECTIVE: To review important developments from the literature. The current state of bacterial genomics, with an emphasis on human pathogens and the clinical pathology laboratory, will be discussed. DATA SOURCES: A comprehensive review was performed of the relevant literature indexed in PubMed (National Library of Medicine) and referenced medical texts. CONCLUSIONS: Many important discoveries bearing on infectious disease research and pathology laboratory practice have been achieved through whole-genome sequencing strategies. Bacterial genomics has improved our understanding of molecular pathogenesis, host-pathogen interactions, and antibiotic-resistance mechanisms. Bacterial genomics has also facilitated the study of population structures, epidemics and outbreaks, and newly identified pathogens. Many opportunities now exist for clinical pathologists to contribute to bacterial genomics, including in the design of new diagnostic tests, therapeutic agents, and vaccines. PMID- 22439810 TI - Cu(II)-promoted methanolysis of N,N-dipicolylacetamide. multistep activation by decoupling of > N-C?O resonance via Cu(II)-N binding, delivery of the Cu(II):(( )OCH3) nucleophile, and metal ion assistance of the departure of the leaving group. AB - The methanolysis of the Cu(II) complex of N-acetyl-N,N-bis(2-picolyl)amine (2) was investigated by a kinetic study as a function of pH in methanol at 25 degrees C and computationally by DFT calculations. The active species is the basic form of the complex (3(-)), or (1:Cu(II))((-)OCH(3))(HOCH(3))), and the rate constant for its solvolysis is k(max) = 1.5 * 10(-4) s(-1). The mechanism involves Cu(II) binding to the amide N lone pair, decoupling it from >N-C?O resonance, concomitant with Cu(II):((-)OCH(3)) delivery to the adjacent >N-C?O unit, followed by Cu(II)-assisted departure of the N,N-bis(2-picolyl)amide from a tetrahedral intermediate. PMID- 22439811 TI - Acute morphine activates satellite glial cells and up-regulates IL-1beta in dorsal root ganglia in mice via matrix metalloprotease-9. AB - BACKGROUND: Activation of spinal cord glial cells such as microglia and astrocytes has been shown to regulate chronic opioid-induced antinociceptive tolerance and hyperalgesia, due to spinal up-regulation of the proinflammatory cytokines such as interleukin-1 beta (IL-1beta). Matrix metalloprotease-9 (MMP-9) has been implicated in IL-1beta activation in neuropathic pain. However, it is unclear whether acute opioid treatment can activate glial cells in the peripheral nervous system. We examined acute morphine-induced activation of satellite glial cells (SGCs) and up-regulation of IL-1beta in dorsal root ganglia (DRGs), and further investigated the involvement of MMP-9 in these opioid-induced peripheral changes. RESULTS: Subcutaneous morphine injection (10 mg/kg) induced robust peripheral glial responses, as evidenced by increased GFAP expression in DRGs but not in spinal cords. The acute morphine-induced GFAP expression is transient, peaking at 2 h and declining after 3 h. Acute morphine treatment also increased IL-1beta immunoreactivity in SGCs and IL-1beta activation in DRGs. MMP-9 and GFAP are expressed in DRG neurons and SGCs, respectively. Confocal analysis revealed a close proximity of MMP-9 and GFAP immunostaining. Importantly, morphine-induced DRG up-regulation of GFAP expression and IL-1beta activation was abolished after Mmp9 deletion or naloxone pre-treatment. Finally, intrathecal injections of IL 1beta-selective siRNA not only reduced DRG IL-1beta expression but also prolonged acute morphine-induced analgesia. CONCLUSIONS: Acute morphine induces opioid receptors- and MMP-9-dependent up-regulation of GFAP expression and IL-1beta activation in SGCs of DRGs. MMP-9 could mask and shorten morphine analgesia via peripheral neuron-glial interactions. Targeting peripheral glial activation might prolong acute opioid analgesia. PMID- 22439812 TI - Extensive sympatry, cryptic diversity and introgression throughout the geographic distribution of two coral species complexes. AB - The identification of species is one of the most basic, and yet critically important, issues in biology with far-reaching potential implications for fields such as biodiversity conservation, population ecology and epidemiology. Morphology has long been the primary tool biologists have used to categorize life. However, we now know that a significant portion of natural diversity is morphologically hidden, and therefore, we must integrate nonmorphological tools into the description of biodiversity. Here, we demonstrate the utility of multilocus population genetic data for identifying and characterizing cryptic species complexes, even when species share large amounts of genetic variability. Specifically, we have used DNA sequence data from 12 genomic regions to characterize two widespread species complexes in the coral genus Acropora: A. cytherea and A. hyacinthus. These two morphospecies have each been sampled from 5 to 7 locations throughout their Indo-Pacific distributions, and with the use of structure and hierarchical clustering, we demonstrate the presence of at least six widespread cryptic species within these two morphospecies complexes. After identifying cryptic lineages, we then utilize the genetic data to examine the history of introgressive hybridization within and between these morphospecies complexes. Our data indicate that these two complexes form a global syngameon with consistent patterns of introgression between species across large geographic distributions. PMID- 22439813 TI - A recurring nodule on the nose. PMID- 22439814 TI - A randomised controlled feasibility trial for an educational school-based mental health intervention: study protocol. AB - BACKGROUND: With the burden of mental illness estimated to be costing the English economy alone around L22.5 billion a year 1, coupled with growing evidence that many mental disorders have their origins in adolescence, there is increasing pressure for schools to address the emotional well-being of their students, alongside the stigma and discrimination of mental illness. A number of prior educational interventions have been developed and evaluated for this purpose, but inconsistency of findings, reporting standards, and methodologies have led the majority of reviewers to conclude that the evidence for the efficacy of these programmes remains inconclusive. METHODS/DESIGN: A cluster randomised controlled trial design has been employed to enable a feasibility study of 'SchoolSpace', an intervention in 7 UK secondary schools addressing stigma of mental illness, mental health literacy, and promotion of mental health. A central aspect of the intervention involves students in the experimental condition interacting with a young person with lived experience of mental illness, a stigma reducing technique designed to facilitate students' engagement in the project. The primary outcome is the level of stigma related to mental illness. Secondary outcomes include mental health literacy, resilience to mental illness, and emotional well-being. Outcomes will be measured pre and post intervention, as well as at 6 month follow up. DISCUSSION: The proposed intervention presents the potential for increased engagement due to its combination of education and contact with a young person with lived experience of mental illness. Contact as a technique to reduce discrimination has been evaluated previously in research with adults, but has been employed in only a minority of research trials investigating the impact on youth. Prior to this study, the effect of contact on mental health literacy, resilience, and emotional well-being has not been evaluated to the authors' knowledge. If efficacious the intervention could provide a reliable and cost effective method to reduce stigma in young people, whilst increasing mental health literacy, and emotional well-being. TRIAL REGISTRATION: ISRCTN: ISRCTN07406026. PMID- 22439815 TI - Quantifying the centre of rotation pattern in a multi-body model of the lumbar spine. AB - Understanding the kinematics of the spine provides paramount knowledge for many aspects of the clinical analysis of back pain. More specifically, visualisation of the instantaneous centre of rotation (ICR) enables clinicians to quantify joint laxity in the segments, avoiding a dependence on more inconclusive measurements based on the range of motion and excessive translations, which vary in every individual. Alternatively, it provides motion preserving designers with an insight into where a physiological ICR of a motion preserving prosthesis can be situated in order to restore proper load distribution across the passive and active elements of the lumbar region. Prior to the use of an unconstrained dynamic musculoskeletal model system, based on multi-body models capable of transient analysis, to estimate segmental loads, the model must be kinematically evaluated for all possible sensitivity due to ligament properties and the initial locus of intervertebral disc (IVD). A previously calibrated osseoligamentous model of lumbar spine was used to evaluate the changes in ICR under variation of the ligament stiffness and initial locus of IVD, when subjected to pure moments from 0 to 15 Nm. The ICR was quantified based on the closed solution of unit quaternion that improves accuracy and prevents coordinate singularities, which is often observed in Euler-based methods and least squares principles. The calculation of the ICR during flexion/extension revealed complexity and intrinsic nonlinearity between flexion and extension. This study revealed that, to accommodate a good agreement between in vitro data and the multi-body model predictions, in flexion more laxity is required than in extension. The results showed that the ICR location is concentrated in the posterior region of the disc, in agreement with previous experimental studies. However, the current multi-body model demonstrates a sensitivity to the initial definition of the ICR, which should be recognised as a limitation of the method. Nevertheless, the current simulations suggest that, due to the constantly evolving path of the ICR across the IVD during flexion-extension, a movable ICR is a necessary condition in multi body modelling of the spine, in the context of whole body simulation, to accurately capture segmental kinematics and kinetics. PMID- 22439816 TI - PEGylation is effective in reducing immunogenicity, immunotoxicity, and hepatotoxicity of alpha-momorcharin in vivo. AB - BACKGROUND AND AIM: alpha-momorcharin (alpha-MMC), a type I ribosome-inactivating protein (RIP) from Momordica charantia, is well known for its antitumor and antivirus activities. However, the immunotoxicity and hepatotoxicity hampers its potential therapeutic usage. In order to reduce its toxicity, we had modified the alpha-MMC with polyethylene glycol (PEG), and detected the toxicity of the PEGylated alpha-MMC conjugates (alpha-MMC-PEG) in vivo. MATERIALS AND METHODS: After alpha-MMC purified from bitter melon seeds, alpha-MMC-PEG was constructed with a branched 20 kDa (mPEG) 2-Lys-NHS, the tests of immunogenicity, immunotoxicity, and general toxicity of alpha-MMC-PEG were conducted in guinea pig and rat. RESULTS: The titer of specific IgG in rats, immunized by alpha-MMC PEG, were approximately one-third of those that by alpha-MMC, all the guinea pigs treated with alpha-MMC died of anaphylaxis shock within 5 min, while no animals treated with alpha-MMC-PEG died in the active systemic anaphylaxis (ASA) test. The passive cutaneous anaphylaxis (PCA) reaction of alpha-MMC-PEG challenge in rats was significantly smaller than that of the alpha-MMC. The liver damage was greatly released, such as the change of globulin (GLB), aspartate aminotransferase (AST), total bilirubin (TBIL) cholesterol (CHOL), albumin (ALB), and the degree of hepatocyte necrosis in repeated toxicity study. CONCLUSIONS: PEGylation is effective in reducing the immunogenicity, immunotoxicity, and hepatotoxicity of alpha-MMC in vivo. PMID- 22439817 TI - Identification of genes expressed in cultures of E. coli lysogens carrying the Shiga toxin-encoding prophage Phi24B. AB - BACKGROUND: Shigatoxigenic E. coli are a global and emerging health concern. Shiga toxin, Stx, is encoded on the genome of temperate, lambdoid Stx phages. Genes essential for phage maintenance and replication are encoded on approximately 50% of the genome, while most of the remaining genes are of unknown function nor is it known if these annotated hypothetical genes are even expressed. It is hypothesized that many of the latter have been maintained due to positive selection pressure, and that some, expressed in the lysogen host, have a role in pathogenicity. This study used Change Mediated Antigen Technology (CMAT)TM and 2D-PAGE, in combination with RT-qPCR, to identify Stx phage genes that are expressed in E. coli during the lysogenic cycle. RESULTS: Lysogen cultures propagated for 5-6 hours produced a high cell density with a low proportion of spontaneous prophage induction events. The expression of 26 phage genes was detected in these cultures by differential 2D-PAGE of expressed proteins and CMAT. Detailed analyses of 10 of these genes revealed that three were unequivocally expressed in the lysogen, two expressed from a known lysogenic cycle promoter and one uncoupled from the phage regulatory network. CONCLUSION: Propagation of a lysogen culture in which no cells at all are undergoing spontaneous lysis is impossible. To overcome this, RT-qPCR was used to determine gene expression profiles associated with the growth phase of lysogens. This enabled the definitive identification of three lambdoid Stx phage genes that are expressed in the lysogen and seven that are expressed during lysis. Conservation of these genes in this phage genome, and other Stx phages where they have been identified as present, indicates their importance in the phage/lysogen life cycle, with possible implications for the biology and pathogenicity of the bacterial host. PMID- 22439818 TI - B-type natriuretic peptide is an independent predictor of endothelial function in man. AB - BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1+/-4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFalpha (tumour necrosis factor alpha) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH. PMID- 22439820 TI - Characterization of a disordered protein during micellation: interactions of alpha-synuclein with sodium dodecyl sulfate. AB - To better understand the interaction of alpha-synuclein (alphaSyn) with lipid membranes, we carried out self-assembly molecular dynamics simulations of alphaSyn with monomeric and micellar sodium dodecyl sulfate (SDS), a widely used membrane mimic. We find that both electrostatic and hydrophobic forces contribute to the interactions of alphaSyn with SDS. In the presence of alphaSyn, our simulations suggest that SDS aggregates along the protein chain and forms small size micelles at very early times. Aggregation is followed by formation of a collapsed protein-SDS micelle complex, which is consistent with experimental results. Finally, interaction of alphaSyn with preformed micelles induces alterations in the shape of the micelle, and the N-terminal helix (residues 3 through 37) tends to associate with micelles. Overall, our simulations provide an atomistic description of the early time scale alphaSyn-SDS interaction during the self-assembly of SDS into micelles. PMID- 22439821 TI - Cation-pi interactions in lipocalins: structural and functional implications. AB - The cation-pi interaction impacts protein folding, structural stability, specificity, and molecular recognition. Cation-pi interactions have been overlooked in the lipocalin family. To fill this gap, these interactions were analyzed in the 113 crystal and solution structures from the lipocalin family. The cation-pi interactions link previously identified structurally conserved regions and reveal new motifs, which are beyond the reach of a sequence alignment algorithm. Functional and structural significance of the interactions were tested experimentally in human tear lipocalin (TL). TL, a prominent and promiscuous lipocalin, has a key role in lipid binding at the ocular surface. Ligand binding modulation through the loop AB at the "open" end of the barrel has been erroneously attributed solely to electrostatic interactions. Data revealed that the interloop cation-pi interaction in the pair Phe28-Lys108 contributes significantly to stabilize the holo-conformation of the loop AB. Numerous energetically significant and conserved cation-pi interactions were uncovered in TL and throughout the lipocalin family. Cation-pi interactions, such as the highly conserved Trp17-Arg118 pair in TL, were educed in low temperature experiments of mutants with Trp to Tyr substitutions. PMID- 22439822 TI - Pharmacokinetics of quercetin absorption from apples and onions in healthy humans. AB - A high-throughput method for the extraction and analysis of quercetin in human plasma using 96-well SPE and LC-(ESI)MS/MS (7 min/run) is described. Quercetin exists as a range of glycosides in foods. The dominant types of quercetin glycosides vary depending on genetics (i.e., species and cultivar). Dietary sources include onions and apples (i.e., the peel). Herein the quercetin glycoside composition was determined in a composite standard of dried apple peel and in onion powder. The predominant forms of quercetin in apple peel include quercetin O-arabinoside, 3-O-galactoside, 3-O-glucoside, and 3-O-rhamnoside. In the onion powder, quercetin occurred as the quercetin 3,4'-O-glucoside and 4'-O glucoside. Pharmacokinetics relating to absorption (C(max), t(max), and AUC(0-24 h)) and elimination (k(el) and t(1/2)) were compared after the consumption of apple peel powder (AP), onion powder (OP), or a mixture of the apple peel and onion powder enriched applesauce (MP) by healthy volunteers (eight females and eight males). The enriched applesauce delivered ~100 mg of quercetin aglycone equivalents. Consumption of the OP resulted in C(max) = 273.2 +/- 93.7 ng/mL, t(max) = 2.0 +/- 1.7 h, and t(1/2) = 14.8 +/- 4.8 h, whereas the AP resulted in C(max) = 63.8 +/- 22.4 ng/mL, t(max) = 2.9 +/- 2.0 h, and t(1/2) = 65.4 +/- 80.0 h. The MP resulted in an intermediate response with C(max) = 136.5 +/- 45.8 ng/mL, t(max) = 2.4 +/- 1.5 h, and t(1/2) = 18.7 +/- 6.8 h. Consumption of the OP led to faster absorption, higher concentration, and greater bioavailability as compared to the AP. No significant gender-related differences were observed in the absorption of quercetin, whereas significant gender-related differences in the elimination half-time (t(1/2)) were observed. PMID- 22439823 TI - Distance dependence of single-fluorophore quenching by gold nanoparticles studied on DNA origami. AB - We study the distance-dependent quenching of fluorescence due to a metallic nanoparticle in proximity of a fluorophore. In our single-molecule measurements, we achieve excellent control over structure and stoichiometry by using self assembled DNA structures (DNA origami) as a breadboard where both the fluorophore and the 10 nm metallic nanoparticle are positioned with nanometer precision. The single-molecule spectroscopy method employed here reports on the co-localization of particle and dye, while fluorescence lifetime imaging is used to directly obtain the correlation of intensity and fluorescence lifetime for varying particle to dye distances. Our data can be well explained by exact calculations that include dipole-dipole orientation and distances. Fitting with a more practical model for nanosurface energy transfer yields 10.4 nm as the characteristic distance of 50% energy transfer. The use of DNA nanotechnology together with minimal sample usage by attaching the particles to the DNA origami directly on the microscope coverslip paves the way for more complex experiments exploiting dye-nanoparticle interactions. PMID- 22439824 TI - Angiogenic potential of gellan-gum-based hydrogels for application in nucleus pulposus regeneration: in vivo study. AB - Hydrogels for nucleus pulposus (NP) regeneration should be able to comprise a nonangiogenic or even antiangiogenic feature. Gellan gum (GG)-based hydrogels have been reported to possess adequate properties for being used as NP substitutes in acellular and cellular strategies, due to its ability to support cell encapsulation, adequate mechanical properties, and noncytotoxicity. In this study, the angiogenic response of GG-based hydrogels was investigated by performing the chorioallantoic membrane assay. The convergence of macroscopic blood vessels toward the GG, ionic-crosslinked methacrylated GG (iGG-MA), and photo-crosslinked methacrylated GG (phGG-MA) hydrogel discs was quantified. Gelatin sponge (GSp) and filter paper (FP) alone and with vascular endothelial growth factor were used as controls of angiogenesis. The images obtained were digitally processed and analyzed by three independent observers. The macroscopic blood vessel quantification demonstrated that the GG-based hydrogels are not angiogenic as compared with FP controls. No statistical differences between the GG-based hydrogels tested in respect to its angiogenic ability were observed. Hematoxylin and eosin staining and SNA-lectin immunohistochemistry assay indicated that the iGG-MA and phGG-MA hydrogels do not allow the ingrowth of chick endothelial cells, following 4 days of implantation. On the contrary, GG, GSp, and FP controls allowed cell infiltration. The histological data also indicated that the GG-based hydrogels do not elicit any acute inflammatory response. The results showed that the GG, iGG-MA, and phGG-MA hydrogels present different permeability to cells but functioned as a physical barrier for vascular invasion. These hydrogels present promising and tunable properties for being used as NP substitutes in the treatment of degenerative intervertebral disc. PMID- 22439825 TI - Formation mechanism and optical properties of InAs quantum dots on the surface of GaAs nanowires. AB - Formation mechanism and optical properties of InAs quantum dots (QDs) on the surface of GaAs nanowires (NWs) were investigated. This NW-QDs hybrid structure was fabricated by Au-catalyzed metal organic chemical vapor deposition. We found that the formation and distribution of QDs were strongly influenced by the deposition time of InAs as well as the diameter of GaAs NWs. A model based on the adatom diffusion mechanism was proposed to describe the evolution process of the QDs. Photoluminescence emission from the InAs QDs with a peak wavelength of 940 nm was observed at room temperature. The structure also exhibits a decoupling feature that QDs act as gain medium, while NW acts as Fabry-Perot cavity. This hybrid structure could serve as an important element in high-performance NW-based optoelectronic devices, such as near-infrared lasers, optical detectors, and solar cells. PMID- 22439826 TI - Oligonucleotides with 1,4-dioxane-based nucleotide monomers. AB - An epimeric mixture of H-phosphonates 5R and 5S has been synthesized in three steps from known secouridine 1. Separation of the epimers has been accomplished by RP-HPLC, allowing full characterization and incorporation of monomers X and Y into 9-mer oligonucleotides using H-phosphonates building blocks 5R and 5S, respectively. A single incorporation of either monomer X or monomer Y in the central position of a DNA 9-mer results in decreased thermal affinity toward both DNA and RNA complements (DeltaT(m) = -3.5 degrees C/-3.5 degrees C for monomer X and DeltaT(m) = -11.0 degrees C/-6.5 degrees C for monomer Y). CD measurements do not reveal major rearrangements of the duplexes formed, but molecular modeling suggests that local rearrangement of the sugar phosphate backbone and decreased base interactions with neighboring bases might be the origin of the decreased stability of duplexes. PMID- 22439827 TI - Effect of local zoledronate on implant osseointegration in a rat model. AB - BACKGROUND: An implant coating with poly(D, L-lactide) (PDLLA) releasing incorporated zoledronic acid (ZOL) has already proven to positively effect osteoblasts, to inhibit osteoclasts and to accelerate fracture healing. Aim of this study was to investigate the release kinetics of the chosen coating and the effect of different concentrations of ZOL locally released from this coating on the osseointegration of implants. METHODS: For release kinetics the release of C14-labled ZOL out of the coating was monitored over a period of six weeks in vitro. For testing the osseointegration, titanium Kirschner wires were implanted into the medullary canal of right femurs of 100 Sprague Dawley rats. The animals were divided into five groups receiving implants either uncoated or coated with PDLLA, PDLLA/ZOL low (1.2% w/w) or PDLLA/ZOL high (2% w/w). Additionally, a group with uncoated implants received ZOL intravenously (i.v.). After 56 days animals were sacrificed, femurs dissected and either strength of fixation or histological bone/implant contacts and newly formed bone around the implants were determined. RESULTS: Release kinetics revealed an initial peak in the release of C14-ZOL with a slight further progression over the following weeks. There was no significant enhancement of osseointegration for both groups who received ZOL-coated implants or ZOL i.v. compared to the controls in biomechanical or histological analyses, except for a significant raise in strength of fixation of ZOL i.v. versus PDLLA. CONCLUSIONS: Even though the investigated local ZOL application did not enhance the osseointegration of the implant, the findings might support its application in fracture treatment, since fracture stabilization devices are often explanted after consolidation. PMID- 22439828 TI - Platelet-mediated vascular dysfunction during acute lung injury. AB - CONTEXT: Platelets have significant roles in initiating and mediating reduced alveolar blood flow, microvascular leak, and ventilation/perfusion mismatch caused by metabolic changes and altered signal transduction caused by ischemia reperfusion. OBJECTIVE: This review focuses on platelet mechanisms of vascular dysfunction in the lung and presents a hypothesis for interplay between platelet activation, endothelial damage and fibrinogen. The purpose is to discuss current knowledge regarding mechanisms of platelet-mediated endothelial injury and implications for new strategies to treat vascular dysfunction associated with acute lung injury (ALI). METHODS: Literature from a number of fields was searched using Medline and Google Scholar. RESULTS: Activated platelets contribute to redox imbalance through reactive oxygen species production, pro-leak molecules such as PAF and serotonin, and recruitment of inflammatory cytokines and leukocytes to the damaged endothelium. CONCLUSION: Platelets are a critical component of pulmonary ALI, acting in conjunction with fibrinogen to mediate endothelial damage through multiple signal transduction pathways. PMID- 22439830 TI - Protein elemental sparing and codon usage bias are correlated among bacteria. AB - Highly expressed proteins can exhibit relatively small material costs, in terms of the quantities of carbon (C), nitrogen (N) or sulphur (S) atoms they contain. This 'elemental sparing' probably reflects selection to reduce the quantities of potentially growth-limiting elements in abundant proteins, but the evolutionary mechanisms for adaptive elemental sparing are still poorly understood. Here, we predict that the extent of 'elemental sparing' in highly expressed proteins will vary among organisms, according to the effectiveness of selection in determining the fate of mutations. We test this hypothesis in bacteria by asking whether 'elemental sparing' is correlated with codon usage bias. Bacteria exhibit extraordinary variation in their life histories and demography and consequently in the effectiveness of selection in determining whether preferred codons are used in highly expressed genes. We find that C sparing and S sparing, but not N sparing, are significantly correlated with adaptive codon usage bias among 148 genera of bacteria, suggesting that selection for elemental sparing and codon bias are promoted by similar bacterial traits. Our study helps identify principles that determine how nutrient scarcity can shape the elemental composition of proteins. PMID- 22439831 TI - MiR-34b is associated with clinical outcome in triple-negative breast cancer patients. AB - BACKGROUND: Breast cancer is the most common malignancy with the highest incidence rates among women worldwide. Triple-negative breast cancer (TNBC) represents the major phenotype of basal-like molecular subtype of breast cancer, characterized by higher incidence in young women and a very poor prognosis. MicroRNAs (miRNAs) are small non-coding RNAs playing significant role in the pathogenesis of many cancers including breast cancer. Therefore, miRNAs are also potential prognostic and/or predictive biomarkers in triple-negative breast cancer patients. METHODS: Thirty-nine TNBC patients with available formalin-fixed paraffin-embedded (FFPE) tissues were enrolled in the study. MiR-34a, miR-34b, and miR-34c were analyzed using qRT-PCR and correlated to clinico-pathological features of TNBC patients. RESULTS: Expression levels of miR-34b significantly correlate with disease free survival (DFS) (p = 0.0020, log-rank test) and overall survival (OS) (p = 0.0008, log-rank test) of TNBC patients. No other significant associations between miR-34a, miR-34b, and miR-34c with available clinical pathological data were observed. CONCLUSIONS: MiR-34b expression negatively correlates with disease free survival and overall survival in TNBC patients. Thus, miR-34b may present a new promising prognostic biomarker in TNBC patients, but independent validations are necessary. PMID- 22439832 TI - Fostering scholarly activities and encouraging publications. AB - Scholarly activities and publications go hand-in-hand with the positive progression of academic life. The development of a systematic approach to scholarly activities will permit a better outlook for publications, presentations, and grants. In this way, scholarly activities represent the essential part of the academic arena. Without scholarly activity, there is no advancement in academics. Thus, fostering scholarly activities and encouraging publications would be crucial when developing the academic faculty of the future. PMID- 22439833 TI - History of antibiotics. From salvarsan to cephalosporins. AB - Infections have represented for a long time the leading cause of death in humans. During the 19th century, pneumonia, tuberculosis, diarrhea and diphtheria were considered the main causes of death in children and adults. Only in the late 19th century did it become possible to correlate the existence of microscopic pathogens with the development of various diseases. Within a few years the introduction of antiseptic procedures had begun to reduce mortality due to postsurgical infections. Sanitation and hygiene played a significant role in the reduction of the mortality due to several infectious diseases. The introduction of the first compounds with antimicrobial activity succeeded in conquering many diseases. In this review we analyzed, from a historical perspective, the development of antibiotics and the circumstances that led to their discovery. The first compound with antimicrobial activity was introduced in 1911 by Erlich. He focused his research activity on the discovery of a "magic bullet" to treat syphilis. Afterwards, Foley and colleagues brought penicillin to the forefront. Streptomycin represents the first drug discovered for the treatment of tuberculosis, and its development included the first use of clinical trials. Finally, with the development of cephalosporins, the introduction of new antimicrobial compounds with broad activity against gram-positive and also some gram-negative bacteria began. PMID- 22439834 TI - Nuclear factor-kappa B mediates one-lung ventilation-induced acute lung injury in rabbits. AB - INTRODUCTION: Several studies have revealed the adverse effect of one-lung ventilation (OLV) on pulmonary function. Nuclear factor-kappa B (NF-kappaB) is a principal transcription factor of proinflammatory genes. This study was designed to investigate the role of NF-kappaB in OLV-mediated lung injury. METHODS: Male rabbits, weighing 2.2 +/- 0.3 kg, were randomly divided into five groups: sham tracheostomized (Sham), OLV (V(T) = 10 ml/kg, FiO(2) = 1.0), two-lung ventilation (TLV, V(T) = 10 ml/kg, FiO(2) = 1.0), OLV preceded by the treatment with NF kappaB inhibitor pyrrolidine dithiocarbamate (PDTC, 50 mg/kg, i.v.), and TLV with the PDTC pretreatment. Arterial blood gases, lung pathological changes, and production of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-8) were assessed. NF-kappaB activation was determined by electrophoretic mobility shift assay (EMSA) and western blotting of nuclear NF kappaB p65. RESULTS: The OLV significantly decreased the ratio of partial pressure of oxygen and fraction inspired oxygen (PaO(2)/FiO(2)) compared to the Sham group (p < .01). However, the TLV had no evident effect on the PaO(2)/FiO(2) ratio. The pretreatment with PDTC significantly reversed the OLV-induced reduction in the PaO(2)/FiO(2) ratio. The PDTC pretreatment also markedly attenuated the OLV-mediated lung injury and proinflammatory cytokine production. The OLV potentiated the NF-kappaB DNA binding activity assessed by EMSA and the NF-kappaB nuclear translocation. The OLV-mediated NF-kappaB activation was markedly inhibited by the PDTC pretreatment. CONCLUSION: Our data collectively demonstrate that OLV can cause lung injury through the activation of NF-kappaB and the production of proinflammatory cytokines. Blocking NF-kappaB reduces lung inflammation and may be an effective strategy in the management of OLV-induced lung damage. PMID- 22439835 TI - Neuroblastoma management in Chinese children. AB - BACKGROUND: This study assesses the clinical features of neuroblastoma and survival. Data for 98 patients between January 2000 and December 2006 at Children's Hospital of Fudan University, Shanghai, China, were retrospectively analyzed. PATIENTS AND METHODS: Diagnostic methods included imaging, 24-hr urine catecholamines, bone marrow biopsies, and histopathology analyses. Treatment followed the modified Japanese Study Group Protocol. Clinical characteristics, treatment, and outcome were depicted, and difficulties encountered were analyzed. RESULTS: The median age of patients was 48 months. There were 3, 13, 31, 49, and 2 patients in stages 1, 2, 3, 4, and 4s disease, respectively. Positive urinary vanillylmandelic acid (VMA) prevalence was low in localized disease (51.1%) and high in disseminated disease (70.6%, p = .03). Gross total resection rate was 60.8%. The five-year overall survival (OS) rate was 80% for stages 1 and 2, 48.3% for stage 3, and 20% for stage 4. The five-year OS rates significantly decreased in children older than 18 months (p < .01), and were higher after gross total resection was performed (p = .023). In stage 4 patients, gross total resection significantly improved the five-year OS rate (p = .029). CONCLUSION: From these data, we suggest that positive urinary VMA, age greater than 18 months, incomplete tumor resection, and advanced stage predict poor prognosis. The results in children with advanced neuroblastoma were not satisfactory in our center. We speculated that lack of multidisciplinary teamwork, nonstandardized treatment, resource limitation, and indigence were the main causes for poorer outcome in late stages. PMID- 22439836 TI - Nonpalliative surgical resection for gastric cancer patients with distant metastasis. AB - OBJECTIVE: The purpose of this study was to determine the influence of clinicopathological and treatment factors on survival in gastric cancer patients with distant metastasis after gastrectomy. METHODS: From 1990 to 2002, 111 gastric cancer patients with distant metastasis underwent nonpalliative gastrectomy at the Department of Surgery, Ruijin Hospital, China. Variables including demographic data, clinicopathological characteristics, and type of surgery were analyzed for survival by using univariate and multivariate methods. RESULTS: The median overall survival for all patients was 11.8 months. The overall survival at one-, three-, and five-year was 48.5%, 12.4%, and 5.8%, respectively. Univariate analysis demonstrated that five-year survival of patients without liver metastasis was significantly longer than that of those with liver metastasis (5.3% versus 0%, p = .006). But, multivariate analysis showed that the status of liver metastasis, as well as the other variables including gender, age, location of tumor, Borrmann type, depth of tumor invasion, lymph node involvement, peritoneal dissemination, number of metastatic sites, pathological differentiation, and types of gastrectomy, was not an independent prognostic factor associated with survival. CONCLUSIONS: Long-term survival for gastric cancer patients with distant metastasis is very poor after gastrectomy. The multivariate analysis failed to determine the independent factors of improved survival. So, only highly selected candidates should be considered for management with surgical resection. PMID- 22439837 TI - Evaluation of a barbed suture device versus conventional suture in a canine enterotomy model. AB - BACKGROUND: Unidirectional, barbed suture allows knotless wound closure with potential value for the progression of advanced suturing techniques. This study compared an absorbable barbed suture device to a monofilament suture in a single layer enterotomy closure model. METHODS: A series of 10 enterotomies were created in the stomach, jejunum, and colon through midline laparotomy in 13 mongrels. The enterotomies were closed in a simple continuous pattern and randomized to either conventional suture secured with three square knots or a barbed suture device without knots. Closure time was recorded for each sample. Adhesion scores and biomechanical wound strengths were assessed at postoperative days 3, 10, and 21 by burst pressure testing. RESULTS: Barbed suture provided a faster closure compared to conventional suture (p <= .02). There was no significant difference in burst pressures or adhesion scores between barbed suture and monofilament suture enterotomy closures at day 3, 10, or 21. CONCLUSION: Enterotomy closure was faster using the barbed device as compared to conventional suture, with no significant difference in burst strength or adhesion scores at any time point. PMID- 22439838 TI - Feasibility of the runt cow for in vivo testing of a spinal interbody prosthesis with preliminary results. AB - BACKGROUND: The optimal lumbar spinal disc prosthesis has yet to be developed. Failures of clinical device studies may be minimized by appropriate large animal preclinical studies. The lumbar spine of the mature "runt" cow, Corrientes breed, has been shown to have a number of desirable characteristics to the human. This study assessed the feasibility of the "runt" cow for in vivo testing of human sized lumbar interbody implants and the ability to perform common analyses of explants. METHODS: Eight cows (four experimental and four controls) were compared. The experimental animals had transosseous implantation of the disc prosthesis at L4-L5, and their spines were harvested at four or six months. They were evaluated for the ease of surgical access and healing, motion segment mobility, ability to remove the implant nondestructively, and microradiography and histomorphology. RESULTS: All animals had successful implantation. All explantations were performed without alteration to the devices. All animals had surgical healing and intended device motion, and histology found device stability by demonstrating bone ingrowth into the device's porous plates. There was a significant 46% increase in the amount of trabecular bone adjacent to the implants. CONCLUSION: The mature runt cow allows for implantation of human-sized interbody and intrabody spinal prostheses. This animal model allowed for macro- and histological analysis of the implant and surrounding tissues. In vivo stability was demonstrated for the disc prosthesis while also allowing for evaluation of intended mobility. Additionally, this is the first study to suggest increased bone density supporting an interbody prosthesis. PMID- 22439839 TI - The effect of repetitive intraperitoneal anesthesia by application of fentanyl medetomidine and midazolam in laboratory rats. AB - BACKGROUND: Literature reviews show numerous options for anesthesia in the small laboratory animals. Many methods are associated with complications, such as high technical effort, difficult monitoring, respiratory and cardiovascular depression, and prolonged sedation. In the present study, we report first time results after repeated use of an intraperitoneal combined anesthesia with a high tolerability. METHODS: Three hundred and seventy-four anesthesias were performed on 38 adult male Lewis rats (280-460 g). Each animal was anesthetized repeatedly over a period of three months, using an intraperitoneal combination of Fentanyl Medetomidine and Midazolam (FMM). The time required for the animals to lose ear pinch response and the ability to perform a righting and pedal withdrawal reflex was measured. For evaluation of the clinical state, a four-point vitality scale was developed. The anesthesia was antagonized with Naloxone, Flumazenil, and Atipamezole (s.c.). RESULTS: The animals lost all three reflex responses within 5 (+/- 2.4) min of injection. Without antagonism of anesthesia, the ear pinch response returned on average within 125 (+/- 21.5) min. After antagonism of anesthesia, the rats needed 5 (+/- 2.9) min to regain all three reflex responses. No significant differences of vitality-index were measured after repeated use of FMM during the investigation period. CONCLUSIONS: A repeatable and secure anesthesia is indispensable for any experimental studies that require multiple anesthesia of a single animal. Intraperitoneal combination of FMM provides an adequate procedure to induce a well tolerable, repeatable state of anesthesia, which conforms to all the necessary requirements for laboratory rats. PMID- 22439841 TI - Anti-obesity drugs: a review about their effects and their safety. AB - INTRODUCTION: Amphetamines, rimonabant and sibutramine licenses as anti-obesity drugs have been withdrawn because of their adverse effects. In fact, orlistat is the only available long-term treatment for obesity. AREAS COVERED: The efficacy and safety of long-term drug therapy is very important in the management obesity; for this reason, the authors decided to conduct a review on the efficacy and safety of current, past and future pharmacotherapies for weight loss. EXPERT OPINION: Orlistat is a good choice for the treatment of obesity, because of its safety on cardiovascular events and its positive effects on diabetic control, even if it is not as effective as rimonabant or sibutramine in reducing body weight. Regarding emerging anti-obesity therapies in diabetic people, we currently have drugs that have already been marketed including the glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide; other than improving glycemic control, they also suppress appetite reducing body weight. Moreover, some other drugs are currently in study such as tesofensine, phentermine + topiramate, bupropion + naltrexone and bupropion + zonisamide. Furthermore, several additional gut hormone-based treatments for obesity are under investigation in Phase II and III clinical trials, with particular focus on ghrelin, peptide YY, pancreatic polypeptide, amylin and oxyntomodulin. PMID- 22439842 TI - Serum angiogenin levels are decreased in patients with psoriasis. PMID- 22439843 TI - Discovery of Plasmodium vivax N-myristoyltransferase inhibitors: screening, synthesis, and structural characterization of their binding mode. AB - N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity. PMID- 22439844 TI - Adenosine A(2a) receptor stimulation prevents hepatocyte lipotoxicity and non alcoholic steatohepatitis (NASH) in rats. AB - NEFA (non-esterified 'free' fatty acid)-mediated lipotoxicity plays a critical role in the pathogenesis of NASH (non-alcoholic steatohepatitis). In the light of the growing need for new therapeutic options for NASH, we investigated the action of A2aR (adenosine A(2a) receptor) stimulation against lipotoxicity. The effects of the A(2a)R agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N ethylcarboxyamidoadenosine] were evaluated 'in vitro' in liver cells exposed to SA (stearic acid) and 'in vivo' in rats with NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). In cultured hepatocytes, SA promoted apoptosis by inducing MKK4 (mitogen-activated protein kinase kinase 4)/SEK1 (stress-activated protein kinase/extracellular-signal-regulated kinase kinase-1) and JNK-1/2 (c-Jun N-terminal kinase-1/2) activation. CGS21680 addition prevented JNK-1/2 activation and reduced apoptosis without interfering with lipid accumulation. CGS21680 action required PI3K (phosphoinositide 3-kinase)/Akt mediated block of MKK4/SEK1. Consistently, PI3K inhibition with wortmannin abolished the cytoprotective action of CGS21680 and reverted MKK4 inhibition. SA lipotoxicity was also prevented by transfecting HTC cells with a specific MKK4/SEK1 siRNA (small interfering RNA). In rats receiving the MCD diet, the development of NASH was associated with MKK4/SEK1 and JNK-1/2 activation. CGS21680 (0.5 mg/kg of body weight, intraperitoneal) administration to MCD-fed rats prevented JNK-1/2 activation by acting on MKK4/SEK1. CGS21680 also effectively reduced NASH-associated ALT (alanine aminotransferase) release, hepatocyte apoptosis, liver inflammation and fibrosis without affecting hepatic steatosis. Taken together, these results demonstrate that, by inhibiting JNK-1/2, A(2a)R stimulation reduces lipotoxicity and ameliorates NASH, giving a rationale to investigate A(2a)R agonists as possible new therapeutic agents in preventing fatty liver progression to NASH. PMID- 22439846 TI - Identification and phenotypic description of new wheat: six-rowed winter barley disomic additions. AB - To increase the allelic variation in wheat-barley introgressions, new wheat barley disomic addition lines were developed containing the 2H, 3H, 4H, 6H, and 7H chromosomes of the six-rowed Ukrainian winter barley 'Manas'. This cultivar is agronomically much better adapted to Central European environmental conditions than the two-rowed spring barley 'Betzes' previously used. A single 'Asakaze' * 'Manas' wheat * barley hybrid plant was multiplied in vitro and one backcross plant was obtained after pollinating 354 regenerant hybrids with wheat. The addition lines were selected from the self-fertilized seeds of the 16 BC(2) plants using genomic in situ hybridization. The addition lines were identified by fluorescence in situ hybridization using repetitive DNA probes (HvT01, GAA, pTa71, and Afa family), followed by confirmation with barley SSR markers. The addition lines were grown in the phytotron and in the field, and morphological parameters (plant height, fertility, tillering, and spike characteristics) were measured. The production of the disomic additions will make it possible to incorporate the DNA of six-rowed winter barley into the wheat genome. Addition lines are useful for genetic studies on the traits of six-rowed winter barley and for producing new barley dissection lines. PMID- 22439848 TI - Regioisomers of perylenediimide: synthesis, photophysical, and electrochemical properties. AB - A series of conjugation extended donor-acceptor 1,6- and 1,7-regiomers of perylenediimide were synthesized, separated, and characterized. The photophysical, electrochemical, and thermal properties of these compounds were investigated and compared. The absorption spectra of 1,6-substituted PDI showed blue shift as compared to its 1,7-substituted PDI. At the same time, the emission spectrum showed no significant differences among the regiomers. Both 1,6- and 1,7 regiomers were thermally stable up to 450 degrees C and showed different melting and crystallization transitions. The electrochemical studies did not show significant differences in oxidation and redox potentials owing to similar HOMO/LUMO gap of 1,6- and 1,7-regiomers, which is also supported by theoretical calculations. Comparison of properties of a series of 1,6- or 1,7-substituted PDIs showed significant differences. Such regiomerically pure compounds can offer certain advantages in applications, which are currently being investigated. PMID- 22439847 TI - Control of progesterone receptor transcriptional synergy by SUMOylation and deSUMOylation. AB - BACKGROUND: Covalent modification of nuclear receptors by the Small Ubiquitin like Modifier (SUMO) is dynamically regulated by competing conjugation/deconjugation steps that modulate their overall transcriptional activity. SUMO conjugation of progesterone receptors (PRs) at the N-terminal lysine (K) 388 residue of PR-B is hormone-dependent and suppresses PR-dependent transcription. Mutation of the SUMOylation motif promotes transcriptional synergy. RESULTS: The present studies address mechanisms underlying this transcriptional synergy by using SUMOylation deficient PR mutants and PR specifically deSUMOylated by Sentrin-specific proteases (SENPs). We show that deSUMOylation of a small pool of receptors by catalytically competent SENPs globally modulates the cooperativity-driven transcriptional synergy between PR observed on exogenous promoters containing at least two progesterone-response elements (PRE2). This occurs in part by raising PR sensitivity to ligands. The C terminal ligand binding domain of PR is required for the transcriptional stimulatory effects of N-terminal deSUMOylation, but neither a functional PR dimerization interface, nor a DNA binding domain exhibiting PR specificity, are required. CONCLUSION: We conclude that direct and reversible SUMOylation of a minor PR protein subpopulation tightly controls the overall transcriptional activity of the receptors at complex synthetic promoters. Transcriptional synergism controlled by SENP-dependent PR deSUMOylation is dissociable from MAPK catalyzed receptor phosphorylation, from SRC-1 coactivation and from recruitment of histone deacetylases to promoters. This will provide more information for targeting PR as a part of hormonal therapy of breast cancer. Taken together, these data demonstrate that the SUMOylation/deSUMOylation pathway is an interesting target for therapeutic treatment of breast cancer. PMID- 22439849 TI - Interaction of the histone mRNA hairpin with stem-loop binding protein (SLBP) and regulation of the SLBP-RNA complex by phosphorylation and proline isomerization. AB - In metazoans, the majority of histone proteins are generated from replication dependent histone mRNAs. These mRNAs are unique in that they are not polyadenylated but have a stem-loop structure in their 3' untranslated region. An early event in 3' end formation of histone mRNAs is the binding of stem-loop binding protein (SLBP) to the stem-loop structure. Here we provide insight into the mechanism by which SLBP contacts the histone mRNA. There are two binding sites in the SLBP RNA binding domain for the histone mRNA hairpin. The first binding site (Glu129-Val158) consists of a helix-turn-helix motif that likely recognizes the unpaired uridines in the loop of the histone hairpin and, upon binding, destabilizes the first G-C base pair at the base of the stem. The second binding site lies between residues Arg180 and Pro200, which appears to recognize the second G-C base pair from the base of the stem and possibly regions flanking the stem-loop structure. We show that the SLBP-histone mRNA complex is regulated by threonine phosphorylation and proline isomerization in a conserved TPNK sequence that lies between the two binding sites. Threonine phosphorylation increases the affinity of SLBP for histone mRNA by slowing the off rate for complex dissociation, whereas the adjacent proline acts as a critical hinge that may orient the second binding site for formation of a stable SLBP-histone mRNA complex. The nuclear magnetic resonance and kinetic studies presented here provide a framework for understanding how SLBP recognizes histone mRNA and highlight possible structural roles of phosphorylation and proline isomerization in RNA binding proteins in remodeling ribonucleoprotein complexes. PMID- 22439850 TI - The R-spondin protein family. AB - The four vertebrate R-spondin proteins are secreted agonists of the canonical Wnt/beta-catenin signaling pathway. These proteins are approximately 35 kDa, and are characterized by two amino-terminal furin-like repeats, which are necessary and sufficient for Wnt signal potentiation, and a thrombospondin domain situated more towards the carboxyl terminus that can bind matrix glycosaminoglycans and/or proteoglycans. Although R-spondins are unable to initiate Wnt signaling, they can potently enhance responses to low-dose Wnt proteins. In humans, rare disruptions of the gene encoding R-spondin1 cause a syndrome of XX sex reversal (phenotypic male), palmoplantar keratosis (a thickening of the palms and soles caused by excess keratin formation) and predisposition to squamous cell carcinoma of the skin. Mutations in the gene encoding R-spondin4 cause anonychia (absence or hypoplasia of nails on fingers and toes). Recently, leucine-rich repeat containing G-protein-coupled receptor (Lgr)4, Lgr5 and Lgr6, three closely related orphans of the leucine-rich repeat family of G-protein-coupled receptors, have been identified as receptors for R-spondins. Lgr5 and Lgr6 are markers for adult stem cells. Because R-spondins are potent stimulators of adult stem cell proliferation in vivo and in vitro, these findings might guide the therapeutic use of R-spondins in regenerative medicine. PMID- 22439851 TI - Community assembly, species richness and nestedness of arbuscular mycorrhizal fungi in agricultural soils. AB - Understanding how communities assemble is a central goal of ecology. This is particularly relevant for communities of arbuscular mycorrhizal fungi (AMF), because the community composition of these beneficial plant symbionts influences important ecosystem processes. Moreover, AMF may be used as sensitive indicators of ecological soil quality if they respond to environmental variation in a predictable way. Here, we use a molecular profiling technique (T-RFLP of 25S rRNA gene fragments) to test which factors determine AM fungal community composition in 40 agricultural soils in the Netherlands. In particular, we test whether species richness, dominance structure and community nestedness are influenced by management type (in pairs of organically and conventionally farmed fields), and we examine the contribution of crop species (maize vs. potato), soil type (sand vs. clay-textured soils) and habitat (plant root vs. bulk soil) on AMF community characteristics. AMF richness varied from 1 to 11 taxa per field. Communities from species-poor fields were found to be subsets of those in richer fields, indicating nestedness and a progressive 'loss' from the species pool. AMF taxa richness and occurrence in soil and plant roots were highly correlated, and richness was related to management intensity (phosphate availability and grass cropping history together explained 32% and 50% of richness in roots and soils). Soil type together with soil chemical parameters explained only 17% of variance in AMF community structure. We synthesize these results by discussing the potential contribution of a 'bottleneck effect' on AMF communities through increased stochastic effects under environmental stress. PMID- 22439852 TI - Reflections on a decade of lymphatic research and biology. PMID- 22439855 TI - Room-temperature long-lived triplet excited states of naphthalenediimides and their applications as organic triplet photosensitizers for photooxidation and triplet-triplet annihilation upconversions. AB - Naphthalenediimide (NDI) derivatives with 2,6- or 2,3,6,7-tetrabromo or amino substituents were prepared. N,N'-dialkyl-2,6-dibromo NDI (compound 2) and N,N' dialkyl-2,3,6,7-tetrabromo NDI (compound 4) show phosphorescence emission at 610 or 667 nm, respectively. Phosphorescence was never observed for NDI derivatives. Conversely, N,N'-dialkyl-2,6-dibromo-3,7-diamino NDI (compound 5) shows strong absorption at 526 nm and fluorescence at 551 nm, and no phosphorescence was observed. However, nanosecond time-resolved transient difference absorption spectroscopy confirmed that the triplet excited state of 5 was populated upon photoexcitation. 2,3,6,7-Tetraamino NDI (6) shows fluorescence, and no triplet excited state was populated upon excitation. The compounds were used as singlet oxygen ((1)O(2)) photosensitizers for the photooxidation of 1,5 dihydroxylnaphthalene (DHN). We found that 5 is more efficient than the conventional photosensitizer, such as Ir(ppy)(2)(bpy)[PF(6)]. The compounds were also used as organic triplet photosensitizers for triplet-triplet annihilation based upconversions. An upconversion quantum yield up to 18.5% was observed. PMID- 22439856 TI - Exxon Valdez vs. Deepwater Horizon: ES&T's top feature article 2011. PMID- 22439857 TI - Paternal drug use: before and during pregnancy. AB - OBJECTIVE: Exploratory investigation on drug use by fathers before and during pregnancy with regard to the number of pregnancies. RESEARCH DESIGN AND METHODS: Data of Dutch community pharmacies were used in which fathers were linked to children. The prevalence of the 15 most prescribed drug groups were calculated per trimester for one trimester preconception and three trimesters during pregnancy. Drugs with possible harmful effect on the semen and/or embryo based on recent safety issues were analyzed for two trimesters before conception. Descriptive statistics was used. RESULTS: During the four trimesters, fathers had used one or more drugs in 73% of the pregnancies. Per trimester, drug use ranged from 35 to 39%, with the highest prevalence in the third trimester, statistically significant for the use of one or two drugs. Drugs used most frequently belong to 'anti-inflammatory and antirheumatic products'. Drugs such as SSRIs with possible harmful effect on the semen and/or embryo are used in 1.4% by fathers before conception. CONCLUSION: A proportion of 73% of fathers used drugs before and during pregnancy, increasing toward the third trimester. To increase the knowledge on possible effects, organizations like EUROCAT and (EN)(O)TIS might be encouraged to also collect paternal drug use. PMID- 22439858 TI - A novel PCR-based method for high throughput prokaryotic expression of antimicrobial peptide genes. AB - BACKGROUND: To facilitate the screening of large quantities of new antimicrobial peptides (AMPs), we describe a cost-effective method for high throughput prokaryotic expression of AMPs. EDDIE, an autoproteolytic mutant of the N terminal autoprotease, Npro, from classical swine fever virus, was selected as a fusion protein partner. The expression system was used for high-level expression of six antimicrobial peptides with different sizes: Bombinin-like peptide 7, Temporin G, hexapeptide, Combi-1, human Histatin 9, and human Histatin 6. These expressed AMPs were purified and evaluated for antimicrobial activity. RESULTS: Two or four primers were used to synthesize each AMP gene in a single step PCR. Each synthetic gene was then cloned into the pET30a/His-EDDIE-GFP vector via an in vivo recombination strategy. Each AMP was then expressed as an Npro fusion protein in Escherichia coli. The expressed fusion proteins existed as inclusion bodies in the cytoplasm and the expression levels of the six AMPs reached up to 40% of the total cell protein content. On in vitro refolding, the fusion AMPs was released from the C-terminal end of the autoprotease by self-cleavage, leaving AMPs with an authentic N terminus. The released fusion partner was easily purified by Ni-NTA chromatography. All recombinant AMPs displayed expected antimicrobial activity against E. coli, Micrococcus luteus and S. cerevisia. CONCLUSIONS: The method described in this report allows the fast synthesis of genes that are optimized for over-expression in E. coli and for the production of sufficiently large amounts of peptides for functional and structural characterization. The Npro partner system, without the need for chemical or enzymatic removal of the fusion tag, is a low-cost, efficient way of producing AMPs for characterization. The cloning method, combined with bioinformatic analyses from genome and EST sequence data, will also be useful for screening new AMPs. Plasmid pET30a/His-EDDIE-GFP also provides green/white colony selection for high-throughput recombinant AMP cloning. PMID- 22439859 TI - Novel septoria speckled leaf blotch resistance loci in a barley doubled-haploid population. AB - The genetics of resistance to Septoria speckled leaf blotch (SSLB), caused by Septoria passerinii, was studied in the Leger * CIho9831 barley doubled-haploid population. The 140 lines in the population segregated as 102 resistant and 38 susceptible, approximating a 3:1 ratio. A recombination map was developed using diversity arrays technology and other molecular markers. Quantitative trait locus (QTL) analysis demonstrated that resistance is primarily conferred either by having the CIho9831 allele at a QTL on 6HS or by having the CIho9831 allele at both of two QTLs on 3H and 2HL. In addition, ~1/16 of the lines were resistant for unidentified reasons. This model predicts a resistant/susceptible ratio of 11:5, which fits the phenotypic observations. Minor QTLs were detected on 2HS and 1H. DNA sequences of linked markers suggest that the 6HS, 3H, and 2HS QTLs are part of resistance gene clusters and that the 6HS and 3H QTLs share homology. The 6HS QTL is identical to or closely linked to the SSLB resistance locus Rsp4 and the 1H QTL to the Rsp2 or Rsp3 locus. The 3H and 2HS QTLs are unique and offer new opportunities for pyramiding resistance genes through marker-assisted breeding for resistance to S. passerinii. PMID- 22439860 TI - Molecular mapping of the major resistance quantitative trait locus qHS2.09 with simple sequence repeat and single nucleotide polymorphism markers in maize. AB - The major quantitative trait locus (QTL) qHS2.09 plays an important role in resistance to head smut during maize breeding and production. In this study, a near-isogenic line (NIL), L34, which harbors the major QTL qHS2.09 in bin 2.09, was developed using a resistant donor 'Mo17' in a susceptible genetic background 'Huangzao4'. Using 18,683 genome-wide polymorphic loci, this major QTL was finely mapped into an interval of ~1.10 Mb, flanked by single nucleotide polymorphism (SNP) markers PZE-102187307 and PZE-102188421. Moreover, the favorable allele from 'Mo17' for SNP PZE-102187611 in this interval that was most significantly associated with resistance to head smut (P = 1.88 E-10) and accounted for 39.7 to 44.4% of the phenotypic variance in an association panel consisting of 80 inbred lines. With combined linkage and association mapping, this major QTL was finally located between SNP PZE-102187486 and PZE-102188421 with an interval of ~1.00 Mb. Based on the pedigrees of 'Mo17' and its derivatives widely used in temperate maize breeding programs, the favorable haplotype from 'Mo17' is shown to be the main source of resistance to head smut in these lines. Therefore, the SNPs closely linked to the major QTL qHS2.09, detected in both linkage and association mapping, and could be useful for marker-assisted selection in maize breeding programs. PMID- 22439861 TI - Transmission of six ampeloviruses and two vitiviruses to grapevine by Phenacoccus aceris. AB - Grapevine leafroll disease is caused by grapevine leafroll-associated viruses (GLRaVs). These viruses are common in vineyards worldwide and often associated with vitiviruses that are involved in the rugose wood complex of grapevine. Ten mealybug species are known as vectors of one or several of these grapevine viruses, including the apple mealybug Phenacoccus aceris which is widespread in Holarctic regions and able to transmit Grapevine leafroll-associated virus-1 and 3 (GLRaV-1 and -3). Our aim was to characterize the transmission features of leafroll viruses by Phenacoccus aceris in order to better understand the contribution of this mealybug to leafroll epidemics. Results showed that Phenacoccus aceris is able to transmit GLRaV-1, -3, -4, -5, -6, and -9 to grapevine but not GLRaV-7. This is the first report of GLRaV-6 transmission by a mealybug. Also, for the first time it was shown that Phenacoccus aceris could vector vitiviruses Grapevine virus A (GVA) and Grapevine virus B (GVB). First instar nymphs were the most efficient stage in transmitting GLRaV-1, -3, and GVA. This research sheds light on the transmission biology of grapevine viruses by Phenacoccus aceris and represents a step forward to leafroll disease management. PMID- 22439862 TI - Magnetic nanoparticles in primary neural cell cultures are mainly taken up by microglia. AB - BACKGROUND: Magnetic nanoparticles (MNPs) offer a large range of applications in life sciences. Applications in neurosciences are one focus of interest. Unfortunately, not all groups have access to nanoparticles or the possibility to develop and produce them for their applications. Hence, they have to focus on commercially available particles. Little is known about the uptake of nanoparticles in primary cells. Previously studies mostly reported cellular uptake in cell lines. Here we present a systematic study on the uptake of magnetic nanoparticles (MNPs) by primary cells of the nervous system. RESULTS: We assessed the internalization in different cell types with confocal and electron microscopy. The analysis confirmed the uptake of MNPs in the cells, probably with endocytotic mechanisms. Furthermore, we compared the uptake in PC12 cells, a rat pheochromocytoma cell line, which is often used as a neuronal cell model, with primary neuronal cells. It was found that the percentage of PC12 cells loaded with MNPs was significantly higher than for neurons. Uptake studies in primary mixed neuronal/glial cultures revealed predominant uptake of MNPs by microglia and an increase in their number. The number of astroglia and oligodendroglia which incorporated MNPs was lower and stable. Primary mixed Schwann cell/fibroblast cultures showed similar MNP uptake of both cell types, but the Schwann cell number decreased after MNP incubation. Organotypic co-cultures of spinal cord slices and peripheral nerve grafts resembled the results of the dispersed primary cell cultures. CONCLUSIONS: The commercial MNPs used activated microglial phagocytosis in both disperse and organotypic culture systems. It can be assumed that in vivo application would induce immune system reactivity, too. Because of this, their usefulness for in vivo neuroscientific implementations can be questioned. Future studies will need to overcome this issue with the use of cell-specific targeting strategies. Additionally, we found that PC12 cells took up significantly more MNPs than primary neurons. This difference indicates that PC12 cells are not a suitable model for natural neuronal uptake of nanoparticles and qualify previous results in PC12 cells. PMID- 22439863 TI - Synthesis and biological evaluation of 1-arylsulfonyl-5-(N hydroxyacrylamide)indoles as potent histone deacetylase inhibitors with antitumor activity in vivo. AB - A series of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indoles has been identified as a new class of histone deacetylase inhibitors. Compounds 8, 11, 12, 13, and 14 demonstrated stronger antiproliferative activities than 1 (SAHA) with GI(50) values ranging from 0.36 to 1.21 MUM against Hep3B, MDA-MB-231, PC-3, and A549 human cancer cell lines. Lead compound 8 showed remarkable HDAC 1, 2, and 6 isoenzymes inhibitory activities with IC(50) values of 12.3, 4.0, 1.0 nM, respectively, which are comparable to 1. In in vivo efficacy evaluation against lung A549 xenograft model, 8 displayed better antitumor activity than compound 1. PMID- 22439865 TI - Xylem sap collection and extraction methodologies to determine in vivo concentrations of ABA and its bound forms by gas chromatography-mass spectrometry (GC-MS). AB - BACKGROUND: Accurate quantification of xylem sap ABA concentrations is important to underpin models of root-to-shoot ABA signalling to predict the physiological effects of soil drying. Growing tomato plants in a whole plant pressure chamber allowed sequential xylem sap collection from a detached leaf, the petiole stub of an otherwise intact plant and finally the de-topped root system of the same plant, to determine the impact of xylem sap sampling methodology on xylem ABA concentration. Since xylem sap can contain bound forms of ABA, a novel gas chromatography-mass spectrometry (GC-MS) procedure was developed to chemically separate free ABA from two in planta bound ABA forms known as Adducts I and II and ABA-glucose-ester (ABA-GE). RESULTS: Xylem sap ABA concentrations were highly dependent on the sampling methodology used: the highest concentrations were detected in sap collected by applying an overpressure to detached leaves following the measurement of leaf water potential. Irrespective of xylem sap source, the wild-type cultivars Ailsa Craig and Rheinlands Ruhm had higher free ABA concentrations than a range of ABA-deficient mutants (notabilis, flacca and sitiens). However, in the mutants, concentrations of bound forms of ABA were similar to wild-type plants, and similar to free ABA concentrations. CONCLUSIONS: Although xylem concentrations of these bound ABA forms and ABA-GE suggest they have a limited physiological impact on ABA homeostasis in tomato, the methods developed here will allow a more complete understanding of ABA biochemistry and root-to-shoot signalling in species known to have higher concentrations of these compounds. PMID- 22439867 TI - New immunosuppressive cyclomyrsinol diterpenes from Euphorbia kopetdaghi Prokh. AB - Aceton: chloroform (1:2) extracts of the aerial parts of Euphorbia kopetdaghi Prokh. (Euphorbiaceae) were investigated for its diterpenoids and afforded three new five-membered ring, pentacyclic myrisinane polyester comprised of 3,5,10-O triacetyl-8-O-isobutanoyl-14-O-benzoylcyclomyrsinol (1), 3,5,10,14-O-tetraacetyl 8-O-(2'-methyl butanoyl)-cyclomyrsinol (2) and 3,5,10,14-O-tetracetyl-8-O isobutanoylcyclomyrsinol (3). The structures were elucidated based on (13)C- and (1)H-NMR as well as 2D-NMR, IR and different MS spectra and the immunomodulation activity for compound 1 was evaluated through lymphocyte proliferation assay, IL 2 assay, oxidative burst of phagocytic leukocytes and through their cytotoxicity on two cell lines. Compound 1 showed significant suppressive activity against phytohemagglutinin-activated T-cell proliferation with an IC(50) of 1.83 ug mL( 1), IL-2 suppressive activity with an IC(50) of 19.0 ug mL(-1) and oxidative burst suppressive activity with an IC(50) of 1.6 ug mL(-1) and ignorable cytotoxic effect on the CC-1 rat hepatocyte and 3T3-L1 mouse fibroblast cell lines. PMID- 22439866 TI - c-Myb regulates matrix metalloproteinases 1/9, and cathepsin D: implications for matrix-dependent breast cancer cell invasion and metastasis. AB - BACKGROUND: The c-Myb transcription factor is essential for the maintenance of stem-progenitor cells in bone marrow, colon epithelia, and neurogenic niches. c Myb malfunction contributes to several types of malignancies including breast cancer. However, the function of c-Myb in the metastatic spread of breast tumors remains unexplored. In this study, we report a novel role of c-Myb in the control of specific proteases that regulate the matrix-dependent invasion of breast cancer cells. RESULTS: Ectopically expressed c-Myb enhanced migration and ability of human MDA-MB-231 and mouse 4T1 mammary cancer cells to invade Matrigel but not the collagen I matrix in vitro. c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. The gene coding for cathepsin D was suggested as the c-Myb responsive gene and downstream effector of the migration-promoting function of c Myb. Finally, we demonstrated that c-Myb delayed the growth of mammary tumors in BALB/c mice and affected the metastatic potential of breast cancer cells in an organ-specific manner. CONCLUSIONS: This study identified c-Myb as a matrix dependent regulator of invasive behavior of breast cancer cells. PMID- 22439868 TI - A pilot study of silver-loaded cellulose fabric with incorporated seaweed for the treatment of atopic dermatitis. AB - Because clothing has the longest and most direct contact with human skin, it is important to carefully choose suitable fabrics for atopic patients who have disrupted skin. To evaluate the clinical effectiveness and biophysical properties of a newly developed silver-loaded cellulose fabric with incorporated seaweed, we enrolled 12 subjects with mild to moderate atopic dermatitis into a clinical control study. The subjects wore a two-piece garment (top and leggings), each piece of which was divided into two parts: one side was made of SkinDoctor((r)) fabric, and the other of 100% cotton. Treatment efficacy was measured with the modified SCORing Atopic Dermatitis (mSCORAD) index, transepidermal water loss (TEWL) and the patients' subjective impressions. All three of these measures had significantly better scores on the side covered with SkinDoctor. These results suggest that SkinDoctor is a beneficial fabric that can improve the comfort of patients with AD. PMID- 22439869 TI - A case of strawberry gingivitis. PMID- 22439870 TI - Long time response of soft magnetorheological gels. AB - Swollen physical magnetorheological (MR) gels were obtained by self-assembling of triblock copolymers containing dispersed soft magnetic particles. The transient rheological responses of these systems were investigated experimentally. Upon sudden application of a homogeneous magnetic field step change, the storage modulus of MR gels continued to increase with time. Such increase trend of the storage modulus could be expressed by a double-exponential function with two distinct modes, a fast and a slow one. The result was compared with the transient rheological response of equivalent MR fluids (paraffin oil without copolymer) and a MR elastomer (PDMS) and interpreted as the consequence of strong rearrangement of the original particle network under magnetic field. Similar to the structure evolution of MR fluids, the ensemble of results suggests that "chaining" and "clustering" processes are also happening inside the gel and are responsible for the rheological behavior, provided they are happening on a smaller length scale (long chains and clusters are hindered). We show that response times of several minutes are typical for the slow response of MR gels. The characteristic time t(2) for the slow process is significantly dependent on the magnetic flux density, the matrix viscoelastic property, particle volume fraction, and sample's initial particle distribution. In order to validate our results, the role of dynamic strain history was clarified. We show that, in the linear viscoelastic region, the particle rearrangement of MR gels was not hindered or accelerated by the dynamic strain history. PMID- 22439871 TI - Migration patterns and changes in population biology associated with the worldwide spread of the oilseed rape pathogen Leptosphaeria maculans. AB - Pathogen introductions into novel areas can lead to the emergence of new fungal diseases of plants. Understanding the origin, introduction pathways, possible changes in reproductive system and population size of fungal pathogens is essential in devising an integrated strategy for the control of these diseases. We used minisatellite markers to infer the worldwide invasion history of the fungal plant pathogen Leptosphaeria maculans, which causes stem canker (blackleg) of oilseed and vegetable brassicas. Clustering analyses partitioned genotypes into distinct populations corresponding to major geographic regions, along with two differentiated populations in Western Canada. Comparison of invasion scenarios using Approximate Bayesian Computation suggested an origin of the pathogen in the USA, the region where epidemics were first recorded, and independent introductions from there over the last few decades into Eastern Canada (Ontario), Europe and Australia. The population in Western Canada appeared to be founded from a source in Ontario and the population in Chile resulted from an admixture between multiple sources. A bottleneck was inferred for the introduction into Western Canada but not into Europe, Ontario or Australia. Clonality appeared high in Western Canada, possibly because environmental conditions there were less conducive to sexual reproduction. Leptosphaeria maculans is a model invasive pathogen with contrasting features in different regions: shallow population structure, high genetic variability and regular sexual recombination in some regions, by comparison with reduced genetic variability, high rates of asexual multiplication, strong population structure or admixture in others. PMID- 22439872 TI - Dual approach utilizing self microemulsifying technique and novel P-gp inhibitor for effective delivery of taxanes. AB - In the present work, concomitant use of self-microemulsifying drug delivery systems (SMEDDS) and a novel third-generation P-gp inhibitor, GF120918 (elacridar), for the effective transport of taxanes (paclitaxel and docetaxel) across an in vitro model of the intestinal epithelium and uptake into tumor cells were investigated. On the basis of solubility studies and ternary phase diagrams, different SMEDDS formulations of taxanes were prepared and characterized. In caco 2 cell permeation study, paclitaxel-loaded SMEDDS along with GF120918 showed a four-fold increase in apparent permeability, while docetaxel-loaded SMEDDS in combination with GF120918 showed a nine-fold increase in permeability, as compared to plain drug solution. Cell uptake studies on A549 cells were performed with microemulsions formed from both SMEDDS formulations loaded with rhodamine 123 dye and showed good uptake than plain dye solution. Confocal laser scanning microscopic images further confirmed the higher uptake of both SMEDDS formulations in the presence of GF120918. PMID- 22439873 TI - Double-face activity of resveratrol in voluntary runners: assessment of DNA damage by comet assay. AB - Voluntary runners are subjected to a massive increase in reactive oxygen/nitrogen species production, which can promote different oxidative stress-related diseases such as premature aging, neurodegenerative disorders, and cancer. The aims of this work were to evaluate the following in peripheral blood cells of voluntary runners: (i) DNA status; (ii) susceptibility to the in vitro insult induced by hydrogen peroxide (H(2)O(2)) as a breaking agent; (iii) capabilities of 3,5,4' trihydroxystilbene (RESV) in counteracting DNA damage. Twenty-five male voluntary runners were compared with 20 sedentary men, as age-matched controls, and DNA status was evaluated with different versions of comet assay: alkaline, neutral, and Fpg enzyme-modified version to measure 8-OH-deoxyguanosine (8-oxo-dG) levels. The H(2)O(2) and/or RESV treatments were performed directly on agarose-embedded cells (atypical comet assay). The results evidenced DNA damage and levels of 8 oxo-dG higher in runners than in sedentary control subjects. The runners' DNA was more prone to the in vitro-induced oxidative insult (200 MUM H(2)O(2)) than that of the control group. Resveratrol (100 MUM), depending on the individual basal DNA status, was able to switch from antioxidant to pro-oxidant. Our results, on the one hand, validated the proposed in vitro experimental protocol in order to measure individual DNA status. On the other hand, our data point out the importance of monitoring the athletes' redox status before subjecting them to dietary supplementation treatment. PMID- 22439874 TI - Pretreatment with the total flavone glycosides of Flos Abelmoschus manihot and hyperoside prevents glomerular podocyte apoptosis in streptozotocin-induced diabetic nephropathy. AB - Diabetic nephropathy (DN) is an important diabetic complication, and podocyte apoptosis plays a critical role in the development of DN. In the present study, we examined the preventive effect of the total flavone glycosides of Flos Abelmoschus manihot (TFA) on urinary microalbumin and glomerular podocyte apoptosis in experimental DN rats. The preliminary oral administration of TFA (200 mg/kg/day) for 24 weeks significantly decreased the urinary microalbumin to creatinine ratio and 24-h urinary total protein in streptozotocin-induced DN rats. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay indicated glomerular cell apoptosis in DN rats was significantly improved by pretreatment with TFA. Furthermore, fluorescence-activated cell sorting and Hoechst 33342 staining suggested preincubation with hyperoside (50 and 200 MUg/mL), the major active constituent of TFA, could significantly mitigate cultured podocyte apoptosis induced by the advanced glycation end-products (AGEs). Western blot analysis showed that increased caspase-3 and caspase-8 expressions induced by AGEs were also inhibited by pretreatment with hyperoside at both doses. Our results demonstrate that TFA pretreatment can decrease urinary albumin excretion in early-stage DN, which might be accomplished by preventing renal damage and podocyte apoptosis. PMID- 22439875 TI - Chitosan reduces plasma adipocytokines and lipid accumulation in liver and adipose tissues and ameliorates insulin resistance in diabetic rats. AB - Chitosan is a natural product derived from chitin. To investigate the hypoglycemic and anti-obesity effects of chitosan, male Sprague-Dawley rats were divided into four groups: normal control, diabetic, and diabetic fed 5% or 7% chitosan. Diabetes was induced in rats by injecting streptozotocin/nicotinamide. After 10 weeks of feeding, the elevated plasma glucose, tumor necrosis factor alpha, and interleukin-6 and lower adiponetin levels caused by diabetes were effectively reversed by chitosan treatment. In addition, 7% chitosan feeding also elevated plasma glucagon-like peptide-1 levels and lowered the insulin resistance index (homeostasis model assessment) in diabetic rats. Lower adipocyte granular intensities and higher lipolysis rates in adipose tissues were noted in the 7% chitosan group. Moreover, chitosan feeding reduced hepatic triglyceride and cholesterol contents and increased hepatic peroxisomal proliferator-activated receptor alpha expression in diabetic rats. Our results indicate that long-term administration of chitosan may reduce insulin resistance through suppression of lipid accumulation in liver and adipose tissues and amelioration of chronic inflammation in diabetic rats. PMID- 22439876 TI - Looking for treasure in stereochemistry-land. A path marked by curiosity, obstinacy, and serendipity. AB - Over the past 40 years, much of my research has evolved around various topics of conformational analysis and asymmetric synthesis. This Perspective describes some of my salient contributions in eight different areas of organic stereochemistry: (1) conformational analysis of six-membered rings, (2) evaluation of stereoelectronic interactions in (1)J(C-H) one-bond coupling constants in six membered rings, (3) eclipsed conformation in cis-2-tert-butyl-5-(tert butylsulfonyl)-1,3-dioxane, (4) determination of enthalpic and entropic contributions to DeltaG degrees (CH(2)Ph) and DeltaG degrees (t-Bu), (5) study of the "attractive gauche effect" in O-C-C-O segments, (6) examination of salt effects on conformational equilibria, (7) asymmetric synthesis of beta-amino acids, and (8) asymmetric organocatalysis and "Green" chemistry. It will be appreciated that a basic understanding of the principles of physical organic chemistry has been essential in all projects. Furthermore, curiosity, enthusiasm, obstinacy, and paying attention to unexpected observations will lead to many new (stereo)chemical discoveries. PMID- 22439877 TI - Variation of chemical composition of essential oils in wild populations of Thymus algeriensis Boiss. et Reut., a North African endemic species. AB - ABSBACKGROUND: Thymus algeriensis is an endemic aromatic plant to Tunisia largely used in folk medicine and as a culinary herb. The bulks aromatic plants come from wild populations whose essential oils compositions as well as their biological properties are severely affected by the geographical location and the phase of the plant development. Therefore, the aim of the present work is to provide more information on the variation of essential oil composition of T. algeriensis collected during the vegetative and the flowering phases and from eight different geographical regions. Besides, influence of population location and phenological stage on yield and metal chelating activity of essential oils is also assessed. METHODS: The essential oil composition of Thymus algeriensis was determined mainly by GC/FID and GC/MS. The chemical differentiation among populations performed on all compounds was assessed by linear discriminate analysis and cluster analysis based on Euclidean distance. RESULTS: A total of 71 compounds, representing 88.99 to 99.76% of the total oil, were identified. A significant effect of the population location on the chemical composition variability of T. algeriensis oil was observed. Only 18 out of 71 compounds showed a statistically significant variation among population locations and phenological stages. Chemical differentiation among populations was high. Minor compounds play an important role to distinguish between chemical groups. Five chemotypes according to the major compounds have been distinguished. Chemotypes distribution is linked to the population location and not to bioclimate, indicating that local selective environmental factors acted on the chemotype diversity. CONCLUSIONS: The major compounds at the species level were alpha-pinene (7.41-13.94%), 1,8-cineole (7.55 22.07%), cis-sabinene hydrate (0.10-12.95%), camphor (6.8-19.93%), 4-terpineol (1.55-11.86%), terpenyl acetate (0-14.92%) and viridiflorol (0-11.49%). Based on major compounds, the populations were represented by (alpha-pinene/1,8 cineole/cis-sabinene hydrate/camphor/viridiflorol), (1,8-cineole/camphor/terpenyl acetate), (alpha-pinene/1,8-cineole/camphor), (1,8-cineole/camphor/4-terpineol) and (alpha-pinene/1,8-cineole/cis-sabinene hydrate/camphor/4-terpineol) chemotypes. Variation of phenological stage did not have a statistically significant effect on the yield and metal chelating activity of the essential oil. These results can be used to investigate the geographical location and the harvesting time of this plant for relevant industries. PMID- 22439878 TI - The fine-scale architecture of structural variants in 17 mouse genomes. AB - BACKGROUND: Accurate catalogs of structural variants (SVs) in mammalian genomes are necessary to elucidate the potential mechanisms that drive SV formation and to assess their functional impact. Next generation sequencing methods for SV detection are an advance on array-based methods, but are almost exclusively limited to four basic types: deletions, insertions, inversions and copy number gains. RESULTS: By visual inspection of 100 Mbp of genome to which next generation sequence data from 17 inbred mouse strains had been aligned, we identify and interpret 21 paired-end mapping patterns, which we validate by PCR. These paired-end mapping patterns reveal a greater diversity and complexity in SVs than previously recognized. In addition, Sanger-based sequence analysis of 4,176 breakpoints at 261 SV sites reveal additional complexity at approximately a quarter of structural variants analyzed. We find micro-deletions and micro insertions at SV breakpoints, ranging from 1 to 107 bp, and SNPs that extend breakpoint micro-homology and may catalyze SV formation. CONCLUSIONS: An integrative approach using experimental analyses to train computational SV calling is essential for the accurate resolution of the architecture of SVs. We find considerable complexity in SV formation; about a quarter of SVs in the mouse are composed of a complex mixture of deletion, insertion, inversion and copy number gain. Computational methods can be adapted to identify most paired-end mapping patterns. PMID- 22439879 TI - Serum protein profiles as potential biomarkers for infectious disease status in pigs. AB - BACKGROUND: In veterinary medicine and animal husbandry, there is a need for tools allowing the early warning of diseases. Preferably, tests should be available that warn farmers and veterinarians during the incubation periods of disease and before the onset of clinical signs. The objective of this study was to explore the potential of serum protein profiles as an early biomarker for infectious disease status. Serum samples were obtained from an experimental pig model for porcine circovirus-associated disease (PCVAD), consisting of Porcine Circovirus type 2 (PCV2) infection in combination with either Porcine Parvovirus (PPV) or Porcine Reproductive and Respiratory Syndrome virus (PRRSV). Sera were collected before and after onset of clinical signs at day 0, 5 and 19 post infection. Serum protein profiles were evaluated against sera from non-infected control animals. RESULTS: Protein profiles were generated by SELDI-TOF mass spectrometry in combination with the ProteominerTM technology to enrich for low abundance proteins. Based on these protein profiles, the experimentally infected pigs could be classified according to their infectious disease status. Before the onset of clinical signs 88% of the infected animals could be classified correctly, after the onset of clinical sigs 93%. The sensitivity of the classification appeared to be high. The protein profiles could distinguish between separate infection models, although specificity was moderate to low. Classification of PCV2/PRRSV infected animals was superior compared to PCV2/PPV infected animals. Limiting the number of proteins in the profiles (ranging from 568 to 10) had only minor effects on the classification performance. CONCLUSIONS: This study shows that serum protein profiles have potential for detection and identification of viral infections in pigs before clinical signs of the disease become visible. PMID- 22439880 TI - Acupuncture as a therapeutic treatment option for threatened miscarriage. AB - BACKGROUND: Threatened miscarriage involves vaginal bleeding in a pregnancy that remains viable. This is a common early pregnancy complication with increased risk factors for early pregnancy loss, preterm premature rupture of membranes (PPROM), preterm delivery, low birth weight babies and maternal antepartum haemorrhage. Currently there are no recommended medical treatment options, rather women receive advice that centres on a 'wait and see' approach. For women with a history of unexplained recurrent miscarriage providing supportive care in a subsequent pregnancy improves live birthing outcomes, but the provision of supportive care to women experiencing threatened miscarriage has to date not been examined. DISCUSSION: While it is known that 50-70% of miscarriages occur due to chromosomal abnormalities, the potential for therapeutic intervention amongst the remaining percentage of women remains unknown. Complementary and alternative medicine (CAM) therapies have the potential to provide supportive care for women presenting with threatened miscarriage. Within fertility research, acupuncture demonstrates beneficial hormonal responses with decreased miscarriage rates, raising the possibility acupuncture may promote specific beneficial effects in early pregnancy. With the lack of current medical options for women presenting with threatened miscarriage it is timely to examine the possible treatment benefits of providing CAM therapies such as acupuncture. SUMMARY: Despite vaginal bleeding being a common complication of early pregnancy there is often reluctance from practitioners to discuss with women and medical personal how and why CAM may be beneficial. In this debate article, the physiological processes of early pregnancy together with the concept of providing supportive care and acupuncture are examined. The aim is to raise awareness and promote discussion as to the beneficial role CAM may have for women presenting with threatened miscarriage. PMID- 22439881 TI - Synthesis, binding affinity, and functional in vitro activity of 3 benzylaminomorphinan and 3-benzylaminomorphine ligands at opioid receptors. AB - A series of 3-benzylamino-3-desoxymorphinan (I) and 3-benzylamino-3 desoxymorphine (II) derivatives were synthesized and evaluated for their binding affinities, and functional activity data are presented at MOR, KOR, and DOR. Some of these ligands were found to have high binding affinity at MOR and KOR and displayed increased selectivity at MOR over KOR and DOR compared to butorphan or cyclorphan. The most selective compound, 3-(3'-hydroxybenzyl)amino-17 methylmorphinan (4g) (24-fold MOR to KOR and 1700-fold MOR to DOR) also showed high binding affinity (0.42 nM to MOR) and was a full agonist in the [(35)S]GTPgammaS binding assay. 2-(3'-Hydroxybenzyl)amino-17 cyclopropylmethylmorphinan (17) was found to be a KOR-selective ligand (150-fold over MOR and >10000-fold over the DORs). Most 3-benzylaminomorphinan derivatives were partial agonists at MOR and full agonists at KOR in the [(35)S]GTPgammaS binding assay. PMID- 22439882 TI - Error adaptation in mental arithmetic. AB - Until now, error and conflict adaptation have been studied extensively using simple laboratory tasks. A common finding is that responses slow down after errors. According to the conflict monitoring theory, performance should also improve after an error. However, this is usually not observed. In this study, we investigated whether the characteristics of the experimental paradigms normally used could explain this absence. More precisely, these paradigms have in common that behavioural adaptation has little room to be expressed. We therefore studied error and conflict adaptation effects in a task that encounters the richness of everyday life's behavioural adaptation--namely, mental arithmetic, where multiple solution strategies are available. In accordance with our hypothesis, we observed that post-error accuracy increases after errors in mental arithmetic. No support for conflict adaptation in mental arithmetic was found. Implications for current theories of conflict and error monitoring are discussed. PMID- 22439883 TI - Essential oils composition of Periploca laevigata Aiton subsp. angustifolia (Labill.) Markgraf (Apocynaceae-Periplocoideae). AB - The essential oil of roots, branches, leaves, flowers and fruits of Periploca laevigata Aiton subsp. angustifolia (Apocynaceae) from Lampedusa Island has been obtained by hydrodistillation and its composition analysed. The analyses allowed the identification and quantification of 86 volatile compounds. Branches showed the higher diversity with 57 compounds followed by fruits with 33, roots with 23, flowers with 16 and leaves with six compounds, respectively. In the matrices examined three constituents, heneicosane, docosane and tricosane are in common, although with different percentages. At least the most abundant compounds found in the matrices have been reported to have several biological activities. 2 Hydroxy-4-methoxybenzaldehyde identified in the roots as the most abundant component (70.7%) and present with 8.3% in the branches is a potent tyrosinase inhibitor present in several African medicinal plants, and thus being used as an ingredient in cosmetic and other medicinal products, primarily in relation to hyperpigmentation. Among the compounds identified, several play a role as semiochemicals for many animals, and 28 allomones, 43 pheromones, 21 kairomones have been identified. P. laevigata subsp. angustifolia in Lampedusa Island is host to a community of visitors, and the possible ecological role of the volatiles found is briefly discussed. PMID- 22439884 TI - Recent trends in publication of basic science and clinical research by United States investigators in anesthesia journals. AB - BACKGROUND: United States anesthesia research production declined sharply from 1980-2005. Whether this trend has continued despite recent calls to improve output is unknown. We conducted an observational internet analysis to quantify American basic science and clinical anesthesia research output in 14 anesthesia journals with impact factors greater than one at three-year intervals during the past decade. RESULTS: American investigators published 1,486 (21.7%) of the total of 6,845 research articles identified in anesthesia journals in 2001, 2004, 2007, and 2010. Approximately two-thirds of all US articles were published in Anesthesiology and Anesthesia and Analgesia. There was a significant correlation (r2 = 0.316; P = 0.036) between the number of articles published by American authors in each anesthesia journal and the corresponding journal's impact factor in 2010. Significantly (P < 0.05; Pearson's Chi-square) fewer basic science articles were published in 2007 and 2010 compared with 2001. US clinical research output also declined in 2007 (201; 15.7%) compared with 2001 (266; 19.1%) and 2004, but an increase occurred in 2010 (279; 21.8%, P < 0.05 versus 2007). CONCLUSIONS: The results indicate that US anesthesia research output continued to decrease from 2001 to 2007. An increase in clinical but not basic science research was observed in 2010 compared with 2007, suggesting that a modest recovery in clinical research production may have begun. PMID- 22439885 TI - Sarcomatoid carcinoma of the hand: a clinical case with an aggressive and uncommon presentation. AB - Cutaneous sarcomatoid carcinoma is a high-grade malignancy. We describe a clinical case of an aggressive sarcomatoid carcinoma in an 87-year-old woman, who presented to the outpatients department with a haemorrhagic nodule on the dorsum of her right hand. By the time of excision 3 weeks later, the nodule had enlarged to 100 * 90 * 65 mm in size. On histological examination, a poorly differentiated carcinoma was seen, with both carcinomatous and sarcomatous elements, in keeping with a sarcomatoid carcinoma. The tumour was positive for cytokeratin, epithelial, smooth-muscle actin, and vimentin stains. Two months later, the patient presented with a recurrent growth on the excised scar along with numerous large right axillary lymph nodes. A right axillary dissection along with excision of the growth confirmed tumour recurrence with metastasis to lymph nodes. Soon after, the patient developed cerebral metastasis, which proved fatal. This case thus highlights the aggressive potential of sarcomatoid carcinoma. PMID- 22439886 TI - Hypothyroidism-related onycholysis with Aureobasidium pullulans colonization successfully treated with antifungal therapy. AB - This is a report, the first to my knowledge, of secondary nail-apparatus involvement by Aureobasidium pullulans in a patient with onycholysis related to hypothyroidism. Complete cure of the lesions was seen after 2 weeks of itraconazole and 2 months of local bifonazole therapy. This case raises concern about the extent of involvement of this yeast in onycholysis of diverse clinical aetiologies. PMID- 22439887 TI - Recognition memory for emotional faces in amnestic mild cognitive impairment: an event-related potential study. AB - This study examined the temporal course of emotional face recognition in amnestic mild cognitive impairment (aMCI). Patients and healthy controls (HC) performed a face recognition task, giving old/new responses to previously studied and novel faces displaying a negative or neutral expression. In aMCI patients, recognition accuracy was preserved for negative faces. Event-related potentials (ERPs) revealed disease-related changes in early perceptual components but not in ERP indices of explicit recognition. Specifically, aMCI patients showed impaired recognition effects for negative faces on the amplitudes of N170 and P2, suggesting deficient memory-related processing of negative faces at the stage of structural encoding and during an early recognition stage at which faces are individuated, respectively. Moreover, while a right-lateralized emotion effect specifically observed for correctly recognized faces on the amplitude of N170 was absent in aMCI, a similar emotion effect for successfully recognized faces on P2 was preserved in the patients, albeit with a different distribution. This suggests that in aMCI facilitated processing of successfully recognized emotional faces starts later in the processing sequence. Nonetheless, an early frontal old/new effect confined to negative faces and a parietal old/new effect unaffected by facial emotion were observed in both groups. This indicates that familiarity and conceptual priming processes may specifically contribute to recognition of negative faces in older adults and that aMCI patients can recruit the same retrieval mechanisms as controls, despite disease-related changes on early perceptual ERP components. PMID- 22439888 TI - Surface potential studies on adsorption processes of clay nanosheets onto a floating molecular film of an amphiphilic alkylammonium cation. AB - A floating molecular film was formed when a chloroform solution of dimethyldioctadecylammonium bromide (DMDOA(+)Br(-)) was spread on an aqueous dispersion of a clay mineral (sodium montmorillonite). At a low concentration (<50 ppm: ppm = mg dm(-3)), a clay mineral was exfoliated into negatively charged layers (denoted by clay nanosheets). Clay nanosheets in a dispersion were adsorbed onto a floating film because of electrostatic interactions. At various clay concentrations (0-50 ppm), surface potential was measured as a function of time to obtain the quantitative information about the adsorption of clay nanosheets on a condensed floating film of DMDOA(+) ions. It was concluded that the adsorption equilibrium obeyed the Langmuir adsorption isotherm, which was supported by the atomic force microscopy (AFM) observation. The rate constants of adsorption and desorption processes were determined by the fitting analyses based on the Langmuir type kinetics. Interestingly, the delay of the adsorption was observed in the early stage indicating that clay nanosheets were removed from the surface region through the repulsion by a counteranion (Br(-)). This explanation was supported by the model simulation using the forward difference method. PMID- 22439889 TI - A care bundle approach for prevention of ventilator-associated pneumonia. AB - Implementation of care bundles for prevention of ventilator-associated pneumonia (VAP) and its impact on patient outcomes requires validation with long-term follow-up. A collaborative multi-centre cohort study was conducted in five Spanish adult intensive-care units. A care bundle approach based on five measures was implemented after a 3-month baseline period, and compliance, VAP rates, intensive-care unit length of stay (ICU LOS) and duration of mechanical ventilation were prospectively recorded for 16 months. There were 149 patients in the baseline period and 885 after the intervention. Compliance with all measures after intervention was <30% (264/885). In spite of this, VAP incidence decreased from 15.5% (23/149) to 11.7% (104/885), after the intervention (p <0.05). This reduction was significantly associated with hand hygiene (OR = 0.35), intra-cuff pressure control (OR = 0.21), oral hygiene (OR = 0.23) and sedation control (OR = 0.51). Use of the care bundle was associated with an incidence risk ratio of VAP of 0.78 (95% CI 0.15-0.99). We documented a reduction of median ICU LOS (from 10 to 6 days) and duration of mechanical ventilation (from 8 to 4 days) for patients with full bundle compliance (intervention period). Efforts on VAP prevention and outcome improvement should focus on achieving higher compliance in hand and oral hygiene, sedation protocols and intracuff pressure control. PMID- 22439890 TI - Spatial orientation of cross-sectional images of coronary arteries: point of view in intracoronary imaging. AB - BACKGROUND: In studies where cross-sectional images of coronary arteries obtained with different imaging modalities are compared, the importance of correct co localization and matching of images along the coronary artery longitudinal axis is obvious. However, it appears neglected that correct spatial orientation of the cross-sectional plane may not be obtainable just by rotating the images to ensure co-localization of identifiable landmarks such as sidebranches. A cross-section has two sides, one facing proximally and the other distally, and pairs of images reconstructed corresponding to these opposite points of view are mirror images of each other and not superimposable. This may be difficult if not impossible to recognize and unrecognized it will give rise to flawed results in the development and validation of imaging technologies aimed at plaque characterization (tissue mapping). We determined the imagined point of view for three commercially available intracoronary imaging systems used by invasive cardiologists and illustrate its importance in imaging modality validation. METHODS AND RESULTS: We made an asymmetric phantom and investigated it with two different intravascular ultrasound (IVUS) systems and one optical coherence tomography (OCT) system. The asymmetry of the phantom allowed determination of the spatial orientation of the cross-sectional images. On all tested systems, an observer should imagine herself/himself standing proximal to the cross-section when looking at the intravascular images. CONCLUSIONS: The tested intracoronary imaging modalities displayed cross-sectional images with a spatial orientation corresponding to a proximal point of view. Knowledge of the spatial orientation is mandatory when comparing and validating different imaging modalities aimed at plaque characterization. PMID- 22439891 TI - New treatment strategies and emerging drugs in endometriosis. AB - Introduction: Endometriosis, histologically defined as the presence of endometrium-like tissue - glands and stroma - that develops outside of the uterine cavity, is still an enigmatic disease responsible for pelvic pain and infertility. The current treatments of endometriosis are surgery and hormonal therapies that act by suppressing ovulation and/or directly on steroid receptors located in endometriotic lesions. Areas covered: New hormonal and non hormonal therapies are being developed for the treatment of endometriosis-related pain. The authors review the state of advancement and the results of novel treatments studied in registered trials ( www.ClinicalTrials.gov ). Cellular signaling pathways activated in endometriotic cells, which constitute potential targets for future treatments, are also described. Expert opinion: Therapeutic research efforts should focus on identifying and testing substances capable of acting locally on the lesions themselves, without interfering with ovulation, in order to be efficacious on both pain symptoms and infertility. PMID- 22439892 TI - A noncanonical cysteine protease USP1 is activated through active site modulation by USP1-associated factor 1. AB - Ubiquitin-specific proteases (USPs) constitute the largest family of the human deubiquitinating enzymes. USP1 belongs to the cysteine protease family and contains a catalytic triad comprised of C90, H593, and D751. Notably, the catalytic activity of USP1 is stimulated through the formation of a tight complex with a WD40 repeat protein UAF1 (USP1-associated factor 1). Our kinetic analyses revealed a general base catalysis in USP1/UAF1, in contrast to an ion-pair mechanism as demonstrated for papain and cathepsin. The pK(a) value of the catalytic cysteine was determined to be 8.67 +/- 0.07 in a pH-dependent inactivation study of USP1/UAF1 by iodoacetamide. A normal solvent kinetic isotope effect of 2.8 for k(cat) and 3.0 for k(cat)/K(m) was observed in the USP1/UAF1-catalyzed hydrolysis of ubiquitin-AMC substrate. Moreover, proton inventory analysis supported the transfer of a single solvent-derived proton in the transition state. Our study also revealed the molecular basis for the activation of USP1 by UAF1. Although the pK(a) of the catalytic cysteine in USP1 and USP1/UAF1 was almost identical, the pK(a) of the catalytic histidine in USP1/UAF1 was 0.43 pH unit lower than that in USP1, which facilitates general base catalysis at a neutral pH and contributes to the elevated catalytic efficiency. We ruled out that the higher catalytic efficiency is due to a tighter binding of ubiquitin. Our results support a regulatory mechanism in which UAF1 activates USP1 by modulating its active site conformation. This finding has a general implication for the regulation of USPs that form complex with partner proteins. PMID- 22439893 TI - Patient attitudes towards medical students at Damascus University teaching hospitals. AB - BACKGROUND: The cooperation of patients and their consent to involve medical students in their care is vital to clinical education, but large numbers of students and lack of experience as well as loss of privacy may evoke negative attitudes of patients, which may sometimes adversely affect the clinical teaching environment. This study aimed to explore the attitudes of patients towards medical students at Damascus University hospitals, and to explore the determinants of those attitudes thus discussing possible implications applicable to clinical teaching. METHODS: This cross-sectional study was conducted at three teaching hospitals affiliated to the Faculty of Medicine at Damascus University. Four hundred patients were interviewed between March and April 2011 by a trained sociologist using a structured questionnaire. RESULTS: Of the patients interviewed, 67.8% approved the presence of medical students during the medical consultation and 58.2% of them felt comfortable with the presence of students, especially among patients with better socio-economic characteristics. 81.5% of the patients agreed to be examined by students in the presence of the supervisor, while 40.2% gave agreement even in the absence of the supervisor. Privacy was the most important factor in the patients' reticence towards examination by the students, whilst the relative safety and comfort if a supervisor was available determined patients' agreement. CONCLUSIONS: The study concluded overall positive attitudes to the medical students' involvement in medical education. However, it is essential that students and clinical supervisors understand and adhere to professional and ethical conduct when involving patients in medical education. PMID- 22439894 TI - Defining the molecular profile of planarian pluripotent stem cells using a combinatorial RNAseq, RNA interference and irradiation approach. AB - BACKGROUND: Planarian stem cells, or neoblasts, drive the almost unlimited regeneration capacities of freshwater planarians. Neoblasts are traditionally described by their morphological features and by the fact that they are the only proliferative cell type in asexual planarians. Therefore, they can be specifically eliminated by irradiation. Irradiation, however, is likely to induce transcriptome-wide changes in gene expression that are not associated with neoblast ablation. This has affected the accurate description of their specific transcriptomic profile. RESULTS: We introduce the use of Smed-histone-2B RNA interference (RNAi) for genetic ablation of neoblast cells in Schmidtea mediterranea as an alternative to irradiation. We characterize the rapid, neoblast-specific phenotype induced by Smed-histone-2B RNAi, resulting in neoblast ablation. We compare and triangulate RNA-seq data after using both irradiation and Smed-histone-2B RNAi over a time course as means of neoblast ablation. Our analyses show that Smed-histone-2B RNAi eliminates neoblast gene expression with high specificity and discrimination from gene expression in other cellular compartments. We compile a high confidence list of genes downregulated by both irradiation and Smed-histone-2B RNAi and validate their expression in neoblast cells. Lastly, we analyze the overall expression profile of neoblast cells. CONCLUSIONS: Our list of neoblast genes parallels their morphological features and is highly enriched for nuclear components, chromatin remodeling factors, RNA splicing factors, RNA granule components and the machinery of cell division. Our data reveal that the regulation of planarian stem cells relies on posttranscriptional regulatory mechanisms and suggest that planarians are an ideal model for this understudied aspect of stem cell biology. PMID- 22439895 TI - Periorbital milia-like calcinosis. PMID- 22439896 TI - Age-related changes to the neural correlates of social evaluation. AB - Recent work suggests the existence of a specialized neural system underlying social processing that may be relatively spared with age, unlike pervasive aging related decline occurring in many cognitive domains. We investigated how neural mechanisms underlying social evaluation are engaged with age, and how age-related changes to socioemotional goals affect recruitment of regions within this network. In a functional MRI study, 15 young and 15 older adults formed behavior based impressions of individuals. They also responded to a prompt that was interpersonally meaningful, social but interpersonally irrelevant, or non-social. Both age groups engaged regions implicated in mentalizing and impression formation when making social relative to non-social evaluations, including dorsal and ventral medial prefrontal cortices, precuneus, and temporoparietal junction. Older adults had increased activation over young in right temporal pole when making social relative to non-social evaluations, suggesting reliance on past experiences when evaluating others. Young adults had greater activation than old in posterior cingulate gyrus when making interpersonally irrelevant, compared to interpersonally meaningful, evaluations, potentially reflecting enhanced valuation of this information. The findings demonstrate the age-related preservation of the neural correlates underlying social evaluation, and suggest that functioning in these regions might be mediated by age-related changes in socioemotional goals. PMID- 22439897 TI - Novel TEMPO-PEG-RGDs conjugates remediate tissue damage induced by acute limb ischemia/reperfusion. AB - We have recently developed new Tempo-PEG-RGDs conjugates and have quantitatively examined their antithrombotic and antioxidant capabilities. These compounds were therapeutically beneficial when characterized in both in vitro platelet aggregation assays and a rat model of arterial thrombosis. Moreover, these compounds demonstrated significant protection from organ damage in a rat model of ischemia/reperfusion. Our data indicate that Tempo-PEG-RGDs represent a new class of adjuvants with therapeutic efficacy in acute and transient ischemic damage. PMID- 22439898 TI - Class action of oral coumarins in the treatment of a patient with chronic spontaneous urticaria and delayed-pressure urticaria. AB - Chronic spontaneous urticaria is a common condition, with a lifetime prevalence of 0.5-1.0%. It has a significant effect on quality of life, comparable to having triple-vessel coronary artery disease. Warfarin and nicoumalone are synthetic derivatives of the plant toxin coumarin. We report the first case of successful response to both warfarin and nicoumalone in the same patient, thereby demonstrating a class action of synthetic coumarins in the disease. Complete response with both coumarins occurred once an INR above 2.0 was achieved, and was maintained during a 12-month follow-up. The mechanism of action of coumarins on urticaria is not known, but may be related to decrease in thrombin production or to interference of activation of other inflammatory proteins produced during the coagulation process. Side-effects of anticoagulation can be catastrophic, and coumarin treatment currently remains reserved for restricted severe recalcitrant cases only. PMID- 22439899 TI - Outcomes from ovarian hyperstimulation following the sole administration of gonadotrophin-releasing hormone agonist in the context of in vitro fertilization: report of two cases and review of the literature. AB - OBJECTIVE: To report the outcomes from two cases of ovarian stimulation following the sole administration of gonadotrophin-releasing hormone agonist (GnRHa) in the context of in vitro fertilization (IVF). DESIGN: A case study was conducted. SETTING: National Referral Unit of Reproductive Medicine. PATIENTS: Two infertile women undergoing IVF participated in the study. INTERVENTIONS: Controlled ovarian hyperstimulation using a long protocol. GnRHa (Buserelin) was started in the luteal phase, in a dose of 600 ug/day, for 12 days. MAIN OUTCOME MEASURES: Number of retrieved oocytes, fertilization rate, number of embryos transferred, implantation rate, ongoing pregnancy, and live birth. RESULTS: Both women underwent egg retrieval and transfer of good quality embryos. One of them conceived and recently gave birth to a healthy full-term baby. CONCLUSIONS: The ovarian hyperstimulation after the sole administration of GnRHa is a rare condition. Oocyte retrieval may be a reasonable treatment under these circumstances instead of cycle cancellation. As far as it is known, this is the third case reported of a live birth following the sole administration of GnRHa in the context of IVF. PMID- 22439900 TI - Office and 24-hour heart rate and target organ damage in hypertensive patients. AB - BACKGROUND: We investigated the association between heart rate and its variability with the parameters that assess vascular, renal and cardiac target organ damage. METHODS: A cross-sectional study was performed including a consecutive sample of 360 hypertensive patients without heart rate lowering drugs (aged 56 +/- 11 years, 64.2% male). Heart rate (HR) and its standard deviation (HRV) in clinical and 24-hour ambulatory monitoring were evaluated. Renal damage was assessed by glomerular filtration rate and albumin/creatinine ratio; vascular damage by carotid intima-media thickness and ankle/brachial index; and cardiac damage by the Cornell voltage-duration product and left ventricular mass index. RESULTS: There was a positive correlation between ambulatory, but not clinical, heart rate and its standard deviation with glomerular filtration rate, and a negative correlation with carotid intima-media thickness, and night/day ratio of systolic and diastolic blood pressure. There was no correlation with albumin/creatinine ratio, ankle/brachial index, Cornell voltage-duration product or left ventricular mass index. In the multiple linear regression analysis, after adjusting for age, the association of glomerular filtration rate and intima-media thickness with ambulatory heart rate and its standard deviation was lost. According to the logistic regression analysis, the predictors of any target organ damage were age (OR = 1.034 and 1.033) and night/day systolic blood pressure ratio (OR = 1.425 and 1.512). Neither 24 HR nor 24 HRV reached statistical significance. CONCLUSIONS: High ambulatory heart rate and its variability, but not clinical HR, are associated with decreased carotid intima-media thickness and a higher glomerular filtration rate, although this is lost after adjusting for age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01325064. PMID- 22439901 TI - Effects of Corni fructus on ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of allergic asthma. AB - BACKGROUND: Allergic asthma is a chronic inflammatory lung disease that is characterized by airway hyperresponsiveness (AHR) to allergens, airway oedema, increased mucus secretion, excess production of T helper-2 (Th2) cytokines, and eosinophil accumulation in the lungs. Corni fructus (CF) is a fruit of Cornus officinalis Sieb. Et. Zucc. (Cornaceae) and has been used in traditional Korean medicine as an anti-inflammatory, analgesic, and diuretic agent. To investigate the anti-asthmatic effects of CF and their underlying mechanism, we examined the influence of CF on the development of pulmonary eosinophilic inflammation and airway hyperresponsiveness in a mouse model of allergic asthma. METHODS: In this study, BALB/c mice were systemically sensitized to ovalbumin (OVA) by intraperitoneal (i.p.), intratracheal (i.t.) injections and intranasal (i.n.) inhalation of OVA. We investigated the effect of CF on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, and OVA-specific immunoglobulin E (IgE) production. RESULTS: The CF-treated groups showed suppressed eosinophil infiltration, allergic airway inflammation, and AHR via reduced production of interleuin (IL) -5, IL-13, and OVA-specific IgE. CONCLUSIONS: Our data suggest that the therapeutic effects of CF in asthma are mediated by reduced production of Th2 cytokines (IL-5), eotaxin, and OVA-specific IgE and reduced eosinophil infiltration. PMID- 22439902 TI - NOx and N2O precursors from biomass pyrolysis: nitrogen transformation from amino acid. AB - Large quantities of NO(x) and N(2)O emissions can be produced from biomass burning. Understanding nitrogen behavior during biomass pyrolysis is crucial. Nitrogen in biomass is mainly in forms of proteins (amino acids). Phenylalanine, aspartic acid, and glutamic acid were used as the model compounds for the nitrogen in biomass. Release behavior tests of nitrogen species from the three amino acids during pyrolysis in argon and gasification with O(2) and CO(2) were performed using a thermogravimetric analyzer (TGA) coupled with a Fourier transform infrared (FTIR) spectrometer. The results indicate that although the influence of oxygen and CO(2) in the atmosphere on nitrogen behavior is different for the amino acids, it is interesting to find some phenomenon in common. The presence of oxygen promotes NO and HNCO formation for all the three amino acids; HCN and HNCO formation are suppressed by introduced CO(2) for all the three amino acids. This can reveal the N-conversion mechanism from biomass in depth under the same conditions. PMID- 22439903 TI - Prevalence and risk factors of feline leukaemia virus and feline immunodeficiency virus in peninsular Malaysia. AB - BACKGROUND: Feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) are major causes of morbidity and mortality in domestic and wild felids. Despite the clinical importance of feline retroviruses and the growing interest in cats as pets, information about FeLV and FIV in Malaysia is presently insufficient to properly advise veterinarians and pet owners. A cross-sectional study was carried out from January 2010 to December 2010 to determine the prevalence and risk factors associated with FeLV and FIV among domestic cats in peninsular Malaysia. Plasma samples were harvested from the blood of 368 domestic cats and screened for evidence of FeLV p27 antigen and FIV antibodies, using an immunochromatographic kit. Additionally, data on cat demographics and health were collected using a structured questionnaire, and were evaluated as potential risk factors for FeLV or FIV status. RESULTS: Of the 368 cats that were evaluated in this study, 12.2% (45/368; 95% CI = 8.88 - 15.58) were positive for FeLV p27 antigen, 31.3%, (115/368; 95% CI = 26.51 - 35.99) were seropositive to FIV antibodies, and 4.3% (16/368; 95% CI = 2.27 - 6.43) had evidence of both viruses. Factors found to significantly increase the risk for FeLV seropositivity include sex, age, behaviour, sickness, and living in a multi-cat household. Seropositive response to FIV was significantly associated with sex, neuter status, age, behaviour, and health status. CONCLUSIONS: The present study indicates that FeLV and FIV are common among domestic cats in peninsular Malaysia, and that factors related to cat demographics and health such as age, sex, behaviour, health status and type of household are important predictors for seropositive status to FeLV or FIV in peninsular Malaysia. High prevalence of FeLV or FIV observed in our study is of concern, in view of the immunosuppressive potentials of the two pathogens. Specific measures for control and prevention such as screening and routine vaccination are needed to ensure that FeLV and FIV are controlled in the cat population of peninsular Malaysia. PMID- 22439904 TI - Super-paramagnetic iron oxide nanoparticles for use in extrapulmonary tuberculosis diagnosis. AB - The limited sensitivity of serological tests for mycobacterial antigens has encouraged the development of a nanoparticle probe specific for the extrapulmonary form of Mycobacterium tuberculosis (Mtb). We developed an innovative probe comprised of super-paramagnetic iron oxide (SPIO) nanoparticles conjugated with Mtb surface antibody (MtbsAb-nanoparticles) to provide ultrasensitive imaging of biomarkers involved in extrapulmonary Mtb infection. MtbsAb-nanoparticles were significantly conjugated with Mtb bacilli. The extent of contrast enhancement reduction on magnetic resonance imaging (MRI) for Mtb and human monocytic THP1 cells was proportional to the concentration of MtbsAb nanoparticles. When MtbsAb-nanoparticles were intravenously injected into mice bearing Mtb granulomas, the granulomatous site showed a 14-fold greater reduction in signal intensity enhancement on T(2) -weighted MR images compared with an opposing site that received PBS injection. Mtb sAb-nanoparticles represent a new non-invasive technology for the diagnosis of extrapulmonary Mtb. PMID- 22439905 TI - Temporal control over cellular targeting through hybridization of folate-targeted dendrimers and PEG-PLA nanoparticles. AB - Polymeric nanoparticles (NPs) and dendrimers are two major classes of nanomaterials that have demonstrated great potential for targeted drug delivery. However, their targeting efficacy has not yet met clinical needs, largely because of a lack of control over their targeting kinetics, which often results in rapid clearance and off-target drug delivery. To address this issue, we have designed a novel hybrid NP (nanohybrid) platform that allows targeting kinetics to be effectively controlled through hybridization of targeted dendrimers with polymeric NPs. Folate (FA)-targeted generation 4 poly(amidoamine) dendrimers were encapsulated into poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) NPs using a double emulsion method, forming nanohybrids with a uniform size (~100 nm in diameter) at high encapsulation efficiencies (69-85%). Targeted dendrimers encapsulated within the NPs selectively interacted with FA receptor (FR) overexpressing KB cells upon release in a temporally controlled manner. The targeting kinetics of the nanohybrids were modulated using three different molecular weights (MW) of the PLA block (23, 30, and 45 kDa). The release rates of the dendrimers from the nanohybrids were inversely proportional to the MW of the PLA block, which dictated their binding and internalization kinetics with KB cells. Our results provide evidence that selective cellular interactions can be kinetically controlled by the nanohybrid design, which can potentially enhance targeting efficacy of nanocarriers. PMID- 22439906 TI - Development and testing of PFFSol1.1, a new polarizable atomic force field for calculation of molecular interactions in implicit water environment. AB - A detailed calculation of protein interactions with explicitly considered water molecules takes enormous time. If water is considered implicitly (as media rather than as molecules), calculations become faster. These calculations are less precise, unless one uses voluminous computations of solvent-accessible areas. Our goal is to obtain parameters for nonbonded atom-atom interactions in implicitly considered water without computation of solvent-accessible areas. Because the "in vacuum" interactions of atoms are obtained from experimental structures of crystals and enthalpies of their sublimation, the "in-water" interactions must be corrected using solvation free energies obtained from Henry's constants. Thus, we obtained parameters for the in-water van der Waals, electrostatic, and polarized interactions for atoms typical of protein structures. Parameters of covalent interactions were taken from the ENCAD force field and partial charges of atoms from quantum-mechanical calculations. The sought parameters of the in-water nonbonded interactions were optimized to achieve the best description of crystal structures and their sublimation and solvation at the room temperature. With the optimized parameters, the correlation between the calculated and experimental cohesion of molecules in crystals is 98.3% in the in-vacuum case (the supplementary force field PFFSubl1.1) and 95.4% the in-water case (the sought force field PFFSol1.1). PMID- 22439907 TI - Amyloid beta (Abeta) peptide modulators and other current treatment strategies for Alzheimer's disease (AD). AB - Introduction: Alzheimer's disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing "amyloid cascade hypothesis," which maintains that the aberrant proteolysis of beta-amyloid precursor protein (betaAPP) into neurotoxic amyloid beta (Abeta) peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Abeta42 peptide generation in an effort to ameliorate the tragedy of AD. Areas covered: This review utilized online data searches at various open online-access websites including the Alzheimer Association, Alzheimer Research Forum; individual drug company databases; the National Institutes of Health (NIH) Medline; Pharmaprojects database; Scopus; inter University research communications; and unpublished research data. Expert opinion: Anti-acetylcholinesterase-, chelation-, N-methyl-D-aspartate (NMDA) receptor antagonist-, statin-, Abeta immunization-, beta-secretase-, gamma secretase-based, and other strategies to modulate betaAPP processing, have dominated pharmacological approaches directed against AD-type neurodegenerative pathology. Cumulative clinical results of these efforts remain extremely disappointing, and have had little overall impact on the clinical management of AD. While a number of novel approaches are in consideration and development, to date there is still no effective treatment or cure for this expanding healthcare concern. PMID- 22439908 TI - The positive impact of a facilitated peer mentoring program on academic skills of women faculty. AB - BACKGROUND: In academic medicine, women physicians lag behind their male counterparts in advancement and promotion to leadership positions. Lack of mentoring, among other factors, has been reported to contribute to this disparity. Peer mentoring has been reported as a successful alternative to the dyadic mentoring model for women interested in improving their academic productivity. We describe a facilitated peer mentoring program in our institution's department of medicine. METHODS: Nineteen women enrolled in the program were divided into 5 groups. Each group had an assigned facilitator. Members of the respective groups met together with their facilitators at regular intervals during the 12 months of the project. A pre- and post-program evaluation consisting of a 25-item self-assessment of academic skills, self-efficacy, and academic career satisfaction was administered to each participant. RESULTS: At the end of 12 months, a total of 9 manuscripts were submitted to peer-reviewed journals, 6 of which are in press or have been published, and another 2 of which have been invited to be revised and resubmitted. At the end of the program, participants reported an increase in their satisfaction with academic achievement (mean score increase, 2.32 to 3.63; P = 0.0001), improvement in skills necessary to effectively search the medical literature (mean score increase, 3.32 to 4.05; P = 0.0009), an improvement in their ability to write a comprehensive review article (mean score increase, 2.89 to 3.63; P = 0.0017), and an improvement in their ability to critically evaluate the medical literature (mean score increased from 3.11 to 3.89; P = 0.0008). CONCLUSIONS: This facilitated peer mentoring program demonstrated a positive impact on the academic skills and manuscript writing for junior women faculty. This 1-year program required minimal institutional resources, and suggests a need for further study of this and other mentoring programs for women faculty. PMID- 22439909 TI - Photochemical aging of alpha-pinene secondary organic aerosol: effects of OH radical sources and photolysis. AB - This study addresses photochemical aging of secondary organic aerosol (SOA) produced from alpha-pinene ozonolysis. The SOA is aged via hydroxyl radical (OH) reactions with first-generation vapors and UV photolysis. OH radicals are created through tetramethylethylene ozonolysis, HOOH photolysis, or HONO photolysis, sources that vary in OH concentration and the presence or absence of UV illumination. Aging strongly influences observed SOA mass concentrations, but the behavior is complex. In the dark or with high concentrations of OH, vapors are functionalized, lowering their volatility, resulting in an increase in OA by a factor of 2-3. However, with lower concentrations of OH under UV illumination SOA mass concentrations decrease over time. We attribute this decrease to evaporation driven by photolysis of the highly functionalized second-generation products. The photolysis rates are rapid, a few percent of the NO(2) photolysis frequency, and can thus be highly competitive with other aging mechanisms in the atmosphere. PMID- 22439911 TI - Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype. AB - AIMS: Epithelial-mesenchymal transition (EMT) is characterized by a loss of epithelial nature and the acquisition of a mesenchymal form. The aim of this study was to assess the role of EMT in human mammary carcinogenesis, by performing immunohistochemical studies of EMT markers with tissue microarrays. METHODS AND RESULTS: A total of 492 cases were evaluated and classified as hormone receptor (HR)-positive type, HER2 type and triple-negative (TN) type by the use of immunohistochemistry and in-situ hybridization. We compared these groups in terms of epithelial and mesenchymal marker expression patterns. Of the 102 cases of TN-type breast cancer, 24.5% expressed vimentin, 13.7% expressed N cadherin, and 9.8% expressed smooth muscle actin (SMA). Of the 221 cases of HR type breast cancer, 4.1% expressed vimentin, 5.9% expressed N-cadherin, and 0.4% expressed SMA. Regarding epithelial markers, decreased expression was seen in 16.7% of cases for E-cadherin, in 45.1% for cytokeratin (CK)19 and in 60.8% for CK8 and CK18 (CAM5.2) in TN-type breast cancer cases. Decreased expression was seen in 11.8% of cases for E-cadherin, in 6.8% for CK19 and in 3.2% for CAM5.2 in HR-type cases. CONCLUSIONS: EMT features were particularly seen in TN-type breast cancer (P < 0.001). EMT was also significantly associated with high histological grade (P < 0.001). PMID- 22439910 TI - Genome-wide analysis of plant nat-siRNAs reveals insights into their distribution, biogenesis and function. AB - BACKGROUND: Many eukaryotic genomes encode cis-natural antisense transcripts (cis NATs). Sense and antisense transcripts may form double-stranded RNAs that are processed by the RNA interference machinery into small interfering RNAs (siRNAs). A few so-called nat-siRNAs have been reported in plants, mammals, Drosophila, and yeasts. However, many questions remain regarding the features and biogenesis of nat-siRNAs. RESULTS: Through deep sequencing, we identified more than 17,000 unique siRNAs corresponding to cis-NATs from biotic and abiotic stress-challenged Arabidopsis thaliana and 56,000 from abiotic stress-treated rice. These siRNAs were enriched in the overlapping regions of NATs and exhibited either site specific or distributed patterns, often with strand bias. Out of 1,439 and 767 cis-NAT pairs identified in Arabidopsis and rice, respectively, 84 and 119 could generate at least 10 siRNAs per million reads from the overlapping regions. Among them, 16 cis-NAT pairs from Arabidopsis and 34 from rice gave rise to nat-siRNAs exclusively in the overlap regions. Genetic analysis showed that the overlapping double-stranded RNAs could be processed by Dicer-like 1 (DCL1) and/or DCL3. The DCL3-dependent nat-siRNAs were also dependent on RNA-dependent RNA polymerase 2 (RDR2) and plant-specific RNA polymerase IV (PolIV), whereas only a fraction of DCL1-dependent nat-siRNAs was RDR- and PolIV-dependent. Furthermore, the levels of some nat-siRNAs were regulated by specific biotic or abiotic stress conditions in Arabidopsis and rice. CONCLUSIONS: Our results suggest that nat-siRNAs display distinct distribution patterns and are generated by DCL1 and/or DCL3. Our analysis further supported the existence of nat-siRNAs in plants and advanced our understanding of their characteristics. PMID- 22439912 TI - Alignment of druglike compounds in lipid bilayers analyzed by solid-state (19)F NMR and molecular dynamics, based on dipolar couplings of adjacent CF3 groups. AB - Solid-state (19)F-NMR spectroscopy is frequently used to analyze the structure and dynamics of lipophilic drugs and peptides embedded in biomembranes. The homonuclear dipolar couplings of trifluoromethyl (CF3) labels can provide valuable parameters such as orientational constraints and/or distances. To characterize the complex dipolar patterns of multiple (19)F spin interactions, three different model compounds carrying two CF3 groups in meta-position on a phenyl ring were incorporated in macroscopically aligned DMPC bilayers. The dipolar patterns obtained with the CPMG (Carr-Purcell-Meiboom-Gill) multipulse sequence were analyzed to yield simultaneously the intra-CF3 and intergroup dipolar coupling values. The fluorine-fluorine distances were predicted by a density functional calculation, and the alignment of the labeled molecular segment could be determined from these distances and the dipolar coupling values. The different compounds were found to align in the lipid bilayer according to their amphiphilic properties, though with a weak anisotropic preference that is typical of solutes in liquid crystals. The residual dipolar couplings were used to calculate Saupe order parameters. For the least complex molecule, (CF3)2-BA, an orientational probability function for the solute in the lipid matrix could be derived. The overall description of how (CF3)2-BA is embedded in the bilayer was independently assessed by molecular dynamics simulations, and compared in structural and dynamical terms with the results of the NMR experiments. PMID- 22439913 TI - A tetravalent dengue nanoparticle stimulates antibody production in mice. AB - BACKGROUND: Dengue is a major public health problem worldwide, especially in the tropical and subtropical regions of the world. Infection with a single Dengue virus (DENV) serotype causes a mild, self-limiting febrile illness called dengue fever. However, a subset of patients experiencing secondary infection with a different serotype progresses to the severe form of the disease, dengue hemorrhagic fever/dengue shock syndrome. Currently, there are no licensed vaccines or antiviral drugs to prevent or treat dengue infections. Biodegradable nanoparticles coated with proteins represent a promising method for in vivo delivery of vaccines. FINDINGS: Here, we used a murine model to evaluate the IgG production after administration of inactivated DENV corresponding to all four serotypes adsorbed to bovine serum albumin nanoparticles. This formulation induced a production of anti-DENV IgG antibodies (p < 0.001). However, plaque reduction neutralization assays with the four DENV serotypes revealed that these antibodies have no neutralizing activity in the dilutions tested. CONCLUSIONS: Our results show that while the nanoparticle system induces humoral responses against DENV, further investigation with different DENV antigens will be required to improve immunogenicity, epitope specicity, and functional activity to make this platform a viable option for DENV vaccines. PMID- 22439915 TI - CH...O interaction lowers hydrogen transfer barrier to keto-enol tautomerization of beta-cyclohexanedione: combined infrared spectroscopic and electronic structure calculation study. AB - Molecular association and keto-enol tautomerization of beta-cyclohexanedione (beta-CHD) have been investigated in argon matrix and also in a thin solid film prepared by depositing pure beta-CHD vapor on a cold (8 K) KBr window. Infrared spectra reveal that, in low-pressure vapor and argon matrix, the molecules are exclusively in diketo tautomeric form. The CH...O hydrogen bonded dimers of the diketo tautomer are produced by annealing the matrix at 28 K. No indication is found for keto-enol tautomerization of beta-CHD in dimeric complexes in argon matrix within the temperature range of 8-28 K. On the other hand, in thin film of pure diketo tautomer, the conversion initiates only when the film is heated at temperatures above 165 K. The observed threshold appears to be associated with excitation of the intermolecular modes, and the IR spectra recorded at high temperatures display narrowing of vibrational bandwidths, which has been associated with reorientations of the molecules in the film. The nonoccurrence of tautomerization of the matrix isolated dimer is consistent with the barrier predicted by electronic structure calculations at B3LYP/6-311++G** and MP2/6 311++G** levels of theory. The transition state calculation predicts that CH...O interaction has a dramatic effect on lowering of the tautomerization barrier, from more than 60 kcal/mol for the bare molecule to ~35-45 kcal/mol for dimers. PMID- 22439916 TI - Emotion recognition and marital satisfaction in stroke. AB - Deficits in the comprehension of facial and prosodic expressions are commonly associated with right hemisphere stroke. However, little is known regarding the impact of these disorders on social relations. We examined facial and prosodic processing, mood, and marital satisfaction in 12 right hemisphere damaged (RHD) stroke patients and nine controls. Results revealed significant impairments in the comprehension of facial expressions and prosody among RHD stroke patients. Nonparametric correlations in the RHD group showed significant associations between marital satisfaction and facial affect discrimination and matching, and nonaffective prosody discrimination. We conclude that deficits in the recognition of nonverbal expressions are associated with reduced relationship satisfaction. PMID- 22439917 TI - Lifetimes of triplet dissolved natural organic matter (DOM) and the effect of NaBH4 reduction on singlet oxygen quantum yields: implications for DOM photophysics. AB - The natural lifetimes of triplet dissolved organic matter ((3)DOM) were determined by an O(2) saturation kinetics study of singlet oxygen quantum yields (Phi(1O2)) in buffered D(2)O. At least two distinct (3)DOM pools are present, and the observed lifetime range (~20 to 80 MUs) leads to a dependence of Phi(1O2) on O(2) concentrations between 29 and 290 MUM. Thus, steady-state (1)O(2) concentrations will depend on [O(2)] in natural waters. The lifetimes are essentially identical for DOM samples of different origins and do not vary with excitation wavelength. However, Phi(1O2) varies greatly between samples and decreases with excitation wavelength. These data strongly suggest that (3)DOM quantum yields decrease with excitation wavelength, which gives rise to the Phi(1O2) variation. Borohydride reduction of several samples in both D(2)O and H(2)O lowers the absorbance and (1)O(2) production rates, but it does not alter Phi(1O2). This is consistent with a model in which (1)O(2) sensitizing chromophores are borohydride reducible groups in DOM, such as aromatic ketones. Interpreted in the framework of a charge transfer (CT) model for DOM optical properties, the collective data suggest a model in which electron acceptor moieties are important (1)O(2) sensitizers and where CT interactions of these moieties disrupt their ability to produce (1)O(2). PMID- 22439918 TI - Mycobacterium genavense in the Netherlands: an opportunistic pathogen in HIV and non-HIV immunocompromised patients. An observational study in 14 cases. AB - Mycobacterium genavense is an opportunistic non-tuberculous mycobacterium previously mostly associated with HIV-infected patients with CD4 counts below 100/MUL. In this retrospective observational study of medical charts we studied all Dutch patients in whom M. genavense was detected between January 2002 and January 2010. Of the 14 patients identified, 13 (93%) showed clinically relevant M. genavense disease. All patients with M. genavense disease were severely immunocompromised, including HIV-infected patients, solid organ transplant recipients, those with chronic steroid use in combination with other immune modulating drugs, recipients of chemotherapy for non-Hodgkin lymphoma, and those with immunodeficiency syndromes. Two patients had non-disseminated pulmonary M. genavense disease. Of the 12 patients treated, eight (75%) showed a favourable outcome. Four patients died in this study, three despite treatment for M. genavense disease. We conclude that M. genavense is a clinically relevant pathogen in severely immunocompromised patients that causes predominantly disseminated disease with serious morbidity and mortality. M. genavense is increasingly seen among non-HIV immunocompromised patients. PMID- 22439919 TI - Targeting children of substance-using parents with the community-based group intervention TRAMPOLINE: a randomised controlled trial--design, evaluation, recruitment issues. AB - BACKGROUND: Children of substance-abusing parents are at risk for developing psychosocial development problems. In Germany it is estimated that approx. 2.65 million children are affected by parental substance abuse or dependence. Only ten percent of them receive treatment when parents are treated. To date, no evaluated programme for children from substance-affected families exists in Germany. The study described in this protocol is designed to test the effectiveness of the group programme TRAMPOLINE for children aged 8-12 years with at least one substance-abusing or -dependent caregiver. The intervention is specifically geared to issues and needs of children from substance-affected families. METHODS/DESIGN: The effectiveness of the manualised nine-session group programme TRAMPOLINE is tested among N = 218 children from substance-affected families in a multicentre randomised controlled trial. Outpatient counselling facilities across the nation from different settings (rural/urban, Northern/Southern/Eastern/Western regions of the country) will deliver the interventions, as they hold the primary access to the target group in Germany. The control condition is a group programme with the same duration that is not addiction-specific. We expect that participants in the intervention condition will show a significant improvement in the use of adaptive coping strategies (in general and within the family) compared to the control condition as a direct result of the intervention. Data is collected shortly before and after as well as six months after the intervention. DISCUSSION: In Germany, the study presented here is the first to develop and evaluate a programme for children of substance abusing parents. Limitations and strengths are discussed with a special focus on recruitment challenges as they appear to be the most potent threat to feasibility in the difficult-to-access target group at hand (Trial registration: ISRCTN81470784). PMID- 22439920 TI - Care management for Type 2 diabetes in the United States: a systematic review and meta-analysis. AB - BACKGROUND: This systematic review and meta-analysis aims at assessing the composition and performance of care management models evaluated in the last decade and their impact on patient important outcomes. METHODS: A comprehensive literature search of electronic bibliographic databases was performed to identify care management trials in type 2 diabetes. Random effects meta-analysis was used when feasible to pool outcome measures. RESULTS: Fifty-two studies were eligible. Most commonly reported were surrogate outcomes (such as HbA1c and LDL), followed by process measures (clinic visit or testing frequency). Less frequently reported were quality of life, patient satisfaction, self-care, and healthcare utilization. Most care management modalities were carved out from primary care. Meta-analysis demonstrated a statistically significant but trivial reduction of HbA1c (weighted difference in means -0.21%, 95% confidence interval -0.40 to 0.03, p < .03) and LDL-cholesterol (weighted difference in means -3.38 mg/dL, 95% confidence interval -6.27 to -0.49, p < .02). CONCLUSIONS: Most care management programs for patients with type 2 diabetes are 'carved-out', accomplish limited effects on metabolic outcomes, and have unknown effects on patient important outcomes. Comparative effectiveness research of different models of care management is needed to inform the design of medical homes for patients with chronic conditions. PMID- 22439921 TI - Uncommon aetiology for autophony: patulous eustachian tube. AB - We report the case of a patient with autophony diagnosed with a patulous Eustachian tube. The patient was treated according to the technique described by Bluestone and Cantekin, inserting an indwelling catheter into the tube. Good results were obtained after one year of monitoring. PMID- 22439922 TI - [Ear, nose and throat manifestations of Wegener's granulomatosis (granulomatosis with polyangiitis)]. AB - INTRODUCTION AND OBJECTIVES: Granulomatosis with polyangiitis (GPA), previously called Wegener's granulomatosis, is a small vessel vasculitis often associated with clinical head and neck manifestations, which are sometimes the presenting symptoms of the disease. The aim of our study was to identify ear, nose and throat (ENT) manifestations associated with GPA and propose a work-up for the management and diagnosis for patients with suspicion or confirmed diagnosis of this ENT pathology. PATIENTS AND METHODS: Retrospective review of the medical records of all patients diagnosed with GPA who were seen at the Department of Otolaryngology from a tertiary public hospital in Cantabria (Spain) over a 20 year period. Clinical and laboratory data, in particular those concerning ENT manifestations, were retrieved from the patients' medical records. RESULTS: Twenty-five patients (age range: 30-81 years) were included in the study. Of these, 88% had ENT manifestations at some point in the course of the disease. In 28% of the cases, ENT features were the presenting manifestations. The most frequent ENT manifestations were sinonasal symptoms (52%), followed by otological manifestations (32%). CONCLUSIONS: Patients with GPA often present with clinical ENT manifestations. Consequently, routine ENT physical examination must be performed in patients with suspected vasculitis to establish a diagnosis of GPA or to better determine the degree of organ system involvement in patients with GPA. PMID- 22439923 TI - Novel protein extraction approach using micro-sized chamber for evaluation of proteins eluted from formalin-fixed paraffin-embedded tissue sections. AB - We describe a novel antigen-retrieval method using a micro-sized chamber for mass spectrometry (MS) analysis to identify proteins that are preferentially eluted from formalin-fixed paraffin-embedded (FFPE) samples. This approach revealed that heat-induced antigen retrieval (HIAR) from an FFPE sample fixed on a glass slide not only improves protein identification, but also facilitates preferential elution of protein subsets corresponding to the properties of antigen-retrieval buffers. Our approach may contribute to an understanding of the mechanism of HIAR. PMID- 22439924 TI - Cancer stem cells: impact, heterogeneity, and uncertainty. AB - The differentiation of tumorigenic cancer stem cells into nontumorigenic cancer cells confers heterogeneity to some cancers beyond that explained by clonal evolution or environmental differences. In such cancers, functional differences between tumorigenic and nontumorigenic cells influence response to therapy and prognosis. However, it remains uncertain whether the model applies to many, or few, cancers due to questions about the robustness of cancer stem cell markers and the extent to which existing assays underestimate the frequency of tumorigenic cells. In cancers with rapid genetic change, reversible changes in cell states, or biological variability among patients, the stem cell model may not be readily testable. PMID- 22439926 TI - Accessories to the crime: functions of cells recruited to the tumor microenvironment. AB - Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy. PMID- 22439925 TI - Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. AB - Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer. PMID- 22439927 TI - Targeting epigenetic misregulation in synovial sarcoma. AB - Like many sarcomas, synovial sarcoma is driven by a characteristic oncogenic transcription factor fusion, SS18-SSX. In this issue of Cancer Cell, Su et al. elucidate the protein partners necessary for target gene misregulation and demonstrate a direct effect of histone deacetylase inhibitors on the SS18-SSX complex composition, expression misregulation, and apoptosis. PMID- 22439928 TI - ALK and MYCN: when two oncogenes are better than one. AB - Mutations of ALK are frequently observed in MYCN-amplified neuroblastomas and correlate with poor clinical outcome, but how these oncogenes cooperate in neuroblastoma development remains unclear. In this issue of Cancer Cell, Zhu et al. describe a mechanism by which ALK and MYCN synergistically induce neuroblastoma in the zebrafish model system. PMID- 22439929 TI - Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer? AB - Pancreatic ductal adenocarcinoma (PDA) responds poorly to chemotherapy. In this issue of Cancer Cell, Provenzano et al. identify hyaluronan as a pivotal determinant of elevated interstitial fluid pressures (IFP) and vascular collapse in PDA. PEGPH20 treatment ablates stromal hyaluronan, normalizes IFP, and increases accessibility of tumor cells to anticancer drugs. PMID- 22439930 TI - A tell-tail sign of chromatin: histone mutations drive pediatric glioblastoma. AB - Recent genomic analyses of pediatric glioblastoma, a poorly understood tumor with dismal outcome, have identified mutations in histone H3 variants that affect critical amino acids in the tail. The findings extend discoveries of chromatin regulator inactivation and gain-of-function mutations by documenting alteration of a modifiable histone residue in human cancer. PMID- 22439931 TI - Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. AB - Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18 SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma. PMID- 22439932 TI - NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. AB - We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an "Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer. PMID- 22439933 TI - Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. AB - Amplification of the MYCN oncogene in childhood neuroblastoma is often accompanied by mutational activation of ALK (anaplastic lymphoma kinase), suggesting their pathogenic cooperation. We generated a transgenic zebrafish model of neuroblastoma in which MYCN-induced tumors arise from a subpopulation of neuroblasts that migrate into the adrenal medulla analog following organogenesis. Coexpression of activated ALK with MYCN in this model triples the disease penetrance and markedly accelerates tumor onset. MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. Coexpression of activated ALK with MYCN provides prosurvival signals that block this apoptotic response and allow continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma. PMID- 22439934 TI - The crosstalk of mTOR/S6K1 and Hedgehog pathways. AB - Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-alpha/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of the Hedgehog (HH) pathway, has been observed in EAC. In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC. PMID- 22439935 TI - Treatment-emergent mutations in NAEbeta confer resistance to the NEDD8-activating enzyme inhibitor MLN4924. AB - MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEbeta as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEbeta mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEbeta mutations. PMID- 22439936 TI - Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. AB - The nature and site of tumor-antigen presentation to immune T cells by bone marrow-derived cells within the tumor microenvironment remains unresolved. We generated a fluorescent mouse model of spontaneous immunoevasive breast cancer and identified a subset of myeloid cells with significant similarity to dendritic cells and macrophages that constitutively ingest tumor-derived proteins and present processed tumor antigens to reactive T cells. Using intravital live imaging, we determined that infiltrating tumor-specific T cells engage in long lived interactions with these cells, proximal to the tumor. In vitro, these cells capture cytotoxic T cells in signaling-competent conjugates but do not support full activation or sustain cytolysis. The spatiotemporal dynamics revealed here implicate nonproductive interactions between T cells and antigen-presenting cells on the tumor margin. PMID- 22439937 TI - Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival. PMID- 22439939 TI - SnapShot: non-small cell lung cancer. PMID- 22439938 TI - Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. AB - Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management. PMID- 22439940 TI - Fate of hazardous air pollutants in oxygen-fired coal combustion with different flue gas recycling. AB - Experiments were performed to characterize transformation and speciation of hazardous air pollutants (HAPs), including SO(2)/SO(3), NO(x), HCl, particulate matter, mercury, and other trace elements in oxygen-firing bituminous coal with recirculation flue gas (RFG) from 1) an electrostatic precipitator outlet or 2) a wet scrubber outlet. The experimental results showed that oxycombustion with RFG generated a flue gas with less volume and containing HAPs at higher levels, while the actual emissions of HAPs per unit of energy produced were much less than that of air-blown combustion. NO(x) reduction was achieved in oxycombustion because of the elimination of nitrogen and the destruction of NO in the RFG. The elevated SO(2)/SO(3) in flue gas improved sulfur self-retention. SO(3) vapor could reach its dew point in the flue gas with high moisture, which limits the amount of SO(3) vapor in flue gas and possibly induces material corrosion. Most nonvolatile trace elements were less enriched in fly ash in oxycombustion than air-firing because of lower oxycombustion temperatures occurring in the present study. Meanwhile, Hg and Se were found to be enriched on submicrometer fly ash at higher levels in oxy-firing than in air-blown combustion. PMID- 22439941 TI - [Churg-Strauss syndrome with neuropathic involvement simulating man in the barrel syndrome]. PMID- 22439942 TI - Prostate radiation in non-metastatic castrate refractory prostate cancer provides an interesting insight into biology of prostate cancer. AB - BACKGROUND: The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory. FINDINGS: Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011) was 60 months, with median survival from RT 42 months. CONCLUSION: Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care. PMID- 22439943 TI - The Norwegian standardization of the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery. AB - This is the first international reference study of neurocognitive function as assessed by the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB). Two hundred and fifty healthy Norwegian men and women between the ages of 12 and 59 years were tested. The results were broken down across gender, age, and education level. In the adult group, women performed better than men on Speed of Processing and Verbal Learning, and men outperformed women on Attention/Vigilance and Reasoning/Problem Solving tasks. There were substantial reductions in most domains of cognitive function with increasing age. The effect of education on cognitive performance was more modest. Although our results are somewhat divergent from the US normative study, we conclude that the MCCB is well suited for research purposes and clinical use in Norway. PMID- 22439945 TI - The integration of 'omic' disciplines and systems biology in cattle breeding. AB - Enormous progress has been made in the selection of animals, including cattle, for specific traits using traditional quantitative genetics approaches. Nevertheless, considerable variation in phenotypes remains unexplained, and therefore represents potential additional gain for animal production. In addition, the paradigm shift in new disciplines now being applied to animal breeding represents a powerful opportunity to prise open the 'black box' underlying the response to selection and fully understand the genetic architecture controlling the traits of interest. A move away from traditional approaches of animal breeding toward systems approaches using integrative analysis of data from the 'omic' disciplines represents a multitude of exciting opportunities for animal breeding going forward as well as providing alternatives for overcoming some of the limitations of traditional approaches such as the expressed phenotype being an imperfect predictor of the individual's true genetic merit, or the phenotype being only expressed in one gender or late in the lifetime of an animal. This review aims to discuss these opportunities from the perspective of their potential application and contribution to cattle breeding. Harnessing the potential of this paradigm shift also poses some new challenges for animal scientists - and they will also be discussed. PMID- 22439946 TI - Sexual dimorphism in Hucul horses using discriminant analysis. AB - The purpose of this study has been to evaluate the applicability of discriminant function analysis to determine gender dimorphism in Hucul horses, based on morphological indices obtained in different stages of life. A total of 243 horses, divided into six age groups, have been examined in its course. For each horse we have measured 12 metric traits, which were then used to calculate 13 biometric indices commonly used in horse breeding in Poland. These have become the basis for defining functions classifying the animals by gender in each of the six age groups. This study answers the question of what parameters play the greatest role in the course of shaping of body proportions of male and female horses in post-foetal development. The following indices have been found to significantly contribute in discriminant models: boniness, smaller trunk length, height at the croup, pelvis width and width of chest. PMID- 22439947 TI - Red clover polyphenol oxidase and lipid metabolism. AB - Increasing the polyunsaturated fatty acid (PUFA) composition of milk is acknowledged to be of benefit to consumer health. Despite the high PUFA content of forages, milk fat contains only about 3% of PUFA and only about 0.5% of n-3 fatty acids. This is mainly due to intensive lipid metabolism in the rumen (lipolysis and biohydrogenation) and during conservation (lipolysis and oxidation) such as drying (hay) and ensiling (silage). In red clover, polyphenol oxidase (PPO) has been suggested to protect lipids against degradation, both in the silage as well as in the rumen, leading to a higher output of PUFA in ruminant products (meat and milk). PPO mediates the oxidation of phenols and diphenols to quinones, which will readily react with nucleophilic binding sites. Such binding sites can be found on proteins, resulting in the formation of protein-bound phenols. This review summarizes the different methods that have been used to assess PPO activity in red clover, and an overview on the current understanding of PPO activity and activation in red clover. Knowledge on these aspects is of major importance to fully harness PPO's lipid-protecting role. Furthermore, we review the studies that evidence PPO-mediated lipid protection and discuss its possible importance in lab-scale silages and further in an in vitro rumen system. It is demonstrated that high (induction of) PPO activity can lead to lower lipolysis in the silage and lower biohydrogenation in the rumen. There are three hypotheses on its working mechanism: (i) protein-bound phenols could directly bind to enzymes (e.g. lipases) as such inhibiting them; (ii) binding of quinones in and between proteins embedded in a lipid membrane (e.g. in the chloroplast) could lead to encapsulation of the lipids; (iii) direct binding of quinones to nucleophilic sites in polar lipids also could lead to protection. There is no exclusive evidence on which mechanism is most important, although there are strong indications that only lipid encapsulation in protein-phenol complexes would lead to an effective protection of lipids against ruminal biohydrogenation. From several studies it has also become apparent that the degree of PPO activation could influence the mode and degree of protection. In conclusion, this review demonstrates that protein-bound phenols and encapsulation in protein-phenol complexes, induced by PPO-mediated diphenol oxidation, could be of interest when aiming to protect lipids against pre-ruminal and ruminal degradation. PMID- 22439948 TI - Prepartal wheat grain feeding improves energy and calcium status of periparturient Holstein heifers. AB - Wheat grain (WG) is unique in possessing extensive starch and nitrogen fermentation (i.e. >85% in ground and steam-processed WG), low cation-anion difference and high-intake properties, making it a potentially useful prepartal dietary choice. The objective was to determine the effects of WG provision to pre partum first-calf heifers on metabolic, health and productive criteria during the transition period. WG replaced barley grain that was commonly used earlier. Fifteen Holstein heifers at 31 +/- 6 days pre partum were blocked based on expected calving date and assigned to three treatments or feeding totally mixed rations containing either (i) barley grain (13.8%) and wheat bran (6.1%), (ii) 10% WG (WG10) or (iii) 18% WG (WG18; dry matter (DM) basis) from 31 days pre partum until calving. In replacing WG for barley grains, some changes in WG use and slight changes in soybean and cottonseed meals use were made to properly formulate balanced rations for net energy for lactation, CP, calcium and P. Prepartal diets contained no supplemental anionic salts. Cows were monitored until 21-day post partum and received the same early lactation diet. The prepartal provision of WG and related dietary changes reduced urine pH at 7-day pre partum, and elevated blood calcium and glucose at 7-day pre partum and at 3 day post partum. Milk fat and protein yields were increased during the 21 days post partum by prepartal WG provision and related diet changes. Blood albumin, globulins, total proteins and urea concentrations were similar among treatments. Feeding diets with WG did not affect body condition score, calving difficulty, calf weight, placenta weight and the time interval from calving to placenta expulsion. It is suggested that prepartal provision of WG with necessary dietary changes led to simultaneous improvements in energy and calcium status of the heifers experiencing their first periparturient phase without compromising parturition status. PMID- 22439949 TI - Effect of maize silage to grass silage ratio and feed particle size on ruminal fermentation in vitro. AB - The effect of the forage source on ruminal fermentation in vitro was investigated for fine (F) and coarse (C) milled diets, using a modified Hohenheim gas production test and a semi-continuous rumen simulation technique (Rusitec). It was hypothesised that the replacement of maize silage by grass silage might lead to associative effects and that interactions related to particle size variation could occur. Five diets with a maize silage to grass silage ratio of 100 : 0, 79 : 21, 52 : 48, 24 : 76 and 0 : 100 differed in their content of CP and carbohydrate fractions, as well as digestible crude nutrients, derived from a digestibility trial with wether sheep. For in vitro investigations, the diets were ground to pass a sieve of either 1 mm (F) or 4 mm (C) perforation. Cumulative gas production was recorded during 93 h of incubation and its capacity decreased with increasing proportion of grass silage in the diet. Across all diets, gas production was delayed in C treatments compared with F treatments. Degradation of crude nutrients and detergent fibre fractions was determined in a Rusitec system. Daily amounts of NH3-N and short-chain fatty acids (SCFA) were measured in the effluent. Degradation of organic matter (OM) and fibre fractions, as well as amounts of NH3-N, increased with stepwise replacement of maize silage by grass silage. Degradability of CP was unaffected by diet composition, as well as total SCFA production. In contrast to the results of the gas production test, degradation of OM and CP was higher in C than in F treatments, accompanied by higher amounts of NH3-N and SCFA. Interactions of silage ratio and particle size were rare. It was concluded that the stepwise replacement of maize silage by grass silage might lead to a linear response of most fermentation characteristics in vitro. This linear effect was also supported by total tract digestibility data. However, further investigations with silages of variable quality seem to be necessary. PMID- 22439950 TI - Effect of maize silage to grass silage ratio and feed particle size on protein synthesis and amino acid profile in different microbial fractions in a semi continuous rumen simulation. AB - The objective was to investigate the effect of variation in forage source and feed particle size of a diet, including interactions, on the amount and the composition of microbial crude protein (CP) in a semi-continuous culture system (Rusitec). Different microbial CP fractions were compared. Five diets with mean forage proportion of 0.88 and different maize silage to grass silage ratios (100 : 0, 79 : 21, 52 : 48, 24 : 76 and 0 : 100) were used. Diets were ground through sieves with a pore size of either 1 or 4 mm, matching the particle size of fine (F) and coarse (C), respectively. Diets were characterised by increasing concentrations of CP and fibre fractions, and decreasing concentrations of starch with ascending inclusion rates of grass silage. Microbial mass was isolated from feed residues after incubation from the liquid phase of the fermenter and from the liquid effluent. The amount of synthesised microbial CP was determined on the basis of 15N balance. It increased quite linearly by the stepwise replacement of maize silage by grass silage, and was higher in C treatments compared to F treatments. Efficiency of microbial CP synthesis (EMPS) was improved from 29 to 43 mg microbial N/g degraded organic matter (OM) by increasing the proportion of grass silage in the diet, but was unaffected by particle size. The N content as well as the profiles of amino acids of the three microbial fractions was affected by diet composition and particle size. The ratio of solid- to liquid-associated microbes was affected by diet composition and feed particle size. The amount and EMPS seemed to be improved by degradation of OM from grass silage and an increasing availability of N. Moreover, the results of this study indicated a shift in the composition of the microbial community caused by variation in forage composition and feed particle size. PMID- 22439951 TI - Effects of pig genotype (Iberian v. Landrace * Large White) on nutrient digestibility, relative organ weight and small intestine structure at two stages of growth. AB - Although the effects of pig genotype on total-tract apparent digestibility (TTAD) have been widely reported in the literature, there is controversial information on the digestive capacity of indigenous breeds compared with lean-type pigs. The strategy of this study was to test the effects of pig genotype and crude protein (CP) supply on performance, digestive utilization of nutrients, relative organ weight and morphometric analysis of the small intestine. Thirty-eight Iberian (IB) and Landrace * Large White (LD) pigs were used. Three pigs per genotype were slaughtered at approximately 15 kg BW. The remaining pigs were fed one of two diets differing in CP content (13% or 17% as fed) using a pair-fed procedure. Feeding level was restricted at 0.8 * ad libitum of IB pigs. Nutrient digestibility and nitrogen (N) balance trials were performed at 30 and 80 kg BW. Four pigs per dietary treatment and genotype were slaughtered at approximately 50 and 115 kg BW. The gastrointestinal tract and the rest of the visceral organs were weighed and samples of the small intestine were taken to carry out histological and histometrical studies. Daily gain and gain-to-feed ratio were higher in LD than in IB pigs during the fattening and growing-fattening periods (P < 0.01). N TTAD was significantly higher for LD pigs at 30 kg BW (P < 0.05), whereas at 80 kg BW we observed greater values for digestibility of organic matter and energy in IB pigs (averaging 1.5%, P < 0.01). Both N retention (NR) and efficiency of NR were increased in LD pigs at 30 and 80 kg BW (30% as mean value). The proportional weight of the small intestine was greater in LD than in IB pigs at 50 and 115 kg BW. Histometry showed that IB presented a lower muscle layer thickness than LD pigs in ileum, irrespective of the BW (P < 0.05). In contrast, LD pigs showed approximately 10% higher ileal villi length and villi-to crypt ratio than IB pigs at 115 kg BW. CP supply affected to a larger extent the small intestinal micro-anatomical structure of LD pigs at 50 kg BW. In conclusion, our results suggests that although the higher growth rate, NR and efficiency of NR observed in LD pigs might be associated with presumably more efficient structural aspects of the small intestine, the main differences between the two genotypes should be attributed to a larger extent to protein and energy utilization in tissues with consequences for the overall efficiency of energy use. PMID- 22439952 TI - Growth performance, digestibility and faecal coliform bacteria in weaned piglets fed a cereal-based diet including either chicory (Cichorium intybus L) or ribwort (Plantago lanceolata L) forage. AB - Twenty-five weaned 35-day-old piglets were used in a 35-day growth experiment to evaluate the effect of inclusion of chicory and ribwort forage in a cereal-based diet on growth performance, feed intake, digestibility and shedding of faecal coliform bacteria. A total of seven experimental diets were formulated, a cereal based basal diet (B), and six diets with inclusion of 40, 80 and 160 g/kg chicory (C40, C80 and C160) or ribwort (R40, R80 and R160). Piglets had ad libitum access to feed and water throughout the experiment. Three and five weeks post-weaning faeces samples for determination of digestibility were collected once a day for five subsequent days. Additional faeces samples for determination of coliform counts were collected at days 1, 16 and 35 post-weaning. Piglets fed diet R160 had the lowest average daily feed intake (DFI) and daily weight gain (DWG), and differed (P < 0.05) from piglets fed diets B, R40 and R80. There were no differences in DFI and DWG between the chicory diets and diet B. Inclusion of chicory or ribwort had a minor negative impact on the coefficient of total tract apparent digestibility (CTTAD) of dry matter, organic matter and crude protein, whereas inclusion of both chicory and ribwort resulted in higher CTTAD of non starch polysaccharides and neutral detergent fibre (NDF). The CTTAD of arabinose were higher for diets C160 and R160 than for diet B (P < 0.05), and the CTTAD of uronic acid was higher for diets C40, C80, C160, R80 and R160 than for diet B (P < 0.05). Age affected the CTTAD for all parameters (P < 0.05) except for NDF, with higher values at 5 than at 3 weeks post-weaning. The coliform counts decreased with increasing age (P < 0.05), but was not affected by treatment. The results indicate that inclusion of up to 160 g/kg of chicory do not negatively affect performance, whereas high inclusion of ribwort have a negative impact on feed consumption and consequently on growth rate. Both herbs have a higher digestibility of fibre compared to cereal fibre. Chicory and ribwort are both promising as feedstuffs to weaned piglets, but the low palatability of ribwort limits the inclusion level. PMID- 22439953 TI - Activation of protein kinase C suppresses fragmentation of pig oocytes aged in vitro. AB - When cultured for an extended time, pig oocytes that matured in vitro to the stage of metaphase II undergo the complex process designated as ageing. Under our conditions, some pig oocytes aged 3 days remained at the stage of metaphase II (22%), but others underwent spontaneous parthenogenetic activation (45%), and still others perished through fragmentation (28%) or lysis (5%). Activation of protein kinases C (PKCs) using phorbol-12-myristate-13-acetate (PMA) protects oocytes from fragmentation. None of the oocytes were fragmented after 3 days of aging in 50 nM of PMA. A similar effect (8% of fragmented oocytes) was observed after a 3-day treatment of aging oocytes with 100 MUM of 1-stearoyl-2arachidonoyl sn-glycerol (STEAR). PMA and STEAR activate both calcium-dependent and calcium independent PKCs. This combined effect on PKCs seems to be essential for the protection of oocytes from fragmentation. Neither the specific activator of calcium-dependent PKCs 1-oleoyl-2-acetyl-sn-glycerol (OLE) nor the specific activator of calcium-independent PKCs dipalmitoyl-l-alpha-phosphatidylinositol 3,4,5-triphosphate heptaammonium salt (DIPALM) suppressed the fragmentation of aging pig oocytes. Twenty-one percentage of oocytes fragmented when aged for 3 days in 10 MUM OLE and 26% of aged oocytes fragmented in 100 nM of DIPALM. However, fragmentation was significantly suppressed to 7% when the oocytes were exposed to the combination of both 10 MUM OLE and 100 nM DIPALM. Aging pig oocytes cultured for 1 day with PMA maintained a high capability of being parthenogenetically activated (86% of activated oocytes), using calcium ionophore with 6-dimethylaminopurine. Ageing oocytes treated with PMA also had high capability of cleavage (82%) after their artificial parthenogenetic activation. However, their ability to develop to the stage of blastocyst (12%) was suppressed when compared with oocytes activated immediately after their maturation (29%). PMID- 22439954 TI - Use of milk epithelial cells to study regulation of cell activity and apoptosis during once-daily milking in goats. AB - Generally, once-daily milking (ODM) decreases milk yield. This effect may be the consequence of a decrease in mammary epithelial cell (MEC) activity or a reduction in their number. The aim of this study was to determine the effect of ODM on the synthetic activity and rate of apoptosis of MEC using a non-invasive method. Eight Alpine goats were subjected to ODM or twice-daily milking for two 5 week periods. MECs were purified by centrifugation and immunocytochemical binding in milk after 1 and 5 weeks of each period. mRNA levels of some proteins involved in lactose and milk protein synthesis and in apoptosis were evaluated using real time PCR. Isolation of MEC from milk was a useful method to investigate transcriptional regulation in a timeline study. ODM induced greater decreases in milk, lactose and protein yields after 1 week than after 5 weeks. This suggests an adaptation of the mammary gland to ODM, which reduces the inhibitory effect of this practice. Reductions in milk component yields were associated with lower alpha-lactalbumin transcripts, suggesting a transcriptional decrease of lactose synthesis during ODM. Glucose transporter GLUT1 transcripts were downregulated under ODM, suggesting that lactose precursor uptake by MEC might be involved in the regulation of lactose synthesis. kappa-Casein mRNA levels tended to be lower during ODM. ODM increased levels of the pro-apoptotic transcript Bax after both 1 and 5 weeks, but no variation was observed in the Bax/Bcl-2 ratio. ODM affected cell synthetic activity through transcriptional regulation and may have induced apoptosis. The reduction of the negative effect of ODM on milk yield suggests that Alpine goats are able to adapt to ODM. Further studies are needed to investigate the effect of ODM on MEC turnover. PMID- 22439955 TI - Alternative farrowing systems: design criteria for farrowing systems based on the biological needs of sows and piglets. AB - The construction of a suitable farrowing environment is a continuing dilemma: the piglet's needs must be matched with those of the sow and the farmer during the main phases that constitute farrowing: nest building, parturition and lactation. Difficulties exist in resolving the various conflicts of interest between and within these three parties (e.g. sow v. farmer: space needed for nest building v. space needed to maximise the amount of farrowing accommodation, or sow v. sow: ensuring the survival of the current litter v. maintaining condition for future litters). Thus, the challenge is to resolve these conflicts and design a system that maximises sow and piglet welfare while maintaining an economically efficient and sustainable enterprise. In order to successfully design a farrowing and lactation environment, it is necessary to consider the biological needs of both the sow and her litter. The natural behaviour of the sow has been well documented and very little variation exists between reports of peri-parturient behaviour observed in extensively kept domestic sows and their wild counterparts. The failure for domestication to significantly alter these behavioural patterns provides evidence that they are biologically significant and that the commercial farrowing environment should attempt to accommodate this behavioural repertoire. In addition, the behavioural needs of the piglets, as well as the physiological needs of both sows and their offspring should be considered. This article aims to review the considerable body of literature detailing the behavioural repertoire of sows and their offspring during the different phases of farrowing, and the accompanying physiological processes. The focus is on identifying biological needs of the animals involved in order to synthesise the appropriate design criteria for farrowing and lactation systems, which should optimise both welfare and animal production. PMID- 22439956 TI - Individual piglets' contribution to the development of tail biting. AB - Conflicting hypotheses exist about the contribution of individual pigs to the development of a tail-biting outbreak, but there is limited quantitative information to support or dismiss them. This study aims to quantify the development of tail-biting behaviour at pen and individual piglet level, before and after the first visible tail damage. Video recordings of 14 pens with tail biting outbreaks and individually marked weaned piglets were used to observe tail biting incidents (TBIs; piglet biting a penmate's tail). When visible tail damage was first observed in a pen (i.e. day of tail biting outbreak; D0), the video recordings of the previous 6 (till D-6) and the following 6 days (till D6) were analysed every other day for TBIs and the identities of the biter and bitten piglet were recorded. The average TBIs per individual piglet (within each pen) per observation day were analysed to quantify the development of tail-biting behaviour and to identify pronounced biters and/or bitten piglets. The (absence of) coherence for TBIs in a pen was used to test whether biters preferred a specific penmate. There was an exponential increase in the intensity (linear on log scale) of the TBIs from an average of 0.7 bites/h at D-6 to 2.3 bites/h at D6. An additional negative quadratic component suggests that a plateau for tail biting behaviour was reached by the end of the observation period. Before any visible tail damage was observed (i.e. before D0), 82% of the piglets performed and 96% of them received tail bites. After D0, the figures were 99% and 100%, respectively. One or a few pronounced biters could be identified in almost all pens. These biters already showed more tail biting at D-6 than their penmates. Furthermore, these biters showed a greater increase in tail-biting behaviour during the observation period than the average scores of their penmates. In contrast, there was no apparent increase in the receipt of bites among the piglets that had already been bitten more than their penmates at D-6. Finally, there was no significant coherence between biters and bitten piglets, indicating that biters showed no preference for biting particular penmates, even when some of them had a damaged tail. These results show that, by using observations of TBIs, possible biters or bitten piglets can already be identified 6 days before tail damage is first apparent in a pen. PMID- 22439957 TI - Maternal behaviour and peripartum levels of oestradiol and progesterone show little difference in Merino ewes selected for calm or nervous temperament under indoor housing conditions. AB - Temperament influences the expression of maternal behaviour in sheep under experimental field conditions. We investigated whether maternal behaviour between ewes selected for a calm or nervous temperament is independent from environmental conditions. In addition, the level of maternal behaviour expressed by mothers is correlated with the concentration of hormones during the peripartum period. Therefore, we investigated whether the selection for temperament had resulted in hormonal differences between the two lines with regard to the hormones that could be involved in the onset of maternal behaviour. Oestradiol, progesterone and cortisol concentrations from 4 days before parturition to 24 h after parturition were determined from blood samples collected from 10 calm and 12 nervous ewes. Behavioural interactions between ewe and lamb were also recorded for 2 h starting at parturition. Mothers of both temperament lines showed adequate maternal behaviour under the controlled conditions of the study. Therefore, the results of the study do not suggest that selection for a calm or nervous temperament has profoundly affected the intrinsic ability of mothers to display adequate maternal behaviour. Hormonal differences between the two temperament lines were generally small and their possible influence on the display of maternal behaviour in the two temperament lines would have to be demonstrated. PMID- 22439958 TI - Breeding replacement gilts for organic pig herds. AB - In this study, breeding structures and commercial sow lines were evaluated by economic and genetic simulation studies for their suitability to provide the Dutch organic pig sector with replacement gilts. Sow and litter performance from over 2000 crossbred sows from 2006 to 2007 were collected on 11 to 14 Dutch organic pig herds, respectively, and compared with conventional herds. Results showed that organic herds had lower farrowing rates (3.6% to 7.5%), more live born piglets per litter (0.4% to 1.2%) and higher preweaning mortality rates (7% to 13%) compared to conventional herds. These results were used to simulate economic performance of various combinations of breeding structures and sow lines under organic conditions, under the assumption of absence of genotype-environment interactions. Sow and litter performance data under organic conditions (total piglets born/litter, stillborn piglets/litter, mortality until weaning, lactation length, interval weaning-oestrus and sow culling rate) and the costprice calculation for the Dutch organic pig sector were used as input for the economic simulation studies. The expected genetic progress was simulated for three potential breeding structures of the organic sector: organic breeding herds producing F1 gilts (OrgBS), a flower breeding system (FlowerBS) and a two-line rotation breeding system (RotBS). In FlowerBS, an organic purebred sow line is bred, using on-farm gilt replacement. The OrgBS with a Yorkshire * Landrace cross had the highest margin per sow place (?779), followed by RotBS with Yorkshire * Landrace cross (?706) and FlowerBS with Yorkshire sow line (?677). In case that an organic purebred sow population of 5000 sows would be available, FlowerBS gave the highest genetic progress in terms of cost price reduction (?3.72/slaughter pig per generation), followed by RotBS and OrgBS (?3.60/slaughter pig per generation). For FlowerBS, additional costs will be involved for maintaining a dedicated breeding programme. In conclusion, OrgBS using conventional genetics is economically the most viable option for the organic pig sector. However, this structure has clear disadvantages in terms of risks with regard to disease transmission and market demand. FlowerBS using a dedicated purebred organic line will only be cost-effective if sow population size is sufficiently large. RotBS might be a viable alternative, especially in combination with artificial insemination (AI) boars that are ranked according to an organic selection index. Regardless of breeding structure, the Yorkshire sow line gave the highest prolificacy and the highest economic returns on organic herds. PMID- 22439959 TI - Effect of biofuel co-products in pig diets on the excretory patterns of N and C and on the subsequent ammonia and methane emissions from pig effluent. AB - This study was conducted to investigate the effects of incorporation into pig diets of 20% of different co-products from the biofuel industries, which are rich in fibre, on animal growth performance, on nitrogen (N) and carbon (C) excretions, and on the subsequent ammonia volatilisation and methane production during the storage of slurry. Five experimental diets mainly based on wheat and soyabean meal were formulated: two control diets, a control high-protein (CHP) diet with 17.5% of crude protein (CP) and a control low-protein (CLP) diet with 14.0% of CP and three experimental diets with 20% of (i) dried distiller's grain with solubles (DDGS), (ii) sugar beet pulp (SBP) or (iii) fatty rapeseed meal (FRM). The animals used (20 castrated males) were housed individually in metabolism cages and fed one of the five diets (i.e. four pigs per diet). Urine and faeces were collected separately from each pig in order to measure nutrient digestibility and the excretory patterns of N and C. For each diet, ammonia volatilisation was measured from samples of slurry subsequently produced, over a 16-day storage period in a laboratory pilot scale system. The ultimate methane potential (B0, expressed in litres CH4/kg organic matter (OM)) was measured from the same slurry, for each diet, in anaerobic storage conditions over 100 days. The addition of sources of fibres to the diet decreased (P < 0.05) the animal growth performance by 13% and increased (P < 0.05) the amount of faeces excreted by 100%, whereas the amount of urine was not affected. For the high-fibre diets, there was a shift of N partitioning from urine to faeces, resulting in a much higher faecal N excretion (10 v. 5 g N/pig per day). Concurrently, the fibre enrichment in diets significantly increased (P < 0.05) the C content of the faeces by 68%. Ammonia emission from slurry was significantly reduced (P < 0.05) by 19% to 33% for the high-fibre diets, compared to the CHP diet. Ammonia emission was also reduced (P < 0.05) by 33% for the CLP compared to the CHP diet. B0 values ranged from 428 to 484 l CH4/kg OM. When these are expressed per pig and per day, the B0 from slurry was, on average, 70 l for the two control diets, and 121, 91 and 130 l for the slurry originating from the DDGS, SBP and FRM diets, respectively. PMID- 22439960 TI - Which preventive measures against mastitis can increase the technical efficiency of dairy farms? AB - The aim of this paper was to explore if, and in that case how, various preventive measures against mastitis influenced the whole-farm economic outcome, measured as technical efficiency, of a sample of specialised dairy farms in Sweden. In particular, the paper aimed at analysing whether a change to preventive measures applied by fully efficient farms would be a way for inefficient farms to become fully efficient. First, technical efficiency was assessed for each farm in the sample based on farm-level accounting data and the data envelopment analysis. In a second step, the effects of preventive measures against mastitis (collected through a mail questionnaire) on technical efficiency were assessed with logistic regression. Keeping cows in a loose-housing barn, stimulating udders manually during milking, and having cows standing on clean bedding during milking were found to significantly increase the probability of a farm being fully efficient. Once the farmer considers the somatic cell count (SCC) to be too high, undertaking measures such as contacting a veterinarian, checking overall hygiene routines, and culling cows with high SCC were found to significantly increase the probability of a farm being fully efficient. Thus, these measures may be plausible targets for advisory services aimed at assisting farmers to become fully efficient, especially if they are confirmed in future studies. Several common preventive measures against mastitis, that is, choice of bedding material, frequency of cleaning stalls, pre-milking, post-milking teat disinfection, applying a milking order based on the SCC of cows, and milking high-SCC cows with a separate cluster, were found to have no statistically significant effect on farm economic outcome. However, these measures may still be valuable for non economic goals, such as increased animal welfare, and the results imply that they can be implemented without negative impact on the economic performance of the farm. PMID- 22439961 TI - Traceability of grass feeding in beef: terpenes, 2,3-octanedione and skatole accumulation in adipose tissue of young bulls. AB - The development of analytical methods to verify the production system of meat products requires the identification of biomarkers that can trace the product's origin, and secondly the factors that govern the deposition of these markers in animal tissue need to be defined. In this study, 2,3-octanedione, skatole and terpenes were selected as biomarkers, and their deposition was investigated in bull calves reared under three different strategies. All of the animals were reared indoors until approximately 150 days of age. They were suckled twice a day by their mothers, and both calves and cows had free access to cocksfoot hay. Then the first two groups of animals were kept indoors, suckled by their mothers twice a day and received either cocksfoot hay (HL) or freshly cut-green herbage (GL) and a limited quantity of concentrate. The third group of calves (PH) was kept on pasture with their mothers and offered concentrate ad libitum. The pasture supporting the PH animals was highly diversified, containing several terpene-rich plant species, whereas the herbage for the GL animals contained no species known to be aromatic. Perirenal and subcutaneous adipose tissues were analysed for volatile compounds. The perirenal fat was found to be more responsive to the treatment and a more reliable substrate than the subcutaneous adipose tissue. Higher levels of 2,3-octanedione (P < 0.05) were found in PH and GL than in HL fat (6.56, 6.51 and 5.77 area arbitrary units, respectively, in perirenal fat), confirming the ability of this molecule to trace green herbage feeding. Skatole was detected in the perirenal and subcutaneous fat of all the animals. Animals receiving high concentrate level (PH group) presented lower (P < 0.05) skatole values (5.83 area arbitrary units in perirenal fat) than animals receiving low concentrate level (HL and GL groups, 6.23 and 6.71 area arbitrary units, respectively, in perirenal fat). Terpenoids, and especially sesquiterpenes, were found at higher levels and diversities in the PH than in the GL and HL animals. Two monoterpenoids allowed group discrimination considering perirenal or subcutaneous fat without distinction, whereas 11 and 5 sesquiterpenoids from perirenal and subcutaneous fat, respectively, allowed it. PMID- 22439962 TI - Further development of a tissue engineered muscle repair construct in vitro for enhanced functional recovery following implantation in vivo in a murine model of volumetric muscle loss injury. AB - Volumetric muscle loss (VML) can result from trauma and surgery in civilian and military populations, resulting in irrecoverable functional and cosmetic deficits that cannot be effectively treated with current therapies. Previous work evaluated a bioreactor-based tissue engineering approach in which muscle derived cells (MDCs) were seeded onto bladder acellular matrices (BAM) and mechanically preconditioned. This first generation tissue engineered muscle repair (TEMR) construct exhibited a largely differentiated cellular morphology consisting primarily of myotubes, and moreover, significantly improved functional recovery within 2 months of implantation in a murine latissimus dorsi (LD) muscle with a surgically created VML injury. The present report extends these initial observations to further document the importance of the cellular phenotype and composition of the TEMR construct in vitro to the functional recovery observed following implantation in vivo. To this end, three distinct TEMR constructs were created by seeding MDCs onto BAM as follows: (1) a short-term cellular proliferation of MDCs to generate primarily myoblasts without bioreactor preconditioning (TEMR-1SP), (2) a prolonged cellular differentiation and maturation period that included bioreactor preconditioning (TEMR-1SPD; identical to the first generation TEMR construct), and (3) similar treatment as TEMR-1SPD but with a second application of MDCs during bioreactor preconditioning (TEMR 2SPD); simulating aspects of "exercise" in vitro. Assessment of maximal tetanic force generation on retrieved LD muscles in vitro revealed that TEMR-1SP and TEMR 1SPD constructs promoted either an accelerated (i.e., 1 month) or a prolonged (i.e., 2 month postinjury) functional recovery, respectively, of similar magnitude. Meanwhile, TEMR-2SPD constructs promoted both an accelerated and prolonged functional recovery, resulting in twice the magnitude of functional recovery of either TEMR-1SP or TEMR-1SPD constructs. Histological and molecular analyses indicated that TEMR constructs mediated functional recovery via regeneration of functional muscle fibers either at the interface of the construct and the native tissue or within the BAM scaffolding independent of the native tissue. Taken together these findings are encouraging for the further development and clinical application of TEMR constructs as a VML injury treatment. PMID- 22439963 TI - Synthesis and antifungal activity of novel sclerotiorin analogues. AB - Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a1, 3d2, 3e2, 3f2 and 3k2) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity. PMID- 22439964 TI - Direct in situ observation of nanoparticle synthesis in a liquid crystal surfactant template. AB - Controlled and reproducible synthesis of tailored materials is essential in many fields of nanoscience. In order to control synthesis, there must be a fundamental understanding of nanostructure evolution on the length scale of its features. Growth mechanisms are usually inferred from methods such as (scanning) transmission electron microscopy ((S)TEM), where nanostructures are characterized after growth is complete. Such post mortem analysis techniques cannot provide the information essential to optimize the synthesis process, because they cannot measure nanostructure development as it proceeds in real time. This is especially true in the complex rheological fluids used in preparation of nanoporous materials. Here we show direct in situ observations of synthesis in a highly viscous lyotropic liquid crystal template on the nanoscale using a fluid stage in the STEM. The nanoparticles nucleate and grow to ~5 nm particles, at which point growth continues through the formation of connections with other nanoparticles around the micelles to form clusters. Upon reaching a critical size (>10-15 nm), the clusters become highly mobile in the template, displacing and trapping micelles within the growing structure to form spherical, porous nanoparticles. The final products match those synthesized in the lab ex situ. This ability to directly observe synthesis on the nanoscale in rheological fluids, such as concentrated aqueous surfactants, provides an unprecedented understanding of the fundamental steps of nanomaterial synthesis. This in turn allows for the synthesis of next-generation materials that can strongly impact important technologies such as organic photovoltaics, energy storage devices, catalysis, and biomedical devices. PMID- 22439965 TI - Two-layer tissue engineered urethra using oral epithelial and muscle derived cells. AB - PURPOSE: We fabricated novel tissue engineered urethral grafts using autologously harvested oral cells. We report their viability in a canine model. MATERIALS AND METHODS: Oral tissues were harvested by punch biopsy and divided into mucosal and muscle sections. Epithelial cells from mucosal sections were cultured as epithelial cell sheets. Simultaneously muscle derived cells were seeded on collagen mesh matrices to form muscle cell sheets. At 2 weeks the sheets were joined and tubularized to form 2-layer tissue engineered urethras, which were autologously grafted to surgically induced urethral defects in 10 dogs in the experimental group. Tissue engineered grafts were not applied to the induced urethral defect in control dogs. The dogs were followed 12 weeks postoperatively. Urethrogram and histological examination were done to evaluate the grafting outcome. RESULTS: We successfully fabricated 2-layer tissue engineered urethras in vitro and transplanted them in dogs in the experimental group. The 12-week complication-free rate was significantly higher in the experimental group than in controls. Urethrogram confirmed urethral patency without stricture in the complication-free group at 12 weeks. Histologically urethras in the transplant group showed a stratified epithelial layer overlying well differentiated submucosa. In contrast, urethras in controls showed severe fibrosis without epithelial layer formation. CONCLUSIONS: Two-layer tissue engineered urethras were engineered using cells harvested by minimally invasive oral punch biopsy. Results suggest that this technique can encourage regeneration of a functional urethra. PMID- 22439966 TI - Individual and social determinants of multiple chronic disease behavioral risk factors among youth. AB - BACKGROUND: Behavioral risk factors are known to co-occur among youth, and to increase risks of chronic diseases morbidity and mortality later in life. However, little is known about determinants of multiple chronic disease behavioral risk factors, particularly among youth. Previous studies have been cross-sectional and carried out without a sound theoretical framework. METHODS: Using longitudinal data (n = 1135) from Cycle 4 (2000-2001), Cycle 5 (2002-2003) and Cycle 6 (2004-2005) of the National Longitudinal Survey of Children and Youth, a nationally representative sample of Canadian children who are followed biennially, the present study examines the influence of a set of conceptually related individual/social distal variables (variables situated at an intermediate distance from behaviors), and individual/social ultimate variables (variables situated at an utmost distance from behaviors) on the rate of occurrence of multiple behavioral risk factors (physical inactivity, sedentary behavior, tobacco smoking, alcohol drinking, and high body mass index) in a sample of children aged 10-11 years at baseline. Multiple behavioral risk factors were assessed using a multiple risk factor score. All statistical analyses were performed using SAS, version 9.1, and SUDAAN, version 9.01. RESULTS: Multivariate longitudinal Poisson models showed that social distal variables including parental/peer smoking and peer drinking (Log-likelihood ratio (LLR) = 187.86, degrees of freedom (DF) = 8, p < .001), as well as individual distal variables including low self-esteem (LLR = 76.94, DF = 4, p < .001) increased the rate of occurrence of multiple behavioral risk factors. Individual ultimate variables including age, sex, and anxiety (LLR = 9.34, DF = 3, p < .05), as well as social ultimate variables including family socioeconomic status, and family structure (LLR = 10.93, DF = 5, p = .05) contributed minimally to the rate of co-occurrence of behavioral risk factors. CONCLUSIONS: The results suggest targeting individual/social distal variables in prevention programs of multiple chronic disease behavioral risk factors among youth. PMID- 22439967 TI - Quantum light signatures and nanosecond spectral diffusion from cavity-embedded carbon nanotubes. AB - Single-walled carbon nanotubes (SWCNTs) are considered for novel optoelectronic and quantum photonic devices, such as single photon sources, but methods must be developed to enhance the light extraction and spectral purity, while simultaneously preventing multiphoton emission as well as spectral diffusion and blinking in dielectric environments of a cavity. Here we demonstrate that utilization of nonpolar polystyrene as a cavity dielectric completely removes spectral diffusion and blinking in individual SWCNTs on the millisecond to multisecond time scale, despite the presence of surfactants. With these cavity embedded SWCNT samples, providing a 50-fold enhanced exciton emission into the far field, we have been able to carry out photophysical studies for the first time with nanosecond timing resolution. We uncovered that fast spectral diffusion processes (1-3 ns) remain that make significant contributions to the spectral purity, thereby limiting the use of SWCNTs in quantum optical applications requiring indistinguishable photons. Measured quantum light signatures reveal pronounced photon antibunching (g(2)(0) = 0.15) accompanied by side-peak bunching signatures indicative of residual blinking on the submicrosecond time scale. The demonstrated enhanced single photon emission from cavity-embedded SWCNTs is promising for applications in quantum key distribution, while the demonstrated passivation effect of polystyrene with respect to the stability of the optical emission opens a novel pathway toward optoelectronic devices with enhanced performance. PMID- 22439968 TI - Mass spectrometry-based proteomics and network biology. AB - In the life sciences, a new paradigm is emerging that places networks of interacting molecules between genotype and phenotype. These networks are dynamically modulated by a multitude of factors, and the properties emerging from the network as a whole determine observable phenotypes. This paradigm is usually referred to as systems biology, network biology, or integrative biology. Mass spectrometry (MS)-based proteomics is a central life science technology that has realized great progress toward the identification, quantification, and characterization of the proteins that constitute a proteome. Here, we review how MS-based proteomics has been applied to network biology to identify the nodes and edges of biological networks, to detect and quantify perturbation-induced network changes, and to correlate dynamic network rewiring with the cellular phenotype. We discuss future directions for MS-based proteomics within the network biology paradigm. PMID- 22439969 TI - Management and outcome of acute coronary syndrome patients in relation to prior history of atrial fibrillation. AB - BACKGROUND: The prognostic impact of atrial fibrillation (AF) in the setting of acute coronary syndrome (ACS) is controversial. Furthermore, there are limited real-world data on the management of ACS patients with history of AF. METHODS: The Global Registry of Acute Coronary Events (GRACE/GRACE2) and Canadian Registry of Acute Coronary Events (CANRACE) enrolled 14,285 patients across Canada between 1999 and 2008. Patients were stratified by the presence of history of AF. We compared clinical characteristics, medical therapies, cardiac procedures, and clinical outcomes between the 2 groups. RESULTS: Overall, 1333 of the enrolled patients (9.3%) had history of AF, of whom 51.5% presented with non-ST-segment elevation myocardial infarction, 29.5% with unstable angina, and 19.1% with ST segment elevation myocardial infarction. Compared with the group without, patients with a history of AF less frequently received evidence-based antiplatelet and antithrombin therapies, left ventricle ejection fraction assessment, and coronary angiography (all P < 0.001); they also had higher unadjusted rates of in-hospital death, myocardial (re)infarction, and heart failure. However, in multivariable analysis, history of AF was not found to be independently associated with in-hospital mortality (adjusted odds ratio [OR] = 1.12; 95% confidence interval (CI), 0.73-1.73; P = 0.61) or death and/or myocardial reinfarction (adjusted OR = 1.15; 95% CI, 0.87-1.5; P = 0.34). CONCLUSIONS: History of AF is common among ACS patients. They received less evidence-based medical and invasive therapies than ACS patients without history of AF. History of AF is a negative independent predictor of in-hospital coronary angiography but was not found to be independently associated with adverse outcomes. PMID- 22439970 TI - Electrocatalytically active graphene-porphyrin MOF composite for oxygen reduction reaction. AB - Pyridine-functionalized graphene (reduced graphene oxide) can be used as a building block in the assembly of metal organic framework (MOF). By reacting the pyridine-functionalized graphene with iron-porphyrin, a graphene-metalloporphyrin MOF with enhanced catalytic activity for oxygen reduction reactions (ORR) is synthesized. The structure and electrochemical property of the hybrid MOF are investigated as a function of the weight percentage of the functionalized graphene added to the iron-porphyrin framework. The results show that the addition of pyridine-functionalized graphene changes the crystallization process of iron-porphyrin in the MOF, increases its porosity, and enhances the electrochemical charge transfer rate of iron-porphyrin. The graphene metalloporphyrin hybrid shows facile 4-electron ORR and can be used as a promising Pt-free cathode in alkaline Direct Methanol Fuel Cell. PMID- 22439971 TI - Preface: uranium mining legacy issue in Central Asia. PMID- 22439972 TI - Relative frequency of odontogenic tumors in Sri Lanka: Analysis of 1677 cases. AB - Odontogenic tumors (OTs) constitute a heterogeneous group of lesions with diverse histopathological features and clinical manifestations. The present study is to determine the frequency of odontogenic tumors (OTs) in Sri Lankan population. A total of 1677 cases of OTs were retrieved and analyzed for age, gender and primary site of the tumors. Cases were re-classified according to the 2005 WHO classification of OTs. The relative frequency of different types of tumors was also analyzed and compared with the literature. OTs represent 3.75% of all cases received during a period of 30 years. Ninety-eight percent of these tumors were benign and the rest malignant. Mandible to maxilla ratio is 2.8:1. The posterior part, the molar region, is the most frequently affected site for the mandible whilst it is the anterior region for the maxilla. The age ranges from 1 to 80 years, with a mean age of 30.6 years. Ameloblastoma of solid/multicystic and unicystic types showed a high preponderance for the mandible (>90%) with a ratio of 12.9:1 and 10.8:1, respectively. Out of 1677 cases, 48.7% were ameloblastoma, and other tumors, such as keratocystic odontogenic tumor (KCOT) and odontoma, were 25.7% and 10.1%, respectively. There is a significant change in the frequency of OTs after the inclusion of odontogenic keratocyst as a tumor. Although odontoma is said to be the commonest in western countries, our results showed ameloblastoma as the commonest followed by KCOT, and the relative frequencies of different tumors have changed significantly as a result of inclusion of KCOT in the new classification. PMID- 22439973 TI - Thermoresponsive self-assemblies of cyclic and branched oligosaccharide-block poly(N-isopropylacrylamide) diblock copolymers into nanoparticles. AB - This paper discusses the thermoresponsive nanoparticles obtained by self assemblies of nonlinear oligosaccharide-based diblock copolymer systems. These diblock copolymers were synthesized by Cu(I)-catalyzed 1,3-dipolar azide/alkyne cycloaddition ("click" reaction) of propargyl-functionalized beta-cyclodextrin (betaCyD) and xyloglucooligosaccharide (XGO) with poly(N-isopropylacrylamide) (PNIPAM) having a terminal azido group prepared by atom transfer radical polymerization (ATRP). Elastic and quasi-elastic light scattering analysis of the dibock copolymers in H(2)O indicated that thermodynamic phase transitions of the PNIPAM blocks at their cloud points (T(cp)s ~ 34 degrees C), around lower critical solution temperatures (LCSTs), triggered their self-assemblies into the nanoparticles. These nanoparticles had narrow size distributions and small interphases (i.e., sharp boundaries). The mean hydrodynamic radii (R(h)s) of the betaCyD and XGO-based nanoparticles were determined to be around 150 and 250 nm upon slow heating (i.e., step-by-step heating), and 364 and 91.5 nm upon fast heating, respectively, depending on a predominance of the interchain association or the intrachain contraction. Transmission electron microscope (TEM) and field emission gun-scanning electron microscopy (FEG-SEM) images of the nanoparticles clearly showed compact spherical nanoparticles whose cores are mainly made with the PNIPAM blocks, whereas the rough shells consist in the oligosaccharidic blocks. PMID- 22439974 TI - Design and synthesis of pyrrolo[3,2-d]pyrimidine human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors: exploration of novel back-pocket binders. AB - To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC(50), 0.98/2.5 nM; and GI activity BT-474 cells, GI(50), 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg. PMID- 22439975 TI - Enhanced antimalarial activity of lumefantrine nanopowder prepared by wet-milling DYNO MILL technique. AB - Lumefantrine (LMF) is an antimalarial drug that exhibits poor oral bioavailability, owing to its poor aqueous solubility. To improve its antimalarial activity, nanopowder formulation using DYNO MILL was prepared. Combination of HPMC E3 (4%, w/v) and Tween 80 (2.5%, w/v) as dispersing agents, favored the production of smaller LMF particles with mean size of 0.251 MUm. LMF nanopowder showed enhanced dissolution rate attributed to nanonization of LMF. The IC(50) value of nano-sized LMF was found to be 0.1 ng/mL, which was 175-times lower than the IC(50) value of unmilled LMF powder (17.5 ng/mL) and 42-times lower than the IC(50) value of chloroquine (4.2 ng/mL). The in vivo antimalarial activity demonstrated an enhanced antimalarial potential of LMF nanopowder against P. Yoelii nigeriensis compared to unmilled drug. Wet-milling using DYNO MILL offers a highly effective approach to produce stable drug nanopowders. Furthermore, LMF nanopowder makes the Coartem therapy more effective. PMID- 22439976 TI - Relationship between quantity of IFNT estimated by IFN-stimulated gene expression in peripheral blood mononuclear cells and bovine embryonic mortality after AI or ET. AB - BACKGROUND: Interferon tau (IFNT), which is secreted into the uterine cavity during the maternal recognition period (MRP), is a key factor for establishment of pregnancy. The present study aims to clarify the relationship between the ability of a bovine conceptus to produce IFNT during the MRP and the conceptus's ability to establish pregnancy. METHODS: In the first experiment, IFNT (0, 500, or 1000 micrograms) was administered into the uterine horn ipsilateral to the CL 16 or 17 d after standing estrus, and mRNA levels of IFN-stimulated gene 15-kDa protein (ISG15) and Mx2 in peripheral blood mononuclear cells (PBMCs) were determined. In the second experiment, we investigated ISG15 mRNA expression in PBMCs during the MRP in cattle after either artificial insemination (AI) or embryo transfer (ET). RESULTS: Intrauterine administration of IFNT stimulated ISG15 and Mx2 gene expressions in PBMCs in cattle, and there was a positive correlation between the expressions of peripheral markers and the quantity of IFNT administered. In pregnant and normal interestrous interval (< 25 d) cattle (nIEI cattle), expression levels of the ISG15 gene showed similar patterns after AI and ET, and ISG15 mRNA expression was increased in pregnant cattle but unchanged in nIEI cattle. In contrast, ISG15 gene expression in extended interestrous interval (greater than or equal to 25 d) cattle (eIEI cattle) differed after ET compared with AI. In eIEI cattle after ET, ISG15 gene expression increased, such that the value on day 18 was intermediate between those of pregnant and nIEI cattle. In eIEI cattle after AI, ISG15 gene expression did not increase throughout the observation period. CONCLUSIONS: The results of the current study indicate that the quantity of conceptus-derived IFNT can be estimated by measuring ISG15 mRNA levels in PBMCs from cattle. Using this approach, we demonstrate that ISG15 gene expression during the MRP in eIEI cattle differed after ET compared with AI. In addition, the modest increase in ISG15 gene expression in eIEI cattle after ET suggests that late embryo losses were due to delayed or insufficient growth of the conceptus during the MRP in cattle. PMID- 22439977 TI - Identification of disulfide bonds in wheat gluten proteins by means of mass spectrometry/electron transfer dissociation. AB - Disulfide bonds within gluten proteins play a key role in the breadmaking performance of wheat flour. In the present study, disulfide bonds of wheat gluten proteins were identified by using a new liquid chromatography-mass spectrometry (LC-MS) technique with alternating electron transfer dissociation (ETD)/collision induced dissociation (CID). Wheat flour was partially hydrolyzed with thermolysin (pH 6.5, 37 degrees C, 16 h), and the digest was subjected to LC-MS with alternating ETD/CID fragmentation. Whereas CID provided peptide fragments with intact disulfide bonds, cleavage of disulfide bonds was preferred over peptide backbone fragmentations in ETD. The simultaneous observation of disulfide-linked and disulfide-cleaved peptide ions in the mass spectra not only provided distinct interpretation with high confidence but also simplified the conventional approach for determination of disulfide bonds, which often requires two separate experiments with and without chemical reduction. By application of the new method 14 cystine peptides were identified. Eight peptides confirmed previously established disulfide bonds within gluten proteins, and the other six cystine peptides were identified for the first time. One of the newly identified cystine peptides represented a "head-to-tail" cross-link between high molecular weight glutenin subunits. This type of cross-link, which has been postulated as an integral part of glutenin models published previously, has now been proven experimentally for the first time. From the six remaining cystine peptides interchain disulfide bonds between alpha-gliadins, gamma-gliadins, and low molecular weight glutenin subunits were established. PMID- 22439978 TI - Growth of ultrahigh density single-walled carbon nanotube forests by improved catalyst design. AB - We have grown vertically aligned single-walled carbon nanotube forests with an area density of 1.5 * 10(13) cm(-2), the highest yet achieved, by reducing the average diameter of the nanotubes. We use a nanolaminate Fe-Al(2)O(3) catalyst design consisting of three layers of Al(2)O(3), Fe, and Al(2)O(3), in which the lower Al(2)O(3) layer is densified by an oxygen plasma treatment to increase its diffusion barrier properties, to allow a thinner catalyst layer to be used. This high nanotube density is desirable for using carbon nanotubes as interconnects in integrated circuits. PMID- 22439979 TI - Motivational and cognitive inhibitory control in recreational cannabis users. AB - Substance use disorders have been associated with impaired decision making and increased impulsive behavior. Lack of inhibitory control may underlie such higher order cognitive difficulties and behavior problems. This study examined inhibitory control in 53 recreational cannabis users and 48 controls. Inhibitory control was tested with two computer tasks, one with a motivational component and one without such a component. Impulsive behavior was assessed using the Barratt Impulsiveness Scale. Results showed that the recreational cannabis users had poorer motivational inhibition (i.e., were more inclined to "gamble") than controls. There were no group differences in the cognitive inhibition task. Cannabis users also reported more impulsive behavior in daily life. This behavior was related to response style in the motivational inhibition task, but not to performance in the cognitive inhibition task. It is concluded that, among recreational cannabis users, lack of inhibitory control depends on contextual or situational factors-that is, it becomes evident only when situations or tasks involve a motivational component. PMID- 22439980 TI - Anterior cruciate ligament fixation: is radial force a predictor of the pullout strength of soft-tissue interference devices? AB - BACKGROUND: In anterior cruciate ligament (ACL) reconstruction, an interference device achieves soft-tissue graft fixation by radially compressing the graft against the bone. PURPOSE: The objective of this study was to measure the radial force generated by different interference devices and evaluate the effect of this radial force on the pullout strength of graft-device constructs. STUDY DESIGN: Controlled laboratory study. METHODS: A resultant force (F(R)) was used as a representative measure of the total radial force generated. Bovine tendons were fixated in either synthetic bone or porcine tibia using one of following devices: (1) RCI titanium screw, (2) PEEK screw, (3) IntraFix sheath-and-screw device, and (4) ExoShape sheath-and-insert device. F(R) was measured while each device was inserted into synthetic bone mounted on a test machine (n=5 for each device). In a subsequent test series, graft-device constructs were loaded to failure at 50mm/min. The pullout strength was measured as the ultimate load before failure (n=10 for each device). RESULTS: The F(R) values generated during insertion into synthetic bone were 777 +/- 86N, 865 +/- 140N, 1313 +/- 198N, and 1780 +/- 255N for the RCI screw, PEEK screw, IntraFix, and ExoShape, respectively. The pullout strengths in synthetic bone for the RCI screw, PEEK screw, IntraFix and ExoShape were 883 +/- 125N, 716 +/- 249N, 1147 +/- 142N, and 1233 +/- 190N, respectively. CONCLUSIONS: These results suggest that the F(R) generated during interference fixation affects the pullout strength with sheath-based devices providing superior F(R) compared with interference screws. The use of synthetic bone was validated by comparing the pullout strengths to those when tested in porcine tibia. CLINICAL RELEVANCE: These results could be valuable to a surgeon when determining the best fixation device to use in the clinical setting. PMID- 22439981 TI - Identification and pathogenicity analysis of a novel non-tuberculous mycobacterium clinical isolate with nine-antibiotic resistance. AB - With mycobacteriosis increasing, the study of non-tuberculous mycobacteria is imperative for clinical therapy and management. Non-tuberculous mycobacteria are naturally resistant to most anti-tuberculosis drugs. Accordingly, it is important to decipher the biology of the novel non-tuberculous mycobacteria through complete genomic analysis of novel pathogenic mycobacteria. We describe Mycobacterium sinense JDM601, a novel, slow-growing mycobacterium of the Mycobacterium terrae complex resistant to nine antibiotics, by clinical presentation, cultural and biochemical characteristics, minimal inhibitory concentrations, and genome-sequencing analysis. JDM601 is closest to Mycobacterium nonchromogenicum according to mycolic acid composition, but closest to Mycobacterium algericum sp. nov according to 16S rDNA. JDM601 is resistant to isoniazid, streptomycin, rifampin, euteropas, protionamide, capromycin, ciprofloxacin, amikacin and levofloxacin but not ethambutol. The clinical information, mycolic acid composition, and virulence genes indicate that JDM601 is an opportunistic pathogen. PMID- 22439982 TI - On summary measure analysis of linear trend repeated measures data: performance comparison with two competing methods. AB - BACKGROUND: The summary measure approach (SMA) is sometimes the only applicable tool for the analysis of repeated measurements in medical research, especially when the number of measurements is relatively large. This study aimed to describe techniques based on summary measures for the analysis of linear trend repeated measures data and then to compare performances of SMA, linear mixed model (LMM), and unstructured multivariate approach (UMA). METHODS: Practical guidelines based on the least squares regression slope and mean of response over time for each subject were provided to test time, group, and interaction effects. Through Monte Carlo simulation studies, the efficacy of SMA vs. LMM and traditional UMA, under different types of covariance structures, was illustrated. All the methods were also employed to analyze two real data examples. RESULTS: Based on the simulation and example results, it was found that the SMA completely dominated the traditional UMA and performed convincingly close to the best-fitting LMM in testing all the effects. However, the LMM was not often robust and led to non sensible results when the covariance structure for errors was misspecified. The results emphasized discarding the UMA which often yielded extremely conservative inferences as to such data. CONCLUSIONS: It was shown that summary measure is a simple, safe and powerful approach in which the loss of efficiency compared to the best-fitting LMM was generally negligible. The SMA is recommended as the first choice to reliably analyze the linear trend data with a moderate to large number of measurements and/or small to moderate sample sizes. PMID- 22439983 TI - Monitoring sinew contraction during formation of tissue-engineered fibrin-based ligament constructs. AB - The ability to study the gross morphological changes occurring during tissue formation is vital to producing tissue-engineered structures of clinically relevant dimensions in vitro. Here, we have used nondestructive methods of digital imaging and optical coherence tomography to monitor the early-stage formation and subsequent maturation of fibrin-based tissue-engineered ligament constructs. In addition, the effect of supplementation with essential promoters of collagen synthesis, ascorbic acid (AA) and proline (P), has been assessed. Contraction of the cell-seeded fibrin gel occurs unevenly within the first 5 days of culture around two fixed anchor points before forming a longitudinal ligament like construct. AA+P supplementation accelerates gel contraction in the maturation phase of development, producing ligament-like constructs with a higher collagen content and distinct morphology to that of unsupplemented constructs. These studies highlight the importance of being able to control the methods of tissue formation and maturation in vitro to enable the production of tissue engineered constructs with suitable replacement tissue characteristics for repair of clinical soft-tissue injuries. PMID- 22439984 TI - Orientation-dependent interfacial mobility governs the anisotropic swelling in lithiated silicon nanowires. AB - Recent independent experiments demonstrated that the lithiation-induced volume expansion in silicon nanowires, nanopillars, and microslabs is highly anisotropic, with predominant expansion along the <110> direction but negligibly small expansion along the <111> direction. The origin of such anisotropic behavior remains elusive. Here, we develop a chemomechanical model to study the phase evolution and morphological changes in lithiated silicon nanowires. The model couples the diffusive reaction of lithium with the lithiation-induced elasto-plastic deformation. We show that the apparent anisotropic swelling is critically controlled by the orientation-dependent mobility of the core-shell interface, i.e., the lithiation reaction rate at the atomically sharp phase boundary between the crystalline core and the amorphous shell. Our results also underscore the importance of structural relaxation by plastic flow behind the moving phase boundary, which is essential to quantitative prediction of the experimentally observed morphologies of lithiated silicon nanowires. The study sheds light on the lithiation-mediated failure in nanowire-based electrodes, and the modeling framework provides a basis for simulating the morphological evolution, stress generation, and fracture in high-capacity electrodes for the next-generation lithium-ion batteries. PMID- 22439985 TI - Sexual risk behaviors among youth heads of household in Gikongoro, south province of Rwanda. AB - BACKGROUND: As a result of the 1994 genocide and AIDS, Rwanda has a crisis of orphans. In 2005, the Ministry of Local Governance and Social Affairs of Rwanda has reported one million vulnerable children. Many of these are not only orphans but also youth heads of households (YHH). The purpose of this study was to: (a) identify risk behaviors that expose YHH to HIV infection, (b) determine gender specific high risk profiles and, (c) determine predictors of sexual onset. METHODS: A household survey was conducted among 692 YHH, aged 12-24, all beneficiaries of a World Vision basic needs program in Gikongoro, Rwanda, from January to March 2004. Participants were interviewed using a structured questionnaire. Data was collected on socio-demographic variables, HIV/AIDS prevention knowledge and sexual risk behaviors. Bivariate analyses of the study variables were performed to examine differences between males and females. A logistic regression analysis was conducted to analyze factors that were independently associated with the debut of having sex. RESULTS: Forty-one percent of respondents reported sexual onset before age 15. Males were more likely to start earlier than females (50.4% versus 26.7%) but females reported more sexual onset with an older partner. Fifty-eight percent of females had their first intercourse with a partner who was four or more years older than themselves. While sexual activity was low (1.75 mean lifetime sexual partner, 0.45 mean sexual partner last twelve months), sexual experience was related to less social connectedness and use of drugs. Having a close friend also appeared to be protective for sexual debut. The analysis also found that although YHH were aware of some prevention measures against HIV/AIDS, there was low (19.8%) knowledge of the "ABC" prevention program promoted by the government. In addition, despite 85% of respondents knowing someone who had died of AIDS, only 31% perceived themselves at risk of HIV infection, and there was very low (13.2%) condom use among the sexually experienced. CONCLUSIONS: Results suggest the urgent need of HIV prevention programs tailored to YHH that provide knowledge, enhance negotiations skills, and increase the perception of HIV infection risk among YHH in Rwanda. PMID- 22439986 TI - Arthroscopic management of C3 tibial plafond fractures: a technical guide. AB - Tibial plafond fractures are technically challenging and have the potential for serious complications. Minimizing soft tissue trauma can compromise visualization of articular reduction. There has been recent interest in the use of arthroscopy to improve visualization of plafond fractures while preserving the soft tissue envelope. Here the authors offer some technical points in order to simplify a technically demanding procedure. PMID- 22439987 TI - Breeding for robustness: the role of cortisol. AB - Robustness in farm animals was defined by Knap as 'the ability to combine a high production potential with resilience to stressors, allowing for unproblematic expression of a high production potential in a wide variety of environmental conditions'. The importance of robustness-related traits in breeding objectives is progressively increasing towards the production of animals with a high production level in a wide range of climatic conditions and production systems, together with a high level of animal welfare. Current strategies to increase robustness include selection for 'functional traits', such as skeletal and cardiovascular integrity, disease resistance and mortality in various stages. It is also possible to use global evaluation of sensitivity to the environment (e.g. reaction norm analysis or canalization), but these techniques are difficult to implement in practice. The hypothalamic-pituitary-adrenocortical (HPA) axis is the most important stress-responsive neuroendocrine system. Cortisol (or corticosterone) released by the adrenal cortices exerts a large range of effects on metabolism, the immune system, inflammatory processes and brain function, for example. Large individual variations have been described in the HPA axis activity with important physiopathological consequences. In terms of animal production, higher cortisol levels have negative effects on growth rate and feed efficiency and increase the fat/lean ratio of carcasses. On the contrary, cortisol has positive effects on traits related to robustness and adaptation. For instance, newborn survival was shown to be directly related to plasma cortisol levels at birth, resistance to bacteria and parasites are increased in animals selected for a higher HPA axis response to stress, and tolerance to heat stress is better in those animals that are able to mount a strong stress response. Intense selection for lean tissue growth during the last decades has concomitantly reduced cortisol production, which may be responsible for the negative effects of selection on piglet survival. One strategy to improve robustness is to select animals with higher HPA axis activity. Several sources of genetic polymorphism have been described in the HPA axis. Hormone production by the adrenal cortices under stimulation by adrenocorticotropin hormone is a major source of individual differences. Several candidate genes have been identified by genomic studies and are currently under investigation. Bioavailability of hormones as well as receptor and post-receptor mechanisms are also subject to individual variation. Integration of these different sources of genetic variability will allow the development of a model for marker-assisted selection to improve animal robustness without negative side effects on production traits. PMID- 22439988 TI - Myosin heavy chain pattern in the Akhal-Teke horses. AB - This study investigates the myosin heavy chain (MyHC) isoform composition in the gluteus medius muscle of the Akhal-Teke horses using SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis). Fifteen horses aged between 1.5 and 23.5 years were used in this study and divided into three age groups: 1.5 to 4 (n = 6), 9 to 13 (n = 5) and 18.5 to 23.5 years (n = 4). The average content of the MyHC I isoform was 11.72 +/- 1.07% (variation between individuals: 7.09% to 20.14%). The relative content of the MyHC IIa and IIx isoforms was subsequently 38.20 +/- 1.46% (30.73% to 48.78%) and 50.07 +/- 1.10% (43.8% to 56.78%) from the total MyHC. The MyHC pattern in the skeletal muscles of the Akhal-Teke horses shows that the muscles of these horses have a high capacity both for endurance and speed. PMID- 22439989 TI - A sensitised mutagenesis screen in the mouse to explore the bovine genome: study of muscle characteristics. AB - Meat yield and quality are closely related to muscle development. The muscle characteristics mainly take place during embryonic and postnatal phases. Thus, genetic control of muscle development in early stages represents a significant stake to improve product quality and production efficiency. In bovine, several programmes have been developed to detect quantitative trait loci (QTL) affecting growth, carcass composition or meat quality traits. Such strategy is incontestably very powerful yet extremely cumbersome and costly when dealing with large animals such as ruminants. Furthermore, the fine mapping of the QTL remains a real challenge. Here, we proposed an alternative approach based on chemical mutagenesis in the mouse combined with comparative genomics to identify regions or genes controlling muscle development in cattle. At present, we isolated seven independent mouse lines of high interest. Two lines exhibit a hypermuscular phenotype, and the other five show various skeletomuscular phenotypes. Detailed characterisation of these mouse mutants will give crucial input for the identification and the mapping of genes that control muscular development. Our strategy will provide the opportunity to understand the function and control of genes involved in improvement of animal physiology. PMID- 22439990 TI - Evidence for additional functional genetic variation within the porcine IGF2 gene affecting body composition traits in an experimental Pietrain * Large White/Landrace cross. AB - The aim of this study was to test for the existence of causative genetic variation affecting body composition traits within or adjacent to the porcine insulin-like growth factor 2 (IGF2) gene beyond the known IGF2-intron3-G3072A mutation. A focussed quantitative trait loci analysis using four microsatellite markers within the telomeric region of porcine chromosome 2p was conducted in a large resource population comprising 2741 F2 offspring. The analysis of two subsets of animals that were alternatively homozygous for the in3G3072A mutation provides evidence for additional genetic variation significantly contributing to the overall quantitative trait nucleotide variance within our population. PMID- 22439991 TI - Adaptations of hepatic amino acid uptake and net utilisation contributes to nitrogen economy or waste in lambs fed nitrogen- or energy-deficient diets. AB - We investigated the effect of relative changes in dietary nitrogen (N) and energy supply and the subsequent variations in net portal appearance (NPA) of nitrogenous and energy nutrients on the net amino acid (AA) uptake by the liver and net N supply to the peripheral tissues. Six lambs were catheterised across the splanchnic tissues and received, in a replicated Latin square, one of three dietary treatments. The diets were formulated to either match the requirements of N and energy (C), or supply only 0.8 of the N requirement (LN) or 0.8 of the energy requirement (LE). Net fluxes of AA and urea-N were measured across the portal-drained viscera, and estimation of arterial hepatic flow allowed the estimation of hepatic fluxes. Catheters were implanted into the portal and hepatic veins as well as in the abdominal aorta for the measurement of AA fluxes. Animals fed the LN diet showed more efficient N retention (0.59 of digested N) than did the C and LE diet (0.50 and 0.33, respectively; P < 0.001). The NPA of total AA-N for the LN diet was only 0.60 of the value measured for the control (C) diet (P < 0.01). Despite this, the total estimated AA-N net splanchnic fluxes were not significantly different across the three diets (3.3, 1.9 and 2.6 g total AA-N/day for C, LN and LE, respectively, P = 0.52). Thus, different metabolic regulations must have taken place across the liver between the three experimental diets. A combination of decreased net uptake of total AA-N by the liver of animals in the LN diet (0.61 of the C diet; P = 0.002) and reduced urinary urea-N production (0.52 of the C diet; P = 0.001) spared AA from catabolism in the LN diet relative to the other two diets. For the LE diet, the urinary urea-N output was 1.3 times the value of the C diet (P = 0.01). This may relate to an increased catabolism of AA by the muscle and/or, to a lesser extent, to an increased utilisation of AA for gluconeogenesis in the liver. These effects may explain the reduced whole body protein retention observed with the LE diet. PMID- 22439992 TI - Integration of the effects of animal and dietary factors on total dry matter intake of dairy cows fed silage-based diets. AB - An empirical regression model for the prediction of total dry matter intake (DMI) of dairy cows was developed and compared with four published intake models. The model was constructed to include both animal and dietary factors, which are known to affect DMI. For model development, a data set based on individual cow data from 10 change-over and four continuous milk production studies was collected (n = 1554). Relevant animal (live weight (LW), days in milk (DIM), parity and breed) and dietary (total and concentrate DMI, concentrate composition, forage digestibility and fermentation quality) data were collected. The model factors were limited to those that are available before the diets are fed to animals, that is, standardized energy corrected milk (sECM) yield, LW, DIM and diet quality (total diet DMI index (TDMI index)). As observed ECM yield is a function of both the production potential of the cow and diet quality, ECM yield standardized for DIM, TDMI index and metabolizable protein concentration was used in modelling. In the individual data set, correlation coefficients between sECM and TDMI index or DIM were much weaker (0.16 and 0.03) than corresponding coefficients with observed ECM (0.65 and 0.46), respectively. The model was constructed with a mixed model regression analysis using cow within trial as a random factor. The following mixed model was estimated for DMI prediction: DMI (kg DM/day) = -2.9 (+/-0.56)+0.258 (+/-0.011) * sECM (kg/day) + 0.0148 (+/ 0.0009) * LW (kg) -0.0175 (+/-0.001) * DIM -5.85 (+/-0.41) * exp (-0.03 * DIM) + 0.09 (+/-0.002) * TDMI index. The mixed DMI model was evaluated with a treatment mean data set (207 studies, 992 diets), and the following relationship was found: Observed DMI (kg DM/day) = -0.10 (+/-0.33) + 1.004 (+/-0.019) * Predicted DMI (kg DM/day) with an adjusted residual mean square error of 0.362 kg/day. Evaluation of the residuals did not result in a significant mean bias or linear slope bias, and random error accounted for proportionally >0.99 of the error. In conclusion, the DMI model developed is considered robust because of low mean prediction error, accurate and precise validation, and numerically small differences in the parameter values of model variables when estimated with mixed or simple regression models. The Cornell Net Carbohydrate and Protein System was the most accurate of the four other published DMI models evaluated using individual or treatment mean data, but in most cases mean and linear slope biases were relatively high, and, interestingly, there were large differences in both mean and linear slope biases between the two data sets. PMID- 22439993 TI - Advances in research on the prenatal development of skeletal muscle in animals in relation to the quality of muscle-based food. I. Regulation of myogenesis and environmental impact. AB - Skeletal muscle development in vertebrates - also termed myogenesis - is a highly integrated process. Evidence to date indicates that the processes are very similar across mammals, poultry and fish, although the timings of the various steps differ considerably. Myogenesis is regulated by the myogenic regulatory factors and consists of two to three distinct phases when different fibre populations appear. The critical times when myogenesis is prone to hormonal or environmental influences depend largely on the developmental stage. One of the main mechanisms for both genetic and environmental effects on muscle fibre development is via the direct action of the growth hormone-insulin-like growth factor (GH-IGF) axis. In mammals and poultry, postnatal growth and function of muscles relate mainly to the hypertrophy of the fibres formed during myogenesis and to their fibre-type composition in terms of metabolic and contractile properties, whereas in fish hyperplasia still plays a major role. Candidate genes that are important in skeletal muscle development, for instance, encode for IGFs and IGF-binding proteins, myosin heavy chain isoforms, troponin T, myosin light chain and others have been identified. In mammals, nutritional supply in utero affects myogenesis and the GH-IGF axis may have an indirect action through the partitioning of nutrients towards the gravid uterus. Impaired myogenesis resulting in low skeletal myofibre numbers is considered one of the main reasons for negative long-term consequences of intrauterine growth retardation. Severe undernutrition in utero due to natural variation in litter or twin-bearing species or insufficient maternal nutrient supply may impair myogenesis and adversely affect carcass quality later in terms of reduced lean and increased fat deposition in the progeny. On the other hand, increases in maternal feed intake above standard requirement seem to have no beneficial effects on the growth of the progeny with myogenesis not or only slightly affected. Initial studies on low and high maternal protein feeding are published. Although there are only a few studies, first results also reveal an influence of nutrition on skeletal muscle development in fish and poultry. Finally, environmental temperature has been identified as a critical factor for growth and development of skeletal muscle in both fish and poultry. PMID- 22439994 TI - Advances in research on the prenatal development of skeletal muscle in animals in relation to the quality of muscle-based food. II--Genetic factors related to animal performance and advances in methodology. AB - Selective breeding is an effective tool to improve livestock. Several selection experiments have been conducted to study direct selection responses as well as correlated responses in traits of skeletal muscle growth and function. Moreover, comparisons of domestic with wild-type species and of extreme breeds provide information on the genetic background of the skeletal muscle phenotype. Structural muscular components that differed with increasing distance in lean growth or meat quality in mammals were found to be myofibre number, myofibre size, proportions of fibre types as well as the numbers and proportions of secondary and primary fibres. Furthermore, markers of satellite cell proliferation, metabolic enzyme activities, glycogen and fat contents, the expression of myosin heavy chain isoforms, of activated AMPKalpha and other proteins in skeletal muscle tissue and circulating IGF1 and IGF-binding proteins have been identified to be involved in selection responses observed in pigs, cattle and/or chicken. The use of molecular methods for selective breeding of fish has only recently been adopted in aquaculture and studies of the genetic basis of growth and flesh quality traits are scarce. Some of the molecular markers of muscle structure/metabolism in livestock have also been identified in fish, but so far no studies have linked them with selection response. Genome scans have been applied to identify genomic regions exhibiting quantitative trait loci that control traits of interest, for example, muscle structure and meat quality in pigs and growth rate in chicken. As another approach, polymorphisms in candidate genes reveal the relationship between genetic variation and target traits. Thus, in large-scale studies with pigs' associations of polymorphisms in the HMGA2, CA3, EPOR, NME1 and TTN genes with traits of carcass and meat quality were detected. Other studies revealed the significance of mutations in the IGF2 and RYR1 genes for carcass lean and muscle fibre traits in pigs. Mutations in the myostatin (MSTN) gene in fish were also examined. Advances in research of the genetic and environmental control of traits related to meat quality and growth have been made by the application of holistic 'omics' techniques that studied the whole muscle-specific genome, transcriptome and proteome in relation to muscle and meat traits, the development of new methods for muscle fibre typing and the adaptation of biophysical measures to develop parameters of muscle fibre traits as well as the application of in vitro studies. Finally, future research priorities in the field are defined. PMID- 22439995 TI - Dairy cows' reproductive response to feeding level differs according to the reproductive stage and the breed. AB - Reproductive performance has decreased over the last decades in many dairy systems. This study aimed at comparing the effects of a high- and a low-feeding level on reproductive stages (cyclicity, oestrus and fertility) of Holstein and Normande cows in a grass-based winter compact calving system. High-fed cows received a total mixed ration composed of 55% maize silage, 15% dehydrated alfalfa pellets and 30% concentrate in winter and 4 kg/day concentrate supply at grazing. Low-fed cows only received 50% grass silage and 50% haylage in winter and no concentrate at grazing. Low-fed cows produced less milk over 44 weeks, but lost more body condition (BC) than high-fed ones (5207 v. 7457 kg, -1.28 v. -0.96 unit, P < 0.001). Normande cows produced less milk and lost less BC than Holstein ones (5596 v. 7068 kg, -0.89 v. -1.36 unit, P < 0.001). Post-partum ovarian activity was little affected by the feeding level. In both breeds, ovulation detection rate was higher in low-fed cows (74% v. 59%, P < 0.001) and detection relied more frequently on standing behaviour (67% v. 55%, P = 0.022). In both breeds, the recalving rate following the first and second inseminations was not significantly affected by the feeding level, although more non-fertilisations or early embryo mortalities occurred in low-fed cows (43% v. 26%, P = 0.004). For the Holstein breed, this was clearly explained by more late embryo mortalities in high-fed cows (30% v. 9%, P = 0.004). Finally, pregnancy rate by the end of the 13-week breeding period was similar between feeding groups. Conversely, the Normande dual-purpose cows had a higher pregnancy rate by the end of the breeding period than the Holstein dairy cows (72% v. 54%, P = 0.007), owing to a better ovarian activity (79% v. 54% normal, P < 0.001) and a higher recalving rate following insemination (53% v. 37%, P = 0.007). In conclusion, this study demonstrates that feeding levels with converse effects on milk yield and BC score also have converse effects on reproductive stages and lead to quite similar final reproductive performance in compact calving systems. Normande cows benefit from an overall better reproductive performance, but do not suit high feeding levels for very compact calving systems owing to depressed oestrous behaviour. PMID- 22439996 TI - Effect of match or mismatch of maternal-offspring nutritional environment on the development of offspring in broiler chickens. AB - In mammals, maternal food restriction around conception and during pregnancy results in low birth weight and an adjusted growth trajectory of offspring. If, subsequently, the offspring are born into a food-abundant environment, they are at increased risk of developing obesity, type 2 diabetes, hypertension and renal dysfunction. Here, we show similar effects of maternal undernutrition on hatch weight, growth and fat deposition in offspring of birds (domestic chicken). Both mothers and offspring were fed either ad libitum or restricted in a two-by-two factorial design, resulting in two matched and two mismatched maternal-offspring nutritional environments. Offspring of ad libitum mothers grew heavier than those of restricted mothers, possibly due to the larger muscle mass. Ad libitum-fed offspring, especially females, of restricted mothers were lighter at hatch, and were heavier and had more abdominal fat at 6 weeks of age than daughters of ad libitum-fed mothers. These results suggest a common mechanism in mammals and birds in response to a mismatch in the maternal-offspring nutritional environment. They also indicate that the common practice of restrictive feeding of the broiler breeders and subsequent ad libitum feeding of the broilers may result in reduced growth and increased abdominal fat as compared to broilers of less restricted broiler breeders. PMID- 22439997 TI - Effect of compensatory growth on performance, carcass composition and plasma IGF 1 in grower finisher pigs. AB - A total of 48 female pigs (Large White * Landrace * Duroc cross) were used to determine whether a compensatory feed regime influenced performance, carcass composition and the level of plasma IGF-1. Pigs of initial age 73 days were fed a commercial diet at 0.70 of ad libitum (R) for 40 days followed by a return to ad libitum feeding for a further 42 days. The control group was fed ad libitum (A) throughout. Groups of animals on R and A feed regimes were slaughtered at the end of restriction period (SL1), 2 days after refeeding ad libitum (SL2) to establish the more immediate effects of refeeding on IGF levels, and after 42 days refeeding (SL3; n = 8 for each group). As expected, during the restriction period, average daily live weight gain in all the slaughter groups of R pigs was significantly lower than A pigs (P < 0.01); there was no significant difference in feed conversion ratios. In the re-alimentation period of SL3, R pigs grew 12.9% faster (P = 0.033), indicating compensatory growth. At SL1, there was a trend for carcass weight (P = 0.108) of A pigs to be higher than R pigs, but at SL2 live weight and carcass weight of A pigs were significantly heavier than R pigs (P < 0.05), but not at SL3. For killing-out percentage, there was no difference in SL1. After refeeding for 2 days (SL2) and 42 days (SL3), R pigs had significantly lower killing-out percentage than A pigs (P < 0.05). As a proportion of live weight, R pigs had smaller heart, kidney and liver (P < 0.05) than A pigs at SL1. At SL2, only the kidney was smaller in the restricted group (P < 0.05) and there were no significant differences in SL3. As a proportion of carcass weight, Longissimus dorsi was heavier in the R pigs at SL1 (P = 0.108) and SL2 (P < 0.05), but not at SL3. At SL1, there was a trend for intramuscular fat of A pigs to be higher than R pigs. The plasma IGF-1 level was lower in R pigs than A pigs (P = 0.010) at SL1, and slightly lower at SL2 (P = 0.110), with no significant differences at SL3. Dietary restriction period influenced plasma IGF-1 levels, which returned to the ad libitum group levels when animals were refed, as did live weight and carcass weight. It appears that the internal organs and possibly fat, but not muscles, underwent a compensatory response when animals were refed. PMID- 22439998 TI - Decubital shoulder ulcers in sows: a review of classification, pain and welfare consequences. AB - Decubital shoulder ulcers are lesions on the shoulders of sows kept in production systems, reported to have a relatively high prevalence, and to some extent be comparable with human pressure ulcers. In sows, the ulcers are caused by pressure inflicted by the flooring, leading to oxygen deficiency in the skin and the underlying tissue. This paper reviews existing knowledge about decubital shoulder ulcers in sows, focusing on the pathogenesis, classification and consequences in terms of pain and animal welfare. On the basis of available human as well as animal literature, we describe the primary causal factors, underlying mechanisms, suggested direction of progression as well as temporal development. We review suggested scales for the classification of decubital shoulder ulcers, and argue that none of these are useful for the classification of decubital shoulder ulcers in live sows. The knowledge of the welfare consequences of decubital shoulder ulcers is limited. On the basis of the tissue structures that are involved, we assume that the development and presence of decubital shoulder ulcers in sows are a painful and prolonged condition. It is concluded that the extent of the welfare problem related to decubital shoulder ulcers cannot be fully determined until a valid ante-mortem classification system is available, and knowledge about the duration of the condition (including the various stages), as well as the possible consequences in terms of pain or discomfort have been established. PMID- 22439999 TI - Characteristics of biter and victim piglets apparent before a tail-biting outbreak. AB - Little is known about the characteristics of biters and victims before the appearance of a tail-biting outbreak in groups of pigs. This study aimed to characterise biters and victims (according to gender and performance) and to quantify their behavioural development during the 6 days preceding the tail biting outbreak. The hypotheses tested were: (a) biters are more often female, are the lighter pigs in the group, are more restless and perform more aggressive behaviour; and (b) victims are more often male, heavier and less active. Using video recordings we carried out a detailed study of 14 pens with a tail-biting outbreak among the weaned piglets. All piglets were individually marked and we observed the behaviour of biters, victims and control piglets (piglet types). In every pen, each piglet type was observed every other day from 6 days before (D-6) to the day of the first visible tail damage (i.e. day of tail biting outbreak; D0). While the number of male biters (6 of the 14 biters) and male victims (11 of the 14 victims) was not significantly different (P = 0.13), this numerical contrast was considerable. The start weight of victims was significantly (P = 0.03) higher (8.6 kg) than those of biters (7.5 kg) and control piglets (8.0 kg). Biters tended (P = 0.08) to spend longer sitting/kneeling (3.1 min/h) than controls (1.7 min/h), but no differences were seen in the time spent lying or standing. Victims tended (P = 0.07) to change posture more often (restlessness) than controls and chased penmates more (P = 0.04) than biters. Victims also performed more (P = 0.04) aggressive behaviour than biters and controls. In contrast, biters tended (P = 0.08) to be chased by penmates more often and tended (P = 0.06) to receive more aggressive behaviour than controls. Furthermore, biters spent longer manipulating the enrichment device (P = 0.01) and the posterior/tail (P = 0.02) of their penmates than controls and tended (P = 0.06) to perform more tail bites than victims. Victims received more posterior/tail manipulation (P = 0.02) and tail bites (P = 0.04) than controls. It was also noticed that, independent of piglet type, restlessness (P = 0.03) increased and the frequency of performed tail bites tended (P = 0.08) to increase in the 6 days preceding a tail-biting outbreak. These findings may contribute to the early identification of biters or victims and support the development of strategies to minimise the occurrence of tail biting. PMID- 22440000 TI - Development and validation of on-farm behavioural scoring systems to assess birth assistance and lamb vigour. AB - Lamb mortality remains a significant welfare and economic issue for sheep production. Lamb survival is to a degree dependent upon an easy delivery and the expression of appropriate behaviours from both mother and offspring, such as rapid standing, udder seeking and sucking by the lamb. Genetic solutions have the potential to improve birth assistance and lamb behaviour but large amounts of data are needed. Therefore, to achieve this objective, simple, proxy methods (scoring systems) were developed to quantify the level of birth difficulties and lamb vigour on farm. In the first study, detailed historical behavioural data from 1156 lambs (Scottish Blackface and Suffolk (S)) were analysed to develop criteria for 3 scores: birth assistance, lamb vigour and sucking assistance. The birth assistance score was developed by analysing the relationships between birth presentation and intervention levels, and intervention level and labour length. Lambs with abnormal birth positions required more assistance than normally presented lambs and lambs with long labours required more and greater assistance than those with short labours. Lamb vigour score was developed by analysing the latencies for the lamb to first perform specific behaviours; more vigorous lambs reach landmark behaviours faster than low vigour lambs. The sucking assistance score was developed from the relationship between the latency to suck successfully and assistance level, where lambs that were slow to suck required more assistance than lambs that were quick to suck. In the second study, the behaviour scoring systems (5-point categorical scales) were validated using a commercial flock of 80 twin-bearing crossbred ewes mated with either Texel (T) or S sires by simultaneously recording scores and the latency to perform specific landmark behaviours (i.e. to stand, seek the udder and suck). The vigour scores (recorded at 5 min of age) were compared with the latency from birth to standing and showed that lambs with lower (better) vigour scores were faster to stand after birth than those with higher scores. The sucking assistance scores were compared with the latency from birth to sucking, and showed that lambs with lower sucking assistance scores are quicker to suck than those with high scores. These results showed that the scoring systems could provide a practical and reliable assessment of birth assistance and lamb behaviour on farm and were sufficiently sensitive to discriminate vigour levels between lambs sired by either S or T rams. PMID- 22440001 TI - Meta-analysis of the impact of stocking rate on the productivity of pasture-based milk production systems. AB - The objective of this study is to quantify the milk production response per cow and per hectare (ha) for an incremental stocking rate (SR) change, based on a meta-analysis of published research papers. Suitable experiments for inclusion in the database required a comparison of at least two SRs under the same experimental conditions in addition to details on experimental length and milk production results per cow and per ha. Each additional increased SR treatment was also described in terms of the relative milk production change per cow and per ha compared to the lower base SR (b_SR). A database containing 109 experiments of various lengths with 131 comparisons of SR was sub-divided into Type I experiments (common experimental lengths) and Type II experiments (variable experimental lengths). Actual and proportional changes in milk production according to SR change were analysed using linear mixed model procedures with study included as a random effect in the model. Low residual standard errors indicated a good precision of the predictive equations with the exception of proportional change in milk production per cow. For all milk yield variables analysed, the results illustrate that while production per cow is reduced, a strong positive relationship exists between SR and milk production per ha. An SR increase of one cow/ha resulted in a decrease in daily milk yield per cow of 7.4% and 8.7% for Type I and Type II data, respectively, whereas milk yield per ha increased by 20.1% and 19.6%, respectively. Within the Type II data set, a one cow/ha increase in SR also resulted in a 15.1% reduction in lactation length (equivalent to 42 days). The low predictability of proportional change in milk production per cow according to the classical SR definition of cows per ha over a defined period suggests that SR may be more appropriately defined in terms of the change in available feed offered per animal within each treatment. PMID- 22440002 TI - Effects of replacing palm oil with maize oil and Curcuma longa supplementation on the performance, carcass characteristics, meat quality and fatty acid profile of the perirenal fat and muscle of growing rabbits. AB - An experiment has been conducted to study the effects of the inclusion of plant oil in rabbit diets. This study was aimed at evaluating the beneficial effects of the inclusion of maize oil (MO), rich in unsaturated fatty acids (UFAs), compared to palm oil (PO) containing saturated fatty acids (SFAs), on the meat fatty acid (FA) profile. As UFAs are susceptible to rancidity, Curcuma longa (CL), which is known for its antioxidant properties, was also added (3 g/kg) to the diet with two plant oils. CL contains curcuminoids, volatile oils, sugars, proteins, resins and polyunsaturated fatty acids (PUFAs). We also evaluated the influence of CL inclusion in the diet on the FA profile of the meat. Furthermore, the possibility of using these oil-enriched diets and the ability to assimilate CL in rabbits was evaluated by analysing the performance, carcass characteristics and meat quality. At the end of the experiment, there were no significant differences between the groups concerning the live weight, live weight gain, feed consumption, feed efficiency, carcass yield or the percentages of edible organs. The hind legs, forelegs, loins and abdominal wall, breast and ribs, skin and limbs and head were not affected by the oil type or by the inclusion of CL. The chemical composition, pH and oxidative status of the Longissimus dorsi muscle of the rabbits fed the experimental diets were not affected by the oil source or by the CL supplementation. Conversely, it has been shown that it is possible to modify the FA profile of rabbit meat and fat by dietary means. The SFA/PUFA ratio significantly decreased from -18% to -16% in the meat and from -25% to -23% in the perirenal fat of the rabbits fed diets containing MO without or with CL supplementation, respectively, compared to same tissues of the rabbits fed diets containing PO without or with CL supplementation, respectively. Similar trends were found for the atherogenic index, which decreased from -20% to -17% in the meat and from -26% to -23% in the perirenal fat, respectively, and the thrombogenic index, which decreased from -19% to -24% in the meat and from -24% to -23% in the perirenal fat, respectively. CL increased the alpha-Linolenic acid and PUFA n-3 contents and reduced the vaccenic acid content and the n-6/n-3 ratio in the meat of the rabbits fed the PO or MO diets. PMID- 22440003 TI - Effects of weaning and finishing feeding treatment on fatty acids, especially cis and trans C18:1 isomers, in the Longissimus thoracis muscle of Galician Blond calves. AB - Seven- to 10-month-old calves are the typical production of Galician Blond (GB), the most important bovine local beef breed in Spain. As meat lipid repercussions on human health depend on their fatty acid (FA) profile, this study aimed at analysing the individual FA at weaning and at the end of the feeding finishing period, especially trans and cis 18:1 isomers in total lipids of the Longissimus thoracis muscle in GB male calves. Distribution of main FA in veal lipids was characterized by gas-liquid chromatography (GLC) analysis on a high polar glass capillary column. Total trans and cis 18:1 isomers were purified, from total FA (TFA) methyl esters, by preparative reversed-phase high-performance liquid chromatography, to allow subsequent specific analysis of their different isomers by GLC. Calves stayed with their mothers at pasture for 2 or 5 months in intensive or semi-extensive systems, followed by an indoor feeding period. The weaned (W) group was finished on concentrate and hay, whereas the non-weaned (NW) group was finished on concentrate and hay and it continued suckling until slaughter. The studied effects did not present interactions. The duration of the indoor finishing period hardly had a significant influence on the parameters analysed. Compared to W calves, NW calves had higher proportions (% TFA) of 18:3n 3 (+38%, P < 0.0001), 20:5n-3 (+22%, P = 0.005), 22:5n-3 (+13%, P = 0.042), cis monounsaturated FA (MUFA; +8%, P = 0.032), total MUFA (+8%, P = 0.013), n-3 polyunsaturated FA (PUFA; +25%, P = 0.0001) and conjugated linoleic acid (CLA; +48%, P < 0.0001) to the detriment of 18:0 (-10%, P = 0.002), 18:2n-6 (-25%, P = 0.004) and n-6 PUFA (-20%, P = 0.011). With regard to cis and trans 18:1 isomers, NW calves had higher proportions (% total cis or trans 18:1) of Delta11trans and Delta16trans (+25% and +22%, respectively, P < 0.01) and Delta13 + 14trans (+13%, P < 0.05) and lower proportions of Delta6 to 8 and Delta10trans (-28% and 58%, respectively, P < 0.001). NW calves' meat might be more suitable for human health than W calves' meat due to the increase of anti-atherogenous FA such as n-3 PUFA, CLA and 18:1 Delta11trans. PMID- 22440004 TI - Mitochondrial respiratory and antioxidative enzyme activities in broiler meat in relation to age and gender of the animals. AB - Colour is an important quality parameter of broiler meat influencing the consumer buying behaviour. The alterations of the colour after slaughter are related to the oxidative status of the tissue. This in turn is influenced by an interaction between the mitochondria and the antioxidative enzymes. In this study, breast muscles were collected from hens and cocks of a commercial line slaughtered at the ages of 28 and 41 day. Analysis of the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) was performed with samples obtained 20 min and 48 h after slaughter (post mortem, p.m.), whereas the mitochondrial respiratory activity was analysed in permeabilised breast muscle fibres collected 20 min p.m. The carcass characteristics of breast muscle and leg weight as well as breast yield were significantly higher, and the leg yields lower, in the 41-day-old broiler. The 28-day-old hens and cocks had comparable carcass characteristics (P > 0.05), whereas 41-day-old cocks had significantly higher carcass, breast and leg weight in comparison to the hens. The pH20 min p.m. and the L*48 h p.m. were significantly higher, and the a* and b* values of the 20 min and 48 h p.m. samples as well as the drip loss were significantly lower in the 41-day-old broiler. Mitochondrial respiratory rates were comparable (P > 0.05) between the 28- and 41-day-old cocks and hens. The same result could be found with regard to the activities of the SOD, GPx and GR except for lower activities of the SOD20 min p.m. and higher of the GR48 h min p.m. in the 41-day-old broiler. The concentrations of thiobarbituric acid reactive substances were generally higher in the breast muscles of the 41-day-old broiler. Assorting the data according to their mean pH20 min p.m. indicates a positive influence of higher pH values (>6.34) on the mitochondrial function, whereas a low pH20 min p.m. results in tendentially and significantly higher activities of the antioxidative enzymes and drip loss values. These results indicate a relation between the meat quality and the oxidative metabolism as well as antioxidative capacity of the meat. PMID- 22440005 TI - Endogenous granulocyte colony-stimulating factor: a biomarker in acute ischemic stroke. AB - Granulocyte colony-stimulating factor (G-CSF) may protect ischemic brain injury either in animal or human. No studies have reported that endogenous G-CSF (enG CSF) level is related to the severity of ischemic stroke. This study was designed to assess the severity of ischemic patients correlated with the alteration of enG CSF on the 1st day after an ischemic event. Patient's plasma enG-CSF and scoring of National Institute of Health Stroke Scale were measured on the 1st day after ischemic stroke. The acute ischemic stroke could significantly induce enG-GCF secretion as compared with healthy control group (16.77 vs. 22.86 MUg/L, p = 0.001). Elevated enG-CSF concentration was positively correlated with the severity of stroke patients on day 1 after the event (p = 0.006; Spearman correlation coefficient = 0.268). The enG-CSF is a good biomarker for prediction of severity of acute ischemic stroke. PMID- 22440006 TI - Half-metallicity in organic single porous sheets. AB - The unprecedented applications of two-dimensional (2D) atomic sheets in spintronics are formidably hindered by the lack of ordered spin structures. Here we present first-principles calculations demonstrating that the recently synthesized dimethylmethylene-bridged triphenylamine (DTPA) porous sheet is a ferromagnetic half-metal and that the size of the band gap in the semiconducting channel is roughly 1 eV, which makes the DTPA sheet an ideal candidate for a spin selective conductor. In addition, the robust half-metallicity of the 2D DTPA sheet under external strain increases the possibility of applications in nanoelectric devices. In view of the most recent experimental progress on controlled synthesis, organic porous sheets pave a practical way to achieve new spintronics. PMID- 22440007 TI - TRAF6 activation in multiple myeloma: a potential therapeutic target. AB - Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-kappaB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM. PMID- 22440009 TI - N-tosylcarboxamide as a transformable directing group for Pd-catalyzed C-H ortho arylation. AB - The N-tosylcarboxamide group offers the possibility of directing the Pd-catalyzed C-H arylation of arenes providing a new entry to biarylcarboxamides. Moreover, its ability to react according to different reaction conditions including intramolecular reactions makes it a pivotal directing group for a divergent synthesis of biaryl-based compounds. PMID- 22440008 TI - Discovery of small molecule cancer drugs: successes, challenges and opportunities. AB - The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the 'Valley of Death' between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients. PMID- 22440010 TI - Automated radioanalytical system incorporating microwave-assisted sample preparation, chemical separation, and online radiometric detection for the monitoring of total 99Tc in nuclear waste processing streams. AB - An automated fluidic instrument is described that rapidly determines the total (99)Tc content of aged nuclear waste samples, where the matrix is chemically and radiologically complex and the existing speciation of the (99)Tc is variable. The monitor links microwave-assisted sample preparation with an automated anion exchange column separation and detection using a flow-through solid scintillator detector. The sample preparation steps acidify the sample, decompose organics, and convert all Tc species to the pertechnetate anion. The column-based anion exchange procedure separates the pertechnetate from the complex sample matrix, so that radiometric detection can provide accurate measurement of (99)Tc. We developed a preprogrammed spike addition procedure to automatically determine matrix-matched calibration. The overall measurement efficiency that is determined simultaneously provides a self-diagnostic parameter for the radiochemical separation and overall instrument function. Continuous, automated operation was demonstrated over the course of 54 h, which resulted in the analysis of 215 samples plus 54 hly spike-addition samples, with consistent overall measurement efficiency for the operation of the monitor. A sample can be processed and measured automatically in just 12.5 min with a detection limit of 23.5 Bq/mL of (99)Tc in low activity waste (0.495 mL sample volume), with better than 10% RSD precision at concentrations above the quantification limit. This rapid automated analysis method was developed to support nuclear waste processing operations planned for the Hanford nuclear site. PMID- 22440011 TI - Ape Plasmodium parasites as a source of human outbreaks. AB - Recent studies have revealed a remarkable molecular diversity of Plasmodium parasites in great apes in Africa, as well as parasite exchange events between these primates and humans. We review the different points of view proposed on the origin of human malaria, and discuss ape Plasmodium parasites as a source of human outbreaks. PMID- 22440012 TI - Effect of adipose tissue-derived osteogenic and endothelial cells on bone allograft osteogenesis and vascularization in critical-sized calvarial defects. AB - The use of processed bone allograft to repair large osseous defects of the skull has been limited, given that it lacks the osteogenic cellularity and intrinsic vascular supply which are essential elements for successful graft healing and, at the same time, the areas to be targeted through tissue-engineering applications. In this study, we investigated the effect of predifferentiated rat adipose tissue derived osteoblastic cells (OBs) and endothelial cells (ECs) on calvarial bone allograft healing and vascularization using an orthotopic critical-sized calvarial defect model. For this purpose, thirty-seven 8 mm critical calvarial defects in Lewis rats were treated with bone allografts seeded with no cells, undifferentiated adipose tissue-derived stem cells (ASC), OBs, ECs, and OBs and ECs simultaneously. After 8 weeks, the bone volume and mineral density were calculated using microcomputed tomography and the microvessel formation using immunohistochemical staining and imaging software. The amount of bone within the 8 mm defect was significantly higher for the allografts treated with ECs compared with the allografts treated with OBs (p=0.05) and simultaneously with the two cell lineages (p=0.02). There were no significant differences in bone formation between the latter two groups and the control groups (allografts treated with no cells and undifferentiated ASC). There were no significant differences in bone mineral density among the groups. The amount of microvessels was significantly higher in the group treated with ECs relative to all groups (p=< 0.05). Our results show that the implantation of ASC-derived ECs improves the vascularization of calvarial bone allografts at 8 weeks after treatment. This cell-based vascularization strategy can be used to improve the paucity of perfusion in allogenic bone implants. However, in this study, the treatment of allografts with OBs alone or in combination with ECs did not support bone formation or vascularization. PMID- 22440013 TI - Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. AB - BACKGROUND: There is no standard serum biomarker used for diagnosis or early detection of recurrence for renal cell carcinoma (RCC) patients. MicroRNAs (miRNAs) are abundant and highly stable in blood serum, and have been recently described as powerful circulating biomarkers in a wide range of solid cancers. Our aim was to identify miRNA signature that can distinguish the blood serum of RCC patients and matched healthy controls and validate identified miRNAs as potential biomarkers for RCC. METHODS: In the screening phase of the study, blood serum of 15 RCC patients and 12 matched healthy controls were analyzed by use of the TaqMan Low-Density Arrays enabling parallel identification of expression levels of 667 miRNAs through qRT-PCR-based approach. In the validation phase, identified miRNAs were further evaluated on the independent group of 90 RCC patients and 35 matched healthy controls by use of individual qRT-PCR assays and statistically evaluated. RESULTS: We identified 30 miRNAs differentially expressed between serum of RCC patients and healthy controls: 19 miRNAs were up regulated and 11 miRNAs were down-regulated in RCC patients. MiR-378, miR-451 and miR-150 were further evaluated in the independent group of patients, and two of them were successfully validated: levels of miR-378 were increased (p = 0.0003, AUC = 0.71), miR-451 levels were decreased (p < 0.0001, AUC = 0.77) in serum of RCC patients. Combination of miR-378 and miR-451 enable identification of RCC serum with the sensitivity of 81%, specificity 83% and AUC = 0.86. CONCLUSIONS: Circulating miRNAs in serum are promising biomarkers in RCC. PMID- 22440014 TI - The loss of conceptual associations in mild Alzheimer's dementia. AB - Changes in semantic memory are a controversial topic in research on cognitive decline in aging. In this study, we analyzed whether the semantic deficits in mild Alzheimer's disease (AD) reflect the information acquisition process, and whether the deficits are related to when the information was initially stored. We hypothesized that in the earlier stages of dementia, the ability to access semantic associative relations reflects the use of these associations during different developmental stages. Specifically, we asserted that Alzheimer's patients might be able to access the relations that are learned earlier in life for the longest amount of time compared to those that are learned later. In this study, 254 subjects were divided into four groups (child, adult, senior, and Alzheimer's patients groups) and were evaluated with an experimental semantic association task that incorporated five semantic associative relations that were used to compare performance by age group. An analysis of variance (ANOVA) 4 * 5 test showed a significant main group effect, F(3, 250) = 97.1, p < .001, and an associative relations effect, F(4, 1000) = 23.1, p < .001, as well as an interaction of Group * Associative Relations, F(12, 1000) = 8.5, p < .001. The results demonstrated that the semantic associative relations that were acquired in later developmental stages were less preserved in persons with mild AD (i.e., superordinate relation, p < .0001). On the contrary, the semantic relations acquired earlier in childhood were better preserved in persons with mild AD. Our results suggest that semantic impairment begins with difficulties in using the associative relations that link concepts together in the semantic memory of patients with mild AD dementia (and possibly in individuals with mild cognitive impairment). PMID- 22440015 TI - Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity. AB - To discover new possible therapies for Chagas' disease, we evaluated against all Trypanosoma cruzi life stages the in vitro trypanocidal and synergistic activity of terpenes isolated from Copaifera oleoresins collected in the Amazon and investigated their possible mechanism of action. Seven acid diterpenes and one sesquiterpene were tested. Terpenes promoted changes in oxidative metabolism followed by autophagic processes in the parasite cell leading to selective death. Furthermore, they were more effective against replicative forms, in particular amastigotes. A synergistic effect occurred. Cytotoxicity to erythrocytes and nucleated cells was moderate. This is the first study showing synergic activity between two terpenes against T. cruzi. Combinations of natural compounds can show high activity and may lead to new alternative treatments in the future. PMID- 22440016 TI - Carbohydrates inhibit salivary proteins precipitation by condensed tannins. AB - Condensed tannins are a group of polyphenols that are associated with the astringency sensation, as they readily interact and precipitate salivary proteins. As this interaction is affected by carbohydrates, the aim of this work was to study the effect of some carbohydrates used in the food industry [arabic gum (AG), pectin, and poligalacturonic acid (PGA)] on the salivary proteins/grape seed procyanidins interaction. This was assessed monitoring the salivary proteins that remain soluble in the presence of condensed tannins with the addition of carbohydrates (HPLC) and analysis of the respective precipitates (SDS-PAGE). The results show that pectin was the most efficient in inhibiting protein/tannin precipitation, followed by AG and PGA. The results suggest that pectin and PGA exert their effect by formation of a ternary complex protein/polyphenol/carbohydrate, while AG competes with proteins for tannin binding (competition mechanism). The results also point out that both hydrophilic and hydrophobic interactions are important for the carbohydrate effects. PMID- 22440017 TI - Dynamics of pneumococcal nasopharyngeal carriage in healthy children attending a day care center in northern Spain. Influence of detection techniques on the results. AB - BACKGROUND: Pneumococcal nasopharyngeal carriage precedes invasive infection and is the source for dissemination of the disease. Differences in sampling methodology, isolation or identification techniques, as well as the period (pre or post-vaccination) when the study was performed, can influence the reported rates of colonization and the distribution of serotypes carried. OBJECTIVES: To evaluate the prevalence and dynamics of pneumococcal nasopharyngeal colonization in healthy children aged 6-34 months attending a day care center with a high level of hygiene and no overcrowding. The study was performed 3-4 years after the 7-valent pneumococcal vaccine was introduced, using multiple methodologies to detect and characterize the isolates. METHODS: Over 12 months, 25 children were sampled three times, 53 children twice and 27 children once. Three Streptococcus pneumoniae typing techniques were used: Quellung, Pneumotest-Latex-kit and multiplex-polymerase chain reaction (PCR). The similarity of isolates of the same serotype was established by pulsed field gel electrophoresis (PFGE) and occasionally the multilocus sequence type (ST) was also determined. RESULTS: Overall pneumococcal carriage and multiple colonization rates were 89.5% (94/105) and 39%, respectively. Among 218 pneumococci detected, 21 different serotypes and 13 non-typeable isolates were found. The most prevalent serotypes were 19A, 16F and 15B. Serotypes 15B, 19A and 21 were mainly found as single carriage; in contrast serotypes 6B, 11A and 20, as well as infrequent serotypes, were isolated mainly as part of multiple carriage. Most 19A isolates were ST193 but most serotypes showed high genetic heterogeneity. Changes in the pneumococci colonizing each child were frequent and the same serotype detected on two occasions frequently showed a different genotype. By multiplex-PCR, 100% of pneumococci could be detected and 94% could be serotyped versus 80.3% by the Quellung reaction and Pneumotest-Latex in combination (p < 0.001). CONCLUSIONS: Rates of S. pneumoniae carriage and multiple colonization were very high. Prevalent serotypes differed from those found in similar studies in the pre vaccination period. In the same child, clearance of a pneumococcal strain and acquisition of a new one was frequent in a short period of time. The most effective technique for detecting pneumococcal nasopharyngeal carriers was multiplex-PCR. PMID- 22440018 TI - Assessment of utilization of provider-initiated HIV testing and counseling as an intervention for prevention of mother to child transmission of HIV and associated factors among pregnant women in Gondar town, North West Ethiopia. AB - BACKGROUND: Detection of maternal HIV infection early in pregnancy is critical for prevention of mother to child transmission of HIV/AIDS. Most efforts have focused on VCT as the primary means of encouraging people to become aware of their HIV status. However, its uptake is low in many parts of sub-Saharan Africa including Ethiopia. Provider-initiated HIV testing and counseling provides a critical opportunity to diagnose HIV infection, to begin chronic care, and to prevent mother to child transmission. However, little is known about its acceptance and associated factors among pregnant women in the country and particularly in the present study area. METHODS: Health institution based cross sectional quantitative study was conducted in Gondar town from July 22-August 18, 2010. A total of 400 pregnant women were involved in the study using stratified sampling technique and multiple logistic regression analysis was employed using SPSS version 16. RESULTS: A total of 400 pregnant women actively participated in this study and 330 (82.5%) of them accepted provider-initiated HIV testing and counseling to be tested for HIV and 70(17.5%) of them refused. Acceptance of provider-initiated HIV testing and counseling was positively associated with greater number of antenatal care visits [Adj. OR (95%CI) = 2.64(1.17, 5.95)], residing in the urban areas[Adj. OR (95%CI) = 2.85(1.10, 7.41)], having comprehensive knowledge on HIV [Adj. OR (95%CI) = 4.30(1.72, 10.73)], positive partners reaction for HIV positive result [Adj. OR (95%CI) = 8.19(3.57, 18.80)] and having knowledge on prevention of mother to child transmission of HIV[Adj. OR (95%CI) = 3.27(1.34, 7.94)], but negatively associated with increased maternal age and education level. CONCLUSION: Utilization of provider-initiated HIV testing and counseling during antenatal care was relatively high among pregnant women in Gondar town. Couple counseling and HIV testing should be strengthened to promote provider-initiated HIV testing and counseling among male partners and to reduce HIV related violence of women from their partner and access to and consistent use of antenatal care should be improved to increase the uptake of provider-initiated HIV testing and counseling service. PMID- 22440019 TI - Gold nanoparticles located at the interface of anatase/rutile TiO2 particles as active plasmonic photocatalysts for aerobic oxidation. AB - Visible-light irradiation (lambda > 450 nm) of gold nanoparticles loaded on a mixture of anatase/rutile TiO(2) particles (Degussa, P25) promotes efficient aerobic oxidation at room temperature. The photocatalytic activity critically depends on the catalyst architecture: Au particles with <5 nm diameter located at the interface of anatase/rutile TiO(2) particles behave as the active sites for reaction. This photocatalysis is promoted via plasmon activation of the Au particles by visible light followed by consecutive electron transfer in the Au/rutile/anatase contact site. The activated Au particles transfer their conduction electrons to rutile and then to adjacent anatase TiO(2). This catalyzes the oxidation of substrates by the positively charged Au particles along with reduction of O(2) by the conduction band electrons on the surface of anatase TiO(2). This plasmonic photocatalysis is successfully promoted by sunlight exposure and enables efficient and selective aerobic oxidation of alcohols at ambient temperature. PMID- 22440020 TI - Opportunities to improve nutrient efficiency in pigs and poultry through breeding. AB - Efficiency of food and nutrient (including energy) use are considered the key factors in the economic and environmental performance of livestock systems. The aim of this paper is to consider the basis of genetic variation in the components that constitute dietary nutrient efficiency; and to conclude whether there would be benefit, in any relevant terms, in including these components in breeding programmes that aim to improve nutrient efficiency within pig and poultry systems of production. The components considered are (i) external, pre-ingestion losses, such as food spillage and its relation to feeding behaviour traits, (ii) digestive efficiency, (iii) maintenance requirements, (iv) net efficiency of energy and nutrient utilisation and (v) partitioning of scarce resources within productive and between productive and fitness functions. It is concluded that opportunities to exploit genetic variation exist mainly in the potential to improve the digestive efficiency of pigs and to reduce the maintenance requirements for resources mainly in hens, but also potentially in pigs. Current evidence suggests that there are very weak genetic and phenotypic correlations between components of feeding behaviour and productive traits, and little genetic variation in the net efficiency of nutrient utilisation among poultry and pig genotypes. The implication of the latter is that there would be little exploitable genetic variation in the partitioning of scarce nutrients between productive functions. Currently, there is a lack of understanding of the genetic basis of the partitioning of scarce nutrients between productive and fitness functions, and how this may impact upon the efficiency of nutrient use in pig and poultry systems. This is an area of research to which further effort might usefully be devoted. PMID- 22440021 TI - Use of partial least squares regression to predict single nucleotide polymorphism marker genotypes when some animals are genotyped with a low-density panel. AB - High-density single nucleotide polymorphism (SNP) platforms are currently used in genomic selection (GS) programs to enhance the selection response. However, the genotyping of a large number of animals with high-throughput platforms is rather expensive and may represent a constraint for a large-scale implementation of GS. The use of low-density marker (LDM) platforms could overcome this problem, but different SNP chips may be required for each trait and/or breed. In this study, a strategy of imputation independent from trait and breed is proposed. A simulated population of 5865 individuals with a genome of 6000 SNP equally distributed on six chromosomes was considered. First, reference and prediction populations were generated by mimicking high- and low-density SNP platforms, respectively. Then, the partial least squares regression (PLSR) technique was applied to reconstruct the missing SNP in the low-density chip. The proportion of SNP correctly reconstructed by the PLSR method ranged from 0.78 to 0.97 when 90% and 50%, respectively, of genotypes were predicted. Moreover, data sets consisting of a mixture of actual and PLSR-predicted SNP or only actual SNP were used to predict genomic breeding values (GEBVs). Correlations between GEBV and true breeding values varied from 0.74 to 0.76, respectively. The results of the study indicate that the PLSR technique can be considered a reliable computational strategy for predicting SNP genotypes in an LDM platform with reasonable accuracy. PMID- 22440022 TI - Estimates of genetic parameters for visual scores and daily weight gain in Brangus animals. AB - (Co)variance components were estimated for visual scores of conformation (CY), early finishing (PY) and muscling (MY) at 550 days of age (yearling), average daily gain from weaning to yearling (GWY), conformation (CW), early finishing (PW) and muscling (MW) scores at weaning, and average daily gain from birth to weaning (GBW) in animals forming the Brazilian Brangus breed born between 1986 and 2002 from the livestock files of GenSys Consultants Associados S/C Ltda. The data set contained 53 683; 45 136; 52 937; 56 471; 24 531; 21 166; 24 006 and 25 419 records for CW, PW, MW, GBW, CY, PY, MY and GWY, respectively. Data were analyzed by the restricted maximum likelihood method using single- and two-trait animal models. Direct heritability estimates obtained by single-trait analysis were 0.12, 0.14, 0.13 and 0.14 for CY, PY and MY scores and GWY, respectively. A positive association was observed between the same visual scores at weaning and yearling, with correlations ranging from 0.64 to 0.94. Estimated correlations between GBW and weaning and yearling scores ranged from 0.60 to 0.77. The genetic correlation between GBW and GWY was low (0.10), whereas correlations of 0.55, 0.37 and 0.47 were observed between GWY and CY, PY and MY, respectively. Moreover, GWY showed a weak correlation with CW (0.10), PW (-0.08) and MW (-0.03) scores. These results indicate that selection of the traits that was studied would result in a small response. In addition, selection based on average daily gain may have an indirect effect on visual scores as the correlations between GWY and visual scores were generally strong. PMID- 22440023 TI - Assessment of a natural dietary extract, titrated in phenylpropanoid glycosides, on blood parameters and plasma oxidative status in intensively reared Italian hares (Lepus corsicanus). AB - Two different doses of a natural extract titrated in phenylpropanoid glycosides (PPGs) were evaluated for their effect on blood parameters and plasma oxidative status in pairs of intensively reared Italian hares. The study lasted 210 days, during which 45 couples of hares were divided into three homogeneous groups. A control group (CON) was fed a control diet while the two experimental groups were fed a diet supplemented with 1 or 2 kg/t of a supplement titrated in PPGs. Blood samples were obtained at 0, 70, 140 and 210 days and assayed for plasma lipid profiles, bilirubin, haematological parameters and indicators of oxidative status (reactive oxygen metabolites (ROMs), thiobarbituric acid reactive substances (TBARS), vitamins A and E). Although dietary treatment did affect the levels of triglycerides, total cholesterol and total bilirubin, all of which decreased markedly (P < 0.05), while significantly increasing the (P < 0.01) HDL cholesterol values, it also significantly improved the oxidative status of the blood, which displayed an increase in both vitamin E (P < 0.01) and vitamin A (P < 0.05) and a decrease in ROMs (P < 0.01) and TBARS (P < 0.05). The improvements in the blood parameters, lipid profile and plasma oxidative status continued to increase significantly as the trial progressed, indicating a positive effect with increased length of treatment. The results of this study demonstrate an important role for feed supplementation with respect to antioxidant activity on some blood parameters, including the lipid profile and the oxidative status of blood. PMID- 22440024 TI - The effect of a diet with fructan-rich chicory roots on intestinal helminths and microbiota with special focus on Bifidobacteria and Campylobacter in piglets around weaning. AB - The restrictions on the use of antibiotic and anthelmintic treatments in organic pig farming necessitate alternative non-medical control strategies. Therefore, the antibiotic and parasite-reducing effect of a fructan-rich (prebiotic) diet of dried chicory was investigated in free-ranging piglets. Approximately half of 67 piglets from nine litters were experimentally infected with Ascaris suum and Trichuris suis in the suckling period (1 to 7 weeks of age) and 58 of the piglets were challenged daily with Eschericia coli O138:F8 for 9 days after weaning to induce weaning diarrhoea. The litters were fed either chicory (30% dry matter) or a control diet. The effect of chicory on intestinal helminths, intestinal microbiota, especially Bifidobacteria and Campylobacter spp. and E. coli post weaning diarrhoea was assessed. The weight gain of the piglets was not impaired significantly by chicory. The intestinal A. suum worm burden was reduced by 64% (P = 0.034) in the chicory-fed piglets, whereas these same piglets had 63% more T. suis worms (P = 0.016). Feeding with chicory elicited no changes among the main bacterial groups in ileum according to terminal restriction fragment length polymorphism analysis. However, the terminal-restriction fragment (T-RF) 208 bp, which may belong to Lachnospiraceae, was stimulated by the chicory feed (P = 0.03), and T-RF 370 bp that matches Enterobacter belonging to the Enterobacteria was reduced (P = 0.004). In addition, chicory increased the level of Bifidobacteria (P = 0.001) and the faecal Campylobacter excretion level was transitorily reduced in chicory-fed piglets at 7 weeks of age (P = 0.029). Unfortunately, it was not possible to assess the effect of chicory on post weaning diarrhoea as it did not develop. In conclusion, feeding piglets chicory around the time of weaning caused complex changes of the microbiota and parasite communities within the intestinal tract, and feeding piglets chicory may therefore serve as an animal-friendly strategy to control pathogens. PMID- 22440025 TI - Use of the Affymetrix Human GeneChip array and genomic DNA hybridisation probe selection to study ovine transcriptomes. AB - Affymetrix GeneChip microarrays are a powerful tool to study global gene expression profiles and have been used on many species. However, no sheep specific Affymetrix GeneChip is currently available and the bovine array is fairly limited in its coverage and annotation. Previously, a probe-selection method based on hybridisation of genomic DNA (gDNA) was developed, which enables GeneChips to be used for species that they were not designed for. This approach can greatly increase the number of potential annotated genes that can be studied beyond that which is currently available, particularly for species that do not have comprehensively characterised genomes. In this study, we demonstrate that gDNA-based probe selection on the Affymetrix Human U133+2 GeneChip array can be used to study gene expression profiles in sheep tissues. More than 20 000 transcripts were detected in triplicate ovine skeletal muscle and liver samples, which is more than would be possible using the commercially available sheep specific microarray. The majority of the top 15 differentially expressed genes for each tissue were known to either be expressed in a tissue-specific manner or relate to specific functions of that tissue. Gene ontology analysis of the differentially expressed genes revealed the expected differences in gene expression profiles between the two tissues. Besides demonstrating that the probe selection method can be used to study the ovine transcriptome, the benefits of this approach are that it can greatly increase the number of annotated and novel genes that can be studied beyond those currently possible using ovine- or bovine specific microarrays. This same method also has the potential to allow the study of other species where species-specific microarrays are not available or whose genomes have not been comprehensively characterised. PMID- 22440026 TI - Expression of DNAJA1 in bovine muscles according to developmental age and management factors. AB - We have recently shown that the expression of the DNAJA1 gene encoding a heat shock protein (Hsp40) is a negative marker of meat tenderness in Charolais bulls. To acquire knowledge on the regulation of DNAJA1 expression, we analysed the abundance of DNAJA1 transcripts and protein during development and according to management factors (e.g. feeding treatments, growth path and stress status) in different bovine muscles during postnatal life. We report here a developmental expression profile for DNAJA1 with decreased levels of transcript and protein during the progression of myogenesis. During postnatal life, we found the highest expression of DNAJA1 in the most oxidative muscles. No effect was detected for dietary treatment (pasture v. maize-based diet), growth path (compensatory growth after a restriction period) or pre-slaughter stress status. Therefore, the genetic background and muscle type could be considered as the main factors regarding the level of DNAJA1. Integration of the knowledge gained from this study should help to predict muscle metabolic properties and the ability of the live animals to give high sensory quality meat. PMID- 22440027 TI - Beef cattle selected for increased muscularity have a reduced muscle response and increased adipose tissue response to adrenaline. AB - The aim of this experiment was to evaluate the impact of selection for greater muscling on the adrenaline responsiveness of muscle, adipose and liver tissue, as reflected by changes in plasma levels of the intermediary metabolites lactate, non-esterified fatty acids (NEFA) and glucose. This study used 18-month-old steers from an Angus herd visually assessed and selected for divergence in muscling for over 15 years. Ten low muscled (Low), 11 high muscled (High) and 3 high muscled heterozygotes for myostatin mutation (High(Het)) steers were challenged with adrenaline doses ranging between 0.2 to 3.0 MUg/kg live weight. For each challenge, 16 blood samples were taken between -30 and 130 min relative to adrenaline administration. Plasma was analysed for NEFA, lactate and glucose concentration and area under curve (AUC) over time was calculated to reflect the tissue responses to adrenaline. Sixteen basal plasma samples from each animal were also assayed for growth hormone. Muscle glycogen and lactate concentration were analysed from four muscle biopsies taken from the semimembranosus, semitendinosus and longissimus thoracis et lumborum of each animal at 14, 90 and 150 days on an ad libitum grain-based diet and at slaughter on day 157. In response to the adrenaline challenges, the High steers had 30% lower lactate AUC than the Low steers at challenges greater than 2 MUg/kg live weight, indicating lower muscle responsiveness at the highest adrenaline doses. Aligning with this decrease in muscle response in the High animals were the muscle glycogen concentrations which were 6.1% higher in the High steers. These results suggest that selection for muscling could reduce the incidence of dark, firm, dry meat that is caused by low levels of glycogen at slaughter. At all levels of adrenaline challenge, the High steers had at least 30% greater NEFA AUC, indicating that their adipose tissue was more responsive to adrenaline, resulting in greater lipolysis. In agreement with this response, the High steers had a higher plasma growth hormone concentration, which is likely to have contributed to the increased lipolysis evident in these animals in response to adrenaline. This difference in lipolysis may in part explain the reduced fatness of muscular cattle. There was no effect of selection for muscling on liver responsiveness to adrenaline. PMID- 22440028 TI - Variations in the abundance of 24 protein biomarkers of beef tenderness according to muscle and animal type. AB - Some proteins have been revealed as biomarkers for beef tenderness by previous studies. These markers could be used in immunological tests to predict beef tenderness, in living animals as well as in carcasses. It is well known that rearing practices modify the amounts of mRNA and proteins. Therefore, the reliability of protein tests could be affected by livestock and biological effects such as production systems, breed, muscle and animal type. This study analysed the effects of animal and muscle type on 24 proteins. The animals studied were 67 young bulls and 44 steers of the Charolais breed, and muscles were Longissimus thoracis and Semitendinosus. Protein amounts were determined by Dot blot, an immunological technique. Results showed that expressions of 20 proteins were influenced by animal and/or muscle type. These results could lead to modifications and adaptations of prediction tests according to rearing practice, bovine breed and beef cut. PMID- 22440029 TI - The role of mathematical models of host-pathogen interactions for livestock health and production - a review. AB - Compared with the application of mathematical models to study human diseases, models that describe animal responses to pathogen challenges are relatively rare. The aim of this review is to explain and show the role of mathematical host pathogen interaction models in providing underpinning knowledge for improving animal health and sustaining livestock production. Existing host-pathogen interaction models can be assigned to one of three categories: (i) models of the infection and immune system dynamics, (ii) models that describe the impact of pathogen challenge on health, survival and production and (iii) models that consider the co-evolution of host and pathogen. State-of-the-art approaches are presented and discussed for models belonging to the first two categories only, as they concentrate on the host-pathogen dynamics within individuals. Models of the third category fall more into the class of epidemiological models, which deserve a review by themselves. An extensive review of published models reveals a rich spectrum of methodologies and approaches adopted in different modelling studies, and a strong discrepancy between models concerning diseases in animals and models aimed at tackling diseases in humans (most of which belong to the first category), with the latter being generally more sophisticated. The importance of accounting for the impact of infection not only on health but also on production poses a considerable challenge to the study of host-pathogen interactions in livestock. This has led to relatively simplistic representations of host-pathogen interaction in existing models for livestock diseases. Although these have proven appropriate for investigating hypotheses concerning the relationships between health and production traits, they do not provide predictions of an animal's response to pathogen challenge of sufficient accuracy that would be required for the design of appropriate disease control strategies. A synthesis between the modelling methodologies adopted in categories 1 and 2 would therefore be desirable. The progress achieved in mathematical modelling to study immunological processes relevant to human diseases, together with the current advances in the generation and analysis of biological data related to animal diseases, offers a great opportunity to develop a new generation of host-pathogen interaction models that take on a fundamental role in the study and control of disease in livestock. PMID- 22440030 TI - Furnished cages for laying hens: study of the effects of group size and litter provision on laying location, zootechnical performance and egg quality. AB - The furnished cage is a new housing system for layers. A current trend in furnished cage design is to increase group size and replace the litter box with a mat provided with litter. An experiment was set up to determine the effects of group size and litter provision on laying performance and egg quality of beak trimmed ISA Brown hens housed in large furnished cages with more than 12 hens. Six treatments, each of 18 furnished cages (768 cm(2)/hen including nest and litter area) were compared in a 3 * 2 experimental trial: three group sizes (S20 (20 hens per cage), S40 (40) and S60 (60)), with or without feed as litter distributed on the mat of the litter area. The provision of facilities per hen was equal in all treatments. Mortality, laying rate, mean egg weight, feed intake and feed conversion ratio were unaffected by group size over the 53-week laying period, and performance exceeded the ISA production standards. The overall percentage of eggs laid in the nest exceeded 95% except that it was slightly lower in group S20 (92.0% +/- 6.4% v. S40: 96.0% +/- 3.3% and S60: 96.2% +/- 2.7%) leading to a higher proportion of dirty eggs (S20: 1.6% +/- 2.2%, S40: 1.4% +/- 1.5%, S60: 1.0% +/- 1.0%). At 66 to 70 weeks, eggs laid outside the nest had a slightly higher count of mesophilic bacteria on the eggshell (5.0 log CFU/egg +/- 0.4) than those laid in the nest (4.8 log CFU/egg +/- 0.5) but no difference in contamination was observed between group sizes. Litter provision had no effect on mortality, egg weight or egg quality traits except for a higher proportion of broken eggs in cages with litter (5.3% +/- 6.2% v. 4.6% +/- 5.7%). Providing hens with feed for litter was associated with a higher laying rate (97.3% +/- 3.2% v. 94.8% +/- 4.4% at 23 weeks) and an apparent improvement in feed efficiency at the beginning of the laying period (feed conversion ratio based on feed consumption at the trough: 2.18 +/- 0.06 with litter v. 2.28 +/- 0.09 without litter at 25 weeks). The results of this study showed that a high level of productivity and good egg quality could be obtained in large furnished cages. Further research is needed to assess the impact on hens' welfare and performance of using more economically competitive substrates than feed for litter. PMID- 22440031 TI - Stray voltage threshold is better determined under choice test conditions in sheep. AB - Stray voltage (usually <10 V) can occur in farms. However, very little information is available related to sheep. In addition, little work has been carried out on the effects of the contextual conditions under which the animals are submitted to stray voltage. The aims of this study were (i) to determine the threshold voltage at which lambs start to express avoidance behaviour and (ii) to test if the contextual conditions (i.e. choice v. no-choice conditions) influence the determination of the threshold voltage inducing avoidance behaviour. Six month-old female lambs fed ad libitum were trained to eat palatable pellets from one or two metallic feeders situated at the end of a 4-m long raceway. Voltage was then applied during a 2-min test to either the only feeder available (no choice test, 1F, n = 13) or to the first of the two feeders in which the lamb started to eat (choice test, 2F, n = 13). The 1F lambs had to stop eating to avoid the voltage, whereas the 2F lambs were allowed to switch to the non electrified feeder to carry on eating without any stray voltage. Stray voltage was applied every day, in steps of 0.5 V (AC, 50 Hz), from 0 up to 8 V. For voltages higher than 4.5 V, 2F lambs spent less time eating and ate less in the electrified feeder compared with the non-electrified feeder, and their latency to switch to the non-electrified feeder was shorter. In addition, a transient modification of behaviour was observed at 1.5 V. For 1F lambs, a decrease in the quantity of feed eaten was found for voltages higher than 5 V, although the time spent eating in the electrified feeder was not modified. Finally, 1F lambs urinated more during or just after the 2 min test than 2F lambs for voltages above 5 V. Although lambs with no choice experienced stray voltage as a negative event (increased occurrence of urination), they carried on eating in the electrified feeder whatever the voltage. Therefore, the contextual conditions in which animals are exposed to stray voltage influence their subsequent reactions: the first clear behavioural reaction threshold is easier to detect in choice than in no-choice conditions. PMID- 22440032 TI - Podolian beef production on pasture and in confinement. AB - From February to August 2007 the effect of rearing system (confined (C) v. free ranging (FR)) and season (spring v. summer) was evaluated on behaviour, immune and blood parameters and beef production (experiment 1). From February to August 2008, the effect of rearing system was only evaluated on beef production (experiment 2). A total of 12 Podolian young bulls were used each year. They were slaughtered at 18 and 15 months of age in 2007 and 2008, respectively. Herbage mass and pasture composition were monitored during the 2 years. Pasture availability, in terms of herbage mass and composition, as well as its seasonal development, was similar in the 2 years. In the first experiment, FR animals spent more time walking (P < 0.05), feeding (P < 0.001) and standing (P < 0.01) and showed a lower number of agonistic (P < 0.05) and non-agonistic social interaction than C animals (P < 0.01). Significant lower concentrations of serum urea nitrogen (P < 0.001) and creatinine (P < 0.10) in FR animals indicated a lower protein nutritional status due to inadequate protein availability at pasture. As a consequence, average daily gains (P < 0.05), slaughter weight (P < 0.05) and body condition score (P < 0.01) were lower in grazing animals as compared with C bulls. Cellular immune responsiveness was higher in FR animals (P < 0.05). Similarly, antibody titre to keyhole limpet hemocyanin was higher in FR bulls at the 2nd and 3rd month after antigen injection (P < 0.05), whereas it tended to be higher at the 4th month (P < 0.10). In both experiments, grazing negatively affected meat colour in terms of lightness. Eighteen-month-old bulls also showed lower final weight, weight gain and body conditions when kept outdoor: a possible consequence of nutrient deficits, as suggested by the metabolic status of FR animals. The same animals, however, benefited from FR in terms of natural behaviour expression and immune responsiveness. When the experiment was replicated the subsequent year, on animals slaughtered at 15 months of age, no differences between the performances of FR and C animals were detected. The earlier slaughter age system was also proportionally less dependent on external inputs as grazing was not extended to the dry season when herbage mass availability was lower. PMID- 22440033 TI - Devaluation of low-quality food during early experience by sheep. AB - A ruminant's early experience with low-quality food (LQF) is expected to increase its acceptance and preference in adulthood. Contrarily, we found that experienced sheep (ES) exposed to mature oat hay early in life ate less of this LQF than inexperienced sheep (IS). A possibility is that ES might have devaluated the LQF through continuous comparisons against high-quality food (HQF) supplements (sunflower meal and ground corn) that were simultaneously available during early experience. In this study, we tested the devaluation hypothesis with a successive negative contrast (SNC) procedure. In a consummatory SNC procedure, 'shift' subjects are unexpectedly changed from HQF to LQF, and their consumption is then compared against the consumption of 'unshift' subjects that receive LQF all throughout the SNC procedure. The magnitude of the difference in consumption between preshift and postshift is regarded as a measure of the degree to which both foods (HQF and LQF) are perceived to differ hedonically. When sheep from our previous study were 300 days old, both ES and IS were randomly assigned to either shift (ES-S and IS-S) or unshift conditions (ES-U and IS-U; n = 6 in each group). Groups ES-S and IS-S were fed HQF (alfalfa hay) during the preshift phase, and then suddenly changed to LQF (oat hay) in the postshift phase. Groups ES-U and IS U (controls) were fed only LQF throughout the SNC procedure. Subjects in ES-S showed a significantly lower intake of LQF than those in ES-U in the first postshift session (i.e. they showed an SNC effect), which was not observed in IS. These results agree with ES subjects having devalued LQF during early experience. We discuss the possibility that high levels of nutrient supplementation can result in devaluation of LQF (i.e. decrease in preference and acceptance), whereas restricted levels of supplementation may promote a positive experience with LQF. PMID- 22440034 TI - Validating indicators of sheep welfare through a consensus of expert opinion. AB - A consensus of expert opinion was used to provide both face and consensual validity to a list of potential indicators of sheep welfare. This approach was used as a first step in the identification of valid welfare indicators for sheep. The consensus methodology of the National Institute of Health, using pre-meeting consultation and focus group discussions, was used to ascertain the consensus opinion of a panel of sheep welfare experts. The Farm Animal Welfare Council's five freedoms were used as a framework to organise a list of current on-farm welfare issues for sheep. The five freedoms were also the welfare criterion used to identify potential on-farm welfare indicators for sheep. As a result, experts identified 193 welfare issues for sheep and lambs managed on farms across England and Wales. Subsequently, a combination of animal- (n = 26), resource- (n = 13) and management- (n = 22) based indicators was suggested for (i) adult rams, (ii) adult ewes (male and female sheep, over 1 year old), (iii) growing lambs (male and female sheep, over 6 weeks to 1 year old) and (iv) young lambs (male and female lambs, 6 weeks old and under). The results from this study could therefore be used to inform the further development of valid methods of assessing the on farm welfare of sheep. PMID- 22440035 TI - Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves. AB - The effects of hydrolyzed yeast supplementation on growth performance, health and immune-physiological parameters in neonatal calves challenged with vaccine were investigated. Twelve Holstein calves were started in the experiment at 2 +/- 1 days of age and were studied for 35 days. Calves were randomly assigned to each of two dietary treatments, a control (CON) and hydrolyzed yeast (HY) group. The calves in the HY group received control calf starter supplemented with 0.2% HY. All calves were given calf starter ad libitum for 5 weeks starting in week 1. Calves were also given whole milk according to a step-down milking protocol. In order to induce immune responses, all calves were challenged with Hog cholera and Erysipelothrix insidiossa live vaccines by intramuscular injection at 3 weeks of age. Growth performance and feed intake were not affected by dietary treatment throughout the experimental period, except that the HY group had significantly higher (P < 0.05) milk intake than did the CON group at 3 weeks of age. Calves in the HY group showed significantly better (P < 0.05) fecal and health scores at 3 weeks compared to those in the control group. After vaccine challenge, neutropenia, lymphophilia and thrombocytopenia were observed in the CON group, but calves in the HY group did not show significant changes of leukocytes. The average concentration of serum haptoglobin in the HY group was significantly higher (P < 0.05) at 1 and 3 days post-vaccine challenge (DPVC) than that of CON group. Feeding HY supplemented calf starter resulted in a higher (P < 0.05) relative amount of bacterial and viral - specific IgA than in the CON group at 5 DPVC. Although the percentage of CD4+ T cells was significantly (P < 0.05) higher in the HY group than in the CON group at -2 DPVC, significant differences between groups after vaccine challenge was not observed during the experimental period. These results suggest that 0.2% HY supplementation in calf starter can improve the health status and immune-related serum protein production and affect blood cell composition in neonatal calves after vaccine challenge. PMID- 22440036 TI - Involvement of small-scale dairy farms in an industrial supply chain: when production standards meet farm diversity. AB - In certain contexts, dairy firms are supplied by small-scale family farms. Firms provide a set of technical and economic recommendations meant to help farmers meet their requirements in terms of the quantity and quality of milk collected. This study analyzes how such recommendations may be adopted by studying six farms in Brazil. All farms are beneficiaries of the country's agrarian reforms, but they differ in terms of how they developed their activities, their resources and their milk collection objectives. First, we built a technical and economic benchmark farm based on recommendations from a dairy firm and farmer advisory institutions. Our analysis of the farms' practices and technical and economic results show that none of the farms in the sample apply all of the benchmark recommendations; however, all farms specialized in dairy production observe the main underlying principles with regard to feeding systems and breeding. The decisive factors in whether the benchmark is adopted and successfully implemented are (i) access to the supply chain when a farmer establishes his activity, (ii) a grasp of reproduction and forage production techniques and (iii) an understanding of dairy cattle feed dietary rationing principles. The technical problems observed in some cases impact the farms' dairy performance and cash position; this can lead to a process of disinvestment. This dynamic of farms facing production standards suggests that the diversity of specialized livestock farmers should be taken into account more effectively through advisory approaches that combine basic zootechnical training with assistance in planning farm activities over the short and medium term. PMID- 22440037 TI - Selection for nutrients by pregnant goats on a microphyll desert scrub. AB - The behavioral consequences of pregnancy in goats were studied to test the hypothesis that pregnant females on rangeland select a diet richer in nutrients once the demands of gestation increase, and that nutrient content in goat diets changes with the grazing season. A total of 12 mature mixed breed goats either pregnant (n = 6) or non-pregnant (n = 6) were used during the dry period (February to May). Dietary samples obtained from the oral cavity of grazing goats (restrained with a short light rope permanently tightened around their neck) were used for chemical analyses. Across months, pregnant goats selected diets higher (P < 0.01) in crude protein (CP) than non-pregnant goats; this nutrient did not meet the requirements of late gestating goats. Pregnant goats made use of less (P < 0.01) fibrous feeds than non-pregnant goats. In order to cope with changing nutrient demands for pregnancy, goats adjusted their diet by increasing the selection of plants with 32% higher calcium content compared to forages selected by non-pregnant goats. The physiological state of goats did not alter the levels of phosphorus (P), magnesium (Mg) and sodium (Na) in their diets; these minerals were adequate to meet the demands of pregnancy. There were no effects of physiological state on concentrations of copper (Cu), zinc (Zn), manganese (Mn) and iron (Fe) in the goat diets during the dry season, with levels adequate for sustainability of pregnancy. Pregnant goats did not seek forages lower in tannins, alkaloids, saponins and terpenes. It was concluded that to cope with increasing pregnancy costs, goats adjusted their diets increasing selection of forages or plant parts with high nutritional value to maximize their net nutrient budget. PMID- 22440038 TI - Number of females in cattle, sheep, pig, goat and horse breeds predicted from a single year's registration data. AB - An objective and accountable method is needed for deducing the number of registered animals in a breed from registration data. By following the principle that individual breeders register sufficient young females to be certain of having enough replacements for their current breeding stock, the ratios were calculated of the number of adult females in a breed to the number of female registrations, in a given year. Number of breeds considered were 8 cattle, 16 sheep, 8 pigs, 1 goat and 2 equines, all in the United Kingdom or Ireland. This yielded multipliers (4.4 for cattle, 3.3 for sheep, 3.1 for pigs, with confidence limits; and a point estimate of 5.2 for goats) enabling total adult female population to be predicted from a single year's registration data. There was considerable variation between breeds in values of the multiplier, apparently for reasons of breed history and function. This was particularly evident for equines where the two breeds yielded multipliers of 3.8 and 13.9. Multipliers, using registration data that are already in the public domain, can provide an estimate of breed numerical size, which a breed society can either accept or replace with an audited census. PMID- 22440039 TI - Radiosurgery for para-IAC meningiomas: the effect of radiation dose to the cochlea on hearing outcome. AB - PURPOSE: This study was performed to assess the radiosurgical results of meningiomas extending into the internal acoustic canal (para-IAC meningiomas), with a particular focus on the effect of radiation dose to the cochlea on hearing outcome. METHODS AND MATERIALS: A total of 50 patients who underwent radiosurgery for para-IAC meningiomas between 1998 and 2009, which were followed for 2 years, were enrolled. The mean age was 55.8 years (range, 15-75). The mean tumor volume was 6.1 cm(3) (range, 1.0-19.0), the mean tumor length in the IAC was 6.9 mm (range, 1.3-13.3), and the mean prescribed marginal dose was 13.1 Gy (range, 10 15) at an isodose line of 50%. The mean follow-up duration was 46 months (range, 24-122). RESULTS: Eight (16.0%) patients had nonserviceable hearing at the time of surgery. At the last follow-up, the tumor control rate was 94%; unchanged in 17 patients, decreased in 30 patients, and increased in 3 patients. Among 42 patients with serviceable hearing at the time of radiosurgery, it was preserved in 41 (97.6%) patients at the last follow-up. The maximal and mean radiation doses to the cochleae of these 41 patients were 5.8 Gy +/- 0.3 (range, 3.1-11.5) and 4.3 Gy +/- 0.2 (range, 2.2-7.5), respectively. The maximal dose to the cochlea of the patient who lost hearing after radiosurgery was 4.7 Gy. CONCLUSIONS: The radiation dose to the cochlea may have the minimal toxic effect on the hearing outcome in patients who undergo radiosurgery for para-IAC meningiomas. PMID- 22440040 TI - Quantifying the interfractional displacement of the gastroesophageal junction during radiation therapy for esophageal cancer. AB - PURPOSE: Accounting for interfractional changes in tumor location improves the accuracy of radiation treatment delivery. The purpose of this study was to quantify the interfractional displacement of the gastroesophageal junction (GEJ) based on standard treatment setup in patients with esophageal cancer undergoing radiation therapy. METHODS AND MATERIALS: Free-breathing four-dimensional computed tomography (4D-CT) datasets were acquired weekly from 22 patients during treatment for esophageal adenocarcinoma. Scans were registered to baseline (simulation) 4D-CT scans by using bony landmarks. The distance between the center of the GEJ contour on the simulation scan and the mean location of GEJ centers on subsequent scans was used to assess changes in GEJ location between fractions; displacement was also correlated with clinical and respiratory variables. RESULTS: The mean absolute random error was 1.69 mm (range, 0.11-4.11 mm) in the lateral direction, 1.87 mm (range, 0.51-4.09 mm) in the anterior-posterior (AP) direction, and 3.09 mm (range, 0.99-6.16 mm) in the superior-inferior (SI) direction. The mean absolute systemic GEJ displacement between fractions was 2.88 mm lateral (>= 5 mm in 14%), mostly leftward; 2.90 mm (>= 5 mm in 14%) AP, mostly anterior; and 6.77 mm (>= 1 cm in 18%) SI, mostly inferior. Variations in tidal volume and diaphragmatic excursion during treatment correlated strongly with systematic SI GEJ displacement (r = 0.964, p < 0.0001; and r = 0.944, p < 0.0001, respectively) and moderately with systematic AP GEJ displacement (r = 0.678, p = 0.0005; r = 0.758, p < 0.0001, respectively). Systematic displacement in the inferior direction resulted in higher-than-intended doses (>= 60 Gy) to the GEJ, with increased hot-spot to the adjacent stomach and lung base. CONCLUSION: We found large (>1-cm) interfractional displacements in the GEJ in the SI (especially inferior) direction that was not accounted for when skeletal alignment alone was used for patient positioning. Because systematic displacement in the SI direction had dosimetric impact and correlated with tidal volume, better accounting for depth of breathing is needed to reduce interfractional variability. PMID- 22440041 TI - Hyperbaric oxygen therapy for radiation-induced cystitis and proctitis. AB - PURPOSE: To provide a retrospective analysis of the efficacy of hyperbaric oxygen therapy (HBOT) for treating hemorrhagic cystitis (HC) and proctitis secondary to pelvic- and prostate-only radiotherapy. METHODS AND MATERIALS: Nineteen patients were treated with HBOT for radiation-induced HC and proctitis. The median age at treatment was 66 years (range, 15-84 years). The range of external-beam radiation delivered was 50.0-75.6 Gy. Bleeding must have been refractory to other therapies. Patients received 100% oxygen at 2.0 atmospheres absolute pressure for 90-120 min per treatment in a monoplace chamber. Symptoms were retrospectively scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale to evaluate short-term efficacy. Recurrence of hematuria/hematochezia was used to assess long-term efficacy. RESULTS: Four of the 19 patients were lost to follow-up. Fifteen patients were evaluated and received a mean of 29.8 dives: 11 developed HC and 4 proctitis. All patients experienced a reduction in their LENT-SOMA score. After completion of HBOT, the mean LENT-SOMA score was reduced from 0.78 to 0.20 in patients with HC and from 0.66 to 0.26 in patients with proctitis. Median follow-up was 39 months (range, 7-70 months). No cases of hematuria were refractory to HBOT. Complete resolution of hematuria was seen in 81% (n = 9) and partial response in 18% (n = 2). Recurrence of hematuria occurred in 36% (n = 4) after a median of 10 months. Complete resolution of hematochezia was seen in 50% (n = 2), partial response in 25% (n = 1), and refractory bleeding in 25% (n = 1). CONCLUSIONS: Hyperbaric oxygen therapy is appropriate for radiation-induced HC once less time-consuming therapies have failed to resolve the bleeding. In these conditions, HBOT is efficacious in the short and long term, with minimal side effects. PMID- 22440042 TI - A phase I clinical and pharmacology study using amifostine as a radioprotector in dose-escalated whole liver radiation therapy. AB - PURPOSE: Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. METHODS AND MATERIALS: We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed. RESULTS: Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 +/- 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 MUM with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients. CONCLUSION: These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer. PMID- 22440043 TI - Examining barriers to care: provider and client perspectives on the stigmatization of HIV-positive Asian Americans with and without viral hepatitis co-infection. AB - Between 1999 and 2003, Asian Americans and Pacific Islanders (APIs) in the US experienced more rapid growth in the number of AIDS cases than any other racial or ethnic group. In addition, the prevalence of HBV and HIV co-infection is estimated to be significantly higher among APIs in the US than in other racial/ethnic groups. High rates of HIV and hepatitis B or C (HBV and/or HCV) co infection, in concert with language and cultural barriers, create significant challenges to effective coordination of treatment. The purpose of this study is to identify barriers to care and treatment in APIs with HIV with and without hepatitis co-infection. Specifically, we analyze results from semi-structured interviews with health care providers (N=23) and Asian Americans who are HIV and hepatitis (HBV and/or HCV) co-infected (N =17) in order to clarify how stigma in particular may impede/limit access to coordinated health care provision. Providers and clients recognize the need for integrated, culturally and linguistically appropriate access to care while simultaneously acknowledging that stigma is a severe barrier to access to care. This article sheds light on the complexities of the stigma experienced by HIV and hepatitis co-infected Asian Americans and suggests a need for further research and renewed efforts by caregivers to reduce stigma in these communities. PMID- 22440044 TI - Clinical implication of urinary tubular markers in the early stage of nephropathy with type 2 diabetic patients. AB - AIM: The aim of this study was to evaluate the association of urinary tubular markers, interleukin-18 (IL-18) and angiotensinogen with albuminuria in early nephropathy of type 2 diabetics. METHODS: Urine levels of tubular markers (kidney injury molecule [KIM]-1, neutrophil gelatinase-associated lipocalin [NGAL] and liver-type fatty acid-binding protein [L-FABP]), proinflammatory marker (IL-18), and a marker of intrarenal renin-angiotensin system (RAS) status (angiotensinogen) were determined in 118 patients with type 2 diabetes mellitus and 25 non-diabetic controls with estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m(2). RESULTS: Urinary levels of KIM-1, NGAL, IL-18 and angiotensinogen were significantly higher in macroalbuminuria group compared with control and normo- and microalbuminuria groups but not significantly different between control and normoalbuminuria group. Urinary tubular markers were positively correlated with urinary IL-18 and angiotensinogen, respectively. The urinary albuminuria was correlated with all investigated urinary markers in univariate analysis. After adjusting for several clinical parameters, urinary KIM 1, NGAL and angiotensinogen were significantly associated with albuminuria. CONCLUSIONS: The results of this study suggest that urinary tubular markers may be independently associated with albuminuria in the early stage of nephropathy in type 2 diabetics (eGFR >= 60 mL/min/1.73 m(2)) and may reflect inflammatory processing and the activation of the intrarenal RAS. PMID- 22440045 TI - [Benefits of subcutaneous continuous insulin infusion in type 1 diabetic patients with high glycemic variability]. AB - BACKGROUND: Hypoglycemia limits the efficacy of intensive insulin therapy, especially in patients with great glucose variability. The extent to which continuous subcutaneous insulin infusion (CSII) overcomes this limitation is unclear. Our aim was to determine whether CSII is helpful for decreasing glucose variability and hypoglycemia, mainly in patients with the greatest variability. METHOD: Twenty-four patients with type 1 diabetes wore a continuous glucose monitoring system sensor for three days before starting therapy with CSII and 6 months later. Glucose variability (SD, MAGE, M) and hypoglycemia duration (area under the curve (AUC) <70mg/dL) were compared in all patients and in those with the greatest MAGE (highest quartile). RESULTS: At 6 months, a decreased glucose variability was seen, as measured by MAGE, M, and SD (median: -28mg/dL (interquartile range, -48 to 1), p=0.03; -22(-40 to 0), p=0.04; -11(-23 to 0), p=0.009; respectively). Patients with the greatest initial glucose variability (MAGE quartile 4) showed a greater decrease in both MAGE (-47mg/dL (-103 to -34) vs -20 (-36 to 17), p=0.01) and AUC <70 (-10.7mg/dL x day (-15 to 0) vs -1.1 ( 4.7 to 3.8), p=0.03) as compared to all others. Patients with longer initial hypoglycemia (AUC quartile 4) achieved a greater reduction in AUC <70 (-9.7mg/dL x day(-15 to -6.5) vs -0.08 (-2.9 to 3.8), p=0.003). A correlation was found between DeltaMAGE-DeltaAUC (r 0.4, p=0.03). CONCLUSIONS: During CSII, glucose variability significantly decreased, especially in patients with the greatest initial variability. Hypoglycemia was also markedly less in patients with greater variability, with the greatest reduction occurring in those who experienced more marked hypoglycemia with CSII. PMID- 22440046 TI - Monitoring HSV-TK/ganciclovir cancer suicide gene therapy using CdTe/CdS core/shell quantum dots. AB - To be able to label a gene and monitor its migration are key important approaches for the clinical application of cancer suicide gene therapy. Photonic nanomaterials are introduced in this work. One of the most promised suicide genes - herpes simplex virus thymidine kinase (HSV-TK) gene - is successfully linked with CdTe/CdS core/shell quantum dots (QDs) via EDC/NHS coupling method. From confocal microscopy it was demonstrated that plasmid TK intracellular trafficking can be effectively and distinctly traced via monitoring the luminescence of the QDs up to 96 h after transfection of QDs-TK conjugates into Hela cells. MTT results show that the QDs-TK conjugates have a high efficient cytotoxicity after adding GCV into Hela cells, whereas the QDs exert no detectable deleterious effects on the cellular processes. The apoptosis induced by QDs-TK conjugates with GCV is distinctly traced partly due to the strong luminescence of the QDs. Our results indicate that photonic nanomaterials, e.g. QDs, provide a tool for monitoring TK gene delivery and anti-cancer activity. PMID- 22440047 TI - Rapid aggregation of heterogeneous cells and multiple-sized microspheres in methylcellulose medium. AB - We report a method for the rapid production of cellular aggregates without electric power and cell modification. We focused on the swelling property of a solution containing a high molecular material, methylcellulose (MC), which immediately absorbs a small amount of solvent and fills the space occupied by the solvent. When 1 MUl of a suspension of 1000 animal cells in normal culture medium was injected into the 3% MC medium, the normal medium was rapidly absorbed by the surrounding MC medium. Suspended cells were simultaneously trapped on the interfaces between the normal and MC media; they were finally pulled together and held in the MC medium. This event was nearly complete within the first 10 min. Moreover, MC medium-dependent aggregation was observed when polystyrene microspheres of different sizes (diameter, 100 nm-100 MUm) were added. Furthermore, we demonstrated the stepwise fabrication of multi-layered aggregates with embedded structures. These methods for creating engineered aggregates should enhance the study of three-dimensional cultures comprising two or more cell types with well-designed structures. PMID- 22440048 TI - The concept of in vivo airway tissue engineering. AB - We investigated whether decellularized pig tracheas could regenerate in vivo, without being recellularized before transplantation, using the own body as bioreactor. Decellularized pig tracheal scaffolds were intraoperative conditioned with mononuclear cells and growth and differentiation factors. During the postoperative period, the in situ regeneration was boosted by administering bioactive molecules to promote peripheral mobilization and differentiation of stem/progenitor cells and ultimately the regenerative process. Results revealed, after 2 weeks, a nearly normal trachea, with respiratory epithelium and a double banded cartilage but without any mechanical differences compared to the native tissue. The growth factor administration resulted in a mobilization of progenitor and stem cells into the peripheral circulation and in an up-regulation of anti apoptotic genes. Isolated stem/progenitor cells could be differentiated in vitro into several cell types, proving their multipotency. We provide evidence that the own body can be used as bioreactor to promote in vivo tissue engineering replacement. Moreover, we demonstrated the beneficial effect of additional pharmaceutical intervention for an improved engraftment of the transplant. PMID- 22440049 TI - Effects of co-culturing BMSCs and auricular chondrocytes on the elastic modulus and hypertrophy of tissue engineered cartilage. AB - Co-culture of BMSCs and chondrocytes is considered as a promising strategy to generate tissue engineered cartilage as chondrocytes induce the chondrogenesis of BMSCs and inhibit the hypertrophy of engineered cartilage. Because the tissue specific stem/progenitor cells have been isolated from mature tissues including auricular cartilage, we hypothesized that adding stem cells to auricular chondrocytes in co-culture would also enhance the quality of engineered cartilage. In the present study, using the histological assay, biomechanical evaluation, and quantitative analysis of gene expression, we compared different strategies of auricular chondrocytes, BMSCs induction, and co-culture at different ratios on PGA/PLA scaffolds to construct tissue engineered elastic cartilage in vitro and in vivo. The up-regulation of RUNX2 and down-regulation of SOX9 were found in BMSCs chondrogenic induction group, which might imply a regulatory mechanism for the hypertrophy and potential osteogenic differentiation. Engineered cartilage in co-culture 5:5 group showed the densest elastic fibers and the highest Young's modulus, which were consistent with the expression profile of cartilage matrix-related genes including DCN and LOXL2 genes. Moreover, the better proliferative and chondrogenic potentials of engineered cartilage in co-culture 5:5 group were demonstrated by the stronger expression of Ki67 and Dlk1. PMID- 22440050 TI - Diaminododecane-based cationic bolaamphiphile as a non-viral gene delivery carrier. AB - The advancement in gene therapy relies upon the discovery of safe and efficient delivery agents and methods. In this study, we report the design and synthesis of a cationic bolaamphiphile as a non-viral gene delivery agent. The bolaamphiphile is composed of 1,12-diaminododecane as the central hydrophobic unit linked to the hydrophilic pentaethylenehexamine via thioether-based glycidyl units. This bolaamphiphile condensed DNA efficiently into nanoparticles of sizes around 150 200 nm with positive zeta potential of 30-35 mV. In vitro luciferase expression levels and percentage of GFP expressing cells induced by the bolaamphiphile/DNA complexes were higher than those mediated by the often used "golden" standard of non-viral systems, polyethyleneimine (PEI, branched, 25 kDa) at its optimal N/P ratio in HEK293, HepG2, NIH3T3, HeLa and 4T1 cells. In vitro cytotoxicity testing revealed that the DNA complexes fabricated from this cationic bolaamphiphile displayed marginal toxicity towards all the cell lines tested. In addition, in vivo transfection studies carried out in a 4T1 mouse breast cancer model showed that the cationic bolaamphiphile delivered DNA more efficiently than PEI. This cationic bolaamphiphile may make a promising gene delivery vector for future gene therapy. PMID- 22440051 TI - Ileal leiomyosarcoma and lymph node granuloma. Relevance of a rare association. AB - Leiomyosarcoma is rare in ileal location. We report the case of a 61 years old female patient presenting with ileal leiomyosarcoma occurring at 14 years after a uterine carcinoma treated by radiotherapy. The ileal tumor was treated by surgical resection. This tumor was peculiar by the macroscopic polypoid appearance and by expression of PDGFRA protein together with muscle differentiation proteins: smooth muscle actin, desmin and h-caldesmon. Lymph node necrotizing granuloma diagnosis on the surgical resection specimen lead to the diagnosis of tuberculosis and the patient was treated accordingly. At 3 years after the diagnosis, the patient was well, without recurrence or metastases. In conclusion, we report the case of a patient diagnosed with ileal leiomyosarcoma occurring 14 years after adjuvant radiotherapy for uterine carcinoma. Analysis of the intestinal resection specimen lead to the diagnosis of associated tuberculosis. Moreover, the leiomyosarcoma was peculiar by PDGFRA expression, feature which might be of clinical relevance since the treatment options in radioinduced tumors associated with other conditions are limited. PMID- 22440052 TI - Determination of the beginning age for colonoscopic screening among colonoscopy naive individuals. AB - OBJECTIVE: This study purported to analyze the results of colonoscopy for different age groups and to identify the optimal beginning age for colonoscopic screening. METHODS: A total of 3102 cases of asymptomatic, average-risk, colonoscopy-naive individuals who underwent colonoscopy at the Health Promotion Center at the Kyungpook National University Hospital during the period from January 2005 to December 2010 and colonoscopy results were analyzed. RESULTS: The prevalence of any colorectal neoplasia in 30s, 40s, 50s and over 60 group was 14.9%, 28.9%, 43.1% and 45.1% respectively. Compared with the 30s age group, the adjusted odd ratios (aOR) for any colorectal neoplasia in 40s, 50s and over 60 group was 2.38, 4.73 and 5.42 respectively (P<0.001), and the aOR for advanced neoplasia in 40s, 50s and over 60 group was 4.34, 9.68 and 14.71 respectively (P<0.001). Based on the results of the ROC curve analysis, the optimal beginning age for CRC screening was found to be below age 46 for any neoplasia and below age 47 for advanced neoplasia. CONCLUSION: The prevalence of colorectal neoplasms significantly increased from age 40s in asymptomatic, average-risk, colonoscopy naive individuals and the beginning age for colonoscopic screening was approximately age 46. PMID- 22440053 TI - Baseline evaluation of serum markers of inflammation and their utility in clinical practice in paediatric liver transplant recipients. AB - BACKGROUND: Several biomarkers of penetrating infections vs. rejection in liver transplant (LT) have been suggested; however, baseline values in paediatric LT recipients have not been studied. AIM: We evaluated the baseline concentration of procalcitonin (PCT), C-reactive protein (CRP) and interleukin-6 (IL-6) in a post LT paediatric group. METHODS: We measured serum PCT, CRP and IL-6 in 58 consecutive paediatric LT recipients. Specimens were collected for group 1 (n=22) at day 1, group 2 (n=12) at day 7 post-LT and group 3 (n=24) at onset of febrile episode. Day 7 samples were obtained from patients who had no graft dysfunction or signs/symptoms of sepsis. RESULTS: Median values for PCT were: group 1 was 5.16 MUg/L (95% CI, 2.18-21.13); group 2: 0.170 MUg/L (95% CI, 0.15-0.36) and, group 3: 1.93 MUg/L (95% CI, 1.36-2.66) for bacterial and fungal infection, 0.19 MUg/L (95% CI, 0.10-0.48) for rejection, and 0.31 MUg/L (95% CI, 0.15-0.44) for viral infection. The area under the ROC (AUROC) for PCT, CRP and IL-6 in bacterial infection vs. rejection was 1.0 (P<0.0001), 0.842 (95% CI 0.686-0.998; P<0.0001) and 0.739 (95% CI 0.559-0.919; P 0.0046), respectively. CONCLUSION: PCT levels were significantly higher in bacterial and fungal infection in comparison to other inflammatory markers. PCT proved to be the most specific parameter in differentiating bacterial infection from viral infection and allograft rejection. PMID- 22440054 TI - [Can the presence of anemia on admission improve the predictive value of the GRACE risk score for short- and medium-term mortality after acute coronary syndrome?]. PMID- 22440055 TI - Relevance of the c-statistic when evaluating risk-adjustment models in surgery. AB - BACKGROUND: The measurement of hospital quality based on outcomes requires risk adjustment. The c-statistic is a popular tool used to judge model performance, but can be limited, particularly when evaluating specific operations in focused populations. Our objectives were to examine the interpretation and relevance of the c-statistic when used in models with increasingly similar case mix and to consider an alternative perspective on model calibration based on a graphical depiction of model fit. STUDY DESIGN: From the American College of Surgeons National Surgical Quality Improvement Program (2008-2009), patients were identified who underwent a general surgery procedure, and procedure groups were increasingly restricted: colorectal-all, colorectal-elective cases only, and colorectal-elective cancer cases only. Mortality and serious morbidity outcomes were evaluated using logistic regression-based risk adjustment, and model c statistics and calibration curves were used to compare model performance. RESULTS: During the study period, 323,427 general, 47,605 colorectal-all, 39,860 colorectal-elective, and 21,680 colorectal cancer patients were studied. Mortality ranged from 1.0% in general surgery to 4.1% in the colorectal-all group, and serious morbidity ranged from 3.9% in general surgery to 12.4% in the colorectal-all procedural group. As case mix was restricted, c-statistics progressively declined from the general to the colorectal cancer surgery cohorts for both mortality and serious morbidity (mortality: 0.949 to 0.866; serious morbidity: 0.861 to 0.668). Calibration was evaluated graphically by examining predicted vs observed number of events over risk deciles. For both mortality and serious morbidity, there was no qualitative difference in calibration identified between the procedure groups. CONCLUSIONS: In the present study, we demonstrate how the c-statistic can become less informative and, in certain circumstances, can lead to incorrect model-based conclusions, as case mix is restricted and patients become more homogenous. Although it remains an important tool, caution is advised when the c-statistic is advanced as the sole measure of a model performance. PMID- 22440056 TI - Surgical site infection after colon surgery: National Healthcare Safety Network risk factors and modeled rates compared with published risk factors and rates. PMID- 22440057 TI - Serum brain naturietic peptide measurements reflect fluid balance after pancreatectomy. AB - BACKGROUND: Overaggressive fluid resuscitation in elderly patients requiring pancreatectomy can delay recovery and increase morbidity. Despite advancements, no accurate and reproducible methods exist to evaluate effective intravascular volume status in the postoperative setting. We hypothesized that sequential measurement of currently available serum proteins will indicate fluid balance. STUDY DESIGN: Clinicopathologic (n = 44) and echocardiogram (echo) data (n = 18) were collected on patients receiving pancreatectomy or diagnostic laparoscopy (n = 5). Measured fluid balance, serum BUN, creatinine (CR), and brain natriuretic peptide (BNP) levels were recorded on postoperative days (POD) 1 to 7 (only POD1 for diagnostic laparoscopy). ANOVA and bivariate random effect models examined the correlation between BNP and BUN/CR and fluid balance. Linear mixed-effect models examined the correlation between factors associated with vascular stiffness and BNP, BUN/CR, and fluid balance. RESULTS: On POD1 after diagnostic laparoscopy, the fluid balance was positive by 3,265 mL and was accompanied by a >300-point increase in BNP (p = 0.0083). After pancreatectomy, a similar increase in BNP (250 pg/mL) and fluid balance (4,492 mL) on POD1 was observed. During the return to euvolemia, the change in serum BNP levels correlated with fluid balance changes during POD 1 to 3 (p = 0.039), and BUN/CR levels correlated with fluid balance during POD 4 to 7. Patients with risk factors associated with cardiovascular stiffness or echo evidence of poor compliance experienced higher BNP during the postoperative period. CONCLUSIONS: Fluid loading at surgery is accompanied by an increase in serum BNP, and return to a balanced fluid state after pancreatectomy is paralleled by changes in BNP and BUN/CR levels. PMID- 22440058 TI - Cascade intermolecular Michael addition-intramolecular azide/internal alkyne 1,3 dipolar cycloaddition reaction in one pot. AB - A rapid one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction has been described. The generality of the method has been demonstrated by treating a series of aromatic/aliphatic 2-alkynyl indoles with substituted (E)-1-azido-2-(2 nitrovinyl)benzenes to furnish annulated tetracyclic indolo[2,3 c][1,2,3]triazolo[1,5-a][1]benzazepines in good yields. PMID- 22440059 TI - Test effort in persons with Chronic Fatigue Syndrome when assessed using the Validity Indicator Profile. AB - The current study examined the potential contribution of suboptimal effort to the cognitive deficits that are associated with Chronic Fatigue Syndrome (CFS) using the Validity Indicator Profile (VIP). Unlike most tests of effort, the VIP distinguishes between intentional and unintentional poor performance and does not assess cognitive functions that are affected by CFS, thereby reducing the risk of mistakenly attributing genuinely poor performance to reduced effort. The VIP was administered to 54 persons with CFS and 54 matched healthy community controls, and performance categorized into 1 of 4 response styles (valid: compliant; invalid: suppressed, irrelevant, inconsistent), based on the level of effort expended (high or low) and the intention to perform well or not. VIP performance was classified as valid for the majority of participants (CFS and controls), indicating high levels of effort and an intention to perform well. Three participants in the CFS group and four in the control group showed low levels of effort but an intention to do well (invalid: inconsistent). No participant performed in a manner indicative of an intent to perform poorly (invalid: suppressed, inconsistent). These findings suggest that poor effort is unlikely to contribute to cognitive test performance of persons with CFS. PMID- 22440060 TI - [Recent progress in Marfan syndrome]. AB - For 20 years, the clinical, genetic and therapeutic knowledge of Marfan syndrome made great progress. The new classification, allowing the diagnosis and published in 2010, is easier to use. The diagnosis remains sometimes difficult particularly during childhood, because of the great variability of expression of the disease, from neonatal Marfan syndrome, to a weak clinical expression and especially because of the evolution of the signs with the age, which no classification takes into account. The search for amutation in the FBN1 gene is long and expensive and must be reserved only for patients having a very strong diagnostic suspicion. The therapeutics is preventive and based on patient education, limitation of the sport, beta blockade therapy, regular echocardiography as well as aorta replacement. New treatments are at present on approval but did not make the proof of their efficiency. The global care of the patient, by taking into account difficulties about genetic origin of the disease, aesthetic and psychological consequences, allows an improvement of the quality of life. PMID- 22440061 TI - Direct-to-consumer marketing of evidence-based psychological interventions: introduction. AB - The dissemination and implementation of evidence-based psychological interventions (EBPIs) to service provision settings has been a major challenge. Most efforts to disseminate and implement EBPIs have focused on clinicians and clinical systems as the consumers of these treatments and thus have targeted efforts to these groups. An alternative, complementary approach to achieve more widespread utilization of EBPIs is to disseminate directly to patients themselves. The aim of this special section is to explore several direct-to consumer (i.e., patient) dissemination and education efforts currently underway. This manuscript highlights the rationale for direct-to-patient dissemination strategies as well as the application of marketing science to dissemination efforts. Achieving greater access to EBPIs will require the use of multiple approaches to overcome the many and varied barriers to successful dissemination and implementation. PMID- 22440062 TI - Consumer engagement and the development, evaluation, and dissemination of evidence-based parenting programs. AB - A consumer perspective can contribute much to enhancing the "ecological fit" of population-level parenting interventions so they meet the needs of parents. This approach involves building relationships with consumer groups and soliciting consumer input into the relevance and acceptability of interventions, clarifying the enablers and barriers to engagement and involvement of parents, and clarifying variables that influence a parent's program completion. The adoption of a more collaborative approach to working with consumers is important if meaningful population-level change in the prevalence of serious social, emotional, and behavioral problems in children and young people is to be achieved. Parents seeking assistance for their children's behavior come from a diverse range of socioeconomic backgrounds, educational levels, cultures, and languages. This paper examines consumer engagement strategies that can be employed throughout the process of program development, evaluation, training, and dissemination, and in "scaling up" the intervention. We argue that a multilevel public health approach to parenting intervention requires a strong consumer perspective to enable interventions to be more responsive to the preferences and needs of families and to ensure improved population reach of interventions. Examples from large-scale dissemination trials are used to illustrate how consumer input can result in an increasingly differentiated suite of evidence based parenting programs. PMID- 22440063 TI - Using direct-to-consumer marketing strategies with obsessive-compulsive disorder in the nonprofit sector. AB - Three to four million individuals struggle with obsessive-compulsive disorder (OCD) in the United States at any given time. OCD can be a debilitating disorder associated with significant quality-of-life and occupational impairment. First line treatments for OCD (selective serotonin reuptake inhibitors and exposure and response prevention therapy) have been shown to be effective; yet, many individuals suffering from OCD experience multiple barriers to accessing these treatments. In fact, it can take as many as 17 years from onset of symptoms to effective treatment. Given the need to increase access to and utilization of effective treatments, direct-to-consumer marketing in the context of OCD appears crucial. The International OCD Foundation (formerly the Obsessive Compulsive Foundation) was established as a nonprofit organization with a mission to educate the public and mental health professionals about appropriate practice guidelines, raise awareness of the disorder, and ensure that individuals looking for treatment find the necessary resources. This paper reviews the obstacles those struggling with OCD face in their attempts to alleviate suffering, as well as the direct-to-consumer strategies and tactics used by the International OCD Foundation to improve access to empirically supported, effective treatment. PMID- 22440064 TI - Using consumer preference information to increase the reach and impact of media based parenting interventions in a public health approach to parenting support. AB - Within a public health approach to improving parenting, the mass media offer a potentially more efficient and affordable format for directly reaching a large number of parents with evidence-based parenting information than do traditional approaches to parenting interventions that require delivery by a practitioner. Little is known, however, about factors associated with parents' interest in and willingness to watch video messages about parenting. Knowledge of consumer preferences could inform the effective design of media interventions to maximize parental engagement in the parenting messages. This study examined parents' preferred formats for receiving parenting information, as well as family sociodemographic and child behavior factors that predict parents' ratings of acceptability of a media-based parenting intervention. An ethnically diverse sample of 162 parents of children ages 3-6 years reported their preferences for various delivery formats for parenting information and provided feedback on a prototype episode of a video-format parenting program based on the Triple P Positive Parenting Program. Parents reported the strongest preference for self administered delivery formats such as television, online programs, and written materials; the least preferred formats were home visits, therapists, and multiweek parenting groups. Parents' ratings of engagement, watchability, and realism of the prototype parenting episode were quite strong. Parents whose children exhibited clinical levels of problem behaviors rated the episode as more watchable, engaging, and realistic. Mothers also rated the episodes as more engaging and realistic than did fathers. Lower income marginally predicted higher watchability ratings. Minority status and expectations of future problems did not predict acceptability ratings. The results suggest that the episode had broad appeal across groups. PMID- 22440065 TI - Coping skills and exposure therapy in panic disorder and agoraphobia: latest advances and future directions. AB - Although cognitive-behavioral treatments for panic disorder have demonstrated efficacy, a considerable number of patients terminate treatment prematurely or remain symtpomatic. Cognitive and biobehavioral coping skills are taught to improve exposure therapy outcomes but evidence for an additive effect is largely lacking. Current methodologies used to study the augmenting effects of coping skills test the degree to which the delivery of coping skills enhances outcomes. However, they do not assess the degree to which acquisition of coping skills and their application during exposure therapy augment outcomes. We examine the extant evidence on the role of traditional coping skills in augmenting exposure for panic disorder, discuss the limitations of existing research, and offer recommendations for methodological advances. PMID- 22440066 TI - Attentional control moderates fearful responding to a 35% CO(2) challenge. AB - Attentional control (AC) is an individual difference variable indexing the ability to voluntarily focus attention and shift attention when desired. AC is thought to impact the experience of fear by facilitating the disengagement of attention from threat and promoting the deployment of attentional resources toward regulatory or coping strategies. Whereas previous research has focused on visual threat cues, in the current study we examined whether this model also applies to interoceptive threat by evaluating the extent to which individual differences in AC moderated the relationship between trait anxiety and self reported fear in response to a single vital capacity inhalation of a 35% CO(2), 65% balanced O(2) gas mixture. The sample comprised a large nonclinical group of young adults (N=128). Results indicated that AC moderated the relationship between trait anxiety and fearful responding to the challenge. Findings suggest that AC plays a significant and clinically important role in modulating self reported fear. PMID- 22440067 TI - Concreteness of positive, negative, and neutral repetitive thinking about the future. AB - Consistent with assertions that the adaptiveness of repetitive thinking is influenced by both its valence and style, Stober (e.g., Stober & Borkovec, 2002) has argued that worry is characterized by a reduced concreteness of thought content and that the resulting abstractness contributes to its inhibition of some aspects of anxious responding. However, extant research does not provide a direct test of Stober's reduced concreteness theory of worry. We sought to test Stober's theory and to examine the adaptiveness of repetitive worrisome thinking by randomly assigning 108 participants to engage in five consecutive periods of repetitive thinking about positively, negatively, or neutrally valenced potential future events. Results based on coding of thought data indicated that (a) repetitive thinking became increasingly less concrete as periods progressed; (b) contrary to Stober's theory, both negative and positive repetitive future thinking were more concrete than neutral repetitive future thinking (and did not differ from each other); and (c) abstractness of thought during negative repetitive future thinking was associated with reduced reports of imagery-based activity. Results based on self-reported affect indicated that negatively valenced repetitive future thinking was uniquely associated with initial decreases in anxious affect, followed by increased anxious affect that coincided with increased imagery-based activity. This suggests that worry is associated with a sequential mitigation of anxious meaning followed by a strengthening of anxious meaning over time. Theoretical and clinical implications of these findings are discussed. PMID- 22440069 TI - Being deluded after being excluded? How emotion regulation deficits in paranoia prone individuals affect state paranoia during experimentally induced social stress. AB - Emotion regulation (ER) has become a relevant construct to understanding paranoia. While the ER strategy called expressive suppression (e.g., poker face) may foster state paranoia by increasing arousal, another strategy called reappraisal (e.g., changing the perspective on situations) may reduce negative emotions and state paranoia when adaptively used. However, if reappraisal fails, this could increase paranoia. The aim of this study was to test the proposed effects of the ER strategies on state paranoia in the socially stressful situation of being excluded in paranoia-prone individuals. We conducted an experimental online study with N=116 participants who were randomized to a social inclusion or an exclusion condition using a virtual Cyberball ball-tossing game. They completed questionnaires on paranoia proneness and habitual ER strategies. Before and after the Cyberball task, participants rated their level of state paranoia. The impact of habitual ER strategies, paranoia proneness, and social stress on changes in state paranoia was investigated using linear regression analysis. The three-way interaction of social stress, paranoia proneness, and habitual reappraisal use significantly predicted state paranoia, t(114)=2.62, p=0.010. The decomposition of the interaction term revealed that in the social stress condition, the impact of reappraisal on state paranoia was moderated by the level paranoia proneness. Specifically, in high paranoia-prone individuals the use of reappraisal predicted higher state paranoia. The findings regarding habitual use of suppression were not significant. Although reappraisal is generally considered a functional strategy, its use in distressing social situations seems to be impaired in persons with higher paranoia proneness. A working model of emotion dysregulation in delusions is presented and possible implications for cognitive therapy of psychosis are discussed. PMID- 22440068 TI - The multidimensional nature and multicultural validity of a new measure of social anxiety: the Social Anxiety Questionnaire for Adults. AB - Much has been written about the situations most often feared by persons with social phobia, and several self-report measures are frequently used to assess such feared situations. However, it is not clear whether the situations feared by persons with social phobia form unidimensional or multidimensional factors. If these situations are multidimensional, reliance on a total score of feared situations would not reflect important differences between those dimensions. This research examined the multidimensional nature and multicultural validity of a newly developed instrument (the Social Anxiety Questionnaire for Adults [SAQ-A]) in two studies with a total of 539 patients diagnosed with social phobia and 15,753 nonpatients from 20 different countries. The structure (five clear and solid factors) and psychometric properties of the final instrument (the SAQ-A30) support the multidimensional nature of social anxiety and provide a new perspective in the assessment of social phobia. PMID- 22440070 TI - Using session-by-session measurement to compare mechanisms of action for acceptance and commitment therapy and cognitive therapy. AB - Debate continues about the extent to which postulated mechanisms of action of cognitive behavior therapies (CBT), including standard CBT (i.e., Beckian cognitive therapy [CT]) and acceptance and commitment therapy (ACT) are supported by mediational analyses. Moreover, the distinctiveness of CT and ACT has been called into question. One contributor to ongoing uncertainty in this arena is the lack of time-varying process data. In this study, 174 patients presenting to a university clinic with anxiety or depression who had been randomly assigned to receive either ACT or CT completed an assessment of theorized mediators and outcomes before each session. Hierarchical linear modeling of session-by-session data revealed that increased utilization of cognitive and affective change strategies relative to utilization of psychological acceptance strategies mediated outcome for CT, whereas for ACT the mediation effect was in the opposite direction. Decreases in self-reported dysfunctional thinking, cognitive "defusion" (the ability to see one's thoughts as mental events rather than necessarily as representations of reality), and willingness to engage in behavioral activity despite unpleasant thoughts or emotions were equivalent mediators across treatments. These results have potential implications for the theoretical arguments behind, and distinctiveness of, CT and ACT. PMID- 22440071 TI - The effects of analytical rumination, reappraisal, and distraction on anger experience. AB - The manner in which individuals recall negative life events has important affective consequences. The present experiment investigated the effects of emotion regulation strategies on anger experience. One hundred and twenty-one undergraduates recalled an anger-inducing memory and were instructed to engage in either analytical rumination, cognitive reappraisal, or distraction for 20 minutes. In the remaining (control) condition, participants were instructed to write about their thoughts but were not given any emotion regulation instructions. Rumination maintained anger, whereas participants in the remaining conditions reported decreased anger following the writing task. Our results suggest that reappraisal facilitates adaptive processing of anger-inducing memories and distraction facilitates rapid reductions in anger experience. These findings have implications for the management of clinical populations that commonly experience difficulty with anger regulation. PMID- 22440073 TI - Predicting psychotherapy benefit: a probabilistic and individualized approach. AB - We describe the development of the probability of treatment benefit (PTB) chart that incorporates, integrates, and extends more recent approaches to describing treatment effects, such as the Reliable Change Index (Jacobson & Truax, 1991) and normative comparisons (Kendall, Marrs-Garcia, Nath, & Sheldrick, 1999), by including parameters that are simultaneously probabilistic and individualized. To illustrate the PTB chart, data are taken from an effectiveness trial (N=139) of a modular treatment for disruptive behavior disorders. The results highlight both individual variability and the probabilistic nature of psychotherapy benefit. Finally, we discuss the utility of the PTB chart in terms of research, policy, and practice implications. Probability tables, such as the PTB chart, have the potential to be used as simple clinical tools to supplement traditional effect sizes and help patients make truly informed decisions about treatment participation. PMID- 22440072 TI - Mindfulness-based cognitive therapy improves emotional reactivity to social stress: results from a randomized controlled trial. AB - The high likelihood of recurrence in depression is linked to a progressive increase in emotional reactivity to stress (stress sensitization). Mindfulness based therapies teach mindfulness skills designed to decrease emotional reactivity in the face of negative affect-producing stressors. The primary aim of the current study was to assess whether Mindfulness-Based Cognitive Therapy (MBCT) is efficacious in reducing emotional reactivity to social evaluative threat in a clinical sample with recurrent depression. A secondary aim was to assess whether improvement in emotional reactivity mediates improvements in depressive symptoms. Fifty-two individuals with partially remitted depression were randomized into an 8-week MBCT course or a waitlist control condition. All participants underwent the Trier Social Stress Test (TSST) before and after the 8 week trial period. Emotional reactivity to stress was assessed with the Spielberger State Anxiety Inventory at several time points before, during, and after the stressor. MBCT was associated with decreased emotional reactivity to social stress, specifically during the recovery (post-stressor) phase of the TSST. Waitlist controls showed an increase in anticipatory (pre-stressor) anxiety that was absent in the MBCT group. Improvements in emotional reactivity partially mediated improvements in depressive symptoms. Limitations include small sample size, lack of objective or treatment adherence measures, and non-generalizability to more severely depressed populations. Given that emotional reactivity to stress is an important psychopathological process underlying the chronic and recurrent nature of depression, these findings suggest that mindfulness skills are important in adaptive emotion regulation when coping with stress. PMID- 22440074 TI - Mood as input and perseverative worrying following the induction of discrete negative moods. AB - Previous research has demonstrated that a combination of negative mood and rigorous "as many as can" stop rules can be used to help explain a range of perseverative psychopathologies such as pathological worrying, compulsive checking, and depressive rumination (known as the mood-as-input hypothesis). The aim of the present study was to extend this work and examine whether specific emotions of the same valence will have similar or differential effects on task perseveration. The study experimentally induced discrete moods and manipulated task stop rules in an analog population. Results showed that perseveration at a worry-based interview task conformed to standard mood-as-input predictions in which perseveration was significantly greater when an "as many as can" stop rule was paired with a negative mood or a "feel like continuing" stop rule was paired with a positively valenced mood. The pattern of results revealed no significant inherent differences in processing depending on the type of discrete negative mood being experienced. These findings support a view of mood-as-input effects where overall valency is the important factor in determining perseveration. PMID- 22440075 TI - Adaptive disclosure: an open trial of a novel exposure-based intervention for service members with combat-related psychological stress injuries. AB - We evaluated the preliminary effectiveness of a novel intervention that was developed to address combat stress injuries in active-duty military personnel. Adaptive disclosure (AD) is relatively brief to accommodate the busy schedules of active-duty service members while training for future deployments. Further, AD takes into account unique aspects of the phenomenology of military service in war in order to address difficulties such as moral injury and traumatic loss that may not receive adequate and explicit attention by conventional treatments that primarily address fear-inducing life-threatening experiences and sequelae. In this program development and evaluation open trial, 44 marines received AD while in garrison. It was well tolerated and, despite the brief treatment duration, promoted significant reductions in PTSD, depression, negative posttraumatic appraisals, and was also associated with increases in posttraumatic growth. PMID- 22440076 TI - Relationship distress in partners of combat veterans: the role of partners' perceptions of posttraumatic stress symptoms. AB - Partners of combat veterans with posttraumatic stress disorder report elevated relationship and psychological distress, but little is known about the mechanisms by which such distress develops. In two separate samples, we examined partners' perceptions of veterans' PTSD symptoms, with a specific focus on the simultaneous associations of partners' distress with their perceptions of veterans' reexperiencing, withdrawal/numbing, and hyperarousal symptom clusters. The first sample consisted of 258 partners of Operation Enduring- and Iraqi Freedom-era veterans who completed questionnaires. The second sample consisted of 465 partners of Vietnam-era veterans who completed interviews as part of the National Vietnam Veterans Readjustment Study. In both samples, path analyses revealed that, when examined simultaneously, partners' perceptions of withdrawal/numbing symptoms were associated with greater distress, but perceptions of reexperiencing symptoms were unrelated to psychological distress and significantly associated with lower levels of relationship distress. Given the cross-sectional nature of the data in both samples, there are multiple plausible interpretations of the results. However, the pattern is consistent with an attributional model of partner distress, whereby partners are less distressed when symptoms are more overtly related to an uncontrollable mental illness. Potential clinical implications are discussed. PMID- 22440077 TI - An acceptance-based behavioral intervention for weight loss: a pilot study. AB - On average, participants in behavioral weight-loss interventions lose 8 kilograms (kg) at 6 months, but there is marked variability in outcomes with some participants losing little or no weight. Individuals with difficulties with internal disinhibition (i.e., eating in response to emotions or thoughts) typically lose less weight in such programs and may require an innovative, specialized approach. This pilot study examined the preliminary acceptability and efficacy of a 24-week acceptance-based behavioral intervention for weight loss among overweight and obese adults reporting difficulty with eating in response to emotions and thoughts. Participants were 21 overweight or obese men and women (mean age=52.2+/-7.6 years; baseline mean body mass index=32.8+/-3.4). Eighty-six percent completed the 6-month program and a 3-month follow-up assessment. Ratings of program satisfaction averaged 4.9 on a five-point scale. Multilevel modeling analyses indicated participants lost an average of 12.0 kg (SE=1.4) after 6 months of treatment and 12.1 kg (SE=1.9) at 3-month follow-up, thus exceeding the weight losses typically seen in behavioral treatment programs. Decreases in internal disinhibition and weight-related experiential avoidance were found at 6- and 3-months follow-up. Greater decreases in weight-related experiential avoidance were associated with greater weight loss at the end of the program (r=.64, p=.002), suggesting a potential mechanism of action. Although there have been a few preliminary studies using acceptance-based approaches for obesity, this is the first study to specifically target emotional overeaters, a subgroup that might be particularly responsive to this new approach. Our findings provide initial support for the feasibility, efficacy, and acceptability of this approach for this subgroup of participants. Further study with longer follow-up, a more diverse sample, and comparison to a standard behavioral program is clearly warranted. PMID- 22440078 TI - Perceptions of the acceptability of parent training among Chinese immigrant parents: contributions of cultural factors and clinical need. AB - Parent training (PT) is well established for reducing child externalizing problems; however, lower rates of engagement in PT among ethnic minority/immigrant families have been found. We assessed PT acceptability among Chinese immigrant parents and explored clinical and cultural factors that may be associated with acceptability. Participants were a community sample of 145 Chinese immigrant parents (84% mothers) between the ages of 32 and 65 years (M=43.3 years, SD=6.2) who had children (84 boys, 59 girls) between the ages of 4 and 17 years (M=10.7 years, SD=3.6). Results suggest that parents found positive reinforcement techniques significantly more acceptable, less problematic, and more likely to be supported by others than punishment-based techniques. Parents who endorsed the Chinese child-rearing value of shaming were less likely to find PT acceptable. Parents who reported greater dysfunction in parent-child interactions rated PT as more acceptable, and families with prior Child Protective Services (CPS) involvement rated PT as less acceptable. However, previous mental health treatment appears to bolster acceptability among parents with prior CPS involvement. Clinical implications for addressing barriers to PT engagement and future research directions are discussed. PMID- 22440079 TI - Prevention of anxiety symptoms in children: results from a universal school-based trial. AB - The present study evaluated the effectiveness of a universal school-based cognitive behavior prevention program (the FRIENDS program) for childhood anxiety. Participants were 638 children, ages 9 to 12 years, from 14 schools in North Rhine-Westphalia, Germany. All the children completed standardized measures of anxiety and depression, social and adaptive functioning, coping strategies, social skills, and perfectionism before and after the 10-week FRIENDS program and at two follow-up assessments (6 and 12 months) or wait period. Children who participated in the FRIENDS program exhibited significantly fewer anxiety and depressive symptoms, and lower perfectionism scores than children in the control group at 12-month follow-up. Younger children (9-10-year-olds) displayed treatment gains immediately after the intervention, whereas older children (11-12 year-olds) showed anxiety reduction only at 6- and 12-month follow-up. Perfectionism and avoidant coping acted as mediators of pre- to postintervention changes in anxiety scores. This study provides empirical evidence for the utility of the FRIENDS program in reducing anxiety and depressive symptoms among German children. PMID- 22440081 TI - Private practice management of hospital endoscopy/under arrangements. PMID- 22440083 TI - Chemicals management and environmental assessment of chemicals in China. PMID- 22440082 TI - Bisphosphonate-based strategies for bone tissue engineering and orthopedic implants. AB - Bisphosphonates (BPs) are a group of well-established drugs that are applied in the development of metabolic bone disorder-related therapies. There is increasing interest also in the application of BPs in the context of bone tissue engineering, which is the topic of this review, in which an extensive overview of published studies on the development and applications of BPs-based strategies for bone regeneration is provided with special focus on the rationale for the use of different BPs in three-dimensional (3D) bone tissue scaffolds. The different alternatives that are investigated to address the delivery and sustained release of these therapeutic drugs in the nearby tissues are comprehensively discussed, and the most significant published approaches on bisphosphonate-conjugated drugs in multifunctional 3D scaffolds as well as the role of BPs within coatings for the improved fixation of orthopedic implants are presented and critically evaluated. Finally, the authors' views regarding the remaining challenges in the fields and directions for future research efforts are highlighted. PMID- 22440084 TI - Growth inhibition and mechanism of action of p-dodecylaminophenol against refractory human pancreatic cancer and cholangiocarcinoma. AB - Pancreatic cancer and cholangiocarcinoma are aggressive and drug-resistant refractory cancers. Based on N-(4-hydroxyphenyl)retinamide (3), a synthetic amide of all-trans-retinoic acid (RA), p-dodecylaminophenol (1) was developed to be an effective anticancer agent without key side-effects of these agents. Compound 1 suppresses cell growth of pancreatic cancer (MIA Paca2) and cholangiocarcinoma (HuCCT1), potentially by inhibiting ras expression and signaling through ERK pathways in MIA Paca2 cells and both ERK and Akt pathways in HuCCT1 cells. Compound 1 inhibits proliferation of these cells to a greater extent than either RA or 3. Compound 1 may represent a potent and useful anti-cancer drug for use against pancreatic cancer and cholangiocarcinoma that lacks their key side effects. PMID- 22440085 TI - A preliminary quantitative analysis of REM sleep chin EMG in Parkinson's disease with or without REM sleep behavior disorder. AB - OBJECTIVES: To compare REM sleep chin EMG quantitative features between Parkinson's disease (PD) patients with or without REM sleep behavior disorder (RBD). SUBJECTS AND METHODS: Twenty-seven consecutive PD patients (mean age 67.9 years) and 19 normal controls (mean age 67.5 years) were enrolled. Detailed clinical, laboratory, and polysomnographic studies were obtained in all participants and characteristics of chin electromyographic amplitude during rapid eye movements sleep were analyzed by means of an automatic quantitative approach (Atonia Index). RESULTS: Sixteen of the 27 patients were affected by RBD. An Atonia Index below 0.90 showed high sensitivity (0.938) and specificity (0.909) for the diagnosis of RBD within the group of PD patients. CONCLUSION: This study recommends the Atonia Index as an objective measure to support and aid the diagnosis of RBD in PD. PMID- 22440086 TI - Severe sleep-related movement disorder induced by sertraline. PMID- 22440087 TI - Epicatechin: endothelial function and blood pressure. AB - Epidemiological studies indicate an inverse relationship between flavanol intake and the risk of cardiovascular disease. Potential mechanisms include their effects on endothelial function and hypertension. A number of studies have shown that flavanol-rich cocoa reduces blood pressure and endothelial dysfunction, whereas black tea may have opposite effects. These results highlight the importance of the different effects of the multitude of phytochemical constituents in these foods and the need for studying the individual flavanols. Epicatechin seems to be a major bioactive constituent of cocoa and other flavanol rich foods and beverages. It has been shown to improve endothelial function in animals and humans. In salt-sensitive animal models of hypertension, epicatechin lowers blood pressure and the associated end-organ damage. Nitric oxide (NO) seems to play a key role in the protection of both hypertension and endothelial dysfunction. PMID- 22440088 TI - Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide. AB - BACKGROUND: Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCalpha subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure. METHODS: We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P <= 0.01 in one cohort and replication by P <= 0.05 in the other cohort considered significant. RESULTS: In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed. CONCLUSIONS: Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation. PMID- 22440089 TI - Short sleep duration and its association with energy metabolism. AB - A growing body of observational evidence suggests that short sleep duration is a risk factor for the development of obesity. Although increased energy intake is the most prevailing causal explanation for this association, we should also consider possible effects on energy metabolism to understand fully the potential impact of short sleep duration on the regulation of energy balance. We performed a search of the literature from 1970 to 2011, including original papers, investigating the relation between short sleep and energy metabolism in animals and humans. Although the limited number of experimental studies in humans precludes any definitive conclusions about causality, short sleep duration does not seem to substantially affect total daily energy expenditure, nor is there sufficient evidence in support of any meaningful effect of restricted sleep on the specific components of energy metabolism (i.e. resting metabolic rate, intentional as well as unintentional physical activity, diet-induced thermogenesis, and substrate utilization). As studies on rats suggest that other factors that can potentially influence energy metabolism could be affected (i.e. hormonal systems and thermoregulation), we included these factors in our literature search and found some indications in support of an up-regulation of thyroid hormones and glucocorticoids as well as increased heat dissipation following total or severe sleep deficit. Although we found some evidence also in humans that suggests a possible effect on energy metabolism, the limitations of the studies make it difficult to draw conclusions on the effect of short sleep on energy metabolism under relevant free living conditions. To explore this area further, more studies using suitable methodology under relevant conditions to mimic real-life situations are needed. PMID- 22440090 TI - Multicentre RCT and economic evaluation of a psychological intervention together with a leaflet to reduce risk behaviour amongst men who have sex with men (MSM) prescribed post-exposure prophylaxis for HIV following sexual exposure (PEPSE): a protocol. AB - BACKGROUND: Post-exposure prophylaxis (PEP) following sexual exposure to HIV has been recommended as a method of preventing HIV infection in the UK. Men who have sex with men (MSM) are the group most affected by HIV in the UK and their sexual risk taking behaviour is reported to be increasing. One-to-one behavioural interventions, such as motivational interviewing (MI) have been recommended to reduce HIV in high risk groups. The Information, Motivation and Behavioral skills (IMB) model has been shown to provide a good basis for understanding and predicting HIV-relevant health behaviour and health behaviour change, however the IMB has yet to be applied to PEP after risky sexual exposure. The primary aim of this trial is to examine the impact of MI augmented with information provision and behavioural skills building (informed by the IMB Model), over and above usual care, on risky sexual behaviour in MSM prescribed PEP after potential sexual exposure. A secondary aim of this research is to examine the impact of the intervention on adherence to PEP. This study will also provide estimates of the cost-effectiveness of the intervention. METHODS: A manualised parallel group randomised controlled trial with economic evaluation will be conducted. The primary outcome is the proportion of risky sexual practices. Secondary outcomes include: i) Levels of adherence to PEP treatment; ii) Number of subsequent courses of PEP; iii) Levels of motivation to avoid risky sexual behaviours; iv) Levels of HIV risk-reduction information/knowledge; v) Levels of risk reduction behavioural skills; vi) Diagnosis of anal gonorrhoea, Chlamydia and/or HIV. 250 participants will be asked to self-complete a questionnaire at four time points during the study (at 0,3,6,12 months). The intervention will consist of a two session, fixed duration, telephone administered augmented MI intervention based on the IMB model. A newly developed treatment manual will guide the selection of persuasive communication strategies as appropriate for each participant and will be based on underlying change mechanisms specified by the IMB theoretical framework. Information provision and skills building will also be included in the intervention package through the use of information leaflets and tailored action plans. Fidelity of intervention delivery will be assessed. DISCUSSION: The results from this NIHR funded study will identify whether it is appropriate and cost-effective to intervene using one-to-one telephone calls with MSM seeking PEP. If the intervention is effective, further work will be needed on training staff to deliver the intervention competently. TRIAL REGISTRATION NUMBERS: UKCRN ID:11436; ISRCTN00746242. PMID- 22440091 TI - Further evidence for the existence of major susceptibility of nasopharyngeal carcinoma in the region near HLA-A locus in Southern Chinese. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is a multi-factorial malignancy closely associated with environmental factors, genetic factors and Epstein-Barr virus infection. Human leukocyte antigen (HLA) complex, specially the region near HLA-A locus, was regarded as a major candidate region bearing NPC genetic susceptibility loci in many previous studies including two recent genome-wide association (GWA) studies. To provide further evidence for the NPC susceptibility in the region near HLA-A locus based on other previous studies, we carried out a two-stage hospital-based case control association study including 535 sporadic NPC patients and 525 cancer-free control subjects from Guangdong, a high prevalence area of NPC in China. METHODS: 38 tag SNPs were initially selected by Heploview from the segment around HLA-A locus (from D6S211 to D6S510) and genotyped on GenomeLab SNPstream platform in 206 cases and 180 controls in the stage 1. Subsequently, the stage 1 significant SNPs and 17 additional SNPs were examined on another platform (Sequenom iPlex Assay) in another independent set of study population including 329 cases and 345 controls. RESULTS: Totally eight SNPs from the segment from D6S211 to D6S510 within HLA complex were found to be significantly associated with NPC. Two of the most significant SNPs (rs9260734 and rs2517716) located near to HLA-A and HCG9 respectively were in strong LD with some other SNPs of this region reported by two previous GWA studies. Meanwhile, Meanwhile, novel independent susceptibility loci (rs9404952, Pcombined = 6.6 * 10 5, OR combined = 1.45) was found to be close to HLA-G. CONCLUSION: Therefore, our present study supports that the segment from D6S211 to D6S510 in HLA complex region might contain NPC susceptibility loci which indeed needs to be fully investigated in the future. PMID- 22440092 TI - Cardiovascular disease and air pollution in Scotland: no association or insufficient data and study design? AB - BACKGROUND: Coronary heart disease and stroke are leading causes of mortality and ill health in Scotland, and clear associations have been found in previous studies between air pollution and cardiovascular disease. This study aimed to use routinely available data to examine whether there is any evidence of an association between short-term exposure to particulate matter (measured as PM10, particles less than 10 micrograms per cubic metre) and hospital admissions due to cardiovascular disease, in the two largest cities in Scotland during the years 2000 to 2006. METHODS: The study utilised an ecological time series design, and the analysis was based on overdispersed Poisson log-linear models. RESULTS: No consistent associations were found between PM10 concentrations and cardiovascular hospital admissions in either of the cities studied, as all of the estimated relative risks were close to one, and all but one of the associated 95% confidence intervals contained the null risk of one. CONCLUSIONS: This study suggests that in small cities, where air quality is relatively good, then either PM10 concentrations have no effect on cardiovascular ill health, or that the routinely available data and the corresponding study design are not sufficient to detect an association. PMID- 22440093 TI - Preconditioning chemotherapy with cisplatin enhances the antitumor activity of cytokine-induced killer cells in a murine melanoma model. AB - Accumulating evidence has indicated that preconditioning chemotherapy could eliminate the suppressive factors in antitumor immune response, thereby leading to the full release of the efficacy of the subsequent immunotherapy. In this study, a single subtoxic dose (5 mg/kg, intraperitoneally) of cisplatin was chosen as the preconditioning chemotherapy in combination with cytokine-induced killer (CIK) cells (4*10(6), intravenously) to treat the murine B16 melanoma xenografts. It was found that cisplatin pretreatment could enhance the antitumor activity of CIK cells. To explore the potential mechanisms underlying the efficacy-enhancing effect of cisplatin, the in vivo trafficking and distribution of the infused CIK cells were traced. It was found that cisplatin could augment the homing ability of CIK cells into the tumor, tumor-draining lymph nodes (TDLNs), and spleen tissues. The endogenous effector cells, CD3(+) T lymphocytes also had an increased accumulation in the tumor and TDLNs after cisplatin precondition. Moreover, cisplatin could also modulate the percentages of myeloid cells, thus encouraging immune responses by increasing the percentages of dendritic cells and relieving the immunosuppression by preferentially eliminating the myeloid-derived suppressor cells. In conclusion, our findings suggested that cisplatin preconditioning chemotherapy could enhance the antitumor activity of CIK cells in a murine melanoma model, and this efficacy-enhancing effect was attributed to the augmented homing ability of exogenous and endogenous effector cells and the modulation of the myeloid cells. PMID- 22440094 TI - Genetic parameters for fatty acid composition and feed efficiency traits in Japanese Black cattle. AB - We estimated the genetic parameters related to feed intake (FI), feed efficiency traits (including feed conversion ratio (FCR) and residual feed intake (RFI) of digestible crude protein (DCP) and total digestible nutrients (TDN)), beef marbling score (BMS), melting point of fat (MP) and fatty acid composition. Fat and meat (Musculus trapezius) samples were taken from the carcasses of 863 Japanese Black steers derived from 65 sires, for determination of the MP and fatty acid composition of the total lipid in intramuscular adipose tissue. Genetic parameters were estimated using uni- and bivariate animal models. In addition, pedigree information for 4841 animals was used. Heritability estimates for BMS, MP, individual fatty acids, monounsaturated fatty acids (MUFA), the ratio of saturated fatty acids to MUFA (MUS) and the ratio of elongation (ELONG) were generally high. The FI values of TDN and DCP were also high, but FCRs and RFIs of those were low (0.09 to 0.22). Genetic correlation of BMS with MP was 0.34 (favorable) and with C18:1, MUFA, MUS and ELONG values were 0.40, 0.28, 0.29 and 0.37, respectively (favorable). Genetic correlations of MP with C18:1, MUFA, MUS and ELONG were negative (also favorable) and high (-0.85, -0.98, -1.00 ( 0.996) and -0.66, respectively). The correlation estimates for feed efficiency traits of DCP were quite similar to those of TDN. Genetic correlations of BMS with FCRs and RFIs of TDN and DCP were all positive (unfavorable; 0.21 to 0.51), and in particular, the correlations with RFIs of those were high. The correlations of C18:1, MUFA, MUS and ELONG with RFIs of TDN and DCP were positive (unfavorable) but low (0.06 to 0.17), whereas the corresponding correlations with FCRs of those were all negative (favorable; -0.38 to -0.10). These results suggest that the quantity and quality of beef fat can be simultaneously improved and that the quality of beef fat (fatty acid composition) can be improved directly or indirectly with MP. Furthermore, selecting MP or fatty acid traits does not significantly affect feed efficiency. PMID- 22440095 TI - Congruence between selection on breeding values and farmers' selection criteria in sheep breeding under conventional nucleus breeding schemes. AB - Designing breeding schemes suitable for smallholder livestock production systems in developing regions has hitherto been a challenge. The suggested schemes either do not address farmers' breeding goals (centralized station-based nucleus schemes) or yield slow genetic progress (village-based schemes). A new breeding scheme that integrates the merits of previously suggested schemes has been designed for Menz sheep improvement in Ethiopia. It involves selection based on breeding values in nucleus flocks to produce elite rams, a one-time only provision of improved rams to villagers and a follow-up village-based selection to sustain genetic progress in village flocks. Here, we assessed whether conventional selection of breeding rams based on breeding values for production traits, which is the practice in station-based nucleus flocks, meets farmers' breeding objectives. We also elicited determinants of farmers' ram choice. Low but significant correlations were found between rankings of rams based on farmers' selection criteria, estimated breeding values (EBV) and body weight (BW). Appearance traits (such as color and horn) and meat production traits (BW and linear size traits) significantly determined farmers' breeding ram choice. The results imply that conventional selection criteria based solely on EBV for production traits do not address farmers' trait preferences fully, but only partially. Thus, a two-stage selection procedure involving selection on breeding values in nucleus centers followed by farmers' selection among top- ranking candidate rams is recommended. This approach accommodates farmers' preferences and speeds up genetic progress in village-based selection. The Menz sheep scheme could be applied elsewhere with similar situations to transform conventional station-based nucleus breeding activities into participatory breeding programs. PMID- 22440096 TI - NIRS prediction of the feed value of temperate forages: efficacy of four calibration strategies. AB - Near infrared reflectance spectroscopy (NIRS) of 924 fresh temperate forages were used to develop calibration models for chemical composition - crude ash (CA) and crude protein (CP) - organic matter digestibility (OMD) and voluntary intake (VI). We used 110 samples to assess the models. Four calibration strategies for determining forage quality were compared: (i) species-specific calibration, (ii) family-specific calibration, (iii) a global procedure and (iv) a local approach. Forage calibration data sets displayed CA values ranging from 52 to 205 g/kg of dry matter (DM), CP values from 50 to 280 g/kg DM, OMD values from 0.48 to 0.85 g/g and VI values from 22.5 to 115.2 g DM/kg metabolic body weight (BW0.75). The calibration models performed well for all the variables except for VI. For CA, local procedure showed lower standard error of prediction (SEP) than species specific, family-specific or global models. For CP, the calibration models all showed similar SEP values (11.13, 11.08, 11.38 and 11.34 g/kg DM for species specific, family-specific, global and local approaches). For OMD, the local procedure gave a similar SEP (0.024 g/g) to specific species and global procedures (0.027 g/g) and a lower SEP than the family-specific approach (0.028 g/g). For VI, the local approach and species-specific calibration showed lower SEP (7.08 and 7.16 g/kg BW0.75) than the broad-based calibrations (8.09 and 8.34 g/kg BW0.75 for family-specific model and global procedure, respectively). Local calibration may thus offer a practical way to develop robust universal equations for animal response determinations. PMID- 22440097 TI - Re-defining efficiency of feed use by livestock. AB - Livestock, particularly ruminants, can eat a wider range of biomass than humans. In the drive for greater efficiency, intensive systems of livestock production have evolved to compete with humans for high-energy crops such as cereals. Feeds consumed by livestock were analysed in terms of the quantities used and efficiency of conversion of grassland, human-edible ('edible') crops and crop by products into milk, meat and eggs, using the United Kingdom as an example of a developed livestock industry. Some 42 million tonnes of forage dry matter were consumed from 2008 to 2009 by the UK ruminant livestock population of which 0.7 was grazed pasture and 0.3 million tonnes was conserved forage. In addition, almost 13 million tonnes of raw material concentrate feeds were used in the UK animal feed industry from 2008 to 2009 of which cereal grains comprised 5.3 and soyabean meal 1.9 million tonnes. The proportion of edible feed in typical UK concentrate formulations ranged from 0.36 for milk production to 0.75 for poultry meat production. Example systems of livestock production were used to calculate feed conversion ratios (FCR - feed input per unit of fresh product). FCR for concentrate feeds was lowest for milk at 0.27 and for the meat systems ranged from 2.3 for poultry meat to 8.8 for cereal beef. Differences in FCR between systems of meat production were smaller when efficiency was calculated on an edible input/output basis, where spring-calving/grass finishing upland suckler beef and lowland lamb production were more efficient than pig and poultry meat production. With the exception of milk and upland suckler beef, FCR for edible feed protein into edible animal protein were >1.0. Edible protein/animal protein FCR of 1.0 may be possible by replacing cereal grain and soyabean meal with cereal by-products in concentrate formulations. It is concluded that by accounting for the proportions of human-edible and inedible feeds used in typical livestock production systems, a more realistic estimate of efficiency can be made for comparisons between systems. PMID- 22440098 TI - Effects of dam breed and dietary source of n-3 polyunsaturated fatty acids on the growth and carcass characteristics of lambs sourced from hill sheep flocks. AB - The objectives of this study were to investigate the effect of dietary lipid source on the growth and carcass characteristics of lambs sourced from a range of crossbred hill ewes. Over a 2-year period, 466 lambs representing the progeny of Scottish Blackface (BF * BF), Swaledale (SW) * BF, North Country Cheviot (CH) * BF, Lleyn (LL) * BF and Texel (T) * BF ewes were sourced from six commercial hill flocks and finished on one of four diets: grass pellets (GP), cereal-based concentrate (CC), CC enriched with oilseed rape (CR) and CC enriched with fish oil (CF). Dry matter intake (DMI) was highest (P < 0.001) in lambs offered GP; however, carcass weight gain (CWG) and feed conversion efficiency were higher (P < 0.001) in lambs fed concentrate-based diets. For lambs offered concentrate based diets, DMI and live weight gain were lower (P < 0.001) for CF than CC or CR. Lambs with T * BF dams achieved a higher (P < 0.05) daily CWG and CWG/kg DMI than BF * BF, SW * BF or LL * BF dams. When lambs were slaughtered at fat score 3, CH * BF, LL * BF and T * BF dams increased carcass weight by 0.8 to 1.4 kg (P < 0.001) and conformation score (CS) by 0.2 to 0.4 units (P < 0.001) compared with BF * BF or SW * BF dams. However, breed effects on carcass conformation were reduced by 50% when lambs were slaughtered at a constant carcass weight. Diets CC and CR increased carcass weight by 0.8 to 1.6 kg (P < 0.001) and CS by 0.1 to 0.3 units (P < 0.001) compared with GP and CF. Both, dam breed and dietary effects on carcass conformation were associated with an increase (P < 0.001) in shoulder width of the lambs. Lambs fed CF and slaughtered at a constant carcass weight had more subcutaneous fat over the Longissumus dorsi (P < 0.05), Iliocostalis thoracis (P < 0.001) and Obliquus internus abdominis (P < 0.001) compared with those fed CC. However, these effects were removed when lambs were slaughtered at a constant fat score. At both endpoints, lambs from T * BF dams contained less (P < 0.05) perinephric and retroperitoneal fat than SW * BF or LL * BF dams fed GP or CC, respectively. The results from this study show that using crossbred ewes sired by CH, LL or T sires will increase carcass weight and improve carcass conformation of lambs sourced from hill flocks. Inclusion of oilseed rape in lamb finishing diets had only minor effects on performance compared with a standard CC but feeding fish oil or GP impacted negatively on lamb growth and carcass quality. PMID- 22440099 TI - Systems biology in animal sciences. AB - Systems biology is a rapidly expanding field of research and is applied in a number of biological disciplines. In animal sciences, omics approaches are increasingly used, yielding vast amounts of data, but systems biology approaches to extract understanding from these data of biological processes and animal traits are not yet frequently used. This paper aims to explain what systems biology is and which areas of animal sciences could benefit from systems biology approaches. Systems biology aims to understand whole biological systems working as a unit, rather than investigating their individual components. Therefore, systems biology can be considered a holistic approach, as opposed to reductionism. The recently developed 'omics' technologies enable biological sciences to characterize the molecular components of life with ever increasing speed, yielding vast amounts of data. However, biological functions do not follow from the simple addition of the properties of system components, but rather arise from the dynamic interactions of these components. Systems biology combines statistics, bioinformatics and mathematical modeling to integrate and analyze large amounts of data in order to extract a better understanding of the biology from these huge data sets and to predict the behavior of biological systems. A 'system' approach and mathematical modeling in biological sciences are not new in itself, as they were used in biochemistry, physiology and genetics long before the name systems biology was coined. However, the present combination of mass biological data and of computational and modeling tools is unprecedented and truly represents a major paradigm shift in biology. Significant advances have been made using systems biology approaches, especially in the field of bacterial and eukaryotic cells and in human medicine. Similarly, progress is being made with 'system approaches' in animal sciences, providing exciting opportunities to predict and modulate animal traits. PMID- 22440100 TI - Do genetically modified crops affect animal reproduction? A review of the ongoing debate. AB - In the past few years, genetically modified (GM) crops aimed at producing food/feed that became part of the regular agriculture in many areas of the world. However, we are uncertain whether GM food and feed can exert potential adverse effects on humans or animals. Of importance, the reproductive toxicology of GM crops has been studied using a number of methods, and by feeding GM crops to a number species of animals to ensure the safety assessment of GM food and feed. It appears that there are no adverse effects of GM crops on many species of animals in acute and short-term feeding studies, but serious debates of effects of long term and multigenerational feeding studies remain. The aims of this review are to focus on the latest (last 3 to 4 years) findings and debates on reproduction of male and female animals after feeding daily diets containing the GM crops, and to present the possible mechanism(s) to explain their influences. PMID- 22440101 TI - Progeny of high muscling sires have reduced muscle response to adrenaline in sheep. AB - This study investigated the impact of variation in Australian sheep breeding values (ASBVs) for yearling eye muscle depth (YEMD) within Merino and Poll Dorset sires on intermediary metabolism of progeny. Specifically, the change in the blood concentrations of lactate, non-esterified fatty acids (NEFA) and glucose in response to administration of an exogenous dose of adrenaline was studied. The experiment used 20 Merino and Merino cross Poll Dorset mixed sex sheep. The sires were selected across a range of YEMD ASBVs. The sheep were fitted with indwelling jugular catheters and administered seven levels of adrenaline over a period of 4 days at 4 months of age (0.1, 0.2, 0.4, 0.6, 0.9, 1.2 and 1.6 MUg/kg liveweight (LW)) and 16 months of age (0.1, 0.2, 0.6, 1.2, 1.8, 2.4 and 3.0 MUg/kg LW). A total of 16 blood samples were collected between -30 min and 130 min relative to administration of the adrenaline challenge and were later measured for the plasma concentrations of lactate, NEFA and glucose. These data were then used to calculate the time to maximum substrate concentration, the maximum concentration and the area under curve (AUC) between 0 and 10 min, thus reflecting the substrate's response to exogenous adrenaline. Selection for muscling led to decreased muscle response due to adrenaline, as indicated by lower maximum concentrations and AUC for lactate. The muscles' response to adrenaline was more prominent at 16 months of age than at 4 months of age. Thus, animals selected for increased muscling have lower levels of glycogenolysis in situations where endogenous adrenaline levels are increased like pre-slaughter. This may minimise the risk of poor meat quality in these animals, as they will express higher muscle concentrations of glycogen at slaughter. Adipose tissue was more sensitive to adrenaline in young lambs from high YEMD sires. This shows that high muscled growing lambs utilise their adipose tissue deposits in times of stress to produce energy. This may explain the phenotypic leanness of these animals. Blood glucose levels that are indicative of liver response to adrenaline decreased with selection for muscling. This response may indicate a potential limiting of glucose that is available within animals selected for muscling, leanness and growth for brain function. PMID- 22440102 TI - Gene expression profiling in developing pig adipose tissue: non-secreted regulatory proteins. AB - The expression of many genes encoding secreted and non-secreted factors have been studied in human and rodent adipose tissue with cDNA microarrays, but few such studies in adipose tissue from growing pigs have been reported. Total RNA was collected at slaughter from outer subcutaneous adipose tissue (OSQ) and middle subcutaneous adipose tissue (MSQ) samples from gilts at 90, 150 and 210 days (n = 5/age). Dye-labeled cDNA probes were hybridized to custom microarrays (70-mer oligonucleotides) representing about 600 pig genes involved in growth and reproduction. Gene expression intensity ratios changed little with age for 100 transcription factors, nuclear receptors, enzymes and other regulatory proteins in OSQ and MSQ from pigs between 90 and 210 days of age. However, the relative expression of 13 genes distinguished OSQ and MSQ depots in growing pigs. The expression of several genes were influenced by age including an increase in CCND3, HSF1 and PTGR1 expression in MSQ and a decrease in UCP2 and REA (prohibitin-2) expression in OSQ. These studies demonstrate for the first time the expression of several key regulatory genes in pig adipose tissue. Simple linear regression analysis showed that leptin gene expression was associated with expression of some of these regulatory genes. Negative associations between expression of some regulatory factors and leptin gene expression indicated that local leptin may decrease or antagonize adipogenesis. PMID- 22440103 TI - Comparison of the novel compounds creatine and pyruvateon lipid and protein metabolism in broiler chickens. AB - The effects of pyruvate (Pyr), creatine pyruvate (Cr-Pyr) and creatine (Cr) on lipid and protein metabolism were compared in broiler chickens. A total of 400 1 day-old male birds (Aconred) were allocated to four groups, each of which included four replicates (25 birds per replicate). Treatments consisted of unsupplemented basal diet (Control), basal diet containing 2% Pyr, basal diet containing 3% Cr and basal diet containing 5% Cr-Pyr. Cr-Pyr and Pyr significantly decreased the hepatic triglyceride and serum total cholesterol concentration (P < 0.01). Cr-Pyr markedly increased the serum non-esterified fatty acid and high-density lipoprotein cholesterol concentrations (P < 0.05), whereas the expression of carnitine palmitoyl transferase I (P < 0.05) and peroxisome proliferators-activated receptor-alpha (P < 0.01) mRNA in the liver were both decidedly enhanced in the Cr-Pyr group. The relative leg muscle weight was higher in the Cr-Pyr group than in the control group, whereas the serum uric acid content and hepatic glutamic-oxaloacetic transaminase activity were lower in the Cr-Pyr and Cr groups (P < 0.05), respectively. Muscle insulin-like growth factor I (P < 0.05) expression was enhanced, and the myostatin (P < 0.01) mRNA level was reduced in both the Cr-Pyr and Cr groups. In addition, Cr-Pyr did not alter body weight or the feed conversion ratio. These results indicate that, compared with Pyr and Cr alone, Cr-Pyr has a bifunctional role in broiler chickens, in that it influences both lipid and protein metabolism. PMID- 22440104 TI - Distinct metabolism of linoleic and linolenic acids in liver and adipose tissues of finishing Normande cull cows. AB - Feeding strategies based on the addition of plant lipids rich in polyunsaturated fatty acids (PUFAs) in diets of bovines during the finishing period are common to enhance the nutritional value of meat. However, following rumen biohydrogenations, these FAs could still be metabolised in various tissues/organs involved in the FA metabolism such as the liver and adipose tissues (ATs), thus affecting their subsequent deposition in muscles. In this context, the objective of this study was to characterise the various metabolic pathways of linoleic acid (LA) and alpha-linolenic acid (ALA) in the liver and ATs (subcutaneous (SC) and inter-muscular (IM)) of Normande cull cows fed a diet supplemented (LR) or not (C) with extruded linseeds and rapeseeds, using the ex vivo incubated tissue slice method. Hepatic uptake of both FAs was higher with the LR than with the C diet (P = 0.02). For the two diets, ALA uptake was higher than that of LA (+46%, P = 0.04). ALA was much more degraded by beta-oxidation (>50% of ALA present in cells) than LA (~27%) with both diets (P = 0.015). Whatever the diet, ALA was not converted into longer and/or more unsaturated FA, whereas about 14% of LA was converted into 20:4n-6. The intensity of the esterification pathway was higher (+70%, P = 0.004) with the LR than with the C diet, for both FAs. Hepatic secretion of ALA as part of the very-low-density lipoprotein particles was lower than that of LA (-58% and -23% for C and LR diets respectively, P = 0.02). In SC and IM ATs, dietary lipid supplementation did not alter metabolic pathways of LA and ALA. They were efficiently taken up by ATs (>68% of FA present in the medium), with uptake being higher for IM than for SC AT (+12%, P = 0.01). Moreover, LA uptake by ATs was higher than ALA uptake (+10.7%, P = 0.027). Both FAs were mainly esterified (>97% of FA present in adipocytes) into neutral lipids (>85% of esterified FA). Around 9.5% of LA was converted into 20:4n-6, whereas only around 1.3% of ALA was converted into 20:5n-3. We concluded that, in our experimental conditions, liver was highly active in ALA catabolism limiting its subsequent deposition in muscles. However, bovine liver and ATs were inefficient at converting ALA into long-chain n-3 PUFA, but actively converted LA into 20:4n 6. PMID- 22440105 TI - Effects of the prebiotics inulin and lactulose on intestinal immunology and hematology of preruminant calves. AB - Prebiotics are suggested as an alternative to antibiotics in animal rearing. Fermentable substances such as inulin or lactulose have been proposed to stimulate the immune system and health by modulation of the intestinal flora and its fermentation products. In this study, effects of inulin and lactulose on the intestinal health and hematology of calves have been investigated. Both prebiotics significantly decreased thrombocyte counts in peripheral blood. Only inulin was able to increase hemoglobin concentration and hematocrit. Total leukocyte count was decreased by lactulose while both prebiotics tended to lower monocyte proportions. mRNA expression of inflammation-related markers in the intestine was also affected by both prebiotics hinting at a decreased inflammatory status. This may be due to a possible decrease in intestinal pathogen load that remains to be verified. Only mRNA amounts of interleukin 8 were increased by lactulose in mesenteric lymph nodes. In the ileum, expression of a proliferation marker was increased by inulin while an apoptosis-related gene was increased by both prebiotics. The results of this study show a clear effect of prebiotics on certain parameters associated with animal health and performance that remain to be studied in detail in future investigations. PMID- 22440106 TI - Consumer response to the possible use of a vaccine method to control boar taint v. physical piglet castration with anaesthesia: a quantitative study in four European countries. AB - In most European countries, male piglets being reared for meat are physically castrated without anaesthesia in order to avoid boar taint and to safeguard sensory meat quality. This method is increasingly criticised for its violation of piglet welfare. Alternative methods are being researched and castration with anaesthesia or analgesia and vaccination (immunisation) against gonadotropin releasing hormone (using Improvac(r), Pfizer GmbH) have been proposed as possible solutions. In addition to efficacy, the successful introduction and adoption of the vaccine method by stakeholders in pig supply chains are expected to depend on a favourable reception by consumers. This large-scale quantitative cross-country study (n = 4031) involving representative samples of consumers in France, Germany, the Netherlands and Belgium does not support the reserved attitude of stakeholders who fear potential low market acceptance. The vaccine method was actually preferred by the majority of consumers surveyed (69.6% of the participants) and it was perceived as equally effective in terms of avoiding boar taint; 43.8% of the consumers reported an intention to seek out pork from pigs where the vaccine had been used to control boar taint, whereas 33.7% reported an intention to avoid pork from pigs physically castrated with anaesthesia. Consumers' favourable dispositions to the vaccine method were independent of dominant ethical, health or price orientations when purchasing pork. PMID- 22440107 TI - Considerations on the performance of immunocastrated male pigs. AB - With the ongoing social pressure on surgical castration of pigs, an increase in the population of pigs that are either not castrated or immunocastrated (IC) can be expected. In both cases, their nutrient requirements and performance will differ from surgically castrated pigs and will require changes in their management. Immunocastration is performed by giving two injections of a modified gonadotrophin-releasing hormone component along with an adjuvant, at least 4 weeks apart. This paper describes the reported differences in growth performance and carcass quality of IC male pigs in comparison with boars (BO) and barrows (BA). Theoretically, IC pigs remain physiologically boar until the second vaccination and therefore, growth may be comparable with BO until this second vaccination. From then on, IC male pigs consume more feed than BO and grow faster when fed ad libitum. IC showed a faster growth and better feed conversion ratio than BA. When fed restrictedly, BO grow faster and more efficiently than BA and IC. IC have a lower carcass yield than BA and BO, whereas meat percentage is intermediate. PMID- 22440108 TI - Effect of dietary saponins from Quillaja saponaria L. on fatty acid composition and cholesterol content in muscle Longissimus dorsi of lambs. AB - The purpose of this study was to evaluate the effects of increasing levels of saponins from Quillaja saponaria on fatty acid (FA) composition and cholesterol content in muscle Longissimus dorsi of lambs. A total of 24 Barbarine lambs were assigned to four dietary treatments: control diet (C) consisting of oat hay ad libitum and 400 g of concentrate (80% barley, 17.5% soybean meal and 2.5% vitamin and mineral supplement); C diet plus 30 ppm of Q. saponaria L. (QS30); C diet plus 60 ppm of Quillaja (QS60); C diet plus 90 ppm of Quillaja (QS90). Saponin supplementation reduced the concentration of C14:1 cis-9 (P = 0.001) and of its desaturation index (P = 0.002). None of the FA intermediates of ruminal biohydrogenation (BH) was affected by Quillaja saponin supplementation (P > 0.05). The concentration of C20:4n-6 was higher in the meat of animals receiving 60 ppm of Quillaja than C and QS30 groups. Supplementing 60 ppm of Quillaja reduced the ratio between alpha-linolenic and linoleic acids compared with the C group (P = 0.023). We did not find any significant effect of Quillaja saponins on muscle cholesterol level. Further investigations are necessary to assess the metabolic fate of saponins in the rumen and to understand whether there is an effect of saponin on Delta9-desaturase enzyme activity, ruminal BH and cholesterol metabolism in ruminants. Supplementing up to 90 ppm of Quillaja saponins did not produce detrimental effects on the overall meat FA profile. PMID- 22440109 TI - Productive performance, carcass and meat quality of intact and castrated gilts slaughtered at 106 or 122 kg BW. AB - A total of 200 (Landrace * Large White dam * Pietrain * Large White sire) gilts of 50 +/- 3 days of age (23.3 +/- 1.47 kg BW) were used to investigate the effects of castration (intact gilt, IG v. castrated gilt, CG) and slaughter weight (SW; 106 v. 122 kg BW) on productive performance, carcass and meat quality. Four treatments were arranged factorially and five replicates of 10 pigs each per treatment. Half of the gilts were ovariectomized at 58 days of age (8 days after the beginning of the trial at 29.8 +/- 1.64 kg BW), whereas the other half remained intact. The pigs were slaughtered at 106 or 122 kg BW. Meat samples were taken at Musculus longissimus thoracis at the level of the last rib and subcutaneous fat samples were taken at the tail insertion. For the entire experimental period, CG had higher (P < 0.05) BW gain and higher (P < 0.001) backfat and Musculus gluteus medius fat thickness than IG. However, IG had higher (P < 0.05) loin and trimmed primal cut yields than CG. Meat quality was similar for IG and CG but the proportion of linoleic acid in subcutaneous fat was higher (P < 0.001) for IG. Pigs slaughtered at 122 kg BW had higher (P < 0.001) feed intake and poorer feed efficiency than pigs slaughtered at 106 kg BW. An increase in SW improved (P < 0.001) carcass yield but decreased (P < 0.05) trimmed primal cut yield. Meat from pigs slaughtered at the heavier BW was redder (a*; P < 0.001) and had more (P < 0.01) intramuscular fat and less thawing (P < 0.05) and cooking (P < 0.10) loss than meat from pigs slaughtered at the lighter BW. In addition, pigs slaughtered at 122 kg BW had less (P < 0.01) linoleic acid content in subcutaneous fat than pigs slaughtered at 106 kg BW. Castration of gilts and slaughtering at heavier BW are useful practices for the production of heavy pigs destined to the dry-cured industry in which a certain amount of fat in the carcass is required. In contrast, when the carcasses are destined to fresh meat production, IG slaughtered at 106 kg BW is a more efficient alternative. PMID- 22440110 TI - Influence of vitamins A, D3 and E status on post-mortem meat quality in steers under winter housing or pasture finishing systems. AB - We investigated the influence of Swedish recommended vitamins A, D3 and E supplementation levels on muscle tenderness and fatty acid (FA) composition under indoor or outdoor finishing programmes. Swedish Red breed steer calves were divided into vitamin supplemented (n = 12) and non-supplemented (n = 15) groups while on pasture prior to the finishing period. This trial began at the beginning of the winter housing period during which the steers were fed a 55 : 45 dry matter barley : grass silage diet indoors. The indoor finished group was comprised of vitamin supplemented (n = 6) and non-supplemented (n = 8) steers slaughtered after about 155 days on feed. Vitamin supplemented steers were provided with 100 g mineral supplement providing 400 000 IU vitamin A, 100 000 IU D3 and 3000 IU E daily as recommended for Swedish production practices. In spring, outdoor finished vitamin supplemented (n = 6) and non-supplemented (n = 7) steers grazed semi-natural grassland for an additional 120 days before slaughter. During pasture, vitamin supplemented steers had free-choice access to a mineral supplement containing vitamins A, D3 and E. The mineral supplement for the non-supplemented steers did not contain vitamins A, D3 and E and was provided at the same amount as the vitamin supplemented steers. Shear force values were similar between vitamin supplemented and non-supplemented steers after ageing 2, 7 and 14 days within indoor and outdoor finishing programmes. The shear force values had decreased by 14 days of ageing within all programmes. The MU- and m calpain activity did not differ between vitamin supplemented and non-supplemented steers for either the indoor or outdoor finishing programmes. The calpastatin activity was higher for the indoor, vitamin supplemented steers. Indoor finished vitamin supplemented steers had a greater proportion of C18:1c-9 and total monounsaturated fatty acids, whereas the non-supplemented steers had a greater proportion of total saturated fatty acids. We concluded that the meat quality from steers not receiving vitamin supplementation was similar to that of steers receiving vitamins A, D3 and E supplementation at Swedish recommended levels under indoor and outdoor finishing programmes. PMID- 22440111 TI - Impact of high-pressure processing on vitamin E (alpha-, gamma-, and delta tocopherol), vitamin D (cholecalciferol and ergocalciferol), and fatty acid profiles in liquid foods. AB - In the present study, four high-pressure (HP) treatments (100, 200, 300, and 400 MPa) of 9 min duration were evaluated to assess their effect on the lipid fraction (fat-soluble vitamins and fatty acid profile) of an orange juice-milk and a vegetable beverage. After HP treatment, nonsignificant changes in vitamin D(2) and D(3) contents were observed for both beverages. An increase in vitamin E activity was observed in HP beverages when pressures >100 MPa were applied, mainly due to an increase in alpha-tocopherol content. Only a small reduction in fat content was found for the orange juice-milk beverage, but no changes were observed for the vegetable beverage. A significant decrease in SFA levels was observed in HP-treated (300-400 MPa) orange juice-milk. With regard to MUFA, a significant increase in oleic acid (C(18:1)) was found in both liquid foods. Nonsignificant differences in the PUFA profiles were observed after HP processing. PMID- 22440112 TI - Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. AB - BACKGROUND: Long-term follow-up of randomised trials of aspirin in prevention of vascular events showed that daily aspirin reduced the incidence of colorectal cancer and several other cancers and reduced metastasis. However, statistical power was inadequate to establish effects on less common cancers and on cancers in women. Observational studies could provide this information if results can be shown to be reliable. We therefore compared effects of aspirin on risk and outcome of cancer in observational studies versus randomised trials. METHODS: For this systematic review, we searched for case-control and cohort studies published from 1950 to 2011 that reported associations between aspirin use and risk or outcome of cancer. Associations were pooled across studies by meta-analysis and stratified by duration, dose, and frequency of aspirin use and by stage of cancer. We compared associations from observational studies with the effect of aspirin on 20-year risk of cancer death and on metastasis in the recent reports of randomised trials. FINDINGS: In case-control studies, regular use of aspirin was associated with reduced risk of colorectal cancer (pooled odds ratio [OR] 0.62, 95% CI 0.58-0.67, p(sig)<0.0001, 17 studies), with little heterogeneity (p(het)=0.13) in effect between studies, and good agreement with the effect of daily aspirin use on 20-year risk of death due to colorectal cancer from the randomised trials (OR 0.58, 95% CI 0.44-0.78, p(sig)=0.0002, p(het)=0.45). Similarly consistent reductions were seen in risks of oesophageal, gastric, biliary, and breast cancer. Overall, estimates of effect of aspirin on individual cancers in case-control studies were highly correlated with those in randomised trials (r(2)=0.71, p=0.0006), with largest effects on risk of gastrointestinal cancers (case-control studies, OR 0.62, 95% CI 0.55-0.70, p<0.0001, 41 studies; randomised trials, OR 0.54, 95% CI 0.42-0.70, p<0.0001). Estimates of effects in cohort studies were similar when analyses were stratified by frequency and duration of aspirin use, were based on updated assessments of use during follow up, and were appropriately adjusted for baseline characteristics. Although fewer observational studies stratified analyses by the stage of cancer at diagnosis, regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis (OR 0.69, 95% CI 0.57-0.83, p(sig)<0.0001, p(het)=0.89, five studies), but not with any reduction in regional spread (OR 0.98, 95% CI 0.88 1.09, p(sig)=0.71, p(het)=0.88, seven studies), consistent again with the findings in randomised trials. INTERPRETATION: Observational studies show that regular use of aspirin reduces the long-term risk of several cancers and the risk of distant metastasis. Results of methodologically rigorous studies are consistent with those obtained from randomised controlled trials, but sensitivity is particularly dependent on appropriately detailed recording and analysis of aspirin use. FUNDING: None. PMID- 22440113 TI - Antihyperglycemic and antioxidant activity of water extract from Anoectochilus roxburghii in experimental diabetes. AB - The hypoglycemic and antioxidant effects of the water extract from Anoectochilus roxburghii in alloxan-induced diabetic mice were examined. Compared with untreated diabetic mice, the daily oral administration of the water extract from A. roxburghii at 0.5 or 2 g/kg for 14 days caused a significant decrease (p<.05) in blood glucose levels with similar effect but no evidence of dose-related effect. Simultaneously, the alteration in lipid metabolism was partially attenuated as evidenced by decreased serum total cholesterol and triglyceride levels and by increased high-density lipoprotein cholesterol concentration in diabetic mice (p<.05) but no dose-related effect was observed. In addition, the water extract from A. roxburghii caused a significant increase (p<.05) in the activities of enzymic antioxidants and the levels of vitamin E in liver and kidney of diabetic mice. Our results suggest that water extract from A. roxburghii possesses hypoglycemic and antioxidant properties after oral administration to mice showing alloxan-induced diabetes. PMID- 22440114 TI - Recent trends in hospitalization for acute myocardial infarction. AB - Rates of acute myocardial infarction (AMI) hospitalizations for elderly Medicare patients decreased during the previous decade. However, trends in population rates of AMI hospitalizations for all adults by subgroups have not been described. Using data from a large all-payer administrative database of hospitalizations, we calculated annual AMI hospitalization rates from 2001 through 2007. Trend analysis was performed across age, gender, and ethnicity categories using survey regression. Overall rate decreased from 314 to 222 AMI hospitalizations per 100,000 patients from 2001 through 2007, representing a 29.2% decrease. Significant decreases were observed in AMI hospitalization rate for each group by age categories (p <0.001) and by gender (p <0.001). When stratified by ethnicity and gender, age-adjusted AMI hospitalization rates in white men and women decreased by 30.8% and 31.4%, whereas black men and women had significantly slower rates of decrease of 13.6% and 12.6%, respectively. In conclusion, although the overall rate of AMI hospitalizations decreased from 2001 through 2007, the observed decrease was smaller for black patients compared to white patients across all age groups studied. PMID- 22440115 TI - Cardiac adaptation in acute hypertensive pulmonary edema. AB - The aim of this study was to evaluate the role of left ventricular (LV) dysfunction (global and regional, systolic and diastolic) acute dyssynchrony, ischemic mitral regurgitation (MR), and afterload changes in acute hypertensive pulmonary edema (AHPE). Forty-four consecutive patients were evaluated by comprehensive echocardiography during clinical and radiologic pulmonary edema (63 +/- 29 minutes after first dose of treatment) and after 48 to 92 hours. Twenty age- and gender-matched asymptomatic hypertensive and diabetic subjects served as controls. AHPE was associated with increased afterload (estimated arterial elastance 3.0 vs 2.3 mm Hg/ml, p = 0.024) and subsequent decreased longitudinal LV systolic function (mean strain of 6 basal segments -11.0% vs -15.4%; p = 0.015) compared to the stable follow-up state. However, global LV systolic function was maintained (estimated ventricular elastance 1.7 vs 1.6 mm Hg/ml, stroke work 76.7 vs 84.5 cJ, ejection fraction 0.33 vs 0.37, all nonsignificant). Except for diastolic filling time (ratio to cardiac cycle 0.41 vs 0.49, p <0.001), other indexes of diastolic function, dyssynchrony, and MR severity were similar between evaluations. Patients with AHPE had worse ventricular-arterial coupling, systolic function, estimated diastolic stiffness, and filling pressures compared to asymptomatic controls, suggesting a decreased capacity to adapt to changes in loading. In conclusion, acute alterations of systolic and diastolic LV function, myocardial synchrony, and ischemic MR are unlikely mechanisms of AHPE. Rather, AHPE is likely to develop in patients with decreased systolic and diastolic capacity to adapt to acute changes in loading. PMID- 22440116 TI - Within-hospital and 30-day outcomes in 107,994 patients undergoing invasive coronary angiography with different low-osmolar iodinated contrast media. AB - Comparative clinical outcomes after exposure to alternate low osmolar contrast media (LOCM) during invasive coronary angiography (ICA) and/or percutaneous coronary intervention (PCI) have been incompletely examined. From a retrospective multicenter observational study, we identified 107,994 adults without previous hemodialysis undergoing ICA and/or PCI with iohexol, iopamidol, or ioversol. We created a propensity score for contrast media type using age, gender, coverage status, route of hospitalization, illness severity, physician specialty, co morbidities, and procedure type. Propensity matching was performed in a 1:1 fashion for iohexol (n = 10,204) and iopamidol (n = 10,204) and in a 1:1 fashion for iohexol (n = 19,482) and ioversol (n = 19,482). Groups were examined for differences in in-hospital mortality or subsequent hemodialysis, length of stay, and 30-day readmission for contrast-induced nephropathy (CIN). Compared to patients exposed to iohexol, no differences were observed for patients exposed to iopamidol or ioversol for in-hospital hemodialysis (0.5% vs 0.4%, p = 0.45; 0.3% vs 0.5%, p = 0.05), in-hospital mortality (0.7% vs 0.6%, p = 0.60; 0.5% vs 0.6%, p = 0.42), or composite hemodialysis or mortality (1.1% vs 1.0%, p = 0.58; 0.8% vs 1.0%, p = 0.06); for hospital length of stay (2.9 +/- 2.7 vs 2.9 +/- 2.7 days, p = 0.05; 2.8 +/- 2.6 vs 2.9 +/- 3.1 days, p = 0.35); or for 30-day readmission for CIN (0.1% vs 0.1%, p = 0.82; 0.1% vs 0.1%, p = 0.52). In conclusion, for patients undergoing ICA and/or PCI exposed to alternate LOCM, in-hospital death, need for hemodialysis, or readmission for CIN are uncommon, with no apparent clinical advantage among LOCM agents. PMID- 22440117 TI - Comparison of late (3-year) registry data outcomes using bare metal versus drug eluting stents for treating ST-segment elevation acute myocardial infarctions. AB - Clinical trial data have supported the safety and efficacy of drug-eluting stents (DES) in the treatment of patients with ST-segment elevation myocardial infarctions (STEMIs), but contemporary "real-world" registry data regarding the late safety profiles of DES are limited. This prospective registry-based study included 1,569 consecutive unselected patients with STEMIs who underwent emergency primary percutaneous coronary intervention from January 2001 to December 2009. Of the study cohort, 200 patients (12.7%) received DES, while 1,369 patients (87.3%) underwent bare-metal stent (BMS) placement. The primary end points of the study were all-cause mortality and target vessel revascularization at 1, 2, and 3 years. Survival status was assessed by municipal civil registries. Repeat revascularization procedures were prospectively collected in the hospital database. All-cause mortality was significantly lower in the DES group at 3 years (4.2% vs 13.5%, p = 0.007) compared to BMS-treated patients, but DES use was not an independent predictor of all-cause mortality (adjusted odds ratio 0.5, 95% confidence interval 0.2 to 1.2, p = 0.10). Target vessel revascularization was significantly lower in the DES group compared to the BMS group at 3 years (10.5% vs 21%, p = 0.001). DES use was an independent predictor of reduced target vessel revascularization (adjusted odds ratio 0.44, 95% confidence interval 0.25 to 0.77, p = 0.004). Late definite stent thrombosis occurring after 1 year occurred in 4 (2.5%) patients in the DES group compared to 6 (0.7%) in the BMS group (p = 0.05). DES use was an independent predictor of late stent thrombosis (adjusted odds ratio 8.6, 95% confidence interval 1.9 to 38, p = 0.004). In conclusion, this contemporary registry-based study of patients who underwent primary percutaneous coronary intervention for STEMI demonstrated improved revascularization rates without increased 3-year hazard of adverse clinical outcomes in DES-treated patients. PMID- 22440118 TI - Intravascular ultrasound findings that are predictive of no reflow after percutaneous coronary intervention for saphenous vein graft disease. AB - The aim of this study was to investigate the relation between intravascular ultrasound (IVUS) findings and the no-reflow phenomenon and long-term outcome after percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) lesions. No reflow was defined as Thrombolysis In Myocardial Infarction grade 0, 1, or 2 flow after PCI. Of 311 patients who underwent IVUS before and after stenting, no reflow was observed in 39 patients (13%). Degenerated SVG (62% vs 36%, p = 0.002), IVUS-detected intraluminal mass (82% vs 43%, p <0.001), culprit lesion multiple plaque ruptures (23% vs 6%, p <0.001), and tissue prolapse (51% vs 35%, p = 0.043) were observed more frequently in patients with no reflow. In multivariate logistic regression analysis, an intraluminal mass (odds ratio [OR] 4.84, 95% confidence interval [CI] 1.98 to 10.49, p = 0.001), culprit lesion multiple plaque ruptures (OR 3.46, 95% CI 1.46 to 8.41, p = 0.014), and degenerated SVGs (OR 3.17, 95% CI 1.17 to 6.56, p = 0.024) were the independent predictors of no reflow after PCI. At 5-year clinical follow-up, rates of death (14, 36%, vs 55, 20%, p = 0.036) and myocardial infarction (13, 33%, vs 52, 19%, p = 0.039) were significantly higher in the no-reflow group. However, rate of target vessel revascularization was not significantly different between the 2 groups (15, 38%, vs 90, 33%, p = 0.3). IVUS-detected intraluminal mass, multiple plaque ruptures, and degenerated SVGs were associated with no reflow in SVG lesions after PCI. In conclusion, no reflow was associated with poor long-term clinical outcomes after PCI for SVG lesions. PMID- 22440119 TI - Comparison of frail patients versus nonfrail patients >=65 years of age undergoing percutaneous coronary intervention. AB - Frailty is a geriatric syndrome characterized by functional impairments and is associated with poor outcomes; however, the prevalence of frailty and its association with health status in patients treated with percutaneous coronary intervention (PCI) are unknown. To assess the prevalence of frailty and its association with health status in PCI-treated patients, we studied 629 patients >=65 years old undergoing PCI from October 2005 through September 2008. Frailty was characterized using the Fried criteria: weight loss >10 lbs. in previous 1 year, exhaustion, low physical activity, poor gait speed, and poor grip strength (3 features = frail; 1 feature to 2 features = intermediate frailty; 0 feature = not frail). Health status was assessed using the Short-Form 36 and the Seattle Angina Questionnaire (SAQ). Multivariable linear regression models were used to estimate the independent association between frailty and health status. Complete data on 545 patients demonstrated that 19% (n = 117) were frail, 47% (n = 298) had intermediate frailty, and 21% (n = 130) were not frail. Frail patients had more co-morbidities and more frequent left main coronary artery or multivessel disease after adjusting for age and gender (p <0.05 across groups). Multivariable linear regression demonstrated poorer health status in frail patients compared to nonfrail patients as evidenced by lower Short-Form 36 scores, lower SAQ scores for physical limitation, and lower SAQ scores for quality of life (p <0.001 for each health status domain). In conclusion, 1/5 of older patients are frail at the time of PCI and have greater comorbid burden, angiographic disease severity, and poorer health status than nonfrail adults. PMID- 22440120 TI - Are the results of a regional ST-elevation myocardial infarction system reproducible? AB - Primary percutaneous coronary intervention (PCI) is the preferred reperfusion method in patients with ST-elevation myocardial infarction (STEMI) if it can be performed in a timely manner in high-volume centers. Regional STEMI networks improve timely access to PCI but are frequently criticized for being single center. To determine if results of regional STEMI systems could be replicated and achieve similar outcomes in 2 separate geographic regions, we examined the prospective databases of 2 large regional STEMI networks that use identical standardized protocols and integrated transfer systems. The Minneapolis Heart Institute (MHI) database included 2,266 patients with STEMI from 31 hospitals (498 at the PCI hospital, 1,033 transferred from 11 hospitals <60 miles away, and 735 transferred from 19 hospitals 60 to 210 miles away). The Iowa Heart Center (IHC) database included 1,206 patients with STEMI from 24 hospitals (710 at the PCI hospital, 266 transferred from 10 hospitals <60 miles away, and 230 transferred from 13 hospitals 60 to 120 miles away). Median total door-to-balloon times for the PCI hospital, zone 1, and zone 2 patients were 64, 95, and 123 minutes for the MHI and 59, 102, and 136 for the IHC (p <0.05 for each comparison between MHI and IHC). Overall in-hospital, 30-day, and 1-year mortalities was 4.8%, 5.4%, and 8.0% respectively (p = NS for each comparison between MHI and IHC). In conclusion, the use of identical protocols in 2 large regional STEMI systems in geographically separate locations produced nearly identical outcomes, adding to evidence that regional STEMI centers expand timely access to PCI. PMID- 22440121 TI - Meta-analysis of dietary glycemic load and glycemic index in relation to risk of coronary heart disease. AB - A high glycemic diet may increase cardiovascular risk, yet whether the risk differs by gender or adiposity is inconclusive. Our goal was to determine the associations between dietary glycemic load (GL) and glycemic index (GI), and coronary heart disease (CHD) risk by conducting a meta-analysis of prospective studies. We searched the PubMed and Embase databases in July 2011 to identify eligible studies. The random-effects model was used to calculate pooled relative risks (RRs) comparing the highest categories of exposure to the lowest. Prespecified subgroup analyses were performed by gender and body mass index. We identified 8 prospective studies for meta-analysis, consisting of 220,050 participants and 4,826 incident CHD cases. Pooled RRs of CHD in relation to dietary GL were 1.08 (95% confidence interval [CI] 0.92 to 1.27) for men, 1.69 (95% CI 1.32 to 2.16) for women, and 1.36 (95% CI 1.13 to 1.63) for men and women combined. For dietary GI, corresponding pooled RRs were 0.99 (95% CI 0.84 to 1.16), 1.26 (95% CI 1.12 to 1.43), and 1.13 (95% CI 1.00 to 1.28), respectively. Limited evidence suggested the associations appeared more evident in the overweight and obese. There was no indication of publication bias. In conclusion, high dietary GL and GI significantly increased the risk of CHD in women but not in men, and the unfavorable effects may be more pronounced in overweight and obese patients. Further studies are needed to verify these findings and elucidate the underlying mechanisms. PMID- 22440122 TI - Usefulness of SUM of ST-segment elevation on electrocardiograms (limb leads) for predicting in-hospital complications in patients with stress (takotsubo) cardiomyopathy. AB - Although the prognosis of patients with stress (takotsubo) cardiomyopathy is relatively favorable, serious complications occur in some patients. It is generally accepted that electrocardiography is an essential tool for the diagnosis of stress cardiomyopathy, with findings highly suggestive of the characteristics of myocardial damage. We tested the hypothesis that the quantitative analysis of electrocardiograhic changes can predict complications in stress cardiomyopathy. The study subjects were 85 patients with stress cardiomyopathy. A total of 34 patients developed >=1 in-hospital complications (heart failure, intraventricular pressure gradient [>30 mm Hg], cardiogenic shock, ventricular tachycardia/fibrillation, and embolism). Patients with complications were likely to have a higher heart rate (96 +/- 25 vs 76 +/- 17 beats/min, p <0.001), larger sum of ST-segment elevation in 12 leads (median 10.5 mm; interquartile range 5.0 to 17.5 vs 3.0 mm, interquartile range 0 to 7.0; p <0.001) and extension of ST-segment elevation to limb leads (50% vs 12%, p <0.001) than those without complications. Multivariate logistic regression analysis identified heart rate (odds ratio 1.05, 95% confidence interval 1.02 to 1.07, p = 0.001) and sum of ST-segment elevation in 12 leads (odds ratio 1.24, 95% confidence interval 1.11 to 1.39, p <0.001) as significant and independent predictors of complications. Receiver operating characteristic analysis selected 5.5 mm as the best cutoff value of sum of ST-segment elevation in 12 leads for the prediction of complications, with a sensitivity and specificity of 74% and 73%, respectively, and area under the curve of 0.81 (95% confidence interval 0.72 to 0.90, p <0.001). The results suggest that the extent and magnitude of ST segment elevation on the electrocardiogram are potentially useful predictors of in-hospital complications in patients with stress cardiomyopathy. PMID- 22440123 TI - Comparison of effects of atorvastatin (20 mg) versus rosuvastatin (10 mg) therapy on mild coronary atherosclerotic plaques (from the ARTMAP trial). AB - High-dose rosuvastatin induces regression of coronary atherosclerosis, but it remains uncertain whether usual-dose statin has similar effects. We compared the effects of atorvastatin 20 mg/day versus rosuvastatin 10 mg/day on mild coronary atherosclerotic plaques (20% to 50% luminal narrowing and lesion length >10 mm) using intravascular ultrasound (IVUS). Three hundred fifty statin-naive patients with mild coronary atherosclerotic plaques were randomized to receive atorvastatin 20 mg/day or rosuvastatin 10 mg/day. IVUS examinations were performed at baseline and 6-month follow-up. Primary end point was percent change in total atheroma volume (TAV) defined as (TAV at 6 months - TAV at baseline)/(TAV at baseline) * 100. Evaluable IVUS was obtained for 271 patients (atorvastatin in 143, rosuvastatin in 128). Clinical characteristics, lipid levels, and IVUS measurements at baseline were similar between the 2 groups. At 6 month follow-up, percent change in TAV was significantly less in the atorvastatin group than in the rosuvastatin group (-3.9 +/- 11.9% vs -7.4 +/- 10.6%, respectively, p = 0.018). In contrast, change in percent atheroma volume was not different between the 2 groups (-0.3 +/- 4.2 vs -1.1 +/- 3.5, respectively, p = 0.157). Compared to baseline, TAV and TAV at the most diseased 10-mm subsegment were significantly decreased in the 2 groups (p <0.001). Changes in lipid profiles at 6-month follow-up were similar between the 2 groups. In conclusion, usual doses of atorvastatin and rosuvastatin induced significant regression of coronary atherosclerosis in statin-naive patients, with a greater decrease in favor of rosuvastatin. PMID- 22440124 TI - Comparison of lipid profiles and attainment of lipid goals in patients <65 years versus patients >=65 years (from the Lipid Treatment Assessment Project [L-TAP] 2). AB - There is a well-established link between dyslipidemia and cardiovascular events, although this risk is modified by age. Little is known about how treatment of dyslipidemia and low-density lipoprotein (LDL) cholesterol goal attainment differ between older and younger patients. We obtained clinical data from 9,926 dyslipidemic patients across 9 countries in North and Latin America, Europe, and Asia from 2006 through 2007. Multivariate regressions were performed to determine predictors of lipid level goal attainment. The study sample consisted of 5,733 adults <65 and 4,193 adults >=65 years old. Compared with younger patients, older patients were more likely to have diabetes (32.5% vs 30.0%, p = 0.0014) and hypertension (73.4% vs 57.0%, p <0.0001), to be classified as high risk (68.6% vs 53.2%, p <0.0001), and to be taking a statin (79.1% vs 72.0%, p <0.0001). However, they were less likely to smoke (8.2% vs 17.6%, p <0.0001) or to have metabolic syndrome (29.0% vs 34.4%, p <0.0001). Older patients had lower LDL cholesterol levels (95.1 vs 103.9 mg/dl, p <0.0001) and higher levels of high density lipoprotein cholesterol (54.2 vs 51.5 mg/dl, p <0.0001). LDL cholesterol goal attainment was 74.7% in older and 71.1% in younger patients (p = 0.036). Older patients were more likely to achieve LDL targets whether low risk (89.8% vs 84.6%, p = 0.002), moderate risk (79.0% vs 71.9%, p = 0.0006), or high risk (70.5% vs 64.4%, p <0.0001). In conclusion, older patients had different risk profiles and better lipid levels compared with their younger counterparts. They were more likely to attain their LDL cholesterol goal, perhaps because of greater statin use, different risk profiles, or survival bias. PMID- 22440125 TI - Relation of reduction in urinary albumin excretion to ten-year cardiovascular mortality in patients with type 2 diabetes and systemic hypertension. AB - Microalbuminuria is one of the strongest predictors of both adverse renal and cardiovascular disease (CVD) outcomes in patients with type 2 diabetes mellitus. Although measurement of urinary albumin excretion (UAE) is widely recommended, limited data are available to suggest that reducing UAE translates into a reduction in long-term cardiovascular mortality, particularly among patients without overt nephropathy, who constitute most patients with type 2 diabetes worldwide. We assessed whether changes in the UAE at 1 year were associated with cardiovascular mortality in 393 patients with hypertension and type 2 diabetes during a 10-year period. On univariate analysis, CVD history, age, diabetes duration, and change in UAE at 1 year were associated with cardiovascular mortality risk (hazard ratio 2.60 for those with CVD history, 95% confidence interval [CI] 1.47 to 4.62; hazard ratio 1.59 per 10 years of diabetes duration, 95% CI 1.12 to 2.25; and hazard ratio 1.49 per log UAE increase, 95% CI 1.13 to 1.96). In a stepwise Cox regression model that included baseline UAE and CVD history, the 10-year predicted mortality of those with a decrease in UAE of 2 logs at 1 year was 4.7% (95% CI 1.4% to 7.8%). For those with an increase in UAE of 2 logs at 1 year, it was 24.5% (95% CI 10.1% to 36.5%). In conclusion, these data support current guideline recommendations to screen for UAE in all patients with type 2 diabetes, even in the absence of nephropathy, and suggest that serial UAE measurements even after the initiation of antihypertensive therapy has prognostic value independent of traditional cardiovascular risk factors. PMID- 22440126 TI - Long-term outcomes of percutaneous coronary interventions with stent implantation in patients <=40 years old. AB - Data on the long-term prognosis of percutaneous coronary intervention (PCI) in young patients are limited. The aim of the present study was to report the immediate and long-term clinical outcomes in a consecutive series of young patients with premature coronary artery disease who underwent PCI with stent implantation. During the study period (2005 to 2010), 214 consecutive patients aged <=40 years who had undergone PCI with a bare metal stent or drug-eluting stent implantation were retrospectively selected and analyzed. Primary end point of this study was the incidence of major adverse cardiac and cerebrovascular events at short- and long-term follow-up. Mean age was 36.3 +/- 3.5 years and 88.3% of patients were men. Three-quarters were active smokers and all patients had >=1 conventional cardiovascular risk factor. The total number of implanted stents was 272 (154 bare metal stent and 118 drug-eluting stent). During the hospital stay, no patient died, and the incidence of major adverse cardiac and cerebrovascular events was 2.3%. No additional events had occurred at 30 days of follow-up. At a median follow-up of 757 days (interquartile range 365 to 1,818), the overall death rate was 0.9%, and a new revascularization procedure was needed in 12.6% of patients. The major adverse cardiac and cerebrovascular event-free survival rate at the median follow-up point and 1,818 days was 89.6% and 84.2%, respectively. Active smoking and left ventricular ejection fraction <50% were independent predictors of major adverse cardiac and cerebrovascular events. In conclusion, PCI in young patients lead to excellent results in short- and long term follow-up and should be considered as the treatment of choice. Traditional risk factors are important prognostic determinants of adverse events and might help identify higher risk patients within this cohort. PMID- 22440127 TI - Recessively inherited severe aortic aneurysm caused by mutated EFEMP2. AB - Familial aortic aneurysm (AA) is mostly inherited as an autosomal dominant disorder. However, recessively inherited AA has also been observed but in association with skin manifestations of cutis laxa, which is caused by a mutated EFEMP2 gene. In the present study, we recruited 9 patients, from 4 unrelated consanguineous families, with recessively inherited AA. The index cases, their parents, and siblings underwent clinical evaluation and cardiac imaging. In the affected subjects, the clinical presentation ranged from sweating and cyanosis at 3 months of age to incidental findings in an asymptomatic adult. The echocardiogram revealed a wide spectrum of severity of the AA, with a Z-score varying from 5 to 33. Intrafamilial variability was also evident; 2 unrelated subjects were detected at 17 and 20 years of age through family screening. The skin manifestations of cutis laxa were not found in any patient. In 1 family, genome-wide single-nucleotide polymorphism analysis detected a homozygous block, shared by 2 affected siblings, on chromosome 11 at q13. Sequence analysis of EFEMP2, located on chromosome 11 at q13, identified a novel homozygous mutation (p.E161K) in all 9 affected subjects. In this largest cohort of reported patients with a mutated EFEMP2 gene, we illustrate the phenotypic spectrum of inherited AA due to a novel EFEMP2 mutation. In conclusion, our work suggests that in families with apparently recessively inherited AA, molecular analysis of EFEMP2 gene might be warranted. PMID- 22440128 TI - Comparison of left ventricular outflow geometry and aortic valve area in patients with aortic stenosis by 2-dimensional versus 3-dimensional echocardiography. AB - The present study sought to elucidate the geometry of the left ventricular outflow tract (LVOT) in patients with aortic stenosis and its effect on the accuracy of the continuity equation-based aortic valve area (AVA) estimation. Real-time 3-dimensional transesophageal echocardiography (RT3D-TEE) provides high resolution images of LVOT in patients with aortic stenosis. Thus, AVA is derived reliably with the continuity equation. Forty patients with aortic stenosis who underwent 2-dimensional transthoracic echocardiography (2D-TTE), 2-dimensional transesophageal echocardiography (2D-TEE), and RT3D-TEE were studied. In 2D-TTE and 2D-TEE, the LVOT areas were calculated as pi * (LVOT dimension/2)(2). In RT3D TEE, the LVOT areas and ellipticity ([diameter of the anteroposterior axis]/[diameter of the medial-lateral axis]) were evaluated by planimetry. The AVA is then determined using planimetry and the continuity equation method. LVOT shape was found to be elliptical (ellipticity of 0.80 +/- 0.08). Accordingly, the LVOT areas measured by 2D-TTE (median 3.7 cm(2), interquartile range 3.1 to 4.1) and 2D-TEE (median 3.7 cm(2), interquartile range 3.1 to 4.0) were smaller than those by 3D-TEE (median 4.6 cm(2), interquartile range 3.9 to 5.3; p <0.05 vs both 2D-TTE and 2D-TEE). RT3D-TEE yielded a larger continuity equation-based AVA (median 1.0 cm(2), interquartile range 0.79 to 1.3, p <0.05 vs both 2D-TTE and 2D TEE) than 2D-TTE (median 0.77 cm(2), interquartile range 0.64 to 0.94) and 2D-TEE (median 0.76 cm(2), interquartile range 0.62 to 0.95). Additionally, the continuity equation-based AVA by RT3D-TEE was consistent with the planimetry method. In conclusion, RT3D-TEE might allow more accurate evaluation of the elliptical LVOT geometry and continuity equation-based AVA in patients with aortic stenosis than 2D-TTE and 2D-TEE. PMID- 22440129 TI - Effect of type of atrial fibrillation on prognosis in acute myocardial infarction treated invasively. AB - To assess the incidence of atrial fibrillation (AF) and the clinical impact of AF types on outcomes in patients with acute myocardial infarction (AMI) treated invasively, we analyzed 2,980 consecutive patients with AMI admitted to our department from 2003 through 2008. Data collected by the insurer were screened to identify patients who died during the median follow-up of 41 months. AF was recognized in 282 patients (9.46%, AF group); the remaining 2,698 patients (90.54%) were free of this arrhythmia (control group). The AF group was divided into 3 subgroups: prehospital paroxysmal AF (n = 92, 3.09%), new-onset AF (n = 109, 3.66%), and permanent AF (n = 81, 2.72%). In-hospital and long-term mortalities were significantly higher (p <0.001 for the 2 comparisons) in the AF than in the control group (14.9% vs 5.3%, 37.2% vs 17.0%, respectively). Long term mortality was significantly higher (p <0.001 for the 2 comparisons) in the new-onset AF (35.8%) and permanent AF (54.3%) groups than in the control group but did not differ significantly between the prehospital AF and control groups (21.7% vs 17.0%, p = NS). Considering types of arrhythmia separately, only permanent AF (hazard ratio 2.59) was an independent risk factor for death in the studied population. In conclusion, AF occurs in 1 of 10 patients with AMI treated invasively, with nearly equal distributions among prehospital, new-onset, and permanent forms. Although arrhythmia is a marker of worse short- and long-term outcomes, only permanent AF is an independent predictor for death in this population. PMID- 22440130 TI - Associations of reactive hyperemia index and intravascular ultrasound-assessed coronary plaque morphology in patients with coronary artery disease. AB - Although reactive hyperemia index (RHI) predicts future coronary events, associations with intravascular ultrasound (IVUS)-assessed coronary plaque structure have not been reported. This study therefore investigated associations between RHI and IVUS-assessed coronary plaques. In 362 patients RHI was measured by noninvasive peripheral arterial tonometry and coronary plaque components (fibrous, fibrofatty, necrotic core, and dense calcium) were identified by IVUS in 594 vessel segments of the left anterior descending, circumflex, and/or right coronary arteries. RHI values <1.67 were considered abnormal. Analysis of variance was used to detect independent associations between RHI and plaque composition. Patients with an abnormal RHI had greater plaque burden (41% vs 39% in patients with normal RHI, p = 0.047). Compared to patients with normal RHI, plaque of patients with abnormal RHI had more necrotic core (21% vs 17%, p <0.001) and dense calcium (19% vs 15%, p <0.001) and less fibrous (49% vs 54%, p <0.001) and fibrofatty (11% vs 14%, p = 0.002) tissue. After adjustment for age, gender, cardiovascular risk factors, and drug therapy, abnormal RHI remained significantly associated with fibrous (F ratio 14.79, p <0.001), fibrofatty (F ratio 5.66, p = 0.018), necrotic core (F ratio 14.47, p <0.001), and dense calcium (F ratio 10.80, p = 0.001) volumes. In conclusion, coronary artery plaques of patients with abnormal RHI had a larger proportion of necrotic core and dense calcium. The association of an abnormal RHI with a plaque structure that is more prone to rupture may explain why these patients exhibit a greater risk of coronary events. PMID- 22440131 TI - Variation in effects of four OP insecticides on photosynthetic pigment fluorescence of Chlorella vulgaris Beij. AB - Effects of the insecticides quinalphos, chlorfenvinphos, dimethoate and phorate on photosystem activity of Chlorella vulgaris were investigated by different chlorophyll fluorescence measurements. Exposure to each of the insecticides increased the proportion of inactivated PS II reaction center. Quinalphos and chlorfenvinphos caused OJIP fluorescence reduction at all levels by decreasing the proportion of Q(A)-reducing PS II reaction centers (RCs). The other two insecticides affected OJIP fluorescence rise by hindering the electron transport beyond Q(A). Insecticide treatment resulted in decrease of the density of active RC and performance indices (PI) by enhanced dissipated energy flux per active RC. Antenna size was severely minimized by quinalphos and chlorfenvinphos treatment whereas other two insecticides had no such effect. Each insecticide treatment caused increase of photosystem antenna/core and PS II/PS I fluorescence ratios. Quinalphos and chlorfenvinphos affected the donor sides of photosystems whereas dimethoate and phorate inhibited electron transfer beyond Q(A) (acceptor side). PMID- 22440132 TI - Synthesis of highly oxidized quinolizidine via reduction of acylpyridinium cations, and total syntheses of quinolizidines 207I and 1-epi-207I. AB - A new strategy for synthesizing quinolizidine skeletons by reductive cyclization via acylpyridinium cations was developed. Several functional groups, including carbonyl, silyl, and acetal, were tolerated under mild reaction conditions. The reaction was successfully extended to a one-pot synthesis of a bicyclic compound, and the synthetic strategy was applied to concise total syntheses of quinolizidines 207I and 1-epi-207I, without protecting groups. PMID- 22440134 TI - Immunocytochemical and structural comparative study of committed versus multipotent stem cells cultured with different biomaterials. AB - The aim of this work was the comparison of the behavior of committed (human osteoblast cells - hOB - from bone biopsies) versus multipotent (human dental pulp stem cells - hDPSC - from extracted teeth) cells, cultured on shot-peened titanium surfaces, since the kind of cell model considered has been shown to be relevant in techniques widely used in studies on composition/morphology of biomaterial surfaces. The titanium surface morphology, with different roughness, and the behavior of cells were analyzed by confocal microscope (CM), scanning electron microscope (SEM) and X-ray microanalysis. The best results, in terms of hOB adhesion/distribution, were highlighted by both CM and SEM in cultured plates having 20-MUm-depth cavities. On the contrary, CM and SEM results highlighted the hDPSC growth regardless the different surface morphology, arranged in overlapped layers due to their high proliferation rate, showing their unfitness in biomaterial surface test. Nevertheless, hDPSC cultured inside 3D-matrices reproduced an osteocyte-like three-dimensional network, potentially useful in the repair of critical size bone defects. The behavior of the two cell models suggests a different use in biomaterial cell cultures: committed osteoblast cells could be appropriate in selecting the best surfaces to improve osseointegration, while multipotent cells could be suitable to obtain in vitro osteocyte-like network for regenerative medicine. The originality of the present work consists in studying for the first time two different cell models (committed versus multipotent) compared in parallel different biomaterial cultures, thus suggesting distinct targets for each cellular model. PMID- 22440135 TI - Cefepime for Gram-negative bacteremia in long-term hemodialysis: a single-center experience. PMID- 22440136 TI - Synthesis design and structure of a multipore zeolite with interconnected 12- and 10-MR channels. AB - A new molecular sieve, ITQ-38, containing interconnected large and medium pores in its structure has been synthesized. The rational combination of dicationic piperidine-derivative molecules as organic structure directing agents (OSDAs) with germanium and boron atoms in alkaline media has allowed the synthesis of ITQ 38 zeolite. High-resolution transmission electron microscopy (HRTEM) has been used to elucidate the framework topology of ITQ-38, revealing the presence of domains of perfect ITQ-38 crystals as well as very small areas containing nanosized ITQ-38/ITQ-22 intergrowths. The structure of ITQ-38 is highly related to ITQ-22 and the recently described polymorph C of ITQ-39 zeolite. It shares a common building layer with ITQ-22 and contains the same building unit as the polymorph C of ITQ-39. All three structures present similar framework density, 16.1 T atoms/1000 A(3). PMID- 22440137 TI - [Sporadic lymphangioleiomyomatosis and pulmonary hypertension. Clinical and pathologic study in patients undergoing lung transplantation]. AB - BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare disease characterized by an aberrant immature smooth muscle cells proliferation. This excessive growth of LAM cells around airways, parenchyma, lymphatic ganglia and lung vessels, produces cystic damages. LAM affects mainly women and can lead to pulmonary hypertension (PH). The aim of this research is the clinical study, as well as the analysis of the morphological features, expressing PH, of the native lungs from lung transplant (LT) patients. PATIENTS AND METHODS: Several clinical variables were studied in 7 patients who had a LAM and who were subjected to LT. The variables analyzed using morphologic and immunohistochemistry techniques were: histological alterations in native lungs, their severity rate, the presence of haemosiderosis in the air spaces and correlation index between thickness of the middle layer and the pulmonary arterial vascular diameter, morphological expression of HP. RESULTS: The average age was 34 years old and the predominant symptom was dyspnea. The respiratory functional pattern was mixt, with decrease of DLCO% and KCO%, serious hypoxemia and normocapnia. In the cardiological study, subclinical signs of HP were found. The immunohistochemistry was positive for smooth muscle and melanic expression markers, estrogen receptor in 6 cases and progesterone receptor in 4. Vascular correlation index showed HP criteria at all. CONCLUSIONS: This research shows the presence of clinical and morphological HP criteria in advanced LAM patients. Therefore, cardiological assessment before LT with right catheterization will be justified. Future research should be addressed to clarify whether the HP should be criteria for LT in LAM patients. PMID- 22440138 TI - [Improvement in quality of life and exercise capacity without muscular biology changes after general training in patients with severe chronic obstructive pulmonary disease]. AB - BACKGROUND AND OBJECTIVE: Despite the beneficial effects of exercise training in chronic obstructive pulmonary disease (COPD) patients, several studies have revealed functional and biological abnormalities in their peripheral muscles. The objective was to determine whether exercise training of high intensity and long duration modifies oxidative stress levels and structure of respiratory and peripheral muscles of severe COPD patients, while also improving their exercise capacity and quality of life. METHODS: Multicenter study (Warsaw and Barakaldo) in which 25 severe COPD out-patients were recruited from the COPD clinics. In all patients, lung and muscle functions, exercise capacity (walking test and cycloergometer) and quality of life (QoL) were assessed, and open muscle biopsies from the vastus lateralis and external intercostals (n=14) were obtained before and after an exercise training program of high intensity (respiratory rehabilitation area, 70% maximal tolerated load in a cycloergometer) and long duration (10 weeks). Oxidative stress and muscle structural modifications were evaluated in all muscle biopsies using immunoblotting and immunohistochemistry. RESULTS: In all patients, after the training program, without any drop-outs, exercise capacity and QoL improved significantly, whereas oxidative stress, muscle damage and structure were not modified in their respiratory or limb muscles compared to baseline. CONCLUSIONS: In patients with severe COPD, exercise training of high intensity and long duration significantly improves their exercise capacity and QoL, without inducing significant modifications on oxidative stress levels or muscle structure in their respiratory or peripheral muscles. These results may have future clinical therapeutic implications. PMID- 22440139 TI - [Clinical factors and biomarkers associated with subclinical atherosclerosis in the human immunodeficiency virus infection]. AB - BACKGROUND AND OBJECTIVE: HIV-infected patients present accelerated cardiovascular disease (CVD) and CVD is among the most important causes of mortality in this population. We aimed to identify biomarkers and clinical factors associated with subclinical atherosclerosis in HIV-infected patients. PATIENTS AND METHODS: Carotid intima-media thickness (cIMT) and cardiovascular biomarkers were measured in 235 HIV-infected patients. Individuals with a cIMT >= 75th percentile or plaque were classified as having subclinical atherosclerosis and compared with patients without subclinical atherosclerosis. RESULTS: Age was 46 (11) years old. Mean cIMT was 0.58 (0.13)mm. Sixty-five (27.8%) patients had subclinical atherosclerosis. These subjects had more frequently lipodystrophy (OR:2.7; CI95%:1.4-4.9), immunosuppression (OR:2.5; CI95%:1.1-5.8), longer time to HIV diagnosis (>= p50 [10 years], OR:1.4; CI95%:1.1-2.9), longer exposure to nucleoside analogues (>= p50 [132 months], OR:3.2; CI95%:1.7-6) and to protease inhibitors (>= p50 [24 months], OR:2.2; CI95%:1.1-3.6). They also showed higher levels of several biomarkers such as NT-proBNP (>= p75 [72.6 pg/ml], OR:2.0; CI95%:1-4.1) and albumin/creatinine urine ratio (>= p50 [5mg/g], OR:3.8; CI95%:1.3-11). After the multivariate analysis, subclinical atherosclerosis was associated with age (OR:6.6; CI95%:2.2-19.5; P=.001), a longer time to HIV diagnosis (OR:3.1; CI95%:1.0-11.0; P=.044) and immunosuppression (OR:2.8; CI95%:1 8.3; P=.048). CONCLUSIONS: Among HIV-infected patients, time to HIV diagnosis and immunosuppression were independently associated with subclinical atherosclerosis. Patients with subclinical atherosclerosis showed increased levels of vascular damage biomarkers, especially albumin/creatinine urine ratio and NT-proBNP. PMID- 22440140 TI - [Asbestos pulmonary content in workers of Ferrol shipyards, Spain]. AB - BACKGROUND AND OBJECTIVE: In the last years, a study is being conducted about exposure to asbestos among shipyards workers in order to know the diagnosis of the diseases associated with the exposure. Our goal was to know the asbestos pulmonary contents in this population. MATERIAL AND METHODS: We obtained autopsy pulmonary samples from individuals who had worked in Ferrol shipyards. We analyzed samples from both lungs in most cases. After removing the lung organic matter with sodium hypochlorite, the inorganic residue was analyzed with optic microscopy. Results were expressed as asbestos bodies (AB) per gram of dry tissue. We considered as disease causative levels those above 1,000 AB/g. RESULTS: We studied 30 males, with a mean age of 67 years (r: 56-89 years). Twenty-six were smokers or former smokers, and 4 had never smoked. All had a lung, pleural or peritoneal disease related to asbestos exposure (16 lung cancer, 6 mesothelioma, 25 benign pleural disease). Only in 6 out of the 16 lung cancer cases there was coexisting asbestosis. The median (interval) of AB was 6,171 (249 4,660,059) AB/g. Ninety-seven per cent of individuals had levels above 1,000 AB/g. There was a correlation between AB and age (r=.5676; P=.0011). CONCLUSIONS: Workers from Ferrol shipyards who were analyzed had increased pulmonary levels of asbestos. It is essential to raise clinical suspicion of asbestos as a factor that can potentially cause lung disease in this group. PMID- 22440141 TI - [Scientific societies and their economic relationship with the companies. Situation in Spain]. PMID- 22440142 TI - [Measuring appropriately blood pressure. A precision or a simplicity question?]. PMID- 22440143 TI - [WITHDRAWN: Prevalence and associated factors of Chlamydia trachomatis infection in young prisoners of Catalonia, Spain.] PMID- 22440144 TI - [Saving with clinical criteria from the perspective of the hospital setting]. PMID- 22440145 TI - [Measurement of blood pressure in consultation and automated mesurement (BPTru((r))) to evaluate the white coat effect]. AB - BACKGROUND AND OBJECTIVE: White coat effect (WCE) is one of the main bias that can affect office blood pressure (BP) measurement. Therefore, it is a factor must be considered in hypertensives to avoid mistakes in diagnosis and/or treatment. Employment of automated office BP (AOBP) devices could diminish that effect. METHODS: Two studies were designed with the objective of evaluating differences between routinely office and AOBP measurements. WCE was also assessed. First, the TRUE-ESP study included normotensive and hypertensive patients attending specialized consultations at Cardiology, Nephrology, Internal Medicine, Endocrinology and Family Practice. Second, the TRUE-HTA study included hypertensives attending a protocoled Hypertension Unit, with a trained staff. RESULTS: TRUE-ESP study included 300 patients, 76% being hypertensives. A significant difference between office BP and AOBP measurement (SBP/DBP 9.8+/ 11.6/3.4+/-7.9 mmHg, P<.001) was observed. Percentage of patients gathering WCE criteria was 27.7%. TRUE-HTA study included 101 hypertensive patients. A significant difference between office BP and AOBP measurement (SBP/DBP 5.7+/ 9.3/2.1+/-5.3 mmHg, P<.001) and activity period-ABPM (SBP/DBP 8.5+/-6.7/3.5+/-2.5 mmHg, P<.001) was observed. Percentage of WCE patients was 32.1%. CONCLUSIONS: Use of AOBP devices can contribute to decrease WCE and to improve accuracy of office BP measurement. PMID- 22440146 TI - [Outcome and treatment among patients with multidrug-resistant tuberculosis]. AB - BACKGROUND AND OBJECTIVE: Although progress has been made to reduce the global incidence of tuberculosis, the emergence of multidrug-resistant tuberculosis during the past decade threatens to limit these results. The aim of this study is to evaluate the geographic distribution, clinical and microbiological characteristics and outcomes of multidrug-resistant tuberculosis patients in Spain. PATIENTS AND METHODS: Retrospective study between January 1998 and December 2010 of patients attended in Cantoblanco-La Paz Hospital Isolation Internal Medicine Unit. RESULTS: Forty-seven patients were studied, with a mean age of 36 years. There were 33 male. Sixty-four per cent were immigrants and the mean residence time in Spain was 12 months. Twenty-six patients (55.3%) were new cases. Patients were resistant to a median of 5 drugs (interquartile range [IQR] 3-7) and 3 patients had extensively drug-resistant tuberculosis. Cultures became negative after a median of 68.5 days (IQR 49.5-91.8). The median length of hospitalization was 2.75 months (IQR 1.3-4.6). They were treated during a median of 22.4 months (IQR 15.3-24.3). The overall success rate was 93%. A directly observed treatment was carried out in 79% of patients. Sixty-eight per cent patients presented side effects. In 75% of the cases the effects were mild and moderate with no need to replace the drug. Fourteen patients were followed up for a median of 40.5 months (IQR 7.4-55) and no clinical or bacteriological manifestation of disease was detected. CONCLUSIONS: Most patients with multidrug resistant tuberculosis can be cured with the use of appropriate and intensive regimens, management of side effects and implementation of strategies to improve adherence to treatment. PMID- 22440147 TI - Photodynamic therapy of bladder cancer - a phase I study using hexaminolevulinate (HAL). AB - OBJECTIVES: To assess the safety and feasibility of hexaminolevulinate (HAL) based photodynamic therapy (PDT) as adjuvant treatment after transurethral resection of the bladder (TURB) in patients with intermediate or high-risk urothelial cell carcinoma (UCC) of the bladder. MATERIALS AND METHODS: Seventeen patients received 50 ml of either a 16 mM (4 patients) or 8 mM HAL (13 patients) solution instilled intravesically. Bladder wall irradiation was performed using an incoherent white light source coupled via a quartz fiber assembled into a flexible transurethral irrigation catheter. Each patient received 3 treatments with HAL-PDT 6 weeks apart. After PDT, patients were followed by regular cystoscopy for up to 21 months to assess time to recurrence. Reported adverse events (AEs) were coded according the World Health Organization Adverse Reaction Terminology (WHO-ART). Efficacy was assessed by cystoscopy, cytology, and histology, and was defined as the number of patients who were tumor-free at 6 or 21 months after initial PDT treatment. Transient bladder irritability was reported by 15 of the 17 patients and resolved completely in all patients. No evidence of a cumulative effect of treatment on the incidence of AEs could be detected. PDT treatment was performed without any technical complications. Furthermore preliminary assessment of efficacy showed that of the 17 patients included, 9 (52.9%; 95% CI: 27.8-77.0) were tumor-free at 6 months, 4 (23.5%; 95% CI: 6.8-49.9) were tumor-free at 9 months, and 2 (11.8%, 95% CI: 1.5-36.4) were tumor-free after 21 months. CONCLUSIONS: PDT using hexaminolevulinate and an incoherent white light system with the special flexible irradiation catheter system is technically feasible and safe and may offer an alternative in the treatment of non-muscle-invasive intermediate and high-risk bladder cancer. PMID- 22440148 TI - T-2 toxin induced Salmonella Typhimurium intoxication results in decreased Salmonella numbers in the cecum contents of pigs, despite marked effects on Salmonella-host cell interactions. AB - The mycotoxin T-2 toxin and Salmonella Typhimurium infections pose a significant threat to human and animal health. Interactions between both agents may result in a different outcome of the infection. Therefore, the aim of the presented study was to investigate the effects of low and relevant concentrations of T-2 toxin on the course of a Salmonella Typhimurium infection in pigs. We showed that the presence of 15 and 83 MUg T-2 toxin per kg feed significantly decreased the amount of Salmonella Typhimurium bacteria present in the cecum contents, and a tendency to a reduced colonization of the jejunum, ileum, cecum, colon and colon contents was noticed. In vitro, proteomic analysis of porcine enterocytes revealed that a very low concentration of T-2 toxin (5 ng/mL) affects the protein expression of mitochondrial, endoplasmatic reticulum and cytoskeleton associated proteins, proteins involved in protein synthesis and folding, RNA synthesis, mitogen-activated protein kinase signaling and regulatory processes. Similarly low concentrations (1-100 ng/mL) promoted the susceptibility of porcine macrophages and intestinal epithelial cells to Salmonella Typhimurium invasion, in a SPI-1 independent manner. Furthermore, T-2 toxin (1-5 ng/mL) promoted the translocation of Salmonella Typhimurium over an intestinal porcine epithelial cell monolayer. Although these findings may seem in favour of Salmonella Typhimurium, microarray analysis showed that T-2 toxin (5 ng/mL) causes an intoxication of Salmonella Typhimurium, represented by a reduced motility and a downregulation of metabolic and Salmonella Pathogenicity Island 1 genes. This study demonstrates marked interactions of T-2 toxin with Salmonella Typhimurium pathogenesis, resulting in bacterial intoxication. PMID- 22440149 TI - Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion. AB - Hot-melt extrusion was applied to improve dissolution behavior of poorly soluble model drug fenofibrate. Blends of polymers were used as carrier: copovidone (COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (PVCL-PVAc-PEG) and hypromellose 2910/5 (HPMC). The ratio of fenofibrate to COP remained constantly 1+3 (weighted parts) with varying amounts of PVCL-PVAc-PEG and HPMC. Solid state of fenofibrate was characterized by X-ray diffractometry and differential scanning calorimetry. Dissolution performance was compared to marketed formulations Lipidil and Lipidil-Ter. Stability studies were conducted at 25 degrees C/60%rH. The dissolution rate from extrudates was significantly increased when compared to pure fenofibrate powder or physical mixture of the components. A supersaturation of 7.6-12.1 was reached with the pelletized extrudates. All extrudates were superior to marketed formulations. No recrystallization was observed after 26 weeks of storage for fenofibrate-COP extrudates 1+3 (weighted parts) with or without polymeric additives. Even so, both degree and duration of supersaturation decreased with increasing storage periods with the exception of fenofibrate-HPMC extrudates. Of particular interest is the finding that by adding polymers with differing release characteristics to the drug-carrier mixture, the dissolution performance of hot-melt extruded solid dosage forms can be readily adapted to meet specific requirements. PMID- 22440150 TI - Improving matrix metalloproteinase-2 specific response of a hydrogel system using electrophoresis. AB - Matrix metalloproteinases (MMPs) overexpression plays a critical role in cancer invasion and metastasis. We utilized this key feature of tumor microenvironment to develop a disease-stimuli triggered drug delivery system. Poly(acrylic acid) hydrogels were synthesized by UV polymerization and pendant MMP-2 sensitive peptides (Gly-Pro-Leu-Gly-Val-Arg-Gly-Lys) conjugated throughout using EDC/sulfo NHS chemistry. There were significantly more peptides released in the presence of MMP-2 compared with the control groups. The released peptide fragments were analyzed by HPLC and MALDI-MS and confirmed to be the expected fragments. In order to avoid nonspecific release of nonconjugated (i.e. unreacted) peptides, a novel method of electrophoretic washing was developed disrupting the strong electrostatic interactions between the peptides and the pendant groups of the hydrogel. After electrophoresis, the nonspecific peptide release in the absence of MMP-2 was minimized. This newly developed purification system significantly improved the control of release to be in response of the magnitude of the stimuli, i.e. MMP. Specifically, peptides were released proportionally to the concentration of MMP-2 present. Now that many of the design parameters have been examined, anticancer drugs will be conjugated to the MMP sensitive peptide linkers with the goal of implantation in a tumor void releasing anticancer reagent in response to elevated level of MMPs. PMID- 22440151 TI - Breaking the mode degeneracy of surface plasmon resonances in a triangular system. AB - In this paper, we present a systematic investigation of symmetry-breaking in the plasmonic modes of triangular gold nanoprisms. Their geometrical C(3v) symmetry is one of the simplest possible that allows degeneracy in the particle's mode spectrum. It is reduced to the nondegenerate symmetries C(v) or E by positioning additional, smaller gold nanoprisms in close proximity, either in a lateral or a vertical configuration. Corresponding to the lower symmetry of the system, its eigenmodes also feature lower symmetries (C(v)), or preserve only the identity (E) as symmetry. We discuss how breaking the symmetry of the plasmonic system not only breaks the degeneracy of some lower order modes, but also how it alters the damping and eigenenergies of the observed Fano-type resonances. PMID- 22440152 TI - Methotrexate in psoriasis: do we need to give a test dose? PMID- 22440153 TI - Family structure and breakfast consumption of 11-15 year old boys and girls in Scotland, 1994-2010: a repeated cross-sectional study. AB - BACKGROUND: The benefits of breakfast during childhood and adolescence have been reported previously though few studies have considered family structure inequalities in breakfast consumption. The proportion of young people living in non-traditional family types has increased in recent years, strengthening the need to describe and monitor the impact of the changing family unit on adolescent breakfast consumption. This study aimed to describe changes in daily breakfast consumption among adolescents in Scotland between 1994 and 2010, while also considering family structure inequalities, and the degree to which these have changed over time. METHODS: Data from the 1994, 1998, 2002, 2006 and 2010 Scottish Health Behaviour in School-aged Children (HBSC) surveys were analysed using logistic multilevel regression models for binary outcome variable daily breakfast consumption. RESULTS: Daily breakfast consumption among adolescents increased between 1994 and 2010, although there were differences by age and sex. In fact those aged over 14.5 years saw decreases in breakfast consumption, and girls saw significantly larger increases than boys. Daily breakfast consumption was more prevalent among adolescents from 'both parent' families, with lowest prevalence among those from single parent families. Trends in daily breakfast consumption between 1994 and 2010 also varied by family structure. While prevalence of daily breakfast consumption increased among those living with 'both parents', the largest proportion of the population, prevalence decreased over time among adolescents of single parent families, and particularly among those living with their father. CONCLUSIONS: Family structure inequalities in daily breakfast consumption increased between 1994 and 2010, while breakfast consumption across the population as a whole increased. As the proportion of young people living in an alternative family structure continues to grow it is important to understand why these inequalities have increased and how these may be overcome. Possible reasons for family structure inequalities and their increase in recent years are discussed. PMID- 22440154 TI - Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT. AB - BACKGROUND: Pacemakers can automatically identify and catalog atrial high-rate episodes (AHREs). While most AHREs represent true atrial tachyarrhythmia/atrial fibrillation (AT/AF), a review of stored electrograms suggests that a substantial proportion do not. As AHREs may lead to the initiation of oral anticoagulation, it is crucial to understand the relationship between AHREs and true AT/AF. OBJECTIVE: To compare the positive predictive value of AHREs for electrogram confirmed AT/AF for various atrial rates and episode durations. METHODS: By using data from 2580 patients who participated in the ASymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the AF Reduction atrial pacing Trial, all AHREs >6 minutes and >190 beats/min with available electrograms were reviewed to determine whether they represented true AT/AF. The positive predictive value of these AHREs was assessed for episode durations of 6 minutes, 30 minutes, 6 hours, and 24 hours at atrial rates of 190 and 250 beats/min. RESULTS: Of 5769 AHREs >6 minutes and >190 beats/min, 82.7% were true AT/AF and 17.3% were false positives (predominantly due to repetitive non-re-entrant ventriculoatrial synchrony). False positives dropped to 6.8%, 3.3%, and 1.8% when the threshold duration was increased to 30 minutes, 6 hours, and 24 hours, respectively. Increasing the threshold heart rate to 250 beats/min added little to the positive predictive value when longer threshold durations were used. CONCLUSIONS: By using a cutoff of >6 minutes and >190 beats/min, the rate of false-positive AHREs is 17.3%, making physician review of electrograms essential. For AHREs lasting >6 hours, the rate of false positives is 3.3%, making physician review less crucial. PMID- 22440155 TI - Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea. AB - BACKGROUND: Obesity and obstructive sleep apnea (OSA) are risk factors for atrial fibrillation (AF), but the underlying mechanisms are poorly understood. OBJECTIVE: The purpose of this study was to assess the mechanisms underlying AF promotion by obesity and OSA in rat models. METHODS: Zucker obese rats (ORs) and lean rats (LRs) were intubated and ventilated with air and 2% isoflurane. OSA was mimicked by stopping the ventilator and closing the airway for 40 seconds. For nonobstructive control periods, the protocol was repeated with an open airway. Fifteen seconds after apnea onset, AF susceptibility was tested with 6 atrial burst pacing cycles (25 Hz, 3 seconds, 1-second intercycle pauses). RESULTS: AF was not inducible in ORs or LRs at baseline or in nonobstructive control periods. AF was induced in 24 of 28 ORs (85.7%) vs 5 of 18 LRs (27.8%) during obstructive apnea (P <.001). Negative intrathoracic pressure generation (esophageal pressure monitoring) was substantial during obstructive apnea. Echocardiography showed left ventricular hypertrophy with diastolic dysfunction in ORs. Obstructive apnea caused acute left atrial (LA) dilation, increasing LA diameter significantly more in ORs than in LRs. To clarify AF mechanisms, 24 AF-inducible ORs were divided into 4 groups: saline (n = 5), pharmacologic autonomic blockade (n = 7), respiratory muscle paralysis with rocuronium (n = 6), and inferior vena cava (IVC) balloon occlusion to unload the LA (n = 6). Balloon catheter-induced IVC occlusion prevented LA distension during obstructive apnea, leading to 83.3% AF prevention (P <.05). Rocuronium also was protective (66.7%), but autonomic blockade had smaller effects (42.9% prevention). CONCLUSION: Obesity and acute obstructive apnea interacted to promote AF in this model. Forced inspiration induced acute LA distension related to diastolic dysfunction may be an important component of the arrhythmogenic substrate for AF during OSA episodes in obese patients. PMID- 22440156 TI - Assessing repolarization: alternate hypotheses. PMID- 22440157 TI - A long RP-interval tachycardia: what is the mechanism? PMID- 22440158 TI - CFB/C2 gene polymorphisms and risk of age-related macular degeneration: a systematic review and meta-analysis. AB - PURPOSE: To investigate whether the polymorphisms of CFB/C2 gene are associated with age-related macular degeneration (AMD), and to evaluate the magnitude of gene effect. METHODS: We performed a meta-analysis of the association between four SNPs in CFB/C2 gene (rs9332739, rs547154, rs4151667, and rs641153) and risk of AMD using data from 15 case-control studies involving 8905 subjects. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effects models. The Q and I(2) statistics were used to evaluate between-study heterogeneity. Harbord's modified test was used to detect small study effects. Sensitivity analysis, cumulative meta-analysis, and meta regression were also performed. RESULTS: For rs9332739, rs547154, rs4151667, and rs641153, the pooled ORs in a dominant genetic model were 0.474 (fixed effects, P < 0.001, 95% CI 0.378-0.596), 0.399 (random effects, 95% CI 0.289-0.551, P < 0.001), 0.496 (fixed effects, 95% CI 0.390-0.632, P < 0.001), and 0.557 (random effects, P = 0.008, 95% CI 0.362-0.856), respectively. These results suggested that variant alleles of all the four SNPs has significant protective effect against AMD. Contour-enhanced funnel plots and Harbord's test showed moderate small study effects for rs9332739 and rs4151667. Heterogeneity were found for rs547154 and rs641153, subgroup analysis suggested that ethnicity was the main source for heterogeneity. Stratification by ethnicity indicated stronger protective effects of rare alleles in Caucasians. Genotype distribution analysis also suggested that frequencies of rare homozygous genotype were higher in Caucasian group. CONCLUSIONS: Our meta-analysis indicated strong protective effects of the variant alleles of four SNPs in CFB/C2 gene (rs9332739, rs547154, rs4151667, and rs641153) against AMD. The disease risk descended to nearly one half for individuals carrying at least one copy of the rare alleles. The protective effects seemed to be stronger in Caucasians, of which the genotype frequencies were also higher. PMID- 22440159 TI - Eye injury risk from water stream impact: biomechanically based design parameters for water toy and park design. AB - PURPOSE: Interactive water displays are becoming increasingly popular and can result in direct eye contact. Therefore, the purpose of this study is to investigate eye injury risk from high speed water stream impacts and to provide biomechanically based design parameters for water toys and water park fountains. METHODS: An experimental matrix of 38 tests was developed to impact eight porcine eyes with water streams using a customized pressure system. Two stream diameters (3.2 mm and 6.4 mm) were tested at water velocities between 3.0 m/s and 8.5 m/s. Intraocular pressure was measured with a small pressure sensor inserted through the optic nerve and used to determine the injury risk for hyphema, lens dislocation, retinal damage, and globe rupture for each impact. RESULTS: Experimental water stream impacts created a range of intraocular pressures between 3156 mmHg and 7006 mmHg (61 psi to 135 psi). Injury risk varied between 4.4%-27.8% for hyphema, 0.0%-3.0% for lens dislocation, and 0.1%-3.3% for retinal damage. All tests resulted in 0.0% injury risk for globe rupture. The two water stream diameters did not result in significantly different water stream velocities (P = 0.32); however, the variation in water stream diameter did result in significantly different intraocular pressures (P = 0.03) with higher pressures for the 6.4 mm stream. CONCLUSIONS: This is the first study to experimentally measure intraocular pressure from high speed water stream impacts and quantify the corresponding eye injury risk. It is recommended that toy water guns and water park fountains use an upper threshold of 8.5 m/s for water stream velocities to minimize the risk of serious acute eye damage from impacts. PMID- 22440160 TI - Chloroquine keratopathy of rheumatoid arthritis patients detected by in vivo confocal microscopy. AB - AIM: To investigate microscopic changes in corneal morphology in chloroquine (CQ) treated patients without corneal abnormalities being diagnosable by slit lamp microscopy. METHODS: Thirty-six eyes of 36 patients with rheumatoid arthritis (RA) were divided into two groups: group 1 included 26 patients receiving chloroquine therapy; group 2 included the other 10 patients, not receiving chloroquine therapy. The control group included 15 healthy subjects. Best spectacle-corrected visual acuity (BSCVA), intraocular pressure (IOP) and slit lamp microscopy and in vivo confocal microscopy examinations were performed on all subjects. RESULTS: In group 1, hyperreflective abnormal particles were found in different layers of the cornea in 19 (75%) of 26 eyes by confocal microscopy. The deposits were present within the superficial epithelium (14/19), basal epithelium (8/19) and anterior stroma (5/19). In both RA groups, more beaded and tortuous fibers were seen in the sub-basal corneal nerve bundles, and the sub epithelial and stromal nerves had much more branches, than did normal controls. The anterior keratocyte density in group 1 was lower than in group 2 (P < 0.05) and the number of sub-basal nerves was larger than in group 2 (P < 0.05). Cumulative dosage had a statistically significant correlation with anterior keratocyte density, the number of sub-basal nerves and the density of abnormal particles. CONCLUSION: Corneal microdeposits are an important manifestation of chloroquine-induced keratopathy. Corneal stroma cell density and corneal nerve number and morphology changes are also useful for detecting early chloroquine induced keratopathy. This would be proved in our future longitudinal studies. PMID- 22440161 TI - The role of dyslipidemia on ocular surface, lacrimal and meibomian gland structure and function. AB - PURPOSE: Dyslipidemia is characterized by high lipid blood levels that are risk factors for cardiovascular diseases, which are leading causes of death. However, it is unclear whether dyslipidemia is a cause of the dry eye syndrome (DES). Therefore we determined in transgenic mice models of dyslipidemia, whether there is an association with DES development. METHODS: Dyslipidemic models included male and female adult mice overexpressing apolipoprotein CIII (Apo CIII), LDL receptor knockout (LDLR-KO) and ApoE knockout (ApoE-KO). They were compared with age- and gender-matched C57BL/6 mice. Ocular health was evaluated based on corneal slit lamp assessment, phenol red thread test (PRT) and impression cytology. Blood lipid profiles and histology of meibomian and lacrimal glands were also evaluated. Effects of high-fat diet and aging were observed in LDLR-KO and ApoCIII strains, respectively. RESULTS: Body weight and lacrimal gland weight were significantly higher in male mice compared to females of the same strain (P < 0.05). Body weight was significantly lower in LDLRKO mice receiving high lipid diet compared to their controls (P = 0.0043). ApoE-KO were hypercholesterolemic and ApoCIII hypertriglyceridemic while LDLR-KO showed increases in both parameters. The PRT test was lower in male LDLR-KO mice with high-fat diet than control mice with standard diet (P = 0.0273). Aging did not affect lacrimal structural or functional parameters of ApoCIII strain. CONCLUSIONS: DES development is not solely dependent on dyslipidemia in relevant mice models promoting this condition. On the other hand, lacrimal gland structure and function are differentially impacted by lipid profile changes in male and female mice. This dissociation suggests that other factors beside dyslipidemia impact on tear film dysfunction and DES development. PMID- 22440162 TI - Ocular surface changes in eyes with glaucoma filtering blebs. AB - PURPOSE: To analyse the ocular surface changes in eyes with functioning filtering blebs and to correlate with the size of the bleb. MATERIALS AND METHODS: Forty eyes of 40 glaucomatous patients with functioning blebs and 40 normal control subjects underwent double vital staining for ocular surface evaluation, tear film break-up-time (BUT) and Schirmer I-test in a standardized fashion. Mann-Whitney U test and Spearman's rank correlation were used to correlate bleb height and horizontal extent with BUT, Schirmer I-test, rose bengal and fluorescein staining scores. RESULTS: Eyes with functioning blebs presented minimal, but significantly, higher rose bengal and fluorescein staining than controls (p < 0.000). The staining correlated poorly with the height and extent of the bleb. The Schirmer test in the study group showed greater measurements than controls, however, BUT showed shorter values in the study group as compared to controls (p < 0.05). CONCLUSION: Filtering blebs can interfere with the ocular surface stability causing few dry eyes like signs. PMID- 22440163 TI - Association analysis of TGFBR3 gene with Vogt-Koyanagi-Harada disease and Behcet's disease in the Chinese Han population. AB - OBJECTIVES: Transforming growth factor-beta (TGF-beta) has important regulating roles in the immune system, especially in the differentiation of the type 17 helper T cells (Th17 cells). In this study, we analysed the potential association of the type III TGF-beta receptor (TGFBR3) genetic variations (rs2489188 and rs1805110) in the Chinese Han population for patients with either Vogt-Koyanagi Harada (VKH) disease or Behcet's disease (BD), two uveitis entities presumably mediated by Th17 cells. METHODS: Two single-nucleotide polymorphisms (SNPs), rs2489188 and rs1805110, in TGFBR3 were genotyped in 451 VKH patients, 330 BD patients and 468 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism assay. The association of the two SNPs with both diseases was analysed using the chi-square test. The Bonferroni correction was applied for multiple testing. A binary logistic regression analysis was used to assess the influence of the gender on the association of TGFBR3 polymorphisms with BD. RESULTS: A significantly decreased frequency of rs1805110 CC genotype (corrected P (P(c)) = 0.03, odds ratio = 0.617, 95% CI = 0.441-0.863) was observed in BD patients compared with controls. After logistic regression analysis, this association was maintained (P(c) = 0.036). Frequencies of genotype and allele of rs2489188 were not different between VKH disease or BD patients and controls. Stratification analysis according to clinical features of VKH disease or BD failed to find any association of the tested SNPs with both diseases. CONCLUSIONS: The results suggest that rs1805110 CC genotype in TGFBR3 is probably associated with the protection from BD. The tested two TGFBR3 SNPs are not associated with VKH disease. PMID- 22440164 TI - Evaluation of cystoid macular edema using optical coherence tomography and fundus fluorescein angiography after uncomplicated phacoemulsification surgery. AB - PURPOSE: To evaluate the central macular thickness (CMT) and the cystoid macular edema (CME) after uncomplicated phacoemulsification surgery. MATERIAL AND METHODS: Ninety-one eyes of 88 patients who underwent uncomplicated phacoemulsification surgery between December 2008 and May 2009 were included in the study. Detailed ophthalmologic examinations and spectral domain optical coherence tomography (OCT) measurements were done preoperatively and at postoperative 1st, 4th, 12th, and 24th weeks. Best corrected visual acuity (BCVA) was measured as logMAR units at preoperative and all postoperative visits. Mean CMT, and perifoveal macular thickness in superior, inferior, nasal and temporal quadrants were recorded. CME was defined as three standard deviations (SD) above the preoperative mean CMT in OCT measurements. Fundus fluorescein angiography (FFA) was performed at postoperative 12th weeks. Data was analyzed statistically by using ANOVA test, and paired samples t test with Bonferroni correction. RESULTS: The mean preoperative CMT was 255.68 +/- 23.04 um. The increase in CMT was statistically significant at postoperative 1st, 4th, 12th, and 24th weeks (p = 0.043). The most significant increase in CMT was seen at 12th weeks (p = 0.028). The change in perifoveal macular thickness measurements in the temporal, nasal, superior and inferior quadrant was statistically significant at postoperative 12th weeks (p < 0.001, for all measurements). The increase in macular thickness did not correlate with BCVA at postoperative 1st and 4th weeks but there was a significant correlation at postoperative 12th and 24th weeks. The incidence of angiographic CME at postoperative 12th weeks was 3.2%. The appearance of CME in OCT was observed in 5.5% of eyes at postoperative 12th weeks. CONCLUSION: Macular thickness changes after uncomplicated phacoemulsification surgery and Spectral domain OCT is helpful in detecting cystoid abnormalities and any increase in macular thickness at postoperative early periods. Changes seen on OCT do not completely correlate with FFA findings. PMID- 22440165 TI - Protective effect of grape seed extract against oxidative stress-induced cell death in a staurosporine-differentiated retinal ganglion cell line. AB - OBJECTIVE: Grape seed extract (GSE) is a potent antioxidant. We examined the effect of GSE on oxidative stress-induced cell death in a transformed retinal ganglion cell line, RGC-5. METHODS: Staurosporine-differentiated RGC-5 (ssdRGC-5) cells obtained by treating RGC-5 cells with 1 uM staurosporine were incubated with GSE for 2 h and then exposed to buthionine sulfoximine plus glutamate (B/G) for 24 h. Cell death was detected using the LIVE/DEAD viability assay and the type of cell death was evaluated using fluorescein isothiocyanate-conjugated Annexin-V/propidium iodide staining. To investigate the mechanism underlying cell death, we determined the caspase-3 activity and level of reactive oxygen species (ROS) formation. RESULTS: Treatment of ssdRGC-5 cells with B/G increased intracellular ROS and induced apoptosis (not necrosis) with increasing caspase-3 activity. GSE rescued the ssdRGC-5 cells from oxidative stress-induced cell death by inhibiting both intracellular ROS production and caspase-3 activation. CONCLUSION: GSE had a neuroprotective effect against oxidative stress-induced apoptotic death in ssdRGC-5 cells. PMID- 22440166 TI - Confirmation of two quantitative trait loci regions for nematode resistance in commercial British terminal sire breeds. AB - Sheep internal parasites (nematodes) remain a major health challenge and are costly for pasture-based production systems. Most current breeding programmes for nematode resistance are based on indicator traits such as faecal egg counts (FEC), which are costly and laborious to collect. Hence, genetic markers for resistance would be advantageous. However, although some quantitative trait loci (QTL) have been identified, these QTL are often not consistent across breeds and few breeding strategies for nematode resistance in sheep are currently using molecular information. In this study, QTL for nematode resistance on ovine chromosomes (OAR) 3 and 14, previously identified in the Blackface breed, were explored using commercial Suffolk (n = 336) and Texel lambs (n = 879) sampled from terminal sire breeder flocks in the United Kingdom. FEC were used as the indicator trait for nematode resistance, and these were counted separately for Nematodirus and Strongyles genera. Microsatellite markers were used to map the QTL and the data were analysed using interval mapping regression techniques and variance component analysis. QTL for Nematodirus and Strongyles FEC were found to be segregating on OAR3 at 5% chromosome region-wide significance threshold in both Suffolk and Texel sheep, and Nematodirus FEC QTL were segregating on OAR14 in both breeds. In addition, QTL for growth traits were also found to be segregating at 5% chromosome region-wide on OAR3 and OAR14. The confirmation that FEC QTL segregate in the same position in three widely used breeds widens their potential applicability to purebred Blackface, Suffolk and Texel sheep, with benefits likely to be observed in their commercial crossbred progeny. PMID- 22440167 TI - Gene expression profile in white alpaca (Vicugna pacos) skin. AB - A cDNA library from white alpaca (Vicugna pacos) skin was constructed using SMART technology to investigate the global gene expression profile in alpaca skin and identify genes associated with physiology of alpaca skin and pigmentation. A total of 5359 high-quality EST (expressed sequence tag) sequences were generated by sequencing random cDNA clones from the library. Clustering analysis of sequences revealed a total of 3504 unique sequences including 739 contigs (assembled from 2594 ESTs) and 2765 singletons. BLAST analysis against GenBank nr database resulted in 1287 significant hits (E-value < 10(-10)), of which 863 were annotated through gene ontology analysis. Transcripts for genes related to fleece quality, growth and coat color (e.g. collagen types I and III, troponin C2 and secreted protein acidic and rich in cysteine) were abundantly present in the library. Other genes, such as keratin family genes known to be involved in melanosome protein production, were also identified in the library. Members (KRT10, 14 and 15) of this gene family are evolutionarily conserved as revealed by a cross-species comparative analysis. This collection of ESTs provides a valuable resource for future research to understand the network of gene expression linked to physiology of alpaca skin and development of pigmentation. PMID- 22440168 TI - Imputation of genotypes from low- to high-density genotyping platforms and implications for genomic selection. AB - The objective of this study was to quantify the accuracy achievable from imputing genotypes from a commercially available low-density marker panel (2730 single nucleotide polymorphisms (SNPs) following edits) to a commercially available higher density marker panel (51 602 SNPs following edits) in Holstein-Friesian cattle using Beagle, a freely available software package. A population of 764 Holstein-Friesian animals born since 2006 were used as the test group to quantify the accuracy of imputation, all of which had genotypes for the high-density panel; only SNPs on the low-density panel were retained with the remaining SNPs to be imputed. The reference population for imputation consisted of 4732 animals born before 2006 also with genotypes on the higher density marker panel. The concordance between the actual and imputed genotypes in the test group of animals did not vary across chromosomes and was on average 95%; the concordance between actual and imputed alleles was, on average, 97% across all SNPs. Genomic predictions were undertaken across a range of production and functional traits for the 764 test group animals using either their real or imputed genotypes. Little or no mean difference in the genomic predictions was evident when comparing direct genomic values (DGVs) using real or imputed genotypes. The average correlation between the DGVs estimated using the real or imputed genotypes for the 15 traits included in the Irish total merit index was 0.97 (range of 0.92 to 0.99), indicating good concordance between proofs from real or imputed genotypes. Results show that a commercially available high-density marker panel can be imputed from a commercially available lower density marker panel, which will also have a lower cost, thereby facilitating a reduction in the cost of genomic selection. Increased available numbers of genotyped and phenotyped animals also has implications for increasing the accuracy of genomic prediction in the entire population and thus genetic gain using genomic selection. PMID- 22440169 TI - Effect of rearing environment and dietary zinc oxide on the response of group housed weaned pigs to enterotoxigenic Escherichia coli O149 challenge. AB - A 2 * 2 factorial experiment was conducted to determine the effects of rearing environment (indoor (In) v. outdoor (Out)) and dietary zinc oxide (ZnO) supplementation (0 (-Zn) v. 3100 (+Zn) mg/kg feed) on the response of weaned pigs to a challenge infection with enterotoxigenic Escherichia coli (ETEC). Pigs from the two rearing environments were weaned onto trial diets at 4 weeks of age, moved into conventional accommodation and infected 3 days later with 109 CFU ETEC per os. Faecal ETEC shedding was determined before and after challenge. After 7 days of ETEC infection, all pigs were euthanized for gut lactic acid bacteria (LAB)-to-coliform ratio, pH and small intestine morphological measurements. Both ZnO and outdoor rearing reduced ETEC excretion, and these effects were additive. Outdoor rearing increased small intestine and colon tissue weight. ZnO increased villus height and goblet cell number in the upper small intestine, LAB-to coliform ratio (through reduced coliforms) in the lower small intestine and proximal colon, and improved growth performance. There were interactive effects of rearing environment and ZnO supplementation on upper small intestine villus height and daily gain, as outdoor rearing conferred advantages on these variables only with ZnO dietary supplementation. Daily gains were 233, 174, 277 and 347 (s.e.m. 27.2) g/day for the In - Zn, Out - Zn, In + Zn and Out + Zn, respectively. These results suggest different, but complementary mechanisms of intestinal health and performance in outdoor-reared pigs and those offered ZnO supplemented diets. The results indicate that the benefits of ZnO to the weaned pig extend beyond suppression of ETEC and appear mediated through altered development of the small intestine mucosa. PMID- 22440170 TI - Effect of decreasing dietary protein level and replacing starch with soluble fibre on digestive physiology and performance of growing rabbits. AB - At weaning (33 days of age), 246 hybrid rabbits (782 +/- 53 g live weight) were divided into six experimental groups and fed ad libitum six iso-ADF diets formulated according to a bifactorial arrangement with two protein levels (152 and 162 g/kg) and three soluble fibre-to-starch ratios (0.2, 0.6 and 1.5), the latter obtained by replacing starch (from 209 to 91 g/kg) with soluble fibre (from 48 to 136 g/kg). The trial lasted for 42 days until slaughter. The rabbits that were fed the diet with the highest protein level and the lowest soluble fibre-to-starch ratio showed the highest mortality rate (17.1% v. 1.7% on average; P < 0.001) and sanitary risk (mortality + morbidity: 20.0% v. 8.1%; P = 0.04) compared with the rabbits fed the other diets. With increasing dietary crude protein level, the digestibility of dry matter (DM; 0.615 to 0.626) and gross energy (0.620 to 0.630) as well as aNDF (without sodium sulphite; 0.298 to 0.323) and hemicelluloses (0.417 to 0.461) significantly (0.001 < P < 0.10) improved. Moreover, total volatile fatty acids (VFAs) in the caecal content increased (59.0 to 68.4 mmol/l; P = 0.01) and ileum crypt depth tended to reduce (P = 0.07). Neither growth performance nor slaughter results were affected by the protein level. When increasing soluble fibre-to-starch ratio, the digestibility of DM and gross energy did not change, whereas the digestibility of aNDF (0.264 to 0.352), ADF (0.167 to 0.267) and hemicelluloses (0.400 to 0.470) linearly increased (P < 0.001). At caecum, N-ammonia tended to decrease linearly (P = 0.08), total VFA concentration (56.0 to 67.3 mmol/l) and acetate proportion (80.4 to 83.3 mmol/100 mmol VFA) linearly increased (P < 0.01), whereas butyrate and valerate proportions decreased (0.01 < P < 0.05). Growth performance was similar among groups, whereas at slaughter the proportion of the gastrointestinal tract linearly increased (177 to 184 g/kg; P < 0.01) without effect on dressing percentage, however. As soluble fibre-to-starch ratio increased, meat pH linearly decreased and lightness (L*), redness (a*) and yellowness (b*) colour indexes increased (0.01 < P < 0.05). PMID- 22440171 TI - In vitro efficiency of combined acid-heat treatments for protecting sunflower meal proteins against ruminal degradation. AB - Efficacy of combined acid-heat treatments to protect crude protein (CP) against ruminal degradation has not been extensively researched. Four in vitro trials (Daisy technology) with orthophosphoric and malic acids were performed to examine effects on protection of sunflower meal protein. In Trial 1, effects of the solution volume for adding two doses of orthophosphoric acid (0.4 and 1.2 eq/kg sunflower meal) were tested using five dilution volumes (80, 160, 240, 320 and 400 ml/kg of feed) for each acid dose. Samples were heated at 60 degrees C. The quantity of CP that remained undegraded after 20 h in vitro (IVUCP) increased with the amount of acid added (P = 0.01). Increasing the dilution volume also tended (P = 0.065) to increase IVUCP. Therefore, a dilution volume of 400 ml/kg was employed in all further trials. In Trial 2, treatments with solutions of orthophosphoric and malic acids (1.2, 2.4, 3.6 and 4.8 eq/kg) and 60 degrees C of drying temperature were used. Increased CP protection with increased acid doses was described. In this and further trials, higher protective effects of malic acid than orthophosphoric acid were also shown. In Trial 3, the effects of both these acids, four acid concentrations (0.6, 1.2, 1.8 and 2.4 eq/kg) and three levels of heat treatment required for drying the samples (100, 150 and 200 degrees C for 60, 30 and 20 min, respectively) were evaluated. An interaction acid type * concentration * temperature was shown. In addition, interactions concentration * temperature was shown in each acid. With heat treatments of 100 degrees C to 150 degrees C, benefits were not obtained after increasing the acid dose over 0.8 eq/kg. The increase of the heat treatments to 200 degrees C and the acid dose up to 1.2 eq/kg increased protection, but to exceed this dose did not improve protection. In Trial 4, available lysine, CP solubility in McDougall buffer and IVUCP were compared after treatment with water or solutions (0.8 eq/kg) of orthophosphoric or malic acids using 100 degrees C and 150 degrees C heat treatments as described in Trial 3. No effects on available lysine were observed. Both CP solubility and IVUCP were reduced to a greater degree by acids than by water treatment. The results showed a high effectiveness of acid-heat treatments. Levels of protection are dependent on the acid dose, its dilution, acid type and drying conditions. PMID- 22440172 TI - Nutritional intervention during gestation alters growth, body composition and gene expression patterns in skeletal muscle of pig offspring. AB - Variations in maternal nutrition during gestation can influence foetal growth, foetal development and permanently 'programme' offspring for postnatal life. The objective of this study was to analyse the effect of increased maternal nutrition during different gestation time windows on offspring growth, carcass quality, meat quality and gene expression in skeletal muscle. A total of 64 sows were assigned to the following feeding treatments: a standard control diet at a feed allocation of 2.3 kg/day throughout gestation, increased feed allowance of 4.6 kg/day from 25 to 50 days of gestation (dg), from 50 to 80 dg and from 25 to 80 dg. At weaning, Light, Medium and Heavy pigs of the same gender, within litter, were selected based on birth weight, individually penned and monitored until slaughter at 130 days post weaning. Carcass and meat quality traits of the semimembranosus (SM) muscle were recorded post mortem. A cross section of the semitendinosus (ST) muscle encompassing the deep and superficial regions were harvested from pigs (n = 18 per treatment) for RNA extraction and quantification of gene expression by real-time PCR. The results showed that doubling the feed intake from 25 to 50 dg reduced offspring growth, carcass weight, intramuscular fat content and increased drip loss of the SM muscle. Interestingly, protein phosphatase 3 catalytic subunit - alpha-isoform, which codes for the transcription factor calcineurin, was upregulated in the ST muscle of offspring whose mothers received increased feed allowance from 25 to 50 dg. This may provide an explanation for the previous observed increases in Type IIa muscle fibres of these offspring. Increasing the maternal feed intake from 50 to 80 dg negatively impacted pig growth and carcass weight, but produced leaner male pigs. Extending the increased maternal feed intake from 25 to 80 dg had no effect on offspring over the standard control gestation diet. Although intra-litter variation in pig weight is a problem for pig producers, increased maternal feeding offered no improvement throughout life to the lighter birth weight littermates in our study. Indeed, increased maternal nutrition at the three gestation time windows selected provided no major benefits to the offspring. PMID- 22440173 TI - Salt intake and reproductive function in sheep. AB - Producers have the possibility to combat human-induced dryland salinity by planting salt-tolerant plants such as saltbush. Saltbush has the potential to be used as a source of food for livestock at a time and place where pasture is not viable. However, saltbush contains high concentrations of sodium chloride salt and some other anti-nutritional factors that have the potential to affect feed and water intake and, directly or indirectly, the reproductive capacity of sheep. High-salt diet during gestation induces a small modification of the activity of the renin-angiotensin system (RAS) that has an important role in the maintenance of the salt-water balance in non-pregnant and pregnant sheep. In contrast, the main effect of salt ingestion during pregnancy is observed on the biology of the offspring, with changes in the response of the RAS to salt ingestion and altered thirst threshold in response to an oral salt ingestion. These changes, observed later in life, are the result of fetal programming following the ingestion of salt by the mother. It seems that the exposure to salt during pregnancy could provide an advantage to the offspring because of this adaptive response. The response may be particularly useful, for example, when grazing herbivores are fed halophytic forages adapted to saline soils. PMID- 22440174 TI - Alteration of gene expression in mammary gland tissue of dairy cows in response to dietary unsaturated fatty acids. AB - The aim of this study was to determine the effects of supplementing unprotected dietary unsaturated fatty acids (UFAs) from different plant oils on gene expression in the mammary gland of grazing dairy cows. A total of 28 Holstein Friesian dairy cows in mid-lactation were blocked according to parity, days in milk, milk yield and fat percentage. The cows were then randomly assigned to four UFA sources based on rapeseed, soybean, linseed or a mixture of the three oils for 23 days, after which, all 28 cows were switched to a control diet for an additional 28 days. On the last day of both periods, mammary gland biopsies were taken to study genome-wide differences in gene expression on Affymetrix GeneChip(r) Bovine Genome Arrays (no. 900493) by ServiceXS (Leiden, The Netherlands). Supplementation with UFAs resulted in increased milk yield but decreased milk fat and protein percentages. Furthermore, the proportion of de novo fatty acids (FAs) in the milk was reduced, whereas that of long-chain FAs increased. Applying a statistical cut-off of false discovery rate of q-values <0.05 together with an absolute fold change of 1.3, a total of 972 genes were found to be significantly affected through UFA supplementation, indicating that large transcriptional adaptations occurred in the mammary gland when grazing dairy cows were supplemented with unprotected dietary UFA. Gene sets related to cell development and remodeling, apoptosis, nutrient metabolic process, as well as immune system response were predominantly downregulated during UFA supplementation. Such molecular knowledge on the physiology of the mammary gland might provide the basis for further functional research on dairy cows. PMID- 22440175 TI - Oral and intranasal administration of somatostatin DNA vaccine mediated by attenuated Salmonella enterica serovar Typhimurium to promote growth of piglets. AB - An attenuated strain of Salmonella typhimurium has been used as a carrier for oral and intranasal genetic immunization. Here, we evaluate the efficacy of a vaccine strain of S. typhimurium. CSO22 (pGM-CSF/SS, plasmid granulocyte macrophage colony-stimulating factor/somatostatin) expressing two copies of SS genes. A total of 115 piglets, aged 2 months old, were either orally or intranasally immunized against the vaccine strain CSO22 (pGM-CSF/SS) with three dosages (5 * 10(10) colony forming units (CFU), 5 * 10(9) CFU and 5 * 10(8) CFU). For oral immunization, the specific anti-SS antibodies were detected in the immunized piglets. The levels of SS antibodies in the high-dose immunized group (5 * 10(10) CFU) were significantly higher than that in the phosphate buffered saline immunized group (P < 0.01) and 40% of animals were positive in SS antibodies in the high-dose immunized group. Moreover, the weight gain of the high-dose group was increased by 20.86%, 10.26% and 15.30% during 4, 8 and 12 weeks, respectively, after immunization in comparison to the control. For intranasal immunization, the growth of the low-dose group was increased by 10.23% in the whole test period (12 weeks). In conclusion, our results suggest that the recombinant strain could elicit anti-SS antibodies and improve the growth performance of immunized piglets, and that the oral immunization program is better than the intranasal program. PMID- 22440176 TI - The effect of local or general anesthesia on the physiology and behavior of tail docked pigs. AB - Tail docking of pigs is a routine procedure on farms to help control tail-biting behavior; however, docking can cause pain. The objective of this research was to evaluate the effect of local or general anesthesia on the physiology (experiment 1) and behavior (experiment 2) of tail docked pigs. Pigs were allocated to one of six treatment groups: (i) sham docking (CON); (ii) docking using conventional cutting (CUT) with side-cutting pliers; (iii) CUT docking plus local anesthesia injected immediately before docking (LA); (iv) CUT docking plus short-acting local anesthesia applied topically to the tail wound (SHORT); (v) CUT docking plus long-acting anesthesia applied topically to the tail wound (LONG) and (vi) CUT docking while the pig was anesthetized with carbon dioxide gas (CO(2)). In experiment 1, blood samples were collected from pigs (10 pigs per treatment) before and 30, 60 and 120 min after docking to measure leukocyte counts and percentages and cortisol concentrations. In experiment 2, the above treatments were repeated (10 pigs per treatment); the percentage of stress vocalizations were recorded during the administration of the treatments and behavior was recorded for up to 120 min after docking or handling. All pigs were weighed before and 24 h after docking and wound healing was recorded until weaning. The neutrophil/lymphocyte ratio was greater (P < 0.05) in CUT, LA, SHORT and LONG compared with CON pigs. At 30 min, cortisol concentrations were greater (P < 0.05) in CUT, LA, LONG and CO(2) compared with CON pigs. Cortisol concentrations did not differ (P > 0.05) between SHORT and CON pigs 30 min after docking. Cortisol concentrations did not differ (P > 0.05) among pigs given pain relief at the time of docking compared with pigs' docked without pain relief. Body weight change and wound scores did not differ (P > 0.05) among treatments. The percentage of stress vocalizations increased (P < 0.05) in CUT, SHORT and LONG, but not in CON, LA and CO(2) pigs in response to docking or handling. The percentage of time pigs spent lying without contact after docking tended to be greater (P = 0.06) in CUT pigs compared with all other docking treatments and CON pigs. In this study, none of the anesthesia treatments tested were effective at significantly changing the physiological or behavioral response to tail docking in pigs. PMID- 22440177 TI - Proportion of insoluble fibre in the diet affects behaviour and hunger in broiler breeders growing at similar rates. AB - With a view to alleviate the feeling of hunger in broiler breeders, different types of fibre sources were used in high-fibre diets to increase feed quantity while limiting growth to industry recommended levels. Using scatter feeding, three diets (C1: commercial control diet, 1 * fibre content, 80% insoluble fibre (ISF); H2: 2 * fibre content, 89% ISF; and L2: 2 * fibre content, 71% ISF) were each fed to 10 groups of 16 broiler breeder chickens. Similar growth rates were obtained on different quantities of food with all birds reaching commercial target weight at 15 weeks of age. In a hunger test, birds fed C1 ate significantly faster and showed a higher compensatory feed intake than birds on diets H2 and L2, indicating that the two high-fibre diets did reduce the level of hunger experienced by the birds. Behavioural observations carried out at 14 weeks of age showed high levels of tail pecking in birds fed C1 and almost none in birds fed L2, whereas birds fed H2 were intermediate. Stereotypic pecking at fixtures was seen twice as frequently in birds fed C1. Birds on diet L2 displayed behavioural signs indicative of discomfort, and the high water usage on this diet created problems with litter quality. Birds on diet H2 continued to show foraging behaviour throughout the day, and were more frequently engaged in dust bathing and other comfort behaviour. This experiment indicates that high-fibre diets can alleviate the feeling of hunger currently experienced by broiler breeders, and a high ratio of ISF may improve the well-being of the birds. PMID- 22440178 TI - Influence of digital dermatitis and sole ulcer on dairy cow behaviour and milk production. AB - The aim of the study was to investigate whether the presence of digital dermatitis (DD) and sole ulcer (SU) in dairy cows was associated with changes in behaviour and milk production. Swedish Red and Swedish Holstein cows (mostly in the first to second lactation) were housed in a cubicle system with automatically scraped passageways. After maintenance claw trimming of all the cows in the herd, 10 cows with DD and 10 cows with SU were selected. For each DD- or SU-affected cow, a healthy control cow, matched according to breed, age, parity and lactation stage, was selected. The behaviour of each of the 20 focal cows was observed for 1 h during 2 to 3 weeks after claw trimming (WACT; period 1) and for 1 h during 5 to 6 WACT (period 2). Milk production parameters: energy-corrected milk (ECM), fat and protein percentages and somatic cell counts (SCCs) were recorded once monthly. Lameness was scored once at the start of the study and cows with SU and DD showed more score 2 lameness (42% v. 31%) than the healthy cows (12%). Most differences in behaviour were found during 2 to 3 WACT when DD- and SU-affected cows were lying less (P = 0.001 and P = 0.012, respectively) than healthy cows. Ruminating while standing was performed more in DD-affected cows (P < 0.001) and tended to be performed more in SU-affected cows (P = 0.079) than their controls. Vigilance was performed more in DD- and SU-affected cows than in healthy cows (P < 0.001 and P = 0.047). Cows with DD produced approximately 5.5 kg less ECM per day both at 2 to 3 WACT (P = 0.022) and at 5 to 6 WACT (P = 0.017) than healthy cows, whereas SU-affected cows tended to produce less ECM at 5 to 6 WACT (P = 0.059). No differences in milk fat and protein or SCC were found. It may be concluded that DD-affected cows showed a stronger behavioural response to the claw disease than the SU-affected cows. This shows the importance of regular claw checking and claw trimming of the cows in order to avoid the negative effects on behaviour and milk production. PMID- 22440179 TI - Behavioral and physiological changes in early-weaned multiparous and primiparous beef cows. AB - Early weaning is used to advance postpartum ovulation in beef cows, but triggers a stress response, affecting cows' and calves' welfare. Our aim was to compare the response to early weaning in multiparous and primiparous cows. Seventy-one days after birth, calves from 14 primiparous and 11 multiparous cows were weaned. Since birth, cow's body weight (BW), body condition (BC), milk yield and calves' BW were recorded. Basophil/neutrophil relationship, total protein and albumin concentrations were measured before and after weaning. The distance between each cow and its calf before weaning, as well as main behaviors of the cows before and after weaning were recorded using 10 min scan sampling. BW and BC were greater in multiparous than in primiparous cows (P < 0.0001 for both). There was an interaction between parity (P = 0.004) and gender of the calf (P = 0.007): both BW and BC were greater in multiparous than primiparous cows, but multiparous cows with male calves had lower BW and BC than those with females (P < 0.001 for both variables). Milk yield was greater in multiparous than in primiparous cows (P = 0.02), and there was an interaction, with greatest milk yield in multiparous cows that calved males (P = 0.02). Total protein blood concentration increased with time (P < 0.0001), similarly in both groups. Albumin concentration profiles were similar despite parity, and decreased since 10 days after weaning (P < 0.0001). Basophil/neutrophil ratio was not affected by parity, and increased the day of weaning, remaining high until day 10 (P < 0.05). Frequency of standing decreased during the 2 days after weaning, with a greater decrease in multiparous than in primiparous cows (P < 0.0001). Pacing increased after weaning (P = 0.001), but increased significantly more in multiparous cows (P = 0.006), with a significant time after weaning by parity interaction (P = 0.01) reflected in greater frequencies in multiparous cows in the 2 days. Walking increased with time (P < 0.0001), and was more frequent in primiparous cows (P = 0.008). Ruminating, which was less frequent in multiparous cows (P = 0.014), decreased and remained low during the 3 days following weaning (P < 0.0001), but there was a significant time by parity interaction (P < 0.0001). The frequency of vocalizations increased dramatically after weaning (P < 0.0001), and was greater in multiparous cows (P = 0.006), and decreased more slowly during the 2nd and 3rd days after weaning (P = 0.005) in these animals. In conclusion, behavioral changes induced by weaning were greater in multiparous than primiparous cows, indicating a more intense response to cow-calf separation in the multiparous animals. PMID- 22440180 TI - Is the establishment rate and fecundity of Haemonchus contortus related to body or abomasal measurements in sheep? AB - The relationship among parasitological parameters, abomasal size and body size measurements was investigated in lambs following an experimental infection with Haemonchus contortus. In total, 100 lambs from five different genotypes (German Merino (GM), Texel * GM, Suffolk * GM, German Blackhead Mutton * GM and Ile de France * GM) were experimentally infected with 5000 infective third stage larvae of H. contortus at the time of weaning at 12 weeks of age. Four and six weeks after infection, individual faecal samples were collected for estimation of faecal egg counts (FECs). Furthermore, wither height, shoulder width, heart girth, loin girth and body length were taken at 18 weeks of life. Lambs were slaughtered and necropsied 7 weeks post-infection, and worm counts, abomasal volume and surface area were determined. Positive correlations were found between different body size parameters, body weight and abomasal sizes. FEC and worm counts were not significantly correlated either with body size parameters or with abomasal size. The mean worm burden was higher in GM than in crossbred lambs. There was no significant difference in abomasal size between GM and crossbred lambs. The results suggest that the variations between animals in worm burden following an experimental infection with H. contortus (worm resistance) are not influenced by body size parameters or abomasal sizes. Therefore, other factors, including genetic-based differences in resistance, must cause these findings between and within breeds. PMID- 22440181 TI - Influence of breed and slaughter weight on boar taint prevalence in entire male pigs. AB - Pietrain (P), Large White (LW) and Belgian Landrace stress negative (BN) boars were slaughtered at 50, 70, 90 or 110 kg live weight to investigate breed differences and the effect of slaughter weight on boar taint prevalence. Boar taint was quantified by four different methodologies: sensory evaluation of neckfat heated with a hot iron in the slaughterhouse, sensory evaluation of meat by consumer panels, sensory evaluation of fat and meat by expert panels and laboratory analysis of indole, skatole and androstenone in backfat. Skatole levels in backfat were significantly higher for LW and BN than for P boars. The androstenone levels and the hot iron method revealed a significant interaction between breed and slaughter weight. On the other hand, experts detected an effect of weight on the androstenone odour perception, which was significantly higher in fat from boars slaughtered at 90 kg compared with 50 kg, and significantly higher in meat from boars slaughtered at 110 kg compared with 50 kg. Consumers did not detect differences in the sensory characteristics among breeds or slaughter weight. These results indicate opportunities to minimise the risk of boar taint in entire male pigs by carefully selecting a combination of breed and slaughter weight. Along with the optimal slaughter weight, the effectiveness of reducing boar taint by lowering slaughter weight appeared to be breed dependent. PMID- 22440182 TI - Effect of dietary crude protein levels in a commercial range, on the nitrogen balance, ammonia emission and pollutant characteristics of slurry in fattening pigs. AB - An experiment was conducted to investigate the effect of dietary levels of crude protein (CP), close to the range used commercially and to the European Commission recommended values, on the nitrogen (N) balance, ammonia (NH(3)) emission and pollutant characteristics of the slurry from growing and finishing pigs. Three feeding programmes with different CP levels were compared during the growing and the finishing periods of fattening. Diets were formulated to be isoenergetic and for the digestible lysine : metabolisable energy ratio to be similar in all the diets for each phase, but differed in CP concentration (160, 150 and 140 g CP/kg for the growing phase and 155, 145 and 135 g CP/kg for the finishing phase). Faeces and urine from barrows (eight replicates per diet) allocated in metabolism cages were collected separately for 5 days to calculate the N balance and for 2 days to measure NH(3) emission in a laboratory system for 240 h. Excreta were analysed for pH, volatile fatty acids (VFA), total N, electrical conductivity (EC), total solids (TS), volatile solids (VS), biochemical oxygen demand (BOD(5)), chemical oxygen demand (COD) and NH(4)-N reduction of dietary CP content led to a linear decrease of urinary (P < 0.05) and total (P < 0.05) N excretion, and N excretion/feed intake (P < 0.001). The emission of NH3 was similar in all diets (P > 0.05) during the 240 h of study. However, in the growing phase, the NH(3)-N level in slurry was lower (P < 0.05) for the low-CP diet. In addition, the CP level had no significant effect (P > 0.05) on total VFA, EC, TS, VS, COD or BOD(5) contents of excreta. These parameters were higher (P < 0.05) in slurry from the finishing phase than from the growing phase. However, NH(4)-N in the slurry decreased (P < 0.05) by 20.3% and 28.4% when the CP level was decreased by 9.30 or 21.40 g/kg, respectively. It is concluded that lowering dietary CP levels even by small amounts and using CP levels close to these used in commercial diets and close to the European Commission recommended values will decrease urinary and total N excretion in the slurry of growing finishing pigs. The slurry from finishing pigs is more concentrated than that from growing pigs. PMID- 22440183 TI - Response of milk fat concentration and yield to nutrient supply in dairy cows. AB - Dietary changes alter dairy cow milk fat concentration (MFC) and yield (MFY) through modifications in the supply of nutrients, which act as precursors or inhibitors of mammary fat synthesis. The current models used to formulate dairy cow diets cannot predict changes in milk fat. The knowledge of the effects of the nutrients on milk fat would help to progress toward this prediction. To this end, we quantified and compared the milk fat responses to variations in the supply of seven nutrients derived from digestion: volatile fatty acids, glucose, proteins, long-chain fatty acids (LCFA) and t10,c12-conjugated linoleic acid (CLA). A database was compiled from studies involving digestive infusions of these nutrients in dairy cows. It included 147 comparisons between a nutrient infusion and a control treatment. The nutrient infusions were limited to the range of physiological variations to mimic nutrient changes after dietary modifications. We established models for the response of MFC, MFY and milk fatty acid (FA) composition to the supply of each nutrient. MFC and MFY responses to the nutrients were significant and linear, except for the MFC response to glucose that was curvilinear. The nutrients differed in their effects on MFC and MFY: acetate, butyrate and LCFA increased MFC and MFY, whereas propionate, glucose and t10,c12-CLA decreased them. Protein infusions increased MFY and decreased MFC because of an increase in milk yield. The effects of numerous interfering factors related to animals, diets or experimental conditions were tested on the residuals of the response models. The responses of milk FA percentages are also provided. When adjusted to the in vivo variations in the nutrients observed after dietary changes, the effects of the different nutrients were moderate. Finally, this study showed that several of these nutrients could contribute to the changes in milk fat production and composition observed after dietary changes. This is a first step toward predicting milk fat response to changes in nutrient supply. PMID- 22440184 TI - Effect of replacing calcium salts of palm oil distillate with incremental amounts of conventional or high oleic acid milled rapeseed on milk fatty acid composition in cows fed maize silage-based diets. AB - Based on potential benefits to human health, there is increasing interest in altering the composition of ruminant-derived foods. Including rapeseeds in the dairy cow diet is an effective strategy for replacing medium-chain saturated fatty acids (SFA) with cis-monounsaturated fatty acids (MUFA) in bovine milk, but there is limited information on the optimum level of supplementation. Decreases in SFA due to plant oils are also accompanied by increases in milk trans fatty acid (FA) content and it is possible that high oleic acid rapeseeds may result in a higher enrichment of cis-9 18:1 and lower increases in trans FAs in milk compared with conventional varieties. Seven multiparous lactating Holstein Friesian cows were allocated to one of seven treatments in an incomplete Latin square design with five 28-day experimental periods, to evaluate the effect of replacing calcium salts of palm oil distillate (CPO; 41 g/kg diet dry matter, DM) with 128, 168 or 207 g/kg diet DM of conventional (COR) or a high oleic acid (HOR) rapeseed fed as a supplement milled with wheat. Rapeseed variety and inclusion level had no effect (P > 0.05) on DM intake, milk yield and composition. Both rapeseed varieties decreased linearly (P < 0.001) milk fat SFA content, which was partially compensated for by a linear increase (P < 0.001) in cis-9 18:1 concentration. Reductions in milk SFA were also associated with increases (P < 0.05) in trans 18:1 and total trans FA content, with no difference (P > 0.05) between rapeseed varieties. Replacing CPO in the diet with milled rapeseeds had no effect (P > 0.05) on total milk conjugated linoleic acid (CLA) concentration. Relative to a COR, inclusion of a high oleic acid variant in the diet increased (P = 0.01) the ratio of trans-MUFA : trans-polyunsaturated fatty acids in milk that may have implications with respect to cardiovascular disease risk in humans. In conclusion, data indicated that replacing CPO with milled rapeseeds at levels up to 1150 g oil/day could be used as a nutritional strategy to lower milk SFA content without inducing adverse effects on DM intake and milk production. HOR reduced milk fat SFA content to a greater extent than a conventional variety, but did not minimise associated increases in trans FA concentrations. However, the high oleic acid variant did alter the relative abundance of specific trans 18:1, CLA and trans 18:2 isomers compared with conventional rapeseeds. PMID- 22440185 TI - Effect of germination temperatures on proteolysis of the gluten-free grains sorghum and millet during malting and mashing. AB - Our study showed that sorghum and millet followed a similar pattern of changes when they were malted under similar conditions. When the malt from these cereals was mashed, both cereal types produced wide spectra of substrates (sugars and amino acids) that are required for yeast fermentation when malted at either lower or higher temperatures. At the germination temperatures of 20, 25, and 30 degrees C used in malting both cereal types, production of reducing sugars and that of free amino nitrogen (FAN) were similar. This is an important quality attribute for both cereals because it implies that variation in temperature during the malting of sorghum and millet, especially when malting temperature is difficult to control, and also reflecting temperature variations, experienced in different countries, will not have an adverse effect on the production and release of amino acids and sugars required by yeast during fermentation. Such consistency in the availability of yeast food (substrates) for metabolism during fermentation when sorghum and millet are malted at various temperatures is likely to reduce processing issues when their malts are used for brewing. Although sorghum has gained wide application in the brewing industry, and has been used extensively in brewing gluten-free beer on industrial scale, this is not the case with millet. The work described here provides novel information regarding the potential of millet for brewing. When both cereals were malted, the results obtained for millet in this study followed patterns similar to those of sorghum. This suggests that millet, in terms of sugars and amino acids, can play a role similar to that of sorghum in the brewing industry. This further suggests that millet, like sorghum, would be a good raw material for brewing gluten-free beer. Inclusion of millet as a brewing raw material will increase the availability of suitable materials (raw material sustainability) for use in the production of gluten-free beer, beverages, and other products. The availability of wider range of raw materials will not only help to reduce costs of beer production, but by extension, the benefit of reduced cost of production can be gained by consumers of gluten-free beer as the product would be cheaper and more widely available. PMID- 22440186 TI - Cohesin, CTCF and lymphocyte antigen receptor locus rearrangement. AB - The somatic recombination of lymphocyte antigen receptor loci is integral to lymphocyte differentiation and adaptive immunity. Here we review the relation of this highly choreographed process with the zinc finger protein CTCF and with cohesin, a protein complex best known for its essential functions in post replicative DNA repair and chromosome segregation during the cell cycle. At lymphocyte antigen receptor loci, CTCF and cohesin shape long-range interactions and contribute to V(D)J recombination by facilitating lineage- and developmental stage-specific transcription and accessibility. PMID- 22440187 TI - Multi-visceral resection of malignant tumors with left-sided portal hypertension. AB - BACKGROUND/AIMS: Left-sided portal hypertension (LSPH) is an uncommon clinical syndrome which may lead to bleeding from isolated gastric varices and pancreatitis is the most common etiology. Despite the particular rare incidence of LPSH caused by malignant tumor, the optimal management remains undefined. METHODOLOGY: From January 2006 to December 2009, a total of 8 patients of left sided portal hypertension caused by malignancies were admitted into the department of surgery of our hospital. Medical records of those patients were retrieved and analyzed, including etiologies, clinical presentations, diagnostic methods and surgical approaches. RESULTS: Of current series, pancreatic tumors (5/8) and retroperitoneal tumors (3/8) were the primary etiologies. Those patients mainly presented with upper gastrointestinal bleeding or irregular left upper abdominal pain and isolated gastric varices became important clinical evidence. All those patients were performed multi-visceral resection. No recurrent upper gastrointestinal bleeding occurred during the follow-up period and three patients died 6, 18 and 21 months postoperatively. CONCLUSIONS: Although LSPH caused by malignant tumor is uncommon and difficult to deal with, deliberate evaluation of preoperative CT images will ensure the success of an aggressive multi-visceral resection and the prognoses in those patients are relatively promising. PMID- 22440188 TI - Impact of graft steatosis on the post-transplantation biliary complications for living donor liver transplant recipients in China. AB - BACKGROUND/AIMS: After living donor liver transplantation (LDLT), the prevalence of complications related to the biliary system is 6-35%. In spite of great improvements in both surgical techniques and postoperative and long-term medical treatment, the biliary complications are still considered a relatively high risk for LDLT. The aim of this retrospective study was to analyze the incidence of biliary complications and identify predisposing risk factors. METHODOLOGY: The clinical and follow-up data of 175 adult patients receiving LDLT (right lobe or left lobe) between 2002 and December 2008 were collected and retrospectively analyzed. Patients were divided into 2 groups: with biliary complications (n=30) and without biliary complications (n=145). RESULTS: Thirty patients (17.1%) had post-transplantation biliary complications. Eight patients (4.6%) were diagnosed with bile leakage, while 24 patients (13.7%) developed biliary stricture. Percentage of steatosis of the graft and hepatic artery thrombosis after LDLT were two factors upon univariate analysis (p=0.034, p=0.01, respectively). In multivariate logistic analysis, 20-50% macrovesicular steatosis emerged as a new defined risk factor by us (p=0.001). There was no difference in patient survival rate in different groups and sorts of graft steatosis (p>0.05). CONCLUSIONS: We consider that using a graft with macro-vesicular steatosis in 20-50% should be put on the table carefully, balancing both sides of positive and negative. PMID- 22440189 TI - Roles of Kupffer cells in liver transplantation. AB - Kupffer cells, the resident macrophages of the liver, not only exert phagocytosis but also excrete proinflammatory cytokines. Large amounts of cytokines, produced by activated Kupffer cells, can induce aggravate liver ischemia/reperfusion (I/R) injury. Also, Kupffer cells that express protective genes protect from I/R injury after liver transplantation. Due to their key location, Kupffer cells might function as antigen-presenting cells and participate in transplantation immunity. They also seem to play a key role in innate immune responses and host defence through the expression and secretion of soluble inflammatory mediators. With this review we want to assist in improving the understanding of the contribution of Kupffer cells in liver I/R injury and the development of the transplantation immune. We hope that the delineation of the complex mechanisms of dysregulation may inspire the design and development of novel treatment approaches. PMID- 22440190 TI - Food resources influence spatial ecology, habitat selection, and foraging behavior in an ambush-hunting snake (Viperidae: Bothrops asper): an experimental study. AB - Prey availability affects many aspects of predators' life history and is considered a primary factor influencing individuals' decisions regarding spatial ecology and behavior, but few experimental data are currently available. Snakes may represent ideal model organisms relative to other animal groups for addressing such resource dependency, due to a presumably more direct link between food resources and many aspects of behavior and natural history. We experimentally investigated the relationship between food intake and spatial behavior in a population of the snake Bothrops asper in a Costa Rican lowland rainforest. Six adult snakes were allowed to forage naturally while six were offered supplemental food in the field, with both groups monitored using radiotelemetry. Mean home range size did not differ between groups presumably due to small sample size, but supplementally fed snakes demonstrated altered patterns of macro- and microhabitat selection, shorter and less frequent movements, and increased mass acquisition. Fed snakes also devoted less time to foraging efforts, instead more frequently remaining inactive and utilizing shelter. Because snakes were always fed in situ and not at designated feeding stations, observed shifts in habitat selection are not explained by animals simply moving to areas of higher food availability. Rather, B. asper may have moved to swamps in order to feed on amphibians when necessary, but remained in preferred forest habitat when food was otherwise abundant. The strong behavioral and spatiotemporal responses of snakes in this population may have been influenced by an overall scarcity of mammalian prey during the study period. PMID- 22440191 TI - Review of linagliptin for the treatment of type 2 diabetes mellitus. AB - BACKGROUND: Linagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in 2011 by the US Food and Drug Administration as a treatment adjunctive to diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM). OBJECTIVE: The purpose of this article is to review the pharmacology, pharmacokinetic properties, efficacy, tolerability including drug drug interactions, contraindications/precautions, and dosage and administration of linagliptin, and the potential role of linagliptin in the management of glycemia in adults with T2DM. METHODS: MEDLINE (1966-January 12, 2012), PubMed (1950-January 12, 2012), Science Direct (1994-January 12, 2012), Web of Science (1980-January 12, 2012), and the American Diabetes Association Scientific Abstracts (2008-2011) were searched using the term linagliptin. Articles and abstracts published in English, both original research and review articles, were identified for review. Reference lists from identified articles were also searched for additional references of interest. Manufacturers' prescribing information was additionally examined. RESULTS: Data from clinical trials of linagliptin suggest clinical efficacy in terms of reductions in hemoglobin A(1c) (A(1c)), fasting plasma glucose, and postprandial glucose when linagliptin was administered as monotherapy or in combination with other oral antidiabetic agents, with placebo-subtracted A(1c) changes ranging from -0.47% to -0.69% in placebo-controlled trials. Adverse events that occurred in >=2% of patients treated with linagliptin and at a prevalence of >=2-fold greater compared with placebo were nasopharyngitis, hyperlipidemia, cough, hypertriglyceridemia, and weight increase (when used in combination with a thiazolidinedione [TZD]). Although linagliptin administered as monotherapy or in combination with metformin or a TZD may convey a low risk for hypoglycemia (0%-1.2%), caution is warranted when linagliptin is administered in combination with insulin secretagogues due to an increased risk for hypoglycemic events. Dosage adjustments based on renal or hepatic function are not required. Additionally, according to the currently approved prescribing information, the efficacy of linagliptin may be limited in patients receiving concurrent inducers of the cytochrome P450 3A4 isozyme or P glycoprotein (eg, rifampin). CONCLUSIONS: Based on the findings from the present review, patients and clinicians should be aware of the risk for hypoglycemia when linagliptin is prescribed as a treatment adjunctive to a regimen of an insulin secretagogue. An initial dose decrease in the secretagogue should be considered to prevent hypoglycemic events. Dosage adjustment of linagliptin is not required in patients with renal impairment. PMID- 22440192 TI - Evaluation of the efficacy and tolerability of combination therapy with candesartan cilexetil and amlodipine besilate compared with candesartan cilexetil monotherapy and amlodipine besilate monotherapy in Japanese patients with mild-to moderate essential hypertension: a multicenter, 12-week, randomized, double blind, placebo-controlled, parallel-group study. AB - BACKGROUND: Blood pressure is reported to be insufficiently controlled in >50% of patients with hypertension. Guidelines for the management of hypertension recommend using drugs with different mechanisms of action when >1 agent is needed to achieve the blood pressure target. The combination of an angiotensin II receptor blocker and a calcium channel blocker is recommended as the preferred antihypertensive medication combination, and candesartan cilexetil (CC) and amlodipine besilate (AML) are commonly used in Japan. OBJECTIVE: The objective of our study was to determine if the combination of CC 8 mg and AML 5 mg has a greater blood pressure-lowering effect than monotherapy with either component, and if the combination of CC 4 mg and AML 2.5 mg has a greater blood pressure lowering effect than placebo. METHODS: This was a multicenter, randomized, double blind, placebo-controlled, parallel-group study in Japanese patients with mild-to moderate essential hypertension. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive the combination of CC 4 or 8 mg with AML 2.5 or 5 mg, CC 8 mg monotherapy, AML 5 mg monotherapy, or placebo once daily in the fasting or fed state for 12 weeks. The primary end point was change from baseline in trough diastolic blood pressure, and the secondary end point was change from baseline in trough systolic blood pressure at the end of treatment. Tolerability was assessed based on adverse events, vital signs, and physical findings. RESULTS: Of 548 patients who received placebo during the run-in period, 444 were randomized to receive CC 8 mg/AML 5 mg (CC/AML 8/5 mg) (n = 101), 8/2.5 mg (n = 36), 4/5 mg (n = 36), 4/2.5 mg (n = 35), CC 8 mg (n = 100), AML 5 mg (n = 100), or placebo (n = 36). These 444 patients included 272 men and 172 women. The mean (SD) age was 56.9 (10.7) years and the mean baseline BP was 153.4/95.7 mm Hg. The antihypertensive effect in the CC/AML 8/5 mg group (-27.4/-16.3 mm Hg) was significantly higher than in the CC 8 mg group (-13.9/-7.8 mm Hg) or the AML 5 mg group (-19.9/-11.2 mm Hg) in terms of reduction in the seated trough diastolic blood pressure and systolic blood pressure (both P < 0.0001). The incidence and severity of adverse events in the CC/AML combination groups did not differ significantly from those in the monotherapy and placebo groups. CONCLUSIONS: In Japanese adult patients with mild to-moderate essential hypertension, CC/AML 8/5 mg combination therapy was more effective in lowering blood pressure than CC 8 mg or AML 5 mg monotherapy. These combinations were also well tolerated. Japan Pharmaceutical Information Center registration number: Japic CTI-101054. PMID- 22440193 TI - Effects of thiazolidinediones on cardiovascular events in patients with type 2 diabetes mellitus after drug-eluting stent implantation: a retrospective cohort study using the national health insurance database in Taiwan. AB - BACKGROUND: Thiazolidinediones (TZDs) may reduce in-stent restenosis and improve clinical outcomes in type 2 diabetic patients after bare-metal stent implantation. However, it is still unknown whether diabetic patients with drug eluting stents (DESs) could benefit from treatment with TZDs. OBJECTIVE: The objective was to evaluate the clinical outcomes of TZDs in type 2 diabetic patients within 1 year of receiving DESs. METHODS: This retrospective cohort study was performed in 1743 Taiwanese type 2 diabetic patients (1137 men; 606 women) who received DESs between December 1, 2006 and December 31, 2007. Patients were classified into TZD (n = 268) or non-TZD groups (n = 1,475) using medication records within 3 months of the index hospitalization. Follow-up data were available through December 31, 2008. Clinical outcome measurements included death, myocardial infarction (MI), and repeat revascularization within 1 year after the index date of hospitalization. Cox proportional hazards model and other analyses were performed for the study. RESULTS: For the TZD and non-TZD groups, the mean ages were 65.07 and 66.09 years, respectively, for those with limus eluting stents (LESs) and 65.61 and 65.81 years, respectively, for those with paclitaxel-eluting stents (PESs). With or without TZD medication, there were no significant differences in the adjusted hazard ratios of death, MI, or repeat revascularization for diabetic patients who received LESs or PESs. TZD treatment in patients who received LESs and had a history of MI was associated with a higher risk of MI (hazard ratio = 5.292; 95% CI, 1.028-27.232). CONCLUSIONS: TZDs did not improve the clinical outcomes in Taiwanese type 2 diabetes patients who received DESs. TZDs might have been a contributor to higher risk of MI in patients with LESs and a history of MI. Larger clinical trials are still needed to study this issue further. PMID- 22440194 TI - Open innovation in health care: analysis of an open health platform. AB - Today, integration of the public in research and development in health care is seen as essential for the advancement of innovation. This is a paradigmatic shift away from the traditional assumption that solely health care professionals are able to devise, develop, and disseminate novel concepts and solutions in health care. The present study builds on research in the field of open innovation to investigate the adoption of an open health platform by patients, care givers, physicians, family members, and the interested public. Results suggest that open innovation practices in health care lead to interesting innovation outcomes and are well accepted by participants. During the first three months, 803 participants of the open health platform submitted challenges and solutions and intensively communicated by exchanging 1454 personal messages and 366 comments. Analysis of communication content shows that empathic support and exchange of information are important elements of communication on the platform. The study presents first evidence for the suitability of open innovation practices to integrate the general public in health care research in order to foster both innovation outcomes and empathic support. PMID- 22440195 TI - Mergers and acquisitions in Western European health care: exploring the role of financial services organizations. AB - Recent policy developments in Western European health care - for example in the Netherlands - aim to enhance efficiency and curb public expenditures by strengthening the role of private sector. Mergers and acquisitions (M&As) play an important role in this respect. This article presents an analysis of 1606 acquisition deals targeting health care provider organizations in Western Europe between 1990 and 2009. We particularly investigate the role of financial services organisations as acquirers. Our analysis highlights (a) a rise of M&As in Western Europe since 2000, (b) an increase of M&As with financial service organisations acting as acquirer in absolute terms, and (c) a dominant role of the latter type of M&As in cross-border deals. To explain these developments, we make a distinction between an integration and a diversification rationale for M&As and we argue that the deals with financial services organisations in the role of acquirer are driven by a diversification rationale. We then provide arguments why health care, from the acquirer's perspective, can be considered as an interesting target in a diversification strategy and we advance reasons why health care providers may welcome this development. Although caution in drawing conclusions is needed, our findings suggest a penetration of private capital into health care provision that may be interpreted as a specific form of privatisation. Furthermore, they point to a rising internationalisation of health care. Both findings may entail far-reaching implications for health care, as they may induce both cultural privatisation and cultural internationalisation. PMID- 22440197 TI - Environmental exposures: how to counsel preconception and prenatal patients in the clinical setting. AB - A growing body of scientific evidence suggests that preconception and prenatal exposures can impact fetal development adversely and lead to potential long lasting health effects. Reproductive health professionals have little training on these exposures and how to counsel patients effectively. We present short summaries of some of the most common environmental exposures and give providers practical tools with which to counsel patients in the clinical setting. These tools may enable practitioners to help prevent harmful environmental exposures and to reduce the risk of future adverse health impacts for the prenatal and preconception patient population. PMID- 22440198 TI - Concurrent urinary and intestinal schistosomiasis and intestinal helminthic infections in schoolchildren in Ilobu, South-western Nigeria. AB - A cross-sectional study was conducted in a schistosome-endemic rural community in Southwestern Nigeria. We assessed prevalence and intensity of soil-transmitted nematodes and the co-occurrence with Schistosoma haematobium and Schistosoma mansoni. Urine and stool samples from 419 schoolchildren were examined, and a questionnaire was administered to obtain socio-demographic characteristics. In total, 78.3% (328/419) were infected with at least one helminth species, with a prevalence (mean egg-count) of 55.1% (3069.2) of Ascaris lumbricoides, 41.1% (127.5) of S. haematobium, 22.7% (98.6) of hookworms, 17.9% (161.3) of Trichuris trichiura, and 10.3% (12.9) of S. mansoni. Multiple infections were significantly more common among children from households with more playmates, absence of toilet facilities and low income level (all p<0.001). Children with heavy hookworm burden were at a significantly higher chance of acquiring S. mansoni (OR=36.35; 95% Cl: 13.22-100.97; p<0.0001). The risk of S. mansoni and A. lumbricoides infections was increased in co-infections with S. haematobium. Logistic regression analysis revealed infections by hookworms and S. mansoni (adjusted odds ratio [aOR]=3.90, 95% Cl: 2.03-7.46; p<0.0001), and by hookworms and T. trichiura (aOR=2.46, 95% Cl: 1.44-4.22; p=0.001) as significant risk factors for multiple infections. Our study shows that polyparasitism is common in the study area. Focused interventions such as mass treatment with anthelminthics and health education are needed to improve the well-being of the affected population. PMID- 22440199 TI - Reductions in genetic diversity of Schistosoma mansoni populations under chemotherapeutic pressure: the effect of sampling approach and parasite population definition. AB - Detecting potential changes in genetic diversity in schistosome populations following chemotherapy with praziquantel (PZQ) is crucial if we are to fully understand the impact of such chemotherapy with respect to the potential emergence of resistance and/or other evolutionary outcomes of interventions. Doing so by implementing effective, and cost-efficient sampling protocols will help to optimise time and financial resources, particularly relevant to a disease such as schistosomiasis currently reliant on a single available drug. Here we explore the effect on measures of parasite genetic diversity of applying various field sampling approaches, both in terms of the number of (human) hosts sampled and the number of transmission stages (miracidia) sampled per host for a Schistosoma mansoni population in Tanzania pre- and post-treatment with PZQ. In addition, we explore population structuring within and between hosts by comparing the estimates of genetic diversity obtained assuming a 'component population' approach with those using an 'infrapopulation' approach. We found that increasing the number of hosts sampled, rather than the number of miracidia per host, gives more robust estimates of genetic diversity. We also found statistically significant population structuring (using Wright's F-statistics) and significant differences in the measures of genetic diversity depending on the parasite population definition. The relative advantages, disadvantages and, hence, subsequent reliability of these metrics for parasites with complex life-cycles are discussed, both for the specific epidemiological and ecological scenario under study here and for their future application to other areas and schistosome species. PMID- 22440200 TI - Prevalence of adenomas and advanced adenomas in patients in the 40- to 49-year age group undergoing screening colonoscopy because of a family history of adenoma/polyp in a first-degree relative. AB - BACKGROUND: Per current guidelines, patients with a first-degree relative (FDR) with adenomas should get screened at age 40. Data on the prevalence of adenomas and advanced adenomas (AAs) in these patients are lacking. OBJECTIVE: To examine the prevalence of adenomas and AAs in 40- to 49-year-old individuals undergoing screening colonoscopy because of a family history (FH) of polyps and to compare these data with those of a control population of similar age. DESIGN: Retrospective cross-sectional study. SETTING: Tertiary care academic medical center and Veterans Affairs medical center. PATIENTS: Study subjects included all 40- to 49-year-old asymptomatic individuals undergoing initial screening colonoscopy at our institution from January 1, 2006, to June 1, 2009, because of an FDR with polyps. The control population consisted of all 40- to 49-year-old individuals who underwent their first colonoscopy during the same period because of abdominal pain, diarrhea, or constipation without an FH of polyps or colorectal cancer. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: The prevalence of adenomas of any size, AAs, and risk factors associated with adenomas. RESULTS: The prevalence of adenomas was greater in the FH of polyps group (n = 176) compared with the control sample (n = 178) (26.7% vs 13.5%; P = .002) but was not statistically greater for AAs (5.7% vs 3.4%; P = .3). After adjusting for confounders, FH of a polyp was associated with an increased prevalence of adenomas (odds ratio 2.8 [95% CI, 1.4-5.5]). LIMITATIONS: Limited data on polyp histology in FDRs and limited sample size. CONCLUSIONS: Among 40- to 49-year-old patients undergoing screening colonoscopy because of an FDR with polyps, the prevalence of adenomas was greater than in a control population. Prospective research is needed to quantify the prevalence of AAs in this group and to determine whether these individuals should undergo screening colonoscopy at age 40. PMID- 22440201 TI - Between Scylla and Charybdis: high-risk endoscopic procedures and anticoagulant therapy. PMID- 22440202 TI - The art of salary negotiation in academic medicine: lessons from a 32-year career. PMID- 22440203 TI - A rare cause of hematemesis: gastric metastases from renal cell carcinoma. PMID- 22440204 TI - Oncocytic intraductal papillary mucinous neoplasm with carcinomatous degeneration. PMID- 22440205 TI - Diagnosis of isolated pancreatic tuberculosis: the role of EUS-guided FNA cytology. PMID- 22440206 TI - Radiofrequency ablation of esophageal lesions and recurrent fever. PMID- 22440207 TI - Dysplasia detection in inflammatory bowel diseases: is narrow-band imaging in the race at all? PMID- 22440208 TI - Human taeniasis diagnosed by radiography/endoscopy and morphology. PMID- 22440210 TI - Midgut volvulus as an adverse event of postsphincterotomy bleeding. PMID- 22440211 TI - Colonic stent placement via colostomy for recurrent metastatic rectal carcinoma. PMID- 22440212 TI - Cardiovascular abnormalities in sickle cell disease. AB - Sickle cell disease is characterized by recurrent episodes of ischemia reperfusion injury to multiple vital organ systems and a chronic hemolytic anemia, both contributing to progressive organ dysfunction. The introduction of treatments that induce protective fetal hemoglobin and reduce infectious complications has greatly prolonged survival. However, with increased longevity, cardiovascular complications are increasingly evident, with the notable development of a progressive proliferative systemic vasculopathy, pulmonary hypertension (PH), and left ventricular diastolic dysfunction. Pulmonary hypertension is reported in autopsy studies, and numerous clinical studies have shown that increased pulmonary pressures are an important risk marker for mortality in these patients. In epidemiological studies, the development of PH is associated with intravascular hemolysis, cutaneous leg ulceration, renal insufficiency, iron overload, and liver dysfunction. Chronic anemia in sickle cell disease results in cardiac chamber dilation and a compensatory increase in left ventricular mass. This is often accompanied by left ventricular diastolic dysfunction that has also been a strong independent predictor of mortality in patients with sickle cell disease. Both PH and diastolic dysfunction are associated with marked abnormalities in exercise capacity in these patients. Sudden death is an increasingly recognized problem, and further cardiac investigations are necessary to recognize and treat high-risk patients. PMID- 22440213 TI - Aortic regurgitation index defines severity of peri-prosthetic regurgitation and predicts outcome in patients after transcatheter aortic valve implantation. AB - OBJECTIVES: The aim of this study was to provide a simple, reproducible, and point-of-care assessment of peri-prosthetic aortic regurgitation (periAR) during transcatheter aortic valve implantation (TAVI) and to decipher the impact of this peri-procedural parameter on outcome. BACKGROUND: Because periAR after TAVI might be associated with adverse outcome, precise quantification of periAR is of paramount importance but remains technically challenging. METHODS: The severity of periAR was prospectively evaluated in 146 patients treated with the Medtronic CoreValve (Minneapolis, Minnesota) prosthesis by echocardiography, angiography, and measurement of the aortic regurgitation (AR) index, which is calculated as ratio of the gradient between diastolic blood pressure (DBP) and left ventricular end-diastolic pressure (LVEDP) to systolic blood pressure (SBP): [(DBP - LVEDP)/SBP] * 100. RESULTS: After TAVI, 53 patients (36.3%) showed no signs of periAR and 71 patients (48.6%) showed only mild periAR, whereas 18 patients (12.3%) and 4 patients (2.7%) suffered from moderate and severe periAR, respectively. The AR index decreased stepwise from 31.7 +/- 10.4 in patients without periAR, to 28.0 +/- 8.5 with mild periAR, 19.6 +/- 7.6 with moderate periAR, and 7.6 +/- 2.6 with severe periAR (p < 0.001), respectively. Patients with AR index <25 had a significantly increased 1-year mortality risk compared with patients with AR index >=25 (46.0% vs. 16.7%; p < 0.001). The AR index provided additional prognostic information beyond the echocardiographically assessed severity of periAR and independently predicted 1-year mortality (hazard ratio: 2.9, 95% confidence interval: 1.3 to 6.4; p = 0.009). CONCLUSIONS: The assessment of the AR index allows a precise judgment of periAR, independently predicts 1-year mortality after TAVI, and provides additional prognostic information that is complementary to the echocardiographically assessed severity of periAR. PMID- 22440214 TI - Impact of QRS duration and morphology on the risk of sudden cardiac death in asymptomatic patients with aortic stenosis: the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) Study. AB - OBJECTIVES: The aim of the study was to examine the predictive value of QRS duration and morphology during watchful waiting in asymptomatic patients with aortic stenosis (AS). BACKGROUND: QRS duration and morphology are associated with poor prognosis in many different populations, but the predictive value, particularly of the risk of sudden cardiac death (SCD), in asymptomatic patients with AS has not been well studied. METHODS: Data were obtained in asymptomatic AS patients randomized to simvastatin/ezetimibe combination versus placebo in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. The impact of QRS duration, evaluated as a categorical variable of <85 ms versus 85 to 99 ms and >=100 ms (excluding bundle branch block [BBB]) and QRS morphology in those with BBB, on cardiovascular morbidity and mortality was assessed by adjusting for clinical and echocardiographic covariates. RESULTS: QRS data were available in 1,542 patients who were followed for a mean of 4.3 +/- 0.8 years (6,631 patient years of follow-up). There were 68 cardiovascular deaths (4.6%), including 27 SCDs (1.8%). QRS duration was <85 ms in 900 patients (58.4%), 85 to 99 ms in 396 (25.7%), >=100 ms in those without BBB in 144 (9.3%), and 102 (6.6%) in those with BBB. In multivariable analyses, those with QRS duration >=100 ms had, compared with those with QRS duration <85 ms, a 5-fold higher risk of SCD (95% confidence interval: 1.8 to 13.7, p = 0.002) and a 2.5-fold higher risk of cardiovascular death (95% confidence interval: 1.2 to 5.1, p = 0.01). CONCLUSIONS: QRS duration and morphology in asymptomatic patients with AS are independently associated with a poor prognosis, particularly the risk of SCD. PMID- 22440215 TI - Pulmonary hypertension associated with advanced systolic heart failure: dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1. AB - OBJECTIVES: This study sought to examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and to explore possible mechanisms of arginine dysregulation in human heart failure. BACKGROUND: Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear. METHODS: This study prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR = arginine/(ornithine + citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (n = 68) and with stable chronic heart failure (n = 57). RESULTS: Compared with chronic heart failure subjects, plasma ADMA was significantly higher (median [interquartile range]: 1.29 [1.04 to 1.77] MUmol/l vs. 0.87 [0.72 to 1.05] MUmol/l, p < 0.0001), and global arginine bioavailability ratio significantly lower (median [interquartile range]: 0.90 [0.69 to 1.22] vs. 1.13 [0.92 to 1.37], p = 0.002) in advanced decompensated heart failure subjects. Elevated ADMA and diminished global arginine bioavailability ratio were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 were increased in chronic heart failure without elevated sPAP (<50 mm Hg), but diminished with elevated sPAP (>=50 mm Hg, difference with sPAP <50 mm Hg, p = 0.02). CONCLUSIONS: Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared with hearts of control subjects, we observed higher amounts of ADMA-degradation enzyme dimethylarginine dimethylaminohydrolase-1 (but similar amounts of ADMA producing enzyme, protein methyltransferase-1) in the human failing myocardium. PMID- 22440216 TI - Calf muscle characteristics, strength measures, and mortality in peripheral arterial disease: a longitudinal study. AB - OBJECTIVES: This study analyzed whether lower calf muscle density and poorer upper and lower extremity strength are associated with higher mortality rates in men and women with peripheral arterial disease (PAD). BACKGROUND: Men and women with lower extremity PAD have lower calf muscle density and reduced lower extremity strength compared with individuals without PAD. METHODS: At baseline, participants underwent measurement of calf muscle density with computed tomography in addition to knee extension power and isometric knee extension, plantar flexion, and hand grip strength measures. Participants were followed up annually for up to 4 years. Results were adjusted for age, sex, race, body mass index, ankle-brachial index, smoking, physical activity, and comorbidities. RESULTS: Among 434 PAD participants, 103 (24%) died during a mean follow-up of 47.6 months. Lower calf muscle density was associated with higher all-cause mortality (lowest density tertile hazard ratio [HR]: 1.80 [95% confidence interval (CI): 1.07 to 3.03], second tertile HR: 0.91 (95% CI: 0.51 to 1.62); highest density tertile HR: 1.00; p trend = 0.020) and higher cardiovascular disease mortality (lowest density tertile HR: 2.39 [95% CI: 0.90 to 6.30], second tertile HR: 0.85 [95% CI: 0.27 to 2.71]; highest density tertile HR: 1.00; p trend = 0.047). Poorer plantar flexion strength (p trend = 0.004), lower baseline leg power (p trend = 0.046), and poorer handgrip (p trend = 0.005) were associated with higher all-cause mortality. CONCLUSIONS: These data demonstrate that lower calf muscle density and weaker plantar flexion strength, knee extension power, and hand grip were associated with increased mortality in these participants with PAD, independently of the ankle-brachial index and other confounders. PMID- 22440217 TI - Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance. AB - OBJECTIVES: This study examined survival after surgical palliation in children with single-ventricle physiology. BACKGROUND: Contemporary surgical outcomes for the entire population of newborns undergoing single-ventricle palliation are unclear. METHODS: In a single-center review of 499 consecutive patients undergoing univentricular palliation from 1990 to 2008, predictors of mortality were determined using multivariate risk analysis, stratified for each post operative stay and interim states. RESULTS: After 2000, the population comprised more patients with dominant right ventricle (66% vs. 36%) and hypoplastic left heart syndrome (HLHS) (47% vs. 13%). Median age at bidirectional cavopulmonary shunt (BCPS) decreased from 15 months (10 to 22 months) before 2000 to 4 months (3.3 to 9 months) thereafter. Survival rates at 1, 5, and 10 years were, respectively, 82% (95% confidence interval [CI]: 79% to 85%), 74% (95% CI: 70% to 78%), and 71% (95% CI: 67% to 75%). Throughout the study, atrioventricular valve regurgitation (hazard ratio [HR]: 1.8; p = 0.008), not having transposition (HR: 2.0; p = 0.013), and heterotaxia (HR: 2.0; p = 0.026) were predictors of mortality. The most potent risk factor was right ventricular (RV) dominance (HR: 2.2; p = 0.001) because of its impact before BCPS. HR for death in patients with RV dominance went from 2.8 (95% CI: 1.4 to 5.7; p = 0.005) before BCPS to 1.0 (95% CI: 0.5 to 2.1; p = 0.98) thereafter. Survival of patients with RV dominance, adjusted for the risk factors noted here, improved over the study period (p = 0.001). CONCLUSIONS: Considerable mortality is still observed during the first years of life among patients with single ventricle. RV dominance is the most important risk factor for death but only before BCPS. PMID- 22440218 TI - The functionally univentricular heart: which is better--right or left ventricle? PMID- 22440219 TI - The Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS): a cluster randomized trial. PMID- 22440220 TI - Hypertrophied papillary muscles as a masquerade of apical hypertrophic cardiomyopathy. PMID- 22440222 TI - Is acute hemodynamic response a predictor of long-term outcome in cardiac resynchronization therapy? PMID- 22440223 TI - ACCF and AHA Presidents' Letter on MEDCAC. PMID- 22440224 TI - Adequate pulmonary stenosis allowed long-term survival in a patient with unoperated single ventricle. PMID- 22440225 TI - Neuronal connectivity and interactions between the auditory and limbic systems. Effects of noise and tinnitus. AB - Acoustic experience such as sound, noise, or absence of sound induces structural or functional changes in the central auditory system but can also affect limbic regions such as the amygdala and hippocampus. The amygdala is particularly sensitive to sound with valence or meaning, such as vocalizations, crying or music. The amygdala plays a central role in auditory fear conditioning, regulation of the acoustic startle response and can modulate auditory cortex plasticity. A stressful acoustic stimulus, such as noise, causes amygdala mediated release of stress hormones via the HPA-axis, which may have negative effects on health, as well as on the central nervous system. On the contrary, short-term exposure to stress hormones elicits positive effects such as hearing protection. The hippocampus can affect auditory processing by adding a temporal dimension, as well as being able to mediate novelty detection via theta wave phase-locking. Noise exposure affects hippocampal neurogenesis and LTP in a manner that affects structural plasticity, learning and memory. Tinnitus, typically induced by hearing malfunctions, is associated with emotional stress, depression and anatomical changes of the hippocampus. In turn, the limbic system may play a role in the generation as well as the suppression of tinnitus indicating that the limbic system may be essential for tinnitus treatment. A further understanding of auditory-limbic interactions will contribute to future treatment strategies of tinnitus and noise trauma. PMID- 22440226 TI - A comparison of patellar vascularity between the medial parapatellar and subvastus approaches in total knee arthroplasty. AB - A complication of total knee arthroplasty is patellar avascular necrosis. Surgical approaches for total knee arthroplasty include the medial parapatellar approach (MPa) and, less commonly, the subvastus approach (SVa). The argument that SVa retains better patellar vascularity than the MPa was investigated on 20 participants, (SVa, n = 10; MPa, n = 10) 18 months postoperatively. Outcomes were a radionuclide bone imaging technique, a new bone vascularity scale, and an anterior knee pain numerical assessment scale. Results indicated no significant difference between groups on imaging (P = .935), the components of the bone vascularity scale, or anterior knee pain (P > .999). The SVa appears to offer no benefit over the MPa in terms of patellar vascularity or anterior knee pain. PMID- 22440227 TI - Do previous operative reports provide the critical information necessary for revision total hip arthroplasty? AB - An operative note is a vital component of a patient's medical-legal record, permitting the surgical team to safely administer perioperative care. Despite this critical function, operative note contents are neither standardized nor regulated; this is especially concerning in orthopedic surgery. As younger patients undergo total hip arthroplasty (THA) and outlive their prostheses, the need for revision THA cannot be ignored. Surgeons performing primary THA must be cognizant to record detailed implant characteristics to ensure that if necessary, the revision surgeon will have all pertinent information to optimally treat the patient. Our survey of operative notes reveals the dismal nature of component documentation during primary THA; implementation of a standardized procedure specific operative note guideline may minimize incomplete dictations and drive surgeons to include all pertinent information. PMID- 22440228 TI - Accelerometer-based computer navigation for performing the distal femoral resection in total knee arthroplasty. AB - The use of intramedullary alignment guides for performing the distal femoral resection in total knee arthroplasty (TKA) have not been shown to be highly accurate. Forty-eight knees underwent a TKA using a portable, accelerometer-based surgical navigation system for performing the distal femoral resection (KneeAlign 2 system; OrthAlign, Inc, Aliso Viejo, Calif). Of the femoral components, 95.8% were placed within 90 degrees +/- 2 degrees to the femoral mechanical axis in the coronal plane, and 93.8% of the TKAs had an overall lower extremity alignment within 3 degrees of neutral to the mechanical axis, based on postoperative, standing, hip-to-ankle radiographs. The KneeAlign 2 is highly accurate in positioning the femoral component in TKA, and accelerometer-based navigation is able to reliably determine the hip center of rotation and femoral mechanical axis. PMID- 22440229 TI - Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience. AB - BACKGROUND: Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. PATIENTS AND METHODS: We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers. RESULTS: Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1-5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS. CONCLUSIONS: These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen. PMID- 22440230 TI - Nature and structure of aluminum surface sites grafted on silica from a combination of high-field aluminum-27 solid-state NMR spectroscopy and first principles calculations. AB - The determination of the nature and structure of surface sites after chemical modification of large surface area oxides such as silica is a key point for many applications and challenging from a spectroscopic point of view. This has been, for instance, a long-standing problem for silica reacted with alkylaluminum compounds, a system typically studied as a model for a supported methylaluminoxane and aluminum cocatalyst. While (27)Al solid-state NMR spectroscopy would be a method of choice, it has been difficult to apply this technique because of large quadrupolar broadenings. Here, from a combined use of the highest stable field NMR instruments (17.6, 20.0, and 23.5 T) and ultrafast magic angle spinning (>60 kHz), high-quality spectra were obtained, allowing isotropic chemical shifts, quadrupolar couplings, and asymmetric parameters to be extracted. Combined with first-principles calculations, these NMR signatures were then assigned to actual structures of surface aluminum sites. For silica (here SBA-15) reacted with triethylaluminum, the surface sites are in fact mainly dinuclear Al species, grafted on the silica surface via either two terminal or two bridging siloxy ligands. Tetrahedral sites, resulting from the incorporation of Al inside the silica matrix, are also seen as minor species. No evidence for putative tri-coordinated Al atoms has been found. PMID- 22440231 TI - Self-assemblies of triskelion A2B-type amphiphilic polypeptide showing pH responsive morphology transformation. AB - A pH-responsive rolled-sheet morphology was prepared from a triskelion A(2)B-type amphiphilic polypeptide having a histidine residue as a pH-responsive unit. The dimensions of the rolled sheet were 85 nm diameter and 210 nm length with a sheet turn number of 2.0 at pH 7.4. Upon decreasing the pH from 7.4 to 5.0, the layer spacing of the rolled sheets was widened from ca. 9 to ca. 19 nm due to electrostatic repulsion caused by histidine protonation. This morphology change occurred reversibly with a pH change between 7.4 and 5.0. The molecular packing in the rolled sheets was shown to be loosened at pH 5.0 on the basis of electron diffraction measurements. The tightness of the rolled sheets was thus controlled reversibly by a pH change due to a single protonation in the amphiphilic polypeptide. PMID- 22440232 TI - Animal models of neuropsychiatry revisited: a personal tribute to Teitelbaum. AB - Several themes and principles of behavioural neuroscience are evident in the work of Phillip Teitelbaum. He has emphasised the importance of studying behaviour in simple preparations, of re-synthesising complex behavioural patterns from these elemental 'building-blocks' and understanding their often hierarchical organisation. He also more recently has become interested in the possible power of behavioural endophenotypes. His work has resulted in a new emphasis on animal neuropsychology which is highly relevant to human psychopathology. This article illustrates these themes from examples taken from animal models of sensory neglect, drug addiction and cognitive syndromes associated with schizophrenia and other neuropsychiatric disorders. PMID- 22440233 TI - Involvement of NMDA receptors in the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice. AB - INTRODUCTION: Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARgamma) agonist, is widely used in clinical medicine as a treatment for type 2 diabetes and is recently proved to have beneficial effects on improving cognition in early stages of Alzheimer's disease (AD). Moreover, it has been shown that pioglitazone reduces N-methyl-D-aspartate (NMDA, a glutamate agonist) mediated calcium currents and transients. Since enhanced calcium transients are present in AD models, we tested the hypothesis whether pioglitazone manifests its acquisition memory enhancement role through glutamatergic pathway. MATERIAL AND METHODS: Memory performance was evaluated in a two-trial recognition Y-maze test and passive avoidance in mice. Pioglitazone (20 or 40 mg/kg, p.o.) was administered 2h before each trial, NMDA (75 mg/kg i.p.), 15 min before pioglitazone, and scopolamine, an M1 (muscarinic) receptor antagonist (0.3 or 1.0 mg/kg i.p.) and MK-801 (dizocilpine) (0.01, 0.03 or 0.1 mg/kg, i.p.), the highly selective, non-competitive NMDA antagonist--30 min beforehand. RESULTS: (1) We induced the memory impairment by scopolamine or MK-801 before trials. (2) Pioglitazone did not improve the memory impairment induced by MK-801. (3) Pioglitazone significantly improved the memory impairment induced by scopolamine. (4) Subeffective dose of MK-801 nullified the beneficial effects of pioglitazone in scopolamine induced memory impaired mice. (5) NMDA promoted the effects of subeffective dose of pioglitazone on memory impaired by scopolamine. DISCUSSION: In conclusion, the present study suggests that glutamatergic pathway is involved in the pioglitazone induced memory performance. PMID- 22440234 TI - Naked mole-rats: behavioural phenotyping and comparison with C57BL/6 mice. AB - Naked mole-rats (NMR) live underground in large eusocial colonies in East Africa. They are extremely long-lived, some individuals having a lifespan of over 30 years. This has attracted research into longevity and possibly neurodegenerative disorders. However, very little is known about their basic behaviour, particularly in tests commonly used to characterise the behaviour of the laboratory rat and mouse, for which there is an enormous database. Recently the authors carried out comprehensive behavioural phenotyping on NMRs, comparing them on most tasks directly with C57BL/6 mice, the strain for which there is the largest behavioural database. The NMR colony had been obtained from the wild originally, but housed in an animal facility for about two years. Large inter species differences in behaviour were seen between the mice and the NMRs. The latter had generally poor sensorimotor function, including cutaneous sensation, strength and even grasp reflexes. They were often reluctant to enter or head-dip into small holes that mice readily entered. Their vision (generally considered to be very poor) was sufficient to distinguish the two zones of a light-dark box. Although, as expected, the NMRs were capable of burrowing and digging, when individually housed they did not shred cotton material to make nests. Shredding was seen in a colony cage containing a queen, but no nests were made there even when a nesting box was provided. In cognitive testing, although, unlike mice and rats, they did not spontaneously alternate in a T-maze, they learnt rewarded alternation and a cued position task well. This study demonstrates how behaviour uniquely reflects the natural environment in which these unusual animals have evolved and live, and provides baseline data for future work. PMID- 22440235 TI - No differences in perioperative outcome between symptomatic and asymptomatic AAAs after EVAR: an analysis from the ENGAGE Registry. AB - AIM: This study aimed to compare the differences in perioperative outcome after endovascular repair of symptomatic abdominal aneurysms (S-AAAs) and elective non symptomatic AAAs (E-AAAs). Data from the ENGAGE Registry were used for the analysis. METHODS: Between March 2009 and December 2010, 1200 AAA patients were enrolled from 79 sites in 30 countries and treated with an Endurant Stent Graft. S-AAAs defined as AAAs accompanied by abdominal or back pain, without rupture, were present in 185 (15.4%) patients and E-AAAs in 1015 (84.6%) patients. Multivariate logistic regression was used to compare results. RESULTS: At baseline, E-AAA patients had larger aneurysms on average (P = 0.006) and scored higher ASA classification more often (P = 0.001). Further analyses were corrected for baseline differences. Operation time and technical success were comparable, and S-AAAs were admitted to the Intensive Care Unit (ICU) as often as E-AAAs (35.7% vs. 33.4%, P = 0.479). Post-operative hospitalisation was similar (4.83 +/ 5.29 in E-AAAs and 4.37 +/- 3.49 in S-AAAs, P = 0.360). No differences in the occurrence of major adverse events, including mortality, within the 30-day post implantation were seen between S-AAA and E-AAA patients, respectively, 3.2% and 4.2% (P = 0.572). CONCLUSION: With contemporary devices and technical proficiency, there is no difference in outcome between symptomatic AAA and elective non-symptomatic AAA patients if treated with endovascular techniques. PMID- 22440236 TI - Comparison of (99m)Tc activity measurements at the KRISS using the new SIRTI of the BIPM. AB - In 2010, a comparison of activity measurements of (99m)Tc was carried out at the KRISS using the BIPM's Transfer Instrument of the International Reference System (SIRTI). The transfer instrument and the KRISS coincidence measurement method are briefly described. The degrees of equivalence with the key comparison reference value and between the present KRISS result and the earlier participants in the SIRTI and SIR comparisons have been evaluated. World-wide consistency of activity measurements of (99m)Tc is demonstrated. PMID- 22440237 TI - Proficiency test for clearance mixed-nuclide samples. AB - In 2010, the National Radiation Standard Laboratory held a proficiency test for measurement and analysis of clearance mixed-nuclide samples. Two types of samples, box-shape and drum-shape, containing (60)Co and (137)Cs mixed solutions were measured by the participating laboratories and their results were then compared with the reference values. Seven participants used plastic scintillator counting systems and two participants used HPGe spectrometer systems to join in this study, obtaining 40 measurement results. The evaluation results showed that all the participants passed the requirements of this proficiency test, E(n)?1, and the discrepancy was between -25% and 50%. PMID- 22440238 TI - Performance assessment by Monte Carlo simulations of a prospective assembly of up to three HPGe detectors designed for superior detection efficiency and sensitivity. AB - The present work reports on the results of Monte Carlo simulations performed with MCNP on an assembly of two HPGe detectors facing each other regarding detector efficiencies. Report is also made when a third detector is added to the previous configuration from below. Moreover cross talk between detectors is investigated and found of limited impact. The choice for an actual detector goes to the three detector configuration for accommodating most geometries while cost and engineering constrains remain acceptable. PMID- 22440239 TI - A new approach in gamma-ray scanning of rotating drums containing radioactive waste. AB - The paper presents a new approach in the integral gamma scanning of rotating waste drums based on solving a first-kind Fredholm integral equation using a small number of measurements. Both numerical experiments and experimental results show that the nuclide inventory of waste drums can be determined accurately using the new approach especially when the waste drums contain multi-gamma emitters. PMID- 22440240 TI - Vinyl chloride exposure and cirrhosis: a systematic review and meta-analysis. AB - BACKGROUND: It has been proposed that vinyl chloride exposure is associated with increased risk of death from cirrhosis, although epidemiologic evidence is limited. METHODS: We analyzed the risk of death from cirrhosis by occupational vinyl chloride exposure by conducting a meta-analysis on seven available studies, including more than 40,000 workers exposed to vinyl chloride mostly in North America and Europe, with a total of 203 deaths from cirrhosis. RESULTS: All epidemiological studies on vinyl chloride exposure and risk of death from cirrhosis resulted in an overall relative risk of 0.73 (95% confidence interval 0.61-0.87). Thus, the epidemiologic evidence does not suggest an excess mortality from cirrhosis in vinyl chloride-exposed workers; this is consistent with histopathological observations in livers of angiosarcoma patients and of vinyl chloride-exposed rodents revealing no signs of cirrhosis. CONCLUSION: Overall, our findings indicate the absence of increased risk of death from cirrhosis in vinyl chloride-exposed workers. PMID- 22440241 TI - Nuclear factor-kappaB predicts outcome in locally advanced rectal cancer patients receiving neoadjuvant radio-chemotherapy. AB - BACKGROUND: NF-kappaB expression has been shown to be responsible for resistance to antineoplastic agents. AIMS: The aim of our study was to investigate the importance of NF-kappaB expression as prognostic factor in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy. METHODS: We retrospectively analysed the immunoreactivity for NF-kappaB in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (chemotherapy and/or radiotherapy) in our Institution between March 2003 and June 2006. RESULTS: Seventy-four consecutive patients were enrolled into this study. Immunohistochemistry analysis for NF-kappaB was performed both in biopsies and in primary tumour samples. NF-kappaB was considered positive when at least 1% of the tumour cells showed nuclear positivity. A significant correlation between a positive NF-kappaB nuclear expression, both in biopsies and in tumour samples, and a worse overall survival was observed. Moreover, median time to progression was significantly shorter in the NF-kappaB-positive subgroup of patients. CONCLUSION: Globally, our findings seem to suggest that NF-kappaB could represent an important parameter able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. It also could be useful in order to select patients to receive adjuvant chemotherapy, intensifying the adjuvant therapy and, in the next future, obviating the use of drugs involving NF-kappaB system in their mechanism of action in NF-kappaB-positive patients. PMID- 22440242 TI - Mineralization of peptide amphiphile nanofibers and its effect on the differentiation of human mesenchymal stem cells. AB - One of the important targets in regenerative medicine is to design resorbable materials that can promote formation of new bone in large skeletal defects. One approach to this challenge is to use a bioactive and biodegradable organic matrix that can promote cellular adhesion and direct differentiation. We have here studied matrices composed of peptide amphiphiles (PAs) that self-assemble into nanofibers and create self-supporting gels under cell culture conditions. The bioactivity of PAs was designed by incorporating in their peptide sequences phosphoserine residues, to promote hydroxyapatite formation in the culture medium, and the cell adhesion epitope RGDS. In osteogenic medium supplemented with calcium the PA nanofibers were found to nucleate spheroidal nanoparticles of crystalline carbonated hydroxyapatite approximately 100 nm in diameter. This mineralization mode is not epitaxial relative to the long axis of the nanofibers and occurs in the presence of serine or phosphoserine residues in the peptide sequence of the amphiphiles. Mixing of the phosphoserine-containing PAs with 5 wt.% RGDS-containing PA molecules does not inhibit formation of the mineral nanoparticles. Quantitative real time reverse transcription polymerase chain reaction and immunohistochemistry analysis for alkaline phosphatase (ALP) and osteopontin expression suggest that these mineralized matrices promote osteogenic differentiation of human mesenchymal stem cells. Based on ALP expression, the presence of phosphoserine residues in PA nanofibers seems to favor osteogenic differentiation. PMID- 22440243 TI - Immunohistochemical investigation of Foxp3 expression in the intestine in healthy and diseased dogs. AB - Intestinal immune regulation including development of oral tolerance is of great importance for the maintenance of intestinal homeostasis. Concerning this, regulatory T cells (Tregs) occupy a pivotal role in cell-mediated immunosuppression. Dysregulation of mucosal immunology leading to an abnormal interaction with commensal bacteria is suggested to play a key role in the pathogenesis of Inflammatory Bowel Disease (IBD) in men and dogs. The aim of this study was to characterise the expression of Foxp3 in the normal canine gut of 18 dogs (mean age: 6.03 years), in 16 dogs suffering from IBD (mean age: 5.05 years), and of 6 dogs with intestinal nematode infection (mean age: 0.87 years) using immunohistochemistry. In the duodenum, Tregs in healthy dogs declined from villi (median: 10.67/62 500 MUm2) to crypts (median: 1.89/62 500 MUm2). Tregs were further increased in the villi of middle-aged dogs (median: 18.92/62 500 MUm2) in contrast to juvenile (median: 3.50/62 500 MUm2) and old (median: 9.56/62 500 MUm2) individuals. Compared to healthy controls, animals suffering from IBD revealed reduced numbers of Tregs in duodenal villi (median: 4.13/62 500 MUm2). Dogs with intestinal nematode infection displayed increased numbers of Tregs (median: 21.06/62 500 MUm2) compared to healthy animals.Age-related changes indicate a progressive establishment of oral tolerance and immunosenescence in the canine elderly. The results further suggest that a defect in Treg homeostasis may be involved in the pathogenesis of canine IBD. In contrast, increased numbers of Tregs in the duodenum may be due to nematode infection. PMID- 22440244 TI - Motor, mental and behavioral developments in infancy are associated with fatty acid pattern in breast milk and plasma of premature infants. AB - The objective of this study was to investigate any association between infants' early development and PUFA concentrations in early breast milk and infants' plasma phospholipids at 44 weeks gestational age. Fifty-one premature infants were included. The quality of general movement was assessed at 3 months, and motor, mental and behavioral development at 3, 6, 10 and 18 months corrected age using Bayley's Scales of Infant Development (BSID-II). Linoleic acid, the major n 6/n-3 FA ratios, Mead acid and the EFA deficiency index in early breast milk were negatively associated with development up to 18 months of age. DHA and AA, respectively, in infants' plasma phospholipids was positively, but the AA/DHA ratio negatively, associated with development from 6 to 18 months of age. Our data suggest that the commonly found high n-6 concentration in breast milk is associated with less favorable motor, mental and behavioral development up to 18 months of age. PMID- 22440245 TI - Morbidity and mortality after the closure of a protective loop ileostomy: analysis of possible predictors. AB - BACKGROUND/AIMS: A diverting loop ileostomy is often created to protect distal colorectal, coloanal and ileoanal anastomoses. Ileostomy closure is associated with somewhat morbidity and mortality. The aim of this study was to determine the morbidity and morbidity related factors of ileostomy closure. METHODOLOGY: Prospectively recorded data of 255 patients who underwent diverting loop ileostomy between October 2000 and May 2011 were analyzed retrospectively. RESULTS: The study consisted of 139 male and 116 female patients with a median age of 54 years (range 17-79) who underwent ileostomy closure. The morbidity rate of ileostomy closure was 18.4% (47 patients) and the mortality rate was 1.2% (3 patients). When patients with morbidity and without morbidity were compared in terms of gender; age, American Society of Anesthesiology Score, primary pathology, surgeon factor; setting of ileostomy creation and time to stoma closure, only American Society of Anesthesiology Score was found as a predictor for morbidities. CONCLUSIONS: Closure of loop ileostomy is a simple procedure with low morbidity and a small but significant risk of mortality. Surgeons must consider the known risks in conjunction with the overall benefit/risk analysis before deciding between a temporary fecal diversion and a discontinuous colonic resection. PMID- 22440246 TI - Efficacy of laparoscopic colorectal resection for risk patients with severe comorbidity. AB - BACKGROUND/AIMS: This study assessed the short term results of laparoscopic colorectal resection for high risk patients. METHODOLOGY: Five hundred and fifty seven consecutive patients underwent an elective laparoscopic colorectal cancer resection by the same surgical team between April 2007 and December 2010. No risk patients in ASA class 1 (Group N, n=222), low risk patients with the systemic disease under the control in ASA class 2 and 3 (Group L, n=320), high risk patients with severe comorbidities in ASA class 4 (Group H, n=15) were respectively compared. RESULTS: The median blood loss count was significantly higher than the other group (N: 26 g, L: 22 g) in group H (59 g; p<0.05). On the other hands, the less lymphadenectomy was performed and a reconstruction with anastomosis was denied in group H. The incidence of postoperative complications was not significantly different in each group (N: 12%, L: 18%, H: 26%; p>0.05). There was the significant difference of the incidence with systemic complication (respiratory failure, ascites and delirium) in group H. The median postoperative hospital stay was not significantly different in each group (POD7; p>0.05). Hospitalization death occurred in three patients (0.5%) by uncontrollability of the systemic disease, two patients in group L and one patient in group H. CONCLUSIONS: Laparoscopic colorectal resection for high risk patients was performed safely without increasing complications and postoperative hospital stay. PMID- 22440247 TI - Neoadjuvant chemotherapy rather than neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer with high tumor burden. AB - BACKGROUND/AIMS: We investigated the characteristics of locally advanced rectal cancer (LARC) patients who had received neoadjuvant chemoradiotherapy (NCRT), and who developed early metastasis during the perioperative period. METHODOLOGY: LARC who were treated and followed-up were included in this study. Patients' files were reviewed retrospectively and the data on patients were recorded. RESULTS: Totally, 182 stage II and III rectal cancer patients who received NCRT were retrospectively evaluated. Seventeen (9.3%) patients were metastatic during the perioperative period. Of them, metastases developed preoperatively in 3 (17.6%) patients after NCRT, while 14 (82.4%) developed metastases postoperatively before adjuvant chemotherapy (CT). Twelve (70.6%) patients had clinical stage T4N+ disease. The median time interval between pathological diagnosis and metastasis development was 4 (3-5) months. The median survival was 24 months. CONCLUSIONS: More effective treatment is warranted in patients with LARC with a high tumor burden. PMID- 22440248 TI - The expression of the phosphatase regenerating liver 3 gene is associated with outcome in patients with colorectal cancer. AB - BACKGROUND/AIMS: The phosphatase of regenerating liver-3 (PRL-3) is over expressed in several human cancers and associated with tumor progression, invasion and metastasis. However, the correlation between PRL-3 expression and clinical outcome in colorectal cancer (CRC) has not been investigated. This study examined the relationship between the relative expression of the PRL-3 gene to the clinicopathological factors and outcomes in patients with CRC. METHODOLOGY: Surgical specimens of cancer tissue and adjacent normal mucosa were obtained from 202 patients with untreated CRC. The relative expression level of PRL-3 mRNA in cancer and in the normal adjacent mucosa was measured using the quantitative real time reverse-transcriptase PCR. RESULTS: PRL-3 expression was higher in cancer tissue than in the adjacent normal mucosa. The tumor location and liver metastasis were found to be related to the PRL-3 expression level. The overall survival differed significantly between patients with high PRL-3 expression and those with low expression. CONCLUSIONS: High expression of the PRL-3 gene might be a useful predictor of poor postoperative outcome in patients with CRC. PMID- 22440249 TI - Elevated serum synuclein-gamma in patients with gastrointestinal and esophageal carcinomas. AB - BACKGROUND/AIMS: We aimed to evaluate whether elevated serum synuclein-gamma levels were of clinical significance as a serological marker in cancer diagnosis and monitoring. METHODOLOGY: Pre-treatment serum synuclein-gamma levels of patients with gastrointestinal and esophageal squamous cell carcinomas, benign disease and healthy controls were analyzed by a specific sandwich ELISA for synuclein-gamma. RESULTS: Statistically significant differences in serum synuclein-gamma levels between patients with colo rectal cancer, gastric adenocarcinomas, esophageal cancer and healthy individuals were observed (p<0.001). When a cut-off value for synuclein-gamma was determined at >=4 ng/mL by receiver operating characteristic curves, sensitivity and specificity were 16.4% and 97.7% in colorectal cancer, 23.0% and 99.3% in gastric adenocarcinomas, and 19.5% and 98.7% in esophageal cancer, respectively. Compared with carcinoembryonic antigen and carbohydrate antigen 19-9, synuclein-gamma was more sensitive in early detection of colorectal cancer (17.3% vs. 9.6% and 7.5%), gastric adenocarcinomas (20.6% vs. 0% and 3.2%) and esophageal cancer (22.2% vs. 3.4% and 0%), respectively. A combined analysis of the above markers yielded incremental positive rates compared with anyone alone. CONCLUSIONS: These results indicated that serum synuclein-gamma provided a promising diagnostic biomarker for early detection and was a complementary biomarker of carcinoembryonic antigen and/or CA19-9 in gastrointestinal and esophageal cancer. PMID- 22440250 TI - Relationship between elevation of glycated albumin to glycated hemoglobin ratio in patients with a high bleeding risk of esophageal varices. AB - BACKGROUND/AIMS: Variceal hemorrhaging due to portal hypertension is a severe complication of liver cirrhosis. Although several biomarkers have been reported as predictors of the presence of varices, it is still difficult to assess the risk of variceal bleeding without esophagogastroduodenoscopy (EGD). The ratio of glycated albumin (GA) to glycated hemoglobin (HbA1c) was reported to increase with the progression of liver fibrosis. The aim of the study was to investigate whether the GA/HbA1c ratio is related to the severity and bleeding-risk of the varices. METHODOLOGY: We measured the GA/HbA1c ratio of HCV-related cirrhotic patients with Child-Pugh class A status and analyzed its relationship with the presence and bleeding risk of varices. RESULTS: The GA/HbA1c ratio was higher in the patients who had the varices with a high risk of hemorrhage than in the patients with a low risk of bleeding. In addition, the GA/HbA1c ratio was higher in patients with varices than that in patients without varices. Furthermore, the GA/HbA1c ratio was the most significantly different parameter of all the factors examined, including the platelet count, prothrombin activity and albumin level. CONCLUSIONS: The GA/HbA1c ratio is increased in patients with varices and with the bleeding risk of the varices. PMID- 22440252 TI - Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. AB - OBJECTIVE: To determine whether the high lipid content of human follicular fluid influences oocyte maturation. DESIGN: Mouse oocytes as substitutes for human oocytes were exposed to follicular fluids of differing lipid content with outcome monitoring. SETTING: Private infertility clinic and university laboratory. PATIENT(S): Seventy-four women seeking assisted reproduction, and gonadotropin stimulated mice. INTERVENTION(S): Assay of follicular fluids for triglyceride and free fatty acids, and stimulation of mouse cumulus-oocyte complexes (COCs) to maturity in vitro in the presence of lipid-rich or lipid-poor follicular fluid. MAIN OUTCOME MEASURE(S): Oocyte lipid content, expression of endoplasmic reticulum stress marker genes, and oocyte maturation assessed in mouse COCs exposed to lipid-rich follicular fluid were compared with complexes exposed to lipid-poor follicular fluid and complexes matured in vivo. RESULT(S): Follicular fluids were obtained from women of known body mass index undergoing oocyte aspiration at a private infertility clinic, and the follicular fluids were assayed for triglyceride and free fatty acids; those with the highest and lowest levels of these lipids were selected. The mouse COCs exposed to lipid-rich follicular fluid during their maturation had increased oocyte lipid content, induction of endoplasmic reticulum stress markers, and impaired oocyte nuclear maturation. CONCLUSION(S): Increased body mass index is associated with elevated triglycerides and free fatty acids in ovarian follicular fluid. Maturation within this lipid-rich environment is detrimental to oocytes. PMID- 22440253 TI - Vitrification carriers and European regulation. PMID- 22440254 TI - Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation. AB - In pancreatic ductal adenocarcinoma (PDAC), the fibroblast growth factor receptor 1 (FGFR-1) IIIb isoform correlates with the inhibition of cancer cell proliferation, migration, and invasion, whereas FGFR-1 IIIc enhances cancer cell proliferation. The FGFR-2 IIIb isoform is expressed in PDAC, and its expression correlates with increased venous invasion. We examined the role of FGFR-2 IIIc in PDAC. FGFR-2 IIIc was expressed in all six pancreatic cancer cell lines examined and was highest in PANC-1 cells. FGFR-2 IIIc was abundant in the cancer cells from 83 of 117 PDAC cases, which correlated with decreased duration to development of liver metastasis after surgery. FGFR-2 IIIc-transfected cells exhibited increased proliferation in vitro and formed larger subcutaneous and orthotopic tumors, the latter producing more liver metastases. Moreover, FGF-2 exerted a more rapid stimulatory effect on the levels of phosphorylated extracellular signal-regulated kinase (p-ERK) in FGFR-2 IIIc stably transfected PANC-1 cells, compared with control cells. FGFR-2 IIIc-transfected cells also formed more spheres and contained more side population cells. Suppression of FGFR 2 IIIc expression inhibited the proliferation of PANC-1 cells, whereas an anti FGFR-2 IIIc antibody inhibited the proliferation and migration of PANC-1 cells. Thus, high FGFR-2 IIIc levels in PDAC contribute to disease aggressiveness and confer to pancreatic cancer cells features suggestive of cancer stem cells, indicating that FGFR-2 IIIc may be a novel and important therapeutic target in PDAC. PMID- 22440255 TI - Age-related dysfunction of the lacrimal gland and oxidative stress: evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice. AB - An imbalance between free radical generation and radical scavenging antioxidant systems results in oxidative stress, which has been associated with cell injury observed in many age-related diseases. The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase-1 (Sod1) in mice leads to many different phenotypes that resemble accelerated aging. In this study we examined the morphologic features and the secretory functions of the lacrimal glands in Sod1(-/-) mice. Lacrimal glands showed atrophy of acinar units; fibrosis; infiltration with CD4(+) T cells, monocytes, and neutrophils; increased staining with both 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine; increases in apoptotic cells; and the presence of the epithelial-mesenchymal transition in senescent Sod1(-/-) mice. Electron microscopy findings revealed evidence of epithelial-mesenchymal transition, presence of swollen and degenerated mitochondria, and the presence of apoptotic cell death in the lacrimal glands of senescent Sod1(-/-) mice. These alterations were also associated with the accumulation of secretory vesicles in acinar epithelial cells, decreased production of both stimulated and nonstimulated tears, and a decline in total protein secretion from the lacrimal glands. Our results suggest that Sod1(-/-) mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated lacrimal gland alterations. PMID- 22440256 TI - Yin Yang 1 plays an essential role in breast cancer and negatively regulates p27. AB - Yin Yang 1 (YY1) is highly expressed in various types of cancers and regulates tumorigenesis through multiple pathways. In the present study, we evaluated YY1 expression levels in breast cancer cell lines, a breast cancer TMA, and two gene arrays. We observed that, compared with normal samples, YY1 is generally overexpressed in breast cancer cells and tissues. In functional studies, depletion of YY1 inhibited the clonogenicity, migration, invasion, and tumor formation of breast cancer cells, but did not affect the clonogenicity of nontumorigenic cells. Conversely, ectopically expressed YY1 enhanced the migration and invasion of nontumorigenic MCF-10A breast cells. In both a monolayer culture condition and a three-dimensional Matrigel system, silenced YY1 expression changed the architecture of breast cancer MCF-7 cells to that resembling MCF-10A cells, whereas ectopically expressed YY1 in MCF-10A cells had the opposite effect. Furthermore, we detected an inverse correlation between YY1 and p27 expression in both breast cancer cells and xenograft tumors with manipulated YY1 expression. Counteracting the changes in p27 expression attenuated the effects of YY1 alterations on these cells. In addition, YY1 promoted p27 ubiquitination and physically interacted with p27. In conclusion, our data suggest that YY1 is an oncogene and identify p27 as a new target of YY1. PMID- 22440257 TI - Interaction of clusterin and matrix metalloproteinase-9 and its implication for epithelial homeostasis and inflammation. AB - Uncontrolled increases of matrix metalloproteinase-9 (MMP-9) activity have been causally linked to epithelial barrier disruption and severe symptoms of inflammatory diseases such as dry eye (DE). The data presented here show that the anti-inflammatory, cytoprotective intracellular and extracellular chaperone protein clusterin (CLU) interacts with MMP-9 both inside and outside epithelial cells. CLU bound very strongly to active MMP-9, with an affinity constant K(D) of 2.63 nmol/L. Unexpectedly, CLU had a much higher affinity for pro-MMP-9 than for active MMP-9 or pro-MMP-2, requiring the N-terminal propeptide domain of pro-MMP 9. The significance of the interaction between CLU and MMP-9 was demonstrated by the observation that CLU prevents stress-induced MMP-9 aggregation and inhibits MMP-9 enzymatic activity. Furthermore, CLU inhibited MMP-9-mediated disintegration of the tight junction structure formed between human epithelial cells. Additionally, CLU inhibited enzymatic activities of MMP-2, MMP-3, and MMP 7. Treatment with proinflammatory cytokines, which are known to increase MMP-9 transcription under inflammatory conditions, reduced the expression of CLU in human epithelial cells. Similarly, in a mouse model of human DE, inflammatory stress depleted CLU in the ocular surface epithelium but allowed MMP-9 to prevail therein. The present results thus provide novel insights into previously unrecognized mechanisms by which CLU maintains fluid-epithelial interface homeostasis, thereby preventing the onset of inflammatory conditions, especially where MMP-9 is actively involved. PMID- 22440258 TI - The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. AB - The Cancer Genome Atlas (TCGA) project has generated gene expression data that divides glioblastoma (GBM) into four transcriptional classes: proneural, neural, classical, and mesenchymal. Because transcriptional class is only partially explained by underlying genomic alterations, we hypothesize that the tumor microenvironment may also have an impact. In this study, we focused on necrosis and angiogenesis because their presence is both prognostically and biologically significant. These features were quantified in digitized histological images of TCGA GBM frozen section slides that were immediately adjacent to samples used for molecular analysis. Correlating these features with transcriptional data, we found that the mesenchymal transcriptional class was significantly enriched with GBM samples that contained a high degree of necrosis. Furthermore, among 2422 genes that correlated with the degree of necrosis in GBMs, transcription factors known to drive the mesenchymal expression class were most closely related, including C/EBP-beta, C/EBP-delta, STAT3, FOSL2, bHLHE40, and RUNX1. Non mesenchymal GBMs in the TCGA data set were found to become more transcriptionally similar to the mesenchymal class with increasing levels of necrosis. In addition, high expression levels of the master mesenchymal factors C/EBP-beta, C/EBP-delta, and STAT3 were associated with a poor prognosis. Strong, specific expression of C/EBP-beta and C/EBP-delta by hypoxic, perinecrotic cells in GBM likely account for their tight association with necrosis and may be related to their poor prognosis. PMID- 22440259 TI - Mitragyna speciosa use in the northern states of Malaysia: a cross-sectional study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The consumption of Mitragyna speciosa (MS) for its psychoactive effects is widely reported amongst people in the villages in Thailand and Malaysia even though its use is illegal. AIM OF THE STUDY: This study examined the pattern of MS use, its reported effects and explored its potential to cause dependence. MATERIALS AND METHODS: We used both convenience and snowball-sampling methods to recruit participants in a border town between two northern states in Malaysia. Face-to-face interviews were conducted with the use of a structured questionnaire on 562 respondents who gave oral consent to participate in the study. RESULTS: The response rate was 91%. The majority of the respondents (88%) reported daily use of MS. The main mode of using MS was by drinking the MS extract as tea (90%). The mean age of starting MS use was 28.3 (SD=8.1) years. A variety of reasons were given for using MS including for social and recreational needs, stamina and physical endurance, pain relief and improved sexual performance. Despite its reported usefulness in weaning off opiate addiction, 460 (87%) admitted they were not able to stop using MS. Only education level had a statistically significant association with the ability to stop or not stop the use of MS (chi(2)=31.0, df=1, p<0.001). Significantly higher proportions of those with a lower education level (38%) were able to stop using MS compared to respondents with a higher education level. CONCLUSIONS: Our study provides important information on the pattern of MS use, its effects and its potential to cause addiction, as there has been growing interest in MS as evidenced by the number of advertisements for its sale on the Internet. Future study is required to explore its psychological and social impact on users. PMID- 22440260 TI - Anti-proliferative and apoptosis induction activities of extracts from Thai medicinal plant recipes selected from MANOSROI II database. AB - ETHONOPHARMACOLOGICAL RELEVANCES: Traditional medicines have long been used by the Thai people. Several medicinal recipes prepared from a mixture of plants are often used by traditional medicinal practitioners for the treatment of many diseases including cancer. The recipes collected from the Thai medicinal text books were recorded in MANOSROI II database. Anticancer recipes were searched and selected by a computer program using the recipe indication keywords including Ma reng and San which means cancer in Thai, from the database for anticancer activity investigation. AIM OF STUDY: To investigate anti-cancer activities of the Thai medicinal plant recipes selected from the "MANOSROI II" database. MATERIALS AND METHODS: Anti-proliferative and apoptotic activities of extracts from 121 recipes selected from 56,137 recipes in the Thai medicinal plant recipe "MANOSROI II" database were investigated in two cancer cell lines including human mouth epidermal carcinoma (KB) and human colon adenocarcinoma (HT-29) cell lines using sulforhodamine B (SRB) assay and acridine orange (AO) and ethidium bromide (EB) staining technique, respectively. RESULTS AND CONCLUSIONS: In the SRB assay, recipes NE028 and, S003 gave the highest anti-proliferation activity on KB and HT29 with the IC(50) values of 2.48+/-0.24 and 6.92+/-0.49MUg/ml, respectively. In the AO/EB staining assay, recipes S016 and NE028 exhibited the highest apoptotic induction in KB and HT-29 cell lines, respectively. This study has demonstrated that the three Thai medicinal plant recipes selected from "MANOSROI II" database (NE028, S003 and S016) gave active anti-cancer activities according to the NCI classification which can be further developed for anti-cancer treatment. PMID- 22440261 TI - Antiparasitic activities of two sesquiterpenic lactones isolated from Acanthospermum hispidum D.C. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Acanthospermum hispidum D.C. are often used by traditional healers in Benin for various diseases and especially for malaria. AIM OF THE STUDY: To identify active compounds from extracts of Acanthospermum hispidum D.CV. leaves previously shown to possess antimalarial properties and analyse in vivo activity and toxicity of crude extracts. MATERIALS AND METHODS: Compounds were isolated from aerial part of Acanthospermum hispidum D.C. and structurally elucidated using extensive spectroscopic analysis. Antiplasmodial activity was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity and in vivo against Plasmodium berghei berghei by the 4-day suppressive test. Selectivity of extract and purified compounds on Plasmodium parasites were evaluated by using MTT test on J774 macrophage like murine cells and WI38 human normal fibroblasts and also against two other parasites: Trypanosoma brucei brucei and Leishmania mexicana mexicana. Acute and sub-acute toxicities of a crude extract were evaluated on mice. RESULTS: Two known sesquiterpenic lactones were isolated: 1 (15-acetoxy-8beta-[(2 methylbutyryloxy)]-14-oxo-4,5-cis-acanthospermolide) and 2 (9alpha-acetoxy-15 hydroxy-8beta-(2-methylbutyryloxy)-14-oxo-4,5-trans-acanthospermolide). 1 and 2 showed in vitro antiplasmodial activity against the chloroquine-sensitive strain (3D7) with IC(50) of 2.9+/-0.5 and 2.23+/-0.09MUM respectively. Only 2 showed a high selectivity index (SI: 18.4) on Plasmodium compared to cytotoxicity against human fibroblasts cell line (WI38). 1 and 2 also showed interesting antiparasitic activities in vitro against Trypanosoma brucei brucei (IC(50) of 2.45+/-0.49 and 6.36+/-1.42MUM respectively) and Leishmania mexicana mexicana (IC(50) of 0.94+/ 0.05 and 2.54+/-0.19MUM respectively). Furthermore, crude acidic water extract and fractions containing one of the two isolated compounds displayed a weak in vivo antimalarial activity against Plasmodium berghei berghei with a long half life causing a delayed effect. In vivo acute (2000mg/kg) and sub-acute (1000mg/kg) toxicity tests on the crude acidic water extract did not show toxicity. CONCLUSION: Crude acidic water extract, fractions and pure isolated compounds from Acanthospermum hispidum showed promising in vitro antiplasmodial activity. Despite our study did not show in vivo acute and subacute toxicities of the crude acidic water extract, its weak in vivo antimalarial activity and the in vitro cytotoxicity of pure compounds and enriched extracts containing 1 and 2 indicate that the aerial parts of Acanthospermum hispidum should be used with caution for malaria treatments. PMID- 22440262 TI - In vitro and in vivo immunomodulatory activities of iridoids fraction from Barleria prionitis Linn. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Barleria prionitis Linn. (Family: Acanthaceae), one of the important Ayurvedic medicinal plant in India, has long been used to treat variety of ailments including swellings, gout, arthritic and rheumatic disorders, nervine and skin diseases, and also acts as immunorestorative. AIM OF THE STUDY: The present study was aimed to explore in vitro and in vivo immunomodulatory activities of the iridoids fraction i.e. n-butanol fraction of methanol extract from Barleria prionitis aerial parts (IFBp). MATERIALS AND METHODS: IFBp was studied for in vitro [nitroblue tetrazolium (NBT) test and neutrophils candidacidal assay] and in vivo immunomodulatory activity on cellular and humoral immune responses to the antigenic challenge by sheep red blood cells (SRBCs) and by neutrophil adhesion test, phagocytic activity and cyclophosphamide induced myelosuppression. The study comprised the preliminary phytochemical screening, HPTLC standardization and maximum tolerable dose determination of IFBp. RESULTS: IFBp (50, 100 and 200MUg/ml) significantly (P<=0.01) increased the intracellular killing activity of stimulated neutrophils assayed by in vitro NBT reduction test and neutrophils candidacidal assay. Pretreatment of IFBp (100 and 200mg/kg; p.o.) evoked a significant increase in percent neutrophils and neutrophils adhesion to nylon fibres. Oral administration of IFBp augmented the humoral immune response to SRBCs, evidenced by increase in antibody titres and dose dependently potentiated the delayed-type hypersensitivity reaction induced by SRBCs in mice. IFBp potentiated significantly (P<=0.01) the macrophage phagocytic activity and ameliorated the red blood cells, total white blood cells and platelets count and haemoglobin concentration, and also restored the myelosuppressive effects induced by cyclophosphamide. The content (% w/w; mean+/ SD, n=3) of main iridoids i.e. shanzhiside methyl ester and barlerin was found to be 21.55+/-2.40 and 10.03+/-1.69 in IFBp of BP, respectively. CONCLUSION: The present investigation reveals that IFBp is a potent immunostimulant, stimulating both the specific and non-specific immune mechanisms. PMID- 22440263 TI - Variations in the reported prevalence of gastroesophageal reflux disease in Taiwan. PMID- 22440264 TI - Antimullerian hormone: a marker for prediction of ovarian function and polycystic ovary syndrome. PMID- 22440265 TI - Risk factors of hypoxia during flexible bronchoscopy use in infants. PMID- 22440266 TI - Does extended prostate needle biopsy improve the concordance of Gleason scores between biopsy and prostatectomy in the Taiwanese population? AB - BACKGROUND: Discordance between the Gleason scores of prostate needle biopsies and radical prostatectomy specimens has been reported by several investigators. We conducted this study to determine if increasing the number of prostate needle biopsies in patients with prostate cancer improves the accuracy of Gleason scores in the Taiwanese population. METHODS: Between March 2000 and September 2009, 281 patients underwent radical prostatectomy at Taipei Veterans General Hospital. All of these patients had prostate cancer that was diagnosed and graded either by extended needle biopsy (121 patients, >= 10 cores/patient, range: 10-13, median: 12) or by traditional sextant transrectal biopsy (160 patients, <10 cores/patient, range: 6-9, median: 6). We analyzed the patients' Gleason scores of their biopsies and radical prostatectomy specimens. RESULTS: The concordance rate, defined as similarity between the Gleason score of a patient's biopsy and prostatectomy specimens, was 57.9% in the extended biopsy group and 45.6% in the nonextended biopsy group (chi(2) test: p = 0.042). The primary Gleason pattern was accurately predicted by extended needle biopsy in 81% of cases (98/121 cases), higher than the 70% accuracy rate of the nonextended biopsies (112/160 cases, p = 0.036). Undergrading was found in 43/121 cases (32%) and 63/160 cases (39.4%) (p = 0.511). However, overgrading was found in 8/121 cases (6.6%) and in 24/160 cases (15.0%) (p = 0.028) by extended and nonextended biopsies, respectively. Forty-seven (16.7%) of those patients who fit the criteria of active surveillance were upgraded to a Gleason score >7 after radical prostatectomy. CONCLUSION: The addition of an extended transrectal needle biopsy increases the accuracy of the Gleason score for predicting the final prostate cancer grade in the Taiwanese population. PMID- 22440267 TI - Clinical characteristics of Acinetobacter baumannii complex bacteremia in patients receiving total parenteral nutrition. AB - BACKGROUND: Acinetobacter baumannii complex (Abc) comprises at least three phenotypically undifferentiated species, including A baumannii, Acinetobacter genomic species 3 (AGS 3) and Acinetobacter genomic species 13TU (AGS 13TU). Abc bacteremia had rarely been described in patients receiving total parenteral nutrition (TPN). In this study, we aimed to determine any differences in the clinical features of patients having TPN and bacteremia due to A baumannii and those due to nonbaumannii Abc (including AGS 3 and AGS 13TU). METHODS: The data of patients who had received TPN and had Abc bacteremia in Taipei Veterans General Hospital between August 1998 and December 2007 were retrospectively reviewed. The Acinetobacter isolates were identified to genomic species level. RESULTS: A total of 23 patients with A baumannii and 23 patients with nonbaumannii Abc (15 AGS 13TU and 8 AGS 3) bacteremia were identified. The two groups of the patients were comparable regarding their gender, age and APACHE II score at the onset of bacteremia. However, several clinical features were different between the two groups of the patients in the univariate analysis. Furthermore, A baumannii isolates were resistant to more classes of antibiotics than nonbaumannii Abc isolates. The multivariate analysis showed that a higher number of patients with A baumannii bacteremia had received TPN for >= 15 days before their onset of bacteremia [odds ratio (OR) 7.214, 95% confidence interval (CI) (1.108-46.989), p = 0.039]. Nevertheless, the 14-day (30.4% vs. 21.7%, p = 0.737) and all-cause in-hospital mortality rate (60.9% vs. 39.1%, p = 0.238) did not differ significantly between these two groups. CONCLUSION: The patients with A baumannii bacteremia demonstrated a longer timeframe in the treatment of TPN prior to the onset of bacteremia than those with nonbaumannii Abc bacteremia, however the clinical outcomes between the two groups of the patients did not differ significantly. PMID- 22440268 TI - Shrinkage of head and neck cancer specimens after formalin fixation. AB - BACKGROUND: We conducted this study to investigate whether formalin fixation is associated with the shrinkage of head and neck cancer specimens. METHODS: Patients scheduled to undergo operation were eligible for enrollment. Fresh specimens were measured immediately in the operating room, and the measurements were repeated after formalin fixation. RESULTS: A total of 100 specimens were collected. Nearly half of them were obtained from the oral cavity (n=49), and a large majority were squamous cell carcinoma (n=69). The average decreases in length, width, and depth after formalin fixation were 1.50mm (4.40%), 1.52 mm (6.18%), and 0.67 mm (4.10%), respectively. There was no significant difference in the shrinkage percentage associated with gender, age, tumor site, tumor size, or histology. CONCLUSION: We found that head and neck cancer specimens shrink after formalin fixation. Therefore, we recommend that the specimen be measured immediately in order to avoid the underestimation of tumor size. PMID- 22440269 TI - Patient controlled epidural analgesia for bilateral versus unilateral total knee arthroplasty: a retrospective study of pain control. AB - BACKGROUND: Patient controlled epidural analgesia (PCEA) has been used commonly for postoperative pain management following total knee arthroplasty (TKA). The purpose of this study was to compare a single standardized PCEA protocol in patients who received unilateral TKA with patients who received simultaneous bilateral TKA. METHODS: From October 2003 to October 2008, 912 patients were enrolled. Patient-machine interaction data were retrieved from PCA machines and stratified into 12 hour intervals. The data were analyzed according to the side of surgery, gender and methods of anesthesia. Patient demographic data, pain scores and side effect scores were compared to evaluate clinical efficacy. RESULTS: There was no significant difference between the unilateral and bilateral TKA groups for pain scores, severity of side effects, and total drug use. However, there was a paradoxical increase in demand, delivery, and demand/delivery ratio of analgesics for unilateral rather than bilateral TKA. This was only noted in the first 12 hours. Both genders demanded more bolus doses than set by the standard protocol. Women with unilateral TKA received more delivery doses. All of the patients who received general anesthesia had a higher demand/delivery ratio while spinal anesthesia patients had no significant ratio difference. CONCLUSION: PCEA provided equal analgesia for patients with unilateral or bilateral TKA. However, the paradoxical increase in demand suggested that psychological factors may play a role in pain perception. A comprehensive pain management program that addresses gender and anesthesia methods in the first 12 hours will improve clinical efficacy and patient satisfaction of PCEA. PMID- 22440270 TI - Relationship between quality of life and aerobic capacity of patients entering phase II cardiac rehabilitation after coronary artery bypass graft surgery. AB - BACKGROUND: This cross-sectional study examined the relationship between patients' aerobic fitness and general health perceptions and how they correspond with functional aerobic impairment (%FAI) and quality of life (QOL). METHODS: One hundred and two patients were administered a version of the World Health Organization Quality of Life brief form questionnaire (WHOQOL-BREF). Then, each patient underwent cardiopulmonary exercise tests to determine their aerobic fitness and %FAI. We performed Pearson's and Spearman's correlation analyses to assess the association between variables on the WHOQOL-BREF questionnaire and the each patient's aerobic fitness. RESULTS: Pearson's correlation coefficient demonstrated a significant association between WHOQOL-BREF scores and peak oxygen uptake (peak VO(2)) in the physical domain (p = 0.006) and environment domain (p = 0.011). Spearman's correlation coefficient also demonstrated a significant association between WHOQOL-BREF scores and the %FAI in the environmental domain (p = 0.036). CONCLUSION: QOL of patients who have undergone coronary artery bypass graft surgery is influenced not only by impaired aerobic fitness but also by poor physical and psychological well-being. The implementation of proper lifestyle modifications and the strengthening of social support networks following CABG surgery are very important for maximizing cardiovascular fitness and improving the QOL of these patients. PMID- 22440271 TI - Efficacy of spinal magnetic stimulation in elderly persons with chronic constipation. AB - BACKGROUND: The development of primary constipation in elderly adults usually has a multifactorial etiology. Slow transit constipation and pelvic floor dysfunction (PFD) are the two most commonly seen constipation subtypes in the elderly. PFD is usually a persistent condition that remains unresponsive to treatment in spite of various therapies currently available to relieve constipation. The aim of this study was to assess the usefulness of spinal magnetic stimulation (SMS) in controlling intractable constipation in elderly patients. METHODS: Nineteen patients over the age of 65 with intractable constipation were enrolled in this study, and participated in a 12-session magnetic conditioning protocol consisting of a 20-minute stimulation session once daily. Colonic transit time (CTT) and the dynamics of evaluation as revealed in defecography were measured, and the Knowles Eccersley-Scott Symptom (KESS) Questionnaire was administered before the intervention, and after finishing the protocol. RESULTS: There was a statistically significant improvement in CTT and defecography following the intervention. The difference in the anorectal angles between resting and evacuation (p = 0.001) and the changes in pelvic floor descent (p = 0.011) both reached significance after the intervention. The mean CTT (p = 0.001), Knowles Eccersley-Scott Symptom score (p = 0.001), frequency of bowel movement (p = 0.005), unsuccessful evacuation (p = 0.018), and time needed for bowel hygiene (p = 0.032) all showed marked improvement after SMS conditioning. CONCLUSION: Our findings reveal that SMS intervention may benefit elderly patients with severe constipation. The amelioration of geriatric bowel dysfunction across the subtypes of slow transit constipation and PFD indicated that SMS, featuring broad-spectrum applications, can be an effective form of adjuvant treatment in the care of elderly adults. PMID- 22440272 TI - Solitary neurofibroma of the pancreas body not associated with type 1 neurofibromatosis. AB - Neurofibromas arise from peripheral nerve cells. They are rarely found within the pancreas, especially not associated with type I neurofibromatosis. Here, we report a case of a neurofibroma in a 44-year-old woman who initially presented with epigastralgia. Imaging revealed one large cystic mass of 5.7 * 8 * 5.8 cm in the pancreatic body, which was resected with distal pancreatectomy. The postoperative course of treatment was without complication, and no signs of recurrence were observed after 1 year and 6 months' follow-up. PMID- 22440273 TI - An omental abscess mimicking an intra-abdominal tumor. AB - Here, we report the case of a 12-year-old boy who presented with intermittent lower abdominal pain; subsequently, an intra-abdominal mass found by abdominal ultrasound. Initially, an intra-abdominal tumor was suspected according to the results of the physical examinations, laboratory data, and imaging studies. A surgical excision was performed, and pathological examination revealed an omental abscess without evidence of intestinal perforation or a residual foreign body. The patient's history consisted solely of receiving an open appendectomy for a ruptured appendicitis 2 years prior. This is an extremely rare case of a post appendectomy omental abscess forming after such a long interval, but no evidence of residual appendiceal tissue or foreign bodies could be identified. PMID- 22440274 TI - The combat experience of military surgical assets in Iraq and Afghanistan: a historical review. AB - BACKGROUND: The Forward Surgical Team and Combat Support Hospital have been used extensively only during the past decade in Iraq and Afghanistan. The scope of their operational experience and historical development remain to be described. METHODS: The literature was searched to obtain publications regarding the historical development of Forward Surgical Teams and Combat Support Hospitals, as well as their surgical experiences in Iraq and Afghanistan. Relevant publications were reviewed in full and their results summarized. RESULTS: The doctrine behind the use of modern military surgical assets was not well developed at the start of the Iraq and Afghanistan conflicts. The Forward Surgical Team and Combat Support Hospital were used in practice only over the past decade. Because of the nature of these conflicts, both types of modern military surgical assets have not been used as intended and such units have operated in various roles, including combat support elements and civilian medical treatment facilities. CONCLUSIONS: As more research comes to light, a better appreciation for the future of American military medicine and surgery will develop. PMID- 22440275 TI - Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. AB - OBJECTIVE: To assess the efficacy and safety of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye in eyes with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: Multicenter, randomized, prospective, controlled trial. PARTICIPANTS: One hundred eighty-nine eyes with macular edema secondary to CRVO. METHODS: Eyes were randomized 3:2 to receive VEGF Trap-Eye 2 mg or sham injection monthly for 6 months. MAIN OUTCOME MEASURES: The proportion of eyes with a >=15-letter gain or more in best-corrected visual acuity (BCVA) at week 24 (primary efficacy end point), mean changes in BCVA and central retinal thickness (CRT), and proportion of eyes progressing to neovascularization of the anterior segment, optic disc, or elsewhere in the retina. RESULTS: At week 24, 56.1% of VEGF Trap-Eye treated eyes gained 15 letters or more from baseline versus 12.3% of sham-treated eyes (P<0.001). The VEGF Trap-Eye treated eyes gained a mean of 17.3 letters versus sham-treated eyes, which lost 4.0 letters (P<0.001). Central retinal thickness decreased by 457.2 MUm in eyes treated with VEGF Trap-Eye versus 144.8 MUm in sham-treated eyes (P<0.001), and progression to any neovascularization occurred in 0 and 5 (6.8%) of eyes treated with VEGF Trap Eye and sham-treated eyes, respectively (P = 0.006). Conjunctival hemorrhage, reduced visual acuity, and eye pain were the most common adverse events (AEs). Serious ocular AEs were reported by 3.5% of VEGF Trap-Eye patients and 13.5% of sham patients. Incidences of nonocular serious AEs generally were well balanced between both groups. CONCLUSIONS: At 24 weeks, monthly intravitreal injection of VEGF Trap-Eye 2 mg in eyes with macular edema resulting from CRVO improved visual acuity and CRT, eliminated progression resulting from neovascularization, and was associated with a low rate of ocular AEs related to treatment. PMID- 22440276 TI - Hyporeflective wedge-shaped band in geographic atrophy secondary to age-related macular degeneration: an underreported finding. AB - OBJECTIVE: To describe and interpret the frequently observed spectral-domain optical coherence tomography (SD-OCT) finding of a marked hyporeflective wedge shaped structure at the boundaries of the areas of atrophy. DESIGN: A prospective, longitudinal follow-up study. PARTICIPANTS: Consecutive patients (n = 71) 50 years of age and older with geographic atrophy (GA) secondary to age related macular degeneration (AMD) were examined between January 2010 and June 2011. METHODS: Patients were evaluated with the use of imaging techniques that included 35 degrees fundus photography, infrared, fundus autofluorescence (FAF), and SD-OCT. Visualization of the fundus with FAF was done simultaneously with OCT. Two acquisition protocols were followed: a macular cube for coverage (19 horizontal B-scans centered on the fovea) and high-resolution horizontal B-scan for qualitative foveal detail. MAIN OUTCOMES MEASURES: Estimation of the prevalence of a hyporeflective wedge-shaped band among patients with GA. RESULTS: A marked hyporeflective wedge-shaped structure, with its base on Bruch's membrane and its apex pointing toward the inner limit of the outer plexiform layer (OPL) adjacent to the margin between the atrophied area and the preserved retina, was observed in 72.9% of eyes (70/96; 95% confidence interval, 63.9-82.0). This hyporeflective band appeared to be within the OPL. Using eccentric SD-OCT acquisition, the boundaries between the outer nuclear layer (ONL) and Henle's fiber layer (HFL) were well defined, showing that the ONL ends before the margin of atrophy of the retinal pigment epithelium (RPE). A narrow hyperreflective band separated the margin of the ONL and RPE from the hyporeflective band, already within the atrophic area. CONCLUSIONS: A hyporeflective wedge-shaped structure appears frequently within the boundaries of the OPL in patients with GA secondary to AMD, corresponding to an increase in the width of the HFL, presumably because of axonal swelling or interaxonal edema. This finding may improve the interpretation of SD-OCT images of the outer layers, may help in understanding better the interactions between photoreceptor cells and the RPE, and may help in the development of monitoring techniques and therapies for GA secondary to AMD. PMID- 22440277 TI - Relative breed contributions to neutral genetic diversity of a comprehensive representation of Iberian native cattle. AB - This study is aimed at establishing priorities for the optimal conservation of genetic diversity among a comprehensive group of 40 cattle breeds from the Iberian Peninsula. Different sets of breed contributions to diversity were obtained with several methods that differ in the relative weight attributed to the within- and between-breed components of the genetic variation. The contributions to the Weitzman diversity and the expected heterozygosity (He) account for between- and within-breed variation only, respectively. Contributions to the core set obtained for several kinship matrices, incorporate both sources of variation, as well as the combined contributions of Ollivier and Foulley and those of Caballero and Toro. In general, breeds that ranked high in the different core set applications also ranked high in the contribution to the global He, for example, Sayaguesa, Retinta, Monchina, Berrenda en Colorado or Marismena. As expected, the Weitzman method prioritised breeds with low contributions to the He, like Mallorquina, Menorquina, Berrenda en Negro, Mostrenca, Vaca Palmera or Mirandesa, all showing highly negative contributions to He - that is, their removal would significantly increase the average He. Weighing the within- and between-breed components with the FST produced a balanced set of contributions in which all the breeds ranking high in both approaches show up. Unlike the other methods, the contributions to the diversity proposed by Caballero and Toro prioritised a good number of Portuguese breeds (Arouquesa, Barrosa, Mertolenga and Preta ranking highest), but this might be caused by a sample size effect. Only Sayaguesa ranked high in all the methods tested. Considerations with regard to the conservation scheme should be made before adopting any of these approaches: in situ v. cryoconservation, selection and adaptation within the breeds v. crossbreeding or the creation of synthetic breeds. There is no general consensus with regard to balancing within- and between-breed diversity and the decision of which source to favour will depend on the particular scenario. In addition to the genetic information, other factors, such as geographical, historical, economic, cultural, etc., also need to be considered in the formulation of a conservation plan. All these aspects will ultimately influence the distribution of resources by the decision-makers. PMID- 22440278 TI - Polymorphisms in the autosomal genes for mitochondrial function TFAM and UCP2 are associated with performance and longevity in dairy cows. AB - The autosomal genes mitochondrial transcription factor A (TFAM) and uncoupling protein 2 (UCP2) are both involved in moderating mitochondrial energy production. This study investigated single nucleotide polymorphisms (SNPs) in TFAM and UCP2 and their associations with growth, fertility, milk production and survival in UK dairy cows. Holstein-Friesian heifers (n = 509) were recruited at birth and monitored until they either reached the end of their second lactation or were culled. Weight, height, length and girth were measured at 1, 6 and 15 months of age to assess growth. Fertility records were obtained for both heifers and cows and production traits (milk per day, peak yield and 305-day yield) were recorded in the first and second lactation. Mixed model and survival analyses revealed that TFAM3 GG homozygotes, representing 49% of the population, were larger than the AG heterozygotes throughout the growing period, had worse fertility, produced less milk in both lactations and were more likely to be culled. TFAM3 AA homozygotes (7% of population) were generally smaller as heifers, had slightly worse fertility and also produced less milk. This suggests a clear advantage for maximizing the heterozygotic population for this SNP. Furthermore, the results for milk per day suggest an overdominant effect, as both homozygotes of TFAM3 had significantly lower yields than the heterozygote. For UCP2, the minority CG heterozygotes (6% of population) were larger as heifers, had a reduced age at first conception and a delayed return to cyclicity after calving, when compared against the majority (94%) GG homozygotes. PMID- 22440279 TI - Effects of ad libitum and restricted feeding on early production performance and body composition of Yorkshire pigs selected for reduced residual feed intake. AB - Residual feed intake (RFI), defined as the difference between observed and expected feed intake based on growth and backfat, has been used to investigate genetic variation in feed efficiency in cattle, poultry and pigs. However, little is known about the biological basis of differences in RFI in pigs. To this end, the objective of this study was to evaluate the fifth generation of a line of pigs selected for reduced RFI against a randomly selected Control line for performance, carcass and chemical carcass composition and overall efficiency. Here, emphasis was on the early grower phase. A total of 100 barrows, 50 from each line, were paired by age and weight (22.6 +/- 3.9 kg) and randomly assigned to one of four feeding treatments in 11 replicates: ad libitum (Ad), 75% of Ad (Ad75), 55% of Ad (Ad55) and weight stasis (WS), which involved weekly adjustments in intake to keep body weight (BW) constant for each pig. Pigs were individually penned (group housing was used for selection) and were on treatment for 6 weeks. Initial BW did not significantly differ between the lines (P > 0.17). Under Ad feeding, the low RFI pigs consumed 8% less feed compared with Control line pigs (P < 0.06), had less carcass fat (P < 0.05), but with no significant difference in growth rate (P > 0.85). Under restricted feeding, low RFI pigs under the Ad75 treatment had a greater rate of gain while consuming the same amount of feed as Control pigs. Despite the greater gain, no significant line differences in carcass composition or carcass traits were observed. For the WS treatment, low RFI pigs had similar BW (P > 0.37) with no significant difference in feed consumption (P > 0.32). Overall, selection for reduced RFI has decreased feed intake, with limited differences in growth rate but reduced carcass fat, as seen under Ad feeding. Collectively, results indicate that the effects of selection for low RFI are evident during the early grower stage, which allows for greater savings to the producer. PMID- 22440280 TI - Dietary addition of Lactobacillus rhamnosus GG impairs the health of Escherichia coli F4-challenged piglets. AB - Lactobacillus rhamnosus GG (LGG) is a probiotic for humans and is normally not found in pigs; however, it has been shown to protect the human-derived intestinal Caco-2 cells against the damage induced by an important intestinal pathogen, enterotoxigenic Escherichia coli F4 (ETEC). An experiment was conducted to test whether the dietary addition of LGG improves the growth and health of weaned pigs when orally challenged by E. coli F4. Thirty-six pigs were weaned at 21 days and assigned to a standard weaning diet with or without 1010 CFU LGG (ATCC 53103) per day. The pigs, individually penned, were orally challenged with 1.5 ml of a 1010 CFU E. coli F4 suspension on day 7 and slaughtered on day 12 or 14. With the addition of LGG, the average daily gain and the average daily feed intake were reduced after the challenge with ETEC and for the entire trial (P < 0.05). The average faecal score tended to worsen from day 11 to the end of the trial and the concentration of ETEC in the faeces tended to increase (P = 0.07) with the LGG supplementation. The counts of lactic acid bacteria, enterobacteria and yeasts in the colonic digesta were not affected. The pH values in ileal, colonic and caecal digesta, and the small intestine size were also unchanged. Regardless of the site of measurement (duodenum, jejunum or ileum), a trend of decreased villus height was seen with LGG (P = 0.10). Crypt depth and villus to crypt ratio were unchanged by the diet. A gradual increase of total seric IgA was seen after 1 week and after the challenge, in the control (P < 0.05), but not in the treated group. After the challenge, the LGG reduced the total IgA in the blood serum (P < 0.05), v. the control. The total IgA in the saliva and in the jejunum secretion were not affected by the diet. The F4-specific IgA activity was not affected by the diet at all the samplings. Our result shows that, the administration of LGG do not prevent or reduce the detrimental effect of the E. coli F4 infection on the growth performance and health status of weaned piglet. PMID- 22440281 TI - Stress reactivity and its relationship to beef quality in Nguni steers supplemented with Acacia karroo leaves. AB - The objective of this study was to determine the levels of catecholamines and their relationship to beef quality in Nguni steers fed on Acacia karroo leaves. A total of 30 19-month-old steers were randomly assigned to A. karroo leaves (AK), sunflower cake (SF) and the control with no supplement (CN) diets. The AK and SF diets provided the steers with an additional 150 g of protein per day for 60 days. Catecholamine levels were determined from urine samples collected from each steer before and after slaughter. The Musculus longissimus thoracis et lumborum was sampled for selected meat quality measurements. Nguni steers on the CN diet had higher (P < 0.05) concentrations of post-mortem urinary norepinephrine and dopamine compared with those that received the AK and SF diets. Norepinephrine was negatively linearly related (P < 0.05) to the Warner-Bratzler shear force value of meat aged for 21 days and cooking loss of meat aged for 2 days (CL2) in steers that were given the SF diet. Meat pH and drip loss values were inversely related (P < 0.05) to epinephrine concentration in steers that received the AK diet. Dopamine concentration was negatively linearly related (P < 0.05) to water holding capacity and CL2 for steers on the CN diet. For steers on the CN diet, lightness (L*) values increased (P < 0.05) with increase in dopamine concentration. It was concluded that stress responsiveness and its relationship to certain beef quality attributes could be positively manipulated by supplementation with A. karroo leaves. PMID- 22440282 TI - Fenugreek (Trigonella foenum-graecum L.) as an alternative forage for dairy cows. AB - Fenugreek is a novel forage crop in Canada that is generating interest as an alternative to alfalfa for dairy cows. To evaluate the value of fenugreek haylage relative to alfalfa haylage, six, second lactation Holstein cows (56 +/- 8 days in milk), which were fitted with rumen cannulas (10 cm i.d., Bar Diamond Inc., Parma, ID, USA) were used in a replicated three * three Latin square design with 18-day periods. Diets consisting of 400 g/kg haylage, 100 g/kg barley silage and 500 g/kg concentrate on a dry matter (DM) basis were fed once daily for ad libitum intake. The haylage component constituted the dietary treatments: (i) Agriculture and Agri-Food Canada F70 fenugreek (F70), (ii) Crop Development Center Quatro fenugreek (QUAT) and (iii) alfalfa (ALF). DM intake (DMI), milk yield and milk protein and lactose yields were higher (P < 0.001) for cows fed ALF than fenugreek (FEN, average of F70 and QUAT). Milk fat of cows fed FEN contained lower concentrations of saturated, medium-chain and hypercholestrolemic fatty acids (FAs; P < 0.05) than that of cows fed ALF. Apparent total tract digestibility of DM and nutrients was not affected by treatments. Similarly, individual ruminal volatile FA concentrations and rumen pH (5.9) were not affected by treatments. Rumen ammonia-N concentration was higher for FEN than ALF (P < 0.001). Estimates of neutral detergent fiber (NDF) passage rate (P < 0.05) and NDF turnover rate (P < 0.001) in the rumen were higher for ALF than FEN. Our results suggest that although the digestibility of the FEN diets was not different from that of the ALF diet, fenugreek haylage has a lower feeding value than ALF for lactating dairy cows due in part to lower DMI and subsequently lower milk yield. PMID- 22440283 TI - Birth weight and postnatal dietary protein level affect performance, muscle metabolism and meat quality in pigs. AB - Intrauterine growth restriction (IUGR), resulting in low birth body weight (LBW) occurs naturally in pigs. However, IUGR may also cause persistent changes in physiology and metabolism resulting in poorer performance, organogenesis and meat quality. As IUGR pigs have a lower daily gain from birth to slaughter they may differ in utilization of nutrients and requirements for dietary protein compared with their larger littermates. Thus, the objective in this study was to examine the interaction between birth body weight (BW) and the postnatal dietary protein level, in relation to postnatal performance, organogenesis, muscle metabolism and meat quality. The experiment was carried out with offspring from 16 purebred Danish Landrace gilts mated to Danish Landrace boars. The female and entire male pigs with LBW that survived at weaning were compared with the female and male pigs with the highest/high birth body weight (HBW) within each litter. The offspring were reared individually from weaning and were fed ad libitum a diet containing either a normal level of protein (NP) for optimal growth or an isocaloric diet containing a 30% lower protein content (LP) from 3 weeks to 150 days of age. At slaughter, we found no interactions between birth weight group and dietary protein level for any of the measured traits. The relative crown-rump length (cm/kg) at birth indicates that LBW pigs were thinner than HBW pigs. Daily gain and feed intake were reduced by 14% and 10%, respectively, while the kg feed/kg gain was slightly increased by 3% in LBW pigs compared with HBW pigs. The LP diet reduced daily gain by 27% due to reduced feed intake and increased kg feed/kg gain by 12% and 21%, respectively compared with the NP diet. LBW male pigs produced meat with a higher shear force than male HBW pigs and also LP pigs produced meat with higher shear force than NP pigs. The activity of lactate dehydrogenase in the Longissimus dorsi muscle (LD) was reduced in pigs fed the LP diet. Calpastatin was increased in LD of LBW pigs and decreased in pigs fed the NP diet. In conclusion, these results suggest a rejection of our hypothesis that low birth weight littermates have a lower requirement for dietary protein compared with heavy weight littermates. Furthermore, LBW male pigs and LP fed pigs of both genders produced less tender meat than HBW pigs or NP fed pigs, respectively. PMID- 22440284 TI - Production and composition of Iberian sow's milk and use of milk nutrients by the suckling Iberian piglet. AB - Sixteen purebred Iberian (IB) sows were used in two consecutive trials to determine the efficiency of conversion of sow's milk into piglet body weight (BW) gain and the relationship between milk protein and body protein retention and between milk energy yield and body energy retention in the nursing IB piglet. In each trial, four sows were selected in order to evaluate their milk production, litter growth and nutrient balance measurements, together with four additional sows for milk sampling. Litter size was equalized to six piglets. Daily milk yield (MY) was determined weekly by the weigh-suckle-weigh technique over a 34 day lactation period. Piglets were weighed individually at birth and then weekly from day 5 of lactation. Milk samples were collected on days 5, 12, 19, 26 and 34 post partum. The comparative slaughter procedure was used to determine piglet nutrient and energy retention. One piglet from each litter was slaughtered at birth and four on the morning of day 35. Total MY was on average 5.175 +/- 0.157 kg/day. The average chemical composition (g/kg) of the milk was 179 +/- 4 dry matter, 53.4 +/- 1.0 CP, 58.5 +/- 3.8 fat, 10.4 +/- 0.3 ash and 56.9 +/- 2.3 lactose. Milk gross energy (GE) was 4.626 +/- 0.145 MJ/kg. Milk intake per piglet tended to increase in trial 2 (832 v. 893 g/day; P = 0.066). Piglet BW gain contained (g/kg) 172.1 +/- 1.3 protein, 151.5 +/- 3.5 fat, 41.4 +/- 0.6 ash and 635 +/- 3 water and 10.127 +/- 0.126 MJ GE/kg. Throughout the 34-day nursing period, the piglets grew at an average rate of 168 +/- 3 g/day. The ratio of daily piglet BW gain to daily MY was 0.195 +/- 0.002 g/g and the gain per MJ milk GE intake was 41.9 +/- 0.5 g/MJ. The overall efficiency of protein accretion (g CP gain/g CP milk intake) was low and declined in trial 2 (0.619 v. 0.571; P = 0.016). Nutrient and energy deposition between birth and weaning were 27.4 +/- 0.5 g/day protein, 24.2 +/- 0.8 g/day fat and 1615 +/- 40 kJ/day energy. Piglet energy requirements for maintenance were 404 kJ metabolizable energy (ME)/kg BW0.75. ME was used for growth with a net efficiency of 0.584. These results suggest that poor efficiency in the use of sow's milk nutrients rather than a shortage in milk nutrient supply might explain the low growth rate of the suckling IB piglet. PMID- 22440285 TI - Nitric oxide and meiotic competence of porcine oocytes. AB - Reproductive biotechnology such as in vitro fertilization, the creation of transgenic animals or cloning by nuclear transfer depends on the use of fully grown, meiotically competent oocytes capable of completing meiotic maturation by reaching the stage of metaphase II. However, there exists only a limited quantity of these oocytes in the ovaries of females. In view of their limited number, growing oocytes without meiotic competence represent a possible source. The mechanisms controlling the acquisition of meiotic competence, however, are still not completely clear. A gas with a short half-life, nitric oxide (NO), produced by NO-synthase (NOS) enzyme can fulfill a regulatory role in this period. The objective of this study was to ascertain the role of NO in the growth phase of pig oocytes and its influence on the acquisition of meiotic competence with the help of NOS inhibitors, NO donors and their combinations. We demonstrated that the selective competitive iNOS inhibitor aminoguanidine and also the non selective NOS inhibitor l-NAME block meiotic maturation of oocytes with partial or even full meiotic competence at the very beginning. NOS inhibitors influence even competent oocytes in the first stage of meiotic metaphase. However, blockage is less effective than at the beginning of meiotic maturation. The number of parthenogenetically activated competent oocytes greatly increased in a pure medium after inhibitor reversion. A large quantity of NO externally added to the in vitro cultivation environment disrupts the viability of oocytes. The effectiveness of the inhibitor can be reversed in oocytes by an NO donor in a very low concentration. However, the donor is not capable of pushing the oocytes farther than beyond the first stage of meiotic metaphase. The experiments confirmed the connection of NO with the growth period and the acquisition of meiotic competence. However, it is evident from the experiments that NO is not the only stimulus controlling the growth period. PMID- 22440286 TI - The effects of short-term manipulation of thyroid hormone status coinciding with primary wool follicle development on fleece characteristics in Merino sheep. AB - Thyroidectomy surgery performed late in gestation results in perturbations in wool follicle development in foetal sheep, showing the importance of thyroid hormones for wool follicle development. The aim of this study was to determine the influence of transient manipulation of thyroid hormone status at a time corresponding with foetal primary wool follicle initiation. Pregnant Merino ewes (n = 12 per treatment) were treated daily between gestational days 55 and 64 with control (vehicle), exogenous thyroxine (T4) or propylthiouracil (PTU), an inhibitor of T4 synthesis, and conversion to the active form of the thyroid hormone (triiodothyronine). There were no significant differences in birth weight, gestational lengths and birth coat scores of the resultant lambs. The total primary and secondary follicle densities were significantly lower in lambs exposed to exogenous T4 compared with other treatments (P < 0.05). However, the T4 group displayed a higher proportion of mature secondary follicles (reflected by increased mature secondary follicle densities and mature secondary/primary follicle ratios) than the other treatment groups (P < 0.05). The skin morphology of the lambs differed 12 months later, with the T4 group having significantly higher total follicle densities compared with the PTU group, largely attributed to increased mature and total secondary follicle densities. However, this increase in wool follicle densities did not translate to differences in the fleece yields and weight, fibre diameter, staple lengths or any other fibre parameters. This study showed that transient manipulation of thyroid hormone status during foetal primary follicle initiation does have long-term consequences on the morphology of wool follicles, in particular the maturity of secondary wool follicles. PMID- 22440287 TI - Artificial long days in addition to exogenous melatonin and daily contact with bucks stimulate the ovarian and oestrous activity in Mediterranean goat females. AB - One experiment was conducted to determine whether the treatment with artificial long days and exogenous melatonin can induce reproductive activity during spring (seasonal anoestrus) in Mediterranean goats that are in daily contact with bucks and whether this treatment causes a variation in the reactivation of the reproductive activity in the normal breeding season. The experiment started on 4 November 2005 and finished on 27 October 2006. Thirty-four adult and barren does were used, distributed into two groups balanced according to their live weight (LW) and body condition score (BCS). Seventeen females were exposed to long days (16 h of light/day) from 14 November 2005 to 20 February 2006. On 20 February, they received one s.c. melatonin implant (LD-M group) and were exposed to natural photoperiodic changes in an open shed. The other females during the experiment were placed in an open shed under natural photoperiod and remained as the control group (C group). The C and LD-M groups were keeping in contact with males during the whole experiment. During the experiment, the LW, BCS and plasma progesterone concentrations were measured weekly, oestrous activity was tested daily using entire aproned bucks, and ovulation rate was evaluated by laparoscopy 7 days after positive identification of the oestrus. A clear treatment-time interaction was observed for plasma progesterone concentrations (P < 0.001), with a period of high progesterone concentrations during the natural seasonal anoestrus in the LD M group. Although 94.1% of females in the LD-M group presented ovarian activity during this period, no female in group C did. Resumption of ovarian activity in the subsequent natural breeding season was 2 weeks later in the LD-M group in comparison with group C (P < 0.05). We can conclude that in Mediterranean goat breeding systems, when females are in daily contact with bucks, the treatment with 3 months of long days and melatonin implant at the end of the light photoperiodic treatment can induce ovarian and oestrous activity during the seasonal anoestrus. Finally, this treatment causes a short delay in the subsequent reactivation of ovarian activity in the natural breeding season. PMID- 22440288 TI - Effect of exogenous insulin and fasting on growth hormone receptor and IGF-I expression in the pre-ovulatory follicle of ewes. AB - The aim of this study was to investigate the effect of fasting and exogenous insulin administration on the expression of growth hormone receptor (GHR) and IGF I mRNA in the pre-ovulatory follicle of ewes. Fifteen ewes received an intravaginal progesterone releasing device that was removed 6 days later (day of removal = day 0). On day -2, the ewes were divided into three groups: (i) fasting group (n = 5) that was fasted from day -2 to day 2; (ii) control group (n = 5) that received a maintenance diet; and (iii) insulin group (n = 5) that received insulin injections (0.25 IU/kg) every 12 h from day -2 to day 2 under the same diet as the control group. Follicular samples were obtained on day 2. Fasting increased plasma non-esterified fatty acids concentrations from day -1 to day 2 (P < 0.001). There was no difference (P > 0.05) in the number of follicles, although there was a tendency for an increase in the pre-ovulatory follicle diameter for the insulin group in comparison to the control group (P = 0.12). Thecal GHR mRNA expression was very low and was considered insignificant. Moreover, granulosa cells GHR mRNA expression increased (P < 0.05) in the insulin group. Expression of IGF-I mRNA was not different among groups in both tissues. In conclusion, insulin administration increases GHR mRNA but not IGF-I mRNA expression in granulosa cells of the pre-ovulatory follicle. However, fasting did not change the pattern of GHR/IGF-I mRNA expression in the pre-ovulatory follicle. PMID- 22440289 TI - Piglets' weaning behavioural response is influenced by quality of human-animal interactions during suckling. AB - The aim of this study was to compare the short-term post-weaning behaviour of piglets treated either neutrally or aversively during the suckling period. A total of 24 lactating sows and their litters were housed in different rooms according to treatment. A female experimenter (P1) was in charge of feeding and cleaning from days 10 to 27 after birth. For the aversive treatment (Aver), P1 was noisy, moved harshly and unpredictably and shouted frequently during routine cleaning of facilities and animal handling. For the neutral treatment (Neut), P1 used a soft tone of voice and was careful during the same routine. At weaning, the avoidance response of piglets to an approaching experimenter in a novel place was assessed in four piglets from each litter. Scores ranged from 1 (experimenter could touch piglet) to 4 (piglet escaped as soon as person moved). The test was repeated twice, with a 1-h interval, with P1, who wore blue trousers and white T shirt, and a second handler unfamiliar to the piglets (P2, who wore blue coveralls). Thereafter, litters from the same treatment were mixed and housed in separate rooms, balanced for gender and live weight (n = 12 groups of 4 piglets/treatment). Behaviour time budgets were registered by scan sampling every 2-min, for 4 h per day, for 4 days. Piglets were weighed at birth, at weaning and on day 5. Effects of treatment and handler on responses to the avoidance test were analysed with non-parametric tests and effects of treatment with a mixed model for repeated measures. Avoidance score was higher for Aver than Neut piglets when tested with P1 (P = 0.04) but not with P2 (P = 0.8). When piglets' responses to the different handlers were compared within each treatment, no significant differences were found. Frequencies of resting were lower (P < 0.001), whereas escape attempts (P < 0.03), agonistic interactions (P < 0.02) and frequency of presence at feeder (P < 0.001) were higher in the Aver than in the Neut groups. Feed and water intake and weight gain did not differ between treatments. We conclude that 4-week-old piglets can discriminate a handler according to the nature of treatment received during suckling. In addition, piglets treated aversively seem to have more difficulty adapting to weaning than those treated neutrally during the suckling period. PMID- 22440290 TI - Grassland systems of red meat production: integration between biodiversity, plant nutrient utilisation, greenhouse gas emissions and meat nutritional quality. AB - Government policies relating to red meat production take account of the carbon footprint, environmental impact, and contributions to human health and nutrition, biodiversity and food security. This paper reviews the impact of grazing on these parameters and their interactions, identifying those practices that best meet governments' strategic goals. The recent focus of research on livestock grazing and biodiversity has been on reducing grazing intensity on hill and upland areas. Although this produces rapid increases in sward height and herbage mass, changes in structural diversity and plant species are slower, with no appreciable short term increases in biodiversity so that environmental policies that simply involve reductions in numbers of livestock may not result in increased biodiversity. Furthermore, upland areas rely heavily on nutrient inputs to pastures so that withdrawal of these inputs can threaten food security. Differences in grazing patterns among breeds increase our ability to manage biodiversity if they are matched appropriately to different conservation grazing goals. Lowland grassland systems differ from upland pastures in that additional nutrients in the form of organic and inorganic fertilisers are more frequently applied to lowland pastures. Appropriate management of these nutrient applications is required, to reduce the associated environmental impact. New slurry-spreading techniques and technologies (e.g. the trailing shoe) help reduce nutrient losses but high nitrogen losses from urine deposition remain a key issue for lowland grassland systems. Nitrification inhibitors have the greatest potential to successfully tackle this problem. Greenhouse gas (GHG) emissions are lower from indoor-based systems that use concentrates to shorten finishing periods. The challenge is to achieve the same level of performance from grass-based systems. Research has shown potential solutions through the use of forages containing condensed tannins or establishing swards with a high proportion of clover and high-sugar grasses. Relative to feeding conserved forage or concentrates, grazing fresh grass not only reduces GHG emissions but also enhances the fatty acid composition of meat in terms of consumer health. It is possible to influence biodiversity, nutrient utilisation, GHG emissions and the nutritional quality of meat in grass-based systems, but each of these parameters is intrinsically linked and should not be considered in isolation. Interactions between these parameters must be considered carefully when policies are being developed, in order to ensure that strategies designed to achieve positive gains in one category do not lead to a negative impact in another. Some win-win outcomes are identified. PMID- 22440291 TI - The herd, a source of flexibility for livestock farming systems faced with uncertainties? AB - 'Adapt to endure' has become a necessity in agriculture, but the means to do so remain largely undefined. The aim of this literature review is to analyse how the herd contributes to a livestock farming system's capacity to adapt to a changing world and evolve when the future is uncertain. We identify six categories of elements linked to the herd, called 'sources of flexibility', that are used to manage perturbation. The first three are: using the animal's adaptive capacities, using the diversity of species and breeds and combining the diversity of animal products. The last three are: organising the mobility of animals and livestock farmers, juggling the herd numbers and mastering the balance between productivity and herd survival. These sources of flexibility are described in the literature by studying the different ways in which they are used. For example, the 'juggle herd numbers' source is described by volume, categories of animals, type of transfer, such as births, purchases or gifts, and timing of use, especially linked to the timing of the perturbation. Identified studies also compare or rank sources and analyse the connections between them. The flexibility framework (management science) is used for this analysis according to the levels of organisation of a livestock farming system: a strategic level referring to long term options and to the capacity to modify the system structure, and an operational level referring to adjustment decisions during the productive cycle, the presence or absence of intervention by the livestock farmer, and the time scales involved. We conclude that the decision to use one or another source (in terms of modalities, alternatives, scheduling and combinations) is made according to the production objectives, the structural means, the type/frequency/intensity of perturbations and the context/environment. Consequently, the flexibility of a livestock farming system cannot be assessed in absolute terms. Enhancing flexibility needs management of all elements and scales involved (and not only the herd), and requires diversity to be organised at different scales. PMID- 22440292 TI - The sociocultural sustainability of livestock farming: an inquiry into social perceptions of dairy farming. AB - Over the past 50 years, the scale and intensity of livestock farming have increased significantly. At the same time, Western societies have become more urbanised and fewer people have close relatives involved in farming. As a result, most citizens have little knowledge or direct experience of what farming entails. In addition, more people are expressing concerns over issues such as farm animal welfare. This has led to increasing public demand for more sustainable ways of livestock farming. To date, little research has been carried out on the social pillar of sustainable livestock farming. The aim of this study is to provide insights into the sociocultural sustainability of livestock farming systems. This study reviews the key findings of earlier published interdisciplinary research about the social perceptions of dairy farming in the Netherlands and Norway (Boogaard et al., 2006, 2008, 2010a and 2010b) and synthesises the implications for sociocultural sustainability of livestock farming. This study argues that the (sociocultural) sustainable development of livestock farming is not an objective concept, but that it is socially and culturally constructed by people in specific contexts. It explains the social pillar of the economics/ecological/social model sustainability in terms of the fields of tensions that exist between modernity, traditions and naturality - 'the MTN knot' - each of which has positive and negative faces. All three angles of vision can be seen in people's attitudes to dairy farming, but the weight given to each differs between individuals and cultures. Hence, sociocultural sustainability is context dependent and needs to be evaluated according to its local meaning. Moreover, sociocultural sustainability is about people's perceptions of livestock farming. Lay people might perceive livestock farming differently and ascribe different meanings to it than experts do, but their 'reality' is just as real. Finally, this study calls for an ongoing collaboration between social and animal scientists in order to develop livestock farming systems that are more socioculturally sustainable. PMID- 22440293 TI - Diet selection and performance of cattle and horses grazing in heathlands. AB - As the number of horses is steadily increasing in Cantabrian less-favoured areas, mostly occupied by nutritionally poor heathland communities, the objective of this research was to study and compare diet selection and performance of crossbred horses and beef cattle (Asturiana de los Valles breed) grazing these areas during the summer. A total of 20 cows (seven lactating their calves and thirteen dry) and 20 mares (eight lactating their foals and twelve dry) were managed during 3 years on a heathland area from June to September and October. The proportion of grass (mostly Pseudarrhenatherum longifolium) and heather (Erica umbellata, E. cinerea and Calluna vulgaris) in the diet selected by cows and mares was estimated in two occasions (July and September) each year using the alkane markers. All animals were weighed at the beginning, middle and end of the summer grazing season. Mares selected heath grasses and rejected heather species more than did the cows (P < 0.001), particularly in early summer (0.85 v. 0.65 herbage proportion in July; 0.63 v. 0.55 in September). Lactating state did not affect diet composition. Mares achieved more favourable (P < 0.001) body weight (BW) changes than cows, but there was also an interaction with season (P < 0.001). From June to August, cows lost BW, being the daily changes (in percentage of initial BW) -0.15%/day in lactating and -0.05%/day in dry cows, whereas both lactating and dry mares gained BW (0.16 and 0.12%/day, respectively). From August to October, lactating cows and mares lost more BW (P < 0.01) compared with their non-lactating counterparts (-0.19 v. -0.10%/day in cows, -0.14 v. -0.05%/day in mares). With regard to the offspring, BW gains between June and August were similar in calves and foals (0.83 and 0.90%/day, respectively), but thereafter calves achieved higher (P < 0.05) BW gains than foals (0.37 v. 0.16%/day). It is concluded that the low nutritive quality of these heathlands restricts, both cattle and horse performance, even during short summer grazing season, being more penalized lactating animals, especially the cows. Although calves were able to maintain acceptable growth rates, foals showed reduced ones during the second half of the grazing season. Other plant communities with better nutritive quality should be provided to assure replenishment of body reserves in dams, and enhance offspring gains to maintain sustainable grazing systems with productive herds of cattle and horses in these heathland areas. PMID- 22440294 TI - Variation in carbon footprint of milk due to management differences between Swedish dairy farms. AB - To identify mitigation options to reduce greenhouse gas (GHG) emissions from milk production (i.e. the carbon footprint (CF) of milk), this study examined the variation in GHG emissions among dairy farms using data from previous CF studies on Swedish milk. Variations between farms in these production data, which were found to have a strong influence on milk CF, were obtained from existing databases of 1051 dairy farms in Sweden in 2005. Monte Carlo (MC) analysis was used to analyse the impact of variations in seven important parameters on milk CF concerning milk yield (energy-corrected milk (ECM) produced and delivered), feed dry matter intake (DMI), enteric CH4 emissions, N content in feed DMI, N fertiliser rate and diesel used on farm. The largest between-farm variations among the analysed production data were N-fertiliser rate (kg/ha) and diesel used (l/ha) on farm (CV = 31% to 38%). For the parameters concerning milk yield and feed DMI, the CV was approximately 11% and 8%, respectively. The smallest variation in production data was found for N content in feed DMI. According to the MC analysis, these variations in production data led to a variation in milk CF of between 0.94 and 1.33 kg CO2 equivalents (CO2e)/kg ECM, with an average value of 1.13 kg CO2e/kg ECM. We consider that this variation of +/-17%, which was found to be based on the used farm data, would be even greater if all Swedish dairy farms were included, as the sample of farms in this study was not totally unbiased. The variation identified in milk CF indicates that a potential exists to reduce GHG emissions from milk production on both the national and farm levels through changes in management. As milk yield and feed DMI are two of the most influential parameters for milk CF, feed conversion efficiency (i.e. units ECM produced/unit DMI) can be used as a rough key performance indicator for predicting CF reductions. However, it must be borne in mind that feeds have different CF due to where and how they are produced. PMID- 22440295 TI - Evaluation of the Chinese indigenous pig breed Dahe and crossbred Dawu for growth and carcass characteristics, organ weight, meat quality and intramuscular fatty acid and amino acid composition. AB - The objectives of the experiment were to evaluate growth and carcass characteristics, organ weight, meat quality and intramuscular fatty acid (FA) and amino acid composition between the Chinese indigenous pig breed Dahe and the crossbred Dawu. The Dahe pigs had lower average daily gain (P < 0.001) and a higher feed conversion ratio (P < 0.001) compared with the Dawu pigs. The Dahe pigs contained less lean meat percentage (P < 0.001) and more carcass fat percentage (P < 0.001) compared with the Dawu pigs. For organ weight, the Dahe pigs had lower relative heart weight and small intestine weight, respectively, compared with that of the Dawu pigs (P < 0.001). In addition, the Dahe pigs showed higher pH values (at 45 min and 24 h, P < 0.001 and P < 0.001, respectively), higher Marbling score (P < 0.05), lower Minolta L values (at 45 min and 24 h, P < 0.001 and P < 0.05, respectively) and lower muscle fiber area (P < 0.05) than did the Dawu pigs. C18:1, C16:0, C18:0 and C18:2 were the main FAs and nine essential amino acids were found in the Longissimus dorsi of the two breeds. PMID- 22440296 TI - Red blood cell distribution width adds prognostic value for outpatients with chronic heart failure. AB - INTRODUCTION AND OBJECTIVES: Red blood cell distribution width has emerged as a new prognostic biomarker in cardiovascular diseases. Its additional value in risk stratification of patients with chronic heart failure has not yet been established. METHODS: A total of 698 consecutive outpatients with chronic heart failure were studied (median age 71 years [interquartile range, 62-77], 63% male, left ventricular ejection fraction 40 [14]%). On inclusion, the red cell distribution width was measured and clinical, biochemical, and echocardiographic variables were recorded. The median follow-up period was 2.5 years [interquartile range 1.2-3.7]. RESULTS: A total of 211 patients died and 206 required hospitalization for decompensated heart failure. Kaplan-Meier analysis showed an increase in the probability of death and hospitalization for heart failure with red cell distribution width quartiles (log rank, P<.001). A ROC analysis identified a red cell distribution width of 15.4% as the optimal cut-off point for a significantly higher risk of death (P<.001; hazard ratio=2.63; 95% confidence interval, 2.01-3.45) and hospitalization for heart failure (P<.001; hazard ratio=2.37; 95% confidence interval, 1.80-3.13). This predictive value was independent of other covariates, and regardless of the presence or not of anaemia. Importantly, the addition of red cell distribution width to the clinical risk model for the prediction of death or hospitalization for heart failure at 1 year had a significant integrated discrimination improvement of 33% (P<.001) and a net reclassification improvement of 10.3% (P=.001). CONCLUSIONS: Red cell distribution width is an independent risk marker and adds prognostic information in outpatients with chronic heart failure. These findings suggest that this biological measurement should be included in the management of these patients. Full English text available from:www.revespcardiol.org. PMID- 22440297 TI - Disesquiterpene and sesquiterpene coumarins from Ferula pseudalliacea, and determination of their absolute configurations. AB - The first disesquiterpene coumarin, sanandajin, five sesquiterpene coumarins, kamolonol acetate, fekrynol acetate, ethyl galbanate, methyl galbanate, farnesiferol B, and a sesquiterpene, aristolone, were isolated from a n-hexane extract of Ferula pseudalliacea roots. The structures were elucidated by 1D and 2D NMR, HR-ESIMS data, and kamolonol acetate was confirmed by single-crystal X ray analysis. The absolute configuration of compounds was established by comparison of experimental and simulated ECD spectra using time dependence density function theory (TDDFT). In vitro antiplasmodial activity against Plasmodium falciparum K1 strain was determined. sanandajin, kamolonol acetate and methyl galbanate showed moderate antiplasmodial activity, with IC(50) values of 2.6, 16.1 and 7.1 MUM, respectively. PMID- 22440298 TI - [Short quality of life respiratory questionnaires: clinical and scientific issues]. PMID- 22440299 TI - [Respiratory impact of biomass exposure in developing countries: an underestimated emergent risk?]. PMID- 22440300 TI - [A story of respiratory genes]. PMID- 22440301 TI - [The place of surgery in metastatic non-small cell lung cancer]. AB - BACKGROUND: Metastatic lung cancer may be M1a (contralateral lung nodule, malignant pleural or pericardial effusion or pleural nodules) or M1b (distant metastases). Surgery is not usually considered in their treatment. METHOD: After exclusion of contralateral lung nodules, we reviewed the demographics, management, survival and prognostic factors in M1 patients, among a total of 4668 patients who underwent surgery for lung cancer between January 1983 and December 2006. RESULTS: There were 164 patients (70 M1a, 94 M1b). Surgical procedures included exploratory thoracotomy (n=40), lobectomy (n=88), and pneumonectomy (n=38). Histology revealed adenocarcinoma (n=97), squamous cell carcinoma (n=36) or other (n=27). Nodal extension was N0 (n=60), N1 (n=23), N2 (n=64), or not available (n=17). Overall median survival was 14 months and 5-year survival was 12.7%. In M1a median survival was 15 months and 5-year survival 9%. In M1b, median survival was 11 months and 5-year survival 15%, regardless of whether the metastasis was resected or not. The 5-year survival rates were 0% after exploratory thoracotomy, 3.9% after pneumonectomy, 14.8% after lobectomy; 15.2% in adenocarcinoma, 30.4% after induction chemotherapy, and 31.5% in N0 patients. In cases of M1a disease, complete surgical resection resulted in a 5-year survival rate of 16.2%. In case of M1b disease undergoing pulmonary resection, surgical metastasis management did not change the prognosis, with 5-year survival rates of 16.7% in case of metastasis resection (n=66) versus 15.6% without resection (n=19, P=0.67). CONCLUSION: In patients with M1a disease, complete surgical resection allowed some long-term survivals, suggesting that surgery may be underestimated. Conversely, in patients with M1b disease undergoing pulmonary resection, surgical resection of the metastasis is not associated with better survival than non-surgical management, suggesting that surgery may be overestimated. PMID- 22440302 TI - [Conservative surgery in pulmonary aspergilloma]. AB - INTRODUCTION: Pulmonary aspergilloma is a mycotic infection due to the deposit of mycelial fibres, usually in a pre-existing cavity within the lung. Surgical resection is the treatment of choice, with anatomical resection the most practiced technique. Simple aspergillomas are becoming more and more frequent urging this review of the place of conservative surgery. AIM: The aim of this study was to establish the characteristics of aspergillomas which may benefit from a conservative surgery. METHODS: We undertook a retrospective study of 64 cases that were operated on in the thoracic surgery unit in Abderrahmen-Mami Ariana's hospital between 1984 and 2008. RESULTS: Fourteen patients had conservative surgical treatment, with an atypical resection to remove the aspergilloma. The other 50 patients had undergone anatomical resection; segmental resection, lobectomy or pneumonectomy. The perioperative mortality rate was 5%. One case of aspergilloma recurrence had been recorded in a patient who had had conservative surgery for a complex aspergilloma. CONCLUSION: Surgery is the only effective treatment of aspergilloma. Conservative surgery may be an alternative in simple-peripheral forms, which have a diameter less than 4cm. PMID- 22440303 TI - [Evaluation of the COPD Assessment Test in patients with stable COPD]. AB - INTRODUCTION: The COPD Assessment Test (CAT) is a new simple tool developed for assessing health-related quality of life in patients with COPD. The characteristics of the score derived from the CAT as a function of various parameters of evaluation of the severity of COPD remain to be described. METHODS: The CAT was submitted prospectively to 213 consecutive stable ambulatory COPD patients assessed in a tertiary care hospital. The discriminative value of the CAT was analysed as well as its association with various parameters of interest. RESULTS: The progressive increase in the CAT score with the severity of the disease as assessed by the GOLD stages and the BODE index, as well as the level of dyspnoea, demonstrates the discriminative capacity of the CAT. In multivariate analysis, only the RV/TLC (residual volume/total lung capacity) and the 6-minute walk distance were significantly associated with the CAT score, explaining only 27 % of its variability. The inclusion of dyspnoea in the model explained 42 % of the CAT score variability, only dyspnoea and the RV/TLC ratio being significantly associated. CONCLUSION: The CAT has good discriminative characteristics that are similar to more complex tools designed to assess health-related quality of life in patients with COPD. PMID- 22440304 TI - [Clinical manifestations related to kitchen biomass smoke in African women]. AB - CONTEXT: Fires of wood and charcoal play an essential part in the cooking of food in Africa. These fires emit thick smoke that has definite health consequences. OBJECTIVES: To determine the clinical manifestations related to kitchen smoke and to identify the type of fire most often incriminated. METHODS: It was a transverse study comparing the clinical features in women using three types of fire: wood, charcoal and gas. We questioned 200 women in each group who used one type of fire exclusively for five days a week for at least five years. RESULTS: Clinical manifestations associated with the smoke were reported in all the women using wood as opposed to 98.5% using charcoal and 45.5% using gas. More than 80% had physical signs. These comprised 89.1% upper respiratory and 77% pulmonary signs. Upper respiratory signs were the most common, mainly sneezing and nasal obstruction. At the pulmonary level, a predominance of signs was found in women using wood fires (47.3%) and charcoal (36.2%), the difference being statistically significant. The signs included chronic cough, chest pain and dyspnoea. Wheezes were found in 15% of the women. CONCLUSION: Cooking smoke exposes women to complications which are most frequently associated with the use of wood or charcoal. PMID- 22440305 TI - [Non-tuberculous pleural infections versus tuberculous pleural infections]. AB - INTRODUCTION: In countries where tuberculosis is endemic, the main differential diagnosis for pleural infection by common bacteria is pleural tuberculosis. OBJECTIVE: The purpose of our study was to determine the differences between pleural infection by common bacteria and that caused by pleural tuberculosis. METHODOLOGY: Our study was a retrospective analysis and compared the characteristics of confirmed pleural infection by common bacteria (PIB) and that due to pleural tuberculosis (PT). RESULTS: For the PIB, the signs evolved for 2.4 +/- 1.4 weeks versus 5.6 +/- 2.2 weeks for the PT (P=0.01). In multivariate analysis, for PIB the onset of symptoms was more abrupt (OR=3.8 [1.5; 9.9]; P=0.01), asthenia was less frequent (OR=0.3 [0.1; 0.9]; P=0.03), pleural liquid was more purulent (OR=40.0 [15.0; 106.7]; P<0.01). The blood neutrophil count was more frequently raised in cases of PIB (OR=2.5 [1.2; 5.4]; P=0.02). Pneumothorax/hydropneumothorax was less frequent in PIB (OR=0.3 [0.1; 1.0]; P=0.04). CONCLUSION: Clinical differences exist between pleural effusions caused by tuberculosis (TB) and those due to other bacterial infections. However, they are not sufficiently sensitive and therefore the search for the tuberculous bacillus must be systematic while waiting for implementation of new diagnostic tests for the organism. PMID- 22440306 TI - [Predictive factors for recurrence of pulmonary tuberculosis in Tunisia: a retrospective study]. AB - INTRODUCTION: Tuberculosis is still endemic in Tunisia. Even though recurrent TB (RT) is rare, there is an increased risk of resistance. The purpose of this study is to investigate predictors of RT. PATIENTS AND METHODS: This was a case controlled retrospective study, comparing two groups of patients with confirmed pulmonary tuberculosis: a relapse group (GR) of 64 patients with RT and a control group (GT) of 105 patients. RESULTS: Between September 1995 and December 2007, the incidence of RT was 9.48%. All the patients were male. There was no difference in the average age of the two groups. A smoking history of greater than 20 pack-years was more common in the GR (44.89% versus 21.4%, P=0.055). No difference was found regarding the history and clinical signs except that chest pain and dyspnoea were more frequent in the GR. A low haemoglobin was more common in the GR (11.33 +/- 1.57g/dL versus 12.41 +/- 1.66g/dL, P=0.008). The tuberculin skin test was negative in 73.7% of GR versus 31.1% of GT (P=0.001). Adverse liver reactions are more frequent in the GR (27.3% versus 8.6%, P<0.05). Discontinuation of TB treatment was more common in the GR (36.7% versus 3.8%, P<0.001). The achievement of sputum negativity was delayed in the GR (46.32 +/- 54.01 versus 9.35 +/- 11.84 days, P<0.001). Despite this, we have noted no significant difference in drug resistance. In multivariate analysis, hepatic cytolysis and a negative tuberculin skin test were independent predictive factors for RT. CONCLUSION: All tuberculous patients should have a carefully adapted treatment regimen, particularly the presence of factors predictive for recurrence. PMID- 22440307 TI - [The yellow nail syndrome: a series of five cases]. AB - INTRODUCTION: The yellow nail syndrome is a rare disorder described for the first time in 1964. The pathophysiology remains unclear. Its definition is based on a clinical triad of yellow nails, lymphoedema and chronic respiratory disorders including pleural effusions and bronchiectasis. CASES REPORTS: We describe a retrospective series of five patients diagnosed with the yellow nail syndrome. All the patients were male, aged from 52 to 71 years (median=56). Three patients were diagnosed with the classic triad, whereas the other two had only yellow nails and bronchiectasis. Yellow nails and chronic sinusitis were present in all five patients. We also report atypical manifestations such as a transudative pleural effusion and facial oedema. The yellow nail syndrome was associated with cancer in two cases. CONCLUSION: More common alternative diagnoses must be excluded. The association with cancer should be explored. The treatment is only symptomatic. PMID- 22440308 TI - [The congenital central hypoventilation syndrome (CCHS): a late presentation]. AB - BACKGROUND: The congenital central hypoventilation syndrome (CCHS) or Ondine's curse is a rare autosomal dominant disease, characterized by disorders of the autonomic nervous system, with abnormal ventilatory responses to hypercapnia and hypoxia. PHOX2B has been identified as the major gene causing CCHS. It results from polyalanine repeat expansion mutations. It typically presents in the newborn period but some cases have been described in adults (late onset CCHS) reflecting the variable penetrance of PHOX2B mutations. CASE REPORT: A 48 year-old woman presented, after ovarian cyst surgery, with severe hypoventilation requiring intubation. Arterial blood gases revealed a PaO2 of 6.6kPa (50mmHg), a PaCO2 of 10kPa (80mmHg) and a pH of 7.22. The past medical history revealed nocturnal symptoms for a few years. These included apnoeas, fitful sleep and awakening with headaches. Physical examination, pulmonary function tests, lung tomography and magnetic resonance imaging of the brainstem were all normal. Polysomnography revealed numerous central and obstructive apnoeas and hypopnoeas, with severe hypoxaemia and hypercapnia. Hypoxic and hypercapnic stimulation tests showed no adaptation of the ventilatory responses. Genetic analysis showed a heterozygous five alanine expansion mutation of the 20-residue polyalanine tract in exon 3 of the PHOX2B gene. CONCLUSION: The diagnosis of late onset CCHS should be considered in patients with unexplained hypoventilation, and physiological evaluation should be undertaken to document the abnormal ventilatory responses. The presence of a PHOX2B mutation confirms the diagnosis. PMID- 22440309 TI - [Clomipramine hypersensitivity with predominantly pulmonary involvement]. AB - Drug hypersensitivity (DRESS syndrome) is a rare disorder with diverse systemic and visceral manifestations. Pulmonary involvement is uncommon and is mainly characterized by eosinophilic infiltration. We report a case of DRESS syndrome induced by clomipramine with predominant pulmonary involvement. PMID- 22440310 TI - [Chronic necrotizing pulmonary aspergillosis following an infection by Mycobacterium malmoense]. AB - Pneumonia due to Mycobacterium malmoense is rare and usually occurs in damaged lung as is the case with Aspergillus infections. We report the case of a patient who developed chronic necrotizing pulmonary aspergillosis following an infection by atypical mycobacteria. A 53-year-old woman was hospitalized because of weight loss and fever. Direct examination of sputum smear was positive for acid fast bacilli and PCR and culture led to the diagnosis of infection with M. malmoense. Treatment was begun with clarithromycin, rifampicin and ethambutol. Despite initial improvement and excellent adherence to treatment, fever and weight loss recurred 6 months later. Relapse of the mycobacterial infection was excluded and the final diagnosis was necrotizing pulmonary aspergillosis. Infection with A. fumigatus complicating the treatment of M. malmoense is unusual. The management is challenging because of strong interactions between voriconazole and rifampicin, and thus requires a multidisciplinary and specialized approach. PMID- 22440311 TI - [A lung cavity with an air crescent]. PMID- 22440312 TI - 115 kDa serine protease confers sustained protection to visceral leishmaniasis caused by Leishmania donovani via IFN-gamma induced down-regulation of TNF-alpha mediated MMP-9 activity. AB - Visceral leishmaniasis caused by the intracellular parasite Leishmania donovani is a major public health problem in the developing world. The emergence of increasing number of L. donovani strains resistance to antimonial drugs recommended worldwide requires the intervention of effective vaccine strategy for treatment of VL. In the present study L. donovani culture derived, soluble, secretory serine protease (pSP) has been shown to be vaccine target of VL. Protection from VL could be achieved by the use of safer vaccine which generally requires an adjuvant for induction of strong Th1 response. To assess the safety, immunogenicity and efficacy of pSP as vaccine candidate in mouse model we used IL 12 as adjuvant. BALB/c mice immunized with pSP+IL-12 were protected significantly from challenged infection even after four months by reducing the parasite load in liver and spleen and suppressed the development of the disease along with an increase in IgG2a antibody level in serum, enhanced delayed type hypersensitivity and strong T-cell proliferation. Groups receiving pSP+IL-12 had an augmented pSP antigen specific Th1 cytokines like IFN-gamma and TNF-alpha response with concomitant decrease of Th2 cytokines IL-4 and IL-10 after vaccination. In this study the vaccine efficacy of pSP was further assessed for its prophylactic potential by enumerating matrix metalloprotease-9 (MMP-9) profile which has been implicated in various diseases. MMP-9 associated with different microbial infections is controlled by their natural inhibitors (TIMPS) and by some cytokines. In this study pSP was found to regulate excessive inflammation by modulating the balance between MMP-9 and TIMP-1 expression. This modulatory effect has also been demonstrated by IFN-gamma mediated down regulation of TNF alpha induced MMP-9 expression in activated murine macrophages. This is the first report where a secretory L. donovani serine protease (pSP) adjuvanted with IL-12 could also act as protective imunogen by modifying cytokine mediated MMP-9 expression in experimental VL. These findings elucidate the mechanisms of regulation of MMP-9 following infection of L. donovani in vaccinated animals and thus pave the way for developing new immunotherapeutic interventions for VL. PMID- 22440313 TI - Effects of one-lung ventilation on thermodilution-derived assessment of cardiac output. AB - BACKGROUND: Cardiac output (CO) monitoring can be useful in high-risk patients during one-lung ventilation (OLV), but it is unclear whether thermodilution derived CO monitoring is valid during OLV. Therefore, we compared pulmonary artery (CO(PATD)) and transcardiopulmonary thermodilution (CO(TPTD)) with an experimental reference in a porcine model. METHODS: CO(PATD) and CO(TPTD) were measured in 23 pigs during double-lung ventilation (DLV) and 15 min after the onset of OLV, during conditions of normovolaemia and after haemorrhage. An ultrasonic flow probe placed around the pulmonary artery (CO(PAFP)) was used for reference. RESULTS: The range of CO in these experiments was 1.5-3 litre min(-1). Normovolaemia: during DLV and conditions of normovolaemia, the mean (95% limits of agreement) bias for CO(PATD) compared with CO(PAFP) was -0.05 (-0.92 and 0.83) litre min(-1), and 0.58 (-0.40 and 1.55) litre min(-1) for CO(TPTD). During OLV, the bias for CO(PATD) remained unchanged at 0.08 (-0.51 and 0.66) litre min(-1), P=0.15, and the bias for CO(TPTD) increased significantly to 0.85 (0.05 and 1.64) litre min(-1), P=0.047. Hypovolaemia: during DLV, the bias for CO(PATD) compared with CO(PAFP) was 0.22 (-0.20 and 0.66) litre min(-1) and for CO(TPTD) was 0.60 (0.12 and 1.10) litre min(-1). There was no significant change of bias during OLV for CO(PATD) [0.30 (-0.10 and 0.70) (litre min(-1)), P=0.25] or bias CO(TPTD) [0.72 (0.21 and 1.22) (litre min(-1)), P=0.14]. Trending ability during OLV, quantified by the mean of angles theta, showed good values for both CO(PATD) (theta=11.2 degrees ) and CO(TPTD) (theta=1.3 degrees ). CONCLUSIONS: CO(TPTD) is, to some extent, affected by OLV, whereas CO(PATD) is unchanged. Nonetheless, both methods provide an acceptable estimation of CO and particularly of relative changes of CO during OLV. PMID- 22440314 TI - Intravenous boluses of fentanyl, 1 MUg kg-1, and remifentanil, 0.5 MUg kg-1, give similar maximum ventilatory depression in awake volunteers. AB - BACKGROUND: The relative respiratory effects of fentanyl and remifentanil, administered as i.v. bolus, have not previously been studied. We determined what remifentanil bolus dose gave the same maximum depression of ventilation as 1 ug kg(-1) of fentanyl. METHODS: Twelve healthy volunteers rebreathed in a system designed to dampen variations in end-tidal carbon dioxide tension PE'CO2 so that measurements would be obtained at similar levels of CO(2) stimulation. The minute ventilation was measured before (V(preinj)) and after injection (V(nadir)) of fentanyl, 1 ug kg(-1), and remifentanil, 0.25, 0.5, and 1 ug kg(-1). The remifentanil doses were plotted against V(nadir)/V(preinj) in a log-probit diagram to determine what amount gave the same maximum ventilatory depression as the fentanyl dose. RESULTS: V(nadir) was [median (inter-quartile range)] 51 (38 64)% of V(preinj) after fentanyl, and 70 (61-77), 50 (46-56), and 29 (24-38)%, respectively, after remifentanil. The nadir occurred 5.0 (4.4-7.0) min after fentanyl, and 3.8 (2.7-4.6), 2.9 (2.7-3.2), and 3.0 (2.7-3.2) min after remifentanil injection. PE'CO2 at ventilation nadir was 6.26 (5.98-6.62) kPa after fentanyl, and 6.18 (6.12-6.50), 6.11 (5.91-6.45), and 6.11 (5.93-6.45) kPa after remifentanil 0.25, 0.5, and 1 ug kg(-1), respectively. A remifentanil dose of 0.47 (0.42-0.62) ug kg(-1) was equidepressant to 1 ug kg(-1) of fentanyl. Fifteen minutes after fentanyl injection, the median minute ventilation was 30 40% less than after injection of remifentanil, 0.25 and 0.5 ug kg(-1) (P<0.05). CONCLUSIONS: Fentanyl, 1 ug kg(-1), and remifentanil, 0.5 ug kg(-1), gave similar maximum ventilatory depression. The onset of and recovery from ventilatory depression were faster with remifentanil. PMID- 22440315 TI - Wave technique for treatment of lower lip cancer. AB - PURPOSE: This article reports the authors' experience with treatment of lower lip cancer using the wave technique. PATIENTS AND METHODS: Twenty-one patients (16 males, 5 females) were treated using the wave technique between September 2009 and October 2010. Patients undergoing the procedure had tumors that were classified as either T1N0M0 or T2N0M0. Lateral defects less than 2 cm in size are generally treated with unilateral flaps, and median defects are closed with bilateral symmetric flaps. If the defect is paramedian and greater than 2 cm in width, two asymmetric flaps are used. RESULTS: No recurrence was observed during a 6- to 32 months follow-up (mean 19 months). All patients showed excellent esthetic results with no microstomia. CONCLUSIONS: We modified the straight lines of the staircase technique into round lines of the wave technique, resulting in an esthetic improvement. The goal of the broken lines and round lines is to create less visible scars. The wave technique can be used to close defects of up to two-thirds of the lower lip. PMID- 22440316 TI - Neurosensory disturbances one year after bilateral sagittal split osteotomy of the mandibula performed with separators: a multi-centre prospective study. AB - Bilateral sagittal split osteotomy (BSSO) is an effective and commonly used treatment to correct mandibular hypo- and hyperplasia. Hypoesthesia of the inferior alveolar nerve (IAN) is a common complication of this surgical procedure. This prospective multi-centre study aimed to determine the incidence of neurosensory disturbances of the IAN after BSSO procedures performed without the use of chisels. Our study group comprised 158 patients, with a follow-up period of 1 year, who underwent BSSO (with or without Le Fort I) that incorporated the use of sagittal split separators and splitters but no chisels. The percentage of BSSO split procedures that resulted in IAN damage was 5.1%. The percentage of patients (without genioplasty) who experienced IAN damage was 8.9%. The concomitant genioplasty in combination with BSSO was significantly associated with hypoesthesia. Peri-operative removal of the wisdom tooth or a Le Fort I procedure did not influence post-operative hypoesthesia. We believe that the use of splitting forceps and elevators without chisels leads to a lower incidence of persistent post-operative hypoesthesia 1 year after BSSO of the mandible, without increasing the risk of a bad split. PMID- 22440317 TI - The sequential hypothesis of impaction of maxillary canine - a hypothesis based on clinical and radiographic findings. AB - The aetiology of impacted maxillary canines remains obscure. Numerous researchers have focused on identifying specific and non-specific aetiological factors responsible for canine displacement. Currently, the two most popular hypotheses that have gained consensus worldwide are the guidance theory and the genetic theory. However, no single hypotheses, can completely explain the aetiology of impaction of maxillary canines. This retrospective study was used to develop and postulate the aetiology of both buccally and palatally impacted maxillary canines. The study was conducted on a sample of 533 patients for whom the pattern and distribution of the impacted maxillary canines, sex differences, the dental age of the patients, dental anomalies and various geometric measurements which were made on the panoramic radiographs were recorded. Based on these findings, the sequential hypothesis of impaction of the maxillary canine was postulated. The hypothesis states that both buccally and palatally impacted canines have similar aetiological factors leading to their impaction. It is suggested that genetic mechanisms strongly influence the potential of the maxillary canine to be impacted and the guidance from the lateral incisor and the stage of development plays a vital role in determining the ultimate position of the impacted canine. PMID- 22440319 TI - Asynchronous idiopathic bone cavity: a case report. AB - Idiopathic bone cavity (IBC) is a non-odontogenic intra-osseous lesion that affects the jaws and others bones. The aetiology of IBC remains unknown. IBC is frequently observed as a single radiolucent area with a corticated, well-defined border, a scalloped shape and a minimal effect on the surrounding structures. A case report of asynchronous IBC in a 17-year-old woman is presented. The first lesion occurred in the mandibular symphysis region, and the second IBC occurred in the right mandibular ramus. Both lesions were surgically treated, and the patient has been disease-free for 5 years. PMID- 22440318 TI - Comparison of various approaches for the treatment of fractures of the mandibular condylar process. AB - Fractures of the mandibular condyle process are the most common fractures of the lower jaw. Unfortunately, the type of treatment is still a matter of debate. PURPOSE: The aim of this investigation was to compare the outcome of different treatment approaches regarding function and surgical side-effects. PATIENTS AND METHODS: 111 fractures of the mandibular condyle representing all types according to the classification of Spiessl and Schroll were included. Both closed reduction (CR) and open reduction with internal fixation (ORIF) including the retromandibular/transparotid, submandibular, preauricular and intraoral approach were performed. The clinical examination included functional and aesthetic aspects at least 1 year after the fracture. RESULTS: The majority of fractures (45%) were classified into Type II and IV according to Spiessl and Schroll followed by fractures without any displacement or dislocation (29.7%). The submandibular approach showed the worst outcome regarding permanent palsy of the facial nerve and hypertrophic scarring. No significant differences between the various approaches were detected in the functional status in any diagnosis group. CONCLUSION: Inferior condylar neck fractures benefit from ORIF by an intraoral approach whereas in high condylar neck fractures the retromandibular/transparotid approach shows the best results. Fractures of the condylar head were almost all treated by CR and our results cannot contribute to the debate of CR vs. ORIF in this type of fracture. PMID- 22440320 TI - A hematogenous spread brain abscess invading the right damaged temporomandibular joint. AB - We report a rare case of a brain abscess which drained spontaneously in a temporomandibular joint damaged by osteoarthritis. The female patient presented to our hospital with a severe headache and pain in the temporomandibular joint. She showed elevated inflammatory parameters with unknown cause. Magnetic resonance imaging of her whole body revealed a large temporal brain abscess extending into the glenoid fossa of the temporomandibular joint. The brain abscess was incised and drained by neurosurgeons in our hospital and in the same operation we resected the articular disc and the affected part of the right temporomandibular joint. Histological examination confirmed a chronic arthrosis in the resected bone of the temporomandibular joint and an inflammatory abscess in the resected brain tissue. The patient recovered well and the inflammation resolved as seen in postoperative investigations. Magnetic resonance imaging a month later confirmed local consolidation in the brain with no sign of residual inflammation. PMID- 22440321 TI - The aging musculoskeletal system and obesity-related considerations with exercise. AB - Advancing age and adiposity contribute to musculoskeletal degenerative diseases and the development of sarcopenic obesity. The etiology of muscle loss is multifactorial, and includes inflammation, oxidative stress and hormonal changes, and is worsened by activity avoidance due to fear of pain. The risk for mobility disability and functional impairment rises with severity of obesity in the older adult. Performance measures of walking distance, walking speed, chair rise, stair climb, body transfers and ability to navigate obstacles on a course are adversely affected in this population, and this reflects decline in daily physical functioning. Exercise training is an ideal intervention to counteract the effects of aging and obesity. The 18 randomized controlled trials of exercise studies with or without diet components reviewed here indicate that 3-18 month programs that included aerobic and strengthening exercise (2-3 days per week) with caloric restriction (typically 750 kcal deficit/day), induced the greatest change in functional performance measures compared with exercise or diet alone. Importantly, resistance exercise attenuates muscle mass loss with the interventions. These interventions can also combat factors that invoke sarcopenia, including inflammation, oxidative stress and insulin resistance. Therefore, regular multimodal exercise coupled with diet appears to be very effective for counteracting sarocpenic obesity and improving mobility and function in the older, obese adult. PMID- 22440322 TI - Prevalence and characteristics of nonlactate and lactate expressors in septic shock. AB - PURPOSE: The study's objective was to determine the proportion and patient characteristics of patients in vasopressor-dependent septic shock who presented without lactatemia. METHODS: A retrospective review of patients presenting to an urban tertiary-care emergency department between December 2007 and September 2008 was conducted. Patients with a final diagnosis of septic shock requiring vasopressors were divided, based on initial lactate, to nonlactate expressors (0 2.4 mmol/L), intermediate (2.5-3.9 mmol/L), and high (>4.0 mmol/L) lactate groups. RESULTS: Among 123 patients with vasopressor-dependent septic shock, 55 (45%) were nonlactate expressors (lactate <= 2.4 mmol/L). Acute liver injury, history of liver disease, and presence of bacteremia were associated with elevated lactate. CONCLUSION: Almost one-half of patients with vasopressor dependent septic shock did not express lactate on presentation, although a high mortality rate remains in this population. We found a significant association between lactate expressors and liver disease and between lactate expressors and positive blood cultures. The use of lactatemia as the sole indicator of need for additional intravenous fluid or an end point of resuscitation in septic shock may be inadequate. PMID- 22440323 TI - Prediction of extubation failure in medical intensive care unit patients. AB - PURPOSE: The purpose of this study was to evaluate prediction factors for extubation failure (need for reintubation within 48 hours) in medical intensive care unit patients. MATERIALS AND METHODS: Sixty-one patients extubated after mechanical ventilation for more than 48 hours were included in the study. A retrospective analysis of medical records and a prospectively maintained database on respiratory parameters was conducted. RESULTS: Low serum anion gap (P = .001), low serum anion gap corrected for serum albumin (P = .010), and low arterial partial pressure of oxygen (Pao(2))/fraction of inspired oxygen (Fio(2)) ratio (P = .032) were significantly associated with extubation failure. Binary logistic regression analysis revealed low uncorrected and corrected serum anion gap (P = .006 and P = .025, respectively; odds ratio, 0.59 for both) and low Pao(2)/Fio(2) ratio (P = .038; odds ratio, 0.99) as risk factors for extubation failure. Regarding extubation failure, receiver operating characteristic curve (ROC) analysis demonstrated good predictive capabilities of serum anion gap (ROC area under the curve, 0.835; P = .004; cutoff, 7.7 mEq/L; sensitivity, 70.4%; specificity, 85.7%) and corrected serum anion gap (ROC area under the curve, 0.808; P = .009; cutoff, 8.8 mEq/L; sensitivity, 87.5%; specificity, 71.4%). A significantly higher risk for extubation failure was observed in patients with serum anion gap 5.2 mEq/L or less (relative risk, 8.8; 95% confidence interval, 2.4-32.4; P = .004) and corrected serum anion gap 8.6 mEq/L or less (relative risk, 10.0; 95% confidence interval, 2.2-44.9; P = .004). CONCLUSIONS: Low preextubation serum anion gap values and low preextubation Pao(2)/Fio(2) ratio might help to predict extubation failure in medical intensive care unit patients. PMID- 22440324 TI - Low serum leptin level is associated with zonisamide-induced weight loss in overweight female epilepsy patients. AB - Because iatrogenic obesity may hinder medication compliance, it would be a reasonable approach to consider antiepileptic drugs (AEDs) that promote weight loss in overweight patients. We performed an open-label, observational study to assess the effects of zonisamide on weight in overweight female epilepsy patients. In particular, we studied how the basal serum leptin level is related to changes in the weight of these patients. We recruited female epilepsy patients with basal body mass index 25 or more. Laboratory findings including serum leptin level were measured and zonisamide was administered as a monotherapy at a dose of 200 to 400mg/day. Six months later, we measured changes in the body weight. Thirty-seven female epilepsy patients enrolled in the study, and 23 of them completed the treatment. Weight loss after zonisamide treatment was correlated with initial body weight (p=0.020), follow-up weight (p=0.010), and basal serum leptin level (p=0.008), but was not correlated with patients' age, results of lipid profile, and dosage of zonisamide. The correlation of the serum leptin level with weight loss was still significant after the effect of the initial weight was adjusted (p=0.042). Our study shows that low serum leptin level is associated with weight loss in overweight female epilepsy patients. This result may be beneficial for selecting AEDs and provide clues for the pathophysiology of zonisamide-induced weight loss. PMID- 22440325 TI - Mitochondrial-mediated antiviral immunity. AB - Mitochondria, cellular powerhouses of eukaryotes, are known to act as central hubs for multiple signal transductions. Recent research reveals that mitochondria are involved in cellular innate antiviral immunity in vertebrates, particularly mammals. Mitochondrial-mediated antiviral immunity depends on the activation of the retinoic acid-inducible gene I (RIG-I)-like receptors signal transduction pathway and on the participation of a mitochondrial outer membrane adaptor protein, called the "mitochondrial antiviral signaling (MAVS)". In this review, we discuss unexpected discoveries that are revealing how the organelles contribute to the innate immune response against RNA viruses. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology. PMID- 22440326 TI - Understanding selenoprotein function and regulation through the use of rodent models. AB - Selenium (Se) is an essential micronutrient. Its biological functions are associated with selenoproteins, which contain this trace element in the form of the 21st amino acid, selenocysteine. Genetic defects in selenocysteine insertion into proteins are associated with severe health issues. The consequences of selenoprotein deficiency are more variable, with several selenoproteins being essential, and several showing no clear phenotypes. Much of these functional studies benefited from the use of rodent models and diets employing variable levels of Se. This review summarizes the data obtained with these models, focusing on mouse models with targeted expression of individual selenoproteins and removal of individual, subsets or all selenoproteins in a systemic or organ specific manner. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID- 22440328 TI - Distribution of Candida species causing bloodstream infections. PMID- 22440327 TI - Ferroportin-mediated iron transport: expression and regulation. AB - The distinguishing feature between iron homeostasis in single versus multicellular organisms is the need for multicellular organisms to transfer iron from sites of absorption to sites of utilization and storage. Ferroportin is the only known iron exporter and ferroportin plays an essential role in the export of iron from cells to blood. Ferroportin can be regulated at many different levels including transcriptionally, post-transcriptionally, through mRNA stability and post-translationally, through protein turnover. Additionally, ferroportin may be regulated in both cell-dependent and cell-autonomous fashions. Regulation of ferroportin is critical for iron homeostasis as alterations in ferroportin may result in either iron deficiency or iron overload. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID- 22440329 TI - Factors determining the fluorescence yield of fucoxanthin-chlorophyll complexes (FCP) involved in non-photochemical quenching in diatoms. AB - Fucoxanthin-chlorophyll complexes (FCP) from the centric diatom Cyclotella meneghiniana were isolated and the trimeric FCPa complex was reconstituted into liposomes at different lipid to Chl a ratios. The fluorescence yield of the complexes in different environments was calculated from room temperature fluorescence emission spectra and compared to the aggregated state of FCPa. FCPa surrounded by high amounts of lipids resembled detergent solubilised complexes and with decreasing lipid levels, i.e. in a situation where protein contacts were increasingly favoured, the fluorescence yield of FCPa gradually decreased. In addition, the yield displayed a strong pH-dependency in case of lower lipid contents. The further reduction in fluorescence yield brought about by the conversion of diadinoxanthin to diatoxanthin was pH independent and only depended on the amount of diatoxanthin synthesised. The implications of these data for non photochemical quenching in centric diatoms are discussed. PMID- 22440330 TI - Characterization of a novel Y2K-type dehydrin VrDhn1 from Vigna radiata. AB - A novel dehydrin gene (VrDhn1) was isolated from an embryo cDNA library of Vigna radiata (L.) Wilczek (mungbean) variety VC1973A. The intronless VrDhn1 gene encodes a protein belonging to the Y(2)K-type dehydrin family. VrDhn1 protein accumulated in embryos and cotyledons during seed maturation and disappeared 2 days after seed imbibition (DAI). The expression of VrDhn1 mRNA and accumulation of VrDhn1 protein were at high levels in mature seeds, but neither mRNA nor protein was detected in mungbean vegetative tissues under normal growth conditions. The VrDhn1 mRNA level was extremely high in mature seeds and decreased to ~30% at 1 DAI, and was not detectable at ~7 DAI. Tissue dehydration, salinity and exogenous ABA markedly induced VrDhn1 transcripts in plants as measured by quantitative real-time reverse transcription-PCR (qRT-PCR). VrDhn1 protein was not detected using immunoblots in seedlings under stress treatments. In mature seeds or 1 DAI seedlings, VrDhn1 proteins were immunolocalized in the nucleus and cytoplasm. VrDhn1 exhibited low affinity for non-specific interaction with DNA using electrophoretic mobility shift assays (EMSAs), and the exogenous addition of Zn(2+) or Ni(2+) stimulated interaction. The His-tagged VrDhn1 (30.17 kDa) protein showed a molecular mass of 63.1 kDa on gel filtration, suggesting a dimer form. This is the first report showing that a Y(2)K-type VrDhn1 enters the nucleus and interacts with DNA during seed maturation. PMID- 22440331 TI - Advanced endoscopic imaging: from the top of the fold to the single bacterium. PMID- 22440332 TI - Duodenal perforation due to plastic stent migration successfully treated by endoscopy. PMID- 22440333 TI - Pregnancy outcomes of women with and without a history of anorexia nervosa. AB - BACKGROUND: When women have a history of anorexia nervosa (AN), the advice given about becoming pregnant, and about the management of pregnancies, has usually been cautious. This study compared the pregnancy outcomes of women with and without a history of AN. METHOD: Women with a confirmed diagnosis of AN who had presented to psychiatric services in North East Scotland from 1965 to 2007 were identified. Those women with a pregnancy recorded in the Aberdeen Maternal and Neonatal Databank (AMND) were each matched by age, parity and year of delivery of their first baby with five women with no history of AN. Maternal and foetal outcomes were compared between these two groups of women. Comparisons were also made between the mothers with a history of AN and all other women in the AMND. RESULTS: A total of 134 women with a history of AN delivered 230 babies and the 670 matched women delivered 1144 babies. Mothers with AN delivered lighter babies but this difference did not persist after adjusting for maternal body mass index (BMI) in early pregnancy. Standardized birthweight (SBW) scores suggested that the AN mothers were more likely to produce babies with intrauterine growth restriction (IUGR) [relative risk (RR) 1.54, 95% confidence interval (CI) 1.11 2.13]. AN mothers were more likely to experience antepartum haemorrhage (RR 1.70, 95% CI 1.09-2.65). CONCLUSIONS: Mothers with a history of AN are at increased risk of adverse pregnancy outcomes. The magnitude of these risks is relatively small and should be appraised holistically by psychiatric and obstetric services. PMID- 22440334 TI - Characterization and expression analysis of six MADS-box genes in maize (Zea mays L.). AB - MADS-box genes encode a family of transcription factors, which control diverse developmental processes in flowering plants, with organs ranging from roots, flowers and fruits. In this study, six maize cDNAs encoding MADS-box proteins were isolated. BLASTX searches and phylogenetic analysis indicated that the six MADS-box genes belonging to the AGL2-like clade. qRT-PCR analysis revealed that these genes had differential expression patterns in different organs in maize. The results of yeast one-hybrid system indicated that the protein ZMM3-1, ZMM3-2, ZMM6, ZMM7-L, ZMM8-L and ZMM14-L had transcriptional activation activity. Subcellular localization of ZMM7-L demonstrated that the fluorescence of ZMM7-L GFP was mainly detected in the nuclei of onion epidermal cells. qRT-PCR analysis for expression pattern of ZMM7-L showed that the gene was up-regulated by abiotic stresses and down-regulated by exogenous ABA. The germination rates of over expression transgenic lines were lower than that of the wild type on medium with 150 mM NaCl, 350 mM mannitol. These results indicated that ZMM7-L might be a negative transcription factor responsive to abiotic stresses. PMID- 22440335 TI - Cortisol and self-report measures of anxiety as predictors of neuropsychological performance. AB - Although increased anxiety and cortisol reactivity can disrupt neural activity and impact cognition, little research has evaluated associations between anxiety, cortisol, and performance on neuropsychological instruments. The current study investigated the relationship between exogenous salivary cortisol activity and self-report state anxiety on measures tapping a variety of cognitive domains. Fifty-eight male participants were randomly assigned to either a control (no stress induction) or an experimental condition simulating testing anxiety. Self report state anxiety measures and saliva samples were jointly collected on three occasions. The experimental group generally performed worse than controls on declarative memory and working memory tests. Cortisol and self-report anxiety were not correlated. Inverse relationships were demonstrated between self-report anxiety and neuropsychological test scores. Baseline levels of cortisol at session arrival were positively associated with facilitative memory effects, though there was little association between changes in cortisol and cognitive performance. This study highlights the importance of considering the impact of anxiety during neuropsychological evaluations. PMID- 22440336 TI - Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer. AB - We present the rationale and design for MARQUEE, a phase III, randomized, double blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer (NSCLC). The design of MARQUEE is based on preclinical data, the current understanding of the role of cellular N-methyl N'-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) in NSCLC, and clinical data from a randomized phase II study. The available evidence suggests that dual inhibition of MET and the epidermal growth factor receptor (EGFR) may overcome resistance to EGFR inhibitors. In the phase II study, the combination of tivantinib plus erlotinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus erlotinib in the subset of patients with nonsquamous histology, a population enriched for MET overexpression. The primary endpoint in MARQUEE is OS. Secondary and exploratory objectives include determination of PFS, OS in molecular subgroups (defined by EGFR and KRAS mutation status, amplification or overexpression of MET, and serum hepatocyte growth factor), and safety. All patients will be tested for biomarkers, and the results will provide a wealth of information on the role of tivantinib in treating nonsquamous NSCLC. PMID- 22440337 TI - Editorial overview. Lymphocyte development. PMID- 22440339 TI - Genetic parameters of fat quality in pigs measured by near-infrared spectroscopy. AB - Subcutaneous fat from Norwegian Landrace (n=3230) and Duroc (n=1769) pigs was sampled to investigate the sources of variation and genetic parameters of various fatty acids, fat moisture percentage and fat colour, with the lean meat percentage (LMP) also included as a trait representing the leanness of the pig. The pigs were from half-sib groups of station-tested boars included in the Norwegian pig breeding scheme. They were fed ad libitum to obtain an average of 113 kg live weight. Near-infrared spectroscopy (NIRS) was applied for prediction of the fatty acids and fat moisture percentage, and Minolta was used for the fat colour measurements. Heritabilities and genetic correlations were estimated with a multi-trait animal model using average information-restricted maximum likelihood (AI-REML) methodology. Fat from Landrace pigs had considerably more monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs) and fat moisture, as well as less saturated fatty acids (SFAs) than fat from Duroc pigs. The heritability estimates (s.e. 0.03 to 0.08) for the various fatty acids were as follows: Palmitic, C16:0 (0.39 and 0.51 for Landrace and Duroc pigs, respectively); Palmitoleic, C16:1n-7 (0.41 and 0.50); Steric, C18:0 (0.46 and 0.54); Oleic, C18:1n-9 (0.67 and 0.57); Linoleic, C18:2n-6 (0.44 and 0.46); alpha linolenic, C18:3n-3 (0.37 and 0.25) and n-6/n-3 ratio (0.06 and 0.01). The other fat quality traits revealed the following heritabilities: fat moisture (0.28 and 0.33), colour values in subcutaneous fat: L* (whiteness; 0.22 and 0.21), a* (redness; 0.13 and 0.24) and b* (yellowness; 0.07 and 0.17) and LMP (0.46 and 0.47). LMP showed high positive genetic correlations to PUFA (C18:2n-6 and C18:3n 3), which implies that selecting leaner pigs changes the fatty acid composition and deteriorates the quality of fat. Higher concentrations of PUFA are not beneficial as the ratio of n-6 and n-3 fatty acids becomes unfavourably high. Owing to the high genetic correlation between C18:2n-6 and C18:3n-3 and a low heritability for this ratio, the latter is difficult to change through selection. However, a small reduction in the ratio should be expected if selection aims at reducing the level of C18:2n-6. Selection for more C18:1n-9 is possible in view of the genetic parameters, which are favourable for eating quality, technological quality and human nutrition. The NIRS technology and the high heritabilities found in this study make it possible to implement fat quality traits to achieve the breeding goal in the selection of a lean pig with better fat quality. PMID- 22440338 TI - Does thoracoscopic mobilisation of the oesophagus during oesophageal resection result in improved outcomes as compared to open thoracotomy? AB - A best evidence topic was written according to structured protocol. The question addressed was in patients undergoing trans-thoracic oesophagectomy for carcinoma of oesophagus, does a thoracoscopic mobilisation result in improved outcomes as compared to open thoracotomy. 88 papers were found using the reported search strategy of which five papers were selected as representing the best evidence to answer this question are discussed. Overall the evidence on this topic is poor with no prospective randomised controlled trials. We conclude that thoracoscopic mobilisation is a safe alternative to open resection with comparable results in overall short term morbidity and mortality rates. The thoracoscopic approach may have some benefits in terms of reduced blood loss and shorter hospital stay without compromising lymph node clearance and oncological value, but more studies are required to confirm these findings. PMID- 22440340 TI - Estimating the requirement of dietary crude protein for growing blue-breasted quail (Excalfactoria chinensis). AB - Two experiments were conducted to investigate the requirement for dietary crude protein (CP) in growing blue-breasted quail (BBQ). In Experiment 1, 300 1-day-old quails were randomly assigned to 10 groups according to a 2*5 factorial arrangement of treatments with two metabolisable energy (ME) levels (12.13 and 13.39 MJ/kg) and five CP concentrations (160, 190, 220, 250 and 280 g/kg) for 8 weeks. In Experiment 2, 300 1-day-old quails were subjected to a different factorial arrangement of treatments with two ME levels (11.51 and 12.13 MJ/kg) and five CP concentrations (210, 220, 230, 240 and 250 g/kg) for 28 days. Experiment 1 revealed that an interaction existed in weight gain between ME and CP levels in weeks 1 to 4. In both ME groups, quails receiving CP of 160 g/kg showed the least weight gains (P<0.05). No differences (P>0.05) existed in weight gain between the ME groups in which quails ingested CP of 250 and 280 g/kg, whereas quails consuming CP of 220 g/kg with an ME of 13.39 MJ/kg had smaller weight gain than did those ingesting higher CP concentrations (P<0.05). Of main effects for weeks 1-4, quails treated with an ME of 12.13 MJ/kg consumed more feed than did those receiving another ME level, whereas quails in both ME treatments showed similar feed efficiencies. For weeks 5 to 8, no difference (P>0.05) in weight gain, feed intake and feed efficiency was seen regardless of ME levels, and no interaction existed between ME and CP levels. In Experiment 2, the best weight gain and feed efficiency were achieved when the dietary CP concentration was more than 210 g/kg, and quails treated with 11.51 MJ/kg showed better weight gain and feed efficiency (P<0.05) than did those that received 12.13 MJ/kg. Furthermore, the weight gains and protein intakes on the basis of per MJ from the two experiments were pooled together to estimate the protein intake necessary for the best growth performance by two mathematic models; they were then converted to dietary CP concentrations of 204 (minimum) and 233 g/kg (maximum) when ME was 11.51 MJ/kg. In conclusion, BBQ will achieve good growth performance with dietary CP of more than 204 g/kg on the basis of an ME of 11.51 MJ/kg in weeks 1 to 4. PMID- 22440341 TI - Apportioning protein requirements for maintenance v. growth for blue-breasted quail (Excalfactoria chinensis) from 7 to 21 days of age. AB - The aim of this study was to investigate protein requirements for the maintenance and growth of blue-breasted quail (Excalfactoria chinensis) from 7 to 21 days of age. A total of 180 quails, 7 days old, were randomly assigned to 36 cages and for 2 weeks were fed diets with a metabolisable energy concentration of 12.13 MJ/kg and a dietary CP concentration of 125, 150, 175, 200, 225 or 250 g/kg. The average BW per cage and the feed intake per cage were recorded daily. The results showed that quails fed 125 g/kg CP could not maintain their BW and had negative feed efficiency. There were linear and quadratic relationships between CP level and response criteria, including BW, weight gain, feed intake, feed efficiency, final body nitrogen mass and body nitrogen accretion (P<0.05). The dietary CP requirements, as calculated using a one-slope quadratic broken-line model, were 211 and 202 g/kg according to weight gain and feed efficiency, respectively. The regression equations, on the basis of metabolic BW, of daily weight gain on daily protein intake according to the model were Y=0.137-2.128(0.113-X) if X<0.113 and Y=0.137 if X>or=0.113 (R2=0.96, P<0.001), which meant that the protein requirement for maintenance was 0.049 times the metabolic BW and that to gain 1 g weight quails needed to ingest an extra 0.47 g protein after the maintenance requirement was satisfied. The regression equations, on the basis of metabolic BW, of daily body nitrogen accretion on daily protein intake according to the model were Y=5.667-76.700(0.119-X) if X<0.119 and Y=5.667 if X>or=0.119 (R2=0.95, P<0.001), which meant that quails had to receive an amount of protein equal to their metabolic BW multiplied by 0.045 to satisfy the requirement for maintenance and then ingest an extra 13 g protein to accrete 1 g body nitrogen. In conclusion, growth or protein accretion rates should be regulated according to dietary CP for specific experimental purposes via apportioning protein requirements for maintenance v. growth. PMID- 22440342 TI - Effect of chestnut and quebracho tannins on fatty acid profile in rumen liquid- and solid-associated bacteria: an in vitro study. AB - Tannins are phenolic compounds that interfere with biohydrogenation (BH) of polyunsaturated fatty acids (FAs). The aim of the present in vitro study was to investigate the effects of two different sources of tannins on FA profiles of rumen bacteria, with particular reference to rumenic and vaccenic acid. A control diet (C; composed of 300 g/kg of wheat straw, 132 g/kg of soyabean meal, 96 g/kg of barley meal, 152 g/kg of maize meal, 300 g/kg of maize gluten and 20 g/kg of mineral vitamin premix, all expressed on dry matter (DM)) and four diets, obtained by adding to C two different types of tannins from chestnut (TC) and from quebracho (TQ) at two concentration levels (49 and 82 g/kg DM), were compared. The content of the main unsaturated FAs (C18:1 cis9, C18:1 trans11, C18:2 cis9, cis12 and C18:3 cis9, cis12, cis15) from solid-associated bacteria (SAB) and liquid-associated bacteria (LAB) was affected by the presence of tannins in the diets. In particular, C18:1 trans11 content was significantly increased, especially with TC1, whereas the decreasing of C18:1 cis9 was unaffected, regardless of the presence or the kind of tannins added to feeds. SAB contained higher amounts of intermediates of polyunsaturated FA BH (as C18:1 trans11 and C18:2 cis9, trans11) than LAB that were characterized by a higher amount of C18:0. In the concentration range adopted in this study, the effect of TC and TQ on changes of bacterial FA profile was comparable. Tannins seem to be a good means to modulate the FA profile of rumen bacteria, favouring the accumulation of C18:1 trans11 during in vitro rumen fermentation. PMID- 22440343 TI - Effect of dietary supplementation with different sources of selenium on growth response, selenium blood levels and meat quality of intensively finished Charolais young bulls. AB - The study aimed at comparing three strategies of supplementing selenium (Se) during the finishing period of Charolais young bulls: (1) administration of sodium selenite throughout the finishing (NaSe); (2) administration of an Se enriched yeast strain (Saccharomyces cerevisiae NCYC R397) throughout the finishing (Se-Y); (3) administration of sodium selenite for 140 days replaced by Se-enriched yeast during the last 70 days of finishing (Switch). Eighty-four young bulls (mean initial BW=434.2+/-31.9 kg; mean age=382+/-52 days) were stratified by live weight and equally assigned to one of three Se treatments. Experimental groups were fed the same diets and the inclusion rate of the different treatments was targeted to achieve 0.3 mg of Se/kg of dry matter (DM) in the complete feed. The average daily gain of bulls was 1.36 kg/d and no differences due to Se treatment were recorded. Dry matter intake and feed conversion ratio were not affected by Se treatment resulting in, on average, 10.3 kg/d and 7.65, respectively. Repeated blood samples were taken at days 0, 120, 180 and 210 of finishing to assess the Se status of the animals. As compared to NaSe, both organic Se treatments (Se-Y and Switch) increased plasma Se in the last two sampling sessions according to a significant treatment*time interaction (P<0.001). A similar trend was observed for serum total antioxidant status of the young bulls, whereas there was only a significant time effect (P<0.001) on glutathione peroxidase activity that was raised by all Se treatments. The finishing period lasted 210 days and at the abattoir there were no differences across Se treatments in carcass weight and dressing percentage. A higher Se content in the Longissimus thoracis (LT) muscle was instead observed in Se-Y samples as compared with NaSe (0.85 v. 0.47 mg/kg DM; P<0.05). Meat quality evaluation was carried out on LT samples after 6 and 11 days of ageing under a vacuum package. Regardless of ageing time, meat from young bulls supplemented with Se yeast had higher colour lightness (L*) values than those receiving NaSe (38.1 v. 36.6; P<0.01) and showed a significant decrease in shear force (3.69 v. 4.22 kg/cm2; P<0.01). The outcomes of the study suggest that the provision of Se yeast throughout the finishing period is a strategy to increase the benefits of the replacement of sodium selenite with organic selenium in beef cattle. PMID- 22440344 TI - Effects of dietary molybdenum, sulfur and zinc on the excretion and tissue accumulation of trace elements in sheep fed palm kernel cake-based diets. AB - Twelve male 8-month-old lambs were used in a 6-month feeding experiment to determine the effects of dietary Mo, Mo + S and Zn supplements on the body retention and tissue accumulation of dietary Cu, Zn and Fe. The lambs were divided into four groups of three lambs each and each group was fed ad libitum one of four diets. A control diet was based on palm kernel cake (PKC) and grass hay. Three additional diets were the control supplemented with either Mo or Mo+S or Zn. At 3 months of the experiment, feces and urine were collected and sampled for 6 days. At the end of the experiment (6 months), blood was sampled and then the sheep were slaughtered. The liver and kidney were removed and sampled for chemical analysis. In comparison with the control, each dietary supplement decreased (P<0.05) the Cu concentration in the liver, but only the Mo+S supplement decreased it to a safe range of below 350 MUg/g dry matter. This was accompanied by the body retention of dietary Cu of 24.6%, 6.7%, 2.5% and 6.5% for the control, Mo, Mo+S and Zn treatments, respectively. The blood plasma concentration of Cu was decreased (P<0.05) by the Zn supplement, but was not affected by other supplements (P>0.05). It was concluded that from the supplements tested, only Mo+S appeared to be effective in reducing the retention and liver accumulation of the dietary Cu to prevent chronic Cu toxicity in sheep fed PKC-based diets. PMID- 22440345 TI - Colostrum production by sows: variability of colostrum yield and immunoglobulin G concentrations. AB - Colostrum provides newborn piglets with energy, immunoglobulins and growth, thereby playing an essential role in piglet survival. However, colostrum yield and composition are highly variable among sows. Some of the factors involved in this variability have been identified. The aim of the study was to confirm previous findings on a large number of animals and to investigate other potential factors of variation, such as the process of farrowing and the morphological changes of the mammary epithelium that occur during the 24 h post partum. The experiment was conducted on 16 Large White (LW) and 56 Landrace (LR)*Large White (LR*LW) crossbred sows of mixed parities and their litters. Most farrowings were induced at 113 days of gestation and all farrowings were attended. Each piglet was weighed at birth and 24 h after farrowing started (t24). Colostrum ingestion by individual piglets was estimated using piglet weight gains from birth to t24. Colostrum production by sows was estimated by summing up colostrum intakes by each piglet of the litter. Colostrum was collected at the onset of farrowing (t0) and at t24 to determine concentrations of immunoglobulins G (IgG), Na and K. Analyses of correlations and multiple regressions were performed to identify the variables involved in variation of colostrum yield and IgG concentrations. Colostrum yield was not related to litter size and weight (P>0.1). It was negatively correlated with the number of stillborn piglets (r=-0.33, P=0.005) and within-litter variation of piglet birth weight (r=-0.24, P=0.04). It was not related to the Na/K ratio in the colostrum, which is an indicator of the integrity of the mammary epithelium. When sows were categorised according to their level of colostrum yield, sows that produced a low yield of colostrum had more stillborn piglets at birth than the other sows (P<0.05) and tended to have a longer birth interval during the early process of parturition (P<0.1). At t24, concentrations of IgG in the colostrum were positively correlated with the Na/K ratio in the colostrum (r=0.53, P<0.001), which indicates the concomitance of the cessation of IgG transfer to the colostrum and the changes in the morphology of the mammary epithelium. This study points out the need for future research on the role of the hormones involved in both the process of parturition and lactogenesis in the relationship between stillbirth, process of parturition and colostrum production. PMID- 22440346 TI - The impact of incorporation of n-3 fatty acids into eggs on ovarian follicular development, immune response, antioxidative status and tibial bone characteristics in aged laying hens. AB - The objectives of this study were to investigate the effects of different dietary sources of unsaturated fatty acids (fish oil (FO) and/or linseed oil (LO)) on laying performance, egg yolk fatty acid composition, ovarian follicular development, antioxidative properties, immune response and tibial bone characteristics in aged laying hens. A total of 100 Hisex Brown hens at 56 weeks of age were housed individually in laying cages in an open-sided building under a 16 h light:8 h dark lighting schedule. Hens were randomly divided into four experimental treatments (n=25 each). Birds were fed ad libitum diets containing 2.5% vegetable oil (C, control), 2.5% FO, 2.5% LO and a mixture of 1.25% LO+1.25% FO (LO+FO) from 56 to 68 weeks of age. Egg production, egg quality characteristics and yolk lipid profile were analyzed. At 68 weeks of age, ovarian follicles were classified and tibial bone characteristics were determined. Serum thiobarbituric acid reactive substance (TBARS), glutathione peroxidase (GSH-Px) activity and total antioxidant capacity were measured. Incorporation of n-3 polyunsaturated fatty acids (n-3PUFA) into the egg yolks has been successful by using dietary FO and/or LO. There were no significant effects of treatments on hen-day egg production, feed intake, egg weight, egg shape index, albumen height, Haugh units and yolk height. However, dietary FO and/or LO supplementation had a significantly positive effect on eggshell percentage, eggshell thickness and yolk color. At 68 weeks of age, there was no significant difference among dietary treatments for tibial bone measurements. Also, no negative effects were detected in ovarian follicular development and weights of the ovary and oviduct, expressed in both absolute terms and relative to body weight. Dietary 2.5% LO, 2.5% FO and a mixture of 1.25% FO+1.25% LO enhanced GSH-Px activity, total antioxidant capacity and antibody titers significantly in comparison with control. It could be concluded that inclusion of mixed sources of n-3PUFA in diets at moderate levels (2.5%) increased the n-3PUFA content and decreased the n-6/n-3 ratio content in the yolk, improved the antioxidative status, reduced lipid peroxidation, enhanced the antibody response and did not have any negative influence on ovarian follicular development and tibial bone characteristics in aged laying hens. PMID- 22440347 TI - Subsequent effect of subacute T-2 toxicosis on spermatozoa, seminal plasma and testosterone production in rabbits. AB - Pannon White (n=12) male rabbits (weight: 4050 to 4500 g, age: 9 months) received 2 ml of a suspension containing purified T-2 toxin by gavage for 3 days. The daily toxin intake was 4 mg/animal (0.78 to 0.99 mg/kg body weight (BW)). Control animals (n=12) received toxin-free suspension for 3 days. Since a feed-refusal effect was observed on the second day after T-2 administration, a group of bucks (n=10) were kept as controls (no toxin treatment) but on a restricted feeding schedule, that is, the same amount of feed was provided to them as was consumed by the exposed animals. On day 51 of the experiment (i.e. 48 days after the 3-day toxin treatment), semen was collected, and pH, concentration, motility and morphology of the spermatozoa, as well as concentration of citric acid, zinc and fructose in the seminal plasma, were measured. After gonadotropin-releasing hormone (GnRH) analogue treatment, the testosterone level was examined. One day of T-2 toxin treatment dramatically decreased voluntary feed intake (by 27% compared to control, P<0.05) and remained lower (P<0.05) during the first 2 weeks after the withdrawal of the toxin. BW of the contaminated rabbits decreased by 88% on days 17 and 29 compared to controls (P<0.05). No effect of toxin treatment was detected on pH and quantity of the semen or concentration of spermatozoa. The ratio of spermatozoa showing progressive forward motility decreased from 65% to 53% in the semen samples of toxin-treated animals compared to controls (P>0.05). The ratio of spermatozoa with abnormal morphology increased (P<0.05) in the ejaculates collected from the toxin-treated animals. T-2 toxin applied in high doses decreased the concentration of citric acid in seminal plasma (P<0.05). No effect of T-2 toxin on the concentrations of the other seminal plasma parameters (fructose and zinc) was observed. T-2 toxin decreased the basic testosterone level by 45% compared to control (P<0.01) and resulted in lower (P<0.05) GnRH induced testosterone concentration. Feed restriction, that is, less nutrient intake, resulted in more morphologically abnormal spermatozoa in the semen, but it did not cause significant loss in BW, motility of the spermatozoa, composition of the seminal plasma or testosterone concentration--its effect needs further examination. PMID- 22440348 TI - Dietary supplementation with ovine serum immunoglobulin attenuates acute effects on growth, organ weights, gut morphology and intestinal mucin production in the growing rat challenged with Salmonella enteritidis. AB - The aim was to determine the effect of orally administered ovine serum immunoglobulin (Ig) on growth performance, organ weight, gut morphology and mucin production in the Salmonella enteritidis--gavaged growing rat. Four groups consisted of non-gavaged rats fed a casein-based control basal diet (BD) and three groups of rats gavaged with 1*10(7) CFU S. enteritidis and fed a casein based diet, a diet containing freeze-dried ovine Ig (FDOI) or a casein-based diet containing inactivated ovine Ig (IOI). The rats were randomly allocated to one of the four groups (n=15/group) and received their respective diets for an 18-day experimental study. Gavaging took place on day 15. Average daily gain and body gain : feed ratio (post-gavage, 3 days) were significantly (P<0.05) higher for the Salmonella-challenged rats fed the FDOI diet compared to those fed the BD and IOI diets. At the end of the study, the small intestine and colon were significantly (P<0.05) heavier for the gavaged rats fed the FDOI diet compared to the gavaged rats fed either the BD or IOI diet. Moreover, the relative weights of the caecum, liver and spleen of the gavaged rats fed the BD or IOI diet were significantly (P<0.05) heavier compared to the gavaged rats fed the FDOI diet. Generally, the gavaged rats fed the FDOI diet had significantly (P<0.05) higher goblet cell counts and luminal mucin protein contents than the gavaged rats fed either the BD or IOI diet and had a more functional gut morphology. Overall, the FDOI fraction prevented the acute effects of S. enteritidis. PMID- 22440349 TI - Whole body insulin responsiveness is higher in beef steers selected for increased muscling. AB - The aim of this experiment was to evaluate the impact of selection for greater muscling on whole body insulin responsiveness in cattle, as reflected by greater uptake of glucose in response to constant insulin infusion and greater glucose disappearance following an intravenous glucose tolerance test. This study used 18 month-old steers from an Angus herd visually assessed and selected for divergence in muscling over 15 years. Eleven high-muscled (High), 10 low-muscled (Low) and 3 high-muscled steers, which were heterozygous for a myostatin polymorphism (HighHet), were infused with insulin using the hyperinsulineamic-euglyceamic clamp technique. Insulin was constantly infused at two levels, 0.6 MUIU/kg per min and 6.0 MUIU/kg per min. Glucose was concurrently infused to maintain euglyceamia and the steady state glucose infusion rate (SSGIR) indicated insulin responsiveness. An intravenous glucose tolerance test was also administered at 200 mg/kg live weight. Sixteen blood samples were collected from each animal between -30 and 130 min relative to the administration of intravenous glucose, plasma glucose and insulin concentration was determined in order to analyse insulin secretion and glucose disappearance. Insulin-like growth factor-1 (IGF-1) was also measured in basal plasma samples. At the low insulin infusion rate of 0.6 mU/kg per min, the SSGIR was 73% higher for the High muscling genotype animals when compared to the Low (P<0.05). At the high insulin infusion rate of 6.0 mU/kg per min, these differences were proportionately less with the High and the HighHet genotypes having only 27% and 34% higher SSGIR (P<0.05) than the Low muscled genotype. The High-muscled cattle also had 30% higher plasma IGF-1 concentrations compared to the Low-muscled cattle. There was no effect of muscling genotype on basal insulin or basal glucose concentrations, glucose disappearance or insulin secretion following an intravenous glucose tolerance test. The increased whole body insulin responsiveness in combination with higher IGF-1 concentrations in the High-muscled steers is likely to initiate a greater level of protein synthesis, which may partially explain the increased muscle accretion in these animals. PMID- 22440350 TI - Thermoregulation and water balance in fat-tailed sheep and Kacang goat under sunlight exposure and water restriction in a hot and dry area. AB - The objective of this study was to analyze differences in thermoregulation and water balance under conditions of heat load and water restriction between fat tailed sheep (S) and Kacang goats (G). The daily intakes of food and water, daily outputs of urine and feces, rectal temperature, respiration rates, hematocrit values and plasma volumes of five shorn S and five G were determined over 10 days of four consecutive experimental conditions: (1) indoor--unrestricted water; (2) indoor--restricted water; (3) 10 h sunlight exposure--unrestricted water; and (4) 10 h sunlight exposure--restricted water. There was a 6- to 7-day adjustment period between two consecutive conditions. The study was conducted during the dry season. The animals were placed in individual cages, fed chopped native grass ad libitum and had free access to a urea-molasses multi-nutrient block. Under sunlight exposure with unrestricted water availability, S and G record an increase in the maximum rectal temperatures from 39.2 degrees C to 40.2 degrees C and from 39.9 degrees C to 41.8 degrees C, respectively. The thermoregulatory strategy used by S for maintaining a lower rectal temperature mostly depends on increasing the respiration rate as the main cooling mechanism. On the other hand, G apparently used sweating as the predominant mechanism for cooling. Moreover, G seemed to be more tolerable to higher heat storage and body temperature than S with a significant increase in plasma volume (P<0.01), and this may be beneficial to the animals for the prevention of water loss. Under restricted water condition in either indoor or outdoor environment, both species decreased their plasma volume significantly, but rectal temperatures were relatively maintained. In all experimental conditions, the daily total water exchanges (ml/kg0.82 per day) of S were significantly higher than G (P<0.01). However, when the percentages of the total daily water exchange were considered, the water lost through urination (38% to 39%), defecation (11% to 14%) and evaporation (46% to 49%) by S and G was not significantly different. Therefore, the results from this study clearly showed that S and G have different homeostatic strategies for the regulation of body temperature and fluid to cope with heat load and water restriction. These differences may have an important impact on the production management of S and G. PMID- 22440351 TI - New insights into the influence of breed and time of the year on the response of ewes to the 'ram effect'. AB - Exposure of anoestrous ewes to rams induces an increase in LH secretion, eventually leading to ovulation. This technique therefore is an effective, low cost and hormone-free way of mating sheep outside the breeding season. However, the use of this technique is limited by the variability of the ewes' responses. In this study, our objective was to understand more completely the origins of this variability and to determine the relative roles of breed, the point in time during anoestrus and the depth of anoestrus on the response to the 'ram effect'. In the first experiment, the pattern of anoestrus on the basis of the concentration of progesterone determined weekly, was determined in four breeds including two less seasonal (Merinos d'Arles and Romane), one highly seasonal (Mouton Vendeen) and one intermediate (Ile-de-France) breeds. Anoestrus was longer and deeper in Mouton Vendeen and Ile-de-France than in Romane or Merinos d'Arles. In the second experiment, we used the same four breeds and tested their hypophyseal response to a challenge with a single dose of 75 ng gonadotrophin releasing hormone (GnRH) in early, mid and late anoestrus, and then we examined their endocrine and ovarian responses to the 'ram effect'. Most (97%) ewes responded to GnRH and most (93%) showed a short-term increase in LH pulsatility following the 'ram effect'. The responses in both cases were higher in females that went on to ovulate, suggesting that the magnitude of the hypophyseal response to a GnRH challenge could be a predictor of the response to the 'ram effect'. As previously observed, the best ovarian response was in Merinos d'Arles at the end of anoestrus. However, there was no relationship between the proportion of females in the flock showing spontaneous ovulation and the response to the 'ram effect' of anoestrous ewes from the same flock. PMID- 22440352 TI - Influence of colostrum intake on piglet survival and immunity. AB - Colostrum intake from birth to 24 h after the onset of parturition (T24) was estimated for 526 piglets from 40 litters. Plasma concentrations of immunoglobulin G (IgG), lactate, glucose and cortisol were determined at T24 for six piglets per litter. Plasma IgG concentration was also assayed at weaning (28 days) on the same piglets. Rectal temperature was measured at T24 on all piglets. Mortality was recorded until weaning and comparisons were made between piglets that died before weaning and those that were still alive at weaning. The piglets that died before weaning had lower birth weight, lower colostrum intake, lower weight gain between birth and T24, and had a lower rectal temperature, higher plasma cortisol concentration and lower plasma IgG and glucose concentrations at T24 than piglets still alive at weaning. In addition, a higher proportion of piglets that died before weaning had difficulty taking their first breath after birth and were affected by splayleg. Considering all piglets, colostrum intake was positively related to rectal temperature and plasma glucose concentration and negatively related to plasma cortisol concentration at T24. Plasma IgG concentration at T24 was explained by colostrum intake, IgG concentration in the ingested colostrum, birth weight and birth rank (P<0.0001). Plasma IgG concentration at weaning was related to plasma IgG concentration at T24 (r=0.54; P<0.0001) and to colostrum intake (r=0.32; P<0.0001). Finally, body weight was explained by colostrum intake, birth weight and age until 6 weeks of age (P<0.0001). These results show that colostrum intake is the main determinant of piglet survival through provision of energy and immune protection and has potential long-term effects on piglet growth and immunity. PMID- 22440353 TI - Identifying risk factors for poor hind limb cleanliness in Danish loose-housed dairy cows. AB - The objective of this study was to identify possible risk factors for poor cow hind limb cleanliness in Danish loose-housed, lactating dairy cows. The study was conducted as a cross-sectional study of 1315 cows in 42 commercial Danish dairy herds with primarily Danish Holstein cows. The effect of four cow-level factors (parity, days in milk, daily lying time and lameness) and eight herd-level factors (herd size, milk production, milking system, floor type, access to pasture grazing, floor scraping frequency, hoof bathing frequency and hoof washing frequency) on the risk of having dirtier hind limbs were analysed using ordinal logistic regression fitting a proportional odds model. Cow hind limb cleanliness was scored using an ordinal score from 1 to 4: 1 being clean and 4 being covered in dirt. The odds ratios (ORs) estimated from the proportional odds model depict the effect of a risk factor on the odds of having a higher rather than a lower cleanliness score. First parity cows had an increased risk of being dirtier compared with third parity or older cows (OR=1.70). Compared with late lactation, early and mid lactation were associated with an increased risk of being dirtier (OR=2.07 and 1.33, respectively). Decreasing the daily time lying by 30 min was associated with an increased risk of being dirtier (OR=1.05). Furthermore, an increased risk of being dirtier was found in herds with no pasture access (OR=3.75). PMID- 22440354 TI - Alternative rearing systems in pigs: consequences on stress indicators at slaughter and meat quality. AB - The objective of this study was to evaluate the effects of three alternative (ALT) rearing systems for growing pigs (outdoor: 150 m2/pig; straw bedding: 1.30 m2/pig; and hut with access to a courtyard: 1.30 m2/pig) compared with a conventional system (fully slatted floor: 0.65 m2/pig, considered as control), on pre-slaughter stress indicators in relation with meat quality. To that end, the number of skin lesions on whole carcasses, as well as blood creatine kinase (CK) activity and urine levels in cortisol and catecholamines (adrenaline and noradrenaline) were determined at slaughter. Glycolytic potential (GP) and ultimate pH of the semimembranosus muscle were also measured. The global correlation network calculated between all these parameters shows that the indicators of pre-slaughter muscle activity (plasma CK) and/or stress indicators (e.g. adrenaline) are negatively (r=-0.26, P<0.01; r=-0.29, P<0.05, respectively) correlated with muscle GP and positively (r=0.17, P<0.05; r=0.44, P<0.001, respectively) with meat ultimate pH. Although some traits measured were sensitive to the degree of pre-slaughter mixing, they differed across rearing systems. The differences were most pronounced for the comparison of outdoors v. slatted floor. The lower levels of plasma CK and urinary catecholamines, and the lower number of carcass skin lesions of pigs reared outdoors, were related to a lower meat ultimate pH. Thus, ALT rearing systems influence animal welfare and meat quality, by providing enriched environmental conditions to the animals. PMID- 22440355 TI - Associations between herd size, rate of expansion and production, breeding policy and reproduction in spring-calving dairy herds. AB - Dairy herd size is expected to increase in many European countries, given the recent policy changes within the European Union. Managing more cows may have implications for herd performance in the post-quota era. The objective of this study was to characterise spring-calving herds according to size and rate of expansion, and to determine trends in breeding policy, reproduction and production performance, which will inform industry of the likely implications of herd expansion. Performance data from milk recording herds comprising 775,795 lactations from 2,555 herds for the years 2004 to 2008 inclusive were available from the Irish Cattle Breeding Federation. Herds were classified into Small (average of 37 cows), Medium (average of 54 cows) and Large (average of 87 cows) and separately into herds that were not expanding (Nil expansion), herds expanding on average by three cows per year (Slow expansion) and herds expanding on average by eight cows per year (Rapid expansion). There was no association between rate of expansion and 305-day fat and protein yield. However, 305-day milk yield decreased and milk protein and fat percentage increased with increasing rate of expansion. There were no associations between herd size and milk production except for protein and fat percentage, which increased with increasing herd size. Average parity number of the cows decreased as rate of expansion increased and tended to decrease as herd size increased. In rapidly expanding herds, cow numbers were increased by purchasing more cattle. The proportion of dairy sires relative to beef sires used in the breeding programme of expanding herds increased and there was more dairy crossbreeding, albeit at a low rate. Similarly, large herds were using more dairy sires and fewer beef sires. Expanding herds and large herds had superior reproductive performance relative to non-expanding and small herds. Animals in expanding herds calved for the first time at a younger age, had a shorter calving interval and were submitted for breeding by artificial insemination at a higher rate. The results give confidence to dairy producers likely to undergo significant expansion post quota such that, despite managing more cows, production and reproductive performance need not decline. The management skills required to achieve these performance levels need investigation. PMID- 22440356 TI - Inter-laboratory comparison of methods to measure androstenone in pork fat. AB - Today, different analytical methods are used by different laboratories to quantify androstenone in fat tissue. This study shows the comparison of methods used routinely in different laboratories for androstenone quantification: Time resolved fluoroimmunoassay in Norwegian School of Veterinary Science (NSVS; Norway), gas chromatography coupled to mass spectrometry in Co-operative Central Laboratory (CCL; The Netherlands) and in Institut de Recerca i Tecnologia Agroalimentaries (IRTA; Spain), and high-pressure liquid chromatography in Agroscope Liebefeld-Posieux Research Station (ALP; Switzerland). In a first trial, a set of adipose tissue (AT) samples from 53 entire males was sent to CCL, IRTA and NSVS for determination of androstenone concentration. The average androstenone concentration (s.d.) was 2.47 (2.10) MUg/g at NSVS, 1.31 (0.98) MUg/g at CCL and 0.62 (0.52) MUg/g at IRTA. Despite the large differences in absolute values, inter-laboratory correlations were high, ranging from 0.82 to 0.92. A closer look showed differences in the preparation step. Indeed, different matrices were used for the analysis: pure fat at NSVS, melted fat at CCL and AT at IRTA. A second trial was organised in order to circumvent the differences in sample preparation. Back fat samples from 10 entire males were lyophilised at the ALP labortary in Switzerland and were sent to the other laboratories for androstenone concentration measurement. The average concentration (s.d.) of androstenone in the freeze-dried AT samples was 0.87 (0.52), 1.03 (0.55), 0.84 (0.46) and 0.99 (0.67) MUg/g at NSVS, CCL, IRTA and ALP, respectively, and the pairwise correlations between laboratories ranged from 0.92 to 0.97. Thus, this study shows the influence of the different sample preparation protocols, leading to major differences in the results, although still allowing high inter laboratory correlations. The results further highlight the need for method standardisation and inter-laboratory ring tests for the determination of androstenone. This standardisation is especially relevant when deriving thresholds of consumer acceptance, whereas the ranking of animals for breeding purposes will be less affected due to the high correlations between methods. PMID- 22440357 TI - Length of concentrate finishing affects the fatty acid composition of grass-fed and genetically lean beef: an emphasis on trans-18:1 and conjugated linoleic acid profiles. AB - Intensively finishing cattle on a high-grain diet is generally used to enhance marbling, whereas extensively finishing on grass is known to provide improved muscle fatty acid profiles. The objective of this study was to evaluate to what extent intensive concentrate finishing (0, 1 or 2 months) can be combined with forage feeding without negatively affecting the fatty acid profile of genetically lean animals. Bulls from the 'Asturiana de los Valles' breed were reared under grazing conditions with/without final finishing on a barley-based concentrate: 0 months (control; n=7), 1 month (n=10) and 2 months (n=7). Yearling bulls were slaughtered commercially at an average live weight of 516+/-9.8 kg. Increasing the finishing time on concentrate significantly increased the saturated and monounsaturated fatty acids, whereas polyunsaturated fatty acids (PUFAs) tended to decrease and it was not possible to increase the long-chain PUFA content in muscle tissue of this breed. An increase was observed for total trans-18:1 (average 5.5% with grain v. 3.7% for grass). The 11t-18:1/10t-18:1 ratio was significantly higher in grass-fed (average 8.1) compared with grain-finished animals (average 1.1). Grass or limited concentrate finishing reduced the n-6/n-3 ratio in muscle tissue (average 3.6 for 0 and 1 month, and 4.9 for 2 months on grain finishing). The beef was within or close to the recommended values for human consumption (i.e. polyunsaturated/saturated>0.45, n-6/n-3<4.0), and total trans-FA content was low. However, finishing increased the content of undesirable trans-18:1 and conjugated linoleic acid isomers, particularly after 2 months, whereas grass finishing was judged to provide a healthier beef fatty acid profile. PMID- 22440358 TI - Effectiveness of mid-infrared spectroscopy to predict fatty acid composition of Brown Swiss bovine milk. AB - Mid-infrared spectroscopy (MIR) is used to predict fatty acid (FA) composition of individual milk samples (n=267) of Brown Swiss cows. FAs were analyzed by gas chromatography as a reference method. Samples were scanned (4000 to 900 cm-1) by MIR, and predictive models were developed using modified partial least squares regressions with full cross-validation. The methods using a first derivative or multiplicative scatter corrected plus first derivative resulted, on average, in the best predictions. Coefficients of correlation between measured and predicted C8:0, C10:0, C12:0, C14:0, anteiso-C17:0, c9-C18:1, and medium- and long-chain FA, and saturated, monounsaturated and unsaturated FA ranged from 0.71 to 0.77, suggesting that prediction models can be implemented in milk recording schemes to routinely collect information on FA composition from the whole Brown Swiss population for breeding purposes. PMID- 22440359 TI - Feeding vegetable oils to lactating ewes modifies the fatty acid profile of suckling lambs. AB - The objective of this study was to evaluate the effects of vegetable oil supplementation of ewe diets on the performance and fatty acid (FA) composition of their suckling lambs. Forty-eight pregnant Churra ewes (mean BW 64.3+/-0.92 kg) with their 72 newborn lambs (prolificacy=1.5) were assigned to one of four experimental diets, supplemented with 3% of hydrogenated palm (PALM), olive (OLI), soya (SOY) or linseed (LIN) oil. Lambs were nourished exclusively by suckling from their respective mothers. Ewes were milked once daily, and milk samples were taken once a week. When lambs reached 11 kg, they were slaughtered and samples were taken from musculus longissimus dorsi (intramuscular fat) and subcutaneous fat tissue. No changes were observed in milk yield, proximal composition or lamb performance (P>0.10). Milk and lamb subcutaneous and intramuscular fat samples from the PALM diet had the highest saturated fatty acid concentration, whereas those of the OLI, SOY and LIN diets had the lowest (P<0.05). The greatest monounsaturated fatty acid concentration was observed in milk from ewes fed OLI, and the least in milk and in lamb subcutaneous and intramuscular fat samples from LIN and PALM diets. Milk and lamb fat from ewes fed PALM displayed the highest 16:0 proportion and the lowest 18:0 (P<0.05). There were higher concentrations of cis-9 18:1 in OLI samples (P<0.05), more 18:2n-6 in SOY lambs and milk fat (P<0.001) and the highest levels of 18:3n-3 and 20:5n-3 in LIN samples (P<0.01). Milk and lamb subcutaneous and intramuscular samples from SOY and LIN diets contained the most cis-9, trans-11 conjugated linoleic acid, whereas PALM samples had the least (P<0.01). Sheep diet supplementation with different oils, constituting up to 3% of their diets, resulted in changes in the FA composition of milk and the subcutaneous and intramuscular fat of suckling lambs, but did not affect either milk production or lamb performance. PMID- 22440360 TI - 43 year old male with a right pelvic mass. PMID- 22440361 TI - [The spine throughout time]. PMID- 22440362 TI - Analysis of cartilage oligomeric matrix protein and matrix metalloproteinase-9 in cerebrospinal fluid of miniature dachshund with intervertebral disc herniation. AB - We evaluated whether the cerebrospinal fluid (CSF) concentration of cartilage oligomeric matrix protein (COMP) is related to disease severity, prognosis and matrix metalloproteinase (MMP)-9 activity of the CSF in miniature dachshund with intervertebral disc herniation. Samples were obtained from 23 patients and 6 normal dogs, and all patients received hemilaminectomy. Twenty dogs recovered successfully and 3 of 11 dogs without deep nociception had MMP-9 activity in the CSF and an unsuccessful outcome. The COMP levels from patients were significantly higher than those from normal dogs. MMP-9 activity and neurological severity were not related to the COMP levels. However, the COMP levels from 3 unsuccessful cases that had MMP-9 activity were significantly lower than those from all recovered cases and/or successful cases without deep nociception. Concerning severe cases, increased proteolytic activity might affect the COMP concentration and prognosis due to MMP-9 associated deleterious effects. PMID- 22440363 TI - Mitral replacement or repair for functional mitral regurgitation in dilated and ischemic cardiomyopathy: is it really the same? AB - BACKGROUND: This was a study to compare the results of mitral valve (MV) repair and MV replacement for the treatment of functional mitral regurgitation (MR) in advanced dilated and ischemic cardiomyopathy (DCM). METHODS: One-hundred and thirty-two patients with severe functional MR and systolic dysfunction (mean ejection fraction 0.32 +/- 0.078) underwent mitral surgery in the same time frame. The decision to replace rather than repair the MV was taken when 1 or more echocardiographic predictors of repair failure were identified at the preoperative echocardiogram. Eighty-five patients (64.4%) received MV repair and 47 patients (35.6%) received MV replacement. Preoperative characteristics were comparable between the 2 groups. Only ejection fraction was significantly lower in the MV repair group (0.308 +/- 0.077 vs 0.336 +/- 0.076, p = 0.04). RESULTS: Hospital mortality was 2.3% for MV repair and 12.5% for MV replacement (p = 0.03). Actuarial survival at 2.5 years was 92 +/- 3.2% for MV repair and 73 +/- 7.9% for MV replacement (p = 0.02). At a mean follow-up of 2.3 years (median, 1.6 years), in the MV repair group LVEF significantly increased (from 0.308 +/- 0.077 to 0.382 +/- 0.095, p < 0.0001) and LV dimensions significantly decreased (p = 0.0001). On the other hand, in the MV replacement group LVEF did not significantly change (from 0.336 +/- 0.076 to 0.31 +/- 0.11, p = 0.56) and the reduction of LV dimensions was not significant. Mitral valve replacement was identified as the only predictor of hospital (odds ratio, 6; 95% confidence interval, 1.1 to 31; p = 0.03) and overall mortality (hazard ratio, 3.1; 95% confidence interval, 1.1 to 8.9; p = 0.02). CONCLUSIONS: In patients with advanced dilated and ischemic cardiomyopathy and severe functional MR, MV replacement is associated with higher in-hospital and late mortality compared with MV repair. Therefore, mitral repair should be preferred whenever possible in this clinical setting. PMID- 22440364 TI - Early experience with robotic lung resection results in similar operative outcomes and morbidity when compared with matched video-assisted thoracoscopic surgery cases. AB - BACKGROUND: Robotic lung resection is gaining popularity despite limited published evidence. Comparative studies are needed to provide information about the safety and effectiveness of robotic resection. Therefore, we compared our initial experience with robotic anatomic resection to our most recent video assisted thoracoscopic surgery (VATS) cases. METHODS: A case-control analysis of consecutive anatomic lung resections by robot or VATS from 2009 through 2011 was performed. RESULTS: In the robotic group, 52 resections were attempted. Three conversions and 3 wedges were excluded, leaving 40 lobectomies, 5 segments, and 1 conversion to VATS. In the VATS group, 35 resections were attempted with 1 conversion. The distribution of resected lobes or segments and demographics was similar. Clinical outcomes between robotics and VATS were similar in tumor size (2.8 versus 2.3 cm), operative time (213 versus 208 minutes), blood loss (153 versus 134 mL), intensive care unit stay (0.9 versus 0.6 days), and length of stay (4.0 versus 4.5 days). There was no operative mortality. Major (n=8; 17%) and minor morbidity (n=12; 26%) with robotics was similar to VATS. The percentage of expected nodal stations sampled was similar. The duration of narcotic use after discharge (p=0.039) and the time to return to usual activities (p=0.001) was shorter in the robotic group. CONCLUSIONS: Early experience with robotic resection resulted in similar outcomes compared with mature VATS cases. A potential benefit of robotics may relate to postoperative pain reduction and earlier return to usual activities. Robotic lung resection should be studied further in selected centers and compared with VATS in a randomized fashion to better define its potential advantages and disadvantages. PMID- 22440365 TI - Number of lymph nodes and metastatic lymph node ratio are associated with survival in lung cancer. AB - BACKGROUND: The non-small cell lung cancer TNM classification system uses only the anatomic extent of lymph node (LN) metastases to define the N category. The number of LNs resected and the ratio of positive LNs to total examined LNs are prognostic in other solid tumors. We used the Surveillance, Epidemiology and End Results database to investigate the effect of these factors on the overall survival of non-small cell lung cancer. METHODS: All patients with non-small cell lung cancer in the Surveillance, Epidemiology and End Results database from 1988 through 2007 who had curative resections and had at least one LN examined were included. The prognostic value of age, race, sex, tumor size, histologic grade, number of examined LNs, and ratio of positive LNs to total examined LNs was assessed using a multivariate Cox proportional hazards model for overall survival. The number of LNs examined was categorized into four levels. The percentage of positive LNs was stratified into three levels. RESULTS: Among patients with localized disease, fewer LNs examined corresponded with a worse prognosis. Prognosis improved as more LNs were examined. For patients with regional disease, the differences were significant only at the extremes. Older patients, males, and those with higher grade or larger tumors did worse. Patients with low or moderate ratios of positive to total LNs had better prognoses than those with high ratios. CONCLUSIONS: More LNs resected and lower ratios of positive LNs to total examined LNs are associated with better patient survival after non-small cell lung cancer resection independent of age, sex, grade, tumor size, and stage of disease. PMID- 22440366 TI - Do pericardial bioprostheses improve outcome of elderly patients undergoing aortic valve replacement? AB - BACKGROUND: Pericardial bioprostheses have favorable echocardiographic hemodynamics in the aortic position compared with porcine valves; however, there are few data comparing clinical outcomes. Our objective was to assess the late results of the two valve types. METHODS: We reviewed 2,979 patients aged 65 years or older undergoing aortic valve replacement with pericardial (n=1,976) or porcine (n=1,003) prostheses between January 1993 and December 2007. The most common pericardial prostheses were Carpentier-Edwards Perimount and Mitroflow, and the most common porcine valves were Medtronic Mosaic, Carpentier-Edwards, Hancock modified orifice, and St. Jude Biocor. Follow-up extended to a maximum of 16 years (mean, 5.2+/-3.5 years). RESULTS: Survival at 5, 10 and 12 years was, respectively, 68%, 33%, and 21% overall, was 68%, 30%, and 16% for patients with pericardial bioprosthesis, and was 69%, 38% and 27% for the porcine group. In a multivariate model, long-term survival was reduced in patients with diabetes, renal failure, prior myocardial infarction, congestive heart failure, and older age, but late survival was not higher in the pericardial valve group. Overall freedom from reoperation was 96%, 92%, and 90% at 5, 10, and 12 years, and freedom from explant was 98%, 96%, and 94% during the same period. The reason for explant was structural valve deterioration in 50 patients (2%). CONCLUSIONS: Despite the better hemodynamic performance documented in prior investigations, pericardial valves do not confer any survival advantage over porcine valves in patients aged 65 years or older undergoing aortic valve replacement. PMID- 22440367 TI - Free jejunal graft for esophageal reconstruction using end-to-side vascular anastomosis and extended pharyngo-jejunostomy. AB - BACKGROUND: Pharyngo-esophageal reconstruction using free jejunal grafts (FJGs) has been widely used, but the procedure is technically demanding and requires the involvement of multiple departments. We performed simplified reconstruction with FJGs using end-to-side vascular anastomosis and extended pharyngo-jejunostomy. METHODS: The jejunal artery and vein were anastomosed to the neck vessels in an end-to-side fashion without microvascular anastomosis. Pharyngo-jejunostomy with extended end-to-end anastomosis was performed to reduce size mismatch. We retrospectively analyzed the medical records of 32 patients diagnosed with pharyngeal, esophageal, or pyriform sinus cancer who received a FJG. RESULTS: The mean age was 61.5+/-9.4 years, and there were 25 male patients. Jejunal vessels were commonly anastomosed to the right common carotid artery and the right internal jugular vein (22, 68.8%). The mean ischemic times of the FJG and carotid artery clamping time were 46.5+/-8.1 and 15.8+/-4.4 minutes, respectively. During the procedure, 3 patients suffered from inadequate reperfusion of the FJG requiring removal of the initial graft and replacement with another FJG. There were no neurologic complications, postoperative deaths, or adverse events directly related to FJG except for leakage of the pharyngo-jejunostomy site in 1 patient, which was primarily repaired. During the follow-up period, 5 patients (15.6%) suffered from dysphagia, but only 3 patients had evidence of anastomotic strictures at the jejuno-esophagostomy site. Thirteen patients (40.6%) received postoperative adjuvant radiotherapy. CONCLUSIONS: Our technique of FJG with end to-side vascular anastomosis and extended pharyngo-jejunostomy is simple and safe. PMID- 22440368 TI - Clinical and molecular predictors of recurrence in stage I non-small cell lung cancer. AB - BACKGROUND: Patients with stage I lung cancer undergoing a complete resection have a 25% risk of recurrence. Factors predictive for recurrence are critically needed. In the present study, we prospectively examined clinical and molecular factors that may predict a poor outcome. METHODS: Patients with stage I non-small cell lung cancer undergoing surgical resection were enrolled into an institutional registry. Clinical demographics and outcomes data were prospectively collected. Patients who received neoadjuvant therapy or patients who died within 30 days of surgery were excluded from this analysis. Molecular factors involved in cell proliferation, cell cycle control, apoptosis, and angiogenesis were analyzed. The primary endpoint was recurrence-free survival. RESULTS: One hundred and two patients were enrolled between March 2006 and April 2009. There were 25 (25%) documented recurrences. In univariate analysis, male sex, increased tumor standard uptake value, tumor size, final pathology stage, arterial invasion, percent nuclear phosphorylated AKT, vascular endothelial growth factor score, negative cyclin D1 protein expression, and percent nuclear cyclin D1 expression were predictive of decreased recurrence-free survival. All factors with a p value of 0.1 or less were included in multivariate analysis. Male sex, final pathology stage, vascular endothelial growth factor score, and percent nuclear cyclin D1 expression were significant independent predictors for poor prognosis. CONCLUSIONS: Four clinical and molecular factors were associated with prognosis in a prospective study of stage I non-small cell lung cancer. PMID- 22440369 TI - Stem cells in thoracic aortic aneurysms and dissections: potential contributors to aortic repair. AB - BACKGROUND: The hallmark of thoracic aortic aneurysms and dissections (TAAD) is progressive medial degeneration, which can result from excessive tissue destruction and insufficient repair. Although multipotent stem cells (SCs) are important in tissue repair, their role in TAAD is unknown. We sought to determine whether SCs are more abundant in TAAD tissue than in control tissues, and whether SCs within the diseased aortic wall differentiate into functionally relevant cell types. METHODS: Using immunohistochemistry, we compared the abundance of STRO-1+ cells, c-kit+ cells, and CD34+ cells in aortic tissue from patients with descending thoracic aortic aneurysms (n=12), patients with chronic descending thoracic aortic dissections (n=18), and age-matched organ donors (n=5). Using double immunofluorescence staining, we evaluated SC differentiation into smooth muscle cells, fibroblasts, and macrophages. RESULTS: All three cell types were significantly more abundant in the media and adventitia of TAAD tissues than in control tissues. We identified subsets of STRO-1+ cells, c-kit+ cells, and CD34+ cells that also expressed the smooth muscle cell marker SM22-alpha or fibroblast specific protein-1, suggesting SC differentiation into smooth muscle cells or fibroblasts. Other STRO-1+ cells expressed the macrophage marker CD68, suggesting differentiation into inflammatory cells. CONCLUSIONS: Stem cells are more abundant in TAAD tissue than in normal aortic tissue. Differentiation of SCs into smooth muscle cells, fibroblasts, and inflammatory cells within the diseased aortic wall suggests that SCs might be involved in both reparative and destructive remodeling processes in TAAD. Understanding the regulation of SC mediated aortic remodeling will be a critical step toward designing strategies to promote aortic repair and prevent adverse remodeling. PMID- 22440370 TI - Scientific articles' titles: thanks for the information contained in your title. PMID- 22440371 TI - Cigarette smoking and the effect of dexmedetomidine and fentanyl on tracheal intubation. AB - BACKGROUND AND OBJECTIVES: To compare the effect of dexmedetomidine and fentanyl on hemodynamic changes in chronic male smokers. METHODS: This is a prospective, randomized, blinded study. Were selected 60 chronic male smokers (aged 16 to 60 years). The patients were randomly divided into two groups: Group D (n=30) received 1MUg.kg(-1) dexmedetomidine and Group F (n=30) received 3MUg.kg(-1) fentanyl in 150mL of normal saline, beginning 10 minutes before anesthesia induction. Before intubation, the heart rate and blood pressure of patients were measured. After anesthesia induction for endotracheal intubation, heart rate and blood pressure values were measured at 1, 3, and 5 minutes after intubation. RESULTS: Heart rate was low in Group D before anesthesia induction, intubation, and at the 1st and 3rd minutes after intubation. Systolic arterial pressure was low in Group F before intubation. Although diastolic arterial pressure was lower before anesthesia induction and at 5 minutes after intubation in both groups, it was already low in Group F before intubation. Whereas the mean arterial pressure was low in Group D before anesthesia induction, it was low in Group F before intubation. The values for rate-pressure product were low in Group D before induction and at 1 and 3 minutes after intubation. CONCLUSIONS: Dexmedetomidine, which was applied via infusion at a loading dose of 1MUg.kg(-1) 10 minutes before anesthesia induction in chronic male smokers, better suppressed increases in heart rate and rate-pressure product at 1 and 3 minutes after intubation compared to the group receiving 3MUg.kg(-1) fentanyl. PMID- 22440372 TI - Assessment of induction, recovery, agitation upon awakening, and consumption with the use of two brands of sevoflurane for ambulatory anesthesia. AB - BACKGROUND AND OBJECTIVES: Due to its pharmacological characteristics, sevoflurane is the ideal anesthetic for short-duration procedures. There are two brands of sevoflurane in the Brazilian market, Sevocris(r) and Sevorane(r), with different formulations and packaging. The objective of this study was to assess whether there are differences between the two anesthetics regarding induction, maintenance, recovery, and consumption. METHODS: One hundred and thirty children were included, divided into two groups according to the brand used: Group 1 was assigned to sevoflurane Cristalia(r) and Group 2 to sevoflurane Abbott(r). The following parameters were assessed: heart rate, systolic and diastolic blood pressure, fraction of inspired and expired sevoflurane, BIS values, tympanic temperature, induction and recovery time, agitation upon awakening measured by the PAED scale, and anesthetic consumption by weighing the vaporizers. Anesthesia was induced with 1 MAC and increased every three breaths at 0.5 MAC, up to 3 MAC. RESULTS: There was no difference between groups regarding the duration of the procedure, the anesthesia, and the parameters evaluated at induction. In Group 1, the number of children who required additional bolus of sevoflurane for anesthesia maintenance was higher than in Group 2 (p<0.05). The fraction of inspired and expired sevoflurane at the end of the procedure was lower in Group 1 (p<0.001). Upon awakening, BIS value was lower in Group 1 (p=0.045). Other parameters evaluated in recovery showed no difference between groups. The use of anesthesia was similar between groups. PMID- 22440373 TI - Treatment of hemicrania continua: case series and literature review. AB - BACKGROUND AND OBJECTIVES: Hemicrania Continua (HC) is a primary, disabling headache characterized by a continuous unilateral pain and responsive to indomethacin. There are symptoms common to the trigeminal-autonomic cephalalgias and migraine that complicate the diagnosis. This review aims to describe HC in a case series and review the best available evidence on alternative therapies. METHOD: A systematic review of medical records and diaries of pain of 1,600 patients treated between January 1992 and January 2011 in a headache outpatient clinic. RESULTS: Ten patients with a possible diagnosis of hemicrania continua were selected; seven were diagnosed with HC according to the II International Classification of Headache Disorders. None of the patients had received the correct diagnosis before being treated at the outpatient clinic and the average time for treatment was 12 years. Prophylactic treatment was effective in 66.6% of cases with amitriptyline, 20% with gabapentin and 10% with topiramate. CONCLUSIONS: HC should be considered among the diagnostic hypotheses of patients with continuous headache, with no change in neurological examination and additional tests, regardless the age of onset. The standard treatment with indomethacin (100-150mg.day(-1)) has significant risks associated with both short and long term use and may not be a good choice for continuous use. Recent studies point out possible alternatives: gabapentin, topiramate, cyclooxygenase-2 inhibitors, piroxicam, beta-cyclodextrin, amitriptyline, melatonin. Other drugs were described in different reports as efficient, but most of them were considered inefficient in other HC cases. PMID- 22440374 TI - Minor postoperative complications related to anesthesia in elective gynecological and orthopedic surgical patients at a teaching hospital in Kingston, Jamaica. AB - BACKGROUND AND OBJECTIVES: Minor postoperative anesthetic complications may increase patient discomfort and dissatisfaction and delay recovery. This paper sought to determine the frequency of minor complications in the first 48 hours postoperatively reported by elective gynecological and orthopedic surgical patients at the University Hospital of the West Indies, Jamaica. Overall satisfaction with anesthetic care and possible risk factors for developing complications were also assessed. METHODS: A prospective, descriptive cohort study was undertaken with patient interviews 24 to 48 hours after anesthesia. Data were analyzed using SPSS version 12 and assessed using the chi(2)-square test and multiple logistic regression models. RESULTS: Five hundred and five (505) patients were included, with 374 females (74%). Most were ASA I (55%) or ASA II (38%) and had general anesthesia (80%). A total of 419 (83%) patients reported at least one complication postoperatively. The most frequently reported complications were sore throat (44%), nausea (30%), vomiting (24%), and thrombophlebitis (20%). The mode of the Verbal Numerical Rating Score (VNRS) for each complication ranged between 2 and 5, suggesting that most did not cause severe distress. Age less than 45 years (OR 2.22, 95% CI 1.34-3.69, p=0.002) and female gender (OR 3.64, 95% CI 2.14-6.20, p<0.001) were identified as significant independent variables. Most patients regarded their anesthetic experience as excellent (51%) or very good (22%). CONCLUSION: This study showed a comparatively high incidence of minor postoperative complications (83%), but low reported severity of symptoms and a high overall satisfaction rate. Special attention should be paid to reduce these minor complications through more meticulous anesthetic technique. PMID- 22440375 TI - Receptiveness and humanization from the perspective of anesthesiologists. AB - BACKGROUND AND OBJECTIVES: Receptiveness is a tool that brings contributions for health care humanization, especially with regard to its practice in the field of Anesthesiology. The aim was to investigate through the report of anesthesiologists the understanding of the receptiveness phenomenon among these professionals. METHODS: This is a descriptive qualitative research held at the Hospital Universitario Lauro Wanderley (HULW), in the city of Joao Pessoa, PB. The sample consisted of 16 attending anesthesiologists, 25% female doctors and 75% male doctors. Data were collected through interviews guided by two semi structured questions from September to October 2010. Data analysis was performed using the technique of Collective Subject Discourse (CSD). RESULTS: The anesthesiologists' answer to the following question was considered as this study's result: "What do you think about the practice of receptiveness as a strategy to humanize the doctor-patient relationship?" The doctors' CSD presented two central ideas: 1) a holistic approach to the patient; 2) a strategy that improves the doctor-patient relationship. When asked about the strategies adopted by them to humanize the relationship with the patient at the time of reception, their reports were organized based on three central ideas: 1) observation of patients' rights; 2) therapeutic communication; 3) preanesthetic visit. It was found that the physicians involved in the research recognized the value of receptiveness as a strategy to humanize the doctor-patient relationship. CONCLUSIONS: The receptivity to the patient in the course of anesthesia is very important because it allows the professional to perform a qualified hearing of the patient's history, together with the humanized care process, which enables the improvement of the interaction between doctor and patient. PMID- 22440376 TI - Use of tablet (iPad(r)) as a tool for teaching anesthesiology in an orthopedic rotation. AB - BACKGROUND AND OBJECTIVES: The goal of this study was to compare scores on house staff evaluations of "overall teaching quality" during a rotation in anesthesia for orthopedics in the first six months (n=11 residents were provided with curriculum in a printed binder) and in the final six months (n=9 residents were provided with the same curriculum in a tablet computer (iPad, Apple(r), Inc, Cupertino, Ca)). METHODS: At the beginning of the two-week rotation, the resident was given an iPad containing: a syllabus with daily reading assignments, rotation objectives according to the ACGME core competencies, and journal articles. Prior to the study, these curriculum materials had been distributed in a printed binder. The iPad also provided peer reviewed internet sites and direct access to online textbooks, but was not linked to the electronic medical record. At the end of the rotation, residents anonymously answered questions to evaluate the rotation on an ordinal scale from 1 (unsatisfactory) to 5 (outstanding). All residents were unaware that the data would be analyzed retrospectively for this study. RESULTS: The mean global rating of the rotation as assessed by "overall teaching quality of this rotation" increased from 4.09 (N=11 evaluations before intervention, SD 0.83, median 4, range 3-5) to 4.89 (N=9 evaluations after intervention, SD 0.33, median 5, range 4-5) p=0.04. CONCLUSIONS: Residents responded favorably to the introduction of an innovative iPad based curriculum for the orthopedic anesthesia rotation. More studies are needed to show how such mobile computing technologies can enhance learning, especially since residents work at multiple locations, have duty hour limits, and the need to document resident learning in six ACGME core competencies. PMID- 22440377 TI - Analysis of the acute cytotoxic potential of bupivacaine and 50% enantiomeric excess bupivacaine (s75-r25) incorporated into microspheres in rat sciatic nerves. AB - BACKGROUND AND OBJECTIVES: The duration of Local Anesthetic (LA) effects can be expanded by its incorporation into systems of sustained release microspheres. However, the possibility that LA sustained release systems are neurotoxic has not received due attention in literature. The objective of this study was to investigate the effects of pure microspheres of poly(lactic-co-glycolic acid), filled with 50% enantiomeric excess bupivacaine or bupivacaine (BP), as well as the effects of 50% enantiomeric excess bupivacaine in the sciatic nerve of Wistar rats. METHODS: The rats were allocated into four groups according to the evaluation time (two, four, six, and eight days) and nominated according to the injected solution on the sciatic nerve: Microspheres with 50% Enantiomeric excess Bupivacaine (MEB), Microspheres with Bupivacaine (MB), Pure Microspheres (PM), and 50% Enantiomeric excess Bupivacaine (EB). RESULTS: In semi-fine histologic sections, no regular homogeneous distribution of collagen fibers in the endoneurium or degenerative changes of axons and myelin sheaths were observed. In ultrathin sections, we found myelinated axons and normal Remak fibers with axoplasm showing homogeneous distribution of neurofilaments and microtubules. Histomorphometric analysis of axons revealed no significant difference between the axon diameters of the studied groups. PMID- 22440378 TI - Neuraxial anesthesia compared to general anesthesia for procedures on the lower half of the body: systematic review of systematic reviews. AB - BACKGROUND AND OBJECTIVES: Systematic reviews organize literature data by combining results from published studies in order to resolve conflicts in the area of medical knowledge describing the interventions. The inadequate reporting of systematic reviews can damage the credibility and interfere in the results' quality. The objective of this study was to determine the frequency of good quality systematic reviews comparing neuraxial anesthesia with general anesthesia for procedures on the lower half of the body. METHODS: Systematic review of systematic reviews. Primary variable: The frequency of good quality systematic reviews. The information was analyzed from the following databases: LILACS (January 1982 to December 2010); PubMed (January 1950 to December 2010); The Cochrane Database of Systematic Review and Database of Abstracts of Reviews of Effects (volume 10, 2010); and SciELO (December 2010). The quality of systematic reviews was determined by the Overview Quality Assessment Questionnaire. The sample size calculation showed that it was necessary to analyze eight systematic reviews, taking into account that the frequency of good quality systematic reviews was 5%, an absolute precision of 15%, and a significance level of 5%. RESULTS: Were identified 1,995 articles. The selection process eliminated 1,968 articles. Twenty-seven articles of systematic reviews were read in full, 9 were excluded due to incompatibility with the inclusion criteria, and 8 were duplicate publications. Ten systematic reviews were assessed for their quality. The frequency of good quality systematic reviews was 40% (4/10; 95% CI 9.6 to 70.4%). CONCLUSION: The frequency of good quality systematic reviews was 40%. PMID- 22440379 TI - Topical analgesics. AB - BACKGROUND AND OBJECTIVES: Pain treatment involves the usage of common and opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant analgesics. Traditionally, these drugs are administered systemically or into the neuraxis. However, when analgesics are applied through these pathways, they are associated with significant side effects, which can hinder its use. Topical administration of analgesics is an alternative. The objective of this paper is to discuss topical analgesics, the mechanisms of action and clinical efficacy. CONTENT: This is a review paper addressing the usage of the topical local anesthetics: capsaicin, clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids, discussing mechanism of action and effectiveness. CONCLUSIONS: Topical analgesics are promising as a strategy for pain treatment, as they are associated with lower incidence of side effects. The benefit of local anesthetics, NSAID's and capsaicin is well established. However, the efficacy of clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids is still questionable. Studies have shown that the multimodal approach is an alternative, but studies are needed to confirm this hypothesis. PMID- 22440380 TI - Occupational exposure to noise pollution in anesthesiology. AB - BACKGROUND AND OBJECTIVES: The harmful effects of workplace noise pollution are well known and described in the literature. The effects of prolonged exposure to noise in areas demanding high level of concentration, such as operating rooms, depend on the variability of individual responses and intensity of different generation sources. The aim of this paper is to present a review of occupational exposure to noise in anesthesiology. CONTENT: The results of the main articles in literature on the subject are discussed, concerning the sources of noise pollution and its effects on workers, particularly the anesthesiologist. Emphasis is given to legislation and recommendations to minimize the effects caused by noise. PMID- 22440381 TI - The importance of transesophageal echocardiography in heart harvesting for cardiac transplantation. AB - BACKGROUND AND OBJECTIVES: The use of transesophageal echocardiography (TEE) during heart harvesting for transplantation can guide the heart assessment, as harvesting a marginal heart can jeopardize the cardiac transplantation. CASE REPORT: Male, 30 years old, suffered a car crash that resulted in a severe traumatic brain injury (TBI) that evolved to brain death. The patient was intubated and ventilated with a fraction of inspired oxygen of 0.6, presetting Vt 500 mL, RR 14 bpm, PEEP of 3 mm Hg, 99% O(2) saturation, and normal blood gases. He was also hypovolemic, with urine output of 9,300 mL.day(-1), sodium level of 157 mEq.L(-1), hematocrit of 27%, and BP 90/60 mm Hg maintained by infusion of norepinephrine 0.5 mcg.kg.min(-1). The patient was clinically optimized and evaluated by TEE, which showed normal size cardiac chambers, ejection fraction 66%, anatomical and functional heart valves with no changes, and foramen ovale integrity. Immediately after the confirmation of cardiac viability and clinical stabilization, the patient was taken to the operating room and the harvest began. The ischemic period lasted two hours and the heart was successfully transplanted. CONCLUSIONS: In most heart transplant services, the cardiac assessment is made subjectively by the surgeon who often does not have the anesthesiologist support to clinically optimize the donor. At the Instituto Nacional de Cardiologia (INC/MS), the anesthesiologist is part of the harvesting team in order to perform intraoperative TEE, evaluating objectively the harvested heart. In doing so, it provides greater chances of heart transplantation success with lower costs for the Brazilian public health system. PMID- 22440382 TI - Anesthesia for lung lavage in pediatric patient with pulmonary alveolar proteinosis. AB - BACKGROUND AND OBJECTIVES: Pulmonary Alveolar Proteinosis (PAP) is a rare disorder first described in 1958. The Whole-Lung Lavage (WLL) proposed in the 1960s, remains the treatment of choice. Several techniques have been described to perform lung lavage in pediatric patients; however, all have limitation and risks. CASE REPORT: Female patient, aged 6 years and 8 months, 25 kg, diagnosed with pulmonary alveolar proteinosis, who underwent whole-lung lavage by sequential lobar fiberoptic bronchoscopy under general anesthesia and spontaneous ventilation. PMID- 22440383 TI - Anesthesia in patient with shrinking lung syndrome: case report. AB - BACKGROUND AND OBJECTIVES: The incidence of pulmonary involvement in systemic lupus erythematosus (SLE) may be presented as a syndrome called shrinking lung syndrome (SLS). SLS has quite a controversial pathophysiology, which can induce to a mechanical ventilation dependency. Due to its rarity, there is a limited number of publications on the subject. The objective of this report is to present the case of a patient with SLS who underwent incisional hernia repair under epidural anesthesia. CASE REPORT: Female patient with SLE, hypertensive and obese, diagnosed with SLS 18 years ago. She was dependent on nocturnal oxygen at home, had dyspnea on minimal exertion and spirometry with severe restrictive ventilatory defect. In a previous post-operative period under general anesthesia, she remained on mechanical ventilation for 9 days with difficult weaning. She underwent incisional hernia repair for 3 hours under thoracic epidural anesthesia without any pre- or post-operative respiratory complication. CONCLUSIONS: Shrinking lung syndrome is a rare disease that requires a prior knowledge of the clinical and laboratory history of the patient by the anesthesiologist. The thoracic epidural anesthesia technique proved to be a satisfactory option for this patient, with highly satisfactory respiratory evolution. PMID- 22440384 TI - Reversal of profound neuromuscular blockade with sugammadex after failure of rapid sequence endotracheal intubation: a case report. AB - BACKGROUND AND OBJECTIVES: Sugammadex is a reversal agent that acts as a selective antagonist of neuromuscular blockade induced by rocuronium and vecuronium. This is a case report of an elderly female patient who had sugammadex just after rocuronium induction. CASE REPORT: An 88-year-old female patient, 34 kg, presented a femoral fracture and had to undergo general anesthesia after spinal anesthesia failure. Induction was performed with propofol 1.5mg.kg(-1), rocuronium 1.2mg.kg(-1), fentanyl 100 mcg, and lidocaine 2mg.kg(-1). There was no success in either tracheal intubation or laryngeal mask positioning maneuvers. The use of sugammadex at a dose of 16 mg.kg(-1) was required and respiratory function returned to normal. CONCLUSION: Literature recommends sugammadex at a dose of 16 mg.kg(-1) for patients with profound blockade. It was used in our patient with rapid and effective reversal of neuromuscular blockade allowing the patient to undergo another procedure to ensure the airway patency without clinical impairment of her general condition. PMID- 22440385 TI - 2011 In review. PMID- 22440386 TI - Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. AB - PURPOSE: The purpose of the study was to determine the effects of Plasma-Lyte 148 (PL) vs 0.9% saline (NS) fluid resuscitation in diabetic ketoacidosis (DKA). METHODS: A multicenter retrospective analysis of adults admitted for DKA to the intensive care unit, who received almost exclusively PL or NS infusion up until 12 hours, was performed. RESULTS: Nine patients with PL and 14 patients with NS were studied. Median serum bicarbonate correction was higher in the PL vs NS groups at 4 to 6 hours (8.4 vs 1.7 mEq/L) and 6 to 12 hours (12.8 vs 6.2 mEq/L) from baseline (P < .05). Median standard base excess improved by 10.5 vs 4.2 mEq/L at 4 to 6 hours and by 16.0 vs 9.1 mEq/L at 6 to 12 hours in the PL and NS groups, respectively (P < .05). Chloride levels increased significantly in the NS vs PL groups over 24 hours. Potassium levels were lower at 6 to 12 hours in the PL group. Mean arterial blood pressure was higher at 2 to 4 hours in the PL group, whereas cumulative urine output was lower at 4 to 6 hours in the NS group. There were no differences in glycemic control or duration of intensive care unit stay. CONCLUSION: Patients with DKA resuscitated with PL instead of NS had faster initial resolution of metabolic acidosis and less hyperchloremia, with a transiently improved blood pressure profile and urine output. PMID- 22440387 TI - The association of mean glucose level and glucose variability with intensive care unit mortality in patients with severe acute pancreatitis. AB - PURPOSE: The objective of this study was to retrospectively analyze the association of mean glucose level (MGL) and glycemic lability index (GLI; as a measure of glucose variability) with intensive care unit (ICU) mortality in patients with severe acute pancreatitis (SAP). MATERIALS AND METHODS: Paper-based medical records of patients with SAP who were admitted to the ICU of West China Hospital between July 1, 2005, and July 1, 2010, were analyzed. Glucose measurements, demographic characteristics, clinical features, data on the first and second 24-hour Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and outcomes were obtained. Time-weighted glucose parameters were used. We statistically analyzed the relationship between these variables and both ICU and hospital mortality. RESULTS: A total of 294 patients with 34,796 glucose measurements were included in the final analysis. The time-weighted MGL was 9.31 +/- 1.91 mmol/L, and the median of GLI was 55.27 (mmol/L)(2) h-(1) wk-(1). Intensive care unit mortality was 43.5% and increased progressively as GLI increased, reaching 62.5% of patients with GLI above 115.89 (mmol/L)(2) h-(1) wk (1). The highest odds ratio for ICU death was found in patients with the highest quartile of GLI: odds ratio, 3.47 (95% confidence interval, 1.76-6.86; P < .000). No such relationship could be found with MGL. Glycemic lability index was better able to predict ICU death than was MGL (the area under the curves were 0.642 vs 0.561, respectively; z test was 2.677; P = .0074). The logistic regression analysis showed that GLI, the second 24-hour APACHE II score, and the number of organ failures upon ICU admission contributed independently to the risk of mortality. CONCLUSIONS: We observed that GLI was a better predictor of ICU and hospital mortality than was MGL. Together with the second 24-hour APACHE II score and the number of organ failures upon ICU admission, GLI is an independent predictor of mortality in patients with SAP. PMID- 22440388 TI - Involvement of AmphiREL, a Rel-like gene identified in Brachiastoma belcheri, in LPS-induced response: implication for evolution of Rel subfamily genes. AB - Rel/NF-kappaB family genes are important transcriptional factors regulating vital activities of immunity response, but no Rel/NF-kappaB gene has been identified in amphioxus. In this study, we have not only identified and characterized a Rel like gene from Brachiastoma belcheri, but also extensively studied the evolution of Rel gene subfamily. We found that: 1) the amphioxus genome contains an AmphiREL gene encoding a Rel/NF-kappaB homolog, and AmphiREL gene was involved in the innate immune response of LPS stimulation in amphioxus. 2) Gene synteny comparison and structure comparison suggested that AmphiREL is an orthologous gene of human RELB, and is a paralogous gene of human RELA and REL. 3) Structural changes of Rel subfamily proteins are diverse during the evolution process, and imply their functional diversity. 4) The Rel subfamily genes have undergone very strong purifying selection. Together, our results provide important clues for understanding the evolution and function of Rel subfamily genes. PMID- 22440389 TI - Novel broad host range shuttle vectors for expression in Escherichia coli, Bacillus subtilis and Pseudomonas putida. AB - Novel shuttle vectors named pEBP were constructed to allow the gene expression in different bacterial hosts including Escherichia coli, Bacillus subtilis and Pseudomonas putida. These vectors share the inducible promoters P(T7) and P(Xyl) and a cos site to enable packaging of plasmid DNA into phage, and carry different multiple cloning sites and antibiotic resistance genes. Vector pEBP41 generally replicates episomally while pEBP18 replicates episomally in Gram-negative bacteria only, but integrates into the chromosome of B. subtilis. Plasmid copy numbers determined for E. coli and P. putida were in the range of 5-50 per cell. The functionality of pEBP18 and pEBP41 was confirmed by expression of two lipolytic enzymes, namely lipase A from B. subtilis and cutinase from the eukaryotic fungus Fusarium solani pisi in three different host strains. Additionally, we report here the construction of a T7 RNA polymerase-based expression strain of P. putida. PMID- 22440390 TI - Anaplastic large cell lymphoma, ALK-positive. AB - Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) is an aggressive CD30-positive T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene and the expression of ALK protein. No particular risk factor has been clearly identified for ALCL. ALK+ ALCL shows a broad morphologic spectrum, but all cases contain a variable proportion of cells with eccentric, horseshoe- or kidney-shaped nuclei often with an eosinophilic region near the nucleus (hallmark cells). Five morphologic patterns can be recognized. ALK+ ALCL occurs in young subjects (median age ~35 years), with male predominance, and frequently presents at an advanced stage, with systemic symptoms and extranodal involvement. Near 40% of patients are low risk according to the International Prognostic Index (IPI). Overall, the prognosis of ALK+ ALCL is remarkably better than other T-cell lymphomas. The IPI and the PIT scores in general predict survival in patients with ALK+ ALCL. Standard first-line treatment for ALK+ ALCL consists of doxorubicin-containing polychemotherapy, which is associated with an overall response rate of ~90%, a 5 year relapse-free survival of ~60%, and a 5-year overall survival of 70%. Excellent results have been reported with a variety of anthracycline-based chemotherapy regimens including CHOP, CHOEP or MACOP-B. Consolidative high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) has also been evaluated in patients in first remission with favourable results, however, superiority to standard chemotherapy is unproven and this approach remains investigational. Following universally accepted guidelines for the treatment of failed aggressive lymphomas, HDC/ASCT can effectively salvage a proportion of patients with relapsed or refractory ALK+ ALCL. Recently, the development of novel therapies targeting CD30 and ALK appear promising. PMID- 22440391 TI - Non-adherence and non-response in the treatment of anxiety disorders. AB - Among the best established treatments for anxiety disorders are cognitive behavioral interventions and serotonin reuptake inhibitors. Although clinically useful, these therapies are far from universally efficacious; some patients are unable to complete treatment, and many treatment completers fail to achieve clinically significant improvement. A review of meta-analyses on the treatment of anxiety disorders reveals that about a fifth of patients drop out prematurely and a third of treatment completers are classified as non-responders. In this article we examine the predictors of, and potential solutions for, the problems of treatment non-adherence and non-response to cognitive-behavioral and serotonergic treatments of adult anxiety disorders. Despite decades of research, few reliable predictors have been identified, and no predictor has been consistently supported in the literature. However, there is suggestive evidence that risk of premature dropout is associated with low treatment motivation, side effects, and practical barriers to attending sessions. There is also suggestive evidence that poor response is associated with severe pretreatment psychopathology and comorbidity, as well as high expressed emotion in the patient's family environment. Methods for better estimating treatment prognosis are proposed and possible directions for improving treatment outcome are discussed. PMID- 22440392 TI - Obsessive-compulsive disorder in children and adolescents: parental understanding, accommodation, coping and distress. AB - Parental accommodation of pediatric OCD is common and is associated with negative affect in parents. Qualitative accounts of caring for a child with OCD are limited and no studies have assessed differences between mothers and fathers in accommodation, coping and distress. The current study used a mixed methods approach to understand parental accommodation, negative affect and coping. Forty one mothers and 29 fathers of 43 children with OCD were asked to write narratives about their understanding and management of OCD and to complete measures of accommodation, coping, and distress. Symptom accommodation was high with almost half of the parents watching the child complete rituals or waiting for the child on a daily basis. Analysis of parental narratives indicated a distressing struggle between engaging in and resisting accommodation in order to manage their own and their child's anger and distress. T-tests and correlation analysis indicated that accommodation did not differ significantly between mothers and fathers but was more strongly associated with negative affect in mothers. Analyses indicated that mothers reported using all types of coping strategy more often than fathers, particularly escape-avoidance, taking responsibility and using social support. Escape-avoidance coping was positively correlated with accommodation and negative affect in both mothers and fathers. Interventions that target parental constructions of OCD and their behavioural and emotional responses to it may assist in reducing the occurrence of accommodation, avoidant coping and parental distress. PMID- 22440393 TI - Chinese herbal medicine for insomnia: a systematic review of randomized controlled trials. AB - Chinese herbal medicine (CHM), either in single herb or in herbal formula, has been used to treat insomnia for more than 2000 years. A systematic review including Chinese and English literature of randomized controlled trials was conducted to examine the efficacy, safety, and composition of CHM for insomnia. Among the 217 studies we have reviewed, only eight had a Jadad score >=3, and seven out of these eight studies had at least one domain with high risks of bias. Meta-analyses of the studies with Jadad score >=3 found that CHM was similar to Western medication (three studies) and placebo (three studies) in treating insomnia. Due to the poor methodological quality of the studies and the small number of trials included in meta-analyses, the current evidence is insufficient to support the efficacy of CHM for insomnia. The frequency of adverse events associated with CHM was similar to that of placebo, but lower than with Western medication. Gui Pi Tang was the most commonly used standardized formula, while Suan Zao Ren (Ziziphus jujuba) was the most frequently used single herb. Further studies with a double-blind placebo-controlled design are needed to accurately determine the benefits and risks of CHM for insomnia. PMID- 22440394 TI - Native expression and purification of hormone-sensitive lipase from Psychrobacter sp. TA144 enhances protein stability and activity. AB - Psychrobacter, a micro-organism originally isolated from Antarctic sea water, expresses an extremely active hormone-sensitive lipase (HSL) which catalyzes the hydrolysis of fatty acid esters at very low temperature and is therefore of great potential industrial and pharmaceutical interest. An insoluble form of the entire enzyme has previously been cloned and expressed in Escherichia coli, subsequently refolded and shown to be active, whilst a shorter but completely inactive version, lacking the N-terminal 98 amino acids has been expressed in soluble form. In this study the entire enzyme has been expressed as a fully soluble protein in E. coli in the presence of either the osmolyte trehalose, plus high salt concentration, or the membrane fluidizer benzyl alcohol. Trehalose promotes protein mono-dispersion by increasing the viscosity of the growth medium for bacterial cells, thereby helping circumvent protein aggregation, whilst the heat shock inducer benzyl alcohol stimulates the production of a network of endogenous chaperones which actively prevent protein misfolding, whilst also converting recombinant aggregates to native, correctly folded proteins. The resultant recombinant protein proved to be more stable than its previously expressed counterpart, as shown by CD and enzymatic activity data which proved the enzyme to be more active at a higher temperature than its refolded counterpart. By light scattering analysis it was shown that the newly expressed protein was monomeric. The stability of the full length native protein will help in understanding the structure of PsyHSL and the role of its regulatory N-terminal for eventual application in a myriad of biotechnological processes. PMID- 22440395 TI - Chondroitin sulfate-E fine-tunes osteoblast differentiation via ERK1/2, Smad3 and Smad1/5/8 signaling by binding to N-cadherin and cadherin-11. AB - Bone formation in the vertebrate skeleton occurs via the processes of endochondral and membranous ossification. Bone matrices contain chondroitin sulfate (CS) chains that regulate endochondral ossification. However, the function of CS in membranous ossification is unclear. Here, using preosteoblastic MC3T3-E1 cells we demonstrate that chondroitin sulfate-E (CS-E) promotes osteoblast differentiation by binding to both N-cadherin and cadherin-11. Differentiated MC3T3-E1 cells exhibited an increase in the total amount of CS and of E-disaccharide units of CS over time. In addition, CS-E polysaccharide, but not CS-A polysaccharide, bound to N-cadherin and cadherin-11 and enhanced osteoblast differentiation. In contrast, osteoblast differentiation was inhibited in chondroitinase ABC-digested MC3T3-E1 cells. Notably, CS-E polysaccharide and hexasaccharide activated intracellular signaling during osteoblast differentiation in non-contacting MC3T3-E1 cells, decreased ERK1/2 phosphorylation, and activated Smad3 and Smad1/5/8; these reactions were blocked by neutralizing antibodies against N-cadherin or cadherin-11, even though cell cell adhesion is reported to be required for initiation of MC3T3-E1 cell differentiation. Furthermore, CS-E-unit overexpression in MC3T3-E1 cells increased adhesion of the cells to N-cadherin and cadherin-11, and promoted osteoblast differentiation. Collectively, these results suggest that CS-E is a selective ligand for the potential CS receptors, N-cadherin and cadherin-11, leading to osteoblast differentiation of MC3T3-E1 cells. PMID- 22440396 TI - Identification of a novel cis-element that regulates alternative splicing of Bcl x pre-mRNA. AB - Alternative splicing plays an important role in the control of apoptosis. A number of genes related to apoptosis undergo alternative splicing. Among them, the apoptotic regulator Bcl-x produces two major isoforms, Bcl-xL and Bcl-xS, through the alternative splicing of exon 2 in its pre-mRNA. These isoforms have antagonistic function in apoptotic pathway; Bcl-xL is pro-apoptotic, while Bcl-xS is anti-apoptotic. The balanced ratio of two isoforms is important for cell survival. However, regulatory mechanisms of Bcl-x splicing remain poorly understood. Using a mini-gene system, we have found that a 105 nt exonic region (E3b) located within exon 3 affects exon 2 splicing in the Bcl-x gene. Further deletion and mutagenesis studies demonstrate that this 105 nt sequence contains various functional elements which promote skipping of exon 2b. One of these elements forms a stem-loop structure that stimulates skipping of exon 2b. Furthermore our results prove that the stem-loop structure functions as an enhancer in general pre-mRNA splicing. We conclude that we have identified a cis regulatory element in exon 3 that affects splicing of exon 2 in the Bcl-x gene. This element could be potentially targeted to alter the ratio of Bcl-xL and Bcl xS for treatment of tumors through an apoptotic pathway. PMID- 22440397 TI - Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology. AB - Anti-NMDAR encephalitis is a newly characterized syndrome with a progressive, predictable clinical course and the possibility of effective treatment. Accurate and timely diagnosis is critical to selection and implementation of treatments, and optimal patient outcomes. Outcomes are improved with early diagnosis via indirect immunofluorescence or cell-based assays, and the rapid and appropriate administration of immunosuppressant and anti-psychotic therapies. Three possible scenarios accounting for the immunopathogenesis of anti-NMDAR encephalitis are presented, with the most probable one being that of paraneoplastic autoimmunity. Future efforts in this disorder should focus on elucidating the mechanisms that contribute to initiation of this antibody response, as well as exploring the role of tumors, infectious triggers and immune-reactivation. Finally, accessible tools need to be developed that allow for reliable identification of specific antibody markers against synaptic proteins. PMID- 22440398 TI - Antiphospholipid antibodies as non-traditional risk factors in atherosclerosis based cardiovascular diseases without overt autoimmunity. A critical updated review. AB - The role of antiphospholipid antibodies (aPL) associated with cardiovascular diseases has been extensively studied in autoimmune patients, however it was largely unknown whether and how aPL associate with coronary artery disease (CAD), ishemic stroke (IS) and peripheral artery disease (PAD) in non-autoimmune patients. The current review attempts to prioritize for the first time clinical studies based on cause-outcome and strengths relationships in reference to aPL and CAD/PAD, in addition to supplementing Brey's comprehensive review on IS with other, additional studies. Our overview indicates that all case-control and cross sectional studies found an aPL association with CAD, PAD and IS, while cohort and nested case-control studies reported a prevailing negative risk association between aPL and IS (confirming Brey), with an unclear/unresolved risk association between aPL and CAD. The only cohort, follow-up study found in PAD reported on positive risk association between aPL and disease. The most frequently associated aPL in all studies reported, irrespective of disease, was aCL, with a less frequent association reported for LA, abeta2GPI and other aPL. PMID- 22440399 TI - Black yeast-like fungi associated with Lethargic Crab Disease (LCD) in the mangrove-land crab, Ucides cordatus (Ocypodidae). AB - Lethargic Crab Disease (LCD) caused extensive epizootic mortality of the mangrove land crab Ucides cordatus (Brachyura: Ocypodidae) along the Brazilian coast, mainly in the Northeastern region. The disease was named after the symptoms of slow movement of infected crabs. Causative agents were suspected to be two black yeast-like fungi of the family Herpotrichiellaceae (ascomycete order Chaetothyriales), judged by infected tissue biopsies from moribund U. cordatus. The aim of the present study is to prove that two species are involved in the disease: the recently described black yeast Exophiala cancerae, but also a less virulent, hitherto undescribed fonsecaea-like species, introduced here as the novel species Fonsecaea brasiliensis. Strains were identified by ITS rDNA sequencing, and species borderlines were established by multilocus sequencing and AFLP analysis. Fonsecaea brasiliensis proved to be closely related to the pathogenic species Cladophialophora devriesii which originally was isolated from a systemic infection in a human patient. The virulence of F. brasiliensis is lower than that of E. cancerae, as established by artificial inoculation of mangrove crabs. PMID- 22440400 TI - Hair repigmentation associated with the use of lenalidomide: graying may not be an irreversible process! AB - We report the first case of progressive hair repigmentation associated with the use of lenalidomide in an elderly patient with multiple myeloma. The influence of lenalidomide on follicular melanogenesis may involve removing the inhibitory influences of some cytokines such as IL-1, IL-6 and TNF-alpha. In addition, certain endocrine effects of lenalidomide on the hypophyseal-adrenal axis could explain its action on hair pigmentation. We further hypothesize that lenalidomide may be capable of stimulating migration and/or differentiation of melanocytes to promote repigmentation of gray hair follicles. Pending the clarification of how hair repigmentation occurs with lenalidomide, our observation materializes the concept that hair graying may not be an irreversible process, which opens avenues for targeted therapeutics in the fields of cosmetics and anti-aging medicine. PMID- 22440401 TI - The relationship between executive functions and fluid intelligence in Parkinson's disease. AB - BACKGROUND: We recently demonstrated that decline in fluid intelligence is a substantial contributor to frontal deficits. For some classical 'executive' tasks, such as the Wisconsin Card Sorting Test (WCST) and Verbal Fluency, frontal deficits were entirely explained by fluid intelligence. However, on a second set of frontal tasks, deficits remained even after statistically controlling for this factor. These tasks included tests of theory of mind and multitasking. As frontal dysfunction is the most frequent cognitive deficit observed in early Parkinson's disease (PD), the present study aimed to determine the role of fluid intelligence in such deficits. METHOD: We assessed patients with PD (n=32) and control subjects (n=22) with the aforementioned frontal tests and with a test of fluid intelligence. Group performance was compared and fluid intelligence was introduced as a covariate to determine its role in frontal deficits shown by PD patients. RESULTS: In line with our previous results, scores on the WCST and Verbal Fluency were closely linked to fluid intelligence. Significant patient control differences were eliminated or at least substantially reduced once fluid intelligence was introduced as a covariate. However, for tasks of theory of mind and multitasking, deficits remained even after fluid intelligence was statistically controlled. CONCLUSIONS: The present results suggest that clinical assessment of neuropsychological deficits in PD should include tests of fluid intelligence, together with one or more specific tasks that allow for the assessment of residual frontal deficits associated with theory of mind and multitasking. PMID- 22440402 TI - Impact of case volumes on the outcomes of percutaneous nephrolithotomy. AB - BACKGROUND: Previous studies have demonstrated relationships between case volumes and outcomes in surgery. Little is known about the impact of case volumes on the outcomes of percutaneous nephrolithotomy (PCNL). OBJECTIVE: To investigate the influence of case volumes on the efficacy and safety outcomes of PCNL. DESIGN, SETTING, AND PARTICIPANTS: From November 2007 to December 2009, prospective data were collected by the Clinical Research Office of the Endourological Society from consecutive patients over a 1-yr period in 96 centers globally. Data of 3933 patients in the Global PCNL study database were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were divided into low- and high volume groups based on the median annual case volume of their respective treatment center. Preoperative characteristics and outcomes were compared between the two groups. Case volume was treated as a continuous variable. The relationship between case volume and stone-free (SF) rate, complication rate, and duration of hospital stay was explored using multivariate regression analysis. RESULTS AND LIMITATIONS: SF rates were higher in high-volume centers (82.5% vs 75.1%; p value <0.001). Complication rates were lower in high-volume centers (15.9% vs 21.7%; p value 0.002), whereas the mean (standard deviation [SD]) duration of stay was shorter in high-volume centers (3.4 [2.6] vs 4.9 [3.7] d; p value <0.001). SF rate increased with case volume, whereas complication rate and duration of stay diminished with increasing case volumes after adjusting for stone burden, urine culture status, American Society of Anesthesiologists score, and the presence of staghorn stones. The highest SF rates were observed in centers with >120 cases per year. CONCLUSIONS: Centers that perform high numbers of PCNLs per year achieve better results. Both the efficacy and safety outcomes of PCNL improve with the number of surgeries performed in a given center per year. PMID- 22440403 TI - A novel polypeptide extracted from Ciona savignyi induces apoptosis through a mitochondrial-mediated pathway in human colorectal carcinoma cells. AB - BACKGROUND: Sessile marine animals such as sponges, ascidians, and bryozoans are a rich source of bioactive natural products, many of which exhibit potent anticancer activity. MATERIALS AND METHODS: We extracted and purified a polypeptide with potent antitumor activity from Ciona savignyi by acetone fractionation, ultrafiltration, ion exchange chromatography, gel chromatography, and high-performance liquid chromatography. An MTT assay was used to study the cytotoxicity of the isolated fraction and the purified polypeptide. Cell cycle and Western blot analysis were performed to study the mode of action of the purified polypeptide. RESULTS: A novel polypeptide with potent antitumor activity was purified. The molecular weight of the polypeptide, designated CS5931, was 5931 Da, and use of the genome basic local alignment search tool (BLAST) revealed that the N-terminal sequence of CS5931 is identical to that of granulin A from C savignyi. CS5931 exhibited significant cytotoxicity for several cancer cell types and induced apoptotic death in HCT-8 cells in a dose- and time-dependent manner. Cell cycle analysis demonstrated that CS5931 caused cell cycle arrest at the G(2)/M phase, and a sub-G(1) peak appeared after treating the cells with CS5931 for 12 hours. The mitochondrial-mediated pathway was implicated in CS5931-induced apoptosis. CONCLUSION: Our observations clearly demonstrate the antiproliferative and proapoptotic activities of the polypeptide CS5931 from C savignyi and the mitochondrial-mediated pathway involved in the polypeptide-induced cell death. PMID- 22440404 TI - Properties of mortars made by uncalcined FGD gypsum-fly ash-ground granulated blast furnace slag composite binder. AB - A series of novel mortars were developed from composite binder of uncalcined FGD gypsum, fly ash (FA) and ground granulated blast furnace slag (GGBFS) for the good utilization of flue gas desulphurization (FGD) gypsum. At a fixed ratio (20%) of GGBFS to the composite binder, keeping consistency of the mortar between 9.5 and 10.0 cm, the properties of the composite mortar were studied. The results show that higher water/binder (W/B) is required to keep the consistency when increasing the percentage of FGD gypsum. No obvious influences of the W/B and content of FGD gypsum on the bleeding of paste were observed which keeps lower than 2% under all experimental conditions tried. The highest compressive and flexural strengths (ratio is 20% FGD gypsum, 20% GGBFS and 60% FA) are 22.6 and 4.3 MPa at 28 days, respectively. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) results indicate that massive ettringite crystals and C-S-H gels exist in the hydration products. At 90 days the mortars with FGD gypsum is dramatically smaller drying shrinkage (563-938 micro strain) than that without FGD gypsum (about 2250 micro strain). The release of the SO(4)(2-) from the mortar was analyzed, indicating that the dissolution of sulfate increases with FGD gypsum. The concentration of SO(4)(2-) releasing from the mortar with 10% FGD gypsum is almost equal to that obtained from the mortar without FGD gypsum. The release of SO(4)(2-) from the mortar with 20% FGD gypsum is 9200 mg.m(-2), which is lower than that from the mortar with 95% cement clinker and 5% FGD gypsum. PMID- 22440405 TI - Electrolysis-assisted sonication for removal of proteinaceous contamination from surgical grade stainless steel. AB - BACKGROUND: Current methods used for the detection of residual proteinaceous contamination vary in sensitivity and specificity. This is of concern because it increases the risk for transmission of neurodegenerative diseases such as spongiform encephalopathies. AIM: To determine the effectiveness of electrolysis assisted sonication (EAS) for removing residual proteinaceous contamination from surgical grade stainless steel. METHODS: EAS was used to clean surgical grade 316L stainless steel that had been contaminated with the protein bovine serum albumin. Using nitrogen, an abundant element in proteins, as a marker for the presence of protein, X-ray photoelectron spectroscopy (XPS) was used to quantify the amount of protein remaining on the substrate surface. Cathodic, anodic and dual polarization modes of EAS were investigated using 0.1% NaCl solution (w/v, in deionized water) as the electrolyte medium and 13 V as the polarization voltage. FINDING: EAS under dual polarization was found to be the most effective method for removing the residual protein layer down to an estimated XPS detection limit of 10 ng/cm(2). Surface roughness and hardness of the stainless steel remained unchanged following EAS treatment, indicating that the procedure does not compromise the material's properties. CONCLUSION: This relatively inexpensive and quick method of cleaning medical devices using an easily accessible salt based electrolyte solution may offer a cost-effective strategy for cleaning medical and dental devices made of stainless steel in the future. PMID- 22440406 TI - Regulation of proliferation and differentiation of mouse tooth germ epithelial cells by distinct isoforms of p51/p63. AB - OBJECTIVES: p51/p63 gene, one of the p53 families, is specifically expressed in tooth germ epithelial cells and is essential for tooth development. This study aims to elucidate roles of p51/p63 in ameloblastic cell differentiation. MATERIALS AND METHODS: We determined expression pattern of each of p51/p63 isoforms by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting using emtg (epithelium of molar tooth germ)-1, -2, -3, -4, and -5 cell lines established from a mandibular molar tooth germ of p53-deficient mice and SF2 cells which differentiates into ameloblasts upon exposure to NT4. Furthermore, we investigated the function of p51/p63 in these cells by Tet system, which enables inducible expression and knock down of the target genes of interest by exposing cells to doxycycline. RESULTS: The expression of DeltaNp51B/DeltaNp63alpha, an isoform without transactivation domain, was detected at high level in immature cells, while the expression of TAp51/TAp63 isoforms, isoforms of with the transactivation domain, was detected at high level in mature cells. Moreover, induction of TAp51A/TAp63gamma expression led to down regulation of DeltaNp51B/DeltaNp63alpha expression and cell proliferation. Interestingly, this also led to up-regulation of ameloblastin expression, a differentiation marker of amelogenesis. CONCLUSIONS: The results suggested that p51/p63 might regulate the cell proliferation and differentiation of tooth germ epithelial cells. PMID- 22440407 TI - Assessing the genetic diversity in small farm animal populations. AB - Genetic variation is vital for the populations to adapt to varying environments and to respond to artificial selection; therefore, any conservation and development scheme should start from assessing the state of variation in the population. There are several marker-based and pedigree-based parameters to describe genetic variation. The most suitable ones are rate of inbreeding and effective population size, because they are not dependent on the amount of pedigree records. The acceptable level for effective population size can be considered from different angles leading to a conclusion that it should be at least 50 to 100. The estimates for the effective population size can be computed from the genealogical records or from demographic and marker information when pedigree data are not available. Marker information could also be used for paternity analysis and for estimation of coancestries. The sufficient accuracy in marker-based parameters would require typing thousands of markers. Across breeds, diversity is an important source of variation to rescue problematic populations and to introgress new variants. Consideration of adaptive variation brings new aspects to the estimation of the variation between populations. PMID- 22440408 TI - Management of genetic diversity in small farm animal populations. AB - Many local breeds of farm animals have small populations and, consequently, are highly endangered. The correct genetic management of such populations is crucial for their survival. Managing an animal population involves two steps: first, the individuals who will be permitted to leave descendants are to be chosen and the number offspring they will be permitted to produce has to be determined; second, the mating scheme has to be identified. Strategies dealing with the first step are directed towards the maximisation of effective population size and, therefore, act jointly on the reduction in the loss of genetic variation and in the increase of inbreeding. In this paper, the most relevant methods are summarised, including the so-called 'Optimum Contribution' methodology (contributions are proportional to the coancestry of each individual with the rest), which has been shown to be the best. Typically, this method is applied to pedigree information, but molecular marker data can be used to complete or replace the genealogy. When the population is subjected to explicit selection on any trait, the above methodology can be used by balancing the response to selection and the increase in coancestry/inbreeding. Different mating strategies also exist. Some of the mating schemes try to reduce the level of inbreeding in the short term by preventing mating between relatives. Others involve regular (circular) schemes that imply higher levels of inbreeding within populations in the short term, but demonstrate better performance in the long term. In addition, other tools such as cryopreservation and reproductive techniques aid in the management of small populations. In the future, genomic marker panels may replace the pedigree information in measuring the coancestry. The paper also includes the results of several experiments and field studies on the effectiveness and on the consequences of the use of the different strategies. PMID- 22440409 TI - Estimates of the genetic parameters of turkey body weight using random regression analysis. AB - Random regression (RR) analysis has been recommended to estimate the genetic parameters of longitudinal data. The objective of this study was to evaluate the growth of turkeys using RR models. Data were collected from 957 turkeys and included 15,478 individual body weight recorded during the first week of life and between weeks 2 and 32 by 2-week intervals. To take into account the repeated measurements of weight for each animal, a specific overall growth curve was modelled using a cubic smoothing spline. Animal deviation to this curve was also modelled using an RR function. All data were analysed with the ASReml package. The results showed an increase in heritability estimates over the trajectory and peaked at 0.60 around 20 to 32 weeks of age. Genetic correlations showed that turkeys could be selected at earlier time points, at 12 weeks of age, in order to increase the growth rate. In general, genetic correlation estimates were higher among adjacent ages, decreasing markedly with the increase of distance between ages. Negative genetic correlations were observed between ages. PMID- 22440410 TI - Bio-economic model to evaluate twinning rate using sexed embryo transfer in dairy herds. AB - A stochastic bio-economic model has been used to determine the effects of new reproductive technologies over a 15-year period. A strategy of using conventional artificial insemination (AI) or embryo transfer (ET) using two sex-controlled embryos at different conception rates (CRs) and herd sizes resulted in a 24 state model. The genetic means of AI population increased over the years, and the genetic means of milk production for all of the embryo strategies were greater than those of AI. In addition, the genetic means of milk yield using different embryo-based scenarios in the expanding herds were greater than those for the fixed herds. The net profit of using sexed ET in the expanding herds was greater (P < 0.05) than that of fixed size herds. In general, there was a roughly consistent trend in net profit per cow for sexed ET strategies in the expanding herds over the years, but there was an increasing trend in net profit per cow for sexed ET strategies in the fixed herds over the years. Medium to high CRs for ET and the use of sex-controlled embryo systems, especially for induction of twin births to produce dairy replacements, will be critical elements of a system that produces significant numbers of female calves. The greater number of female calves produced in the sex-controlled scenarios allows the farmer to select animals with the best genetic potential as dairy replacement heifers; therefore, the rate of genetic gain increased in the dairy herd. Results of sensitivity analyses showed that a significant decrease in the production costs and increase in the ET performance are essential for embryo-based technologies to be profitable. PMID- 22440411 TI - Genetic variation in wholesale carcass cuts predicted from digital images in cattle. AB - The objective of this study was to quantify the genetic variation in carcass cuts predicted using digital image analysis in commercial cross-bred cattle. The data set comprised 38,404 steers and 14,318 heifers from commercial Irish herds. The traits investigated included the weights of lower value cuts (LVC), medium value cuts (MVC), high value cuts (HVC), very high value cuts (VHVC) and total meat weight. In addition, the weights of total fat and total bones were available on the steers. Heritability of carcass cut weights, within gender, was estimated using an animal linear model, whereas genetic and phenotypic correlations among cuts were estimated using a sire linear model. Carcass weight was included as a covariate in all models. In the steers, heritability ranged from 0.13 (s.e. = 0.02) for VHVC to 0.49 (s.e. = 0.03) for total bone weight, and in the heifers heritability ranged from 0.15 (s.e. = 0.04) for MVC to 0.72 (s.e. = 0.06) for total meat weight. The coefficient of genetic variation for the different cuts varied from 1.4% to 3.6%. Genetic correlations between the different cut weights were all positive and ranged from 0.45 (s.e. = 0.08) to 0.89 (s.e. = 0.03) in the steers, and from 0.47 (s.e. = 0.14) to 0.82 (s.e. = 0.06) in the heifers. Genetic correlations between the wholesale cut weights and carcass conformation ranged from 0.32 (s.e. = 0.06) to 0.45 (s.e. = 0.07) in the steers, and from 0.10 (s.e. = 0.12) to 0.38 (s.e. = 0.09) in the heifers. Genetic correlations between the same wholesale cut traits in steers and heifers ranged from 0.54 (s.e. = 0.14) for MVC to 0.79 (s.e. = 0.06) for total meat weight; genetic correlations between carcass weight and carcass classification for conformation and fat score in both genders varied from 0.80 to 0.87. The existence of genetic variation in carcass cut traits, coupled with the routine availability of predicted cut weights from digital image analysis, clearly shows the potential to genetically improve carcass value. PMID- 22440412 TI - Prion protein gene (PrP) polymorphisms in healthy sheep in Turkey. AB - Scrapie, a transmissible spongiform encephalopathy (TSE) or prion disease, is a fatal, neurodegenerative disease in sheep and goats. This disease has been known in Europe for more than 250 years. Susceptibility to scrapie is associated with polymorphisms in the sheep prion protein gene (PrP) gene. In sheep, polymorphism in the PrP gene has been identified at a number of codons, and polymorphisms at codons 136, 154 and 171 have reported linkage with susceptibility to scrapie. Polymorphisms at the PrP locus were studied in 413 animals representing three native sheep breeds (Imroz, Chios and Kivircik) in Turkey. Genomic DNA was obtained from blood, and genotypes were screened using PCR and direct DNA sequencing. We report 17 genotypes derived from seven different alleles. The most frequent genotype in the Kivircik sheep is ARQ/ARQ, whereas the ARR/ARQ genotype is predominant in the Chios and Imroz breeds. In general, the ARQ haplotype was the predominant haplotype. ARQ haplotype was also predominant in the Kivircik and Chios sheep breeds, whereas the Imroz sheep predominantly had the ARR haplotype. The susceptibility-associated VRQ haplotype was found in 2.38%, 0.35% and 0.81% of the Imroz, Kivircik and Chios sheep, respectively. Moreover, seven additional polymorphisms have been detected at codons G127S, G127V, H143R, G145S, Y172D, N174Y and Q189L. Among these polymorphisms, the N174Y allele is a novel polymorphism, and the G145S allele is a novel allele for a known polymorphic locus. PMID- 22440413 TI - Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids. AB - The branched-chain amino acids (BCAA) valine (Val) and isoleucine (Ile) are considered to be among the next-limiting amino acids for growth in piglets. In earlier studies, we estimated the standardized ileal digestible (SID) Val : Lys (lysine) requirement to be at least 70%, whereas the Ile : Lys requirement may be as low as 50%. Because the BCAA partially share a common route of catabolism, the supply of one BCAA may affect the availability of the other BCAA. Four experiments were conducted to determine the response of 6-week-old piglets to the Val supply in relation to the other BCAA. A deficient supply of Val or Ile typically results in a reduction in average daily feed intake (ADFI). Experiment 1 was designed to determine the effect of a limiting Val supply, independent of the effect on feed intake. In a dose-response study using restrictively fed piglets, nitrogen retention did not increase for an SID Val : Lys supply greater than 64%. In the remaining experiments, piglets were offered feed ad libitum using ADFI, average daily gain (ADG) and gain-to-feed ratio as response criteria. The interaction between the Val and leucine (Leu) was studied in Experiment 2 in a 2 * 2 factorial design (60% and 70% SID Val : Lys, and 111% and 165% SID Leu : Lys). Performance was considerably lower in piglets receiving 60% Val : Lys compared with those receiving 70% Val : Lys and was lowest in piglets receiving the diet with low Val and high Leu content. To further evaluate the interaction between Val and Leu, a dose-response study was carried out in which the response to Val supply was studied in combination with high Leu supply (165% Leu : Lys). Using a curvilinear-plateau model, the average SID Val : Lys requirement was 72%. However, low Val supply (60% SID Val : Lys) reduced performance by 13% to 38%, which was much greater than what we observed in earlier studies. Experiment 4 was carried out to test the hypothesis that the Val requirement is not affected by low Ile supply (50% SID Ile : Lys). Performance was not improved for Val : Lys supplies greater than 65%, which may indicate that Ile (and not Lys) was second limiting in this study. In conclusion, the first response of piglets to deficient Val supply appears to be a reduction in ADFI, rather than a reduction in ADG or nitrogen retention. A large supply of Leu may not affect the Val requirement per se, but may aggravate the consequences of Val deficiency. PMID- 22440414 TI - Responses of feeding prebiotics on nutrient digestibility, faecal microbiota composition and short-chain fatty acid concentrations in dogs: a meta-analysis. AB - The effects of prebiotics on digestibility, short-chain fatty acid (SCFA) concentrations and bacterial populations in the faeces and immunity in dogs were evaluated by meta-analyses. Overall, data from 15 published studies containing 65 different treatment means of 418 observations from different breeds of dogs were included in the data set. Feeding of prebiotics to dogs did not affect the nutrient intake (P > 0.10), nor did prebiotics change (P > 0.10) the digestibility of dry matter (DM) and fat. However, crude protein (CP) digestibility tended to decrease quadratically (P = 0.06) with increasing dosages of prebiotics, although the degree of prediction was low (R(2) = 0.33). The concentration of total SCFA (P = 0.08; R(2) = 0.90) tended to increase linearly, whereas concentration of acetate (R(2) = 0.25), propionate (R(2) = 0.88) and butyrate (R(2) = 0.85) increased quadratically with increasing dosage of prebiotics in the faeces of dogs. The numbers of beneficial bifidobacteria (P < 0.01; R(2) = 0.62) increased quadratically, but lactobacilli (P < 0.01; R(2) = 0.66) increased linearly with increasing supplementation of prebiotics. The changes in healthy bacterial numbers were affected by the interaction of initial bacterial numbers and dose of prebiotics; bacterial numbers increased relatively more when initial bacterial numbers were low. Dietary composition did not influence the response of prebiotics on lactobacilli and bifidobacterial numbers in this study. The numbers of pathogenic Clostridium perfringens and Escherichia coli were not affected by prebiotics. Prebiotics did not affect the serum immunoglobulin (Ig) concentrations such as IgG, IgA and IgM in dogs. Although prebiotics may tend to have an adverse effect on CP digestibility, prebiotics at doses up to 1.40% food intake (DM basis) might increase the beneficial bacterial populations and SCFA concentrations in the faeces of dogs. Thus, the feeding of prebiotics has a great prospective to improve the intestinal health of dogs. PMID- 22440415 TI - Effect of dietary supplementation with selenium-enriched yeast or sodium selenite on selenium tissue distribution and meat quality in commercial-line turkeys. AB - The objective of this study was to determine the concentration of total selenium (Se) and proportions of total Se comprised as selenomethionine (SeMet) and selenocysteine (SeCys) in the tissues of female turkeys offered diets containing graded additions of selenized-enriched yeast (SY), or sodium selenite (SS). Oxidative stability and tissue glutathione peroxidase (GSH-Px) activity of breast and thigh muscle were assessed at 0 and 10 days post mortem. A total of 216 female turkey poults were enrolled in the study. A total of 24 birds were euthanized at the start of the study and samples of blood, breast, thigh, heart, liver, kidney and gizzard were collected for determination of total Se. Remaining birds were blocked by live weight and randomly allocated to one of four dietary treatments (n = 48 birds/treatment) that differed either in Se source (SY v. SS) or dose (Con [0.2 mg/kg total Se], SY-L and SS-L [0.3 mg/kg total Se as SY and SS, respectively] and SY-H [0.45 mg total Se/kg]). Following 42 and 84 days of treatment 24 birds per treatment were euthanized and samples of blood, breast, thigh, heart, liver, kidney and gizzard were retained for determination of total Se and the proportion of total Se comprised as SeMet or SeCys. Whole blood GSH-Px activity was determined at each time point. Tissue GSH-Px activity and thiobarbituric acid reactive substances were determined in breast and thigh tissue at the end of the study. There were responses (P < 0.001) in all tissues to the graded addition of dietary Se, although rates of accumulation were highest in birds offered SY. There were notable differences between tissue types and treatments in the distribution of SeMet and SeCys, and the activity of tissue and erythrocyte GSH-Px (P < 0.05). SeCys was the predominant form of Se in visceral tissue and SeMet the predominant form in breast tissue. SeCys contents were greater in thigh when compared with breast tissue. Muscle tissue GSH-Px activities mirrored SeCys contents. Despite treatment differences in tissue GSH Px activity, there were no effects of treatment on any meat quality parameter. PMID- 22440416 TI - Rapid adaptation of the bacterial community in the growing rabbit caecum after a change in dietary fibre supply. AB - This work aimed to study the response of the growing rabbit caecal ecosystem (bacterial community and caecal environmental parameters) after a switch from a control to a low-fibre diet (LFD). A group of 160 rabbits were fed ad libitum a control diet (ADF: 20.4%) from weaning (36 days). At 49 days of age (day 0), 75 rabbits were switched to a LFD group (ADF: 10.7%), whereas 85 others (control group) remained on the control diet, for 39 days. Caecal contents were regularly sampled throughout the trial (60 rabbits per group). The bacterial community structure was characterized using CE-SSCP (capillary electrophoresis single strand conformation polymorphism) and total bacteria were quantified using real time PCR. Redox potential (Eh), pH, NH(3)-N, volatile fatty acid (VFA) were measured in the caecum to characterize environmental parameters. The reduction of fibre in the diet modified the CE-SSCP profiles (P < 0.001) but not the diversity index (5.6 +/- 0.8, ns). The number of 16S rRNA gene copies of total bacteria decreased (P < 0.01) in LFD rabbits compared with controls. In LFD rabbits, the caecal environment was less acid (+0.2 units; P < 0.01), more reductive (-11 mV; P < 0.05) and drier (+3.4 g 100 per g; P < 0.001), with an increase in NH3-N (+77%; P < 0.001) and a decrease in total VFA concentration (-17%; P < 0.001). We found significant correlations between the bacterial community, the quantity of bacteria and the caecal traits of the caecal ecosystem. Indeed, in both groups, the caecal traits barely constrained the total inertia of the CE-SSCP profile set (less than 14%), whereas total bacteria were positively related to total VFA, acetic acid and butyric acid levels, and Eh, and negatively related to pH. All the microbial and environmental modifications had occurred by day 2 and remained stable thereafter. These results suggest that the bacterial community in the growing rabbit caecum is able to adapt quickly after a change to in the dietary fibre supply to reach a new steady-state equilibrium. PMID- 22440417 TI - Feed intake, milk production and composition of crossbred cows fed with insect protected Bollgard II(r) cottonseed containing Cry1Ac and Cry2Ab proteins. AB - Twenty crossbred lactating multiparous cows were used in a 28-day study to compare dry matter intake (DMI), milk yield, milk composition and Bacillus thuringiensis (Bt) protein concentrations in plasma when fed diets containing Bollgard II((r)) cottonseed (BGII) or a control non-genetically modified isogenic cottonseed (CON). Bollgard II cottonseed contains the Cry1Ac and Cry2Ab insecticidal proteins that protect cotton plants from feeding damage caused by certain lepidopteran insects. Cows were assigned randomly to the BGII or CON treatments after a 2-week adjustment period. Cows consumed a concentrate containing 40% crushed cottonseed according to milk yield and green maize forage ad libitum. All cows received the same diet but with different crushed cottonseed sources. Cottonseed was included to provide approximately 2.9 kg per cow daily (dry matter basis). The ingredient composition of the concentrate was 40% crushed cottonseed, 15% groundnut cake, 20% corn, 22% wheat bran, 1% salt and 2% mineral mixture. Milk and blood plasma were analyzed for Cry1Ac and Cry2Ab proteins. DMI, BW, milk yield and milk components did not differ between cows on the BGII and CON treatments. Although milk yield and milk fat percentage were not affected by treatment, 4% fat-corrected milk (FCM) production and FCM/kg DMI for cows on the BGII treatment (14.0 kg/cow per day, 1.12 kg/kg) were significantly improved compared with cows on the CON treatment (12.1 kg/cow per day, 0.97 kg/kg). Gossypol contents in BGII cottonseed and conventional cottonseed were similar. Cry1Ac and Cry2Ab2 proteins in Bollgard II cottonseed were 5.53 and 150.8 MUg/g, respectively, and were not detected in the milk or plasma samples. The findings suggested that Bollgard II cottonseed can replace conventional cottonseed in dairy cattle diets with no adverse effects on performance and milk composition. PMID- 22440418 TI - Oxidative stress status of highly prolific sows during gestation and lactation. AB - Elevated oxidative stress is reported to be associated with pregnancy complications in highly prolific sows. Oxidative DNA damage and the antioxidant status were determined in blood samples collected during the course of gestation and lactation in multiparous sows. Blood samples were drawn from sows (n = 5) on days 30, 60, 90 and 110 of gestation (G30, G60, G90 and G110, respectively), on day 3, 10 and 18 of lactation (L3, L10 and L18, respectively) and on day 5 of postweaning (W5). Lymphocytes were isolated from the fresh blood and cryopreserved in each time point. Lymphocyte DNA damage was analyzed by alkaline single-cell gel electrophoresis (comet assay) to determine the single- and double strand brakes and endogenous antioxidant concentrations using an HPLC system with UV detection. The comet assay showed elevated (P < 0.05) DNA damage (between 38% and 47%) throughout the gestational and lactational periods than during early gestation (G30; 21%). Plasma retinol concentration was reduced (P < 0.05) at the end of gestation (G110) compared with G30. Plasma alpha-tocopherol concentrations also showed a similar trend as to retinol. This study indicates that there is an increased systemic oxidative stress during late gestation and lactation, which are not fully recovered until the weaning compared with the G30, and that antioxidant nutrients in circulation substantially reduced in the mother pig at G110. PMID- 22440419 TI - Modelling of lactation curves of dairy cows based on monthly test day milk yield records under inconsistent milk recording scenarios. AB - The objective of this study was to describe the lactation curve of dairy cattle in Kenya using a suitable lactation function in order to facilitate inclusion of partial lactations in national dairy cattle evaluation and to assess the effect of data characteristics on lactation curve parameters. Six functions were fitted to test day (TD) milk yield records from six parities of Ayrshire, Guernsey, Holstein Friesian, Jersey and Sahiwal cattle. Five datasets: DS-1 (12-TD dataset with randomly missing records), DS-2 (10-TD dataset without missing records), DS 3 (10-TD dataset with randomly missing records), DS-4 (7-TD dataset, with only TD 4 to 10 records) and DS-5 (7-TD dataset, with TD 1 to 4, 6, 8 and 10 records) depicting various recording circumstances were derived to assess the effects of data characteristics on lactation curves and to assess the feasibility of reducing the number of TD samples per lactation. The fit of the functions was evaluated using adjusted R(2) and their predictive abilities were compared using mean square prediction error, percentage of squared bias and the correlation between the predicted and actual milk yield. These criteria plus the changes in the parameters of curve functions and their associated standard errors were used in determining the effects of data characteristics on lactation curves. The mechanistic functions of Dijkstra (DIJ) and Pollott (APOL), and the incomplete gamma function of Wood (WD) had the highest adjusted R(2) > 0.75. The APOL function was eliminated due to convergence failures when analysis of individual lactations within breeds was carried out. Both DIJ and WD had good predictive ability, although DIJ performed slightly better. Convergence difficulties were noted in some DIJ analysis where data were limiting. Missing records, especially at the beginning of a lactation, greatly influenced parameters a and b of the functions. It also resulted in estimates with large standard errors. Missing records in later lactation hardly affected the parameter estimates. The WD and DIJ functions showed superior fit to the data. The WD function demonstrated higher adaptability to various data characteristics than DIJ and could be used in situations where animal recording is not consistently practised and where recording of animal performance is routinely practised. DIJ function had high data requirements, which restricts it to dairy systems with consistent recording, despite easy physiological interpretation of its parameters. The number of TD per lactation could be reduced by minimising sampling frequency in the later lactation while maintaining the monthly sampling frequency in early lactation. PMID- 22440420 TI - Traversing the ovine cervix - a challenge for cryopreserved semen and creative science. AB - This review brings together research findings on cervical relaxation in the ewe and its pharmacological stimulation for enhancement of the penetration needed for transcervical insemination and embryo transfer. On the basis that the success of artificial insemination is the percentage of ewes lambing, a review is made of recent research aimed at understanding and minimising the sub-lethal effects of freezing and thawing on the viability of spermatozoa, their membrane integrity and their ability to migrate through cervical mucus, as these characteristics have a major influence on fertility, particularly when semen is deposited, artificially, in the os cervix. Milestones of achievement are given for transcervical intrauterine insemination, embryo recovery and transfer and the birth of lambs of pre-determined sex, firstly following intracytoplasmic sperm injection, then laparoscopic intrauterine insemination using highly diluted flow cytometrically sorted fresh semen and subsequently by os cervix insemination using sexed semen that had been frozen and thawed. Diversity of research endeavour (applied, cellular, molecular), research discipline (anatomy, histology, immunology, endocrinology) and research focus (cell, tissue, organ, whole animal) is embraced within the review as each has significant contributions to make in advancing recent scientific findings from the laboratory into robust on-farm transcervical insemination and embryo transfer techniques. PMID- 22440421 TI - Restricting dairy cow access time to pasture in early lactation: the effects on milk production, grazing behaviour and dry matter intake. AB - One of the main aims of pasture-based systems of dairy production is to increase the proportion of grazed grass in the diet. This is most easily achieved by increasing the number of grazing days. However, periods of inclement weather conditions can reduce the number of days at pasture. The two objectives of this experiment were: (i) to investigate the effect of restricting pasture access time on animal production, grazing behaviour and dry matter intake (DMI) of spring calving dairy cows in early lactation; and (ii) to establish whether silage supplementation is required when cows return indoors after short grazing periods. In all, 52 Holstein-Friesian spring calving dairy cows were assigned to a four treatment study from 25 February to 26 March 2008. The four treatments were: full time access to pasture (22H; control); 4.5-h- pasture access after both milkings (2 * 4.5H); 3-h pasture access after both milkings (2 * 3H); 3-h pasture access after both milkings with silage supplementation by night (2 * 3SH). All treatments were offered 14.4 kg DM/cow per day herbage from swards, with a mean pre-grazing yield of 1739 kg DM/ha above 4 cm, - and were supplemented with 3 kg DM/cow per day of concentrate. The 2 * 3SH treatment was offered an additional 4 kg DM/cow of grass silage by night. Restricting pasture access time (2 * 3H, 2 * 3SH and 2 * 4.5H) had no effect on milk (28.3 kg/cow per day) and solids corrected milk (27.2 kg/cow per day) yield when compared with the treatment grazing full time. Supplementing animals with grass silage did not increase milk production when compared with all other treatments. Milk protein concentration tended to be lower (P = 0.08; 32.2 g/kg) for the 2 * 3SH animals when compared with the 22H animals (33.7 g/kg). The grass DMI of the 2 * 3SH treatment was significantly lower (-2.3 kg DM/cow per day) than all other treatments (11.9 kg DM/cow per day), yet the total DMI of these animals was highest (16.6 kg DM/cow per day). The 22H cows grazed for 481 min/cow per day, which is significantly longer than all other treatments. The 2 * 3H animals grazed for 98% of the time, whereas the 2 * 3SH grazed for 79% of their time at pasture. Restricting pasture access time did not affect end body weight or body condition score. The results of this study indicate that restricting pasture access time of dairy cows in early lactation does not affect milk production performance. Furthermore, supplementing cows with grass silage does not increase milk production but reduces grazing efficiency. PMID- 22440422 TI - Efficacy of non-nutritive sorbent materials as intestinal-binding agents for the control of boar taint. AB - In many countries, male pigs are castrated to prevent boar taint, but this practice raises concerns about animal welfare and reduces the production efficiency of pork. The objective of this study was to develop dietary manipulations to prevent boar taint. We evaluated the effectiveness of adding activated carbon (AC) or Tween-60 (Tween; polyoxyethylene sorbitan monostearate) to pig finishing diets to reduce levels of androstenone (AND) and skatole in plasma and fat of entire male pigs. Boars (159 +/- 2 days of age at the start of the experiment) were fed diets supplemented with either 5% AC or 5% Tween for 28 days followed by either 14 or 28 days of recovery. Plasma samples were collected at experimental days 0, 7, 14, 21, 28, 42 and 56, and backfat biopsies were taken at experimental days 0, 28, 42 and 56. Feeding AC significantly (P < 0.05) reduced the levels of AND in plasma by day 28 compared to day 0 and by day 42 in fat compared to day 0. AC treatment also decreased levels of oestrone sulphate (E(1)S) in plasma by day 7 compared to day 0. Treatment with Tween significantly decreased (P < 0.05) the levels of plasma AND by day 28 from levels at day 0. Tween treatment did not significantly affect levels of fat AND or plasma E(1)S compared to day 0; however, fat AND levels decreased between days 28 and 42 following treatment with Tween (P < 0.05). Levels of plasma E(1)S, plasma AND and fat AND for control boars remained constant throughout the experiment. Skatole plasma concentrations were very low and did not vary significantly (P > 0.05) from day 0 for any treatment, but fat skatole levels decreased by day 42 in the Tween treatment group. Importantly, there was no difference in growth rate between the control and experimental groups. We conclude that adding AC or Tween to finishing diets for boars can reduce the levels of plasma and fat AND, but further work is needed to confirm the effects of these treatments on reducing fat skatole levels. PMID- 22440423 TI - In vitro assessment of the effectiveness of non-nutritive sorbent materials as binding agents for boar taint compounds. AB - Boar taint, an off-odor and an off-flavor in the meat from some uncastrated male pigs, is due to high levels of the testicular steroid hormone, androstenone, and the indole, skatole. Thus far, there are no known methods for controlling both androstenone and skatole through dietary means. We tested the adsorbent agents, cholestyramine (CH), activated carbon (AC), tween-60 (Tween), bentonite (BNT) and polyvinylpolypyrrolidone (PVPP) for binding androstenone, estrone (E(1)), estrone sulfate (E(1)S) and skatole from buffer solutions in an in vitro system. The goal was to determine the potential utility of these binding agents as feed additives to control boar taint. Michaelis-Menten analysis was utilized to determine the effectiveness of the adsorbents. At pH 7.4, E(1)S was bound to AC and CH with the highest B(max) (maximum binding), whereas Tween and AC had the greatest B(max) for E(1). The B(max) for skatole at pH 7.4 was highest for AC, CH and PVPP. AC had a higher B(max) for androstenone than CH and Tween. The B(max) values at pH 3.0 with E(1)S for AC and CH were essentially 100%, whereas the binding of Tween to E(1)S at pH 3.0 decreased by 49.5% from binding at pH 7.4 (P < 0.05). The Ad(int) values, which represent efficiency of binding, illustrated that AC bound E(1), androstenone and skatole with greater efficiency than the other binding agents at pH 7.4, whereas AC bound E(1)S as efficiently as CH. We conclude that AC was the most effective adsorbent agent for binding E(1), E(1)S, androstenone and skatole in vitro, followed by CH, Tween, PVPP and lastly BNT. These adsorbent agents may be useful for binding boar taint compounds in in vivo studies to decrease the risk of boar taint. PMID- 22440424 TI - Prediction of fat quality in pig carcasses by near-infrared spectroscopy. AB - This study was conducted to evaluate the potential of near-infrared (NIR) spectroscopy (NIRS) technology for prediction of the chemical composition (moisture content and fatty acid composition) of fat from fast-growing, lean slaughter pig samples coming from breeding programmes. NIRS method I: a total of 77 samples of intact subcutaneous fat from pigs were analysed with the FOSS FoodScan NIR spectrophotometer (850 to 1050 nm) and then used to predict the moisture content by using partial least squares (PLS) regression methods. The best equation obtained has a coefficient of determination for cross-validation (CV; R(2)(cv)) and a root mean square error of a CV (RMSECV) of 0.88 and 1.18%, respectively. The equation was further validated with (n = 15) providing values of 0.83 and 0.42% for the coefficient of determination for validation (R(2)(val)) and root mean square error of prediction (RMSEP), respectively. NIRS method II: in this case, samples of melted subcutaneous fat were analysed in an FOSS XDS NIR rapid content analyser (400 to 2500 nm). Equations based on modified PLS regression methods showed that NIRS technology could predict the fatty acid groups, the main fatty acids and the iodine value accurately with R(2)(cv), RMSECV, R(2)(val) and RMSEP of 0.98, 0.38%, 0.95 and 0.49%, respectively (saturated fatty acids), 0.94, 0.45%, 0.97 and 0.65%, respectively (monounsaturated fatty acids), 0.97, 0.28%, 0.99 and 0.34%, respectively (polyunsaturated fatty acids), 0.76, 0.61%, 0.84 and 0.87%, respectively (palmitic acid, C16:0), 0.75, 0.16%, 0.89 and 0.10%, respectively (palmitoleic acid, C16:1n-7), 0.93, 0.41%, 0.96 and 0.64%, respectively (steric acid, C18:0), 0.90, 0.51%, 0.94 and 0.44%, respectively (oleic acid, C18:1n-9), 0.97, 0.25%, 0.98 and 0.29% (linoleic acid, C18:2n-6), 0.68, 0.09%, 0.57 and 0.16% (alpha linolenic acid, C18:3n-3) and 0.97, 0.57, 0.97 and 1.22, respectively (iodine value, calculated). The magnitude of this error showed quite good accuracy using these rapid methods in prediction of the moisture and fatty acid composition of fat from pigs involved in breeding schemes. PMID- 22440425 TI - Comparison of cardiac computed tomography examination appropriateness under the 2010 revised versus the 2006 original Appropriate Use Criteria. AB - BACKGROUND: The 2006 Cardiac CT Appropriate Use Criteria (AUC) were recently revised in 2010. In addition to rating an expanded number of indications, the new criteria adjusted the appropriateness of existing indications to reflect changes in clinical practice and new evidence since 2006. OBJECTIVE: We sought to determine how the appropriateness of cardiac CT examinations performed at a tertiary-care hospital changed under the revised criteria compared with the original AUC. METHODS: Data were collected from the medical records and personal interview of 267 consecutive patients referred for cardiac CT in 2008. With the use of the 2010 and 2006 AUCs, two physicians designated each examination's indication as appropriate, inappropriate, uncertain, or "not classified" if examination indication could not be assigned. RESULTS: With the use the new 2010 AUC, a highly significant change was observed in the classification of examination appropriateness (P < 0.001), with 40% of examinations changing appropriateness level compared with the 2006 AUC. Under the 2010 AUC, there were an increased proportion of both appropriate examinations (59% vs. 45%; P < 0.001) and inappropriate examinations (15% vs. 10%; P < 0.001), and approximately the same proportion with uncertain appropriateness (13% vs. 16%; P = 0.33). Consequently, the proportion of examinations that were not classified was significantly reduced under the 2010 AUC (29% vs. 13%; P < 0.001). CONCLUSION: The revision of the AUC for cardiac CT had a significant effect on examination appropriateness. In comparison to the 2006 AUC, the 2010 AUC provided improved clarification of examination appropriateness. This shift was because of the inclusion of many previously unaddressed indications and the designation of more examinations as either appropriate or inappropriate. PMID- 22440426 TI - Prospective evaluation of the updated 2010 ACCF Cardiac CT Appropriate Use Criteria. AB - BACKGROUND: The cardiac CT Appropriate Use Criteria (AUC) were updated in 2010 to reflect technical advances, evolving expert consensus, and rapidly expanding clinical evidence. OBJECTIVE: We evaluated the effect of the AUC update on their clinical performance, including the completeness and distribution of appropriateness ratings and test outcomes among a consecutive series of patients referred for CT angiography (CTA). METHODS: The 2006 and 2010 criteria were prospectively applied at the point of service to a consecutive series of patients referred for CTA at a single center (n = 1216). Patient interview and review of available health records were used to determine the CTA indication. The proportions of patients within categories of appropriate (A), uncertain (U), inappropriate (I), and not covered were described and compared between the 2006 and 2010 criteria. RESULTS: The 2010 criteria significantly reduced the proportion of uncertain (30.5%-11.4%), inappropriate (16.0%-12.9%), and no covered (12.1%-4.7%; P < 0.001) indications, while increasing the proportion of appropriate tests from 41.4% to 71%. By the 2010 criteria, appropriate indications were more likely to lead to the detection of coronary artery stenosis (11.5% vs 6.7%; P = 0.03) and complete examinations (95.0% vs 90.8%; P = 0.03). CONCLUSION: The 2010 cardiac CT AUC update lead to more complete classification and to large shifts in the appropriateness ratings, underscoring the importance of ensuring the periodic revision of AUCs for evolving imaging technologies such that they perform optimally as quality measurement and reimbursement tools. PMID- 22440427 TI - Temperament and character dimensions of patients with adult separation anxiety disorder. AB - BACKGROUND: There is growing evidence suggesting that separation anxiety can occur in adults. We aimed to determine temperament and character dimensions in patients with adult separation anxiety disorder (ASAD) compared to patients with panic disorder (PD) and healthy subjects. METHODS: The study sample included 77 outpatients with ASAD, 44 outpatients with a PD with or without agoraphobia diagnosis, and 35 healthy subjects. ASAD diagnoses were confirmed with Structured Clinical Interview for Separation Anxiety Symptoms. Other measures included Adulthood Separation Anxiety Checklist, Separation Anxiety Symptom Inventory, and Temperament and Character Inventory (TCI). Group comparisons according to presence or absence of PD comorbidity in ASAD were also done. RESULTS: Patients with ASAD scored higher in harm avoidance (HA) and scored lower in self directedness (SD) compared to PD and control groups. Moreover, both PD patients and ASAD patients scored higher in RD, and self-transcendence dimensions than control subjects. All subscales of HA (anticipatory worry, fear of uncertainty, shyness, and fatigability) were significantly higher than controls. While HA scores were not different between ASAD and 'ASAD+PD' patients, HA levels of both groups were higher than PD alone and control groups. SD scores of patients with ASAD were lower than PD and control groups. LIMITATIONS: Cross-sectional design and ASAD group have other anxiety disorders comorbidity which might affect the results. CONCLUSION: Similar to PD and other anxiety disorders HA and RD was higher, and SD was lower in patients with ASAD compared to healthy subjects. Observed TCI profile is related to the ASAD itself since depression comorbidity was controlled. PMID- 22440428 TI - Practical aspects of high-sensitivity multidimensional 13C MAS NMR spectroscopy of perdeuterated proteins. AB - The double nucleus enhanced recoupling (DONER) experiment employs simultaneous irradiation of protons and deuterons to promote spin diffusion processes in a perdeuterated protein. This results in 4-5 times higher sensitivity in 2D (13)C (13)C correlation experiments as compared to PDSD [1]. Here, a quantitative comparison of PDSD, (1)H-DARR, (2)H-DARR, and (1)H+(2)H DONER has been performed to analyze the influence of spin diffusion on polarization transfer processes. Cross peak buildup curves were analyzed to obtain guidelines for choosing the best experimental parameters. The largest cross peak intensities were observed for the DONER experiments. The fastest build-up rate was observed in the (2)H DARR experiment within a buildup range of ~18-45 ms, whereas values between 24 and 69 ms are observed for the DONER experiment. Furthermore, the effects of direct excitation and cross polarization (CP) are compared. A comparison between DONER and RFDR experiments reveal ~50% more intense cross peaks in the C(alpha) CO and C(alpha)-C(alip) regions of the 2D (13)C-(13)C DONER spectrum applying proton CP ((1)H-(13)C). As a parameter determining the S/N in (13)C-(13)C correlation experiments, proton CP efficiency is investigated using deuterated samples with proton/deuterium ratios at 20%, 40%, and 100% H(2)O. Sufficiently strong (13)C CPMAS signal intensity is observed for such proteins even with very low proton concentration. The effect of proton and/or deuterium decoupling is analyzed at various MAS spinning frequencies. Deuterium decoupling was found most crucial for obtaining high resolution. Long range correlations are readily observed representing distances up to ~6 A by using DONER approach. PMID- 22440429 TI - Ligands located within a cholesterol domain enhance gene delivery to the target tissue. AB - Targeted gene delivery provides enormous potential for clinical treatment of many incurable diseases. Liposomes formulated with targeting ligands have been tested extensively both in vitro and in vivo, and many studies have strived to identify more efficacious ligands. However, the environment of the ligand within the delivery vehicle is generally not considered, and this study assesses the effect of ligand microenvironment by utilizing a lipoplex possessing a cholesterol domain. Our recent work has shown that the presence of the targeting ligand within the cholesterol domain promotes more productive transfection in cultured cells. In the present study, lipoplexes having the identical lipid composition were formulated with different conjugates of the folate ligand such that the ligand was included in, or excluded from, the cholesterol domain. The effect of locating the ligand within the cholesterol domain was then tested in a xenograft tumor model in mice. Lipoplexes that included the ligand within the cholesterol domain showed significantly higher luciferase expression and plasmid accumulation in tumors as compared to lipoplexes in which the ligand was excluded from the domain. These results demonstrate that the microenvironment of the ligand can affect gene delivery to tumors, and show that ligand-mediated delivery can be enhanced by locating targeting ligands within a cholesterol domain. PMID- 22440430 TI - beta2 long-acting and anticholinergic drugs control TGF-beta1-mediated neutrophilic inflammation in COPD. AB - We quantified TGF-beta1 and acetylcholine (ACh) concentrations in induced sputum supernatants (ISSs) from 18 healthy controls (HC), 22 healthy smokers (HS) and 21 COPDs. ISSs from HC, HS and COPD as well as rhTGF-beta1 were also tested in neutrophil adhesion and in mAChR2, mAChR3 and ChAT expression experiments in human bronchial epithelial cells (16-HBE). Finally, we evaluated the effects of Olodaterol (a novel inhaled beta(2)-adrenoceptor agonist) and Tiotropium Spiriva(r), alone or in combination, on neutrophil adhesion and mAChRs and ChAT expression in stimulated 16-HBE. The results showed that 1) TGF-beta1 and ACh concentrations are increased in ISSs from COPD in comparison to HC and HS, and TGF-beta1 in HS is higher than in HC; 2) ISSs from COPD and HS caused increased neutrophil adhesion to 16-HBE when compared to ISSs from HC. The effect of ISSs from COPD was significantly reduced by TGF-beta1 depletion or by the pretreatment with Olodaterol or Tiotropium alone or in combination, while the effect of ISSs from HS was significantly reduced by the pretreatment with Olodaterol alone; 3) mAChR2, mAChR3 and ChAT expression was increased in 16-HBE stimulated with ISSs from COPD and TGF-beta1 depletion significantly reduced this effect on mAChR3 and ChAT expression; 4) rhTGF-beta1 increased mAChR2, mAChR3 and ChAT expression in 16-HBE; 5) Olodaterol did not affect the expression of mAChRs and ChAT in 16-HBE. Our findings support the use of beta2 long-acting and anticholinergic drugs to control the bronchoconstriction and TGF-beta1-mediated neutrophilic inflammation in COPD. PMID- 22440431 TI - Astigmatic manipulation with modern small-incision intraocular lens surgery. PMID- 22440432 TI - Middle prechop: Fracturing the middle portion of the nucleus. AB - To decrease the use of ultrasound power, prechop techniques such as preslice and Akahoshi prechop have been developed. We describe a technique that fractures the nucleus through the center of the lens before chopping. After a continuous curvilinear capsulorhexis is created, an ophthalmic viscosurgical device is injected into the anterior chamber and 2 modified cystotomes are inserted into the lens with a back-and-forth movement; a small amount of pressure from opposite sides is applied to fracture the nucleus. Hydrodissection is then performed, followed by phacoemulsification. PMID- 22440433 TI - Intraocular lens power calculation after previous myopic laser vision correction based on corneal power measured by Fourier-domain optical coherence tomography. AB - PURPOSE: To use Fourier-domain optical coherence tomography (OCT) to measure corneal power and calculate intraocular lens (IOL) power in cataract surgeries after laser vision correction. SETTING: Doheny Eye Institute, Los Angeles, California, and Cullen Eye Institute, Houston, Texas, USA. DESIGN: Prospective comparative case series. METHODS: Patients with previous myopic laser vision correction who had monofocal IOL implantation were enrolled. A Fourier-domain OCT system was used to measure corneal power and pachymetry. Axial length and anterior chamber depth were measured with partial coherence biometry. An OCT based IOL formula was developed, and the mean absolution error (MAE) of postoperative refraction was compared with that for the Haigis-L formula. At Doheny, corneal power was also measured using the clinical history method, the contact lens overrefraction method, and slit-scanning tomography total optical power. RESULTS: Sixteen eyes of 16 patients were enrolled at the 2 sites. Previous laser vision correction ranged from -9.81 to -0.88 diopter (D). The MAE was 0.50 D for OCT-based IOL calculation and 0.76 D for the Haigis-L formula (P=.14). In the 6 eyes enrolled at Doheny, the MAE of OCT-based IOL calculation was 0.60 D. In comparison, the contact lens overrefraction (MAE = 1.46 D, P<.05) and clinical history (MAE = 1.78 D, P<.05) methods were worse. Slit-scanning tomography gave an MAE of 1.28 D (P>.05). CONCLUSION: The predictive accuracy of OCT-based IOL power calculation was equal to or better than current standards in post-laser vision correction eyes. PMID- 22440434 TI - Corneal wavefront-guided photorefractive keratectomy with mitomycin-C for hyperopia after radial keratotomy: two-year follow-up. AB - PURPOSE: To assess corneal wavefront-guided photorefractive keratectomy (PRK) to correct hyperopia after radial keratotomy (RK). SETTING: Sadalla Amin Ghanem Eye Hospital, Joinville, Santa Catarina, Brazil. DESIGN: Case series. METHODS: Excimer laser corneal wavefront-guided PRK with intraoperative mitomycin-C (MMC) 0.02% was performed. Main outcome measures were uncorrected (UDVA) and corrected (CDVA) distance visual acuities, spherical equivalent (SE), corneal aberrations, and haze. RESULTS: The mean time between RK and PRK in the 61 eyes (39 patients) was 18.8 years +/- 3.8 (SD). Before PRK, the mean SE was +4.17 +/- 1.97 diopters (D); the mean astigmatism, -1.39 +/- 1.04 D; and the mean CDVA, 0.161 +/- 0.137 logMAR. At 24 months, the mean values were 0.14 +/- 0.99 D (P<.001), -1.19 +/- 1.02 D (P=.627), and 0.072 +/- 0.094 logMAR (P<.001), respectively; the mean UDVA was 0.265 +/- 0.196 (P<.001). The UDVA was 20/25 or better in 37.7% of eyes and 20/40 or better in 68.9%. The CDVA improved by 1 or more lines in 62.3% of eyes. Two eyes (3.3%) lost 2 or more lines, 1 due to corneal ectasia. Thirty eyes (49.2%) were within +/- 0.50 D of intended SE and 45 (73.8%) were within +/- 1.00 D. From 6 to 24 months, the mean SE regression was +0.39 D (P<.05). A significant decrease in coma, trefoil, and spherical aberration occurred. Three eyes developed peripheral haze more than grade 1. CONCLUSION: Corneal wavefront-guided PRK with MMC for hyperopia after RK significantly improved UDVA, CDVA, and higher order corneal aberrations with a low incidence of visually significant corneal haze. PMID- 22440435 TI - Corneal deformation signal waveform analysis in keratoconic versus post femtosecond laser in situ keratomileusis eyes after statistical correction for potentially confounding factors. AB - PURPOSE: To evaluate and compare corneal biomechanical waveform parameters between keratoconic and post-femtosecond laser in situ keratomileusis (LASIK). SETTING: Jules Stein Eye Institute, University of California, Los Angeles, California, USA. DESIGN: Comparative case series. METHODS: The Ocular Response Analyzer was used to obtain the corneal hysteresis (CH), corneal resistance factor (CRF), and 39 biomechanical waveform parameters in manifest keratoconic eyes and post-femtosecond LASIK eyes. Univariate tests were used to assess the difference in each parameter between the 2 groups of eyes. After controlling for central corneal thickness (CCT) and age, a logistic regression model was used to select the parameters most useful in distinguishing between the 2 groups. RESULTS: After statistically controlling for the differences in CCT and age, 7 parameters were found to be the most useful in distinguishing between groups: aplhf (high frequency noise in the region between peaks [P1 and P2]; P<.0001), w2 (width of P2 at base; P=.001), dslop1 (down-slope of P1 of wave; P<.0001), aindex (degree of "non-monotonicity" of rising and falling edges of first peak of wave, P=.0007), uslope1 (upslope of the P1 of wave; P=.001), CH (P=.035), and P1area (area under P1 of wave; P=.006). The area under the receiver operating characteristic curve for the model using these parameters was 0.932. CONCLUSIONS: Differences in multiple biomechanical waveform parameters between the keratoconus and post-LASIK groups suggests that waveform analysis may be useful to differentiate between healthy and diseased biomechanical conditions. PMID- 22440436 TI - Computer-based tutorial to enhance the quality and efficiency of the informed consent process for cataract surgery. AB - PURPOSE: To assess whether informing patients with an interactive computer-based tool in addition to the face-to-face discussion with their physician is more effective than the conventional informed-consent procedure. SETTING: Hanusch Hospital, Vienna, Austria. DESIGN: Randomized controlled triple-masked clinical trial. METHODS: Patients with bilateral cataract scheduled for cataract surgery at the same center were randomly allocated to a study group or a control group. Patients in the study group were given an interactive computer-based tool (CatInfo) containing a detailed audiovisual presentation about cataract and its treatment. Patients in the control group watched a short sham computer presentation without cataract-related information. Then, all patients had a face to-face informed-consent discussion with a physician masked to group allocation. Afterward, patients in both groups received the same validated questionnaire with cataract-related questions. RESULTS: The study group comprised 60 patients and the control group, 30 patients. The mean age was 73 years (range 51 to 90 years) and 75 years (range 48 to 94 years), respectively. Patients in the study group answered statistically significantly more questions correctly than patients in the control group (15 versus 12 of 19). There was an age effect in the study group, with the computerized tool having a greater impact on elderly patients. CONCLUSIONS: Patients in the study group were significantly better informed than patients in the control group. These findings show that the interactive computer based tool is a useful tutorial to achieve a better informed-consent process for cataract surgery. PMID- 22440437 TI - Effects of steep meridian incision on corneal astigmatism in phacoemulsification cataract surgery. AB - PURPOSE: To evaluate surgically induced astigmatism (SIA) when the clear corneal incision is located on the preoperative steep meridian of the corneal astigmatism in phacoemulsification cataract surgery. SETTING: Seoul St. Mary's Hospital, Seoul, South Korea. DESIGN: Comparative case series. METHODS: Patients with preoperative corneal astigmatism greater than 0.50 diopter (D) were evaluated. The corneal incision meridian was chosen by rounding the steep corneal meridian to the closest 10 degrees. All incisions were enlarged to 3.0 mm before intraocular lens implantation. Patients were grouped according to incision location (temporal, superotemporal, superior). Preoperative keratometric data were compared with data collected 2 months postoperatively. Polar value analysis was used to analyze the SIA. The Hotelling trace test was used for comparison of intraindividual changes. RESULTS: The study evaluated 95 patients (30 eyes temporal incision, 32 eyes superotemporal incision, 33 eyes superior incision). Two months postoperatively, the combined mean polar values for SIA changed significantly in the temporal group (Hotelling T(2) = 0.418; P=.008), superotemporal group (Hotelling T(2) = 1.078; P<.001), and superior incision group (Hotelling T(2) = 1.175; P<.001). The SIA was 0.28 @ 79, 0.40 @ 85, and 0.46 @ 92, respectively. CONCLUSIONS: Choosing the corneal incision based on the preoperative steep meridian significantly decreased keratometric astigmatism at the temporal, superotemporal, and superior locations. Thus, it is desirable to place the corneal incision on the steep meridian in eyes with corneal astigmatism higher than 0.50 D. PMID- 22440438 TI - Graft profile and thickness as a function of cut transition speed in Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To determine the profile of endothelial keratoplasty lenticules prepared using a microkeratome and evaluate the impact of varying cut transition speed on cut depth and profile using anterior segment optical coherence tomography (AS OCT). SETTING: Department of Cornea and External Diseases, Moorfields Eye Hospital, London. United Kingdom. DESIGN: Experimental study. METHODS: Fourier domain AS-OCT was used to image 25 corneal specimens before and after microkeratome dissection with a 350 MUm head. A pilot series of 7 corneas were cut and imaged with the following 18 corneas divided into regular cut transition speed and slow cut transition speed groups (9 in each). Proximal, central, and distal precut corneal thickness and post-cut residual bed thickness were measured using the integrated caliper tools of the Fourier-domain AS-OCT device. Cut depth was calculated by subtraction. RESULTS: The slower microkeratome pass speed produced significantly thinner donor lenticules (mean 148 +/- 45 MUm [SD]) than the standard pass speed (mean 234 +/- 35 MUm) (P <=.0001). In both groups, significant asymmetry was observed in donor lenticules with a deeper cut depth and a thinner lenticule at the beginning of the microkeratome pass (proximal stromal bed). The mean difference between the proximal and distal stromal bed thickness was 61 +/- 63 MUm in the standard group and 52 +/- 22 MUm in the slow pass group (P=.159). CONCLUSIONS: Reducing the transition speed in microkeratome dissection produced thinner donor lenticules. Thickness asymmetry is an inherent flaw with current microkeratome dissection that cannot be easily corrected by altering preparation technique. PMID- 22440439 TI - Safety of repeated topical ocular administration of a polycarbophil-based formulation in several models of ocular surgery in rabbits. AB - PURPOSE: To evaluate the safety of the polycarbophil-based formulation Durasite in rabbits when administered chronically to intact eyes and acutely to eyes compromised by a corneal epithelial defect, penetrating corneal incision, or laser in situ keratomileusis (LASIK) flap. The rheological properties were evaluated to characterize the behavior of the formulation on the ocular surface. SETTING: Bausch & Lomb, Rochester, New York, USA. DESIGN: Experimental study. METHODS: Intact eyes of albino rabbits received polycarbophil (0.6% or 1.3%) 3 times a day for 1 year. The compromised models using polycarbophil 0.9% were an epithelial defect, penetrating corneal incision, or LASIK flap. Eyes with the epithelial defects were dosed 10 times for 24 hours and then 2 times a day for 2 days, and the defect was monitored with fluorescein. The incision or LASIK eyes were dosed 4 times a day for 11 days starting the day before surgery, with 1 drop just before the surgical procedure. The eyes were examined microscopically. The rheological properties were evaluated using a controlled-stress rheometer with a synthetic tear fluid. RESULTS: No adverse ocular or systemic effects were observed with polycarbophil after chronic administration. In the compromised models, there were no adverse effects of the polycarbophil. There was no evidence of an anterior chamber reaction or qualitative effects on the corneal endothelium. Rheologically, the polycarbophil-based formulation behaved as a sheer-thinning fluid under physical conditions similar to the ocular surface. CONCLUSION: Results suggest that the polycarbophil-based formulation, like other shear-thinning formulations, is safe to use in topical ophthalmic pharmaceutical products indicated for chronic use and for treatment of conditions with compromise of the ocular surface. PMID- 22440440 TI - Consultation section. Cataract surgical problem. PMID- 22440449 TI - Residual astigmatism after toric intraocular lens implantation. PMID- 22440451 TI - Hydrorupture of the posterior capsule in femtosecond-laser cataract surgery. PMID- 22440454 TI - Epi-LASIK versus LASEK and PRK. PMID- 22440455 TI - Intraocular lens power calculation errors in long eyes. PMID- 22440457 TI - Effect of vaccination against gonadotropin-releasing factor (GnRF) with Bopriva(r) in the prepubertal bull calf. AB - The aim of this study was to evaluate the effect of immunization against gonadotropin-releasing factor (GnRF) with Bopriva((r)) (Pfizer Animal Health, Parkville, Australia) in prepubertal bull calves. For the study, 6 calves were vaccinated at the age of 3 and 6 weeks with 1 mL Bopriva((r)), and 6 animals served as matched controls. Concentrations of GnRF antibodies, testosterone and LH were determined in serum samples out to 30 weeks after the first immunization. Body weight and scrotal circumference were measured for 59 weeks. At slaughter, 65 weeks after the first immunization, the quality of epididymal sperm was evaluated. The results showed that vaccination against GnRF influenced (P<0.05) anti-GnRF titer, LH and testosterone concentrations as well as scrotal circumference. Antibody titers significantly (P<0.05) increased after the booster vaccination and reached peak values 2 weeks later. Compared to control animals, inhibition (P<0.05) of the prepubertal LH secretion was observed in vaccinated calves at weeks 10 and 12-14 after the first vaccination. In vaccinated calves testosterone concentrations decreased after the booster injection to values below 0.5 ng/mL serum and remained for at least 22 weeks at this low level. Animals vaccinated with Bopriva((r)) showed a delay in testes growth and smaller scrotal circumference. Puberty occurred at the age between 46 and 55 weeks in vaccinated and between 38 and 52 weeks in control animals and body weight gain was similar in both groups. All vaccinated bulls attained spermatogenic capacity at slaughter when they were 68 weeks old. PMID- 22440458 TI - Tones inferior to eye movements in the EMDR treatment of PTSD. AB - Eye Movement Desensitization and Reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder (PTSD). During EMDR, patients make eye movements (EMs) while recalling traumatic memories, but recently therapists have replaced EMs by alternating beep tones. There are no outcome studies on the effects of tones. In an earlier analogue study, tones were inferior to EMs in the reduction of vividness of aversive memories. In a first EMDR session, 12 PTSD patients recalled trauma memories in three conditions: recall only, recall + tones, and recall + EMs. Three competing hypotheses were tested: 1) EMs are as effective as tones and better than recall only, 2) EMs are better than tones and tones are as effective as recall only, and 3) EMs are better than tones and tones are better than recall only. The order of conditions was balanced, each condition was delivered twice, and decline in memory vividness and emotionality served as outcome measures. The data strongly support hypothesis 2 and 3 over 1: EMs outperformed tones while it remained unclear if tones add to recall only. The findings add to earlier considerations and earlier analogue findings suggesting that EMs are superior to tones and that replacing the former by the latter was premature. PMID- 22440459 TI - Different manufacturers of syringes: a new source of variability in blood gas, acid-base balance and related laboratory test? AB - OBJECTIVE: Evaluate whether four different brands/types of heparin coated syringes can represent a source of variability in blood gas analysis (BGA). DESIGN AND METHODS: Blood was collected from one hundred volunteers into different syringes: Syringe I (lithium heparin and calcium balanced); Syringe II: in-house prepared (sodium heparin); Syringe III: (spray-dried calcium-balanced lithium heparin); Syringe IV (lyophilized electrolyte-balanced lithium heparin). RESULTS: Significant differences were as follows: a) Syringe I vs II: pO(2), sO(2), pCO(2)(t), cHCO(3)(-), ctCO(2), base excess (BE), total hemoglobin (tHb), sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)), glucose (Glu), lactate (Lac), O(2) Hb and p 50; b) Syringe I vs III: pH, pO(2), cHCO(3)(-), ctCO(2), BE, Na(+), Glu, Lac and p 50; c) Syringe I vs IV: pH, pO(2), sO(2), pCO(2)(t), BE, Na(+), K(+), Ca(2+), Glu, Lac and O(2) Hb; d) Syringe II vs III: pH, pO(2), sO(2), pCO(2)(t), cHCO(3)(-), ctCO(2), ctO(2), tHb, Na(+), K(+), Ca(2+), Lac and p 50; e) Syringe II vs IV: pH, pO(2), sO(2), pCO(2)(t), cHCO(3)(-), ctCO(2), BE, tHb, Na(+), K(+), Ca(2+), Lac, O(2) Hb and p 50; f) Syringe III vs IV: pH, pO(2), sO(2), cHCO(3)(-), ctCO(2), ctO(2), BE, Na(+), K(+), Ca(2+), O(2) Hb and p 50. CONCLUSION: The different manufacturers of syringes can represent new source of variability on BGA. PMID- 22440460 TI - Body development in sows, feed intake and maternal capacity. Part 1: performance, pre-breeding and lactation feed intake traits of primiparous sows. AB - This study examined the genetic and phenotypic associations between finisher performance, pre-breeding body condition of the gilt, subsequent lactation feed intake and survival of the primiparous sow to farrow in the second parity. Complete data were available on ~2200 sows, along with additional cohort and historical performance data. Genetic variation was observed for average lactation feed intake (heritability: 0.18 +/- 0.04), with a significant proportion of observed variation in average intake attributable to variation in lactation length. Weight and body condition (fatness) at finishing were very highly correlated genetically (0.89 +/- 0.03 and 0.90 +/- 0.02) and moderately correlated phenotypically (0.58 +/- 0.01 and 0.58 +/- 0.01) with weight and body condition before mating. Estimates of genetic (r(g)) and phenotypic (r(p)) correlations between feed intake recorded at finishing and average lactation feed intake (LADI) were moderate (r(g) = 0.26 +/- 0.16 and 0.42 +/- 0.22) and low (r(p) = 0.07 +/- 0.02 and 0.08 +/- 0.03), with r(g) dependent on the models and data subsets used for lactation intake. Non-unity genetic correlations imply that different genetic control mechanisms regulate feed intake during growth and lactation. Moderate genetic correlations between lactation feed intake with live weight (TWT) or growth rate (TADG) recorded at selection and live weight before mating (0.42 +/- 0.11, 0.42 +/- 0.11 and 0.37 +/- 0.15) were considerably higher than the corresponding phenotypic correlations for LADI with TADG or 29WT (0.09 +/- 0.02 and 0.08 +/- 0.02). Correlations between fatness at selection (TFAT) or mating (29FT) and LADI were negative but not significantly different from 0. Overall, these data suggest that there is exploitable genetic variation for feed intake during lactation, and that selection is possible if lactation feed intakes are recorded. However, genetic correlations suggest that early growth seems to be related to lactation feed intake capacity. There was generally no strong evidence that selection for lean growth potential in dam lines will substantially diminish sow lactation intake capacity as a correlated response. PMID- 22440461 TI - Body development in sows, feed intake and maternal capacity. Part 2: gilt body condition before and after lactation, reproductive performance and correlations with lactation feed intake. AB - Data on sow body weight (BW) and fatness (n = ~2250 pregnant sows) and reproductive data (including historical: n = ~18 000) were used to examine the genetic and phenotypic associations between body condition before and after farrowing, gestational outcomes, lactation feed intake and the gilts' ability to survive unculled to farrow in the second parity. Within-trait genetic correlations were very high between weight (0.77 +/- 0.06) and fat depth (0.91 +/ 0.04) recorded before farrowing and at weaning. Litter size traits were generally uncorrelated genetically with aspects of sow BW and body condition. However, genetic correlations indicated that sows producing heavier piglets at birth had litters with increased gain (0.36 +/- 0.16), and were characterised by greater weight (-0.72 +/- 0.08) and fat change (-0.19 +/- 0.15) during lactation, reflected to a lesser extent by lower weight (-0.12 +/- 0.11) and fatness (-0.17 +/- 0.10) at weaning. Genetic correlations (r(a)) between reproductive traits and lactation feed intake were generally low, but favourable. However, lactation intake was positively correlated with measures of sow size (r(a) = ~0.55), such that selection for lactation feed intake would likely be accompanied by increased mature sow size. Phenotypic correlations (r(p)) showed that sow survival to the second parity (FAR12) was positively influenced by litter size and fat depth at weaning, supporting attributes of increased fatness before farrowing, less weight loss during lactation and an increased lactation intake. PMID- 22440462 TI - The origin of the Tibetan Mastiff and species identification of Canis based on mitochondrial cytochrome c oxidase subunit I (COI) gene and COI barcoding. AB - DNA barcoding is an effective technique to identify species and analyze phylogenesis and evolution. However, research on and application of DNA barcoding in Canis have not been carried out. In this study, we analyzed two species of Canis, Canis lupus (n = 115) and Canis latrans (n = 4), using the cytochrome c oxidase subunit I (COI) gene (1545 bp) and COI barcoding (648 bp DNA sequence of the COI gene). The results showed that the COI gene, as the moderate variant sequence, applied to the analysis of the phylogenesis of Canis members, and COI barcoding applied to species identification of Canis members. Phylogenetic trees and networks showed that domestic dogs had four maternal origins (A to D) and that the Tibetan Mastiff originated from Clade A; this result supports the theory of an East Asian origin of domestic dogs. Clustering analysis and networking revealed the presence of a closer relative between the Tibetan Mastiff and the Old English sheepdog, Newfoundland, Rottweiler and Saint Bernard, which confirms that many well-known large breed dogs in the world, such as the Old English sheepdog, may have the same blood lineage as that of the Tibetan Mastiff. PMID- 22440463 TI - Gene flow in a national cross-breeding beef population. AB - Future progress in genetic improvement and the monitoring of genetic resources in beef cattle requires a detailed understanding of the population under selection. This study examines the gene flow in the UK beef population with an uncommon breeding structure involving interaction between the beef and dairy populations. British Cattle Movement Service records were used as the primary source of information, and these data were triangulated with UK government statistics, other industry information sources and existing literature to build up a profile of the UK beef industry. Estimates were made of the breed composition of suckler cows, breeding bulls and the prime slaughter population. Cross-bred animals made up 85% and 94%, respectively, of the commercial beef breeding cow and prime slaughter populations. Holstein/Friesian (through cross-breeding) made up the largest proportion of genes in both these populations with 33% and 28%, respectively. The next five most popular breeds were specialist beef breeds: Limousin (22% and 18%), Charolais (11% and 6%), Simmental (9% and 11%), Angus (7% and 8%) and Belgian Blue (6% and 6%). Combined, the top seven beef breeds accounted for 94% of beef genetics in the prime slaughter population, and 80% of this came from non-native breeds. The influence of dairy breeds in the commercial beef breeding population was highlighted by the fact that 44% of replacement commercial beef breeding females were sourced from beef-sired crosses in the dairy herd, and in total 74% of all maternal grand dams of prime slaughter animals were Holstein/Friesian. The use of selection index technology was also investigated by analysing breeding bull sale results, with the correlation between the terminal sire index and sale price of young breeding bulls being generally moderate but significant, ranging from 0.21 to 0.38 across the major beef breeds. The most influential source of genetics in the commercial suckler beef herd was natural service breeding bulls. These were mostly sourced from pedigree breeders, and accounted for 47.8% of the genetics in the prime beef population. Artificial insemination sires were responsible for 16.6% of prime beef genetics, with the remaining 35.6% coming from dairy breeds, 95% of which was Holstein/Friesian. PMID- 22440464 TI - Effect of including genetic progress in milk yield on evaluating the use of sexed semen and other reproduction strategies in a dairy herd. AB - The objective of this study was to explore the importance of including genetic progress in milk yield when evaluating different reproductive strategies in a dairy herd by simulation modeling. The model used in this study was SimHerd V, a dynamic and mechanistic Monte Carlo simulation model of a dairy herd including young stock. A daily increasing trend describing genetic milk yield potential of the sire population was included in the model. The inaccuracy of assuming that replacement heifers have the same (milk yield) potential as the cows present in the herd was hereby dealt with. Improving estrus detection rate from 0.45 to 0.80 increased gross margin (GM) per cow-year by ?20 when genetic progress was not included in the model. When genetic progress was included in the model, then the same improvement in estrus detection decreased the GM per cow-year by ?7.4. This reduced effect was explained by a lower replacement rate in consequence of the improved estrus detection and thereby a slower genetic progress in the herd. There was a reduced effect of including genetic progress on GM when surplus heifers were sold selectively based on breeding values. Repeated insemination with sexed semen on the superior half of all heifers reduced GM by ?8 per cow year when genetic progress was not included and increased the GM by ?16 per cow year when genetic progress was included in the model. Including genetic progress reduced the losses caused by lower conception and estrus detection rates and had a minimal effect with regard to postponing first insemination. This study has proven that it is important to include genetic progress in decisions on reproduction strategies in a dairy herd. PMID- 22440465 TI - Genetic evaluation of ovulatory disorders in Austrian Fleckvieh cows: a comparison between linear models and survival analysis. AB - The objective of this study was to compare linear models and survival analysis for genetic evaluation of ovulatory disorders, which included veterinary treatments of silent heat/anestrus and cystic ovaries. Data of 23 450 daughters of 274 Austrian Fleckvieh sires were analyzed. For linear model analyses, ovulatory disorders were defined as a binary response (presence or absence) in the time periods from calving to 150 days after calving and from calving to 300 days after calving. For survival analysis, ovulatory disorders were defined either as the number of days from calving to the day of the first treatment for an ovulatory disorder (uncensored record) or from calving to the day of culling, or the last day of the period under investigation (until 150 or 300 days after calving; censored record). Estimates of heritability were very similar (0.016 to 0.020) across methods and periods. Correlations between sire estimated breeding value from linear model and survival analysis were 0.98, whereas correlations between different time periods were somewhat lower (0.95 and 0.96). The results showed that the length of time period had a larger effect on genetic evaluation than methodology. PMID- 22440466 TI - Regulation of soy isoflavones on weight gain and fat percentage: evaluation in a Chinese Guangxi minipig model. AB - This study was conducted to determine the effects of soy isoflavones on changes in body and tissue weight and on insulin-like factor I (IGF-I) and peroxisome proliferator-activated receptor-gamma (PPARgamma) gene and protein expression in muscle and adipose tissues in Chinese Guangxi minipig, as a model for studying human nutrition. A total of 72 male Chinese Guangxi minipigs were fed basal diet (control, Con), low dose of soy isoflavones and high dose of soy isoflavones (HSI). The results showed that HSI increased the body weight (BW) gain and fat percentage of minipigs (P < 0.05). In addition, the serum concentrations of IGF-I and interleukin-6 were increased by high levels of soy isoflavones (P < 0.05). Furthermore, a diet containing soy isoflavones enhanced IGF-I mRNA expression levels in longissimus muscle, but decreased these levels in perirenal fat. However, the mRNA and protein expression levels of PPARgamma in longissimus muscle and subcutaneous adipose tissue were both increased when compared with the Con. The data indicated that soy isoflavones regulated the BW gain and fat percentage of Chinese Guangxi minipigs, which also showed changes in IGF-I system and PPARgamma. However, further research is required to clarify the causative relationship. PMID- 22440467 TI - Effects of dietary lipids and Clostridium butyricum on serum lipids and lipid related gene expression in broiler chickens. AB - The effect of dietary lipids and Clostridium butyricum supplementation on circulating lipids and the transcription of selected genes involved in lipid metabolism were investigated in broiler chickens. One hundred and sixty-day-old broilers (Arbor Acres) were divided into four treatment groups in a 2 * 2 factorial arrangement and fed four diets with two lipid sources (soybean oil or fish oil) and two levels of C. butyricum (0 or 5 g/kg) for a period of 6 weeks. Serum concentrations of total cholesterol and low-density lipoprotein cholesterol were lower (P < 0.05) in broilers fed diets containing fish oil than in those fed diets containing soybean oil. Fish oil significantly reduced (P < 0.05) hepatic fatty acid synthase and lipoprotein lipase (LPL) activities in abdominal fat. In contrast, fish oil significantly increased (P < 0.05) breast muscle LPL activity and hepatic peroxisome proliferator-activated receptor-alpha and LPL gene expression. The addition of C. butyricum significantly increased (P < 0.05) LPL activity in abdominal fat and liver-type fatty acid-binding protein gene expression in jejunal mucosa. The results of this study indicated that the reduced abdominal fat in broilers fed fish oil as observed may be due to augmented hepatic fatty acid catabolism and lower hepatic fat synthesis. The increased intramuscular fat content in breast muscle of broilers fed C. butyricum as described may be the result of enhanced fatty acid uptake. PMID- 22440468 TI - Dietary supplementation with ovine serum immunoglobulin is associated with an increased gut luminal mucin concentration in the growing rat. AB - The mucus layer covering the gut epithelium is pivotal to host defence and is affected by various dietary components. Part of the reported beneficial effect of dietary immunoglobulins (Igs) on gut health may be due to effects on the gut mucus layer. The aim was to determine whether orally administered ovine serum Ig influence goblet cell count, mucin gene expression and digesta mucin protein content in the gut of the growing rat. Fourteen Sprague-Dawley male growing rats were used in a 21-day study and were fed either a casein-based control diet (CON; no Ig) or a similar diet but containing freeze-dried ovine Ig (FDOI). Daily food intake and growth rate were not affected by the dietary treatments. When compared to the rats consuming CON diet, those consuming the FDOI diet had significantly (P < 0.05) more intact and cavitated goblet cells in the intestinal villi. A similar result was found for crypt goblet cells in the small intestine and colon. Ileal Muc2, Muc3, Muc4 and stomach Muc5Ac mRNA expressions for the FDOI animals were higher (P < 0.05) compared to the the CON animals. Mucin protein content was higher (P < 0.05) in the stomach, ileum and colonic digesta of rats fed the FDOI diet. In conclusion, orally administered FDOI influenced gut mucins in the growing rat as evidenced by increased mucin gene expression and digesta mucin protein concentrations as well as an increased goblet cell count. PMID- 22440469 TI - Effects of supplementation with fish oil and barium selenate on performance, carcass characteristics and muscle fatty acid composition of late season lamb finished on grass-based or concentrate-based diets. AB - The objectives of this study were to investigate the effects of fish oil supplementation on performance and muscle fatty acid composition of hill lambs finished on grass-based or concentrate-based diets, and to examine the interaction with selenium (Se) status. In September 2006, 180 entire male lambs of mixed breeds were sourced from six hill farms after weaning and finished on five dietary treatments: grazed grass (GG), grass +0.4 kg/day cereal-based concentrate (GC), grass +0.4 kg/day cereal-based concentrate enriched with fish oil (GF), ad libitum cereal-based concentrate (HC) and ad libitum fish oil enriched concentrate (HF). Within each treatment, half of the lambs were also supplemented with barium selenate by subcutaneous injection. At the start of the trial, the proportion of lambs with a marginal (<0.76 MUmol/l) or deficient (<0.38 MUmol/l) plasma Se status was 0.84 and 0.39, respectively. Compared with control lambs, GG lambs treated with Se had higher (P < 0.01) plasma Se levels, whereas erythrocyte glutathione peroxidase activity was higher (P < 0.01) for Se supplemented lambs fed diets GG and GF. However, Se supplementation had no effects on any aspect of animal performance. Fish oil increased (P < 0.05) levels of 22:5n-3 and 22:6n-3 in the Longissimus dorsi of HF lambs but otherwise had no effect on the health attributes of lamb meat. There were no significant effects of fish oil on dry matter intake, animal performance or lamb carcass characteristics. Daily carcass weight gain (CWG; P < 0.001), carcass weight (P < 0.01) and conformation score (P < 0.01) increased with increasing concentrate inputs. Lambs fed concentrate-based diets achieved a higher mean CWG (P < 0.001), dressing proportion (P < 0.001) and carcass weight (P < 0.011), and were slaughtered up to 8.3 days earlier (P < 0.05) and at 1.2 kg lower (P < 0.05) live weight than pasture-fed lambs. However, carcasses from grass-fed lambs contained lower levels of perinephric and retroperitoneal fat (P < 0.05), and had less fat over the Iliocostalis thoracis (P < 0.001) and Obliquus internus abdominis (P < 0.05). Meat from grass-fed lambs also had lower levels of 18:2n-6 and total n-6 fatty acids compared with those finished indoors. The results of this study demonstrate that fish oil supplementation has some benefits for the health attributes of meat from lambs fed concentrate-based diets but not grass-based diets. Supplementing Se-deficient lambs with barium selenate will improve Se status of lambs fed zero-concentrate diets, but has no additional benefit when lambs are already consuming their daily Se requirement from concentrates or when fish oil-enriched diets are fed. PMID- 22440470 TI - Peripheral cytokine expression in Standardbred mares at different adiposity during the periparturient period. AB - The aim of this study was to evaluate whether the peripheral cytokine expression could be affected by differences in fat thickness in healthy mares during the periparturient period (last weeks of pregnancy and first weeks of lactation). At the beginning of the 11th month of gestation, 18 mares with normal body condition score (BCS; 5) were divided into two groups with low (L; <=12 mm; n = 12) and high (H; >12 mm; n = 6) fat thickness. Blood samples were collected every 10 days from the 11th month of gestation to 20 days post partum. Peripheral blood mononuclear cells were separated and tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), -1beta (ILbeta), -2 (IL-2) and -6 (IL-6) gene expressions were performed by using reverse transcriptase PCR. TNF-alpha and IFN-gamma expressions were affected by fatness group, as the sampling period influenced the expression of all cytokines with the exception of IFN-gamma. The interaction between fatness group and sampling period tended to be significant (P < 0.10) only for IL-1beta, TNF-alpha and IL-2. In H group, compared with L group, IL-1beta and IL-2 significantly (P < 0.05) increased at parturition. TNF-alpha peripheral expression increased from parturition to reach the peak at +10 days (P < 0.05) only in H group. In conclusion, in normal BCS periparturient mares, small body fat thickness variations influence the peripheral cytokine expression, showing a possible role for cytokines in parturition and lactation, events strongly linked to adipose tissue availability. PMID- 22440471 TI - Hypothalamic expression of genes for appetite regulators and estrogen alpha, estrogen beta and leptin receptors in obese dams and their fetuses. AB - Under- and over-nutrition during gestation may influence fetal hypothalamic development resulting in individuals predisposed to adverse health effects. This study examined fetuses from obese and control ewes to determine whether dam obesity alters hypothalamic expression of fetal appetite regulatory genes. A second objective was to contrast the expression of appetite regulatory genes in ewes that become the most obese to those that remained in moderate body condition on the same energy-rich diet. Multiparous, western white-faced ewes were weighed and individually fed 100% (control) or 150% (obese) of National Research Council requirements from day 60 before mating until day 75 of gestation. At day 75 of gestation, fetuses were collected and weighed. Hypothalamic tissue from fetal lambs and dams was collected and frozen for mRNA extraction. Dam obesity (P >= 0.16), fetal sex (P >= 0.44) or their interaction (P >= 0.42) did not affect the relative expression of fetal hypothalamic regulators of appetite, including neuropeptide Y, agouti-related protein, pro-opiomelanocortin, cocaine- and amphetamine-regulated transcript and receptors for leptin. Maternal obesity at day 75 of gestation in ewes did not affect developmental mechanisms responsible for the expression of fetal appetite regulatory genes and would not be expected to predispose offspring to adult-onset obesity through disrupted appetite regulation at this developmental time point. In the ewe, appetite regulatory genes did not differ (P > 0.20) with ewe adiposity; however, expression of estrogen receptor alpha, but not beta (P = 0.37), in the medial basal hypothalamus was greater (P = 0.04) in obese than in control ewes. PMID- 22440472 TI - Differential mesenteric fat deposition in bovines fed on silage or concentrate is independent of glycerol membrane permeability. AB - In the meat industry, the manipulation of fat deposition in cattle is of pivotal importance to improve production efficiency, carcass composition and ultimately meat quality. There is an increasing interest in the identification of key factors and molecular mechanisms responsible for the development of specific fat depots. This study aimed at elucidating the influence of breed and diet on adipose tissue membrane permeability and fluidity and their interplay on fat deposition in bovines. Two Portuguese autochthonous breeds, Alentejana and Barrosa, recognized as late- and early-maturing breeds, respectively, were chosen to examine the effects of breed and diet on fat deposition and on adipose membrane composition and permeability. Twenty-four male bovines from these breeds were fed on silage-based or concentrate-based diets for 11 months. Animals were slaughtered to determine their live slaughter and hot carcass weights, as well as weights of subcutaneous and visceral adipose depots. Mesenteric fat depots were excised and used to isolate adipocyte membrane vesicles where cholesterol content, fatty acid profile as well as permeability and fluidity were determined. Total accumulation of neither subcutaneous nor visceral fat was influenced by breed. In contrast, mesenteric and omental fat depots weights were higher in concentrate-fed bulls relative to silage-fed animals. Membrane fluidity and permeability to water and glycerol in mesenteric adipose tissue were found to be independent of breed and diet. Moreover, the deposition of cholesterol and unsaturated fatty acids, which may influence membrane properties, were unchanged among experimental groups. Adipose membrane lipids from the mesenteric fat depot of ruminants were rich in saturated fatty acids, and unaffected by polyunsaturated fatty acids dietary levels. Our results provide evidence against the involvement of cellular membrane permeability to glycerol on fat accumulation in mesenteric fat tissue of concentrate-fed bovines, which is consistent with the unchanged membrane lipid profile found among experimental groups. PMID- 22440473 TI - Modelling as a tool to redesign livestock farming systems: a literature review. AB - Livestock farming has recently come under close scrutiny, in response especially to environmental issues. Farmers are encouraged to redesign their livestock farming systems in depth to improve their sustainability. Assuming that modelling can be a relevant tool to address such systemic changes, we sought to answer the following question: 'How can livestock farming systems be modelled to help farmers redesign their whole farming systems?' To this end, we made a literature review of the models of livestock farming systems published from 2000 to mid-2009 (n = 79). We used an analysis grid based on three considerations: (i) system definition, (ii) the intended use of the model and (iii) the way in which farmers' decision-making processes were represented and how agricultural experts and farmers were involved in the modelling processes. Consistent rationales in approaches to supporting changes in livestock farming were identified in three different groups of models, covering 83% of the whole set. These could be defined according to (i) the way in which farmers' decisions were represented and (ii) the model's type of contribution to supporting changes. The first type gathered models that dynamically simulated the system according to different management options; the farmers' decision-making processes are assumed to consist in choosing certain values for management factors. Such models allow long-term simulations and endorse different disciplinary viewpoints, but the farmers are weakly involved in their design. Models of the second type can indicate the best combination of farm activities under given constraints, provided the farmers' objectives are profit maximisation. However, when used to support redesigning processes, they address neither how to implement the optimal solution nor its long-term consequences. Models of the third type enable users to dynamically simulate different options for the farming system, the management of which is assumed to be planned according to the farmers' general objectives. Although more comprehensive, these models do not easily integrate different disciplinary viewpoints and different subsystems, which limits their usefulness as support tools for redesigning processes. Finally, we concluded about what specific requirements should be for modelling approaches if farmers were to be supported in redesigning their whole livestock farming systems using models. PMID- 22440474 TI - Evaluation of the environmental implications of the incorporation of feed-use amino acids in the manufacturing of pig and broiler feeds using Life Cycle Assessment. AB - The incorporation of feed-use (FU) amino acids (AAs) in diets results in a reduced use of protein-rich ingredients such as soybean meal, recognized to have elevated contributions to environmental impacts. This study investigated whether the incorporation of L-lysine.HCl, L-threonine and FU-methionine reduces the environmental impacts of pig and broiler feeds using Life Cycle Assessment. The following impact categories were considered: climate change, eutrophication, acidification, terrestrial ecotoxicity, cumulative energy demand and land occupation. Several feeds were formulated either to minimize the cost of the formulation (with or without AA utilization), to maximize AA incorporation (i.e. the cost of AA was considered to be similar to that of soybean meal), or to minimize greenhouse gas emissions. For both pig and broiler feeds, calculations were made first using only cereals and soybean meal as main ingredients and then using cereals and several protein-rich ingredients (soybean meal, rapeseed meal and peas). In addition, these calculations were performed using two types of soybean meal (from Brazil, associated with recent deforestation or not). For broiler feeds, two types of maize (from France, irrigated, with mineral fertilization v. not irrigated, with animal manure fertilization) were also tested. Regarding the feeds formulated to minimize cost, incorporation of AA decreased the values for eutrophication, terrestrial ecotoxicity and cumulative energy demand of both pig and broiler feeds, regardless of the base ingredients. Reduction in climate change and acidification due to the incorporation of AA depended on the nature of the feed ingredients, with the effect of AA incorporation being greater when combined with ingredients with high impacts such as soybean meal associated with deforestation. Feeds formulated to maximize AA incorporation generally had a similar composition to those formulated to minimize cost, suggesting that the costs of AA were not the limiting factor in their incorporation. Feeds formulated to minimize greenhouse gas emissions had the lowest values for climate change and cumulative energy demand, but not for other impacts. Further research is needed to elucidate whether the incorporation of additional AA (tryptophan and valine) along with L-lysine, L-threonine and FU methionine could decrease on the environmental impacts of pig and broiler feeds further. PMID- 22440475 TI - Identification of smallholder farmers and pastoralists' preferences for sheep breeding traits: choice model approach. AB - Identification of breeding objective traits pertinent to specific production environments with the involvement of target beneficiaries is crucial to the success of a breed improvement program. A choice experiment was conducted in four locations representing different production systems and agro-ecologies that are habitat to four indigenous sheep breeds (Afar, Bonga, Horro and Menz) of Ethiopia with the objective of identifying farmers'/pastoralists' preferences for sheep breeding traits. Following a synthesis of secondary information and diagnostic surveys, two communities per location consisting of 60 households each having at least four breeding ewes were identified. Producers' priority attributes used in the choice sets were identified through in-depth production system studies conducted from December 2007 to March 2008. On the basis of prior information, four to seven attributes were used to design choice sets with different profiles in order to capture results that mimic real life of the different communities. The attributes and levels chosen for the sheep profile were as follows: body size (large/small), coat color (brown/white/black), tail type (good/bad) for both rams and ewes; horn (polled/horned) and libido (active/poor) for rams; and lambing interval (three lambings in 2 years/two lambings in 2 years time), mothering ability (good mother/bad mother), twinning rate (twin bearer/single bearer) and milk yield (two cups per milking/one cup per milking) for ewes. A fractional factorial design was implemented to construct the alternatives included in the choice sets. The design resulted in a randomized selection of 48 sheep profiles (24 sets) for both sexes, which were grouped into four blocks with six choice sets each. An individual respondent was presented with one of the four blocks to make his/her choices. Results indicate that producers' trait preferences were heterogeneous except for body size in rams and mothering ability in ewes where nearly homogeneous preferences were investigated. In the pastoral production system, attention was given to coat color of both breeding rams and ewes, favoring brown and white colors over black. Ram libido influenced producers' decisions in Bonga, Horro and Menz areas. The influence of milk yield and twinning on respondents' decision making was high in Afar and Horro, respectively. Breeders in all areas attempt to combine production and reproduction traits as well as they can in order to maximize benefits from their sheep. The elicited measurable objective traits were used to design alternative community-based sheep breeding plans for the four indigenous sheep breeds in their production environments that have been implemented since. PMID- 22440476 TI - Effect of a linseed diet on lipogenesis, fatty acid composition and stearoyl-CoA desaturase in rabbits. AB - The aim of the study was to examine the effect of a linseed diet on meat quality and on lipogenesis in rabbits. Twelve rabbits were fed a control or a linseed diet. There was no diet effect on growth, food consumption, carcass characteristics and meat ultimate pH and colour. Feeding the linseed diet increased the n-3 polyunsaturated fatty acids (PUFA) levels in perirenal and interscapular fats, in the Longissimus dorsi muscle and in the liver. The linseed diet produced lower linoleic acid/alpha-linolenic acid ratios in adipose tissues and in the Longissimus dorsi muscle, but not in the liver. Diet did not affect lipogenic enzyme activities in the Longissimus dorsi muscle, whereas the linseed diet decreased the lipogenic potential in perirenal and interscapular fats, and in the liver. Feeding rabbits with a high n-3 PUFA diet led to a decrease in the oxidative stability of perirenal fat and the Longissimus dorsi muscle, and to an inhibition of stearoyl-CoA-desaturase activity in liver and in adipose tissues, but not in muscle. PMID- 22440477 TI - Comparison of meat and carcass quality in organically reared and conventionally reared pasture-fed lambs. AB - The 'Organic' product label guarantees a production process that avoids the use of synthetic fertilisers, pesticides and hormones and minimises recourse to pharmaceuticals or veterinary drugs; however, the product's quality remains an issue that needs to be addressed in response to consumer demand. Consequently, this study was conducted to compare the sensory and nutritional qualities of meat and carcasses from pasture-fed lambs reared organically (O) or conventionally (C). Mean lamb growth profile was kept similar between the two treatments to avoid confounding effects with lamb age or weight at slaughter. The experiment was conducted over 3 years (2005 to 2007) with 12 O and 12 C lambs each year. The O and C treatments differed in the level of on-pasture mineral N fertilisation inducing a higher proportion of white clover in the organic pasture than the conventional pasture. Lambs were slaughtered when they attained a fat class of 2 to 3, and carcass and meat quality were evaluated. Lambs were slaughtered at an average weight and age of 35.3 kg and 156 days in the O treatment, respectively, and 35.2 kg and 155 days in the C treatment, respectively. Sensory evaluation indicated that loin chops from the O treatment had a higher level of abnormal fat odour compared with the C treatment. Carcasses from the O treatment had a softer subcutaneous fat one among 3 years (2007) compared to the C treatment. These results are probably due to a higher proportion of white clover in the diet. Organically reared lambs did offer the slight advantage of muscle fatty acid containing a higher level of stearic acid, which may have positive effects in the prevention of cardiovascular disease in humans. This may be the result of a higher rumen bio-hydrogenation of C18:3n-3 due to differences in the botanical composition between the O and the C pasture. Production system had no effect on the colour characteristics of the meat and subcutaneous fat, except lightness of subcutaneous dorsal fat, which was slightly higher in the O lambs. There were no differences between O and C lambs in terms of colour stability and lipid oxidation of the meat during the 6-day refrigerated storage under gas-permeable film. PMID- 22440478 TI - Effect of alpha-tocopherol tissue levels on beef quality. AB - To evaluate meat quality of beef with different alpha-tocopherol tissue levels, 55 feedlot steers were fed a barley-based finisher diet with four vitamin E supplementation levels (0, 350, 700 and 1400 IU DL-alpha-tocopheryl acetate/animal per day) for 120 days. Although the increase in oxidation levels overtime was much smaller (P < 0.001) in the high-medium and high groups, alpha tocopherol tissue levels did not affect (P > 0.05) pH, proximate analysis, drip and cooking losses, and shear force of steaks. No effect of alpha-tocopherol tissue levels was found in retail evaluation of steaks after a short ageing time of 6 days, but with 21 days of ageing, a delay in formation of metmyoglobin (P = 0.008) was observed in steaks with higher tissue levels of alpha-tocopherol. Similar results were found for ground beef (25% fat) prepared from 6-day aged meat. Thus, higher alpha-tocopherol tissue levels protect ground beef and long aged steaks from discolouration and lipid oxidation. PMID- 22440479 TI - Mechanisms for recurrent and complex human genomic rearrangements. AB - During the last two decades, the importance of human genome copy number variation (CNV) in disease has become widely recognized. However, much is not understood about underlying mechanisms. We show how, although model organism research guides molecular understanding, important insights are gained from study of the wealth of information available in the clinic. We describe progress in explaining nonallelic homologous recombination (NAHR), a major cause of copy number change occurring when control of allelic recombination fails, highlight the growing importance of replicative mechanisms to explain complex events, and describe progress in understanding extreme chromosome reorganization (chromothripsis). Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed. PMID- 22440480 TI - Combinatorial complexity in chromatin structure and function: revisiting the histone code. AB - Covalent modifications of histone proteins play key roles in transcription, DNA repair, recombination, and other such processes. Over a hundred histone modifications have been described, and a popular idea in the field is that the function of a single histone mark cannot be understood without understanding its combinatorial co-occurrence with other marks, an idea generally called the 'histone code hypothesis.' This idea is hotly debated, with increasing biochemical evidence for chromatin regulatory factors that bind to specific histone modification combinations, but functional and localization studies finding minimal combinatorial complexity in histone modification patterns. This review will focus on these contrasting results, and will briefly touch on possible ways to reconcile these conflicting views. PMID- 22440481 TI - Development of a computerized adaptive testing system of the Fugl-Meyer motor scale in stroke patients. AB - OBJECTIVE: To develop a computerized adaptive testing system of the Fugl-Meyer motor scale (CAT-FM) to efficiently and reliably assess motor function in patients with stroke. DESIGN: First, a simulation study was used to develop and examine the psychometric properties of the CAT-FM. Second, a field study was employed to determine the administration efficiency of the CAT-FM. SETTING: One medical center and 1 teaching hospital. PARTICIPANTS: Patients' responses (n=301) were used for the simulation study; 49 patients participated in the field study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The 2 CAT-FM item banks (upper extremity and lower extremity) include 37 items from the original Fugl Meyer scale. The reliability, validity, and responsiveness of the CAT-FM were determined by the simulation study. RESULTS: Two stopping rules (reliability >=0.9 or an increase of reliability <.01 after testing an item) were used. The simulation study showed that the CAT-FM had high reliability (>=.93 for upper extremity and lower-extremity subscales) and concurrent validity (Pearson r>=.91 for the upper-extremity and lower-extremity subscales and motor scale). The responsiveness was moderate (standardized response mean for the upper extremity=.67, lower extremity=.79, and motor=.77) for the 226 patients who completed both assessments at 14 and 90 days after stroke. The field study found that, on average, the time needed to administer the CAT-FM was 242 seconds with 4.7 items. CONCLUSIONS: The CAT-FM is an efficient, reliable, valid, and responsive clinical tool for assessing motor function in patients with stroke. PMID- 22440482 TI - Depression improvement is related to social role functioning after stroke. AB - OBJECTIVES: To (1) examine the relationships between baseline demographic, clinical, and psychological characteristics and social role functioning (SRF) at 4 months after stroke, and (2) assess whether depression improvement is associated with 4-month SRF. DESIGN: We completed a secondary data analysis using data from a completed cohort study including people with stroke with or without depression. We used multiple linear regression to identify variables independently associated with 12-week SRF. SETTING: Hospital and patients' homes. The intervention was via phone calls. PARTICIPANTS: People with a new stroke recruited during the inpatient stay (N=371, depressed only n=176). All survived an ischemic stroke, were 18 years and older, spoke and understood English, owned a telephone, had no severe language or cognitive impairments, and were expected to live at least 6 months. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured depression with the Patient Health Questionnaire-9 (PHQ-9), and depression improvement was defined by a 50% decrease in PHQ-9 scores from baseline to 12 weeks or a 12-week PHQ-9 score <10. SRF was measured with the social domain of the Stroke-Specific Quality of Life Scale. RESULTS: Depression and comorbidities were found to be independently associated with 12-week SRF. Importantly, depression response (or depression improvement) was the only variable to independently predict SRF in the depressed-only group. CONCLUSIONS: Among stroke survivors with depression, improvement of that depression was independently associated with improved SRF. This is a reminder of the importance for rehabilitation providers to screen for and treat poststroke depression. PMID- 22440483 TI - Three-year follow-up results of a residential community reintegration program for patients with chronic acquired brain injury. AB - OBJECTIVE: To evaluate outcomes of a residential community reintegration program 3 years after treatment on independent living, societal participation, emotional well-being, and quality of life in patients with chronic acquired brain injury and psychosocial problems hampering societal participation. DESIGN: A follow-up assessment 3 years after treatment was compared with the 1-year follow-up assessment in a prospective cohort study. SETTING: A tertiary rehabilitation center for acquired brain injury. PARTICIPANTS: Of the 67 patients assessed at the 1-year follow-up, 63 subjects (94%; 42 men; mean age at admission to treatment 24.7y; mean time postonset 5.1y) were available at the 3-year follow-up and taken into account in the analyses. INTERVENTION: A structured residential treatment program directed at improving independence in domestic life, work, leisure time, and social interactions. MAIN OUTCOME MEASURES: Community Integration Questionnaire, Employability Rating Scale, living situation, school, work situation, work hours, Center for Epidemiological Studies-Depression scale, and the World Health Organization Quality of Life Scale Abbreviated (5 scales). RESULTS: There were no significant differences for any of the outcome measures between the 1-year and 3-year follow-up assessment. CONCLUSIONS: These results indicate that the established significant and clinically relevant improvements after a residential community reintegration program remain stable in the long term. PMID- 22440484 TI - An exploration of modifiable risk factors for depression after spinal cord injury: which factors should we target? AB - OBJECTIVE: To identify modifiable risk factors for depression in people with spinal cord injury (SCI). DESIGN: Cross-sectional survey. SETTING: Outpatient and community settings. PARTICIPANTS: Community-residing people with SCI (N=244; 77% men, 61% white; mean age, 43.1y; 43% with tetraplegia) who were at least 1 month postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Depression severity (Patient Health Questionnaire-9 [PHQ-9]), physical activity (International Physical Activity Questionnaire [IPAQ]), pleasant and rewarding activities (Environment Rewards Observation Scale [EROS]), and self-efficacy to manage the effects of SCI (Modified Lorig Chronic Disease Self-Management Scale). RESULTS: Greater depression severity was associated with being 20 to 29 years of age, not completing high school, not working or attending school, and being <=4 years post-SCI. After controlling for demographic and injury characteristics (adjusted R(2)=.13), lower EROS scores (change in adjusted R(2)=.34) and lower self-efficacy (change in R(2)=.13) were independent predictors of higher PHQ-9 scores. Contrary to predictions, physical activity as measured by the IPAQ did not predict depression severity. CONCLUSIONS: Our findings suggest that having fewer rewarding activities, and to a lesser extent, having less confidence in one's ability to manage the effects of SCI are independent predictors of greater depression severity after SCI. Interventions such as behavior activation, designed to increase rewarding activities, may represent an especially promising approach to treating depression in this population. PMID- 22440485 TI - Self-reported fatigue and energy cost during walking are not related in patients with multiple sclerosis. AB - OBJECTIVES: To determine whether there is a relationship between self-reported fatigue and the energy cost of walking (ECw), and how self-reported fatigue and ECw relate to physical functioning in patients with multiple sclerosis (MS). DESIGN: Cross-sectional cohort study, using structural equation modeling. SETTING: Home environment and at a university medical center. PARTICIPANTS: Patients (N=75) were obtained from a longitudinal study on outcome measurement and functional prognosis in early MS. Patients were included if they were able to walk for 6 minutes without being assisted by a person. The age range was between 28.0 and 69.7 years and the median Expanded Disability Status Scale was 2.5 (range, 1.0-6.5). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Self reported fatigue was measured with the Fatigue Severity Scale, the vitality subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and a visual analog scale. Physical functioning was determined with the physical functioning subscale of the SF-36, fast walking speed, and comfortable walking speed. The ECw (J.kg(-1).m(-1)) was measured with the energy cost of the walking test. RESULTS: The relationship between ECw and latent variable fatigue had a beta=-.188 (P=.236), that between ECw and physical functioning (SF-36 physical functioning) had a beta=-.344 (P=.001), and that between fatigue and physical functioning had a beta=-.448 (P=.000). CONCLUSIONS: Fatigue and ECw are not related in patients with MS with mild to moderate walking problems. ECw and fatigue are independent determinants of physical functioning. PMID- 22440486 TI - Contribution of ankle dorsiflexor strength to walking endurance in people with spastic hemiplegia after stroke. AB - OBJECTIVES: (1) To determine the relationships of ankle dorsiflexor strength, ankle plantarflexor strength, and spasticity of the ankle plantarflexors with walking endurance; (2) to determine whether affected ankle dorsiflexor strength makes an independent contribution to walking endurance; and (3) to quantify its relative contribution to the walking endurance of people with spastic hemiplegia after stroke. DESIGN: A cross-sectional study. SETTING: University-based rehabilitation center. PARTICIPANTS: Subjects (N=62) with spastic hemiplegia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Walking endurance was measured by the distance covered in the six-minute walk test (6MWT). Ankle dorsiflexor and plantarflexor strength were measured using a load-cell mounted on a custom-built foot support. Plantarflexor spasticity was measured using the Composite Spasticity Scale. RESULTS: The six-minute walk distances showed stronger positive correlation with affected dorsiflexor strength (r=.793, P<=.000) when compared with affected plantarflexor strength (r=.349, P=.005). Results of the regression model showed that after adjusting for basic demographic and stroke-related impairments, affected ankle dorsiflexor strength remained independently associated with six-minute walk distance, accounting for 48.8% of the variance. CONCLUSIONS: This is the first study, to our knowledge, to document the importance of ankle dorsiflexor strength as an independent determinant of walking endurance in stroke survivors with spastic plantarflexors. Our findings suggest that stroke rehabilitation programs aiming to improve walking endurance should include strengthening exercises for the ankle dorsiflexors. PMID- 22440487 TI - Prevalence and population structure of Staphylococcus aureus nasal carriage in healthcare workers in a general population. The Tromso Staph and Skin Study. AB - Healthcare workers (HCWs) may be a reservoir for Staphylococcus aureus transmission to patients. We examined whether HCW status is associated with S. aureus nasal carriage and population structure (spa types) in 1302 women (334 HCWs) and 977 men (71 HCWs) aged 30-69 years participating in the population based Tromso Study in 2007-2008. Multivariable logistic regression models were used. While no methicillin-resistant S. aureus (MRSA) was isolated, overall, 26.2% of HCWs and 26.0% of non-HCWs were S. aureus nasal carriers. For women overall and women residing with children, the odds ratios for nasal carriage were 1.54 [95% confidence interval (CI) 1.09-2.19] and 1.86 (95% CI 1.14-3.04), respectively, in HCWs compared to non-HCWs. Moreover, HCWs vs. non-HCWs had a 2.17 and 3.16 times higher risk of spa types t012 and t015, respectively. This supports the view that HCWs have an increased risk of S. aureus nasal carriage depending on gender, family status and spa type. PMID- 22440488 TI - Ibuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories. AB - STUDY OBJECTIVE: Acute mountain sickness occurs in more than 25% of the tens of millions of people who travel to high altitude each year. Previous studies on chemoprophylaxis with nonsteroidal anti-inflammatory drugs are limited in their ability to determine efficacy. We compare ibuprofen versus placebo in the prevention of acute mountain sickness incidence and severity on ascent from low to high altitude. METHODS: Healthy adult volunteers living at low altitude were randomized to ibuprofen 600 mg or placebo 3 times daily, starting 6 hours before ascent from 1,240 m (4,100 ft) to 3,810 m (12,570 ft) during July and August 2010 in the White Mountains of California. The main outcome measures were acute mountain sickness incidence and severity, measured by the Lake Louise Questionnaire acute mountain sickness score with a diagnosis of >= 3 with headache and 1 other symptom. RESULTS: Eighty-six participants completed the study; 44 (51%) received ibuprofen and 42 (49%) placebo. There were no differences in demographic characteristics between the 2 groups. Fewer participants in the ibuprofen group (43%) developed acute mountain sickness compared with those receiving placebo (69%) (odds ratio 0.3, 95% confidence interval 0.1 to 0.8; number needed to treat 3.9, 95% confidence interval 2 to 33). The acute mountain sickness severity was higher in the placebo group (4.4 [SD 2.6]) than individuals receiving ibuprofen (3.2 [SD 2.4]) (mean difference 0.9%; 95% confidence interval 0.3% to 3.0%). CONCLUSION: Compared with placebo, ibuprofen was effective in reducing the incidence of acute mountain sickness. PMID- 22440489 TI - Renal denervation for hypertension. AB - Systemic hypertension is a major burden to the individual and society. Its association with major adverse cardiac and cerebral events and favorable effects of antihypertensive therapy are undisputed. However, despite multidrug therapy, blood pressures are frequently suboptimally controlled. Moreover, adverse drug effects often interfere with patients' lifestyles and affect compliance. Therefore, alternative treatment strategies have been explored. Most recently, attention has been redirected to the sympathetic nervous system (SNS) in the pathogenesis of hypertension. In addition, interruption of the renal SNS in humans with resistant hypertension has been studied with promising results. The following review provides an overview of the anatomy and physiology of the renal SNS, the rational for manipulating the SNS, and the results of therapeutic renal sympathetic denervation. PMID- 22440490 TI - Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction. AB - OBJECTIVES: This study compared the prognostic role of high on-treatment platelet reactivity (HTPR) in predicting thrombotic events in a Korean population undergoing percutaneous coronary intervention (PCI) in the acute myocardial infarction (AMI) and non-AMI setting. BACKGROUND: The prognostic significance and optimal cutoff of HTPR might differ according to a given clinical condition, such as AMI and ethnicity. METHODS: On-treatment platelet reactivity was measured with a VerifyNow P2Y12 assay (Accumetrics, San Diego, California) in 1,226 patients (824 men; age 65 +/- 10 years), including 413 AMI cases, 12 to 24 h after PCI between March 2008 and March 2010. The prevalence of cardiovascular (CV) events defined as a composite of death from CV causes, nonfatal myocardial infarction, or stent thrombosis at 1-year follow-up were compared according to HTPR between patients with and without AMI. RESULTS: The optimal cutoff for HTPR was 272 IU of the P2Y(12) reaction unit (PRU) (area under the curve: 0.708; 95% confidence interval [CI]: 0.607 to 0.809, p = 0.03), which was the upper-tertile threshold. Among AMI patients, 1-year CV events occurred more frequently in patients with versus without HTPR (n = 14 [8.8%] vs. n = 1 [0.4%], p < 0.001), whereas there was no difference in the composite endpoint on the basis of HTPR in patients without AMI (n = 7 [2.8%] vs. n = 8 [1.4%], p = 0.193). CONCLUSIONS: Increased residual platelet reactivity is related to post-discharge CV events in subjects with AMI, whereas the prognostic significance of HTPR seems to be attenuated in patients with stable coronary disease after PCI. PMID- 22440491 TI - Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. AB - OBJECTIVES: The authors sought to compare the effect on inhibition of platelet aggregation (IPA) of prasugrel therapy versus tirofiban bolus with or without a post-bolus short drug infusion in ST-segment elevation myocardial infarction (STEMI) patients. BACKGROUND: The degree and rapidity of IPA after prasugrel alone with or without concomitant glycoprotein IIb/IIIa inhibition in STEMI patients is unknown. METHODS: A total of 100 STEMI patients randomly received prasugrel 60 mg versus 25 MUg/kg tirofiban bolus with or without post-bolus 2-h infusion of tirofiban, with or without concomitant prasugrel. IPA at light transmission aggregometry was performed throughout 24 h. The primary endpoint was IPA stimulated with 20 MUmol/l adenosine diphosphate (ADP) at 30 min. RESULTS: At 30 min, patients in the prasugrel group showed a significantly lower IPA to 20 MUmol/l ADP stimulation as compared with tirofiban-treated patients (36 +/- 35 vs. 87 +/- 31, p < 0.0001). Similarly, patients taking prasugrel showed a suboptimal degree of platelet inhibition for at least 2 h compared with tirofiban patients. Post-bolus tirofiban infusion was necessary to maintain a high level of IPA beyond 1 h after bolus administration if concomitant clopidogrel was given, whereas the bolus-only tirofiban and concomitant prasugrel led to the higher and more consistent IPA levels after both ADP and thrombin receptor-activating peptide stimuli than either therapy alone. CONCLUSIONS: Our study shows that prasugrel administration leads to a suboptimal IPA for at least 2 h in STEMI patients. Yet, prasugrel, given in association with a bolus only of glycoprotein IIb/IIIa inhibitor, obviates the need of post-bolus infusion and almost completely abolishes residual variability of IPA after treatment. (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse [The FABOLUS PRO trial]; NCT01336348). PMID- 22440492 TI - The illusion of "optimal" platelet inhibition. PMID- 22440493 TI - A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study. AB - OBJECTIVES: This study sought to validate the ability of the VerifyNow P2Y12 assay (Accumetrics, San Diego, California) in predicting both ischemic and bleeding events after elective percutaneous coronary intervention (PCI). BACKGROUND: High and low levels of platelet reactivity are associated with ischemic and bleeding events, respectively, after PCI. METHODS: A total of 732 patients on dual antiplatelet therapy undergoing elective PCI were recruited. Platelet reactivity was measured before PCI. The primary endpoint was the 30-day incidence of net adverse clinical events (NACE), defined as the occurrence of ischemic or bleeding events, in relation to P2Y(12) reaction unit (PRU) distribution. RESULTS: At receiver-operating characteristic curve analysis, PRU values could significantly discriminate between patients with and without bleeding events (area under the curve [AUC]: 0.72; 95% confidence interval [CI]: 0.65 to 0.80; p < 0.0001) and those with and without ischemic events (AUC: 0.68; 95% CI: 0.61 to 0.76; p < 0.0001). The optimal cutoffs for bleeding (PRU <= 178) and ischemic events (PRU >= 239) were used to define 3 groups: low platelet reactivity (LPR) (LPR = PRU <= 178), normal platelet reactivity (NPR) (NPR = PRU 179 to 238), and high platelet reactivity (HPR) (HPR = PRU >= 239). The incidence of NACE was 14.1% in the LPR group, 7.8% in the NPR group (p = 0.025 vs. LPR group), and 15.4% in the HPR group (p = 0.005 vs. NPR group). At multivariate analysis, PRU values in the NPR group were an independent predictor of reduced risk of 30-day NACE (odds ratio: 0.47, 95% CI: 0.27 to 0.81). CONCLUSIONS: A therapeutic window for platelet reactivity measured with the VerifyNow P2Y12 assay can be identified using specific thresholds that define a group of patients at lower risk for both ischemic and bleeding events. Adjunctive measures may be beneficial in patients with higher or lower platelet reactivity in order to improve clinical outcomes after PCI. PMID- 22440494 TI - Platelet function measurement in elective percutaneous coronary intervention patients: exploring the concept of a P2Y12 inhibitor therapeutic window. PMID- 22440495 TI - Cigarette smoking is associated with a dose-response effect in clopidogrel treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. AB - OBJECTIVES: This study sought to assess the presence of a dose-response effect of cigarette smoking and its impact on high on-treatment platelet reactivity (HPR) in patients with diabetes mellitus treated with clopidogrel. BACKGROUND: Cigarette smoking is an inducer of cytochrome P450 1A2, a hepatic enzyme involved in clopidogrel metabolism. If cigarette smoking is associated with a dose response effect on pharmacodynamic measures in clopidogrel-treated patients is unknown. METHODS: A total of 134 type 2 diabetes mellitus patients on maintenance aspirin and clopidogrel therapy were studied. Patients were divided into 3 groups according to cotinine levels: <3 ng/ml (nonsmokers), 3 to 199 ng/ml (light smokers), and >= 200 ng/ml (heavy smokers). Platelet function was assessed by light transmittance aggregometry, VerifyNow P2Y12 assay (Accumetrics, San Diego, California), and vasodilator-stimulated phosphoprotein. Rates of HPR were defined using established cutoff values. RESULTS: A dose-response effect was observed for all pharmacodynamic parameters tested. Serum cotinine levels were inversely associated with platelet reactivity as assessed by light transmittance aggregometry using 5 and 20 MUmol/l adenosine diphosphate (p < 0.0001 for all). Accordingly, platelet disaggregation increased with levels of serum cotinine (p < 0.0001). Similar results were found with P2Y(12) reaction units (p < 0.0001) and inhibition of platelet aggregation (p = 0.005) as defined by VerifyNow P2Y12 testing, and platelet reactivity index (p = 0.002) as assessed by vasodilator stimulated phosphoprotein. Higher serum cotinine levels were significantly associated with lower rates of HPR, as defined according to various pharmacodynamic cutoff measures. CONCLUSIONS: Cigarette smoking is associated with a dose-response effect on clopidogrel-induced antiplatelet effects and lower rates of HPR in diabetes mellitus patients. PMID- 22440496 TI - Impact of sex on clinical and angiographic outcomes among patients undergoing revascularization with drug-eluting stents. AB - OBJECTIVES: The goal of this study was to investigate sex-based differences in long-term clinical and angiographic outcomes after coronary revascularization with drug-eluting stents (DES). BACKGROUND: The impact of sex on clinical and angiographic outcomes following revascularization with DES is not well established. METHODS: Individual patient data from 3 all-comers randomized DES trials (SIRTAX, LEADERS, RESOLUTE All-Comers) were pooled. Of 5,011 patients, 4,885 (97.5%) completed 2-year follow-up (1,164 women, 3,721 men). Protocol mandated angiographic follow-up was available for 1,561 lesions (351 among women, 1,210 among men). The primary endpoint was the composite of cardiac death and myocardial infarction (MI) at 2 years. RESULTS: At baseline, women, as compared with men, were older, more frequently had diabetes, obesity, and hypertension, less frequently had smoking habits, previous MI, and previous surgical revascularization, and had a smaller reference diameter of the target vessel as well as a lower SYNTAX score. After adjustment for baseline differences, women and men had a similar risk of cardiac death or MI (odds ratio [OR]: 1.13, 95% confidence interval [CI]: 0.82 to 1.56, p = 0.44), cardiac death (OR: 1.04, 95% CI: 0.61 to 1.80, p = 0.87), and MI (OR: 1.07, 95% CI: 0.75 to 1.53, p = 0.71) at 2 years. Similarly, risks of target lesion revascularization (OR: 1.09, 95% CI: 0.77 to 1.54, p = 0.62), target vessel revascularization (OR: 0.88, 95% CI: 0.63 to 1.22, p = 0.43), and definite or probable stent thrombosis (OR: 0.73, 95% CI: 0.38 to 1.38, p = 0.33) were comparable for women and men. Follow-up angiography showed no differences in terms of in-stent late loss (0.18 +/- 0.54 mm vs. 0.20 +/- 0.99 mm, p = 0.76) and in-segment binary restenosis (8.5% vs. 8.5%, p = 0.76). CONCLUSIONS: The unrestricted use of DES is associated with similar long term safety and efficacy among women and men with coronary artery disease. (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization [SIRTAX]; NCT00297661, LEADERS Trial Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS]; NCT00389220, RESOLUTE-III All comers Trial: A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention [RESOLUTE All Comers]; NCT00617084). PMID- 22440497 TI - Sex differences in the drug-eluting stent era: do they still exist? PMID- 22440498 TI - Comparison of drug-eluting and bare-metal stents for primary percutaneous coronary intervention with or without abciximab in ST-segment elevation myocardial infarction: DEBATER: the Eindhoven reperfusion study. AB - OBJECTIVES: The goal of this study was to demonstrate superiority of sirolimus eluting stents (SES) over bare-metal stents (BMS) and of abciximab over no abciximab in primary percutaneous coronary intervention (PCI). BACKGROUND: Drug eluting stents (DES) are increasingly used in primary PCI, but the recommendations for use in primary PCI are based on a few randomized controlled trials with selected patients. The usefulness of abciximab in primary PCI is not established. METHODS: Nine hundred seven patients referred to the Catharina Hospital were randomized to SES or BMS, and to abciximab or no abciximab in a prospective, randomized, open 2 * 2 factorial trial with blinded evaluation. Primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of death, myocardial infarction (MI), stroke, repeat revascularization, and bleeding at 1 year (stent arm) and the composite of death, target vessel MI, target vessel revascularization (TVR), and bleeding at 30 days (abciximab arm). RESULTS: At 1 year, the rate of MACCE was lower in the SES arm (16.5% vs. 25.8%, p = 0.001), mainly driven by less repeat revascularization (9.8% vs. 16.8%; p = 0.003) and without influencing the cumulative incidence of death and MI (5.2% vs. 5.8%; p = 0.68). At 30 days, the rate of the composite of death, target vessel MI, TVR, and bleeding was lower in the abciximab arm (8.2% vs. 12.4%, p = 0.04), mainly driven by less TVR due to less stent thrombosis (1.2% vs.7.4%, p < 0.001). However, bleeding complications occurred more frequently in the abciximab group (5.7% vs. 2.8%, p = 0.03). CONCLUSIONS: Primary PCI with SES reduces adverse events at 1 year, mainly by reduction of repeat revascularization, whereas abciximab reduces early stent thrombosis, at the expense of more bleeding complications. (Comparison of Drug Eluting and Bare Metal Stents With or Without Abciximab in ST Elevation Myocardial Infarction [DEBATER]; NCT00986050). PMID- 22440499 TI - Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. AB - OBJECTIVES: This study presents long-term clinical follow-up, including binary restenosis rate and major adverse cardiovascular events, of the PACCOCATH-ISR (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons) I and II trial. BACKGROUND: The PACCOCATH-ISR trial was a first-in-human study with a drug coated balloon catheter and the first study for the treatment of coronary ISR with a drug-coated balloon. So, far no long-term follow-up data have been presented. METHODS: This study enrolled 108 patients in a randomized, double blinded multicenter trial on the efficacy and safety of a paclitaxel-coated balloon (3 MUg/mm(2) balloon surface; PACCOCATH [Bayer AG, Germany]) compared with an uncoated balloon. The main inclusion criteria were a diameter stenosis of >= 70% and <30-mm length with a vessel diameter of 2.5 to 3.5 mm. The primary endpoint was angiographic late lumen loss in-segment after 6 months. Combined antiplatelet therapy was continued only for 1 month followed by treatment with aspirin alone. RESULTS: During a follow-up of 5.4 +/- 1.2 years, the clinical event rate was significantly reduced in patients treated with the drug-coated balloon (major adverse cardiovascular events: 59.3% vs. 27.8%, p = 0.009), which was mainly driven by the reduction of target lesion revascularization from 38.9% to 9.3% (p = 0.004). CONCLUSIONS: Treatment of coronary ISR with paclitaxel coated balloon catheters is safe and persistently reduces repeat revascularization during long-term follow-up. The initial results were sustained over the 5-year period. (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons [PACCOCATH ISR I]; NCT00106587. Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons [PACCOCATH ISR II]; NCT00409981). PMID- 22440500 TI - Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12-month results from a multicenter Italian registry. AB - OBJECTIVES: This study evaluated the use of a paclitaxel-eluting balloon (PEB) for treatment of femoropopliteal arterial disease. BACKGROUND: Conventional balloon angioplasty and stenting in this setting is associated with high restenosis rates within 12 months. Recent data suggest that PEB use may reduce restenosis. Twelve-month outcomes following PEB use with provisional stenting are described. METHODS: This prospective registry enrolled patients (Rutherford class 2 to 4) with reference vessel diameter of 3 to 7 mm and lesion/occlusion length <= 15 cm. Endpoints included primary patency rate, target lesion revascularization, and changes in Rutherford class and ankle-brachial index. Walking capacity, absolute claudication distance, and quality of life were also assessed. RESULTS: The registry enrolled 105 patients. Baseline ankle-brachial index was 0.56 +/- 0.15. Baseline Rutherford classification was class 2 or 3 for most patients (91.5%). Most lesions were located in the superficial femoral artery (77.1%). Mean lesion length was 76.3 +/- 38.3 mm; 29.8% of lesions were total occlusions. The device was successfully used in all patients and only 12.3% of lesions required stenting. At 12-month follow-up, 92 of 105 patients (87.6%) were evaluable; the primary patency rate was 83.7%; the target lesion revascularization rate was 7.6%; 85.6% of patients were Rutherford class 0 or 1; and mean ankle-brachial index was 0.86 +/- 0.15. Quality of life and absolute claudication distance showed significant improvement from baseline to 12-month follow-up. CONCLUSIONS: PEB treatment of femoropopliteal arterial disease resulted in consistent clinical improvement across multiple endpoints with a low rate of stenting and target lesion revascularization. PMID- 22440501 TI - Treatment paradigms for the superficial femoral artery: are they a-changin? PMID- 22440502 TI - Transcatheter mitral valve-in-valve implantation in patients with degenerated bioprostheses. AB - OBJECTIVES: This study reports the results of a series of transapical mitral valve-in-valve implantations and aims to offer guidance on technical aspects of the procedure. BACKGROUND: Mitral valve reoperations due to failing bioprostheses are associated with high morbidity and mortality. Transcatheter techniques may evolve as complementary approaches to surgery in these high-risk patients. METHODS: Six patients (age 75 +/- 15 years) received transapical implantation of a balloon-expandable pericardial heart valve into a degenerated bioprosthesis (range 27 to 31 mm) in mitral position at our institution. All patients were considered high risk for surgical valve replacement (logistic EuroSCORE: 33 +/- 15%) after evaluation by an interdisciplinary heart team. Procedural and clinical outcomes were analyzed. RESULTS: Implantation was successful in all patients with reduction of mean transvalvular gradients from 11.3 +/- 5.2 mm Hg to 5.5 +/- 3.6 mm Hg (p = 0.016) and median regurgitation from grade 3.0 (interquartile range [IQR]: 2.7 to 3.1) to 0 (IQR: 0 to 1.0, p = 0.033) with trace paravalvular regurgitation remaining in 2 patients. Apical bleeding occurred in 2 patients requiring rethoracotomy in 1 and resuscitation in a second patient, the latter of whom died on postoperative day 6. In the remaining patients, median New York Heart Association functional class improved from 3.0 (IQR: 3.0 to 3.5) to 2.0 (IQR: 1.5 to 2.0, p = 0.048) over a median follow-up of 70 (IQR: 25.5 to 358) days. CONCLUSIONS: With acceptable results in a high-risk population, transapical mitral valve-in-valve implantation can be considered as a complementary approach to reoperative mitral valve surgery in select patients. PMID- 22440503 TI - Incidence of overall bleeding in patients treated with intra-aortic balloon pump during percutaneous coronary intervention: 12-year Milan experience. AB - OBJECTIVES: This study aims to report a "real-world" experience of in hospital complications and clinical outcome of a large cohort of consecutive patients who underwent percutaneous coronary intervention (PCI) with intra-aortic balloon pump counterpulsation (IABP) support, from a tertiary care center over a 12-year period. BACKGROUND: The incidence of vascular complications in patients treated with PCI and IABP is expected to be higher due to simultaneous puncture of femoral arteries, larger IABP sheath size, and longer duration of IABP therapy. METHODS: A total of 360 consecutive patients (mean age of 65.9 +/- 11.2 years; 80.6% male) who required an IABP support during percutaneous PCI were classified into 3 groups: Urgent: 133 patients (36.9%) admitted with acute coronary syndrome in whom IABP therapy was started before urgent PCI; Emergent: 56 patients (15.6%) in whom emergent IABP insertion was required to manage hypotension during PCI; and Elective: 171 patients (47.5%) with stable angina pectoris in whom IABP was inserted before elective PCI. Overall bleeding was defined according to the newest the Bleeding Academic Research Consortium (BARC) definition criteria. RESULTS: BARC bleeding occurred in 68 patients (19%), with the highest incidence noted in the Urgent group (31.1%), in comparison with the Emergent (26.8%) and Elective (7%) groups, p < 0.0001. Bleeding related to the IABP access site was 7.5%, which accounted for 82% of any access site-related bleeding. It was significantly higher in the Urgent group (12.8%) compared with the Elective (4.1%) and Emergent (5.4%) groups. At multivariate analysis, IABP treatment duration and renal impairment were the only independent predictors of BARC bleeding. CONCLUSIONS: Bleeding related to the IABP access site was significantly higher in the Urgent group and accounted for more than two-thirds of overall access site-related bleeding. IABP treatment duration and renal impairment were independent predictors of overall bleeding. PMID- 22440504 TI - Percutaneous transcatheter closure of the native aortic valve to treat de novo aortic insufficiency after implantation of a left ventricular assist device. PMID- 22440505 TI - Iatrogenic subclavian artery pseudoaneurysm complicating a transradial percutaneous coronary intervention. PMID- 22440507 TI - Why similar stent designs cause new clinical issues. PMID- 22440508 TI - Times they are a-changin. PMID- 22440509 TI - Delamination of abluminal polymer of biolimus-eluting stent. PMID- 22440510 TI - A freestyle problem. PMID- 22440511 TI - Ultrastructure and distribution of the taste buds in the buccal cavity in relation to the food and feeding habit of a herbivorous fish: Oreochromis niloticus. AB - The buccal cavity of an herbivorous fish Oreochromis niloticus was investigated by means of scanning electron microscopy. The buccal cavity distinguished into the roof and the floor. Three different types of taste buds (type I, II and III) are distributed in the buccal cavity. The proximal part of the buccal cavity bears relatively high epidermal papillae in which type I TBs was found. The middle region of the buccal cavity is mostly occupied by low epidermal papillae containing type II TBs. Type III TBs which are present within the metabranchial buccal cavity; never rise above the normal level of the epithelium. The different types of TBs are useful for ensuring full utilization of the gustatory ability of the fish. It is postulated that the TBs serve different functions: TBs type I and II may act as chemoreceptors and mechanoreceptors. TBs type III acts predominantly as a chemoreceptors. TBs of each type show two kinds of receptor villi within their receptor areas: tall villi and small villi. The surface of the lining epithelial cells shows a delicate microridge system. These structures protect against physical abrasion potentially caused during food maneuvering and swallowing. Furthermore, protection of the epithelium from abrasion is enhanced with goblet cells secretion. PMID- 22440512 TI - Auditory neuropathy secondary to cryptococcal central nervous system infection in 2 immunocompromised patients. PMID- 22440513 TI - Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data. AB - BACKGROUND: Postmenopausal osteoporosis results from bone loss and decreased bone strength mediated by an increased rate of bone remodeling secondary to reduced estrogen levels. Remodeling cycles are initiated by osteoclasts, the formation, function, and survival of which depend on RANK ligand (RANKL). RANKL inhibition therefore represents a novel strategy for reducing remodeling and its effects on fracture risk. OBJECTIVES: The goal of this study was to review the preclinical and clinical evidence supporting the value of RANKL inhibition in conditions of bone loss and to provide the rationale for the use of the fully human antibody denosumab, a RANKL inhibitor, in such conditions. METHODS: We searched PubMed from January 2005 to May 2011 using the following terms: RANK Ligand, RANKL, denosumab, and NOT cancer, metastatic bone, or rheumatoid in the title. RESULTS: The search method retrieved 111 articles. Preclinical evidence from several bone disease models suggests that RANKL inhibition leads to increased bone volume, density, and strength. Denosumab prevents RANKL from binding to its receptor, decreasing osteoclast activity and thereby reducing bone resorption and increasing cortical and trabecular bone mass and strength. It has consistently been reported to reduce bone turnover, increase bone density, and reduce the risk of fracture in clinical studies of postmenopausal women. Phase III head-to-head trials comparing denosumab with the bisphosphonate alendronate reported that denosumab was associated with significantly greater increases in bone density. Eczema as an adverse event and cellulitis as a serious adverse event were more common with denosumab than with placebo. CONCLUSIONS: Preclinical studies defined the role of RANKL in bone remodeling and provided evidence for the therapeutic potential of RANKL inhibition in conditions of bone loss. Clinical studies evaluating RANKL inhibition with denosumab in postmenopausal women have reported significant reductions in vertebral, nonvertebral, and hip fractures, providing evidence compatible with the use of denosumab in postmenopausal women with osteoporosis. PMID- 22440514 TI - Relationship between bitter-taste receptor genotype and solid medication formulation usage among young children: a retrospective analysis. AB - BACKGROUND: Children often refuse to take medication in liquid formulation because of its unpleasant taste. Recent advances in taste genetics have provided some insight into individual differences in taste among children: due to their genotype, some prefer more intense sweetness and are more sensitive to bitter tastes and thus may have different needs for medication formulation. OBJECTIVE: The aims of this study were to: (1) test the a priori hypothesis that children with the bitter-sensitive genotypes are more likely to have experienced solid medication formulations than those with the bitter-insensitive genotype; and (2) conduct post hoc analyses to examine the relationship between genotype and most preferred level of sucrose in water because sweeteners are a common component of liquid formulations. METHODS: The following data were obtained from healthy, 3- to 10-year-old children who participated in 1 of 5 taste-research studies: taste genotype for alleles of the bitter-taste receptor TAS2R38; data from retrospective reports of solid medication formulation usage and favorite beverage; and most preferred level of sucrose in water, as determined psychophysically. RESULTS: Data from 448 children were included (245 girls, 203 boys; mean age, 7.8 years). Children with >=1 bitter-sensitive allele (TAS2R38 PP or AP genotype) were more likely to have taken medication in solid formulation than were bitter-insensitive (AA genotype) children. Children with the PP genotype preferred higher concentrations of sucrose in water, and their favorite beverage contained more grams of sugar compared with children with the AA genotype. CONCLUSIONS: Taste genotype was associated with experience with solid medication formulations and preference for more intense sweetness. This finding suggests that taste genetics might be an important factor in formulation choice and compliance in the pediatric population. PMID- 22440515 TI - Phosphoproteomic analysis of seed maturation in Arabidopsis, rapeseed, and soybean. AB - To characterize protein phosphorylation in developing seed, a large-scale, mass spectrometry-based phosphoproteomic study was performed on whole seeds at five sequential stages of development in soybean (Glycine max), rapeseed (Brassica napus), and Arabidopsis (Arabidopsis thaliana). Phosphopeptides were enriched from 0.5 mg of total peptides using a combined strategy of immobilized metal affinity and metal oxide affinity chromatography. Enriched phosphopeptides were analyzed by Orbitrap tandem mass spectrometry and mass spectra mined against cognate genome or cDNA databases in both forward and randomized orientations, the latter to calculate false discovery rate. We identified a total of 2,001 phosphopeptides containing 1,026 unambiguous phosphorylation sites from 956 proteins, with an average false discovery rate of 0.78% for the entire study. The entire data set was uploaded into the Plant Protein Phosphorylation Database (www.p3db.org), including all meta-data and annotated spectra. The Plant Protein Phosphorylation Database is a portal for all plant phosphorylation data and allows for homology-based querying of experimentally determined phosphosites. Comparisons with other large-scale phosphoproteomic studies determined that 652 of the phosphoproteins are novel to this study. The unique proteins fall into several Gene Ontology categories, some of which are overrepresented in our study as well as other large-scale phosphoproteomic studies, including metabolic process and RNA binding; other categories are only overrepresented in our study, like embryonic development. This investigation shows the importance of analyzing multiple plants and plant organs to comprehensively map the complete plant phosphoproteome. PMID- 22440516 TI - [Probable serotonin syndrome due to linezolid and meperidine interaction]. PMID- 22440517 TI - [Indirect comparisons in drug assessment reports on the GENESIS group (SEFH) webpage]. AB - OBJECTIVE: Quantify use of indirect comparisons (IC) in drug evaluation reports published on the GENESIS Group web page for new drug assessment, standardisation, and drug selection research. METHOD: Retrospective study of drug reports written between 2008 and 2009. DATA COLLECTED: presence of an active comparator and details from any direct and indirect comparative studies included. RESULTS: An active comparator was present in 95% of the 337 analysed reports; 50% included a direct comparative study vs comparator. In 114 reports (34%), an IC was used; 69% of the ICs were made by the report author. Most ICs were narrative and none were adjusted. An IC could have been made in an additional 16% of the cases and possibly in 24% more. CONCLUSIONS: Most evaluated drugs have an active comparator but studies comparing them directly are not as common. ICs could be included in more reports along with quality control criteria. PMID- 22440518 TI - [Exposure to cytotoxic drugs among health care professionals]. AB - OBJECTIVE: To quantify levels of exposure to cytotoxic drugs among health professionals in order to establish an exposure threshold and implement measures to increase protection and safety. MATERIAL AND METHOD: Contamination with 5 fluorouracil, gemcitabine and cyclophosphamide was measured on work surfaces in the following areas: a class II type B3 biological safety cabinet (S(1)), a treatment prep table in an antechamber (S(2)) and a desk from the administrative room in the Outpatient Unit (S(3)). We took samples from the work surfaces by wiping them with an absorbent cloth at time t(0), prior to the work session, and at t(1) after three hours of work. For each surface, we calculated the median mass value with respect to the baseline value and the 90th, 75th, 50th and 25th percentiles for each cytotoxin in MUg/m(2). Distribution normality was assessed using the Shapiro-Wilk test. Statistical analysis included the Kruskal-Wallis and Mann-Whitney-Wilcoxon tests. Statistical significance was established for values of P<.05. RESULTS: We gathered a total of 90 samples, 30 from each of the studied work surfaces. The mean recorded mass of any of the cytotoxic compounds was higher for S(1) and t(1), with values of P=.017 and P=.004 respectively. The target value for each cytotoxic drug was established at the 25th percentile, where undetectable contamination values were obtained. CONCLUSIONS: Introducing a continuous programme to monitor work surfaces for an array of cytotoxic compounds is fundamental in order to establish acceptable levels of residual contamination and reduce exposure in the workplace. PMID- 22440519 TI - [Multidisciplinary perspective on support for antiretroviral therapy adherence in Andalusia. Andhalusida study]. AB - OBJECTIVE: To analyse physicians', pharmacists' and nurses' perspectives on the importance of different antiretroviral treatment adherence support activities and identify the main obstacles to meeting established recommendations which health professionals encounter. METHOD: Cross-sectional observational and analytical study. Three questionnaires were designed based on 2008 GESIDA/SEFH/PNS recommendations for improving treatment adherence: "ideal measures" (IM), "real measures" (RM) and "adherence support problems" (ASP). Cronbach's Alpha index was determined to analyse questionnaire reliability and correlation coefficients between the MI and MR scales. We applied the Chi-square test or Monte Carlo method to analyse the correlation between health providers and items on the three questionnaires. RESULTS: Participants consisted of 58 health professionals. The response rate was 76%. The Cronbach Alpha indices for the IM, RM and ASP questionnaires were 0.852, 0.933 and 0.818 respectively. The resulting intraclass correlation coefficient was 0.280. Significant differences were found for multiple comparisons of IM and RM questionnaires among physicians and pharmacists. The analysis of relationships between providers also found significant differences for one of the answers on the IM questionnaire, three on the RM and five on the ASP. CONCLUSIONS: We observed that several health professionals have different perspectives on measures of support for treatment adherence, with differences arising mainly due to lack of time and training. PMID- 22440520 TI - Flow cytometric chromosome sorting in plants: the next generation. AB - Genome analysis in many plant species is hampered by large genome size and by sequence redundancy due to the presence of repetitive DNA and polyploidy. One solution is to reduce the sample complexity by dissecting the genomes to single chromosomes. This can be realized by flow cytometric sorting, which enables purification of chromosomes in large numbers. Coupling the chromosome sorting technology with next generation sequencing provides a targeted and cost effective way to tackle complex genomes. The methods outlined in this article describe a procedure for preparation of chromosomal DNA suitable for next-generation sequencing. PMID- 22440521 TI - Synthesis, DNA binding, photo-induced DNA cleavage and cell cytotoxicity studies of a family of light rare earth complexes. AB - A family of light rare earth complexes, [RE(acac)(3)(dpq)] (RE=La (1), Ce (2), Pr (3), Nd (4), Sm (5)) and [RE(acac)(3)(dppz)].CH(3)OH (RE=La (6), Ce (7), Pr (8), Nd (9), Sm (10) viz. acetylacetonate (acac), dipyrido[3,2-d:20,30-f]quinoxaline (dpq), dipyrido[3,2-a:20,30-c] phenazine (dppz)), have been synthesized and structurally characterized. Binding interactions of these complexes with CT-DNA and their photo-induced DNA cleavage activity with pBR 322 DNA are also investigated. These complexes have strong DNA binding interaction (K(b)~10(5)M( 1) and K(app)~10(5)M(-1))and the binding propensity to CT-DNA decrease with the order: dppz complexes>dpq complexes. Furthermore, DNA photocleavage experiments indicate that these complexes are efficient DNA cleaving agents in UV-A (365 nm) and ambient light in the absence of any external reagents. Hydroxyl radical (HO(*)) and singlet oxygen ((1)O(2)) are the major cleavage active species from the machanistic studies. Moreover, cell cytotoxicity studies of these complexes on HeLa, K562 and MDA-MB-231 cells indicate that they have the potential to act as effective metal-based anti-cancer drugs. PMID- 22440522 TI - Analysis of monocyte subsets and toll-like receptor 4 expression in peripheral blood monocytes of women in preterm labor. AB - Preterm labor is associated with both localized inflammation of the uterus and elevated proinflammatory cytokines. Recently, specific roles have been suggested for distinct monocyte subsets and toll-like receptor 4 (TLR4) expression in inflammation. The aim of this study was to determine whether specific monocyte subsets and increased TLR4 expression in monocyte subsets contribute to preterm labor. The study included 30 preterm labor, 40 full-term labor and 20 pregnant women (not in labor). Four-color flow cytometry was used to examine the distribution of three monocyte subsets (CD14(+)CD16(-), CD14(high)CD16(+), and CD14(low)CD16(+)) and the TLR4 expression in each monocyte subset in each group of women. A larger percentage of CD14(high)CD16(+) cells was found in the preterm labor group than in the other groups (P=0.08, P=0.06). Women in preterm labor also showed significantly higher TLR4 expression in all monocyte subsets and increased fluorescence intensity in the CD14(+)CD16(-) and CD14(high)CD16(+) cells. Expression of TLR4 and mean fluorescence intensity on each monocyte subset were also significantly correlated. We conclude that women with preterm labor have higher CD16 monocytes, with high concomitant expression of CD14 and enhanced TLR4 expression in monocytes, and that monocyte TLR4 levels could be used as a marker to predict preterm delivery. PMID- 22440523 TI - Dendritic cells in the circulation of women with preeclampsia demonstrate a pro inflammatory bias secondary to dysregulation of TLR receptors. AB - Toll-like receptors (TLRs) are central components of the innate immune system that recognize both microbial ligands and host products released during tissue damage. Data from epidemiologic studies and animal models suggest that inappropriate activation of the immune system plays a critical role in the development of preeclampsia. This study evaluates in a systematic fashion the expression and function of TLRs in the circulation of patients with preeclampsia compared to healthy pregnant controls. We evaluated TLR expression and function in primary dendritic cells (DCs) of 30 patients with preeclampsia and 30 gestational age-matched healthy pregnant controls. DCs were stimulated with the different TLR ligands engaging TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9. The expression of TLR-induced production of TNF-alpha, IFN-alpha, IL-6, and IL-12 were measured by multicolor flow cytometry. Basal expression of TLR3, TLR4 and TLR9 was significantly increased in DCs isolated from women with preeclampsia. Preeclamptic DCs also expressed significantly higher basal levels of cytokines. In contrast, preeclamptic DCs demonstrated a less robust response to stimulation with various TLR ligands as compared with healthy pregnant controls. Under basal conditions, DCs from preeclamptic individuals express higher levels of select TLRs and produce more pro-inflammatory cytokines as compared with healthy controls. As such, the ability of these cells to mount an inflammatory reaction in response to a TLR ligand is limited. These data demonstrate a dysregulated pattern of TLR expression and cytokine production in DCs from PE patients that may limit further activation by TLR engagement. PMID- 22440525 TI - Cellular and synaptic network defects in autism. AB - Many candidate genes are now thought to confer susceptibility to autism spectrum disorders (ASDs). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this context, progress in deciphering the molecular architecture of cellular protein-protein interactions together with the unraveling of synaptic dysfunction in neural networks may prove pivotal to advancing our understanding of ASDs. PMID- 22440526 TI - Retrospective evaluation of colistin versus tigecycline for the treatment of Acinetobacter baumannii and/or carbapenem-resistant Enterobacteriaceae infections. AB - BACKGROUND: Therapeutic options are limited for infections because of Acinetobacter baumannii and carbapenem-resistant Enterobacteriaceae (CRE). Study aim was to compare the efficacy of colistin to tigecycline for the treatment of these types of infections. METHODS: A retrospective study was conducted at the Detroit Medical Center. Adult patients with infections because of A baumannii or CRE in 2009 who received >=2 doses of colistin or tigecycline were studied. Risk factors, outcomes, and costs were analyzed. RESULTS: There were 82 patients with infections because of A baumannii, 12 with CRE, and 12 with A baumannii and CRE coinfection. Seventy-one patients received colistin, 16 received tigecycline, and 19 received both colistin and tigecycline. Seven isolates were nonsusceptible to colistin and 79 to tigecycline. Patients receiving colistin alone or in combination were more likely to die during their hospitalization than patients receiving only tigecycline (P = .002). However, patients receiving colistin had higher severity of acute illness and had notable delays in initiation of effective antimicrobial therapy (P < .001). CONCLUSION: Compared with patients who received tigecycline alone, patients who received colistin alone or in combination had a higher severity of acute illness indices and delays in initiation of effective therapy. This increased severity of illness contributed to the increased rate of mortality among patients treated with colistin for A baumannii or CRE infections. PMID- 22440527 TI - Compliance with hand hygiene and glove change in a general hospital, Mashhad, Iran: an observational study. AB - BACKGROUND: Hand hygiene is the single most important element of strategies to prevent health care-associated infections. However, handwashing rates among health care workers have ranged from 9% to 50%. This observation took place as a structured, overt strategy to assess the hospital staff's hand hygiene compliance. The study was carried out in Imam Reza General Hospital, Mashhad, Iran. METHODS: All hospital staff, including physicians, nurses, and unlicensed assistive personnel in 4 randomly selected wards, were observed by 2 infection control nurse specialists for 5 observation periods on each ward. The observation was overt, and observers compiled data by filling out 2 checklists. All staff knew that they were being observed, and the observers made no interventions. RESULTS: The overall compliance with hand hygiene activities was 47.9% (438 episodes out of 913 potential opportunities) and, with sole emphasis on handwashing, was only 8.5%. CONCLUSION: Inappropriate glove use might be a component of poor hand hygiene compliance. Training campaigns should be implanted for health care personnel and all hospital staff to re-emphasize the importance of adherence to hand hygiene protocols. PMID- 22440528 TI - Oseltamivir adherence and tolerability in health care workers treated prophylactically after occupational influenza exposure. AB - This survey of health care workers who were prescribed oseltamivir prophylaxis after occupational exposure to 2009 pandemic influenza A (H1N1) documents their adherence, adverse effects, development of influenza-like illness, and knowledge and beliefs about the treatment and transmission of influenza. Adverse effects occurred in 15 of 36 participants evaluated (41.6%). The majority of the participants understood that influenza is highly infective and would take oseltamivir again, although 40.5% (15 of 37) thought they had not been given sufficient information about adverse effects. PMID- 22440529 TI - Designing a protocol to reduce catheter-associated urinary tract infections among hospitalized patients. AB - Hospital-acquired urinary tract infections comprise 40% of hospital-acquired infections with over 80% of these hospital-acquired urinary tract infections associated with the use of urinary catheters. The process that was used to establish a new hospital protocol using the "IAIMS" (identifying, assessing, implementing, modifying/maintaining, spread/surveillance) model to reduce the incidence of catheter-associated urinary tract infections is described. The example is intended to serve as a framework for the development of protocols to address other hospital-acquired infections. PMID- 22440530 TI - Lessons learned from the experience of visceral military surgeons in the French role 3 Medical Treatment Facility of Kabul (Afghanistan): an extended skill mix required. AB - OBJECTIVE: To evaluate the activity of visceral surgeons assigned to the Medical Treatment Facility (MTF) (role 3) in Kabul International Airport (KAIA) and identify the skills and qualifications required by these specialists. PATIENTS AND METHODS: Between July 2009 and December 2010, all the patients operated by the visceral surgeons were eligible for inclusion in this study. They were International Security and Assistance Force (ISAF), Afghan National Security Forces (ANSF) soldiers, non-afghan civilians personnel and local nationals (LNs). They sustained war-related injuries, non-war related trauma emergencies, non trauma related emergencies or had elective surgical care. The mechanisms and types of injuries, the affected organs and the surgical procedures were collected. RESULTS: Over the period of study, the visceral surgeons treated 261 over 971 patients (26.9%) achieving a total of 438 surgical procedures. Thirty one percent of these procedures were war-related, 26% non-war related, 24.2% non trauma related emergencies and 18.1% elective surgery. Non-trauma related emergencies and elective surgery required the same skills as in civilian practice. War-related injuries and non-war related trauma emergencies were more challenging. Combined injuries represented 56% of the cases requiring damage control resuscitation procedures and/or treatment of severe burns. Life threatening thoracic or vascular injuries (30%) required life-saving emergency surgical procedures. CONCLUSION: A visceral surgeon in a role 3 MTF should master a wide range of skills and expertise to be able to deal with many complex situations, in particular life-threatening situations such as thoracic and vascular wounds. A comprehensive surgical training programme for surgeons in abroad deployment (Advance Course for Deployment Surgery - CACHIRMEX) has been designed and settled up in 2007 to provide these necessary skills. The feedback obtained from each previous deployment demonstrates that the advanced course for deployment surgery provides visceral surgeons the necessary skills required to deliver surgical healthcare in a role 3 MTF. However, a regular assessment of this programme is mandatory to ensure that this training stays appropriate and contributes to better outcomes and a decreased mortality rate. PMID- 22440531 TI - Socioeconomic deprivation predicts outcome following radial head and neck fractures. AB - INTRODUCTION: There is increasing evidence demonstrating an association between fracture epidemiology and socioeconomic status. However, the influence of socioeconomic deprivation on fracture outcome has not been documented before. The aim of this study was to determine if socioeconomic deprivation influenced the short-term outcome following a fracture of the radial head or neck. METHODS: We identified from a prospective database all patients who sustained a radial head or neck fracture over an 18-month period. The primary outcome measure for this study was the patient-reported short musculoskeletal function assessment (SMFA). The Index of Multiple Deprivation (IMD) was used to quantify deprivation, and any correlation with functional outcome was determined. Multivariate regression analysis was used to determine the influence of deprivation on outcome once other significant demographic and fracture characteristics had been accounted for. RESULTS: There were 200 patients in the study cohort, of which 107 (53.5%) were female and the mean age was 44 years (16-83). At a mean follow-up of 6 months the median SMFA score was 0.54 (0-55.4). The SMFA was found to be influenced by the IMD, with increasing deprivation associated with a poorer outcome (p=0.006). On multivariate analysis, the AO fracture classification, compensation and increasing deprivation were the only independent predictors of outcome (all p<0.05). CONCLUSIONS: We have a shown a clear correlation between functional outcome and socioeconomic status, with the most deprived patients reporting a poorer outcome. Future work should be aimed at determining which aspects of deprivation influence patient outcome, with modifiable factors targeted in future health-care planning. PMID- 22440532 TI - New patient-centered care standards from the commission on cancer: opportunities and challenges. AB - The Commission on Cancer of the American College of Surgeons publishes accreditation standards that hospitals and cancer treatment centers implement to ensure quality care to cancer patients. These standards address the full spectrum of cancer care, from cancer prevention to survivorship and end-of-life care. The most recent revisions of these standards included new standards in "patient centered areas," including the provision of palliative care services, treatment and survivorship plans, psychological distress screening, and patient navigation programs. Unified by their emphasis on the early identification of patients at risk of receiving suboptimal care and the importance of ensuring that issues arising during and after completion of cancer treatment are addressed, they are a welcome expansion of the standards guiding cancer care. As with all standards, however, the next steps will be to further define how they will be implemented and to determine how success will be assessed. This will require ongoing critical evaluation of the standards and their implementation, including the need for member institutions to define successful implementation methods and measurable outcomes and identification of areas most in need of further research. PMID- 22440533 TI - Reporting clinical research: guidance to encourage accurate and transparent research reporting. AB - To encourage accurate, complete, and transparent reporting of research studies we provide a brief overview of generic guidelines for reporting the main types of clinical research: randomised trials, observational studies in epidemiology, and systematic reviews. These and many other guidelines developed to help authors to achieve the highest standards in their research publications are available on the EQUATOR (Enhancing the Quality and Transparency of Health Research) Network website (www.equator-network.org). PMID- 22440534 TI - Long-term follow-up of atomic bomb survivors. AB - The Life Span Study (LSS) is a follow-up study of atomic bomb (A-bomb) survivors to investigate the radiation effects on human health and has collected data for over 60 years. The LSS cohort consists of 93,741 A-bomb survivors and another 26,580 age and sex-matched subjects who were not in either city at the time of the bombing. Radiation doses have been computed based on individual location and shielding status at the time of the bombings. Age at death and cause of death are gathered through the Japanese national family registry system and cancer incidence data have been collected through the Hiroshima and Nagasaki cancer registries. Noncancer disease incidence and health information are collected through biannual medical examinations among a subset of the LSS. Radiation significantly increases the risks of death (22% at 1 Gy), cancer incidence (47% at 1 Gy), death due to leukemia (310% at 1 Gy), as well as the incidence of several noncancer diseases (e.g. thyroid nodules, chronic liver disease and cirrhosis, uterine myoma, and hypertension). Significant effects on maturity (e.g. growth reduction and early menopause) were also observed. Long-term follow up studies of the A-bomb survivors have provided reliable information on health risks for the survivors and form the basis for radiation protection standards for workers and the public. PMID- 22440535 TI - Development of a telemedical monitoring concept for the care of malnourished geriatric home-dwelling patients: a pilot study. AB - Elderly patients are at high risk of malnutrition and sarcopenia, promoting further morbidity which in turn decreases quality of life and increases the claiming of medical services and associated costs. Early and sustained administration of oral nutritional supplements has been shown to improve the nutritional status with robust clinical benefit. Many patients however, poorly adhere to prescribed supplements, so consistent monitoring is needed. Clinical monitoring usually ends with the discharge rendering the continuation of nutritional supplement therapy in the patient's home problematic. We developed a telemedicine based health care concept for intensive home monitoring. In a first randomized controlled prospective study we analyzed the feasibility of this innovative approach. The intervention group received oral nutritional supplements and telemedical monitoring with daily assessment of body weight, number of taken oral energy supplements and state of health. The control group received usual care. 13 patients were included in each group, eight patients of the intervention group left the study prematurely, five patients were closely monitored and used the devices for a mean 67 +/- 63.5 days. Follow up data of body weight and BMI showed no relevant differences between both groups. The results and experiences gained in this pilot study demonstrate that telemedical systems provide encouraging new options to enable an intensive monitoring of malnourished patients. A continuous intensive therapy monitoring of this patient group however, is a particular challenge. Albeit possibilities, limitations and useful parameters were identified, which will be used to improve the conception in an ongoing prospective randomized trial. PMID- 22440536 TI - A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families. AB - Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature from two unrelated consanguineous families of Arab-Muslim ancestry. The adult height of the affected individuals is between 112 cm and 127 cm, and is due to pre- and post-natal growth retardation, which probably manifests as early as the second trimester of pregnancy. At a young age, the phenotype is characterized by a short stature, a relatively large head, and a long triangular face, and this phenotype later evolves to one with in which the head is relatively small, the mandible is large and pointy. The affected individuals have normal cognitive abilities and lack any neurological deficits. Other typical features include a prominent nose, a voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, a waddling gait, and sparse hair post-pubertally. Typical skeletal changes include short long bones, especially the femurs and humeri, with mild metaphyseal changes and very short femoral necks. After due consideration of the other hereditary causes of disproportionate short stature and close examination of the pedigrees of the two families, we concluded that these eight individuals have the same hitherto unreported form of severe disproportionate short stature that is inherited in the autosomal recessive mode. PMID- 22440537 TI - Mutation screening of IRF6 among families with non-syndromic oral clefts and identification of two novel variants: review of the literature. AB - Non-syndromic oral clefts share the main clinical features of Van der Woude Syndrome (VWS), with the exception of the lower lip pit. Thus, about 15% of VWS cases are indistinguishable from cases with non-syndromic oral clefts. IRF6 mutations are the major cause of VWS; however, variants in this gene show strong association with non-syndromic oral clefts, with a higher increased risk among cases with cleft lip only (CLO). A total of 39 individuals, including 16 patients with CLO and 23 patients with a family history of cleft, were examined for IRF6 mutations in the present study. Seven variants, including five known (c.-75-4 A>; G, c.-73T>; C, c.459G>; T 5, c.820G>; A, and c.1060 + 37C>; T) and two novel (c. 75-23G>; C and c.1380G>; T), were found. Both novel variants were inherited from non-affected parents and we did not find also in the 120 control chromosomes. In silico analysis revealed that both c.1380G>; T and c.-75-23G>; C variants may disrupts a putative exonic splicing enhancer and intronic splicing binding site for SC35, respectively. Taken together, the presence of deleterious IRF6 variants in patients with non-syndromic oral clefts could be most likely an evidence for VWS. While, IRF6 variants could, at best, contribute to clefting as part of a complex inheritance pattern, with both additional genes and environmental factors having a role. PMID- 22440538 TI - The science on front-of-package food labels. AB - OBJECTIVE: The U.S. Food and Drug Administration and Institute of Medicine are currently investigating front-of-package (FOP) food labelling systems to provide science-based guidance to the food industry. The present paper reviews the literature on FOP labelling and supermarket shelf-labelling systems published or under review by February 2011 to inform current investigations and identify areas of future research. DESIGN: A structured search was undertaken of research studies on consumer use, understanding of, preference for, perception of and behaviours relating to FOP/shelf labelling published between January 2004 and February 2011. RESULTS: Twenty-eight studies from a structured search met inclusion criteria. Reviewed studies examined consumer preferences, understanding and use of different labelling systems as well as label impact on purchasing patterns and industry product reformulation. CONCLUSIONS: The findings indicate that the Multiple Traffic Light system has most consistently helped consumers identify healthier products; however, additional research on different labelling systems' abilities to influence consumer behaviour is needed. PMID- 22440539 TI - Weight-of-evidence environmental risk assessment of dumped chemical weapons after WWII along the Nord-Stream gas pipeline in the Bornholm Deep. AB - In connection with installation of two natural gas pipelines through the Baltic Sea between Russia and Germany, there has been concern regarding potential re suspension of historically dumped chemical warfare agents (CWA) in a nearby dump site and the potential environmental risks associated. 192 sediment and 11 porewater samples were analyzed for CWA residues, both parent and metabolites in 2008 and 2010 along the pipeline corridor next to the dump site. Macrozoobenthos and background variables were also collected and compared to the observed CWA levels and predicted potential risks. Detection frequencies and levels of intact CWA found were low, whereas CWA metabolites were more frequently found. Re suspension of CWA residue-containing sediment from installation of the pipelines contributes marginally to the overall background CWA residue exposure and risk along the pipeline route. The multivariate weight-of-evidence analysis showed that physical and background parameters of the sediment were of higher importance for the biota than observed CWA levels. PMID- 22440540 TI - Design and scale-up of an oxidative scrubbing process for the selective removal of hydrogen sulfide from biogas. AB - Reliable and selective removal of hydrogen sulfide (H(2)S) is an essential part of the biogas upgrading procedure in order to obtain a marketable and competitive natural gas substitute for flexible utilization. A promising biogas desulfurization technology has to ensure high separation efficiency regardless of process conditions or H(2)S load without the use or production of toxic or ecologically harmful substances. Alkaline oxidative scrubbing is an interesting alternative to existing desulfurization technologies and is investigated in this work. In experiments on a stirred tank reactor and a continuous scrubbing column in laboratory-scale, H(2)S was absorbed from a gas stream containing large amounts of carbon dioxide (CO(2)) into an aqueous solution prepared from sodium hydroxide (NaOH), sodium bicarbonate (NaHCO(3)) and hydrogen peroxide (H(2)O(2)). The influence of pH, redox potential and solution aging on the absorption efficiency and the consumption of chemicals was investigated. Because of the irreversible oxidation reactions of dissolved H(2)S with H(2)O(2), high H(2)S removal efficiencies were achieved while the CO(2) absorption was kept low. At an existing biogas upgrading plant an industrial-scale pilot scrubber was constructed, which efficiently desulfurizes 180m(3)/h of raw biogas with an average removal efficiency of 97%, even at relatively high and strongly fluctuating H(2)S contents in the crude gas. PMID- 22440541 TI - Transmural compensation of myocardial deformation to preserve left ventricular ejection performance in chronic aortic regurgitation. AB - BACKGROUND: In patients with chronic aortic regurgitation (AR), systolic wall stress and volume overload affects left ventricular (LV) systolic function and remodeling. The aim of this study was to assess transmural rearrangements of myocardial deformation to preserve LV ejection performances using speckle tracking echocardiography in patients with chronic AR. METHODS: Ninety patients with AR were enrolled. On LV short-axis images, total, inner, and outer radial strain and circumferential strain at the inner, mid, and outer layers were calculated. On apical four-chamber images, endocardial longitudinal strain was calculated. End-systolic wall stresses were calculated using previous methods. RESULTS: AR severities were classified as moderate in 31 patients, severe and preserved LV ejection fraction (LVEF) (>=50%) in 42 patients, and severe and reduced LVEF (<50%) in 17 patients. Longitudinal strain was decreased even in the moderate AR group, despite normal end-systolic wall stress. Inner radial strain progressively decreased with increasing end-systolic wall stress, whereas outer radial strain in the moderate and severe AR and preserved LVEF groups was higher than in the control group. Consequently, total radial strain was preserved even in the severe AR and preserved LVEF groups with increased end-systolic wall stress. Similarly, despite reduced inner circumferential strain, outer circumferential strain was higher in the severe AR and preserved LVEF group than in the control group. All strain parameters were lower in the severe AR and reduced LVEF group with dramatically increased end-systolic wall stress than in other groups. CONCLUSIONS: Transmural strain analysis revealed that subendocardial dysfunction accompanied by increased wall thickening at the subepicardium may be a compensatory mechanism of wall thickening to preserve LVEF in patients with chronic AR. PMID- 22440542 TI - Expression and characterization of hydrophobin HGFI fused with the cell-specific peptide TPS in Pichia pastoris. AB - The cell-specific peptide TPS (TPSLEQRTVYAK) has been proposed as a potential candidate for fabricating tissue engineering scaffolds based on its ability of binding to human endothelial progenitor cells (EPC) with high affinity and specificity. In this study, the class I hydrophobin hgfI gene from Grifola frondosa and the tps were fused and cloned into pPIC9. The fusion gene was expressed in Pichia pastoris under the control of alcohol oxidase 1 promoter. Tricine-SDS-PAGE and Western blotting confirmed that the fusion protein TPS linker-HGFI (TLH) was successfully secreted into the culture medium. The fusion protein TLH was purified by ultrafiltration and reverse-phase high performance liquid chromatography (RP-HPLC). Water contact angle (WCA) demonstrated that similar to recombinant HGFI (rHGFI), the purified TLH could convert the surface wettability of polystyrene and mica. X-ray photoelectron spectroscopy (XPS) measurements indicated that the purified TLH could form stable films on the hydrophobic siliconized glass surface. The cell adhesion examination showed that the TLH modified poly(epsilon-caprolactone) (PCL) could specially facilitate the EPC (particularly EPC derived from human) binding, while rHGFI modified PCL could nonselectively enhance cells adhesion. To the best of our knowledge, this is the first report that demonstrates that the TPS peptide was immobilized on biomaterial-PCL surface by fusion with hydrophobin. The potential application of this finding in combination with biomedical devices for EPC culture, will facilitate the current techniques used for cell-based therapies. PMID- 22440543 TI - Periodontitis and diabetes associations with measures of atherosclerosis and CHD. AB - OBJECTIVE: Diabetes has been linked with more severe periodontal disease and with coronary heart disease (CHD). The purpose of this study was to determine if periodontal infection was a significant modifier in the risk that diabetes poses for increased carotid artery intimal-medial wall thickness (IMT) and more advanced atheroma lesions as reflected in atherosclerotic plaque calcification measured by acoustic shadowing. METHODS AND RESULTS: Comparisons for analyses of cardiovascular outcomes were performed based upon periodontitis and diabetes status. Periodontitis was measured using pocket depth and attachment loss at six sites per tooth. Cross-sectional data on 6048 persons aged 52-74 years were obtained from the Dental Atherosclerosis Risk in Communities Study. Participants without diabetes (n=5257) were compared to those with diabetes (n=791). Dependent variables were thick IMT (>1 mm), presence of acoustic shadowing, and prevalent CHD. All models were adjusted for the following covariates: gender, age, race/center, LDL and HDL cholesterol, BMI, triglycerides, hypertension, smoking, income and education. For multivariate model building, all non-normally distributed variables were transformed and multivariable logistic regression analyses were performed to evaluate the relationship between periodontal infection, diabetes, and cardiovascular outcomes. Individuals with diabetes and with severe periodontitis were found to be significantly more likely to have IMT>1 mm [OR=2.2, (1.4-3.5)], acoustic shadowing [OR=2.5, (1.3-4.6)], and CHD [OR=2.6, (1.6-4.2)] compared to those without diabetes or periodontal disease. CONCLUSION: Results from this study suggest that among people with diabetes, periodontal disease may increase the likelihood of subclinical atherosclerotic heart disease and CHD. PMID- 22440544 TI - Estimating HIV incidence among female partners of bisexual men in China. AB - BACKGROUND: HIV prevalence among men who have sex with men (MSM) in China is rapidly increasing. The majority of Chinese MSM engage in bisexual behaviors and their female partners may be at high risk of HIV infection. METHODS: Through a comprehensive literature review and the utilization of a mathematical optimization approach, this study infers quantitative distributions of sexual behavioral practices between Chinese MSM and their female partners over the past decade, and consequently estimates the trends in HIV incidence rates among female partners of Chinese MSM. RESULTS: The average Chinese MSM had approximately 0.89 (95% confidence interval (CI) 0.68-1.23) female sexual partners, with a mean number of total penetrative acts with the female partners of 0.57 (95% CI 0.52 0.62), in the past 6 months. Condom usage increased slightly from 23.57% (95% CI 14.20-32.93%) in 2002 to 27.33% (95% CI 19.88-34.78%) in 2010. Thus, the substantially increasing HIV prevalence among MSM has led to an increase in HIV incidence among partners of bisexual MSM of approximately 5.3-fold, from 0.18 per 1000 person-years in 2002 to 0.88 per 1000 person-years in 2010. CONCLUSIONS: Bisexual Chinese MSM may be a bridge group to the general female population for HIV transmission. There has been a substantial HIV incidence increase among their female partners. PMID- 22440545 TI - Does the Internet offer social opportunities for individuals with schizophrenia? A cross-sectional pilot study. AB - Web-browsing habits of 143 individuals with psychotic disorders were compared to individuals with non-psychotic disorders (n=118) and healthy volunteers (n=100). The psychotic group created social interactions via Internet use similarly to the control groups. Individuals with schizophrenia benefit from Internet use, as it bypasses some of their social difficulties. PMID- 22440546 TI - A longitudinal study of the predictors of quality of life in patients with major depressive disorder utilizing a linear mixed effect model. AB - We set out in this study to examine a longitudinal dataset using a linear mixed effects model. Our ultimate aim is to identify predictors of the quality of life (QOL) domains and items amongst patients suffering from major depressive disorders. Four categories of variables are included in our analysis, composed of 'personal predisposition', 'psychosocial', 'illness-related' and 'time', while the outcome variables for this study are the 'physical', 'psychological', 'social' and 'environmental' domains of QOL, in conjunction with all of the items within the scale. A total of 104 subjects from an outpatient clinic of a university-affiliated hospital participated in this longitudinal study, with a one-time follow up being carried out on 70 of these subjects (67.3%) who agreed to participate in the follow-up study. The 'severity of depression', 'sense of competence' and 'sense of mastery', 'use of anti-depressant medication' and 'environmental resources' are found to be significant predictors of the detailed aspects of QOL. Of these, 'symptom severity', 'sense of competence' and 'sense of mastery' were found to occur most often. Finally, the results of the present study demonstrate that 'illness-related' and 'psychosocial' categories are capable of predicting the various QOL domains for patients suffering from depression. PMID- 22440547 TI - Participant evaluation of a telephone-based osteoarthritis self-management program, 2006-2009. AB - INTRODUCTION: Self-management support interventions can help improve osteoarthritis outcomes but are underused. Little is known about how participants evaluate the helpfulness of these programs. We describe participants' evaluations of a telephone-based, osteoarthritis self-management support intervention that yielded improved outcomes in a clinical trial. METHODS: Participants were 140 people in the intervention arm of the trial who completed an end-of-trial survey. We used mixed methods to describe participants' perceived helpfulness of the program and its components. We compared ratings of helpfulness according to participant characteristics and analyzed themes from open-ended responses with a constant comparison approach. We calculated Pearson correlation coefficients between perceived helpfulness and changes in pain, function, affect, and self efficacy. RESULTS: The average rating of overall helpfulness on a scale from 1 to 10 was 7.6 (standard deviation, 2.3), and more than 80% of participants agreed that each component (phone calls, educational material, setting goals and action plans) was helpful. Participants had better perceived helpfulness ratings than their counterparts if they were nonwhite, had limited health literacy, had no college education, had perceived inadequate income, were older, had a spouse or were living together in a committed relationship, and had greater symptom duration and less pain. Ratings of helpfulness increased with greater improvement in outcomes. Participants frequently mentioned the health educator's calls as being helpful for staying on task with self-management behaviors. CONCLUSION: Participants viewed this intervention and each of its components as helpful for improving osteoarthritis symptoms. In addition to the improvements in objective outcomes seen in the clinical trial, these results provide further support for the dissemination of self-management support interventions. PMID- 22440548 TI - Replicating the EnhanceFitness physical activity program in Hawai'i's multicultural population, 2007-2010. AB - BACKGROUND: Despite evidence of the benefits of regular physical activity, many older adults are not physically active. Health professionals are challenged to replicate evidence-based programs to address low levels of physical activity among members of their communities. COMMUNITY CONTEXT: EnhanceFitness is an evidence-based group exercise program developed in Seattle to increase the strength, flexibility, and balance of older adults. Hawai'i's Healthy Aging Partnership supported the rural island of Kaua'i to select, adapt, implement, and evaluate EnhanceFitness to increase physical activity among older adult residents (75% Asian/Pacific Islander [API]). METHODS: Evaluation measures of the replication of EnhanceFitness included fidelity of EnhanceFitness delivery and participants' attendance, satisfaction with the program, confidence to exercise regularly, and pre-post fitness check measures of physical performance (chair stands, arm curls, and the up-and-go test). OUTCOMES: Between July 2007 and December 2010, 223 Kaua'i residents enrolled in EnhanceFitness; 178 (80%) participated at least 4 months and completed the 4-month fitness checks. EnhanceFitness classes were offered with a high degree of fidelity, and both API and white participants significantly improved their physical performance (chair stands, t = -11.06, P < .001; arm curls, t = -6.66, P < .001; and up-and-go test, t = 6.56, P < .001). Participants reported high satisfaction with the program and instructors and high confidence to continue to exercise regularly. INTERPRETATION: EnhanceFitness is replicable in Hawai'i and increased physical performance among API and white older adults. This case study outlines a replication process that other communities can follow. PMID- 22440549 TI - Disparities in premature mortality between high- and low-income US counties. AB - INTRODUCTION: Several well-established determinants of health are associated with premature mortality. Using data from the 2010 County Health Rankings, we describe the association of selected determinants of health with premature mortality among counties with broadly differing levels of income. METHODS: County-level data on 3,139 US counties from the 2010 County Health Rankings were linked to county mortality data from the Centers for Disease Control and Prevention Compressed Mortality database. We divided counties into 3 groups, defined by sample median household income levels: low-income (<=25th percentile, $29,631), mid-income (25th-75th percentile, $29,631-$39,401), and high-income (>=75th percentile, >=$39,401). We analyzed group differences in geographic, sociodemographic, racial/ethnic, health care, social, and behavioral factors. Stratified multivariable linear regression explored the associations of these health determinants with premature mortality for high- and low-income groups. RESULTS: The association between income and premature mortality was stronger among low income counties than high-income counties. We found differences in the pattern of risk factors between high- and low-income groups. Significant geographic, sociodemographic, racial/ethnic, health care, social, and behavioral disparities exist among income groups. CONCLUSION: Geographic location and the percentages of adult smokers and adults with a college education were associated with premature mortality rates in US counties. These relationships varied in magnitude and significance across income groups. Our findings suggest that population health policies aimed at reducing mortality disparities require an understanding of the socioeconomic context within which modifiable variables exist. PMID- 22440550 TI - Prevalence of self-reported sleep problems among people with diabetes in the United States, 2005-2008. AB - INTRODUCTION: Sleep problems, including insomnia, apnea, and restless legs syndrome, are common, burdensome, and under-recognized in the United States. We sought to examine the association of sleep problems with diabetes among community dwelling US adults. METHODS: We examined self-reported sleep problems in 9,848 adults (aged >=20 y) participating in the National Health and Nutrition Examination Survey 2005 through 2008. Sleep problem information was elicited via validated questionnaire. Diabetes was defined by self-reported diagnosis or glycohemoglobin of 6.5% or higher. Multivariable logistic regression with US population-based weighting was used to obtain adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for various sleep problems by diabetes status. RESULTS: Sleep problems were common (>90% for any problem; 10%-40% for individual problems) overall, and people with diabetes were more likely than those without diabetes to report multiple problems (mean, 3.1 vs 2.5, respectively, P < .001). After adjustment for potential confounders (including demographics, body mass index, cardiovascular and kidney disease, and alcohol use), restless legs symptoms (OR, 1.40; 95% CI, 1.12-1.78), sleep apnea (OR, 1.45; 95% CI, 1.06 1.98), and nocturia (OR, 1.51; 95% CI, 1.22-1.87) were all positively associated with diabetes status. CONCLUSION: Diabetes is associated with a higher risk of sleep problems, including not only sleep apnea but also inadequate sleep, excessive sleepiness, leg symptoms, and nocturia, independent of body mass index. Clinicians should be aware of the high prevalence of sleep problems among their patients with diabetes and should consider screening and treatment, which may improve patients' quality of life. PMID- 22440551 TI - Safety assessment of methanol extract of red dragon fruit (Hylocereus polyrhizus): acute and subchronic toxicity studies. AB - Recently, the fruits of Hylocereus polyrhizus, known as red dragon fruit, have received much attention from growers worldwide. However, there is little toxicological information regarding the safety of repeated exposure to these fruits. The present study evaluated the potential toxicity of a methanol extract of H. polyrhizus fruit after acute and subchronic administration in rats. In the acute toxicity study, single doses of fruit extract (1250, 2500 and 5000 mg/kg) were administered to rats by oral gavage, and the rats were then monitored for 14 days. In the subchronic toxicity study, the fruit extract was administered orally to rats at doses of 1250, 2500 and 5000 mg/kg/day for 28 days. There was no mortality or signs of acute or subchronic toxicity. There was no significant difference in body weight, relative organ weight or hematological parameters in the subchronic toxicity study. Biochemical analysis showed some significant changes, including creatinine, globulin, total protein and urea levels. No abnormality of internal organs was observed between treatment and control groups. The lethal oral dose of the fruit extract is more than 5000 mg/kg and the no observed-adverse-effect level (NOAEL) of the extract for both male and female rats is considered to be 5000 mg/kg per day for 28 days. PMID- 22440552 TI - Risk assessment of gamma-hydroxybutyric acid (GHB) in the Netherlands. AB - The Dutch Minister of Health requested the Coordination point Assessment and Monitoring new drugs (CAM) to re-assess the overall risk of GHB. The present paper is a extended redraft of a state of art report used in the risk evaluation procedure. The prevalence of GHB use is low, but the relative proportion of GHB intoxications compared to other illicit drugs is high resulting in a substantial number of GHB related incidents. In recent years the number of GHB intoxications has increased because many inexperienced users seemed unaware of the potential adverse effects, like 'passing out' upon overdosing, a condition where the user is unconsciousness (or comatose) for several hours. The dependence potential of frequent GHB use is now judged by the CAM to be rather high, but users appear not well informed about this risk. In the Netherlands, last month prevalence of GHB use is relatively low (0.2%) and treatment demand is limited (524 of a total of 76,295 referrals to the addiction treatment services in 2010). So far, no public nuisance or criminality associated with GHB use has been reported. The CAM estimated the overall risk potential of GHB use as moderate to high. The Dutch Minister of Health endorsed this conclusion and decided to upgrade GHB to Schedule I (hard drugs) of the Dutch Opium Act. PMID- 22440553 TI - Assessment of diurnal systemic dose of agrochemicals in regulatory toxicity testing--an integrated approach without additional animal use. AB - Integrated toxicokinetics (TK) data provide information on the rate, extent and duration of systemic exposure across doses, species, strains, gender, and life stages within a toxicology program. While routine for pharmaceuticals, TK assessments of non-pharmaceuticals are still relatively rare, and have never before been included in a full range of guideline studies for a new agrochemical. In order to better understand the relationship between diurnal systemic dose (AUC(24h)) and toxicity of agrochemicals, TK analyses in the study animals is now included in all short- (excluding acute), medium- and long-term guideline mammalian toxicity studies including reproduction/developmental tests. This paper describes a detailed procedure for the implementation of TK in short-, medium- and long-term regulatory toxicity studies, without the use of satellite animals, conducted on three agrochemicals (X11422208, 2,4-D and X574175). In these studies, kinetically-derived maximum doses (KMD) from short-term studies instead of, or along with, maximum tolerated doses (MTD) were used for the selection of the high dose in subsequent longer-term studies. In addition to leveraging TK data to guide dose level selection, the integrated program was also used to select the most appropriate method of oral administration (i.e., gavage versus dietary) of test materials for rat and rabbit developmental toxicity studies. The integrated TK data obtained across toxicity studies (without the use of additional/satellite animals) provided data critical to understanding differences in response across doses, species, strains, sexes, and life stages. Such data should also be useful in mode of action studies and to improve human risk assessments. PMID- 22440554 TI - Visceral responses to spinal manipulation. AB - While spinal manipulation is widely seen as a reasonable treatment option for biomechanical disorders of the spine, such as neck pain and low back pain, the use of spinal manipulation to treat non-musculoskeletal complaints remains controversial. This controversy is due in part to the perception that there is no robust neurobiological rationale to justify using a biomechanical treatment of the spine to address a disorder of visceral function. This paper therefore looks at the physiological evidence that spinal manipulation can impact visceral function. A structured search was conducted, using PubMed and the Index to Chiropractic Literature, to construct of corpus of primary data studies in healthy human subjects of the effects of spinal manipulation on visceral function. The corpus of literature is not large, and the greatest number of papers concerns cardiovascular function. Authors often attribute visceral effects of spinal manipulation to somato-autonomic reflexes. While this is not unreasonable, little attention is paid to alternative mechanisms such as somato humoural pathways. Thus, while the literature confirms that mechanical stimulation of the spine modulates some organ functions in some cohorts, a comprehensive neurobiological rationale for this general phenomenon has yet to appear. PMID- 22440555 TI - Electromyographic models to assess muscle fatigue. AB - Muscle fatigue is a common experience in daily life. Many authors have defined it as the incapacity to maintain the required or expected force, and therefore, force, power and torque recordings have been used as direct measurements of muscle fatigue. In addition, the measurement of these variables combined with the measurement of surface electromyography (sEMG) recordings (which can be measured during all types of movements) during exercise may be useful to assess and understand muscle fatigue. Therefore, there is a need to develop muscle fatigue models that relate changes in sEMG variables with muscle fatigue. However, the main issue when using conventional sEMG variables to quantify fatigue is their poor association with direct measures of fatigue. Therefore, using different techniques, several authors have combined sets of sEMG parameters to assess muscle fatigue. The aim of this paper is to serve as a state-of-the-art summary of different sEMG models used to assess muscle fatigue. This paper provides an overview of linear and non-linear sEMG models for estimating muscle fatigue, their ability to assess power loss and their limitations due to neuromuscular changes after a training period. PMID- 22440556 TI - Number needed to screen to detect adenomas, advanced adenomas and colorectal cancer is higher in women than in similarly aged men. PMID- 22440557 TI - In irritable bowel syndrome, antispasmodics and antidepressants improve abdominal pain and global assessment and symptom scores, but there is no evidence for the effectiveness of bulking agents. PMID- 22440558 TI - Response to Drs Hoberman and Paradise. PMID- 22440559 TI - Population benefits of HPV vaccination for boys: a complex equation. PMID- 22440561 TI - Too smart to fail-how viruses exploit the complexity of host cells during entry. PMID- 22440562 TI - Innate immunity modulation in virus entry. AB - Entry into a cell submits viruses to detection by pattern recognition receptors (PRRs) leading to an early innate anti-viral response. Several viruses evolved strategies to avoid or subvert PRR recognition at the step of virus entry to promote infection. Whereas viruses mostly escape from soluble PRR detection, endocytic/phagocytic PRRs, such as the mannose receptor or DC-SIGN, are commonly used for virus entry. Moreover, virion-incorporated proteins may also offer viruses a way to dampen anti-viral innate immunity upon virus entry, and entering viruses might usurp autophagy to improve their own infectivity. PMID- 22440563 TI - Lipoprotein component associated with hepatitis C virus is essential for virus infectivity. AB - Many chronic hepatitis patients with hepatitis C virus (HCV) are observed to have a degree of steatosis which is a factor in the progression of liver diseases. Transgenic mice expressing HCV core protein develop liver steatosis before the onset of hepatocellular carcinoma, suggesting active involvement of HCV in the de regulation of lipid metabolism in host cells. However, the role of lipid metabolism in HCV life cycle has not been fully understood until the establishment of in vitro HCV infection and replication system. In this review we focus on HCV production with regard to modification of lipid metabolism observed in an in vitro HCV infection and replication system. The importance of lipid droplet to HCV production has been recognized, possibly at the stage of virus assembly, although the precise mechanism of lipid droplet for virus production remains elusive. Association of lipoprotein with HCV in circulating blood in chronic hepatitis C patients is observed. In fact, HCV released from culture medium is also associated with lipoprotein. The fact that treatment of HCV fraction with lipoprotein lipase (LPL) abolished infectivity indicates the essential role of lipoprotein's association with virus particle in the virus life cycle. In particular, apolipoprotein E (ApoE), a component of lipoprotein associated with HCV plays a pivotal role in HCV infectivity by functioning as a virus ligand to lipoprotein receptor that also functions as HCV receptor. These results strongly suggest the direct involvement of lipid metabolism in the regulation of the HCV life cycle. PMID- 22440564 TI - Emerging zoonotic viruses: new lessons on receptor and entry mechanisms. AB - Viruses enter the host cell by binding cellular receptors that allow appropriate delivery of the viral genome. Although the horizontal propagation of viruses feeds the continuous emergence of novel pathogenic viruses, the genetic variation of cellular receptors can represent a challenging barrier. The SARS coronavirus, henipaviruses and filoviruses are zoonotic RNA viruses that use bats as their reservoir. Their lethality for man has fostered extensive research both on the cellular receptors they use and their entry pathways. These studies have allowed new insights into the diversity of the molecular mechanisms underlying both virus entry and pathogenesis. PMID- 22440565 TI - Late-penetrating viruses. AB - Many enveloped and non-enveloped animal viruses delay the penetration into the cytosol of host cells until they have arrived to endocytic vacuoles deep in the cytoplasm. The late timing is generally determined by a low pH-threshold for the acid-activated penetration process (pH 6.2-4.9), but there can be a combination of other reasons for a delay. Since late-penetrating viruses (L-PVs) must be sorted into the degradative pathway, they are particularly sensitive to perturbations that interfere with molecular sorting and proper maturation of endosomes, including switching of Rabs, formation of intraluminal vesicles, and microtubule-mediated transport. In this short review, we focus on L-PVs from several virus families, and their interactions with the endocytic machinery. PMID- 22440566 TI - Environmental viruses from biodiversity to ecology. PMID- 22440567 TI - Virophages to viromes: a report from the frontier of viral oceanography. AB - The investigation of marine viruses has advanced our understanding of ecology, evolution, microbiology, oceanography and virology. Significant findings discussed in this review include the discovery of giant viruses that have genome sizes and metabolic capabilities that distort the line between virus and cell, viruses that participate in photosynthesis and apoptosis, the detection of communities of viruses of all genomic compositions and the preeminence of viruses in the evolution of marine microbes. Although we have made great progress, we have yet to synthesize the rich archive of viral genomic data with oceanographic processes. The development of cutting edge methods such as single virus genomics now provide a toolset to better integrate viruses into the ecology of the ocean. PMID- 22440568 TI - Giant viruses in the environment: their origins and evolution. AB - The recent identification of giant viruses has raised important questions, not only regarding their origin and evolution, but also regarding the differentiation between viruses and living organisms. These viruses possess large genomes encoding genes potentially involved in various metabolic processes and even protein synthesis, indicating their putative autonomy. Giant viruses of the Phycodnaviridae and Mimiviridae families appear to share a common evolutionary ancestor with members of the nucleo-cytoplasmic large DNA viruses. Many giant viruses are associated with protists in aquatic environments and might have evolved in protist cells. They may therefore play important roles in material cycling in natural ecosystems. With the advent of environmental metagenomic projects, there will be more chances to encounter novel giant viruses in the future. PMID- 22440569 TI - The big unknown: plant virus biodiversity. AB - Studies on plant virus biodiversity are in their infancy, but with new technologies we can expect to see more information about novel plant viruses in the near future. The challenge for virus biodiversity work is that viruses do not have any universal coding sequence, such as ribosomal RNAs found in all cellular life. These obstacles are being overcome in clever ways. Understanding what exists in our natural environment will help us to tackle big issues in agriculture, such as disease emergence and the use of beneficial viruses and other microbes. PMID- 22440570 TI - The role of viruses in biological invasions: friend or foe? AB - Biological invasions occur when plants, animals, or microbes are introduced to a new geographic region, then spread and have negative consequences for the local ecosystem. Across both plant and animal hosts, viruses can play diverse roles in biological invasions. First, viruses can either decrease or increase the impacts of biological invasions by their hosts. Introduced hosts commonly leave behind many viruses from their native ranges, which may allow the hosts to achieve greater fitness and thus dominate in their introduced ranges. Viruses that do infect introduced hosts may reduce invasive host fitness and impacts. However, many viruses that infect introduced hosts also infect native hosts and may have more severe impacts on the native hosts. Second, viruses can also be invasive species themselves. While many viruses are believed to be introduced, it is challenging to differentiate between those that are native and those that are not. Third, many viruses are transmitted by vectors, which can also be introduced to new regions. Introduced vectors can increase virus transmission rates, altering host communities and ecosystems. Further advancing our understanding of the role of viruses in biological invasions will require research that integrates the systematics, biogeography and ecological history of hosts, vectors, and viruses. PMID- 22440571 TI - Complex dynamics at the interface between wild and domestic viruses of finfish. AB - Viral traffic occurs readily between wild and domesticated stocks of finfish because aquatic environments have greater connectivity than their terrestrial counterparts and because the global expansion and dynamic nature of intensive aquaculture provide multiple pathways of transmission and unique drivers of virus adaptation. Supported by examples from the literature, we provide reasons why viruses move from wild fish reservoirs to infect domestic fish in aquaculture more readily than 'domestic' viruses move across the interface to infect wild stocks. We also hypothesize that 'wild' viruses moving across the interface to domestic populations of finfish are more frequently associated with disease outbreaks and host switches compared to domestic viruses that cross the interface to infect wild fish. PMID- 22440572 TI - Biodiesel from Siberian apricot (Prunus sibirica L.) seed kernel oil. AB - In this paper, Siberian apricot (Prunus sibirica L.) seed kernel oil was investigated for the first time as a promising non-conventional feedstock for preparation of biodiesel. Siberian apricot seed kernel has high oil content (50.18 +/- 3.92%), and the oil has low acid value (0.46 mg g(-1)) and low water content (0.17%). The fatty acid composition of the Siberian apricot seed kernel oil includes a high percentage of oleic acid (65.23 +/- 4.97%) and linoleic acid (28.92 +/- 4.62%). The measured fuel properties of the Siberian apricot biodiesel, except cetane number and oxidative stability, were conformed to EN 14214-08, ASTM D6751-10 and GB/T 20828-07 standards, especially the cold flow properties were excellent (Cold filter plugging point -14 degrees C). The addition of 500 ppm tert-butylhydroquinone (TBHQ) resulted in a higher induction period (7.7h) compliant with all the three biodiesel standards. PMID- 22440573 TI - The potential of Yucca schidigera extract to reduce the ammonia pollution from shrimp farming. AB - This study investigated the feasibility of using Yucca schidigera extract (YUPE) to reduce ammonia pollution resulting from shrimp farming. YUPE was added at ratios of 18, 36, and 72 mg L(-1) to effluent from an experimental shrimp culture system containing total ammonia nitrogen (TAN) of 0.592, 0.672, and 0.718 mg L( 1). TAN reduction increased with an increase in YUPE, and at 18 mg L(-1) reduced TAN by 71-72% and 86-87% at 6 and 24h, respectively. Shrimp feed containing YUPE at 300, 600, and 1200 mg kg(-1) was submerged, allowing the ammonia to leach out. The addition of YUPE in feed reduced TAN leaching by 50-83% compared with the control. The application of YUPE in water or feed could considerably reduce the accumulation of ammonia in waste water discharge during shrimp production, thereby providing a feasible solution to ammonia pollution in coastal environments. PMID- 22440574 TI - The structure activity relationship of non-dissolved redox mediators during azo dye bio-decolorization processes. AB - Structure activity relationships were elucidated by applying chemical structure, electrochemistry and quantum chemical calculations for non-dissolved redox mediators (RM, quinones) with similar chemical structure. The decolorization efficiencies of acid red B by a Halomonas sp. GYW were enhanced 2.68, 2.58, 1.91 and 1.49 times with 1,5-dichloroanthraquinone, 1,8-dichloroanthraquinone, anthraquinone, and 1,4,5,8-tetrachloroanthraquinone, respectively. The order of oxidation reduction potential (ORP) during the decolorization process with four redox mediators agreed with their order of reduction potential (Ea) from cyclic voltammetry. The decolorization rate (k) with four redox mediators has a linear relation with their Ea values (k=269.05Ea+85.782, R(2)=0.9226). The calculated rho(r(c)) at the Ring Critical Point (RCP) based on Atoms in Molecules (AIM) and the inductive/resonance effects of the four redox mediators were also consistent with the accelerating effects on the decolorization. These established relationships might to be predictive models and mechanistic explanations for the accelerating decolorization with redox mediator. PMID- 22440575 TI - Vermicomposting of herbal pharmaceutical industry waste: earthworm growth, plant available nutrient and microbial quality of end materials. AB - Efforts were made to decompose herbal pharmaceutical industrial waste (HPIW) spiked with cow dung (CD) using Eisenia fetida. A total of five vermibeds: T(1) - HPIW (0%+CD 100%, control), T(2) - HPIW (25%), T(3) - HPIW (50%), T(4) - HPIW (75%) and T(5) - HPIW (100%) were used for vermicomposting. The changes in biology and chemistry of vermibeds were measured after ten days interval. E. fetida showed high growth and cocoon production rate in all vermibeds. The vermicomposted material contained great population of fungi 6.0-40.6 (CFU * 10(5)g(-1)), bacteria 220-1276.0 (CFU * 10(8)g(-1)) and actinomycetes 410.0 2962.0 (CFU * 10(5)g(-1)) than initial material. Vermicomposted material was rich in plant-available forms of nutrients (N-NO(3)(-),PO(4)(3-),available K and SO(4)(-2)). Results suggested that noxious industrial waste can be converted into valuable product for sustainable soil fertility programme. PMID- 22440576 TI - A new procedure for the hydrophobization of cellulose fibre using laccase and a hydrophobic phenolic compound. AB - A new biotechnological procedure using laccase in combination with a hydrophobic phenolic compound (lauryl gallate) for the hydrophobization of cellulose fibres and internal sizing of paper was developed. Cellulose fibres from hardwood kraft pulp were incubated with laccase (Lac), in combination with lauryl gallate (LG). The Lac-LG treatment resulted in the internal sizing of paper, and also in significantly reduced water penetration in the handsheets and wettability of the paper surface. Paper was found not to be effectively rendered hydrophobic by LG alone. SEM images of the fibre network revealed the presence of the sizing agent: a product of the reaction between laccase and lauryl gallate. Binding of lauryl gallate to cellulose fibres was suggested by the increase in kappa number of the pulp and further confirmed by IR spectroscopy. PMID- 22440577 TI - Impacts of transient salinity shock loads on Anammox process performance. AB - The effect of salinity shock (5-60 g l(-1) NaCl) on anaerobic ammonium oxidation (Anammox) process performance was investigated. The response to the shock loads can be divided into three stages: a sensitive period, an interim stable period and a recovery period which lasted 6-26 d. When exposed to NaCl shocks for 12h, the sludge retention time (SRT) of the reactor decreased with increasing NaCl shock loads, ranging between 2.9 and 22.5d, meanwhile the biomass decreased by 0.8-37.4%. When shock loads were higher than 10 g l(-1) NaCl, the reactor was at risk of losing too much biomass. The granular surface was rough due to rapid growth of filamentous bacteria and extracellular polymeric substances (EPS), also the EPS amount changed during all NaCl shock loads. In the latter of shocks, the microorganisms in the reactor showed a little adaption to the NaCl shock. PMID- 22440578 TI - CO2 supplementation to domestic wastewater enhances microalgae lipid accumulation under mixotrophic microenvironment: effect of sparging period and interval. AB - Bio-sequestration of CO(2) through microalgae cultivation is considered as a viable option for biofuel production as well as CO(2) mitigation. Influence of CO(2) sparging period and interval was evaluated on the growth and lipid accumulation of microalgae cultivated in domestic wastewater under mixotrophic microenvironment. Process performance was assessed in two phases viz., growth (GP) and starvation phases (SP) each with 8 days of retention time. Experimental variations depicted marked influence on biomass growth and lipid accumulation of microalgae with the function of harvesting period. Sparging period of 120 s documented maximum biomass growth (GP, 3.4 mg/ml) and lipid productivity (SP, 27.3%) while in intervals, 4h (120 s) condition showed maximum biomass (3.2mg/ml) and lipid productivity (27.8%). Total chlorophyll components documented higher concentrations of Chl b supporting the observed higher lipid productivity. Fatty acid composition varied with the experimental variations and represented higher degree of saturation indicating their utility as biodiesel. PMID- 22440579 TI - The cost of major lower limb amputation: a 12-year experience. AB - BACKGROUND: The amputee population is elderly, has significant medical co morbidities and perioperative mortality leading to high financial implications. Commonly used outcomes in the literature are survival, prosthetic use and mobility. OBJECTIVES: Our study aims to share our 12-year experience of amputee care, concentrating on perioperative mortality and patient rehabilitation. STUDY DESIGN: Observational study in the form of a retrospective case series. METHODS: In total, 130 amputations, performed between January 1998 and December 2009, were followed up for a mean of three and a half years and analyzed for demographics, vascular history, operation details, prosthetic use, mobility and mortality. RESULTS: The population was 59.2% male, had a mean age of 73 and the most common indication for amputation was critical ischaemia (78.5%). The average length of acute inpatient stay was 63 days with a 30-day mortality rate of 15.3% and inpatient mortality of 29.3%. In total, 63.3% of patients were issued with a prosthesis with 48.2% of all patients achieving at least indoor mobility, transtibial (49.9%) rehabilitated better than transfemoral amputees (24.3%). CONCLUSIONS: Our data support the urgent need for action to improve perioperative mortality in the amputee population, with the added advantage of reducing its financial impact. Clinical relevance Our study gives an overview of the clinical journey taken by a 12-year amputee population. By following this cohort from initial procedure through to rehabilitation or mortality we provide the reader with a valuable insight into the difficulties of managing this population and the likely outcomes for these patients. PMID- 22440580 TI - Variability of kinetic variables during gait in unilateral transtibial amputees. AB - BACKGROUND: Prosthetic gait increases demands on stability. Some variability measures can be used to investigate the stability of movement for prosthetic feet. OBJECTIVES: The purpose of this study was to determine the influence of the prosthetic foot on ground reaction force variability for transtibial amputee gait. STUDY DESIGN: Comparative analysis. METHODS: Eleven male unilateral transtibial amputees participated in this study. Each subject walked at self selected speed with both conventional (SACH) and energy storing (Sureflex) feet. Time and ground reaction force variables and their coefficients of variation were calculated for each foot type and limb. RESULTS: Mediolateral force variables had high variability for all conditions. The Sureflex had a larger variability than the SACH foot for the braking peak (p < 0.05), which may have been caused by gait instability after the heel strike. There were significant differences between intact and prosthetic limbs in total loading (force impulses) with the SACH foot (p < 0.05). CONCLUSIONS: The prosthetic foot and alignment issues related to the foot influence GRF variability. During the braking phase the SACH foot is characterized by higher variability in mediolateral direction and Sureflex by higher variability in anterior-posterior direction. CLINICAL RELEVANCE: Differences in variability in ground reaction force variables can represent a person's stability. Observing variability can contribute to better understanding of critical events in gait cycle with the use of various prosthetic feet. PMID- 22440581 TI - Validation of presence of supermarkets and fast-food outlets in Copenhagen: case study comparison of multiple sources of secondary data. AB - OBJECTIVE: We examined the quality of food outlet addresses provided by secondary sources and determined whether they could be physically located in the field. DESIGN: Addresses of food outlets in fourteen school districts in the northern part of Copenhagen were obtained from multiple business locators. We geocoded 202 addresses using a geographic information system and cross-referenced the sources against each other using a validation grid. Physical presence was determined via street survey. We applied gamma statistics and calculated positive predictive value, sensitivity and percentage agreement to assess the overall correspondence between our test of physical presence and each source of secondary information. SETTING: The study took place within city boundaries of Copenhagen, Denmark. SUBJECTS: Food outlets within fourteen school districts within Copenhagen. RESULTS: Positive predictive value between field results and secondary sources indicated good to excellent correspondence (range: 0.81-0.98), comparable with other studies. Gamma coefficients indicated low to high positive correspondence (range: 0.23-0.98). CONCLUSIONS: Despite moderately high correspondence between secondary sources of address information and field observation, the findings illustrate that the use of combined sources is recommended. PMID- 22440582 TI - The age at death assessment in a multi-ethnic sample of pelvic bones using nature inspired data mining methods. AB - Recently published studies showed that age assessment methods are population specific. Authors analyse the senescence changes in pubic symphysis and sacro pelvic surface of a pelvic bone using data mining methods. The multi-ethnic data set consists of 956 adult individuals ranging from 19 to 100 years of age derived from 9 different populations with known age and sex. The results show that accurate and reliable age assessment is possible to three age classes (less than 30, 30-60, 60 and more). The study confirms that population specificity of the methods exists and the variable "sex" is not important in age classification. PMID- 22440583 TI - Cloning of a heat shock protein 90 (HSP90) gene and expression analysis in the ridgetail white prawn Exopalaemon carinicauda. AB - Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone contributing to the folding, maintenance of structural integrity and proper regulation of a subset of cytosolic proteins. In this study, a heat shock protein 90 cDNA named EcHSP90 was cloned from the hepatopancreas of ridgetail white prawn Exopalaemon carinicauda by reverse transcription polymerase chain reaction (RT PCR) coupled with rapid amplification of cDNA ends (RACE) approaches. The full length cDNA of EcHSP90 was of 2695 bp, including an open reading frame (ORF) of 2163 bp encoding a polypeptide of 720 amino acids with an estimated molecular mass of 82.73 kDa and an estimated isoelectric point of 4.83. BLAST analysis revealed that the EcHSP90 shared high similarity (87.6%-75.24%) with other known HSP90s. The five conserved amino acid blocks defined as HSP90 protein family signatures were also identified in EcHSP90, which indicated that EcHSP90 should be a cytosolic member of the HSP90 family. Quantitative real-time RT-PCR analysis revealed that EcHSP90 transcript could be detected in all the tested tissues, and strongly expressed in ovary of E. carinicauda. The transcript of EcHSP90 in hepatopancreas of E. carinicauda showed different expression profiles after pH and ammonia-N stresses. The results indicated that EcHSP90 was a constitutive and inducible expressed protein and could be induced by various stresses from environment. PMID- 22440584 TI - Hilyses(r), fermented Saccharomyces cerevisiae, enhances the growth performance and skin non-specific immune parameters in rainbow trout (Oncorhynchus mykiss). AB - Effects of Hilyses((r)), fermented Saccharomyces cerevisiae (S. cerevisiae), on growth, body composition and skin mucus immune components in rainbow trout were quantified. Ninety rainbow trout (105 +/- 5 g) were randomly assigned to 2 groups in triplicates and fed dietary Hilyses((r)) (5 g kg(-1)) or control diet without Hilyses((r)) for 50 days. Results of this study demonstrated that growth performance increased significantly by the dietary yeast supplement; however body composition was not affected in treatment group. At the 45th and 50th day of feeding trial, results of mucus samples demonstrated that yeast supplementation in treatment group significantly promoted enzyme activities, namely lysozyme, protease, alkaline phosphatase and esterase compared to control group. Significant increases were also observed in hemagglutination and antibacterial activity against Yersinia ruckeri in fish fed treatment diet. The present study suggests that fermented S. cerevisiae may effectively promote the growth performance and skin non-specific immune parameters in rainbow trout. PMID- 22440585 TI - Analysing stratified medicine business models and value systems: innovation regulation interactions. AB - Stratified medicine offers both opportunities and challenges to the conventional business models that drive pharmaceutical R&D. Given the increasingly unsustainable blockbuster model of drug development, due in part to maturing product pipelines, alongside increasing demands from regulators, healthcare providers and patients for higher standards of safety, efficacy and cost effectiveness of new therapies, stratified medicine promises a range of benefits to pharmaceutical and diagnostic firms as well as healthcare providers and patients. However, the transition from 'blockbusters' to what might now be termed 'niche-busters' will require the adoption of new, innovative business models, the identification of different and perhaps novel types of value along the R&D pathway, and a smarter approach to regulation to facilitate innovation in this area. In this paper we apply the Innogen Centre's interdisciplinary ALSIS methodology, which we have developed for the analysis of life science innovation systems in contexts where the value creation process is lengthy, expensive and highly uncertain, to this emerging field of stratified medicine. In doing so, we consider the complex collaboration, timing, coordination and regulatory interactions that shape business models, value chains and value systems relevant to stratified medicine. More specifically, we explore in some depth two convergence models for co-development of a therapy and diagnostic before market authorisation, highlighting the regulatory requirements and policy initiatives within the broader value system environment that have a key role in determining the probable success and sustainability of these models. PMID- 22440586 TI - Developing predictive models of excellent and devastating outcome after stroke. AB - BACKGROUND: models to predict functional status post-stroke have utility in balancing groups in randomised trials, for outcome comparison between stroke centres and may assist in outcome prediction. This study aimed to develop models of both excellent [modified Rankin score (mRS) 0-1] and devastating outcomes (mRS of 5-6). METHODS: patients admitted with ischaemic or haemorrhagic stroke in 2001 02 to the Halifax Infirmary, Canada, were enrolled. Sixteen clinical variables from the first neurological assessment and six radiological variables from the acute CT scan were used to the model outcome at 6 months. RESULTS: five hundred and thirty-eight stroke patients were enrolled. Thirty per cent had an excellent outcome and 30% had a devastating outcome. Three models of the excellent outcome were developed [area under the receiver operator curve (AUC) 0.866-882] including the variables age, pre-stroke functional status, stroke severity, ability to lift both arms, walk independently, normal verbal Glasgow Coma Scale and leukoaraiosis. Predictive models of the devastating outcome (AUC of 0.859-0.874) included additional variables living alone pre-stroke and total anterior circulation stroke. The simplest models of both outcomes were externally validated (AUC of 0.856-0.885). CONCLUSION: this study demonstrates new externally validated predictive models of both excellent and devastating outcomes. Leukoaraiosis was the only independent radiological predictor of both outcomes. Living alone pre-stroke predicted devastating outcome post-stroke. PMID- 22440587 TI - Clinical characteristics and mortality risk in relation to obstructive and central sleep apnoea in community-dwelling elderly individuals: a 7-year follow up. AB - BACKGROUND: little is known about demographic and clinical characteristics associated with sleep-disordered breathing (SDB) and obstructive sleep apnoea (OSA) or central sleep apnoea (CSA) in community-dwelling elderly. We also examined these (OSA and CSA) associations to all-cause and cardiovascular (CV) mortality. METHODS: a total of 331 community-dwelling elderly aged 71-87 years underwent a clinical examination and one-night polygraphic recordings in their homes. Mortality data were collected after seven years. RESULTS: a total of 55% had SDB, 38% had OSA and 17% had CSA. Compared with those with no SDB and OSA, more participants with CSA had a left ventricular ejection fraction <50% (LVEF <50%) ischaemic heart disease (IHD) and transient ischaemic attack (TIA)/stroke. There was no difference in the rate of IHD and TIA/stroke between OSA and no SDB, but more LVEF <50% was found in those with OSA. CSA significantly increased the risk for all-cause (P=0.002) and CV mortality (P=0.018) by more than two times. After adjustments for CV disease, diabetes and the biomarker NT-pro-brain natriuretic peptide CSA associations to all-cause mortality and CV mortality lost significance. CONCLUSION: OSA, in persons >75 years does not appear to be associated with cardiovascular disease (CVD) disease or mortality, whereas CSA might be a pathological marker of CVD and impaired systolic function associated with higher mortality. PMID- 22440588 TI - The relationship between visceral adiposity and cognitive performance in older adults. AB - BACKGROUND: a direct association between visceral adiposity on abdominal computed tomography (CT) and cognitive performance has not been reported. OBJECTIVES: to investigate the associations between total and regional adiposity measured with abdominal CT, and cognitive performance in elderly persons and to explore their modification by age. DESIGN: cross-sectional study. SETTING: a health promotion centre of a tertiary university hospital. SUBJECTS: two-hundred and fifty individuals aged 60 years and above who underwent anthropometric measurements, abdominal CT and cognitive testing. METHODS: adiposity measures included body mass index (BMI), waist circumference and visceral and subcutaneous adiposity by abdominal CT. Poor cognitive performance was defined as Mini-Mental State Examination score being at or below 1 SD of age, sex and education-normative values. RESULTS: in multivariate logistic regression analyses obesity [odds ratio (OR) 2.61, 95% confidence interval (CI)=1.21-6.01, P=0.015] and being in the top tertile of the visceral adiposity area (OR: 2.58, 95% CI=1.001-6.62, P=0.045) were associated with poor cognitive performance in subjects younger than 70 years, but not in those 70 years and older. CONCLUSION: high adiposity, particularly visceral adiposity, was associated with poor cognitive functioning in younger elderly persons. PMID- 22440589 TI - Calcified fibrin sheath masquerading as retained catheter. PMID- 22440590 TI - Feasibility of ultrasound-guided intranodal lymphangiogram for thoracic duct embolization. AB - PURPOSE: To show the feasibility of opacifying the thoracic duct using ultrasound guided intranodal lymphangiogram (IL) for thoracic duct embolization (TDE). MATERIALS AND METHODS: Six patients (two women and four men, mean age, 59.2 y [range, 43-74 y]) underwent IL and TDE for chylothorax. Under ultrasound guidance, a needle was positioned in a groin lymph node, and lipiodol was injected. The thoracic duct was catheterized, and embolization was performed as indicated. Cumulative times from start of the procedure until initiation of the lymphangiogram, until identification of target lymphatic, until catheterization of the thoracic duct, and until completion of the procedure were collected. Times were compared with times of a control group of six patients (two women and four men, mean age, 66.7 y [range, 49-82 y]) who had undergone TDE using pedal lymphangiography (PL). RESULTS: The procedure of opacification, catheterization, and embolization of the thoracic duct was successful in all cases. Cumulative times (mean +/- standard deviation) in the IL and PL groups from start of the procedure until (i) initial lymphangiogram were 20.5 minutes +/- 8.6 and 46.5 minutes +/- 22.6, (ii) identification of a target lymphatic for catheterization were 60.5 minutes +/- 18.2 and 110.5 minutes +/- 31.6, (iii) catheterization of the thoracic duct were 79.0 minutes +/- 28.9 and 128.2 minutes +/- 37.0, and (iv) completion of procedure were 125.8 minutes +/- 49.0 and 152.8 minutes +/- 36.4. CONCLUSIONS: IL is a feasible technique to visualize the thoracic duct for embolization. Using IL, the thoracic duct may be more quickly visualized and catheterized for TDE than with PL. PMID- 22440591 TI - Utero-ovarian anastomoses and their influence on uterine fibroid embolization. AB - PURPOSE: To correlate clinical outcomes after uterine artery embolization (UAE) performed to treat uterine fibroids with the presence of varying types of utero ovarian anastomoses (UOA). MATERIALS AND METHODS: A retrospective analysis was performed of all uterine angiograms from 202 patients (mean age 42 y, range 28-54 y) who underwent UAE because of heavy menstrual bleeding, dysmenorrhea, or anemia or a combination of these symptoms. UOA were classified as absent or present, unilateral or bilateral. The effects of UOA on long-term outcomes (clinical endpoints such as control of bleeding and pain) and complications (amenorrhea) were assessed statistically using Kaplan-Meier curves and chi(2) and log-rank tests. RESULTS: Of the UOA in 104 women, 38 anastomoses were bilateral, and 66 were unilateral. Type III was the most common type of anastomosis (66 cases) followed by type Ia (22 cases) and type Ib (18 cases); there were no type II anastomoses. Amenorrhea was reported in 27 (14%) women at 5-year follow-up after UAE (only 3% in women < 45 y old). There were 10 cases of clinical failure with a median follow-up of > 4 years. Bilateral or unilateral presence of UOA had no statistically significant effect on outcomes or on complications. CONCLUSIONS: Recurrence rates, clinical failure, and amenorrhea after UAE do not seem to be influenced by the presence or absence of UOA. However, further studies are needed to confirm these findings. PMID- 22440592 TI - Radiation emission from patients treated with selective hepatic radioembolization using yttrium-90 microspheres: are contact restrictions necessary? AB - PURPOSE: To estimate the possible radiation dose to other individuals from patients treated with yttrium-90 ((90)Y). MATERIALS AND METHODS: Dosimetry data were analyzed after 143 consecutive administrations of (90)Y (124 resin, 19 glass) in 86 patients. External radiation exposure levels from patients were measured immediately after infusion. Total effective dose equivalent (TEDE) to maximally exposed individuals was calculated based on total body residence time and measured dose rate. These values were compared to Nuclear Regulatory Commission (NRC) regulations (maximum, 1 mSv) and other potential guidelines for caregivers, extensive caregivers, or pregnant contacts. RESULTS: Mean administered activity for resin microspheres was 0.71 GBq +/- 0.35 (range, 0.07 1.6GBq). Mean TEDE dose to the maximally exposed contact was 0.03 mSv (range, 0.0005-0.16 mSv). For glass microspheres, mean administered activity was 2.8 GBq +/- 1.5 (range, 0.37-5.14 GBq). Mean TEDE dose to the maximally exposed contact was 0.06 mSv (range, 0.0023-0.23 mSv). All (90)Y treatments were within current NRC regulations for release without instructions. One, three, and one infusion were beyond potential thresholds for caregivers, extensive caregivers, or pregnant contacts, respectively. For any contact scenario, release without instruction was appropriate when administered activity was less than 3 GBq. CONCLUSIONS: All patients treated with (90)Y hepatic radioembolization to a maximum administered activity of 5.14 GBq and maximum dose rate of 10 uSv/h were releasable without contact restrictions according to the NRC contact scenario. Patients who receive more than 3 GBq during infusion may require dose rate measurement if more restrictive contact scenarios are considered. PMID- 22440593 TI - Evaluation of the mechanisms of the effect of ultrasound on Microcystis aeruginosa at different ultrasonic frequencies. AB - Blooms of cyanobacteria are now considered to be a common environmental issue. They are hazardous to both domestic and wild animals and humans. Current treatments are unable to effectively control such blooms as they become tolerant to biocides and it is difficult to degrade cyanobacterial toxins in water. Alternative methods for control are currently under investigation. One potential effective method is ultrasonic irradiation. Ultrasound inactivates algal and cyanobacteria cells through cavitation by generating extreme conditions, resulting in a number of physical, mechanical and chemical effects. The aim of this study was to investigate the effect of ultrasound at different frequencies on Microcystis aeruginosa. Flow cytometry was used to measure cyanobacterial metabolic cell viability in addition to the more commonly used haemocytometry, optical density and fluorimetry. Results indicate low frequency 20 kHz ultrasound with high intensity (0.0403 W cm(-3)) is effective for the inactivation of cyanobacterial cells. Higher frequencies of 580 kHz (0.0041 W cm(-3)) also resulted in an inactivation effect, but 1146 kHz (0.0018 W cm(-3)) showed a declumping effect as evidenced by flow cytometry. Ultrasonic treatment over time under different sonication conditions demonstrates the following: 1. Acoustic cavitation via mechanical effects can induce sufficient shear forces to directly rupture cyanobacteria cells. 2. At higher ultrasonic frequencies the mechanical energy of cavitation is less but a larger proportion of free radicals are produced from the ultrasonic degradation of water, which chemically attacks and weakens the cyanobacteria cell walls. 3. At higher frequencies free radicals also damage chlorophyll a leading to a loss in photosynthetic cell viability. 4. At low powers ultrasonic energy results in declumping of cyanobacteria. PMID- 22440594 TI - Tongue entrapment in aluminum water bottle: discussion of removal and airway management. AB - Tongue entrapment in a bottle neck is rare, with few cases reported in the literature. Reported here is the case of a child who presented to the Emergency Department with her tongue entrapped in an aluminum bottle. This case is unique in that the patient had a delayed presentation resulting in significant tongue edema, requiring advanced methods for removal and airway management. These include sedated mechanical removal of the strangulating object and transnasal fiberoptic intubation. We review published cases and the options for removal of an entrapped tongue from a bottle neck, and we discuss the importance of airway management. PMID- 22440595 TI - Five to ten years follow-up after coiling of 241 patients with acutely ruptured aneurysms. A single centre experience. AB - Endovascular treatment has assumed a role of first choice in the management of ruptured intracranial aneurysms. We describe the clinical and morphological data after the treatment of 258 ruptured intracranial aneurysms in 241 patients, in order to evaluate the safety and the efficacy of the endovascular treatment. Two hundred and forty-one patients with saccular ruptured aneurysms were treated at our institution between 2000 and 2005. After the endovascular treatment a clinical and angiographic follow-up was conducted. The clinical follow-up was carried out with a medical examination and telephonic interviews and mRS was used for evaluation. Two hundred and forty-nine acutely ruptured aneurysms were successfully treated and immediately after the endovascular procedure 81.9% of the aneurysms resulted completely occluded, 12.1% had a residual neck and 6% revealed a residual sac. The evolution of each grade was evaluated at six months and two years. During the follow-up we observed five early and one late re bleedings. Twenty-four patients underwent a second procedure. After the discharge and up to ten years 73.1% of patients had a good clinical outcome (mRS0-1), 8.9% died and the remainder showed moderate-severe disability (mRS2-3). The long term stability of the anatomical result is a critic-al issue of this approach because eventual re-bleedings may occur even after several months or years. A careful clinical and radiological follow-up for up to two years after the embolization may prevent recurrences but may not be sufficient. PMID- 22440596 TI - Endovascular treatment of recurrent coiled aneurysms: assessment of complications and rebleeding during a decade in a single center. AB - Recurrence is the main drawback of aneurysmal coiling. Additional coiling must sometimes be considered in patients with reopened aneurysms and expose the patient to the risk of a new procedure. Our purpose was to assess the procedural complications of additional endovascular treatments in patients with previously coiled but recurrent aneurysms treated by two neurointerventionalists during a decade in a single center. Between 1999 and 2009, 637 intracranial aneurysms were coiled and had a clinical and angiographic follow-up at our institution. Following the first embolization, 44 aneurysms were retreated with coils and 11 were retreated a second time. Retreatment was decided when a recurrence showed at angiographic follow-up. Early retreatments, performed in the first month after an incomplete or failed initial coiling, were excluded. We retrospectively analysed the procedural complications, rebleeding, clinical and angiographic outcomes of the retreatments. No death or bleeding occurred in these 55 additional procedures. We had three periprocedural thromboembolic complications and the procedural permanent morbidity was 1.8%. Clinical and angiographic follow-ups ranged from six months to nine years (mean: 37 months, median: 36 months). Thirty seven of the 44 retreated aneurysms (84%) showed a stable occlusion at follow-up. Seven showed a recurrence but were not retreated due to the stability of the packing. No rebleeding was observed during the follow-up period. Our results show that endovascular treatment of recurrent aneurysms is associated with a low procedural risk. PMID- 22440597 TI - Stent-assisted coil embolization of complex wide-necked bifurcation cerebral aneurysms using the "waffle cone" technique. A review of ten consecutive cases. AB - Endovascular treatment of complex, wide-necked bifurcation cerebral aneurysms is challenging. Intra/extra-aneurysmal stent placement, the "waffle cone" technique, has the advantage of using a single stent to prevent coil herniation without the need to deliver the stent to the efferent vessel. The published data on the use of this technique is limited. We present our initial and follow-up experience with the waffle cone stent-assisted coiling (SAC) of aneurysms to evaluate the durability of the technique. We retrospectively identified ten consecutive patients who underwent SAC of an aneurysm using the waffle cone technique from July 2009 to March 2011. Clinical and angiographic outcomes after initial treatment and follow-up were evaluated. Raymond Class I or II occlusion of the aneurysm was achieved in all cases with the waffle cone technique. No intraoperative aneurysm rupture was noted. The parent arteries were patent at procedure completion. Clinical follow-up in nine patients (median 12.9 months) revealed no aneurysm rupture. Two patients had a transient embolic ischemic attack at 18 hours and three months after treatment, respectively. Catheter angiography or MRA at six-month follow-up demonstrated persistent occlusions of aneurysms in seven out of eight patients. Another patient had stable aneurysm occlusion at three-month follow-up study. Our experience in the small series suggests the waffle cone technique could be performed on complex, wide-necked aneurysms with relative safety, and it allowed satisfactory occlusions of the aneurysms at six months in most cases. PMID- 22440598 TI - Direct vertebral artery access for the endovascular treatment of basilar artery aneurysms. AB - The femoral approach has been considered the preferred technique for the endovascular treatment of intracranial aneurysms. Occasionally, aneurysms are not amenable to the standard femoral approach. We describe four cases of basilar artery aneurysm that were treated by the direct vertebral artery access of V1 at the cervical region. The direct vertebral artery access technique can provide an alternative route in selected cases for the treatment of basilar artery aneurysms. PMID- 22440599 TI - Persistent neurological deficit from iodinated contrast encephalopathy following intracranial aneurysm coiling. A case report and review of the literature. AB - Neurotoxicity from iodinated contrast agents is a known but rare complication of angiography and neurovascular intervention. Neurotoxicity results from contrast penetrating the blood-brain barrier with resultant cerebral oedema and altered neuronal excitability. Clinical effects include encephalopathy, seizures, cortical blindness and focal neurological deficits. Contrast induced encephalopathy is extensively reported as a transient and reversible phenomenon. We describe a patient with a persistent motor deficit due to an encephalopathy from iodinated contrast media administered during cerebral aneurysm coiling. This observation and a review of the literature highlights that contrast-induced encephalopathy may not always have a benign outcome and can cause permanent deficits. This potential harmful effect should be recognised by the angiographer and the interventionalist. PMID- 22440600 TI - Measurement of blood flow in arteriovenous malformations before and after embolization using arterial spin labeling. AB - The assessment of shunt reduction after an embolization of an arteriovenous malformation (AVM) or fistula (AVF) from conventional angiography is often difficult and may be subjective. Here we present a completely non-invasive method using magnetic resonance imaging (MRI) to measure shunt reduction. Using pulsed arterial spin labeling (PASL), we determined the relative amount of signal attributed to the shunt over 1.75 s and 6 different slices covering the lesion. This amount of signal from the shunt was related to the total signal from all slices and measured before and after embolization. The method showed a fair agreement between the PASL results and the judgement from conventional angiography. In the case of a total or subtotal shunt occlusion, PASL showed a shunt reduction between 69% and 92%, whereas in minimal shunt reduction as judged by conventional angiography, the ASL result was -6% (indicating slightly increased flow) to 35% in a partially occluded vein of Galen aneurysm. The PASL method proved to be fairly reproducible (up to 2% deviation between three measurements without interventions). On conclusion, PASL is able to reliably measure the amount of shunt reduction achieved by embolization of AVMs and AVFs. PMID- 22440601 TI - Life-threatening arteriovenous malformation of the maxillomandibular region and treatment outcomes. AB - We report on cases of life-threatening maxillomandibular arteriovenous malformations (AVM) whereby patients had successful endovascular treatment with good outcomes. Out of a total 93 facial AVMs treated endovascularly between 1991 and 2009, five patients (5.4%) had maxillomandibular AVMs. All presented with uncontrolled dental bleeding. Endovascular procedure was the primary treatment of choice in all cases, either transfemoral approach with arterial feeder embolization or transosseous puncture, depending on the accessible route in each patient. NBCA (glue) was the only embolic agent used. Tooth extraction and dental care were performed after bleeding was controlled. All five patients (8-18 years) with a mean age of 12.4 years presented with massive dental bleeding following loosening of teeth, dental extraction and/or cheek trauma. The plain films and CT scans of four patients with AVMs of mandibles and one of maxilla, revealed expansile osteolytic lesions. The mean follow-up period was 6.6 years (ranging between one and 19 years). Three cases developed recurrent bleeding between two weeks to three months after first embolization, resulting from residual AVM and infection. Late complications occurred in two patients from chronic localized infection and osteonecrosis, which were successfully eradicated with antibiotic therapy and bony curettage. Complications occurring in two patients which included soft tissue infection, osteomyelitis and osteonecrosis were successfully treated with antibiotics, curettage and bone resection. No patient had a recurrence of bleeding after the disease had cured Initial glue embolization is recommended as the effective treatment of dental AVMs for emergent bleeding control, with the aim to complete eradicate the intraosseous venous pouches either by means of transarterial superselection or direct transosseous puncture. Patient care by a multidisciplinary team approach is important for sustained treatment results. PMID- 22440602 TI - Endovascular treatment of tentorial dural arteriovenous fistulae. AB - Tentorial dural arteriovenous fistula (DAVF) is a rare vascular disease, which accounts for less than 4% of all cases of intracranial DAVF. Because of the high risk of intracranial hemorrhage, patients with tentorial DAVF need aggressive treatment. Management approaches are still controversial, and endovascular treatment has emerged as an effective alternative. In the current work, we describe our experience with the endovascular approach in the treatment of these deep and complex DAVF of the tentorium. Eight patients were treated between January 2006 and July 2009. Six patients (75%) presented with intracranial hemorrhage related to the DAVF rupture. Four patients (50%) had subarachnoid bleeding and two had intraparenchymal hematoma. Endovascular treatment was performed via the transarterial route alone in five cases (62.5%), by the transvenous approach in two cases (25.0%) and in a combined procedure using both arterial and venous routes in one patient (12.5%). Complete obliteration of the fistula was achieved in all cases. The outcome at 15 months was favorable (modified Rankin scale 0-3) in seven (87.5%) patients. Complete cure of the lesion was confirmed in these cases. This paper reports on the effectiveness of endovascular treatment in tentorial DAVF management. The choice of the venous versus the arterial approach is determined by regarding different anatomical dispositions. PMID- 22440603 TI - Endovascular treatment of hemifacial spasm associated with a petrosal DAVF using transarterial Onyx embolization. A case report. AB - This paper reports that decompression of the facial nerve by transarterial Onyx embolization may relieve hemifacial spasm (HFS) caused by dilated veins due to a right petrosal dural arteriovenous fistula (DAVF). A 56-year-old man suffered severe chronic right HFS associated with a dilated right petrosal vein lying in the vicinity of the facial nerve. The right petrosal DAVF was reached through the middle meningeal artery using a transfemoral arterial approach and was occluded with Onyx 18 (M.T.I.- ev3, Irvine, CA, USA). There was complete remission of HFS without recurrence after two months of follow-up. This case supports vascular compression in the pathogenesis of HFS and suggests that facial nerve injury caused by a DAVF could be treated with transarterial Onyx embolization. PMID- 22440604 TI - Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. AB - Arterial dissections account for 2% of strokes in all age groups, and up to 25% in patients aged 45 years or younger. The safety of endovascular intervention in this patient population is not well characterized. We identified all patients in the Merci registry - a prospective, multi-center post-market database enrolling patients treated with the Merci Retriever thrombectomy device - with arterial dissection as the most likely stroke etiology. Stroke presentation and procedural details were obtained prospectively; data regarding procedural complications, intracerebral hemorrhage (ICH), and the use of stenting of the dissected artery were obtained retrospectively. Of 980 patients in the registry, ten were identified with arterial dissection (8/10 ICA; 2/10 vertebrobasilar). The median age was 48 years with a baseline NIH stroke scale score of 16 and median time to treatment of 4.9 h. The procedure resulted in thrombolysis in cerebral ischemia (TICI) scores of 2a or better in eight out of ten and TICI 2b or better in six out of ten patients. Stenting of the dissection was performed in four of nine (44%). The single complication (1/9; 11%) - extension of a dissected carotid artery - was treated effectively with stenting. No symptomatic ICH or stroke in a previously unaffected territory occurred. A favorable functional outcome was observed in eight out of ten patients. Despite severe strokes on presentation, high rates of recanalization (8/10) and favorable functional outcomes (8/10) were observed. These results suggest that mechanical thrombectomy in patients with acute stroke resulting from arterial dissection is feasible, safe, and may be associated with favorable functional outcomes. PMID- 22440605 TI - Balloon-expandable stent placement in patients with immediate reocclusion after initial successful thrombolysis of acute middle cerebral arterial obstruction. AB - We present the results of our approach for treating 12 consecutive cases of acute middle cerebral artery (MCA) stroke by performing balloon-expandable stent (BES) placement after immediate reocclusion due to the underlying stenosis after intra arterial thrombolysis (IAT). We retrospectively reviewed the clinical outcomes of 12 patients with acute MCA stroke who underwent recanalization by BES placement in an underlying stenosis after IAT. The time to treatment, urokinase dose, duration of the procedure, recanalization rates and symptomatic hemorrhage were analyzed. Clinical outcome measures were assessed on admission and at discharge (the National Institutes of Health stroke scores [NIHSS]) as well as three months after treatment (modified Rankin scales [mRS]). The median NIHSS score on admission was 8.6. Four patients received IV rtPA. The median time from symptom onset to IAT was 236 minutes and the median duration of IAT was 62 minutes. The median dose of urokinase was 140,000 units. Initial recanalization after stent deployment (thrombolysis in cerebral ischemia attack grade of II or III) was achieved in all patients. Two patients died in the hospital due to aspiration pneumonia during medical management. In two patients, in-stent reocclusion occurred within 48 hours after stent deployment. At discharge, the median NIHSS score in ten patients (including the patients with reobstruction) was 2.4. The three-month outcome was excellent (mRS, 0-1) in eight patients. In this study, BES deployment was safe and effective in patients with an immediately reoccluded MCA after successful IAT. PMID- 22440606 TI - Treatment of progressive cerebral sinuses thrombosis with local thrombolysis. AB - Cerebral venous thrombosis (CVT) is a potentially serious disease, with nonspecific clinical symptoms and an unpredictable outcome. Despite adequate anticoagulation, a patient's clinical condition can rapidly deteriorate. The aim of this study was to evaluate the efficacy of local thrombolysis in these patients. Consecutive patients with progressive cerebral venous thrombosis between October 2008 and January 2011 were enrolled prospectively. Progressive CVT was defined as the persistence of neurologic findings (headache, blurred vision, and visual field defects) despite at least four days (or 48 hours in patients with involvement of more than one sinus) on full anticoagulation therapy with heparin and development of focal neurologic deficits or cortical hemorrhage. We excluded patients with large hematomas and predisposing malignancies like leukemia. All patients underwent local thrombolysis with 30 mg recombinant tissue plasminogen activator (rtPA). Overall, 26 patients were enrolled with a mean age of 35.5 years (range 18 to 56 years). Six patients (23%) were male and twenty patients (77%) were female. The most common presenting feature was headache and the most common neurologic finding was papilledema, which was present in all patients. Eighty-five percent of women had a history of oral contraceptive pill consumption. Successful recanalization was achieved in all patients except one (96.2%). Neurological examinations and follow-up assessments were based on a modified Rankin scale (mRS). Favorable outcome and recovery was defined as a mRS score of 0-1. Follow-up assessments at the third week showed that 25 out of 26 recovered, with 18 having a mRS score of 0 and 7 with a mRS score of 1. There were no procedure-related neurological complications. Our results show that local thrombolysis is a safe and effective treatment modality for patients suffering from progressive CVT. PMID- 22440607 TI - A minimally invasive treatment for lumbar disc herniation: DiscoGel(r) chemonucleolysis in patients unresponsive to chemonucleolysis with oxygen-ozone. AB - A multitude of therapies is available to treat disc herniation, ranging from conservative methods (medication and physical therapy) to minimally invasive (percutaneous) treatments and surgery. O2-O3 chemonucleolysis (O2-O3 therapy) is one of the minimally invasive treatments with the best cost/benefit ratio and lowest complication rate. Another substance recently made available exploiting the chemical properties of pure ethanol is DiscoGel(r), a radiopaque gelified ethanol more viscous than absolute alcohol 8,9. The present study aimed to assess the therapeutic outcome of DiscoGel(r) chemonucleolysis in patients with lumbar disc herniation unresponsive to O2-O3 therapy. Thirty-two patients aged between 20 and 79 years were treated by DiscoGel(r) chemonucleolysis between December 2008 and January 2010. The treatment was successful (improvement in pain) in 24 out of 32 patients. DiscoGel(r) is safe and easy to handle and there were no complications related to product diffusivity outside the treatment site. The therapeutic success rate of DiscoGel(r) chemonucleolysis in patients unresponsive to O2-O3 therapy was satisfactory. Among other methods used to treat lumbar disc herniation, DiscoGel(r) chemonucleolysis can be deemed an intermediate procedure bridging conservative medical treatments and surgery. PMID- 22440608 TI - Bone healing using a bi-phasic ceramic bone substitute demonstrated in human vertebroplasty and with histology in a rabbit cancellous bone defect model. AB - A non-exothermic material that demonstrates clinical pain relief comparable to polymethylacrylate (PMMA) for vertebroplasty and promotes bone healing is desirable. The purpose of this investigation is to demonstrate clinical pain score improvement and bone healing following vertebroplasty with a novel bi phasic ceramic cement. Twenty patients were prospectively treated for compression fractures in a single center in the USA with the injectable bi-phasic ceramic bone substitute. Statistical comparison of pain scores was made during a 12 month follow-up retrospectively against a matched cohort of patients treated with PMMA vertebroplasty by the same neuroradiologist (HPH) in the same setting. The bone remodeling material was also evaluated with histology in a New Zealand white rabbit model. The bi-phasic material demonstrated a pre-operative mean VAS score of 8.5 (+/- 1.6) with a significant post-operative pain relief mean VAS score of 1.8 (+/- 2.5) after one week, which was maintained throughout the 12 month follow-up period. These data are in line with the pain scores for the PMMA treated cohort. CT scans six and 12 months after surgery with the bi-phasic cement showed healing of the osteoporotic fractures. In the rabbit model, histology with the study material showed evidence of incorporation, new bone growth and bone healing in a cancellous bone defect. Both the clinical results and the histologic evidence of bone healing and new bone growth support the application of this new bioinjectable material as an alternative to the use of PMMA for vertebroplasty. PMID- 22440610 TI - Involvement of intracellular oxidative stress-sensitive pathway in phloxine B induced photocytotoxicity in human T lymphocytic leukemia cells. AB - We investigated the molecular mechanisms underlying phloxine B (PhB)-induced photocytotoxicity in human T lymphocytic leukemia Jurkat cells. In addition to apoptosis-related biochemical events, photo-irradiated PhB generated intracellular reactive oxygen species (ROS), induced phosphorylation of c-Jun-N terminal kinase (JNK) in an oxidative stress-dependent manner and up-regulated the gene expression of interferon (IFN)-gamma, an inducer of diverse apoptosis related molecules in activated T cells. PhB-induced apoptosis was significantly inhibited by N-acetyl-l-cysteine, but not by catalase, indicating that ROS generation occurred intracellularly, and by SP600125 and AG490, specific inhibitors of JNK and IFN-gamma signaling, respectively, confirming their roles in the apoptotic pathway. IFN-gamma up-regulation was also inhibited by SP600125, indicating that it was downstream of JNK activation. These results suggest that PhB-induced apoptosis in Jurkat cells partially involves the intracellular oxidative stress-sensitive and T cell-specific IFN-gamma pathway. These data present a novel insight into the mechanisms of photocytotoxicity induced by artificial food colorants in human T lymphocytic leukemia cells. PMID- 22440611 TI - Reduced knee joint moment in ACL deficient patients at a cost of dynamic stability during landing. AB - The current study aimed to examine the effect of anterior cruciate ligament deficiency (ACLd) on joint kinetics and dynamic stability control after a single leg hop test (SLHT). Twelve unilateral ACLd patients and a control subject group (n=13) performed a SLHT over a given distance with both legs. The calculation of joint kinetics was done by means of a soft-tissue artifact optimized rigid full body model. Margin of stability (MoS) was quantified by the difference between the base of support and the extrapolated center of mass. During landing, the ACLd leg showed lower external knee flexion moments but demonstrated higher moments at the ankle and hip compared to controls (p<0.05). The main reason for the joint moment redistribution in the ACLd leg was a more anterior position of the ground reaction force (GRF) vector, which affected the moment arms of the GRF acting about the joints (p<0.05). For the ACLd leg, trunk angle was more flexed over the entire landing phase compared to controls (p<0.05) and we found a significant correlation between moment arms at the knee joint and trunk angle (r2 = 0.48;p<0.01). The consequence of this altered landing strategy in ACLd legs was a more anterior position of the center of mass reducing the MoS (p<0.05). The results illustrate the interaction between trunk angle, joint kinetics and dynamic stability during landing maneuvers and provide evidence of a feedforward adaptive adjustment in ACLd patients (i.e. more flexed trunk angle) aimed at reducing knee joint moments at the cost of dynamic stability control. PMID- 22440612 TI - Autophagy links inflammasomes to atherosclerotic progression. AB - We investigated the role of autophagy in atherosclerosis. During plaque formation in mice, autophagic markers colocalized predominantly with macrophages (mphi). Atherosclerotic aortas had elevated levels of p62, suggesting that dysfunctional autophagy is characteristic of plaques. To determine whether autophagy directly influences atherogenesis, we characterized Beclin-1 heterozygous-null and mphi specific ATG5-null (ATG5-mphiKO) mice, commonly used models of autophagy haploinsufficiency and deficiency, respectively. Haploinsufficent Beclin-1 mice had no atherosclerotic phenotype, but ATG5-mphiKO mice had increased plaques, suggesting an essential role for basal levels of autophagy in atheroprotection. Defective autophagy is associated with proatherogenic inflammasome activation. Classic inflammasome markers were robustly induced in ATG5-null mphi, especially when coincubated with cholesterol crystals. Moreover, cholesterol crystals appear to be increased in ATG5-mphiKO plaques, suggesting a potentially vicious cycle of crystal formation and inflammasome activation in autophagy-deficient plaques. These results show that autophagy becomes dysfunctional in atherosclerosis and its deficiency promotes atherosclerosis in part through inflammasome hyperactivation. PMID- 22440613 TI - Pedicled buccal fat pad in the management of oroantral fistula: a clinical study of 15 cases. AB - This study evaluated the long term effectiveness of pedicled buccal fat pad (BFP) with or without buccal advancement flap in the closure of oroantral fistula (OAF). A prospective clinical study involving 15 patients with chronic OAF was carried out. All cases were managed with pedicled BFP as the primary or secondary procedure. Cases with doubtful outcome were closed in two layers using BFP along with buccal advancement flap. Cases were followed for 3 months (1, 4, 8 and 12 weeks) to evaluate any postoperative complications such as wound dehiscence, necrosis or infection. Females (66.7%) in their third to fourth decade were commonly affected in the right posterior region (75%). Dental extraction (73.3%) followed by maxillofacial pathology was the most common causes for developing OAF. Only 2 of 15 cases were closed in two layers. Complete epithelialisation of all the cases was observed with no postoperative complications. Pedicled BFP is an effective and reliable flap for the repair of OAF. Cases of larger oral defects with doubtful outcome can be closed in two layers using BFP along with buccal advancement flap. PMID- 22440614 TI - Determination of a safety zone for transbuccal trocar placement: an anatomical study. AB - The identification of a safe and accurate technique for facial incisions for transbuccal approaches to the mandibular angle fractures remains a challenge. An alternative method of safely and accurately placing the buccal skin incision is described in this cadaveric study. Thirty-two dissections were performed on 16 bilateral embalmed adult cadaveric heads. In order to identify a safety zone for transbuccal trocar placement, a triangle shaped zone created by three lines was determined. The branches of the facial nerve in this zone were reflected by sharp and blunt dissections. Of 32 sides, marginal mandibular branch was encountered in 1 and marginal mandibular branch and buccal branch of the facial nerve were found in 2 of the predetermined triangle. In 29 of 32 specimens, the marginal mandibular branch was encountered out of the triangle and deep to the platysma muscles. The triangle determined in the present anatomosurgical study presents an easy identifiable and safe zone for trocar placement. PMID- 22440615 TI - Mechanistic classification of neural circuit dysfunctions: insights from neuroeconomics research in animals. AB - Many psychiatric conditions present complex behavioral symptoms, and the type and magnitude of underlying neural dysfunction may vary drastically. This review introduces a classification scheme for psychiatric symptoms, describing them in terms of the state of a dysfunctional neural circuit. We provide examples of two kinds of functional deficits: variance-shifted functionality, in which a damaged circuit continues to function albeit suboptimally, and state-shifted functionality, resulting in an absent or qualitatively different functional state. We discuss, from the perspective of neuroeconomics and related areas of behavioral investigation, three broad classes of commonly occurring symptoms in psychopathology based on selected studies of decision making in animals: temporal discounting, social preferences, and decision making under environmental volatility. We conclude that the proposed mechanistic categorization scheme offers promise for understanding neural circuit dysfunctions underlying psychopathology. PMID- 22440616 TI - Neural correlates of the formation and retention of cocaine-induced stimulus reward associations. AB - BACKGROUND: Cocaine can elicit drug-seeking behavior for drug-predicting stimuli, even after a single stimulus-cocaine pairing. Although orbitofrontal cortex is thought to be important during encoding and maintenance of stimulus-reward value, we still lack a comprehensive model of the neural circuitry underlying this cognitive process. METHODS: We studied the conditioned effects of cocaine with monkey functional magnetic resonance imaging and classical conditioning by pairing a visual shape (conditioning stimulus [CS+]) with a noncontingent cocaine infusion; a control stimulus was never paired. We correlated the behavioral preference of the monkey for the CS+, as measured offline, with the activity induced by the CS+ relative to the control stimulus as function of time. RESULTS: We observed that during formation of stimulus-cocaine associations strong CS+ induced functional magnetic resonance imaging activations emerged in frontal cortex that correlated significantly with behavioral CS+ preference. Afterward, CS+ preference correlated only with activity in early visual cortex. Control experiments suggest that these findings cannot be explained by increased familiarity for the CS+. CONCLUSIONS: Our findings suggest a complex interaction between frontal and occipital cortex during cocaine conditioning. Frontal cortex is important for establishing novel representations of stimulus valence when cocaine is used as reinforcer, whereas early visual cortex is involved in retaining these cocaine-stimulus associations. PMID- 22440617 TI - Habitual alcohol seeking: time course and the contribution of subregions of the dorsal striatum. AB - BACKGROUND: Addictions are defined by a loss of flexible control over behavior. The development of response habits might reflect early changes in behavioral control. The following experiments examined the flexibility of alcohol-seeking after different durations of self-administration training and tested the role of the dorsal striatum in the control of flexible and habitual alcohol self administration. METHODS: Rats were trained to lever-press to earn unsweetened ethanol (EtOH) (10%). The sensitivity of the lever-press response to devaluation was assessed by prefeeding the rats either EtOH or sucrose before an extinction test after different amounts of training (1, 2, 4, and 8 weeks). We subsequently tested the role of the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) in controlling alcohol seeking with reversible inactivation techniques (baclofen/muscimol: 1.0/.1 mmol/L, .3 MUL/side). RESULTS: We find that operant responding for EtOH early in training is goal-directed and reduced by devaluation, but after 8 weeks of daily operant training, control has shifted to a habit-based system no longer sensitive to devaluation. Furthermore, after relatively limited training, when responding is sensitive to devaluation, inactivation of the DMS greatly attenuates the alcohol-seeking response, whereas inactivation of the DLS is without effect. In contrast, responding that is insensitive to devaluation after 8 weeks of training becomes sensitive to devaluation after inactivation of the DLS but is unaffected by inactivation of the DMS. CONCLUSIONS: These experiments demonstrate that extended alcohol self administration produces habit-like responding and that response control shifts from the DMS to the DLS across the course of training. PMID- 22440619 TI - [Hydatic cyst of the fallopian tube]. AB - Hydatic cyst of the Fallopian tube is an exceptional localization, the diagnosis of which is frequently confirmed preoperatively. A 44-year-old woman was addressed for pelvic mass with fortuitous discovery. The diagnosis preoperatively confirmed by the extemporaneous histological study was hydatic cyst of the Fallopian tube. Salpingectomy was required. The pelvic hydatic cyst, particularly in the Fallopian tube, is a rare complaint. Clinics and biology were very important for diagnosis but only anatomopathology can confirm diagnosis of hydatic cyst. The treatment of Fallopian tube hydatic cyst is surgival and often radical (salpingectomy). PMID- 22440618 TI - Shining light on wakefulness and arousal. AB - Alterations in arousal states are associated with multiple neuropsychiatric disorders, including generalized anxiety disorders, addiction, schizophrenia, and depression. Therefore, elucidating the neurobiological mechanisms controlling the boundaries between arousal, hyperarousal, and hypoarousal is a crucial endeavor in biological psychiatry. Substantial research over several decades has identified distinct arousal-promoting neural populations in the brain; however, how these nuclei act individually and collectively to promote and maintain wakefulness and various arousal states is unknown. We have recently applied optogenetic technology to the repertoire of techniques used to study arousal. Here, we discuss the recent results of these experiments and propose future use of this approach as a way to understand the complex dynamics of neural circuits controlling arousal and arousal-related behaviors. PMID- 22440620 TI - Current opinion in virology: structural virology. PMID- 22440621 TI - Viral attachment strategies: the many faces of adenoviruses. AB - The engagement of a cell-surface receptor by a virus is the first step in a complex process that culminates in the infection of the cell. Human adenoviruses are important pathogens that, depending on serotype, can utilize an impressive number of cellular receptors for attachment. Several structures of adenovirus attachment proteins in complex with their cognate ligands have been determined, enhancing our understanding of the underlying molecular recognition processes. Moreover, two new receptors for adenoviruses have also recently been identified. Using adenoviruses as an example, we examine the different attachment strategies that highly similar viral proteins within a single virus family can employ to engage different protein and carbohydrate receptors. For many viruses, consequences of such differences are altered tropism and pathogenicity. A better understanding of the parameters that determine specificity will therefore help to establish links between receptor tropism, spread, and disease. Moreover, it has relevance for the design and use of adenovirus-based gene delivery vehicles with improved properties and for the development of new antiviral strategies. PMID- 22440622 TI - Double-stranded DNA viruses: 20 families and only five different architectural principles for virion assembly. AB - The number of viral particles in the biosphere is enormous. Virus classification helps to comprehend the virosphere and to understand the relationship between different virus groups. However, the evolutionary reach of the currently employed sequence-based approaches in virus taxonomy is rather limited, producing a fragmented view of the virosphere. As a result, viruses are currently classified into 87 different families. However, studies on virion architectures have unexpectedly revealed that their structural diversity is far more limited. Here we describe structures of the major capsid proteins of double-stranded DNA viruses infecting hosts residing in different domains of life. We note that viruses belonging to 20 different families fall into only five distinct structural groups, suggesting that optimal virus classification approach should equally rely on both sequence and structural information. PMID- 22440623 TI - Single-molecule studies of viral DNA packaging. AB - Assembly of many dsDNA viruses involves packaging of DNA molecules into pre assembled procapsids by portal molecular motor complexes. Techniques have recently been developed using optical tweezers to directly measure the packaging of single DNA molecules into single procapsids in real time and the forces generated by the molecular motor. Three different viruses, phages phi29, lambda, and T4, have been studied, revealing interesting similarities and differences in packaging dynamics. Single-molecule fluorescence methods have also been used to measure packaging kinetics and motor conformations. Here we review recent discoveries made using these new techniques. PMID- 22440624 TI - Design, synthesis, synergistic antimicrobial activity and cytotoxicity of 4-aryl substituted 3,4-dihydropyrimidinones of curcumin. AB - 3,4-Dihydropyrimidinones of curcumin were synthesized in excellent yield by multi component one-pot condensation of curcumin, substituted aromatic aldehydes and urea/thiourea under solvent free conditions using SnCl(2).2H(2)O catalyst. All the synthesized compounds have been characterized by IR, (1)H NMR, (13)C NMR, Mass spectra as well as elemental analyses. The synthesized compounds 4a-n were evaluated for their synergistic antimicrobial (antibacterial and antifungal) activity against bacteria and fungi. Zone of inhibition was measured by adopting disc diffusion method. In vitro minimum inhibitory concentrations were measured using broth microdilution and food poisoning method. In addition to this in vitro cytotoxicity of synthesized compounds against three human cancer lines Hep-G2, HCT-116 and QG-56 were also evaluated. Most of the compounds showed interesting antimicrobial and cytotoxic activity as compared to curcumin, that is, the compounds derived from 2-hydroxy benzaldehyde, 4-hydroxy benzaldehyde and 4 hydroxy-3-methoxy benzaldehyde showed the highest biological activity as compared to other compounds. PMID- 22440625 TI - Synthesis and evaluation of piperidine urea derivatives as efficacious 11beta hydroxysteroid dehydrogenase type 1 inhibitors in diabetic ob/ob mice. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention as a potential target for the treatment of diabetes and metabolic syndrome. Herein we report the design, synthesis and efficacy evaluation of novel amide and urea 11beta-HSD1 inhibitors. Structure-activity relationship studies led to the identification of 10c, which was efficacious in a diabetic ob/ob mouse model and reduced fasting and non-fasting blood glucose levels after ip dosing. PMID- 22440626 TI - Synthesis of highly potent novel anti-tubercular isoniazid analogues with preliminary pharmacokinetic evaluation. AB - Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3 yl) isonicotinamide (17) inhibited MTB with MIC of 0.12 MUM and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10 mg/kg body weight) in male Wistar rats viz. t(1/2), K(el), mean plasma clearance and mean volume of distribution were found to be 1.14+/ 0.20 h, 0.62+/-0.10 h(-1), 22.48+/-0.16 mL/kg/min and 1.99+/-0.49 L, respectively. The systemic absorption was slow after oral administration (50 mg/kg body weight). The peak plasma concentration was found to be 1.31+/-0.06 MUg/mL attained in 3 h. The bioavailability was found to be 16.7%. PMID- 22440627 TI - Design, synthesis and cytotoxic activities of novel hybrid compounds between 2 phenylbenzofuran and imidazole. AB - A series of novel hybrid compounds between 2-phenylbenzofuran and imidazole have been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that substitution of the imidazolyl-3-position with a naphthylacyl or bromophenacyl group, were vital for modulating cytotoxic activity. In particular, hybrid compound 15 was found to be the most potent compound against 4 strains human tumor cell lines and more active than cisplatin (DDP), and exhibited cytotoxic activity selectively against liver carcinoma (SMMC 7721). PMID- 22440628 TI - Structural polymorphism of human telomere G-quadruplex induced by a pyridyl carboxamide molecule. AB - In this work, we described a kinetically slow (hour-scale) but thermodynamically favored G-quadruplex conversion induced by a pyridyl carboxamide molecule. This slow transition was observed through CD spectra and gels, and its final stable parallel conformation was identified by 2-aminopurine experiments. Kinetic experiments indicated that this slow process was a first-order reaction, implying it was a unimolecular conversion. Quite distinctly from other reported ligand driven G-quadruplex conformation alteration, this slow conversion reveals a novel insight into G-quadruplex polymorphism, in accordance with the behavior of human telomere G-quadruplex in a molecular crowding environment in K(+) solution, further enriching the known structural polymorphism of human telomere DNA and providing new consideration for drug design based on G-quadruplexes. PMID- 22440630 TI - Factors affecting career choice among the next generation of academic vascular surgeons. AB - OBJECTIVE: Few studies have examined factors that influence an individual's decision to enter an academic medical career after residency training. We sought to evaluate whether sex, ethnicity, child care issues, and debt burden influenced residents' choice for a career in academic vascular surgery. METHODS: A 39-item Web survey, designed to elucidate which factors motivated residents to seek a career in academic vascular surgery, was sent to 295 vascular surgery residents currently enrolled in Accreditation Council on Graduate Medical Education accredited training programs. RESULTS: A total of 128 responses (43%) were received. Of these, 53% of respondents were white and 47% were nonwhite and 34 (27%) were women and 94 (73%) were men. Fifty-seven percent of minorities anticipate a career in academic vascular surgery. There were no statistical differences between sex and ethnicity for factors influencing career choice, including training paradigm, presence of a life partner or dependents, mentorship role, participation in research, service, and teaching, anticipated salary, and debt burden (P > .05). Seventy-seven percent of respondents carry significant debt; of those with debt, 81% owe >$100,000 and 40% owe >$200,000. Seventy-three percent of 0+5 trainees anticipated choosing an academic practice compared with 42% of 5+2 trainees (P < .01). Respondents planning an academic career cited procedural variation, breadth and depth of practice/tertiary referral experience, and research opportunities as the most important drivers of career choice. Income potential, strength of the job market, and child care needs were deemed less important. CONCLUSIONS: This study shows that academic vascular surgery is a popular career option for current vascular surgery trainees, especially those in 0+5 programs. Choosing a career in academic vascular surgery appears not to be influenced by sex, ethnicity, child care concerns, salary expectations, or debt burden, even though most trainees carry enormous debt. The data imply future academic vascular surgeons will likely have greater gender and ethnic variability than is currently seen. PMID- 22440631 TI - Treatment of acute iliofemoral deep vein thrombosis. AB - OBJECTIVE: The objective of this systematic review and meta-analysis was to compare the efficacy of three available treatments for acute iliofemoral deep vein thrombosis (DVT): systemic anticoagulation, surgical thrombectomy, and catheter-directed thrombolysis. METHODS: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, and Scopus) and sought additional references from experts. Eligible studies enrolled participants with acute iliofemoral DVT and measured the outcomes of interest. Reviewers working independently in duplicate extracted study characteristics, quality, and outcome data (death, pulmonary embolism, local complications, hemorrhagic complications, postthrombotic syndrome, pain, quality of life, and surrogate markers of venous function such as valve competence and patency). We pooled relative risks (RRs) from each study using the random effects model and estimated the 95% confidence intervals (CIs). Bayesian indirect comparison techniques were used to compare thrombectomy to catheter-directed thrombolysis. RESULTS: We found 15 unique studies that fulfilled eligibility criteria. When compared to systemic anticoagulation, thrombectomy was associated with a statistically significant reduction in the risk of developing postthrombotic syndrome (RR, 0.67; 95% CI, 0.52-0.87), venous reflux (RR, 0.68; 95% CI, 0.46-0.99), and a trend for reduction in the risk of venous obstruction (RR, 0.84; 95% CI, 0.60-1.19). When compared to systemic anticoagulation, pharmacologic catheter-directed thrombolysis was associated with statistically significant reduction in the risk of postthrombotic syndrome (RR, 0.19; 95% CI, 0.07-0.48), venous obstruction (RR, 0.38; 95% CI, 0.18-0.37), and a trend for reduction in the risk of venous reflux (RR, 0.39; 95% CI, 0.16-1.00). Overall, the quality of evidence was low; downgraded due to the observational nature of the majority of studies, lack of comparability of study cohorts at baseline, loss to follow-up, imprecision, and indirectness of outcomes (surrogacy). There were insufficient data to compare the outcomes of thrombectomy to catheter-directed thrombolysis. CONCLUSIONS: Low quality evidence suggests that surgical thrombectomy decreases the incidence of postthrombotic syndrome and venous reflux. Catheter-directed pharmacologic thrombolysis decreases the incidence of postthrombotic syndrome and venous obstruction. PMID- 22440632 TI - Nutritional quality and acceptability of a weekly vegetarian lunch in primary school canteens in Ghent, Belgium: 'Thursday Veggie Day'. AB - OBJECTIVES: To determine the nutritional adequacy and acceptability to children of vegetarian lunches served on 'Thursday Veggie Day' - a public health initiative in Ghent (Belgium) primary schools. DESIGN: A comparison of food leftovers from main courses on regular days and Thursdays was made using a visual plate waste method. The nutritional value of the vegetarian meat analogue and meat components of main courses served on five 'Thursday Veggie Days' and five comparable conventional main courses was evaluated using three criteria (maximum 30 % of energy from fat, maximum of one-third of fat as saturated fat and minimum 1.5 g of dietary fibre per 420 kJ). SETTING: Two canteens from primary schools in Ghent, Belgium, participating in the 'Thursday Veggie Day' campaign. SUBJECTS: Primary-school children aged between 6 and 12 years. RESULTS: In total, 1242 and 472 main course plate waste observations of conventional and vegetarian menus, respectively, were evaluated. There was no significant difference in plate waste between vegetarian (16.7 %) and conventional (17.3 %) main courses. Overall, the five vegetarian components were found to be nutritionally adequate with a mean score of 2.2 out of 3, compared with 0.4 for the meat component. However, three of the vegetarian components provided >30 % of energy from fat and, in one, the amount of saturated fat exceeded one-third of total fat. CONCLUSIONS: Vegetarian canteen meals offered as part of 'Thursday Veggie Day' appear to be nutritionally appropriate and as acceptable as conventional main courses to children in primary schools in Ghent. PMID- 22440633 TI - A dynamic contaminant fate model of organic compound: a case study of Nitrobenzene pollution in Songhua River, China. AB - A one-dimensional dynamic contaminant fate model, coupling kinematic wave flow option with advection-dispersion-reaction equation, has been applied to predict Nitrobenzene pollution emergency in Songhua River, China that occurred on November 13, 2005. The model includes kinetic processes including volatilization, photolysis and biodegradation, and diffusive mass exchange between water column and sediment layer as a function of particles settling and resuspension. Four kinds of quantitative statistical tests, namely Nash-Sutcliffe efficiency, percent bias, ratio of root-mean-square to the standard deviation of monitoring data and Theil's inequality coefficient, are adopted to evaluate model performance. The results generally show that the modeled and detected concentrations exhibit good consistency. Flow velocity in the river is most sensitive parameter to Nitrobenzene concentration in water column based on sensitivity analysis of input parameters. It indicates flow velocity has important impact on both distribution and variance of contaminant concentration. The model performs satisfactory for prediction of organic pollutant fate in Songhua River, with the ability to supply necessary information for pollution event control and early warning, which could be applied to similar long natural rivers. PMID- 22440634 TI - Arsenic methylation, GSTO1 polymorphisms, and metabolic syndrome in an arseniasis endemic area of southwestern Taiwan. AB - Previous studies have shown that hair arsenic (As) levels are associated with an increased prevalence of metabolic syndrome (MetS), which is a strong predictor for type 2 diabetes. The objective of this study was to evaluate whether urinary arsenic methylation is related to MetS in an arseniasis endemic area of southwestern Taiwan, taking genetic factors into account. Subjects were from a community-based cohort recruited in 1990 from three villages in Putai Township. In 2002-2003, we successfully followed 247 subjects and measured their urinary arsenic species including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the coding region polymorphisms of three genes known to involve in arsenic methylation. Results showed that subjects of MetS had a history of consuming well water of higher arsenic concentration as compared to those without MetS. We also found a significant association between urinary arsenic species and risk for MetS, where the odds ratio of MetS was increased with decreasing proportion of MMA and low rate of primary methylation (defined as MMA/inorganic As). The increased risk associated with low primary methylation rate was further modified by the GSTO1 A140D polymorphism, with the D allele carriers showing a slightly higher risk for MetS. Our results suggest that a low MMA% is associated with increased risk for MetS among As-exposed subjects and the genetic polymorphism of GSTO1, an enzyme responsible for the reduction of pentavalent arsenic species, may also play a modest modification role. PMID- 22440635 TI - Phytotoxicity of low-weight carboxylic acids. AB - Presence of low-weight carboxylic acids (LWCAs) can be the reason for phytotoxicity of green manures, treated bio-waste or digestates from biogas production applied to soils. As the phytotoxic concentrations of LWCA are poorly known, this work presents data on six acids (C(1)C(6): formic, acetic, propionic, butyric, valeric, and caproic). Phytotoxicity was measured in acute (72 or 120 h) and subchronic (21 d) assays for seed germination, seedling elongation, and plant growth for garden cress Lepidium sativum and ryegrass Lolium multiflorum. The dose-response relationship was modeled using Weibull model. Results showed a trend that toxicity of LWCA increases with the length of the carbon chain, formic acid (C(1)) being the least and caproic acid (C(6)) the most toxic. EC50 values in the acute seed germination of cress ranged between 1.9 and 4.2mM and for ryegrass between 1.8 and 6.4mM. In subchronic assays EC50 values for germination were in a range from 11 to 46mMkg(-1)dm for cress, and from 18 to 127 mM kg(-1) dm for ryegrass. EC50 values for early seedling growth of cress based on acute assays ranged from 0.7 to 2.3mM and that of ryegrass from 1.2 to 1.8mM. Range of EC50 values for shoot biomass of cress was between 8 and 40 mM kg(-1) dm and of ryegrass between 12 and 93 mM kg(-1) dm. PMID- 22440636 TI - Acute contact toxicity test of insecticides (Cipermetrina 25, Lorsban 48E, Thionex 35) on honeybees in the southwestern zone of Uruguay. AB - Glyphosate-resistant soybean cultivation is expanding rapidly in Uruguay, with its land area having increased by 95 times during the past 10 years. Because of the region's Neotropical conditions, insecticide use is required to ensure adequate soybean productivity. However, in areas shared by soybean crops and beekeepers - such as the southwestern zone of Uruguay (SWZU) - the use of insecticides can increase the risks of honeybee death and honey contamination. Uruguayan commercial and legal guidelines set out practices and field doses designed to prevent acute intoxication with insecticides. However, honeybees in the SWZU are predominantly a polyhybrid subspecies different from that used to set international reference values, and hence they may have a different acute toxicity response, thus rendering such precautions ineffective. The aim of this work was to assess the acute toxicity response of polyhybrid honeybees in the SWZU to cypermethrin (commercial formulation: Cipermetrina 25 Agrin(r)), chlorpyrifos (commercial formulation: Lorsban 48E(r)), and endosulfan (commercial formulation: Thionex 35(r)). Acute toxicity bioassays were conducted to determine the median lethal dose (LD(50)) of each insecticide for the honeybees. The results indicate that, compared with EU reference values, SWZU honeybees have a higher toxicological sensitivity to chlorpyrifos and endosulfan, and a lower toxicological sensitivity to cypermethrin, based on the commercial formulations tested. However, when these results were adjusted according to their field dose equivalents, only chlorpyrifos emerged as a potential problem for beekeeping, as the maximum recommended field dose of Lorsban 48E(r) for soybean crops in Uruguay is 23 times the corresponding LD(50) for honeybees in the SWZU. PMID- 22440637 TI - Quantitative analysis of perfluorinated chemicals in media for in vitro fertilization and related samples. AB - The actual standard in vitro fertilization (IVF) protocol recommends an overnight gamete co-incubation. All of the culture media used for human IVF are supplemented with serum or albumin. In the present study, we determined the concentrations of perfluorinated chemicals (PFCs) in IVF media (IVFM) and related samples by liquid chromatography with tandem mass spectrometry (LC/MS/MS). The results indicated that the concentrations of PFOS and PFOA in the protein source were higher than those in the IVFM samples. Compared with human plasma concentrations of PFCs, PFCs in all of the IVFM samples, such as PFBS, PFHxS and PFOA, were either not detected or present at only trace levels, even when protein source was added. LC/MS/MS could be used to determine PFCs in IVFM samples in future studies of the effects of PFC exposure on intrauterine insemination. PMID- 22440638 TI - The electronic properties of trimethylnaphthalenes as properties for the prediction of biodegradation rates: ab initio and DFT study. AB - There is little information on trimethylnaphthalenes (TMNs) which are constituents of diesel fuel and bitumen emissions. In this study, a theoretical investigation of the electronic properties of all trimethylnaphthalene (TMN) isomers and their relation to biodegradation are presented. Equilibrium geometries, ionization potentials (IPs), electron affinities (EAs), dipole moments and electronic dipole polarizabilities of TMN isomers calculated by ab initio and Density Functional Theory (DFT) methods are reported. Polarizability and dipole moment computations have been performed in gas and in water solution using the polarizable continuum model (PCM). The results obtained show that the IP value varies little along the series of isomers while averaged static dipole polarizabilities () increase on passing from alpha,alpha,alpha-TMN to beta,beta,beta-TMN isomers. This indicates that the binding affinity between TMNs and active site of bacterial enzymes is mainly determined by dispersive and inductive effects. Therefore, the computed polarizability values of TMNs can be used as predictors of the rates of biodegradation of TMNs. PMID- 22440639 TI - Chlorpyrifos degradation in a biomixture of biobed at different maturity stages. AB - The biomixture is a principal element controlling the degradation efficacy of the biobed. The maturity of the biomixture used in the biobed affects its overall performance of the biobed, but this is not well studied yet. The aim of this research was to evaluate the effect of using a typical composition of Swedish biomixture at different maturity stages on the degradation of chlorpyrifos. Tests were made using biomixture at three maturity stages: 0 d (BC0), 15 d (BC15) and 30 d (BC30); chlorpyrifos was added to the biobeds at final concentration of 200, 320 and 480 mg kg(-1). Chlorpyrifos degradation in the biomixture was monitored over time. Formation of TCP (3,5,6-trichloro-2-pyrinidol) was also quantified, and hydrolytic and phenoloxidase activities measured. The biomixture efficiently degraded chlorpyrifos (degradation efficiency >50%) in all the evaluated maturity stages. However, chlorpyrifos degradation decreased with increasing concentrations of the pesticide. TCP formation occurred in all biomixtures, but a major accumulation was observed in BC30. Significant differences were found in both phenoloxidase and hydrolytic activities in the three maturity stages of biomixture evaluated. Also, these two biological activities were affected by the increase in pesticide concentration. In conclusion, our results demonstrated that chlorpyrifos can be degraded efficiently in all the evaluated maturity stages. PMID- 22440640 TI - Pump blood processing, salvage and re-transfusion improves hemoglobin levels after coronary artery bypass grafting, but affects coagulative and fibrinolytic systems. AB - Cell saving systems are commonly used during cardiac operations to improve hemoglobin levels and to reduce blood product requirements. We analyzed the effects of residual pump blood salvage through a cell saver on coagulation and fibrinolysis activation and on postoperative hemoglobin levels. Thirty-four elective coronary artery bypass graft (CABG) patients were randomized. In 17 patients, residual cardiopulmonary bypass (CPB) circuit blood was transfused after the cell saving procedure (cell salvage group). In the other 17 patients, residual CPB circuit blood was discarded (control group). Activation of the coagulative, fibrinolytic and inflammatory systems was evaluated pre-operatively (Pre), 2 hours after the termination of CPB (T0) and 24 hours postoperatively (T1), measuring prothrombin fragment 1.2 (PF 1.2), plasmin-anti-plasmin (PAP), plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6). The cell salvage group of patients had a significant improvement in hemoglobin levels after processed blood infusion (2.7 +/- 1.7 g/dL vs 1.2 +/- 1.1 g/dL; p=0.003). PF1.2 levels were significantly higher after infusion (T0: 1175 +/- 770 pmol/L vs 730 +/- 237 pmol/L; p=0.037; T1: 331 +/- 235 pmol/L vs 174 +/- 134 pmol/L; p=0.026). Also, PAP levels were higher in the cell salvage group, although not significantly (T0: 253 +/- 251 ng/mL vs 168 +/- 96 ng/mL; p: NS; T1: 95 +/- 60 ng/mL vs 53 +/- 32 ng/mL; p: NS). No differences were found for PAI-1, IL-6, heparin levels or for red blood cell (RBC) transfusions. The cell salvage group of patients had increased chest tube drainage (749 +/- 320 vs 592 +/- 264; p: NS) and fresh frozen plasma transfusion rate (5 (29%) pts vs 0 pts; p<0.04). Pump blood salvage with a cell saving system improved postoperative hemoglobin levels, but induced a strong thrombin generation, fibrinolysis activation and lower fibrinolysis inhibition. These conditions could generate a consumption coagulopathy. PMID- 22440641 TI - Do attentional biases for pain depend on threat value of pain and competing motivation toward non-pain goals? PMID- 22440643 TI - Subfields of the hippocampal formation at 7 T MRI: in vivo volumetric assessment. AB - Animal and human autopsy studies suggest that subfields of the hippocampal formation are differentially affected by neuropsychiatric diseases. Therefore, subfield volumes may be more sensitive to effects of disease processes. The few human studies that segmented subfields of the hippocampal formation in vivo either assessed the subfields only in the body of the hippocampus, assessed only three subfields, or did not take the differential angulation of the head of the hippocampus into account. We developed a protocol using 7 Tesla MRI with isotropic voxels to reliably delineate the entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, CA3, dentate gyrus (DG)&CA4 along the full-length of the hippocampus. Fourteen subjects (aged 54-74 years, 2 men and 12 women) were scanned with a 3D turbo spin echo (TSE) sequence with isotropic voxels of 0.7 * 0.7 * 0.7 mm(3) on a 7 T MRI whole body scanner. Based on previous protocols and extensive anatomic atlases, a new protocol for segmentation of subfields of the hippocampal formation was formulated. ERC, SUB, CA1, CA2, CA3 and DG&CA4 were manually segmented twice by one rater from coronal MR images. Good-to-excellent consistency was found for all subfields (Intraclass Correlation Coefficient's (ICC) varying from 0.74 to 0.98). Accuracy as measured with the Dice Similarity Index (DSI) was above 0.82 for all subfields, with the exception of the smaller subfield CA3 (0.68-0.70). In conclusion, this study shows that it is possible to delineate the main subfields of the hippocampal formation along its full-length in vivo at 7 T MRI. Our data give evidence that this can be done in a reliable manner. Segmentation of subfields in the full-length of the hippocampus may bolster the study of the etiology neuropsychiatric diseases. PMID- 22440642 TI - Is optical imaging spectroscopy a viable measurement technique for the investigation of the negative BOLD phenomenon? A concurrent optical imaging spectroscopy and fMRI study at high field (7 T). AB - Traditionally functional magnetic resonance imaging (fMRI) has been used to map activity in the human brain by measuring increases in the Blood Oxygenation Level Dependent (BOLD) signal. Often accompanying positive BOLD fMRI signal changes are sustained negative signal changes. Previous studies investigating the neurovascular coupling mechanisms of the negative BOLD phenomenon have used concurrent 2D-optical imaging spectroscopy (2D-OIS) and electrophysiology (Boorman et al., 2010). These experiments suggested that the negative BOLD signal in response to whisker stimulation was a result of an increase in deoxy haemoglobin and reduced multi-unit activity in the deep cortical layers. However, Boorman et al. (2010) did not measure the BOLD and haemodynamic response concurrently and so could not quantitatively compare either the spatial maps or the 2D-OIS and fMRI time series directly. Furthermore their study utilised a homogeneous tissue model in which is predominantly sensitive to haemodynamic changes in more superficial layers. Here we test whether the 2D-OIS technique is appropriate for studies of negative BOLD. We used concurrent fMRI with 2D-OIS techniques for the investigation of the haemodynamics underlying the negative BOLD at 7 Tesla. We investigated whether optical methods could be used to accurately map and measure the negative BOLD phenomenon by using 2D-OIS haemodynamic data to derive predictions from a biophysical model of BOLD signal changes. We showed that despite the deep cortical origin of the negative BOLD response, if an appropriate heterogeneous tissue model is used in the spectroscopic analysis then 2D-OIS can be used to investigate the negative BOLD phenomenon. PMID- 22440644 TI - Inferring consistent functional interaction patterns from natural stimulus FMRI data. AB - There has been increasing interest in how the human brain responds to natural stimulus such as video watching in the neuroimaging field. Along this direction, this paper presents our effort in inferring consistent and reproducible functional interaction patterns under natural stimulus of video watching among known functional brain regions identified by task-based fMRI. Then, we applied and compared four statistical approaches, including Bayesian network modeling with searching algorithms: greedy equivalence search (GES), Peter and Clark (PC) analysis, independent multiple greedy equivalence search (IMaGES), and the commonly used Granger causality analysis (GCA), to infer consistent and reproducible functional interaction patterns among these brain regions. It is interesting that a number of reliable and consistent functional interaction patterns were identified by the GES, PC and IMaGES algorithms in different participating subjects when they watched multiple video shots of the same semantic category. These interaction patterns are meaningful given current neuroscience knowledge and are reasonably reproducible across different brains and video shots. In particular, these consistent functional interaction patterns are supported by structural connections derived from diffusion tensor imaging (DTI) data, suggesting the structural underpinnings of consistent functional interactions. Our work demonstrates that specific consistent patterns of functional interactions among relevant brain regions might reflect the brain's fundamental mechanisms of online processing and comprehension of video messages. PMID- 22440645 TI - Age-specific CT and MRI templates for spatial normalization. AB - Spatial normalization reshapes an individual's brain to match the shape and size of a template image. This is a crucial step required for group-level statistical analyses. The most popular standard templates are derived from MRI scans of young adults. We introduce specialized templates that allow normalization algorithms to be applied to stroke-aged populations. First, we developed a CT template: while this is the dominant modality for many clinical situations, there are no modern CT templates and popular algorithms fail to successfully normalize CT scans. Importantly, our template was based on healthy individuals with ages similar to what is commonly seen in stroke (mean 65 years old). This template allows studies where only CT scans are available. Second, we derived a MRI template that approximately matches the shape of our CT template as well as processing steps that aid the normalization of scans from older individuals (including lesion masking and the ability to generate high quality cortical renderings despite brain injury). The benefit of this strategy is that the resulting templates can be used in studies where mixed modalities are present. We have integrated these templates and processing algorithms into a simple SPM toolbox (http://www.mricro.com/clinical-toolbox/spm8-scripts). PMID- 22440646 TI - Brain activation during anticipation of interoceptive threat. AB - The current study investigated the neural networks activated during the anticipation of potentially threatening body symptoms evoked by a guided hyperventilation task in a group of participants reporting either high or low fear of unexplained somatic sensations. 15 subjects reporting high and 14 subjects reporting low fear of somatic symptoms first learned that one of two cues predicted the occurrence of a hyperventilation task reliably producing body symptoms in all participants that were rated as more intense and unpleasant in the high fear group. During anticipation of unpleasant symptoms, high fear participants reported more intense body symptoms and showed potentiation of the startle reflex. After this learning session, participants were taken into the fMRI where the same cues either predicted the occurrence of hyperventilation or normoventilation, although the task was never performed in the scanner. During anticipation of hyperventilation all participants showed an increased activation of anterior insula/orbitofrontal cortex and rostral parts of the dorsal anterior cingulate cortex/dorsomedial prefrontal cortex (dACC/dmPFC). Brain activation of high compared to low fear participants differed in two ways. First, high fear participants showed an overall stronger activation of this network during threat and safe conditions indexing stronger anxious apprehension during the entire context. Second, while low fear participants no longer responded with stronger activation to the threat cue after experiencing that the hyperventilation challenge did not follow this cue, high fear participants continued to show stronger activation of the network to this cue. Activation of the rostral dACC/dmPFC was significantly correlated with reported fear of somatic symptoms. These data demonstrate that anticipation of interoceptive threat activates the same network that has been found to be active during anticipation of exteroceptive threat cues. Thus, the current paradigm might provide an innovative method to study anxious apprehension and treatment effects in patients with panic disorder. PMID- 22440647 TI - Medial orbitofrontal cortex is associated with shifting decision thresholds in self-serving cognition. AB - Recent research has begun to identify neural regions associated with self-serving cognition, that is, the tendency to make claims that cast the self in an overly flattering light, yet little is known about the mechanisms supported by neural activation underlying self-serving cognition. One possibility suggested by current research is that MOFC, a region that shows reduced recruitment in relation to self-serving cognition, may support changes in the decision thresholds that influence whether information should be expressed in an evaluation. The current fMRI study addresses this question by combining a signal detection approach and a contextual manipulation that permits the measurement of changes in decision threshold. Participants evaluated their familiarity with blocks of existent and nonexistent information when they believed that self serving claims of knowledge could either be exposed (accountable condition) or not (unaccountable condition). When held accountable, participants tended to shift their decision thresholds in a conservative (i.e., less self-serving) direction and showed greater activation in orbitofrontal cortex (OFC), medial prefrontal cortex (MPFC) and dorsal anterior cingulate cortex (dACC). Furthermore, the extent to which participants adopted more conservative (i.e., less self-serving) decision thresholds as a function of context (i.e., accountability), the more they recruited MOFC activation. These findings refine current knowledge about the mechanisms performed by neural regions involved in self-serving cognition and suggest a role for MOFC in changing decision thresholds that influence whether information should be expressed in an evaluation. PMID- 22440648 TI - A convergent functional architecture of the insula emerges across imaging modalities. AB - Empirical evidence increasingly supports the hypothesis that patterns of intrinsic functional connectivity (iFC) are sculpted by a history of evoked coactivation within distinct neuronal networks. This, together with evidence of strong correspondence among the networks defined by iFC and those delineated using a variety of other neuroimaging techniques, suggests a fundamental brain architecture detectable across multiple functional and structural imaging modalities. Here, we leverage this insight to examine the functional organization of the human insula. We parcellated the insula on the basis of three distinct neuroimaging modalities - task-evoked coactivation, intrinsic (i.e., task independent) functional connectivity, and gray matter structural covariance. Clustering of these three different covariance-based measures revealed a convergent elemental organization of the insula that likely reflects a fundamental brain architecture governing both brain structure and function at multiple spatial scales. While not constrained to be hierarchical, our parcellation revealed a pseudo-hierarchical, multiscale organization that was consistent with previous clustering and meta-analytic studies of the insula. Finally, meta-analytic examination of the cognitive and behavioral domains associated with each of the insular clusters obtained elucidated the broad functional dissociations likely underlying the topography observed. To facilitate future investigations of insula function across healthy and pathological states, the insular parcels have been made freely available for download via http://fcon_1000.projects.nitrc.org, along with the analytic scripts used to perform the parcellations. PMID- 22440649 TI - Concurrent fNIRS and fMRI processing allows independent visualization of the propagation of pressure waves and bulk blood flow in the cerebral vasculature. AB - Blood Oxygen Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) measures changes in blood oxygenation, which is affected by physiological processes, including cardiac pulsation, breathing, and low frequency oscillations (LFO). It is challenging to identify spatial and temporal effects of these processes on the BOLD signal because the low sampling rate of BOLD leads to aliasing of higher frequency physiological signal components. In this study, we used concurrent functional near infrared spectroscopy (fNIRS) and fMRI on 6 subjects during a resting state scan. To reduce aliasing, the BOLD fMRI acquisition was repeatedly performed on a set of sequentially acquired slice stacks to lower the TR to 0.5s while retaining high spatial resolution. Regressor interpolation at progressive time delays (RIPTiDe) method was used, in which physiological signal acquired by fNIRS (without aliasing) and its temporal shifts were used as regressors in the fMRI analysis to determine the magnitude and timing of the effects of various physiological processes on the BOLD signal. The details of the timing of the passage of the cardiac pulsation wave and of the cerebral blood itself were mapped. The result suggests that the cardiac signal affects the voxels near large blood vessels (arteries and veins) most strongly, while LFO mostly affected the drainage veins. We hypothesize that this could be the result of differences in the cerebral blood path lengths, and differences in the dynamics of the propagation of the signals. Together these results validate and extend a novel imaging technique to dynamically track the pulse-wave and bulk blood flow with concurrent fMRI and fNIRS. PMID- 22440651 TI - Steps toward optimizing motion artifact removal in functional connectivity MRI; a reply to Carp. PMID- 22440650 TI - Multifaceted genomic risk for brain function in schizophrenia. AB - Recently, deriving candidate endophenotypes from brain imaging data has become a valuable approach to study genetic influences on schizophrenia (SZ), whose pathophysiology remains unclear. In this work we utilized a multivariate approach, parallel independent component analysis, to identify genomic risk components associated with brain function abnormalities in SZ. 5157 candidate single nucleotide polymorphisms (SNPs) were derived from genome-wide array based on their possible connections with SZ and further investigated for their associations with brain activations captured with functional magnetic resonance imaging (fMRI) during a sensorimotor task. Using data from 92 SZ patients and 116 healthy controls, we detected a significant correlation (r=0.29; p=2.41 * 10(-5)) between one fMRI component and one SNP component, both of which significantly differentiated patients from controls. The fMRI component mainly consisted of precentral and postcentral gyri, the major activated regions in the motor task. On average, higher activation in these regions was observed in participants with higher loadings of the linked SNP component, predominantly contributed to by 253 SNPs. 138 identified SNPs were from known coding regions of 100 unique genes. 31 identified SNPs did not differ between groups, but moderately correlated with some other group-discriminating SNPs, indicating interactions among alleles contributing toward elevated SZ susceptibility. The genes associated with the identified SNPs participated in four neurotransmitter pathways: GABA receptor signaling, dopamine receptor signaling, neuregulin signaling and glutamate receptor signaling. In summary, our work provides further evidence for the complexity of genomic risk to the functional brain abnormality in SZ and suggests a pathological role of interactions between SNPs, genes and multiple neurotransmitter pathways. PMID- 22440652 TI - Social grasping: from mirroring to mentalizing. AB - Because the way we grasp an object varies depending on the intention with which the object is grasped, monitoring the properties of prehensile movements may provide access to a person's intention. Here we investigate the role of visual kinematics in the implicit coding of intention, by using functional brain imaging while participants observed grasping movements performed with social versus individual intents. The results show that activation within the mirror system is stronger during the observation of socially intended movements relative to individual movements. Moreover, areas that form the mentalizing system are more active during social grasping movements. These findings demonstrate that, in the absence of context information, social information conveyed by action kinematics modulates intention processing, leading to a transition from mirroring to mentalizing. PMID- 22440653 TI - The behavioral significance of coherent resting-state oscillations after stroke. AB - Stroke lesions induce not only loss of local neural function, but disruptions in spatially distributed areas. However, it is unknown whether they affect the synchrony of electrical oscillations in neural networks and if changes in network coherence are associated with neurological deficits. This study assessed these questions in a population of patients with subacute, unilateral, ischemic stroke. Spontaneous cortical oscillations were reconstructed from high-resolution electroencephalograms (EEG) with adaptive spatial filters. Maps of functional connectivity (FC) between brain areas were created and correlated with patient performance in motor and cognitive scores. In comparison to age matched healthy controls, stroke patients showed a selective disruption of FC in the alpha frequency range. The spatial distribution of alpha band FC reflected the pattern of motor and cognitive deficits of the individual patient: network nodes that participate normally in the affected functions showed local decreases in FC with the rest of the brain. Interregional FC in the alpha band, but not in delta, theta, or beta frequencies, was highly correlated with motor and cognitive performance. In contrast, FC between contralesional areas and the rest of the brain was negatively associated with patient performance. Alpha oscillation synchrony at rest is a unique and specific marker of network function and linearly associated with behavioral performance. Maps of alpha synchrony computed from a single resting-state EEG recording provide a robust and convenient window into the functionality and organization of cortical networks with numerous potential applications. PMID- 22440654 TI - Multiple roles for executive control in belief-desire reasoning: distinct neural networks are recruited for self perspective inhibition and complexity of reasoning. AB - Belief-desire reasoning is a core component of 'Theory of Mind' (ToM), which can be used to explain and predict the behaviour of agents. Neuroimaging studies reliably identify a network of brain regions comprising a 'standard' network for ToM, including temporoparietal junction and medial prefrontal cortex. Whilst considerable experimental evidence suggests that executive control (EC) may support a functioning ToM, co-ordination of neural systems for ToM and EC is poorly understood. We report here use of a novel task in which psychologically relevant ToM parameters (true versus false belief; approach versus avoidance desire) were manipulated orthogonally. The valence of these parameters not only modulated brain activity in the 'standard' ToM network but also in EC regions. Varying the valence of both beliefs and desires recruits anterior cingulate cortex, suggesting a shared inhibitory component associated with negatively valenced mental state concepts. Varying the valence of beliefs additionally draws on ventrolateral prefrontal cortex, reflecting the need to inhibit self perspective. These data provide the first evidence that separate functional and neural systems for EC may be recruited in the service of different aspects of ToM. PMID- 22440655 TI - Antiangiogenic and antivascular effects of a recombinant tumstatin-derived peptide in a corneal neovascularization model. AB - Tumstatin, a cleavage fragment of collagen IV, is a potent endogenous inhibitor of angiogenesis. Tumstatin-derived peptide T8 possesses all angiostatic properties of full-length tumstatin and indirectly suppresses tumor growth. The potential of T8 to block pathological angiogenesis in the eye has not been explored yet. Here we assess antiangiogenic effects of a recombinant T8 peptide in rabbit corneal neovascularization models. The fusion protein consisting of T8 and thioredoxin was synthesized in a highly efficient Escherichia coli expression system, isolated using ion-exchange chromatography and cleaved with TEV (tobacco etch virus) protease. The target peptide was purified on an anion-exchange resin and by reversed phase high-performance liquid chromatography. The recombinant peptide suppressed the proliferation of basic fibroblast growth factor-induced SVEC-4-10 endothelial cells (simian virus 40-immortalized murine endothelial cells) and inhibited tube formation in these cells in a dose-dependent manner. In rabbit corneal neovascularization models T8 demonstrated the ability to prevent pathological angiogenesis (when injected simultaneously with the induction of neovascularization) and, moreover, to promote the regression of newly-formed blood vessels (when injected on day 8 after angiogenesis stimulation). Our results suggest that T8 may have a therapeutic potential in the treatment of ocular neovascular diseases. PMID- 22440656 TI - [Antiphospholipid syndrome]. PMID- 22440657 TI - [Clinical usefulness of the reticulocyte hemoglobin equivalent in chronic hemodialysis patients]. AB - BACKGROUND: Iron deficiency is the main cause of failure to respond to erythropoietin (EPO) in haemodialysis patients. Several laboratory tests to detect the deficiency, ferritin and transferrin saturation (TSat) are the most commonly used but its limitations in this patient population are necessary to find other parameters to improve the identification of iron-deficient state. OBJECTIVE: To evaluate the ability of Reticulocyte Hemoglobin Equivalent (RET-He) to predict iron deficiency, taking as a reference standard to the increase of hemoglobin in response to iron intake. MATERIALS AND METHODS: 44 patients on chronic hemodialysis and fixed-dose EPO received 400 mg of intravenous iron. Were measured Hb, Ret-He, IRF, and ferritin prior to iron administration. After 20 to 30 days of completion of loading the patients were classified as responders if hemoglobin increased by at least 0.8 g / L and non-responders if this increase did not occur. RESULT: 25 patients were responders, the ROC curves analysis showed the Ret-He with the largest AUC of 0.862 similar to the AUC of 0.833 that showed the IST, but the first is more sensitive (72% CI 95%: 51-88% vs 52% 95% CI 31-72%) and similar specificity (94.7% CI 95%: 74-100% vs 100% 95% CI 82-100%). Ferritin AUC was 0.772 and finally the IRF AUC was 0.7. The Ret-He, to a cutoff of 29.5 pg was the best combination of sensitivity and specificity (72 and 94.7 respectively), and the sensitivity of the combination Ret-He/IST rose to 80% specificity 94.7%. CONCLUSIONS: According to these results it could consider to Ret-He and the Ret-He/IST combination of clinical utility for the identification of the iron deficit in patients in chronic haemodialysis. PMID- 22440658 TI - [Future therapy in systemic lupus erythematosus]. PMID- 22440659 TI - [Diffuse plane xanthomatosis associated with haematologic disorder and solid tumor. Findings of an autopsy]. AB - Diffuse plane xanthomatosis associated with haematologic disorder and solid tumor. Findings of an autopsy. Diffuse plane xanthomatosis is an uncommon subtype of non-Langerhans histiocytosis. We report a case of a 78 year-old woman with a history of monoclonal gammopathy of undetermined significance and diffuse plane xanthomatosis since 1995. She consulted for malaise and died four days after admission. Autopsy was requested. Findings were diffuse plane xanthomatosis with extensive involvement of internal organs, lymphoplasmacytic lymphoma and cecal adenocarcinoma. Final event was acute bronchopneumonia. This entity is a subtype of histiocytosis. It affects skin and involves mucous membranes in 40% of the cases. Extracutaneous extension has been reported. It is usually associated with haematologic disorders. In this case, the patient had a lymphoplasmacytic lymphoma and colonic adenocarcinoma. We highlight the importance of recognition its association with monoclonal gammopathies and solid tumors in order to make a proper follow up of patients. PMID- 22440660 TI - [Thyroid Burkitt lymphoma]. PMID- 22440661 TI - [Evolution of lung transplant patient with autopsy results]. PMID- 22440662 TI - Advanced ultra high pressure liquid chromatography-tandem mass spectrometric methods for the screening of red wine anthocyanins and derived pigments. AB - Anthocyanins are responsible for the colour of red grapes and wine. In addition to their contribution to the sensory properties of wine, these compounds are also of interest due to their beneficial biological properties. Wine anthocyanins exhibit a large structural diversity due to variations in glycosylation and acylation patterns, which is further exacerbated by the diverse reactions involving grape-derived anthocyanins during wine ageing. Chromatographic as well as mass spectrometric resolution of wine anthocyanins is often precluded due to the complexity of these compounds. In this paper we report a rapid, high efficiency ultra high pressure liquid chromatography (UHPLC) procedure with tandem mass spectrometric (MS/MS) detection for the in-depth screening of wine pigments. Selective detection of wine anthocyanins and derived pigments was achieved utilizing MS/MS in neutral loss scanning mode to observe the loss of dehydrated sugar moieties. This facilitated tentative compound identification based on molar mass information as well as the structured elution order of these compounds. In a second experiment, product ion spectra were recorded to allow identification of the anthocyanidin base using characteristic fragmentation patterns. The proposed methodology therefore involves two analyses for the sensitive and accurate identification of anthocyanins and their derived products in red wines. Mass spectra of wine anthocyanins under high energy collision induced dissociation (CID) conditions are reported, some for the first time. Significantly, chemical alteration of anthocyanins during wine ageing results in an off-set of the predominant fragments for each anthocyanidin base, whilst maintaining similar relative intensities. This allows unambiguous assignment of the derived products of anthocyanidin-glycosides. Using this approach, a total of 121 anthocyanins and derived compounds were identified in wines based on their relative reversed phase elution order as well as mass spectral information. PMID- 22440663 TI - Trace determination of 13 haloacetamides in drinking water using liquid chromatography triple quadrupole mass spectrometry with atmospheric pressure chemical ionization. AB - The haloacetamides (HAcAms) are disinfection by-products (DBPs) in drinking water which are currently receiving increased scientific attention due to their elevated toxicity relative to regulated disinfection by-products. A simultaneous determination method of 13 HAcAms, combining solid-phase extraction (SPE) enrichment, liquid chromatographic (LC) separation, and triple quadrupole mass spectrometry (tqMS) detection with atmospheric pressure chemical ionization (APCI) using selective reaction monitoring in positive mode, was developed to measure HAcAms, including chlorinated, brominated, and iodinated analogs. Ammonium chloride and Oasis HLB were selected as the dechlorinating reagent and polymeric SPE sorbent of HAcAm samples. The used tqMS apparatus showed higher sensitivity for the studied HAcAms in the APCI mode than electrospray ionization. 13 HAcAms were separated by LC in 9.0 min, and the detection limits ranged from 7.6 to 19.7 ng/L. The SPE-LC/tqMS method was successfully applied to quantify 13 HAcAms in drinking water samples for the first time, and first indentified tribromoacetamide and chloroiodoacetamide as DBPs in drinking water. PMID- 22440664 TI - Rapid analysis of organochlorine and pyrethroid pesticides in tea samples by directly suspended droplet microextraction using a gas chromatography-electron capture detector. AB - A simple and efficient directly suspended droplet microextraction (DSDME) has been developed to extract and pre-concentrate organochlorine and pyrethrin pesticides from tea samples prior to analysis by a gas chromatography-electron capture detector (GC-ECD). The optimal experimental conditions of DSDME were: 100 MUL isooctane exposed for 15 min to 5 mL of the tea aqueous sample stirred at 1100 rpm. For most of the target analytes, the optimal pretreatment of DSDME processes led to no significant interference of tea matrices. The approach was applied to the determination of organochlorine and pyrethroid pesticides in tea samples, with a linearity range of 0.0005-2 MUg/mL. The relative recoveries of all the pesticides ranged between 80.0% and 120.8% with relative standard deviations (RSDs) in the range of 0.8-19.9% (n=5). The limits of detections (LODs) ranged between 0.04 and 1 MUg/L for all the target pesticides. PMID- 22440665 TI - Development of anion-exchange/reversed-phase high performance liquid chromatography-inductively coupled plasma-mass spectrometry methods for the speciation of bio-available iodine and bromine from edible seaweed. AB - Anion exchange high performance liquid chromatography hyphenated with inductively coupled plasma-mass spectrometry has been novelly applied to assess inorganic (iodide and iodate) and organic (3-iodotyrosine - MIT, and 3,5-diiodotyrosine - DIT) iodine species in a single chromatographic run. The optimized operating conditions (Dionex IonPac AS7, gradient elution with 175 mM ammonium nitrate plus 15% (v/v) methanol, pH 3.8, as a mobile phase and flow rates within the 0.5-1.5 mL min(-1) range) have also been used to perform inorganic bromine speciation analysis (bromide and bromate). The developed method has been applied for determining the bio-available contents of iodine and bromine species in dialyzates from edible seaweed. Reverse phase high performance liquid chromatography (Zorbax Eclipse XDB-C8, gradient elution with 0.2% (m/m) acetic acid, and 0.2% (m/m) acetic acid in methanol, as mobile phases, and a constant flow rate of 0.75 mL min(-1)) also hyphenated with inductively coupled plasma mass spectrometry was used to confirm the presence of organic iodine species (MIT and DIT) in the dialyzates. The verification of the presence of iodinated amino acids (MIT and DIT) in the extracts was also performed by reverse phase high performance liquid chromatography-electrospray ionization-mass spectrometry (LTQ Orbitrap). The developed methods have provided good repeatability (RSD values lower than 10% for both anion exchange and reverse phase separations) and analytical recoveries within the 90-105% range for all cases. The in vitro bio availability method consisted of a simulated gastric and an intestinal digestion/dialysis (10 kDa molecular weight cut-off - MWCO) two-stage procedure. Iodide and MIT were the main bio-available species quantified, whereas bromide was the major bromine species found in the extracts. PMID- 22440666 TI - Micellar electrokinetic chromatography of aromatic anions and non-ionic aromatic compounds with stepwise changes of the concentration of cetyltrimethylammonium chloride. AB - Micellar electrokinetic chromatography in which the concentration of cetyltrimetylammmonium chloride (CTAC) was sequentially changed in the separation system was investigated using 10 aromatic anions and 11 non-ionic aromatic compounds as model analytes. All separations were performed in the absence of electroosmotic flow (EOF), and thus, analytes were detected in the order of their strength of interaction with micelles in the system. In isocratic elutions without EOF, the model analytes could be separated better with lower concentrations of CTAC but migration times of the analytes possessing relatively higher polarities increased markedly, and thus, long analysis times were required. Therefore, we attempted to increase the concentration of CTAC during a single measurement to reduce the analysis time without hindering the resultant separation of analytes obtained with lower concentrations. Briefly, the present surfactant stepwise elution can be performed by a sequential increase in CTAC concentrations of the running solution in the anodic reservoir from 30 to 50mM for the anions and from 20 to 50 mM for the non-ionic compounds. Additionally, to perform expected gradient separations with good reproducibility, each running solution with a different CTAC concentration was treated with tetraethylammmonium chloride as an additive to adjust electric conductivities of each running solution to be equal. Under this condition, CTAC micelles of each zone of different CTAC concentrations would migrate with practically the same velocity. Consequently, by the present stepwise method, both the 10 anionic analytes and the 11 non-ionic analytes were well separated within reasonable periods which corresponded approximately to two-third and less than half of those by the isocratic elutions, respectively. PMID- 22440667 TI - Multiple, simultaneous, independent gradients for versatile multidimensional liquid chromatography. Part I: Theory. AB - The general method for constructing coupled dual gradients in liquid chromatography (LC) is to begin by filling a reservoir A with a solution of one mobile phase (MP) component at concentration [c(1)(A)] and a second MP component at concentration [c(2)(A)], followed by filling a reservoir B with a solution containing MP component one at concentration [c(1)(B)] and the second MP component at concentration [c(2)(B)]. In another scenario the reservoirs A and B are filled with solutions of only one MP component at different concentrations [c(1)(A)] and [c(1)(B)] and the two solutions are titrated to a different pH value: pH (A) for the reservoir A and pH (B) for the reservoir B respectively. In either case, mixing of flows from the two reservoirs varies the concentrations of the two MP components (MP solutes) or the concentration of one MP component and pH along a particular compositional curve producing an eluent with two compositionally coupled gradients. This is a kind of a two dimensional LC utilizing dual simultaneous dependent gradients (DSDGs) wherein two parameters affecting the binding free energy of an analyte to a stationary phase (SP) are being altered simultaneously. Such a DSDG suffers from a significant limitation in that the gradient concentration of the two solutes or the concentration of one MP component and the pH cannot be varied independently. The only way to attain an optimal multigradient LC system, that promises a remarkable increase in chromatographic resolution of complex analyte mixtures, is to uncouple the multiple (dual) gradients, making each independent of the other(s). In this paper the theory of uncoupling of n such gradients, n >= 2 is developed. It is shown that for n solutes 2(n) reservoirs are required in concert with an LC eluent delivery system capable of freely apportioning the flows among the reservoirs according to equations we develop here. We go on to predict a substantial increase in chromatographic resolution when applying dual simultaneous independent gradients (DSIGs) of salt and pH to fractionate difficult to separate proteins. This prediction is naturally explained by the electrostatic interaction theory of protein binding to an ion exchanger. In subsequent experimental papers it will be shown that the algorithms presented here properly instruct a quad pump HPLC system to produce well controlled independent simultaneous gradients of pH and non-buffering solutes with attendant significant gain in chromatographic resolution of complex mixtures of protein isoforms. PMID- 22440668 TI - Roux-en-Y gastric bypass as revisional procedure after gastric banding: leaving the band in place. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) are frequently used bariatric procedures. With both techniques, LAGB more than RYGB, failures occur. After years of experience with both techniques, we present a series of patients who underwent RYGB after failed LAGB. The band was kept in place. Our objective was to evaluate the safety and short term effectiveness of RYGB after failed LAGB, without removing the band. The setting was a large teaching hospital in Heerlen, The Netherlands. METHODS: We first retrospectively considered the efficacy and complication rate of adding an adjustable band to RYGB. This was safe and effective. The patients lost a median of 7.6 kg within a median period of 21 months. The complication rate was low. Observing the positive results in this group, we began to leave the band in place when converting patients from LAGB to RYGB. RESULTS: A total of 12 patients underwent revision of LAGB to RYGB. There was no mortality. The complication rate and severity were low. During a median period of 16 months, the patients lost a median of 23 kg or 8 points in the body mass index. Also, additional improvement in co-morbidities was observed. CONCLUSION: Our results suggest that performing RYGB after LAGB and leaving the band in place is feasible, safe, and effective in the short term. PMID- 22440670 TI - National prevalence of methicillin-resistant Staphylococcus aureus in inpatients at United States health care facilities, 2010. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) remains one of the most prevalent multidrug-resistant organisms causing health care-associated infections. Limited data are available about how the prevalence of MRSA has changed over the past several years and what MRSA prevention practices have been implemented since the 2006 Association for Professionals in Infection Control and Epidemiology, Inc, MRSA survey. METHODS: We conducted a national prevalence survey of MRSA colonization or infection in inpatients at US health care facilities. The survey was developed, received institutional review board approval, and then was distributed to all US Association for Professionals in Infection Control and Epidemiology, Inc, members. Members were asked to complete the survey on 1 day during the period August 1 to December 30, 2010, reporting the number of inpatients with MRSA infection or colonization and facility- and patient-specific information. RESULTS: Personnel at 590 facilities indicated a state and responded to the survey. All states were represented, except for Alaska and Washington, DC (mean, 12 facilities per state; range, 1-38). Respondents reported 4,476 MRSA-colonized/infected patients in 67,412 inpatients; the overall MRSA prevalence rate was 66.4 per 1,000 inpatients (25.3 infections and 41.1 colonizations per 1,000 inpatients). Active surveillance testing was conducted by 75.7% of the respondents; 39.6% used nonselective media, 37.2% used selective media, and 23.3% used polymerase chain reaction. Detailed data were provided on 3,176 MRSA-colonized/infected patients. Of those in whom colonization/infection status was reported (1,908/3,086 [61.8%] were MRSA colonized and 1,778/3,086 [38.2%] were MRSA infected), most MRSA-colonized or infected patients (78.3%) were detected within 48 hours of admission; the most common site of infection was skin and soft tissue (42.9%); and, using the Centers for Disease Control and Prevention's definitions, approximately 50% would be classified as health care associated infections. CONCLUSION: Our survey documents that the MRSA prevalence in 2010 is higher than that reported in our 2006 survey. However, the majority of facilities currently are performing active surveillance testing, and, compared with 2006, the rate of MRSA infection has decreased while the rate of MRSA colonization has increased. In addition, compared with 2006, the proportion of MRSA strains recovered from MRSA-colonized/infected patients that are health care associated strains has deceased, and community-associated strains have increased. PMID- 22440671 TI - Detection and analysis of Staphylococcus aureus isolates found in ambulances in the Chicago metropolitan area. AB - BACKGROUND: Given the frequency with which many different strains of Staphylococcus aureus are found in various prehospital settings, this study sought to characterize S aureus isolates taken from one such environment. The objectives were to determine the frequency of S aureus in front-line, advanced life support (ALS) ambulances throughout the Chicago metropolitan area, and to generate antibiograms (antibiotic resistance profiles) for each S aureus isolate using 8 clinically relevant antibiotics. METHODS: Samples were obtained from 26 sites in 71 ambulances from 34 different Chicago-area municipalities. Selected colonies that demonstrated a growth pattern consistent with that of S aureus were subjected to a latex agglutination test specific for S aureus. Antibiograms and genetic analyses were performed on all latex agglutination test-positive isolates. RESULTS: At least one S aureus isolate was found in approximately 69% of all ambulances in the study. Of all isolates detected, 77% showed resistance to at least one antibiotic, and 34% displayed resistance to 2 or more antibiotics. Some level of oxacillin resistance was found in 21% of isolates; however, only slightly more than half of these oxacillin-resistant isolates were found to carry the methicillin-resistant S aureus-specific SCCmec cassette. Some 12% of all isolates were ultimately determined to be methicillin-resistant S aureus, whereas the remaining 88% were methicillin-sensitive S aureus with varying antibiograms. CONCLUSIONS: Antibiotic resistance appears to be prevalent in S aureus isolates detected in Chicago area ALS ambulances. Given the ease with which S aureus can survive on inanimate surfaces and exchange antibiotic resistance elements, a conscientious approach to the application of existing cleaning techniques, especially in key ambulance sites, is needed. Future work will include further characterizing isolates using multiple techniques, as well as follow-up studies with interested municipalities. PMID- 22440672 TI - Methicillin-resistant Staphylococcus aureus infection transmission in dental health care settings: myths and facts. PMID- 22440674 TI - Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer's disease. AB - Amyloid plaques associated with Alzheimer's disease (AD) induce inflammatory responses associated with activated microglia and reactive astrocytes, which exacerbate neurodegeneration through release of inflammatory cytokines, reactive oxygen species, and other factors. Inflammation contributes to neurodegeneration at later stages of AD, but it may also play a role in early disease pathogenesis. We found that before plaque deposition, amyloid precursor protein (APP)/presenilin 1 (PSEN1) transgenic mice (PSAPP mice), a well-characterized model of AD, exhibit evidence of cerebrovascular inflammation. Expression of the endothelial cell-specific antigen MECA-32 (mouse endothelial cell antigen-32) was upregulated in the cerebrovasculature of young PSAPP mice (3 months old) and was similar to that observed in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis characterized by neuroinflammation. MECA-32 is normally expressed in central and peripheral vasculature throughout development, but expression in the cerebrovasculature is downregulated on establishment of the blood-brain barrier (BBB). However, CNS inflammation triggers re-expression of MECA-32 in compromised cerebrovasculature. Our study indicates that MECA-32 may be a robust marker of cerebrovascular inflammation and compromised BBB integrity, triggered by soluble amyloid-beta early in disease pathogenesis. PMID- 22440675 TI - The levels of water-soluble and triton-soluble Abeta are increased in Alzheimer's disease brain. AB - Although plaques composed of the amyloid beta-protein (Abeta) are considered a defining feature of Alzheimer's disease (AD), they are also found in cognitively normal individuals and extensive evidence suggests that non-plaque, water-soluble forms of Abeta may play a role in AD pathogenesis. However, the relationship between the levels of water-soluble Abeta and the clinical severity of disease has never been investigated. Here, we present results of a pilot study designed to examine the levels of water-soluble forms of Abeta in brains of individuals who died at clinically distinct stages of AD. Using a serial extraction method, we also investigated the levels of triton-soluble and formic acid-soluble Abeta. We found that water-soluble and detergent-soluble Abeta monomer and SDS-stable dimer were elevated in AD and that the levels of water soluble Abeta did not increase with plaque pathology. These results support the notion that both water- and detergent-soluble Abeta are important in AD and are not simply released from plaques by mechanical disruption. Moreover, the fact that the levels of water- and triton-soluble Abeta were similar in very mild/mild AD and moderate/severe AD suggests that once a certain level of these species is attained, further accumulation is not necessary for the disease to progress. Consequently, therapeutic targeting of water-soluble Abeta should best benefit individuals in earliest phases of the disease process. PMID- 22440676 TI - Docosahexaenoic acid and phosphatidylserine supplementations improve antioxidant activities and cognitive functions of the developing brain on pentylenetetrazol induced seizure model. AB - Epilepsy provoked by pentylenetetrazol (PTZ) is caused by an abnormal excitatory postsynaptic potential, which results in increased production of reactive oxygen species, and finally reducing cognitive functions. The objective of this study was to investigate the effects of dietary supplementation with DHA and PS, administered either alone or in combination, on oxidative stress and behavioral and cognitive spatial memory in neonatal rats with PTZ-induced epileptic seizure. In this study, rat pups received repetitive doses of PTZ for induction of epileptic seizure and docosahexaenoic acid (DHA, C22:6, n-3) and phosphatidylserine (PS) were orally administrated alone or together to the PTZ induced epileptic animals daily for 36 d. The spatial memory, nitric mono-oxide (NO) production, and enzymatic activities of superoxide dismutase (SOD) and catalase in brain and liver tissues were determined. PTZ administration significantly reduced the cell numbers in the hippocampus, shortened the escape latency in the safe target region, decreased activities of SOD and catalase, but increased NO content in both brain and liver tissues, while DHA and PS significantly extended the escape latency, reversed the oxidative parameters observed in the brain, and enhanced SOD activity in the liver. Dietary supplementation with DHA and PS may protect brain tissue from the oxidative stress caused by epileptic seizures and could serve to improve learning and memory ability in vivo. PMID- 22440677 TI - Network meta-analysis of margin threshold for women with ductal carcinoma in situ. AB - BACKGROUND: Negative margins are associated with reduced risk of ipsilateral breast tumor recurrence (IBTR) for women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS). However, there is no consensus about the best minimum margin width. METHODS: We searched the PubMed database for studies of DCIS published in English between January 1970 and July 2010 and examined the relationship between IBTR and margin status after BCS for DCIS. Women with DCIS were stratified into two groups, BCS with or without radiotherapy. We used frequentist and Bayesian approaches to estimate the odds ratios (OR) of IBTR for groups with negative margins and positive margins. We further examined specific margin thresholds using mixed treatment comparisons and meta-regression techniques. All statistical tests were two-sided. RESULTS: We identified 21 studies published in 24 articles. A total of 1066 IBTR events occurred in 7564 patients, including BCS alone (565 IBTR events in 3098 patients) and BCS with radiotherapy (501 IBTR events in 4466 patients). Compared with positive margins, negative margins were associated with reduced risk of IBTR in patients with radiotherapy (OR = 0.46, 95% credible interval [CrI] = 0.35 to 0.59), and in patients without radiotherapy (OR = 0.34, 95% CrI = 0.24 to 0.47). Compared with patients with positive margins, the risk of IBTR for patients with negative margins was smaller (negative margin >0 mm, OR = 0.45, 95% CrI = 0.38 to 0.53; >2 mm, OR = 0.38, 95% CrI = 0.28 to 0.51; >5 mm, OR = 0.55, 95% CrI = 0.15 to 1.30; and >10 mm, OR = 0.17, 95% CrI = 0.12 to 0.24). Compared with a negative margin greater than 2 mm, a negative margin of at least 10 mm was associated with a lower risk of IBTR (OR = 0.46, 95% CrI = 0.29 to 0.69). We found a probability of .96 that a negative margin threshold greater than 10 mm is the best option compared with other margin thresholds. CONCLUSIONS: Negative surgical margins should be obtained for DCIS patients after BCS regardless of radiotherapy. Within cosmetic constraint, surgeons should attempt to achieve negative margins as wide as possible in their first attempt. More studies are needed to understand whether margin thresholds greater than 10 mm are warranted. PMID- 22440678 TI - Biotech crops' seal of safety does not convince skeptics. PMID- 22440679 TI - Margins in ductal carcinoma in situ: is bigger really better? PMID- 22440681 TI - Too early to determine cancer risk from infertility treatments. PMID- 22440682 TI - New pain drugs in pipeline, but challenges to usage remain. PMID- 22440684 TI - Re: novel therapies for metastatic castrate-resistant prostate cancer. PMID- 22440685 TI - Efficacy and safety of single versus dual antiplatelet therapy for coiling of unruptured aneurysms. AB - BACKGROUND: Although the efficacy of antiplatelet therapy for coiling of unruptured cerebral aneurysms has been reported, regimens for this therapy are not yet well established. The aim of this retrospective study was to analyze correlations among the modes of antiplatelet use, aneurysmal configuration, coiling methods, and complications to elucidate the optimal antiplatelet therapy for coiling. METHODS: The study population comprised 154 patients with unruptured aneurysms who underwent coiling with antiplatelet therapy at our institution between 2001 and 2009. The patients were categorized by mode of antiplatelet therapy (single [n = 64] or dual [n = 90]), neck size (wide [n = 80] or narrow [n = 74]), and technique used (simple [n = 42] or adjunctive [n = 112]). The incidences of hemorrhagic/ischemic complications and abnormalities on postprocedural diffusion-weighted magnetic resonance imaging (DWI) in each group were statistically assessed. RESULTS: Hemorrhagic complications occurred in 1 case (1.5%) with single antiplatelet therapy and in 2 cases (2.2%) with dual antiplatelet therapy. Symptomatic ischemic complications occurred in 5 cases (7.8%) with single therapy and in 4 cases (4.4%) with dual therapy. Abnormalities were detected by DWI in 27 cases (42%) with single therapy and in 31 cases (34%) with dual therapy. No significant difference was found between modes of antiplatelet therapy even when the technique used was taken into account. In cases of wide neck, however, there were significant differences in the rate of symptomatic ischemic complications (single, 21.7%; dual, 3.5%; P = .014) and DWI abnormalities (single, 37.8%; dual, 20.9%; P = .048). CONCLUSION: Our data suggest that dual antiplatelet therapy may better prevent ischemic complications from coiling for wide-necked aneurysms compared with single antiplatelet therapy. PMID- 22440686 TI - Prevalence of prominent J waves in patients presenting with ventricular fibrillation without structural heart disease: a single-center study. AB - Association between sudden cardiac arrest and early repolarization (QRS slurring in the inferolateral leads) has drawn recent attention. We retrospectively assessed the prevalence of electrocardiographic J waves in 19 men aged 46.5+/ 13.7 years who, between 1979 and 2011, were resuscitated after cardiac arrest due to ventricular fibrillation. There was no structural heart disease in this group. The J wave is an elevation of the QRS-ST junction of at least 0.1mV from baseline in the inferior or lateral leads, manifested as QRS slurring or notching. Eleven patients (age, 37.3+/-13.9 years) showed J waves in the inferior leads (n=8) or in both the inferior and lateral leads (n=3). Brugada syndrome was diagnosed in 5 patients (age, 46.4+/-15.7 years). The QRS complex was normal in the remaining 3 patients (age, 44.3+/-9.5 years). Ventricular fibrillation was induced by programmed ventricular stimulation with up to 3 extrastimuli from the right ventricular apex or outflow tract in 7 of the 10 J-wave syndrome patients tested, in all 5 Brugada syndrome patients, and in all 3 patients with a normal electrocardiogram. There appears to be an increased prevalence of J-wave syndrome among patients with a history of idiopathic ventricular fibrillation. PMID- 22440687 TI - Young investigators stress alcohol-induced neuroadaptations in extended amygdala. PMID- 22440688 TI - Folate exacerbates the effects of ethanol on peripubertal mouse mammary gland development. AB - Alcohol consumption is linked with increased breast cancer risk in women, even at low levels of ingestion. The proposed mechanisms whereby ethanol exerts its effects include decreased folate levels resulting in diminished DNA synthesis and repair, and/or acetaldehyde-generated DNA damage. Based on these proposed mechanisms, we hypothesized that ethanol would have increased deleterious effects during periods of rapid mammary gland epithelial proliferation, such as peripuberty, and that folate deficiency alone might mimic and/or exacerbate the effects of ethanol. To test this hypothesis, weight-matched 28-35 day old CD2F1 female mice were pair-fed liquid diets +/-3.2% ethanol, +/-0.1% folate for 4 weeks. Folate status was confirmed by assay of liver and kidney tissues. In folate deficient mice, no significant ethanol-induced changes to the mammary gland were observed. Folate replete mice fed ethanol had an increased number of ducts per section, due to an increased number of terminal short branches. Serum estrogen levels were increased by ethanol, but only in folate replete mice. These results demonstrate that folate deficiency alone does not mimic the effects of ethanol, and that folate deficiency in the presence of ethanol blocks proliferative effects of ethanol on the mammary ductal tree. PMID- 22440689 TI - Neonatal screening for prenatal alcohol exposure: assessment of voluntary maternal participation in an open meconium screening program. AB - Meconium fatty acid ethyl esters (FAEEs) are validated biomarkers of fetal alcohol exposure. Meconium FAEE testing can potentially be used as a screen by health-care professionals to identify neonates at-risk for Fetal Alcohol Spectrum Disorder, thereby permitting diagnostic follow-up of these children and early intervention in those who develop disabilities. The purpose of this study was to assess whether women would willingly partake in a screening program of this nature. This was determined by launching a pilot screening program for prenatal alcohol exposure in a high-risk obstetric unit previously shown to have a high prevalence of FAEE-positive meconium via anonymous meconium testing. The program involved voluntary testing of meconium for FAEEs and long-term developmental follow-up of positive cases through an existing public health program. The participation rate in the screening program was significantly lower than when testing was conducted anonymously (78% vs. 95%, respectively; p < 0.05), and the positivity rate was 3% in contrast to 30% observed under anonymous conditions (p < 0.001). These low rates suggest that the majority of mothers who consumed alcohol in pregnancy refused to participate. We conclude that despite the potential benefits of such screening programs, maternal unwillingness to consent, likely due to fear, embarrassment, and guilt, may limit the effectiveness of meconium testing for population-based open screening, highlighting the need for public education and social marketing efforts for such programs to be of benefit. PMID- 22440690 TI - Recognized spontaneous abortion in mid-pregnancy and patterns of pregnancy alcohol use. AB - Alcohol consumption during pregnancy is one potential risk factor for spontaneous abortion (SAb). Prior research suggested that heavy drinking during pregnancy was associated with significantly increased rates of SAb, but results for lower levels of drinking have been inconsistent. We examined the association between different levels and patterns of prenatal alcohol consumption and SAb in a high risk inner-city sample. We hypothesized that higher levels, binge patterns, and more frequent drinking would be associated with increased rates of SAb. The quantity and frequency of self-reported peri-conceptional and repeated in pregnancy maternal drinking volumes per beverage type were assessed with semi structured interviews in a prospective subsample of 302 African-American mothers. Relations between various measures of prenatal alcohol exposure and SAb were assessed using logistic regression. After controlling for various potential confounders, there was a significant positive relation between average absolute alcohol use per day across pregnancy and SAb. Greater frequency of drinking episodes also predicted SAb: an average of even one day of drinking per week across pregnancy was associated with an increase in the incidence of SAb. However, contrary to our hypothesis, neither the amount of alcohol drunk per drinking day nor a measure of binge drinking was significantly related to SAb after controlling for confounders. Differences in when women who drank at risk levels initiated antenatal care may have under-estimated the impact of alcohol on SAb in this low-SES urban African-American sample. Some drinking measures averaged across pregnancy may have under-estimated consumption and overestimated risk of SAb, but other risk drinking measures that avoid this limitation show similar relations to SAb. Identifying fetal risk drinking in pregnant women is critical to increasing the effectiveness of interventions that reduce risk level alcohol consumption and protect from pregnancy loss. PMID- 22440691 TI - Effect of (L)-cysteine on acetaldehyde self-administration. AB - Acetaldehyde (ACD), the first metabolite of ethanol, has been implicated in several behavioural actions of alcohol, including its reinforcing effects. Recently, we reported that l-cysteine, a sequestrating agent of ACD, reduced oral ethanol self-administration and that ACD was orally self-administered. This study examined the effects of l-cysteine pre-treatment during the acquisition and maintenance phases of ACD (0.2%) self-administration as well as on the deprivation effect after ACD extinction and on a progressive ratio (PR) schedule of reinforcement. In a separate PR schedule of reinforcement, the effect of l cysteine was assessed on the break-point produced by ethanol (10%). Furthermore, we tested the effect of l-cysteine on saccharin (0.2%) reinforcement. Wistar rats were trained to self-administer ACD by nose poking on a fixed ratio (FR1) schedule in 30-min daily sessions. Responses on an active nose-poke caused delivery of ACD solution, whereas responses on an inactive nose-poke had no consequences. l-cysteine reduced the acquisition (40 mg/kg), the maintenance and the deprivation effect (100 mg/kg) of ACD self-administration. Furthermore, at the same dose, l-cysteine (120 mg/kg) decreased both ACD and ethanol break point. In addition, l-cysteine was unable to suppress the different responses for saccharin, suggesting that its effect did not relate to an unspecific decrease in a general motivational state. Compared to saline, l-cysteine did not modify responses on inactive nose-pokes, suggesting an absence of a non-specific behavioural activation. Taken together, these results could support the hypotheses that ACD possesses reinforcing properties and l-cysteine reduces motivation to self-administer ACD. PMID- 22440693 TI - Influence of chronic ethanol intake on mouse synaptosomal aspartyl aminopeptidase and aminopeptidase A: relationship with oxidative stress indicators. AB - Aminopeptidase A (APA) and aspartyl aminopeptidase (ASAP) not only act as neuromodulators in the regional brain renin-angiotensin system, but also release N-terminal acidic amino acids (glutamate and aspartate). The hyperexcitability of amino acid neurotransmitters is responsible for several neurodegenerative processes affecting the central nervous system. The purpose of the present work was to study the influence of chronic ethanol intake, a well known neurotoxic compound, on APA and ASAP activity under resting and K(+)-stimulated conditions at the synapse level. APA and ASAP activity were determined against glutamate- and aspartate-beta-naphthylamide respectively in mouse frontal cortex synaptosomes and in their incubation supernatant in a Ca(2+)-containing or Ca(2+) free artificial cerebrospinal fluid. The neurotoxic effects were analyzed by determining free radical generation, peroxidation of membrane lipids and the oxidation of synaptosomal proteins. In addition, the bioenergetic behavior of synaptosomes was analyzed under different experimental protocols. We obtained several modifications in oxidative stress parameters and a preferential inhibitor effect of chronic ethanol intake on APA and ASAP activities. Although previous in vitro studies failed to show signs of neurodegeneration, these in vivo modifications in oxidative stress parameters do not seem to be related to changes in APA and ASAP, invalidating the idea that an excess of free acidic amino acids released by APA and ASAP induces neurodegeneration. PMID- 22440692 TI - Ontogenetic differences in ethanol's motivational properties during infancy. AB - Pairing a conditioned stimulus (CS) with ethanol generally produces aversion for that CS in adult rodents. However, infant rats (PD1-PD3) exposed to ethanol demonstrate appetitive reinforcement to ethanol (Nizhnikov, Varlinskaya, Petrov, & Spear, 2006; Petrov, Varlinskaya, & Spear, 2003). This sensitivity to the appetitive properties of ethanol during infancy may be transient, as during the second postnatal week rat pups tend to exhibit conditioned aversions to flavors paired with ethanol. The present study examined changes in the motivation properties of ethanol through ontogeny and the neurobiology underlying these changes. Rat pups were exposed to a taste conditioning procedure on PD4 or PD12. Rat pups were intraorally infused with 2.5% of their body weight of saccharin solution (0.1%) and immediately after injected intraperitoneolly (i.p.) with one of six doses of ethanol (0.0-2.0 g/kg). A day later pups were given saccharine infusions and percent body weight gain was used as an index of ethanol's reinforcing effects. PD4 pups expressed appetitive reinforcement to ethanol, as indicated by greater saccharin intake, as compared to control counterparts and to the older PD12 pups. Subsequent experiments revealed that PD4 pups were less sensitive to the aversive properties of the drug than PD12 pups. The older pups found high doses of ethanol aversive while PD4 rat pups did not condition aversions to this dose of ethanol after a single trial. A similar pattern of results was observed between the low doses of ethanol and the highest doses of a kappa opioid agonist. The PD12 animals did not condition to the kappa opioid agonist, while the younger rats expressed an appetitive response. These results illustrate an ontogenetic change in the motivational properties of ethanol, with sensitivity to its appetitive properties declining and responsiveness to the aversive properties increasing with age during early infancy. PMID- 22440694 TI - Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma. AB - Fibroblast growth factor receptor 2 is a member of receptor tyrosine kinase family, and fibroblast growth factor receptor 2 gene amplification or missense mutation has been observed in various human cancers, including gastric carcinoma. Recent studies have shown that anti-fibroblast growth factor receptor 2 agents inhibit tumor progression in various human cancers, such as endometrial carcinoma and gastric carcinoma, which remains one of the most frequent causes of cancer related death worldwide. We considered that knowledge of the status of fibroblast growth factor receptor 2 gene amplification in gastric carcinoma might aid in targeted cancer therapy. In this study, fibroblast growth factor receptor 2 amplification status was evaluated by fluorescence in situ hybridization in 313 surgically resected gastric carcinoma tissues, and the results were validated by quantitative real-time polymerase chain reaction. In addition, potential associations between clinicopathologic parameters and the presence of fibroblast growth factor receptor 2 amplification were investigated, and survival analysis was performed. Of the 313 cases, 14 (4.5%) showed fibroblast growth factor receptor 2 amplification by fluorescence in situ hybridization. Fibroblast growth factor receptor 2 amplification was found to be associated with a higher pT stage (P = .023), higher pN stage (P = .038), and distant metastasis (P = .009) and to be significantly associated with lower cancer-specific survival by univariate analysis (P = .012). Gastric carcinoma with fibroblast growth factor receptor 2 amplification was found to be associated with advanced disease and a poor prognosis. We believe that the determination of fibroblast growth factor receptor 2 amplification status could allow the identification of a subset of cancers sensitive to targeted fibroblast growth factor receptor 2 inhibitor-based therapy. PMID- 22440695 TI - Inbred mouse strains and genetic stability: a review. AB - Inbred mice were essential animal models for scientific research during the 20th century and will contribute decisive results in the current and next centuries. Far from becoming an obsolete research tool, the generation of new inbred strains is continuing and such strains are being used in many research fields. However, their genetic properties have been overlooked for decades, although recent research has revealed new insights into their genetic fragility and relative instability. Contrary to what we usually assume, inbred mice are far from being completely isogenic and both single-gene major mutations and polygenic mutational variability are continuously uploading into inbred populations as new sources of genetic polymorphisms. Note that several inbred strains from new major mutations are released every year, whereas small mutations can accumulate up to accounting for a significant percentage of the phenotypic variance (e.g. 4.5% in a recent study on C57BL/6J mice). Moreover, this genetic heterogeneity can be maintained for several generations by heterozygote selection and, if fixed instead of dropping off, genetic drift must be anticipated. The contribution of accidental genetic contamination in inbred strains must also be considered, although its incidence in current breeding stocks should be minimal, or even negligible. This review revisits several relevant topics for current inbred strains, discussing the latest cutting-edge results within the context of the genetic homogeneity and stability of laboratory mice. Inbred mice can no longer be considered as completely isogenic, but provide a remarkably homogeneous animal model with an inevitable moderate-to-low degree of genetic variability. Despite a certain degree of genetic heterogeneity becoming inescapable, inbred mice still provide very useful animal models with evident advantages when compared with outbred, that is, highly variable, populations. PMID- 22440696 TI - Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes. AB - Massese is an Italian dairy sheep breed characterized by animals with black skin and horns and black or apparent grey hairs. Owing to the presence of these two coat colour types, this breed can be considered an interesting model to evaluate the effects of coat colour gene polymorphisms on this phenotypic trait. Two main loci have been already shown to affect coat colour in sheep: Agouti and Extension coding for the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes, respectively. The Agouti locus is affected by a large duplication including the ASIP gene that may determine the Agouti white and tan allele (A(Wt)). Other disrupting or partially inactivating mutations have been identified in exon 2 (a deletion of 5 bp, D(5); and a deletion of 9 bp, D(9)) and in exon 4 (g.5172T>A, p.C126S) of the ASIP gene. Three missense mutations in the sheep MC1R gene cause the dominant black E(D) allele (p.M73K and p.D121N) and the putative recessive e allele (p.R67C). Here, we analysed these ASIP and MC1R mutations in 161 Massese sheep collected from four flocks. The presence of one duplicated copy allele including the ASIP gene was associated with grey coat colour (P = 9.4E-30). Almost all animals with a duplicated copy allele (37 out of 41) showed uniform apparent grey hair and almost all animals without a duplicated allele (117 out of 120) were completely black. Different forms of duplicated alleles were identified in Massese sheep including, in almost all cases, copies with exon 2 disrupting or partially inactivating mutations making these alleles different from the A(Wt) allele. A few exceptions were observed in the association between ASIP polymorphisms and coat colour: three grey sheep did not carry any duplicated copy allele and four black animals carried a duplicated copy allele. Of the latter four sheep, two carried the E(D) allele of the MC1R gene that may be the cause of their black coat colour. The coat colour of all other black animals may be determined by non-functional ASIP alleles (non-agouti alleles, A(a)) and in a few cases by the E(D) Extension allele. At least three frequent ASIP haplotypes ([D(5):g.5172T], [N:g.5172A] and [D(5):g.5172A]) were detected (organized into six different diplotypes). In conclusion, the results indicated that coat colours in the Massese sheep breed are mainly derived by combining ASIP and MC1R mutations. PMID- 22440697 TI - Complete sequence of the Tibetan Mastiff mitochondrial genome and its phylogenetic relationship with other Canids ( Canis, Canidae). AB - In this study, the complete sequence of the Tibetan Mastiff mitochondrial genome (mtDNA) was determined, and the phylogenetic relationships between the Tibetan Mastiff and other species of Canidae were analyzed using the coyote (Canis latrans) as an outgroup. The complete nucleotide sequence of the Tibetan Mastiff mtDNA was 16 710 bp, and included 22 tRNA genes, 2S rRNA gene, 13 protein-coding genes and one non-coding region (D-loop region), which is similar to other mammalian mitochondrial genomes. The characteristics of the protein-coding genes, non-coding region, tRNA and rRNA genes among Canidae were analyzed in detail. Neighbor-joining and maximum-parsimony trees of Canids constructed using 12 mitochondrial protein-coding genes showed that as the coyotes and Tibetan wolves clustered together, so too did the gray wolves and domestic dogs, suggesting that the Tibetan Mastiff originated from the gray wolf as did other domestic dogs. Domestic dogs clustered into four clades, implying at least four maternal origins (A to D). The Tibetan Mastiff, which belongs to clade A, appears to be closely related to the Saint Bernard and the Old English Sheepdog. PMID- 22440698 TI - Genetic relationship between milk urea nitrogen and reproductive performance in Holstein dairy cows. AB - The objective of this study was to describe the genetic and phenotypic relationship between milk urea nitrogen (MUN) and reproductive traits in Iranian Holstein dairy cows. Test-day MUN data obtained from 57 301 dairy cows on 20 large dairy herds in Iran between January 2005 and June 2009. Genetic parameters for MUN and reproductive traits were estimated with a five-trait model using ASREML program. Random regression test-day models were used to estimate heritabilities separately for MUN from first, second and third lactations. Regression curves were modeled using Legendre polynomials of order 3. Herd-year season along with age at calving was included as fixed effects in all models for reproductive traits. Heritabilities for MUN and reproductive traits were estimated separately for first lactation, second lactation and third lactation. The estimated heritabilities for MUN varied from 0.18 to 0.22. The heritability estimate was low for reproductive traits, which ranged from 0.02 to 0.06 for different traits and across parities. Except for days open, phenotypic and genetic correlations of MUN with reproductive performance traits were close to zero. Genetic correlations between MUN and days open were 0.23, 0.35 and 0.45 in first, second and third lactation, respectively. However, the phenotypic correlation between MUN at different parities was moderate (0.28 to 0.35), but the genetic correlation between MUN at different parities was high and ranged from 0.84 to 0.97. This study shows a limited application of MUN for use in selection programs to improve reproductive performance. PMID- 22440699 TI - Estimation of economic values and financial losses associated with clinical mastitis and somatic cell score in Holstein dairy cattle. AB - The objective of this study was to develop a method for calculating economic values of clinical mastitis (CM) and somatic cell score (SCS) for inclusion in a dairy cattle breeding goal in the context of a country where farm production and economic data are scarce. In order to calculate the costs and derive economic values for SCS, a new model, 'milk collection method', has been developed and was compared with the Meijering model with individual and average SCS distributions. For the population, estimated economic values using the milk collection method were 1.3 and 2.4 times higher than those of Meijering method with average and individual SCS, respectively. The milk collection method needs no assumptions about normality of the distribution of SCS and because of a lack of normality in Iranian data for SCS, the Meijering method resulted in economic values that were biased downwards. Failing to account for the fact that milk price penalties for SCS are applied at milk collection rather than individual cow level resulted in a further large downward bias in the economic value of SCS. When the distribution of data is unknown or difficult to approximate or when a transformation to normality is not straightforward, the milk collection method would be preferable. Inclusion of SCS and CM in the breeding goal for Iranian dairy cattle is justified based on these results. The model to calculate mastitis costs proposed here could be used to estimate economic values for CM in other developing countries where farm production and economic data are generally poor. PMID- 22440700 TI - Estimating myostatin gene effect on milk performance traits using estimated gene content for a large number of non-genotyped cows. AB - The objective of this study was to estimate the myostatin (mh) gene's effect on milk, protein and fat yield in a large heterogeneous cow population, of which only a small portion was genotyped. For this purpose, a total of 13 992 889 test day records derived from 799 778 cows were available. The mh gene effect was estimated via BLUP using a multi-lactation, multi-trait random regression test day model with an additional fixed regression on mh gene content. As only 1416 animals, (of which 1183 cows had test-day records) were genotyped, more animals of additional breeds with assumed known genotype were added to estimate the genotype (gene content) of the remaining cows more reliably. This was carried out using the conventional pedigree information between genotyped animals and their non-genotyped relatives. Applying this rule, mean estimated gene content over all cows with test-day records was 0.104, showing that most cows were homozygous +/+. In contrast, when gene content estimation was only based on genotyped animals, mean estimated gene content over all cows with test-day records was with 1.349 overestimated. Therefore, the applied method for gene content estimation in large populations needs additional genotype assumptions about additional animals representing genetic diversity when the breed composition in the complete population is heterogeneous and only a few animals from predominantly one breed are genotyped. Concerning allele substitution effects for one copy of the 'mh' gene variant, significant decreases of -76.1 kg milk, -3.6 kg fat and -2.8 kg protein/lactation were obtained on average when gene content estimation was additionally based on animals with assumed known genotype. Based on this result, knowledge of the mh genotypes and their effects has the potential to improve milk performance traits in cattle. PMID- 22440701 TI - Understanding the equine cecum-colon ecosystem: current knowledge and future perspectives. AB - Having evolved as a grazing animal, a horse's digestive physiology is characterized by rapid gastric transit, a rapid but intense enzymatic digestion along the small intestine, and a long and intense microbial fermentation in the large intestine. The process of understanding and describing feed degradation mechanisms in the equine digestive system in general, and in the hindgut ecosystem in particular, is essential. Regardless of its importance for the nutritional status of the host, the significance of the cecum-colon ecosystem has not yet been fully understood, and few reports have focused deeply on the contribution of the hindgut microbial population to the nitrogen and energy requirements of the horse. Compared to ruminal activity, very little is known about hindgut ecosystem activity in the horse. Information concerning the metabolism of this microbial population and its requirements is lacking. The use of internal bacterial markers for quantifying microbial outflow in ruminants is widely reported. These techniques can be applied to cecum-colon microbial quantification, contributing to a better characterization of this ecosystem. It is likely wrong to believe that the optimization strategy in the hindgut is similar to what happens in the rumen - that is, to maximize microbial growth and, therefore, fermentation. If we consider the type of substrate that, in normal conditions, arrives in the hindgut, we can expect it to be nitrogen limiting, providing limited nitrogen-based substrates for microbial fermentation. In this review paper, we intend to gather existing information on the equine ecosystem and to provide future perspectives of research. PMID- 22440702 TI - Evaluation of n-alkanes and their carbon isotope enrichments (delta(13)C) as diet composition markers. AB - Plant cuticular n-alkanes have been successfully used as markers to estimate diet composition and intake of grazing herbivores. However, additional markers may be required under grazing conditions in botanically diverse vegetation. This study was conducted to describe the n-alkane profiles and the carbon isotope enrichment of n-alkanes of common plant species from the Mid Rift Valley rangelands of Ethiopia, and evaluate their potential use as nutritional markers. A total of 23 plant species were collected and analysed for long-chain n-alkanes ranging from heptacosane to hexatriacontane (C(27) to C(36)), as well as their carbon isotopic ratio ((13)C/(12)C). The analysis was conducted by gas chromatography/combustion isotope ratio mass spectrometry following saponification, extraction and purification. The isotopic composition of the n-alkanes is reported in the delta notation (delta(13)C) relative to the Vienna Pee Dee Belemnite standard. The dominant n-alkanes in the species were C(31) (mean +/- s.d., 283 +/- 246 mg/kg dry matter) and C(33) (149 +/- 98 mg/kg dry matter). The carbon isotopic enrichment of the n-alkanes ranged from -19.370/00 to -37.400/00. Principal component analysis was used to examine interspecies differences based on n-alkane profiles and the carbon isotopic enrichments of individual n-alkanes. Large variability among the pasture species was observed. The first three principal components explained most of the interspecies variances. Comparison of the principal component scores using orthogonal procrustes rotation indicated that about 0.84 of the interspecies variances explained by the two types of data sets were independent of each other, suggesting that the use of a combination of the two markers can improve diet composition estimations. It was concluded that, while the n-alkane profile of the pasture species remains a useful marker for use in the study region, the delta(13)C values of n-alkanes can provide additional information in discriminating diet components of grazing animals. PMID- 22440703 TI - Evaluation of velvet bean meal as an alternative protein ingredient for poultry feed. AB - The effect of certain simple and cost-effective processing methods on the nutritional and anti-nutritional properties of seed materials of an under utilized food legume, Mucuna pruriens (L.) DC. var. utilis (Wall. ex Wight) Baker ex Burck (velvet bean, VB), collected from Valanadu, Kerala, India was analyzed in experiment 1. The raw VB seeds were found to contain appreciable levels of crude protein (263.2 g/kg dry matter (DM)); ether extract (79.6 g/kg DM); crude fiber (95.8 g/kg DM) and ash content (38.4 g/kg DM). Among the different treatments used, soaking in sodium bicarbonate solution + autoclaving was more effective in reducing maximum levels of various anti-nutritional compounds of VB seeds. Furthermore, in experiment 2, the effect of inclusion of different levels of velvet bean meal (VBM; subjected to soaking in sodium bicarbonate solution + autoclaving) as an alternative protein source in poultry feed on the growth performance of commercial-type broiler birds was investigated. The results indicate that the inclusion of VBM up to the 40% level exhibited better growth performance of the broiler birds such as feed intake, body weight gain, feed conversion ratio and protein efficiency ratio in both the starter and finisher phases. PMID- 22440704 TI - Environmental and social cues can be used in combination to develop sustainable breeding techniques for goat reproduction in the subtropics. AB - Goat breeds from subtropical latitudes show different annual reproductive cycles. Some of them display large seasonal variations in their annual breeding season, while others display a moderate seasonality or sexual activity all year round. This reproductive seasonality causes seasonality of milk, cheese and meat productions and, as a consequence, induces wide variation in producer incomes. To solve this problem and provide methods allowing producers to breed animals during the anestrous period and stabilize production all year round, it is necessary to have a deep knowledge of their annual sexual activity and to identify the environmental factors controlling the timing of the annual reproductive cycle. Then, it is possible to build on these knowledge sustainable breeding techniques adapted to the environmental, economic and social characteristics of the local breeding system. In this review, I will illustrate this strategy through the example of our experiments in subtropical goats. First, we determined the characteristics of the annual breeding season in both male and female goats. Second, we identified the photoperiod as the major environmental factor controlling the timing of this annual breeding season. Third, we used the photoperiod to stimulate indirectly the sexual behavior of does. Indeed, we used photoperiodic treatments to stimulate the sexual activity of bucks during the non breeding season. These sexually active male goats were then used to induce and synchronize the estrous behavior and ovulatory activity of anestrous females in confined or grazing conditions by using the 'male effect'. Under subtropical conditions, these results constitute an original manner to control the reproductive activity of local goats using the photoperiod combined with the 'male effect.' PMID- 22440705 TI - Influence of endemic goitre areas on thyroid hormones in horses. AB - The aim of this study was to investigate thyroid hormone levels in horses stabled in two different locations on the island of Sicily. The study was carried out on a total of 72 clinically healthy Sanfratellano horses ranging in age from 5 to 9 years and weighing 585 +/- 40 kg. The results showed higher thyroxine values (P < 0.02) in horses stabled in an endemic goitre area (group II) than those observed in horses in a non-endemic area (group I). Unexpectedly, the T(4)/T(3) and the fT(4)/fT(3) rations were both lower in group I than in group II. The percentages of fT(4) to T(4) and of fT(3) to T(3) were both higher in group I than the percentages for group II. On the basis of gender, comparison between the two groups showed higher T(4) (P < 0.01) and fT(4) levels (P < 0.001) in males, and lower fT(3) (P < 0.001) and fT(4) levels (P < 0.005) in females stabled in the goitre endemic area. On the basis of age, younger horses (<7 years old) showed the highest thyroid hormone levels in both groups. Results suggest a physiological adaptive response of the equine species to an endemic goitre environment. The possibility that hypothyroidism is present in these horses is thus excluded and is supported not only by the lack of clinical signs, but also by the rarity of cases previously reported. PMID- 22440706 TI - Distribution and quantification of beta-3 adrenergic receptor in tissues of sheep. AB - The beta-3 adrenergic receptor (ADRB3) is a G-protein coupled receptor involved in regulating lipolysis, as part of homeostatic regulation. In this study, South African Mutton Merino and Shanxi Dam Line were used to study the distribution and quantification of ADRB3 in adipose (subcutaneous, omental, retroperitoneal, mesenteric and perirenal fat) and non-adipose (heart, liver, spleen, lung and kidney) tissues of sheep. The protein was determined by immunohistochemical technique and by mRNA abundance via real-time polymerase chain reaction. ADRB3 was detected in all studied tissues with abundance in adipose tissues higher than in non-adipose tissues (P < 0.001). For adipose tissues, greater expression was found in deep deposits such as great omental and retroperitoneal fat than in subcutaneous fat (P < 0.05). Significant differences (P < 0.05) both for mRNA and for protein expression also existed between the two sheep flocks. These findings are consistent with the known function of ADRB3 in mediating lipolysis and homeostasis in adipose tissues. PMID- 22440707 TI - Involvement of the metabolic hormones leptin, ghrelin, obestatin, IGF-I and of MAP kinase in control of porcine oocyte maturation. AB - The general aim of our in vitro experiments was to study the role of the metabolic hormones leptin, ghrelin, obestatin and IGF-I and mitogen-activated protein kinase (MAPK)-dependent intracellular mechanisms in the control of nuclear maturation of porcine oocytes. For this purpose, porcine oocytes were isolated from the ovary and cultured in the presence of leptin, ghrelin, obestatin, IGF-I, MAPK blocker PD98059 and the combinations of hormones with PD98059. Proportions of matured oocytes (at metaphase II of meiosis, determined by DAPI staining) and of oocytes containing MAPK/ERK1-2 (determined by immunocytochemistry) were measured before and after culture. It was observed that the majority of oocytes isolated from the ovary before culture were immature and did not contain visible MAPK, but some oocytes were mature, and the majority of these oocytes contained MAPK. Incubation of oocytes resulted in a significant increase in the proportion of matured oocytes and in the percentage of oocytes containing MAPK in both the matured and not matured groups. Addition of IGF-I to the culture medium increased the proportion of matured oocytes, addition of leptin decreased it, and ghrelin and obestatin did not oocyte maturation. Addition of hormones did not affect the expression of MAPK in either immature or mature oocytes. PD98059, when given alone, suppressed the maturation and accumulation of MAPK in both mature and immature oocytes. When given together with hormones, PD98059 was able to reduce the stimulatory effect of IGF-I, to invert the inhibitory action of leptin to stimulatory and to induce the stimulatory action of ghrelin and obestatin on meiosis. IGF-I, ghrelin and obestatin, but not leptin, when given together with PD98059, increased the accumulation of MAPK in both immature and mature oocytes. Association of nuclear maturation and expression of MAPK in oocytes before, but not after culture, as well as the prevention of oocyte maturation by MAPK blocker suggests the involvement of MAPK-dependent intracellular mechanisms in the promotion of reinitiation, but not completion of meiosis. The effect of hormonal additions on meiosis of oocytes suggests that IGF-I is a stimulator, leptin can be an inhibitor, while ghrelin and obestatin probably do not control oocyte maturation. The ability of PD98059 to modify the effect of hormones on oocyte maturation and on MAPK expression suggests possible interference of hormones and MAPK-dependent intracellular mechanisms in oocytes. However, no influence of hormones on MAPK and lack of association between action of hormones and PD98059 on MAPK and meiosis suggest that MAPK is probably not a mediator of effect of IGF-I, leptin, ghrelin and obestatin on porcine oocyte nuclear maturation. PMID- 22440708 TI - Effect of litter size and bacitracin administration on tissue protein synthesis of lactating rabbit does. AB - Bacitracin is an antibiotic used in rabbit husbandry to control microbial digestive pathologies. Collateral effects on absorption and mucosal development have been reported and these may impact on protein metabolism. This study aims to analyse the effect of the antibiotic on protein synthesis in lactating does because mammary gland metabolism and milk output should provide a sensitive index of any undesirable action of bacitracin. Rates of protein synthesis were measured in mammary gland, liver, intestinal mucosa and muscle of lactating rabbits does by injecting a flooding dose of [(2)H(5)]phenylalanine into the auricular artery of two groups (each n = 8) of New Zealand White does fed different experimental diets. The control group (C) received the basal diet and the bacitracin group (B) ingested the same diet but supplemented with bacitracin (100 mg/kg). Animals received the experimental diet from day 28 of pregnancy until day 26 of lactation when they were slaughtered. Just after birth, litter size was adjusted by cross fostering either to five or nine pups (four does per dietary treatment). The relative weight of the liver tended to be greater in those females receiving the B diet (27 v. 22.5 g/kg BW; P < 0.07), while diet did not affect mammary gland weight (255.7 +/- 10.59 g). Fractional protein synthesis rate (FSR) was higher for intestinal mucosa (duodenum; 51.7% +/- 2.09%/day) followed by mammary gland and liver (38.29 +/- 2.62%/day and 40.2 +/- 1.98%/day, respectively), and the lowest value was observed in muscle (2.92 +/- 0.26%/day; P < 0.0001). Bacitracin treatment lowered FSR in the mammary gland by 23% (P = 0.024) and this was independent of litter size. Conversely, FSR in the duodenum was not affected by antibiotic treatment but reduced by 15% (P = 0.021) for the larger litter size. PMID- 22440709 TI - Effects of vitamin E supplementation in the extender on frozen-thawed bovine semen preservation. AB - The maturing sperm cells discard the majority of their cytoplasm during the final stages of spermatogenesis and lose some of their defense enzymes. The purpose of this study was to investigate the effects of vitamin E supplementation on standard semen quality parameters and antioxidant activities of frozen-thawed bovine sperm. Vitamin E was added at concentrations of 0.5, 1.0, 1.5 and 2.0 mg/ml to bovine semen cryoprotective medium. The results showed that the sperm motility and VSL, STR values in the extender supplemented with 1.0 and 1.5 mg/ml of vitamin E, were significantly higher than that of other concentrations (P < 0.05). The percentages of acrosome-intact and membrane-intact sperm were significantly improved (P < 0.05) by supplementing with 1.5 mg/ml of vitamin E. In biochemical assays, the extender supplemented with vitamin E did not exhibit significant improvement in SOD (superoxide dismutase) levels, compared with the control (P > 0.05). Compared with other groups, CAT (catalase) levels were demonstrated to be greater with the supplementation of vitamin E at 1.0 and 1.5 mg/ml (P < 0.05). The extender supplemented with 1.5 mg/ml of vitamin E caused the highest levels of glutathione peroxidase (GSH-Px), compared with other groups (P < 0.05). The glutathione (GSH) activity was significantly higher with the supplementation of 0.5, 1.0 and 1.5 mg/ml of vitamin E, compared with 2.0 mg/ml in the vitamin E group and control (P < 0.05). Moreover, increasing the doses of vitamin E decreased sperm antioxidant activities, the extender supplemented with 2.0 mg/ml of vitamin E, caused the lowest levels of GSH-Px and GSH activities, compared with other treatment groups (P < 0.05). In conclusion, the beneficial effects of vitamin E noted in this study can be attributed to the antioxidant characteristics. Vitamin E supplementation in the extender reduced the lipid peroxidation potential and improved semen quality during freezing-thawing. More researches are needed to evaluate and understand the precise physiological role of vitamin E in reproduction. PMID- 22440710 TI - Grazing lucerne as fattening management for young bulls: technical and economic performance and diet authentication. AB - Three fattening systems were evaluated from weaning to slaughter in order to find alternatives to grain feeding in young bulls, and to test the reliability of carcass subcutaneous fat colour to discriminate among them. After weaning (224 kg), one group of animals was fed concentrates and straw until they reached the target slaughter weight (450 kg; Feedlot), another group grazed rotationally on lucerne supplemented with 1.8 kg DM/day barley until slaughter (LUC), and the third group had the same management as LUC animals for 3 months (period 1) and thereafter was finished on concentrates and straw until slaughter (period 2; LUC + Feedlot). Animals were weighed weekly and sampled monthly for serum IGF-I and leptin, and plasma non-esterified fatty acids and carotenoid pigment concentration analyses. Carcass characteristics and subcutaneous fat colour were recorded after slaughter. In period 1, Feedlot animals had slightly greater weight gains than their grazing counterparts (P < 0.10), and at the end of period 1 they had 66% greater IGF-I and 35% greater leptin concentration (P < 0.01). Plasma carotenoid pigments were undetectable in Feedlot animals, but increased during grazing in LUC and LUC + Feedlot treatments. In period 2, weight gains were lowest for LUC, intermediate for Feedlot and greatest for LUC + Feedlot animals (P < 0.001), conditioning the time taken to reach slaughter weight (73, 58 and 47 days, respectively; P < 0.05). Leptin and IGF-I concentrations increased in all management systems during period 2. Plasma carotenoid pigment concentration reached its maximum at the end of period 2 in LUC animals, but it decreased sharply in LUC + Feedlot animals in this period. Management did not affect carcass traits except for subcutaneous fat colour. Yellowness, Chroma (C*) and the value of the integral of the translated reflectance spectrum (SUM), estimator of carotenoid pigment content in fat, were higher in LUC than in LUC + Feedlot and Feedlot animals (P < 0.001). Two logistic regressions were obtained to discriminate carcasses from LUC treatment: P (LUC) = (1 + e(18.8-5.6 * lightness-36.9 * redness + 0.3 * SUM + 29.8 * C*))(-1) and LUC + Feedlot treatment: P (LUC + Feedlot)=(1 + e(833.7-11.8 * lightness + 4.7 * redness + 0.2 * SUM-2.5 * C*))(-1). The economic margin, calculated as income achieved minus costs, was greatest for LUC, intermediate for LUC + Feedlot and lowest for Feedlot treatment. Therefore, grazing lucerne supplemented with barley was an interesting alternative for fattening young bulls in these conditions, producing carcasses of similar quality, which could be accurately traced by measuring subcutaneous fat colour. PMID- 22440711 TI - Introducing efficiency into the analysis of individual lifetime performance variability: a key to assess herd management. AB - Lifetime performance variability is a powerful tool for evaluating herd management. Although efficiency is a key aspect of performance, it has not been integrated into existing studies on the variability of lifetime performance. The goal of the present article is to analyse the effects of various herd management options on the variability of lifetime performance by integrating criteria relative to feed efficiency. A herd model developed for dairy goat systems was used in three virtual experiments to test the effects of the diet energy level, the segmentation of the feeding plan and the mean production potential of the herd on the variability of lifetime performance. Principal component analysis showed that the variability of lifetime performance was structured around the first axis related to longevity and production and the second related to the variables used in feed efficiency calculation. The intra-management variability was expressed on the first axis (longevity and production), whereas the inter management variability was expressed on the second axis (feed efficiency) and was mainly influenced by the combination of the diet energy level and the mean production potential. Similar feed efficiencies were attained with different management options. Still, such combinations relied on different biological bases and, at the level of the individual, contrasting results were observed in the relationship between the obtained pattern of performance (in response to diet energy) and the reference pattern of performance (defined by the production potential). Indeed, our results showed that over-feeding interacted with the feeding plan segmentation: a high level of feeding plan segmentation generated a low proportion of individuals at equilibrium with their production potential, whereas a single ration generated a larger proportion. At the herd level, the diet energy level and the herd production potential had marked effects on production and efficiency due to dilution of fixed production costs (i.e. maintenance requirements). Management options led to similar production and feed efficiencies at the herd level while giving large contrasts in the proportions of individuals at equilibrium with their production potential. These results suggested that analysing individual variability on the basis of criteria related to production processes could improve the assessment of herd management. The herd model opens promising perspectives in studying whether individual variability represents an advantage for herd performance. PMID- 22440712 TI - The fatty acid profile of muscle and adipose tissue of lambs fed camelina or linseed as oil or seeds. AB - The objective of this study was to evaluate the impact of diets enriched with plant oils or seeds, high in polyunsaturated fatty acids (PUFA), on the fatty acid profile of sheep intramuscular and subcutaneous adipose tissue (SAT). Sixty six lambs were blocked according to initial body weight and randomly assigned to six concentrate-based rations containing 60 g fat/kg dry matter from different sources: (1) Megalac (MG; ruminally protected saturated fat), (2) camelina oil (CO), (3) linseed oil (LO), (4) NaOH-treated camelina seed (CS), (5) NaOH-treated linseed (LS) or (6) CO protected from ruminal saturation by reaction with ethanolamine; camelina oil amides (CA). The animals were offered the experimental diets for 100 days, after which samples of m. longissimus dorsi and SAT were collected and the fatty acid profile determined by GLC. The data were analyzed using ANOVA with 'a priori' contrasts including camelina v. linseed, oil v. NaOH treated seeds and CS v. CA. Average daily gain and total fatty acids in intramuscular adipose tissue were similar across treatments. The NaOH-treatment of seeds was more effective in enhancing cis-9, trans-11 conjugated linoleic acid (CLA) incorporation than the corresponding oil, but the latter resulted in a higher content of trans-11 18:1 in both muscle neutral and polar lipids (P < 0.01, P < 0.001, respectively). Inclusion of LS resulted in the highest PUFA:saturated fatty acid (SFA) ratio in total intramuscular fat (0.22). The NaOH treatment of seeds resulted in a higher PUFA/SFA ratio (0.21 v. 0.18, P < 0.001) than oils and on average, linseed resulted in a higher PUFA/SFA ratio than camelina (P < 0.01). Lambs offered LS had the highest concentration of n-3 PUFA in the muscle, while those offered MG had the lowest (P < 0.001). This was reflected in the lowest (P < 0.001) n-6: n-3 PUFA ratio for LS-fed lambs (1.15) than any other treatment, which ranged from 2.14 to 1.72, and the control (5.28). The trends found in intramuscular fat were confirmed by the data for SAT. This study demonstrated the potential advantage from a human nutrition perspective of feeding NaOH-treated seeds rich in PUFA when compared to the corresponding oil. The use of camelina amides achieved a greater degree of protection of dietary PUFA, but decreased the incorporation of biohydrogenation intermediates such as cis-9, trans-11 CLA and trans-11 18:1 compared to NaOH-treated seeds. PMID- 22440713 TI - Effects of feeding green forage of sulla (Hedysarum coronarium L.) on lamb growth and carcass and meat quality. AB - The nutritional effects of sulla (Hedysarum coronarium L.) forage containing condensed tannins (CT) on growth of lambs, and carcass and meat quality were investigated. Thirty-two male Comisana lambs aged 100 +/- 8 days weighing 19.0 +/ 2.8 kg were fed fresh forage of sulla or CT-free annual ryegrass (Lolium multiflorum Lam. subsp. Wersterwoldicum) for 49 days until slaughter; in addition, each lamb was supplied with 200 g/days of concentrate. Eight lambs per diet had been previously treated with anthelmintic drugs to remove nematode parasites. Measurements of BW and feed intake, and counts of faecal nematode eggs were made. Carcass parameters were recorded after slaughter, and tissue components of the hind leg were determined. Longissimus dorsi meat was evaluated for pH, colour, thawing and cooking losses, Warner-Bratzler shear force, chemical composition and sensory properties based on triangle tests. Relative to ryegrass fed lambs, sulla-fed lambs had significantly greater dry matter (DM) and protein intake, a more favourable feed conversion ratio, and superior growth rate, final BW at 150 days of age, carcass weight, yield and fatness. These results were attributed to the high protein and non-structural carbohydrate content of sulla, and also to the moderate CT content of sulla (16.7 and 20.3 g/kg of DM in offered and consumed sulla forage, respectively). Anthelmintic treatment did not affect lamb growth, as the level of parasitic infection (initial and final) was low. The physical, chemical and sensory properties of the lamb meat were not influenced by diet. PMID- 22440714 TI - Online prediction of fatty acid profiles in crossbred Limousin and Aberdeen Angus beef cattle using near infrared reflectance spectroscopy. AB - The objective of this study was to examine the online use of near infrared reflectance (NIR) spectroscopy to estimate the concentration of individual and groups of fatty acids (FA) as well as intramuscular fat (IMF) in crossbred Aberdeen Angus (AA*) and Limousin (LIM*) cattle. This was achieved by direct application of a fibre-optic probe to the muscle immediately after exposing the meat surface in the abattoir at 48 h post mortem. Samples of M. longissimus thoracis from 88 AA* and 106 LIM* were scanned over the NIR spectral range from 350 to 1800 nm and samples of the M. longissimus lumborum were analysed for IMF content and FA composition. Statistically significant differences (P < 0.001) were observed in most FA between the two breeds studied, with FA concentration being higher in AA* meat mainly. NIR calibrations, tested by cross-validation, showed moderate to high predictability in LIM* meat samples for C16:0, C16:1, C18:0, trans11 C18:1, C18:1, C18:2 n-6, C20:1, cis9, trans11 C18:2, SFA (saturated FA), MUFA (monounsaturated FA), PUFA (polyunsaturated FA) and IMF content with R(2) (SE(CV), mg/100 g muscle) of 0.69 (146), 0.69 (28), 0.71 (62), 0.70 (8.1), 0.76 (192), 0.65 (13), 0.71 (0.9), 0.71 (2.9), 0.68 (235), 0.75 (240), 0.64 (17) and 0.75 (477), respectively. FA such as C14:0, C18:3 n-3, C20:4 n-6, C20:5 n-3, C22:6 n-3, n-6 and n-3 were more difficult to predict by NIR in these LIM* samples (R(2) = 0.12 to 0.62; SECV = 0.5 to 26 mg/100 g muscle). In contrast, NIR showed low predictability for FA in AA* beef samples. In particular for LIM*, the correlations of NIR measurements and several FA in the range from 0.81 to 0.87 indicated that the NIR spectroscopy is a useful online technique for the early, fast and relatively inexpensive estimation of FA composition in the abattoir. PMID- 22440715 TI - Pioneers of pathogenesis: past and present. PMID- 22440716 TI - Contribution of cytokines to pathology and protection in virus infection. AB - Acute and chronic viral infections greatly contribute to global health burden. While concerted action of multiple elements of the immune system help the host cope with most viruses, some infections lead to host damage or death. Cytokines are central drivers and controllers of both immune-mediated virus elimination and of immunopathology. Here, we review recent progress in understanding the protective and damaging roles in viral infections of cytokines and chemokines associated with innate, regulatory, and Th1, Th2 and Th17 responses. PMID- 22440717 TI - Molecular crosstalk between a chemical and a biological stressor and consequences on disease manifestation in rainbow trout. AB - The aim of the present study was to examine the molecular and organism reaction of rainbow trout, Oncorhynchus mykiss, to the combined impact of two environmental stressors. The two stressors were the myxozoan parasite, Tetracapsuloides bryosalmonae, which is the etiological agent of proliferative kidney disease (PKD) and a natural stressor to salmonid populations, and 17beta estradiol (E2) as prototype of estrogen-active chemical stressors in the aquatic environment. Both stressors, the parasite and estrogenic contaminants, co-exist in Swiss rivers and are discussed as factors contributing to the decline of Swiss brown trout populations over the last decades. Using a microarray approach contrasting parasite-infected and non-infected rainbow trout at low or high estrogen levels, it was observed that molecular response patterns under joint exposure differed from those to the single stressors. More specifically, three major response patterns were present: (i) expression responses of gene transcripts to one stressor are weakened by the presence of the second stressor; (ii) expression responses of gene transcripts to one stressor are enhanced by the presence of the second stressor; (iii) expression responses of gene transcripts at joint treatment are dominated by one of the two stressors. Organism-level responses to concurrent E2 and parasite treatment - assessed through measuring parasite loads in the fish host and cumulative mortalities of trout - were dominated by the pathogen, with no modulating influence of E2. The findings reveal function- and level-specific responses of rainbow trout to stressor combinations, which are only partly predictable from the response to the single stressors. PMID- 22440718 TI - Synthesis of 2-(1,5-diaryl-1,4-pentadien-3-ylidene)-hydrazinecarboximidamide hydrochloride catalyzed by p-dodecylbenzenesulfonic acid in aqueous media under ultrasound irradiation. AB - Amidinohydrazone compounds are very important synthetic intermediates and can serve as versatile precursors in synthesis of many natural products and drug molecules. The use of ultrasound, p-dodecylbenzenesulfonic acid (DBSA) and water as solvent improved the synthesis of different 2-(1,5-diaryl-1,4-pentadien-3 ylidene)-hydrazinecarboximidamide hydrochlorides. The best reaction conditions for the condensation of 1,5-diphenyl-1,4-pentadien-3-one with aminoguanidine hydrochloride were as follows: 1,5-diphenyl-1,4-pentadiene-3-one (1, 1 mmol), aminoguanidine hydrochloride (1.1 mmol), DBSA (0.5 mmol), water 10 mL, reaction temperature 25-27 degrees C, irradiation frequency 25 kHz. 2a was achieved in 94% yield within 2h. The other seven amidinohydrazones were obtained in 84-94% yield within 2-3h under the same conditions. Compared to the method involving catalysis by hydrochloric acid in refluxing EtOH, the advantages of present procedure are milder conditions, shorter reaction times, higher yields, and environmental friendly conditions, which make it a useful strategy for the synthesis of analogues. PMID- 22440719 TI - Highly sensitized patients in cardiac transplantation: early outcomes from the Canadian Prioritized Organ Sharing Program. PMID- 22440720 TI - Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity. AB - BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a life threatening disease manifested by progressive pulmonary vascular remodeling, compromised pulmonary blood flow and right heart failure. Most studies have explored how pulmonary endothelial function modulates disease pathogenesis. We hypothesize that IPAH is a progressive panvasculopathy, affecting both pulmonary and systemic vascular beds, and that systemic endothelial dysfunction correlates with disease severity. Recent studies have demonstrated systemic endothelial dysfunction in adults with pulmonary hypertension; however, adults often have additional comorbidities affecting endothelial function. Systemic endothelial function has not been explored in children with IPAH. METHODS: In this single center, prospective, cross-sectional study we examined brachial artery flow mediated dilation (FMD), a nitric oxide-mediated, endothelial-dependent response, in children with IPAH and matched controls. FMD measurements were compared with clinical and echocardiographic measures of IPAH severity. RESULTS: Thirteen patients and 13 controls were studied, ranging in age from 6 to 20 years. FMD was decreased in IPAH subjects compared with controls (5.1 +/- 2.1% vs 9.7 +/- 2.0%; p < 0.0001). In IPAH subjects, FMD correlated directly with cardiac index (R(2) = 0.34, p = 0.035), and inversely with tricuspid regurgitation velocity (R(2) = 0.57, p = 0.019) and right ventricular myocardial performance index (R(2) = 0.44, p = 0.028). CONCLUSIONS: The presence of systemic endothelial dysfunction in children with IPAH and its strong association with IPAH severity demonstrate that IPAH is a global vasculopathy. Although morbidity in IPAH is typically associated with pulmonary vascular disease, systemic vascular changes may also relate to disease pathogenesis and progression. Further study into shared mechanisms of systemic and pulmonary endothelial dysfunction may contribute to future therapies for IPAH. PMID- 22440721 TI - Effect of gender on awareness of cardiovascular risk factors, preventive action taken, and barriers to cardiovascular health in a group of Austrian subjects. AB - BACKGROUND: The incidence of cardiovascular disease (CVD) is increasing in industrialized countries. Preventive action is an important factor in minimizing CVD-associated morbidity and mortality. However, it is not known whether gender differences affect CVD or risk factor awareness influencing self-assessment of personal risk and preventive action. OBJECTIVE: This study was performed to assess individual CVD and risk factor awareness, preventive action taken, and barriers to cardiovascular health. METHODS: The study included 573 women and 336 men, randomly chosen to complete an anonymous questionnaire to assess individual CVD and risk factor awareness, preventive action taken, and barriers to cardiovascular health. The data were analyzed using SAS software. RESULTS: Cardiovascular disease was identified in 75% of patients, in both sexes, as the leading cause of death; however, both groups showed significant lack of knowledge about CVD risk factors. Type 2 diabetes was identified correctly in only 27.5%. Preventive action was linked more often to family members in 66.5% of women and 62.8% of men. The primary barrier to cardiovascular health in adults was incorrect assessment of personal CVD risk. More than half of female respondents (56.4%) and male respondents (52.7%) underestimated their risk of CVD. CONCLUSION: Knowledge about risk factors for CVD needs to be improved in members of both sexes. Because women, in particular, have difficulty in correctly assessing their personal CVD risk, future education programs are warranted to inform both women and men about CVD and its risk factors, thereby helping them to correctly assess their individual risk. However, greater effort is needed to inform men, compared with women, about the various ways in which to prevent CVD and to motivate them to take preventive action. PMID- 22440722 TI - Differences in helminth infections between captive and wild spur-thighed tortoises Testudo graeca in southern Spain: a potential risk of reintroductions of this species. AB - Although the spur-thighed tortoise, Testudo graeca, is one of the most widely distributed species of tortoises, its natural populations are threatened through its whole range. Particularly at south-eastern Spain, the species is mainly threatened by habitat destruction and over-collection, given that this chelonian has been traditionally considered an appreciate pet. As south-eastern Spanish wildlife recovery centers shelter hundreds of captive animals mainly coming from illegal trade or captive-bred, there is a strong debate about what to do with these animals: maintaining them in captivity all along their lives or reintroducing them to wildlife. It is well known that the reintroduction of captive animals supposes a risk for the wild population due to the uncertainty of their genetic origin and to the possible spread of infectious diseases. However, despite the increasing evidence that infectious agents are a potential health hazard for wildlife, little is known about the risk that introduced parasites could suppose for the wild populations of spur-thighed tortoise. The present study investigates for the first time the presence of helminth eggs and worms in faeces from 107 wild and captive individuals collected from mid-March to mid-June 2010, and relates the findings to different environmental and host variables. Sixteen oxyurid species and the ascarid Angusticaecum holopterum were identified. This last nematode and the oxyurid species Tachygonetria palearticus and T. seurati had not been reported in Spanish wild T. graeca previously. The prevalence of oxyurid eggs and worms were 94% and 70%, respectively; while, ascarid eggs and worms were found in 26% and 5% of tortoises, respectively. Ascarid infections affected mostly captive animals and were associated to caparace deformities and symptoms of upper respiratory tract disease (p<0.05). Oxyurid infections were not associated to negative health traits and prevalence increased with age. In free-living tortoises, the distribution of pharingodonid genera also varied according to habitat; moreover, T. longicollis, T. pusilla, T. conica, T. robusta and Mehdiella stylosa where significantly more frequent in wild compared to captive tortoises (p<0.05). Study results highlight important differences in the nematode fauna of captive and free-living tortoises and questions one more time if the reintroductions of captive animals suppose a risk for the wild population since the former ones can harbor and distribute among free populations pathogens like ascarid nematodes. PMID- 22440723 TI - Increased incidence of DNA amplification in follicular than in uterine and blood samples indicates possible tropism of Neospora caninum to the ovarian follicle. AB - This study evaluated the presence of Neospora caninum in ovarian follicle aspirates and uterine flushes obtained from N. caninum seropositive dairy cows. Ninety-two cows that aborted within the previous 90 days were sampled to determine the presence of antibodies against N. caninum. Thirteen seropositive cows were chosen for collection of blood leukocytes, uterine flushes (UF; n=12) and follicular aspirates (OPU; n=13). Samples were centrifuged and the cellular sediment from the follicular fluid, uterine flushes and blood leukocytes were used for DNA extraction and PCR. Follicular aspirates had the highest frequency of DNA amplification for N. caninum (p<0.05, 92.3%; 12/13). Whereas uterine (4/12) and blood leukocyte (5/13) samples had similar (p>0.05) rate of positive results. Nonetheless, there was no agreement between blood leukocytes and follicular samples taken from the same animal (Cohen Kappa=-0.16). Similarly, blood leukocytes and uterine results had moderate agreement between them (Cohen Kappa=0.47). This study indicates that N. caninum is present in the ovarian follicle and uterus of seropositive cows, suggesting a possible risk of neosporosis transmission between females during oocyte and embryo collection and transfer. Hence, precautions should be taken to minimize the risk of N. caninum transmission. Furthermore, the high incidence of positive results in follicle samples, that exceeded that of their paired blood leukocytes, suggests a possible tropism of N. caninum for the ovarian follicle. PMID- 22440725 TI - Influence of the liquid crystal behaviour on the Langmuir and Langmuir-Blodgett film supramolecular architecture of an ionic liquid crystal. AB - A new luminescent ionic liquid crystal, called Ipz-2, has been synthesised and its mesophase behaviour and also at the air-liquid interface has been studied and compared with Ipz, another ionic pyrazole derivative, with a similar molecular structure, previously studied. The X-ray diffraction pattern shows that Ipz-2 exhibits hexagonal columnar mesomorphism, while Ipz adopts lamellar mesophases. Langmuir films of both compounds are flat and homogeneous at large areas per molecule, but create different supramolecular structures under further compression. Ipz-2 Langmuir films have been transferred onto solid substrates, and Atomic Force Microscopy (AFM) images of the Langmuir-Blodgett films have shown that large columnar structures hundreds of nm in diameter are formed on top of the initial monolayer, in contrast with well-defined trilayer LB films obtained for Ipz. Our results show that Ipz-2 has a tendency to stack in columnar arrangements both in liquid crystalline bulk and in Langmuir and Langmuir Blodgett films. PMID- 22440724 TI - Macroevolution of venom apparatus innovations in auger snails (Gastropoda; Conoidea; Terebridae). AB - The Terebridae are a diverse family of tropical and subtropical marine gastropods that use a complex and modular venom apparatus to produce toxins that capture polychaete and enteropneust preys. The complexity of the terebrid venom apparatus suggests that venom apparatus development in the Terebridae could be linked to the diversification of the group and can be analyzed within a molecular phylogenetic scaffold to better understand terebrid evolution. Presented here is a molecular phylogeny of 89 terebrid species belonging to 12 of the 15 currently accepted genera, based on Bayesian inference and Maximum Likelihood analyses of amplicons of 3 mitochondrial (COI, 16S and 12S) and one nuclear (28S) genes. The evolution of the anatomy of the terebrid venom apparatus was assessed by mapping traits of six related characters: proboscis, venom gland, odontophore, accessory proboscis structure, radula, and salivary glands. A novel result concerning terebrid phylogeny was the discovery of a previously unrecognized lineage, which includes species of Euterebra and Duplicaria. The non-monophyly of most terebrid genera analyzed indicates that the current genus-level classification of the group is plagued with homoplasy and requires further taxonomic investigations. Foregut anatomy in the family Terebridae reveals an inordinate diversity of features that covers the range of variability within the entire superfamily Conoidea, and that hypodermic radulae have likely evolved independently on at least three occasions. These findings illustrate that terebrid venom apparatus evolution is not perfunctory, and involves independent and numerous changes of central features in the foregut anatomy. The multiple emergence of hypodermic marginal radular teeth in terebrids are presumably associated with variable functionalities, suggesting that terebrids have adapted to dietary changes that may have resulted from predator-prey relationships. The anatomical and phylogenetic results presented serve as a starting point to advance investigations about the role of predator-prey interactions in the diversification of the Terebridae and the impact on their peptide toxins, which are promising bioactive compounds for biomedical research and therapeutic drug development. PMID- 22440726 TI - Comparison of residual oil cluster size distribution, morphology and saturation in oil-wet and water-wet sandstone. AB - We imaged an oil-wet sandstone at residual oil saturation (S(or)) conditions using X-ray micro-tomography with a nominal voxel size of (9 MUm)(3) and monochromatic light from a synchrotron source. The sandstone was rendered oil-wet by ageing with a North Sea crude oil to represent a typical wettability encountered in hydrocarbon reservoirs. We measured a significantly lower S(or) for the oil-wet core (18.8%) than for an analogue water-wet core (35%). We analysed the residual oil cluster size distribution and find consistency with percolation theory that predicts a power-law cluster size distribution. We measure a power-law exponent tau=2.12 for the oil-wet core which is higher than tau for the water-wet system (tau=2.05), indicating fewer large clusters in the oil-wet case. The clusters are rough and sheet-like consistent with connectivity established through layers in the pore space and occupancy of the smaller pores; in contrast the clusters for water-wet media occupy the centres of the larger pores. These results imply less trapping of oil, but with a greater surface area for dissolution. In carbon storage applications, this suggests that in CO(2)-wet systems, capillary trapping is less significant, but that there is a large surface area for dissolution and reaction. PMID- 22440727 TI - Poly(lactic-co-glycolic acid) as a particulate emulsifier. AB - The structure and stability of emulsions formed in the presence of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) were characterised. From oil-water contact angles on PLGA films, it was deduced that particle surface hydrophobicity is linked to the oil phase polarity. Incorporation of polyvinyl alcohol molecules into the nanoparticle surfaces reduces the particle hydrophobicity sufficiently for oil-in-water emulsions to be preferentially stabilised. PLGA nanoparticles enhance the stability of emulsions formed from a wide range of oils of different polarities. The nanoparticle concentration was found to be a key parameter controlling the average size and coalescence stability of the emulsion drops. Visualisation of the interfacial structure by electron microscopy indicated that PLGA nanoparticles were located at the drop surfaces, evidence of the capacity of these particles to stabilise Pickering-type emulsions. These results provide insights into the mechanism of PLGA nanoparticle stabilisation of emulsions. PMID- 22440728 TI - Optical response of Cu clusters in zeolite template. AB - Optical properties of Cu clusters embedded in mordenite are studied experimentally and theoretically. In this work we discuss spectral features of the system at various reduction steps and compare then with the results of spectra obtained within a theoretical model. The model employed consists of Cu clusters embedded in a homogeneous matrix. A second model employed introduced further variation considering a three component system where air or water can be present. The macroscopic dielectric response of the system is obtained within the Maxwell Garnett approximation. In this approach the complex non-local in homogeneous dielectric response of the zeolite+copper system is replaced by an effective homogeneous dielectric function. Metallic clusters can occupy specific available cavities in the zeolite framework. The presence of clusters that are smaller than the cavities in which they reside can lead to an air-Cu or water-Cu interface which allows shifts in surface plasmon resonance energies. As observed experimentally the energy of the main resonance is seen to be insensitive to the filling fraction ratios and highly susceptible to the embedding matrix properties. Reflectance spectra have been obtained which can be explained within this model. PMID- 22440729 TI - Close-packed monolayers of charged Janus-type nanoparticles at the air-water interface. AB - We present a new method to obtain close-packed monolayers composed of noble metal nanoparticles (NP) possessing well-defined permanent charge of either sign. The method is based on the fact that ligands forming the protecting layer exhibit ability to rearrange at the NPs surface. We demonstrate that if the protecting layer is composed of a mixture of hydrophobic and hydrophilic charged ligands in appropriate proportion, the NP exhibits properties of a Janus-type particle with one of the hemispheres hydrophilic and the other hydrophobic. Such amphiphilic NPs self-assemble into a monolayer of well defined surface charge at the air water interface. Due to strong stabilizing effect of the lateral electrostatic repulsions, such monolayer can be compressed to form close-packed hexagonal structure, and then easily transferred onto a solid substrate with the Langmuir Blodgett technique. PMID- 22440730 TI - Re: Small bowel MRI imaging in the DGH--are you doing it yet? PMID- 22440731 TI - Case report: the CT halo sign: a rare manifestation of squamous cell carcinoma of the lung. PMID- 22440732 TI - Victim sensitivity and the accuracy of social judgments. AB - Recent theorizing on the relation between victim sensitivity and unethical behavior predicts that victim sensitivity is related to an asymmetrical focus on cues associated with untrustworthiness compared to cues associated with trustworthiness. This hypothesis and its consequences for the accuracy of social predictions are investigated in this article. In Study 1, participants rated the trustworthiness of 35 computer-animated faces that differed in their emotional expression. People high in victim sensitivity rated neutral and hostile faces more untrustworthy than people low in victim sensitivity, whereas no such effect was found for friendly faces. In Study 2, participants predicted the cooperativeness of 56 targets on the basis of minimal information. The accuracy of predictions was negatively related to victim sensitivity, and people high in victim sensitivity systematically underestimated targets' cooperativeness. Thus, the asymmetrical focus on untrustworthiness cues among victim-sensitive individuals seems to impair rather than improve their social judgments. PMID- 22440733 TI - Overexpression of nuclear NHERF1 in advanced colorectal cancer: association with hypoxic microenvironment and tumor invasive phenotype. AB - Over 57% of colorectal cancer (CRC) patients have regional or distant spread of their disease at the time of diagnosis. Despite recent advances, there is a compelling need to better characterize prognostic markers for advanced CRC. The present study investigates protein expression of NHERF1, HIF-1alpha and TWIST1 and their relationship in distant normal mucosa (DNM), tumor (T) and adjacent normal mucosa (ANM), lymph node metastasis (LNM) and liver metastasis (LM), determining their role as potential markers in advanced stages of human CRC. Overexpression of nuclear NHERF1 was shown in 47% of tumors, which exhibited a significant association with poor histological grade (P=0.0346). Nuclear NHERF1 showed a higher expression in T, LNM and LM than both DNM (P<0.0001) and ANM (P<0.05). Nuclear HIF-1alpha was significantly higher in T, LNM and LM than DNM and ANM (P<0.05, P<0.001, P<0.0001, respectively). A positive correlation between nuclear NHERF1 and nuclear HIF-1alpha was found in LNM (r=0.331, P=0.020), where an extended co-localization of the two proteins was demonstrated. TWIST1 was more expressed in T than DNM and ANM (P<0.0001) and was higher in T than LNM and LM (P<0.0001). Moreover, nuclear NHERF1 was directly correlated to TWIST1 (r=0.339, P=0.015) in T samples, where a high co-expression of the two proteins was demonstrated both in no longer polarized epithelial cells and in invasive mesenchymal elements adjacent to hypoxic and perinecrotic colonic areas. Overall, nuclear NHERF1 expression was associated with poorer differentiation grade and with higher expression both of HIF-1alpha in lymphatic metastasis and TWIST1 in invasive front of tumor. Our results support the oncogenic role of NHERF1 and promote nuclear NHERF1 as a potential new biomarker of advanced CRC. PMID- 22440734 TI - Merging systems biology with pharmacodynamics. AB - The emerging discipline of systems pharmacology aims to combine analysis and computational modeling of cellular regulatory networks with quantitative pharmacology approaches to drive the drug discovery processes, predict rare adverse events, and catalyze the practice of personalized precision medicine. Here, we introduce the concept of enhanced pharmacodynamic (ePD) models, which synergistically combine the desirable features of systems biology and current PD models within the framework of ordinary or partial differential equations. ePD models that analyze regulatory networks involved in drug action can account for a drug's multiple targets and for the effects of genomic, epigenomic, and posttranslational changes on the drug efficacy. This new knowledge can drive drug discovery and shape precision medicine. PMID- 22440735 TI - Characterization of circulating endothelial cells in acute myocardial infarction. AB - Acute myocardial infarction (MI), which involves the rupture of existing atheromatous plaque, remains highly unpredictable despite recent advances in the diagnosis and treatment of coronary artery disease. Accordingly, a clinical measurement that can predict an impending MI is desperately needed. Here, we characterize circulating endothelial cells (CECs) using an automated and clinically feasible CEC three-channel fluorescence microscopy assay in 50 consecutive patients with ST-segment elevation MI and 44 consecutive healthy controls. CEC counts were significantly elevated in MI cases versus controls, with median numbers of 19 and 4 cells/ml, respectively (P = 1.1 * 10(-10)). A receiver-operating characteristic (ROC) curve analysis demonstrated an area under the ROC curve of 0.95, suggesting near-dichotomization of MI cases versus controls. We observed no correlation between CECs and typical markers of myocardial necrosis (rho = 0.02, creatine kinase-myocardial band; rho = -0.03, troponin). Morphological analysis of the microscopy images of CECs revealed a 2.5 fold increase (P < 0.0001) in cellular area and a twofold increase (P < 0.0001) in nuclear area of MI CECs versus healthy controls, age-matched CECs, as well as CECs obtained from patients with preexisting peripheral vascular disease. The distribution of CEC images that contained from 2 to 10 nuclei demonstrates that MI patients were the only subject group to contain more than 3 nuclei per image, indicating that multicellular and multinuclear clusters are specific for acute MI. These data indicate that CEC counts may serve as a promising clinical measure for the prediction of atherosclerotic plaque rupture events. PMID- 22440736 TI - Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. AB - Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D(2) (PGD(2)), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD(2) levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD(2) receptor G protein (heterotrimeric guanine nucleotide)-coupled receptor 44 (GPR44), but not the PGD(2) receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD(2) as an inhibitor of hair growth in AGA and suggest the PGD(2)-GPR44 pathway as a potential target for treatment. PMID- 22440737 TI - Restoring methicillin-resistant Staphylococcus aureus susceptibility to beta lactam antibiotics. AB - Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to beta-lactam antibiotics paired with beta-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components FtsA, FtsZ, and FtsW-as beta-lactam susceptibility determinants of methicillin resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with beta-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 A crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the beta-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to beta-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections. PMID- 22440738 TI - Prey digestion in the midgut of the predatory bug Podisus nigrispinus (Hemiptera: Pentatomidae). AB - Pre-oral digestion is described as the liquefaction of the solid tissues of the prey by secretions of the predator. It is uncertain if pre-oral digestion means pre-oral dispersion of food or true digestion in the sense of the stepwise bond breaking of food polymers to release monomers to be absorbed. Collagenase is the only salivary proteinase, which activity is significant (10%) in relation to Podisus nigrispinus midgut activities. This suggests that pre-oral digestion in P. nigrispinus consists in prey tissue dispersion. This was confirmed by the finding of prey muscles fibers inside P. nigrispinus midguts. Soluble midgut hydrolases from P. nigrispinus were partially purified by ion-exchange chromatography, followed by gel filtration. Two cathepsin L-like proteinases (CAL1 and CAL2) were isolated with the properties: CAL1 (14.7 kDa, pH optimum (pHo) 5.5, km with carbobenzoxy-Phe-Arg-methylcoumarin, Z-FR-MCA, 32 MUM); CAL2 (17 kDa, pHo 5.5, km 11 MUM Z-FR-MCA). Only a single molecular species was found for the other enzymes with the following properties are: amylase (43 kDa, pHo 5.5, km 0.1% starch), aminopeptidase (125 kDa, pHo 5.5, km 0.11 mM l-Leucine-p nitroanilide), alpha-glucosidase (90 kDa, pHo 5.0, km 5mM with p-nitrophenyl alpha-d-glucoside). CAL molecular masses are probably underestimated due to interaction with the column. Taking into account the distribution of hydrolases along P. nigrispinus midguts, carbohydrate digestion takes place mainly at the anterior midgut, whereas protein digestion occurs mostly in middle and posterior midgut, as previously described in seed- sucker and blood-feeder hemipterans. PMID- 22440739 TI - Exceptional plant penetration and feeding upon cortical parenchyma cells by the woolly poplar aphid. AB - Forty percent of aphids live wholly or partly on trees, most species being associated with leaves or petioles. Species able to exploit woody parts have either specific adaptations, such as extra long stylets that allow them to reach the phloem, or the ability to induce galls. The woolly poplar aphid, Phloeomyzus passerinii (Signoret) (Hemiptera: Aphididae), colonizes the trunks and base of the lower branches of mature poplars and causes cortical necrosis leading to the death of trees where infestation is heavy. Very little is known about the mode of feeding of P. passerinii. This study looked at the feeding behavior of P. passerinii on stem-cuttings of Populus x canadensis Moench using: (i) histological analyses of the feeding site and stylet pathway and (ii) electrical penetration graphs (EPG, DC) based on parthenogenetic apterous females on woody tissues. The histological and EPG results showed that stylets of P. passerinii penetrated into the plant tissues following a straight unbranched extracellular and intracellular pathway to reach the cortical parenchyma. Compared to EPGs for phloem sap feeding aphids, there were differences in the waveforms A and C whereas a new waveform Icp was described. Based on histological analyses and previous descriptions of EPG waveforms, correlations with the stylet tip position and aphid activities within bark tissues are discussed. A pathway and a sustained intracellular phase were distinguished, both occurring in the cortical parenchyma cells. The bark aphid feeding mode is discussed in relation to the damage caused and in terms of changes in the aphid's diet. PMID- 22440740 TI - The psycho-social impact of facial skin cancers. PMID- 22440741 TI - Positive or close margins in breast conserving surgery: is re-excision always necessary? AB - BACKGROUND: More than half of re-excision specimens after breast conserving surgery (BCS) are found to be free of residual tumor at definitive histology. The aim of this study was to identify clinicopathological factors along with intrinsic subtypes of the tumor (luminal A, luminal B, HER2-overexpressing, triple-negative) associated with residual tumor in re-excision or mastectomy specimen. METHODS: Two hundred forty-eight patients with initial BCS, who underwent one or more re-excisions or mastectomy because of close or positive margins were reviewed. RESULTS: Residual cancer was found in 50% of re excision(s) or mastectomy specimens. Patients with multifocality (vs unifocality; OR = 5.2; 95% CI, 2.6-10.4) or positive nodes (vs negative nodes; OR = 2.5; 95% CI, 1.4-4.4), or positive margins (vs close margins; OR = 1.7; 95% CI = 1.0-2.9) were more likely to have residual tumor in re-excision or mastectomy specimen compared to others. CONCLUSION: Our results suggest that further surgery is often indicated in patients with node positive or multifocal cancers or positive margins after BCS since residual disease cannot be ruled out. Re-excision or mastectomy could be omitted in patients with close margins with favorable factors such unifocal tumor or node negative disease. PMID- 22440742 TI - High expression of the transcriptional co-activator p300 predicts poor survival in resectable non-small cell lung cancers. AB - PURPOSE: To investigate the correlation between p300 (a transcriptional co activator) expression and clinical/prognostic characteristics in surgically resected NSCLC patients for the purpose of identifying patients with increased risk of cancer recurrence and providing them with tailored therapy. METHODS: One hundred and sixty-nine completely resected NSCLC patients were included in this study. Paraffin-embedded primary tumour tissues of patients were supplied to produce a tissue microarray, and immunohistochemistry was used for the evaluation of p300 expression. The clinical/prognostic significance of p300 expression was analysed for statistical significance. Survival was calculated by the Kaplan Meier method, and the log-rank test was used to assess differences in survival between the groups. The prognostic impact of clinicopathologic variables and p300 expression was evaluated using a Cox proportional hazards model. RESULTS: High expression of p300 was associated with poor disease-free survival (p = 0.027) and overall survival (p = 0.006) in NSCLC patients. Further analysis suggested that this difference in overall survival also existed in patients with T2 (p = 0.040), positive lymph nodes (p = 0.023), stage IIIA (p = 0.003), adenocarcinoma (p = 0.021), and a well-differentiated histological grade score (p = 0.011). The multivariate Cox regression analysis showed that low p300 expression is an independent marker of better disease-free survival (relative risk = 0.628, p = 0.047) and overall survival (relative risk = 0.545, p = 0.024) in operable NSCLC patients. CONCLUSIONS: Low p300 expression is an independent prognostic marker of better survival in operable NSCLC patients. The combination of clinicopathological TNM staging classification with p300 expression may be useful in identifying patients with increased risk of cancer recurrence to provide them with tailored therapy. PMID- 22440743 TI - Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. AB - BACKGROUND: Occasionally, patients with hepatocellular carcinoma (HCC) who receive radioembolization with palliative intent are downstaged for radical treatments. The aim of this study was to describe and analyze the overall survival (OS) in these patients compared with patients of the same baseline stage (UNOS T3), who were not eligible for radical treatment after radioembolization. METHODS: Between September 2003 and August 2010, 118 patients with HCC received radioembolization with yttrium-90 ((90)Y) resin microspheres. Of these, 21 patients with UNOS T3 stage were retrospectively identified and included in this analysis. RESULTS: In total, 6 of 21 patients were downstaged and treated radically between 2 and 35 months post-radioembolization. Three patients were resected, 2 received liver transplantation and 1 was ablated and then resected. Patients treated radically were significantly younger (62 vs. 73 years, p = 0.006) and had higher tumor volume (583 mL vs. 137 mL, p = 0.001) than patients who did not achieve radical treatment. There were no differences between the groups in number of lesions, BCLC stage, previous cirrhosis, activity administered per tumor volume, or median levels of alpha-fetoprotein or total bilirubin. Across the whole series, the median OS was 27.0 months (95% CI 5.0 48.9), varying significantly between those treated radically (OS not reached after a median follow-up of 41.5 months since radical therapy) and those who received palliative treatment only (22.0 months; 95% CI 15.0-30.9). CONCLUSIONS: Radical therapy following tumor downstaging with radioembolization provides the possibility of long-term survival in a select subgroup (UNOS T3 stage) with otherwise limited options. PMID- 22440744 TI - Evaluation of different antiepileptic drug strategies in medically refractory epilepsy patients following epilepsy surgery. AB - PURPOSE: This study aimed to explore the most appropriate antiepileptic drug strategies after successful epilepsy surgery. METHODS: A total of 131 refractory epilepsy patients who underwent epilepsy surgery from January 2005 to December 2008 in the Department of Neurosurgery, West China Hospital, were retrospectively reviewed. Patients were divided into three groups (monotherapy, duotherapy, and polytherapy) according to drug combinations used immediately after epilepsy surgery. Seizure outcomes were followed up for more than 2 years. Engel classification was used to evaluate seizure outcomes. RESULTS: The mean postoperative follow-up period was 3.7+/-1.0 years. Preoperative baseline data among the three groups were comparable. Seizure recurrence rate in monotherapy was obviously higher than in other groups (34.1% vs. 15.1%, 7.1%) at 6-month follow-up, which showed a statistically significant difference (p=0.02). Seizure outcomes for 2 years were assessed using Engel classification. In the duotherapy group, the rate of Engel class I was definitely higher than in the other two groups (69.9% vs. 47.7%, 57.1%, p=0.02). Seizure relapse rates at the 2-year follow-up, after planned reduction or withdrawal, were 46.4% for monotherapy, 16.9% for duotherapy, and 25.0% for polytherapy (p=0.01). CONCLUSIONS: Monotherapy may be not sufficient enough to control seizures completely. It appears to have a higher risk for seizure relapse when considering drug reduction. It suggests that duotherapy may be more effective and safer than monotherapy. Even after successful epilepsy surgery, duotherapy seems preferable to monotherapy or polytherapy for control of residual seizures. PMID- 22440745 TI - Environments and hominin activities across the FLK Peninsula during Zinjanthropus times (1.84 Ma), Olduvai Gorge, Tanzania. AB - We establish through 13 excavations the landscape context and nature of hominin activities across the Zinjanthropus land surface from which the Leakeys recovered the FLK 22 and FLK NN 1 paleoanthropological assemblages. The land surface was created by fluvial incision of the eastern margin of paleo-Lake Olduvai following a major lake withdrawal. Erosion was uneven, leaving a peninsula bounded by a river channel, the FLK Fault, and a freshwater wetland. This FLK Peninsula supported groves of trees that attracted hominins and carnivores, and that preserved the dense concentrations of carcass remains and stone tools they left behind, including those at FLK 22. Some carcasses appear to have been acquired at the ecotone of the Peninsula and Wetland, where another dense artifact and bone assemblage accumulated. A lesser topographic high at the edge of a Typha marsh in the Wetland was the site of FLK NN 1 and a scatter of large stone tools used possibly for rootstock processing. Our landscape reconstruction delimits the vegetation mosaic indicated by previous work and provides a topographical explanation for the existence of FLK 22 and FLK NN 1. Both are unexpected if the FLK area was the flat, featureless lake margin terrain typical of lake basins similar to paleo-Olduvai. The results show that the Leakeys' sites were not isolated occupation floors but rather parts of a land surface utilized intensively by hominins. Although commonly considered to have been home bases, their likely high predation risk, evidenced by large carnivore feeding traces and the remains of four hominin individuals, suggests visits to them were brief and limited to feeding. Finally, stratigraphic observations confirm that FLK NN 3 accumulated on an older land surface, refuting the hypothesis that the OH 8 foot found there is the same individual as the OH 35 leg from FLK 22. PMID- 22440746 TI - Fossil human remains from Bolomor Cave (Valencia, Spain). AB - Systematic excavations carried out since 1989 at Bolomor Cave have led to the recovery of four Pleistocene human fossil remains, consisting of a fibular fragment, two isolated teeth, and a nearly complete adult parietal bone. All of these specimens date to the late Middle and early Late Pleistocene (MIS 7-5e). The fibular fragment shows thick cortical bone, an archaic feature found in non modern (i.e. non-Homo sapiens) members of the genus Homo. Among the dental remains, the lack of a midtrigonid crest in the M(1) represents a departure from the morphology reported for the majority of Neandertal specimens, while the large dimensions and pronounced shoveling of the marginal ridges in the C(1) are similar to other European Middle and late Pleistocene fossils. The parietal bone is very thick, with dimensions that generally fall above Neandertal fossils and resemble more closely the Middle Pleistocene Atapuerca (SH) adult specimens. Based on the presence of archaic features, all the fossils from Bolomor are attributed to the Neandertal evolutionary lineage. PMID- 22440747 TI - New hominid fossils from Member 1 of the Swartkrans formation, South Africa. AB - Member 1 of the Swartkrans Formation is comprised of two sedimentary infills, the Lower Bank (LB) and the Hanging Remnant (HR). Together, the LB and HR preserve fossils of early Homo and Paranthropus robustus, Earlier Stone Age lithic artifacts, purported bone digging tools and butchered animal bones. Collectively, this evidence was the first to establish the co-existence of two early Pleistocene hominid species and also led to inferences of plant root harvesting and meat-eating by one or both of those species. P. robustus is the more abundant of the two hominids at Swartrkrans, represented in Member 1 by hundreds of fossils that derive from at least 99 individuals. Thus, Swartkrans Member 1 stands as the world's single largest repository of that extinct species. Here we add to the Member 1 sample of hominid fossils with descriptions of 14 newly discovered specimens. PMID- 22440748 TI - Battle of the sexes: conflict over dosage-sensitive genes and the origin of X chromosome inactivation. PMID- 22440749 TI - Locating binding poses in protein-ligand systems using reconnaissance metadynamics. AB - A molecular dynamics-based protocol is proposed for finding and scoring protein ligand binding poses. This protocol uses the recently developed reconnaissance metadynamics method, which employs a self-learning algorithm to construct a bias that pushes the system away from the kinetic traps where it would otherwise remain. The exploration of phase space with this algorithm is shown to be roughly six to eight times faster than unbiased molecular dynamics and is only limited by the time taken to diffuse about the surface of the protein. We apply this method to the well-studied trypsin-benzamidine system and show that we are able to refind all the poses obtained from a reference EADock blind docking calculation. These poses can be scored based on the length of time the system remains trapped in the pose. Alternatively, one can perform dimensionality reduction on the output trajectory and obtain a map of phase space that can be used in more expensive free-energy calculations. PMID- 22440750 TI - Long-distance correlations of rhinovirus capsid dynamics contribute to uncoating and antiviral activity. AB - Human rhinovirus (HRV) and other members of the enterovirus genus bind small molecule antiviral compounds in a cavity buried within the viral capsid protein VP1. These compounds block the release of the viral protein VP4 and RNA from inside the capsid during the uncoating process. In addition, the antiviral compounds prevent "breathing" motions, the transient externalization of the N terminal regions of VP1 and VP4 from the inside of intact viral capsid. The site for externalization of VP1/VP4 or release of RNA is likely between protomers, distant to the binding cavity for antiviral compounds. Molecular dynamics simulations were conducted to explore how the antiviral compound, WIN 52084, alters properties of the HRV 14 capsid through long-distance effect. We developed an approach to analyze capsid dynamics in terms of correlated radial motion and the shortest paths of correlated motions. In the absence of WIN, correlated radial motion is observed between residues separated by as much as 85 A, a remarkably long distance. The most frequently populated path segments of the network were localized near the fivefold symmetry axis and included those connecting the N termini of VP1 and VP4 with other regions, in particular near twofold symmetry axes, of the capsid. The results provide evidence that the virus capsid exhibits concerted long-range dynamics, which have not been previously recognized. Moreover, the presence of WIN destroys this radial correlation network, suggesting that the underlying motions contribute to a mechanistic basis for the initial steps of VP1 and VP4 externalization and uncoating. PMID- 22440751 TI - Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex. AB - Fibrillar collagens, the most abundant proteins in the vertebrate body, are involved in a plethora of biological interactions. Plasma protein von Willebrand factor (VWF) mediates adhesion of blood platelets to fibrillar collagen types I, II, and III, which is essential for normal haemostasis. High affinity VWF-binding sequences have been identified in the homotrimeric collagen types II and III, however, it is unclear how VWF recognizes the heterotrimeric collagen type I, the superstructure of which is unknown. Here we present the crystal structure of VWF domain A3 bound to a collagen type III-derived homotrimeric peptide. Our structure reveals that VWF-A3 interacts with all three collagen chains and binds through conformational selection to a sequence that is one triplet longer than was previously appreciated from platelet and VWF binding studies. The VWF-binding site overlaps those of SPARC (also known as osteonectin) and discodin domain receptor 2, but is more extended and shifted toward the collagen amino terminus. The observed collagen-binding mode of VWF-A3 provides direct structural constraints on collagen I chain registry. A VWF-binding site can be generated from the sequences RGQAGVMF, present in the two alpha1(I) chains, and RGEOGNIGF, in the unique alpha2(I) chain, provided that alpha2(I) is in the middle or trailing position. Combining these data with previous structural data on integrin binding to collagen yields strong support for the trailing position of the alpha2(I) chain, shedding light on the fundamental and long-standing question of the collagen I chain registry. PMID- 22440752 TI - Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity. AB - Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen specific cells while allowing the reconstitution of a naive T-cell pool. PMID- 22440753 TI - A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. AB - Increased nuclear accumulation of beta-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/beta-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the beta-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the beta-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the beta-catenin destruction complex, followed by increased degradation of beta-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of beta-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/beta-catenin signaling through inhibiting the PARP domain of TNKS1/2. PMID- 22440754 TI - Research utilisation and critical thinking among newly graduated nurses- predictors for research use: a quantitative cross-sectional study. PMID- 22440755 TI - The efficacy of psychosocial factors in predicting pain and functional outcomes following knee replacement surgery. PMID- 22440756 TI - Review: Lifestyle modifications and pharmacotherapy for cardiovascular risk factors are associated with improvements in erectile dysfunction. PMID- 22440757 TI - Various vitamin and mineral supplements are observed to increase mortality risk in older women, with the exception of calcium, which decreases risk. PMID- 22440758 TI - Proximal and distal contributions to lower extremity injury: a review of the literature. AB - Excessive or prolonged foot pronation has been linked to the development of numerous overuse injuries affecting the lower limb. The originally proposed pathomechanical model suggests foot motion affects more proximal structures through disruption of distal to proximal coupling between the foot, tibia, femur, and hip. Research evidence supports the presence of a dynamic coupling mechanism between lower limb segments, however, the direction of the coupling is inconclusive. Recent prospective investigations of the role of the lumbo-pelvic hip complex have identified a strong association between proximal dysfunction and increased risk of lower limb injuries. Strength of muscles of the lumbo-pelvic hip complex (core muscles) is suggested to be essential to controlling hip abduction, subsequent internal rotation of the femur and potentially more distal movement. Proximal muscle weakness and altered motor control have also been implicated in the development of numerous lower limb injuries, many of which have previously been attributed to excessive foot pronation. This review discusses the theoretical basis for the role of proximal and distal structures in biomechanical dysfunction of the lower limb and the development of lower limb overuse injury. Current prospective evidence relating to the contributions of excessive foot pronation and core muscle function to the development of lower extremity injury is evaluated. PMID- 22440759 TI - Physical function and associated factors in community-dwelling elderly people in Jalisco, Mexico. AB - PURPOSE: To determine the prevalence of disability in Basic Activities of Daily Living and Instrumental Activities of Daily Living (ADL and IADL, respectively), as well as associated factors in the Mexican community-dwelling elderly population. MATERIALS AND METHODS: This is a cross-sectional study of a population 60 years and older who live in the State of Jalisco (Mexico). A total of 2553 persons were assessed regarding their functional and health conditions. The ADL and IADL were classified as dependent and non-dependent, and crude and adjusted Odds Ratio (OR) were calculated. RESULTS: Mean age of participants was 71.6+/-8.7, 61.2% were women. A disability prevalence of 9.6% was found to perform ADL and of 31.5% for the IADL, 14.3% had cognitive impairment and 30.9% depression. Risk factors were found for dependence: being a woman, being >=75 years old, low education level, having at least one chronic disease, cognitive impairment, depression, previous history of disability, and having been a lifelong housewife. CONCLUSIONS: Functional difficulties are common in Mexican elderly population. These data show key variables for functional disability risk. A better understanding of functional capabilities, as well as of risk factors older adults face every day provide us with a guide to devise a prevention plan, to implement adequate interventions, or to provide appropriate care. PMID- 22440760 TI - Microsatellite mapping of quantitative trait loci affecting meat quality, stress hormones and production traits in Duroc * Large White F2 pigs. AB - An F2 cross between Duroc and Large White pigs was carried out in order to detect quantitative trait loci (QTL) for 11 meat quality traits (L*, a* and b* Minolta coordinates and water-holding capacity (WHC) of two ham muscles, ultimate pH of two ham and one loin muscles), 13 production traits (birth weight, average daily gain during post-weaning and fattening periods, carcass fat depths at three locations, estimated lean meat content, carcass length and weights of five carcass cuts) and three stress hormone-level traits (cortisol, adrenaline and noradrenaline). Animals from the three generations of the experimental design (including 456 F2 pigs) were genotyped for 91 microsatellite markers covering all the autosomes. A total of 56 QTL were detected: 49 reached the chromosome-wide level (suggestive QTL with a maximal probability of 0.05) and seven were significant at the genome-wide level (with a probability varying from 6 * 10(-4) to 3 * 10(-3)). Twenty suggestive QTL were identified for ultimate pH, colour measurements and WHC on chromosome (SSC) 5, 6, 7, 8, 9, 11, 13, 14, 15 and 17. For production traits, 33 QTL were detected on all autosomes except SSC6, 8 and 9. Seven of these QTL, located on SSC2, 3, 10, 13, 16 and 17, exceeded the genome wide significance threshold. Finally, three QTL were identified for levels of stress hormones: a QTL for cortisol level on SSC7 in the cortisol-binding globulin gene region, a QTL for adrenaline level on SSC10 and a QTL for noradrenaline level on SSC13. Among all the detected QTL, seven are described for the first time: a QTL for ultimate pH measurement on SSC5, two QTL affecting birth weight on SSC2 and 10, two QTL for growth rate on SSC15 (during fattening) and 17 (during post-weaning) and two QTL affecting the adrenaline and noradrenaline levels. For each QTL, only one to five of the six F1 sires were found to be heterozygous. It means that all QTL are segregating in at least one of the founder populations used in this study. These results suggest that both meat quality and production traits can be improved in purebred Duroc and Large White pigs through marker-assisted selection. It is of particular interest for meat quality traits, which are difficult to include in classical selection programmes. PMID- 22440761 TI - A hidden Markov model to predict early mastitis from test-day somatic cell scores. AB - In many countries, high somatic cell scores (SCS) in milk are used as an indicator for mastitis because they are collected on a routine basis. However, individual test-day SCS are not very accurate in identifying infected cows. Mathematical models may improve the accuracy of the biological marker by making better use of the information contained in the available data. Here, a simple hidden Markov model (HMM) is described mathematically and applied to SCS recorded monthly on cows with or without clinical mastitis to evaluate its accuracy in estimating parameters (mean, variance and transition probabilities) under healthy or diseased states. The SCS means were estimated at 1.96 (s.d. = 0.16) and 4.73 (s.d. = 0.71) for the hidden healthy and infected states, and the common variance at 0.83 (s.d. = 0.11). The probability of remaining uninfected, recovering from infection, getting newly infected and remaining infected between consecutive test days was estimated at 78.84%, 60.49%, 11.70% and 15%, respectively. Three different health-related states were compared: clinical stages observed by farmers, subclinical cases defined for somatic cell counts below or above 250 000 cells/ml and infected stages obtained from the HMM. The results showed that HMM identifies infected cows before the appearance of clinical and subclinical signs, which may critically improve the power of the studies on the genetic determinants of SCS and reduce biases in predicting breeding values for SCS. PMID- 22440762 TI - Effects of genetic merit for carcass weight, breed type and slaughter weight on performance and carcass traits of beef * dairy steers. AB - Crossbreeding of Holstein-Friesian dairy cows with both early maturing (e.g. Aberdeen Angus (AA)) and late maturing (e.g. Belgian Blue (BB)) beef breeds is commonly practised. In Ireland, genetic merit for growth rate of beef sires is expressed as expected progeny difference for carcass weight (EPD(CWT)). The objective of this study was to compare the progeny of Holstein-Friesian cows, sired by AA and BB bulls of low (L) and high (H) EPD(CWT) for performance and carcass traits. A total of 118 spring-born male progeny from 20 (9 AA and 11 BB) sires (8 L and 12 H) were managed together from shortly after birth to about 19 months of age. They were then assigned to one of two mean slaughter weights (560 kg (light) or 620 kg (heavy)). Following slaughter, carcasses were graded for conformation class and fat class, the 6th to 10th ribs joint was dissected as an indicator of carcass composition, and samples of subcutaneous fat and musculus longissimus were subjected to Hunterlab colour measurements. A sample of m. longissimus was also chemically analysed. Slaughter and carcass weights per day of age for AAL, AAH, BBL and BBH were 747, 789, 790 and 805 (s.e. 10.5) g, and 385, 411, 427 and 443 (s.e. 4.4) g, respectively. Corresponding carcass weight, kill-out proportion, carcass conformation class (scale 1 to 5) and carcass fat class (scale 1 to 5) values were 289, 312, 320 and 333 (s.e. 4.0) kg, 516, 522, 542 and 553 (s.e. 3.5) g/kg, 2.5, 2.4, 3.0 and 3.1 (s.e. 0.10), and 3.4, 3.5, 2.9 and 2.8 (s.e. 0.11). There were few breed type * genetic merit interactions. Delaying slaughter date increased slaughter weight, carcass weight and all measures of fatness. It also reduced the proportion of carcass weight in the hind quarter and the proportions of bone and muscle in the ribs joint. None of these effects accompanied the increase in carcass weight due to higher EPD(CWT). It is concluded that BB have superior production traits to AA. Selection of sires for higher EPD(CWT) increases growth rate, kill-out proportion and carcass weight of progeny with little effect on carcass or muscle traits. The extra carcass weight due to higher EPD(CWT) is more valuable commercially than a comparable carcass weight increment from a delay in slaughter date because it comprises a higher proportion of muscle. PMID- 22440763 TI - A chromosome-wide QTL study on BTA29 affecting temperament traits in German Angus beef cattle and mapping of DRD4. AB - The behaviour of beef cattle is important for the safety and welfare of stockmen and animals. Ten microsatellites spanning BTA29 and, in addition, the candidate gene, dopamine receptor D4 gene, were analysed in 545 German Angus calves of six sires and included in a quantitative trait locus (QTL) study on the basis of three different behaviour tests. A putative QTL for the score while entering the scale (ScE) was detected at BMS764. The DRD4 fragment was mapped in the distal region of BTA29 15.3 cM distal of ILSTS081. The results clearly indicate that BTA29 with a putative QTL in the proximal part and the candidate gene, DRD4, in the distal part plays an important role in the regulation of temperament. During the study one of the sires was detected to be a blood chimera. PMID- 22440764 TI - Responses of prolactin and hair growth to selection for age at puberty in Angus cattle. AB - A trial was carried out over a 7-year period (1999 to 2005 calf crops) to compare indicators of seasonality in Angus cattle, which were part of a long-term genetic selection experiment. Divergent selection was applied for early ('AGE-') or late ('AGE+') age at puberty (AP) in heifers, and selection lines differed over the 7 year period by 62 days (15% of the mean). The primary measures of seasonality studied in 629 heifer progeny (59 sire groups) were serum concentration of prolactin (PRL), and winter and summer hair growth. Serial samples were obtained for PRL from 11 to 18 months of age, and data were analysed with adjustment for cortisol concentration. Using restricted maximum likelihood procedures with an animal model, heritability estimates were: AP, 0.26 +/- 0.03; log(e)PRL concentration, 0.23 +/- 0.07; log(e)cortisol concentration, 0.22 +/- 0.07; hair weight, 0.21 +/- 0.04; and hair length, 0.09 +/- 0.05. Corresponding repeatability estimates for the last four traits were 0.49 +/- 0.03, 0.38 +/- 0.03, 0.21 +/- 0.04, and 0.64 +/- 0.02, respectively. The genetic correlation between AP and log(e)PRL concentration was estimated at -0.29 +/- 0.13 (P < 0.05). PRL concentration in the AGE- line after passing through puberty was 11 +/ 5% lower than in the AGE+ line (P < 0.05). Line effects were not significant for hair weight or hair length. It was concluded that divergent selection for AP changed PRL concentration, which may partly reflect sensitivity to changing day length. PMID- 22440765 TI - Dynamics of energy utilization in male and female turkeys during growth. AB - Determining energy utilization in growing animals enables to adjust the nutritional constraints to nutrient requirements while maximizing the ratio between lean retention and fat retention to improve feed efficiency. In turkey production, the important sexual dimorphism and differences between strains may contribute to differences in basal energy metabolism and the partitioning of energy retention between protein and lipid. The objective of this study was to determine the dynamics of energy utilization in males and females of a heavy strain of turkeys fed ad libitum from 1 to 23 weeks of age. Heat production (HP) was determined by indirect calorimetry and retained energy (RE) was calculated as the difference between metabolizable energy (ME) intake and HP. The RE as protein was determined by a nitrogen balance, while the remaining RE was assumed to be lipid. A modeling procedure allowed partitioning HP between fasting HP (FHP), activity-related HP and thermic effect of feeding. A multiple regression analysis was used to estimate the maintenance energy expenditure (ME(m)) and the energy efficiencies of protein and lipid retention (k(p) and k(f), respectively). Results were expressed either per day or per kg BW(0.75) per day. In comparison with females, males consumed more feed (440 v. 368 g/day), grew faster (163 v. 147 g/day) and retained more protein (38 v. 28 g/day) during the experimental period. Expressed per kg BW(0.75) per day, ME intake decreased linearly with increasing age and was not affected by gender. Similarly, RE as protein decreased with increasing age and tended to be greater in males than in females, whereas RE as lipid increased with increasing age and was lower in males than in females. In addition, HP decreased with increasing age and was greater in males than in females, because of greater activity-related HP and FHP (47% and 9% greater in males compared with females). The FHP averaged 417 kJ/(kg BW)(0.75) per day during the first 3 weeks of age and decreased to 317 and 277 kJ/(kg BW)(0.75) per day in males and females, respectively, from 20 weeks of age onwards. Similar to FHP, ME(m) was lower in females than in males ((586 to 12 * BW) and (586 to 5 * BW) kJ/(kg BW)(0.75) per day, respectively) and the k(p) and k(f) were estimated at 0.63 and 0.87, respectively. This study shows that the partitioning of RE and HP differs between genders in growing turkeys, which likely results in differences in nutrient requirements. PMID- 22440766 TI - Gastrointestinal development of dairy calves fed low- or high-starch concentrate at two milk allowances. AB - The objective was to study the effect of type of concentrate with varying starch and fibre content on growth and gastrointestinal development in preweaned dairy calves. Thirty-two newborn Danish Holstein male calves were allocated to four treatment groups in eight blocks of four calves. An experimental low-starch, high molasses, high-fibre (EXP) concentrate or a traditional high-starch (TRA) concentrate were fed either at a high (HIGH; 2 * 3.2 kg/day) or a low (LOW; 2 * 1.6 kg/day) whole milk allowance in a 2 * 2 factorial design. TRA contained 350 and EXP 107 g starch/kg dry matter (DM), whereas the NDF content was 136 and 296 g/kg DM, respectively. Metabolizable energy (ME) was 11.2 and 12.2 MJ ME/kg DM in EXP and TRA, respectively. All calves had free access to artificially dried grass hay (9.8 MJ ME/kg DM). Four calves were culled during the experiment. The calves were euthanized either at 38 (12 calves) or 56 days (16 calves) of age. Evaluated across both slaughter ages, there was no difference between TRA and EXP in concentrate and hay intake, rumen weight and papillation. EXP resulted in increased villi number in duodenum and jejunum compared with TRA. Concentrate intake and reticulo-rumen weight was higher for LOW compared with HIGH milk allowance, whereas live weight gain was 20% lower. The results show that a low starch, high-molasses, high-fibre concentrate with 8% lower ME content tended to reduce daily gain compared with a traditional calf starter concentrate, but resulted in similar ruminal development in preweaned calves both on a high and a low milk allowance fed along with grass hay. Furthermore, the results suggest that the experimental concentrate stimulated intestinal villi growth over that of the traditional concentrate. PMID- 22440767 TI - Effects of an immunomodulatory feed additive on the development of mastitis in a mouse infection model using four bovine-origin isolates. AB - The goal of this study was to examine the ability of a commercially available feed additive (OmniGen-AF) to reduce mammary infections caused by a single strain of mastitic pathogens (Streptococcus uberis, Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae) and to examine the effects of the additive on markers of mammary immunity. Four experiments were completed using a murine model of bovine mastitis. Infection progression was examined using Sybr-green- and TaqMan-based quantitative PCR assays of 16S ribosomal DNA. Infection of the mammary gland with all pathogens caused rapid (24 to 48 h) appearance of pathogen DNA in mammary tissue. Provision of the feed additive for 2 weeks before infection significantly (P < 0.05) reduced the extent of pathogen DNA accumulation in models of S. uberis, E. coli and S. aureus infection. The additive was ineffective in reducing mammary infections caused by K. pneumoniae. We examined mechanisms of action of the additive through assessment of mammary concentrations of mammary myeloperoxidase (MPO), major histocompatibility complex 2 class II (MHC) and macrophage inflammatory protein-1alpha (MIP) messenger RNA (mRNA) concentrations and by examining serum complement C3 concentration. Infection of the mammary gland increased concentrations of MPO and MHC mRNAs (P < 0.05). Ability of the pathogen to elicit changes in mammary MPO and MHC gene expression was enhanced by the provision of the additive for 2 weeks before infection. These data imply that the additive increased the mammary inflammatory response and increased antigen presentation during a mammary infection. Value of the additive in preventing mastitis in cattle awaits additional studies using a bovine model and further evaluation of additional strains of the pathogens used in this study. PMID- 22440768 TI - Is sequential feeding of whole wheat more efficient than ground wheat in laying hens? AB - The impact of sequential feeding of whole or ground wheat on the performance of layer hen was investigated using ISABROWN hens from 19 to 42 weeks of age. In addition, the effect of reduced dietary energy content of a complete diet was also investigated. Four treatments were tested. Whole wheat was alternated with a protein-mineral concentrate (balancer diet) in a treatment (sequential whole wheat: SWW), while another treatment alternated ground wheat (sequential ground wheat: SGW) with the same balancer diet. The control (C) was fed a complete layer diet conventionally. Another treatment (low energy: LE) was fed a complete diet conventionally. The diet contained lower energy (10.7 v. 11.6 MJ/kg) compared to the C. Each treatment was allocated 16 cages and each cage contained five birds. Light was provided 16 h daily (0400 to 2000 h). Feed offered was controlled (121 g/bird per day) and distributed twice (2 * 60.5 g) at 4 and 11 h after lights on. In the sequential treatment, only wheat (whole or ground) was fed during the first distribution and the balancer diet during the second distribution. Left over feed was always removed before the next distribution. The total feed intake was not different between SWW and SGW, but the two were lower than C (P < 0.05). Wheat intake was however, lowered with SGW compared to SWW (P < 0.05). Egg production and egg mass (EM) were not different between treatments. Egg weight was lower with SGW than with SWW (P < 0.05), but the two were similar to C. Body weight (BW) was lowered (P < 0.01) with SGW relative to SWW and C, SWW BW being also lower than the C one. The efficiency of egg production was increased (P < 0.01) with the SWW and SGW relative to the control. Birds fed LE had higher feed intake (P < 0.05) but they had similar egg production and EM compared to the two sequential treatments. The efficiency of feed utilization was also reduced (P < 0.01) with LE compared to SWW and SGW. It was concluded that sequential feeding is more efficient than conventional feeding. In addition, whole wheat appeared more efficient than ground wheat in terms of egg and BW. PMID- 22440769 TI - Performance and plasma metabolites of dairy calves fed starter containing sodium butyrate, calcium propionate or sodium monensin. AB - This study was conducted to examine the influence of supplementation of sodium butyrate, sodium monensin or calcium propionate in a starter diet on the performance and selected plasma metabolites (plasma glucose, non-esterified fatty acids and beta-hydroxybutyrate) of Holstein calves during pre- and post-weaning periods. Twenty-four newborn Holstein calves were housed in individual hutches until 10 weeks of life, receiving water free choice, and fed four liters of milk daily. Calves were blocked according to weight and date of birth, and allocated to one of the following treatments, according to the additive in the starter: (i) sodium butyrate (150 g/kg); (ii) sodium monensin (30 mg/kg); and (iii) calcium propionate (150 g/kg). During 10 weeks, calves received starter ad libitum, while coast cross hay (Cynodon dactylon (L.) pers.) was offered after weaning, which occurred at the 8th week of age. Weekly, calves were weighted and evaluated for body measurements. Blood samples were taken weekly after the fourth week of age, 2 hours after the morning feeding, for determination of plasma metabolites. No differences were observed among treatments for starter or hay intake, BW and daily gain of the animals. Mean concentrations of selected plasma metabolites were similar in calves fed a starter supplemented with sodium butyrate, sodium monensin and calcium propionate. There was significant reduction in the concentrations of plasma glucose as calves aged. The inclusion of sodium butyrate, calcium propionate or sodium monensin as additives in starter feeds resulted in equal animal performance, before and after weaning, suggesting that sodium monensin may be replaced by organic acid salts. PMID- 22440770 TI - Leptin in farm animals: where are we and where can we go? AB - Fat affects meat quality, value and production efficiency as well as providing energy reserves for pregnancy and lactation in farm livestock. Leptin, the adipocyte product of the obese (ob) gene, was quickly seen as a predictor of body fat content in animals approaching slaughter and an aid to assessing reproductive readiness in females. Its participation in inflammation and immune responses that help animals survive infection and trauma has clear additional relevance to meat and milk production. Furthermore, almost a decade of discoveries of nucleotide polymorphisms in the leptin and leptin receptor genes has suggested useful applications relating to feed intake regulation, the efficiency of feed use, the composition of growth, the timing of puberty, mammogenesis and mammary gland function and fertility in cattle, pigs and poultry. The current review attempts to summarise where research has taken us in each of these aspects and speculates on where future research might lead. PMID- 22440771 TI - High-protein diet during gestation and lactation affects mammary gland mRNA abundance, milk composition and pre-weaning litter growth in mice. AB - We evaluated the effect of a high-protein diet (HP) on pregnancy, lactational and rearing success in mice. At the time of mating, females were randomly assigned to isoenergetic diets with HP (40% w/w) or control protein levels (C; 20%). After parturition, half of the dams were fed the other diet throughout lactation resulting in four dietary groups: CC (C diet during gestation and lactation), CHP (C diet during gestation and HP diet during lactation), HPC (HP diet during gestation and C diet during lactation) and HPHP (HP diet during gestation and lactation). Maternal and offspring body mass was monitored. Measurements of maternal mammary gland (MG), kidney and abdominal fat pad masses, MG histology and MG mRNA abundance, as well as milk composition were taken at selected time points. HP diet decreased abdominal fat and increased kidney mass of lactating dams. Litter mass at birth was lower in HP than in C dams (14.8 v. 16.8 g). Dams fed an HP diet during lactation showed 5% less food intake (10.4 v. 10.9 g/day) and lower body and MG mass. On day 14 of lactation, the proportion of MG parenchyma was lower in dams fed an HP diet during gestation as compared to dams fed a C diet (64.8% v. 75.8%). Abundance of MG alpha-lactalbumin, beta-casein, whey acidic protein, xanthine oxidoreductase mRNA at mid-lactation was decreased in all groups receiving an HP diet either during gestation and/or lactation. Milk lactose content was lower in dams fed an HP diet during lactation compared to dams fed a C diet (1.6% v. 2.0%). On days 14, 18 and 21 of lactation total litter mass was lower in litters of dams fed an HP diet during lactation, and the pups' relative kidney mass was greater than in litters suckled by dams receiving a C diet. These findings indicate that excess protein intake in reproducing mice has adverse effects on offspring early in their postnatal growth as a consequence of impaired lactational function. PMID- 22440772 TI - Myostatin inactivation induces a similar muscle molecular signature in double muscled cattle as in mice. AB - Myostatin (MSTN), a member of the TGF-beta superfamily, is a negative regulator of skeletal muscle mass. We have previously shown that the cell survival/apoptosis pathway is a downstream target of MSTN loss-of-function in mice through the regulation of the expression or abundance of many survival and apoptotic factors. In this study, we used western-blot and quantitative PCR (qPCR) analyses to validate these novel downstream targets of MSTN in double muscled (DM) cattle v. their controls including 260-day-old foetuses and adult cows from the INRA95 strain. MSTN loss-of-function in DM foetuses and DM cows resulted in a glycolytic shift of the muscles (e.g. upregulation of H-MyBP, PGM1 and SNTA1 and downregulation of H-FABP), activation of cell survival pathway through regulation of some components of the PI3K/Akt pathway (e.g. upregulation of DJ-1 and Gsk-3betaser9/Gsk-3betatotal ratio and downregulation of PTEN) and upregulation of cell survival factors translationally controlled tumour protein (14-3-3E, Pink1). We also found a lower abundance of pro-apoptotic transcripts and/or proteins (Caspase-3, caspase-8, caspase-9, BID, ID2 and Daxx) and a higher expression of anti-apoptotic transcripts (Traf2 and Bcl2l2) in DM muscles. All together, these results are in favour of activation of the cell survival pathway and loss of apoptosis pathway within the muscles of DM animals. Alteration of both pathways may increase myonuclear or satellite cell survival, which is crucial for protein synthesis. This could contribute to muscle hypertrophy in DM foetuses and DM cows. PMID- 22440773 TI - Factors associated with mortality of broilers during transport to slaughterhouse. AB - In recent years, broiler mortality during transport to the slaughterhouse has become a cause for concern because of animal welfare considerations and associated economic losses. A descriptive and analytical epidemiological study was carried out to estimate the extent of DoA in poultry broiler production in the main producing regions of France and to determine factors influencing the DoA rate. Data regarding animal characteristics and rearing, catching, transport and lairage conditions were collected on farm and at the slaughterhouse for 404 chicken broiler flocks processed during 2005. The average DoA rate was 0.18% (from 0% to 1.4%). Variables found to be associated (P < 0.05) with the DoA rate in a multivariable negative binomial model were flock cumulative mortality on farm, the catching system (mechanical being more at risk than manual), the density in crates (more space allowance being associated with less mortality) and climatic conditions (rain and wind being associated with more DoA). Mortality during transport is thus related to all production steps from the farm to the slaughterhouse. Efforts have therefore to be made by all professionals to contain mortality on farm and during catching and transportation. PMID- 22440774 TI - Performance, ruminal changes, behaviour and welfare of growing heifers fed a concentrate diet with or without barley straw. AB - Two experiments were conducted to ascertain the effects of feeding an all concentrate diet to growing heifers on performance, ruminal fermentation, behaviour and welfare. In experiment 1, eight tethered rumen fistulated Holstein heifers (143 +/- 8.7 kg, initial BW) were used to study the effects of treatment on intake, ruminal changes and behaviour. In experiment 2, 48 Friesian female calves (initial BW = 84.5 +/- 1.37 kg) were used to study the effects of treatment on performance, behaviour and welfare in feedlot conditions. In both experiments, treatments consisted of concentrate with barley straw (BS) or without barley straw (NBS) and feed was offered at 0830 h on an ad libitum basis. Experiment 1 was performed in four 42-day periods, and sampling was carried out in the last week of each period. Ruminal samples were collected over 3 days at 0, 4, 8 and 12 h post-feeding to measure pH, and volatile fatty acids (VFA) and NH(3)-N concentrations. Maintenance behaviour was video-recorded for 24 h over three consecutive days of each experimental period and feed intake pattern was studied by means of feed bunks mounted on digital platform scales. There were no statistical differences in average daily gain (ADG), concentrate dry matter (DM) intake or CP intake. In contrast, NDF intake and ADF intake were greater in heifers fed BS than NBS. Average ruminal pH was lower, whereas total VFA was greater, in heifers fed NBS diet. There were no differences in NH(3)-N, and in D- and L-lactate concentrations. Time spent in ruminating was shorter, and stereotypies were more frequent in heifers fed diet NBS compared with those fed BS. In experiment 2, nine 28-day periods were established, in which DM intake and ADG were measured, blood and faecal samples were taken for haptoglobin and glucocorticoid metabolites determination, respectively, as welfare indicators, and behaviour was monitored by video recording. Concentrate intake was similar in both treatments, but total feed intake was greater in heifers fed BS diet. As there were no differences in ADG between treatments, gain efficiency was lower in those fed BS than those fed NBS. Blood haptoglobin and faecal glucocorticoids metabolites were not different between treatments. In these competitive conditions, rumination was also reduced and stereotypic behaviour increased by straw exclusion. In conclusion, performance was either not affected or improved by straw exclusion, but animal behaviour was affected, suggesting a negative effect on animal welfare. PMID- 22440775 TI - Effects of dietary allicin on health and growth performance of weanling piglets and reduction in attractiveness of faeces to flies. AB - To investigate the effect of dietary allicin on health and growth performance of weanling piglets, at 21 days of age. Two hundred and twenty-five piglets were weaned and randomly allocated into five groups. Piglets in the control group were fed diets supplemented with antibiotics. Those in the treatment groups were fed diets without antibiotics, but supplemented with allicin product (25% pure allicin oil) in the proportion of 0.10 g/kg, 0.15 g/kg, 0.20 g/kg and 0.25 g/kg in the diet, respectively. During the 28 days of the experiment, average daily weight gain increased linearly (P < 0.0001) and quadratically (P = 0.0014) as the level of dietary allicin increased. The feed gain ratio decreased linearly (P < 0.0001) and quadratically (P < 0.0001). As the dietary allicin level increased, the incidence of diarrhoea in the treatment piglets, especially female piglets decreased linearly (P = 0.0003) and tended to decrease quadratically (P = 0.0716). The number of flies alighting on the surface of the faeces of the piglets at each counting time point decreased linearly (P < 0.0001), quadratically (P < 0.0001) and cubically (P < 0.0001) as the dietary allicin level increased. In conclusion, supplementation of the diet with allicin may improve growth performance, reduce the incidence of diarrhoea and possibly improve their local environmental conditions by reducing the attractiveness of faeces to flies. PMID- 22440776 TI - Effect of fast-, medium- and slow-growing strains on meat quality of chickens reared under the organic farming method. AB - The characteristics of meat quality, chemical and fatty acid composition, from fast-growing (FG) and medium-growing (MG) meat-type and slow-growing (SG) egg type chickens reared under organic conditions were compared. Three-hundred and sixty 1-day-old male chicks, equally divided into three experimental groups represented by strains (FG: Cobb 700, MG: Naked neck Kabir and SG: Brown Classic Lohman) were housed into three poultry houses with outdoor pasture availability of 10 m(2)/bird located in the same Research Centre of the University of Perugia. All the birds were fed ad libitum the same diets formulated according to the European Union (EU) Regulations by using organic raw materials. Birds from the FG and MG groups were raised until 81 days, whereas birds from the SG group were raised until 96 days in order to achieve an acceptable market live weight. SG birds showed significantly (P < 0.01) higher breast meat drip and cook losses, Allo-Kramer shear values and collagen content. In comparison with FG and SG, MG exhibited a higher breast meat pH (5.86% v. 5.79% and 5.78%, respectively; P < 0.01) and a lower lightness (54.88% v. 57.81% and 56.98%, respectively; P < 0.05). Genotype dramatically affected the lipid content as well as the fatty acid composition of both breast and thigh meat. SG exhibited the lowest content of lipid, both in breast and in thigh meat, the lowest proportions of monounsaturated fatty acids (MUFA) and the highest proportions of polyunsaturated fatty acids (PUFA). The total n-3 PUFA of SG breast meat was double that of FG meat and intermediate with respect to MG birds (8.07% v. 4.07% v. 5.14% total fatty acids; P < 0.01). The fatty acid composition of thigh meat is similar to that of breast meat, but the differences among genotypes are less pronounced. Total saturated fatty acids were not affected by the genotype. In conclusion, meat functional properties of FG and MG strains appeared much more attractive both for industry and consumer (lower drip and cook losses and higher tenderness), whereas from a nutritional point of view, meat from SG appeared healthier (less fat and higher content of n-3 PUFA) and thus might better fit with the consumer's expectations of organic products. PMID- 22440777 TI - The effect of equol injection in ovo on posthatch growth, meat quality and antioxidation in broilers. AB - In order to investigate the long-term effects of equol (Eq) on growth and meat quality in broilers, 0 MUg (control, Con), 20 MUg (low dose, L) and 100 MUg (high dose, H) Eq, respectively, were injected into fertile eggs (146 eggs per group) on 7 days of embryos. After hatch, chickens were fed under the same conditions and slaughtered at 49 days of age for sample collection and analysis. The results showed that body weight and composition were marginally affected by Eq administration (P > 0.05). Compared with their male counterparts, the meat quality of female broilers was affected greatly after Eq administration. The redness (a*) of meat color in the L and H groups of female broilers was significantly decreased by 24.10% and 21.50% (P < 0.01), respectively; cooking loss decreased by 12.11% and 16.82%, respectively, in the L and H groups (P < 0.01); 24 h and 48 h drip loss was significantly decreased by 60.27% and 45.72% (P < 0.05), respectively, in the H group. However, for male broilers, only cooking loss was significantly decreased by high dosage of Eq treatment (P < 0.05). The antioxidative status was analyzed for discovering further the mechanism behind the improvement of the water-holding capacity caused by Eq in female broilers. The activity of glutathione peroxidase (GSHPx) in plasma was greatly increased by 15.94% in the L group (P < 0.01), whereas the total superoxide dismutase activity (T-SOD) and the content of malondialdehyde in plasma were not changed (P > 0.05). The T-SOD activity in the breast muscle of the L and H groups were significantly improved by 23.14% and 18.82% (P < 0.05), respectively. GSHPx in the breast muscle of the H group showed a tendency to increase (P = 0.06 < 0.1). These results indicate that Eq injection in ovo does not affect the growth of broilers, but significantly improves the water-holding capacity of the muscle, especially in female broilers, which is related to the improvement of antioxidative status. PMID- 22440778 TI - Sense of place and place identity: review of neuroscientific evidence. AB - The aim of this review is to bring the phenomenological sense of place approach together with current results from neuroscience. We searched in neuroscientific literature for ten dimensions which were beforehand identified to be important in a phenomenological sense of place/place identity model: behaviour, body, emotion, attention, perception, memory, orientation, spirituality, meaning/value and culture/sociality. Neuroscience has identified many neurobiological correlates of phenomenological observations concerning sense of place. The human brain comprises specific and specialised structures and processes to perceive, memorise, link, assess and use spatial information. Specific parts (hippocampus, entorhinal, parahippocampal and parietal cortex), subregions (parahippocampal place area, lingual landmark area), and cells (place cells, grid cells, border cells, head direction cells) have been identified, their specific function could be understood and their interaction traced. Neuroscience has provided evidence that place constitutes a distinct dimension in neuronal processing. This reinforces the phenomenological argumentation of human geography and environmental psychology. PMID- 22440779 TI - Defying deprivation: a cross-sectional analysis of area level health resilience in England. AB - Previous research has found evidence that some economically deprived areas in England exhibit 'health resilience' in terms of lower than expected mortality rates. Consistent with earlier research we analysed area 'resilience' for parliamentary constituencies and our work extends previous research by including measures of morbidity. Standardised Morbidity Ratios (SMRs) of self-reported general health, limiting long-term illness, emergency hospital admissions, and CHD hospital admissions were derived from the 2001 UK Census and 2001 Hospital Episodes Statistics, and combined into a Composite Morbidity Index (CMI). Area variation in the CMI was compared with previous findings about mortality rates. Multiple Correspondence Analysis (MCA) was used to test the associations between area level 'health resilience' and ethnic composition, residential mobility, employment type, housing tenure, and an indicator of social cohesion. Nine areas were 'resilient' in terms of morbidity. Only four areas of England exhibited 'health resilience' in terms of both mortality and morbidity. MCA revealed that there may be several factors associated with greater 'health resilience'. PMID- 22440780 TI - Editorial overview. PMID- 22440781 TI - Innate and adaptive immune responses to viral infection and vaccination. AB - Recent accumulating evidence suggests that the human immune system possesses a variety of innate receptors that recognize, distinguish, and respond to viral infections and to vaccination. These include Toll-like receptors, C-type lectin receptors, RIG-I-like receptors, Nod-like receptors and possibly AIM2-like receptors. However, the precise mechanisms by which these receptors exert their critical roles in the induction of virus-specific adaptive immune responses have not been fully elucidated. In this review, we discuss recent advances in our understanding of the innate immune recognition of viruses and the differential connection to the adaptive immune responses induced by infection or vaccination, with a particular focus on the influenza virus. PMID- 22440782 TI - Selected approaches for increasing HIV DNA vaccine immunogenicity in vivo. AB - The safety, stability, and ability for repeat homologous vaccination makes the DNA vaccine platform an excellent candidate for an effective HIV-1 vaccine. However, the immunogenicity of early DNA vaccines did not translate from small animal models into larger non-human primates and was markedly lower than viral vectors. In addition to improvements to the DNA vector itself, delivery with electroporation, the inclusion of molecular adjuvants, and heterologous prime boost strategies have dramatically improved the immunogenicity of DNA vaccines for HIV and currently makes them a leading platform with many areas warranting further research and clinical development. PMID- 22440783 TI - Ethics of vaccination programs. AB - Ethical issues are present at each stage in the vaccine product life cycle, the period extending from the earliest stages of research through the eventual design and implementation of global vaccination programs. Recent developments highlight fundamental principles of vaccine ethics and raise unique issues for ongoing vaccination activities worldwide. These include the 2009-10 H1N1 pandemic influenza vaccination campaign, renewed attention to the potential global eradication of polio, and the ongoing evaluation of vaccine risk controversies, most notably the alleged link between childhood vaccines and autism. These cases present ethical challenges for public health policy-makers, scientists, physicians, and other stakeholders in their efforts to improve the health of individuals, communities, and nations through vaccination. PMID- 22440784 TI - It's a small world after all-viral genomics and the global dominance of viruses. PMID- 22440785 TI - Exploring the viral world through metagenomics. AB - Viral metagenomics, or shotgun sequencing of purified viral particles, has revolutionized the field of environmental virology by allowing the exploration of viral communities in a variety of sample types throughout the biosphere. The introduction of viral metagenomics has demonstrated that dominant viruses in environmental communities are not well-represented by the cultured viruses in existing sequence databases. Viral metagenomic studies have provided insights into viral ecology by elucidating the genetic potential, community structure, and biogeography of environmental viruses. In addition, viral metagenomics has expanded current knowledge of virus-host interactions by uncovering genes that may allow viruses to manipulate their hosts in unexpected ways. The intrinsic potential for virus discovery through viral metagenomics can help advance a wide array of disciplines including evolutionary biology, pathogen surveillance, and biotechnology. PMID- 22440786 TI - Enduring response to everolimus as third-line therapy in a patient with advanced renal cell carcinoma, including small-bowel metastases: loss of FHIT but normal VHL gene status. PMID- 22440787 TI - Metabolic tumor volume by 18F-FDG PET/CT is prognostic for stage IVB endometrial carcinoma. AB - OBJECTIVE: The objective of this study was to evaluate the potential prognostic factors in patients with primary stage IVB endometrial carcinoma, incorporating parameters from (18)F-FDG PET/CT such as standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). METHODS: Patients with primary M1 endometrial carcinoma who received (18)F-FDG PET/CT before treatment were retrospectively analyzed. Histological type, histological grade, T stage, N stage, age, ECOG performance status, hormone receptor status, metastatic patterns, number of involved metastatic patterns, serum CA125 level, and (18)F-FDG PET/CT derived parameters including total body SUVmax, total body MTV, and total body TLG were considered as potential prognostic factors for overall survival. Cox proportional hazards regression model was used for statistical analysis. RESULTS: Fifteen patients were eligible with a median survival of 17 months. Total body MTV and total body TLG were highly collinear (Pearson's r=0.978) and were found to be significant prognosticators (P=0.010 and 0.011 respectively). Four patients with total body MTV above 450 mL (or total body TLG above 2700 g) had a median survival of two months, while the remaining patients had a median survival of 47 months. CONCLUSION: Total body MTV is a significant prognostic factor for overall survival in patients with stage IVB endometrial carcinoma. Patients with total body MTV above 450 mL had a very poor survival, while more aggressive therapy may be considered in the remaining patients in pursuit of prolonged survival. PMID- 22440788 TI - Targeting high affinity and epitope-distinct oligoclonal nanobodies to HER2 over expressing tumor cells. AB - Modern anti-HER2 antibody therapy tends to exploit a panel of different antibodies against different epitopes on the antigen. For this aim, nanobodies are very striking targeting agents and can be easily produced against any cell specific membrane antigen. The oligoclonal nanobodies can be used to block more than one functional epitope on a target antigen and inhibit the generation of escape variants associated with cancer therapy. In this study, 12 nanobody clones selected from an immune camel library were examined for their ability to differ between tumor markers. These oligoclonal nanobodies targeted breast cancer cells better than each individual nanobody. In epitope mapping, several nanobodies overlapped in the epitope recognized by trastuzumab and some of the non overlapping nanobodies could affect the binding of trastuzumab to HER2. This study demonstrates that the oligoclonal nanobodies are potential therapeutic tools that can be used instead of, or in combination with trastuzumab to assess tumor viability during treatment. PMID- 22440790 TI - [Objectives of hemodynamic resuscitation in severe head injuries. Another point of view]. PMID- 22440789 TI - Is interpolation cognitively encapsulated? Measuring the effects of belief on Kanizsa shape discrimination and illusory contour formation. AB - Contour interpolation is a perceptual process that fills-in missing edges on the basis of how surrounding edges (inducers) are spatiotemporally related. Cognitive encapsulation refers to the degree to which perceptual mechanisms act in isolation from beliefs, expectations, and utilities (Pylyshyn, 1999). Is interpolation encapsulated from belief? We addressed this question by having subjects discriminate briefly-presented, partially-visible fat and thin shapes, the edges of which either induced or did not induce illusory contours (relatable and non-relatable conditions, respectively). Half the trials in each condition incorporated task-irrelevant distractor lines, known to disrupt the filling-in of contours. Half of the observers were told that the visible parts of the shape belonged to a single thing (group strategy); the other half were told that the visible parts were disconnected (ungroup strategy). It was found that distractor lines strongly impaired performance in the relatable condition, but minimally in the non-relatable condition; that strategy did not alter the effects of the distractor lines for either the relatable or non-relatable stimuli; and that cognitively grouping relatable fragments improved performance whereas cognitively grouping non-relatable fragments did not. These results suggest that (1) filling in effects during illusory contour formation cannot be easily removed via strategy; (2) filling-in effects cannot be easily manufactured from stimuli that fail to elicit interpolation; and (3) actively grouping fragments can readily improve discrimination performance, but only when those fragments form interpolated contours. Taken together, these findings indicate that discriminating filled-in shapes depends on strategy but the filling-in process itself may be encapsulated from belief. PMID- 22440791 TI - Influence of HBcAb positivity in the organ donor in heart transplantation. AB - OBJECTIVE: There is a significant risk of hepatitis B transmission from HBsAg ( ), HBcAb (+) donors in liver transplantation, but there is little information about hepatitis B transmission from HBcAb heart donors. The present study examines the influence of HBcAb presence in relation to heart donor acceptance and offers an update of the published studies. DESIGN: Survey and medical database update from 1994 to October 2011. SETTING: Spanish heart transplantation teams. PATIENTS: Not applicable. STUDY VARIABLES: Acceptance of heart transplant from an HBcAb (+) organ donor. RESULTS: Twelve out of 15 surveyed teams were seen to vaccinate against HBV, and two quantify HBsAb titers. Seven teams specifically request donor HBcAb status. If the latter proves positive, two do not accept transplantation, two accept if the donor is also HBsAb (+), one selects the receptor under emergency conditions, and three use drug prophylaxis isolatedly or complementary to the above. Only one case of hepatitis B has been reported in a HBcAb (-) and HBsAb (-) receptor that did not receive prophylactic measures. There have been reports of seroconversion of the HBcAb and HBsAb markers, though with an uncertain etiology. CONCLUSIONS: HBcAb seropositivity influences acceptance of a heart donor, but agreement is lacking. There is limited information on receptor evolution. To date there has been one reported case of hepatitis B after heart transplant. Although rare, an HBcAb (+) donor can harbor occult HBV infection. The risk of infection can be prevented with appropriate HBsAb titers following vaccination or by pharmacological measures. PMID- 22440792 TI - Metacognitive functioning and social cognition as predictors of accuracy of self appraisals of vocational function in schizophrenia. PMID- 22440793 TI - Time for order in microbial systematics. PMID- 22440794 TI - The femoral insertion of the anterior cruciate ligament: discrepancy between macroscopic and histological observations. AB - PURPOSE: To observe the femoral anterior cruciate ligament (ACL) insertion macroscopically, histologically, and immunohistologically. METHODS: We used 20 embalmed cadaveric knees (mean age, 69.8 +/- 5.3 years) for this study. The femoral ACL insertion was observed macroscopically, and areas were measured with digital calipers. The morphology of the ACL insertion was subsequently observed, and the areas were measured histologically and immunohistologically (stained for types I and III collagen). Finally, the macroscopic and microscopic measurements were compared. RESULTS: Macroscopically, in 16 knees, the proximal ACL fibers spread in a fanlike manner on the medial aspect of the lateral femoral condyle and the femoral insertion was oval. The lengths of the long and short axes of the insertion were 17.7 +/- 2.7 mm and 4.6 +/- 0.7 mm, respectively. Microscopically, the insertion was located just behind the lateral intercondylar ridge (resident's ridge) and could be divided into the direct and indirect insertions. The direct insertion was 5.3 +/- 1.1 mm wide and did not continue to the posterior cartilage. The indirect insertion was located behind the direct insertion, and the posterior ACL fiber stained for type I collagen blended into the posterior cartilage on immunohistologic observations. Another bony ridge was found at the posterior margin of the direct insertion. The widths of the direct insertion were similar between microscopic and macroscopic measurements. CONCLUSIONS: The femoral ACL insertion observed macroscopically corresponded to the direct insertion observed microscopically. The posterior portion behind the lateral intercondylar posterior ridge was the indirect insertion microscopically and appeared membrane-like macroscopically. CLINICAL RELEVANCE: Findings from observation of the lateral intercondylar posterior ridge during arthroscopy and consideration of the distance from the posterior cartilage border may contribute to surgeons' decisions about femoral tunnel placement during anatomic ACL reconstruction. PMID- 22440795 TI - Medial meniscus tear morphology and chondral degeneration of the knee: is there a relationship? AB - PURPOSE: The purpose of this study was to examine the association of medial meniscus tear morphology with the pathogenesis of articular cartilage degeneration. METHODS: From May 2006 to December 2007, we prospectively evaluated 103 patients diagnosed with an isolated medial meniscus tear. Meniscus tear morphology and location, cartilage degeneration according to the Noyes score, and covariates including age, body mass index, gender, and injury date were documented. The relationship between severity of articular cartilage degeneration and meniscus tear morphology was analyzed by analysis of variance. Regression analysis was used to analyze predictors of severity of cartilage lesions. RESULTS: Analysis of variance showed significant differences in the severity of articular cartilage lesions based on medial meniscus tear morphology (P < .05). Compared with bucket-handle/vertical tears, root and radial/flap tears were associated with significantly greater degeneration on the medial femoral condyle; root and complex tears were associated with significantly greater degeneration on the medial tibial plateau; and radial/flap tears were associated with significantly greater degeneration on the lateral tibial plateau. Age and gender were significant predictors of the Noyes medial-compartment score, and age, body mass index, and meniscus tear morphology were significant predictors of the Noyes lateral-compartment score. CONCLUSIONS: Meniscus tears with increasing disruption of the circumferential meniscal fibers were significantly associated with cartilage lesions of increasing severity in both the medial and lateral compartments of the knee. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 22440796 TI - Cajal-Retzius cells. PMID- 22440797 TI - Chimpanzee carrying behaviour and the origins of human bipedality. PMID- 22440798 TI - Evolutionary ecology: next generation inference. AB - Oak forests support a rich ecology of fellow travellers, but how do these fare when the forests move during glacial cycles? The answers revealed by a new study are important for ecology, but being able to get answers at all highlights a turning point in evolutionary inference. PMID- 22440799 TI - Pheromones: fish fear factor. AB - Fish, like many other animals, panic when another individual is injured. Now, the chemical nature of a substance that mediates this reaction has been uncovered. PMID- 22440800 TI - Active vision: fixational eye movements help seeing space in time. AB - The significance of the miniature eye movements that we make during visual fixation has been intensely debated for the last 80 years. Recent studies have revealed that these motions of the eyes fulfill an important functional role: helping to extract useful information from natural scenes. PMID- 22440801 TI - Subcellular organization: change of phase in partitioning the cellular milieu. AB - Spatial organization and segregation are essential for the function of a complex and crowded cellular machine. New work demonstrates liquid-gel phase separation, both in vitro and in vivo, driven by the valency of constituent proteins. PMID- 22440802 TI - Speech perception: when to put your money where the mouth is. AB - Visual information augments our understanding of auditory speech. New evidence shows that infants' gaze fixations to the mouth and eye region shift predictably with changes in age and language familiarity. PMID- 22440803 TI - Dendritic patterning: three-dimensional position determines dendritic avoidance capability. AB - Neurons develop mutually exclusive dendritic domains through self-avoidance and tiling mechanisms. Two recent studies establish that this process is dependent on the restriction of dendrites to a two-dimensional plane through interactions with the extracellular matrix. PMID- 22440804 TI - Motor control: learning new moves with old pumps. AB - A recent study has identified a novel form of short-term memory in the spinal cord that employs a ubiquitous mechanism for cellular homeostasis to encode neuronal network activity and adjust locomotor behaviour on the basis of past performance. PMID- 22440805 TI - Learning, attentional control, and action video games. AB - While humans have an incredible capacity to acquire new skills and alter their behavior as a result of experience, enhancements in performance are typically narrowly restricted to the parameters of the training environment, with little evidence of generalization to different, even seemingly highly related, tasks. Such specificity is a major obstacle for the development of many real-world training or rehabilitation paradigms, which necessarily seek to promote more general learning. In contrast to these typical findings, research over the past decade has shown that training on 'action video games' produces learning that transfers well beyond the training task. This has led to substantial interest among those interested in rehabilitation, for instance, after stroke or to treat amblyopia, or training for various precision-demanding jobs, for instance, endoscopic surgery or piloting unmanned aerial drones. Although the predominant focus of the field has been on outlining the breadth of possible action-game related enhancements, recent work has concentrated on uncovering the mechanisms that underlie these changes, an important first step towards the goal of designing and using video games for more definite purposes. Game playing may not convey an immediate advantage on new tasks (increased performance from the very first trial), but rather the true effect of action video game playing may be to enhance the ability to learn new tasks. Such a mechanism may serve as a signature of training regimens that are likely to produce transfer of learning. PMID- 22440806 TI - A case of epididymitis associated with Panton-Valentine leukocidin Staphylococcus aureus. AB - A new pattern of disease caused by Panton-Valentine leukocidin (PVL)-positive strains of Staphylococcus aureus is emerging in the UK and worldwide. Community associated methicillin-resistant S aureus (MRSA) is more likely to produce PVL, a pore-forming cytotoxin inducing leucocyte lysis, which often infects young healthy individuals. The worldwide emergence and continually increasing prevalence of community-acquired PVL-MRSA have recently attracted high-profile media attention and prompted concern regarding the transmissibility and virulence. This paper reports a case of genitourinary tract infection associated with PVL-positive community-associated MRSA in an immunocompetent young man. PMID- 22440807 TI - Suppressed left atrial function in PAF. PMID- 22440808 TI - Improvement in ARDS experimental model installation: low mortality rate and maintenance of hemodynamic stability. AB - INTRODUCTION: Many experimental models using lung lavage have been developed for the study of acute respiratory distress syndrome (ARDS). The original technique has been modified by many authors, resulting in difficulties with reproducibility. There is insufficient detail on the lung injury models used, including hemodynamic stability during animal preparation and drawbacks encountered such as mortality. The authors studied the effects of the pulmonary recruitment and the use of fixed tidal volume (Vt) or fixed inspiratory pressure in the experimental ARDS model installation. METHODS: Adult rabbits were submitted to repeated lung lavages with 30 ml/kg warm saline until the ARDS definition (PaO2/FiO2 <= 100) was reached. The animals were divided into three groups, according to the technique used for mechanical ventilation: 1) fixed Vt of 10 ml/kg; 2) fixed inspiratory pressure (IP) with a tidal volume of 10 ml/kg prior to the first lung lavage; and 3) fixed Vt of 10 ml/kg with pulmonary recruitment before the first lavage. RESULTS: The use of alveolar recruitment maneuvers, and the use of a fixed Vt or IP between the lung lavages did not change the number of lung lavages necessary to obtain the experimental model of ARDS or the hemodynamic stability of the animals during the procedure. A trend was observed toward an increased mortality rate with the recruitment maneuver and with the use of a fixed IP. DISCUSSION: There were no differences between the three study groups, with no disadvantage in method of lung recruitment, either fixed tidal volume or fixed inspiratory pressure, regarding the number of lung lavages necessary to obtain the ARDS animal model. Furthermore, the three different procedures resulted in good hemodynamic stability of the animals, and low mortality rate. PMID- 22440809 TI - Documenting thermoregulatory system activity in burn patients. PMID- 22440810 TI - The Gilles de la Tourette syndrome: the current status. AB - Gilles de la Tourette syndrome (GTS) is characterised by multiple motor and one or more vocal/phonic tics. GTS was once thought to be rare, but many relatively recent studies suggest that the prevalence is about 1% of the worldwide community, apart from in Sub-Saharan Black Africa. Comorbidity and coexistent psychopathology are common, occurring in about 90% of clinical cohorts and individuals in the community. The most common comorbidities are attention deficit hyperactivity disorder, obsessive-compulsive behaviours, and disorder, and autistic spectrum disorders, while the most common coexisting psychopathologies are depression, anxiety and behavioural disorders such as oppositional defiant and conduct disorder. There has been an increasing amount of evidence to show that the quality of life in young people is reduced when compared with normative data or healthy control populations. It is widely accepted that most cases of GTS are inherited, but the genetic mechanisms appear much more complex than previously understood, as evidenced by many recent studies; indeed, there have been suggestions of 'general neurodevelopmental genes' which affect the brain development after which the 'specific GTS gene(s)' may further affect the phenotype. Other aetiopathogenetic suggestions have included environmental factors such as neuro-immunological factors, infections, prenatal and peri-natal difficulties and androgen influences. Few studies have addressed aetiology and phenotype, but initial results are exciting. The search for endophenotypes has followed subsequently. Intriguing neuroanatomical and brain circuitry abnormalities have now been suggested in GTS; the most evidence is for cortical thinning and a reduction in the size of the caudate nucleus. Thorough assessment is imperative and multidisciplinary management is the ideal. Treatment should be 'symptom targeted', and in mild cases, psycho-education and reassurance for the patient and the family may be sufficient. Behavioural treatments such as Comprehensive Behavioural Intervention for Tics including Habit Reversal Training have been shown to be significantly better than other behavioural/psychological treatments and 'placebo'. Medication is often necessary for moderately affected individuals. In more severe cases, medical treatment is not simple and referral to an expert may be advisable. In general, neuroleptics and clonidine or guanfacine are the medications of choice for the tics. Other treatments which may be needed for loud and severe phonic tics include botulinum toxin. In severe adult GTS patients who are refractory to medication and other therapies, deep brain stimulation looks promising. PMID- 22440811 TI - Prenatal polycyclic aromatic hydrocarbon (PAH) exposure and child behavior at age 6-7 years. AB - BACKGROUND: Airborne polycyclic aromatic hydrocarbons (PAH) are widespread urban air pollutants from fossil fuel burning and other combustion sources. We previously reported that a broad spectrum of combustion-related DNA adducts in cord blood was associated with attention problems at 6-7 years of age in the Columbia Center for Children's Environmental Health (CCCEH) longitudinal cohort study. OBJECTIVES: We evaluated the relationship between behavioral problems and two different measures of prenatal exposure--both specific to PAH--in the same cohort. METHODS: Children of nonsmoking African-American and Dominican women in New York City (NYC) were followed from in utero to 6-7 years. Prenatal PAH exposure was estimated by personal air monitoring of the mothers during pregnancy as well as by the measurement of DNA adducts specific to benzo[a]pyrene (BaP), a representative PAH, in maternal and cord blood. At 6-7 years of age, child behavior was assessed using the Child Behavior Checklist (CBCL) (n = 253). Generalized linear models were used to test the association between prenatal PAH exposure and behavioral outcomes. RESULTS: In multivariate analyses, high prenatal PAH exposure, whether characterized by personal air monitoring (greater than the median of 2.27 ng/m3) or maternal and cord adducts (detectable or higher), was positively associated with symptoms of Anxious/Depressed and Attention Problems (p <= 0.05). CONCLUSION: These results provide additional evidence that environmental levels of PAH encountered in NYC air can adversely affect child behavior. PMID- 22440812 TI - Intraocular distribution of melanin in human, monkey, rabbit, minipig and dog eyes. AB - The purpose of this study was to quantify the melanin pigment content in sclera, choroid-RPE, and retina, three tissues encountered during transscleral drug delivery to the vitreous, in human, rabbit, monkey, minipig, and dog models. Strain differences were assessed in NZW * NZR F1 and Dutch belted rabbits and Yucatan and Gottingen minipigs. The choroid-RPE and retina tissues were divided into central (posterior pole area) and peripheral (away from posterior pole) regions while the sclera was analyzed without such division. Melanin content in the tissues was analyzed using a colorimetric assay. In all species the rank order for pigment content was: choroid-RPE >retina >= sclera, except in humans, where scleral melanin levels were higher than retina and central choroid. The melanin content in a given tissue differed between species. Further, while the peripheral tissue pigment levels tended to be generally higher compared to the central regions, these differences were significant in human in the case of choroid-RPE and in human, monkey, and dogs in the case of retina. Strain difference was observed only in the central choroid-RPE region of rabbits (NZW * NZR F1 >Dutch Belted). Species, strain, and regional differences exist in the melanin pigment content in the tissues of the posterior segment of the eye, with Gottingen minipig being closest to humans among the animals assessed. These differences in melanin content might contribute to differences in drug binding, delivery, and toxicity. PMID- 22440813 TI - Retinal blood flow abnormalities following six months of hyperglycemia in the Ins2(Akita) mouse. AB - The aim of this study was to characterize the microvascular flow abnormalities and oxygenation changes that are present following six months of hyperglycemia in the diabetic Ins2(Akita) mouse. Previous studies have shown decreased retinal blood flow in the first several weeks of hyperglycemia in rodents, similar to the decreases seen in the early stages of human diabetes. However, whether this alteration in the mouse retina continues beyond the initial weeks of diabetes has yet to be determined, as are the potential consequences of the decreased flow on retinal oxygenation. In this study, male Ins2(Akita) and age-matched C57BL/6 (non diabetic) mice were maintained for a period of six months, at which time intravital microscopy was used to measure retinal blood vessel diameters, blood cell velocity, vascular wall shear rates, blood flow rates, and transient capillary occlusions. In addition, the presence of hypoxia was assessed using the oxygen-sensitive probe pimonidazole. The diabetic retinal microvasculature displayed decreases in red blood cell velocity (30%, p<0.001), shear rate (25%, p<0.01), and flow rate (40%, p<0.001). Moreover, transient capillary stoppages in flow were observed in the diabetic mice, but rarely in the non-diabetic mice. However, no alterations were observed in retinal hypoxia as determined by a pimonidazole assay, suggesting the possibility that the decreases seen in retinal blood flow may be dictated by a decrease in retinal oxygen utilization. PMID- 22440814 TI - [Sedation and analgesia in emergency structure. Which sedation and/or analgesia for tracheal intubation?]. PMID- 22440815 TI - [Sedation and analgesia in emergency structure. Which sedation and analgesia for the intubated patient under mechanical ventilation?]. PMID- 22440816 TI - [Sedation and analgesia in emergency structure. Which sedation and/or analgesia for emergency external electrical cardioversion?]. PMID- 22440817 TI - [Sedation and analgesia in emergency structure. Which sedation and/or analgesia for painful treatments?]. PMID- 22440818 TI - Ultrasound detection of calcium pyrophosphate dihydrate crystal deposits in menisci: a pilot in vivo and ex vivo study. PMID- 22440819 TI - Frequency and duration of drug-free remission after 1 year of treatment with etanercept versus sulfasalazine in early axial spondyloarthritis: 2 year data of the ESTHER trial. AB - PURPOSE: The aims of this study were (1) to assess the frequency and duration of drug-free remission and efficacy of etanercept (ETA) treatment after flare in patients with early active axial spondyloarthritis who were treated with ETA (n=40) versus sulfasalazine (SSZ, n=36) for 48 weeks and (2) to analyse the efficacy of ETA treatment in patients in year 2 who did not reach remission at week 48. METHOD: At week 48, patients who reached study remission (Assessment of Spondyloarthritis international Society (ASAS) plus MRI remission) were followed up without active treatment up to 1 year. In case of a flare, patients were treated with ETA for another year. All patients who were not in ASAS plus MRI remission at week 48 were treated with ETA in year 2. RESULTS: ASAS plus MRI remission at week 48 was reached significantly more often in ETA-treated compared to SSZ-treated patients (33% vs 11%, p=0.03). However, the flare rate was not different between these two groups: 69% in the ETA group versus 75% in the SSZ group. Only 8% of patients initially treated with ETA versus 3% of those initially treated with SSZ reached permanent drug-free remission (not significant). After treatment with ETA over 1 year, patients with flare showed an improvement in all clinical and imaging variables. CONCLUSION: Patients with axial spondyloarthritis treated with ETA over 1 year did not reach drug-free remission in a higher percentage compared to patients from a control group treated with SSZ. PMID- 22440820 TI - IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. AB - OBJECTIVE: The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. METHODS: The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 - discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 - replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. RESULTS: Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant. CONCLUSION: An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc. PMID- 22440821 TI - Treatment-specific changes in circulating adipocytokines: a comparison between tumour necrosis factor blockade and glucocorticoid treatment for rheumatoid arthritis. AB - OBJECTIVE: There is increasing evidence that adipocytokines may exert proinflammatory and destructive effects in rheumatoid arthritis (RA). Hence, the authors investigated the relationship between adipocytokines and several features associated with RA (inflammation, joint destruction and cardiovascular disease), as well as the effect of treatment with a tumour necrosis factor inhibitor or glucocorticoids (GCs) hereupon. METHODS: Serum levels of adiponectin, leptin, resistin, visfatin, vaspin and lipids were determined in a well-defined cohort of patients with RA before and after 16 weeks of adalimumab treatment (adalimumab cohort). The same parameters were analysed in two other cohorts of patients with RA before and after 2 weeks of high-dose prednisolone (high GC cohort) and before and after 22 weeks of treatment with a combination regimen with tapered high-dose prednisolone (COBRA -GC cohort). Radiographs of hands and feet (adalimumab and COBRA-GC cohorts) were assessed at baseline and after treatment. RESULTS: Treatment with adalimumab or GC showed opposing effects on vaspin and visfatin levels. Lipid levels improved after several months of adalimumab or GC treatment; in the adalimumab cohort, this was related to reduced visfatin levels, independent of C reactive protein levels. After long-term adalimumab or GC treatment, resistin levels declined, which was associated with a decrease in inflammation markers. In the adalimumab cohort, baseline resistin levels were predictive of baseline radiological damage, independent of anticitrullinated peptide antibodies status or C reactive protein levels. CONCLUSION: Changes in serum adipocytokine levels were treatment specific, further strengthening the role of visfatin and resistin in several disease manifestations of RA. PMID- 22440822 TI - Patient and provider barriers to effective management of gout in general practice: a qualitative study. AB - OBJECTIVES: To explore patient and provider illness perceptions and barriers to effective management of gout in general practice. DESIGN AND SETTING: A qualitative study involving semistructured face-to-face interviews with patients and health professionals from 25 Nottinghamshire general practices and one central National Health Service hospital. PARTICIPANTS: Twenty gout sufferers and 18 health professionals (six general practitioners, five hospital physicians, seven practice nurses). RESULTS: A number of key themes emerged suggesting that several factors impact on patients' access to recommended treatments. The main barriers were patient experiences and lay beliefs of their condition which affected seeking advice and adherence to treatment. There was universal lack of knowledge and understanding of the causes and consequences of gout and that it can be treated effectively by lifestyle change and use of urate lowering therapy (ULT). All participants associated gout with negative stereotypical images portrayed in Victorian cartoons. Many viewed it as self-inflicted or part of ageing and only focused on managing acute attacks rather than treating the underlying cause. The main provider barriers that emerged related to health professionals' lack of knowledge of gout and management guidelines, reflected in the suboptimal information they gave patients and their reluctance to offer ULT as a 'curative' long-term management strategy. CONCLUSION: There are widespread misconceptions and lack of knowledge among both patients and health professionals concerning the nature of gout and its recommended management, which leads to suboptimal care of the most common inflammatory joint disease and the only one for which we have 'curative' treatment. PMID- 22440823 TI - Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study. AB - BACKGROUND: Interleukin (IL)-15 levels are increased in serum, synovium and bone marrow of patients with rheumatoid arthritis (RA). IL-15 influences both the innate and the adaptive immune response; its major role is activation and proliferation of T cells. There are also emerging data that IL-15 affects osteoclastogenesis. The authors investigated the association of genetic variants in IL15 with the rate of joint destruction in RA. METHOD: 1418 patients with 4885 x-ray sets of both hands and feet of four independent data sets were studied. First, explorative analyses were performed on 600 patients with early RA enrolled in the Leiden Early Arthritis Clinic. Twenty-five single-nucleotide polymorphisms (SNPs) tagging IL-15 were tested. Second, SNPs with significant associations in the explorative phase were genotyped in data sets from Groningen, Sheffield and Lund. In each data set, the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarised in an inverse weighting meta-analysis. RESULTS: Five SNPs were significantly associated with rate of joint destruction in phase 1 and typed in the other data sets. Patients homozygous for rs7667746, rs7665842, rs2322182, rs6821171 and rs4371699 had respectively 0.94-, 1.04-, 1.09-, 1.09- and 1.09-fold rate of joint destruction compared to other patients (p=4.0*10(-6), p=3.8*10(-4), p=5.0*10(-3), p=5.0*10(-3) and p=9.4*10(-3)). DISCUSSION: Independent replication was not obtained, possibly due to insufficient power. Meta-analyses of all data sets combined resulted in significant results for four SNPs (rs7667746, p<0.001; rs7665842, p<0.001; rs4371699, p=0.01; rs6821171, p=0.01). These SNPs were also significant after correction for multiple testing. CONCLUSION: Genetic variants in IL-15 are associated with progression of joint destruction in RA. PMID- 22440824 TI - No impact of serum uric acid on the outcome of recent-onset arthritis. PMID- 22440825 TI - Relationship between area-level socio-economic deprivation and autoantibody status in patients with rheumatoid arthritis: multicentre cross-sectional study. AB - OBJECTIVES: The aims of this study were to assess the association between area level socio-economic deprivation and the phenotype of rheumatoid arthritis (RA), defined by rheumatoid factor (RF) and anticitrullinated peptide antibody (AC PA) status, and to determine whether any observed association can be explained by smoking. METHODS: The authors performed logistic regression analysis of 6298 patients with RA, defined by American College of Rheumatology classification criteria modified for genetic studies. Analysis was stratified by cohort/recruitment centre. Socio-economic deprivation was measured using the Townsend Index. RESULTS: Deprivation predicted RF but not ACPA positivity, independent of smoking. The ORs for trend across tertiles, adjusted for smoking, gender, period of birth and cohort/recruitment centre, were 1.14 (95% CI 1.01 to 1.29) for RF and 1.01 (95% CI 0.87 to 1.16) for ACPA. Even after adjusting for deprivation, smoking was strongly associated with ACPA positivity (OR 1.38, 95% CI 1.22 to 1.55). There was no evidence of any effect modification by the RA risk alleles (HLA-DRB1 shared epitope and PTPN22 rs2476601) that have previously been shown to modify the effect of smoking on ACPA and RF positivity. CONCLUSIONS: Among patients with RA, deprivation predicted RF positivity but not ACPA positivity. The effect of deprivation did not appear to be explained by smoking. Deprivation may be a marker for previously unrecognised, potentially modifiable environmental influences on the immunological phenotype of RA. Furthermore, given the known associations of RF positivity with prognosis and response to treatment in RA, these findings have potential implications for resource allocation and healthcare delivery. PMID- 22440826 TI - Predicting longitudinal trajectory of bone mineral density in paediatric systemic lupus erythematosus patients. AB - OBJECTIVES: (1) To identify the average lumbar spine (LS) bone mineral density (BMD) trajectory in paediatric systemic lupus erythematosus (pSLE) patients, and (2) to identify predictors of BMD trajectory. METHODS: 68 consecutive newly diagnosed pSLE patients prospectively followed in our lupus cohort with three annual dual energy x-ray absorptiometry (DEXA) examinations were studied. Low LS BMD was defined as z-score <=-2.0. Baseline and longitudinal clinical features including disease activity, treatment and bone physiology markers were collected. Hierarchical linear modelling was used to model trajectory of LS BMD and identify predictors. RESULTS: Women constituted 84% of the cohort and median age at diagnosis was 13.1 years. The mean LS BMD z-scores decreased over time (-0.42 at first, -1.02 at second and -1.11 at third DEXA). Initially 9% of patients had a low BMD, which increased to 19% by 3 years after diagnosis. 35% of patients deteriorated in BMD category from the first to third DEXA. LS BMD (adjusted by height-for-age z-score) followed a general deteriorating trajectory of -0.06 z score/year from diagnosis. Increased rate of deterioration of BMD trajectory was predicted by pubertal status at diagnosis, increased interval cumulative steroid exposure and decreased weight z-scores. CONCLUSIONS: The LS BMD of pSLE patients followed a general deteriorating trend over time and could be predicted by a combination of pubertal status at diagnosis, interval cumulative doses of steroids and weight z-scores. Interval cumulative steroid dose represents an important target that clinicians may modify to ameliorate deteriorating BMD trajectory over time. PMID- 22440827 TI - A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. AB - OBJECTIVES: The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA). METHODS: Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test. RESULTS: In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3*10(-5) and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays. CONCLUSIONS: These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain. PMID- 22440828 TI - A heat-stable cytotoxic factor produced by Achromobacter xylosoxidans isolated from Brazilian patients with CF is associated with in vitro increased proinflammatory cytokines. AB - BACKGROUND: Recently, Achromobacter xylosoxidans has been related to chronic lung diseases in patients suffering from cystic fibrosis (CF), but its involvement has not been elucidated. Some virulence properties of A. xylosoxidans isolated from Brazilian patients with CF were revealed in this work. METHODS: This study examined the production of a cytotoxic factor of A. xylosoxidans capable of stimulating the secretion of inflammatory cytokines (IL-6 and IL-8) from lung mucoepidermoid carcinoma cells (NCI-H292). The cytokines were measured using enzyme-linked immunosorbent (ELISA) assays. To investigate whether the cytotoxic factors may be endotoxins, they were treated with polymyxin B. RESULTS: The culture supernatants of all A. xylosoxidans produced a heat stable, active cytotoxin in NCI-H292 cells capable of leading to intracellular vacuoles and subsequent cell contact loss, chromatin condensation, a picnotic nucleus and cell death. There was a higher concentration of proinflammatory cytokines in the NCI H292 cells after 24 h of incubation, with the fraction greater than 50 kDa from the culture supernatant. The cytotoxin activity remained even after treatment with polymyxin B, which suggested that the release of IL-6 and IL-8 was not stimulated by lipopolysaccharide (LPS). CONCLUSION: The cytotoxic factor produced by A. xylosoxidans may represent an important virulence factor, which when associated with CF chronic lung inflammation, may cause tissue damage and decline of lung function. PMID- 22440829 TI - The apolipoprotein E polymorphism and cardiovascular diseases--an autopsy study. AB - BACKGROUND: Numerous studies have addressed the association between the apolipoprotein E polymorphism and cardiovascular disease, but only a few reports are based on findings at autopsy. In the present retrospective study, we have used autopsy findings from a general hospital population to further investigate this issue. METHODS AND RESULTS: We collected information from 1522 consecutive autopsy reports (886 men, mean age 65.7 years; 636 women, mean age 69.7 years) conducted at Oslo University Hospital, Norway, in the period from 1996 to 2000. Cause of death and signs related to cardiovascular disease including the degree of atherosclerosis in the aorta and the coronary arteries, signs of myocardial infarction, heart weight, and signs of cerebrovascular disease were recorded. The patients were genotyped, and the apolipoprotein E allele frequencies (E2, 8.0%; E3, 72.6%; and E4, 19.4%) were not statistically different from a group of healthy controls. Approximately 35% of the patients died from a cardiovascular disease. Genotypes differed significantly (P<.05), with more E4-carriers (34.3% vs. 29.6%) and fewer E2-carriers (11.8% vs. 13.9%) among patients who died from cardiovascular disease compared to those who died from other causes. A similar distribution of genotypes was seen in patients recorded with myocardial infarction or cerebrovascular disease. There was an association between the presence of E4 and atherosclerosis in the aorta and coronary arteries, but this did not reach statistical significance. Among patients with signs of coronary heart disease, standardized heart weights were significantly higher in E2 carriers compared to E4-carriers. CONCLUSION: The present autopsy study suggests that the risk of developing and dying from cardiovascular disease, including coronary heart disease and cerebrovascular disease, is influenced by the apolipoprotein E polymorphism. PMID- 22440830 TI - Discovering oscillatory interaction networks with M/EEG: challenges and breakthroughs. AB - The systems-level neuronal mechanisms that coordinate temporally, anatomically and functionally distributed neuronal activity into coherent cognitive operations in the human brain have remained poorly understood. Synchronization of neuronal oscillations may regulate network communication and could thus serve as such a mechanism. Evidence for this hypothesis, however, was until recently sparse, as methodological challenges limit the investigation of interareal interactions with non-invasive magneto- and electroencephalography (M/EEG) recordings. Nevertheless, recent advances in M/EEG source reconstruction and clustering methods support complete phase-interaction mappings that are essential for uncovering the large-scale neuronal assemblies and their functional roles. These data show that synchronization is a robust and behaviorally significant phenomenon in task-relevant cortical networks and could hence bind distributed neuronal processing to coherent cognitive states. PMID- 22440831 TI - Cognit activation: a mechanism enabling temporal integration in working memory. AB - Working memory is critical to the integration of information across time in goal directed behavior, reasoning and language, yet its neural substrate is unknown. Based on recent research, we propose a mechanism by which the brain can retain working memory for prospective use, thereby bridging time in the perception/action cycle. The essence of the mechanism is the activation of 'cognits', which consist of distributed, overlapping and interactive cortical networks that in the aggregate encode the long-term memory of the subject. Working memory depends on the excitatory reentry between perceptual and executive cognits of posterior and frontal cortices, respectively. Given the pervasive role of working memory in the structuring of purposeful cognitive sequences, its mechanism looms essential to the foundation of behavior, reasoning and language. PMID- 22440832 TI - Personality subtypes in male patients with eating disorder: validation of a classification approach. AB - In the present study, we investigated personality subtypes and their correlates in a sample of 132 male patients with eating disorder (ED). All patients filled out the Temperament and Character Inventory-Revised, the Eating Disorder Inventory-2, and the Symptom Checklist-90-Revised. Three personality subtypes emerged. Cluster 1, the adaptive-like subtype, was characterized by a high prevalence of eating-disorder-not-otherwise-specified and low levels of ED and general psychopathology. Cluster 2, the average or socially detached subtype, showed a high prevalence of eating-disorder-not-otherwise-specified, more social problems, less motivation for treatment, and an intermediate position on the psychopathology dimension between patients of clusters 1 and 3. Finally, cluster 3, the maladaptive subtype, was characterized the highest prevalence of bulimia nervosa and the highest scores on ED and general psychopathology. Our data support the presence of the 3 personality subtypes in male patients with ED. Future studies need to address whether patients of different subtypes differ with respect to therapy outcome. PMID- 22440833 TI - Psychometric properties of the Peters et al Delusions Inventory 21 in college students. AB - Delusions show high prevalence in the general population and can be considered a risk marker for psychotic disorders. Although the assessment of these experiences has made considerable progress in recent years, there is still room for improvement in the measurement quality of the self-reports available for such assessment. The goal of the present work was to analyze the measurement quality of the Peters et al Delusions Inventory 21 (PDI-21) in Spanish college students. The final sample was made up of 660 participants (29.5% men) with a mean age of 20.3 years (SD, 2.6 years). The results revealed that a high percentage of the sample reported some symptom of paranoia. Analysis of the internal structure of the PDI-21 by means of exploratory factor analysis based on the tetrachoric correlation matrix yielded an essentially unidimensional solution. Cronbach alpha for the total score was .91. Scores on the PDI-21 correlated in a statistically significant fashion with trait and state anxiety and negative affect. These results provide new evidence of the validity of the PDI-21 and endorse its use as a measurement instrument for assessing the extended psychosis phenotype in nonclinical population. PMID- 22440834 TI - Building bridges between plant and animal viruses. PMID- 22440835 TI - Non-template functions of the viral RNA in plant RNA virus replication. AB - In addition to the essential function of the viral RNA as a template during replication of positive-stranded (+)RNA viruses, the RNA also has crucial non template functions. These functions during replication include the recruitment of the viral RNA to the site of replication and assembly of the functional viral replicase complex. The RNA recruitment elements are specifically recognized by the viral replication protein, but also affected by host factors such as elongation factor 1A or P-body proteins. The cis-elements for replicase assembly can partially overlap with RNA recruitment elements and they may provide a platform for the assembly of the replicase complex consisting of viral and host proteins. This review focuses on our current knowledge obtained with tombusviruses and other plant viruses. Altogether, understanding of the non template functions of the viral RNA during viral replication provides new insights into virus-host interactions. PMID- 22440836 TI - The genome-linked protein VPg of plant viruses-a protein with many partners. AB - For some plant positive-sense RNA viruses, a protein known as VPg (short for virus protein, genome linked) is covalently linked to the 5' end of the viral RNA. The VPg is an intrinsically disordered protein, and this property would confer an ability to bind several proteins. Accordingly, the potyvirus VPg interacts with many proteins, notably host factors involved in protein synthesis within viral replication factories or within the nucleus. The number of protein partners, the clustering of the various interactions centering around it, the biological importance for some of these interactions (e.g. VPg-eIF4E) and the intrinsically disordered state of the protein are all elements that support the notion that VPg is a hub protein that controls many processes leading to virus production and spread. PMID- 22440837 TI - The genome-linked protein VPg of vertebrate viruses - a multifaceted protein. AB - Several vertebrate positive-sense RNA viruses, namely the Picornaviridae and Caliciviridae have evolved to use a protein-primed mechanism of genome replication. This results in the covalent linkage of a virus encoded protein, VPg (viral protein genome-linked), to the 5' end of viral RNA. Recent studies have highlighted the pivotal role VPg plays in the life cycle of these viruses, which in the case of the Caliciviridae, includes a role in viral protein synthesis. This article provides an overview of the current knowledge of the functions of vertebrate RNA virus VPg proteins, illustrating their diverse function and the parallels they share with plant virus VPg proteins. PMID- 22440838 TI - 3' Cap-independent translation enhancers of positive-strand RNA plant viruses. AB - Positive-strand RNA plant viruses that are neither 5'-capped nor 3' polyadenylated use nontraditional mechanisms to recruit ribosomes to the 5'-end of their viral genomes. One strategy employed by some of these viruses involves a type of RNA element, termed the 3' cap-independent translation enhancer (3'CITE), located in or near the 3'-untranslated region of viral RNA genomes. 3'CITEs function to mediate efficient translation of 5'-proximally encoded viral proteins and function by recruiting either translation initiation factors or the 60S ribosomal subunit to the viral RNA. Recent mechanistic and structural studies have revealed important new insights and details of how 3'CITEs are able to facilitate viral translation and allow these viruses to compete efficiently against cellular mRNAs for the host translational machinery. PMID- 22440839 TI - Virus factories, double membrane vesicles and viroplasm generated in animal cells. AB - Many viruses reorganise cellular membrane compartments and the cytoskeleton to generate subcellular microenvironments called virus factories or 'viroplasm'. These create a platform to concentrate replicase proteins, virus genomes and host proteins required for replication and also protect against antiviral defences. There is growing interest in understanding how viruses induce such large changes in cellular organisation, and recent studies are beginning to reveal the relationship between virus factories and viroplasm and the cellular structures that house them. In this review, we discuss how three supergroups of (+)RNA viruses generate replication sites from membrane-bound organelles and highlight research on perinuclear factories induced by the nucleocytoplasmic large DNA viruses. PMID- 22440840 TI - Wrapping membranes around plant virus infection. AB - Positive strand RNA viruses cause membrane modifications which are microenvironments or larger intracellular compartments, also called 'viroplasms'. These compartments serve to concentrate virus and host factors needed to produce new genomes. Forming these replication sites often involves virus induced membrane synthesis, changes in fatty acid metabolism, and viral recruitment of cellular factors to subcellular domains. Interacting viral and host factors builds the physical scaffold for replication complexes. Such virus induced changes are a visible cytopathology that has been used by plant and mammalian virologists to describe virus disease. This article describes key examples of membrane modifications that are essential for plant virus replication and intercellular transport. PMID- 22440841 TI - The direct passage of animal viruses between cells. AB - The paradigm that viruses can move directly, and in some cases covertly, between contacting target cells is now well established for several virus families. The underlying mechanisms of cell-to-cell spread, however, remain to be fully elucidated and may differ substantially depending on the viral exit/entry route and the cellular tropism. Here, two divergent cell-to-cell spread mechanisms are exemplified: firstly by human retroviruses, which rely upon transient adhesive structures that form between polarized immune cells termed virological synapses, and secondly by herpesviruses that depend predominantly on pre-existing stable cellular contacts, but may also form virological synapses. Plant viruses can also spread directly between contacting cells, but are obliged by the rigid host cell wall to move across pore structures termed plasmodesmata. This review will focus primarily on recent advances in our understanding of animal virus cell-to-cell spread using examples from these two virus families, and will conclude by comparing and contrasting the cell-to-cell spread of animal and plant viruses. PMID- 22440842 TI - Parallels and distinctions in the direct cell-to-cell spread of the plant and animal viruses. AB - The paradigm that viruses can move directly, and in some cases covertly, between contacting target cells is now well established for several virus families. The underlying mechanisms of cell-to-cell spread, however, remain to be fully elucidated and may differ substantially depending on the viral exit/entry route and the cellular tropism. Here, two divergent cell-to-cell spread mechanisms are exemplified: firstly by human retroviruses, which rely upon transient adhesive structures that form between polarized immune cells termed virological synapses, and secondly by herpesviruses that depend predominantly on pre-existing stable cellular contacts, but may also form virological synapses. Plant viruses can also spread directly between contacting cells, but are obliged by the rigid host cell wall to move across pore structures termed plasmodesmata. This review will focus primarily on recent advances in our understanding of animal virus cell-to-cell spread using examples from these two virus families to highlight differences and similarities, and will conclude by comparing and contrasting the cell-to-cell spread of animal and plant viruses. PMID- 22440843 TI - Virus evolution. PMID- 22440844 TI - Ultra-deep sequencing for the analysis of viral populations. AB - Next-generation sequencing allows for cost-effective probing of virus populations at an unprecedented level of detail. The massively parallel sequencing approach can detect low-frequency mutations and it provides a snapshot of the entire virus population. However, analyzing ultra-deep sequencing data obtained from diverse virus populations is challenging because of PCR and sequencing errors and short read lengths, such that the experiment provides only indirect evidence of the underlying viral population structure. Recent computational and statistical advances allow for accommodating some of the confounding factors, including methods for read error correction, haplotype reconstruction, and haplotype frequency estimation. With these methods ultra-deep sequencing can be more reliably used to analyze, in a quantitative manner, the genetic diversity of virus populations. PMID- 22440845 TI - Lethal mutagenesis of viruses. AB - Lethal mutagenesis aims at extinguishing viruses by increased mutagenesis prompted by virus-specific mutagenic agents, mainly nucleoside analogues. It is derived from the error threshold relationship of quasispecies theory, and it is slowly finding its way towards a clinical application. We summarize the current situation of research in this field of antiviral therapy. PMID- 22440846 TI - Toward a quantitative understanding of viral phylogeography. AB - Phylogeographic approaches help uncover the imprint that spatial epidemiological processes leave in the genomes of fast evolving viruses. Recent Bayesian inference methods that consider phylogenetic diffusion of discretely and continuously distributed traits offer a unique opportunity to explore genotypic and phenotypic evolution in greater detail. To provide a taste of the recent advances in viral diffusion approaches, we highlight key findings arising at the intrahost, local and global epidemiological scales. We also outline future areas of research and discuss how these may contribute to a quantitative understanding of the phylodynamics of RNA viruses. PMID- 22440847 TI - Viral mutation and substitution: units and levels. AB - Viruses evolve within a hierarchy of organisational levels, from cells to host species. We discuss how these nested population structures complicate the meaning and interpretation of two apparently simple evolutionary concepts: mutation rate and substitution rate. We discuss the units in which these fundamental processes should be measured, and explore why, even for the same virus, mutation and substitution can occur at very different tempos at different biological levels. In addition, we explore the ability of whole genome evolutionary analyses to distinguish between natural selection and other population genetic processes. A better understanding of the complexities underlying the molecular evolution of viruses in natural populations is needed before accurate predictions of viral evolution can be made. PMID- 22440848 TI - Evaluating the evidence for virus/host co-evolution. AB - There is currently much debate about the timescales of virus evolution. Some viruses may have co-evolved with human populations for tens of thousands of years, or even with our primate ancestors over many millions of years. However, calibrations of the rate of short-term virus evolution lead to estimates of dates for viral ancestors that are orders of magnitude more recent, and a number of the proposed host-virus co-divergence scenarios have been questioned. Other considerations indicate that the proposed recent timescales for virus evolution are implausible, that co-divergence has been rejected prematurely, and that long term evolutionary rates are very much slower than short-term rates. There is a need to understand the biological basis of this discrepancy and to develop evolutionary models that can accommodate this. PMID- 22440849 TI - PUFAs in serum cholesterol ester and oxidative DNA damage in Japanese men and women. AB - BACKGROUND: PUFAs are susceptible to lipid peroxidation and play a role in inflammation, both of which can induce oxidative stress. However, the relation of PUFA to oxidative DNA damage in humans is elusive. OBJECTIVE: We examined the association between concentrations of circulatory PUFAs and urinary 8-oxo-7,8 dihydroguanine (8-oxoGua) in Japanese men and women. DESIGN: The subjects were 495 participants (290 men and 205 women) in a cross-sectional study in 2 municipal offices in Japan. Serum cholesterol ester (CE) and phospholipid fatty acid composition were measured by gas-liquid chromatography. Urinary 8-oxoGua concentrations were measured by HPLC, and 8-oxoGua values for each tertile of PUFA after adjustment for covariates were calculated by multiple regression. RESULTS: Urinary 8-oxoGua concentrations increased with increasing concentrations of n-3 (omega-3) PUFAs, EPA, and DHA in serum CE (P-trend = 0.001, 0.01, and 0.009, respectively), whereas they decreased with increasing concentrations of n 6 PUFAs and linoleic acid (P-trend = 0.02 and 0.051, respectively). CONCLUSION: Oxidative DNA damage may be greater with higher concentrations of long-chain n-3 PUFAs but lower with higher concentrations of n-6 (omega-6) PUFAs. PMID- 22440850 TI - Relations between obesity, insulin resistance, and 25-hydroxyvitamin D. AB - BACKGROUND: Although low circulating 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and obesity, the relations between these 3 variables have not been completely resolved. OBJECTIVE: The objective was to compare circulating 25(OH)D concentrations in apparently healthy individuals who were matched for degree of obesity or insulin sensitivity. DESIGN: This was a case-control study in which 78 apparently healthy individuals were classified as being normal weight (NW) or obese (OB) on the basis of their BMI and as being insulin sensitive (IS) or insulin resistant (IR) on the basis of their steady state plasma glucose (SSPG) concentration during the insulin suppression test. RESULTS: Groups did not differ in terms of age, sex distribution, race, or mean (+/- SD) plasma 25(OH)D concentration. Values for 25(OH)D were 32 +/- 10, 30 +/- 10, and 28 +/- 8 ng/mL in NW-IS, OB-IS, and OB-IR groups, respectively. These concentrations were essentially identical when comparing IR with IS subjects matched for BMI or when comparing OB with NW subjects matched for SSPG. Concentrations of 25(OH)D <= 30 ng/mL were somewhat more common in OB subjects than in NW subjects (54% compared with 35%), but SSPG concentrations were not different within either the IR or IS groups when subgroups with 25(OH)D concentrations <= 30 or > 30 ng/mL were compared. CONCLUSIONS: In 78 individuals, 47% of whom were vitamin D deficient or insufficient (<= 30 ng/mL), 25(OH)D concentrations did not vary with differences in insulin sensitivity (SSPG concentration) when matched for BMI (OB-IR compared with OB-IS). Similarly, when matched for SSPG concentrations, plasma 25(OH)D concentrations were not different in NW or OB individuals (NW-IS compared with OB-IS). PMID- 22440851 TI - Coffee and tea consumption and the risk of ovarian cancer: a prospective cohort study and updated meta-analysis. AB - BACKGROUND: In 2007 the World Cancer Research Fund Report concluded that there was limited and inconsistent evidence for an effect of coffee and tea consumption on the risk of epithelial ovarian cancer (EOC). OBJECTIVE: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we aimed to investigate whether coffee intakes, tea intakes, or both are associated with the risk of EOC. DESIGN: All women participating in the EPIC (n = 330,849) were included in this study. Data on coffee and tea consumption were collected through validated food-frequency questionnaires at baseline. HRs and 95% CIs were estimated by using Cox proportional hazards models. Furthermore, we performed an updated meta-analysis of all previous prospective studies until April 2011 by comparing the highest and lowest coffee- and tea-consumption categories as well as by using dose-response random-effects meta-regression analyses. RESULTS: During a median follow-up of 11.7 y, 1244 women developed EOC. No association was observed between the risk of EOC and coffee consumption [HR: 1.05 (95% CI: 0.75, 1.46) for the top quintile compared with no intake] or tea consumption [HR: 1.07 (95% CI: 0.78, 1.45) for the top quintile compared with no intake]. This lack of association between coffee and tea intake and EOC risk was confirmed by the results of our meta-analysis. CONCLUSION: Epidemiologic studies do not provide sufficient evidence to support an association between coffee and tea consumption and risk of ovarian cancer. PMID- 22440852 TI - Characterization of transition diets spanning infancy and toddlerhood: a novel, multiple-time-point application of principal components analysis. AB - BACKGROUND: The portrayal of diet over time is a natural progression from the characterization of diet at single time points. The transition dietary period, a dynamic period of rapid dietary change spanning infancy and toddlerhood when children shift from a milk-based to a food-based diet, has not been characterized. OBJECTIVE: The objective was to summarize variation in dietary intakes spanning infancy and toddlerhood. DESIGN: A prospective principal components analysis was applied to dietary intakes from 3 successive follow-ups of children enrolled in the ALSPAC (Avon Longitudinal Study of Parents and Children). The frequency of food and beverage consumption was assessed via questionnaire at ages 6, 15, and 24 mo (n = 2169). RESULTS: Two types of transition diet were identified. The first transition diet was characterized by the consumption of home-prepared and raw foods ("healthy") at all time points and the second by ready-prepared and discretionary foods ("less healthy") consistently over time. Higher educational level and maternal age were associated with higher scores on the "healthy" diet, whereas younger maternal age and a lower educational level were associated with higher scores on the "less healthy" diet. Maternal BMI, number of older siblings, and lower social class were associated with the less-healthy transition diet but not with the healthy transition diet. CONCLUSIONS: Unique transition diets, including a less-healthy type, emerge by age 2 y. These diets are consistent with childhood and adult dietary patterns reported at single time points and show convergent validity both with known maternal sociodemographic predictors of childhood diet and with intake gradients across diet scores. PMID- 22440853 TI - Efficacy of daily intake of Lactobacillus casei Shirota on respiratory symptoms and influenza vaccination immune response: a randomized, double-blind, placebo controlled trial in healthy elderly nursing home residents. AB - BACKGROUND: Age is associated with immune dysregulation, which results in an increased infection rate and reduced effectiveness of vaccination. OBJECTIVE: We assessed whether an intervention with Lactobacillus casei Shirota (LcS) in elderly nursing home residents reduced their susceptibility to respiratory symptoms and improved their immune response to influenza vaccination. DESIGN: Between October 2007 and April 2008, a randomized, double-blind, placebo controlled trial was conducted in 737 healthy people aged >= 65 y in 53 nursing homes in Antwerp, Belgium. Volunteers were randomly assigned to receive a probiotic (n = 375; 2 bottles of fermented milk that contained >= 6.5 * 10(9) live LcS/bottle) or a placebo (n = 362; similar drink with no bacteria) for 176 d. After 21 d, all subjects received an influenza vaccination. Primary outcome parameters were the number of days with respiratory symptoms, the probability of respiratory symptoms, and antiinfluenza antibody titer by hemagglutination inhibition after vaccination. RESULTS: Univariate and multivariate modeling showed no effect of the probiotic on clinical outcome parameters. Generalized linear mixed modeling showed no effect of the probiotic itself on the probability of respiratory symptoms [OR of probiotic: 0.8715; 95% CI: 0.6168, 1.2887). No significant difference regarding the influenza-vaccination immune response was shown. CONCLUSION: The results of this study show that daily consumption of a fermented milk drink that contains LcS has no statistically or clinically significant effect on the protection against respiratory symptoms. This trial was registered at clinicaltrials.gov as NCT00849277. PMID- 22440854 TI - Protection of LDL from oxidation by olive oil polyphenols is associated with a downregulation of CD40-ligand expression and its downstream products in vivo in humans. AB - BACKGROUND: Recently, the European Food Safety Authority approved a claim concerning the benefits of olive oil polyphenols for the protection of LDL from oxidation. Polyphenols could exert health benefits not only by scavenging free radicals but also by modulating gene expression. OBJECTIVE: We assessed whether olive oil polyphenols could modulate the human in vivo expressions of atherosclerosis-related genes in which LDL oxidation is involved. DESIGN: In a randomized, crossover, controlled trial, 18 healthy European volunteers daily received 25 mL olive oil with a low polyphenol content (LPC: 2.7 mg/kg) or a high polyphenol content (HPC: 366 mg/kg) in intervention periods of 3 wk separated by 2-wk washout periods. RESULTS: Systemic LDL oxidation and monocyte chemoattractant protein 1 and the expression of proatherogenic genes in peripheral blood mononuclear cells [ie, CD40 ligand (CD40L), IL-23alpha subunit p19 (IL23A), adrenergic beta-2 receptor (ADRB2), oxidized LDL (lectin-like) receptor 1 (OLR1), and IL-8 receptor-alpha (IL8RA)] decreased after the HPC intervention compared with after the LPC intervention. Random-effects linear regression analyses showed 1) a significant decrease in CD40, ADRB2, and IL8RA gene expression with the decrease of LDL oxidation and 2) a significant decrease in intercellular adhesion molecule 1 and OLR1 gene expression with increasing concentrations of tyrosol and hydroxytyrosol in urine. CONCLUSIONS: In addition to reducing LDL oxidation, the intake of polyphenol-rich olive oil reduces CD40L gene expression, its downstream products, and related genes involved in atherogenic and inflammatory processes in vivo in humans. These findings provide evidence that polyphenol-rich olive oil can act through molecular mechanisms to provide cardiovascular health benefits. This trial was registered at www.controlled-trials.com as ISRCTN09220811. PMID- 22440855 TI - Cerebral interactions of pain and reward and their relevance for chronic pain. AB - Pain and reward are opponent, interacting processes. Such interactions are enabled by neuroanatomical and neurochemical overlaps of brain systems that process pain and reward. Cerebral processing of hedonic ('liking') and motivational ('wanting') aspects of reward can be separated: the orbitofrontal cortex and opioids play an important role for the hedonic experience, and the ventral striatum and dopamine predominantly process motivation for reward. Supported by neuroimaging studies, we present here the hypothesis that the orbitofrontal cortex and opioids are responsible for pain modulation by hedonic experience, while the ventral striatum and dopamine mediate motivational effects on pain. A rewarding stimulus that appears to be particularly important in the context of pain is pain relief. Further, reward, including pain relief, leads to operant learning, which can affect pain sensitivity. Indirect evidence points at brain mechanisms that might underlie pain relief as a reward and related operant learning but studies are scarce. Investigating the cerebral systems underlying pain-reward interactions as well as related operant learning holds the potential of better understanding mechanisms that contribute to the development and maintenance of chronic pain, as detailed in the last section of this review. PMID- 22440856 TI - Brain stimulation enables the solution of an inherently difficult problem. AB - Certain problems are inherently difficult for the normal human mind. Yet paradoxically they can be effortless for those with an unusual mind. We discovered that an atypical protocol for non-invasive brain stimulation enabled the solution of a problem that was previously unsolvable. The majority of studies over the last century find that no participants can solve the nine-dot problem - a fact we confirmed. But with 10 min of right lateralising transcranial direct current stimulation (tDCS), more than 40% of participants did so. Specifically, whereas no participant solved this extremely difficult problem before stimulation or with sham stimulation, 14 out of 33 participants did so with cathodal stimulation of the left anterior temporal lobe together with anodal stimulation of the right anterior temporal lobe. This finding suggests that our stimulation paradigm might be helpful for mitigating cognitive biases or dealing with a broader class of tasks that, although deceptively simple, are nonetheless extremely difficult due to our cognitive makeup. PMID- 22440857 TI - Synthesis, vasorelaxant activity, and molecular modeling study of some new phthalazine derivatives. AB - New phthalazine-based vasodilators were synthesized through the chloroacylation of the starting compound 1-hydrazinophthalazine 4 to give the two key intermediates 5 and 7. These intermediates were used to alkylate various cyclic amines to furnish the final compounds 6a-h and 8a-h. Compounds were tested for their vasorelaxant activities against nor-adrenaline-induced spasm on thoracic rat aorta rings and compared to the reference drug, prazosin. Seven compounds showed higher activity than prazosin, especially compound 8d having an IC(50)=0.10 mM. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as alpha(1)-AR antagonists showed high docking score and fit values. Most vasodilation activities of tested compounds are consistent with their molecular modeling results. PMID- 22440858 TI - Noncovalent inhibition of 20S proteasome by pegylated dimerized inhibitors. AB - We exploited the concept of polyvalent interactions to produce highly selective and efficient inhibitors of eukaryotic proteasome. This multicatalytic protease with the unique topography of its 6 active sites has emerged as a promising target to treat cancer with the use of the covalent inhibitor bortezomib. We used our reference noncovalent inhibitor, a selective TMC-95A tripeptide linear mimic, to design dimeric noncovalent proteasome inhibitors that target two active sites simultaneously. We synthesized pegylated monomer and dimers of the reference inhibitor and evaluated their capacity to inhibit a mammalian 20S proteasome. The inhibitory power of the dimers depended on the average length of their spacer. Lineweaver-Burk double-reciprocal plots indicated competitive inhibition. The best dimer inhibited CT-L activity 800-times more efficiently than the reference inhibitor. PMID- 22440859 TI - Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases. AB - A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme. PMID- 22440860 TI - Identification and characterization of an amphioxus matrix metalloproteinase homolog BbMMPL2 responding to bacteria challenge. AB - Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases mainly involved in extracellular matrix (ECM) degradation. We have cloned and identified BbMMPL2 as homolog of MMPs from adult amphioxus. Recombinant BbMMPL2 proteins underwent self-processing during refolding in vitro. The final ~23 kDa polypeptide displayed proteolytic activity against ECM components like casein, gelatin, collagen IV and fibrinogen, but not laminin, fibronectin or alpha1-PI. This activity could be inhibited by GM6001 and TIMP-1/2. In addition, real-time RT-PCR analysis revealed that BbMMPL2 expressed in all issues/organs in adult amphioxus we tested. Its transcription was significantly up-regulated 12 h post immune challenge by Escherichia coli in epidermis and hepatic diverticulum but only slightly increased by Staphyloccocus aureus in epidermis. Furthermore, recombinant BbMMPL2-EGFP expressed in 293T and NIH/3T3 cells showed aggregation in cytoplasm and induced cell death. Our results provided new evidence that MMP was involved in immune response which could be conserved through evolution. PMID- 22440861 TI - Sebaceous glands as the primary target of EGFR-inhibitors in the development of papulopustular eruption. PMID- 22440862 TI - Volumetric comparisons of supratentorial white matter hyperintensities on FLAIR MRI in patients with migraine and multiple sclerosis. AB - Migraine and multiple sclerosis (MS) can both cause white matter lesions that appear similar on conventional MRI. This study aimed to compare these abnormalities, and to find anatomical biomarkers specific for migraine. Supratentorial white matter hyperintensities (WMH) of 17 migraineurs and 15 patients with MS were counted, volumetrically analyzed, and their lobar distribution assessed on fluid-attenuated inversion recovery MRI. We found that migraine WMH affected mainly the deep white matter and subcortical U-fibers, belonged to the anterior circulation, appeared more frequently in the frontal and parietal lobes, showed no difference in average size between lobes, and were smaller and fewer than in MS. Most of the MS WMH were in the frontal lobe and were the smallest average size, while the fewest WMH with the largest size were in the occipital lobe. The pattern of supratentorial WMH appearance differs between the two groups; however, accurate differential diagnosis of WMH by conventional MRI is probably not possible in individual patients. PMID- 22440863 TI - Current surgical management of insular gliomas. AB - The insula is a functionally and anatomically complex cortical structure that can be affected by both low-grade and high-grade gliomas. This complexity often prevents many neurosurgeons from attempting to surgically manage insular gliomas. This article reviews the anatomic and functional uniqueness of the insula and the surgical outcomes and lessons learned from previously reported surgical series. Successful management of insular gliomas, defined as maximal resection of the tumor without postoperative neurologic morbidity, can be achieved through a sophisticated understanding of the neurovascular structure of the insular region and an intraoperative functional mapping using cortico-subcortical electrical stimulation. PMID- 22440864 TI - The rise and fall of "biopsy and radiate": a history of surgical nihilism in glioma treatment. AB - Many neurosurgeons take a nihilistic approach to surgical treatment of gliomas, stating the inability to achieve a cure. Where this idea comes from is somewhat nebulous to most neurosurgeons. A review of the scientific studies supporting the commonly held beliefs about gliomas shows that these ideas regarding the surgical treatment of gliomas are based on overgeneralizations of data from older studies. One should avoid the temptation to apply them to the greater concept of what gliomas are, how they behave, and what should be done, but rather we should continue to scientifically evaluate the role of surgical resection in glioma treatment. PMID- 22440865 TI - The use of motor mapping to aid resection of eloquent gliomas. AB - Surgery remains one of the oldest and still most important forms of treatment for patients with glioma. The advantages of surgical resection for glioma must be balanced with the potential of operative morbidity to surrounding eloquent brain. To that end, advances in functional brain mapping allow for safer operations with more aggressive surgical resections. A brief history of motor mapping as well as its present day use in aiding resection of eloquent gliomas is discussed. PMID- 22440866 TI - Characteristics and treatment of seizures in patients with high-grade glioma: a review. AB - High-grade gliomas (HGGs), including anaplastic astrocytoma and glioblastoma multiforme, are the most common primary brain tumors, and are often associated with seizures. Seizure control is a critical but often underappreciated goal in the treatment of patients harboring these malignant lesions. Patients with HGG who also have medically intractable seizures should be considered for a palliative resection guided by electrocorticography and functional mapping. Antiepileptic drugs remain the mainstay of seizure treatment in HGG, and antiepileptic medication should be started after a tumor-related seizure, but should not be used prophylactically in the absence of seizure activity. PMID- 22440867 TI - Pathology: commonly monitored glioblastoma markers: EFGR, EGFRvIII, PTEN, and MGMT. AB - The purpose of this article is to update the neurosurgical field on current molecular markers important to glioblastoma biology, treatment, and prognosis. The highlighted biologic markers in this article include epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O6-methylguanine-DNA methyltransferase (MGMT). PMID- 22440868 TI - The role of adjuvant radiation therapy in the management of high-grade gliomas. AB - The purpose of this article is to update the neurosurgical community on the role of adjuvant radiation therapy in the management of patients with high-grade glioma. This information guides clinicians in the multidisciplinary management of these patients via a review of the literature describing current treatment paradigms as well as new avenues of investigation. PMID- 22440869 TI - Radiation options for high-grade gliomas. AB - Radiotherapy has become a part of the standard treatment of high-grade gliomas. Studies have shown that high-dose radiation results in more effective tumor control but at the cost of radionecrosis and other radiation-related side effects. Despite advancing techniques in stereotaxy and precise radiotherapy delivery techniques, studies published for stereotactic radiosurgical treatment of high-grade gliomas have not been unanimous, with large trials showing no survival benefit compared with conventional conformal radiotherapy. New imaging modalities have been studied with the hope to improve accuracy in the planning of radiosurgical treatments. However, further large scale studies are needed to confirm these results. PMID- 22440870 TI - Radiology: criteria for determining response to treatment and recurrence of high grade gliomas. AB - The development of radiologic criteria for the assessment of response to treatment in high-grade gliomas (HGGs) has evolved considerably over the past few decades since the original response criteria based on computed tomography imaging. Accuracy and objectivity in the assessment of response to treatment of HGGs is necessary for altering treatment regimens, establishing accurate provider communication, and improving the quality of clinical trials. Future studies assessing emerging advanced neuroimaging techniques will facilitate the development of even more accurate evidence-based radiologic response criteria. PMID- 22440871 TI - Pseudoprogression and treatment effect. AB - The standard of care for newly diagnosed malignant glioblastoma entails postoperative radiotherapy and adjuvant chemotherapy with temozolomide. There has been an increase in the incidence of enhancing and progressive lesions seen on magnetic resonance imaging (MRI) following treatment. Conventional MRI with gadolinium contrast is unable to distinguish between the effects of treatment and actual tumor recurrence. New modalities have provided additional information for distinguishing treatment effects from tumor progression but are not 100% sensitive or specific in diagnosing progression. Novel radiographic or nonradiographic biomarkers with sensitivity and specificity verified in large randomized clinical trials are needed to detect progression. PMID- 22440872 TI - The role of BCNU polymer wafers (Gliadel) in the treatment of malignant glioma. AB - The 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU; carmustine) polymer wafer (Gliadel) was developed for use in malignant glioma to deliver higher doses of chemotherapy directly to tumor tissue while bypassing systemic side effects. Phase III clinical trials for patients with newly diagnosed malignant gliomas demonstrated a small, but statistically significant, improvement in survival. However, the rate of complications, including an increase in cerebrospinal fluid leaks and intracranial hypertension, has limited their use. This article reviews the current data for use of BCNU wafers in malignant gliomas. PMID- 22440873 TI - Alternative chemotherapeutic agents: nitrosoureas, cisplatin, irinotecan. AB - Irinotecan, cisplatin, and nitrosoureas have a long history of use in brain tumors, with demonstrated efficacy in the adjuvant treatment of malignant gliomas. In the era of temozolomide with concurrent radiotherapy given as the standard of care, their use has shifted to treatment at progression or recurrence. Now with the widespread use of bevacizumab in the recurrent setting, irinotecan and other chemotherapies are seeing increased use in combination with bevacizumab and alone in the recurrent setting. The activity of these chemotherapeutic agents in brain tumors will likely ensure a place in the armamentarium of neuro-oncologists for many years. PMID- 22440874 TI - Temozolomide and other potential agents for the treatment of glioblastoma multiforme. AB - This article provides historical and recent perspectives related to the use of temozolomide for the treatment of glioblastoma multiforme. Temozolomide has quickly become part of the standard of care for the modern treatment of stage IV glioblastoma multiforme since its approval in 2005. Yet despite its improvements from previous therapies, median survival remains approximately 15 months, with a 2-year survival rate of 8% to 26%. The mechanism of action of this chemotherapeutic agent, conferred advantages and limitations, treatment resistance and rescue, and potential targets of future research are discussed. PMID- 22440875 TI - Superselective intra-arterial cerebral infusion of novel agents after blood-brain disruption for the treatment of recurrent glioblastoma multiforme: a technical case series. AB - Glioblastoma multiforme constitutes the most common primary brain tumor and carries a grim prognosis for patients treated with conventional therapy including surgery, radiation therapy, and chemotherapy. There has been a recent revival of selective intra-arterial delivery of targeted agents for the treatment of glioblastoma multiforme. Because these agents are less toxic and their delivery leads to a higher tumor-drug concentration, this combination may provide a better outcome in patients with high-grade glioma. This article discusses early experiences in patients who received superselective intra-arterial cerebral infusion of bevacizumab, cetuximab, and temozolamide after blood-brain barrier disruption with mannitol. PMID- 22440876 TI - The role of avastin in the management of recurrent glioblastoma. AB - Glioblastoma multiforme is a malignant primary brain tumor for which no cure has been developed. However, with aggressive surgical resection, radiation, and the advent of temozolomide, the overall survival of patients with glioblastomas has improved significantly. Despite this multimodal treatment, glioblastoma invariably recurs. Although treatment options for glioblastoma recurrence are limited, one promising therapy is bevacizumab (Avastin). The role of Avastin in the management of recurrent glioblastomas is reviewed. PMID- 22440877 TI - Management of multifocal and multicentric gliomas. AB - The diffuse nature of gliomas has long confounded attempts at achieving a definitive cure. The advent of computed tomography and magnetic resonance imaging made it increasingly apparent that gliomas could have a multifocal or multicentric appearance. Treating these tumors is the summit of an already daunting challenge, because the obstacles that must be surmounted to treat gliomas in general, namely, their heterogeneity, diffuse nature, and ability to insidiously invade normal brain, are more conspicuous in this subset of tumors. PMID- 22440878 TI - Preface. Modern management of high grade glioma, Part I. PMID- 22440880 TI - Track and trigger in an emergency department: an observational evaluation study. AB - OBJECTIVE: To evaluate the utilisation of paper-based track and trigger (T&T) charts in a UK emergency department (ED). METHODS: A single-centre prospective observational cohort study was conducted in the ED of a medium-sized teaching hospital. Charted vital-sign data were collected from adults attending the resuscitation room, majors or observation ward. These data were examined in parallel with clinical notes to identify 'escalation' events. For each set of vital signs, the authors calculated the T&T score retrospectively. RESULTS: Data from 472 patient episodes (2965 sets of vital signs) were examined. 85.8% of patients had at least one full set of observations (CEM standard) and 60.6% had at least one T&T score documented. However, only 34.5% of observation sets had a corresponding T&T score. 20.6% of T&T score totals (1024) were incorrect, potentially preventing a 'trigger' from being recognised. 204 patient episodes had at least one recorded escalation. Physiological escalations were associated with vital-sign scores that met the triggering thresholds (98/104), while patients who had non-physiological escalations or no escalations were more likely to have scores below the triggering thresholds (88/100). Only 26.9% of physiological escalations were associated with a documented T&T score above the triggering threshold. Retrospective completion of the charts increased that figure to 94.2%. CONCLUSION: T&T in the ED is challenged by poor completion rates and numerical errors made during score calculation. However the potential for recognition of a deteriorating patient should not be ignored. The future work of the authors intends to evaluate an electronic system for automatically calculating T&T scores within the ED environment. PMID- 22440881 TI - Effects of water stress on irradiance acclimation of leaf traits in almond trees. AB - Photosynthetic acclimation to highly variable local irradiance within the tree crown plays a primary role in determining tree carbon uptake. This study explores the plasticity of leaf structural and physiological traits in response to the interactive effects of ontogeny, water stress and irradiance in adult almond trees that have been subjected to three water regimes (full irrigation, deficit irrigation and rain-fed) for a 3-year period (2006-08) in a semiarid climate. Leaf structural (dry mass per unit area, N and chlorophyll content) and photosynthetic (maximum net CO(2) assimilation, A(max), maximum stomatal conductance, g(s,max), and mesophyll conductance, g(m)) traits and stem-to-leaf hydraulic conductance (K(s-l)) were determined throughout the 2008 growing season in leaves of outer south-facing (S-leaves) and inner northwest-facing (NW-leaves) shoots. Leaf plasticity was quantified by means of an exposure adjustment coefficient (epsilon=1-X(NW)/X(S)) for each trait (X) of S- and NW-leaves. Photosynthetic traits and K(s-l) exhibited higher irradiance-elicited plasticity (higher epsilon) than structural traits in all treatments, with the highest and lowest plasticity being observed in the fully irrigated and rain-fed trees, respectively. Our results suggest that water stress modulates the irradiance elicited plasticity of almond leaves through changes in crown architecture. Such changes lead to a more even distribution of within-crown irradiance, and hence of the photosynthetic capacity, as water stress intensifies. Ontogeny drove seasonal changes only in the epsilon of area- and mass-based N content and mass-based chlorophyll content, while no leaf age-dependent effect was observed on epsilon as regards the physiological traits. Our results also indicate that the irradiance-elicited plasticity of A(max) is mainly driven by changes in leaf dry mass per unit area, in g(m) and, most likely, in the partitioning of the leaf N content. PMID- 22440882 TI - A controlled test of the dual-isotope approach for the interpretation of stable carbon and oxygen isotope ratio variation in tree rings. AB - Seedlings of a conifer (Pinus radiata D. Don) and a broad leaf angiosperm (Eucalyptus globulus Labill.) were grown for 100 days in two growth cabinets at 45 or 65% relative humidity. The seedlings were exposed to treatments designed to modify carbon assimilation rates and capacities, stomatal conductance and transpiration to test conceptual models that attempt to clarify the interpretation of carbon isotope discrimination (Delta(13)C) by using oxygen isotope enrichment (Delta(18)O). Differences in relative humidity and within cabinet treatments (including lower irradiance, lower nitrogen inputs, higher leaf temperature and lower moisture status than control seedlings) produced significant differences in assimilation rates, photosynthetic capacities, stomatal conductance, leaf transpiration rates and leaf evaporative enrichment. The dual-isotope approach accurately interpreted the cause of variation in wood cellulose Delta(13)C for some of the treatments, but not for others. We also tested whether we could use Delta(13)C variation to constrain the interpretation of delta(18)O variation. Carbon isotope discrimination appears to be influenced by transpiration (providing information on leaf evaporative enrichment), but the results did not provide a clear way to interpret such variation. The dual-isotope approach appears to be valid conceptually, but more work is needed to make it operational under different scenarios. PMID- 22440883 TI - A cost-consequence analysis of long-acting injectable risperidone in schizophrenia: a one-year mirror-image study with national claim-based database in Taiwan. AB - OBJECTIVE: The development of long-acting atypical antipsychotics has provided a new paradigm for schizophrenia treatment. The economic effectiveness of risperidone long-acting injection (RLAI) on service costs has, however, never been studied in the real world with national claim-based database. METHOD: To assess the change of service utilization and costs for schizophrenia before and after RLAI treatment, we conducted this 1-year mirror-image study with Taiwanese national claimed-data. Comparison was made for service sectors (the number of visits, acute admissions and relapse events) and cost components (outpatient, inpatient, emergency, medication and non-medication costs). RESULTS: Service uses reduced in the post-RLAI period, along with a reduction of 34% and 32% on total inpatient services costs and inpatient non-medication costs, respectively (p < 0.005). However, overall psychiatric service costs went up by 26%, with an increase of 190% on total outpatient service costs and 177% on overall medication costs (p < 0.0001). CONCLUSIONS: This 1-year mirror-image analysis showed that RLAI treatment was associated with reductions of service uses; however, overall psychiatric service costs were compromised by costs incurred from increased utilization of outpatient service and RLAI medication costs under the context of healthcare in Taiwan. PMID- 22440884 TI - Characterization of fine particulate matter and associations between particulate chemical constituents and mortality in Seoul, Korea. AB - BACKGROUND: Numerous studies have linked fine particles [<= 2.5 um in aerodynamic diameter (PM(2.5))] and health. Most studies focused on the total mass of the particles, although the chemical composition of the particles varies substantially. Which chemical components of fine particles that are the most harmful is not well understood, and research on the chemical composition of PM(2.5) and the components that are the most harmful is particularly limited in Asia. OBJECTIVES: We characterized PM(2.5) chemical composition and estimated the effects of cause-specific mortality of PM(2.5) mass and constituents in Seoul, Korea. We compared the chemical composition of particles to those of the eastern and western United States. METHODS: We examined temporal variability of PM(2.5) mass and its composition using hourly data. We applied an overdispersed Poisson generalized linear model, adjusting for time, day of week, temperature, and relative humidity to investigate the association between risk of mortality and PM(2.5) mass and its constituents in Seoul, Korea, for August 2008 through October 2009. RESULTS: PM(2.5) and chemical components exhibited temporal patterns by time of day and season. The chemical characteristics of Seoul's PM(2.5) were more similar to PM(2.5) found in the western United States than in the eastern United States. Seoul's PM(2.5) had lower sulfate (SO(4)) contributions and higher nitrate (NO(3)) contributions than that of the eastern United States, although overall PM(2.5) levels in Seoul were higher than in the United States. An interquartile range (IQR) increase in magnesium (Mg) (0.05 MUg/m3) was associated with a 1.4% increase (95% confidence interval: 0.2%, 2.6%) in total mortality on the following day. Several components that were among the largest contributors to PM(2.5) total mass--NO(3), SO(4), and ammonium (NH(4))- were moderately associated with same-day cardiovascular mortality at the p < 0.10 level. Other components with smaller mass contributions [Mg and chlorine (Cl)] exhibited moderate associations with respiratory mortality on the following day (p < 0.10). CONCLUSIONS: Our findings link PM(2.5) constituents with mortality and have implications for policy making on sources of PM(2.5) and on the relevance of PM(2.5) health studies from other areas to this region. PMID- 22440885 TI - Nicotine traces detected in bottled mineral water. PMID- 22440886 TI - Chemical contaminants and parasites: assessment of human health risks associated with consumption of whitefish (Coregonus clupeaformis) from two boreal lakes in northern Saskatchewan, Canada. AB - In Canada there is increasing concern about potential effects of industrial activities on wildlife and human health. In an interdisciplinary study concentrations of inorganic (metals, metalloids) and organic (PCBs, organochlorine pesticides) contaminants, and parasitic infections of lake whitefish (Coregonus clupeaformis) from Montreal and Reindeer lakes, Saskatchewan, were investigated to assess human health risk related to fish consumption. In both lakes contamination of fish with chemical substances and compounds, respectively, were very low and often close to detection limits. Lake whitefish parasite communities consisted of 15 (Montreal Lake) and 12 (Reindeer Lake) species most of which were found in the intestinal tract. Many parasite species showed seasonal differences in prevalence and/or mean intensity of infection. None of the identified parasites are known to be human-pathogenic and overall, whitefish from both locations can be considered safe and healthy food. Nevertheless, women of child-bearing age and young children should limit their consumption to 3 and 2 meals, respectively, of Reindeer Lake whitefish per week to minimize potentially harmful exposure to mercury. As well, intestines of Montreal Lake fish should be removed prior to fish consumption if large parasite cysts containing a yet unidentified cestode species are detected. PMID- 22440887 TI - Compressive suture of the lower uterine segment for the treatment of postpartum hemorrhage due to complete placenta previa: a preliminary study. AB - AIM: To assess the efficacy of a uterine compression suture technique in controlling hemorrhage after removal of complete placenta previa during cesarean section. METHODS: This prospective study was performed in a tertiary referral hospital and included 18 patients with postpartum hemorrhage following removal of complete placenta previa during elective cesarean section. All 18 patients underwent bilateral anteroposterior compression suture of the lower uterine segment. All patients were followed postpartum for evaluation of uterine cavity and menstrual cycles. RESULTS: Anteroposterior compressive suture of the lower uterine segment achieved immediate complete hemostasis in all 18 patients. No surgical complication was observed. All patients recovered normal menstrual cycles. Normal patency of the uterine cavity was documented with sonohysterography in all patients at the 6-month follow-up visit. CONCLUSIONS: This quick and simple suture technique seems to be effective in stopping hemorrhage following complete placenta previa removal during cesarean section. Normal patency of the uterine cavity seems not to be impaired at medium-term follow-up. PMID- 22440889 TI - Re-wiring the spinal cord: introduction to the special issue on plasticity after spinal cord injury. PMID- 22440888 TI - Cardioprotection during cardiac surgery. AB - Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. For a large number of patients with CHD, coronary artery bypass graft (CABG) surgery remains the preferred strategy for coronary revascularization. Over the last 10 years, the number of high-risk patients undergoing CABG surgery has increased significantly, resulting in worse clinical outcomes in this patient group. This appears to be related to the ageing population, increased co morbidities (such as diabetes, obesity, hypertension, stroke), concomitant valve disease, and advances in percutaneous coronary intervention which have resulted in patients with more complex coronary artery disease undergoing surgery. These high-risk patients are more susceptible to peri-operative myocardial injury and infarction (PMI), a major cause of which is acute global ischaemia/reperfusion injury arising from inadequate myocardial protection during CABG surgery. Therefore, novel therapeutic strategies are required to protect the heart in this high-risk patient group. In this article, we review the aetiology of PMI during CABG surgery, its diagnosis and clinical significance, and the endogenous and pharmacological therapeutic strategies available for preventing it. By improving cardioprotection during CABG surgery, we may be able to reduce PMI, preserve left ventricular systolic function, and reduce morbidity and mortality in these high risk patients with CHD. PMID- 22440890 TI - Overcoming non-specific adsorption issues for AZD9164 in human urine samples: consideration of bioanalytical and metabolite identification procedures. AB - A key challenge in the development of robust bioanalytical methods, for the determination of drug analyte in human urine samples, is the elimination of potential analyte losses as a result of non-specific adsorption to container surfaces in which the samples are collected, stored or processed. A common approach to address adsorption issues is to treat the urine samples with additives that serve to increase analyte solubility and/or minimise interaction with the container surfaces. A series of adsorption experiments were performed on human urine samples containing an adsorption-prone in-house development compound (AZD9164). A roller-mixing methodology was employed to maximise sample interaction with container surfaces and quantification of analyte was performed by LC-MS/MS following minimal sample preparation. In the absence of any urine additive, adsorptive losses averaged 35% but were highly variable between different lots of urine. In the presence of a range of additives, including the surfactants Tween 80, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulphonate (CHAPS) and sodium dodecylbenzenesulphonate (SDBS), analyte adsorption was shown to be eliminated. Of particular academic interest was the finding that adsorptive losses could also be reduced upon the addition of phospholipid. The presence of additive generally had no marked impact on the analyte MS response but the use of an isotopically labelled internal standard satisfactorily compensated for instances in which ion suppression was observed, e.g. in the presence of Tween 80. Since metabolite profiling/identification investigations are often performed on urine samples originating from early clinical pharmacology studies, the elution of selected additives was also monitored by MS. CHAPS, dimethylacetamide (DMA) and HP-beta-cyclodextrin eluted as single chromatographic peaks in, or just after, the column void volume whilst polymeric Tween 80, and to a lesser extent SDBS, eluted over a wide retention time window. The potential of the latter surfactants to obscure the detection of unknown metabolites is significant and therefore their use in urine samples, upon which metabolite investigations are to be performed, is not recommended. Upon consideration of other factors such as additive cost and toxicity, CHAPS was selected for use in development of the validated assay. PMID- 22440891 TI - Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases. AB - INTRODUCTION: Serious infections are an important side effect of immunosuppressive therapy used to treat Crohn's disease (CD) and ulcerative colitis (UC). There have been no nationally representative studies examining the spectrum of infection related hospitalizations in patients with IBD. METHODS: Our study consisted of all adult CD and UC related hospitalizations from the Nationwide Inpatient Sample 2007, a national hospitalization database in the United States. We then identified all infection-related hospitalizations through codes for either the specific infections or disease processes (sepsis, pneumonia, etc.). Predictors of infections as well as the excess morbidity associated with infections were determined using multivariate regression models. RESULTS: There were an estimated 67,221 hospitalizations related to infections in IBD patients, comprising 27.5% of all IBD hospitalizations. On multivariate analysis, infections were independently associated with age, co-morbidity, malnutrition, TPN, and bowel surgery. Infection-related hospitalizations had a four-fold greater mortality (OR 4.4, 95% CI 3.7-5.2). However, this varied by type of infection with the strongest effect seen for sepsis (OR 15.3, 95% CI 12.4-18.6), pneumonia (OR 3.6, 95% CI 2.9-4.5) and C. difficile (OR 3.2, 95% CI 2.6-4.0), and weaker effects for urinary infections (OR 1.4, 95%CI 1.1-1.7). Infections were also associated with an estimated 2.3 days excess hospital stay (95% CI 2.2-2.5) and $12,482 in hospitalization charges. CONCLUSION: Infections account for significant morbidity and mortality in patients with IBD and disproportionately impact older IBD patients with greater co-morbidity. Pneumonia, sepsis and C difficile infection are associated with the greatest excess mortality risk. PMID- 22440892 TI - Super resolution SPECT reconstruction with non-uniform attenuation. AB - In this paper, based on Novikov's explicit inversion formula for the attenuated Radon transform, we present a super resolution SPECT reconstruction algorithm with compensation for non-uniform attenuation. Unlike the former methods improving the medical image resolution via super resolution (SR) in the reconstructed image, the proposed method apply the SR algorithm in the low resolution (LR) sinogram, which needs only 1-D shift of the detector, and the PSF is easy to obtain. Simulation results show that our reconstruction algorithm is effective. PMID- 22440893 TI - Screening for cancer associated MiRNAs through co-gene, co-function and co pathway analysis. AB - MicroRNAs (miRNAs) though present themselves as a group of non-coding small RNAs play critical roles in many biological and pathological processes. Among which the regulation of human cancer is one of the most excited potentiality. The goal of this study is to obtain miRNAs robustly associated with cancer by screening all of the possible miRNAs/cancer pairs in three consecutive steps. First, in co gene analysis, gene set enrichment analysis is carried out for all miRNA/cancer pairs. Second, in co-function analysis, information theoretic similarity on GO is calculated for miRNA/cancer pairs screened from the former step. Third, in co pathway analysis, pathway enrichment analysis is performed for miRNA/cancer pairs screened from the second step. In this study, we totally included 776 miRNAs and 25 cancer types. As a result, 94 miRNAs were identified with robust association with 17 types of cancer. Meanwhile, 83 pathways with relevance to both miRNAs and cancer were also singled out. This framework provides an effective way to narrow down miRNAs for cancer and to pinpoint corresponding pathways. PMID- 22440894 TI - Therapy-related acute leukemia in two patients with multiple sclerosis treated with Mitoxantrone. AB - Two cases of therapy-related acute leukemia (TRAL) after the use of Mitoxantrone for the treatment of secondary progressive multiple sclerosis (MS) are reported. They were extracted from the group of 42 consecutive patients with TRAL diagnosed and treated in single centre between 2000-2010. They were the only two with MS and the only two treated with Mitoxantrone. The first patient was a 43-year-old male with a previous history of MS of 15-year-duration, who developed acute promyelocytic leukemia 9 months following Mitoxantrone therapy (cumulative dose 120 mg). The second patient was a 55-year-old female suffering from MS for 16 years, who developed acute mixed-phenotype leukemia, T/myeloid type, with 46,XX,del(7)(p13)[12]/47,XX,idem,+3/[6]/46,XX[2], 15 months after completion of Mitoxantrone therapy (cumulative dose 100mg). Acute mixed-phenotype leukemia, T/myeloid type is for the first time described in the context of prior Mitoxantrone therapy. Although the incidence of TRAL in relation to Mitoxantrone pretreatment is rare, we should be vigilant for the prompt identification of this adverse event. PMID- 22440895 TI - Anti-breast cancer activity of heteroaryl chalcone derivatives. AB - In an attempt to develop effective anticancer therapeutics, a new series of heteroaryl chalcone compounds were designed, synthesized, and examined for their antiproliferative effects on two breast cancer cell lines and one matching non cancer breast cell line. The structure-activity relationship (SAR) analysis suggested that the compounds derived from thiophene chalcones (6-17) exhibited generally better antiproliferative activity than those derived from bioisoteric replacement of furan chalcones (18-29) on MDA-MB231 breast cancer cells. In contrast, the compounds derived from furan chalcones showed generally better antiproliferative activity on MDA-MB468 breast cancer cells. Among 24 compounds examined, compounds 21 and 23 showed significantly improved antiproliferative activity against MDA-MB231 and MDA-MB468 cancer cells. However, compound 23 ((E) 1-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)furan-2-yl)prop-2-en-1-one) is considered to be most desirable among this series, since its antiproliferative activity was 3 to 7-fold higher on cancer than non-cancer cells. Compound 23 showed not only more effective activity than the widely prescribed cisplatin on cancer cells, but it also showed differential antiproliferative activity against cancer cells, a property that is not shown with cisplatin. If this property shown in cell culture stands in vivo test, compound 23 can be an effective and safe anticancer drug. PMID- 22440896 TI - Reversal effect of Tween-20 on multidrug resistance in tumor cells in vitro. AB - Multidrug resistance (MDR) is a major barrier for chemotherapy of many cancers. Non-ionic surfactants have great potential to reverse the MDR by preventing onset or delay progression of the carcinogenic process. However, the role of Tween-20 in the development of MDR remains unknown. The aim of this study was to explore the reversal effect and potential mechanism of Tween-20 on tumor cells in vitro. Alamar Blue assay was used to examine the reversal index of Tween-20 to vincristine (VCR), doxorubicin (DOX) and 5-fluorouracil (5-FU) in KBv200, HepG2/R and Bel-7402/5-FU, respectively. Morphological change was determined by Gimsa and Hoechst 33258 staining. The acumulation of DOX was confirmed by spectrofluorimetric assay. Cell cycle analysis was performed using flow cytometry. The mRNA and protein expression levels of MDR were assessed by semiquantitative RT-PCR and dot blot, respectively. The results showed that Tween 20 at concentrations of 0.0025%, 0.005%, 0.01% had little cytotoxicity. When combined with the cancer drugs, it significantly promoted the sensitivity of MDR cells. Fluorescence staining confirmed that the percentage of apoptotic cell increased when combined with Tween-20. This notion was further supported by the observation that Tween-20 treatment potentiated VIN-induced G2/M arrest of the cell cycle. Furthermore, Tween-20 treatment increased significantly intracellular accumulation of DOX. RT-PCR and dot blot revealed that Tween-20 could downregulate the expression of MDR and P-glycoprotein. Low concentrations of Tween-20 can efficiently reverse the multidrug resistance phenotype by enhancing accumulation of the anticancer drugs. The potential mechanism may be via inhibiting the multidrug-resistant gene expression. PMID- 22440897 TI - Chloride intracellular channel 1 is an important factor in the lymphatic metastasis of hepatocarcinoma. AB - We have previously demonstrated that chloride intracellular channel 1 (CLIC1) is involved in the lymphatic metastasis of tumors. In this study, a self-designed shRNA sequence of mouse CLIC1 gene was synthesized and inserted into a pGPU6/GFP/Neo plasmid, then stably transfected into mouse hepatic carcinoma cell line Hca-F cells to down-regulate the expression of CLIC1 gene. The levels of expression of CLIC1 mRNA and protein were detected by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot (WB) analysis, respectively. The down-regulation of CLIC1 enhanced proliferative activity, increased the ratio of G2/M and decreased percentage of apoptosis. In addition, the capability of migration and invasion decreased significantly. The results indicate that CLIC1 is a critical factor in the development of lymphatic metastasis. PMID- 22440898 TI - In vitro leishmanicidal activity of N-dodecyl-1,2-ethanediamine. AB - Polyamine biosynthesis and inhibition in parasites have been an attractive chemotherapeutic approach in the design of novel antiparasitic drugs. We study in this work the effect of N-dodecyl-1,2-ethylenediamine (NDDE) on the morphology and replication of Leishmania using macrophages cultured from the peritoneal exudate of mice infected in vitro with three species of Leishmania: Leishmania (Leishmania) amazonensis, Leishmania (Viannia) brasiliensis and Leishmania (Leishmania) chagasi. The results showed that NDDE inhibited Leishmania amastigotes multiplication into inflammatory peritoneal cells in concentrations which were not toxic to mammalian cells (0.5-1MUg/mL). An intracellular disorganization of the promastigote forms was observed by transmission electron microscopy after 3 to 24h of treatment with 1MUg/mL NDDE, suggesting that this compound affects the viability of the parasite by an autophagy pathway. PMID- 22440899 TI - Angiotensin II- and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation. AB - Experiments with hyperaldosteronemic animals suggest that, despite lowering plasma aldosterone, salt worsens renal injury by paradoxical activation of the mineralocorticoid receptor (MR). Salt and aldosterone synergistically contribute to renal impairment through Rac1-mediated activation of the MR, but whether angiotensin II also promotes renal injury through this mechanism is unknown. Here, we placed angiotensin II-overproducing double transgenic Tsukuba hypertensive mice on a low- or high-salt intake for 6 weeks and treated some animals with adrenalectomy, the MR antagonist eplerenone, the Rac inhibitor EHT1864, or hydralazine. High-salt intake, but not low-salt intake, led to hypertension and prominent kidney injury. Adrenalectomy prevented angiotensin II/salt-induced nephropathy in mice receiving high-salt intake, which was recapitulated by aldosterone supplementation, suggesting the involvement of aldosterone/MR signaling. Plasma aldosterone levels, however, were lower in high- than low-salt conditions. Instead, angiotensin II/salt-evoked MR activation associated with Rac1 activation and was not dependent on plasma aldosterone level. Both EHT1864 and eplerenone repressed the augmented MR signaling and mitigated kidney injury with partial but significant reduction in BP with high salt intake. Hydralazine similarly reduced BP, but it neither suppressed the Rac1 MR pathway nor ameliorated the nephropathy. Taken together, these results show that angiotensin II and salt accelerate kidney injury through Rac1-mediated MR activation. Rac inhibition may be a promising strategy for the treatment of CKD. PMID- 22440900 TI - Inhibition of integrin alpha2beta1 ameliorates glomerular injury. AB - Mesangial cells and podocytes express integrins alpha1beta1 and alpha2beta1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin alpha1beta1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin alpha2beta1 in renal injury is unclear. Here, we subjected wild-type and integrin alpha2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin alpha2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin alpha2beta1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wild-type mice. This inhibitor significantly reduced collagen synthesis in wild type, but not integrin alpha2-null, mesangial cells in vitro, demonstrating that its effects are integrin alpha2beta1-dependent. Taken together, these results indicate that integrin alpha2beta1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria. PMID- 22440901 TI - Inducible podocyte injury and proteinuria in transgenic zebrafish. AB - Damage or loss of podocytes causes glomerulosclerosis in murine models, and mutations in podocyte-specific genes cause nephrotic syndrome in humans. Zebrafish provide a valuable model for kidney research, but disruption of pronephroi leads to death within a few days, thereby preventing the study of CKD. In this study, we generated an inducible model of podocyte injury in zebrafish (pod::NTR-mCherry) by expressing a bacterial nitroreductase, which converts metronidazole to a cytotoxin, specifically in podocytes under the control of the zebrafish nphs2/podocin promoter. Application of the prodrug metronidazole to the transgenic fish induces acute damage to the podocytes in pronephroi of larval zebrafish and the mesonephroi of adult zebrafish, resulting in foot-process effacement and podocyte loss. We also developed a functional assay of the glomerular filtration barrier by creating transgenic zebrafish expressing green fluorescent protein (GFP)-tagged vitamin D-binding protein (VDBP) as a tracer for proteinuria. In the VDBP-GFP and pod::NTR-mCherry double-transgenic fish, induction of podocyte damage led to whole-body edema, and the proximal tubules reabsorbed and accumulated VDBP-GFP that leaked through the glomeruli, mimicking the phenotype of human nephrotic syndrome. Moreover, expression of wt1b::GFP, a marker for the developing nephron, extended into the Bowman capsule in response to podocyte injury, suggesting that zebrafish have a podocyte-specific repair process known to occur in mammalian metanephros. These data support the use of these transgenic zebrafish as a model system for studies of glomerular pathogenesis and podocyte regeneration. PMID- 22440902 TI - The circadian clock modulates renal sodium handling. AB - The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clock-deficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling. PMID- 22440903 TI - Vasculature and kidney complications in sickle cell disease. AB - Recent developments in sickle cell disease include the concept of a vasculopathic state and the classification of sickle cell disease into a hemolysis-endothelial dysfunction phenotype or a viscosity-vasoocclusion phenotype. The hemolysis endothelial dysfunction phenotype largely reflects deficiency of or resistance to nitric oxide. In addition to discussing these areas, we suggest that the hemolysis-endothelial dysfunction phenotype also reflects the instability of sickle hemoglobin, the release of heme, and the induction of heme oxygenase-1. From these perspectives the renal complications of sickle cell disease are discussed and classified. PMID- 22440904 TI - Quantitative proteomics identifies vasopressin-responsive nuclear proteins in collecting duct cells. AB - Vasopressin controls transport in the renal collecting duct, in part, by regulating transcription. This complex process, which can involve translocation and/or modification of transcriptional regulators, is not completely understood. Here, we applied a method for large-scale profiling of nuclear proteins to quantify vasopressin-induced changes in the nuclear proteome of cortical collecting duct (mpkCCD) cells. Using stable isotope labeling and tandem mass spectrometry, we quantified 3987 nuclear proteins and identified significant changes in the abundance of 65, including previously established targets of vasopressin signaling in the collecting duct. Vasopressin-induced changes in the abundance of the transcription factors JunB, Elf3, Gatad2b, and Hmbox1; transcriptional co-regulators Ctnnb1 (beta-catenin) and Crebbp; subunits of the Mediator complex; E3 ubiquitin ligase Nedd4; nuclear transport regulator RanGap1; and several proteins associated with tight junctions and adherens junctions. Bioinformatic analysis showed that many of the quantified transcription factors have putative binding sites in the 5'-flanking regions of genes coding for the channel proteins Aqp2, Aqp3, Scnn1b (ENaCbeta), and Scnn1g (ENaCgamma), which are known targets of vasopressin. Immunoblotting demonstrated that the increase in beta-catenin in nuclear fractions was accompanied by an even larger increase in its phosphorylated form (pSer552). The findings provide a new online database resource for nuclear proteomics (http://helixweb.nih.gov/ESBL/Database/mNPD/) and generate new hypotheses regarding vasopressin-mediated transcriptional regulation in the collecting duct. PMID- 22440905 TI - Plasma and urinary heme oxygenase-1 in AKI. AB - AKI induces upregulation of heme oxygenase 1 (HO-1), which exerts cytoprotective effects and modulates the renal response to injury, suggesting that a biomarker of intrarenal HO-1 activity may be useful. Because HO-1 largely localizes to the endoplasmic reticulum and has no known secretory pathway, it is unclear whether plasma or urinary levels of HO-1 reflect intrarenal HO-1 expression. We measured plasma and urinary levels of HO-1 by ELISA during the induction and/or maintenance phases of four mouse models of AKI: ischemia/reperfusion, glycerol induced rhabdomyolysis, cisplatin nephrotoxicity, and bilateral ureteral obstruction. In addition, we measured levels of HO-1 mRNA and protein in the renal cortex. Each AKI model increased renal HO-1 gene expression, which corresponded with release of HO-1 into plasma and urine by 4 hours. Over time, the magnitudes of plasma and urinary HO-1 paralleled renal cortical gene expression. AKI and the associated uremia did not seem to affect extrarenal HO-1 gene activity assessed in the liver, lung, and spleen. In iron-challenged, cultured proximal tubule cells, we observed a positive correlation between HO-1 mRNA level and HO-1 release. In humans, 10 patients with AKI demonstrated markedly higher levels of plasma and urine HO-1 levels than 10 critically ill patients without AKI or 20 patients with CKD or ESRD. In summary, these data suggest that plasma and urinary HO-1 levels may serve as biomarkers of AKI and intrarenal HO-1 gene activity. PMID- 22440906 TI - Effects of biocompatible versus standard fluid on peritoneal dialysis outcomes. AB - The clinical benefits of using "biocompatible" neutral pH solutions containing low levels of glucose degradation products for peritoneal dialysis compared with standard solutions are uncertain. In this multicenter, open-label, parallel group, randomized controlled trial, we randomly assigned 185 incident adult peritoneal dialysis patients with residual renal function to use either biocompatible or conventional solution for 2 years. The primary outcome measure was slope of renal function decline. Secondary outcome measures comprised time to anuria, fluid volume status, peritonitis-free survival, technique survival, patient survival, and adverse events. We did not detect a statistically significant difference in the rate of decline of renal function between the two groups as measured by the slopes of GFR: -0.22 and -0.28 ml/min per 1.73 m(2) per month (P=0.17) in the first year in the biocompatible and conventional groups, respectively, and, -0.09 and -0.10 ml/min per 1.73 m(2) per month (P=0.9) in the second year. The biocompatible group exhibited significantly longer times to anuria (P=0.009) and to the first peritonitis episode (P=0.01). This group also had fewer patients develop peritonitis (30% versus 49%) and had lower rates of peritonitis (0.30 versus 0.49 episodes per year, P=0.01). In conclusion, this trial does not support a role for biocompatible fluid in slowing the rate of GFR decline, but it does suggest that biocompatible fluid may delay the onset of anuria and reduce the incidence of peritonitis compared with conventional fluid in peritoneal dialysis. PMID- 22440907 TI - Innate immunity: trolling, responding and protecting against viral infections. PMID- 22440908 TI - Toll-like receptors: key players in antiviral immunity. AB - TLRs are a family of innate receptors whose specificities are predetermined in the germline. Therefore, TLRs have evolved to recognize conserved features of microbes. Viruses typically lack the conserved features common to other pathogen classes, so the innate immune system has evolved to recognize viral nucleic acid as a hallmark of viral infection. In this review we discuss examples of TLR mediated viral recognition and the functional consequences of this recognition for antiviral immunity. PMID- 22440909 TI - Cytosolic surveillance and antiviral immunity. AB - Innate immune surveillance mechanisms lie at the heart of the antiviral response. A growing number of germ-line encoded pattern recognition receptors have been identified which protect the host from infection by sensing the presence of viral molecules and inducing antiviral defenses. Most compartments that viruses gain access to are under active surveillance by one or more pattern recognition receptors. Members of the Toll-like receptor family guard the extracellular milieu and endosomal compartment where they are activated by viral glycoproteins or nucleic acids, respectively. More recently, the cytosolic compartment has emerged as the frontline in the arsenal of the host's antiviral defenses. Families of receptors in the cytosol recognize viral RNA or DNA or perturbations of cellular homeostasis and orchestrate effector responses to eliminate the invader. Here, we review this expanding area of innate immunity by focusing on the molecular mechanisms of cytosolic host-defenses. PMID- 22440911 TI - Resisting viral infection: the gene by gene approach. AB - This review focuses on genes required for resistance to mouse cytomegalovirus (MCMV), as identified through unbiased genetic screening. Components of the developmental, sensing, and effector pathways, functioning in multiple cell types, were detected by infecting 22,000 G3 mutant mice with MCMV at an inoculum easily contained by WT animals. Merging these findings with discoveries from hypothesis-based studies, we present a cohesive picture of the essential elements utilized by the mouse innate immune system to counter MCMV. We believe that many breakthrough discoveries will yet be made using a classical genetic approach. PMID- 22440910 TI - Type I interferons: diversity of sources, production pathways and effects on immune responses. AB - Type I interferons (IFN-I) were first described over 50 years ago as factors produced by cells that interfere with virus replication and promote an antiviral state. Innate and adaptive immune responses to viruses are also greatly influenced by IFN-I. In this article we discuss the diversity of cellular sources of IFN-I and the pathways leading to IFN-I production during viral infections. Finally, we discuss the effects of IFN-I on cells of the immune system with emphasis on dendritic cells. PMID- 22440912 TI - Antiviral drugs and antiviral drug resistance. PMID- 22440913 TI - Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed? AB - We summarize the history of the clinical drug development of maribavir for its use as prophylaxis in stem-cell transplant recipients. We highlight key aspects in the design and interpretation of the results of the dose escalation phase II maribavir study that may have contributed to the negative findings on the phase III trials. We discuss key aspects of study design that should be considered in the study of new interventions needed to advance the prevention and treatment of CMV in transplant recipients. PMID- 22440914 TI - Antivirals and resistance: influenza virus. AB - Influenza causes annual epidemics of respiratory viral infections are associated with significant morbidity and mortality. Influenza vaccines have been shown to reduce the risk of infection and mitigate against some of the virus' sequellae. Likewise, two classes of antivirals, the adamantanes (amantadine and rimantadine) and the neuraminidase inhibitors (laninamivir, oseltamivir, peramivir, and zanamivir) are currently approved for the prevention and treatment of influenza; several other classes of antivirals and immune modulators are also currently under investigation. One of the greatest challenges to our armamentarium of antivirals is the emergence of resistant mutants. In this paper, we will review the currently approved and investigational antiviral agents and the mechanisms of resistance that impact their activity. PMID- 22440915 TI - Fitness of neuraminidase inhibitor-resistant influenza A viruses. AB - Antiviral drugs are important components for the control of influenza. The key question is whether antiviral use or natural virus evolution will lead to the emergence of drug-resistant virus with comparable or superior fitness to drug susceptible counterpart. Currently, neuraminidase (NA) inhibitors (NAIs) are the first choice for influenza prevention and treatment. In this article we will review complex process of the risk assessment for the fitness of NAIs-resistant seasonal H1N1 and H3N2, pandemic 2009 H1N1, and highly pathogenic H5N1 influenza A viruses: identification of antiviral susceptibility, degree of functional NA loss, molecular markers of resistance, and evaluation of replicative ability in vivo, virulence and transmissibility in animal studies (mouse, ferret, and guinea pig models). PMID- 22440916 TI - Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. AB - Roughly 20 years after the discovery of the hepatitis C virus (HCV), and 10 years after the launch of the current standard of care (SOC) therapy, i.e. the combination of pegylated interferon-alpha and ribavirin, antiviral treatment of chronic hepatitis C is at the dawn of a new era. The current SOC will be combined with a direct acting antiviral (DAA), i.e. either the HCV NS3 protease inhibitor Telaprevir or Boceprevir. Combinations of DAAs may have the potential to completely cure chronic HCV infection. Clinical data suggest that ribavirin may remain at least for some time, an important component even in combinations of different DAAs. Ironically, and much in contrast to the DAAs, the precise mechanism(s) by which ribavirin exerts its anti-HCV activity in infected patients still waits to be unravelled. Here we review the current views on the mechanism of action of ribavirin against chronic infections with HCV. Concerted efforts of modern pharmacogenetics, novel insights into innate immunity and contributions from molecular virology will hopefully allow deciphering the precise mechanism(s) that are at the basis of the antiviral effect of this nucleoside analogue. Such insights may help design improved strategies to fight chronic infections with HCV. PMID- 22440917 TI - Resistance to anti-HCV protease inhibitors. AB - The era of direct acting antiviral therapy for HCV infection has dawned with the recent approval of the NS3 protease inhibitors telaprevir and boceprevir. The development of DAA therapy is an exciting advance for clinicians and patients, but it will also bring new challenges. For the first time, drug resistance has become an issue to consider in the management of HCV. This brief review summarizes the current literature concerning resistance to the HCV NS3 protease inhibitors, both experimental and clinical, and identifies the key questions facing the field. PMID- 22440918 TI - Anti-HCV drugs in the pipeline. AB - Several directly acting and host targeting antivirals that inhibit hepatitis C virus replication have entered clinical trials. Among the most advanced of these are RG7128, an inhibitor of the NS5B polymerase; BMS-790052, an inhibitor of NS5A; and alisporivir, an inhibitor of human cyclophilins. These agents have potent antiviral activity in chronic HCV patients, act additively or synergistically with inhibitors of the HCV NS3/4A protease, and improve the rate of virologic response produced by traditional pegylated interferon plus ribavirin therapy. No cross resistance has been observed; moreover, nucleoside NS5B and cyclophilin inhibitors appear to suppress resistance to non-nucleoside NS5B and NS3/4A inhibitors. Several recent reports of virologic responses produced by combinations of agents that inhibit HCV replication in the absence of interferon provide optimism that eradication of HCV will be possible without interferon in the future. PMID- 22440919 TI - Emerging viruses. PMID- 22440920 TI - The search for meaning in virus discovery. AB - The rate of new virus discovery is increasing dramatically with improvements in sequencing and other molecular diagnostic platforms, and investments in sample collection and analysis. However, progress has been more limited in identification and implication of infectious agents that pose threats to human health and welfare. Here we review strategies for targeting research to enable efficient significant virus discovery. PMID- 22440922 TI - RNA virus population diversity: implications for inter-species transmission. AB - RNA viruses are notorious for rapidly generating genetically diverse populations during a single replication cycle, and the implications of this mutant population, often referred to as quasispecies, can be vast. Previous studies have linked RNA virus genetic variability to changes in viral pathogenesis, the ability to adapt to a host during infection, and to the acquisition of mechanisms required to switch hosts entirely. However, these initial studies are just the beginning. With the development of next generation technologies, groups will be able to dig deeper into the sequence space that is generated during an RNA virus infection and more clearly understand the development, role, and consequences of viral genetic diversity. PMID- 22440921 TI - Predicting 'airborne' influenza viruses: (trans-) mission impossible? AB - Repeated transmission of animal influenza viruses to humans has prompted investigation of the viral, host, and environmental factors responsible for transmission via aerosols or respiratory droplets. How do we determine-out of thousands of influenza virus isolates collected in animal surveillance studies each year-which viruses have the potential to become 'airborne', and hence pose a pandemic threat? Here, using knowledge from pandemic, zoonotic and epidemic viruses, we postulate that the minimal requirements for efficient transmission of an animal influenza virus between humans are: efficient virus attachment to (upper) respiratory tissues, replication to high titers in these tissues, and release and aerosolization of single virus particles. Investigating 'airborne' transmission of influenza viruses is key to understand-and predict-influenza pandemics. PMID- 22440923 TI - Mass extinctions, biodiversity and mitochondrial function: are bats 'special' as reservoirs for emerging viruses? AB - For the past 10-15 years, bats have attracted growing attention as reservoirs of emerging zoonotic viruses. This has been due to a combination of factors including the emergence of highly virulent zoonotic pathogens, such as Hendra, Nipah, SARS and Ebola viruses, and the high rate of detection of a large number of previously unknown viral sequences in bat specimens. As bats have ancient evolutionary origins and are the only flying mammals, it has been hypothesized that some of their unique biological features may have made them especially suitable hosts for different viruses. So the question 'Are bats different, special or exceptional?' has become a focal point in the field of virology, bat biology and virus-host co-evolution. In this brief review, we examine the topic in a relatively unconventional way, that is, our discussion will be based on both scientific discoveries and theoretical predictions. This approach was chosen partially because the data in this field are so limited that it is impossible to conduct a useful review based on published results only and also because we believe it is important to provoke original, speculative or even controversial ideas or theories in this important field of research. PMID- 22440924 TI - Henipaviruses-unanswered questions of lethal zoonoses. AB - The highly lethal Hendra and Nipah viruses have been described for little more than a decade, yet within that time have been aetiologically associated with major livestock and human health impacts, albeit on a limited scale. Do these emerging pathogens pose a broader threat, or are they inconsequential 'viral chatter'. Given their lethality, and the evident multi-generational human-to human transmission associated with Nipah virus in Bangladesh, it seems prudent to apply the precautionary principle. While much is known of their clinical, pathogenic and epidemiologic features in livestock species and humans, a number of fundamental questions regarding the relationship between the viruses, their natural fruit-bat host and the environment remain unanswered. In this paper, we pose and probe these questions in context, and offer perspectives based primarily on our experience with Hendra virus in Australia, augmented with Nipah virus parallels. PMID- 22440925 TI - A perspective on lyssavirus emergence and perpetuation. AB - Rabies is propagated globally by viruses in the Family Rhabdoviridae, Genus Lyssavirus. These RNA viruses utilize the mammalian central nervous system as their ultimate niche, and exploit routine social mechanisms, as well as host behavioral alterations, to facilitate transmission by neural transport and innervations of the salivary glands, and ultimately excretion via the saliva, towards circulation thereafter in host populations. All mammals are susceptible to infection, but lyssavirus reservoirs are represented by several species of Carnivora, with viral global diversity and distribution in toto driven by a wide variety of the Chiroptera. Pathogen diversity is maintained by multiple faunas, and facilitated by pronounced host vagility, as exemplified by the ease of routine daily and seasonal movements by bats. Viral 'ensembles', or subpopulations associated with productive transmission events, emerge locally in vivo through a combination of naive host infections in some individuals versus acquired immunity by others, using complex metapopulation dynamics. Enhanced surveillance, improved diagnostics, increased pathogen detection, and an integrated One Health approach, targeting human, domestic animal and wildlife interfaces, provide modern insights to the ecology of bat lyssaviruses to augment future prevention and control. PMID- 22440926 TI - Isolation of meticillin-resistant Staphylococcus aureus sequence type 9 in pigs in Taiwan. PMID- 22440927 TI - Electrophysiological signatures of masked transposition priming in a same different task: evidence with strings of letters vs. pseudoletters. AB - Research on masked transposed-letter priming (i.e., jugde-JUDGE triggers a faster response than jupte-JUDGE) has become a key phenomenon to reveal how the brain encodes letter position. Recent behavioural evidence suggests that the mechanism responsible for position coding in a masked priming procedure works with familiar "object" identities (e.g., letters, digits, symbols) but not with unfamiliar object identities (e.g., pseudoletters). Here we used event-related potentials (ERPs) to explore the time course of masked transposition priming of letters vs. pseudoletters in a cue-target same-different matching task. Target stimuli were preceded by a masked prime that could be: (i) identical to the target; (ii) identical to the target except for the transposition of two internal letters/pseudoletters; or (iii) identical to the target except for the substitution of two internal letters/pseudoletters. Only cue-target 'same' trials were analyzed. The priming manipulation affected the "same" trials of the letter strings between 250 ms and 450 ms: identity and transposition conditions produced less negative amplitudes than the substitution condition. Because of the onset latency of this priming effect, we suggest that masked primes affected mainly the cognitive processes related to the categorization of the trials (match versus mismatch), rather than to the initial stages of orthographic processing. PMID- 22440928 TI - Perianal Crohn's disease: predictive factors and genotype-phenotype correlations. AB - AIM: To investigate genotype-phenotype correlations in patients with perianal Crohn's disease (PCD) in order to determine which factors predispose to development of perianal disease in Crohn's patients. METHODS: Seven-hundred and ninety-five Caucasian individuals (317 CD patients and 478 controls without inflammatory bowel disease, IBD) were prospectively enrolled into a clinical/genetic database. Demographic and clinical data, as well as peripheral blood leukocyte DNA were obtained from all patients. The following were evaluated: three NOD2/CARD15 polymorphisms: R702W, G908R, and 1007insC; five IL 23r risk alleles: rs1004819, rs10489629, rs2201841, rs11465804, and rs11209026; a well-characterized single-nucleotide polymorphism (SNP) on the IBD5 risk haplotype (OCTN1) and two peripheral tag SNPs (IGR2060 and IGR3096). RESULTS: PCD occurred in 147 (46%) of CD patients. There was no significant difference in the age at disease diagnosis between non-PCD and PCD patients (33 vs. 29 years, respectively). PCD patients were more likely to have disease located in the colon and ileocolic regions (79 PCD vs. 57% non-PCD; n = 116 vs. n = 96; p < 0.001), whereas patients with non-PCD were more likely to have Crohn's within the terminal ileum and upper gastrointestinal tract (43% non-PCD vs. 21% PCD; n = 73 vs. n = 31; p < 0.05). Thirty-four percent of patients with PCD required a permanent ileostomy (n = 50) compared to only 4% of non-PCD patients (n = 6; p < 0.05). Mutations in CARD15/NOD2 and IL-23r were risk factors for CD overall; however, in contrast to prior reports, in this patient population, OCTN1 and IGR variations within the IBD5 haplotype were not significant predictors of PCD. CONCLUSION: Colon/ileocolic CD location appears to be a significant predictor of perianal manifestations of CD. Patients with PCD are more likely to require permanent fecal diversion. We did not identify any genetic variations or combination of clinical findings and genetic variations within the CARD15/NOD2, IL-23r, and OCTN1 genes or IGR that were predictive of PCD. PMID- 22440929 TI - Diagnosis and treatment of coats' disease: a review of the literature. AB - Coats' disease is an idiopathic, ophthalmic condition characterized by retinal telangiectasis, intraretinal and subretinal exudation, which can lead to retinal detachment. It is mostly unilateral, progressive and affects mainly males during childhood, although adult cases have also been described. In this review, we make an update of the literature about Coats' disease, emphasizing on diagnosis and treatment, including the most recent treatment modalities, i.e. anti-vascular endothelial growth factor agents. PMID- 22440930 TI - Managing bone and joint infection in children. AB - There is little high quality evidence on which to base the management of bone and joint infections in children. This pragmatic practice note aims to provide a consensus framework of best current practice prior to the availability of data from large national randomised controlled trials. For straightforward infection in previously normal children, recent trends suggest that shorter length of intravenous therapy with switch to oral treatment is acceptable, although this is not the case for the management of complex infections including those with multifocal disease, significant bone destruction, resistant or unusual pathogens, sepsis or in immunosuppressed children. Flowsheets for management based on the evidence reviewed are presented. PMID- 22440931 TI - New anthranilic acid derivative, EAntS-GS, attenuates Freund's complete adjuvant induced acute pain in rats. AB - BACKGROUND: Acute and chronic pain commonly accompany various clinical conditions such as contusion, fracture, osteoarthritis, peripheral neuropathy, and postherpetic neuralgia. Recent studies have found that antioxidative drugs can have analgesic effects. The present study tested the hypothesis that a new anthranilic acid derivative, EAntS-GS, exerts antinociceptive effects on inflammatory pain in a rat model. METHODS: We induced subacute pain with a plantar injection of Freund's complete adjuvant (FCA) in Sprague-Dawley rats. EAntS-GS (1 mg/kg subcutaneous injection or 1% application) was administered every 12 h beginning 24 h after FCA administration, and the plantar test was used to determine its effect on pain. Levels of myeloperoxidase, inducible nitric oxide synthase (iNOS), and protease activated receptor 2 (PAR2) were measured to elucidate the mechanism of action of EAntS-GS. RESULTS: EAntS-GS significantly reduced FCA-induced pain and myeloperoxidase, iNOS, and PAR2 levels. Our findings suggest that the new anthranilic acid derivative, EAntS-GS, exerts antinociceptive effects, and that the mechanism involves iNOS and PAR2. CONCLUSION: We conclude that EAntS-GS should be considered a new therapeutic tool to treat acute and chronic pain. PMID- 22440932 TI - The vitamin E derivative, ESeroS-GS, attenuates renal ischemia-reperfusion injury in rats. AB - BACKGROUND: Acute kidney injury (AKI), which occurs during renal transplantation and cardiovascular surgery, is a major clinical problem associated with high mortality, and has limited treatment options. Anti-inflammation therapy has been suggested to improve the course and outcome of AKI. In this study, we hypothesized that ESeroS-GS, a vitamin E derivative, inhibits cytokine production and prevents renal ischemia-reperfusion (I/R) injury in rats. METHODS: Rats received an intravenous infusion of ESeroS-GS or saline, and underwent experimentally-induced renal I/R injury or sham treatment. Rats were sacrificed after 60 min of ischemia and 24 h of reperfusion. To evaluate the renal protective effects of ESero-GS, renal function was examined, kidneys were histologically assessed, levels of myeloperoxidase (MPO) and serum cytokines were measured, and caspase 3/7 activity was determined. RESULTS: ESeroS-GS attenuated I/R-induced histologic alterations, reduced levels of MPO and serum BUN, Cre, TNF alpha, and IL-6, and decreased caspase 3/7 activity in kidneys of rats subjected to renal I/R injury. CONCLUSIONS: ESeroS-GS attenuated renal injury after I/R by reducing serum cytokine levels. Our findings suggest that ESeroS-GS may have therapeutic potential against various human I/R conditions. PMID- 22440933 TI - Modified map-seeking circuit: use of computer-aided detection in locating postoperative retained foreign bodies. AB - BACKGROUND: More than 98% of intra-operative X-rays taken to search for postoperative retained foreign bodies (RFBs) have negative findings; in over 30% of cases of such X-rays, the finding is a false negative. Newer technologies created to find RFBs must not only reduce the false-negative rate, but also must not increase the burden of detecting RFBs. We have introduced the use of computer aided detection (CAD) to facilitate the detection of RFBs on X-rays utilizing a modified version of map-seeking circuit (MSC) algorithm the referenced map seeking circuit (RMSC), for our proof-of-concept study for detection of needles in plain abdominal X-rays. METHODS: Images were obtained by using a portable cassette-based X-ray machine and a C-arm (digital) machine, both of which are commonly used in the operating room. The images obtained using these machines were divided into subimages of approximately 250 * 250 pixels each, for a total of 455 subimages from the cassette-based machine (A) and 365 from the digital machine (B) for use as test samples. Images obtained from A and B were analyzed separately using our modified MSC algorithm with a minimum (tau = 0) and a maximum threshold (tau = 0.5). RESULTS: The automated detection rate (positive predictive value) was 86%, with a false positive/negative rate of 10% to 15% when tau was zero. CONCLUSION: The CAD-based RMSC algorithm has the potential to improve the accuracy with which RFBs can be found in X-rays. Further research is needed to optimize the detection rate and to identify a wider range of RFBs. PMID- 22440934 TI - Early activation of the inflammatory response in the liver of brain-dead non human primates. AB - BACKGROUND: Donor brain death (BD) triggers a systemic inflammatory response that reduces organ quality and increases immunogenicity of the graft. We characterized the early innate immune response induced by BD in the liver and peripheral blood of hemodinamically stable non-human primates (NHP). METHODS: Rhesus macaques were assigned to either brain death or control group. BD was induced by inflation of a subdurally placed catheter and confirmed clinically and by cerebral angiography. Animals were monitored for 6 h after BD and managed to maintain hemodynamic stability. RESULTS: Cortisol, epinephrine, nor-epinephrine, and IL-6 levels were elevated immediately after BD induction. Neutrophils and monocytes significantly increased in circulation following BD induction, while dendritic cells were decreased at 6 h post-induction. Flow cytometry revealed increased expression of chemokine receptors CxCR1, CxCR2, CCR2, and CCR5 in peripheral blood leukocytes from NHP subjected to BD. Microarray analysis demonstrated a significant up regulation of genes related to innate inflammatory responses, toll-like receptor signaling, stress pathways, and apoptosis/cell death in BD subjects. Conversely, pathways related to glucose, lipid, and protein metabolism were down-regulated. In addition, increased expression of SOCS3, S100A8/A9, ICAM-1, MHC class II, neutrophil accumulation, and oxidative stress markers (carboxy-methyl-lysine and hydroxynonenal) were detected by immunoblot and immunohistochemistry. CONCLUSIONS: Activation of the innate immune response after BD in association with a down-regulation of genes associated with cell metabolism pathways in the liver. These findings may provide a potential explanation for the reduced post transplant function of organs from brain dead donors. In addition, this work suggests potential novel targets to improve donor management strategies. PMID- 22440935 TI - Effective method to remove wound bacteria: comparison of various debridement modalities in an in vivo porcine model. AB - BACKGROUND: Debridement is one of the crucial steps for successful wound care. In addition to removing necrotic tissue, debridement has been shown to reduce wound associated bacteria that delay healing. Using an in vivo porcine model, we compared the effects of various methods of debridement, including hydrosurgery and plasma-mediated bipolar radiofrequency ablation (PBRA), on bacterial removal and wound healing. METHODS: One hundred thirty-five deep dermal wounds were inoculated with methicillin resistant Staphylococcus aureus (MRSA) and covered with a polyurethane dressing for 48 h to allow for biofilm formation. Wounds were then treated with either PBRA (at two settings), hydrosurgery, sharp debridement, or no debridement. Biopsies were collected for microbiology and histologic assessment on d 0, 2, 9, and 21 post-treatment. RESULTS: All treatment groups showed a statistically significant reduction in MRSA counts relative to no debridement at all times points (P < 0.05). PBRA at a maximum setting had the lowest MRSA counts at all recovery times and, compared with all other treatment groups, a statistically significant difference was observed on d 21 (P < 0.05). No detrimental effects on the healing process were noted with any of the debridement methods. CONCLUSION: While sharp debridement has been established as the traditional gold standard for rapid removal of necrotic, infected tissue, our results suggest that novel debridement modalities show clinical promise for the treatment of chronic ulcers and burn wounds, especially when bacteria are present. PMID- 22440936 TI - p16 gene mutations in Barrett's esophagus in gastric metaplasia - intestinal metaplasia - dysplasia - adenocarcinoma sequence. AB - PURPOSE: Barrett's associated esophageal adenocarcinoma (ADC) is one of the malignancies of most rapidly increasing incidence. The aim of the study was to assess p16 tumor suppressor gene alterations in the ADC premalignant conditions. MATERIAL & METHODS: In the present study two p16 gene mutations (A148T and I49S) analysis with PCR- RFLP method have been performed in oesophageal biopsy specimen in 33 patients with Barrett's gastric metaplasia (GM), 27 - with Barrett's intestinal metaplasia (IM), 8 - with dysplasia and 11 - with ADC. RESULTS: We have detected the I49S mutation in 12% (4/33) patients with GM, 18% (5/27) with IM, 50% - with dysplasia (4/8) and in 27% (3/11) - with ADC. The A148T mutation were found in 3% (1/33) patients with GM, 22% (6/27) - IM, 25% (2/8) - dysplasia and 27% patients with ADC (3/11). The frequency of the A148S mutation was rising in GM - IM - dysplasia - ADC sequence and was significantly lower in GM compared to all other grades taken together (p=0.0256). The frequency of the I49S mutation was rising in GM - IM - dysplasia sequence, to drop in ADC cases. There were no significant differences in frequency of the I49S mutation between studied groups. CONCLUSIONS: These findings are consistent with the hypothesis on the role of the p16 mutations in early phase of Barrett's epithelium progression to ADC. The presence of p16 mutations in esophageal metaplastic columnar epithelium without goblet cells suggest that this pathology may have malignancy potential. PMID- 22440937 TI - Estrogen, a female hormone involved in spermatogenesis. AB - In mammalian testes, aromatase irreversibly converts androgens (C19 steroid) into estrogens (C18) and is present in the endoplasmic reticulum of numerous tissues. In purified adult rat germ cells (pachytene spermatocytes and round spermatids) we have shown the presence of a functional aromatase (transcript, protein and biological activity) and the estrogen production is roughly identical to that of Leydig cells. In addition, transcripts of aromatase varied according to the germ cell type and the stages of seminiferous epithelium in an adult rat. In contrast with the androgen receptors mainly localized in somatic cells, estrogen receptors (ERs) are described in all testicular cells. Moreover, besides the presence of high affinity ERalpha and ERbeta a rapid membrane effects have been recently reported and we demonstrated that GPR30 (a transmembrane intracellular estrogen receptor) was expressed in adult rat pachytene spermatocytes and in round spermatids. Thus estrogens through both GPR30 and genomic effects are able to activate the rapid signaling cascade, which in turn triggers an apoptotic mitochondrial pathway (via an increase in Bax expression) and a concomitant decrease of cyclin A1 and B1 gene levels as well as in controlling apoptosis and maturation/differentiation of round spermatids. Hence, the role of estrogen (either intracrine, paracrine or autocrine) in spermatogenesis (proliferation, apoptosis, survival and maturation) is now obvious taking into account the simultaneous presence of a biologically active aromatase and the widespread distribution of estrogen receptors especially during the spermiogenesis steps. PMID- 22440938 TI - 100 obese patients after laparoscopic adjustable gastric banding - the influence on BMI, gherlin and insulin concentration, parameters of lipid balance and co morbidities. AB - PURPOSE: Obesity is a widespread health issue caused by chronic impaired balance between energy supply and its expenditure. It leads to gathering of excessive fat tissue and numerous co-morbidities.The aim of this study is to present the influence of laparoscopic adjustable gastric banding (LAGB) on plasma ghrelin, insulin, glucose, triglycerides, total, HDL- and LDL-cholesterol concentration as well as on alanine and aspartate aminotransferase in obese patients and influence on co-morbidities such as type 2 diabetes mellitus, dislipidemy, hypertension and sleep apnea. MATERIALS AND METHODS: 100 obese patients underwent LAGB: 34 men - average age 39.18 +/- 12.17 years old and 66 women - average age 37.0 +/- 12.6 years old. During 6 months follow-up, particular measurements have been conducted in different time points. Evaluation of body mass loss (%EWL, %EBL) and the homeostatic model assessment insulin resistance (HOMA IR) was conducted. In the same time ghrelin, insulin, glucose, triglycerides, total cholesterol, HDL- and LDL-cholesterol concentration was determined after 7 days, 1, 3 and 6 months after the surgery. RESULTS: Significant decrease in BMI and HOMA IR was observed as well as in insulin and glucose concentration. Increase in ghrelin concentration in comparison to preoperative values was also stated. CONCLUSIONS: LAGB leads to significant body mass loss, improvement in patients' general health state and to normalization of metabolic parameters. Improvement or total resolution of type 2 diabetes (T2DM), hypertension and sleep apnea was also noticed. PMID- 22440939 TI - beta-adrenoreceptor activation in brain, lung and adipose tissue, measured by microdialysis in pig. AB - PURPOSE: The aim of this study is to investigate the effect of local activation of beta-adrenoreceptor by Isoprenaline on metabolism in brain, fat and lung measured by microdialysis. METHODS: We used 8 healthy pigs under general anaesthesia and placed microdialysis catheters in brain, fat, lung and artery. We performed a direct measurement of glucose, lactate, pyruvate and glycerol. The stimulation was performed by one-hour infusion of Isoprenaline, a beta adrenoreceptor agonist. RESULTS: The infusion of isoprenaline did not affect the glucose in any tissue. The levels of lactate (p=0.008) and pyruvate (p=0.011) decreased significantly in lung after isoprenaline infusion. There was a significant increase in L/P ratio in fat tissue (p=0.001) while no significant changes could be found in brain (p=0.086) and lung (p=0.679). The most pronounced and significant change was observed in glycerol in fat (p<0.001) that increased by 95%. CONCLUSION: The prominent increase in glycerol in fat proved to be a good measure of beta-adrenoreceptor activation and a measure of lipolysis. This can be used to online monitor beta-adrenoreceptor activation by glycerol measurement in patients. PMID- 22440940 TI - The rs1801133 polymorphism of methylenetetrahydrofolate reductase gene- the association with 5-year survival in patients with ST-elevation myocardial infarction. AB - PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in endothelial nitric oxide synthase (eNOS) coupling and homocysteine metabolism. The rs1801133 polymorphism of the MTHFR gene affects risk of coronary artery disease. We assessed its influence on 5-year survival of patients with ST elevation acute myocardial infarction (STEMI). MATERIAL/METHODS: The study group comprised consecutive patients with STEMI. Genotyping was performed with a TaqMan SNP Genotyping Assay using the ABI 7500 Real Time PCR System (Applied Biosystems). The analyzed end-point was all-cause 5-year survival. RESULTS: The study group comprised 637 patients (mean age 62.3 +/- 11.9 years; 25.1% females, n=160; 5-year mortality 16.3%, n=104). The percentages of TT, CT and CC genotypes were: 10.8 (n=69), 39.7 (n=253) and 49.45 (n=315), respectively. No significant differences in clinical characteristics were identified between the genotypes (p>0.05 for all parameters). Eleven (15.9%) TT homozygotes, 40 (15.8%) heterozygotes and 53 (16.8%) CC homozygotes died during follow up (p=0.99 log rank test). TT homozygotes presented only weak and insignificant tendency towards higher mortality rates in subgroups of patients <=75 years old (15.6 vs. 11.54%, p=0.35) or with intermediate risk according to the GRACE risk score (13.3% vs. 8.76%, p=0.42). CONCLUSIONS: The rs1801133 polymorphism did not show significant association with 5-year survival. PMID- 22440941 TI - Significance of the cell adhesion molecules and sialic acid in neurodegeneration. AB - The central nervous system (CNS) is a complex and precise mechanism that controls the most highest functions of the body. All of them depend on the cellular and molecular interactions called by neurobiologists "cellular plasticity". The CNS is a flexible structure but its regeneration after damage is strongly limited. Better understanding of cellular and molecular basis of brain repair can open new way in the development of therapeutic tools for neurodegeneration. Among many molecules that participate in the formation of neuronal networks, neural cell adhesion molecule (NCAM) and its sialylated derivative seem to play crucial role in the life of brain. In particular, polysialylated cell adhesion molecule (PSA NCAM) is proposed to participate in the neuroprotective response in neurodegeneration by reducing of AMPA/NMDA receptors sensitivity to glutamate and facilitating disconnection of cell-cell interactions. These mechanisms protect from excitotoxic damage and promote dendritic/spine re-growth. This review briefly focuses on the expression and role of PSA-NCAM in neurodegenerative diseases and its potential application in therapy. PMID- 22440942 TI - Immunohistochemical assessment of apoptosis-associated proteins: p53, Bcl-xL, Bax and Bak in gastric cancer cells in correlation with clinical and pathomorphological factors. AB - PURPOSE: The p53 protein as well as Bcl-2 family proteins such as Bax, Bak and Bcl-xL regulate apoptosis. The study objective was to analyze the expression of p53, Bak, Bcl-xL and Bax in gastric cancer and in healthy gastric mucosa. MATERIAL AND METHODS: The study group consisted of 66 patients with gastric cancer, treated surgically in II Department of General and Gastroenterological Surgery, Medical University of Bialystok. The expression of the studied proteins was assessed using the immunohistochemical method. RESULTS: Significant differences were found in the expressions of the studied proteins as compared to healthy gastric mucosa. The expressions of p53 and Bax were significantly higher (70% vs 13% and 50% vs 13%), whereas those of Bak and Bcl-xL significantly lower (18% vs 83% and 74% vs 97%) in cancer cells than in normal mucosa (p<0.001). Significant differences were also noted in the expressions of Bax and Bcl-xL in relation to histological type. In the intestinal type (Lauren I), the expressions of Bax and Bcl-xL were higher as compared to the diffuse type (Lauren II) (93% vs 43% and 91% vs 43%). Simultaneously, correlations were noted between changes in the expression of Bax vs Bcl-xL and Bak. High expression of Bax showed a positive correlation with reduced Bak and Bcl-xL (p<0.05). Moreover, positive expression of p53 caused poorer distant survival of patients (p<0.05). CONCLUSION: Our study concluded that disturbances in the expression of p53, Bax, Bcl-xL and Bak proteins are associated with their involvement in the process of carcinogenesis in the stomach. It is suggesting that they might appeared in the early phase of carcinogenesis. PMID- 22440944 TI - Secretory miRNAs as novel cancer biomarkers. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that degrade or block target mRNAs at the post-transcriptional level. Many studies have shown that miRNA dysregulation is involved in cancer initiation, invasion, metastasis, and so forth. Notably, recent studies have revealed secretory miRNA levels in blood and other body fluids to correlate significantly with cancer progression, therapeutic response and patient survival. Thus, secretory miRNAs have demonstrated great potential as powerful and non-invasive cancer biomarkers. Herein, we summarize the current progress of secretory miRNAs in different cancer types and analyze the potential mechanisms of miRNA secretion. Then, we discuss the different approaches to miRNA detection in body fluids and the advantages of secretory miRNAs as biomarkers for early cancer diagnosis and the prediction of therapeutic efficacy. Finally, we list the current progress of secretory miRNAs as cancer biomarkers in clinical trials. Although several issues remain to be clarified, such as the mechanisms of miRNA secretion, it is only a matter of time before miRNAs are widely utilized as cancer biomarkers. PMID- 22440943 TI - E-cadherin's dark side: possible role in tumor progression. AB - In the context of cancer, E-cadherin has traditionally been categorized as a tumor suppressor, given its essential role in the formation of proper intercellular junctions, and its downregulation in the process of epithelial mesenchymal transition (EMT) in epithelial tumor progression. Germline or somatic mutations in the E-cadherin gene (CDH1) or downregulation by epigenetic mechanisms have been described in a small subset of epithelial cancers. However, recent evidence also points toward a promoting role of E-cadherin in several aspects of tumor progression. This includes preserved (or increased) E-cadherin expression in microemboli of inflammatory breast carcinoma, a possible "mesenchymal to epithelial transition" (MET) in ovarian carcinoma, collective cell invasion in some epithelial cancers, a recent association of E-cadherin expression with a more aggressive brain tumor subset, as well as the intriguing possibility of E-cadherin involvement in specific signaling networks in the cytoplasm and/or nucleus. In this review we address a lesser-known, positive role for E-cadherin in cancer. PMID- 22440945 TI - Are we ready to recommend aspirin for cancer prevention? PMID- 22440946 TI - Short-term effects of daily aspirin on cancer incidence, mortality, and non vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. AB - BACKGROUND: Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. METHODS: We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. RESULTS: Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0.85, 95% CI 0.76-0.96, p=0.008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0.63, 95% CI 0.49-0.82, p=0.0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0.88, 95% CI 0.78-0.96, p=0.003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0.76, 95% CI 0.66-0.88, p=0.0003) in women (132 vs 176; OR 0.75, 95% CI 0.59-0.94, p=0.01) and in men (192 vs 245; OR 0.77, 95% CI 0.63-0.93, p=0.008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3.13 [95% CI 1.44-4.82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0.32, 95% CI 0.12-0.83, p=0.009). INTERPRETATION: Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. FUNDING: None. PMID- 22440947 TI - Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. AB - BACKGROUND: Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. METHODS: Our analysis included all five large randomised trials of daily aspirin (>=75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. FINDINGS: Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6.5 years (SD 2.0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0.64, 95% CI 0.48-0.84, p=0.001; adenocarcinoma, HR 0.54, 95% CI 0.38-0.77, p=0.0007; other solid cancers, HR 0.82, 95% CI 0.53 1.28, p=0.39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0.52, 95% CI 0.35-0.75, p=0.0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0.69, 95% CI 0.50-0.95, p=0.02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0.45, 95% CI 0.28-0.72, p=0.0009), particularly in patients with colorectal cancer (HR 0.26, 95% CI 0.11-0.57, p=0.0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0.31, 95% CI 0.15-0.62, p=0.0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0.50, 95% CI 0.34-0.74, p=0.0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0.65, 95% CI 0.53-0.82, p=0.0002), but not the risk of other fatal cancers (HR 1.06, 95% CI 0.84-1.32, p=0.64; difference, p=0.003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. INTERPRETATION: That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. FUNDING: None. PMID- 22440948 TI - Duration of targeted therapy for metastatic renal cell carcinoma: a review of current practices. AB - The development of targeted agents has substantially improved clinical outcomes for patients with metastatic renal cell carcinoma. The optimum duration of treatment with these agents is not yet clear, particularly as targeted agents may often result in disease stabilization as well as in tumour response. Some clinicians may choose to switch to an alternative agent in the absence of tumour response or in the event of the occurrence of side effects, which can result in patients moving rapidly through the available treatment options. This review evaluates the duration of treatment observed with targeted agents that are approved for first-line treatment of metastatic renal cell carcinoma and considers the reasons for switching or discontinuing therapy. In addition, practical strategies for achieving optimal treatment duration, through adverse event management, are discussed. PMID- 22440949 TI - An emerging topic on obesity, arterial endothelial function and thrombolysis. PMID- 22440950 TI - Dabigatran and factor Xa inhibitors for stroke prevention in patients with nonvalvular atrial fibrillation. AB - Stroke is a major health problem worldwide, and is often fatal or associated with poor long-term outcomes. Atrial fibrillation (AF) is responsible for up to 20% of all strokes; and the risk of stroke in patients with AF increases with age. Although warfarin is well established for the prevention of stroke in patients with AF, it has some limitations, particularly a narrow therapeutic window, variable/unpredictable pharmacokinetic/pharmacodynamic properties, the restriction of vitamin K intake, and the need for regular coagulation monitoring. Therefore, warfarin is underused for stroke prevention in patients with AF. Several anticoagulants that inhibit thrombin or factor Xa have been developed. Dabigatran is a direct thrombin (factor IIa) inhibitor that overcomes many of the limitations associated with warfarin. The recent Randomized Evaluation of Long Term Anticoagulant Therapy study showed the noninferiority of 110 mg and 150 mg dabigatran twice daily, and the superiority of 150 mg dabigatran twice daily versus adjusted-dose warfarin in the prevention of stroke or systemic embolism in patients with nonvalvular AF. In addition, the rate of intracranial hemorrhage was much lower with both doses of dabigatran than with warfarin. Dabigatran was recently approved in Japan for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular AF. Therefore, in this review, we discuss the properties of dabigatran and its clinical efficacy, safety, and positioning in the prevention of stroke. We also discuss precautions for the use of dabigatran and future perspectives with a view to reducing the risk of stroke with new oral anticoagulants, including factor Xa inhibitors in AF patients. PMID- 22440951 TI - Empowering citizens with access control mechanisms to their personal health resources. AB - BACKGROUND: Advancements in information and communication technologies have allowed the development of new approaches to the management and use of healthcare resources. Nowadays it is possible to address complex issues such as meaningful access to distributed data or communication and understanding among heterogeneous systems. As a consequence, the discussion focuses on the administration of the whole set of resources providing knowledge about a single subject of care (SoC). New trends make the SoC administrator and responsible for all these elements (related to his/her demographic data, health, well-being, social conditions, etc.) and s/he is granted the ability of controlling access to them by third parties. The subject of care exchanges his/her passive role without any decision capacity for an active one allowing to control who accesses what. PURPOSE: We study the necessary access control infrastructure to support this approach and develop mechanisms based on semantic tools to assist the subject of care with the specification of access control policies. This infrastructure is a building block of a wider scenario, the Person-Oriented Virtual Organization (POVO), aiming at integrating all the resources related to each citizen's health-related data. The POVO covers the wide range and heterogeneity of available healthcare resources (e.g., information sources, monitoring devices, or software simulation tools) and grants each SoC the access control to them. METHODS: Several methodological issues are crucial for the design of the targeted infrastructure. The distributed system concept and focus are reviewed from the service oriented architecture (SOA) perspective. The main frameworks for the formalization of distributed system architectures (Reference Model-Open Distributed Processing, RM-ODP; and Model Driven Architecture, MDA) are introduced, as well as how the use of the Unified Modelling Language (UML) is standardized. The specification of access control policies and decision making mechanisms are essential keys for this approach and they are accomplished by using semantic technologies (i.e., ontologies, rule languages, and inference engines). RESULTS: The results are mainly focused on the security and access control of the proposed scenario. An ontology has been designed and developed for the POVO covering the terminology of the scenario and easing the automation of administration tasks. Over that ontology, an access control mechanism based on rule languages allows specifying access control policies, and an inference engine performs the decision making process automatically. The usability of solutions to ease administration tasks to the SoC is improved by the Me-As-An-Admin (M3A) application. This guides the SoC through the specification of personal access control policies to his/her distributed resources by using semantic technologies (e.g., metamodeling, model to-text transformations, etc.). All results are developed as services and included in an architecture in accordance with standards and principles of openness and interoperability. CONCLUSIONS: Current technology can bring health, social and well-being care actually centered on citizens, and granting each person the management of his/her health information. However, the application of technology without adopting methodologies or normalized guidelines will reduce the interoperability of solutions developed, failing in the development of advanced services and improved scenarios for health delivery. Standards and reference architectures can be cornerstones for future-proof and powerful developments. Finally, not only technology must follow citizen-centric approaches, but also the gaps needing legislative efforts that support these new paradigms of healthcare delivery must be identified and addressed. PMID- 22440952 TI - Examine growth inhibition pattern and lactic acid production in Streptococcus mutans using different concentrations of xylitol produced from Candida tropicalis by fermentation. AB - Twenty clinical isolates of Streptococcus sp. were isolated from six clinical samples of dental caries on MSFA. Amongst these isolates, five clinical isolates were identified as S treptococcus mutans on the basis of morphological, biochemical and 16S rDNA sequencing. The isolated strains of S. mutans were exposed to fermented and purified xylitol (0.25-15.0%) and tested for its anti microbial effects against control medium (Brain Heart Infusion without xylitol) after 12 h. The plate assay was developed using bromocresol green as an indicator dye in order to study the relative growth inhibition pattern of clinical sample at different concentrations of an anti-microbial compound in a single petriplate. The morphology of S. mutans cells in brain heart infusion (BHI) medium containing xylitol resulted in a diffused cell wall as observed using gram staining technique. The minimum inhibitory concentration (MIC) is 0.25% for S. mutans obtained from different clinical samples. The MIC(50) and MIC(90) is 5.0% and 10.0% xylitol respectively of the selected S. mutans being designated as clinical isolate B (6). The zone of inhibition was 72 mm and lactic acid production was 0.010 g/l at 10% xylitol concentration in Brain Heart Infusion Broth. PMID- 22440953 TI - gamma-Sitosterol from Acacia nilotica L. induces G2/M cell cycle arrest and apoptosis through c-Myc suppression in MCF-7 and A549 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acacia nilotica is widely distributed in Asia. In India, it occupies an important place in the indigenous system of medicine against anti-inflammatory, antioxidant, cancers, and/or tumors. AIM OF THE STUDY: The purpose of this study is to investigate the inhibitory effect of Acacia nilotica leaves extract and gamma-Sitosterol on cell proliferation, the apoptotic effect and cell cycle arrest in breast and lung cancer cells. MATERIALS AND METHODS: GC-MS and HPLC were used to determine the chemical constituents of this extract and gamma-Sitosterol respectively. Human MCF-7 and A549 cell lines were treated with Acacia nilotica extract and gamma-Sitosterol. Cell viability was determined by MTT assay. Cell proliferation was determined by BrdU incorporation assay. Apoptosis was detected by cell morphologic observation through AO/EtBr staining, cell cycle analysis, and immunoblot analysis on the expression of protein associated with cell cycle arrest. RESULTS: Experimental results of bioactive compound analysis indicate that gamma-Sitosterol, bioactive ingredients of Acacia nilotica extract. The IC(50) value of extract on MCF-7 and A549 cancer cells was 493.3+/-15.2 and 696.6+/-11.5 MUg/ml, respectively. Acacia nilotica extract and gamma-Sitosterol were inhibited the cell proliferation by 54.34+/-1.8 and 42.18+/-3.9% for MCF-7 and 58.26+/-1.5 and 44.36+/-3.05% for A549 cells. The percentage of apoptotic cells observed in the MCF-7 and A549 cell lines were increased to 42.46 and 36.8% of extract; 46.68 and 43.24% for gamma-Sitosterol respectively. Flow cytometric analysis results demonstrate that cells were arrested at the G2/M phase and decrease the c-Myc expression. CONCLUSIONS: This study demonstrates in vitro results, which support the ethnomedical use of gamma Sitosterol against cancer. Experimental results of this study suggest that gamma Sitosterol exerts potential anticancer activity through the growth inhibition, cell cycle arrest and the apoptosis on cancer cells. PMID- 22440954 TI - Facial ulceration in a patient with Crohn's disease. PMID- 22440955 TI - Epigastric pain and an unusual perigastric mass in a 28-year-old man. PMID- 22440956 TI - Interferon-free oral therapy for hepatitis C: "faraway, so close!". PMID- 22440957 TI - A pain in the neck and colon polyps. PMID- 22440958 TI - Gastroenterologists and the US opioid epidemic. PMID- 22440959 TI - The importance of entering cells, non-trivial solutions for serious viruses. PMID- 22440960 TI - Virus entry: old viruses, new receptors. AB - The long-sought entry receptors for rubella, sindbis and respiratory syncytial viruses (RV, SV and RSV), together with the missing measles virus (MV) receptor for infection of epithelial cells, were identified in 2011. These have been major developments in the field of virus entry. In addition, 2011 was rich in new information about the interactions of MV, RSV and phleboviruses with DC-SIGN during infection of dendritic cells, a crucial step allowing the virus to breach the epithelial barrier and gain access to the lymph nodes. This faciliates dissemination to susceptible tissues where it can develop a vigorous and sustained replication, to eventually target specific organs from which it can propagate into the environment and efficiently infect new hosts, closing the merry-go-round of the virus cycle. PMID- 22440961 TI - Hepatitis C virus host cell entry. AB - The hepatitis C virus (HCV) is a major medical problem with at least 130 million infected individuals worldwide. Over the last decade multiple host factors required for HCV cell entry have been identified, but a detailed understanding of their mechanistic interplay remains elusive. Nonetheless, recent advances in defining species-specific barriers of HCV transmission have allowed the identification of a minimal set of entry factors that are required for HCV infection of rodent cells and has culminated in an animal model that recapitulates HCV entry in vivo. A detailed understanding of the viral uptake pathway is imperative to define new drug targets allowing for more effective intervention against this devastating disease. PMID- 22440962 TI - Poxvirus host cell entry. AB - Poxviruses are characterized by their large size, complex composition, and cytoplasmic life cycle. They produce two types of infectious particles: mature virions (MVs) and extracellular virions (EVs). Both MVs and EVs of vaccinia virus, the model poxvirus, take advantage of host cell endocytosis for internalization: they activate macropinocytosis-the most suitable form of endocytosis for large particles. Although largely dependent on the same cellular machinery, MV and EV entry differs with regard to the mechanisms used to trigger macropinocytosis and to undergo fusion. While EVs have to shed an additional membrane to expose the fusion complex, MV fusion requires the inactivation of fusion inhibitory proteins absent in EVs. This review highlights recent advances in the understanding of poxvirus MV and EV cell entry. PMID- 22440963 TI - Viral and cellular contributions to herpes simplex virus entry into the cell. AB - Herpes simplex virus (HSV) entry into the cell involves the fusion of the virion envelope with a cellular membrane and delivery of capsid and tegument proteins to the cytoplasm. Our understanding of this phenomenon has greatly increased in recent years. On the virus side, the multipartite nature of the entry-fusion machinery (made of the glycoproteins gD, the heterodimer gH/gL and gB) entails a mechanism of gD activation promoted by the gD encounter with one of its receptor; and cross-talk among the entry-fusion glycoproteins, which culminates in gB activation and fusion execution. On the cell side, machineries and signalling activities are put in place. The number of known receptors and sentinels is increasing. The cell routes the virus through alternative entry pathways by means of routing factors, exemplified by alphaVbeta3-integrin and paired immunoglobulin like type 2 receptor alpha. Of the signalling events, a key one is the immediate host response to incoming virions. Unexpectedly, this is in part triggered by the same virion components and some cellular factors that also promote virus entry. Hence, a link is emerging between two phenomena so far considered as distinct. PMID- 22440964 TI - Human cytomegalovirus entry into cells. PMID- 22440965 TI - Targeted entry of enveloped viruses: measles and herpes simplex virus I. AB - We compare the receptor-based mechanisms that a small RNA virus and a larger DNA virus have evolved to drive the fusion of viral and cellular membranes. Both systems rely on tight control over triggering the concerted refolding of a trimeric fusion protein. While measles virus entry depends on a receptor-binding protein and a fusion protein only, the herpes simplex virus (HSV) is more complex and requires four viral proteins. Nevertheless, in both viruses a receptor binding protein is required for triggering the membrane fusion process. Moreover, specificity domains can be appended to these receptor-binding proteins to target virus entry to cells expressing a designated receptor. We discuss how principles established with measles and HSV can be applied to targeting other enveloped viruses, and alternatively how retargeted envelopes can be fitted on foreign capsids. PMID- 22440966 TI - Is there a future for antiviral fusion inhibitors? AB - Entry of human immunodeficiency virus type 1 (HIV-1) into cells is mediated by attachment of the envelope glycoproteins, gp120 and gp41, to the CD4 receptor and a chemokine receptor (CCR5 or CXCR4) and subsequent fusion of viral and cellular membranes. Several steps of the entry process can be targeted by drugs. Receptor antagonists prevent virus attachment and fusion inhibitors block conformational changes that are required for membrane fusion. The T20 peptide (Enfuvirtide, Fuzeon), which is homologous to part of the gp41-encoded fusion machinery, is the only clinically approved fusion inhibitor, but over the last decade new generations of T20-like peptides have been developed with improved potency and stability, as well as fusion inhibitors that target alternative gp41 domains. Here, we will review the field of HIV-1 fusion inhibitors. PMID- 22440967 TI - Viruses are everywhere-what do we do? PMID- 22440968 TI - Metagenomics and future perspectives in virus discovery. AB - Monitoring the emergence and re-emergence of viral diseases with the goal of containing the spread of viral agents requires both adequate preparedness and quick response. Identifying the causative agent of a new epidemic is one of the most important steps for effective response to disease outbreaks. Traditionally, virus discovery required propagation of the virus in cell culture, a proven technique responsible for the identification of the vast majority of viruses known to date. However, many viruses cannot be easily propagated in cell culture, thus limiting our knowledge of viruses. Viral metagenomic analyses of environmental samples suggest that the field of virology has explored less than 1% of the extant viral diversity. In the last decade, the culture-independent and sequence-independent metagenomic approach has permitted the discovery of many viruses in a wide range of samples. Phylogenetically, some of these viruses are distantly related to previously discovered viruses. In addition, 60-99% of the sequences generated in different viral metagenomic studies are not homologous to known viruses. In this review, we discuss the advances in the area of viral metagenomics during the last decade and their relevance to virus discovery, clinical microbiology and public health. We discuss the potential of metagenomics for characterization of the normal viral population in a healthy community and identification of viruses that could pose a threat to humans through zoonosis. In addition, we propose a new model of the Koch's postulates named the 'Metagenomic Koch's Postulates'. Unlike the original Koch's postulates and the Molecular Koch's postulates as formulated by Falkow, the metagenomic Koch's postulates focus on the identification of metagenomic traits in disease cases. The metagenomic traits that can be traced after healthy individuals have been exposed to the source of the suspected pathogen. PMID- 22440969 TI - Challenges in environmental detection of human viral pathogens. AB - There is substantial potential for human exposure to viruses in environmental matrixes. Identification of virally contaminated environmental reservoirs requires assays with sufficient sensitivity to detect low copy numbers of viral targets. However, low detection sensitivity frequently requires sample concentration during which inhibitors to downstream assays co-isolate with desired target. Conventional detection assays (e.g., cell culture, polymerase chain reaction) require a priori selection of appropriate cell lines or primers and probes based on the viruses anticipated to be present in the sample. This can underestimate exposure risks by excluding unidentified or unknown virus. Emerging methods including nonspecific adsorption/elution, filtration, and total nucleic acid sequencing, that are capable of concentrating, purifying, and detecting total virus and/or total virus nucleic acid will aid in estimates of exposure risk, source tracking, intervention efficacy, and evaluation of virus fate and transport. Development and implementation of novel virus detection techniques must integrate quality assurance guidelines to validate results and provide opportunities for interstudy comparison. PMID- 22440970 TI - Virus disinfection mechanisms: the role of virus composition, structure, and function. AB - Drinking waters are treated for enteric virus via a number of disinfection techniques including chemical oxidants, irradiation, and heat, however the inactivation mechanisms during disinfection remain elusive. Owing to the fact that a number of significant waterborne virus strains are not readily culturable in vitro at this time (e.g. norovirus, hepatitis A), the susceptibility of these viruses to disinfection is largely unknown. An in-depth understanding of the mechanisms involved in virus inactivation would aid in predicting the susceptibility of non-culturable virus strains to disinfection and would foster the development of improved disinfection methods. Recent technological advances in virology research have provided a wealth of information on enteric virus compositions, structures, and biological functions. This knowledge will allow for physical/chemical descriptions of virus inactivation and thus further our understanding of virus disinfection to the most basic mechanistic level. PMID- 22440971 TI - Environmental factors affecting the transmission of respiratory viruses. AB - Many viruses are capable of infecting the human respiratory tract to cause disease. These viruses display various transmission patterns among humans; however, they all share the ability to transmit from person to person, and their human transmissibility is influenced by the environment in which pathogen and host meet. This review aims to summarize recent and significant observations regarding the impact of environmental factors such as weather and climate, humidity, temperature, and airflow on the transmission of human respiratory viruses. Where possible, knowledge gaps that require further scientific study will be identified. PMID- 22440972 TI - Environmental transmission of norovirus gastroenteritis. AB - The advent of molecular techniques and their increasingly widespread use in public health laboratories and research studies has transformed the understanding of the burden of norovirus. Norovirus is the most common cause of community acquired diarrheal disease across all ages, the most common cause of outbreaks of gastroenteritis, and the most common cause of foodborne disease in the United States. They are a diverse group of single-stranded RNA viruses that are highly infectious and stable in the environment; both symptomatic and asymptomatic infections are common. Through shedding in feces and vomit, norovirus can be transmitted directly through an array of routes: person-to-person, food or the environment. The relative importance of environmental transmission of virus is yet to be fully quantified but is likely to be substantial and is an important feature that complicates control. PMID- 22440973 TI - Transmission of viruses through shellfish: when specific ligands come into play. AB - Shellfish are known as vectors for human pathogens and despite regulation based on enteric bacteria they are still implicated in viral outbreaks. Among shellfish, oysters are the most common vector of contamination, and the pathogens most frequently involved in these outbreaks are noroviruses, responsible for acute gastroenteritis in humans. Analysis of shellfish-related outbreak data worldwide show an unexpected high proportion of NoV GI strains. Recent studies performed in vitro, in vivo and in the environment indicate that oysters are not just passive filters, but can selectively accumulate norovirus strains based on viral carbohydrate ligands shared with humans. These observations contribute to explain the GI bias observed in shellfish-related outbreaks compared to other outbreaks. PMID- 22440974 TI - DAI-10 is as good as DAI-30 in schizophrenia. AB - Drug attitude inventory (DAI-30) is considered to be the best predictor of poor adherence in first-episode schizophrenia. We compared the short version (DAI-10) with DAI-30 in long-term schizophrenia, documented if DAI was associated with poor insight, PANSS and GAF and constructed DAI-10 percentiles. DAI-30 and DAI-10 were homogenous (r = 0.82 and 0.72, respectively) with good test-retest reliability (0.79). The correlation between the DAI versions was high (0.94). Percentile scores of DAI-10 were computed. DAI is an easy-to-use self-report instrument seemingly assessing a unique clinical dimension relevant to non adherence. DAI-10 might be preferred for its simplicity and good psychometric properties. PMID- 22440975 TI - Dexamphetamine reduces auditory P3 delta power and phase-locking while increasing gamma power. AB - Auditory P3 amplitude reduction is one of the most robust and replicated findings in schizophrenia. Recent evidence suggests that these reductions are due to reductions in both power and phase-locking at delta and theta frequencies. We have previously shown that the auditory, but not visual, P3 is reduced in healthy participants given the catecholamine releasing agent dexamphetamine. Our aim was to determine whether the auditory P3 amplitude reduction induced by dexamphetamine has similar power and phase locking characteristics to that seen in schizophrenia. Forty-four healthy participants were given 0.45 mg/kg dexamphetamine and placebo, in a double-blinded, placebo-controlled, cross-over design. The task was a three-stimulus auditory odd-ball task, target stimuli were the major stimuli of interest. Individual target trials underwent wavelet analysis to give power and phase-locking of delta (3 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz) and gamma (30-50 Hz) frequencies for a 50 ms time window centred around the peak of the target P3. Delta power around the P3 peak was significantly reduced when participants were given dexamphetamine. Delta phase-locking was also reduced but only when analysis was targeted at the location of the peak P3 amplitude. In contrast, theta power and phase-locking were not affected by dexamphetamine. These findings suggest that increased catecholamine activity may be responsible for the power and phase-locking reductions of the auditory P3 delta component in patients with schizophrenia. Interestingly, dexamphetamine significantly increased gamma power around the P3 peak. We attempt to link this finding with the gamma alterations that have been found in patients with schizophrenia. PMID- 22440976 TI - Anterior cingulate activation relates to local cortical thickness. AB - Few studies have examined the relationship between local anatomic thickness of the cortex and the activation signals arising from it. Using structural and functional MRI, we examined whether a relationship exists between cortical thickness and brain activation. Twenty-eight participants were asked to perform the Go/NoGo response inhibition task known to activate the anterior cingulate and the prefrontal cortex. Structural data of the same regions were simultaneously collected. We hypothesized that cortical thickness in these brain regions would positively correlate with brain activation. Data from the structural MRI were aligned with those of functional MRI activation. There was a positive linear correlation between cortical thickness and activation during response inhibition in the right anterior cingulate cortex (Brodmann's Area 24). No significant thickness-activation correlations were found in the prefrontal cortex. Correlations between cortical thickness and activation may occur only in certain brain regions. PMID- 22440977 TI - Automatic processing of rare versus novel auditory stimuli reveal different mechanisms of auditory change detection. AB - Automatic detection of rare stimuli or changes in an auditory stimulation can distract ongoing task processing by attracting attention away from task relevant information. Typically, the effectiveness of auditory change detection is tested by rare and unpredictable deviations (compared with an otherwise regular auditory presentation) or by rare environmental sounds. The present study demonstrates that both types of stimuli are capable of triggering automatic orientation of attention and that rare environmental sounds are more effective than deviations in distraction of attention. This finding suggests different mechanisms underlying the detection of auditory change. Moreover, novelty as constituted by unique environmental sounds did not add to the effectiveness of automatic change detection, involuntary control of attention, and distraction. PMID- 22440978 TI - Biological response to porcine xenograft implants: an experimental study in rabbits. AB - PURPOSE: The aim of this study was to evaluate the effect of a new porcine biomaterial and collagen paste in 20 New Zealand rabbits. MATERIALS AND METHODS: Forty implants using a porcine xenograft made up of 80% corticocancellous collagenated bone particles of <=300 MUm in size were placed in the proximal metaphyseal area of both tibiae. Four periods of time were formed: 1h, 5, 8, and 15 months. After implantation, an anteroposterior and lateral radiological study was carried out. Samples were sectioned at 5 MUm and stained using hematoxylin eosin, Masson's trichromic, and Gordon-Switt reticulin stains. RESULTS: These results confirmed the biocompatibility of this porcine biomaterial-collagen paste; only a few, occasional macrophages and scattered lymphocytes were observed. No fibrosis was observed between the implants and the bone. Moreover, the material was osteoconductive acting as a "scaffold" for bone cells, and there was a progressive increase in bone growth in and around the implants. CONCLUSION: This new porcine biomaterial-collagen paste seemed to be biocompatible, bioresorbable, and osteoconductive. PMID- 22440979 TI - On-site drugs of abuse urinary screening tests for the management of opiate addicted patients: a survey among French general practitioners. AB - In France, opiate-addicted patients are mainly managed by general practitioners (GPs). Because on-site abuse drugs urinary screening tests (ODUTs) are now on the market, we investigated French GPs' knowledge and practices concerning drug tests with a focus on ODUTs. We conducted a descriptive cross-sectional study in ambulatory practice. Postal questionnaires were sent to a random sample of GPs in the Midi-Pyrenees area of France in December 2009. Of the 482 GPs in the sample, 116 (24.1%) regularly treated opiate- addicted patients. Only 31 of them (26.7%) used drug tests and 4 of them (3.4%) performed ODUTs in their consultation rooms. Most of the GPs did not perform ODUTs because they were unaware of whether such tests were reliable or available. Many French GPs treating opiate-addicted patients regularly did not perform ODUTs and lacked knowledge of them. PMID- 22440980 TI - Contribution of alternatively activated macrophages to allergic lung inflammation: a tale of mice and men. AB - The concept that macrophages play an active role in inflammatory responses began its development in the late 1800s with the now iconic studies by Elie Metchnikoff using starfish larvae and Daphnia [reviewed in Kaufmann SHE: Nat Immunol 2008;9:705-712 and Cavaillon JM: J Leukoc Biol 2011;90:413-424]. Based on his observation of the phagocyte response to a foreign body (rose thorn) and yeast, he proposed that phagocytes acted in host defense and were active participants in the inflammatory process. Flash forward more than 100 years and we find that these basic tenets hold true. However, it is now appreciated that macrophages come in many different flavors and can adopt a variety of nuanced phenotypes depending on the tissue environment in which the macrophage is found. In this brief review, we discuss the role of one type of macrophage termed the alternatively activated macrophage (AAM), also known as the M2 type of macrophage, in regulating allergic lung inflammation and asthma. Recent studies using mouse models of allergic lung inflammation and samples from human asthma patients contribute to the emerging concept that AAMs are not just bystanders of the interleukin (IL)-4- and IL-13-rich environment found in allergic asthma but are also active players in orchestrating allergic lung disease. PMID- 22440981 TI - Effect of growth hormone replacement therapy on the quality of life in women with growth hormone deficiency who have a history of acromegaly versus other disorders. AB - OBJECTIVE: To compare the response in quality of life (QoL) to growth hormone (GH) replacement in women with GH deficiency (GHD) and a history of acromegaly with that in women with GHD of other causes. METHODS: Fifty-five women with GHD were studied: 17 with prior acromegaly and 38 with other causes of GHD. We compared two 6-month, randomized, placebo-controlled studies of GH therapy in women with hypopituitarism conducted with use of the same design-one in women with a history of acromegaly and one in women with no prior acromegaly. QoL was assessed with the following questionnaires: the QoL-Assessment of Growth Hormone Deficiency in Adults (AGHDA), the Symptom Questionnaire, and the 36-Item Short Form Health Survey (SF-36). RESULTS: The 2 groups had comparable mean pretreatment age, body mass index, and QoL scores and comparable mean GH dose at 6 months (0.61 +/- 0.30 versus 0.67 +/- 0.27 mg daily). After 6 months of GH replacement therapy, women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score, four SF-36 sub-scales (Role Limitations due to Physical Health, Energy or Fatigue, Emotional Well-Being, and Social Functioning), and the Somatic Symptoms subscale of the Symptom Questionnaire than did women with GHD of other causes. Poorer pretreatment QoL was associated with a greater improvement in QoL after administration of GH. CONCLUSION: In this study, GH replacement therapy improved QoL in women with GHD and a history of acromegaly but not in women with GHD due to other hypothalamic and pituitary disorders. Further studies are needed to determine the long-term risks versus benefits of GH replacement in patients who develop GHD after definitive treatment for acromegaly. PMID- 22440982 TI - Erlotinib-associated exacerbation of hypothyroidism with pericardial tamponade. AB - OBJECTIVE: To report a case of erlotinib-associated exacerbation of hypothyroidism complicated by pericardial tamponade. METHODS: We describe the patient's clinical presentation, biochemical workup, and clinical course. RESULTS: Non-small cell lung cancer was diagnosed in a 54-year-old woman. After cisplatin and radiation therapy, she was noted to have subclinical hypothyroidism that did not necessitate treatment. The tyrosine kinase inhibitor erlotinib, 150 mg once daily, was prescribed. Three months later, the patient was documented to have severe hypothyroidism. Levothyroxine was prescribed, but she continued to experience shortness of breath, fatigue, and chest and back pain, which resulted in an emergency department visit. Inpatient workup revealed cardiac tamponade with a large pericardial effusion and a right ventricular diastolic collapse. Pericardiocentesis was performed. CONCLUSIONS: This is the first case report linking erlotinib use and thyroid disease. PMID- 22440983 TI - Medical resource use and costs related to central precocious puberty: a retrospective cohort study. AB - OBJECTIVE: To evaluate the economic burden of central precocious puberty (CPP) by examining direct health care resource utilization and costs. METHODS: Administrative claims from the Medstat MarketScan Commercial Claims database were analyzed, and 2 cohorts of children <= 12 years of age were identified. The CPP cohort included patients newly diagnosed with precocious sexual development and puberty (International Classification of Diseases, Ninth Revision, Clinical Modification code 259.1x) between January 1, 2004, and June 30, 2006 (date of the initial diagnosis of CPP was designated as the "index date") who used gonadotropin-releasing hormone agonists during the 12 months after diagnosis. Each patient with CPP was matched with 4 control patients without CPP on the basis of age, sex, geographic region, and type of health insurance plan. Resource utilization and costs during the 12 months before and the 12 months after the index date were examined. RESULTS: A total of 172 patients with CPP and 688 control patients were identified after matching. Approximately 62% of patients were 7 to 9 years of age, and 87% were female. The patients with CPP had higher annual health care costs than did the control patients during the 12-month pre index ($10,968 versus $783; P<.001) and the 12-month post-index ($21,071 versus $849; P<.001) periods, primarily attributable to outpatient and pharmacy costs. For the patients with CPP, annual health care costs increased by $10,103 after diagnosis. On average, annual CPP-related costs were $10,605. Monthly total health care costs for the patients with CPP increased sharply during the first month after diagnosis and remained high throughout the post-index period. CONCLUSION: In this study, health care resource use and costs among patients with CPP were substantial before and after the initial diagnosis of CPP. PMID- 22440984 TI - Hemorrhagic shock as the initial manifestation of pheochromocytoma: report of a sequential management strategy. AB - OBJECTIVE: To describe a patient presenting with hemorrhagic shock attributable to bleeding pheochromocytomas and the sequential management strategy used for treating this patient. METHODS: We summarize the clinical presentation, diagnostic work-up, surgical management, and pathologic features of our patient and review the pertinent literature. RESULTS: A 38-year-old man with multiple endocrine neoplasia type 2A and bilateral pheochromocytomas presented initially with nearly fatal retroperitoneal and intraperitoneal hemorrhage rather than the characteristic hypertensive paroxysms. After lifesaving operative intervention and a 5-month period of rehabilitation and convalescence, the patient underwent bilateral retroperitoneoscopic adrenalectomy as definitive treatment. Thus, the abdomen that had been operated on multiple times because of hemorrhage was left undisturbed, and the patient had a successful recovery. CONCLUSION: Near-fatal intraperitoneal hemorrhage is a very rare initial manifestation of pheochromocytoma. Our current patient with bilateral pheochromocytomas presented in this dramatic manner. This case shows that a sequential management strategy of damage-control surgical treatment followed by future resection of the tumors after appropriate a-adrenergic blockade is a safe and effective therapeutic option. PMID- 22440985 TI - Association of hyperglycemia with prolonged hospital stay but no effect on engraftment after autologous hematopoietic stem cell transplantation. AB - OBJECTIVE: To determine the effect of hyperglycemia, which is associated with poor outcome of various diseases, on the outcome of hematopoietic stem cell transplantation (HSCT). METHODS: We examined the influence of blood glucose concentration (BGC) on the outcome of autologous HSCT. Patients had at least one BGC determination every morning during their hospitalization. The relationships of BGC with time to engraftment and length of hospital stay (LOHS) after transplantation were analyzed. RESULTS: The correlation of LOHS after transplantation was found only with posttransplant averaged BGC (P=.0004) in patients without diabetes (N = 240) but not with pretransplant averaged BGC or BGC on the morning of transplantation. The correlation remained significant after adjustment for sex, age, and body mass index (P=.0002) and for use of glucocorticoids and total parenteral nutrition (P=.04). No correlation was observed, however, between BGC and timing of engraftment. We further analyzed the entire data set of subjects (N = 335) on the basis of posttransplant morning BGC and divided these patients into 2 groups: those with BGC <150 mg/dL and those with BGC >=150 mg/dL. No difference in engraftment time was noted between these 2 groups, but a correlation was observed with LOHS after transplantation (14 +/- 4 days versus 17 +/- 6 days, respectively; P<.0001). CONCLUSION: We observed that posttransplant averaged BGC significantly correlated with LOHS after transplantation. BGC, however, had no effect on the timing of engraftment. Thus, our results suggest that better glycemic control could potentially shorten hospital stay after HSCT. PMID- 22440986 TI - Role of ultrasonography in the differential diagnosis of thyrotoxicosis: a noninvasive, cost-effective, and widely available but underutilized diagnostic tool. AB - OBJECTIVE: To explore the use of ultrasonography as a diagnostic alternative to the traditional "gold standard" imaging study of nuclear scintigraphy in the evaluation of thyrotoxicosis. METHODS: We review the relevant literature and share our own experience to highlight the promising role of ultrasonography in thyrotoxicosis. In addition, we present a diagnostic algorithm suggesting liberal use of ultrasonography in the evaluation of thyrotoxicosis. RESULTS: Ultrasonography has proved effective not only in the differentiation of Graves disease from other types and causes of thyrotoxicosis but also in the detection of subtle thyroid nodules. The latter role is emphasized in light of the recent observation of an increased risk of occurrence of papillary thyroid carcinoma in patients with Graves disease. CONCLUSION: Ultrasonography is a cost-effective, noninvasive, portable, and safe imaging modality in the evaluation of thyrotoxicosis, both for physiologic assessment and for detection of nonpalpable thyroid cancers that may elude identification on physical examination and nuclear imaging studies. Although thyroid scintigraphy remains a standard radiologic study, thyroid ultrasonography can be a practical alternative in many cases and the primary imaging modality in some situations such as during pregnancy and lactation and for evaluation and management of amiodarone-induced thyrotoxicosis. PMID- 22440987 TI - Bronchogenic cyst masquerading as an adrenal tumor: a case of mistaken identity. AB - OBJECTIVE: To describe a patient with a bronchogenic cyst that was erroneously diagnosed as an adrenal tumor and the surgical management strategy to address the operative challenges. METHODS: We summarize the clinical presentation, diagnostic workup, surgical management, and pathologic features of the study patient and review the pertinent literature. RESULTS: In this report, we present the case of a 23-year-old woman who underwent retroperitoneoscopic exploration after imaging identified an enlarging left adrenal lesion. Preoperative biochemical testing confirmed that the mass was nonfunctional. No lesion was found after a thorough retroperitoneoscopic exploration under standard high insufflation pressure. Serendipitously, low-pressure inspection for hemostasis after failed exploration enabled discovery of an intradiaphragmatic mass that proved to be a bronchogenic cyst rather than an adrenal tumor. Not only was this a difficult operative dilemma, but it was also an unusual presentation for this tumor. CONCLUSIONS: Discovery of a retroperitoneal or intradiaphragmatic bronchogenic cyst is a rare occurrence. The unusual location and tumor characteristics contributed to near surgical failure. The fortuitous surgical strategy of low-pressure inspection allowed visualization of the tumor for definitive resection. PMID- 22440988 TI - How much do I give? Dose estimation formulas for once-nightly insulin glargine and premeal insulin lispro in type 1 diabetes mellitus. AB - OBJECTIVE: To evaluate the mathematical relationships between dosing factors in type 1 diabetic patients using multiple daily injections. METHODS: In this single center, prospective study in type 1 diabetic patients, the basal continuous glucose monitoring glucose target was less than 130 mg/dL with fewer than 10% of 24-hour readings at less than 70 mg/dL. Basal glucose for the 4-hour meal periods was obtained from once-daily serial meal omissions. On an isocaloric, 50% carbohydrate, fixed diet, the insulin to carbohydrate ratio was adjusted to achieve a 2- to 4-hour postbolus glucose value within +/-20% of premeal glucose. For determining dosing formulas, the slope of the linear regression line comparing the variables of weight, total daily dose (TDD), total basal dose (TBD), insulin-to-carbohydrate ratio (ICR), and correction factor (CF) was determined. RESULTS: Forty-nine patients were included. Titrating insulin glargine to the morning glucose led to hypoglycemia during the rest of the day (2 PM to 4 AM). Therefore the basal glucose target was the nondawn phenomenon portion of the day. The resulting estimation formulas could be rounded to the following: TBD = 0.2 x weight (kg) | TBD = 0.33 x TDD | 90/TBD = ICR = CF/4.5. CONCLUSIONS: Smaller insulin glargine doses to achieve control are in contrast to those much larger doses reported in clinical trials in multiple daily injection treated type 1 diabetes in which the morning fasting glucose is the basal insulin target. PMID- 22440989 TI - Treatment with 50,000 IU vitamin D2 every other week and effect on serum 25 hydroxyvitamin D2, 25-hydroxyvitamin D3, and total 25-hydroxyvitamin D in a clinical setting. AB - OBJECTIVE: To examine the effect of 50,000 IU-vitamin D2 supplementation in a clinical setting on serum total 25-hydroxyvitamin D (25[OH]D), 25-hydroxyvitamin D2 (25[OH]D2), and 25-hydroxyvitamin D3 (25[OH]D3). METHODS: This retrospective cohort study was performed in an urban tertiary referral hospital in Boston, Massachusetts. Patients who had been prescribed 50,000 IU vitamin D2 repletion and maintenance programs were identified through a search of our electronic medical record. Baseline and follow-up total serum 25(OH)D, 25(OH)D2, and 25(OH)D3 levels were compared. RESULTS: We examined the medical records of 48 patients who had been prescribed 50,000 IU vitamin D2 in our clinic. Mean +/- standard deviation baseline total 25(OH)D was 31.0 +/- 10.6 ng/mL and rose to 48.3 +/- 13.4 ng/mL after treatment (P<.001). 25(OH)D2 increased from 4.2 +/- 4.3 ng/mL to 34.6 +/- 12.3 ng/mL after treatment (P<.001), for an average of 158 days (range, 35-735 days). Serum 25(OH)D3 decreased from 26.8 +/- 10.8 ng/mL to 13.7 +/- 7.9 ng/mL (P<.001). CONCLUSIONS: Fifty thousand IU vitamin D2 repletion and maintenance therapy substantially increases total 25(OH)D and 25(OH)D2 despite a decrease in serum 25(OH)D3. This treatment program is an appropriate and effective strategy to treat and prevent vitamin D deficiency. PMID- 22440990 TI - Outcomes associated with insulin therapy disruption after hospital discharge among patients with type 2 diabetes mellitus who had used insulin before and during hospitalization. AB - OBJECTIVE: To evaluate outcomes associated with insulin therapy disruption after hospital discharge in patients with type 2 diabetes mellitus who had used insulin before and during hospitalization. METHODS: In this observational, retrospective analysis of medical records obtained from a coordinated health system in the United States, patients with type 2 diabetes mellitus who had used insulin 30 days before and during hospitalization were included. Clinical and cost outcomes were compared between patients who continued insulin therapy and those who had disrupted insulin therapy after hospital discharge. RESULTS: In total, 2160 records were analyzed (851 patients with continued insulin therapy and 1309 patients with disrupted insulin therapy). Mean baseline glycated hemoglobin A1c levels were 8.56% and 7.73% in patients who continued insulin therapy and patients who disrupted insulin therapy, respectively (P<.001), suggesting that patients who discontinued insulin therapy had better glycemic control at baseline. Continued insulin therapy was associated with an expected greater reduction in glycated hemoglobin A1c (P<.001); similar hypoglycemia rates; lower risks of all-cause hospital readmission, diabetes-related readmission, and all cause emergency department visits; and improved survival. Continued insulin therapy was associated with $3432 lower total medical service costs than disrupted therapy over the 6-month postdischarge period. CONCLUSION: Ensuring adherence to insulin therapy in patients who require insulin therapy after hospitalization should be a priority for postdischarge patient care programs. However, the clinical implications of this study are limited by the fact that it could not be determined whether all patients required insulin therapy after hospital discharge. PMID- 22440991 TI - Interobserver and intraobserver agreement in parathyroid scintigraphy: How can parathyroid scintigraphy be made more reliable? AB - OBJECTIVE: To determine the intraobserver and interobserver agreement levels in the evaluation of technetium Tc 99m sestamibi parathyroid scintigraphic images. METHODS: Ninety-eight patients with hyperparathyroidism were included in the study, and their parathyroid images were evaluated by 4 experienced nuclear medicine observers. The 98 cases were evaluated twice by each observer within an interval of 2 weeks. The evaluations were performed directly on workstations with use of digital images. A questionnaire was completed by each observer. The presence of a lesion, the number and the localizations of the lesions, and whether the lesion was clear or doubtful were all evaluated. Cohen kappa statistics and total agreement percentages were calculated by using SPSS version 11.0 software. RESULTS: The 4 observers performed 8 different evaluations and identified a minimum of 38 and a maximum of 43 cases with a parathyroid lesion (or lesions). Both the intraobserver and the interobserver agreements were "very good" for the presence of a parathyroid lesion. The intra-observer agreement was also "very good" and the interobserver agreement was "good" (for only 1 pair of observers) or "very good" for the evaluation of the number of parathyroid lesions. The intraobserver agreement was "very good" or "good" and the interobserver agreement was "good" for the lesion localization and for the presence of a doubtful lesion. CONCLUSION: Parathyroid scintigraphy seems to be an observer independent method in the detection of a parathyroid lesion, in the determination of the number of lesions, and in the localizations of the lesions. The measured high agreement between observers increases the reliability of parathyroid scintigraphy. PMID- 22440992 TI - Determinants of circulating 25-hydroxyvitamin D and bone mineral density in young physicians. AB - OBJECTIVE: To examine determinants of serum 25-hydroxyvitamin D [25(OH)D] and bone mineral density (BMD) in young physicians, a group not well studied previously. METHODS: We analyzed data from a questionnaire completed by young physicians as well as results of serum 25(OH)D, serum parathyroid hormone, and BMD measurements. RESULTS: Among 104 study subjects, 42% were white, 46% were Asian, 12% were "other" (10 Hispanic and 2 African American subjects), and 75% were women. The mean age and body mass index (BMI) were 28.1 years and 23.0 kg/m2, respectively. White subjects had a higher mean serum 25(OH)D level (27.3 ng/mL) than did Asian subjects (15.9 ng/mL) and other subjects (22.3 ng/mL) (P<.0001). White subjects tended to have higher Z-scores than Asian subjects and other subjects for the hip (P = .06), trochanter (P = .08), and lumbar spine (P = .08). The serum 25(OH)D level was negatively associated with serum parathyroid hormone (r = -0.44; P<.01) but not with BMD. The prevalence of vitamin D insufficiency [serum 25(OH)D <30 ng/mL, 77% for the entire group] was higher (P<.01) in Asian subjects (93%) than in white subjects (61%) and other subjects (73%). Significant determinants of serum 25(OH)D included age, ethnicity, exposure to sunlight, use of vitamin D supplements, and family history of osteoporosis (P<.05 for all), and together with sex, calcium supplements, exercise, and BMI, these factors explained 49% of serum 25(OH)D level variability. Significant determinants of low BMD (osteopenia plus osteoporosis, prevalence 37.5%) included sex (P = .002) and BMI (P<.0001) but not serum 25(OH)D; Asian ethnicity reached borderline significance (P = .088). Age, sex, ethnicity, smoking, and BMI explained 20% to 30% of the Z-score variations. CONCLUSION: In young physicians with a healthful lifestyle, determinants of low serum 25(OH)D and BMD included modifiable risk factors. Vitamin D insufficiency and low BMD could be important contributors to future osteoporotic fractures in this population. PMID- 22440993 TI - Effect of an educational Inpatient Diabetes Management Program on medical resident knowledge and measures of glycemic control: a randomized controlled trial. AB - OBJECTIVE: To investigate the effectiveness of an Inpatient Diabetes Management Program (IDMP) on physician knowledge and inpatient glycemic control. METHODS: Residents assigned to General Internal Medicine inpatient services were randomized to receive the IDMP (IDMP group) or usual education only (non-IDMP group). Both groups received an overview of inpatient diabetes management in conjunction with reminders of existing order sets on the hospital Web site. The IDMP group received print copies of the program and access to an electronic version for a personal digital assistant (PDA). A Diabetes Knowledge Test (DKT) was administered at baseline and at the end of the 1-month rotation. The frequency of hyperglycemia among patients under surveillance by each group was compared by using capillary blood glucose values and a dispersion index of glycemic variability. IDMP users completed a questionnaire related to the program. RESULTS: Twenty-two residents participated (11 in the IDMP group and 11 in the non-IDMP group). Overall Diabetes Knowledge Test scores improved in both groups (IDMP: 69% +/- 1.7% versus 83% +/- 2.1%, P = .003; non-IDMP: 76% +/- 1.2% versus 84% +/- 1.4%, P = .02). The percentage of correct responses for management of corticosteroid-associated hyperglycemia (P = .004) and preoperative glycemic management (P = .006) improved in only the IDMP group. The frequency of hyperglycemia (blood glucose level >180 mg/dL) and the dispersion index (5.3 +/- 7.6 versus 3.7 +/- 5.6; P = .2) were similar between the 2 groups. CONCLUSION: An IDMP was effective at improving physician knowledge for managing hyperglycemia in hospitalized patients treated with corticosteroids or in preparation for surgical procedures. Educational programs directed at improving overall health care provider knowledge for inpatient glycemic management may be beneficial; however, improvements in knowledge do not necessarily result in improved glycemic outcomes. PMID- 22440994 TI - Risk of postoperative hypoglycemia in cardiovascular surgical patients receiving computer-based versus paper-based insulin therapy. AB - OBJECTIVE: To evaluate the safety and efficacy of replacing a paper-based protocol with a computer-guided glucose management system (CGMS) for the treatment of postoperative hyperglycemia in the cardiovascular intensive care unit (CVICU). METHODS: With use of a before-and-after analysis, adult patients (>=18 years) discharged from the CVICU and treated with the paper protocol were compared with patients discharged from the CVICU and treated with the CGMS. Of the 1,648 patients analyzed, 991 were in the CGMS group. Clinical end points were evaluated by using the Wilcoxon test. Unadjusted and adjusted hazard ratios (HRs) for each hypoglycemic end point were calculated from Cox models with use of the proportional hazards regression procedure, and clinical end points were adjusted for potential confounders. RESULTS: Patients treated with the paper protocol were 6 times as likely to experience clinical hypoglycemia (blood glucose <=70 mg/dL) as patients treated with the CGMS (adjusted HR = 6.06; P<.0001) and more than 7 times as likely to experience severe hypoglycemia (blood glucose <=40 mg/dL) (adjusted HR = 7.59; P=.01). Despite the increased risk of hypoglycemia, no significant difference in length of stay or mortality was observed between the groups. CONCLUSION: CGMS treatment of postoperative hyperglycemia in CVICU patients can successfully attain goal glucose levels with a significant reduction in hypoglycemia in comparison with a paper protocol. This association persists after controlling for covariates. PMID- 22440995 TI - Reversible mitral and aortic regurgitation due to pioglitazone. AB - OBJECTIVE: To report the occurrence of pioglitazone-induced reversible valvular regurgitant lesions. METHODS: Clinical, laboratory, and imaging data are reported on a patient with known type 2 diabetes mellitus, who was prescribed pioglitazone to achieve better glycemic control. RESULTS: We present a case report of a 50 year-old woman, in whom diabetes had been diagnosed 5 years previously, who developed severe mitral and aortic regurgitation during 5 months of treatment with pioglitazone along with clinical and laboratory indications of fluid retention. Echocardiography 5 months after discontinued use of pioglitazone showed regression of regurgitant lesions and normalization of pertinent laboratory variables. CONCLUSION: Five months of treatment with pioglitazone could potentially induce major cardiac valvular dysfunction, which was reversible in our patient. This report emphasizes the importance of carefully monitoring patients during treatment with thiazolidinediones. PMID- 22440996 TI - Comparative efficacy of vertebroplasty, kyphoplasty, and medical therapy for vertebral fractures on survival and prevention of recurrent fractures. AB - OBJECTIVE: To evaluate the efficacy of surgical and medical therapies on recurrent vertebral fracture and mortality rates. METHODS: A retrospective review of medical records was performed of patients seen at Emory University Spine Center and Hospital (Atlanta, Georgia) for vertebral fracture between 1998 and 2007. Patients with vertebral fracture or who underwent vertebroplasty or kyphoplasty were identified by use of the International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes, respectively. Outcome measures included site and date of recurrent vertebral fractures and mortality. RESULTS: We identified 250 patients with vertebral fractures and classified them into 4 groups: surgical therapy only, surgical plus medical treatment, medical therapy only, and no treatment. There was no significant difference in the cumulative survival rates among the 4 study groups nor between the treatment groups. There was, however, a significant difference in the cumulative refracture-free rates among the 4 study groups (P<.0001). Recurrent fracture-free rates were highest in the group that received no treatment. The 2 year cumulative refracture-free rates were 95.9%, 84.8%, 81.7%, and 68.5%, respectively, for the no treatment, medical therapy only, surgical treatment only, and medical plus surgical therapy groups. Recurrent fracture-free rates were significantly different for patients who received surgical or medical or surgical plus medical therapy (P=.0007), with patients in the medical plus surgical group having the shortest time to refracture, although these patients may have been sicker and more frail than the other groups. CONCLUSION: We found that surgical treatment with vertebroplasty or kyphoplasty did not decrease recurrent vertebral fractures in patients presenting with an initial vertebral fracture. Medical and surgical therapies together may shorten the time to refracture, but the observed elevated risk may be due to other confounding factors. We found no difference in survival in patients undergoing kyphoplasty or vertebroplasty in comparison with medical or no treatment groups. The relationship between surgical and medical therapy and vertebral refracture rates should be further evaluated with use of a prospective cohort design. PMID- 22440997 TI - Elevated amylase and lipase levels in patients using glucagonlike peptide-1 receptor agonists or dipeptidyl-peptidase-4 inhibitors in the outpatient setting. AB - OBJECTIVE: To investigate the effects of glucagonlike peptidase-1 (GLP-1) receptor agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors on serum amylase and serum lipase levels in patients with type 2 diabetes. METHODS: In 90 patients with type 2 diabetes, treatment was initiated with a GLP-1 agonist or a DPP-4 inhibitor. A comparison group consisted of 33 patients with type 2 diabetes and similar characteristics who were not prescribed these agents. Baseline serum amylase and lipase levels were measured in all patients and repeated periodically. We determined the percentage of patients with elevated levels of serum amylase or lipase (or both) in both groups. RESULTS: Among all 90 patients who received a GLP-1 receptor agonist or a DPP-4 inhibitor, 32 (36%) had an increase in serum amylase or lipase (or both) in comparison with 6 of 33 patients (18%) with such increases in the comparison group. Interestingly, the serum lipase levels increased more than the serum amylase values in all groups. To ascertain that this was not a chance laboratory error, serum samples were submitted to a second independent laboratory, and the same results were obtained. Usually, use of the medication was discontinued when serum lipase or amylase values were found to be elevated at any level. CONCLUSION: Both GLP-1 receptor agonists and DPP-4 inhibitors are associated with increased levels of serum lipase more than serum amylase in many patients with type 2 diabetes, possibly suggesting the presence of pancreatic inflammation. Whether this finding may potentially lead to acute pancreatitis or chronic pancreatitis, as reported in rat models, is currently unknown. Careful observation of patients taking these medications may be prudent. PMID- 22440998 TI - Pheochromocytoma with histologic transformation to composite type, complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome. AB - OBJECTIVE: To describe the rare occurrence of histologic transformation of a pheochromocytoma to a composite type of tumor during a long-term follow-up, which was complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome. METHODS: We report the case of a 12-year-old girl who presented with headache, hypertension, and elevated catecholamine levels in the blood and urine. A tumor was found in the right adrenal gland and resected. When she was 15 years of age, multiple metastatic nodules were found in the lung and liver. Intensive chemotherapy was ineffective, and she underwent follow-up with conservative therapy. At 25 years of age, she complained of diarrhea. Laboratory studies revealed hypokalemia and an increase in the level of serum vasoactive intestinal polypeptide (VIP). A year later, she died of extensive metastatic disease. The primary and recurrent tumors at autopsy were histologically examined. RESULTS: The primary tumor was pure pheochromocytoma, and the tumors at autopsy were a composite type of pheochromocytoma and ganglioneuroma. Only a few VIP-positive cells were found in the primary tumor, whereas both pheochromocytoma and ganglioneuroma cells of composite tumors were frequently positive for VIP. CONCLUSION: Our case showed histologic transformation from pheochromocytoma to a composite type of tumor during a 14-year clinical course, which was associated with additional hormone production and a change in symptoms. Careful attention should be paid to the alteration of endocrine symptoms and hormone levels during prolonged follow-up of pheochromocytoma in young patients. PMID- 22440999 TI - Sensorineural hearing loss--a common finding in early-onset type 2 diabetes mellitus. AB - OBJECTIVE: To evaluate the prevalence and potential associations of hearing impairment in patients 30 to 50 years old with diabetes diagnosed before age 40 years-early-onset type 2 diabetes mellitus (T2DM). METHODS: The study cohorts consisted of 46 consecutive patients with early-onset T2DM and 47 age-matched control subjects with rheumatoid arthritis. All study subjects completed clinical, serologic, and auditory assessments. RESULTS: The patients with T2DM had a mean age of 42 +/- 6 years and a mean disease duration of 11 +/- 6 years. Microalbuminuria was present in 26.1%, proliferative retinopathy in 26.1%, and symptomatic peripheral neuropathy in 23.9%. The prevalence of unilateral or bilateral hearing loss was significantly higher in the patients with T2DM than in the patients with rheumatoid arthritis (21.7% versus 6.4%, respectively; P = .01). Most cases of hearing loss were mild and involved high or acute tones. After multivariate analysis with adjustment for age, there was a significant association between hearing loss and hemoglobin A1c (odds ratio, 1.3; 95% confidence interval, 1.02 to 1.81; P = .035). In the patients with T2DM, the lengthening of the brainstem response was not significantly increased; however, the wave morphologic features were abnormal and the reproducibility was poor in both ears in 11 patients (24%). CONCLUSION: Patients with early-onset T2DM and poor glycemic control have an increased prevalence of subclinical hearing loss and impaired auditory brainstem responses. Hearing impairment may be an underrecognized complication of diabetes. PMID- 22441000 TI - Successful long-term treatment of Cushing disease with mifepristone (RU486). AB - OBJECTIVE: We describe a girl with Cushing disease for whom surgery and radiation treatments failed and the subsequent clinical course with mifepristone therapy. METHODS: We present the patient's clinical, biochemical, and imaging findings. RESULTS: A 16-year-old girl presented with classic Cushing disease. After transsphenoidal surgery, Cyberknife radiosurgery, ketoconazole, and metyrapone did not control her disease, and she was prescribed mifepristone, which was titrated to a maximal dosage of 1200 mg daily with subsequent symptom improvement. Mifepristone (RU486) is a high-affinity, nonselective antagonist of the glucocorticoid receptor. There is limited literature on its use as an off label medication to treat refractory Cushing disease. Over her 8-year treatment with mifepristone, her therapy was complicated by hypertension and hypokalemia requiring spironolactone and potassium chloride. She received a 2-month drug holiday every 4 to 6 months to allow for withdrawal menstrual bleeding with medroxyprogesterone acetate. Urinary cortisol, serum cortisol, and corticotropin levels remained elevated during mifepristone drug holidays. While on mifepristone, her signs and symptoms of Cushing disease resolved. Repeated magnetic resonance imaging demonstrated stable appearance of the residual pituitary mass. Bilateral adrenalectomy was performed, and mifepristone was discontinued after 95 months of medical therapy. CONCLUSIONS: We describe the longest duration of mifepristone therapy thus reported for the treatment of refractory Cushing disease. Mifepristone effectively controlled all signs and symptoms of hypercortisolism. Menstruating women who take the drug on a long-term basis should receive periodic drug holidays to allow for menses. The lack of reliable serum biomarkers to monitor the success of mifepristone therapy requires careful clinical judgment and may make its use difficult in Cushing disease. PMID- 22441001 TI - Bilateral adrenalectomy: lifesaving procedure in severe Cushing syndrome. AB - OBJECTIVE: To discuss the role of bilateral adrenalectomy in Cushing syndrome, as illustrated in a case of severe hypercortisolism that was unresponsive to combination agent medical therapy. METHODS: We report the clinical, laboratory, imaging, and pathologic findings in a patient with ectopic Cushing syndrome attributable to an adrenocorticotropic hormone (ACTH)-secreting neuroblastoma. In addition, we provide a literature review regarding olfactory neuroblastoma and discuss current and emerging therapeutic options for Cushing syndrome. RESULTS: A 59-year-old man presented with nasal congestion and neck swelling and was noted to have hypokalemia, hypertension, and hyperglycemia. A nasal biopsy demonstrated a poorly differentiated carcinoma with neuroendocrine features. He was subsequently diagnosed as having ACTH-dependent Cushing syndrome, but despite high-dose combination medical therapy, his condition rapidly deteriorated. Urgent bilateral adrenalectomy provided rapid control of the hypercortisolism, and the patient was later able to undergo an uncomplicated total macroscopic resection of his locally metastatic primary tumor. CONCLUSION: This report describes the challenges in the diagnosis and management of ACTH-dependent Cushing syndrome and highlights the important role that bilateral adrenalectomy can still have in patients with severe hypercortisolism causing life-threatening complications. PMID- 22441002 TI - Familial carotid body tumors in patients with SDHD mutations: a case series. AB - OBJECTIVE: To describe a family with hereditary paraganglioma due to a disease causing mutation in the SDHD gene. METHODS: We present the clinical findings, diagnostic test results, treatment, and genetic test results in a family with hereditary paraganglioma. RESULTS: Three siblings with bilateral carotid body tumors presented at different time points and with varied clinical presentations. While the proband, a 20-year-old man, was not hypertensive and had normal urinary metanephrine and normetanephrine levels, his sister and brother had a more severe clinical picture, with hypertension in both and elevated normetanephrine levels in his brother (his brother had pheochromocytoma and 2 intra-abdominal paragangliomas). Mean age at presentation was 24 years. A 4-base pair frameshift mutation, c.337-340delGACT, was detected in exon 4 of the SDHD gene in all 3 patients. CONCLUSION: This is the first report of the c.337-340delGACT mutation being associated with hereditary paraganglioma; this report emphasizes the need to screen all at-risk first-degree relatives for the disease-causing SDHD mutation once it has been identified in an affected family member. PMID- 22441003 TI - Pheochromocytoma: a cause of ST-segment elevation myocardial infarction, transient left ventricular dysfunction, and takotsubo cardiomyopathy. AB - OBJECTIVE: To report the case of a patient with a pheochromocytoma and apical left ventricular dysfunction that resolved after surgical resection of the pheochromocytoma, to review the effects of catecholamines on myocyte function and the concept that takotsubo cardiomyopathy (TC) is caused by excess catecholamines, and to illustrate the difficulty in the management of an acute coronary syndrome (ACS) during a hypertensive crisis attributable to a pheochromocytoma. METHODS: We present the clinical history, physical findings, laboratory results, and imaging studies in a 60-year-old man with an ACS, TC, and an incidentaloma later diagnosed to be a pheochromocytoma. The association with TC and the pertinent literature are reviewed. RESULTS: A 60-year-old man was suspected of having myocardial ischemia on the basis of symptoms of paroxysmal chest pain extending to the left shoulder, diaphoresis, ST-segment elevation on an electrocardiogram, and elevated serial levels of cardiac enzymes. Coronary angiography did not reveal substantial coronary artery obstruction but detected ballooning of the apical, anterior, and inferior cardiac walls, consistent with TC. He had a history of labile hypertension and palpitations of 3 months' duration. An adrenal mass detected on a prior computed tomographic scan and increased 24-hour urine catecholamine levels were consistent with a pheochromocytoma. Treatment with phenoxybenzamine was initiated, and he underwent a right adrenalectomy, which confirmed that the tumor was a pheochromocytoma and dramatically improved the patient's condition. CONCLUSION: Pheochromocytomas manifest with labile blood pressures and should be considered in the differential diagnosis of ACS. This case also supports the concept that TC is caused by excess catecholamines. PMID- 22441004 TI - Podocyte as a potential target of inflammation: role of pioglitazone hydrochloride in patients with type 2 diabetes. AB - OBJECTIVE: To observe the effects of pioglitazone hydrochloride on urinary sediment podocalyxin and monocyte chemoattractant protein-1 (MCP-1) excretion in patients with type 2 diabetes and to explore its possible renoprotective mechanisms. METHODS: Ninety-eight patients with uncontrolled type 2 diabetes, who were previously prescribed metformin, acarbose, or both, were randomly assigned to a DP group (add-on pioglitazone; n = 49) or a DS group (add-on sulfonylurea; n = 49). RESULTS: After 12 weeks of treatment, both add-on pioglitazone therapy (the DP group) and add-on sulfonylurea therapy (the DS group) demonstrated a similar improvement in fasting blood glucose and hemoglobin A1c, but systolic and diastolic blood pressure declined significantly in only the DP group. Moreover, the DP group showed significantly better efficacy in reducing urinary MCP-1 excretion in comparison with the DS group. Furthermore, both urinary albumin and urinary sediment podocalyxin excretion decreased significantly in the DP group but not in the DS group. The urinary sediment podocalyxin to creatinine ratio had a positive correlation with urinary albumin to creatinine ratio (r = 0.624; P<.01) and urinary MCP-1 to creatinine ratio (r = 0.346; P<.01). CONCLUSION: Pioglitazone treatment revealed a podocyte-protective capacity in patients with type 2 diabetes, and the underlying mechanisms may be partly attributed to its effective suppression of excessive local renal inflammation. PMID- 22441006 TI - Visual vignette. Metastatic lesion of Hurthle cell cancer. PMID- 22441009 TI - Plurihormonal pituitary adenoma immunoreactive for thyroid-stimulating hormone, growth hormone, follicle-stimulating hormone, and prolactin. AB - OBJECTIVE: To describe the case of a patient with an unusual plurihormonal pituitary adenoma with immunoreactivity for thyroid-stimulating hormone (TSH), growth hormone, follicle-stimulating hormone, prolactin, and alpha-subunit. METHODS: We report the clinical, laboratory, imaging, and pathology findings of a patient symptomatic from a plurihormonal pituitary adenoma and describe her outcome after surgical treatment. RESULTS: A 60-year-old woman presented to the emergency department with headaches, blurry vision, fatigue, palpitations, sweaty hands, and weight loss. Her medical history was notable for hyperthyroidism, treated intermittently with methimazole. Magnetic resonance imaging disclosed a pituitary macroadenoma (2.3 by 2.2 by 2.0 cm), and preoperative blood studies revealed elevated levels of TSH at 6.11 mIU/L, free thyroxine at 3.6 ng/dL, and free triiodothyronine at 6.0 pg/mL. She underwent an uncomplicated transsphenoidal resection of the pituitary adenoma. Immunostaining of tumor tissue demonstrated positivity for not only TSH but also growth hormone, follicle stimulating hormone, prolactin, and alpha-subunit. The Ki-67 index of the tumor was estimated at 2% to 5%, and DNA repair enzyme O6-methylguanine-DNA methyltransferase immunostaining was mostly negative. Electron microscopy showed the ultrastructural phenotype of a glycoprotein-producing adenoma. Postoperatively, her symptoms and hyperthyroidism resolved. CONCLUSION: Thyrotropin-secreting pituitary adenomas are rare. Furthermore, recent reports suggest that 31% to 36% of adenomas may show evidence of secretion of multiple pituitary hormones. This case emphasizes the importance of considering pituitary causes of thyrotoxicosis and summarizes the clinical and pathology findings in a patient with a plurihormonal pituitary adenoma. PMID- 22441013 TI - External validation of the cancer of the prostate risk assessment score to predict biochemical relapse after radical prostatectomy for prostate cancer in Japanese patients. AB - OBJECTIVES: The aim of the present study was external validation to determine whether the Cancer of the Prostate Risk Assessment (CAPRA) score predicts biochemical relapse (BCR) after radical prostatectomy (RP) in Japanese patients. METHODS: From 1995 to 2008, 503 Japanese patients undergoing RP for clinically localized prostate cancer were included in the validation cohort. The BCR-free rate was estimated using the Kaplan-Meier method. Performance of the CAPRA score was assessed using Cox proportional hazards regression models, concordance index (c-index) and calibration plots. RESULTS: Unlike the results in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort, the BCR-free rate and the hazard ratio for CAPRA score 4 were inversely better than those for CAPRA scores 2 and 3 in Japanese patients. The c-index of the CAPRA score was 0.673. The calibration plot demonstrated that the CAPRA score was generally well calibrated. CONCLUSIONS: In Japanese patients, the CAPRA score can predict BCR after RP only to some degree. Although our c-index is comparable with the c-index of 0.66 in the original CaPSURE cohort, it is lower than the c-indices reported in other validation cohorts, which range from 0.68 to 0.81. The CAPRA score may not predict BCR after RP in Japanese patients as accurately as it did in Western patients. PMID- 22441014 TI - Targeting autophagy for drug-induced hepatotoxicity. AB - Autophagy is a lysosomal degradation pathway for bulk cytosolic proteins and damaged organelles, and is well known to act as a cell survival mechanism. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing necrosis due to mitochondrial damage. We recently found that pharmacological induction of autophagy by rapamycin protects against, whereas pharmacological suppression of autophagy by chloroquine exacerbates, APAP-induced liver injury in mice. Autophagy is induced to remove APAP-induced damaged mitochondria and thus attenuates APAP-induced hepatocyte necrosis. To our surprise, we found that liver-specific Atg5 knockout mice are not more susceptible, but are resistant to APAP-induced liver injury due to compensatory effects. Our work suggests that pharmacological modulation of autophagy is a novel therapeutic approach to ameliorate APAP-induced liver injury. Moreover, our work also suggests that caution needs to be exercised when using genetic autophagy gene knockout mice for pathophysiological studies. PMID- 22441015 TI - Hypoxia-induced autophagy: a new player in cancer immunotherapy? AB - A major challenge in formulating an effective immunotherapy is to overcome the mechanisms of tumor escape from immunosurveillance. We showed that hypoxia induced autophagy impairs cytotoxic T-lymphocyte (CTL)-mediated tumor cell lysis by regulating phospho-STAT3 in target cells. Autophagy inhibition in hypoxic cells decreases phospho-STAT3 and restores CTL-mediated tumor cell killing by a mechanism involving the ubiquitin proteasome system and SQSTM1/p62. Simultaneously boosting the CTL-response, using a TRP-peptide vaccination strategy, and targeting autophagy in hypoxic tumors, improves the efficacy of cancer vaccines and promotes tumor regression in vivo. Overall, in addition to its immunosuppressive effect, the hypoxic microenvironment also contributes to immunoresistance and can be detrimental to antitumor effector cell functions. PMID- 22441016 TI - MTOR regulates autophagic flux in the glomerulus. AB - Sirolimus (rapamycin), an inhibitor of the mechanistic target of rapamycin (MTOR), was originally proposed as an immunosuppressant to prevent rejection of solid organ transplants. There were expectations that MTOR inhibitors would replace nephrotoxic calcineurin inhibitors (CNIs). Despite its potential advantages, evidence that sirolimus causes de novo or worsening proteinuria is unequivocal. Given the well-recognized proteinuric effect of MTOR inhibitors, we were interested in understanding its role in maintaining the glomerular filtration barrier. To investigate this in vivo, we developed a mouse model with a podocyte selective deletion of the Mtor gene (Mtor pod-KO). PMID- 22441017 TI - LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy. AB - Alterations in autophagy are thought to underlie various neurodegenerative diseases including Parkinson disease (PD). Previous studies have indicated that the PD gene leucine rich repeat kinase 2 (LRRK2) is involved in this process, but its mechanism of action has remained unknown. Our recent work describes how LRRK2 acts through calcium-mediated events originating from acidic stores to regulate autophagy and cell survival, which may give rise to novel therapeutic strategies. PMID- 22441018 TI - A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress. AB - The Atg4 cysteine proteases play crucial roles in the processing of Atg8 proteins during autophagy, but their regulation during cellular stress and differentiation remains poorly understood. We have found that two Atg4 family members--Atg4C and Atg4D--contain cryptic mitochondrial targeting sequences immediately downstream of their canonical (DEVD) caspase cleavage sites. Consequently, caspase-cleaved Atg4D (DeltaN63 Atg4D) localizes to the mitochondrial matrix when expressed in mammalian cells, where it undergoes further processing to a ~42 kDa mitochondrial form. Interestingly, caspase cleavage is not needed for Atg4D mitochondrial import, because ~42 kDa mitochondrial Atg4D is observed in cells treated with caspase inhibitors and in cells expressing caspase-resistant Atg4D (DEVA(63)). Using HeLa cell lines stably expressing DeltaN63 Atg4D, we showed that mitochondrial Atg4D sensitizes cells to cell death in the presence of the mitochondrial uncoupler, CCCP, and that mitochondrial cristae are less extensive in these cells. We further showed that the organization of mitochondrial cristae is altered during the mitochondrial clearance phase in differentiating primary human erythroblasts stably expressing DeltaN63 Atg4D, and that these cells have elevated levels of mitochondrial reactive oxygen species (ROS) during late stages of erythropoiesis. Together these data suggest that the import of Atg4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability. PMID- 22441019 TI - Interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic PCa cells. AB - Autophagy reallocates nutrients and clears normal cells of damaged proteins and organelles. In the context of metastatic disease, invading cancer cells hijack autophagic processes to survive and adapt in the host microenvironment. We sought to understand how autophagy is regulated in the metastatic niche for prostate cancer (PCa) cells where bone marrow stromal cell (BMSC) paracrine signaling induces PCa neuroendocrine differentiation (NED). In PCa, this transdifferentiation of metastatic PCa cells to neuronal-like cells correlates with advanced disease. Because autophagy provides a survival advantage for cancer cells and promotes cell differentiation, we hypothesized that autophagy mediates PCa NED in the bone. Thus, we determined the ability of paracrine factors in conditioned media (CM) from two separate BMSC subtypes, HS5 and HS27a, to induce autophagy in C4-2 and C4-2B bone metastatic PCa cells by characterizing the autophagy marker, LC3. Unlike HS27a CM, HS5 CM induced LC3 accumulation in PCa cells, suggesting autophagy was induced and indicating that HS5 and HS27a secrete a different milieu of paracrine factors that influence PCa autophagy. We identified interleukin-6 (IL-6), a cytokine more highly expressed in HS5 cells than in HS27a cells, as a paracrine factor that regulates PCa autophagy. Pharmacological inhibition of STAT3 activity did not attenuate LC3 accumulation, implying that IL-6 regulates NED and autophagy through different pathways. Finally, chloroquine inhibition of autophagic flux blocked PCa NED; hence autophagic flux maintains NED. Our studies imply that autophagy is cytoprotective for PCa cells in the bone, thus targeting autophagy is a potential therapeutic strategy. PMID- 22441020 TI - Facilitated ethanol metabolism promotes cardiomyocyte contractile dysfunction through autophagy in murine hearts. AB - Chronic drinking leads to myocardial contractile dysfunction where ethanol metabolism plays an essential role. Acetaldehyde, the main ethanol metabolite, mediates alcohol-induced cell injury although the underlying mechanism is still elusive. This study was designed to examine the mechanism involved in accelerated ethanol metabolism-induced cardiac defect with a focus on autophagy. Wild-type FVB and cardiac-specific overexpression of alcohol dehydrogenase mice were placed on a 4% nutrition-balanced alcohol diet for 8 weeks. Myocardial histology, immunohistochemistry, autophagy markers and signal molecules were examined. Expression of micro RNA miR-30a, a potential target of Beclin 1, was evaluated by real-time PCR. Chronic alcohol intake led to cardiac acetaldehyde accumulation, hypertrophy and overt autophagosome accumulation (LC3-II and Atg7), the effect of which was accentuated by ADH. Signaling molecules governing autophagy initiation including class III PtdIns3K, phosphorylation of mTOR and p70S6K were enhanced and dampened, respectively, following alcohol intake. These alcohol-induced signaling responses were augmented by ADH. ADH accentuated or unmasked alcohol induced downregulation of Bcl-2, Bcl-xL and MiR-30a. Interestingly, ADH aggravated alcohol-induced p62 accumulation. Autophagy inhibition using 3-MA abolished alcohol-induced cardiomyocyte contractile anomalies. Moreover, acetaldehyde led to cardiomyocyte contractile dysfunction and autophagy induction, which was ablated by 3-MA. Ethanol or acetaldehyde increased GFP-LC3 puncta in H9c2 cells, the effect of which was ablated by 3-MA but unaffected by lysosomal inhibition using bafilomycin A(1), E64D and pepstatin A. In summary, these data suggested that facilitated acetaldehyde production via ADH following alcohol intake triggered cardiac autophagosome formation along with impaired lysosomal degradation, en route to myocardial defect. PMID- 22441021 TI - Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis. AB - Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death. PMID- 22441022 TI - The Cataract National Dataset electronic multi-centre audit of 55,567 operations: risk indicators for monocular visual acuity outcomes. AB - AIMS: To report risk factors for visual acuity (VA) improvement and harm following cataract surgery using electronically collected multi-centre data conforming to the Cataract National Dataset (CND). METHODS: Routinely collected anonymised data were remotely extracted from the electronic patient record systems of 12 participating NHS Trusts undertaking cataract surgery. Following data checks and cleaning, analyses were performed to identify risk indicators for: (1) a good acuity outcome (VA 6/12 or better), (2) the pre- to postoperative change in VA, and (3) VA loss (doubling or worse of the visual angle). RESULTS: In all, 406 surgeons from 12 NHS Trusts submitted data on 55,567 cataract operations. Preoperative VA was known for 55,528 (99.9%) and postoperative VA outcome for 40,758 (73.3%) operations. Important adverse preoperative risk indicators found in at least 2 of the 3 analyses included older age (3), short axial length (3), any ocular comorbidity (3), age-related macular degeneration (2), diabetic retinopathy (3), amblyopia (2), corneal pathology (2), previous vitrectomy (2), and posterior capsule rupture (PCR) during surgery (3). PCR was the only potentially modifiable adverse risk indicator and was powerfully associated with VA loss (OR=5.74). CONCLUSION: Routinely collected electronic data conforming to the CND provide sufficient detail for identification and quantification of preoperative risk indicators for VA outcomes of cataract surgery. The majority of risk indicators are intrinsic to the patient or their eye, with a notable exception being PCR during surgery. PMID- 22441023 TI - Assessment of a variable frame (polygonal) method to estimate corneal endothelial cell counts after corneal transplantation. AB - PURPOSE: To assess the agreement of the 'polygonal' variable frame cell count option on a confocal microscope after keratoplasty, with planimetry as the reference method. METHODS: One hundred clear corneal grafts of 83 patients attending the cornea clinic at Gartnavel General Hospital in Glasgow underwent slit-scanning in vivoconfocal microscopy. Endothelial cell images were assessed with the Nidek Advanced Vision Information System (NAVIS), using the polygonal variable frame and the manual fixed-frame methods. Planimetry was used as the reference. The agreement between methods was assessed by Bland-Altman analysis. RESULTS: Planimetry provided a mean (+/- SD) endothelial cell density (ECD) of 1348 +/- 726 cells/mm(2), a value that was very similar to that found by the polygonal method (1404 +/- 784 cells/mm(2)). The fixed-frame method provided lower cell counts with a mean ECD of 1026 +/- 610 cells/mm(2) (P<0.001). When compared with the reference ECD, the polygonal method overestimated the ECD only very slightly with a mean difference of 58 cells/mm(2) (limits of agreement, LoA, of -222 and 339 cells/mm(2)). Manual counting underestimated the ECD with a mean difference of -320 cells/mm(2) (LoA -814 and 173 cell/mm(2)). CONCLUSION: Following keratoplasty, endothelial cell counts with the NAVIS polygonal method are in good agreement with planimetry. The 'polygonal' option is proposed as the method of choice for clinical applications with this confocal microscope and a good compromise between reliability and ease of use. PMID- 22441024 TI - Age variations in intraocular pressure in a cohort of healthy Austrian school children. AB - PURPOSE: Limited data exist detailing the normal range of intraocular pressure (IOP) for healthy school age children. This study aims to describe the mean and normal range of IOP measurements that may be expected using the Icare rebound tonometer and to examine associations between visual function measures and IOP. METHODS: Six measurements of IOP from each eye were obtained from 211 normal children aged 6-15 years (79 females and 132 males) using the Icare tonometer. Other measures of visual function obtained included: visual acuity, non cycloplegic retinoscopy, amplitude of accommodation, accommodative facility, and accommodative response. RESULTS: Statistical analysis (Mann-Whitney U test) demonstrated that the male subjects were more likely to have higher IOP measurements than the female subjects (mean IOP males 15.02 mm Hg (SD 2.19), mean IOP females 14.44 (SD 2.01) P=0.041). Analysis (Spearman's rho) showed a statistically significant association between age and IOP (right eye) in males (P<0.001) but no association for females (P=0.459). Using Spearman's rank analysis, statistically significant associations were found between IOP and amplitude of accommodation in males, for the whole data set (P=0.09) and for data up to age 11 (P<0.001). For females no statistically significant association was found for the whole data set (P=0.253) or for data up to age 11 (P=0.08). IOP was not significantly associated with visual acuity, refractive error, accommodative facility, or accommodative response. CONCLUSION: This study provides useful normative IOP data using the Icare tonometer for a European cohort of school age children. PMID- 22441025 TI - Prognostic factors for recurrence after bilateral rectus recession procedure in patients with intermittent exotropia. AB - PURPOSE: The purpose of this study is to evaluate prognostic factors, specifically age, at the time of surgery, for recurrence after bilateral lateral rectus recession (BLR) in patients with intermittent exotropia. METHODS: Medical records of 511 subjects who underwent BLR procedures between the ages of 3 and 10 years with more than 12 months of follow-up were retrospectively reviewed. Patients' surgical outcomes with a deviation of less than 10 prism diopters (PD) exotropia and less than 5 PD esotropia were defined as a success. Outcomes with more than 11 PD exotropia were designated as recurrences, and those with esotropia of more than 5 PD after 3 months of surgery were noted as overcorrection. Prognostic factors for recurrence were analyzed by multivariate logistic regression test. RESULTS: Of the 511 subjects, 371 had successful surgical outcomes and 129 had recurrences, whereas 11 were found to be overcorrected. Age at surgery and immediate postoperative alignment proved to be significant factors influencing a favorable outcome by multivariate logistic regression analysis (P<0.05). However, gender, photophobia, age at onset, spherical equivalent (SE) refractive error, astigmatism, SE anisometropia, and preoperative deviation size were not significantly predictive of success (P>0.05). CONCLUSION: In BLR procedures, increasing patient age at surgery was associated with lower recurrence rates. PMID- 22441026 TI - Surgical approaches to posterior polar cataract: a review. AB - The aim of this study is to provide a comprehensive overview of surgical methods used in the emulsification of posterior polar cataracts (PPCs) that have been devised to minimize the risk of posterior capsule rupture (PCR) and its consequences. A Pubmed and Medline search of relevant literature on PPC was done. Only articles relevant to the treatment of PPC were included. The posterior capsule in eyes with PPC are known to have an abnormal adhesion to the polar opacity or a pre-existing weakness of the capsule that predisposes the eye to PCR. To circumvent the consequences of cleaving the abnormal adhesion, a majority of the surgeons use the anterior approach through the limbus, whereas some advocate the posterior approach through the pars plana. Emulsifying the nucleus and cleaving the central opacity of the PPC off the posterior capsule without disrupting its integrity provides optimal surgical outcomes. To achieve this, various modifications have been applied by surgeons during different phases of surgery. The advantages, disadvantages, complications, and results of each method have been discussed. Phacoemulsification is the preferred technique for removing PPC. This review will provide methods to avoid and /or deal with intraocular surgical difficulties that can arise during emulsification. Employing these would result in least ocular morbidity and satisfactory visual outcomes for the patient. This is particularly relevant given the major advancements in technology and refinements in surgical techniques in phacoemulsification. PMID- 22441028 TI - Prevalence and risk factors of diabetic retinopathy in Chongqing pre-diabetes patients. AB - PURPOSE: To investigate the prevalence of diabetic retinopathy (DR) and relative risk factors among Chongqing pre-diabetes patients. METHODS: A total of 750 participants were recruited in this cross-sectional study. All participants underwent a complete physical examination and an oral glucose-tolerance test. In all, 110 of the 125 newly diagnosed pre-diabetics and their healthy spouses as controls were examined with fluorescence fundus angiographies, and their blood with biochemical analyses. All the pre-diabetics with DR (23 subjects), 23 normal controls and 23 pre-diabetics without DR were compared for serum concentrations of regulated upon activation, normal T-expressed and secreted (RANTES). Student's t-test was used to compare continuous variables, and chi (2) test and analysis of variance to compare proportions among groups. Multiple logistic regression models were used to determine the risk factors for DR in pre-diabetics. RESULTS: In all, 20.91% of the 110 pre-diabetics showed mild non-proliferative DR (NPDR). There was a statistically significant difference in serum concentrations of RANTES between pre-diabetics with and without DR (P<0.01), and also between pre diabetics with DR and normal controls (P<0.01). However, age, body mass index, waist-hip ratio, triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein-C, low-density lipoprotein-C, blood urea nitrogen, blood creatinine, and urine albumin excretion rate seemed to have no reliable relationship with DR in pre-diabetics (P>0.05). CONCLUSION: The prevalence of DR in Chongqing pre diabetes patients in the study was about 20.91% and only mild NPDR was found. It seems that RANTES is one possible risk factor associated with DR in pre diabetics, not age, TG and TC, and others. PMID- 22441029 TI - The clinical effect of the inhibitor of apopotosis protein livin in melanoma. AB - OBJECTIVE: The inhibitor of apoptosis protein (IAP) livin is frequently overexpressed in melanoma. Livin binds caspases and thereby inhibits apoptosis. We found that caspases cleave livin to produce a truncated form with a paradoxical proapoptotic activity. METHODS: We assessed the correlation of livin expression with survival among 114 melanoma patients treated with an autologous melanoma vaccine. In 52 patients, resection resulted in no evidence of disease (NED) and 62 remained with active disease (WAD). Protein levels were assessed using Western blot. RESULTS: We found livin protein expression in 44/114 samples (38.4%). Median overall survival was 1.4 years in NED patients with high levels of livin protein, 8.4 years in those with low-intermediate levels and not reached in patients who did not express livin (p = 0.025). The corresponding overall survival was 2.3 years among WAD patients with high levels of livin protein, 11.3 years in those with low-intermediate levels and, paradoxically, only 4.0 years in patients who did not express livin (p = 0.012). CONCLUSION: Livin protein expression may play a role in the progression of melanoma and correlates with survival. A high level of the protein is associated with a poor prognosis. However, in WAD patients low to intermediate level of livin, rather than absence of the protein, is associated with a favorable prognosis. This is probably due to the paradoxical proapoptotic activity of this important regulator of apoptosis. PMID- 22441027 TI - Observational study of subclinical diabetic macular edema. AB - PURPOSE: To determine the rate of progression of eyes with subclinical diabetic macular edema (DME) to clinically apparent DME or DME necessitating treatment during a 2-year period. METHODS: In all, 43 eyes from 39 study participants with subclinical DME, defined as absence of foveal center edema as determined with slit lamp biomicroscopy but a center point thickness (CPT) between 225 and 299 MUm on time domain (Stratus, Carl Zeiss Meditec) optical coherence tomography (OCT) scan, were enrolled from 891 eyes of 582 subjects screened. Eyes were evaluated annually for up to 2 years for the primary outcome, which was an increase in OCT CPT of at least 50 MUm from baseline and a CPT of at least 300 MUm, or treatment for DME (performed at the discretion of the investigator). RESULTS: The cumulative probability of meeting an increase in OCT CPT of at least 50 MUm from baseline and a CPT of at least 300 MUm, or treatment for DME was 27% (95% confidence interval (CI): 14%, 38%) by 1 year and 38% (95% CI: 23%, 50%) by 2 years. CONCLUSIONS: Although subclinical DME may be uncommon, this study suggests that between approximately one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification. PMID- 22441030 TI - Hepatitis E virus-associated aplastic anaemia: the first case of its kind. AB - Here we report the case of a 32-year-old Pakistani male, who developed severe aplastic anaemia after a severe attack of acute hepatitis E virus (HEV) infection. His laboratory test values were not in normal ranges. The liver enzymes were elevated. Serologic and/or molecular-based tests for hepatitis A, B, C, D, G, transfusion transmitted virus (TTV) and B19 were negative, whereas anti HEV IgM and HEV RNA polymerase chain reaction (PCR) was also detected in the patient sample. The patient received immunosuppressive therapy for 6 months; however, he did not show response to this kind of therapy. The results of our case clearly show the causative role of HEV in the development of aplastic anaemia that might not be ignored. PMID- 22441031 TI - Consequences of handling missing data for treatment response in osteoarthritis: a simulation study. AB - OBJECTIVE: To understand how handling of missing data influences the statistical power and bias of treatment effects in randomised controlled trials of painful knee osteoarthritis (OA). METHODS: We simulated trials with missing data (withdrawals) due to lack-of-efficacy. Outcome measures were response/non response according to the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) set of responder criteria, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function from the WOMAC questionnaire, and patient global assessment. We used five methods for managing missing data: ignoring the missing data, last and baseline observation carried forward (LOCF and BOCF), and multiple imputation with two different strategies. The treatment effect was then analysed by appropriate univariate and longitudinal statistical methods, and power, bias and mean squared error (MSE) was assessed by comparing the estimated treatment effect in the trials with missing data with the estimated treatment effect on the trials without missing data. RESULTS: The best imputation method in terms of high power and low bias/MSE was our implementation of regression multiple imputation. The most conservative method was the data augmentation Markov chain Monte Carlo (MCMC) multiple imputation. The LOCF, BOCF and the complete-case methods were not particularly conservative and gave relatively low power and high bias. The analysis on the WOMAC pain scale gave less bias and higher power than the OMERACT OARSI responder outcome measure. CONCLUSIONS: Multiple imputation of missing data may be used to decrease bias/MSE and increase power in OA trials. These results can guide investigators in the choice of outcome measures and especially how missing data can be handled. PMID- 22441032 TI - Hydrated-ion ordering in electrical double layers. AB - In this work we revisit the surface forces measured between two atomically flat mica surfaces submerged in a reservoir of potassium nitrate (KNO(3)) solution. We consider a comprehensive range of concentrations from 0.08 mM to 2.6 M. The significantly improved resolution available from the extended surface force apparatus (eSFA) allows the distinction of hydration structures and hydrated-ion correlations. Above concentrations of 0.3 mM, hydrated-ion correlations give rise to multiple collective transitions (4 +/- 1 A) in the electrical double layers upon interpenetration. These features are interpreted as the result of hydrated ion ordering (e.g. layering), in contrast to the traditional interpretation invoking water layering. The hydrated-ion layer adjacent to the surface (i.e. outer Helmholtz layer) is particularly well defined and plays a distinctive role. It can be either collectively expelled in a 5.8 +/- 0.3 A film-thickness transition or collectively forced to associate with the surface by external mechanical work. The latter is observed as a characteristic 2.9 +/- 0.3 A film thickness transition along with an abrupt decrease of surface adhesion at concentrations above 1 mM. At concentrations as low as 20 mM, attractive surface forces are measured in deviation to the DLVO theory. The hydration number in the confined electrolyte seems to be significantly below that of the bulk. A 1-3 nm thick ionic layer solidifies at the surfaces at concentrations >100 mM, i.e. below bulk saturation. PMID- 22441033 TI - The scope of the crustacean immune system for disease control. AB - The culture or wild capture of marine and freshwater shellfish, including crustaceans, is without doubt a key source of protein for a burgeoning world population. Historically the expansion of aquaculture has, however, been accompanied by the increased incidence of economically significant diseases, most notably of viral and bacterial origin. Since the late 1970s great progress has been made in our understanding of the generalized protostome innate immune system. Distinct pathways, pathogen receptor proteins and effector molecules have since been identified that are not ancestral or homologous to those of the deuterostomes, including vertebrates. Within the past decade progress has accelerated with the rapid characterisation of new classes of recognition proteins, immune effectors and regulatory pathways. This paper provides a broad overview of our current understanding of invertebrate immunology, taking the crustacean decapod immune system as its focus. Recent developments in the field are described briefly and their implications and potential considered. These advances offer fundamental new insights in our efforts to understand disease in cultured populations and also to develop knowledge of environmental effects on host/pathogen interactions within a fishery context. Of course, challenges do remain, including the lack of an immortal cell line and the limited publically available genomic resources. These are considered in this review as priorities for future research effort. With the continued application of more insightful technologies, coupled with associated investment, it is expected that the speed at which some of these issues are resolved will accelerate. PMID- 22441034 TI - Optogenetic inhibition of Purkinje cell activity reveals cerebellar control of blood pressure during postural alterations in anesthetized rats. AB - The cerebellar uvula (lobule IX), a part of the vestibulocerebellum, is extensively connected to the areas of the brainstem that participate in cardiovascular regulation and vestibular signal processing. This suggests that the uvula regulates blood pressure (BP) during postural alterations. Previous studies showed that lesions of the uvula affected the baroreceptor reflex and cardiovascular responses during postural alterations. To investigate the mechanisms underlying this BP regulation, it is necessary to have a method to selectively modulate the activity of Purkinje cells (PCs), the sole output neurons from the cerebellar cortex, without affecting other neuronal types such as local interneurons or nonlocal neurons that send their axons to the cerebellar cortex. We recently developed a novel technique using optogenetics to manipulate PC activity and showed that activation and inhibition of PCs in the uvula either decreased or increased the resting BP, respectively. This technique was employed in the current study to examine the roles of the uvula in BP regulation during postural alterations in anesthetized rats. Enhanced Natronomonas pharaonis halorhodopsin (eNpHR), a light-driven chloride ion pump, was selectively expressed in uvular PCs using a lentiviral vector containing the PC-specific L7 promoter. The eNpHR-expressing PCs were then illuminated by orange laser (593 nm) either during 30 degrees head-up or 30 degrees head-down tilts. The eNpHR mediated photoinhibition of the uvula attenuated the extent of BP recovery after a BP increase induced by postural changes during head-down tilts. By contrast, photoinhibition had no statistically significant effect on BP recovery during head-up tilts. The effects of photoinhibition on BP during tilts were significantly different from those observed during the resting condition, indicating that cerebellar control of BP during tilts is dynamic rather than static. Taken together, these results suggest that PCs in the uvula dynamically regulates BP maintenance during postural alterations. PMID- 22441035 TI - The dose-response effect of acute intravenous transplantation of human umbilical cord blood cells on brain damage and spatial memory deficits in neonatal hypoxia ischemia. AB - Despite the beneficial effects of cell-based therapies on brain repair shown in most studies, there has not been a consensus regarding the optimal dose of human umbilical cord blood cells (HUCBC) for neonatal hypoxia-ischemia (HI). In this study, we compared the long-term effects of intravenous administration of HUCBC at three different doses on spatial memory and brain morphological changes after HI in newborn Wistar rats. In addition, we tested whether the transplanted HUCBC migrate to the injured brain after transplantation. Seven-day-old animals underwent right carotid artery occlusion and were exposed to 8% O(2) inhalation for 2 h. After 24 h, randomly selected animals were assigned to four different experimental groups: HI rats administered with vehicle (HI+vehicle), HI rats treated with 1*10(6) (HI+low-dose), 1*10(7) (HI+medium-dose), and 1*10(8) (HI+high-dose) HUCBC into the jugular vein. A control group (sham-operated) was also included in this study. After 8 weeks of transplantation, spatial memory performance was assessed using the Morris water maze (MWM), and subsequently, the animals were euthanized for brain morphological analysis using stereological methods. In addition, we performed immunofluorescence and polymerase chain reaction (PCR) analyses to identify HUCBC in the rat brain 7 days after transplantation. The MWM test showed a significant spatial memory recovery at the highest HUCBC dose compared with HI+vehicle rats (P<0.05). Furthermore, the brain atrophy was also significantly lower in the HI+medium- and high-dose groups compared with the HI+vehicle animals (P<0.01; 0.001, respectively). In addition, HUCBC were demonstrated to be localized in host brains by immunohistochemistry and PCR analyses 7 days after intravenous administration. These results revealed that HUCBC transplantation has the dose-dependent potential to promote robust tissue repair and stable cognitive improvement after HI brain injury. PMID- 22441036 TI - Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. AB - The objective of the present study was to assess the neuroprotective role of rutin (vitamin P) and delineate the mechanism of action. Recent evidence indicates that rutin exhibits antioxidant potential and protects the brain against various oxidative stressors. More precisely, the aim of the present study was to examine the modulating impacts of rutin against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ)-infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), whereas sham rats received the same volume of vehicle. After 2 weeks of streptozotocin (STZ) infusion, rats were tested for cognitive performance using Morris water maze tasks and thereafter euthanized for further biochemical, histopathological, and immunohistochemical studies. Rutin pretreatment (25 mg/kg, orally, once daily for 3 weeks) significantly attenuated thiobarbituric acid reactive substances (TBARS), activity of poly ADP-ribosyl polymerase, and nitrite level and decreased level of reduced glutathione (GSH) and activities of its dependent enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and catalase in the hippocampus of ICV-STZ rats. ICV-STZ rats showed significant cognitive deficits, which was improved significantly by rutin supplementation. The results indicate that rutin attenuates STZ-induced inflammation by reducing the expression of cyclooxygenase-2 (COX-2), glial fibrillary acidic protein (GFAP), interleukin-8 (IL-8), inducible nitric oxide synthase (iNOS), nuclear factor-kB, and preventing the morphological changes in hippocampus. The study thereby suggests the effectiveness of rutin in preventing cognitive deficits and might be beneficial for the treatment of sporadic dementia of Alzheimer type (SDAT). PMID- 22441037 TI - The anatomical identification of saccadic omnipause neurons in the rat brainstem. AB - Omnipause neurons (OPNs) represent a crucial component for the generation of saccadic eye movements. They inhibit saccadic premotor neurons in the paramedian pontine reticular formation (PPRF) as well as in the rostral interstitial nucleus of the medial longitudinal fascicle (RIMLF) during the intersaccadic interval. In turn, inhibition of OPNs is a prerequisite in order to generate saccadic eye movements. Although the anatomy of the saccadic system including the OPNs has been extensively studied in primates and cats, no detailed anatomical description of these neurons in rats has been performed so far. The aim of the present study was the identification of putative OPNs in the rat brainstem based on their projection target, localization, and histochemical characteristics. Stereotactic tract-tracer injections into the rostral mesencephalon including the RIMLF in rat resulted in back-labeling of a neuron group adjacent to the midline at the level of traversing fibers of the abducens nerve, which are considered as OPNs lying in the nucleus raphe interpositus. Combined immunohistochemical staining for various markers revealed in these neurons the expression of parvalbumin, chondroitin sulfate proteoglycan, and glycine, but a lack of serotonin. The results of our study demonstrate the striking similarity between individual elements of the premotor saccadic network in rats and primates. The exact knowledge of their location in rats provides a basis for in vitro studies of the OPNs in rat brainstem slices. PMID- 22441039 TI - Arbitrary visuomotor mapping in the grip-lift task: dissociation of performance deficits in right and left middle cerebral artery stroke. AB - The ability to rapidly establish a memory link between arbitrary sensory cues and goal-directed movements is part of our daily motor repertoire. It is unknown if this ability is affected by middle cerebral artery stroke. Eighteen right-handed subjects with a first unilateral middle cerebral artery stroke were studied while performing a precision grip to lift objects of different weights. In a "no cue" condition, a noninformative neutral visual stimulus was presented before each lift, thereby not allowing any judgment about the object weight. In a "cue" condition arbitrary color cues provided advance information about the weight to be lifted in the subsequent trial. Subjects performed both conditions with either hand. During "no cue" trials subjects scaled their grip force according to the weight of the preceding lift, irrespective of the hand performing the lift or the hemisphere affected. The presentation of color cues allowed patients with right hemispheric stroke, but not those with left hemispheric stroke, to scale their grip force according to the weight in the upcoming lift when lifting the weight with the unaffected hand. Color cues did not allow for a predictive scaling of grip force according to the weight of the object to be lifted when lifting with the affected hand, irrespective of the affected hemisphere. These data imply that the ability of visuomotor mapping in the grip-lift task is selectively impaired in the affected hand after right middle cerebral artery stroke, but in both hands after left middle cerebral artery stroke. PMID- 22441038 TI - Postnatal development of Na(+)-K(+)-2Cl(-) co-transporter 1 and K(+)-Cl(-) co transporter 2 immunoreactivity in multiple brain stem respiratory nuclei of the rat. AB - Previously, we reported that in rats, GABA(A) and glycine receptor immunoreactivity increased markedly in multiple brain stem respiratory nuclei around postnatal days (P) 12-13, a critical period when abrupt neurochemical, metabolic, ventilatory, and electrophysiological changes occur in the respiratory network and when the system is under greater inhibition than excitation. Since Na(+)-K(+)-2Cl(-) co-transporter 1 (NKCC1) and K(+)-Cl(-) co-transporter 2 (KCC2) play pivotal roles in determining the responses of GABA(A) and glycine receptors, we hypothesized that NKCC1 and KCC2 undergo significant changes during the critical period. An in-depth immunohistochemical and single neuron optical densitometric study of neurons in seven respiratory-related nuclei (the pre Botzinger complex [PBC], nucleus ambiguus [Amb], hypoglossal nucleus [XII], ventrolateral subnucleus of solitary tract nucleus [NTS(VL)], retrotrapezoid nucleus/parafacial respiratory group [retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG)], dorsal motor nucleus of the vagus nerve [dorsal motor nucleus of the vagus nerve (DMNX)], and inferior olivary nucleus [IO]) and a non-respiratory cuneate nucleus (CN, an internal control) was undertaken in P0 P21 rats. Our data revealed that (1) NKCC1 immunoreactivity exhibited a developmental decrease from P0 to P21 in all eight nuclei examined, being relatively high during the first 11/2 postnatal weeks and decreased thereafter. The decrease was abrupt and statistically significant at P12 in the PBC, Amb, and XII; (2) KCC2 immunoreactivity in these eight nuclei showed a developmental increase from P0 to P21; and (3) the significant reduction in NKCC1 and the greater dominance of KCC2 around P12 in multiple respiratory nuclei of the brain stem may form the basis of an enhanced inhibition in the respiratory network during the critical period before the system stabilizes to a more mature state. PMID- 22441040 TI - 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor mRNA modulation by antidepressant treatment in the chronic mild stress model of depression: sex differences exposed. AB - It is well established that women experience major depression at roughly twice the rate of men. Interestingly, accumulating clinical and experimental evidence shows that the responsiveness of males and females to antidepressant pharmacotherapy, and particularly to tricyclic antidepressants (TCAs), is sex differentiated. Herein, we investigated whether exposure of male and female rats to the chronic mild stress (CMS) model of depression, as well as treatment with the TCA clomipramine may affect serotonergic receptors' (5-HTRs) mRNA expression in a sex-dependent manner. Male and female rats were subjected to CMS for 4 weeks and during the next 4 weeks they concurrently received clomipramine treatment (10 mg/ml/kg). CMS and clomipramine's effects on 5-HT(1A)R, 5-HT(2A)R, and 5-HT(2C)R mRNA expression were assessed by in situ hybridization histochemistry in selected subfields of the hippocampus and in the lateral orbitofrontal cortex (OFC), two regions implicated in the pathophysiology of major depression. CMS and clomipramine treatment induced sex-differentiated effects on rats' hedonic status and enhanced 5-HT(1A)R mRNA expression in the cornu ammonis 1 (CA1) hippocampal region of male rats. Additionally, CMS attenuated 5-HT(1A)R mRNA expression in the OFC of male rats and clomipramine reversed this effect. Moreover, 5-HT(2A)R mRNA levels in the OFC were enhanced in females but decreased in males, while clomipramine reversed this effect only in females. CMS increased 5-HT2CR mRNA expression in the CA4 region of both sexes and this effect was attenuated by clomipramine. Present data exposed that both CMS and clomipramine treatment may induce sex-differentiated and region-distinctive effects on 5-HTRs mRNA expression and further implicate the serotonergic system in the manifestation of sexually dimorphic neurobehavioral responses to stress. PMID- 22441041 TI - SNARE-dependent upregulation of potassium chloride co-transporter 2 activity after metabotropic zinc receptor activation in rat cortical neurons in vitro. AB - The major outward chloride transporter in neurons is the potassium chloride co transporter 2 (KCC2), critical for maintaining an inhibitory reversal potential for GABA(A) receptor channels. In a recent study, we showed that Zn(2+) regulates GABA(A) reversal potentials in the hippocampus by enhancing the activity of KCC2 through an increase in its surface expression. Zn(2+) initiates this process by activating the Gq-coupled metabotropic Zn(2+) receptor/G protein-linked receptor 39 (mZnR/GPR39). Here, we first demonstrated that mZnR/GPR39 is functional in cortical neurons in culture, and then tested the hypothesis that the increase in KCC2 activity is mediated through a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent process. We established the presence of functional mZnR in rat cultured cortical neurons by loading cells with a Ca(2+) indicator and exposing cells to Zn(2+), which triggered consistent Ca(2+) responses that were blocked by the Gq antagonist YM-254890, but not by the metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4 carboxyphenylglycine (MCPG). Importantly, Zn(2+) treatment under these conditions did not increase the intracellular concentrations of Zn(2+) itself. We then measured KCC2 activity by monitoring both the rate and relative amount of furosemide-sensitive NH(4)(+) influx through the co-transporter using an intracellular pH-sensitive fluorescent indicator. We observed that Zn(2+) pretreatment induced a Ca(2+)-dependent increase in KCC2 activity. The effects of Zn(2+) on KCC2 activity were also observed in wild-type mouse cortical neurons in culture, but not in neurons obtained from mZnR/GPR39(-/-) mice, suggesting that Zn(2+) acts through mZnR/GPR39 activation to upregulate KCC2 activity. We next transfected rat cortical neurons with a plasmid encoding botulinum toxin C1 (Botox C1), which cleaves the SNARE proteins syntaxin 1 and synaptosomal associated protein 25 (SNAP-25). Basal KCC2 activity was similar in both transfected and non-transfected neurons. Non-transfected cells, or cells transfected with marker vector alone, showed a Zn(2+)-dependent increase in KCC2 activity. In contrast, KCC2 activity in neurons expressing Botox C1 was unchanged by Zn(2+). These results suggest that SNARE proteins are necessary for the increased activity of KCC2 after Zn(2+) stimulation of mZnR/GPR39. PMID- 22441042 TI - Smilagenin attenuates beta amyloid (25-35)-induced degeneration of neuronal cells via stimulating the gene expression of brain-derived neurotrophic factor. AB - The development of drugs that attenuate neurodegeneration is important for the treatment of Alzheimer's disease (AD). We previously found that smilagenin (SMI), a steroidal sapogenin from traditional Chinese medicinal herbs improves memory in animal models, is neither a cholinesterase inhibitor nor a glutamate receptor antagonist, but can significantly elevate the declined muscarinic receptor (M receptor) density. In this article, to clarify whether SMI represents a new approach for treating neurodegeneration disease, we first demonstrate that SMI pretreatment significantly attenuates the neurodegenerative changes induced by beta amyloid 25-35 (Abeta(25-35)) in cultured rat cortical neurons, including decreased cholinergic neuron number, shortened neurite outgrowth length, and declined M receptor density. Brain-derived neurotrophic factor (BDNF) protein levels in the culture medium were also decreased by Abeta(25-35) and significantly elevated by SMI. Parallel experiments revealed that when the trk receptors were inhibited by K252a or the action of BDNF was inhibited by a neutralizing anti-BDNF antibody, the effects of SMI on the Abeta(25-35)-induced neurodegeneration in rat cortical neurons were almost completely abolished. In the all-trans retinoic acid (RA)-differentiated SH-SY5Y neuroblastoma cells, the BDNF transcription rate measured by a nuclear run-on assay was significantly suppressed by Abeta(25-35) and elevated by SMI, but the BDNF degradation rate measured by half-life determination was unchanged by Abeta(25-35) and SMI. Transcript analysis of the SH-SY5Y cells using quantitative RT-PCR (qRT-PCR) showed that the IV and VI transcripts of BDNF mRNA were significantly decreased by Abeta(25-35) and elevated by SMI. Taken together, we conclude that SMI attenuates Abeta(25-35)-induced neurodegeneration in cultured rat cortical neurons and SH-SY5Y cells mainly through stimulating BDNF mRNA transcription implicating that SMI may represent a novel therapeutic strategy for AD. PMID- 22441043 TI - The literature review: discursive prose. PMID- 22441047 TI - 2012 financial outlook: physicians and podiatrists. AB - Although the nationally unadjusted average Medicare allowable rates have not increased or decreased significantly, the new codes, the new coding regulations, the NCCI edits, and the Medicare contractors' local coverage determinations (LCDs) will greatly impact physicians' and podiatrists' revenue in 2012. Therefore, every wound care physician and podiatrist should take the time to update their charge sheets and their data entry systems with correct codes, units, and appropriate charges (that account for all the resources needed to perform each service or procedure). They should carefully read the LCDs that are pertinent to the work they perform. If the LCDs contain language that is unclear or incorrect, physicians and podiatrists should contact the Medicare contractor medical director and request a revision through the LCD Reconsideration Process. Medicare has stabilized the MPFS allowable rates for 2012-now physicians and podiatrists must do their part to implement the new coding, payment, and coverage regulations. To be sure that the entire revenue process is working properly, physicians and podiatrists should conduct quarterly, if not monthly, audits of their revenue cycle. Healthcare providers will maintain a healthy revenue cycle by conducting internal audits before outside auditors conduct audits that result in repayments that could have been prevented. PMID- 22441048 TI - Financial impact of improved pressure ulcer staging in the acute hospital with use of a new tool, the NE1 Wound Assessment Tool. AB - OBJECTIVE: The NE1 Wound Assessment Tool (NE1 WAT; Medline Industries, Inc, Mundelein, Illinois), previously called the N.E. One Can Stage, was shown to significantly improve accuracy of pressure ulcer (PrU) staging. Improved PrU staging has many potential benefits, including improved care for the patient and better reimbursement. Medicare has incentivized good care and accurate identification of PrUs in the acute care hospital through an additional payment, the Medicare Severity-Diagnosis Related Group (MS-DRG). This article examines the financial impact of NE1 WAT use on the acute care hospital relative to MS-DRG reimbursement. DESIGN: PrU staging accuracy with and without use of the NE1 WAT from previous data was compared with acute care hospital PrU rates obtained from the 2006 National Inpatient Sample. Hill-Rom International Pressure Ulcer Prevalence Survey data were used to estimate the number of MS-DRG-eligible PrUs. MAIN RESULTS: There are between 390,000 and 130,000 MS-DRG-eligible PrUs annually. Given current PrU staging accuracy, approximately $209 million in MS DRG money is being collected. With the improved staging afforded by the NE1 WAT, this figure is approximately $763.9 million. Subtracting the 2 reveals $554.9 million in additional reimbursement that could be generated by using the NE1 WAT. CONCLUSION: There is a tremendous financial incentive to improve PrU staging. The NE1 WAT has been shown to improve PrU staging accuracy significantly. This improvement has the potential to improve the financial health of acute care hospitals caring for patients with PrUs. PMID- 22441049 TI - Comprehensive programs for preventing pressure ulcers: a review of the literature. AB - OBJECTIVE: The objective of this study was to examine the evidence supporting the combined use of interventions to prevent pressure ulcers (PrUs) in acute care and long-term-care facilities. DESIGN: A systematic review of the literature describing multifaceted PrU prevention programs was performed. Articles were included if they described an intervention implemented in acute care settings or long-term-care facilities, incorporated more than 1 intervention component, involved a multidisciplinary team, and included information about outcomes related to the intervention. MAIN RESULTS: Twenty-four studies were identified. Recurring components used in the development and implementation of PrU prevention programs included preparations prior to the start of a program, PrU prevention best practices, staff education, clinical monitoring and feedback, skin care champions, and cues to action. Ten studies reported PrU prevalence rates; 9 of them reported decreased prevalence rates at the end of their programs. Of the 6 studies reporting PrU incidence rates, 5 reported a decrease in incidence rates. Four studies measured care processes: 1 study reported an overall improvement; 2 studies reported improvement on some, but not all, measures; and 1 study reported no change. CONCLUSIONS: There is a growing literature describing multipronged, multidisciplinary interventions to prevent PrUs in acute care settings and long term-care facilities. Outcomes reported in these studies suggest that such programs can be successful in reducing PrU prevalence or incidence rates. However, to strengthen the level of evidence, sites should be encouraged to rigorously evaluate their programs and to publish their results. PMID- 22441051 TI - Checklist for improved wound outcomes (with a focus on pressure ulcers): part 2. PMID- 22441052 TI - Quantitative high-field diffusion tensor imaging of cerebral white matter in asymptomatic high-grade internal carotid artery stenosis. AB - BACKGROUND: Recently, several studies using diffusion-sensitized MRI reported changes in patients with high-grade internal carotid artery stenosis (ICAS) suggestive of subtle brain tissue damage. We used diffusion tensor imaging (DTI) to investigate the microstructural cerebral white matter integrity in asymptomatic patients with high-grade ICAS. METHODS: In 15 asymptomatic patients with unilateral high grade (>70%) ICAS, we used 3T MRI including DTI. We used a region-of-interest approach comparing quantitative DTI metrics between both hemispheres including the so-called border zones. MR images were also assessed for periventricular white matter lesions (PWML) as well as collaterals via the circle of Willis. RESULTS: There was no significant intraindividual difference of fractional anisotropy or mean diffusivity values between the hemispheres for any region. PWML was graded 0 degrees in 6 patients, I degrees in 9 and II degrees in 2. CONCLUSIONS: In clinically asymptomatic patients with high-grade unilateral ICAS, there was no difference between the DTI parameters of the affected and the unaffected hemisphere. These findings contrast with other studies in asymptomatic high-grade ICAS, which is likely due to patient selection. These findings argue against concomitant chronic tissue integrity changes and implicate the benignity of asymptomatic carotid artery disease in individual patients. PMID- 22441053 TI - Post-synthesis dispersion of metal nanoparticles by poly(amidoamine) dendrimers: size-selective inclusion, water solubilization, and improved catalytic performance. AB - Intermetallic Pt(3)Ti nanoparticles are solubilized in water by using a generation-five, hydroxyl-terminated, poly(amidoamine) dendrimer, G5OH, as a post synthesis surfactant. Pt(3)Ti nanoparticles, encapsulated in G5OH and dispersed over the electrode surface, exhibited a superior catalytic activity toward the electro-reduction reaction of oxygen compared to as-prepared, highly agglomerated nanoparticles. PMID- 22441054 TI - Continuity in transition from paediatric to adult healthcare. PMID- 22441055 TI - Referral for diagnosis: effectiveness not activity or expediency is a priority. PMID- 22441056 TI - Short-stay, specialist beds in a UK teaching hospital as a model to integrate palliative care into the acute hospital culture. AB - Hospital patients should have access to effective palliative care. In our study, three short-stay beds were re-allocated to specialist palliative care as part of a pilot programme. This paper describes the first 100 admissions of patients with inadequately controlled symptoms or distress. Median pain and distress scores were both seven out of a maximum of 10 (interquartile ranges [IQR] 4-10 and 1-10 respectively), reducing to 3.5 (IQR 1-5) and 0 (0-5) after 48 hours. Median length of stay was five days (IQR 3-10); 77% of patients were discharged: 32% to home, 26% to a hospice or community hospital, 19% to their original ward for treatment and 23% died in the unit. A unit education programme introduced as part of the study attracted 600 staff members. Pain and distress were rapidly improved by brief, intense palliative care in a small onsite facility. The pilot programme also influenced the understanding of palliative care in the hospital, demonstrating what it offered patients, family and staff. It demonstrated effective, concurrent working alongside an active disease-management approach, and encouraged collaborative discussions about the goals of care. PMID- 22441057 TI - A survey of Core Medical Trainees' opinions on the ePortfolio record of educational activities: beneficial and cost-effective? AB - OBJECTIVES: To evaluate Core Medical Trainees' (CMTs) opinions on the role of the ePortfolio in postgraduate education. DESIGN AND SETTING: Cross-sectional survey of 91 CMTs in five NHS trusts within the South Thames Deanery. PARTICIPANTS: Completed surveys were received from 80 Core Medical Trainees. RESULTS: A total of 84% agreed that an ongoing record of progress is necessary, only 5% felt the ePortfolio represents value for money; 78% of respondents were unclear as to how the Freedom of Information Act (2000) impacts on the ePortfolio, and most were uninformed of the extent to which their entries can be accessed by third parties. CONCLUSIONS: Trainees recognise the importance of recording ongoing progress, but most consider the ePortfolio to be poor value for money. There is uncertainty regarding ownership of information held on ePortfolio, and to what extent it can be accessed. There are inadequate opportunities to discuss concerns. This requires further deliberation and until things are clarified, trainees may not fully engage with the resource. PMID- 22441058 TI - Reducing co-administration of clopidogrel and proton pump inhibitors in acute coronary syndromes. AB - BACKGROUND: Recent concerns about clopidogrel and proton pump inhibitor (PPI) co administration in patients following an acute coronary syndrome (ACS) led us to investigate our practice. Guidance recommends that omeprazole and esomeprazole should not be co-administered with clopidogrel as they can decrease its efficacy. Pantoprazole and lansoprazole are safer for use in these cases. METHODS: Patients discharged between August 2008 and July 2009 with a diagnosis of ACS, on both clopidogrel and any PPI, were identified using the pharmacy database. Their notes were retrospectively reviewed, the indication for a PPI was checked and whether an appropriate one had been prescribed was assessed. As a result of our findings a simple algorithm was introduced to set out guidance on appropriate use and junior doctors were informed of the new procedure. We then performed another audit of patients discharged between August 2009 and February 2010 to ensure that the guidelines were being followed. RESULTS: During the first phase of the audit 43 out of 91 patients (47.5%) received a PPI with clopidogrel. Following our intervention, re-auditing confirmed that clopidogrel and PPI co-administration had decreased significantly to 27 out of 101 patients (26.7%) (p = 0.018). CONCLUSIONS: Through a simple intervention with an algorithm and education of junior doctors we have shown that significant improvement and adherence to guidance can be achieved. PMID- 22441059 TI - Digital gangrene in a patient with primary Raynaud's phenomenon. AB - Digital gangrene is not usually associated with primary Raynaud's phenomenon (RP). Its presence should therefore alert the healthcare provider to look for an alternative explanation. A 19-year-old female patient with primary RP developed digital gangrene following surgical management of acute paronychia. The possible mechanism in this patient appears to be the augmentation of the vasoconstrictive response due to the local infiltration of epinephrine mixed with lignocaine prior to the incision and drainage of her infected finger. PMID- 22441060 TI - Malignant mesothelioma presenting as a breast mass. AB - We present a case of a male patient with a breast mass, found to be a malignant mesothelioma. We discuss the diagnostic challenges, the need for heightened awareness in suspected cases, the histological classification of mesotheliomas and the treatments available. We believe this to be the second reported case of a mesothelioma presenting as a breast mass. PMID- 22441061 TI - Growth hormone for short children--whom should we be treating and why? AB - The objective of this paper was to determine systematically the impact of growth hormone (GH)therapy on adult height of children with (so-called) 'idiopathic short stature' (ISS) using the Cochrane Central Register of Controlled Trials, Medline, and the bibliographic references from retrieved articles of randomised controlled trials (RCTs) and non-RCTs from 1985 to April 2010. Inclusion criteria were initial short stature (defined as height >2 standard deviation[SD] below the mean), peak growth hormone responses>10 micrograms per litre (MUg/L), prepuberty, no previous growth hormone therapy, and no comorbid conditions that would impair growth. Data extracted were adult height and overall gain in height from baseline measurement in childhood.Three RCTs (115 children) met the inclusion criteria.The adult height of the GH treated children exceeded that of the controls by 0.65 SD score (~4 cm). The mean height gain in treated children was 1.2 SD score compared with 0.34 SD score in untreated children. A difference of ~1.2 cm in adult height was observed between two GH dose regimens. In the seven non-RCTs, adult height of the GH-treated group exceeded that of controls by 0.45 SD score (~3 cm).The authors conclude that 1) GH therapy in children with ISS seems effective in partially reducing the deficit in height as adults, although less so than in other conditions for which GH is licensed; treated individuals remain relatively short compared with normal height peers. 2)Individual responses to therapy are highly variable; further studies are needed to identify responders. 3) High quality evidence from long-term RCTs of GH therapy that continue until adult height is necessary to determine the ideal dosage and long-term safety. PMID- 22441062 TI - RCPE UK Consensus Conference on 'approaching the comprehensive management of atrial fibrillation: evolution or revolution?'. PMID- 22441063 TI - Should we be giving high concentration oxygen to all patients treated in an ambulance? AB - Oxygen is one of the most widely used drugs. It is important to recognise that oxygen administration carries risks as well as benefits. While adequate oxygen saturation of arterial blood is an important factor in tissue oxygen delivery, oxygen administration to patients with chronic obstructive pulmonary disease can lead to decompensated type II respiratory failure. In this debate, Dr Lavery makes the case that high concentration oxygen should be given to all patients treated in an ambulance, while Professor Corris argues against this position. PMID- 22441064 TI - Fever in the returning traveller. AB - International travel is increasing and a significant number of travellers will develop a febrile illness during or shortly after their return from the tropics. The differential diagnosis is broad and a systematic approach to the management of these patients is required in order to establish the diagnosis and to initiate prompt and effective treatment. Fever may be due to infectious agents found only in tropical countries, or due to infections unrelated to travel and found worldwide. Important infections that should be considered in all returning travellers include malaria, dengue, enteric fever, rickettsial infections, and HIV seroconversion. Other diagnoses will be considered after a detailed history including countries visited with dates, activities undertaken and symptoms. At a minimum, all travellers from countries where there is malaria transmission should be tested repeatedly for malaria as well as having several sets of blood cultures taken. Many tropical infections are diagnosed serologically at specialist reference laboratories. Specialist advice on the investigation and management of returning travellers should be sought from infectious diseases physicians and microbiologists. Patients with malaria or enteric fever may deteriorate rapidly and travellers should be advised to seek prompt medical attention if they become unwell after travel to the tropics. This review will focus on some of the more important imported infections, diagnostic clues from the history, examination and investigations, and important considerations in their management. PMID- 22441065 TI - Schistosomiasis. AB - Human schistosomiasis is a common blood fluke infection in the tropics and subtropics. The organism requires a specific fresh water snail intermediate as host and this determines its geographical distribution. Humans become infected following water exposure, with rural communities and children having the highest burden of disease. Travellers to areas of high endemicity are at risk of infection as they frequently engage in pursuits that expose them to fresh water. Disease manifestations range from acute hypersensitivity reactions to chronic illness with intestinal, hepatic and bladder disease. Infection can often be asymptomatic and travellers to endemic areas should be screened for schistosomiasis after return. Treatment is highly effective, even in advanced disease, and the diagnosis should be considered in individuals with possible clinical illness who have travelled to or lived in endemic areas. PMID- 22441066 TI - Is the warfarin saga over? AB - Warfarin is the most widely used oral anticoagulant and has been available for more than 65 years. The last decade has brought a host of new orally available anticoagulants with promising features to clinical trials and some have already been approved for limited indications. As patients are starting to be switched to these new agents there is a need to gain understanding of the subsets of patients that will benefit the most from the new alternatives and whether warfarin is still the best choice for some subpopulations. With this knowledge we will provide the individual patient with the drug that has the best benefit/risk ratio at the same time as we conserve drug expenditures. This review discusses the directions we could follow in such a tailored anticoagulation approach, referring to the limited evidence when available. PMID- 22441067 TI - The evolution of human skin colouration and its relevance to health in the modern world. AB - Functionally naked skin which comes in a range of colours is unique to the human species. This review summarises current evidence pertaining to the evolution of these attributes. The biggest changes in the integument occurred during the course of human evolution in equatorial Africa, under regimes of high daytime temperatures and high ultraviolet radiation (UVR). Loss of most functional body hair was accompanied by the evolution of an epidermis with a specialised stratum corneum and permanent, protective, eumelanin pigmentation. The main reason for the evolution of dark pigmentation was to protect against folate deficiency caused by elevated demands for folate in cell division, DNA repair, and melanogenesis stimulated by UVR. Dispersal out of tropical Africa created new challenges for human physiology especially because of lower and more seasonal levels of UVR and ultraviolet B (UVB) outside of the tropics. In these environments, the challenge of producing a vitamin D precursor in the skin from available UVB was met by natural selection acting on mutations capable of producing varying degrees of depigmentation. The range of pigmentation observed in modern humans today is, thus, the product of two opposing clines, one favoring photoprotection near the equator, the other favoring vitamin D photosynthesis nearer the poles. Recent migrations and changes in lifestyle in the last 500 years have brought many humans into UVR regimes different from those experienced by their ancestors and, accordingly, exposed them to new disease risks, including skin cancer and vitamin D deficiency. PMID- 22441068 TI - Organ donation - are we prepared for the future challenges? PMID- 22441069 TI - Tayside's contribution to the early development of cardiology. AB - This paper gives a brief account of how doctors who were either native to or actively working in Tayside helped to shape the early development of cardiology. It exemplifies how important contributions to the understanding and practice of medicine can be made by an exceptional individual or an inspired team, no matter how unlikely the initial setting for their work might appear. The remarkable role that Sir James Mackenzie played in the understanding and fostering of this speciality in its infancy is outlined. The paper also describes the transformation of Dundee Royal Infirmary's meagre facilities after the Second World War into a dynamic centre of excellence in cardiology services in the 1960s, becoming in effect a prototype for the highly acclaimed 'embedding' of clinical care, teaching and research at the new Ninewells Hospital and Medical School in Dundee. PMID- 22441070 TI - Promise cut short: the career of William Anderson. AB - This paper traces the career of William Anderson, naval surgeon and naturalist, who served in Cook's ship Resolution on the second and final voyages, and died of tuberculosis high in the Arctic. PMID- 22441071 TI - Daniel Carrion's experiment: the use of self-infection in the advance of medicine. AB - In 1885, Daniel Carrion (1857-1885), a young Peruvian medical student, was trying to establish the prodromal symptoms of 'verruga disease', an infectious disease rare outside South America but endemic in parts of Peru. As part of this investigation he was inoculated with fluid from a verruga lesion from a patient with the chronic form of the disease. He recorded the clinical features which developed, including fever, malaise, arthralgia, vomiting and anaemia, and it became apparent that he had developed the anaemic, febrile, acute phase of the illness (known as Oroya fever). This did not however progress in his case to the chronic form of the disease, and he died a few weeks later on 5 October 1885. His sacrifice served to establish, supposedly, that Oroya fever and verruga disease had a common aetiology and his death stimulated further research into the cause, now established as the bacterium Bartonella bacilliformis. Carrion is considered a martyr of Peruvian medicine and 5 October has been designated Peruvian Medicine Day in his honour. PMID- 22441072 TI - James Hutton's Theory of the Earth..., 1785. PMID- 22441073 TI - A reappraisal of Benjamin Bell (1749-1806). PMID- 22441074 TI - Central pontine myelinolysis without hyponatraemia. PMID- 22441075 TI - The understanding of angina pectoris in the pre-surgical period. PMID- 22441076 TI - Non-tuberculous mycobacterial infections in the Scottish Borders. PMID- 22441077 TI - Should we be giving enhanced vitamin D intakes to all? PMID- 22441078 TI - Gene-TEQ--a standardized comparative assessment of effects in the comet assay using genotoxicity equivalents. AB - Existing methods for the comparison of genotoxic effects in the comet assay bear considerable disadvantages such as the problem to link information about concentration dependence and severity of effects. Moreover, given the lack of standardized protocols and the use of various standards, it may be extremely difficult to compare different studies. In order to provide a method for standardized comparative assessment of genotoxic effects, the concept of genotoxicity equivalents (Gene-TEQ) was developed. As potential reference compounds for genotoxic effects, three directly acting (N-methyl-N'-nitro-N nitrosoguanidine (MNNG), methyl-methanesulfonate, and N-methyl-N-nitrosourea) and three indirectly acting (cyclophosphamide, dimethylnitrosamine, and 4 nitroquinoline-oxide) genotoxic substances were compared with respect to their cytotoxic (neutral red) and genotoxic (comet assay) concentration-response profiles in the permanent fish cell line RTL-W1. For further comparison, two sediment extracts from the upper Danube River were investigated as environmental samples. Based on the results of cytotoxicity and genotoxicity testing, MNNG was selected as the reference compound. At several exposure levels and durations, genotoxic effects of both the other pure substances and the environmental samples were calculated as percentages of the maximum MNNG effect and related to the absolute MNNG effect (EC values). Thus, genotoxicity equivalent factors (Gene TEQs) relative to MNNG could be calculated. Gene-TEQs can easily be applied to pure substances, mixtures and field samples to provide information about their toxicity relative to the reference compound. Furthermore, the Gene-TEQ concept allows a direct comparison of environmental samples from different laboratories. PMID- 22441079 TI - In the forefront. PMID- 22441080 TI - Lessons from Dr Strangelove. PMID- 22441081 TI - A time has come for wilderness emergency medical service: a new direction. PMID- 22441082 TI - Nifedipine for the treatment of high altitude pulmonary edema. AB - OBJECTIVE: The purpose of this study was to assess the risk factors, patient profile, clinical features, and oral nifedipine as a treatment option for a series of 110 patients with high altitude pulmonary edema (HAPE) in a military hospital in India. METHODS: This was a prospective cross-sectional study in a military hospital. In all, 110 patients with HAPE admitted and treated over a period of 3 years are reported. The following measurements were noted: dyspnea, cough, chest pain, cyanosis, pulse rate, blood pressure, respiratory rate, crepitations, radiographic abnormalities, electrocardiogram, peripheral pulse oximetry (Spo(2)) at admission, Spo(2) normalization time, total leukocyte count, and length of hospital stay. RESULTS: The risk factors identified for development of HAPE in our patients were improper acclimatization/faster rates of ascent, higher defined height (10 500 feet [3200 m]) for first stage acclimatization due to logistic reasons (usually 9000 feet [2743 m]), cold exposure, severe exercise, and respiratory infection. All patients were treated with reduction of altitude, supplemental oxygen therapy with nasal prongs, and bed rest. Oral nifedipine or placebo was administered to alternating patients. None of the patients deteriorated during their hospital stay, and all recovered fully to be discharged an average of 4.01 days (range 2-6 days) after admission. Patients were monitored for time taken for normalization of oxygen saturation, duration of hospital stay, time needed for resolution of lung crepitations, and radiographic infiltrates. Nifedipine administration was not found to be better than placebo for any of these variables (P > .05). CONCLUSIONS: Improper acclimatization remains the foremost risk factor for HAPE. In addition to descent and supplemental oxygen, nifedipine appears to provide no additional benefit in the resolution of HAPE. PMID- 22441083 TI - Background rates of acute mountain sickness-like symptoms at low altitude in adolescents using Lake Louise score. AB - OBJECTIVE: To record the incidence of symptoms consistent with a diagnosis of acute mountain sickness (AMS), using the Lake Louise questionnaire, in adolescents hiking at low altitude. METHODS: The study was carried out on a cohort of 123 adolescents during a 3-day trip on Dartmoor, UK, at an altitude of less than 500 m. The incidence of symptoms experienced was measured using the Lake Louise questionnaire, which was completed twice daily by each participant. An episode consistent with AMS, but in the low altitude setting, was defined as a score of 3 or more on the Lake Louise questionnaire in the presence of a headache. RESULTS: There were 59 boys and 64 girls in the study with an average age of 16.7 years. The response rate was 100%. A total of 59 episodes of scores consistent with AMS was recorded during the 3-day period. Forty-two of these episodes were reported by girls (71%). AMS scores between 3 and 8 were recorded, and the daily incidence rates of scores consistent with AMS but at low altitude were between 7.3% and 11.3%. CONCLUSIONS: This study shows that adolescents at low altitude reported a background incidence of symptoms that at high altitude would lead to a diagnosis of AMS. PMID- 22441084 TI - Peripheral arterial desaturation is further exacerbated by exercise in adolescents with acute mountain sickness. AB - OBJECTIVE: Rapid ascent to altitude can result in the development of high altitude illnesses such as acute mountain sickness (AMS). This study aimed to investigate AMS symptoms in adolescents and study basic cardiopulmonary measurements at altitude. METHODS: Thirty-eight adolescents aged 16 to 19 years flew to 3500 m from 215 m and continued over a 23-day period to ascend to a maximum altitude of 5200 m. Each member of the expedition completed a Lake Louise Self-Assessment Questionnaire (LLSAQ) on a daily basis, and AMS was defined as a score of >= 3, with an associated headache. Physiology measurements included a step test, and both before and after exercise pulse oximetry, blood pressure, and pulse rate. RESULTS: Oxygen saturation inversely correlated with altitude (P = .001). Mean pulse rate increased from 70 beats/min (+/- 6.5) at 215 m to 83 beats/min (+/- 2.2) at 3500 m (P = .01), and a rise in blood pressure with ascent was highlighted (P = .004). The majority of subjects (84%) had an LLSAQ of 3 or more on at least 1 occasion, and they tended to record higher pulse rates (P = .005) and lower oxygen saturations (P = .001). Exercise-induced drops in oxygen saturation and raised pulse rates were more prolonged in subjects with severe AMS compared with subjects not having AMS (P = .046 and P = .005, respectively). CONCLUSIONS: The LLSAQ scoring system appeared to be a simple and effective technique to aid the diagnosis of adolescents who have AMS, and it may help improve the safety of large groups traveling to altitude. The AMS subjects tended to have low oxygen saturations and high pulse rates, highlighting potential areas for further research. PMID- 22441085 TI - Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia. AB - OBJECTIVE: Alveolar hypoxia as a result of high altitude leads to increased pulmonary arterial pressure. The renin-angiotensin system is involved in the regulation of pulmonary arterial pressure through angiotensin-converting enzyme 2 (ACE2). It remains unknown whether ACE2 administration alters pulmonary vascular pressure in hypoxia. METHODS: We investigated 12 anesthetized pigs instrumented with arterial, central venous, and Swan-Ganz catheters exposed to normobaric hypoxia (fraction of inspired oxygen = 0.125) for 180 minutes. After taking baseline measurements in normoxia and hypoxia, ACE2 400 MUg.kg(-1) was administered to 6 animals, and another 6 served as control. Ventilatory variables, arterial blood gases, ventilation/perfusion (VA/Q) relationships, and plasma angiotensin II concentrations were assessed before and at 30, 90, and 150 minutes in hypoxia after ACE2 or placebo administration. Hemodynamic variables and cardiac output were observed every 30 minutes. RESULTS: We observed lower pulmonary arterial pressure (maximum: 30 vs 39 mm Hg, P < .01) and lower pulmonary vascular resistance (maximum: 4.1 vs 7.5 Wood units, P <.01) in animals treated with ACE2. There was a trend (P =.09) toward lower angiotensin II plasma concentrations among ACE2-treated animals. Cardiac variables and systemic arterial pressure in hypoxia remained unaffected by ACE2. Ventilation/perfusion relationships and Pao(2) did not differ between groups. CONCLUSIONS: In acute pulmonary hypertension, administration of ACE2 blunts the rise in pulmonary arterial pressure that occurs in response to hypoxia. Recombinant ACE2 may be a treatment option for high altitude pulmonary edema and hypoxia-associated pulmonary hypertension. PMID- 22441086 TI - Physiological bone responses in the fingers after more than 10 years of high level sport climbing: analysis of cortical parameters. AB - OBJECTIVE: Sports activity can induce bone modeling processes with apposition of new bone and changes in bone morphology. Sport climbing places extreme forces and stress on the hands, especially on the bones of the fingers. This study examines sports-induced physiological adaptations of the finger bones of climbers. METHODS: In this cohort study, the radiographs of 31 high-level (Union Internationale des Associations d'Alpinisme [UIAA] metric scale range 8.33 to 11.33), experienced (median 20 years climbing time) adult climbers were compared with those of a control group of 67 patients. Cortical dimensions and variables were measured and analyzed in a total of 330 fingers. An association analysis of climbing-related variables was also performed. RESULTS: The climber's bones showed a 25% higher cortical proportion than those of the control group. On average, the outer cortical width of the climbers' bones was 6% larger and the medullary canal was 20% narrower than in the control group (P < .05). The differences between groups were more pronounced in the sagittal plane and more pronounced distally in the fingers. No associations were found between age, climbing experience, climbing level, and the cortical hypertrophy. CONCLUSIONS: Differences in bone morphology can be observed in the finger bones of adult climbers when compared with controls. Because the differences are more pronounced at the palmar and dorsal cortices, the analysis of the sagittal plane should always be included in future investigations. To evaluate climbing-related factors influencing these adaptive morphologic differences, further studies with larger, more specific study cohorts are needed. PMID- 22441087 TI - Medical direction of wilderness and other operational emergency medical services programs. AB - Within a healthcare system, operational emergency medical services (EMS) programs provide prehospital emergency care to patients in austere and resource-limited settings. Some of these programs are additionally considered to be wilderness EMS programs, a specialized type of operational EMS program, as they primarily function in a wilderness setting (eg, wilderness search and rescue, ski patrols, water rescue, beach patrols, and cave rescue). Other operational EMS programs include urban search and rescue, air medical support, and tactical law enforcement response. The medical director will help to ensure that the care provided follows protocols that are in accordance with local and state prehospital standards, while accounting for the unique demands and needs of the environment. The operational EMS medical director should be as qualified as possible for the specific team that is being supervised. The medical director should train and operate with the team frequently to be effective. Adequate provision for compensation, liability, and equipment needs to be addressed for an optimal relationship between the medical director and the team. PMID- 22441088 TI - Novel use of a hemostatic dressing in the management of a bleeding leech bite: a case report and review of the literature. AB - Persistent bleeding from leech bites is a common occurrence, although little evidence is available to guide management. Detailed here is the case of a 30-year old American man who presented with two leech bites after a trek through the jungle in Nepal, one of which continued to briskly ooze blood despite standard wound care. The wound was ultimately treated with QuikClot gauze, which allowed for rapid hemostasis without rebleeding. This case report describes the first use of a hemostatic dressing for this purpose, and reviews what is known about hemostatic agents and about leeches in order to discuss how they make us bleed and what to do when a leech bite occurs. PMID- 22441089 TI - Wolf spider envenomation. AB - Although wolf spider venom has been implicated in necrotic arachnidism without acceptably documented verification, limited, prospectively collected data demonstrate a lack of cutaneous necrosis. The infrequent nature of exposure and inherent difficulty in confirming wolf spider bites in humans makes it challenging to study such envenomations. We present the case of a 20 year-old man with confirmed exposure to the wolf spider who developed cutaneous erythema with ulceration following the bite. There was no evidence of skin necrosis. He was treated with aggressive wound care and systemic antibiotics for wound infection, with subsequent resolution of symptoms. This case adds to the limited knowledge regarding wolf spider envenomations and describes the clinical effects and management of wolf spider envenomation. PMID- 22441090 TI - Managing anaphylaxis in a jungle environment. AB - Anaphylaxis is a medical emergency requiring prompt action to prevent death from cardio-respiratory collapse. It can be a biphasic, unpredictable, and challenging reaction to deal with even in a hospital environment. The wilderness environments afforded by expeditions, remote health posts, and military exercises pose additional challenges often involving casualty evacuation. This article identifies and addresses some of these points using a case report from the Costa Rican jungle. PMID- 22441091 TI - Increasing creatine kinase concentrations at the 161-km Western States Endurance Run. AB - OBJECTIVE: Very high blood creatine kinase (CK) concentrations have been observed among recent finishers of the 161-km Western States Endurance Run (WSER), and it has been suggested that there is a link between rhabdomyolysis and hyponatremia. Therefore, the purpose of this study was to compare CK concentrations of finishers in the 2010 WSER with past values, and to determine whether there was an association between blood CK and sodium concentrations. METHODS: Consenting 2010 WSER finishers provided blood samples at the finish for determination of blood CK and sodium concentrations. Finish time, age, and gender were obtained from official race results, and running experience was determined from our database as number of prior 161-km ultramarathon finishes. RESULTS: From 216 (66%) of the 328 finishers, median and mean CK concentrations were found to be 20 850 IU/L and 32 956 IU/L, respectively (range 1500-264 300 IU/L), and 13 (6%) had values greater than 100 000 IU/L. These values were statistically higher (P < .0001) than those reported from the 1995 WSER. The CK concentration was not significantly associated with finish time, age, gender, or running experience. Blood sodium concentrations were obtained from a subgroup of 159 runners, and the relationship between blood CK and sodium concentrations did not reach statistical significance (P = .06, r = -0.12). CONCLUSIONS: Creatine kinase concentrations of 2010 WSER finishers are higher than values previously reported. More research should focus on explaining this observation and on whether there is a possible link between higher CK concentrations and hyponatremia. PMID- 22441092 TI - Improvised traction splints: a wilderness medicine tool or hindrance? AB - OBJECTIVES: To investigate whether a traction splint made from improvised materials is as efficacious as commercially available devices in terms of traction provided and perceived comfort and stability. METHODS: This was a prospective randomized crossover study utilizing 10 healthy, uninjured volunteers. The subjects were randomized to be placed in 4 different traction devices, in differing order, each for 30 minutes. Three of the traction splints are commercially available: The HARE, Sager, and Faretech CT-EMS. The fourth traction device was an improvised splint made as described in Medicine for the Backcountry: A Practical Guide to Wilderness First Aid. At the end of 30 minutes the pounds of force created by each device was measured. The volunteers were also asked at that time to subjectively report the comfort and stability of the splint separately on a scale from 1 to 10. RESULTS: All traction splints performed similarly with regard to the primary outcome measure of mean pounds of traction created at the end of 30 minutes of application with results ranging from 10.4 to 13.3 pounds. There was little difference reported by participants in regard to stability or comfort between the 4 traction devices. CONCLUSIONS: In this small pilot study, an improvised traction splint was not inferior to commercially available devices. Further research in needed in this area. PMID- 22441093 TI - Homemade thermometry instruments in the field. AB - OBJECTIVE: Esophageal temperature is the gold standard for in-the-field temperature monitoring in hypothermic victims with cardiac arrest. For practical reasons, some mountain rescue teams use homemade esophageal thermometers to measure esophageal temperature; these consist of nonmedical inside/outside temperature monitoring instruments that have been modified to allow for esophageal insertion. We planned a study to determine the accuracy of such thermometers. METHODS: Two of the same model of digital cabled indoor/outdoor thermometer were modified and tested in comparison with a reference thermometer. The thermometers were tested in a water bath at different temperatures between 10 degrees C and 35.2 degrees C. Three hundred measurements were taken with each thermometer. RESULTS: Our experimental study showed that both homemade thermometers provided a good correlation and a clinically acceptable agreement in comparison with the reference thermometer. Measurements were within 0.5 degrees C in comparison with the reference thermometer 97.5% of the time. CONCLUSIONS: The homemade thermometers performed well in vitro, in comparison with a reference thermometer. However, because these devices in their original form are not designed for clinical use, their use should be restricted to situations when the use of a conventional esophageal thermometer is impossible. PMID- 22441094 TI - A rash. PMID- 22441095 TI - Snow blindness and other eye problems during the heroic age of Antarctic exploration. AB - During the heroic age of Antarctic exploration, snow blindness was a common problem, but not all the descriptions of it fit the modern view of the disease, and some of the explorers complained of long-term problems. This article describes the snow blindness and other eye problems that occurred during this era. It also describes how snow blindness was prevented and treated. PMID- 22441096 TI - Wilderness medicine within global health. PMID- 22441097 TI - Wilderness medicine within global health: a strategy for less risk and more reward. PMID- 22441098 TI - Mountain clothing and thermoregulation: a look back. PMID- 22441099 TI - Utilizing avalanche safety equipment to prevent snow immersion asphyxiation revisited. PMID- 22441100 TI - Synthesis of monodisperse mesoporous TiO2 spheres with tunable sizes between 0.6 and 3.1 MUm and effects of reaction temperature, Ti source purity, and type of alkylamine on size and monodispersity. AB - We report a novel method for synthesizing monodisperse mesoporous TiO(2) spheres (sizes = 0.6-3.1 MUm) by hydrolysis of titanium isopropoxide (TIP) in a mixture of C(8)-C(16)n-alkylamine, water, and ethanol. The size increases with decreasing temperature, TIP concentration, and water concentration, and upon purifying TIP. n-Dodecylamine gives the highest monodispersity. PMID- 22441101 TI - Low rate of production of apolipoproteins B100 and AI in 2 patients with Anderson disease (chylomicron retention disease). AB - OBJECTIVE: Anderson disease is a rare inherited lipid malabsorption syndrome associated with hypocholesterolemia and linked to SAR1B mutations. The aim of this article was to analyze the mechanisms responsible for the low plasma apolipoprotein Apo-B100 and Apo-AI in 2 patients with Anderson disease. METHODS AND RESULTS: A primed constant infusion of (13)C-leucine was administered for 14 hours to determine the kinetics of lipoproteins. In the 2 patients, total cholesterol (77 and 85 mg/dL versus 155+/-32 mg/dL), triglycerides (36 and 59 versus 82+/-24 mg/dL), Apo-B100 (48 and 43 versus 71+/-5 mg/dL), and Apo-AI (47 and 62 versus 130+/-7 mg/dL) were lower compared with 6 healthy individuals. Very low-density lipoprotein-B100 production rate of the patients was lower (4.08 and 5.52 mg/kg/day versus 12.96+/-2.88 mg/kg/day) as was the fractional catabolic rate (5.04 and 4.32 day(-1) versus 12.24+/-3.84 day(-1)). No difference was observed in intermediate-density lipoprotein-B100 and LDL-B100 kinetic data. The production rate of high-density lipoprotein Apo-AI was lower in the patients (7.92 and 8.64 versus 11.96+/-1.92 mg/kg/day) and the fractional catabolic rate was higher (0.38 and 0.29 versus 0.22+/-0.01 day(-1)). CONCLUSIONS: The low plasma Apo-B100 and Apo-AI concentrations in the patients with Anderson disease were mainly related to low rates of production. PMID- 22441102 TI - Apolipoprotein E4 domain interaction accelerates diet-induced atherosclerosis in hypomorphic Arg-61 apoe mice. AB - OBJECTIVE: Apolipoprotein (apo) E4 is an established risk factor for atherosclerosis, but the structural components underlying this association remain unclear. ApoE4 is characterized by 2 biophysical properties: domain interaction and molten globule state. Substituting Arg-61 for Thr-61 in mouse apoE introduces domain interaction without molten globule state, allowing us to delineate potential proatherogenic effects of domain interaction in vivo. METHODS AND RESULTS: We studied atherosclerosis susceptibility of hypomorphic Apoe mice expressing either Thr-61 or Arg-61 apoE (ApoeT(h/h) or ApoeR(h/h)mice). On a chow diet, both mouse models were normolipidemic with similar levels of plasma apoE and lipoproteins. However, on a high-cholesterol diet, ApoeR(h/h) mice displayed increased levels of total plasma cholesterol and very-low-density lipoprotein as well as larger atherosclerotic plaques in the aortic root, arch, and descending aorta compared with ApoeT(h/h) mice. In addition, evidence of cellular dysfunction was identified in peritoneal ApoeR(h/h) macrophages which released lower amounts of apoE in culture medium and displayed increased expression of major histocompatibility complex class II molecules. CONCLUSIONS: These data indicate that domain interaction mediates proatherogenic effects of apoE4 in part by modulating lipoprotein metabolism and macrophage biology. Pharmaceutical targeting of domain interaction could lead to new treatments for atherosclerosis in apoE4 individuals. PMID- 22441103 TI - Signalling pathways passing Src in pancreatic endocrine tumours: relevance for possible combined targeted therapies. AB - The most frequent molecular abnormalities in pancreatic endocrine tumours (PETs) are mutations of the MEN1 gene, deregulation of the PI3K/AKT/mTOR signalling pathway and overactivation of growth factors and their receptors, such as the VEGF. On this basis, everolimus (Afinitor(r); Novartis) and sunitinib (Sutent(r); Pfizer) have both been approved by the FDA for the treatment of progressive, unresectable, locally advanced or metastatic PETs. However, molecular or surrogate markers able to predict the response of PET patients to treatment with these drugs are not available, and cancer cells treated with targeted therapies might develop escape pathways that evoke pro-survival feedback responses. The existence of cross-talk between different molecular pathways in PETs has been poorly investigated. In the present review, we present data supporting an important role for Src family kinases (SFKs) in PETs, together with the recent observation of a novel role for SFK in modulating the mTOR pathway activity. Of note, while treatment with everolimus triggered the activation of a survival response dependent on PI3K/AKT signalling in vitro, the simultaneous inhibition of SFKs blocked the activation of this unwanted escape signal. These studies might set the ground for the investigation of combined treatment of PETs with SFK and mTOR inhibitors. PMID- 22441104 TI - Improved efficacy by individualized combination therapy with Peg IFN-a 2a and ADV in HBeAg positive chronic hepatitis B patients. AB - BACKGROUND/AIMS: Monotherapy with pegylated interferon alpha (Peg-IFNa) or adefovir dipivoxil (ADV) to HBeAg-positive chronic hepatitis B (CHB) patients has limited effects. This study aims to evaluate therapeutic efficacy and safety of individualized combination therapy with Peg-IFNa and ADV. METHODOLOGY: HBeAg positive CHB patients (n=160) were enrolled in this multi-center, prospective, randomized, 'real-life' cohort study, of which received Peg IFNa-2a monotherapy or combination therapy with ADV base on the baseline features and treatment response. RESULTS: At week 24, percentages of ALT normalization, HBV DNA undetectable were both higher in individualized treatment group (ITG, 57.50%, 43.75%) than that in standard treatment group (STG, 40.00%, 27.50%; p=0.027, 0.032). The superiority of HBeAg clearance and seroconversion rates in ITG maintained from treatment termination (63.75%, 56.25%) to 48 weeks follow-up (57.50%, 53.75%). At week 96 the combined response rates were 46.25% in ITG compared with 30.00% in STG (p=0.034). Furthermore, there was no statistically significant difference in relapse rates and adverse events between the two groups. CONCLUSIONS: Individualized combination therapy can achieve higher antiviral response rates. In particular, it can accelerate undetectable HBV DNA and elevate HBeAg clearance/seroconversion rates to a greater degree than Peg IFNa-2a monotherapy. PMID- 22441105 TI - A novel SRY mutation leads to asymmetric SOX9 activation and is responsible for mixed 46,XY gonadal dysgenesis. AB - BACKGROUND: SRY, located on the Y chromosome, is one of the key genes involved in human sex determination. SRY mutations are responsible for 10-15% of all cases of 46,XY gonadal dysgenesis (GD) but are rarely implicated in the pathogenesis of mixed GD. METHODS: SRY was analyzed by sequence analysis of DNA extracted from blood leukocytes. SRY activity was evaluated by SOX9 immunostaining, one of the targets of SRY. RESULTS: We report a case of mixed GD due to a novel SRY point mutation in a patient with a 46,XY karyotype, without mosaicism or submicroscopic genomic imbalances. Hormonal studies showed low anti-mullerian hormone and histological examination of the gonads showed a streak gonad on the right side and a left dysgenetic testis, thus permitting the diagnosis of mixed GD. Immunostaining for SOX9, a target of SRY, was positive in nuclei of Sertoli and epididymal cells in the left gonad and negative on the right, thus indicating asymmetric activation of SRY. CONCLUSION: Mixed GD can result from SRY mutations without mosaicism, neither in peripheral blood, nor within the gonads. The asymmetric effect of the point mutation implies the presence of local factors modulating SRY expression or action. PMID- 22441106 TI - Should post-traumatic thoracolumbar Frankel A paraplegia be operated as an emergency? Report of three cases and review of the literature. AB - Spinal cord injury is an important contributing factor to morbidity. The thoracolumbar junction is a highly vulnerable axial region due to the biomechanical stresses and the risk of conus medullaris injuries in some cases. In the event of an incomplete neurological injury and if the patient's condition is stable, emergency surgical treatment should be considered. Yet, no clear consensus has emerged regarding the treatment modalities of complete injuries but surgical management is advocated to maximize neurological recovery and reduce the risk of decubitus ulcer formation. We report on the cases of three patients with L1 Frankel A paraplegia resulting from injury to the conus medullaris, treated within the first 6 hours from injury and demonstrating a very satisfactory neurological recovery since independent walking could be resumed at 2.5 years follow-up. Persistent urinary sphincter dysfunctions were observed in two of these patients. Early surgical management appears as an important predictive factor for neurological recovery in conus medullaris injuries. We believe that delayed surgical management in patients with complete paraplegia could be an inappropriate treatment option, which should be further studied. PMID- 22441107 TI - MicroRNAs in autophagy and their emerging roles in crosstalk with apoptosis. AB - Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved self-degradative process, which involves the regular turnover of cellular components via sequestering damaged macromolecules and transporting them for lysosomal degradation. In the past few years, the scientific community has produced remarkable advances in our understanding of the genes that are involved in autophagy and of their profound effects on various diseases. Recently, a new class of noncoding RNAs, known as microRNAs (miRNAs), has been demonstrated to play crucial roles in diverse biological processes including development, cell differentiation and apoptosis. Here, we review the current understanding about miRNAs focusing on their involvement in the autophagy process. Intriguingly, several confirmed targets of these autophagy-miRNAs are also important regulators in the crosstalk between autophagy and apoptosis. Furthermore, transcripts involved in autophagy and apoptosis may indirectly modulate each other by competing for common miRNA binding sites. Thus, miRNAs potentially work as molecular switches between these two intimately connected processes and contribute to the cell fate decision. PMID- 22441108 TI - Colorectal cancer screening: how to stop a moving target. PMID- 22441109 TI - Prognostic and predictive value of cell cycle deregulation in non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is among the most frequently diagnosed malignancy and a leading cause for cancer mortality worldwide. Despite various efforts, practical prognostic and predictive markers are still few. We review recent findings concerning the cell cycle in NSCLC and discuss prognostic and predictive aspects as well as the challenge of targeted therapeutic approaches. Deregulation of the cell cycle is a common event in NSCLC. Usually, several defects of cell cycle regulation are concomitant and have a cumulative adverse effect on prognosis. Therefore, analysis of a variety of interacting molecules is desirable for adequate deductions. Immunohistochemical interpretations should include the subcellular staining localization, since this can reflect the functional properties of a protein. Overexpression of cyclins, especially D-type cyclins, has repeatedly been associated with poor prognosis in NSCLC. Predictive data is less conclusive; however, loss of the expression of cyclin-dependent kinase inhibitors seems to correlate with sensitivity to antiproliferative drugs. Various inhibitors of Aurora kinases are currently being evaluated regarding their potential as targeted therapies in NSCLC. In conclusion, the cell cycle offers several prognostic, predictive and therapeutic possibilities in NSCLC, many still developmental. Progress in this field has the potential to improve the current scenario for NSCLC patients. PMID- 22441110 TI - Multiphasic perfusion computed tomography as a predictor of collateral flow in acute ischemic stroke: comparison with digital subtraction angiography. AB - BACKGROUND: Assessing collateral status is important in acute ischemic stroke. The purpose of this study was to compare multiphasic perfusion computed tomography (MPCT) with digital subtraction angiography (DSA) in predicting leptomeningeal collateral flow in acute middle cerebral artery (MCA) infarction. METHODS: Consecutive patients underwent MPCT and DSA for acute MCA infarction that presented within 6 h of symptom onset. We included patients who showed MCA occlusion in the same location on both modalities and assessed the agreement rate and correlation between the MPCT and DSA collateral grades. RESULTS: Of 54 patients, 44 (81.5%) had proximal MCA (M1) occlusions and 10 (18.5%) had distal MCA (M2) occlusions based on MPCT and DSA. The kappa-coefficients were 0.87 and 0.81 in the MPCT and DSA collateral grade systems, respectively. Forty-four patients (81.5%) belonged to the same category in both collateral-grading systems. MPCT collateral grades correlated positively with those of DSA (Spearman's correlation coefficient 0.827, p < 0.001). CONCLUSION: Our data show that MPCT can predict leptomeningeal collateral flow in acute ischemic stroke. Based on collateral status assessed by MPCT, different therapeutic approaches might be warranted. PMID- 22441111 TI - Probiotics supplementation increases intestinal blood flow velocity in extremely low birth weight preterm infants. AB - OBJECTIVE: To determine whether probiotics supplementation affects intestinal blood flow velocity in extremely low birth weight neonates. STUDY DESIGN: In this randomized, double-blind, placebo-controlled study, probiotics were added to the first enteral feeding and continued until discharge or 34 weeks postmenstrual age. Pulsed Doppler was used to measure preprandial and postprandial (at 30 and 60 min) time-averaged mean velocity (TAMV), peak systolic velocity (PSV) and end diastolic velocity (EDV) during the second week of life after >= 7 days of probiotics supplementation. RESULT: A total of 31 infants were studied, 15 were randomized to the probiotic and 16 to the placebo groups. There was a significant postprandial increase in TAMV for the probiotic vs the placebo group (P=0.035), with PSV and EDV showing a trend. Demographic and clinical variables were similar between the groups. CONCLUSION: Probiotics administration significantly increases postprandial intestinal blood flow in extremely low birth weight preterm neonates when compared with the placebo group. PMID- 22441112 TI - Outcome and cost analysis of implementing selective Coombs testing in the newborn nursery. AB - OBJECTIVE: (1) To determine whether infants born to O+ mothers who had selective cord-blood testing would have higher rates of clinically significant hyperbilirubinemia compared with those newborns who had routine cord-blood testing. (2) To determine the amount of cost savings by implementing a policy of selective cord-blood testing in newborns born to O+ mothers. STUDY DESIGN: We conducted a retrospective pre/post intervention chart review on all infants in the normal newborn nursery at Loyola, born to blood type O+ women between 1 April 2008 and 1 April 2009. The pre-intervention group (routine testing) included infants born within 6 months before implementation of a new policy. The post intervention group (selective testing) included infants born within 6 months following the implementation of a new policy. Data were collected for each of these groups regarding clinically significant hyperbilirubinemia. RESULT: All 250 of the infants in the routine testing group had a cord-blood type and Coombs done, whereas 42 of 164 (25%) infants in the selective group had testing done. By the end of the 6 months following the policy change, only 8% of infants were undergoing cord testing. When comparing routine vs selective testing, there was no statistically significant difference in the 24-h serum bilirubin, rate of phototherapy during the birth hospitalization, rate of readmission for hyperbilirubinemia or peak serum bilirubin level at readmission. The 92% reduction of cord-blood typing and Coombs testing would lead to a cost saving of $4100 per year to our hospital and $18 900 per year to our patients, and 95 h per year of technician time to perform these tests. When extrapolated to Illinois births in 2008, this would lead to an annual cost saving of almost $800 000 to Illinois hospitals and about $3.6 million to patients. CONCLUSION: Selective newborn cord testing of infants born to O+ mothers can decrease the use of resources and costs without increasing the risk of clinically significant hyperbilirubinemia. PMID- 22441113 TI - What does cyclicity on amplitude-integrated EEG mean? AB - In the context of amplitude-integrated electroencephalography (aEEG), the term 'sleep-wake cycling' (SWC), which is frequently used by clinicians and researchers, should be changed to 'cyclicity'. SWC is a technical term that refers to the biological pattern of alternating sleeping and waking states, which is difficult to define with only aEEG and no physical parameters. Additionally, the absence of cyclicity on aEEG is a more robust reflection of the sequence of the suppressed background patterns of an aEEG following cerebral injury or dysfunction than are sleep/wake states. PMID- 22441114 TI - Antenatal steroid use and neonatal outcome: United States 2007. AB - OBJECTIVE: Antenatal steroid use has been associated with reduction in the risk of neonatal mortality in meta-analyses of clinical trials. In 2007, a revised US birth certificate offered information on antenatal steroid use in 22 states. The aim of this study was to review the association between antenatal steroid use and neonatal mortality by gestational age categories for preterm infants (<37 weeks) for the United States for the year 2007. STUDY DESIGN: Data were obtained from the United States Linked Infant Birth and Death Certificate Public Use Period file for the year 2007. Associations between antenatal steroid use and neonatal death were determined by logistic regression adjusting for potentially confounding variables. RESULT: There were 245 453 preterm births and 4220 neonatal deaths available for analysis with complete data on antenatal steroid use. The highest prevalence for antenatal steroid use among neonatal intensive care unit admissions (NICU) was 22% in the 26 to 28 week gestational age category, whereas the lowest prevalence was in the 34- to 36-week group at 7%. Following adjustment for potentially confounding variables by logistic regression, the adjusted odds ratios (95% confidence interval) for neonatal mortality (antenatal steroid use versus non-use) ranged from 0.56 (0.46 to 0.67) at 22 to 25 weeks; 0.66 (0.53 to 0.83) at 26 to 28 weeks; 0.69 (0.55 to 0.85) at 29 to 33 weeks and 0.69 (0.47 to 1.01) at 34 to 36 weeks. CONCLUSION: These data are in accordance with meta-analytical data of randomized clinical trials and network reports on reduction of neonatal mortality with the use of antenatal steroids, and provide support for the use of antenatal steroids for late preterm births. PMID- 22441115 TI - Severe maternal and perinatal outcomes from uterine rupture among women at term with a trial of labor. AB - OBJECTIVE: To describe maternal and perinatal morbidity and mortality associated with uterine rupture (UR) among women with prior cesarean/s, singleton term pregnancies and a trial of labor after cesarean (TOLAC). STUDY DESIGN: Linked hospital discharge files and birth/fetal death certificates identified potential cases of UR in Massachusetts from 1990 to 1998 with definitive identification by medical record abstraction. RESULT: Among the 347 identified URs, severe outcomes occurred in 86 cases (25%), in 49 (14%) of mothers and 49 (14%) of infants. Of the infants, 25 were discharged with a good prognosis. Maternal age and interdelivery interval <18 months (relative risk (RR)=1.55; 95% confidence interval (CI): 1.05, 2.31) were associated with a severe outcome. The type of hospital and labor were not associated with the increased risk of a severe outcome. CONCLUSION: Assuming a 0.7% UR rate among women at term with a TOLAC, the increased rate of severe outcomes related to UR above the baseline risk of elective cesarean is estimated to be 1.3 per 1000 TOLACs. PMID- 22441116 TI - Identification of a novel compound with antiviral activity against influenza A virus depending on PA subunit of viral RNA polymerase. AB - Influenza viruses have developed resistance to current drugs, creating a need for new antiviral targets and new drugs to treat influenza virus infections. In this study, computational and experimental screening of an extensive compound library identified THC19, which was able to suppress influenza virus replication. This compound had no cytotoxic effects and did not disrupt cell cycle progression or induce apoptosis in MDCK cells as confirmed by WST-1 assays, flow cytometry analysis, and caspase-3 assays. Time-of-addition experiments showed that THC19 acts at a relatively early stage of the viral lifecycle. Subsequent mini-genome assays revealed that THC19 inhibited viral genome replication and/or transcription, suggesting that it interferes with one or more of the viral components that form the ribonucleoprotein complexes, namely polymerase basic 2 (PB2), polymerase basic 1 (PB1), polymerase acidic (PA), nucleoprotein (NP) and viral RNA. Finally, mini-genome assays where PB2, PB1, PA or NP from A/WSN/33 (H1N1) virus were replaced with those from A/Udorn/307/1972 (H3N2) virus effectively demonstrated that THC19 inhibited viral multiplication in a manner dependent upon the PA subunit. Taken together, these results suggest that influenza virus PA protein is a potential target for, and may aid the development of, novel compounds that inhibit influenza A virus replication. PMID- 22441120 TI - Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population. AB - BACKGROUND: Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+408C>A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes. OBJECTIVE: To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population. METHODS: We conducted a case-control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory. RESULTS: No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P>0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (P<0.05). In the control group, the subjects with variant genotypes had significantly increased levels of FINS, HOMA-IR compared with Leu72Leu genotype (P<0.05). CONCLUSION: The Leu72Met polymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance. PMID- 22441121 TI - Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. AB - Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event. PMID- 22441122 TI - Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in cancer: a meta analysis. AB - Toll-like receptor 4 (TLR4) is critical in the recognition of Gram-negative bacteria serving as a key immune system effector. Recently, a number of case control studies were conducted to investigate the association between TLR4 gene polymorphism and cancer risk, especially Asp299Gly and Thr399Ile polymorphisms. However, published data were still conflicting. In this paper, we summarized 9463 cancer cases and 10,825 controls from 22 studies and attempted to assess the susceptibility of TLR4 gene polymorphism to cancers by a synthetical meta analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the relationship. Our results suggested that Asp299Gly represented a risk factor on cancers in digestive system (G allele versus A allele, OR=1.64, 95% CI: 1.02-2.64; GA+GG versus AA, OR=1.64, 95% CI: 1.00-2.71) but tend to have a protective effect on prostate cancer (GG versus AA, OR=0.37, 95% CI: 0.14-0.98; GG versus GA+AA, OR=0.37, 95% CI: 0.14-0.98). Thr399Ile polymorphism was significantly associated with an elevated cancer risk in overall analysis (T allele versus C allele, OR=1.72, 95% CI: 1.27-2.33; TC versus CC, OR=1.63, 95% CI: 1.18-2.26; TT+TC versus CC, OR=1.70, 95% CI: 1.24-2.34) and especially in gastrointestinal subgroup (T allele versus C allele, OR=2.01, 95% CI: 1.40-2.89; TC versus CC, OR=1.86, 95% CI: 1.26-2.74; TT+TC versus CC, OR=1.97, 95% CI: 1.35 2.88). Further prospective researches with larger numbers of worldwide participants are warranted to draw comprehensive and true conclusions. PMID- 22441123 TI - Expression and biochemical characterization of two novel feruloyl esterases derived from fecal samples of Rusa unicolor and Equus burchelli. AB - Two novel genes (tvms10a, tvmz2a) were identified in the metagenomic DNA of Rusa unicolor and Equus burchelli fecal samples. The amplified PCR product of tvms10a is composed of 917bp and the gene was found to encode a protein containing 165 amino acids, while the tvmz2a PCR product was 1053bp long encoding 298 amino acid proteins. The gene has 72% primary sequence identity with Clostridiales sp. These amplified PCR products which can encode FAE were cloned into pGEMT Easy TA cloning vector and then sub-cloned into the EcoRI site of pET32a expression vector to generate pET32-tvms10a and pET32-tvmz2a, which was then transformed into Escherichia coli BL21. The recombinants were grown in LB medium and gene expression was induced with IPTG for 6h. Purified recombinant Tvms10a and Tvmz2a proteins showed molecular masses of 18.6 and 31.2kDa respectively, and displayed hydrolytic activity towards substrate ethyl ferulate. The activities of Tvms10a and Tvmz2a produced in E. coli were 15 and 9U/min respectively, and their specific activities 16.6 and 10.4U/mg protein respectively. The optimal pH is between 5.0 and 8.0 and the optimal temperature is 37 degrees C for enzyme reaction. Unusually, these proteins were found to be capable of releasing ferulic acid (FA) and diferulic acid (diFA) from untreated crude plant cell wall materials. The substrate utilization preferences and sequence similarity of these clones place it in the type-D sub-class of FAE. PMID- 22441124 TI - Developing species-specific primers to identify Bulinus truncatus and Bulinus beccari, the intermediate hosts of Schistosoma haematobium in Saudi Arabia. AB - This work aimed to determine the inter- and intra-specific variations in populations of Bulinus truncatus and Bulinus beccari, the intermediate hosts of Schistosoma haematobium in Saudi Arabia, and to develop species-specific primers to identify these snails as a first step in the development of multiplex PCR for simultaneously identifying the snails and diagnosing its infections in a single step. Two populations of B. truncatus were collected from Asser and Bisha (A and B), and two B. beccari populations were collected from Mahial Asser and Merba (C and D). The snails' genomic DNA was extracted and amplified using 5 different primers. The primers displayed variable intra- and inter-specific differences across the populations. The largest RAPD-PCR fragments were cloned into a vector as a preparatory step for sequencing. Similarity searches for the sequenced cloned inserts revealed no similar sequences in the GenBank database or its associated databases. Specific primers used to target the B. truncatus and B. beccari genomes were designed using the Gene Runner program and based on the DNA sequences obtained from RAPD fragment sequence analyses. Using these primers for specific PCRs resulted in expected single-band PCR products of 536 bp for B. beccari and 478 bp for B. truncatus. These results will be helpful for simultaneously identifying B. truncatus and B. beccari snails and diagnosing S. haematobium infections within the snails using single step multiplex PCR. PMID- 22441125 TI - Colocalization and identification of interaction sites between IGFBP-3 and GalNAc T14. AB - GalNAc-T14 was identified as a novel IGFBP-3 binding partner in previous studies. Here, we furtherly confirmed the interaction between them by confocal microscopy, and identified the binding domain and probable interaction sites of GalNAc-T14 with IGFBP-3. The result of subcellular localization indicated that GalNAc-T14 was distributed in the cytosol, whereas IGFBP-3 existed in the cytosol and nucleolus. Confocal analyses demonstrated that IGFBP-3 and GalNAc-T14 colocalized in the cytosol. The result from yeast two hybrid assay showed that the C terminus of GalNAc-T14 (408-552aa) was essential for the interaction between GalNAc-T14 and IGFBP-3, especially Tyr(408), Pro(409), and Glu(410) of GalNAc-T14 may play key roles in the interaction with IGFBP-3. In conclusion, these studies demonstrated that IGFBP-3 and GalNAc-T14 are colocalized in MCF-7 cells and confirmed the interaction between IGFBP-3 and GalNAc-T14. This interaction may play an important role in the functional regulation of IGFBP-3. PMID- 22441126 TI - Cloning and transcript analysis of type 2 metallothionein gene (SbMT-2) from extreme halophyte Salicornia brachiata and its heterologous expression in E. coli. AB - Salicornia brachiata is an extreme halophyte growing luxuriantly in the coastal marshes and frequently exposed to various abiotic stresses including heavy metals. A full length type 2 metallothionein (SbMT-2) gene was isolated using RACE and its copy number was confirmed by southern blot analysis. Transcript expression of SbMT-2 gene was analyzed by semi-quantitative Rt-PCR and real time quantitative (qRT) PCR. Expression of SbMT-2 gene was up-regulated concurrently with zinc, copper, salt, heat and drought stress, down regulated by cold stress while unaffected under cadmium stress. Heterologous expression of SbMT-2 gene enhances metal accumulation and tolerance in E. coli. Metal-binding characteristics of SbMT-2 protein show its possible role in homeostasis and/or detoxification of heavy metals. Significant tolerance was observed by E. coli cells expressing recombinant SbMT-2 for Zn(++), Cu(++) and Cd(++) compared to cells expressing GST only. Sequestration of zinc was 4-fold higher compared to copper and in contrast SbMT-2 inhibits the relative accumulation of cadmium by 1.23-fold compared to GST protein. Fusion protein SbMT-2 showed utmost affinity to zinc (approx. 2.5 fold to Cu(++) and Cd(++)) followed by copper and cadmium ions with same affinity. Halophyte S. brachiata has inherent resilience of varying abiotic tolerance therefore SbMT-2 gene could be a potential candidate to be used for enhanced metal tolerance and heavy metal phytoremediation. PMID- 22441127 TI - Proteomics of a new esophageal cancer cell line established from Persian patient. AB - Although the highest incidence of esophageal squamous cell carcinoma (ESCC) has repeatedly been reported from Persia (Iran), nevertheless the so far proteomic published reports were limited to one study on tissue specimens. Here we report the proteome of a newly established cell line from Persian ESCC patients and compare it with the normal primary cell proteome. Among polypeptides, whose expression was different in cell line sixteen polypeptides were identified by MALDI/TOF/TOF spectrometry. S100-A8 protein, annexin A1, annexin A2, regulatory subunit of calpain, subunit alpha type-3 of proteasome and glutamate dehydrogenase 1 were proteins down-regulated in cell line while peroxiredoxin-5, non-muscle myosin light polypeptide 6, keratin 1, annexin A4, keratin 8, tropomyosin 3, stress-induced-phosphoprotein 1 and albumin were found to be subject of up-regulation in cell line compared to the primary normal cells. The proteomic results were further verified by western blotting and RT-PCR on annexin A1 and keratin 8. In addition, among the aforementioned proteins, glutamate dehydrogenase 1, regulatory subunit of calpain, subunit alpha of type-3 proteasome and annexin A4 are proteins whose deregulation in ESCC is reported for the first time by this study. PMID- 22441128 TI - Synergistic anticancer effect of rAd/P53 combined with 5-fluorouracil or iodized oil in the early therapeutic response of human colon cancer in vivo. AB - Exogenous wild-type p53 (wt-p53) tumor suppression increases the sensitivity of tumor cells to radiotherapy and chemotherapy. An iodized oil emulsion was used as a p53 vector for intra-arterial gene delivery to treat hepatic tumors. Whether the chemotherapeutic agent or the iodized oil affects exogenous wt-p53 activity remains poorly understood. In the present study, the early therapeutic response of rAd/p53, combined with 5-fluorouracil (5-FU) or with iodized oil, was observed in a human colon cancer model. Allograft models in 82 nude mice with human colon carcinoma SW480 were divided randomly into four groups and administered with physiologic saline, rAd/p53, rAd/p53+5-FU, and rAd/p53+iodized oil by intratumoral injection. At 24, 48, 72, 120, and 168 h after treatment, p53 expression, the Ki-67 index (KI), and the degree of tumor necrosis were assessed. The p53 expression and tumor necrosis in the therapeutic groups were higher than those in the control group. p53 expression reached its peak at 120 h in the rAd/p53 group, at 72 h in the rAd/p53+5-FU group, and at 48 h in the rAd/p53+iodized oil group. The p53 expression in the rAd/P53+5-FU group and the iodized oil group was significantly higher than those in the rAd/P53 group at 24 and 48 h. The results revealed that tumor necrosis is positively correlated with p53 expression. The KI of the rAd/p53+5-FU group increased significantly at 24 h. 5-FU and iodized oil increase the anticancer effect of rAd/p53, and 5-FU combined with rAd/p53 has a synergistic anticancer effect. PMID- 22441129 TI - Living with stress: regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax. AB - Lack of oxygen is life threatening for most mammals. It is therefore of biomedical interest to investigate the adaptive mechanisms which enable mammalian species to tolerate extremely hypoxic conditions. The subterranean mole rat Spalax survives substantially longer periods of hypoxia than the laboratory rat. We hypothesized that genes of the antioxidant defense, detoxifying harmful reactive oxygen species generated during hypoxia and hyperoxia, are involved in Spalax underground adaptation. Using quantitative RT-PCR, we analyzed the mRNA expression levels of seven antioxidant defense genes (catalase, glutathione peroxidase 1, glutathione-S-transferase Pi1, heme oxygenase 1, superoxide dismutase 1 and 2) and a master regulator of this stress pathway, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in several tissues of two Israeli Spalax species, S. galili (2n=52) and S. judaei (2n=60), and rat. We also studied the differential expression of these genes after experimental hypoxia and hyperoxia as oxidative stress treatments. We found that mRNA levels and transcriptional responses are species and tissue specific. There are constitutively higher transcript levels of antioxidant genes and their transcription factor Nrf2 in Spalax tissue as compared to rat, suggesting an increased ability in the mole rat to withstand hypoxic/hyperoxic insults. In contrast to Spalax, the rat reacts to experimental oxidative stress by changes in gene regulation. In addition, Spalax Nrf2 reveals unique amino acid changes, which may be functionally important for this transcription factor and indicate positive (Darwinian) selection. Antioxidant defense genes are therefore important targets for adaptive change during evolution of hypoxia tolerance in Spalax. PMID- 22441130 TI - Methylenetetrahydrofolate reductase C677T genetic polymorphisms and risk of leukaemia among the North Indian population. AB - BACKGROUND: Leukaemia is a heterogeneous disease in which haematopoietic progenitor cells acquire genetic lesions that lead to a block in differentiation, increased self-renewal, and unregulated proliferation. The enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR), involved in folate metabolism, plays a crucial role in cells because folate availability is important for DNA integrity. The aim of this case-control study was to evaluate the association of the C677T MTHFR gene polymorphism with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML) and chronic lymphocytic leukaemia (CLL). MATERIALS AND METHODS: A total of 275 leukaemia cases - including AML (n = 112), ALL (n = 81), CML (n = 43), CLL (n = 39) - and 251 age/sex-matched healthy control individuals participated in this study. MTHFR C677T polymorphisms in the cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total leukaemia cases were 68.73%, 19.64%, and 11.64% in cases, and 71.71%, 24.30%, and 3.98% in healthy controls, respectively. The average frequency of the MTHFR 677T allele was 21.45% among the cases compared to 16.13% among the controls. CONCLUSIONS: In the present case-control study we have observed a higher frequency of the MTHFR 677TT genotype in cases of leukaemia (AML, ALL, CML and CLL) as compared with controls; this might be due to ethnic and geographic variation. As per our findings, although the frequency of the MTHFR 677T allele is moderately high in AML, ALL and CLL, no statistically significant association was found; on the other hand statistically significant association was found in the context of CML cases. PMID- 22441131 TI - A quantum dot-intercalating dye dual-donor FRET based biosensor. AB - We report herein the development of a novel quantum dot-intercalating dye dual donor FRET system that can be used for sensitive detection of pM level DNA and protein targets. PMID- 22441132 TI - Comparison of six quantitative methods for the measurement of bone turnover at the hip and lumbar spine using 18F-fluoride PET-CT. AB - AIM: The aim of this study was to evaluate the relationship between different quantification methods used for the measurement of bone plasma clearance (K(i)) using F-PET at the hip and lumbar spine. METHODS: Twelve healthy postmenopausal women aged 52-71 years were recruited. Each participant underwent 60-min dynamic F-PET scans at the lumbar spine and hip on two separate occasions with an injected activity of 90 and 180 MBq, respectively. Image-derived input functions were obtained at the aorta from the lumbar spine scans. K(i) was evaluated using a three-compartment four-parameter model (K(i-4k)), three-compartment three parameter model (K(i-3k)), Patlak analysis (K(i-Pat)), spectral analysis (K(i Spec)) and deconvolution (K(i-Decon)). Standardized uptake values (SUVs) were also measured. RESULTS: The Pearson correlation between K(i-4k) and K(i-3k), K(i Pat), K(i-Spec), K(i-Decon) and SUV were 0.91, 0.97, 0.94, 0.95 and 0.93, respectively, with a significance of P less than 0.0001. The differences between the correlations measured using Fisher's Z-test were not significant (P>0.05). Bland-Altman analysis showed that the limits of agreement for K(i) measured as the SD of the differences were 0.0082 (25.9%), 0.0062 (11.7%), 0.0098 (20.1%) and 0.0056 (25.5%) ml/min/ml, respectively, and the biases were -0.0081 (-23.8%), 0.0075 (-23.7%), -0.0107 (-29.5%) and -0.0015 (0.8%) ml/min/ml, respectively. CONCLUSION: All five methods of quantification (K(i-3k), K(i-Pat), K(i-Spec), K(i Decon) and SUV) strongly correlated with K(i-4k). Although systematic differences of up to 29% were found between K(i-4k) and the other methods (K(i-3k), K(i-Pat), K(i-Spec) and K(i-Decon)), these should not affect the conclusions of clinical studies, provided the methods are applied consistently. However, care should be taken when comparing reports that use different methods of quantification. PMID- 22441133 TI - Diagnosis of pulmonary embolism: planar images generated from V/Q SPECT are not a reliable substitute for traditional planar V/Q scan. AB - OBJECTIVES: The use of summed planar images generated from single-photon emission computed tomography (SPECT) ventilation/perfusion (V/Q) scintigraphy has been proposed as a substitute for planar V/Q scans in order to use the revised PIOPED interpretation criteria when only SPECT acquisition is performed in patients with suspected pulmonary embolism. The aim was to evaluate the accuracy of angular summed planar scans in comparison with true planar images. METHODS: Patients included in the 'SPECT study' assessing the diagnostic performance of V/Q SPECT were analysed. Angular summed planar images were generated from SPECT acquisition data and compared with true planar scans. RESULTS: Angular summed planar images were successfully generated for 246 patients. Regarding interobserver variability, the interpretation result was different for 15 (6%) summed planar scans with an excellent degree of agreement (kappa=0.92; 95% confidence interval 0.88-0.96). With regard to intermodality interpretation variability between conventional planar and angular summed images, the result was different for 63 (26%) of 246 patients with an intermodality degree of agreement of kappa=0.66 (95% confidence interval 0.58-0.73). CONCLUSION: Planar images generated from SPECT V/Q scintigraphy are not a reliable substitute for true planar V/Q images. PMID- 22441134 TI - A max-plus model of ribosome dynamics during mRNA translation. AB - We examine the dynamics of the translation stage of cellular protein production, in which ribosomes move uni-directionally along an mRNA strand, building amino acid chains as they go. We describe the system using a timed event graph-a class of Petri net useful for studying discrete events, which have to satisfy constraints. We use max-plus algebra to describe a deterministic version of the model, where the constraints represent steric effects which prevent more than one ribosome reading a given codon at a given time and delays associated with the availability of the different tRNAs. We calculate the protein production rate and density of ribosomes on the mRNA and find exact agreement between these analytical results and numerical simulations of the deterministic model, even in the case of heterogeneous mRNAs. PMID- 22441135 TI - Impacts of conventional coronary risk factors, diabetes and hypertension, on coronary atherosclerosis during statin therapy: subanalysis of the TRUTH study. AB - OBJECTIVE: Patients with diabetes mellitus (DM) and hypertension (HT) are at a high risk of coronary artery disease. However, the mechanisms underlying this have not been well characterized. The purpose of the present study was to evaluate the impacts of DM and HT on coronary atherosclerosis during statin therapy. MATERIALS AND METHODS: The effects of 8-month statin therapy on coronary atherosclerosis were evaluated in the TRUTH study using virtual histology intravascular ultrasound. Analyzable intravascular ultrasound data were obtained from 119 patients who were divided into four subgroups, namely, group A: DM (+), HT (+); group B: DM (+), HT (-); group C: DM (-), HT (+); and group D: DM (-), HT (-). The pattern of arterial remodeling, extent of coronary atherosclerosis, and plaque composition were compared among the four subgroups. RESULTS: Atheroma volume decreased significantly in group D (-3.9%, P=0.01), whereas it tended to increase in group A (1.0%, P=0.77). A significant difference in the mean percent change of atheroma volume was observed between groups A and D (1.0 vs. -3.9%, P=0.03). Furthermore, the frequency of progression in atheroma volume was significantly higher in group A (60, 33, 45, and 24% in groups A, B, C, and D, respectively; P=0.03). No significant differences in the changes in the four plaque components among the four subgroups were observed. CONCLUSION: A combination of DM and HT attenuates the degree of regression of coronary atherosclerosis, but does not influence changes in plaque composition during statin therapy. PMID- 22441136 TI - Pharmacokinetic modeling of the high-dose bolus regimen of tirofiban in patients with severe renal impairment. AB - For the treatment of patients with acute coronary syndromes in the catheterization laboratory, a high-dose bolus (HDB) regimen of tirofiban (25 ug/kg bolus, followed by an infusion of 0.15 ug/kg/min) leads to a consistent and rapid inhibition of platelet aggregation during the first hour after initiation of therapy. The objective of the present study was to use pharmacokinetic modeling to identify an appropriate dosage of tirofiban that would produce a plasma concentration-time profile in patients with severe renal impairment (creatinine clearance<30 ml/min) as similar as possible to that of the HDB regimen in patients with normal renal function. For patients with severe renal impairment, previous recommendations have been to reduce the dosage by 50%. Pharmacokinetic modeling was performed with the following sets of data: the plasma concentrations of tirofiban from patients with normal renal function who were treated with the HDB regimen of tirofiban and the plasma concentrations of tirofiban from patients with severe renal impairment who were treated with a 0.1 ug/kg/min infusion of tirofiban for 1 h. In conclusion, for patients with severe renal impairment, a 25 ug/kg bolus, followed by a 0.10 ug/kg/min maintenance infusion of tirofiban produced a plasma concentration-time profile similar to that observed with the HDB regimen of tirofiban in patients with normal renal function. PMID- 22441137 TI - Turn-directed folding dynamics of beta-hairpin-forming de novo decapeptide Chignolin. AB - Realistic mechanistic pictures of beta-hairpin formation, offering valuable insights into some of the key early events in protein folding, are accessible through short designed polypeptides as they allow atomic-level scrutiny through simulations. Here, we present a detailed picture of the dynamics and mechanism of beta-hairpin formation of Chignolin, a de novo decapeptide, using extensive, unbiased molecular dynamics simulations. The results provide clear evidence for turn-directed broken-zipper folding and reveal details of turn nucleation and cooperative progression of turn growth, hydrogen-bond formations, and eventual packing of the hydrophobic core. Further, we show that, rather than driving folding through hydrophobic collapse, cross-strand side-chain packing could in fact be rate-limiting as packing frustrations can delay formation of the native hydrophobic core prior to or during folding and even cause relatively long-living misfolded or partially folded states that may nucleate aggregative events in more complex situations. The results support the increasing evidence for turn-centric folding mechanisms for beta-hairpin formation suggested recently for GB1 and Peptide 1 based on experiments and simulations but also point to the need for similar examinations of polypeptides with larger numbers of cross-strand hydrophobic residues. PMID- 22441138 TI - Iron oxide-filled micelles as ligands for fac-[M(CO)3]+ (M = (99m)Tc, Re). AB - Magnetite-filled micelles capture fac-[M(OH(2))(3)(CO)(3)](+) complexes (M = (99m)Tc, Re), creating versatile self-assembled constructs for multimodal SPECT/MR/optical imaging and radiopharmaceutical guided delivery. PMID- 22441139 TI - Reduced serum ceruloplasmin levels in cervical dystonia. PMID- 22441140 TI - Health-related quality of life in short children born small for gestational age: effects of growth hormone treatment and postponement of puberty. AB - AIMS: To investigate health-related quality of life (HRQoL) in short children born small for gestational age (SGA) during growth hormone (GH) treatment and additional postponement of puberty by gonadotropin-releasing hormone analogue (GnRHa). METHODS: HRQoL was studied longitudinally during 2 years of treatment in 97 short SGA children (mean age 11.6 years at start). The children were divided into three groups: prepubertal GH-treated (prep-GH) children, pubertal GH-treated (pub-GH) children, and pubertal GH-treated children with additional GnRHa treatment (pub-GH/GnRHa). HRQoL was measured by generic (TACQOL) and short stature-specific (TACQOL-S) questionnaires. RESULTS: The TACQOL-S showed that prep-GH children experienced significant HRQoL improvement on the subscales 'contact with adults', 'body image' and 'vitality', and pub-GH/GnRHa children on the subscales 'contact with adults', 'contact with peers' and 'physical abilities'. Parents of prep-GH and pub-GH/GnRHa children reported significant HRQoL improvement on most TACQOL-S scales, whereas HRQoL improvement in pub-GH children reached significance for 'future prospects' only. The HRQoL gain was similar in the three groups, also after correction for confounders. The generic questionnaire TACQOL did not reveal any changes. CONCLUSIONS: HRQoL improved in prepubertal and pubertal short SGA children during GH treatment. Additional GnRHa treatment had no adverse effect on the HRQoL gain. Disorder-specific questionnaires were particularly appropriate to evaluate HRQoL in children treated for short stature. PMID- 22441141 TI - Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? AB - Recent work has suggested that environmental chemicals, including those contained in cigarette smoke, can have adverse effects on the exposed individuals as well as their future progeny. The mechanisms underlying transmission of environmentally induced phenotypes through the germ line are not well understood. However, a predominant process appears to be the establishment of permanent heritable epigenetic alterations, and a number of studies have implicated microRNAs in such processes. Here, we show that cigarette smoke induces specific differences in the spermatozoal microRNA content of human smokers compared with non-smokers, and that these altered microRNAs appear to predominantly mediate pathways vital for healthy sperm and normal embryo development, particularly cell death and apoptosis. microRNA-mediated perturbation of such pathways may explain how harmful phenotypes can be induced in the progeny of smokers. PMID- 22441142 TI - Errors in ozone risk assessment using standard conditions for converting ozone concentrations obtained by passive samplers in mountain regions. AB - Passive samplers are often employed to measure ozone concentrations in remote areas such as mountain forests. The potential ozone risk for vegetation is then assessed by calculating the AOT40 exposure index (accumulated hourly ozone concentration exceedances above 40 ppb, i.e. AOT40 = Sigma([O(3)] - 40)Deltat for any hourly ozone concentration [O(3)] > 40 ppb). AOT40 is customary calculated on the basis of ozone concentrations expressed as a volumetric mixing ratio, while lab sheets normally report ozone concentrations from passive samplers in mass units per cubic metre. Concentrations are usually converted from mass units to ppb using a standard conversion factor taking SATP (Standard Ambient Temperature and Pressure) conditions into account. These conditions, however, can vary considerably with elevation. As a consequence, the blanket application of a standard conversion factor may lead to substantial errors in reporting and mapping ozone concentrations and therefore in assessing potential ozone risk in mountain regions. In this paper we carry out a sensitivity analysis of the effects of uncertainties in estimations of air temperature (T) and atmospheric pressure (P) on the concentration conversion factor, and present two examples from two monitoring and mapping exercises carried out in the Italian Alps. We derived P and T at each site from adiabatic lapse rates for temperature and pressure and analysed the magnitude of error in concentration estimations. Results show that the concentration conversion is much more sensitive to uncertainties in P gradient estimation than to air temperature errors. The concentration conversion factor (cf) deviates 5% from the standard transformation at an elevation of 500 m asl. As a consequence, the standard estimated AOT40 at this elevation is about 13% less than the actual value. AOT40 was found to be underestimated by an average between 25% and 34% at typical elevations of mountain forest stands in the Italian Alps when a correct conversion factor for transforming ozone concentrations from MUg m(-3) to ppb is not applied. PMID- 22441143 TI - Anhedonia in borderline personality disorder and its relation to symptoms of impulsivity. AB - BACKGROUND: Patients with borderline personality disorder (BPD) report strong negative affect and show impulsive, disruptive behaviors. The role of anhedonia, or the inability to experience positive affect, has been less examined in BPD. The present study examined the role of anhedonia in BPD patients and its relation to symptoms of impulsivity. SAMPLING AND METHODS: Anhedonia, affect, impulsivity and BPD symptoms were measured in BPD patients and healthy control participants. RESULTS: It was found that BPD patients showed abnormally high anhedonia levels. In addition, anhedonia was found to be positively related to dysfunctional impulsivity in the BPD patient group, while in the control group, anhedonia was related to withdrawal behaviors. A strong relation was found between anhedonia and BPD symptoms, emphasizing the relevance of anhedonia as an important symptom of BPD. Finally, anhedonia was found to be an important contributor to the severity of borderline symptoms, independently of other factors such as affect and impulsivity. CONCLUSIONS: The results underline that anhedonia might be an important but currently overlooked feature of BPD. The results further suggest that anhedonia is associated with the impulsive behaviors that are typically observed in borderline patients. PMID- 22441144 TI - The day when infection is confirmed is a better time point for mortality prediction in patients with severe acute pancreatitis. AB - OBJECTIVES: The objective of the study was to compare the accuracy of predictive methods for mortality in patients with severe acute pancreatitis (SAP) on admission and on the day when infection was confirmed. METHODS: Medical records of patients admitted for SAP in our hospital during January 2000 to November 2010 were retrospectively reviewed. Among those with infectious complications, time when infection was confirmed (TIC) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission and at the time when infection was confirmed (APACHE II OTIC) were studied. The correlations among the APACHE II score on admission, APACHE II OTIC score, and TIC were analyzed. The predictive accuracy was assessed by the area under the receiver operating characteristic curve. RESULTS: Time when infection was confirmed correlated negatively with the APACHE II score on admission and the APACHE II OTIC score (P < 0.05). The optimum cutoff value and the corresponding areas under the receiver operating characteristic curve for APACHE II score on admission, APACHE II OTIC score, and TIC were greater than 8, greater than 5, 12 days or less, and 0.67 (95% confidence interval [CI], 0.54-0.77), 0.84 (95% CI, 0.73-0.91), and 0.73 (95% CI, 0.61-0.82), respectively. Compared with the APACHE II score on admission, the APACHE II OTIC score was more accurate in predicting mortality (P = 0.029). CONCLUSIONS: The time when infection is confirmed is a better time point for the reassessment of the outcome in patients with SAP. PMID- 22441145 TI - Transforming growth factor beta and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor Lefty. AB - OBJECTIVES: The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-beta) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF beta-dependent Lefty up-regulation. METHODS: Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-beta-mediated Lefty up regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002. RESULTS: Transforming growth factor beta upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty up-regulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-beta-Lefty pathway. CONCLUSIONS: Our data suggest that Lefty is a novel TGF-beta target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF beta-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-beta. PMID- 22441146 TI - Recombinant human activated protein C (Xigris) attenuates murine cerulein-induced acute pancreatitis via regulation of nuclear factor kappaB and apoptotic pathways. AB - OBJECTIVES: Microvascular thrombosis occurs in severe acute pancreatitis (AP). Exploiting this knowledge, we used human recombinant activated protein C (Xigris; Eli Lilly, Indianapolis, Ind) known to preserve microvascular patency, in evaluating the role of Xigris in experimental AP. METHODS: In accordance with European union experimentation regulations, AP was induced by hourly injection of cerulein 50 MUg/kg body weight over 6 hours. Male rats of median weight of 231 g (range, 176-312 g) were allocated at random into groups: group 1, control; group 2, vehicle; group 3, AP; group 4, cerulein + Xigris at induction of AP and killing at 24 h; and group 5, cerulein + Xigris 24 hours after induction and killing at 48 hours. In addition to enzymatic and histological markers of pancreatic injury, apoptosis, nuclear factor kappaB (NF-kappaB) p65/IkappaB, cytokine response, and endothelial injury were assessed. Western blot quantified by densitometry was used to assess marker of apoptosis and endothelial injury. RESULTS: Cerulein injection resulted in acute necrotizing pancreatitis. Intervention with recombinant human activated protein C did not modify coagulation parameters or lead to hemorrhage but ameliorated pancreatic injury with preservation of IkappaB and reduction of NF-kappaB p65 and modulation of apoptosis. CONCLUSIONS: Our study indicates that recombinant human activated protein C ameliorates experimental cerulein-induced pancreatitis through apoptotic and NF-kappaB pathways without causing pancreatic hemorrhage. PMID- 22441147 TI - alpha-N-Linked glycopeptides: conformational analysis and bioactivity as lectin ligands. AB - Natural N-glycosylation involves a beta-anomeric linkage connecting the sugar to one asparagine residue of the protein. We herein report NMR- and modelling-based data on glycomimetics containing alpha-glycosidic linkages. The bioactivity of alpha-Gal-containing glycopeptides has been documented by revealing binding to two plant lectins, i.e. a potent beta-trefoil toxin (Viscum album agglutinin) and beta-sandwich lectin (Erythrina corallodendron agglutinin), by NMR protocols. Docking provided insights into the 3D structures of the resulting complexes. These results provide the basis to introduce alpha-substituted neoglycopeptides to the toolbox of scaffold for the design of potent lectin inhibitors. PMID- 22441150 TI - Laser and pneumatic lithotripsy in the endoscopic management of large ureteric stones: a comparative study. AB - OBJECTIVE: We compared the results of holmium laser and pneumatic intracorporeal lithotripsy for large ureteric calculi in terms of efficacy, safety and complications. METHODS: The study was conducted between April 2009 and October 2010. 80 patients divided into two equally matched groups were included in a prospective randomized trial including patients with a ureteric stone size of 0.5 2 cm. A holmium laser with a 550-MUm fiber was employed in the laser lithotripsy (LL) group. The Swiss Lithoclast was used in the pneumatic lithotripsy (PL) group. RESULTS: Mean stone size was comparable in both groups, namely 13.1 mm in the PL group and 12.9 mm in the LL group. The early stone-free rate was equal in both groups, while the delayed stone-free rate was 95% in LL and 85% in PL. Stone migration occurred in 12 PL cases and in 5 LL cases. Ureteric perforation occurred in 3 LL cases and in 2 PL cases. Ureteric stricture occurred in 1 case following LL. CONCLUSION: Both PL and LL are effective and safe modalities in treating large ureteric stones with minor insignificant differences. A pneumatic system may be more efficient with regard to the cost-benefit ratio, which was not studied in the present work; further studies should address this issue. PMID- 22441151 TI - A new TB vaccine blueprint. PMID- 22441152 TI - Creativity in tuberculosis research and discovery. AB - The remarkable advances in TB vaccinology over the last decade have been driven by a pragmatic approach to moving candidates along the development pipeline to clinical trials, fuelled by encouraging data on protection in animal models. Efficacy data from Phase IIb trials of the first generation of new candidates are anticipated over the next 1-2 years. As outlined in the TB Vaccines Strategic Blueprint, to exploit this information and to inspire design of next generation candidates, it is important that this empirical approach is complemented by progress in understanding of fundamental immune mechanisms and improved translational modalities. Current trends towards improved experimental and computational approaches for studying biological complexity will be an important element in the developing science of TB vaccinology. PMID- 22441153 TI - Ten challenges for TB biomarkers. AB - The availability of tuberculosis (TB) biomarkers of protection (or: "surrogate endpoints of protection against active TB" (Biomarkers Definitions Working Group, 2001)) would greatly facilitate and accelerate TB vaccine development and increase the likelihood of success. TB biomarkers of protection could determine which vaccines in clinical trials are the most efficacious; which vaccine candidates and strategies are the most promising in early stages in the preclinical development pipeline (including relevant antigens, antigen delivery, live vaccines); and which combination vaccines (prime/boost) would be the most effective. Here we discuss ten major challenges for biomarker identification and validation in TB. Current major roadblocks and critical limitations in understanding TB pathogenesis are highlighted, and new solutions and strategies proposed. PMID- 22441154 TI - Transforming biomedical research to develop effective TB vaccines: the next ten years. PMID- 22441155 TI - Clinical trials of TB vaccines: harmonization and cooperation. AB - A new efficacious tuberculosis (TB) vaccine has the potential to dramatically assist control efforts for the global TB epidemic. Good progress has been made with the clinical development of new TB vaccine candidates with twelve being actively tested in clinical trials. However, there are many challenges that need to be addressed before a new vaccine is licensed for public use. The diversity of risk in populations needs to be factored into clinical development plans, specific but feasible clinical endpoints need to be agreed upon, and TB vaccines need to be effective in both uninfected and infected populations. An achievable efficacy target needs to be set while standardisation of trial outcomes and critical choices based on the vaccine development pipeline need to be made. Alternative routes of vaccine administration should be thoroughly explored, sufficient adequately prepared trial sites for performing TB vaccine assessments are required and creative use of study designs should be used to expedite progress towards licensure while at the same time containing costs. Lastly, there needs to be sufficient funding to support TB vaccine development. These challenges can be met through commitment by all role-players within the TB vaccine arena and with support from external stakeholders. PMID- 22441156 TI - Rational approach to selection and clinical development of TB vaccine candidates. AB - A rational process is clearly needed and can be extremely helpful for selection, assessing and advancing TB vaccine candidates from entry into preclinical and clinical development and for advancing candidates from early safety and immunogenicity clinical trials to proof-of-concept and pivotal efficacy trials. A joint effort between Aeras and the Tuberculosis Vaccine Initiative has focused on the development of objective criteria for a number of key general vaccine characteristics which can be assessed at critical stages of development. In order to maximize development efficiency, increase likelihood of success, and optimize use of scarce resources, this process includes establishment of gates for moving TB vaccine candidates through progressive development stages based on meeting the established criteria for specific vaccine candidates. PMID- 22441157 TI - Bridging the gap: engaging researchers and advocates to build support for TB vaccine research and development. AB - The success of global efforts to develop new TB vaccines will rely on both addressing the scientific challenges identified throughout this Blueprint and mobilizing sufficient support and resources to sustain and advance the TB vaccine pipeline. As outlined in the TB Vaccine Blueprint, activities over the next decade will include expanding financing to provide sufficient resources, raising awareness of the need for new TB vaccines, and broadening the base of advocates, allies and champions for TB vaccine R&D. These activities will only be successful if advocates and researchers - including scientists, clinicians and product developers - work together. Researchers and advocates play an essential role in promoting the advancement of TB vaccine research and development (R&D), but have too often operated independently of each other, with researchers focusing on the science and advocates and civil society focused on advocacy, communications and resource mobilization. As we look toward the next decade of TB vaccine development, it will be critical for the research and advocacy communities to work more closely together to support the common goal of developing new, more effective TB vaccines. PMID- 22441158 TI - The blueprint for vaccine research & development: walking the path for better TB vaccines. AB - Much progress has been made in TB vaccine research over the past ten years, and a series of new live genetically altered mycobacterial vaccines, viral-vectored vaccines and sub-unit vaccines composed of recombinant antigens are presently in clinical development phases. A series of challenges remain, however, to be addressed in order to develop new and better candidate TB vaccines, especially an expansion of our knowledge of what constitutes protective immunity in TB, the identification of the most suitable vaccination strategies, the capacity and infrastructure to conduct large-scale trials in endemic countries, the investment in vaccine manufacturing capacity, and the development of effective regulatory pathways that shorten review timelines. In this brief paper, we review how the Vaccine Blueprint places itself in the continuation and expansion of two groundbreaking initiatives taking place over the last two years, that is, an invigorated Global Plan to Stop TB 2011-2015 that gives a clear emphasis on Research and Development, and the International Roadmap for TB Research, that identifies key priorities for research on TB vaccines, spanning from the most fundamental research aspects to the more field-based epidemiological aspects. PMID- 22441159 TI - Planning in the context of a virtuous cycle for tuberculosis vaccine development. PMID- 22441160 TI - Tuberculosis vaccines: a strategic blueprint for the next decade. PMID- 22441161 TI - Hypothalamic stimulation enhances hippocampal BDNF plasticity in proportion to metabolic rate. AB - BACKGROUND: Energy metabolism is emerging as a driving force for cellular events underlying cognitive processing. The hypothalamus integrates metabolic signals with the function of centers related to cognitive processing such as the hippocampus. OBJECTIVE/HYPOTHESIS: Hypothalamic activity can influence molecular systems important for processing synaptic plasticity underlying cognition in the hippocampus. The neurotrophin BDNF may act as a mediator for the effects of energy metabolism on synaptic plasticity and cognitive function. METHODS: The hypothalamus of rats confined to a respiratory chamber was electrically stimulated, and energy expenditure (EE) was assessed via indirect calorimetry. MRNA levels for BDNF and molecules related to synaptic plasticity and control of cellular energy metabolism were assessed in the hippocampus. RESULTS: Electrical stimulation of the rat hypothalamus elevates mRNA levels of hippocampal BDNF. BDNF mRNA levels increased according to the metabolic rate of the animals, and in proportion to the mRNA of molecules involved in control of cellular energy metabolism such as ubiquitous mitochondrial creatine kinase (uMtCK). CONCLUSIONS: Results show a potential mechanism by which cellular energy metabolism impacts the substrates of cognitive processing, and may provide molecular basis for therapeutic treatments based on stimulation of deep brain structures. PMID- 22441162 TI - Using nursing clinical decision support systems to achieve meaningful use. AB - The Health Information Technology and Clinical Health Act (one component of the American Recovery and Reinvestment Act) is responsible for providing incentive payments to hospitals and eligible providers in an effort to support the adoption of electronic health records. Future penalties are planned for electronic health record noncompliance. In order to receive incentives and avoid penalties, hospitals and eligible providers must demonstrate "meaningful use" of their electronic health records. One of the meaningful-use objectives established by the Centers for Medicare & Medicaid Services involves the use of a clinical decision support rule that addresses a hospital-defined, high-priority condition. This article describes the Plan-Do-Study-Act process for creating and implementing a nursing clinical decision support system designed to improve guideline adherence for hypoglycemia management. This project identifies hypoglycemia management as the high-priority area. However, other facilities with different high-priority conditions may find the process presented in this article useful for implementing additional clinical decision support rules geared toward improving outcomes and meeting federal mandates. PMID- 22441163 TI - Towards a theory of ecotone resilience: coastal vegetation on a salinity gradient. AB - Ecotones represent locations where vegetation change is likely to occur as a result of climate and other environmental changes. Using a model of an ecotone vulnerable to such future changes, we estimated the resilience of the ecotone to disturbances. The specific ecotone is that between two different vegetation types, salinity-tolerant and salinity-intolerant, along a gradient in groundwater salinity. In the case studied, each vegetation type, through soil feedback loops, promoted local soil salinity levels that favor itself in competition with the other type. Bifurcation analysis was used to study the system of equations for the two vegetation types and soil salinity. Alternative stable equilibria, one for salinity-tolerant and one for salinity intolerant vegetation, were shown to exist over a region of the groundwater salinity gradient, bounded by two bifurcation points. This region was shown to depend sensitively on parameters such as the rate of upward infiltration of salinity from groundwater into the soil due to evaporation. We showed also that increasing diffusion rates of vegetation can lead to shrinkage of the range between the two bifurcation points. Sharp ecotones are typical of salt-tolerant vegetation (mangroves) near the coastline and salt-intolerant vegetation inland, even though the underlying elevation and groundwater salinity change very gradually. A disturbance such as an input of salinity to the soil from a storm surge could upset this stable boundary, leading to a regime shift of salinity-tolerant vegetation inland. We showed, however, that, for our model as least, a simple pulse disturbance would not be sufficient; the salinity would have to be held at a high level, as a 'press', for some time. The approach used here should be generalizable to study the resilience of a variety of ecotones to disturbances. PMID- 22441165 TI - Cobalt-catalyzed arylation of aldimines via directed C-H bond functionalization: addition of 2-arylpyridines and self-coupling of aromatic aldimines. AB - A cobalt-N-heterocyclic carbene catalyst, in combination with an appropriate Grignard reagent, promotes a chelation-assisted aromatic C-H functionalization reaction via addition to an aromatic aldimine. PMID- 22441164 TI - Peroxisome deficiency-induced ER stress and SREBP-2 pathway activation in the liver of newborn PEX2 knock-out mice. AB - Disruption of the Pex2 gene leads to peroxisome deficiency and widespread metabolic dysfunction. We previously demonstrated that peroxisomes are critical for maintaining cholesterol homeostasis, using peroxisome-deficient Pex2(-/-) mice on a hybrid Swiss Webster*129S6/SvEv (SW/129) genetic background. Peroxisome deficiency activates hepatic endoplasmic reticulum (ER) stress pathways, leading to dysregulation of the endogenous sterol response mechanism. Herein, we demonstrate a more profound dysregulation of cholesterol homeostasis in newborn Pex2(-/-) mice congenic on a 129S6/SvEv (129) genetic background, and substantial differences between newborn versus postnatal Pex2(-/-) mice in factors that activate ER stress. These differences extend to relationships between activation of genes regulated by SREBP-2 versus PPARalpha. The SREBP-2 pathway is induced in neonatal Pex2(-/-) livers from 129 and SW/129 strains, despite normal hepatic cholesterol levels. ER stress markers are increased in newborn 129 Pex2(-/-) livers, which occurs in the absence of hepatic steatosis or accumulation of peroxins in the ER. Moreover, the induction of SREBP-2 and ER stress pathways is independent of PPARalpha activation in livers of newborn 129 and SW/129 Pex2(-/-) mice. Two-week-old wild-type mice treated with the peroxisome proliferator WY 14,643 show strong induction of PPARalpha-regulated genes and decreased expression of SREBP-2 and its target genes, further demonstrating that SREBP-2 pathway induction is not dependent on PPARalpha activation. Lastly, there is no activation of either SREBP-2 or ER stress pathways in kidney and lung of newborn Pex2(-/-) mice, suggesting a parallel induction of these pathways in peroxisome deficient mice. These findings establish novel associations between SREBP-2, ER stress and PPARalpha pathway inductions. PMID- 22441166 TI - It's time to let the 'CAT' out...patient!. PMID- 22441167 TI - 6-Substituted quinoline-based ratiometric two-photon fluorescent probes for biological Zn2+ detection. AB - New ratiometric two-photon fluorescent probes are developed from 6-substituted quinolines for biological Zn(2+) detection. They show large red shifts and good ratiometric responses upon Zn(2+) binding. They also exhibit high ion selectivities and large two-photon absorption cross sections at nearly 720 nm. Because the new probes are cell-permeable, they can be used to detect intracellular zinc flux under two-photon excitation. PMID- 22441168 TI - Construction of nanoparticle superstructures on the basis of host-guest interaction to achieve performance integration and modulation. AB - Creation of nanoparticle (NP) architectures via a self-assembly strategy is the current means to integrate and/or modulate the functionalities of NPs. In this paper, we demonstrate the capability for constructing NP spherical superstructures through the specific interaction between host and guest molecules, for instance the model system of alpha-cyclodextrin (alpha-CD) and oleic acid (OA), which are decorated on two different NPs beforehand. Subsequently, the OA-decorated hydrophobic NPs are dispersed in hexane, whereas the alpha-CD-decorated NPs are dispersed in water. The blending of these two immiscible solutions produces NP binary superstructures because of the multiple linkages between the alpha-CD- and OA-decorated NPs. Control experiments indicate that the self-assembly of NPs occurs either at the hexane/water interface to form hybrid films or in the aqueous phase to generate spherical architectures, which strongly depends on the amount and the size of alpha-CD-decorated NPs. The high ratio and small size of the alpha-CD-decorated NPs facilitate the formation of spherical architectures. Competitive experiments with the addition of host alpha CD and guest sodium oleate clearly confirm that the main driving force for the NP co-assembly is the specific interaction between alpha-CD and OA. In addition, the flexible decoration of alpha-CD and OA on the NPs makes the current strategy generally applicable for a variety of NPs, such as the superstructures of Au/Fe(3)O(4), Pt/Fe(3)O(4), and Au/NaYF(4):Yb,Tm, which is expected to promote the further application of NPs in environmental and biological sciences. PMID- 22441169 TI - Neoplastic B-cell growth is impaired by HLA-G/ILT2 interaction. PMID- 22441170 TI - Cross-species transmission of simian retroviruses: how and why they could lead to the emergence of new diseases in the human population. AB - The HIV-1 group M epidemic illustrates the extraordinary impact and consequences resulting from a single zoonotic transmission. Exposure to blood or other secretions of infected animals, through hunting and butchering of bushmeat, or through bites and scratches inflicted by pet nonhuman primates (NHPs), represent the most plausible source for human infection with simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus (STLV) and simian foamy virus. The chance for cross-species transmissions could increase when frequency of exposure and retrovirus prevalence is high. According to the most recent data, human exposure to SIV or STLV appears heterogeneous across the African countries surveyed. Exposure is not sufficient to trigger disease: viral and host molecular characteristics and compatibility are fundamental factors to establish infection. A successful species jump is achieved when the pathogen becomes transmissible between individuals within the new host population. To spread efficiently, HIV likely required changes in human behavior. Given the increasing exposure to NHP pathogens through hunting and butchering, it is likely that SIV and other simian viruses are still transmitted to the human population. The behavioral and socio economic context of the twenty-first century provides favorable conditions for the emergence and spread of new epidemics. Therefore, it is important to evaluate which retroviruses the human population is exposed to and to better understand how these viruses enter, infect, adapt and spread to its new host. PMID- 22441171 TI - Velocity distributions in a micromixer measured by NMR imaging. AB - Velocity distributions (so-called propagators) with two-dimensional spatial resolution inside a chemical micromixer were measured by pulsed-field-gradient spin-echo (PGSE) nuclear magnetic resonance (NMR). A surface coil matching the volume of interest was built to enhance the signal-to-noise ratio. This enabled the acquisition of velocity maps with a very high spatial resolution of 29 MUm * 39 MUm. The measured propagators are compared with theoretical distributions and a good agreement is found. The results show that the propagator data provide much richer information about flow behaviour than conventional NMR velocity imaging and the information is essential for understanding the performance of a micromixer. It reveals, for example, deviations in the shape and size of the channel structures and multicomponent flow velocity distribution of overlapping channels. Propagator data efficiently compensate lost information caused by insufficient 3D resolution in conventional velocity imaging. PMID- 22441172 TI - Seasonal variation, sources, and gas/particle concentrations of PCBs and OCPs at high altitude suburban site in Western Black Sea Region of Turkey. AB - Daily gas and particle phase samples were collected during winter and summer seasons in Bolu, which is located in the high altitude Western Black Sea Region of Turkey. Samples were analyzed to determine the concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs). Concentrations of endosulfan sulfate and methoxychlor were found to be highest in the summer and winter periods, respectively. The measured average concentration of endrin was considerably higher (10-50 fold) than the values reported in the literature for similar sites. The agricultural areas located to the south, south east and south-west of the sampling point were identified as source regions. PCBs were found predominantly in the gas phase in both seasons and 3-chlorinated biphenyls were found to be abundant in the winter period, due to pollutants transported from the city centre and a waste incineration plant by southerly and easterly winds. The concentrations of PCB-180 and PCB-194 were found to be higher than values reported in the literature. The correlation between atmospheric concentrations and temperature was obtained by using Clausius-Clapeyron (CC) plots. The CC plots for most of the OCPs showed shallow negative slopes with low r(2) values, which might be due to the presence of local sources, i.e., agricultural areas around the sampling site and the dominance of evaporation. The CC plots showed steep positive slopes for most of the PCB compounds. Most of the PCB compounds were carried from the ongoing local sources. PMID- 22441173 TI - Nigella sativa reduces tissue damage in rat ovaries subjected to torsion and detorsion: oxidative stress, proinflammatory response and histopathological evaluation. AB - BACKGROUND: To evaluate biochemically and histopathologically the effects of Nigella sativa (NS) in experimental ischemia and ischemia/reperfusion (I/R) injury in rat ovaries. METHODS: Thirty-six female rats were divided into 6 groups: group I = sham operation; group II = 500 mg/kg NS + sham operation; group III = bilateral ovarian ischemia; group IV = 500 mg/kg NS + ischemia; group V = 3 hour period of ischemia + 3-hour reperfusion, and group VI: 3-hour period of ischemia + 500 mg/kg NS 2.5 h after the induction of ischemia + 3-hour reperfusion. At the end of ischemia, the bilateral vascular clips were removed, and 3-hour reperfusion was continued. IL-1beta, IL-6, and TNF-alpha cytokine levels in serum, and superoxide dismutase (SOD), myeloperoxidase (MPO), glutathione (GSH), and malondialdehyde (MDA) levels were determined. RESULTS: I/R increased the MDA level and MPO activity while significantly decreasing the SOD activity and GSH level when compared to the sham. The 500-mg/kg dose of NS before I/R reversed the trend in MDA levels, MPO activity, SOD activity, and GSH levels. Ischemia and I/R increased the serum levels of IL-1beta, IL-6, and TNF-alpha, while the administration of NS decreased the serum levels of these cytokines. CONCLUSIONS: The administration of NS is effective in reversing tissue damage induced by ischemia and/or I/R in ovaries. PMID- 22441174 TI - Beyond the blues: towards a cross-cultural phenomenology of depressed mood. AB - BACKGROUND: There is a great cultural variety in the social phenomenology of depressed mood. The aim of this qualitative study was to compare English and Laotian Hmong semantic and pragmatic differences in depressed mood and to assess their relevance for cross-cultural psychiatric research and practice. SAMPLING AND METHOD: The first author conducted long-term ethnographic fieldwork from 2000 to 2002 among the Hmong in Laos. Methods included participant observation, interviews and focus group interviews in the Hmong language. The semantic and pragmatic context of Hmong depressed mood tu siab, literally translated as 'broken liver', is compared to that of 'sadness' in Western contexts. RESULTS: Hmong 'broken liver' and English 'sadness' are deeply shaped by culture-specific premises concerning notions of social interaction, morality, interiority, socialisation, and cosmology. CONCLUSIONS: Critical attention has to be paid when assessing depressed mood cross-culturally. A social phenomenology combining qualitative and quantitative methods should be developed to analyse important semantic and pragmatic differences of depressed mood across cultural contexts. PMID- 22441175 TI - The global role of kidney transplantation. AB - World Kidney Day on March 8th 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end stage kidney disease include the economic limitations which, in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation and vaccination. Even in high income countries the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit. PMID- 22441176 TI - Cardiac evaluation of patients with chronic kidney disease: what lessons? AB - INTRODUCTION: Patients with chronic kidney disease (CKD) experiment a synergistic effect of the traditional and the emerging uremia-related risk factors for atherosclerosis. OBJECTIVE: Draw the epidemiologic profile of a group of CKD patients who underwent cardiac evaluation. METHODS: Symptomatic patients, patients with ischemia on myocardial scintigraphy and/or systolic dysfunction on echocardiography, patients older than 50 years and diabetes mellitus (DM) as a cause of CKD, and those with two or more risk factors underwent coronary angiography. Asymptomatic, non-diabetic patients and patients with no risk factors were investigated with echocardiography. Those with a single risk factor were investigated with echocardiography and scintigraphy. RESULTS: 46 patients (58.7% men) were enrolled. Their mean age was 50.7 +/- 11.7 years. 91.3% were on dialysis, for 61.96 +/- 55.1 months. Hypertension was the cause of CKD in 56.5%. Of the 28 patients (60.9%) who underwent angiography, 53.6% had coronary artery disease (CAD). The patients were divided into three groups: those with CAD (A), those without CAD (B) and those who didn't undergo coronary angiography (C). A significant difference occurred only between groups B and C, as regards an abnormal ABI (p = 0.026), with no ABI abnormality in group C, and as regards the mean age, which was higher in group B (p = 0.045). In group A, 53.3% of the patients were in the preoperative stage of parathyroidectomy. CONCLUSION: This study confirmed the high rate of cardiovascular disorders, including CAD, in patients with CKD, especially those on dialysis. PMID- 22441177 TI - Prevalence of metabolic syndrome and its associated factors in renal transplant recipients. AB - INTRODUCTION: The population of patients undergoing renal transplantation is considered at highrisk for developing obesity and changes in lipid and glucose metabolism, due to the use of immunosuppressive drugs and increased food freedom in the post-transplant period. OBJECTIVE: This study was designed to assess the prevalence of metabolic syndrome in renal transplant recipients and to identify factors associated with its occurrence. METHODS: A cross-sectional study was performed in renal transplant patients, with more than six months of follow-up. The metabolic syndrome was diagnosed according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III. RESULTS: Among the 87 patients enrolled, 39 (44.8%) presented the phenotype of metabolic syndrome. The mean age of the patients was 43.5 +/- 12.1 years-old, with a predominance of male (69.0%) and white (66.7%). The mean and median times of post transplant follow-up were 64.2 +/- 49.4 and 56 months, respectively. All the 12 patients who developed post-transplant diabetes mellitus also met the criteria for metabolic syndrome, which compromised the inclusion of this variable in the logistic regression. In the univariate analysis, patients with metabolic syndrome had higher mean age (p = 0.008), higher median blood level of cyclosporine (p = 0.021), higher prevalence of history of coronary disease (p = 0.023), and they were more frequent users of beta (p = 0.011) and calcium- channel blockers (p = 0.039). In the multivariate analysis, age (HR = 1.06; 95% CI=1.01-1.11, p=0.006) and use of beta-blockers (HR = 4.02; 95% CI = 1.41 - 11.4, p = 0.009) were associated with increased risk of metabolic syndrome. CONCLUSION: Metabolic syndrome was highly prevalent in the population of renal trans- plant recipients studied, and it was associated with older age, use of beta-blockers, and post-transplant diabetes mellitus. PMID- 22441178 TI - Calculation of Kt/V in haemodialysis: a comparison between the formulas. AB - INTRODUCTION: The quality of delivered dialysis can be measured by the Kt/V ratio, which can be calculated in various ways. OBJECTIVE: To compare the Kt/V ratio obtained with the formulas of Lowrie (L) and Daugirdas (D) with the results measured by an Online Clearance Monitor (OCM). METHOD: Observational, cross sectional study of 59 patients on hemodialysis (HD). Data were collected in the same dialysis session (predialysis and postdialysis urea) and Kt/V was calculated by the OCM of the Fresenius 4008S machine (Fresenius Medical Care AG, Bad Homburg, Germany). RESULTS: A total of 95 sessions were assessed, with a predominance of males 56% (33), and a sample mean age of 57 + 14 years. Hypertension (42%; n = 25), diabetes (12%; n = 7) and glomerulonephritides (8%; n = 5) were the most frequent causes of chronic kidney disease (CKD). Mean Kt/V values obtained with the L and D formulas and the OCM were 1.31, 1.41 and 1.32, respectively. Comparison between the L and D formulas showed a statistically significant difference (p = 0.008), with a Pearson's correlation of 0.950. The difference between the D formula and the OCM was also significant (p = 0.011 and r = 0.346), probably due to convective loss, estimated by the D formula but not by the OCM and L formula. The difference between the L formula and the OCM was not significant (p = 0.999 and r = 0.577). CONCLUSION: These data suggest that the OCM can be used as a guide to the real-time adjustment of the dialysis dose. PMID- 22441179 TI - A comparative analysis of pre- and post-dialysis albumin as indicators of nutritional and morbi-mortality risks in haemodialysis patients. AB - INTRODUCTION: Pre-dialysis albumin is likely to be falsely low due to a dilution effect, making its usefulness in assessing protein status questionable. OBJEVTIVES: The purpose of this study was to assess whether post-dialysis albumin would be a better marker of malnutrition and risk of mortality, when compared to pre-dialysis albumin. METHODS: We evaluated the correlation between pre- and post dialysis albumin and the following parameters: body mass index (BMI), adequacy of muscle arm circumference (MAC) and tricipital skinfold (TS) to the 50th percentile (P50), C-reactive protein (CRP), phase angle (PA), protein equivalent of nitrogen appearance (PNA), the Kt/V index of dialysis adequacy, and the hydration status (Pearson's correlation coefficient). Agreement in the nutritional status according to pre- and post-dialysis (post-HD) albumin and PA was estimated according to the Kappa (K) coefficient (Bland-Altman). RESULTS: A total of 58 haemodialysis (HD) patients were included in this study (30 female; mean age: 49 years). BMI, PA and CRP had a significant correlation with pre- and post-HD albumin, while MAC and PNA correlated only with post-HD albumin. Agreement in the diagnosis of malnutrition according to PA < 5 and pre- and post HD albumin < 3.2 g/dL was regular (K = 0.432). When using an albumin cut-off value of 3.7 g/dL for malnutrition (mild malnutrition or risk of malnutrition), the diagnosis was concordant only in the post-HD period (K = 0.544). CONCLUSIONS: Post-dialysis albumin levels may be a better marker of protein status and mortality risk in cases of mild malnutrition or risk of malnutrition and in patients with low/medium mortality risk. Pre-dialysis fluid overload may be a confounding factor when evaluating albumin levels. PMID- 22441180 TI - Weight loss improves renal hemodynamics in patients with metabolic syndrome. AB - OBJECTIVE: We investigated the impact of weight loss on urinary albumin excretion (UAE) and creatinine clearance in obese patients with metabolic syndrome. METHODS: Thirty-five obese patients undertook a 12-week calorie-restricted diet. The patients underwent a metabolic (oral glucose tolerance test, plasma lipids, and uric acid) and renal hemodynamic evaluations (creatinine clearance and urinary albumin excretion) before (phase 1), and after the 12-week diet (phase 2). RESULTS: After the dietary intervention, the subjects were divided into two groups: patients who achieved the target weight reduction (R: responders, n = 14), and patients who did not (NR: non-responders, n = 21). The patients in Group R showed an improvement in lipid profile, a decrease in UAE (median = 162.5 mg/24 hours, range: 0.8 to 292 mg/24 hours, at phase 1 versus 10.4 mg/24 hours, range: 1.6 to 22.4 mg/24 hours, at phase 2), and a significant reduction in creatinine clearance (121.4 +/- 66.5 mL/min. in phase 1 to 92.9 +/- 35.6 mL/min. at the end of phase 2, p = 0.001). In Group NR, no statistically significant differences were observed between phases 1 and 2. CONCLUSION: Body weight reduction has a positive impact on renal hemodynamics, decreasing urinary albumin excretion as well as glomerular hyperfiltration in obese patients with metabolic syndrome. PMID- 22441181 TI - Similarity between blood pressure values assessed by auscultatory method with mercury sphygmomanometer and automated oscillometric digital device. AB - INTRODUCTION: One of the biggest challenges in the management of hypertension is adequate blood pressure (BP) control. To achieve this goal, home blood pressure measurement (HBPM) with automated devices has been encouraged. However, part of the medical community still disputes its validity, believing that HBPM may lead to incorrect readings. OBJECTIVE: To evaluate the correspondence between the simultaneous measurements of BP with the auscultatory method and an oscillometric digital method, commonly used in HBPM. METHODS: BP was determined simultaneously in 423 individuals (normotensive and hypertensive) with a validated automated digital device (ONROM 705IT) and with the auscultatory method with a mercury sphygmomanometer. Both devices were connected through a Y-shaped connection to a cuff whose size was adjusted to the arm circumference. RESULTS: The values represent mean +/- SD (minimum-maximum values): age 40.8 +/- 16.3 years (18-92), arm circumference 28.2 +/- 3.7 cm (19-42), systolic BP (SBP) auscultatory 127.6 +/- 22.8 mmHg (69-223), SBP automated 129.5 +/- 23.0 mmHg (56-226), diastolic BP (DBP) auscultatory 79.5 +/- 12.6 mmHg (49-135) DBP automated 79.0 +/- 12.6 mmHg (48-123). The mean difference in SBP between the two methods was 1.9 mmHg (-15 to +19) and 0.5 mmHg for DBP (-19 to +13). The Bland-Altman analysis showed clinically acceptable agreement between the methods. CONCLUSION: BP measured with the automated method closely mirrors that determined with the conventional auscultatory method and should be used to improve the diagnosis and control of hypertension. PMID- 22441182 TI - Stressful life events and acute kidney injury in intensive and semi-intensive care unities. AB - INTRODUCTION: Several studies point out that pathophysiological changes related to stress may influence renal function and are associated with disease onset and evolution. However, we have not found any studies about the influence of stress on renal function and acute kidney injury. OBJECTIVE: To evaluate the association between stressful life events and acute kidney injury diagnosis, specifying the most stressful classes of events for these patients in the past 12 months. METHODS: Case-control study. The study was carried out at Hospital Sao Paulo, in Universidade Federal de Sao Paulo and at Hospital dos Servidores do Estado de Sao Paulo, in Brazil. Patients with acute kidney injury and no chronic disease, admitted to the intensive or semi-intensive care units were included. Controls included patients in the same intensive care units with other acute diseases, except for the acute kidney injury, and also with no chronic disease. Out of the 579 patients initially identified, 475 answered to the Social Readjustment Rating Scale (SRRS) questionnaire and 398 were paired by age and gender (199 cases and 199 controls). RESULTS: The rate of stressful life events was statistically similar between cases and controls. The logistic regression analysis to detect associated effects of the independent variables to the stressful events showed that: increasing age and economic classes A and B in one of the hospitals (Hospital Sao Paulo - UNIFESP) increased the chance of a stressful life event (SLE). CONCLUSIONS: This study did not show association between the Acute Kidney Injury Group with a higher frequency of stressful life events, but that old age, higher income, and type of clinical center were associated. PMID- 22441183 TI - Vitamin D deficiency and insufficiency in patients with chronic kidney disease. AB - INTRODUCTION: Vitamin D deficiency is common among patients with chronic kidney disease (CKD). A higher level of serum vitamin D is expected in residents of the tropics in relation to inhabitants of non-tropical regions, due to greater sun exposure and increased production of vitamin D. OBJECTIVE: To analyze serum levels of vitamin D, such as 25-hydroxyvitamin D - 25(OH)D, in Brazilian patients at the predialytic stage with CKD. METHODS: We studied 125 patients (aged 57.4 +/ 16.2 years, 78 were white and 55.2%, male), with creatinine 2.67 +/- 1.73 mg/dL and creatinine clearance 43.7 +/- 34.5 mL/min. Body mass index was 27.4 +/- 4.7 kg/m2, and waist circumference was 95.0 +/- 14.0 cm. Calcium was 9.3 +/- 0.6 mg/dL, intact parathormone (iPTH) 212.6 +/- 221.2 pg/mL and serum albumin 4.2 +/- 0.6 g/dL. The mean 25(OH)D was 23.9 +/- 10.7 ng/mL. RESULTS: Out of the 125 patients, we found that 92 (72.6%) had suboptimal levels of 25(OH)D < 30 ng/mL, and 65 (52%) had vitamin D insufficiency (15-29 ng/mL); 27 (21.5%) had deficiency (5-14 ng/mL) and only one patient had severe vitamin D deficiency <5 ng/mL. No differences were observed among the levels of 25 (H)D in stratified patients as to the CKD stage. Levels of 25(OH)D were higher among males (38.1 +/- 20.6 versus 22.4 +/- 9.7 ng/mL; p < 0.0001), and there was an inverse correlation between levels 25(OH)D and iPTH, proteinuria and abdominal circumference, and a positive correlation between 25(OH)D and calcium and serum albumin. Multivariate analysis only showed inverse correlation between serum 25(OH)D and iPTH and abdominal circumference. CONCLUSION: Even though the Brazilian population live in a tropical region, most patients had suboptimal levels of serum vitamin D, and this pattern may play a role in the development of hyperparathyroidism. PMID- 22441184 TI - Urinary protein/creatinine ratio versus 24-hour proteinuria in the evaluation of lupus nephritis. AB - INTRODUCTION: The urinary protein/creatinine ratio has been used instead of 24 hour proteinuria in Nephrology practice for the follow-up of glomerular diseases, considering the advantages of collection and the low cost. However, there are still doubts as to its applicability both for an isolated evaluation and for the follow-up of patients with lupus nephritis. OBJECTIVE: To evaluate 24-hour proteinuria determinations and random urine samples, performing urinary creatinine correction and urinary protein/creatinine ratio in subjects with lupus nephritis. METHODS: 24-hour proteinuria and urinary protein/creatinine ratio were determined by conventional methods (automated Pyrogallol for proteinuria and alkaline picrate for creatinine). RESULTS: Seventy-eight urine samples of 41 patients diagnosed with systemic lupus erythematosus, according to the American Rheumatology Association, with lupus nephritis, were analyzed, and a good correlation between 24-hour proteinuria and urinary protein/creatinine ratio (r = 0.9010 and r2 = 0.813) was observed. However, a poor correlation between random proteinuria (without creatinine correction) versus 24-hour proteinuria (r = 0.635 and r2 = 0.403) or versus urinary protein/creatinine ratio (r = 0.754 and r2 = 0.569) was seen. CONCLUSION: 24-hour proteinuria and urinary protein/creatinine ratio were useful in the follow-up of each case. However, we observed that the absolute values were different, which did not allow the replacement of one for the other during follow-up, especially when this result is used to define the activity of the disease. Based on these results, we suggest a period of intersection from one to the other (two to three determinations by both methods), and the choice of one marker for proteinuria follow-up, if necessary. PMID- 22441185 TI - Association between laboratory and clinical risk factors and progression of the predialytic chronic kidney disease. AB - INTRODUCTION: Chronic kidney disease (CKD) is a very common condition that has become a public health issue. Knowing more about risk factors associated with the progression of CKD allows therapeutic interventions that may change the natural course of the disease. OBJECTIVE: To evaluate the impact of clinical and laboratory variables at admission on the outcomes death and need for renal replacement therapy (RRT). METHODS: A retrospective cohort study comprised of 211 adult patients with stages 3-5 CKD, followed-up for 56.6 +/- 34.5 months. RESULTS: Mean age of patients was 65.4 +/- 15.1 years and 63.5% were > 60 years. The main causes of CKD were hypertensive nephrosclerosis (29%) and diabetic kidney disease (DKD) (17%). Most patients (47.3%) were on stage 4 CKD. The mean annual loss of glomerular filtration rate (GFR) was 0.6 +/- 2.5 mL/min/1.73 m2 (median 0.77 mL/min/1.73 m2) After the adjustments for demographic, clinical and laboratory variables, DKD [relative risk (RR) 4.4; 95% confidence interval (CI), 1.47 to 13.2; p = 0.008] was predictive of RRT; age (RR 1.09; 95% CI, 1.04 to 1.15; p < 0.0001) and the non-treatment with angiotensin receptor blocker (ARB) (RR 4.18, 95% CI, 1.34 to 12.9; p = 0.01) were predictors of death. Renal and patient survival rates were 70.9% and 68.6%, respectively. CONCLUSION: In this study, patients with stage 3-5 CKD treated conservatively showed stabilization of renal function and low mortality, which were impacted by DKD, age and to not using ARB, respectively. PMID- 22441186 TI - Salmonella peritonitis in a patient on automated peritoneal dialysis. AB - We describe the clinical course of a case of peritonitis caused by Salmonella sp. after an episode of intestinal salmonellosis, and a brief review of the literature is also done. PMID- 22441187 TI - The long-term use of enalapril and hydrochlorothiazide in two novel mutations patients with Dent's disease type 1. AB - Dent's disease type 1 is an X-linked tubular disease caused by mutations in the renal chloride channel CLCN-5, and it is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal failure. Several cases have been described in which the only presenting symptoms were asymptomatic proteinuria, and focal segmental or global glomerulosclerosis. The renal failure in these patients may be caused by hypercalciuria and persistent proteinuria. Therefore, angiotensin converse enzyme inhibitor and thiazides could be useful. Our aim is to report the effects of these drugs in two novel mutations patients with Dent's disease type 1. In this report, no significant correlations between dosage of hydrochlorothiazide and calciuria and no significant correlations between proteinuria and dosage of enalapril were detected. This is important since these are polyuric patients and these drugs could be dangerous to their renal function. PMID- 22441188 TI - Application of molecular biology at the approach of Bartter's syndrome: case report. AB - This paper aims to show the utility of molecular biology for diagnose Bartter syndrome (BS) by the case report of two sisters and to propose a diagram for the molecular approach of this syndrome. The two reported cases presented prematurity, pregnancy complicated with polyhydramnio and low birth weight. During the first year of life, children exhibited polyuria, polydipsia and failure to thrive, leading to the investigation of renal tubular diseases and innate errors of metabolism. The laboratorial exams suggested BS, but the definitive diagnostic was only obtained by the detection of homozygous mutation on the exon 5 of the gene KCNJ1, resulting in a substitution of the aminoacid alanin for valin on codon 214 (A214V) in both DNA stripes in the two sisters and a heterozygous mutation in their parents. The definitive diagnostic of BS is frequently very difficult to be obtained. Consequently, considering the reported cases, we showed the utility of molecular techniques for the definitive diagnostic of BS and we proposed a diagram for the rational use of these techniques. PMID- 22441189 TI - Preeclampsia (marker of chronic kidney disease): from genesis to future risks. AB - Preeclampsia (PE) is a pregnancy-specific disease which, in addition to other hypertensive disorders, is an important cause of maternal and perinatal morbidity and mortality. With an incidence ranging from 3 to 14% of all pregnancies worldwide, the disease can present in different clinical forms. PE and cardiovascular diseases (CVD) have similar pathophysiological mechanisms, such as endothelial dysfunction, metabolic changes and oxidative stress, and they also share some risk factors such as obesity, kidney disease and diabetes. Although the exact relationship between PE and cardiovascular risk has not been fully elucidated, PE-triggered metabolic stress may cause vascular injury, thus contributing to the development of CVD and/or chronic kidney disease (CKD) in the future. This risk appears to be increased especially in women with a history of recurrent, severe PE and eclampsia. The investigation of a history of PE may assist in assessing the future risk of CVD and CKD, their prevention and early diagnosis. PMID- 22441190 TI - Effect of kidney transplantation on cardiac morphology and function. AB - Cardiac involvement is very frequent in patients with chronic kidney disease on dialysis. Kidney transplantation results in reducing morbidity and mortality compared to patients on dialysis. The objective of this review was to address the effect of renal transplantation in cardiac structure and function assessed by echocardiography. Since the 1980s, studies have demonstrated a trend towards improvement in cardiac parameters after kidney transplantation. With the improvement of the Doppler imaging methods, the new studies, although with conflicting results, demonstrated improvement in systolic and diastolic function and reduction of left ventricular mass, especially in the first two years after renal transplantation with stabilization of the parameters in subsequent years. Overall, the body of evidence has demonstrated significant impact of renal transplantation on left ventricular hypertrophy, systolic and diastolic function, but the results are not uniform. PMID- 22441191 TI - A united approach to vascular disease and neurodegeneration. PMID- 22441192 TI - Trade in electronic waste: a poisoned chalice? PMID- 22441193 TI - Gregor Wenning: unravelling the mysteries of MSA. PMID- 22441195 TI - Applicability of stroke-unit care to low-income and middle-income countries. AB - Stroke units have become established as the central component of modern stroke services. However, most stroke-unit trials and service developments have been done in high-income countries, which raises the question of whether such care is relevant and applicable to low-income and middle-income settings. To address this question, we first need to show that stroke units are likely to provide important health gains to populations. Second, we need to identify those components of stroke units that could be important for a low-technology unit, and to learn from examples of stroke units in low-income and middle-income countries. Finally, we need to understand how barriers to the establishment of stroke units could be overcome. Although substantial challenges are present to the development of stroke units more widely across the world, the potential gains from such developments are substantial. PMID- 22441196 TI - Association between pathological and MRI findings in multiple sclerosis. AB - The identification of pathological processes that could be targeted by therapeutic interventions is a major goal of research into multiple sclerosis (MS). Pathological assessment is the gold standard for such identification, but has intrinsic limitations owing to the limited availability of autopsy and biopsy tissue. MRI has gained a leading role in the assessment of MS because it allows doctors to obtain an ante mortem picture of the degree of CNS involvement. A number of correlative pathological and MRI studies have helped to define in vivo the pathological substrates of MS in focal lesions and normal-appearing white matter, not only in the brain, but also in the spinal cord. These studies have resulted in the identification of aspects of pathophysiology that were previously neglected, including grey matter involvement and vascular pathology. Despite these important achievements, numerous open questions still need to be addressed to resolve controversies about how the pathology of MS results in fixed neurological disability. PMID- 22441197 TI - Premotor signs and symptoms of multiple system atrophy. AB - Diagnostic criteria for multiple system atrophy are focused on motor manifestations of the disease, in particular ataxia and parkinsonism, but these criteria often cannot detect the early stages. Non-motor symptoms and signs of multiple system atrophy often precede the onset of classic motor manifestations, and this prodromal phase is estimated to last from several months to years. Autonomic failure, sleep problems, and respiratory disturbances are well known symptoms of established multiple system atrophy and, when presenting early and preceding ataxia or parkinsonism, should be regarded as evidence of premotor multiple system atrophy. An early and accurate diagnosis is becoming increasingly important as new neuroprotective agents are developed. PMID- 22441199 TI - The analysis of major impurities of lipophilic-conjugated phosphorothioate oligonucleotides by ion-pair reversed-phase HPLC combined with MALDI-TOF-MS. AB - A simple and rapid ion-pair reversed phase high-performance liquid chromatography (IP-RP-HPLC) method was developed to analyse the major impurities of lipophilic conjugated phosphorothioate oligonucleotides (ODNs), which provided better separation performance than capillary gel electrophoresis and ion exchange chromatograph methods. The study showed that covalent conjugations of lipophilic group (docosanyl, C(22)) to ODN at 5'-termini (denoted as 5'C(22)-Flu) or 3' termini (denoted as 3'C(22)-Flu) exhibited similar chromatographic retention behavior. Some important analytical conditions of IP-RP-HPLC, including column type, ion-pairing buffer composition, and separation temperature, were investigated for the effects on the separation of crude 5'C(22)-Flu. As expected, the method developed was successfully applied to the analysis of crude 3'C(22) Flu and both purified products. Furthermore, the related impurities derived from the synthetic process were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrum. These MS results are of benefit to understanding the major process-related impurities in lipophilic-ODN conjugates synthesis, thereby elevating the quality of target products. PMID- 22441198 TI - Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. AB - Recent laboratory findings suggest that it might be possible to promote cerebral plasticity and neurological recovery after stroke by use of exogenous pharmacological or cell-based treatments. Brain microvasculature and glial cells respond in concert to ischaemic stressors and treatment, creating an environment in which successful recovery can ensue. Neurons remote from and adjacent to the ischaemic lesion are enabled to sprout, and neural precursor cells that accumulate with cerebral microvessels in the perilesional tissue further stimulate brain plasticity and neurological recovery. These factors interact in a highly dynamic way, facilitating temporally and spatially orchestrated responses of brain networks. In view of the complexity of the systems involved, stroke treatments that stimulate and amplify these endogenous restorative mechanisms might also provoke unwanted side-effects. In experimental studies, adverse effects have been identified when neurorestorative treatments were administered to animals with severe associated illnesses, after thrombolysis with alteplase, and when therapies were initiated outside appropriate time windows. Balancing the opportunities and possible risks, we provide suggestions for the translation of restorative therapies from the laboratory to the clinic. PMID- 22441200 TI - A rapid analytical method for cholecalciferol (vitamin D3) in fortified infant formula, milk and milk powder using Diels-Alder derivatisation and liquid chromatography-tandem mass spectrometric detection. AB - A method for analysing vitamin D(3) (VD3, cholecalciferol) has been established and validated. This method is rapid and cost effective and is intended for use in quality control in the manufacture of fortified infant formulae and milk powders. Milk or reconstituted milk powder was solubilised in methanol and extracted in one step into isooctane, which was separated by centrifugation. A portion of the isooctane layer was then transferred, and an aliquot of 4-phenyl-1,2,4-triazoline 3,5-dione was added to derivatise VD3. The analyte was then re-extracted into a small volume of acetonitrile and analysed by reverse-phase chromatography. Detection was by triple quadrupole mass spectrometer using a selective transition, m/z 560 -> 298. An internal standard, deuterium-labelled VD3, was used to correct for losses in extraction and any variation in derivatisation and ionisation efficiencies. The method has been subjected to a single-laboratory validation and has been found to be linear, highly selective and accurate with respect to National Institute of Standards and Technology Standard Reference Material 1849, analyte spiking experiments and comparison with an LC-UV-based method. The repeatability standard deviation was 4.23 %. Significantly for routine laboratories, the method returns results within 2 h, generates minimal waste and minimises health and safety concerns to the analyst. PMID- 22441201 TI - A convenient approach to beta-heteroarylated (C-N bond) ketones from Cs2CO3 promoted reaction between propargyl alcohols and nitrogen-heterocycles. AB - An efficient and direct approach to beta-heteroarylated (C-N bond) ketones is demonstrated. Base promoted redox isomerization of propargyl alcohol to alpha,beta-unsaturated ketone followed by conjugate addition to NH-heteroarenes affords a wide range of beta-heteroarylated ketones in good to excellent yields. Aryl, heteroaryl, alkyl C(sp), and terminal alkynes containing unactivated propargyl alcohols effectively undergo redox-isomerization conjugate addition (RICA) with NH-heteroarenes. Reaction of 3-substituted pyrazoles or indazole with propargyl alcohols enables highly regioselective products. A diverse range of NH bearing nucleophiles such as: pyrazoles, imidazole, triazoles, pyrrole, indoles and aniline participate in this reaction and deliver the corresponding beta heteroarylated ketones. PMID- 22441202 TI - Bismuth ferrite clusters induced hydrogel formation in human serum albumin. AB - Amyloid-fibril formation in human serum albumin (HSA) led to hydrogel formation in the presence of clusters of bismuth ferrite (BiFeO(3) or BFO) nanoparticles (NPs). Factors responsible for hydrogel formation were size and phase of NPs. PMID- 22441203 TI - Hydrate-phobic surfaces: fundamental studies in clathrate hydrate adhesion reduction. AB - Clathrate hydrate formation and subsequent plugging of deep-sea oil and gas pipelines represent a significant bottleneck for deep-sea oil and gas operations. Current methods for hydrate mitigation are expensive and energy intensive, comprising chemical, thermal, or flow management techniques. In this paper, we present an alternate approach of using functionalized coatings to reduce hydrate adhesion to surfaces, ideally to a low enough level that hydrodynamic shear stresses can detach deposits and prevent plug formation. Systematic and quantitative studies of hydrate adhesion on smooth substrates with varying solid surface energies reveal a linear trend between hydrate adhesion strength and the practical work of adhesion (gamma(total)[1 + cos theta(rec)]) of a suitable probe liquid, that is, one with similar surface energy properties to those of the hydrate. A reduction in hydrate adhesion strength by more than a factor of four when compared to bare steel is achieved on surfaces characterized by low Lewis acid, Lewis base, and van der Waals contributions to surface free energy such that the practical work of adhesion is minimized. These fundamental studies provide a framework for the development of hydrate-phobic surfaces, and could lead to passive enhancement of flow assurance and prevention of blockages in deep sea oil and gas operations. PMID- 22441204 TI - Diagnosis of blastic phase of chronic myeloid leukemia. PMID- 22441205 TI - Discrepancies between parent- and adolescent-perceived problem severity and influences on help seeking from mental health services. AB - OBJECTIVES: Attitudinal and practical barriers prevent many young people who are experiencing mental health problems from seeking professional help. The influence of others can help young people to overcome barriers to help seeking. Understanding the relative influence of parents and others on the help-seeking decision and the extent of parent-child agreement on the severity of the young person's problems, may be helpful in facilitating intake processes in child and adolescent mental health services (CAMHS). METHODS: One hundred and nineteen parent-child (14-18-years-old) dyads attending an initial appointment at a Sydney and regional CAMHS completed the parent and youth Strength and Difficulties Questionnaires (SDQs) prior to their assessment interview. Parents and children also answered three equivalent questions on sources of influence in their decision to access services. RESULTS: Ninety-four per cent of young people reported that others had influenced their decision to access help, with parents being the strongest influence. Higher levels of parental influence in the help seeking process were related to greater disagreement between parent and child on the severity of the problems. Parent and child ratings of influence were related to the severity of externalizing problems. CONCLUSION: The findings are consistent with models that highlight help seeking as a social process involving high degrees of influence particularly from parents. Referral sources and clinicians need to be aware of the effects of discrepant views between parent and child regarding the presenting problem. To facilitate joint therapy it may be helpful for clinicians to address the level of influence involved in having the young person attend their first appointment with parents and children. PMID- 22441206 TI - Clinical features of parricide in patients with schizophrenia. AB - OBJECTIVE: This study aimed to investigate the factors associated with parricide in patients with schizophrenia who committed homicide. METHOD: Among patients with schizophrenia who were in the National Institute of Forensic Psychiatry between November and December 2007, 88 patients who committed homicides were enrolled; 59 had committed parricide, and 29 had killed strangers. Medical charts, written expert opinions, written records of police or prosecutors, and court decisions were reviewed. Direct interviews with patients were also conducted. RESULTS: Significant factors associated with parricide among homicidal patients with schizophrenia were living with the victim, female sex of the victim, and offense-provoking events including scolding, threatening forced hospitalisation, and forcing medication on the patient before the homicide. Capgras syndrome was present at a significantly higher rate in the parricide group than in the stranger group. Drug compliance at the time of the offence was low in both groups. CONCLUSIONS: Untreated psychotic symptoms such as Capgras syndrome, living with elderly parents, especially mothers, and conflicts caused by victims' scolding, threatening forced hospitalisation, and forcing medication on the patients are associated with parricide among homicide offenders with schizophrenia. PMID- 22441207 TI - Finding the needle in the haystack: a review of microarray gene expression research into schizophrenia. AB - BACKGROUND: With an estimated 80% heritability, molecular genetic research into schizophrenia has remained inconclusive. Recent large-scale, genome-wide association studies only identified a small number of susceptibility genes with individually very small effect sizes. However, the variable expression of the phenotype is not well captured in diagnosis-based research as well as when assuming a 'heterogenic risk model' (as apposed to a monogenic or polygenic model). Hence, the expression of susceptibility genes in response to environmental factors in concert with other disease-promoting or protecting genes has increasingly attracted attention. METHOD: The current review summarises findings of microarray gene expression research with relevance to schizophrenia as they emerged over the past decade. RESULTS: Most findings from post mortem, peripheral tissues and animal models to date have linked altered gene expression in schizophrenia to presynaptic function, signalling, myelination, neural migration, cellular immune mechanisms, and response to oxidative stress consistent with multiple small effects of many individual genes. However, the majority of results are difficult to interpret due to small sample sizes (i.e. potential type-2 errors), confounding factors (i.e. medication effects) or lack of plausible neurobiological theory. CONCLUSION: Nevertheless, microarray gene expression research is likely to play an important role in the future when investigating gene/gene and gene/environment interactions by adopting a neurobiologically sound theoretical framework. PMID- 22441208 TI - A general and efficient aldehyde decarbonylation reaction by using a palladium catalyst. AB - A facile decarbonylation reaction of aldehydes has been developed by employing Pd(OAc)(2). A wide variety of substrates are decarbonylated, without using any exogenous ligand for palladium as well as CO-scavenger. PMID- 22441209 TI - Macrophages and systemic iron homeostasis. AB - As a principal aspect of their scavenging function, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recover iron, mainly for the production of hemoglobin in new erythrocytes but also for other carriers and enzymes requiring iron. Splenic red pulp macrophages are specialized for iron recycling with increased expression of proteins for the uptake of hemoglobin, breakdown of heme and the export of iron. In humans, recycling macrophages contribute the majority of the iron flux into extracellular fluid, exceeding the contribution of dietary iron absorption and release of stored iron from hepatocytes. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. In addition to their homeostatic role, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. This review discusses the iron-scavenging function of macrophages in the context of iron homeostasis and host defense. PMID- 22441210 TI - Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. AB - Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had >=1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 +/- 16% vs 95 +/- 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 +/- 12% vs 58 +/- 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL. PMID- 22441211 TI - Different cardiovascular protective effects of quercetin administered orally or intraperitoneally in spontaneously hypertensive rats. AB - We tested whether the administration procedure of quercetin affects its metabolite profile and antihypertensive activity. Spontaneously hypertensive rats (SHR) were randomly assigned to four experimental treatments: (1) 1 mL of 1% methylcellulose by oral gavage and 2% DMSO i.p. (control group); (2) 10 mg kg-1 quercetin by oral gavage once daily and 2% DMSO i.p.; (3) 10 mg kg-1 quercetin by oral gavage divided in two daily doses (5 + 5 at 12 h intervals) and 2% DMSO i.p.; (4) 1 mL of 1% methylcellulose by oral gavage and 10 mg kg-1 quercetin i.p. injection. Rats were treated daily for 5 weeks. Single dose and two daily doses, in a long-term oral treatment were equally efficient, both restoring the impaired aortic endothelium-dependent vasodilatation and reducing mesenteric contractile response to phenylephrine, systolic blood pressure, heart rate, and heart and kidney hypertrophy. Attenuation of vascular NADPH oxidase-driven O2- production was also found in orally treated rats. Intraperitoneal administration reduced, to lesser extent than oral administration, the increased systolic blood pressure, being without effect to the endothelial dysfunction and vascular oxidative stress. In contrast, greater levels of metabolites were quantified following intraperitoneal compared to oral administration at any time point, except for higher plasma methylated quercetin aglycone in oral as compared to intraperitoneal administration at 2 but not at 8 h. In conclusion, oral quercetin was superior to intraperitoneal administration for the protection from cardiovascular complications in SHR. No differences were found between the oral administration as a single daily dose or divided into two daily doses. PMID- 22441212 TI - Expression levels of vascular cell adhesion molecule-1 in young and nonobese women with polycystic ovary syndrome. AB - BACKGROUND/AIMS: The objective of this study was to measure levels of mRNAs for inflammatory markers and resistin in human peripheral blood mononuclear cells (PBMCs) in young and nonobese women with polycystic ovary syndrome (PCOS). METHODS: Fifteen young, nonobese women with PCOS and 10 age-matched controls were enrolled in this study. Levels of mRNAs for resistin and the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human PBMCs were measured using real-time PCR. RESULTS: The mean age and BMI of the women with PCOS were 27.54 +/ 6.3 years and 27.4 +/- 5.7, respectively. The women with PCOS had significantly higher fasting and 2-hour insulin levels, homeostasis model assessment of insulin resistance index (HOMA(IR)) and total cholesterol levels than the controls. VCAM 1 and ICAM-1 mRNA levels were significantly higher in women with PCOS than in controls, whereas no differences in resistin, IL-6, TNF-alpha and MCP-1 mRNA levels were observed between the groups. After adjusting for the BMI, only VCAM-1 mRNA levels were significantly higher in women with PCOS than in controls and correlated with the HOMA(IR) and total cholesterol. CONCLUSION: Elevated VCAM-1 in human PBMCs in young, nonobese women with PCOS is associated with insulin resistance, independent of the BMI. PMID- 22441213 TI - Cerebellar cognitive affective syndrome and autosomal recessive spastic ataxia of charlevoix-saguenay: a report of two male sibs. AB - BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by mutations in the SACS gene (13q12) encoding the protein sacsin. It is characterized by early-onset cerebellar ataxia, lower limb spasticity, sensorimotor axonal polyneuropathy, and atrophy of the superior cerebellar vermis. Cerebellar disorders in general may be accompanied by the cerebellar cognitive affective syndrome (CCAS) which presents with disturbances of executive functioning, spatial cognition, linguistic capacities, and affect. SAMPLING AND METHODS: Two middle-aged brothers with ARSACS, one of whom was referred for behavioral disinhibition, are described. A detailed neuropsychiatric and neuropsychological assessment was performed. RESULTS: Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunctions were present; these were much more pronounced in the older sib. CONCLUSIONS: These observations add to the literature which suggests that the cerebellum, apart from its significance for motor behavior, plays a functional role in human cognition and affect. The nonmotor symptoms of ARSACS are discussed in terms of the CCAS. PMID- 22441214 TI - Superoinferior ventricles with superior left ventricle: an example of hyperstrophic cardiac looping? PMID- 22441215 TI - Association of cardiac changes with serum adiponectin and resistin levels in obese and overweight children. AB - OBJECTIVES: To investigate serum adiponectin and resistin levels in childhood obesity and their relationship with cardiac changes and insulin resistance. METHODS: Seventy-one obese and 24 overweight children and 40 healthy children and adolescents were selected for the study. Height and weight measurements, BMI values and BMI SD score values were obtained for each individual. After blood pressure measurement, left ventricular wall thickness, left ventricular mass, stroke volume, cardiac output, systolic and diastolic functions of the left ventricle were measured using an M-mode, two dimensional color-coded echocardiography device. Blood samples of the individuals were obtained for fasting blood sugar, total blood cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein cholesterol, high density lipoprotein cholesterol, insulin, C-peptide, adiponectin and resistin values. RESULTS: Cholesterol and LDL values, homeostasis model assessment of insulin resistance, fasting insulin and fasting C-peptide values of the obese and overweight groups were higher (P<0.01). Adiponectin level (P<0.001) and resistin level (P<0.05) of the obese and overweight groups were lower than those of the control group (P<0.05). Echocardiographic evaluation showed diastolic dysfunction in addition to increased left ventricular wall thickness and left ventricle mass values in the obese and overweight children. We also detected a significant positive correlation among left ventricular mass, interventricular septum systolic diameter and resistin in obese children. Among the factors, resistin level was determined as an independent predictor of left ventricular mass in obese children. CONCLUSION: In this study, even in asymptomatic obese and overweight children, cardiac structural and functional changes, such as increased left ventricular mass and diastolic dysfunction, were demonstrated. Although decreased adiponectin level was not related to cardiac changes, it was shown that decreased serum resistin levels in the obese cases lead to left ventricle hypertrophy. PMID- 22441216 TI - Acute chest pain with paraplegia. PMID- 22441217 TI - An unusual cause of heart failure. AB - Pelvic arteriovenous malformations (AVMs) are uncommon entities that can present with symptoms resulting from compression of adjacent structures, ischemia due to 'steal phenomenon' or, rarely, heart failure. We present a case of heart failure in a patient who presented to our facilities for heart transplant and a prior diagnosis of idiopathic dilated cardiomyopathy; further evaluation revealed a massive pelvic AVM as causative for the heart failure. This case emphasizes the importance of a thorough physical examination to guide appropriate diagnostic testing. PMID- 22441218 TI - Effect of ramipril on the electrophysiological characteristics of ventricular myocardium after myocardial infarction in rabbits. AB - AIMS: The current study aims to explore the effect of ramipril on the occurrence of ventricular arrhythmias and its possible mechanism after myocardial infarction (MI) in rabbits. METHODS: A total of 24 rabbits were divided into three groups: the sham operation group (SHAM), the MI group, and the ramipril group (RAM). All groups were subjected to thoracotomy under sterile conditions; the MI and RAM groups underwent ligation of the left anterior descending coronary artery. On the second day after surgery, the RAM group was given ramipril (1 mg/kg per day). The rabbits in each group were fed for 12 weeks. The monophasic action potentials of the epicardium, mid-myocardium and endocardium in each group were, respectively, recorded before the MI and at 12 weeks after the MI. Meanwhile, the episodes of ventricular tachycardia or fibrillation (VT/VF) induced by procedure stimulations were counted, and the changes in L-type Ca flux (Ica-L) were recorded by means of the whole-cell patch-clamp technique. RESULTS: The episodes of VT/VF were decreased in the RAM group after MI. At 12 weeks after MI, the transmural dispersion of repolarization (TDR) in the MI group was prolonged significantly compared with the SHAM and RAM groups. The density of Ica-L in the MI group was significantly lower than that any other group. CONCLUSIONS: Ramipril manifestly decreases the incidence of VT/VF after MI in rabbits, and the mechanism may be associated with its inhibitory effect on electrical remodeling after MI. PMID- 22441219 TI - C-reactive protein and P-wave in hypertensive patients after conversion of atrial fibrillation. AB - AIMS: P maximum/P dispersion and high-sensitivity C-reactive protein (hs-C reactive protein) have been proposed as useful markers for predicting the history and recurrence of atrial fibrillation. We tested the association between hs-C reactive protein and maximum P-wave duration (P maximum)/P-wave dispersion (P dispersion) in hypertensive patients after conversion of atrial fibrillation. METHODS: We enrolled 92 patients. Hs-C-reactive protein was assessed before cardioversion, the 12-lead ECG was recorded immediately after sinus rhythm restoration. RESULTS: At univariate analysis P maximum above 120 ms was associated with male sex (P = 0.0009), body mass index at least 25 kg/m (P = 0.03) and hs-C-reactive protein greater than 0.30 mg/dl (P = 0.0001), and left atrium diameter greater than 40 mm nearly significant (P = 0.05). P dispersion above 40 ms was associated with hs-C-reactive protein greater than 0.30 mg/dl (P = 0.0001) and left atrium diameter greater than 0.40 mm (P = 0.03). P maximum/P dispersion (mean +/- SD) was significantly longer in patients with hs-C reactive protein greater than 0.30 mg/dl compared to patients with hs-C-reactive protein 0.30 mg/dl or less (P = 0.0001 for both). At multivariate analysis P maximum above 120 ms was associated with male sex (P = 0.01) and with hs-C reactive protein greater than 0.30 mg/dl (P = 0.002), whereas P dispersion above 40 ms was associated only with hs-C-reactive protein greater than 0.30 mg/dl (P = 0.0006). CONCLUSION: Male sex and hs-C-reactive protein were associated with P maximum above 120 ms; hs-C-reactive protein was also associated with P dispersion above 40 ms in hypertensive patients after conversion of atrial fibrillation. Subclinical inflammation may be associated with delayed/inhomogeneous atrial activation in hypertensive patients affected by atrial fibrillation. PMID- 22441221 TI - The effects of therapeutic exercise on the balance of women with knee osteoarthritis: a systematic review. AB - OBJECTIVE: The objective of this review was to examine evidence regarding the effects of therapeutic exercise on the balance of women with knee osteoarthritis (OA). METHODS: The search was conducted in Pubmed, Medline, Lilacs, SciELO, ISI web of knowledge, PEDro and the Cochrane Collaboration. We used the keywords: "knee", "balance", "women" and "rehabilitation" in combination with "osteoarthritis". We selected randomized controlled clinical trials published in English, Portuguese and Spanish over the last 10 years. To verify the methodological quality of selected clinical trials, the PEDro Scale was applied. RESULTS: A total of 20 studies were found in the electronic search. Of these, only 9 met the inclusion criteria and were analyzed in full. Eight of these 9 studies were classified as having high methodological quality on the PEDro Scale. Although the methods and interventions regarding balance varied widely in these studies, most found significant improvement in the balance of women with knee OA. CONCLUSION: Since the studies included in this systematic review were of high methodological quality, we can conclude that the therapeutic exercises they used improved the balance of women with knee OA. PMID- 22441222 TI - Effect of cathodal high-voltage electrical stimulation on pain in women with TMD. AB - BACKGROUND: Pain is the main symptom of patients with temporomandibular disorder (TMD). OBJECTIVE: To evaluate the effect of cathodal high-voltage electrical stimulation (HVES) on pain intensity in women with TMD. METHODS: Twenty women with TMD (24.25 +/- 8.90 years old) participated in the study. They were divided into experimental group (EG, n=10), which received 10 applications of HVES, and placebo group (PG, n=10), which received sham treatment with disconnected HVES equipment. For the sample selection, we used the Research Diagnostic Criteria for Temporomandibular Disorder (RDC/TMD). Pain level was evaluated using a visual analog scale (VAS) applied prior to and after the tenth application of HVES. Data were analyzed using the Wilcoxon signed-rank test and the Mann-Whitney test. RESULTS: Ten applications of HVES reduced pain intensity in the EG (p=0.01). In the PG, there was no significant difference (p=0.20). After the application of HVES, no difference was found (p=0.65) between the groups. CONCLUSION: The cathodal HVES was effective in reducing pain in women with TMD. Trial Registration RBR-4bk94x. PMID- 22441223 TI - Criterion validity of the Motor Coordination and Dexterity Assessment: MCDA for 7 and 8-years old children. AB - BACKGROUND: Developmental Coordination Disorder (DCD) is characterized by impaired development of motor coordination, with impact on daily life activities and academic performance. The Motor Coordination and Dexterity Assessment (MCDA) was created to offer Brazilian rehabilitation professionals a valid and reliable instrument for detecting DCD. OBJECTIVE: To examine the MCDA criterion validity. METHODS: One hundred and eighty one children aged 7 and 8 years from the metropolitan region of Belo Horizonte, MG, Brazil, pre-selected using the Developmental Coordination Disorder Questionnaire (DCDQ-Brazil), were evaluated with the MCDA and the Movement Assessment Battery for Children (MABC-II). Concurrent validity was assessed using Spearman correlation index and the predictive validity was calculated using sensitivity, specificity, positive and negative predictive values. ROC curves were constructed to determine the optimal cutoff point of MCDA. RESULTS: Spearman correlation between the total scores of MCDA and MABC-II at 7 and 8 years were 0.596 (p=0.000) and 0.730 (p=0.000), respectively. The cutoff points defined by the ROC curves approached the 40th percentile, corresponding to a sensitivity of 0.91 and 0.74 and specificity of 0.74 and 0.90 for children 7 and 8 years old, respectively. CONCLUSION: The results indicate moderate values of concurrent and predictive validity of the MCDA. Future studies should reexamine the cutoff points of the MCDA in other random samples, representative of Brazilian children 4 to 8 years of age. The predictive validity of the full instrument for DCD should be re-examined in well defined clinical samples. PMID- 22441224 TI - Comparison of instruments for sleep, cognition and function evaluation in stroke patients according to the international classification of functioning, disability and health (ICF). AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) should be widely used in research and clinical practice, but there are few studies that do so with the evaluation instruments used in physical therapy. OBJECTIVE: To compare instruments that evaluate sleep, cognition and function in stroke patients according to the ICF. METHODS: Twelve patients (6 women) with a mean age of 55.4 (+/- 6.2) years and a recovery time from 7 to 36 months took part in the study. Patients were evaluated using the Pittsburgh Sleep Quality Index (PSQI), the Mini-Mental State Examination (MMSE) and Barthel Index (BI). A frequency comparison of ICF categories and those of the above-mentioned instruments was performed using Fisher's exact test and chi-square. Agreement regarding the categories was recorded by two evaluators and assessed with the Kappa index. RESULTS: Mean scores of 5.0 (+/- 3.0), 22.5 (+/- 3.4) and 74.6 (+/- 17.2) were found for the PSQI, MMSE and BI, respectively. The changes identified in the other instruments were recorded in 46 ICF categories, with the most frequent component being "Body Functions", followed by "Activities and Participation". We found an inter-rater agreement of 0.87 for the PSQI (substantial), 0.44 for the MMSE (moderate) and 0.39 for BI (fair). CONCLUSIONS: The results indicate that the instruments' concordance differed greatly, which suggests a more thorough use of these instruments in physical therapy to optimize the formulation and standardization of diagnoses. PMID- 22441225 TI - Functional status, respiratory muscle strength, and quality of life in patients with cirrhosis. AB - BACKGROUND: Liver diseases are responsible for metabolic disorders and loss of muscle mass and function that affect functional status and quality of life (QoL). OBJECTIVE: To compare exercise capacity, respiratory muscle strength, and QoL in liver transplant candidates with cirrhosis of the following etiologies: hepatitis C virus (HCV), hepatitis B virus (HBV), and alcoholic cirrhosis (AC). METHODS: Cross-sectional study comprising 86 patients divided into three groups: HCV (40 patients), HBV (14 patients), and AC (32 patients). Patients were evaluated using the Six-Minute Walk Test (6MWT), manometry, and the QoL questionnaire SF-36. RESULTS: The AC group showed the lowest performance in the 6MWT (meters) compared to the HBV and HCV groups (373.50 +/- 50.48, 464.16 +/- 32, and 475.94 +/- 27.84, respectively, p=0.001). In the domains of the SF-36, the AC group had lower scores for functional capacity and physical limitations when compared to the HBV and HCV groups (p=0.001). In the comparison of respiratory muscle strength, the AC group had lower MIP (cmH2O) compared to the HBV and HCV groups (-65.54 +/- 11.28, -71.61 +/- 6.96, -82.44 +/- 13.71, respectively, p=0.001). The MEP (cmH2O) in the AC group was also lower than in the HBV and HCV groups (65.13 +/- 10.74, 82.44 +/- 13.87, 83.44 +/- 12.20, respectively, p=0.001). CONCLUSION: The AC group showed worse exercise capacity, respiratory muscle strength, and QoL compared to patients with HCV and HBV. PMID- 22441226 TI - Patients in treatment for chronic low back pain have higher externalised beliefs: a cross-sectional study. AB - BACKGROUND: People with low back pain (LBP) with higher levels of external locus of control have a poorer prognosis and require greater improvements from active interventions in order to consider these interventions worthwhile. Whether locus of control levels differ between participants with LBP in a patient-health provider relationship and those waiting for treatment is unclear. OBJECTIVE: The aim was to investigate if differences in locus of control exist between participants with non-specific chronic LBP being treated (treatment group) and those waiting treatment (control group). METHODS: 100 participants (50 per group) with low back symptoms for at least three months for the current episode of LBP and aged between 18 and 60 years were recruited. Multidimensional health locus of control questionnaire (MHLC) was used to collect their beliefs. Multiple linear regression adjusted for disability was used to compare health locus of control between both groups. Differences were described as mean differences and 95% confidence intervals. RESULTS: Treatment group scored higher for external locus of control and lower for internal locus of control than control group. Mean differences (95% confidence intervals) were 2.7 points on possible 30-points difference (0.5 to 4.8) for external locus of control and -2.8 points (-5.4 to 0.1) for internal subscale. CONCLUSION: Health locus of control was found to be different between treatment and control groups. Participants being treated had higher external locus of control and lower internal locus of control than control group. PMID- 22441227 TI - Challenges in recruitment, attendance and adherence of acute stroke survivors to a randomized trial in Brazil: a feasibility study. AB - BACKGROUND: There is a high demand for stroke rehabilitation in the Brazilian public health system which should make undertaking clinical trials straightforward. OBJECTIVES: The aims of this study were to 1) determine the rate of recruitment of community-dwelling stroke survivors into a randomized trial of the effects of strength training in addition to task-specific gait training, 2) compare the effectiveness of various recruitment strategies on accrual rates, and 3) determine the attendance at training sessions and adherence to the intervention protocol. METHODS: Participants within six months of a stroke were screened for eligibility and invited to participate. Recruitment strategies were classified as advertisement or referral. The number of people who were screened, eligible and recruited for each strategy was recorded. Attendance at training sessions and adherence to the intervention protocol were recorded. RESULTS: Over the first 14 months, 150 stroke survivors were screened, 10 were recruited, and 35 (23%) were eligible. Twenty-five of these patients (71%) were unable to participate with lack of transport given as the most common reason. The most successful strategy was referral via hospital-based physical therapists (50%). Overall attendance was 72% with lack of transport being the most common reason for non-attendance. Overall adherence to the protocol was 97% with feeling unwell being the most common reason for non-adherence. CONCLUSIONS: Recruitment of stroke survivors was inefficient. Lack of transport was the most common barrier to participate in and attend training sessions. Funding for transport is essential to make carrying out trials in Brazil feasible. Trial Registration ACTRN12609000803291. PMID- 22441228 TI - A description of training characteristics and its association with previous musculoskeletal injuries in recreational runners: a cross-sectional study. AB - BACKGROUND: Running is one of the most popular physical activities in the world and the number of runners has increased over the past 40 years. One of the consequences of the growing running popularity is the increase of musculoskeletal injuries. OBJECTIVES: To describe the routines, training characteristics and history of injury in recreational runners and to evaluate possible associations between the routines and training characteristics with previous musculoskeletal running-related injuries. METHODS: A total of 200 runners participated in this study. The participants completed an electronic form containing questions about personal characteristics, running experience, training characteristics, type of running shoes, foot type and previous injuries history over the last 12 months. The data were analyzed descriptively as well as by using logistic regression models. RESULTS: The majority of the runners was male, aged 43.0 (SD=10.5) years old, have a body mass index of 24.2 (IQR=4.3) kg/m2, and had training volume of 35.0 (IQR=28.0) kilometers per week. Fifty-five percent of runners had injuries over the last 12 months. The most prevalent injuries observed were tendinopathies and muscle injuries. The variable that showed an association with previous running-related injuries was running experience from 5 to 15 years (Odds Ratio (OR)=0.2; 95%CI=0.1 to 0.9). CONCLUSIONS: The prevalence of running-related injuries over the last 12 months was 55%. The variable running experience was associated with the absence of previous musculoskeletal running-related injuries. PMID- 22441229 TI - Photogrammetry on the identification of postural asymmetries in cadets and pilots of the Brazilian air force academy. AB - OBJECTIVE: To identify whether flight training activities cause postural changes in cadets and pilots of the Brazilian Air Force Academy (AFA). METHODS: Eighty subjects were assessed through photographic images in anterior and right side views. Four groups of cadets (n=20 per group) divided according to the year since enlistment and a fifth group of fifteen pilots from the Air Demonstration Squadron (ADS) were included. Pictures were analyzed using the Postural Analysis Program (SAPO) and angles related to head vertical alignment (HVA), head horizontal alignment (HHA), acromion horizontal alignment (AHA) and anterior superior iliac spine horizontal alignment (HAS) were plotted. RESULTS: We did not find statistical significant differences in the angles: HVA, HHA and AHA. However, a significant difference was found for the HAS angle with pilots having lower values than cadets, suggesting greater postural stability for this variable in pilots. CONCLUSION: The horizontal alignment of the anterior-superior iliac spine was the only measure that showed significant difference in the comparison between pilots and cadets. The remaining alignments were not different, possibility because of the strict criteria used for admission of cadets at the AFA and the efficiency of the physical training that is performed periodically. PMID- 22441230 TI - Effects of noninvasive ventilation on dynamic hiperinflation of patients with COPD during activities of daily living with upper limbs. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) complain of dyspnea on activities of daily living (ADLs) with the upper limbs. Dynamic hyperinflation (DH) is one of the ventilatory mechanisms that may contribute towards dyspnea. To minimize the DH it is indicated the use of noninvasive ventilation (NIV). OBJECTIVES: To verify whether there is DH and dyspnea during the performance of ADL with the upper limbs with and without the use of NIV. METHODS: 32 patients with moderate-to-severe COPD, aged 54 to 87 years (mean 69.4, SD 7.4) were evaluated. The subjects lift up containers weighing between 0.5 and 5.0 kg over a five-minute period, starting from the waist level and putting them onto a shelf located above head height, with and without the use of NIV (BiPAP(r); IPAP 10cmH2O; EPAP 4 cmH2O). The inspiratory capacity (IC) and dyspnea (Borg scale) were evaluated on all the patients. The IC was measured before and after simulation of the ADL. In order to analyze the data, Student's t test for dependent samples and the Wilcoxon test were used. RESULTS: There were statistically significant reductions in IC after the ADL with and without NIV (p=0.01). The dyspnea increased after the ADL with and without the NIV, however between both interventional procedures protocols no between-group difference was observed. CONCLUSIONS: The simulation of an ADL with the upper limbs resulted in an increase in DH and dyspnea. The NIV supplied with pre-established pressure was not enough to prevent the DH and dyspnea. PMID- 22441231 TI - Evaluation of a multimedia online tool for teaching bronchial hygiene to physical therapy students. AB - BACKGROUND: Advances in information technology have been widely used in teaching health care professionals. The use of multimedia resources may be important for clinical learning and we are not aware of previous reports using such technology in respiratory physical therapy education. OBJECTIVES: Our approach was to evaluate a conventional bronchial hygiene techniques (BHTs) course with an interactive online environment, including multimedia resources. METHODS: Previous developed audiovisual support material comprised: physiology, physiopathology and BHTs, accessible to students through the Internet in conjunction with BHTs classes. Two groups of students were compared and both attended regular classes: the on-line group (n=8) received access to online resources, while the control group (n=8) received conventional written material. Student's performance was evaluated before and after the course. RESULTS: A preliminary test (score 0 to 10) was applied before the beginning of the course, showing that the initial knowledge of both groups was comparable [online, 6.75 (SD=0.88) vs. control, 6.125 (SD=1.35); p>0.05]. Two weeks after the end of the course, a second test showed that the online group performed significantly better than the control group [respectively, 7.75 (SD=1.28) vs. 5.93 (SD=0.72); p>0.05]. CONCLUSIONS: The use of a multimedia online resource had a positive impact on student's learning in respiratory therapy field in which instrumental and manual resources are often used and can be explored using this technology. PMID- 22441232 TI - Eccentric training for shoulder abductors improves pain, function and isokinetic performance in subjects with shoulder impingement syndrome: a case series. AB - BACKGROUND: Conservative treatments have been proposed for people with shoulder impingement syndrome (SIS), such as strengthening of the rotator cuff and scapular muscles and stretching of the soft tissues of the shoulder. However, there is a lack of studies analyzing the effectiveness of eccentric training in the treatment of SIS. OBJECTIVES: To evaluate the effects of eccentric training for shoulder abductors on pain, function, and isokinetic performance during concentric and eccentric abduction of the shoulder in subjects with SIS. METHODS: Twenty subjects (7 females, 34.2 SD 10.2 years, 1.7 SD 0.1 m, 78.0 SD 16.3 kg) with unilateral SIS completed the study protocol. Bilateral isokinetic eccentric training at 60o/s for shoulder abductors was performed for six consecutive weeks, twice a week, on alternate days. For each training day, three sets of 10 repetitions were performed with a 3-minute rest period between the sets for each side. The range of motion trained was 60 degrees (ranging from 80 degrees to 20 degrees ). The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was used to evaluate functional status and symptoms of the upper limbs. Peak torque, total work and acceleration time were measured during concentric and eccentric abduction of the arm at 60o/s and 180o/s using an isokinetic dynamometer. RESULTS: DASH scores, peak torque, total work and acceleration time improved (p<0.05) after the period of intervention. CONCLUSIONS: This study suggests that isokinetic eccentric training for shoulder abductors improves physical function of the upper limbs in subjects with SIS. PMID- 22441233 TI - Research and scientific publication integrity. PMID- 22441234 TI - Effective feedback: an essential skill. PMID- 22441235 TI - Republished review: Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist. AB - The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and cardiologists need to be prepared if they wish to surf the wave of genomic opportunity. This paper presents an overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic. PMID- 22441236 TI - Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype. AB - Several epidemiological and experimental data support the hypothesis that diabetes could be an independent risk factor for osteoarthritis (OA), at least in some patients, leading to the concept of a diabetes-induced OA phenotype. If confirmed, this new paradigm will have a dramatic impact on prevention of OA initiation and progression. PMID- 22441237 TI - Dumpling soup. PMID- 22441238 TI - Combined experimental and theoretical studies on the photophysical properties of cycloparaphenylenes. AB - We studied the UV-vis absorption and fluorescence in solution/solid states of [n]cycloparaphenylene ([n]CPP: n = 9, 12, 14, 15, and 16), and conducted theoretical studies to better understand the experimental results. The representative experimental findings include (i) the most intense absorption maxima (lambda(abs1)) display remarkably close values (338-339 nm), (ii) the longest-wavelength absorption maxima (lambda(abs2)) are blue-shifted with increasing the ring size (395 -> 365 nm), (iii) the emission maxima (lambda(em)) are blue-shifted with increasing the ring size (494 -> 438 nm for longest wavelength maxima), (iv) the fluorescent quantum yields (Phi(F)) in solution are high (0.73-0.90), (v) the fluorescence lifetimes (tau(s)) of [9]- and [12]CPP are 10.6 and 2.2 ns, respectively, and (vi) the Phi(F) values slightly increase in polymer matrix but significantly decrease in the crystalline state. According to TD-DFT calculations, the longest-wavelength absorption (lambda(abs2)) corresponds to a forbidden HOMO -> LUMO transition and the most intense absorption (lambda(abs1)) corresponds to degenerate HOMO - 1 -> LUMO and HOMO -> LUMO + 1 transitions with high oscillator strength. The interesting and counterintuitive optical properties of CPPs (constant lambda(abs1) and blue shift of lambda(abs2)) could be ascribed mainly to the ring-size effect in frontier molecular orbitals (in particular the increase of the HOMO-LUMO gap as the number of benzene rings increases). On the basis of comparative calculations using hypothetical model geometries, we conclude that the unique behavior of HOMO and LUMO of CPPs is due mainly to their lack of a conjugation length dependence in combination with a significant bending effect (particularly to HOMO) and a torsion effect (particularly to LUMO). PMID- 22441239 TI - Bibliography. Infectious diseases. Current world literature. PMID- 22441241 TI - Hangman effect on hydrogen peroxide dismutation by Fe(III) corroles. AB - Hangman Fe(III) corroles catalyse H(2)O(2) disproportionation at a faster rate and display a more pronounced hangman effect than their one electron oxidized analogues owing to their ability to bypass high energy intermediates by redox leveling derived from the use of the corrole as a non-innocent ligand. PMID- 22441242 TI - Non-linear magnetic behavior around zero field of an assembly of superparamagnetic nanoparticles. AB - The MIAplex(r) device is a miniaturized detector, devoted to the high sensitive detection of superparamagnetic nanoprobes for multiparametric immunoassays. It measures a signal corresponding to the second derivative of the magnetization around zero field. Like any new technology, the real success of the MIAplex(r) detector can only be exploited through a deep understanding of the magnetic signature. In this letter, we study the magnetic behavior around zero-field of diluted lab-made and commercial ferrofluids by comparing together conventional SQUID magnetization and MIAplex(r) signature. PMID- 22441243 TI - Intraoperative ultrasonography: a useful tool in retrolaparoscopic nephron sparing surgery. AB - OBJECTIVE: To evaluate the value of intraoperative laparoscopic ultrasonography (ILUS) in retrolaparoscopic nephron-sparing surgery. METHODS: A total of 81 cases were studied during a 5-year period: 38 patients with a benign renal tumor who underwent enucleation of the tumor and 43 patients with a suspected malignant renal tumor who underwent wedge resection of the tumor. ILUS was used to evaluate renal perfusion, locate the tumor, precisely delineate the tumor border, characterize the tumor, and look for any suspected satellite renal masses. RESULTS: All procedures were successful without conversion to open surgery. The mean operating time was 106 min for enucleation (range 70- 150 min) and 114 min for wedge resection (range 80- 235 min). The mean size of benign tumors was 4.02 cm and that of malignant tumors was 3.13 cm, and all margins were negative. An additional renal artery branch was detected in 11 patients. In 2 cases the operative procedure was changed based on the ILUS findings. No satellite lesion was found in any of the patients with malignant tumors. CONCLUSIONS: ILUS provides significant benefit in retrolaparoscopic nephron-sparing surgery. In a number of situations, especially endogenic lesions, it is an essential surgical tool. PMID- 22441244 TI - Oligo Troger's bases--new molecular scaffolds. AB - Oligo Troger's bases are compounds containing two or more Troger's base subunits (1,5-methanodiareno[b,f][1,5]diazocines) sharing one or more arene parts. Due to their interesting molecular shapes, these compounds are studied as chiral molecular tweezers, clips, cavitands, clefts, calixes, etc. This review includes all available data on oligo Troger's bases, and introduces their preparation and properties to a wide audience. PMID- 22441245 TI - Improved photocatalytic efficiency of a WO3 system by an efficient visible-light induced hole transfer. AB - Amorphous Cu(II) nanoclusters grafted WO(3) particles were coated on a smooth TiO(2) film, and site selective depositions of PbO(2) and metal Ag particles by photocatalytic processes were observed on TiO(2) and WO(3) due to transfer of holes to TiO(2), and accumulation of electrons in WO(3) respectively. As a result, the photocatalytic activity of TiO(2) modified Cu(II)-WO(3) increased ~3.5 fold higher than that of Cu(II)-WO(3). PMID- 22441246 TI - Optogenetic stimulation of a hippocampal engram activates fear memory recall. AB - A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light induced fear memory recall. This freezing was not detected in non-fear conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams. PMID- 22441247 TI - Response to antiretroviral therapy: improved survival associated with CD4 above 500 cells/MUl. AB - OBJECTIVE: We investigated the association between immune response and mortality in four HIV African programs supported by Medecins Sans Frontieres. DESIGN: Multicentric retrospective cohort study. METHODS: All antiretroviral therapy (ART) naive adults (>15 years) who initiated therapy between March 2001 and November 2010 and receiving therapy for 9 months or more were included. We described the evolution of mortality over time. Mixed Poisson models were used to assess the effect of updated CD4 cell counts and other potential risk factors on mortality. FINDINGS: A total of 24 037 patients, of which 68% were women, contributed 69 516.2 person-years of follow-up. At ART initiation, 5718 patients (23.7%) were classified as WHO clinical stage 4, 1587 (6.6%) had a BMI below 16 kg/m and 2568 (10.7%) had CD4 cell count below 50 cells/MUl. A total of 568 (2.4%) deaths were recorded during the study period. In the CD4 response categories 500 cells/MUl or more, 350-499, 200-349, 50-199 cells/MUl and less than 50 cells/MUl, unadjusted mortality rates were 0.36; 0.58; 0.88; 1.91 and 7.43 per 100 person-years, respectively. In multivariate analysis, higher mortality was observed in patients with CD4 response levels 350-499 cells/MUl [adjusted hazard ratio (aHR) 1.70, 95% confidence interval (CI) 1.26-2.30] and for those between 200-349 (aHR 2.56; 95% CI 1.93-3.38), compared to those with 500 cells/MUl or more. INTERPRETATION: The observed higher survival of patients with a CD4 response to ART higher than 500 cells/MUl supports the need of further research to evaluate the individual benefit of initiating ART at higher CD4 levels in sub-Saharan Africa. PMID- 22441248 TI - When should HAART be initiated in pregnancy to achieve an undetectable HIV viral load by delivery? AB - BACKGROUND: HAART dramatically reduces mother-to-child transmission of HIV allowing vaginal delivery if the viral load is low. This study provides data for the optimum timing of short-term HAART in pregnancy. METHODS: Retrospective multicentre cohort study of pregnant women commencing HAART in London and Brighton, UK. Demographics, gestation, drug class, CD4 cell count, and viral load results were collated. Survival curves for reaching a viral load less than 50 copies/ml were stratified by initial HIV viral load. Cox's proportional hazards regression model was adjusted for demographics and immunovirological parameters. RESULTS: Viral load was less than 50 copies/ml in 292 of 378 pregnancies (77.2%) by delivery. Pretreatment viral load was associated with the time taken, and the proportion achieving a viral load less than 50 copies/ml at (P<=0.001). When baseline viral load was less than 10 ,000 copies/ml, gestational age at HAART initiation did not affect success up to 26.3 weeks gestation. When viral load was more than 10 ,000 copies/ml, deferring HAART past 20.4 weeks reduced the probability of reaching less than 50 copies/ml by delivery (P=0.011). When baseline viral load was more than 100, 000 copies/ml the likelihood of reaching a viral load of less than 50 copies/ml was low (37%: hazard ratio 0.31), and dependent on the length of time on HAART. The hazard ratio for a nonnucleoside reverse transcriptase inhibitor regimen achieving a viral load less than 50 copies/ml compared with a protease inhibitor was 0.7 (95% confidence interval 0.52-0.94). CONCLUSION: With a viral load more than 10, 000 copies/ml and especially with a viral load more than 100 ,000 copies/ml, the probability of achieving either less than 50 copies/ml by the time of delivery is compromised by delaying initiation of short-term highly active antiretroviral therapy beyond 20.4 weeks gestation. Current UK and other guidelines for when to commence START may therefore limit the chance of vaginal delivery. PMID- 22441249 TI - PD-1 and its ligand PD-L1 are progressively up-regulated on CD4 and CD8 T-cells in HIV-2 infection irrespective of the presence of viremia. AB - OBJECTIVE: Hyper-immune activation is a main determinant of HIV disease progression, potentially counter-acted by T-cell inhibitory pathways. Here we investigated, for the first time, inhibitory molecules in HIV-2 infection, a naturally occurring attenuated form of HIV disease, associated with reduced viremia and very slow rates of CD4 T-cell decline. DESIGN: Programmed death (PD) 1/PD-L1, an important pathway in limiting immunopathology, and its possible relationship with T-cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a recently identified inhibitory molecule, were studied in untreated HIV 2 and HIV-1 cohorts, matched for degree of CD4 T-cell depletion, and noninfected individuals. METHODS: Flow cytometric analysis of T-cell expression of PD-1, PD L1 and TIM-3, combined with markers of cell differentiation, activation, cycling and survival. Statistical analysis was performed using ANOVA, Mann Whitney/Wilcoxon tests, Spearman's correlations, multiple linear regressions and canonical correlation analysis. RESULTS: T-cell expression of PD-1 and PD-L1 was tightly associated and directly correlated with CD4 T-cell depletion and immune activation in HIV-2 infection. No such correlation was found for PD-L1 expression in HIV-1-positive patients. Central memory and intermediate memory cells, rather than terminally differentiated T-cells, expressed the highest levels of both PD-1 and PD-L1 molecules. Conversely, TIM-3 expression was independent of T-cell differentiation and dissociated from cell cycling, suggesting distinct induction mechanisms. Importantly, in contrast with HIV-1, no significant increases in TIM 3 expression were found in the HIV-2 cohort. CONCLUSIONS: Our data suggest that PD-1/PD-L1 molecules, rather than markers of T-cell exhaustion, may act as modulators of T-cell immune activation, contributing to the slower course of HIV 2 infection. These data have implications for the design of antiretroviral therapy-complementary immune-based strategies. PMID- 22441250 TI - Protecting the public's health: remove the political constraints that hamper the Centers for Disease Control and Prevention. PMID- 22441251 TI - Discontinuation of Atripla as first-line therapy in HIV-1 infected individuals. AB - BACKGROUND: Central nervous system (CNS) adverse events are common with initiation of efavirenz, but these are often described as transient. We aimed to describe the outcomes of individuals commencing Atripla (Gilead Sciences Inc, Foster City, California; Bristol-Myers Squibb Co, Princeton, New Jersey, USA) as a first-line regimen. METHODS: We performed a retrospective case-based analysis of all individuals within our HIV cohort who had received Atripla as their first antiretroviral combination. In individuals who discontinued Atripla data was collected on evolution of adverse events. RESULTS: Four hundred and seventy-two individuals commenced Atripla as first-line therapy at 12 months, 383 individuals (81%) remained on Atripla with 98% achieving HIV-1 RNA less than 50 copies/ml (on treatment analysis). CNS toxicity was the commonest reason for switching therapy in 63 (71%) cases. The median duration of first reported CNS toxicity was 27 days (IQR 7-104 days) and the commonest reported symptoms were nightmares or vivid dreams in 28 (44%), insomnia in 27 (43%) and depression in 22 (35%). In those with CNS toxicity, six (10%) switched at 0-4 weeks, four (6%) at 4-12 weeks, 30 (48%) at 12-52 weeks and 23 (36%) changed regimen 52-96 weeks after commencing Atripla. Among those with available documentation 25 of 63 (40%) had reported improvement or resolution of their CNS side effects. DISCUSSION: One-fifth of all individuals commencing Atripla will need to switch therapy, often for adverse events. The commonest reason for switch in our cohort was CNS toxicity, which although it may develop shortly after initiation may persist, ultimately leading to discontinuation of Atripla months or years later. PMID- 22441252 TI - Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AB - OBJECTIVE: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). DESIGN: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000 copies/ml. METHODS: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100 mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. RESULTS: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400 copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40 copies/ml and 30 had levels 40-200 copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400 copies/ml. CONCLUSION: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity. PMID- 22441253 TI - Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AB - OBJECTIVE: Although HAART can suppress genital shedding and sexual transmission of HIV, men who have sex with men (MSM) have experienced a resurgent HIV epidemic in the HAART era. Many HIV-infected MSM continue to engage in unsafe sex, and sexually transmitted infections (STIs) or other factors may promote genital HIV shedding and transmission in this population despite HAART. In this study, we determined the prevalence of seminal HIV shedding in HIV-infected MSM on stable HAART, and its relationship with a number of clinical, behavioral and biological variables. DESIGN: Sexually active HIV-infected men using HAART were recruited from an MSM health clinic to provide semen and blood samples. METHODS: HIV levels were assessed in paired semen and blood samples by PCR. Clinical and behavioral data were obtained from medical records and questionnaires. Herpes simplex virus 2 (HSV-2) serostatus, seminal HSV-2 DNA, and markers of genital inflammation were measured using standard laboratory methods. RESULTS: Overall, HIV-1 was detected in 18 of 101 (18%) blood and 30 of 101 (30%) semen samples. Of 83 men with undetectable HIV in blood plasma, 25% had HIV in semen with copy numbers ranging from 80 to 2560. Multivariate analysis identified STI/urethritis (P = 0.003), tumor necrosis factor alpha (P = 0.0003), and unprotected insertive anal sex with an HIV-infected partner (P = 0.007) as independent predictors of seminal HIV detection. CONCLUSION: STIs and genital inflammation can partially override the suppressive effect of HAART on seminal HIV shedding in sexually active HIV infected MSM. Low seminal HIV titers could potentially pose a transmission risk in MSM, who are highly susceptible to HIV infection. PMID- 22441254 TI - The adult population impact of HIV care and antiretroviral therapy in a resource poor setting, 2003-2008. AB - OBJECTIVE: To describe the population uptake of HIV care including antiretroviral therapy (ART) and its impact on adult mortality in a rural area of western Kenya with high HIV prevalence during a period of rapid HIV services scale-up. DESIGN: Adult medical chart data were abstracted at health facilities providing HIV care/ART to residents of a Health and Demographic Surveillance System (HDSS) and linked with HDSS demographic and mortality data. METHODS: We evaluated secular trends in patient characteristics across enrollment years and estimated proportions of HIV-positive adult residents receiving care. We evaluated adult (18-64 years) population mortality trends using verbal autopsy findings. RESULTS: From 2003 to 2008, 5421 HDSS-resident adults enrolled in HIV care; 61.4% (n=3331) were linked to HDSS follow-up data. As the number of facilities expanded from 1 (2003) to 17 (2008), receipt of HIV services by HIV-positive residents increased from less than 1 to 29.5%, and ART coverage reached 64.0% of adults with CD4 cell count less than 250 cells/MUl. The proportion of patients with WHO stage 4 at enrollment decreased from 20.4 to 1.9%, and CD4 cell count testing at enrollment increased from 1.0 to 53.4%. Population-level mortality rates for adults declined 34% for all causes, 26% for AIDS/tuberculosis, and 47% for other infectious diseases; noninfectious disease mortality rates remained constant. CONCLUSION: The initial years of rapid HIV service expansion coincided with a drop in adult mortality by a third. Continued expansion of population access to HIV clinical services, including ART, and program quality improvements will be necessary to achieve further progress in reducing HIV-related morbidity and mortality. PMID- 22441255 TI - Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in sub-Saharan Africa. AB - OBJECTIVES: High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men. DESIGN: HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15-49 years who participated in male circumcision trials in Rakai, Uganda. METHODS: Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRRs) and clearance risk ratios (adjRRs). RESULTS: HR-HPV incidence was 66.5/100 person years in HIV-positive men and 32.9/100 person-years among HIV-negative men [IRR=2.02, 95% confidence interval (CI) 1.67-2.44]. Incidence was higher in the unmarried men (adjIRR=1.73, 95% CI 1.19-2.52), and decreased with age (adjIRR for men >35 years=0.64, 95% CI 0.43-0.94) and male circumcision (adjIRR=0.70, 95% CI 0.55-0.89). HR-HPV clearance was 114.7/100 person-years for HIV-positive men and 170.2/100 person-years for HIV-negative men (risk ratio=0.67, 95% CI 0.59-0.77). HR-HPV clearance in HIV-negative men increased with circumcision (adjRR=1.48, 95% CI 1.26-1.74), HSV-2 infection (adjRR=1.20, 95% CI 1.01-1.44), and symptoms of urethral discharge (adjRR=1.35, 95% CI 1.06-1.73). Clearance of HR-HPV was significantly lower for unmarried men (adjRR 0.76, 95% CI 0.59-0.98). CONCLUSION: HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and additional prevention measures, such as HPV vaccination, is critical in sub-Saharan Africa. PMID- 22441256 TI - CD8(+) T cells in preventing HIV infection and disease. AB - The complex interplay between the host immune response and HIV has been the subject of intense research over the last 25 years. HIV and simian immunodeficiency virus (SIV) CD8 T cells have been of particular interest since they were demonstrated to be temporally associated with reduction in virus load shortly following transmission. Here, we briefly review the phenotypic and functional properties of HIV-specific and SIV-specific CD8 T-cell subsets during HIV infection and consider the influence of viral variation with specific responses that are associated with disease progression or control. The development of an effective HIV/AIDS vaccine combined with existing successful prevention and treatment strategies is essential for preventing new infections. In the context of previous clinical HIV/AIDS vaccine trials, we consider the challenges faced by therapeutic and vaccine strategies designed to elicit effective HIV-specific CD8 T cells. PMID- 22441257 TI - Are hemianopic monkeys and a human hemianope aware of visual events in the blind field? AB - In three hemianopic monkeys and one normal monkey who subsequently became hemianopic and in one human hemianope we measured reaction times to touch the remembered position of a brief visual target presented in the normal hemifield or in the blind hemifield, or on the blank trials where no visual target occurred and the correct response was to touch a separate and permanently outlined part of the display. This is the same procedure as first used to demonstrate blindsight in these hemianopic monkeys. In the present experiment physically salient high contrast (0.95) grating stimuli, which we have previously shown are easily detected and localized in the blind field, were used, and the monkeys' reaction times were also measured. With rare exceptions the monkeys indicated that the visual targets in the blind field were blanks, but their otherwise identical motor responses to targets and blanks had significantly different latencies, which were longer for real targets than for blanks. The results indicate that when the monkeys detect that the stimulus has occurred but do not perceive it as a light, or are just guessing, reaction times are longer. Even when the target in the blind field was moving, it was categorized as a blank. In the human hemianope both high- and low-contrast stimuli were used, and the subject had to indicate whether he had been 'aware' or 'unaware' of the target, after making the reaching response. The latencies when he was correct and aware were significantly shorter than when he was unaware and 'just guessing'. However, he was also significantly faster to respond correctly to the blind-field target when he was unaware and correct than when he was unaware and incorrect, a difference reflected in his percentage correct scores even when totally unaware. Collectively, the results support the notion that the hemianopic monkeys, like the human hemianope, know that something has happened in the blind field as long as the stimuli are physically salient even though the stimuli are categorized as blanks, presumably because, like the human hemianope, there was no phenomenal visual percept. PMID- 22441258 TI - Functional connectivity and laterality of the motor and sensory components in the volitional swallowing network. AB - Functional neuroimaging has shown that multiple brain regions are active during volitional swallowing. Little is known, however, about which regions integrate motor execution and sensory feedback in the swallowing system. Although unilateral brain lesions in either hemisphere can produce swallowing deficits, some functional neuroimaging studies indicate that the left hemisphere has greater activation in certain sensory and motor-related swallowing regions. In this study, correlation coefficients were computed for five seed regions during volitional saliva swallowing to determine the functional relationships of these regions with the rest of the brain: the anterior and posterior insula, inferior frontal gyrus (BA44), primary sensory cortex (S1), and primary motor cortex (M1). A laterality index (LI) was derived that accounts for relative differences in total, positive connected voxels for the left/right hemisphere seeds. Clusters of significantly connected voxels were greater from the anterior and posterior insula than from the other three seed regions. Interactions of the insula with other brain regions were greater on the left than on the right during volitional swallowing. Group means showed laterality in the anterior insula (LI = 0.25) and the posterior insula (LI = 0.33). BA44 showed a lesser degree of difference in left versus right hemisphere interactions (LI = 0.12) while S1 did not show lateralization (LI = 0.02) and M1 showed some predominance of interactions in the right hemisphere (LI = -0.19). The greater connectivity from the left hemisphere insula to brain regions within and across hemispheres suggests that the insula is a primary integrative region for volitional swallowing in humans. PMID- 22441259 TI - Brazilian scientific journals: visibility and charm. PMID- 22441260 TI - [Outcomes in late-age pregnancies]. AB - The objective of the present study was to compare perinatal outcomes in women aged 35 or older with women aged 20 to 34 years. This retrospective study was performed by reviewing the obstetric records of 1255 mothers who gave birth at the only hospital in Sarandi-PR, from January 2007 to December 2008. The analyzed variables were: marital status, education, gestational age at birth, type of delivery, newborn birth weight, Apgar score at one and five minutes and stillbirths. Logistic regression showed that advanced maternal age was significantly associated with adverse outcomes such as cesareans (OR 1.23, 95% CI 0.19-0.44) and 5-minute Apgar scores below 7 (OR 5.78 95% CI 0.74-0.76). These results are important to show the risk of complications in pregnant women aged 35 years or older, and the need to provide guidance to women who wish to postpone pregnancy. PMID- 22441261 TI - [The knowledge of women with diabetes mellitus regarding preconception care and maternal-fetal risks]. AB - The objective of this study was to describe the reproductive profile of women with diabetes mellitus (DM) and to identify their knowledge regarding maternal and fetal risks and preconception care. This exploratory study was performed at the Integrated Center for Hypertension and Diabetes, from March to July 2009, on a sample consisting of 106 women. The variables were: number of pregnancies, births and abortions, and planning the pregnancy. The data were collected through interviews that followed a preconceived form. The reproductive profile of women with DM proved to be permeated with risks and showed negative repercussions to maternal and fetal health. Of the 106 (100%) women studied, 44 (41.5%) demonstrated adequate knowledge regarding preconception care, while 58 (54.7%) had limited knowledge regarding maternal and fetal risks. It is necessary to provide information to women with diabetes to promote knowledge of maternal and fetal risks and preconceptional care. PMID- 22441262 TI - [How the workers of a birthing center justify using harmful practices in natural childbirth]. AB - This study was performed with the objective of understanding the reasons why workers of a birthing center in southern Brazil use natural birth practices considered harmful by the World Health Organization. This exploratory study was performed in July 2009 through interviews with 23 workers. The analysis revealed three themes: Actions and behaviors dependent on health workers; Routine practices as facilitators of work; and Restricting the parturients' participation in the decision-making process. Some justifications for using the practices were: perpetuation of inappropriate models, facilitation of the care provided during delivery and authoritarianism that some workers impose over parturients in the erroneous belief that workers have all the knowledge. PMID- 22441263 TI - [Hope in HIV-positive women]. AB - The objective of this study was to assess the hope in the lives of HIV-positive women, using the Herth Hope Scale (HHS). Participants were 111 HIV-positive women who attended a referral outpatient clinic in Fortaleza-CE. From January to May 2009, interviews were held to collect biopsychosocial variables, and the HHS was applied. Data were analyzed using SPSS-8.0 and revealed an average hope index of 34.86, indicating that these women have little hope in life in view of their diagnosis of HIV. The scale item with the highest score was faith. This probably derives from the fact that Aids is incurable, transmissible and generates negative stigma, in addition to its relation with the idea of imminent death. In conclusion, measuring hope among HIV patients through the use of an instrument permits intervention assessment and planning, promoting assistance and motivation to live better and maintain a hopeful attitude. PMID- 22441264 TI - [Caring for newborns in a NICU: dealing with the fragility of living/surviving in the light of complexity]. AB - The objective of this study was to understand the meaning of being a nurse and providing care in the Neonatal Intensive Care Unit (NICU) of a general hospital in Southern Brazil, developing an explanatory theoretical model. The Grounded Theory and the Complexity Paradigm were used to develop the Theoretical Model: Caring for newborns in the NICU: Dealing with the fragility of living/surviving in the light of complexity. Data was collected from 11 subjects through an open interview, and organized using NVIVO software. A central category was identified: Dealing with the fragility of living/surviving: a care that is highly complex, sensitive, unique and shared. Care in the NICU, valuing the everyday interrelationships, aims to address all domains of complex health care, integrating and applying scientific knowledge. It is necessary to practice the strengths already inherent to nursing professionals, in addition to pursuing new strengths, an invitation to new models of care for newborns, their family, and the members of this complex system. PMID- 22441265 TI - [Eating behaviors and the social status of families of malnourished children]. AB - The objective of this study was to learn about the everyday eating behaviors and the social status of the families of malnourished children. This qualitative study involved eight families. Data were collected by participant observation and semi-structured interviews. Thematic analysis revealed the following themes: family eating; the family's social status and eating during childhood; and the presence of social programs and equipment. The family did not gather for meals and their food consisted basically of different sources of carbohydrates. Fruits and vegetables were very limited and considered to be food choices that did not provide sustenance. Differences were observed between the family's' and the children's' eating habits. Social programs and equipment provided important support, especially regarding the positive attachment with institutions and professionals and following the children's health. The family's social status does not allow the offering of appropriate quantities and quality of food throughout the month, thus compromising the nutritional status of the children, who are deprived of appropriate foods of adequate nutritional value. PMID- 22441266 TI - [Hypothermia in patients during the perioperative period]. AB - The objective of this study was to identify the factors that trigger hypothermia in patients in surgery, and the manifestations in the anesthesia recovery room. This study was performed in a large hospital of the City of Santos hospital network. Data were collected from 30 adult patients, whose body temperature when entering the surgical suite was between 36oC and 37.2oC, who underwent elective procedures and received general anesthesia. Results show that the most common methods used to prevent hypothermia were infusing warmed intravenous fluids and using a thermal blanket. From the moment the patient left the surgical suite until 30 minutes post-recovery in the anesthesia recovery room, patients remained hypothermic. Hypothermia was manifested by hypoxemia and shivering. In this study, it was shown that hypothermia in patients is triggered while in the surgical suite due to the lack of appropriate preventive measures, leading to complications in the anesthesia recovery period. PMID- 22441267 TI - [The implementation of a hospital's fall management protocol: results of a four year follow-up]. AB - Inpatient falls are common occurrences with negative effects for patients and institutions. The objective of this descriptive study was to present the results of a fall management protocol used in a private hospital located in Sao Paulo, Brazil. Follow-up consisted of reviewing the fall rates and performing a descriptive analysis of the data. Subjects were the patients admitted between 2005 and 2008, accounting for 284 falls in 207,067 patient-days. The rates showed a monthly variability, with reductions following the implementation of interventions and rises in rates after management actions and training. In 2008, falls were more frequent among patients in clinical units of greater complexity - the elderly - using drugs that affected the central nervous system or having an impaired gait. The performed actions caused a reduction in fall rates, and the characterization of the events permitted staff to redirect interventions focusing on patients who were more susceptible to falls, as well as strengthen educational actions. PMID- 22441268 TI - [Evaluation of the welcoming strategies in the Intensive Care Unit]. AB - This qualitative study was performed at the adult Intensive Care Unit (ICU) of a public hospital in Southern Brazil with the objective to evaluate the implemented welcoming strategies. Participants included 13 patients and 23 relatives. Data collection was performed from July to October 2008, utilizing semi-structured interviews. All interviews were recorded. Data analysis was performed using the Collective Subject Discourse. The collected information yielded two discourses: the family recognized the welcoming strategies and the patients found the ICU team to be considerate. By including the family as a client of nursing care, relatives felt safe and confident. Results show that by committing to the responsibility of making changes in heath care practices, nurses experience a novel outlook towards ICU care, focused on human beings and associating the welcoming to the health care model that promotes the objectivity of care. PMID- 22441269 TI - [Sleep quality of obese workers of a teaching hospital: acupuncture as a complementary therapy]. AB - The objective of this study was to verify the effect of acupuncture on the sleep quality of obese workers in a teaching hospital. Data were collected from July to October 2009, focusing on 37 workers who attended eight weekly acupuncture sessions. The Pittsburgh Sleep Quality Index was used to assess their sleep quality before and after the intervention. Results show that before the intervention, five (13.5%) people experienced good quality of sleep whereas at the end of the study 14 (37.8%) showed this condition. Statistic significance (p=0.0001) was found in comparing the mean scores obtained before and after acupuncture. Acupuncture had effects on the quality of sleep in the studied sample, presenting itself as a complementary technique for treating sleep disorders and consequently improving the quality of life in this population. PMID- 22441270 TI - [The applicability of auriculotherapy with needles or seeds to reduce stress in nursing professionals]. AB - This clinical randomized trial was performed with the objective to evaluate the stress levels of the nursing staff of a hospital and analyze the effectiveness of auriculotherapy with needles and seeds. The 75 participants with mean (44/58.7%) and high (31/41.3%) scores according to the Stress Symptoms List were divided into groups (control, needles, and seeds), who received eight sessions on the Shenmen, Kidney and Brainstem points and were evaluated at the baseline, fourth and eighth sessions and on the 15-day follow-up session. The analysis of variance (ANOVA) showed significant differences among the groups at the third assessment (F=3.963/P=0.023) and follow-up (F=6.136/P=0.003). These differences occurred between the control and needle groups. The 'seeds' and needles groups both showed differences (p<0.05) at the second assessment when compared within the same group. In conclusion, auriculotherapy reduced the stress in the nursing staff, with needles showing better results than seeds for high scores, maintaining the effects for 15 days. PMID- 22441271 TI - [Affection in elderly care from the nurses' perspective]. AB - The objective of this study was to describe, from the nurses' perspective, the meaning of effective/affective care, the interference factors, and the learning promoted from dealing with elderly inpatients, as well as their perception of feeling ready or not to engage in caring. This qualitative study was performed with nurses from a hospital located in the Midwestern region of the State of Sao Paulo. The findings show that the meaning of providing effective/affective care involves knowing the client within his/her social framework, while it crosses the borders of sheer technical care and encompasses fulfilling the client's needs and requirements. Interferences in dealing with the elderly refer to those situations connected with the patients' conditions, work dynamics, and environmental and management adaptations. All surveys showed that despite feeling well prepared, nurses are aware of the need to study fields such as geriatrics and gerontology to a deeper extent. Complete and quality care is only possible if it includes techniques, knowledge and the ability to deal with others with patience and attention to detail. PMID- 22441272 TI - [The perception of hypertensive elderly patients regarding their health needs]. AB - Considering the prevalence of arterial hypertension among the elderly, the present study analyzes their perception of health needs, in a qualitative way, from focal groups with elderly users of Family Health Units. Data analysis was performed according to the hermeneutic-dialectical perspective and resulted in three nuclei of meaning: recognizing the possibility of having access to basic health care together with the desire to consume services of greater complexity and understanding the shortcomings of the State; attachment and welcoming as fundamental elements in the feelings of support and security and autonomy permeated by the tranquility to deal with the disease and the difficulties imposed by conditions inherent to the subjects' life style. Therefore, it is understood that the Family Health Strategy has been complying with its role in terms of the access to the healthcare system and regarding the professional-user attachment. However, health care continues to be centered on the disease rather than the individual. PMID- 22441273 TI - [The coordination of care for tuberculosis control]. AB - This descriptive epidemiological study analyzed the coordination of tuberculosis (TB) patient care in primary healthcare services according to 23 patients, 16 professionals, and 17 administrators from Ribeirao Preto, Sao Paulo, using an instrument adapted to evaluate TB. According to the informants, the coordination of healthcare provided to patients under the treatment of the Tuberculosis Control Program team was considered satisfactory; however, when there is a need to refer the patient to other care units there are weak points in the coordination of healthcare, which include: interruption of communication flow; and patients' incipient participation in the care process, with a need to increase the sense of responsibility for patient care and encourage patients to become active agents in the process. PMID- 22441274 TI - [The scientific production of Psychosocial Care Centers]. AB - The objective of this study was to present a panoramic view of the scientific production regarding Psychosocial Care Centers (CAPS). This literature review was performed using the LILACS, MEDLINE, and SciELO databases. Sixty-eight references were selected, most of which were journal articles (88.24%) and studies related to final graduate study essays (10.29%); 75% of the references found dating from 2003 were included. The following are highlighted among the most frequent objectives: the analysis and evaluation of the new proposal for mental health care, represented by Psychiatric Reform and by CAPS, and the analysis of mental health professionals and their expectations towards the services. The authors hope the present review will help find pathways and implications that lead to new studies and practices in the everyday work of health care services. PMID- 22441275 TI - [The implications of a psychoeducation group on the everyday lives of individuals with bipolar affective disorder]. AB - There is growing evidence that the course of Bipolar Affective Disorder (BAD) can be altered by psychotherapeutic approaches, such as Psychoeducation. Therefore, this study was performed with the objective of identifying the implications of a Psychoeducation group on the everyday lives of individuals with BAD. To do this, the authors chose to perform a qualitative case study. Participants included twelve individuals with BAD who had attended at least six meetings of the Psychoeducation Group held at the Sao Jose do Rio Preto Faculty of Medicine (FAMERP). Semi-structured interviews were performed, which were recorded and then transcribed and subjected to Thematic Analysis. The present study showed that the referred group experience promoted the individuals' knowledge acquisition; their awareness regarding the disease and adherence to treatment; their making positive changes in life; the possibility of helping other patients to benefit from the knowledge learned in the group; and their awareness regarding other realities and coping strategies, obtained by exchanging experiences with other participants. PMID- 22441276 TI - [Colonization by Staphylococcus aureus among the nursing staff of a teaching hospital in Pernambuco]. AB - This study was performed with the objective to identify the prevalence of colonization by Staphylococcus aureus in nursing professionals from a teaching hospital in Pernambuco, and evaluate the resistance profile of these isolates. To do this, we performed a cross-sectional study where biological samples were collected from the hands and nasal cavities of the subjects. S. aureus was identified using agar (blood agar and mannitol salt) via catalase and coagulase tests. The sensitivity profile was determined by Kirby Bauer technique and determination of methicillin resistance was performed with oxacillin screening with sodium chloride (NaCl) addition. Of the 151 professionals evaluated, 39 were colonized which showed a prevalence of 25.8%. Among the variables studied, age and use of PPE were associated with colonization by the organism. Of all the isolates, only five were resistant to methicillin. PMID- 22441277 TI - [The occurrence of headaches and their effect upon nursing undergraduate students]. AB - This study was performed with the objectives of identifying the occurrence of headache as the major cause of pain and characterizing the effect headaches have on the everyday activities of nursing undergraduate students. This cross sectional study was performed at the College of Nursing of the Federal University of Goias, Goiania, Brazil, from May to June 2008. Participants included 203 students (mean age 21 years; s.d.=1.8), 48.5% from economic class A. Headaches were the major cause of pain for 34.5% of students; described as being of strong intensity; referred to as throbbing (74.3%), stabbing (62.9%), and causing nausea and/or vomiting (55.7%); with episodes occurring in the afternoon (52.9%), and lasting for several hours a day (51.4%). Factors related to the onset of pain were: studying (17.1%) and stress (11.4 %). The activities most affected were: their capacity to concentrate (84.3%) and their mood (84.3%) (p<0.05). Headaches are less common in the population compared to other country studies, and they affect the students' everyday activities. PMID- 22441278 TI - [Home care: health professionals at risk for biological exposure]. AB - This prospective, exploratory study was performed using a quantitative approach with the objective of characterizing the healthcare tasks that involved biological risk for professionals working with the Home Care Service of the Sao Carlos Municipal Hospital (Sao Carlos, SP, Brazil). We followed 159 visits from June 2008 to January 2009. A total of 347 procedures were considered to present risks for biological exposure, categorized as follows: dressings (31.1%), capillary blood glucose monitoring (14.4%); and vascular access (3.1%). Of all subjects, 21.5% complied with hand cleansing prior to performing a procedure, 66.3% wore gloves and 83.5% disposed of sharps appropriately. In conclusion, these professionals are subject to biological risks similar to those found in the hospital environment, because they are also exposed to blood and sharps often and have a poor adherence to the standard preventive measures. Further studies to evaluate the influence of the features of the household on the referred risk should be encouraged. PMID- 22441279 TI - [Job Satisfaction: a quality indicator in nursing human resource management]. AB - This descriptive study addresses the job satisfaction of nurse managers and clinical nurses working at the Hematology and Hemotherapy Services of a public hospital in Sao Paulo. The study objectives were to identify the factors that caused job satisfaction among nurse managers and clinical nurses, and support the results in the development of indicators to evaluate the quality of nursing human resource management. The components of the study were: autonomy, interaction, professional status, job requirements, organizational norms and remuneration. Participants were 44 nurses. Data were collected using a Job Satisfaction Index (JSI) questionnaire. In conclusion, this study permitted the identification of the clinical nurse group, which was the most satisfied, with a JSI of 10.5; the managerial group scored 10.0. Regarding the satisfaction levels in regards to the current activity, 88.9% of the nurse managers reported feeling satisfied, as did 90.9% of clinical nurses. For both groups, autonomy was the component with the highest level of professional satisfaction. PMID- 22441280 TI - [Professional development and entering the labor market: the perceptions of nursing graduates]. AB - The professional history of nursing graduates allows for understanding and reflecting on higher education and the characteristics inherent in the job market. The objectives of the present study were to analyze the perceptions that nursing graduates of a private university have regarding their development process, focusing on the conditions of entering the job market and the demands they deal with in their professional life. The Collective Subject Discourse was the method of choice used in this study. Participants included 104 graduates who were divided into three groups according to their position after graduation. Discourse analysis allowed for deep reflection regarding their preparation, indicating the need to review the pedagogical project, particularly in terms of developing competencies in the four dimensions of care: management, healthcare, education, and research. PMID- 22441281 TI - [The development of an instrument to assess nursing care responsiveness at a university hospital]. AB - Responsiveness is a quality indicator presented by the World Health Organization in the field of health evaluation. Therefore, the objective of this study was to develop an instrument to evaluate the clients' opinions regarding the responsiveness of the nursing service of a public university hospital. The research was developed in the following stages: developing the instrument based on a literature review, apparent validation, applicability test and pilot test. The instrument allows the identification of the clients' expectations and perceptions, subdivided into aspects related to the Structure Process and Outcomes, measured using a 7-point Likert scale. Based on the results of the pilot test it was possible to establish a numerical indication of the Relative Satisfaction Rate and its interval. The study promoted the development of an acceptability percentage scale for the interval, which indicates the extent to which the nursing service meets the clients' expectations. PMID- 22441282 TI - [Nurses' perception regarding the implementation of computer-based clinical nursing documentation]. AB - This qualitative, exploratory, descriptive study was performed with the objective of understanding the perception of the nurses working in medical-surgical units of a university hospital, regarding the strategies developed to perform a pilot test of the PROCEnf-USP electronic system, with the purpose of computerizing clinical nursing documentation. Eleven nurses of a theoretical-practical training program were interviewed and the obtained data were analyzed using the Content Analysis Technique. The following categories were discussed based on the references of participative management and planned changes: favorable aspects for the implementation; unfavorable aspects for the implementation; and expectations regarding the implementation. According to the nurses' perceptions, the preliminary use of the electronic system allowed them to show their potential and to propose improvements, encouraging them to become partners of the group manager in the dissemination to other nurses of the institution. PMID- 22441283 TI - [The development and evaluation of software to verify diagnostic accuracy]. AB - This article describes the development and evaluation of software that verifies the accuracy of diagnoses made by nursing students. The software was based on a model that uses fuzzy logic concepts, including PERL, the MySQL database for Internet accessibility, and the NANDA-I 2007-2008 classification system. The software was evaluated in terms of its technical quality and usability through specific instruments. The activity proposed in the software involves four stages in which students establish the relationship values between nursing diagnoses, defining characteristics/risk factors and clinical cases. The relationship values determined by students are compared to those of specialists, generating performance scores for the students. In the evaluation, the software demonstrated satisfactory outcomes regarding the technical quality and, according to the students, helped in their learning and may become an educational tool to teach the process of nursing diagnosis. PMID- 22441284 TI - [Nursing history research groups: a Brazilian reality]. AB - The objective of this study is to examine the activities of Nursing History research groups in Brazil and their relationships with the nursing undergraduate and graduate courses. This exploratory, descriptive, qualitative documental study was performed from July 2008 to March 2010. We identified 34 research groups that had Nursing History as the focus of at least one of the lines of research. Results showed that the groups have produced a great amount of bibliographical material, research lines and broad participation of undergraduate and graduate students. It was also found that there is a communication network among groups working within the same line of research. In conclusion, there is a need to increase interdisciplinarity and also strengthen some lines of research in order to support knowledge of the history of Brazilian nursing. PMID- 22441285 TI - [Hermeneutics and health: reflections on the thinking of Hans-Georg Gadamer]. AB - This article has as its objective the desire to contribute to nursing practice with the use of Gadamer's hermeneutics. It reflects on the incorporation of the conceptual paradigm of health, care and therapeutic dialogue. In the first section the article discusses the Gadamerian concepts of the work Truth and Method, the hermeneutics philosophy proposed by the philosopher, and it concludes with the articulation of the health concept presented in the work The Hidden Character of Health, which proposes care mediated by therapeutic dialogue and its use by nursing professionals. PMID- 22441286 TI - [The use of active methodology in nursing care and teaching in national productions: an integrative review]. AB - The objective of this integrative review was to identify and analyze the scientific publications regarding the use of active methodologies in nursing care and teaching in Brazil. The survey included national publications, from 1999 to 2009, using the following databases: LILACS, BDENF, MEDLINE and SciELO. A total of 28 articles were selected. The results and analysis pointed to problematization as the primary active methodology used, the lack of theoretical frameworks to plan the pedagogical action, and the excessive use of teaching techniques that do not always characterize innovation. In conclusion, the implementation of innovative methodologies requires further studies and more investment in research and dissemination on the subject. PMID- 22441287 TI - [The humanization of care in the education of health professionals in undergraduate courses]. AB - This literature review was performed for the purpose of surveying and analyzing the scientific production in health in Brazilian journals regarding the teaching of health care humanization in undergraduate programs. The bibliographic survey was performed on the LILACS database using the term humanization, including texts published between 2000 and 2010 and examining 42 articles. The analysis of these articles revealed the following central themes: Humanization: some thoughts on its concepts; University and the National Curriculum Guidelines for Undergraduate Programs in Healthcare: relations with the teaching of humanization; Curricular changes, contents and teaching-learning strategies regarding humanized care; and Subjects of the teaching-learning process: students and faculty learning the humanization of care. Some theoretical and practical elements have been created about the teaching of humanization in the context of health; however, it is essential to make greater investments to effectively develop new ways of providing care. PMID- 22441288 TI - [The scientific production regarding leadership in the context of nursing]. AB - The objective of this study is to identify the scientific production in the context of nursing produced in the last decade (1999-2008). This literature review was performed using the LILACS database and included studies published as articles, theses, dissertations, editorials and presentations in events. Studies were written in Portuguese, English, or Spanish with the electronic full-text version available. A form was developed to register the data regarding the production, which included: reference, source of the manuscript, year, category, objective, methodology and theoretical framework. A total of 57 publications were found; most were original, descriptive articles performed in the hospital environment, and very few studies were founded on the Leadership Theory. It is necessary to adopt leadership development programs and permanent education projects within health services, with the purpose of preparing nurses to work as leaders. PMID- 22441289 TI - [The dietary risk factors for colorectal cancer related to meat consumption]. AB - The integrative review is one of the methodologies used for evidence-based practice which, in this study, had the objective of surveying and synthesizing the evidence available in the literature regarding the dietary risks for colorectal cancer related to the consumption of meat. The search was made using the LILACS, MEDLINE, CINAHL, and COCHRANE Library databases, and six studies considered pertinent to the consumption of meat were found. Meta-analyses showed that there is an association between the consumption of red meat and an increased risk for colorectal cancer from 28% to 35%, whereas processed meats are associated with a rise in risk from 20% to 49%. Evidence shows that the consumption of red meat, processed meat, and total meat consumption are risk factors for developing polyps and colorectal cancer. The search did not yield any studies referring to the consumption of chicken or fish as risk factors. PMID- 22441290 TI - [Extension activities aimed at the prevention and treatment of gynecological and breast cancer: an experience report]. AB - The objective of this study was to describe the experience of educational and healthcare activities undertaken in a community regarding gynecological and breast cancer, in women with gynecological or breast cancer undergoing chemotherapy in the postoperative period, and also with their families or caregivers as part of an extension project. Activities were organized in two ways: as prevention strategies, developed with women in basic health units, high schools and in public squares; and as health care activities carried out in wards of a hospital in Minas Gerais and at home. The range of activities involved about 800 users. The themes discussed were health promotion and risk factors for breast and gynecological cancer. The nursing care focused on the postoperative period and chemotherapy treatment, extending to home and families or caregivers. In conclusion, this type of activity promotes comprehensive care and facilitates academic learning. PMID- 22441291 TI - [The virtual environment of a research group: the tutors' perspective]. AB - The Grupo de Estudos e Pesquisas de Tecnologia da Informacao nos Processos de Trabalho em Enfermagem (Study and Research Group for Information Technology in the Nursing Working Processes, GEPETE) has the purpose of producing and socializing knowledge in information technology and health and nursing communication, making associations with research groups in this field and promoting student participation. This study was performed by the group tutors with the objective to report on the development of the virtual learning environment (VLE) and the tutors' experience as mediators of a research group using the Moodle platform. To do this, a VLE was developed and pedagogical mediation was performed following the theme of mentoring. An initial diagnosis was made of the difficulties in using this technology in interaction and communication, which permitted the proposal of continuing to use the platform as a resource to support research activities, offer lead researchers the mechanisms to socialize projects and offer the possibility of giving advice at a distance. PMID- 22441292 TI - Combining competition assays with genetic complementation strategies to dissect mouse embryonic stem cell self-renewal and pluripotency. AB - Substantial scientific interest has been dedicated recently to the crucial factors that control the pluripotent state of stem cells. To gain a comprehensive understanding of the molecular mechanisms regulating mouse embryonic stem cell (mESC) self-renewal and lineage differentiation, we have developed a robust method for studying the role of a particular gene in these processes. This protocol describes detailed procedures for the design and generation of the complementation rescue system and its application in dissecting the network of pluripotency-associated factors, using mESCs as a model. Specifically, three main procedures are described: (i) screening pluripotency-associated factors by competition assay; (ii) setting up an inducible complementation rescue system; and (iii) dynamically studying the pluripotency network response to target depletion. Completion of the competition assay and complementation rescue system takes 35 and 30 d, respectively, and an additional 16 d to study the dynamic molecular effects of a gene of interest in the pluripotency network. PMID- 22441293 TI - An isolated tumor perfusion model in mice. AB - The role of stromal cells in the tumor microenvironment has been extensively characterized. We and others have shown that stromal cells may participate in several steps of the metastatic cascade. This protocol describes an isolated tumor perfusion model that enables studies of cancer and stromal cell shedding. It could also be used to study the effects of therapies interfering with the shedding of tumor cells or fragments, circulating (stem) cells or biomarkers. Primary tumors are grown in a microenvironment in which stromal cells express GFP ubiquitously. Tumors are implanted orthotopically or can be implanted ectopically. As a result, all tumor-associated stromal cells express GFP. This technique can be used to detect and study the role of stromal cells in tumor fragments within the circulation in mice. Studying the role of stromal cells in circulating tumor fragments using this model may take 2-10 weeks, depending on the growth rate of the primary tumor. PMID- 22441294 TI - Studying primary tumor-associated fibroblast involvement in cancer metastasis in mice. AB - Stromal cells have been studied extensively in the primary tumor microenvironment. In addition, mesenchymal stromal cells may participate in several steps of the metastatic cascade. Studying this interaction requires methods to distinguish and target stromal cells originating from the primary tumor versus their counterparts in the metastatic site. Here we illustrate a model of human tumor stromal cell-mouse cancer cell coimplantation. This model can be used to selectively deplete human stromal cells (using diphtheria toxin, DT) without affecting mouse cancer cells or host-derived stromal cells. Establishment of novel genetic models (e.g., transgenic expression of the DT receptor in specific cells) may eventually allow analogous models using syngeneic cells. Studying the role of stromal cells in metastasis using the model outlined above may take 8 weeks. PMID- 22441295 TI - A transient parabiosis skin transplantation model in mice. AB - Parabiosis-conjoined surgery to provide a shared circulation between two mice-has been previously developed to study the hematopoietic system. This protocol describes the use of parabiosis for efficient transplantation of skin from a transgenic to a wild-type mouse. It can be used to study the role of stromal cells in a spontaneous model of distant cancer dissemination (metastasis). We have recently shown that primary tumor-derived stromal cells may facilitate metastasis by providing a provisional stroma at the secondary site. Studying the role of primary tumor-derived stroma cells requires methods for distinguishing and targeting stromal cells originating from the primary tumor versus their counterparts in the metastatic site. Parabiosis may also be used, taking advantage of the shared circulation between the parabiosed mice, to study tumor metastasis from one parabiont to another, or to investigate the role of circulating inflammatory cells or stem cells. Studying the role of stromal cells in metastasis using this model typically takes up to 11 weeks. PMID- 22441296 TI - Polyclonal antibodies: a cheap and efficient tool for screening of enantioselective catalysts. AB - Enantioselective polyclonal antibodies have been produced and characterized to develop a high-throughput screening method for lipase activity fingerprinting, with a view to the enantioselective hydrolysis of azlactones. PMID- 22441297 TI - Synthesis of (S)-(+)-cericlamine through lipase-catalyzed aminolysis of azo acetates. AB - The kinetic enzymatic resolution of azo acetates via aminolysis with Candida antarctica lipase B has been investigated using benzylamine as amine component. The products obtained from this biotransformation in high enantiomeric purity can serve as valuable precursors for various amino alcohols, as exemplified by the synthesis of the serotonin reuptake inhibitor (S)-(+)-cericlamine. PMID- 22441298 TI - Improved eigenanalysis of discrete subpopulations and admixture using the minimum average partial test. AB - Principal components analysis of genetic data has benefited from advances in random matrix theory. The Tracy-Widom distribution has been identified as the limiting distribution of the lead eigenvalue, enabling formal hypothesis testing of population structure. Additionally, a phase change exists between small and large eigenvalues, such that population divergence below a threshold of F(ST) is impossible to detect and above which it is always detectable. I show that the plug-in estimate of the effective number of markers in the EIGENSOFT software often exceeds the rank of the sample covariance matrix, leading to a systematic overestimation of the number of significant principal components. I describe an alternative plug-in estimate that eliminates the problem. This improvement is not just an asymptotic result but is directly applicable to finite samples. The minimum average partial test, based on minimizing the average squared partial correlation between individuals, can detect population structure at smaller F(ST) values than the corrected test. The minimum average partial test is applicable to both unadmixed and admixed samples, with arbitrary numbers of discrete subpopulations or parental populations, respectively. Application of the minimum average partial test to the 11 HapMap Phase III samples, comprising 8 unadmixed samples and 3 admixed samples, revealed 13 significant principal components. PMID- 22441299 TI - Functionalized mesoporous silica materials for controlled drug delivery. AB - In the past decade, non-invasive and biocompatible mesoporous silica materials as efficient drug delivery systems have attracted special attention. Great progress in structure control and functionalization (magnetism and luminescence) design has been achieved for biotechnological and biomedical applications. This review highlights the most recent research progress on silica-based controlled drug delivery systems, including: (i) pure mesoporous silica sustained-release systems, (ii) magnetism and/or luminescence functionalized mesoporous silica systems which integrate targeting and tracking abilities of drug molecules, and (iii) stimuli-responsive controlled release systems which are able to respond to environmental changes, such as pH, redox potential, temperature, photoirradiation, and biomolecules. Although encouraging and potential developments have been achieved, design and mass production of novel multifunctional carriers, some practical biological application, such as biodistribution, the acute and chronic toxicities, long-term stability, circulation properties and targeting efficacy in vivo are still challenging. PMID- 22441300 TI - Limus is not limus--a proposal to adjust terminology in the context of drug eluting stents. PMID- 22441301 TI - Efficacy and safety of aranidipine enteric-coated tablets compared with amlodipine in Chinese patients with mild to moderate essential hypertension: a multicenter, randomized, double-blind, parallel-controlled clinical trial. AB - This is a multicenter, randomized, double-blind, parallel-controlled study, conducted in Chinese patients with mild to moderate essential hypertension. After a 2-week washout period, 236 eligible patients were randomly to receive aranidipine 5-10 mg/d (n = 118) or amlodipine 5-10 mg/d (n = 118) for 10 weeks. The blood pressure and heart rate were evaluated in outpatient clinics, and ambulatory blood pressure monitoring was performed in 24 patients in each group. The blood pressure was significantly decreased in both groups. Compared with amlodipine, the patients who received aranidipine had less response in blood pressure (P < 0.01). The trough/peak ratios of diastolic blood pressure in aranidipine and amlodipine groups were 0.57 +/- 0.20 and 0.68 +/- 0.19, respectively (P = 0.119). Adverse events occurred at 11.86% and 7.63% in the aranidipine and amlodipine groups, respectively (P = 0.348). Headache was observed at an incidence of >3.0% in both groups, and the serum glucose and lipid profile had no significant change in the amlodipine group. In conclusion, once daily administration of aranidipine (5-10 mg) effectively controlled blood pressure, and the short-term treatment might result in it being less effective than amlodipine. It had a stable action over 24-hour period, and the mechanism of that is not yet clear. Aranidipine had a good safety similar to that of amlodipine. PMID- 22441302 TI - Effects of purple grape juice in the redox-sensitive modulation of right ventricular remodeling in a pulmonary arterial hypertension model. AB - The effects of purple grape juice (PGJ) pretreatment in signaling proteins involved in cardiac remodeling in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) were investigated. Male Wistar rats (control, MCT, PGJ, and MCT + PGJ groups) were treated for 6 weeks with water or PGJ (10 mL.kg( 1).d(-1)) by gavage. In the third week, they were administered a single dose of MCT (60 mg/kg i.p.). Pulmonary vascular resistance was determined by echocardiography, and hemodynamic analysis was performed in the right ventricle (RV). Hydrogen peroxide (H2O2) concentration and lipid peroxidation were quantified and thioredoxin-1 (Trx-1), p-ERK1/2/ERK1/2, p-Akt/Akt, p-JNK/JNK, and cleaved caspase-3 were detected at RV by Western blot. Pretreatment with PGJ attenuated pulmonary vascular resistance and improved hemodynamic parameters in MCT-induced PAH. PGJ and MCT groups exhibited increased H2O2 levels, which were reduced to baseline in MCT + PGJ. ERK1/2 phosphorylation showed the same profile of H2O2 changes. No changes in p-JNK/JNK and p-Akt/Akt expressions were found. An enhanced cleaved caspase-3 immunodetection was induced by the model, which was reversed in the MCT + PGJ group and associated with increased Trx-1 and reduced lipid peroxidation. Improvement in functional parameters mediated by PGJ pretreatment may be associated with the induction of Trx-1, influencing the expression of proteins involved in RV remodeling. PMID- 22441303 TI - Influence of hyperpolarization caused by high salt diet on beta-adrenoceptor mediated responses in rat pulmonary artery. AB - The effect of high salt diet on beta-adrenoceptor-mediated response was assessed in rat-isolated pulmonary arteries. Isoprenaline-induced relaxations were not different in tissues from rats on either, high salt or regular diets. However, acidic buffer (pH 6.4) alone and in combination with Ba2+ or Nomega-nitro-L arginine methyl ester (L-NAME) significantly attenuated isoprenaline-induced relaxations in tissues from rats on high salt compared with those on a regular diet. Also, Ba2+ and ouabain together produced a significantly greater inhibition of isoprenaline-induced relaxation in tissues from rats on high salt when compared with those on the regular diet. The resting membrane potential of smooth muscle cells of pulmonary arteries of rats on high salt diet compared with regular diet was more negative (ie, hyperpolarized) than that on the regular diet. This hyperpolarization was reversed on exposure of blood vessels to acidic buffer and/or Ba2+ and ouabain combined but not L-NAME. Treatment with isoprenaline did not cause further hyperpolarization of smooth muscle cells of arteries from rats on the high salt diet. Taken together, the electrical changes due to the high salt diet can be attributed to the opening of K+ channels (2 pore acid-sensitive K+ channels and K(ir2.1)) and the activation of Na+/K+-ATPase. Furthermore, hyperpolarization observed after consumption of high salt diet seems to preserve beta-adrenoceptor-mediated vasorelaxation. PMID- 22441304 TI - Central prolactin modulates insulin sensitivity and insulin secretion in diabetic rats. AB - BACKGROUND: Prolactin secretion is self-regulating as it acts upon hypothalamic dopaminergic systems which inhibit prolactin release from the anterior pituitary. Circulating prolactin improves glucose homeostasis by increasing insulin action and secretion, but central prolactin effects on glucose homeostasis have not been examined. Here, we determined that chronic central infusion of prolactin modulates insulin resistance and beta-cell function and mass in 90% of pancreatectomized diabetic male rats. METHODS: Diabetic rats were divided into three groups according to the dose of intracerebroventricular infusion of prolactin during 4 weeks: (1) low-dose prolactin (Low-PRL; 0.1 ug/h), (2) high dose prolactin (High-PRL; 1 ug/h) and (3) vehicle only (cerebrospinal fluid). Nondiabetic rats were centrally infused with the vehicle. RESULTS: Chronic intracerebroventricular infusion of Low-PRL lowered body weight and epididymal fat pads by increasing hypothalamic dopamine levels that reduced serum prolactin levels and potentiated leptin signaling. However, High-PRL slightly exacerbated energy dysregulation, decreased hypothalamic dopamine levels, and elevated serum prolactin levels. Both dosages promoted beta-cell mass but in a different manner: Low-PRL decreased beta-cell apoptosis, whereas High-PRL increased its proliferation. However, only Low-PRL enhanced first-phase insulin secretion and improved insulin sensitivity at a hyperglycemic state in comparison to the control. Low-PRL also increased glucose infusion rates and decreased hepatic glucose output in hyperinsulinemic states, signifying an improvement in hepatic insulin sensitivity. However, High-PRL exacerbated hepatic insulin resistance compared with the control diabetic rats. CONCLUSIONS: In contrast to the exacerbation of insulin resistance caused by High-PRL, Low-PRL may improve energy and glucose metabolism by increasing hypothalamic dopamine levels in diabetic rats. PMID- 22441305 TI - Effect of including nonfatal events in cardiovascular risk estimation, illustrated with data from The Netherlands. AB - AIMS: European physicians use SCORE risk charts to predict a patient's 10-year risk of cardiovascular diseases (CVD) mortality. We examined whether the inclusion of nonfatal events improved risk estimation and the identification of high-risk persons. METHODS AND RESULTS: In the EPIC-NL cohort, risk factor data were collected between 1993 and 1997 in 6772 men and 9108 women aged 35-65 years. During 10 years of follow up, 540 total (fatal + nonfatal) CVD events occurred, of which 122 (23%) were fatal. Risk equations were developed using Cox proportional hazard models. Discriminating ability and hazard ratios for CVD risk factors did not differ between the two endpoints. Absolute risks for total CVD were approximately 4-fold higher than for CVD mortality. Using the current 5% CVD mortality threshold or the 22% total CVD threshold for identification of high risk persons leaves more than 84% of all male and 98% of all female future cases untreated. Of those exceeding these thresholds, 20% and 27% of the men, respectively, and 16% and 19% of women will get a CVD event in the next 10 years. Cut-off points of 2% for CVD mortality, corresponding to 10% for total CVD, will identify high-risk persons of whom approximately 10% will get an event in the next 10 years. CONCLUSION: CVD mortality comprises a quarter of all total CVD events. Risk functions and the discriminating ability did not differ between the two endpoints. Cut-off points of 2% for CVD mortality or 10% for total CVD could be considered to identify high-risk persons. PMID- 22441306 TI - Expression of membrane-associated proteins within single emulsion cell facsimiles. AB - MreB is a structural membrane-associated protein which is one of the key components of the bacterial cytoskeleton. Although it plays an important role in shape maintenance of rod-like bacteria, the understanding of its mechanism of action is still not fully understood. This study shows how segmented flow and microdroplet technology can be used as a new tool for biological in vitro investigation of this protein. In this paper, we demonstrate cell-free expression in a single emulsion system to express red fluorescence protein (RFP) and MreB linked RFP (MreB-RFP). We follow the aggregation and localisation of the fusion protein MreB-RFP in this artificial cell-like environment. The expression of MreB RFP in single emulsion droplets leads to the formation of micrometer-scale protein patches distributed at the water/oil interface. PMID- 22441307 TI - Tandem-type Pd(II)-catalyzed oxidative Heck reaction/intramolecular C-H amidation sequence: a novel route to 4-aryl-2-quinolinones. AB - A novel catalytic method for synthesizing 4-aryl-2-quinolinones is reported. The process involves two mechanistically independent, sequential Pd(II)-catalyzed reactions--the oxidative Heck reaction and the intramolecular C-H amidation--both of which smoothly proceed in the presence of a single catalytic system in a one pot manner. PMID- 22441308 TI - Comparing a pictorial stroop task to viewing time measures of sexual interest. AB - This study investigated the ability of two viewing time (VT) methodologies and a pictorial Stroop task to differentiate sexual interest in a group of nonoffending heterosexual and homosexual men. The two VT methodologies were investigated given the lack of consistency among published studies supporting this method. The results indicated that the VT methodology in which participants are asked to browse through some images is slightly superior to the method in which participants are asked to rate their attractiveness to the images. The results also indicated that the Pictorial Stroop Task did not adequately differentiate between age categories of sexual interest within the two groups. The results have implications for the methodology used in VT tasks. PMID- 22441309 TI - Mapping the cytokine profile of painful bladder syndrome/interstitial cystitis in human bladder and urine specimens. AB - PURPOSE: This study investigated the cytokine profile in bladder tissue and urine of painful bladder syndrome/interstitial cystitis (PBS/IC) patients. METHODS: Multiplex analysis of 23 cytokines was performed with a multiple antigen bead assay (Luminex 100 IS) on cold cup bladder biopsy and urine specimens collected during cystoscopy with hydrodistention (HD) under general anesthesia from 10 PBS/IC patients (ICS definition). Collected tissue specimens and urine from pre HD and post-HD (mean 27 days) were compared to banked urine and tissue specimens (n = 10) collected from control subjects without PBS/IC symptoms. RESULTS: Univariate comparison of bladder tissue levels found significant elevation of IL 16, IL-18, CTACK, ICAM-1, MCP-3, SCGFbeta, TRAIL, and VCAM-1 in PBS/IC relative to controls. Multivariate analysis revealed VCAM-1 and ICAM-1 were responsible for the discrimination of both tissue and urine of PBS/IC from controls. Urine levels of MCP-3 and TRAIL were significantly reduced a month after HD in concert with improvement in standardized measures of clinical symptoms (pain, urgency, and frequency (PUF) overall score [mean 25.8 +/- 5.5 vs. 20.3 +/- 7, p = 0.04] and symptom score [mean 18.2 +/- 3.2 vs. 12.2 +/- 5.9; p = 0.009]). Post-HD urine levels of MCSF(r = 0.88; p = 0.003), MCP-3 (r = 0.81; p = 0.01), SDF1alpha (r = 0.82; p = 0.01), and IL-18 (r = 0.64; p = 0.08) positively correlated with improved symptom scores. CONCLUSIONS: These results indicate significant elevation of cytokines in PBS/IC bladder tissue relative to controls. Significant reduction in post-HD urine levels of MCP-3 and TRAIL relative to pre-HD in PBS/IC was associated with clinical improvement (as measured by PBS/IC symptom scores) to qualify them as biomarker candidates. PMID- 22441310 TI - Preoperative sex steroids are significant predictors of early biochemical recurrence after radical prostatectomy. AB - PURPOSE: We sought the association of preoperative serum total testosterone (tT), hypogonadism, 17beta estradiol (E2), and sex hormone-binding globulin (SHBG) with early biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: Sex steroids were assessed the day before surgery (7-11 a.m.) in a cohort of 605 patients with a median follow-up of 24 months following RP. Cox regression models tested the association between predictors [including age, body mass index (BMI), prostate-specific antigen (PSA), clinical stage, biopsy Gleason scores, tT, hypogonadism, E2, and SHBG] and early BCR (defined as a PSA >= 0.1 ng/ml that occurred within 24 months after RP). RESULTS: Early BCR was found in 34 (5.6 %) patients. Patients with BCR did not differ in terms of age, BMI, serum PSA, tT, E2, and SHBG levels, rate of hypogonadism, and clinical stage as compared with those without BCR (all p >= 0.05). Conversely, patients with BCR showed a greater prevalence of biopsy Gleason scores >=4 + 3 (all p <= 0.001). At multivariable Cox regression analysis, tT [hazard ratio (HR): 1.43; p = 0.03] E2 (HR: 1.05; p = 0.04), SHBG (HR: 1.29; p = 0.02), and biopsy Gleason scores equal to 4 + 3 (HR: 3.37; p = 0.04) and >=8 (HR: 20.06; p < 0.001) achieved independent predictor status for early BCR. Conversely, no significant associations were found for all the other predictors. CONCLUSIONS: Current findings show that preoperative serum sex steroids are independent predictors of early BCR in a homogeneous, large cohort of nonscreened patients treated with RP. PMID- 22441311 TI - Effect of dorsal vascular complex size on the recovery of continence after radical prostatectomy. AB - PURPOSE: The dorsal vascular complex (DVC) of the prostate is considered to be a functional structure having smooth muscles that are connected to the detrusor apron. We conducted this study to provide basic information regarding DVC size as measured by magnetic resonance imaging and to investigate whether DVC size is related to the recovery of continence following radical prostatectomy (RP). METHODS: We prospectively collected data that included the results of prostate MRI and continence recovery of patients who underwent RP. From April 2006 through February 2010, 862 patients underwent RP. Of these, a total of 731 cases were included in the final analysis. The height and width of the DVC were measured in the T1-weighted axial image at the level that showed the puboprostatic ligament. RESULTS: The continence rate of the total patient cohort at 12 months was 96.7 %. The mean width, height and area of the DVC were 2.0 +/- 0.4 cm, 1.2 +/- 0.3 cm and 1.8 +/- 0.6 cm(2), respectively, and there was no linear correlation between continence recovery and these parameters. However, the patients who had a moderately large-sized DVC (2.3-2.8 cm(2)) regained their continence significantly sooner (mean duration = 2.1 months) than those with small (3.7 months, p = 0.002) or extremely large DVC (4.0 months, p = 0.006). In a multivariate analysis, DVC size, age, transfusion and the length of membranous urethra were significant predictors of continence recovery. CONCLUSION: The patients who had a moderately large DVC regained continence faster following RP. PMID- 22441312 TI - Letter to the editor regarding the article "experience on semirigid ureteroscopy and pneumatic lithotripsy in children at a single center". PMID- 22441313 TI - Macrophage inflammatory protein-1beta: a novel prognostic biomarker in atherosclerosis? PMID- 22441314 TI - Spontaneous ejaculation with the use of noradrenergic reuptake inhibitors. PMID- 22441315 TI - Impact of cachexia on pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients. AB - PURPOSE: Cancer cachexia is characterized by hypoalbuminemia and with the hepatic production of acute-phase proteins in response to malignant growth. The aim of this study was to evaluate the influence of cachexia on the pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients. METHODS: Forty-seven Japanese patients receiving oxycodone extended-release tablets as a starting opioid for cancer pain were enrolled in this study. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone and noroxycodone were determined at the titration dose. RESULTS: Seven patients had a GPS of 0, 21 a GPS of 1, and 19 had a GPS of 2. A higher GPS was significantly correlated with a higher oxycodone concentration and a lower concentration ratio of noroxycodone to oxycodone and significantly associated with a lower incidence of dose escalation and a higher incidence of central adverse reactions. Serum albumin, but not alpha(1)-acid glycoprotein and C reactive protein, was inversely correlated with the free fraction of oxycodone. Serum albumin concentration was significantly associated with the incidence of dose escalation. In contrast, the free fraction of oxycodone and acute-phase proteins were not related to the clinical responses. CONCLUSIONS: Cachexia had an effect on oxycodone metabolism and the clinical responses to oxycodone. The observed reduction in serum albumin concentration was associated with dose escalation. These findings suggest that cachexia affects the clinical responses to oxycodone through metabolic and nutritional disorders in cancer patients. PMID- 22441316 TI - Abscess penetration of cefpirome: concentrations and simulated pharmacokinetic profiles in pus. AB - PURPOSE: Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown. METHODS: Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2 g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied. RESULTS: At abscess incision performed 158 +/- 112 min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from <=0.1 (limit of quantification) to 47 (mean 8.4 +/- 14.1 ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183 +/- 106 mg/L in plasma and 12 +/- 16 mg/L in the abscess. A cefpirome concentration of 2 mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics. CONCLUSIONS: Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates. PMID- 22441317 TI - Ion exclusion and electrokinetic effects resulting from electro-osmotic flow of salt solutions in charged silica nanopores. AB - Silica nanopores are the focus of significant scientific interest due to their potential in a wide variety of applications including desalination membranes. In this paper, the results of extensive all-atom molecular dynamics simulations of the electro-osmotic flow of 0.5 M monovalent (NaCl) and divalent (CaCl(2)) ionic solutions through cylindrical charged silica nanopores are presented. The silica nanopores are produced such that they capture the experimentally observed interfacial properties. The results provide an atomistic description of the ion transport through pores of diameters of 1.5 nm, 2.0 nm, 2.5 nm and 3.0 nm. In doing so, the effect of pore size on ion pairing, ion hydration, and water orientation for each ionic solution was investigated. Also, the transport of the ions through the nanopores is studied, and it is found that in the monovalent solutions the Cl(-) ions are excluded from the nanopores of all sizes. Whereas in the divalent solutions, there is no such preferential exclusion of either ion. This is due to the fact that the interfacial charge is fully compensated for by the Ca(2+) ions while it is not the case for the Na(+) ions. PMID- 22441318 TI - Clostridium difficile colitis: increasing incidence, risk factors, and outcomes in solid organ transplant recipients. AB - BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is an increasingly important diagnosis in solid organ transplant recipients, with rising incidence and mortality. We describe the incidence, risk factors, and outcomes of colectomy for CDAD after solid organ transplantation. METHODS: Patients with CDAD were identified from a prospective transplant database. Complicated Clostridium difficile colitis (CCDC) was defined as CDAD associated with graft loss, total colectomy, or death. RESULTS: From 1999 to 2010, we performed solid organ transplants for 1331 recipients at our institution. The incidence of CDAD was 12.4% (165 patients); it increased from 4.5% (1999) to 21.1% (2005) and finally 9.5% (2010). The peak frequency of CDAD was between 6 and 10 days posttransplantation. Age more than 55 years (hazard ratio [HR]: 1.47, 95% confidence interval [CI]=1.16-1.81), induction with antithymocyte globulin (HR: 1.43, 95% CI=1.075-1.94), and transplant other than kidney alone (liver, heart, pancreas, or combined kidney organ) (HR: 1.41, 95% CI=1.05-1.92) were significant independent risk factors for CDAD. CCDC occurred in 15.8% of CDAD cases. Independent predictors of CCDC were white blood cell count more than 25,000/MUL (HR: 1.08, 95% CI=1.025-1.15) and evidence of pancolitis on computed tomography scan (HR: 2.52, 95% CI=1.195-5.35). Six patients with CCDC underwent colectomy with 83% patient survival and 20% graft loss. Of the medically treated patients with CCDC (n=20), the patient survival was 35% with 100% graft loss. CONCLUSIONS: We have identified significant risk factors for CDAD and predictors of progression to CCDC. Furthermore, we found that colectomy can be performed with excellent survival in selected patients. PMID- 22441319 TI - Preservation of deep inferior epigastric artery at kidney transplantation prevents atrophy of lower rectus abdominis muscle. AB - BACKGROUNDS: The deep inferior epigastric artery (DIEA), which feeds the lower rectus abdominis muscle (lower RAM), is usually transected in kidney transplantation. In this study, we investigated whether preservation of DIEA can prevent lower RAM atrophy. METHODS: Two hundred and forty-five kidney transplant recipients (150 men and 95 women) were enrolled in the study (mean age 39.9 years) and were divided into two groups according to whether DIEA was transected (group A, n = 175) or preserved (group B, n = 70). The extent of lower RAM atrophy calculated in computed tomography (performed 1 year after transplantation) and incidence of lower RAM atrophy were compared between the two groups. The most predictive factors for lower RAM atrophy were assessed using a multivariate logistic regression model. RESULTS: The extent of lower RAM atrophy was significantly lower in group B (15.0 +/- 18.5%) than that in group A (38.9 +/ 25.4%, P = 0.003). The incidence of lower RAM atrophy was less prevalent in group B (20.0%) compared with that in group A (62.9%, P < 0.001). The sacrifice of DIEA was the only independent predictive factor for lower RAM atrophy (P < 0.001). CONCLUSIONS: Preservation of DIEA during kidney transplant can prevent lower RAM atrophy. PMID- 22441320 TI - Hypothermic reconditioning of porcine kidney grafts by short-term preimplantation machine perfusion. AB - BACKGROUND: Clinical trial data suggest that continuous hypothermic machine perfusion (HMP) during the entire preservation period reduces the incidence of delayed graft function and improves graft survival. This study evaluates whether short-term MP after cold storage (CS) is also effective. METHODS: Kidney function after cold preservation (4 degrees C, 21 hr) and transplantation was studied in an autotransplant model using Landrace pigs (25-30 kg; n=5 per group) with 1 week follow-up. Preservation was performed by conventional CS or HMP with a modified Lifeport Kidney Transporter either continuously during the entire preservation period or only for 2 hr of hypothermic reconditioning (HR) subsequent to conventional CS. RESULTS: HMP and HR similarly improved cortical microcirculation and significantly reduced maximal serum creatinine levels and recovery of creatinine clearance to normal values compared with CS. Fractional excretion of Na+ was unaltered after HMP and HR but significantly increased until postoperative day 5 on CS. On a molecular level, HR reduced innate immunoreactivity (toll-like receptor 4 expression and high mobility group protein B1 [HMGB-1] release) and normalized antiinflammatory tissue expression of von Kruppel-like Factor-2. CONCLUSION: Short-term reconditioning after CS proves to be as effective as continuous MP during the whole storage time. Because of its logistical convenience, the concept of an a posteriori treatment recommends itself to be evaluated in clinical trials. PMID- 22441321 TI - T-cell-based immunosuppressive therapy inhibits the development of natural antibodies in infant baboons. AB - BACKGROUND: We set out to determine whether B-cell tolerance to A/B-incompatible alloantigens and pig xenoantigens could be achieved in infant baboons. METHODS: Artery patch grafts were implanted in the abdominal aorta in 3-month-old baboons using A/B-incompatible (AB-I) allografts or wild-type pig xenografts (pig). Group 1 (Gp1) (controls, n=6) received no immunosuppressive therapy (IS) and no graft. Gp2 (n=2) received an AB-I or pig graft but no IS. Gp3 received AB-I grafts+IS (Gp3A: n=2) or pig grafts+IS (Gp3B: n=2). IS consisted of ATG, anti-CD154mAb, and mycophenolate mofetil until age 8 to 12 months. Gp4 (n=2) received IS only but no graft. RESULTS: In Gp1, anti-A/B and cytotoxic anti-pig immunoglobulin-M increased steadily during the first year. Gp2 became sensitized to donor-specific AB-I or pig antigens within 2 weeks. Gp3 and Gp4 infants that received anti CD154mAb made no or minimal anti-A/B and anti-pig antibodies while receiving IS. DISCUSSION: The production of natural anti-A/B and anti-pig antibodies was inhibited by IS with anti-CD154mAb, even in the absence of an allograft or xenograft, suggesting that natural antibodies may not be entirely T-cell independent. These data are in contrast to clinical experience with AB-I allotransplantation in infants, who cease producing only donor-specific antibodies. PMID- 22441322 TI - Health status assessment in routine clinical practice: the chronic obstructive pulmonary disease assessment test score in outpatients. AB - BACKGROUND: The chronic obstructive pulmonary disease (COPD) assessment test (CAT) is a simple, self-completion questionnaire developed to measure health status in patients with COPD, which is potentially suitable for routine clinical use. OBJECTIVES: The purpose of this study was to establish the determinants of the CAT score in routine clinical practice. METHODS: Patients attending the clinic completed the CAT score before being seen. Clinical data, including, where available, plethysmographic lung volumes, transfer factor and arterial blood gas analysis, were recorded on a pro forma in the clinic. RESULTS: In 224 patients (36% female), mean forced expiratory volume in 1 s (FEV1) was 40.1% (17.9) of predicted (%pred); CAT score was associated with exacerbation frequency [0-1/year 20.1 (7.6); 2-4/year 23.5 (7.8); >4/year 28.5 (7.3), p < 0.0001; 41/40/19% in each category] and with Medical Research Council (MRC) dyspnoea score (r2 = 0.26, p < 0.0001) rising approximately 4 points with each grade. FEV(1) %pred had only a weak influence. Using stepwise regression, CAT score = 2.48 + 4.12 [MRC (1-5) dyspnoea score] + 0.08 (FEV(1) %pred) + 1.06 (exacerbation rate/year)] (r2 = 0.36, p < 0.0001). The CAT score was higher in patients (n = 54) with daily sputum production [25.9 (7.5) vs. 22.2 (8.2); p = 0.004]. Detailed lung function (plethysmography and gas transfer) was available in 151 patients but had little influence on the CAT score. CONCLUSION: The CAT score is associated with clinically important variables in patients with COPD and enables health status measurement to be performed in routine clinical practice. PMID- 22441323 TI - Does the attentional demands of walking differ for older men and women living independently in the community? AB - BACKGROUND AND PURPOSE: Walking has been shown to be an attentionally demanding task. For older adults, gender-specific differences in gait and falling reported in the literature could arise as a result of the attentional demands of walking. However, differences in how older men and women allocate attention to walking have not been investigated. The purpose of this study was to use a dual-task voice reaction time paradigm to examine gender-specific differences in the attentional demands of walking in older adults who are independent in community ambulation. METHODS: A dual-task paradigm was used to measure voice reaction time (VRT) in older community-dwelling men (n = 29; mean age = 78.40, SD = 6.17 years) and women (n = 33; mean age = 77.01, SD = 6.07 years) under 3 task conditions: sitting in a chair, standing, and walking on a level surface. Between- and within group differences in dual-task VRT were examined using a 2 (men vs women) by 3 (task condition) repeated-measures analysis of variance. The level of statistical significance was set at 0.05, and a Bonferroni procedure was used for post hoc analyses. RESULTS: Sitting VRT was similar for men (mean = 454.90, SD = 140.05 milliseconds) and women (mean = 454.49, SD = 94.27 milliseconds). While standing, men had a slightly faster VRT (mean = 444.90, SD = 125.31 milliseconds vs mean = 452.09, SD = 92.82 milliseconds). When walking, VRT increased for both groups in comparison to sitting and standing and older men (mean = 509.11, SD = 142.19 milliseconds) responded faster than older women (mean = 537.55, SD = 122.43). However, the main effect of gender (P = .665) and interaction of gender with task (P = .433) were both not statistically significant. A statistically significant main effect for task (P < .001) indicated that walking VRT (mean = 524.25, SD = 131.71 milliseconds) was significantly longer than both sitting (P < .001, mean = 454.68, SD = 116.89 milliseconds) and standing (P < .001, mean = 448.36, SD = 108.37 milliseconds) VRT. DISCUSSION: The results demonstrate that the attentional demands of walking are not different for older adult men and women who are independent in community mobility. However, support was provided for the idea that walking is an attentionally demanding activity. In comparison with sitting and standing, walking was more attentionally demanding for both men and women. CONCLUSIONS.: A dual-task voice reaction time paradigm revealed that walking is not more attentionally demanding on the basis of gender when comparing community-dwelling older adult men with women. PMID- 22441324 TI - Minimal detectable change of knee extension force measurements obtained by handheld dynamometry from older patients in 2 settings. AB - BACKGROUND AND PURPOSE: The measurement properties of handheld dynamometry (HHD) have been studied extensively, but information about the responsiveness of the procedure is scant. The purpose of this study, therefore, was to determine the responsiveness (minimal detectable change [MDC]) for measurements of knee extension force obtained by HHD from older adult patients in 2 different settings. METHODS: This study involved the retrospective retrieval of knee extension force data of the left and right sides from 2 sources (acute rehabilitation [n = 53] and home care [n = 46]). The standard deviation of the forces and the weighted mean intraclass correlation coefficient (ICC) from 3 previous studies (ICC = 0.90) were then used to calculate the MDC95%. RESULTS: The MDC95% ranged from 46.0 to 79.0 N. It was lower for patients measured in a home care setting than for those measured in an acute rehabilitation setting. DISCUSSION AND CONCLUSIONS: By describing the MDC for knee extension force obtained by HHD from older adults in 2 settings, this study provides an indication of the changes in force that would have to be surpassed to conclude that a real change in knee extension strength was observed. The MDCs reported have a role in the interpretation of repeated measurements and in setting goals for changes in knee extension force. PMID- 22441325 TI - Using the Nintendo Wii Fit and body weight support to improve aerobic capacity, balance, gait ability, and fear of falling: two case reports. AB - BACKGROUND & PURPOSE: Lower limb amputation in older adults has a significant impact on balance, gait, and cardiovascular fitness, resulting in diminished community participation. The purpose of this case study was to describe the effects of a balance training program utilizing the Nintendo WiiTM Fit (Nintendo of America, Inc, Redmond, Washington) balance board and body-weight supported gait training on aerobic capacity, balance, gait, and fear of falling in two persons with transfemoral amputation. CASE DESCRIPTIONS: Participant A, a 62 year old male 32 months post traumatic transfemoral amputation, reported fear of falling and restrictions in community activity. Participant B, a 58 year-old male 9 years post transfemoral amputation, reported limited energy and balance deficits during advanced gait activities. INTERVENTION: 6-weeks, 2 supervised sessions per week included 20 minutes of NintendoTM Wii Fit Balance gaming and 20 minutes of gait training using Body Weight Support. OUTCOMES: Measures included oxygen uptake efficiency slope (OUES), economy of movement, dynamic balance (Biodex platform system), Activities-Specific Balance Confidence (ABC) Scale, and spatial-temporal parameters of gait (GAITRite). Both participants demonstrated improvement in dynamic balance, balance confidence, economy of movement, and spatial-temporal parameters of gait. Participant A reduced the need for an assistive device during community ambulation. Participant B improved his aerobic capacity, indicated by an increase in OUES. DISCUSSION: This case study illustrated that the use of Nintendo WiiTM Fit training and Body Weight Support were effective interventions to achieve functional goals for improving balance confidence, reducing use of assistive devices, and increasing energy efficiency when ambulating with a transfemoral prosthesis. PMID- 22441326 TI - ARIEL and AMELIA: testing for an accumulation of rare variants using next generation sequencing data. AB - OBJECTIVES: There is increasing evidence that rare variants play a role in some complex traits, but their analysis is not straightforward. Locus-based tests become necessary due to low power in rare variant single-point association analyses. In addition, variant quality scores are available for sequencing data, but are rarely taken into account. Here, we propose two locus-based methods that incorporate variant quality scores: a regression-based collapsing approach and an allele-matching method. METHODS: Using simulated sequencing data we compare 4 locus-based tests of trait association under different scenarios of data quality. We test two collapsing-based approaches and two allele-matching-based approaches, taking into account variant quality scores and ignoring variant quality scores. We implement the collapsing and allele-matching approaches accounting for variant quality in the freely available ARIEL and AMELIA software. RESULTS: The incorporation of variant quality scores in locus-based association tests has power advantages over weighting each variant equally. The allele-matching methods are robust to the presence of both protective and risk variants in a locus, while collapsing methods exhibit a dramatic loss of power in this scenario. CONCLUSIONS: The incorporation of variant quality scores should be a standard protocol when performing locus-based association analysis on sequencing data. The ARIEL and AMELIA software implement collapsing and allele-matching locus association analysis methods, respectively, that allow the incorporation of variant quality scores. PMID- 22441327 TI - Sub-nanometre sized metal clusters: from synthetic challenges to the unique property discoveries. AB - Sub-nanometre sized metal clusters, with dimensions between metal atoms and nanoparticles, have attracted more and more attention due to their unique electronic structures and the subsequent unusual physical and chemical properties. However, the tiny size of the metal clusters brings the difficulty of their synthesis compared to the easier preparation of large nanoparticles. Up to now various synthetic techniques and routes have been successfully applied to the preparation of sub-nanometre clusters. Among the metals, gold clusters, especially the alkanethiolate monolayer protected clusters (MPCs), have been extensively investigated during the past decades. In recent years, silver and copper nanoclusters have also attracted enormous interest mainly due to their excellent photoluminescent properties. Meanwhile, more structural characteristics, particular optical, catalytic, electronic and magnetic properties and the related technical applications of the metal nanoclusters have been discovered in recent years. In this critical review, recent advances in sub nanometre sized metal clusters (Au, Ag, Cu, etc.) including the synthetic techniques, structural characterizations, novel physical, chemical and optical properties and their potential applications are discussed in detail. We finally give a brief outlook on the future development of metal nanoclusters from the viewpoint of controlled synthesis and their potential applications. PMID- 22441328 TI - Electrochemical investigations into Tau protein phosphorylations. AB - Hyperphosphorylation of Tau, a protein that stabilizes microtubules, leads to the breakdown of the microtubular structure and ultimately to the formation of neurofibrillar tangles within neurons. Here, we report monitoring of Tau phosphorylations electrochemically, using Tau protein films chemically linked to gold surfaces and 5'-gamma-ferrocenyl (Fc) adenosine triphosphate (Fc-ATP) as a co-substrate. Fc-phosphorylation reactions of Tau are explored using the three protein kinases, glycogen synthase kinase (GSK-3beta), sarcoma (Src)-related kinase, and protein kinase A (PKA), which catalyze Fc-phosphorylation of different residues and regions within Tau. The kinetic parameters of the biochemical process (K(M) and V(max)) were determined. PMID- 22441329 TI - Porphyrins for dye-sensitised solar cells: new insights into efficiency determining electron transfer steps. AB - Porphyrin molecules offer immense potential as the light harvesting component of dye-sensitised nanocrystalline TiO(2) solar cells. Synthetic porphyrin dyes were amongst the first dyes trialled for sensitisation of inorganic semiconducting oxides. Today, they exhibit the best performance reported for dye-sensitised solar cells. Accompanying the significant performance improvement over the last two decades is a much improved understanding of efficiency-determining fundamental electron transfer steps, from charge photogeneration to recombination. In this feature article we highlight our recent discoveries of the influence of porphyrin molecule structure on efficiency determining electron transfer kinetics and device performance by systematically changing the molecular structure and observing electron injection and recombination kinetics using time resolved optical and electrical probes. Despite our observation of ultrafast charge injection for all porphyrin dyes studied by transient absorption spectroscopy, the injection yield estimated using an internal standard remains below 100% and depends strongly on the molecular structure. The observed discrepancy between kinetic competition and the injection yield is attributed to non-injecting dyes, probably arising due to inhomogeneity. A very interesting sub ns (0.5 ns to 100 ns) charge recombination channel between photo-injected electrons and porphyrin cations is observed, which is found to be more prominent in free-base porphyrin dyes with a conjugated linker. Charge recombination between the acceptor species in the redox containing electrolyte and injected electrons is shown to be an important limitation of most porphyrin-sensitised solar cells, accelerated by the presence of porphyrin molecules at the TiO(2) electrolyte interface. This recombination reaction is strongly dependent on the porphyrin molecular structure. Bulky substituents, using a porphyrin dimer instead of a porphyrin monomer, a light soaking treatment of freshly prepared films and co-sensitization of TiO(2) with multiple dyes are shown to be successful strategies to improve electron lifetime. Finally, new developments unique to porphyrin dye-sensitised solar cells, including performance enhancements from a light exposure treatment of a zinc porphyrin dye, a significant performance improvement observed after co-sensitisation of TiO(2) with free-base and zinc porphyrin dyes and the use of porphyrin dimers with increased light harvesting in thin-film TiO(2) solar cells are described. PMID- 22441331 TI - A concerted migration mechanism of mixed oxide ion and electron conduction in reduced ceria studied by first-principles density functional theory. AB - Ceria based oxides are regarded as key oxide materials for energy and environmental applications, such as solid oxide fuel cells, oxygen permeation membranes, fuel cell electrodes, oxygen storage, or heterogeneous catalysis. This great versatility in applications is rendered possible by the fact that rare earth-doped ceria is a pure oxygen ion conductor while undoped ceria, CeO(2 delta), is a mixed oxygen ion-electron conductor. To get deeper insight into the mixed conduction mechanism of oxygen ions and electrons from atomistic and electronic level viewpoints we have applied first-principles density functional theory (DFT + U method). The calculation results show that oxygen vacancies strongly attract localized electrons, forming associates between them. The migration energy of an oxygen vacancy in such an associate is substantially lowered compared to the unassociated case due to the simultaneous positional rearrangement of localized electrons during the ionic jump process. Accordingly, we propose a concerted migration mechanism of oxygen vacancies and localized electrons in reduced ceria; this mechanism results in an increased diffusivity of oxygen vacancies supported by localized electrons compared with that in pure oxide ion conductors. PMID- 22441330 TI - Inhibition of ACE activity contributes to the intestinal structural compensation in a massive intestinal resection rat model. AB - BACKGROUND: Intestinal adaptation in short bowel syndrome (SBS) consists of increased epithelial cells (ECs) proliferation as well as apoptosis. Angiotensin converting enzyme (ACE) has been shown to regulate ECs apoptosis. In this study, we investigated the effect of ACE inhibition on intestinal adaptation after small bowel resection (SBR) in a rat model. METHODS: Sprague-Dawley rats were used and were divided into four groups: (1) Sham group received an ileum transection (n = 6); (2) Sham + ACE-I group received an ileum transaction and lavage with ACE inhibitor (ACE-I, enalaprilat, 2 mg/kg/day) (n = 6); (3) SBS group received a 70 % mid-intestinal resection (n = 6); (4) SBS + ACE-I group received a 70 % mid intestinal resection and lavage with enalaprilat (2 mg/kg/day) (n = 6). Sampling was done 10 days after surgery. ECs apoptosis was studied by TUNEL staining. ACE, angiotensin II (ANGII) receptor type 1 (AT1R) and receptor type 2 (AT2R) expressions were detected with RT-PCR and immunofluorescent confocal microscopy. RESULTS: SBR leads to significant intestinal hypertrophy. The addition of ACE-I to SBS rat resulted in a significant decline in ECs apoptosis. ACE mRNA expression was significantly elevated after SBS creation (0.24 +/- 0.07 vs. 0.42 +/- 0.11), and ACE-I administration further increased mucosal ACE mRNA expression (0.54 +/- 0.12). Interestingly, AT1R mRNA expression showed a significant decline in the SBS group compared to Sham levels, and ACE-I administration increased AT1R mRNA expression to Sham levels. No significant difference in AT2R mRNA expression was found between Sham and SBS group. CONCLUSION: These results offer further insight into the role of ACE on intestinal mucosal remolding after massive bowel resection. ACE-I may be beneficial to SBS patients via a reduction of the apoptotic rate, thus facilitating the degree of adaptation. PMID- 22441332 TI - In a 32-year-old woman with chronic neck pain and headaches, will an exercise regimen be beneficial for reducing her reports of neck pain and headaches? PMID- 22441333 TI - Complexation of neutral 1,4-dihalobutanes with simple pillar[5]arenes that is dominated by dispersion forces. AB - The complexation of neutral 1,4-dihalobutanes with simple pillar[5]arenes was investigated. The results indicate the formation of interpenetrated complexes, where the dispersive interactions dominate the complex stability. Typically, 1,4 diiodobutane displays the strongest binding strength with ethylpillar[5]arene [K(a) = (1.0 +/- 0.1) * 10(4) M(-1)], up to 120 fold as compared with 1,4 difluorobutane. PMID- 22441334 TI - Synthesis of a new group of aliphatic hydrazide derivatives and the correlations between their molecular structure and biological activity. AB - In view of the growing demand for new compounds showing biological activity against pathogenic microorganisms, such as pathogenic and phytopathogenic fungi, the objective of this study was to synthesize a new group of aliphatic and aromatic derivatives of hydrazide. In consequence of the reactions observed during synthesis, the resulting compounds retained their linear structure. Their structure and lipophilicity, measured by high-performance liquid chromatography (HPLC), were analyzed. Correlations were determined between the compounds' molecular parameters and biological activity against Fusarium solani and Fusarium oxysporum fungi. The investigated compounds were also examined for their antifungal activity against Aspergillus fumigatus. The obtained results indicate that compounds with fluorine-containing substituents penetrate the cell structure more effectively and are characterized by higher antifungal potential than analogues with different substituents. PMID- 22441335 TI - Regulation of inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 murine macrophage by 7-O-methyl-naringenin. AB - 7-O-Methylnaringenin, extracted from Rhododendron speciferum, belongs to the flavanone class of polyphenols. In the present study, we investigated the anti inflammatory effects of 7-O-methylnaringenin on cytokine production by lipopoly saccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. The results showed that pretreatment with 10, 20 or 40 MUg/mL of 7-O-methylnaringenin could downregulate tumour necrosis factor (TNF-alpha), interleukin (IL-6) and interleukin (IL-1beta) in a dose-dependent manner. Furthermore, we investigated the signal transduction mechanisms to determine how 7-O-methylnaringenin affects RAW 264.7 macrophages. The activation of mitogen-activated protein kinases (MAPK) and IkappaBalpha were measured by Western blotting. The data showed that 7-O methylnaringenin could downregulate LPS-induced levels of phosphorylation of ERK1/2, JNK and IkappaBalpha. These observations indicated that 7-O methylnaringenin modulated inflammatory cytokine responses by blocking NF-?B, ERK1/2 and JNK/MAPKs activation. PMID- 22441337 TI - Sirens versus facts: mastering good old techniques in an era of innovation enthusiasm. PMID- 22441336 TI - Effects of a natural prolyl oligopeptidase inhibitor, rosmarinic acid, on lipopolysaccharide-induced acute lung injury in mice. AB - Rosmarinic acid (RA), a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Mice were pretreated with RA one hour before challenge with a dose of 0.5 mg/kg LPS. Twenty-four hours after LPS was given, bronchoalveolar lavage fluid (BALF) was obtained to measure pro-inflammatory mediator and total cell counts. RA significantly decreased the production of LPS induced TNF-a, IL-6, and IL-1beta compare with the LPS group. When pretreated with RA (5, 10, or 20 mg/kg) the lung wet-to-dry weight (W/D) ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF were decreased significantly. Furthermore, RA may enhance oxidase dimutase (SOD) activity during the inflammatory response to LPS-induced ALI. And we further demonstrated that RA exerts anti-inflammation effect in vivo models of ALI through suppresses ERK/MAPK signaling in a dose dependent manner. These studies have important implications for RA administration as a potential treatment for ALI. PMID- 22441338 TI - Use of nonprescription medicines by patients with COPD: a survey in Chongqing Municipality, China. AB - To study the impact of self-administration of nonprescription medicines (NPMs) on patients with chronic obstructive pulmonary disease (COPD), in Chongqing Municipality, China. A total of 85 patients who had used NPM were assigned to the NPM group. Another 83 patients who had only used prescription medicines (PMs) were assigned to the PM group. Their income, educational levels, health status, public health insurance coverage, the expense of drugs during exacerbation, and the numbers of acute exacerbations during the past year were surveyed, and the approved drugs for COPD were evaluated. The contents of corticosterone in various types of NPMs were determined by high-performance liquid chromatography. The proportion of use of NPM in hospitalized patients with COPD was 12.96%. The percentage of illiteracy and low income was significantly higher in COPD patients in the NPM group than those in the PM group. The cost of drugs per day and the quality of life in the NPM group were lower than those in the PM group. Further analysis revealed that 15 of 21 NPMs contained corticosteroids. More importantly, medical advice from doctors and nurses appeared to be effective. Some Chinese patients with COPD living in the Chongqing area of China used NPMs that contained corticosteroids. Health education and advisement can effectively limit the use of NPMs. PMID- 22441339 TI - Incidence and prognostic significance of second primary cancers in renal cell carcinoma. AB - BACKGROUND: The survival of patients with renal cell carcinoma (RCC) has improved in recent years. However, data on the risk of developing a second cancer after a diagnosis of RCC is limited. We used the data available in the Surveillance Epidemiology and End Results (SEER) database to estimate the risk of second metachronous primary cancers in patients diagnosed with RCC between 1973 and 2006. Furthermore, we also investigated the effect of the second primary cancers (SPCs) on the survival of RCC patients. RESULTS: A total of 3795 cases of SPCs were registered in the SEER between 1973 and 2006. The ratio of observed/expected number of SPCs in RCC was 1.18, which was significantly greater than expected. Solid tumors comprised 90% of all second malignancies in RCC patients, with the most second cancers reported in the prostate gland and the digestive and respiratory systems. The overall risk of second primaries was highest in patients aged over 30 years at the time of diagnosis. The site-specific risk of second cancers varied with the age at diagnosis, sex, race of the patient, size of the primary renal tumor, and history of radiation therapy. Patients with second primaries had a significantly longer overall survival than those without second malignancies. An interval of <1 year between the diagnosis of RCC and the second primary was the strongest predictor of poor overall survival in RCC patients with a second malignancy. CONCLUSIONS: Patients with RCC are at a significantly higher risk of developing a second malignancy, suggesting the need for careful surveillance for their early detection and management. PMID- 22441340 TI - Impact of asian ethnicity on colorectal cancer screening: a population-based analysis. AB - OBJECTIVES: Although research shows that African Americans and Hispanics frequently receive less colorectal cancer screening (CRCS) than whites, few studies have focused on CRCS among Asians. The aims of this study were to compare CRCS between Asians and whites and to evaluate for clinical predictors of CRCS. METHODS: From the 2007 California Health Interview Survey, we identified all Asian and white respondents who were eligible for CRCS. Logistic regression was performed to evaluate for differences in CRCS. We used stratified and interaction analyses to examine whether associations between race and CRCS were modified by insurance status, birthplace, or language skills, while controlling for other confounders. RESULTS: Baseline characteristics were similar between Asians and whites. Only 58% of Asians and 66% of whites reported undergoing up-to-date CRCS (P < 0.01). In multivariate analyses, visiting a physician more than 5 times produced the highest odds of being up-to-date with screening. When compared with whites, Asians had decreased odds of being up-to-date with screening. Stratified analyses showed that this disparity existed mainly in the insured, but not in the uninsured, and it was not modified by place of birth or English language proficiency. CONCLUSIONS: Despite its ability to reduce mortality, CRCS is suboptimal in our US population-based cohort of Asians when compared with whites. A contributing factor to this problem for the Chinese and Koreans may be a lack of awareness regarding CRCS, whereas the source of the problem in the Vietnamese seems to be related to healthcare access. PMID- 22441341 TI - Predictive role of midtreatment changes in survivin, GSTP1, and topoisomerase 2alpha expressions for pathologic complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. AB - INTRODUCTION: The primary aim of this study is to investigate the effect of change in the expression levels of survivin, glutathione-S-transferase P1 (GSTP1), and topoisomerase 2alpha (TOP2A) on the response to antracyclin-based and taxane-based neoadjuvant chemotherapy. METHODS: This study included 32 locally advanced breast cancer patients. Tumoral expressions of survivin, TOP2A, and GSTP1 in serial biopsy specimens obtained before treatment, after sequential 4 cycles of doxorubicin+cyclophosphomide, and 4 cycles of docetaxel were analyzed by real-time polymerase chain reaction. Survivin expressions were additionally analyzed in serial blood samples. RESULTS: The pathologic complete response (pCR) rate and the overall response rate (clinical complete and partial) were 28% (n=9) and 91% (n=29), respectively. There were no statistically significant correlations between serial TOP2A expression levels and response. There was a nonsignificant trend toward an improved response rate with decreased survivin expression. A significant decrease in the GSTP1 expression level throughout treatment (P=0.014), which was also shown to be significantly correlated with a pCR (P=0.0001), was seen. Downregulation of GSTP1 after 4 cycles of anthracycline based combination was independently associated with improved progression-free survival (P=0.01). CONCLUSIONS: Downregulation of GSTP1 is a significant predictor of pCR and improved progression-free survival during anthracycline based and taxane-based neoadjuvant chemotherapy in patients with locally advanced breast cancer. PMID- 22441342 TI - Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. AB - OBJECTIVES: AEG35156 is an antisense oligonucleotide (ASO) that targets the X linked inhibitor of apoptosis mRNA. Preclinical studies showed potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA). A phase I study was conducted to establish the maximum-tolerated dose, safety, and antitumor activity of AEG35156 plus gemcitabine in metastatic PDA. METHODS: Fourteen patients with metastatic PDA were enrolled. Nine patients were treated at 350 mg IV and 5 patients at 500 mg IV of AEG35156, 3 weeks on/1 week off of a 28-day cycle. Gemcitabine was administered at 1000 mg/m(2) IV over 30 minutes immediately after AEG35156 in both groups. Because of perceived neurotoxicity dose deescalation to 350 mg was recommended. RESULTS: All 14 patients were evaluable for tolerability and toxicity. Toxicities include neutropenia (grade 3/4, 6 patients), thrombocytopenia (grade 3, 2 patients), peripheral neuropathy (grade 3, 2 patients), fatigue (grade 3, 4 patients), ascites (grade 3, 2 patients), and nausea/vomiting (grade 4, 2 patients). Five patients (45%) experienced stable disease with a median progression-free survival of 58 days (95% CI, 52-107 d). CONCLUSIONS: The maximum-tolerated dose is AEG35156 500 mg plus gemcitabine 1000 mg/m(2) given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA. PMID- 22441343 TI - Outcome of patients with renal cell carcinoma metastatic to the brain treated with sunitinib without local therapy. AB - OBJECTIVE: To assess the response of brain metastases to sunitinib in patients with renal cell carcinoma (RCC) who did not undergo prior surgical resection or radiation to the brain. METHODS: We retrospectively reviewed the medical records of adult RCC patients who had metastases to the brain and received sunitinib. RESULTS: Six patients with clear-cell RCC were identified between March 2006 and August 2009. All patients had >=3 metastatic sites including the brain. Five patients received upfront sunitinib; 1 received sorafenib followed by sunitinib. Four patients had a solitary brain lesion, 1 patient had 2 lesions, and 1 patient had multiple subcentimeter lesions with the largest measuring 1.5 cm. Two patients achieved a near complete response to therapy with sunitinib and continue on treatment without recurrence in the brain for 47 and 23 months. One patient died of systemic disease without relapse in the brain. Two patients had disease progression in the brain and were salvaged with radiation therapy. One patient progressed systemically and in the brain after initial improvement in the brain. CONCLUSIONS: Clear-cell RCC patients with small asymptomatic supratentorial metastases without hemorrhage or herniation safely received sunitinib as initial therapy with good response. PMID- 22441344 TI - Effect of moderate elevation above sea level on blood oxygen saturation in healthy young adults. AB - BACKGROUND: Arterial hemoglobin oxygen saturation (SaO2) decreases at an altitude of >1,500 m. There are no reports on normal SaO2 at altitudes between 0 and 1,500 m. The clinical significance of decreased SaO2 at such altitudes is unclear. OBJECTIVE: To test the hypothesis that in healthy volunteers normal SaO2 at moderate altitude (MA; 725 m) is lower than that at almost sea level (SL; 43 m). METHODS: SaO2 was measured by transcutaneous pulse oximetry in young healthy volunteers at MA and was compared to equivalent measurements at SL. In addition, a 6-min walk test was performed and SaO2 at the end of the walk was compared between the two locations. RESULTS: 111 males were checked at MA and 101 at SL. At rest, nadir SaO2 was 95% at MA compared to 97% at SL. Mean SaO2 at rest was slightly higher at SL (98.53 +/- 0.52) compared to MA (98.11 +/- 0.8; p < 0.01). In subjects who completed the 6-min walk test, SaO2 slightly decreased after the test in both locations, by 0.38 +/- 0.65% in the SL group and by 0.37 +/- 1.12% in the MA group. This difference is not statistically significant by univariate analysis; however, a multiple regression analysis indicated that the drop in SaO2 was higher at MA than at low altitude. CONCLUSIONS: We found a low but significant difference in SaO2 between near-SL and at an altitude of 725 m. The clinical significance of this difference, in terms of human health, is probably minimal. PMID- 22441345 TI - Sustained decrease in blood pressure following missed doses of aliskiren or telmisartan: the ASSERTIVE double-blind, randomized study. AB - OBJECTIVES: The AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients (ASSERTIVE) study was designed to assess the sustained blood pressure (BP)-lowering effect of aliskiren vs. telmisartan after a 7-day treatment withdrawal in patients with hypertension. METHODS: Patients were randomized to once-daily aliskiren 150 mg (N = 414) or telmisartan 40 mg (N = 408). After 2 weeks, all patients were uptitrated to double the initial dose for 10 weeks; subsequently, all patients were treated with placebo to simulate a 7 day treatment withdrawal. RESULTS: At the end of active treatment (EoA), similar decreases in mean ambulatory BP were observed with aliskiren and telmisartan. From EoA to day 7 of treatment withdrawal (end of withdrawal, EoW), the least squares mean increase in 24-h mean ambulatory SBP was smaller for aliskiren (2.7 mmHg) vs. telmisartan (6.5 mmHg). Between-treatment difference was significant in favour of aliskiren (-3.8 mmHg; P < 0.0001). Similar effects were observed for the increase in 24-h mean ambulatory DBP after EoW (-2.1 mmHg; P < 0.0001). Mean sitting SBP and DBP were also significantly lower with aliskiren than telmisartan after EoW with SBP (2.0 mmHg) and DBP (1.1 mmHg) differences in favour of aliskiren, already evident on day 2 after a single 'missed dose'. CONCLUSION: Aliskiren showed a greater and more sustained BP-lowering effect than telmisartan during a 7-day treatment withdrawal. Aliskiren may provide sustained BP lowering during 1 day or more missed dose. PMID- 22441346 TI - Magnitude and return time of the reflected wave: the effects of large artery stiffness and aortic geometry. AB - BACKGROUND: Increased large artery stiffness is a major determinant of systolic pressure and indicator of cardiovascular events. The reflected wave, its arrival time (return time) and magnitude, contributes to systolic pressure, and is a supposed indicator of aortic stiffness. With aortic stiffening, the return time is assumed to decrease inversely with PWV as 2L/PWV, where L is the aortic length. However, several studies reported that the inflection point of aortic pressure, a surrogate of return time, varies little with aortic stiffness. METHODS: We studied the effects of aortic stiffness on wave reflection in an anatomically accurate arterial model. Return time is time difference of forward, Pf, and backward, Pb, pressure. Return time, inflection and shoulder points, augmentation index, and reflection magnitude (Pb/Pf) were calculated by standard rules. RESULTS: Peripheral resistance does not affect reflection directly, but only through pressure (stiffness) changes. Magnitude of reflected waves depend about equally on aortic geometry (taper, branches) and distal aortic reflection. Therefore, relations of augmentation index and reflection magnitude with stiffness are nonlinear and complex; augmentation index is most sensitive to stiffness. Between PWV 6 and 12 m/s, representing ages of 20-80 years, return time and inflection and shoulder points change differently with stiffness and PWV cannot be derived from them. Pulse pressure is strongly dependent on aortic stiffness. Taper changes return time by a factor 2, but has little effect on reflection magnitude, augmentation index, and inflection point. CONCLUSION: Accurate quantitative information on arterial stiffness cannot be obtained from reflection parameters. The augmentation index is most sensitive to stiffness changes. PMID- 22441347 TI - ECG detection of left ventricular hypertrophy: the simpler, the better? AB - OBJECTIVE: ECG is commonly employed to identify left ventricular hypertrophy (LVH) and a high risk of cardiovascular events (CVE) in hypertensive patients. However, the multiplicity of the existing criteria does not simplify interpretation of the data. We compared a number of common criteria in hypertensive patients by taking as references left ventricular mass (LVM) measured by echocardiography and prediction of incident CVE. METHODS: The population was a cohort of 958 hypertensive patients (mean age 48 years) recruited before any treatment and having benefited from an ECG and an echocardiography. We evaluated their outcomes at regular intervals. We examined the relationships between several ECG criteria of LVH and LVM as well the occurrence of CVE. RESULTS: Among the various parameters tested (Sokoloff, Cornell, Cornell product) the simple measurement of the RaVL wave offered the best correlations to LVM and the best prediction of the existence of an echocardiographic LVH (receiver-operating characteristic curves). Its alterations were best correlated with the changes in LVM during the follow-up period. Moreover, this simple measurement offered the best performance for the prediction of the occurrence of CVE (123 events after a mean lapse of 12 years). CONCLUSION: In the interpretation of an ECG in the hypertensive patient, the single measurement of the R wave in aVL gives results at least as good as those of more complicated indices, which do not appear to contribute further to the diagnosis of LVH and the prediction of cardiovascular risk. PMID- 22441349 TI - Impaired myogenic properties of cerebral arteries from the Brown Norway rat. AB - OBJECTIVES: The Brown Norway rat is highly susceptible to cerebral haemorrhage when hypertension is induced experimentally, compared with the Long Evans. The aims of the study were to compare the myogenic properties and also the collagen staining profile of the middle cerebral artery (MCA) and a small systemic artery (cremaster) from Brown Norway and Long Evans rats. METHODS: In-vitro pressure myography was used to compare the myogenic properties and the distensibility of MCA and cremaster arteries from Brown Norway rat, with those of the Long Evans rat. Histologically prepared arterial sections were stained with picrosirius red to compare the collagen-staining profile of MCA and cremaster from these strains of rat. RESULTS: In the presence of myogenic tone, the active pressure-diameter relationship (20-200 mmHg) was significantly different in MCA from the Brown Norway, but not cremaster arteries, compared with the Long Evans, characterized by in the lack of a myogenic range in the Brown Norway. Midwall collagen staining was significantly increased in MCA from the Brown Norway rat, compared with the Long Evans rat; this difference between rat strains was not observed in the cremaster arteries. However, the stress-strain relationship of MCA and cremaster arteries from the Brown Norway rat was shifted to the right, indicating an increased distensibilty of arteries from both vascular beds, compared with the Long Evans. CONCLUSION: These data demonstrate impaired myogenic properties and differences in the collagen-staining profile of MCA but not cremaster arteries from the Brown Norway rat, compared with the Long Evans. The impaired myogenic properties of MCA from the Brown Norway rat compared with the Long Evans may explain their increased susceptibility to cerebral haemorrhage when hypertension is induced experimentally. PMID- 22441348 TI - Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease 1 (APE1/Ref 1) via recruitment of histone deacetylase 1 corepressor complex. AB - OBJECTIVES: Apurinic/apyrimidinic-endonuclease 1 (APE1) heterozygous mice have chronically elevated blood pressure. Renin of the renin-angiotensin (ANG) system for blood pressure maintenance regulates production of ANG II, a vasoactive hormone. Renin expression and secretion from kidney juxtaglomerular cells are regulated by intracellular calcium. Our objective in this study is to investigate APE1's regulatory role in renin expression. METHODS: Effect of APE1 on calcium mediated modulation of renin expression was examined by real-time reverse transcriptase-PCR, Western analysis and renin promoter-dependent luciferase activity in APE1-knockdown, APE1-overexpressing or control mouse kidney As4.1 cells. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation assays were utilized to examine the association of APE1 with histone deacetylase (HDAC)1 corepressor complex and their recruitment to renin enhancer. Finally, kidney renin mRNA level and plasma-renin activity were measured in wild-type and APE1-heterozygous mice. RESULTS: Here we show that APE1 is involved in calcium mediated repression of renin gene. Our results further indicate that APE1 is a component of HDAC1 corepressor complex bound to renin-enhancer region. Increase in intracellular calcium ion concentration enhances the association of APE1 with HDAC1 corepressor complex and their recruitment to the enhancer region. Furthermore, APE1's N-terminal region is critical for formation and recruitment of the enhancer-bound corepressor complex. Increased renin expression in kidneys and higher plasma-renin activity in APE1 heterozygous mice further supports APE1's corepressor role in vivo. CONCLUSION: This study uncovers APE1's function as a novel negative regulator of renin expression, and thereby in blood pressure maintenance. PMID- 22441350 TI - Early pregnancy soluble E-selectin concentrations and risk of preeclampsia. AB - OBJECTIVE: Circulating biomarkers of endothelial dysfunction and inflammation are elevated in late pregnancy in women with preeclampsia. We examined plasma levels of inflammatory cytokines and adhesion molecules in early pregnancy, to assess their ability to predict preeclampsia. METHODS: In a prospective longitudinal study, 2600 women with singleton pregnancies and no history of hypertension were recruited at their antenatal hospital (booking) visit at gestational week 12-16. Of these, 49 (1.9%) developed preeclampsia, whereas 74 women matched for age and BMI with uncomplicated pregnancies were selected as controls. A subset of women with risk factors for preeclampsia were sampled again at gestational weeks 16 and 28 (11 cases, 39 controls) and postnatally (six cases, 36 controls). RESULTS: From multiplex analysis, soluble E-selectin concentrations were higher at 12-16 weeks in women who subsequently developed preeclampsia (15.1 +/- 4.9 versus 12.9 +/- 4.5 ng/ml, P = 0.02). At gestational week 28, E-selectin concentrations were again higher in women who went on to develop preeclampsia compared with controls (14.4 +/- 5.6 versus 10.7 +/- 3.5 ng/ml, P = 0.010), whereas levels were not different between the two groups in postpartum samples. CONCLUSION: Changes in soluble E-selectin concentration in early pregnancy may reflect underlying pathophysiological processes, potentially providing mechanistic insights into preeclampsia. PMID- 22441351 TI - The association between glomerular filtration rate and stroke in hypertensive patients in rural areas of China. AB - OBJECTIVES: The present study is to explore the association between estimated glomerular filtration rate (eGFR) and stroke in hypertensive patients in rural areas of China. METHODS: The prospective study was based on 3711 hypertensive patients who were aged at least 35 years, free from cardiovascular diseases, and had serum creatinine at baseline. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: During a median follow-up of 4.9 years, 176 first-ever strokes (98 ischemic, 75 hemorrhagic, and three were unspecified strokes) occurred. We found no independent association between eGFR and risk of hemorrhagic stroke. In contrast, with decreasing eGFR, the risk of total and ischemic stroke strongly increased; the sex and age-adjusted hazard ratios for overall and ischemic stroke were 3.34 [95% confidence interval (CI) 1.61-6.93] and 3.79 (95% CI 1.33-10.81) for patients with eGFR below 60 versus eGFR at least 90 ml/min per 1.73 m, respectively. In addition, patients with an eGFR of 60-90 relative to eGFR at least 90 ml/min per 1.73 m had hazard ratios of 2.31 (95% CI 1.53-3.51) and 3.24 (95% CI 1.76-6.00) for overall and ischemic stroke after adjustment for sex and age, respectively. Adjustment for other cardiovascular factors only slightly attenuated the associations. CONCLUSIONS: The patients with decreased eGFR, also included those with eGFR range between 60 and 90 ml/min per 1.73 m, had an independently increased risk of overall and ischemic stroke in hypertensive patients in rural areas of China. PMID- 22441352 TI - Cation exchange in aptamer-conjugated CdSe nanoclusters: a novel fluorescence signal amplification for cancer cell detection. AB - Fluorescence signal amplification by cation exchange in aptamer-conjugated CdSe nanoclusters, a biological self-assembly of CdSe quantum dots, was developed as a novel method for cancer cell detection. PMID- 22441353 TI - Live-cell monitoring of the glutathione-triggered release of the anticancer drug topotecan on gold nanoparticles in serum-containing media. AB - The intracellular glutathione-triggered release of the anticancer drug topotecan from gold nanoparticles in serum-containing media was directly monitored in real time using a label-free fluorescence live-cell imaging technique. PMID- 22441354 TI - Novel pseudo-delocalized anions for lithium battery electrolytes. AB - A novel anion concept of pseudo-delocalized anions, anions with distinct positive and negative charge regions, has been studied by a computer aided synthesis using DFT calculations. With the aim to find safer and better performing lithium salts for lithium battery electrolytes two factors have been evaluated: the cation anion interaction strength via the dissociation reaction LiAn ? Li(+) + An(-) and the anion oxidative stability via a vertical ionisation from anion to radical. Based on our computational results some of these anions have shown promise to perform well as lithium salts for modern lithium batteries and should be interesting synthetic targets for future research. PMID- 22441355 TI - Transitions between sickness absence, work, unemployment, and disability in Denmark 2004-2008. AB - OBJECTIVES: Studies of labor market outcomes like sickness absence are usually restricted to a single outcome. This paper investigates the use of multi-state models for studying multiple transitions between sick-listing, work, unemployment, and disability pension by analyzing longitudinal register data. Every person sick-listed in Denmark during 2004 was followed until the spring of 2008. METHODS: A multi-state model was used to analyze transitions between four states: work, sickness absence, unemployment, and disability pension. The first three are possible recurrent states. The predictor variables include age group, gender, geographical region, chronic disease, temporary disease, self-employment sickness absence insurance, and pregnancy. The relative effects of previous transitions were also studied. RESULTS: Risk of transition from sickness absence to disability pension differs with age and geographical region. Those aged 20-29 years have an increased risk of transitioning from work to sickness absence and from sickness absence to unemployment. The self-employed have increased risk of transitioning from work to sickness absence. Those with chronic disease have increased risk of sickness absence, but also a greater probability of returning to work. Previous sickness absence increases the risk of transitioning from work to sickness absence, from sickness absence to unemployment, from work to unemployment, and from work to disability pension. CONCLUSIONS: The multi-state model is an effective way of analyzing register data and the transitions between sickness absence, work, unemployment, and disability pension. These methods can be used to develop better predictive models of sickness absence, return to work, unemployment, and disability. PMID- 22441356 TI - Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer. AB - PURPOSE: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease. METHODS: Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I-III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance. RESULTS: All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL 13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL 4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p = 0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival. CONCLUSIONS: Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer. PMID- 22441357 TI - Ocular and cervical vestibular evoked myogenic potentials to 500 Hz fz bone conducted vibration in superior semicircular canal dehiscence. AB - OBJECTIVE: The aim of this study was to investigate the effect of superior semicircular canal dehiscence (SSCD) on the n10 component of the ocular vestibular evoked myogenic potential (oVEMP n10) and the p13-n23 component of the cervical vestibular evoked myogenic potential (cVEMP p13-n23) evoked by 500 Hz bone-conducted vibration (BCV) at the midline forehead at the hairline (Fz) in 26 patients with computed tomography-verified SSCD. Previous evidence has led to the proposal that the oVEMP n10 is of utricular origin whereas the cVEMP p13-n23 is of saccular origin. The question is can the oVEMP n10 to 500 Hz BCV indicate SSCD? DESIGN: A hand-held Bruel & Kjaer 4810 Minishaker was used to provide BCV stimulation using surface electromyography electrodes to record oVEMP n10 and cVEMP p13-n23. The stimulus was 7 msec bursts of 500 Hz BCV at either Fz or at the vertex of the skull (Cz). Twenty-seven healthy subjects were tested in the same paradigm. RESULTS: In response to 500 Hz Fz BCV in SSCD patients the oVEMP n10 amplitude beneath the contraSSCD eye was substantially and significantly larger than the oVEMP n10 beneath the ipsiSSCD eye, whereas in these same patients the cVEMP p13-n23 amplitude over the ipsiSSCD sternocleidomastoid muscle to Fz BCV was slightly but significantly larger than the cVEMP p13-n23 amplitude over the contraSSCD sternocleidomastoid muscle. In SSCD patients there was a significant relationship between the size of the dehiscence and the amplitude of the contralateral oVEMP n10 potential. The oVEMP n10 to Cz stimulation was still present in SSCD patients, but small or absent in healthy subjects. CONCLUSIONS: In response to 500 Hz Fz BCV an asymmetrical oVEMP n10 with a significantly increased amplitude of contralesional oVEMP n10 (compared with population values of healthy subjects) is a simple useful indicator of SSCD, confirmed by the Cz response. oVEMP testing with 500 Hz Fz BCV allows very simple, very fast identification of a probable unilateral SSCD. PMID- 22441359 TI - Cochlear implantation in adults with asymmetric hearing loss. AB - OBJECTIVE: Bilateral severe to profound sensorineural hearing loss is a standard criterion for cochlear implantation. Increasingly, patients are implanted in one ear and continue to use a hearing aid in the nonimplanted ear to improve abilities such as sound localization and speech understanding in noise. Patients with severe to profound hearing loss in one ear and a more moderate hearing loss in the other ear (i.e., asymmetric hearing) are not typically considered candidates for cochlear implantation. Amplification in the poorer ear is often unsuccessful because of limited benefit, restricting the patient to unilateral listening from the better ear alone. The purpose of this study was to determine whether patients with asymmetric hearing loss could benefit from cochlear implantation in the poorer ear with continued use of a hearing aid in the better ear. DESIGN: Ten adults with asymmetric hearing between ears participated. In the poorer ear, all participants met cochlear implant candidacy guidelines; seven had postlingual onset, and three had pre/perilingual onset of severe to profound hearing loss. All had open-set speech recognition in the better-hearing ear. Assessment measures included word and sentence recognition in quiet, sentence recognition in fixed noise (four-talker babble) and in diffuse restaurant noise using an adaptive procedure, localization of word stimuli, and a hearing handicap scale. Participants were evaluated preimplant with hearing aids and postimplant with the implant alone, the hearing aid alone in the better ear, and bimodally (the implant and hearing aid in combination). Postlingual participants were evaluated at 6 mo postimplant, and pre/perilingual participants were evaluated at 6 and 12 mo postimplant. Data analysis compared the following results: (1) the poorer-hearing ear preimplant (with hearing aid) and postimplant (with cochlear implant); (2) the device(s) used for everyday listening pre- and postimplant; and (3) the hearing aid-alone and bimodal listening conditions postimplant. RESULTS: The postlingual participants showed significant improvements in speech recognition after 6 mo cochlear implant use in the poorer ear. Five postlingual participants had a bimodal advantage over the hearing aid-alone condition on at least one test measure. On average, the postlingual participants had significantly improved localization with bimodal input compared with the hearing aid-alone. Only one pre/perilingual participant had open-set speech recognition with the cochlear implant. This participant had better hearing than the other two pre/perilingual participants in both the poorer and better ear. Localization abilities were not significantly different between the bimodal and hearing aid alone conditions for the pre/perilingual participants. Mean hearing handicap ratings improved postimplant for all participants indicating perceived benefit in everyday life with the addition of the cochlear implant. CONCLUSIONS: Patients with asymmetric hearing loss who are not typical cochlear implant candidates can benefit from using a cochlear implant in the poorer ear with continued use of a hearing aid in the better ear. For this group of 10, the 7 postlingually deafened participants showed greater benefits with the cochlear implant than the pre/perilingual participants; however, further study is needed to determine maximum benefit for those with early onset of hearing loss. PMID- 22441360 TI - Supramolecular complexation for environmental control. AB - Supramolecular complexes offer a new and efficient way for the monitoring and removal of many substances emanating from technical processes, fertilization, plant and animal protection, or e.g. chemotherapy. Such pollutants range from toxic or radioactive metal ions and anions to chemical side products, herbicides, pesticides to drugs including steroids, and include degradation products from natural sources. The applications involve usually fast and reversible complex formation, due to prevailing non-covalent interactions. This is of importance for sensing as well as for separation techniques, where the often expensive host compounds can then be reused almost indefinitely. Immobilization of host compounds, e.g. on exchange resins or on membranes, and their implementation in smart new materials hold particular promise. The review illustrates how the design of suitable host compounds in combination with modern sensing and separation methods can contribute to solve some of the biggest problems facing chemistry, which arise from the everyday increasing pollution of the environment. PMID- 22441361 TI - S(+)-ketamine for control of perioperative pain and prevention of post thoracotomy pain syndrome: a randomized, double-blind study. AB - BACKGROUND: Post-thoracotomy pain syndrome (PTPS) often complicates the long term outcome of patients; its appearance has been related to perioperative acute pain. The main goal of this study was to evaluate a possible role of S(+)-ketamine in the prevention of PTPS up to 6 months and secondarily its efficacy in the control of perioperative pain when added to thoracic epidural analgesia (TEA) and adjuvants. METHODS: Sixty-six patients underwent thoracotomy under general anesthesia. A thoracic epidural catheter was placed for levobupivacaine and sufentanil administration. Thirty-three patients received an i.v. infusion of S(+)-ketamine (Group S(+)K) for 60 hours and 33 patients received i.v. placebo (Group PLAC). Pain was evaluated by Numeric Rating Scale (NRS) during the whole study. All patients had supplementary doses of analgesics, as needed, to have NRS targeted to a value of <=3 in the 1st and <3 in the following days. Neuropathic Pain Symptom Inventory (NPSI) was evaluated at 1, 3 and 6 months. RESULTS: All patients had NRS <=3 in the early postoperative period and NPSI was less or equal to 1 in the follow-up control for each group with no significant difference at three (P=0.67, OR 0.8 [IC95% 0.3-2.2]) and at six months (P=0.23, OR 1.9 [0.7 5.4]). Incidence of moderate PTPS was 24.6% at 3 and 21.1% at six months while severe PTPS was 6.6% at 3 and 1.8% at six months. No difference was detected in NRS and NPSI at 3 and 6 months between groups. CONCLUSION: S(+)-ketamine had no effects in respect to placebo in the prevention of PTPS at 3 and 6 months but had a significant role in maintaining a NRS<=3 in the early postoperative period. A tight control of perioperative pain seems to be associated with a low incidence of moderate and severe PTPS. PMID- 22441362 TI - Hypersensitivity reactions during anesthesia. Results from the ninth French survey (2005-2007). AB - BACKGROUND: Hypersensitivity reactions occurring during anesthesia remain a major cause of concern for anesthesiologists. We report the results of the ninth consecutive survey of hypersensitivity reactions observed during anesthesia in France. This report will be used as an epidemiologic reference prior to this intervention. METHODS: Between January 1, 2005 to December 31, 2007, 1253 patients who experienced an immune-mediated (IgE-mediated) or non-immune-mediated (non-IgE-mediated) hypersensitivity reaction were referred to one of the 40 participating centers. Diagnosis was established on the basis of clinical history, skin tests and/or specific IgE assay. RESULTS: An IgE-mediated or non IgE-mediated reaction was diagnosed in 786 cases (63%) and 467 cases (37%), respectively. The most common causes of anaphylaxis were neuromuscular blocking agents (NMBA) (N.=373, 47.4%), latex (N.=158, 20%), and antibiotics (N.=141, 18.1%). Succinylcholine (N.=226, 60.6%) was the most frequently incriminated NMBA, whereas the low frequency of reactions involving cis-atracurium was confirmed (N.=22, 5.9%) when market shares of each NMBA were taken into account. An increased number of reactions involving vital dyes was recorded (N.=34, 4.4%). CONCLUSION: These changes in the epidemiology of allergic reactions confirm the need for regular epidemiologic surveys of anaphylaxis in the perioperative period. PMID- 22441365 TI - p53 staining correlates with tumor type and location in sebaceous neoplasms. AB - Sebaceous neoplasms are commonly considered in their relationship to the Muir Torre syndrome and the now well-documented loss of DNA mismatch repair proteins leading to microsatellite instability. However, sebaceous neoplasms showing microsatellite instability comprise only a subset of this group of tumors, and thus, alternative tumorigenic mechanisms must exist. This article explores the relationship of p53, a tumor suppressor implicated in other cutaneous malignancies, and sebaceous neoplasia. We examined 94 sebaceous tumors from 92 patients. Tumors with strong nuclear p53 staining were significantly associated with the diagnosis of sebaceous carcinoma compared with benign sebaceous lesions, most notably for periocular carcinomas. Importantly, nuclear mismatch repair protein expression was intact in all lesions showing p53 alterations, suggesting that p53 dysfunction may represent a divergent pathway in the molecular pathogenesis of these tumors. PMID- 22441366 TI - Predictive factors of relapse in adult with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is an IgA-mediated small vessel vasculitis with a predominant cutaneous involvement. We assessed adult patients with HSP to identify the clinical and histopathological features and evaluate predictive factors of relapse. We reviewed the records of 29 adult patients with HSP who presented at our department between 2002 and 2009. Adult HSP was confirmed by skin biopsy showing leukocytoclastic vasculitis and direct immunofluorescence showing IgA deposit. Among the 29 patients (15 men, 14 women; mean age 36.2 years old), renal involvement was initially found in 22 patients (75.9%). They were divided into 2 groups according to the presence or absence of relapse. We compared clinical and histopathologic differences between 15 patients with relapse and 14 patients without relapse. By univariate analysis, older age at onset, persistent rash, abdominal pain, hematuria, and underlying disease at the onset of HSP are significantly related to relapse. Among the histopathological variables, severity of leukocytoclasis and absence of IgM deposit on the vessel walls are significantly associated to relapsing disease (P < 0.05). Our results are significant, because, they may help to understand the predictive factors related to relapses of HSP in adults. Further studies are necessary to identify whether more aggressive treatment in adults with HSP with these predictive factors can prevent relapse and severe renal sequelae. PMID- 22441367 TI - Expression of MiTF may be helpful in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen. AB - BACKGROUND: Overlapping histopathologic features of cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT), when both are predominantly composed of histiocytoid cells, make distinction between these entities challenging. Some have suggested that CNT and PFHT are related entities. No prior study has demonstrated a reliable immunohistochemical panel to differentiate these entities. METHODS: Skin biopsies diagnosed as CNT and PFHT, from 2004 to 2010 were retrieved with accompanying pathology reports. Each case was reviewed by at least 2 dermatopathologists and 2 soft tissue pathologists for confirmation of diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF). RESULTS: Histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and was consistently negative in the PFHT. CONCLUSIONS: CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Of the stains we evaluated, we found that expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation. PMID- 22441368 TI - Multiple papulonodular lesions on the dorsum of the hand: challenge. Multinucleate cell angiohistiocytoma (MCAH). PMID- 22441369 TI - Linear arrangement of neutrophils along the Basal layer in bullous pemphigoid: a unique histological finding. AB - Bullous pemphigoid is an inflammatory autoimmune subepidermal bullous disease with distinct immunohistological features. We report an unusual case of a 59-year old woman with a bullous eruption whose lesional skin biopsy showed a subepidermal blister with a linear arrangement of neutrophils, mimicking linear IgA bullous dermatosis. However, direct immunofluorescence studies demonstrated IgG and C3 linear deposition along the basement membrane zone, compatible with bullous pemphigoid. We suggest that bullous pemphigoid should therefore be considered in the differential diagnosis of neutrophil-rich subepidermal bullous diseases along with dermatitis herpetiformis and linear IgA. PMID- 22441370 TI - Generalized livedo reticularis induced by silicone implants for soft tissue augmentation. AB - Silicone is one of the most widely used filler for facial cosmetic correction and soft tissue augmentation. Although initially it was considered to be a biologically inert material, many local and generalized adverse effects have been reported after silicone usage for cosmetic purposes. We present a previously healthy woman who developed progressive and persistent generalized livedo reticularis after cosmetic surgery for volume augmentation of buttocks. Histopathologic study demonstrated dermal presence of interstitial vacuoles and cystic spaces of different sizes between the collagen bundles, which corresponded to the silicone particles implanted years ago. These vacuoles were clustered around vascular spaces and surrounded by a few foamy macrophages. General examination and laboratory investigations failed to show any evidence of connective tissue disease or other systemic disorder. Therefore, we believe that the silicone implanted may have induced some kind of blood dermal perturbation resulting in the characteristic violet reticular discoloration of livedo reticularis. PMID- 22441372 TI - Folliculotropic adult T-cell leukemia/lymphoma: a possibly under-recognized variant. PMID- 22441373 TI - Acroangiodermatitis of Mali in protein C deficiency due to a novel PROC gene mutation. AB - Acroangiodermatitis of Mali is a dermatologic condition of kaposiform skin lesions that has been associated with chronic venous insufficiency. Here we report a case of a 28-year-old Chinese man with acroangiodermatitis which co existed with chronic lower limb deep vein thrombosis. Investigations revealed protein C deficiency and a frame shift mutation, c246_247dupCT, of the PROC gene. Our report lengthens the list of male acroangiodermatitis of Mali cases with a Chinese patient harboring a novel PROC mutation with manifest protein C deficiency. PMID- 22441374 TI - An unusual histologic variant of necrobiotic xanthogranuloma. AB - Necrobiotic xanthogranuloma (NXG) usually shows a stereotypical histopathologic presentation. However, few unusual cases have been published. We present a patient with NXG showing exceptional histopathologic features. NXG in our patient presents with exclusively dermal granulomatous inflammation mimicking interstitial granuloma annulare. Not only subcutaneous involvement, but also, evident zones of degenerated collagen, foam cells, and cholesterol clefts were missing. Moreover, the case shows overlaps with recently published granulomatous scleromyxedema. Some common clinical and histopathologic features of NXG and scleromyxedema might be based on shared underlying paraproteinemia. PMID- 22441375 TI - Self-reported smoking status and plasma cotinine concentrations among pregnant women in the Norwegian Mother and Child Cohort Study. AB - INTRODUCTION: Underreporting of smoking in epidemiologic studies is common and may constitute a validity problem, leading to biased association measures. In this prospective study, we validated self-reported tobacco use against nicotine exposure assessed by plasma cotinine in the Norwegian Mother and Child Cohort Study (MoBa). METHODS: The study was based on a subsample of 2,997 women in the MoBa study who delivered infants during the period 2002-2003. Self-reported tobacco use (test variable) and plasma cotinine concentrations (gold standard) were assessed at approximately gestational week 18. RESULTS: Daily smoking was reported by 9% of the women, occasional smoking by 4%, and nonsmoking by 86% of the women. Sensitivity and specificity for self-reported smoking status were calculated using a cotinine cut-off estimated from the study population (30 nmol/l). Plasma cotinine concentrations >=30 nmol/l were found in 94% of self reported daily smokers, 66% of occasional smokers, and 2% of nonsmokers. After the numbers of self-reported nonsmokers with cotinine concentrations above the cut-off limit were added, the daily smoking prevalence increased from 9 to 11%. The sensitivity and specificity for self-reported daily smoking, using 30 nmol/l as the cut-off concentration, were 82 and 99%, respectively. DISCUSSION: These findings suggest that self-reported tobacco use is a valid marker for tobacco exposure in the MoBa cohort. PMID- 22441376 TI - Air-displacement plethysmography for determining body composition in neonates: validation using live piglets. AB - INTRODUCTION: Air-displacement plethysmography (ADP) was developed as a noninvasive tool to assess body composition, i.e., the proportion of fat mass (%FM) and lean body mass. The results of previous studies comparing ADP with labeled water dilution in infants and with chemical analysis in phantoms have validated the ADP approach indirectly. We assessed the precision and accuracy of measurements of % FM proportions in live animals, using ADP in comparison with biochemical analyses. METHODS: Three groups of 12 piglets each underwent four consecutive body composition assessments at 2, 7, and 21 d and were euthanized to determine whole-body lipid content by direct chemical analysis. RESULTS: The average body weights were 1,490, 2,210, and 5,610 g at d2, d7, and d21, respectively. The mean %FM values determined by biochemical analysis and ADP were 8.63 +/- 4.08% and 8.01 +/- 4.03%, respectively. Linear regression and Bland Altman analyses indicated good agreement for %FM. The root mean square coefficient of variation (RMS-CV) for ADP was 17.9%, with a better precision in the higher fat mass range. DISCUSSION: Despite its relatively poor precision in the low range of %FM, ADP measures fat mass with reasonable precision and accuracy in the range of body weight encountered in low-birth-weight infants. PMID- 22441377 TI - Supporting diagnostic decisions using hybrid and complementary data mining applications: a pilot study in the pediatric emergency department. AB - INTRODUCTION: This article demonstrates the capacity of a combination of different data mining (DM) methods to support diagnosis in pediatric emergency patients. By using a novel combination of these DM procedures, a computer-based diagnosis was created. METHODS: A support vector machine (SVM), artificial neural networks (ANNs), fuzzy logics, and a voting algorithm were simultaneously used to allocate a patient to one of 18 diagnoses (e.g., pneumonia, appendicitis). Anonymized data sets of patients who presented in the emergency department (ED) of a pediatric care clinic were chosen. For each patient, 26 identical clinical and laboratory parameters were used (e.g., blood count, C-reactive protein) to finally develop the program. RESULTS: The combination of four DM operations arrived at a correct diagnosis in 98% of the cases, retrospectively. A subgroup analysis showed that the highest diagnostic accuracy was for appendicitis (97% correct diagnoses) and idiopathic thrombocytopenic purpura or erythroblastopenia (100% correct diagnoses). During the prospective testing, 81% of the patients were correctly diagnosed by the system. DISCUSSION: The combination of these DM methods was suitable for proposing a diagnosis using both laboratory and clinical parameters. We conclude that an optimized combination of different but complementary DM methods might serve to assist medical decisions in the ED. PMID- 22441378 TI - Effect of dopamine on peripheral perfusion in very-low-birth-weight infants during the transitional period. AB - INTRODUCTION: Dopamine is one of the most frequently used inotropic drugs in neonatal intensive care units (NICUs); however, it does not seem to improve outcomes in premature infants. Given that the ultimate aim of cardiovascular management is to stabilize and maintain organ perfusion, an understanding of dopamine's effects on organ blood flow will help in judging when to use dopamine and how to titrate the dosage. Such an approach can lead to improved outcomes. This study aimed to evaluate the effects of dopamine on peripheral perfusion in very-low-birth-weight (VLBW) infants within 72 h of birth. METHODS: This prospective observational study identified and sampled 44 instances of initiation of dopamine treatment or increase in dopamine dose in 29 VLBW infants. Blood pressure, heart rate, and skin and subcutaneous blood flow were measured and compared before and after each instance. RESULTS: Blood pressure and skin and subcutaneous blood flow in the lower limbs increased after initiation of dopamine treatment or after dose increase. DISCUSSION: Dopamine increases blood pressure as well as skin and subcutaneous blood flow in VLBW infants despite its supposed vasoconstrictive action, indicating that it increases both perfusion pressure and blood flow and is devoid of overwhelming peripheral vasoconstrictive effects. PMID- 22441379 TI - Atherogenic indices and prehypertension in obese and non-obese children. AB - We evaluate the relationship between different lipoproteins and atherogenic indices with pre-hypertension in 297 obese and 942 non-obese children with Tanner stage 1 enrolled in a multicentre, community-based cross-sectional study. Height, weight, fasting glucose and insulin levels, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), non-HDL-c, LDL/HDL-c, triglycerides/cholesterol and total cholesterol/HDL-c ratios were measured. Mean age was 8.4 +/- 1.2 years; pre hypertension was identified in 104 (8.4%) participants, 46 (15.5%) obese and 58 (6.1%) non-obese children. The pre-hypertensive non-obese children show a high proportion of family history of hypertension (41.6 and 24.7%, p = 0.002) and elevation of insulin at a relatively low body mass index. The triglycerides:HDL-c ratio, but not other lipoproteins or atherogenic indices, was associated with pre hypertension in obese (1.15, 95% confidence intervals 1.06-1.26) and non-obese children (1.38 95% confidence intervals 1.22-1.57). The triglycerides:HDL-c ratio is related to pre-hypertension in children; the family history of hypertension seems to be a risk factor in developing pre-hypertension. PMID- 22441380 TI - Differences in plasma MMPs and TIMPs protein expression and chemotherapy response in patients with tobacco- or wood-smoke-induced lung cancer. AB - BACKGROUND: One of the risk factors associated with lung cancer in never-smoker patients is wood smoke exposure (WS). However, information about its clinical and molecular characteristics remains scant. OBJECTIVE: This was to analyze--in plasma from patients with tobacco- or wood-smoke-induced lung cancer--whether the enzymatic activity and concentration of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) differ, and to determine whether there was a correlation between these indicators of the metastatic potential and the first-line chemotherapy response. METHODS: Patients were classified according to lung cancer associated with: the smoking of tobacco (T), WS and where no association with a known risk factor (N) could be established. The gelatinase activity of plasma MMP was analyzed by radiolabeled substrate degradation and zymography assay. Protein expression of MMPs and TIMPs was evaluated by Western blot densitometry analysis. RESULTS: The 26.9% WS patients had a better response to therapy in comparison with the T group (OR = 4.9, 95% CI = 1.25-20.15; p = 0.019). The lowest gelatinase activity was observed in WS subjects, in comparison with T and N subjects (96.7 +/- 15.9, 182.9 +/- 31.5 and 163.3 +/- 22.7 ug of degraded gelatin/mg of incubated plasma protein, respectively; p < 0.025); this enzymatic activity corresponded to MMP-2. The highest MMP-2, MMP-9, MT1-MMP and TIMP-1 plasma levels were observed in T subjects. CONCLUSION: Tobacco and wood smoke have different effects on MMP and TIMP synthesis and gelatinase activity, directly influencing lung cancer metastatic potential and chemotherapy response. PMID- 22441381 TI - Molecular engineering and solvent dependence of excitation energy hopping in self assembled porphyrin boxes. AB - It has been demonstrated that the direction and magnitude of transition dipole moments, and hence rates in the excitation energy hopping in the self-assembled porphyrin boxes can be tuned by insertion of ethynyl groups as well as the dielectric constant of solvent. PMID- 22441382 TI - Hyperglycemia and risk of acute coronary syndrome: myth or fact? PMID- 22441383 TI - Conformationally flexible chiral supramolecular catalysts for enantioselective Diels-Alder reactions with anomalous endo/exo selectivities. AB - The potential of supramolecular catalysts to realize anomalous regio- and/or stereoselectivity in organic synthesis is highly attractive. To date, there have been a few examples of non-polymeric and non-covalent chiral supramolecular catalysts that induce practical enantioselectivity. In this regard, a metal organic framework (MOF) may be one of the most important techniques for constructing conformationally rigid supramolecular catalysts. However, it is not easy to use the MOF technique to fine-tune a much more precise cage in catalysts for anomalous purposes. To establish high catalytic activity with anomalous regio and/or stereoselectivity, in principle, an artificial cage should be conformationally flexible, like an active pocket in an enzyme with an induced-fit function. In this feature article, we focus on the anomalous endo/exo-selective Diels-Alder reaction, and overview the development of the successive catalysts including our recent highly active, conformationally flexible, and chiral supramolecular catalysts. The evolution from 'ready-made' single-molecule catalysts to 'tailor-made' supramolecular catalysts could offer not only high enantioselectivity but also high anomalous endo/exo-selectivities due to substrate-specific characteristics, as with enzymes. PMID- 22441384 TI - Replicating adenovirus-simian immunodeficiency virus (SIV) vectors efficiently prime SIV-specific systemic and mucosal immune responses by targeting myeloid dendritic cells and persisting in rectal macrophages, regardless of immunization route. AB - Although priming with replicating adenovirus type 5 host range mutant (Ad5hr) human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, followed by HIV/SIV envelope boosting, has proven highly immunogenic, resulting in protection from SIV/simian-human immunodeficiency virus (SHIV) challenges, Ad5hr recombinant distribution, replication, and persistence have not been examined comprehensively in nonhuman primates. We utilized Ad5hr green fluorescent protein and Ad5hr-SIV recombinants to track biodistribution and immunogenicity following mucosal priming of rhesus macaques by the intranasal/intratracheal, sublingual, vaginal, or rectal route. Ad recombinants administered by all routes initially targeted macrophages in bronchoalveolar lavage (BAL) fluid and rectal tissue, later extending to myeloid dendritic cells in BAL fluid with persistent expression in rectal mucosa 25 weeks after the last Ad immunization. Comparable SIV-specific immunity, including cellular responses, serum binding antibody, and mucosal secretory IgA, was elicited among all groups. The ability of the vector to replicate in multiple mucosal sites irrespective of delivery route, together with the targeting of macrophages and professional antigen-presenting cells, which provide potent immunogenicity at localized sites of virus entry, warrants continued use of replicating Ad vectors. PMID- 22441385 TI - Microbiological challenges in the diagnosis of chronic Q fever. AB - Diagnosis of chronic Q fever is difficult. PCR and culture lack sensitivity; hence, diagnosis relies mainly on serologic tests using an immunofluorescence assay (IFA). Optimal phase I IgG cutoff titers are debated but are estimated to be between 1:800 and 1:1,600. In patients with proven, probable, or possible chronic Q fever, we studied phase I IgG antibody titers at the time of positive blood PCR, at diagnosis, and at peak levels during chronic Q fever. We evaluated 200 patients, of whom 93 (46.5%) had proven, 51 (25.5%) had probable, and 56 (28.0%) had possible chronic Q fever. Sixty-five percent of proven cases had positive Coxiella burnetii PCR results for blood, which was associated with high phase I IgG. Median phase I IgG titers at diagnosis and peak titers in patients with proven chronic Q fever were significantly higher than those for patients with probable and possible chronic Q fever. The positive predictive values for proven chronic Q fever, compared to possible chronic Q fever, at titers 1:1,024, 1:2,048, 1:4,096, and >=1:8,192 were 62.2%, 66.7%, 76.5%, and >=86.2%, respectively. However, sensitivity dropped to <60% when cutoff titers of >=1:8,192 were used. Although our study demonstrated a strong association between high phase I IgG titers and proven chronic Q fever, increasing the current diagnostic phase I IgG cutoff to >1:1,024 is not recommended due to increased false-negative findings (sensitivity < 60%) and the high morbidity and mortality of untreated chronic Q fever. Our study emphasizes that serologic results are not diagnostic on their own but should always be interpreted in combination with clinical parameters. PMID- 22441386 TI - Memory B cell and other immune responses in children receiving two doses of an oral killed cholera vaccine compared to responses following natural cholera infection in Bangladesh. AB - Current oral cholera vaccines induce lower protective efficacy and shorter duration of protection against cholera than wild-type infection provides, and this difference is most pronounced in young children. Despite this, there are limited data comparing immune responses in children following wild-type disease versus vaccination, especially with regard to memory responses associated with long-term immunity. Here, we report a comparison of immune responses in young children (2 to 5 years of age; n = 20) and older children (6 to 17 years of age; n = 20) given two doses of an oral killed cholera vaccine containing recombinant cholera toxin B subunit (CtxB) 14 days apart and compare these responses to those induced in similarly aged children recovering from infection with Vibrio cholerae O1 Ogawa in Bangladesh. We found that the two vaccine groups had comparable vibriocidal and lipopolysaccharide (LPS)-specific plasma antibody responses. Vaccinees developed lower levels of IgG memory B cell (MBC) responses against CtxB but no significant MBC responses against LPS. In contrast, children recovering from natural cholera infection developed prominent LPS IgG and IgA MBC responses, as well as CtxB IgG MBC responses. Plasma LPS IgG, IgA, and IgM responses, as well as vibriocidal responses, were also significantly higher in children following disease than after vaccination. Our findings suggest that acute and memory immune responses following oral cholera vaccination in children are significantly lower than those observed following wild-type disease, especially responses targeting LPS. These findings may explain, in part, the lower efficacy of oral cholera vaccination in children. PMID- 22441387 TI - Improvement of immunogenicity of meningococcal lipooligosaccharide by coformulation with lipidated transferrin-binding protein B in liposomes: implications for vaccine development. AB - Among various meningococcal antigens, lipooligosaccharide (LOS) and recombinant lipidated transferrin-binding protein B (rlip-TbpB) are considered to be putative vaccine candidates against group B Neisseria meningitidis. In the present work, we report the development of a new liposome-based vaccine formulation containing both rlip-TbpB and L8 LOS. The endotoxic activity of the liposomal LOS was evaluated in vitro using the Limulus Amebocyte Lysate assay and compared to the endotoxic activity of free LOS. Above a 250:1 lipid/LOS molar ratio, liposomes were shown to effectively detoxify the LOS as the endotoxic activity of the LOS was reduced by more than 99%. Immunogenicity studies in rabbits showed that the presence of rlip-TbpB dramatically increased the immunogenicity of the LOS. While the formulation raised a strong anti-TbpB response, it elicited a higher anti-LOS IgG level than the liposomal LOS alone. Sera from rabbits immunized with rlip TbpB/liposomal LOS displayed increased ability to recognize LOS on live bacteria expressing the L8 immunotype and increased anti-LOS-specific bactericidal activity compared to sera from rabbits immunized with liposomal LOS alone. Measurement of interleukin-8 (IL-8) produced by HEK293 cells transfected with Toll-like receptor (TLR) after stimulation with rlip-TbpB showed that the protein is a TLR2 agonist, which is in accordance with the structure of its lipid. Furthermore, an in vivo study demonstrated that the lipid moiety is not only required for its adjuvant effect but also has to be linked to the protein. Overall, the rlip-TbpB/LOS liposomal formulation was demonstrated to induce an effective anti-LOS response due to the adjuvant effect of rlip-TbpB on LOS. PMID- 22441388 TI - Modulation of anti-tumor necrosis factor alpha (TNF-alpha) antibody secretion in mice immunized with TNF-alpha kinoid. AB - Tumor necrosis factor alpha (TNF-alpha) blockade is an effective treatment for patients with TNF-alpha-dependent chronic inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis. TNF-alpha kinoid, a heterocomplex of human TNF-alpha and keyhole limpet hemocyanin (KLH) (TNF-K), is an active immunotherapy targeting TNF-alpha. Since the TNF-K approach is an active immunization, and patients receiving this therapy also receive immunosuppressant treatment, we evaluated the effect of some immunosuppressive drugs on the generation of anti-TNF-alpha antibodies produced during TNF-K treatment. BALB/c mice were injected intramuscularly with TNF-K in ISA 51 adjuvant. Mice were also injected intraperitoneally with one of the following: phosphate-buffered saline, cyclophosphamide, methylprednisolone, or methotrexate. Anti-TNF-alpha and anti-KLH antibody levels were assessed by enzyme-linked immunosorbent assay and the anti-TNF-alpha neutralizing capacity of sera by L929 bioassay. Our results showed that current treatments used in rheumatoid arthritis, such as methylprednisolone and methotrexate, do not significantly alter anti-TNF-alpha antibody production after TNF-K immunization. In contrast, the administration of cyclophosphamide (200 mg/kg) after immunization significantly reduced anti-TNF-alpha antibody titers and their neutralizing capacity. PMID- 22441389 TI - Comparison of seven commercial antigen and antibody enzyme-linked immunosorbent assays for detection of acute dengue infection. AB - Seven commercial assays were evaluated to determine their suitability for the diagnosis of acute dengue infection: (i) the Panbio dengue virus Pan-E NS1 early enzyme-linked immunosorbent assay (ELISA), second generation (Alere, Australia); (ii) the Panbio dengue virus IgM capture ELISA (Alere, Australia); (iii) the Panbio dengue virus IgG capture ELISA (Alere, Australia); (iv) the Standard Diagnostics dengue virus NS1 antigen ELISA (Standard Diagnostics, South Korea); (v) the Standard Diagnostics dengue virus IgM ELISA (Standard Diagnostics, South Korea); (vi) the Standard Diagnostics dengue virus IgG ELISA (Standard Diagnostics, South Korea); and (vii) the Platelia NS1 antigen ELISA (Bio-Rad, France). Samples from 239 Thai patients confirmed to be dengue virus positive and 98 Sri Lankan patients negative for dengue virus infection were tested. The sensitivities and specificities of the NS1 antigen ELISAs ranged from 45 to 57% and 93 to 100% and those of the IgM antibody ELISAs ranged from 85 to 89% and 88 to 100%, respectively. Combining the NS1 antigen and IgM antibody results from the Standard Diagnostics ELISAs gave the best compromise between sensitivity and specificity (87 and 96%, respectively), as well as providing the best sensitivity for patients presenting at different times after fever onset. The Panbio IgG capture ELISA correctly classified 67% of secondary dengue infection cases. This study provides strong evidence of the value of combining dengue virus antigen- and antibody-based test results in the ELISA format for the diagnosis of acute dengue infection. PMID- 22441390 TI - Cationic liposomes extend the immunostimulatory effect of CpG oligodeoxynucleotide against Burkholderia pseudomallei infection in BALB/c mice. AB - Melioidosis is a severe disease caused by the Gram-negative bacterium Burkholderia pseudomallei. Previously we showed that pretreatment of mice with CpG oligodeoxynucleotide (CpG ODN) 2 to 10 days prior to B. pseudomallei challenge conferred as high as 90% protection, but this window of protection was rather short. In the present study, we therefore aimed to prolong this protective window and to gain further insight into the mechanisms underlying the protection induced by CpG ODN against B. pseudomallei infection. It was found that the CpG ODN incorporated with cationic liposomes (DOTAP) but not zwitterionic liposomes (DOPC) provided complete protection against bacterial challenge. Although marked elevation of gamma interferon (IFN-gamma) was found in the infected animals 2 days postinfection, it was significantly lowered by the DOTAP-plus-CpG ODN pretreatment. When appropriately activated, the phagocytic index and oxidative burst responses of neutrophils appeared not to be elevated. However, macrophages from stimulated mice showed higher levels of nitric oxide production and exhibited higher levels of antimicrobial activities, judging from lower numbers of viable intracellular bacteria. Taken together, our results demonstrate that DOTAP can enhance the protective window period of CpG ODN to at least 30 days and provide 100% protection against B. pseudomallei infection. The protective effect of DOTAP plus CpG ODN could provide an alternative approach to preventing this lethal infection, for which no vaccine is yet available. PMID- 22441391 TI - Analysis of defined combinations of monoclonal antibodies in anthrax toxin neutralization assays and their synergistic action. AB - Antibodies against the protective antigen (PA) component of anthrax toxin play an important role in protection against disease caused by Bacillus anthracis. In this study, we examined defined combinations of PA-specific monoclonal antibodies for their ability to neutralize anthrax toxin in cell culture assays. We observed additive, synergistic, and antagonistic effects of the antibodies depending on the specific antibody combination examined and the specific assay used. Synergistic toxin-neutralizing antibody interactions were examined in more detail. We found that one mechanism that can lead to antibody synergy is the bridging of PA monomers by one antibody, with resultant bivalent binding of the second antibody. These results may aid in optimal design of new vaccines and antibody therapies against anthrax. PMID- 22441392 TI - Hepatitis C virus-multispecific T-cell responses without viremia or seroconversion among Egyptian health care workers at high risk of infection. AB - Hepatitis C virus (HCV)-specific cell-mediated immunity (CMI) has been reported among exposed individuals without viremia or seroconversion. Limited data are available regarding CMI among at-risk, seronegative, aviremic Egyptian health care workers (HCW), where HCV genotype 4 predominates. We investigated CMI responses among HCW at the National Liver Institute, where over 85% of the patients are HCV infected. We quantified HCV-specific CMI in 52 seronegative aviremic Egyptian HCW using a gamma interferon (IFN-gamma) enzyme-linked immunospot assay in response to 7 HCV genotype 4a overlapping 15-mer peptide pools covering most of the viral genome. A positive HCV-specific IFN-gamma response was detected in 29 of 52 HCW (55.8%), where 21 (40.4%) had a positive response for two to seven HCV pools and 8 (15.4%) responded to only one pool. The average numbers of IFN-gamma total spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMC) (+/- standard error of the mean [SEM]) in the 29 responding and 23 nonresponding HCW were 842 +/- 141 and 64 +/- 15, respectively (P < 0.001). Flow cytometry indicated that both CD4(+) and CD4(-) T cells produced IFN-gamma. In summary, more than half of Egyptian HCW demonstrated strong HCV multispecific CMI without viremia or seroconversion, suggesting possible clearance of low HCV exposure(s). These data suggest that detecting anti HCV and viremia to determine past exposure to HCV can lead to an underestimation of the true disease exposure and that CMI response may contribute to the low degree of chronic HCV infection in these HCW. These findings could have strong implications for planning vaccine studies among populations with a high HCV exposure rate. Further studies are needed to determine whether these responses are protective. PMID- 22441393 TI - Programmed death 1 receptor changes ex vivo in HIV-infected adults following initiation of highly active antiretroviral therapy. AB - This study investigates the short-term effects of highly active antiretroviral therapy (HAART) on programmed death 1 receptor (PD-1) expression and lymphocyte function. We compared lymphocytes from human immunodeficiency virus (HIV) infected adults prior to the initiation of HAART with lymphocytes from the same subjects following 2 months of treatment. Short-term HAART resulted in a moderate increase in the expression of PD-1 on both CD4(+) and CD8(+) T cells; yet, there was still a significant reduction in viral load and recovery of CD4(+) T cells. After 2 months of HAART, lymphocytes from the subjects had a reduction in lymphoproliferative responses to phytohemagglutinin (PHA) and an increased response to the Candida recall antigen and the HIV antigen p24 compared to pretreatment lymphocytes. PHA-stimulated peripheral blood mononuclear cells (PBMCs) from samples obtained 2 months after HAART produced higher levels of Th-1 cytokines (gamma interferon [IFN-gamma] and tumor necrosis factor alpha[TNF alpha]) than the levels observed for samples taken before treatment was initiated. There were no significant changes in the proinflammatory cytokine interleukin-2 (IL-2) or Th-2 cytokines (IL-4, IL-5, and IL-10) in the corresponding samples. Ex vivo PD-1 blockade significantly augmented PHA-induced lymphoproliferation as well as the levels of Th-1 cytokines and to a lesser extent the levels of Th-2 cytokines in PBMC cultures. The ability to downregulate PD-1 expression may be important in enhancing immune recovery in HIV infection. PMID- 22441394 TI - Evaluation of eight serological tests for diagnosis of imported schistosomiasis. AB - The diagnosis of schistosomiasis in individuals from countries where the disease is not endemic is challenging, and few data are available on the accuracy of serological diagnosis in those patients. We evaluated the performance of eight serological assays, including four commercial kits, in the diagnosis of imported schistosomiasis in individuals from areas where the disease is not endemic, including six enzyme-linked immunosorbent assays using three different antigens, an indirect hemagglutination assay, and an indirect immunofluorescent-antibody test. To analyze the assays, we used a total of 141 serum samples, with 121 derived from patients with various parasitic infections (among which were 37 cases of schistosomiasis) and 20 taken from healthy volunteers. The sensitivity values for detection of schistosomiasis cases ranged from 41% to 78% and were higher for Schistosoma mansoni than for S. haematobium infections. Specificity values ranged from 76% to 100%; false-positive results were most frequent for samples from patients with cestode infections. By combining two or more tests, sensitivity improved markedly and specificity decreased only moderately. Serological tests are useful instruments for diagnosing imported schistosomiasis in countries where the disease is not endemic, but due to limitations in test sensitivities, we recommend the use of two or more assays in parallel. PMID- 22441395 TI - False-negative hepatitis B virus (HBV) surface antigen in a vaccinated dialysis patient with a high level of HBV DNA in the United States. AB - Screening with hepatitis B surface antigen (HBsAg) is highly recommended for at risk individuals. Mutations in the HBsAg can result in an inability to detect the virus during routine screening. We describe a hemodialysis patient found to have high levels of hepatitis B virus (HBV) DNA and HBV antibody but negative HBsAg on two routine assays. PMID- 22441396 TI - Mono- and multi-layer adsorption of an ionic liquid on Au(110). AB - Ultraviolet photoelectron spectroscopy (UPS), work function measurements, low energy electron diffraction (LEED) and scanning tunnelling microscopy (STM) have been used to study the adsorption and desorption of 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide, [C(2)C(1)Im][Tf(2)N], on the (1*2) clean surface reconstruction of Au(110) in the temperature range 100-674 K. The ionic liquid adsorbed without decomposition, and desorbed without leaving any residue on the surface. For adsorption at room temperature a monolayer of strongly bound ionic liquid was formed with four interface states visible in UP spectra. STM at 100 K showed that the monolayer consisted of well-ordered rows of adsorbed ionic liquid aligned parallel to the close packed rows of surface gold atoms (the [110] direction) with a separation of *2 (the same as the clean surface reconstruction) between the rows in the orthogonal [001] direction. Multilayer adsorption at room temperature occurred by droplet formation followed by smoothing of the droplets to a layered morphology with time. Heating caused multilayer desorption at temperatures in the 363-383 K range, followed by partial monolayer desorption at 548 K to produce a Au(110)-(1*3) reconstructed surface with sub-monolayer domains of ionic liquid. Desorption of the remaining ionic liquid at 600 K caused the gold surface to reconstruct back to the clean (1*2) reconstruction. PMID- 22441397 TI - Leadership responses to The future of nursing: leading change, advancing health IOM report. PMID- 22441398 TI - Empirical outcomes: proof of making a difference. AB - The director of the Magnet Recognition Program(r) provides a comprehensive look at the Magnet(r) Model component Empirical Quality Outcomes. This article examines the importance of outcomes data that the organization already collects and how these should be used. Quantitative benchmarks should be established. These outcomes will represent the "report card" of a Magnet-recognized organization and a simple way of demonstrating excellence. PMID- 22441399 TI - AONE helps hospitals improve care through a 2nd Transforming Care at the Bedside effort. AB - This bimonthly department, sponsored by the American Organization of Nurse Executives (AONE), presents information to assist nurse leaders in shaping the future of healthcare through creative and innovative leadership. The strategic priorities of AONE anchor the editorial content. They reflect contemporary healthcare and nursing practice issues that challenge nurse executives as they strive to meet the needs of patients. PMID- 22441400 TI - Implementation of a caring theoretical framework in a multihospital system. AB - Nursing leaders at a multihospital healthcare system developed a goal to introduce Swanson's theory of caring, to support nursing practice. A descriptive correlational study design was used to measure patient and family perceptions of nurses' caring behaviors. The plan focused on staff education. Significantly higher levels of nurses' caring behaviors were reported posteducation compared with preeducation. Providing care based on a theoretical framework is consistent with Magnet(r) standards and may enhance the perception of caring practices by patients and families. PMID- 22441401 TI - Transformational leadership practices of chief nursing officers in Magnet(r) organizations. AB - OBJECTIVE: This study describes the transformational leadership practices of Magnet(r) chief nursing officers (CNOs). BACKGROUND: It is believed that transformational leadership practices influence quality and are integral to Magnet designation. METHODS: E-mail surveys of 384 Magnet CNOs were conducted in 2011 using the leadership practices inventory (LPI). RESULTS: Enabling others to act and modeling the way are top practices of Magnet CNOs. Those 60 years or older and those with doctorate degrees scored significantly higher in inspiring a shared vision and challenging the process. There was a significant positive relationship between total years as a CNO and inspiring a shared vision and between total scores on the LPI and number of beds in the organization. CONCLUSIONS: As CNOs gain experience and education, they exhibit more transformational leadership characteristics. Magnet organizations should take steps to retain CNOs and support their development and advancement. PMID- 22441402 TI - New BSN nurses' perspectives on the transition to practice in changing economic times. AB - Helping nursing graduates transition to practice is a concern for nursing educators and employers. This article reports graduates' perceptions of transition both when jobs were plentiful and when jobs were scarce. Survey results from comparison of 2008 and 2010 graduates demonstrated few differences. Key indicators of successful transition were positive feedback at the work site, increased self-confidence on the part of the new graduate, and acceptance by the care team. Presence of good role models, ability to ask questions safely, and ongoing feedback on performance assisted successful transition. PMID- 22441403 TI - Strategic considerations during electronic health record implementation. AB - Early decisions during electronic health record (EHR) implementation can determine the long-term success of the EHR within organizations. Questions that should be addressed during EHR implementation are presented with an emphasis on how these questions relate to the success and usability of EHRs. PMID- 22441404 TI - Moderators of the negative outcomes of nurse manager stress. AB - OBJECTIVE: The objective of this study was to examine moderators of the negative effects of nurse managers' stress. BACKGROUND: Nurse managers have important and stressful jobs. Stress affects outcomes such as job satisfaction and intent to quit. METHODS: A quantitative, cross-sectional survey design was used to obtain a convenience sample to examine which factors buffered negative effects of stress. RESULTS: Nurse managers reported high levels of stress, although stress decreased with age. Autonomy was the most effective buffer, followed by social support and predictability. CONCLUSIONS: Nurse managers should be offered autonomy and encouraged to seek support from supervisors and coworkers to reduce the negative effects of stress. PMID- 22441405 TI - Planning for implementation of evidence-based practice. AB - Expectations for evidence-based healthcare are growing, yet the most difficult step in the process, implementation, is often left to busy nursing leaders who may be unprepared for the challenge. Selecting from the long list of implementation strategies and knowing when to apply them are a bit of an "art," matching clinician needs and organizational context. This article describes an application-oriented resource that nursing leaders can use to plan evidence-based practice implementation in complex healthcare systems. PMID- 22441406 TI - Effect of Nurses Living FitTM exercise and nutrition intervention on body mass index in nurses. AB - OBJECTIVE: The hospital-based Nurses Living Fit (NLF) intervention was implemented by nurses to determine its effect on decreasing body mass index (BMI) in nurse participants. BACKGROUND: Although there are limited data on obesity rates of nurses working in the United States, more than half are estimated to be overweight or obese. METHODS: The NLF intervention included exercise (12 weekly sessions), yoga and nutrition (4 monthly sessions), and diary completion (exercise/yoga, food/water consumption, and sleep), addressing healthy lifestyle principles. RESULTS: NLF participants experienced a greater mean reduction in BMI and waist circumference inches. Ninety-three percent of NLF participants recommended the NLF program. CONCLUSIONS: Provision of an evidence-based program such as NLF facilitates nurse education on healthy lifestyle principles. PMID- 22441407 TI - Structural analysis of the Leptospiral sphingomyelinases: in silico and experimental evaluation of Sph2 as an Mg-dependent sphingomyelinase. AB - BACKGROUND: Leptospiral sphingomyelinases are candidate virulence factors present only in pathogenic Leptospira spp. Leptospira interrogans serovar Lai encodes Sph1, Sph2, Sph3, Sph4 and SphH. Except for Sph4, they all possess the exo-endo phosphatase domain that groups them under the DNase I superfamily. METHODS, RESULTS AND CONCLUSIONS: Modeling of exo-endo-phosphatase domains reveals high level structural similarity of Sph2 with the crystal structure of SmcL and BC SMase sphingomyelinases from Listeria ivanovii and Bacillus cereus, respectively. A beta-hairpin loop, essential for host cell membrane interaction, is absent in leptospiral sphingomyelinases. Instead, several aromatic amino acids were oriented outward from the surface of these molecules and formed clusters of hydrophobic regions that possibly enables the anchoring of these molecules into the host cell membrane, as demonstrated in Sph2 and Sph3. Sph2 is unique and possesses the Mg(++)-binding Glu53 residue in the metal-binding site and two His residues (His151 and His286) in the catalytic site. We demonstrate experimentally the Mg(++)-dependent hemolysis of erythrocytes by rSph2 and its ability to cleave sphingomyelin to ceramide. Anti-Sph2 antibodies neutralized the hemolytic activity of Sph2. In conclusion, we provide evidence showing that Sph2 is a Mg(++)-dependent hemolysin with both sphingomyelinase and hemolytic activities. PMID- 22441409 TI - Sudden death in Leigh syndrome: an autopsy case. AB - The present report describes the sudden death of a 3-year-old female child who had been clinically diagnosed with Leigh syndrome.Leigh syndrome is a heterogeneous progressive neurodegenerative disorder, which is characterized by focal or bilateral lesions in the thalamus, basal ganglia, brainstem, cerebellum, and spinal cord. Affected patients exhibit a variable clinical picture that frequently includes psychomotor retardation or regression, recurrent episodes of vomiting, failure to thrive, and signs of brainstem and basal ganglia dysfunction.The child was found dead in bed. Autopsy described the presence of symmetrical, necrotizing lesions scattered within the basal ganglia, thalamus, diencephalon, brainstem, and spinal-cord gray matter and revealed the presence of gastric contents in the upper and lower airways. We report the results of genetic investigations and describe the histological and immunohistochemical features that confirmed the diagnosis. These findings suggest that Leigh syndrome should be regarded as predisposing children to sudden death, especially by asphyxia secondary to the neurological disorder. PMID- 22441408 TI - Systematic approaches to central nervous system myelin. AB - Rapid signal propagation along vertebrate axons is facilitated by their insulation with myelin, a plasma membrane specialization of glial cells. The recent application of 'omics' approaches to the myelinating cells of the central nervous system, oligodendrocytes, revealed their mRNA signatures, enhanced our understanding of how myelination is regulated, and established that the protein composition of myelin is much more complex than previously thought. This review provides a meta-analysis of the > 1,200 proteins thus far identified by mass spectrometry in biochemically purified central nervous system myelin. Contaminating proteins are surprisingly infrequent according to bioinformatic prediction of subcellular localization and comparison with the transcriptional profile of oligodendrocytes. The integration of datasets also allowed the subcategorization of the myelin proteome into functional groups comprising genes that are coregulated during oligodendroglial differentiation. An unexpectedly large number of myelin-related genes cause-when mutated in humans-hereditary diseases affecting the physiology of the white matter. Systematic approaches to oligodendrocytes and myelin thus provide valuable resources for the molecular dissection of developmental myelination, glia-axonal interactions, leukodystrophies, and demyelinating diseases. PMID- 22441410 TI - Biomolecular theorem proving on a chip: a novel microfluidic solution to a classical logic problem. AB - Biomolecules inside a microfluidic system can be used to solve computational problems, such as theorem proving, which is an important class of logical reasoning problems. In this article, the Boolean variables (literals) were represented using single-stranded DNA molecules, and theorem proving was performed by the hybridization and ligation of these variables into a double stranded "solution" DNA. Then, a novel sequential reaction mixing method in a microfluidic chip was designed to solve a theorem proving problem, where a reaction loop and three additional chambers were integrated and controlled by pneumatic valves. DNA hybridization, ligation, toehold-mediated DNA strand displacement, exonuclease I digestion, and fluorescence detection of the double stranded DNA were sequentially performed using this platform. Depending on the computational result, detection of the correct answer was demonstrated based on the presence of a fluorescence signal. This result is the first demonstration that microfluidics can be used to facilitate DNA-based logical inference. PMID- 22441411 TI - [Thrombosis prophylaxis in geriatric patients]. AB - Older, multimorbid patients carry a high risk of suffering from a thromboembolic disease. The incidence of deep vein thrombosis in the outpatient setting is, depending on age, between 71 and 132 cases per 100,000 inhabitants and year. The rates increase significantly in the hospital setting and with increasing age. Today, pharmacological thrombolytic prophylaxis is the gold standard in patients needing surgical and internal medical care and is described in international evidence-based guidelines. However, the percentage of patients, who despite the guidelines do not receive pharmacological thrombolytic prophylaxis, is still very high. This is especially true for the group of multimorbid, very old patients. In the present work, the pathophysiological and clinical background for the increased susceptibility of thromboembolism in geriatric patients is summarized and the drugs currently available for pharmacological thromboembolic prophylaxis are presented. Hereby, special emphasis is placed on aspects of application in the elderly. PMID- 22441412 TI - Redox tuning of two biological copper centers through non-covalent interactions: same trend but different magnitude. AB - The same non-covalent interactions previously found to affect the redox potential (E(m)) of the mononuclear T1 Cu protein azurin (Az) are shown to also fine-tune the E(m) of the dinuclear Cu(A) center in the same Az protein scaffold. The effects of these mutations are in the same direction but with smaller magnitude in the Cu(A) site, due to dissipation of the effects by the dinuclear Cu(A) center. PMID- 22441413 TI - Combined treatment of odontogenic keratocysts: initial marsupialization and successive enucleation with peripheral ostectomy plus Carnoy's solution application. A five-year follow-up experience. AB - AIM: The odontogenic keratocyst (KCOT) is a locally aggressive, cystic jaw lesion with a high growth potential and a propensity for recurrence. Considering its neoplastic features, treatments of keratocysts are required and they are generally classified as conservative or aggressive. However, although in literature there are several studies, the choice of treatment strategies remains controversial. We report a two-stage protocol based on initial marsupialization and successive enucleation. METHODS: Three cases of large KCOTs have been treated by initial marsupialization and, after a mean period of six months, successive enucleation with peripheral ostectomy and application of Carnoy's solution was performed. RESULTS: All patients were instructed in daily irrigation using chlorhexidine 0.2% during the period of marsupialization. After enucleation, good healing was obtained in all cases and from two up to five years of follow-up, there is no evidence of recurrence. CONCLUSION: Two-stage surgical treatment protocol of keratocyst leads to complete healing, preservation of important anatomical structures and absence of recurrence. PMID- 22441414 TI - Benefits of the simplified edentulous treatment (SET) method in communicating with the laboratory. AB - AIM: According to the literature, a high quality prosthetic rehabilitation consists of physical and psychological acceptance of the denture by the patient, an empathic relationship between the clinician and the patient and correct application of complete denture construction principles. To apply these principles correctly, it is important to establish excellent communication with the technician. Interactions between dentists and technical laboratories is typically characterised by minimal communication, which is considered to be the most significant problem for achieving a qualitatively elevated prosthetic manufacture. The aim of the simplified edentulous treatment (SET) method is to correctly transmit clinical data to the laboratory and maintain these data throughout the entire treatment period. METHODS: One hundred twenty-three completely edentulous, Caucasian patients (71 men and 52 women; medium age: 66 years; range 27 to 85 years) were recruited for this study. The inclusion criteria were total edentulism, both maxillary and mandibular, both in patients wearing and not wearing a complete denture. To complete the denture, the patients were entrusted to 65 teams of two students each, attending the fifth year of their degree course in dentistry and performing their first rehabilitation of an edentulous patient, under the supervision of six skilled tutors. The denture manufacturing was performed by 12 technical laboratories. RESULTS: In the rehabilitation of an edentulous patient, transmission of clinical data to the technical laboratory is effective and reliable. CONCLUSION: The data transfer block allows one to transfer all of the necessary information to the laboratory at one time. PMID- 22441415 TI - RME: influences on the nasal septum. AB - AIM: The aim of this work consists in analyzing the consequences of RME on the nasal septum. METHODS: The sample included 140 patients presenting a skeletal maxillary transverse constriction. Two groups were constructed. The first group containing 100 patients presenting a septal deviation more than 1 mm was treated by a Hyrax expander, to correct the transverse dimension. The second group containing 40 patients was not treated because the patients were under pharmacological treatment for neurovascular headache. The protocol of activation in group 1 consisted by activation of the transverse screw one-quarter turn twice a day for 15 days. Then the appliance was left in place for passive retention. The skeletal variations induced by RME have been made through cephalometric evaluations obtained before therapy (T0), at the removal of the appliance (T1) and after 6 months of manteinance (T2). A lapse of time of six months passed between T0 and T1. RESULTS: This study demonstrates how RME can increase the length of the septum, improving its possible deviations and growth disturbance. CONCLUSION: Palatal expansion technique is a valid therapeutic option, which allows to increase nasal cavity volume and it can also have a favorable effects on the growth of the maxillary complex. PMID- 22441416 TI - Bacterial survival in the radiographic processes. AB - AIM: The purpose of this study was to investigate the microbial contamination in hand-operated and automatic radiographic solutions and on contact surfaces during radiographic procedures such as X-ray cone and button and surface of hand operated and automatic radiographic solution tanks in dental clinics. METHODS: A 10 mL liquid solution was taken with syringe at 5, 10, 24, and 48 hour time intervals from freshly prepared hand-operated and automatic processing solution. The swab samples were taken from the surfaces of radiographic solution tanks, X ray cone and its button. The specimens were inoculated into blood agar and Eosin Methylene-Blue (EMB) agar. The plates were incubated in an incubator for 48 hours at 37 degrees C. Becton Dickinson Phoenix Automated Microbiology System was used for determining the microorganisms. RESULTS: Although the microbiologic analyses of the samples revealed no microbial growth in the hand-operated and automatic radiographic solutions in all observation periods, the microbial growth on the contact surfaces was observed. Staphylococcus epidermidis, metisillin resistant from the surface of radiographic solution tanks, X-ray cone and switch. Streptococcus mitis was found on the X-ray switch. CONCLUSION: Radiographic procedures can cause cross contamination; clinicians should therefore apply disinfection protocols in all radiographic procedures. PMID- 22441417 TI - Use of fresh frozen bone graft in rehabilitation of maxillar atrophy. AB - AIM: Fresh frozen bone (FFB) is homologous bone obtained from human donors, provided by Tissue Banks. It is a graft material in reconstructive surgery; it is currently and widely used in orthopedic surgery and lately it has been introduced in oral and maxillofacial surgery. The purpose of this work was to show the use of fresh frozen homologous bone for bony augmentation of the maxilla and mandible in preparation for dental reconstruction with endosseous implants, as an effective alternative to harvesting and grafting autogenous bone from intra- or extra-oral donor sites. METHODS: The case presented clinically demonstrates the use of FFB grafts in the vertical augmentation of a severe maxillary atrophy in general anesthesia, and the outpatient treatment with implants insertion and prosthetic restoration. Histologic evaluation of graft biopsy six months after surgery is added to clinical assessments. RESULTS: Clinical outcome is shown with good volumetric and morphological reconstruction of the alveolar ridge without the need of a donor site. Excellent graft integration and bleeding newly formed bone was seen at the second surgical step (six months after FFB grafting), when fixation screws were removed and implant placement procedure was performed. CONCLUSION: The use of FFB in major preprosthetic surgery may be an acceptable therapeutic alternative to the autogenous block graft (harvested from iliac crest or calvarium) for its success rate as graft material. Benefits include: surgical procedure with reduced discomfort and infection risk as a second operation field to harvest the graft is avoided; FFB is safe, cheap and available in programmed amounts, its use can significantly reduce operating time. PMID- 22441418 TI - Differing therapeutic approaches to cleidocranial dysplasia (CCD). AB - Cleidocranial dysplasia (CCD) (MIM 119600) is a genetic skeletal disorder characterised by skeletal alterations at numerous bone segments (cranium, clavicles, pelvis) and a typical hyperdontia. It is a hereditary disease of the dominant autosomal type with wide variability of expression. The constant presence of numerous supernumerary teeth poses two orders of problems. On one hand, if these supplementary teeth are impacted, they may constitute a mechanical obstacle to the eruption of normal teeth. If on the contrary they have erupted, they cause aesthetic and functional damage. Surgical therapy is indispensable to restore a correct architecture to the alveolar-dental arches, and it is recommended during childhood to avoid or at least reduce complications in adulthood. Two cases of cleidocranial dysplasia are here reported. The adult patient (Case 1), reached our observation with a poor oral situation, manifested relapsing odontogenic abscesses at several impacted supernumerary teeth. The surgical treatment was complex and invasive, requiring percutaneous access in order to remove a tooth embedded in the mandible and the extraction of almost all residual teeth. This outcome was avoided in the second case, through combined surgical-orthodontic treatment that entailed extraction of the supernumerary teeth and subsequent orthodontic treatment, with restoration of a normal occlusion. In conclusion, management of patients suffering from very rare pathologies should be carefully evaluated in relation to clinical characteristics and possible local and systemic complications. The aim of this study is to illustrate two cases managed in a paradigmatically opposite way. It is paramount for the surgeon to intercept cases of hyperodontia typical of CCD at an early phase. It is possible, through correct surgical-orthodontic treatment, not only to avoid local and general complications, but also to achieve proper occlusion. PMID- 22441419 TI - Digital radiological research in forensic dental investigation: case studies. AB - The advent of dental digital radiology and new portable X-ray devices allows the execution of periapical X-ray images not only in the dental surgery but also in hitherto difficult locations such as field military hospitals, archaeological excavation sites, morgues and in cases of house arrest. In this work authors evaluated the feasibility of Nomad Examiner (Aribex inc.) handheld X-ray device combined with a digital sensor and a portable pc in forensic odontology applications. Employed for the first time forensically during the 2004 Tsunami victim identification process, the Nomad Examiner has now passed all security and conformity requirements of US and EU regulations. Examples of the practical use and the technical features of this device are seen when employed in odontological assessment of skeletonised and carbonized individuals and the assessment of individuals under house arrest complaining dental lesions. Results from the use this portable device demonstrate the benefits of a dental radiological assessment during an autopsy with the aim of human identification and the importance of a complete dental assessment (clinical and radiological) when evaluating dental traumatic lesions of individuals who cannot visit a dental surgery. In the first example forensic dentist would work alongside a forensic pathologist. On the other hand in the second example an odontologist - dentist could be appointed as an expert witness directly by a Court. PMID- 22441420 TI - Carbon-based ionogels: tuning the properties of the ionic liquid via carbon-ionic liquid interaction. AB - The behavior of two ionic liquids (ILs), 1-ethyl-3-methylimidazolium dicyanamide [Emim][DCA] and 1-ethyl-3-methylimidazolium triflate [Emim][TfO], in (meso)porous carbonaceous hosts was investigated. Prior to IL incorporation into the host, the carbon matrix was thermally annealed between 180 and 900 degrees C to control carbon condensation and surface chemistry. The resulting materials have an increasing "graphitic" carbon character with increasing treatment temperature, reflected in a modified behavior of the ILs when impregnated into the carbon host. The two ILs show significant changes in the thermal behavior as measured from differential scanning calorimetry; these changes can be assigned to anion-pi interaction between the IL anions and the pore wall surfaces of these flexible carbonaceous support materials. PMID- 22441421 TI - Revision of structural properties of GdBO3 nanopowders doped with Eu3+ ions through spectroscopic studies. AB - Monoclinic Gd(1-x)Eu(x)BO(3) nanopowders were successfully synthesized using a modified Pechini method. The crystal structure of the prepared materials was revised and confirmed using several techniques such as: IR, XRD, TEM, Raman spectroscopy and EDX analysis. The obtained material was comprised of particles, consisting of parts with the average size 350 nm. The luminescence properties of the prepared phosphors with different concentrations of Eu(3+) ions were characterized by excitation and emission spectra and its kinetic decay. The Judd Ofelt parameters (Omega(2), Omega(4)), quantum efficiency, eta, and chromaticity coordinates were also calculated. PMID- 22441422 TI - The clinical and sociodemographic profile of persistent delusional disorder. PMID- 22441423 TI - beta-Defensins: multifunctional modulators of infection, inflammation and more? AB - Defensins comprise one of the largest groups of host defence peptides, present throughout evolution, in fungi and flowering plants as well as in invertebrates and vertebrates. These cysteine-rich, cationic peptides have a common ability to kill a broad range of microorganisms including bacteria, yeast and viruses. As such, they are a strong component of the arsenal that is an organism's innate immunity. It is becoming increasingly clear, however, that antimicrobial action is only one of the numerous roles of these multifunctional peptides. In recent years, the functions of defensins in immunomodulation have been widely investigated, and their involvement in other processes (such as fertility) is becoming evident. This review addresses recent advances in the immunomodulatory activity of beta-defensins as well as the involvement of beta-defensins in fertility, development, wound healing and cancer. PMID- 22441424 TI - Toxicology and carcinogenesis studies of kava kava extract (CAS No. 9000-38-8) in F344/N rats and B6C3F1 mice (Gavage Studies). AB - Kava beverages, made from dried roots of the shrub Piper methysticum, have been used ceremonially and socially in the South Pacific and in Europe since the 1700s. The drink is reported to have pleasant mild psychoactive effects, similar to alcoholic beverages. In the United States, kava kava is an herbal product used extensively as an alternative to anti-anxiety drugs such as Xanax and Valium. It has also been reported as being used to help children with hyperactivity and as a skin-conditioning agent in cosmetics. Kava kava was nominated by the National Cancer Institute for study because of its increasing use as a dietary supplement in the mainstream United States market and reports of liver toxicity among humans. Male and female F344/N rats and B6C3F1 mice received kava kava extract in corn oil by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg body weight, 5 days per week for 16 days. One female rat administered 2.0 g/kg kava kava extract died on day 3 of the study. Mean body weights of all dosed groups of rats were similar to those of the vehicle controls. Clinical findings included abnormal breathing, ataxia, and lethargy in the 2.0 g/kg groups of males and females and ataxia and lethargy in the 1.0 g/kg group of females. Liver weights were significantly increased in 1.0 and 2.0 g/kg males and in 0.5 g/kg or greater females compared to the vehicle controls. Minimal hepatocellular hypertrophy occurred in all 2.0 g/kg males and in all females administered 0.25 g/kg or greater. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg body weight, 5 days per week for 17 days. In the 2.0 g/kg group of males, one died on day 2 and one died on day 3. Mean body weights of all dosed groups of mice were similar to those of the vehicle controls. Clinical findings included abnormal breathing, ataxia, and lethargy in males and females in the 1.0 and 2.0 g/kg groups. Liver weights of 2.0 g/kg males and females were significantly increased. The incidence of hepatocellular hypertrophy in 2.0 g/kg female mice was significantly greater than that in the vehicle control group. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg, 5 days per week for 14 weeks. Deaths attributed to kava kava extract administration included three males and four females in the 2.0 g/kg groups and one female in the 1.0 g/kg group. One 0.25 g/kg male and one vehicle control female also died before the end of the study. The mean body weights of males in the 1.0 and 2.0 g/kg groups and females in the 2.0 g/kg group were significantly less than those of the vehicle controls. Ataxia and lethargy were observed in males and females in the 1.0 g/kg groups during week 1 and in the 2.0 g/kg groups throughout the study. Increased glutamyltransferase activity in 1.0 g/kg females and 2.0 g/kg males and females may represent enzyme induction. However, the hepatocellular hypertrophy observed in the 2.0 g/kg females may have contributed to the increased glutamyltransferase activity. The liver weights of 0.25 g/kg or greater males and 0.5 g/kg or greater females were significantly increased compared to the vehicle controls. The kidney weights of 0.5 g/kg or greater males and females were significantly increased compared to the vehicle controls. The incidence of hepatocellular hypertrophy in 2.0 g/kg females was significantly greater than that in the vehicle controls. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg, 5 days per week for 14 weeks. Four male and three female 2.0 g/kg mice died during week 1; these deaths were attributed to kava kava extract administration. One additional 2.0 g/kg female died during week 6 due to a gavage accident. The mean body weights of dosed males and females were similar to those of the vehicle controls. Ataxia and lethargy occurred in males and females in the 1.0 and 2.0 g/kg groups during week 1. The liver weights of 2.0 g/kg males and 1.0 and 2.0 g/kg females were significantly increased compared to those of the vehicle control groups. The incidences of centrilobular hypertrophy in the liver of 0.5 g/kg or greater males and 1.0 and 2.0 g/kg females were significantly greater than those in the vehicle controls. 2-YEAR STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.1, 0.3, or 1.0 g/kg, 5 days per week for 104 (males) or 105 (females) weeks. Survival of dosed groups of males and females was similar to that of the vehicle controls. Mean body weights of males administered 1.0 g/kg were less than those of the vehicle controls after week 65, and those of the 1.0 g/kg females were less than those of the vehicle controls after week 41. Clinical findings included ataxia and lethargy that occurred in 21 males and 14 females in the 1.0 g/kg groups during the first 4 weeks of the study. After week 5, ataxia and lethargy were noted in 10 males and eight females in the 1.0 g/kg groups and these findings were observed randomly and intermittently throughout the study. At approximately 1 year into the study, twitching and seizures were observed in males and females in all dosed groups but mainly in the 1.0 g/kg groups. There was a dose-related increase in the incidences of interstitial cell adenoma in the testis with increased incidences of bilateral neoplasms. The incidences of hepatocellular hypertrophy in 1.0 g/kg males and females were significantly greater than those in the vehicle controls. Increased -glutamyltransferase activity and/or bile salt concentrations in males and females may represent a cholestatic event related to the hepatocellular hypertrophy observed in rats. Enzyme induction may have played a role in the increased -glutamyltransferase activity. Significantly increased incidences of centrilobular fatty change occurred in 0.1 and 1.0 g/kg males. The incidences of inflammation, ulcer, and epithelial hyperplasia in the forestomach were significantly increased in 1.0 g/kg males and females. The severity of nephropathy was increased in 1.0 g/kg male rats, and the incidence of nephropathy was significantly increased in 1.0 g/kg females. Incidences of transitional epithelial hyperplasia of the pelvis of the kidney were significantly increased in 1.0 g/kg males and 0.3 and 1.0 g/kg females. The incidences of retinal degeneration in the eye were significantly increased in 1.0 g/kg males and females. The incidences of metaplasia of pancreatic acinar cells to a hepatocytic morphology increased in 1.0 g/kg males and females, and the increase in males was significant. Significantly decreased incidences of pars distalis adenoma in the pituitary gland occurred in 1.0 g/kg males and in 0.1 and 1.0 g/kg females. The incidence of fibroadenoma of the mammary gland in 1.0 g/kg females was significantly less than that in the vehicle control group. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice received kava kava extract in corn oil by gavage at doses of 0, 0.25, 0.5, or 1.0 g/kg, 5 days per week for 105 weeks. Survival of dosed groups of males and females was similar to that of the vehicle controls. Mean body weights of males administered 1.0 g/kg were generally similar to those of the vehicle controls until the end of the study; however, those of 1.0 g/kg females were less than those of the vehicle controls after week 21. Clinical findings included ataxia and lethargy that occurred in 13 males and 31 females in the 1.0 g/kg groups during the first week of the study. Decreasing numbers of animals exhibited ataxia or lethargy during the remainder of the study, but these findings were observed in 1.0 g/kg females as late as week 101. The incidences of hepatoblastoma in 0.5 and 1.0 g/kg males were significantly increased compared to the vehicle controls. The incidences of hepatocellular carcinoma or hepatoblastoma (combined) were significantly increased in 0.5 g/kg males. Incidences of hepatocellular carcinoma were increased in all dosed groups of females, and the increase was significant in the 0.25 g/kg group. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in 0.25 and 0.5 g/kg females. In the liver, the incidences of centrilobular hypertrophy in all dosed groups of males and females were significantly greater than those in the vehicle control groups. Significantly increased incidences of eosinophilic foci occurred in 0.5 g/kg males and in 1.0 g/kg males and females, and the incidence of angiectasis was significantly increased in the 1.0 g/kg males. The incidences of hepatocellular necrosis were significantly increased in 0.25 and 1.0 g/kg males. In the forestomach, the incidences of chronic inflammation, epithelial hyperplasia, and erosion were significantly increased in 0.5 and 1.0 g/kg females, and the incidence of ulceration was significantly increased in 1.0 g/kg females. GENETIC TOXICOLOGY: Kava kava extract was tested for bacterial mutagenicity over a broad range of concentrations in two independent assays using several strains of bacteria (S. typhimurium tester strains TA97, TA98, TA100, and TA1535 and E. coli strain WP2 uvrA/pKM101), with and without exogenous metabolic activation. No increase in mutant colonies was seen in any of the tester strains, under any activation condition. (ABSTRACT TRUNCATED) PMID- 22441425 TI - [Prevalence of undetected diabetes mellitus in invasive and interventional cardiology. Silent diabetes in the catheterization laboratory]. AB - In most randomized controlled trials on revascularization therapy for patients with ischemic coronary artery disease (CAD), the diabetes prevalence ranges between 15% and 35%. However, the true prevalence of diabetes is probably considerably underestimated in these trials. The European heart survey diabetes and the heart published in 2004 supplied strong evidence that there are many additional cases of undetected prediabetics and diabetics in any cardiology patient cohort. The long-term outcome of newly detected diabetics was found to be comparable to patients with already known diabetes mellitus. With this in mind, the Dresden silent diabetes study investigated the prevalence of undetected diabetes mellitus by oral glucose tolerance testing (OGTT) and comparative HbA1c sampling in 1,015 patients admitted for coronary angiography. Patients with known diabetes were excluded from the study.According to the OGTT only 513 patients (51%) were classified with normal glucose tolerance (NGT), 10 (1%) with isolated impaired fasting glucose (IFG), 349 (34%) with impaired glucose tolerance (IGT) and 143 (14%) were diagnosed with newly detected diabetes mellitus (DM). According to the HbA1c measurements 588 patients (58%) were classified as normal, 385 (38%) as borderline and only 42 (4%) were diagnosed with diabetes (DM). There was a significant correlation between the extent of CAD and glycemic status as defined by the OGTT. The number of patients with IGT and diabetes increased with the extent of CAD (IGT group p<0.001, diabetes group p=0.01). However, no such correlation was observed when glycemic status was defined by HbA1c testing.Based on these results an OGTT should be routinely performed in patients with known or suspected coronary artery disease undergoing coronary angiography for diagnosis of diabetes, as HbA1c measurements alone appear to miss a substantial proportion of patients. These findings are of high clinical relevance with regard to optimal coronary revascularization procedure chosen in catheterization laboratories, preferably drug-eluting stents in cases of diabetes mellitus or newly detected diabetes mellitus and preferably coronary bypass surgery in diabetics with multi vessel disease and high SYNTAX scores. PMID- 22441426 TI - The HIF1A C85T single nucleotide polymorphism influences the number of branches of the human coronary tree. AB - OBJECTIVES: Hypoxia is required for the development of the cardiovascular system. Tissue adaptation to low oxygen is mediated through hypoxia-inducible factor 1. Hypoxia-driven gradients of vascular endothelial growth factor within the heart drive vessel tip sprouting and the angiogenic phase of vasculogenesis. We hypothesized that functional variants of the HIF1A C85T single nucleotide polymorphism (SNP) are associated with the number of coronary artery branches in humans. METHODS: Coronary artery branching in 88 individuals was assessed by dynamic counting of the arterial branches detected in coronary angiograms. Values were classified on the basis of the branches emerging from the right and left coronary arteries. HIF1A C85T genotypes were determined using TaqMan-based assays. A generalized linear model was used to measure the effect of each SNP on the response variables. RESULTS: The presence of the T allele in the HIF1A C85T SNP was associated with few branches of the coronary arteries: 81.03 +/- 1.79 for individuals with the CC genotype versus 74.09 +/- 2.48 for T-carrying ones (p = 0.042). CONCLUSIONS: The functionality of HIF1A may influence the degree of branching of the human coronary tree. We propose that the HIF1A C85T SNP is a genetic marker that determines interindividual differences in the human coronary artery pattern. PMID- 22441427 TI - Biosynthesis of iminodiacetic acid from iminodiacetonitrile by immobilized recombinant Escherichia coli harboring nitrilase. AB - Iminodiacetic acid (IDA) is widely used as an intermediate in the manufacture of chelating agents, glyphosate herbicides and surfactants. In the current work, the fragment with the length of 1,110 bp encoding the Acidovorax facilis nitrilase was obtained. The recombinant nitrilase expressed in Escherichia coli BL21 (DE3) was successfully used in the production of IDA from iminodiacetonitrile. To improve the stability of operation, the recombinant cells were entrapped in polyvinyl alcohol (PVA) and sodium alginate (SA) copolymer. The maximum relative nitrilase activity with 98.1% was further observed at 1.0% SA, 8.0% PVA, 1.0% CaCl(2), and 5.0% wet cells, under conditions of 1.0% iminodiacetonitrile in distilled water and a temperature of 40 degrees C, respectively. The entrapped cells facilitated easy separation and good recycling compared with free cells. Moreover, the immobilized cells showed good operation and storage stability. This report is the first to describe IDA preparation using immobilized recombinant E. coli harboring nitrilase. PMID- 22441428 TI - Dolastatin 15, a mollusk linear peptide, and Celecoxib, a selective cyclooxygenase-2 inhibitor, prevent preneoplastic colonic lesions and induce apoptosis through inhibition of the regulatory transcription factor NF-kappaB and an inflammatory protein, iNOS. AB - The marine ecosystem is a unique and enormously rich source of natural products with potential chemopreventive applications in cancer. In the present study, we explored the chemopreventive role and the molecular mechanism of Dolastatin, a linear peptide from an Indian Ocean mollusk, and Celecoxib, a well-established cyclooxygenase-2 (COX-2) inhibitor in an individual as well as in a combination regimen in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon carcinogenesis in a rat model. After a 6-week treatment with DMH, morphological analysis revealed a marked occurrence of preneoplastic features in the colonic mucosa, whereas histologically well-characterized dysplasia and hyperplasia were observed in DMH-treated animals. Simultaneous administration of Celecoxib and Dolastatin reduced these features significantly. DMH treatment affected the number of apoptotic cells in colonic enterocytes, which reverted to the normal level with the use of Celecoxib and Dolastatin. Inflammation remains the dominant molecular mechanism in the development of multiple plaque lesions, the carcinogenic lesions in a DMH-induced process that may be mediated by COX-2. Western blot and immunofluorescence analysis revealed a higher expression of COX 2 and nuclear factor-kappaB, the transcription factors responsible for proinflammatory proteins such as TNFalpha, and also the inducible nitric oxide synthase in the DMH group, which was further recovered significantly with the use of Celecoxib and Dolastatin. In-silico molecular docking analysis of Dolastatin as a ligand with various regulatory proteins suggests that although the peptide failed to dock to COX-2, it successfully did so with inducible nitric oxide synthase, thereby indicating the potential of this inflammatory protein as a molecular anticancer target in colon carcinogenesis. PMID- 22441429 TI - Photoacoustic and luminescence characterization of nitrogen heterocyclic aromatic UV-MALDI matrices in solution. AB - A group of nitrogen heterocyclic aromatic compounds used, among others, as UV MALDI matrices was studied. By using spectroscopic, luminescence and photoacoustic techniques, as well as time resolved phosphorescence for singlet oxygen production determination, the behaviour of 9-aminoacridine (9AA), 3 aminoquinoline (3AQ), 2-(2-aminoethylamino)-5-nitropyridine (AAN) and 3,4-dihydro 7-methoxy-1-methyl-9H-pyrido[3,4-b] indole (harmaline, HLA) in acetonitrile solutions is described. The results show that for these compounds radiationless processes that release prompt heat to the media are a quite important deactivation mechanism. PMID- 22441430 TI - Chylous ascites complicating pediatric renal transplantation. AB - BACKGROUND: Chylous ascites (CA) is an unusual complication of pediatric abdominal surgery which can be difficult to manage. Little data are available to guide therapy. CASE-DIAGNOSIS/TREATMENT: We describe the presentation, clinical course and management of two patients, a 7-year-old boy and 2.5-year-old girl, who experienced CA following intraperitoneal renal transplantation. Both cases failed medical management, and the patients required surgical intervention. One required a peritoneovenous shunt while the other required an external abdominal drain. Both patients eventually experienced resolution of the CA and excellent long-term renal function. CONCLUSIONS: These case descriptions highlight the challenges of optimizing nutrition while controlling chylous output. We also review some of the risk factors associated with CA and draw attention to the consideration of this diagnosis in any renal transplant recipient with post operative abdominal distention and ascites. PMID- 22441431 TI - Unimolecular ligand-initiator dual functional systems (ULIS) for low copper ATRP of vinyl monomers including acrylic/methacrylic acids. AB - A novel approach for ATRP has been developed which enables the polymerization of vinyl monomers including those bearing carboxylic acid groups such as acrylic/methacrylic acid in the free acid form with ppm amounts of copper. The quantity of copper used in the polymerization is comparable to those left in purified polymers obtained by a conventional ATRP process. PMID- 22441432 TI - An ounce of breast cancer prevention--let's try for a pound. PMID- 22441433 TI - Hypothermia amplifies somatosensory-evoked potentials in uninjured rats. AB - Temperature fluctuations significantly impact neurological injuries in intensive care units. As the benefits of therapeutic hypothermia continue to unfold, many of these discoveries are generated by studies in animal models undergoing experimental procedures under the influence of anesthetics. We studied the effect of induced hypothermia on neural electrophysiological signals of an uninjured brain in a rodent model while under isoflurane. Fourteen rats were divided into 2 groups (n=7 each), on the basis of electrode placement at either frontal occipital or primary somatosensory cortical locations. Neural signals were recorded during normothermia (T=36.5 to 37.5 degrees C), mild hypothermia (T=32 to 34 degrees C), and hyperthermia (T=38.5 to 39.5 degrees C). The burst suppression ratio was used to evaluate electroencephalography (EEG), and amplitude-latency analysis was used to assess somatosensory-evoked potentials (SSEPs). Hypothermia was characterized by an increased burst-suppression ratio (mean+/-SD) of 0.58+/-0.06 in hypothermia versus 0.16+/-0.13 in normothermia, P<0.001 in frontal-occipital; and 0.30+/-0.13 in hypothermia versus 0.04+/-0.04 in normothermia, P=0.006 in somatosensory. There was potentiation of SSEP (2.89+/ 1.24 times the normothermic baseline in hypothermia, P=0.02) and prolonged peak latency (N10: 10.8+/-0.4 ms in hypothermia vs. 9.1+/-0.3 ms in normothermia; P15: 16.2+/-0.8 ms in hypothermia vs. 13.7+/-0.6 ms in normothermia; P<0.001), whereas hyperthermia was primarily marked by shorter peak latencies (N10: 8.6+/-0.2 ms, P15: 12.6+/-0.4 m; P<0.001). In the absence of brain injury in a rodent model, hypothermia induces significant increase to the SSEP amplitude while increasing SSEP latency. Hypothermia also suppressed EEGs at different regions of the brain by different degrees. The changes to SSEP and EEG are both reversible with subsequent rewarming. PMID- 22441434 TI - Please remember that the spinal cord, like the brain, autoregulates in a similar manner! PMID- 22441435 TI - Lasagna-type arrays with halide-nitromethane cluster filling. The first recognition of the Hal(-)...HCH2NO2 (Hal = Cl, Br, I) hydrogen bonding. AB - The previously predicted ability of the methyl group of nitromethane to form hydrogen bonding with halides is now confirmed experimentally based on X-ray data of novel nitromethane solvates followed by theoretical ab initio calculations at the MP2 level of theory. The cationic (1,3,5-triazapentadiene)Pt(II) complexes [Pt{HN=C(NC(5)H(10))N(Ph)C(NH(2))=NPh}(2)](Cl)(2), [1](Hal)(2) (Hal = Cl, Br, I), and [Pt{HN=C(NC(4)H(8)O)N(Ph)C(NH(2))=NPh}(2)](Cl)(2), [2](Cl)(2), were crystallized from MeNO(2)-containing systems providing nitromethane solvates studied by X-ray diffraction. In the crystal structure of [1][(Hal)(2)(MeNO(2))(2)] (Hal = Cl, Br, I) and [2][(Cl)(2)(MeNO(2))(2)], the solvated MeNO(2) molecules occupy vacant spaces between lasagna-type layers and connect to the Hal(-) ion through a weak hydrogen bridge via the H atom of the methyl thus forming, by means of the Hal(-)...HCH(2)NO(2) contact, the halide nitromethane cluster "filling". The quantum-chemical calculations demonstrated that the short distance between the Hal(-) anion and the hydrogen atom of nitromethane in clusters [1][(Hal)(2)(MeNO(2))(2)] and [2][(Cl)(2)(MeNO(2))(2)] is not just a consequence of the packing effect but a result of the moderately strong hydrogen bonding. PMID- 22441436 TI - A hierarchically ordered porous novel vanado-silicate catalyst for highly efficient oxidation of bulky organic molecules. AB - A novel hierarchically ordered porous vanado-silicate nanocomposite with interconnecting macroporous windows and meso-microporous walls containing well dispersed vanadyl species has been fabricated and used as a heterogeneous catalyst for the oxidation of a bulky organic molecule, namely cyclooctene. PMID- 22441437 TI - Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the effect of early administration of aspirin on the risk of preterm and term preeclampsia. METHOD: A systematic review and meta-analysis of randomized controlled trials were performed. Women who were randomized to low dose aspirin or placebo/no treatment at or before 16 weeks of gestation were included. The outcomes of interest were preterm preeclampsia (delivery <37 weeks) and term preeclampsia. Pooled relative risks (RR) with their 95% confidence intervals (CI) were computed. RESULTS: The search identified 7,941 citations but only five trials on a combined total of 556 women fulfilled the inclusion criteria. When compared to controls, aspirin initiated <=16 weeks of gestation was associated with a major reduction of the risk of preterm preeclampsia (RR 0.11, 95% CI 0.04-0.33) but had no significant effect on term preeclampsia (RR 0.98, 95% CI 0.42-2.33). CONCLUSION: Low-dose aspirin administrated at or before 16 weeks of gestation reduces the risk of preterm but not term preeclampsia. PMID- 22441438 TI - Mechanism investigation of ketone hydrogenation catalyzed by ruthenium bifunctional catalysts: insights from a DFT study. AB - In this paper, the mechanism of ketone hydrogenation catalyzed by five Ru bifunctional catalysts with different structural frameworks was studied in detail using density functional theory (DFT). This mechanism contains hydrogen transfer, dehydrogenation of alcohol, and dihydrogen activation fundamental reactions. The involvement of alcohol is also discussed and found with different activities in hydrogen transfer, dehydrogenation and dihydrogen activation steps in five systems. Our calculated results indicate that the weak Ru-H bond, stronger basicity of hydride and stronger X-H acidity will decrease the barrier of the HT step, and that the polar micro-environment of dihydrogen coordinating with Ru catalysts and short hydrogen transfer distance would be able to facilitate the heterolytic splitting of dihydrogen in the dihydrogen activation step. PMID- 22441439 TI - Radiosensitizing effect of the novel Hsp90 inhibitor NVP-AUY922 in human tumour cell lines silenced for Hsp90alpha. AB - BACKGROUND: Hsp90 inhibitors can enhance the tumour sensitivity to ionising radiation (IR). However, Hsp90 inhibition leads to the up-regulation of anti apoptotic Hsp90 and Hsp70, which might diminish the radiosensitizing effects of the inhibitors. Therefore, inhibition of the up-regulation of Hsp90 by siRNA might be a promising strategy to enhance drug-mediated radiosensitization. MATERIALS AND METHODS: The expression of Hsp90alpha was silenced in A549 and GaMG tumour cell lines by siRNA treatment. Pre-silenced for Hsp90alpha cells were treated with NVP-AUY922, a novel Hsp90 inhibitor, for 24 h and then irradiated. Radiation response was determined by colony-forming ability. The expression of several marker proteins was analysed by Western blot. DNA damage and repair were assessed by histone gammaH2AX measurements. RESULTS: We found that transfection with siRNA against Hsp90alpha reduced Hsp90alpha at mRNA and protein levels. Pre silencing of Hsp90alpha reduced NVP-AUY922-mediated up-regulation of Hsp90alpha but it did not increase drug-mediated radiosensitization in both tumour cell lines. As revealed by Western blot, pre-silencing of Hsp90alpha followed by NVP AUY922 did not change the expression of Hsp90 client proteins (Akt, Raf-1, Cdk1 and Cdk4) compared with drug treatment alone, suggesting unchanged chaperone function in transfected cells. CONCLUSION: Pre-silencing of Hsp90alpha followed by Hsp90 inhibition did not enhance the radiosensitizing effect of NVP-AUY922 in both tested tumour cell lines. Future work will be done on stable transfection with shRNA against Hsp90alpha or simultaneous silencing of both Hsp90 isoforms, Hsp90alpha and Hsp90beta, in order to optimize tumour cell killing. PMID- 22441440 TI - One life saved by four prevented recurrences? Update of the Early Breast Cancer Trialists confirms: postoperative radiotherapy improves survival after breast conserving surgery. PMID- 22441441 TI - Respiratory gated [18F]FDG PET/CT for target volume delineation in stereotactic radiation treatment of liver metastases. AB - PURPOSE: The use of 4D-[(18)F]fluorodeoxyglucose (FDG) PET/CT in combination with respiratory gated magnet resonance imaging (MRI) in target volume definition for stereotactic radiation of liver metastases was investigated. METHODS AND MATERIALS: A total of 18 patients received respiration gated FDG-PET/CT and MRI. Data were fused using a rigid co-registration algorithm. The quality of the co registration was rated on a scale from 1 (excellent) to 5 (poor) for co registration of MRI with gated PET and ungated PET. Gross tumor volume (GTV) was delineated in CT (GTV (CT)), MRI (GTV(MRI)), and PET (GTV(PET)). MRI- and PET based GTVs were defined by three observers each. Interobserver variability was calculated for all patients as well as for subgroups with and without previous treatment of liver metastases. All GTVs were compared for all patients and separately for patients with previous local therapy. In addition, a semiautomatic segmentation algorithm was applied on the PET images. RESULTS: Co-registration between MR and PET images was rated with 3.3 in average when non-gated PET was used and improved significantly (p < 0.01) to 2.1 using gated PET. The average GTV(CT) was 51.5 ml, GTV(MRI) 51.8 ml, and the average GTV(PET) 48.1 ml. Volumes delineated in MRI were 9.9% larger compared to those delineated in CT. Volumes delineated in PET were 13.8% larger than in MRI. The differences between the GTVs were more pronounced in patients with previous treatment. The GTVs defined in MRI showed an interobserver variability of 47.9% (84.1% with previous treatment and 26.2% without previous treatment). The PET-defined GTVs showed an interobserver variability of 21% regardless of previous treatment. Semiautomatic segmentation did not provide satisfying results. CONCLUSION: FDG-PET can distinguish vital tumor tissue and scar tissue, and therefore alters the GTV especially in patients with previous local treatment. In addition, it reduces the interobserver variability significantly compared to MRI. However, respiratory gated PET is necessary for good co-registration of PET and MRI. PMID- 22441442 TI - Cardiac noradrenergic denervation in a patient with multiple symmetric lipomatosis. AB - INTRODUCTION: Multiple symmetric lipomatosis (MSL) is a rare disease of unknown etiology characterized by multiple subcutaneous lipomas with a symmetrical distribution. One interesting aspect about MSL is a high incidence of sudden cardiac death despite a low incidence of metabolic syndrome and coronary arterial disease. Autonomic nervous system dysfunction may probably explain this feature of MSL. CASE REPORT: A 74-year-old man was admitted with acute heart failure and atrial fibrillation. He had a morphotype suggestive of MLS. A (123)I metaiodobenzylguanidine myocardial scintigraphy was conducted for evaluation of cardiac autonomic nervous integrity, since atrial fibrillation precluded the classical approach. The heart-to-mediastinum ratio was 1.68 (normal >2.2). Ischemia was not detected in myocardial perfusion scintigraphy. CONCLUSION: We present the first reported case of MSL autonomic neuropathy detected by (123)I- metaiodobenzylguanidine scintigraphy and suggest that this approach could play a role in MSL stratification by risk of sudden cardiac death and in exploring MSL disease mechanisms. PMID- 22441444 TI - Effects of custom-made insole on gait pattern of patients with unilateral displaced intra-articular calcaneal fracture: evaluation with computerized gait analysis. AB - OBJECTIVE: The aim of this study was to investigate whether use of custom fabricated insoles improves the gait pattern in patients with displaced intra articular calcaneal fractures. METHODS: Fourteen patients (7 female, 7 male; mean age: 39 +/- 12 years) and 11 healthy individuals (mean age: 42 +/- 13 years) were included in the study. Treatment protocol included conservative treatment involving immobilization, with or without closed reduction, active exercises, wear of a custom-fabricated insole and prospective follow-up. All patients were evaluated by physical examination, axial and lateral radiographs, computerized tomography, and computerized gait analysis. RESULTS: The use of custom-made insoles significantly improved step and stride lengths and the peak values of fore-aft component in the involved foot and tended to increase plantar flexor moment and total ankle power. The majority of patients (71%) continued to have substantial mechanical abnormalities by computerized gait analysis. Plantar flexion moment, total ankle power, vertical component of ground reaction forces (GRFs), and total sagittal plane excursion were significantly decreased in the involved foot when compared to the uninvolved foot. Plantar flexion moment, total ankle power, vertical, fore-aft and mediolateral components of GRFs were significantly decreased in the involved foot when compared to the healthy control group. CONCLUSION: Use of a custom-made insole improves advancement of limb and weight-bearing in patients with a displaced intra-articular calcaneal fracture. Nevertheless, mechanical abnormalities persist in the affected limb, which does not appear to recover a gait pattern similar to that of normal walking. PMID- 22441445 TI - Avoiding iatrogenic radial nerve injury during humeral fracture surgery: a modified approach to the distal humerus. AB - OBJECTIVE: Our aim was to assess the results of posterior retraction technique to prevent iatrogenic radial nerve injury during humeral fracture surgery. METHODS: Seventy-two patients who underwent surgery for a distal humerus fracture between 1996 and 2002 were reviewed. These 72 patients comprised Group 1. Following a cadaveric study on the vascularization of the radial nerve, a modified surgical approach was undertaken starting in 2002. Sixty-one patients who underwent this new surgical approach were included in Group 2. The rates of radial nerve deficit of the groups were compared using the Pearson chi-square test. RESULTS: In Group 1, 19 iatrogenic nerve deficits occurred. After defining the blood circulation of the nerve, the lateral approach was modified. The anterolateral side of the nerve was released and the nerve was left attached to the triceps muscle. In Group 2, one patient developed postoperative transient nerve deficit. CONCLUSION: The radial nerve is supplied by the branches of the deep brachial artery in close relation with the triceps muscle. Anterior dissection and posterior retraction of the radial nerve during lateral approach may preserve its blood supply and reduces the risk of iatrogenic injury. PMID- 22441446 TI - The effect of component position on clinical outcomes in resurfacing hip arthroplasty. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between component position and clinical results in resurfacing hip arthroplasty. METHODS: Resurfacing hip arthroplasty was performed on 41 hips of 38 patients (22 male, 16 female; mean age: 53.7 years; mean follow-up time: 20.1 +/- 5.8 months). The femoral and acetabular component orientation angles in the coronal plane were evaluated on anteroposterior radiographs. Harris and Oxford hip scores were used in the clinical evaluation. RESULTS: The mean angle between the collum and diaphysis was 139.5 +/- 8.8 degrees. In 22 hips, the femoral component angle between collum and diaphysis was less than 5 degrees valgus position when compared with the same anatomical femur angle. In the other 19 hips, the femoral component angle was greater than 5 degrees valgus position. The mean inclination angle of the acetabular component was 46.1 +/- 7 degrees. In 22 hips, the mean inclination angle of the acetabular components was 45 degrees or less. There was no significant difference in the clinical outcomes between patients with femoral component angles of greater than 5 degrees valgus position and those with angles of less than 5 degrees valgus position (p>0.05). There was also no significant difference between the clinical results of patients with an acetabular inclination of 45 degrees or less and those with an acetabular inclination exceeding 45 degrees (p>0.05). CONCLUSION: The orientation of femoral and acetabular components in the coronal plane does not appear to have an effect on clinical outcomes in resurfacing hip arthroplasty. PMID- 22441447 TI - Results of volar locking plating for unstable distal radius fractures. AB - OBJECTIVE: The aim of this study was to analyze the complications and functional and radiographic results of volar locking plating in the treatment of unstable distal radius fractures. METHODS: Forty-six patients (mean age: 48.7 years) with Type C distal radius fractures were treated with volar locking plates and evaluated over a mean follow-up period of 19 months. Range of motion, strength, DASH questionnaire and MAYO wrist score were assessed. Shortening, inclination and palmar tilt were recorded on standard radiographs and tenosynovitis and tendon ruptures were assessed using ultrasound. The uninjured wrists were examined as controls. Statistical analysis was made using t-tests. RESULTS: All fractures achieved union. Postoperative MAYO scores revealed 14 excellent results, 11 good, 20 satisfactory and one poor result. The mean postoperative DASH score was 15.9 (range: 0 to 72). Active wrist motion averaged 52.3 degrees of flexion, 57.7 degrees of extension, 79.2 degrees of supination and 79.3 degrees of pronation. Mean grip strength was 82% of the uninjured side and mean loss of radial inclination was 0.6 degrees and palmar tilt was 6.6 degrees as compared to normal side. Carpal tunnel syndrome was observed in one patient, flexor tenosynovitis in one patient, extensor tendon rupture in one patient and extensor tenosynovitis in eleven patients. Functional and clinical limitations were most evident in the patients with tendon tear or tenosynovitis. CONCLUSION: Fixation of unstable distal radius fractures with volar locking plates provides sufficient stability, and satisfactory clinical outcomes. However, these systems have complication potential that may limit better outcomes. PMID- 22441448 TI - Evaluation of injection techniques in the treatment of lateral epicondylitis: a prospective randomized clinical trial. AB - OBJECTIVE: We aimed to compare the efficacy of two different injection techniques of local corticosteroid and local anesthetic in the management of lateral epicondylitis. METHODS: This prospective study followed 80 consecutive patients who were diagnosed with lateral epicondylitis at our hospital outpatient clinic between 2005 and 2006. Patients were randomly assigned into two equal groups. Group 1 received a single injection of 1 ml betamethasone and 1 ml prilocaine on the lateral epicondyle at the point of maximum tenderness. Group 2 patients received an injection of the same drug mixture. Following the initial injection, the needle tip was redirected and reinserted down the bone approximately 30 to 40 times without emerging from the skin, creating a hematoma. Patients were evaluated with the Turkish version of the Disabilities of the Arm, Shoulder and Hand questionnaire before injection and at the final follow-up. The unpaired t test and chi-square tests were used to compare results. RESULTS: Sixteen patients in Group 1 and 15 patients in Group 2 were lost during follow-up. The average follow-up period of the remaining 49 patients was 21.6 months. There were no significant differences between the two groups with regard to gender, age, follow up period, symptom duration, involvement side and number of dominant limbs. The Turkish DASH scores of Group 2 were significantly lower than those of Group 1 (p=0.017). CONCLUSION: Long-term clinical success in the treatment of lateral epicondylitis depends on the injection method. The peppering technique appears to be more effective than the single injection technique in the long-term. PMID- 22441449 TI - Correction of nascent malunion of distal radius fractures. AB - OBJECTIVE: Early correction of malunion of distal radius fractures may be necessary in young, active patients. The aim of this study was to report the advantages and disadvantages of early correction of distal radius malunion. METHODS: Eleven patients (10 male, 1 female; average age 36 years, range: 20 to 54 years) with nascent malunion of distal radius fractures were included in this study. The malunions occurred after initial conservative treatment of unstable distal radius fractures. Mean interval between injury and corrective surgery was 12 (range: 8 to 15) weeks. Two patients had intra- and extra-articular malunion and 9 had an extra-articular malunion. Volar correction was made in seven patients and dorsal correction in four. Results were evaluated radiologically and functionally using the Mayo wrist score. RESULTS: Bony healing was established after correctional osteotomies at an average of 8 (range: 5 to 16) weeks. The average preoperative dorsal deformity was 28 degrees and was corrected to 4 degrees of volar tilt postoperatively. Patients had a positive ulnar variance with an average of 5 mm initially and less than 1 mm postoperatively. Radial inclination was corrected from an average of 9 degrees preoperatively to an average of 20 degrees and the average postoperative Mayo wrist score was 82.5. Tenotomy of brachioradialis was useful for the correction of radial inclination, especially in old cases. Structural (corticocancellous) grafting was used in one patient. All patients returned to their previous functional level. CONCLUSION: Advantages of early corrective osteotomy include anatomic restoration at the original fracture line, a shortened healing period and a decreased need for structural bone grafting. Disadvantages are that the recreation of the original fracture line is technically demanding and patients must be cooperative to achieve a successful outcome. PMID- 22441450 TI - The results of Pemberton's pericapsular osteotomy in patients with developmental hip dysplasia. AB - OBJECTIVE: The aim of this study was to investigate the radiological and clinical outcomes of Pemberton's pericapsular osteotomy in toddlers and preschool children with developmental hip dysplasia. METHODS: Ninety-one hips of 86 patients (81 girls, 5 boys) with developmental hip dysplasia who underwent Pemberton's pericapsular osteotomy were included in this study. The mean age of the patients was 34 (range: 18 to 96) months. The mean duration of follow-up was 60 (range: 24 to 158) months. All patients underwent open reduction and Pemberton's pericapsular osteotomy, including 12 hips in which proximal femur osteotomy had been performed earlier. Clinical results were evaluated according to McKay's clinical evaluation criteria, radiological results according to Sever's radiological evaluation criteria, and the presence of avascular necrosis according to Kalamchi-MacEwen's classification criteria. RESULTS: At the final examinations the mean acetabular index was 12.04 degrees (range: 5 degrees to 24 degrees ) and the mean Wiberg's center-edge angle was 35.5 degrees (range: 20 degrees to 52 degrees ). Clinically, excellent results were obtained in 81 (89.0%) hips, good results were obtained in 2 (2.2%) hips, and fair results in 8 (8.8%) hips. Radiologically, excellent results were obtained in 79 (86.8%) hips, good results in 7 (7.7%) and fair results in 5 (5.5%) hips. Clinically and radiologically no poor results were noted. Type 1 avascular necrosis was detected in 9 (9.9%) hips, Type 2 in 7 (7.7%) hips, and Type 3 in one (1.1%) hip. There were no cases with Type 4 avascular necrosis. CONCLUSION: Pemberton's pericapsular osteotomy is a safe and effective procedure for the surgical treatment of developmental hip dysplasia in toddlers and preschool children. PMID- 22441451 TI - Functional results of lower extremity lengthening by motorized intramedullary nails. AB - OBJECTIVE: The aim of this study was to evaluate the outcome of patients undergoing limb lengthening using motorized intramedullary nails. METHODS: This study included eleven femora and 4 tibiae from 14 patients (9 male, 5 female; mean age: 26.9 years; range: 14 to 51 years) who underwent limb lengthening using motorized intramedullary femoral nails (Fitbone((r)) TAA). Average preoperative limb shortening was 4.9 (range: 2.5 to 7.5) cm. Distraction was initiated on the seventh postoperative day. Serial radiographs and Paley's bone and functional outcome scoring systems were used to evaluate the results. RESULTS: Mean follow up period was 33.5 (range: 7 to 88) months. Mean distraction index value was 1.2 (range: 0.7 to 2.1) days/mm and mean bone-healing index value was 43.7 (range: 13.8 to 144) days/cm. The average lengthening achieved was 51.7 (range: 25 to 75) mm. The distraction mechanism of the nail did not function properly in two patients, restricted transient knee motion was observed in four patients, and delayed consolidation was observed in four patients. Other complications included valgus deformities and superficial infections surrounding the antenna of the intramedullary nail, as well as femur fractures at the proximal end of the nail. Bone scores were excellent in 11 segments and were good in one segment. Functional scores were excellent for all 12 patients. CONCLUSION: While usual complications related to the external fixators, such as pin-track infections and mobilization difficulties were not encountered, the development of additional complications such as dysfunction of the distraction mechanism should be monitored with the use of motorized intramedullary nails in limb lengthening. PMID- 22441452 TI - Predictive value of Tokuhashi and Tomita scores in patients with metastatic spine disease. AB - OBJECTIVE: Our aim was to determine the best preoperative prognostic score to safely propose operative intervention for patients with metastatic spinal disease. METHODS: This prospective cohort study included 52 consecutive patients who underwent surgery between 1997 and 2007 to alleviate pain and preserve or restore neurological function. All patients were prospectively evaluated with the Tokuhashi score and retrospectively with the Tomita score to compare their surgery indications. The relationship between the scores and overall survival time were compared. P values of less than 0.05 were considered significant. RESULTS: In predicting survival time, the Tokuhashi score was statistically significant (r=0.574, p=0.01), and the Tomita score borderline significant (r= 0.394, p=0.05). For overall survival after initial diagnosis, the Tokuhashi score was borderline significant for survival (r=0.380, p=0.05) and the Tomita score was not significant. CONCLUSION: The prognostic Tokuhashi score appears to be more valuable for surgical indications than the Tomita score in patients with spinal metastases. PMID- 22441453 TI - Glove perforation time and frequency in total hip arthroplasty procedures. AB - OBJECTIVE: The aim of the present study was to investigate glove perforation rate and time and evaluate the factors affecting glove perforation in total hip arthroplasty (THA). METHODS: Nine hundred seventy-nine gloves used in 57 THA procedures were assessed according to the perforation. Forty-four (77.2%) procedures were primary THA and 13 (22.8%) were revision THA. Gloves were changed when perforated, become dirty with blood or blood products, and before bone cementing. All gloves were filled with water at the end of the operation and controlled for perforation. Two hundred and one surgical gloves used during scrubbing and removed after draping the patient were examined as the control group. The location (which finger), number and time of the perforation, surgery type and duration, and distribution of the perforation location according to the surgical team were assessed. RESULTS: Patients' mean age was 62.9 +/- 14.6 (range: 33 to 97) years and the mean surgery duration was 162.9 +/- 32.0 minutes. Thirty-two glove perforations were noted in 19 of the operations. Of these perforations, 28 belonged to the surgeons and first assistants. There was no significant difference between the dominant or non-dominant hand according to the location of perforations. Perforations in the first and second fingers of the gloves accounted for 81.3% of all perforations. There was no significant difference in terms of number of gloves used, perforation numbers and operation duration between the primary and revision THA procedures. Two perforated gloves (0.99%) were found in the control group and the difference between the number of perforations in the control and study groups was significant (p=0.048). CONCLUSION: We recommend the use of two pairs of gloves to avoid the risk of contamination and protect the surgical team from infectious disease in major surgeries like THA. Surgical gloves should be changed when they are excessively contaminated with surgical fluids and the surgeon and first assistant should also change their outer gloves at an average of every 90 minutes. PMID- 22441454 TI - Effects of intra-articular administration of autologous bone marrow aspirate on healing of full-thickness meniscal tear: an experimental study on sheep. AB - OBJECTIVE: The aim of this study was to evaluate the effects of bone marrow derived mesenchymal stem cell and bone marrow elements on the healing of meniscal tears. METHODS: This study was performed on twelve, 2-year-old male Tahirova sheep. In each subject, one knee was used for experiment purposes and the other knee was used as a control. After creating a longitudinal full-thickness tear in the red-white zone of the medial meniscus, aspirated autologous bone marrow material was injected into the tear site in the experiment group. The control group received no intervention for secondary healing. RESULTS: In the macroscopic evaluation of meniscus, a bridging reparation tissue and adhesion were observed between the rims of the tear in the experiment group. There was no statistical difference in collagen fibril formation between the groups (p=0.16). There was significantly more neovascularization in the experiment group than the control group (p=0.003). The cell count was also a significantly higher in the experiment group (p=0.004) and formation of cartilage plaques was more frequent in the experiment group (p=0.016). There was no evidence suggesting intrinsic repair in the meniscus of control group by light and electron microscopy. CONCLUSION: An injection of bone marrow into the meniscus tear site improves healing in a meniscal tear model as demonstrated by both light and electron microscopic findings. PMID- 22441455 TI - Isolated carpal scaphoid dislocation. AB - Isolated scaphoid dislocations are very rare. Options for the treatment of dislocation of the scaphoid include closed reduction and casting, closed reduction and percutaneous pinning, and open reduction and ligament repair. We report a case of this rare injury which was treated with open reduction, pinning and ligament repair. PMID- 22441456 TI - Heterotopic bone formation following anterior cruciate ligament reconstruction with BPTB autograft. AB - In this study, we present a 36-year-old male patient who developed heterotopic ossification after anterior cruciate ligament (ACL) reconstruction performed using bone-patellar tendon-bone autograft harvested from the 1/3 middle part of the patellar tendon. This ossified part, which restricted range of motion of the affected knee, was excised surgically 1 year after diagnosis. Physical examination, conducted 36 months later, revealed the achievement of full range of motion without any complaints or recurrences. Heterotopic ossification following ACL reconstruction is a very rare complication, which should be removed with open surgery. PMID- 22441457 TI - Open reduction technique for overlapping and locked pubic symphysis. AB - A locked pubic symphysis can occur following a lateral compression injury of the pelvic ring when one pubic bone becomes entrapped behind the contralateral pubis or obturator foramen. In selecting the treatment modality, it is important to know the mechanism of injury. We presented the use of an open reduction technique in the treatment of a locked pubic symphysis in which open reduction external fixation application failed in the emergency department. PMID- 22441459 TI - Singlet oxygen production by pyrano and furano 1,4-naphthoquinones in non-aqueous medium. AB - The influence of ring size on the photobehaviour of condensed 1,4-naphthoquinone systems, such as pyrano- and furano-derivatives (1 and 2, respectively) has been investigated. The absorption spectra for both families of naphthoquinones reveal clear differences; in the case of 2 they extend to longer wavelengths. A solvatochromic red shift in polar solvents is consistent with the pi,pi* character of the S(0)-> S(1) electronic transition in all cases. Theoretical (B3LYP) analysis of the HOMO and LUMO Kohn-Sham molecular orbitals of the S(0) state indicates that they are pi and pi* in nature, consistent with the experimental observation. A systematic study on the efficiency of singlet oxygen generation by these 1,4-naphthoquinones is presented, and values larger than 0.7 were found in every case. In accordance with these results, laser flash photolysis of deoxygenated acetonitrile solutions led to the formation of detectable triplet transient species with absorptions at 390 and 450 nm (1) and at 370 nm (2), with phi(ISC) close to 1. Additionally, the calculated energies for the T(1) states relative to the S(0) states at UB3LYP/6-311++G** are ca. 47 kcal mol(-1) for 1 and 43 kcal mol(-1) for 2. A comparison of the geometrical parameters for the S(0) and T(1) states reveals a marked difference with respect to the arrangement of the exocyclic phenyl ring whilst a comparison of electronic parameters revealed the change from a quinone structure to a di-dehydroquinone diradical structure. PMID- 22441460 TI - Facile one-pot synthesis of unprecedented beta,beta'-linked porphyrin-chlorin heterodimers. AB - A type of porphyrin-chlorin heterodimers have been synthesized in a one-pot reaction, and their porphyrin and chlorin moieties are directly beta,beta'-linked through an sp(3) carbon. These species have been characterized by mass spectroscopy, (1)H NMR, X-ray crystallography, cyclic voltammetry, UV-vis and fluorescence spectroscopy. PMID- 22441461 TI - Superstructured fiber-optic contact force sensor with minimal cosensitivity to temperature and axial strain. AB - In this work a new superstructured, in-fiber Bragg grating (FBG)-based, contact force sensor is presented that is based on birefringent D-shape optical fiber. The sensor superstructure comprises a polyimide sheath, a stress-concentrating feature, and an alignment feature that repeatably orients the sensor with respect to contact forces. A combination of plane elasticity and strain-optic models is used to predict sensor performance in terms of sensitivity to contact force and axial strain. Model predictions are validated through experimental calibration and indicate contact force, axial strain, and temperature sensitivities of 169.6 pm/(N/mm), 0.01 pm/MUepsilon, and -1.12 pm/ degrees C in terms of spectral separation. The sensor addresses challenges associated with contact force sensors that are based on FBGs in birefringent fiber, FBGs in conventional optical fiber, and tilted FBGs. Relative to other birefringent fiber sensors, the sensor has contact force sensitivity comparable to the highest sensitivity of commercially available birefringent fibers and, unlike other birefringent fiber sensors, is self-aligning with respect to contact forces. Unlike sensors based on Bragg gratings in conventional fiber and tilted Bragg gratings, the sensor has minimal cosensitivity to both axial strain and changes in temperature. PMID- 22441462 TI - Testing of Lagrange multiplier damped least-squares control algorithm for woofer tweeter adaptive optics. AB - A Lagrange multiplier-based damped least-squares control algorithm for woofer tweeter (W-T) dual deformable-mirror (DM) adaptive optics (AO) is tested with a breadboard system. We show that the algorithm can complementarily command the two DMs to correct wavefront aberrations within a single optimization process: the woofer DM correcting the high-stroke, low-order aberrations, and the tweeter DM correcting the low-stroke, high-order aberrations. The optimal damping factor for a DM is found to be the median of the eigenvalue spectrum of the influence matrix of that DM. Wavefront control accuracy is maximized with the optimized control parameters. For the breadboard system, the residual wavefront error can be controlled to the precision of 0.03 MUm in root mean square. The W-T dual-DM AO has applications in both ophthalmology and astronomy. PMID- 22441463 TI - Spectroscopic ellipsometry studies on various zinc oxide films deposited by ion beam sputtering at room temperature. AB - Various zinc oxide films were deposited by ion-beam sputter deposition (IBSD) under different oxygen partial pressures (P(O2)) at room temperature. The as deposited ZnO films fabricated at P(O2)>1.0*10(-4) Torr had poly-crystalline structures to absorb water on the surface at ambient condition. Simultaneously, the film surfaces were covered and smoothed by the surface layers formed with the water, hydroxyl (OH(-)) groups, and ZnO materials investigated by X-ray photoelectron spectroscopy (XPS). When the compositions of the surface layers were used in a multilayer fitting model of spectroscopic ellipsometry, the actual optical refractive index of the ZnO film deposited at P(O2)=1.2*10(-4) Torr was found to be about 1.9618 at lambda=550 nm. PMID- 22441464 TI - Simultaneous velocity and temperature measurements in gaseous flowfields using the vibrationally excited nitric oxide monitoring technique: a comprehensive study. AB - The performance of the vibrationally excited nitric oxide monitoring (VENOM) technique for simultaneous velocity and temperature measurements in gaseous flowfields is presented. Two different schemes were investigated, employing different methods to "write" a transient NO grid in the flow using the 355 nm photolysis of NO(2), which was subsequently probed by planar laser induced fluorescence imaging to extract velocity maps. We find that only one scheme provides full-frame temperature maps. The most accurate velocity measurement was attained by writing an NO pattern in the flow using a microlens array and then comparing the line displacement with respect to a reference image. The demonstrated uncertainty of this approach was 1.0%, corresponding to 7 m/s in a 705 m/s uniform flow. We found that the uncertainty associated with the instantaneous temperature measurements using the NO two-line thermometry technique was largely determined by the shot-to-shot power fluctuations of the probe lasers and, for the flows employed, were determined to range from 6% to 7% of the mean freestream temperature. Finally, simultaneous and local velocity/temperature measurements were performed in the wake of a cylinder in a uniform Mach 4.6 flowfield. The mean and fluctuation velocity and temperature maps were computed from 5000 single-shot measurements. The wake temperature and velocity fluctuations, with respect to the freestream values, were 15% to 30% and 5% to 20%, respectively. The spatial distributions agree with the results of computational fluid dynamics (CFD) simulations. Our results suggest that the VENOM technique holds promise for interrogating high-speed unsteady flowfields. PMID- 22441465 TI - 2 cm spatial-resolution and 2 km range Brillouin optical fiber sensor using a transient differential pulse pair. AB - We report a high-spatial-resolution and long-range distributed temperature sensor through optimizing differential pulse-width pair Brillouin optical time-domain analysis (DPP-BOTDA). In DPP-BOTDA, the differential signal suffers from a signal to-noise ratio (SNR) reduction with respect to the original signals, and for a fixed pulse-width difference the SNR reduction increases with the pulse width. Through reducing the pulse width to a transient regime (near to or less than the phonon lifetime) to decrease the SNR reduction after the differential process, the optimized 8/8.2 ns pulse pair is applied to realize a 2 cm spatial resolution, where a pulse generator with a 150 ps fall-time is used to ensure the effective resolution of DPP-BOTDA. In the experiment, a 2 cm spatial-resolution hot-spot detection with a 2 degrees C temperature accuracy is demonstrated over a 2 km sensing fiber. PMID- 22441466 TI - Tunable, Q-switched Tm,Ho:LLF laser with a conductively cooled triangular prism rod. AB - We have developed a conductively cooled, Q-switched 2 MUm laser with a triangular prism Tm,Ho:LLF rod. Using a fused-silica acousto-optic Q-switch, the laser produced an output energy of 30 mJ in a single Q-switched pulse at a pulse repetition frequency of 5 Hz. Although the laser rod had polished lateral surfaces, no parasitic oscillation occurred, even at the maximum pumping level. In addition, broadly tunable laser performance was achieved with a birefringent filter plate under relatively large output coupling. The laser could be continuously tuned from 2051 to 2069 nm. Measured tuning characteristics were in reasonable agreement with calculated results. PMID- 22441467 TI - 1.86 W cw single-frequency 1319 nm ring laser pumped at 885 nm. AB - A 1.86 W cw single-frequency 1319 nm laser was produced by using an 885 nm-pumped Nd:YAG crystal with a compact four-mirror ring cavity, for the first time to our knowledge. The Nd:YAG produced a slope efficiency of 21% and an optical-to optical efficiency of 18% with respect to the absorbed diode pump power. A near diffraction-limited beam with M(2)=1.2 was achieved under the maximum output power. PMID- 22441468 TI - Optimized angle scanning method for array sample detection in surface plasmon resonance biosensor. AB - An optimized angle scanning method is presented for array sample detection in a surface plasmon resonance biosensor. It provides a way to find the optimal rotation axis in the prism to resolve the drifting problem of the light incidence point on samples in the plane prism-coupling mode. The detection of array samples can be achieved by the translation of the prism along a particular direction. The validity of this method is theoretically analyzed and demonstrated by experiments. PMID- 22441469 TI - Athermal arrayed waveguide gratings in silicon-on-insulator by overlaying a polymer cladding on narrowed arrayed waveguides. AB - Athermal arrayed waveguide gratings (AWGs) in silicon-on-insulator (SOI) are experimentally demonstrated for the first time to our knowledge. By using narrowed arrayed waveguides, and then overlaying a polymer layer, the wavelength temperature dependence of the AWGs is successfully reduced to -1.5 pm/ degrees C, which is more than 1 order of magnitude less than that of normal SOI AWGs. The athermal behavior of the AWGs is obtained with little degradation of their performance. For the central channel, the cross talk is less than -15 dB and the insertion loss is around 2.6 dB. Good characteristics can be maintained with temperatures up to 75 degrees C. The total size of the device is 350 MUm * 250 MUm. PMID- 22441470 TI - Phase recovering without phase unwrapping in phase-shifting interferometry by cubic and average interpolation. AB - A simple phase estimation employing cubic and average interpolations to solve the oversampling problem in smooth modulated phase images is described. In the context of a general phase-shifting process, without phase-unwrapping, the modulated phase images are employed to recover wavefront shapes with high fringe density. The problem of the phase reconstruction by line integration of its gradient requires a form appropriate to the calculation of partial derivatives, especially when the phase to recover has higher-order aberration values. This is achieved by oversampling the modulated phase images, and many interpolations can be implemented. Here an oversampling procedure based on the analysis of a quadratic cost functional for phase recovery, in a particular case, is proposed. PMID- 22441471 TI - Modal analysis and device considerations of thin high index dielectric overlay slab waveguides. AB - The effect of adding a thin high index dielectric overlay layer onto a 3-layer slab waveguide demonstrates several interesting features that can be exploited in integrated optical device configurations. A simple modal analysis is employed to examine the behavior of guided light launched from a 3-layer waveguide structure then coupled and propagated in the 4-layer overlay region. Modal properties typically overlooked in conventional slab waveguides are made use of in the design and theoretical analysis of an MMI device and optical index of refraction sensor. The optical structure presented here can form the backdrop waveguide design for more complex and active devices. PMID- 22441472 TI - Three-dimensional shape measurement of large-aperture aspheric mirrors by off axis null Ronchi test. AB - An off-axis null Ronchi test is presented to measure the three-dimensional (3D) shape of a large-aperture aspheric mirror. The method designs curved fringe patterns as null sinusoidal gratings by means of phase information and ray tracing. In the process of measurement, the curved fringe patterns are displayed on a transmission-type liquid crystal display (T-LCD) screen, and a CCD camera records the fringe patterns containing the information of deviations of the mirror. The slopes of the deviations of the mirror are obtained by using the recorded fringe patterns. The deviations are restored by integrating, and then the 3D shape of the mirror can be reconstructed. Compared with the classical null Ronchi test, the method can provide enough measured data points and avoid the jagged edges of bands on the null gratings. Moreover, the method can conveniently change period and direction of the curved fringes and accurately control phase shifting. Computer simulations and a preliminary experiment are presented to show the performance of the method. PMID- 22441473 TI - Passively mode-locked Yb3+:Sc2SiO5 laser with reflection-type single-walled carbon nanotube absorber. AB - A reflection-type single-walled carbon nanotube saturable absorber fabricated by a vertical evaporation method was to our knowledge first used in a passively mode locked Yb(3+):Sc(2)SiO(5)(Yb:SSO) laser. The laser operated at a repetition frequency of 94 MHz with a central wavelength of 1062.6 nm. A short pulse duration of 1.8 ps was produced with an average power of 349 mW; and the highest pulse energy of 3.7 nJ, corresponding to its maximum peak power, can reach 2.1 kW. PMID- 22441474 TI - Modified annular photonic crystals for enhanced band gap properties and iso frequency contour engineering. AB - In this paper complete photonic bandgap (PBG) and iso-frequency contours (IFCs) of two-dimensional modified annular photonic crystals (MAPC) for four different configurations are numerically studied and calculated by applying plane wave expansion method. The effects of opto-geometric parameters of the designed unit cell structures are clearly demonstrated in terms of opening frequency gaps and appearing tilted band curves. Optimal structures with large PBGs are reported. The absolute gap can be increased to a maximum value of Deltaomega/omega=0.1766(2pic/a), where a is the lattice constant and c is the speed of light. The incorporation of additional parameters inside the unit cell of photonic crystal enables an extra degree of freedom for controlling the flow of light even in the absence of structural defects. The finite-difference time domain method is utilized to depict the MAPC's light deflection and guiding characteristics. These proposed structures are likely to be promising candidates for applications that require polarization insensitivity due to providing large complete PBGs and possessing special IFCs. PMID- 22441475 TI - Security optical data storage in Fourier holograms. AB - We have proposed and demonstrated a holographic security storage system that is implemented with a shift multiplexing technique. The security function of this storage system is achieved by using a microdiffuser (MD) for random phase encoding of the reference beams. The apparatus of random phase encoding in this system offers an additional and flexible function during the recording processes. The system can generate holographic security memory or nonsecurity holographic memory via using the MD or not. The storage capacity and the average signal-to noise value of the security storage system are 16 bits/MUm(2) and 3.5, respectively. Lateral shifting selectivity in this holographic security storage system is theoretically analyzed and experimentally investigated. PMID- 22441476 TI - Generation of photorealistic 3D image using optical digitizer. AB - A technique to generate a photorealistic three-dimensional (3D) image and color textured model using a dedicated optical digitizer is presented. The proposed technique is started with the range and texture image acquisition from different viewpoints, followed by the registration and integration of multiple range images to get a complete and nonredundant point cloud that represents a real-life object. The accuracy of the range image and the precision of correspondence between the range image and texture image are guaranteed by sensor system calibration. Based on the point cloud, a geometric model is established by considering the connectivity of adjacent range image points. In order to enhance the photorealistic effect, we suggest a texture blending technique that utilizes a composite-weight strategy to blend the texture images within the overlapped region. This technique allows more efficient removal of the artifacts existing in the registered texture image, leading to a 3D image with photorealistic quality and color-texture modeling. Experimental results are also presented to testify to the validity of the proposed method. PMID- 22441477 TI - Multiple-wavelength quasi-phase-matching for efficient idler generation in MgO:LiNbO3 based nanosecond optical parametric oscillator. AB - We present numerical results for optimization of the overall idler conversion efficiency of a nanosecond optical parametric oscillator (OPO), wherein the signal generated in the OPO process is also used as the pump for a difference frequency generation (DFG) process in a quasi-periodic MgO:LiNbO(3) crystal. The phase-matching conditions are considered such that the generated idler frequencies in both the processes (i.e., OPO and DFG) coincide. Optimization for the idler generation has been performed with respect to the different parameters, such as input pump power, pump pulse duration, and the output coupler reflectivity, for quasi-phase-matched interaction in MgO:LiNbO(3). Wavelength of the pump, signal, and idler waves considered in the optimization are 1.064 MUm, 1.456 MUm, and 3.95 MUm, respectively. A maximum overall idler generation efficiency of ~33% could be obtained in the simultaneous OPO+DFG process for a pump pulse duration of 72 ns and output coupler reflectivity (R(s)) of 90%, whereas for the stand-alone OPO process, the maximum idler generation efficiency was found to be ~15%. The optimization has been illustrated for an average pump power of 8 W at a pulse repetition frequency (PRF) of 10 kHz. This approach of simultaneous OPO+DFG process can be employed to significantly enhance the idler generation efficiency of nanosecond OPOs. PMID- 22441478 TI - Response analysis of holography-based modal wavefront sensor. AB - The crosstalk problem of holography-based modal wavefront sensing (HMWS) becomes more severe with increasing aberration. In this paper, crosstalk effects on the sensor response are analyzed statistically for typical aberrations due to atmospheric turbulence. For specific turbulence strength, we optimized the sensor by adjusting the detector radius and the encoded phase bias for each Zernike mode. Calibrated response curves of low-order Zernike modes were further utilized to improve the sensor accuracy. The simulation results validated our strategy. The number of iterations for obtaining a residual RMS wavefront error of 0.1lambda is reduced from 18 to 3. PMID- 22441479 TI - Free-space optical crossbar network integrated in a single block of LiNbO3 crystal. AB - A free-space optical crossbar network integrated in a single block of LiNbO(3) crystal is proposed, which consists of stages of 2*2 switches making use of the electro-optic effect of crystal and in-between routing devices for permutation based on double refraction and internal double reflection on interfaces. Two basic configurations are suggested. A control algorithm for the crossbar network is discussed, which may control a nonblocking interconnection between any input and output. The integrated crossbar network is low energy loss, nonblocking, easy to assemble, and insensitive to environment. A 3*3 crossbar network is designed and the experiment is demonstrated. PMID- 22441480 TI - Measurement of light absorption by aquatic particles: improvement of the quantitative filter technique by use of an integrating sphere approach. AB - Determination of particulate absorption in natural waters is often made by measuring the transmittance of samples on glass-fiber filters with the so-called quantitative filter technique (QFT). The accuracy of this technique is limited due to variations in the optical properties of the sample/filter composite, and due to uncertainties in the path-length amplification induced by multiple scattering inside the filter. Some variations in the optical properties of the sample/filter composite can be compensated by additional measurements of the filter's reflectance (transmittance-reflectance method [T-R] [S. Tassan and G. M. Ferrari, Limnol. Oceanogr. 40, 1358 (1995)]). We propose a different, rarely used approach, namely to measure the filter's absorptance in the center of a large integrating sphere, to avoid problems with light losses due to scattering. A comparison with other QFTs includes a sensitivity study for different error sources and determination of path-length amplification factors for each measurement technique. Measurements with a point-source integrating-cavity absorption meter were therefore used to determine the true absorption. Filter to filter variability induced a much lower error in absorptance compared to a measured transmittance. This reduced error permits more accurate determination of the usually low absorption coefficient in the near IR spectral region. The error of the T-R method was lower than that of the transmittance measurement but slightly higher than that of an absorptance measurement. The mean path-length amplification was much higher for the absorptance measurement compared to the T-R method (4.50 versus 2.45) but was found to be largely independent of wavelength and optical density. With natural samples the path-length amplification was less variable for the absorptance measurement, reducing the overall error for absorption to less than +/-14%, compared to +/-25% for the T-R method. PMID- 22441481 TI - Opaque optics thickness measurement using a cyclic path optical configuration setup and polarization phase shifting interferometry. AB - Thickness measurement of an opaque optics using a cyclic path optical configuration (CPOC) setup and polarization phase shifting interferometry (PPSI) is presented. The CPOC setup is used to simultaneously focus two orthogonally polarized counterpropagating converging beams at its hypotenuse arm. The opaque optics is placed at the hypotenuse arm of the CPOC setup such that one of its surfaces reflects back one of the counterpropagating focusing beams. Because of the thickness of the opaque optics, the other focusing beam suffers a longitudinal shift in the beam focus. Applying PPSI, the longitudinal shift in the beam focus which is twice the thickness of the opaque optics is determined. The results obtained for a silicon plate of thickness 0.660 mm with a measurement uncertainty of 0.013 mm are presented. PMID- 22441482 TI - Comparison of surface plasmon resonance responses to dry/wet air for Ag, Cu, and Au/SiO2. AB - We investigated the optical absorption spectra of Ag-, Cu-, and Au-mesoporous SiO(2) systems, respectively, after the samples were heated in dry air and in wet air. As expected, dry air at high temperature leads to the surface plasmon resonance (SPR) disappearance of Ag-SiO(2) and Cu-SiO(2) and a slight SPR increase of Au-SiO(2). However, a small amount of water vapor in air induces a strong SPR appearance for both Ag- and Au-containing samples, indicating that water vapor plays an abnormal reduction effect on both Ag and Au species in mesoporous SiO(2), despite the fact that it usually plays an oxidation role on Pt group metals, but it cannot induce the SPR appearance for the Cu-containing sample under the same condition. PMID- 22441483 TI - Full-field optical coherence tomography using nematic liquid-crystal phase shifter. AB - We present a polarization Linnik interference microscope with a nematic liquid crystal (NLC) phase shifter for full-field optical coherence tomography of high quality images. The rotating half-wave plate in conventional achromatic phase shifters was replaced by three liquid-crystal (LC) half-wave plates for implementing three-step phase-shifting interferometry. Thus, the NLC device generates phase shifts quickly and has no vibrations. In addition, the phase shift can be set to an arbitrary value between 0 and 2pi by altering the azimuth angles of the LC cells. A tomographic image is retrieved from three sequential phase-shifted interferograms by using a three-step algorithm. The experimental results confirm the feasibility of the proposed technology. PMID- 22441484 TI - Spectrum evolution of cascaded mismatching long-period fiber gratings. AB - Two identical long-period fiber gratings (LPFGs) are difficult to produce in practice, notably for CO(2)-laser or arc-discharge induced LPFGs. So it is meaningful to study the spectrum evolution of cascaded LPFGs with some deviation, named "mismatching" LPFGs. Theory and experiment demonstrate that the upper envelope of the fringe pattern is intrinsically curved but less dramatically than the lower envelope. Bending the grating pair to introduce proper cladding-mode loss can improve the contrast of the fringe pattern at a desired wavelength, which indicates that cascaded mismatching LPFGs can be used as high-quality comb filters or fiber sensors. PMID- 22441485 TI - Generation of Bessel beam arrays through Dammann gratings. AB - In this work we apply the Dammann grating concept to generate an equal-intensity square array of Bessel quasi-free diffraction beams that diverge from a common center. We generate a binary phase mask that combines the axicon phase with the phase of a Dammann grating. The procedure can be extended to include vortex spiral phases that generate an array of optical pipes. Experimental results are provided by means of a twisted nematic liquid crystal display operating as a binary pi phase spatial light modulator. PMID- 22441486 TI - Intracavity second-harmonic generation at 320 nm of an actively Q-switched Pr:LiYF4 laser. AB - We demonstrate pulse laser operation of a Pr:LiYF(4) laser pumped by InGaN laser diodes (444 nm) using an acousto-optic modulator. We obtained a maximum laser peak power of 167 W (4 MUJ/pulse) with a pulse width of 24 ns at an 11 kHz repetition rate for a 63 nm wavelength. Employing an 8 mm long lithium triborate nonlinear crystal in the laser cavity, we obtained a maximum peak power of 55 W (2.7 MUJ/pulse) at 320 nm, which corresponds to a conversion efficiency of 69% with respect to the fundamental laser energy. The UV laser pulse width was 36 ns. PMID- 22441487 TI - Quantitative phase microscopy using dual-plane in-line digital holography. AB - We present detailed theoretical evaluation and thorough experimental investigation of quantitative phase imaging using our previously demonstrated dual-plane in-line digital holographic microscopy technique [Opt. Lett. 35, 3426 (2010)]. This evaluation is based on the recording of two interferograms at slightly different planes and numerically reconstructing the object information. The zero-order diffracted wave is eliminated by using the method of subtraction of average intensity of the entire hologram, and the twin-image diffracted wave is removed by Fourier domain processing of the two recorded holograms. Experiments are performed using controlled amplitude and phase objects and human muscle cells to demonstrate the potential of this technique. PMID- 22441488 TI - Spatial filtering velocimetry of objective speckles for measuring out-of-plane motion. AB - This paper analyzes the dynamics of objective laser speckles as the distance between the object and the observation plane continuously changes. With the purpose of applying optical spatial filtering velocimetry to the speckle dynamics, in order to measure out-of-plane motion in real time, a rotational symmetric spatial filter is designed. The spatial filter converts the speckle dynamics into a photocurrent with a quasi-sinusoidal response to the out-of-plane motion. The spatial filter is here emulated with a CCD camera, and is tested on speckles arising from a real application. The analysis discusses the selectivity of the spatial filter, the nonlinear response between speckle motion and observation distance, and the influence of the distance-dependent speckle size. Experiments with the emulated filters illustrate performance and potential applications of the technology. PMID- 22441489 TI - Analytic model for the direct and diffuse components of downwelling spectral irradiance in water. AB - The direct and diffuse components of downwelling irradiance have in general different path lengths in water, and hence they decrease differently with sensor depth. Furthermore, the ever-changing geometry of a wind-roughened and wave modulated water surface induces uncorrelated intensity changes to these components. To cope with both effects, an analytic model of the downwelling irradiance in water was developed that calculates the direct and diffuse components separately. By assigning weights f(dd) and f(ds) to the intensities of the two components, measurements performed at arbitrary surface conditions can be analyzed by treating f(dd) and f(ds) as fit parameters. The model was validated against HydroLight and implemented into the public-domain software WASI. It was applied to data from three German lakes to determine the statistics of f(dd) and ff(ds), to derive the sensor depth of each measurement and to estimate the concentrations of water constituents. PMID- 22441490 TI - Optimization of pump absorption in MOF lasers via multi-long-period gratings: design strategies. AB - Different strategies for designing optical couplers, optimized to enhance the pump absorption in the rare-earth-doped core of microstructured fiber lasers, are illustrated. Three kinds/configurations of optical couplers have been designed and compared as examples of the different design strategies which can be followed. Their effectiveness to enhance the performance of an ytterbium-doped, double cladding, microstructured optical fiber laser has been accurately simulated. They consist of a suitable cascade of multiple long-period gratings (MLPGs) inscribed in the fiber core region. The characteristics of the MLPG couplers have been simulated via a homemade computer code based on both rate equations and an extended coupled mode theory. The proposed MLPG couplers seem particularly useful in the case of low rare-earth concentration but, even for a middle-high ytterbium concentration, as N(Yb)=5*10(25) ions/m(3), the slope efficiency S can be increased up to 20%, depending on the fiber length. PMID- 22441491 TI - Vibration detection using focus analysis of interferograms. AB - This paper proposed an automated technique for vibration detection using statistical focus measure to evaluate interferogram contrast. An interferogram sequence from a Mach-Zehnder interferometer setup is recorded (frame rate: 24 fps) and the gray-level variance (GLVA) is plotted versus time. Occurrence of induced vibration in the setup causes a decrease in the interferogram contrast which, in turn, manifests as an evident rapid drop in the variance plot. The technique is demonstrated experimentally using periodic microvibrations (frequency range, <=6 Hz) and aperiodic disturbances. PMID- 22441492 TI - Shorter time between opioid prescriptions associated with reduced work disability among acute low back pain opioid users. AB - OBJECTIVE: To explore whether average time between opioid prescriptions is associated with shorter time off work. METHODS: Claims from 1422 work-related acute low back pain cases with at least two opioid prescriptions during the first month and at least 1 day of disability after the first month. Intended duration of first month opioid prescriptions was computed and averaged. RESULTS: After controlling for demographic and severity indicators, each additional week between opioid prescriptions predicted 14% longer disability (risk ratio, 1.14; 95% confidence interval, 1.06 to 1.22). This association remained robust in sensitivity analyses. CONCLUSIONS: Fewer days between opioid prescriptions were associated with shorter time off work. The mechanism of this effect is unknown but may be related to provider's close monitoring of the patient's pain and function, as well as addressing barriers that may prevent workers from returning to work. PMID- 22441493 TI - Impact of a Web-based worksite health promotion program on absenteeism. AB - OBJECTIVE: To evaluate the effect of participation in a comprehensive, Web-based worksite health promotion program on absenteeism. METHODS: Study population consists of Dutch workers employed at a large financial services company. Linear regression was used to assess the impact of program attendance on the difference between baseline and follow-up absenteeism rates, controlling for gender, age, job level, years of employment, and noncompletion of the program. RESULTS: Data from 20,797 individuals were analyzed; 3826 individuals enrolled in the program during the study period. A 20.3% reduction in absenteeism was shown among program attendees compared with nonparticipants during a median follow-up period of 23.3 months. CONCLUSIONS: Participating in the worksite health promotion program led to an immediate reduction in absenteeism. Improved psychological well-being, increased exercise, and weight reduction are possible pathways toward this reduction. PMID- 22441494 TI - Correlation between tear matrix metalloproteinases and the Schirmer's test. PMID- 22441495 TI - Morphometric characteristics of central retinal artery and vein in the optic nerve head of patients with diabetes. PMID- 22441497 TI - Diurnal variation of retinal thickness measured by optical coherence tomography in normal adults. PMID- 22441499 TI - The use of multimedia as an adjunct to the informed consent process for ankle ligament reconstruction surgery. AB - BACKGROUND: Obtaining "informed consent" is an integral aspect of surgery that can be fraught with difficulty. This study assessed the efficacy of a multimedia education tool in improving patients' understanding when used as an adjunct to the traditional verbal consent process regarding ankle lateral ligament reconstruction surgery. METHODS: A total of 56 patients (28 males and 28 females) were recruited with a mean age of 36 years. A standardized verbal discussion regarding surgical treatment was provided to each patient. Understanding was then assessed using a knowledge questionnaire. Subsequently, each patient observed a multimedia educational program following which the knowledge questionnaire was repeated. Additional supplementary questions were then given regarding the ease of understanding and satisfaction with the 2 methods of education delivery. RESULTS: The patients answered 75% of the questions correctly before the multimedia module compared with 88% after it (P < .001). Patients rated the ease of understanding and the amount of information provided by the module highly (9.5 cm and 9.0 cm on a 10-cm Visual Analogue Scale scale, respectively), and 61% of patients considered that the multimedia tool performed as well as the treating surgeon. CONCLUSION: Multimedia tools used in sequence after a verbal consent resulted in improved patient understanding of pertinent information regarding ankle lateral ligament reconstruction surgery. LEVELS OF EVIDENCE: Therapeutic Level II. PMID- 22441500 TI - Isolated tarsal navicular fracture dislocation: a case report. AB - Injuries to the midtarsal joints are rare. They occur in the form of various combinations such as fracture, fracture subluxation, and fracture dislocation. The largest series of 71 cases has been reported by Main and Jowett in 1975. Isolated tarsal navicular dislocations are rare injuries. Being rare, these injuries remain poorly understood. Only few case reports exist, which describe the probable mechanism of injury and optimal treatment. Of the few case reports, only one describes closed reduction with external fixator and percutaneous fixation as the treatment modality. This case report emphasizes the use of external fixation with pins in the calcaneum and not in talus as described by the earlier report. LEVELS OF EVIDENCE: Therapeutic, Level IV. PMID- 22441501 TI - Bilateral osteonecrosis of the navicular and medial cuneiform in a patient with systemic lupus erythematosus: a case report. AB - INTRODUCTION: Atraumatic avascular necrosis (AVN) is an unusual pathology to the foot. Risk factors include the use of corticosteroids, smoking, alcohol, rheumatologic disorders, hematologic disorders, and metabolic disorders. To the authors' knowledge, this study presents the first case of bilateral atraumatic AVN to the navicular and medial cuneiform in a patient with systemic lupus erythamatosus (SLE). CASE DESCRIPTION: A 40-year-old man presented with a past medical history of SLE in which he developed AVN of the tarsal navicular and medial cuneiform. This occurred first on the subject's right foot and then while recovering from surgical intervention, on his left foot. Talonaviculocuneiform arthrodesis was performed with the use of distal tibial autograft on both extremities. The subject's American Orthopaedic Foot and Ankle Society midfoot score improved from 34 to 80 at 21 months on the right and 37 to 90 at 15 months to the left. DISCUSSION: Patients with SLE carry a significant risk of developing AVN. Comorbidities such as vasculitis, corticosteroid use, cytotoxic medication, and peripheral neuropathy are known risk factors in the development of AVN. Unusual features such as multifocal AVN and unusual anatomic locations can occur with SLE. AVN of the foot is generally treated with surgical intervention. Treatments such as core decompression, open reduction and internal fixation, and arthrodesis have been recommended based on the symptoms and presentation. CONCLUSION: The authors present a very rare presentation of bilateral osteonecrosis of the tarsal navicular and first cuneiform in a patient with SLE. The patient was treated with bilateral talonaviculocuneiform arthrodesis. The patient demonstrated considerable improvement to both extremities. LEVELS OF EVIDENCE: Therapeutic, Level IV. PMID- 22441502 TI - Are we being overly cautious? A qualitative inquiry into the experiences and perceptions of treatment-focused germline BRCA genetic testing amongst women recently diagnosed with breast cancer. AB - PURPOSE: Women with breast cancer, who are found to be BRCA1/2 mutation carriers, have a high risk of ovarian cancer and metachronous breast cancer. Treatment focused genetic testing (TFGT), offered around the time of diagnosis, allows genetic test results to inform surgical treatment decisions. However, concern has been raised that offering TFGT at this time may overly increase psychological burden. This study aimed to qualitatively explore women's attitudes and experiences of TFGT. METHODS: Women who had been diagnosed with breast cancer at age 50 years or less undertook a semi-structured telephone interview (n = 26). The sample included women who had been offered TFGT, based on family history and/or other risk criteria (n = 14), and women who had been diagnosed within the past 6-12 months and had not been offered TFGT (n = 12). Interviews explored women's attitudes towards TFGT, perceived benefits and disadvantages, implications of TFGT and impact on surgical decision making. Interviews were transcribed verbatim and thematically analysed. RESULTS: Women expressed positive attitudes towards TFGT and felt it was highly relevant to their surgical decision making. They did not feel that an offer of TFGT shortly after, or at the time of diagnosis, added undue psychological burden. The majority of women interviewed felt that TFGT should be incorporated into standard clinical care. CONCLUSIONS: TFGT is viewed favourably by women newly diagnosed with breast cancer. Future randomized controlled trials are needed to examine the long-term impact of TFGT. We conclude that an offer of TFGT is not perceived as 'too much, too soon' by relevant patients. PMID- 22441503 TI - Mechanochemical and solution synthesis, and crystal structures and IR and solid state (CPMAS) NMR spectroscopy of some bis(triphenylphosphine)silver(I) mono- and di-hydrogencitrate systems. AB - The complex [(Ph(3)P)(2)Ag(H(2)cit)].EtOH (1; H(2)cit(-) = dihydrogencitrate = C(6)H(7)O(7)(-)) contains [(Ph(3)P)(2)Ag(H(2)cit)] molecules in which the silver atom is coordinated to two PPh(3) molecules and the two oxygen atoms of one of the 'terminal'/1-carboxylate groups of the dihydrogencitrate group. The molecules form centrosymmetric hydrogen-bonded dimers in the solid. In [{(Ph(3)P)(2)Ag}(2)(Hcit)], (2), unsymmetrical deprotonation of the citrate grouping is found, from the 1- and 3- (i.e. terminal and central) carboxylates: [(Ph(3)P)(2)Ag(O(2)CCH(2)C(OH) (CH(2)COOH)CO(2))Ag(PPh(3))(2)]. The above complexes, as well as [(Ph(3)P)(3)Ag(H(2)cit)] (3) were prepared via conventional solution methods, involving the reaction of trisilver(I) citrate, citric acid and triphenylphosphine, and by a mechanochemical method involving the reaction of silver(I) oxide, citric acid and triphenylphosphine. IR studies of 1-3 show the presence of coordinated carboxylate and free carboxylic acid groups in the mono- and di-hydrogencitrate ligands, and the formation of 2 from 1 shows that dihydrogencitrate deprotonation can occur upon dissolution of 1 in protic solvents. High-field (9.40 T) (31)P CPMAS NMR spectra were recorded and analysed, yielding heteronuclear (1)J((107/109)Ag,(31)P) and homonuclear (2)J((31)P,(31)P) spin-spin coupling constants. PMID- 22441504 TI - Limb constriction secondary to pseudoamniotic band syndrome after selective fetoscopic laser surgery: report of a case with a favorable outcome. AB - Pseudoamniotic band syndrome (PABS) is an iatrogenic complication that causes entanglement of fetal parts in a constrictive sheet of detached or ruptured amniotic membrane after an invasive procedure, namely amniocentesis, amnioreduction or septostomy in twins. The incidence and risk factors for PABS after fetoscopy-guided laser have not been documented [Winer et al.: Am J Obstet Gynecol 2008;198:393.e1-393.e5]. We report a case of monochorionic biamniotic twin pregnancy submitted to selective fetoscopic laser photocoagulation for twin to-twin transfusion syndrome at 16 weeks of gestation. The procedure was complicated by the death of one of the fetuses at 24 weeks of gestation. Moreover, the surviving twin was diagnosed postnatally with pseudoamniotic band syndrome, presenting with affected limbs. The newborn was submitted to surgical correction of these lesions with a successful outcome and was discharged on day 15. PMID- 22441505 TI - Psychological impact of the tsunami on elderly survivors. AB - OBJECTIVE: The study aimed at comparing the psychiatric morbidity in geriatric versus nongeriatric (NG) adults during the initial 3 months following the December 2004 tsunami involving the Andaman and Nicobar Islands, India. METHODS: This observational study was undertaken during the relief operation of tsunami. There were 12,784 survivors sheltered across 74 relief camps with 4,684 displaced survivors in Port Blair, and 8,100 nondisplaced survivors in Car Nicobar Island. All persons who accessed mental health assistance within the camps constituted the study sample. Diagnoses were made by qualified psychiatrists using the International Classification of Diseases, Tenth Revision. There were 438 adult patients, of which 75 (17%) were geriatric (60 years or older) and 363 (83%) were NG (aged 19-59 years). RESULTS: The geriatric sample had greater levels of adjustment disorder than NG group. The two groups differed in terms of displacement as the elderly preferred to stay in their own locality. A comparison between displaced geriatric and NG groups showed that major depression was less common in the geriatric sample. However, in the nondisplaced group, geriatric subgroup showed a higher incidence of posttraumatic stress disorder. Within the geriatric sample, there were higher levels of adjustment disorder in the nondisplaced group whereas the displaced group suffered more depressive episodes and unspecified anxiety disorders. CONCLUSION: Greater levels of adjustment disorder in geriatric group may indicate grief reaction and survivor guilt, especially in nondisplaced group. In addition, lower occurrences of depressive episodes in nondisplaced geriatric sample may indicate that the elderly need to be rehabilitated in their own habitats after major disasters. PMID- 22441506 TI - Time does not heal all wounds: trauma, stress, and resilience among older adults. PMID- 22441507 TI - Predictors of antihypertensive medication adherence in two urban health-care systems. AB - BACKGROUND: Most studies on patient-related predictors of adherence used self reported measures or pharmacy databases to measure adherence. We identified predictors of antihypertensive medication adherence measured by Medication Event Monitoring System (MEMS), the gold standard for adherence assessment, in uncontrolled, predominantly African-American (AA) hypertensives from large urban public and private primary care clinics. METHODS: As part of the baseline data collection of a cluster-randomized trial for hypertension control, we measured adherence in a random sample of 124 participants using MEMS caps. We also included the data of 52 patients in intervention clinics who subsequently completed MEMS monitoring on referral from their provider. Participants were classified as adherent if they took >= 80% of all prescribed doses. Multivariate logistic regression was used to predict adherence. RESULTS: Of 176 patients monitored, 61 (34.6%) took <80% of prescribed doses. AA ethnicity (odds ratio (OR) AA vs. Hispanic = 0.36; 95% confidence interval (CI) 0.15-0.86), female sex (OR = 0.38; 95% CI 0.15-0.91), and public clinics as source of care (OR public clinics vs. private clinics = 0.45; 95% CI 0.20-0.97) were independently associated with lower adherence. Higher adherence was seen in patients monitored by clinician order in the intervention clinics (OR intervention sample vs. random baseline sample = 2.15; 95% CI 0.96-4.81) and diabetic patients (OR = 2.05; 95% CI 1.01-4.15). All analyses were adjusted for education, employment status, and other potentially confounding factors. CONCLUSIONS: AA ethnicity, female gender and attending a publicly funded primary care clinic were associated with lower adherence. Whether targeting these groups for special interventions would improve overall adherence needs further study. PMID- 22441508 TI - The relationship of poor linear growth velocity with neonatal illness and two year neurodevelopment in preterm infants. AB - BACKGROUND: Poor postnatal weight gain in very low birth weight (VLBW) preterm infants has been shown to have a negative effect on neurodevelopment. However, the dose-dependent neurodevelopmental consequences of linear stunting in this population have not previously been assessed. Understanding this relationship is important because organ growth and differentiation are more tightly linked to lean body mass and thus linear growth. OBJECTIVE: To assess the duration and clinical determinants of poor linear growth and its relationship to neurodevelopment in preterm infants. METHODS: Weight, recumbent length and head circumference were recorded at birth, hospital discharge, and at 4, 12 and 24 months corrected age (CA) in 62 VLBW infants. Standardized Z-scores for weight (WZ), length (LZ) and head circumference (HCZ) were calculated and assessed as a function of inpatient clinical factors using linear regression models. Twenty four-month neurodevelopmental function was analyzed as a function of growth status. RESULTS: Mean LZ was lower than WZ (p = 0.004) at hospital discharge, was related in part to illness severity and remained lower than baseline LZ until 24 months CA. Controlling for WZ and HCZ at each age, lower LZ at 4 and 12 months CA was associated with lower cognitive function scores at 24 months CA (p <= 0.03). CONCLUSIONS: Nutritional and non-nutritional factors influenced the degree of pre and postdischarge linear growth suppression in VLBW infants, which in turn was negatively associated with developmental outcomes at 24 months CA. Since linear growth correlates with brain growth and indexes a number of clinical factors, it is an important biomarker that can be used in VLBW infants to predict long-term developmental outcomes. PMID- 22441509 TI - Azaphthalocyanines with fused triazolo rings: formation of sterically stressed constitutional isomers. AB - The presented work deals with synthesis and isolation of constitutional isomers of triazolo-fused azaphthalocyanines. Distribution of the isomers did not follow the statistical calculations due to steric effects of the substituents preferring the least sterically stressed C(4h) isomer. PMID- 22441510 TI - High-sensitivity C-reactive protein levels predict survival and are related to haemodynamics in alcoholic cirrhosis. AB - OBJECTIVES: Inflammation may be implicated in the haemodynamic deterioration and in the development of complications in patients with cirrhosis. High-sensitivity C-reactive protein (hsCRP) is a marker of low-grade inflammation, and predicts outcomes in patients at risk of ischaemic heart disease. Proinflammatory cytokines reflect immune activation and have been found to be elevated in cirrhosis. We investigated a possible association between markers of inflammation and splanchnic and systemic haemodynamics, complications and survival in patients with cirrhosis. METHODS: In 45 stable patients with cirrhosis on the basis of alcohol consumption, we measured hsCRP, as well as monocyte chemoattractant protein-1, tumour necrosis factor-alpha, interleukin-6, interleukin-8 and vascular endothelial growth factor in patients and in 12 healthy controls. Systemic and splanchnic haemodynamics were investigated in patients. RESULTS: hsCRP levels were significantly higher in patients compared with controls (P<0.05) and the highest in patients belonging to Child-Pugh class C. hsCRP levels correlated with markers of liver dysfunction and with the hepatic venous pressure gradient (r=0.48, P<0.001). hsCRP values above the median level of 5.3 mg/l were associated with a highly increased mortality (P=0.001). Model for End Stage Liver Disease score (P=0.01) and hsCRP (P<0.05) provided independent prognostic information. Cytokines had no discernible value in predicting survival. CONCLUSION: hsCRP is elevated in patients with cirrhosis and is associated with portal hypertension and decreased survival. hsCRP is a promising prognostic marker in cirrhosis, which may improve the selection of candidates for liver transplantation. PMID- 22441511 TI - Incidence and 30-day mortality of peptic ulcer bleeding in Korea. AB - OBJECTIVES: To estimate the rates of peptic ulcer bleeding (PUB) incidence and the association of demographic factors with 30-day mortality after PUB. METHODS: Diagnostic algorithms for PUB were derived and validated on the basis of 115 true PUB patients at one tertiary hospital in 2005, followed by estimation of age specific PUB incidence and 30-day mortality rates, using the Korean National Health Insurance claim database. A Cox proportional hazard model was used to determine the impact of demographic factors on the 30-day mortality rate ratio (MRR) after PUB. RESULTS: The diagnostic algorithm showed 89 and 88% positive predictive value and sensitivity, respectively. On the basis of this algorithm, the rate of PUB incidence was 22.1 per 100 000 during 2006-2007 and the age specific incidence rate increased with advanced age. This incidence rate was more than three times higher among men than women. Among 21 107 PUB patients, the overall 30-day mortality rate was 2.15%, but it ranged from 0.83% for patients younger than 60 years to 7.65% for patients older than 80 years. The adjusted 30 day mortality rate ratio for patients older than 80 was 8.13 (95% confidence interval 6.10-10.8) compared with those younger than 60 and 7.09 (95% confidence interval 2.78-4.51) for patients with a high level of comorbidity compared with a low level of comorbidity. CONCLUSION: PUB incidence was higher among men and increased with advanced age. Increased 30-day mortality was observed in association with increasing age, after adjusting for comorbidity. PMID- 22441512 TI - Impact of colonoscopy on quality of life. AB - INTRODUCTION: Colonoscopy of asymptomatic, healthy individuals for colorectal cancer screening rarely causes complications and adverse events. Thus, quality of life (QOL) of the participants should not be affected by the procedure. AIM: The aim of the study was to isolate the influence of colonoscopy, by investigation QOL before and after the procedure in a cohort of consecutive patients with different indications. METHODS: This study is a prospective, longitudinal study, designed to compare the potential influence of colonoscopy on QOL. For a cohort of consecutive patients undergoing colonoscopy for various reasons and indications, we filled a QOL short form-36 and a short feedback questionnaire before, immediately after, and a month after the procedure. We also measured the quality of the endoscopy, the outcome in patients, and acceptability among patients. RESULTS: There was no significant change before and immediately after colonoscopy in any of the short form-36 parameters. Physical functioning, role limitation physical, pain, general health, vitality, social functioning, role limitation mental, and mental health had very similar scores before and 2-3 h after the procedure. There was a decrease in the physical functioning a month after the procedure (P=0.01). The same was found for non-inflammatory bowel disease patients, but not for inflammatory bowel disease patients. CONCLUSION: Colonoscopy did not affect QOL in the short or the long duration after the procedure. As such, colonoscopy may be suitable as a part of screening programs. We believe that QOL estimation should be an integral part of assessment of a screening program. PMID- 22441513 TI - [Long-term survivors]. PMID- 22441514 TI - [Life years gained. Long-term trends in mortality by causes of death in Germany and in an international perspective]. AB - In Germany life expectancy is continuously increasing. Differently to the increases in the nineteenth century, which were mainly driven by decreasing mortality from infectious diseases, the recent rise in life expectancy is the result of a mortality decline in all major groups of causes of death. Contrary to mortality, the incidence and prevalence of a large number of diseases, in particular cancer and cardiovascular diseases (CVD), is rising. However, this increase is mainly the result of changes in the population's age structure, differences in lifestyle, improvements in diagnostic techniques, and increasing prevention. Age-standardized death rates and survival rates indicate significant improvements in most of the diseases over the last decades. Important exceptions are cancer of the lung and bronchia for females as well as mental diseases for both sexes. Therefore, these diseases will grow in importance for public health measures in the next decades. A major potential for a further increase in female life expectancy lies in the reduction of CVD mortality. In contrast, decreases in mortality due to various types of cancer, diseases of the respiratory system, and diseases of the digestive system in addition to CVD mortality may lead to a significant rise in male life expectancy. Although declining mortality is strongly linked to an increase in the prevalence of multi-morbidity and the number of years with disability, it is also paralleled by an increase in healthy life years. PMID- 22441515 TI - [Instrumentality of the International Classification of Functioning, Disability and Health (ICF) in classification of long-term consequences of diseases]. AB - The ICF (International Classification of Functioning, Disability and Health) is an international classification of disease consequences and phenomena associated with health conditions. It is complementary to the already established classification of diseases (ICD). The ICF provides both a framework and a classification that comprehensively cover relevant domains of functioning to describe long-term consequences of diseases. The classification can be used as a universal language understood by medical doctors, health professionals, researchers, patients and other groups. The ICF is based on an integrative biopsychosocial model of functioning. Functioning is used as an umbrella term for all non-problematic body functions, body structures, activities and participation. Based on the biopsychosocial model the ICF comprises a hierarchical classification to describe functioning as well as environmental factors. Problems of long-term survivors as well as persons suffering from chronic diseases, relevant findings, treatment goals and treatment concepts can be managed by applying the ICF to the patients. PMID- 22441516 TI - [Costs of diseases with long-term survival]. AB - In the past decades medical progress in the treatment of fatal diseases has led to substantial improvement of survival. This long-term survival has financial consequences for health care and society. In this article methodological challenges of measuring the costs of long-term survival are presented. In this regard the costs of long-term treatment, indirect costs, unrelated future health care costs and discounting of costs are highlighted and illustrated by examples. A methodological challenge related to the economic evaluation of therapies leading to long-term survival is the consideration of unrelated future health care costs occurring in life years gained. In the literature the issue of unrelated future health care costs is discussed comprehensively on a methodological-theoretical basis. In economic evaluations published in the literature, these costs have rarely been considered so far, which may cause biased results. Concerning the comparability of study results, a standardization of the methods of measuring costs is desirable. PMID- 22441517 TI - [The life of the oldest old. Well-being in the face of physical restrictions]. AB - Demographic change is increasingly determined by development associated with very old age. The reduction of mortality in very old age will continue, so that an age between 80 and 100 years will become common. Present research findings suggest that, with respect to their physical resources, humans are not well equipped for a very long life. Very old individuals are characterized by a high prevalence of chronic diseases and functional limitations that endanger independent living. Centenarians are faced with these restrictions to a large extent. In contrast to increasing physical constraints, old and very old individuals' psyche seems to be rather robust. Well-being and valuation of life reveal only little decline up to the highest ages. Of particular importance are psychological strengths, which include adaptive strategies and self-referent convictions. They remain relatively stable even in very old age and seem to balance the effects of diseases, resource restrictions and loss. PMID- 22441518 TI - [Survivors of pediatric cancer. Developmental paths and outcomes between trauma and resilience]. AB - In Europe and North America, about 80% of all patients with cancer in childhood and adolescence survive their leukemia, lymphomas or tumors. Therefore, neuropsychological impairments, psychopathological comorbidity and health-related quality of life become relevant parameters for treatment evaluation and conceptualization of future therapy protocols. During the last decade, a number of patient registries, multicenter studies and meta-analyses have analyzed the interaction of disease- and treatment-associated risk factors with pre-existing socio-demographic and psychosocial vulnerability factors. Brain tumors and treatment strategies including CNS surgery, cranial radiotherapy and intrathecal chemotherapy carry an increased risk for neurological and neuropsychological long term outcomes, which in turn also threatens the patients' psychosocial and vocational participation. In the area of psychosocial adaptation, a wide range of developmental paths results, ranging from increased psychological comorbidity, to subclinical impairments in quality of life, to normal courses to resilient outcomes, even with a developmental benefit. A hypothetical model is presented to explain this enormous variance in outcomes. Protective cognitive-emotional schemata already established at the premorbid stage predispose patients to be able to cope successfully with cancer-related challenges and thus further enhance the patients' future adaptability. In contrast, dysfunctional schemata at the premorbid level increase risks of coping failure and thus intensify the long-term risk for psychopathological comorbidity in terms of post-traumatic stress disorder, anxiety disorder or depression. PMID- 22441519 TI - [Long-term sequelae of cancer survivors]. AB - Multimodal treatment modalities enable an increasing number of patients with malignant diseases to become candidates for a curatively intended treatment strategy. Furthermore, for numerous patients with incurable cancer disease, new therapeutic developments (including molecular "targeted" agents) allow control of further progression of tumor growth for months up to years - and therefore, even those patients may be regarded as having a "chronic" disease. Taken together, both patient groups increase the number of "long-term cancer survivors" markedly. However, complex interdisciplinary therapeutic strategies and the increasing number of options for sequential treatments also result in higher rates of acute and chronic toxicities and sequelae. Even years after completion of the initial treatment, many cancer survivors still suffer from sequelae of both malignant disease and therapy. This refers to both psychosocial and somatic involvement. In consequence, a focus of (future) oncology care - beyond successful oncology treatment rates - is to carefully investigate the somatic and psychosocial aspects of long-term sequelae in order to treat them, or - using appropriate preventative measures - to limit or even prevent their occurrence. PMID- 22441520 TI - [Psychosocial issues of long-term cancer survivors]. AB - Although cancer incidence rates are increasing, recent statistical studies suggest that cancer patients are showing higher cure rates as well as improved overall survival rates for most cancer locations. These advances are explained by improved strategies in early diagnoses as well as improved cancer therapies. Therefore, the number of long-term cancer survivors has also increased, but only few studies, especially within the last years, have focused on psychosocial issues of this subgroup. Some studies show that overall quality of life of long term cancer survivors is quite high and comparable to that of the normal population. Nevertheless, a substantial percentage of former patients shows reduced quality of life and suffers from various sequelae of cancer and its treatment. This review focuses on the most common psychosocial issue of long-term survivors such as reduced psychological wellbeing, neuropsychological deficits and cancer-related fatigue syndrome. Finally, recommendations for problem oriented interventions as well as improvement of psychosocial care of long-term survivors are given. PMID- 22441521 TI - [Long-term effects of cancer. Aftercare and rehabilitation requirements]. AB - Long-term and late effects of cancer and treatment are playing an increasingly important role within the care of cancer patients. International and national guidelines emphasize the importance of a comprehensive survivorship care plan forcancer patients. A comprehensive survivorship care plan aims at ensuring continuity of care and improving communication and cooperation amongthe inpatient, outpatient and rehabilitative care professions involved. Thus, cancer rehabilitation has a high priority within a comprehensive aftercare plan. The article identifies requirements concerning rehabilitation assessment and rehabilitation treatment planning, and refers to the significance of providing interventions tailored to the individual problems and rehabilitation goals of the patient as well as flexible service offerings. Furthermore, the article emphasizes the importance of cooperation between different in- and outpatient cancer care facilities ensuring the continuity of care. Thus, rehabilitation requirements involve the expansion of the community outpatient rehabilitation services that are involved in care at cancer centers. PMID- 22441522 TI - [Gender-related aspects of returning to work in cancer survivors. A systematic review]. AB - Due to improved prognosis most cancer survivors are nowadays able to return to work. This review explored gender-related differences in work-related outcomes after cancer. A systematic search of studies on work-related issues in cancer survivors published between January 2001 and July 2011 was conducted. 44 original publications met the inclusion criteria (adult cancer survivors, focus on work related outcomes, gender-specific report of results). The results of these studies indicate that impaired work ability is more common among female cancer survivors than among male cancer survivors as well as the reduction of working hours and income losses. Supportive work environments seem to be particularly helpful for the successful and long-lasting re-integration of female survivors. More systematic research and separate analyses for women and men are needed to fully comprehend gender differences in work-related outcomes. Broader knowledge can then be helpful in creating gender-specific return-to-work interventions. PMID- 22441523 TI - [AIDS. New challenges for social and medical prevention]. AB - Anti-retroviral therapy (ART) produces spectacular improvements in life expectancy and quality of life for people infected with HIV, and contributes to primary prevention in the wider population by reducing the viral load. Many people infected with HIV begin therapy later than indicated, while, despite ongoing prevention efforts, the number of new HIV diagnoses is increasing, along with the incidence of other STIs and, in identifiable sub-groups, of hepatitis C, above all among men who have sex with men (MSM). The prevention consequences of this complex situation are discussed in the context of the alternative between control and containment (Suchstrategie) and inclusion and cooperation (Lernstrategie), arguing for HIV prevention to be integrated in the broader paradigm of sexual health and sub-group-specific efforts to increase the willingness to undergo testing both through community-based campaigns and in the health care context on the basis of informed consent and counseling. Above all ethical considerations mitigate against an undifferentiated test-and-treat approach. The contribution identifies research gaps and institutional obstacles that stand in the way of achievable advances and productive linkage of social and medical prevention. PMID- 22441524 TI - [Long-term outcome with end-stage renal disease - survival is not enough: does dialysis or kidney transplantation matter?]. AB - Patients with end-stage renal disease require renal replacement therapy with either dialysis or kidney transplantation. Survival and quality of life (QoL) after transplantation are superior to chronic dialysis. Early living donor kidney transplantation is best for patient and graft survival. Preemptive living-related kidney transplantation therefore is the best medical treatment option for these patients. Patients with end-stage renal disease suffer from multiple physical and psychological complaints. The prevalence of depressive disorders is 20-25% in this population. Studies on QoL in children after kidney transplantation show a reduced physical QoL, but an overall good psychological QoL. Alarming results of numerous studies are the high non-adherence rates in adolescents. Especially exercise interventions during dialysis and after kidney transplantation show promising results. Whether QoL of patients will improve with new approaches to immunosuppressive therapy remains to be evaluated in future studies. PMID- 22441525 TI - [Improvements in survival in patients with heart failure]. AB - The aim of this study is to describe improvements in survival of patients with heart failure. In addition, factors that may have contributed to these improvements are discussed. The extent of improvement in survival is substantial. This is presumably mainly due to a broad spectrum of new therapeutic options and the introduction of clinical guidelines, and the increasing level of awareness and adherence. For the near future, the increasing implementation of disease management programs and complex interventions has the potential to have a further positive influence on the survival of patients with heart failure. PMID- 22441526 TI - [Adults with cystic fibrosis. It's not just about longevity]. AB - Cystic fibrosis (CF) is one example of serious disorders for which medical progress and the integration of chronic treatment into the patients' daily routines have led to markedly better longevity. Formerly known as a 'killer disease' of childhood, CF is now considered a disorder with childhood onset, but is well known in adult medicine. Since 2009, for the first time CF adults have made up the majority of patients in the German CF registry. The drawbacks of improved longevity are long-term complications (e.g., CFRD, osteoporosis) that were rarely seen before. In particular, unwanted effects of treatments that today are performed for decades rather than years are becoming pressing problems. Unwanted effects as well as the ever-increasing treatment burden must be carefully weighed against the expected benefits of treatment. However, CF medicine has always been aware that it is not just about longevity, but that prolonged life has to have meaning. Therefore, the marked increase in longevity is also a psychosocial challenge. So far, empirical data suggest that the majority of people with CF courageously struggle for a normal life. PMID- 22441527 TI - [Long-term survival of preterm neonates]. AB - In view of the increased survival rate of very preterm neonates, several longitudinal studies were done to assess the quality of life of the survivors. They revealed a fairly constant rate of 25-30% of sensorineural and/or motor impairment. Beyond those "major handicaps," further problems may arise in every single period of life, which, albeit less severe, add to the burden of prematurity. These include growth retardation and cognitive delay in the school age, affected psychosocial behavior during adolescence, and the "metabolic syndrome" of formerly malnourished fetuses in adulthood. Thus, the epidemiologic studies not only confirmed the role of regionalization in the quality of perinatology, but also supported a more farsighted approach to the sequelae of prematurity. Like in young adults who grew up with congenital heart defects, also in former preterm neonates, appropriate medical care has to be provided for an increasing number of long-term survivors. Moreover, the life-long effects of metabolic imprinting in growth-retarded fetuses underline the primary-preventive role of perinatal medicine, extending far beyond the "baby" stage of human development. PMID- 22441528 TI - Prevalence and patterns of morbidity among adults in Germany. Results of the German telephone health interview survey German Health Update (GEDA) 2009. AB - To describe the prevalence and patterns of morbidity among adults in Germany, we collected self-reported information on 22 chronic health conditions in a nationally representative health survey among 21,262 participants (51.5% women, aged 18-100 years). Age- and sex-specific prevalences were calculated for single health conditions, disease categories, the most prevalent disease dyads and triads, and for multimorbidity defined by condition count. In both sexes, hypertension, hyperlipidemia, chronic back pain, obesity, and osteoarthritis were the most prevalent single health conditions and significantly increased with age. Cardiometabolic and musculoskeletal conditions were the two most prevalent disease categories in all age and sex groups. The most prevalent disease category dyads and triads included combinations between cardiometabolic conditions, cardiovascular and musculoskeletal disease, depression, sensory limitations, and cancer. The prevalence and magnitude of multimorbidity strongly increased with age in both sexes. Among German adults, the prevalence of chronic health conditions varies greatly by age and sex. In contrast, patterns of morbidity and comorbidity differ according to age, but are highly consistent between men and women. The predominant role of cardiometabolic conditions in all groups underlines the need for preventive efforts. The co-occurrence of chronic health conditions among older is highly prevalent and this calls for tailoring health care towards specific disease combinations. PMID- 22441529 TI - [Addendum to the list and procedures of the Robert Koch Institute, tested and approved disinfectants (15th edition)]. PMID- 22441530 TI - Visible-to-infrared quantum cutting by phonon-assisted energy transfer in YPO4:Tm(3+), Yb(3+) phosphors. AB - Quantum cutting (QC) of one visible photon into two infrared ones has been reported for the lanthanide ion couple (Tm(3+), Yb(3+)) in a variety of host lattices. The mechanism responsible for QC was assumed to be a cooperative energy transfer (ET) process from Tm(3+) to two Yb(3+) ions, however, no solid evidence was presented. Herein we report visible-to-infrared QC for (Tm(3+), Yb(3+)) in YPO4 phosphors. The ET process from the excited (1)G4 level of Tm(3+) to Yb(3+) was investigated in detail by means of optical spectroscopy. By monitoring the steady-state photoluminescence (PL) and PL decay of the intermediate (3)F4 level of Tm(3+) as a function of the Yb(3+) concentration, we demonstrated the QC of one incident blue photon into one near-infrared emitting photon at 1004 nm from Yb(3+) and simultaneously into one mid-infrared emitting photon at 1791 nm from Tm(3+), rather than two emitting photons from Yb(3+). It was revealed that such visible-to-infrared QC was induced by phonon-assisted ET instead of cooperative ET as previously reported. This kind of QC phosphors may have potential as solar spectral converters to enhance the external quantum efficiency in multi-junction solar cells based on narrow band-gap semiconductors such as Ge, PbS or In1-xGaxN. PMID- 22441531 TI - Association of CASP7 polymorphisms and survival of patients with non-small cell lung cancer with platinum-based chemotherapy treatment. AB - BACKGROUND: CASP7 plays a crucial role in cancer development and chemotherapy efficacy. We, therefore, explored whether single nucleotide polymorphisms (SNPs) of the CASP7 gene can modulate outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy. METHODS: We systematically genotyped 17 SNPs of CASP7 first in a discovery set of 279 patients with advanced NSCLC treated with platinum-based chemotherapy and then replicated the results in an independent set of 384 patients, in whom we evaluated associations with overall survival (OS) and progress-free survival (PFS) by Kaplan-Meier analysis and Cox hazards regression analysis. RESULTS: In both discovery and validation sets as well as in the pooled analysis, heterozygotes of CASP7 rs2227310 and rs4353229 as well as rs12415607 variant allele were strongly associated with a better OS of NSCLC (in the pooled sample: adjusted hazard ratio [HR], 0.73; 95% CI = 0.59-0.90; P = .003; HR, 0.72; 95% CI = 0.59-0.89; P = .002; and HR, 0.76; 95% CI = 0.62-0.94; P = .009; respectively). In stratified analyses of the pooled data set, treated with paclitaxel, individuals carrying variant allele of rs2227310, rs4353229, and rs12415607 had significantly improved OS (HR, 0.60; 95% CI = 0.41-0.87; P = .008; HR, 0.58; 95% CI = 0.39-0.84; P = .004; and HR, 0.61; 95% CI = 0.42-0.89; P = .010; respectively). CONCLUSIONS: This study provides evidence that genetic variations of CASP7 may modulate OS and PFS of patients with advanced NSCLC treated with platinum-based chemotherapy. PMID- 22441532 TI - The impact of narrow band imaging for colon polyp detection: a multicenter randomized controlled trial by tandem colonoscopy. AB - BACKGROUND: Previous studies have yielded conflicting results on the adenoma detection rate with narrow band imaging (NBI) compared with white light imaging (WLI). To overcome the confounding factors of these studies, we aimed to evaluate the colonic adenoma detection rate with primary NBI versus that with primary WLI by using consistent NBI system, endoscope, and imaging settings, and experienced colonoscopists. METHODS: In this multicenter prospective trial, 813 patients were randomized to undergo high-definition, tandem colonoscopy in the right colon with either NBI followed by WLI (NBI-WLI group) or WLI followed by NBI (WLI-NBI group). The NBI settings were fixed at surface structure enhancement level A-5 and adaptive index of hemoglobin color enhancement level 3. All detected polyps were resected or biopsied for histopathological analysis. The primary and secondary outcome measures were the adenoma detection rates and miss rates, respectively, with primary imaging. RESULTS: The NBI-WLI and WLI-NBI groups comprised 389 and 393 patients, respectively, who met the inclusion criteria. The groups did not differ significantly in age, gender, institution, indication for colonoscopy, bowel preparation, or observation time. The adenoma detection rates of primary NBI and WLI were 42.3 and 42.5 %, respectively [difference not significant (NS)]. The adenoma miss rate was significantly less with primary NBI than with primary WLI (21.3 vs. 27.8 %; p = 0.03). CONCLUSIONS: NBI does not improve the adenoma detection rate during primary colonoscopy; however, it has a lower miss rate for adenoma lesions in the proximal colon than WLI. PMID- 22441533 TI - A high value of serum des-gamma-carboxy prothrombin before hepatocellular carcinoma treatment can be associated with long-term liver dysfunction after treatment. AB - BACKGROUND: Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC), but it sometimes makes liver function worse. The pre-TACE prediction of liver dysfunction after TACE would be helpful to avoid long-term liver dysfunction. METHODS: We performed a case control study in 100 HCC patients who underwent TACE at Kobe University Hospital. Urinary/blood biochemical examinations were performed before TACE. As an indicator of liver function, Child's score was also evaluated before and 3 months after TACE. Cases with and without an increase of 2 points or more in the Child's score were compared, and independent risk factors were statistically examined. A pre-TACE predictive model of an increase of 2 points or more in the Child's score after TACE was developed using logistic regression. RESULTS: Univariate analyses showed that des-gamma-carboxy prothrombin (DCP) and lactate dehydrogenase (LDH) before TACE were significantly higher in the Child's score-deteriorated group than in the group with no deterioration (p = 0.036 and 0.003, respectively). All possible multivariate regressions showed that DCP (p = 0.003) and LDH (p = 0.002) were independent factors determining the deterioration of Child's class. A predictive model was developed, as follows: exp(0.014 * LDH + 0.572 * ln(DCP) - 8.655)/(1 + exp(0.014 * LDH + 0.572 * ln(DCP) - 8.655)). The model discriminated well, with AUC being 0.837 (95 % confidence interval [CI] 0.662-1.000). The optimal cut-off point was 0.073, and the sensitivity and specificity were 90.9 and 69.7 %, respectively. CONCLUSIONS: High values of DCP and LDH before TACE were associated with the long-term deterioration of liver function. Our pre therapeutic prediction model could be useful to identify high-risk cases. PMID- 22441535 TI - Tailoring ordered taper-nanopore arrays by combined nanosphere self-assembling, imprinting, anodizing and etching. AB - We report a simple and effective method for tailoring ordered three-dimensional alumina taper-nanopore arrays, dispensing with any unavailable and expensive top down equipment. PMID- 22441534 TI - Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotype 1b and high viral load. AB - BACKGROUND: This study explores pretreatment predictive factors for ultimate virological responses to pegylated interferon-alpha (1.5 MUg/kg/week) and ribavirin (600-1000 mg/day) (PEG-IFN/RBV) combination therapy for patients infected with hepatitis C virus (HCV)-1b and a high viral load. METHODS: A total of 75 patients underwent PEG-IFN/RBV combination therapy for 48 weeks. HCV amino acid (aa) substitutions in non-structural protein 5a, including those in the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region and the core regions, as well as the genetic variation (rs8099917) near the interleukin 28B (IL28B) gene (genotype TT) were analyzed. RESULTS: Of the 75 patients, 49 % (37/75) achieved a sustained virological response (SVR), 27 % (20/75) showed relapse, and 24 % (18/75) showed null virological response (NVR). Multivariate logistic regression analysis identified IRRDR with 6 or more mutations (IRRDR >=6) [odds ratio (OR) 11.906, p < 0.0001] and age <60 years (OR 0.228, p = 0.015) as significant determiners of SVR and IL28B minor (OR 14.618, p = 0.0019) and platelets <15 * 10(4)/mm(3) (OR 0.113, p = 0.0096) as significant determiners of NVR. A combination of IRRDR >=6 and age <60 years improved SVR predictability (93.3 %), and that of IRRDR <=5 and age >=60 years improved non SVR predictability (84.0 %). Similarly, a combination of IL28B minor and platelets <15 * 10(4)/mm(3) improved NVR predictability (85.7 %), and that of IL28B major and platelets >=15 * 10(4)/mm(3) improved non-NVR (response) (97.1 %) predictability. CONCLUSION: IRRDR >=6 and age <60 years were significantly associated with SVR. IL28B minor and platelets <15 * 10(4)/mm(3) were significantly associated with NVR. Certain combinations of these factors improved SVR and NVR predictability and could, therefore, be used to design therapeutic strategies. PMID- 22441536 TI - Fluoxetine promotes remission in acute experimental autoimmune encephalomyelitis in rats. AB - OBJECTIVE: This study was carried out to clarify the effects of the antidepressant fluoxetine, a selective serotonin reuptake inhibitor, for its potential use in autoimmune diseases like multiple sclerosis in a rat model of experimental autoimmune encephalomyelitis (EAE). METHODS: The rat EAE model was induced by subcutaneous injection of guinea pig spinal cord homogenate. Rats received fluoxetine via daily intragastric administration, starting 2 weeks prior to immune induction (fluoxetine pretreatment). Clinical scores and pathological changes in EAE rats were analyzed. Changes in serum cytokine levels were assessed by ELISA. RESULTS: Fluoxetine pretreatment significantly promoted remission in EAE. Histologically, fluoxetine-induced neuroprotection was accompanied by reductions in inflammatory foci and in the degree of demyelination in the spinal cord of EAE rats. The increase in serum IFN-gamma in the EAE model was also suppressed by fluoxetine administration. CONCLUSIONS: These findings suggest that the prophylactic use of fluoxetine can relieve symptoms during remission in the acute EAE model, and these neuroprotective effects are associated with its anti inflammatory effects. PMID- 22441537 TI - 3,4-methylenedioxymethamphetamine (ecstasy) decreases inflammation and airway reactivity in a murine model of asthma. AB - OBJECTIVE: 3,4-Methylenedioxymethamphetamine (MDMA), or ecstasy, is a synthetic drug used recreationally, mainly by young people. It has been suggested that MDMA has a Th cell skewing effect, in which Th1 cell activity is suppressed and Th2 cell activity is increased. Experimental allergic airway inflammation in ovalbumin (OVA)-sensitized rodents is a useful model to study Th2 response; therefore, based on the Th2 skewing effect of MDMA, we studied MDMA in a model of allergic lung inflammation in OVA-sensitized mice. METHODS: We evaluated cell trafficking in the bronchoalveolar lavage fluid, blood and bone marrow; cytokine production; L-selectin expression and lung histology. We also investigated the effects of MDMA on tracheal reactivity in vitro and mast cell degranulation. RESULTS: We found that MDMA given prior to OVA challenge in OVA-sensitized mice decreased leukocyte migration into the lung, as revealed by a lower cell count in the bronchoalveolar lavage fluid and lung histologic analysis. We also showed that MDMA decreased expression of both Th2-like cytokines (IL-4, IL-5 and IL-10) and adhesion molecules (L-selectin). Moreover, we showed that the hypothalamus pituitary-adrenal axis is partially involved in the MDMA-induced reduction in leukocyte migration into the lung. Finally, we showed that MDMA decreased tracheal reactivity to methacholine as well as mast cell degranulation in situ. CONCLUSIONS: Thus, we report here that MDMA given prior to OVA challenge in OVA sensitized allergic mice is able to decrease lung inflammation and airway reactivity and that hypothalamus-pituitary-adrenal axis activation is partially involved. Together, the data strongly suggest an involvement of a neuroimmune mechanism in the effects of MDMA on lung inflammatory response and cell recruitment to the lungs of allergic animals. PMID- 22441538 TI - Variability in laboratory immune parameters is associated with stress hormone receptor polymorphisms. AB - OBJECTIVES: Interpretation of laboratory immune data in healthy human subjects is often challenging due to wide inter-subject variability. Since endocrine and immune mediators have been mutually interlinked, a potential explanation for the significant variability seen in immune data even when controlled for technical variability and demographics is differences in the binding affinity of ligand with hormone receptors on the surface of immune cells, which can be associated with single nucleotide polymorphisms (SNP). METHODS: We categorized immunoregulatory cellular profiles from PBMC of 207 healthy volunteers according to glucocorticoid receptor (GR: Bcl1, TthIIII, and A3669G) and beta2-adrenergic receptor (beta2AR: Gly16Arg and Gln27Glu) polymorphisms. Subjects were genotyped for each SNP, and Th1, Th2, Th1/Th2 ratio, regulatory T cell (T(reg)), Tr1, and Th3 cell numbers were assessed. Immune parameters in the SNP groups were compared to the wild type (WT). RESULTS: Significant differences were observed in Th2 and the Th1/Th2 ratio for the beta2AR SNP Gly16Arg. Th1, the Th1/Th2 ratio, and Tr1 differed significantly by SNP of Gln27Glu. In addition, the effect of age on Th2 and the effect of the body mass index on the Th1/Th2 ratio significantly differed across subtypes of the Gly16Arg SNP. Significant differences based on allergic status and gender were also seen for T(reg), Th1, and Th2 across Gly16Arg, Gln27Glu, and TthIIII SNP. CONCLUSIONS: These data suggest that SNP from various components of the stress-immune network may be useful for subgrouping of immune responses to more accurately categorize psychoneuroimmunological components of stress risk in individual subjects. This approach may have significant research and clinical potential. PMID- 22441539 TI - Withdrawal from morphine reduces cell-mediated immunity against herpes simplex virus generated by natural immunization. AB - In a previous study, the authors have shown that herpes simplex virus type 1 (HSV 1) glycoprotein B DNA vaccine but not live vaccine (non-virulent KOS strain) failed to induce protective immunity against acute HSV-1 challenge in morphine dependent mice. The present study reports the effect of morphine withdrawal on protective immunity induced by live HSV-1 immunization. BALB/c mice were vaccinated with KOS strain as a live vaccine. Three weeks later, they were exposed to morphine for 14 days. On day 14, withdrawal was induced by administration of normal saline instead of morphine. One day later, immune responses against HSV-1 were assessed by measuring cytotoxicity, lymphocyte proliferation and interferon-gamma production. Protection against HSV-1 was assessed by measuring the mortality rate after acute HSV-1 challenge. The results showed that withdrawal from morphine reduces protective immunity against acute HSV-1 challenge. These findings raise the possibility that withdrawal from morphine may increase the susceptibility of drug addicts to infectious diseases. PMID- 22441540 TI - Interferon-alpha enhances excitatory transmission in substantia gelatinosa neurons of rat spinal cord. AB - OBJECTIVE: It has been shown that interferon-alpha (IFN-alpha) is synthesized and secreted by macrophages, monocytes, T lymphocytes, glial cells and neurons. IFN alpha has been shown to have an antinociceptive effect at the supraspinal level in the nerve system. However, it is unclear how IFN-alpha is involved in the modulation of nociceptive transmission in the spinal cord. METHODS: In the present study, IFN-alpha was used to test the potential functional roles in the nociceptive transmission. Using the whole-cell patch-clamp technique, we examined the effects of IFN-alpha on substantia gelatinosa (SG) neurons in the dorsal root attached spinal cord slice prepared from adult rats. RESULTS: We found that IFN alpha increased glutamatergic excitatory postsynaptic currents evoked by the stimulation of either Adelta or C afferent fibers. Further studies showed that IFN-alpha treatment dose-dependently increased spontaneous excitatory postsynaptic current frequency in SG neurons, while not affecting the amplitude. Moreover, intrathecal antibody of IFN-alpha could reduce nociceptive responses in formalin test. CONCLUSIONS: These results suggest that IFN-alpha presynaptically facilitates the excitatory synaptic transmission to SG neurons. The nociceptive responses could be inhibited by IFN-alpha antibody in the formalin test. Thus, IFN-alpha enhances the nociceptive transmission, which contributes to the behavioral nociceptive responses. PMID- 22441541 TI - Upregulated expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in BALB/c mouse brain challenged with Japanese encephalitis virus. AB - BACKGROUND: Uncontrolled immune responses in the nervous system are potentially damaging following Japanese encephalitis virus (JEV) infection. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) act together to control the proteolysis of extracellular matrix. Disbalances in the MMP/TIMP system during virally induced neurodegenerative processes and inflammations are responsive to changes in the progression of diseases. METHODS: The expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-3 in JEV-infected mouse brain was analyzed by RT-PCR for semiquantitation and ELISA for estimation of protein along with brain histopathology at different days postinoculation (dpi). Gelatin gel zymography was performed for MMP-2 and MMP-9 activities. RESULTS: In the virus infected group, expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-3 was found to be increased from 1 dpi to 6 dpi as compared to controls by both RT-PCR and ELISA. The expressions of MMPs and TIMPs at mRNA and protein levels were in concordance with each other. Post hoc multiple comparison analysis between days revealed that, in the virus-infected groups, significant increases (p < 0.05) in MMP and TIMP levels were observed between various dpi at both mRNA and protein levels. Only the MMP-7 protein level at 6 dpi was not significant compared to 5 dpi (p = 0.99). CONCLUSION: Overexpression of MMPs and TIMPs is associated with disease severity in the central nervous system (CNS) during JEV infection. Our results showed that JEV infection can alter the expression of MMPs and TIMPs in the CNS. Thus, assessing these important immune mediators in CNS infection appears to play an important role in the development of symptoms and may help to understand the JEV-induced neurological disorders. More studies are required on this important enzymatic system to study their role in immune mediated pathogenesis. PMID- 22441542 TI - Nicotinic acetylcholine receptor expression and susceptibility to cholinergic immunomodulation in human monocytes of smoking individuals. AB - OBJECTIVE: Smoking is generally accepted as a factor that affects the disease course in inflammatory bowel disease patients. Whether these effects can be contributed to the immunomodulatory effects of nicotine via nicotinic acetylcholine receptor (nAChR) activation is unclear. As previous data suggest that the alpha7 nicotinic acetylcholine receptor (CHRNA7) and its duplicated variant CHRFAM7A may specifically participate in the inflammatory response of monocytes, we evaluated whether repeated nicotine exposure or smoking affects monocyte CHRNA7 and CHRFAM7A expression and cholinergic immunomodulation. METHODS: The human monocyte cell line THP-I was incubated with nicotine for different time points before endotoxin exposure. In a pilot volunteer study using smoking (n = 4) and nonsmoking (n = 7) individuals, vagal output was stimulated by olive oil administration after which monocytes were analyzed for nicotinic receptor expression. Serum tumor necrosis factor (TNF) levels were determined using ELISA and expression levels of the nAChR subunits CHRNA7, CHRNB2 or CHRFAM7A were analyzed using QPCR. RESULTS: Repeated nicotine exposure upregulated CHRNA7 expression on THP-I monocytes and led to an enhanced potential of alpha7 nAChR agonist GSK1345038A to reduce TNF levels. Furthermore, CHRNA7 was only detectable in isolated blood monocytes of smokers. On the other hand, the expression of CHRFAM7A and CHRNB2 was not affected by nicotine exposure. Lipopolysaccharides-induced TNF secretion was inhibited by nicotinic receptor activation in THP-I monocytes, but this response was not consistently seen in blood monocytes from smoking individuals. CONCLUSIONS: We conclude that CHRNA7 expression on blood monocytes is upregulated in smoking individuals, which may contribute to cholinergic immunomodulation. PMID- 22441543 TI - Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model. AB - BACKGROUND: There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion. METHODS: We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model. RESULTS: Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes. CONCLUSIONS: Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine. PMID- 22441544 TI - Particulate air pollution and hospital admissions for cardiac diseases in potentially sensitive subgroups. AB - BACKGROUND: Although numerous studies have provided evidence of an association between ambient air pollution and acute cardiac morbidity, little is known regarding susceptibility factors. METHODS: We conducted a time-stratified case crossover study in 9 Italian cities between 2001 and 2005 to estimate the short term association between airborne particles with aerodynamic diameter <10 MUm (PM10) and cardiac hospital admissions, and to identify susceptible groups. We estimated associations between daily PM10 and all cardiac diseases, acute coronary syndrome, arrhythmias and conduction disorders, and heart failure for 167,895 hospitalized subjects >= 65 years of age. Effect modification was assessed for age, sex, and a priori-defined hospital diagnoses (mainly cardiovascular and respiratory conditions) from the previous 2 years as susceptibility factors. RESULTS: The increased risk of cardiac admissions was 1.0% (95% confidence interval [CI] = 0.7% to 1.4%) per 10 MUg/m PM10 at lag 0. The effect was slightly higher for heart failure (lag 0, 1.4% [0.7% to 2.0%]) and acute coronary syndrome (lag 0-1, 1.1% [0.4% to 1.9%]) than for arrhythmias (lag 0, 1.0% [0.2% to 1.8%]). Women were at higher risk of heart failure (2.0% [1.2% to 2.8%]; test for interaction, P = 0.022), whereas men were at higher risk of arrhythmias (1.9% [0.8% to 3.0%]; test for interaction, P = 0.020). Subjects aged 75-84 years were at higher risk of admissions for coronary events (2.6% [1.5% to 3.8%]; test for interaction, P = 0.001). None of the identified chronic conditions was a clear marker of susceptibility. CONCLUSIONS: An important effect of PM10 on hospitalizations for cardiac diseases was found in Italian cities. Sex and older age were susceptibility factors. PMID- 22441545 TI - Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. AB - BACKGROUND: The study of probiotics to prevent allergic conditions has yielded conflicting results in children. We undertook a meta-analysis of randomized controlled trials to investigate whether probiotic use during pregnancy and early life decreases the incidence of atopic dermatitis and immunoglobulin E (IgE) associated atopic dermatitis in infants and young children. METHODS: We performed a systematic literature search in Medline, Embase, and Cochrane Library, updated to October 2011. The intervention was diet supplementation with probiotics versus placebo. Primary outcomes were incidence of atopic dermatitis and IgE-associated atopic dermatitis. We calculated summary relative risks (RRs) and corresponding 95% confidence intervals (CIs), using both fixed- and random-effects models. We computed summary estimates across several strata, including study period, type of patient, dose, and duration of intervention, and we assessed the risk of bias within and across trials. RESULTS: We identified 18 publications based on 14 studies. Meta-analysis demonstrated that probiotic use decreased the incidence of atopic dermatitis (RR = 0.79 [95% CI = 0.71-0.88]). Studies were fairly homogeneous (I = 24.0%). The corresponding RR of IgE-associated atopic dermatitis was 0.80 (95% CI = 0.66-0.96). No appreciable difference emerged across strata, nor was there evidence of publication bias. CONCLUSIONS: This meta-analysis provided evidence in support of a moderate role of probiotics in the prevention of atopic dermatitis and IgE-associated atopic dermatitis in infants. The favorable effect was similar regardless of the time of probiotic use (pregnancy or early life) or the subject(s) receiving probiotics (mother, child, or both). PMID- 22441546 TI - Inhibiting protein biofouling using graphene oxide in droplet-based microfluidic microsystems. AB - Biofouling or adsorption of biomolecules onto surfaces in microfluidic devices limits the type of samples which can be handled. In this paper, we take advantage of the high adsorption capacity of graphene oxide (GO) for proteins as a strategy to limit biofouling, while preserving their activity for droplet-based lab-on chip applications. PMID- 22441547 TI - Pulmonary cysts of Birt-Hogg-Dube syndrome: a clinicopathologic and immunohistochemical study of 9 families. AB - Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling. PMID- 22441548 TI - Pathologic diagnosis of recurrent glioblastoma: morphologic, immunohistochemical, and molecular analysis of 20 paired cases. AB - To evaluate the prognostic value of the volume of residual viable tumor versus therapy-induced necrosis in resection material and the diagnostic value of ancillary tests in recurrent glioblastoma (GBM), we conducted a retrospective review of 20 patients whose initial and recurrent specimens were available. Recurrent GBMs were graded according to the extent of histopathologic parameters: recurrent tumor with high-grade, non-high-grade, and pure high-grade tumor components and therapy-related necrosis. We also examined MIB-1 labeling, isocitrate dehydrogenase 1 mutation, and epidermal growth factor receptor amplification in primary and recurrent GBMs. To evaluate patient outcomes according to clinical and pathologic parameters, a survival analysis was performed, and correlations between histopathologic parameters and each ancillary test were assessed. Among clinical parameters, age above 60 years was associated with decreased survival (P=0.022), but other clinical parameters showed no significant association with overall survival. Among the 3 histopathologic parameters, the extent of recurrent tumor, including high-grade and non-high grade components, revealed a significant association with overall survival (P=0.042), but neither the extent of pure high-grade components nor therapy related necrosis showed any prognostic value. MIB-1 labeling, isocitrate dehydrogenase 1 mutation, and epidermal growth factor receptor amplification were useful for the diagnosis of recurrent GBMs but showed no prognostic value. Our data suggest that histopathologic evaluation on the basis of tumor extent in resected recurrent GBM specimens may provide additional prognostic information on the survival of patients with recurrent GBM. PMID- 22441549 TI - Ultrafast soft-mode driven charge relocation in an ionic crystal. AB - Transient electron density maps of potassium dihydrogen phosphate (KH(2)PO(4), KDP) are derived from femtosecond X-ray powder diffraction patterns. Upon photoexcitation, the low-frequency TO soft mode is elongated impulsively and modulates the electronic charge distribution on the length scale of interatomic distances, much larger than the vibrational amplitude. The results demonstrate a charge transfer from the volumes around the P-atoms and K(+)-ions to those containing the O-HO units and a quadrupolar distortion of the K(+) charge distribution. This behavior reflects the interplay of nuclear motions and electric polarizations in the ionic crystal lattice. PMID- 22441550 TI - [Spontaneous change of malignancy of solid malignant tumors : statistical investigations of colorectal and pancreatic carcinoma]. AB - The distribution curves of grades of malignancy for colorectal carcinomas and pancreatic carcinomas have not been stable over the years and investigations have shown a clear variability in the temporal distribution. Colon carcinomas were found to diminish considerably in aggressiveness in different time periods and colorectal carcinomas were found to increase in aggressiveness in some years. However, the distribution curve of grades of malignancy varies in both carcinomas over time and this variation follows a random distribution. In contrast to colorectal carcinomas, pancreatic carcinomas have not been followed up for very long time periods. While the distribution curve of malignancy was unchanged in most countries an increase in malignancy was observed in two countries. For colorectal and pancreatic carcinomas increases in malignancy are linked to a highly significant decrease in the number of cancers with lowest grades of malignancy. Even though the exact nature of variations in these malignancy distribution curves is incompletely understood, these variations appear important for comparative outcome statistics in cancer therapy as the aggressiveness of these malignancies has a direct bearing on the overall prognosis. PMID- 22441551 TI - Ultrasound-guided and radiographic monitoring-assisted peripherally inserted central catheterization. PMID- 22441552 TI - Amphioxus genomics. PMID- 22441553 TI - The cephalochordate amphioxus: a key to reveal the secrets of nuclear receptor evolution. AB - The members of the nuclear receptor (NR) superfamily are transcription factors characterized by a particular mode of function, which is related to the conserved nature of their molecular structure. NR proteins usually contain a DNA-binding domain (DBD) and a ligand-binding domain (LBD) allowing them to directly bind to DNA and regulate target gene expression in a ligand-dependent manner. In this review, we are summarizing our current understanding of the NR diversity in the cephalochordate amphioxus, which represents the best available proxy for the last common chordate ancestor both in terms of morphology and genome organization. The amphioxus genome encodes 33 NRs, which is more than expected based on its phylogenetic position, with at least one representative of all major NR groups, excepting NR1E and NR1I/J. This elevated number of receptor genes shows that the amphioxus NR complement has experienced some secondary modifications that are most evident in the NR1H group, which is characterized by three members in humans and ten representatives in amphioxus. By highlighting specific examples of the NR repertoire, including the receptors for retinoic acid, thyroid hormone, estrogen and steroids as well as the bile acid and oxysterol receptors of the NR1H group, we are illustrating the functional diversity of these receptors in amphioxus. We conclude that the amphioxus NRs are valuable models for assessing the evolutionary interplay between receptors and their ligands and that more integrative and comparative approaches are required for assessment of the evolutionary plasticity of receptor-ligand interactions revealed by the studies of amphioxus NRs. PMID- 22441554 TI - A genome-wide view of transcription factor gene diversity in chordate evolution: less gene loss in amphioxus? AB - Previous studies of gene diversity in the homeobox superclass have shown that the Florida amphioxus Branchiostoma floridae has undergone remarkably little gene family loss. Here we use a combined BLAST and HMM search strategy to assess the family level diversity of four other transcription factor superclasses: the Paired/Pax genes, Tbx genes, Fox genes and Sox genes. We apply this across genomes from five chordate taxa, including B. floridae and Ciona intestinalis, plus two outgroup taxa. Our results show scattered gene family loss. However, as also found for homeobox genes, B. floridae has retained all ancient Pax, Tbx, Fox and Sox gene families that were present in the common ancestor of living chordates. We conclude that, at least in terms of transcription factor gene complexity, the genome of amphioxus has experienced remarkable stasis compared to the genomes of other chordates. PMID- 22441555 TI - CoBr2-TMTU-zinc catalysed-Pauson-Khand reaction. AB - A cobalt-TMTU complex, derived from the in situ reduction of CoBr(2) with Zn in the presence of TMTU, can catalyze Pauson-Khand reaction at a balloon pressure of CO, which enables the synthesis of structurally diverse cyclopentenones. This catalytic system works efficiently for both intermolecular and intramolecular PK reactions. PMID- 22441556 TI - Running injuries: is it a question of evolution, form, tissue properties, mileage, or shoes? PMID- 22441557 TI - Emerging perspectives related to quadriceps central activation deficits in patients with total knee arthroplasty. PMID- 22441558 TI - Interface modification of 8-hydroxyquinoline aluminium with combined effects in quasi-solid dye-sensitized solar cells. AB - In this paper, 8-hydroxyquinoline aluminium (Alq(3)) was used in interface modification of dye-sensitized solar cells (DSCs). Alq(3) was the first discovered interface modification material with combined effects of retarding charge recombination and Forster resonant energy transfer (FRET). Results of dark current curve and AC impedance showed that Alq(3) could retard charge recombination in DSCs. I-V curves showed that conversion efficiency increased with Alq(3) modification. Besides the interface modification effect, it was discovered that Alq(3) also acted as energy relay dye with the FRET effect between itself and N3, which increased photoresponse and electron injection. The application of Alq(3) with combined effects opened a new door to explore more novel multi-functional interface modification materials to improve the performance of DSCs. PMID- 22441559 TI - In vitro-induced response patterns of antileukemic T cells: characterization by spectratyping and immunophenotyping. AB - Myeloid leukemic cells can be induced to differentiate into leukemia-derived dendritic cells (DCleu) regaining the stimulatory capacity of professional DCs while presenting the leukemic antigen repertoire. But so far, the induced antileukemic T-cell responses are variable both in specificity and in efficacy. In an attempt to elucidate the underlying causes of different T-cell response patterns, T-cell receptor (TR) Vbeta chain rearrangements were correlated with the T cells corresponding immunophenotypic profile, as well as their proliferative response and cytolytic capacities. In three different settings, donor T cells, either human leukocyte antigen matched or mismatched (haploidentical), or autologous T cells were repeatedly stimulated with myeloid blasts or leukemia-derived DC/DCleus from the corresponding patients diseased from acute myeloid leukemia (AML). Although no significant differences in T-cell proliferation were observed, the T-cell-mediated cytolytic response pattern varied considerably and even caused blast proliferation in two cases. Spectratyping revealed a remarkable restriction (>75% of normal level) of the CD4+ or CD8+-TR repertoire of blast- or DC/DCleu-stimulated T cells. Although in absolute terms, DC/DCleu stimulation induced the highest grade of restriction in the CD8+ T-cell subset, the CD4+ T-cell compartment seemed to be relatively more affected. But most importantly, in vitro stimulation with DC/DCleu resulted into an identical TR restriction pattern (beta chain) that could be identified in vivo in a patient sample 3 months after allo-SCT. Thus, in vitro tests combining functional flow cytometry with spectratyping might provide predictive information about T cellular response patterns in vivo. PMID- 22441560 TI - [Multiple myeloma: current recommendations for imaging]. AB - CLINICAL/METHODICAL ISSUE: Imaging in monoclonal plasma cell disease serves to detect end organ damage, i.e., osteoporosis or bone destruction. Diffuse or circumscribed bone marrow infiltration without damage to mineralized bone is so far not regarded as end organ damage. STANDARD RADIOLOGICAL METHODS: Skeletal plain x-ray film survey to detect bone destruction, osteoporosis or fractures. METHODICAL INNOVATIONS: Whole body low-dose computed tomography (CT) and whole body magnetic resonance imaging (MRI) allow a more sensitive assessment of both mineralized bone and bone marrow, with greater patient comfort and in the case of MRI without ionizing radiation. PERFORMANCE: According to the literature, cross sectional imaging is clearly superior to skeletal surveys and MRI is more sensitive than CT. Every locally destructive lesion will be detectable with MRI but for assessing the damage to mineralized bone CT is indispensible. The sensitivities of positron emission tomography (PET)/CT and MRI are comparable. ACHIEVEMENTS: If available whole body MRI and whole body low dose CT should replace conventional skeletal surveys. This has already been implemented in several centers in Germany. PRACTICAL RECOMMENDATIONS: For the initial diagnosis of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma or symptomatic multiple myeloma, a whole-body MRI and a whole body low dose CT should be performed. For MGUS and asymptomatic myeloma, whole body MRI only should be performed for follow-up until detection of first bone destruction. Patients with symptomatic multiple myeloma and known bone destruction will usually have whole body low-dose CT, supplemented by MRI studies where clinically required. PMID- 22441561 TI - An inertia enhanced passive pumping mechanism for fluid flow in microfluidic devices. AB - We describe and characterize a pumping mechanism that leverages the momentum present in small droplets ejected from a micro-nozzle to drive flow in an open microfluidic device. This approach allows driving flow in a microfluidic device in a regime that offers unique features different to those achievable with typical passive pumping or syringe-pump driven flow. Two flow regimes with specific flow characteristics are described: inertia enhanced passive pumping, in which fluid exchange times in the channel are significantly reduced, and inertia actuated flow, in which it is possible to initiate flow in an empty channel or against natural pressure gradients. Momentum is leveraged to create rapid fluid exchanges, instantaneous flow reversal, filling and mixing inside the microfluidic device. PMID- 22441562 TI - Impact of deep extensor muscle-preserving approach on clinical outcome of laminoplasty for cervical spondylotic myelopathy: comparative cohort study. AB - INTRODUCTION: This study aimed to compare patients undergoing deep extensor muscle-preserving laminoplasty and conventional open-door laminoplasty for the treatment of cervical spondylotic myelopathy (CSM). We specifically assessed axial pain, cervical spine function, and quality of life (QOL) with a minimum follow-up period of 3 years. PATIENTS AND METHODS: Ninety patients were divided into two groups and underwent either conventional open-door laminoplasty (CL group) or laminoplasty using the deep extensor muscle-preserving approach (MP group). The latter approach was undertaken by preserving the multifidus and semispinalis cervicis attachments followed by open-door laminoplasty and resuturing of the bisected spinous processes at each decompression level. The mean follow-up period was 7.7 years (range, 36-128 months). Preoperative and follow-up evaluations included the Japanese Orthopaedic Association (JOA) score, a tentative version of the JOA Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) including cervical spine function and QOL, and a visual analog scale (VAS) for axial pain. Radiological analyses included cervical lordosis and flexion-extension range of motion (C2-7), as well as deep extensor muscle areas on axial magnetic resonance imaging (MRI). RESULTS: The mean number of decompressed laminae was 3.9 and 3.3 in CL and MP groups, respectively, which was statistically equivalent. Japanese Orthopaedic Association recovery was statistically equivalent between the two groups. The MP group demonstrated a superior QOL score (57 vs. 46%) compared with the CL group at final follow-up (p < 0.05). Mean VAS scores at final follow-up were 2.2 and 4.3 in MP and CL groups, respectively (p < 0.05). Cervical lordosis and flexion-extension range of motion were statistically equivalent. The percentage deep muscle area on MRI was significantly lesser in the CL group compared with the MP group (58 vs. 102%; p < 0.01). CONCLUSION: We demonstrated the superiority of deep extensor muscle preserving laminoplasty in terms of postoperative axial pain, QOL, and prevention of atrophy of the deep extensor muscles over conventional open-door laminoplasty for the treatment of CSM. PMID- 22441563 TI - The impact of change in volume and left-ventricular hypertrophy on left ventricular mechanical dyssynchrony in children with end-stage renal disease. AB - Left-ventricular dyssynchrony (LVD) adversely affects systolic performance and has not been previously evaluated in children with end-stage renal disease (ESRD). We hypothesized (1) that LVD in children with ESRD would be significantly increased compared with controls and (2) that volume load and left-ventricular hypertrophy (LVH) would be associated with increased LVD. This was a prospective observational study in which real-time three-dimensional echocardiographic data were acquired in 27 stable children with ESRD (13 peritoneal dialysis [PD] and 14 hemodialysis [HD]) and 29 normal controls. Data were acquired before and after an HD session. Dyssynchrony index (SDI) was defined per standard formulae and was normalized to cardiac cycle duration (SDIp). Left-ventricular mass (LVM) was obtained from M-mode echocardiography and was normalized to height(2.7) (LVM index). The mean age (13.8 vs. 11.3 years) and SDI, SDIp, LVM, and LVM index were significantly greater among children with ESRD than among controls (p < 0.05). Demographics and heart rates were comparable between HD and PD subgroups, whereas SDI 16 and 12 segments, SDIp 16 segments, and LVM were significantly greater in the HD group. SDI and SDIp 16 segments improved after an HD session (p < 0.05); LVM and LVM index remained unchanged. LVD was significantly greater in patients with LVH compared with those without LVH. Children with ESRD had significant LVD and increased LVM compared with controls. Increased LVD in those undergoing HD rather than PD, as well as the improvement in synchrony after HD, suggest that volume may modulate LVD. LVD was increased in children with LVH. LVD in children with ESRD may have pathogenic implications. PMID- 22441564 TI - Successful implantation of an intracardiac defibrillator in an infant with long QT syndrome and isolated noncompaction of the ventricular myocardium. AB - Congenital long QT syndrome (LQTS) is an inherited disorder characterized by QT prolongation and polymorphic ventricular tachycardia known as torsade de pointes. The underlying cellular mechanism is prolonged ventricular repolarization caused by mutations in genes encoding cardiac ion channels or membrane adaptors. The disease can be diagnosed at any age and, very rarely, it can be diagnosed prenatally or in the neonatal period. Isolated noncompaction of the ventricular myocardium (INCVM) is defined as the presence of prominent ventricular trabeculations and deep intertrabecular recesses within the endomyocardium. This report describes a newborn baby presenting with polymorphic ventricular tachycardia whose diagnosis was LQTS and INCVM. Ventricular tachycardia did not respond to medical treatment, and a transient epicardial pacemaker was inserted surgically on his 30th day of life for atrioventricular block and bradycardia. The transient epicardial pacemaker was upgraded to an epicardial intracardiac defibrillator on his 40th day. The concomitant occurrence of INCVM, LQTS, and atrioventricular block needs to be evaluated further. PMID- 22441565 TI - Octahedrality versus tetrahedrality in stoichiometric ceria nanoparticles. AB - We predict that tetrahedral Ce(n)O(2n) nanoparticles <2 nm in size become more stable than those experimentally observed at larger sizes with truncated octahedral morphologies, based on global optimisation and density functional calculations. PMID- 22441566 TI - Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis. AB - KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57%) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin. PMID- 22441567 TI - Antitumor activity of lobaplatin alone or in combination with antitubulin agents in non-small-cell lung cancer. AB - OBJECTIVE: Lobaplatin is used to treat patients with breast cancer, small-cell lung cancer, and chronic myelogenous leukemia in China. In this study, we assessed the in-vitro and in-vivo activities of lobaplatin alone or in combination with antitubulin agents against human non-small-cell lung cancer (NSCLC). METHODS: The cytotoxicities of lobaplatin against NSCLC cells were determined by the sulforhodamine B (SRB) assay. Cell cycle analysis and apoptosis were assessed using flow cytometry, and the in-vivo antitumor activities were evaluated in human NSCLC xenografts in nude mice. RESULTS: The cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with a mean IC(50) of 2.5 MUmol/l in a variety of NSCLC cells. In addition, lobaplatin arrested cells in the S phase and triggered apoptosis. The combination of lobaplatin with antitubulin agents yielded synergistic cytotoxic activity in vitro. In NSCLC xenografts, lobaplatin alone showed significant antitumor activity. The combination of lobaplatin with antitubulin agents, especially with paclitaxel, led to significantly enhanced activity, which was superior to that of cisplatin combined with antitubulin agents. CONCLUSION: These data demonstrate that the use of lobaplatin alone or in combination with antitubulin agents might be a rational and novel therapeutic strategy for human NSCLC and warrants further clinical investigation. PMID- 22441568 TI - Prasinoxanthin is absent in the green-colored dinoflagellate Lepidodinium chlorophorum strain NIES-1868: pigment composition and 18S rRNA phylogeny. AB - Green-colored plastids in the dinoflagellates Lepidodinium chlorophorum and L. viride have been widely believed as the remnant of an endosymbiotic prasinophyte. This hypothesis for the origin of the Lepidodinium plastids is solely based on an unpublished result quoted in Elbrachter and Schnepf (Phycologia 35:381-393, 1996) hinting at the presence of a characteristic carotenoid in prasinophytes, prasinoxanthin, in the L. chlorophorum cells. On the other hand, a recent work failed to detect prasinoxanthin in a culture of L. chlorophorum. Unfortunately, we cannot conduct any additional experiments to examine whether the two strains considered in the previous studies are truly of L. chlorophorum, as neither of the two strains is publicly available. We here investigated the pigment composition of L. chlorophorum strain NIES-1868 maintained as a mono-algal culture under laboratory conditions, and detected no sign of prasinoxanthin. The pigment composition of strain NIES-1868 is consistent with previous phylogenetic analyses based on plastid-encoded genes of the same strain, which successfully excluded prasinoxanthin-containing algae from the origin of the L. chlorophorum plastid. We also determined nucleus-encoded 18S ribosomal RNA (rRNA) genes from four Lepidodinium strains (including strain NIES-1868). Analyses of 18S rRNA sequences showed an extremely close relationship among strain NIES-1868 and other Lepidodinium cells/strains originating from different geological locations, suggesting that the cells/strains corresponding to these rRNA sequences lack prasinoxanthin. PMID- 22441569 TI - Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. AB - AIMS/HYPOTHESIS: The aim of the study was to investigate the timing of the appearance of autoantibodies associated with type 1 diabetes between birth and puberty, the natural fate of these autoantibodies and the predictive power of autoantibody concentrations for early progression to clinical diabetes. METHODS: Children were recruited to the Type 1 Diabetes Prediction and Prevention Project, an ongoing study based on HLA-conferred genetic risk. Autoantibodies against islet cells, insulin, GAD65 and islet antigen 2 were analysed at 3-12 month intervals, starting from birth. RESULTS: During the follow-up, 1,320 children (18.4% of the cohort of 7,165 children) were autoantibody positive in at least one sample. Altogether, 184 autoantibody-positive children progressed to type 1 diabetes. Seroconversion occurred at an early age in the progressors (median 1.5 years), among whom 118 (64%) and 150 (82%) seroconverted to autoantibody positivity before the age of 2 and 3 years, respectively. The incidence of seroconversion peaked at 1 year of age. Compared with other autoantibody-positive children, the median autoantibody levels were already markedly higher 3 to 6 months after the seroconversion in children who later progressed to diabetes. CONCLUSIONS/INTERPRETATION: Early initiation of autoimmunity and rapid increases in autoantibody titres strongly predict progression to overt diabetes before puberty, emphasising the importance of early life events in the development of type 1 diabetes. PMID- 22441570 TI - Application of surface enhanced Raman spectroscopy to the study of SOFC electrode surfaces. AB - SERS provided by sputtered silver was employed to detect trace amounts of chemical species on SOFC electrodes. Considerable enhancement of Raman signal and lowered detection threshold were shown for coked nickel surfaces, CeO(2) coatings, and cathode materials (LSM and LSCF), suggesting a viable approach to probing electrode degradation and surface catalytic mechanism. PMID- 22441571 TI - Enhanced bile canaliculi formation enabling direct recovery of biliary metabolites of hepatocytes in 3D collagen gel microcavities. AB - Analysis of biliary metabolites is essential to predict pharmacokinetics and hepatotoxicity during drug development. In this paper, we present a hepatocyte culture configuration that enables the direct recovery of bile acid that accumulates in bile canaliculi by embedding the hepatocytes in a 3D micropatterned collagen gel substrate. We investigated the formation of bile canaliculi in hepatocytes embedded in circular microcavities of various sizes and made from collagen gel. Image analyses using fluorescently labeled bile acid revealed that the area of bile canaliculi in embedded hepatocytes in a microcavity of 60 or 80 MUm in diameter was enlarged when compared with other sized microcavities and those of hepatocytes cultured using conventional hepatocyte sandwich cultures. We successfully recovered bile acid from the enlarged bile canaliculi of hepatocytes cultured in microcavities using a glass capillary and quantified the amount recovered. Using our approach, the direct recovery of biliary metabolites, using hepatocyte cultures with enhanced biliary excretion and geometrically enlarged bile canaliculi, may enable accurate screening of pharmacokinetics and drug-drug interactions against drug transporters. PMID- 22441572 TI - Effects of elevated CO2 on communities of denitrifying bacteria and methanogens in a temperate marsh microcosm. AB - The effects of elevated CO(2) on soil bacterial community with upland vegetation have been widely studied, but limited information is available regarding responses of denitrifier and methanogen communities to elevated CO(2) in wetland ecosystems. Using restriction fragment length polymorphism (RFLP), terminal RFLP analysis, and real-time quantitative PCR, we compared communities of denitrifiers and methanogens in a laboratory-scale wetland system planted with one of three macrophytes, Typha latifolia, Scirpus lacustris, or Juncus effusus, after 110 days of incubation. Our study showed that elevated CO(2) could affect community structures of both denitrifiers and methanogens, each of which had a unique response pattern. In particular, elevated CO(2) shifted nirS-containing community with a unique structure irrespective of vegetation type. mcrA-containing community appeared to shift to community with unique types of hydrogenotrophs under elevated CO(2) conditions. The change of dissolved organic carbon driven by elevated CO(2) appeared to be related with the shift of both denitrifiers and methanogens. Overall, this study indicates that elevated CO(2) could change the community structure of denitrifiers and methanogens temporarily. These results also suggest a presence of stable dominant populations that were not substantially affected by changes in CO(2) concentration. PMID- 22441573 TI - Cancer gene prioritization by integrative analysis of mRNA expression and DNA copy number data: a comparative review. AB - A variety of genome-wide profiling techniques are available to investigate complementary aspects of genome structure and function. Integrative analysis of heterogeneous data sources can reveal higher level interactions that cannot be detected based on individual observations. A standard integration task in cancer studies is to identify altered genomic regions that induce changes in the expression of the associated genes based on joint analysis of genome-wide gene expression and copy number profiling measurements. In this review, we highlight common approaches to genomic data integration and provide a transparent benchmarking procedure to quantitatively compare method performances in cancer gene prioritization. Algorithms, data sets and benchmarking results are available at http://intcomp.r-forge.r-project.org. PMID- 22441575 TI - Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. AB - Colistin is the last resort for treatment of multidrug-resistant Acinetobacter baumannii. Unfortunately, resistance to colistin has been reported all over the world. The highest resistance rate was reported in Asia, followed by Europe. The heteroresistance rate of A. baumannii to colistin is generally higher than the resistance rate. The mechanism of resistance might be loss of lipopolysaccharide or/and the PmrAB two-component system. Pharmacokinetic/pharmacodynamic studies revealed that colistin monotherapy is unable to prevent resistance, and combination therapy might be the best antimicrobial strategy against colistin resistant A. baumannii. Colistin/rifampicin and colistin/carbapenem are the most studied combinations that showed promising results in vitro, in vivo and in the clinic. New peptides showing good activity against colistin-resistant A. baumannii are also being investigated. PMID- 22441574 TI - Differentiating rectal carcinoma by an immunohistological analysis of carcinomas of pelvic organs based on the NCBI Literature Survey and the Human Protein Atlas database. AB - The treatments and prognoses of pelvic organ carcinomas differ, depending on whether the primary tumor originated in the rectum, urinary bladder, prostate, ovary, or uterus; therefore, it is essential to diagnose pathologically the primary origin and stages of these tumors. To establish the panels of immunohistochemical markers for differential diagnosis, we reviewed 91 of the NCBI articles on these topics and found that the results correlated closely with those of the public protein database, the Human Protein Atlas. The results revealed the panels of immunohistochemical markers for the differential diagnosis of rectal adenocarcinoma, in which [+] designates positivity in rectal adenocarcinoma and [-] designates negativity in rectal adenocarcinoma: from bladder adenocarcinoma, CDX2[+], VIL1[+], KRT7[-], THBD[-] and UPK3A[-]; from prostate adenocarcinoma, CDX2[+], VIL1[+], CEACAM5[+], KLK3(PSA)[-], ACPP(PAP)[-] and SLC45A3(prostein)[-]; and from ovarian mucinous adenocarcinoma, CEACAM5[+], VIL1[+], CDX2[+], KRT7[-] and MUC5AC[-]. The panels of markers distinguishing ovarian serous adenocarcinoma, cervical carcinoma, and endometrial adenocarcinoma were also represented. Such a comprehensive review on the differential diagnosis of carcinomas of pelvic organs has not been reported before. Thus, much information has been accumulated in public databases to provide an invaluable resource for clinicians and researchers. PMID- 22441576 TI - Low frequency of skin reactions in a cohort of patients on raltegravir. PMID- 22441577 TI - Variability of intestinal colonization with third-generation cephalosporin resistant Enterobacteriaceae and antibiotic use in intensive care units. AB - OBJECTIVES: Healthcare-associated infections due to third-generation cephalosporin-resistant Enterobacteriaceae (CRE) have become a major public health threat, especially in intensive care units (ICUs). We assessed and compared beta-lactam use, the prevalence of colonization with CRE at admission and the incidence of CRE acquisition across ICUs. PATIENTS AND METHODS: A cohort study was conducted in 10 ICUs of the Paris (France) metropolitan area between November 2005 and February 2006. Antibiotic use was recorded prospectively in all patients admitted during the study period. Rectal swabs were collected at admission, twice weekly thereafter, before beta-lactam prescription and before discharge. RESULTS: A total of 893 patients provided 3453 rectal swabs; 793 of the patients were newly admitted, mostly for medical reasons (80.7%). On admission, 74 patients (9.6%) were colonized with CRE, including 32 with an extended-spectrum beta-lactamase (ESBL)-producing strain. Among the remaining 694 naive patients, 94 acquired CRE during their follow-up, including 31 with an ESBL producing strain. Incidence rates of colonization ranged from 8.8 to 21.0/1000 patient-days for all CRE, and from 1.4 to 10.9/1000 patient-days for ESBL producers. A majority of patients (68.3%) were prescribed beta-lactams during their ICU stay, with defined daily doses ranging from 428 to 985/1000 patient days. Across ICUs, prescriptions of all antibiotics, beta-lactams and carbapenems were significantly correlated to incidence rates of colonization with ESBL producing CRE. CONCLUSIONS: The standardized and systematic follow-up of patients in 10 ICUs revealed great heterogeneity in the rates of colonization with ESBL- and non-ESBL-producing CRE, as well as in antimicrobial prescription practices. PMID- 22441578 TI - Characterization of beta-lactamase and porin mutants of Enterobacteriaceae selected with ceftaroline + avibactam (NXL104). AB - OBJECTIVES: Ceftaroline + avibactam (NXL104) is a novel inhibitor combination active against Enterobacteriaceae with class A and C beta-lactamases. We investigated its risk of mutational resistance. METHODS: Single- and multi-step mutants were sought and characterized from Enterobacteriaceae with extended spectrum beta-lactamases (ESBLs), AmpC beta-lactamases and KPC beta-lactamases. RESULTS: Overgrowth occurred on agar with low MIC multiples of ceftaroline + avibactam, but frequencies for single-step mutants were <10(-9). Most mutants were unstable, with only three remaining resistant on subculture. For one, from an CTX-M-15-positive Escherichia coli, the ceftaroline + avibactam MIC was raised, but the organism had reduced resistance to ceftaroline and lost resistance to other oxyimino-cephalosporins, with this profile retained when the mutant bla(CTX-M-15) was cloned into E. coli DH5alpha. Sequencing identified a Lys237Gln substitution in the CTX-M-15 variant. The other two stable single-step mutants were from an AmpC-derepressed Enterobacter cloacae strain; these had unaltered or slightly reduced resistance to other beta-lactams. Both had amino acids 213-226 deleted from the Omega loop of AmpC. Further stable mutants were obtained from AmpC-inducible and -derepressed E. cloacae in multi-step selection, and these variously had reduced expression of OmpC and OmpF, and/or Asn366His/Ile substitutions in AmpC. CONCLUSIONS: Stable resistant mutants were difficult to select. Those from AmpC-derepressed E. cloacae had porin loss or AmpC changes, including Omega loop deletions. A Lys237Gln substitution in CTX-M-15 conferred resistance, but largely abolished ESBL activity. PMID- 22441580 TI - Low-frequency electrotherapy for female patients with detrusor underactivity due to neuromuscular deficiency. AB - INTRODUCTION AND HYPOTHESIS: The aim of the study was to assess the efficacy of low-frequency electrotherapy (LFE) for female patients with early-stage detrusor underactivity (DUA) due to neuromuscular deficiency. METHODS: A total of 102 female patients were divided randomly into four groups: LFE-NC (normal compliance), LFE-LC (low compliance), CON (control)-NC and CON-LC. Patients in the LFE-NC and LFE-LC groups received LFE, and those in the CON-NC and CON-LC groups received conservative treatment. Urodynamic evaluation was performed before and after treatment. RESULTS: After treatment, 82 % of the LFE-NC regained detrusor contractility, whereas only 2 (8 %) of the CON-NC had normal detrusor contraction. None of LFE-LC or CON-LC regained detrusor contractility (p < 0.01). The per cent of LFE-NC who relied on catheterization for bladder emptying decreased by 43 % (p < 0.01). Those in the LFE-LC, CON-NC and CON-LC groups decreased by only 4, 12 or 0 % (p > 0.05). CONCLUSIONS: LFE was more effective for DUA patients with normal compliance; these patients benefited from LFE, but DUA patients with low compliance did not. PMID- 22441579 TI - Atorvastatin inhibits the inflammatory response caused by anti-M(3) peptide IgG in patients with primary Sjogren's syndrome. AB - Experimental and clinical investigations have revealed that statins can down regulate acute and chronic inflammatory processes. Whether statins express anti inflammatory activities in the salivary glands in patients with primary Sjogren's syndrome (pSS) is not known. The in vitro and in vivo effect of atorvastatin on rat submandibular gland treated with anti-M(3) peptide IgG purified from SS patients was studied. The anti-inflammatory effects of atorvastatin were assessed by measuring the levels of IL-1beta, PGE(2) and MMP-3 by ELISA. Atorvastatin inhibited the increase in the production of IL-1beta, PGE(2) and MMP-3 in submandibular glands treated with anti-M(3) peptide IgG. A positive correlation between IL-1beta production with accumulation of PGE(2) and MMP-3 was observed. Rats pre-treated orally with atorvastatin (30 mg kg(-1)) or vehicle (phosphate buffered solution) once a day for three consecutive days impaired the increment in the production of IL-1beta, PGE(2) and MMP-3 in the submandibular gland in the presence of anti-M(3) peptide IgG. In conclusion, the anti-inflammatory effects of atorvastatin are dependent upon inhibition of production of a pro-inflammatory cytokine (IL-1beta) and pro-inflammatory mediators such as PGE(2) and MMP-3. These data suggest that atorvastatin may constitute an anti-inflammatory effect in SS. PMID- 22441581 TI - Microvascular decompression on patients with trigeminal neuralgia caused by ectatic vertebrobasilar artery complex: technique notes. AB - BACKGROUND: Due to its anatomical features, the vertebrobasilar artery complex (VBA) seldom contributes to the neurovascular conflict in patient with trigeminal neuralgia (TN). However, once it offends the trigeminal root, this large artery is really difficult to manipulate during microvascular decompression (MVD) surgery. Therefore, the surgical strategy for such cases needs to be detailed in order to obtain a satisfactory outcome. METHODS: From 2009 through 2011, 475 consecutive TN patients underwent MVDs in our department. Among them, ten were found in which an ipsilateral deviating ectatic vertebrobasilar artery complex (VBA) offended the trigeminal nerve. Those cases were focused on in this study and each operation was analyzed retrospectively. RESULTS: During the operation, the vertebral artery was regarded as the direct culprit in six (60 %) patients, while the basilar artery in four (40 %). As companions, some smaller vessels were also observed to be close to the nerve, including the superior cerebellar artery (SCA) in five, veins in two and anterior inferior cerebellar artery (AICA) in two. The neurovascular conflict was discovered in the cisternal segment of the trigeminal root in eight, while in the root entry zone (REZ) in two. In six out of the ten cases, the affected nerves were demonstrated to be squeezed towards the tentorium by the ectatic VBA. Postoperatively, the symptom of pain totally disappeared immediately in eight (80 %) patients, while it was relieved apparently in two (20 %). During the follow-up period of 3-30 months, no recurrence or complication was found, except for one patient who had numbness of the face. CONCLUSION: With a proper strategy, MVD is probably the most effective therapy for the TN cases caused by ectatic vertebrobasilar artery complex. The substance of the surgery is to withdraw the proximal vertebral artery caudally via a lateroinferior cerebellar approach. PMID- 22441582 TI - Longitudinal imaging of Alzheimer pathology using [11C]PIB, [18F]FDDNP and [18F]FDG PET. AB - PURPOSE: [(11)C]PIB and [(18)F]FDDNP are PET tracers for in vivo detection of the neuropathology underlying Alzheimer's disease (AD). [(18)F]FDG is a glucose analogue and its uptake reflects metabolic activity. The purpose of this study was to examine longitudinal changes in these tracers in patients with AD or mild cognitive impairment (MCI) and in healthy controls. METHODS: Longitudinal, paired, dynamic [(11)C]PIB and [(18)F]FDDNP (90 min each) and static [(18)F]FDG (15 min) PET scans were obtained in 11 controls, 12 MCI patients and 8 AD patients. The mean interval between baseline and follow-up was 2.5 years (range 2.0-4.0 years). Parametric [(11)C]PIB and [(18)F]FDDNP images of binding potential (BP(ND)) and [(18)F]FDG standardized uptake value ratio (SUVr) images were generated. RESULTS: A significant increase in global cortical [(11)C]PIB BP(ND) was found in MCI patients, but no changes were observed in AD patients or controls. Subsequent regional analysis revealed that this increase in [(11)C]PIB BP(ND) in MCI patients was most prominent in the lateral temporal lobe (p < 0.05). For [(18)F]FDDNP, no changes in global BP(ND) were found. [(18)F]FDG uptake was reduced at follow-up in the AD group only, especially in frontal, parietal and lateral temporal lobes (all p < 0.01). Changes in global [(11)C]PIB binding (rho = -0.42, p < 0.05) and posterior cingulate [(18)F]FDG uptake (rho = 0.54, p < 0.01) were correlated with changes in Mini-Mental-State Examination score over time across groups, whilst changes in [(18)F]FDDNP binding (rho = 0.18, p = 0.35) were not. CONCLUSION: [(11)C]PIB and [(18)F]FDG track molecular changes in different stages of AD. We found increased amyloid load in MCI patients and progressive metabolic impairment in AD patients. [(18)F]FDDNP seems to be less useful for examining disease progression. PMID- 22441583 TI - Measuring steady-state oxygen uptake during the 6-min walk test in adults with cerebral palsy: feasibility and construct validity. AB - This study evaluated the feasibility of measuring steady-state oxygen uptake (VO2) during the 6-min walk test (6MWT) in adults with cerebral palsy (CP) who walk without support and whether there is construct validity for net 6MWT VO2 as a measure of their walking ability. Cardiorespiratory variables were assessed at rest and during the 6MWT in 15, independently ambulatory adults, 21-41 years old, with CP. The Gross Motor Function Measure dimensions D and E (GMFM-D and GMFM-E) quantified walking-related skills. Steady-state VO2 was achieved during the 6MWT. After controlling for body mass and speed, the net 6MWT VO2 was strongly related to GMFM-D (r=-0.58, rho=0.03) and GMFM-E scores (r=-0.66, rho=0.007). We conclude that for young adults with CP who walk without support, it is feasible to measure steady-state VO2 during the 6MWT and that the net 6MWT VO2 has construct validity as a measure of walking ability. PMID- 22441584 TI - Palladium-catalyzed deamidative arylation of azoles with arylamides through a tandem decarbonylation-C-H functionalization. AB - A highly chemo-, regio-selective, and efficient palladium-catalyzed deamidative arylation of azoles with arylamides, as an aryl metal equivalent, has been developed. The reaction proceeds smoothly to generate the corresponding products in good yields via a tandem decarbonylation-C-H activation. PMID- 22441585 TI - Hepatic lipid composition differs between ob/ob and ob/+ control mice as determined by using in vivo localized proton magnetic resonance spectroscopy. AB - OBJECT: Hepatic lipid accumulation is associated with nonalcoholic fatty liver disease, and the metabolic syndrome constitutes an increasing medical problem. In vivo proton magnetic resonance spectroscopy ((1)H MRS) allows the assessment of hepatic lipid levels noninvasively and also yields information on the fat composition due to its high spectral resolution. MATERIALS AND METHODS: We applied (1)H MRS at 9.4T to study lipid content and composition in eight leptin deficient ob/ob mice as a model of obesity and in four lean ob/+ control mice at 24 weeks of age. PRESS sequence was used. For accurate estimation of signal intensity, differences in relaxation behavior of individual signals were accounted for each mouse individually. Also, in order to minimize spectral degrading due to motion artifacts, respiration gating was applied. RESULTS: Significant differences between ob/ob and ob/+ control mice were found in both lipid content and composition. The mean chain length was found to be significantly longer in ob/ob mice with a higher fraction of monounsaturated lipids. CONCLUSION: (1)H MRS enables accurate assessment in hepatic lipids in mice, which is attractive for mechanistic studies of altered metabolism given the large number of genetically engineered mouse models available. PMID- 22441586 TI - FTEC: a coalescent simulator for modeling faster than exponential growth. AB - SUMMARY: Recent genetic studies as well as recorded history point to massive growth in human population sizes during the recent past. To model and understand this growth accurately we introduce FTEC, an easy-to-use coalescent simulation program capable of simulating haplotype samples drawn from a population that has undergone faster than exponential growth. Samples drawn from a population that has undergone faster than exponential growth show an excess of very rare variation and more rapid LD decay when compared with samples drawn from a population that has maintained a constant size over time. AVAILABILITY: Source code for FTEC is freely available for download from the University of Michigan Center for Statistical Genetics Wiki at http://genome.sph.umich.edu/wiki/FTEC PMID- 22441587 TI - Disseminated Cryptococcus with ocular cryptococcoma in a human immunodeficiency virus-negative patient. AB - A human immunodeficiency virus-negative 63-year-old male with autoimmune hemolytic anemia presented with decreased vision, photophobia and hearing loss. After initial testing seemed consistent with sarcoidosis, he was found to have disseminated Cryptococcus with a cryptococcoma of the left eye. Treatment with systemic anti-fungal therapy improved the patient's condition. PMID- 22441588 TI - A case of ectopic cilia in nail-patella syndrome. AB - Both ectopic cilia and nail-patella syndrome (NPS) are rare entities. To our knowledge we report the first case of the two anomalies coexisting in one patient. We present the case of a 2-year-old girl, with no other ophthalmic complication of NPS, who had an excellent cosmetic outcome and no lesion recurrence following surgical excision of ectopic cilia. PMID- 22441590 TI - Publications in the field of Agrarian Sciences in the Anais da Academia Brasileira de Ciencias: what next? PMID- 22441589 TI - The hidden function of photosynthesis: a sensing system for environmental conditions that regulates plant acclimation responses. AB - Plants convert light energy from the sun into chemical energy by photosynthesis. Since they are sessile, they have to deal with a wide range of conditions in their immediate environment. Many abiotic and biotic parameters exhibit considerable fluctuations which can have detrimental effects especially on the efficiency of photosynthetic light harvesting. During evolution, plants, therefore, evolved a number of acclimation processes which help them to adapt photosynthesis to such environmental changes. This includes protective mechanisms such as excess energy dissipation and processes supporting energy redistribution, e.g. state transitions or photosystem stoichiometry adjustment. Intriguingly, all these responses are triggered by photosynthesis itself via the interplay of its light reaction and the Calvin-Benson cycle with the residing environmental condition. Thus, besides its primary function in harnessing and converting light energy, photosynthesis acts as a sensing system for environmental changes that controls molecular acclimation responses which adapt the photosynthetic function to the environmental change. Important signalling parameters directly or indirectly affected by the environment are the pH gradient across the thylakoid membrane and the redox states of components of the photosynthetic electron transport chain and/or electron end acceptors coupled to it. Recent advances demonstrate that these signals control post-translational modifications of the photosynthetic protein complexes and also affect plastid and nuclear gene expression machineries as well as metabolic pathways providing a regulatory framework for an integrated response of the plant to the environment at all cellular levels. PMID- 22441591 TI - A note on the connectedness locus of the families of polynomials P(c)(z)=z(n) - cz(n-j). AB - Let j be a positive integer. For each integer n > j we consider the connectedness locus M(n) of the family of polynomials P(c)(z)=z(n) - cz(n-j), where c is a complex parameter. We prove that lim n->infinity M(n) = D in the Hausdorff topology, where D is the unitary closed disk {c;|c|<=1}. PMID- 22441592 TI - Preparation and evaluation of a biomimetic scaffold with porosity gradients in vitro. AB - A novel biodegradable scaffold based on mimetic a natural bone tissue morphology with a porosity gradient structure was prepared in this paper. The result of surface morphology indicated that a graded porous structure was formed in the fabricated scaffold, where the dense layer (0%) was connected with the most porous layer (60%) by a middling porous layer (30%). To evaluate the degradability, graded porous scaffolds compared with homogeneous scaffolds were placed into a Tris-HCl buffer solution (pH = 7.4) for 28 days. It was found that both scaffolds presented the same degradation trend, and the graded porous structure did not change the original degradability of the scaffold. Moreover, the compressive strength of the graded porous scaffold was better than that of conventional homogeneous scaffold with the increase of degradation time, and the graded porous structure can enhanced the mechanical property of the scaffold. These findings suggest that this biodegradable and porosity-graded scaffold may be a new promising scaffold for loaded bone implant. PMID- 22441593 TI - Inventory of the Sponge Fauna of the cemiterio Paleolake, Catalao, Goias, Brazil. AB - The Cemiterio Paleolake, Catalao, Goias, is a lacustrine deposit that is rich in spicules of continental sponges. These spicules, which are present in three sections (1-3), were analyzed for the taxonomic identification of the species in order to reconstruct the late Quaternary palaeoenvironment. An indigenous assemblage of lentic sponges was found, consisting of Metania spinata (Carter 1881), Dosilia pydanieli Volkmer-Ribeiro (1992), Radiospongilla amazonensis Volkmer-Ribeiro and Maciel (1983), Trochospongilla variabilis Bonetto and Ezcurra de Drago (1973), Corvomeyenia thumi (Traxler 1895), Heterorotula fistula Volkmer Ribeiro and Motta (1995), plus Corvoheteromeyenia australis (Bonetto and Ezcurra de Drago 1966), which here has its first record in an assemblage formed by biosiliceous deposits. Furthermore, at the base of the sections, spicules of sponges from lotic environments were detected, including Corvospongilla seckti Bonetto and Ezcurra de Drago (1966), Oncosclera navicella (Carter 1881) and Eunapius fragilis (Leidy 1851), which suggests a contribution from flowing water. We identified 25 spongofacies horizons caused by sponge assemblages typical of a lentic environment, dated from at least 39,700 years BP., and currently occurring in lakes typical of the Cerrado Biome. PMID- 22441594 TI - Quantification and classification of the main environmental impacts on a Halodule wrightii seagrass meadow on a tropical island in northeastern Brazil. AB - Multiple stress mechanisms have caused a worldwide decrease in seagrasses, which are vulnerable to environmental and/or anthropogenic pressure. The loss of seagrass meadows of Halodule wrightii is reported for the littoral of Itamaraca Island (Northeastern Brazil). The present study identified the main anthropogenic factors that negatively influenced over the abundance and distribution of seagrass meadows between July and September 2007 at the Jaguaribe and Pilar Beaches, Eastern littoral of Itamaraca. Anthropogenic impact included the discharge of untreated sewage through fluvial channels, urban and commercial development along the coast, the anchoring of motorized and non-motorized boats, diverse fishing techniques and the dumping of solid waste. The data indicates that the Pilar is an environment with a higher impact index (71.43%) when compared with the Jaguaribe (57.14%), standing out the number of boats with a central motor, the total number of boats, the presence of shellfish gatherers and coastal urban development. The present study reinforces the need for defining management and conservation measures for this ecosystem, which has high ecological and economic value. PMID- 22441595 TI - Dispersal syndromes of fossil seeds from the Lower Permian of Parana Basin, Rio Grande do Sul, Brazil. AB - The morphological analysis of seeds has been an important subject in modern ecological studies, once it provides evidence about the biology and adaptations of the parent plant. However, this kind of study has been restricted to the ecology of modern plants and is rarely used in interpretations of Paleozoic data. From the understanding of dispersal syndromes analysis as an important tool to paleoecological reconstruction, this study provides a first approach using this tool with seeds from the Lower Permian strata of southern Parana Basin in Rio Grande do Sul. Based on previously classified seeds and using their biological and taphonomic data, the syndrome of dispersal was interpreted, and their placement in successional groups (pioneer, early-successional and later successional) was suggested. Seven morphospecies were analyzed: Samaropsis gigas, representing a later-successional species living in water bodies with hydrochory as its dispersal syndrome; Samaropsis kurtzii, typical of early-successional species showing anemochory as its dispersal syndrome and living in distal areas in relation to water bodies; Samaropsis aff. S. millaniana, Cordaicarpus aff. C. brasilianus, Cordaicarpus cerronegrensis and Cordaicarpus truncata have typical characteristics of pioneer plants, exhibiting barochory as their primary dispersal syndrome with other syndromes associated. PMID- 22441596 TI - The impacts of land use changes in the mercury flux in the Madeira River, Western Amazon. AB - Changes in hydrochemistry and Hg distribution in the Madeira River from Porto Velho to the confluence with the Amazon River were studied in two cruises in 1997 and 2002. Water conductivity was similar in both periods, but the pH was significantly higher in 2002, in particular along the middle reaches of the river. Total suspended matter concentrations also increased from 1997 to 2002 along the same river portion, which is a result of forest conversion to other land uses, in particular pastures and agriculture accelerated during the interval between the cruises. Dissolved Hg concentrations were similar along the river in both cruises, but particulate Hg concentrations increased significantly along the middle portion of the river, although the suspended matter from 2002 was relatively poorer in Hg compared to that from 1997. Since particulate Hg represents more than 90% of the total Hg present in the river water, there was a significant increase in the total Hg transport in the Madeira River. Although gold mining has nearly ceased to exist in the region, the remobilization of Hg from forest soils through conversion to other land uses is responsible for maintaining relatively high Hg content in the Madeira River environment. PMID- 22441597 TI - Redescription of Tijubina pontei, an Early Cretaceous lizard (Reptilia; Squamata) from the Crato Formation of Brazil. AB - The record of Gondwanan Mesozoic lizards is very poor. Among the few species described for this region there is Tijubina pontei, an Early Cretaceous lizard from the Crato Formation (late Aptian) of northeast Brazil. Its description is very brief and lacks most of its diagnostic characters and clear delimitation from other lizard species. Here, a full redescription of the holotype is provided. T. pontei is demonstrated to be a valid species and a new diagnosis is provided with reference to Olindalacerta brasiliensis, a contemporary species of the Crato Formation. It lacks the posteroventral and posterodorsal processes of the dentary; the tibial/fibular length equals the femoral length and its posterior dentary teeth are robust, cylindrically based, unsculptured and bear no cuspids. The systematic position of T. pontei still needs further clarification, but preliminary analyses indicate that it lies in a rather basal position among the Squamata, similarly to O. brasiliensis. PMID- 22441598 TI - Abundance and instantaneous transport of Petrolisthes armatus (Gibbes, 1850) planktonic larvae in the Catuama inlet, Northeast Brazil. AB - The influence of tidal and diel changes on the exchange of Petrolisthes armatus planktonic larvae was studied at the Catuama inlet, which represents an intermediate system of marine and estuarine environments in the Northeast Brazil. To characterize the larval abundance and vertical distribution, samplings were carried out in August 2001 at neap tide and 3 stations, with 3 hours interval over 24 hours. Samples were taken at three or two depths at each station, with a plankton pump coupled to a 300 um mesh size net. Petrolisthes armatus zoea I and II showed a mean of 26.3 +/- 83.6 and 12 +/- 38.8 ind m-3, respectively. During flood tides, the larvae were more concentrated in the midwater and surface, which avoided the transport to internal regions. In contrast, during ebb tides when the larvae were distributed in the three layers, the higher concentrations were found in the bottom, which avoided a major exportation. The diel dynamic of the larval fluxes was characterized by vertical migration behavior associated to the tidal regime, which suggested that the development of this decapod apparently occurs in the inner shelf (instead of the outer shelf) off this peculiar ecosystem. PMID- 22441599 TI - Reproduction and structure of the population of the Chaetognath Parasagitta friderici in Guanabara Bay (Brazil) based on short term sampling. AB - The aim of this study was to describe the total density, densities of developmental stages and the reproduction period of Parasagitta friderici. Weekly samples were collected at one station in the channel of Guanabara Bay, Rio de Janeiro, during one year. Three vertical hauls were made for each sample, and P. friderici was separated, the developmental stages were identified, and body length (BL), ovary length (OL) and seminal vesicle width (SVW) were measured. Throughout the year P. friderici was the most abundant chaetognath species occurring in all four developmental stages, the densities of which varied from week to week. Higher densities of adults occurred in the spring, followed by peaks of juveniles in the summer. Although P. friderici seems to reproduce continuously in Guanabara Bay, a reproductive peak was apparent during the spring. The intensification of reproduction during the spring, with juveniles occurring in the summer, seems to be related to the period of higher food supply during the rainy season and intrusions of the South Atlantic Central Water. PMID- 22441600 TI - Gastroprotective effect of Byrsonima sericea DC leaf extract against ethanol induced gastric injury and its possible mechanisms of action. AB - Byrsonima sericea leaves are extensively used in folk medicine in Brazil against gastric disorders. This study investigated the chemical constituents of B. sericea leaf ethanolic extract (BSLE) and its potential gastroprotective activity, with its possible mechanism of the action using ethanol to induce gastric mucosal damage in mice. The phytochemical analysis was carried out to identify the active constituents present in the extract, and the HPLC analysis was performed for the identification of flavonoids. BSLE at oral doses of 125, 250 and 500 mg/kg markedly attenuated the ethanol-evoked gastric lesions by 53.2, 84.9 and 87.6 %, respectively. The BSLE (250 mg/kg) prevented the depletion of gastric mucus and gastric mucosal nonproteic-sulfhydryl groups, SOD and CAT, as well as the increase in the MDA content promoted by absolute ethanol. Moreover, the effect of BSLE against ethanol damage was found to be significantly reduced in mice pretreated with Capsazepine (i.p.), L-NAME (i.p.) or glibenclamide (i.p.), the respective blockers/inhibitors of TRPV1, NO synthase and K+ATP channel. The phytochemical investigation on BSLE revealed the presence of flavonoids rutin, isoquercitrin, kaempferol 3-O-rutinoside and quercetin, which are compounds well known for their antioxidant and gastroprotective properties. These results suggest that BSLE affords gastroprotection through multiple mechanisms, which may be helpful in the treatment of pathologies associated with gastric dysfunctions. PMID- 22441601 TI - Mercury in the sea turtle Chelonia mydas (Linnaeus, 1958) from Ceara coast, NE Brazil. AB - Mercury concentrations in carapace fragments of the green turtle Chelonia mydas from the Ceara coast in NE Brazil are reported. Concentrations varied from <0.34 to 856.6 ng.g(-1) d.w., and were highest (average of 154.8 ng.g(-1) d.w.) in juveniles (n = 22), whereas lowest concentrations (average of 2.5 ng.g(-1) d.w.) were observed in adult/sub-adult animals (n = 3). There was a significant negative correlation between animal size and Hg concentration probably due to different diets between juveniles and sub-adults/adults. Carapace fragments, which are non-invasive, non-lethal substrates, may be of importance for monitoring purposes of these generally endangered species. PMID- 22441602 TI - Population ecology of the blue crab Callinectes danae (Crustacea: Portunidae) in a Brazilian tropical estuary. AB - This paper aims at describing the population ecology of the swimming crab Callinectes danae Smith, 1869 in one of the most productive estuaries of Brazil, the Santa Cruz Channel. These crabs were monthly collected from January to December/2009 at four stations along the channel, two in the upper and two in the lower estuary. A total of 2373 specimens of C. danae were collected during the study. Males had a larger average carapace width than non-ovigerous females (60.0 +/- 15.6 mm and 52.9 +/- 12.4 mm, respectively), an adaptation that gives greater protection for females during the copulation. Overall sex ratio did not differ significantly from 1:1. However, evaluating sex-ratio by sampling area, males and juveniles of both sexes occurred preferentially in the upper estuary (p < 0.05), while adult females, including ovigerous, inhabited the lower estuary, an area of major marine influence (p < 0.05). While juveniles look for estuarine waters due to the benefit from the shelter and abundance of food, ovigerous females migrate to areas of greater depth and higher salinity in order to provide a more favorable environment for embryonic and larval development and to enhance larval dispersal. Recruitment of juveniles was continuous along the year, but intensified from March to June and, with less intensity, from October to December. PMID- 22441603 TI - Micropropagation, antinociceptive and antioxidant activities of extracts of Verbena litoralis Kunth (Verbenaceae). AB - This work describes an efficient micropropagation protocol for Verbena litoralis and the study of the antinociceptive and antioxidant activities in extracts of this species. For the establishment in vitro, surface-sterilization procedures and PVPP showed high efficiency in fungal-bacterial contamination and phenol oxidation controls. Nodal segments cultivation in MS medium supplemented with 6 benzyladenine (7.5 uM)/alpha-naphthaleneacetic acid (NAA; 0.005 uM) induced multiple shoots. Elongated shoots were rooted with IAA (0.2 uM). Acclimatization rates were elevated and the plants showed the typical features of this species. The hexanic fraction (HF) of powdered leaves presented a radical scavenging activity with IC(50) = 169.3 ug mL(-1). HF showed a non-dose dependent analgesic activity in the writhing test; its antinociceptive activity in the hot plate test was restricted to 500 mg kg(-1), which is the highest dose. The results of this study showed the potential of tissue culture on conservation and large scale multiplication and confirmed the traditional folk medicine use of V. litoralis. PMID- 22441604 TI - Assessment of Duguetia furfuracea genotoxic and cytotoxic activity in bacteria and mice. AB - Duguetia furfuracea (St. Hil.) Benth & Hook f. (1862), popularly known as "sofre do-rim-quem-quer" and "araticum-seco", is a shrub of the Annonaceae family that occurs in several regions of Brazil. In folk medicine the infusion of its leaves and twigs is used to treat rheumatism and renal colic, whereas the seed powder is mixed with water to treat pediculosis. Previous studies have described biological activities of this plant with cytotoxic, antitumoral, trypanocidal, leishmanicidal, antiplasmodial and antiprotozoal effects. In the present work, genotoxicity and cytotoxicity of Duguetia furfuracea lyophilized leaf extract were evaluated using the prophage lambda induction test (SOS-Inductest) and mouse bone marrow micronucleus test. Our results showed that Duguetia furfuracea lyophilized leaf extract did not present an increase either in the induction of prophage lambda (P>0.05) using the SOS-inductest or in the micronucleated polychromatic erythrocytes (P>0.05) using the micronucleus test, suggesting absence of genotoxicity in both tests. On the other hand, a significant decrease in the number of bacteria, (P<0.05), as well as a significant decrease in the polychromatic erythrocytes and normochromatic erythrocytes ratio, (P<0.05), were observed, showing the cytotoxic action of Duguetia furfuracea lyophilized leaf extract. Thus, Duguetia furfuracea did not present the genotoxic action, but showed a cytotoxic effect in both assays utilized in the present work. PMID- 22441605 TI - Prey selectivity of the octocoral Carijoa riisei at Pernambuco, Brazil. AB - This study was designed to evaluate prey selection (type and size) by the octocoral Carijoa riisei at Porto de Galinhas beach, Northeast Brazil, relating prey availability in plankton with the content inside polyps. Diatoms and cyanophytes were the predominant items found in both polyp gastric cavity and plankton. A correlation between prey abundance in the plankton and in the gastric cavity of C. riisei polyps was observed. Mastogloia sp. showed the highest positive electivity index (0.99). Benthonic items were found, with 0.51% of total consumed preys. The size amplitude of prey items in the plankton was similar to those found inside the polyps, although the mean prey size in the polyps (112.7 um) was significantly lower than the value found in the plankton (240.5 um). Thus, the study indicates some size selectivity in this species or at least size limitation. From the results, we concluded that the octocoral C. riisei is an opportunistic polyphagous species in the Brazilian northeast coast, showing suspensivorous passive filtering feeding habit with a preference for small prey items and evidencing its important ecological role in the reefal ecosystem as responsible for bidirectional energy transference between pelagic zones and the benthos. PMID- 22441606 TI - A new species of Sarax Simon, 1892 from the Philippines (Arachnida: Amblypygi: Charinidae). AB - A new species of the genus Sarax Simon, 1892 is described from Panay Island, Philippines. Sarax curioi sp. n. is the second species of the genus from the country and can be distinguished from the other Philippine species (Sarax brachydactylus Simon, 1892) by the sclerotized granules of the pedipalp surface, the spines of the pedipalp distitibia, the number of denticles of the chelicerae claw and the shape of the denticles of the chelicerae basal segment. Sarax newbritainensis Rahmadi and Kojima, 2010 is newly recorded from New Ireland Island, Papua New Guinea. PMID- 22441607 TI - Glutathione redox cycle in small intestinal mucosa and peripheral blood of pediatric celiac disease patients. AB - The celiac disease is an autoimmune gastrointestinal disorder caused by gluten from wheat, rye or barley. In genetically predisposed persons, gluten induces the immune-mediated inflammation of small intestinal mucosa. Histological lesions include intraepithelial lymphocytosis, crypt hypertrophy and villous atrophy, resulting in malabsorption of micro- and macronutrients. The only treatment for celiac patients is a permanent gluten-free diet (GFD). Reactive oxygen species (ROS) and oxidative stress are strongly associated with the celiac disease. Glutathione (GSH) is a main detoxifier of endogenous and exogenous ROS in the intestine. In order to explain the role of glutathione redox cycle in celiac patients, we examined the activities of GSH-related antioxidant (AO) enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the concentration of GSH in small intestinal biopsies and peripheral blood of children affected by the celiac disease. The concentration of lipid hydroperoxides (LOOH) as markers of oxidative damage was measured in the same samples. The results clearly demonstrate a significant malfunction of GSH redox cycle with a concomitant decrease in the capacity to regenerate GSH and detoxify LOOH in celiac patients, even after several years of GFD. The oral administration of GSH and a diet rich in natural antioxidants, as well as appropriate dietary supplements, could be of great benefit to the patients. PMID- 22441608 TI - A brief report on some health aspects of rats fed with crescent levels of recombinant chagasin, a potential plant defense protein. AB - Chagasin may be considered a potential plant-incorporated protectant (PIP) protein due to its deleterious effects on insect pests. However, extensive safety studies with PIP's are necessary before introducing them into the target plant. Thus, a short-term feeding trial in rats with high doses of r-chagasin was conducted to provide evidences about its safety. Three test diets containing casein + r-chagasin (0.25, 0.5 and 1% of total protein) were offered to rats (10 days). The test diets did not show adverse effects upon the development, organ weight, hematological parameters and serum protein profiles of rats, providing preliminary information on the safety of r-chagasin. PMID- 22441609 TI - Germination of Croton urucurana L. seeds exposed to different storage temperatures and pre-germinative treatments. AB - The present work evaluated the germinability and vigor of Croton urucurana seeds. 1) Seeds were sorted by color (caramel, gray and black) and were subjected to seven different pre-germination treatments followed by incubation at 20oC, 25 degrees C or 20/30 degrees C. 2) Seeds were stored in cold chambers or at room temperature for up to 300 days and were subsequently incubated at 20/30oC in a germination chamber or under greenhouse conditions. Only gray seeds showed significant germination rates. The highest first count percentages of total germination and the highest germination speed indices were observed in control seeds and in those which were treated with water or 200 mg.L(-1) gibberellic acid for 12 hours. Seeds stored under refrigeration showed the highest values for all of the characteristics examined, as well as less electrical conductivity of the imbibing solution. Seedlings were more vigorous when seeds were stored for 300 days in a cold chamber. The seedlings production can be increased by incubating the seeds at alternating temperatures (20/30 degrees C). The seeds do not need pre-germination treatments. PMID- 22441610 TI - Trichomes and hydrocarbons associated with the tomato plant antixenosis to the leafminer. AB - The objective of this work was to study the density of trichomes and hydrocarbons associated with the resistance by antixenosis of 42 subsamples of tomato plants from the Horticultural Germplasm Bank of the Universidade Federal de Vicosa (HGB UFV) to Liriomyza trifolii. These subsamples were studied in addition to 'Santa Clara' cultivar, which was used as a standard of susceptibility to leafminers. The evaluated characteristics were the number of mined leaflets per plant, mines per plant, trichome density and chemical compounds in the leaves. Differences were detected among the subsamples in the variables studied. We identified 20 peaks in the chromatograms of leaf hexane extract the subsamples tested. The subsamples HGBs - 216, 813, 985, 987, 991, 992, 993, 1532, 1989, 1991, 2048, 2055, 2064, 2068, 2073, 2075, 2089, 2096 and 2097 were selected as sources of resistance to L. trifolii. The resistance mechanism associated to these subsamples was antixenosis. In addition, the low density of trichomes and the chemical compounds in the subsamples can be possible causes of pest resistance. PMID- 22441611 TI - Effects of light intensity on the distribution of anthocyanins in Kalanchoe brasiliensis Camb. and Kalanchoe pinnata (Lamk.) Pers. AB - This paper compares two medicinal species of Kalanchoe, which are often used interchangeably by the population, regarding the distribution of anthocyanins under the influence of four luminosity levels for 6 months. For the morphoanatomical analysis, the 6th stem node of each plant was sectioned. Usual histochemical tests revealed the presence of anthocyanins by cross sections of the stems, petioles and leaf blades. The petioles and leaf blades were submitted to the extraction with acidified methanol, and the anthocyanins were quantified by spectrophotometric readings. At the macroscopic level, it was noticed for both species a higher presence of anthocyanins in stems and petioles of plants under full sunlight. The microscopy of K. brasiliensis stems evidenced the deposition of anthocyanins in the subjacent tissue to the epidermis and cortex, which increased with light intensity. In K. pinnata a subepidermal collenchyma was observed, which interfered in the visualization of anthocyanins. In petioles and leaf blades of K. brasiliensis the deposition of anthocyanins was peripheral, and in K. pinnata it was also throughout the cortex. The quantification of anthocyanins in petioles showed in 70% of light higher averages than in 25%, but in leaf blades there were no significant results. This study contributes to the pharmacognosy of Kalanchoe and it is sustained by the description of flavonoids as biological markers of the genus. PMID- 22441612 TI - Mining method selection by integrated AHP and PROMETHEE method. AB - Selecting the best mining method among many alternatives is a multicriteria decision making problem. The aim of this paper is to demonstrate the implementation of an integrated approach that employs AHP and PROMETHEE together for selecting the most suitable mining method for the "Coka Marin" underground mine in Serbia. The related problem includes five possible mining methods and eleven criteria to evaluate them. Criteria are accurately chosen in order to cover the most important parameters that impact on the mining method selection, such as geological and geotechnical properties, economic parameters and geographical factors. The AHP is used to analyze the structure of the mining method selection problem and to determine weights of the criteria, and PROMETHEE method is used to obtain the final ranking and to make a sensitivity analysis by changing the weights. The results have shown that the proposed integrated method can be successfully used in solving mining engineering problems. PMID- 22441613 TI - Techniques of liver resection. PMID- 22441614 TI - How much remnant is enough in liver resection? AB - BACKGROUND: Liver resection represents the first choice of treatment for primary and secondary liver malignancies, offering the patient the best chance of long term survival. The extensive use of major hepatectomy increases the risk of post hepatectomy liver failure (PHLF), which is associated with a high frequency of postoperative complications, mortality and increased length of hospital stay. AIMS: The aim of this review is to investigate the different risk factors related to the occurrence of PHLF and to identify the limits for a safe liver resection in patients with normal liver and injured liver (cirrhosis, cholestasis, steatosis and post-chemotherapy liver injury). METHODS: A literature search was undertaken in PubMed and related search engines, looking for articles relating to hepatic failure following hepatectomy in normal liver or injured liver. RESULTS: In spite of improvements in surgical and postoperative management, the parameters determining how much liver can be resected are still largely undefined. A number of preoperative, intraoperative and postoperative factors all contribute to the likelihood of liver failure after surgery. The safe limits for liver resection can be estimated from the data of the literature for patients with normal liver and for those with different types of liver injury. CONCLUSIONS: Preoperative assessment that includes evaluation of liver volume and function of the remnant liver is a mandatory prerequisite before major hepatectomy. The critical residual liver volume for patients able to predict PHLF is mainly related to the presence of pre-existing liver disease and liver function. Among patients with normal liver, the limit for safe resection ranges from 20 to 30% future remnant liver of total liver volume. In patients with injured liver (cirrhosis, cholestasis or steatosis), preoperative assessment of the risk of PHLF should include future remnant liver volumetry and accurate liver function evaluation, including different dynamic liver function tests. PMID- 22441615 TI - Extrahepatic versus intrahepatic hilar control for right hepatectomy: an updated experience. AB - BACKGROUND: Inflow control prior to transection for right hepatectomy may be achieved either by dissection and ligation of the individual hilar structures outside of the liver (EHD) or by mass stapling of the inflow structures within the hepatic parenchyma. Our preference is for the anterior intrahepatic approach (AIA) with mass stapling, in order to minimise the risk of inadvertent injury of the left-sided inflow and to preserve as much parenchyma as possible. In this paper, we present our experience over the last 10 years and compare it with results from the EHD technique. METHODS: Data for a 10-year period from 2000 to 2010 were extracted retrospectively from a prospectively collected database. Results in each group were measured by a combination of technical and oncological outcomes. Groups were compared by way of descriptive statistics and differences tested for significance by appropriate statistical means. RESULTS: 411 right hepatectomies were performed for colorectal metastases. Of these, 242 were by AIA and 169 by EHD. Both groups were well matched in demographic terms and according to disease burden, although more extended resections were performed in the EHD group. Operative duration (433 vs. 350 min), blood loss (420 vs. 348 ml) and incidence of bile leaks (4 vs. 2) were all lower in the AIA group. All other technical and oncological outcomes were equivalent. CONCLUSION: The AIA approach provides equivalent morbidity, mortality and oncological outcome to the EHD dissection technique and may confer the benefits of being safer and providing greater scope to preserve hepatic parenchyma. PMID- 22441616 TI - Portal vein embolization before extended hepatectomy for biliary cancer: current technique and review of 494 consecutive embolizations. AB - BACKGROUNDS: Portal vein embolization (PVE) has been widely applied before extended hepatectomy; however, its clinical utility for patients with biliary cancer has not been fully addressed. METHODS: Between 1991 and 2010, 494 patients with cholangiocarcinoma (n = 353) or gallbladder cancer (n = 141) underwent PVE before extended hepatectomy. PVE was performed by a transhepatic ipsilateral approach using fibrin glue or absolute ethanol with steel coils. Surgical outcomes of this cohort were retrospectively reviewed. RESULTS: PVE-related complications requiring interventions were found in 3 (0.6%) of the 494 patients; no patient died of these complications. Among the 494 patients, 122 (24.7%) did not undergo subsequent hepatectomy. The unresectability rate was significantly higher in patients with gallbladder cancer than in those with cholangiocarcinoma [43.2% (61/141) and 17.3% (61/353), respectively, p < 0.001]. The remaining 372 patients underwent hepatectomy, and 24 (6.5%) died of postoperative complications [13 of 80 (16.3%) with gallbladder cancer vs. 11 of 292 (3.8%) with cholangiocarcinoma, p < 0.05]. The overall survival for patients with cholangiocarcinoma was significantly better than that for patients with gallbladder cancer, where the 5-year survival rate was 39 and 23%, respectively (p < 0.001). Thirty-six patients with cholangiocarcinoma and 10 patients with gallbladder cancer survived more than 5 years after extended surgery. CONCLUSION: PVE can be performed safely in patients with cholestatic liver, and it has a potential benefit for patients with advanced biliary cancer who are to undergo extended, difficult hepatectomy. PMID- 22441617 TI - How to transect the liver? A history lasting more than a century. AB - There is a close relationship between blood loss during transection and unfavorable outcome. Many different methods have been used in order to cut the parenchyma, while leaving vital structures intact, coagulate small vessels and seal small biliary ducts. The first method described was the finger-fracture technique and, alternatively, the clamp-crushing method using a small forceps. With this technique, the liver is crushed between the 'jaws', and the vessels and bile ducts are successively ligated and divided. Technological research using different sources of energy developed the water jet dissectors and the ultrasonic dissectors. The CUSA(r) has been widely adopted for the fascinating way it could selectively destroy and aspirate parenchyma leaving vascular structures almost intact. Several studies have been addressed to clarify these critical points. However, in the majority of cases they are underpowered to demonstrate clear advantages of one method over the others. In conclusion, the evidence suggested no superiority of other techniques over clamp-crushing. But it must be taken into account that it requires strictly hepatic pedicle clamping. The devices available should be used within the limits of each instrument, as well as the surgical skills of the surgeon. Probably the best option should be a combined approach. PMID- 22441618 TI - Vascular occlusion or not during liver resection: the continuing story. AB - BACKGROUND: Vascular occlusion can be applied during liver resection to reduce blood loss. Herein, we provide an update of the current evidence concerning vascular occlusion. METHODS: A systematic literature search was conducted to review the effects of liver in- and outflow occlusion techniques during liver resection, focusing on blood loss and hepatic ischemia-reperfusion injury. RESULTS: The Pringle maneuver (PM) is effective in controlling blood loss; however, there is no indication for routine vascular clamping during hepatic resection in uncomplicated patients. During complex resections and in patients with abnormal liver parenchyma, the intermittent PM is preferred over continuous clamping. Total hepatic vascular exclusion (THVE) is indicated only in resection of tumors involving the inferior caval vein or the caval hepatic junction. THVE can be applied with the preservation of caval vein flow. This mode of selective hepatic vascular exclusion results in less blood loss in combination with the PM. CONCLUSION: If clamping is necessary during complex resections or in abnormal liver parenchyma, intermittent PM is advised. THVE or selective hepatic vascular exclusion may be considered in tumors involving the inferior caval vein or the caval hepatic junction. There is no evidence supporting the use of ischemic preconditioning, maintenance of a low central venous pressure or of pharmacological interventions during liver resection. PMID- 22441619 TI - Use of bipolar radiofrequency in parenchymal transection of the liver, pancreas and kidney. AB - BACKGROUND: Intraoperative blood loss has been shown to be an important factor correlating with increased morbidity and mortality in oncological surgery. Despite technological advances in parenchymal transection devices, bleeding remains the single most important complication. To address this, we designed and developed a bipolar radiofrequency (RF) device, the Habib 4X (Angiodynamics, Inc., Queensbury, N.Y., USA), which was initially used specifically for liver resections. METHODS: A search using Medline, Embase and GoogleTM Scholar was performed for the period January 2001 to August 2011. The following Mesh terms were used: 'bipolar radiofrequency', 'Habib 4X', 'laparoscopic', 'liver resection', 'partial nephrectomy' and 'distal pancreatectomy'. The references of the studies included were also reviewed. Series from our centre were excluded. RESULTS: There were seven series published, reporting a total of 188 liver resections [113 minor (< 3 segments) and 75 major (>= 3 segments)] assisted by the bipolar RF (Habib 4X) device over this period. The median blood loss reported ranged from 15 to 427 ml with a transfusion rate of 0-14% In addition, five series of partial nephrectomies were also identified, reporting a total of 149 (45 open and 104 laparoscopic) cases. Hilar clamping was not used in any of the cases, and the mean blood loss reported was 100-337 ml whilst the transfusion rate ranged from 0 to 7.1%. There was only one published series of distal pancreatectomies; these were laparoscopic and included 14 patients. CONCLUSION: This review of bipolar RF-assisted liver resections, partial nephrectomies and distal pancreatectomies reported in the literature to date shows that there are significant advantages in using this device in these types of operation. PMID- 22441620 TI - Posthepatectomy bile leakage: how to manage. AB - BACKGROUND: Biliary leakage after liver resection continues to be reported. Management of bile leakage has changed in recent years, with nowadays non surgical procedures as the preferred treatment. METHODS: Biliary leakage and management were assessed in 381 patients who underwent liver resection between January 2005 and April 2011. RESULTS: The overall rate of biliary leakage after liver resection was 5.0%, with a higher incidence in patients who had undergone concomitant hepaticojejunostomy (HJ; 13.6 vs. 3.2%). Hospital stay (p = 0.047), major resections (p = 0.018), operation time (p = 0.011), and relaparotomy (p = 0.002) were risk factors for postoperative bile leakage. Multivariate analysis identified relaparotomy as an independent factor (OR 4.216, p = 0.034). Bile leakage in patients without HJ (n = 10) was managed in 6 patients by percutaneous transhepatic biliary drainage (PTD), and in 3 patients by endoscopic drainage. One patient was treated surgically. All patients with an HJ and postoperative bile leakage (n = 9) underwent PTD. CONCLUSION: The incidence of posthepatectomy biliary leakage has decreased over time, while PTD and endoscopic stenting are effective treatment modalities. PTD is the treatment of choice in bile leakage after resection combined with HJ. PMID- 22441621 TI - Role of fibrin sealants in liver surgery. AB - BACKGROUND: Fibrin sealants are widely used in liver surgery. The aim of this article is to review the literature on evidence of hemostatic and biliostatic capacities of different fibrin sealants in liver surgery. METHODS: In PubMed, a literature search was done with the search terms 'fibrin sealant' or 'fibrin glue' combined with 'liver resection' or 'bile leakage'. Thirteen comparative fibrin sealant studies were selected. RESULTS: In general, these studies have shown a reduced time to hemostasis when fibrin sealants were used. So far, only a few studies have been published that have focused on postoperative resection surface-related complications. There is no strong evidence that fibrin sealants reduce the incidence of bile leakage after liver resection. Important new evidence shows that bile contains profibrinolytic activity that causes lysis of the clot formed by the fibrin sealant at least in vitro. CONCLUSIONS: Fibrin sealants can be effective as an adjunct to achieve hemostasis during liver resections. However, considering lack of evidence on the efficacy of fibrin sealants in reducing postoperative resection surface-related complications, routine use of fibrin sealants in liver surgery cannot be recommended. PMID- 22441622 TI - Laparoscopic liver resection: is there a learning curve? AB - BACKGROUND: Laparoscopic liver resection (LLR) is becoming an accepted treatment option for resecting both benign and malignant tumours. However, it is critical that the laparoscopic approach does not compromise the technical quality of the liver resection. The aim of this paper was to review the learning curve of LLR in a specialist HPB unit. METHODS: A prospective database was searched to identify patients undergoing LLR over a 4-year period. To assess the effect of the learning curve on outcome, the series was evaluated during two eras--early versus late. RESULTS: Fifty-one (27 males, median age 68 years) patients were identified with 37 having LLR. The most common indication was for colorectal liver metastases, and the most common procedure was a non-anatomical metastectomy. Changes in management decisions (n = 14) occurred more frequently during the first era (9 vs. 5; p > 0.05). More patients underwent right hepatectomy in the late group (3 vs. 1; p < 0.05). There did not appear to be any difference in duration of surgery for laparoscopic left lateral resection between the eras (200 vs. 240 min; p > 0.05) which probably reflected trainees performing more operations during the late era. Left hepatectomy was most commonly performed in the early era compared to more right hepatectomies during the late era. CONCLUSION: LLR is associated with a learning curve, but once this has been overcome it can be safely utilised in the management of malignant liver lesions even for major resections, surgical training and simultaneous resections. PMID- 22441623 TI - Laparoscopic liver resection in the Netherlands: how far are we? AB - BACKGROUND: The objective of this study was to provide a systematic review on the introduction of laparoscopic liver surgery in the Netherlands, to investigate the initial experience with laparoscopic liver resections and to report on the current status of laparoscopic liver surgery in the Netherlands. METHODS: A systematic literature search of laparoscopic liver resections in the Netherlands was conducted using PubMed/MEDLINE. Analysis of initial experience with laparoscopic liver surgery was performed by case-control comparison of patients undergoing laparoscopic left lateral sectionectomy matched with patients undergoing the open procedure in the Netherlands between the years 2000 and 2008. Furthermore, a nationwide survey was conducted in 2011 on the current status of laparoscopic liver surgery. RESULTS: The systematic review revealed only 6 Dutch reports on actual laparoscopic liver surgery. Matched case-control comparison showed significant differences in the length of hospital stay, blood loss and operation time. Complications did not differ significantly between the two groups (26 vs. 21%). The 2011 survey showed that 21 centers in the Netherlands performed formal liver resections and that 49 (5% of total) laparoscopic liver resections were performed in 2010. CONCLUSION: The systematic review revealed that very few laparoscopic liver resections were performed in the Netherlands in the previous millennium. The matched case-control comparison of laparoscopic and open left lateral resection showed a reduction in hospital length of stay with comparable morbidity. The laparoscopic technique has been slowly adopted in the Netherlands, but its popularity seems to increase in recent years. PMID- 22441624 TI - Posthepatectomy liver failure. AB - BACKGROUND: Posthepatectomy liver failure (PHLF) is one of the most serious complications after liver resection and is still reported in up to 8% after liver resection. AIMS: To provide an overview about the current status of risk analysis and definition of PHLF. Prevention and treatment is also discussed. METHODS: A literature review was carried out on PubMed using the terms 'liver failure', 'posthepatectomy' and 'liver surgery' to search relevant papers. DISCUSSION: PHLF remains a serious problem in patients undergoing major liver resection. Adequate preoperative risk assessment and an optimal postoperative treatment are essential for PHLF prevention. PMID- 22441625 TI - PbPt(IO3)6(H2O): a new polar material with two types of stereoactive lone-pairs and a very large SHG response. AB - A new polar material containing two types of stereoactive lone-pairs has been synthesized. The unique parallel alignment of the stereoactive lone-pairs on Pb(2+) cations and the synergistic effect of two types of stereoactive lone-pairs on I(5+) and Pb(2+) cations make it exhibit a very large second-harmonic generation response of about 8 * KDP (KH(2)PO(4)). PMID- 22441626 TI - Mercury-based traditional herbo-metallic preparations: a toxicological perspective. AB - This review aims to explore the toxicological aspects of mercury-based herbo metallic preparations like cinnabar and "Rasasindura" that are primarily composed of mercuric sulfide (HgS). Cinnabar-containing preparations have been used extensively in Indian and Chinese systems of medicine for treatment of chronic ailments like syphilis, high fever, pneumonia, insomnia, nervous disorders, deafness, and paralysis of the tongue. Contrary to Western medicine, which does not promote the use of mercury due to its toxic effects, Indian and Chinese traditional practitioners believe that mercury-based formulations have potent therapeutic efficacy, while there is no toxicity due to the unique and repeated purification processes employed during preparation. However, lack of proper pharmacovigilance and widespread self-medication has resulted in undesirable effects to certain sections of the consumers of these preparations, which have contributed to the negative publicity for these forms of medicine. Variations in the quality of the preparations coupled with the lack of understanding of the differences in the recommended dosages and treatment strategies adopted by traditional medicine practitioners, further fuels concerns in the Western world on the safety and efficacy of traditional medicine. But in spite of these concerns, concerted efforts to understand the biological interactions and transformations of these preparations are yet to gain momentum. Although scattered reports on the toxicity of these preparations are available in literature, their mechanism of action has not been conclusively established. Long term pharmacotherapeutic and in-depth toxicity studies are needed to address the apprehensions raised by these herbo-metallic preparations. This review highlights the lacunae in the studies conducted thus far, and assesses the need for further studies to provide significant data to establish the safety and efficacy of such preparations, as well as develop gold standards for stringent quality control of these preparations. PMID- 22441627 TI - Measuring disease activity in Crohn's disease. AB - In the last few years the management of Crohn's disease (CD) has changed due to the introduction of new therapeutic agents that provide more alternative options in patients with severe diseases, introducing new concepts regarding treatment timing. At the moment, the absence of good predictors of disease outcome and a subclinical marker available to predict relapse during clinical remission are major problems in the management of CD. In recent decades, the evaluation of several variables has been proposed to address this issue, including disease behavior, clinical-endoscopic activity and intestinal damage. In particular, definition of mucosal restitution or healing after therapy has been proposed as a surrogate of efficacy and new goal of the therapy. Regarding this concept, several criticisms have been raised, such as the need to better define the role of mucosal healing in a transmural disease. In order to address this issue, new alternative techniques providing both extraluminal and luminal intestinal damage have been proposed, including ultrasonography, computed tomography and magnetic resonance imaging. PMID- 22441630 TI - The studies of phase equilibria and efficiency assessment for self-emulsifying lipid-based formulations. AB - The study was designed to build up a database for the evaluation of the self emulsifying lipid formulations performance. A standard assessment method was constructed to evaluate the self-emulsifying efficiency of the formulations based on five parameters including excipients miscibility, spontaneity, dispersibility, homogeneity, and physical appearance. Equilibrium phase studies were conducted to investigate the phase changes of the anhydrous formulation in response to aqueous dilution. Droplet size studies were carried out to assess the influence of lipid and surfactant portions on the resulted droplet size upon aqueous dilution. Formulations containing mixed glycerides showed enhanced self-emulsification with both lipophilic and hydrophilic surfactants. Increasing the polarity of the lipid portion in the formulation leaded to progressive water solubilization capacity. In addition, formulations containing medium chain mixed glycerides and hydrophilic surfactants showed lower droplet size compared with their long chain and lipophilic counterparts. The inclusion of mixed glycerides in the lipid formulations enormously enhances the formulation efficiency. PMID- 22441631 TI - Self-reported history of anorexia nervosa and current quality of life: findings from a community-based study. AB - PURPOSE: To evaluate the impact of a lifetime history of anorexia nervosa (AN) on current quality of life (QoL) and eating disorder (ED) symptomatology. METHOD: 3,034 participants from a randomly selected sample of households in the Australian population were interviewed for current ED symptoms and QoL (SF-36). RESULTS: 89 participants (2.9 %) reported a history of AN, 73 of whom were female. These participants scored lower on six of the eight subscales on the SF 36, including all of the mental health subscales, and were more likely to report binge eating and extreme weight or shape concerns than participants who did not report a history of AN. On the other hand, participants who reported a history of AN were less likely to be overweight. None of the participants who reported a history of AN met current criteria for AN; however, one met criteria for bulimia nervosa non-purging subtype and four met criteria for binge eating disorder. The endorsement of current ED symptoms was found to moderate the impact of a history of AN on scores of the social functioning and role limitations due to emotional health SF-36 subscales, such that participants who reported a history of AN scored lower on these subscales if they also reported current ED symptoms. CONCLUSIONS: A history of AN has a deleterious impact on current QoL, despite remittance from the disorder. This may be explained in part by the presence of certain ED symptoms, including objective binge eating and the persistence of extreme weight and shape concerns. PMID- 22441632 TI - A low-cost 2D fluorescence detection system for MUm sized beads on-chip. AB - In this paper we describe a compact fluorescence detection system for on-chip analysis of beads, comprising a low-cost optical HD-DVD pickup. The complete system consists of a fluorescence detection unit, a control unit and a microfluidic chip containing microchannels and optical markers. With these markers the laser beam of the optical pickup can be automatically focused at the centre of the microchannel. With the complete system a two-dimensional fluorescent profile across the channel width can be obtained such that there is no need for hydrodynamic or electrokinetic focusing of the particles in a specific part of the channel. Fluorescent MUm sized beads suspended in medium have been detected with the system. Since on both sides of the main beam two additional laser beams at a known distance are generated, also the velocity of individual beads has been determined. PMID- 22441633 TI - Role of sphingosine-1-phosphate inbeta-adrenoceptor desensitization via Ca(2+) sensitization in airway smooth muscle. AB - BACKGROUND: The correlation between inflammatory cells and airway smooth muscle plays fundamental roles in the pathophysiology of asthma. This study was designed to determine whether pre-exposure of airway smooth muscle to sphingosine-1 phosphate (S1P), which is released from mast cells by allergic reactions, causes a deterioration of beta-adrenoceptor function. METHODS: Isometric tension and the ratio of fluorescence intensities at 340 and 380 nm (F(340)/F(380)), an indicator of intracellular Ca2+ levels, were simultaneously measured using fura-2 loaded guinea-pig tracheal tissues. Intracellular cAMP levels were also measured. RESULTS: Pre-exposure to S1P caused a reduction in the inhibitory effects of 0.3MUM isoprenaline, a beta-adrenoceptor agonist, and 10MUM forskolin, a direct activator of adenylyl cyclase, against 1MUM methacholine-induced contraction in concentration- and time- dependent manners. In contrast, the values of F(340)/F(380) were not augmented under this experimental condition. After incubation with S1P in the presence of 0.001-1MUM Y-27632, a Rho-kinase inhibitor, the reduced responsiveness to forskolin induced by S1P was reversed in a concentration-dependent manner. Moreover, pre-treatment with pertussis toxin (PTX), an inhibitor of G(i), suppressed the loss of forskolin-induced relaxation induced by S1P. Pre-exposure to S1P markedly inhibited the augmentation of cAMP accumulation induced by forskolin. However, addition of Y-27632 and pre-exposure to PTX returned forsokin-induced cAMP accumulation to the control level. CONCLUSIONS: Pre-exposure to S1P causes heterologus desensitization of beta adrenoceptors by increasing the sensitivity of airway smooth muscle to intracellular Ca2+. Ca2+ sensitization regulated by G(i) and Rho-kinase is involved in this phenomenon. PMID- 22441634 TI - Early interventional treatment with intranasal mometasone furoate in Japanese cedar/cypress pollinosis: a randomized placebo-controlled trial. AB - BACKGROUND: Little is known about the safety and effectiveness of early interventional treatment (EIT) with intranasal corticosteroids for seasonal allergic rhinitis. We designed a double-blinded, randomized, placebo-controlled 12-week trial of EIT with mometasone furoate nasal spray (MFNS) for Japanese cedar/cypress pollinosis (JCCP). METHODS: A total of 50 JCCP patients received MFNS (200MUg once daily: n = 25) or placebo (n = 25) starting on February 1, 2010. Treatments continued until the end of April. The primary endpoint was the comparison of the total nasal symptom score (TNSS) between the MFNS and placebo groups. The secondary endpoints included comparisons of QOL, daytime sleepiness, nasal ECP levels, and safety. RESULTS: Continuous dispersion of Japanese cedar pollen began on February 22. Although the placebo group showed a significant worsening of symptoms after the start of the continuous dispersion, no worsening occurred in the MFNS group. A significant difference in the TNSS between the two groups was seen starting at 4 weeks after the treatment. Similar results were seen for QOL and sleepiness. Nasal ECP levels in March were significantly lower in the MFNS group. A total of 56% of the MFNS group progressed to a persistent allergic rhinitis state in accordance with the ARIA classification, as opposed to 84% of the placebo group. MFNS was well tolerated, and the plasma cortisol concentrations were similar between the two groups. CONCLUSIONS: EIT with MFNS for JCCP is both safe and effective. This treatment can potentially lessen symptoms and help pollinosis patients remain in the intermittent state. PMID- 22441635 TI - Effect of switching from salmeterol/fluticasone to formoterol/ budesonide combinations in patients with uncontrolled asthma. AB - BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and a long acting beta(2)-agonist (LABA) in a single inhaler is the mainstay of asthma management and salmeterol/fluticasone combination (SFC) and fixed-dose formoterol/budesonide combination (FBC) are currently available in Japan; however, there is nothing to choose between the two. The purpose of this study was to clarify the effect of switching from SFC to FBC in patients with asthma not adequately controlled under the former treatment regimen. METHODS: This was a prospective, multicenter, open-label, uncontrolled longitudinal study in 87 adult patients with an Asthma Control Questionnaire, 5-item version (ACQ5) score of greater than 0.75 under treatment with SFC 50/250MUg one inhalation twice daily (bid). SFC was switched to FBC 4.5/160MUg two inhalations bid. Study outcomes included ACQ5 score, peak expiratory flow (PEF), FEV(1), and fractional exhaled nitric oxide (FeNO) at the end of treatment period. RESULTS: Eighty-three patients completed the study. ACQ5 scores improved and exceeded the clinically meaningful difference after 12 weeks of treatment and well-controlled asthma (ACQ5 score <=0.75) was attained in 37 (44.6%) patients. Minimum and maximum PEF and FEV(1) values improved significantly, but not FeNO values, after switching from SFC to FBC. CONCLUSIONS: Switching ICS/LABA combination therapy is a useful option in the management of asthma that is not optimally controlled. PMID- 22441636 TI - Mannose-binding lectin gene polymorphisms in infants with bronchiolitis and post bronchiolitis wheezing. AB - BACKGROUND: Mannose-binding lectin (MBL) encoded by the MBL2 gene, is an important component of the innate immunity. Low levels have been linked with respiratory infections and both high and low levels with allergy and asthma. The aims of the study were to evaluate the connection between polymorphisms of the MBL2 gene and viral findings, clinical characteristics and subsequent wheezing in young infants with bronchiolitis. METHODS: In all, 129 full-term infants hospitalized for bronchiolitis at age less than 6 months have been followed-up until the mean age of 1.5 years. The genotyping of the MBL2 gene mutations was made by pyrosequencing for a simultaneous detection of three single nucleotide polymorphisms (SNP). RESULTS: The MBL genotypes or allele frequencies had no significant associations with clinical characteristics of bronchiolitis. The 41 children with variant genotypes were more often infected by multiple viruses (21.9%, p = 0.047) than children with wild-type A/A genotypes (9.1%). In addition, more children with variant genotypes (31.7%, p = 0.016) had used corticosteroids because of post-bronchiolitis wheezing, compared to those with wild-type A/A genotypes (13.6%). No other significant associations with viral findings or post-bronchiolitis outcomes were found. CONCLUSIONS: Preliminary evidence was found that the variant non-A/A genotypes may be associated with susceptibility to multiple viral infections and more severe post-bronchiolitis wheezing requiring treatment with corticosteroids. PMID- 22441637 TI - Evaluation of eosinophilic inflammation in a novel murine atopic keratoconjunctivitis model induced by crude Dermatophagoides farinae antigen. AB - BACKGROUND: The purpose of this study is to conduct a histopathological research of the conjunctival findings and eosinophilic inflammation of novel atopic keratoconjunctivitis in a NC/Nga mouse model using crude Dermatophagoides farina. METHODS: NC/Nga mice were sensitized by repeated topical applications of an ointment containing Dermatophagoides farinae body (Dfb). They were then divided into 4 groups depending on the following topical ophthalmic treatment: DFb group undergoing topical ophthalmic ointment containing Dfb; DFco group undergoing topical instillation of allergen extracts of Dermatophagoides farinae; Ba group undergoing topical ointment with substrate alone and NT group without after topical ophthalmic treatment. At 24 hours after the last ophthalmic treatment, histopathological examination was performed. The density of the subepithelial infiltration of the eosinophils was determined. Serum total IgE and house-dust mite (HDM)-specific IgE antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the DFb group, the conjunctiva showed similar findings to those of atopic keratoconjunctivitis, i.e. intraepithelial pseudotubular formation, Torus-form infiltration due to massive lymphocytes in the palpebral conjunctiva and gelatinous hyperplasia in the limbus with subepithelial granuloma composed of lymphocytes and eosinophils. Subepithelial infiltration of eosinophil density in the DFb group [878.4 +/- 399.7cells/mm2 (mean +/- SD)] was significantly higher than in the other 2 groups (DFco 85.6 +/- 40.1 Ba 49.2 +/- 32.3) (P < 0.001). Total serum IgE concentration and HDM specific serum IgE antibody concentration in the DFb group and the DFco group were significantly higher compared with those in the NT group. CONCLUSIONS: Topical application of an ointment containing DFb to both the skin and eyes of NC/Nga mice can induce an atopic keratoconjunctivitis (AKC) model in these mice. PMID- 22441638 TI - Nakajo-Nishimura syndrome: an autoinflammatory disorder showing pernio-like rashes and progressive partial lipodystrophy. AB - Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040) is a distinct inherited inflammatory and wasting disease, originally reported from Japan. This disease usually begins in early infancy with a pernio like rash, especially in winter. The patients develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint contractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. At present, about 10 cases are confirmed to be alive only in the Kansai area, including one infant case in Wakayama. However, more cases are expected to be added in the near future. Although cause of the disease has long been undefined, a homozygous mutation of the PSMB8 gene, which encodes the beta5i subunit of immunoproteasome, has been identified to be responsible in 2011. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to immunoproteasome dysfunction causes hyperactivation of p38 mitogen-activated protein kinase and interleukin-6 overproduction. Since similar diseases with PSMB8 mutations have recently been reported from Europe and the United States, it is becoming clear that Nakajo-Nishimura syndrome and related disorders form proteasome disability syndromes, a new category of autoinflammatory diseases distributed globally. PMID- 22441639 TI - Cutaneous manifestations of Hyper IgE syndrome. AB - Hyper-IgE syndrome (HIES) is a primary immunodeficiency disorder characterized by atopic manifestations and susceptibility to infections with extracellular bacteria and fungi. Atopic manifestations include atopic dermatitis-like skin lesion and extremely high serum IgE levels. Most of the extracellular bacterial infections are caused by Staphylococcus aureus, which is associated with milder inflammation compared to normal. Recent studies have revealed that the most cases of the HIES are caused by dominant negative mutations in STAT3 gene. Cutaneous manifestations of HIES includes newborn rash, eczematoid dermatitis, cold abscesses, mucocutaneous candidiasis, and coarse texture of the facial skin. Impaired Th17 cell development due to the defective IL-6 signaling in T cells and impaired induced regulatory T (iTreg) cell generation due to defective IL-10 signaling in dendritic cells may, at least in part, account for the cutaneous pathology of HIES. PMID- 22441640 TI - The effects of clopidogrel (Plavix) and other oral anticoagulants on early hip fracture surgery. AB - OBJECTIVE: Risk for bleeding complications during and after early hip fracture surgery for patients taking clopidogrel and other anticoagulants have not been defined. The purpose of this study is to assess the perioperative bleeding risks and clinical outcome after early hip fracture surgery performed on patients taking clopidogrel (Plavix) and other oral anticoagulants. DESIGN: Study design is a retrospective cohort analysis using data extracted from hospital records and state death records. SETTING: Regional medical center (level II trauma). METHODS: Data for 1118 patients >=60 years of age who had surgical treatment for a hip fracture between 2004 and 2008 were reviewed. Eighty-two patients undergoing late surgery (>3 days after admission) were excluded. Patients taking clopidogrel were compared against those not taking clopidogrel. In addition, patients taking clopidogrel only were compared against cohorts of patients taking both clopidogrel and aspirin, aspirin only, warfarin only, or no anticoagulant. RESULTS: Seventy-four of 1036 patients (7%) were taking clopidogrel, although control groups included 253 patients on aspirin alone, 90 patients on warfarin, and 619 taking no anticoagulants. No significant differences were noted between patients taking clopidogrel and those not taking clopidogrel in estimated blood loss, transfusion requirement, final blood count, hematoma evacuation, hospital length of stay (LOS), or mortality while in hospital or at 1 year. A higher American Society of Anesthesiologists score was seen in the clopidogrel and warfarin groups (P = 0.05 each), increased LOS in the clopidogrel group (P = 0.05), and higher rate of deep vein thrombosis seen in those patients taking warfarin (P = 0.05). Clopidogrel only versus aspirin versus both aspirin and clopidogrel, versus no anticoagulant versus warfarin showed no significant differences in estimated blood loss, transfusion requirement, final blood count, bleeding or perioperative complications, or mortality. CONCLUSIONS: Patients undergoing early hip fracture surgery who are taking clopidogrel, aspirin, or warfarin (with regulated international normalized ratio) are not at substantially increased risk for bleeding, bleeding complications, or mortality. Comorbidities and American Society of Anesthesiologists scores were significantly higher in the clopidogrel group, which may have resulted in the increased postoperative LOS in this group. PMID- 22441641 TI - A comparison of pediatric forearm fracture reduction between conscious sedation and general anesthesia. AB - OBJECTIVES: The purpose of this study was to compare the outcomes of children whose fractures were manipulated with nitrous oxide with those fractures manipulated under a general anesthetic. DESIGN: We undertook a retrospective analysis of all children who presented to the emergency department with an angulated or displaced nonphyseal forearm fracture requiring manipulation over a 6-month period. PATIENTS/PARTICIPANTS: Twenty-eight forearm fractures were manipulated using conscious sedation, whereas 27 were manipulated in the operating theatre under general anesthesia. MAIN OUTCOME MEASUREMENTS: The quality of reduction, the Cast Index, Padding Index, and Canterbury Index were similar between the 2 groups. RESULTS: There was a significant difference between the need for remanipulation in the nitrous oxide group (9) compared with the need for remanipulation in the theatre group (3). CONCLUSIONS: Despite a higher failure, manipulation of fractures in the emergency department using conscious sedation can achieve an adequate reduction and a high quality of cast. Failures were due to inherently more unstable fracture personalities. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22441642 TI - Invited commentary. PMID- 22441643 TI - Cost-effectiveness of cervical cancer screening with primary human papillomavirus testing in Norway. AB - BACKGROUND: New screening technologies and vaccination against human papillomavirus (HPV), the necessary cause of cervical cancer, may impact optimal approaches to prevent cervical cancer. We evaluated the cost-effectiveness of alternative screening strategies to inform cervical cancer prevention guidelines in Norway. METHODS: We leveraged the primary epidemiologic and economic data from Norway to contextualise a simulation model of HPV-induced cervical cancer. The current cytology-only screening was compared with strategies involving cytology at younger ages and primary HPV-based screening at older ages (31/34+ years), an option being actively deliberated by the Norwegian government. We varied the switch-age, screening interval, and triage strategies for women with HPV-positive results. Uncertainty was evaluated in sensitivity analysis. RESULTS: Current cytology-only screening was less effective and more costly than strategies that involve switching to primary HPV testing in older ages. For unvaccinated women, switching at age 34 years to primary HPV testing every 4 years was optimal given the Norwegian cost-effectiveness threshold ($83,000 per year of life saved). For vaccinated women, a 6-year screening interval was cost-effective. When we considered a wider range of strategies, we found that an earlier switch to HPV testing (at age 31 years) may be preferred. CONCLUSIONS: Strategies involving a switch to HPV testing for primary screening in older women is expected to be cost effective compared with current recommendations in Norway. PMID- 22441644 TI - Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis. AB - BACKGROUND: A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity. METHODS: Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model. RESULTS: In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations. CONCLUSION: Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy. PMID- 22441645 TI - Friendship context matters: examining the domain specificity of alcohol and depression socialization among adolescents. AB - Driven by existing socialization theories, this study describes specific friendship contexts in which peer influence of alcohol misuse and depressive symptoms occurs. In the fall and spring of the school year, surveys were administered to 704 Italian adolescents (53 % male, M (age) = 15.53) enrolled in Grades 9, 10 and 11. Different friendship contexts were distinguished based on two dimensions referring to the level (i.e., best friendships and friendship networks) and reciprocity (i.e., unilateral and reciprocal) of the relationships. Social network and dyadic analyses were applied in a complementary manner to estimate peer socialization effects across the different friendship contexts. Results showed that within friendship networks both male and female adolescents' alcohol misuse was affected by friends' alcohol misuse, regardless of whether the relationship was reciprocated or not. Conversely, peer socialization of depressive symptoms only emerged within very best friendship dyads of female adolescents. Findings suggest that the effects of peer socialization depend on the friendship context and specific types of behaviors. The theoretical and methodological implications of the findings are discussed. PMID- 22441646 TI - Synthesis, structural characterization and catalytic activity of a multifunctional enzyme mimetic oxoperoxovanadium(V) complex. AB - The synthesis and structural characterization of a novel oxoperoxovanadium(V) complex [VO(O(2))(PAH)(phen)] containing the ligands 2-phenylacetohydroxamic acid (PAHH) and 1,10-phenanthroline (phen) has been accomplished. The oxoperoxovanadium(V) complex was found to mimic both vanadate-dependent haloperoxidase (VHPO) activity as well as nuclease activity through effective interaction with DNA. The complex is the first example of a structurally characterized stable oxoperoxovanadium(V) complex with a coordinated bi-dentate hydroximate moiety (-CONHO(-)) from 2-phenylacetohydroximate (PAH). The oxoperoxovanadium(V) complex has been used as catalyst for the peroxidative bromination reaction of some unsaturated alcohols (e.g. 4-pentene-1-ol, 1-octene 3-ol and 9-decene-1-ol) in the presence of H(2)O(2) and KBr. The catalytic products have been characterized by GC-MS analysis and spectrophotometric methods. The DNA binding of this complex has been established with CT DNA whereas the DNA cleavage was demonstrated with plasmid DNA. The interactions of the complex with DNA have been monitored by electronic absorption and fluorescence emission spectroscopy. Viscometric measurements suggest that the compound is a DNA intercalator. The nuclease activity of this complex was confirmed by gel electrophoresis studies. PMID- 22441647 TI - Hypoxia-mediated prior induction of monocyte-expressed HSP72 and HSP32 provides protection to the disturbances to redox balance associated with human sub-maximal aerobic exercise. AB - HSP72 is rapidly expressed in response to a variety of stressors in vitro and in vivo (including hypoxia). This project sought a hypoxic stimulus to elicit increases in HSP72 and HSP32 in attempts to confer protection to the sub-maximal aerobic exercise-induced disturbances to redox balance. Eight healthy recreationally active male subjects were exposed to five consecutive days of once daily hypoxia (2,980 m, 75 min). Seven days prior to the hypoxic acclimation period, subjects performed 60 min of cycling on a cycle ergometer (exercise bout 1-EXB1), and this exercise bout was repeated 1 day post-cessation of the hypoxic period (exercise bout 2-EXB2). Blood samples were taken immediately pre- and post exercise and 1, 4 and 8 h post-exercise for HSP72 and immediately pre, post and 1 h post-exercise for HSP32, TBARS and glutathione [reduced (GSH), oxidised (GSSG) and total (TGSH)], with additional blood samples obtained immediately pre-day 1 and post-day 5 of the hypoxic acclimation period for the same indices. Monocyte expressed HSP32 and HSP72 were analysed by flow cytometry, with measures of oxidative stress accessed by commercially available kits. There were significant increases in HSP72 (P < 0.001), HSP32 (P = 0.03), GSSG (t = 9.5, P < 0.001) and TBARS (t = 5.6, P = 0.001) in response to the 5-day hypoxic intervention, whereas no significant changes were observed for GSH (P = 0.22) and TGSH (P = 0.25). Exercise-induced significant increases in HSP72 (P < 0.001) and HSP32 (P = 0.003) post-exercise in EXB1; this response was absent for HSP72 (P >= 0.79) and HSP32 (P >= 0.99) post-EXB2. The hypoxia-mediated increased bio-available HSP32 and HSP72 and favourable alterations in glutathione redox, prior to exercise commencing in EXB2 compared to EXB1, may acquiesce the disturbances to redox balance encountered during the second physiologically identical exercise bout. PMID- 22441648 TI - Q fever pneumonia in French Guiana: prevalence, risk factors, and prognostic score. AB - BACKGROUND: Community-acquired pneumonia (CAP) is the major manifestation of Q fever, an emerging disease in French Guiana. Consequently, the empirical antibiotherapy used for the treatment of CAP combines doxycycline and the recommended amoxicillin. Our objectives were to estimate the prevalence of Q fever pneumonia and to build a prediction rule to identify patients with Q fever pneumonia for empirical antibiotic guidance. METHODS: A retrospective case control study was conducted on inpatients admitted with CAP in the Department of Infectious Diseases of Cayenne Hospital from 2004 to 2007. Serodiagnosis for Coxiella burnetii was performed for all patients. Risk factor analysis was performed using multivariate logistic regression, and a prognostic score was computed using bootstrap procedures. The score performance characteristics were used to choose the best prediction rule to identify patients with Q fever pneumonia. RESULTS: One hundred thirty-one patients with CAP were included and the Q fever pneumonia prevalence was 24.4% (95% confidence interval [CI], 17.1 31.9). In multivariate analysis, male sex, middle age (age, 30-60 years), headache, leukocyte count <10 * 10(9)/L and C-reactive protein level >185 mg/L were independently associated with Q fever pneumonia. Patients with a predictive score <=3 had a low risk of Q fever pneumonia with a negative predictive value of 0.97 (95% CI, .90-1) and a sensitivity of 0.97 (95% CI, .89-1). CONCLUSIONS: The prediction rule described here accurately identifies patients with low risk of Q fever pneumonia and may help physicians to make more rational decisions about the empirical use of antibiotherapy. Further prospective studies should be performed to validate this score. PMID- 22441649 TI - Antenatal receipt of sulfadoxine-pyrimethamine does not exacerbate pregnancy associated malaria despite the expansion of drug-resistant Plasmodium falciparum: clinical outcomes from the QuEERPAM study. AB - BACKGROUND: Antenatal intermittent preventive therapy with 2 doses of sulfadoxine pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads. METHODS: We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes. RESULTS: The prevalence of parasites with highly SP-resistant haplotypes increased from 17% to 100% (P < .001), and the proportion of women receiving full IPTp (>=2 doses) increased from 25% to 82% (P < .001). Women who received full IPTp with SP had lower peripheral (P = .018) and placental (P < .001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity. CONCLUSIONS: In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care. PMID- 22441650 TI - Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA NP+M1, in humans. AB - BACKGROUND: The novel influenza vaccine MVA-NP+M1 is designed to boost cross reactive T-cell responses to internal antigens of the influenza A virus that are conserved across all subtypes, providing protection against both influenza disease and virus shedding against all influenza A viruses. Following a phase 1 clinical study that demonstrated vaccine safety and immunogenicity, a phase 2a vaccination and influenza challenge study has been conducted in healthy adult volunteers. METHODS: Volunteers with no measurable serum antibodies to influenza A/Wisconsin/67/2005 received either a single vaccination with MVA-NP+M1 or no vaccination. T-cell responses to the vaccine antigens were measured at enrollment and again prior to virus challenge. All volunteers underwent intranasal administration of influenza A/Wisconsin/67/2005 while in a quarantine unit and were monitored for symptoms of influenza disease and virus shedding. RESULTS: Volunteers had a significantly increased T-cell response to the vaccine antigens following a single dose of the vaccine, with an increase in cytolytic effector molecules. Intranasal influenza challenge was undertaken without safety issues. Two of 11 vaccinees and 5 of 11 control subjects developed laboratory-confirmed influenza (symptoms plus virus shedding). Symptoms of influenza were less pronounced in the vaccinees and there was a significant reduction in the number of days of virus shedding in those vaccinees who developed influenza (mean, 1.09 days in controls, 0.45 days in vaccinees, P = .036). CONCLUSIONS: This study provides the first demonstration of clinical efficacy of a T-cell-based influenza vaccine and indicates that further clinical development should be undertaken. CLINICAL TRIALS REGISTRATION: NCT00993083. PMID- 22441651 TI - Emergence of gastrointestinal basidiobolomycosis in the United States, with a review of worldwide cases. AB - BACKGROUND: We examined the epidemiology, clinical manifestations, histopathology, management, and outcomes of gastrointestinal basidiobolomycosis, an uncommon manifestation of infection caused by the fungus Basidiobolus ranarum. METHODS: In this retrospective observational cohort study, cases of gastrointestinal basidiobolomycosis in the United States were identified by reviewing medical records from Mayo Clinic Hospital (Phoenix, AZ) and contacting local infectious diseases specialists, pathologists, gastroenterologists, the Arizona Department of Health Services, health departments of adjacent states, the Armed Forces Institute of Pathology, and the US Centers for Disease Control and Prevention. A comprehensive literature review identified additional cases worldwide. RESULTS: Of 44 patients (mean age, 37 years [range, 2-81 years]) with gastrointestinal basidiobolomycosis, most were from the United States (19 patients [43%], of whom 17 [89%] were from Arizona) or Saudi Arabia (11 [25%]). Most (28 [64%]) were previously healthy. Common chronic medical conditions among 15 patients (34%) were diabetes mellitus (8 patients [18%]) and gastric disorders (7 [16%]). Common findings were abdominal pain (37 patients [84%]) and a palpable abdominal mass (19 [43%]). Intraabdominal malignancy was the leading provisional diagnosis (19 patients [43%]). The large bowel was involved in 36 (82%), the small intestine in 16 (36%), and the liver or gallbladder in 13 (30%). Characteristic histopathologic findings were observed in 43 (98%). Eight patients (18%) died. Combined surgical intervention and antifungal therapy was the preferred treatment. CONCLUSIONS: Gastrointestinal basidiobolomycosis is an emerging invasive fungal infection in desert regions of the US Southwest. Clinical findings mimic malignancy and inflammatory bowel disease. Surgical excision and prolonged antifungal therapy are associated with favorable outcomes. PMID- 22441652 TI - Postlicensure safety surveillance for high-dose trivalent inactivated influenza vaccine in the Vaccine Adverse Event Reporting System, 1 July 2010-31 December 2010. AB - BACKGROUND: In December 2009, a new high-dose, trivalent, inactivated influenza vaccine (TIV-HD) was licensed for adults aged >=65 years. We characterized clinical patterns of reports to the Vaccine Adverse Event Reporting System (VAERS) among older adults who received TIV-HD. METHODS: We searched VAERS for reports involving persons aged >=65 years who received TIV-HD or TIV (standard dose) from 1 July 2010 through 31 December 2010. Medical records were requested for serious reports (ie, those associated with death, hospitalization or prolonged hospitalization, life-threatening illness, or disability). Clinicians reviewed information and assigned a diagnostic category to each report. Empirical Bayesian data mining was used to identify disproportional reporting following TIV HD in VAERS. Reporting rates were calculated for reports of Guillain-Barre syndrome and anaphylaxis. RESULTS: VAERS received 606 reports after TIV-HD in persons aged >=65 years (8.2% of reports involved serious events). The number of reports yielded by searches using the terms "ocular hyperemia" and "vomiting" exceeded the data mining threshold; >80% of these reports were nonserious. Clinical review of serious reports found that a greater proportion involving gastrointestinal events were made after TIV-HD receipt (5 of 51 [9.8%]) than after TIV receipt (1 of 123 [0.8%]). Four persons who received TIV-HD had gastroenteritis, and 1 had multiple gastrointestinal symptoms; all recovered. A higher proportion of cardiac events were noted after receipt of TIV-HD (9 of 51 [17.6%]) than after receipt of TIV (6 of 123 [4.9%]). No concerning clinical pattern was apparent. The reporting rates of Guillain-Barre syndrome and anaphylaxis after TIV-HD receipt were 1.4 and 1.0 reports per million doses distributed, respectively. CONCLUSIONS: During the first year after US licensure of TIV-HD, no new serious safety concerns were identified in VAERS. Our analyses suggested a clinically important imbalance between the reported and expected number of gastrointestinal events after TIV-HD receipt. Future studies should assess this potential association. PMID- 22441653 TI - Immune responses driven by protective human leukocyte antigen alleles from long term nonprogressors are associated with low HIV reservoir in central memory CD4 T cells. AB - BACKGROUND: The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whether and how these alleles influence the immune distribution of the HIV reservoirs. METHODS: Cell-associated HIV-DNA levels were quantified in blood sorted resting CD4 T-cell subsets from 8 LTNPs with and 10 without HLA-B*27 or HLA-B*57 alleles (HLA-B27/B57). RESULTS: A remarkably lower infection level of central memory CD4 T cells (T(CM)) was an exclusive feature that distinguished the HLA-B27/B57 HIV reservoirs from the other ones. In LTNPs, T(CM) protection was correlated with preservation of T(CM) counts, which correlated positively with the magnitude of HIV Gag-specific CD8 T cells. In HLA B27/B57 LTNPs, a lower activation level of their memory CD4 T cells was associated with lower amounts of cell HIV-DNA in each resting memory CD4 subset and were also associated with higher ratios of HIV Gag-specific CD8 T cells per infected resting CD4 T cell (effector/target [E/T]). As a result, HLA-B27/B57 E/T ratios were negatively correlated with the contribution of memory CD4 T-cell subsets to the total HIV reservoirs. CONCLUSIONS: The potent antiviral immunity governed by the protective HLA-B27/B57 alleles, by limiting T(CM) infection and pool exhaustion, are associated with a reduced T(CM) contribution to the HIV reservoir. PMID- 22441654 TI - Low-voltage electroosmotic pumps fabricated from track-etched polymer membranes. AB - Track-etched polymer membranes are used to realize low-voltage electroosmotic (EO) pumps. The nanopores in polycarbonate (PC) and polyethylene terephthalate (PET) membranes were fabricated by the track-etching technique, the pore diameter was controlled in the range of 100 to 250 nm by adjusting the etching time. The results show that these EO pumps can provide high flow rates at low applied voltages (2-5 V). The maximum normalized flow rate is as high as 0.12 ml min(-1) V(-1) cm(-2), which is comparable to the best values of previously demonstrated EO pumps. We attribute this high performance to the unique properties of the track-etched nanopores in the membranes. PMID- 22441655 TI - Nonvolatile resistive memory of ferrocene covalently bonded to reduced graphene oxide. AB - Recently, the number of studies concerning organic memory devices has grown rapidly due to increase in the demand for electronic devices. Among the organic memory devices, the development of organic nonvolatile memory materials and devices is becoming an important research topic due to their low power consumption. PMID- 22441656 TI - Optimized adoptive T-cell therapy for the treatment of residual mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm with few patients achieving long-term survival with current treatment regimens. High-dose therapy is effective in reducing the tumor burden; however, patients eventually relapse due to minimal residual disease. Having demonstrated efficacy in other malignancies, the effectiveness of dendritic cell-based immunotherapy for minimal residual MCL was examined. We demonstrated that dendritic cells (DC) primed with MCL antigens stimulated the activation of MCL-specific T cells that recognized and destroyed both MCL cell lines and primary MCL in vitro. In addition, in vivo studies demonstrated that adoptively transferred MCL-specific T cells were able to significantly inhibit tumor growth in mice with minimal residual MCL. Subsequently, when combined with CHOP chemotherapy, adoptive T-cell therapy was able to significantly extend the survival of the mice by further reducing the tumor burden. These results clearly show that MCL-specific cellular immunotherapy is effective in treating minimal residual MCL, paving the way for future clinical studies. PMID- 22441657 TI - CXCR1 as a novel target for directing reactive T cells toward melanoma: implications for adoptive cell transfer immunotherapy. AB - Adoptive cell transfer therapy with reactive T cells is one of the most promising immunotherapeutic modalities for metastatic melanoma patients. Homing of the transferred T cells to all tumor sites in sufficient numbers is of great importance. Here, we seek to exploit endogenous chemotactic signals in order to manipulate and enhance the directional trafficking of transferred T cells toward melanoma. Chemokine profiling of 15 melanoma cultures shows that CXCL1 and CXCL8 are abundantly expressed and secreted from melanoma cultures. However, the complimentary analysis on 40 melanoma patient-derived tumor-infiltrating lymphocytes (TIL) proves that the corresponding chemokine receptors are either not expressed (CXCR2) or expressed at low levels (CXCR1). Using the in vitro transwell system, we demonstrate that TIL cells preferentially migrate toward melanoma and that endogenously expressing CXCR1 TIL cells are significantly enriched among the migrating lymphocytes. The role of the chemokines CXCL1 and CXCL8 is demonstrated by partial abrogation of this enrichment with anti-CXCL1 and anti-CXCL8 neutralizing antibodies. The role of the chemokine receptor CXCR1 is validated by the enhanced migration of CXCR1-engineered TIL cells toward melanoma or recombinant CXCL8. Cytotoxicity and IFNgamma secretion activity are unaltered by CXCR1 expression profile. Taken together, these results mark CXCR1 as a candidate for genetic manipulations to enhance trafficking of adoptively transferred T cells. This approach is complimentary and potentially synergistic with other genetic strategies designed to enhance anti-tumor potency. PMID- 22441658 TI - Preliminary study on the effects of carbon dioxide and nitrogen pneumoperitoneums on endometriotic lesions. AB - OBJECTIVE: To determine the effects of carbon dioxide (CO(2)) and nitrogen (N(2)) pneumoperitoneums on endometriosis (EMs) lesions. METHODS: Female Wistar rats were randomized into the following 3 groups: CO(2) (N = 20), N(2) (N = 22) and air pneumoperitoneums (N = 9). After 5 weeks of establishment models, do the pneumoperitoneums. Then measure the size of EMs lesions and the related factors of serum and tissue after 1, 2, and 4 weeks of pneumoperitoneums. RESULTS: (1) One week after the pneumoperitoneum was established, the EMs lesions in the CO(2) group were largest in volume, whereas at 4 weeks the EMs lesions in the CO(2) group were smaller than the N(2) group. (2) The level of ICAM-1 and TIMP-2 of serum in CO(2) and N(2) group after 2 weeks of pneumoperitoneum were higher than air group. (3) The expression of CD44v6, ICAM-1, MMP-2 and VEGF of tissue in CO(2) and N(2) group after 1, 2 and 4 weeks of pneumoperitoneum were lower than air group, TIMP-2 and ENS were higher than air group. CONCLUSION: After a CO(2) pneumoperitoneum, EMs lesions were reduced in volume, suggesting an inhibitory effect on EMs lesions. PMID- 22441660 TI - Age at menarche in childhood cancer survivors: results of a nationwide survey in Germany. AB - BACKGROUND/AIMS: With rising cure rates of childhood cancer, side effects of treatment are attracting increasing interest. The present analysis evaluates the influence of tumor localization, radiotherapy and chemotherapy on the age of menarche. METHODS: 4,689 former pediatric oncology patients, diagnosed 1980-2004, were contacted in collaboration with the German Childhood Cancer Registry. RESULTS: 1,036 out of 1,461 female participants reported their age at menarche and had an oncological diagnosis before menarche. The median age at menarche was 13 years, compared to 12.8 years in the German general population. A significant delay of menarche was seen in patients with pituitary radiation doses of >=30 Gy (mean 13.6 years, SD 2.2) compared to <30 Gy (mean 12.5 years, SD 1.4, p = 0.05). Patients with additional spinal radiation were even older at menarche (mean 14.4 years, SD 2.5). Pelvic and pelvic-near radiation significantly delayed onset of menarche (mean 14.0 years, SD 1.9 and mean 14.3, SD 2.6, respectively, p < 0.001). Only some chemotherapeutic agents (carboplatin/cisplatin, etoposide) were associated with a menarcheal delay of <1 year. CONCLUSION: Overall, female childhood cancer survivors showed a normal menarcheal age. Pituitary radiation dosage of >=30 Gy, spinal and pelvic radiotherapy were associated with a moderate delay in the occurrence of menarche. PMID- 22441659 TI - Are executive function and impulsivity antipodes? A conceptual reconstruction with special reference to addiction. AB - RATIONALE: Although there is considerable interest in how either executive function (EF) or impulsivity relate to addiction, there is little apparent overlap between these research areas. OBJECTIVES: The present paper aims to determine if components of these two constructs are conceptual antipodes--widely separated on a shared continuum. METHODS: EFs and impulsivities were compared and contrasted. Specifically, the definitions of the components of EF and impulsivity, the methods used to measure the various components, the populations of drug users that show deficits in these components, and the neural substrates of these components were compared and contrasted. RESULTS: Each component of impulsivity had an antipode in EF. EF, however, covered a wider range of phenomena, including compulsivity. CONCLUSIONS: Impulsivity functions as an antipode of certain components of EF. Recognition of the relationship between EF and impulsivity may inform the scientific inquiry of behavioral problems such as addiction. Other theoretical implications are discussed. PMID- 22441661 TI - Polymorphisms and variants in the prion protein sequence of European moose (Alces alces), reindeer (Rangifer tarandus), roe deer (Capreolus capreolus) and fallow deer (Dama dama) in Scandinavia. AB - The prion protein (PrP) sequence of European moose, reindeer, roe deer and fallow deer in Scandinavia has high homology to the PrP sequence of North American cervids. Variants in the European moose PrP sequence were found at amino acid position 109 as K or Q. The 109Q variant is unique in the PrP sequence of vertebrates. During the 1980s a wasting syndrome in Swedish moose, Moose Wasting Syndrome (MWS), was described. SNP analysis demonstrated a difference in the observed genotype proportions of the heterozygous Q/K and homozygous Q/Q variants in the MWS animals compared with the healthy animals. In MWS moose the allele frequencies for 109K and 109Q were 0.73 and 0.27, respectively, and for healthy animals 0.69 and 0.31. Both alleles were seen as heterozygotes and homozygotes. In reindeer, PrP sequence variation was demonstrated at codon 176 as D or N and codon 225 as S or Y. The PrP sequences in roe deer and fallow deer were identical with published GenBank sequences. PMID- 22441663 TI - Perineal stapled prolapse resection for complete external rectal prolapse: preliminary experience and literature review. AB - PURPOSE: Perineal stapled prolapse resection (PSP) for external rectal prolapse is a new surgical technique. METHODS: Between April 2009 and January 2011, 5 female patients (mean age, 67 years; range, 53-76) underwent PSP for full thickness external rectal prolapse. Patients were placed in a slight Trendelenburg position to free the pouch of Douglas from any deep enterocele. Laparoscopic control of the PSP procedure was performed to avoid injury to the bowel in one patient with anorexia. The prolapse was completely resected continuously counterclockwise using a curved Contour(r) TranstarTM stapler placed parallel to the dentate line. After completion of resection, the neorectum fell back into place spontaneously. RESULTS: Mean operating time was 56 min (range, 40 90). No intraoperative or postoperative complications occurred. No recurrence appeared. The mean hospital stay was 4 days (range, 3-6); the mean follow-up was 6.5 months (range, 2-15). The mean Wexner fecal incontinence score was 9.2 before and 4.6 at 3 months after surgery (p = 0.010); the mean obstructed defecation syndrome score decreased from 16 to 4.75 (p < 0.001). CONCLUSIONS: PSP is an easy, fast and safe procedure. Early functional results are good. Long-term results and recurrence rates need to be investigated further. PMID- 22441662 TI - The undervalued potential of positional therapy in position-dependent snoring and obstructive sleep apnea-a review of the literature. AB - PURPOSE: Research during the past 10-20 years shows that positional therapy (PT) has a significant influence on the apnea-hypopnea index. These studies are predominantly performed as case series on a comparably small number of patients. Still, results have not found their way into the daily diagnostic and treatment routine. An average of 56 % of patients with obstructive sleep apnea (OSA) have position-dependent OSA (POSA), commonly defined as a difference of 50 % or more in apnea index between supine and non-supine positions. A great deal could be gained in treating patients with POSA with PT. The aim of this paper was to perform a thorough review of the literature on positional sleep apnea and its therapy. METHODS: A broad search strategy was run electronically in the MEDLINE and EMBASE databases using synonyms for position and sleep apnea. RESULTS: Sixteen studies were found which examined the effect of PT on OSA. In this literature review, we discuss the various techniques, results, and compliance rates. CONCLUSION: Long-term compliance for PT remains an issue, and although remarkable results have been shown using innovative treatment concepts for PT, there is room for both technical improvement of the devices and for further research. PMID- 22441664 TI - External landmark, body surface, and volume data of a mid-sized male in seated and standing postures. AB - The purpose of this study was to acquire external landmark, undeformed surface, and volume data from a pre-screened individual representing a mid-sized male (height 174.9 cm, weight 78.6 +/- 0.77 kg) in the seated and standing postures. The individual matched the 50th percentile value of 15 measures of external anthropometry from previous anthropometric studies with an average deviation of 3%. As part of a related study, a comprehensive full body medical image data set was acquired from the same individual on whom landmark data were collected. Three dimensional bone renderings from this data were used to visually verify the landmark and surface results. A total of 54 landmarks and external surface data were collected using a 7-axis digitizer. A seat buck designed in-house with removable back and seat pan panels enabled collection of undeformed surface contours of the back, buttocks, and posterior thigh. Eight metrics describing the buck positioning are provided. A repeatability study was conducted with three trials to assess intra-observer variability. Total volume and surface area of the seated model were found to be 75.8 * 10(3) cm(3) and 18.6 * 10(3) cm(2) and match the volume and surface area of the standing posture within 1%. Root mean squared error values from the repeatability study were on average 5.9 and 6.6 mm for the seated and standing postures respectively. The peak RMS error as a percentage of the centroid size of the landmark data sets were 3% for both the seated and standing trials. The data were collected as part of a global program on the development of an advanced human body model for blunt injury simulation. In addition, the reported data can be used for many diverse applications of biomechanical research such as ergonomics and morphometrics studies. PMID- 22441665 TI - Involvement of p38MAPK/NF-kappaB signaling pathways in osteoblasts differentiation in response to mechanical stretch. AB - Bone morphogenetic proteins (BMPs) are known to be important in osteoblasts' response to mechanical stimuli. BMPs/Smad signaling pathway has been demonstrated to play a regulatory role in the mechanical signal transduction in osteoblasts. However, little is currently known about the Smad independent pathway in osteoblasts differentiation in mechanical loading. In this study, MC3T3-E1 cells were subjected to mechanical stretch of 2000 micro-stain (MUepsilon) at 0.5 Hz, in order to investigate the involvement of p38MAPK and NF-kappaB signaling pathways in mechanical response in osteoblasts. We found BMP-2/BMP-4 were up regulated by mechanical stretch via the earlier activation of p38MAPK and NF kappaB signaling pathways, which enhanced osteogenic gene expressions including alkaline phosphatase (ALP), collagen type I (Col I) and osteocalcin (OCN), and the expressions of these osteogenic genes were remarkably decreased with Noggin (an inhibitor for BMPs signals) pretreatment. Furthermore, BMP-2/BMP-4 expressions were suppressed by PDTC, an inhibitor of NF-kappaB pathway and SB203580, an inhibitor of p38MAPK pathway, respectively, leading to the declined levels of ALP, Col I and OCN. Interestingly, blocking in p38MAPK pathway can also cause the inactivation of NF-kappaB pathway in mechanical stretch. Collectively, the results indicate during mechanical stretch p38MAPK and NF-kappaB signaling pathways are activated first, and then up-regulate BMP-2/BMP-4 to enhance osteogenic gene expressions. Moreover, p38MAPK and NF-kappaB signals have cross talk in regulation of BMP-2/BMP-4 in mechanical response. PMID- 22441666 TI - Automatic scan planning for magnetic resonance imaging of the knee joint. AB - Automatic scan planning for magnetic resonance imaging of the knee aims at defining an oriented bounding box around the knee joint from sparse scout images in order to choose the optimal field of view for the diagnostic images and limit acquisition time. We propose a fast and fully automatic method to perform this task based on the standard clinical scout imaging protocol. The method is based on sequential Chamfer matching of 2D scout feature images with a three dimensional mean model of femur and tibia. Subsequently, the joint plane separating femur and tibia, which contains both menisci, can be automatically detected using an information-augmented active shape model on the diagnostic images. This can assist the clinicians in quickly defining slices with standardized and reproducible orientation, thus increasing diagnostic accuracy and also comparability of serial examinations. The method has been evaluated on 42 knee MR images. It has the potential to be incorporated into existing systems because it does not change the current acquisition protocol. PMID- 22441667 TI - Modeling brain injury response for rotational velocities of varying directions and magnitudes. AB - An estimated 1.7 million people in the United States sustain a traumatic brain injury (TBI) annually. To investigate the effects of rotational motions on TBI risk and location, this study modeled rotational velocities of five magnitudes and 26 directions of rotation using the Simulated Injury Monitor finite element brain model. The volume fraction of the total brain exceeding a predetermined strain threshold, the Cumulative Strain Damage Measure (CSDM), was investigated to evaluate global model response. To evaluate regional response, this metric was computed relative to individual brain structures and termed the Structure Cumulative Strain Damage Measure (SCSDM). CSDM increased as input magnitude increased and varied with the direction of rotation. CSDM was 0.55-1.7 times larger in simulations with transverse plane rotation compared to those without transverse plane rotation. The largest SCSDM in the cerebrum and brainstem occurred with rotations in the transverse and sagittal planes, respectively. Velocities causing medial rotation of the cerebellum resulted in the largest SCSDM in this structure. For velocities of the same magnitude, injury risk calculated from CSDM varied from 0 to 97% with variations in the direction of rotation. These findings demonstrate injury risk, as estimated by CSDM and SCSDM, is affected by the direction of rotation and input magnitude, and these may be important considerations for injury prediction. PMID- 22441668 TI - RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation. AB - Adipose tissue structure is altered during obesity, leading to deregulation of whole-body metabolism. Its function depends on its structure, in particular adipocytes number and differentiation stage. To better understand the mechanisms regulating adipogenesis, we have investigated the role of an endoribonuclease, endoribonuclease L (RNase L), using wild-type and RNase L-knockout mouse embryonic fibroblasts (RNase L(-/-)-MEFs). Here, we identify C/EBP homologous protein 10 (CHOP10), a dominant negative member of the CCAAT/enhancer-binding protein family, as a specific RNase L target. We show that RNase L is associated with CHOP10 mRNA and regulates its stability. CHOP10 expression is conserved in RNase L(-/-)-MEFs, maintaining preadipocyte state while impairing their terminal differentiation. RNase L(-/-)-MEFs have decreased lipids storage capacity, insulin sensitivity and glucose uptake. Expression of ectopic RNase L in RNase L( /-)-MEFs triggers CHOP10 mRNA instability, allowing increased lipids storage, insulin response and glucose uptake. Similarly, downregulation of CHOP10 mRNA with CHOP10 siRNA in RNase L(-/-)-MEFs improves their differentiation in adipocyte. In vivo, aged RNase L(-)/(-) mice present an expanded adipose tissue, which, however, is unable to correctly store lipids, illustrated by ectopic lipids storage in the liver and in the kidney. These findings highlight RNase L as an essential regulator of adipogenesis via the regulation of CHOP10 mRNA. PMID- 22441669 TI - PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death. AB - To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death. PMID- 22441670 TI - Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response. AB - Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program. PMID- 22441671 TI - Processing and characterization of innovative scaffolds for bone tissue engineering. AB - A new protocol, based on a modified replication method, is proposed to obtain bioactive glass scaffolds. The main feature of these samples, named "shell scaffolds", is their external surface that, like a compact and porous shell, provides both high permeability to fluids and mechanical support. In this work, two different scaffolds were prepared using the following slurry components: 59 % water, 29 % 45S5 Bioglass((r)) and 12 % polyvinylic binder and 51 % water, 34 % 45S5 Bioglass((r)), 10 % polyvinylic binder and 5 % polyethylene. All the proposed samples were characterized by a widespread microporosity and an interconnected macroporosity, with a total porosity of 80 % vol. After immersion in a simulated body fluid (SBF), the scaffolds showed strong ability to develop hydroxyapatite, enhanced by the high specific surface of the porous systems. Moreover preliminary biological evaluations suggested a promising role of the shell scaffolds for applications in bone tissue regeneration. As regards the mechanical behaviour, the shell scaffolds could be easily handled without damages, due to their resistant external surface. More specifically, they possessed suitable mechanical properties for bone regeneration, as proved by compression tests performed before and after immersion in SBF. PMID- 22441672 TI - Propionibacterium acnes delayed infection following spinal surgery with instrumentation. AB - Propionibacterium acnes detection in culture media was previously considered a contamination but recently its infectious role was discovered in post-spinal surgery infections. P. acnes might be introduced during surgery. Its diagnosis is based on non-specific clinical signs, image indications of infection, and the conclusive microbiological sign. Furthermore, its diagnosis is difficult because of slow growth rate and low virulence, delaying its presentation. Usually, the infection is manifested after a couple of months or years. Here, a 65-year-old man presented with drainage at the site of instrumented spinal surgery performed 13 years ago. P. acnes infection was confirmed by culture with extended incubation. Our review of the literature revealed only two other reported cases of delayed P. acnes infection presenting a decade following a spinal surgery with instrumentation. This article sheds light on such delayed infections and discusses their presentation and management. PMID- 22441673 TI - Ectopic expression of Capsicum-specific cell wall protein Capsicum annuum senescence-delaying 1 (CaSD1) delays senescence and induces trichome formation in Nicotiana benthamiana. AB - Secreted proteins are known to have multiple roles in plant development, metabolism, and stress response. In a previous study to understand the roles of secreted proteins, Capsicum annuum secreted proteins (CaS) were isolated by yeast secretion trap. Among the secreted proteins, we further characterized Capsicum annuum senescence-delaying 1 (CaSD1), a gene encoding a novel secreted protein that is present only in the genus Capsicum. The deduced CaSD1 contains multiple repeats of the amino acid sequence KPPIHNHKPTDYDRS. Interestingly, the number of repeats varied among cultivars and species in the Capsicum genus. CaSD1 is constitutively expressed in roots, and Agrobacterium-mediated transient overexpression of CaSD1 in Nicotiana benthamiana leaves resulted in delayed senescence with a dramatically increased number of trichomes and enlarged epidermal cells. Furthermore, senescence- and cell division-related genes were differentially regulated by CaSD1-overexpressing plants. These observations imply that the pepper-specific cell wall protein CaSD1 plays roles in plant growth and development by regulating cell division and differentiation. PMID- 22441674 TI - Antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. AB - Reactive oxygen species (ROS) generation is linked to dynamic actin cytoskeleton reorganization, which is involved in tumor cell motility and metastasis. Thus, inhibition of ROS generation and actin polymerization in tumor cells may represent an effective anticancer strategy. However, the molecular basis of this signaling pathway is currently unknown. Here, we show that the Ecklonia cava derived antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Steady state intracellular ROS levels were higher in malignant B16F10 cells than in parental, nonmetastatic B16F0 cells. Elevation of ROS by H(2)O(2) treatment increased migration and invasion ability of B16F0 cells to level similar to that of B16F10 cells, suggesting that intracellular ROS signaling mediates the prometastatic properties of B16 mouse melanoma cells. ROS levels and the cell migration and invasion ability of B16 melanoma cells correlated with Rac1 activation and WAVE2 expression. Overexpression of dominant negative Rac1 and depletion of WAVE2 by siRNA suppressed H(2)O(2)-induced cell invasion of B16F0 and B16F10 cells. Similarly, dieckol attenuates the ROS-mediated Rac1 activation and WAVE2 expression, resulting in decreased migration and invasion of B16 melanoma cells. In addition, we found that dieckol decreases association between WAVE2 and NADPH oxidase subunit p47(phox). Therefore, this finding suggests that WAVE2 acts to couple intracellular Rac1/ROS signaling to the invasive migration of B16 melanoma cells, which is inhibited by dieckol. PMID- 22441675 TI - Neurotensin modulates pacemaker activity in interstitial cells of Cajal from the mouse small intestine. AB - Neurotensin, a tridecapeptide localized in the gut to discrete enteroendocrine cells of the small bowel mucosa, is a hormone that plays an important role in gastrointestinal secretion, growth, and motility. Neurotensin has inhibitory and excitatory effects on peristaltic activity and produces contractile and relaxant responses in intestinal smooth muscle. Our objective in this study is to investigate the effects of neurotensin in small intestinal interstitial cells of Cajal (ICC) and elucidate the mechanism. To determine the electrophysiological effects of neurotensin on ICC, whole-cell patch clamp recordings were performed in cultured ICC from the small intestine. Exposure to neurotensin depolarized the membrane of pacemaker cells and produced tonic inward pacemaker currents. Only neurotensin receptor1 was identified when RT-PCR and immunocytochemistry were performed with mRNA isolated from small intestinal ICC and c-Kit positive cells. Neurotensin-induced tonic inward pacemaker currents were blocked by external Na+ free solution and in the presence of flufenamic acid, an inhibitor of non selective cation channels. Furthermore, neurotensin-induced action is blocked either by treatment with U73122, a phospholipase C inhibitor, or thapsigargin, a Ca2+-ATPase inhibitor in ICC. We found that neurotensin increased spontaneous intracellular Ca2+ oscillations as seen with fluo4/AM recording. These results suggest that neurotensin modulates pacemaker currents via the activation of non selective cation channels by intracellular Ca2+-release through neurotensin receptor1. PMID- 22441676 TI - A single-amino-acid variant of the H60 CD8 epitope generates specific immunity with diverse TCR recruitment. AB - TCR of CD8 T cells recognizes peptides of 8-9 amino acids in length (epitope) complexed with MHC class I. Peptide ligands differing from an epitope by one or two amino acids are thought to modulate the immune response specific to that epitope. H60 is a minor histocompatibility antigen for which the specific CD8 T cell response dominates during alloresponse after MHC-matched allogeneic transplantation. In the present study, we developed a transgenic mouse (designated H60H Tg) expressing a variant of H60, designated H60H, in which the arginine residue at position 4 of the H60 epitope sequence (LTFNYRNL) is replaced by a histidine residue (LTFHYRNL). Immunization of female C57BL/6 mice with splenocytes from male H60H Tg induced a CD8 T cell primary response and memory response after re-challenge. The response was CD4 help-dependent, demonstrating the potency of H60H as a cellular antigen. The response induced by the H60H cellular antigen was comparable to that induced by H60 in its peak magnitude and overall immune kinetics. H60H challenge recruited broadly diverse TCRs to the specific response, shaping a TCR repertoire different from that of the natural H60 epitope. However, some of the TCRs did overlap between the H60H- and H60 specific CD8 T cells, suggesting that H60H might modulate the H60-specific response. These results may provide a basis for the modulation of the H60 specific CD8 T-cell response. PMID- 22441677 TI - MYO5B mutations in patients with microvillus inclusion disease presenting with transient renal Fanconi syndrome. AB - BACKGROUND AND OBJECTIVE: : Microvillus inclusion disease (MVID) is a rare congenital enteropathy associated with brush border atrophy and reduced expression of enzymes at the enterocytes' apical surface. MVID is associated with mutations in the MYO5B gene, which is expressed in all epithelial tissues. Whether organs other than the intestine are affected in MVID is unclear. We report 2 patients with MVID that developed renal Fanconi syndrome while receiving total parenteral nutrition. Renal Fanconi syndrome has been correlated to apical plasma membrane defects in kidney proximal tubular epithelial cells. The aim of the present study was to determine whether MYO5B mutations in these patients correlate with similar apical plasma membrane defects in renal tubular epithelial cells as observed in the intestine. METHODS: : Biopsies from kidney, duodenum, ileum, jejunum, and colon of 2 patients with MVID carrying MYO5B mutations and of age-matched controls were fixed in paraffin and analyzed with immunohistochemistry and transmission electron microscopy. RESULTS: : Structural defects of the brush border and apical recycling endosome organization are observed in enterocytes of all of the segments of the small intestine and colon. MYO5B mutations in patients with MVID with renal Fanconi syndrome do not correlate with aberrant apical plasma membrane morphology or altered apical recycling endosome organization in renal tubular epithelial cells. CONCLUSIONS: : MYO5B mutations have divergent effects on the apical membrane system in kidney and intestinal epithelial cells. Epithelial defects presented in MVID are therefore likely triggered by intestine-specific factors, the identification of which may provide new targets and open avenues for the development of alternative therapeutic strategies to combat this devastating disease. PMID- 22441678 TI - Monomeric organoantimony(III) sulphide and selenide with terminal Sb-E bond (E = S, Se). Synthesis, structure and theoretical consideration. AB - NCN chelated monomeric chalcogenides, LSbE (E = S (1), Se (2), L = 2,6-bis[N (2',6'-dimethylphenyl)ketimino]phenyl), were synthesized and characterized with the help of elemental analysis, NMR spectroscopy and single-crystal X-ray diffraction analyses. The terminal Sb-E (E = S, Se) bonds in 1 and 2 were subjected to theoretical investigation and the results are compared with the hypothetical molecules, PhSb=E (E = S, Se, Te), and earlier reported analogues. PMID- 22441679 TI - Lipopolysaccharide neutralization by antimicrobial peptides: a gambit in the innate host defense strategy. AB - Antimicrobial peptides (AMPs) are nowadays understood as broad multifunctional tools of the innate immune system to fight microbial infections. In addition to its direct antimicrobial action, AMPs can modulate the host immune response by promoting or restraining the recruitment of cells and chemicals to the infection focus. Binding of AMPs to lipopolysaccharide is a critical step for both their antimicrobial action and their immunomodulatory properties. On the one hand, removal of Gram-negative bacteria by AMPs can be an effective strategy to prevent a worsened inflammatory response that may lead to septic shock. On the other hand, by neutralizing circulating endotoxins, AMPs can successfully reduce nitric oxide and tumor necrosis factor-alpha production, hence preventing severe tissue damage. Furthermore, AMPs can also interfere with the Toll-like receptor 4 recognition system, suppressing cytokine production and contributing to modulate the inflammatory response. Here, we review the immune system strategies devised by AMPs to avoid an exacerbated inflammatory response and thus prevent a fatal end to the host. PMID- 22441680 TI - Endoscopic management of congenital bilateral posterior choanal atresia: value of using stents. AB - Objective of this study is to evaluate the efficacy and safety of using stents after endoscopic repair of bilateral posterior choanal atresia. Twenty cases of congenital bilateral posterior choanal atresia were managed by endoscopic transnasal approach which was performed using a nasal stent in 10 cases and without stenting in the other 10 cases. The stent was left for 4 weeks and patients had 1-5 years of follow-up. Patients have been evaluated subjectively and objectively: clinical and by endoscopic examination. Closure occurs in 20% of the stent group compared to 30% of the non-stent group, with no statistically significant difference between the two groups. On the other hand, choanal narrowing and stenosis occurs in 40% of the stent group compared to 20% of the non-stent group with a statistically significant difference between the two groups. Granulation tissue formation was detected in 50%, erosion of the nares in 10%, premature extrusion in 10%, and dislodgement in 10% of stent group. Granulation tissue formation was detected in 20%, hemorrhage occurred in 10% of the non-stent group patients. There was a statistically significant difference between the two groups (P-value < 0.05) regarding granulation tissue formation. The use of stents after endoscopic repair of congenital bilateral posterior choanal atresia does not seem to decrease the incidence of re-closure and restenosis of the posterior choana. On the other hand, there are higher complication rate from using the stents like granulation tissue formation, excoriation or erosion of the nares, premature extrusion, dislodgement, stent blockage, and the unsightly aspect of having stents protrude from the nose. PMID- 22441681 TI - Synthesis and biological evaluation of (--)-linarinic acid derivatives as neuroprotective agents against OGD-induced cell damage. AB - A series of novel (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed and synthesized. All of the prepared compounds were screened for their neuroprotective effects using an in vitro oxygen glucose deprivation (OGD) model of ischemic stroke. Some of the target compounds exhibited moderate to excellent protective potency. In particular, compounds 9d, 9e, 9g, and 9h showed significant protective effects in the SH-SY(5) Y cell line at all three concentrations tested. PMID- 22441682 TI - [Conflicts in organ donation]. PMID- 22441683 TI - [End-of-life decisions - what is important for our routine duties in critical care medicine?]. AB - End-of-life decisions (EOLD) are frequently used in patients who die in the intensive care unit. The decision to limit life support and the extent of limitation depends on the nature of the disease, its progress and the presumed prognosis and, equally important, the patient's preferences. These preferences should be stated by the patient if he or she is able to do so. If not, the patient's assumed will can be elicited by using written advance directives or with the help of surrogate decision makers.Primarily withholding life-sustaining treatment is reasonable in patients who present with an endstage, irreversibly progressive disease or if the patient explicitly rejects intensive care treatment.Limiting the extent of intensive care medicine by withholding specific procedures (e.g. resuscitation) should be discussed in critically ill patients whose prognosis would become futile with an additional serious medical problem.Withdrawing life-sustaining treatment and changing to palliative care should be considered if intensive care medicine is futile because of the severity of the patient's condition.It is vital to find an interdisciplinary consensus about EOLD within the medical team as well as with the patient/surrogate decision maker. The agreement is documented in the patient's chart. PMID- 22441684 TI - [Mental disorders in intensive care medicine - part 1: Principles and diagnostics]. AB - This two-part article on mental disorders in intensive care medicine aims to provide an understanding of the most frequent mental disorders in critical care medicine. Part 1 highlights the basic principles, disturbances and diagnostics and part 2 deals with prevention and therapeutic approaches. The most frequent mental disorders in the intensive care unit are delirium, substance abuse or, respectively, intoxication, suicide attempts, anxiety disorders, depression or psychosis. Mental disorders may be the reason for admission or can develop in the course of intensive care treatment, such as, for example, a post-traumatic stress disorder. The consequences thereof include increased morbidity, mortality, and duration of hospitalization. The early participation of a psychiatrist in the diagnostic process is to be recommended. PMID- 22441685 TI - [Transthoracic echocardiography in anesthesia - case studies]. AB - Transthoracic echocardiography (TTE) is a well established tool in cardiology and cardiosurgery. The rapid availability of TTE, combined with high quality and quantity of diagnostic messages, provides the user an interesting option in the area of anesthesia and intensive care medicine. The presenting case reports describe the importance and possibilities of transthoracic echocardiography for anaesthetists in the non-cardiosurgical area. PMID- 22441686 TI - [Pssst ... AINS-secrets! - today in vascular surgery]. PMID- 22441687 TI - [Management of organ donors and organ recipients - a challenge transplantation medicine]. PMID- 22441688 TI - [Anaesthesia in patients after transplantation]. AB - More than 17000 patients currently live in Germany who have had organ transplants. The implications of this for the anaesthetists are that they are very likely to be confronted by such a patient at some point during their active career. Besides the preoperative assessment which includes that of the function of the transplanted organ, appropriate immunosuppression poses a particular challenge. Close collaboration with both patients and their transplant specialists is essential to preempt the perioperative consequences and plan continuation of immunosuppression. Strictly aseptic measures are mandatory as well as detailed evaluation of the risk-benefit balance of all invasive procedures.There are no significant differences between the anaesthetic approaches and agents in transplant and non-transplant patients. However, in the latter group, homeostasis of all organ systems should be more focused on. PMID- 22441689 TI - [Diagnostic of brain death]. AB - Despite of some discussion, there is general acceptance of the brain death criterion. As for Germany, there is a quasi legal regulation (TPG S16): two physicians with a longstanding experience in the management of patients with severe brain lesions are personally responsive for the diagnostic procedure lege artis. No false positive diagnosis has been published, hitherto. Before any organ explantation, diagnosis of brain death is mandatory. Nevertheless, discussions on brain death should not be instrumentalized by circumstances of organ explantation. Brain death should be part of a good educational background, to anticipate reflections free from the emotional binding of an acute incident. PMID- 22441690 TI - [Management of brain death organ donor]. AB - The demand for donor organs continues to exceed the number of organs available for transplantation. The assistance to the family members of a potential donor in forefront of transplantation is as much important as to maintain donor organ function. Caring for a brain dead potential organ donor is therefore major challenge for nurses and physicians.The pathophysiological changes following brain death entail a high incidence of complications including hemodynamic instability, endocrine and metabolic disturbances, that jeopardize potentially transplantable organs. The knowledge of the complex physiologic changes is crucial to the development of effective donor management strategies.The management of potential organ donors is similar to the management of patients with severe sepsis. The main goal of that treatment is to achieve hemodynamic stability as well as the normalization of endocrine and metabolic disturbances. Donor optimization leads to increased organ procurement and contributes to improved organ function in the recipient. PMID- 22441691 TI - Neurl4, a novel daughter centriole protein, prevents formation of ectopic microtubule organizing centres. AB - Here we identify Neuralized homologue 4 (Neurl4) as a protein that interacts with CP110, a centrosomal protein that regulates centrosome duplication. Neurl4 uses a Neuralized homology repeat to preferentially localize to procentrioles and daughter centrioles. Neurl4 depletion results in ectopic microtubular organizing centres (MTOCs), leading to accumulation of CP110 and recruitment of a cohort of centrosomal proteins. We show that these ectopic MTOCs persist through mitosis and assemble aberrant mitotic spindles. Interestingly, Neurl4 promotes ubiquitylation of CP110, thereby destabilizing this protein. Our results indicate that Neurl4 counteracts accumulation of CP110, thereby maintaining normal centriolar homeostasis and preventing formation of ectopic MTOCs. PMID- 22441692 TI - JNK regulates the photic response of the mammalian circadian clock. AB - The posttranslational regulation of mammalian clock proteins has been assigned a time-keeping function, but seems to have more essential roles. Here we show that c-Jun N-terminal kinase (JNK), identified by inhibitor screening of BMAL1 phosphorylation at Ser 520/Thr 527/Ser 592, confers dynamic regulation on the clock. Knockdown of JNK1 and JNK2 abrogates BMAL1 phosphorylation and lengthens circadian period in fibroblasts. Mice deficient for neuron-specific isoform JNK3 have altered behavioural rhythms, with longer free-running period and compromised phase shifts to light. The locomotor rhythms are insensitive to intensity variance of constant light, deviating from Aschoff's rule. Thus, JNK regulates a core characteristic of the circadian clock by controlling the oscillation speed and the phase in response to light. PMID- 22441693 TI - Gallbladder cancer in the Netherlands: incidence, treatment and survival patterns since 1989. AB - BACKGROUND: To examine recent trends in gallbladder cancer (GBC) in the general population in the Western world, cancer registration data on GBC in the Netherlands were analyzed. METHODS: Trends in incidence, treatment and survival, according to gender, age and stage of disease, between 1989 and 2008 for 3,917 patients were studied. Rates were age-standardized to the European standard population (European Standardized Rates - ESR). RESULTS: The incidence rate for GBC in the Netherlands decreased rapidly during the period of 1989-2008, except for males younger than 60 years. Overall survival remained stable, short-term (3 month) and long-term (5-year) relative survival among surgically treated patients increased significantly. Treatment patterns for GBC changed. Surgery decreased from 55% in 1989 to 38% in 2008 (p < 0.001). Chemotherapy and/or irradiation increased from 1.0 to 5.8% (p < 0.001). Receiving best supportive care increased from 44% in 1989 to 57% in 2008 (p < 0.001). CONCLUSION: The incidence rate for GBC in the Netherlands has decreased rapidly. Treatment patterns for GBC have changed and survival among surgically treated patients has increased. PMID- 22441694 TI - An ultrasensitive electrochemical DNA sensor based on the ssDNA-assisted cascade of hybridization reaction. AB - We have developed a simple and ultrasensitive E-DNA sensor based on the ssDNA assisted cascade of a hybridization reaction mechanism to form a long concatamers structure to improve its sensitivity, significantly. The proposed sensor was applied to sequence-specific DNA and ATP detection. Experimental results showed a quantitative measurement with the detection limit as low as 1 aM for specific DNA and 10 fM for ATP. PMID- 22441695 TI - Conservation and management of the endangered Fiji sago palm, Metroxylon vitiense, in Fiji. AB - Recovery planning is a key component of many threatened species conservation initiatives and can be a powerful awareness raising tool. One of the largest impediments to conservation efforts in the Pacific region however, is the lack of ecological data and its subsequent effects on the development of feasible and useful recovery plans for threatened species. Without these plans, the understaffed, underfunded and often technically ill-equipped conservation agencies face huge difficulties in planning, prioritizing and conducting conservation activities to adequately protect biodiversity. The Fiji sago palm, Metroxylon vitiense, is an endemic endangered palm species whose survival is heavily dependent on a feasible species recovery plan. It is geographically restricted and threatened by habitat destruction and overexploitation for thatch for the tourism industry and palm heart consumption by local consumers. Despite its threatened status, M. vitiense is not currently protected by national or international legislation. Recent field surveys and extensive stakeholder consultation have resulted in the production of a species recovery plan highlighting the importance of the species and advocating sustainable harvesting rather than complete bans to promote conservation. This article summarizes the recovery plan and its current effects on the status of M. vitiense in Fiji. We also discuss the role of different stakeholders in the conservation of M. vitiense, including the absence of significant behavioral changes by the largest consumer - the tourism industry, and the importance of recovery plans for biodiversity conservation in the Pacific. PMID- 22441696 TI - Developing an action plan for patient radiation safety in adult cardiovascular medicine: proceedings from the Duke University Clinical Research Institute/American College of Cardiology Foundation/American Heart Association think tank held on February 28, 2011. AB - Technological advances and increased utilization of medical testing and procedures have prompted greater attention to ensuring the patient safety of radiation use in the practice of adult cardiovascular medicine. In response, representatives from cardiovascular imaging societies, private payers, government and nongovernmental agencies, industry, medical physicists, and patient representatives met to develop goals and strategies toward this end; this report provides an overview of the discussions. This expert "think tank" reached consensus on several broad directions including: the need for broad collaboration across a large number of diverse stakeholders; clarification of the relationship between medical radiation and stochastic events; required education of ordering and providing physicians, and creation of a culture of safety; development of infrastructure to support robust dose assessment and longitudinal tracking; continued close attention to patient selection by balancing the benefit of cardiovascular testing and procedures against carefully minimized radiation exposures; collation, dissemination, and implementation of best practices; and robust education, not only across the healthcare community, but also to patients, the public, and media. Finally, because patient radiation safety in cardiovascular imaging is complex, any proposed actions need to be carefully vetted (and monitored) for possible unintended consequences. PMID- 22441697 TI - Microbial community responses to bioremediation treatments for the mitigation of low-dose anthracene in marine coastal sediments of Bizerte lagoon (Tunisia). AB - PURPOSE: The main goals of this study were to investigate (1) the behavior of microbial communities in response to low-dose bioavailable anthracene addition in lightly contaminated sediment from Bizerte Lagoon and (2) the effects of bioremediation treatments on microbial biomass, activity, and community structure. METHODS: Sediment microcosms amended with 1 ppm anthracene were incubated in triplicate during 30 days. Biostimulation (addition of nitrogen and phosphorus fertilizer) and bioaugmentation (inoculation of a hydrocarbonoclastic bacterium) were used as bioremediation treatments. Bacterial biomass was estimated using flow cytometry. Sediment oxygen consumption was measured with oxygen microelectrodes. Bacterial community structure was assessed by molecular fingerprints (terminal restriction fragment length polymorphism; T-RFLP) analysis. RESULTS: Anthracene contamination resulted in a significant reduction of bacterial abundance with an impact on cell integrity. Concomitantly, sediment oxygen consumption was strongly inhibited. Correspondence analysis on T-RFLP data indicated that bacterial community structures from anthracene-contaminated microcosms were different from that of the control. Interestingly, the changes observed in microbial biomass, structure, and activities as a result of anthracene contamination were not alleviated even with the use of biostimulation and combination of biostimulation and bioaugmentation strategy for anthracene bioremediation. Nevertheless, both treatment methods resulted in different community structures relative to the contaminated and control microcosms with the appearance of distinct populations. CONCLUSION: Anthracene spiking severely affected microbial communities, suggesting dominance of nontolerant populations in this lightly-contaminated sediment. Although biostimulation and/or bioaugmentation treatments did not alleviate the anthracene toxic effects, the changes observed in microbial population and structure suggest that the proposed treatments might be promising to promote bacterial growth. Further works are still required to propose a more efficient strategy to stimulate biodegradation that takes into account the complex interactions between species for resource access. PMID- 22441698 TI - Perfluorooctane sulfonate increases beta-oxidation of palmitic acid in chicken liver. AB - PURPOSE: Perfluorooctane sulfonate (PFOS) belongs to a group of chemicals called perfluoroalkyl acids that have been extensively used in various applications such as stain and oil resistant treatments for fabrics, fire-fighting foams, and insecticides. These chemicals present an environmental and health risk being present in many samples both in wildlife and humans. In this study, we investigate the effect of PFOS on fatty acid beta-oxidation in developing chicken embryos. METHODS: Fertilized chicken eggs were exposed in ovo to PFOS at day 4 of incubation. On day 10, the eggs were dissected and livers were incubated in vitro with (3)H-palmitic acid for 2 h. The media were collected, and after clean up, the amount of tritiated water was measured with liquid scintillation counting to determine the rate of palmitic acid beta-oxidation. RESULTS: PFOS was found to induce fatty acid beta-oxidation at doses starting from a lowest observed effect level (LOEL) of 0.1 MUg/g egg weight. Maximum induction of 77% compared to control was seen at 0.3 MUg/g. CONCLUSIONS: The administered doses in which effects are seen are around and even lower than the levels that can be found in wild populations of birds. General population human levels are a factor of two to three times lower than the LOEL value of this study. The environmental contamination of PFOS therefore presents a possibility of effects in wild populations of birds. PMID- 22441699 TI - Dietary L-arginine supplementation alleviates liver injury caused by Escherichia coli LPS in weaned pigs. AB - This study was conducted to evaluate whether dietary supplementation with L arginine (Arg) could attenuate Escherichia coli LPS-induced liver injury through the TLR4 signaling pathway in weaned pigs. Eighteen weaned pigs were allotted to three treatments: non-challenged control, LPS challenged control and LPS + 0.5% Arg. On d 18, pigs were injected with LPS at 100 ug/kg of body weight (BW) or sterile saline. Blood samples were obtained at 4 h post-injection. Pigs were then sacrificed for the collection of liver samples. Arg supplementation (0.5%) alleviated liver morphological impairment, including hepatocyte caryolysis, karyopycnosis and fibroblast proliferation induced by LPS challenge; it mitigated the increase of serum aspartate aminotransferase and alkaline phosphatase activities induced by LPS (P < 0.05); it prevented the increase of hepatic TNF alpha, malondialdehyde contents and mast cell number induced by LPS administration (P < 0.05); and it attenuated the elevation of hepatic NF-kappaB and TLR4-positive cell percentages (P < 0.05). These results indicate that Arg supplementation has beneficial effects in attenuating hepatic morphological and functional injury induced by LPS challenge in piglets. Additionally, it is possible that the protective effects of Arg on the liver are associated with a decreased release of liver pro-inflammatory cytokines and free radicals through inhibiting TLR4 signaling. PMID- 22441700 TI - Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes. AB - Much evidence indicates that bacterial LPS (endotoxin) is removed from the bloodstream mainly by the liver, yet the hepatic uptake mechanisms remain uncertain and controversial. In plasma, LPS can be either 'free' (as aggregates, bacterial membrane fragments or loosely bound to albumin, CD14, or other proteins) or 'bound' (complexed with lipoproteins). Whereas most free LPS is taken up by Kupffer cells (KCs), lipoprotein-bound LPS has seemed to be cleared principally by hepatocytes. Here, we compared the liver's ability to take up and deacylate free LPS aggregates and the LPS in preformed LPS-high density lipoprotein (HDL) complexes. In mice examined from 1 h to 7 d after a small amount of fluorescent (FITC-)LPS was injected into a lateral tail vein, we found FITC-LPS almost entirely within, or adjacent to, KCs. As expected, FITC-LPS complexed with HDL (FITC-LPS-HDL) disappeared more slowly from the circulation and a smaller fraction of the injected dose of FITC-LPS was found in the liver. Unexpectedly, the FITC-LPS injected as FITC-LPS-HDL complexes was also found within sinusoids, adjacent to, or within, KCs. In other experiments, we found that both free and HDL-bound radiolabeled LPS underwent enzymatic deacylation by acyloxyacyl hydrolase (AOAH), the LPS-inactivating enzyme that is principally produced within the liver by KCs. Our observations suggest that KCs and AOAH play important roles in clearing and catabolizing both free LPS and the LPS in circulating LPS-HDL complexes. PMID- 22441701 TI - alpha-Fe2O3 nanotubes-reduced graphene oxide composites as synergistic electrochemical capacitor materials. AB - We present a facile approach for the fabrication of a nanocomposite comprising alpha-Fe(2)O(3) nanotubes (NTs) anchored on reduced graphene oxide (rGO) for electrochemical capacitors (ECs). The hollow tubular structure of the alpha Fe(2)O(3) NTs presents a high surface area for reaction, while the incorporation of rGO provides an efficient two-dimensional conductive pathway to allow fast, reversible redox reaction. As a result, the nanocomposite materials exhibit a specific capacitance which is remarkably higher (~7 times) than alpha-Fe(2)O(3) NTs alone. In addition, the nanocomposites show excellent cycling life and large negative potential window. These findings suggest that such nanocomposites are a promising candidate as negative electrodes in asymmetrical capacitors with neutral electrolytes. PMID- 22441702 TI - Integrating sleep management into clinical practice. AB - Although the basic function of sleep remains a mystery, insufficient sleep is associated with mood disturbance, fatigue and daytime lethargy, cognitive impairments, daytime behavior problems, academic problems, use of stimulants, work absenteeism, lost work production and an increase in healthcare utilization. The International Classification of Sleep Disorders distinguishes 90 different disorders, many of which can be effectively treated, but when left untreated can be costly in terms of quality of life, health and healthcare cost. Over the past 50 years we have become more effective in measuring sleep and have honed our treatments to better address the sleep disorders that most impact us. This article will focus on the three sleep disorders for which patients most frequently seek care, including insomnia, obstructive sleep apnea syndrome and restless leg syndrome. PMID- 22441703 TI - Low molecular weight cyclin E is associated with p27-resistant, high-grade, high stage and invasive bladder cancer. AB - Expression of low molecular weight (LMW) isoforms of cyclin E is a strong predictor of poor outcome in patients with breast cancer. The purpose of this study was to examine the expression of full-length and LMW cyclin E in bladder cancer cell lines and patient tumors. We used western blotting, immunoprecipitation and kinase assays to examine the expression and activity of key cell cycle-regulatory proteins in various human bladder cell lines, both tumorigenic and non-tumorigenic. We also analyzed cyclin E expression, kinase activity and immune complex binding partners in 43 tissue samples from grade 2 and 3 transitional cell carcinomas. Cyclin E was overexpressed and LMW isoforms were present only in bladder cancer cells. Overexpression of LMW isoforms of cyclin E and increased cyclin E kinase activity were both significantly associated with tumorigenicity of the bladder cell lines (p = 0.005 and 0.022, respectively). Binding of the cyclin-dependent kinase inhibitors p21 and p27 to LMW cyclin E did not inhibit the kinase activity of cyclin E and cyclin-dependent kinase 2 in primary tumor samples overexpressing LMW cyclin E. Full-length and LMW cyclin E were significantly overexpressed in grade 3 tumors compared with grade 2 tumors (p = 0.004). Finally, LMW cyclin E levels were significantly associated with a non-papillary growth pattern (p = 0.031) and invasiveness (p = 0.021) of the bladder tumors and poor overall survival (p = 0.06). These results suggest that LMW cyclin E can be used as a new prognostic marker for bladder cancer. PMID- 22441705 TI - First structural evidence for multiple alkali metals between sandwich decks in a metallocene. AB - A tetralithio salt (1) derived by treating 1,4-bis(trimethylsilyl) cyclooctatriene with (n)BuLi serves as the first structural evidence for a multi alkali metallocene. Single-crystal XRD confirms two Li(+) each asymmetrically bind to eta(3) and eta(4) between two COT'' rings and two Li(+) terminally bind to eta(3). Solid-state NMR studies confirm the presence of two distinct lithium ion sites while the solution NMR studies suggest the formation of an (COT'' dianion) ion-pair in solution. Further treating of the tetralithio salt with NaCl leads to linear sodium polymeric chains. Therefore, simply changing the ionic radius changes the molecular structure. PMID- 22441706 TI - Feasibility of T-wave alternans testing in patients considered for a cardioverter defibrillator implantation. PMID- 22441707 TI - Hydrido(hydrosilylene)tungsten complexes: dynamic behavior and reactivity toward acetone. AB - Reaction of a labile tungsten nitrile complex, [(Cp*)W(CO)(2)(NCMe)Me] (Cp*=eta(5)-C(5)Me(5)), with H(3)SiC(SiMe(3))(3) gave the hydrido(hydrosilylene) complex [(Cp*)(CO)(2)(H)W=Si(H){C(SiMe(3))(3)}] (1a). The hydrido(silylene) complex [(eta(5)-C(5)Me(4)Et)(CO)(2)(H)W=SiMes(2)] (2) (Mes=2,4,6-Me-C(6)H(2)) was synthesized by a similar reaction with H(2)SiMes(2). There is a strong interligand interaction between the hydrido and silylene ligands of these complexes; this was confirmed by a neutron diffraction study of [D(2)]1b, that is, the deuterido and eta(5)-C(5)Me(4)Et derivative of 1a. The exchange between the W-H and the Si-D groups was observed in the deuterido complex [D]1a. This H/D exchange proceeded slowly at room temperature, but very rapidly under UV irradiation. Variable-temperature NMR spectroscopy measurements show the dynamic behavior of carbonyl ligands in 1a. Complex 1a reacted with acetone at room temperature to give mainly a hydrosilylation product, [(Cp*)(CO)(2)(H)W=Si(OiPr){C(SiMe(3))(3)}] (3a), along with a siloxy complex, [(Cp*)(CO)(2)WO(Si(H)iPr{C(SiMe(3))(3)})] (4a). At low temperature, a different reaction, namely, alpha-H abstraction, proceeded to give an equilibrium mixture of 1a and a dihydrido(silyl) complex, [(Cp*)(CO)(2)(H)(2)W(Si(H){OC(=CH(2))Me}{C(SiMe(3))(3)})] (5). PMID- 22441708 TI - Peritransplant psychiatric evaluation of patients with fanconi anemia. AB - Patients with Fanconi anemia (FA) referred for stem cell transplantation (SCT) have multiple psychosocial risk factors and often present in distress in the peritransplant period. Twenty-two patients with FA were referred for psychiatry consultation before, during, or after SCT, across a 13-year period at Memorial Sloan-Kettering Cancer Center. The most common diagnoses were mood (50%), adjustment (46%), and anxiety (23%) disorders and delirium (23%); the most common psychiatric symptoms were anxious/depressed (86%), withdrawn (64%), and aggressive (59%) symptoms. Etiology of the diagnoses and symptoms included: chronic childhood illness, physical and/or neurodevelopmental disability, presence of a genetic syndrome, presence of a cancer predisposition syndrome, exposure to therapeutic androgens, and exposure to pediatric SCT. However, the degree of influence of the different factors could not be determined. In addition, other factors such as impact of sibling illness or loss, extent of treatment nonadherence, level and significance of neurodevelopmental pathologies were identified. Future prospective and possibly multicenter studies will need to be generated for a better understanding and more complete factor analysis. PMID- 22441709 TI - Does umbilical cord blood-derived CD34+ cell concentration depend on the weight and sex of a full-term infant? AB - Umbilical cord blood has recently been considered as an alternative source of hematopoietic progenitor cells for clinical application. Patient survival in allogenic cord blood transplantation is critically dependent on the cord blood derived total nucleated cell count and the total CD34 cell count/kg of the body weight. A number of factors such as maternal age, gestational age, newborn's sex and weight, umbilical cord length, and placental weight can influence the volume, amount of mononuclear cells, and the CD34 cell concentration. Cord blood was collected from normal vaginal and cesarean deliveries. It was immediately processed and assessed for the total nucleated cell count and CD34 cell concentration. Assessment of maternal and neonatal parameters such as gestational age, baby's birth weight, and sex was carried out with the CD34 cell concentration. The mean CD34 cell concentration was 0.21+/-0.24% for the group with <2500 g (low birth weight) birth weight of the baby (n=104). The mean CD34 cell concentration was 1.84+/-1.12% for the group with >=2500 g (normal birth weight) birth weight of the baby (n=396). A strong positive correlation was found between birth weight of the baby with cord blood-derived CD34 cell concentration (*P<0.0001, r=0.81). A positive correlation was found between gestational age and cord blood-derived CD34 cell concentration (*P<0.0001, r=0.31). No significant correlation was found between the baby's sex with the CD34 cell concentration and the total nucleated cell count. This study concludes that the higher the birth weight of the baby, the better the yield of the CD34 cell concentration, and hence these should be the preferred samples for infusion. PMID- 22441710 TI - Health-related quality of life in pediatric cancer survivors: a multifactorial assessment including parental factors. AB - AIM: We aimed to evaluate the health-related quality of life (HRQOL) and the effect of associated factors such as cancer type, treatment strategies, sex, age, and parental factors like education and psychopathology in pediatric cancer survivors and make a comparison with healthy children. PATIENTS AND METHODS: "Pediatric Quality of Life Inventory (PedsQL) 4.0 TM, Generic Core Scale" for children and parents, and "Brief Symptom Inventory" for parents were used. Three hundred and two survivors without major mental or motor deficit and 272 healthy controls of 8 to 18 years of age were enrolled to study. RESULTS: Comparison of scores according to child self-report between survivor and control groups revealed lower points in physical and school subscale of survivor group (P<0.01 and P<0.001, respectively). Female survivors had reported significantly worse HRQOL in physical and emotional subscales of PedsQL than male survivors (P<0.001). Female survivors of >=16 years of age had reported worse scores in school subscale than females of younger age groups and male survivors of same age group. Parents of control group reported better results in school subscales (P<0.001) and social functioning subscales (P<0.05) than parents of survivor group. Brief Symptom Inventory score had significant effect on child self-report and parent proxy-report of physical functioning (P<0.001), emotional functioning (P<0.001), social functioning (P<0.001), and school subscales (P<0.001) of PedsQL. Significantly better scores of physical functioning subscale in the survivors whose parents are university graduate than the survivors whose parents are primary school graduate were detected (P<0.001). The survivors with central nervous system tumors had reported lower scores in the social, emotional, physical, and school functioning subscales of PedsQL than patients with non Hodgkin and Hodgkin lymphoma (P<0.001). Child self-report school subscale scores were lower in survivors treated with radiotherapy in combination or as sole therapy than survivors in whom radiotherapy was not given (P<0.001). CONCLUSIONS: Our study has provided evidence about less-studied determinants of HRQOL like parental factors such as psychopathology or educational level in childhood cancer survivors. Future research can build on this evidence to obtain additional factors other than well-known medical and treatment-related factors. PMID- 22441711 TI - Pseudo-Chediak-Higashi anomaly in acute myeloid leukemia with t (8;21). PMID- 22441712 TI - Neuroendocrine carcinoma in an adolescent with hypercortisolemia. AB - We present a 16-year-old boy with weakness, hypercortisolemia, and markedly elevated adrenocorticotropic hormone. Computed tomographic imaging revealed hepatic lesions and a calcified pancreatic mass. Biopsy of the hepatic lesions revealed moderately differentiated neuroendocrine carcinoma. The primary tumor could not be determined. The patient received neoadjuvant chemotherapy with carboplatin and etoposide followed by therapeutic bilateral adrenalectomy and tumor debulking. Despite significant clinical improvement, restaging revealed progressive hepatic disease. The patient died 9 months after diagnosis. Autopsy revealed disseminated neuroendocrine carcinoma. The rarity of this tumor compels a cooperative investigational model involving pediatric and adult oncologists. PMID- 22441713 TI - Concomitant hypohydrotic ectodermal dysplasia and Ebeta-thalassemia in a child. PMID- 22441714 TI - Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients. AB - Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia. PMID- 22441715 TI - A comparison of adolescent- and adult-onset first-episode, non-affective psychosis: 2-year follow-up. AB - This study aimed to compare 2-year outcome among individuals with early-onset (EO; <18 years) versus adult-onset (AO) first-episode, non-affective psychosis. We compared clinical and treatment characteristics of 43 EO and 189 AO patients 2 years after their inclusion in a clinical epidemiologic population-based cohort study of first-episode psychosis. Outcome variables included symptom severity, remission status, drug abuse, treatment utilization, cognition and social functioning. At baseline, EO patients were more symptomatically compromised. However, these initial baseline differences were no longer significant at the 2 year follow-up. This study challenges the findings of a larger and older literature base consisting primarily of non-comparative studies concluding that teenage onset indicates a poor outcome. Our results indicate that adolescent onset and adult-onset psychosis have similar prognostic trajectories, although both may predict a qualitatively different course from childhood-onset psychosis. PMID- 22441716 TI - Precise local resection for hepatocellular carcinoma based on tumor-surrounding vascular anatomy revealed by 3D analysis. AB - PURPOSES: Local resection for hepatocellular carcinoma (HCC) has been traditionally performed non-anatomically. The purpose of this study is to evaluate the feasibility of precise local resection of HCC according to the anatomy of tumor-surrounding vessels revealed by three-dimensional (3D) analysis technique. METHODS: The CT datasets of the livers of the patients with HCC were analyzed three-dimensionally. The tumor-bearing vessels were identified and virtually resected, and the depending parenchymal volume was calculated for definition of an optimal liver division plane. The actual local resections were then carried out according to the simulations. RESULTS: Precise local resection based on tumor-surrounding vascular anatomy was performed in 13 HCC patients. Both resection margin and volume were significantly correlated with those predicted by preoperative simulations. After precise local resection, neither ischemia nor congestion was observed in the remnant livers. All patients obtained adequate resection margins, without recurrences in the resection sites after a median follow-up time of 18 months. CONCLUSIONS: Local resection for HCC can be carried out precisely according to the anatomy of tumor-surrounding vessels when guided by a 3D analysis. This precise procedure will enhance both the accuracy and safety of traditional local resection. PMID- 22441717 TI - Acid-labile delta-ketal-beta-hydroxy esters by asymmetric hydrogenation of corresponding delta-ketal-beta-keto esters in the presence of CaCO3. AB - A series of acid-labile, optically pure epsilon-substituted delta-ketal-beta hydroxy esters were obtained by a Ru-SunPhos catalyzed asymmetric hydrogenation of the corresponding epsilon-substituted delta-ketal-beta-keto esters. CaCO(3) played a dual role in the hydrogenation reaction--removing the acid generated during the formation of the catalyst and maintaining the activity of the catalyst. PMID- 22441718 TI - A beam-splitter-type 3-D endoscope for front view and front-diagonal view images. AB - PURPOSE: In endoscopic surgery, surgeons must manipulate an endoscope inside the body cavity to observe a large field-of-view while estimating the distance between surgical instruments and the affected area by reference to the size or motion of the surgical instruments in 2-D endoscopic images on a monitor. Therefore, there is a risk of the endoscope or surgical instruments physically damaging body tissues. To overcome this problem, we developed a O7- mm 3-D endoscope that can switch between providing front and front-diagonal view 3-D images by simply rotating its sleeves. METHODS: This 3-D endoscope consists of a conventional 3-D endoscope and an outer and inner sleeve with a beam splitter and polarization plates. The beam splitter was used for visualizing both the front and front-diagonal view and was set at 25 degrees to the outer sleeve's distal end in order to eliminate a blind spot common to both views. Polarization plates were used to avoid overlap of the two views. We measured signal-to-noise ratio (SNR), sharpness, chromatic aberration (CA), and viewing angle of this 3-D endoscope and evaluated its feasibility in vivo. RESULTS: Compared to the conventional 3-D endoscope, SNR and sharpness of this 3-D endoscope decreased by 20 and 7 %, respectively. No significant difference was found in CA. The viewing angle for both the front and front-diagonal views was about 50 degrees . In the in vivo experiment, this 3-D endoscope can provide clear 3-D images of both views by simply rotating its inner sleeve. CONCLUSIONS: The developed 3-D endoscope can provide the front and front-diagonal view by simply rotating the inner sleeve, therefore the risk of damage to fragile body tissues can be significantly decreased. PMID- 22441719 TI - Stronger association of common variants in TCF7L2 gene with nonobese type 2 diabetes in the Latvian population. AB - Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the strongest common genetic risk factors for type 2 diabetes (T2D) across multiple ethnicities. This study was conducted to evaluate an association between TCF7L2 variants and diabetes susceptibility in the population of Latvia. We genotyped 4 single nucleotide polymorphisms (SNP) rs7901695, rs7903146, rs11196205 and rs12255372 in 1 093 controls and 1 043 diabetic subjects. Association with T2D was found for 3 SNPs rs7901695, rs7903146 and rs12255372 in the whole sample (under an additive genetic model, the adjusted odds ratios (OR) were 1.26, 95% CI [1.08-1.48], P=0.003; OR=1.32, 95% CI [1.12-1.55], P=0.001 and OR=1.35, 95% CI [1.15-1.60], P=0.0004 respectively). In addition observed effects on T2D susceptibility for analysed SNPs were higher among subjects with BMI under 30 kg/m2. The impact of TCF7L2 variation on T2D risk in Latvian population is compatible with that demonstrated by a range of studies conducted in various ethnic groups. PMID- 22441720 TI - Anemia due to coadministration of renin-angiotensin-system inhibitors and PPARgamma agonists in uncomplicated diabetic patients. AB - Therapy with either angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB) or thiazolidinediones (TZD) is associated with dose dependent decrements in hematocrit and hemoglobin levels. We aimed to investigate the impact of the coadministration of TZD and ACEI/ARB on hematocrit and hemoglobin values in uncomplicated patients with type 2 diabetes mellitus and normal serum creatinine.Data from patients with type 2 diabetes currently followed, were reviewed and patients treated with ACEI/ARB and/or TZD were identified. For the purpose of this study the following 4 groups of 30 stable non anemic diabetic patients each matched for age, gender, and BMI were formed. Group ACEI/ARB included patients on ACEI/ARB without TZD, group TZD included patients on TZD and antihypertensive agents other than ACEI/ARB, group ACEI/ARB/TZD consisted of patients on combined therapy with ACEI/ARB and TZD and the control group C included patients never exposed to ACEI/ARB or TZD. Clinical and laboratory data were collected prior to initiation of treatment and after 6 months.Neither hematocrit nor hemoglobin showed any significant change from baseline at the end of the study in group C. In both group ACEI/ARB and group TZD a small, but statistically significant reduction in hematocrit (~ 1% point) and hemoglobin levels (~ 0.3 g/dl) was seen. A greater statistically and clinically important reduction in hematocrit (~ 3% points) and hemoglobin (~ 1 g/dl) levels was observed in group ACEI/ARB/TZD. Furthermore, incident anemia at the end reached 7% in group TZD and 23% in group ACEI/ARB/TZD.Coadministration of RAS inhibitors and PPAR-gamma agonists should be considered in the differential diagnosis of hematocrit lowering and anemia in uncomplicated type 2 diabetic patients with normal serum creatinine. Further studies are required to clarify the mechanism(s), the cardiovascular consequences and the cost utility of anemia workup in such patients. PMID- 22441721 TI - Diabetes 'epidemic' in Germany? A critical look at health insurance data sources. AB - The German diabetes prevalence is considered to be one of the highest in Europe. It is often estimated based on claims data of a regional health insurance (Allgemeine Ortskrankenkasse; AOK). We studied the prevalence of diabetes within AOK members compared to other types of funds.We pooled data of the German National Telephone Health Interview Surveys 2003 and 2004 comprising a nationally representative sample of 15 354 adults aged 18 years and older. We first estimated the crude prevalence of diabetes stratified by funds. To analyze the association between diabetes prevalence and membership in different health insurance funds, we fitted logistic regression models and stepwise adjusted for age, sex, region, comorbidities, anthropometric measures, and lifestyle variables.The overall prevalence of diabetes was 6.5%. Compared to all other statutory health insurance funds, the prevalence of diabetes was nearly twice as high within the AOK (10.1% vs. 5.4%; Odds Ratio [OR]: 1.96; 95% confidence interval [CI]: 1.67-2.31). Although continuously decreasing, significant differences remained after controlling for demographic variables (OR: 1.62; 95% CI: 1.38-1.90) and in the fully adjusted model (OR: 1.36; 95% CI: 1.14-1.62). Persons privately insured had a prevalence of 4.8%, which was not significantly different than for members of statutory health insurance funds other than the AOK.The prevalence of diabetes was roughly twice as high in the AOK compared to all other statutory health insurance funds. The estimated German prevalence of diabetes is likely to be too high when it is based on these data. PMID- 22441722 TI - Hypogonadism secondary to hyperprolactinaemia: successful treatment but adverse consequences. AB - It is accepted that care must be taken in initiating testosterone replacement in hypogonadal individuals with historically low androgen levels. However less is reported about the influence of restoration of normal endogenous testosterone production on behaviour.Here we report how the adverse sequelae of successful treatment of hypogonadism secondary to hyperprolactinaemia, manifesting as irritability and low threshold to aggression, were managed through a joint approach between psychiatrist and physician. PMID- 22441723 TI - Diabetes mellitus in children and adolescents with genetic syndromes. AB - BACKGROUND: Several genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alstrom syndrome (AS), Klinefelter syndrome (KS), Bardet Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS). METHODS: Longitudinal data for 43 521 patients with DM onset at age < 20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA 1c , micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis. RESULTS: In total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA. CONCLUSION: Despite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions. PMID- 22441724 TI - Is circulating osteocalcin related to adipokines and overweight/obesity in children and adolescents? AB - Osteocalcin (OC) has recently been described to be involved in the regulation of glucose and energy metabolism. We aimed to evaluate whether or not OC serum levels were related to parameters of overweight and serum adipokine levels of healthy children and adolescents in dependence on gender and pubertal stage.In a cross sectional study (Leipzig Schoolchildren Project) 497 healthy, caucasian children and adolescents of all pubertal stages were included. We measured anthropometric data height, weight, fat mass, waist-to-hip ratio, pubertal development and performed biochemical analyses of osteocalcin, leptin, adiponectin and resistin serum levels by immunoassay.OC serum levels were associated with pubertal development achieving peak values at Tanner stage 3. There was no significant association of OC serum levels with overweight and obesity as measured by BMI and WHR. In addition, OC demonstrated no significant association with serum levels of leptin and adiponectin but a negative association with resistin in both genders independent of pubertal stages (r= - 0.329, p<0.0001).We conclude that there is no major relationship between OC and metabolism, but we can not exclude minor relations between OC and metabolism. The negative relationship with serum resistin levels might rather point to a link between OC and inflammatory states. PMID- 22441725 TI - Assessing water-electrolyte changes of hyperglycaemic hyperosmolar coma. AB - AIM: We reported new methods to accurately estimate salt and water deficits during hyperglycaemic hyperosmolar coma (HC), valid under restricted boundary conditions. The accuracy of these estimates is herein verified over the unrestricted spectrum of abnormalities, to correctly evaluate any patient with just one algorithm that recognizes the boundary conditions pertaining to each abnormality, choosing the appropriate calculations. METHODS: A large number of cases of HC was simulated on computer by subtracting an exhaustive combination of water, sodium and chloride losses coupled to a large variety of gains in glucose. Altered solute concentrations were generated. From these true plasma concentrations generated by the computer, the losses of water and electrolytes were back-calculated with our new computational algorithm, by knowing in addition only the normal total body water and extra-cellular volume. The accuracy of the method was tested by comparing true to calculated values over the entire range of deranged values. In 100 patients admitted to hospital for HC these same computations were performed, where calculated data were validated by comparing them to true data obtained by balance studies performed during correction of the abnormality. RESULTS: Both in simulated and real cases of HC true and calculated data for the changes in Na and volume were significantly correlated (R (2)=0.76 and 0.50, respectively, P<0.01), while their mean values were not significantly different by paired "t" tests (P>0.05 for all). CONCLUSION: Our new computation algorithm, applicable to the bed-side, useful in accurately assessing the average water-electrolyte deficits of HC, can be used to guide correct re-infusion strategies. PMID- 22441726 TI - Effect of cosolvents on nano-confined water: a molecular dynamics study. AB - We present results from atomistic molecular dynamics simulations to characterize the effects of cosolvents, such as urea and guanidinium (Gdm) salts, on the water confined in hydrophobic carbon nanotubes. We observed complete drying of the nanotube interiors of diameter ranging from 8 to 17 A in urea. In contrast, the water population within nanotube cores smaller than 12 A remains unaffected in GdmCl solution, whereas larger nanotube interiors become partially dehydrated with prevailing presence of stable Gdm(+)-Gdm(+) dimers. The molecular arrangement and the lifetime inside the nanotube were found to be characteristics of a particular cosolvent. In both urea and GdmCl solutions, preferential cosolvent intrusion resulting in nanotube dehydration is driven by the stronger dispersion interaction of cosolvent than water with the nanotube. The partial drying of the hydrophobic core is attributed to guanidinium's better hydration and weaker self-association propensity compared to urea, as well as to its moderate ion-pairing with strongly hydrated chloride ions. The Gdm(+) induced dehydration varies with the charge density of counter-ions, as the presence of high charge-density sulfate ions impedes penetration of guanidinium, and consequent dehydration of the nanotube. These findings provide important insights into the effect of cosolvents on the nano-confined water in a hydrophobic environment. PMID- 22441727 TI - Bowel preparation may be an important adjunct to ERAS in rectal surgery. PMID- 22441728 TI - Endovascular versus open approach to aortic aneurysm repair surgery: rates of postoperative delirium. AB - PURPOSE: Our objective was to compare open and endovascular aortic aneurysm repair with respect to postoperative delirium. METHODS: After Institutional Ethics Review Board approval, we conducted a retrospective review of all patients who underwent abdominal and thoraco-abdominal aortic aneurysm repair surgery at Toronto General Hospital during June 2006 to December 2007. Patients were classed into either the OPEN or the endovascular (EVAR) group based on the type of surgery and were assessed for the presence of delirium after surgery. The NEECHAM Confusion Scale and the validated chart review instrument were used for diagnosis of delirium. Patients with dementia and/or abnormal levels of consciousness preoperatively were excluded. RESULTS: There were 256 patients included in the study, 149 (58%) in the OPEN group and 107 (42%) in the EVAR group. Patients in the EVAR group were considerably older, 74 (10) yr vs 68 (9) yr, and they had shorter duration of surgery, 150 [119, 180] min vs 200 [165, 260] min, respectively, P < 0.0001. Postoperative delirium was present in 43 (29%) patients in the OPEN group and 14 (13%) patients in the EVAR group (95% confidence interval [CI], 22 to 36 vs 95% CI, 7 to 19, respectively; P = 0.003). Hospital length of stay was 8.3 [6.6, 13.4] days in the OPEN group and 4.5 [3.1, 6.4] days in the EVAR group, P < 0.0001. CONCLUSIONS: Perioperative management of patients undergoing endovascular aortic aneurysm repair was associated with lower rates of delirium after surgery than that of patients undergoing open aortic aneurysm repair. PMID- 22441729 TI - The role of a state-level prevention support system in promoting high-quality implementation and sustainability of evidence-based programs. AB - Although numerous evidence-based programs (EBPs) have been proven effective in research trials and are being widely promoted through federal, state, and philanthropic dollars, few have been "scaled up" in a manner likely to have a measurable impact on today's critical social problems. The Interactive Systems Framework for Dissemination and Implementation (ISF) explicates three systems that are critical in addressing the barriers that prevent these programs from having their intended public health impact. In this article we describe the relevance of these systems in a real-world context with a specific focus on the Prevention Support System (PSS). We expand on the ISF model by presenting funders and policy-makers as active and engaged stakeholders, and demonstrate how a state level PSS has used empirical evidence to inform general and program-specific capacity-building and support interactions among researchers, funders, and practitioners in Pennsylvania. By embracing this expanded ISF framework as a conceptual model for the wide-scale dissemination and support of EBPs, and recognizing the need for a distinct state-level PSS, Pennsylvania has created an infrastructure to effectively address the primary barriers to moving from lists of EBPs to achieving population-level public health improvement. PMID- 22441730 TI - Comments on 'Therapist variation within randomized trials of psychotherapy: implications for precision, internal and external validity'. PMID- 22441731 TI - Why use Markov simulation models for estimating the effect of cancer screening policies when randomised controlled trials provide better evidence? PMID- 22441732 TI - Cerebrospinal fluid cathepsin B and S. AB - Cathepsins are increased in the brain of elderly animals. We investigate the presence of cathepsin B and S in human cerebrospinal fluid (CSF) plasma and the associations with cystatin C, age and sex. We measured cathepsin B and S concentrations in CSFs from 118 persons, undergoing elective surgical procedures, with ELISA. Both cathepsin B and cathepsin S were positively correlated with age. No correlation was observed between cathepsin B or S and length, height or body mass index. Both cathepsin B and S were positively correlated to the cystatin C concentration in CSF. Calculated reference intervals were 4,893-17,636 pg/mL for cathepsin B and 2,681-11,459 pg/mL for cathepsin S. Elderly individuals had significantly higher levels of both cathepsin B (r s = 0.38, p = 0.00002) and cathepsin S (r s = 0.35, p = 0.0001) in CSF. PMID- 22441733 TI - The EvA study: aims and strategy. AB - The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD. PMID- 22441734 TI - CHRNA3 genotype, nicotine dependence, lung function and disease in the general population. AB - The CHRNA3 rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case-control studies with high smoking exposure; however, its influence on lung function and COPD severity in the general population is largely unknown. We genotyped 57,657 adult individuals from the Copenhagen General Population Study, of whom 34,592 were ever-smokers. Information on spirometry, hospital admissions, smoking behaviour and use of nicotinic replacement therapy was recorded. In homozygous (11%), heterozygous (44%) and noncarrier (45%) ever-smokers, forced expiratory volume in 1 s (FEV(1)) was 94.1% predicted, 95.3% pred and 96.5% pred, forced vital capacity (FVC) was 97.1% pred, 97.5% pred and 98.3% pred, and FEV(1)/FVC was 0.770, 0.773 and 0.777, respectively (all p<0.001 for trend). Smoking interacted with genotype on FEV(1) % pred and FEV(1)/FVC (both p<0.001). When adjusted for cumulative tobacco consumption, these associations remained significant. In ever-smokers, odds ratios for COPD in homozygotes versus noncarriers were 1.3 (95% CI 1.2-1.4) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV, 1.4 (95% CI 1.2-1.6) for GOLD II-IV and 1.7 (95% CI 1.3-2.1) for GOLD III-IV. The corresponding value for lung cancer was 1.8 (95% CI 1.2-2.6). Genotype was also associated with daily and cumulative tobacco consumption and with use of nicotinic replacement therapy in former smokers. In ever-smokers, the CHRNA3 rs1051730 genotype associated with reduced lung function and increased COPD severity. PMID- 22441735 TI - Reduced nuclear factor-kappaB repressing factor: a link toward systemic inflammation in COPD. AB - Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-kappaB repressing factor (NRF), a DNA binding, protein-inhibiting NF-kappaB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production. NRF expression, NF-kappaB activation, IL 8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H(2)O(2) were used to elucidate the mechanisms. Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-kappaB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H(2)O(2)-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs. NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation. PMID- 22441736 TI - Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction. AB - Apoptotic cell clearance by macrophages and neighbouring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key role in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells enhances HGF production, resulting in attenuation of pulmonary injury. We investigated the direct effect of in vivo exposure to apoptotic cells in bleomycin-stimulated lungs (2 days old) on HGF induction. Furthermore, sequential changes of bleomycin-induced HGF production following apoptotic cell instillation related to the changes in inflammatory and fibrotic responses were assessed. At 2 h after apoptotic cell instillation into bleomycin stimulated lungs, the levels of HGF mRNA and protein production, and apoptotic cell clearance by alveolar macrophages were enhanced. Furthermore, HGF induction persistently increased following apoptotic cell instillation up to 21 days after bleomycin treatment. Apoptotic cell instillation attenuated bleomycin-induced pro inflammatory mediator production, inflammatory cell recruitment and total protein levels. Apoptotic cell instillation also induced antiapoptotic and antifibrotic effects. These anti-inflammatory and antiapoptotic effects could be reversed by co-administration of HGF-neutralising antibody. These findings indicate that in vivo exposure to apoptotic cells enhances transcriptional HGF production in bleomycin-stimulated lungs, resulting in attenuation of lung injury and fibrosis. PMID- 22441737 TI - Increased frequencies of pulmonary regulatory T-cells in latent Mycobacterium tuberculosis infection. AB - Regulation of specific immune responses following exposure to Mycobacterium tuberculosis in humans and the role of regulatory T (Treg) cells in the immune control of latent infection with M. tuberculosis are incompletely understood. Latent infection was assayed by an interferon-gamma release assay (IGRA) in healthcare workers regularly exposed to tuberculosis (TB) patients and in household TB contacts in Germany. Immunophenotypes of bronchoalveolar lavage (BAL) mononuclear cells and peripheral blood mononuclear cells (PBMCs) were analysed by fluorescence-activated cell sorting. All TB contacts with latent infection (n=15) had increased (p<0.0001) frequencies of CD4+ CD25+ CD127- Treg cells (median 2.12%, interquartile range (IQR) 1.63-3.01%) among BAL mononuclear cells compared with contacts (n=25) with negative IGRA results (median 0.68%, IQR 0.32-0.96%) No differences were seen when PBMC immunophenotypes of IGRA+ and IGRA TB contacts were compared (IGRA+ median 9.6%, IQR 5.9-10.1%; IGRA- median 7.7%, IQR 4.6-11.3%; p=0.47). Five out of 25 contacts with negative blood IGRAs showed a positive IGRA from BAL cells, possibly indicating a limited local immune response. In Germany, latent infection with M. tuberculosis, as defined by a positive M. tuberculosis-specific IGRA response on cells from the peripheral blood, is characterised by an increased frequency of Treg cells in the BAL. PMID- 22441738 TI - A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells. AB - Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism. Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression. Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-alpha. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R) hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation. 12R-LOX is involved in MUC5AC expression. This occurs via ERK- and Sp1-signalling pathways. PMID- 22441739 TI - Sleep apnoea, anxiety, depression and somatoform pain: a community-based high risk sample. AB - Community-based studies that measure both psychiatric diagnoses and obstructive sleep apnoea (OSA) are lacking. This study reports current psychiatric disorders in community-dwelling adults at high risk for OSA identified by the Berlin Questionnaire. Furthermore, associations between OSA and current psychiatric disorders, unadjusted and adjusted for putative confounders, are reported. A subsample of the Akershus Sleep Apnoea Project consisting of 290 adults, aged 30 65 yrs, with positive Berlin Questionnaire screening underwent the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, version IV and polysomnography. Auxiliary analyses of depression are provided. The median apnoea/hypopnoea index score in the sample was 7.7 (interquartile range 2.4-22.2). Major depressive disorder, current anxiety and somatoform pain disorder were diagnosed in 12.4%, 14.8% and 19.3% of participants, respectively. At least one psychiatric disorder was diagnosed in 110 participants. The odds ratio of participants with OSA having a psychiatric disorder compared with participants without OSA was 0.54 (95% CI 0.33-0.88). A negative association did not exist among Berlin Questionnaire low-risk participants. In conclusion, more than one-third of participants in a community-based, Berlin Questionnaire high risk sample were diagnosed with a psychiatric disorder. A negative association between OSA and psychiatric morbidity was found. PMID- 22441740 TI - Streptococcus pneumoniae-induced regulation of cyclooxygenase-2 in human lung tissue. AB - The majority of cases of community-acquired pneumonia are caused by Streptococcus pneumoniae and most studies on pneumococcal host interaction are based on cell culture or animal experiments. Thus, little is known about infections in human lung tissue. Cyclooxygenase-2 and its metabolites play an important regulatory role in lung inflammation. Therefore, we established a pneumococcal infection model on human lung tissue demonstrating mitogen-activated protein kinase (MAPK) dependent induction of cyclooxygenase-2 and its related metabolites. In addition to alveolar macrophages and the vascular endothelium, cyclooxygenase-2 was upregulated in alveolar type II but not type I epithelial cells, which was confirmed in lungs of patients suffering from acute pneumonia. Moreover, we demonstrated the expression profile of all four E prostanoid receptors at the mRNA level and showed functionality of the E prostanoid(4) receptor by cyclic adenosine monophosphate production. Additionally, in comparison to previous studies, cyclooxygenase-2/prostaglandin E(2) related pro- and anti-inflammatory mediator regulation was partly confirmed in human lung tissue after pneumococcal infection. Overall, cell type-specific and MAPK-dependent cyclooxygenase-2 expression and prostaglandin E(2) formation in human lung tissue may play an important role in the early phase of pneumococcal infections. PMID- 22441741 TI - High-altitude treatment in atopic and nonatopic patients with severe asthma. AB - The beneficial effects of high-altitude treatment in asthma have been attributed to allergen avoidance. Recent evidence shows that this treatment also improves airway inflammation in nonallergic patients. We hypothesised that high-altitude treatment is clinically equally effective in patients with severe refractory asthma, with or without allergic sensitisation. In a prospective observational cohort study, 137 adults with severe refractory asthma (92 with allergic sensitisation), referred for high-altitude (1,600 m) treatment in Davos, Switzerland, were consecutively included. We measured asthma control (Asthma Control Questionnaire (ACQ)), asthma-related quality of life (Asthma-Related Quality of Life Questionnaire (AQLQ)), sino-nasal symptoms (Sino-Nasal Outcome Test (SNOT-20)), medication requirement, postbronchodilator (post-BD) forced expiratory volume in 1 s (FEV(1)), 6-min walking distance (6MWD), total immunoglobulin (Ig)E, blood eosinophils and exhaled nitric oxide fraction (F(eNO)) at admission and after 12 weeks. Sensitised and nonsensitised patients showed similar improvements in ACQ (-1.4 and -1.5, respectively; p = 0.79), AQLQ (1.6 and 1.5, respectively; p = 0.94), SNOT-20 (-0.7 and -0.5, respectively; p = 0.18), post-BD FEV(1) (6.1% and 5.8% pred, respectively; p = 0.87), 6MWD (+125 m and +147 m, respectively; p = 0.43) and oral steroids (40% versus 44%, respectively; p = 0.51). Sensitised patients showed a larger decrease in total IgE, blood eosinophils and F(eNO). High-altitude treatment improves clinical and functional parameters, and decreases oral corticosteroid requirement in patients with severe refractory asthma, irrespective of allergic sensitisation. PMID- 22441742 TI - The minimal important difference for residual volume in patients with severe emphysema. AB - Residual volume (RV) measured by body plethysmography is a routine measurement in clinical pulmonary practice and is often an important outcome variable in clinical trials. However, it is not known what size of improvement can be regarded as being important in severe emphysema patients. Therefore, the aim of the study is to establish the minimal important difference (MID) for RV in severe emphysema patients undergoing bronchoscopic lung volume reduction. 91 severe emphysema patients were included. RV and total lung capacity (TLC) were measured by body plethysmography. MID estimates were calculated by anchor-based and distribution-based methods. Forced expiratory volume in 1 s, 6-min walk distance and St George's Respiratory Questionnaire total score were used as anchors and Cohen's effect size was used as distribution-based method. The calculated MID estimates according to the different anchors and methods ranged between -0.31 and -0.43 L for RV, -6.1 and -8.6% for percentage change in RV (RV%) from baseline, and -2.8 and -4.0% for RV/TLC. These MID estimates are useful for sample size determination in new studies on interventions aimed at reducing RV and for interpreting the results from clinical trials in severe emphysema patients. PMID- 22441743 TI - Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. AB - The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 MUg or 400 MUg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV(1)) at week 24. Other end points included peak FEV(1), health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI). Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 MUg and 400 MUg versus placebo for trough FEV(1) (99 and 128 mL; both p<0.0001) and peak FEV(1) (185 and 209 mL; both p<0.0001). Peak FEV(1) improvements on day 1 were comparable with week 24. Aclidinium 200 MUg and 400 MUg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo. Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD. PMID- 22441744 TI - Natural course of sleep-disordered breathing after acute myocardial infarction. AB - The aim of this study was to test whether an improvement of left ventricular ejection fraction (EF) in the early phase after acute myocardial infarction is associated with a reduction of the severity of central and obstructive sleep apnoea. 40 consecutive patients with acute myocardial infarction underwent polysomnography and cardiovascular magnetic resonance imaging within 5 days and 12 weeks after the event to assess sleep apnoea and cardiac function. We stratified the sample in patients who improved their left ventricular EF within 12 weeks by >= 5% (improved EF group, DeltaEF 9 +/- 1%, n=16) and in those who did not (unchanged EF group, DeltaEF -1 +/- 1%, n=24). Prevalence of sleep apnoea (>= 15 apnoea and hypopnoea events.h(-1)) within <= 5 days after myocardial infarction was 55%. Apnoea and hypopnoea events.h(-1) were significantly more reduced in the improved EF group compared with the unchanged EF group (-10 +/- 3 versus 1 +/- 3 events.h(-1); p=0.036). This reduction was based on a significant alleviation of obstructive events (-7 +/- 2 versus 4 +/- 3 events.h(-1); p=0.009), while the reduction of central events was similar between groups (p=0.906). An improvement of cardiac function early after myocardial infarction is associated with an alleviation of sleep apnoea. This finding suggests that re evaluation of treatment indication for sleep apnoea is needed when a change in cardiac function occurs. PMID- 22441745 TI - Pre-treatment with mesenchymal stem cells reduces ventilator-induced lung injury. AB - Bone marrow-derived mesenchymal stem cells (MSCs) reduce acute lung injury in animals challenged by bleomycin or bacterial lipopolysaccaride. It is not known, however, whether MSCs protect from ventilator-induced lung injury (VILI). This study investigated whether MSCs have a potential role in preventing or modulating VILI in healthy rats subjected to high-volume ventilation. 24 Sprague-Dawley rats (250-300 g) were subjected to high-volume mechanical ventilation (25 mL.kg(-1)). MSCs (5 * 10(6)) were intravenously or intratracheally administered (n=8 each) 30 min before starting over-ventilation and eight rats were MSC-untreated. Spontaneously breathing anesthetised rats (n=8) served as controls. After 3 h of over-ventilation or control the animals were sacrificed and lung tissue and bronchoalveolar lavage fluid (BALF) were sampled for further analysis. When compared with controls, MSC-untreated over-ventilated rats exhibited typical VILI features. Lung oedema, histological lung injury index, concentrations of total protein, interleukin-1beta, macrophage inflammatory protein-2 and number of neutrophils in BALF and vascular cell adhesion protein-1 in lung tissue significantly increased in over-ventilated rats. All these indices of VILI moved significantly towards normalisation in the rats treated with MSCs, whether intravenously or intratracheally. Both local and systemic pre-treatment with MSCs reduced VILI in a rat model. PMID- 22441746 TI - Joint effects of birth outcomes and childhood body mass index on respiratory symptoms. AB - Thinness in infancy and higher childhood body mass index (BMI) are risk factors for poor respiratory health. However, few studies have examined the joint effects of birth outcomes and childhood BMI on the occurrence of respiratory symptoms. A total of 78,011 Taiwanese middle-school children were investigated between 1995 and 1996 in a nationwide International Study of Asthma and Allergies in Childhood (ISAAC) survey, with standardised height/weight measurement. Their survey data was compared successfully with the birth registration dataset. Childhood BMI was positively associated with all respiratory symptoms, with greater effects and significant risks associated with serious phenotypes in the video questionnaire. Children with a history of low birth weight (LBW), those who were born prematurely (pre-term), or those who were small for gestational age (SGA) were also more likely to have allergic respiratory symptoms. As birthweight and gestational age were not positively associated with childhood BMI, we proposed that LBW, pre-term birth and childhood BMI were independent factors for respiratory symptoms. LBW, pre-term birth and childhood BMI are all independent risk factors for respiratory symptoms in children. Children with a history of LBW, pre-term birth or SGA and a higher current BMI might have larger respiratory burden. PMID- 22441747 TI - Exercise testing to predict outcome in idiopathic versus associated pulmonary arterial hypertension. AB - We tested the ability of exercise testing to predict not only survival, but also time to clinical worsening (TTCW) in idiopathic versus associated pulmonary arterial hypertension (PAH). 136 patients with PAH (85 idiopathic and 51 with associated conditions) underwent cardiopulmonary exercise testing and a 6-min walk test. Death or transplantation, and clinical worsening events were recorded. 32 patients died and four had lung transplantation. In a univariate analysis, PAH patients survival was associated with oxygen uptake (V'(O(2))) at peak exercise and at the anaerobic threshold, ventilatory equivalent for carbon dioxide (minute ventilation (V'(E))/carbon dioxide production (V'(CO(2))) at the anaerobic threshold ((at))), V'(E)/V'(CO(2)) slope and distance walked. TTCW was associated with peak V'(O(2)) and V'(O(2),at), V'(E)/V'(CO(2),at), end-tidal carbon dioxide tension measured at the anaerobic threshold, peak oxygen pulse, increase in oxygen pulse and distance walked. In a multivariable analysis, distance walked and V'(E)/V'(CO(2),at) predicted survival, and only peak V'(O(2)) predicted TTCW. The receiver operating characteristic curve-derived cut-off values were 305 m for the 6-min walk distance, 54 for V'(E)/V'(CO(2),at) and 11.6 mL.kg(-1).min for peak V'(O(2)). In the subgroup with associated PAH, no variable independently predicted either survival or clinical worsening. We conclude that several exercise variables predict survival and clinical stability in idiopathic PAH. Exercise variables are less accurate predictors of outcome in associated PAH. PMID- 22441748 TI - Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. AB - Pleuroparenchymal fibroelastosis (PPFE) is a rare condition characterised by predominantly upper lobe pleural and subjacent parenchymal fibrosis, the latter being intra-alveolar with accompanying elastosis of the alveolar walls. The aim of this study was to review cases fulfilling published imaging and histological criteria, and identify any common clinical features that may suggest an underlying aetiology for a condition that has previously been regarded as idiopathic. Of 12 patients (seven females, median age 57 yrs), the presenting symptoms were shortness of breath (11 out of 12 patients) and dry cough (six out of 12 patients). Seven patients reported recurrent infections during the course of their disease. Five demonstrated nonspecific autoantibody positivity. Two patients had a family history of interstitial lung disease (ILD). High-resolution computed tomography features of lung disease remote from the pleuroparenchymal changes were present in six out of 12 patients (coexistent fibrosis, n=5; bronchiectasis, n=1). Of seven patients with tissue sampled from the lower lobes, four patients showed less intense PPFE changes (one with additional features of hypersensitivity pneumonitis) and three showed usual interstitial pneumonia. PPFE is a distinct clinicopathological entity, with clinical data suggesting a link to recurrent pulmonary infection. Genetic and autoimmune mechanisms may also contribute to the development of these changes. PPFE may also present with more diffuse involvement than previously reported, and coexist with different patterns of ILD. PMID- 22441749 TI - What shall we do with the damaged proteins in lung disease? Ask the proteasome! AB - The proteasome constitutes the main protein waste disposal and recycling system of the cell. Together with endoplasmic reticulum stress and the autophagosome pathway, it takes centre stage in cellular protein quality control. In lung research, the proteasome is, first of all, a promising therapeutic target to intervene in the malignant growth of lung cancer cells. Therapeutic targeting of the proteasome has also been extended to pulmonary fibrosis and asthma using animal models. Moreover, the proteasome is involved in lung pathogenesis. In cystic fibrosis, rapid proteasomal degradation of mutant cystic fibrosis transmembrane conductance regulator contributes to loss of function of lung epithelial cells. In chronic obstructive pulmonary disease (COPD), pulmonary proteasome expression and activity are downregulated and inversely correlate with lung function. In addition, as the proteasome degrades signalling mediators that have been oxidatively modified in COPD, it contributes to further compromise cellular function. The consequences of proteasomal dysfunction are loss of protein quality control, accumulation of misfolded proteins and exacerbation of cellular stress, which are also hallmarks of protein quality diseases and premature ageing. This suggests that proteasome dysfunction can be regarded as a new pathomechanism for chronic lung diseases, awaiting further therapeutic exploration in the future. PMID- 22441750 TI - Sarcoidosis-associated fatigue. AB - Sarcoidosis-associated fatigue is globally recognised as a disabling symptom. Fatigue has been reported in up to 50-70% of sarcoidosis patients, causing impaired quality of life. The aetiology of this troublesome problem remains elusive and is usually multifactorial. Fatigue can be a consequence of treatment itself, including as a complication of corticosteroid therapy. The diagnosis of sarcoidosis-associated fatigue requires an extensive evaluation to identify and treat potentially reversible causes. Granuloma formation and cytokine release may be involved in its aetiology. However, despite adequate sarcoidosis treatment, many patients continue to experience fatigue. Comorbidities associated with sarcoidosis, including depression, anxiety, hypothyroidism and altered sleep patterns, may all contribute to fatigue. Despite an exhaustive search for treatable clinical causes of fatigue, most patients' complaints of fatigue are not correlated with clinical parameters of disease activity. Recent studies have demonstrated the effectiveness of various neurostimulants, including methylphenidate, for the treatment of sarcoidosis-associated fatigue. These and other agents may be useful adjuncts for the treatment of sarcoidosis-associated fatigue. Obviously, there is a need for studies evaluating the causes and new therapeutic options of sarcoidosis-associated fatigue. Psychological interventions should also be examined. PMID- 22441751 TI - A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice. AB - Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-beta1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-beta1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF beta1 levels and relative changes of TGF-beta1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-beta activation and inflammatory cell recruitment in the lung. PMID- 22441752 TI - Serial computed tomography and lung function testing in pulmonary Langerhans' cell histiocytosis. AB - Little is known about longitudinal lung function variation in patients with pulmonary Langerhans' cell histiocytosis (LCH). The contribution of serial lung computed tomography (CT) to managing these patients has not been evaluated. This long-term retrospective study included 49 patients who were serially evaluated by lung CT and pulmonary function tests. The lung function variation was categorised as improvement or deterioration. The extent of the CT lesions was correlated with lung function. Lung function deteriorated in ~60% of the patients. Forced expiratory volume in 1 s (FEV(1)) and diffusing capacity of the lung for carbon monoxide (D(L,CO)) were the parameters that most frequently deteriorated. A subgroup of patients experienced a dramatic decline in FEV(1) within 2 yrs of diagnosis. Airway obstruction was the major functional pattern observed. In a multivariate analysis, % predicted FEV(1)at diagnosis was the only factor associated with the incidence of airway obstruction. The increase in cystic lesions on the lung CTs was associated with impaired lung function but did not anticipate the decline in FEV(1) or D(L,CO). Serial lung function tests are essential for following patients with pulmonary LCH, who frequently develop airway obstruction. A lung CT at diagnosis is informative, but routine sequential CTs seem less useful. A prospective study is needed to characterise those patients with early progressive disease. PMID- 22441753 TI - A novel chemosensor based on rhodamine derivative for colorimetric and fluorometric detection of Cu2+ in aqueous solution. AB - A new rhodamine-based reversible chemosensor (2) was synthesized, which exhibits high sensitivity and selectivity for Cu(2+) but no significant response toward other competitive metal ions in aqueous solution. Upon the addition of Cu(2+), the spirolactam ring of 2 was opened and the solution color changed from colorless to red. Strangely, an unexpected fluorescence quenching was observed, which is contrary to the fluorescence turn-on of the most rhodamine-based chemosensors. The likely novel sensing mechanism has been proposed. PMID- 22441754 TI - Synthesis and characterization of silver/alanine nanocomposites for radiation detection in medical applications: the influence of particle size on the detection properties. AB - Silver/alanine nanocomposites with varying mass percentage of silver have been produced. The size of the silver nanoparticles seems to drive the formation of the nanocomposite, yielding a homogeneous dispersion of the silver nanoparticles in the alanine matrix or flocs of silver nanoparticles segregated from the alanine crystals. The alanine crystalline orientation is modified according to the particle size of the silver nanoparticles. Concerning a mass percentage of silver below 0.1%, the nanocomposites are homogeneous, and there is no particle aggregation. As the mass percentage of silver is increased, the system becomes unstable, and there is particle flocculation with subsequent segregation of the alanine crystals. The nanocomposites have been analyzed by transmission electron microscopy (TEM), UV-Vis absorption spectroscopy, X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy and they have been tested as radiation detectors by means of electron spin resonance (ESR) spectroscopy in order to detect the paramagnetic centers created by the radiation. In fact, the sensitivity of the radiation detectors is optimized in the case of systems containing small particles (30 nm) that are well dispersed in the alanine matrix. As the agglomeration increases, particle growth (up to 1.5 MUm) and segregation diminish the sensitivity. In conclusion, nanostructured materials can be used for optimization of alanine sensitivity, by taking into account the influence of the particles size of the silver nanoparticles on the detection properties of the alanine radiation detectors, thus contributing to the construction of small-sized detectors. PMID- 22441755 TI - Anodic formation of high aspect ratio, self-ordered Nb2O5 nanotubes. AB - In the present work, we demonstrate the feasibility to form an aligned Nb(2)O(5) nanotube layer by self-organizing anodization of Nb in a NH(4)F-glycerol electrolyte. In order to achieve a nanotubular rather than a nanoporous layer, careful optimization of the anodization electrolyte is required. We show that only in a narrow window of electrolyte parameters highly aligned nanotubes of 50 nm inner diameter and several micrometres in length can be formed. PMID- 22441756 TI - Factors influencing the miss rate of polyps in a back-to-back colonoscopy study. AB - BACKGROUND AND STUDY AIMS: In patients undergoing colonoscopy, 22 % - 28 % of polyps and 20 % - 24 % of adenomas are missed. It is unclear which factors contribute to polyp miss rates, but colorectal cancer detected within 3 years after colonoscopy may originate from missed lesions. The aim of the current study was to determine patient- and polyp-related factors that influence the miss rates of polyps and adenomas during colonoscopy. PATIENTS AND METHODS: Data from 406 patients were obtained from a multicenter, randomized back-to-back colonoscopy study investigating the Third Eye Retroscope (TER) in improving polyp detection rate by visualizing hidden areas such as folds and curves. Patients were randomized to undergo standard colonoscopy followed by colonoscopy with TER, or vice versa. Miss rates were calculated for all polyps and adenomas. All lesions were categorized for size and location within the colon/rectum. Odds ratios (ORs) were computed using adjusted logistic regression models to identify factors independently associated with missed lesions. RESULTS: The miss rate was 25 % (150 /611) for all polyps and 26 % (90 /350) for adenomas. Miss rates were significantly lower (21 % vs. 29 %) in patients randomized to TER as the first procedure (P < 0.03). Taking all groups together, > 2 polyps compared with <= 2 polyps detected during the first colonoscopy increased the risk of missing additional polyps (adjusted OR = 2.83; 95 % confidence interval [CI] 1.22 - 6.70). Adenomas in the left colon compared with adenomas in the right colon were also more frequently missed (adjusted OR = 1.65; 95 %CI 1.06 - 2.58). CONCLUSIONS: A quarter of polyps were missed during colonoscopy. Physicians should be aware that the risk of missing a polyp is related to patient factors (presence of > 2 polyps) and polyp factors (left colon location). PMID- 22441757 TI - Toxicity of doxorubicin on pig liver after chemoembolization with doxorubicin loaded microspheres: a pilot DNA-microarrays and histology study. AB - PURPOSE: The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques. METHODS: The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. RESULTS: At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. CONCLUSIONS: DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models. PMID- 22441758 TI - In situ hydrothermal synthesis of dysprosium(III) single-molecule magnet with lanthanide salt as catalyst. AB - A family of six dinuclear lanthanide complexes have been obtained via in situ hydrothermal synthesis with lanthanide ions as catalyst. These six complexes are formulated as [Ln(2)(3-Htzba)(2)(3-tzba)(2)(H(2)O)(8)].4H(2)O [Ln = Gd, 1; Dy, 2; Eu, 3; Tb, 4; Sm, 5; Er, 6; 3-H(2)tzba = 3-(1H-tetrazol-5-yl)benzoic acid]. The magnetic investigations show that complex 2 behaves as a single-molecule magnet (SMM) with a quantum relaxation time of ~10(-2) s. PMID- 22441759 TI - A unique variant of afferent limb syndrome after ileal pouch-anal anastomosis: a case series and review of the literature. AB - BACKGROUND: Afferent limb syndrome is a relatively rare cause of small bowel obstruction after restorative total proctocolectomy with ileal pouch-anal anastomosis for patients with ulcerative colitis or familial adenomatous polyposis. DISCUSSION: This report describes three patients who developed recurrent small bowel obstruction after ileal pouch-anal anastomosis. The bowel obstruction was caused by torsion of the ileum at the inlet of the ileal J-pouch, which was thought to be a variant of afferent limb syndrome. This variant of afferent limb syndrome is characterized by a flexible afferent limb of the pelvic pouch due to the lack adhesion of the ileum in the abdominal cavity. Preoperative diagnosis required multiple series of contrast small bowel enemas. Strictureplasty and ileopexy effectively resolved the recurrent bowel obstruction caused by this variant of afferent limb syndrome. PMID- 22441760 TI - Quality of sperm obtained by penile vibratory stimulation and percutaneous vasal sperm aspiration in men with spinal cord injury. AB - The aim of this study was to explore sperm chromosomal aneuploidy and DNA integrity in infertile patients with spinal cord injury (SCI). Semen samples were collected from 12 infertile men with SCI by percutaneous vasal sperm aspiration (PVSA) and from 14 male SCI patients by penile vibratory stimulation (PVS). These semen samples as well as samples from 16 donors were analyzed using the hypo osmotic swelling (HOS) test, the sperm chromatin dispersion test, terminal deoxynucleotidyl transferase-mediated terminal uridine nick-end labeling assay, and multicolor fluorescence in situ hybridization with probes specific for the chromosomes 13, 18, 21, X, and Y. There were significant differences in the percentages of motile sperm, normal morphologic sperm, normal HOS/eosin staining, and sperm DNA fragmentation between the infertile men with SCI and the control group (P < .05 and P < .01). The sperm forward motility was significantly greater in the PVSA group than in the PVS group (P < .01). The number of round cells per milliliter of semen obtained from the 14 SCI patients by PVS was between 1 million and 12 million. The rate of sperm DNA fragmentation, as identified by the sperm chromatin dispersion test, was higher in the PVS group than in the PVSA group (P < .05). The aneuploidy rates for the SCI patients were 1.5- to 1.6-fold higher for chromosomes 13, 18, and 21, and were 2.3- to 2.4-fold higher for chromosomes X and Y than for patients in the control group (P < .001). These results suggest that for men with SCI, the semen quality is poorer, the prevalence of abnormal HOS/eosin staining is greater, and sperm DNA fragmentation and sperm chromosomal aneuploidies are seen at a higher rate compared with healthy, fertile, and normospermic men. PMID- 22441761 TI - Influence of dihydroergotoxine, bromocriptine, and ergotamine on penile erection in Wistar rats. AB - The pilot study presented was conducted to determine as to whether ergot alkaloids (alpha-adrenergic blockers) have a potential effect on penile erectile function. The influence of dihydroergotoxine, bromocriptine, and ergotamine was studied on the erection ability in intact, two-grade outbred male Wistar albino rats that were out of their estrous phase. The experimental animals were injected intrapenially with the substances under examination: dihydroergotoxine mesylate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1 mg/0.1 mL), bromocriptine mesylate (0.3 mg/0.1 mL, 1 mg/0.1 mL, and 3 mg/0.1 mL), and ergotamine tartrate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1mg/0.1 mL). Every dose was tested on a pattern of 30 rats. These mentioned substances were injected in the amount of 1 mm to the left of the proximal part of the superficial dorsal vein of the penis, in the region of the penis root. After injection, the animals were then observed within the next 90 minutes. In the trial, the following was observed: the number of rats with an erection achieved, the period of time from intrapenial application to the appearance of the first erection, and the duration of the erection. Ultimately, the research results confirm the efficiency of dihydroergotoxine and bromocriptine as erectogenic agents, as well as ergotamine as a detumescent compared with saline solutions. PMID- 22441762 TI - Activity of the Na,K-ATPase alpha4 isoform is regulated during sperm capacitation to support sperm motility. AB - The alpha4 polypeptide is a testis-specific isoform of the catalytic subunit of the Na,K-ATPase, which is essential for sperm motility and fertility. In the present study, we have investigated the regulation of activity of the alpha4 isoform and the relevance of this event for sperm capacitation. We have performed this by taking advantage of the selective high affinity of alpha4 for the inhibitor ouabain. Our results show that ouabain-sensitive hydrolysis of ATP and uptake of (86)Rb, corresponding to the enzymatic and ion transport activities of alpha4, respectively, increased during sperm capacitation in a time-dependent manner. Specific labeling of alpha4 with the fluorescent indicator bodipy-ouabain and immunoblot analysis of biotinylated and streptavidin-precipitated sperm plasma membrane proteins indicated a capacitation- and time-dependent rise in levels of active alpha4 isoform at the sperm surface. Ouabain inhibition of alpha4 blocked the increase in total sperm motility and the hyperactive motility pattern characteristic of sperm capacitation. Moreover, interference of alpha4 activity with ouabain partially prevented the intracellular decrease in Na(+) and the plasma membrane hyperpolarization that typically accompany sperm capacitation. In contrast, ouabain inhibition of alpha4 did not affect the spontaneous sperm acrosomal reaction following capacitation. Together, these results demonstrate that Na,K ATPase alpha4 activity is up-regulated during sperm capacitation through mechanisms that involve both increases in molecular activity and levels of alpha4 at the sperm plasma membrane. This increase in alpha4 activity helps maintain the changes in motility that are associated with sperm capacitation, emphasizing the biologic relevance of the Na,K-ATPase alpha4 isoform in sustaining sperm function. PMID- 22441763 TI - Ion channels in sperm physiology and male fertility and infertility. AB - Ion channels regulate the membrane potential and intracellular ionic concentration and thus serve a central role in various cellular processes. Several ion channels have been identified in the germ cells, including sperm, emphasizing their importance in male fertility and reproduction. The molecular mechanism of ion transport and the nature of the ion channels involved have begun to emerge only recently despite the fact that several ligand-gated and voltage-gated channels have been identified and localized on sperm. The presence of the sperm-associated cation channel (CatSper1-4) gene family, proton voltage gated ion channel (Hv1), potassium voltage-gated ion channel (SLO3/KCNU1), sodium voltage-gated channel (NaV1.1-1.9), and the members of the transient receptor potential (TRP) channel family suggest an indispensable role for ion channels in sperm physiology and fertility potential. Ion channels are the key players in very important processes such as capacitation and the acrosome reaction, which are critical steps in sperm physiology preparing for fertilization. For example, CatSper, Hv1, SLO3, and TRP channel family members have been proposed to participate in the acrosome reaction, thereby making them most important for sperm fertility. Similarly, NaV channels could play a crucial role in noncapacitated sperm and in the initial capacitation steps. The role of ion channels seems indispensable for sperm fertility as evidenced by studies on animal models; however, the functional defects in infertile human males await further exploration. This article represents an update on the role of ion channels in sperm physiology, male fertility, and infertility. PMID- 22441764 TI - Methylation-specific PCR allows for fast diagnosis of X chromosome disomy and reveals skewed inactivation of the X chromosome in men with Klinefelter syndrome. AB - Klinefelter syndrome (KS) remains the most common, yet often undiagnosed, chromosomal aberration in men. Early diagnosis and treatment can improve the health of patients with KS. The aim of this study was to evaluate the inactivation pattern of supernumerary X chromosomes. The secondary aim was to design a reliable and cost-effective molecular test for detection of X chromosome disomy. Methylation-specific polymerase chain reaction (M-PCR), with primers for familial mental retardation (FMR1) and X chromosome inactive specific transcript (XIST) genes, was used to detect the presence of X chromosome disomy in men. Seventeen fertile males, 12 females, and 35 males with KS (28 with 47,XXY karyotype, and 7 with 47,XXY/46,XY mosaics) were included in the study. Results of the karyotype were compared with the results of semiquantitative M-PCR. Inactivation of X chromosomes was measured by XIST/FMR-1 methylation ratio. Differences in the methylation patterns of FMR1 and XIST genes between 46,XY men and men with X chromosome disomy allowed for rapid detection of the presence of an additional X chromosome, achieving 100% sensitivity and specificity using M-PCR. The methylated:unmethylated FMR1 amplicon ratio allowed the detection of 1 additional X chromosome per 100 normal XY cells (1% of XX/XY mosaicism). In our series, 50% of 47,XXY men showed skewed inactivation of the X chromosome. Men with KS can have incomplete inactivation of supernumerary X chromosomes. M-PCR is a sensitive, specific, fast, and relatively inexpensive test for the diagnosis of X chromosome disomy. PMID- 22441765 TI - High-fat diet obesity associated with insulin resistance increases cell proliferation, estrogen receptor, and PI3K proteins in rat ventral prostate. AB - In this study, we evaluated the effects of obesity and insulin resistance induced by a high-fat diet on prostate morphophysiology, focusing on cell proliferation, expression of androgen (AR) and estrogen receptors (ER) and proteins of the insulin signaling pathway. Adult male Wistar rats were fed a high-fat diet (20% fat) for 15 weeks, whereas control animals received a balanced diet (4% fat). Both groups were then divided and treated for 2 weeks with 1 mg/kg body weight/day of the aromatase inhibitor letrozole or vehicle only. The ventral prostate was analyzed with immunohistochemical, histopathological, stereological, and Western blotting methods. Obese rats showed insulin resistance, hyperinsulinemia, and reduced plasma testosterone levels. The incidence of prostatic intraepithelial neoplasia (PIN) was 2.7 times higher in obese rats and affected 0.4% of the gland compared with 0.1% PIN areas found in control rats. Obesity doubled cell proliferation in both prostate epithelium and stroma. AR content decreased in the prostate of obese rats and estrogen receptor beta (ERbeta) increased in this group. Protein levels of insulin receptor substrate 1 and protein kinase B diminished in the obese group, whereas phosphatidylinositol 3-kinase (PI3K) increased significantly. Most structural changes observed in the prostate of obese rats normalized after letrozole treatment, except for increased stromal cell proliferation and ERbeta expression, which might be associated with insulin resistance. This experimental model of obesity and insulin resistance induced by a high-fat diet increases cell proliferation in rat prostate. Such alterations are associated with decreased levels of AR and increased ERbeta and PI3K proteins. This change can facilitate the establishment of proliferative lesions in rat prostate. PMID- 22441766 TI - Abeta oligomers-induced toxicity is attenuated in cells cultured with NbActiv4TM medium. AB - Pathogenic Abeta-derived diffusible ligands (ADDLs) bind to post-synaptic targets, induce excessive reactive oxygen species (ROS) and stimulate tau hyperphosphorylation in cultured neurons. Recently, NbActiv4TM medium was reported to increase neuron synapse densities in cultured hippocampal neurons. We aimed to investigate the effect of this novel medium on ADDL-induced toxicity. We found that ADDL-induced ROS was attenuated in cells cultured with NbActiv4TM. ADDL binding assay was performed in neurons cultured by different feeding conditions with NbActiv4TM. Feeding cells with 30 % medium once a week, ADDL binding sites were abundant at days in vitro (DIV) 18. However, changing 50 % medium once a week decreased ADDL binding about 80 %. NbActiv4TM produced about 40 % more glial fibrillary acidic protein (GFAP) positive astrocytes than the widely used hippocampal culture medium, neurobasal supplemented with B27 (neurobasal/B27). Astrocytes are reported to produce kinds of trophic factors including insulin-like growth factor 1 (IGF-1). Consistently, when cultured with NbActiv4TM, neurons were sensitive to inhibitors of insulin/IGF-1 signaling in response to ADDL attack. Overall, this study supports the important role of astrocytes in neuroprotection and indicates that targeting astrocytes dysfunction may lead to new therapeutic strategies for Alzheimer's disease. PMID- 22441767 TI - A hard-template method for the preparation of IrO(2) , and its performance in a solid-polymer-electrolyte water electrolyzer. AB - Morphological control by SBA-15: The performance of catalysts for the oxygen evolution reaction (OER) depends strongly on their structural and morphological properties. An IrO(2) nanomaterial with a morphology suitable for the OER is prepared by using a synthetic scheme involving a zeolite template, and shows enhanced activity and stability compared to IrO(2) fabricated by the traditional Adams-fusion method. PMID- 22441768 TI - Targeting bacterial toxins. AB - Protein toxins constitute the main virulence factors of several species of bacteria and have proven to be attractive targets for drug development. Lead candidates that target bacterial toxins range from small molecules to polymeric binders, and act at each of the multiple steps in the process of toxin-mediated pathogenicity. Despite recent and significant advances in the field, a rationally designed drug that targets toxins has yet to reach the market. This Review presents the state of the art in bacterial toxin targeted drug development with a critical consideration of achieved breakthroughs and withstanding challenges. The discussion focuses on A-B-type protein toxins secreted by four species of bacteria, namely Clostridium difficile (toxins A and B), Vibrio cholerae (cholera toxin), enterohemorrhagic Escherichia coli (Shiga toxin), and Bacillus anthracis (anthrax toxin), which are the causative agents of diseases for which treatments need to be improved. PMID- 22441769 TI - Sex guilt mediates the relationship between religiosity and sexual desire in East Asian and Euro-Canadian college-aged women. AB - Research has examined the relationship between religiosity and sexuality but few studies have explored the mechanisms by which sexual variables are influenced by religiosity. The purpose of the present study was to investigate the role of sex guilt in the relationship between religiosity and sexual desire in women. Euro Canadian (n = 178) and East Asian (n = 361) female university students completed a battery of questionnaires. Higher levels of religious fundamentalism, intrinsic religiosity and spirituality were associated with higher levels of sex guilt in both ethnic groups. Paranormal belief was not associated with sex guilt in either ethnic group. The Euro-Canadian women reported significantly higher levels of sexual desire and significantly less sex guilt than the East Asian women. Among the Euro-Canadian women, sex guilt mediated the relationships between spirituality and sexual desire, and fundamentalism and sexual desire; among the East Asian women, sex guilt mediated the relationships between spirituality and sexual desire, fundamentalism and sexual desire, and intrinsic religiosity and sexual desire. These findings suggest that sex guilt may be one mechanism by which religiosity affects sexual desire among women. PMID- 22441770 TI - Is religiosity a barrier to sexual and reproductive health? Results from a population-based study of young Croatian adults. AB - Following the demise of socialism in 1989, religious identification substantially increased in most countries of Central, East, and Southeast Europe. Considering that there is evidence that religiosity is associated with reduced sexual risk taking among young people, this study explored associations between religiosity- assessed at three different levels (religious upbringing, personal religiosity, and social network religiosity)--and sexual risks among young Croatian adults. In addition, we examined whether religiosity predicted chlamydial infection among women and men aged 18-25. The data were collected in a national probability survey carried out in 2010 (n = 1,005). Overall, the effects of religiosity were sporadic, present primarily among women, and of small size. This lack of a sizeable impact of religiosity on young adults' sexuality was likely related to a particular type of religiosity, characterized by individualized morality, found among young people in the country. Although Croatia seems to be one of the most religious countries in Europe, our findings suggest that promoting religious morality--as recently attempted by an abstinence-based educational program--may not be an efficient tool in reducing sexual risks. PMID- 22441771 TI - Testing putative causal associations of risk factors for early intercourse in the study of twin adults: genes and environment (STAGE). AB - Adverse childhood experiences and substance use have been identified as potential causal risk factors for early-onset sexual intercourse. While it is possible that exposure to these risk factors directly increases the likelihood of engaging in early intercourse, an alternative explanation is that observed associations between these variables are due to shared familial confounds. These unmeasured confounds may increase the likelihood of being exposed to these risk factors and of engaging in early intercourse. Participants drawn from a population-based study of Swedish adult twins (ages 19-47 years; N = 12,126) reported on their history of exposure to early physical and sexual trauma, cigarette use, and cannabis use. We investigated the nature of the association between these risk factors and young age at first intercourse, using a comparison of twins differentially exposed to each risk factor. When compared to non-exposed, unrelated individuals, participants who reported adverse childhood experiences or who engaged in early cigarette use or cannabis use were more likely to engage in early intercourse. However, co-twin comparisons indicated that observed associations between these risk factors and early intercourse may be due to familial factors shared within twin pairs, and risk factor exposure may not lead directly to early intercourse. Our results suggest that preventing trauma exposure or preventing or delaying adolescents' cigarette smoking or cannabis use may not effectively delay intercourse onset; instead, other aspects of the adolescent's environment should be addressed. PMID- 22441772 TI - Legumain: a biomarker for diagnosis and prognosis of human ovarian cancer. AB - Legumain is a member of the asparaginyl endopeptidase family that is over expressed in response to hypoxic stress on mammary adenocarcinoma, colorectal cancer, proliferating endothelial cells, and tumor-associated macrophages (TAMs). Here, we demonstrate that elevated expression of legumain in ovarian cancer by a proteomic approach using isobaric tags for relative and absolute quantification (iTRAQ) followed by liquid chromatography-mass spectrometry (LC-MS/MS). To investigate the relationship between legumain expression and ovarian cancer development, we tested legumain expression in malignant human ovarian tumors (n = 60), borderline ovarian tumors (n = 20), benign ovarian tumors (n = 20), and normal ovary samples (n = 20) using immunohistochemical assay (IHC). A correlation between legumain expression, and clinocopathologic and biological variables was also established. Importantly, increased legumain expression was validated by real-time PCR and Western blots, correlated positively with an increased malignancy of ovarian tumors (P < 0.01). In fact, patients with strong legumain expression had a worse prognosis (P = 0.03). In addition, results of in vitro experiments revealed that over-expression of legumain correlates with increased cell migration and invasion of ovarian cancer cells. Although legumain's functional role and clinical utility remain to be established, our results indicated that a sensitive assay for early expression of legumain may serve as both a potential biomarker and a molecular target for treatment of ovarian cancer. PMID- 22441774 TI - Anxiety sensitivity moderates prognostic importance of rhythm-control versus rate control strategies in patients with atrial fibrillation and congestive heart failure: insights from the Atrial Fibrillation and Congestive Heart Failure Trial. AB - BACKGROUND: Patients with high anxiety sensitivity (AS) become extremely anxious with heart rate increases, palpitations, and symptoms of psychological arousal. AS predicts panic attacks. In atrial fibrillation (AF), AS correlates with symptom preoccupation and reduced quality of life. We assessed whether AS is associated with outcomes of rhythm-control versus rate-control in congestive heart failure (CHF) patients with AF. METHODS AND RESULTS: Before random assignment, 933 participants (172 women) in the Atrial Fibrillation and Congestive Heart Failure Trial completed the Anxiety Sensitivity Inventory (ASI). Cox proportional hazards models showed no main effects of treatment (P=0.61) or AS (P=0.72) for time to cardiovascular death, but these factors interacted significantly (P=0.020). High AS patients (upper quartile, ASI >=33) randomly assigned to rhythm-control had significantly lower cardiovascular mortality than those receiving rate-control (hazard ratio, 0.54; 95% confidence interval, 0.32 0.93; P=0.022). With lower ASI scores (<33), treatments did not differ (hazard ratio, 1.12; 95% confidence interval, 0.83-1.51; P=0.46). The interaction between treatment and dichotomized ASI scores remained significant (P=0.009) after adjustment for covariates including age, sex, hypertension, diabetes, creatinine, ejection fraction, time since first diagnosis of AF, New York Heart Association functional class, depression symptoms, marital status, and baseline beta blockers, angiotensin-converting enzyme inhibitors, oral anticoagulants, and implantable cardioverter-defibrillators. CONCLUSIONS: Atrial fibrillation and congestive heart failure patients with high AS had better long-term prognosis with rhythm- than rate-control. If replicated, AS should be considered in treatment selection. Research is also needed concerning mechanisms and possible joint AS-AF treatments. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT88597077. PMID- 22441773 TI - Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction: impact of the new Chronic Kidney Disease-Epidemiology Collaboration Group formula. AB - BACKGROUND: Prior studies in heart failure (HF) have used the Modification of Diet in Renal Disease (MDRD) equation to calculate estimated glomerular filtration rate (eGFR). The Chronic Kidney Disease-Epidemiology Collaboration Group (CKD-EPI) equation provides a more-accurate eGFR than the MDRD when compared against the radionuclide gold standard. The prevalence and prognostic import of renal dysfunction in HF if the CKD-EPI equation is used rather than the MDRD is uncertain. METHODS AND RESULTS: We used individual patient data from 25 prospective studies to stratify patients with HF by eGFR using the CKD-EPI and the MDRD equations and examined survival across eGFR strata. In 20 754 patients (15 962 with HF with reduced ejection fraction [HF-REF] and 4792 with HF with preserved ejection fraction [HF-PEF]; mean age, 68 years; deaths per 1000 patient years, 151; 95% CI, 146-155), 10 589 (51%) and 11 422 (55%) had an eGFR <60 mL/min using the MDRD and CKD-EPI equations, respectively. Use of the CKD-EPI equation resulted in 3760 (18%) patients being reclassified into different eGFR risk strata; 3089 (82%) were placed in a lower eGFR category and exhibited higher all-cause mortality rates (net reclassification improvement with CKD-EPI, 3.7%; 95% CI, 1.5%-5.9%). Reduced eGFR was a stronger predictor of all-cause mortality in HF-REF than in HF-PEF. CONCLUSIONS: Use of the CKD-EPI rather than the MDRD equation to calculate eGFR leads to higher estimates of renal dysfunction in HF and a more-accurate categorization of mortality risk. Renal function is more closely related to outcomes in HF-REF than in HF-PEF. PMID- 22441775 TI - Risk factors for Clostridium difficile toxin-positive diarrhea: a population based prospective case-control study. AB - Increased incidence and severity of Clostridium difficile infections (CDIs) is of major concern. However, by minimizing known risk factors, the incidence can be decreased. The aim of this investigation was to calculate the incidence and assess risk factors for CDI in our population. A 1-year prospective population based nationwide study in Iceland of CDIs was carried out. For risk factor evaluation, each case was matched with two age- and sex-matched controls that tested negative for C. difficile toxin. A total of 128 CDIs were identified. The crude incidence was 54 cases annually per 100,000 population >18 years of age. Incidence increased exponentially with older age (319 per 100,000 population >86 years of age). Community-acquired origin was 27 %. Independent risk factors included: dicloxacillin (odds ratio [OR]: 7.55, 95 % confidence interval [CI]: 1.89-30.1), clindamycin (OR: 6.09, 95 % CI: 2.23-16.61), ceftriaxone (OR: 4.28, 95 % CI: 1.59-11.49), living in a retirement home (OR: 3.9, 95 % CI: 1.69-9.16), recent hospital stay (OR: 2.3, 95 % CI: 1.37-3.87). Proton pump inhibitors (PPIs) were used by 60/111 (54 %) versus 91/222 (41 %) (p = 0.026) and ciprofloxacin 19/111 (17 %) versus 19/222 (9 %) (p = 0.027) for cases and controls, respectively. In all, 75 % of primary CDIs treated with metronidazole recovered from one course of treatment. CDI was mostly found among elderly patients. The most commonly identified risk factors were broad-spectrum antibiotics and recent contact with health care institutions. PPI use was significantly more prevalent among CDI patients. PMID- 22441776 TI - The chemopreventive and clinically used agent curcumin sensitizes HPV (-) but not HPV (+) HNSCC to ionizing radiation, in vitro and in a mouse orthotopic model. AB - Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV (-) cell lines was significantly higher than the HPV (+) cell lines used in our study. Notably, all of the HPV (-) cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV (-) cell lines it had no effect on the HPV (+) cells. Based on these findings we employed an orthotopic, HPV (-) HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV (-) HNSCC. PMID- 22441777 TI - First quadrivalent flu vaccine approved. PMID- 22441778 TI - Evidence lacking on anticoagulation therapy practices, guidelines say. PMID- 22441779 TI - Pharmacy integral to collaborative care at Mass General. PMID- 22441780 TI - Diagnosis codes don't always aptly describe patients' conditions. PMID- 22441782 TI - Female representation on editorial boards of pharmacy journals. PMID- 22441783 TI - Drug diversion by anesthesiologists: identification through intensive auditing. PMID- 22441784 TI - Medication reconciliation campaign in a clinic for homeless patients. PMID- 22441785 TI - Writing letters of recommendation: where should you start? PMID- 22441786 TI - Quality of life and economic costs associated with postthrombotic syndrome. AB - PURPOSE: Published evidence on quality-of-life (QOL) outcomes and health care costs in patients with postthrombotic syndrome (PTS), a common and difficult-to diagnose complication of venous thromboembolism (VTE), is reviewed. SUMMARY: Occurring in as many as 70% of patients with VTE, PTS remains a challenging and costly disorder, partly due to the lack of a standard diagnostic definition and varying classification systems. Searches of Medline and EMBASE identified 12 articles on humanistic and economic outcomes associated with PTS. The results of U.S. and international studies indicate that PTS is a key determinant of long term QOL among patients with VTE. In one large study, 37% of patients with VTE developed PTS within two years of a diagnosis of deep venous thrombosis (DVT), and 4% developed severe PTS, with the occurrence of PTS linked to clinically relevant declines in measures of physical and mental health. Research indicates that the economic burden of PTS in the United States may be as high as $200 million annually. Recent progress in efforts to develop standard PTS terminology may facilitate the dissemination of clear consensus guidelines to assist in timely PTS detection and optimal care. CONCLUSION: Appropriate measures to decrease PTS-related burdens may include the prevention of DVT, clear diagnostic criteria for PTS, and an education campaign aimed at increased standardization in the management of DVT. Gaps in the current understanding of the risk factors, diagnostic criteria, preventive strategies, and even treatment modalities for PTS hamper the ability of clinicians to employ measures that could reduce the occurrence of this disorder and the associated morbidity. PMID- 22441787 TI - Safety and efficacy of glucagon for the relief of acute esophageal food impaction. AB - PURPOSE: The safety and efficacy of i.v. glucagon for the relief of acute esophageal food impaction were evaluated. SUMMARY: The medical literature was reviewed to identify published trials and case series on the use of i.v. glucagon for the relief of acute esophageal food impaction. Individual case reports and limited case series were excluded from the analysis. This search yielded two retrospective reviews, three prospective reviews, and one randomized, placebo controlled trial. Only two of the studies analyzed the effect of glucagon alone. Two studies combined this therapy with benzodiazepines, and the other two combined this therapy with an effervescent product and water. Of the two studies that had a control group, one demonstrated no significant difference in the success rate of dislodgement and one showed a nonsignificantly lower success rate in the treatment group. The majority of reports excluded patients with known esophageal strictures and treated a variety of different food-type impactions, making it difficult to determine if the success of this therapy may be tied to a specific subgroup. Few studies documented the adverse effects of this therapy, the most common being nausea and vomiting. Although limited, the available data do not support the use of glucagon for the relief of acute esophageal food impaction. CONCLUSION: Based on the available data, the use of i.v. glucagon for the relief of acute esophageal food impaction is not supported by the literature. In addition, glucagon has the potential to cause adverse effects and decrease the likelihood of spontaneous resolution. PMID- 22441788 TI - Pancytopenia, mucositis, and hepatotoxicity after intralesional methotrexate injection in a patient treated with peritoneal dialysis. AB - PURPOSE: A case of methotrexate toxicity from intralesional treatment of squamous cell carcinoma of the hands in a peritoneal dialysis patient is reported. SUMMARY: A 68-year-old Caucasian man receiving peritoneal dialysis for end-stage renal disease complained to his primary care physician of shortness of breath, mouth and hand sores, nausea, and general malaise. Four days before his office visit, the patient received 25 mg of methotrexate intralesionally for refractory squamous cell carcinoma of his hands. The patient had several pustular lesions on both hands. On admission, the patient had a normal complete blood cell count and elevated liver enzyme levels. On hospital day 3, the patient's white blood cell count was 1,300 cells/MUL, platelet count was 134,000 platelets/MUL, hemoglobin value was 12.4 g/dL, and hematocrit was 37%. Folic acid 1 mg i.v. every six hours and leucovorin 10 mg/m(2) (20 mg) i.v. every six hours was initiated. His serum methotrexate concentration was 0.03 MUmol/L on hospital day 6. The leucovorin dosage was increased to 200 mg i.v. every six hours. Platelets were administered, and the patient was switched to four-hour treatments of high-flux membrane hemodialysis for two consecutive days. The patient was discharged on hospital day 14. Mild mucositis was still present, but the patient had improved substantially and was discharged to a rehabilitation facility. CONCLUSION: A 68-year-old peritoneal dialysis patient who was treated with 25 mg of intralesional methotrexate for squamous cell carcinoma of the hands developed pancytopenia, mucositis, and hepatotoxicity as a result of systemic absorption and prolonged elimination. PMID- 22441789 TI - Probable rifaximin-induced neutropenia. AB - PURPOSE: The development of neutropenia in a patient treated with rifaximin is reported. SUMMARY: A 45-year-old Caucasian woman with severe ulcerative colitis arrived at the emergency department with complaints of worsening abdominal pain, nausea, and vomiting and was found to have extensive portal vein and superior mesenteric vein thrombosis with additional thrombi in the distal aortic and left common iliac arteries on an abdominal computed tomography angiography scan. A heparin i.v. drip was started, and the following day the patient underwent thrombectomy and thrombolysis with tissue plasminogen activator of the superior mesenteric vein thrombus. Secondary to rectal bleeding and a decrease of approximately 2 g in the patient's hemoglobin concentration while receiving heparin, the decision was made to forego additional use of tissue plasminogen activator for the portal vein thrombosis, and a transjugular intrahepatic portosystemic shunt (TIPS) procedure was performed to improve portal blood flow. After consultation with the gastroenterology and hepatology departments, the decision was made to initiate rifaximin 400 mg orally every eight hours for the prevention of hepatic encephalopathy after the TIPS procedure. The patient's white blood cell (WBC) count was 6800/MUL on the day of rifaximin initiation. On day 4 of rifaximin treatment, the patient's WBC count reached its nadir at 1200/MUL. The primary internal medicine team then decided to discontinue rifaximin therapy. During this time, the patient showed no other signs of infection. The patient's WBC count rebounded to 3300/MUL three days after discontinuation of rifaximin therapy. CONCLUSION: A 45-year-old Caucasian woman with severe ulcerative colitis developed neutropenia after the initiation of rifaximin. PMID- 22441790 TI - Effects of atmospheric pressure conditions on flow rate of an elastomeric infusion pump. AB - PURPOSE: The effects of pressure conditions, both hyperbaric and hypobaric, on the flow rate of an elastomeric infusion pump were investigated. METHODS: The altered pressure conditions were tested with the restrictor outlet at two different conditions: (1) at the same pressure condition as the Infusor elastomeric balloon and (2) with the outlet exposed to ambient conditions. Five different pressure conditions were tested. These included ambient pressure (98 101 kilopascals [kPa]) and test pressures controlled to be 10 or 20 kPa below or 75 or 150 kPa above the ambient pressure. A theoretical calculation based on the principles of fluid mechanics was also used to predict the pump's flow rate at various ambient conditions. RESULTS: The conditions in which the Infusor elastomeric pump and restrictor outlet were at the same pressure gave rise to average flow rates within the +/-10% tolerance of the calculated target flow rate of 11 mL/hr. The flow rate of the Infusor pump decreased when the pressure conditions changed from hypobaric to ambient. The flow rate increased when the pressure conditions changed from hyperbaric to ambient. CONCLUSION: The flow rate of the Infusor elastomeric pump was not affected when the balloon reservoir and restrictor outlet were at the same pressure. The flow rate varied from 58.54% to 377.04% of the labeled flow rate when the pressure applied to the reservoir varied from 20 kPa below to 150 kPa above the pressure applied to the restrictor outlet, respectively. The maximum difference between observed flow rates and those calculated by applying fluid mechanics was 4.9%. PMID- 22441791 TI - Stability of an extemporaneously prepared tadalafil suspension. AB - PURPOSE: The stability of an extemporaneously prepared tadalafil oral suspension was studied. METHODS: An oral suspension of tadalafil 5 mg/mL was prepared by thoroughly grinding 15 20-mg tadalafil tablets in a glass mortar. Thirty milliliters of Ora-Plus and 30 mL of Ora-Sweet were mixed and added to the powder to make a final volume of 60 mL. Three identical samples of the formulation were prepared and placed in 2-oz amber plastic bottles with child-resistant caps and stored at room temperature (23-25 degrees C). A 1-mL sample was withdrawn from each of the three bottles with a micropipette immediately after preparation and at 7, 14, 28, 57, and 91 days. After double dilution (1:10 and 0.1:5 v/v) to an expected concentration of 10 MUg/mL with methanol and mobile phase, respectively, the samples were assayed in duplicate using stability-indicating high-performance liquid chromatography. The samples were visually examined for any color change and evaluated for pH changes on each day of analysis. Taste evaluation was performed at the beginning and end of the study. Stability was defined as the retention of at least 90% of the initial concentration. RESULTS: At least 99% of the initial tadalafil concentration remained throughout the 91-day study period. There were no detectable changes in color, odor, taste, and pH, and no visible microbial growth was observed in any sample. CONCLUSION: An extemporaneously prepared suspension of tadalafil 5 mg/mL in a 1:1 mixture of Ora-Plus and Ora Sweet was stable for at least 91 days when stored in amber plastic bottles at room temperature. PMID- 22441792 TI - Stability of dexmedetomidine 4 MUg/mL in polypropylene syringes. AB - PURPOSE: The results of a study to determine the long-term (up to 14 days) stability of diluted dexmedetomidine kept in polypropylene syringes under typical pharmacy storage conditions are presented. METHODS: Four samples of dexmedetomidine injection diluted to 4 MUg/mL in 0.9% sodium chloride were prepared and divided into 25-mL portions for storage in syringes at ambient room temperature (20-25 degrees C) with light exposure or under refrigeration (5 degrees C) in darkness. At 24 and 48 hours, the percentage of the initial dexmedetomidine concentration remaining in all samples was assessed via high performance liquid chromatography with diode-array detection; further stability testing of the refrigerated samples was performed on days 7 and 14. At each time point, the test samples were visually inspected for color, clarity, and signs of formation of particulate matter. RESULTS: As determined by chromatographic analyses, the samples of diluted dexmedetomidine stored in syringes at room temperature exhibited a loss of drug concentration of <10% over 48 hours; the refrigerated samples exhibited a loss of drug concentration of <5% over 14 days. All of the syringe-stored samples remained clear and colorless on visual inspection for the duration of the study. CONCLUSION: Dexmedetomidine diluted to 4 MUg/mL in 0.9% sodium chloride injection was stable for at least 48 hours at 20 25 degrees C and 14 days at 5 degrees C when stored in polypropylene syringes. PMID- 22441793 TI - Antibiogram compliance in University HealthSystem Consortium participating hospitals with Clinical and Laboratory Standards Institute guidelines. AB - PURPOSE: The degree of compliance with antibiogram guidance among University HealthSystem Consortium (UHC) hospitals was analyzed. METHODS: The UHC Pharmacy Council Pharmacy Practice Advancement Committee conducted a survey to evaluate hospital policies regarding the generation, reporting, and utilization of antibiograms among UHC hospitals. The survey was distributed via a UHC online survey tool to pharmacy directors at 237 UHC hospitals. Responses were collected from April 13 to May 14, 2010. RESULTS: Of the 237 hospitals to which surveys were sent, 49 hospitals (21%) from 28 states submitted survey responses. Forty eight hospitals reported that they routinely generated antibiograms, and 36 reported that they adopted all or most of the standards recommended by the 2009 guidelines on antibiograms published by the Clinical and Laboratory Standards Institute (CLSI). The compliance rates to the four key CLSI recommendations were as follows: 98% reported data at least annually, 89% eliminated duplicate isolates, 83% did not include surveillance isolates, and 64% required at least 30 isolates for each reported species. Thirty-eight hospitals had an antimicrobial stewardship program; 35 of them formally reviewed antibiograms and 19 implemented new programs based on the antibiogram data. In 16 hospitals, formulary changes were made as a consequence of antibiogram results. In 30 hospitals, pharmacists had significant involvement in compiling, reviewing, and reporting antibiograms. CONCLUSION: Among respondents from 47 UHC hospitals, the compliance rates to four key CLSI recommendations for antibiograms ranged from 64% to 98%. Respondents from 30 hospitals reported significant involvement of pharmacists in compiling, reviewing, and reporting antibiograms. PMID- 22441794 TI - Implementing smart pumps for epidural infusions in an academic medical center. AB - PURPOSE: A hospital's initial experience with the implementation of new smart pump technology for epidural drug delivery is described, with a discussion of challenges and lessons learned during the implementation process. SUMMARY: After a focused review of epidural medication use and prescribing patterns at the University of North Carolina Hospitals and Clinics (UNCH), a multidisciplinary team guided the selection of new smart pumps and the development of associated software tools. The new devices were programmed to display a "master drug library" of recommended drug concentrations, doses, and rates, which were consistent with newly created order sets intended to standardize prescriber ordering and nurse administration intended to help standardize prescriber ordering and nurse administration of adult and pediatric epidural infusions. However, data retrieved from the new units after several months of use indicated that nurses were still programming about 60% of epidural smart-pump infusions without using the onboard drug library (in effect circumventing the units' patient-safety software). In a survey of UNCH nursing staff, respondents indicated they were having difficulty in accessing the library and (when necessary) in manually programming the new devices. The hospital's experience highlighted a number of key points for institutions to consider during the implementation of new smart-pump technology. CONCLUSION: The implementation of new smart-pump technology for epidural infusions at UNCH revealed the importance of pump features and design in determining the devices' impact on patient safety. In particular, factors pertaining to ease of use (e.g., protocol-selection functions, programming procedures, data recording and retrieval capabilities) are crucial to the overall success of smart-pump implementation. PMID- 22441795 TI - Managing the outlander syndrome. PMID- 22441796 TI - ATP-binding cassette transporter G2 activity in the bovine spermatozoa is modulated along the epididymal duct and at ejaculation. AB - During their epididymal maturation, stabilizing factors such as cholesterol sulfate are associated with the sperm plasma membrane. Cholesterol is sulfated in epididymal spermatozoa by the enzyme estrogen sulfotransferase. Because of its role in the efflux of sulfate conjugates formed intracellularly by sulfotransferases, the ATP-binding cassette membrane transporter G2 (ABCG2) might have a role in the translocation of this compound across the plasma membrane. In the present study we showed that ABCG2 is present in the plasma membrane overlaying the acrosomal region of spermatozoa recovered from testis, epididymis, and after ejaculation. Although ABCG2 is also present in epididymosomes, the transporter is not transferred to spermatozoa via this mechanism. Furthermore, although epididymal sperm ABCG2 was shown to be functional, as determined by its ability to extrude Hoechst 33342 in the presence of the specific inhibitor Fumitremorgin C, ABCG2 present in ejaculated sperm was found to be nonfunctional. Additional experiments demonstrated that phosphorylation of ABCG2 tyrosyl residues, but not its localization in lipid rafts, is the mechanism responsible for its functionality. Dephosphorylation of ABCG2 in ejaculated spermatozoa is proposed to cause a partial protein relocalization to other intracellular compartments. Prostasomes are proposed to have a role in this process because incubation with this fraction of seminal plasma induces a decrease in the amount of ABCG2 in the associated sperm membrane fraction. These results demonstrate that ABCG2 plays a role in epididymal sperm maturation, but not after ejaculation. The loss of ABCG2 function after ejaculation is proposed to be regulated by prostasomes. PMID- 22441797 TI - Ovarian Kaleidoscope database: ten years and beyond. AB - Ovarian Kaleidoscope database (OKdb) is an online, searchable, public database containing text-based and DNA microarray data to facilitate research by ovarian researchers. Using key words and predetermined categories, users can search ovarian gene information based on gene function, cell type of expression, cellular localization, hormonal regulation, mutant phenotypes, chromosomal location, ligand-receptor relationship, and other criteria, either alone or in combination. For individual genes, users can access more than 10 extensive DNA microarray datasets to interrogate gene expression patterns in a development specific and cell type-specific manner. All ligand and receptor genes expressed in the ovary are matched to facilitate investigation of paracrine/autocrine signaling. More than 3500 ovarian genes in the database are matched to 185 gene pathways in the Kyoto Encyclopedia of Genes and Genomes to allow for elucidation of gene interactions and relationships. In addition to >400 genes with infertility or subfertility phenotypes when mutated in mice or humans, the OKdb also lists ~50 and ~40 genes associated with polycystic ovarian syndrome and primary ovarian insufficiency, respectively. The expanding OKdb is updated weekly and allows submission of new genes by ovarian researchers to allow instant access to DNA microarray datasets for newly submitted genes. The present database is a virtual community for ovarian researchers and allows users to instantaneously provide their comments for individual gene pages based on an automated Web discussion system. In the coming years, we will continue to add new features to serve the ovarian research community. PMID- 22441798 TI - The effect of Trp53 gene-dosage and parent-of-origin of inheritance on mouse gamete and embryo function in vitro. AB - The transformation-related protein 53 (TRP53) has a canonical role as the "guardian of the genome," serving to protect against the propagation of cells with genomic damage. Autocrine trophic signals act to block the accumulation of TRP53 in the normal preimplantation embryo. Culture of the early embryo at limiting dilutions in simple defined media limits autocrine signaling, resulting in the accumulation of TRP53. This TRP53 reduces the rate of development of embryos. In this study we show that deletion of the Trp53 gene improved development in vitro in a dose-dependent manner. Development to morphological blastocysts increased as the dose of Trp53 was reduced, and this was accompanied by a Trp53-dependent increase in the allocation of cells to the inner cell mass. The intermediate developmental response of heterozygous mice provides evidence for haploinsufficiency of this trait. This haploinsufficiency was evident irrespective of the parent-of-origin of the null allele; however, zygotes with paternal inheritance of the Trp53-null allele had better development in vitro than those with maternal inheritance. There was a beneficial effect of the Trp53 null allele on the number of oocytes released by Trp53(+/-) females, and heterozygous males produced higher fertilization rates than controls, although this was independent of the genotype of the fertilizing sperm. The study shows that ovulation induction or culture of embryos in limiting conditions creates conditions that favor the early development of embryos inheriting loss of Trp53 function. This occurs even in the heterozygous state, showing that the conditions provide a potential basis for accelerated accumulation of deleterious mutations within a population. PMID- 22441799 TI - Hybridization of testis-derived stem cells with somatic cells and embryonic stem cells in mice. AB - Somatic cell hybridization is widely used to study the control of gene regulation and the stability of differentiated states. In contrast, the application of this method to germ cells has been limited in part because of an inability to culture germ cells. In this study, we produced germ cell hybrids using germ-line stem (GS) cells and multipotent germ-line stem (mGS) cells. While GS cells are enriched for spermatogonial stem cell (SSC) activity, mGS cells are similar to embryonic stem (ES) cells and originally derived from GS cells. Hybrids were successfully obtained between GS cells and ES cells, between GS cells and mGS cells, and between mGS cells and thymocytes. All exhibited ES cell markers and a behavior similar to ES cells, formed teratomas, and differentiated into somatic cell tissues. However, none of the hybrid cells were able to reconstitute spermatogenesis after microinjection into seminiferous tubules. Analyses of the DNA methylation patterns of imprinted genes also showed that mGS cells do not possess a DNA demethylation ability, which was found in embryonic germ cells derived from primordial germ cells. However, mGS cells reactivated the X chromosome and induced Pou5f1 expression in female thymocytes in a manner similar to ES cells. These data show that mGS cells possess ES-like reprogramming potential, which predominates over-SSC activity. PMID- 22441800 TI - IGF-2R-mediated signaling results in hypertrophy of cultured cardiomyocytes from fetal sheep. AB - Activation of the insulin-like growth factor-1 receptor (IGF-1R) is known to play a role in cardiomyocyte hypertrophy. While IGF-2R is understood to be a clearance receptor for IGF-2, there is also evidence that it may play a role in the induction of pathological cardiomyocyte hypertrophy. It is not known whether IGF 2R activates cardiomyocyte hypertrophy during growth of the fetal heart. Fetal sheep hearts (125 +/- 0.4 days gestation) were dissected, and the cardiomyocytes isolated from the left and right ventricles for culturing. Cultured cardiomyocytes were treated with either LONG R(3)IGF-1, an IGF-1R agonist; picropodophyllin, an IGF-1R autophosphorylation inhibitor; U0126, an inhibitor of extracellular signal-regulated protein kinase (ERK); Leu(27)IGF-2, an IGF-2R agonist; Go6976, a protein kinase C inhibitor; KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII); or KN-92, an L-type calcium channel inhibitor and negative control for KN-93. The cross-sectional area of cultured cardiomyocytes was determined relative to control cardiomyocytes treated with serum-free culture medium. IGF-1R and IGF-2R activation each resulted in ERK signaling, but IGF-2R activation alone induced CaMKII signaling, resulting in hypertrophy of cardiomyocytes in the late gestation sheep fetus. These data suggest that changes in the intrauterine environment that result in increased cardiac IGF-2R may also lead to cardiomyocyte hypertrophy in the fetus and potentially an increased risk of cardiovascular disease in adult life. PMID- 22441801 TI - Complement C5A regulates prolabor mediators in human placenta. AB - Human preterm and term parturition is associated with inflammatory cascades in the uteroplacental unit. Activation of the complement cascade releases potent proinflammatory mediators, including the anaphylatoxin C5a, which exerts its biological effects through its receptors, C5AR (also known as CD88) and C5L2, official symbol GPR77. To date, there are few data available on the role of C5a and CD88 in human pregnancy, so the aim of this study was to determine the effect of C5a and CD88 on some key inflammatory pathways involved in human parturition. Placental tissue samples were obtained from normal pregnancies at the time of Cesarean section. Human placental and fetal membranes were incubated in the absence (basal control) or presence of 0.5 MUg/ml (~60 nM) human recombinant C5a for 24 h. Concentrations of proinflammatory cytokines, prostaglandins, and 8 isoprostane (a marker of oxidative stress) were quantified by ELISA and secretory matrix metalloproteinases (MMPs) activity by zymography. NFKB DNA binding activity and NFKBIA (IkappaB-alpha; inhibitor of NFKB) protein degradation were analyzed by ELISA and Western blotting, respectively. In the presence of C5a, proinflammatory cytokines (IL6 and IL8), cyclooxygenase (COX)-2; official symbol PTGS2) expression, and subsequent prostaglandin (PGE(2) and PGF(2alpha)), MMP9 enzyme production, and NFKB DNA activation were all significantly increased. The C5a-induced prolabor responses were significantly reduced by treatment with the selective CD88 antagonist PMX53 and the NFKB inhibitor BAY 11-7082. We conclude that C5a upregulates prolabor mediators in human gestational tissues via CD88 mediated NFKB activation. PMID- 22441802 TI - Hyponatraemia and brain oedema in newborns following oral water intoxication during prolonged labour. PMID- 22441803 TI - Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network. AB - The German Neonatal Network (GNN) is a prospective cohort study with the focus on long term development of very-low-birth-weight infants. It was the aim of this study to determine detailed information on causes of mortality in the GNN birth cohort 2010.Major contributors to hospital mortality were recorded by the attending neonatologists for the cohort of very-low-birth-weight (VLBW) infants born in centres of the German Neonatal Network (GNN) in 2010. The data quality was approved by on-site monitoring.2 221 VLBW infants were born in GNN centres in 2010, and death occurred in 221 infants. Male infants carried a higher risk than females (58.8% males among non-survivors vs. 51.7% among survivors, p=0.047). In 11 infants, the major contributor to death was not determined by the attending neonatologist. In 25 infants born at the limit of viability, comfort palliative care was primarily initiated and 14 infants had lethal malformations. The majority of non-survivors suffered from inflammatory diseases including sepsis- or necrotizing enterocolitis (NEC)-associated death (n=56). Respiratory pathology was a major contributor to death in 65 infants including 11 infants who died from pulmonary haemorrhage.Potentially preventable complications of preterm birth such as sepsis, NEC and pulmonary haemorrhage predominate the major contributors to mortality in the GNN 2010 cohort. In order to decrease the rate of these associated deaths, future trials should focus on prophylaxis and therapy optimization strategies for these outcomes. PMID- 22441804 TI - Prioritisation in haemophilia A: a qualitative study of stakeholder attitudes and preferences. AB - To learn more about prioritisation in the health care system, we performed an exploratory qualitative study on haemophilia A. The aim was to generate haemophilia disease-specific criteria and to learn more about reasoning in the decision-making process. The 40 participants (patients, relatives, physicians, nurses) were asked in semi-structured interviews about their experiences regarding the German health care system in general and the management of haemophilia A. The 4 stakeholder groups agreed that treatment in haemophilia A was very good; there were complaints about increased bureaucracy. Arguments originated in personal past experiences (patients, relatives) and in the professional background (healthcare professionals). Decision-making criteria ranking high were the maintenance of mobility, social responsibility and the prospect of a long working life span. Criteria with lower ranking were a high social professional status and age. There was ambivalence as to whether savings in the healthcare system in general were necessary or inacceptable. Prophylactic factor administration was rejected when high-risk sports were practiced regularly. Decision-making among actual individuals was rejected as 'immoral'. Patient representatives should be included in the political decision-making process. In conclusion, solidarity in the German health insurance is a highly esteemed principle, but was not well comprehended. The findings demonstrate the variety of individual attitudes with strong context affinity to the disease and the background of the stakeholder groups. The challenge will be to find ways of prioritising in an accountable and transparent way to maintain an excellent health care service for the individual haemophilia patient while also serving the public good. PMID- 22441805 TI - Prophylactic use of clopidogrel in paediatric cardiac patients. AB - Thromboembolic complications in infants with congenital heart defects are common despite inhibition of platelet function with acetylsalicylic acid (ASS). Yet there is still insufficient pharmacologic data on the use of clopidogrel in infants. The adult dose of 75 mg/d is significantly higher than the dose lately recommended in infants (0.2 mg/kg/d). Moreover, we know of nonresponders to both acetylsalicylic acid and clopidogrel. Normal coagulation tests fail to identify those patients.Prospective monocentric study on 14 children (median age 5, range 0.7-84 months, 9 male, 5 female). Shunt thrombosis had occurred in 4 infants on ASS therapy. Seven days after starting clopidogrel (0.2 mg/kg/d), platelet function was tested by stimulation with ADP (4 and 10 umol/l). We considered the range for the clopidogrel effect to be optimal if the maximum aggregation on ADP 4 umol/l was between 30-50%.Clopidogrel 0.18-0.24 mg/kg/d in addition to ASS 2-4 mg/kg/d resulted in effective inhibition of platelet function in 93% (ADP 4 umol/l: median 38%, range 30-63). All patients were responders. We observed neither any thromboembolic events nor severe bleeding episodes during the median 11-month follow-up period (range 1-30 mo).Testing platelet function makes clopidogrel dosing safer, and simplifies therapy adjustments in long-term treatment. A clopidogrel dose of 0.2 mg/kg/d was safe and effective in combination with ASS in this small patient cohort. PMID- 22441806 TI - Electronic conductivity of alkyne-capped ruthenium nanoparticles. AB - Ruthenium nanoparticles (2.12 +/- 0.72 nm in diameter) were stabilized by the self-assembly of alkyne molecules (from 1-hexyne to 1-hexadecyne) onto the Ru surface by virtue of the formation of Ru-vinylidene interfacial linkages. Infrared measurements depicted three vibrational bands at 2050 cm(-1), 1980 cm( 1) and 1950 cm(-1), which were ascribed to the vibrational stretches of the terminal triple bonds that were bound onto the nanoparticle surface. Thermogravimetric analysis showed that there were about 65 to 96 alkyne ligands per nanoparticle (depending on the ligand chainlength), corresponding to a molecular footprint of 20 to 15 A(2). This suggests that the ligands likely adopted a head-on configuration on the nanoparticle surface, consistent with a vinylidene bonding linkage due to interfacial tautomeric rearrangements. With this conjugated interfacial bonding interaction, electronic conductivity measurements of the corresponding nanoparticle solid films showed that the nanoparticles all exhibited linear current-potential curves within the potential range of -0.8 V to +0.8 V at varied temperatures (200 to 300 K). The ohmic characters were partly ascribed to the spilling of core electrons into the organic capping layer that facilitated interparticle charge transfer. Furthermore, based on the temperature dependence of the nanoparticle electronic conductivity, the activation energy for interparticle charge transfer was estimated to be in the range of 70 to 90 meV and significantly, the coupling coefficient (beta) was found to be 0.31 A(-1) for nanoparticles stabilized by short-chain alkynes (1-hexyne, 1-octyne, and 1-decyne), and 1.44 A(-1) for those with long alkynes such as 1-dodecyne, 1-tetradecyne, and 1-hexadecyne. This may be accounted for by the relative contributions of the conjugated metal-ligand interfacial bonding interactions versus the saturated aliphatic backbones of the alkyne ligands to the control of interparticle charge transfer. PMID- 22441807 TI - Single-port transumbilical laparoscopic excision of retroperitoneal schwannoma mimicking a nonfunctional endocrine tumor in the body of the pancreas: a case report. AB - Schwannomas are benign tumors that arise from neural sheath Schwann cells. Solitary benign schwannoma is generally located in the head and neck and is a rare neoplasm among the tumors of the retroperitoneal space. Reports of laparoscopic excision of retroperitoneal schwannomas have recently been on the increase. However, few cases of single-port laparoscopic excision of these tumors have been reported. Moreover, there are no reports of single-port excision of schwannomas attached to the body of pancreas and around the splenic vessels. This is the first report of a schwannoma lying adjacent to the body of the pancreas between the splenic artery and vein that was excised by single-port laparoscopic surgery. The most notable aspect of our procedure is the use of bipolar forceps. Single-port laparoscopic excision using bipolar forceps is a feasible and safe procedure for retroperitoneal solitary tumors, even when they are close to the splenic artery and vein. PMID- 22441808 TI - Designing an integrated environmental monitoring plan for land-based marine fish farms located at exposed and hard bottom coastal areas. AB - The increase in aquaculture activities in the last few decades has not been accompanied by a corresponding increase in environmental controls and regulations. In this context, the application of environmental monitoring plans (EMPs) has become necessary to assess the environmental impact associated with fish farming wastes. The objective of this review paper is to evaluate the suitability of experimental and analytical procedures as monitoring tools for inclusion in EMPs for intensive land-based marine fish farms (LBMFFs). The strong hydrodynamics and, in particular, the lack of sediment on the rocky coasts where LBMFFs are usually located, greatly limit the monitoring tools that can be used. We propose EMPs that employ a weight-of-evidence approach to evaluate: contamination, trophic and toxic effects, and ecological integrity. Laboratory tests, in situ bioassays and field surveys of local species are presented as key tools for assessing the impact of LBMFFs on ecosystems. The delta(15)N signal along a spatial gradient is proposed for evaluating exposure to contaminants. Trophic effects can be determined by growth of transplanted macro- and microalgae. Toxic effects can be evaluated by responses at different levels of biological organization, including biochemical and histological changes, physiological alterations and survival, in species from different trophic levels. Fouling tests and analysis of community structures are recommended for assessing ecological integrity. This review contributes to the development of environmental controls for intensive LBMFFs, and for other activities that discharge wastewater to rocky shores. PMID- 22441809 TI - Direct-to-consumer genetic testing: introduction to the special issue. AB - This issue of the Journal of Genetic Counseling is devoted to direct-to-consumer (DTC) genetic testing. The 15 articles in this special issue address practice considerations for genetic counselors and other health care professionals; the benefits and limitations of DTC genetic testing; consumer and provider attitudes towards and experience with DTC testing; and the roles and educational needs of genetic counselors and other health care providers in providing and interpreting DTC genetic testing. In this introduction to the special issue, we provide a brief background on DTC genetic testing, summarize the important contribution of the articles included in this issue, and outline the essential work that still needs to be done as genetic counselors are increasingly engaged in discussions, education, and research about DTC genetic testing. PMID- 22441810 TI - Visual and anatomical outcomes of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroids. AB - BACKGROUND: To evaluate the visual and anatomic outcomes after systemic steroid treatment in non-arteritic anterior ischemic optic neuropathy (NAION). METHODS: Ten eyes from ten patients diagnosed with NAION and treated during the acute phase with 80 mg daily, tapering-down dose of corticosteroids were compared with a non-contemporary cohort of 27 patients that received no treatment. The visual outcomes of treated and untreated group were compared. Patients underwent complete ophthalmic examination including determination of Snellen visual acuity (VA), visual fields (VFs) (standard automated perimetry, Swedish Interactive Testing Algorithm 24-2 strategy), and optical coherence tomography (OCT) scanning of the optic nerve head at diagnosis, 6-8 weeks and 6 months after presentation. RESULTS: No statistical differences were found between steroid-treated and untreated NAION for the median change in VA (Mann-Whitney P = 0.28), median change in VF mean deviation (MD) and median change in VF pattern standard deviation (PSD) (Mann-Whitney P = 0.213 and P = 0.07 respectively). Statistical analysis showed no differences when comparing average RNFL loss (P = 0.871) and RNFL loss for superior, nasal, inferior and temporal optic disc quadrants between both groups. Complications occurred in three of the ten treated patients (30%); in one of them, steroid therapy had to be discontinued. Another two patients developed a NAION in their fellow eye after 2 and 3 months while on low-dose prednisone. No complications developed in the control group. The study was interrupted early due to a significantly higher rate of complications observed in the treated group (P = 0.002) CONCLUSION: High-dose systemic steroid treatment did not show any beneficial effect in visual and anatomic outcomes when given during the acute phase of NAION. Furthermore, it caused serious complications in a third of the patients treated. PMID- 22441811 TI - Effect of preoperative retinal sensitivity and fixation on long-term prognosis for idiopathic macular holes. AB - BACKGROUND: To study the roles of preoperative retinal sensitivity and fixation exams in predicting the long-term prognosis of idiopathic macular hole (IMH) patients after successful vitrectomy. METHODS: A total of 39 IMH patients (39 eyes) were included in this prospective cohort case series study. Twenty-three gauge pars plana vitrectomy was performed on each patient. Results of best corrected visual acuity (BCVA), macular hole diameter, MP - 1 microperimetry (MP 1) tests, and continuity of the photoreceptor inner and outer segment (IS/OS) junction were recorded for analysis. RESULTS: Postoperative BCVA at 12 months was significantly correlated with macular hole diameters (p < 0.05), preoperative BCVA (p = 0.020), mean retinal sensitivity (p < 0.001), and fixation location percentage (p < 0.001). However, merely preoperative mean retinal sensitivity (r = 0.5448, p < 0.001) and fixation location percentage (r = 0.5624, p < 0.001) were suggested to be quantitatively predictive for the visual prognosis by multiple stepwise linear regression analysis. Moreover, patients that had smaller hole sizes (p < 0.01), better mean retinal sensitivity (p = 0.003), higher fixation quality scores, and higher fixation location percentage (p = 0.008) before surgery were prone to get continuous IS/OS junction 12 months after surgery. CONCLUSIONS: MP-1 exams evaluate the dysfunctional hole margin and thus provide more comprehensive information of the preoperative visual function of IMH patients. Both mean retinal sensitivity and fixation behaviors are ideal measurements in predicting the prognosis after successful macular hole surgery. PMID- 22441812 TI - Merging chemical synthesis and biosynthesis: a new chapter in the total synthesis of natural products and natural product libraries. PMID- 22441813 TI - A keyhole-shaped sternal defect in an ancient human skeleton. AB - We observed a sternal foramen contiguous with a small sternal cleft in a human skeleton coming from North-Eastern Italy and dating back to between the sixteenth and seventeenth century AD. Both of these types of anomalies result from a defective midline fusion of the developing sternum. Sternal foramen is a relatively common bony defect that usually comes to light as an incidental finding. Sternal cleft is a rarer morphological anomaly that can have a wide spectrum of clinical manifestations and outcomes, depending on the extent of the bony defect as well as on the presence and severity of other abnormalities. The coexistence of a sternal foramen and a sternal cleft has very rarely been described in the literature. We report here one such unusual association and discuss its potential practical implications. In most cases, sternal foramina and small sternal clefts are clinically uneventful; yet, lack of awareness about the existence of these subtle anatomical variations can sometimes lead to misinterpretation of radiological and pathological findings or make sternal biopsy and acupuncture unsafe. PMID- 22441814 TI - Controlling size, amount, and crystalline structure of nanoparticles deposited on graphenes for highly efficient energy conversion and storage. AB - A facilitated electrochemical reaction at the surface of electrodes is crucial for highly efficient energy conversion and storage. Herein, various nanoparticles (NPs) including Au, Pt, Pd, Ru, and RuO(2), were synthesized in situ and directly deposited on the ionic liquid (IL)-functionalized reduced graphene oxides (RGOs) in a controlled manner. The size, amount, and crystalline structures of discrete NPs were readily controlled, giving rise to enhanced methanol oxidation and pseudocapacitance. The well-defined nanostructure of decorated NPs and the favorable interaction between ILs and RGOs (or NPs) facilitated the electrochemical reaction, where NPs acted as electrocatalysts for energy conversion and played the role of redox-active electrodes for energy storage. PMID- 22441815 TI - Remission of insulin resistance in type 2 diabetic patients after gastric bypass surgery or exenatide therapy. AB - BACKGROUND: Gastric bypass surgery and exenatide therapy represent two relatively new methods in treating morbid obesity and type 2 diabetes, although there are many differences between them. With the data supported from our hospital, we just want to investigate the differences between bypass surgery and exenatide injection and want to answer the question: Which one is the best? And Why? METHODS: Data from January 2009 to January 2010 were summarized for comparison at Shengjing hospital, including weight loss, plasma glucose and insulin changes, glycosylated hemoglobin, and the subjective scores of patients themselves. Plasma lipoprotein and serum ions were measured to evaluate the nutrition status. RESULTS: Patients in the GB group received more weight loss and better glucose control compared with the EX group. At 6 months, feeding insulin level in the GB group was 18.1 +/- 3.2 mU/L, which was much lower than that in the EX group (64.5 +/- 13.2 mU/L, P < 0.01). The Hb1AC level in the GR group was 6.08 +/- 0.56 %, much lower than that in the EX group (7.19 +/- 0.72 %, P < 0.01). We did not find any statistical differences in lipoprotein, plasma ions, and subjective scores between the GB and EX groups. CONCLUSIONS: Gastric bypass surgery is better in weight control and in the remission of insulin resistance compared with exenatide therapy. Both methods were safe and have no nutritional disorder in early stage, although the transferring in the GB group was higher than the EX group. The subjective scores from both groups declared that both methods could be accepted by patients. PMID- 22441816 TI - Growth hormone-releasing hormone receptor splice variant 1 is frequently expressed in oral squamous cell carcinomas. AB - The expression of growth hormone-releasing hormone (GHRH) splice variant 1 (SV1) receptor in neoplastic lesions of the oral cavity was assessed. The sensitivity of HaCaT keratinocytes to GHRH analogs was also evaluated. Thirty-three benign precancerous oral lesions and 27 squamous cell carcinomas of the oral cavity were evaluated by immunohistochemistry for SV1 expression. SV1 expression in HaCaT keratinocytes was assessed by western blot. HaCaT proliferation was evaluated by cell counting. Anti-SV1 immunoreactivity was detected in only 9% (three of 33) precancerous lesions (one hyperplasia and two dysplasias), while 44% (12 of 27) carcinomas were positive for SV1 (p<0.002). GHRH(1-29)NH(2) and GHRH agonist JI 38 stimulated HaCaT proliferation in vitro, and this effect was blocked by GHRH antagonists. These results indicate that SV1 expression may be associated with the transition of precancerous lesions to carcinomas of the oral epithelium. GHRH antagonists may be useful for the management of the disease. PMID- 22441817 TI - Angiogenesis inhibitors increase tumor stem cells. AB - The clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway has recently been met with numerous phase III failures that showed modest survival benefits. Understanding the resistance mechanisms of antiangiogenic therapy is essential to overcoming the limited effectiveness of VEGF-pathway inhibitors. A recent study published in the Proceedings of the National Academy of Sciences provides a novel explanation to the treatment limitations of angiogenesis inhibitors and suggests a potential strategy to improve the clinical utility of these agents. PMID- 22441818 TI - Nuclear expression of Twist promotes lymphatic metastasis in esophageal squamous cell carcinoma. AB - Twist-1 protein (also called Twist) has been suggested to be involved in tumor epithelial-mesenchymal transition (EMT) related progression, however, the mechanism by which twist promotes lymph node metastasis is not fully understood. In the present study, we found that nuclear twist expression is clearly correlated with lymph node (LN) metastasis as determined by immunohistochemistry (IHC). A highly invasive EC109 cell subline, EC109-P, was established by repeated in vitro transwell isolations for the cell model. Immunofluorescence (IF) assay demonstrated that nuclear twist expression was markedly higher in the highly invasive EC109-P cell line when compared with EC109 and EC9706 cells. Based on our cell model, the function and mechanism by which twist regulates LN metastasis in ESCC was investigated. The results showed that the overexpression of Twist could significantly increase the invasion and VEGF-C expression of EC9706 cells, whereas the knockdown of twist expression results in the opposite effects. This finding was further strengthened by the results of the analysis of co-expression of twist and VEGF-C by IHC in ESCC clinical samples. In summary, our study indicates that nuclear twist plays an important role in ESCC lymphatic metastasis by increasing the expression of VEGF-C. The combination of twist and VEGF-C detection could be a reliable prediction of LN metastasis in ESCC. PMID- 22441819 TI - Combination of HDAC and topoisomerase inhibitors in small cell lung cancer. AB - Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). SCLC cell lines were exposed to increasing concentrations of single-agent HDAC inhibitors and topoisomerase inhibitors, in various combinations, to assess for cell viability, additivity or synergy, and apoptosis. We found that MGCD0103 and vorinostat decreased cell viability by at least 60% and 80%, respectively. In the majority of cell lines, the strongest synergism was seen when vorinostat was followed by either etoposide or topotecan; concurrent therapy led to antagonism in most cell lines. Synergistic effects were seen when MGCD0103 was given concurrently or sequentially with both amrubicin and epirubicin. Enhanced additive effects leading to caspase activation were noted for the combination of MGCD0103 or vorinostat with a topoisomerase inhibitor vs. either agent alone. Thus, the combination of HDAC inhibitors and topoisomerase inhibitors showed enhanced cytotoxic effects in SCLC cell lines. Further evaluation in a clinical setting may be warranted. PMID- 22441820 TI - A high-flux isopore micro-fabricated membrane for effective concentration and recovering of waterborne pathogens. AB - A high-flux metallic micro/nano-filtration membrane has been fabricated and validated for isolation of waterborne pathogens from drinking water. Obtained membrane with smooth surface and perfectly ordered pores was achieved by a high yield and cost effective multilevel lithography and electroplating technique. The micro-fabricated membrane was also strengthened with an integrated back-support, which can withstand a high pressure during filtration. The results of microfiltration tests with model particles revealed the superior performance of the micro-fabricated filter than current commercial filters in sample throughput, recovery ratio, and reusability. This study highlighted the potential application of micro-fabricated filer in rapid filtration and recovery of C. parvum oocysts for downstream analysis. PMID- 22441821 TI - Conformational studies of common protein templates in macromolecularly imprinted polymers. AB - Unlike the molecular imprinting of small molecule templates, molecularly imprinted polymers specific to large templates (>1,500 Da), have achieved limited success to date. Conformational stability of these labile macromolecules is one of the main factors that prevent the direct extension of successful procedures from the small molecule regime. We continue our systematic investigation of the effect of common components in macromolecular MIPs on the conformation of protein templates. Circular dichroism was used to show that frequently employed monomers and crosslinkers induce significant changes in the secondary structures of lysozyme and bovine hemoglobin. The extent to which this change occurs, at ligand concentrations far below what are typically used reported work, is cause for concern and provides as rational explanation for the lack of success in this arena. This is because a change in the template structure prior to polymerization would lead to the binding sites formed during polymerization to be specific to this alternate conformation. Subsequent studies with the macromolecule in its native state and the crosslinked network would not be successful. Using this information as a guide, we offer suggestions as to where work in macromolecular imprinted polymers should focus going forward in order for these antibody mimics to reach their vast potential as a new class of biomedical diagnostic devices. PMID- 22441822 TI - Selective coordination bonding in metallo-supramolecular systems on surfaces. PMID- 22441823 TI - PKC-dependent phosphorylation of p27 at T198 contributes to p27 stabilization and cell cycle arrest. AB - In this manuscript, we present experimental evidence that PKCs phosphorylate p27 at T198 in vitro and in vivo, resulting in p27 stabilization and cell cycle arrest in MCF-7 and HeLa cells. Our findings indicate that (1) recombinant PKCalpha, betaII, delta, eta and theta isoforms phosphorylate, in in vitro kinase assays, wild-type recombinant p27 protein expressed in E. coli and wild-type p27 protein immunoprecpitated from transfected HEK-293 cells but not the T198A mutant, (2) adoptive expressed PKCalpha and delta phosphorylate both transfected and endogenous p27 at T198 in HEK-293 cells, (3) T198 phosphorylation of transfected and endogenous p27 is increased by PKC activators [Phorbol 12 myristate 13-acetate (PMA)] and suppressed by PKC inhibitors (Rottlerin A, G06976, Calphostin C), (4) in parallel with increased T198 phosphorylation, PMA induces stabilization of p27 protein in HeLa cells, whereas PKC inhibitors induce a decrease in p27 stability and, finally, (5) PMA-induced p27 upregulation is necessary for growth arrest of HeLa and MCF-7 cells induced by PKC activation by PMA. Overall, these results suggest that PKC-dependent upregulation of p27 induced by its phosphorylation at T198 represents a mechanism that mediates growth arrest promoted by PMA and provide novel insights on the ability of different PKC isoforms to play a role in controlling cell cycle progression. PMID- 22441824 TI - An approach for building a personal health information system using conceptual domain knowledge. AB - In this paper we present the development of a Personal Health Information System (PHIS) by capturing the domain knowledge in the form of concept maps. The software architecture based on capturing the conceptual domain knowledge is demonstrated using a working prototype for patients suffering from diabetes mellitus. Cited current literature predicts that this user based information system has the potential to improve patient care, reduce medical errors, and lower health care costs. PMID- 22441825 TI - Bundling dynamics regulates the active mechanics and transport in carbon nanotube networks and their nanocomposites. AB - High-density carbon nanotube networks (CNNs) continue to attract interest as active elements in nanoelectronic devices, nanoelectromechanical systems (NEMS) and multifunctional nanocomposites. The interplay between the network nanostructure and its properties is crucial, yet current understanding remains limited to the passive response. Here, we employ a novel superstructure consisting of millimeter-long vertically aligned single walled carbon nanotubes (SWCNTs) sandwiched between polydimethylsiloxane (PDMS) layers to quantify the effect of two classes of mechanical stimuli, film densification and stretching, on the electronic and thermal transport across the network. The network deforms easily with an increase in the electrical and thermal conductivities, suggestive of a floppy yet highly reconfigurable network. Insight from atomistically informed coarse-grained simulations uncover an interplay between the extent of lateral assembly of the bundles, modulated by surface zipping/unzipping, and the elastic energy associated with the bent conformations of the nanotubes/bundles. During densification, the network becomes highly interconnected yet we observe a modest increase in bundling primarily due to the reduced spacing between the SWCNTs. The stretching, on the other hand, is characterized by an initial debundling regime as the strain accommodation occurs via unzipping of the branched interconnects, followed by rapid rebundling as the strain transfers to the increasingly aligned bundles. In both cases, the increase in the electrical and thermal conductivity is primarily due to the increase in bundle size; the changes in network connectivity have a minor effect on the transport. Our results have broad implications for filamentous networks of inorganic nanoassemblies composed of interacting tubes, wires and ribbons/belts. PMID- 22441826 TI - Electrochemical synthesis of adiponitrile from the renewable raw material glutamic acid. AB - Current affairs: Adiponitrile, used to produce nylon 6.6, is prepared from the renewable compound glutamic acid by an electrochemical route, involving electro oxidative decarboxylation and Kolbe coupling reactions. The new route is an example of the use of glutamic acid as a versatile substrate in the transformation of biomass into chemicals. Also, it highlights the use of electrochemical methods in biomass conversion. PMID- 22441827 TI - A novel TBP-TAF complex on RNA polymerase II-transcribed snRNA genes. AB - Initiation of transcription of most human genes transcribed by RNA polymerase II (RNAP II) requires the formation of a preinitiation complex comprising TFIIA, B, D, E, F, H and RNAP II. The general transcription factor TFIID is composed of the TATA-binding protein and up to 13 TBP-associated factors. During transcription of snRNA genes, RNAP II does not appear to make the transition to long-range productive elongation, as happens during transcription of protein-coding genes. In addition, recognition of the snRNA gene-type specific 3' box RNA processing element requires initiation from an snRNA gene promoter. These characteristics may, at least in part, be driven by factors recruited to the promoter. For example, differences in the complement of TAFs might result in differential recruitment of elongation and RNA processing factors. As precedent, it already has been shown that the promoters of some protein-coding genes do not recruit all the TAFs found in TFIID. Although TAF5 has been shown to be associated with RNAP II-transcribed snRNA genes, the full complement of TAFs associated with these genes has remained unclear. Here we show, using a ChIP and siRNA-mediated approach, that the TBP/TAF complex on snRNA genes differs from that found on protein-coding genes. Interestingly, the largest TAF, TAF1, and the core TAFs, TAF10 and TAF4, are not detected on snRNA genes. We propose that this snRNA gene specific TAF subset plays a key role in gene type-specific control of expression. PMID- 22441828 TI - Carbon dioxide laser and bonding materials reduce enamel demineralization around orthodontic brackets. AB - Altering the structure of the enamel surface around the orthodontic bracket by reducing its content of carbonate and phosphate resulting from application of CO(2) laser may represent a more effective strategy in preventing caries in this region. This study aimed at determining whether irradiation with a CO(2) laser combined with fluoride-releasing bonding material could reduce enamel demineralization around orthodontic brackets subjected to cariogenic challenge. Ninety bovine enamel slabs were divided into five groups (n = 18): non-inoculated brain-heart infusion broth group, non-fluoride-releasing composite resin (NFRCR- control group), resin-modified glass ionomer cement (RMGIC), CO(2) laser + Transbond (L+NFRCR) and CO(2) laser + Fuji (L+RMGIC). Slabs were submitted to a 5 day microbiological caries model. The Streptococcus mutans biofilm formed on the slabs was biochemically and microbiologically analysed, and the enamel Knoop hardness number (KHN) around the brackets was determined. The data were analysed by ANOVA and Tukey tests (alpha = 0.05). Biochemical and microbiological analyses of the biofilm revealed no statistically significant differences among the groups. Lased groups presented the highest KHN means, which statistically differed from NFRCR; however, no difference was found between these lased groups. RMGIC did not differ from NFRCR which presented the lowest KHN mean. The CO(2) laser (lambda = 10.6 MUm; 10.0 J/cm(2) per pulse) use with or without F-bonding materials was effective in inhibiting demineralization around orthodontic brackets. However, no additional effect was found when the enamel was treated with the combination of CO(2) laser and an F-releasing material. PMID- 22441829 TI - Dynamic response characteristics of hyperaemia in the human calf muscle: effect of exercise intensity and relation to electromyographic activity. AB - To clarify the structure of the muscle hyperaemic response during submaximal exercise in the supine position, we tested the hypotheses that this response measured in human calf muscle is biphasic or triphasic (growth-only) at low moderate or high forces, respectively. Ten subjects performed four series of 5 min bout of intermittent contractions from a resting baseline to 30, 60 and 90% of peak force, as well as from an exercise baseline to higher forces. For each exercise transition, leg blood flow (LBF: plethysmography) and leg vascular conductance (LVC) were measured between contractions and averaged across four trials. Six 'growth-only' and 'growth and decay' models were fitted to these averaged responses and significant differences between their goodness-of-fit were tested statistically. For rest-exercise transitions, triphasic or quadphasic 'growth and decay' models provided the best fit to the majority of LBF and LVC responses. The intensity-dependent growth in hyperaemia was due mainly to a significant increase in amplitude of the rapid growth phase. A fast decay in LBF and LVC occurred at all intensities (mean tau = 4-5 s, mean TD = 9-14 s). A slower decay appeared at the lowest intensity (mean tau = 18-28 s, TD ? 90 s) that coincided with a monoexponential decline in EMG activity (mean tau = 23, TD = 87 s). Thus, although biphasic growth is an essential feature of muscle hyperaemia, rapid and slow decay phases also exist that highlight additional mechanisms which contribute to this dynamic response during exercise. PMID- 22441830 TI - Energetics of basic karate kata. AB - Knowledge about energy requirements during exercises seems necessary to develop training concepts in combat sport Karate. It is a commonly held view that the anaerobic lactic energy metabolism plays a key role, but this assumption could not be confirmed so far. The metabolic cost and fractional energy supply of basic Karate Kata (Heian Nidan, Shotokan style) with duration of about 30 s were analyzed. Six male Karateka [mean +/- SD (age 29 +/- 8 years; height 177 +/- 5 cm, body mass 75 +/- 9 kg)] with different training experience (advanced athletes, experts, elite athletes) were examined while performing one time and two time continuously the sport-specific movements. During Kata performance oxygen uptake was measured with a portable spirometric device, blood lactate concentrations were examined before and after testing and fractional energy supply was calculated. The results have shown that on average 52 % of the energy supply for one Heian Nidan came from anaerobic alactic metabolism, 25 % from anaerobic lactic and 23 % from aerobic metabolism. For two sequentially executed Heian Nidan and thus nearly doubling the duration, the calculated percentages were 33, 25 and 42 %. Total energy demand for one Kata and two Kata was approximately 61 and 99 kJ, respectively. Despite measured blood lactate concentrations up to 8.1 mmol l(-1), which might suggest a dominance of lactic energy supply, a lactic fraction of only 17-31 % during these relatively short and intense sequences could be found. A heavy use of lactic energy metabolism had to be rejected. PMID- 22441832 TI - Current limitations and future perspectives of the Athlete Blood Passport. PMID- 22441833 TI - Metabolic profiling assisted quality assessment of Rhodiola rosea extracts by high-performance liquid chromatography. AB - In this work, fast and sensitive high-performance liquid chromatography (HPLC) coupled with multivariate analysis was utilized to assist the quality assessment of Rhodiola rosea extracts (RREs). 131 peaks were separated and detected in RREs on a fused-core C18 column. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) of the chromatographic data demonstrated that 10 batches of RREs could be well-differentiated and categorized into three groups which were closely related to the origins of RREs. Partial least square-discriminant analysis (PLS-DA) showed that the quality differentiation might be explained by at least 6 components, in which rosavin was characterized by an external reference, rosiridine was identified by liquid chromatography-mass spectrometry (LC-MS), and the mass spectra of the others were provided. The observation that the level of rosavin was more relevant to the multivariate chromatographic data than the ones of salidroside and tyrosol, the other two components commonly used to standardize RREs, was confirmed by the PLS prediction models. Results of the present study not only indicated that rosavin was a rational marker to represent the quality of RREs, but also demonstrated the power of HPLC-based metabolic profiling in the quality assessment of herbal extracts. PMID- 22441834 TI - Neolignans and sesquiterpenes from cell cultures of Stellera chamaejasme. AB - Two new neolignans (1, 2) and six sesquiterpenes (3- 8) were isolated from the cell cultures of Stellera chamaejasme. Their structures and absolute configurations were elucidated by extensive spectroscopic and computational methods. Compound 4 exhibited significant protective effects against CCl (4) induced hepatotoxicity in HepG2 cells, reducing aspartate aminotransferase release by 29.49 % at 10 uM. These compounds have not been isolated from plant material, which implies that in vitro plant cell cultures may offer alternative and effective sources of bioactive natural compounds. PMID- 22441835 TI - Seven new secoiridoids with anti-hepatitis B virus activity from Swertia angustifolia. AB - Seven new secoiridoids, swertianglide (1) and swertianosides A-F (2-7), together with fifteen known compounds, were isolated from the whole plants of Swertia angustifolia. Their structures were elucidated on the basis of extensive spectroscopic analyses ([alpha](D), UV, IR, MS, 1D- and 2D-NMR). Fourteen compounds were evaluated for their anti-hepatitis B virus (HBV) activities on the Hep G 2.2.15 cell line in vitro. Compound 2, an unusual secoiridoid glycoside dimer, showed significant activities inhibiting the secretion of HBsAg (IC50 0.18 mM, SI 3.11) and HBeAg (IC50 0.12 mM, SI 4.67). PMID- 22441836 TI - In vitro and in vivo antimalarial activity of essential oils and chemical components from three medicinal plants found in northeastern Brazil. AB - The prophylactic and therapeutic arsenal against malaria is quite restricted and all the antimalarials currently in use have limitations. Thus, there is a need to investigate medicinal plants in the search for phytochemicals which can be developed into drugs. In our investigation, essential oils (EOs) were obtained from Vanillosmopsis arborea (Gardner) Baker, Lippia sidoides Cham. and Croton zehntneri Pax & K. Hoffm., aromatic plants abundant in northeastern Brazil, which are found in the caatinga region and are used in traditional medicine. The chemical composition of these EOs was characterized by GC-MS, and monoterpenes and sesquiterpenes were well represented. We assessed the in vitro activity of these EOs and also individual EO chemical components against the human malaria parasite Plasmodium falciparum (K1 strain) and the in vivo activity of EOs in mice infected with Plasmodium berghei. The acute toxicity of these oils was assessed in healthy mice and in vitro cytotoxicity was determined at different concentrations against HeLa cells and mice macrophages. The EO of V. Arborea was partially active only when using the subcutaneous route (inhibited from 33 up to 47 %). In relation to the EOs, L. sidoides and C. zehntneri were active only by the oral route (per gavage) and partially inhibited the growth of P. berghei from 43 up to 55 % and showed good activity against P. falciparum in vitro (IC (50) = 7.00, 10.50, and 15.20 ug/mL, respectively). Individual EO constituents alpha bisabolol, estragole, and thymol also exhibited good activity against P. falciparum (IC (50) = 5.00, 30.70, and 4.50 ug/mL, respectively). This is the first study showing evidence for the antimalarial activity of these species from northeastern Brazil and the low toxicity of their EOs. PMID- 22441837 TI - Consecutive signal amplification for DNA detection based on de novo fluorophore synthesis and host-guest chemistry. PMID- 22441838 TI - Alcohol withdrawal-induced Takotsubo. PMID- 22441839 TI - Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy. AB - Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells (iPSC) represent new promises for liver disease study and drug discovery. Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many functional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and facilitate drug development process. In this review, we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes. PMID- 22441840 TI - Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: a case series. AB - OBJECTIVE: To assess clinical features and general health status of adult patients with mucopolysaccharidosis (MPS) VI. METHODS: This report includes the clinical history of patients older than 18 years with slowly progressing MPS VI and the retrospective analysis of the outcomes of available data collected between September 2003 and October 2008 at the Center of Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University of Mainz, Germany. Variables included were urinary glycosaminoglycan (uGAG) level, mutation analysis, body height, forced vital capacity (FVC), 6-minute walk test, echocardiographic findings, the need for craniocervical decompression surgery, orthopaedic findings and ophthalmological assessments. RESULTS: The analysis included nine patients with MPS VI aged 19-29 years. The median age at diagnosis was 12 (range 6-20) years. At the time of the assessment (median age 25 years), median uGAG was 29 (range 15-149) MUg/mg creatinine and median height 152 (range 136-161) cm. All patients had a FVC below standard values, seven showed reduced endurance in the 6-minute-walk test, all had valve changes with valve replacement in three, two underwent craniocervical decompression surgery, two underwent carpal tunnel surgery, five had ear/nose/throat (ENT) interventions, seven had hip pain/dysplasia, seven had corneal clouding and two were visually impaired. CONCLUSIONS: Although patients with slowly progressing MPS VI are a heterogeneous group showing disease manifestations in several organs, they seem to have some typical characteristics in common. Despite the attenuated clinical course, many of these patients show severe morbidity. Therefore, early diagnosis and proper follow-up and treatment are essential. PMID- 22441841 TI - Long-term bone mineral density response to enzyme replacement therapy in a retrospective pediatric cohort of Gaucher patients. AB - Osteopenia is described as a relevant sign of bone involvement in Gaucher disease (GD) both in pediatric and adult patients. Furthermore, abnormal bone metabolism is considered to play a role in growth and pubertal delay. To analyze the long term effect of enzyme replacement therapy (ERT) on bone mineral density (BMD), a retrospective observational study was conducted in a cohort of 18 GD pediatric patients (13 males, 5 females; median age 9.2 years). They received biweekly infusions of 20-60 IU/kg of alglucerase/imiglucerase. Clinical, laboratory and imaging parameters were evaluated every 2 years. According to the International Society of Clinical Densitometry guidelines, a Z-score <= -2.0 was considered pathological. Nine patients (group P0) began ERT during infancy and nine (group P1) during puberty. At baseline, in three patients (16.6 %; 1P0, 2P1) Z-score was <= -2.0 (range -2.47 to -2.25). In patient P0 it normalized after 2 years, while in the 2P1 patients (splenectomized siblings) it persisted abnormal. The remaining 15 patients (83.4 %) always presented a normal value. In group P0, Z score improved in infancy but showed a significant decrease during puberty, on the contrary it constantly improved in group P1. Furthermore, at baseline group P0 showed a higher median Z-score than group P1: 0.79 (0.38; 1.50) and -1.61 ( 2.25; -1.56) respectively. The use of correct BMD standards to interpret bone loss during pediatric age suggests a limited significance of bone loss in these patients. Moreover, the persistence of residual disease activity may affect normal bone growth during puberty in GD populations. PMID- 22441842 TI - MicroRNAs miR-96, miR-124, and miR-199a regulate gene expression in human bone marrow-derived mesenchymal stem cells. AB - MicroRNAs are small non-coding RNAs that control gene expression at the post transcriptional level by binding to 3'-untranslated regions (3'-UTR) of their target mRNAs. They present a promising tool to delineate the molecular mechanisms regulating differentiation of human mesenchymal stromal cells (hMSCs) and to improve the controlled differentiation of hMSCs in therapeutic applications. Here we show that three microRNAs, miR-96, miR-124, and miR-199a, were differentially expressed during osteogenic, adipogenic, and chondrogenic induction of human bone marrow-derived MSCs. miR-96 expression was increased during osteogenesis and adipogenesis, but not during chondrogenesis. miR-124 was exclusively expressed in adipocytes, whereas miR-199a was upregulated in osteoblasts and chondrocytes. Furthermore, functional studies with synthetic miRNA precursors and inhibitors demonstrated that miR-96, miR-124, and miR-199a regulated the expression of genes important for hMSC differentiation, such as aggrecan, transcription factor SOX9, and fatty acid binding protein 4 (FABP4). Modulation of miR-96, miR-124, and miR 199a expression may thus be useful in specific targeting of hMSC differentiation, for e.g., MSC-based therapies. J PMID- 22441843 TI - Performance of the Duke Religion Index and the spiritual well-being scale in online samples of men who have sex with men. AB - Religiosity is associated with behaviors that reduce the risk of HIV/STI infection among general-population and heterosexual-specific samples. Whether this association is similar to homosexual persons is unknown. Measures of religiosity have not been evaluated psychometrically among men who have sex with men (MSM), a population who, because of stigma, experience religiosity differently than heterosexual persons. We assessed the duke religion index and the spiritual well-being in two samples of MSM. Neither instrument produced adequate model fit. To study the association between religiosity and HIV/STI risk behaviors among MSM, scales are needed that measure the religious and spiritual experiences of MSM. PMID- 22441844 TI - Asymmetric chromatid segregation in cardiac progenitor cells is enhanced by Pim-1 kinase. AB - RATIONALE: Cardiac progenitor cells (CPCs) in the adult heart are used for cell based treatment of myocardial damage, but factors determining stemness, self renewal, and lineage commitment are poorly understood. Immortal DNA strands inherited through asymmetric chromatid segregation correlate with self-renewal of adult stem cells, but the capacity of CPCs for asymmetric segregation to retain immortal strands is unknown. Cardioprotective kinase Pim-1 increases asymmetric cell division in vivo, but the ability of Pim-1 to enhance asymmetric chromatid segregation is unknown. OBJECTIVE: We aimed to demonstrate immortal strand segregation in CPCs and the enhancement of asymmetric chromatid distribution by Pim-1 kinase. METHODS AND RESULTS: Asymmetric segregation is tracked by incorporation of bromodeoxyuridine. The CPC DNA was labeled for several generations and then blocked in second cytokinesis during chase to determine distribution of immortal versus newly synthesized strands. Intensity ratios of binucleated CPCs with bromodeoxyuridine of >=70:30 between daughter nuclei indicative of asymmetric chromatid segregation occur with a frequency of 4.57, and asymmetric chromatid segregation is demonstrated at late mitotic phases. Asymmetric chromatid segregation is significantly enhanced by Pim-1 overexpression in CPCs (9.19 versus 4.79 in eGFP-expressing cells; P=0.006). CONCLUSIONS: Asymmetric segregation of chromatids in CPCs is increased nearly two fold with Pim-1 kinase overexpression, indicating that Pim-1 promotes self renewal of stem cells. PMID- 22441846 TI - Strengthening the trauma chain of survival. PMID- 22441845 TI - Asymptomatic cerebral bleeds in patients with aplastic anemia. AB - Several studies suggest that cerebral microbleeds (CMB) seen on gradient echo magnetic resonance imaging (GE-MRI) of brain increase the future risk of intracranial hemorrhage (ICH). We investigated 26 newly diagnosed patients of aplastic anemia (AA) with GE-MRI of brain who were otherwise neurologically asymptomatic. These patients were then further followed up for a period of 6 months for development of overt ICH. The median age of patients was 20.5 years (range 12-40 years). The median values of complete blood counts at the time of diagnosis were hemoglobin 5.7 gm/dl (range 2.5-9.2 gm/dl), white cell count 2,320/MUl (800-7,000/MUl), and platelet count 11,500/MUl (7000-45,000/MUl). Three patients were detected to have CMB while two patients had asymptomatic cerebral macrobleeds (>1 cm). During the follow-up period of 6 months, two patients developed spontaneous ICH. None of the two patients had CMB at diagnosis. In conclusion, asymptomatic CMB were found in 11.5 % of patients with AA. The overall prevalence of asymptomatic ICH (CMB & macrobleeds) was 19.2 %. Further studies with larger number of patients are required to clearly delineate the association. PMID- 22441847 TI - A strategy for future trauma research. PMID- 22441848 TI - Ethical and practical issues in trauma care research. PMID- 22441849 TI - The truth about road traffic accidents. PMID- 22441850 TI - The beginning of the end for damage control surgery. PMID- 22441851 TI - Trauma alarmins as activators of damage-induced inflammation. AB - BACKGROUND: A systemic inflammatory response syndrome (SIRS) is frequently observed after traumatic injury. The response is sterile and the activating stimulus is tissue damage. Endogenous molecules, called alarmins, are reputed to be released by injured tissues but the precise identity of these mediators is unclear. This review summarizes current preclinical and clinical evidence for trauma alarmins and their role in innate immune activation. METHODS: A comprehensive literature review of putative alarmins in tissue damage after traumatic injury was conducted. RESULTS: The presence of SIRS at admission is an independent predictor of mortality after trauma. The primary initiators of the human immune response are unclear. Several endogenous substances display alarmin characteristics in vitro. Preclinical studies demonstrate that blockade of certain endogenous substances can reduce adverse clinical sequelae after traumatic injury. Human evidence for trauma alarmins is extremely limited. CONCLUSION: The magnitude of acute inflammation is predictive of outcome after trauma, suggesting that an early opportunity for immune modulation may exist. An understanding of the mechanisms of innate immune activation following trauma may lead to new therapeutic agents and improved patient survival. PMID- 22441852 TI - Resuscitative strategies to maintain homeostasis during damage control surgery. AB - BACKGROUND: Successful outcome from damage control surgery (DCS) depends as much on elements of resuscitation and non-operative management as on details of the procedure itself. The early management of patients in haemorrhagic shock has undergone substantial revision in the past decade and is now known as 'haemostatic resuscitation'. METHODS: An updated literature review describing the anaesthetic and resuscitative management of patients with active, ongoing traumatic haemorrhage was distilled to present the current knowledge of the pathophysiology, recommended treatments and areas of active controversy. RESULTS: Current practice in military and civilian trauma centres is described, along with the degree of evidence in support of clinical decisions. Resuscitation of patients with ongoing traumatic haemorrhage has changed substantially in the past two decades. Optimal management now includes deliberate hypotension to minimize blood loss, early use of blood products (especially plasma) and administration of antifibrinolytic therapy. Areas of debate include the role of clotting factor concentrates and depth of anaesthesia. CONCLUSION: Resuscitation strategies during DCS may be as important as the anatomical repair itself. Recommendations include avoidance of hypothermia, maintenance of a lower than normal blood pressure, and early support of the coagulation system in patients likely to require massive transfusion. Controversies include the optimal ratio of plasma to red blood cells for empirical resuscitation, the ideal role of clotting factor concentrates, and the potential benefit of early, deep anaesthesia. Future research will centre on the complex interaction between the humoral elements of coagulation and the vascular endothelium that regulates perfusion, clotting and integrity of the circulation. PMID- 22441853 TI - Translational barriers and opportunities for emergency preservation and resuscitation in severe injuries. AB - BACKGROUND: Hypothermia is commonly used for organ and tissue preservation in multiple clinical settings, but its role in the management of injured patients remains controversial. There is no doubt that temperature modulation is a powerful tool, and hypothermia has been shown to protect cells during ischaemia and reperfusion, decrease organ damage and improve survival. Yet hypothermia is a double-edged sword: unless carefully managed, its induction can be associated with a number of complications. METHODS: A literature review was performed to include important papers that address the impact of hypothermia on key biological processes, and explore the potential therapeutic role of hypothermia in trauma/haemorrhage models. RESULTS: No clinical studies have been conducted to test the therapeutic benefits of hypothermia in injured patients. However, numerous well designed animal studies support this concept. Despite excellent preclinical data, there are several potential barriers to translating hypothermia into clinical practice. CONCLUSION: Therapeutic hypothermia is a promising life saving strategy. Appropriate patient selection requires a thorough understanding of how temperature modulation affects various biological mechanisms. PMID- 22441854 TI - Emerging treatment strategies for trauma-induced coagulopathy. AB - BACKGROUND: Trauma-induced coagulopathy has a multifactorial aetiology. Coagulopathy is related to blood loss including consumption of clotting factors and platelets and haemodilution. Additionally hyperfibrinolysis, hypothermia, acidosis and metabolic changes affect the coagulation system. METHODS: This is a review of pathophysiology and new treatment strategies for trauma-induced coagulopathy. RESULTS: Paradigms are actively changing and there is still a shortage of data. The aim of any haemostatic therapy is to control bleeding and minimize blood loss and transfusion requirements. Transfusion of allogeneic blood products as well as trauma-induced coagulopathy cause increased morbidity and mortality. Current opinion is based on present studies and results from small case series, combined with findings from experimental studies in animals, in vitro studies and expert opinions, as opposed to large, randomized, placebo controlled studies. A summary of new and emerging strategies, including medical infusion and blood products, to beneficially manipulate the coagulation system in the critically injured patient is suggested. CONCLUSION: Future treatment of trauma-induced coagulopathy may be based on systemic antifibrinolytics, local haemostatics and individualized point-of-care-guided rational use of coagulation factor concentrates such as fibrinogen, prothrombin complex concentrate, recombinant factor VIIa and factor XIII. The authors speculate that timely and rational use of coagulation factor concentrates will be more efficacious and safer than ratio-driven use of transfusion packages of allogeneic blood products. Copyright (c) 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. PMID- 22441855 TI - Emerging treatment strategies for trauma-induced coagulopathy (Br J Surg 2012; 99(Suppl 1): 40-50). PMID- 22441856 TI - Systematic review and meta-analysis of immediate total-body computed tomography compared with selective radiological imaging of injured patients. AB - BACKGROUND: The aim of this review was to assess the value of immediate total body computed tomography (CT) during the primary survey of injured patients compared with conventional radiographic imaging supplemented with selective CT. METHODS: A systematic search of the literature was performed in MEDLINE, Embase, Web of Science and Cochrane Library databases. Reports were eligible if they contained original data comparing immediate total-body CT with conventional imaging supplemented with selective CT in injured patients. The main outcomes of interest were overall mortality and time in the emergency room (ER). RESULTS: Four studies were included describing a total of 5470 patients; one study provided 4621 patients (84.5 per cent). All four studies were non-randomized cohort studies with retrospective data collection. Mortality was reported in three studies. Absolute mortality rates differed substantially between studies, but within studies mortality rates were comparable between immediate total-body CT and conventional imaging strategies (pooled odds ratio 0.91, 95 per cent confidence interval 0.79 to 1.05). Time in the ER was described in three studies, and in two was significantly shorter in patients who underwent immediate total body CT: 70 versus 104 min (P = 0.025) and 47 versus 82 min (P < 0.001) respectively. CONCLUSION: This review showed differences in time in the ER in favour of immediate total-body CT during the primary trauma survey compared with conventional radiographic imaging supplemented with selective CT. There were no differences in mortality. The substantial reduction in time in the ER is a promising feature of immediate total-body CT but well designed and larger randomized studies are needed to see how this will translate into clinical outcomes. PMID- 22441857 TI - Non-operative management and immune function after splenic injury. AB - BACKGROUND: There is still considerable controversy about the importance and method of preserving splenic function after trauma. Recognition of the immune function of the spleen and the risk of overwhelming postsplenectomy infection led to the development of spleen-preserving surgery and non-operative management. More recently angiographic embolization has been used to try to reduce failure of conservative management and preserve splenic function. METHODS: A literature review was performed of the changing treatment of splenic injury over the last century, focusing on whether and how to maintain splenic immune function. RESULTS: Non-operative management continues to be reported as a successful approach in haemodynamically stable patients without other indications for laparotomy, achieving high success rates in both children and adults. Except for haemodynamic instability, reported predictors of failure of conservative treatment should not be seen as absolute contraindications to this approach. Angiographic embolization is generally reported to increase success rates of non operative management, currently approaching 95 per cent. However, the optimal use of angioembolization is still debated. Splenic immunocompetence after angioembolization remains questionable, although existing studies seem to indicate preserved splenic function. CONCLUSION: Non-operative management has become the treatment of choice to preserve splenic immune function. Current knowledge suggests that immunization is unnecessary after angiographic embolization for splenic injury. Identifying a diagnostic test of splenic function will be important for future studies. Most importantly, in efforts to preserve splenic function, care must be taken not to jeopardize patients at risk of bleeding who require early surgery and splenectomy. PMID- 22441858 TI - Reperfusion strategies in the management of extremity vascular injury with ischaemia. AB - BACKGROUND: Extremity injury with ischaemia is the most common pattern of vascular trauma and is a challenge for surgeons who must make decisions about the timing and mechanism of limb reperfusion. In modern military conflicts, effective use of limb tourniquets and rapid transport of the injured have increased the number of casualties who reach a medical service with potentially survivable vascular trauma. This report provides a review of extremity ischaemia and reperfusion following vascular trauma. METHODS: A review was undertaken of extremity vascular injury with ischaemia, including a focus on adjuncts aimed at reducing reperfusion injury and improving neuromuscular recovery and limb salvage. RESULTS: Findings from basic and clinical research support the need to restore perfusion to an ischaemic limb as soon as possible in order to achieve optimal neuromuscular recovery. Large-animal studies demonstrate that haemorrhagic shock worsens the impact of ischaemia on the neuromuscular structures of the limb and reduces the ischaemic threshold to as little as 1 h. Surgical adjuncts such as vascular shunts, fasciotomy, regional limb cooling and ischaemic conditioning may reduce the severity of ischaemic injury. Medical therapies have also been described including hypertonic saline, statins and ethyl pyruvate, which reduce the inflammatory response following limb reperfusion. CONCLUSION: Contemporary translational research refutes a casual approach to extremity vascular injury with ischaemia, instead emphasizing expedited reperfusion. Surgical and medical adjuncts exist to expedite reperfusion and mitigate reperfusion injury. Additional research and development of these adjuncts is necessary to improve quality or functional limb salvage after vascular trauma. PMID- 22441859 TI - Factors affecting outcome after traumatic limb amputation. AB - BACKGROUND: Traumatic leg amputation commonly affects young, active people and leads to poor long-term outcomes. The aim of this review was to describe common causes of disability and highlight therapeutic interventions that may optimize outcome after traumatic leg amputation. METHODS: A comprehensive search of MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature databases was performed, using the terms 'leg injury', 'amputation' and 'outcome'. Articles reporting outcomes following traumatic leg amputation were included. RESULTS: Studies demonstrated that pain, psychological illness, decreased physical and vocational function, and increased cardiovascular morbidity and mortality were common causes of disability after traumatic leg amputation. The evidence highlights that appropriate preoperative management and operative techniques, in conjunction with suitable rehabilitation and postoperative follow-up, can lead to improved treatment outcome and patient satisfaction. CONCLUSION: Patients who undergo leg amputation after trauma are at risk of poor long-term physical and mental health. Clinicians involved in their care have many opportunities to improve their outcome using a variety of therapeutic variables. Copyright (c) 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. PMID- 22441860 TI - Tibial fracture with degloving injury of the foot. PMID- 22441861 TI - Systematic review of multidisciplinary rehabilitation in patients with multiple trauma. AB - BACKGROUND: Multiple trauma is a cause of significant disability in adults of working age. Despite the implementation of trauma systems for improved coordination and organization of care, rehabilitation services are not yet routinely considered integral to trauma care processes. METHODS: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine, Physiotherapy Evidence Database, Latin American and Caribbean Literature on Health Sciences and Cochrane Library databases were searched up to May 2011 for randomized clinical trials, as well as observational studies, reporting outcomes of injured patients following multidisciplinary rehabilitation that addressed functional restoration and societal reintegration based on the International Classification of Functioning, Disability and Health. RESULTS: No randomized and/or controlled clinical trials were identified. Fifteen observational studies involving 2386 participants with injuries were included. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach assessed methodological quality as 'poor' in all studies, with selection and observer bias. Although patients with low functional scores showed improvement after rehabilitation, they were unable to resume their pretrauma level of activity. Their functional ability was significantly associated with motor independence on admission and early acute rehabilitation, which contributed to a shorter hospital stay. Injury location, age, co-morbidity and education predicted long-term functional consequences. Trauma care systems were associated with reduced mortality. The gaps in evidence include: rehabilitation settings, components, intensity, duration and types of therapy, and long-term outcomes for survivors of multiple trauma. CONCLUSION: Rehabilitation is an expensive resource and the evidence to support its justification is needed urgently. The issues in study design and research methodology in rehabilitation are challenging. Opportunities to prioritize trauma rehabilitation, disability management and social reintegration of multiple injury survivors are discussed. PMID- 22441862 TI - Indicators of the quality of trauma care and the performance of trauma systems. AB - BACKGROUND: Valid and reliable measures of trauma system performance are needed to guide improvement activities, benchmarking and public reporting, future investment and research. Traditional measures of in-hospital mortality fail to take into account prehospital and posthospital care, recovery after discharge, and the nature and costs of long-term disability. METHODS: Drawing on recent systematic reviews, an overview was conducted of existing and emerging trauma care performance indicators. Changes in the nature and purpose of indicators were assessed. RESULTS: Among a large number of existing, mostly locally developed performance indicators, only peer review of deaths has evidence of validity or reliability. The usefulness of the traditional performance measure of in-hospital mortality has been challenged. There is an emerging shift in focus from mortality to non-mortality outcomes, from hospital-based to long-term community-based outcome assessment, and from single measures of trauma centre performance to measures better suited to monitoring the performance of systems of care spanning the entire patient journey. As a result, a new generation of indicators is emerging that are both feasible and potentially more useful for commissioners and payers of population-based services. CONCLUSION: A global endeavour is now under way to agree on a set of standardized performance indicators that are meaningful to patients, carers, clinicians, managers and service funders, are likely to contribute to desired outcomes, and are valid, reliable and have a strong evidence base. PMID- 22441863 TI - Randomized clinical trial comparing the effect of computed tomography in the trauma room versus the radiology department on injury outcomes. AB - BACKGROUND: Computed tomography (CT) of injured patients in the radiology department requires potentially dangerous and time-consuming patient transports and transfers. It was hypothesized that CT in the trauma room would improve patient outcome and workflow. METHODS: A randomized trial compared the effect of locating a CT scanner in the trauma room versus the radiology department in two Dutch trauma hospitals. Injured patients aged at least 16 years were assigned randomly to one of these hospitals at the time of transport. The primary outcome measure was the number of non-institutionalized days within the first year after randomization. Subgroup analyses were performed in patients with multiple trauma or severe traumatic brain injury (TBI). RESULTS: Some 1124 patients were included, of whom 1045 were available for analysis. The median number of non institutionalized days was 360 days in the intervention group versus 362 days for the control group (P = 0.068). The time from arrival to the first CT imaging was 13 min shorter in the intervention group (36 versus 49 min; P < 0.001). Patient transfers and transports were reduced by more than half in the intervention group. For both multiple trauma (265 patients) and TBI (121) subgroups, differences in mortality and out-of-hospital days favoured the intervention group, but were not statistically significant. CONCLUSION: A CT scanner located in the trauma room reduces the time to acquire CT images and improves workflow, but does not lead to substantial improvements in clinical outcomes in a general trauma population. Observed beneficial effects on outcomes in patients with multiple trauma or severe TBI were not statistically significant. REGISTRATION NUMBER: ISRCTN55332315 (http://www.controlled-trials.com). PMID- 22441864 TI - Epidemiological burden of minor, major and fatal trauma in a national injury pyramid. AB - BACKGROUND: The impact of trauma on population health is underestimated because comprehensive overviews of the entire severity spectrum of injuries are scarce. The aim of this study was to measure the total health impact of fatal and non fatal unintentional injury in the Netherlands. METHODS: Epidemiological data for the four levels of the injury pyramid (general practitioner (GP) registry, emergency department (ED) registers, hospital discharge and mortality data) were obtained for the whole country. For all levels, the incidence and years of life lost (YLL) owing to premature death, years lived with disability (YLD) and disability-adjusted life-years (DALYs) were calculated. RESULTS: Unintentional injury resulted in 67 547 YLL and 161 775 YLD respectively, amounting to 229 322 DALYs (14.1 per 1000 inhabitants). Home and leisure, and traffic injuries caused most DALYs. Minor injury (GP and ED treatment) contributed 37.3 per cent (85 504 DALYs; 5.2 per 1000) to the total burden of injury, whereas injuries requiring hospital admission contributed 33.3 per cent (76 271 DALYs; 4.7 per 1000) and fatalities contributed 29.5 per cent (67 547 DALYs; 4.1 per 1000). Men aged 15-65 years had the greatest burden of injury, resulting in a share of 39.6 per cent for total DALYs owing to unintentional injury. The highest individual burden resulted from death (19 DALYs per patient). CONCLUSION: Trauma causes a major burden to society. For priority setting in public health and the identification of opportunities for prevention it is important that burden-of-injury estimates cover the entire spectrum of injuries, ranging from minor injury to death. PMID- 22441865 TI - Epidemiological burden of minor, major and fatal trauma in a national injury pyramid (Br J Surg 2012; 99(Suppl 1): 114-121). PMID- 22441866 TI - Pupil evaluation in addition to Glasgow Coma Scale components in prediction of traumatic brain injury and mortality. AB - BACKGROUND: Early diagnosis and prediction of traumatic brain injury (TBI) is essential for determining treatment strategies and allocating resources. This study evaluated the predictive accuracy of Glasgow Coma Scale (GCS) verbal, motor and eye components alone, or in addition to pupil size and reactivity, for TBI. METHODS: A retrospective cohort analysis of data from 51 425 severely injured patients registered in the Trauma Registry of the German Society for Trauma Surgery from 1993 to 2009 was undertaken. Only directly admitted patients alive on admission and with complete data on GCS, pupil size and pupil reactivity were included. The unadjusted predictive roles of GCS components and pupil parameters, alone or in combination, were modelled using area under the receiver operating characteristic (AUROC) curve analyses and multivariable logistic regression regarding presence of TBI and death. RESULTS: Some 24 115 patients fulfilled the study inclusion criteria. Best accuracy for outcome prediction was found for pupil reactivity (AUROC 0.770, 95 per cent confidence interval 0.761 to 0.779) and GCS motor component (AUROC 0.797, 0.788 to 0.805), with less accuracy for GCS eye and verbal components. The combination of pupil reactivity and GCS motor component (AUROC 0.822, 0.814 to 0.830) outmatched the predictive accuracy of GCS alone (AUROC 0.808, 0.800 to 0.815). Pupil reactivity and size were significantly correlated (r(s) = 0.56, P < 0.001). Patients displaying both unequal pupils and fixed pupils were most likely to have TBI (95.1 per cent of 283 patients). Good outcome (Glasgow Outcome Scale score 4 or more) was documented for only 1929 patients (8.0 per cent) showing fixed and bilateral dilated pupils. CONCLUSION: The best predictive accuracy for presence of TBI was obtained using the GCS components. Pupil reactivity together with the GCS motor component performed best in predicting death. PMID- 22441867 TI - Pupil evaluation in addition to Glasgow Coma Scale components in prediction of traumatic brain injury and mortality (Br J Surg 2012; 99(Suppl 1): 122-130). PMID- 22441868 TI - Simulation of survivorship bias in observational studies on plasma to red blood cell ratios in massive transfusion for trauma. AB - BACKGROUND: Observational studies on injured patients requiring massive transfusion have found a survival advantage associated with use of equivalent number of units of fresh frozen plasma (FFP) and packed red blood cells (RBCs) compared with use of FFP based on conventional guidelines. However, a survivorship bias might have favoured the higher use of FFP because patients who died early never had the chance to receive sufficient FFP to match the number of RBC units transfused. METHODS: A Markov model using trauma data from local hospitals was constructed and various FFP transfusion scenarios were applied in Monte Carlo simulations in which the relative risk of death associated with exposure to high FFP transfusion was set at 1.00, so that the FFP : RBC ratio had no influence on mortality outcome. RESULTS: Simulation results showed that the relative risk associated with exposure to high FFP transfusion was less than 1.00 (0.33-0.56 based on programmed delays in achieving an FFP : RBC ratio of 1 : 1 2), thus demonstrating a survivorship bias in favour of FFP : RBC equal to or more than 1 : 1-2 in certain observational trauma studies. This bias was directly proportional to the delay in achieving a FFP : RBC ratio of 1 : 1-2 during resuscitation. CONCLUSION: Some observational studies comparing low and high FFP administration in injured patients requiring massive transfusion probably involve survivorship bias that inflates or creates a survival advantage in favour of a higher FFP : RBC ratio. PMID- 22441869 TI - Surgical management and outcome of civilian gunshot injuries to the pancreas. AB - BACKGROUND: Pancreatic injuries are uncommon but result in substantial morbidity and mortality. This study evaluated the factors associated with morbidity and mortality in civilian patients with pancreatic gunshot wounds. METHODS: This was a single-institution, retrospective review of patients with gunshot wounds of the pancreas treated from 1976 to 2009 in Cape Town, South Africa. Univariable and multivariable analyses were performed. RESULTS: A total of 219 patients (205 male, median age 27 years) had pancreatic American Association for the Surgery of Trauma grade I-II (111 patients) and grade III-V (108) gunshot injuries to the pancreatic head (72), neck (8), body (75) and tail (64). The patients underwent 239 laparotomies, including drainage of the pancreas (169), distal pancreatectomy (59) and pancreaticoduodenectomy (11). Some 218 patients had 642 associated intra abdominal and 91 vascular injuries. Forty-three (19.6 per cent) required an initial damage control procedure. A total of 150 patients (68.5 per cent) had 407 postoperative complications (median 4, range 1-7). The 46 patients (21.0 per cent) who died had a median of 3 (range 1-7) complications. Median (range) intensive care unit and total hospital stay were 5 (1-153) and 11 (1-255) days respectively. Multivariable analyses identified age, high-grade pancreatic injury, associated vascular injuries and need for repeat laparotomy as predictors of morbidity. Age, shock on admission, need for damage control surgery, high grade pancreatic injuries and associated vascular injuries were significant factors associated with mortality. CONCLUSION: Morbidity and mortality rates were high after gunshot injuries to the pancreas. Initial shock and severe injury combined with need for damage control surgery were associated with the highest risk of death. PMID- 22441870 TI - Management of penetrating neck injuries. AB - BACKGROUND: Routine surgical exploration after penetrating neck injury (PNI) leads to a large number of negative neck explorations and potential iatrogenic injury. Selective non-operative management (SNOM) of PNI is gaining favour. The present study assessed the feasibility of SNOM in PNI. METHODS: Seventy-seven consecutive patients with PNI presenting to a tertiary trauma centre were included in this prospective study from September 2009 to December 2009. All patients were managed according to Advanced Trauma Life Support guidelines, and either underwent emergency surgery or were managed without surgery, based on clinical presentation and/or outcome of special investigations. RESULTS: Eight patients (10 per cent) were haemodynamically unstable at presentation. Foley catheter balloon tamponade (FCBT) was successful in stopping active bleeding in six of these patients, and diagnostic angiography revealed an arterial injury in five. The remaining 69 patients were managed using SNOM. Angiography or computed tomography was done in 41 patients (53 per cent), and showed arterial injury in 15. These injuries were treated surgically (7 patients), radiologically (stenting in 3) or conservatively. Contrast swallow and/or endoscopy were performed in 37 patients (48 per cent) for suspected oesophageal injury, but yielded no positive results. During follow-up no missed injuries were detected. CONCLUSION: FCBT was useful in patients with PNI and active bleeding. Stable patients should undergo additional investigation based on clinical findings only. PMID- 22441871 TI - Outcome of selective non-operative management of penetrating abdominal injuries from the North American National Trauma Database. AB - BACKGROUND: The aim of this study was to investigate trends in the practice of selective non-operative management (SNOM) for penetrating abdominal injury (PAI) and to determine factors associated with its failure. METHODS: The National Trauma Data Bank for 2002-2008 was reviewed. Patients with PAI were categorized as those who underwent successful SNOM (operative management not required) and those who failed SNOM (surgery required more than 4 h after admission). Yearly rates of SNOM versus non-therapeutic laparotomy (NTL) were plotted. Multivariable regression analysis was performed to identify factors associated with failed SNOM and mortality. RESULTS: A total of 12 707 patients with abdominal gunshot and 13 030 with stab wounds were identified. Rates of SNOM were 22.2 per cent for gunshot and 33.9 per cent for stab wounds, and increased with time (P < 0.001). There was a strong correlation between the rise in SNOM and the decline in NTL (r = - 0.70). SNOM failed in 20.8 and 15.2 per cent of patients with gunshot and stab wounds respectively. Factors predicting failure included the need for blood transfusion (odds ratio (OR) 1.96, 95 per cent confidence interval 1.11 to 3.46) and a higher injury score. Failed SNOM was independently associated with mortality in both the gunshot (OR 4.48, 2.07 to 9.70) and stab (OR 9.83, 3.44 to 28.00) wound groups. CONCLUSION: The practice of SNOM is increasing, with an associated decrease in the rate of NTL for PAI. In most instances SNOM is successful; however, its failure is associated with increased mortality. Careful patient selection and adherence to protocols designed to decrease the failure rate of SNOM are recommended. PMID- 22441872 TI - Selective non-operative management in 25 737 patients with penetrating abdominal injuries (Br J Surg 2011; 99(Suppl 1): 157-167). PMID- 22441873 TI - Trauma from the dawn of time. PMID- 22441875 TI - Novel protein pp3501 mediates the inhibitory effect of sodium butyrate on SH-SY5Y cell proliferation. AB - Sodium butyrate, a new potential therapeutic drug, improves the efficacy of chemo and immunotherapy of cancer under unknown mechanisms. A novel gene pp3501 is significantly induced in SH-SY5Y neuroblastoma cells upon sodium butyrate treatment. Therefore, this study has cloned pp3501 cDNA by RT-PCR and generated its recombinant fusion protein and anti-serum subsequently. The pp3501 protein localized mainly in the nucleus, as detected by immunocytochemistry and the expression of pp3501-EGFP fusion protein. pp3501 inhibited the proliferation of SH-SY5Y cells, arrested the cell cycle at G1 phase, and sensitized the SH-SY5Y cells to sodium butyrate treatment. These results provide a new mechanism of sodium butyrate inhibiting cancer cell proliferation as well as a new avenue for the future research on the functions of pp3501. PMID- 22441874 TI - Huntington's disease and the striatal medium spiny neuron: cell-autonomous and non-cell-autonomous mechanisms of disease. AB - Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is > 40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. PMID- 22441876 TI - Ionothermal synthesis of aluminophosphate molecular sieve membranes through substrate surface conversion. PMID- 22441877 TI - Electrically pumped random lasers fabricated from ZnO nanowire arrays. AB - Vertically aligned ZnO nanowires have been prepared, and structural characterization shows that the nanowires have relatively high crystalline quality. The dominant free exciton emission and the appearance of B-type exciton emissions at low temperatures reveal the high optical quality of the nanowires. Au-MgO-ZnO nanowire structures have been constructed, and random lasing has been observed from the structure under the injection of continuous current. PMID- 22441878 TI - Obesity and colorectal cancer screening among black and white adults. AB - PURPOSE: To examine whether body mass index is associated with reduced colorectal cancer (CRC) screening in a large population of black and white adults. METHODS: Cross-sectional data collected at baseline for 9,547 black men, 14,515 black women, 3,519 white men, and 7,245 white women aged 50-79 enrolled in the Southern Community Cohort Study from 2002 to 2009 were used to examine odds ratios (OR) with 95 % confidence intervals (CI) for the use of colonoscopy or sigmoidoscopy in relation to body mass index (BMI) categories (<18.5, 18.5-24.9 (referent), 25 29.9, 30-34.9, 35-39.9, and 40+ (extreme obesity), kg/m(2)) using logistic regression controlling for age, education, income, health insurance status, last physician visit, cigarette smoking, and alcohol consumption. RESULTS: Increased BMI was not associated with reduced CRC screening among whites (OR (95 % CI) for BMI >= 40 = 1.02 (0.71-1.46) for white men and 0.99 (0.83-1.19) for white women), and odds of CRC screening were increased with high BMI among blacks (OR (95 % CI) for BMI >= 40 = 1.34 (1.03-1.74) for black men and 1.13 (0.98-1.29) for black women). Extreme obesity was associated with reduced odds of CRC screening only among white women in subgroup analyses limited to those with health insurance or income >=$25,000/year. CONCLUSIONS: Elevated BMI was not a deterrent to CRC screening overall in this population. In light of low overall screening rates for colorectal cancer nationally, efforts to increase screening in all individuals should remain the focus of public health initiatives. PMID- 22441879 TI - Synthesis of cyclic carbonates: catalysis by an iron-based composite and the role of hydrogen bonding at the solid/liquid interface. AB - Say it with flowers: Flower-like Fe(3)O(4)@Fe(OH)(3) composite catalysts show good activity and stability in the synthesis of cyclic carbonates from epoxides and CO(2). The role of hydrogen bonding between the surface hydroxyl groups of the solid and the epoxides at the solid/liquid interface is proposed as a key factor in activating the epoxide and stabilizing the ring-opened carbonate intermediates. PMID- 22441881 TI - Clinical significance of KRAS gene mutation and epidermal growth factor receptor expression in Japanese patients with squamous cell carcinoma of the larynx, oropharynx and hypopharynx. AB - PURPOSE: The significance of epidermal growth factor receptor (EGFR) signaling has been recognized in various cancers and anti-EGFR therapies in Japan are currently under consideration in squamous cell carcinoma of the head and neck (SCCHN) similar to colorectal cancer. However, there was no established survey regarding heterogeneous EGFR protein expression in Japanese SCCHN patients. The purpose of this study is to examine the relationship between EGFR expression or KRAS mutation (related to the alteration of EGFR pathway) and the clinicopathological characteristics of SCCHN. MATERIALS AND METHODS: We retrospectively examined the expression of EGFR protein by immunohistochemistry and KRAS gene mutation at codons 12 and 13 by using paraffin-embedded and formalin-fixed primary tumor tissues from 205 patients with SCCHN who underwent surgery at National Cancer Center Hospital East. RESULTS: In 200 of the 205 patients (97.6 %), EGFR protein was expressed despite intratumoral heterogeneity. No patients had KRAS mutation at codons 12 or 13, and all 183 tumors showed wild type KRAS. Positive rate of EGFR protein expression was significantly associated with better disease free survival (DFS) (P = 0.0471) and the intensity of EGFR protein expression showed a tendency for better DFS (P = 0.1034). Both higher EGFR positive rate and more intense EGFR expression were significantly associated with well differentiated subtype of squamous cell carcinoma (P = 0.0003 and P = 0.0007, respectively). CONCLUSION: Most SCCHN patients may be good candidates for the anti-EGFR therapies. PMID- 22441883 TI - [Psychological morbidity in spouses of laryngectomized cancer patients: factors related to the probability of its occurrence]. AB - In a multicenter cross-sectional study of 106 spouses of laryngectomized patients differences between spouses with a mental disorder and spouses without were analyzed. The probability of occurrence was mainly related to relationship factors: Spouses, who reported a better quality of their relationship with the patient (OR=0.77; 95% CI: 0.631-0.939; p=0.010), whose sexual desire was not diminished in response to their partner's disease (OR=0.077; 95% CI: 0.011-0.527; p=0.009) and who had no problems in dealing with the tracheostomy (OR=0.062; 95% CI: 0.006-0.619; p=0.018) presented a mental disorder less frequently. The cross sectional nature of this study does not allow conclusions regarding causality. The results should be reappraised in a longitudinal study. However, the findings suggest that patients with laryngectomy and their families should be also offered couple interventions besides individual counseling. PMID- 22441882 TI - Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury. AB - Treatment during early tumor development has greater success because tissue growth remains largely confined to its original locus. At later stages, malignant cells migrate from their original location, invade surrounding normal areas, and can disseminate widely throughout the body. Remodeling of the extracellular matrix (ECM) serves as a key facilitator of this dissemination. Proteolytic enzymes including plasmin and matrix metalloproteinases (MMPs) play an integral role in degrading the surrounding ECM proteins and clearing a path for tumor cell migration. Specific MMPs are highly expressed late during malignant tumor invasion. It is not understood whether early changes in MMPs influence apoptotic and necrotic cell death, processes known to govern the early stages of carcinogenesis. Similarly, the interaction between MDM2 and p53 is tightly controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of both p53 and MDM2. The present studies examine the hypothesis that model hepatotoxin dimethylnitrosamine (DMN), which is also a model carcinogen, will induce the MMP family of proteins after administration in hepatotoxic doses. Doses of 25, 50, and 100 mg/kg DMN were administered i.p. to male C3H mice. Changes in parameters associated with apoptotic and necrotic cell death, DNA damage, cell proliferation, and extracellular proteinases were examined in liver at 24 h. Serum ALT activity, oxidative stress [malondialdehyde], and caspase-activated DNAse mediated DNA laddering increased in a dose-dependent manner, as did the level of MDM2 protein. MMP-9, -10 and -12 (gelatinase-B, stromelysin-2, macrophage elastase), and p53 protein levels increased following 25 mg/kg DMN, but were successively decreased after higher DMN doses. The results of this study demonstrate changes in MDM2 and MMPs during DMN-induced acute liver injury and provide a plausible linkage between DMN-induced oxidative stress-mediated genomic injury and its likely involvement in setting the stage for initiating subsequent metastatic disease at later circumstances. PMID- 22441884 TI - [Family caregivers of palliative cancer patients: health-related quality of life and care-related burden]. AB - Family caregivers of palliative cancer patients are usually much burdened. In order to avoid the failure of home care, family caregivers need support. The current study evaluates support needs in family caregivers of palliative cancer patients. 53 family caregivers of palliative cancer patients answered the questionnaire. Health-related quality of life was assessed using the EORTC QLQ C30 questionnaire. Home care burden was assessed using the "Burden Scale for Family Caregivers" (BSFC). Family caregivers suffered of reduced social and emotional function. Female and older caregivers reported a stronger home care burden than male and younger caregivers. For female and older family caregivers of palliative cancer patients, home care is very burdensome. Thus, female caregivers need, above all, psychosocial support, whereas older caregivers need the most support in a physical and social level. PMID- 22441885 TI - Acetobacter pasteurianus strain AB0220: cultivability and phenotypic stability over 9 years of preservation. AB - Acetobacter species are members of the alpha-subclass of Proteobacteria, which harbors a large number of bacteria recalcitrant to cultivation. Strain AB0220 was isolated from a superficial acetification system and preserved for 9 years by short and long time methods. Under short time preservation it was estimated that 540.54 number of generations occurred, whereas in long time preservation conditions the number of generations was 17.40. Ethanol oxidation to acetic acid was stable and confirmed, as well as acetate assimilation during long time preservation. Cultivability checks showed persistence of phenotypic traits (growth on ethanol and methanol, growth on different carbon sources and cellulose production) over the extended preservation time. 16S rRNA gene sequences analysis showed 100 % of similarity with A. pasteurianus (Accession number GQ240636). Stability of subcultures related to the culture age and subcultures frequency, tested by ERIC/PCR, confirmed the suitability of long term preservation at least over a period of 9 years. PMID- 22441886 TI - Semiconducting polymers prepared by direct arylation polycondensation. PMID- 22441887 TI - Overexpression of forkhead box J2 can decrease the migration of breast cancer cells. AB - The prognosis of breast cancer patients with metastases is generally poor, so it is essential to elucidate related molecules mechanisms. Forkhead Box J2 (FOXJ2) is a member of Forkhead Box transcription factors, many of which have been reported to participate in tumor migration and invasion. In this study, we showed the expression of FOXJ2 was higher in primary breast cancer tissues without lymph nodes metastases than those with, and there was statistical significance between the expression of FXOJ2 and the clinical factors. Hence, we identified a novel function of metastasis, which was not previously known for FOXJ2. Overexpression of FOXJ2 decreased the motility property of highly migrative MDA-MB-231 cells in vitro by wound healing assays and trans-well migration assays, and it was concurrent with the increased expression of epithelial marker E-cadherin and the decreased expression of mesenchymal marker vimentin by Western blot analysis, reverse transcription PCR analysis, and immunofluorescence analysis. Consistent with these observations, the repression of FOXJ2 in weakly metastatic MCF-7 cells remarkably promoted cellular motility. Our study demonstrates that FOXJ2 can inhibit the metastasis of human breast cancer by regulating the EMT key markers E cadherin and vimentin. PMID- 22441888 TI - The impact of persisting hyperactivity on social relationships: a community based, controlled 20-year follow-up study. AB - OBJECTIVE: The purpose of this study was to examine whether persisting hyperactivity into adulthood was associated with impaired family, friendship, and partner relationships or poor coping skills in everyday life. METHOD: A 20-year community-based follow-up of 6- to 7-year-old boys showing pervasive hyperactivity (n = 40) and unaffected controls (n = 25) was conducted. At age 27 years, participants were assessed with detailed interview techniques as well as self-report ratings. RESULTS: ADHD in adulthood was associated with problems in intimate relationships and negotiation skills. Antisocial behavior did not influence the association, but remitting childhood hyperactivity was not associated with social relationship difficulties in adulthood. CONCLUSION: In an untreated, community-based sample of hyperactive children, the risk for unsatisfactory social relationships is largely confined to those patients who still show ADHD in adulthood. The majority of patients who experience childhood hyperactivity have positive social relationships in adulthood. PMID- 22441889 TI - German validation of the conners adult ADHD rating scale-self-report: confirmation of factor structure in a large sample of participants with ADHD. AB - OBJECTIVE: The Conners Adult ADHD Rating Scales (CAARS) assess symptoms specific to adults that are frequently used and have been translated into German. The current study tests the factor structure of the CAARS in a large sample of German adults with ADHD and compares the means of the CAARS subscales with those of healthy German controls. METHOD: CAARS were completed by 466 participants with ADHD and 851 healthy control participants. Confirmatory factor analysis was used to establish model fit with the American original. Comparisons between participants with ADHD and healthy controls and influences of gender, age, and degree of education were analyzed. RESULTS: Confirmatory factor analysis showed a very good fit with the model for the American original. Differences between ADHD participants and healthy controls on all Conners Adult ADHD Rating Scales-Self Report (CAARS-S) subscales were substantial and significant. CONCLUSION: The factor structure of the original American model was successfully replicated in this sample of adult German ADHD participants. PMID- 22441890 TI - Comparison of mother, father, and teacher reports of ADHD core symptoms in a sample of child psychiatric outpatients. AB - OBJECTIVE: To explore the significance of adding father ratings to mother and teacher ratings in the assessment of ADHD symptoms in children. METHOD: The ADHD Rating Scale-IV, the Child Behavior Checklist, and the Teacher Report Form were filled out by all three informants for a sample of 48 clinically referred children (79% boys) aged 6 to 15 (M = 10.1) years. RESULTS: Correspondence between father and teacher reports on ADHD-specific symptoms (intraclass correlation coefficient [ICC] = .38) exceeded that between mothers and teachers (ICC = .23). Fathers rated their children as having fewer problems than did mothers and teachers on Total scale scores and the Inattention subscale of the ADHD Rating Scale-IV. Mother ratings were more sensitive to an ADHD diagnosis, whereas father ratings better predicted an ADHD diagnosis requiring the two setting criterion. CONCLUSION: The choice of parent informant and informant combination had a considerable impact on parent-teacher concordance and estimates of ADHD symptoms and subtypes in the child. PMID- 22441891 TI - Sluggish cognitive tempo among young adolescents with ADHD: relations to mental health, academic, and social functioning. AB - OBJECTIVE: This study investigated the role of sluggish cognitive tempo (SCT) in relation to externalizing and internalizing mental health problems, academic functioning, and social functioning among young adolescents with attention deficit/hyperactivity disorder (ADHD). METHOD: In all, 57 youth ages 10 to 14 participated in the study. Parents rated SCT, internalizing, and externalizing symptoms, as well as social and academic impairment. Teachers rated academic and peer impairment, and intelligence and academic achievement also were assessed. RESULTS: Above and beyond ADHD and conduct problem symptoms, SCT was associated with internalizing mental health symptoms and social problems. The association between SCT and externalizing problems or academic functioning was not significant when accounting for ADHD symptomatology and intelligence. CONCLUSION: SCT is consistently associated with internalizing symptoms and is also associated with young adolescents' general social difficulties. When controlling for important related constructs, SCT is not associated with externalizing symptoms or academic impairment among young adolescents with ADHD. PMID- 22441892 TI - Statin-induced immunomodulation alters peripheral invariant natural killer T-cell prevalence in hyperlipidemic patients. AB - PURPOSE: To assess the difference in the prevalence of invariant Natural Killer T (iNKT) lymphocytes between hyperlipidemic and control individuals and to evaluate changes in iNKT cell levels after 6 months lipid lowering therapy. METHODS: A total of 77 hyperlipidemic individuals (54 +/- 5 years) were assigned to simvastatin 40 mg or ezetimibe 10 mg daily for 6 months. Fifty individuals with normal cholesterol levels were used as control. iNKT cells were measured by flow cytometry in peripheral blood. RESULTS: Patients with hypercholesterolemia had significantly lower iNKT cell levels (percentage on the lymphocyte population) compared to control group (0.16 +/- 0.04% vs 0.39 +/- 0.08%, p = 0.03). iNKT cells significantly increased after 6 months treatment with simvastatin (from 0.15 +/- 0.04% to 0.28 +/- 0.11%, p = 0.03) but not with ezetimibe (from 0.16 +/- 0.05% to 0.17 +/- 0.06%, p = 0.55). Simvastatin treatment did not alter the activation status of iNKT cells as measured by HLA-DR expression. Changes of iNKT cells were independent from changes in total (r(2) = 0.009, p = 0.76) or LDL cholesterol (r(2) = 0.008, p = 0.78) reached by simvastatin. CONCLUSIONS: Hyperlipidemic patients have reduced numbers of iNKT in peripheral circulation compared to individuals with normal cholesterol levels. Their number is increasing after long term administration of simvastatin 40 mg but not after ezetimibe. PMID- 22441893 TI - Forward for translation research seminars. PMID- 22441894 TI - The quest for diagnostic molecular markers for thyroid nodules with indeterminate or suspicious cytology. AB - Thyroid nodules are very common and fine needle aspiration (FNA) is a very sensitive means of diagnosis. However, its limitations include the fact that the cytology reports are often indeterminate or suspicious only. The quest for adjunctive measures to improve its specificity has been ongoing for decades, but significant results have remained elusive. The potential use of diagnostic molecular markers appears to be the most promising area of research at this time. PMID- 22441895 TI - Translational advances regarding hereditary breast cancer syndromes. AB - Approximately 5-10% of breast cancers may be inheritable, up to 90% of which are due to mutations in BRCA1 and BRCA2. A substantial minority are caused by non BRCA mutations, such as TP53, PTEN, STK11, CHEK2, ATM, BRIP1, and PALB2 mutations. This review highlights translational research advances with regard to the development of probabilistic models for hereditary breast cancer syndromes, the identification of specific genetic mutations responsible for these syndromes, as well as their testing and interpretations. PMID- 22441896 TI - The GP2 peptide: a HER2/neu-based breast cancer vaccine. AB - Preclinical studies suggest that GP2, a HER2/neu-derived peptide, is immunogenic. Subsequent phase I clinical trials demonstrated that GP2-based vaccines are safe and effective in stimulating peptide-specific immunity. A GP2 peptide vaccine is currently being evaluated in a phase II efficacy trial enrolling breast cancer patients. This article reviews initial studies characterizing GP2, clinical trials investigating GP2-based vaccines, and novel immunotherapy strategies incorporating GP2 in combination with other peptides or with the monoclonal antibody trastuzumab. PMID- 22441897 TI - Novel molecular screening approaches in colorectal cancer. AB - Traditional methods for colorectal cancer (CRC) screening have reduced rates of malignancy and death; however, low compliance and morbidities associated with invasive techniques have encouraged efforts for establishing equally effective, less invasive novel screening approaches. We review the current state of novel screening approaches in CRC to include CT colonography, fecal DNA, DNA methylation, micro-RNA, and protein and molecular markers. PMID- 22441899 TI - A new heart: somatic stem cells and myocardial regeneration. AB - End-stage heart failure is a global scourge. Current therapies merely delay its inexorable progression. Heart transplantation is resource-intensive and limited by organ availability. Bone marrow-derived and cardiac-specific stem cells have demonstrated potential for cardiac regeneration and repair, but the magnitude and durability of these promising findings are inconsistent. The purpose of this review is to (1) describe cells currently being investigated, (2) outline the status of current trials, and (3) discuss key objectives of future research. PMID- 22441898 TI - Molecular staging individualizing cancer management. AB - Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, approximately 30% of patients who are node negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy. PMID- 22441900 TI - Robotic surgery applications in the management of gynecologic malignancies. AB - This review evaluates the use of robotic-assisted laparoscopic surgery in the treatment of gynecologic malignancies and objectively evaluates the use of these systems in performing radical hysterectomies and surgical staging of gynecologic malignancies. The review focuses on surgical length, blood loss, complications, recovery time, and adequacy of surgical staging of robotic-assisted surgery compared to abdominal and non-robotically assisted laparoscopic surgery for malignancies. PMID- 22441901 TI - Translational advances in pain and anesthesia for cancer patients. AB - Effective cancer pain management requires multidisciplinary approaches for multimodal analgesia. Although opioids have been the cornerstone, developments such as regional anesthesia and interventional pain techniques, complementary and alternative medicine, and new pharmaceuticals also have shown promise to relieve cancer pain. This overview of relevant clinical efforts and the modern day state of the science will afford a better understanding of pain mechanisms and multimodal approaches beneficial in optimizing analgesia for cancer patients. PMID- 22441902 TI - The application of genomic and molecular data in the treatment of chronic cancer pain. AB - Many cancer patients will develop complex pain syndromes requiring aggressive, innovative, and comprehensive multimodal pain management strategies. Recently, data from both animal studies and clinical trials have allowed clinical research to focus on creating applicable clinical treatment strategies. This article is a review of genomic and molecular data, which has contributed to creating novel modalities for use in clinical pain management of patients with cancer-induced pain. PMID- 22441903 TI - Clinical decision support systems: potential with pitfalls. AB - Clinical Decision Support Systems (CDSS), an important part of clinical practice, are comprised of a: knowledge base; program for integrating patient-specific information with the knowledge-base; and, user-interface to allow clinicians to interact with the system and get the right information needed to make the right decision for the right patient at the right time. We review the common approaches to CDSS, their strengths and weaknesses and how they are evaluated and developed for clinical use. PMID- 22441904 TI - Graphophonological processes in dyslexic readers of French: a longitudinal study of the explicitness effect of tasks. AB - Given the well-acknowledged phonological deficit found in dyslexic children, this study was aimed at investigating graphophonological processes in dyslexic readers of French over a 1-year period. Among the different types of phonological processing can be distinguished those related to phonological awareness based on knowledge of the oral language and graphophonological processes based on correspondences between the oral and the written language. In this study, we evaluated graphophonemic and graphosyllabic processes using, in each case, two different tasks varying in the degree of cognitive constraint associated with the task (CC- vs CC+). Twenty 11 year-old dyslexic students were compared with younger normal-readers of the same reading level (RA, n=26) and to normal-readers of the same age (CA, n=24). Two variables were considered in the analyses: accuracy and response latency. Results show that dyslexic readers do process written items at the graphophonological level. Also, results indicate main effects of task (CC- vs CC+), time (T1 vs T2), and group (DYS vs RA vs CA). In general, dyslexic participants' performances are comparable to those of RA and differ from those of CA. PMID- 22441905 TI - Chemiluminescence from alkoxy-substituted acridinium dimethylphenyl ester labels. AB - Chemiluminescent acridinium dimethylphenyl ester labels are used in automated immunoassays for clinical diagnostics. Light emission from these labels is triggered by alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride (CTAC). The surfactant plays a critical role in the chemiluminescence process of these labels by both accelerating their emission kinetics and increasing total light output enabling high throughout and improved assay sensitivity in automated immunoassays. Despite the surfactant's crucial role in the chemiluminescent reaction, no study has investigated how structural perturbations in the acridinium ring could impact the influence of the surfactant. We describe herein the synthesis and properties of three new alkoxy substituted, acridinium dimethylphenyl esters where the nature of the alkoxy group in the acridinium ring was varied (hydrophobic or hydrophilic). Chemiluminescence measurements of these alkoxy-substituted labels indicate that hydrophilic functional groups in the acridinium ring, in particular sulfobetaine zwitterions, disrupt surfactant-mediated compression of emission times but not enhancement of light yield. These results support the hypothesis that surfactant mediated effects require the binding of two different reaction intermediates to surfactant aggregates and, that surfactants influence light emission from acridinium esters by two separate mechanisms. Our studies also indicate that preservation of both surfactant effects on acridinium ester chemiluminescence and low non-specific binding of the label can be achieved with a relatively hydrophobic acridinium ring coupled to a hydrophilic phenolic ester leaving group. PMID- 22441906 TI - Gendered endings: narratives of male and female suicides in the South African Lowveld. AB - Durkheim's classical theory of suicide rates being a negative index of social solidarity downplays the salience of gendered concerns in suicide. But gendered inequalities have had a negative impact: worldwide significantly more men than women perpetrate fatal suicides. Drawing on narratives of 52 fatal suicides in Bushbuckridge, South Africa, this article suggests that Bourdieu's concepts of 'symbolic violence' and 'masculine domination' provide a more appropriate framework for understanding this paradox. I show that the thwarting of investments in dominant masculine positions have been the major precursor to suicides by men. Men tended to take their own lives as a means of escape. By contrast, women perpetrated suicide to protest against the miserable consequences of being dominated by men. However, contra the assumption of Bourdieu's concept of 'habitus', the narrators of suicide stories did reflect critically upon gender constructs. PMID- 22441907 TI - The competency-based mandate for emergency bedside sonography training and a tale of two residency programs. PMID- 22441908 TI - Submandibular sonography: assessment of hyomental distances and ratio, tongue size, and floor of the mouth musculature using portable sonography. AB - OBJECTIVES: The aim of this study was to evaluate the feasibility of sonography as a tool to measure the hyomental distance ratio and tongue size in obese patients with a large neck circumference. The hyomental distance ratio is a predictor of difficult laryngoscopy that may result in difficult intubation. METHODS: Five obese and 7 morbidly obese adult patients with a history of either difficult or easy intubation had a submandibular sonographic examination performed in the supine position. The hyomental distance was measured while the head was placed in the neutral position and then in a hyperextended position, and the ratio of two distances (hyomental distance ratio) was calculated. Their tongue volumes were derived from multiplication of the midsagittal cross sectional area of the tongue by its width obtained from transverse sonograms. RESULTS: The mean hyomental distance ratios +/- SD in 6 patients with difficult intubation and 6 with easy intubation were 1.02 +/- 0.01 and 1.14 +/- 0.02 (P < .002), respectively. Tongue volumes did not differ statistically between the two groups: 137 +/- 29 cm(3) (difficult intubation) and 168 +/- 34 cm(3) (easy intubation). The mean body mass indices were 36.3 +/- 6.0 and 43.2 +/- 7.2 kg/m(2) in the difficult and easy intubation groups. The mean neck circumferences were 44.5 +/- 7.4 and 46.8 +/- 7.0 cm in the difficult and easy intubation groups. CONCLUSIONS: Sonography allows bedside measurements of the hyomental distance ratio and tongue size in morbidly obese patients. Preoperative assessment of the hyomental distance ratio may predict difficult laryngoscopy resulting in difficult intubation. PMID- 22441909 TI - Comparison of Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading. AB - OBJECTIVES: To determine the relative wash-out of hepatocellular carcinomas and dysplastic nodules using Kupffer-phase sonography with Sonazoid (Daiichi-Sankyo, Tokyo, Japan) enhancement and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging (MRI) in the evaluation of the histopathologic grades of individual nodules. METHODS: This retrospective study included 66 consecutive patients with 78 histologically confirmed hepatocellular carcinomas and dysplastic nodules. In patients with carcinomas, 33 were well differentiated; 29 were moderately differentiated; and 11 were poorly differentiated; and there were 5 dysplastic nodules. All patients underwent both gadoxetic acid-enhanced MRI and Sonazoid-enhanced sonography. The interval between the two imaging examinations was less than 30 days. Six radiologists independently reviewed both images and rated the degree of relative wash-out between the tumorous and nontumorous areas on Kupffer- and hepatobiliary-phase images using a continuous rating scale. We compared these results with the histopathologic grade of each nodule, and the results were then analyzed with multireader multicase receiver operating characteristic analysis. RESULTS: The average Kupffer-phase (P < .001) and hepatobiliary-phase (P = .004) rating scores increased as the carcinomas became less differentiated (Kruskal-Wallis test). The diagnostic accuracies of the average area under the receiver operating characteristic curve, which were estimated using the confidence levels of the relative wash-out of the Kupffer- and hepatobiliary-phase images, were 0.705 and 0.785 for dysplastic nodules versus well-, moderately, and poorly differentiated carcinomas (P = .517), 0.791 and 0.687 for dysplastic nodules and well-differentiated carcinomas versus moderately and poorly differentiated carcinomas (P = .093), and 0.871 and 0.716 for dysplastic nodules and well-and moderately differentiated carcinomas versus poorly differentiated carcinomas (P = .005), respectively. CONCLUSIONS: Kupffer phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid enhanced MRI may be useful in estimating the histologic grade, although Kupffer phase Sonazoid-enhanced sonography may be more accurate in distinguishing hepatocellular carcinomas, especially moderately and poorly differentiated types. PMID- 22441910 TI - Splenic hemangiomas: contrast-enhanced sonographic findings. AB - OBJECTIVES: The purpose of this study was to illustrate the baseline appearance and enhancement patterns of splenic hemangiomas on contrast-enhanced sonography. METHODS: Two experienced radiologists retrospectively reviewed by consensus baseline and contrast-enhanced sonographic examinations of 27 patients (14 women and 13 men; mean age, 58.7 years) with 27 splenic hemangiomas (mean size, 2 cm) confirmed by splenectomy, biopsy, computed tomography, and magnetic resonance imaging and follow-up. RESULTS: On baseline sonography, 77.8% of the lesions showed a homogeneous echo texture that was mainly hyperechoic. Color Doppler imaging did not show any signal in 81.5% of the cases. After contrast agent injection, 59.2% of the splenic hemangiomas showed different degrees of contrast enhancement in the arterial phase followed by isoenhancement in the late parenchymal phase. Among these, 2 hemangiomas showed peripheral globular enhancement in the arterial phase, followed by progressive centripetal fill-in. In 29.6% of the cases, some degree of contrast enhancement was appreciable, but the hemangiomas remained substantially hypoechoic throughout the contrast enhanced sonographic examinations, whereas in 11.1%, the combination of contrast enhancement in the arterial phase followed by wash-out in the late parenchymal phase was evident. CONCLUSIONS: Isoechogenicity to spleen parenchyma in all phases is the most frequent typical enhancement pattern of splenic hemangiomas observed on contrast-enhanced sonography. Nevertheless, these lesions may show atypical contrast enhancement patterns; therefore, further assessment with cross sectional techniques is needed. PMID- 22441911 TI - Prevalence of noncardiac structural anomalies in twin-twin transfusion syndrome. AB - OBJECTIVES: Compared to singleton pregnancies, monochorionic twins have increased rates of perinatal morbidity and mortality, believed due in part to both twin twin transfusion syndrome and an increased risk of congenital anomalies. Here we describe the prevalence of noncardiac structural anomalies in monochorionic twins with twin-twin transfusion syndrome who underwent laser surgery. METHODS: In a retrospective study of 221 consecutive cases of twin-twin transfusion syndrome treated with laser surgery, noncardiac anomalies were identified by review of antepartum and neonatal medical records. RESULTS: Of 377 live-born twins, 19 (5.0%) had a noncardiac anomaly. This rate was increased for donor versus recipient twins (8.5% versus 2.0%; P < .01). The presence of an anomaly was unrelated to the Quintero stage, the presence of donor intrauterine growth restriction, or 30-day survival of the donor or recipient. CONCLUSIONS: The prevalence of noncardiac anomalies in pregnancies complicated by twin-twin transfusion syndrome who underwent laser surgery was higher in donors versus recipients. PMID- 22441912 TI - Diagnosis of congenital heart disease by early and second-trimester fetal echocardiography. AB - OBJECTIVES: The aim of this study was to compare the cardiac findings at 11 to 14 weeks' gestation with the second-trimester findings to evaluate the reliability of first-trimester echocardiography and the possibility of congenital heart disease evolution. METHODS: The database of our fetal medicine unit was searched for all patients who had undergone fetal echocardiography at 11 to 14 and 18 to 22 weeks' gestation from 2005 to 2010. In all of the antenatally suspected cases of congenital heart disease, the diagnosis was established conclusively by postnatal echocardiography, surgery, or autopsy. RESULTS: Among the 870 fetuses included in the study, 802 were considered to have no abnormalities on both examinations. Thirty-six cases had abnormal findings on both examinations, and 32 had discordant findings. Among the 32 discordant findings, 6 cases had a false positive diagnosis of congenital heart disease on early echocardiography, and 26 had a different diagnosis. In 14 of these 26 cases, the diagnosis was slightly different on the second-trimester examination, or the defect misdiagnosed in the first trimester was a minor one. In 6 of the remaining 12 fetuses, a major congenital heart disease was missed on the early echocardiography. In 6 cases, the congenital heart disease developed or progressed in severity in the second trimester. CONCLUSIONS: First-trimester echocardiography is feasible and seems to allow considerably earlier detection of major congenital heart disease. However, it should be kept in mind that although most forms of heart defects can be diagnosed early in pregnancy, some may develop and become apparent only later in gestation. PMID- 22441913 TI - Craniofacial inclination at 14 to 39 weeks' gestation in normal Korean fetuses. AB - OBJECTIVES: The purpose of this study was to evaluate a normal range for prenatal craniofacial inclination using images of fetal profiles at 14 to 39 weeks' gestation in normal Korean fetuses. METHODS: We conducted a cross-sectional study of 308 normal fetuses at 14 to 39 weeks' gestation. After the exclusion of images with inadequate quality, the sagittal plane of the sonographic fetal facial profile from 250 normal fetuses was evaluated. The frontomaxillary facial, frontonasal, maxilla-nasion-mandibular, and mandibulomaxillary facial angles were measured and are presented according to gestational age. RESULTS: The overall mean frontomaxillary facial angle +/- SD was 86.0 degrees +/- 7.6 degrees between 14 weeks 6 days' and 39 weeks 2 days' gestation without a significant association between the frontomaxillary facial angle and gestational week. The overall mean frontonasal, maxilla-nasion-mandibular, and mandibulomaxillary facial angles were 125.8 degrees +/- 7.2 degrees , 4.7 degrees +/- 3.3 degrees , and 83.2 degrees +/- 8.5 degrees between 14 weeks and 39 weeks 6 days. There was a significant linear correlation between gestational age and the frontonasal angle (r = -0.1534; P = .0187; y = -0.188 * gestational age + 130.7), maxilla nasion-mandibular angle (r = -0.2773; P < .0001; y = -0.160 * gestational age + 9.0), and mandibulomaxillary facial angle (r = -0.2861; P < .0001; y = -0.432 * gestational age + 94.6). CONCLUSIONS: We provide preliminary normative data for fetal facial angles related to craniofacial inclination across gestational ages in normal Korean fetuses. These data may be of help not only for the understanding of normal facial growth in utero but also for diagnosis of abnormal fetal facial dimensions. PMID- 22441914 TI - Resolution of complete placenta previa: does prior cesarean delivery matter? AB - OBJECTIVES: The purpose of this study was to prospectively assess the rate of resolution of complete placenta previa diagnosed at second-trimester sonography in patients with and without previous cesarean delivery. METHODS: This prospective study evaluated patients at 3 institutions with complete placenta previa diagnosed at second-trimester screening sonography. All patients were followed with sonography every 4 to 6 weeks until either resolution of the previa or delivery occurred. Patients with persistent/nonresolving complete placenta previa underwent cesarean delivery. RESULTS: A total of 67 patients were enrolled in the study; 18 patients had a prior cesarean delivery. Resolution of placenta previa occurred in 11 of 18 patients (61%) with a prior cesarean delivery, whereas 44 of 49 patients (90%) without a prior cesarean delivery had resolution of placenta previa (P = .012, Fisher exact test). Placental location per se (anterior or posterior) was not associated with resolution of placenta previa (P = .22). Complete placenta previa persisted to delivery in 5 of 9 patients (56%) with a prior cesarean delivery and an anterior placental location. CONCLUSIONS: This prospective study indicates that patients with a prior cesarean delivery and complete placenta previa diagnosed at second-trimester sonography are less likely to have subsequent resolution of the previa when compared to those without a history of cesarean delivery. PMID- 22441915 TI - Complex breast masses: assessment of malignant potential based on cyst diameter. AB - OBJECTIVES: The purpose of this study was to assess whether cyst diameter might contribute to the prediction of malignancy in complex breast masses. METHODS: In this cross-sectional study, we identified 48 breast masses that had sonographic features suggestive of benign breast lesions (oval shape, circumscribed margins, parallel axis, and abrupt limits). However, these masses were classified as Breast Imaging Reporting and Data System (BI-RADS) category 4 because of the presence of at least 1 cyst (complex echogenicity). All breast masses were biopsied (25 core needle and 23 core needle and excision). Subsequent histologic analysis was performed, and 12 malignancies (25%) were identified. Mammographic features were reviewed. Different sonographic measurements (largest diameters of the mass and cyst and vascular pattern) were assessed for the detection of malignancy. RESULTS: Among the sonographic features, the vascular pattern, ie, the detection of blood flow (present in the lesion [P >.99] or present immediately adjacent to the lesion [P = .46]), was not associated with malignancy, whereas the largest mass and cyst dimensions had significantly positive correlations (P = .02; P < .001, respectively) with tumor malignancy. In receiver operating characteristic curve analysis, the point with the highest sum of sensitivity and specificity corresponded to a maximum cyst diameter of 8 mm (sensitivity, 67%; specificity, 86%). The positive and negative predictive values at that cutoff point were 61% and 86%, respectively. The area under the curve was 0.772. In this study, all masses with cysts smaller than 3 mm in diameter (7 cases) were benign, and all masses with cysts larger than 13 mm in diameter (4 cases) were malignant. CONCLUSIONS: Cyst diameter is a good predictor of malignancy in complex breast masses, which, except for the presence of internal cysts, would be otherwise classified as BI-RADS category 3. PMID- 22441916 TI - Thyroid lymphoma: correlation of radiologic and pathologic features. AB - OBJECTIVES: The purpose of this study was to correlate the clinicoradiologic and pathologic features of thyroid lymphoma and to identify the most useful diagnostic method for thyroid lymphoma as the first line. METHODS: Our study population included 16 patients with a diagnosis of thyroid lymphoma by fine needle aspiration, core biopsy, or surgery from 1995 to 2010. We retrospectively reviewed imaging and medical records. Sonographic findings were correlated with histopathologic results. RESULTS: Of the 16 patients, primary lymphomas were found in 13 and secondary in 3. The mean ages of the patients with primary and secondary lymphomas were 60.8 and 42.7 years, respectively. Most patients with primary lymphomas had symptoms of rapid neck swelling or a mass sensation. All primary lymphomas revealed non-Hodgkin B-cell lymphoma, and secondary lymphomas included a B-cell origin in 2 and a T-cell origin in 1. On sonography, 10 (77%) of 13 primary lymphomas showed diffuse heterogeneous hypoechoic parenchyma with intervening echogenic septa-like structures, whereas all secondary lymphomas showed markedly hypoechoic nodules. Markedly hypoechoic parenchyma was correlated with lymphoepithelial lesions and neoplastic cells, whereas the intervening echogenic septa-like structures were consistent with fibrosis on pathologic examination. The exact diagnosis of thyroid lymphoma was possible with core biopsy in all 9 cases (100%) but with fine-needle aspiration in only 3 of 10 (30%), which included 7 under sonographic guidance and 3 under palpation (P = .0030). CONCLUSIONS: Diffuse hypoechoic parenchyma with intervening echogenic septa on sonography under the impression of a primary thyroid lymphoma, particularly in the setting of a rapidly enlarging mass, should prompt core biopsy rather than fine-needle aspiration. PMID- 22441917 TI - Assessment of quantitative perfusion parameters by dynamic contrast-enhanced sonography using a deconvolution method: an in vitro and in vivo study. AB - OBJECTIVES: The purpose of this study was to investigate the impact of the arterial input on perfusion parameters measured using dynamic contrast-enhanced sonography combined with a deconvolution method after bolus injections of a contrast agent. METHODS: The in vitro experiments were conducted using a custom made setup consisting of pumping a fluid through a phantom made of 3 intertwined silicone pipes, mimicking a complex structure akin to that of vessels in a tumor, combined with their feeding pipe, mimicking the arterial input. In the in vivo experiments, B16F10 melanoma cells were xenografted to 5 nude mice. An ultrasound scanner combined with a linear transducer was used to perform pulse inversion imaging based on linear raw data throughout the experiments. A mathematical model developed by the Gustave Roussy Institute (patent WO/2008/053268) and based on the dye dilution theory was used to evaluate 7 semiquantitative perfusion parameters directly from time-intensity curves and 3 quantitative perfusion parameters from the residue function obtained after a deconvolution process developed in our laboratory based on the Tikhonov regularization method. We evaluated and compared the intraoperator variability values of perfusion parameters determined after these two signal-processing methods. RESULTS: In vitro, semiquantitative perfusion parameters exhibited intraoperator variability values ranging from 3.39% to 13.60%. Quantitative parameters derived after the deconvolution process ranged from 4.46% to 11.82%. In vivo, tumors exhibited perfusion parameter intraoperator variability values ranging from 3.74% to 29.34%, whereas quantitative ones varied from 5.00% to 12.43%. CONCLUSIONS: Taking into account the arterial input in evaluating perfusion parameters improves the intraoperator variability and may improve the dynamic contrast enhanced sonographic technique. PMID- 22441918 TI - A novel saline infusion sonohysterography-based strain imaging approach for evaluation of uterine abnormalities in vivo: preliminary results. AB - In this article, we demonstrate the feasibility of saline infusion sonohysterography-based strain imaging for the determination of stiffness variations in uterine masses in vivo. Strain images are estimated using a 2 dimensional multilevel hybrid algorithm developed for sector array ultrasound transducers. Coarse displacements are initially estimated using envelope echo signals, followed by a guided finer displacement estimation using window lengths on the order of 6 wavelengths and 7 A-lines on radiofrequency data. Strain images are obtained by estimating displacement slopes using least squares estimation. In this prospective study, we show that stiffer masses such as fibroids appear darker or as regions with low strain on strain images and are thus clearly differentiated when compared to normal uterine tissue. A high strain boundary around stiffer masses referred to as a "halo" due to increased slipping or sliding of the mass during the applied deformation is also visualized. Uterine polyps, on the other hand, are visualized as masses that are brighter or regions with high strain when compared to the background myometrium, indicating the presence of a softer mass. Axial strain images provide additional new information that may supplement current clinical B-mode imaging used for the diagnosis of uterine abnormalities. Our results show the feasibility of improving clinical diagnosis based on strain imaging. PMID- 22441919 TI - Sonographically guided percutaneous intralesional triamcinolone injection: a new treatment for mammillary fistulas: preliminary results. AB - We describe a new procedure, sonographically guided intralesional triamcinolone injection, for the treatment of mammillary fistulas. Six patients with mammillary fistulas were enrolled in this prospective study. Clinical improvement was rapid after the first triamcinolone injection. The initial response to treatment was assessed as complete in 4 cases, and the remaining 2 cases resolved successfully with additional injections. On the basis of the excellent results obtained in this study, it is thought that intralesional triamcinolone injection may be a good alternative to surgery. PMID- 22441921 TI - Lithium nephropathy: unique sonographic findings. AB - This case series describes a unique sonographic appearance consisting of numerous microcysts and punctate echogenic foci seen on renal sonograms of 10 adult patients receiving chronic lithium therapy. Clinically, chronic renal insufficiency was present in 6 and nephrogenic diabetes insipidus in 2. Sonography showed numerous microcysts and punctate echogenic foci. Computed tomography in 5 patients confirmed microcysts and microcalcifications, which were fewer in number than on sonography. Magnetic resonance imaging in 2 patients confirmed microcysts in each case. Renal biopsy in 1 patient showed chronic interstitial nephritis, microcysts, and tubular dilatation. The diagnosis of lithium nephropathy should be considered when sonography shows these findings. PMID- 22441920 TI - Overview of therapeutic ultrasound applications and safety considerations. AB - Applications of ultrasound in medicine for therapeutic purposes have been accepted and beneficial uses of ultrasonic biological effects for many years. Low power ultrasound of about 1 MHz has been widely applied since the 1950s for physical therapy in conditions such as tendinitis and bursitis. In the 1980s, high-pressure-amplitude shock waves came into use for mechanically resolving kidney stones, and "lithotripsy" rapidly replaced surgery as the most frequent treatment choice. The use of ultrasonic energy for therapy continues to expand, and approved applications now include uterine fibroid ablation, cataract removal (phacoemulsification), surgical tissue cutting and hemostasis, transdermal drug delivery, and bone fracture healing, among others. Undesirable bioeffects can occur, including burns from thermal-based therapies and severe hemorrhage from mechanical-based therapies (eg, lithotripsy). In all of these therapeutic applications of ultrasound bioeffects, standardization, ultrasound dosimetry, benefits assurance, and side-effect risk minimization must be carefully considered to ensure an optimal benefit to risk ratio for the patient. Therapeutic ultrasound typically has well-defined benefits and risks and therefore presents a manageable safety problem to the clinician. However, safety information can be scattered, confusing, or subject to commercial conflicts of interest. Of paramount importance for managing this problem is the communication of practical safety information by authoritative groups, such as the American Institute of Ultrasound in Medicine, to the medical ultrasound community. In this overview, the Bioeffects Committee of the American Institute of Ultrasound in Medicine outlines the wide range of therapeutic ultrasound methods, which are in clinical use or under study, and provides general guidance for ensuring therapeutic ultrasound safety. PMID- 22441922 TI - Sonographic and magnetic resonance imaging findings in uterine incarceration. AB - We show the sonographic and magnetic resonance imaging features of uterine incarceration. Clinical data and imaging findings were retrospectively reviewed for 8 confirmed cases identified by sonography from 2000 to 2010. Two patients had magnetic resonance imaging. Seven of 8 patients (87.5%) presented with abdominal pain; 4 of 8 (50.0%) also had urinary symptoms. All had a retroverted uterus with an elongated anterosuperiorly displaced or poorly visualized cervix on sonography. Magnetic resonance imaging showed similar features, but in both cases, the placental position was misinterpreted because of severe uterine retroversion. Radiologists should be aware of this condition and its imaging features to reduce associated morbidity and mortality. PMID- 22441923 TI - Sonography should be the first imaging examination done to evaluate patients with suspected endometriosis. PMID- 22441924 TI - Prenatal diagnosis of a fetal double-outlet right ventricle with tricuspid valve atresia, a straddling mitral valve, and a hypoplastic left ventricle. PMID- 22441925 TI - Sonographic and computed tomographic fusion: imaging features of nonseminomatous testicular carcinoma in transverse testicular ectopia. PMID- 22441926 TI - Deep vein thrombosis simulating hamstring injury on sonography. PMID- 22441927 TI - Minimum menstrual age and embryonic death. PMID- 22441929 TI - In the measurement of amniotic fluid vertical pockets, are all pockets of similar depth the same? PMID- 22441932 TI - Effect of chemotherapy on survival after whole brain radiation therapy for brain metastases: a single-center retrospective analysis. AB - BACKGROUND AND PURPOSE: Whether chemotherapy for systemic disease affects survival of patients with brain metastases or not has not been elucidated before. We performed comprehensive analysis of patients with newly-diagnosed brain metastases primarily treated with whole brain radiation therapy (WBRT) alone. MATERIALS AND METHODS: Data from 134 patients with newly-diagnosed brain metastases primarily treated with WBRT from 2007 to 2008 was retrospectively reviewed. Univariate and multivariate analyses were performed to identify significant prognostic factors. RESULTS: Median survival time (MST) of this cohort from the start of WBRT was 5.7 months. MST of patients with RPA Class 1, 2 and 3 were 10.3, 7.8 and 2.2 months, respectively. Multivariate analysis revealed that karnofsky performance status (>= 70, p < 0.0001), gender (female, p < 0.0001), activity of extracranial disease (stable, p = 0.015), time to develop brain metastasis (<3 months, p = 0.042) and use of chemotherapy after WBRT (multiple regimens, p < 0.0001) were independent prognostic factors for better survival. CONCLUSIONS: Systemic chemotherapy for chemo-responsive cancer prolongs survival despite the presence of treated brain metastases. Irradiated brain metastases will lose their prognostic significance in a large number of patients. Systemic chemotherapy will be a treatment of choice for patients who have systemic disease after WBRT for brain metastases. These results should be validated in the future prospective clinical trials. PMID- 22441933 TI - Clinical outcomes of adult and childhood rhabdomyosarcoma treated with vincristine, d-actinomycin, and cyclophosphamide chemotherapy. AB - BACKGROUND: Outcomes in adult patients with rhabdomyosarcoma are poor, with a 5 year survival rate of approximately 30 %. The current study aimed to compare the clinical outcomes of adult and childhood rhabdomyosarcoma patients with local and metastatic disease and to examine the impact and timing of local therapy on metastasis. METHODS: Clinicopathological features and patient outcomes were reviewed retrospectively for rhabdomyosarcoma patients receiving chemotherapy between 1981 and 2010 at our institution. Adults were defined as those aged 21 years or older. RESULTS: Of the 98 patients identified, 36 were adults (median age, 29; range, 21-72) and 62 were children (median age, 11; range, 0.6-20). Median progression-free survival of localized and metastatic disease for children and adults was as follows: localized disease, 166.9 versus 22.4 months (p = 0.005), and metastatic disease, 13.3 versus 13.3 months (p = 0.949), respectively. Multivariate regression analysis revealed that older age (>= 21 vs. <21) was a significant poor prognostic factor in localized disease. Conversely, age was not related to survival in metastatic disease. Receiving radiotherapy to the primary site was an independent factor indicating a better prognosis. An analysis of the optimal timing of local therapy was performed for 53 patients; however, its significance on survival could not be determined. CONCLUSIONS: Age was a negative prognostic factor in rhabdomyosarcoma patients with localized disease, but it did not affect the survival in metastatic disease. For metastatic disease, although local therapies may be effective for survival, the timing of such therapies should be determined individually. PMID- 22441934 TI - Overexpression and ratio disruption of DeltaNp63 and TAp63 isoform equilibrium in endometrial adenocarcinoma: correlation with obesity, menopause, and grade I/II tumors. AB - PURPOSE: p63 plays an important role in several intracellular processes such as transcription activation and apoptosis. p63 has two N-terminal isoforms, TAp63 and DeltaNp63. TAp63 isoform has p53-like functions, while DeltaNp63 acts as a dominant negative inhibitor of the p53 family and is considered oncogenic. Although p63 and its isoforms are overexpressed in a wide variety of human malignancies such as cervical, head and neck, and lung cancer, their role in endometrial carcinoma has not been investigated. METHODS: We measured by quantitative real-time polymerase chain reaction the mRNA expression of TAp63 and DeltaNp63 in a series of 20 endometrioid adenocarcinomas paired with adjacent normal tissue. RESULTS: TAp63 isoform exhibited 1.8-fold overexpression in malignant samples, while DeltaNp63 was 4.3-fold overexpressed in cancer specimens. Further analysis revealed that the DeltaN/TA isoform ratio shifted from 0.5 in normal samples to 1.2 in tumor specimens. Statistical analysis also revealed an association of TAp63 expression with high body mass index (p = 0.034), late menopause (p = 0.020), and lower tumor grade (p = 0.034). DeltaNp63 was also correlated with grade I/II tumors (p = 0.044). CONCLUSIONS: These results indicate that both p63 isoforms and especially DeltaNp63 play an important role in the development and progression of grade I/II endometrial adenocarcinoma, especially in obese and late-menopause women. PMID- 22441935 TI - Comparative outcomes for patients who do and do not undergo percutaneous coronary intervention for stable coronary artery disease in New York. AB - BACKGROUND: Little is known about what treatments patients receive after being diagnosed with stable coronary artery disease or what the comparative outcomes are for routine medical treatment (RMT) versus percutaneous coronary intervention (PCI) with RMT for patients in a setting apart from randomized controlled trials. METHODS AND RESULTS: Patients with stable coronary artery disease undergoing cardiac catheterization in New York State between 2003 and 2008 were followed up to determine the treatment they received. Patients receiving RMT and patients receiving PCI with RMT were propensity matched through the use of 20 factors that could have a bearing on outcomes. The resulting cohort of 933 matched pairs was used to compare mortality/myocardial infarction (MI), mortality, MI, and subsequent revascularization rates. A total of 89% of all patients underwent PCI with RMT. PCI/RMT patients had significantly lower adverse outcome rates at 4 years for mortality/MI (16.5% versus 21.2%; P=0.003), mortality (10.2% versus 14.5%; P=0.02), MI (8.0% versus 11.3%; P=0.007), and subsequent revascularization (24.1% versus 29.1%; P=0.005). Adjusted RMT versus (PCI with RMT) hazard ratios were 1.49 (95% confidence interval, 1.16-1.93) for mortality/MI and 1.46 (95% confidence interval, 1.08-1.97) for mortality. There were no differences for patients <= 65 years of age or for patients with single-vessel disease. CONCLUSIONS: Most patients with stable coronary artery disease in New York undergoing catheterization between 2003 and 2008 received PCI. Patients who received PCI experienced lower mortality, mortality/MI, and revascularization rates. The reasons for this finding need to be better understood, including the possible role of low medication adherence rates that have been found in other studies. PMID- 22441936 TI - Weighing the evidence for decision making about percutaneous coronary intervention in patients with stable coronary artery disease. PMID- 22441937 TI - An efficient flow-photochemical synthesis of 5H-furanones leads to an understanding of torquoselectivity in cyclobutenone rearrangements. PMID- 22441938 TI - PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells. AB - PDE inhibitors could increase cellular cGMP levels and are used to treat erectile dysfunction as well as pulmonary arterial hypertension. cGMP production was reported to be necessary for UVB-induced melanin synthesis, however, the effect of PDE5 inhibitor on melanin synthesis has not been examined. We found that PDE5 inhibitor (sildenafil or vardenafil) and the cGMP analog 8-CPT-cGMP stimulated CREB phosphorylation, leading to increased tyrosinase expression and melanin synthesis, which was counteracted by KT5823, a selective cGMP-dependent protein kinase (PKG) inhibitor. However, KT5823 did not affect cAMP-elevating agent mediated melanin synthesis, indicating that KT5823 selectively inhibited cGMP induced melanin synthesis. This is the first study to find that PDE5 inhibitor can promote melanin synthesis and reveal that PKG-dependent CREB phosphorylation and tyrosinase expression is involved in cGMP-induced melanin synthesis. Our results suggest that PDE5 inhibitor may be beneficial for the treatment of hypopigmentation diseases. PMID- 22441939 TI - Antiviral effect of the egg wax of Amblyomma cajennense (Acari: Ixodidae). AB - The control of viral infections, especially those caused by influenza viruses, is of great interest in Public Health. Bio prospection has shown the presence of active principles in the hemolymph of arthropods, and in the salivary gland of ticks, and some of these are of interest for the development of new pharmacological drugs. Ticks lay their eggs in the environment, and to protect them from desiccation and microbial attack they involve the eggs in a waxy layer produced by an organ known as Gene's Organ. In this study, the eggs wax from tick Amblyomma cajennense (Fabricius) was extracted using ice cold phosphate buffer. The antiviral activity was evaluated with picornavirus and influenza virus. In both cases egg wax was able to inhibit virus replication. For influenza virus, an amount as small as 12 MUg/mL of crude egg wax suspension neutralized 128 UHA (hemaglutinant unit) of H(1)N(1) influenza virus. With picornavirus, egg wax led to a 256-fold reduction in virus production by L929 cells. Egg wax was not cytotoxic to VERO, MDCK and L929 cell, being observed that the cell morphology was preserved with concentration as high as 2 mg/mL. In addition no genotoxic effect was observed for Vero cells, suggesting a very interesting potential antiviral activity. PMID- 22441940 TI - [Pulmonary alveolar proteinosis]. PMID- 22441954 TI - [Prohibition of competition clauses in group practice contracts - under what circumstances are these allowed?]. PMID- 22441956 TI - Standard errors and confidence intervals in within-subjects designs: generalizing Loftus and Masson (1994) and avoiding the biases of alternative accounts. AB - Repeated measures designs are common in experimental psychology. Because of the correlational structure in these designs, the calculation and interpretation of confidence intervals is nontrivial. One solution was provided by Loftus and Masson (Psychonomic Bulletin & Review 1:476-490, 1994). This solution, although widely adopted, has the limitation of implying same-size confidence intervals for all factor levels, and therefore does not allow for the assessment of variance homogeneity assumptions (i.e., the circularity assumption, which is crucial for the repeated measures ANOVA). This limitation and the method's perceived complexity have sometimes led scientists to use a simplified variant, based on a per-subject normalization of the data (Bakeman & McArthur, Behavior Research Methods, Instruments, & Computers 28:584-589, 1996; Cousineau, Tutorials in Quantitative Methods for Psychology 1:42-45, 2005; Morey, Tutorials in Quantitative Methods for Psychology 4:61-64, 2008; Morrison & Weaver, Behavior Research Methods, Instruments, & Computers 27:52-56, 1995). We show that this normalization method leads to biased results and is uninformative with regard to circularity. Instead, we provide a simple, intuitive generalization of the Loftus and Masson method that allows for assessment of the circularity assumption. PMID- 22441957 TI - The structure of short-term memory scanning: an investigation using response time distribution models. AB - A classic question in cognitive psychology concerns the nature of memory search in short-term recognition. Despite its long history of investigation, however, there is still no consensus on whether memory search takes place serially or in parallel or is based on global access. In the present investigation, we formalize a variety of models designed to account for detailed response time distribution data in the classic Sternberg (Science 153: 652-654, 1966) memory-scanning task. The models vary in their mental architectures (serial exhaustive, parallel self terminating, and global access). Furthermore, the component processes within the architectures that make match/mismatch decisions are formalized as linear ballistic accumulators (LBAs). In fast presentation rate conditions, the parallel and global access models provide far better accounts of the data than does the serial model. LBA drift rates are found to depend almost solely on the lag between study items and test probes, whereas response thresholds change with memory set size. Under slow presentation rate conditions, even simple versions of the serial-exhaustive model provide accounts of the data that are as good as those of the parallel and global access models. We provide alternative interpretations of the results in our General Discussion. PMID- 22441958 TI - Using ecphoric confidence ratings to discriminate seen from unseen faces: the effects of retention interval and distinctiveness. AB - Theories of confidence processing for recognition judgments suggest that confidence indexes the degree of match between a presented stimulus and an image in memory (ecphoric similarity). Recent research has demonstrated that having participants rate their confidence that a face had been previously seen provides an equivalent or a better index of the stimulus's status than does eliciting a simple binary response (Sauer, Brewer, & Weber, Journal of Experimental Psychology: General 137: 528-547, 2008). Using a face recognition paradigm, we manipulated retention interval and stimulus distinctiveness to directly test the suggestion that confidence indexes ecphoric similarity and to probe the boundary conditions for using confidence ratings to discriminate seen from unseen faces. Consistent with the proposed ecphoric basis for confidence ratings, mean confidence was higher for previously seen than for unseen faces, and conditions conducive to the formation of strong memories improved confidence-based discrimination. In all conditions, after the application of a classification algorithm, confidence ratings provided a more sensitive index of face status (i.e., seen or unseen) than did binary responses. PMID- 22441959 TI - Analgesic effect of electroacupuncture on inflammatory pain in collagen-induced arthritis rats: mediation by alpha2- and beta-adrenoceptors. AB - This study was designed to investigate whether alpha- and beta-adrenergic systems mediate the analgesic effect of electroacupucture (EA) on inflammatory pain in a rat model of collagen-induced arthritis (CIA). To induce CIA, male Sprague-Dawley rats were immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant, followed by a booster injection 14 days later. After induction of arthritis, the inflammatory pain threshold by the tail flick latency decreased as time passed and reached the minimum value at 4th week. Four weeks after the first immunization, low-frequency EA stimulation (2 Hz, 0.07 mA, 0.3 ms) delivered to Zusanli (ST(36)) for 30 min showed the analgesic effect. And also, the analgesic effect of EA was blocked by pretreatment with yohimbine (alpha2-adrenoceptor antagonist, 2 mg/kg, i.p.), but not by pretreatment with prazosin (alpha1-adrenoceptor antagonist, 1 mg/kg, i.p.) and propranolol (non selective beta-adrenoceptor antagonist, 10 mg/kg, i.p.). These results suggest that the low-frequency EA can relieve the inflammatory pain in CIA, and the analgesic effect of EA can be mediated by alpha2- and beta-adrenoceptor, but not by alpha1-adrenoceptor. PMID- 22441960 TI - Changes in synovial fluid biochemical markers following arthroscopic surgery in patients with knee osteoarthritis. AB - Although arthroscopic surgery (AS) for knee osteoarthritis has been widely employed, scientific evidence is lacking. The purpose of this study was to investigate temporal changes in synovial fluid levels of biochemical markers associated with cartilage metabolism following AS. Twenty-five knees of 24 patients with medial knee osteoarthritis (mean age 70.5 years) were included in this study. Synovial fluids were sampled immediately before surgery and 2, 4, 8, and 12 weeks after AS. Levels of the biochemical markers chondroitin 6-sulfate (C6S), chondroitin 4-sulfate (C4S), and keratan sulfate (KS) were measured and correlations among the biochemical markers were analyzed before and after surgery. C6S, C4S, and total CS levels were the same before and after surgery; however, the KS level decreased significantly at 2 weeks after AS. A strong, positive correlation was detected between C6S and KS levels at 12 weeks, differing from the weaker correlation seen before surgery. Seven of the patients required total or unicompartmental knee arthroplasties in the 2 years following AS. In this study, the significant reduction in KS levels and the strong correlation between C6S and KS levels were shown, which indicates suppressed cartilage turnover after AS. Exploring predictive factors indicating favorable or unfavorable outcomes from AS will be important future studies. PMID- 22441961 TI - Sleep disturbance in Moroccan patients with ankylosing spondylitis: prevalence and relationships with disease-specific variables, psychological status and quality of life. AB - Sleep disturbance is often reported by the patients with ankylosing spondylitis (AS), with awakenings produced by inflammatory pain. There are limited studies about sleep disturbance on these patients, and especially its association with psychological state and quality of life to examine the prevalence of sleep disturbance and to assess its association with disease-specific variables, psychological status and quality of life. One hundred and ten patients were included in this cross-sectional study according to the modified New York criteria for AS. Clinical and biological parameters were evaluated. Sleep disturbance was assessed by the fourth item of Hamilton Anxiety Scale. Psychological status was assessed by The Hospital Anxiety and Depression Scale including depression subscale and anxiety subscale. The quality of life was evaluated by the short form-36 (SF-36). Sleep disturbance was found in 64.5 %, depression in 55.5 % and anxiety in 60.9 % amongst our patients. Significantly, worse pain, higher disease activity and functional disability were present in patients with sleep disturbance. Likewise, sleep problems were significantly higher in patients with depression, anxiety and in patients with low scores of the SF36. Multivariate logistic regression analysis revealed that the pain (OR = 1.019) and depression (OR = 1.304) were independent risk factors that influenced sleep disturbance. Sleep problems are prevalent amongst Moroccan patients with AS. Our findings suggest that pain and depression were the independent risk factors that influenced the sleep disturbance and hence, the need for evaluation and optimal management of pain and depression to improve sleep quality in AS patients. PMID- 22441962 TI - Effects of short-term aerobic exercise with and without external loading on bone metabolism and balance in postmenopausal women with osteoporosis. AB - The aim of this study is to evaluate the effect of submaximal aerobic exercise with and without external loading on bone metabolism and balance in postmenopausal women with osteoporosis (OP). Thirty-six volunteer, sedentary postmenopausal women with OP were randomly divided into three groups: aerobic, weighted vest, and control. Exercise for the aerobic group consisted of 18 sessions of submaximal treadmill walking, 30 min daily, 3 times a week. The exercise program for the weighted-vest group was identical to that of the aerobic group except that the subjects wore a weighted vest (4-8 % of body weight). Body composition, bone biomarkers, bone-specific alkaline phosphatase (BALP) and N terminal telopeptide of type 1 collagen (NTX), and balance (near tandem stand, NTS, and star-excursion, SE) were measured before and after the 6-week exercise program. Fat decreased (p = 0.01) and fat-free mass increased (p = 0.005) significantly in the weighted-vest group. BALP increased and NTX decreased significantly in both exercise groups (p <= 0.05). After 6 weeks of exercise, NTS score increased in the exercise groups and decreased in the control group (aerobic: +49.68 %, weighted vest: +104.66 %, and control: -28.96 %). SE values for all directions increased significantly in the weighted-vest group. Results showed that the two exercise programs stimulate bone synthesis and decrease bone resorption in postmenopausal women with OP, but that exercise while wearing a weighted vest is better for improving balance. PMID- 22441963 TI - Significantly higher estimated 10-year probability of fracture in lupus patients with bone mineral density comparable to that of healthy individuals. AB - This study aimed at comparing the FRAX 10-year fracture risk between SLE patients and demographically- and anthropometrically matched healthy individuals. Consecutive SLE patients aged >= 40 were analyzed for the FRAX 10-year probability of major osteoporotic and hip fractures and their risk was compared with healthy controls matched for age, gender and body mass index. Potential determinants associated with higher 10-year fracture probability in the SLE patients were studied by regression models. Ninety subjects (45 SLE patients and 45 healthy controls) were studied. While the bone mineral density (BMD) of the lumbar spine and dominant hip was comparable between the two groups, the FRAX 10 year probability of major and hip fractures was significantly higher in SLE patients. Significantly more SLE patients had high 10-year fracture risk as defined by the National Osteoporosis Foundation compared with healthy controls (16 vs. 2 %, p = 0.026). After controlling for glucocorticoid use and premature menopause which were significant univariate risk factors, the difference in the 10-year fracture risk became insignificant. Amongst SLE patients, increasing age, lower hip BMD and cumulative glucocorticoid dose independently predicted higher 10-year major fracture risk while higher anti-dsDNA level independently predicted higher hip fracture risk in addition to age and lower hip BMD. Chronic glucocorticoid use and premature menopause led to higher 10-year probability of major osteoporotic and hip fractures in SLE patients compared with their healthy counterparts although their BMD was comparable. Advanced age, lower hip BMD, cumulative glucocorticoid and higher anti-dsDNA level independently predicted higher 10-year fracture risk amongst SLE patients. PMID- 22441964 TI - Imaging in rheumatology: ultrasafe + ultrasure = ultrasound. AB - Technological advances in ultrasonography (US) in recent years has allowed for improvements to the imaging quality of gray-scale ultrasound and the development of more advanced forms of this imaging technique such as 3D and Doppler US. These improvements mean that US now has an accepted place in rheumatology not only in diagnosis, but also in the determination of disease progression and pathology and in facilitating guidance of interventional therapies. The increasing use of US guided intervention by rheumatologists in the last 20 years is evidenced by the almost exponential increase in the number of publications in the relevant subjects. PMID- 22441965 TI - Increased levels of matrix metalloproteinase-3 in the sera and synovial fluids of patients with pustulotic arthro-osteitis associated with palmoplantar pustulosis: report of 2 cases. AB - Pustulotic arthro-osteitis (PAO) is occasionally seen in patients with palmoplantar pustulosis (PPP); however, its pathogenesis is still obscure. Herein, two patients with PAO associated with PPP were described. Both patients developed hydrarthrosis on the knees, along with sternocostoclavicular pain. Detail examination revealed odontogenic infection in both cases. Matrix metalloproteinase-3 (MMP-3) is a useful marker reflecting the activity of rheumatoid arthritis. In this study, MMP-3 levels in the sera as well as joint fluids were examined. Serum MMP-3 levels were increased in both cases (274 ng/ml in Case 1 and 242 ng/ml in Case 2, normal; 17.3-59.7). Also, MMP-3 concentration in the joint fluids was markedly elevated (Case 1 > 80,000 ng/ml and 48,000 ng/ml in Case 2). Our studies suggest that MMP-3 may play a role in the pathogenesis of joint involvement of PPP. PMID- 22441966 TI - Rheumatoid factor appearance after tocilizumab treatment seems to predict bad therapeutical response in rheumatoid arthritis. PMID- 22441967 TI - Vaccine history knowledge of subcutaneous anti-TNF receiving rheumatology patients. PMID- 22441968 TI - Multiclinical experiences in erythema nodosum: rheumatology clinics versus dermatology and infection diseases clinics. AB - Erythema nodosum (EN) is the most common cause of inflammatory nodules and usually affects the lower extremities and especially pretibial regions. EN may be idiopathic or associated with a wide spectrum of conditions including systemic diseases, infection, treatment with various drugs, pregnancy, and exceptionally with malignancies. The purpose of this study is to investigate the EN patients with different etiologies and laboratory features admitted to the rheumatology department and to compare them with other EN patients admitted to different departments including dermatology and infectious diseases. Totally, 107 patients diagnosed with EN (male/female: 37/70) were enrolled in the study. Of the 107 EN patients, 37 participants who were categorized as primary (idiopathic) EN (34.6 %) had not any underlying diseases or precipitating events. Majority of the participants were women (male/female: 12/25; mean age: 42.9 +/- 9.2 years). Precisely, 70 EN (secondary EN) patients (65.4 %) had an underlying disease (male/female: 25/45; mean age: 36.1 +/- 10.1). Behcet's disease (BD) was the foremost (n = 40, 37.4 %), followed by sarcoidosis (n = 17, 15.9 %), post streptococcal (n = 9, 8.4 %), and other rheumatologic disease (one patient temporal arthritis, one patient Sjogren's syndrome, 1.9 %). Consequently, it is observed that BD, sarcoidosis, and post-streptococcal infection were found as the main etiologies of EN patients treated in our rheumatology department. These diseases should be kept in mind as an etiological factor in the management of EN. PMID- 22441969 TI - High-density lipoprotein and atherosclerosis: the role of antioxidant activity. AB - Levels of high-density lipoprotein (HDL) cholesterol are generally inversely associated with the risk for the development of atherosclerosis. The mechanism by which HDL imparts protection from the initiation and progression of occlusive vascular disease is complex and multifactorial. The major anti-atherosclerotic effect of HDL is felt to be reverse cholesterol transport. HDL has been demonstrated to scavenge cholesterol from the peripheral vasculature with transport to the liver, where is it excreted in the biliary system. However, HDL exhibits multiple other physiologic effects that may play a role in the reduced risk for atherosclerosis. HDL has been demonstrated to exhibit beneficial effects on platelet function, endothelial function, coagulation parameters, inflammation, and interactions with triglyceride-rich lipoproteins. Increasing amounts of clinical and experimental data have shown that HDL cholesterol has significant antioxidant effect that may significantly contribute to protection from atherosclerosis. PMID- 22441970 TI - Patient rated outcomes and survivorship following cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS + HIPEC). AB - BACKGROUND: Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS + HIPEC) is a treatment combining cytoreductive surgery with hyperthermic chemotherapy directly into the peritoneal cavity. Recipients may gain extended life when compared with best supportive care; yet results often are achieved with substantial morbidity and health-related quality of life (HRQOL) deficits. The purpose of this study was to record patient rated outcomes and the HRQOL of long term survivors. METHODS: One hundred and two patients living 12+ months post treatment completed a survey including the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), Functional Assessment of Cancer Therapy-Colon (FACT C), and Pittsburgh Sleep Quality Index. RESULTS: SF-36 Physical Component scores were significantly lower than general population norms (46.7, z= -2.943, P=0.003), while Mental Component scores were significantly higher (53.6, z=4.208, P <= 0.001). FACT scores were higher than general FACT normative scores. The majority (56%) of these survivors reported significant sleep quality impairment. CONCLUSION: Although most HRQOL scores were comparable to or higher than those of the general population, long-term physical and functional deficits remain. These deficits, along with the poor sleep quality of recipients, may be improved by survivorship programs or targeted psychosocial interventions. PMID- 22441971 TI - The features of a "Mediterranean" Bioethics. AB - Even if somebody considers inappropriate any geographic adjective for Bioethics, nevertheless we think that there are some specific features of "Mediterranean" Bioethics that could distinguish it from a "Northern-European and Northern American" one. First of all we must consider that medical ethics was born and grew in Mediterranean area. First by the thought of great Greek philosophers as Aristotle (that analyse what ethics is), then by Hippocrates, the "father" of medical ethics. The ethical pattern of Aristotle was based on "virtues" and their practice. In this perspective we can already note a strong difference with actual North-European or American principialist ethics. But a second consideration concerns the role that great Mediterranean religions (Judaism, Christianity and Islam) had in the construction of the ethical thought especially on the matter of life and its respect. So, in our pluralistic and multicultural society is absolutely necessary to rescue an approach that considers both "lungs" of ethical thought (Mediterranean and Northern one) and highlights the role that Mediterranean Ethics still has in this way. PMID- 22441972 TI - Enantioselective synthesis of 2,5-dihydrobenzo[b]azepine derivatives via iridium catalyzed asymmetric allylic amination with 2-allylanilines and ring-closing metathesis reaction. AB - Iridium-catalyzed asymmetric allylic amination of allylic carbonates with 2 allylanilines was realized. With a catalyst generated from 2 mol% of [Ir(dbcot)Cl](2) (dbcot = dibenzo[a,e]cyclooctatetraene) and 4 mol% of phosphoramidite ligand (L3), the amination products were obtained in up to 99% yield and 99% ee. Subjecting amination products to trifluoroacetyl protection and ring-closing-metathesis reaction provided an efficient synthesis of enantioenriched 2,5-dihydrobenzo[b]azepine derivatives. PMID- 22441973 TI - Enantioselective synthesis of 4-hydroxytetrahydropyridine derivatives by intramolecular addition of tertiary enamides to aldehydes. PMID- 22441975 TI - Staple-line reinforcement during laparoscopic sleeve gastrectomy using three different techniques: a randomized trial. AB - BACKGROUND: The main drawback of laparoscopic sleeve gastrectomy (LSG) is the severity of postoperative complications. Staple line reinforcement (SLR) is strongly advocated. The purpose of this study was to compare prospectively and randomly three different techniques of SLR during LSG. METHODS: From April 2010 to April 2011, patients submitted to LSG were randomly selected for the following three different techniques of SLR: oversewing (group A); buttressed transection with a polyglycolide acid and trimethylene carbonate (group B); and staple-line roofing with a gelatin fibrin matrix (group C). Primary endpoints were reinforcement operative time, incidence of postoperative staple-line bleeding, and leaks. Operative time was calculated as follows: oversewing time in group A; positioning of polyglycolide acid and trimethylene carbonate over the stapler in group B; and roofing of the entire staple line in group C. RESULTS: A total of 120 patients were enrolled in the study (82 women and 38 men). Mean age was 44.6 +/- 9.2 (range, 28-64) years. Mean preoperative body mass index was 47.2 +/- 6.6 (range, 40-66) kg/m2. Mean time for SLR was longer in group A (14.2 +/- 4.2 (range, 8-18) minutes) compared with group B (2.4 +/- 1.8 (range, 1-4) minutes) and group C (4.4 +/- 1.6 (range, 3-6) minutes; P < 0.01). Four major complications were observed (3.3 %): one leak and one bleeding in group A; one bleeding in group B; and one leak in group C, with no significant differences between the groups. No mortality was observed. CONCLUSIONS: SLR with either polyglycolide acid with trimethylene carbonate or gelatin fibrin matrix is faster compared with oversewing. No significant differences were observed regarding postoperative staple-line complications. PMID- 22441976 TI - The feasibility of short-stay laparoscopic appendectomy for acute appendicitis: a prospective cohort study. AB - BACKGROUND: Short-stay laparoscopic appendectomy for acute appendicitis (AA) has not yet been validated. This study was designed to prospectively evaluate the hospital length of stay (LOS) after laparoscopic appendectomy for AA and to determine predictive factors for successful short-stay surgery (LOS <24 h). METHODS: Between January and December 2010, all consecutive adults admitted for AA were prospectively treated with LOS <24 h as a patient management goal. The proportion of patients with LOS <24 h was analyzed for the intention-to-treat (ITT) population and for the population eligible for short-stay surgery. Predictive factors for LOS <24 h were analyzed. RESULTS: Of the 123 patients included in this study, 71.5 % (88/123) were eligible for short-stay surgery. The proportion of LOS <24 h cases was 52 % (64/123) in the ITT population and 72.7 % (64/88) in the eligible population. LOS <12 h was achieved in 17.8 % (22/123) in the ITT patients and 25 % (22/88) of the eligible patients. The main cause of unexpected readmission was postoperative pain (n = 10, 8.1 %). Age <23 years and a serum C-reactive protein level <18 mg/l had a positive predictive value of 100 % for LOS <24 h. Of the eligible patients, 27.2 % (24/88) were subject to unplanned overnight admissions and postsurgery readmissions. CONCLUSIONS: LOS <24 h was feasible for 52 % of patients admitted for AA and for 72.7 % of the patients eligible for short-term surgery. Low age and a low preoperative serum CRP level are predictive factors for the feasibility of short-stay laparoscopic appendectomy for AA. PMID- 22441977 TI - [Is the patient age a negative predictive factor in the reconstruction of SLAP lesions?]. AB - BACKGROUND: The treatment strategy of SLAP (superior labrum anterior posterior) lesions is generally a matter of controversy, particularly in patients over 40 years of age. Various factors, such as the increasing number of associated injuries in older age, play a role in the decision-making process. There currently is no empirical evidence for the greater efficacy of treatment planning for SLAP repair as compared to tenodesis/tenotomy. The aim of this study was to analyse, as part of a cohort comparison, the results after SLAP repair in patients under and over 40 years of age. METHODS: We followed 45 patients after surgical treatment of a SLAP lesion, with a mean follow-up of 60 months (5 years), clinically using the Constant score (CS), the Rowe score, and the "subjective shoulder value" (SSV). Of these, 18 patients in group 1 (age at surgery<40 years, mean age at surgery 29 years, range: 21-39 years) and 27 patients in group 2 (age>=40 years at surgery, mean age at surgery 50 years, range: 40-60 years). RESULTS: A mean CS of 89% (min 16%-max 105%) resulted. The Rowe score averaged 90 points (min. 35 points-max 100 points), while the SSV averaged 90% (min 20%-max 100%). In comparing the two groups, neither displayed a significant difference in the CS (p=0.198) (group 1: min 58%-max 105%, median 92%, group 2: min 16%-max 105%, median 89%) nor in the Rowe score (p=0.5) (group 1: min 55-max 100 points, median 85 points, group 2: min 35-max 100 points, median 92.5 points). The SSV also showed no significant difference in level (p=0.068) between the two groups (group 1: min 60%-max 100%, median 95%, group 2: min 20%-max 100%, median 90%), although the SSV in group 1 had a better correlation with the CS than in group 2. DISCUSSION: The patient's age seems to have less influence on the outcome after reconstruction of SLAP than previously thought. Even at age>=40 years results show that the reconstruction results of the complex SLAP are comparable with the known literature data, and that it is good clinical practice. Impact on the long-term outcome seems to be particularly dependent on the number and severity of associated injuries, not the patient's age. PMID- 22441979 TI - New ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. AB - This review highlights an important novel aspect of the 2011 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the recommendations of a rapid rule-out protocol (0h and 3h) when high-sensitive cardiac troponin assays are available. The controversy relates to the scientific question how reliably patients can recall the onset or maximum of acute chest pain and the general question how conservative clinical practice guidelines should be. Several important arguments support the novel recommendations, particularly when accepting that guidelines should highlight treatment principles rather than individualised details. I hope that many physicians caring for patients with acute chest pain will actually take the time to read the new 2011 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Certainly, application of the principles highlighted in there will help them in their daily clinical work. PMID- 22441978 TI - Acetylcholine induces mesenchymal stem cell migration via Ca2+ /PKC/ERK1/2 signal pathway. AB - Acetylcholine (ACh) plays an important role in neural and non-neural function, but its role in mesenchymal stem cell (MSC) migration remains to be determined. In the present study, we have found that ACh induces MSC migration via muscarinic acetylcholine receptors (mAChRs). Among several mAChRs, MSCs express mAChR subtype 1 (m1AChR). ACh induces MSC migration via interaction with mAChR1. MEK1/2 inhibitor PD98059 blocks ERK1/2 phosphorylation while partially inhibiting the ACh-induced MSC migration. InsP3Rs inhibitor 2-APB that inhibits MAPK/ERK phosphorylation completely blocks ACh-mediated MSC migration. Interestingly, intracellular Ca(2+) ATPase-specific inhibitor thapsigargin also completely blocks ACh-induced MSC migration through the depletion of intracellular Ca(2+) storage. PKCalpha or PKCbeta inhibitor or their siRNAs only partially inhibit ACh induced MSC migration, but PKC-zeta siRNA completely inhibits ACh-induced MSC migration via blocking ERK1/2 phosphorylation. These results indicate that ACh induces MSC migration via Ca(2+), PKC, and ERK1/2 signal pathways. PMID- 22441980 TI - First reported cases of rabies in the Republic of Macedonia. PMID- 22441981 TI - Mechanisms of LRRK2-mediated neurodegeneration. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of familial Parkinson's disease (PD), whereas common variation at the LRRK2 locus is associated with an increased risk of idiopathic PD. Considerable progress has been made toward understanding the biological functions of LRRK2 and the molecular mechanisms underlying the pathogenic effects of disease-associated mutations. The development of neuronal culture models and transgenic or viral-based rodent models have proved useful for identifying a number of emerging pathways implicated in LRRK2-dependent neuronal damage, including the microtubule network, actin cytoskeleton, autophagy, mitochondria, vesicular trafficking, and protein quality control. However, many important questions remain to be posed and answered. Elucidating the molecular mechanisms and pathways underlying LRRK2-mediated neurodegeneration is critical for the identification of new molecular targets for therapeutic intervention in PD. In this review we discuss recent advances and unanswered questions in understanding the pathophysiology of LRRK2. PMID- 22441982 TI - Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. AB - Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1 (13)C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (F(i)o(2) 10%, arterial oxygen saturation 72 +/- 10%, mean +/- sd). Whole-body lactate turnover increased 3.5 fold and 9-fold at two workloads in normoxia and 18-fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 +/- 0.1 to 0.8 +/- 0.6 mmol min(-1) (P<0.05), corresponding to ~10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 +/- 0.9 mmol min(-1) (P<0.05), of which 57 +/- 9% was oxidized, demonstrating that lactate oxidation may account for up to ~33% of the energy substrate used by the brain. These results support the existence of a cell-cell lactate shuttle that may involve neurons and astrocytes. PMID- 22441983 TI - LNK (SH2B3) is a key regulator of integrin signaling in endothelial cells and targets alpha-parvin to control cell adhesion and migration. AB - Focal adhesion (FA) formation and disassembly play an essential role in adherence and migration of endothelial cells. These processes are highly regulated and involve various signaling molecules that are not yet completely identified. Lnk [Src homology 2-B3 (SH2B3)] belongs to a family of SH2-containing proteins with important adaptor functions. In this study, we showed that Lnk distribution follows that of vinculin, localizing Lnk in FAs. Inhibition of Lnk by RNA interference resulted in decreased spreading, whereas sustained expression dramatically increases the number of focal and cell-matrix adhesions. We demonstrated that Lnk expression impairs FA turnover and cell migration and regulates beta1-integrin-mediated signaling via Akt and GSK3beta phosphorylation. Moreover, the alpha-parvin protein was identified as one of the molecular targets of Lnk responsible for impaired FA dynamics and cell migration. Finally, we established the ILK protein as a new molecular partner for Lnk and proposed a model in which Lnk regulates alpha-parvin expression through its interaction with ILK. Collectively, our results underline the adaptor Lnk as a novel and effective key regulator of integrin-mediated signaling controlling endothelial cell adhesion and migration. PMID- 22441984 TI - Norepinephrine causes epigenetic repression of PKCepsilon gene in rodent hearts by activating Nox1-dependent reactive oxygen species production. AB - Heart disease is the leading cause of death in the United States. Recent studies demonstrate that fetal programming of PKCepsilon gene repression results in ischemia-sensitive phenotype in the heart. The present study tests the hypothesis that increased norepinephrine causes epigenetic repression of PKCepsilon gene in the heart via Nox1-dependent reactive oxygen species (ROS) production. Prolonged norepinephrine treatment increased ROS production in fetal rat hearts and embryonic ventricular myocyte H9c2 cells via a selective increase in Nox1 expression. Norepinephrine-induced ROS resulted in an increase in PKCepsilon promoter methylation at Egr-1 and Sp-1 binding sites, leading to PKCepsilon gene repression. N-acetylcysteine, diphenyleneiodonium, and apocynin blocked norepinephrine-induced ROS production and the promoter methylation, and also restored PKCepsilon mRNA and protein to control levels in vivo in fetal hearts and in vitro in embryonic myocyte cells. Accordingly, norepinephrine-induced ROS production, promoter methylation, and PKCepsilon gene repression were completely abrogated by knockdown of Nox1 in cardiomyocytes. These findings provide evidence of a novel interaction between elevated norepinephrine and epigenetic repression of PKCepsilon gene in the heart mediated by Nox1-dependent oxidative stress and suggest new insights of molecular mechanisms linking the heightened sympathetic activity to aberrant cardioprotection and increased ischemic vulnerability in the heart. PMID- 22441985 TI - Goldfish transposase Tgf2 presumably from recent horizontal transfer is active. AB - Hobo/Activator/Tam3 (hAT) superfamily transposons occur in plants and animals and play a role in genomic evolution. Certain hAT transposons are active and have been developed as incisive genetic tools. Active vertebrate elements are rarely discovered; however, Tgf2 transposon was recently discovered in goldfish (Carassius auratus). Here, we found that the endogenous Tgf2 element can transpose in goldfish genome. Seven different goldfish mRNA transcripts, encoding three lengths of Tgf2 transposase, were identified. Tgf2 transposase mRNA was detected in goldfish embryos, mainly in epithelial cells; levels were high in ovaries and mature eggs and in all adult tissues tested. Endogenous Tgf2 transposase mRNA is active in mature eggs and can mediate high rates of transposition (>30%) when injected with donor plasmids harboring a Tgf2 cis element. When donor plasmid was coinjected with capped Tgf2 transposase mRNA, the insertion rate reached >90% at 1 yr. Nonautonomous copies of the Tgf2 transposon with large-fragment deletions and low levels of point mutations were also detected in common goldfish. Phylogenetic analysis indicates the taxonomic distribution of Tgf2 in goldfish is not due to vertical inheritance. We propose that the goldfish Tgf2 transposon originated by recent horizontal transfer and maintains a highly native activity. PMID- 22441986 TI - Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-alpha. TNF-alpha signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-alpha-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to beta-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-alpha-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD. PMID- 22441987 TI - Loss of giant obscurins promotes breast epithelial cell survival through apoptotic resistance. AB - Obscurins (~70 - 870 kDa), encoded by the single OBSCN gene, are cytoskeletal proteins originally identified in striated muscles with structural and regulatory roles. Recently, analysis of 13,023 genes in breast and colorectal cancers identified OBSCN as one of the most frequently mutated genes, implicating it in cancer formation. Herein we studied the expression profile of obscurins in breast, colon, and skin cancer cell lines and their involvement in cell survival. Immunoblot analysis demonstrated significant reduction of obscurin proteins [corrected] in cancer cells, resulting from decreased mRNA levels and/or the presence of mutant transcripts. In normal epithelium, obscurins localize in cytoplasmic puncta, the cell membrane, and the nucleus. Accordingly, subcellular fractionation demonstrated the presence of 2 novel nuclear isoforms of ~110 and ~120 kDa. Nontumorigenic MCF10A breast epithelial cells stably transduced with shRNAs targeting giant obscurins exhibited increased viability (~30%) and reduced apoptosis (~20%) following exposure to the DNA-damaging agent etoposide. Quantitative RT-PCR further indicated that the antiapoptotic genes BAG4 and HAX1 were up-regulated (1.5- and 1.4-fold, respectively), whereas initiator caspase-9 and death caspase-3 transcripts were down-regulated (0.8- and 0.6-fold, respectively). Our findings are the first to pinpoint critical roles for obscurins in cancer development by contributing to the regulation of cell survival. PMID- 22441988 TI - Transition metal-catalysed intermolecular reaction of allenes with oxygen nucleophiles: a perspective. AB - Transition metal catalysed hydroalkoxylation of allenes has received much attention in recent years, and both the intra- and intermolecular versions have been reported. Gold(I) complexes are among the most active catalysts for these processes. This critical perspective article will cover the progress in this field, analysing the intermolecular metal-catalysed reaction of allenes using palladium, iridium, rhodium, ruthenium, gold and platinum, in the presence of alcohols, water or carboxylic acids, and the mechanistic implications of these processes depending on the metal used. PMID- 22441990 TI - Intra-aortic balloon pump implantation does not affect long-term survival after isolated CABG in patients with acute myocardial infarction (Thorac Cardiov Surg 2011;59:406-410). PMID- 22441991 TI - A photoflow reactor for the continuous photoredox-mediated synthesis of C glycoamino acids and C-glycolipids. PMID- 22441992 TI - Freedom of choice. PMID- 22441993 TI - Jeannette Wilkins Award: Can locally delivered gadolinium be visualized on MRI? A pilot study. AB - BACKGROUND: Management of orthopaedic infections relies on debridement and local delivery of antimicrobials; however, the distribution and concentration of locally delivered antimicrobials in postdebridement surgical sites is unknown. Gadolinium-DTPA (Gd-DTPA) has been proposed as an imaging surrogate for antimicrobials because it is similar in size and diffusion coefficient to gentamicin. QUESTIONS/PURPOSES: Is in vivo distribution of locally delivered Gd DTPA (1) visible on MRI; (2) reliably visualized by different observers; (3) affected by the anatomic delivery site; and (4) affected by the in vitro release rate from the delivery vehicle? METHODS: Twenty-four local delivery depots were imaged in nine rabbits using two anatomic sites (intramedullary canal, quadriceps) with Gd-DTPA in intermediate-porosity polymethylmethacrylate (PMMA) or high-porosity PMMA; six of the nine rabbits also had Gd-DTPA delivered in collagen at a third site (hamstring). A total of 45,000 fat-suppressed T1 weighted RARE scans were acquired using a 7-T Bruker Biospec MRI: nine rabbits, 2 mm slices over 10 cm, four TR values, 25 time periods (pre, every 15 minutes for 6 hours). T1 maps were constructed at every time period. Gd-DTPA distribution was observed qualitatively on the T1 maps. Interobserver reliability was determined. RESULTS: Locally delivered Gd-DTPA was visible. Interobserver agreement was excellent. Intramuscular delivery followed intermuscular planes; intramedullary delivery was contained within the canal by bone. Distribution from collagen decreased after 1 hour but from PMMA increased over 6 hours. CONCLUSIONS: Locally delivered Gd-DTPA can be visualized on MRI; distribution is affected by anatomical location and delivery vehicle. CLINICAL RELEVANCE: Contrast-based imaging using locally delivered Gd-DTPA may be useful as an antibiotic surrogate to determine antibiotic distribution in surgical sites. PMID- 22441994 TI - What is the prevalence of MRSA colonization in elective spine cases? AB - BACKGROUND: The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection is increasing. However, the prevalence of MRSA colonization among patients undergoing spine surgery is unclear. QUESTIONS/PURPOSES: We therefore (1) determined the prevalence of MRSA colonization in a population of patients scheduled for elective spine surgery; and (2) evaluated whether MRSA screening and treatment reduce the rate of early wound complications. METHODS: We retrospectively reviewed prospectively collected data from 1002 patients undergoing elective spine surgery in 2010. There were 719 primary and 283 revision surgeries. Instrumentation was used in 72.0% cases and autologous iliac crest bone graft was taken in 65.1%. Twelve patients were lost to followup; of the remaining 990 patients, 503 were screened for MRSA and 487 were not. MRSA colonized patients were treated with mupirocin and chlorhexidine. An early wound complication was defined as wound drainage or the presence of an abscess. Patients were followed for a minimum of 3 months (average, 7 months; range, 3-545 days). RESULTS: Of the patients undergoing elective spine surgery and screened for MRSA, 14 of 503 (2.8%) were colonized with MRSA. The rates of early wound complications were similar for patients who were screened and pretreated for MRSA (17 of 503 [3.4%]) compared with those who were not (17 of 487 [3.5%]). CONCLUSIONS: The colonization rate for MRSA in our elective spine surgery population was comparable to that in the arthroplasty literature. LEVEL OF EVIDENCE: Level III, retrospective comparative study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22441995 TI - Insulin-like growth factor I receptor involvement in proliferation of NOR-P1 cells in serum-free media. AB - Insulin-like growth factor (IGF)-I is up-regulated in pancreatic cancer tissues. Pancreatic cancer cell lines were analyzed in serum-free media as a model of the fibrous tissues that these cells often invade. Pancreatic cancer surgical specimens were immunostained with anti-IGF-I receptor (IGF-IR)beta antibody. The growth of pancreatic cancer cells in serum-free media was also analyzed. Cell lysates were analyzed for protein by western blot analysis. Cells cultured in the presence of picropodophyllin (PPP), LY294002, or PD98059, were subjected to cell proliferation and scratch assays. In addition, BrdU uptake and apoptosis were analyzed in these cells. IGF-IRbeta was detected in pancreatic cancer cells invading fibrous tissues. NOR-P1 grew most rapidly in serum-free media. The concentrations of IGF-I and IGF-II in the media were higher in NOR-P1 than the other cell lines. Cell proliferation in NOR-P1 cells was enhanced by IGF-I or IGF II treatment more than in MIA-Paca2 or PK-1 cells. PPP, LY294002, and PD98059 suppressed proliferation and motility of NOR-P1 cells and inhibited BrdU uptake, while PPP induced apoptosis. IGF-IRbeta may be a potential therapeutic target to inhibit invasion of pancreatic cancer. PMID- 22441996 TI - Moral distress and the contemporary plight of health professionals. AB - Once a term used primarily by moral philosophers, "moral distress" is increasingly used by health professionals to name experiences of frustration and failure in fulfilling moral obligations inherent to their fiduciary relationship with the public. Although such challenges have always been present, as has discord regarding the right thing to do in particular situations, there is a radical change in the degree and intensity of moral distress being expressed. Has the plight of professionals in healthcare practice changed? "Plight" encompasses not only the act of pledging, but that of predicament and peril. The author claims that health professionals are increasingly put in peril by healthcare reform that undermines their efficacy and jeopardizes ethical engagement with those in their care. The re-engineering of healthcare to give precedence to corporate and commercial values and strategies of commodification, service rationing, streamlining, and measuring of "efficiency," is literally demoralizing health professionals. Healthcare practice needs to be grounded in a capacity for compassion and empathy, as is evident in standards of practice and codes of ethics, and in the understanding of what it means to be a professional. Such grounding allows for humane response to the availability of unprecedented advances in biotechnological treatments, for genuine dialogue and the raising of difficult, necessary ethical questions, and for the mutual support of health professionals themselves. If healthcare environments are not understood as moral communities but rather as simulated marketplaces, then health professionals' moral agency is diminished and their vulnerability to moral distress is exacerbated. Research in moral distress and relational ethics is used to support this claim. PMID- 22441997 TI - [NASH (non-alcoholic steatohepatitis): fatty liver or fatal liver disease?]. AB - INTRODUCTION: Non-alcoholic steatohepatitis (NASH) was first described in 1980 and has emerged from an anecdotal disease to a widely distributed liver disease in the current decade. METHODS: This review is based on publications in PubMed and our own experiences and deals with basic pathophysiological aspects, diagnostic, and therapeutic tools as well as with the modern management of this serious liver disease. RESULTS: For a long time the potenial for serious liver destruction and enhanced liver mortality by NASH has been observed. The recognition of the metabolic origin of NASH has contributed to diagnostic as well as therapeutic approaches. Since then patients with metabolic syndrome are often screened for liver disease. NASH might worsen other chronic liver diseases but should be judged as an independent illness rather than the exclusion of other potential liver diseases. Furthermore, non-alcoholic steatohepatitis has systemic consequences concerning insulin resistance, metabolic complications and cardiovascular diseases. PERSPECTIVES: Future research should concentrate on non invasive screening strategies, identification of risk factors, evaluation of hepatocellular carcinogenesis and new therapeutic targets. PMID- 22441998 TI - Secondary cytoreductive surgery outcomes of selected patients with paclitaxel/platinum sensitive recurrent epithelial ovarian cancer. AB - OBJECTIVE: The aim of this study was to evaluate the effect of secondary cytoreductive surgery (SCRS) on survival and to determine prognostic factors that may predict surgical and survival outcome. STUDY DESIGN: Between 1999 and 2011, data of 67 patients who had SCRS for epithelial ovarian cancer were evaluated. Factors that had an impact on survival were determined by statistical analysis. RESULTS: Univariate analysis showed that the number of chemotherapy cycles after primary surgery, CA 125 level at SCRS, number of recurrent tumors, recurrence before SCRS, disease dissemination, and number of chemotherapy cycles after SCRS were significantly associated with disease free survival after SCRS. In multivariate analysis, serum CA125 level, tumor dissemination, and number of chemotherapy cycles after SCRS were significantly associated with disease free survival. Moreover, univariate analysis showed that recurrence before SCRS was significantly associated with overall survival. CONCLUSION: SCRS may be beneficial for first relapsed, localized paclitaxel/platinum sensitive epithelial ovarian tumors and patients with a low serum CA 125 level and those who will receive >= 6 chemotherapy cycles after SCRS. This procedure should be considered in selected patient populations. PMID- 22441999 TI - Traumatic brain injury and disturbed sleep and wakefulness. AB - Traumatic brain injury is a frequent condition worldwide, and sleep-wake disturbances often complicate the course after the injuring event. Current evidence suggests that the most common sleep-wake disturbances following traumatic brain injury include excessive daytime sleepiness and posttraumatic hypersomnia, that is, increased sleep need per 24 h. The neuromolecular basis of posttraumatic sleep pressure enhancement is not entirely clear. First neuropathological and clinical studies suggest that impaired hypocretin (orexin) signalling might contribute to sleepiness, but direct or indirect traumatic injury also to other sleep-wake modulating systems in the brainstem and the mesencephalon is likely. Posttraumatic insomnia may be less common than posttraumatic sleepiness, but studies on its frequency revealed conflicting results. Furthermore, insomnia is often associated with psychiatric comorbidities, and some patients with posttraumatic disruption of their circadian rhythm may be misdiagnosed as insomnia patients. The pathophysiology of posttraumatic circadian sleep disorders remains elusive; however, there is some evidence that reduced evening melatonin production due to traumatic brain damage may cause disruption of circadian regulation of sleep and wakefulness. PMID- 22442000 TI - Organoaluminum boryl complexes. PMID- 22442001 TI - [Nickel allergy and painful unicondylar knee arthroplasty]. AB - A 56-year-old woman with unicondylar knee arthroplasty (Oxford III, Biomet) complained of persistent, burning pain in her knee. The arthroplasty failure was caused by a nickel allergy. The diagnosis was confirmed by positive patch testing, lymphocyte transformation test and histological analysis of the neosynovia around the implant. The unicondylar knee arthroplasty was explanted and replaced by a titanium-coated knee prosthesis (INNEX CR, Zimmer). PMID- 22442002 TI - The effects of angiotensin peptides and angiotensin receptor antagonists on the cell growth and angiogenic activity of GH3 lactosomatotroph cells in vitro. AB - The local renin-angiotensin system (RAS) is present in the pituitary gland, and inhibitory effects of angiotensins on the lactosomatotroph (GH3) cell growth have been revealed. The aim of this study was to examine the influence of various angiotensin peptides and angiotensin AT1, AT2, and AT4 receptors antagonists on the cell proliferation, viability, and VEGF secretion in pituitary lactosomatotroph GH3 cell culture in order to identify receptors involved in antiproliferative effects of angiotensins on GH3 tumor cells. Cell viability and proliferation using Mosmann method and BrdU incorporation during DNA synthesis, and VEGF secretion using ELISA assay were estimated. The inhibitory effects of ang II, ang IV, and ang 5-8 on the cell viability and BrdU incorporation in GH3 culture were not abolished by AT1, AT2, and AT4 receptors antagonists. Ang II, as well as ang III and ang IV at lower concentrations stimulated the secretion of VEGF in GH3 cell culture. The secretion of VEGF was inhibited by ang III and ang IV at higher concentrations. AT1 and AT2 receptors antagonists prevented the proangiogenic effects of ang II. Ang II, ang IV, and ang 5-8 decrease the cell number and proliferation in GH3 cell culture independently of the AT1, AT2, and AT4 receptors. These peptides affect also secretion of VEGF in culture examined. Both the AT1 and AT2 receptors appear to mediate the proangiogenic effects of ang II. PMID- 22442003 TI - Beneficial effects of preoperative lipiodolization for resectable large hepatocellular carcinoma (>= 5 cm in diameter). AB - BACKGROUND: The effects of preoperative lipiodolization (LPD) for large hepatocellular carcinoma (HCC) are controversial. METHODS: A retrospective review was undertaken for 137 patients with initial solitary resectable HCC >= 5 cm who underwent hepatic resection between 1995 and 2008. Forty-two patients underwent preoperative LPD, and clinical data and prognosis were compared to those of patients without preoperative LPD (n=95). RESULTS: Surgical results of the LPD group, such as surgical time, surgical blood loss, and the mortality and morbidity rate were statistically equal to those of the nonLPD group. The disease free and overall survival of the LPD group were significantly better than those of the nonLPD group, and early tumor recurrence within 1-year of the LPD group was significantly lower than that of the nonLPD group. According to the multivariate analysis, the absence of preoperative LPD was an independent poor prognostic factor of patients with hepatic resection for HCC >= 5 cm. CONCLUSION: Preoperative LPD suppressed early tumor recurrence and improved patient survival after hepatic resection for HCC >= 5 cm. PMID- 22442004 TI - Examination of the coordination sphere of Al(III) in trifluoromethyl heteroarylalkenolato complex ions by gas-phase IRMPD spectroscopy and computational modelling. AB - A series of aluminium complex ions with trifluoromethyl-heteroarylalkenolato (TMHA) ligands are studied by gas-phase infrared multiphoton-dissociation (IRMPD) spectroscopy and computational modelling. The selected series of aluminium TMHA complex ions are promising species for the initial study of intrinsic binding characteristics of Al(III) cations in the gas phase as corresponding molecular ions. They are readily available for examination by (+) and (-) electrospray ionization mass spectrometry (ESI-MS) by spraying of [Al(3+)?(L(-))(3)] solutions. The complex ions under investigation contain trivalent Al(3+) cations with two chelating anionic enolate ligands, [Al(3+)?(L(-))(2)](+), providing insights in the nature of the heteroatom-Al bonds. Additionally, the structure of a deprotonated benzimidazole ligand, L(-,) and an anionic complex ion of Al(III) with two doubly deprotonated benzimidazole ligands, [Al(3+)?(L(2-))(2)](-), are examined by (-)ESI-IRMPD spectroscopy. Experimental and computational results are highly consistent and allow a reliable identification of the ion structures. In all complex ions examined the planar TMHA ligands are oriented perpendicular to each other around the metal ion, leading to a tetrahedral coordination sphere in which aluminium interacts with the enolate oxygen and heteroaryl nitrogen atoms available in each of the bidentate ligands. PMID- 22442006 TI - Discrimination of meniscal cell phenotypes using gene expression profiles. AB - The lack of quantitative and objective metrics to assess cartilage and meniscus cell phenotypes contributes to the challenges in fibrocartilage tissue engineering. Although functional assessment of the final resulting tissue is essential, initial characterization of cell sources and quantitative description of their progression towards the natural, desired cell phenotype would provide an effective tool in optimizing cell-based tissue engineering strategies. The purpose of this study was to identify quantifiable characteristics of meniscal cells and thereby find phenotypical markers that could effectively categorize cells based on their tissue of origin (cartilage, inner, middle, and outer meniscus). The combination of gene expression ratios collagen VI/collagen II, ADAMTS-5/collagen II, and collagen I/collagen II was the most effective indicator of variation among different tissue regions. We additionally demonstrate a possible application of these quantifiable metrics in evaluating the use of serially passaged chondrocytes as a possible cell source in fibrocartilage engineering. Comparing the ratios of the passaged chondrocytes and the native meniscal cells may provide direction to optimize towards the desired cell phenotype. We have thus shown that measurable markers defining the characteristics of the native meniscus can establish a standard by which different tissue engineering strategies can be objectively assessed. Such metrics could additionally be useful in exploring the different stages of meniscal degradation in osteoarthritis and provide some insight in the disease progression. PMID- 22442005 TI - Investigation of NK cell function and their modulation in different malignancies. AB - NK cells have become a subject of investigation not only in the field of tumor immunology and infectious diseases, but also within all aspects of immunology, such as transplantation, autoimmunity, and hypersensitivity. Our early studies aside from investigating NK cell activity in experimental animals and humans included studies of perforin expression and modulation in this lymphocyte subset. As NK cell activity is modified by their environment, we showed clinical stage dependent impairment of their activity and in vitro effect of different sera, Th1 cytokines, and their combination in breast cancer, Hodgkin's disease, and non Hodgkin's lymphoma patients, especially with respect to metabolic and cell membrane changes of peripheral blood lymphocytes evaluated by spontaneous release of the enzyme lactate dehydrogenase (LDH) that led to the correction of the LDH enzyme release assay for natural cytotoxicity. By long-term immuno-monitoring of patients with malignancies, we also showed the kinetics of NK cell modulation during chemo-immunotherapy. In our more recent studies, we give data of NK function and novel families of NK cell receptor expression in healthy individuals that may be of help in NK cell profiling, by giving referent values of basic and cytokine-induced expression of some NK cell receptors either in evaluation of disease or in immuno-monitoring during cytokine therapy of patients with malignancies. Moreover, we give novel aspects of modulation of NK cell activity by cytokines approved for immunotherapy, IFN and IL-2, in melanoma and other malignancies with respect to alterations in new activating (NKG2D and CD161) and inhibitory (CD158a and CD158b) receptor characteristics and signaling molecules in CD16- and CD56-defined NK cells and their small immunoregulatory and large cytotoxic subsets in peripheral blood and lymph nodes, as NK cell-mediated killing of tumor cells depends on the balance between stimulatory and inhibitory signaling. PMID- 22442007 TI - Buttock claudication after interventional occlusion of the hypogastric artery--a mid-term follow-up. AB - BACKGROUND: Interventional occlusion of the hypogastric artery (HA) can be used for endovascular aneurysm repair (EVAR) in the iliac arteries. Most frequent ischemic complication is buttock claudication (BC). AIM: To investigate the frequency and progression of BC after interventional occlusion of the HA prior to EVAR. METHODS: A retrospective analysis was performed in patients with EVAR and occlusion of the HA between September 2004 and August 2010. Acute and persistent BC symptoms were assessed. RESULTS: Fifty-four catheter occlusions of the HA were performed. In 10 cases, claudication could not be evaluated. During a mean follow up of 17 months, 23 occlusions (52.3%) of the HA showed BC, in 52% symptoms were persistent. Of the 5 patients, 3 patients who underwent bilateral occlusion had BC and in 2 cases, persistent in the follow-up. CONCLUSION: Buttock claudication after occlusion of the HA prior to EVAR is a frequent complication, which often persists during follow-up. Alternatives that maintain pelvic perfusion should be considered. PMID- 22442008 TI - Economic model of observation versus immediate resection of hepatic adenomas. AB - BACKGROUND AND OBJECTIVES: For small asymptomatic hepatic adenomas (HA), available data are insufficient to establish the superiority of either observation or surgery. We sought to investigate the cost-effectiveness of two initial management strategies. METHODS: We performed a comparative analysis of two theoretical cohorts of 100 patients with small (<5 cm), asymptomatic HA. Discounted cash flow (DCF) models compared the net present value (NPV) of both treatment options at year 10 under three distinct progression rate scenarios. A break-even (BE) analysis was used to determine the BE point at which the NPV for observation and immediate surgery intersect. RESULTS: The NPV for immediate surgery was $1,733,955. The NPV for observation varied between $2,065,315 $2,745,631 for computed tomography (CT), $2,264,575-$2,929,541 for magnetic resonance imaging (MRI), and $802,837-$1,580,413 for ultrasound (US). The BE point was between 6 and 8 years for CT and 5-7 years for MRI. The BE point for US was not reached except in the highest progression rate scenario (12 years). CONCLUSIONS: This study highlights the importance of the underlying progression rate and the cost of imaging when following patients with asymptomatic HA. Overall, US surveillance is the most cost-efficient approach to observing small asymptomatic HA. If cross-sectional imaging is utilized, then immediate surgery is the most cost-effective decision at 5-8 years. PMID- 22442009 TI - Coding exons function as tissue-specific enhancers of nearby genes. AB - Enhancers are essential gene regulatory elements whose alteration can lead to morphological differences between species, developmental abnormalities, and human disease. Current strategies to identify enhancers focus primarily on noncoding sequences and tend to exclude protein coding sequences. Here, we analyzed 25 available ChIP-seq data sets that identify enhancers in an unbiased manner (H3K4me1, H3K27ac, and EP300) for peaks that overlap exons. We find that, on average, 7% of all ChIP-seq peaks overlap coding exons (after excluding for peaks that overlap with first exons). By using mouse and zebrafish enhancer assays, we demonstrate that several of these exonic enhancer (eExons) candidates can function as enhancers of their neighboring genes and that the exonic sequence is necessary for enhancer activity. Using ChIP, 3C, and DNA FISH, we further show that one of these exonic limb enhancers, Dync1i1 exon 15, has active enhancer marks and physically interacts with Dlx5/6 promoter regions 900 kb away. In addition, its removal by chromosomal abnormalities in humans could cause split hand and foot malformation 1 (SHFM1), a disorder associated with DLX5/6. These results demonstrate that DNA sequences can have a dual function, operating as coding exons in one tissue and enhancers of nearby gene(s) in another tissue, suggesting that phenotypes resulting from coding mutations could be caused not only by protein alteration but also by disrupting the regulation of another gene. PMID- 22442010 TI - Comparison of clinical outcomes for patients with clinical N0 and pathologic N2 non-small cell lung cancer after thoracoscopic lobectomy and open lobectomy: a retrospective analysis of 76 patients. AB - OBJECTIVE: To compare outcomes between thoracoscopic and thoracotomy lobectomy for patients with cN0-pN2 NSCLC. METHODS: One hundred eighty-two cN0 patients (including 29 pN2) underwent VATS lobectomy between September 2006 and December 2009, and 204 cN0 patients (including 47 pN2) underwent thoracotomy lobectomy between July 2000 and December 2009. Pre- and intraoperative status and postoperative survival between two groups were compared. RESULTS: There was no difference in preoperative conditions between two groups except Quantity of smoking. Operation time and blood loss of VATS group was significantly lower than thoracotomy group. Number of dissected lymph node (LN) stations was 3.3 +/- 1.1 in VATS group versus 3.3 +/- 1.3 in thoracotomy group, and the total number of LN was 12.7 +/- 8.9 in VATS group versus 10.5 +/- 7.2 in thoracotomy group. One- and 3-year disease-free survival rate was 82.6% in VATS group versus 72.0% in thoracotomy group, and 49.3% in VATS group versus 51.3% in thoracotomy group (P=0.996). One- and 3-year survival rate was 84.9% in VATS group versus 71.2% in thoracotomy group, and 64.0% in VATS group versus 42.7% in thoracotomy group (P=0.121). CONCLUSIONS: VATS lobectomy is comparable with thoracotomy in both safety and curability for the treatment of cN0-pN2 NSCLC, without necessity of conversion to open surgery. PMID- 22442011 TI - Lipid biosynthesis monitored at the single-cell level in Saccharomyces cerevisiae. AB - There is increasing interest in bioengineering of lipids for use in functional foods, pharmaceuticals, and biofuels. Saccharomyces cerevisiae is a widely utilized cell factory for biotechnological production, thus a tempting alternative. Herein, we show how its neutral lipid accumulation varies throughout metabolic phases under nutritional conditions relevant for large-scale fermentation. Population-averaged metabolic data were correlated with lipid storage at the single-cell level monitored at submicron resolution by label-free coherent anti-Stokes Raman scattering (CARS) microscopy. While lipid droplet sizes are fairly constant, the number of droplets is a dynamic parameter determined by glucose and ethanol levels. The lowest number of lipid droplets is observed in the transition phase between glucose and ethanol fermentation. It is followed by a buildup during the ethanol phase. The surplus of accumulated lipids is then mobilized at concurrent glucose and ethanol starvation in the subsequent stationary phase. Thus, the highest amount of lipids is found in the ethanol phase, which is about 0.3 fL/cell. Our results indicate that the budding yeast, S. cerevisiae, can be used for the biosynthesis of lipids and demonstrate the strength of CARS microscopy for monitoring the dynamics of lipid metabolism at the single-cell level of importance for optimized lipid production. PMID- 22442012 TI - Irregular osteotomy in limb salvage for juxta-articular osteosarcoma under computer-assisted navigation. AB - BACKGROUND: Joint-preserving limb salvage surgery has been expected to have good functional outcomes. However, it is still a unsolved problem to perform a joint preserving resection for patients with juxta-articular osteosarcoma invading epiphyseal line. We determined whether irregular osteotomy under image-guided navigation make joint-saving resection possible for juxta-articular osteosarcoma while adhering oncological principles. METHODS: We performed joint-preserving limb salvage surgeries on six patients with juxta-articular osteosarcoma of the long bone. Three lesions located in humerus, two in tibia and one in femur. Two tumors extend to and four beyond the epiphyseal line. CT and MRI data fusion images were applied for intraoperative navigation. Planned irregular osteotomy under image-guided navigation was employed for obtaining clear surgical margin while maximizing host tissue preservation. All tumors were en bloc removed and intercalary defect were reconstructed by allograft in one and combination of allograft with vascularized fibula graft in five patients. All specimens were examined for resection margin. Patients were followed up for average of 17.5 months for evaluating of functional and oncology outcomes. RESULT: Entire joint were preserved in three patients and part of joint were saved in another three patients. Clear surgical margin was obtained in all specimens with a minimum of 6 mm distance between tumor and osteotomy line. No patient experienced a local recurrence. One patient developed lung metastasis and had no evidence of disease at the most recent follow-up. All allografts but one healed during the study period. The MSTS average score was 88.8% at final follow-up. CONCLUSIONS: With careful patient selection, the irregular osteotomy under navigation guidance was proved to be an effective and safe technique for precise tumor resection in joint preserving limb salvage procedures for treating patients with juxta-articular osteosarcomas. PMID- 22442015 TI - Administration of PRN medications and use of nonpharmacologic interventions in acute geropsychiatric settings: implications for practice. AB - Despite the known risks and the widespread administration of PRN (pro re nata or "as needed") psychotropic medications in inpatient settings, little is known about their use with hospitalized older adults. This exploratory descriptive study examined the use of PRN psychotropic medications and nonpharmacologic interventions to manage symptoms in older adults hospitalized in two acute care geropsychiatric settings. A retrospective chart audit was conducted. A major finding was the lack of documentation regarding PRN administration. In 81.3% of cases at Site A and 55.3% of cases at Site B, no reason for administration was documented. No medication response was documented in 92.4% of cases at Site A and 47.5% of cases at Site B. No nonpharmacologic interventions were documented for 69% of Site A patients or 64% of Site B patients. To ensure patient safety and to inform best clinical practice, the lack of documentation surrounding administration of PRN medications and nonpharmacologic interventions must be resolved. PMID- 22442016 TI - Psychiatric patients are at increased risk of falling and choking. AB - Acutely ill psychiatric patients experience symptoms and take medications that increase their risk of both falling and choking; however, nurses and other caregivers may not be keenly aware of these risks. This article will provide a brief review of the literature related to risk factors for falls and choking and interventions to prevent falls and choking. Increased education for nursing students and staff employed at inpatient psychiatric units has the potential to reduce both incidence and injuries related to falls and choking. PMID- 22442017 TI - A change in culture: violence prevention in an acute behavioral health setting. AB - A multilayered implementation of safety measures in an inpatient psychiatric facility created a sustained change in culture related to patient and staff safety. The model was developed over a 5-year period in a freestanding 80-bed behavioral health facility that is part of a Level II trauma center in the Midwest. The model has nine components that the nursing leadership team saw as integral to maintaining a safe environment. The nine elements include trauma informed care principles, aggression management, code event review, leadership involvement, quality feedback, recovery orientation, patient assessment, education, and collaboration. The metrics collected to determine the effectiveness of the model included patient violence events and staff injuries. This article describes the development of this model and its impact on the reduction of patient violence events and staff injuries at this facility. The recommendations include considerations for the replication of this model at other facilities. PMID- 22442018 TI - Strategic planning: part I--APNA's inclusionary process. PMID- 22442020 TI - Stereotactic radiosurgery for central neurocytoma: a quantitative systematic review. AB - Central neurocytoma was originally described as a rare benign neuronal tumor. However, progression and local recurrences after surgery are well recognized. Stereotactic radiosurgery is another option for treatment of CN. In order to evaluate the efficacy of SRS, we performed a quantitative systematic review of the available data on SRS for CN. To identify eligible studies, systematic searches for all CNs treated with SRS were conducted in major scientific publication databases. English studies published prior to May 2011 were reviewed and summarized with reference to the inclusion and exclusion criteria. Tumor local control was analyzed. Heterogeneity and publication bias were assessed, and the summary control rate and 95%confidence interval (CI) were calculated from the raw data.Of 35 eligible studies, five with a total of 64 CNs were included in this quantitative analysis. Four studies reported a mean or median follow-up time of[60 months. The test of heterogeneity was non-significant among the included studies. Publication bias was observed as indicated by an asymmetric funnel plot. There was non-significance in Begg's test and Egger's test. The estimated cumulative rate of neuro-imaging tumor control was 91.1% (95%CI = 80.2-96.3%) at a mean follow-up of 59.3 months(range 6-140 months). The P-value was?0.0001 under a random-effect model. Sensitivity analysis showed a similar summary control rates (89.5-93.7%). Based on the summary local control rate of SRS for CN found in this quantitative analysis, we suggest that single session SRS is an effective and safe alternative therapy for recurrent or residual CN. However, the results of our analysis are limited by the predominance of case series studies due to scarcity of published research. Further randomized trials of CN patients via multicenter consortia should be considered for supplementing the weak points in our quantitative analysis. PMID- 22442021 TI - ATF5, a possible regulator of osteogenic differentiation in human adipose-derived stem cells. AB - The regulatory pathways involved in maintaining the pluripotency of embryonic stem cells are partially known, whereas the regulatory pathways governing adult stem cells and their "stem-ness" are characterized to an even lesser extent. We, therefore, screened the transcriptome profiles of 20 osteogenically induced adult human adipose-derived stem cell (ADSC) populations and investigated for putative transcription factors that could regulate the osteogenic differentiation of these ADSC. We studied a subgroup of donors' samples that had a disparate osteogenic response transcriptome from that of induced human fetal osteoblasts and the rest of the induced human ADSC samples. From our statistical analysis, we found activating transcription factor 5 (ATF5) to be significantly and consistently down-regulated in a randomized time-course study of osteogenically differentiated adipose-derived stem cells from human donor samples. Knockdown of ATF5 with siRNA showed an increased sensitivity to osteogenic induction. This evidence suggests a role for ATF5 in the regulation of osteogenic differentiation in adipose-derived stem cells. To our knowledge, this is the first report that indicates a novel role of transcription factors in regulating osteogenic differentiation in adult or tissue specific stem cells. PMID- 22442022 TI - Estimation of changes in instantaneous aortic blood flow by the analysis of arterial blood pressure. AB - The purpose of this study was to introduce and validate a new algorithm to estimate instantaneous aortic blood flow (ABF) by mathematical analysis of arterial blood pressure (ABP) waveforms. The algorithm is based on an autoregressive with exogenous input (ARX) model. We applied this algorithm to diastolic ABP waveforms to estimate the autoregressive model coefficients by requiring the estimated diastolic flow to be zero. The algorithm incorporating the coefficients was then applied to the entire ABP signal to estimate ABF. The algorithm was applied to six Yorkshire swine data sets over a wide range of physiological conditions for validation. Quantitative measures of waveform shape (standard deviation, skewness, and kurtosis), as well as stroke volume and cardiac output from the estimated ABF, were computed. Values of these measures were compared with those obtained from ABF waveforms recorded using a Transonic aortic flow probe placed around the aortic root. The estimation errors were compared with those obtained using a windkessel model. The ARX model algorithm achieved significantly lower errors in the waveform measures, stroke volume, and cardiac output than those obtained using the windkessel model (P < 0.05). PMID- 22442023 TI - Discharge properties of motor units during steady isometric contractions performed with the dorsiflexor muscles. AB - The purpose of this study was to record the discharge characteristics of tibialis anterior motor units over a range of target forces and to import these data, along with previously reported observations, into a computational model to compare experimental and simulated measures of torque variability during isometric contractions with the dorsiflexor muscles. The discharge characteristics of 44 motor units were quantified during brief isometric contractions at torques that ranged from recruitment threshold to an average of 22 +/- 14.4% maximal voluntary contraction (MVC) torque above recruitment threshold. The minimal [range: 5.8-19.8 pulses per second (pps)] and peak (range: 8.6-37.5 pps) discharge rates of motor units were positively related to the recruitment threshold torque (R(2) >= 0.266; P < 0.001). The coefficient of variation for interspike interval at recruitment was positively associated with recruitment threshold torque (R(2) = 0.443; P < 0.001) and either decreased exponentially or remained constant as target torque increased above recruitment threshold torque. The variability in the simulated torque did not differ from the experimental values once the recruitment range was set to ~85% MVC torque, and the association between motor twitch contraction times and peak twitch torque was defined as a weak linear association (R(2) = 0.096; P < 0.001). These results indicate that the steadiness of isometric contractions performed with the dorsiflexor muscle depended more on the distributions of mechanical properties than discharge properties across the population of motor units in the tibialis anterior. PMID- 22442024 TI - Functional and morphological assessment of early impairment of airway function in a rat model of emphysema. AB - The aim of this study was to evaluate airway structure-function relations in elastase-induced emphysema in rats. Sprague-Dawley rats were treated intratracheally with 50 IU porcine pancreatic elastase (PPE, n = 8) or saline (controls, n = 6). Six weeks later, lung volumes [functional residual capacity (FRC), residual volume (RV), and total lung capacity (TLC)] and low-frequency impedance parameters (Newtonian resistance, R(N); tissue damping; tissue elastance, H) were measured, and tracheal sounds were recorded during slow inflation to TLC following in vivo degassing. The lungs were fixed and stained for standard morphometry, elastin, and collagen. In the PPE group, FRC and RV were higher [4.53 +/- 0.7 (SD) vs. 3.28 +/- 0.45 ml; P = 0.003 and 1.06 +/- 0.35 vs. 0.69 +/- 0.18 ml; P = 0.036, respectively], and H was smaller in the PPE treated rats than in the controls (1,344 +/- 216 vs. 2,178 +/- 305 cmH(2)O/l; P < 0.001), whereas there was no difference in R(N). The average number of crackles per inflation was similar in the two groups; however, the crackle size distributions were different and the lower knee of the pressure-volume curves was higher in the PPE group. Microscopic images revealed different alveolar size distributions but similar bronchial diameters in the two groups. The treatment caused a slight but significant decrease in the numbers of alveolar attachments, no difference in elastin and slightly increased mean level and heterogeneity of collagen in the bronchial walls. These results suggest that tissue destruction did not affect the conventionally assessed airway resistance in this emphysema model, whereas the alterations in the recruitment dynamics can be an early manifestation of impaired airway function. PMID- 22442025 TI - Acute impact of intermittent pneumatic leg compression frequency on limb hemodynamics, vascular function, and skeletal muscle gene expression in humans. AB - The mechanisms by which intermittent pneumatic leg compression (IPC) treatment effectively treats symptoms associated with peripheral artery disease remain speculative. With the aim of gaining mechanistic insight into IPC treatment, the purpose of this study was to investigate the effect of IPC frequency on limb hemodynamics, vascular function, and skeletal muscle gene expression. In this two study investigation, healthy male subjects underwent an hour of either high frequency (HF; 2-s inflation/3-s deflation) or low-frequency (LF; 4-s inflation/16-s deflation) IPC treatment of the foot and calf. In study 1 (n = 11; 23.5 +/- 4.7 yr), subjects underwent both HF and LF treatment on separate days. Doppler/ultrasonography was used to measure popliteal artery diameter and blood velocity at baseline and during IPC treatment. Flow-mediated dilation (FMD) and peak reactive hyperemia blood flow (RHBF) were determined before and after IPC treatment. In study 2 (n = 19; 22.0 +/- 4.6 yr), skeletal muscle biopsies were taken from the lateral gastrocnemius of the treated and control limb at baseline and at 30- and 150-min posttreatment. Quantitative PCR was used to assess mRNA concentrations of genes associated with inflammation and vascular remodeling. No treatment effect on vascular function was observed. Cuff deflation resulted in increased blood flow (BF) and shear rate (SR) in both treatments at the onset of treatment compared with baseline (P < 0.01). BF and SR significantly diminished by 45 min of HF treatment only (P < 0.01). Both treatments reduced BF and SR and elevated oscillatory shear index compared with baseline (P < 0.01) during cuff inflation. IPC decreased the mRNA expression of cysteine-rich protein 61 from baseline and controls (P <0 .01) and connective tissue growth factor from baseline (P < 0.05) in a frequency-dependent manner. In conclusion, a single session of IPC acutely impacts limb hemodynamics and skeletal muscle gene expression in a frequency-dependent manner but does not impact vascular function. PMID- 22442026 TI - Why is the force-velocity relationship in leg press tasks quasi-linear rather than hyperbolic? AB - Force-velocity relationships reported in the literature for functional tasks involving a combination of joint rotations tend to be quasi-linear. The purpose of this study was to explain why they are not hyperbolic, like Hill's relationship. For this purpose, a leg press task was simulated with a musculoskeletal model of the human leg, which had stimulation of knee extensor muscles as only independent input. In the task the ankles moved linearly, away from the hips, against an imposed external force that was reduced over contractions from 95 to 5% of the maximum isometric value. Contractions started at 70% of leg length, and force and velocity values were extracted when 80% of leg length was reached. It was shown that the relationship between leg extension velocity and external force was quasi-linear, while the relationship between leg extension velocity and muscle force was hyperbolic. The discrepancy was explained by the fact that segmental dynamics canceled more and more of the muscle force as the external force was further reduced and velocity became higher. External power output peaked when the imposed external force was ~50% of maximum, while muscle power output peaked when the imposed force was only ~15% of maximum; in the latter case ~70% of muscle power was buffered by the leg segments. According to the results of this study, there is no need to appeal to neural mechanisms to explain why, in leg press tasks, the force-velocity relationship is quasi-linear rather than hyperbolic. PMID- 22442027 TI - Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O2 toxicity. AB - In hyperbaric oxygen (HBO(2)) at or above 3 atmospheres absolute (ATA), autonomic pathways link central nervous system (CNS) oxygen toxicity to pulmonary damage, possibly through a paradoxical and poorly characterized relationship between central nitric oxide production and sympathetic outflow. To investigate this possibility, we assessed sympathetic discharges, catecholamine release, cardiopulmonary hemodynamics, and lung damage in rats exposed to oxygen at 5 or 6 ATA. Before HBO(2) exposure, either a selective inhibitor of neuronal nitric oxide synthase (NOS) or a nonselective NOS inhibitor was injected directly into the cerebral ventricles to minimize effects on the lung, heart, and peripheral circulation. Experiments were performed on both anesthetized and conscious rats to differentiate responses to HBO(2) from the effects of anesthesia. EEG spikes, markers of CNS toxicity in anesthetized animals, were approximately four times as likely to develop in control rats than in animals with central NOS inhibition. In inhibitor-treated animals, autonomic discharges, cardiovascular pressures, catecholamine release, and cerebral blood flow all remained below baseline throughout exposure to HBO(2). In control animals, however, initial declines in these parameters were followed by significant increases above their baselines. In awake animals, central NOS inhibition significantly decreased the incidence of clonic-tonic convulsions or delayed their onset, compared with controls. The novel findings of this study are that NO produced by nNOS in the periventricular regions of the brain plays a critical role in the events leading to both CNS toxicity in HBO(2) and to the associated sympathetic hyperactivation involved in pulmonary injury. PMID- 22442028 TI - Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia. AB - Blood flow and vasodilatory responses are altered by age in a number of vascular beds, including the cerebral circulation. To test the role of prostaglandins as regulators of cerebral vascular function, we examined cerebral vasodilator responses to CO(2) (cerebrovascular reactivity) in young (26 +/- 5 yr; 6 males/6 females) and older (65 +/- 6 yr, 5 males/5 females) healthy humans before and after cyclooxygenase inhibition (using indomethacin). Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured before and 90 min after indomethacin. Changes in MCAv during the recovery from hypercapnia (vasoconstrictor responses) were also evaluated before and after indomethacin. Cerebrovascular reactivity was calculated using linear regression between MCAv and end-tidal CO(2). Young adults demonstrated greater MCAv (55 +/- 6 vs. 39 +/- 5 cm/s: P < 0.05) and MCAv reactivity (1.67 +/- 0.20 vs. 1.09 +/- 0.19 cm.s( 1).mmHg(-1); P < 0.05) to hypercapnia compared with older adults (P < 0.05). In both groups MCAv and MCAv reactivity decreased between control and indomethacin. Furthermore, the age-related differences in these cerebrovascular variables were abolished by indomethacin. During the recovery from hypercapnia, there were no age-related differences in MCAv reactivity; however, indomethacin significantly reduced the MCAv reactivity in both groups. Taken together, these results suggest that cerebral blood flow velocity and cerebrovascular reactivity are attenuated in aging humans, and may be due to a loss of prostaglandin-mediated vasodilation. PMID- 22442029 TI - Similar muscle protein synthesis rates in young men and women: men aren't from Mars and women aren't from Venus. PMID- 22442030 TI - The measurement of endogenous carbon monoxide production. AB - Recent findings that heme oxygenase-1 can be induced by oxidative stress and inflammation in many different cellular systems, and that carbon monoxide (CO) produced as a by-product of this enzyme is a signaling molecule, have generated a major research area with hundreds of studies published over the last few years. The measurement of expired CO concentration has been used in humans as a biomarker of induced heme oxygenase resulting from inflammation or oxidative stress, but a precise method of measuring endogenous CO production that can be easily used to study patients is needed. The present study describes such a method. The described method allows calculation of the rate of heme catabolism with a precision of +/-2 MUmol/h, ~10% of the mean normal rate in subjects used in this investigation. This method, which is subject-patient friendly, precise, and inexpensive to perform, should be applicable to studies performed on humans with induced heme oxygenase and studies of effects of therapy for inflammatory and hemolytic diseases. PMID- 22442031 TI - Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men. AB - Fat accumulates in the bone marrow of lumbar vertebrae with bed rest. Exercise with or without whole body vibration may counter this effect. Our objectives were to measure 1) the vertebral fat fraction (VFF) of men subjected to bed rest who performed resistive exercises with (RVE, n = 7) or without whole body vibration(RE, n = 8) or no exercise (CTR, n = 9) using three MRI techniques; and 2) changes in peripheral blood counts. Twenty-four healthy men (age: 20-45 yr) underwent -6 degrees head-down tilt (HDT) bed rest for 60 days. MRI was performed using three techniques (fat saturation, proton spectroscopy, and in and out of phase) to measure the fat fraction of L(3), L(4), and/or L(5) at baseline, mid-HDT, and end-HDT. Erythrocytes and leukocytes were counted at HDT days 19, 33, 47, 54, and 60. The mean absolute VFF was increased in the CTR group at mid HDT and end-HDT (+3.9 +/- 1.3 and +3.6 +/- 1.2%, respectively, both P < 0.05). The RE group had a smaller VFF change than the CTR group at mid-HDT (-0.9 +/- 1.2 vs. +3.9 +/- 1.3%, P < 0.05). The RVE group had a smaller VFF change than the CTR group at end-HDT (-2.6 +/- 1.9 vs. +3.5 +/- 1.2%, P < 0.05). Erythrocyte counts were increased in all groups at HDT day 19 and HDT day 33 and in the RE group at HDT day 54 (all P < 0.05). Bed rest for 60 days at -6 degrees HDT increased lumbar VFF in men beyond natural involution. RVE and RE regimens effectively prevented VFF accumulation. Higher erythrocyte counts were not altered by RVE or RE. Whole body vibration, along with RE administered to people with prolonged immobility, may prevent fat accumulation in their bone marrow. PMID- 22442032 TI - What does the transcriptome signature of resistance exercise tell us about aging and skeletal muscle adaptation? PMID- 22442033 TI - The 2011 Most Influential Bioelectromagnetics Journal Paper by Citation Award to Dr. Jonna Wilen, Dr. Amanda Johansson, Dr. Nebojsa Kalezic, Dr. Eugene Lyskov, and Dr. Monica Sandstrom. PMID- 22442034 TI - Recombinant protein expression and purification: a comprehensive review of affinity tags and microbial applications. AB - Protein fusion tags are indispensible tools used to improve recombinant protein expression yields, enable protein purification, and accelerate the characterization of protein structure and function. Solubility-enhancing tags, genetically engineered epitopes, and recombinant endoproteases have resulted in a versatile array of combinatorial elements that facilitate protein detection and purification in microbial hosts. In this comprehensive review, we evaluate the most frequently used solubility-enhancing and affinity tags. Furthermore, we provide summaries of well-characterized purification strategies that have been used to increase product yields and have widespread application in many areas of biotechnology including drug discovery, therapeutics, and pharmacology. This review serves as an excellent literature reference for those working on protein fusion tags. PMID- 22442035 TI - Plastid genome evolution in mycoheterotrophic Ericaceae. AB - Unlike parasitic plants, which are linked to their hosts directly through haustoria, mycoheterotrophic (MHT) plants derive all or part of their water and nutrients from autothrophs via fungal mycorrhizal intermediaries. Ericaceae, the heather family, are a large and diverse group of plants known to form elaborate symbiotic relationships with mycorrhizal fungi. Using PHYA sequence data, we first investigated relationships among mycoheterotrophic Ericaceae and their close autotrophic relatives. Phylogenetic results suggest a minimum of two independent origins of MHT within this family. Additionally, a comparative investigation of plastid genomes (plastomes) grounded within this phylogenetic framework was conducted using a slot-blot Southern hybridization approach. This survey encompassed numerous lineages of Ericaceae with different life histories and trophic levels, including multiple representatives from mixotrophic Pyroleae and fully heterotrophic Monotropeae and Pterosporeae. Fifty-four probes derived from all categories of protein coding genes typically found within the plastomes of flowering plants were used. Our results indicate that the holo mycoheterotrophic Ericaceae exhibit extensive loss of genes relating to photosynthetic function and expression of the plastome but retain genes with possible functions outside photosynthesis. Mixotrophic taxa tend to retain most genes relating to photosynthetic functions but are varied regarding the plastid ndh gene content. This investigation extends previous inferences that the loss of the NDH complex occurs prior to becoming holo-heterotrophic and it shows that the pattern of gene losses among mycoheterotrophic Ericaceae is similar to that of haustorial parasites. Additionally, we identify the most desirable candidate species for entire plastome sequencing. PMID- 22442036 TI - Influence of an ER-retention signal on the N-glycosylation of recombinant human alpha-L-iduronidase generated in seeds of Arabidopsis. AB - Processes associated with late events of N-glycosylation within the plant Golgi complex are a major limitation to the use of plant-based systems to produce recombinant pharmaceutical proteins for parenteral administration. Specifically, sugars added to the N-glycans of a recombinant protein during glycan maturation to complex forms (e.g. beta1,2 xylose and alpha1,3 fucose) can render the product immunogenic. In order to avoid these sugars, the human enzyme alpha-L-iduronidase (IDUA, EC 3.2.1.76), with a C-terminal ER-retention sequence SEKDEL, was expressed in seeds of complex-glycan-deficient (cgl) mutant and wild-type (Col-0) Arabidopsis thaliana, under the control of regulatory (5'-, signal-peptide encoding-, and 3'-) sequences from the arcelin 5-I gene of Phaseolus vulgaris (cgl-IDUA-SEKDEL and Col-IDUA-SEKDEL, respectively). The SEKDEL motif had no adverse effect on the specific activity of the purified enzyme. Surprisingly, the majority of the N-glycans of Col-IDUA-SEKDEL were complex N-glycans (i.e. contained xylose and/or fucose) (88 %), whereas complex N-glycans comprised a much lower proportion of the N-glycans of cgl-IDUA-SEKDEL (26 %), in which high mannose forms were predominant. In contrast to the non-chimeric IDUA of cgl seeds, which is mainly secreted into the extracellular spaces, the addition of the SEKDEL sequence to human recombinant IDUA expressed in the same background led to retention of the protein in ER-derived vesicles/compartments and its partial localization in protein storage vacuoles. Our data support the contention that the use of a C-terminal ER retention motif as an effective strategy to prevent or reduce complex N-glycan formation, is protein specific. PMID- 22442037 TI - Maturation of mammalian H/ACA box snoRNAs: PAPD5-dependent adenylation and PARN dependent trimming. AB - Small nucleolar and small Cajal body RNAs (snoRNAs and scaRNAs) of the H/ACA box and C/D box type are generated by exonucleolytic shortening of longer precursors. Removal of the last few nucleotides at the 3' end is known to be a distinct step. We report that, in human cells, knock-down of the poly(A) specific ribonuclease (PARN), previously implicated only in mRNA metabolism, causes the accumulation of oligoadenylated processing intermediates of H/ACA box but not C/D box RNAs. In agreement with a role of PARN in snoRNA and scaRNA processing, the enzyme is concentrated in nucleoli and Cajal bodies. Oligo(A) tails are attached to a short stub of intron sequence remaining beyond the mature 3' end of the snoRNAs. The noncanonical poly(A) polymerase PAPD5 is responsible for addition of the oligo(A) tails. We suggest that deadenylation is coupled to clean 3' end trimming, which might serve to enhance snoRNA stability. PMID- 22442038 TI - Does C2 monitoring have benefit over C0 level in solid organ transplantation? PMID- 22442039 TI - Dynamic parathyroid CT: are 2 phases sufficient? PMID- 22442040 TI - Acute stroke imaging: CT with CT angiography and CT perfusion before management decisions. PMID- 22442041 TI - Predicting breakdown of the blood-brain barrier in multiple sclerosis without contrast agents. AB - BACKGROUND AND PURPOSE: Disruption of the BBB in MS is associated with the development of new lesions and clinical relapses and signifies the presence of active inflammation. It is most commonly detected as enhancement on MR imaging performed with contrast agents that are costly and occasionally toxic. We investigated whether the BBB status in white matter lesions may be indirectly ascertained via examination of features on T1- and T2-weighted images obtained before the injection of a contrast agent. MATERIALS AND METHODS: We considered 93 brain MR imaging studies on 16 patients that included T1-, T2-, and T2-weighted FLAIR images and predicted voxel wise enhancement after intravenous injection of a gadolinium chelate. We then used these voxel-level predictions to determine the presence or absence of abnormal enhancement anywhere in the brain. RESULTS: On a voxel-by-voxel basis, enhancement can be predicted by using contrast-free measures with an AUC of 0.83 (95% CI, 0.80-0.87). At the whole-brain level, enhancement can be predicted with an AUC of 0.72 (95% CI, 0.62-0.82). CONCLUSIONS: In many cases, breakdown of the BBB in acute MS lesions may be inferred without the need to inject an MR imaging contrast agent. The inference relies on intrinsic properties of tissue damage in acute lesions. Although contrast studies are more accurate, they may sometimes be unnecessary. PMID- 22442042 TI - MR imaging findings of the intraspinal meningeal melanocytoma: correlation with histopathologic findings. AB - Our aim was to better understand and improve the accuracy of the preoperative diagnosis of intraspinal MM by a combined analysis of MR imaging and pathologic findings. All 5 patients had undergone unenhanced and contrast-enhanced MR imaging examinations. All tumor samples had immunohistochemical reactions to HMB 45, vimentin, S-100, EMA, and Leu-7 antibodies. All 5 cases were located in the intradural extramedullary compartment. Two cases had multifocal lesions, and 3 cases were solitary. Two cases showed homogeneously strong enhancement, and 3 cases showed moderate enhancement on contrast-enhanced T1WI. The tumor cells had positive reactions to HMB-45, vimentin, and S-100 antibodies. MR imaging plays an important role in the detection and diagnosis of intraspinal MM. Final diagnosis should be based on histopathology and IHC examinations. PMID- 22442043 TI - Automated versus manual in vivo segmentation of carotid plaque MRI. AB - BACKGROUND AND PURPOSE: Automatically identifying carotid plaque composition using MR imaging remains a challenging task in vivo. The purpose of our study was to compare the detection and quantification of carotid artery atherosclerotic plaque components based on in vivo MR imaging data using manual and automated segmentation. MATERIALS AND METHODS: Sixty patients from a multicenter study were split into a training group (20 patients) and a study group (40 patients). Each MR imaging study consisted of 4 high-resolution carotid wall sequences (T1, T2, PDw, TOF). Manual segmentation was performed by delineation of the vessel wall and different plaque components. Automated segmentation was performed in the study group by a supervised classifier trained on images from the training group of patients. RESULTS: For the detection of plaque components, the agreement between the visual and automated analysis was moderate for calcifications (kappa = 0.59, CI 95% [0.36-0.82]) and good for hemorrhage (0.65 [0.42-0.88]) and lipids (0.65 [0.03-1.27]). For quantification of plaque volumes, the intraclass correlation was high for hemorrhage (0.80 [0.54-0.92]) and fibrous tissue (0.80 [0.65-0.89]), good for lipids (0.65 [0.43-0.80]), and poor for calcifications. CONCLUSIONS: In 40 patients with carotid stenosis, our results indicated that it was possible to automatically detect carotid plaque components with substantial or good agreement with visual identification, and that the volumes obtained manually and automatically were reasonably consistent for hemorrhage and lipids but not for calcium. PMID- 22442044 TI - Cranioplasty sinking should affect normal brain function mimicking other neurologic illness. PMID- 22442045 TI - Elastase-induced rabbit aneurysms model complicated by thoracic aortic aneurysms. PMID- 22442046 TI - Diagnostic accuracy of dynamic contrast-enhanced MR imaging using a phase-derived vascular input function in the preoperative grading of gliomas. AB - BACKGROUND AND PURPOSE: The accuracy of tumor plasma volume and K(trans) estimates obtained with DCE MR imaging may have inaccuracies introduced by a poor estimation of the VIF. In this study, we evaluated the diagnostic accuracy of a novel technique by using a phase-derived VIF and "bookend" T1 measurements in the preoperative grading of patients with suspected gliomas. MATERIALS AND METHODS: This prospective study included 46 patients with a new pathologically confirmed diagnosis of glioma. Both magnitude and phase images were acquired during DCE MR imaging for estimates of K(trans)_phi and V(p_)phi (calculated from a phase derived VIF and bookend T1 measurements) as well as K(trans)_SI and V(p_)SI (calculated from a magnitude-derived VIF without T1 measurements). RESULTS: Median K(trans)_phi values were 0.0041 minutes(-1) (95 CI, 0.00062-0.033), 0.031 minutes(-1) (0.011-0.150), and 0.088 minutes(-1) (0.069-0.110) for grade II, III, and IV gliomas, respectively (P <= .05 for each). Median V(p_)phi values were 0.64 mL/100 g (0.06-1.40), 0.98 mL/100 g (0.34-2.20), and 2.16 mL/100 g (1.8-3.1) with P = .15 between grade II and III gliomas and P = .015 between grade III and IV gliomas. In differentiating low-grade from high-grade gliomas, AUCs for K(trans)_phi, V(p_phi), K(trans)_SI, and V(p_)SI were 0.87 (0.73-1), 0.84 (0.69 0.98), 0.81 (0.59-1), and 0.84 (0.66-0.91). The differences between the AUCs were not statistically significant. CONCLUSIONS: K(trans)_phi and V(p_)phi are parameters that can help in differentiating low-grade from high-grade gliomas. PMID- 22442047 TI - Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization. AB - BACKGROUND AND PURPOSE: Intra-arterial chemotherapy is a very effective treatment option for intraocular retinoblastoma. However, direct catheterization of the OA is not always possible. The purpose of this work was to report our initial results with intra-arterial chemotherapy for intraocular retinoblastoma when delivery of the drug was not via direct catheterization of the OA. MATERIALS AND METHODS: Retrospective review of 110 eyes (89 patients) undergoing a total of 351 intra-arterial treatments at our institution between 2006 and 2010 identified 18 eyes (14 patients) that received at least 1 infusion via a vascular route other than direct OA catheterization. Alternatives included catheterization of the orbital branch of the MMA and temporary balloon occlusion of the ICA. RESULTS: Tumor control was observed in 17 of 18 eyes at a mean follow-up of 18.9 months (median, 17.5 months; range, 8-36 months). The mean number of intra-arterial infusions was 3.7 per eye (median, 3; range, 2-9). Treatment routes included the following: MMA only, 3 eyes; MMA + OA, 4 eyes; MMA + balloon, 2 eyes; balloon only, 1 eye; balloon + OA, 7 eyes; balloon + OA + MMA, 1 eye. Intra-arterial chemotherapies included melphalan, topotecan, and carboplatin. Complications were all transient. ERG readings were the following: stable, 10 eyes; improved, 3 eyes; reduced, 5 eyes. One patient died from a second malignancy (pinealoblastoma). CONCLUSIONS: This initial experience shows that when direct OA catheterization is not possible, using alternative routes of intra-arterial chemotherapy saves eyes and preserves vision with acceptable side effects. PMID- 22442048 TI - Quantification of orbital apex crowding for screening of dysthyroid optic neuropathy using multidetector CT. AB - BACKGROUND AND PURPOSE: DON, a serious complication of GO, is frequently difficult to diagnose clinically in its early stages because of confounding signs and symptoms of congestive orbitopathy. We evaluated the ability of square area measurements of orbital apex crowding, calculated with MDCT, to detect DON. MATERIALS AND METHODS: Fifty-six patients with GO were studied prospectively with complete neuro-ophthalmologic examination and MDCT scanning. Square measurements were taken from coronal sections 12 mm, 18 mm, and 24 mm from the interzygomatic line. The ratio between the extraocular muscle area and the orbital bone area was used as a CI. Intracranial fat prolapse through the superior orbital fissure was recorded as present or absent. Severity of optic nerve crowding was also subjectively graded on coronal images. Orbits were divided into 2 groups (with or without clinical evidence of DON) and compared. RESULTS: Ninety-five orbits (36 with and 59 without DON) were studied. The CIs at all 3 levels and the subjective crowding score were significantly greater in orbits with DON (P < .001). No significant difference was observed regarding intracranial fat prolapse (P = .105). The area under the ROC curves was 0.91, 0.93, and 0.87 for CIs at 12, 18, and 24 mm, respectively. The best performance was at 18 mm, where a cutoff value of 57.5% corresponded to 91.7% sensitivity, 89.8% specificity, and an odds ratio of 97.2 for detecting DON. A significant correlation (P < .001) between the CIs and VF defects was observed. CONCLUSIONS: Orbital CIs based on area measurements were found to predict DON more reliably than subjective grading of orbital crowding or intracranial fat prolapse. PMID- 22442049 TI - Protein arginine methylation of SERBP1 by protein arginine methyltransferase 1 affects cytoplasmic/nuclear distribution. AB - Protein arginine methylation regulates a broad array of cellular processes. SERBP1 implicated in tumor progression through its putative involvement in the plaminogen activator protease cascade, is an RNA-binding protein containing an RG rich domain and an RGG box domain that might be methylated by protein arginine N methyltransferases (PRMTs). Asymmetric dimethylarginine (aDMA) was detected in SERBP1 and an indirect methyltransferase inhibitor adenosine dialdehyde (AdOx) significantly reduced the methylation signals. Arginines in the middle RG and C terminal RGG region of SERBP1 are methylated based on the analyses of different deletion constructs. The predominant type I protein arginine methyltransferase PRMT1 co-immunoprecipitated with SERBP1 and the level of bound PRMT1 decreased upon the addition of AdOx. Recombinant PRMT1 methylated SERBP1 and knockdown of PRMT1 significantly reduced the aDMA level of SERBP1, indicating that SERBP1 is specifically methylated by PRMT1. Immunofluorescent analyses of endogenous SERBP1 showed predominant cytoplasmic localization of SERBP1. Treatment of AdOx or PRMT1 siRNA increased the nuclear localization of SERBP1. Analyses of different deletions indicated that the middle RG region is important for the nuclear localization while both N- and C- terminus are required for nuclear export. Low methylation of the C-terminal RGG region also favors nuclear localization. In conclusion, the RG-rich and RGG box of SERBP1 is asymmetrically dimethylated by PRMT1 and the modification affects protein interaction and intracellular localization of the protein. These findings provide the basis for dissecting the roles of SERBP1. PMID- 22442050 TI - Catalytic arylation of a C-H bond in pyridine and related six-membered N heteroarenes using organozinc reagents. AB - Despite significant advances in the catalytic direct arylation of heteroarenes, the application of this reaction to pyridines has been met with limited success. An oxidative nucleophilic arylation strategy has been developed to overcome this problem. Pyridine, pyrazine, quinolone, and related electron-deficient N heteroarenes can be arylated at the most electrophilic site using the developed nickel-catalyzed reaction. This protocol serves as a complementary method to catalytic direct arylation reactions. PMID- 22442051 TI - Extracellular vesicles--vehicles that spread cancer genes. AB - Once regarded as cellular 'debris' extracellular vesicles (EVs) emerge as one of the most intriguing entities in cancer pathogenesis. Intercellular trafficking of EVs challenges the notion of cancer cell autonomy, and highlights the multicellular nature of such fundamental processes as stem cell niche formation, tumour stroma generation, angiogenesis, inflammation or immunity. Recent studies reveal that intercellular exchange mediated by EVs runs deeper than expected, and includes molecules causative for cancer progression, such as oncogenes (epidermal growth factor receptor, Ras), and tumour suppressors (PTEN). The uptake of oncogenic EVs (oncosomes) by various cells may profoundly change their biology, signalling patterns and gene expression, and in some cases cause their overt tumorigenic conversion. Moreover, EVs circulating in blood and present in body fluids provide an unprecedented access to the molecular circuitry driving cancer cells, and new technologies are being developed to exploit this property as a source of unique cancer biomarkers. PMID- 22442052 TI - Early regression of the dental lamina underlies the development of diphyodont dentitions. AB - Functional tooth germs in mammals, reptiles, and chondrichthyans are initiated from a dental lamina. The longevity of the lamina plays a role in governing the number of tooth generations. Monophyodont species have no replacement dental lamina, while polyphyodont species have a permanent continuous lamina. In diphyodont species, the dental lamina fragments and regresses after initiation of the second tooth generation. Regression of the lamina seems to be an important mechanism in preventing the further development of replacement teeth. Defects in the complete removal of the lamina lead to cyst formation and has been linked to ameloblastomas. Here, we show the previously unknown mechanisms behind the disappearance of the dental lamina, involving a combination of cell migration, cell-fate transformation, and apoptosis. Lamina regression starts with the loss of the basement membrane, allowing the epithelial cells to break away from the lamina and migrate into the surrounding mesenchyme. Cells deactivate epithelial markers (E-cadherin, cytokeratin), up-regulate Slug and MMP2, and activate mesenchymal markers (vimentin), while residual lamina cells are removed by apoptosis. The uncovering of the processes behind lamina degradation allows us to clarify the evolution of diphyodonty, and provides a mechanism for future manipulation of the number of tooth generations. PMID- 22442053 TI - Rediscovering Sig Socransky, the genius and his legacy. AB - Some individuals make contributions so vital to their field of knowledge that their names become almost synonymous with that field. This is the case of Sig Socransky and the field of periodontal microbiology. Sig Socransky, or simply Sig, was born in Toronto, Canada and received his DDS degree from the University of Toronto in 1957. He studied microbiology and periodontology at Harvard, receiving a certificate in 1961. That same year he was recruited to work as a Research Associate at the Forsyth Dental Center. In 1968, he was nominated Senior Member of the Staff and Head of the Department of Periodontology. During his 50 year career at Forsyth, Sig published over 300 manuscripts, keeping an average of 7 publications per year. His work had an indelible impact in the fields of periodontology and oral microbiology. All these accomplishments pale in comparison with the impact that Sig had on a personal level. We have collected testimonials from some of his former students, closest collaborators, and friends in an attempt to give readers an insight into Sig's personality. We hope we can offer those who knew him through his work a glimpse of how it felt to interact with this remarkable individual. PMID- 22442054 TI - Crassulacean acid metabolism (CAM) in an epiphytic ant-plant, Myrmecodia beccarii Hook.f. (Rubiaceae). AB - This study demonstrates unequivocally the presence of crassulacean acid metabolism (CAM) in a species of the Rubiaceae, the fourth largest angiosperm plant family. The tropical Australian endemic epiphytic ant-plant, Myrmecodia beccarii Hook.f., exhibits net CO(2) uptake in the dark and a concomitant accumulation of titratable acidity in plants in the field and in cultivation. Plants growing near Cardwell, in a north Queensland coastal seasonally dry forest of Melaleuca viridiflora Sol. ex Gaertn., accumulated ~50 % of their 24 h carbon gain in the dark during the warm wet season. During the transition from the wet season to the dry season, 24 h carbon gain was reduced whilst the proportion of carbon accumulated during the dark increased. By mid dry season many plants exhibited zero net carbon uptake over 24 h, but CO(2) uptake in the dark was observed in some plants following localised rainfall. In a shade-house experiment, droughted plants in which CO(2) uptake in the light was absent and dark CO(2) uptake was reduced, were able to return to relatively high rates of CO(2) uptake in the light and dark within 12 h of rewatering. PMID- 22442055 TI - Polyclonal antibodies against the TLA1 protein also recognize with high specificity the D2 reaction center protein of PSII in the green alga Chlamydomonas reinhardtii. AB - The Chlamydomonas reinhardtii DNA-insertional transformant truncated light harvesting antenna 1 (tla1) mutant, helped identify the novel TLA1 gene (GenBank Accession # AF534570-71) as an important genetic determinant in the chlorophyll antenna size of photosynthesis. Down-regulation in the amount of the TLA1 23 kDa protein in the cell resulted in smaller chlorophyll antenna size for both photosystems (in Tetali et al. Planta 225:813-829, 2007). Specific polyclonal antibodies, raised against the recombinant TLA1 protein, showed a cross-reaction with the predicted 23 kDa TLA1 protein in C. reinhardtii protein extracts, but also showed a strong cross-reaction with a protein band migrating to 28.5 kDa. Questions of polymorphism, or posttranslational modification of the TLA1 protein were raised as a result of the unexpected 28.5 kDa cross-reaction. Work in this paper aimed to elucidate the nature of the unexpected 28.5 kDa cross-reaction, as this was deemed to be important in terms of the functional role of the TLA1 protein in the regulation of the chlorophyll antenna size of photosynthesis. Immuno-precipitation of the 28.5 kDa protein, followed by LC-mass spectrometry, showed amino acid sequences ascribed to the psbD/D2 reaction center protein of PSII. The common antigenic determinant between TLA1 and D2 was shown to be a stretch of nine conserved amino acids V-F-L(V)LP-GNAL in the C-terminus of the two proteins, constituting a high antigenicity "GNAL" domain. Antibodies raised against the TLA1 protein containing this domain recognized both the TLA1 and the D2 protein. Conversely, antibodies raised against the TLA1 protein minus the GNAL domain specifically recognized the 23 kDa TLA1 protein and failed to recognize the 28.5 kDa D2 protein. D2 antibodies raised against an oligopeptide containing this domain also cross-reacted with the TLA1 protein. It is concluded that the 28.5 kDa cross-reaction of C. reinhardtii protein extracts with antiTLA1 antibodies is due to antibody affinity for the GNAL domain of the D2 protein and has no bearing on the identity or function of the TLA1 protein. PMID- 22442056 TI - Dynamically applied B1+ shimming solutions for non-contrast enhanced renal angiography at 7.0 Tesla. AB - The purpose of this study was to detail a strategy for performing non-contrast enhanced renal magnetic resonance angiography studies at 7.0 T. It is demonstrated that with proper B1+ management, these studies can be successfully performed at ultrahigh field within local specific absorption rate constraints. An inversion prepared gradient echo acquisition, standard for non-contrast renal magnetic resonance angiography studies, required radiofrequency pulse specific B 1+ shimming solutions to be dynamically applied to address the field dependent increases in both B(0) and B1+ inhomogeneity as well as to accommodate limitation in available power. By using more efficient B1+ shimming solutions for the inversion preparation and more homogeneous solutions for the excitation, high quality images of the renal arteries were obtained without venous and background signal artifacts while working within hardware and safety constraints. Finite difference time domain simulations confirmed in vivo measurements with respect to B1+ distributions and homogeneity for the range of shimming strategies used and allowed the calculation of peak local specific absorption rate values normalized by input power and B1+. Increasing B1+ homogeneity was accompanied by decreasing local specific absorption rate per Watt and increasing maximum local specific absorption rate per [B1+](2), which must be considered, along with body size and respiratory rate, when finalizing acquisition parameters for a given individual. PMID- 22442057 TI - Has removal of excess cysteine led to the evolution of pheomelanin? Pheomelanogenesis as an excretory mechanism for cysteine. AB - Pheomelanogenesis may have evolved as an excretory mechanism to remove excess cysteine, and in humans this might potentially confer a greater ability to avoid disease such as Parkinson's and Alzheimer's disease, in which excess cysteine is a contributory cause. PMID- 22442059 TI - Will Hsp90 inhibitors prove effective in BRAF-mutant melanomas? AB - The RAF inhibitor vemurafenib has unprecedented activity in BRAF-mutant melanomas, but resistance invariably develops. As Hsp90 is required for the stability of several of the oncoproteins that mediate RAF inhibitor resistance, inhibitors of this cellular chaperone may be effective in patients with intrinsic or acquired resistance to RAF inhibitors. PMID- 22442060 TI - For breast cancer prognosis, immunoglobulin kappa chain surfaces to the top. AB - The stromal immunoglobulin kappa chain (IGKC) has been validated as an immunologic biomarker of prognosis and response to therapy in human breast cancer and other cancers. This validation emphasizes the key role of humoral immunity in control of cancer progression and has major implications for determining prognosis of patients with cancer. PMID- 22442061 TI - Disrupting the networks of cancer. AB - Ecosystems are interactive systems involving communities of species and their abiotic environment. Tumors are ecosystems in which cancer cells act as invasive species interacting with native host cell species in an established microenvironment within the larger host biosphere. At its heart, to study ecology is to study interconnectedness. In ecologic science, an ecologic network is a representation of the biotic interactions in an ecosystem in which species (nodes) are connected by pairwise interactions (links). Ecologic networks and signaling network models have been used to describe and compare the structures of ecosystems. It has been shown that disruption of ecologic networks through the loss of species or disruption of interactions between them can lead to the destruction of the ecosystem. Often, the destruction of a single node or link is not enough to disrupt the entire ecosystem. The more complex the network and its interactions, the more difficult it is to cause the extinction of a species, especially without leveraging other aspects of the ecosystem. Similarly, successful treatment of cancer with a single agent is rarely enough to cure a patient without strategically modifying the support systems conducive to survival of cancer. Cancer cells and the ecologic systems they reside in can be viewed as a series of nested networks. The most effective new paradigms for treatment will be developed through application of scaled network disruption. PMID- 22442062 TI - Cell adhesion complexes localize presynaptic vesicles by regulating local actin polymerization. PMID- 22442063 TI - Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice. AB - Influenza is a common and highly contagious viral pathogen, yet its effects on the structure and function of the CNS remain largely unknown. Although there is evidence that influenza strains that infect the brain can lead to altered cognitive and emotional behaviors, it is unknown whether a viral strain that is not neurotropic (A/PR/8/34) can result in a central inflammatory response, neuronal damage, and neurobehavioral effects. We hypothesized that neuroinflammation and alterations in hippocampal neuron morphology may parallel cognitive dysfunction following peripheral infection with live influenza virus. Here, we show that influenza-infected mice exhibited cognitive deficits in a reversal learning version of the Morris water maze. At the same time point in which cognitive impairment was evident, proinflammatory cytokines (IL-1beta, IL 6, TNF-alpha, IFN-alpha) and microglial reactivity were increased, while neurotrophic (BDNF, NGF) and immunomodulatory (CD200, CX3CL1) factors were decreased in the hippocampus of infected mice. In addition, influenza induced architectural changes to hippocampal neurons in the CA1 and dentate gyrus, with the most profound effects on dentate granule cells in the innermost portion of the granule cell layer. Overall, these data provide the first evidence that neuroinflammation and changes in hippocampal structural plasticity may underlie cognitive dysfunction associated with influenza infection. In addition, the heightened inflammatory state concurrent with reduced neurotrophic support could leave the brain vulnerable to subsequent insult following influenza infection. A better understanding of how influenza impacts the brain and behavior may provide insight for preventing inflammation and neuronal damage during peripheral viral infection. PMID- 22442064 TI - Synapsin selectively controls the mobility of resting pool vesicles at hippocampal terminals. AB - Presynaptic terminals are specialized sites for information transmission where vesicles fuse with the plasma membrane and are locally recycled. Recent work has extended this classical view, with the observation that a subset of functional vesicles is dynamically shared between adjacent terminals by lateral axonal transport. Conceptually, such transport would be expected to disrupt vesicle retention around the active zone, yet terminals are characterized by a high density vesicle cluster, suggesting that counteracting stabilizing mechanisms must operate against this tendency. The synapsins are a family of proteins that associate with synaptic vesicles and determine vesicle numbers at the terminal, but their specific function remains controversial. Here, using multiple quantitative fluorescence-based approaches and electron microscopy, we show that synapsin is instrumental for resisting vesicle dispersion and serves as a regulatory element for controlling lateral vesicle sharing between synapses. Deleting synapsin disrupts the organization of presynaptic vesicle clusters, making their boundaries hard to define. Concurrently, the fraction of vesicles amenable to transport is increased, and more vesicles are translocated to the axon. Importantly, in neurons from synapsin knock-out mice the resting and recycling pools are equally mobile. Synapsin, when present, specifically restricts the mobility of resting pool vesicles without affecting the division of vesicles between these pools. Specific expression of synapsin IIa, the sole isoform affecting synaptic depression, rescues the knock-out phenotype. Together, our results show that synapsin is pivotal for maintaining synaptic vesicle cluster integrity and that it contributes to the regulated sharing of vesicles between terminals. PMID- 22442065 TI - Broadening of cortical inhibition mediates developmental sharpening of orientation selectivity. AB - Orientation selectivity (OS) of visual cortical neurons is progressively sharpened during development. However, synaptic circuit mechanisms underlying the OS sharpening remain unclear. In the current study, in vivo whole-cell voltage clamp recordings from layer 4 excitatory neurons in the developing mouse primary visual cortex revealed changes of orientation tuning profiles of their excitatory and inhibitory inputs during a post-eye-opening period when OS of their spiking responses becomes sharpened. In addition to a parallel strengthening of excitation and inhibition during this developmental period, the orientation tuning of excitatory inputs keeps relatively constant, whereas the tuning of inhibitory inputs is broadened, and becomes significantly broader than that of excitatory inputs. Neuron modeling and dynamic-clamp recording demonstrated that this developmental broadening of the inhibitory tuning is sufficient for sharpening OS. Depriving visual experience by dark rearing impedes the normal developmental strengthening of excitation, but a similar broadening of inhibitory tuning, likely caused by a nonselective strengthening of inhibitory connections, results in the apparently normal OS sharpening in excitatory neurons. Our results thus provide the first demonstration that an inhibitory synaptic mechanism can primarily mediate the functional refinement of cortical neurons. PMID- 22442066 TI - Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons. AB - The NMDAR plays a unique and vital role in subcellular signaling. Calcium influx initiates signaling cascades important for both synaptic plasticity and survival; however, overactivation of the receptor leads to toxicity and cell death. This dichotomy is partially explained by the subcellular location of the receptor. NMDARs located at the synapse stimulate cell survival pathways, while extrasynaptic receptors signal for cell death. Thus far, this interplay between synaptic and extrasynaptic NMDARs has been studied exclusively in cortical (CTX) and hippocampal neurons. It was unknown whether other cell types, such as GABAergic medium-sized spiny projection neurons of the striatum (MSNs), which bear the brunt of neurodegeneration in Huntington's disease, follow the same pattern. Here we report synaptic versus extrasynaptic NMDAR signaling in striatal MSNs and resultant activation of cAMP response element binding protein (CREB), in rat primary corticostriatal cocultures. Similarly to CTX, we found in striatal MSNs that synaptic NMDARs activate CREB, whereas extrasynaptic NMDARs dominantly oppose CREB activation. However, MSNs are much less susceptible to NMDA-mediated toxicity than CTX cells and show differences in subcellular GluN2B distribution. Blocking NMDARs with memantine (30 MUm) or GluN2B-containing receptors with ifenprodil (3 MUm) prevents CREB shutoff effectively in CTX and MSNs, and also rescues both neuronal types from NMDA-mediated toxicity. This work may provide cell and NMDAR subtype-specific targets for treatment of diseases with putative NMDAR involvement, including neurodegenerative disorders and ischemia. PMID- 22442067 TI - Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. AB - Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti inflammatory effects. However, in this context, little is known about how selective activation of the cannabinoid type-2 receptor (CB2R) affects the activated state of the brain endothelium and blood-brain barrier (BBB) function. Using human brain tissues and primary human brain microvascular endothelial cells (BMVECs), we demonstrate that the CB2R is highly upregulated during inflammatory insult. We then examined whether the CB2R agonists could attenuate inflammatory responses at the BBB using a mouse model of LPS-induced encephalitis and highly selective CB2R agonists. Visualization by intravital microscopy revealed that administration of JWH133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro 6,6,9-trimethyl-6H-dibenzo[b,d]pyran] or a novel resorcinol-based compound, O 1966 (1-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-3-methyl-cyclohexanol), greatly attenuated leukocyte adhesion in surface pial vessels and in deep ascending cortical postcapillary venules. BBB permeability assessments with small and large fluorescent tracers showed that CB2R agonists were effective at preventing barrier leakiness after LPS administration. To determine whether the effects by CB2R agonists on barrier protection are not only due to the CB2R modulation of immune cell function, we tested the agonists in vitro with barrier forming primary BMVECs. Remarkably, the addition of CB2R agonist increased transendothelial electrical resistance and increased the amount of tight junction protein present in membrane fractions. Furthermore, CB2R agonists decreased the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 surface expression in BMVECs exposed to various proinflammatory mediators. Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation. PMID- 22442068 TI - Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain. AB - Severe head trauma causes widespread neuronal shear injuries and acute seizures. Shearing of neural processes might contribute to seizures by disrupting the transmembrane ion gradients that subserve normal synaptic signaling. To test this possibility, we investigated changes in intracellular chloride concentration ([Cl(-)](i)) associated with the widespread neural shear injury induced during preparation of acute brain slices. In hippocampal slices and intact hippocampal preparations from immature CLM-1 mice, increases in [Cl(-)](i) correlated with disruption of neural processes and biomarkers of cell injury. Traumatized neurons with higher [Cl(-)](i) demonstrated excitatory GABA signaling, remained synaptically active, and facilitated network activity as assayed by the frequency of extracellular action potentials and spontaneous network-driven oscillations. These data support a more inhibitory role for GABA in the unperturbed immature brain, demonstrate the utility of the acute brain slice preparation for the study of the consequences of trauma, and provide potential mechanisms for both GABA mediated excitatory network events in the slice preparation and early post traumatic seizures. PMID- 22442069 TI - Understanding low reliability of memories for neutral information encoded under stress: alterations in memory-related activation in the hippocampus and midbrain. AB - Exposure to an acute stressor can lead to unreliable remembrance of intrinsically neutral information, as exemplified by low reliability of eyewitness memories, which stands in contrast with enhanced memory for the stressful incident itself. Stress-sensitive neuromodulators (e.g., catecholamines) are believed to cause this low reliability by altering neurocognitive processes underlying memory formation. Using event-related functional magnetic resonance imaging, we investigated neural activity during memory formation in 44 young, healthy human participants while incidentally encoding emotionally neutral, complex scenes embedded in either a stressful or neutral context. We recorded event-related pupil dilation responses as an indirect index of phasic noradrenergic activity. Autonomic, endocrine, and psychological measures were acquired to validate stress manipulation. Acute stress during encoding led to a more liberal response bias (more hits and false alarms) when testing memory for the scenes 24 h later. The strength of this bias correlated negatively with pupil dilation responses and positively with stress-induced heart rate increases at encoding. Acute stress, moreover, reduced subsequent memory effects (SMEs; items later remembered vs forgotten) in hippocampus and midbrain, and in pupil dilation responses. The diminished SMEs indicate reduced selectivity and specificity in mnemonic processing during memory formation. This is in line with a model in which stress induced catecholaminergic hyperactivation alters phasic neuromodulatory signaling in memory-related circuits, resulting in generalized (gist-based) processing at the cost of specificity. Thus, one may speculate that loss of specificity may yield less discrete memory representations at time of encoding, thereby causing a more liberal response bias when probing these memories. PMID- 22442070 TI - Regulation of GABA and glutamate release from proopiomelanocortin neuron terminals in intact hypothalamic networks. AB - Hypothalamic proopiomelanocortin (POMC) neurons and their peptide products mediate important aspects of energy balance, analgesia, and reward. In addition to peptide products, there is evidence that POMC neurons can also express the amino acid transmitters GABA and glutamate, suggesting these neurons may acutely inhibit or activate downstream neurons. However, the release of amino acid transmitters from POMC neurons has not been thoroughly investigated in an intact system. In the present study, the light-activated cation channel channelrhodopsin 2 (ChR2) was used to selectively evoke transmitter release from POMC neurons. Whole-cell electrophysiologic recordings were made in brain slices taken from POMC-Cre transgenic mice that had been injected with a viral vector containing a floxed ChR2 sequence. Brief pulses of blue light depolarized POMC-ChR2 neurons and induced the release of GABA and glutamate onto unidentified neurons within the arcuate nucleus, as well as onto other POMC neurons. To determine whether the release of GABA and glutamate from POMC terminals can be readily modulated, opioid and GABA(B) receptor agonists were applied. Agonists for MU- and kappa-, but not delta-opioid receptors inhibited transmitter release from POMC neurons, as did the GABA(B) receptor agonist baclofen. This regulation indicates that opioids and GABA released from POMC neurons may act at presynaptic receptors on POMC terminals in an autoregulatory manner to limit continued transmission. The results show that, in addition to the relatively slow and long-lasting actions of peptides, POMC neurons can rapidly affect the activity of downstream neurons via GABA and glutamate release. PMID- 22442071 TI - The mechanism of orientation selectivity in primary visual cortex without a functional map. AB - Neurons in primary visual cortex (V1) display substantial orientation selectivity even in species where V1 lacks an orientation map, such as in mice and rats. The mechanism underlying orientation selectivity in V1 with such a salt-and-pepper organization is unknown; it is unclear whether a connectivity that depends on feature similarity is required, or a random connectivity suffices. Here we argue for the latter. We study the response to a drifting grating of a network model of layer 2/3 with random recurrent connectivity and feedforward input from layer 4 neurons with random preferred orientations. We show that even though the total feedforward and total recurrent excitatory and inhibitory inputs all have a very weak orientation selectivity, strong selectivity emerges in the neuronal spike responses if the network operates in the balanced excitation/inhibition regime. This is because in this regime the (large) untuned components in the excitatory and inhibitory contributions approximately cancel. As a result the untuned part of the input into a neuron as well as its modulation with orientation and time all have a size comparable to the neuronal threshold. However, the tuning of the F0 and F1 components of the input are uncorrelated and the high-frequency fluctuations are not tuned. This is reflected in the subthreshold voltage response. Remarkably, due to the nonlinear voltage-firing rate transfer function, the preferred orientation of the F0 and F1 components of the spike response are highly correlated. PMID- 22442072 TI - TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry. AB - Dysfunction of basal forebrain cholinergic neurons (BFCNs) is an early pathological hallmark of Alzheimer's disease (AD). Numerous studies have indicated that nerve growth factor (NGF) supports survival and phenotypic differentiation of BFCNs. Consistent with a potential link to AD pathogenesis, TrkA, a NGF receptor, is expressed in cholinergic forebrain neuronal populations including those in BF and striatum, and is markedly reduced in individuals with mild cognitive impairment (MCI) without dementia and early-stage AD. To investigate the role of TrkA in the development, connectivity, and function of the BF cholinergic system and its contribution to AD pathology, we have generated a forebrain-specific conditional TrkA knock-out mouse line. Our findings show a key role for TrkA signaling in establishing the BF cholinergic circuitry through the ERK pathway, and demonstrate that the normal developmental increase of choline acetyltransferase expression becomes critically dependent on TrkA signaling before neuronal connections are established. Moreover, the anatomical and physiological deficits caused by lack of TrkA signaling in BFCNs have selective impact on cognitive activity. These data demonstrate that TrkA loss results in cholinergic BF dysfunction and cognitive decline that is reminiscent of MCI and early AD. PMID- 22442073 TI - N-glycosylation of acid-sensing ion channel 1a regulates its trafficking and acidosis-induced spine remodeling. AB - Acid-sensing ion channel-1a (ASIC1a) is a potential therapeutic target for multiple neurological diseases. We studied here ASIC1a glycosylation and trafficking, two poorly understood processes pivotal in determining the functional outcome of an ion channel. We found that most ASIC1a in the mouse brain was fully glycosylated. Inhibiting glycosylation with tunicamycin reduced ASIC1a surface trafficking, dendritic targeting, and acid-activated current density. N-glycosylation of the two glycosylation sites, Asn393 and Asn366, has differential effects on ASIC1a biogenesis. Maturation of Asn393 increased ASIC1a surface and dendritic trafficking, pH sensitivity, and current density. In contrast, glycosylation of Asn366 was dispensable for ASIC1a function and may be a rate-limiting step in ASIC1a biogenesis. In addition, we revealed that acidosis reduced the density and length of dendritic spines in a time- and ASIC1a dependent manner. ASIC1a N366Q, which showed increased glycosylation and dendritic targeting, potentiated acidosis-induced spine loss. Conversely, ASIC1a N393Q, which had diminished dendritic targeting and inhibited ASIC1a current dominant-negatively, had the opposite effect. These data tie N-glycosylation of ASIC1a with its trafficking. More importantly, by revealing a site-specific effect of acidosis on dendritic spines, our findings suggest that these processes have an important role in regulating synaptic plasticity and determining long term consequences in diseases that generate acidosis. PMID- 22442074 TI - Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. AB - Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNF(Met)) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNF(Met) polymorphism and stress are unclear. We found that heterozygous BDNF(+/Met) mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF(+/Met) mice exhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF(+/Met) mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNF(Met) polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF(+/Met) mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF. PMID- 22442075 TI - KIF21A-mediated axonal transport and selective endocytosis underlie the polarized targeting of NCKX2. AB - We have previously shown that K(+)-dependent Na(+)/Ca(2+) exchanger (NCKX) is a major calcium clearance mechanism at the large axon terminals of central neurons, whereas their somata display little NCKX activity. We investigated mechanisms underlying the axonal polarization of NCKX2 in rat hippocampal neurons. We identified NCKX2 as the first neuron-specific cargo molecule of kinesin family member 21A (KIF21A). The intracellular loop of NCKX2 specifically interacted with the WD-40 repeats, a putative cargo-binding domain, of KIF21A. Dominant-negative mutant or depletion of KIF21A inhibited the transport of NCKX2-GFP to axon fibers. Knockdown of KIF21A caused calcium dysregulation at axonal boutons but not at somatodendritic regions. Despite the axonal polarization of the NCKX activity, both somatodendritic and axonal regions were immunoreactive to NCKX2. The surface expression of NCKX2 revealed by live-cell immunocytochemistry, however, displayed highly polarized distribution to the axon. Inhibition of endocytosis increased the somatodendritic surface NCKX2 and thus abolished the axonal polarization of surface NCKX2. These results indicate that KIF21A-mediated axonal transport and selective somatodendritic endocytosis underlie the axonal polarized surface expression of NCKX2. PMID- 22442076 TI - Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioral discrimination between structurally similar odorants. AB - ERK5 MAP kinase is highly expressed in the developing nervous system and has been implicated in promoting the survival of immature neurons in culture. However, its role in the development and function of the mammalian nervous system has not been established in vivo. Here, we report that conditional deletion of the erk5 gene in mouse neural stem cells during development reduces the number of GABAergic interneurons in the main olfactory bulb (OB). Our data suggest that this is due to a decrease in proliferation and an increase in apoptosis in the subventricular zone and rostral migratory stream of ERK5 mutant mice. Interestingly, ERK5 mutant mice have smaller OB and are impaired in odor discrimination between structurally similar odorants. We conclude that ERK5 is a novel signaling pathway regulating developmental OB neurogenesis and olfactory behavior. PMID- 22442077 TI - Toxic role of K+ channel oxidation in mammalian brain. AB - Potassium (K(+)) channels are essential to neuronal signaling and survival. Here we show that these proteins are targets of reactive oxygen species in mammalian brain and that their oxidation contributes to neuropathy. Thus, the KCNB1 (Kv2.1) channel, which is abundantly expressed in cortex and hippocampus, formed oligomers upon exposure to oxidizing agents. These oligomers were ~10-fold more abundant in the brain of old than young mice. Oxidant-induced oligomerization of wild-type KCNB1 enhanced apoptosis in neuronal cells subject to oxidative insults. Consequently, a KCNB1 variant resistant to oxidation, obtained by mutating a conserved cysteine to alanine, (C73A), was neuroprotective. The fact that oxidation of KCNB1 is toxic, argues that this mechanism may contribute to neuropathy in conditions characterized by high levels of oxidative stress, such as Alzheimer's disease (AD). Accordingly, oxidation of KCNB1 channels was exacerbated in the brain of a triple transgenic mouse model of AD (3xTg-AD). The C73A variant protected neuronal cells from apoptosis induced by incubation with beta-amyloid peptide (Abeta(1-42)). In an invertebrate model (Caenorhabditis elegans) that mimics aspects of AD, a C73A-KCNB1 homolog (C113S-KVS-1) protected specific neurons from apoptotic death induced by ectopic expression of human Abeta(1-42). Together, these data underscore a novel mechanism of toxicity in neurodegenerative disease. PMID- 22442078 TI - Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. AB - Alterations in mitochondrial dynamics (fission, fusion, and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders such as Charcot-Marie-Tooth disease, to common conditions including Alzheimer's disease. However, the relationship between altered mitochondrial dynamics and neurodegeneration is incompletely understood. Here we show that disease associated MFN2 proteins suppressed both mitochondrial fusion and transport, and produced classic features of segmental axonal degeneration without cell body death, including neurofilament filled swellings, loss of calcium homeostasis, and accumulation of reactive oxygen species. By contrast, depletion of Opa1 suppressed mitochondrial fusion while sparing transport, and did not induce axonal degeneration. Axon degeneration induced by mutant MFN2 proteins correlated with the disruption of the proper mitochondrial positioning within axons, rather than loss of overall mitochondrial movement, or global mitochondrial dysfunction. We also found that augmenting expression of MFN1 rescued the axonal degeneration caused by MFN2 mutants, suggesting a possible therapeutic strategy for Charcot Marie-Tooth disease. These experiments provide evidence that the ability of mitochondria to sense energy requirements and localize properly within axons is key to maintaining axonal integrity, and may be a common pathway by which disruptions in axonal transport contribute to neurodegeneration. PMID- 22442079 TI - Neuroplasticity in cigarette smokers is altered under withdrawal and partially restituted by nicotine exposition. AB - Nicotine improves cognitive functions by modulating neuroplasticity and cortical excitability in nonsmoking subjects. As shown recently, the positive effect of nicotine on cognition might at least partially be caused by a focusing effect of nicotine on neuroplasticity in these subjects. Concordant to this, smokers under nicotine withdrawal show reduced cognitive abilities, which are at least partially restituted by nicotine consumption. We aimed to explore the neurophysiological foundation of these effects by exploring nonfocal and focal plasticity-inducing protocols in human smokers under nicotine withdrawal and exposition. Focal, synapse-specific plasticity was induced by paired associative stimulation (PAS), while nonfocal plasticity was induced by transcranial direct current stimulation (tDCS). Each subject (12) received placebo and nicotine patches combined with one of the stimulation protocols to the primary motor cortex. Corticospinal excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. In smokers during nicotine withdrawal, facilitatory plasticity induced by tDCS and PAS was abolished, but restituted by nicotine. In contrast, excitability-diminishing plasticity was not affected by nicotine withdrawal. Under nicotine, the inhibitory aftereffects of PAS were delayed and prolonged, while the tDCS-generated excitability reduction was abolished. Thus, absent facilitatory plasticity in smokers during nicotine withdrawal is restituted by nicotine, favoring the deficit-compensating hypothesis of nicotine consumption. These results might shed further light on the proposed mechanism of nicotine on cognition and attention, which might be connected to nicotine addiction and probability of relapse in smokers. PMID- 22442080 TI - Repetitive convulsant-induced seizures reduce the number but not precision of hippocampal place cells. AB - Repetitive one-per-day seizures induced in otherwise normal rats by the volatile convulsant flurothyl decrease the accuracy of locating a hidden goal without changing the mean location of goal selection. We now show that an 8-d series of such seizures degrades the spatial signal carried by the firing of hippocampal pyramidal cells and specifically reduces the information conveyed by the place cell subset of pyramidal cells. This degradation and a concomitant slowing of the hippocampal theta rhythm occur over time courses parallel to the development of the behavioral deficit and plausibly account for the impairment. The details of how pyramidal cell discharge weakens are, however, unexpected. Rather than a reduction in the precision of location-specific firing distributed evenly over all place cells, the number of place cells decreases with seizure number, although the remaining place cells remain quite intact. Thus, with serial seizures there is a cell-specific conversion of robust place cells to sporadically firing (<0.1 spike/s) "low-rate" cells as opposed to gradual loss of place cell resolution. This transformation occurs in the absence of significant changes in the discharge rate of hippocampal interneurons, suggesting that the decline in the number of place cells is not a simple matter of increased inhibitory tone. The cumulative transformation of place cells to low-rate cells by repetitive seizures may reflect a homeostatic, negative-feedback process. PMID- 22442081 TI - Perceptual inference predicts contextual modulations of sensory responses. AB - Sensory receptive fields (RFs) vary as a function of stimulus properties and measurement methods. Previous stimuli or surrounding stimuli facilitate, suppress, or change the selectivity of sensory neurons' responses. Here, we propose that these spatiotemporal contextual dependencies are signatures of efficient perceptual inference and can be explained by a single neural mechanism, input targeted divisive inhibition. To respond both selectively and reliably, sensory neurons should behave as active predictors rather than passive filters. In particular, they should remove input they can predict ("explain away") from the synaptic inputs to all other neurons. This implies that RFs are constantly and dynamically reshaped by the spatial and temporal context, while the true selectivity of sensory neurons resides in their "predictive field." This approach motivates a reinvestigation of sensory representations and particularly the role and specificity of surround suppression and adaptation in sensory areas. PMID- 22442083 TI - Binaural interactions develop in the auditory brainstem of children who are deaf: effects of place and level of bilateral electrical stimulation. AB - Bilateral cochlear implants (CIs) might promote development of binaural hearing required to localize sound sources and hear speech in noise for children who are deaf. These hearing skills improve in children implanted bilaterally but remain poorer than normal. We thus questioned whether the deaf and immature human auditory system is able to integrate input delivered from bilateral CIs. Using electrophysiological measures of brainstem activity that include the Binaural Difference (BD), a measure of binaural processing, we showed that a period of unilateral deprivation before bilateral CI use prolonged response latencies but that amplitudes were not significantly affected. Tonotopic organization was retained to some extent as evidenced by an elimination of the BD with large mismatches in place of stimulation between the two CIs. Smaller place mismatches did not affect BD latency or amplitude, indicating that the tonotopic organization of the auditory brainstem is underdeveloped and/or not well used by CI stimulation. Finally, BD amplitudes decreased when the intensity of bilateral stimulation became weighted to one side and this corresponded to a perceptual shift of sound away from midline toward the side of increased intensity. In summary, bilateral CI stimulation is processed by the developing human auditory brainstem leading to perceptual changes in sound location and potentially improving hearing for children who are deaf. PMID- 22442082 TI - Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development. AB - In a genetic screen for regulators of synaptic morphology, we identified the single Caenorhabditis elegans flamingo-like cadherin fmi-1. The fmi-1 mutants exhibit defective axon pathfinding, reduced synapse number, aberrant synapse size and morphology, as well as an abnormal accumulation of synaptic vesicles at nonsynaptic regions. Although FMI-1 is primarily expressed in the nervous system, it is not expressed in the ventral D-type (VD) GABAergic motorneurons, which are defective in fmi-1 mutants. The axon and synaptic defects of VD neurons could be rescued when fmi-1 was expressed exclusively in non-VD neighboring neurons, suggesting a cell nonautonomous action of FMI-1. FMI-1 protein that lacked its intracellular domain still retained its ability to rescue the vesicle accumulation defects of GABAergic motorneurons, indicating that the extracellular domain was sufficient for this function of FMI-1 in GABAergic neuromuscular junction development. Mutations in cdh-4, a Fat-like cadherin, cause similar defects in GABAergic motorneurons. The cdh-4 is expressed by the VD neurons and seems to function in the same genetic pathway as fmi-1 to regulate GABAergic neuron development. Thus, fmi-1 and cdh-4 cadherins might act together to regulate synapse development and axon pathfinding. PMID- 22442084 TI - Interneurons provide circuit-specific depolarization and hyperpolarization. AB - Perisoma-inhibiting interneurons (PIIs) control fundamental aspects of cortical network function by means of their GABAergic output synapses. However, whether they depolarize or hyperpolarize their target cells in the mature circuitry remains controversial. By using unitary field potential and gramicidin D perforated-patch recordings, we provide evidence that the postsynaptic effect of GABAergic synapses is fundamentally different in two regions of rat hippocampus. Signaling at PII output synapses is hyperpolarizing in CA1 principal cells (PCs) but depolarizing in dentate gyrus (DG) PCs. While the reversal potential of GABA(A) receptor-mediated currents is identical in both areas, ~15 mV more negative resting potentials of DG compared with CA1 PCs underlie the opposing effects of perisomatic GABAergic transmission. Thus, the nature of PII output signaling is circuit-dependent and may therefore contribute differentially to information processing in the two brain areas. PMID- 22442085 TI - Cerebellar contributions to reach adaptation and learning sensory consequences of action. AB - When we use a novel tool, the motor commands may not produce the expected outcome. In healthy individuals, with practice the brain learns to alter the motor commands. This change depends critically on the cerebellum as damage to this structure impairs adaptation. However, it is unclear precisely what the cerebellum contributes to the process of adaptation in human motor learning. Is the cerebellum crucial for learning to associate motor commands with novel sensory consequences, called forward model, or is the cerebellum important for learning to associate sensory goals with novel motor commands, called inverse model? Here, we compared performance of cerebellar patients and healthy controls in a reaching task with a gradual perturbation schedule. This schedule allowed both groups to adapt their motor commands. Following training, we measured two kinds of behavior: in one case, people were presented with reach targets near the direction in which they had trained. The resulting generalization patterns of patients and controls were similar, suggesting comparable inverse models. In the second case, participants reached without a target and reported the location of their hand. In controls, the pattern of change in reported hand location was consistent with simulation results of a forward model that had learned to associate motor commands with new sensory consequences. In patients, this change was significantly smaller. Therefore, in our sample of patients, we observed that while adaptation of motor commands can take place despite cerebellar damage, cerebellar integrity appears critical for learning to predict visual sensory consequences of motor commands. PMID- 22442086 TI - Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity. AB - The autophagy-lysosomal pathway plays an important role in the clearance of long lived proteins and dysfunctional organelles. Lysosomal dysfunction has been implicated in several neurodegenerative disorders including Parkinson's disease and related synucleinopathies that are characterized by accumulations of alpha synuclein in Lewy bodies. Recent identification of mutations in genes linked to lysosomal function and neurodegeneration has offered a unique opportunity to directly examine the role of lysosomes in disease pathogenesis. Mutations in lysosomal membrane protein ATP13A2 (PARK9) cause familial Kufor-Rakeb syndrome characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While previous data suggested a role of ATP13A2 in alpha-synuclein misfolding and toxicity, the mechanistic link has not been established. Here we report that loss of ATP13A2 in human fibroblasts from patients with Kufor-Rakeb syndrome or in mouse primary neurons leads to impaired lysosomal degradation capacity. This lysosomal dysfunction results in accumulation of alpha-synuclein and toxicity in primary cortical neurons. Importantly, silencing of endogenous alpha-synuclein attenuated the toxicity in ATP13A2-depleted neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least in part via the accumulation of alpha synuclein. Our findings implicate lysosomal dysfunction in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of alpha-synuclein represent important therapeutic strategies for this disorder. PMID- 22442087 TI - fMRI repetition suppression for familiar but not arbitrary actions with tools. AB - For humans, daily life is characterized by routine interaction with many different tools for which corresponding actions are specified and performed according to well-learned procedures. The current study used functional MRI (fMRI) repetition suppression (RS) to identify brain areas underlying the transformation of visually defined tool properties to corresponding motor programs for conventional use. Before grasping and demonstrating how to use a specific tool, participants passively viewed either the same (repeated) tool or a different (non-repeated) tool. Repetition of tools led to reduced fMRI signals (RS) within a selective network of parietal and premotor areas. Comparison with newly learned, arbitrarily defined control actions revealed specificity of RS for tool use, thought to reflect differences in the extent of previous sensorimotor experience. The findings indicate that familiar tools are visually represented within the same sensorimotor areas underlying their dexterous use according to learned properties defined by previous experience. This interpretation resonates with the broader concept of affordance specification considered fundamental to action planning and execution whereby action-relevant object properties (affordances) are visually represented in sensorimotor areas. The current findings extend this view to reveal that affordance specification in humans includes learned object properties defined by previous sensorimotor experience. From an evolutionary perspective, the neural mechanisms identified in the current study offer clear survival advantage, providing fast efficient transformation of visual information to appropriate motor responses based on previous experience. PMID- 22442088 TI - Changes in auditory feedback connections determine the severity of speech processing deficits after stroke. AB - We compared brain structure and function in two subgroups of 21 stroke patients with either moderate or severe chronic speech comprehension impairment. Both groups had damage to the supratemporal plane; however, the severe group suffered greater damage to two unimodal auditory areas: primary auditory cortex and the planum temporale. The effects of this damage were investigated using fMRI while patients listened to speech and speech-like sounds. Pronounced changes in connectivity were found in both groups in undamaged parts of the auditory hierarchy. Compared to controls, moderate patients had significantly stronger feedback connections from planum temporale to primary auditory cortex bilaterally, while in severe patients this connection was significantly weaker in the undamaged right hemisphere. This suggests that predictive feedback mechanisms compensate in moderately affected patients but not in severely affected patients. The key pathomechanism in humans with persistent speech comprehension impairments may be impaired feedback connectivity to unimodal auditory areas. PMID- 22442089 TI - LIM domain only 4 (LMO4) regulates calcium-induced calcium release and synaptic plasticity in the hippocampus. AB - The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 long-term potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior. PMID- 22442090 TI - P2X2 and P2X5 subunits define a new heteromeric receptor with P2X7-like properties. AB - Ligand-gated ion channels are prototypic oligomeric membrane proteins whose stoichiometry determines their functional properties and subcellular localization. Deciphering the quaternary structure of such protein complexes is an arduous task and usually requires the combination of multiple approaches. ATP gated P2X receptors are formed by the association of three subunits, but the quaternary arrangement of the seven P2X subunits at the plasma membrane remains poorly characterized. By combining bioluminescence resonance energy transfer, bifunctional fluorescence complementation and protein biochemistry, we developed an experimental approach that allows precise determination of rat P2X receptor quaternary assembly. We found that P2X5 subunits associate with P2X1, P2X2, and P2X4 subunits. We demonstrate that P2X5 and P2X2 subunits interact to form as yet uncharacterized heteromeric receptors with alternate stoichiometries, both present at the plasma membrane. P2X2/5 receptors display functional properties such as pore dilatation, membrane blebbing, and phosphatidylserine exposure that were previously thought to be characteristic hallmarks of the P2X7 receptor. In mouse, P2X2 and P2X5 subunits colocalize and physically interact in specific neuronal populations suggesting that other P2X receptors might contribute to cellular responses typically attributed to P2X7 receptor. PMID- 22442091 TI - Dynamic causal modeling of spatiotemporal integration of phonological and semantic processes: an electroencephalographic study. AB - Integration of phonological and lexicosemantic processes is essential for visual word recognition. Here we used dynamic causal modeling of event-related potentials, combined with group source reconstruction, to estimate how those processes translate into context-dependent modulation of effective connectivity within the temporal-frontal language network. Fifteen healthy human subjects performed a phoneme detection task in pseudo-words and a semantic categorization task in words. Cortical current densities revealed the sequential activation of temporal regions, from the occipital-temporal junction toward the anterior temporal lobe, before reaching the inferior frontal gyrus. A difference of activation between phonology and semantics was identified in the anterior temporal lobe within the 240-300 ms peristimulus time window. Dynamic causal modeling indicated this increase of activation of the anterior temporal lobe in the semantic condition as a consequence of an increase of forward connectivity from the posterior inferior temporal lobe to the anterior temporal lobe. In addition, fast activation of the inferior frontal region, which allowed a feedback control of frontal regions on the superior temporal and posterior inferior temporal cortices, was found to be likely. Our results precisely describe spatiotemporal network mechanisms occurring during integration of phonological and semantic processes. In particular, they support the hypothesis of multiple pathways within the temporal lobe for language processing, where frontal regions would exert a top-down control on temporal regions in the recruitment of the anterior temporal lobe for semantic processing. PMID- 22442092 TI - Topologically convergent and divergent structural connectivity patterns between patients with remitted geriatric depression and amnestic mild cognitive impairment. AB - Alzheimer's disease (AD) can be conceptualized as a disconnection syndrome. Both remitted geriatric depression (RGD) and amnestic mild cognitive impairment (aMCI) are associated with a high risk for developing AD. However, little is known about the similarities and differences in the topological patterns of white matter (WM) structural networks between RGD and aMCI. In this study, diffusion tensor imaging and deterministic tractography were used to map the human WM networks of 35 RGD patients, 38 aMCI patients, and 30 healthy subjects. Furthermore, graph theoretical methods were applied to investigate the alterations in the global and regional properties of the WM network in these patients. First, both the RGD and aMCI patients showed abnormal global topology in their WM networks (i.e., reduced network strength, reduced global efficiency, and increased absolute path length) compared with the controls, and there were no significant differences in these global network properties between the patient groups. Second, similar deficits of the regional and connectivity characteristics in the WM networks were primarily found in the frontal brain regions of RGD and aMCI patients compared with the controls, while a different nodal efficiency of the posterior cingulate cortex and several prefrontal brain regions were also observed between the patient groups. Together, our study provides direct evidence for the association of a great majority of convergent and a minority of divergent connectivity of WM structural networks between RGD and aMCI patients, which may lead to increasing attention in defining a population at risk of AD. PMID- 22442093 TI - Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice. AB - Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E(2) (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway. PMID- 22442094 TI - Multifractal signatures of infectious diseases. AB - Incidence of infection time-series data for the childhood diseases measles, chicken pox, rubella and whooping cough are described in the language of multifractals. We explore the potential of using the wavelet transform maximum modulus (WTMM) method to characterize the multiscale structure of the observed time series and of simulated data generated by the stochastic susceptible-exposed infectious-recovered (SEIR) epidemic model. The singularity spectra of the observed time series suggest that each disease is characterized by a unique multifractal signature, which distinguishes that particular disease from the others. The wavelet scaling functions confirm that the time series of measles, rubella and whooping cough are clearly multifractal, while chicken pox has a more monofractal structure in time. The stochastic SEIR epidemic model is unable to reproduce the qualitative singularity structure of the reported incidence data: it is too smooth and does not appear to have a multifractal singularity structure. The precise reasons for the failure of the SEIR epidemic model to reproduce the correct multiscale structure of the reported incidence data remain unclear. PMID- 22442095 TI - Label-free magnetic resonance imaging to locate live cells in three-dimensional porous scaffolds. AB - Porous scaffolds are widely tested materials used for various purposes in tissue engineering. A critical feature of a porous scaffold is its ability to allow cell migration and growth on its inner surface. Up to now, there has not been a method to locate live cells deep inside a material, or in an entire structure, using real-time imaging and a non-destructive technique. Herein, we seek to demonstrate the feasibility of the magnetic resonance imaging (MRI) technique as a method to detect and locate in vitro non-labelled live cells in an entire porous material. Our results show that the use of optimized MRI parameters (4.7 T; repetition time = 3000 ms; echo time = 20 ms; resolution 39 * 39 um) makes it possible to obtain images of the scaffold structure and to locate live non-labelled cells in the entire material, with a signal intensity higher than that obtained in the culture medium. In the current study, cells are visualized and located in different kinds of porous scaffolds. Moreover, further development of this MRI method might be useful in several three-dimensional biomaterial tests such as cell distribution studies, routine qualitative testing methods and in situ monitoring of cells inside scaffolds. PMID- 22442096 TI - Hexafluorobenzene in comparison with perfluoro-15-crown-5-ether for repeated monitoring of oxygenation using 19F MRI in a mouse model. AB - Hexafluorobenzene (HFB) and perfluoro-15-crown-5-ether (15C5) were compared as fluorine reporter probes of tissue oxygenation using (19)F MRI for dynamic assessment of muscle oxygenation, with special focus on muscle tissue toxicity of the probes, and consecutive alteration of animal behavior. The latter were also compared in terms of sensitivity to changes in oxygenation as well as of signal to-noise ratio for accurate pO(2) measurements. For that purpose, mouse muscles were imaged at 11.7 T, at 2- and 36-h after intramuscular injection of HFB or 15C5. Histological analysis of the muscle tissue revealed a lack of toxicity for 15C5 from 2 up to 36-h postinjection, whereas HFB induced tissue necrosis, blood clots and thrombosis as soon as 24-h postinjection. This muscle toxicity led to a limitation in mice mobility 24-h after injection of HFB as evidenced by behavioral testing (open-field, grip strength, and catwalk tests), which was not the case after 15C5 intramuscular injection. Finally, pO(2) measurements assessed 2-h postinjection showed consistent values with both probes, evidencing cross validation of the (19)F MRI oximetry technique for acute measurements. However, the measurement at 36-h was hampered for HFB, which showed significant lower values of muscle pO(2), whereas 15C5 was able to reliably assess muscle pO(2) at 36-h postinjection. PMID- 22442097 TI - Extraesophageal manifestations of gastroesophageal reflux disease: cough, asthma, laryngitis, chest pain. AB - GER is a common condition affecting many patients in different parts of the world. It usually presents with the classic manifestations of heartburn and regurgitation; however, in some it can also present with extraesophageal manifestations such as chronic cough, laryngitis, asthma or chest pain. Commonly employed diagnostic tests such as EGD and ambulatory pH or impedance monitoring in GER, are less useful in extraesophageal syndromes due to their poor sensitivity and specificity. In contrast, empiric trials of PPI's are shown to be cost effective; however, patients may require long-term treatment to establish effectiveness. Diagnostic testing with pH and impedance monitoring are commonly reserved for patients with partial or poor response to the initial treatment with PPI's. Poor response to PPI therapy may be an important indicator for non-GER causes for patients' symptoms and should initiate a search for other potential causes. PMID- 22442098 TI - Public recognition of mental disorders and beliefs about treatment: changes in Australia over 16 years. AB - BACKGROUND: A 1995 Australian national survey of mental health literacy showed poor recognition of disorders and beliefs about treatment that differed from those of health professionals. A similar survey carried out in 2003/4 showed some improvements over 8 years. AIMS: To investigate whether recognition of mental disorders and beliefs about treatment have changed over a 16-year period. METHOD: A national survey of 6019 adults was carried out in 2011 using the same questions as the 1995 and 2003/4 surveys. RESULTS: Results showed improved recognition of depression and more positive ratings for a range of interventions, including help from mental health professionals and antidepressants. CONCLUSIONS: Although beliefs about effective medications and interventions have moved closer to those of health professionals since the previous surveys, there is still potential for mental health literacy gains in the areas of recognition and treatment beliefs for mental disorders. This is particularly the case for schizophrenia. PMID- 22442099 TI - Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study. AB - BACKGROUND: The association between autoimmune diseases and schizophrenia has rarely been systematically investigated. AIMS: To investigate the association between schizophrenia and a variety of autoimmune diseases and to explore possible gender variation in any such association. METHOD: Taiwan's National Health Insurance Research Database was used to identify 10 811 hospital in patients with schizophrenia and 108 110 age-matched controls. Univariate and multiple logistic regression analyses were performed, separately, to evaluate the association between autoimmune diseases and schizophrenia. We applied the false discovery rate to correct for multiple testing. RESULTS: When compared with the control group, the in-patients with schizophrenia had an increased risk of Graves' disease (odds ratio (OR) = 1.32, 95% CI 1.04-1.67), psoriasis (OR = 1.48, 95% CI 1.07-2.04), pernicious anaemia (OR = 1.71, 95% CI 1.04-2.80), celiac disease (OR = 2.43, 95% CI 1.12-5.27) and hypersensitivity vasculitis (OR = 5.00, 95% CI 1.64-15.26), whereas a reverse association with rheumatoid arthritis (OR = 0.52, 95% CI 0.35-0.76) was also observed. Gender-specific variation was found for Sjogren syndrome, hereditary haemolytic anaemia, myasthenia gravis, polymyalgia rheumatica and dermatomyositis. CONCLUSIONS: Schizophrenia was associated with a greater variety of autoimmune diseases than was anticipated. Further investigation is needed to gain a better understanding of the aetiology of schizophrenia and autoimmune diseases. PMID- 22442100 TI - Trends in prescriptions and costs of drugs for mental disorders in England, 1998 2010. AB - BACKGROUND: Increasing rates of prescriptions for antidepressants, antipsychotics and stimulants have been reported from various countries. AIMS: To examine trends in prescriptions and the costs of all classes of psychiatric medication in England. METHOD: Data from the Prescription Cost Analysis 1998-2010 was examined, using linear regression analysis to examine trends. RESULTS: Prescriptions of drugs used for mental disorders increased by 6.8% (95% CI 6.3-7.4) per year on average, in line with other drugs, but made up an increasing proportion of all prescription drug costs (P = 0.001). There were rising trends in prescriptions of all classes of psychiatric drugs, except anxiolytics and hypnotics (which did not change). Antidepressant prescriptions increased by 10% (95% CI 9.0-11) per year on average, and antipsychotics by 5.1% (95% CI 4.3-5.9). Antipsychotics overtook antidepressants as the most costly class of psychiatric medication, with costs rising 22% (95% CI 17-27) per year. CONCLUSIONS: Rising prescriptions may be partly explained by longer-term treatment and increasing population. Nevertheless, it appears that psychiatric drugs make an increasing contribution to total prescription drug costs, with antipsychotics becoming the most costly. Low-dose prescribing of some antipsychotics is consistent with other evidence that their use may not be restricted to those with severe mental illness. PMID- 22442101 TI - Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs. AB - BACKGROUND: Second-generation antipsychotics have been thought to cause fewer extrapyramidal side-effects (EPS) than first-generation antipsychotics, but recent pragmatic trials have indicated equivalence. AIMS: To determine whether second-generation antipsychotics had better outcomes in terms of EPS than first generation drugs. METHOD: We conducted an intention-to-treat, secondary analysis of data from an earlier randomised controlled trial (n = 227). A clinically significant difference was defined as double or half the symptoms in groups prescribed first- v. second-generation antipsychotics, represented by odds ratios greater than 2.0 (indicating advantage for first-generation drugs) or less than 0.5 (indicating advantage for the newer drugs). We also examined EPS in terms of symptoms emergent at 12 weeks and 52 weeks, and symptoms that had resolved at these time points. RESULTS: At baseline those randomised to the first-generation antipsychotic group (n = 118) had similar EPS to the second-generation group (n = 109). Indications of resolved Parkinsonism (OR = 0.5) and akathisia (OR = 0.4) and increased tardive dyskinesia (OR = 2.2) in the second-generation drug group at 12 weeks were not statistically significant and the effects were not present by 52 weeks. Patients in the second-generation group were dramatically (30-fold) less likely to be prescribed adjunctive anticholinergic medication, despite equivalence in terms of EPS. CONCLUSIONS: The expected improvement in EPS profiles for participants randomised to second-generation drugs was not found; the prognosis over 1 year of those in the first-generation arm was no worse in these terms. The place of careful prescription of first-generation drugs in contemporary practice remains to be defined, potentially improving clinical effectiveness and avoiding life-shortening metabolic disturbances in some patients currently treated with the narrow range of second-generation antipsychotics used in routine practice. This has educational implications because a generation of psychiatrists now has little or no experience with first generation antipsychotic prescription. PMID- 22442102 TI - Email-based promotion of self-help for subthreshold depression: Mood Memos randomised controlled trial. AB - BACKGROUND: Subthreshold depression is common, impairs functioning and increases the risk of major depression. Improving self-help coping strategies could help subthreshold depression and prevent major depression. AIMS: To test the effectiveness of an automated email-based campaign promoting self-help behaviours. METHOD: A randomised controlled trial was conducted through the website: www.moodmemos.com. Participants received automated emails twice weekly for 6 weeks containing advice about self-help strategies. Emails containing general information about depression served as a control. The principal outcome was depression symptom level on the nine-item Patient Health Questionnaire (PHQ 9) (trial registration: ACTRN12609000925246). RESULTS: The study recruited 1326 adults with subthreshold depression. There was a small significant difference in depression symptoms at post-intervention, favouring the active group (d = 0.17, 95% CI 0.01-0.34). There was a lower, although non-significant, risk of major depression in the active group (number needed to treat (NNT) 25, 95% CI 11 to infinity to NNT(harm) 57). CONCLUSIONS: Emails promoting self-help strategies were beneficial. Internet delivery of self-help messages affords a low-cost, easily disseminated and highly automated approach for indicated prevention of depression. PMID- 22442103 TI - In vivo measurement of gadolinium diffusivity by dynamic contrast-enhanced MRI: a preclinical study of human xenografts. AB - Compartmental tracer kinetic models currently used for analysis of dynamic contrast-enhanced MRI data yield poor fittings or parameter values that are unphysiological in necrotic regions of the tumor, as these models only describe microcirculation in perfused tissue. In this study, we explore the use of Fick's law of diffusion as an alternative method for analysis of dynamic contrast enhanced MRI data in the necrotic regions. Xenografts of various human cancer cell lines were implanted in 14 mice that were subjected to dynamic contrast enhanced MRI performed using a spoiled gradient recalled sequence. Tracer concentration was estimated using the variable flip angle technique. Poorly perfused and necrotic tumor regions exhibiting delayed and slow enhancement were identified using a k-means clustering algorithm. Tracer behavior in necrotic regions was shown to be consistent with Fick's diffusion equation and the in vivo gadolinium diffusivity was estimated to be 2.08 (+/-0.88) * 10(-4) mm(2)/s. This study proposes the use of gadolinium diffusivity as an alternative parameter for quantifying tracer transport within necrotic tumor regions. PMID- 22442104 TI - A broader importance of NOPR to the future of nuclear imaging. PMID- 22442105 TI - Abuse of medication during international football competition in 2010 - lesson not learned. AB - BACKGROUND: The use of medication in professional football has previously been shown to defy clinical guidelines. MATERIALS AND METHODS: Physicians of the teams who participated at the 2010 FIFA World Cup provided the list of medications used by each player within the 72 h preceding every match. RESULTS: During the tournament 71.7% of all players took medication, and 60.3% (444 of 736 players) took painkilling agents at least once. Over a third of players (39.0%) took a painkilling agent before every game. More medications were used during the finals than during the qualifying round of matches (pool games) (0.87+/-0.09 vs 0.77+/ 0.03, p<0.01). Players from North and South America took almost twice the number of medications than did players from other continents (1.18+/-0.08 vs 0.64+/ 0.03; p<0.01). CONCLUSION: The use of medication reported by the team physicians in international football competition is increasing. Systematic use - medication for every match - appeared to be the norm in certain teams. This has implications for player health. These data encourage efforts to better understand, and to address, this potential disastrous practice in professional sports. PMID- 22442106 TI - Rehabilitation following meniscal repair. AB - It has become increasingly more evident that the meniscus plays an important role in contributing to knee joint longevity. Advances in surgical techniques by orthopaedic surgeons to repair traumatized menisci have led to better long term outcomes, decreasing the incidence of articular cartilage degeneration. Advances have also been made in rehabilitative techniques following meniscal repair. These techniques along with sound rehabilitation principles to include a criteria based progression have contributed to excellent outcomes and earlier return to function and sport. The role of the meniscus, recent advances in surgical repair and the current post-operative rehabilitation techniques employed by sports rehabilitation specialists today are discussed. PMID- 22442107 TI - Prediction and verification of centrifugal dewatering of P. pastoris fermentation cultures using an ultra scale-down approach. AB - Recent years have seen a dramatic rise in fermentation broth cell densities and a shift to extracellular product expression in microbial cells. As a result, dewatering characteristics during cell separation is of importance, as any liquor trapped in the sediment results in loss of product, and thus a decrease in product recovery. In this study, an ultra scale-down (USD) approach was developed to enable the rapid assessment of dewatering performance of pilot-scale centrifuges with intermittent solids discharge. The results were then verified at scale for two types of pilot-scale centrifuges: a tubular bowl equipment and a disk-stack centrifuge. Initial experiments showed that employing a laboratory scale centrifugal mimic based on using a comparable feed concentration to that of the pilot-scale centrifuge, does not successfully predict the dewatering performance at scale (P-value <0.05). However, successful prediction of dewatering levels was achieved using the USD method (P-value >=0.05), based on using a feed concentration at small-scale that mimicked the same height of solids as that in the pilot-scale centrifuge. Initial experiments used Baker's yeast feed suspensions followed by fresh Pichia pastoris fermentation cultures. This work presents a simple and novel USD approach to predict dewatering levels in two types of pilot-scale centrifuges using small quantities of feedstock (<50 mL). It is a useful tool to determine optimal conditions under which the pilot-scale centrifuge needs to be operated, reducing the need for repeated pilot-scale runs during early stages of process development. PMID- 22442108 TI - Fast 3D contrast enhanced MRI of the liver using temporal resolution acceleration with constrained evolution reconstruction. AB - Time-resolved imaging is crucial for the accurate diagnosis of liver lesions. Current contrast enhanced liver magnetic resonance imaging acquires a few phases in sequential breath-holds. The image quality is susceptible to bolus timing errors, which could result in missing the critical arterial phase. This impairs the detection of malignant tumors that are supplied primarily by the hepatic artery. In addition, the temporal resolution may be too low to reliably separate the arterial phase from the portal venous phase. In this study, a method called temporal resolution acceleration with constrained evolution reconstruction was developed with three-dimensional volume coverage and high-temporal frame rate. Data is acquired using a stack of spirals sampling trajectory combined with a golden ratio view order using an eight-channel coil array. Temporal frames are reconstructed from vastly undersampled data sets using a nonlinear inverse algorithm assuming that the temporal changes are small at short time intervals. Numerical and phantom experimental validation is presented. Preliminary in vivo results demonstrated high spatial resolution dynamic three-dimensional images of the whole liver with high frame rates, from which numerous subarterial phases could be easily identified retrospectively. PMID- 22442109 TI - Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger. AB - Altered metabolism is a hallmark of cancer. Oncogenic events that lead to cancerous states reorganize metabolic pathways to increase nutrient uptake, which promotes biosynthetic capabilities and cell-autonomous behavior. Increased biosynthesis dictates metabolic demand for ATP, building blocks, and reducing equivalents, rendering cancer cells metabolically in a perpetually hungry state. Moreover, most chemotherapy agents induce acute metabolic stress that cancer cells must overcome for their survival. These metabolic stress cues in cancer cells can activate and cause dependence on the self-cannibalization mechanism of macroautophagy (autophagy hereafter) for the lysosomal turnover and recycling of organelles and proteins for energy and stress survival. For example, activating mutations in Ras or Ras-effector pathways induce autophagy, and cancer cell lines with Ras activation show elevated levels of basal autophagy that is essential for starvation survival and tumor growth. The metabolic implications of this are profound and multifaceted. First, autophagy-mediated degradation and recycling of cellular substrates can support metabolism and promote survival and tumor growth. Second, acute autophagy activation in response to cancer therapy can potentially lead to refractory tumors resistant to conventional chemotherapy. For example, a specific form of autophagy that targets mitochondria (mitophagy) may also function to promote cell survival by the clearance of damaged mitochondria that are potential sources of reactive oxygen species (ROS). These point to the possibility that autophagy is a unique metabolic need, important for survival as well as therapy resistance in cancer cells. Targeting autophagy in single-agent therapy to sensitize aggressive cancers that are dependent on autophagy for survival or in combination with therapeutic agents that induce autophagy as a resistance mechanism may be an effective therapeutic strategy to treat cancer. PMID- 22442110 TI - Type-specific interaction between human papillomavirus type 58 E2 protein and E7 protein inhibits E7-mediated oncogenicity. AB - Human papillomavirus type 58 (HPV-58) is a very common HPV type in eastern Asia. Little is known about its biology and tumorigenesis. In this study, HPV-58 E2 protein (58E2) was found to interact with E7 protein (58E7), and the hinge domain of 58E2 was shown to be responsible for binding to the 58E7 protein. Interestingly, the E2-E7 interaction appears to be HPV type-specific, as we found that the HPV-16 E2 could not bind to the 58E7 protein, and neither did 58E2 interact with HPV-16 E7. The biological consequence(s) of the E2-E7 interaction in HPV-58, especially in viral tumorigenesis, was investigated. Results showed that, through interacting with 58E7, 58E2 prevented E7-induced retinoblastoma protein (pRb) degradation and prolonged the half-life of pRb in cells. Additionally, 58E2 abrogated 58E7-induced cell proliferation. These observations collectively suggest that direct interaction with 58E7 is another mechanism for 58E2 to inhibit 58E7-associated carcinogenesis in addition to regulating expression of the 58E7 gene. PMID- 22442111 TI - Murine cytomegalovirus infection of cultured mouse cells induces expression of miR-7a. AB - One goal of virus infection is to reprogramme the host cell to optimize virus replication. As part of this process, viral microRNAs (miRNAs) may compete for components of the miRNA/small interfering RNA pathway, as well as regulate cellular targets. Murine cytomegalovirus (MCMV) has been described to generate large numbers of viral miRNAs during lytic infection and was therefore used to analyse the impact of viral miRNAs on the host-cell small-RNA system, as well as to check for sorting of viral small RNAs into specific Argonaute (Ago) proteins. Deep-sequencing analysis of MCMV-infected cells revealed that viral miRNAs represented only ~13% of all detected miRNAs. All previously described MCMV miRNAs with the exception of miR-m88-1* were confirmed, and for the MCMV miR-m01 1 hairpin, an additional miRNA, designated miR-m01-1-3p, was found. Its presence was confirmed by quantitative real-time PCR and Northern blotting. Deep sequencing after RNA-induced silencing complex (RISC) immunoprecipitation with antibodies specific for either Ago1 or Ago2 showed that all MCMV miRNAs were loaded into both RISCs. The ratio of MCMV to mouse miRNAs was not increased after immunoprecipitation of Ago proteins. Viral miRNAs therefore did not overwhelm the host miRNA processing system, nor were they incorporated preferentially into RISCs. Three mouse miRNAs were found that showed altered expression as a result of MCMV infection. Downregulation of miR-27a, as described previously, could be confirmed. In addition, miR-26a was downregulated, and upregulation of miR-7a dependent on viral protein expression could be observed. PMID- 22442112 TI - Kinetic expression analysis of the cluster mdv1-mir-M9-M4, genes meq and vIL-8 differs between the lytic and latent phases of Marek's disease virus infection. AB - Marek's disease virus (GaHV-2) is an alphaherpesvirus that induces T-cell lymphoma in chickens. The infection includes both lytic and latent stages. GaHV-2 encodes three clusters of microRNAs (miRNAs) located in the internal (I)/terminal (T) repeat (R) regions. We characterized transcripts encompassing the mdv1-mir-M9 M4 and mir-M11-M1 clusters located in the IR(L)/TR(L) region, upstream and downstream from the meq oncogene, respectively. By 5'- and 3'-RACE-PCR and targeted RT-PCR, we showed that mdv1-mir-M9-M4 could be transcribed from an unspliced transcript or from at least 15 alternatively spliced transcripts covering the IR(L)/TR(L) region, encompassing the meq and vIL-8 genes and localizing the mdv1-mir-M9-M4 cluster to the first intron at the 5'-end. However, all these transcripts, whether spliced or unspliced, seemed to start at the same transcriptional start site, their transcription being driven by a single promoter, prmiRM9M4. We demonstrated alternative promoter usage for the meq and vIL-8 genes, depending on the phase of GaHV-2 infection. During the latent phase, the prmiRM9M4 promoter drove transcription of the meq and vIL-8 genes and the mdv1-mir-M9-M4 cluster in the first intron of the corresponding transcripts. By contrast, during the lytic phase, this promoter drove the transcription only of the mdv1-mir-M9-M4 cluster to generate unspliced mRNA, the meq and vIL-8 genes being transcribed principally from their own promoters. Despite the expression of meq and the mdv1-mir-M9-M4 cluster under two different transcriptional processes during the latent and lytic phases, our data provide an explanation for meq expression and mdv1-mir-M4-5P overexpression in miRNA libraries from GaHV-2 infected cells, regardless of the phase of infection. PMID- 22442113 TI - Production of in vivo-biotinylated rotavirus particles. AB - Although inserting exogenous viral genome segments into rotavirus particles remains a hard challenge, this study describes the in vivo incorporation of a recombinant viral capsid protein (VP6) into newly assembled rotavirus particles. In vivo biotinylation technology was exploited to biotinylate a recombinant VP6 protein fused to a 15 aa biotin-acceptor peptide (BAP) by the bacterial biotin ligase BirA contextually co-expressed in mammalian cells. To avoid toxicity of VP6 overexpression, a stable HEK293 cell line was constructed with tetracycline inducible expression of VP6-BAP and constitutive expression of BirA. Following tetracycline induction and rotavirus infection, VP6-BAP was biotinylated, recruited into viroplasms and incorporated into newly assembled virions. The biotin molecules in the capsid allowed the use of streptavidin-coated magnetic beads as a purification technique instead of CsCl gradient ultracentrifugation. Following transfection, double-layered particles attached to beads were able to induce viroplasm formation and to generate infective viral progeny. PMID- 22442114 TI - Rotavirus variant replicates efficiently although encoding an aberrant NSP3 that fails to induce nuclear localization of poly(A)-binding protein. AB - The rotavirus (RV) non-structural protein NSP3 forms a dimer that has binding domains for the translation initiation factor eIF4G and for a conserved 3' terminal sequence of viral mRNAs. Through these activities, NSP3 has been proposed to promote viral mRNA translation by directing circularization of viral polysomes. In addition, by disrupting interactions between eIF4G and the poly(A) binding protein (PABP), NSP3 has been suggested to inhibit translation of host polyadenylated mRNAs and to stimulate relocalization of PABP from the cytoplasm to the nucleus. Herein, we report the isolation and characterization of SA11 4Fg7re, an SA11-4F RV derivative that contains a large sequence duplication initiating within the genome segment (gene 7) encoding NSP3. Our analysis showed that mutant NSP3 (NSP3m) encoded by SA11-4Fg7re is almost twice the size of the wild-type protein and retains the capacity to dimerize. However, in comparison to wild-type NSP3, NSP3m has a decreased capacity to interact with eIF4G and to suppress the translation of polyadenylated mRNAs. In addition, NSP3m fails to induce the nuclear accumulation of PABP in infected cells. Despite the defective activities of NSP3m, the levels of viral protein and progeny virus produced in SA11-4Fg7re- and SA11-4F-infected cells were indistinguishable. Collectively, these data are consistent with a role for NSP3 in suppressing host protein synthesis through antagonism of PABP activity, but also suggest that NSP3 functions may have little or no impact on the efficiency of virus replication in widely used RV-permissive cell lines. PMID- 22442115 TI - VPS13 regulates membrane morphogenesis during sporulation in Saccharomyces cerevisiae. AB - The hereditary disorders chorea acanthocytosis and Cohen syndrome are caused by mutations in different members of a family of genes that are orthologs of yeast VPS13. In vegetatively growing yeast, VPS13 is involved in the delivery of proteins to the vacuole. During sporulation, VPS13 is important for formation of the prospore membrane that encapsulates the daughter nuclei to give rise to spores. We report that VPS13 is required for multiple aspects of prospore membrane morphogenesis. VPS13 (1) promotes expansion of the prospore membrane through regulation of phosphatidylinositol phosphates, which in turn activate the phospholipase D, Spo14; (2) is required for a late step in cytokinesis that gives rise to spores; and (3) regulates a membrane-bending activity that generates intralumenal vesicles. These results demonstrate that Vps13 plays a broader role in membrane biology than previously known, which could have important implications for the functions of VPS13 orthologs in humans. PMID- 22442116 TI - Simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) imaging for carotid atherosclerotic disease evaluation. AB - A simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) MR imaging technique is proposed to detect both luminal stenosis and hemorrhage in atherosclerosis patients in a single scan. Thirteen patients with diagnosed carotid atherosclerotic plaque were admitted after informed consent. All scans were performed on a 3T MR imaging system with SNAP, 2D time-of-flight and magnetization-prepared 3D rapid acquisition gradient echo sequences. The SNAP sequence utilized a phase sensitive acquisition, and was designed to provide positive signals corresponding to intraplaque hemorrhage and negative signals corresponding to lumen. SNAP images were compared to time-of-flight images to evaluate lumen size measurements using linear mixed models and the intraclass correlation coefficient. Intraplaque hemorrhage identification accuracy was evaluated by comparing to magnetization-prepared 3D rapid acquisition gradient echo images using Cohen's Kappa. Diagnostic quality SNAP images were generated from all subjects. Quantitatively, the lumen size measurements by SNAP were strongly correlated (intraclass correlation coefficient = 0.96, P < 0.001) with those measured by time-of-flight. For intraplaque hemorrhage detection, strong agreement (kappa = 0.82, P < 0.001) was also identified between SNAP and magnetization-prepared 3D rapid acquisition gradient echo images. In conclusion, a SNAP imaging technique was proposed and shows great promise for imaging both lumen size and carotid intraplaque hemorrhage with a single scan. PMID- 22442117 TI - Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors. AB - 3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3 nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24 h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist. PMID- 22442118 TI - Salvianolic acid B exerts vasoprotective effects through the modulation of heme oxygenase-1 and arginase activities. AB - Salvia miltiorrhiza (Danshen), a traditional Chinese herbal medicine, is commonly used for the prevention and treatment of cardiovascular disorders including atherosclerosis. However, the mechanisms responsible for the vasoprotective effects of Danshen remain largely unknown. Salvianolic acid B (Sal B) represents one of the most bioactive compounds that can be extracted from the water-soluble fraction of Danshen. We investigated the effects of Danshen and Sal B on the inflammatory response in murine macrophages. Danshen and Sal B both induced the expression of heme oxygenase-1 (HO-1) and inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Inhibition of HO activity using Sn-protoporphyrin-IX (SnPP) abolished the inhibitory effect of Sal B on NO production and iNOS expression. Sal B increased macrophage arginase activity in a dose-dependent manner and diminished LPS-inducible tumor necrosis factor-alpha production. These effects were also reversed by SnPP. These data suggest that HO-1 expression plays an intermediary role in the anti-inflammatory effects of Sal B. In contrast to the observations in macrophages, Sal B dose-dependently inhibited arginase activity in murine liver, kidney, and vascular tissue. Furthermore, Sal B increased NO production in isolated mouse aortas through the inhibition of arginase activity and reduction of reactive oxygen species production. We conclude that Sal B improves vascular function by inhibiting inflammatory responses and promoting endothelium-dependent vasodilation. Taken together, we suggest that Sal B may represent a potent candidate therapeutic for the treatment of cardiovascular diseases associated with endothelial dysfunction. PMID- 22442119 TI - Active curve recovery of region boundary patterns. AB - This study investigates the recovery of region boundary patterns in an image by a variational level set method which drives an active curve to coincide with boundaries on which a feature distribution matches a reference distribution. We formulate the scheme for both the Kullback-Leibler and the Bhattacharyya similarities, and apply it in two conditions: the simultaneous recovery of all region boundaries consistent with a given outline pattern, and segmentation in the presence of faded boundary segments. The first task uses an image-based geometric feature, and the second a photometric feature. In each case, the corresponding curve evolution equation can be viewed as a geodesic active contour (GAC) flow having a variable stopping function which depends on the feature distribution on the active curve. This affords a potent global representation of the target boundaries, which can effectively drive active curve segmentation in a variety of otherwise adverse conditions. Detailed experimentation shows that the scheme can significantly improve on current region and edge-based formulations. PMID- 22442120 TI - Gradient response maps for real-time detection of textureless objects. AB - We present a method for real-time 3D object instance detection that does not require a time-consuming training stage, and can handle untextured objects. At its core, our approach is a novel image representation for template matching designed to be robust to small image transformations. This robustness is based on spread image gradient orientations and allows us to test only a small subset of all possible pixel locations when parsing the image, and to represent a 3D object with a limited set of templates. In addition, we demonstrate that if a dense depth sensor is available we can extend our approach for an even better performance also taking 3D surface normal orientations into account. We show how to take advantage of the architecture of modern computers to build an efficient but very discriminant representation of the input images that can be used to consider thousands of templates in real time. We demonstrate in many experiments on real data that our method is much faster and more robust with respect to background clutter than current state-of-the-art methods. PMID- 22442121 TI - Improving color constancy by photometric edge weighting. AB - Edge-based color constancy methods make use of image derivatives to estimate the illuminant. However, different edge types exist in real-world images, such as material, shadow, and highlight edges. These different edge types may have a distinctive influence on the performance of the illuminant estimation. Therefore, in this paper, an extensive analysis is provided of different edge types on the performance of edge-based color constancy methods. First, an edge-based taxonomy is presented classifying edge types based on their photometric properties (e.g., material, shadow-geometry, and highlights). Then, a performance evaluation of edge-based color constancy is provided using these different edge types. From this performance evaluation, it is derived that specular and shadow edge types are more valuable than material edges for the estimation of the illuminant. To this end, the (iterative) weighted Gray-Edge algorithm is proposed in which these edge types are more emphasized for the estimation of the illuminant. Images that are recorded under controlled circumstances demonstrate that the proposed iterative weighted Gray-Edge algorithm based on highlights reduces the median angular error with approximately 25 percent. In an uncontrolled environment, improvements in angular error up to 11 percent are obtained with respect to regular edge-based color constancy. PMID- 22442122 TI - Meaningful matches in stereovision. AB - This paper introduces a statistical method to decide whether two blocks in a pair of images match reliably. The method ensures that the selected block matches are unlikely to have occurred "just by chance." The new approach is based on the definition of a simple but faithful statistical background model for image blocks learned from the image itself. A theorem guarantees that under this model, not more than a fixed number of wrong matches occurs (on average) for the whole image. This fixed number (the number of false alarms) is the only method parameter. Furthermore, the number of false alarms associated with each match measures its reliability. This a contrario block-matching method, however, cannot rule out false matches due to the presence of periodic objects in the images. But it is successfully complemented by a parameterless self-similarity threshold. Experimental evidence shows that the proposed method also detects occlusions and incoherent motions due to vehicles and pedestrians in nonsimultaneous stereo. PMID- 22442123 TI - Nonlinear shape registration without correspondences. AB - In this paper, we propose a novel framework to estimate the parameters of a diffeomorphism that aligns a known shape and its distorted observation. Classical registration methods first establish correspondences between the shapes and then compute the transformation parameters from these landmarks. Herein, we trace back the problem to the solution of a system of nonlinear equations which directly gives the parameters of the aligning transformation. The proposed method provides a generic framework to recover any diffeomorphic deformation without established correspondences. It is easy to implement, not sensitive to the strength of the deformation, and robust against segmentation errors. The method has been applied to several commonly used transformation models. The performance of the proposed framework has been demonstrated on large synthetic data sets as well as in the context of various applications. PMID- 22442124 TI - Optimized data fusion for kernel k-means clustering. AB - This paper presents a novel optimized kernel k-means algorithm (OKKC) to combine multiple data sources for clustering analysis. The algorithm uses an alternating minimization framework to optimize the cluster membership and kernel coefficients as a nonconvex problem. In the proposed algorithm, the problem to optimize the cluster membership and the problem to optimize the kernel coefficients are all based on the same Rayleigh quotient objective; therefore the proposed algorithm converges locally. OKKC has a simpler procedure and lower complexity than other algorithms proposed in the literature. Simulated and real-life data fusion applications are experimentally studied, and the results validate that the proposed algorithm has comparable performance, moreover, it is more efficient on large-scale data sets. (The Matlab implementation of OKKC algorithm is downloadable from http://homes.esat.kuleuven.be/~sistawww/bio/syu/okkc.html.). PMID- 22442125 TI - Restricted trivariate polycube splines for volumetric data modeling. AB - This paper presents a volumetric modeling framework to construct a novel spline scheme called restricted trivariate polycube splines (RTP-splines). The RTP spline aims to generalize both trivariate T-splines and tensor-product B-splines; it uses solid polycube structure as underlying parametric domains and strictly bounds blending functions within such domains. We construct volumetric RTP splines in a top-down fashion in four steps: 1) Extending the polycube domain to its bounding volume via space filling; 2) building the B-spline volume over the extended domain with restricted boundaries; 3) inserting duplicate knots by adding anchor points and performing local refinement; and 4) removing exterior cells and anchors. Besides local refinement inherited from general T-splines, the RTP-splines have a few attractive properties as follows: 1) They naturally model solid objects with complicated topologies/bifurcations using a one-piece continuous representation without domain trimming/patching/merging. 2) They have guaranteed semistandardness so that the functions and derivatives evaluation is very efficient. 3) Their restricted support regions of blending functions prevent control points from influencing other nearby domain regions that stay opposite to the immediate boundaries. These features are highly desirable for certain applications such as isogeometric analysis. We conduct extensive experiments on converting complicated solid models into RTP-splines, and demonstrate the proposed spline to be a powerful and promising tool for volumetric modeling and other scientific/engineering applications where data sets with multiattributes are prevalent. PMID- 22442126 TI - Maintaining large time steps in explicit finite element simulations using shape matching. AB - We present a novel hybrid method to allow large time steps in explicit integrations for the simulation of deformable objects. In explicit integration schemes, the time step is typically limited by the size and the shape of the discretization elements as well as by the material parameters. We propose a two step strategy to enable large time steps for meshes with elements potentially destabilizing the integration. First, the necessary time step for a stable computation is identified per element using modal analysis. This allows determining which elements have to be handled specially given a desired simulation time step. The identified critical elements are treated by a geometric deformation model, while the remaining ones are simulated with a standard deformation model (in our case, a corotational linear Finite Element Method). In order to achieve a valid deformation behavior, we propose a strategy to determine appropriate parameters for the geometric model. Our hybrid method allows taking much larger time steps than using an explicit Finite Element Method alone. The total computational costs per second are significantly lowered. The proposed scheme is especially useful for simulations requiring interactive mesh updates, such as for instance cutting in surgical simulations. PMID- 22442127 TI - Direct isosurface visualization of hex-based high-order geometry and attribute representations. AB - In this paper, we present a novel isosurface visualization technique that guarantees the accurate visualization of isosurfaces with complex attribute data defined on (un)structured (curvi)linear hexahedral grids. Isosurfaces of high order hexahedral-based finite element solutions on both uniform grids (including MRI and CT scans) and more complex geometry representing a domain of interest that can be rendered using our algorithm. Additionally, our technique can be used to directly visualize solutions and attributes in isogeometric analysis, an area based on trivariate high-order NURBS (Non-Uniform Rational B-splines) geometry and attribute representations for the analysis. Furthermore, our technique can be used to visualize isosurfaces of algebraic functions. Our approach combines subdivision and numerical root finding to form a robust and efficient isosurface visualization algorithm that does not miss surface features, while finding all intersections between a view frustum and desired isosurfaces. This allows the use of view-independent transparency in the rendering process. We demonstrate our technique through a straightforward CPU implementation on both complex-structured and complex-unstructured geometries with high-order simulation solutions, isosurfaces of medical data sets, and isosurfaces of algebraic functions. PMID- 22442128 TI - A space-filling visualization technique for multivariate small-world graphs. AB - We introduce an information visualization technique, known as GreenCurve, for large multivariate sparse graphs that exhibit small-world properties. Our fractal based design approach uses spatial cues to approximate the node connections and thus eliminates the links between the nodes in the visualization. The paper describes a robust algorithm to order the neighboring nodes of a large sparse graph by solving the Fiedler vector of its graph Laplacian, and then fold the graph nodes into a space-filling fractal curve based on the Fiedler vector. The result is a highly compact visualization that gives a succinct overview of the graph with guaranteed visibility of every graph node. GreenCurve is designed with the power grid infrastructure in mind. It is intended for use in conjunction with other visualization techniques to support electric power grid operations. The research and development of GreenCurve was conducted in collaboration with domain experts who understand the challenges and possibilities intrinsic to the power grid infrastructure. The paper reports a case study on applying GreenCurve to a power grid problem and presents a usability study to evaluate the design claims that we set forth. PMID- 22442129 TI - Ambiguity-free edge-bundling for interactive graph visualization. AB - Graph visualization has been widely used to understand and present both global structural and local adjacency information in relational data sets (e.g., transportation networks, citation networks, or social networks). Graphs with dense edges, however, are difficult to visualize because fast layout and good clarity are not always easily achieved. When the number of edges is large, edge bundling can be used to improve the clarity, but in many cases, the edges could be still too cluttered to permit correct interpretation of the relations between nodes. In this paper, we present an ambiguity-free edge-bundling method especially for improving local detailed view of a complex graph. Our method makes more efficient use of display space and supports detail-on-demand viewing through an interactive interface. We demonstrate the effectiveness of our method with public coauthorship network data. PMID- 22442130 TI - High performance computational systems biology. PMID- 22442131 TI - Gene classification using parameter-free semi-supervised manifold learning. AB - A new manifold learning method, called parameter-free semi-supervised local Fisher discriminant analysis (pSELF), is proposed to map the gene expression data into a low-dimensional space for tumor classification. Motivated by the fact that semi-supervised and parameter-free are two desirable and promising characteristics for dimension reduction, a new difference-based optimization objective function with unlabeled samples has been designed. The proposed method preserves the global structure of unlabeled samples in addition to separating labeled samples in different classes from each other. The semi-supervised method has an analytic form of the globally optimal solution, which can be computed efficiently by eigen decomposition. Experimental results on synthetic data and SRBCT, DLBCL, and Brain Tumor gene expression data sets demonstrate the effectiveness of the proposed method. PMID- 22442132 TI - On the application of active learning and Gaussian processes in postcryopreservation cell membrane integrity experiments. AB - Biological cell cryopreservation permits storage of specimens for future use. Stem cell cryostorage in particular is fast becoming a broadly spread practice due to their potential for use in regenerative medicine. For the optimal cryopreservation process, ultralow temperatures are needed. However, elevated temperatures are often unavoidable in a typical sample handling cycle which in turn negatively affects the postcryopreservation integrity of cells. In this paper, we present an application of active learning using an underlying Gaussian Process (GP) model in an experimental study on postcryopreservation membrane integrity response to a range of elevated temperature conditions. We tailored this technique for the current investigation and developed an algorithm which enabled identification of the sampling locations for the experiments in order to obtain the highest information return about the process from a limited size sample set. We applied this algorithm in the experimental study investigating the effects of severe temperature elevation (ranging from -40 to 20 degrees C) over a short term event (48 hours) on the postcryopreservation membrane integrity of Mesenchymal Stem Cells (MSCs) derived from human bone marrow. The algorithm showed excellent performance by selecting the locations which maximized the reduction of variance of the process response estimate. An approximating GP model developed from this experimental data shows that the elevated temperatures during cryopreservation have an imminent detrimental effect on cell integrity. PMID- 22442133 TI - Quantitative analysis of the self-assembly strategies of intermediate filaments from tetrameric vimentin. AB - In vitro assembly of intermediate filaments from tetrameric vimentin consists of a very rapid phase of tetramers laterally associating into unit-length filaments and a slow phase of filament elongation. We focus in this paper on a systematic quantitative investigation of two molecular models for filament assembly, recently proposed in (Kirmse et al. J. Biol. Chem. 282, 52 (2007), 18563-18572), through mathematical modeling, model fitting, and model validation. We analyze the quantitative contribution of each filament elongation strategy: with tetramers, with unit-length filaments, with longer filaments, or combinations thereof. In each case, we discuss the numerical fitting of the model with respect to one set of data, and its separate validation with respect to a second, different set of data. We introduce a high-resolution model for vimentin filament self-assembly, able to capture the detailed dynamics of filaments of arbitrary length. This provides much more predictive power for the model, in comparison to previous models where only the mean length of all filaments in the solution could be analyzed. We show how kinetic observations on low-resolution models can be extrapolated to the high-resolution model and used for lowering its complexity. PMID- 22442134 TI - Quantifying long-term microelectrode array functionality using chronic in vivo impedance testing. AB - Long-term acquisition of high-quality neural recordings is a cornerstone of neuroprosthetic system design. Mitigating the experimental variability of chronically implanted arrays has been a formidable task because the sensor recording sites can be influenced by biotic and abiotic responses. Several studies have implicated changes in electrical interface impedance as a preliminary marker to infer electrode viability. Microelectrode impedance plays an important role in the monitoring of low amplitude and high-resolution extracellular neural signals. In this work, we seek to quantify long-term microelectrode array functionality and derive an impedance-based predictor for electrode functionality that correlates the recording site electrical properties with the functional neuronal recordings in vivo. High temporal resolution metrics of this type would allow one to assess, predict, and improve electrode performance in the future. In a large cohort of animals, we performed daily impedance measurements and neural signal recordings over long periods (up to 21 weeks) of time in rats using tungsten microwire arrays implanted into the somatosensory cortex. This study revealed that there was a time-varying trend in the modulation of impedance that was related to electrode performance. Single units were best detected from electrodes at time points when the electrode entered into the 40-150 KOmega impedance range. This impedance trend was modeled across the full cohort of animals to predict future electrode performance. The model was tested on data from all animals and was able to provide predictions of electrode performance chronically. Insight from this study can be combined with knowledge of electrode materials and histological analysis to provide a more comprehensive predictive model of electrode failure in the future. PMID- 22442135 TI - Triple quantum dots as charge rectifiers. AB - We theoretically analyze electronic spin transport through a triple quantum dot in series, attached to electrical contacts, where the drain contact is coupled to the central dot. We show that current rectification is observed in the device due to current blockade. The current blocking mechanism is originated by a destructive interference of the electronic wavefunction at the drain dot. There, the electrons are coherently trapped in a singlet two-electron dark state, which is a coherent superposition of the electronic wavefunction in the source dot and in the dot isolated from the contacts. Its formation gives rise to zero current and current rectification as the voltage is swept. We analyze this behavior analytically and numerically for both zero and finite magnetic dc fields. On top of that, we include phenomenologically a finite spin relaxation rate and calculate the current numerically. Our results show that triple dots in series can be designed to behave as quantum charge rectifiers. PMID- 22442136 TI - Rag GTPases and AMPK/TSC2/Rheb mediate the differential regulation of mTORC1 signaling in response to alcohol and leucine. AB - Leucine (Leu) and insulin both stimulate muscle protein synthesis, albeit at least in part via separate signaling pathways. While alcohol (EtOH) suppresses insulin-stimulated protein synthesis in cultured myocytes, its ability to disrupt Leu signaling and Rag GTPase activity has not been determined. Likewise, little is known regarding the interaction of EtOH and Leu on the AMPK/TSC2/Rheb pathway. Treatment of myocytes with EtOH (100 mM) decreased protein synthesis, whereas Leu (2 mM) increased synthesis. In combination, EtOH suppressed the anabolic effect of Leu. The effects of EtOH and Leu were associated with coordinate changes in the phosphorylation state of mTOR, raptor, and their downstream targets 4EBP1 and S6K1. As such, EtOH suppressed the ability of Leu to activate these signaling components. The Rag signaling pathway was activated by Leu but suppressed by EtOH, as evidenced by changes in the interaction of Rag proteins with mTOR and raptor. Overexpression of constitutively active (ca)RagA and caRagC increased mTORC1 activity, as determined by increased S6K1 phosphorylation. Furthermore, the caRagA-caRagC heterodimer blocked the inhibitory effect of EtOH. EtOH and Leu produced differential effects on AMPK signaling. EtOH enhanced AMPK activity, resulting in increased TSC2 (S1387) and eEF2 phosphorylation, whereas Leu had the opposite effect. EtOH also decreased the interaction of Rheb with mTOR, and this was prevented by Leu. Collectively, our results indicate that EtOH inhibits the anabolic effects that Leu has on protein synthesis and mTORC1 activity by modulating both Rag GTPase function and AMPK/TSC2/Rheb signaling. PMID- 22442137 TI - The role of aspartic acid residues 405 and 416 of the kidney isotype of sodium bicarbonate cotransporter 1 in its targeting to the plasma membrane. AB - The NH(2) terminus of the sodium-bicarbonate cotransporter 1 (NBCe1) plays an important role in its targeting to the plasma membrane. To identify the amino acid residues that contribute to the targeting of NBCe1 to the plasma membrane, polarized MDCK cells were transfected with expression constructs coding for green fluorescent protein (GFP)-tagged NBCe1 NH(2)-terminal deletion mutants, and the localization of GFP-tagged proteins was analyzed by confocal microscopy. Our results indicate that the amino acids between residues 399 and 424 of NBCe1A contain important sequences that contribute to its localization to the plasma membrane. Site-directed mutagenesis studies showed that GFP-NBCe1A mutants D405A and D416A are retained in the cytoplasm of the polarized MDCK epithelial cells. Examination of functional activities of D405A and D416A reveals that their activities are reduced compared with the wild-type NBCe1A. Similarly, aspartic acid residues 449 and 460 of pancreatic NBCe1 (NBCe1B), which correspond to residues 405 and 416 of NBCe1A, are also required for its full functional activity and accurate targeting to the plasma membrane. In addition, while replacement of D416 with glutamic acid did not affect the targeting or functional activity of NBCe1A, substitution of D405 with glutamic acid led to the retention of the mutated protein in the intracellular compartment and impaired functional activity. These studies demonstrate that aspartic acid residues 405 and 416 in the NH(2) terminus of NBCe1A are important in its accurate targeting to the plasma membrane. PMID- 22442138 TI - Skeletal muscle fibrosis develops in response to desmin deletion. AB - Skeletal muscle is a dynamic composite of proteins that responds to both internal and external cues to facilitate muscle adaptation. In cases of disease or altered use, these messages can be distorted resulting in myopathic conditions such as fibrosis. In this work, we describe a mild and progressive fibrotic adaptation in skeletal muscle lacking the cytoskeletal intermediate filament protein desmin. Muscles lacking desmin become progressively stiffer, accumulate increased collagen, and increase expression of genes involved in extracellular matrix turnover. Additionally, in the absence of desmin, skeletal muscle is in an increased state of inflammation and regeneration as indicated by increased centrally nucleated fibers, elevated inflammation and regeneration related gene expression, and increased numbers of inflammatory cells. These data suggest a potential link between increased cellular damage and the development of fibrosis in muscles lacking the cytoskeletal support of the desmin filament network. PMID- 22442139 TI - Subcellular relocation of histone deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV. AB - Regulatory mechanisms of chondrocyte differentiation in the growth plate are incompletely understood. Here, we find that histone deacetylase 4 (HDAC4) is located in the nucleus of chondrocytes in the proliferation zone and relocates to the cytoplasm of chondrocytes in the prehypertrophic zone in vivo. This suggests that the relocation of HDAC4 from the nucleus to the cytoplasm may play a role during chondrocyte differentiation. Expression of active CaMKIV in chondrocytes promotes HDAC4 relocation into cytoplasm in primary chondrocytes. Conversely, HDAC4 relocation is blocked by a Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) inhibitor. This indicates that CaMKIV signaling plays an important role in regulating HDAC4 relocation. In addition, CaMKIV is required for HDAC4 phosphorylation, which is required for HDAC4 association with the cytoplasmic protein 14-3-3. Active CaMKIV also stimulates runt-related transcription factor-2 (RunX2) and type X collagen (Col X) promoter activities and overcomes repression of these promoter activities by HDAC4. Furthermore, CaMKIV increases gene expression of the chondrocyte differentiation markers Ihh and Col X. Our results demonstrate that CaMKIV induces chondrocyte differentiation through regulation of HDAC4 subcellular relocation, from the nucleus to the cytoplasm, which results in increased activity of RunX2 and transition of chondrocytes from the proliferative to the prehypertrophic stage. Thus, CaMKIV plays an important regulatory role during chondrocyte differentiation. PMID- 22442140 TI - Metformin, metabolic stress, and mitochondria. Focus on "A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells". PMID- 22442141 TI - Size-dependent phonon transmission across dissimilar material interfaces. AB - In this paper, we study the size effects on the phonon transmission across material interfaces using the atomistic Green's function method. Layered Si and Ge or Ge-like structures are modeled with a variety of confined sizes in both transverse and longitudinal directions. The dynamical equation of the lattice vibration (phonon waves) is solved using the Green's function method and the phonon transmission is calculated through the obtained Green's function. Phonon transmission across a single interface of semi-infinite Si and Ge materials is studied first for the validation of the methodology. We show that phonon transmission across an interface can be tuned by changing the mass ratio of the two materials. Multi-layered superlattice-like structures with longitudinal size confinement are then studied. Frequency-dependent phonon transmission as a function of both the number of periods and the period thickness is reported. A converged phonon transmission after ten periods is observed due to the formation of phonon minibands. Frequency-dependent phonon transmission with transverse size confinement is also studied for the interface of Si and Ge nanowire-like structures. The phonon confinement induces new dips and peaks of phonon transmission when compared with the results for a bulk interface. With increasing size in the transverse direction, the phonon transmission approaches that of a bulk Si/Ge interface. PMID- 22442142 TI - Targeted taste cell-specific overexpression of brain-derived neurotrophic factor in adult taste buds elevates phosphorylated TrkB protein levels in taste cells, increases taste bud size, and promotes gustatory innervation. AB - Brain-derived neurotrophic factor (BDNF) is the most potent neurotrophic factor in the peripheral taste system during embryonic development. It is also expressed in adult taste buds. There is a lack of understanding of the role of BDNF in the adult taste system. To address this, we generated novel transgenic mice in which transgene expression was driven by an alpha-gustducin promoter coupling BDNF expression to the postnatal expression of gustducin in taste cells. Immunohistochemistry revealed significantly stronger BDNF labeling in taste cells of high BDNF-expressing mouse lines compared with controls. We show that taste buds in these mice are significantly larger and have a larger number of taste cells compared with controls. To examine whether innervation was affected in Gust BDNF mice, we used antibodies to neural cell adhesion molecule (NCAM) and ATP receptor P2X3. The total density of general innervation and specifically the gustatory innervation was markedly increased in high BDNF-expressing mice compared with controls. TrkB and NCAM gene expression in laser capture microdissected taste epithelia were significantly up-regulated in these mice. Up regulation of TrkB transcripts in taste buds and elevated taste cell-specific TrkB phosphorylation in response to increased BDNF levels indicate that BDNF controls the expression and activation of its high affinity receptor in taste cells. This demonstrates a direct taste cell function for BDNF. BDNF also orchestrates and maintains taste bud innervation. We propose that the Gust-BDNF transgenic mouse models can be employed to further dissect the specific roles of BDNF in the adult taste system. PMID- 22442143 TI - The AT-hook motif-containing protein AHL22 regulates flowering initiation by modifying FLOWERING LOCUS T chromatin in Arabidopsis. AB - Coordination of the onset of flowering with developmental status and seasonal cues is critical for reproductive success in plants. Molecular genetic studies on Arabidopsis mutants that have alterations in flowering time have identified a wide array of genes that belong to distinct genetic flowering pathways. The flowering time genes are regulated through versatile molecular and biochemical mechanisms, such as controlled RNA metabolism and chromatin modifications. Recent studies have shown that a group of AT-hook DNA-binding motif-containing proteins plays a role in plant developmental processes and stress responses. Here, we demonstrate that the AT-hook protein AHL22 (AT-hook motif nuclear localized 22) regulates flowering time by modifying FLOWERING LOCUS T (FT) chromatin in Arabidopsis. AHL22 binds to a stretch of the AT-rich sequence in the FT locus. It interacts with a subset of histone deacetylases. An Arabidopsis mutant overexpressing the AHL22 gene (OE-AHL22) exhibited delayed flowering, and FT transcription was significantly reduced in the mutant. Consistent with the delayed flowering and FT suppression in the OE-AHL22 mutant, histone 3 (H3) acetylation was reduced and H3 lysine 9 dimethylation was elevated in the FT chromatin. We propose that AHL22 acts as a chromatin remodeling factor that modifies the architecture of FT chromatin by modulating both H3 acetylation and methylation. PMID- 22442144 TI - Crystal structure of Brucella abortus deoxyxylulose-5-phosphate reductoisomerase like (DRL) enzyme involved in isoprenoid biosynthesis. AB - Most bacteria use the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for the synthesis of their essential isoprenoid precursors. The absence of the MEP pathway in humans makes it a promising new target for the development of much needed new and safe antimicrobial drugs. However, bacteria show a remarkable metabolic plasticity for isoprenoid production. For example, the NADPH-dependent production of MEP from 1-deoxy-D-xylulose 5-phosphate in the first committed step of the MEP pathway is catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in most bacteria, whereas an unrelated DXR-like (DRL) protein was recently found to catalyze the same reaction in some organisms, including the emerging human and animal pathogens Bartonella and Brucella. Here, we report the x-ray crystal structures of the Brucella abortus DRL enzyme in its apo form and in complex with the broad-spectrum antibiotic fosmidomycin solved to 1.5 and 1.8 A resolution, respectively. DRL is a dimer, with each polypeptide folding into three distinct domains starting with the NADPH-binding domain, in resemblance to the structure of bacterial DXR enzymes. Other than that, DRL and DXR show a low structural relationship, with a different disposition of the domains and a topologically unrelated C-terminal domain. In particular, the active site of DRL presents a unique arrangement, suggesting that the design of drugs that would selectively inhibit DRL-harboring pathogens without affecting beneficial or innocuous bacteria harboring DXR should be feasible. As a proof of concept, we identified two strong DXR inhibitors that have virtually no effect on DRL activity. PMID- 22442145 TI - Advanced bone formation in mice with a dominant-negative mutation in the thyroid hormone receptor beta gene due to activation of Wnt/beta-catenin protein signaling. AB - Thyroid hormone (T(3)) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance, but the signaling pathways mediating these effects are poorly understood. Thrb(PV/PV) mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant negative mutant T(3) receptor (TRbeta(PV)) that cannot bind T(3) and interferes with the actions of wild-type TR. Thrb(PV/PV) mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and Thrb(PV/PV) mice. Activation of the canonical Wnt signaling in Thrb(PV/PV) mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during postnatal growth. By contrast, T(3) treatment inhibited Wnt signaling in osteoblastic cells, suggesting that T(3) inhibits the Wnt pathway by facilitating proteasomal degradation of beta-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in Thrb(PV/PV) mice, however, results from a gain of function for TRbeta(PV) that stabilizes beta-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation. PMID- 22442146 TI - Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation. AB - Isocitrate dehydrogenase (IDH) is a reversible enzyme that catalyzes the NADP(+) dependent oxidative decarboxylation of isocitrate (ICT) to alpha-ketoglutarate (alphaKG) and the NADPH/CO(2)-dependent reductive carboxylation of alphaKG to ICT. Reductive carboxylation by IDH1 was potently inhibited by NADP(+) and, to a lesser extent, by ICT. IDH1 and IDH2 with cancer-associated mutations at the active site arginines were unable to carry out the reductive carboxylation of alphaKG. These mutants were also defective in ICT decarboxylation and converted alphaKG to 2-hydroxyglutarate using NADPH. These mutant proteins were thus defective in both of the normal reactions of IDH. Biochemical analysis of heterodimers between wild-type and mutant IDH1 subunits showed that the mutant subunit did not inactivate reductive carboxylation by the wild-type subunit. Cells expressing the mutant IDH are thus deficient in their capacity for reductive carboxylation and may be compromised in their ability to produce acetyl CoA under hypoxia or when mitochondrial function is otherwise impaired. PMID- 22442147 TI - Cell type-specific beta2-adrenergic receptor clusters identified using photoactivated localization microscopy are not lipid raft related, but depend on actin cytoskeleton integrity. AB - Recent developments in the field of optical super-resolution techniques allow both a 10-fold increase in resolution as well as an increased ability to quantify the number of labeled molecules visualized in the fluorescence measurement. By using photoactivated localization microscopy (PALM) and an experimental approach based on the systematic comparison with a nonclustering peptide as a negative control, we found that the prototypical G protein-coupled receptor beta2 adrenergic receptor is partially preassociated in nanoscale-sized clusters only in the cardiomyocytes, such as H9C2 cells, but not in other cell lines, such as HeLa and Chinese hamster ovary (CHO). The addition of the agonist for very short times or the addition of the inverse agonist did not significantly affect the organization of receptor assembly. To investigate the mechanism governing cluster formation, we altered plasma membrane properties with cholesterol removal and actin microfilament disruption. Although cholesterol is an essential component of cell membranes and it is supposed to be enriched in the lipid rafts, its sequestration and removal did not affect receptor clustering, whereas the inhibition of actin polymerization did decrease the number of clusters. Our findings are therefore consistent with a model in which beta2 receptor clustering is influenced by the actin cytoskeleton, but it does not rely on lipid raft integrity, thus ruling out the possibility that cell type-specific beta2 receptor clustering is associated with the raft. PMID- 22442148 TI - Signal transducer and activator of transcription 5b (Stat5b) serine 193 is a novel cytokine-induced phospho-regulatory site that is constitutively activated in primary hematopoietic malignancies. AB - Signal transducer and activator of transcription 5b (Stat5b) is a critical node in the signaling network downstream of external (cytokines or growth factors) or internal (oncogenic tyrosine kinases) stimuli. Maximum transcriptional activation of Stat5b requires both tyrosine and serine phosphorylation. Although the mechanisms governing tyrosine phosphorylation and activation of Stat5b have been extensively studied, the role of serine phosphorylation remains to be fully elucidated. Using mass spectrometry and phospho-specific antibodies, we identified Ser-193 as a novel site of cytokine-induced phosphorylation within human Stat5b. Stat5b Ser(P)-193 was detected in activated primary human peripheral blood mononuclear cells or lymphoid cell lines in response to several gamma common (gammac) cytokines, including interleukin (IL)-2, IL-7, IL-9, and IL 15. Kinetic and spatial analysis indicated that Stat5b Ser-193 phosphorylation was rapid and transient and occurred in the cytoplasmic compartment of the cell prior to Stat5b translocation to the nucleus. Moreover, inducible Stat5b Ser-193 phosphorylation was sensitive to inhibitors of mammalian target of rapamycin (mTOR), whereas inhibition of protein phosphatase 2A (PP2A) induced phosphorylation of Ser-193. Reconstitution assays in HEK293 cells in conjunction with site-directed mutagenesis, EMSA, and reporter assays indicated that Ser(P) 193 is required for maximal Stat5b transcriptional activity. Indeed, Stat5b Ser 193 was found constitutively phosphorylated in several lymphoid tumor cell lines as well as primary leukemia and lymphoma patient tumor cells. Taken together, IL 2 family cytokines tightly control Stat5b Ser-193 phosphorylation through a rapamycin-sensitive mechanism. Furthermore, constitutive Ser-193 phosphorylation is associated with Stat5b proto-oncogenic activity and therefore may serve as a novel therapeutic target for treating hematopoietic malignancies. PMID- 22442149 TI - Low temperature and chemical rescue affect molecular proximity of DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC). AB - An imbalance of chloride and sodium ion transport in several epithelia is a feature of cystic fibrosis (CF), an inherited disease that is a consequence of mutations in the cftr gene. The cftr gene codes for a Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Some mutations in this gene cause the balance between Cl(-) secretion and Na(+) absorption to be disturbed in the airways; Cl(-) secretion is impaired, whereas Na(+) absorption is elevated. Enhanced Na(+) absorption through the epithelial sodium channel (ENaC) is attributed to the failure of mutated CFTR to restrict ENaC-mediated Na(+) transport. The mechanism of this regulation is controversial. Recently, we have found evidence for a close association of wild type (WT) CFTR and WT ENaC, further underscoring the role of ENaC along with CFTR in the pathophysiology of CF airway disease. In this study, we have examined the association of ENaC subunits with mutated DeltaF508-CFTR, the most common mutation in CF. Deletion of phenylalanine at position 508 (DeltaF508) prevents proper processing and targeting of CFTR to the plasma membrane. When DeltaF508-CFTR and ENaC subunits were co-expressed in HEK293T cells, we found that individual ENaC subunits could be co-immunoprecipitated with DeltaF508-CFTR, much like WT CFTR. However, when we evaluated the DeltaF508-CFTR and ENaC association using fluorescence resonance energy transfer (FRET), FRET efficiencies were not significantly different from negative controls, suggesting that DeltaF508-CFTR and ENaC are not in close proximity to each other under basal conditions. However, with partial correction of DeltaF508-CFTR misprocessing by low temperature and chemical rescue, leading to surface expression as assessed by total internal reflection fluorescence (TIRF) microscopy, we observed a positive FRET signal. Our findings suggest that the DeltaF508 mutation alters the close association of CFTR and ENaC. PMID- 22442150 TI - A fluorescent biosensor reveals conformational changes in human immunoglobulin E Fc: implications for mechanisms of receptor binding, inhibition, and allergen recognition. AB - IgE binding to its high affinity receptor FcepsilonRI on mast cells and basophils is a key step in the mechanism of allergic disease and a target for therapeutic intervention. Early indications that IgE adopts a bent structure in solution have been confirmed by recent x-ray crystallographic studies of IgEFc, which further showed that the bend, contrary to expectation, is enhanced in the crystal structure of the complex with receptor. To investigate the structure of IgEFc and its conformational changes that accompany receptor binding in solution, we created a Forster resonance energy transfer (FRET) biosensor using biologically encoded fluorescent proteins fused to the N- and C-terminal IgEFc domains (Cepsilon2 and Cepsilon4, respectively) together with the theoretical basis for quantitating its behavior. This revealed not only that the IgEFc exists in a bent conformation in solution but also that the bend is indeed enhanced upon FcepsilonRI binding. No change in the degree of bending was seen upon binding to the B cell receptor for IgE, CD23 (FcepsilonRII), but in contrast, binding of the anti-IgE therapeutic antibody omalizumab decreases the extent of the bend, implying a conformational change that opposes FcepsilonRI engagement. HomoFRET measurements further revealed that the (Cepsilon2)(2) and (Cepsilon4)(2) domain pairs behave as rigid units flanking the conformational change in the Cepsilon3 domains. Finally, modeling of the accessible conformations of the two Fab arms in FcepsilonRI-bound IgE revealed a mutual exclusion not seen in IgG and Fab orientations relative to the membrane that may predispose receptor-bound IgE to cross-linking by allergens. PMID- 22442151 TI - Transglutaminase-2 interaction with heparin: identification of a heparin binding site that regulates cell adhesion to fibronectin-transglutaminase-2 matrix. AB - Heparan sulfate proteoglycans are critical binding partners for extracellular tranglutaminase-2 (TG2), a multifunctional protein involved in tissue remodeling events related to organ fibrosis and cancer progression. We previously showed that TG2 has a strong affinity for heparan sulfate (HS)/heparin and reported that the heparan sulfate proteoglycan syndecan-4 acts as a receptor for TG2 via its HS chains in two ways: by increasing TG2-cell surface trafficking/externalization and by mediating RGD-independent cell adhesion to fibronectin-TG2 matrix during wound healing. Here we have investigated the molecular basis of this interaction. Site-directed mutagenesis revealed that either mutation of basic RRWK (262-265) or KQKRK (598-602) clusters, forming accessible heparin binding sequences on the TG2 three-dimensional structure, led to an almost complete reduction of heparin binding, indicating that both clusters contribute to form a single binding surface. Mutation of residues Arg(19) and Arg(28) also led to a significant reduction in heparin binding, suggesting their involvement. Our findings indicate that the heparin binding sites on TG2 mainly comprise two clusters of basic amino acids, which are distant in the linear sequence but brought into spatial proximity in the folded "closed" protein, forming a high affinity heparin binding site. Molecular modeling showed that the identified site can make contact with a single heparin-derived pentasaccharide. The TG2-heparin binding mutants supported only weak RGD-independent cell adhesion compared with wild type TG2 or mutants with retained heparin binding, and both heparin binding clusters were critical for TG2-mediated cell adhesion. These findings significantly advance our knowledge of how HS/heparin influences the adhesive function of TG2. PMID- 22442152 TI - Extra-domain B in oncofetal fibronectin structurally promotes fibrillar head-to tail dimerization of extracellular matrix protein. AB - The type III extra-domain B (ED-B) is specifically spliced into fibronectin (Fn) during embryogenesis and neoangiogenesis, including many cancers. The x-ray structure of the recombinant four-domain fragment Fn(III)7B89 reveals a tightly associated, extended head-to-tail dimer, which is stabilized via pair-wise shape and charge complementarity. A tendency toward ED-B-dependent dimer formation in solution was supported by size exclusion chromatography and analytical ultracentrifugation. When amending the model with the known three-dimensional structure of the Fn(III)10 domain, its RGD loop as well as the adhesion synergy region in Fn(III)9-10 become displayed on the same face of the dimer; this should allow simultaneous binding of at least two integrins and, thus, receptor clustering on the cell surface and intracellular signaling. Insertion of ED-B appears to stabilize overall head-to-tail dimerization of two separate Fn chains, which, together with alternating homodimer formation via disulfide bridges at the C-terminal Fn tail, should lead to the known macromolecular fibril formation. PMID- 22442153 TI - Hairless plays a role in formation of inner root sheath via regulation of Dlx3 gene. AB - The Hairless (Hr), a transcription factor, is expressed in the suprabasal cell layer of the interfollicular epidermis and the lower portion of the hair follicle epithelium, where its expression is dependent on the hair cycle. Recently, we reported a new Hr mutant mouse, Hr(Hp), in which the hairless protein (HR) was overexpressed. In this study, we documented abnormal formation of inner root sheath (IRS), suppressed expression of Dlx3, and IRS keratins in the Hr(Hp)/Hr(Hp) skin. We also found that HR down-regulated Dlx3 mRNA expression through suppression of Dlx3 promoter activity. In addition, we showed that Dlx3 regulated the expression of IRS keratins. Our results demonstrate that regulation of Dlx3 by HR affects the IRS keratin expression, thus modulating the formation of IRS of hair follicle. PMID- 22442154 TI - Trypanosoma brucei thymidine kinase is tandem protein consisting of two homologous parts, which together enable efficient substrate binding. AB - Trypanosoma brucei causes African sleeping sickness, a disease for which existing chemotherapies are limited by their toxicity or lack of efficacy. We have found that four parasites, including T. brucei, contain genes where two or four thymidine kinase (TK) sequences are fused into a single open reading frame. The T. brucei full-length enzyme as well as its two constituent parts, domain 1 and domain 2, were separately expressed and characterized. Of potential interest for nucleoside analog development, T. brucei TK was less discriminative against purines than human TK1 with the following order of catalytic efficiencies: thymidine > deoxyuridine ? deoxyinosine > deoxyguanosine. Proteins from the TK1 family are generally dimers or tetramers, and the quaternary structure is linked to substrate affinity. T. brucei TK was primarily monomeric but can be considered a two-domain pseudodimer. Independent kinetic analysis of the two domains showed that only domain 2 was active. It had a similar turnover number (k(cat)) as the full-length enzyme but could not self-dimerize efficiently and had a 5-fold reduced thymidine/deoxyuridine affinity. Domain 1, which lacks three conserved active site residues, can therefore be considered a covalently attached structural partner that enhances substrate binding to domain 2. A consequence of the non-catalytic role of domain 1 is that its active site residues are released from evolutionary pressure, which can be advantageous for developing new catalytic functions. In addition, nearly identical 89-bp sequences present in both domains suggest that the exchange of genetic material between them can further promote evolution. PMID- 22442155 TI - Enhanced dielectric constant resolution of thin insulating films by electrostatic force microscopy. AB - Electrostatic force microscopy has been shown to be a useful tool to determine the dielectric constant of insulating films of nanometer thicknesses that play a key role in many electrical, optical and biological phenomena. Previous approaches have made use of simple analytical formulas to analyze the experimental data for thin insulating films deposited directly on a metallic substrate. Here we show that the sensitivity of the EFM signal to changes in the dielectric constant of the thin film can be enhanced by using dielectric substrates with low dielectric constants. We present detailed numerical calculations of the tip-sample electrostatic interaction in the following setup: an insulating thin film, a dielectric substrate (or spacing layer) of known low dielectric constant and a metallic electrode. The EFM sensitivity to the dielectric constant increases with the thickness of the spacing layer and saturates for thicknesses above 100-300 nm, when it is close to that of an infinite medium. PMID- 22442156 TI - Cu/Zn superoxide dismutase (SOD1) induction is implicated in the antioxidative and antiviral activity of acetylsalicylic acid in HCV-expressing cells. AB - We evaluated the participation of oxidative stress in the negative regulation of hepatitis C virus (HCV)-RNA induced by acetylsalicylic acid (ASA). We used the HCV subgenomic replicon cell system that stably expresses HCV-nonstructural proteins (Huh7 HCV replicon cells) and the parental cell line. Cells were exposed to 4 mM ASA at different times (12-72 h), and pyrrolidine dithiocarbamate (PDTC) was used as an antioxidant control. Reactive oxygen species (ROS) production, oxidized protein levels, cytosolic superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GPx) activity were measured to evaluate oxidative stress. In addition, viral RNA and prostaglandin (PGE(2)) levels were determined. We observed that ASA treatment decreased ROS production and oxidized protein levels in a time-dependent fashion in both parental and HCV replicon cells with a greater extent in the latter. Similar results were found with PDTC exposure. Average GPx activity was decreased, whereas a striking increase was observed in average cytosolic SOD activity at 48 and 72 h in both cells exposed to ASA, compared with untreated cells. HCV replicon cells showed higher levels of Cu/Zn SOD expression (mRNA and protein) with ASA treatment (48 and 72 h), whereas NS5A protein levels showed decreased expression. In addition, we found that inhibition of SOD1 expression reversed the effect of ASA. Interestingly, PDTC downregulated HCV-RNA expression (55%) and PGE(2) (60%) levels, imitating ASA exposure. These results suggest that ASA treatment could reduce cellular oxidative stress markers and modify Cu/Zn-SOD expression, a phenomenon that may contribute to the mechanisms involved in HCV downregulation. PMID- 22442157 TI - Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis. AB - Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor (CCK-BR), which has been found to be overexpressed in pancreatic cancer. In this study, we proposed that the CCK-BR drives growth of pancreatic cancer; hence, interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics. The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents. The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA, respectively, and the effects on cell growth and apoptosis were assessed. CCK-BR downregulation resulted in reduced cancer cell proliferation, decreased DNA synthesis, and cell cycle arrest as demonstrated by an inhibition of G(1) to S phase progression. Furthermore, CCK-BR downregulation increased caspase-3 activity, TUNEL-positive cells, and decreased X-linked inhibitor of apoptosis protein expression, suggesting apoptotic activity. Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated, as assessed by a migration assay. These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer. Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer. PMID- 22442158 TI - Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. AB - Inflammatory cell infiltration in the liver is a hallmark of nonalcoholic steatohepatitis (NASH). The chemokine-chemokine receptor interaction induces inflammatory cell recruitment. CC-chemokine receptor (CCR)2 is expressed on hepatic macrophages and hepatic stellate cells. This study aims to investigate the therapeutic potential of CCR2 to NASH. Twenty-two weeks on a choline deficient amino acid-defined (CDAA) diet induced steatosis, inflammatory cell infiltration, and liver fibrosis with increased CCR2 and monocyte chemoattractant protein (MCP)-1 expression in the wild-type livers. The infiltrated macrophages expressed CD68, CCR2, and a marker of bone marrow-derived monocytes, Ly6C. CCR2( /-) mice had less steatosis, inflammatory cell infiltration, and fibrosis, and hepatic macrophages expressing CD68 and Ly6C were decreased. Toll-like receptor (TLR)4(-/-), TLR9(-/-), and MyD88(-/-) mice had reduced hepatic macrophage infiltration with decreased MCP-1 and CCR2 expression because TLR signaling is a potent inducer of MCP-1. To assess the role of Kupffer cells at the onset of NASH, Kupffer cells were depleted by liposomal clodronate. The Kupffer cell depletion ameliorated steatohepatitis with a decrease in the MCP-1 expression and recruitment of Ly6C-expressing macrophages at the onset of NASH. Finally, to test the therapeutic potential of targeting CCR2, a CCR2 inhibitor was administered to mice on a CDAA diet. The pharmaceutical inhibition of CCR2 prevented infiltration of the Ly6C-positive macrophages, resulting in an inhibition of liver inflammation and fibrosis. We concluded that CCR2 and Kupffer cells contribute to the progression of NASH by recruiting bone marrow-derived monocytes. PMID- 22442159 TI - Stroke volume obtained by electrical interrogation of the brachial artery: transbrachial electrical bioimpedance velocimetry. AB - The goal of this study is to measure left ventricular stroke volume (SV) from the brachial artery (BA) using electrical bioimpedance. Doppler-derived SV was used for comparison. Twenty-nine healthy adults were recruited for study. Doppler echocardiographic-derived SV was obtained from the product of distal left ventricular outflow tract cross-sectional area and systolic velocity integral. SV from the BA was obtained by transbrachial electrical bioimpedance velocimetry (TBEV). Application of a current field across the left brachium was effected by injection of a constant magnitude, high frequency, low amperage, alternating current. Therein, a static voltage (U(0)) and pulsatile voltage change (DeltaU(t)) were measured and converted to their corresponding impedances, Z(0) and DeltaZ(t). TBEV-derived SV was obtained by multiplying a square root value of the normalized, acceleration-based, peak first time derivative of DeltaZ(t) by a volume conductor and systolic flow time. Inter-method agreement was determined by the Bland-Altman method. To assess the contribution of blood resistivity variations to DeltaZ(t), BA diameters were measured at end-diastole and peak systolic expansion. Results indicate that since the BA demonstrates parabolic, laminar flow, with minimal diameter changes, blood resistivity variations are likely responsible for the derived impedance changes. Bland-Altman analysis shows that SV is obtainable by TBEV from healthy humans at rest. PMID- 22442160 TI - Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice. AB - OBJECTIVE: Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. DESIGN: Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. RESULTS: Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation. CONCLUSION: These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease. PMID- 22442161 TI - Factors determining the quality of screening colonoscopy: a prospective study on adenoma detection rates, from 12,134 examinations (Berlin colonoscopy project 3, BECOP-3). AB - BACKGROUND: Screening colonoscopy (SC) outcome quality is best determined by the adenoma detection rate (ADR). The substantial variability in the ADRs between endoscopists may reflect different skills, experience and/or equipment. OBJECTIVE: To analyse the potential factors that may influence ADR variance, including case volume. DESIGN: 12,134 consecutive SCs (mean age 64.5 years, 47% men) from 21 Berlin private-practice colonoscopists were prospectively studied during 18 months. The data were analysed using a two-level mixed linear model to adequately address the characteristics of patients and colonoscopists. The ADR was regressed after considering the following factors: sex, age, bowel cleanliness, NSAID intake, annual SC case volume, lifetime experience, instrument withdrawal times, instrument generations used, and the number of annual continuing medical education (CME) meetings attended by the physician. The case volume was also retrospectively analysed from the 2007 national SC registry data (312,903 colonoscopies and 1004 colonoscopists). RESULTS: The patient factors that correlated with the ADR were sex, age (p<0.001) and low quality of bowel preparation (p=0.005). The factors that were related to the colonoscopists were the number of CME meetings attended (p=0.012) and instrument generation (p=0.001); these factors accounted for approximately 40% of the interphysician variability. Within a narrow range (6-11 min), the withdrawal time was not correlated with the ADR. Annual screening case volume did not correlate with the ADR, and this finding was confirmed by the German registry data. CONCLUSIONS: The outcome quality of screening colonoscopies is mainly influenced by individual colonoscopist factors (ie, CME activities) and instrument quality. CLINICAL TRIAL REGISTRATION NUMBER: Clinical Trial Gov Registration number: NCT00860665. PMID- 22442162 TI - Offering people a choice for colorectal cancer screening. AB - OBJECTIVES: To assess the population coverage and diagnostic yield of offering an immunochemical faecal occult blood test (FIT) to non-responders to a flexible sigmoidoscopy (FS) invitation. DESIGN: A cohort study conducted in a population based colorectal cancer (CRC) screening programme. In this programme, eligible men and women aged 58 (Turin; 43,748 subjects) or 60 (Verona; 19,970 subjects) are invited, with a personal letter signed by their general practitioner, to undergo an FS. Bowel preparation is limited to a single enema self-administered at home. Subjects in whom one distal polyp >5 mm (>= 10 mm in Turin) or at least one adenoma (one advanced adenoma or more than two adenomas in Turin) is detected at FS are referred for colonoscopy. People who do not respond to the invitation to undergo an FS are invited to have an FIT (OC-Sensor; Eiken, Tokyo, Japan; single sample, cut-off 100 ng/ml). Attendance rate and neoplasia yield were analysed in four consecutive birth cohorts. RESULTS: Overall participation rate for the FS invitation was 39.3% in Verona and 29.9% in Turin. Of the eligible non responders to the FS invitation, 19.3% (95% CI 18.9% to 19.7%) underwent an FIT. As a result, the proportion of people undergoing screening by FS or FIT was 55.2% in Verona and 39.3% in Turin, with no gender differences in either centre. FIT detected 8.3% of all advanced adenomas and 20.4% of all CRCs diagnosed at screening. CONCLUSIONS: A strategy involving the sequential offer of FS and FIT is a feasible and efficient approach. FIT in people not attending for FS increases screening uptake and detection of advanced adenomas and CRCs. PMID- 22442163 TI - Spontaneous bacterial peritonitis prophylaxis in the era of healthcare associated infection. PMID- 22442164 TI - Protein kinase C isozymes regulate matrix metalloproteinase-1 expression and cell invasion in Helicobacter pylori infection. AB - BACKGROUND: Protein kinase C (PKC) signalling is often dysregulated in gastric cancer and therefore represents a potential target in cancer therapy. The Gram negative bacterium Helicobacter pylori, which colonises the human stomach, plays a major role in the development of gastritis, peptic ulcer and gastric adenocarcinoma. OBJECTIVE: To analyse the role of PKC isozymes as mediators of H pylori-induced pathogenesis. METHODS: PKC phosphorylation was evaluated by immunoblotting and immunohistochemistry. Gene reporter assays, RT-PCR and invasion assays were performed to assess the role of PKC in the regulation of activator protein-1 (AP-1), matrix metalloproteinase-1 (MMP-1) and the invasion of H pylori-infected epithelial cells. RESULTS: H pylori induced phosphorylation of PKC isozymes alpha, delta, theta in AGS cells, which was accompanied by the phosphorylation of PKC substrates, including PKCMU and myristoylated alanine-rich C kinase substrate (MARCKS), in a CagA-independent manner. Phospholipase C, phosphatidylinositol 3-kinase and Ca(2+) were crucial for PKC activation on infection; inhibition of PKC diminished AP-1 induction and, subsequently, MMP-1 expression. Invasion assays confirmed PKC involvement in H pylori-induced MMP-1 secretion. In addition, analysis of biopsies from human gastric mucosa showed increased phosphorylation of PKC in active H pylori gastritis and gastric adenocarcinoma. CONCLUSION: The targeting of certain PKC isozymes might represent a suitable strategy to interfere with the MMP-1-dependent remodelling of infected tissue and to overcome the invasive behaviour of gastric cancer cells. PMID- 22442165 TI - Lgr5 expression is absent in human premalignant lesions of the stomach. PMID- 22442166 TI - Statin use and the risk of Clostridium difficile in academic medical centres. AB - OBJECTIVES: To estimate the possible relationship between statin use and the risk of healthcare facility onset Clostridium difficile. METHODS: Patients over 18 years of age admitted to hospitals contributing data to the University HealthSystem Consortium between 2002 and 2009 were eligible. Patients with the ICD-9-CM code 008.45 who received a minimum 3-day course of either metronidazole or oral vancomycin on/after day 5 of admission were considered incident cases of C difficile infection. 31,472 incident cases of C difficile infection were identified and matched to five controls, on hospital, year/quarter of admission date, and age +/-10 years (N=78,096). Patients who were administered one drug in the statin class (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) before the index date were considered to be exposed. Conditional logistic regression modelling provided adjusted odds ratios and 95% CI. RESULTS: Compared with non-users, users of any drug within the statin class were 0.78 times less likely to develop C difficile infection in the hospital (95% CI 0.75 to 0.81) adjusting for potential confounders. Differences in estimates for specific statins were minimal. Niacin, fibrates and selective cholesterol absorption inhibitors showed no association with the risk of C difficile infection. CONCLUSIONS: Our data were consistent with a growing body of literature demonstrating a reduced risk of infections with statin use. Statins' pleiotropic properties may provide protection against C difficile infection. PMID- 22442167 TI - Application of the ABCD2 score to identify cerebrovascular causes of dizziness in the emergency department. AB - BACKGROUND AND PURPOSE: Dizziness can herald a cerebrovascular event. The ABCD(2) score predicts the risk of stroke after transient ischemic attack partly by distinguishing transient ischemic attack from mimics. We evaluated whether this score would also identify cerebrovascular events among emergency department patients with dizziness. METHODS: We retrospectively identified consecutive adults presenting to a university emergency department with a primary symptom of dizziness, vertigo, or imbalance. Two neurologists independently reviewed medical records to determine whether the presenting symptom was caused by a cerebrovascular event (ischemic stroke, transient ischemic attack, or intracranial hemorrhage). ABCD(2) scores were then assigned using clinical information from the medical record. The ability of the score to discriminate between patients with cerebrovascular events and those with other diagnoses was quantified using the c statistic. RESULTS: Among 907 dizzy patients (mean age, 59 years; 58% female), 37 (4.1%) had a cerebrovascular cause, the majority of which were ischemic strokes (n=24). The median ABCD(2) score was 3 (interquartile range, 3-4). The ABCD(2) score predicted ultimate diagnosis of a cerebrovascular event (c statistic, 0.79; 95% CI, 0.73-0.85). Only 5 of 512 (1.0%) patients with a score of <= 3 had a cerebrovascular event compared to 25 of 369 patients (6.8%) with a score of 4 or 5 and 7 of 26 patients (27.0%) with a score of 6 or 7. CONCLUSIONS: The ABCD(2) score may provide useful information on dizzy emergency department patients at low-risk for having a cerebrovascular diagnosis and may aid frontline providers in acute management if validated prospectively. PMID- 22442168 TI - Silent infarcts and cerebral microbleeds modify the associations of white matter lesions with gait and postural stability: population-based study. AB - BACKGROUND AND PURPOSE: Although cerebral white matter lesions (WMLs), silent infarcts (SIs), and microbleeds (MBs) are individually associated with poorer gait and balance, it is unknown if they interact. We studied the interactions of WML volume with SI and MB on gait and postural stability. METHODS: Participants in a population-based study aged 60 to 86 years underwent brain MRI, computerized gait measurement, and a physiological profile assessment of postural stability. Segmentation procedures and standard rating methods were used to measure WML, SI, and MB. Linear regression was used to test interactions between lesions on gait and postural stability, adjusting for age, sex, and total intracranial volume. RESULTS: There were 395 participants (mean age, 72 years; SD, 7.0). SIs were predominantly located in subcortical frontal white matter and in deep gray structures, and MBs were largely lobar. Participants with SI or MB had higher WML volumes than those without (P<0.001 and P=0.05, respectively). The presence of SI (P for interaction=0.01) or MB (P for interaction <0.01) magnified the adverse association of WML volume with gait. SI (P for interaction=0.02), but not MB, magnified the adverse association of WML volume with postural stability. CONCLUSIONS: Subclinical cerebrovascular lesions are adversely associated with gait and postural stability in older people in a cumulative fashion. PMID- 22442169 TI - Predictors of rapid brain imaging in acute stroke: analysis of the Get With the Guidelines-Stroke program. AB - BACKGROUND AND PURPOSE: National guidelines recommend patients with acute stroke undergo brain imaging within 25 minutes of emergency department arrival. Delayed brain imaging may reduce the effectiveness of thrombolysis or render patients ineligible. METHODS: Data from the Get With The Guidelines-Stroke program from 2003 to 2009 were analyzed to determine overall imaging rates, temporal trends, and predictive variables associated with door-to-imaging times in patients who presented to an emergency department within 2 hours of stroke symptom onset and did not have clear reasons for withholding thrombolysis. Multivariable logistic regression adjusting for within-hospital clustering was performed to identify independent predictors of brain imaging within 25 minutes of emergency department arrival. RESULTS: Brain imaging was performed within 25 minutes in 41.7% of patients. Rates of imaging within 25 minutes increased from 2003 to 2009 (33.3% 44.5%). In the multivariable model, the following variables were associated with less likelihood of imaging being completed within 25 minutes: age >70 years; female gender; nonwhite race; history of diabetes, peripheral vascular disease, or prosthetic heart valve; transportation other than ambulance; arrival >60 minutes after symptom onset; and hospital location in the Northeast. Patients with National Institutes of Health Stroke Scale scores of 16 to 25 (compared with other strata) were most likely to have imaging completed within 25 minutes. CONCLUSIONS: Most patients with acute stroke symptoms do not have brain imaging performed within the recommended 25 minutes. Future quality improvement initiatives should focus on reducing door-to-imaging times with a specific emphasis on the predictive variables identified in this analysis. PMID- 22442170 TI - Letter by Kerr and Lees regarding article, "country comparisons of human stroke research since 2001: a bibliometric study". PMID- 22442171 TI - Long-term outcomes after carotid endarterectomy: can the past be used to predict the future? PMID- 22442172 TI - Association of statins and statin discontinuation with poor outcome and survival after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Studies suggest a protective role for statins after intracerebral hemorrhage, but many failed to assess statin discontinuation, did not include postdischarge outcomes, or did not account for withdrawal of care. We studied the relationship between preintracerebral hemorrhage statin use and in hospital statin discontinuation on stroke severity and 30-day mortality. METHODS: We analyzed data from the Registry of the Canadian Stroke Network and determined the adjusted ORs for statin use and outcomes, controlling for stroke severity and other covariates. RESULTS: We analyzed 2466 consecutive patients with intracerebral hemorrhage from 2003 to 2008: median age was 71 years, 53.6% were male, and 30-day mortality rate was 36.5%. Overall, 537 (21.7%) were taking statins before presentation. Compared with nonusers, statin users were less likely to have severe strokes on presentation (54.7% versus 63.3%) but had similar rates of poor outcome (70% versus 67%) and 30-day mortality (36% versus 37%). Statins were discontinued on admission in 158 of 537 (29.4%); these patients were more likely to have severe stroke (65% versus 27%, P<0.01), poor outcome (90% versus 62%, P<0.01), and to have died by 30 days (71% versus 21%, P<0.01). After adjusting for stroke severity, statin discontinuation was still associated with poor outcome (adjusted OR, 2.4; 95% CI, 1.13-4.56) and higher mortality (adjusted OR, 2.0; 95% CI, 1.30-3.04). However, these associations were attenuated and no longer significant after excluding patients treated palliatively. CONCLUSIONS: We found no association between preadmission statin use and outcomes in intracerebral hemorrhage. Statin discontinuation may worsen outcomes or may simply be a marker of worse underlying prognosis. PMID- 22442173 TI - 25-Hydroxyvitamin D levels and the risk of stroke: a prospective study and meta analysis. AB - BACKGROUND AND PURPOSE: Despite evidence suggesting that vitamin D deficiency may lead to elevated cardiovascular disease risk, results regarding the association of 25-hydroxyvitamin D (25[OH]D) levels with stroke risk are inconclusive. We aimed to examine this association in a prospective study in women and to summarize all existing data in a meta-analysis. METHODS: We measured 25(OH)D levels among 464 women who developed ischemic stroke and an equal number of control subjects who were free of stroke through 2006 in the Nurses' Health Study (NHS). We searched MEDLINE and EMBASE for articles published through March 2011 that prospectively evaluated 25(OH)D levels in relation to stroke. RESULTS: After multivariable adjustment for lifestyle and dietary covariates, lower 25(OH)D levels were associated with an elevated risk of ischemic stroke in the NHS: the OR (95% CI) comparing women in the lowest versus highest tertiles was 1.49 (1.01 2.18; P(trend)=0.04). We found 6 other prospective studies that examined 25(OH)D in relation to stroke outcomes. After pooling our results with these prospective studies that included 1214 stroke cases in total, low 25(OH)D levels were associated with increased risk of developing stroke outcomes in comparison to high levels: the pooled relative risk (95% CI) was 1.52 (1.20-1.85; I(2)=0.0%, P(heterogeneity)=0.63). In 2 studies that explicitly examined ischemic stroke, this association was 1.59 (1.07-2.12; I(2)=0.0%, P(heterogeneity)=0.80). CONCLUSIONS: These data provide evidence that low vitamin D levels are modestly associated with risk of stroke. Maintaining adequate vitamin D status may lower the risk of stroke in women. PMID- 22442174 TI - Eligibility for Intravenous Recombinant Tissue-Type Plasminogen Activator Within a Population: The Effect of the European Cooperative Acute Stroke Study (ECASS) III Trial. AB - BACKGROUND AND PURPOSE: The publication of the European Cooperative Acute Stroke Study (ECASS III) expanded the treatment time to thrombolysis for acute ischemic stroke from 3 to 4.5 hours from symptom onset. The impact of the expanded time window on treatment rates has not been comprehensively evaluated in a population based study. METHODS: All patients with an ischemic stroke presenting to an emergency department during calendar year 2005 in the 17 hospitals that compromise the large 1.3 million Greater Cincinnati/Northern Kentucky population were included in the analysis. Criteria for exclusion from thrombolytic therapy are analyzed retrospectively for both the standard and expanded timeframes with varying door-to-needle times. RESULTS: During the study period, 1838 ischemic strokes presenting to an emergency department were identified. A small proportion of them arrived in the expanded time window (3.4%) compared with the standard time window (22%). Only 0.5% of those who arrived in this timeframe met eligibility criteria for thrombolysis compared with 5.9% using standard eligibility criteria in the standard timeframe. These results did not vary significantly by repeated analysis varying the door-to-needle time or the expanded time window's exclusion criteria. CONCLUSIONS: In reality, the expanded time window for thrombolysis in acute ischemic stroke benefits few patients. If we are to improve recombinant tissue-type plasminogen activator administration rates, our focus should be on improving stroke awareness, transport to facilities with ability to administer thrombolysis, and familiarity of physicians with acute stroke treatment guidelines. PMID- 22442175 TI - Clinical prediction rule to estimate the absolute 3-year risk of major cardiovascular events after carotid endarterectomy. AB - BACKGROUND AND PURPOSE: Prognosis after carotid endarterectomy is mainly determined by the occurrence of major adverse cardiovascular events (MACEs). Optimal medical treatment to reduce risk is the mainstay of MACE prevention. The level of risk of MACE may determine the initiation and aggressiveness of medical treatment, yet a prediction rule to assess that absolute MACE risk after carotid endarterectomy is currently unavailable. METHODS: The prediction model was developed in a consecutive cohort of 1138 patients who underwent carotid endarterectomy between 2002 and 2009. Primary end point was MACE and encompassed myocardial infarction, stroke, and cardiovascular death. Fourteen potential clinical predictors were entered into a Cox proportional hazard model. After backward stepwise regression, internal validation was conducted with bootstrapping techniques to correct for overfitting. To provide an easily applicable clinical tool, a score chart was constructed, dividing patients into 4 risk groups. Model performance was assessed in terms of discrimination, calibration, and risk stratification. RESULTS: During a mean follow-up of 2.28 (+/- 0.95) years, 148 events occurred, corresponding to a cumulative incidence of 13%. Clinical predictors in the final model were age, history of coronary or peripheral artery disease, smoking, systolic blood pressure, use of antihypertensive drugs, clinical presentation, presence of contralateral carotid stenosis, and serum creatinine levels. Discrimination of the final model, in terms of a C statistic, was 0.69 (0.64-0.73) and calibration showed a good overall fit (Gronnesby and Borgan, P=0.39). The observed incidence of MACE in the 4 risk groups was 6%, 9%, 19%, and 35%, respectively, indicating good overall risk stratification. CONCLUSIONS: The clinical prediction model for MACE in the first 3 years after carotid endarterectomy may be used to identify high-risk patients to help optimize medical treatment and risk factor management as part of secondary prevention to increase life expectancy free from MACE. Despite our success in stratifying risk among these patients, even the lowest stratum remains at high risk and all of these patients should receive maximal secondary preventive measures. PMID- 22442176 TI - Single-center experience of cerebral artery thrombectomy using the TREVO device in 60 patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke. METHODS: We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b-3), good outcome (modified Rankin Scale score 0-2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment >= 4 points) were prospectively assessed. RESULTS: Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12-22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173-296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45-114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected. CONCLUSIONS: The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials. PMID- 22442177 TI - Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature. AB - BACKGROUND AND PURPOSE: PHACE is an acronym for posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Several case reports of arterial ischemic stroke (AIS) in individuals with PHACE have been published, but risk factors for AIS in PHACE have not been clearly defined. The objective of this article is to review all cases of stroke in PHACE in children and describe clinical characteristics that may be associated with an increased risk of AIS. METHODS: A literature and registry search was conducted to identify patients with PHACE who had experienced AIS. Data were analyzed to determine age of onset, presenting signs and symptoms, and clinical features among this cohort compared with PHACE without AIS. RESULTS: Twenty-two individuals with PHACE and AIS were identified. Imaging of the arteries of the head and neck was reported in 20 of 22. Narrowing or nonvisualization of at least 1 great cerebral vessel was present in 19 of 20 and of those, 15 had >= 2 vessels involved. Aortic arch anomalies were reported in 13 of 22 individuals. CONCLUSIONS: Aplasia, hypoplasia, or occlusion of a major cerebral artery appears to be a significant risk factor for AIS in children with PHACE, especially when >1 vessel is involved or if there is coarctation of the aorta. PMID- 22442178 TI - Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. AB - BACKGROUND AND PURPOSE: Symptomatic intracerebral hemorrhage (SICH) is a serious complication in patients with acute ischemic stroke treated with intravenous thrombolysis. We aimed to develop a clinical score that can easily be applied to predict the risk of SICH. METHODS: We analyzed data from 31 627 patients treated with intravenous alteplase enrolled in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register. The outcome measure was SICH per the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS MOST) definition: a Type 2 parenchymal hemorrhage with deterioration in National Institutes of Health Stroke Scale score of >= 4 points or death. Univariate risk factors associated with the outcome were entered into a logistic regression model after stratification of continuous variables. Adjusted ORs for the independent risk factors were converted into points, which were summated to produce a risk score. RESULTS: We identified 9 independent risk factors for SICH: baseline National Institutes of Health Stroke Scale, serum glucose, systolic blood pressure, age, body weight, stroke onset to treatment time, aspirin or combined aspirin and clopidogrel, and history of hypertension. The overall rate of SICH was 1.8%. The risk score ranged from 0 to 12 points and showed a >70-fold graded increase in the rate of SICH for patients with a score >= 10 points (14.3%) compared with a score of 0 point (0.2%). The prognostic discriminating capability by C statistic was 0.70. CONCLUSIONS: The SITS SICH risk score predicts large cerebral parenchymal hemorrhages associated with severe clinical deterioration. The score could aid clinicians to identify patients at high as well as low risk of SICH after intravenous alteplase. PMID- 22442179 TI - The effect of volume conductor modeling on the estimation of cardiac vectors in fetal magnetocardiography. AB - Previous studies based on fetal magnetocardiographic (fMCG) recordings used simplified volume conductor models to estimate the fetal cardiac vector as an unequivocal measure of the cardiac source strength. However, the effect of simplified volume conductor modeling on the accuracy of the fMCG inverse solution remains largely unknown. Aiming to determine the sensitivity of the source estimators to the details of the volume conductor model, we performed simulations using fetal-maternal anatomical information from ultrasound images obtained in 20 pregnant women in various stages of pregnancy. The magnetic field produced by a cardiac source model was computed using the boundary-element method for a piecewise homogeneous volume conductor with three nested compartments (fetal body, amniotic fluid and maternal abdomen) of different electrical conductivities. For late gestation, we also considered the case of a fourth highly insulating layer of vernix caseosa covering the fetus. The errors introduced for simplified volume conductors were assessed by comparing the reconstruction results obtained with realistic versus spherically symmetric models. Our study demonstrates the significant effect of simplified volume conductor modeling, resulting mainly in an underestimation of the cardiac vector magnitude and low goodness-of-fit. These findings are confirmed by the analysis of real fMCG data recorded in mid-gestation. PMID- 22442180 TI - There are important reasons for delaying implementation of the new ICD-10 coding system. AB - Federal authorities have recently signaled that they would consider delaying some aspects of implementation of the newest version of the International Classification of Diseases, known as ICD-10-CM, a coding system used to define health care charges and diagnoses. Some industry groups have reacted with dismay, and many providers with relief. We are concerned that adopting this new classification system for reimbursement will be disruptive and costly and will offer no material improvement over the current system. Because the health care community is also working to integrate health information technology and federal meaningful-use specifications that require the adoption of other complex coding standardization systems (such as the system called SNOMED CT), we recommend that the Centers for Medicare and Medicaid Services consider delaying the adoption of ICD-10-CM. Policy makers should also begin planning now for ways to make the coming transition to ICD-11 as tolerable as possible for the health care and payment community. PMID- 22442181 TI - Evaluation of clinical outcomes and renal vascular pathology among patients with lupus. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to determine the clinical significance of renal vascular lesions in lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal vascular lesions defined as thrombotic microangiopathy, lupus vasculopathy, uncomplicated vascular immune deposits, and arterial sclerosis were evaluated in relation to renal and vascular morbidity and overall mortality. RESULTS: Biopsies from 161 patients revealed thrombotic microangiopathy (13), lupus vasculopathy (5), and arterial sclerosis (93). No renal vascular lesions were found in 24.8% of patients. At the time of biopsy, arterial sclerosis or lupus vasculopathy patients were older (arterial sclerosis=37.9+/-13.0 and lupus vasculopathy=44.4+/-8.9 versus controls=33.1+/ 8.9 years, P<0.05), and the mean arterial pressure was higher in all groups compared with controls. Nephritis subtype, activity indices, and proteinuria were similar between groups, estimated GFR was lower in arterial sclerosis (70.5+/ 33.3 versus 84.5+/-26.6 ml/min per 1.73 m(2), P=0.03), and chronicity index (thrombotic microangiopathy=3.5, lupus vasculopathy=4.5, and arterial sclerosis=2.5) was higher in all renal vascular lesions subgroups versus controls (1.0, P<0.05). In 133 patients with similar follow-up, the association between renal vascular lesions and vascular events was significant (Fisher exact test, P=0.002) and remained so after multivariate analysis (exact conditional scores test, P=0.04), where the difference between arterial sclerosis and uncomplicated vascular immune deposits was most noticeable (odds ratio [95% confidence interval]=8.35[0.98, 83.12], P=0.05). The associations between renal vascular lesions, renal outcomes, and death were not significant, likely because of insufficient power. CONCLUSIONS: Renal vascular lesions are common in SLE patients with nephritis and may be associated with arterial vascular events. PMID- 22442182 TI - Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology. AB - Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis. PMID- 22442183 TI - Ongoing clinical trials in AKI. AB - AKI is an important public health issue. AKI is a common hospital complication associated with increased in-hospital and long-term mortality, extensive morbidity (including prolonged hospital length of stay), and an estimated annual cost of at least $10 billion in the United States. At present, no specific therapy has been developed to prevent AKI, hasten recovery of kidney function, or abrogate the deleterious systemic effects of AKI. However, recent progress includes establishing a consensus definition of AKI and discovery of novel biomarkers that may allow early detection of AKI. Furthermore, significant insights into the pathophysiology of AKI and its deleterious systemic effects have been gleaned from animal studies. Urgently needed are large, definitive randomized clinical trials testing interventions to prevent and/or treat AKI. This review summarizes and analyzes current ongoing clinical trials registered with clinicaltrials.gov that address prevention or management of AKI. The purpose of this review is to provide a resource for people interested in potential prophylactic and therapeutic approaches to patient care and investigators hoping to plan and execute the next round of randomized clinical trials. Finally, this review discusses research needs that are not addressed by the current clinical trials portfolio and suggests key areas for future research in AKI. PMID- 22442184 TI - Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings. AB - AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients. PMID- 22442185 TI - Designing clinical trials in acute kidney injury. PMID- 22442186 TI - Type 2 diabetes: the best transplant option is still uncertain. PMID- 22442187 TI - Living donor age and kidney allograft half-life: implications for living donor paired exchange programs. AB - BACKGROUND AND OBJECTIVES: Living donor paired exchange programs assume that kidneys from living donors are of comparable quality and anticipated longevity. This study determined actual allograft t(1/2) within different recipient age groups (10-year increments) as a function of donor age (5-year increments), and juxtaposed these results against the probabilities of deceased donor transplantation, and exclusion from transplantation (death or removal from the wait-list). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the US Renal Data System (transplant dates 1988-2003 with follow-up through September 2007) were used to determine allograft t(1/2), whereas data from patients on the United Network for Organ Sharing waiting list between 2003 and 2005 (with follow-up through February 2010) were used to determine wait-list outcomes. RESULTS: With the exception of recipients aged 18-39 years, who had the best outcomes with donors aged 18-39 years, living donor age between 18 and 64 years had minimal effect on allograft t(1/2) (difference of 1-2 years with no graded association). The probability of deceased donor transplantation after 3 years of wait-listing ranged from 21% to 66% by blood type and level of sensitization, whereas the probability of being excluded from transplantation ranged from 6% to 27% by age, race, and primary renal disease. CONCLUSIONS: With the exception of recipients aged 18-39 years, living donor age between 18 and 64 years has minimal effect on allograft survival. PMID- 22442188 TI - Design of clinical trials in acute kidney injury: a report from an NIDDK workshop -prevention trials. AB - AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI. PMID- 22442189 TI - Blood pressure variability and cardiovascular autonomic control during hemodialysis in peripheral vascular disease patients. AB - Hemodialysis (HD) patients with peripheral vascular disease (PVD) are at higher risk of mortality. The main objectives of this work were to investigate the hypothesis of an association between the PVD and an altered control system on peripheral resistance in response to volume depletion induced by HD treatment; and to investigate whether HD induced increase of pulse pressure (PP) is associated with PVD. Continuous blood pressure (BP) was recorded during HD treatment at the beginning and at the end of HD. The overhydration condition was evaluated by means of whole body bioimpedance spectroscopy, measured before each HD treatment. BP variability, heart rate variability and baroreflex sensitivity were then analyzed. Patients affected by PVD reported a prevalence of peripheral local control as shown by higher values of very low frequency in diastolic blood pressure (DBP) variability and a reduced cardiac baroreflex with respect to patients not affected by this pathology. HD treatment induced a significant increase of PP and LF% in DBP series in PVD patients only. Our results suggested that differences in BP variability and PP changes could be related not only to an underlying vascular disease, but also to an alteration in autonomic control. PMID- 22442190 TI - Progressive resistance strength training can reduce physical disability in older adults. PMID- 22442191 TI - Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. AB - BACKGROUND: This study examines sickle cell trait (SCT) as a cause of sudden death in National Collegiate Athletic Association (NCAA) athletes and explores the cost-effectiveness of different screening models. METHODS: The authors reviewed the cause of all cases of sudden death in NCAA student-athletes from January 2004 through December 2008. The authors also explored the cost effectiveness of screening for this condition in selected populations assuming that identifying athletes with SCT would prevent death. RESULTS: There were 273 deaths and a total of 1 969 663 athlete-participant-years. Five (2%) deaths were associated with SCT. In football athletes, there were 72 (26%) deaths. Of these, 52 (72%) were due to trauma unrelated to sports activity and 20 (28%) were due to medical causes; nine deaths were cardiac (45%), five were associated with SCT (25%). Thirteen of the 20 deaths due to medical causes occurred during exertion; cardiac (6, 46%) SCT associated (5, 39%), and heat stroke unrelated to SCT (2, 15%). All deaths associated with SCT occurred in black Division I football athletes. The risk of exertional death in Division I football players with SCT was 1:827 which was 37 times higher than in athletes without SCT. The cost per case identified varied widely depending on the population screened and the price of the screening test. CONCLUSIONS: Exertional death in athletes with SCT occurs at a higher rate than previously appreciated. More research is needed to (1) understand the pathophysiology of death in SCT-positive athletes and (2) determine whether screening high-risk populations reduces mortality. PMID- 22442192 TI - A to Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance--part 31. PMID- 22442193 TI - Is the general time-reversible model bad for molecular phylogenetics? PMID- 22442195 TI - Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats. AB - This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5(BN) (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5(BN) rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 +/- 1 to 183 +/- 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 +/- 5 mmHg in SS.5(BN) rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5(BN) rats compared with SS rats. Protein excretion rose to 354 +/- 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 +/- 13 mg/day in the SS.5(BN) rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5(BN) rats (43 +/- 1 mmHg) and Dahl S (44 +/- 2 mmHg) rats. However, Pgc increased to 59 +/- 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5(BN) rats (43 +/- 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20 HETE (HET0016, 10 mg.kg(-1).day(-1) iv) reversed the antihypertensive phenotype seen in the SS.5(BN) rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5(BN) consomic strain. PMID- 22442196 TI - Nesfatin-1 influences the excitability of neurons in the nucleus of the solitary tract and regulates cardiovascular function. AB - Nesfatin-1 has been identified as one of the most potent centrally acting anorexigenic peptides, and it has also been shown to play important roles in the control of cardiovascular function. In situ hybridization and immunohistochemical studies have revealed the expression of nesfatin-1 throughout the brain and, in particular, in the medullary autonomic gateway known as the nucleus of the solitary tract (NTS). The present study was thus undertaken to explore the cellular correlates and functional roles of nesfatin-1 actions in the medial NTS (mNTS). Using current-clamp electrophysiology recordings from mNTS neurons in slice preparation, we show that bath-applied nesfatin-1 directly influences the excitability of the majority of mNTS neurons by eliciting either depolarizing (42%, mean: 7.8 +/- 0.8 mV) or hyperpolarizing (21%, mean: -8. 2 +/- 1.0 mV) responses. These responses were observed in all electrophysiologically defined cell types in the NTS and were site specific and concentration dependent. Furthermore, post hoc single cell reverse transcriptase polymerase reaction revealed a depolarizing action of nesfatin-1 on NPY and nucleobindin-2-expressing mNTS neurons. We have also correlated these actions of nesfatin-1 on neuronal membrane potential with physiological outcomes, using in vivo microinjection techniques to demonstrate that nesfatin-1 microinjected into the mNTS induces significant increases in both blood pressure (mean AUC = 3354.1 +/- 750.7 mmHg.s, n = 6) and heart rate (mean AUC = 164.8 +/- 78.5 beats, n = 6) in rats. Our results provide critical insight into the circuitry and physiology involved in the profound effects of nesfatin-1 and highlight the NTS as a key structure mediating these autonomic actions. PMID- 22442194 TI - Role of gut nutrient sensing in stimulating appetite and conditioning food preferences. AB - The discovery of taste and nutrient receptors (chemosensors) in the gut has led to intensive research on their functions. Whereas oral sugar, fat, and umami taste receptors stimulate nutrient appetite, these and other chemosensors in the gut have been linked to digestive, metabolic, and satiating effects that influence nutrient utilization and inhibit appetite. Gut chemosensors may have an additional function as well: to provide positive feedback signals that condition food preferences and stimulate appetite. The postoral stimulatory actions of nutrients are documented by flavor preference conditioning and appetite stimulation produced by gastric and intestinal infusions of carbohydrate, fat, and protein. Recent findings suggest an upper intestinal site of action, although postabsorptive nutrient actions may contribute to flavor preference learning. The gut chemosensors that generate nutrient conditioning signals remain to be identified; some have been excluded, including sweet (T1R3) and fatty acid (CD36) sensors. The gut-brain signaling pathways (neural, hormonal) are incompletely understood, although vagal afferents are implicated in glutamate conditioning but not carbohydrate or fat conditioning. Brain dopamine reward systems are involved in postoral carbohydrate and fat conditioning but less is known about the reward systems mediating protein/glutamate conditioning. Continued research on the postoral stimulatory actions of nutrients may enhance our understanding of human food preference learning. PMID- 22442197 TI - Mitochondrial reactive oxygen species and calcium uptake regulate activation of phagocytic NADPH oxidase. AB - Production of superoxide (O(2)(.-)) by NADPH oxidases contributes to the development of hypertension and atherosclerosis. Factors responsible for activation of NADPH oxidases are not well understood; interestingly, cardiovascular disease is associated with both altered NADPH oxidase activity and age-associated mitochondrial dysfunction. We hypothesized that mitochondrial dysfunction may contribute to activation of NADPH oxidase. The effect of mitochondrial inhibitors on phagocytic NADPH oxidase in human lymphoblasts and whole blood was measured at the basal state and upon PKC-dependent stimulation with PMA using extracellular 1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl trimethylammonium or mitochondria-targeted 1-hydroxy-4-[2-triphenylphosphonio) acetamido]-2,2,6,6-tetramethylpiperidine spin probes and electron spin resonance (ESR). Intracellular cytosolic calcium [Ca(2+)](i) was measured spectrofluorometrically using fura-2 AM. Incubation of lymphoblasts with the mitochondrial inhibitors rotenone, antimycin A, CCCP, or ruthenium red (an inhibitor of mitochondrial Ca(2+) uniporter) did not significantly change basal activity of NADPH oxidase. In contrast, preincubation with the mitochondrial inhibitors prior to PMA stimulation of lymphoblasts resulted in two- to three fold increase of NADPH oxidase activity compared with stimulation with PMA alone. Most notably, the intracellular Ca(2+)-chelating agent BAPTA-AM abolished the effect of mitochondrial inhibitors on NADPH oxidase activity. Cytosolic Ca(2+) measurements with fura-2 AM showed that the mitochondrial inhibitors increased [Ca(2+)](i), while BAPTA-AM abolished the increase in [Ca(2+)](i). Furthermore, depletion of cellular Ca(2+) with thapsigargin attenuated CCCP- and antimycin A mediated activation of NADPH oxidase in the presence of PMA by 42% and 31%, correspondingly. Our data suggest that mitochondria regulate PKC-dependent activation of phagocytic NADPH oxidase. In summary, increased mitochondrial O(2)(.-) and impaired buffering of cytosolic Ca(2+) by dysfunctional mitochondria result in enhanced NADPH oxidase activity, which may contribute to the development of cardiovascular diseases. PMID- 22442198 TI - Efficacy and safety of colchicine for pericarditis prevention. Systematic review and meta-analysis. AB - OBJECTIVES: The purpose of this study was to investigate the efficacy and safety of colchicine for pericarditis prevention. BACKGROUND: Recurrent pericarditis prevention is a major management goal that may reduce morbidity and management costs. Although empiric anti-inflammatory therapy is considered the mainstay of treatment, no specific drug has been proven to be efficacious for prevention but colchicine. METHODS: Controlled clinical studies were searched in several databases and were included provided they focused on the pharmacologic primary or secondary prevention of pericarditis. We performed a meta-analysis including studies primary outcome, adverse events, and drug withdrawal. RESULTS: From the initial sample of 127 citations, five controlled clinical trials were finally included (795 patients): three studies were double-blind randomised controlled trials, and two studies were open-label randomised controlled trials. Trials followed patients for a mean of 13 months. Meta-analytic pooling showed that colchicine use was associated with a reduced risk of pericarditis during follow up (RR=0.40, 95% CI 0.30 to 0.54, p for effect <0.001, p for heterogeneity = 0.95, I(2)=0%) either for primary or secondary prevention without a significant higher risk of adverse events compared with placebo (RR=1.22, 95% CI 0.71 to 2.10, p for effect 0.48, p for heterogeneity = 0.44, I(2)=0%), but more cases of drug withdrawals (RR=1.85, 95% CI 1.04 to 3.29, p for effect 0.04, p for heterogeneity = 0.42, I(2)=0%). Gastrointestinal intolerance is the most frequent side effect (mean incidence 8%), but no severe adverse events were recorded. CONCLUSIONS: Available evidence suggests that colchicine is safe and efficacious for the primary and secondary prevention of pericarditis. PMID- 22442199 TI - Pathogenesis and diagnosis of myocarditis. AB - Acute myocarditis is an inflammatory disease of the heart muscle that may progress to dilated cardiomyopathy and chronic heart failure. A number of factors including the sex hormone testosterone, components of innate immunity, and profibrotic cytokines have been identified in animal models as important pathogenic mechanisms that increase inflammation and susceptibility to chronic dilated cardiomyopathy. The clinical presentation of acute myocarditis is non specific and mimics more common causes of heart failure and arrhythmias. Suspected myocarditis is currently confirmed using advanced non-invasive imaging and histopathologic examination of heart tissue. However, the diverse presentations of myocarditis and the lack of widely available, safe, and accurate non-invasive diagnostic tests remain major obstacles to early diagnosis and population based research. Recent advances in the understanding of disease pathogenesis described in this review should lead to more accurate diagnostic algorithms and non-invasive tests. PMID- 22442200 TI - Early repolarisation: controversies and clinical implications. AB - Early repolarisation was previously considered a benign variant but in recent years has emerged as a marker of risk for sudden death. In part, this appears to reflect a change in the definition. ECG territory, degree of J-point elevation and ST-segment morphology are associated with different degrees of risk for subsequent ventricular arrhythmia. At present the dataset is insufficient to allow risk stratification in asymptomatic individuals and further epidemiological and mechanistic research is required. PMID- 22442201 TI - Antielastin B-cell and T-cell immunity in patients with chronic obstructive pulmonary disease. AB - RATIONALE: Antielastin autoimmunity has been hypothesised to drive disease progression in chronic obstructive pulmonary disease (COPD). The proposed mechanism is currently disputed by conflicting data. The authors aimed to explore antibody responses against elastin in a large and extensively characterised COPD population and to assess elastin-specific peripheral T-cell reactivity in a representative subgroup. METHODS: Antielastin antibodies were analysed with indirect ELISA on the plasma of 320 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease 1-4) and 143 smoking controls. In a second group of 40 patients with COPD and smoking controls, T-cell responses against extracellular matrix (elastin, collagen I and collagen V) were determined with enzyme-linked immunosorbent spot (EliSpot) (interferon gamma (IFNgamma) and interleukin-2) on peripheral blood mononuclear cells and compared with the responses of 11 never-smoking controls. RESULTS: Antielastin antibody titres were not elevated in patients with COPD compared with smoking controls and even decreased significantly with increasing severity of COPD (p<0.001). Lower antielastin antibody titres were also found in a subgroup of patients with CT proven emphysema. Elastin-specific INFgamma-mediated T helper 1 responses could not be revealed in smoking subjects with and without COPD. Collagen I-mediated T cell responses were also absent, which contrasted with a significant increased anticollagen V response in the smoking controls and patients with COPD compared with the never smokers (p=0.008). Collagen V-mediated T-cell responses could not discriminate between patients with COPD and smoking controls. CONCLUSION: A systemic immune response against elastin could not be identified in patients with COPD. By contrast, collagen V-mediated autoimmunity was increased in the subgroup of smokers and may potentially contribute to the pathogenesis of COPD. PMID- 22442202 TI - A pilot study evaluating the effect of mindfulness-based stress reduction on psychological status, physical status, salivary cortisol, and interleukin-6 among advanced-stage cancer patients and their caregivers. AB - PURPOSE: To investigate whether a mindfulness-based stress reduction program for cancer (MBSR-C) improved psychological and physical symptoms, quality of life (QOL), and stress markers among advanced-stage cancer patients and caregivers. DESIGN: A pilot within-subject design was used. METHOD: Patients previously diagnosed with advanced-stage breast, colon, lung, or prostate cancer and on treatment were recruited from the Moffitt Cancer Center and Research Institute. Twenty-six patient-caregiver dyads completed a modified 6-week, self-study MBSR-C program based on the Kabat-Zinn model. Psychological and physical symptoms and QOL were compared pre- and post-MBSR-C sessions. Salivary cortisol and interleukin-6 were assessed pre- and post-MBSR-C session at 1, 3, and 6 weeks. FINDINGS: Following the 6-week MBSR program, patients showed improvements in stress and anxiety (p < .05); caregivers' psychological and QOL also improved but were not statistically significant. Both patients and caregivers had decreases in cortisol at Weeks 1 and 3 (p < .05) but not at Week 6. Similar to cortisol levels at Week 6, salivary interleukin-6 levels were lower overall (before/after an MBSR C session), compared with Week 1 for patients and caregivers. CONCLUSIONS: MBSR-C may be a beneficial intervention for reducing stress, anxiety, cortisol levels, and symptoms in advanced-stage cancer patients and may also benefit caregivers. PMID- 22442203 TI - Singapore nursing students' perceptions and attitudes about spirituality and spiritual care in practice: a qualitative study. AB - PURPOSE: This exploratory study investigated nursing students' perceptions and attitudes about spirituality and spiritual care in practice. STUDY DESIGN: A qualitative interpretative approach was used to investigate the research question. METHOD: In-depth interviews were conducted with 16 final-year preregistration nursing students from 3 different educational institutions offering a degree or diploma program in Singapore. Data were analyzed using the Miles and Huberman's method of thematic analysis. FINDINGS: Thematic analysis identified three themes: (a) students' perceptions of spirituality, (b) spiritual care, and (c) factors influencing spiritual care in practice. CONCLUSIONS: The study informed that though young, spirituality matters to the nursing students. Accordingly, nursing is perceived to play an integral role in spiritual care. Enabling factors need to be systematically addressed both in the education and practice arenas before the perennial issue of disconnect between development and implementation of spirituality in practice can be bridged. PMID- 22442204 TI - Severe disturbance in the Ca2+ signaling in astrocytes from mouse models of human infantile neuroaxonal dystrophy with mutated Pla2g6. AB - Infantile neuroaxonal dystrophy (INAD; OMIM #no. 256600) is an inherited degenerative nervous system disorder characterized by nerve abnormalities in brain, spinal cord and peripheral nerves. About 85% of INAD patients carry mutations in the PLA2G6 gene that encodes for a Ca(2+)-independent phospholipase A(2) (VIA iPLA(2)), but how these mutations lead to disease is unknown. Besides regulating phospholipid homeostasis, VIA iPLA(2) is emerging with additional non canonical functions, such as modulating store-regulated Ca(2+) entry into cells, and mitochondrial functions. In turn, defective Ca(2+) regulation could contribute to the development of INAD. Here, we studied possible changes in ATP induced Ca(2+) signaling in astrocytes derived from two mutant strains of mice. The first strain carries a hypomorphic allele of the Pla2g6 that reduces transcript levels to 5-10% of that observed in wild-type mice. The second strain carries a point mutation in Pla2g6 that results in inactive VIA iPLA(2) protein with postulated gain in toxicity. Homozygous mice from both strains develop pathology analogous to that observed in INAD patients. The nucleotide ATP is the most important transmitter inducing Ca(2+) signals in astroglial networks. We demonstrate here a severe disturbance in Ca(2+) responses to ATP in astrocytes derived from both mutant mouse strains. The duration of the Ca(2+) responses in mutant astrocytes was significantly reduced when compared with values observed in control cells. We also show that the reduced Ca(2+) responses are probably due to a reduction in capacitative Ca(2+) entry (2.3-fold). Results suggest that altered Ca(2+) signaling could be a central mechanism in the development of INAD pathology. PMID- 22442206 TI - The effects of workplace physical activity interventions in men: a systematic review. AB - The workplace is cited as a promising setting for physical activity (PA) promotion, but workplace PA interventions tend not to specifically target men. The aim of this article was to review the literature on workplace PA interventions for men and to identify key issues for future intervention development. Articles targeting PA at the workplace were located through a structured database search. Information on intervention strategies and PA outcomes were extracted. Only 13 studies (10.5%) reviewed focused on men, of which 5 showed significant increases in PA. These studies used generic, multicomponent, health promotion strategies with a variety of timeframes, self report PA measures, and PA outcomes. The systematic review identified that evidence on the effectiveness of workplace PA interventions for men is equivocal and highlighted methodological concerns. Future research should use reliable and valid measures of PA and interventions that focus specifically on men's needs and PA preferences. PMID- 22442207 TI - Impact of partial urethral obstruction on bladder function: time-dependent changes and functional correlates of altered expression of Ca2+ signaling regulators. AB - In animal models of partial urethral obstruction (PUO), altered smooth muscle function/contractility may be linked to changes in molecules that regulate calcium signaling/sensitization. PUO was created in male rats, and urodynamic studies were conducted 2 and 6 wk post-PUO. Cystometric recordings were analyzed for the presence or absence of nonvoiding contractions [i.e., detrusor overactivity (DO)]. RT-PCR and Western blots were performed on a subpopulation of rats to study the relationship between the expression of RhoA, L-type Ca(2+) channels, Rho kinase-1, Rho kinase-2, inositol 1,4,5-trisphosphate, ryanodine receptor, sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 and protein kinase C (PKC) potentiated phosphatase inhibitor of 17 kDa, and urodynamic findings in the same animal. Animals displayed DO at 2 (38%) and 6 wk (43%) post-PUO, increases were seen in in vivo pressures at 2 wk, and residual volume at 6 wk. Statistical analysis of RT-PCR and Western blot data at 2 wk, during the compensatory phase of detrusor hypertrophy, documented that expression of molecules that regulate calcium signaling and sensitization was consistently lower in obstructed rats without DO than those with DO or control rats. Among rats with DO at 2 wk, linear regression analysis revealed positive correlations between in vivo pressures and protein and mRNA expression of several regulatory molecules. At 6 wk, in the presence of overt signs of bladder decompensation, no clear or consistent alterations in expression of these same targets were observed at the protein level. These data extend prior work to suggest that molecular profiling of key regulatory molecules during the progression of PUO-mediated bladder dysfunction may shed new light on potential biomarkers and/or therapeutic targets. PMID- 22442208 TI - Renal IL-17 expression in human ANCA-associated glomerulonephritis. AB - Interleukin-17A (IL-17) promotes inflammatory renal tissue damage in mouse models of crescentic glomerulonephritis, including murine experimental autoimmune anti myeloperoxidase glomerulonephritis, which most likely depends on IL-17-producing Th17 cells. In human anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, however, the cellular sources of IL-17 remain to be elucidated. Therefore, we analyzed human kidney biopsies of active necrotizing and crescentic ANCA-associated glomerulonephritis by immunohistochemistry using an IL-17-specific antibody and by immunofluorescent colocalization with cell type markers. We detected numerous IL-17-expressing (IL-17(+)) cells in the glomeruli and in the tubulointerstitium. Unexpectedly, most of these IL-17(+) cells were polymorphonuclear neutrophilic granulocytes, while IL-17(+) T cells and IL-17(+) mast cells were present at significantly lower frequencies. IL-17 was not detected in other infiltrating or resident kidney cells. In those patients who had not received immunosuppressive treatment before biopsy, serum creatinine levels were positively correlated with tubulointerstitial IL-17(+) neutrophils as well as IL-17(+) T cells. Furthermore, we could demonstrate that purified human blood neutrophils expressed IL-17 protein and released it upon stimulation in vitro. In conclusion, these results support a pathogenic role for IL-17 in human ANCA-associated glomerulonephritis. Our data suggest that in the acute stage of the disease neutrophils may act as an important immediate-early innate source of IL-17 and may thereby initiate and promote ongoing renal inflammation. IL-17 may thus be a target for treating acute ANCA-associated glomerulonephritis. PMID- 22442209 TI - Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity. AB - ANG II is a potent renal vasoconstrictor and profibrotic factor and its activity is enhanced by oxidative stress. We sought to determine whether renal oxidative stress was persistent following recovery from acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) injury in rats and whether this resulted in increased ANG II sensitivity. Rats were allowed to recover from bilateral renal I/R injury for 5 wk and renal blood flow responses were measured. Post-AKI rats showed significantly enhanced renal vasoconstrictor responses to ANG II relative to sham-operated controls and treatment of AKI rats with apocynin (15 mM, in the drinking water) normalized these responses. Recovery from AKI for 5 wk resulted in sustained oxidant stress as indicated by increased dihydroethidium incorporation in renal tissue slices and was normalized in apocynin-treated rats. Surprisingly, the renal mRNA expression for common NADPH oxidase subunits was not altered in kidneys following recovery from AKI; however, mRNA screening using PCR arrays suggested that post-AKI rats had decreased renal Gpx3 mRNA and an increased expression other prooxidant genes such as lactoperoxidase, myeloperoxidase, and dual oxidase-1. When rats were infused for 7 days with ANG II (100 ng.kg(-1).min(-1)), renal fibrosis was not apparent in sham-operated control rats, but it was enhanced in post-AKI rats. The profibrotic response was significantly attenuated in rats treated with apocynin. These data suggest that there is sustained renal oxidant stress following recovery from AKI that alters both renal hemodynamic and fibrotic responses to ANG II, and may contribute to the transition to chronic kidney disease following AKI. PMID- 22442210 TI - Protective role for CCR5 in murine lupus nephritis. AB - Leukocyte infiltration is a characteristic feature of human and experimental lupus nephritis and is closely correlated with loss of renal function. The chemokine receptor CCR5 is expressed on monocyte and T cell subsets and is thought to play an important role in recruiting these cells into inflamed organs. To investigate the functional role of CCR5 in lupus nephritis, CCR5-deficient mice were backcrossed onto the lupus-prone MRL-Fas(lpr) (MRL/lpr) genetic background. Unexpectedly, CCR5(-/-) MRL/lpr mice developed an aggravated course of lupus nephritis in terms of glomerular tissue injury and albuminuria. Deterioration of the nephritis was associated with an overall increase in mononuclear cell infiltration into the kidney, whereas renal leukocyte subtype balance, systemic T cell response, and autoantibody formation were unaffected by CCR5 deficiency. Renal and systemic protein levels of the CCR5 ligand CCL3, which can also attract leukocytes via its alternate receptor CCR1, were significantly increased in nephritic CCR5(-/-) MRL/lpr mice. Further studies revealed that the systemic increase in the CCR5/CCR1 ligand is also observed in nonimmune CCR5(-/-) C57BL/6 mice and that this increase was due to a reduced clearance, rather than an overproduction, of CCL3. Taken together, our data support the hypothesis that CCR5-dependent consumption of its own ligands may act as a negative feedback loop to restrain local chemokine levels within inflamed tissues, thereby limiting inflammatory cell influx. PMID- 22442211 TI - Nicotine and the kidney: Mr. Hyde, and perhaps some Dr. Jekyll. PMID- 22442212 TI - The sodium-activated sodium channel is expressed in the rat kidney thick ascending limb and collecting duct cells and is upregulated during high salt intake. AB - Increased dietary salt triggers oxidative stress and kidney injury in salt sensitive hypertension; however, the mechanism for sensing increased extracellular Na(+) concentration ([Na(+)]) remains unclear. A Na(+)-activated Na(+) channel (Na sensor) described in the brain operates as a sensor of extracellular fluid [Na(+)]; nonetheless, its presence in the kidney has not been established. In the present study, we demonstrated the gene expression of the Na sensor by RT-PCR and Western blotting in the Sprague-Dawley rat kidney. Using immunofluorescence, the Na sensor was localized to the luminal side in tubular epithelial cells of collecting ducts colocalizing with aquaporin-2, a marker of principal cells, and in thick ascending limb, colocalizing with the glycoprotein Tamm-Horsfall. To determine the effect of a high-salt diet (HSD) on Na sensor gene expression, we quantified its transcript and protein levels primarily in renal medullas from control rats and rats subjected to 8% NaCl for 7 days (n = 5). HSD increased Na sensor expression levels (mRNA: from 1.2 +/- 0.2 to 5.1 +/- 1.3 au; protein: from 0.98 +/- 0.15 to 1.74 +/- 0.28 au P < 0.05) in the kidney medulla, but not in the cortex. These data indicate that rat kidney epithelial cells of the thick ascending limb and principal cells of the collecting duct possess a Na sensor that is upregulated by HSD, suggesting an important role in monitoring changes in tubular fluid [Na(+)]. PMID- 22442213 TI - JNK-dependent AP-1 activation is required for aristolochic acid-induced TGF-beta1 synthesis in human renal proximal epithelial cells. AB - Chronic aristolochic acid nephropathy (CAAN) is a chronic and progressive tubulointerstitial nephropathy characterized by extensive interstitial fibrosis. Aristolochic acid (AA) could induce overexpression of transforming growth factor beta1 (TGF-beta1) in a human renal proximal tubule epithelial cells line (HKC), which has been implicated in the pathogenesis of CAAN. The present studies in HKC cells showed 1) AA could activate JNK in time- and dose-dependent manners and JNK inhibitor SP600125 could inhibit AA-induced TGF-beta1 promoter activity and TGF beta1 synthesis; 2) AA-induced JNK activation and TGF-beta1 synthesis were significantly inhibited by kinase-inactive mutants of MEKK4, MKK4, or MKK7; 3) AA could upregulate luciferase activity derived by a wild-type TGF-beta1 promoter, but not by an AP-1 binding-deficient TGF-beta1 promoter; and 4) AA could upregulate expression of c-Fos, phospho-c-Jun, and phospho-ATF2. The above data suggest AA-induced TGF-beta1 overexpression in HKC cells may be mainly mediated by the JNK signaling pathway. Both the upstream kinases of JNK including MEKK4, MKK4, and MKK7, and the downstream transcription factor of JNK, AP-1, may also participate in this process. PMID- 22442214 TI - Evidence that renal arginine transport is impaired in spontaneously hypertensive rats. AB - Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired l-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the l-arginine transport inhibitor l-lysine (10 MUmol.kg(-1).min(-1); 30 min) and subsequent superimposition of l-arginine (100 MUmol.kg(-1).min(-1); 30 min), the NO synthase inhibitor N(G)-nitro-l-arginine (2.4 mg/kg; iv bolus), and the NO donor sodium nitroprusside (0.24 MUg.kg(-1).min(-1)) were examined in Sprague Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 +/- 3 nM) compared with SD rats (108 +/- 12 nM; P = 0.004). l-Lysine tended to reduce medullary perfusion (-15 +/- 7%; P = 0.07) and reduced medullary NO concentration (-9 +/- 3%; P = 0.03) while subsequent superimposition of l-arginine reversed these effects of l-lysine in SD rats. In SHR, l-lysine and subsequent superimposition of l-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal l-arginine transport is impaired in SHR. Renal l [(3)H]arginine transport was less in SHR compared with SD rats (P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney. PMID- 22442215 TI - Call for a crystallization ontology. PMID- 22442216 TI - On the need for an international effort to capture, share and use crystallization screening data. AB - When crystallization screening is conducted many outcomes are observed but typically the only trial recorded in the literature is the condition that yielded the crystal(s) used for subsequent diffraction studies. The initial hit that was optimized and the results of all the other trials are lost. These missing results contain information that would be useful for an improved general understanding of crystallization. This paper provides a report of a crystallization data exchange (XDX) workshop organized by several international large-scale crystallization screening laboratories to discuss how this information may be captured and utilized. A group that administers a significant fraction of the world's crystallization screening results was convened, together with chemical and structural data informaticians and computational scientists who specialize in creating and analysing large disparate data sets. The development of a crystallization ontology for the crystallization community was proposed. This paper (by the attendees of the workshop) provides the thoughts and rationale leading to this conclusion. This is brought to the attention of the wider audience of crystallographers so that they are aware of these early efforts and can contribute to the process going forward. PMID- 22442217 TI - Structure of a bacterial cytoplasmic cyclophilin A in complex with a tetrapeptide. AB - Cyclophilins constitute a class of peptidyl-prolyl isomerases which participate in processes related to protein folding, signalling and chaperoning. The crystal structure of the cytoplasmic cyclophilin A (CyPA) from the bacterium Azotobacter vinelandii complexed with a synthetic tetrapeptide was determined by molecular replacement at 2 resolution. The proline in the tetrapeptide is observed to adopt the cis-isomer conformation. Comparisons of this structure with other CyPA structures provide insights into the conformational variability, effects of peptide binding and structure-function relationships of this enzyme. PMID- 22442218 TI - Structural analysis of 3-isopropylmalate dehydrogenase from the obligate piezophile Shewanella benthica DB21MT-2 and the nonpiezophile Shewanella oneidensis MR-1. AB - Organisms living in deep seas such as the Mariana Trench must be adapted to the extremely high pressure environment. For example, the 3-isopropylmalate dehydrogenase from the obligate piezophile Shewanella benthica DB21MT-2 (SbIPMDH) remains active in extreme conditions under which that from the land bacterium S. oneidensis MR-1 (SoIPMDH) becomes inactivated. In order to unravel the differences between these two IPMDHs, their structures were determined at ~1.5 A resolution. Comparison of the structures of the two enzymes shows that SbIPMDH is in a more open form and has a larger internal cavity volume than SoIPMDH at atmospheric pressure. This loosely packed structure of SbIPMDH could help it to avoid pressure-induced distortion of the native structure and to remain active at higher pressures than SoIPMDH. PMID- 22442219 TI - Structure of recombinant human carboxylesterase 1 isolated from whole cabbage looper larvae. AB - The use of whole insect larvae as a source of recombinant proteins offers a more cost-effective method of producing large quantities of human proteins than conventional cell-culture approaches. Human carboxylesterase 1 has been produced in and isolated from whole Trichoplusia ni larvae. The recombinant protein was crystallized and its structure was solved to 2.2 resolution. The results indicate that the larvae-produced enzyme is essentially identical to that isolated from cultured Sf21 cells, supporting the use of this expression system to produce recombinant enzymes for crystallization studies. PMID- 22442220 TI - Crystallization and X-ray structure analysis of a thermostable penicillin G acylase from Alcaligenes faecalis. AB - The enzyme penicillin G acylase (EC 3.5.1.11) catalyzes amide-bond cleavage in benzylpenicillin (penicillin G) to yield 6-aminopenicillanic acid, an intermediate chemical used in the production of semisynthetic penicillins. A thermostable penicillin G acylase from Alcaligenes faecalis (AfPGA) has been crystallized using the hanging-drop vapour-diffusion method in two different space groups: C222(1), with unit-cell parameters a = 72.9, b = 86.0, c = 260.2 , and P4(1)2(1)2, with unit-cell parameters a = b = 85.6, c = 298.8 . Data were collected at 293 and the structure was determined using the molecular-replacement method. Like other penicillin acylases, AfPGA belongs to the N-terminal nucleophilic hydrolase superfamily, has undergone post-translational processing and has a serine as the N-terminal residue of the beta-chain. A disulfide bridge has been identified in the structure that was not found in the other two known penicillin G cylase structures. The presence of the disulfide bridge is perceived to be one factor that confers higher stability to this enzyme. PMID- 22442221 TI - Purification, crystallization and preliminary X-ray analysis of PPD6, a PsbP domain protein from Arabidopsis thaliana. AB - The PsbP protein is an extrinsic component of photosystem II that together with PsbO and PsbQ forms the thylakoid lumenal part of the oxygen-evolving complex in higher plants. In addition to PsbP, the thylakoid lumen contains two PsbP-like proteins (PPLs) and six PsbP-domain proteins (PPDs). While the functions of the PsbP-like proteins PPL1 and PPL2 are currently under investigation, the function of the PsbP-domain proteins still remains completely unknown. PPD6 is unique among the PsbP family of proteins in that it contains a conserved disulfide bond which can be reduced in vitro by thioredoxin. The crystal structure determination of the PPD6 protein has been initiated in order to elucidate its function and to gain deeper insights into redox-regulation pathways in the thylakoid lumen. PPD6 has been expressed, purified and crystallized and preliminary X-ray diffraction data have been collected. The crystals belonged to space group P2(1), with unit cell parameters a = 47.0, b = 64.3, c = 62.0 A, beta = 94.2 degrees , and diffracted to a maximum d-spacing of 2.1 A. PMID- 22442222 TI - Crystallization and preliminary X-ray crystallographic analysis of a blue-light absorbing proteorhodopsin. AB - Proteorhodopsins (PRs), seven-transmembrane chromoproteins with retinal as a chromophore, are light-driven proton pumps. To elucidate the light-driven proton pumping mechanism of PRs, a pET28a vector containing the blue-light-absorbing proteorhodopsin (BPR) gene was constructed and the protein was overexpressed in Escherichia coli. The protein was purified by immobilized metal-ion affinity chromatography (IMAC). The purified BPR D97N mutant protein (BPR_D97N) was crystallized using the vapour-diffusion method. Preliminary X-ray diffraction data analysis showed that the crystal belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 161.6, b = 168.6, c = 64.7 A. A complete data set was collected to 3.3 A resolution using synchrotron radiation on beamline X06 of the Swiss Light Source (SLS). Molecular replacement was unsuccessful. To solve the structure of BPR_D97N by experimental phasing, selenomethionine-substituted protein crystals were prepared. These crystals diffracted to 3.0 A resolution and a complete data set was collected on beamline BL17U of the Shanghai Synchrotron Radiation Facility (SSRF). Heavy-atom substructure determination and phasing by SAD clearly showed that the crystal contained five molecules in the asymmetric unit, with a V(M) of 3.26 A(3) Da(-1) and a solvent content of 62.3%. PMID- 22442223 TI - Expression, purification, crystallization and preliminary crystallographic analysis of PilA from the nontypeable Haemophilus influenzae type IV pilus. AB - The type IV pili of nontypeable Haemophilus influenzae (NTHi) are involved in twitching motility, adherence, competence and biofilm formation. They are potential virulence factors for this important human pathogen and are thus considered to be vaccine targets. To characterize these pili, an attempt to solve the atomic structure of the major pilin subunit PilA was initiated. A 1.73 A resolution X-ray diffraction data set was collected from native N-terminally truncated PilA (DeltaN-PilA). Data processing indicated a hexagonal crystal system, which was determined to belong to space group P6(1) or P6(5) based on the systematic absences and near-perfect twinning of the crystal. The unit-cell parameters were a = b = 68.08, c = 197.03 A with four molecules in the asymmetric unit, giving a solvent content of 50%. Attempts to solve the DeltaN-PilA structure by molecular replacement with existing type IV pilin and type II secretion pseudopilin structures are in progress. PMID- 22442224 TI - Crystallization and preliminary X-ray crystallographic studies of succinic semialdehyde dehydrogenase from Streptococcus pyogenes. AB - Succinic semialdehyde dehydrogenase (SSADH) plays a critical role in the metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and catalyzes the NAD(P)(+)-coupled oxidation of succinic semialdehyde (SSA) to succinic acid (SA). SSADH from Streptococcus pyogenes has been purified and crystallized as the apoenzyme and in a complex with NAD(+). The crystals of native and NAD(+)-complexed SSADH diffracted to resolutions of 1.6 and 1.7 A, respectively, using a synchrotron-radiation source. Both crystals belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 93.3, b = 100.3, c = 105.1 A for the native crystal and a = 93.3, b = 100.3, c = 105.0 A for the complex crystal. Preliminary molecular replacement confirmed the presence of one dimer in both crystals, corresponding to a Matthews coefficient (V(M)) of 2.37 A(3) Da(-1) and a solvent content of 48.0%. PMID- 22442225 TI - Purification, crystallization and preliminary X-ray diffraction analysis of enoyl acyl carrier protein reductase (FabK) from Streptococcus mutans strain UA159. AB - A triclosan-resistant flavoprotein termed FabK is the sole enoyl-acyl carrier protein reductase in Streptococcus pneumoniae and Streptococcus mutans. In this study, FabK from S. mutans strain UA159 was overexpressed in Escherichia coli, purified and crystallized. Diffraction data were collected to 2.40 A resolution using a synchrotron-radiation source. The crystal belonged to space group P6(2), with unit-cell parameters a = b = 105.79, c = 44.15 A. The asymmetric unit contained one molecule, with a corresponding V(M) of 2.05 A(3) Da(-1) and a solvent content of 39.9%. PMID- 22442226 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of mammalian translation elongation factor eEF1A2. AB - Translation elongation factor eEF1A2 was purified to homogeneity from rabbit muscle by two consecutive ion-exchange column-chromatography steps and this mammalian eEF1A2 was successfully crystallized for the first time. Protein crystals obtained using ammonium sulfate as precipitant diffracted to 2.5 A resolution and belonged to space group P6(1)22 or P6(3)22 (unit-cell parameters a = b = 135.4, c = 304.6 A). A complete native data set was collected to 2.7 A resolution. PMID- 22442227 TI - Crystallization and preliminary X-ray crystallographic studies of casein kinase I like protein from rice. AB - Casein kinase I (CKI) is a serine/threonine protein kinase that performs various functions in the cell, such as DNA repair, cell-cycle regulation, cytokinesis, vesicular trafficking, morphogenesis and circadian-rhythm regulation. CKI proteins contain a highly conserved catalytic domain at the N-terminus and a highly diverse regulatory domain that is responsible for substrate specificity at the C-terminus. In this study, CKI from rice (riceCKI) was overexpressed in Escherichia coli with an engineered C-terminal His tag. RiceCKI was then purified to homogeneity and crystallized at 293 K. X-ray diffraction data were collected to a resolution of 2.0 A from a crystal belonging to the monoclinic space group C2, with unit-cell parameters a = 108.83, b = 69.60, c = 55.85 A, beta = 109.47 degrees . The asymmetric unit was estimated to contain one monomer. PMID- 22442228 TI - Crystallization and preliminary X-ray diffraction characterization of the XccFimX(EAL)-c-di-GMP and XccFimX(EAL)-c-di-GMP-XccPilZ complexes from Xanthomonas campestris. AB - c-di-GMP is a major secondary-messenger molecule in regulation of bacterial pathogenesis. Therefore, the c-di-GMP-mediated signal transduction network is of considerable interest. The PilZ domain was the first c-di-GMP receptor to be predicted and identified. However, every PilZ domain binds c-di-GMP with a different binding affinity. Intriguingly, a noncanonical PilZ domain has recently been found to serve as a mediator to link FimX(EAL) to the PilB or PilT ATPase to control the function of type IV pili (T4P). It is thus essential to determine the structure of the FimX(EAL)-PilZ complex in order to determine how the binding of c-di-GMP to the FimX(EAL) domain induces conformational change of the adjoining noncanonical PilZ domain, which may transmit information to PilB or PilT to control T4P function. Here, the preparation and preliminary X-ray diffraction studies of the XccFimX(EAL)-c-di-GMP and XccFimX(EAL)-c-di-GMP-XccPilZ complexes from Xcc (Xanthomonas campestris pv. campesteris) are reported. Detailed studies of these complexes may allow a more thorough understanding of how c-di-GMP transmits its effects through the degenerate EAL domain and the noncanonical PilZ domain. PMID- 22442229 TI - Crystallization and preliminary X-ray diffraction analysis of endoglucanase III from Trichoderma harzianum. AB - Endoglucanases are enzymes that hydrolyze cellulose and are important components of the cellulolytic complex. In contrast to other members of the complex, they cleave internal beta-1,4-glycosidic bonds in the cellulose polymer, allowing cellulose to be used as an energy source. Since biomass is an important renewable source of energy, the structural and functional characterization of these enzymes is of interest. In this study, endoglucanase III from Trichoderma harzianum was produced in Pichia pastoris and purified. Crystals belonging to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 47.54, b = 55.57, c = 157.3 A, were obtained by the sitting-drop vapour-diffusion method and an X-ray diffraction data set was collected to 2.07 A resolution. PMID- 22442230 TI - Crystallization and preliminary X-ray analysis of FlgA, a periplasmic protein essential for flagellar P-ring assembly. AB - Salmonella FlgA, a periplasmic protein essential for flagellar P-ring assembly, has been crystallized in two forms. The native protein crystallized in space group C222, with unit-cell parameters a = 107.5, b = 131.8, c = 49.4 A, and diffracted to about 2.0 A resolution (crystal form I). In this crystal, the asymmetric unit is likely to contain one molecule, with a solvent content of 66.8%. Selenomethionine-labelled FlgA protein crystallized in space group C222(1), with unit-cell parameters a = 53.2, b = 162.5, c = 103.5 A, and diffracted to 2.7 A resolution (crystal form II). In crystal form II, the asymmetric unit contained two molecules with a solvent content of 48.0%. The multiple-wavelength and single-wavelength anomalous dispersion methods allowed the visualization of the electron-density distributions of the form I and II crystals, respectively. The two maps suggested that FlgA is in two different conformations in the two crystals. PMID- 22442231 TI - Recombinant expression and purification of the tomato defensin TPP3 and its preliminary X-ray crystallographic analysis. AB - Class II defensins have been shown to have potent antifungal activity and are being exploited to protect agricultural crops against fungal pathogens. TPP3 is a poorly characterized member of the class II plant defensin family from tomato. To gain structural insight into the function of TPP3, soluble recombinant TPP3 was expressed and purified using the Pichia pastoris expression system, and the crystallization and preliminary X-ray crystallographic analysis of the protein are reported. Crystals of rTPP3 were obtained using the sitting-drop vapour diffusion method at 293 K. Diffraction data were collected to 1.7 A resolution. The crystals belonged to the hexagonal space group P6(1)22, with unit-cell parameters a = 64.97, b = 64.97, c = 82.40 A, alpha = 90, beta = 90, gamma = 120 degrees . PMID- 22442232 TI - Crystallization and preliminary X-ray analysis of alginate importer from Sphingomonas sp. A1. AB - Sphingomonas sp. A1 directly incorporates alginate polysaccharides through a 'superchannel' comprising a pit on the cell surface, alginate-binding proteins in the periplasm and an ABC transporter (alginate importer) in the inner membrane. Alginate importer, consisting of four subunits, AlgM1, AlgM2 and two molecules of AlgS, was crystallized in the presence of the binding protein AlgQ2. Preliminary X-ray analysis showed that the crystal diffracted to 3.3 A resolution and belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 72.5, b = 136.8, c = 273.3 A, suggesting the presence of one complex in the asymmetric unit. PMID- 22442233 TI - Crystallization and preliminary X-ray diffraction of the surfactant protein Lv ranaspumin from the frog Leptodactylus vastus. AB - Lv-ranaspumin is a natural surfactant protein with a molecular mass of 23.5 kDa which was isolated from the foam nest of the frog Leptodactylus vastus. Only a partial amino-acid sequence is available for this protein and it shows it to be distinct from any protein sequence reported to date. The protein was purified from the natural source by ion-exchange and size-exclusion chromatography and was crystallized by sitting-drop vapour diffusion using the PEG/Ion screen at 293 K. A complete data set was collected to 3.5 A resolution. The crystal belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 51.96, b = 89.99, c = 106.00 A. Assuming the presence of two molecules in the asymmetric unit, the solvent content was estimated to be 54%. PMID- 22442234 TI - Crystallization and preliminary X-ray studies of an electron-transfer complex of ferredoxin and ferredoxin-dependent glutamate synthase from the cyanobacterium Leptolyngbya boryana. AB - Ferredoxin (Fd) dependent glutamate synthase (Fd-GOGAT) is a key enzyme involved in nitrogen assimilation that catalyzes the two-electron reductive conversion of Gln and 2-oxoglutarate to two molecules of Glu. Fd serves as an electron donor for Fd-GOGAT and the two proteins form a transient electron-transfer complex. In this study, these two proteins were cocrystallized using the hanging-drop vapour diffusion method. Diffraction data were collected and processed at 2.65 A resolution. The crystals belonged to space group P4(3), with unit-cell parameters a = b = 84.95, c = 476.31 A. PMID- 22442235 TI - Crystallization and preliminary X-ray analysis of a hyperthermophilic endoglucanase from Pyrococcus furiosus. AB - The hyperthermophilic glycoside hydrolase family 12 endocellulase from the archaeon Pyrococcus furiosus (EGPf) catalyzes the hydrolytic cleavage of the beta 1,4-glucosidic linkage in beta-glucans in biomass. EGPf (Gene ID PF0854; EC 3.2.1.4) contains a signal sequence and proline- and hydroxyl-rich regions at the N-terminus. Truncated EGPf (EGPfDeltaN30) without the proline- and hydroxyl-rich regions at the N-terminus was prepared and subjected to crystallization experiments. Crystals were obtained using the hanging-drop vapour-diffusion method at 303 K. An X-ray diffraction data set was collected to 1.07 A resolution at 100 K. The crystal belonged to space group P2(1)2(1)2, with unit-cell parameters a = 58.01, b = 118.67, c = 46.76 A. The presence of one molecule of enzyme per asymmetric unit gives a crystal volume per protein mass (V(M)) of 2.63 A(3) Da(-1) and a solvent content of 53.3%(v/v). PMID- 22442236 TI - Expression, purification, crystallization and preliminary X-ray diffraction analysis of a galactose 1-phosphate uridylyltransferase from the hyperthermophilic archaeon Pyrobaculum aerophilum. AB - A galactose 1-phosphate uridylyltransferase from the hyperthermophilic archaeon Pyrobaculum aerophilum was crystallized using the sitting-drop vapour-diffusion method with polyethylene glycol 8000 as the precipitant. The crystals belonged to the tetragonal space group P4(1), with unit-cell parameters a = b = 73.3, c = 126.1 A, and diffracted to 2.73 A resolution on beamline BL5A at the Photon Factory. The overall R(merge) was 7.3% and the data completeness was 99.8%. PMID- 22442237 TI - Crystallization and preliminary X-ray crystallographic analysis of the catalytic domain of human dihydrouridine synthase. AB - Dihydrouridine synthases catalyse the reduction of uridine to dihydrouridine in the D-loop and variable loop of tRNA. The human dihydrouridine synthase HsDus2L has been implicated in the development of pulmonary carcinogenesis. Here, the purification, crystallization and preliminary X-ray characterization of the HsDus2L catalytic domain are reported. The crystals belonged to space group P2(1) and contained a single molecule of HsDus2L in the asymmetric unit. A complete data set was collected to 1.9 A resolution using synchrotron radiation. PMID- 22442238 TI - Crystallization and preliminary X-ray crystallographic characterization of a cyclic nucleotide-binding homology domain from the mouse EAG potassium channel. AB - The members of the family of voltage-gated KCNH potassium channels play important roles in cardiac and neuronal repolarization, tumour proliferation and hormone secretion. These channels have a C-terminal cytoplasmic domain which is homologous to cyclic nucleotide-binding domains (CNB-homology domains), but it has been demonstrated that channel function is not affected by cyclic nucleotides and that the domain does not bind nucleotides in vitro. Here, the crystallization and preliminary crystallographic analysis of a CNB-homology domain from a member of the KCNH family, the mouse EAG channel, is reported. X-ray diffraction data were collected to 2.2 A resolution and the crystal belonged to the hexagonal space group P3(1)21. PMID- 22442239 TI - Crystallization and preliminary crystallographic analysis of Arabidopsis thaliana BRI1-associated kinase 1 (BAK1) cytoplasmic domain. AB - BRI1-associated kinase 1 (BAK1) is a member of the plant receptor-like kinase (RLK) superfamily. BAK1 has been shown to initiate brassinosteroid (BR) signalling and innate immune responses in plants by forming receptor complexes with both brassinosteroid-insensitive 1 (BRI1) and flagellin-sensing 2 (FLS2). To gain a better understanding of the structural details and the mechanism of action of the BAK1 kinase domain, recombinant BAK1 cytoplasmic domain has been expressed, purified and crystallized at 291 K using PEG 3350 as a precipitant. A 2.6 A resolution data set was collected from a single flash-cooled crystal at 100 K. This crystal belonged to space group C2, with unit-cell parameters a = 70.3, b = 75.6, c = 71.9 A, beta = 93.1 degrees . Assuming the presence of one molecule in the asymmetric unit, the Matthews coefficient was 2.6 A(3) Da(-1). PMID- 22442240 TI - Crystallization and preliminary X-ray analysis of the subclass B3 metallo-beta lactamase SMB-1 that confers carbapenem resistance. AB - The carbapenem-hydrolyzing subclass B3 metallo-beta-lactamase SMB-1 was expressed in Escherichia coli and purified. Diffraction data were collected from two types of SMB-1 crystals that were obtained under different conditions. One crystal (SMB 1a) belonged to the trigonal space group P3(1) with unit-cell parameters a = b = 67.83, c = 48.67 A, while the other crystal (SMB-1b) also belonged to space group P3(1) but with unit-cell parameters a = b = 67.25, c = 46.83 A. Both crystals contained one molecule per asymmetric unit. Initial phases were determined by molecular replacement; further refinement and model building are in progress. PMID- 22442241 TI - Cloning, purification, crystallization and preliminary X-ray analysis of the Burkholderia pseudomallei L1 ribosomal protein. AB - The gene encoding the L1 ribosomal protein from Burkholderia pseudomallei strain D286 has been cloned into the pETBLUE-1 vector system, overexpressed in Escherichia coli and purified. Crystals of the native protein were grown by the hanging-drop vapour-diffusion technique using PEG 3350 as a precipitant and diffracted to beyond 1.65 A resolution. The crystals belonged to space group P2(1)2(1)2, with unit-cell parameters a = 53.6, b = 127.1, c = 31.8 A and with a single molecule in the asymmetric unit. PMID- 22442242 TI - Overproduction, purification and crystallization of PfTic22, a component of the import apparatus from the apicoplast of Plasmodium falciparum. AB - Tic22 is a component of the protein-import apparatus of the chloroplasts of plants and algae and the apicoplasts of the Apicomplexa, a large group of organisms that includes the parasites that cause malaria. Tic22 is important for protein import into these organelles and for organelle biogenesis. It lies between the two membranes of chloroplasts, making interactions with components of both the TIC and TOC complexes. In the apicoplast, it is predicted to be located between the inner two membranes and to play a similar role in import. Although Tic22 is ubiquitous, its function is as yet uncertain. Tic22 from Plasmodium falciparum was therefore overproduced, purified and crystallized. A data set extending to 2.15 A resolution has been collected from a crystal containing selenomethionine-labelled protein and structure determination is under way. PMID- 22442243 TI - Expression, purification and crystallization of an indole prenyltransferase from Aspergillus fumigatus. AB - CdpNPT from Aspergillus fumigatus is a dimethylallyltryptophan synthase/indole prenyltransferase that catalyzes reverse prenylation at position N1 of tryptophan containing cyclic dipeptides. Residues 38-440 of CdpNPT were expressed in Escherichia coli and crystallized using the sitting-drop vapour-diffusion and microseeding techniques. The crystals belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 84.4, b = 157.1, c = 161.8 A, alpha = beta = gamma = 90.0 degrees . PMID- 22442244 TI - Purification, crystallization and preliminary X-ray diffraction analysis of the Fyn SH2 domain and its complex with a phosphotyrosine peptide. AB - SH2 domains are widespread protein-binding modules that recognize phosphotyrosines and play central roles in intracellular signalling pathways. The SH2 domain of the human protein tyrosine kinase Fyn has been expressed, purified and crystallized in the unbound state and in complex with a high-affinity phosphotyrosine peptide. X-ray data were collected to a resolution of 2.00 A for the unbound form and 1.40 A for the protein in complex with the phosphotyrosine peptide. PMID- 22442245 TI - Maternal HIV infection associated with small-for-gestational age infants but not preterm births: evidence from rural South Africa. AB - BACKGROUND: Human immunodeficiency virus (HIV) is prevalent in many countries where small-for-gestational age (SGA) and premature delivery are also common. However, the associations between maternal HIV, preterm delivery and SGA infants remain unclear. We estimate the prevalence of SGA and preterm (<37 weeks) births, their associations with antenatal maternal HIV infection and their contribution to infant mortality, in a high HIV prevalent, rural area in South Africa. METHODS: Data were collected, in a non-randomized intervention cohort study, on all women attending antenatal clinics (2001-2004), before the availability of antiretroviral treatment. Newborns were weighed and gestational age was determined (based on last menstrual period plus midwife assessment antenatally). Poisson regression with robust variance assessed risk factors for preterm and SGA birth, while Cox regression assessed infant mortality and associated factors. RESULTS: Of 2368 live born singletons, 16.6% were SGA and 21.4% were preterm. HIV infected women (n= 1189) more commonly had SGA infants than uninfected women (18.1 versus 15.1%; P = 0.051), but percentages preterm were similar (21.8 versus 20.9%; P = 0.621). After adjustment for water source, delivery place, parity and maternal height, the SGA risk in HIV-infected women was higher [adjusted relative risk (aRR) 1.28, 95% confidence interval (CI): 1.06-1.53], but the association between maternal HIV infection and preterm delivery remained weak and not significant (aRR: 1.07, 95% CI: 0.91-1.26). In multivariable analyses, mortality under 1 year of age was significantly higher in SGA and severely SGA than in appropriate-for-gestational-age infants [adjusted hazard ratio (aHR): 2.12, 95% CI: 1.18-3.81 and 2.77, 95% CI: 1.56-4.91], but no difference in infant mortality was observed between the preterm and term infants (aHR: 1.18 95% CI: 0.79-1.79 for 34-36 weeks and 1.31, 95% CI: 0.58-2.94 for <34 weeks). CONCLUSIONS: Maternal HIV infection increases the risk of SGA, but not preterm births, in this cohort. PMID- 22442246 TI - Induction of endometriosis alters the peripheral and endometrial regulatory T cell population in the non-human primate. AB - BACKGROUND: Endometriosis is a gynecological condition that is characterized by extreme abdominal pain and also decreased fertility. Regulatory T cells (Tregs) have immunosuppressive activity critical for embryonic implantation and likewise the acceptance of tissue engraftment. Utilizing the induced non-human primate (Papio anubis) model of endometriosis, we hypothesize that endometriosis decreases the peripheral and endomet rial Treg profile, whereas ectopic lesions have increased Treg localization. METHODS: Peripheral blood and endometrium were obtained throughout the menstrual cycle prior to and after induction of disease. Animals were randomly assigned to control (n = 7) or diseased (n = 16) treatment groups. Endometriosis was induced by i.p. injection of autologous menstrual tissue for 2 consecutive months during menses. Peripheral blood and endometrial tissue were collected at d9-11PO at 1, 3, 6, 9, 12 and 15 months post-induction of disease for fluorescence-activated cell sorting, quantitative RT-PCR and immunohistochemistry. Ectopic lesions were excised at 1 and 6 months post inoculation and also harvested at necropsy (15 months) and processed for RNA of IHC. Identification of Tregs through analysis of FOXP3 expression was conducted utlilizing several methodologies. Differences were determined by non-parametric statistical analysis between all treatment groups and time points. RESULTS: In control animals, the proportion of peripheral natural Tregs (nTregs) was reduced (P < 0.05) during the mid- and late secretory stages of the menstrual cycle compared with menses. The induction of disease decreased peripheral Treg expression at early time points (P < 0.05) and this remained low throughout the time course, compared with the pre-inoculatory level of an individual. FOXP3 gene expression and Treg populations were also decreased in the eutopic endometrium (P < 0.05) compared with control animals, whereas these parameters were increased in ectopic lesions (P < 0.05), compared with the eutopic endometrium. CONCLUSIONS: Our data suggest that a reduction in peripheral Tregs may be a causative factor for endometriosis-associated infertility, while the increase in ectopic Treg expression may aid lesion development. Furthermore, endometriosis appears to disrupt Treg recruitment in both eutopic and ectopic endometrium. PMID- 22442247 TI - The influence of patient and cohort parameters on the incidence and developmental potential of embryos with poor quality traits for use in human embryonic stem cell derivation. AB - BACKGROUND: Human embryonic stem cells (hESCs) are most commonly derived from the inner cell mass (ICM) of blastocyst stage embryos. While the majority of hESC lines originate from good-quality embryos donated after cryogenic storage, poor quality embryos (PQEs) not suitable for clinical use have also been shown to generate hESC. This provides a newfound function for embryos that would otherwise be discarded following IVF or ICSI. Owing to their lack of clinical importance, however, data on the poorest embryos in a cohort go largely unreported in the literature. It is therefore of interest to better understand the availability of PQEs from IVF/ICSI cycles and to determine their ability to develop into blastocysts with good-quality ICMs for use in hESC derivation. In this study, we investigate the influence of patient parameters and embryo cohort on PQE incidence, blastocyst development, ICM quality and successful hESC derivation from donated PQEs. METHODS: PQEs from 736 patient cycles that did not meet our clinical criteria for transfer or cryopreservation were cultured until Day 6 of development and assessed for blastocyst formation and ICM quality. A subset of blastocysts with good-quality ICMs were then used for hESC derivation attempts. Anonymous patient data such as maternal age, embryo history and cohort parameters were then retrospectively compiled and analysed. RESULTS: PQEs made up 46.8% of two pronucleate embryos created from IVF/ICSI. Including embryos with abnormal fertilization, a mean of 3.6 +/- 2.8 embryos were donated per cycle with 32.6% developing to the blastocyst stage. Good-quality ICM were produced in 13.9% of PQEs cultured. Of good-quality ICM, 15.4% of those used in hESC derivation attempts resulted in a novel line. The PQEs that originated from older patients (>37 year) or from cycles that did not result in pregnancy had significantly diminished blastocyst development and ICM quality. Maternal age was also shown to further influence the ability of good-quality ICMs to generate hESC. CONCLUSIONS: PQEs are an abundant source of embryos capable of developing to blastocysts with good-quality ICMs and subsequently generating novel hESC. We have shown that prognostic variables used to predict IVF/ICSI outcome can also help predict which PQEs have the best hESC developmental potential. Owing to the diversity of PQE origin, experiments designed to compare hESC derivation techniques or efficiency using PQEs should consider clinical IVF/ICSI parameters to establish groups with equal developmental competence. Additional investigation is needed to determine if these results are applicable to hESC derivation using good-quality embryos. PMID- 22442248 TI - Consistent and predictable delivery rates after oocyte vitrification: an observational longitudinal cohort multicentric study. AB - BACKGROUND: An efficient method for cryopreservation of human oocytes may offer solutions to legal and ethical problems in routine infertility programs and may also be used for fertility preservation for medical and social reasons. METHODS: We conducted an observational longitudinal cohort multicentric study to investigate the efficacy and reproducibility of oocyte cryopreservation outcomes in IVF/ICSI cycles. Moreover, the effects of patient and cycle characteristics on the delivery rate (DR) were analyzed. RESULTS: In 486 cycles performed in 450 couples, 2721 oocytes were warmed and 2304 of them survived cryopreservation (84.7%). Of the 2182 oocytes subjected to ICSI, the rates of fertilization and development to top-quality embryos were 75.2 and 48.1%, respectively. A total of 128 deliveries were obtained (26.3% per cycle and 29.4% per transfer) for 450 patients (28.4%) and 147 babies were live born from 929 embryos transferred (15.8%). The forward logistic regression analysis on a per patient basis showed that female age [odds ratio (OR): 0.93, 95% confidence interval (CI): 0.88-0.98], number of vitrified oocytes (OR: 1.08, 95% CI: 1.01-1.17) and the day of transfer (OR: 1.97, 95% CI: 1.14-3.42) influenced DR. By recursive partitioning analysis, it can be estimated that more than eight oocytes vitrified are required to improve the outcome (22.6 versus 46.4% DR, respectively). When fewer oocytes are available in women aged >38 years, results are dramatically reduced (12.6 versus 27.5% DR, respectively). Conversely, when >8 oocytes are available, blastocyst culture represents the most efficient policy (62.1% DR; data from one center only). CONCLUSIONS: Oocyte vitrification is an efficient and reliable approach, with consistent results between centers and predictable DRs. It should be applied routinely for various indications. A predictive model is proposed to help patient counselling and selection. PMID- 22442249 TI - Misleading and reliable markers to differentiate between primate testis-derived multipotent stromal cells and spermatogonia in culture. AB - BACKGROUND: Several studies have reported the generation of spermatogonia-derived pluripotent stem cells from human testes. The initial aim of the present study was the derivation of equivalent stem cells from an established and experimentally accessible non-human primate model, the common marmoset monkey (Callithrix jacchus). However, an essential prerequisite in the absence of transgenic reporters in primates and man is the availability of validated endogenous markers for the identification of specific cell types in vitro. METHODS AND RESULTS: We cultured marmoset testicular cells in a similar way to that described for human testis-derived pluripotent cells and set out to characterize these cultures under different conditions and in differentiation assays applying established marker panels. Importantly, the cells emerged as testicular multipotent stromal cells (TMSCs) instead of (pluripotent) germ cell derived cells. TMSCs expressed many markers such as GFR-alpha, GPR125, THY-1 (CD90), ITGA6, SSEA4 and TRA-1-81, which were considered as spermatogonia specific and were previously used for the enrichment or characterization of spermatogonia. Proliferation of TMSCs was highly dependent on basic fibroblast growth factor, a growth factor routinely present in germ cell culture media. As reliable markers for the distinction between spermatogonia and TMSCs, we established VASA, in combination with the spermatogonia-expressed factors, MAGEA4, PLZF and SALL4. CONCLUSIONS: Marmoset monkey TMSCs and spermatogonia exhibit an overlap of markers, which may cause erroneous interpretations of experiments with testis-derived stem cells in vitro. We provide a marker panel for the unequivocal identification of spermatogonia providing a better basis for future studies on primate, including human, testis-derived stem cells. PMID- 22442250 TI - Thermal artifact after three techniques of loop excision of the transformation zone: a comparative study. AB - AIMS: To compare a surgical-margin thermal artifact in 3 techniques of loop excision of the transformation zone (LETZ). METHODS: The histopathologic specimens from 140 patients who underwent 3 techniques of LETZ with different electrosurgical units (large loop used with a Valleylab, large loop used with an Ellman Surgitron, and contoured loop with a Utah Finesse) performed in Rajavithi Hospital between January 2003 and June 2007 were reevaluated by one pathologist with regard to degree and width of diathermy artifact. RESULTS: All of the specimens exhibited thermal tissue artifacts but there were varying degrees of extent and severity. Overall, the mean thermal artifact zone was 0.85 +/- 0.94, 0.57 +/- 0.47, and 0.49 +/- 0.51 mm for the endocervical margin, ectocervical margin, and stromal margin, respectively. However, the thermal artifact did not interfere with the histological diagnosis or the assessment of the margins in all cases. There were no statistical differences in the thermal artifact measurements in the 3 groups. The 3 LETZ techniques provided comparable thermal artifacts in terms of qualitative and quantitative measurement. CONCLUSIONS: The thermal artifacts, both in severity and extent, are not significantly different in the 3 LETZ techniques. For routine LETZ in clinical practice, those techniques can be used with a comparable outcome. PMID- 22442251 TI - Test differences in diagnosing reading comprehension deficits. AB - The authors examined the implications of test differences for defining and diagnosing comprehension deficits using reading comprehension tests. They had 995 children complete the Gray Oral Reading Test-3, the Qualitative Reading Inventory 3, the Woodcock-Johnson Passage Comprehension-3, and the Peabody Individual Achievement Test and compared which children were identified by each test as being in the lowest 10%. Although a child who performs so poorly might be expected to do poorly on all tests, the authors found that the average overlap between tests in diagnosing comprehension difficulties was only 43%. Consistency in diagnosis was greater for younger children, when comprehension deficits are the result of weaker decoding skills, than for older children. Inconsistencies between tests were just as evident when identifying the top performers. The different children identified as having a comprehension deficit by each test were compared on four profile variables-word decoding skill, IQ, ADHD symptoms, and working memory skill-to understand the nature of the different deficits assessed by each test. Theoretical and practical implications of these test differences in defining and diagnosing comprehension deficits are discussed. PMID- 22442252 TI - Socioemotional self-perceptions, family climate, and hopeful thinking among students with learning disabilities and typically achieving students from the same classes. AB - This study aimed at examining the adjustment of students with learning disabilities (LD) and at exploring the mediating role of hope. By means of a multidimensional approach, the interactions between risk and protective factors emerging from internal and external resources among 856 high school students (10th to 12th grades) were analyzed. A total of 529 typically achieving students and 327 students with LD attending general education classes in seven high schools completed seven instruments measuring sense of coherence, basic psychological needs, loneliness, family climate, hope, academic self-efficacy, and effort. The students' achievements in English, history, and mathematics were collected. The analysis used structural equation modeling, and the results emphasized the significant role of hope as a mediator between risk and protective factors and academic self-efficacy and its significance for students with and without LD in explaining achievements and effort investment. PMID- 22442253 TI - Policy and practice considerations for response to intervention: reflections and commentary. PMID- 22442254 TI - Academic procrastination, emotional intelligence, academic self-efficacy, and GPA: a comparison between students with and without learning disabilities. AB - Academic procrastination has been seen as an impediment to students' academic success. Research findings suggest that it is related to lower levels of self regulated learning and academic self-efficacy and associated with higher levels of anxiety, stress, and illness. Emotional intelligence (EI) is the ability to assess, regulate, and utilize emotions and has been found to be associated with academic self-efficacy and a variety of better outcomes, including academic performance. Students with learning disabilities (LD) are well acquainted with academic difficulty and maladaptive academic behavior. In comparison to students without LD, they exhibit high levels of learned helplessness, including diminished persistence, lower academic expectations, and negative affect. This study examined the relationships among academic procrastination, EI, and academic performance as mediated by academic self-efficacy in 287 LD and non-LD students. Results indicated that the indirect effect of EI on academic procrastination and GPA was stronger in LD students than in non-LD students. In addition, results indicated that LD students scored lower than non-LD students on both EI and academic self-efficacy and higher on academic procrastination. No difference was found in GPA. PMID- 22442255 TI - Super-SILAC allows classification of diffuse large B-cell lymphoma subtypes by their protein expression profiles. AB - Correct classification of cancer patients into subtypes is a prerequisite for acute diagnosis and effective treatment. Currently this classification relies mainly on histological assessment, but gene expression analysis by microarrays has shown great promise. Here we show that high accuracy, quantitative proteomics can robustly segregate cancer subtypes directly at the level of expressed proteins. We investigated two histologically indistinguishable subtypes of diffuse large B-cell lymphoma (DLBCL): activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes, by first developing a general lymphoma stable isotope labeling with amino acids in cell culture (SILAC) mix from heavy stable isotope-labeled cell lines. This super-SILAC mix was combined with cell lysates from five ABC-DLBCL and five GCB-DLBCL cell lines. Shotgun proteomic analysis on a linear ion trap Orbitrap mass spectrometer with high mass accuracy at the MS and MS/MS levels yielded a proteome of more than 7,500 identified proteins. High accuracy of quantification allowed robust separation of subtypes by principal component analysis. The main contributors to the classification included proteins known to be differentially expressed between the subtypes such as the transcription factors IRF4 and SPI1/PU.1, cell surface markers CD44 and CD27, as well as novel candidates. We extracted a signature of 55 proteins that segregated subtypes and contained proteins connected to functional differences between the ABC and GCB-DLBCL subtypes, including many NF-kappaB-regulated genes. Shortening the analysis time to single-shot analysis combined with use of the new linear quadrupole Orbitrap analyzer (Q Exactive) also clearly differentiated between the subtypes. These results show that high resolution shotgun proteomics combined with super-SILAC-based quantification is a promising new technology for tumor characterization and classification. PMID- 22442256 TI - Quantitative assessment of chromatin immunoprecipitation grade antibodies directed against histone modifications reveals patterns of co-occurring marks on histone protein molecules. AB - The defining step in most chromatin immunoprecipitation (ChIP) assays is the use of an antibody to enrich for a particular protein or histone modification state associated with segments of chromatin. The specificity of the antibody is critical to the interpretation of the experiment, yet this property is rarely reported. Here, we present a quantitative method using mass spectrometry to characterize the specificity of key histone H3 modification-targeting antibodies that have previously been used to characterize the "histone code." We further extend the use of these antibody reagents to the observation of long range correlations among disparate histone modifications. Using purified human histones representing the mixture of chromatin states present in living cells, we were able to quantify the degree of target enrichment and the specificity of several commonly used, commercially available ChIP grade antibodies. We found significant differences in enrichment efficiency among various reagents directed against four frequently studied chromatin marks: H3K4me2, H3K4me3, H3K9me3, and H3K27me3. For some antibodies, we also detected significant off target enrichment of alternate modifications at the same site (i.e., enrichment of H3K4me2 by an antibody directed against H3K4me3). Through cluster analysis, we were able to recognize patterns of co-enrichment of marks at different sites on the same histone protein. Surprisingly, these co-enrichments corresponded well to "canonical" chromatin states that are exemplary of activated and repressed regions of chromatin. Altogether, our findings suggest that 1) the results of ChIP experiments need to be evaluated with caution given the potential for cross reactivity of the commonly used histone modification recognizing antibodies, 2) multiple marks with consistent biological interpretation exist on the same histone protein molecule, and 3) some components of the histone code may be transduced on single proteins in living cells. PMID- 22442257 TI - Interleukin enhancer-binding factor 3/NF110 is a target of YM155, a suppressant of survivin. AB - Survivin is responsible for cancer progression and drug resistance in many types of cancer. YM155 selectively suppresses the expression of survivin and induces apoptosis in cancer cells in vitro and in vivo. However, the mechanism underlying these effects of YM155 is unknown. Here, we show that a transcription factor, interleukin enhancer-binding factor 3 (ILF3)/NF110, is a direct binding target of YM155. The enhanced survivin promoter activity by overexpression of ILF3/NF110 was attenuated by YM155 in a concentration-dependent manner, suggesting that ILF3/NF110 is the physiological target through which YM155 mediates survivin suppression. The results also show that the unique C-terminal region of ILF3/NF110 is important for promoting survivin expression and for high affinity binding to YM155. PMID- 22442258 TI - Intercellular variation in signaling through the TGF-beta pathway and its relation to cell density and cell cycle phase. AB - Fundamental open questions in signal transduction remain concerning the sequence and distribution of molecular signaling events among individual cells. In this work, we have characterized the intercellular variability of transforming growth factor beta-induced Smad interactions, providing essential information about TGF beta signaling and its dependence on the density of cell populations and the cell cycle phase. By employing the recently developed in situ proximity ligation assay, we investigated the dynamics of interactions and modifications of Smad proteins and their partners under native and physiological conditions. We analyzed the kinetics of assembly of Smad complexes and the influence of cellular environment and relation to mitosis. We report rapid kinetics of formation of Smad complexes, including native Smad2-Smad3-Smad4 trimeric complexes, in a manner influenced by the rate of proteasomal degradation of these proteins, and we found a striking cell to cell variation of signaling complexes. The single cell analysis of TGF-beta signaling in genetically unmodified cells revealed previously unknown aspects of regulation of this pathway, and it provided a basis for analysis of these signaling events to diagnose pathological perturbations in patient samples and to evaluate their susceptibility to drug treatment. PMID- 22442259 TI - Absolute quantitation of isoforms of post-translationally modified proteins in transgenic organism. AB - Post-translational modification isoforms of a protein are known to play versatile biological functions in diverse cellular processes. To measure the molar amount of each post-translational modification isoform (P(isf)) of a target protein present in the total protein extract using mass spectrometry, a quantitative proteomic protocol, absolute quantitation of isoforms of post-translationally modified proteins (AQUIP), was developed. A recombinant ERF110 gene overexpression transgenic Arabidopsis plant was used as the model organism for demonstration of the proof of concept. Both Ser-62-independent (14)N-coded synthetic peptide standards and (15)N-coded ERF110 protein standard isolated from the heavy nitrogen-labeled transgenic plants were employed simultaneously to determine the concentration of all isoforms (T(isf)) of ERF110 in the whole plant cell lysate, whereas a pair of Ser-62-dependent synthetic peptide standards were used to quantitate the Ser-62 phosphosite occupancy (R(aqu)). The P(isf) was finally determined by integrating the two empirically measured variables using the following equation: P(isf) = T(isf) . R(aqu). The absolute amount of Ser-62 phosphorylated isoform of ERF110 determined using AQUIP was substantiated with a stable isotope labeling in Arabidopsis-based relative and accurate quantitative proteomic approach. The biological role of the Ser-62-phosphorylated isoform was demonstrated in transgenic plants. PMID- 22442260 TI - Balancing ovulation and anovulation: integration of the reproductive and energy balance axes by neuropeptides. AB - BACKGROUND: Because of the substantial energy demands of reproduction, the brain must temper the fertility of individuals to match nutritional availability. Under nutrition is associated with infertility in humans and animals. The brain uses adipose- and gut-derived hormones, such as leptin, insulin and ghrelin, to modulate the activity of the GnRH neuronal network that drives reproduction. It is becoming clear that there are both direct and indirect pathways acting on GnRH neurones. METHODS: A PubMed search was performed using keywords associated with neuropeptides and metabolic hormones that are associated with reproductive and energy balance axes. RESULTS: Evidence that neurones which produce galanin, galanin-like peptide, kisspeptin, alpha-melanocyte-stimulating hormone, neuropeptide Y and oxytocin convey metabolic information to the reproductive axis is presented. The extent to which these neurones express receptors for metabolic hormones is variable but interactions between them allows for complex intermingling of information. Available metabolic fuels modulate hormone input to these neurones, leading in turn to altered GnRH release and appropriate drive to the gonads. The consequent change in sex steroid production is likely to contribute to co-ordination of the network. CONCLUSIONS: We hypothesize that the absence of an estrogenic milieu during anovulation compared with presence of estradiol during follicular maturation is important for the regulation of most of the neuropeptides. An improved understanding of the normal responses to energy deprivation may also help to identify novel therapeutic targets for infertility that often accompanies metabolic disorders, such as diabetes, obesity and polycystic ovary syndrome. PMID- 22442261 TI - Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes. AB - BACKGROUND: Uterine adenomyosis was initially thought to be found only in parous women, and final diagnosis was made at histology after hysterectomy. With better imaging techniques and with women attending clinics at older ages, adenomyosis is diagnosed with increasing frequency in women attending infertility clinics. A dozen conservative interventions have been advocated, with variable reports of their impact on fertility. This presents a dilemma for clinicians managing such patients. Hence, this systematic review of adenomyosis was performed to determine (i) the prevalence in a subfertile population, (ii) the accuracy of diagnostic tests, (iii) the efficacy of fertility sparing treatment options and (iv) the reproductive and obstetric/perinatal outcomes in women with adenomyosis. METHODS: Systematic searches of various databases were performed independently by two reviewers, and data were extracted according to predefined criteria by two reviewers. RESULTS: There is little data on the epidemiology of adenomyosis associated with subfertility. Both magnetic resonance imaging and ultrasound are non-invasive tests with equivalent accuracy in diagnosing adenomyosis (area under curve 0.91 and 0.88, respectively). Most studies on treatments have been uncontrolled and outcomes are usually reported in the form of case series. Hence, the true impact of various treatments on fertility is not known. There are variable reports of the impact of adenomyosis on the success of IVF. Increased incidence of preterm labour and premature rupture of membranes has been reported in women with adenomyosis. CONCLUSIONS: Further studies are needed to determine the natural history of adenomyosis and implications for fertility and reproductive outcomes, with and without treatment. Currently, there is no evidence that we should find and treat adenomyosis in patients who wish to conceive. PMID- 22442262 TI - Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH): a French nationwide series of 21 cases. AB - CONTEXT: Ectopic GHRH secretion is a rare cause of acromegaly, and case reports are mainly isolated. SETTING: From the registry of the sole laboratory performing plasma GHRH assays in France, we identified cases of ectopic GHRH secretion presenting with acromegaly between 1983 and 2008. PATIENTS: Twenty-one patients aged 14-77 yr were identified from 12 French hospitals. Median GHRH was 548 (270 9779) ng/liter. MAIN OUTCOME MEASURES: Outcome measures included description of tumor features and outcome and the relation between plasma GHRH values and tumor site, size, and spread. RESULTS: The primary neuroendocrine tumor was identified for 20 of 21 patients (12 pancreatic, seven bronchial, one appendicular). Tumors were large (10-80 mm), identified on computed tomography scan in 18 cases and by endoscopic ultrasound and somatostatin receptor scintigraphy in two. Somatostatin receptor scintigraphy had a similar sensitivity to computed tomography scan (81 vs. 86%). Tumors were all well differentiated; 47.6% had metastasized at the time of diagnosis of acromegaly. After a median follow-up of 5 yr, 85% of patients were alive. Ninety-one percent of patients whose tumor was completely removed were considered in remission, and most had normalized plasma GHRH. The remaining patients were treated with somatostatin analogs: IGF-I normalized except for one patient who required pegvisomant, but GHRH levels remained elevated. No correlations were found between GHRH levels and tumor site or size or the existence of metastases. Identification of increased plasma GHRH during follow-up was an accurate indicator of recurrence. CONCLUSIONS: The prognosis of endocrine tumors responsible for GHRH secretion appears relatively good. Plasma GHRH assay is an accurate tool for diagnosis and follow-up. PMID- 22442263 TI - Low serum 25-hydroxyvitamin D is associated with increased risk of the development of the metabolic syndrome at five years: results from a national, population-based prospective study (The Australian Diabetes, Obesity and Lifestyle Study: AusDiab). AB - CONTEXT: Serum 25-hydroxyvitamin D [25(OH)D] concentration has been inversely associated with the prevalence of metabolic syndrome (MetS), but the relationship between 25(OH)D and incident MetS remains unclear. OBJECTIVE: We evaluated the prospective association between 25(OH)D, MetS, and its components in a large population-based cohort of adults aged 25 yr or older. DESIGN: We used baseline (1999-2000) and 5-yr follow-up data of the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). PARTICIPANTS: Of the 11,247 adults evaluated at baseline, 6,537 returned for follow-up. We studied those without MetS at baseline and with complete data (n = 4164; mean age 50 yr; 58% women; 92% Europids). OUTCOME MEASURES: We report the associations between baseline 25(OH)D and 5-yr MetS incidence and its components, adjusted for age, sex, ethnicity, season, latitude, smoking, family history of type 2 diabetes, physical activity, education, kidney function, waist circumference (WC), and baseline MetS components. RESULTS: A total of 528 incident cases (12.7%) of MetS developed over 5 yr. Compared with those in the highest quintile of 25(OH)D (>=34 ng/ml), MetS risk was significantly higher in people with 25(OH)D in the first (<18 ng/ml) and second (18-23 ng/ml) quintiles; odds ratio (95% confidence interval) = 1.41 (1.02 1.95) and 1.74 (1.28-2.37), respectively. Serum 25(OH)D was inversely associated with 5-yr WC (P < 0.001), triglycerides (P < 0.01), fasting glucose (P < 0.01), and homeostasis model assessment for insulin resistance (P < 0.001) but not with 2-h plasma glucose (P = 0.29), high-density lipoprotein cholesterol (P = 0.70), or blood pressure (P = 0.46). CONCLUSIONS: In Australian adults, lower 25(OH)D concentrations were associated with increased MetS risk and higher WC, serum triglyceride, fasting glucose, and insulin resistance at 5 yr. Vitamin D supplementation studies are required to establish whether the link between vitamin D deficiency and MetS is causal. PMID- 22442264 TI - Elimination half-life of anti-Mullerian hormone. AB - CONTEXT: Anti-Mullerian hormone (AMH) is a glycoprotein that is secreted by the granulosa cells in the human ovary. In the postpubertal female, circulating AMH reflects the number of follicles within the ovary. It is mandatory to know the serum elimination half-life (t(1/2)) of AMH to study in vivo short-term changes of the hormone. OBJECTIVE: Our objective was to determine the kinetics of decay of AMH in the human female. PATIENTS, DESIGN, AND SETTING: Premenopausal women undergoing total abdominal hysterectomy plus bilateral salpingo-oophorectomy participated in this cohort study (n = 21) at an academic tertiary referral center. INTERVENTIONS: Serum samples were obtained immediately before surgery and in 12-h intervals thereafter for 8 d. MAIN OUTCOME MEASURE: AMH elimination was calculated, applying a one-compartment model with first-order kinetics. RESULTS: Mean preoperative AMH levels were 0.67 ng/ml (range, 0.1-1.78 ng/ml) and dropped to 0.08 ng/ml within 84 h after surgery. The AMH decay followed first-order kinetics. The mean terminal t(1/2) of AMH was calculated as 27.6 +/- 0.8 h. CONCLUSION: AMH elimination reaches approximately 84% after 3 d, approximately 91% after 4 d, approximately 95% after 5 d, and can be considered complete after 8 d. PMID- 22442265 TI - Intrahepatic insulin exposure, intrahepatocellular lipid and regional body fat in nonalcoholic fatty liver disease. AB - CONTEXT: Insulin is pivotal in regulating hepatic lipid synthesis, metabolism, and export. OBJECTIVE: We tested the hypothesis that intrahepatic insulin exposure is an important determinant of intrahepatocellular lipid (IHCL), taking into account regional adiposity and both glucoregulatory and antilipolytic insulin sensitivity. RESEARCH DESIGN AND METHODS: We compared 21 European males with known nonalcoholic fatty liver disease (NAFLD) with 19 healthy male controls. Insulin sensitivity, secretion, and percentage hepatic extraction were derived from iv glucose tolerance test (IVGTT) glucose, insulin, and C-peptide concentrations. Intrahepatic insulin exposure was calculated as percentage hepatic insulin extraction multiplied by basal or IVGTT insulin secretion. IHCL was quantified by proton magnetic resonance spectroscopy. Total and regional adipose tissue was measured using whole body magnetic resonance imaging. RESULTS: Percentage hepatic extraction of newly secreted insulin differed between cases with NAFLD and controls at borderline significance (median, 76 vs. 83%; P = 0.07). Cases had higher intrahepatic insulin exposure than controls, both in the basal (34 vs. 18 pmol; P = 0.0002) and glucose-stimulated states (58 vs. 24 pmol; P = 0.01). IHCL was significantly related to both basal (r(s) = 0.62; P < 0.0001) and IVGTT intrahepatic insulin exposure (r(s) = 0.47; P = 0.002). As predictors of IHCL, both basal and IVGTT intrahepatic insulin exposure were dependent on the waist-to-hip ratio and homeostasis model assessment insulin resistance, but not on magnetic resonance imaging fat measures or IVGTT insulin sensitivity. CONCLUSIONS: Men with NAFLD have higher intrahepatic insulin exposure than controls. This correlates with IHCL, but the principal determinants of IHCL were fat distribution and hepatic rather than peripheral insulin resistance. PMID- 22442266 TI - Update on energy homeostasis and insufficient sleep. AB - Driven by the demands and opportunities of modern life, many people habitually sleep less than 6 h a night. In the sleep clinic, chronic sleep restriction is recognized by the diagnosis of insufficient sleep syndrome (ICSD-9, 307.49-4), which is receiving increased scrutiny as a potential risk to metabolic health. Its relevance for the practicing endocrinologist is highlighted by a stream of epidemiological data that show an association of insufficient sleep with increased incidence of obesity and related morbidities. A central theme of this update is the notion that sleep loss incurs additional metabolic cost, which triggers a set of neuroendocrine, metabolic, and behavioral adaptations aimed at increasing food intake and conserving energy. Although this coordinated response may have evolved to offset the metabolic demands of extended wakefulness in natural habitats with limited food availability, it can be maladaptive in the context of a modern environment that allows many to overeat while maintaining a sedentary lifestyle without sufficient sleep. Importantly, such sleep loss related metabolic adaptation may undermine the success of behavioral interventions based on reduced caloric intake and increased physical activity to lower metabolic risk in obesity-prone individuals. This emerging perspective is based on data from recently published human interventional studies and requires further experimental support. Nevertheless, it now seems prudent to recommend that overweight and obese individuals attempting to reduce their caloric intake and maintain increased physical activity should obtain adequate sleep and, if needed, seek effective treatment for any coexisting sleep disorders. PMID- 22442267 TI - Sex dimorphism in the relation between early adiposity and cardiometabolic risk in adolescents. AB - CONTEXT: Birth weight and childhood adiposity are associated with subsequent cardiovascular risk. OBJECTIVE: We investigated the associations between metabolic clusters in young adults with body fat distribution from early childhood, focusing on sex differences. DESIGN, SETTING, AND PATIENTS: A total of 1053 17 yr olds from an Australian birth cohort had measures of anthropometry, blood pressure, and fasting insulin, glucose, and lipids. MAIN OUTCOME MEASURES: Two-step cluster analysis identified 17 yr olds at high metabolic risk. The two risk groups were compared by sex with regard to birth weight and serial anthropometry, including skinfold thickness from nine time-points. RESULTS: The "high-risk" metabolic cluster at age 17 yr included 16% of males and 19% of females. Compared to the "low-risk" group, the high-risk cluster participants had greater waist circumference, triglycerides, insulin, and systolic blood pressure and lower high-density lipoprotein-cholesterol (all P <0.0001). There was a significant birth weight by sex interaction upon the metabolic cluster outcome (P = 0.011). Compared to their low-risk counterparts, females in the high-risk cluster at 17 yr were heavier from birth (odds ratio, 1.8; 95% confidence interval, 1.0, 3.2) (P = 0.034), with consistently higher body mass index and skinfold thickness thereafter. In contrast, there was no statistical difference in birth weight between high- and low-risk males (odds ratio, 0.62; 95% confidence interval, 0.38, 1.02). CONCLUSIONS: These data show sexual dimorphism in effects of early life body mass index and fat distribution upon cardiometabolic risk factors. Females in a contemporary population are particularly prone to increased risk when born heavier. This has implications for targeted prevention of obesity and metabolic diseases with increasing maternal obesity and gestational diabetes. PMID- 22442268 TI - Activation of the RAS/RAF/ERK signaling pathway contributes to resistance to sunitinib in thyroid carcinoma cell lines. AB - CONTEXT: Sunitinib is currently being evaluated in advanced human thyroid carcinomas, based on the rationale that the vascular endothelial growth factor and platelet-derived growth factor receptors and the RET/PTC rearrangement are valuable targets for the treatment of this malignancy. However, criteria for selecting thyroid tumors that may benefit from sunitinib are lacking. DESIGN: The effect of activating somatic mutations in the KRAS and BRAF genes on the responsiveness to sunitinib was evaluated in a panel of thyroid cancer cell lines harboring wild-type KRAS and BRAF genes, the RET/PTC1 rearrangement, the G12R KRAS, or the V600E BRAF mutation. RESULTS: Sunitinib was found to selectively inhibit cell proliferation, induce cell accumulation in the G0-G1 phase, and inhibit the phosphorylation of ERK1/2 in both KRAS/BRAF wild-type thyroid cancer cells and in tumor cells harboring the RET/PTC rearrangement, whereas it was completely ineffective in KRAS- or BRAF-mutated thyroid carcinoma cells. This differential antitumor activity of sunitinib did not correlate with the expression profile of the vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor-alpha and cKIT genes. Of note, the constitutive activation of RAS/RAF/ERK signaling in KRAS/BRAF wild-type cells by transfection of the R12 HRAS or V600E BRAF mutants or stimulation with epithelial growth factor resulted in the loss of responsiveness to sunitinib, whereas pharmacological inhibition of MAPK kinase activity resulted in the resensitization of KRAS- or BRAF-mutated cells to the multikinase inhibitor. CONCLUSIONS: The constitutive activation of the RAS/RAF/ERK pathway may favor resistance to sunitinib in thyroid carcinoma cells. PMID- 22442269 TI - Gender-dependent skeletal effects of vitamin D deficiency in a younger generation. AB - CONTEXT: The major health threats caused by vitamin D deficiency in the young generation have not been fully elucidated. OBJECTIVE: The aim of this study was to investigate skeletal and nonskeletal effects of vitamin D deficiency and to study the optimal level of serum 25-hydroxyvitamin D [25(OH)D] in young people. DESIGN AND SETTING: The Fourth Korea National Health and Nutrition Examination Surveys (KNHANES IV) was conducted in 2008-2009. PARTICIPANTS: A total of 4276 people (1926 men and 2350 women) aged 10-40 yr were selected from 16 administrative districts of South Korea. MAIN OUTCOME MEASURES: We measured age specific changes in bone mineral density (BMD) according to serum 25(OH)D. RESULTS: Serum 25(OH)D was less than 25 nmol/liter in 18.8% of participants, 25 to less than 50 nmol/liter in 50.0%, 50 to less than 75 nmol/liter in 27.0%, and 75 nmol/liter or greater in 4.2%. Vitamin D deficiency was more frequent in women than in men. There were gender differences in the skeletal effects of vitamin D deficiency. In men between 10 and 22 yr old, BMD was significantly higher in the vitamin D-sufficient group, and in men between 23 and 40 yr old, a positive correlation between serum 25(OH)D and BMD was observed. However, in women, we could not find significant differences in BMD according to vitamin D status. Vitamin D deficiency in younger generations had no remarkable effects on most nonskeletal parameters or on the prevalence of concomitant diseases except for rheumatoid arthritis. CONCLUSIONS: Vitamin D plays an essential role in skeletal health of young people. Moreover, the presence of gender-dependent skeletal effects was an important observation of this study. Reassurance of serum 25(OH)D up to 20-30 ng/ml or higher is necessary, especially during the modeling phase in men. PMID- 22442270 TI - Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study. AB - BACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown. STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010. RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10% decreases over time in IGF-I levels (CM = 29.6%), individuals who had at least 10% increases over time in IGF-I levels (CM = 24.7%), and individuals who had IGF-I levels remaining within +/-10% over time (CM = 23.5%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP 1 increased markedly over time by 38% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality. CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality. PMID- 22442271 TI - Impact of hyperglycemia on neuropathological alterations during critical illness. AB - CONTEXT: Although preventing excessive hyperglycemia during critical illness may provide clinical neuroprotection, it remains debated whether normoglycemia is without risk for the brain. OBJECTIVE: To address this question, we compared the neuropathological alterations in microglia, astrocytes, and neurons, with uncontrolled hyperglycemia, moderately controlled hyperglycemia, and normoglycemia during human critical illness. We further investigated the time course in an animal model. DESIGN AND SETTING: We analyzed brain specimens from patients who died in the intensive care unit and from critically ill rabbits randomized to hyper- or normoglycemia. PATIENTS/OTHER PARTICIPANTS: We compared 10 critically ill patients randomized to normoglycemia (104 +/-9 mg/dl) or moderate hyperglycemia (173 +/-32 mg/dl), and five patients with uncontrolled hyperglycemia (254 +/-83 mg/dl) with 16 controls (out of hospital sudden deaths). Critically ill rabbits were randomized to hyperglycemia (315 +/-32 mg/dl) or normoglycemia (85 +/-13 mg/dl) and studied after 3 and 7 d. INTERVENTIONS: Insulin was infused to control blood glucose. MAIN OUTCOME MEASURES AND RESULTS: Patients with uncontrolled hyperglycemia showed 3.7-6-fold increased microglial activation, 54-95% reduced number and activation of astrocytes, more than 9-fold increased neuronal and glial apoptosis, and a 1.5-2-fold increase in damaged neurons in hippocampus and frontal cortex (all P <= 0.05). Most of these abnormalities were attenuated with moderate hyperglycemia and virtually absent with normoglycemia. Frontal cortex of hyperglycemic rabbits that had been critically ill for 3 d only revealed microglial activation, followed after 7 d by astrocyte and neuronal abnormalities similar to those observed in patients, all prevented by normoglycemia. CONCLUSIONS: Preventing hyperglycemia with insulin during critical illness reduced neuropathological abnormalities, with microglial activation being the earliest preventable event. Whether these pathological findings associate with neurological outcome remains unknown. PMID- 22442272 TI - Growth hormone receptor blockade inhibits growth hormone-induced chemoresistance by restoring cytotoxic-induced apoptosis in breast cancer cells independently of estrogen receptor expression. AB - CONTEXT: GH and IGF-I play a role in breast cancer (BC) development. We previously demonstrated that GH protects the estrogen receptor (ER) positive BC derived MCF7 cell line toward the cytotoxic effects of doxorubicin (D), independently of IGF-I. This issue may be important in ER negative BC cells that are more aggressive and more likely to develop chemoresistance. AIM OF THE STUDY: The aim of this study was to evaluate whether GH may impact chemoresistance phenotype of ER-negative BC-derived MDA-MB-231 cell line and investigate the possible mechanisms implicated in the protective action of GH toward the cytotoxic effects of D in both ER-positive and ER-negative BC-derived cell lines. RESULTS: GH protects ER-negative MDA-MB-231 cells from the cytotoxic effects of D and GH receptor antagonist pegvisomant reduces GH-induced DNA synthesis also in these cells. In both MDA-MB-231 and MCF7 cells, GH does not revert D-induced G2/M accumulation but significantly reduces basal and D-induced apoptosis, an effect blocked by pegvisomant. Glutathione S-transferase activity is not implicated in the protective effects of GH, whereas D-induced apoptosis depends on c-Jun N terminal kinase (JNK) activation. GH reduces both basal and D-stimulated JNK transcriptional activity and phosphorylation. CONCLUSIONS: In human BC cell lines, GH directly promotes resistance to apoptosis induced by chemotherapeutic drugs independently of ER expression by modulating JNK, further broadening the concept that GH excess may hamper cytotoxic BC treatment. These findings support the hypothesis that blocking GH receptor may be viewed as a potential new therapeutic approach to overcome chemoresistance, especially in ER-negative BC. PMID- 22442273 TI - The changes in plasma serotonin levels after hormone therapy and their relationship with estrogen responsiveness on bone in postmenopausal women. AB - CONTEXT: Selective serotonin reuptake inhibitors have shown to be associated with an increased risk of fractures. It has been suggested that circulating serotonin is an important regulatory factor and that estrogen may regulate bone metabolism through the serotonin pathway. OBJECTIVE: Our objective was to determine the association between plasma serotonin level and bone turnover before and after hormone therapy (HT) in postmenopausal women. PARTICIPANTS AND DESIGN: In this parallel comparative study using age-matched controls, 80 postmenopausal women (21 control, 59 receiving HT) aged 46-64 yr were assessed. The plasma levels of serotonin, serum concentrations of osteocalcin and carboxyterminal telopeptides, and bone mineral density (BMD) were measured at baseline and after 3 months and 1 yr of HT. RESULTS: The plasma serotonin level was significantly correlated with serum total alkaline phosphatase level at baseline (r = -0.223, P = 0.048) but not with serum osteocalcin (r = -0.217, P = 0.056) or carboxyterminal telopeptides (r = -0.217, P = 0.054). There was no significant association between baseline serotonin and BMD measured at the spine or femur. The median decrements of circulating serotonin from baseline were -9.3% (interquartile range -34.0 to 53.6%) and -7.2% (-25.5 to 64.5%) at 3 months and 1 yr of HT, respectively. These changes were not significantly different from those in the control group. The short-term changes of circulating serotonin at 3 months after HT did not show significant association with the changes in BMD measured at the lumbar spine or proximal femur 1 year after HT. CONCLUSIONS: Our results suggest that circulating serotonin may reflect bone turnover status, but it is not a strong enough predictor of bone loss to use as a bone marker. Moreover, serial measurements of plasma serotonin after short-term treatment with estrogen cannot predict the long-term responsiveness of bone to estrogen, suggesting that the bone-preserving effect of estrogen is independent of the peripheral action of serotonin on bone. PMID- 22442274 TI - Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. PMID- 22442275 TI - Update on insulin therapy for type 2 diabetes. AB - Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion at diagnosis and by progressive beta-cell dysfunction over time. Insulin therapy is thus frequently required during the course of the disease to maintain glycemic control and prevent diabetes complications. Insulin should be initiated when alternative antihyperglycemic agents have failed or when symptomatic or marked hyperglycemia is present. Recent studies demonstrate that the addition of basal, prandial, basal/bolus, or premixed insulins to existing antihyperglycemic regimens effectively lowers glycosylated hemoglobin (HbA(1c)). The long-acting insulin analogs cause less nocturnal hypoglycemia than bedtime NPH, with comparable HbA(1c) reductions. Insulin detemir confers a weight advantage over glargine or NPH. Rapid-acting insulin analogs control postprandial hyperglycemia more effectively than regular insulin and modestly lower HbA(1c). For selected patients with severe insulin resistance, U-500 is a less expensive and potentially more effective alternative to U-100 insulin. Adverse effects of insulin, including weight gain and hypoglycemia, can be minimized by initial use of basal insulins in combination with metformin, incretin mimetics, or dipeptidyl peptidase-IV inhibitors. Although in vitro studies suggest that hyperinsulinemia may promote tumorigenesis, no currently available insulin has been shown to increase cancer rates. Targeting near-normal glucose levels in insulin-treated patients should be reserved for those of younger age with a longer life expectancy, a shorter duration of diabetes, and little or no end-organ complications. A higher HbA(1c) target of 7-8% is more appropriate for patients less likely to benefit from intensive control and in those at high risk for severe hypoglycemia. PMID- 22442276 TI - Association of intact parathyroid hormone levels with subsequent hip BMD loss: the Osteoporotic Fractures in Men (MrOS) Study. AB - INTRODUCTION: There is little information on the association between intact PTH (iPTH) and longitudinal changes in bone mineral density (BMD) in older men. This association was evaluated in relation to conditions related to higher iPTH [e.g. decreased renal function, low serum 25-hydroxyvitamin D (25[OH]D)]. METHODS: Eligible men were part of a random sample of 1593 community-dwelling individuals aged 65 yr or older participating in the Osteoporotic Fractures in Men study with baseline iPTH data. Of these, 1227 had at least two BMD measurements at the total hip and femoral neck over a mean follow-up of 4.5 yr. Annualized BMD change across iPTH quartiles was estimated using mixed-effects regression models, adjusting for age, serum calcium, serum 25(OH)D, estimated glomerular filtration rate, and other factors. Splines were used to identify more optimal iPTH thresholds associated with less BMD loss. RESULTS: Among the cohort of 1138 eligible men, men in the highest quartile of iPTH (>=38 pg/ml) lost 0.46% per year at the total hip compared with men in the lowest iPTH quartile who lost 0.22% per year (P = 0.0004). Results were similar at the femoral neck. The association between iPTH and BMD loss was not modified by baseline estimated glomerular filtration rate or 25(OH)D status. Spline results suggested that iPTH levels below 30 pg/ml were more physiologically optimal than higher iPTH values in reducing BMD loss, although an exact threshold for optimal iPTH was not identified. CONCLUSION: Older men with higher iPTH levels had approximately a 2 fold greater rate of BMD loss compared with men with lower iPTH levels, irrespective of estimated glomerular filtration rate and 25(OH)D. PMID- 22442277 TI - Improvement of vitamin D status via daily intake of fortified yogurt drink either with or without extra calcium ameliorates systemic inflammatory biomarkers, including adipokines, in the subjects with type 2 diabetes. AB - CONTEXT: Systemic inflammation is thought to have a central role in diabetic long term complications. OBJECTIVE: The aim of this study was to investigate the effects of vitamin D either with or without extra calcium on certain inflammatory biomarkers in the subjects with type 2 diabetes (T2D). DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomized, controlled trial conducted over 12 wk in 90 T2D subjects aged 30-60 yr from both sexes. INTERVENTION: Subjects were randomly allocated to one of three groups to receive two 250-ml bottles a day of plain Persian yogurt drink or doogh (PD, containing 150 mg calcium and no detectable vitamin D(3)/250 ml), vitamin D-fortified doogh (DD, containing 500 IU vitamin D(3) and 150 mg calcium/250 ml), or calcium + vitamin D(3)-fortified doogh (CDD, containing 500 IU vitamin D(3) and 250 mg calcium/250 ml). OUTCOME MEASURES: The changes in inflammatory markers were evaluated. RESULTS: Compared to the baseline values, highly sensitive C-reactive protein, IL 1beta, IL-6, fibrinogen, and retinol binding protein-4 concentrations significantly decreased in both the DD and CDD groups. Although the decrement in highly sensitive C-reactive protein and fibrinogen was more in CDD compared to DD (-4.0 +/- 8.5 vs. -1.3 +/- 2.8 mg/liter, and -0.40 +/- 0.74 and -0.20 +/- 0.52 mg/liter, respectively), the differences were not significant. There was a significant increase in serum adiponectin in both the DD and CDD groups (51.3 +/- 65.3 vs. 57.1 +/- 33.8 MUg/liter; P < 0.05). Mean adiponectin changes in CDD were significantly higher than in PD (P = 0.021). CONCLUSIONS: Daily intake of vitamin D-fortified doogh improved inflammatory markers in T2D subjects, and extra calcium conferred additional benefit only for the antiinflammatory adipokine, i.e. adiponectin. PMID- 22442278 TI - IOM committee members respond to Endocrine Society vitamin D guideline. AB - In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25 hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population. PMID- 22442279 TI - Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. AB - CONTEXT: Aldosterone-producing adenomas (APA) are heterogeneous. The recent finding of somatic KCNJ5 mutations suggests a genetic explanation. OBJECTIVES: The objectives of this study were the following: 1) to compare transcriptional profiles in APA and adjacent adrenal gland (AAG); 2) to test whether gene expression profile clusters with different cell histology; and 3) to measure the frequency of KCNJ5 mutations and determine the genotype-phenotype relationship. DESIGN/SETTING: The design of the study included laboratory analyses of 46 unselected APA. PATIENTS: The patients in this study had primary hyperaldosteronism with unilateral APA. INTERVENTIONS: The objectives of this study were the following: 1) Illumina beadchip analysis of RNA from eight paired APA-AAG; 2) a blinded review of cell histology for 46 APA; 3) laser capture microdissection of zona glomerulosa (ZG) and zona fasciculata (ZF) cells; and 4) sequencing of KCNJ5 in 46 APA. MAIN OUTCOME MEASURES: The main outcome measures of this study were the following: 1) a difference in gene expression profile and a correlation with histological markers of ZF; 2) a frequency of KCNJ5 mutations and phenotypic comparisons of wild type with mutant APA. RESULTS: The results of the study were the following: 1) a cluster analysis of microarray data separated APA from AAG. APA at opposite ends of the APA cluster had an approximately 800 fold difference in CYP17A1 mRNA expression, whereas histology showed 0% ZF-like cells in one vs. 100% in the other. A heat map ranking APA by CYP17A1 expression correctly predicted several genes (e.g. KCNK1, SLC24A3) to be enriched in laser capture microdissection samples of ZG; 2) known or novel mutations of KCNJ5 were found in 20 of 46 consecutive APA [43% (95% confidence interval [CI] (29, 58)%)]. The APA with KCNJ5 gene mutations were larger compared with tumors harboring the wild type, 1.63 [95% CI (1.37, 1.88)] vs. 1.14 [0.97, 1.30] cm (P = 0.0013), had predominantly ZF-like cells, and their CYP17A1 (log(2)-fold change) was higher than in wild type: -0.96 [95% CI (-0.07, -1.85)] vs. -2.54 [-1.61, -3.46], (P = 0.017). CONCLUSIONS: KCNJ5 mutations are common in APA, particularly those arising from ZF. The long-recognized heterogeneity among APA may have a genetic basis. PMID- 22442280 TI - Hedonic eating is associated with increased peripheral levels of ghrelin and the endocannabinoid 2-arachidonoyl-glycerol in healthy humans: a pilot study. AB - BACKGROUND: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. In this condition, the subject eats also when not in a state of short-term energy depletion, and food is consumed uniquely because of its gustatory rewarding properties. The physiological mechanisms underlying this eating behavior are not deeply understood, but endogenous rewarding mediators like ghrelin and endocannabinoids are likely involved. OBJECTIVE AND DESIGN: To explore the role of these substances in hedonic eating, we measured changes in their plasma levels in eight satiated healthy subjects after ad libitum consumption of highly palatable food as compared with the consumption of nonpalatable food in isoenergetic amounts with the same nutrient composition of the palatable food. RESULTS: The consumption of food for pleasure was characterized by increased peripheral levels of both the peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol. Levels of the other endocannabinoid anandamide and of anandamide-related mediators oleoylethanolamide and palmitoylethanolamide, instead, progressively decreased after the ingestion of both highly pleasurable and isoenergetic nonpleasurable food. A positive correlation was found between plasma 2-arachidonoyl glycerol and ghrelin during hedonic but not nonhedonic, eating. CONCLUSIONS: The present preliminary findings suggest that when motivation to eat is generated by the availability of highly palatable food and not by food deprivation, a peripheral activation of two endogenous rewarding chemical signals is observed. Future research should confirm and extend our results to better understand the phenomenon of hedonic eating, which influences food intake and, ultimately, body mass. PMID- 22442281 TI - Investigating the use of traditional and spectral biofeedback approaches to intervention for /r/ misarticulation. AB - PURPOSE: Misarticulation of /r/ is among the most challenging developmental speech errors to remediate. Case studies suggest that visual biofeedback treatment can establish perceptually accurate /r/ in clients who have not responded to traditional treatments. This investigation studied the response of children with persistent /r/ misarticulation to a course of traditional treatment and a course of biofeedback treatment. METHOD: Eleven children with /r/ misarticulation completed 10 weeks of individual treatment consisting of 4-6 weeks of traditional treatment followed by 4-6 weeks of biofeedback treatment. Progress was measured by tracking correct /r/ productions within treatment and probing /r/ in words at 3 time points. RESULTS: At the group level, there was no difference in independent judges' ratings of /r/ sounds produced by the children before and after traditional treatment. However, /r/ sounds produced after biofeedback treatment were significantly more likely to be rated by the judges as perceptually correct. Eight of the 11 children made measurable gains in the accuracy of isolated /r/ produced within treatment, with 4 showing significant generalization to untreated /r/ in words. CONCLUSION: This descriptive study shows that treatment incorporating spectral biofeedback can facilitate accurate /r/ production in children with treatment-resistant errors. A follow-up period using traditional intervention methods may be necessary to encourage generalization. PMID- 22442282 TI - Stuttering and language ability in children: questioning the connection. AB - PURPOSE: This article explains why it is reasonable to question the view that stuttering and language ability in children are linked-the so-called "stuttering language connection." METHOD: Studies that focused on syntactic, morphologic, and lexical development in children who stutter (CWS) are examined for evidence to support the following claims: (a) that CWS, as a group, are more likely to have disordered or weak language skills ("language deficits") than children who do not stutter (CWNS); (b) that language deficits play a causal role in the onset of stuttering; and (c) that stuttering, over time, restricts children's language development. RESULTS: Analysis of the evidence suggests that CWS, like CWNS, show the full range of language abilities (high, average, low); that language deficits are not associated with stuttering onset or persistence; and that stuttering has little or no impact on language development. CONCLUSIONS: A connection between stuttering and language ability was not supported. An alternative perspective is that CWS have a compromised motor control system that makes it difficult for them to move forward in speech and that the tie to language lies not in a deficient linguistic system but in difficulty expressing the intended meaning via a fully functional speech system. PMID- 22442283 TI - Script training and generalization for people with aphasia. AB - PURPOSE: To examine the effects and generalization of a modified script training intervention, delivered partly via videoconferencing, on dialogue scripts that were produced by 2 individuals with aphasia. METHOD: Each participant was trained on 2 personally relevant scripts. Intervention sessions occurred 3 times per week, with a combination of in-person meetings and videoconferencing, and lasted for 3 weeks per script. This study followed a multiple baseline design across scripts. Measures of accuracy, grammatical productivity, speaking rate, and articulatory fluency were obtained during baseline, intervention, and maintenance phases. Generalization probes were administered by challenging participants to engage in a conversation about their script topic with conversation partners who did not follow the script. RESULTS: Both participants showed improvement on all dependent variables for both scripts during and after the intervention phase. Generalization samples showed improved grammatical morpheme use and increased rate of speech over prebaseline samples. CONCLUSION: There is evidence that script training intervention can improve accuracy, grammatical productivity, speaking rate, and articulatory fluency in script production tasks as well as in more functional conversational tasks. Videoconferencing is a viable method of conducting script training intervention when it is supported by face-to-face intervention sessions, slight modifications to the procedure, and an emphasis on self-cuing skills. PMID- 22442284 TI - Feedback frequency in treatment for childhood apraxia of speech. AB - PURPOSE: To examine the role of feedback frequency in treatment for childhood apraxia of speech (CAS). Reducing the frequency of feedback enhances motor learning, and recently, such feedback frequency reductions have been recommended for the treatment of CAS. However, no published studies have explicitly compared different feedback frequencies in this population. METHOD: Using an alternating treatments single-subject design with multiple baselines across behaviors, retention and transfer of learning were compared following high-frequency feedback and low-frequency feedback in 4 children with CAS. Feedback frequency was manipulated in the context of an integral stimulation treatment. Changes in perceptual accuracy were quantified with effect sizes and were compared across conditions. RESULTS: Findings were mixed, with 2 children showing an advantage for low-frequency feedback, 1 child showing a small advantage for high-frequency feedback, and 1 child showing no clear improvement in either condition. CONCLUSION: These findings suggest that reducing the frequency of feedback may be beneficial for some children with CAS, although this may vary with the child's age or severity of apraxia. Caution is warranted in extrapolating from the nonspeech motor learning literature to speech treatment for CAS. Finally, this study contributes another replication to the literature on the efficacy of integral stimulation treatment for children with CAS. PMID- 22442285 TI - Tone discrimination as a window into acoustic perceptual deficits in Parkinson's disease. AB - PURPOSE: Deficits in auditory perception compromise a range of linguistic processes in persons with Parkinson's disease (PD), including speech perception and sensitivity to affective and linguistic prosody. An unanswered question is whether this deficit exists not only at the level of speech perception, but also at a more pervasive level of auditory perception. It is possible that PD produces a selective impairment in the perception of a salient acoustic feature such as frequency, amplitude, or duration. METHOD: Auditory perception in persons with PD was investigated using a tone discrimination task where clients ( N = 12) and age matched controls ( N = 15) made same/different judgments for pairs of pure tones that were factorially varied by acoustic feature (i.e., frequency, amplitude, or duration) crossed with perceptual distance (i.e., close vs. far). RESULTS: Relative to healthy age-matched controls, persons with PD showed marked impairment in tone discrimination. Persons with PD showed an acoustic feature by perceptual distance interaction that was characterized by deficits in detecting frequency and amplitude differences for perceptually near tones. CONCLUSION: These results suggest that persons with PD show a reduced ability to notice change in frequency and amplitude as compared to normal older adults. More generally, these findings implicate a frontal-striatal contribution to auditory perception. PMID- 22442287 TI - Elevated risk of preeclampsia in pregnant women with depression: depression or antidepressants? AB - A previous study suggested an increased risk of preeclampsia among women treated with selective serotonin reuptake inhibitors (SSRIs). Using population-based health-care utilization databases from British Columbia (1997-2006), the authors conducted a study of 69,448 pregnancies in women with depression. They compared risk of preeclampsia in women using SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) between gestational weeks 10 and 20 with risk in depressed women not using antidepressants. Among prepregnancy antidepressant users, the authors compared the risk in women who continued antidepressants between gestational weeks 10 and 24 with the risk in those who discontinued. Relative risks and 95% confidence intervals were estimated. The risk of preeclampsia in depressed women not treated with antidepressants (2.4%) was similar to that in women without depression (2.3%). Compared with women with untreated depression, women treated with SSRI, SNRI, and TCA monotherapy had adjusted relative risks of 1.22 (95% confidence interval (CI): 0.97, 1.54), 1.95 (95% CI: 1.25, 3.03), and 3.23 (95% CI: 1.87, 5.59), respectively. Within prepregnancy antidepressant users, the relative risk for preeclampsia among continuers compared with discontinuers was 1.32 (95% CI: 0.95, 1.84) for SSRI, 3.43 (95% CI: 1.77, 6.65) for SNRI, and 3.26 (95% CI: 1.04, 10.24) for TCA monotherapy. Study results suggest that women who use antidepressants during pregnancy, especially SNRIs and TCAs, have an elevated risk of preeclampsia. These associations may reflect drug effects or more severe depression. PMID- 22442288 TI - Femoroacetabular impingement in former high-level youth soccer players. AB - BACKGROUND: Femoroacetabular impingement (FAI) can be a source of hip pain in young adults. Repetitive kicking associated with youth soccer may lead to morphologic changes of the proximal femur that predispose a person to the development of FAI. HYPOTHESIS: Young adults who participated in high-level soccer competition as youths are more likely to demonstrate radiographic changes consistent with FAI and to have increased alpha angles as compared with controls. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Pelvic radiographs (anteroposterior and frog-lateral) were obtained on 50 individuals who participated in high-level soccer during skeletal immaturity and 50 controls who did not participate in high-level soccer. There were 25 men and 25 women in each group. All subjects were between 18 and 30 years of age, had a body mass index of less than 30, and had not sought or received treatment for hip disorders. Radiographs were analyzed independently for the presence of FAI, and alpha angles were measured. Hips with alpha angles that measured greater than or equal to 55 degrees were deemed to have cam deformity. RESULTS: Fifteen of the 25 male subjects had evidence of cam deformity, compared with 14 male controls. Nine of the 25 female subjects had evidence of cam deformity, compared with 8 female controls. Neither of these differences was statistically significant. There was a significantly higher prevalence of cam deformity in men as compared with women (29 vs 17, P = .016). CONCLUSION: Participation in high-level soccer during skeletal immaturity is not associated with a higher risk of development of cam deformity in the young adult years. There is a high prevalence of cam deformity in the young adult population. Males demonstrate a higher prevalence of cam deformity than do females. PMID- 22442289 TI - Salmonella enterica serovar Typhi strain producing extended-spectrum beta lactamases in Dhaka, Bangladesh. PMID- 22442290 TI - Epidemiological and molecular characteristics of clinical isolates of Streptococcus pyogenes collected between 2005 and 2008 from Chinese children. AB - The aim of this study was to explore the epidemiological and molecular characteristics of Streptococcus pyogenes in children from different cities in mainland China who were diagnosed with scarlet fever, impetigo and pharyngitis, as well as to detect asymptomatic carriers, between 2005 and 2008, and to compare the results with isolates from rural Chinese children with acute glomerulonephritis in 2005 and in the 1990s. Susceptibility tests to determine MICs and analysis of the presence of erythromycin-resistant genes (mefA, ermB and ermA) and emm gene typing were performed on 466 S. pyogenes isolates from Beijing, Shanghai, Chongqing and Shenzhen. Superantigen genes (speA and speC) were examined by performing PCR on isolates with the most prevalent emm genotype. All isolates were sensitive to penicillin, cefradine and ofloxacin. The highest rate of resistance was against clarithromycin (98.1 %), followed by erythromycin (97.6 %), azithromycin and clindamycin (both 97.2 %), and tetracycline (94.0 %). Among the 466 isolates, 421 (90.3 %) harboured the ermB gene, 145 (31.1 %) were speA-positive and 273 (58.6 %) were speC-positive. The speA gene was common in emm1.0 (88.8 %) and emm6.5 (83.3 %) genotypes. The speC gene was frequently observed in emm4.0 (90.0 %), emm12.0 (69.6 %), emm18.0 (66.7 %), emm22.0 (75.9 %) and emm80.0 (80.0 %) genotypes. The most prevalent emm genotypes in mainland China in recent years were emm1.0 and emm12.0. All isolates remained sensitive to beta-lactams and quinolone. PMID- 22442291 TI - Granulicatella infection: diagnosis and management. AB - Granulicatella species, along with the genus Abiotrophia, were originally known as 'nutritionally variant streptococci'. They are a normal component of the oral flora, but have been associated with a variety of invasive infections in man and are most noted as a cause of bacterial endocarditis. It is often advised that Granulicatella endocarditis should be treated in the same way as enterococcal endocarditis. We review here the published data concerning diagnosis and treatment of Granulicatella infection, and include some observations from local cases, including four cases of endocarditis. PMID- 22442292 TI - Penicillin resistance and serotype distribution of Streptococcus pneumoniae in nasopharyngeal carrier children under 5 years of age in Dar es Salaam, Tanzania. AB - This study aimed to determine the magnitude of nasopharyngeal carriage, antimicrobial resistance and serotype distribution of Streptococcus pneumoniae in healthy children under 5 years of age in Tanzania. Nasopharyngeal swabs were obtained from 300 healthy children attending a child health clinic at Muhimbili National Hospital in Dar es Salaam, Tanzania. S. pneumoniae was isolated and identified using conventional methods. Antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Penicillin MICs and serotypes were determined by an agar gradient diffusion method and the Quellung reaction, respectively. A total of 105 samples (35 .0%) were positive for S. pneumoniae and 115 serotypes were detected (ten specimens yielded two serotypes each). Overall, 78 of 115 isolates (67.8 %) were penicillin-non-susceptible pneumococci (PNSP). The resistance levels of S. pneumoniae to trimethoprim sulfamethoxazole, tetracycline, erythromycin, chloramphenicol and ceftriaxone were 82.6, 10.4, 6.0, 3.5 and 0.0 %, respectively. Multidrug resistance was detected in 19 isolates (16.5 %). The most prevalent serotypes were 19F (n = 25, 21.7 %), 6B (n = 15, 13.0 %), 9V (n = 14, 12.2 %) and 13 (n = 14, 12.2 %). Of the 64 pneumococcal isolates potentially covered by the seven-valent pneumococcal conjugate vaccine (PCV7), 44 (68.8 %) were PNSP. A high prevalence of PNSP, common pneumococcal serotypes circulating worldwide, was found, and many of the resistant pneumococci strains are covered by the PCV7. These findings indicate that the carriage rate of such resistant strains could be influenced by an appropriate vaccination programme in the study setting and by reinforcing regulations on the rational use of antimicrobial agents. PMID- 22442293 TI - ISCOMATRIX: a novel adjuvant for use in prophylactic and therapeutic vaccines against infectious diseases. AB - The ISCOMATRIX adjuvant has antigen delivery and presentation properties as well as immunomodulatory capabilities, which combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as CD4(+) and CD8(+) T-cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have now been tested in clinical trials and have been shown to be generally safe and well tolerated as well as immunogenic, generating both antibody (Ab) and T-cell responses. The mechanisms by which ISCOMATRIX adjuvant facilitates its immune effects are the scope of significant study and indicate that ISCOMATRIX adjuvant (i) rapidly traffics antigen into the cytosol of multiple dendritic cell subsets, (ii) induces the induction of an array of cytokines and chemokines and (iii) links the innate and adaptive immune responses in vivo in a Toll-like-receptor independent but MyD88-dependent manner. These data highlight the clinical utility of ISCOMATRIX adjuvant in the development of prophylactic and therapeutic vaccines for infectious disease. PMID- 22442294 TI - The natural history and incidence of Yersinia pestis and prospects for vaccination. AB - Plague is an ancient, serious, infectious disease which is still endemic in regions of the modern world and is a potential biothreat agent. This paper discusses the natural history of the bacterium and its evolution into a flea vectored bacterium able to transmit bubonic plague. It reviews the incidence of plague in the modern world and charts the history of vaccines which have been used to protect against the flea-vectored disease, which erupts as bubonic plague. Current approaches to vaccine development to protect against pneumonic, as well as bubonic, plague are also reviewed. The considerable challenges in achieving a vaccine which is licensed for human use and which will comprehensively protect against this serious human pathogen are assessed. PMID- 22442295 TI - The clinical potential of C-peptide replacement in type 1 diabetes. PMID- 22442296 TI - Is insulin action in the brain clinically relevant? PMID- 22442297 TI - Smokeless weight loss. PMID- 22442298 TI - Insulin resistance and type 2 diabetes. PMID- 22442299 TI - ER stress as a trigger for beta-cell dysfunction and autoimmunity in type 1 diabetes. PMID- 22442300 TI - Islet beta-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. AB - Type 1 diabetes is preceded by islet beta-cell dysfunction, but the mechanisms leading to beta-cell dysfunction have not been rigorously studied. Because immune cell infiltration occurs prior to overt diabetes, we hypothesized that activation of inflammatory cascades and appearance of endoplasmic reticulum (ER) stress in beta-cells contributes to insulin secretory defects. Prediabetic nonobese diabetic (NOD) mice and control diabetes-resistant NOD-SCID and CD1 strains were studied for metabolic control and islet function and gene regulation. Prediabetic NOD mice were relatively glucose intolerant and had defective insulin secretion with elevated proinsulin:insulin ratios compared with control strains. Isolated islets from NOD mice displayed age-dependent increases in parameters of ER stress, morphologic alterations in ER structure by electron microscopy, and activation of nuclear factor-kappaB (NF-kappaB) target genes. Upon exposure to a mixture of proinflammatory cytokines that mimics the microenvironment of type 1 diabetes, MIN6 beta-cells displayed evidence for polyribosomal runoff, a finding consistent with the translational initiation blockade characteristic of ER stress. We conclude that beta-cells of prediabetic NOD mice display dysfunction and overt ER stress that may be driven by NF-kappaB signaling, and strategies that attenuate pathways leading to ER stress may preserve beta-cell function in type 1 diabetes. PMID- 22442301 TI - Preventing beta-cell loss and diabetes with calcium channel blockers. AB - Although loss of functional beta-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate beta-cell TXNIP expression, and TXNIP overexpression induces beta-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous beta-cell survival and prevents streptozotocin (STZ) and obesity-induced diabetes. Finding an oral medication that could inhibit beta cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and beta-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted beta-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic beta-cell TXNIP expression, enhance beta-cell survival and function, and prevent and even improve overt diabetes. PMID- 22442303 TI - Genetic requirements for replication initiation of the staphylococcal multiresistance plasmid pSK41. AB - Replication of staphylococcal multiresistance plasmid pSK41 is initiated by binding of the replication initiator protein (Rep) to the Rep boxes, a series of four direct repeats located centrally within the rep gene. A Staphylococcus aureus strain was engineered to provide Rep in trans, allowing localization of the pSK41 origin of replication (oriV) to a 185 bp segment, which included the Rep boxes and a series of downstream direct repeats. Deletion analysis of individual Rep boxes revealed that all four Rep boxes are required for maximum origin activity, with the deletion of one or more Rep boxes having a significant effect on the proficiency of replication. However, a hierarchy of importance was identified among the Rep boxes, which appears to be mediated by the minor sequence variations that exist between them. DNA binding studies with truncated Rep proteins have enabled the DNA binding domain to be localized to the N terminal 134 amino acids of the protein. PMID- 22442304 TI - Suppression of in vivo Rho-dependent transcription termination defects: evidence for kinetically controlled steps. AB - The conventional model of Rho-dependent transcription termination in bacteria requires RNA-dependent translocase activity of the termination factor Rho as well as many kinetically controlled steps to execute efficient RNA release from the transcription elongation complex (EC). The involvement of the kinetically controlled steps, such as RNA binding, translocation and RNA release from the EC, means that this termination process must be kinetically coupled to the transcription elongation process. The existence of these steps in vivo has not previously been delineated in detail. Moreover, the requirement for translocase activity in Rho-dependent termination has recently been questioned by a radical view, wherein Rho binds to the elongating RNA polymerase (RNAP) prior to loading onto the mRNA. Using growth assays, microarray analyses and reporter-based transcription termination assays in vivo, we showed that slowing of the transcription elongation rate by using RNAP mutants (rpoB8 and rpoB3445) and growth of the strains in minimal medium suppressed the termination defects of five Rho mutants, three NusG mutants defective for Rho binding and the defects caused by two Rho inhibitors, Psu and bicyclomycin. These results established the existence of kinetically controlled steps in the in vivo Rho-dependent termination process and further reinforced the importance of 'kinetic coupling' between the two molecular motors, Rho and RNAP, and also argue strongly that the Rho translocation model is an accurate representation of the in vivo situation. Finally, these results indicated that one of the major roles of NusG in in vivo Rho-dependent termination is to enhance the speed of RNA release from the EC. PMID- 22442305 TI - Novel regulation targets of the metal-response BasS-BasR two-component system of Escherichia coli. AB - The BasS-BasR two-component system is known as an iron- and zinc-sensing transcription regulator in Escherichia coli, but so far only a few genes have been identified to be under the direct control of phosphorylated BasR. Using Genomic SELEX (systematic evolution of ligands by exponential enrichment) screening, we have identified a total of at least 38 binding sites of phosphorylated BasR on the E. coli genome, and based on the BasR-binding sites, have predicted more than 20 novel targets of regulation. By DNase I footprint analysis for high-affinity BasR-binding sites, a direct repeat of a TTAAnnTT sequence was identified as the BasR box. Transcription regulation in vivo of the target genes was confirmed after Northern blot analysis of target gene mRNAs from both wild-type E. coli and an otherwise isogenic basR deletion mutant. The BasR regulon can be classified into three groups of genes: group 1 includes the genes for the formation and modification of membrane structure; group 2 includes genes for modulation of membrane functions; and group 3 includes genes for stress response cell functions, including csgD, the master regulator of biofilm formation. PMID- 22442306 TI - Characterization of a phage-like pyocin from the plant growth-promoting rhizobacterium Pseudomonas fluorescens SF4c. AB - R-type and F-type pyocins are high-molecular-mass bacteriocins produced by Pseudomonas aeruginosa that resemble bacteriophage tails. They contain no head structures and no DNA, and are used as defence systems. In this report, we show that Pseudomonas fluorescens SF4c, a strain isolated from the wheat rhizosphere, produces a high-molecular-mass bacteriocin which inhibits the growth of closely related bacteria. A mutant deficient in production of this antimicrobial compound was obtained by transposon mutagenesis. Sequence analysis revealed that the transposon had disrupted a gene that we have named ptm, since it is homologous to that encoding phage tape-measure protein in P. fluorescens Pf0-1, a gene belonging to a prophage similar to phage-like pyocin from P. aeruginosa PAO1. In addition, we have identified genes from the SF4c pyocin cluster that encode a lytic system and regulatory genes. We constructed a non-polar ptm mutant of P. fluorescens SF4c. Heterologous complementation of this mutation restored the production of bacteriocin. Real-time PCR was used to analyse the expression of pyocin under different stress conditions. Bacteriocin was upregulated by mitomycin C, UV light and hydrogen peroxide, and was downregulated by saline stress. This report constitutes, to our knowledge, the first genetic characterization of a phage tail-like bacteriocin in a rhizosphere Pseudomonas strain. PMID- 22442307 TI - Staphylococcus aureus clumping factor B mediates biofilm formation in the absence of calcium. AB - Staphylococcus aureus is the leading cause of nosocomial infections and a major cause of community-acquired infections. Biofilm formation is a key virulence determinant in certain types of S. aureus infection, especially those involving inserted medical devices. We found in a previous study that the calcium chelators sodium citrate and EGTA inhibit biofilm formation in certain strains of S. aureus but actually augment biofilm formation in other strains. Even two closely related strains, Newman and 10833, exhibited strikingly different biofilm phenotypes in the presence of calcium chelators, in that biofilm formation was inhibited in Newman but augmented in 10833. We also found that the surface protein clumping factor B (ClfB) plays a role in this phenomenon. In this study, we confirm that ClfB is required for biofilm formation under calcium-depleted conditions. We investigated the post-translational regulation of ClfB-mediated biofilm formation and found evidence that both calcium and the protease aureolysin disrupt established ClfB-dependent biofilms. Finally, we investigated the genetic basis for the biofilm-negative phenotype in strain Newman versus the biofilm-positive phenotype in strain 10833 under calcium-depleted conditions and found that strain 10833 contains a deletion that results in a stop codon within the aureolysin gene (aur). When 10833 expressed Newman aur, surface-associated ClfB and the ability to form a biofilm in chelating conditions was lost. Thus, the positive effect of chelating agents on biofilm formation in certain strains can be explained by increased ClfB activity in the absence of calcium and the discrepancy in the response of strains 10833 and Newman can be explained by point mutations in aur. This study reveals a previously unknown, to our knowledge, role for ClfB in biofilm formation and underscores the potential for striking phenotypic variability resulting from minor differences in strain background. PMID- 22442308 TI - Therapeutic significance of estrogen receptor beta agonists in gliomas. AB - Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two estrogen receptor (ER) subtypes: ERalpha, which functions as tumor promoter, and ERbeta, which functions as tumor suppressor. We examined the potential use of ERbeta agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERbeta with little or no ERalpha. Treatment of glioma cells with ERbeta agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ERbeta expression is downregulated in high-grade gliomas. We found that ERbeta agonists promote both expression and tumor-suppressive functions of ERbeta in glioma cells. Liquiritigenin, a plant derived ERbeta agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ERbeta expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERbeta signaling has a tumor-suppressive function in gliomas. Because ERbeta agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERbeta agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients. PMID- 22442309 TI - Multiple antigenic peptides based on H-2K(b)-restricted CTL epitopes from murine heparanase induce a potent antitumor immune response in vivo. AB - Accumulating research suggests that heparanase may be a universal tumor associated antigen (TAA). Several heparanase T-cell epitopes from humans and mice have already been identified. However, because of low immunogenicity, polypeptide vaccines usually have difficulty inducing effective antitumor immune responses in vivo. In this study, to increase the immunogenicity of polypeptide vaccines, we designed and synthesized two four-branch multiple antigenic peptides (MAP) on the basis of mouse heparanase (mHpa) T-cell epitopes (mHpa398 and mHpa519). The dendritic cells (DC) from mice bone marrow loaded with above MAP vaccines from heparanase were used to evaluate immune response against various tumor cell lines, compared with immune response to their corresponding linear peptides, ex vivo and in vivo. We further assessed IFN-gamma release both in CD4(+) T-cell depleted and nondepleted mice. The results showed that effectors generated from DCs, loaded with MAP-vaccinated mice splenocytes, induced a stronger immune response against target cells expressing both heparanase and H-2K(b) than did effectors generated from mice vaccinated with their corresponding linear peptides. Heparanase-specific CD8(+) T-cell responses induced by MAP and linear peptide vaccination required synergy of CD4(+) T cells. In addition, heparanse derived MAP vaccines significantly inhibited the growth of B16 murine melanoma in C57BL/6 mice, while also increasing the survival rate of tumor-bearing mice. Our data suggest that MAP vaccines based on T-cell epitopes from heparanase are efficient immunogens for tumor immunotherapy. PMID- 22442310 TI - Evading Pgp activity in drug-resistant cancer cells: a structural and functional study of antitubulin furan metotica compounds. AB - Tumor resistance to antitubulin drugs resulting from P-glycoprotein (Pgp) drug efflux activity, increased expression of the betaIII tubulin isotype, and alterations in the drug-binding sites are major obstacles in cancer therapy. Consequently, novel antitubulin drugs that overcome these challenges are of substantial interest. Here, we study a novel chemotype named furan metotica that localizes to the colchicine-binding site in beta-tubulin, inhibits tubulin polymerization, and is not antagonized by Pgp. To elucidate the structure activity properties of this chiral chemotype, the enantiomers of its most potent member were separated and their absolute configurations determined by X-ray crystallography. Both isomers were active and inhibited all 60 primary cancer cell lines tested at the U.S. National Cancer Institute. They also efficiently killed drug-resistant cancer cells that overexpressed the Pgp drug-efflux pump 10(6)-fold. In vitro, the R-isomer inhibited tubulin polymerization at least 4 fold more potently than the S-isomer, whereas in human cells the difference was 30-fold. Molecular modeling showed that the two isomers bind to beta-tubulin in distinct manners: the R-isomer binds in a colchicine-like mode and the S-isomer in a podophyllotoxin-like fashion. In addition, the dynamic binding trajectory and occupancy state of the R-isomer were energetically more favorable then those of the S-isomer, explaining the observed differences in biologic activities. The ability of a racemic drug to assume the binding modes of two prototypical colchicine-site binders represents a novel mechanistic basis for antitubulin activity and paves the way toward a comprehensive design of novel anticancer agents. PMID- 22442311 TI - Two adenovirus serotype 3 outbreaks associated with febrile respiratory disease and pharyngoconjunctival fever in children under 15 years of age in Hangzhou, China, during 2011. AB - Adenovirus serotype 3 and 7 outbreaks have occurred periodically in northern, eastern, and southern China since 1955, but there has been no report since the adenovirus serotype 7 outbreak first occurred in Hangzhou, China, in 1991. Here we explored the epidemiology and etiology of two adenovirus serotype 3 outbreaks in Hangzhou in 2011. One acute respiratory outbreak was found in Chun'an County, where a total of 371 cases were confirmed in 5 of 23 towns from 4 to 31 May 2011. The outbreak affected 18.57% (13/70) of schools and 14.49% (90/621) of classes. The incidence was 5.18% (371/7,163). The population was distributed among individuals ages 7 to 15 years. No parents or teachers were infected. Another pharyngoconjunctival fever outbreak was discovered in the Chenjinglun Swimming Center located in the Xihu District between 1 and 15 July 2011. A total of 134 cases were confirmed in 900 amateur swimmers, with an incidence of 14.89% (134/900). The ages ranged from 4 to 9 years. The two outbreaks had no severe complications or death. The viruses in 66.67% (10/15) of throat swabs from children with acute respiratory infections and 100% (10/10) of the swabs from children with pharyngoconjunctival fever were confirmed to be adenovirus serotype 3 with 100% homology by PCR. Of these samples, 60.0% (12/20) had a classical characteristic cytopathic effect, presented as grape-like clusters at 72 h after infection in HEp-2 cells. In conclusion, the acute respiratory infection and pharyngoconjunctival fever outbreak in Hangzhou were caused by the completely homologous type 3 adenovirus in subgenus B. Moreover, these outbreaks demonstrated rapid transmission rates, possibly due to close contact and droplet transmission. PMID- 22442312 TI - PCR detection of Babesia ovata from cattle reared in Japan and clinical significance of coinfection with Theileria orientalis. AB - We describe here the clinical significance of coinfection with Theileria orientalis and Babesia ovata in cattle. Anemia status in a herd of dairy cattle in Japan was investigated in relation to infection with these parasites. Our findings indicate that while B. ovata infection might not be the primary cause of anemia in the cattle, it may contribute to the clinical development of anemia in animals coinfected with both B. ovata and T. orientalis. PMID- 22442313 TI - Concurrent serotyping and genotyping of pneumococci by use of PCR and electrospray ionization mass spectrometry. AB - A pneumococcal serotyping/genotyping system (PSGS) was developed based upon targeted PCR, followed by electrospray ionization mass spectrometry and amplicon base composition analysis. Eight multiplex PCRs, 32 targeting serotype determining capsular biosynthetic loci, and 8 targeting multilocus sequence typing (MLST) loci were employed for each of 229 highly diverse Streptococcus pneumoniae isolates. The most powerful aspect of the PSGS system was the identification of capsular serotypes accounting for the majority of invasive and carried pneumococcal strains. Altogether, 45 different serotypes or serogroups were correctly predicted among the 196 resolvable isolates, with only 2 unexpected negative results. All 33 isolates that represented 23 serotypes not included in the PSGS yielded negative serotyping results. A genotyping database was constructed using the base compositions of 65- to 100-bp sections of MLST alleles compiled within http://www.mlst.net. From this database, one or more MLST sequence types (STs) that comprised a PSGS genotype were identified. The end result of more PSGS genotypes (163) than conventional STs actually tested (155) was primarily due to amplification failures of 1 to 3 targets. In many instances, the PSGS genotype could provide resolution of single- and double-locus variants. This molecular serotyping/genotyping scheme is well suited to rapid characterization of large sets of pneumococcal isolates. PMID- 22442314 TI - Population genetic structures of Staphylococcus aureus isolates from cats and dogs in Japan. AB - We determined the population genetic structures of feline and canine Staphylococcus aureus strains in Japan by multilocus sequence typing (MLST). Ecological analyses suggested that multiple feline-related S. aureus clones, including ST133, naturally occur as commensals and can cause endogenous infections in felines. In contrast, S. aureus populations do not likely include any clone that exhibits tropism in domestic dogs. Even if S. aureus infections occur in dogs, the pathologies are likely exogenous infections. PMID- 22442315 TI - Towards improved accuracy of Bordetella pertussis nucleic acid amplification tests. AB - In many clinical microbiology laboratories, nucleic acid amplification tests such as PCR have become the routine methods for the diagnosis of pertussis. While PCR has greatly increased the ability of laboratories to detect Bordetella pertussis infections, it has also been associated with false-positive results that can, given the tendency of B. pertussis to cause outbreaks, result in unnecessary and costly control measures. The species specificity of Bordetella gene targets and their number of copies per genome greatly impact the performance characteristics of nucleic acid amplification tests for B. pertussis. It is crucial that laboratorians recognize these characteristics, to limit false-positive test results and prevent pseudo-outbreaks. PMID- 22442316 TI - Molecular detection of rifabutin-susceptible Mycobacterium tuberculosis. AB - Rapid assays are still needed to detect rifabutin (RFB) susceptibility for proper tuberculosis treatment. To assess the use of the GenoType MTBDRplus assay and subsequent rpoB gene sequencing on detection of RFB susceptibility, we analyzed 800 multidrug-resistant Mycobacterium tuberculosis isolates, and 13% (104/800) were RFB susceptible. Of the 104 RFB-susceptible isolates, 71 (68.3%) isolates were rapidly identified using two molecular assays, while the remaining isolates could be determined using conventional drug-susceptibility testing according to the clinician's decision. PMID- 22442317 TI - Effect of glacial acetic acid treatment of liquid-based cytology collections on performance of Cervista HPV HR for detection of high-risk human papillomavirus. AB - Inadequate cervical cytological analysis can be facilitated by glacial acetic acid (GAA) treatment of primary liquid-based collections to remove mucus, erythrocytes, inflammatory cells, and cellular debris. In the context of a commercial human papillomavirus (HPV) hybridization assay performed on 465 tandem specimens with and without GAA treatment, we show that GAA treatment significantly reduces genomic DNA content (P < 0.0001) and creates an increased potential for indeterminate and false-negative results. In the context of cytological workflow, laboratories should consider providing a specimen aliquot for HPV DNA detection prior to GAA treatment. PMID- 22442318 TI - Automated pangenomic analysis in target selection for PCR detection and identification of bacteria by use of ssGeneFinder Webserver and its application to Salmonella enterica serovar Typhi. AB - With the advent of high-throughput DNA sequencing, more than 4,000 bacterial genomes have been sequenced and are publicly available. We report a user-friendly web platform, ssGeneFinder Webserver (http://147.8.74.24/ssGeneFinder/), which is updated weekly for the automated pangenomic selection of specific targets for direct PCR detection and the identification of clinically important bacteria without the need of gene sequencing. To apply the ssGeneFinder Webserver for identifying specific targets for Salmonella enterica serovar Typhi, we analyzed 11 S. Typhi genomes, generated two specific targets, and validated them using 40 S. Typhi, 110 non-Typhi Salmonella serovars (serovar Paratyphi A, n = 4; Paratyphi B, n = 1; Typhimurium, n = 5; Enteritidis, n = 12; non-Paratyphi group A, n = 6; non-Paratyphi group B, n = 29; non-Paratyphi group C, n = 12; non-Typhi group D, n = 35; group E and others, n = 6), 115 Enterobacteriaceae isolates (Escherichia, n = 78; Shigella, n = 2; Klebsiella, n = 13; Enterobacter, n = 9; others, n = 13), and 66 human stool samples that were culture negative for S. Typhi. Both targets successfully detected all typical and atypical S. Typhi isolates, including an H1-j flagellin gene mutant, an aflagellated mutant which reacted with 2O Salmonella antiserum, and the Vi-negative attenuated vaccine strain Ty21a. No false positive was detected from any of the bacterial isolates and stool samples. DNA sequencing confirmed the identity of all positive amplicons. The PCR assays have detection limits as low as 100 CFU per reaction and were tested using spiked stool samples. Using a pangenomic approach, ssGeneFinder Webserver generated targets specific to S. Typhi. These and other validated targets should be applicable to the identification and direct PCR detection of bacterial pathogens from uncultured, mixed, and environmental samples. PMID- 22442319 TI - Cost savings associated with testing of antibodies, antigens, and nucleic acids for diagnosis of acute HIV infection. AB - Efforts to identify all persons infected with HIV in the United States are driven by the hope that early diagnosis will lower risk behaviors and decrease HIV transmission. Identification of HIV-infected people earlier in the course of their infection with HIV antigen/antibody (Ag/Ab) combination assays (4th generation HIV assays) should help achieve this goal. We compared HIV RNA nucleic acid test (NAT) results to the results of a 4th-generation Ag/Ab assay (Architect HIV Ag/Ab Combo [HIV Combo] assay; Abbott Diagnostics) in 2,744 HIV antibody negative samples. Fourteen people with acute HIV infection (HIV antibody negative/NAT positive) were identified; the HIV Combo assay detected nine of these individuals and was falsely negative in the remaining five. All five persons missed by the HIV Combo assay were in the stage of exponential increase in plasma virus associated with acute HIV infection (3, 7, 20, 35, 48). In contrast, most acutely infected persons detected by the HIV Combo assay demonstrated either a plateauing or decreasing plasma viral load. The HIV Combo assay also classified as positive five other samples which were negative by NAT. Taken together, the HIV Combo assay had a sensitivity of 73.7% and a specificity of 99.8%. Using published data, we estimated secondary transmission events had HIV infection in these five individuals remained undiagnosed. Screening of our population with NAT cost more than screening with the HIV Combo assay but achieved new diagnoses that we predict resulted in health care savings that far exceed screening costs. These findings support the use of more sensitive assays, like NAT, in HIV screening of populations with a high prevalence of acute HIV infection. PMID- 22442320 TI - A multidrug-resistant Staphylococcus epidermidis clone (ST2) is an ongoing cause of hospital-acquired infection in a Western Australian hospital. AB - We report the molecular epidemiology of 27 clinical multidrug-resistant Staphylococcus epidermidis (MDRSE) isolates collected between 2003 and 2007 in an Australian teaching hospital. The dominant genotype (sequence type 2 [ST2]) accounted for 85% of the isolates tested and was indistinguishable from an MDRSE genotype identified in European hospitals, which may indicate that highly adaptable health care-associated genotypes of S. epidermidis have emerged and disseminated worldwide in the health care setting. PMID- 22442321 TI - A new and highly divergent Enterocytozoon bieneusi genotype isolated from a renal transplant recipient. AB - A 49-year-old renal transplant recipient was admitted to our hospital due to abundant liquid diarrhea and dehydration. Parasitological investigations, including genotyping, led to the diagnosis of intestinal microsporidiosis due to a new and highly divergent internal transcribed spacer (ITS) genotype of Enterocytozoon bieneusi. The potential route of transmission through horse stools is discussed. PMID- 22442322 TI - Cepheid Xpert MRSA cycle threshold in discordant colonization results and as a quantitative measure of nasal colonization burden. AB - We analyzed the cycle threshold (C(T)) of PCR surveillance MRSA swabs obtained from veterans. Lower C(T) on admission was associated with a positive culture from nasal swabs at discharge. Compared to PCR, direct plating of nasal swabs performed poorly, especially for patients with an elevated C(T). The C(T) is strongly correlated with quantitative nasal cultures. Clinical and infection control applications of the C(T) have yet to be defined and warrant further evaluation. PMID- 22442323 TI - Detection of dengue virus genome in urine by real-time reverse transcriptase PCR: a laboratory diagnostic method useful after disappearance of the genome in serum. AB - The reemergence of dengue virus (DENV) infection has created a requirement for improved laboratory diagnostic procedures. In this study, DENV genome detection in urine was evaluated as a diagnostic method. The DENV genome was detected by real-time reverse transcriptase PCR (RT-PCR) in urine and serum of dengue patients. The detection rate of DENV genome in urine was 25% (2/8) on disease days 0 to 3 and 32% (7/22) on days 4 to 5. The rate was 50% or higher on days 6 to 16, 52% (11/21) on days 6 to 7, 78% (7/9) on days 8 to 9, 80% (4/5) on days 10 to 11, 50% (2/4) on days 12 to 13, and 60% (3/5) on days 14 to 16. The last positive urine sample was on day 16. The detection rates in serum were highest on days 0 to 3 and were greater than 50% on days 0 to 7. Detection rates decreased thereafter, and the last positive detection was on day 11. These results indicate that the time frames for positive detection differ between urine and serum samples, whereby detection rates of 50% or higher are evident between days 6 to 16 for urine samples and days 0 to 7 for serum samples. Nucleotide sequences of PCR products were identical between urine and serum samples. The detection of DENV genome in urine samples by real-time RT-PCR is useful to confirm DENV infection, particularly after viremia disappears. PMID- 22442324 TI - Detection of amphotericin B resistance in Candida haemulonii and closely related species by use of the Etest, Vitek-2 yeast susceptibility system, and CLSI and EUCAST broth microdilution methods. AB - The emerging fungal pathogens Candida haemulonii and Candida pseudohaemulonii often show high-level resistance to amphotericin B (AMB). We compared the utilities of five antifungal susceptibility testing methods, i.e., the Etest using Mueller-Hinton agar supplemented with glucose and methylene blue (Etest MH), the Etest using RPMI agar supplemented with glucose (Etest-RPG), the Vitek-2 yeast susceptibility system, and the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution methods, for the detection of AMB-resistant isolates of C. haemulonii and closely related species. Thirty-eight clinical isolates (8 C. haemulonii, 10 C. pseudohaemulonii, and 20 Candida auris isolates) were analyzed. Of the 18 C. haemulonii and C. pseudohaemulonii isolates, 18, 15, 18, 10, and 9 exhibited AMB MICs of >1 MUg/ml by the Etest-MH, Etest-RPG, Vitek-2, CLSI, and EUCAST methods, respectively. All 20 C. auris isolates showed AMB MICs of <=1 MUg/ml by all five methods. Of the methods, the Etest-MH generated the broadest distribution of AMB MICs for all 38 isolates and showed the best discrimination between the C. haemulonii and C. pseudohaemulonii isolates (4 to 32 MUg/ml) and those of C. auris (0.125 to 0.5 MUg/ml). Taking the Etest-MH as the reference method, the essential agreements (within two dilutions) for the Etest-RPG, Vitek 2, CLSI, and EUCAST methods were 84, 92, 55, and 55%, respectively; the categorical agreements were 92, 92, 79, and 76%, respectively. This study provides the first data on the efficacy of the Etest-MH and its excellent agreement with Vitek-2 for discriminating AMB-resistant from AMB-susceptible isolates of these Candida species. PMID- 22442325 TI - Extensive genetic diversity within the Dutch clinical Cryptococcus neoformans population. AB - A set of 300 Dutch Cryptococcus neoformans isolates, obtained from 237 patients during 1977 to 2007, was investigated by determining the mating type, serotype, and AFLP and microsatellite genotype and susceptibility to seven antifungal compounds. Almost half of the studied cases were from HIV-infected patients, followed by a patient group of individuals with other underlying diseases and immunocompetent individuals. The majority of the isolates were mating type alpha and serotype A, followed by alphaD isolates and other minor categories. The most frequently observed genotype was AFLP1, distantly followed by AFLP2 and AFLP3. Microsatellite typing revealed a high genetic diversity among serotype A isolates but a lower diversity within the serotype D set of isolates. One patient was infected by multiple AFLP genotypes. Fluconazole and flucytosine had the highest geometric mean MICs of 2.9 and 3.5 MUg/ml, respectively, while amphotericin B (0.24 MUg/ml), itraconazole (0.08 MUg/ml), voriconazole (0.07 MUg/ml), posaconazole (0.06 MUg/ml), and isavuconazole (0.03 MUg/ml) had much lower geometric mean MICs. One isolate had a high flucytosine MIC (>64 MUg/ml), while decreased susceptibility (>=16 MUg/ml) for flucytosine and fluconazole was found in 9 and 10 C. neoformans isolates, respectively. PMID- 22442326 TI - Molecular detection of Capillaria aerophila, an agent of canine and feline pulmonary capillariosis. AB - Capillaria aerophila, a trichuroid nematode causing pulmonary infections in wild and domestic carnivores, is occasionally and potentially poorly recognized in infections of humans due to clinicopathological mimicry and a lack of accurate, robust laboratory diagnostics. The present work evaluated the efficiency of a DNA based assay amplifying a partial cytochrome c oxidase subunit 1 (cox1) gene of C. aerophila in the diagnosis of lung capillariosis. Fecal samples from 34 dogs and 10 cats positive at parasitological examination for C. aerophila and other endoparasites (i.e., other lungworms, whipworms, roundworms, hookworms, tapeworms, and/or coccidia) and from 44 animals negative for C. aerophila but positive for other endoparasites were molecularly examined. Of the 44 samples positive for C. aerophila at copromicroscopy, 43 scored positive (i.e., 33/34 dogs and 10/10 cats) in seminested PCR, resulting in a sensitivity of 97 to 100%. Samples that were copromicroscopy negative for C. aerophila although positive for other endoparasites never produced a PCR product or nonspecific amplicons. The specific PCR amplification of C. aerophila (i.e., specificity of 100%) was confirmed by a nucleotide sequence analysis of the cox1 amplicons. The potential implications of the molecular diagnosis of lung capillariosis are discussed. PMID- 22442327 TI - Comparison of TaqMan PCR assays for detection of the melioidosis agent Burkholderia pseudomallei in clinical specimens. AB - Melioidosis is an emerging infectious disease caused by the soil bacterium Burkholderia pseudomallei. In diagnostic and forensic settings, molecular detection assays need not only high sensitivity with low limits of detection but also high specificity. In a direct comparison of published and newly developed TaqMan PCR assays, we found the TTS1-orf2 assay to be superior in detecting B. pseudomallei directly from clinical specimens. The YLF/BTFC multiplex assay (targeting the Yersinia-like fimbrial/Burkholderia thailandensis-like flagellum and chemotaxis region) also showed high diagnostic sensitivity and provides additional information on possible geographic origin. PMID- 22442328 TI - Detection of human bocaviruses 1 to 4 from nasopharyngeal swab samples collected from patients with respiratory tract infections. AB - Human bocaviruses (HBoV) 1, 2, 3, and 4 (HBoV1-4) were detected in 132 (15.5%), 5 (0.6%), 3 (0.4%), and 5 (0.6%) of 850 nasopharyngeal swab samples collected from children with respiratory tract infections, respectively. Out of the 145 HBoV1-4 positive samples, 62 (42.8%) were codetected with other respiratory viruses. PMID- 22442329 TI - Novel molecular method for identification of Streptococcus pneumoniae applicable to clinical microbiology and 16S rRNA sequence-based microbiome studies. AB - The close phylogenetic relationship of the important pathogen Streptococcus pneumoniae and several species of commensal streptococci, particularly Streptococcus mitis and Streptococcus pseudopneumoniae, and the recently demonstrated sharing of genes and phenotypic traits previously considered specific for S. pneumoniae hamper the exact identification of S. pneumoniae. Based on sequence analysis of 16S rRNA genes of a collection of 634 streptococcal strains, identified by multilocus sequence analysis, we detected a cytosine at position 203 present in all 440 strains of S. pneumoniae but replaced by an adenosine residue in all strains representing other species of mitis group streptococci. The S. pneumoniae-specific sequence signature could be demonstrated by sequence analysis or indirectly by restriction endonuclease digestion of a PCR amplicon covering the site. The S. pneumoniae-specific signature offers an inexpensive means for validation of the identity of clinical isolates and should be used as an integrated marker in the annotation procedure employed in 16S rRNA based molecular studies of complex human microbiotas. This may avoid frequent misidentifications such as those we demonstrate to have occurred in previous reports and in reference sequence databases. PMID- 22442330 TI - When monocyte life hangs by a thread. PMID- 22442331 TI - Good T cells for bad B cells. PMID- 22442332 TI - Platelet size: finding the right balance. PMID- 22442333 TI - EPCR encryption induces cellular APC resistance. PMID- 22442334 TI - A donor's a person, no matter how small. PMID- 22442335 TI - BCR-ABL expression in leukemic progenitors and primitive stem cells of patients with chronic myeloid leukemia. PMID- 22442336 TI - The EUTOS CML score aims to support clinical decision-making. PMID- 22442337 TI - Dietary eicosapentaenoic acid (EPA) to produce antileukemic cyclopentenone prostaglandin J3? PMID- 22442339 TI - Glandulocalyx upatoiensis, a fossil flower of Ericales (Actinidiaceae/Clethraceae) from the Late Cretaceous (Santonian) of Georgia, USA. AB - BACKGROUND AND AIMS: Ericales are a major group of extant asterid angiosperms that are well represented in the Late Cretaceous fossil record, mainly by flowers, fruits and seeds. Exceptionally well preserved fossil flowers, here described as Glandulocalyx upatoiensis gen. & sp. nov., from the Santonian of Georgia, USA, yield new detailed evidence of floral structure in one of these early members of Ericales and provide a secure basis for comparison with extant taxa. METHODS: The floral structure of several fossil specimens was studied by scanning electron microscopy (SEM), light microscopy of microtome thin sections and synchrotron-radiation X-ray tomographic microscopy (SRXTM). For direct comparisons with flowers of extant Ericales, selected floral features of Actinidiaceae and Clethraceae were studied with SEM. KEY RESULTS: Flowers of G. upatoiensis have five sepals with quincuncial aestivation, five free petals with quincuncial aestivation, 20-28 stamens arranged in a single series, extrorse anther orientation in the bud, ventral anther attachment and a tricarpellate, syncarpous ovary with three free styles and numerous small ovules on axile, protruding-diffuse and pendant placentae. The calyx is characterized by a conspicuous indumentum of large, densely arranged, multicellular and possibly glandular trichomes. CONCLUSIONS: Comparison with extant taxa provides clear evidence for a relationship with core Ericales comprised of the extant families Actinidiaceae, Roridulaceae, Sarraceniaceae, Clethraceae, Cyrillaceae and Ericaceae. Within this group, the most marked similarities are with extant Actinidiaceae and, to a lesser degree, with Clethraceae. More detailed analyses of the relationships of Glandulocalyx and other Ericales from the Late Cretaceous will require an improved understanding of the morphological features that diagnose particular extant groups defined on the basis of molecular data. PMID- 22442340 TI - Suppressive effects of PG201, an antiarthritic botanical formulation, on lipopolysaccharide-induced inflammatory mediators in Raw264.7 cells. AB - PG201, an ethanol extract from a mixture of 12 herbs, has strong antiarthritic activity. To understand the molecular mechanisms underlying its anti-inflammatory effects, PG201-mediated suppression of inflammatory mediators was studied in Raw264.7, a mouse macrophage cell line. PG201 decreased the expression of interleukin (IL)-1beta, IL-6 and CC chemokine ligand-2, but not tumor necrosis factor-alpha, at the protein and mRNA levels in lipopolysaccharide-stimulated Raw264.7 cells. Results from a gel retardation assay indicated that PG201 substantially reduced the DNA-binding activity of the activator protein-1 and cyclic adenosine monophosphate-responsive element-binding protein transcription factors, but not nuclear factor-kappaB. Western blot and Northern blot analyses showed that PG201 reduced inducible nitric oxide synthase and cytosolic phospholipase A(2) (cPLA(2)) protein expression, but did not affect mRNA expression, ultimately resulting in decreased nitric oxide and prostaglandin E(2). The protein expression of cPLA(2) was decreased by PG201 in the presence of cycloheximide, an inhibitor of translation, suggesting that PG201 may facilitate the degradation of cPLA(2). Taken together, these results suggest that PG201 selectively affects the expression of proteins that play key roles in the inflammatory response at transcriptional and post-translational levels. PMID- 22442341 TI - Helicobacter pylori CagA induces ornithine decarboxylase upregulation via Src/MEK/ERK/c-Myc pathway: implication for progression of gastric diseases. AB - Helicobacter pylori (H. pylori) dysregulates the expression of various genes resulting in gastric precursor lesions and cancer. Meanwhile, ornithine decarboxylase (ODC) is a key enzyme that catalyzes the formation of polyamines which are critical for cell growth. So far, the possible regulation of ODC by H. pylori and its virulence factors, and the associated mechanism in gastric epithelial cells remains undefined. In the present study, we found that cellular ODC protein was upregulated by wild-type H. pylori infection and ectopic expression of a cytotoxin-associated gene A (CagA). As a negative control, there was no such effect by cagA-mutant H. pylori infection. Results of signal protein inhibitor treatment demonstrated that the Src, MEK (mitogen-activated protein kinase kinase) and ERK (extracellular signal-regulated kinase) pathway was involved. Moreover, when c-Myc was inhibited, the stimulatory effect of CagA on ODC expression was abolished. Clinically, a positive correlation between c-Myc and ODC expression was observed in patient-derived abnormal gastric tissues. These results implied that the Src/MEK/ERK/c-Myc pathway was required for CagA mediated ODC induction. Finally, inhibition of ODC expression led to decreased foci formation of gastric epithelial cells before and after H. pylori infection, and ODC protein was over-expressed in precancerous gastric lesions and primary gastric cancer. Collectively, our findings provide new insights into the mechanism behind H. pylori-infection-associated gastric diseases. PMID- 22442342 TI - Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence. AB - Inflammatory bowel disease (IBD) comprises primarily the chronic relapsing inflammatory disorders, Crohn's disease and ulcerative colitis, with the former affecting any part of the gastrointestinal tract and the latter mainly afflicting the colon. The precise etiology of IBD remains unclear, and it is thought that interactions among various factors, including genetic factors, the host immune system and environmental factors, cause disruption of intestinal homeostasis, leading to dysregulated inflammatory responses of the gut. As inflammation is intimately related to formation of reactive intermediates, including reactive oxygen and nitrogen species (ROS/RNS), oxidative stress has been proposed as a mechanism underlying the pathophysiology of IBD. This review is intended to summarize succinctly recent new experimental and clinical evidence supporting oxidative stress as a pathophysiological component of IBD and point to the potential of using antioxidant compounds as promising therapeutic modalities of human IBD. The sources of ROS/RNS and the redox signaling mechanism underlying oxidative stress and inflammation in IBD are discussed to provide insight into the molecular basis of oxidative stress as a pathophysiological factor in IBD. PMID- 22442343 TI - Mistletoes and mutant albino shoots on woody plants as mineral nutrient traps. AB - BACKGROUND AND AIMS: Potassium, sulphur and zinc contents of mistletoe leaves are generally higher than in their hosts. This is attributed to the fact that chemical elements which are cycled between xylem and phloem in the process of phloem loading of sugars are trapped in the mistletoe, because these parasites do not feed their hosts. Here it is hypothesized that mutant albino shoots on otherwise green plants should behave similarly, because they lack photosynthesis and thus cannot recycle elements involved in sugar loading. METHODS: The mineral nutrition of the mistletoe Scurrula elata was compared with that of albino shoots on Citrus sinensis and Nerium oleander. The potential for selective nutrient uptake by the mistletoe was studied by comparing element contents of host leaves on infected and uninfected branches and by manipulation of the haustorium-shoot ratio in mistletoes. Phloem anatomy of albino leaves was compared with that of green leaves. KEY RESULTS: Both mistletoes and albino leaves had higher contents of potassium, sulphur and zinc than hosts or green leaves, respectively. Hypothetical discrimination of nutrient elements during the uptake by the haustorium is not supported by our data. Anatomical studies of albino leaves showed characteristics of release phloem. CONCLUSIONS: Both albino shoots and mistletoes are traps for elements normally recycled between xylem and phloem, because retranslocation of phloem mobile elements into the mother plant or the host is low or absent. It can be assumed that the lack of photosynthetic activity in albino shoots and thus of sugars needed in phloem loading is responsible for the accumulation of elements. The absence of phloem loading is reflected in phloem anatomy of these abnormal shoots. In mistletoes the evolution of a parasitic lifestyle has obviously eliminated substantial feeding of the host with photosynthates produced by the mistletoe. PMID- 22442344 TI - Interspecific prediction of photosynthetic light response curves using specific leaf mass and leaf nitrogen content: effects of differences in soil fertility and growth irradiance. AB - BACKGROUND AND AIMS: Previous work has shown that the entire photosynthetic light response curve, based on both Mitscherlich and Michaelis-Menten functions, could be predicted in an interspecific context through allometric relations linking the parameters of these functions to two static leaf traits: leaf nitrogen (N) content and leaf mass per area (LMA). This paper describes to what extent these allometric relations are robust to changes in soil fertility and the growth irradiance of the plants. METHODS: Plants of 25 herbaceous species were grown under controlled conditions in factorial combinations of low/high soil fertility and low/high growth irradiance. Net photosynthetic rates per unit dry mass were measured at light intensities ranging from 0 to 700 umol m(-2) s(-1) photosynthetically active radiation (PAR). KEY RESULTS: The differing growth environments induced large changes in N, LMA and in each of the parameter estimates of the Mitscherlich and Michaelis-Menten functions. However, the differing growth environments induced only small (although significant) changes in the allometric relationships linking N and LMA to the parameters of the two functions. As a result, 88 % (Mitcherlich) and 89 % (Michaelis-Menten) of the observed net photosynthetic rates over the full range of light intensities (0-700 umol m(-2) s(-1) PAR) and across all four growth environments could be predicted using only N and LMA using the same allometric relations. CONCLUSIONS: These results suggest the possibility of predicting net photosynthetic rates in nature across species over the full range of light intensities using readily available data. PMID- 22442345 TI - DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues. AB - Mouse CD8alpha(+) dendritic cells (DCs) in lymphoid organs and CD103(+) CD11b(-) DCs in nonlymphoid tissues share phenotypic and functional similarities, as well as a unique shared developmental dependence on the transcription factor Batf3. Human DCs resembling mouse CD8alpha(+) DCs in phenotype and function have been identified in human blood, spleen, and tonsil. However, it is not clear whether such cells are also present in human nonlymphoid organs, and their equivalence to mouse CD8alpha(+) DC has recently been questioned. Furthermore, the identification of "CD8alpha(+) DC-like" cells across different tissues and species remains problematic because of the lack of a unique marker that can be used to unambiguously define lineage members. Here we show that mouse CD8alpha(+) DCs and CD103(+) CD11b(-) DCs can be defined by shared high expression of DNGR-1 (CLEC9A). We further show that DNGR-1 uniquely marks a CD11b(-) human DC population present in both lymphoid and nonlymphoid tissues of humans and humanized mice. Finally, we demonstrate that knockdown of Batf3 selectively prevents the development of DNGR-1(+) human DCs in vitro. Thus, high expression of DNGR-1 specifically and universally identifies a unique DC subset in mouse and humans. Evolutionarily conserved Batf3 dependence justifies classification of DNGR-1(hi) DCs as a distinct DC lineage. PMID- 22442346 TI - Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. AB - Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991. PMID- 22442347 TI - IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. AB - Modulation of regulatory T cell (Treg) suppression has important implications for vaccine development, the effectiveness of tumor surveillance, and the emergence of autoimmunity. We have previously shown that the cytokine IL-21 can counteract Treg suppression. However, whether this reflects an effect of IL-21 on Treg, conventional T cells, or antigen-presenting cells is not known. Here we have used lymphocyte populations from IL-21R-deficient mice to pinpoint which cell type needs to be targeted by IL-21 for Treg suppression to be overcome. We show that IL-21 counteracts suppression by acting on conventional T cells and that this is associated with inhibition of IL-2 production. Despite the lack of IL-2, conventional T-cell responses proceed unimpaired because IL-21 can substitute for IL-2 as a T cell growth factor. However, IL-21 is unable to substitute for IL-2 in supporting the Treg compartment. Thus, IL-21 signaling in conventional T cells indirectly impacts Treg homeostasis by decreasing IL-2 availability. These data demonstrate that IL-21 and IL-2 can have overlapping roles in promoting conventional T-cell responses but play distinct roles in controlling Treg homeostasis and function. The data also suggest a new paradigm whereby cytokines can promote immunity by inhibiting IL-2. PMID- 22442348 TI - Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis. AB - Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-alpha levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks. PMID- 22442349 TI - Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity. AB - In 2008, the World Health Organization introduced CEBPA (encoding the CCAAT/enhancer binding protein)-mutated acute myeloid leukemia (AML) as a provisional entity. However, the classification of CEBPA-mutated AML with multilineage dysplasia (MLD; >= 50% dysplastic cells in 2-3 lineages) remains to be clarified. In the present study, we investigated 108 CEBPA-mutated AML patients for the impact of MLD, karyotype, and additional mutations. MLD(+) patients differed from MLD(-) patients only by lower mean WBC counts, not by biologic characteristics, cytogenetic risk profiles, or additional mutations. Survival was better for female patients, patients < 60 years of age, for intermediate versus adverse karyotypes, and, in the case of FLT3-ITD negativity, biallelic versus monoallelic/homozygous CEBPA mutations. In contrast, 2-year overall survival and event-free survival did not differ significantly between MLD(+) and MLD(-) patients. By univariable Cox regression analysis, sex, age, WBC count, and cytogenetic risk category were related to overall survival, but MLD was not. Therefore, because dysplasia is not relevant for this subtype, CEBPA mutated AML patients should be characterized only according to mutation status, cytogenetic risk group, or additional mutations. PMID- 22442350 TI - Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. AB - To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy. Two hundred sixty patients having received an autologous-SCT fulfilled the criteria to be included, 138 patients without an HLA-identical sibling donor and 122 patients with a donor. After a median follow-up of 77 months, complete remission, progression-free survival (PFS), and overall survival were not significantly different between the 2 groups. PFS at 6 years was 28% for patients with a donor versus 22% for patients without a donor (P = .19) and overall survival at 6 years from high-dose melphalan was 55%, irrespective of having a donor (P = .68). Cumulative incidence of nonrelapse mortality at 6 years after autologous-SCT was 16% in the donor group versus 3% in the no-donor group (P < .001). However, PFS was significantly prolonged in the 99 patients who actually proceeded to allo-SCT compared with the 115 patients who continued maintenance or received a second high-dose melphalan, but the difference did not translate into a prolonged survival benefit. These results do not support a general application of allo-SCT in all myeloma patients as part of first-line therapy. PMID- 22442352 TI - How the FDA forgot the evidence: the case of donepezil 23 mg. PMID- 22442351 TI - A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer. AB - Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcgammaR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer. PMID- 22442353 TI - A returning traveller with fever, facial swelling, and skin lesions. PMID- 22442354 TI - Health literacy. PMID- 22442355 TI - Cancer patients should have access to device to treat fluid retention at home, says NICE. PMID- 22442356 TI - NICE backs leukaemia drug after manufacturer drops price. PMID- 22442357 TI - Neopterin, inflammation-associated product, prolongs erythropoiesis suppression in aged SAMP1 mice due to senescent stromal-cell impairment. AB - Anemia induced by inflammation is well known to be more serious in the elderly than in non-elderly adults; however, the reason why this is so remains unclear. Neopterin produced by monocytes during inflammation promotes myelopoiesis but suppresses B-lymphopoiesis and erythropoiesis, by activating stromal cells in mice. Here, age-related changes in the erythropoietic response to neopterin were determined using senescence accelerated mice (SAMP1) with senescence stromal-cell impairment. Intravenous injection of neopterin into young mice (8-12 weeks old) resulted in a decrease in erythroid progenitor cell number in the bone marrow (BM), concomitant with an increase in myeloid progenitor cell number over one week. Intravenous injection of neopterin into aged mice (30-36 weeks old) resulted in a prolonged decrease in erythroid progenitor cell number in the BM over three weeks and a limited increase in myeloid progenitor cell number over one day. Neopterin treatment induced a decrease in serum erythropoietin concentrations in young mice but not in aged mice. The gene expression of tumor necrosis factor alpha (TNF-alpha), a negative regulator of erythropoiesis, was up regulated in the BM of both young and aged mice, and the degree of TNF-alpha up regulation was the same in both groups. The gene expression of interleukin (IL) 11, a positive regulator of erythropoiesis, was also up-regulated over one day in both young and aged mice. However, IL-11 gene expression remained up-regulated thereafter in young mice, whereas it was rapidly down-regulated in aged mice. These data suggest that prolonged suppression of erythropoiesis in aged mice may be due to a decrease in the production of positive regulators rather than to an increase in the production of negative regulators. Our combined data suggest that age-related impairment of stromal cells induces serious anemia in the elderly during inflammation. PMID- 22442358 TI - Effect of catch-up growth by various dietary patterns and resveratrol intervention on bone status. AB - Catch-up growth (CUG) after food restriction can increase the risks for insulin resistance-related diseases, and to our knowledge, no previous studies have addressed how bone is influenced by CUG when refeeding diet content differs. The objective of this study was to investigate the bone status resulting from CUG induced by varying refeeding dietary patterns, and to assess the potential influencing factors and the effect of resveratrol on bone status during CUG. Experimental rats were randomly divided into five groups: normal chow (NC) group; CUG group (CUG, containing two subgroups, respectively, refeeding with normal chow or high-fat diet); high-fat diet (HF) group; and resveratrol intervention groups (CUGE and HFE). Bone parameters were detected by dual-energy X-ray absorptiometry. Serum concentrations of tumor necrosis factor (TNF)-alpha, body weight and food intake were also recorded. Our results showed that food restriction induced a significant decrease in bone parameters. Eight-week CUG by normal chow had a greater degree of improvement in bone mineral density than high fat diet, and even returned to normal level similar to NC. Bone parameters were elevated in varying degrees in the HF group compared with the NC group. In the resveratrol intervention groups, bone parameters significantly increased. Furthermore, bone parameters were inversely related with serum TNF-alpha concentrations, but showed positive correlation with body weight. In conclusion, the study shows that CUG can partially reverse the deleterious effects of caloric restriction on bone health, especially in the refeeding with normal chow group. Moreover, resveratrol has a protective effect on bone status during the period of CUG. Serum TNF-alpha levels and body weight also seem to play an important role in regulating bone parameters. PMID- 22442359 TI - Mechanism of copper transport at the blood-cerebrospinal fluid barrier: influence of iron deficiency in an in vitro model. AB - Copper (Cu) is an essential trace element that requires tight homeostatic regulation to ensure appropriate supply while not causing cytotoxicity due to its strong redox potential. Our previous in vivo study has shown that iron deficiency (FeD) increases Cu levels in brain tissues, particularly in the choroid plexus, where the blood-cerebrospinal fluid (CSF) barrier resides. This study was designed to elucidate the mechanism by which FeD results in excess Cu accumulation at the blood-CSF barrier. The effect of FeD on cellular Cu retention and transporters Cu transporter-1 (Ctr1), divalent metal transporter 1 (DMT1), antioxidant protein-1 (ATOX1) and ATP7A was examined in choroidal epithelial Z310 cells. The results revealed that deferoximine treatment (FeD) resulted in 70% increase in cellular Cu retention (P < 0.05). A significant increase in the mRNA levels of DMT1, but not Ctr1, was also observed after FeD treatment, suggesting a critical role of DMT1 in cellular Cu regulation during FeD. Knocking down Ctr1 or DMT1 resulted in significantly lower Cu uptake by Z310 cells, whereas the knocking down of ATOX1 or ATP7A led to substantial increases of cellular retention of Cu. Taken together, these results suggest that Ctr1, DMT1, ATOX1 and ATP7A contribute to Cu transport at the blood-CSF barrier, and that the accumulation of intracellular Cu found in the Z310 cells during FeD appears to be mediated, at least in part, via the upregulation of DMT1 after FeD treatment. PMID- 22442360 TI - Clinical results after coil embolization of the ovarian vein in patients with primary and recurrent lower-limb varices with respect to vulval varices. AB - OBJECTIVE: To study the effect of coil embolization of the insufficient ovarian vein (IOV) on varices of the lower limb (VLL). METHOD: From December 2005 until May 2008, we selected all patients with phlebograms that were performed in our hospital to confirm the diagnosis of insufficiency of the ovarian vein. The CEAP (clinical, aetiological, anatomical and pathological elements) classification was used to classify the lower-limb venous disease in each patient. All patients with suspected IOV in combination with VLL underwent a phlebography. If IOV was found, coil embolization of the ovarian vein(s) was performed. RESULTS: IOV was found in 43 of 44 patients (98%). After coil embolization of the ovarian vein(s), VLL disappeared in five patients (12%) without any further treatment. Improvement in CEAP classification was measured in 13 patients (31%). In 21 (88%) of 24 patients with vulval varices, coil embolization of the ovarian vein(s) resulted in disappearance of vulval varices. CONCLUSIONS: In only 31% of the patients with IOV in combination with VLL, phlebography and coil embolization of the ovarian vein(s) did improve CEAP classification. However, coil embolization of the ovarian vein resulted in disappearance of the vulval varices in 88% of the patients. PMID- 22442361 TI - The diversity of hydrostatic skeletons. AB - A remarkably diverse group of organisms rely on a hydrostatic skeleton for support, movement, muscular antagonism and the amplification of the force and displacement of muscle contraction. In hydrostatic skeletons, force is transmitted not through rigid skeletal elements but instead by internal pressure. Functioning of these systems depends on the fact that they are essentially constant in volume as they consist of relatively incompressible fluids and tissue. Contraction of muscle and the resulting decrease in one of the dimensions thus results in an increase in another dimension. By actively (with muscle) or passively (with connective tissue) controlling the various dimensions, a wide array of deformations, movements and changes in stiffness can be created. An amazing range of animals and animal structures rely on this form of skeletal support, including anemones and other polyps, the extremely diverse wormlike invertebrates, the tube feet of echinoderms, mammalian and turtle penises, the feet of burrowing bivalves and snails, and the legs of spiders. In addition, there are structures such as the arms and tentacles of cephalopods, the tongue of mammals and the trunk of the elephant that also rely on hydrostatic skeletal support but lack the fluid-filled cavities that characterize this skeletal type. Although we normally consider arthropods to rely on a rigid exoskeleton, a hydrostatic skeleton provides skeletal support immediately following molting and also during the larval stage for many insects. Thus, the majority of animals on earth rely on hydrostatic skeletons. PMID- 22442362 TI - Digesting blood of an auxiliary host in fleas: effect of phylogenetic distance from a principal host. AB - Fleas are haematophagous ectoparasites that exhibit varying degrees of host specificity. Flea abundance is highest on principal hosts and lower on auxiliary hosts but may vary greatly among auxiliary hosts. We investigated the feeding and energy expenditure for digestion in two flea species Parapulex chephrenis and Xenopsylla ramesis on a principal host (Acomys cahirinus and Meriones crassus, respectively) and eight auxiliary host species. We predicted that fleas would perform better - that is (i) a higher proportion of fleas would take a blood meal, (ii) fleas would take larger blood meals and (iii) fleas would spend less energy on digestion - if they fed on (i) a principal host compared with an auxiliary host and (ii) an auxiliary host phylogenetically close to a principal host compared with an auxiliary host phylogenetically distant from a principal host. Energy costs of digestion were estimated using CO(2) emission and represented energy cost during the first stage of blood digestion. Contrary to our predictions, fleas did not always perform better on a principal than on an auxiliary host or on auxiliary hosts phylogenetically closer to the principal host than on auxiliary hosts phylogenetically distant from a principal host. Variation in flea feeding performance may result from the interplay of several factors including co-occurrence between hosts and susceptibility of a host to flea attacks, the species-specific level of immunocompetence of a host and the level of host specificity of a flea. This study describes the first investigation into the metabolic expenditure of parasitism and its relationship to phylogenetic relationships amongst hosts. PMID- 22442363 TI - Evaporation dynamics of tarsal liquid footprints in flies (Calliphora vicina)and beetles (Coccinella septempunctata). AB - Insect tarsal adhesive structures secrete a thin layer of fluid into the contact area. It was previously reported that the presence of this fluid significantly increases adhesion on various substrata. Previous data obtained from representatives of different insect groups suggest a difference not only in the chemical composition of the fluid, but also in its physical properties. In the present study, we have measured for the first time changes in the droplet geometry over time and the evaporation rate of the fluid in flies (Calliphora vicina) and beetles (Coccinella septempunctata) by the use of atomic force microscopy. Flattened droplets of the beetle had lower evaporation rates than hemispherical footprints of the fly. Within 1 h, the droplet volume reduced to 21% of the initial volume for the fly, and to 65% for the beetle, suggesting a larger fraction of volatile compounds in the fly fluid. It was revealed that drop geometry changes significantly during evaporation and shows pinning effects for the fly footprints due to an assumed self-organizing oil layer on top of the water fraction of the micro-emulsion. The data obtained suggest that the adhesion strength in capillarity-based switchable adhesive systems must be time-dependent because of the specific evaporation rate of the adhesive fluid. These results are important for our understanding of the functional mechanism of insect adhesive systems and also for biomimetics of artificial capillarity-based adhesive systems. PMID- 22442364 TI - Relative contributions of pigments and biophotonic nanostructures to natural color production: a case study in budgerigar (Melopsittacus undulatus) feathers. AB - Understanding the mechanistic bases of natural color diversity can provide insight into its evolution and inspiration for biomimetic optical structures. Metazoans can be colored by absorption of light from pigments or by scattering of light from biophotonic nanostructures, and these mechanisms have largely been treated as distinct. However, the interactions between them have rarely been examined. Captive breeding of budgerigars (Aves, Psittacidae, Melopsittacus undulatus) has produced a wide variety of color morphs spanning the majority of the spectrum visible to birds, including the ultraviolet, and thus they have been used as examples of hypothesized structure-pigment interactions. However, empirical data testing these interactions in this excellent model system are lacking. Here we used ultraviolet-visible spectrometry, light and electron microscopy, pigment extraction experiments and optical modeling to examine the physical bases of color production in seven budgerigar morphs, including grey and chromatic (purple to yellow) colors. Feathers from all morphs contained quasi ordered air-keratin 'spongy layer' matrices, but these were highly reduced and irregular in grey and yellow feathers. Similarly, all feathers but yellow and grey had a layer of melanin-containing melanosomes basal to the spongy layer. The presence of melanosomes likely increases color saturation produced by spongy layers whereas their absence may allow increased expression of yellow colors. Finally, extraction of yellow pigments caused some degree of color change in all feathers except purple and grey, suggesting that their presence and contribution to color production is more widespread than previously thought. These data illustrate how interactions between structures and pigments can increase the range of colors attainable in birds and potentially in synthetic systems. PMID- 22442365 TI - Blue-light-receptive cryptochrome is expressed in a sponge eye lacking neurons and opsin. AB - Many larval sponges possess pigment ring eyes that apparently mediate phototactic swimming. Yet sponges are not known to possess nervous systems or opsin genes, so the unknown molecular components of sponge phototaxis must differ fundamentally from those in other animals, inspiring questions about how this sensory system functions. Here we present molecular and biochemical data on cryptochrome, a candidate gene for functional involvement in sponge pigment ring eyes. We report that Amphimedon queenslandica, a demosponge, possesses two cryptochrome/photolyase genes, Aq-Cry1 and Aq-Cry2. The mRNA of one gene (Aq Cry2) is expressed in situ at the pigment ring eye. Additionally, we report that Aq-Cry2 lacks photolyase activity and contains a flavin-based co-factor that is responsive to wavelengths of light that also mediate larval photic behavior. These results suggest that Aq-Cry2 may act in the aneural, opsin-less phototaxic behavior of a sponge. PMID- 22442366 TI - Do ants need to be old and experienced to teach? AB - Learning is widespread in invertebrates. However, whether social insects improve their recruitment skills with experience is only beginning to be investigated. Tandem running is a one-to-one form of recruitment used by certain species of ant. It is a remarkable communication system that meets widely accepted criteria for teaching in non-human animals. Here, we determined experimentally to what extent participation in, and efficient execution of, tandem running depends on either the age or the experience of worker ants. To investigate these issues, we constructed colonies of the ant Temnothorax albipennis with different compositions of inexperienced and experienced workers from different age cohorts and then examined which ants participated in tandem runs when they emigrated. Our results show that the ability to participate actively in recruitment by tandem running is present in all worker age groups but the propensity to participate varies with experience rather than age per se. Experienced individuals were more likely to engage in tandem runs, either as leaders or as followers, than young inexperienced individuals, and older experienced ants were more likely to lead tandems than older inexperienced ants. Young inexperienced ants led faster, more rapidly dispersing and less accurately orientated tandem runs than the older experienced ants. Our study suggests that experience (rather than age per se) coupled to stimulus threshold responses might interact to promote a division of labour so that a suitable number of workers actively participate in tandem runs. PMID- 22442367 TI - Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill. AB - The killifish Fundulus heteroclitus is abundant in osmotically dynamic estuaries and it can quickly adjust to extremes in environmental salinity. We performed a comparative osmotic challenge experiment to track the transcriptomic and physiological responses to two salinities throughout a time course of acclimation, and to explore the genome regulatory mechanisms that enable extreme osmotic acclimation. One southern and one northern coastal population, known to differ in their tolerance to hypo-osmotic exposure, were used as our comparative model. Both populations could maintain osmotic homeostasis when transferred from 32 to 0.4 p.p.t., but diverged in their compensatory abilities when challenged down to 0.1 p.p.t., in parallel with divergent transformation of gill morphology. Genes involved in cell volume regulation, nucleosome maintenance, ion transport, energetics, mitochondrion function, transcriptional regulation and apoptosis showed population- and salinity-dependent patterns of expression during acclimation. Network analysis confirmed the role of cytokine and kinase signaling pathways in coordinating the genome regulatory response to osmotic challenge, and also posited the importance of signaling coordinated through the transcription factor HNF-4alpha. These genome responses support hypotheses of which regulatory mechanisms are particularly relevant for enabling extreme physiological flexibility. PMID- 22442368 TI - Active echolocation beam focusing in the false killer whale, Pseudorca crassidens. AB - The odontocete sound production system is highly complex and produces intense, directional signals that are thought to be focused by the melon and the air sacs. Because odontocete echolocation signals are variable and the emitted click frequency greatly affects the echolocation beam shape, investigations of beam focusing must account for frequency-related beam changes. In this study we tested whether the echolocation beam of a false killer whale changed depending on target difficulty and distance while also accounting for frequency-related changes in the echolocation beam. The data indicate that the false killer whale changes its beam size according to target distance and difficulty, which may be a strategy of maximizing the energy of the target echo. We propose that the animal is using a strategy of changing the focal region according to target distance and that this strategy is under active control. PMID- 22442369 TI - Honey bee drones maintain humoral immune competence throughout all life stages in the absence of vitellogenin production. AB - Drones are haploid male individuals whose major social function in honey bee colonies is to produce sperm and mate with a queen. In spite of their limited tasks, the vitality of drones is of utmost importance for the next generation. The immune competence of drones - as compared to worker bees - is largely unexplored. Hence, we studied humoral and cellular immune reactions of in vitro reared drone larvae and adult drones of different age upon artificial bacterial infection. Haemolymph samples were collected after aseptic and septic injury and subsequently employed for (1) the identification of immune-responsive peptides and/or proteins by qualitative proteomic analyses in combination with mass spectrometry and (2) the detection of antimicrobial activity by inhibition-zone assays. Drone larvae and adult drones responded with a strong humoral immune reaction upon bacterial challenge, as validated by the expression of small antimicrobial peptides. Young adult drones exhibited a broader spectrum of defence reactions than drone larvae. Distinct polypeptides including peptidoglycan recognition protein-S2 and lysozyme 2 were upregulated in immunized adult drones. Moreover, a pronounced nodulation reaction was observed in young drones upon bacterial challenge. Prophenoloxidase zymogen is present at an almost constant level in non-infected adult drones throughout the entire lifespan. All observed immune reactions in drones were expressed in the absence of significant amounts of vitellogenin. We conclude that drones - like worker bees - have the potential to activate multiple elements of the innate immune response. PMID- 22442370 TI - The contribution of air breathing to aerobic scope and exercise performance in the banded knifefish Gymnotus carapo L. AB - The contribution of air breathing to aerobic metabolic scope and exercise performance was investigated in a teleost with bimodal respiration, the banded knifefish, submitted to a critical swimming speed (U(crit)) protocol at 30 degrees C. Seven individuals (mean +/- s.e.m. mass 89+/-7 g, total length 230+/-4 mm) achieved a U(crit) of 2.1+/-1 body lengths (BL) s(-1) and an active metabolic rate (AMR) of 350+/-21 mg kg(-1) h(-1), with 38+/-6% derived from air breathing. All of the knifefish exhibited a significant increase in air-breathing frequency (f(AB)) with swimming speed. If denied access to air in normoxia, these individuals achieved a U(crit) of 2.0+/-0.2 BL s(-1) and an AMR of 368+/-24 mg kg(-1) h(-1) by gill ventilation alone. In normoxia, therefore, the contribution of air breathing to scope and exercise was entirely facultative. In aquatic hypoxia (P(O(2))=4 kPa) with access to normoxic air, the knifefish achieved a U(crit) of 2.0+/-0.1 BL s(-1) and an AMR of 338+/-29 mg kg(-1) h(-1), similar to aquatic normoxia, but with 55+/-5% of AMR derived from air breathing. Indeed, f(AB) was higher than in normoxia at all swimming speeds, with a profound exponential increase during exercise. If the knifefish were denied access to air in hypoxia, U(crit) declined to 1.2+/-0.1 BL s(-1) and AMR declined to 199+/-29 mg kg(-1) h(-1). Therefore, air breathing allowed the knifefish to avoid limitations to aerobic scope and exercise performance in aquatic hypoxia. PMID- 22442371 TI - Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'. AB - Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual high intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity walking in these taxa, and eCB signaling does not significantly increase in the non cursorial ferrets following exercise at any intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and why non-cursorial mammals avoid such locomotor behaviors. PMID- 22442372 TI - Intracellular pH regulation in unstimulated Calliphora salivary glands is Na+ dependent and requires V-ATPase activity. AB - Salivary gland cells of the blowfly Calliphora vicina have a vacuolar-type H(+) ATPase (V-ATPase) that lies in their apical membrane and energizes the secretion of a KCl-rich primary saliva upon stimulation with serotonin (5 hydroxytryptamine). Whether and to what extent V-ATPase contributes to intracellular pH (pH(i)) regulation in unstimulated gland cells is unknown. We used the fluorescent dye BCECF to study intracellular pH(i) regulation microfluorometrically and show that: (1) under resting conditions, the application of Na(+)-free physiological saline induces an intracellular alkalinization attributable to the inhibition of the activity of a Na(+) dependent glutamate transporter; (2) the maintenance of resting pH(i) is Na(+), Cl(-), concanamycin A and DIDS sensitive; (3) recovery from an intracellular acid load is Na(+) sensitive and requires V-ATPase activity; (4) the Na(+)/H(+) antiporter is not involved in pH(i) recovery after a NH(4)Cl prepulse; and (5) at least one Na(+)-dependent transporter and the V-ATPase maintain recovery from an intracellular acid load. Thus, under resting conditions, the V-ATPase and at least one Na(+)-dependent transporter maintain normal pH(i) values of pH 7.5. We have also detected the presence of a Na(+)-dependent glutamate transporter, which seems to act as an acid loader. Despite this not being a common pH(i)-regulating transporter, its activity affects steady-state pH(i) in C. vicina salivary gland cells. PMID- 22442373 TI - Maternal influences on early development: preferred temperature prior to oviposition hastens embryogenesis and enhances offspring traits in the Children's python, Antaresia childreni. AB - Embryonic life is particularly sensitive to its surroundings, and the developmental environment can have long-lasting effects on offspring. In oviparous species, the impacts of the developmental environment on offspring traits are mostly examined during development within the egg. However, as more than 25% of the development of squamate reptiles can occur prior to oviposition, we explored the effect of thermal conditions on development prior to oviposition in an oviparous snake species, the Children's python (Antaresia childreni). We housed gravid female pythons under three thermal cycles: an optimal regime that reflected maternal preference in a non-constrained environment (constant preferred body temperature of gravid females, T(set)=31.5 degrees C) and two mildly suboptimal regimes that shared the same mean temperature of 27.7 degrees C, but differed in the duration at T(set). In one of the constraining regimes, females had access to T(set) for 4 h daily whereas in the other regime, females never reached T(set) (maximal temperature of 29.0 degrees C). Thermal treatments were maintained throughout gravidity in all three groups, but, after oviposition, all eggs were incubated at T(set) until hatching. Compared with the optimal regime, the two suboptimal regimes had a longer duration of gravidity, which resulted in delayed hatching. Between the two suboptimal regimes, gravidity was significantly shorter in the treatment that included time at T(set). Furthermore, suboptimal regimes influenced offspring traits at hatching, including body morphology, antipredator behavior, strength and metabolism. However, partial access to maternal T(set) significantly enhanced several offspring traits, including performance. Our results demonstrate the importance of time at T(set) on early development and suggest an adaptive significance of maternal thermoregulation prior to oviposition. PMID- 22442374 TI - Exceptional cardiac anoxia tolerance in tilapia (Oreochromis hybrid). AB - Anoxic survival requires the matching of cardiac ATP supply (i.e. maximum glycolytic potential, MGP) and demand (i.e. cardiac power output, PO). We examined the idea that the previously observed in vivo downregulation of cardiac function during exposure to severe hypoxia in tilapia (Oreochromis hybrid) represents a physiological strategy to reduce routine PO to within the heart's MGP. The MGP of the ectothermic vertebrate heart has previously been suggested to be ~70 nmol ATP s(-1) g(-1), sustaining a PO of ~0.7 mW g(-1) at 15 degrees C. We developed an in situ perfused heart preparation for tilapia (Oreochromis hybrid) and characterized the routine and maximum cardiac performance under both normoxic (>20 kPa O(2)) and severely hypoxic perfusion conditions (<0.20 kPa O(2)) at pH 7.75 and 22 degrees C. The additive effects of acidosis (pH 7.25) and chemical anoxia (1 mmol l(-1) NaCN) on cardiac performance in severe hypoxia were also examined. Under normoxic conditions, cardiac performance and myocardial oxygen consumption rate were comparable to those of other teleosts. The tilapia heart maintained a routine normoxic cardiac output (Q) and PO under all hypoxic conditions, a result that contrasts with the hypoxic cardiac downregulation previously observed in vivo under less severe conditions. Thus, we conclude that the in vivo downregulation of routine cardiac performance in hypoxia is not needed in tilapia to balance cardiac energy supply and demand. Indeed, the MGP of the tilapia heart proved to be quite exceptional. Measurements of myocardial lactate efflux during severe hypoxia were used to calculate the MGP of the tilapia heart. The MGP was estimated to be 172 nmol ATP s(-1) g(-1) at 22 degrees C, and allowed the heart to generate a PO(max) of at least ~3.1 mW g(-1), which is only 30% lower than the PO(max) observed with normoxia. Even with this MGP, the additional challenge of acidosis during severe hypoxia decreased maximum ATP turnover rate and PO(max) by 30% compared with severe hypoxia alone, suggesting that there are probably direct effects of acidosis on cardiac contractility. We conclude that the high maximum glycolytic ATP turnover rate and levels of PO, which exceed those measured in other ectothermic vertebrate hearts, probably convey a previously unreported anoxia tolerance of the tilapia heart, but a tolerance that may be tempered in vivo by the accumulation of acidotic waste during anoxia. PMID- 22442375 TI - Metabolism and energy supply below the critical thermal minimum of a chill susceptible insect. AB - When exposed to temperatures below their critical thermal minimum (CT(min)), insects enter chill-coma and accumulate chilling injuries. While the critical thermal limits of water-breathing marine animals may be caused by oxygen- and capacity-limitation of thermal tolerance (OCLT), the mechanisms are poorly understood in air-breathing terrestrial insects. We used thermolimit respirometry to characterize entry into chill-coma in a laboratory population of fall field crickets (Gryllus pennsylvanicus). To detect potential oxygen limitation, we quantified muscle ATP, lactate and alanine concentrations in crickets following prolonged exposure to 0 degrees C (a temperature that causes chill-coma, chilling injury and eventual death). Although there was a sharp (44%) drop in the rate of CO(2) emission at the CT(min) and spiracular control was lost, there was a low, continuous rate of CO(2) release throughout chill-coma, indicating that the spiracles were open and gas exchange could occur through the tracheal system. Prolonged exposure to 0 degrees C caused muscle ATP levels to increase marginally (rather than decrease as OCLT would predict), and there was no change in muscle lactate or alanine concentration. Thus, it appears that insects are not susceptible to OCLT at low temperatures but that the CT(min) may instead be set by temperature effects on whole-animal ion homeostasis. PMID- 22442376 TI - Adiponectin effects and gene expression in rainbow trout: an in vivo and in vitro approach. AB - Here we present the presence of adiponectin and adiponectin receptors [type 1 (adipoR1) and type 2 (adipoR2)] in rainbow trout (Oncorhynchus mykiss) tissues and cell cultures together with the response to different scenarios. In response to fasting, adiponectin expression was up-regulated in adipose tissue, while the expression of its receptors increased in white and red muscle. Insulin injection decreased adipoR1 expression in white and red muscles. We deduce that the adipoRs in trout muscle show opposite responses to increasing insulin plasma levels, which may maintain sensitivity to insulin in this tissue. Adiponectin expression was inhibited by the inflammatory effect of lipopolysaccharide (LPS) in adipose tissue and red muscle. Moreover, results indicate that LPS may lead to mobilization of fat reserves, increasing adipoR1 expression in adipose tissue. The effects of LPS could be mediated through tumour necrosis factor alpha (TNFalpha), at least in red muscle. Insulin, growth hormone and TNFalpha all diminished expression of adipoR2 in adipocytes and adipoR1 in myotubes, while insulin increased the expression of adipoR2 in the muscle cells. Adiponectin activates Akt in rainbow trout myotubes, which may lead to an increase in fatty acid uptake and oxidation. Overall, our results show that the adiponectin system responds differently to various physiological challenges and that it is hormonally controlled in vivo and in vitro. To the best of our knowledge, this is the first time this has been demonstrated in teleosts, and it may be a valuable contribution to our understanding of adipokines in fish. PMID- 22442377 TI - Autotrophic carbon budget in coral tissue: a new 13C-based model of photosynthate translocation. AB - Corals live in symbiosis with dinoflagellates of the genus Symbiodinum. These dinoflagellates translocate a large part of the photosynthetically fixed carbon to the host, which in turn uses it for its own needs. Assessing the carbon budget in coral tissue is a central question in reef studies that still vexes ecophysiologists. The amount of carbon fixed by the symbiotic association can be determined by measuring the rate of photosynthesis, but the amount of carbon translocated by the symbionts to the host and the fate of this carbon are more difficult to assess. In the present study, we propose a novel approach to calculate the budget of autotrophic carbon in the tissue of scleractinian corals, based on a new model and measurements made with the stable isotope (13)C. Colonies of the scleractinian coral Stylophora pistillata were incubated in H(13)CO (-)(3)-enriched seawater, after which the fate of (13)C was followed in the symbionts, the coral tissue and the released particulate organic carbon (i.e. mucus). Results obtained showed that after 15 min, ca. 60% of the carbon fixed was already translocated to the host, and after 48 h, this value reached 78%. However, ca. 48% of the photosynthetically fixed carbon was respired by the symbiotic association, and 28% was released as dissolved organic carbon. This is different from other coral species, where <1% of the total organic carbon released is from newly fixed carbon. Only 23% of the initially fixed carbon was retained in the symbionts and coral tissue after 48 h. Results show that our (13)C-based model could successfully trace the carbon flow from the symbionts to the host, and the photosynthetically acquired carbon lost from the symbiotic association. PMID- 22442378 TI - The effects of muscimol and AMN082 injections into the medial prefrontal cortex on the expression and extinction of conditioned fear in mice. AB - The medial prefrontal cortex (mPFC), in particular its infralimbic part, is a key region in mediating the extinction of conditioned fear. There is some evidence that the metabotropic glutamate receptor 7 (mGluR7) may be involved in the mediation or modulation of extinction. The aim of present study was to assess the potential role of mGluR7 in the mPFC in the extinction of conditioned fear in mice by local injections of AMN082, a positive allosteric modulator of mGluR7. Furthermore, for comparison we injected the GABA-A receptor agonist muscimol, which should lead to a temporary inactivation of mPFC. We found impaired between session extinction of conditioned fear for the muscimol group as well as a decrease in fear expression. However, local injections of AMN082 into the mPFC had no effects. Overall, the results of the experiment add to a growing body of evidence that mPFC, especially the infralimbic region, is crucial in the extinction of fear memory. PMID- 22442379 TI - The metabolism of histamine in the Drosophila optic lobe involves an ommatidial pathway: beta-alanine recycles through the retina. AB - Flies recycle the photoreceptor neurotransmitter histamine by conjugating it to beta-alanine to form beta-alanyl-histamine (carcinine). The conjugation is regulated by Ebony, while Tan hydrolyses carcinine, releasing histamine and beta alanine. In Drosophila, beta-alanine synthesis occurs either from uracil or from the decarboxylation of aspartate but detailed roles for the enzymes responsible remain unclear. Immunohistochemically detected beta-alanine is present throughout the fly's entire brain, and is enhanced in the retina especially in the pseudocone, pigment and photoreceptor cells of the ommatidia. HPLC determinations reveal 10.7 ng of beta-alanine in the wild-type head, roughly five times more than histamine. When wild-type flies drink uracil their head beta-alanine increases more than after drinking l-aspartic acid, indicating the effectiveness of the uracil pathway. Mutants of black, which lack aspartate decarboxylase, cannot synthesize beta-alanine from l-aspartate but can still synthesize it efficiently from uracil. Our findings demonstrate a novel function for pigment cells, which not only screen ommatidia from stray light but also store and transport beta-alanine and carcinine. This role is consistent with a beta-alanine dependent histamine recycling pathway occurring not only in the photoreceptor terminals in the lamina neuropile, where carcinine occurs in marginal glia, but vertically via a long pathway that involves the retina. The lamina's marginal glia are also a hub involved in the storage and/or disposal of carcinine and beta alanine. PMID- 22442380 TI - Not all sugars are created equal: some mask aversive tastes better than others in an herbivorous insect. AB - Manduca sexta caterpillars are unusual because they exhibit strong peripheral gustatory responses to sugars, but nevertheless fail to show immediate appetitive responses to them. We hypothesized that the primary function of the peripheral gustatory response to sugars is to mask the taste of noxious compounds, which abound in host plants of M. sexta. We compared 10 s biting responses to water with those to mixtures of a noxious compound [caffeine (Caf) or aristolochic acid (AA)] and various combinations of sugars [i.e. sucrose (Suc), glucose (Glu), inositol (Ino), Suc+Glu, Suc+Ino or Glu+Ino]. The biting assays indicated that the aversive taste of AA was completely masked by Suc+Ino, and partially masked by Suc+Glu, Glu+Ino and Suc, whereas that of Caf was completely masked by Suc+Ino and Suc+Glu, and partially masked by Glu+Ino, Suc and Ino. To examine the contribution of the peripheral taste system to the masking phenomenon, we recorded responses of the maxillary gustatory sensilla to each stimulus mixture. The sugars differed greatly in their capacity to suppress peripheral gustatory responses to AA and Caf: Suc+Ino and Suc+Glu produced the greatest suppression, and Glu and Ino the least. Further, the extent to which each sugar stimulus suppressed the peripheral gustatory responses to AA reliably predicted the extent to which it masked the taste of AA in biting assays; no such predictive relationship was observed for the sugar/Caf mixtures. We conclude that some, but not all, sugars act on both peripheral and central elements of the gustatory system to mask the taste of noxious compounds. PMID- 22442381 TI - Use of Zenith TX2 endografts in endovascular abdominal aortic aneurysm repair for large-diameter aortic necks. AB - The purpose of this case report is to describe the use of thoracic endografts in endovascular repair of abdominal aortic aneurysms (AAAs) with large-diameter aortic necks. We present four patients who underwent elective repair of AAAs. Preoperative imaging demonstrated all to have large aortic necks (35-37 mm) precluding treatment with standard abdominal aortic devices. All underwent endovascular treatment, which included the use of a Zenith TX2 endograft (Cook Medical Incorporated, Bloomington, IN, USA) as a proximal aortic cuff. There was 100% technical success. One patient developed gastrointestinal bleeding and a myocardial infarction. All were subsequently discharged home. On follow-up, there was one aneurysm-related death at three months. The remaining three patients are alive at a mean of 25.7 months after their operation. In conclusion, large proximal aortic necks preclude endovascular treatment with standard abdominal endograft components. The use of a thoracic endograft as a proximal aortic cuff is a feasible technique for patients unable to tolerate open aortic reconstruction. PMID- 22442382 TI - Acute superior mesenteric artery embolism: reperfusion with AngioJet hydrodynamic suction thrombectomy and pharmacologic thrombolysis with the EKOS catheter. AB - Acute mesenteric ischemia is commonly treated by surgical exploration and open thrombectomy. Very few reports describe using newer, minimally invasive methods which utilize catheter-based mechanical and pharmacological thrombolysis. Herein, we report a case of acute superior mesenteric embolism successfully treated with AngioJet hydrodynamic mechanical thrombectomy and EKOS catheter pharmacological thrombolysis. A 76-year-old man with new onset atrial fibrillation presented with abdominal pain of 48 hours duration. Subsequent contrast computed tomography scan of the abdomen revealed a filling defect in the superior mesenteric artery (SMA), suggestive of an acute embolus, which was confirmed by SMA angiogram. The AngioJet aspiration device was used for hydrodynamic suction thrombectomy. The repeat angiogram demonstrated only a partial restoration of blood flow, and thus the EKOS tissue plasminogen activator catheter was left in the SMA for continuous thrombolysis. The patient underwent continuous thrombolysis for two days, with two subsequent sessions of angiography. Thereafter, the patient improved symptomatically and serum lactate was normalized. In conclusion, the AngioJet suction thrombectomy and pharmaco-mechanical thrombolysis using the EKOS catheter is associated with minimal morbidity and can be rapidly performed. It may be used as an alternative to open surgical thrombectomy in selected cases of acute SMA embolism. PMID- 22442383 TI - Microbial exposure during early life has persistent effects on natural killer T cell function. AB - Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures. PMID- 22442384 TI - A lineage of myeloid cells independent of Myb and hematopoietic stem cells. AB - Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11b(high) monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia--cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny. PMID- 22442385 TI - Enantioselective C-H crotylation of primary alcohols via hydrohydroxyalkylation of butadiene. AB - The direct, by-product-free conversion of basic feedstocks to products of medicinal and agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum cracking and is produced on an enormous scale (about 12 * 10(6) metric tons annually). Here, with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report the direct redox triggered carbon-carbon coupling of alcohols and butadiene to form products of carbonyl crotylation with high levels of anti-diastereoselectivity and enantioselectivity in the absence of stoichiometric by-products. PMID- 22442386 TI - Translate plant metabolism into modern agriculture: a starting point. PMID- 22442387 TI - Unveiling plant mTERF functions. PMID- 22442388 TI - Structure and dynamics of the isoprenoid pathway network. AB - Isoprenoids are functionally and structurally the most diverse group of plant metabolites reported to date. They can function as primary metabolites, participating in essential plant cellular processes, and as secondary metabolites, of which many have substantial commercial, pharmacological, and agricultural value. Isoprenoid end products participate in plants in a wide range of physiological processes acting in them both synergistically, such as chlorophyll and carotenoids during photosynthesis, or antagonistically, such as gibberellic acid and abscisic acid during seed germination. It is therefore expected that fluxes via isoprenoid metabolic network are tightly controlled both temporally and spatially, and that this control occurs at different levels of regulation and in an orchestrated manner over the entire isoprenoid metabolic network. In this review, we summarize our current knowledge of the topology of the plant isoprenoid pathway network and its regulation at the gene expression level following diverse stimuli. We conclude by discussing agronomical and biotechnological applications emerging from the plant isoprenoid metabolism and provide an outlook on future directions in the systems analysis of the plant isoprenoid pathway network. PMID- 22442389 TI - Establishment of a photoautotrophic cell suspension culture of Arabidopsis thaliana for photosynthetic, metabolic, and signaling studies. PMID- 22442391 TI - Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects. AB - BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent worldwide. Furthermore, obesity is now a global problem with major health implications. There is a clear association between obesity and the development of CKD but it is not known whether obesity is a risk factor for the progression of pre-existing kidney disease. We examined the relationship between the body mass index (BMI) and the rate of progression of CKD in non-diabetic adults. METHODS: The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a prospective observational study in a predominantly white population in Greater Manchester. From the CRISIS database, we assessed rate of progression of CKD in 499 adults attending the hospital. Baseline measurements including BMI were obtained and estimated glomerular filtration rate (eGFR) was monitored. The rate of deterioration of eGFR was derived over time, defined as DeltaeGFR (mL/min/1.73 m2/year) and assessed using univariate analysis of variance. RESULTS: In the groups as a whole, no relationship between BMI and DeltaeGFR was shown. Dividing the subjects into obese (BMI>=30) and non-obese (BMI<30) groups and further breakdown into CKD stages 3, 4 and 5, also showed no relationship between BMI and DeltaeGFR. Univariate analysis of variance was used. CONCLUSIONS: Neither BMI as a continuous variable nor obesity (BMI>=30) as a categorical variable was associated with an increased rate of progression of existing CKD in this predominantly white population. PMID- 22442392 TI - Chronic kidney disease and life expectancy. AB - BACKGROUND: Life expectancy is commonly used as an indicator of health and reflects disease burden in the population. The life expectancy for patients with lower levels of kidney function has not been reported. METHODS: The abridged life table method was applied to calculate the life expectancies of men and women from age 30 to 85 years, by levels of kidney function as defined by estimated glomerular filtration rate (eGFR): >= 60, 45-59, 30-44 and 15-29 mL/min/1.73 m(2). RESULTS: Men and women aged 40 years had a life expectancy of 30.5 and 34.6 years at eGFR >= 60 mL/min/1.73 m(2), 24.5 and 28.7 years at eGFR 45-59 mL/min/1.73 m(2), 14.5 and 16.5 years at eGFR 30-44 mL/min/1.73 m(2) and 10.4 and 9.1 years at eGFR 15-29 mL/min/1.73 m(2), respectively. Life expectancy was longer for women compared with men at all ages and eGFR categories, other than for eGFR 15-29 mL/min/1.73 m(2) where there was no difference in life expectancy by gender. CONCLUSION: A lower level of kidney function is associated with a reduction in life expectancy for both men and women. PMID- 22442393 TI - Steps toward the meaningful translation of prevention strategies for type 2 diabetes. PMID- 22442394 TI - Diabetes prevention: how important is geographic divergence regarding the role of fish intake? PMID- 22442395 TI - The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. AB - OBJECTIVE: The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) demonstrated that either intensive lifestyle intervention or metformin could prevent type 2 diabetes in high-risk adults for at least 10 years after randomization. We report the 10-year within-trial cost-effectiveness of the interventions. RESEARCH DESIGN AND METHODS: Data on resource utilization, cost, and quality of life were collected prospectively. Economic analyses were performed from health system and societal perspectives. RESULTS: Over 10 years, the cumulative, undiscounted per capita direct medical costs of the interventions, as implemented during the DPP, were greater for lifestyle ($4,601) than metformin ($2,300) or placebo ($769). The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ($24,563 lifestyle vs. $25,616 metformin vs. $27,468 placebo). The cumulative, combined total direct medical costs were greatest for lifestyle and least for metformin ($29,164 lifestyle vs. $27,915 metformin vs. $28,236 placebo). The cumulative quality adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.81) than metformin (6.69) or placebo (6.67). When costs and outcomes were discounted at 3%, lifestyle cost $10,037 per QALY, and metformin had slightly lower costs and nearly the same QALYs as placebo. CONCLUSIONS: Over 10 years, from a payer perspective, lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo. Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent. PMID- 22442396 TI - Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. AB - OBJECTIVE: Metformin produced weight loss and delayed or prevented diabetes in the Diabetes Prevention Program (DPP). We examined its long-term safety and tolerability along with weight loss, and change in waist circumference during the DPP and its long-term follow-up. RESEARCH DESIGN AND METHODS: The randomized double-blind clinical trial of metformin or placebo followed by a 7-8-year open label extension and analysis of adverse events, tolerability, and the effect of adherence on change in weight and waist circumference. RESULTS: No significant safety issues were identified. Gastrointestinal symptoms were more common in metformin than placebo participants and declined over time. During the DPP, average hemoglobin and hematocrit levels were slightly lower in the metformin group than in the placebo group. Decreases in hemoglobin and hematocrit in the metformin group occurred during the first year following randomization, with no further changes observed over time. During the DPP, metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 +/- 5.65% vs. 0.02 +/- 5.52%, P < 0.001, and waist circumference by 2.13 +/- 7.06 cm vs. 0.79 +/- 6.54 cm, P < 0.001 in metformin vs. placebo, respectively). The magnitude of weight loss during the 2-year double-blind period was directly related to adherence (P < 0.001). Throughout the unblinded follow-up, weight loss remained significantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P < 0.001), and this was related to the degree of continuing metformin adherence (P < 0.001). CONCLUSIONS: Metformin used for diabetes prevention is safe and well tolerated. Weight loss is related to adherence to metformin and is durable for at least 10 years of treatment. PMID- 22442397 TI - Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. AB - OBJECTIVE: The evidence on the association between fish consumption, dietary long chain n-3 fatty acids, and risk of type 2 diabetes is inconsistent. We therefore performed a systematic review and meta-analysis of the available prospective evidence. RESEARCH DESIGN AND METHODS: Studies were identified by searching the PubMed and EMBASE databases through 15 December 2011 and by reviewing the reference lists of retrieved articles. Prospective studies were included if they reported relative risk (RR) estimates with 95% CIs for the association between fish consumption and/or dietary long-chain n-3 fatty acids and incidence of type 2 diabetes. A dose-response random-effects model was used to combine study specific RRs. Potential sources of heterogeneity were explored by prespecified stratifications. RESULTS: Sixteen studies involving 527,441 participants and 24,082 diabetes cases were included. Considerable statistical heterogeneity in the overall summary estimates was partly explained by geographical differences. For each serving per week increment in fish consumption, the RRs (95% CIs) of type 2 diabetes were 1.05 (1.02-1.09), 1.03 (0.96-1.11), and 0.98 (0.97-1.00) combining U.S., European, and Asian/Australian studies, respectively. For each 0.30 g per day increment in long-chain n-3 fatty acids, the corresponding summary estimates were 1.17 (1.09-1.26), 0.98 (0.70-1.37), and 0.90 (0.82-0.98). CONCLUSIONS: Results from this meta-analysis indicate differences between geographical regions in observed associations of fish consumption and dietary intake of long-chain n-3 fatty acids with risk of type 2 diabetes. In consideration of the heterogeneous results, the relationship warrants further investigation. Meanwhile, current public health recommendations on fish consumption should be upheld unchanged. PMID- 22442398 TI - Fish Consumption and Incidence of Diabetes: meta-analysis of data from 438,000 individuals in 12 independent prospective cohorts with an average 11-year follow up. AB - OBJECTIVE: Ecological data suggest an inverse correlation between fish consumption and diabetes prevalence. However, epidemiological data on fish intake and diabetes incidence are controversial and inconclusive. Therefore, we aimed to assess the literature and determine the association between fish consumption and diabetes risk quantitatively. RESEARCH DESIGN AND METHODS: Prospective cohort studies published through August 2011 in peer-reviewed journals indexed in PubMed were selected. Additional information was retrieved through Google or a hand search of the references from relevant articles. The weighted relative risk (RR) and corresponding 95% CI for incident diabetes was estimated using random-effects models. RESULTS: A database was derived from nine eligible studies (12 independent cohorts), including 438,214 individuals with an average 11.4-year follow-up. Compared with those who never consumed fish or ate fish less than once per month, the pooled RR of incident diabetes was 0.99 (95% CI 0.85-1.16) for individuals who ate fish five or more times per week (P(trend) = 0.80). Similar results were found for long-chain n-3 polyunsaturated fatty acid intake. Study location was an effect modifier. An inverse association between fish intake and diabetes incidence was found by combining studies conducted in Eastern but not Western countries. CONCLUSIONS: Accumulated evidence generated from this meta analysis does not support an overall inverse association of fish or fish oil intake with incidence of diabetes. The null association was modified by study location (Eastern vs. Western countries), which may reflect the possible difference between Eastern and Western dietary patterns. Further studies are warranted. PMID- 22442400 TI - A novel model to deliver advanced eye care for people with diabetes living in resource-poor settings: results of care provided to date. PMID- 22442401 TI - Antepartum oral disposition index as a predictor of glucose intolerance postpartum. PMID- 22442402 TI - Comment on: Monami et al. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 2011;34:2474-2476. PMID- 22442403 TI - Pipeline, aneurysms and the FDA. PMID- 22442404 TI - Pharyngo-occipital artery variant arising from the internal carotid artery impacting surgical technique during carotid endarterectomy. AB - BACKGROUND AND IMPORTANCE: Extracranial carotid artery atherosclerotic stenosis typically occurs at the junction of the common carotid, external carotid and internal carotid arteries. Although rare, anatomical arterial variants can influence surgical strategy and can have a significant impact on surgical complications and patient outcome. An unusual case of atherosclerotic stenosis of the internal carotid artery (ICA) at the origin of a pharyngo-occipital variant off of the ICA is reported here. CLINICAL PRESENTATION: A 60-year-old man presented with symptomatic severe left cervical ICA stenosis. The stenosis was related to the origin of the pharyngo-occipital common trunk which arose from the ICA rather than the typical origin off of the external carotid artery. The patient underwent successful left carotid endarterectomy with special attention to this variant anatomy. CONCLUSION: Anomalies of the extracranial ICA, although rare, can influence the location of atherosclerotic disease and the surgical endarterectomy strategy. A detailed anatomical study should be performed prior to surgery to minimize risk and improve patient outcome. PMID- 22442405 TI - Authors' reply. PMID- 22442406 TI - Response to ready or not! Here comes ICD-10. PMID- 22442407 TI - Identification of distinct quantitative trait loci associated with defence against the closely related aphids Acyrthosiphon pisum and A. kondoi in Medicago truncatula. AB - Aphids are a major family of plant insect pests. Medicago truncatula and Acyrthosiphon pisum (pea aphid, PA) are model species with a suite of resources available to help dissect the mechanism underlying plant-aphid interactions. A previous study focused on monogenic and relatively strong resistance in M. truncatula to PA and other aphid species. In this study a moderate resistance to PA was characterized in detail in the M. truncatula line A17 and compared with the highly susceptible line A20 and the more resistant line Jester. The results show that PA resistance in A17 involves both antibiosis and tolerance, and that resistance is phloem based. Quantitative trait locus (QTL) analysis using a recombinant inbred line (RIL) population (n=114) from a cross between A17 and A20 revealed that one locus, which co-segregated with AIN (Acyrthosiphon-induced necrosis) on chromosome 3, is responsible for the reduction of aphid biomass (indicator of antibiosis) for both PA and bluegreen aphid (BGA, A. kondoi), albeit to a lesser degree for PA than BGA. Interestingly, two independent loci on chromosomes 5 and 3 were identified for the plant biomass reduction (indicator of plant tolerance) by PA and BGA, respectively, demonstrating that the plant's tolerance response to these two closely related aphid species is distinct. Together with previously identified major resistant (R) genes, the QTLs identified in this study are powerful tools to understand fully the spectrum of plant defence against sap-sucking insects and provide opportunities for breeders to generate effective and sustainable strategies for aphid control. PMID- 22442408 TI - Properties of photosystem I antenna protein complexes of the diatom Cyclotella meneghiniana. AB - Analysis of photosystem I (PSI) complexes from Cyclotella meneghiniana cultured under different growth conditions led to the identification of three groups of antenna proteins, having molecular weights of around 19, 18, and 17 kDa. The 19 kDa proteins have earlier been demonstrated to be more peripherally bound to PSI, and their amount in the PSI complexes was significantly reduced when the iron supply in the growth medium was lowered. This polypeptide was almost missing, and thus the total amount of fucoxanthin-chlorophyll proteins (Fcps) bound to PSI was reduced as well. When treating cells with high light in addition, no further changes in antenna polypeptide composition were detected. Xanthophyll cycle pigments were found to be bound to all Fcps of PSI. However, PSI of high light cultures had a significantly higher diatoxanthin to diadinoxanthin ratio, which is assumed to protect against a surplus of excitation energy. PSI complexes from the double-stressed cultures (high light plus reduced iron supply) were slightly more sensitive against destruction by the detergent treatment. This could be seen as a higher 674-nm emission at 77 K in comparison to the PSI complexes isolated from other growth conditions. Two major emission bands of the Fcps bound to PSI at 77 K could be identified, whereby chlorophyll a fluorescing at 697 nm was more strongly coupled to the PSI core than those fluorescing at 685 nm. Thus, the build up of the PSI antenna of several Fcp components enables variable reactions to several stress factors commonly experienced by the diatoms in vivo, in particular diatoxanthin enrichment under high light and reduction of antenna size under reduced iron conditions. PMID- 22442409 TI - Identification of lipids and lipid-binding proteins in phloem exudates from Arabidopsis thaliana. AB - The phloem plays a crucial role in assimilate and nutrient transport, pathogen response, and plant growth and development. Yet, few species have yielded pure phloem exudate and, if proteins need to be analysed, those species may not have sequenced genomes, making identification difficult. The enrichment of Arabidopsis thaliana phloem exudate in amounts large enough to allow for metabolite and protein analysis is described. Using this method, it was possible to identify 65 proteins present in the Arabidopsis phloem exudate. The majority of these proteins could be grouped by response to pathogens, stress, or hormones, carbon metabolism, protein interaction, modification, and turnover, and transcription factors. It was also possible to detect 11 proteins that play a role in lipid/fatty acid metabolism (aspartic protease, putative 3-beta-hydroxysteroid dehydrogenase, UDP-sulphoquinovose synthase/SQD1, lipase, PIG-P-like protein: phosphatidylinositol-N-acetylglucosaminyltransferase), storage (glycine-rich protein), binding (annexin, lipid-associated family protein, GRP17/oleosin), and/or signalling (annexin, putative lipase, PIG-P-like protein). Along with putative lipid-binding proteins, several lipids and fatty acids could be identified. Only a few examples exist of lipids (jasmonic acid, oxylipins) or lipid-binding proteins (DIR1, acyl-CoA-binding protein) in the phloem. Finding hydrophobic compounds in an aqueous environment is not without precedence in biological systems: human blood contains a variety of lipids, many of which play a significant role in human health. In blood, lipids are transported while bound to proteins. The present findings of lipids and lipid-binding proteins in phloem exudates suggest that a similar long-distance lipid signalling exists in plants and may play an important role in plant growth and development. PMID- 22442410 TI - Calcium deprivation disrupts enlargement of Chara corallina cells: further evidence for the calcium pectate cycle. AB - Pectin is a normal constituent of cell walls of green plants. When supplied externally to live cells or walls isolated from the large-celled green alga Chara corallina, pectin removes calcium from load-bearing cross-links in the wall, loosening the structure and allowing it to deform more rapidly under the action of turgor pressure. New Ca(2+) enters the vacated positions in the wall and the externally supplied pectin binds to the wall, depositing new wall material that strengthens the wall. A calcium pectate cycle has been proposed for these sub reactions. In the present work, the cycle was tested in C. corallina by depriving the wall of external Ca(2+) while allowing the cycle to run. The prediction is that growth would eventually be disrupted by a lack of adequate deposition of new wall. The test involved adding pectate or the calcium chelator EGTA to the Ca(2+) containing culture medium to bind the calcium while the cycle ran in live cells. After growth accelerated, turgor and growth eventually decreased, followed by an abrupt turgor loss and growth cessation. The same experiment with isolated walls suggested the walls of live cells became unable to support the plasma membrane. If instead the pectate or EGTA was replaced with fresh Ca(2+)-containing culture medium during the initial acceleration in live cells, growth was not disrupted and returned to the original rates. The operation of the cycle was thus confirmed, providing further evidence that growth rates and wall biosynthesis are controlled by these sub-reactions in plant cell walls. PMID- 22442411 TI - Low relative humidity triggers RNA-directed de novo DNA methylation and suppression of genes controlling stomatal development. AB - Environmental cues influence the development of stomata on the leaf epidermis, and allow plants to exert plasticity in leaf stomatal abundance in response to the prevailing growing conditions. It is reported that Arabidopsis thaliana 'Landsberg erecta' plants grown under low relative humidity have a reduced stomatal index and that two genes in the stomatal development pathway, SPEECHLESS and FAMA, become de novo cytosine methylated and transcriptionally repressed. These environmentally-induced epigenetic responses were abolished in mutants lacking the capacity for de novo DNA methylation, for the maintenance of CG methylation, and in mutants for the production of short-interfering non-coding RNAs (siRNAs) in the RNA-directed DNA methylation pathway. Induction of methylation was quantitatively related to the induction of local siRNAs under low relative humidity. Our results indicate the involvement of both transcriptional and post-transcriptional gene suppression at these loci in response to environmental stress. Thus, in a physiologically important pathway, a targeted epigenetic response to a specific environmental stress is reported and several of its molecular, mechanistic components are described, providing a tractable platform for future epigenetics experiments. Our findings suggest epigenetic regulation of stomatal development that allows for anatomical and phenotypic plasticity, and may help to explain at least some of the plant's resilience to fluctuating relative humidity. PMID- 22442412 TI - T-DNA insertion mutants reveal complex expression patterns of the aldehyde dehydrogenase 3H1 locus in Arabidopsis thaliana. AB - The Arabidopsis thaliana aldehyde dehydrogenase 3H1 gene (ALDH3H1; AT1G44170) belongs to family 3 of the plant aldehyde dehydrogenase superfamily. The full length transcript of the corresponding gene comprises an open reading frame of 1583 bp and encodes a protein of 484 amino acid residues. Gene expression studies have shown that this transcript accumulates mainly in the roots of 4-week-old plants following abscisic acid, dehydration, and NaCl treatments. The current study provided experimental data that the ALDH3H1 locus generates at least five alternative transcript variants in addition to the previously described ALDH3H1 mRNA. The alternative transcripts accumulated in wild-type plants at a low level but were upregulated in a mutant that carried a T-DNA insertion in the first exon of the gene. Expression of the transcript isoforms involved alternative gene splicing combined with an alternative promoter. The transcript isoforms were differentially expressed in the roots and shoots and showed developmental stage- and tissue-specific expression patterns. These data support the hypothesis that alternative isoforms produced by gene splicing or alternative promoters regulate the abundance of the constitutively spliced and functional variants. PMID- 22442413 TI - An altered hydrotropic response (ahr1) mutant of Arabidopsis recovers root hydrotropism with cytokinin. AB - Roots are highly plastic and can acclimate to heterogeneous and stressful conditions. However, there is little knowledge of the effect of moisture gradients on the mechanisms controlling root growth orientation and branching, and how this mechanism may help plants to avoid drought responses. The aim of this study was to isolate mutants of Arabidopsis thaliana with altered hydrotropic responses. Here, altered hydrotropic response 1 (ahr1), a semi dominant allele segregating as a single gene mutation, was characterized. ahr1 directed the growth of its primary root towards the source of higher water availability and developed an extensive root system over time. This phenotype was intensified in the presence of abscisic acid and was not observed if ahr1 seedlings were grown in a water stress medium without a water potential gradient. In normal growth conditions, primary root growth and root branching of ahr1 were indistinguishable from those of the wild type (wt). The altered hydrotropic growth of ahr1 roots was confirmed when the water-rich source was placed at an angle of 45 degrees from the gravity vector. In this system, roots of ahr1 seedlings grew downward and did not display hydrotropism; however, in the presence of cytokinins, they exhibited hydrotropism like those of the wt, indicating that cytokinins play a critical role in root hydrotropism. The ahr1 mutant represents a valuable genetic resource for the study of the effects of cytokinins in the differential growth of hydrotropism and control of lateral root formation during the hydrotropic response. PMID- 22442414 TI - The interaction of the novel 30C02 cyst nematode effector protein with a plant beta-1,3-endoglucanase may suppress host defence to promote parasitism. AB - Phytoparasitic nematodes secrete an array of effector proteins to modify selected recipient plant cells into elaborate and essential feeding sites. The biological function of the novel 30C02 effector protein of the soybean cyst nematode, Heterodera glycines, was studied using Arabidopsis thaliana as host and the beet cyst nematode, Heterodera schachtii, which contains a homologue of the 30C02 gene. Expression of Hg30C02 in Arabidopsis did not affect plant growth and development but increased plant susceptibility to infection by H. schachtii. The 30C02 protein interacted with a specific (AT4G16260) host plant beta-1,3 endoglucanase in both yeast and plant cells, possibly to interfere with its role as a plant pathogenesis-related protein. Interestingly, the peak expression of 30C02 in the nematode and peak expression of At4g16260 in plant roots coincided at around 3-5 d after root infection by the nematode, after which the relative expression of At4g16260 declined significantly. An Arabidopsis At4g16260 T-DNA mutant showed increased susceptibility to cyst nematode infection, and plants that overexpressed At4g16260 were reduced in nematode susceptibility, suggesting a potential role of host beta-1,3-endoglucanase in the defence response against H. schachtii infection. Arabidopsis plants that expressed dsRNA and its processed small interfering RNA complementary to the Hg30C02 sequence were not phenotypically different from non-transformed plants, but they exhibited a strong RNA interference-mediated resistance to infection by H. schachtii. The collective results suggest that, as with other pathogens, active suppression of host defence is a critical component for successful parasitism by nematodes and a vulnerable target to disrupt the parasitic cycle. PMID- 22442415 TI - The rice ERF transcription factor OsERF922 negatively regulates resistance to Magnaporthe oryzae and salt tolerance. AB - Rice OsERF922, encoding an APETELA2/ethylene response factor (AP2/ERF) type transcription factor, is rapidly and strongly induced by abscisic acid (ABA) and salt treatments, as well as by both virulent and avirulent pathovars of Magnaporthe oryzae, the causal agent of rice blast disease. OsERF922 is localized to the nucleus, binds specifically to the GCC box sequence, and acts as a transcriptional activator in plant cells. Knockdown of OsERF922 by means of RNAi enhanced resistance against M. oryzae. The elevated disease resistance of the RNAi plants was associated with increased expression of PR, PAL, and the other genes encoding phytoalexin biosynthetic enzymes and without M. oryzae infection. In contrast, OsERF922-overexpressing plants showed reduced expression of these defence-related genes and enhanced susceptibility to M. oryzae. In addition, the OsERF922-overexpressing lines exhibited decreased tolerance to salt stress with an increased Na(+)/K(+) ratio in the shoots. The ABA levels were found increased in the overexpressing lines and decreased in the RNAi plants. Expression of the ABA biosynthesis-related genes, 9-cis-epoxycarotenoid dioxygenase (NCED) 3 and 4, was upregulated in the OsERF922-overexpressing plants, and NCED4 was downregulated in the RNAi lines. These results suggest that OsERF922 is integrated into the cross-talk between biotic and abiotic stress-signalling networks perhaps through modulation of the ABA levels. PMID- 22442416 TI - When ABC becomes ACB. AB - Understanding how the information contained in genes is mapped onto the phenotypes, and deriving formal frameworks to search for generic aspects of developmental constraints and evolution remains one of the main challenges of contemporary biological research. The Mexican endemic triurid Lacandonia schismatica (Lacandoniaceae), a mycoheterotrophic monocotyledonous plant with hermaphroditic reproductive axes is alone among 250,000 species of angiosperms, as it has central stamens surrounded by a peripheral gynoecium, representing a natural instance of a homeotic mutant. Based on the classical ABC model of flower development, it has recently been shown that the B-function gene APETALA3 (AP3), essential for stamen identity, was displaced toward the flower centre in L. schismatica (ABC to ACB) from the early stages of flower development. A functional conservation of B-function genes from L. schismatica through the rescue of B-gene mutants in Arabidopsis thaliana, as well as conserved protein interactions, has also been demonstrated. Thus, it has been shown that relatively simple genetic alterations may underlie large morphological shifts fixed in extant natural populations. Nevertheless, critical questions remain in order to have a full and sufficient explanation of the molecular genetic mechanisms underlying L. schismatica's unique floral arrangement. Evolutionary approaches to developmental mechanisms and systems biology, including high-throughput functional genomic studies and models of complex developmental gene regulatory networks, constitute two main approaches to meet such a challenge. In this review, the aim is to address some of the pending questions with the ultimate goal of investigating further the mechanisms of L. schismatica's unique homeotic flower arrangement and its evolution. PMID- 22442417 TI - Developmental effects on ureide levels are mediated by tissue-specific regulation of allantoinase in Phaseolus vulgaris L. AB - The ureides allantoin and allantoate are key molecules in the transport and storage of nitrogen in ureide legumes. In shoots and leaves from Phaseolus vulgaris plants using symbiotically fixed nitrogen as the sole nitrogen source, ureide levels were roughly equivalent to those of nitrate-supported plants during the whole vegetative stage, but they exhibited a sudden increase at the onset of flowering. This rise in the level of ureides, mainly in the form of allantoate, was accompanied by increases in allantoinase gene expression and enzyme activity, consistent with developmental regulation of ureide levels mainly through the tissue-specific induction of allantoate synthesis catalysed by allantoinase. Moreover, surprisingly high levels of ureides were also found in non-nodulated plants fertilized with nitrate, at both early and late developmental stages. The results suggest that remobilized N from lower leaves is probably involved in the sharp rise in ureides in shoots and leaves during early pod filling in N(2) fixing plants and in the significant amounts of ureides observed in non-nodulated plants. PMID- 22442418 TI - Transcriptional profiling analysis in Populus yunnanensis provides insights into molecular mechanisms of sexual differences in salinity tolerance. AB - Physiological responses to abiotic stress in plants exhibit sexual differences. Females usually experience greater negative effects than males; however, little is known about the molecular mechanisms of sexual differences in abiotic stress responses. In the present study, transcriptional responses to salinity treatments were compared between male and female individuals of the poplar Populus yunnanensis. It was found that several functional groups of genes involved in important pathways were differentially expressed, including photosynthesis related genes, which were mainly up-regulated in males but down-regulated in females. This gene expression pattern is consistent with physiological observations showing that salinity inhibited photosynthetic capacity more in females than in males. Furthermore, genes located in autosomes rather than in the female-specific region of the W chromosome are the major contributors to the sexual differences in the salinity tolerance of poplars. In conclusion, this study provided molecular evidence of sexual differences in the salinity tolerance of poplars. The identified sex-related genes in salinity tolerance and their functional groups will enhance our understanding of sexual differences in salinity stress at the transcription level. PMID- 22442419 TI - The BnGRF2 gene (GRF2-like gene from Brassica napus) enhances seed oil production through regulating cell number and plant photosynthesis. AB - Seed yield and oil content are two important agricultural characteristics in oil crop breeding, and a lot of functional gene research is being concentrated on increasing these factors. In this study, by differential gene expression analyses between rapeseed lines (zy036 and 51070) which exhibit different levels of seed oil production, BnGRF2 (Brassica napus growth-regulating factor 2-like gene) was identified in the high oil-producing line zy036. To elucidate the possible roles of BnGRF2 in seed oil production, the cDNA sequences of the rapeseed GRF2 gene were isolated. The Blastn result showed that rapeseed contained BnGRF2a/2b which were located in the A genome (A1 and A3) and C genome (C1 and C6), respectively, and the dominantly expressed gene BnGRF2a was chosen for transgenic research. Analysis of 35S-BnGRF2a transgenic Arabidopsis showed that overexpressed BnGRF2a resulted in an increase in seed oil production of >50%. Moreover, BnGRF2a also induced a >20% enlargement in extended leaves and >40% improvement in photosynthetic efficiency because of an increase in the chlorophyll content. Furthermore, transcriptome analyses indicated that some genes associated with cell proliferation, photosynthesis, and oil synthesis were up-regulated, which revealed that cell number and plant photosynthesis contributed to the increased seed weight and oil content. Because of less efficient self-fertilization induced by the longer pistil in the 35S-BnGRF2a transgenic line, Napin-BnGRF2a transgenic lines were further used to identify the function of BnGRF2, and the results showed that seed oil production also could increase >40% compared with the wild type control. The results suggest that improvement to economically important characteristics in oil crops may be achieved by manipulation of the GRF2 expression level. PMID- 22442420 TI - Cotton GhMKK5 affects disease resistance, induces HR-like cell death, and reduces the tolerance to salt and drought stress in transgenic Nicotiana benthamiana. AB - Mitogen-activated protein kinase (MAPK) cascades are involved in various processes from plant growth and development to biotic and abiotic stress responses. MAPK kinases (MAPKKs), which link MAPKs and MAPKK kinases (MAPKKKs), play crucial roles in MAPK cascades to mediate a variety of stress responses in plants. However, few MAPKKs have been functionally characterized in cotton (Gossypium hirsutum). In this study, a novel gene, GhMKK5, from cotton belonging to the group C MAPKKs was isolated and characterized. The expression of GhMKK5 can be induced by pathogen infection, abiotic stresses, and multiple defence related signal molecules. The overexpression of GhMKK5 in Nicotiana benthamiana enhanced the plants' resistance to the bacterial pathogen Ralstonia solanacearum by elevating the expression of pathogen resistance (PR) genes, including PR1a, PR2, PR4, PR5, and NPR1, but increased the plants' sensitivity to the oomycete pathogen Phytophthora parasitica var. nicotianae Tucker. Importantly, GhMKK5 overexpressing plants displayed markedly elevated expression of reactive oxygen species-related and cell death marker genes, such as NtRbohA and NtCDM, and resulted in hypersensitive response (HR)-like cell death characterized by the accumulation of H(2)O(2). Furthermore, it was demonstrated that GhMKK5 overexpression in plants reduced their tolerance to salt and drought stresses, as determined by statistical analysis of seed germination, root length, leaf water loss, and survival rate. Drought obviously accelerated the cell death phenomenon in GhMKK5-overexpressing plants. These results suggest that GhMKK5 may play an important role in pathogen infection and the regulation of the salt and drought stress responses in plants. PMID- 22442421 TI - Reactive oxygen species form part of a regulatory pathway initiating trans differentiation of epidermal transfer cells in Vicia faba cotyledons. AB - Various cell types can trans-differentiate to a transfer cell (TC) morphology characterized by deposition of polarized ingrowth walls comprised of a uniform layer on which wall ingrowths (WIs) develop. WIs form scaffolds supporting amplified plasma membrane areas enriched in transporters conferring a cellular capacity for high rates of nutrient exchange across apo- and symplasmic interfaces. The hypothesis that reactive oxygen species (ROS) are a component of the regulatory pathway inducing ingrowth wall formation was tested using Vicia faba cotyledons. Vicia faba cotyledons offer a robust experimental model to examine TC induction as, on being placed into culture, their adaxial epidermal cells rapidly (hours) form ingrowth walls on their outer periclinal walls. These are readily visualized by electron microscopy, and epidermal peels of their trans differentiating cells allow measures of cell-specific gene expression. Ingrowth wall formation responded inversely to pharmacological manipulation of ROS levels, indicating that a flavin-containing enzyme (NADPH oxidase) and superoxide dismutase cooperatively generate a regulatory H(2)O(2) signature. Extracellular H(2)O(2) fluxes peaked prior to the appearance of WIs and were followed by a slower rise in H(2)O(2) flux that occurred concomitantly, and co-localized, with ingrowth wall formation. De-localizing the H(2)O(2) signature caused a corresponding de-localization of cell wall deposition. Temporal and epidermal cell-specific expression profiles of VfrbohA and VfrbohC coincided with those of extracellular H(2)O(2) production and were regulated by cross-talk with ethylene. It is concluded that H(2)O(2) functions, downstream of ethylene, to activate cell wall biosynthesis and direct polarized deposition of a uniform wall on which WIs form. PMID- 22442422 TI - Transcriptional analysis of the Arabidopsis ovule by massively parallel signature sequencing. AB - The life cycle of flowering plants alternates between a predominant sporophytic (diploid) and an ephemeral gametophytic (haploid) generation that only occurs in reproductive organs. In Arabidopsis thaliana, the female gametophyte is deeply embedded within the ovule, complicating the study of the genetic and molecular interactions involved in the sporophytic to gametophytic transition. Massively parallel signature sequencing (MPSS) was used to conduct a quantitative large scale transcriptional analysis of the fully differentiated Arabidopsis ovule prior to fertilization. The expression of 9775 genes was quantified in wild-type ovules, additionally detecting >2200 new transcripts mapping to antisense or intergenic regions. A quantitative comparison of global expression in wild-type and sporocyteless (spl) individuals resulted in 1301 genes showing 25-fold reduced or null activity in ovules lacking a female gametophyte, including those encoding 92 signalling proteins, 75 transcription factors, and 72 RNA-binding proteins not reported in previous studies based on microarray profiling. A combination of independent genetic and molecular strategies confirmed the differential expression of 28 of them, showing that they are either preferentially active in the female gametophyte, or dependent on the presence of a female gametophyte to be expressed in sporophytic cells of the ovule. Among 18 genes encoding pentatricopeptide-repeat proteins (PPRs) that show transcriptional activity in wild-type but not spl ovules, CIHUATEOTL (At4g38150) is specifically expressed in the female gametophyte and necessary for female gametogenesis. These results expand the nature of the transcriptional universe present in the ovule of Arabidopsis, and offer a large-scale quantitative reference of global expression for future genomic and developmental studies. PMID- 22442423 TI - A comparison of hydroponic and soil-based screening methods to identify salt tolerance in the field in barley. AB - Success in breeding crops for yield and other quantitative traits depends on the use of methods to evaluate genotypes accurately under field conditions. Although many screening criteria have been suggested to distinguish between genotypes for their salt tolerance under controlled environmental conditions, there is a need to test these criteria in the field. In this study, the salt tolerance, ion concentrations, and accumulation of compatible solutes of genotypes of barley with a range of putative salt tolerance were investigated using three growing conditions (hydroponics, soil in pots, and natural saline field). Initially, 60 genotypes of barley were screened for their salt tolerance and uptake of Na(+), Cl(-), and K(+) at 150 mM NaCl and, based on this, a subset of 15 genotypes was selected for testing in pots and in the field. Expression of salt tolerance in saline solution culture was not a reliable indicator of the differences in salt tolerance between barley plants that were evident in saline soil-based comparisons. Significant correlations were observed in the rankings of genotypes on the basis of their grain yield production at a moderately saline field site and their relative shoot growth in pots at EC(e) 7.2 [Spearman's rank correlation (rs)=0.79] and EC(e) 15.3 (rs=0.82) and the crucial parameter of leaf Na(+) (rs=0.72) and Cl(-) (rs=0.82) concentrations at EC(e) 7.2 dS m(-1). This work has established screening procedures that correlated well with grain yield at sites with moderate levels of soil salinity. This study also showed that both salt exclusion and osmotic tolerance are involved in salt tolerance and that the relative importance of these traits may differ with the severity of the salt stress. In soil, ion exclusion tended to be more important at low to moderate levels of stress but osmotic stress became more important at higher stress levels. Salt exclusion coupled with a synthesis of organic solutes were shown to be important components of salt tolerance in the tolerant genotypes and further field tests of these plants under stress conditions will help to verify their potential utility in crop-improvement programmes. PMID- 22442424 TI - Thiol synthetases of legumes: immunogold localization and differential gene regulation by phytohormones. AB - In plants and other organisms, glutathione (GSH) biosynthesis is catalysed sequentially by gamma-glutamylcysteine synthetase (gammaECS) and glutathione synthetase (GSHS). In legumes, homoglutathione (hGSH) can replace GSH and is synthesized by gammaECS and a specific homoglutathione synthetase (hGSHS). The subcellular localization of the enzymes was examined by electron microscopy in several legumes and gene expression was analysed in Lotus japonicus plants treated for 1-48 h with 50 MUM of hormones. Immunogold localization studies revealed that gammaECS is confined to chloroplasts and plastids, whereas hGSHS is also in the cytosol. Addition of hormones caused differential expression of thiol synthetases in roots. After 24-48 h, abscisic and salicylic acids downregulated GSHS whereas jasmonic acid upregulated it. Cytokinins and polyamines activated GSHS but not gammaECS or hGSHS. Jasmonic acid elicited a coordinated response of the three genes and auxin induced both hGSHS expression and activity. Results show that the thiol biosynthetic pathway is compartmentalized in legumes. Moreover, the similar response profiles of the GSH and hGSH contents in roots of non-nodulated and nodulated plants to the various hormonal treatments indicate that thiol homeostasis is independent of the nitrogen source of the plants. The differential regulation of the three mRNA levels, hGSHS activity, and thiol contents by hormones indicates a fine control of thiol biosynthesis at multiple levels and strongly suggests that GSH and hGSH play distinct roles in plant development and stress responses. PMID- 22442425 TI - Late activation of the 9-oxylipin pathway during arbuscular mycorrhiza formation in tomato and its regulation by jasmonate signalling. AB - The establishment of an arbuscular mycorrhizal (AM) symbiotic interaction is a successful strategy for the promotion of substantial plant growth, development, and fitness. Numerous studies have supported the hypothesis that plant hormones play an important role in the establishment of functional AM symbiosis. Particular attention has been devoted to jasmonic acid (JA) and its derivates, which are believed to play a major role in AM symbiosis. Jasmonates belong to a diverse class of lipid metabolites known as oxylipins that include other biologically active molecules. Recent transcriptional analyses revealed up regulation of the oxylipin pathway during AM symbiosis in mycorrhizal tomato roots and indicate a key regulatory role for oxylipins during AM symbiosis in tomato, particularly those derived from the action of 9-lipoxygenases (9-LOXs). Continuing with the tomato as a model, the spatial and temporal expression pattern of genes involved in the 9-LOX pathway during the different stages of AM formation in tomato was analysed. The effects of JA signalling pathway changes on AM fungal colonization were assessed and correlated with the modifications in the transcriptional profiles of 9-LOX genes. The up-regulation of the 9-LOX oxylipin pathway in mycorrhizal wild-type roots seems to depend on a particular degree of AM fungal colonization and is restricted to the colonized part of the roots, suggesting that these genes could play a role in controlling fungal spread in roots. In addition, the results suggest that this strategy of the plant to control AM fungi development within the roots is at least partly dependent on JA pathway activation. PMID- 22442426 TI - Metabolite profiling and quantitative genetics of natural variation for flavonoids in Arabidopsis. AB - Little is known about the range and the genetic bases of naturally occurring variation for flavonoids. Using Arabidopsis thaliana seed as a model, the flavonoid content of 41 accessions and two recombinant inbred line (RIL) sets derived from divergent accessions (Cvi-0*Col-0 and Bay-0*Shahdara) were analysed. These accessions and RILs showed mainly quantitative rather than qualitative changes. To dissect the genetic architecture underlying these differences, a quantitative trait locus (QTL) analysis was performed on the two segregating populations. Twenty-two flavonoid QTLs were detected that accounted for 11-64% of the observed trait variations, only one QTL being common to both RIL sets. Sixteen of these QTLs were confirmed and coarsely mapped using heterogeneous inbred families (HIFs). Three genes, namely TRANSPARENT TESTA (TT)7, TT15, and MYB12, were proposed to underlie their variations since the corresponding mutants and QTLs displayed similar specific flavonoid changes. Interestingly, most loci did not co-localize with any gene known to be involved in flavonoid metabolism. This latter result shows that novel functions have yet to be characterized and paves the way for their isolation. PMID- 22442427 TI - Neurobehavioral dysfunction in ALS has a negative effect on outcome and use of PEG and NIV. AB - OBJECTIVE: To assess the effect of neurobehavioral dysfunction on amyotrophic lateral sclerosis (ALS) survival and on the use of life-prolonging therapies in a population-based setting. METHODS: Of the 132 patients diagnosed with ALS in the province of Torino, Italy, between January 1, 2007, and June 30, 2008, 128 participated in the study. Neurobehavioral dysfunction was assessed with the Frontal Systems Behavior Scale (FrSBe), using the Family Rating forms, administered within 4 months from diagnosis. RESULTS: The 128 patients included 71 men and 57 women, with a mean age at onset of 64.7 (SD 11) years. Forty-one patients (32.0%) had a neurobehavioral dysfunction and 9 (7.0%) an isolated dysexecutive behavior. Enteral nutrition (EN) and noninvasive ventilation (NIV) were performed with similar frequencies in patients with and without neurobehavioral dysfunction. Patients with neurobehavioral dysfunction had a significantly shorter survival than those with a normal FrSBe score (median survival, 3.3 vs 4.3 years; p = 0.02). Patients with isolated dysexecutive behavior had a shorter survival than those without neurobehavioral dysfunction (median survival, 2.5 vs 4.5 years; p = 0.03). Patients with neurobehavioral dysfunction had a shorter survival after EN and NIV, while patients with isolated dysexecutive behavior had a shorter survival after NIV but not after EN. The negative effect of comorbid neurobehavioral dysfunction and of isolated dysexecutive behavior on survival persisted under the Cox multivariate model. CONCLUSIONS: The presence of neurobehavioral dysfunction or of isolate dysexecutive behavior in ALS at diagnosis is a strong predictor of a poor outcome, partially related to a reduced efficacy of life-prolonging therapies. PMID- 22442428 TI - Epilepsy surgery trends in the United States, 1990-2008. AB - OBJECTIVE: To examine national time trends of resective surgery for the treatment of medically refractory epilepsy before and after Class I evidence demonstrating its efficacy and subsequent practice guidelines recommending early surgical evaluation. METHODS: We performed a population-based cohort study with time trends of patients admitted to US hospitals for medically refractory focal epilepsy between 1990 and 2008 who did or did not undergo lobectomy, as reported in the Nationwide Inpatient Sample. RESULTS: Weighted data revealed 112,026 hospitalizations for medically refractory focal epilepsy and 6,653 resective surgeries (lobectomies and partial lobectomies) from 1990 to 2008. A trend of increasing hospitalizations over time was not accompanied by an increase in surgeries, producing an overall trend of decreasing surgery rates (F = 13.6, p < 0.01). Factors associated with this trend included a decrease in epilepsy hospitalizations at the highest-volume epilepsy centers, and increased hospitalizations to lower-volume hospitals that were found to be less likely to perform surgery. White patients were more likely to have surgery than racial minorities (relative risk [RR], 1.13; 95% confidence interval [CI], 1.10-1.17), and privately insured individuals were more likely to receive lobectomy than those with Medicaid or Medicare (RR, 1.28; 95% CI, 1.25-1.30). CONCLUSION: Despite Class I evidence and subsequent practice guidelines, the utilization of lobectomy has not increased from 1990 to 2008. Surgery continues to be heavily underutilized as a treatment for epilepsy, with significant disparities by race and insurance coverage. Patients who are medically refractory after failing 2 antiepileptic medications should be referred to a comprehensive epilepsy center for surgical evaluation. PMID- 22442429 TI - Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. AB - OBJECTIVE: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). METHODS: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. RESULTS: Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). CONCLUSION: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD. PMID- 22442430 TI - Role of cortisol in mood and memory in patients with intractable temporal lobe epilepsy. AB - OBJECTIVE: This study prospectively examined the relationships among late night salivary cortisol (NSC) levels and depressive symptoms, memory performance, and hippocampal volumes in patients with medically intractable temporal lobe epilepsy (TLE) and the potential mediating effects of cortisol in the relationships between these variables. METHODS: Participants included 24 adults with well characterized medically refractory TLE (right = 11; left = 12; bitemporal = 1). All patients provided saliva samples and completed measures of mood, anxiety, and memory (objective and subjective). MRI-based volumetric analyses of the hippocampi were also conducted. RESULTS: As hypothesized, cortisol was found to be negatively related to several memory measures such that patients with higher cortisol levels demonstrated lower memory performance. However, unexpectedly, cortisol was not related to current symptoms of depression or anxiety, subjective memory ratings, or hippocampal volumes. Consistent with previous findings in the literature, a number of other relationships among the study variables were observed (objective memory and hippocampal volume; subjective memory and mood/anxiety). Results of mediator analyses suggested that cortisol does not mediate the relationship between depression and memory dysfunction or the relationship between depression and hippocampal atrophy. CONCLUSIONS: While cortisol may play a role in memory performance in patients with TLE, it does not fully explain the relationship between depression and mesial temporal dysfunction, likely reflecting the complex and multifactorial relationships among these variables. Results confirm the relationship between memory performance and structural brain integrity and provide further support for a role of depression in subjective memory complaints. PMID- 22442431 TI - Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. AB - OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon beta-1a in early, active relapsing remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon beta-1a (IFNbeta-1a) through extended follow up (up to 60 months from baseline). METHODS: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNbeta-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months. RESULTS: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNbeta-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNbeta-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNbeta-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNbeta-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNbeta 1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNbeta-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab. CONCLUSIONS: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNbeta-1a, with a safety profile consistent with previous reports. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab is more effective than interferon beta-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period. PMID- 22442432 TI - Are neurologists really data driven in selecting epilepsy treatment? PMID- 22442433 TI - Cerebral vasospasm following temporal lobe epilepsy surgery. AB - OBJECTIVE: Selective amygdalohippocampectomy (AHE) has been associated with postoperative cerebral vasospasm (CVS) in patients with medically intractable temporal lobe epilepsy. The incidence in temporal lobe resection (TLR) is unknown. This retrospective cohort study evaluates the incidence of and risk factors for the development of CVS in patients with TLR and AHE. METHODS: A total of 119 patients were included between 1998 and 2009. All patients were evaluated by standardized preoperative and postoperative transcranial Doppler sonography (TCD) evaluations and neurologic examinations. Postoperative CT scans were evaluated by an independent radiologist and the volume of bleeding within the resection cavity was quantified. RESULTS: Of 107 patients with longitudinal TCD data, 35 (32.7%) developed postoperative CVS. The incidence of CVS did not differ between patients with TLR and AHE. CVS was associated with female gender and a higher bleeding volume in the postoperative CT scan (p = 0.035 and 0.046). Patients with CVS showed a significantly higher incidence of postoperative neurologic signs and symptoms (48.6%) compared to patients without CVS (25%, p = 0.015). The mean length of stay was significantly prolonged in patients with diffuse CVS compared to patients with localized CVS or no CVS (28.8 +/- 10.9, 24.2 +/- 6.6, and 18.2 +/- 6.1 days, p < 0.001). CONCLUSION: CVS is a frequent complication of surgery for temporal lobe epilepsy irrespective of the resection method. Important risk factors for the development of postoperative CVS are female gender and a higher amount of bleeding in the postoperative CT. Patients with CVS more frequently have neurologic signs and symptoms resulting in prolonged hospital stay. PMID- 22442434 TI - Cognitive decline after hospitalization in a community population of older persons. AB - OBJECTIVE: To test the hypothesis that hospitalization in old age is associated with subsequent cognitive decline. METHODS: As part of a longitudinal population based cohort study, 1,870 older residents of an urban community were interviewed at 3-year intervals for up to 12 years. The interview included a set of brief cognitive tests from which measures of global cognition, episodic memory, and executive function were derived. Information about hospitalization during the observation period was obtained from Medicare records. RESULTS: During a mean of 9.3 years, 1,335 of 1,870 persons (71.4%) were hospitalized at least once. In a mixed-effects model adjusted for age, sex, race, and education, the global cognitive score declined a mean of 0.031 unit per year before the first hospitalization compared with 0.075 unit per year thereafter, a more than 2.4 fold increase. The posthospital acceleration in cognitive decline was also evident on measures of episodic memory (3.3-fold increase) and executive function (1.7-fold increase). The rate of cognitive decline after hospitalization was not related to the level of cognitive function at study entry (r = 0.01, p = 0.88) but was moderately correlated with rate of cognitive decline before hospitalization (r = 0.55, p = 0.021). More severe illness, longer hospital stay, and older age were each associated with faster cognitive decline after hospitalization but did not eliminate the effect of hospitalization. CONCLUSION: In old age, cognitive functioning tends to decline substantially after hospitalization even after controlling for illness severity and prehospital cognitive decline. PMID- 22442435 TI - Should patients be routinely assessed for cerebral vasospasm after temporal lobe epilepsy surgery? PMID- 22442436 TI - Long-term remission of CIDP after pulsed dexamethasone or short-term prednisolone treatment. AB - OBJECTIVE: Achieving long-term remission after a limited more intense treatment period would prevent prolonged use of corticosteroids or IV immunoglobulin (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this prospective cohort study we present long-term follow-up data on patients included in a multicenter randomized controlled trial comparing 6 monthly pulses of dexamethasone with 8 months of daily prednisolone. METHODS: Treatment effect was assessed with the Inflammatory Neuropathy Cause and Treatment disability scale and the Rivermead Mobility Index and was categorized using the CIDP Disease Activity Status (CDAS) scale. RESULTS: By March 2011, 39 out of 40 patients were included with a median follow-up of 4.5 years. Cure (>5 years off treatment) or remission according to the CDAS criteria after 1 or 2 courses of pulsed dexamethasone or daily prednisolone was achieved in 10 out of 39 patients (26%). Half of the patients who were in remission after initial treatment experienced a relapse (median treatment-free interval: 17.5 months for dexamethasone, 11 months for prednisolone). Alternative diagnosis was made in 7 out of 12 (58%) who did not respond to any therapy and in none of the treatment-responsive patients. CONCLUSIONS: Cure or long-term remission can be achieved in about one-quarter of patients with CIDP after 1 or 2 courses of pulsed dexamethasone or 8-month daily prednisolone. In treatment-nonresponsive patients, the diagnosis CIDP should be reconsidered. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that pulsed dexamethasone or 8-month daily prednisolone can lead to long-term remission in CIDP. PMID- 22442437 TI - Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation. PMID- 22442438 TI - Predicting outcome after acute basilar artery occlusion based on admission characteristics. AB - OBJECTIVE: To develop a simple prognostic model to predict outcome at 1 month after acute basilar artery occlusion (BAO) with readily available predictors. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational, international registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO. We considered predictors available at hospital admission in multivariable logistic regression models to predict poor outcome (modified Rankin Scale [mRS] score 4-5 or death) at 1 month. We used receiver operator characteristic curves to assess the discriminatory performance of the models. RESULTS: Of the 619 patients, 429 (69%) had a poor outcome at 1 month: 74 (12%) had a mRS score of 4, 115 (19%) had a mRS score of 5, and 240 (39%) had died. The main predictors of poor outcome were older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIH Stroke Scale (NIHSS) score, and longer time to treatment. A prognostic model that combined demographic data and stroke risk factors had an area under the receiver operating characteristic curve (AUC) of 0.64. This performance improved by including findings from the neurologic examination (AUC 0.79) and CT imaging (AUC 0.80). A risk chart showed predictions of poor outcome at 1 month varying from 25 to 96%. CONCLUSION: Poor outcome after BAO can be reliably predicted by a simple model that includes older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIHSS score, and longer time to treatment. PMID- 22442439 TI - No consistent evidence for association between mtDNA variants and Alzheimer disease. AB - OBJECTIVE: Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain. METHODS: We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis. RESULTS: In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD. CONCLUSION: The current evidence linking common mtDNA variations with AD is not compelling. PMID- 22442440 TI - Early visual memory deficits: a neuropsychological marker of GBA mutations in PD? PMID- 22442441 TI - Semaphorin 4A exerts a proangiogenic effect by enhancing vascular endothelial growth factor-A expression in macrophages. AB - The axon guidance cues semaphorins (Semas) and their receptors plexins have been shown to regulate both physiological and pathological angiogenesis. Sema4A plays an important role in the immune system by inducing T cell activation, but to date, the role of Sema4A in regulating the function of macrophages during the angiogenic and inflammatory processes remains unclear. In this study, we show that macrophage activation by TLR ligands LPS and polyinosinic-polycytidylic acid induced a time-dependent increase of Sema4A and its receptors PlexinB2 and PlexinD1. Moreover, in a thioglycollate-induced peritonitis mouse model, Sema4A was detected in circulating Ly6C(high) inflammatory monocytes and peritoneal macrophages. Acting via PlexinD1, exogenous Sema4A strongly increased macrophage migration. Of note, Sema4A-activated PlexinD1 enhanced the expression of vascular endothelial growth factor-A, but not of inflammatory chemokines. Sema4A stimulated macrophages were able to activate vascular endothelial growth factor receptor-2 and the PI3K/serine/threonine kinase Akt pathway in endothelial cells and to sustain their migration and in vivo angiogenesis. Remarkably, in an in vivo cardiac ischemia/reperfusion mouse model, Sema4A was highly expressed in macrophages recruited at the injured area. We conclude that Sema4A activates a specialized and restricted genetic program in macrophages able to sustain angiogenesis and participates in their recruitment and activation in inflammatory injuries. PMID- 22442442 TI - Activation of the classical complement pathway by Bacillus anthracis is the primary mechanism for spore phagocytosis and involves the spore surface protein BclA. AB - Interactions between spores of Bacillus anthracis and macrophages are critical for the development of anthrax infections, as spores are thought to use macrophages as vehicles to disseminate in the host. In this study, we report a novel mechanism for phagocytosis of B. anthracis spores. Murine macrophage-like cell line RAW264.7, bone marrow-derived macrophages, and primary peritoneal macrophages from mice were used. The results indicated that activation of the classical complement pathway (CCP) was a primary mechanism for spore phagocytosis. Phagocytosis was significantly reduced in the absence of C1q or C3. C3 fragments were found deposited on the spore surface, and the deposition was dependent on C1q and Ca(2+). C1q recruitment to the spore surface was mediated by the spore surface protein BclA, as recombinant BclA bound directly and specifically to C1q and inhibited C1q binding to spores in a dose-dependent manner. C1q binding to spores lacking BclA (DeltabclA) was also significantly reduced compared with wild-type spores. In addition, deposition of both C3 and C4 as well as phagocytosis of spores were significantly reduced when BclA was absent, but were not reduced in the absence of IgG, suggesting that BclA, but not IgG, is important in these processes. Taken together, these results support a model in which spores actively engage CCP primarily through BclA interaction with C1q, leading to CCP activation and opsonophagocytosis of spores in an IgG independent manner. These findings are likely to have significant implications on B. anthracis pathogenesis and microbial manipulation of complement. PMID- 22442443 TI - Antigen recognition is facilitated by invadosome-like protrusions formed by memory/effector T cells. AB - Adaptive immunity requires that T cells efficiently scan diverse cell surfaces to identify cognate Ag. However, the basic cellular mechanisms remain unclear. In this study, we investigated this process using vascular endothelial cells, APCs that possess a unique and extremely advantageous, planar morphology. High resolution imaging revealed that CD4 memory/effector T cells dynamically probe the endothelium by extending submicron-scale, actin-rich "invadosome/podosome like protrusions" (ILPs). The intimate intercellular contacts enforced by ILPs consistently preceded and supported T cell activation in response to endothelial MHC class II/Ag. The resulting calcium flux stabilized dense arrays of ILPs (each enriched in TCR, protein kinase C-theta, ZAP70, phosphotyrosine, and HS1), forming what we term a podo-synapse. Similar findings were made using CD8 CTLs on endothelium. Furthermore, careful re-examination of both traditional APC models and professional APCs suggests broad relevance for ILPs in facilitating Ag recognition. Together, our results indicate that ILPs function as sensory organelles that serve as actuators of immune surveillance. PMID- 22442444 TI - Inflammatory spleen monocytes can upregulate CD11c expression without converting into dendritic cells. AB - Monocytes can differentiate into various cell types with unique specializations depending on their environment. Under certain inflammatory conditions, monocytes upregulate expression of the dendritic cell marker CD11c together with MHC and costimulatory molecules. These phenotypic changes indicate monocyte differentiation into a specialized subset of dendritic cells (DCs), often referred to as monocyte-derived DCs or inflammatory DCs (iDCs), considered important mediators of immune responses under inflammatory conditions triggered by infection or vaccination. To characterize the relative contribution of cDCs and iDCs under conditions that induce strong immunity to coadministered Ags, we analyzed the behavior of spleen monocytes in response to anti-CD40 treatment. We found that under sterile inflammation in mice triggered by CD40 ligation, spleen monocytes can rapidly and uniformly exhibit signs of activation, including a surface phenotype typically associated with their conversion into DCs. These inflammatory monocytes remain closely related to their monocytic lineage, preserving expression of CD115, scavenging function, tissue distribution and poor capacity for Ag presentation characteristic of their monocyte precursors. In addition, 3-4 d after delivery of the inflammatory stimuli, these cells reverted to a monocyte-associated phenotype typical of the steady state. These findings indicate that, in response to anti-CD40 treatment, spleen monocytes are activated and express certain DC surface markers without acquiring functional characteristics associated with DCs. PMID- 22442446 TI - America's community colleges. PMID- 22442445 TI - Langerhans cells require MyD88-dependent signals for Candida albicans response but not for contact hypersensitivity or migration. AB - Langerhans cells (LC) are a subset of skin-resident dendritic cells (DC) that reside in the epidermis as immature DC, where they acquire Ag. A key step in the life cycle of LC is their activation into mature DC in response to various stimuli, including epicutaneous sensitization with hapten and skin infection with Candida albicans. Mature LC migrate to the skin-draining LN, where they present Ag to CD4 T cells and modulate the adaptive immune response. LC migration is thought to require the direct action of IL-1beta and IL-18 on LC. In addition, TLR ligands are present in C. albicans, and hapten sensitization produces endogenous TLR ligands. Both could contribute to LC activation. We generated Langerin-Cre MyD88(fl) mice in which LC are insensitive to IL-1 family members and most TLR ligands. LC migration in the steady state, after hapten sensitization and postinfection with C. albicans, was unaffected. Contact hypersensitivity in Langerin-Cre MyD88(fl) mice was similarly unaffected. Interestingly, in response to C. albicans infection, these mice displayed reduced proliferation of Ag-specific CD4 T cells and defective Th17 subset differentiation. Surface expression of costimulatory molecules was intact on LC, but expression of IL-1beta, IL-6, and IL-23 was reduced. Thus, sensitivity to MyD88-dependent signals is not required for LC migration, but is required for the full activation and function of LC in the setting of fungal infection. PMID- 22442451 TI - Ecological restoration. Seeking cures for North Korea's environmental ills. PMID- 22442452 TI - Newsmaker interview: Christof Koch. A vision of how mouse vision can reveal consciousness' secrets. Interview by Yudhijit Bhattacharjee. PMID- 22442453 TI - Immunology. Gut microbes keep rare immune cells in line. PMID- 22442454 TI - India. Field biologists cry foul over ban. PMID- 22442455 TI - Avionics. A flapping of wings. PMID- 22442456 TI - Avionics. It's a bird, it's a plane, it's a ... spy? PMID- 22442457 TI - Computational science. Materials scientists look to a data-intensive future. PMID- 22442458 TI - Seismology. Learning how to not make your own earthquakes. PMID- 22442459 TI - Finding a good research question, in theory. PMID- 22442460 TI - Science in Nepal needs neighborly aid. PMID- 22442461 TI - India lacks scientific leadership. PMID- 22442463 TI - Comment on "Productivity is a poor predictor of plant species richness". AB - Adler et al. (Reports, 23 September 2011, p. 1750) analyzed the standardized sampling data from 48 herbaceous-dominated plant communities and concluded that "Productivity is a poor predictor of plant species richness" at fine-scale. However, their method was biased toward site-number-dominated plant communities. They also failed to provide enough data for regional analysis and detailed information for within-site analysis. PMID- 22442464 TI - Comment on "Productivity is a poor predictor of plant species richness". AB - Adler et al. (Reports, 23 September 2011, p. 1750) reported "weak and variable" relationships between productivity and species richness and dispute the "humped back" model (HBM) of plant diversity. We show that their analysis lacks sufficient high-productivity sites, ignores litter, and excludes anthropogenic sites. If corrected, the data set of Adler et al. would apparently yield strong HBM support. PMID- 22442466 TI - Education. Entrepreneurship training for the developing world. PMID- 22442467 TI - Medicine. Old drug, new hope for Alzheimer's disease. PMID- 22442468 TI - Geophysics. At the bottom of the oceanic plate. PMID- 22442469 TI - Ecology. Keystones in a tangled bank. PMID- 22442470 TI - Plant science. How plants see the invisible. PMID- 22442471 TI - Paleontology. The hunters did it. PMID- 22442472 TI - Engineering. Searching for a better thermal battery. PMID- 22442473 TI - Neuroscience. The imaginary mind of a mouse. PMID- 22442474 TI - Retrospective. Oscar Miller (1925-2012). PMID- 22442475 TI - Photoacoustic tomography: in vivo imaging from organelles to organs. AB - Photoacoustic tomography (PAT) can create multiscale multicontrast images of living biological structures ranging from organelles to organs. This emerging technology overcomes the high degree of scattering of optical photons in biological tissue by making use of the photoacoustic effect. Light absorption by molecules creates a thermally induced pressure jump that launches ultrasonic waves, which are received by acoustic detectors to form images. Different implementations of PAT allow the spatial resolution to be scaled with the desired imaging depth in tissue while a high depth-to-resolution ratio is maintained. As a rule of thumb, the achievable spatial resolution is on the order of 1/200 of the desired imaging depth, which can reach up to 7 centimeters. PAT provides anatomical, functional, metabolic, molecular, and genetic contrasts of vasculature, hemodynamics, oxygen metabolism, biomarkers, and gene expression. We review the state of the art of PAT for both biological and clinical studies and discuss future prospects. PMID- 22442476 TI - Actinide topological insulator materials with strong interaction. AB - Topological band insulators have recently been discovered in spin-orbit coupled two-and three-dimensional systems. We theoretically predict a class of topological insulators where interaction effects play a dominant role. In actinide elements, simple rocksalt compounds formed by Pu and Am lie on the boundary between metals and insulators. We show that interaction drives a quantum phase transition to a topological insulator phase with a single Dirac cone on the surface. These putative topological insulators may provide a setting for both applied and fundamental investigation. PMID- 22442477 TI - Experimental realization of a magnetic cloak. AB - Invisibility to electromagnetic fields has become an exciting theoretical possibility. However, the experimental realization of electromagnetic cloaks has only been achieved starting from simplified approaches (for instance, based on ray approximation, canceling only some terms of the scattering fields, or hiding a bulge in a plane instead of an object in free space). Here, we demonstrate, directly from Maxwell equations, that a specially designed cylindrical superconductor-ferromagnetic bilayer can exactly cloak uniform static magnetic fields, and we experimentally confirmed this effect in an actual setup. PMID- 22442478 TI - Renewable cathode materials from biopolymer/conjugated polymer interpenetrating networks. AB - Renewable and cheap materials in electrodes could meet the need for low-cost, intermittent electrical energy storage in a renewable energy system if sufficient charge density is obtained. Brown liquor, the waste product from paper processing, contains lignin derivatives. Polymer cathodes can be prepared by electrochemical oxidation of pyrrole to polypyrrole in solutions of lignin derivatives. The quinone group in lignin is used for electron and proton storage and exchange during redox cycling, thus combining charge storage in lignin and polypyrrole in an interpenetrating polypyrrole/lignin composite. PMID- 22442479 TI - Iron-catalyzed cyclopropanation in 6 M KOH with in situ generation of diazomethane. AB - Diazomethane is a common and versatile reagent in organic synthesis whose broader use is generally impeded by its explosiveness and toxicity. Here we report that a simple iron porphyrin complex catalyzes the cyclopropanation of styrenes, enynes, and dienes under the demanding conditions [aqueous 6 molar potassium hydroxide (KOH) solution, open to air] necessary for the in situ generation of diazomethane from a water-soluble diazald derivative. A biphasic reaction medium arising from the immiscibility of the olefin substrates with water appears essential to the overall efficiency of the process. The work we describe highlights an approach to catalysis with untoward reactive intermediates, in which the conditions for their generation under operationally safe regimes dictate catalyst selection. PMID- 22442480 TI - The Gutenberg discontinuity: melt at the lithosphere-asthenosphere boundary. AB - The lithosphere-asthenosphere boundary (LAB) beneath ocean basins separates the upper thermal boundary layer of rigid, conductively cooling plates from the underlying ductile, convecting mantle. The origin of a seismic discontinuity associated with this interface, known as the Gutenberg discontinuity (G), remains enigmatic. High-frequency SS precursors sampling below the Pacific plate intermittently detect the G as a sharp, negative velocity contrast at 40- to 75 kilometer depth. These observations lie near the depth of the LAB in regions associated with recent surface volcanism and mantle melt production and are consistent with an intermittent layer of asthenospheric partial melt residing at the lithospheric base. I propose that the G reflectivity is regionally enhanced by dynamical processes that produce melt, including hot mantle upwellings, small scale convection, and fluid release during subduction. PMID- 22442481 TI - The aftermath of megafaunal extinction: ecosystem transformation in Pleistocene Australia. AB - Giant vertebrates dominated many Pleistocene ecosystems. Many were herbivores, and their sudden extinction in prehistory could have had large ecological impacts. We used a high-resolution 130,000-year environmental record to help resolve the cause and reconstruct the ecological consequences of extinction of Australia's megafauna. Our results suggest that human arrival rather than climate caused megafaunal extinction, which then triggered replacement of mixed rainforest by sclerophyll vegetation through a combination of direct effects on vegetation of relaxed herbivore pressure and increased fire in the landscape. This ecosystem shift was as large as any effect of climate change over the last glacial cycle, and indicates the magnitude of changes that may have followed megafaunal extinction elsewhere in the world. PMID- 22442482 TI - Specialization and rarity predict nonrandom loss of interactions from mutualist networks. AB - The loss of interactions from mutualistic networks could foreshadow both plant and animal species extinctions. Yet, the characteristics of interactions that predispose them to disruption are largely unknown. We analyzed 12 pollination webs from isolated hills ("sierras"), in Argentina, ranging from tens to thousands of hectares. We found evidence of nonrandom loss of interactions with decreasing sierra size. Low interaction frequency and high specialization between interacting partners contributed additively to increase the vulnerability of interactions to disruption. Interactions between generalists in the largest sierras were ubiquitous across sierras, but many of them lost their central structural role in the smallest sierras. Thus, particular configurations of interaction networks, along with unique ecological relations and evolutionary pathways, could be lost forever after habitat reduction. PMID- 22442483 TI - Evolutionary conservation of species' roles in food webs. AB - Studies of ecological networks (the web of interactions between species in a community) demonstrate an intricate link between a community's structure and its long-term viability. It remains unclear, however, how much a community's persistence depends on the identities of the species present, or how much the role played by each species varies as a function of the community in which it is found. We measured species' roles by studying how species are embedded within the overall network and the subsequent dynamic implications. Using data from 32 empirical food webs, we find that species' roles and dynamic importance are inherent species attributes and can be extrapolated across communities on the basis of taxonomic classification alone. Our results illustrate the variability of roles across species and communities and the relative importance of distinct species groups when attempting to conserve ecological communities. PMID- 22442484 TI - MARF1 regulates essential oogenic processes in mice. AB - Development of fertilization-competent oocytes depends on integrated processes controlling meiosis, cytoplasmic development, and maintenance of genomic integrity. We show that meiosis arrest female 1 (MARF1) is required for these processes in mammalian oocytes. Mutations of Marf1 cause female infertility characterized by up-regulation of a cohort of transcripts, increased retrotransposon expression, defective cytoplasmic maturation, and meiotic arrest. Up-regulation of protein phosphatase 2 catalytic subunit (PPP2CB) is key to the meiotic arrest phenotype. Moreover, Iap and Line1 retrotransposon messenger RNAs are also up-regulated, and, concomitantly, DNA double-strand breaks are elevated in mutant oocytes. Therefore MARF1, by suppressing levels of specific transcripts, is an essential regulator of important oogenic processes leading to female fertility and the development of healthy offspring. PMID- 22442485 TI - Trim28 is required for epigenetic stability during mouse oocyte to embryo transition. AB - Phenotypic variability in genetic disease is usually attributed to genetic background variation or environmental influence. Here, we show that deletion of a single gene, Trim28 (Kap1 or Tif1beta), from the maternal germ line alone, on an otherwise identical genetic background, results in severe phenotypic and epigenetic variability that leads to embryonic lethality. We identify early and minute epigenetic variations in blastomeres of the preimplantation embryo of these animals, suggesting that the embryonic lethality may result from the misregulation of genomic imprinting in mice lacking maternal Trim28. Our results reveal the long-range effects of a maternal gene deletion on epigenetic memory and illustrate the delicate equilibrium of maternal and zygotic factors during nuclear reprogramming. PMID- 22442486 TI - Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. AB - The hippocampus and entorhinal cortex play a pivotal role in spatial learning and memory. The two forebrain regions are highly interconnected via excitatory pathways. Using optogenetic tools, we identified and characterized long-range gamma-aminobutyric acid-releasing (GABAergic) neurons that provide a bidirectional hippocampal-entorhinal inhibitory connectivity and preferentially target GABAergic interneurons. Activation of long-range GABAergic axons enhances sub- and suprathreshold rhythmic theta activity of postsynaptic neurons in the target areas. PMID- 22442487 TI - Generation of a synthetic memory trace. AB - We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning. PMID- 22442488 TI - Comment on "Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b(+)Gr1(+) cells". PMID- 22442489 TI - Comment on "Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors". PMID- 22442490 TI - Colonel Bruton's kinase defined the molecular basis of X-linked agammaglobulinemia, the first primary immunodeficiency. PMID- 22442491 TI - Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. 1993. PMID- 22442492 TI - The gene involved in X-linked agammaglobulinaemia is a member of the Src family of protein-tyrosine kinases. 1993. PMID- 22442493 TI - Inhibitory receptors on lymphocytes: insights from infections. AB - Costimulatory and inhibitory receptors are critical regulators of adaptive immune cell function. These pathways regulate the initiation and termination of effective immune responses to infections while limiting autoimmunity and/or immunopathology. This review focuses on recent advances in our understanding of inhibitory receptor pathways and their roles in different diseases and/or infections, emphasizing potential clinical applications and important unanswered mechanistic questions. Although significant progress has been made in defining the influence of inhibitory receptors at the cellular level, relatively little is known about the underlying molecular pathways. We discuss our current understanding of the molecular mechanisms for key inhibitory receptor pathways, highlight major gaps in knowledge, and explore current and future clinical applications. PMID- 22442494 TI - Secreted virulence factors and immune evasion in visceral leishmaniasis. AB - Evasion or subversion of host immune responses is a well-established paradigm in infection with visceralizing leishmania. In this review, we summarize current findings supporting a model in which leishmania target host regulatory molecules and pathways, such as the PTP SHP-1 and the PI3K/Akt signaling cascade, to prevent effective macrophage activation. Furthermore, we describe how virulence factors, secreted by leishmania, interfere with macrophage intracellular signaling. Finally, we discuss mechanisms of secretion and provide evidence that leishmania use a remarkably adept, exosome-based secretion mechanism to export and deliver effector molecules to host cells. In addition to representing a novel mechanism for trafficking of virulence factors across membranes, recent findings indicate that leishmania exosomes may have potential as vaccine candidates. PMID- 22442495 TI - Highly pathogenic avian influenza viruses inhibit effective immune responses of human blood-derived macrophages. AB - Systemic infections with HPAIVs, such as H5N1, are characterized by cytokine burst and sepsis. We investigated the role of human monocyte-derived macrophages in these events after infection with different influenza virus strains. Macrophages were infected with low pathogenic H1N1 (PR8) or high pathogenic H7N7 (FPV) and H5N1 (KAN-1) subtypes. Macrophages were found to be nonpermissive for influenza virus propagation. Surprisingly, transcriptome analysis revealed an insufficient innate immune response of macrophages only to HPAIV infections. Induction of inflammatory cytokines, as well as type I IFNs, was significantly attenuated in H5N1- and H7N7-infected cells, contradicting a primary role of macrophages for the cytokine burst. Furthermore, inflammasome activation was impaired significantly in HPAIV-infected macrophages. Interestingly, this finding correlated with a complete suppression of viral protein M2 expression after HPAIV infection, which is known to be involved in influenza viral inflammasome activation. In summary, our data provide first evidences for a strategy of how HPAIVs avoid initial inflammatory responses of macrophages facilitating virus spreading and progression to the systemic stage of disease. PMID- 22442496 TI - The multiple facets of thymic stromal lymphopoietin (TSLP) during allergic inflammation and beyond. AB - Originally shown to promote the growth and activation of B cells, TSLP is now known to have wide-ranging impacts on hematopoietic and nonhematopoietic cell lineages, including DCs, basophils, eosinophils, mast cells, CD4(+), CD8(+), and NK T cells, B cells, and epithelial cells. Whereas the role of TSLP in the promotion of TH2 responses has been studied extensively in the context of lung- and skin-specific allergic disorders, it is becoming increasingly clear that TSLP may impact multiple disease states within multiple organ systems, including the blockade of TH1/TH17 responses and the promotion of cancer and autoimmunity. This review will highlight recent advances in the understanding of TSLP signal transduction, as well as the role of TSLP in allergy, autoimmunity, and cancer. Importantly, these insights into the multifaceted roles of TSLP could potentially allow for novel, therapeutic manipulations of these disorders. PMID- 22442497 TI - Cardiac-specific knockout of ET(A) receptor mitigates low ambient temperature induced cardiac hypertrophy and contractile dysfunction. AB - Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ET(A) receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4 degrees C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca(2+) properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1alpha were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca(2+) release, prolonged intracellular Ca(2+) decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1alpha as well as upregulated UCP2 and activation of GSK3beta, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1 induced cardiac anomalies. The GSK3beta inhibitor SB216763 ablated cold stress induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function. PMID- 22442499 TI - Enantioselective Pictet-Spengler Reactions of Isatins for the Synthesis of Spiroindolones. AB - The condensation cyclization between isatins and 5-methoxy tryptamine catalyzed by chiral phosphoric acids provides spirooxindole tetrahydro-beta-carboline products in excellent yields (up to 99%) and enantioselectivity (up to 98:2 er). A comparison of catalysts provides insight for the substrate scope and factors responsible for efficient catalytic activity and selectivity in the spirocyclization. Chiral phosphoric acids with different 3,3'-substitution on the binaphthyl system and opposite axial chirality afford the spiroindolone product with the same absolute configuration. PMID- 22442500 TI - Computational Development of Jacobian Matrices for Complex Spatial Manipulators. AB - Current methods for developing manipulator Jacobian matrices are based on traditional kinematic descriptions such as Denavit and Hartenberg parameters. The resulting symbolic equations for these matrices become cumbersome and computationally inefficient when dealing with more complex spatial manipulators, such as those seen in the field of biomechanics. This paper develops a modified method for Jacobian development based on generalized kinematic equations that incorporates partial derivatives of matrices with Leibniz's Law (the product rule). It is shown that a set of symbolic matrix functions can be derived that improve computational efficiency when used in MATLAB((r)) M-Files and are applicable to any spatial manipulator. An articulated arm subassembly and a musculoskeletal model of the hand are used as examples. PMID- 22442501 TI - JGES: An Open Access Peer Reviewed Journal is Born. PMID- 22442502 TI - A new journal and a new beginning in knowledge creation and dissemination. PMID- 22442503 TI - Entry complications in laparoscopic surgery. AB - To review the complications associated with laparoscopic surgery and provide clinical direction regarding the best practice based on the best available evidence. The laparoscopic entry techniques and technologies reviewed include the classic pneumoperitoneum (Veress/trocar), the open (Hasson), the direct trocar insertion, the use of disposable shielded trocars, radially expanding trocars and visual entry systems. Medline, Pubmed and Cochrane Databases were searched for English language articles published before December 2008. It is an evidence based fact that minimal access surgery is superior to conventional open surgery since this is beneficial to the women, community and the healthcare system.Over the past 50 years, many techniques, technologies and guidelines have been introduced to eliminate the risks associated with laparoscopic entry. No single technique or instrument has been proved to eliminate laparoscopic entry associated injury. Proper evaluation of the women, supported by surgical skills and good knowledge of the technology and instrumentation is the keystone to safe access and prevention of complications during laparoscopic surgery. PMID- 22442504 TI - Hydrosalpinx functional surgery or salpingectomy? The importance of hydrosalpinx fluid in assisted reproductive technologies. AB - The first IVF baby, Louise Brown, was born in a natural cycle IVF of a woman who had bilateral tubal block making IVF the only option for having a child. The last 3 decades has seen astounding progress in the field of ART. Today thanks to ART, tubal disease and tubal factor infertility is easily overcome. The accepted theory today is that the hydrosalpinx fluid plays a causative role in the reduced pregnancy rate with ART. It is well known that the success of ART for patients with tubal disease with hydrosalpinx is reduced by half compared with patients without hydrosalpinx. Ideal would be removal of a hydrosalpinx by laparoscopic salpingectomy to improve pregnancy rates. However in some cases this is not feasible due to dense pelvic adhesions making access difficult. In such cases it is recommended that even de-linking the tube from the uterus would help in improving the ART outcome. There is suggestion that sonographically visible hydrosalpinges and those affected bilaterally have a poorer prognosis than those seen incidentally at laparoscopy. While there is clinical evidence supporting the causative role of the fluid itself, there is a lack of knowledge as to how the fluid exerts its negative effects. It is generally believed that the fluid holds a key position in impairing implantation potential. The aim of this review is to highlight the importance of identifying hydrosalpinges and its association with reduced fertility outcome using assisted reproductive technologies. Here we have discussed the different options available for the same, and highlighted the current modes of treatment. PMID- 22442505 TI - Reproductive performance after hysteroscopic metroplasty in women with primary infertility and septate uterus. AB - BACKGROUND: There is enough evidence in the literature to support that removal of septum improves pregnancy rates in women with bad obstetric history. However, its role in patients with otherwise unexplained infertility is still not clear due to paucity of enough evidence. OBJECTIVE: To assess reproductive performance in women with septate uterus and otherwise unexplained infertility after hysteroscopic metroplasty. MATERIALS AND METHODS: 72 women with septate uterus and otherwise unexplained primary infertility were included in the study. All these women underwent hysteroscopic septal resection. Reproductive performance of these women within one year of surgery was studied and analysed. RESULT: 33 women (45.83%) conceived within one year of surgery. Only 4 women (12%) had spontaneous abortions and only 5 (15%) had preterm delivery. CONCLUSION: Hysteroscopic metroplasty in women with septate uterus significantly improves the reproductive performance. PMID- 22442506 TI - Detorsion and conservative therapy for twisted adnexa: our experience. AB - OBJECTIVE: 1) To determine if detorsion of the twisted adnexa is better than traditional adnexectomy to conserve the adnexa and preserve its function. 2) To determine the feasibility of detorsion in conservation of adnexa. DESIGN: Prospective Study from September 2004 to September 2008. SETTING: Private IVF and Endoscopy Centre. PATIENTS: 22 patients with twisted adnexa (15 non-pregnant and 7 pregnant). INTERVENTION: Surgical intervention and either detorsion of adnexa or adnexectomy. MAIN OUTCOME MEASURES: Ovarian preservation and conservation of ovarian function in 77.2% cases determined by: a) Follicular development on sonography (performed for one year after adnexectomy). b) Subsequent surgery for unrelated cause showing healthy ovaries. c) controlled ovarian hyperstimulation and successful oocyte retrieval subsequently. RESULTS: We could conserve the adenexa in 77.2% cases. Laparoscopic detorsion was performed in 11/15(73.33 %) of non-pregnant women and adnexectomy done in four women 26.66%. Among the seven pregnant women, adnexa could be preserved in 6/7(85.7%) and only one woman required adnexectomy. Laparotomy was required in 2/22(9%) women both of which were in late second trimester of pregnancy. In one case (4.54%) we had recurrence of torsion. 88.23% of the women with conserved adnexa showed preservation of ovarian function. CONCLUSION: Our study showed that timely diagnosis and intervention could make the difference between ovarian loss and salvage- an outcome of great importance in population of reproductive age females. Laparoscopy with its many benefits proves to be superior to laparotomy. PMID- 22442507 TI - Role of hysteroscopy prior to assisted reproductive techniques. AB - BACKGROUND: There have been numerous advances in the area of assisted reproduction. Among the various reasons of implantation failure, intrauterine lesions play an important role. OBJECTIVE: The aim of the present study is to evaluate the role of hysteroscopy prior to any assisted reproductive technique. MATERIALS AND METHODS: It is a retrospective study of 292 women who attended our infertility clinic over a period of 18 months, who had a variable number of failed IVF cycles previously. RESULTS: Out of the 292 women studied, in 74 women, that is 25%, intrauterine pathology was detected, which when rectified by hysteroscopy, gave a considerable increase in pregnancy rate. CONCLUSION: According to this study it can be concluded that evaluating the uterine cavity is an important step before any assisted reproductive procedures. PMID- 22442508 TI - Thermal balloon endometrial ablation in dysfunctional uterine bleeding. AB - INTRODUCTION: Dysfunctional uterine bleeding (DUB) affects a large number of women in the reproductive and perimenopausal age group. It significantly impairs the quality of life in otherwise healthy women. There are many different techniques for the conservative management of DUB. Medical management, LNG-IUD, hysteroscopic resection and various global ablation techniques. MATERIALS AND METHODS: We did a retrospective analysis of 156 women with dysfunctional uterine bleeding who had completed childbearing and who underwent uterine balloon ablation therapy using the Thermachoice device. Majority of the women (72%) were done using short general anesthesia while in the others sedation or local anesthesia was used. RESULTS: 49% women had amenorrhea while 41 % had oligomenorhoea or eumenorrhoea. 90% were satisfied with the procedure. There were no major complications during this study. CONCLUSIONS: Thermal balloon endometrial ablation is a simple, safe and effective technique for the permanent treatment of DUB in well selected cases. PMID- 22442509 TI - Total laparoscopic hysterectomy for large uterus. AB - AIM: In this review, we assessed the feasibility of total laparoscopic hysterectomy (TLH) in cases of very large uteri weighing more than 500 grams. We have analyzed whether it is possible for an experienced laparoscopic surgeon to perform efficient total laparoscopic hysterectomy for large myomatous uteri regardless of the size, number and location of the myomas. DESIGN: Retrospective review (Canadian Task Force Classification II-1) SETTING: Dedicated high volume Gynecological laparoscopy centre. PATIENTS: 173 women with symptomatic myomas who underwent total laparoscopic hysterectomy at our center. There were no exclusion criteria based on the size number or location of myomas. INTERVENTION: TLH and modifications of performing the surgery by ligating the uterine arteries prior, myomectomy followed by hysterectomy, direct morcellation after uterine artery ligation. RESULTS: 72% of patients had previous normal vaginal delivery and 28% had previous cesarean section. Average clinical size of the uterus was 18 weeks (10, 32). The average weight of the specimen was 700 grams (500, 2240). The average duration of surgery was 107 min (40, 300) and the average blood loss was 228 ml (10, 3200). CONCLUSION: Total laparoscopic hysterectomy is a technically feasible procedure. It can be performed by experienced surgeons for large uteri regardless of the size, number or location of the myomas. PMID- 22442510 TI - Comparison of Complications Rates in Endoscopic Surgery Performed by a Clinical Assistant vs. An Experienced Endoscopic Surgeon. AB - STUDY OBJECTIVES: (a) To find out the actual incidence of complications during endoscopic surgeries. (b) Comparison of complication rate between an experienced laparoscopic surgeon (> 10 years of experience in endoscopic surgery) and a clinical assistant (> 3 years of experience in endoscopic surgery). (c) How to manage complications in endoscopic surgery. (d) Concrete suggestions to reduce the complication rate. DESIGN: Retrospective study (Canadian Task Force classification ii-2). SETTING: Tertiary gynecologic endoscopic unit. PATIENTS: A total of 3204 cases of gynecologic endoscopic surgery out of which 2001 were laparoscopic and 1203 were hysteroscopic surgeries. INTERVENTIONS: Laparoscopic and hysteroscopic gynecologic surgeries in indicated cases. MEASUREMENTS AND MAIN RESULTS: The study was carried out between April 2003 and October 2007 at a referral center for endoscopic surgery. A total of 3204 cases of gynecologic endoscopic surgery were studied. There were five significant complications in laparoscopic surgeries and four significant complications in hysteroscopic surgeries seen in four years and six months. All the complications could be managed with no mortality. Conversion to laparotomy was needed in eight cases of laparoscopic surgeries and none in hysteroscopic surgeries. CONCLUSION: The risk of complication reduces with the experience in endoscopic surgery. However, the proper grooming of a novice in experienced hands, for a sufficient period of time, can minimize the complication rate in the initial learning phase. The complication may be utilized as a stepping-stone to overcome any given situation without panic, but with adequate safety. PMID- 22442511 TI - Predisposing factors for fibroids and outcome of laparoscopic myomectomy in infertility. AB - INTRODUCTION: Fibroids are very common tumors affecting women for centuries, however surprising that no significant data is still available as to what could be the cause of fibroid? What could be the predisposing or risk factors? Does it has any impact on fertility? Outcomes of Laparoscopic myomectomy in infertility? SETTING: Advanced Tertiary Gynecologic endoscopic unit. AIMS AND OBJECTIVES: 1) What are the predisposing factors to develop fibroids? 2) Do fibroids lead to infertility? 3) What are the indications for removal of fibroids in infertility? 4) Is laparoscopic surgery better than open surgery? 5) Is the risk of rupture uterus more after laparoscopic myomectomy? 6) What is the success in terms of pregnancy rate after myomectomy? 7) What are the chances of abortions with or without myomectomy? MATERIALS AND METHODS: A retrospective research study was carried out on 2540 women at the National Institute of Laser and Endoscopic Surgery and Aakar IVF Centre, Mumbai, a referral centre in India. This study was done over a period of 14 years. Women varied in age from 23 to 51 years and infertility of at least more than three years. The woman had fibroids from one to seventeen in number and two centimeters to eighteen centimeters in size which were either submucous, intramural, serosal, cervical or broad ligament. The women requiring hysteroscopic myoma resection were excluded in this study and Laparoscopic myomectomy done in woman other than infertility are also excluded from the study. RESULTS: During the course of our study we found that the diet, weight, hypertension, habits had a bearing on incidence of fibroid. In one of the most promising research fact we found that fibroids itself produce prolactin and due to three times high level of aromatase had higher level of estradiol locally compared to normal myometrium. This was detrimental to fertility. A mild elevation of blood levels of prolactin usually in the range of 40 - 60 ng/ml was noticed in nearly 42% of the cases. Fibroids with infertility as a major complaint along with excessive vaginal bleeding in 33%, pain abdomen and dysmenorhea 10%, pressure symptoms in 3%, accidental finding of a large mass in 5% were the major indications for laparoscopic myomectomy. The pregnancy rate after removal of fibroids with active fertility treatment was 42 % and in donor oocyte IVF was 50%, abortion rate was 5%, 64% LSCS, 31% vaginal deliveries. There was no scar rupture in all pregnancies post laparoscopic myomectomy. CONCLUSION: Presence of fibroids in first degree female relative, predominantly red meat eating women, excess weight and high Blood pressure increased incidence of fibroids. Pregnancies & oral contraceptives decreased chances of fibroids. In infertile patient fibroids of significant size, multiple, had high local prolactin & aromatase level affecting fertility. Laparoscopic removal of fibroids increased pregnancy rate to 37.2% & 50% in donor oocyte IVF. PMID- 22442512 TI - Large bowel injury during total laparoscopic hysterectomy. AB - Large bowel injuries are unfortunate complications of laparoscopic surgery, with an incidence of 0.62 to 1.6 per 1000 laparoscopies. One-third of these injuries can be diagnosed intraoperatively, with the rest going unnoticed and revealed later. Rectal injury, a very rare complication, may be caused during pelvic dissection of dense adhesions. Injury at the rectosigmoid junction due to traction with a rectal probe is extremely rare and highly underreported. We report a case of rectal injury during total laparoscopic hysterectomy in a case with dense pelvic adhesions. PMID- 22442513 TI - Unusual laparoscopy finding with previous laparotomy for endometrioma: a rare case report. AB - An unmarried girl with severe dysmenorrhea had laparotomy for bilateral endometriomas, later treated with danazol and GnRHa Depo injection for more than three years. On laparoscopy she had a large, noncommunicating, functioning rudimentary horn with ipsilateral renal agenesis. Laparoscopic excision of the rudimentary horn gave major relief from the suspected endometrioma, which was not the cause of her severe pain. PMID- 22442515 TI - JGES as a Platform for Knowledge Dissemination. PMID- 22442514 TI - President's Message for IAGE Journal. PMID- 22442516 TI - Law demands "care" - not "cure". AB - In today's medicolegal scenario specially related to endoscopic surgery, patient expects a miraculous result or a definite cure. However the author who has experience of both the fields i.e. gynecological endoscopy and medicolegal aspects, clears that the law doesn't expect a 100% cure but expects proper medical care by the concerned gynecologist, gynecological endoscopist. Patient also has to be informed about this important fact. PMID- 22442517 TI - Laparoscopic management of large myomas. AB - The objective of this article is to review the different techniques that have been adopted for removal of large myomas laparoscopically. We have also quoted literature about the impact of myomas on Pregnancy and obstetrical outcome and the effect of laparoscopic myomectomy on the same. Technical modifications to remove large myomas have been described along with methods to reduce intraoperative bleeding. This comprehensive review describes all possibilities of laparoscopic myomectomy irrespective of size, site and number. PMID- 22442518 TI - Do new vessel sealing devices and harmonic ace increase ureteric injury in total laparoscopic hysterectomy? AB - OBJECTIVES: To compare the risk of ureteric injury in total laparoscopic hysterectomy (TLH) using new vessel sealing devices (VSDs) and harmonic scalpel with simple scissors, bipolar and suturing. This was an evaluation of 1209 cases, carried out from May 1999 to April 2010. DESIGN AND SETTING: A retrospective comparative study was carried out at a tertiary gynecological endoscopic unit. MATERIALS AND METHODS: Out of 1209 patients, who had hysterectomies for various indications, TLH was done in 892 patients, 273 had vaginal hysterectomy and 44 had abdominal hysterectomy. We evaluated the incidence of ureteric injury in these cases. RESULTS: There was no mortality. In the group of vaginal and abdominal hysterectomy, there were no ureteric injuries. In the TLH group, we had 390 cases with simple scissors, bipolar and suturing with no ureteric injury. In 502 cases, new VSDs, e.g., plasma kinetic gyrus, Martin Maxim with Robi grasper, with or without harmonic 5 mm scalpel/ace were used. There were five ureteric injuries, all on the right side (one double ureter): first case was with Martin Maxim and Robi grasper, two with plasma kinetic gyrus 10 mm trissector, one with harmonic scalpel and the last one with scissors. We evaluated the reasons for such ureteric injuries, with experienced laparoscopic surgeons and the best possible set up. There were seven conversions to open surgery out of 892 cases of TLH, more due to poor case selection. PMID- 22442519 TI - Hysteroscopy in postmenopausal bleeding. AB - OBJECTIVES: 1) To study the etiology of postmenopausal bleeding (PMB). 2) To study the significance of hysteroscopy in evaluation of the etiopathogenic factors. 3) Correlating the diagnosis after transvaginal sonography (TVS), hysteroscopy and histopathologic diagnosis. 4) Feasibility of conservative management with hysteroscopy in PMB. DESIGN: Prospective study from January 2008 to June 2009. SETTING: Department of Obstetrics and Gynecology of Ruby Hall Clinic, Pune. PATIENTS: Sixty postmenopausal women with complaint of bleeding per vaginum. INTERVENTIONS: Clinical and sonographic evaluation, followed by diagnostic and/or therapeutic hysteroscopy and guided biopsy. Hysteroscopic images were analyzed and compared with histopathologic results. MEASUREMENTS AND MAIN RESULTS: On hysteroscopy, endometrium was classified as suggestive of normal, atrophic, endometrial hyperplasia or endometrial carcinoma. Histopathologic diagnosis is taken as a gold standard to determine the efficacy of hysteroscopy in diagnosing endometrial pathologies. The sensitivity and specificity of hysteroscopy in diagnosing endometrial pathologies was assessed. CONCLUSIONS: In women with PMB, hysteroscopy is the basic tool that allows precise diagnosis of various endouterine pathologies. The average sensitivity of hysteroscopy was 97% in our study and the specificity was 98.66%. Hence, we can conclude that it is highly accurate for evaluating endometrial pathologies. For obvious benign lesions, it also provides treatment in the same sitting, therefore avoiding an extensive, morbid, and expensive procedure like hysterectomy. PMID- 22442520 TI - Laparoscopic management of large ovarian cysts at a rural hospital. AB - OBJECTIVE: To assess the feasibility and outcome of laparoscopic surgery for the management of large ovarian cysts at a rural hospital. MATERIALS AND METHODS: Fifteen patients from March 2004 to February 2007, with large ovarian cysts, with diameter >10 cm, were managed laparoscopically. The masses were cystic and were not associated with ascites or enlarged lymph nodes on ultrasound. Serum CA-125 levels were within the normal range (35 U/ml). Preoperative evaluation included history, clinical examination, sonographic images and serum markers. The management of these ovarian cysts included aspiration, cystectomy or salphingo oophorectomy, depending on the patient's age, obstetric history and desire of future fertility. In large, solid, fixed or irregular adnexal masses, suspicious of malignancy, laparotomy was done. RESULTS: Five patients presented with pain in the abdomen and 10 patients with abdominal distension and discomfort. The average maximum diameter of the ovarian cysts was 16.75 cm (range 10-24 cm). The mean duration of the operation was 80 min. The postoperative hospital stay was from 4 to 6 days. No intraoperative complications occurred and the hospital course of all patients was uncomplicated. In one case, laparoscopy was converted to laparotomy. One patient had minor wound infection at umbilical port site. The patients did not report any complaints during follow up and the clinical examination findings were normal in all, up to 9 months after discharge. CONCLUSION: With proper patient selection, the size of an ovarian cyst is not necessarily a contraindication for laparoscopic surgery. PMID- 22442521 TI - Role of diagnostic hysteroscopy in abnormal uterine bleeding and its histopathologic correlation. AB - AIMS AND OBJECTIVES: To study the accuracy of hysteroscopy in evaluation of abnormal uterine bleeding and to correlate hysteroscopic findings with histopathologic findings. MATERIALS AND METHODS: A prospective study was carried out in the Department of Obstetrics and Gynecology at AVBRH and JNMC, Sawangi (M), Wardha, from May 2006 to September 2008. One hundred cases were selected for this study from patients of age group 18 and above, who were admitted with the history of abnormal uterine bleeding. Hysteroscopic examination was done in all patients post-menstrually, whenever possible, except in those cases where menstrual cycles were grossly irregular or patients came with continuous bleeding per vaginum. The patients then underwent dilatation and curettage and endometrium was sent for histopathologic examination. The correlation between findings on hysteroscopy and histopathologic examination was tabulated. RESULTS: FOLLOWING WERE THE FINDINGS ON HYSTEROSCOPY: proliferative 34%, secretary 16%, hyperplasia 18%, atrophic 8%, endometrial polyp 9%, submucous myoma 11%, carcinoma of endometrium 03%, misplaced Cu-T 1%. CONCLUSION: In patients with abnormal uterine bleeding, hyster-oscopy provides more accurate dia-gnosis than dilatation and curettage. PMID- 22442522 TI - A Comparative Evaluation of Suburethral and Transobturator Sling in 209 Cases with Stress Urinary Incontinence in 8 years. AB - AIMS AND OBJECTIVES: To evaluate the outcome of suburethral and transobturator sling in treatment of female stress urinary incontinence in 209 cases from 2002 to 2010. The criteria evaluated were success, failure, complications, operating time, ease of the procedure, availability and cost effectivity of the sling. DESIGN AND SETTING: A retrospective comparative study was carried out at a tertiary referral centre for female urinary incontinence. MATERIAL AND METHODS: A total of 209 patients (females from 27 to 79 years of age) with proven stress urinary incontinence were treated by suburethral transvaginal tape (TVT) type of slings in 101 cases and transobturator Monarc type of sling in 108 cases at the National Institute of Endoscopic Surgery and Urinary Incontinence Center, Mumbai, India, from March 2002 to June 2010. The maximum follow up was for 8 years. RESULTS: The TVT type of slings had higher complication rate like needle entering the bladder, retention of urine necessitating to cut the tape in the center and had a success rate of 94.5% compared to Monarc/Trivedi obturator tape (TrOT) type of sling with outside-in technique, which had a negligible complication (less than 1%), pain in groin or leg movement that reduced in 6 weeks and a success rate of 95%. Specially, the Indian design Trivedi's stress urinary incontinence tape (TSUIT) and TrOT with reusable needles, the cost was only 15-20% of the international brands. PMID- 22442523 TI - Parasitic myoma after morcellation. AB - We report an interesting case of parasitic fibroid which developed from a morcellation remnant following laparoscopic myomectomy. The patient presented with incidental finding of pelvic mass in 2005. She underwent laparoscopic myomectomy for a myoma extending from the Pouch of Douglas to both sides of broad ligament. She subsequently presented with abdominal pain 3 years later in 2008. She underwent total laparoscopic hysterectomy with removal of broad ligament fibroids. During her hysterectomy, a right lumbar mass attached to the omentum was detected, which was excised laparoscopically. Histopathology of the mass confirmed it to be consistent with leiomyoma. This mass could probably be a morcellation remnant that has grown to this size taking blood supply from the omentum. We report this case to emphasize that all tissue pieces that are morcellated should be diligently removed. Even small bits displaced into the upper abdomen can result in parasitic fibroids. Thus, it can be concluded that parasitic myomas can arise from morcellated remnants and grow depending on the blood supply. PMID- 22442524 TI - Angioleiomyoma of broad ligament. AB - Angioleiomyoma is an uncommon benign mesenchymal neoplasm that originates from smooth muscle cells and contains numerous thick-walled blood vessels. Here, we are presenting a case report of a huge broad ligament angioleiomyoma because of its rarity. PMID- 22442525 TI - The magic lies in the magician, not in the wand. PMID- 22442526 TI - President's Message for IAGE Journal. PMID- 22442527 TI - Laparoscopic myomectomy with uterine artery ligation: review article and comparative analysis. AB - Uterine leiomyomas are one of the most common benign smooth muscle tumors in women, with a prevalence of 20 to 40% in women over the age of 35 years. Although many women are asymptomatic, problems such as bleeding, pelvic pain, and infertility may necessitate treatment. Laparoscopic myomectomy is one of the treatment options for myomas. The major concern of myomectomy either by open method or by laparoscopy is the bleeding encountered during the procedure. Most studies have aimed at ways of reducing blood loss during myomectomy. There are various ways in which bleeding during laparoscopic myomectomy can be reduced, the most reliable of which is ligation of the uterine vessels bilaterally. In this review we propose to discuss the benefits and possible disadvantages of ligating the uterine arteries bilaterally before performing laparoscopic myomectomy. PMID- 22442528 TI - Single-port access laparoscopic hysterectomy: a new dimension of minimally invasive surgery. AB - The fundamental idea is to have all of the laparoscopic working ports entering the abdominal wall through the same incision. Single-incision laparoscopic surgery is an alternative to conventional multiport laparoscopy. Single-access laparoscopy using a transumbilical port affords maximum cosmetic benefits because the surgical incision is hidden in the umbilicus and reduces morbidity of minimally invasive surgery. The advantages of single-access laparoscopic surgery may include less bleeding, infection, and hernia formation and better cosmetic outcome and less pain. The disadvantages and limitations include longer surgery time, difficulty in learning the technique, and the need for specialized instruments. This review summarizes the history of SPAL hysterectomy (single-port access laparoscopy), and emphasizes nomenclature, surgical technique, instrumentation, and perioperative outcomes. Specific gynecological applications of single-port hysterectomy to date are summarized. Using the PubMed database, the English-language literature was reviewed for the past 40 years. Keyword searches included scarless, scar free, single-port/trocar/incision, single-port access laparoscopic hysterectomy. Within the bibliography of selected references, additional sources were retrieved. The purpose of the present article was to review the development and current status of SPAL hysterectomy and highlight important advances associated with this innovative approach. PMID- 22442529 TI - Anesthesia concerns in laparoscopic myomectomy. AB - Recent advances in the practice of anesthsiology ensure that we move closer to our goal of zero morbidity. It is of critical importance that we couple our clinical expertise with the sophisticated monitoring equipment and get the best out of them. PMID- 22442530 TI - Adhesion prevention in myomectomy. AB - Adhesions are abnormal fibrous connections, joining tissue surfaces in abnormal locations. Adhesions form after any trauma involving the peritoneum and the injured tissue surface or directly between the injured tissue surfaces. The ideal anti-adhesion agent should be safe, efficacious, easy to use in all types of surgery, and economical. It should prevent adhesions at the site of surgery as well as throughout the peritoneal cavity. Needless to say, the ideal agent is still elusive. PMID- 22442531 TI - Actionable 'deficiencies' in medical practice. AB - Services provided by healthcare providers have been the subject matter of judicial review time and again. The Consumer Disputes Redressal Commissions have laid down decisively what is and what is not 'deficiency' in the services provided by a healthcare provider. 'Deficiency' means, any fault, imperfection, shortcoming or inadequacy in the quality, nature, and manner of performance that is required to be maintained by or under any law for the time being in force or has been undertaken to be performed by a person in pursuance of a contract or otherwise, in relation to any service. PMID- 22442532 TI - Handling cervical myomas. AB - Compared to myomas that occur in the uterine corpus, cervical myomas are closer to other organs such as the bladder, ureter, and rectum, and the approach needs to be modified, as the organs that have to be considered differ depending on the location of the myoma. Surgical difficulties associated with these cases are, poor access to the operative field, difficulty in suturing the repairs, increased blood loss, and distortion of the anatomy of the vital neighboring structures in the pelvic cavity. PMID- 22442533 TI - Laparoscopic myomectomy: methods to control bleeding. AB - Most of the surgeons find it difficult to perform myomectomy when it bleeds during the procedure as it becomes difficult to get into the correct plane of dissection. If this bleeding or blood staining of tissues is prevented it will be easier to get into the correct plane of dissection. In several studies, it is found that bilateral uterine artery ligation, at origin, does not interfere with future fertility as the end vessels and collaterals of the uterus are not interfered with. As no energy source is used to incise the myoma once Vasopressin has been used, the myomectomy scar integrity is better, as noted by various surgeons. PMID- 22442534 TI - Fibroids, infertility and laparoscopic myomectomy. AB - OBJECTIVE: To review the literature and summarize the available evidence about the relationship of fibroids with infertility and to review the role of laparoscopic myomectomy in infertility. MATERIALS AND METHODS: Medline, PubMed, and Cochrane Databases were searched for articles published between 1980 and 2010. RESULTS: Fertility outcomes are decreased in women with submucosal fibroids, and myomectomy is of value. Subserosal fibroids do not affect fertility outcomes, and removal may not confer benefit. Intramural fibroids appear to decrease fertility, but the results of therapy are unclear. Although pregnancy rates for women with leiomyomata, managed endoscopically, are similar to those after laparotomy, there is a risk of uterine rupture. The risk is essentially unknown. Finally, the risk of recurrence seems higher after laparoscopic myomectomy compared to laparotomy. CONCLUSIONS: Laparoscopic myomectomy, when performed by an experienced surgeon, can be considered a safe technique, with an extremely low failure rate and good results in terms of the outcome of pregnancy. PMID- 22442535 TI - Multiple layer closure of myoma bed in laparoscopic myomectomy. AB - OBJECTIVE: To assess the feasibility and outcome of laparoscopic myomectomy and multiple layer closure of the myoma bed, for management of myomas, at a tertiary care hospital. MATERIALS AND METHODS: From September 2005 to September 2010, 417 patients, with large and moderate size myomas, were managed by laparoscopic myomectomy. Indications were subfertility, menorrhagia, and abdominal mass. Preoperative evaluation included history, clinical examination, and sonographic mapping. The myomas were enucleated and retrieved laparoscopically. Myoma beds were sutured in multiple layers by endoscopic intracorporeal suturing. RESULTS: Three hundred and fifteen patients presented with subfertility, 45 with menorrhagia, and 57 with abdominal mass. The average maximum diameter of a myoma was 9 cm. The mean duration of surgery was 120 minutes. The mean postoperative stay was 24 hours. No intraoperative complication occurred and the hospital course was uncomplicated. In one case, a minilap incision was performed for retrieval of the myoma with suturing of the bed. Two patients had minor delayed wound healing of the morcellator port site. The patients did not report any complaints during the follow-up, except one patient who developed omental hernia at the morcellator port site. There was no rupture of the scar and very low adhesion scores in the subsequent cesarean sections or second-look scopies. CONCLUSION: With proper multilayer closure of the myoma bed, laparoscopic myomectomy was feasible for moderate and even large myomas and had excellent outcomes. PMID- 22442536 TI - Laparoscopic myomectomy with aquadissection and barbed sutures. AB - The objective of this study was to evaluate the efficacy of aquadissection technique to reduce the blood loss in myomectomy and to assess the benefits and feasibility of the use of barbed suture for myometrial defect closure. Vasopressin is diluted with saline as 10 units of vasopressin for every 100 ml of saline. For a fibroid of about 8 cm size, 40 units of vasopressin is diluted in 400 ml of normal saline. The whole of 400 ml of this saline is injected in the myometrium. Incision is made on the uterus with just simple scissors (no energy source is required). As the uterus is cut, instead of bleeding, saline leakage takes place. This helps to keep the field clear and it is easier to get the correct plane between the fibroid and the myometrium. The separation of the fibroid is helped due to the dissection of the correct plane by the saline injection. PMID- 22442537 TI - Robotic sacrocolpopexy: an observational experience at mayoclinic, USA. AB - Although there are many studies the ongoing debate on the management of posthysterectomy vault prolapse whether it should be abdominal, vaginal, or laparoscopic still continues. However there is no clear consensus. Though the incidence of vaginal vault prolapse is said to range from 0.2 to 45%, the choice of the optimal treatment depends on the surgeon's experience, suitability for surgery, age, symptoms, quality of life impairment, and prolapse grade. Abdominal sacrocopopexy (ASCP) with mesh interposition is the traditional surgical procedure for treating pelvic organ prolapse and has been shown to have one of the highest long-term success rates for vaginal vault prolapse. The laparoscopic approach offers reduced morbidity, shorter hospitalization, and decreased post operative pain. The disadvantages of the laparoscopic approach include longer operating time and need for advanced laparoscopic surgical skills including suturing. Robot-assisted laparoscopic procedure allows the performance of complex laparoscopic maneuvers with less difficulty, and thereby simplifies the complex procedure. The aim is to describe and demonstrate the use and benefit of robot assisted laparoscopic sacrocolpopexy in the treatment of posthysterectomy vaginal vault prolapse in obese patients along with mid-urethral sling application. PMID- 22442538 TI - Laparoscopic Trachelectomy for Cervical Stump 'Carcinoma in situ'. AB - A 43-year-old, who underwent a subtotal hysterectomy for postpartum hemorrhage following a normal delivery, 10 years ago, presented with a history of persistent vaginal discharge and post-coital bleeding. A pap smear reported moderate dysplasia, and a subsequent colposcopic biopsy reported severe dysplasia with crypt extension. The patient underwent a laparoscopic trachelectomy, and histology of the stump reported cervical squamous carcinoma in situ, with no microinvasion. PMID- 22442539 TI - Single incision laparoscopic myomectomy. AB - Single port laparoscopic surgery (SPLS), also called SILS is the natural extension of multi-incisional laparoscopic surgery, in the quest for reduction of traumatic insult and residual scarring to the patient. Today with the evolution of newer instruments, bidirectional self-retaining sutures, and surgical experience we are able to perform many surgeries in gynecology. PMID- 22442540 TI - Laparoscopic management of broad ligament fibroids. AB - Two cases of true broad ligament fibroids and thirty cases of false broad ligament fibroids were operated. All were removed through the laparoscopic route, with very minimal blood loss and without a need for blood transfusion. We traced the course of the ureters in all cases. No complications were met with. PMID- 22442541 TI - Medpore versus osseous augmentation in genioplasty procedure: A comparison. AB - BACKGROUND: Genioplasty deals with small area of craniofacial complex, namely, chin. Alloplastic chin implants and sliding genioplasty represent the two currently accepted methods of chin augmentation. Chin augmentation with medpore has become popular in the recent years. MATERIAL AND METHODS: The study comprised 16 patients having retruded chin, out of whom 8 patients underwent sliding genioplasty while the other 8 underwent chin augmentation using medpore. The versatility and benefits of the two techniques are discussed. RESULT AND CONCLUSION: All the patients achieved satisfactory results with no complication. Both the techniques can be used for mild to moderate retrogenia, while in the case of severe retrogenia, sliding genioplasty is recommended. Medpore is especially used for revision of chin shape. Medpore can give the same satisfactory result as osseous genioplasty in cases of mild to moderate horizontal chin deficiency. All the patients from both the groups showed significant improvement in facial profile and high degree of satisfaction resulting in improved self-esteem. PMID- 22442542 TI - Buccal fat pad versus sandwich graft for treatment of oroantral defects: A comparison. AB - AIM: To compare the efficacy of buccal fat pad (BFP) graft with sandwich graft (hydroxyapatite crystals embedded within collagen sheath) in closure of oroantral defects. MATERIALS AND METHODS: A 2-year prospective study was conducted; 20 patients were included in the study were divided into two groups having 10 patients in each. Group I patients underwent surgical closure of oroantral fistula with sandwich graft and Group II patients with buccal pad of fat. RESULTS: In Group I, the mean pain scores were 7.60 +/- 0.84, 3.90 +/- 1.10, 2.30 +/- 1.16, 1.10 +/- 0.99 and 0.40 +/- 0.70 at immediate post-op., 1, 3, 6 and 12 week time intervals, respectively, whereas in Group II these were 7.30 +/- 0.67, 3.50 +/- 0.53, 1.70 +/- 0.48, 1.00 +/- 0.47 and 0.30 +/- 0.48, respectively, at the corresponding time intervals. In Group I, swelling was seen to be present in 10 (100%), 7 (70%), 2 (20%) and nil (0%) patients at 1, 3, 6 and 12 weeks, respectively, whereas in Group II, it was seen to be present in 10 (100%), 10 (100%), 2 (20%) and nil (0%) patients at the corresponding time intervals. At 1 week, infection was seen to be present in 1 (10%) patient of Group I and 2 (20%) patients of Group II. At 3 and 6 weeks, infection was seen to be present in 1 (10%) patient of Group I and none of the patients of group II. No radiologic evidence of bone formation was seen in either group up to 1 week. At 3 week interval, there were 6 (60%) patients in Group I and nil (0%) in Group II showing bone formation, thus showing a statistically significant difference between the two groups. By 6 week time interval, radiologic evidence of bone formation was seen in 9 (90%) patients of Group I but in no patients of Group II, thereby showing a statistically very highly significant (P < 0.001) difference between the two groups. In Group I, in 1 (10%) patient, graft was rejected by first week; however, no further graft rejection took place. In Group II, no case of graft rejection was reported. CONCLUSIONS: The sandwich graft technique yielded a more promising closure of oroantral communication by provision of a more biologically apt base in terms of regeneration of lost bone structure at the floor of the maxillary sinus. PMID- 22442543 TI - Comparison of octyl-2-cyanoacrylate and conventional sutures in facial skin closure. AB - INTRODUCTION: Closure of wounds to achieve an esthetically pleasing result has always been a challenge. Since time immemorial, surgeons have strived to produce "invisible scars". This, however, has always been elusive. The introduction of tissue adhesives heralded the era of suture free closures which led to better results. AIMS AND OBJECTIVES: The aim of this study is to compare the efficacy of octyl- 2-cyanoacrylate with that of the conventional sutures, in facial skin closure. RESULTS AND CONCLUSION: The use of octyl-2-cyanoacrylate offers many advantages such as rapidity and ease of application and superior results. PMID- 22442544 TI - Role of surgical stents in determining the position of implants. AB - AIM: Demand from implant patients for quality and efficient treatment is increasing. Fortunately dental implant treatment is evolving with patients expectations. MATERIALS AND METHODS: The study comprised of 45 patients for whom 89 implants were placed at different sites. Efficacy of the stents is evaluated in determining the position and diameter of the implants. CONCLUSION: this study shows the extreme accuracy of this surgical stents in implant installation in terms of position and diameter. PMID- 22442545 TI - A new and easy technique for maxillomandibular fixation. AB - Maxillomandibular fixation (MMF) is important in the treatment of maxillofacial fractures and is usually applied by wiring together the fixed upper and lower arch bars. Here, we report a new type of MMF technique, Rohtak Dental College (RDC) technique using 26-gauze stainless steel wires. It is a simple, quick, economical and minimally invasive technique. Its mechanical principle provides an advantage in preventing postoperative periodontal problems. Typical indications for its use are minimally displaced fractures, orthognathic surgeries and in tumor resection surgeries. PMID- 22442546 TI - Endosseous dental implant vis-a-vis conservative management: Is it a dilemma? AB - To overview the current prospective of endosseous dental implant and conservative management. Although emphasis has been made in reinstating the oral functions, less consideration has been given to formulate the best treatment tactics in a particular situation. Properly restored, root canal treated natural teeth surrounded by healthy periodontium tissues yield a very high longevity, and periodontally compromised teeth that are treated and maintained regularly may have longer survival rate. Current trends in implantology have weakened the conservative paradigm, and practitioner's objectivity has been inclined more toward providing the tooth substitutes often flaunted as equal or even superior to conservation of natural tooth. PMID- 22442547 TI - Temporary anchorage devices - Mini-implants. AB - Orthodontists are accustomed to using teeth and auxiliary appliances, both intraoral and extraoral, to control anchorage. These methods are limited in that it is often difficult to achieve results commensurate with our idealistic goals. Recently, a number of case reports have appeared in the orthodontic literature documenting the possibility of overcoming anchorage limitations via the use of temporary anchorage devices-biocompatible devices fixed to bone for the purpose of moving teeth, with the devices being subsequently removed after treatment. Although skeletal anchorage is here to stay in orthodontics, there are still many unanswered questions. This article describes the development of skeletal anchorage and provides an overview of the use of implants for orthodontic anchorage. PMID- 22442548 TI - Role of oral health professional in pediatric obstructive sleep apnea. AB - Sleep disordered breathing (SDB) in children is common. The impact of SDB on the growth and development of child may have detrimental effects on health, neuropsychological development, quality of life, and economic potential; therefore, SDB in children should be recognized as a public health problem as in the adult population. The coexistence of obesity and obstructive sleep apnea (OSA) not only appears to yield increased morbidity rates and poorer responses to therapy, but also is altogether associated with a distinct and recognizable clinical phenotype. Therapeutic options have somewhat expanded since the initial treatment approaches were conducted, to include not only surgical extraction of hypertrophic adenoids and tonsils, but also nonsurgical alternatives such as continuous positive air pressure, anti-inflammatory agents and oral appliances (OAs). Now, American academy of sleep medicine (AAOSM) has recommended OAs for OSA, hence the therapeutic interventions that are directed at the site of airway obstruction in the maxillofacial region are within the scope of dentistry. Among the physicians treating the children, dentists are more likely to identify adenotonsillar hypertrophy. Hence, the dentist can play an important role in identifying and treating those cases with OAs, who refuse the surgery, or those with structural abnormality in which myofunctional appliances are beneficial. PMID- 22442549 TI - A critical review of the implication of nanotechnology in modern dental practice. AB - Curiosity has its own reason for existing. For thousands of years, mankind has been harnessing its curiosity into inquiry and the process of scientific methodology. If we consider technology as an engine, then science is its fuel. Science of miniaturization (nanotechnology) is manipulating matter at nanometer level and the application of the same to medicine is called nanomedicine. Nanotechnology holds promise for advanced diagnostics, targeted drug delivery, and biosensors. When we gain access to hold the nanorobots, we will be able to treat very rapidly a number of diseases that are a continuous threat for mankind today. The present article aims to provide an early glimpse on the impact and future implication of nanotechnology in dentistry, especially in oral surgery and orthodontics. PMID- 22442550 TI - Arteriovenous malformation of mandible: Extracorporeal curettage with immediate replantation technique. AB - Arteriovenous malformations of jaw are extremely rare conditions that can result in disastrous complications, if handled carelessly. Although various treatment modalities have been advocated in the literature, there seems to be no complete consensus on a suitable treatment in these cases. This report highlights the importance of correct diagnosis and early treatment in management of vascular malformations. Extracorporeal curettage followed by immediate replantation yielded good results in our case and this technique can emerge as a valid alternative, especially in developing countries. PMID- 22442551 TI - Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome is an inherited autosomal dominant disorder with complete penetrance and extreme variable expressivity. The authors present a case of an 11 year-old girl with typical features of Gorlin-Goltz syndrome with special respect to medical and dental problems which include multiple bony cage deformities like spina bifida with scoliosis having convexity to the left side, presence of an infantile uterus and multiple odonogenic keratocysts in the maxillofacial region. PMID- 22442552 TI - Interdisciplinary approach to palatally impacted canine. AB - Interdisciplinary approach for the management of malocclusion provides a holistic approach of patient management. Prudent treatment planning is necessary to achieve the various treatment goals. The article highlights the salient features and various surgical and orthodontic considerations to approach cases with impacted canines. It is exemplified with a case in which a palatally impacted canine and a highly placed canine in the buccal vestibule have been surgically intervened and orthodontically extruded with sequential traction and aligned in the arch. PMID- 22442553 TI - Gorlin-Goltz syndrome with situs oppositus. AB - Gorlin-Goltz syndrome, also known as nevoid basal cell carcicoma syndrome, is caused due to a genetic alteration produced by a mutation in the "Patched" tumor suppressor gene, and it is inherited in a dominant autosomal way, though sporadic cases have been found. This syndrome shows a high penetrance and variable expressiveness. It is a multisystemic process that is characterized by the presence of multiple pigmented basocellular carcinomas, keratocysts in the jaws, palmar and/or plantar pits and calcification of the falx cerebri. Together with these major features, a great number of processes considered as minor features have also been described. The latter include numerous skeletal, dermatology related and neurological anomalies, among others. In some occasions, the presence of very aggressive basocellular carcinomas has been described as well as other malignant neoplasia. Due to the importance of oral maxillofacial manifestations of this syndrome, it is fundamental to know its characteristics in order to make a diagnosis, to provide an early preventive treatment and to establish right genetic advice. We report a rare association of Gorlin-Goltz syndrome with situs oppositus. PMID- 22442554 TI - Metastatic malignant melanoma of palate: A review of literature and report of an unusual case. AB - Oral malignant melanoma is a rare tumor, accounting 0.8to 1.8 % of all oral malignancies. It occurs most commonly in Japanese and Negros. Radical surgery is mainstay of the treatment. Prognosis is very poor with 5 years survival rate. We present a case of malignant melanoma in a 55 years female, metastatizing to liver spleen and vertebrae. PMID- 22442555 TI - A rare case of odontome in a 65-year-old lady. AB - Odontomes are considered to be hamartomas rather than a true neoplasm. They are comparatively common odontogenic tumors, and may lead to interference with eruption of associated tooth. Compound odontomes are commonly seen in young adults, but if they occur in children they are usually associated with permanent dentition and prevent eruption of the associated tooth. We hereby report a case of large compound odontome in the mandibular body region of a 65-year-old woman. Because of difficulty in denture fabrication and associated pain on mastication, surgical removal of the lesion was done. PMID- 22442556 TI - Trigeminal neuralgia secondary to posterior fossa tumor. AB - Trigeminal neuralgia (TN) is by no means an uncommon entity presenting as typical or atypical pain syndrome with a standard treatment protocol consisting of medical and surgical therapies. The diagnosis of TN is mainly dependent on the characteristics of symptoms conveyed by the patient and the clinical presentation. Careful history taking, proper interpretation of the signs and symptoms and cranial nerve assessment are necessary for proper diagnosis. Here, we report a case of TN, treated for dental problems and then for neuralgia with only short-term relief. Subsequently, the patient underwent neuroimaging and was found to be having an uncommon space-occupying lesion in the posterior cranial fossa. PMID- 22442557 TI - Submental intubation: A useful adjunct in panfacial trauma. AB - Complex maxillofacial trauma requires a modification of intubation as it precludes both oral and nasal intubation. Tracheostomy is not preferred due to its associated complications. Submental intubation comes as a rescue in such situations as it provides an uninterrupted access to the operative field with due control over airway and minimal side effects. PMID- 22442558 TI - Bifid mandibular condyle: Report of two cases of varied etiology. AB - Bifid condyle is a rare anatomic variation of mandibular condyle. It can be symptomatic or diagnosed incidentally on routine radiographic examination. No definite etiologic factor has been identified. It is suggested that bifid condyle could be a developmental anomaly or secondary to trauma. We are reporting two cases of bifid mandibular condyle. Both were diagnosed using computed tomography scan, which additionally revealed the associated pathosis in the angle of the mandible in first patient and the ankylosis of temporomandibular joint in the second patient. PMID- 22442559 TI - Cystic hygroma. AB - Surgical management of cystic hygroma is very challenging since it has a thin wall consisting of endothelium which can easily be torn during its enucleation leading to recurrence. The other treatment options are intralesional injection of OK-432, triamcinolone followed by surgical excision, if necessary, injection of sclerosing agents, repeated aspiration, radiotherapy and finally spontaneous regression without any form of treatment. This is a case report of cystic hygroma of parotid region where regression occurred without any form of treatment. PMID- 22442560 TI - Unusual causes of reduced mouth opening and it's suitable surgical management: Our experience. AB - Reduced mouth opening is a common clinical problem and many individuals experience it at least once in his or her life and most dental practitioners see patients with restricted mouth opening quite often. It can occur due to a variety of underlying conditions which may involve complex factors. Hence, it is essential for the clinician to thoroughly investigate and examine these cases for proper diagnosis and its appropriate management. PMID- 22442561 TI - A feeding appliance for a newborn baby with cleft lip and palate. AB - A child born with cleft lip and palate may experience difficulties while feeding. Obtaining a good seal of the oral cavity can be difficult due to the incomplete facial and palatal structures. Nasal regurgitation and choking are common in infants with cleft palate because of inability of the palate to separate the nasal and oral cavities. The case presented here is a 3-day-old neonate born with cleft lip and palate, assisted with a new feeding appliance made with ethylene vinyl acetate using pressure moulding technique in biostar machine for proper feeding. PMID- 22442562 TI - Stance-phase force on the opposite limb dictates swing-phase afferent presynaptic inhibition during locomotion. AB - Presynaptic inhibition is a powerful mechanism for selectively and dynamically gating sensory inputs entering the spinal cord. We investigated how hindlimb mechanics influence presynaptic inhibition during locomotion using pioneering approaches in an in vitro spinal cord-hindlimb preparation. We recorded lumbar dorsal root potentials to measure primary afferent depolarization-mediated presynaptic inhibition and compared their dependence on hindlimb endpoint forces, motor output, and joint kinematics. We found that stance-phase force on the opposite limb, particularly at toe contact, strongly influenced the magnitude and timing of afferent presynaptic inhibition in the swinging limb. Presynaptic inhibition increased in proportion to opposite limb force, as well as locomotor frequency. This form of presynaptic inhibition binds the sensorimotor states of the two limbs, adjusting sensory inflow to the swing limb based on forces generated by the stance limb. Functionally, it may serve to adjust swing-phase sensory transmission based on locomotor task, speed, and step-to-step environmental perturbations. PMID- 22442563 TI - TRPV4 channels mediate the infrared laser-evoked response in sensory neurons. AB - Infrared laser irradiation has been established as an appropriate stimulus for primary sensory neurons under conditions where sensory receptor cells are impaired or lost. Yet, development of clinical applications has been impeded by lack of information about the molecular mechanisms underlying the laser-induced neural response. Here, we directly address this question through pharmacological characterization of the biological response evoked by midinfrared irradiation of isolated retinal and vestibular ganglion cells from rodents. Whole cell patch clamp recordings reveal that both voltage-gated calcium and sodium channels contribute to the laser-evoked neuronal voltage variations (LEVV). In addition, selective blockade of the LEVV by micromolar concentrations of ruthenium red and RN 1734 identifies thermosensitive transient receptor potential vanilloid channels as the primary effectors of the chain reaction triggered by midinfrared laser irradiation. These results have the potential to facilitate greatly the design of future prosthetic devices aimed at restoring neurosensory capacities in disabled patients. PMID- 22442565 TI - Mislocalization of stationary and flashed bars after saccadic inward and outward adaptation of reactive saccades. AB - Recent studies have shown that saccadic inward adaptation (i.e., the shortening of saccade amplitude) and saccadic outward adaptation (i.e., the lengthening of saccade amplitude) rely on partially different neuronal mechanisms. There is increasing evidence that these differences are based on differences at the target registration or planning stages since outward but not inward adaptation transfers to hand-pointing and perceptual localization of flashed targets. Furthermore, the transfer of reactive saccade adaptation to long-duration overlap and scanning saccades is stronger after saccadic outward adaptation than that after saccadic inward adaptation, suggesting that modulated target registration stages during outward adaptation are increasingly used in the execution of saccades when the saccade target is visually available for a longer time. The difference in target presentation duration between reactive and scanning saccades is also linked to a difference in perceptual localization of different targets. Flashed targets are mislocalized after inward adaptation of reactive and scanning saccades but targets that are presented for a longer time (stationary targets) are mislocalized stronger after scanning than after reactive saccades. This link between perceptual localization and adaptation specificity suggests that mislocalization of stationary bars should be higher after outward than that after inward adaptation of reactive saccades. In the present study we test this prediction. We show that the relative amount of mislocalization of stationary versus flashed bars is higher after outward than that after inward adaptation of reactive saccades. Furthermore, during fixation stationary and flashed bars were mislocalized after outward but not after inward adaptation. Thus, our results give further evidence for different adaptation mechanisms between inward and outward adaptation and harmonize some recent research. PMID- 22442564 TI - Modulation of neuronal sodium channels by the sea anemone peptide BDS-I. AB - Blood-depressing substance I (BDS-I), a 43 amino-acid peptide from sea anemone venom, is used as a specific inhibitor of Kv3-family potassium channels. We found that BDS-I acts with even higher potency to modulate specific types of voltage dependent sodium channels. In rat dorsal root ganglion (DRG) neurons, 3 MUM BDS-I strongly enhanced tetrodotoxin (TTX)-sensitive sodium current but weakly inhibited TTX-resistant sodium current. In rat superior cervical ganglion (SCG) neurons, which express only TTX-sensitive sodium current, BDS-I enhanced current elicited by small depolarizations and slowed decay of currents at all voltages (EC(50) ~ 300 nM). BDS-I acted with exceptionally high potency and efficacy on cloned human Nav1.7 channels, slowing inactivation by 6-fold, with an EC(50) of approximately 3 nM. BDS-I also slowed inactivation of sodium currents in N1E-115 neuroblastoma cells (mainly from Nav1.3 channels), with an EC(50) ~ 600 nM. In hippocampal CA3 pyramidal neurons (mouse) and cerebellar Purkinje neurons (mouse and rat), BDS-I had only small effects on current decay (slowing inactivation by 20-50%), suggesting relatively weak sensitivity of Nav1.1 and Nav1.6 channels. The biggest effect of BDS-I in central neurons was to enhance resurgent current in Purkinje neurons, an effect reflected in enhancement of sodium current during the repolarization phase of Purkinje neuron action potentials. Overall, these results show that BDS-I acts to modulate sodium channel gating in a manner similar to previously known neurotoxin receptor site 3 anemone toxins but with different isoform sensitivity. Most notably, BDS-I acts with very high potency on human Nav1.7 channels. PMID- 22442566 TI - Theoretical principles underlying optical stimulation of a channelrhodopsin-2 positive pyramidal neuron. AB - Optogenetics is an emerging field of neuromodulation that permits scaled, millisecond temporal control of the membrane dynamics of genetically targeted cells using light. Optogenetic technology has revolutionized neuroscience research; however, numerous biophysical questions remain on the optical and neuronal factors impacting the modulation of neural activity with photon sensitive ion channels. To begin to address such questions, we developed a computational tool to explore the underlying principles of optogenetic neural stimulation. This "light-neuron" model consists of theoretical representations of the light dynamics generated by a fiber optic in brain tissue, coupled to a multicompartment cable model of a cortical pyramidal neuron embedded with channelrhodopsin-2 (ChR2) membrane dynamics. Simulations revealed that the large energies required to generate an action potential are primarily due to the limited conductivity of ChR2, and that the major determinants of stimulation threshold are the surface area of illuminated cell membrane and proximity to the light source. Our results predict that the activation threshold is sensitive to many of the properties of ChR2 (density, conductivity, and kinetics), tissue medium (scattering and absorbance), and the fiber-optic light source (diameter and numerical aperture). We also illustrate the impact of redistributing the ChR2 expression density (uniform vs. nonuniform) on the activation threshold. The model system developed in this study represents a scientific instrument to characterize the effects of optogenetic neuromodulation, as well as an engineering design tool to help guide future development of optogenetic technology. PMID- 22442567 TI - Functional characterization of dI6 interneurons in the neonatal mouse spinal cord. AB - Our understanding of the neural control of locomotion has been greatly enhanced by the ability to identify and manipulate genetically defined populations of interneurons that comprise the locomotor central pattern generator (CPG). To date, the dI6 interneurons are one of the few populations that settle in the ventral region of the postnatal spinal cord that have not been investigated. In the present study, we utilized a novel transgenic mouse line to electrophysiologically characterize dI6 interneurons located close to the central canal and study their function during fictive locomotion. The majority of dI6 cells investigated were found to be rhythmically active during fictive locomotion and could be divided into two electrophysiologically distinct populations of interneurons. The first population fired rhythmic trains of action potentials that were loosely coupled to ventral root output and contained several intrinsic membrane properties of rhythm-generating neurons, raising the possibility that these cells may be involved in the generation of rhythmic activity in the locomotor CPG. The second population fired rhythmic trains of action potentials that were tightly coupled to ventral root output and lacked intrinsic oscillatory mechanisms, indicating that these neurons may be driven by a rhythm-generating network. Together these results indicate that dI6 neurons comprise an important component of the locomotor CPG that participate in multiple facets of motor behavior. PMID- 22442568 TI - Timing-dependent modulation of the posterior parietal cortex-primary motor cortex pathway by sensorimotor training. AB - Interplay between posterior parietal cortex (PPC) and ipsilateral primary motor cortex (M1) is crucial during execution of movements. The purpose of the study was to determine whether functional PPC-M1 connectivity in humans can be modulated by sensorimotor training. Seventeen participants performed a sensorimotor training task that involved tapping the index finger in synchrony to a rhythmic sequence. To explore differences in training modality, one group (n = 8) learned by visual and the other (n = 9) by auditory stimuli. Transcranial magnetic stimulation (TMS) was used to assess PPC-M1 connectivity before and after training, whereas electroencephalography (EEG) was used to assess PPC-M1 connectivity during training. Facilitation from PPC to M1 was quantified using paired-pulse TMS at conditioning-test intervals of 2, 4, 6, and 8 ms by measuring motor-evoked potentials (MEPs). TMS was applied at baseline and at four time points (0, 30, 60, and 180 min) after training. For EEG, task-related power and coherence were calculated for early and late training phases. The conditioned MEP was facilitated at a 2-ms conditioning-test interval before training. However, facilitation was abolished immediately following training, but returned to baseline at subsequent time points. Regional EEG activity and interregional connectivity between PPC and M1 showed an initial increase during early training followed by a significant decrease in the late phases. The findings indicate that parietal-motor interactions are activated during early sensorimotor training when sensory information has to be integrated into a coherent movement plan. Once the sequence is encoded and movements become automatized, PPC-M1 connectivity returns to baseline. PMID- 22442569 TI - Visual gravity influences arm movement planning. AB - When submitted to a visuomotor rotation, subjects show rapid adaptation of visually guided arm reaching movements, indicated by a progressive reduction in reaching errors. In this study, we wanted to make a step forward by investigating to what extent this adaptation also implies changes into the motor plan. Up to now, classical visuomotor rotation paradigms have been performed on the horizontal plane, where the reaching motor plan in general requires the same kinematics (i.e., straight path and symmetric velocity profile). To overcome this limitation, we considered vertical and horizontal movement directions requiring specific velocity profiles. This way, a change in the motor plan due to the visuomotor conflict would be measurable in terms of a modification in the velocity profile of the reaching movement. Ten subjects performed horizontal and vertical reaching movements while observing a rotated visual feedback of their motion. We found that adaptation to a visuomotor rotation produces a significant change in the motor plan, i.e., changes to the symmetry of velocity profiles. This suggests that the central nervous system takes into account the visual information to plan a future motion, even if this causes the adoption of nonoptimal motor plans in terms of energy consumption. However, the influence of vision on arm movement planning is not fixed, but rather changes as a function of the visual orientation of the movement. Indeed, a clear influence on motion planning can be observed only when the movement is visually presented as oriented along the vertical direction. Thus vision contributes differently to the planning of arm pointing movements depending on motion orientation in space. PMID- 22442570 TI - Human neural responses involved in spatial pooling of locally ambiguous motion signals. AB - Early visual motion signals are local and one-dimensional (1-D). For specification of global two-dimensional (2-D) motion vectors, the visual system should appropriately integrate these signals across orientation and space. Previous neurophysiological studies have suggested that this integration process consists of two computational steps (estimation of local 2-D motion vectors, followed by their spatial pooling), both being identified in the area MT. Psychophysical findings, however, suggest that under certain stimulus conditions, the human visual system can also compute mathematically correct global motion vectors from direct pooling of spatially distributed 1-D motion signals. To study the neural mechanisms responsible for this novel 1-D motion pooling, we conducted human magnetoencephalography (MEG) and functional MRI experiments using a global motion stimulus comprising multiple moving Gabors (global-Gabor motion). In the first experiment, we measured MEG and blood oxygen level-dependent responses while changing motion coherence of global-Gabor motion. In the second experiment, we investigated cortical responses correlated with direction-selective adaptation to the global 2-D motion, not to local 1-D motions. We found that human MT complex (hMT+) responses show both coherence dependency and direction selectivity to global motion based on 1-D pooling. The results provide the first evidence that hMT+ is the locus of 1-D motion pooling, as well as that of conventional 2-D motion pooling. PMID- 22442571 TI - Baroreflex mechanisms regulating the occurrence of neural spikes in human muscle sympathetic nerve activity. AB - This study tested the hypothesis that the discharge patterns of action potentials (APs) within bursts of postganglionic muscle sympathetic nerve activity (MSNA) are subject to arterial baroreflex control but in a manner that varies inversely with AP size. MSNA data were collected over 5 min of supine rest in 15 young and healthy individuals (8 males; 24 +/- 4 yr of age; means +/- SD). The baroreflex threshold and sensitivity diagrams were constructed for both the integrated sympathetic bursts and for the AP clusters. For the integrated bursts, a strong linear relationship between burst probability and diastolic blood pressure (DBP) was observed (P < 0.05). There was little relationship between integrated burst strength (amplitude) and DBP. On average, 12 AP clusters were observed across individuals. Larger APs tended to appear in the larger bursts. Linear regression analysis was used to study the baroreflex threshold (probability of AP cluster occurrence vs. DBP) as well as the baroreflex sensitivity (AP cluster size vs. DBP). A significant reflex threshold relationship was observed in 75-100% of AP clusters across all individuals. In contrast, significant reflex sensitivity relationships were observed in only 9 of 15 individuals and for limited APs. Overall, the slope of the AP baroreflex threshold relationship was greater for the small-medium sized AP clusters than that of the larger APs. Therefore, within each burst, the small-medium sized APs are governed by the baroreflex mechanism. However, the large APs, which tend to appear in the large integrated bursts, are weakly associated with a baroreflex control feature. The variable impact of baroreflex control over AP occurrence provides a plausible explanation for the overall weak baroreflex control over integrated burst strength, a feature that is determined by both the number and size of the AP complement. PMID- 22442572 TI - Trace fear conditioning enhances synaptic and intrinsic plasticity in rat hippocampus. AB - Experience-dependent synaptic and intrinsic plasticity are thought to be important substrates for learning-related changes in behavior. The present study combined trace fear conditioning with both extracellular and intracellular hippocampal recordings to study learning-related synaptic and intrinsic plasticity. Rats received one session of trace fear conditioning, followed by a brief conditioned stimulus (CS) test the next day. To relate behavioral performance with measures of hippocampal CA1 physiology, brain slices were prepared within 1 h of the CS test. In trace-conditioned rats, both synaptic plasticity and intrinsic excitability were significantly correlated with behavior such that better learning corresponded with enhanced long-term potentiation (LTP; r = 0.64, P < 0.05) and a smaller postburst afterhyperpolarization (AHP; r = 0.62, P < 0.05). Such correlations were not observed in pseudoconditioned rats, whose physiological data were comparable to those of poor learners and naive and chamber-exposed control rats. In addition, acquisition of trace fear conditioning did not enhance basal synaptic responses. Thus these data suggest that within the hippocampus both synaptic and intrinsic mechanisms are involved in the acquisition of trace fear conditioning. PMID- 22442573 TI - Regulation of presynaptic strength by controlling Ca2+ channel mobility: effects of cholesterol depletion on release at the cone ribbon synapse. AB - Synaptic communication requires proper coupling between voltage-gated Ca(2+) (Ca(V)) channels and synaptic vesicles. In photoreceptors, L-type Ca(V) channels are clustered close to synaptic ribbon release sites. Although clustered, Ca(V) channels move continuously within a confined domain slightly larger than the base of the ribbon. We hypothesized that expanding Ca(V) channel confinement domains should increase the number of channel openings needed to trigger vesicle release. Using single-particle tracking techniques, we measured the expansion of Ca(V) channel confinement domains caused by depletion of membrane cholesterol with cholesterol oxidase or methyl-beta-cyclodextrin. With paired whole cell recordings from cones and horizontal cells, we then determined the number of Ca(V) channel openings contributing to cone Ca(V) currents (I(Ca)) and the number of vesicle fusion events contributing to horizontal cell excitatory postsynaptic currents (EPSCs) following cholesterol depletion. Expansion of Ca(V) channel confinement domains reduced the peak efficiency of release, decreasing the number of vesicle fusion events accompanying opening of each Ca(V) channel. Cholesterol depletion also inhibited exocytotic capacitance increases evoked by brief depolarizing steps. Changes in efficiency were not due to changes in I(Ca) amplitude or glutamate receptor properties. Replenishing cholesterol restored Ca(V) channel domain size and release efficiency to control levels. These results indicate that cholesterol is important for organizing the cone active zone. Furthermore, the finding that cholesterol depletion impairs coupling between channel opening and vesicle release by allowing Ca(V) channels to move further from release sites shows that changes in presynaptic Ca(V) channel mobility can be a mechanism for adjusting synaptic strength. PMID- 22442574 TI - The relative importance of retinal error and prediction in saccadic adaptation. AB - When saccades systematically miss their visual target, their amplitude adjusts, causing the position errors to be progressively reduced. Conventionally, this adaptation is viewed as driven by retinal error (the distance between primary saccade endpoint and visual target). Recent work suggests that the oculomotor system is informed about where the eye lands; thus not all "retinal error" is unexpected. The present study compared two error signals that may drive saccade adaptation: retinal error and prediction error (the difference between predicted and actual postsaccadic images). Subjects made saccades to a visual target in two successive sessions. In the first session, the target was extinguished during saccade execution if the amplitude was smaller (or, in other experiments, greater) than the running median, thereby modifying the average retinal error subjects experienced without moving the target during the saccade as in conventional adaptation paradigms. In the second session, targets were extinguished at the start of saccades and turned back on at a position that reproduced the trial-by-trial retinal error recorded in the first session. Despite the retinal error in the first and second sessions having been identical, adaptation was severalfold greater in the second session, when the predicted target position had been changed. These results argue that the eye knows where it lands and where it expects the target to be, and that deviations from this prediction drive saccade adaptation more strongly than retinal error alone. PMID- 22442575 TI - Egocentric and allocentric alignment tasks are affected by otolith input. AB - Gravicentric visual alignments become less precise when the head is roll-tilted relative to gravity, which is most likely due to decreasing otolith sensitivity. To align a luminous line with the perceived gravity vector (gravicentric task) or the perceived body-longitudinal axis (egocentric task), the roll orientation of the line on the retina and the torsional position of the eyes relative to the head must be integrated to obtain the line orientation relative to the head. Whether otolith input contributes to egocentric tasks and whether the modulation of variability is restricted to vision-dependent paradigms is unknown. In nine subjects we compared precision and accuracy of gravicentric and egocentric alignments in various roll positions (upright, 45 degrees , and 75 degrees right ear down) using a luminous line (visual paradigm) in darkness. Trial-to-trial variability doubled for both egocentric and gravicentric alignments when roll tilted. Two mechanisms might explain the roll-angle-dependent modulation in egocentric tasks: 1) Modulating variability in estimated ocular torsion, which reflects the roll-dependent precision of otolith signals, affects the precision of estimating the line orientation relative to the head; this hypothesis predicts that variability modulation is restricted to vision-dependent alignments. 2) Estimated body-longitudinal reflects the roll-dependent variability of perceived earth-vertical. Gravicentric cues are thereby integrated regardless of the task's reference frame. To test the two hypotheses the visual paradigm was repeated using a rod instead (haptic paradigm). As with the visual paradigm, precision significantly decreased with increasing head roll for both tasks. These findings propose that the CNS integrates input coded in a gravicentric frame to solve egocentric tasks. In analogy to gravicentric tasks, where trial-to-trial variability is mainly influenced by the properties of the otolith afferents, egocentric tasks may also integrate otolith input. Such a shared mechanism for both paradigms and frames of reference is supported by the significantly correlated trial-to-trial variabilities. PMID- 22442576 TI - Message from Head OMFS, Medical University Lucknow. PMID- 22442577 TI - Pattern of bear maul maxillofacial injuries in Kashmir. AB - OBJECTIVE: Bears are strong and agile wild animals that defend themselves, their young ones and their territory, if they feel threatened. Conflicts between humans and bears are common in bear-prevalent areas of the world. Our valley, which is surrounded all around by forests, is a habitat for black bears (U. thiabetanus) only. Maulings inflicted by these black bears are catastrophic events and such attacks have increased considerably in the recent past due to merciless deforestation. The rising incidences of such attacks, especially in maxillofacial region, have urged our department to undertake a study of such attacks and injuries. MATERIALS AND METHODS: The present study is both a retrospective and prospective study of 200 patients of bear maulings who were admitted and treated in the Department of OMFS, Govt. Dental College, Srinagar, from January 2005 to October 2009. RESULTS: Majority of the patients were from villages. Most of them belonged to fourth decade and majority was males. Black bears only were involved in all the encounters. Claws, paws and combination of both, were the used for attack. In majority of cases, no defense was used for the termination of attack. All the patients had soft tissue injury, deep lacerations, facial viscera, eyes, salivary glands and facial nerve commonly involved. PMID- 22442578 TI - Analysis of cephalometrics for orthognathic surgery: Determination of norms applicable to Rajasthani population. AB - AIMS: To determine the hard tissue surgical cephalometric norms statistically and geometrically in well-balanced faces having clinically acceptable facial profile in the Rajasthan population. To compare the cephalometric analyses of Rajasthanis males and females and to compare the craniofacial pattern of Rajasthani population with Caucasian norms. MATERIALS AND METHODS: Lateral cephalograms of 200 subjects (100 males and 100 females) in the age group of 18-25 years, class I malocclusion and acceptable facial profile were obtained. Cephalometric analysis was performed and studied. RESULTS: The study revealed that parameters, such as all horizontal skeletal parameters, PNS-N, PNS-ANS, Ar-Go, Go-Pg and upper OP to HP angle show no statistical significant difference between Rajasthani males and females. When comparing Rajasthani males and Caucasian males, the study suggested statistically significant difference in the mean values of parameters, such as PTM-N, L1-MP, 6-MP, Go-Pog, B-Pog, Ar-Go-Gn, U1 to NF and L1 to MP. When comparing Rajasthani females and Caucasian females, the study revealed no statistically significant difference between the mean values of parameters, such as N-A-Pg, N-A, N-B, L1-MP, Ar-Go-Gn, upper OP to HP angle and AB-OP and rest of the parameters showed highly significant difference between Caucasian females and Rajasthani females. CONCLUSION: This study indicates that Rajasthani population has a bimaxillary protrusion with predominant tendency toward horizontal growth pattern of the mandible and this tendency is further exaggerated in females. Rajasthani females also showed an increased length of the anterior cranial base, maxilla and mandible and in dental parameters they showed increased maxillary dental height and both Males and females showed decreased mandibular dental height. PMID- 22442579 TI - Outcomes of management of early temporomandibular joint disorders: How effective is nonsurgical therapy in the long-term? AB - AIM: The first step in the management of Temporomandibular Disorders (TMD) is usually noninvasive, especially if the disorder is in the early stages. Clinically, pain and clicking are early signs and symptoms of TMD. The management of TMD usually includes "splint therapy" and analgesics. In this study, we report our long-term outcomes in the treatment of patients suffering from early TMD. MATERIALS AND METHODS: We assessed the records of 138 patients who were referred for management of TMD. Selection was based on pain and/or clicking of the Temporomandibular Joint (TMJ), no pathologic lesions of the TMJ, no anterior disc displacement without reduction (closed lock), no Degenerative Joint Disease, no history of migraine, trauma, osteoarthritis, metabolic disease, or malocclusion (deep bite, cross bite, jaw deformity, etc). The patients were treated with an acrylic maxillary Interocclusal Splint (IOS) cuspid-rise type and were told to refrain from biting, yawning and chewing hard food. The outcome of the treatment, potential etiologic factors (Bruxism), signs and symptoms and patient demographics (such as age, sex, treatment duration, etc.) were assessed. The data were analyzed using the Chi-square test to correlate significance. RESULTS: One hundred thirty-eight patients (26 males and 112 females) with early signs and symptoms of TMD (pain and/or click of the TMJ) were treated from 2001 to 2010; 81% were females and 19% were males. All the 138 patients used the IOS at night only. The patients were followed-up for 1-9 years. Data analysis showed that 64% of the patients were completely relieved of signs and symptoms; 22% were moderately relieved (decreased severity of signs and symptoms) and 14% had no noticeable post-treatment changes in clicking or pain (P = 0.001). Patients with bruxism and those presenting with both pain and clicking showed a better response to IOS treatment (P = 0.046 and P = 0.001, respectively). The results also showed that age, sex, severity of symptoms and duration of the treatment did not influence treatment results in this group of patients with early TMD. CONCLUSION: In this population, TMD was significantly higher in females. Treatment of early TMD with IOS was effective and moderately effective in long-term in over 80% of the patients during the follow-up period of 1-9 years. Bruxism had a significant etiologic role in TMD; occlusal attrition of the dentition, pain of all the teeth, early morning pain of the masticatory muscles and the TMJ are signs and symptoms to suspect nocturnal bruxism. Use of an IOS is recommended to prevent potential damage to the dentition, periodontium and the TMJ in early TMD. PMID- 22442580 TI - Continuous ropivacaine infusion vs transdermal fentanyl for providing postoperative analgesia following temporomandibular joint interpositional gap arthroplasty. AB - AIM: The purpose of this study was to evaluate the postoperative pain control and mouth opening in patients undergoing temporomandibular joint interpositional gap arthroplasty by either placing an epidural catheter in the incision wound and infusing ropivacaine 0.25% or by using a transdermal fentanyl patch. MATERIALS AND METHODS: The study was prospective, randomized and double blind. Eighty patients belonging to American Society of Anesthesiologists grade I and II, 18-32 years of age, scheduled for temporomandibular joint interpositional gap arthroplasty were randomized into 2 groups; ropivacaine group (G rop): to receive 0.25% ropivacaine infusion and transdermal fentanyl group (G tf): to receive transdermal fentanyl patch. For postoperative pain (Visual Analog Score [VAS]) and analgesic requirements were assessed 2, 4 and 8 h after surgery and each morning, until and 4 days after surgery. RESULTS: Time to first analgesic requirement was found to be significantly (P < 0.0001) higher in G rop (49 +/- 6.7) as compared with G tf (32 +/- 9.1) VAS were also significantly lower in G rop throughout the postoperative period. Postoperatively, mouth opening was better in G rop as compared with G tf, which was statistically significant. CONCLUSION: It was concluded that by placing an epidural catheter at the incision wound and continuously infusing with ropivacaine 0.25% effectively controls the postoperative pain in patients undergoing temporomandibular joint interpositional gap arthroplasty and provides better postoperative mouth opening. PMID- 22442581 TI - Efficiency of ultrasonography in assessing cervical lymph node metastasis in oral carcinoma. AB - OBJECTIVES: The study was conducted to assess the value of ultrasonography (USG) for lymph node metastasis in patients with carcinoma of oral cavity. MATERIALS AND METHODS: A total of 20 cases were selected with primary tumor of oral cavity. Ninety-two lymph nodes were detected by ultrasound of 5 mm or more in diameter. The patients were examined preoperatively for palpable lymph nodes clinically and ultrasonographic examination of bilateral neck. Ultrasonographic parameters, such as size, shape, boundaries (well-delineated/ poorly delineated) and internal echoes for the lymph nodes were recorded. RESULTS: The histologic positive rate was 25%, 80% and 93% for nodes between 5 and 10 mm, 10 and 15 mm and for nodes 15 mm or more in size, respectively. Ultrasonographic findings showed a high significance as the size of nodes increases. The positive rate of 86% for the round nodes of 9 mm or more in size showed a high significance. The positive rate was 93% for well-delineated nodes and 68% for poorly delineated nodes. The most frequent echo pattern was homogenous followed by hypoechoic with positive rate for metastasis ranging from 83% to 88%. CONCLUSION: The diagnostic validity of USG as compared with histopathology showed sensitivity of 86% and specificity of 73% with overall efficiency of about 82% in detecting lymph node metastasis. USG is useful for preoperative evaluation of the neck, as the most reliable, inexpensive and easily available method. It is essential for diagnosis, staging and therapy choices. PMID- 22442582 TI - Impacted lower third molars: Can preoperative salivary pH influence postoperative pain? AB - AIM: The literature focuses little attention on factors that influence third molar post extraction pain (PEP). One factor that may play a role in PEP is saliva. We undertook a study in patients subjected to third molar extraction with the aim of assessing the influence of salivary pH on PEP. MATERIALS AND METHODS: Thirty-one healthy patients with one impacted inferior lower third molar with mean age of 21.02 +/- 2.05 years, underwent surgery for similar impactions. The process of pH measuring was carried out without delay after saliva collection, with a combination electrode connected to a PHM 62 pH meter. Pain assessment was done at 4, 8, 12, 18 and 24 hours on the first day. The scale ranged from 0 to 10 in which 0 and 10 denoted 'no pain' and 'maximum pain,' respectively. RESULTS: The multivariate analysis suggests that the factors that influence pain are patients' sex (B = - 0.466) and the saliva pH (B = - 1.093). According to the findings of our study, PEP intensity is assumed to have a reverse correlation with salivary pH and is also assumed to be greater in females. CONCLUSION: Due to the fact that no previous study has indicated such findings so far, further studies are needed to assess the importance of preoperative pH value and its clinical significance on the level of PEP. PMID- 22442583 TI - Prevention and management of antineoplastic therapy induced oral mucositis. AB - With the scientific advancements in the management of malignant diseases, the treatment is expensive and bears high morbidity in term of oral mucositis. It is a debilitating condition and has been researched extensively for its pathogenesis and treatment. Various treatment options include barrier forming, mucosal protectants, mouth rinses, growth factors, lasers and midline-sparing procedures. Some agents are used locally while others are administered systemically. Despite the availability of a wide range of treatment options for mucositis, a cost effective treatment is yet to be evolved. PMID- 22442584 TI - Cervical necrotizing fasciitis caused by dental infection: A review and case report. AB - Necrotizing fasciitis of the head and neck is an uncommon, potentially fatal , soft tissue infection characterized by extensive necrosis and gas formation in the subcutaneous tissue and fascia. The purpose of this report is to heighten the awareness of this infection. The article also outlines an appropriate management strategy for use in the treatment of these patients and reviews the literature along with a report of a case which was successfully managed. PMID- 22442585 TI - Management of mandibular fracture in a medically compromised pediatric patient. AB - Maxillofacial injuries in pediatric population warrant special attention because of anatomic considerations, potential for growth disturbances and rapidity of healing. We report a case of displaced mandibular fracture in a child who tested positive for hepatitis B surface antigen (HbsAg) and, therefore, was managed conservatively by closed reduction stabilized with acrylic dental splints fabricated on reduced dental models. PMID- 22442586 TI - Surgical-orthodontic treatment of a skeletal class III malocclusion. AB - For patients whose orthodontic problems are so severe that neither growth modification nor camouflage offers a solution, surgery to realign the jaws or reposition dentoalveolar segments is the only possible treatment option left. One indication for surgery obviously is a malocclusion too severe for orthodontics alone. It is possible now to be at least semiquantitative about the limits of orthodontic treatment, in the context of producing normal occlusion as the diagrams of the "envelope of discrepancy" indicate. In this case report we present orthognathic treatment plan of an adult female patient with skeletal class III malocclusion. Patient's malocclusion was decompensated by orthodontic treatment just before the surgery and then normal jaw relationship achieved by bilateral sagittal split osteotomy. PMID- 22442587 TI - Oro-mandibular dystonia. AB - Dystonia is an involuntary, repetitive, sustained (tonic), or spasmodic (rapid or clonic) muscle contraction. The spectrum of dystonias can involve various regions of the body. Oromandibular dystonia (OMD) can involve the masticatory, lower facial and the tongue muscles which may results in trismus, bruxism, involuntary jaw opening or closure and involuntary tongue movement. Here, we report a case of OMD in a 68 year old man. PMID- 22442588 TI - Chronic suppurative osteomyelitis of maxilla mimicking actinimycotic osteomyelitis: A rare case report. AB - Osteomyelitis is a disease which is heterogeneous in its pathophysiology, clinical presentation and management. It is considered to be one of the most difficult-to-treat infectious diseases. Progressive bony destruction and the formation of sequestra are hallmarks of osteomyelitis. We hereby report a rare case of maxillary osteomyelitis, which had actinomycotic osteomyelitis like presentation but was histopathologically diagnosed as a severe form of chronic suppurative osteomyelitis. PMID- 22442589 TI - The odontomes: Report of five cases. AB - Odontoma seems to result from budding of extra-odontogenic epithelial cells from the dental lamina. This cluster of cells forms a large mass of tissues that may be deposited in an abnormal arrangement, but consists of normal enamel, dentin, cementum and pulp. World Health Organization (WHO) classification defines a lesion as a malformation in which all the dental tissues are represented in a more orderly pattern than in the complex odontoma so that the lesion consists of many tooth-like structures. This article presents a report of five cases of odontomes. PMID- 22442590 TI - Surgical management of oral submucous fibrosis in an edentulous patient: A procedural challenge. AB - Prosthetic rehabilitation of patients with oral submucous fibrosis (OSMF) offers a formidable challenge due to restricted mouth opening. Physiotherapy via interocclusal force application is the mainstay for surgical treatment. Herein, we report a case of a man with OSMF requiring construction of dentures. The main objective was to deliver intra-operative and post operative inter occlusal forces without fracturing the mandible and thus providing rehabilitation to the patient prosthetically. An edentulous male patient reported with grade IVA OSMF to our department to improve his mouth opening for denture construction. The patient was managed successfully using surgical sectioning of the fibrous bands. Inter occlusal force application for mouth opening during the operation and post operative physiotherapy were facilitated using custom-made occlusal splints. Satisfactory mouth opening was achieved, with good healing and no event of infection or fracture. Here, we propose an easy method to achieve adequate mouth opening in an edentulous patient of OSMF, with atrophic ridges; without the chances of fracture of either jaw. PMID- 22442591 TI - Buccal fat pad reconstruction for oral submucous fibrosis. AB - Oral submucous fibrosis is a chronic debilitating disease characterized by gradually increasing fibrosis of the oral cavity and pharynx, mainly the buccal mucosa, resulting in trismus. Prepotency of the disease is seen in the Indian subcontinent, with its highest incidence in South India due to various deleterious habits. In spite of the numerous medical modalities employed in the management of oral submucous fibrosis, occasionally surgical intervention becomes inevitable. Various flaps have been used to reconstruct the surgical defects following excision of fibrous bands. Undoubtedly; the buccal fat pad remains the most versatile because of its excellent blood supply and minimal donor site morbidity. Here we present a case of severe oral submucous fibrosis surgically treated and reconstructed using buccal fat pad. PMID- 22442592 TI - Multiple dentigerous cysts in a nonsyndromic minor patient: Report of an unusual case. AB - A dentigerous cyst is an odontogenic cyst, thought to be of developmental origin. It is associated with the crown of an unerupted (or partially erupted) tooth. The cyst cavity is lined by epithelial cells derived from the reduced enamel epithelium of the tooth forming organ. Most dentigerous cysts are solitary. Multiple/bilateral cysts are usually found in association with a number of syndromes including cleidocranial dysplasia, Maroteaux-Lamy syndrome and Gorlin- Goltz syndrome (multiple OKCs). In the absence of these syndromes, the occurrence of multiple dentigerous cysts is rare. Here, we report the unusual occurrence of non-syndromic multiple dentigerous cysts. PMID- 22442593 TI - Transitional prosthesis for a dentulous hemimaxillectomy patient. AB - Hemimaxillectomy patients present with abrupt alterations in the physiologic processes of the maxillae, along with increased anxiety levels due to sudden impairment in esthetics, mastication, speech, deglutition and hypernasal speech. Such patients should be rehabilitated as early as possible, in the postoperative phase with the help of careful preoperative planning by the surgeon and the prosthodontist. This case report illustrates the multidisciplinary approach to rehabilitate a patient, who had undergone maxillectomy on the right side, due to carcinoma alveolus. The transitional prosthesis given in this case used Tissue conditioners, which, because of their viscoelastic nature, ensure continuous adaptation, helping peripheral seal and retention. This greatly reduces discomfort and nasal reflux and improves speech. PMID- 22442594 TI - Management of atrophic mandibular ridge with mini dental implant system. AB - Mini dental implants (MDI) are ultra-small diameter (l.8 mm width), biocompatible titanium alloy implant screws, conceived and designed over 20 years ago by a board-certified Manhattan dentist, Sendax Victor. Dr. R. A. Bulard added a single piece "O-ball" design to Dr. Sendax Victor concept. These implants can be used in atrophic ridges, flabby ridges, or in other cases where there is denture instability or lack of retention due to poor availability of residual bone. In this article, a case report of 55-year-old female patient is presented, with a severely atrophic mandibular ridge that was managed by the MDI system with an overdenture. PMID- 22442595 TI - Trigeminal neuralgia involving supraorbital and infraorbital nerves. AB - Supraorbital neuralgia is a rare disorder accounting for 4% of incidence with hallmark of localized pain in or above the eyebrow, clinically characterized by the following triad: (1) forehead pain in the area supplied by the supraorbital nerve, (2) tenderness on either the supraorbital notch and (3) absolute, but transitory relief of symptoms upon supraorbital nerve blockade. The pain presents with a chronic or intermittent pattern. The persistence of protracted unilateral forehead/occular pain, tenderness over the nerve and repeated blockade effect strongly suggest the diagnosis. Surgical treatment can be used when the medical treatment fails or in patients who do not tolerate the pharmacological treatment. PMID- 22442596 TI - Odontogenic myxoma: Report of two cases. AB - Odontogenic tumors represents a broad spectrum of lesions ranging from benign to malignant to dental hamartomas all arising from odontogenic residues, that is, the odontogenic epithelium, ectomesenchyme with variable amounts of dental hard tissues formed in the same sequence as in normal tooth development. We report two cases of myxoma, which were misdiagnosed initially and latter, reported as odontogenic myxoma; and were treated by conservative surgical excision in one case and radical resection with hemimandibulectomy in the other case. PMID- 22442597 TI - Isolated congenital bifid tongue. AB - Human growth and development is a meticulously planned and precisely executed process. Even a mild disturbance can have clinically significant manifestations later on. Even today, ancient beliefs and practices override/delay patient's aspiration for seeking treatment as seen in the case report presented here. Congenital bifid tongue in association with various other orofacial abnormalities has been reported, many of which have been linked to various syndromes. But congenital bifid tongue occurring in the absence of other orofacial abnormalities is very rare. Here, we discuss a case of bifid tongue involving the anterior one third of tongue, reported in a 45-year-old male patient unusually with no other intraoral abnormalities. PMID- 22442598 TI - Ameloblastoma relapse after 16 years of resection in symphysis of mandible sparing the bone graft. AB - Ameloblastoma is a tumor derived from epithelium involved in odontogenesis. Although it is considered a benign tumor, its clinical behavior may be regarded as lying between benign and malignant. It is characterized by slow but persistent growth, local infiltration into adjacent tissues and recurrences; however, metastases are rare. Diagnosis mainly from tissue biopsy and characteristic finding on plain X-rays does assist in differentiating between types of ameloblastoma. The challenges in the management of this tumor are to provide complete excision as recurrence may occur in incomplete removal and also to reconstruct the bony defect in order to give reasonable cosmetic and functional outcome to the patient. PMID- 22442599 TI - Message from Head OMFS, Medical University Lucknow. PMID- 22442600 TI - Foregut duplication cyst presenting as lingual swelling: Case report and review of literature. AB - Congenital lingual cystic masses are challenging entities that can be detected prenatally or are discovered in various forms after birth. Foregut duplication cyst of tongue is an extremely rare condition. Here we present the eleventh case in literature on foregut duplication cyst in tongue lined with gastric mucosa. Complete excision was curative with no recurrence on followup. PMID- 22442601 TI - Probiotics and oral health. AB - Probiotics utilize the naturally occurring bacteria to confer health benefits. Traditionally, probiotics have been associated with gut health, and are being mainly utilized for prevention or treatment of gastrointestinal infections and disease; however, recently, several studies have suggested the use of probiotics for oral health purposes. The aim of this review is to understand the potential mechanism of action of probiotic bacteria in the oral cavity and summarize their observed effects with respect to oral health. PMID- 22442602 TI - Supplemental oxygen therapy: Important considerations in oral and maxillofacial surgery. AB - The administration of supplemental oxygen is an essential element of appropriate management for a wide range of clinical conditions; crossing different medical and surgical specialities. The present review summarizes the role of supportive oxygen therapy in various clinical conditions encountered in our day-to-day practice in the speciality of oral and maxillofacial surgery; including major trauma, shock, sepsis; perioperative and postoperative considerations and in patients with various other medical comorbidities. Regular and judicious use of oxygen as a drug is thus recommended in our day-to-day practice in oral and maxillofacial surgery to reduce the morbidity and improve the prognosis of patients. PMID- 22442603 TI - Oral lichen planus - Review on etiopathogenesis. AB - Oral lichen planus (OLP) is a chronic mucocutaneous disease of uncertain etiopathogenesis. Several factors including stress, genetics, systemic diseases, viruses, dental restorative materials and drugs have been implicated as causative agents. The disease seems to be mediated by an antigen specific mechanism, activating cytotoxic T cells, and non specific mechanisms like mast cell degranulation and matrix metalloproteinase activation. Further clarity on the pathogenesis will aid in modifying therapeutic interventions, thus significantly reducing the morbidity of OLP patients. PMID- 22442604 TI - Overexpression of COX-2 in oral squamous cell carcinoma patients undergoing chemoradiotherapy. AB - AIMS AND OBJECTIVES: To evaluate the prognostic significance of cyclooxygenase-2 (COX-2) overexpression in oral squamous cell carcinoma (OSCC) patients undergoing chemoradiation therapy. Purpose of the study was to determine whether COX-2 could be used as a diagnostic and prognostic index in OSCC. MATERIALS AND METHODS: Forty-four patients of SCC were included in the present study and immunohistochemical examination was done for COX-2 expression. Negative and <5% COX-2 positivity were taken as negative expression and >=5% COX-2 positivity as positive expression group. >=30% COX-2 positivity was taken as overexpressed group and <30% COX-2 positivity was taken as underexpressed group. All the data were analyzed statistically. RESULTS: COX-2 overexpression in OSCC was found in 15.90% cases. The proportion of COX-2 overexpression was higher in patients with large tumor size than in those with small tumor size. The proportions of COX-2 positive expression cases were higher with cervical lymph node metastasis. Negative COX-2 expression was higher in well-differentiated OSCC and positive expression was higher in moderately differentiated tumors. COX-2 underexpressed cases had better response to chemoradiation therapy as compared to cases with overexpressed COX-2. CONCLUSION: COX-2 expression in OSCC can be used as a prognostic marker. Studies with large sample size and long-term follow-up are required to find out the exact role and prognostic significance of COX-2 expression in OSCC. PMID- 22442605 TI - Surgical management of ameloblastoma: Conservative or radical approach. AB - AIM: The ameloblastoma is a benign odontogenic tumor of epithelial origin that exhibits a locally aggressive behavior with a high level of recurrence, being believed theoretically to come from dental lamina remains, the enamel organ in development, epithelial cover of odontogenic cysts or from the cells of the basal layer of the oral mucosa. Especially larger, aggressive lesions require a more radical surgical approach resulting in large jaw defects. This paper discusses our experiences in the management of ameloblastoma tumor in 20 such patients. MATERIALS AND METHODS: A review of 20 cases of ameloblastoma (6 in the maxillary and 14 in the mandibular region) is presented. The lesions were between 4 and 8 cm in diameter. The methods of treatment consisted of radical surgery (i.e., segmental resection) and conservative treatments (i.e., enucleation with bone curettage). Half the cases were treated conservatively and others surgically. RESULTS: Enucleation with curettage was done in 10 cases, out of which six (60%) showed recurrence, whereas one (10%) case in the surgical group showed recurrence. Relatively higher tendencies of recurrence were observed in the cases treated conservatively. The aesthetic and functional outcomes were satisfying in all patients. CONCLUSION: According to our opinion, radical surgical resection of ameloblastoma is the treatment of choice, followed by the reconstruction of the defects, allowing good functional and aesthetic outcome. PMID- 22442606 TI - Efficacy of 2-mm locking miniplates in the management of mandibular fractures without maxillomandibular fixation. AB - BACKGROUND: The management of trauma has evolved greatly over the past many years. Various bone plating systems have been developed to provide stable fixation of mandibular fractures. The introduction of the locking plate/screw system has offered certain advantages over the conventional plating systems. This system does not require intimate adaptation of the miniplates to the underlying bone and has greater stability. This study evaluates the efficacy of locking miniplate/screw system in the treatment of mandibular fractures without maxillomandibular fixation. MATERIALS AND METHODS: This was a prospective study analyzing 20 patients with undisplaced or minimally displaced mandibular fractures, who reported to Department of Oral and Maxillofacial Surgery, Government Dental College and Research Institute, Bangalore. The selected cases were treated by open reduction and internal fixation using the 2.0 mm locking plate/screw system. RESULTS: Open reduction and internal fixation with the 2.0 mm locking plate/screw system were achieved in all the 20 cases with satisfactory stability of the fracture fragments. The system was found to be reliable and effective intraoperatively. Only two complications were noted in the study. CONCLUSION: The locking miniplate system was found to be reliable and effective in management of mandibular fractures without postoperative intermaxillary fixation, however further studies with more sample size is required. PMID- 22442607 TI - Cephalometric norms for orthognathic surgery for North India (Eastern Uttar Pradesh). AB - AIM: The present study was aimed at development of the cephalometric norms for orthognathic surgery for the population of eastern Uttar Pradesh in North India. SETTINGS AND DESIGN: This study was conducted at a dental college. MATERIALS AND METHODS: The study sample consisted of 50 males and 50 females. Each lateral cephalogram was taken in occlusion and subsequently traced. All reference points, landmarks, and measurements were made according to cephalometrics for orthognathic surgery (COGS) system. STATISTICAL ANALYSIS USED: The statistical analysis involved calculation of mean and standard deviation for each of the 23 parameters assessed for each subject. The data was subsequently compared with COGS study by using Normal (Z) test. RESULTS: The norms were derived for the purvanchal population of North India and these were found to be quite distinct compared to those obtained from COGS study with respect to specific parameters. CONCLUSION: Male subjects indicated greater prominence of chin relative to the face, decreased posterior divergence, infraeruption of upper and lower molar as well as lower incisors, decreased total effective length of the maxilla, tendency towards Class III occlusion, and procumbent lower incisors. Female subjects, however, indicated increased anterior cranial base length, greater prominence of chin relative to the face, prognathic maxilla and mandible, increased middle third facial height, infraerupted lower incisors, increased mandibular body length, and procumbent lower incisors. PMID- 22442608 TI - Expression of p53 protein and ki-67 antigen in oral premalignant lesions and oral squamous cell carcinomas: An immunohistochemical study. AB - AIM: To study expression of p53 protein and ki-67 antigen in normal, non dysplastic, dysplastic, premalignant and malignant lesions of the oral mucosa. MATERIALS AND METHODS: The standard immunohistochemical method along with MIB-1 and DO-7; DAKO antibodies was used to study the expression of p53 and ki-67 in paraffin-embedded tissue specimens. RESULTS: All samples studied showed positive staining for p53 and ki-67. Only one case each from leukoplakia and oral squamous cell carcinoma (OSCC) groups showed negative staining for ki-67. The staining was confined to basal layer in most of the cases except OSCC in which it was seen in all layers. The intensity of staining was moderate to intense. The percentage of p53-positive cells in normal mucosa was 15-25% which was increased to 95% in malignant mucosa. Statistical analysis revealed that the expression of p53 and ki 67 increases as normal oral mucosa becomes dysplastic and undergoes malignant transformation. CONCLUSION: These results emphasize the potential use of p53 protein and ki-67 antigen as markers of malignant transformation and carcinogenesis in oral premalignant lesions, conditions and OSCC, respectively; and in future they may serve as prognostic tools in the early detection of malignant transformation in oral premalignant lesions and conditions. PMID- 22442609 TI - Single miniplate osteosynthesis in angle fracture. AB - AIM: The present study was designed to study the feasibility of single miniplate osteosynthesis in the fracture of angle of mandible. MATERIALS AND METHODS: in this study 110 patient were included and treated with single miniplate osteosynthesis at upper border along champy's line of osteosynthesis. RESULTS: All the cases were treated successfully, common complications which we have observed in this study, cosmetic disfigurement, delayed union, infection, wound dehiscence and paresthesia. CONCLUSION: Single miniplate fixation in unfavorable fracture is questionable and hence these fracture require some alternative method (locking plate, etc.) for fixation. PMID- 22442610 TI - Anomalous formation of external jugular vein and its clinical implication. AB - INTRODUCTION: The superficial veins, especially the external jugular vein (EJV), are increasingly being utilized for cannulation to conduct diagnostic procedures or intravenous therapies. EJV is also used in microsurgical procedures,used as a recipient for the free flaps. MATERIALS AND METHODS: During routine dissection a variation was observed in the formation of EJV unilaterally on the left side. RESULT: In the anterior triangle of the neck submandibular vein joined with the anterior jugular vein to form a large venous trunk (V1). Facial vein joined this venous trunk (V1) to form another common channel (V2). The retromandibular vein divided into unusually long anterior and posterior divisions. Anterior division did not join the facial vein but drained into the common channel V2.The posterior division of retromandibular vein also drained into V2 which further continued as EJV and drained into the subclavian vein. CONCLUSION: The knowledge of variations in the patterns of superficial veins is important for the surgeons to avoid any intraoperative error which might lead to unnecessary bleeding. PMID- 22442611 TI - Evaluation of implants placed immediately or delayed into extraction sites. AB - AIMS AND OBJECTIVES: To compare the success rate of implant placed immediately in extraction socket vs implant placed delayed in extraction socket. MATERIALS AND METHODS: The study comprised of 8 patients (6 male and 2 female, aged from 14 to 58 year) for evaluation of implant placement immediately (i.e. Group - A) or delayed (i.e. Group - B) into extraction site, in which at 12 sites implants were placed. RESULTS: The inclusion criteria for implantation was tooth/teeth with one or two degree mobility, root stumps, tooth with failure root canal treatment and extraction sockets. HI-TEC TRX-OP (Life Care) with abutment, non-submerged, tapered at apical 5 mm, sand-blasted & acid etched surfaced implants were used. These are one stage single implants made of commercially pure titanium. The length of implants used was 10 mm and 13 mm and diameter was 3.70 mm and 4.50 mm. The vertical bone dimension was determined by palpation and radiograph (intra oral periapical, orthopantomograph and dentascan in some patients). Gingival condition, bone condition was examined clinically and radiographically. DISCUSSION: Post-operative evaluation was done under clinical parameters (i.e. Pain (VAS), Swelling, Stability (By Glickman method), Gingival status, Probing depth (By Williams Periodontal probe), Patient's compliance / satisfaction, Complications (If any) and Radiological parameters was (Intra-oral periapical radiograph, orthopantomograph, Dentascan). CONCLUSION: Overall conclusion drawn from this study was that both the groups are showing similar results but Group-A is slightly better than Group-B. PMID- 22442612 TI - Rehablitation of mandibular fracture with anterior teeth loss. AB - We report here on rehabilitating a case with mandibular fracture and lower anterior teeth loss. Three double-staged implants were placed in the lower anterior region; in an attempt to rehabilitate the condition of five missing lower teeth, two natural teeth were prepared to act as natural abutments. Teeth implant-supported prosthesis was fabricated. Patient with a right mandibular fracture and loss of lower anterior missing teeth was successfully rehabilitated with teeth implant-supported prosthesis and titanium bony plates. PMID- 22442613 TI - Pleomorphic adenoma of submandibular gland: An uncommon occurrence. AB - Pleomorphic adenoma (PA) is the most common tumor of the benign salivary gland neoplasms, and the most common gland to be involved is the parotid gland. Its occurrence in the submandibular or the sublingual gland is uncommon. We present a case of a histologically proven PA involving the submandiblular gland. PMID- 22442614 TI - Esthetic correction of depressed frontal bone fracture. AB - Depressed frontal bone fractures are occasionally seen in maxillofacial trauma patient. If untreated, they look un-esthetic. Although there are numerous options available for correction of these defects, use of bone cement (polymethylmethacrylate or PMMA) is simple and reliable. This is the report of one such case. PMID- 22442615 TI - Ossifying fibroma of maxilla in a male child: Report of a case and review of the literature. AB - Ossifying fibroma is a rare benign fibro-osseous neoplasm of the jaw characterized by substitution of normal bone by fibrous tissues and newly formed calcified products such as bone, cementum or both. It is a well-demarcated lesion that differentiates it from fibrous dysplasia. This case report describes a rare case of ossifying fibroma arising in the maxilla of an 11-year-old child treated with enucleation. The clinical, radiographical, surgical and histological findings are presented. Controversies regarding the terminology and classification along with the differential diagnosis are discussed and a review is provided of the literature on the subject. PMID- 22442616 TI - Post operative pain relief through intermittent mandibular nerve block. AB - Mandibular nerve block is often performed for diagnostic, therapeutic and anesthetic purposes for surgery involving mandibular region. Advantages of a nerve block include excellent pain relief and avoidance of the side effects associated with the use of opiods or Non-steroidal anti-inflammatory drug (NSAIDs). A patient with maxillo facial trauma was scheduled for open reduction and internal fixation of right parasymphyseal mandibular fracture. The mandibular nerve was approached using the lateral extraoral approach with an 18-gauge i.v. cannula under general anesthesia. He received 4 ml boluses of 0.25% plain bupivacaine for intraoperative analgesia and 12 hourly for 48 h post operatively. VAS scores remained less than 4 through out observation period. The only side effect was numbness of ipsilateral lower jaw line, which subsided after local anesthetic administration was discontinued. Patient was discharged after four days. PMID- 22442617 TI - Diplopia with local anesthesia. AB - A variety of local and systemic complications can occur during the administration of local anesthesia (LA). Diplopia is one of the very rare complications that follow a posterior superior alveolar (PSA) nerve block. This article describes a very rare case report and the possible mechanisms are discussed in detail. Diplopia is defined as double vision. The patient was administered PSA nerve block for the extraction of the upper right third molar tooth. After the extraction, the patient complained of double vision and not being able to gaze laterally with the right eye. The patient recovered completely after the anesthetic effect. Local and systemic complications do occur during and after administration of local anesthesia. The clinician needs to be aware of the complications and management. PMID- 22442618 TI - Lymphangioma of the tongue. AB - Lymphangiomas are developmental malformations and have a marked predilection for the head and neck region. They are benign proliferation of lymphatic vessels and represents hamartomas of malformed lymphatics. The most common location in the mouth is the dorsum of tongue, followed by lips, buccal mucosa, soft palate, and floor of the mouth. In the tongue, they may present as a localized or a diffused growth which may enlarge to cause macroglossia, impaired speech and difficulty in mastication. These tumors are typically present at birth, but may go unnoticed until after dentition erupts or even after puberty. Presenting here is a case of localized lymphangioma of the tongue in a five year old child and its surgical management. PMID- 22442619 TI - Unicystic ameloblastoma: A diagnostic dilemma. AB - Ameloblastoma is a slow-growing, persistent and locally aggressive neoplasm of epithelial origin accounting for 10% out of 30% of all odontogenic tumors. According to the World Health Organization, ameloblastomas are classified into the following types: conventional, unicystic, and peripheral. Unicystic ameloblastoma (UA) refers to those cystic lesions that show clinical, radiographic, or gross features of a mandibular cyst, but on histologic examination show a typical ameloblastomatous epithelium lining part of the cyst cavity, with or without luminal and/or mural tumor growth. We report a case of young female with a radiolucent lesion in the right posterior mandible. Surgical removal of the lesion was performed, with differential diagnosis of a radicular cyst. However, histopathologic examination revealed UA. The patient was kept under observation and showed signs of local bone regeneration. The purpose of presenting this report of a clinical case of UA previously misdiagnosed as radicular cyst is to emphasize the significance of histopathologic examination of all tissue specimens recovered in surgery even when clinical and radiological finding are innocuous. PMID- 22442620 TI - A rare ocular complication following treatment of oral submucous fibrosis with steroids. AB - Oral submucous fibrosis (OSMF) is one of the most commonly found pre-cancerous conditions prevalent in Southeast Asian countries. The treatment method used by most patients is the use of intralesional steroids. With intralesional steroids used commonly, one might come across an unusual ocular complication - central serous chorioretinopathy (CSCR). We report a case of a patient with OSMF who was treated by corticosteroids, subsequent to which he developed CSCR. He was put off steroidal treatment and treated conservatively to which he responded positively. PMID- 22442621 TI - Surgical management of masseteric hypertrophy and mandibular retrognathism. AB - Masseter hypertrophy is a rare condition. It is mostly idiopathic with no known cause. It is recognized as an enlargement of one or both masseter muscles. Most patients complain of facial asymmetry; however, symptoms such as trismus, protrusion, and bruxism may also occur. This article reports a case of bilateral masseter hypertrophy with retrognathic mandible in which comprehensive treatment was rendered to the patient by using a combination approach. PMID- 22442622 TI - An unusual case of labial cysticercosis with a natural history. AB - Cysticercosis is a common disease in developing countries. Labial lesions produced by this parasitic infestation are rare. The most frequently involved oral locations are the tongue, labial or buccal mucosa, and mouth floor. We present here a case report of a 33-year-old-female patient from Maharashtra, who reported to our department with a swelling in the left lower lip, which was diagnosed as cysticercosis on histpathological examination. PMID- 22442623 TI - A simple intraoral technique for sinus lavage. PMID- 22442624 TI - Chronic ulcer: Common problem uncommon diagnosis. PMID- 22442625 TI - Gene Selection using a High-Dimensional Regression Model with Microarrays in Cancer Prognostic Studies. AB - Mining of gene expression data to identify genes associated with patient survival is an ongoing problem in cancer prognostic studies using microarrays in order to use such genes to achieve more accurate prognoses. The least absolute shrinkage and selection operator (lasso) is often used for gene selection and parameter estimation in high-dimensional microarray data. The lasso shrinks some of the coefficients to zero, and the amount of shrinkage is determined by the tuning parameter, often determined by cross validation. The model determined by this cross validation contains many false positives whose coefficients are actually zero. We propose a method for estimating the false positive rate (FPR) for lasso estimates in a high-dimensional Cox model. We performed a simulation study to examine the precision of the FPR estimate by the proposed method. We applied the proposed method to real data and illustrated the identification of false positive genes. PMID- 22442626 TI - A Systems Biology Approach in Therapeutic Response Study for Different Dosing Regimens-a Modeling Study of Drug Effects on Tumor Growth using Hybrid Systems. AB - Motivated by the frustration of translation of research advances in the molecular and cellular biology of cancer into treatment, this study calls for cross disciplinary efforts and proposes a methodology of incorporating drug pharmacology information into drug therapeutic response modeling using a computational systems biology approach. The objectives are two fold. The first one is to involve effective mathematical modeling in the drug development stage to incorporate preclinical and clinical data in order to decrease costs of drug development and increase pipeline productivity, since it is extremely expensive and difficult to get the optimal compromise of dosage and schedule through empirical testing. The second objective is to provide valuable suggestions to adjust individual drug dosing regimens to improve therapeutic effects considering most anticancer agents have wide inter-individual pharmacokinetic variability and a narrow therapeutic index. A dynamic hybrid systems model is proposed to study drug antitumor effect from the perspective of tumor growth dynamics, specifically the dosing and schedule of the periodic drug intake, and a drug's pharmacokinetics and pharmacodynamics information are linked together in the proposed model using a state-space approach. It is proved analytically that there exists an optimal drug dosage and interval administration point, and demonstrated through simulation study. PMID- 22442627 TI - Evaluation of ischemia-modified albumin and C-reactive protein in type 2 diabetics with and without ketosis. AB - OVERVIEW: To investigate whether serum ischemia-modified albumin or C-reactive protein is reliable for predicting type 2 diabetic patients with ketosis. APPROACH: One hundred and four diabetic patients, 48 with diabetic ketosis, and 33 controls were enrolled in the study. Serum ischemia-modified albumin and C reactive protein were measured and evaluated for their ability to distinguish diabetic ketosis. RESULTS: Compared to the controls, the ischemia-modified albumin and C-reactive protein levels were higher in patients with diabetic ketosis and type 2 diabetes at the baseline. The levels of ischemia-modified albumin were higher in patients with type 2 diabetes than in the controls. C reactive protein and ischemia-modified albumin levels were reduced after insulin treatment. The level of ischemia-modified albumin was an independent risk marker for diabetic ketosis (OR = 1.085, P = 0.008, 95% CI: 1.022-1.152). Receiver operating characteristic curves revealed that the areas under the curve were 0.917 for the modified albumin and 0.357 for C-reactive protein. CONCLUSION: This study indicates that ischemia-modified albumin was significantly associated with diabetic ketosis and was more sensitive than C-reactive protein in reflecting diabetic ketosis. PMID- 22442628 TI - Psychological and sociodemographic predictors of premature discontinuation of a 1 year multimodal outpatient weight-reduction program: an attrition analysis. AB - OBJECTIVE: Attrition rates of up to 77% have been reported in conservative weight reduction programs for the treatment of obesity. In view of the cost of such programs to the health system, there is a need to identify the variables that predict premature discontinuation of treatment. Previous studies have focused mainly on somatic and sociodemographic parameters. The prospective influence of psychological factors has not been systematically investigated to date. METHODS: A total of 164 patients (138 of whom were women) with a mean age of 45 years and a mean body mass index of 39.57 participated in a 1-year outpatient weight reduction program at the Charite - Universitatsmedizin Berlin University Hospital. The program included movement therapy, dietary advice, psychoeducational and behavioral interventions, relaxation procedures, and consultations with a specialist in internal medicine and a psychologist. Patients also underwent regular laboratory and psychological testing. The results were evaluated using a t-test, chi(2)-test, and logistic regression analysis. RESULTS: Seventy-one of the 164 patients (61 women, mean age = 43 years, mean body mass index = 39.53) withdrew before the end of the program (attrition rate = 43.3%). While there were no differences between the somatic and metabolic characteristics of those who withdrew and those who remained, the sociodemographic and psychological factors had some relevance. In particular, "expectation of self efficacy" (Fragebogen zu Selbstwirksamkeit, Optimismus und Pessimismus [SWOP]), "not working," "tiredness" (Berliner Stimmungsfragebogen [BSF]), "pessimism" (SWOP) and "positive reframing" (Brief-COPE) were found to play a role in whether participants subsequently dropped out of the treatment. "Support coping" (Brief COPE) and "older age" prior to the start of treatment were identified as variables that promoted treatment adherence. CONCLUSION: The results are discussed in light of previous findings and with regard to whether the modules of the weight-reduction program should be adapted. PMID- 22442629 TI - Can a feedback report and training session on medication counseling for general practitioners improve patient satisfaction with information on medicines? AB - BACKGROUND: Regular intake of medicines prevents hospitalization and improves treatment outcomes in patients with chronic diseases; however, requires good patient-physician communication. Yet, this communication is often insufficient and characterized by misunderstandings. This paper aimed to explore whether a training session on medication counseling for general practitioners (GPs) can improve patient satisfaction about information on medicines. METHODS: Within a seamless care project (HeiCare((r))), a questionnaire to assess patient satisfaction with information on medicines and other questions related to medication issues was distributed among 370 patients. Results were returned to physicians in a feedback report, discussed in a training session, and a subsequent second questionnaire was sent to patients. RESULTS: Patients showed a significant increase in satisfaction with overall information on medicines and with information on potential problems when experiencing medication counseling after their GP received a feedback report and/or training session. CONCLUSION: Individual feedback and training sessions can improve medication counseling and GPs' awareness of patients' attitudes toward medicines and thus increase patients' satisfaction with medicines information received. Regular feedback to the GP on patients' satisfaction with information and patients' beliefs in medicines can be obtained by patient surveys or by addressing these issues in regular medication counseling encounters. Physicians need to be trained to listen to patients' views and concerns on medication. PMID- 22442630 TI - Update on the role of antipsychotics in the treatment of Tourette syndrome. AB - Tourette syndrome (TS) is a neuropsychiatric disorder with typical onset in childhood and characterized by chronic occurrence of motor and vocal tics. The disorder can lead to serious impairments of both quality of life and psychosocial functioning, particularly for those individuals displaying complex tics. In such patients, drug treatment is recommended. The pathophysiology of TS is thought to involve a dysfunction of basal ganglia-related circuits and hyperactive dopaminergic innervations. Congruently, dopamine receptor antagonism of neuroleptics appears to be the most efficacious approach for pharmacological intervention. To assess the efficacy of the different neuroleptics available, a systematic, keyword-related search in PubMed (National Library of Medicine, Washington, DC) was undertaken. Much information on the use of antipsychotics in the treatment of TS is based on older data. Our objective was to give an update and therefore we focused on papers published in the last decade (between 2001 and 2011). Accordingly, the present review aims to summarize the current and evidence based knowledge on the risk-benefit ratio of both first and second generation neuroleptics in TS. PMID- 22442631 TI - Boceprevir and telaprevir for the treatment of chronic hepatitis C genotype 1 infection: an indirect comparison meta-analysis. AB - BACKGROUND: The aim of this study was to examine the relative efficacy and safety of boceprevir and telaprevir, when used in combination with pegylated interferon alpha and ribavirin, using an indirect comparison meta-analysis. METHODS: Published phase II and phase III randomized placebo-controlled trials examining the efficacy of boceprevir and telaprevir in chronic hepatitis C virus genotype 1 infected adult populations were included. The primary outcomes were sustained virologic response, relapse, and discontinuation of all study drugs. Secondary outcomes included the adverse events of anemia, neutropenia, rash, and pruritus. RESULTS: Four boceprevir trials and six telaprevir trials were included. No significant differences were observed for sustained virologic response among either naive (relative risk [RR] 1.14, 95% confidence interval [CI] 0.93-1.37, P = 0.20) or experienced patients (RR 0.81, 95% CI 0.52-1.23, P = 0.30). Similarly, for relapse among naive (RR 0.80, 95% CI 0.18-3.45, P = 0.77) and experienced patients (RR 1.71, 95% CI 0.90-3.24, P = 0.10), or discontinuation of therapy for naive (RR 0.80, 95% CI 0.28-2.29, P = 0.72) and experienced patients (RR 0.88, 95% CI 0.69-1.12, P = 0.30). Telaprevir was more likely to be associated with rash and pruritus, and boceprevir was more likely to be associated with neutropenia in certain patient populations. CONCLUSION: Boceprevir and telaprevir appear comparable in terms of sustained virologic response, relapse, or discontinuation of therapy for patients treated with standard-dose therapy durations and response-guided therapy durations. PMID- 22442632 TI - Embodiment of the interpersonal nexus: revealing qualitative research findings on shoulder surgery patients. AB - BACKGROUND: The paper reports on the importance of the interpersonal nexus within qualitative research processes, from a recent research project on patient experiences of shoulder surgery. Our aim is to reveal the importance of qualitative research processes and specifically the role of the interpersonal nexus in generating quality data. Literature related to the importance of human interactions and interpersonal communication processes in health-related research remains limited. Shoulder surgery has been reported to be associated with significant postoperative pain. While shoulder surgery research has investigated various analgesic techniques to determine key efficacy and minimization of adverse side effects, little has been reported from the patient perspective. METHODS: Following institutional ethics approval, this project was conducted in two private hospitals in Victoria, Australia, in 2010. The methods included a survey questionnaire, semistructured interviews, and researcher-reflective journaling. Researcher-reflective journaling was utilized to highlight and discuss the interpersonal nexus. RESULTS: This research specifically addresses the importance of the contributions of qualitative methods and processes to understanding patient experiences of analgesic efficacy and shoulder surgery. The results reveal the importance of the established research process and the interwoven interpersonal nexus between the researcher and the research participants. The interpersonal skills of presencing and empathetic engagement are particularly highlighted. CONCLUSION: The authors attest the significance of establishing an interpersonal nexus in order to reveal patient experiences of shoulder surgery. Interpersonal emotional engagement is particularly highlighted in data collection, in what may be otherwise understated and overlooked qualitative findings in patient experiences of shoulder surgery. PMID- 22442633 TI - Comparative efficacy of uncontrolled and controlled intermittent preventive treatment during pregnancy (IPTp) with combined use of LLTNs in high resistance area to sulfadoxine-pyrimethamine in Cote d'Ivoire. AB - INTRODUCTION: In recent years, intermittent preventive treatment for pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) has become policy in much of sub Saharan Africa. But resistance to SP has been spreading across sub-Saharan Africa and thus the effectiveness of IPTp-SP has been questioned. The present study therefore sought to assess the incidence of placental malaria, low birth weight, and anemia of two IPTp-SP approaches (directly observed treatment scheme versus no directly observed treatment) in Anonkoua-Koute and Samo, Cote d'Ivoire where the reported prevalence of dfr single mutant 108 was 62% and 52.2%, respectively. METHODS: The study was a longitudinal design involving pregnant women and was conducted in Anonkoua-Koute, a suburban area, and Samo, a rural area, from January 2008 through March 2009. Women of a pregnancy less than 28 weeks duration were randomized to receive SP (1.5 g/0.075 g SP) in a single intake twice and were followed up monthly until delivery. Doses were administered under supervision in the controlled IPTp group, while SP was given free to women in the uncontrolled IPTp group with a recommendation to take it at home. The primary end point was the proportion of low birth weight infants (body weight < 2500 g) and the secondary end point was the rate of severe anemia and placental malaria detected at delivery. RESULTS: A total of 420 pregnant women were enrolled (212 and 208, respectively, in the controlled and uncontrolled groups). Delivery outcome was available for 378 women. In the modified intention-to-treat analysis, low birth weight infants were born from 15.5% of women of the uncontrolled IPTp group and from 11.9% of women in the controlled IPTp group (P = 0.31). The per protocol population analysis showed consistent results. The proportion of women with placental malaria infection, moderate anemia (hemoglobin < 11 g/dL), and severe anemia (hemoglobin < 8 g/dL) at delivery were similar between the two groups (P > 0.05). CONCLUSION: The study showed that the two approaches were equivalent, suggesting that unsupervised IPTp-SP free of charge should be used in areas where implementation of the directly observed treatment scheme suffers from many constraints. PMID- 22442635 TI - Children and young adults with parents with cancer: a population-based study. AB - BACKGROUND: Today many people are choosing to have children later in life. Additionally, the use of sophisticated diagnostic tools and screening modalities has increased over recent years. Because of these factors, cancer is being diagnosed more frequently during the child-rearing years. Sociodemographic and cancer-related information on families and minor (0-18 years) and young adult (YA) (19-25 years) children experiencing parental cancer is scarce, but this information is vital for healthcare initiatives aimed toward those potentially adversely affected. Therefore, the aim of this study was to describe features of families and minor and YA children affected by parental cancer in a nationwide population. METHODS: Complete Norwegian birth cohort data were obtained from national registries. Descriptive prevalence and incidence statistics were collected for parents and minor and YA children. Logistic regression models were used to assess factors likely to influence parental death. RESULTS: Every year around 0.3% of all families with children under the age of 18 years encounter parental cancer, and 3.1% of minors and 8.4% of YAs have a parent who has been diagnosed with cancer. This study found skin, breast, testicular, and colorectal cancers were the most common forms of cancer diagnosed. The sociodemographic features of those affected were fairly similar to those of the general population. One in five children experienced parental death from cancer; parental death was more often paternal than maternal and was most common in parents diagnosed with leukemia or brain, colorectal, and lung tumors. Deaths are uncommon among parents without cancer. CONCLUSION: Adequate assistance for minor and YA children affected by parental cancer requires knowledge of their number and characteristics. Parental cancer is more common than previously suggested: the annual incidence of parental cancer for children under 18 years of age is 0.3%, whereas approximately 4% of children aged 0-25 years have or have had parents diagnosed with cancer, corresponding to a population prevalence of 1.4%. Around 20% of these children experience parental death, and surveys of live respondents should account for this. PMID- 22442634 TI - Attenuation of niacin-induced prostaglandin D(2) generation by omega-3 fatty acids in THP-1 macrophages and Langerhans dendritic cells. AB - Niacin, also known as nicotinic acid, is an organic compound that has several cardio-beneficial effects. However, its use is limited due to the induction of a variable flushing response in most individuals. Flushing occurs from a niacin receptor mediated generation of prostaglandins from arachidonic acid metabolism. This study examined the ability of docosahexaenoic acid, eicosapentaenoic acid, and omega-3 polyunsaturated fatty acids (PUFAs), to attenuate niacin-induced prostaglandins in THP-1 macrophages. Niacin induced both PGD(2) and PGE(2) generation in a dose-dependent manner. Niacin also caused an increase in cytosolic calcium and activation of cytosolic phospholipase A(2). The increase in PGD(2) and PGE(2) was reduced by both docosahexaenoic acid and eicosapentaenoic acid, but not by oleic acid. Omega-3 PUFAs efficiently incorporated into cellular phospholipids at the expense of arachidonic acid, whereas oleic acid incorporated to a higher extent but had no effect on arachidonic acid levels. Omega-3 PUFAs also reduced surface expression of GPR109A, a human niacin receptor. Furthermore, omega-3 PUFAs also inhibited the niacin-induced increase in cytosolic calcium. Niacin and/or omega-3 PUFAs minimally affected cyclooxygenase-1 activity and had no effect on cyclooxygenase -2 activity. The effects of niacin on PGD(2) generation were further confirmed using Langerhans dendritic cells. Results of the present study indicate that omega-3 PUFAs reduced niacin-induced prostaglandins formation by diminishing the availability of their substrate, as well as reducing the surface expression of niacin receptors. In conclusion, this study suggests that the regular use of omega-3 PUFAs along with niacin can potentially reduce the niacin-induced flushing response in sensitive patients. PMID- 22442636 TI - Epidemiology of invasive fungal infections in kidney transplant patients. PMID- 22442637 TI - Coadministration of cyclosporin a with prednisolone in acute interstitial pneumonia complicating polymyositis/dermatomyositis. AB - OBJECTIVE: To investigate clinical effectiveness of prednisolone (PSL) and cyclosporin A (CyA), particularly continuous intravenous administration of the latter, in patients with interstitial pneumonia (IP) associated with polymyositis/dermatomyositis (PM/DM). METHODS: We reviewed the clinical findings and therapeutic outcomes of patients with PM/DM who had received PSL and CyA (PSL + CyA, n = 21 for DM and 2 for PM) or the former alone (n = 12 for DM and 7 for PM). All patients receiving PSL + CyA had active IP. RESULTS: Fifteen of the 21 DM patients receiving PSL + CyA showed favorable therapeutic outcomes of IP (recovery group), while the remaining 6 died of respiratory failure (death group). Before treatment PaO(2) in room air and %VC were significantly lower, and the total CT score was significantly higher in the death group than in the recovery one. Continuous intravenous administration of CyA was performed in 6 patients for severe IP requiring oxygen therapy, and of these 2 showed complete recovery from it. CONCLUSIONS: Coadministration of PSL and CyA, particularly continuous intravenous infusion of the latter, from the early phase of illness may be a potent therapeutic option for PM/DM patients with decreases in PaO(2) and %VC and/or a high total CT score suggestive of a poor prognosis. PMID- 22442638 TI - Rosuvastatin: a review of the pharmacology and clinical effectiveness in cardiovascular disease. AB - Rosuvastatin is a new generation HMG-CoA reductase inhibitor which exhibits some unique pharmacologic and pharmacokinetic properties. It has low extrahepatic tissue penetration, low potential for CYP3A4 interactions and substantial LDL-C lowering capacity and therefore has distinct advantages. We conducted a Medline literature search to identify rosuvastatin papers published in English. In this review, we outline the pharmacology of rosuvastatin, highlighting its efficacy and safety. We also review the major clinical trials with reference to primary and secondary prevention, familial hypercholesterolaemia and comparison with other statins. Finally we address its place in clinical practice. PMID- 22442639 TI - Immediate results of percutaneous trans-luminal mitral commissurotomy in pregnant women with severe mitral stenosis. AB - BACKGROUND: Valvular heart diseases and mainly rheumatic heart diseases complicate about 1% of pregnancies. During pregnancy physiological hemodynamic changes of the circulation are the main cause of mitral stenosis (MS) decompensation. Prior to introduction of percutaneous mitral balloon commissuroplasty (PTMC), surgical comissurotomy was the preferred method of treatment in patients with refractory symptoms. PTMC is an established non surgical treatment of rheumatic mitral stenosis. The study aimed to assess the safety and efficacy of PTMC in pregnant women with severs mitral stenosis. MATERIAL AND METHOD: Thirty three consecutive patients undergoing PTMC during pregnancy enrolled in this prospective study. Mitral valve area (MVA), transmitral valve gradient (MVG), and severity of mitral regurgitation (MR) were assessed before and 24 hour after the procedure by transthoracic and transesophageal echocardiography. Mitral valve morphology was evaluated before the procedure using Wilkin's criteria. Patient followed for one month and neonates monitored for weight and height and adverse effect of radiation. RESULT: Mitral valve area increased from 0.83 +/- 0.13 cm(2) to 1.38 +/- 0.29 cm(2) (P = 0.007). Mean gradient of mitral valve decreased from 15.5 +/- 7.4 mmHg to 2.3 +/- 2.3 mmHg (P = <0.001). Pulmonary artery pressure decreased from 65.24 +/- 17.9 to 50.45 +/- 15.33 (P = 0.012). No maternal death, abortion, intrauterine growth restriction was observed and only one stillbirth occurred. CONCLUSION: PTMC in pregnant women has favorable outcome and no harmful effect on children noted. PMID- 22442640 TI - Quadricuspid aortic valve defined by echocardiography and cardiac computed tomography. AB - A 54 year old female presented with lower extremity edema, fatigue, and shortness of breath with physical findings indicative of advanced aortic insufficiency. Echocardiography showed severe aortic regurgitation and a probable quadricuspid aortic valve. In anticipation of aortic valve replacement, cardiac computed tomography (Cardiac CT) was performed using 100 kV, 420 mA which resulted in 6 mSv of radiation exposure. Advanced computing algorithmic software was performed with a non-linear interpolation to estimate potential physiological movement. Surgical photographs and in-vitro anatomic pathology exam reveal the accuracy and precision that preoperative Cardiac CT provided in this rare case of a quadricuspid aortic valve. While there have been isolated reports of quadricuspid diagnosis with Cardiac CT, we report the correlation between echocardiography, Cardiac CT, and similar appearance at surgery with confirmed pathology and interesting post-processed rendered images. Cardiac CT may be an alternative to invasive coronary angiography for non-coronary cardiothoracic surgery with the advantage of providing detailed morphological dynamic imaging and the ability to define the coronary arteries non-invasively. The reduced noise and striking depiction of the valve motion with advanced algorithms will require validation studies to determine its role. PMID- 22442641 TI - beta(3)-Adrenoceptor Antagonist SR59230A Attenuates the Imbalance of Systemic and Myocardial Oxygen Transport Induced by Dopamine in Newborn Lambs. AB - BACKGROUND: In neonates, the increase in O(2)-delivery (DO(2)) by dopamine is offset by a greater increase in O(2)-consumption (VO(2)). This has been attributed to beta(3)-adrenergic receptors in neonatal brown fat tissue. beta(3) receptors in the heart have negative inotropic properties. We evaluated the effects of SR59230A, a beta(3)-antagonist, on the balance of systemic and myocardial O(2)-transport in newborn lambs treated with dopamine. METHODS: Lambs (2-5 days old, n = 12) were anesthetized and mechanically ventilated. Heart rate (HR) and rectal temperature were monitored. VO(2) was measured by respiratory mass spectrometry and cardiac output (CO) by a pulmonary artery transonic flowmeter. Arterial, jugular bulb venous and coronary sinus blood gases and lactate were measured to calculate DO(2), O(2) extraction ratio (ERO(2)), myocardial O(2) and lactate extraction ratios (mERO(2), mERlac). After baseline measurements, lambs were randomized to receive SR59230A at 5 mg/kg iv (SRG) or placebo. Both groups received incremental doses of a dopamine infusion (0-5-10-15 20 mcg/kg/min) every 15 min. Measurements were repeated at the end of each dose. RESULTS: After SR59230A infusion, CO and HR trended to decrease (P = 0.06), but no significant changes occurred in other parameters. Over the incremental doses of dopamine, temperature increased in both groups (P < 0.0001) but to a lesser degree in SRG (P = 0.004). CO and HR increased (P = 0.005 and 0.04) and similarly in both groups (P > 0.1). DO(2) trended to a small increase (P = 0.08). VO(2) increased in both groups (P < 0.0001) but to a lesser degree in SRG (P < 0.0001). As a result, ERO(2) increased in both groups (P < 0.0001), but to a lesser degree in SRG (P < 0.0001). mERO(2) was lower in SRG (P = 0.01) with a faster increase (P < 0.0001). mERlac was higher in SRG (P = 0.06) with a faster decrease (P = 0.04). CONCLUSION: Although SR59230A tends to induce an initial drop in CO, it significantly attenuates the rise in VO(2) and hence the imbalance of systemic and myocardial O(2) transport induced by dopamine at higher doses. Studies are warranted to examine the effect of SR59230A in cases of cardiac dysfunction and increased VO(2), observed after cardiac surgery. PMID- 22442642 TI - Asymptotic results for fitting marginal hazards models from stratified case cohort studies with multiple disease outcomes. AB - In stratified case-cohort designs, samplings of case-cohort samples are conducted via a stratified random sampling based on covariate information available on the entire cohort members. In this paper, we extended the work of Kang & Cai (2009) to a generalized stratified case-cohort study design for failure time data with multiple disease outcomes. Under this study design, we developed weighted estimating procedures for model parameters in marginal multiplicative intensity models and for the cumulative baseline hazard function. The asymptotic properties of the estimators are studied using martingales, modern empirical process theory, and results for finite population sampling. PMID- 22442643 TI - Nutrition transition, food retailing and health equity in Thailand. AB - AIM: Here we examine the influence of changes in food retailing, the food supply and the associated nutrition transition on health equity in Thailand, a middle income country experiencing rapid economic development. METHODS: The dietary transition underway in Thailand is reviewed along with theories regarding convergence to a globalised energy dense obesogenic diet and subsequent socio economically related dietary divergence along with the implications for health inequity. RESULTS: Thailand is part way through a dietary, nutrition and health transition. The food distribution and retailing system is now 50% controlled by modern supermarkets and convenience stores. The problem of increasing availability of calorie dense foods is especially threatening because a substantial proportion of the adult population is short statured due to child malnutrition. Obesity is an emerging problem and for educated Thai women has already developed an inverse relationship to socio-economic status as found in high income countries. CONCLUSIONS: Thailand has reached an important point in its nutrition transition. The challenge for the Thai government and population is to boost affordable healthy diets and to avoid the socio-economic inequity of nutritional outcomes observed in many rich countries. PMID- 22442646 TI - At your service! Publishing and dissemination of scientific research. PMID- 22442645 TI - Neurogenesis drives stimulus decorrelation in a model of the olfactory bulb. AB - The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb--the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells--are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures. PMID- 22442647 TI - In Search of the 'New Informal Legitimacy' of Medecins Sans Frontieres. AB - FOR MEDICAL HUMANITARIAN ORGANIZATIONS, MAKING THEIR SOURCES OF LEGITIMACY EXPLICIT IS A USEFUL EXERCISE, IN RESPONSE TO: misperceptions, concerns over the 'humanitarian space', controversies about specific humanitarian actions, challenges about resources allocation and moral suffering among humanitarian workers. This is also a difficult exercise, where normative criteria such as international law or humanitarian principles are often misrepresented as primary sources of legitimacy. This essay first argues for a morally principled definition of humanitarian medicine, based on the selfless intention of individual humanitarian actors. Taking Medecins Sans Frontieres (MSF) as a case in point, a common source of moral legitimacy for medical humanitarian organizations is their cosmopolitan appeal to distributive justice and collective responsibility. More informally, their legitimacy is grounded in the rightfulness of specific actions and choices. This implies a constant commitment to publicity and accountability. Legitimacy is also generated by tangible support from the public to individual organizations, by commitments to professional integrity, and by academic alliances to support evidence-based practice and operational research. PMID- 22442648 TI - Plasma Proteomic Signature in Overweight Girls Closely Correlates with Homeostasis Model Assessment (HOMA), an Objective Measure of Insulin Resistance. AB - Obesity is known to be associated with a large number of long-term morbidities, and while in some cases the relationship of obesity and the consequences is clear (for example, excess weight and lower extremity orthopedic problems) in others the mechanism is not as clear. One common system of categorizing overweight in terms of the likelihood of negative consequences involves using the concept of "metabolic syndrome". We hypothesized that the development of a plasma protein profile of overweight adolescents with and without the metabolic syndrome might give a more precise and informative picture of the disease process than the current clinical categorization and permit early targeted intervention. For this paper, we used antibody microarrays to analyze the plasma proteome of a group of 15 overweight female adolescent patients. Upon analysis of the proteome, the overweight patients diverged from the nonoverweight female controls. Furthermore, the overweight patients were divided by the analysis into two population clusters, each with distinctive protein expression patterns. Interestingly, the clusters were characterized by differences in insulin resistance, as measured by HOMA. Categorization according to the presence or absence of the metabolic syndrome did not yield such clusters. PMID- 22442649 TI - A sticky sight: cyanoacrylate 'superglue' injuries of the eye. AB - A 64-year-old man presented to casualty with blurred vision and pain in his left eye, 2 h after inadvertently instilling clear nail glue into his eye instead of postoperative Timolol eye drops. The glue was removed at the slit lamp revealing a corneal abrasion, which was managed with topical antibiotics. Inadvertent ocular cyanoacrylate, or 'superglue', instillation has been reported frequently since 1982 when superglue was repackaged into ophthalmic style dropper bottles. This case report highlights the continuing problem of cyanoacrylate eye injuries and serves as a reminder to healthcare professionals to report such incidents to manufacturers and regulatory bodies, on behalf of their patients, to promote the introduction of universal safety mechanisms on all household chemical containers. Failure of glue manufacturers to introduce safety cap mechanisms has resulted in significant ocular morbidity over the last 27 years, and such incidents are expected to occur until superglue bottles are redesigned. PMID- 22442650 TI - Fragile XE: an important differential diagnosis. AB - Fragile X is a common cause of mental retardation in boys that can also affect girls. We present the case of a 21-year-old woman with Fragile X E (FRAXE) with learning difficulty, behavioural problems and epilepsy. Her diagnosis was made after investigations spanning several years, highlighting the importance of considering FRAXE and the benefits of reviewing genetic test results in the light of advancing technology. PMID- 22442651 TI - Chronic optic disc swelling overlooked in a diabetic patient with a devastating outcome. AB - We present a case of asymmetrical but bilateral, progressive, painless visual deterioration over 5 years to no perception of light, in a 61-year-old male diabetic patient referred for a second opinion. The patient had a chronic history of bilateral diabetic maculopathy and unexplained swelling of the optic discs. He was diagnosed with optic atrophy secondary to pseudotumour cerebri (termed idiopathic intracranial hypertension when underlying causes have been excluded), which was associated with obstructive sleep apnoea. The case highlights the critical importance of identifying and investigating chronic papilloedema for reversible causes; the sometimes subtle presentation of pseudotumour cerebri; and the vital role of visual field testing and diagnostic lumbar puncture for timely diagnosis. It also reminds us that chronic bilateral optic disc swelling is not a normal feature of diabetic eye disease, and that alarm bells should sound if reduced visual acuity seems disproportionate to the degree of maculopathy. PMID- 22442652 TI - Osteopetrorickets: a twin paradox. PMID- 22442653 TI - PEComa in a 12-year-old boy. AB - PEComas (perivascular epithelioid cell tumours) are rare mesenchymal tumours, characterised by epithelioid, clear cell morphology with coexpression of melanocytic and smooth muscle markers. They are usually seen in adult females in a variety of anatomical locations, of which, kidney, lung and the gynaecologic tract are the most common. We present a case of PEComa arising from the kidney of a 12-year-old boy. PMID- 22442654 TI - Was magnetic resonance imaging scan contraindicated? AB - An intravenous drug abuser with a retained needle posed a management problem at a neurosurgical unit, having declined magnetic resonance imaging (MRI) on safety grounds. However, later, having been assessed by the senior radiologist, she went though the MRI scan safely. PMID- 22442655 TI - Intervening into primary health care services in Benghazi. PMID- 22442656 TI - The prevalence of thoracolumbar kyphosis in achondroplasia: a systematic review. AB - PURPOSE: Thoracolumbar kyphosis (TLK) is described as a common presentation in children with achondroplasia. However, the prevalence and development of TLK are ill-defined, as well as its clinical implications. The goal of this study was to assess the existing evidence on the prevalence and development of TLK from the literature. METHODS: A systematic literature review was performed in PubMed, EMBASE, and Thomson Reuters (ISI) Web of Knowledge. Articles were selected and evaluated with the Newcastle-Ottawa Scale in duplicate. Articles were included when the included patients were diagnosed with achondroplasia and the prevalence of TLK in this population was reported. RESULTS: Seven studies were included. The prevalence of TLK varied between 50 and 100%, but the populations differed significantly. Also, the measurement method and definition of TLK was not given in any of the included studies. Two studies reported TLK in different age categories, but the development of TLK through age could not be inferred. Overall, the methodological quality was low. CONCLUSIONS: The prevalence rates of TLK in achondroplasia could not be assessed from the literature because the populations differed and the definition of TLK in the studies was not described. In future studies, this definition needs to be given and patients need to be assessed over a longer period of time, with repeated assessments. PMID- 22442658 TI - Translocation of a Bak C-terminus mutant from cytosol to mitochondria to mediate cytochrome C release: implications for Bak and Bax apoptotic function. AB - BACKGROUND: One of two proapoptotic Bcl-2 proteins, Bak or Bax, is required to permeabilize the mitochondrial outer membrane during apoptosis. While Bax is mostly cytosolic and translocates to mitochondria following an apoptotic stimulus, Bak is constitutively integrated within the outer membrane. Membrane anchorage occurs via a C-terminal transmembrane domain that has been studied in Bax but not in Bak, therefore what governs their distinct subcellular distribution is uncertain. In addition, whether the distinct subcellular distributions of Bak and Bax contributes to their differential regulation during apoptosis remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: To gain insight into Bak and Bax targeting to mitochondria, elements of the Bak C-terminus were mutated, or swapped with those of Bax. Truncation of the C-terminal six residues (C-segment) or substitution of three basic residues within the C-segment destabilized Bak. Replacing the Bak C-segment with that from Bax rescued stability and function, but unexpectedly resulted in a semi-cytosolic protein, termed Bak/BaxCS. When in the cytosol, both Bax and Bak/BaxCS sequestered their hydrophobic transmembrane domains in their hydrophobic surface groove. Upon apoptotic signalling, Bak/BaxCS translocated to the mitochondrial outer membrane, inserted its transmembrane domain, oligomerized, and released cytochrome c. Despite this Bax-like subcellular distribution, Bak/BaxCS retained Bak-like regulation following targeting of Mcl-1. CONCLUSIONS/SIGNIFICANCE: Residues in the C-segment of Bak and of Bax contribute to their distinct subcellular localizations. That a semi-cytosolic form of Bak, Bak/BaxCS, could translocate to mitochondria and release cytochrome c indicates that Bak and Bax share a conserved mode of activation. In addition, the differential regulation of Bak and Bax by Mcl-1 is predominantly independent of the initial subcellular localizations of Bak and Bax. PMID- 22442659 TI - A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization. AB - Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Abeta peptide, and thus, reducing amyloid burden by preventing Abeta aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Abeta aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Abeta aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin. PMID- 22442660 TI - Milk fermented by Propionibacterium freudenreichii induces apoptosis of HGT-1 human gastric cancer cells. AB - BACKGROUND: Gastric cancer is one of the most common cancers in the world. The "economically developed countries" life style, including diet, constitutes a risk factor favoring this cancer. Diet modulation may lower digestive cancer incidence. Among promising food components, dairy propionibacteria were shown to trigger apoptosis of human colon cancer cells, via the release of short-chain fatty acids acetate and propionate. METHODOLOGY/PRINCIPAL FINDINGS: A fermented milk, exclusively fermented by P. freudenreichii, was recently designed. In this work, the pro-apoptotic potential of this new fermented milk was demonstrated on HGT-1 human gastric cancer cells. Fermented milk supernatant induced typical features of apoptosis including chromatin condensation, formation of apoptotic bodies, DNA laddering, cell cycle arrest and emergence of a subG1 population, phosphatidylserine exposure at the plasma membrane outer leaflet, reactive oxygen species accumulation, mitochondrial transmembrane potential disruption, caspase activation and cytochrome c release. Remarkably, this new fermented milk containing P. freudenreichii enhanced the cytotoxicity of camptothecin, a drug used in gastric cancer chemotherapy. CONCLUSIONS/SIGNIFICANCE: Such new probiotic fermented milk may thus be useful as part of a preventive diet designed to prevent gastric cancer and/or as a food supplement to potentiate cancer therapeutic treatments. PMID- 22442661 TI - Conformational temperature-dependent behavior of a histone H2AX: a coarse-grained Monte Carlo approach via knowledge-based interaction potentials. AB - Histone proteins are not only important due to their vital role in cellular processes such as DNA compaction, replication and repair but also show intriguing structural properties that might be exploited for bioengineering purposes such as the development of nano-materials. Based on their biological and technological implications, it is interesting to investigate the structural properties of proteins as a function of temperature. In this work, we study the spatial response dynamics of the histone H2AX, consisting of 143 residues, by a coarse grained bond fluctuating model for a broad range of normalized temperatures. A knowledge-based interaction matrix is used as input for the residue-residue Lennard-Jones potential.We find a variety of equilibrium structures including global globular configurations at low normalized temperature (T* = 0.014), combination of segmental globules and elongated chains (T* = 0.016,0.017), predominantly elongated chains (T* = 0.019,0.020), as well as universal SAW conformations at high normalized temperature (T* >= 0.023). The radius of gyration of the protein exhibits a non-monotonic temperature dependence with a maximum at a characteristic temperature (T(c)* = 0.019) where a crossover occurs from a positive (stretching at T* <= T(c)*) to negative (contraction at T* >= T(c)*) thermal response on increasing T*. PMID- 22442662 TI - Suppression of adenosine-activated chloride transport by ethanol in airway epithelia. AB - Alcohol abuse is associated with increased lung infections. Molecular understanding of the underlying mechanisms is not complete. Airway epithelial ion transport regulates the homeostasis of airway surface liquid, essential for airway mucosal immunity and lung host defense. Here, air-liquid interface cultures of Calu-3 epithelial cells were basolaterally exposed to physiologically relevant concentrations of ethanol (0, 25, 50 and 100 mM) for 24 hours and adenosine-stimulated ion transport was measured by Ussing chamber. The ethanol exposure reduced the epithelial short-circuit currents (I(SC)) in a dose dependent manner. The ion currents activated by adenosine were chloride conductance mediated by cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel. Alloxazine, a specific inhibitor for A(2B) adenosine receptor (A(2B)AR), largely abolished the adenosine-stimulated chloride transport, suggesting that A(2B)AR is a major receptor responsible for regulating the chloride transport of the cells. Ethanol significantly reduced intracellular cAMP production upon adenosine stimulation. Moreover, ethanol suppression of the chloride secretion was able to be restored by cAMP analogs or by inhibitors to block cAMP degradation. These results imply that ethanol exposure dysregulates CFTR-mediated chloride transport in airways by suppression of adenosine-A(2B)AR-cAMP signaling pathway, which might contribute to alcohol associated lung infections. PMID- 22442663 TI - Meloneis gen. Nov., a new epipsammic genus of Rhaphoneidaceae (Bacillariophyceae). AB - The diatom family Rhaphoneidaceae is characterized by high generic diversity and low species diversity with most genera known to have long stratigraphic ranges. The genera within this family are neritic marine, and mostly epipsammic. A new modern and epipsammic genus, Meloneis gen. nov., is described herein and is compared to all genera within Rhaphoneidaceae and especially to Rhaphoneis Ehrenberg s.l. Within Meloneis three new species and one variety are distinguished and described herein: M. mimallis sp. nov., M. mimallis var. zephyria var. nov., M. akytos sp. nov., and M. gorgis sp. nov. PMID- 22442664 TI - Statistical inference of in vivo properties of human DNA methyltransferases from double-stranded methylation patterns. AB - DNA methyltransferases establish methylation patterns in cells and transmit these patterns over cell generations, thereby influencing each cell's epigenetic states. Three primary DNA methyltransferases have been identified in mammals: DNMT1, DNMT3A and DNMT3B. Extensive in vitro studies have investigated key properties of these enzymes, namely their substrate specificity and processivity. Here we study these properties in vivo, by applying novel statistical analysis methods to double-stranded DNA methylation patterns collected using hairpin bisulfite PCR. Our analysis fits a novel Hidden Markov Model (HMM) to the observed data, allowing for potential bisulfite conversion errors, and yields statistical estimates of parameters that quantify enzyme processivity and substrate specificity. We apply this model to methylation patterns established in vivo at three loci in humans: two densely methylated inactive X (Xi)-linked loci (FMR1 and G6PD), and an autosomal locus (LEP), where methylation densities are tissue-specific but moderate. We find strong evidence for a high level of processivity of DNMT1 at FMR1 and G6PD, with the mean association tract length being a few hundred base pairs. Regardless of tissue types, methylation patterns at LEP are dominated by DNMT1 maintenance events, similar to the two Xi-linked loci, but are insufficiently informative regarding processivity to draw any conclusions about processivity at that locus. At all three loci we find that DNMT1 shows a strong preference for adding methyl groups to hemi-methylated CpG sites over unmethylated sites. The data at all three loci also suggest low (possibly 0) association of the de novo methyltransferases, the DNMT3s, and are consequently uninformative about processivity or preference of these enzymes. We also extend our HMM to reanalyze published data on mouse DNMT1 activities in vitro. The results suggest shorter association tracts (and hence weaker processivity), and much longer non-association tracts than human DNMT1 in vivo. PMID- 22442665 TI - TLR2 controls intestinal carcinogen detoxication by CYP1A1. AB - Intestinal cytochrome P450 subclass 1A1 (CYP1A1) contributes to a metabolic "shield" protecting the host from ingested carcinogens such as polycyclic aromatic hydrocarbons (PAH). The expression of CYP1 (including CYP1A2 and CYP1B1) is considered to depend solely on a heterodimeric transcription factor consisting of the arylhydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT). So far, no interference has been noted between the regulation of CYP1 and the activation of Toll-like receptor 2 (TLR2), which modulates the inflammatory response to bacterial cell wall components in immune cells and enterocytes. Here we report that intestinal CYP1A1 is silenced in TLR2-deficient mice, even when under exposure to the carcinogenic PAH benzo[a]pyrene (BaP). In contrast, hepatic CYP1A1 was moderately induced in TLR2-deficient mice without restoring their ability to clear BaP from systemic circulation, as present in wild-type animals. After feeding of BaP for 21 days, only TLR2(-/-) mice, but not their wild type littermates developed polyps in the colon. Gene expressions and protein concentrations of AHR and ARNT in the intestine did not differ between the genotypes. In conclusion, the presence of ligands for TLR2 of bacterial origin seems to be crucial for detoxication of luminal carcinogens by CYP1A1 in the intestine. This unprecedented finding indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxication mechanisms. This highlights the relevance of intestinal microbiota when trying to unravel pathways present in mammals and opens new perspectives for research in human health. PMID- 22442666 TI - A morbidity survey of South African primary care. AB - BACKGROUND: Recent studies have described the burden of disease in South Africa. However these studies do not tell us which of these conditions commonly present to primary care providers, how these conditions may present and how providers make sense of them in terms of their diagnoses. Clinical nurse practitioners are the main primary care providers and need to be better prepared for this role. This study aimed to determine the range and prevalence of reasons for encounter and diagnoses found among ambulatory patients attending public sector primary care facilities in South Africa. METHODOLOGY/PRINCIPAL FINDINGS: The study was a multi-centre prospective cross-sectional survey of consultations in primary care in four provinces of South Africa: Western Cape, Limpopo, Northern Cape and North West. Consultations were coded prior to analysis by using the International Classification of Primary Care-Version 2 in terms of reasons for encounter (REF) and diagnoses. Altogether 18856 consultations were included in the survey and generated 31451 reasons for encounter (RFE) and 24561 diagnoses. Women accounted for 12526 (66.6%) and men 6288 (33.4%). Nurses saw 16238 (86.1%) and doctors 2612 (13.9%) of patients. The top 80 RFE and top 25 diagnoses are reported and ongoing care for hypertension was the commonest RFE and diagnosis. The 20 commonest RFE and diagnoses by age group are also reported. CONCLUSIONS/SIGNIFICANCE: Ambulatory primary care is dominated by non-communicable chronic diseases. HIV/AIDS and TB are common, but not to the extent predicted by the burden of disease. Pneumonia and gastroenteritis are commonly seen especially in children. Women's health issues such as family planning and pregnancy related visits are also common. Injuries are not as common as expected from the burden of disease. Primary care providers did not recognise mental health problems. The results should guide the future training and assessment of primary care providers. PMID- 22442667 TI - N-acetylcysteine protects against apoptosis through modulation of group I metabotropic glutamate receptor activity. AB - The activation of group I metabotropic glutamate receptor (group I mGlus) has been shown to produce neuroprotective or neurotoxic effects. In this study, we investigated the effects of N-acetylcysteine (NAC), a precursor of the antioxidant glutathione, on group I mGlus activation in apoptosis of glial C6 and MN9D cell lines, and a rat model of Parkinson's disease (PD). We demonstrated that NAC protected against apoptosis through modulation of group I mGlus activity. In glial C6 cells, NAC promoted phosphorylation of ERK induced by (s) 3,5-dihydroxy-phenylglycine (DHPG), an agonist of group I mGlus. NAC enhanced the group I mGlus-mediated protection from staurosporine (STS)-induced apoptosis following DHPG treatment. Moreover, in rotenone-treated MN9D cells and PD rat model, NAC protected against group I mGlus-induced toxicity by compromising the decrease in phosphorylation of ERK, phosphorylation or expression level of TH. Furthermore, the results showed that NAC prohibited the level of ROS and oxidation of cellular GSH/GSSG (E(h)) accompanied by activated group I mGlus in the experimental models. Our results suggest that NAC might act as a regulator of group I mGlus-mediated activities in both neuroprotection and neurotoxicity via reducing the oxidative stress, eventually to protect cell survival. The study also suggests that NAC might be a potential therapeutics targeting for group I mGlus activation in the treatment of PD. PMID- 22442668 TI - Mutagenesis-mediated virus extinction: virus-dependent effect of viral load on sensitivity to lethal defection. AB - BACKGROUND: Lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. Viral load and virus fitness are known to influence virus extinction. Here we examine the effect or the multiplicity of infection (MOI) on progeny production of several RNA viruses under enhanced mutagenesis. RESULTS: The effect of the mutagenic base analogue 5 fluorouracil (FU) on the replication of the arenavirus lymphocytic choriomeningitis virus (LCMV) can result either in inhibition of progeny production and virus extinction in infections carried out at low multiplicity of infection (MOI), or in a moderate titer decrease without extinction at high MOI. The effect of the MOI is similar for LCMV and vesicular stomatitis virus (VSV), but minimal or absent for the picornaviruses foot-and-mouth disease virus (FMDV) and encephalomyocarditis virus (EMCV). The increase in mutation frequency and Shannon entropy (mutant spectrum complexity) as a result of virus passage in the presence of FU was more accentuated at low MOI for LCMV and VSV, and at high MOI for FMDV and EMCV. We present an extension of the lethal defection model that agrees with the experimental results. CONCLUSIONS: (i) Low infecting load favoured the extinction of negative strand viruses, LCMV or VSV, with an increase of mutant spectrum complexity. (ii) This behaviour is not observed in RNA positive strand viruses, FMDV or EMCV. (iii) The accumulation of defector genomes may underlie the MOI-dependent behaviour. (iv) LCMV coinfections are allowed but superinfection is strongly restricted in BHK-21 cells. (v) The dissimilar effects of the MOI on the efficiency of mutagenic-based extinction of different RNA viruses can have implications for the design of antiviral protocols based on lethal mutagenesis, presently under development. PMID- 22442669 TI - MiR-128 inhibits tumor growth and angiogenesis by targeting p70S6K1. AB - MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs for translational repression or degradation. In this study, we showed that miR-128 expression levels were decreased in glioma, and identified p70S6K1 as a novel direct target of miR-128. Overexpression of miR 128 suppressed p70S6K1 and its downstream signaling molecules such as HIF-1 and VEGF expression, and attenuated cell proliferation, tumor growth and angiogenesis. Forced expression of p70S6K1 can partly rescue the inhibitory effect of miR-128 in the cells. Taken together, these findings will shed light to the role and mechanism of miR-128 in regulating glioma tumor angiogenesis via miR 128/p70S6K1 axis, and miR-128 may serve as a potential therapeutic target in glioma in the future. PMID- 22442670 TI - Effect of operating and sampling conditions on the exhaust gas composition of small-scale power generators. AB - Small stationary diesel engines, like in generator sets, have limited emission control measures and are therefore responsible for 44% of the particulate matter (PM) emissions in the United States. The diesel exhaust composition depends on operating conditions of the combustion engine. Furthermore, the measurements are influenced by the used sampling method. This study examines the effect of engine loading and exhaust gas dilution on the composition of small-scale power generators. These generators are used in different operating conditions than road transport vehicles, resulting in different emission characteristics. Experimental data were obtained for gaseous volatile organic compounds (VOC) and PM mass concentration, elemental composition and nitrate content. The exhaust composition depends on load condition because of its effect on fuel consumption, engine wear and combustion temperature. Higher load conditions result in lower PM concentration and sharper edged particles with larger aerodynamic diameters. A positive correlation with load condition was found for K, Ca, Sr, Mn, Cu, Zn and Pb adsorbed on PM, elements that originate from lubricating oil or engine corrosion. The nitrate concentration decreases at higher load conditions, due to enhanced nitrate dissociation to gaseous NO at higher engine temperatures. Dilution on the other hand decreases PM and nitrate concentration and increases gaseous VOC and adsorbed metal content. In conclusion, these data show that operating and sampling conditions have a major effect on the exhaust gas composition of small-scale diesel generators. Therefore, care must be taken when designing new experiments or comparing literature results. PMID- 22442671 TI - miR-181a post-transcriptionally downregulates oncogenic RalA and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML). AB - MicroRNAs (miRNAs) are a class of short RNAs that regulate gene expression through either translational repression or mRNA cleavage. miRNA-181a (miR-181a), one of the many miRNAs conserved among vertebrates, is differentially expressed in a variety of leukemia. However, its function in leukemia, particularly chronic myelogenous leukemia (CML), is poorly understood. Here we have reported the identification of miR-181a targets by combining TargetScan software prediction and expression profiling through overexpression of miR-181a mimic in leukemic K562 cells. Four overlapping genes were found to be the likely targets of miR 181a. Among the four genes, RalA is a downstream molecule of bcr-abl fusion protein in ras signaling pathway. However, its role in CML remains elusive. Luciferase reporter and Western blot assays confirmed that RalA is a direct target of miR-181a. overexpression of miR-181a effectively suppresses cell growth and induces G2-phase arrest and apoptosis partially by targeting RalA in leukemic K562 cells. Using the KEGG database combined with recent publications, downstream signaling pathway of RalA was graphed by cytoscape software. Therefore, our study is the first to report that RalA is directly regulated by miR-181a and plays an important role in CML. The approach of computational prediction combined with expression profiling might be valuable for the identification of miRNA targets in animal. PMID- 22442672 TI - Genetic continuity in the Franco-Cantabrian region: new clues from autochthonous mitogenomes. AB - BACKGROUND: The Late Glacial Maximum (LGM), ~20 thousand years ago (kya), is thought to have forced the people inhabiting vast areas of northern and central Europe to retreat to southern regions characterized by milder climatic conditions. Archaeological records indicate that Franco-Cantabria might have been the major source for the re-peopling of Europe at the beginning of the Holocene (11.5 kya). However, genetic evidence is still scarce and has been the focus of an intense debate. METHODS/PRINCIPAL FINDINGS: Based on a survey of more than 345,000 partial control region sequences and the analysis of 53 mitochondrial DNA (mtDNA) genomes, we identified an mtDNA lineage, HV4a1a, which most likely arose in the Franco-Cantabrian area about 5.4 kya and remained confined to northern Iberia. CONCLUSIONS/SIGNIFICANCE: The HV4a1a lineage and several of its younger branches reveal for the first time genetic continuity in this region and long term episodes of isolation. This, in turn, could at least in part explain the unique linguistic and cultural features of the Basque region. PMID- 22442673 TI - The effects of centralised and specialised intervention in the early course of severe unipolar depressive disorder: a randomised clinical trial. AB - BACKGROUND: Little is known on whether centralised and specialised combined pharmacological and psychological intervention in the early phase of severe unipolar depression improve prognosis. The aim of the present study was to assess the benefits and harms of centralised and specialised secondary care intervention in the early course of severe unipolar depression. METHODS: A randomised multicentre trial with central randomisation and blinding in relation to the primary outcome comparing a centralised and specialised outpatient intervention program with standard decentralised psychiatric treatment. The interventions were offered at discharge from first, second, or third hospitalisation due to a single depressive episode or recurrent depressive disorder. The primary outcome was time to readmission to psychiatric hospital. The data on re-hospitalisation was obtained from the Danish Psychiatric Central Register. The secondary and tertiary outcomes were severity of depressive symptoms according to the Major Depression Inventory, adherence to medical treatment, and satisfaction with treatment according to the total score on the Verona Service Satisfaction Scale-Affective Disorder (VSSS-A). These outcomes were assessed using questionnaires one year after discharge from hospital. RESULTS: A total of 268 patients with unipolar depression were included. There was no significant difference in the time to readmission (unadjusted hazard ratio 0.89, 95% confidence interval 0.60 to 1.32; log rank: chi(2) = 0.3, d.f. = 1, p = 0.6); severity of depressive symptoms (mood disorder clinic: median 21.6, quartiles 9.7-31.2 versus standard treatment: median 20.2, quartiles 10.0-29.8; p = 0.7); or the prevalence of patients in antidepressant treatment (73.9% versus 80.0%, p = 0.2). Centralised and specialised secondary care intervention resulted in significantly higher satisfaction with treatment (131 (SD 31.8) versus 107 (SD 25.6); p<0.001). CONCLUSIONS: Centralised and specialised secondary care intervention in the early course of severe unipolar depression resulted in no significant effects on time to rehospitalisation, severity of symptoms, or use of antidepressants, but increased patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov NCT00253071. PMID- 22442674 TI - Formulation of a mmaA4 gene deletion mutant of Mycobacterium bovis BCG in cationic liposomes significantly enhances protection against tuberculosis. AB - A new vaccination strategy is urgently needed for improved control of the global tuberculosis (TB) epidemic. Using a mouse aerosol Mycobacterium tuberculosis challenge model, we investigated the protective efficacy of a mmaA4 gene deletion mutant of Mycobacterium bovis BCG (DeltammaA4BCG) formulated in dimethyl dioctadecyl ammonium bromide (DDA) - D(+) trehalose 6,6 dibenenate (TDB) (DDA/TDB) adjuvant. In previous studies, deletion of the mmaA4 gene was shown to reduce the suppression of IL-12 production often seen after mycobacterial infections. While the non-adjuvanted DeltammaA4BCG strain did not protect mice substantially better than conventional BCG against a tuberculous challenge in four protection experiments, the protective responses induced by the DeltammaA4BCG vaccine formulated in DDA/TDB adjuvant was consistently increased relative to nonadjuvanted BCG controls. Furthermore, the DeltammaA4BCG-DDA/TDB vaccine induced significantly higher frequencies of multifunctional (MFT) CD4 T cells expressing both IFNgamma and TNFalpha (double positive) or IFNgamma, TNFalpha and IL-2 (triple positive) than CD4 T cells derived from mice vaccinated with BCG. These MFT cells were characterized by having higher IFNgamma and TNFalpha median fluorescence intensity (MFI) values than monofunctional CD4 T cells. Interestingly, both BCG/adjuvant and DeltammaA4BCG/adjuvant formulations induced significantly higher frequencies of CD4 T cells expressing TNFalpha and IL-2 than nonadjuvanted BCG or DeltammaA4BCG vaccines indicating that BCG/adjuvant mixtures may be more effective at inducing central memory T cells. Importantly, when either conventional BCG or the mutant were formulated in adjuvant and administered to SCID mice or immunocompromised mice depleted of IFNgamma, significantly lower vaccine-derived mycobacterial CFU were detected relative to immunodeficient mice injected with non-adjuvanted BCG. Overall, these data suggest that immunization with the DeltammaA4BCG/adjuvant formulation may be an effective, safe, and relatively inexpensive alternative to vaccination with conventional BCG. PMID- 22442675 TI - Transient expression of hemagglutinin antigen from low pathogenic avian influenza A (H7N7) in Nicotiana benthamiana. AB - The influenza A virus is of global concern for the poultry industry, especially the H5 and H7 subtypes as they have the potential to become highly pathogenic for poultry. In this study, the hemagglutinin (HA) of a low pathogenic avian influenza virus of the H7N7 subtype isolated from a Swedish mallard Anas platyrhynchos was sequenced, characterized and transiently expressed in Nicotiana benthamiana. Recently, plant expression systems have gained interest as an alternative for the production of vaccine antigens. To examine the possibility of expressing the HA protein in N. benthamiana, a cDNA fragment encoding the HA gene was synthesized de novo, modified with a Kozak sequence, a PR1a signal peptide, a C-terminal hexahistidine (6*His) tag, and an endoplasmic retention signal (SEKDEL). The construct was cloned into a Cowpea mosaic virus (CPMV)-based vector (pEAQ-HT) and the resulting pEAQ-HT-HA plasmid, along with a vector (pJL3:p19) containing the viral gene-silencing suppressor p19 from Tomato bushy stunt virus, was agro-infiltrated into N. benthamiana. The highest gene expression of recombinant plant-produced, uncleaved HA (rHA0), as measured by quantitative real time PCR was detected at 6 days post infiltration (dpi). Guided by the gene expression profile, rHA0 protein was extracted at 6 dpi and subsequently purified utilizing the 6*His tag and immobilized metal ion adsorption chromatography. The yield was 0.2 g purified protein per kg fresh weight of leaves. Further molecular characterizations showed that the purified rHA0 protein was N-glycosylated and its identity confirmed by liquid chromatography-tandem mass spectrometry. In addition, the purified rHA0 exhibited hemagglutination and hemagglutination inhibition activity indicating that the rHA0 shares structural and functional properties with native HA protein of H7 influenza virus. Our results indicate that rHA0 maintained its native antigenicity and specificity, providing a good source of vaccine antigen to induce immune response in poultry species. PMID- 22442676 TI - Deep annotation of Populus trichocarpa microRNAs from diverse tissue sets. AB - Populus trichocarpa is an important woody model organism whose entire genome has been sequenced. This resource has facilitated the annotation of microRNAs (miRNAs), which are short non-coding RNAs with critical regulatory functions. However, despite their developmental importance, P. trichocarpa miRNAs have yet to be annotated from numerous important tissues. Here we significantly expand the breadth of tissue sampling and sequencing depth for miRNA annotation in P. trichocarpa using high-throughput smallRNA (sRNA) sequencing. miRNA annotation was performed using three individual next-generation sRNA sequencing runs from separate leaves, xylem, and mechanically treated xylem, as well as a fourth run using a pooled sample containing vegetative apices, male flowers, female flowers, female apical buds, and male apical and lateral buds. A total of 276 miRNAs were identified from these datasets, including 155 previously unannotated miRNAs, most of which are P. trichocarpa specific. Importantly, we identified several xylem enriched miRNAs predicted to target genes known to be important in secondary growth, including the critical reaction wood enzyme xyloglucan endo transglycosylase/hydrolase and vascular-related transcription factors. This study provides a thorough genome-wide annotation of miRNAs in P. trichocarpa through deep sRNA sequencing from diverse tissue sets. Our data significantly expands the P. trichocarpa miRNA repertoire, which will facilitate a broad range of research in this major model system. PMID- 22442677 TI - Treelength optimization for phylogeny estimation. AB - The standard approach to phylogeny estimation uses two phases, in which the first phase produces an alignment on a set of homologous sequences, and the second phase estimates a tree on the multiple sequence alignment. POY, a method which seeks a tree/alignment pair minimizing the total treelength, is the most widely used alternative to this two-phase approach. The topological accuracy of trees computed under treelength optimization is, however, controversial. In particular, one study showed that treelength optimization using simple gap penalties produced poor trees and alignments, and suggested the possibility that if POY were used with an affine gap penalty, it might be able to be competitive with the best two phase methods. In this paper we report on a study addressing this possibility. We present a new heuristic for treelength, called BeeTLe (Better Treelength), that is guaranteed to produce trees at least as short as POY. We then use this heuristic to analyze a large number of simulated and biological datasets, and compare the resultant trees and alignments to those produced using POY and also maximum likelihood (ML) and maximum parsimony (MP) trees computed on a number of alignments. In general, we find that trees produced by BeeTLe are shorter and more topologically accurate than POY trees, but that neither POY nor BeeTLe produces trees as topologically accurate as ML trees produced on standard alignments. These findings, taken as a whole, suggest that treelength optimization is not as good an approach to phylogenetic tree estimation as maximum likelihood based upon good alignment methods. PMID- 22442678 TI - Ablation of the pro-apoptotic protein Bax protects mice from glucocorticoid induced bone growth impairment. AB - Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax. PMID- 22442679 TI - Zinc-alpha 2-glycoprotein gene expression in adipose tissue is related with insulin resistance and lipolytic genes in morbidly obese patients. AB - OBJECTIVE: Zinc-alpha(2) glycoprotein (ZAG) stimulates lipid loss by adipocytes and may be involved in the regulation of adipose tissue metabolism. However, to date no studies have been made in the most extreme of obesity. The aims of this study are to analyze ZAG expression levels in adipose tissue from morbidly obese patients, and their relationship with lipogenic and lipolytic genes and with insulin resistance (IR). METHODS: mRNA expression levels of PPARgamma, IRS-1, IRS 2, lipogenic and lipolytic genes and ZAG were quantified in visceral (VAT) and subcutaneous adipose tissue (SAT) of 25 nondiabetic morbidly obese patients, 11 with low IR and 14 with high IR. Plasma ZAG was also analyzed. RESULTS: The morbidly obese patients with low IR had a higher VAT ZAG expression as compared with the patients with high IR (p = 0.023). In the patients with low IR, the VAT ZAG expression was greater than that in SAT (p = 0.009). ZAG expression correlated between SAT and VAT (r = 0.709, p<0.001). VAT ZAG expression was mainly predicted by insulin, HOMA-IR, plasma adiponectin and expression of adiponectin and ACSS2. SAT ZAG expression was only predicted by expression of ATGL. CONCLUSIONS: ZAG could be involved in modulating lipid metabolism in adipose tissue and is associated with insulin resistance. These findings suggest that ZAG may be a useful target in obesity and related disorders, such as diabetes. PMID- 22442680 TI - One-step purification of recombinant human amelogenin and use of amelogenin as a fusion partner. AB - Amelogenin is an extracellular protein first identified as a matrix component important for formation of dental enamel during tooth development. Lately, amelogenin has also been found to have positive effects on clinical important areas, such as treatment of periodontal defects, wound healing, and bone regeneration. Here we present a simple method for purification of recombinant human amelogenin expressed in Escherichia coli, based on the solubility properties of amelogenin. The method combines cell lysis with recovery/purification of the protein and generates a >95% pure amelogenin in one step using intact harvested cells as starting material. By using amelogenin as a fusion partner we could further demonstrate that the same method also be can explored to purify other target proteins/peptides in an effective manner. For instance, a fusion between the clinically used protein PTH (parathyroid hormone) and amelogenin was successfully expressed and purified, and the amelogenin part could be removed from PTH by using a site-specific protease. PMID- 22442681 TI - Rational diversification of a promoter providing fine-tuned expression and orthogonal regulation for synthetic biology. AB - Yeast is an ideal organism for the development and application of synthetic biology, yet there remain relatively few well-characterised biological parts suitable for precise engineering of this chassis. In order to address this current need, we present here a strategy that takes a single biological part, a promoter, and re-engineers it to produce a fine-graded output range promoter library and new regulated promoters desirable for orthogonal synthetic biology applications. A highly constitutive Saccharomyces cerevisiae promoter, PFY1p, was identified by bioinformatic approaches, characterised in vivo and diversified at its core sequence to create a 36-member promoter library. TetR regulation was introduced into PFY1p to create a synthetic inducible promoter (iPFY1p) that functions in an inverter device. Orthogonal and scalable regulation of synthetic promoters was then demonstrated for the first time using customisable Transcription Activator-Like Effectors (TALEs) modified and designed to act as orthogonal repressors for specific PFY1-based promoters. The ability to diversify a promoter at its core sequences and then independently target Transcription Activator-Like Orthogonal Repressors (TALORs) to virtually any of these sequences shows great promise toward the design and construction of future synthetic gene networks that encode complex "multi-wire" logic functions. PMID- 22442682 TI - Differences in gene expression between first and third trimester human placenta: a microarray study. AB - BACKGROUND: The human placenta is a rapidly developing organ that undergoes structural and functional changes throughout the pregnancy. Our objectives were to investigate the differences in global gene expression profile, the expression of imprinted genes and the effect of smoking in first and third trimester normal human placentas. MATERIALS AND METHODS: Placental samples were collected from 21 women with uncomplicated pregnancies delivered at term and 16 healthy women undergoing termination of pregnancy at 9-12 weeks gestation. Placental gene expression profile was evaluated by Human Genome Survey Microarray v.2.0 (Applied Biosystems) and real-time polymerase chain reaction. RESULTS: Almost 25% of the genes spotted on the array (n = 7519) were differentially expressed between first and third trimester placentas. Genes regulating biological processes involved in cell proliferation, cell differentiation and angiogenesis were up-regulated in the first trimester; whereas cell surface receptor mediated signal transduction, G-protein mediated signalling, ion transport, neuronal activities and chemosensory perception were up-regulated in the third trimester. Pathway analysis showed that brain and placenta might share common developmental routes. Principal component analysis based on the expression of 17 imprinted genes showed a clear separation of first and third trimester placentas, indicating that epigenetic modifications occur throughout pregnancy. In smokers, a set of genes encoding oxidoreductases were differentially expressed in both trimesters. CONCLUSIONS: Differences in global gene expression profile between first and third trimester human placenta reflect temporal changes in placental structure and function. Epigenetic rearrangements in the human placenta seem to occur across gestation, indicating the importance of environmental influence in the developing feto-placental unit. PMID- 22442683 TI - Waterborne outbreak of gastroenteritis: effects on sick leaves and cost of lost workdays. AB - BACKGROUND: In 2007, part of a drinking water distribution system was accidentally contaminated with waste water effluent causing a gastroenteritis outbreak in a Finnish town. We examined the acute and cumulative effects of this incidence on sick leaves among public sector employees residing in the clean and contaminated areas, and the additional costs of lost workdays due to the incidence. METHODS: Daily information on sick leaves of 1789 Finnish Public Sector Study participants was obtained from employers' registers. Global Positioning System-coordinates were used for linking participants to the clean and contaminated areas. Prevalence ratios (PR) for weekly sickness absences were calculated using binomial regression analysis. Calculations for the costs were based on prior studies. RESULTS: Among those living in the contaminated areas, the prevalence of participants on sick leave was 3.54 (95% confidence interval (CI) 2.97-4.22) times higher on the week following the incidence compared to the reference period. Those living and working in the clean area were basically not affected, the corresponding PR for sick leaves was 1.12, 95% CI 0.73-1.73. No cumulative effects on sick leaves were observed among the exposed. The estimated additional costs of lost workdays due to the incidence were 1.8-2.1 million euros. CONCLUSIONS: The prevalence of sickness absences among public sector employees residing in affected areas increased shortly after drinking water distribution system was contaminated, but no long-term effects were observed. The estimated costs of lost workdays were remarkable, thus, the cost-benefits of better monitoring systems for the water distribution systems should be evaluated. PMID- 22442684 TI - The STF2p hydrophilin from Saccharomyces cerevisiae is required for dehydration stress tolerance. AB - The yeast Saccharomyces cerevisiae is able to overcome cell dehydration; cell metabolic activity is arrested during this period but restarts after rehydration. The yeast genes encoding hydrophilin proteins were characterised to determine their roles in the dehydration-resistant phenotype, and STF2p was found to be a hydrophilin that is essential for survival after the desiccation-rehydration process. Deletion of STF2 promotes the production of reactive oxygen species and apoptotic cell death during stress conditions, whereas the overexpression of STF2, whose gene product localises to the cytoplasm, results in a reduction in ROS production upon oxidative stress as the result of the antioxidant capacity of the STF2p protein. PMID- 22442685 TI - PGH1, the precursor for the anti-inflammatory prostaglandins of the 1-series, is a potent activator of the pro-inflammatory receptor CRTH2/DP2. AB - Prostaglandin H(1) (PGH(1)) is the cyclo-oxygenase metabolite of dihomo-gamma linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as "anti-inflammatory". Herein we present evidence that PGH(1) is a potent activator of the pro-inflammatory PGD(2) receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca(2+) flux studies reveal that PGH(1) activates CRTH2 as PGH(2), PGD(2) or PGD(1) do. The PGH(1) precursor DGLA and the other PGH(1) metabolites did not display such effect. PGH(1) specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH(1) is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH(1) mediates migration of and Ca(2+) flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH(1) as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase. PMID- 22442686 TI - Adverse fetal and neonatal outcomes associated with a life-long high fat diet: role of altered development of the placental vasculature. AB - Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON--16% of calories from fat) or high fat diet (HF--45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival. PMID- 22442687 TI - Whip use by jockeys in a sample of Australian Thoroughbred races--an observational study. AB - The use of whips by jockeys is an issue. The current study viewed opportunistic high-speed footage of 15 race finishes frame-by-frame to examine the outcomes of arm and wrist actions (n = 350) on 40 horses viewed from the left of the field. Any actions fully or partially obscured by infrastructure or other horses were removed from the database, leaving a total of 104 non-contact sweeps and 134 strikes. For all instances of arm actions that resulted in fully visible whip strikes behind the saddle (n = 109), the outcomes noted were area struck, percentage of unpadded section making contact, whether the seam made contact and whether a visible indentation was evident on impact. We also recorded use of clockwise or counter-clockwise arm action from each jockey's whip, whether the whip was held like a tennis racquet or a ski pole, whether the hind leg on the side of the impact was in stance or swing phase and whether the jockey's arm was seen traveling above shoulder height. The goal of the study was to characterize the area struck and the visual impact of whip use at the level of the horse. We measured the ways in which both padded and unpadded sections of the whip made impact. There was evidence of at least 28 examples, in 9 horses, of breaches of the whip rules (one seam contact, 13 contacts with the head, and 14 arm actions that rose above the height of the shoulder). The whip caused a visible indentation on 83% of impacts. The unpadded section of the whip made contact on 64% of impacts. The results call into question the ability of Stewards to effectively police the rules concerning whip use and, more importantly, challenge the notion that padding the distal section of whips completely safeguards horses from any possible whip-related pain. PMID- 22442688 TI - Deformed epidermal autoregulatory factor-1 (DEAF1) interacts with the Ku70 subunit of the DNA-dependent protein kinase complex. AB - Deformed Epidermal Autoregulatory Factor 1 (DEAF1) is a transcription factor linked to suicide, cancer, autoimmune disorders and neural tube defects. To better understand the role of DEAF1 in protein interaction networks, a GST-DEAF1 fusion protein was used to isolate interacting proteins in mammalian cell lysates, and the XRCC6 (Ku70) and the XRCC5 (Ku80) subunits of DNA dependent protein kinase (DNA-PK) complex were identified by mass spectrometry, and the DNA PK catalytic subunit was identified by immunoblotting. Interaction of DEAF1 with Ku70 and Ku80 was confirmed to occur within cells by co-immunoprecipitation of epitope-tagged proteins, and was mediated through interaction with the Ku70 subunit. Using in vitro GST-pulldowns, interaction between DEAF1 and the Ku70 subunit was mapped to the DEAF1 DNA binding domain and the C-terminal Bax-binding region of Ku70. In transfected cells, DEAF1 and Ku70 colocalized to the nucleus, but Ku70 could not relocalize a mutant cytoplasmic form of DEAF1 to the nucleus. Using an in vitro kinase assay, DEAF1 was phosphorylated by DNA-PK in a DNA independent manner. Electrophoretic mobility shift assays showed that DEAF1 or Ku70/Ku80 did not interfere with the DNA binding of each other, but DNA containing DEAF1 binding sites inhibited the DEAF1-Ku70 interaction. The data demonstrates that DEAF1 can interact with the DNA-PK complex through interactions of its DNA binding domain with the carboxy-terminal region of Ku70 that contains the Bax binding domain, and that DEAF1 is a potential substrate for DNA-PK. PMID- 22442689 TI - Crystal structure of Diedel, a marker of the immune response of Drosophila melanogaster. AB - BACKGROUND: The Drosophila melanogaster gene CG11501 is up regulated after a septic injury and was proposed to act as a negative regulator of the JAK/STAT signaling pathway. Diedel, the CG11501 gene product, is a small protein of 115 residues with 10 cysteines. METHODOLOGY/PRINCIPAL FINDINGS: We have produced Diedel in Drosophila S2 cells as an extra cellular protein thanks to its own signal peptide and solved its crystal structure at 1.15 A resolution by SIRAS using an iodo derivative. Diedel is composed of two sub domains SD1 and SD2. SD1 is made of an antiparallel beta-sheet covered by an alpha-helix and displays a ferredoxin-like fold. SD2 reveals a new protein fold made of loops connected by four disulfide bridges. Further structural analysis identified conserved hydrophobic residues on the surface of Diedel that may constitute a potential binding site. The existence of two conformations, cis and trans, for the proline 52 may be of interest as prolyl peptidyl isomerisation has been shown to play a role in several physiological mechanisms. The genome of D. melanogaster contains two other genes coding for proteins homologous to Diedel, namely CG43228 and CG34329. Strikingly, apart from Drosophila and the pea aphid Acyrthosiphon pisum, Diedel-related sequences were exclusively identified in a few insect DNA viruses of the Baculoviridae and Ascoviridae families. CONCLUSION/SIGNIFICANCE: Diedel, a marker of the Drosophila antimicrobial/antiviral response, is a member of a small family of proteins present in drosophilids, aphids and DNA viruses infecting lepidopterans. Diedel is an extracellular protein composed of two sub-domains. Two special structural features (hydrophobic surface patch and cis/trans conformation for proline 52) may indicate a putative interaction site, and support an extra cellular signaling function for Diedel, which is in accordance with its proposed role as negative regulator of the JAK/STAT signaling pathway. PMID- 22442690 TI - Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors. AB - Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4 mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88 independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4 mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection. PMID- 22442691 TI - Mechanism of RPE cell death in alpha-crystallin deficient mice: a novel and critical role for MRP1-mediated GSH efflux. AB - Absence of alpha-crystallins (alphaA and alphaB) in retinal pigment epithelial (RPE) cells renders them susceptible to oxidant-induced cell death. We tested the hypothesis that the protective effect of alpha-crystallin is mediated by changes in cellular glutathione (GSH) and elucidated the mechanism of GSH efflux. In alpha-crystallin overexpressing cells resistant to cell death, cellular GSH was >2 fold higher than vector control cells and this increase was seen particularly in mitochondria. The high GSH levels associated with alpha-crystallin overexpression were due to increased GSH biosynthesis. On the other hand, cellular GSH was decreased by 50% in murine retina lacking alphaA or alphaB crystallin. Multiple multidrug resistance protein (MRP) family isoforms were expressed in RPE, among which MRP1 was the most abundant. MRP1 was localized to the plasma membrane and inhibition of MRP1 markedly decreased GSH efflux. MRP1 suppressed cells were resistant to cell death and contained elevated intracellular GSH and GSSG. Increased GSH in MRP1-supressed cells resulted from a higher conversion of GSSG to GSH by glutathione reductase. In contrast, GSH efflux was significantly higher in MRP1 overexpressing RPE cells which also contained lower levels of cellular GSH and GSSG. Oxidative stress further increased GSH efflux with a decrease in cellular GSH and rendered cells apoptosis prone. In conclusion, our data reveal for the first time that 1) MRP1 mediates GSH and GSSG efflux in RPE cells; 2) MRP1 inhibition renders RPE cells resistant to oxidative stress-induced cell death while MRP1 overexpression makes them susceptible and 3) the antiapoptotic function of alpha-crystallin in oxidatively stressed cells is mediated in part by GSH and MRP1. Our findings suggest that MRP1 and alpha crystallin are potential therapeutic targets in pathological retinal degenerative disorders linked to oxidative stress. PMID- 22442692 TI - A risk score to predict type 2 diabetes mellitus in an elderly Spanish Mediterranean population at high cardiovascular risk. AB - INTRODUCTION: To develop and test a diabetes risk score to predict incident diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk. MATERIALS AND METHODS: A diabetes risk score was derived from a subset of 1381 nondiabetic individuals from three centres of the PREDIMED study (derivation sample). Multivariate Cox regression model beta-coefficients were used to weigh each risk factor. PREDIMED-personal Score included body-mass-index, smoking status, family history of type 2 diabetes, alcohol consumption and hypertension as categorical variables; PREDIMED-clinical Score included also high blood glucose. We tested the predictive capability of these scores in the DE-PLAN-CAT cohort (validation sample). The discrimination of Finnish Diabetes Risk Score (FINDRISC), German Diabetes Risk Score (GDRS) and our scores was assessed with the area under curve (AUC). RESULTS: The PREDIMED-clinical Score varied from 0 to 14 points. In the subset of the PREDIMED study, 155 individuals developed diabetes during the 4.75-years follow-up. The PREDIMED-clinical score at a cutoff of >=6 had sensitivity of 72.2%, and specificity of 72.5%, whereas AUC was 0.78. The AUC of the PREDIMED-clinical Score was 0.66 in the validation sample (sensitivity = 85.4%; specificity = 26.6%), and was significantly higher than the FINDRISC and the GDRS in both the derivation and validation samples. DISCUSSION: We identified classical risk factors for diabetes and developed the PREDIMED clinical Score to determine those individuals at high risk of developing diabetes in elderly individuals at high cardiovascular risk. The predictive capability of the PREDIMED-clinical Score was significantly higher than the FINDRISC and GDRS, and also used fewer items in the questionnaire. PMID- 22442693 TI - Investigation of indazole unbinding pathways in CYP2E1 by molecular dynamics simulations. AB - Human microsomal cytochrome P450 2E1 (CYP2E1) can oxidize not only low molecular weight xenobiotic compounds such as ethanol, but also many endogenous fatty acids. The crystal structure of CYP2E1 in complex with indazole reveals that the active site is deeply buried into the protein center. Thus, the unbinding pathways and associated unbinding mechanisms remain elusive. In this study, random acceleration molecular dynamics simulations combined with steered molecular dynamics and potential of mean force calculations were performed to identify the possible unbinding pathways in CYP2E1. The results show that channel 2c and 2a are most likely the unbinding channels of CYP2E1. The former channel is located between helices G and I and the B-C loop, and the latter resides between the region formed by the F-G loop, the B-C loop and the beta1 sheet. Phe298 and Phe478 act as the gate keeper during indazole unbinding along channel 2c and 2a, respectively. Previous site-directed mutagenesis experiments also supported these findings. PMID- 22442694 TI - PpiA, a surface PPIase of the cyclophilin family in Lactococcus lactis. AB - BACKGROUND: Protein folding in the envelope is a crucial limiting step of protein export and secretion. In order to better understand this process in Lactococcus lactis, a lactic acid bacterium, genes encoding putative exported folding factors like Peptidyl Prolyl Isomerases (PPIases) were searched for in lactococcal genomes. RESULTS: In L. lactis, a new putative membrane PPIase of the cyclophilin subfamily, PpiA, was identified and characterized. ppiA gene was found to be constitutively expressed under normal and stress (heat shock, H(2)O(2)) conditions. Under normal conditions, PpiA protein was synthesized and released from intact cells by an exogenously added protease, showing that it was exposed at the cell surface. No obvious phenotype could be associated to a ppiA mutant strain under several laboratory conditions including stress conditions, except a very low sensitivity to H(2)O(2). Induction of a ppiA copy provided in trans had no effect i) on the thermosensitivity of an mutant strain deficient for the lactococcal surface protease HtrA and ii) on the secretion and stability on four exported proteins (a highly degraded hybrid protein and three heterologous secreted proteins) in an otherwise wild-type strain background. However, a recombinant soluble form of PpiA that had been produced and secreted in L. lactis and purified from a culture supernatant displayed both PPIase and chaperone activities. CONCLUSIONS: Although L. lactis PpiA, a protein produced and exposed at the cell surface under normal conditions, displayed a very moderate role in vivo, it was found, as a recombinant soluble form, to be endowed with folding activities in vitro. PMID- 22442695 TI - Brain-derived neurotrophic factor ameliorates brain stem cardiovascular dysregulation during experimental temporal lobe status epilepticus. AB - BACKGROUND: Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox) subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47(phox) subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses. CONCLUSIONS/SIGNIFICANCE: We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a reduction in baroreflex-mediated sympathetic vasomotor tone during experimental TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of p47(phox) phosphorylation. This information offers a new vista in devising therapeutic strategy towards minimizing mortality associated with TLSE. PMID- 22442696 TI - Food quality affects secondary consumers even at low quantities: an experimental test with larval European lobster. AB - The issues of food quality and food quantity are crucial for trophic interactions. Although most research has focussed on the primary producer herbivore link, recent studies have shown that quality effects at the bottom of the food web propagate to higher trophic levels. Negative effects of poor food quality have almost exclusively been demonstrated at higher food quantities. Whether these negative effects have the same impact at low food availability in situations where the majority if not all of the resources are channelled into routine metabolism, is under debate. In this study a tri-trophic food chain was designed, consisting of the algae Rhodomonas salina, the copepod Acartia tonsa and freshly hatched larvae of the European lobster Homarus gammarus. The lobster larvae were presented with food of two different qualities (C:P ratios) and four different quantities to investigate the combined effects of food quality and quantity. Our results show that the quality of food has an impact on the condition of lobster larvae even at very low food quantities. Food with a lower C:P content resulted in higher condition of the lobster larvae regardless of the quantity of food. These interacting effects of food quality and food quantity can have far reaching consequences for ecosystem productivity. PMID- 22442697 TI - Computational identification and analysis of the key biosorbent characteristics for the biosorption process of reactive black 5 onto fungal biomass. AB - The performances of nine biosorbents derived from dead fungal biomass were investigated for their ability to remove Reactive Black 5 from aqueous solution. The biosorption data for removal of Reactive Black 5 were readily modeled using the Langmuir adsorption isotherm. Kinetic analysis based on both pseudo-second order and Weber-Morris models indicated intraparticle diffusion was the rate limiting step for biosorption of Reactive Black 5 on to the biosorbents. Sorption capacities of the biosorbents were not correlated with the initial biosorption rates. Sensitivity analysis of the factors affecting biosorption examined by an artificial neural network model showed that pH was the most important parameter, explaining 22%, followed by nitrogen content of biosorbents (16%), initial dye concentration (15%) and carbon content of biosorbents (10%). The biosorption capacities were not proportional to surface areas of the sorbents, but were instead influenced by their chemical element composition. The main functional groups contributing to dye sorption were amine, carboxylic, and alcohol moieties. The data further suggest that differences in carbon and nitrogen contents of biosorbents may be used as a selection index for identifying effective biosorbents from dead fungal biomass. PMID- 22442698 TI - Interplay of magnetic interactions and active movements in the formation of magnetosome chains. AB - Magnetotactic bacteria assemble chains of magnetosomes, organelles that contain magnetic nano-crystals. A number of genetic factors involved in the controlled biomineralization of these crystals and the assembly of magnetosome chains have been identified in recent years, but how the specific biological regulation is coordinated with general physical processes such as diffusion and magnetic interactions remains unresolved. Here, these questions are addressed by simulations of different scenarios for magnetosome chain formation, in which various physical processes and interactions are either switched on or off. The simulation results indicate that purely physical processes of magnetosome diffusion, guided by their magnetic interactions, are not sufficient for the robust chain formation observed experimentally and suggest that biologically encoded active movements of magnetosomes may be required. Not surprisingly, the chain pattern is most resembling experimental results when both magnetic interactions and active movement are coordinated. We estimate that the force such active transport has to generate is compatible with forces generated by the polymerization or depolymerization of cytoskeletal filaments. The simulations suggest that the pleiotropic phenotypes of mamK deletion strains may be due to a defect in active motility of magnetosomes and that crystal formation in magneteosome vesicles is coupled to the activation of their active motility in M. gryphiswaldense, but not in M. magneticum. PMID- 22442699 TI - Tumor cell plasticity and angiogenesis in human melanomas. AB - Recent molecular studies provide evidence for a significant transcriptional plasticity of tumor cell subpopulations that facilitate an active contribution to tumor vasculature. This feature is accompanied by morphological changes both in vitro and in vivo. Herein, we investigated the morphological plasticity of tumor cells with special focus on vasculogenic mimicry and neovascularisation in human melanoma and mouse xenografts of human melanoma cell lines. In melanoma xenograft experiments, different vessel markers and green fluorescent protein expression were used to show how melanoma cells contribute to neovascularization. Additionally, we analyzed neovascularization in 49 primary melanomas and 175 melanoma metastases using immunostaining for blood (CD34) and lymphatic (D2-40) vessel-specific markers. We found significantly more lymphatic vessels in primary melanomas than in melanoma metastases (p<0.0001). In contrast to the near absence of lymphatic vessels within metastases, we found extensive blood micro neovascularization. Blood micro-neovascularization was absent in micro metastases (less than 2 mm). A significant inverse correlation between Glut-1 expression (implying local hypoxia) and the presence of microvessels indicates their functional activity as blood vessels (p<0.0001). We suggest that the hypoxic microenvironment in metastases contributes to a phenotype switch allowing melanoma cells to physically contribute to blood vessel formation. PMID- 22442700 TI - Surface plasmon resonance reveals a different pattern of proinsulin autoantibodies concentration and affinity in diabetic patients. AB - Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31+/-4.20) and 23 adult-onset diabetic patients (>=65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12*10(-9) M and 3.50*10(7) M(-1), respectively) than the adults (median 167.4*10(-9) M and 0.84*10(7) M(-1), respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction. PMID- 22442701 TI - Cigarette smoke affects keratinocytes SRB1 expression and localization via H2O2 production and HNE protein adducts formation. AB - Scavenger Receptor B1 (SR-B1), also known as HDL receptor, is involved in cellular cholesterol uptake. Stratum corneum (SC), the outermost layer of the skin, is composed of more than 25% cholesterol. Several reports support the view that alteration of SC lipid composition may be the cause of impaired barrier function which gives rise to several skin diseases. For this reason the regulation of the genes involved in cholesterol uptake is of extreme significance for skin health. Being the first shield against external insults, the skin is exposed to several noxious substances and among these is cigarette smoke (CS), which has been recently associated with various skin pathologies. In this study we first have shown the presence of SR-B1 in murine and human skin tissue and then by using immunoblotting, immunoprecipitation, RT-PCR, and confocal microscopy we have demonstrated the translocation and the subsequent lost of SR B1 in human keratinocytes (cell culture model) after CS exposure is driven by hydrogen peroxide (H(2)O(2)) that derives not only from the CS gas phase but mainly from the activation of cellular NADPH oxidase (NOX). This effect was reversed when the cells were pretreated with NOX inhibitors or catalase. Furthermore, CS caused the formation of SR-B1-aldheydes adducts (acrolein and 4 hydroxy-2-nonenal) and the increase of its ubiquitination, which could be one of the causes of SR-B1 loss. In conclusion, exposure to CS, through the production of H(2)O(2), induced post-translational modifications of SR-B1 with the consequence lost of the receptor and this may contribute to the skin physiology alteration as a consequence of the variation of cholesterol uptake. PMID- 22442702 TI - Replication fork reactivation in a dnaC2 mutant at non-permissive temperature in Escherichia coli. AB - Replicative helicases unwind double-stranded DNA in front of the polymerase and ensure the processivity of DNA synthesis. In Escherichia coli, the helicase loader DnaC as well as factors involved in the formation of the open complex during the initiation of replication and primosomal proteins during the reactivation of arrested replication forks are required to recruit and deposit the replicative helicase onto single-stranded DNA prior to the formation of the replisome. dnaC2 is a thermosensitive allele of the gene specifying the helicase loader; at non-permissive temperature replication cannot initiate, but most ongoing rounds of replication continues through to completion (18% of dnaC2 cells fail to complete replication at non-permissive temperature). An assumption, which may be drawn from this observation, is that only a few replication forks are arrested under normal growth conditions. This assumption, however, is at odds with the severe and deleterious phenotypes associated with a null mutant of priA, the gene encoding a helicase implicated in the reactivation of arrested replication forks. We developed an assay that involves an abrupt inactivation of rounds of synchronized replication in a large population of cells, in order to evaluate the ability of dnaC2 cells to reactivate arrested replication forks at non-permissive temperature. We compared the rate at which arrested replication forks accumulated in dnaC2 priA(+) and dnaC2 priA2 cells and observed that this rate was lower in dnaC2 priA(+) cells. We conclude that while replication cannot initiate in a dnaC2 mutant at non-permissive temperature, a class of arrested replication forks (PriA-dependent and DnaC-independent) are reactivated within these cells. PMID- 22442703 TI - The RhoGEF trio functions in sculpting class specific dendrite morphogenesis in Drosophila sensory neurons. AB - BACKGROUND: As the primary sites of synaptic or sensory input in the nervous system, dendrites play an essential role in processing neuronal and sensory information. Moreover, the specification of class specific dendrite arborization is critically important in establishing neural connectivity and the formation of functional networks. Cytoskeletal modulation provides a key mechanism for establishing, as well as reorganizing, dendritic morphology among distinct neuronal subtypes. While previous studies have established differential roles for the small GTPases Rac and Rho in mediating dendrite morphogenesis, little is known regarding the direct regulators of these genes in mediating distinct dendritic architectures. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that the RhoGEF Trio is required for the specification of class specific dendritic morphology in dendritic arborization (da) sensory neurons of the Drosophila peripheral nervous system (PNS). Trio is expressed in all da neuron subclasses and loss-of-function analyses indicate that Trio functions cell-autonomously in promoting dendritic branching, field coverage, and refining dendritic outgrowth in various da neuron subtypes. Moreover, overexpression studies demonstrate that Trio acts to promote higher order dendritic branching, including the formation of dendritic filopodia, through Trio GEF1-dependent interactions with Rac1, whereas Trio GEF-2-dependent interactions with Rho1 serve to restrict dendritic extension and higher order branching in da neurons. Finally, we show that de novo dendritic branching, induced by the homeodomain transcription factor Cut, requires Trio activity suggesting these molecules may act in a pathway to mediate dendrite morphogenesis. CONCLUSIONS/SIGNIFICANCE: Collectively, our analyses implicate Trio as an important regulator of class specific da neuron dendrite morphogenesis via interactions with Rac1 and Rho1 and indicate that Trio is required as downstream effector in Cut-mediated regulation of dendrite branching and filopodia formation. PMID- 22442704 TI - Efficiency of spermatogonial dedifferentiation during aging. AB - BACKGROUND: Adult stem cells are critical for tissue homeostasis; therefore, the mechanisms utilized to maintain an adequate stem cell pool are important for the survival of an individual. In Drosophila, one mechanism utilized to replace lost germline stem cells (GSCs) is dedifferentiation of early progenitor cells. However, the average number of male GSCs decreases with age, suggesting that stem cell replacement may become compromised in older flies. METHODOLOGY/PRINCIPAL FINDINGS: Using a temperature sensitive allelic combination of Stat92E to control dedifferentiation, we found that germline dedifferentiation is remarkably efficient in older males; somatic cells are also effectively replaced. Surprisingly, although the number of somatic cyst cells also declines with age, the proliferation rate of early somatic cells, including cyst stem cells (CySCs) increases. CONCLUSIONS: These data indicate that defects in spermatogonial dedifferentiation are not likely to contribute significantly to an aging-related decline in GSCs. In addition, our findings highlight differences in the ways GSCs and CySCs age. Strategies to initiate or enhance the ability of endogenous, differentiating progenitor cells to replace lost stem cells could provide a powerful and novel strategy for maintaining tissue homeostasis and an alternative to tissue replacement therapy in older individuals. PMID- 22442705 TI - Identifying new therapeutic targets via modulation of protein corona formation by engineered nanoparticles. AB - BACKGROUND: We introduce a promising methodology to identify new therapeutic targets in cancer. Proteins bind to nanoparticles to form a protein corona. We modulate this corona by using surface-engineered nanoparticles, and identify protein composition to provide insight into disease development. METHODS/PRINCIPAL FINDINGS: Using a family of structurally homologous nanoparticles we have investigated the changes in the protein corona around surface-functionalized gold nanoparticles (AuNPs) from normal and malignant ovarian cell lysates. Proteomics analysis using mass spectrometry identified hepatoma-derived growth factor (HDGF) that is found exclusively on positively charged AuNPs ((+)AuNPs) after incubation with the lysates. We confirmed expression of HDGF in various ovarian cancer cells and validated binding selectivity to (+)AuNPs by Western blot analysis. Silencing of HDGF by siRNA resulted s inhibition in proliferation of ovarian cancer cells. CONCLUSION: We investigated the modulation of protein corona around surface-functionalized gold nanoparticles as a promising approach to identify new therapeutic targets. The potential of our method for identifying therapeutic targets was demonstrated through silencing of HDGF by siRNA, which inhibited proliferation of ovarian cancer cells. This integrated proteomics, bioinformatics, and nanotechnology strategy demonstrates that protein corona identification can be used to discover novel therapeutic targets in cancer. PMID- 22442706 TI - The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. AB - BACKGROUND: Several pieces of evidence indicate that tumor-infiltrating neutrophils (TINs) are correlated to tumor progression. In the current study, we explore the relationship between TINs and clinicopathological features of gastric adenocarcinoma patients. Furthermore, we investigated the prognostic value of TINs. PATIENTS AND METHODS: The study was comprised of two groups, training group (115 patients) and test group (97 patients). Biomarkers (intratumoral CD15+ neutrophils) were assessed by immunohistochemistry. The relationship between clinicopathological features and patient outcome were evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: Immunohistochemical detection showed that the tumor-infiltrating neutrophils (TINs) in the training group ranged from 0.00-115.70 cells/high-power microscopic field (HPF) and the median number was 21.60 cells/HPF. Based on the median number, the patients were divided into high and low TINs groups. Chi-square test analysis revealed that the density of CD15+ TINs was positively associated with lymph node metastasis (p = 0.024), distance metastasis (p = 0.004) and UICC (International Union Against Cancer) staging (p = 0.028). Kaplan-Meier analysis showed that patients with a lower density of TINs had a better prognosis than patients with a higher density of TINs (p = 0.002). Multivariate Cox's analysis showed that the density of CD15+ TINs was an independent prognostic factor for overall survival of gastric adenocarcinoma patients. Using another 97 patients as a test group and basing on the median number of TINs (21.60 cells/HPF) coming from the training group, Kaplan-Meier analysis also showed that patients with a lower density of TINs had a better prognosis than patients with a higher density of TINs (p = 0.032). The results verify that the number of CD15+ TINs can predict the survival of gastric adenocarcinoma surgical patients. CONCLUSIONS: The presence of CD15+ TINs is an independent and unfavorable factor in the prognosis of gastric adenocarcinoma patients. Targeting CD15+ TINs may be a potential intervenient therapy in the future. PMID- 22442707 TI - DEAD-box protein Ddx46 is required for the development of the digestive organs and brain in zebrafish. AB - Spatially and temporally controlled gene expression, including transcription, several mRNA processing steps, and the export of mature mRNA to the cytoplasm, is essential for developmental processes. It is well known that RNA helicases of the DExD/H-box protein family are involved in these gene expression processes, including transcription, pre-mRNA splicing, and rRNA biogenesis. Although one DExD/H-box protein, Prp5, a homologue of vertebrate Ddx46, has been shown to play important roles in pre-mRNA splicing in yeast, the in vivo function of Ddx46 remains to be fully elucidated in metazoans. In this study, we isolated zebrafish morendo (mor), a mutant that shows developmental defects in the digestive organs and brain, and found that it encodes Ddx46. The Ddx46 transcript is maternally supplied, and as development proceeds in zebrafish larvae, its ubiquitous expression gradually becomes restricted to those organs. The results of whole mount in situ hybridization showed that the expression of various molecular markers in these organs is considerably reduced in the Ddx46 mutant. Furthermore, splicing status analysis with RT-PCR revealed unspliced forms of mRNAs in the digestive organ and brain tissues of the Ddx46 mutant, suggesting that Ddx46 may be required for pre-mRNA splicing during zebrafish development. Therefore, our results suggest a model in which zebrafish Ddx46 is required for the development of the digestive organs and brain, possibly through the control of pre-mRNA splicing. PMID- 22442708 TI - Protective effect of ginseng polysaccharides on influenza viral infection. AB - Ginseng polysaccharide has been known to have multiple immunomodulatory effects. In this study, we investigated whether Panax ginseng polysaccharide (GP) would have a preventive effect on influenza infection. Administration of mice with GP prior to infection was found to confer a survival benefit against infection with H1N1 (A/PR/8/34) and H3N2 (A/Philippines/82) influenza viruses. Mice infected with the 2009 H1N1 virus suspended in GP solution showed moderately enhanced survival rates and lower levels of lung viral titers and the inflammatory cytokine (IL-6). Daily treatment of vaccinated mice with GP improved their survival against heterosubtypic lethal challenge. This study demonstrates the first evidence that GP can be used as a remedy against influenza viral infection. PMID- 22442709 TI - The cortisol response to anticipated intergroup interactions predicts self reported prejudice. AB - OBJECTIVES: While prejudice has often been shown to be rooted in experiences of threat, the biological underpinnings of this threat-prejudice association have received less research attention. The present experiment aims to test whether activations of the hypothalamus-pituitary-adrenal (HPA) axis, due to anticipated interactions with out-group members, predict self-reported prejudice. Moreover, we explore potential moderators of this relationship (i.e., interpersonal similarity; subtle vs. blatant prejudice). METHODOLOGY/PRINCIPAL FINDINGS: Participants anticipated an interaction with an out-group member who was similar or dissimilar to the self. To index HPA activation, cortisol responses to this event were measured. Then, subtle and blatant prejudices were measured via questionnaires. Findings indicated that only when people anticipated an interaction with an out-group member who was dissimilar to the self, their cortisol response to this event significantly predicted subtle (r = .50) and blatant (r = .53) prejudice. CONCLUSIONS: These findings indicate that prejudicial attitudes are linked to HPA-axis activity. Furthermore, when intergroup interactions are interpreted to be about individuals (and not so much about groups), experienced threat (or its biological substrate) is less likely to relate to prejudice. This conclusion is discussed in terms of recent insights from social neuroscience. PMID- 22442710 TI - Platelet function in stored heparinised autologous blood is not superior to in patient platelet function during routine cardiopulmonary bypass. AB - BACKGROUND: In cardiac surgery, cardiopulmonary bypass (CPB) and unfractionated heparin have negative effects on blood platelet function. In acute normovolemic haemodilution autologous unfractionated heparinised blood is stored ex-vivo and retransfused at the end of the procedure to reduce (allogeneic) transfusion requirements. In this observational study we assessed whether platelet function is better preserved in ex vivo stored autologous blood compared to platelet function in the patient during CPB. METHODOLOGY/PRINCIPAL FINDING: We measured platelet aggregation responses pre-CPB, 5 min after the start of CPB, at the end of CPB, and after unfractionated heparin reversal, using multiple electrode aggregometry (Multiplate(r)) with adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP) and ristocetin activated test cells. We compared blood samples taken from the patient with samples taken from 100 ml ex-vivo stored blood, which we took to mimick blood storage during normovolemic haemodilution. Platelet function declined both in ex-vivo stored blood as well as in blood taken from the patient. At the end of CPB there were no differences in platelet aggregation responses between samples from the ex vivo stored blood and the patient. CONCLUSION/SIGNIFICANCE: Ex vivo preservation of autologous blood in unfractionated heparin does not seem to be profitable to preserve platelet function. PMID- 22442711 TI - A deadenylase assay by size-exclusion chromatography. AB - The shortening of the 3'-end poly(A) tail, also called deadenylation, is crucial to the regulation of mRNA processing, transportation, translation and degradation. The deadenylation process is achieved by deadenylases, which specifically catalyze the removal of the poly(A) tail at the 3'-end of eukaryotic mRNAs and release 5'-AMP as the product. To achieve their physiological functions, all deadenylases have numerous binding partners that may regulate their catalytic properties or recruit them into various protein complexes. To study the effects of various partners, it is important to develop new deadenylase assay that can be applied either in vivo or in vitro. In this research, we developed the deadenylase assay by the size-exclusion chromatography (SEC) method. The SEC analysis indicated that the poly(A) or oligo(A) substrate and the product AMP could be successfully separated and quantified. The enzymatic parameters of deadenylase could be obtained by quantifying the AMP generation. When using the commercial poly(A) as the substrate, a biphasic catalytic process was observed, which might correlate to the two distinct states of poly(A) in the commercial samples. Different lots of commercial poly(A) had dissimilar size distributions and were dissimilar in response to the degradation of deadenylase. The deadenylation pattern, processive or distributive, could also be investigated using the SEC assay by monitoring the status of the substrate and the generation kinetics of AMP and A2. The SEC assay was applicable to both simple samples using the purified enzyme and complex enzyme reaction conditions such as using protein mixtures or crude cell extracts as samples. The influence of solutes with absorption at 254 nm could be successfully eliminated by constructing the different SEC profiles. PMID- 22442712 TI - The role of fibrocytes in sickle cell lung disease. AB - BACKGROUND: Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease. METHODOLOGY/PRINCIPAL FINDINGS: Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology. CONCLUSIONS: These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease. PMID- 22442713 TI - TSH-CHECK-1 test: diagnostic accuracy and potential application to initiating treatment for hypothyroidism in patients on anti-tuberculosis drugs. AB - BACKGROUND: Thyroid-stimulating hormone (TSH) promotes expression of thyroid hormones which are essential for metabolism, growth, and development. Second-line drugs to treat tuberculosis (TB) can cause hypothyroidism by suppressing thyroid hormone synthesis. Therefore, TSH levels are routinely measured in TB patients receiving second-line drugs, and thyroxin treatment is initiated where indicated. However, standard TSH tests are technically demanding for many low-resource settings where TB is prevalent; a simple and inexpensive test is urgently needed. METHODS: As a proof of concept study TSH was measured in routinely collected sera at the University Medical Center Utrecht, Netherlands, using the TSH-CHECK-1 (VEDALAB, Alencon, France), a lateral-flow rapid immunochromatographic assay with a TSH cut-off value of 10 uIU/mL, the standard threshold for initiating treatment. These results were compared with TSH levels measured by a reference standard (UniCel DXi 800 imunoassay system, Beckman Coulter, USA). Sensitivity, specificity, and likelihood ratios were then calculated. RESULTS: A total of 215 serum samples were evaluated: 107 with TSH values <10 uIU/mL and 108 with values >=10 uIU/mL. TSH-CHECK-1 test sensitivity was found to be 100.0% (95% CI: 96.6 100.0) and specificity was 76.6% (95% CI: 67.5-84.3). Predictive values (PV) were modelled for different levels of prevalence. For a prevalence of 10% and 50%, the positive PV was 32.2% (95% CI: 25.0-39.7%) and 81.1% (95% CI: 75.0-85.5%), respectively; the negative PV was 100% (95% CI: 98.9-100%) and 100% (95% CI: 91.3 100%) respectively. DISCUSSION/CONCLUSIONS: The TSH-CHECK-1 rapid test was practical and simple to perform but difficult to interpret on weak positive results. All sera with TSH>=10 uIU/mL were correctly identified, but the test lacked sufficient specificity. Given its excellent negative PV in this evaluation, the test shows promise for ruling out hypothyroidism. However, so far it appears that samples testing positive with TSH-CHECK-1 would require confirmation using another method. PMID- 22442714 TI - Neonatal colonisation expands a specific intestinal antigen-presenting cell subset prior to CD4 T-cell expansion, without altering T-cell repertoire. AB - Interactions between the early-life colonising intestinal microbiota and the developing immune system are critical in determining the nature of immune responses in later life. Studies in neonatal animals in which this interaction can be examined are central to understanding the mechanisms by which the microbiota impacts on immune development and to developing therapies based on manipulation of the microbiome. The inbred piglet model represents a system that is comparable to human neonates and allows for control of the impact of maternal factors. Here we show that colonisation with a defined microbiota produces expansion of mucosal plasma cells and of T-lymphocytes without altering the repertoire of alpha beta T-cells in the intestine. Importantly, this is preceded by microbially-induced expansion of a signal regulatory protein alpha-positive (SIRPalpha(+)) antigen-presenting cell subset, whilst SIRPalpha(-)CD11R1(+) antigen-presenting cells (APCs) are unaffected by colonisation. The central role of intestinal APCs in the induction and maintenance of mucosal immunity implicates SIRPalpha(+) antigen-presenting cells as orchestrators of early-life mucosal immune development. PMID- 22442715 TI - Diversity of Melissococcus plutonius from honeybee larvae in Japan and experimental reproduction of European foulbrood with cultured atypical isolates. AB - European foulbrood (EFB) is an important infectious disease of honeybee larvae, but its pathogenic mechanisms are still poorly understood. The causative agent, Melissococcus plutonius, is a fastidious organism, and microaerophilic to anaerobic conditions and the addition of potassium phosphate to culture media are required for growth. Although M. plutonius is believed to be remarkably homologous, in addition to M. plutonius isolates with typical cultural characteristics, M. plutonius-like organisms, with characteristics seemingly different from those of typical M. plutonius, have often been isolated from diseased larvae with clinical signs of EFB in Japan. Cultural and biochemical characterization of 14 M. plutonius and 19 M. plutonius-like strain/isolates revealed that, unlike typical M. plutonius strain/isolates, M. plutonius-like isolates were not fastidious, and the addition of potassium phosphate was not required for normal growth. Moreover, only M. plutonius-like isolates, but not typical M. plutonius strain/isolates, grew anaerobically on sodium phosphate supplemented medium and aerobically on some potassium salt-supplemented media, were positive for beta-glucosidase activity, hydrolyzed esculin, and produced acid from L-arabinose, D-cellobiose, and salicin. Despite the phenotypic differences, 16S rRNA gene sequence analysis and DNA-DNA hybridization demonstrated that M. plutonius-like organisms were taxonomically identical to M. plutonius. However, by pulsed-field gel electrophoresis analysis, these typical and atypical (M. plutonius-like) isolates were separately grouped into two genetically distinct clusters. Although M. plutonius is known to lose virulence quickly when cultured artificially, experimental infection of representative isolates showed that atypical M. plutonius maintained the ability to cause EFB in honeybee larvae even after cultured in vitro in laboratory media. Because the rapid decrease of virulence in cultured M. plutonius was a major impediment to elucidation of the pathogenesis of EFB, atypical M. plutonius discovered in this study will be a breakthrough in EFB research. PMID- 22442716 TI - Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques. AB - Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-gamma T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-alpha and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans. PMID- 22442717 TI - Peripheral effects of FAAH deficiency on fuel and energy homeostasis: role of dysregulated lysine acetylation. AB - BACKGROUND: FAAH (fatty acid amide hydrolase), primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH(-/-) mice. METHODOLOGY/PRINCIPAL FINDINGS: FAAH(-/ ) mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). FAAH(-/-) mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol synthesis was decreased 22% in FAAH(-/-) mice. Dysregulated hepatic FAAH(-/-) lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH(-/-) acetyl-CoA (85%, p<0.01) corresponded to similar increases in citrate levels (45%). Altered FAAH(-/-) mitochondrial malate dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25% decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone P and glycerol-3-P levels in FAAH(-/-) mice was consistent with a compensating contribution from decreased acetylation of fed FAAH(-/-) aldolase B. Fed FAAH(-/ ) alcohol dehydrogenase (ADH) acetylation was also decreased. CONCLUSIONS/SIGNIFICANCE: Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH(-/-) mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver's role in fostering the pre-diabetic state, and may reflect part of the mechanism underlying the hepatic effects of endocannabinoids in alcoholic liver disease mouse models. PMID- 22442718 TI - Chronic nicotine modifies skeletal muscle Na,K-ATPase activity through its interaction with the nicotinic acetylcholine receptor and phospholemman. AB - Our previous finding that the muscle nicotinic acetylcholine receptor (nAChR) and the Na,K-ATPase interact as a regulatory complex to modulate Na,K-ATPase activity suggested that chronic, circulating nicotine may alter this interaction, with long-term changes in the membrane potential. To test this hypothesis, we chronically exposed rats to nicotine delivered orally for 21-31 days. Chronic nicotine produced a steady membrane depolarization of ~3 mV in the diaphragm muscle, which resulted from a net change in electrogenic transport by the Na,K ATPase alpha2 and alpha1 isoforms. Electrogenic transport by the alpha2 isoform increased (+1.8 mV) while the activity of the alpha1 isoform decreased (-4.4 mV). Protein expression of Na,K-ATPase alpha1 or alpha2 isoforms and the nAChR did not change; however, the content of alpha2 subunit in the plasma membrane decreased by 25%, indicating that its stimulated electrogenic transport is due to an increase in specific activity. The physical association between the nAChR, the Na,K-ATPase alpha1 or alpha2 subunits, and the regulatory subunit of the Na,K ATPase, phospholemman (PLM), measured by co-immuno precipitation, was stable and unchanged. Chronic nicotine treatment activated PKCalpha/beta2 and PKCdelta and was accompanied by parallel increases in PLM phosphorylation at Ser(63) and Ser(68). Collectively, these results demonstrate that nicotine at chronic doses, acting through the nAChR-Na,K-ATPase complex, is able to modulate Na,K-ATPase activity in an isoform-specific manner and that the regulatory range includes both stimulation and inhibition of enzyme activity. Cholinergic modulation of Na,K-ATPase activity is achieved, in part, through activation of PKC and phosphorylation of PLM. PMID- 22442719 TI - Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. AB - The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3'UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3'-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR DIM is likely to have clinical impact. PMID- 22442720 TI - Transcriptome profiling of testis during sexual maturation stages in Eriocheir sinensis using Illumina sequencing. AB - The testis is a highly specialized tissue that plays dual roles in ensuring fertility by producing spermatozoa and hormones. Spermatogenesis is a complex process, resulting in the production of mature sperm from primordial germ cells. Significant structural and biochemical changes take place in the seminiferous epithelium of the adult testis during spermatogenesis. The gene expression pattern of testis in Chinese mitten crab (Eriocheir sinensis) has not been extensively studied, and limited genetic research has been performed on this species. The advent of high-throughput sequencing technologies enables the generation of genomic resources within a short period of time and at minimal cost. In the present study, we performed de novo transcriptome sequencing to produce a comprehensive transcript dataset for testis of E. sinensis. In two runs, we produced 25,698,778 sequencing reads corresponding with 2.31 Gb total nucleotides. These reads were assembled into 342,753 contigs or 141,861 scaffold sequences, which identified 96,311 unigenes. Based on similarity searches with known proteins, 39,995 unigenes were annotated based on having a Blast hit in the non-redundant database or ESTscan results with a cut-off E-value above 10(-5). This is the first report of a mitten crab transcriptome using high-throughput sequencing technology, and all these testes transcripts can help us understand the molecular mechanisms involved in spermatogenesis and testis maturation. PMID- 22442721 TI - A cohort study of lymphatic filariasis on socio economic conditions in Andhra Pradesh, India. AB - BACKGROUND: To assess the impact of socioeconomic variables on lymphatic filariasis in endemic villages of Karimnagar district, Andhra Pradesh, India. METHODS: A pilot scale study was conducted in 30 villages of Karimnagar district from 2004 to 2007. These villages were selected based on previous reports from department of health, Government of Andhra Pradesh, epidemiology, entomology and socioeconomic survey was conducted as per protocol. Collected data were analysed statistically by Chi square test, Principal Component Analysis, Odds ratio, Bivariate, multivariate logistic regression analysis. RESULTS: Total of 5,394 blood samples collected and screened for microfilaria, out of which 199 were found to be positive (3.7%). The socioeconomic data of these respondents/participants were correlated with MF prevalence. The socioeconomic variables like educational status (Odds Ratio (OR) = 2.6, 95% Confidence Interval (CI) = 1.1-6.5), house structure (hut OR = 1.9, 95% CI = 1.2-3.1; tiled OR = 1.3, 95% CI = 0.8-2) and participation in mass drug administration program (OR = 1.8, 95% CI = 1.3-2.6) were found to be highly associated with the occurrence of filarial disease. The socioeconomic index was categorized into low (3.6%; OR-1.1, 95% CI: 0.7-1.5) medium (4.9%; OR-1.5, 95% CI = 1-2.1) and high (3.3%) in relation to percentage of filarial parasite prevalence. A significant difference was observed among these three groups while comparing the number of cases of filaria with the type of socioeconomic conditions of the respondents (P = 0.067). CONCLUSIONS: From this study it is inferred that age, education of family, type of house structure and awareness about the filarial disease directly influenced the disease prevalence. Beside annual mass drug administration program, such type of analysis should be undertaken by health officials to target a few socioeconomic factors to reduce the disease burden. Health education campaigns in the endemic villages and imparting of protection measures against mosquitoes using insecticide treated bed nets would substantially reduce the disease in these villages. PMID- 22442722 TI - Functional consequences of necdin nucleocytoplasmic localization. AB - BACKGROUND: Necdin, a MAGE family protein expressed primarily in the nervous system, has been shown to interact with both nuclear and cytoplasmic proteins, but the mechanism of its nucleocytoplasmic transport are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We carried out a large-scale interaction screen using necdin as a bait in the yeast RRS system, and found a wide range of potential interactors with different subcellular localizations, including over 60 new candidates for direct binding to necdin. Integration of these interactions into a comprehensive network revealed a number of coherent interaction modules, including a cytoplasmic module connecting to necdin through huntingtin-associated protein 1 (Hap1), dynactin and hip-1 protein interactor (Hippi); a nuclear P53 and Creb-binding-protein (Crebbp) module, connecting through Crebbp and WW domain containing transcription regulator protein 1 (Wwtr1); and a nucleocytoplasmic transport module, connecting through transportins 1 and 2. We validated the necdin-transportin1 interaction and characterized a sequence motif in necdin that modulates karyopherin interaction. Surprisingly, a D234P necdin mutant showed enhanced binding to both transportin1 and importin beta1. Finally, exclusion of necdin from the nucleus triggered extensive cell death. CONCLUSIONS/SIGNIFICANCE: These data suggest that necdin has multiple roles within protein complexes in different subcellular compartments, and indicate that it can utilize multiple karyopherin-dependent pathways to modulate its localization. PMID- 22442723 TI - Modification of Salmonella Typhimurium motility by the probiotic yeast strain Saccharomyces boulardii. AB - BACKGROUND: Motility is an important component of Salmonella enterica serovar Typhimurium (ST) pathogenesis allowing the bacteria to move into appropriate niches, across the mucus layer and invade the intestinal epithelium. In vitro, flagellum-associated motility is closely related to the invasive properties of ST. The probiotic yeast Saccharomyces boulardii BIOCODEX (S.b-B) is widely prescribed for the prophylaxis and treatment of diarrheal diseases caused by bacteria or antibiotics. In case of Salmonella infection, S.b-B has been shown to decrease ST invasion of T84 colon cell line. The present study was designed to investigate the impact of S.b-B on ST motility. METHODOLOGY/PRINCIPAL FINDINGS: Experiments were performed on human colonic T84 cells infected by the Salmonella strain 1344 alone or in the presence of S.b-B. The motility of Salmonella was recorded by time-lapse video microscopy. Next, a manual tracking was performed to analyze bacteria dynamics (MTrackJ plugin, NIH image J software). This revealed that the speed of bacterial movement was modified in the presence of S.b-B. The median curvilinear velocity (CLV) of Salmonella incubated alone with T84 decreased from 43.3 um/sec to 31.2 um/sec in the presence of S.b-B. Measurement of track linearity (TL) showed similar trends: S.b-B decreased by 15% the number of bacteria with linear tract (LT) and increased by 22% the number of bacteria with rotator tract (RT). Correlation between ST motility and invasion was further established by studying a non-motile flagella-deficient ST strain. Indeed this strain that moved with a CLV of 0.5 um/sec, presented a majority of RT and a significant decrease in invasion properties. Importantly, we show that S.b-B modified the motility of the pathogenic strain SL1344 and significantly decreased invasion of T84 cells by this strain. CONCLUSIONS: This study reveals that S.b-B modifies Salmonella's motility and trajectory which may account for the modification of Salmonella's invasion. PMID- 22442724 TI - Contribution of pollinators to seed production as revealed by differential pollinator exclusion in Clerodendrum trichotomum (Lamiaceae). AB - A diverse assemblage of pollinators, such as bees, beetles, flies, and butterflies, will often visit a single plant species. However, evaluating the effect of several insects on fruit and seed production is difficult in plants visited by a variety of insects. Here, we analyzed the effect of three types of pollinators, Papilio spp., Macroglossum pyrrhosticta, and Xylocopa appendiculata on fruit and seed production in Clerodendrum trichotomum by using a flower visitor barrier experiment with nets of specific mesh sizes. As a result, fruit/flower and seed/ovule ratios were significantly lower under Papilio exclusion than under natural conditions. On the other hand, ratios were not significantly different between Papilio excluded and both Papilio and M. pyrrhosticta excluded treatments. Therefore, Papilio and X. appendiculata are effective pollinators, whereas M. pyrrhosticta, which was the most frequent visitor, of C. trichotomum, is not. From our observations of visiting behaviors, we believe that because M. pyrrhosticta probably promotes self- pollination, this species is a non-effective pollinator. This is the first study to separate and compare the contribution of various visitors to the reproductive success of a plant. PMID- 22442725 TI - The origin and evolution of G protein-coupled receptor kinases. AB - G protein-coupled receptor (GPCR) kinases (GRKs) play key role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors, promoting high affinity binding of arrestins, which precludes G protein coupling. Direct binding to active GPCRs activates GRKs, so that they selectively phosphorylate only the activated form of the receptor regardless of the accessibility of the substrate peptides within it and their Ser/Thr-containing sequence. Mammalian GRKs were classified into three main lineages, but earlier GRK evolution has not been studied. Here we show that GRKs emerged at the early stages of eukaryotic evolution via an insertion of a kinase similar to ribosomal protein S6 kinase into a loop in RGS domain. GRKs in Metazoa fall into two clades, one including GRK2 and GRK3, and the other consisting of all remaining GRKs, split into GRK1 GRK7 lineage and GRK4-GRK5-GRK6 lineage in vertebrates. One representative of each of the two ancient clades is found as early as placozoan Trichoplax adhaerens. Several protists, two oomycetes and unicellular brown algae have one GRK-like protein, suggesting that the insertion of a kinase domain into the RGS domain preceded the origin of Metazoa. The two GRK families acquired distinct structural units in the N- and C-termini responsible for membrane recruitment and receptor association. Thus, GRKs apparently emerged before animals and rapidly expanded in true Metazoa, most likely due to the need for rapid signalling adjustments in fast-moving animals. PMID- 22442726 TI - SS18 together with animal-specific factors defines human BAF-type SWI/SNF complexes. AB - BACKGROUND: Nucleosome translocation along DNA is catalyzed by eukaryotic SNF2 type ATPases. One class of SNF2-ATPases is distinguished by the presence of a C terminal bromodomain and is conserved from yeast to man and plants. This class of SNF2 enzymes forms rather large protein complexes that are collectively called SWI/SNF complexes. They are involved in transcription and DNA repair. Two broad types of SWI/SNF complexes have been reported in the literature; PBAF and BAF. These are distinguished by the inclusion or not of polybromo and several ARID subunits. Here we investigated human SS18, a protein that is conserved in plants and animals. SS18 is a putative SWI/SNF subunit which has been implicated in the etiology of synovial sarcomas by virtue of being a target for oncogenic chromosomal translocations that underlie synovial sarcomas. METHODOLOGY/PRINCIPAL FINDINGS: We pursued a proteomic approach whereby the SS18 open reading frame was fused to a tandem affinity purification tag and expressed in amenable human cells. The fusion permitted efficient and exclusive purification of so-called BAF type SWI/SNF complexes which bear ARID1A/BAF250a or ARID1B/BAF250b subunits. This demonstrates that SS18 is a BAF subtype-specific SWI/SNF complex subunit. The same result was obtained when using the SS18-SSX1 oncogenic translocation product. Furthermore, SS18L1, DPF1, DPF2, DPF3, BRD9, BCL7A, BCL7B and BCL7C were identified. 'Complex walking' showed that they all co-purify with each other, defining human BAF-type complexes. By contrast,we demonstrate that human PHF10 is part of the PBAF complex, which harbors both ARID2/BAF200 and polybromo/BAF180 subunits, but not SS18 and nor the above BAF-specific subunits. CONCLUSIONS/SIGNIFICANCE: SWI/SNF complexes are found in most eukaryotes and in the course of evolution new SWI/SNF subunits appeared. SS18 is found in plants as well as animals. Our results suggest that in both protostome and deuterostome animals, a class of BAF-type SWI/SNF complexes will be found that harbor SS18 or its paralogs, along with ARID1, DPF and BCL7 paralogs. Those BAF complexes are proteomically distinct from the eukaryote-wide PBAF-type SWI/SNF complexes. Finally, our results suggests that the human bromodomain factors BRD7 and BRD9 associate with PBAF and BAF, respectively. PMID- 22442727 TI - A cost-consequences analysis of a primary care librarian question and answering service. AB - BACKGROUND: Cost consequences analysis was completed from randomized controlled trial (RCT) data for the Just-in-time (JIT) librarian consultation service in primary care that ran from October 2005 to April 2006. The service was aimed at providing answers to clinical questions arising during the clinical encounter while the patient waits. Cost saving and cost avoidance were also analyzed. The data comes from eighty-eight primary care providers in the Ottawa area working in Family Health Networks (FHNs) and Family Health Groups (FHGs). METHODS: We conducted a cost consequences analysis based on data from the JIT project. We also estimated the potential economic benefit of JIT librarian consultation service to the health care system. RESULTS: The results show that the cost per question for the JIT service was $38.20. The cost could be as low as $5.70 per question for a regular service. Nationally, if this service was implemented and if family physicians saw additional patients when the JIT service saved them time, up to 61,100 extra patients could be seen annually. A conservative estimate of the cost savings and cost avoidance per question for JIT was $11.55. CONCLUSIONS: The cost per question, if the librarian service was used at full capacity, is quite low. Financial savings to the health care system might exceed the cost of the service. Saving physician's time during their day could potentially lead to better access to family physicians by patients. Implementing a librarian consultation service can happen quickly as the time required to train professional librarians to do this service is short. PMID- 22442728 TI - Preparations of meiotic pachytene chromosomes and extended DNA fibers from cotton suitable for fluorescence in situ hybridization. AB - Fluorescence in situ hybridization (FISH) has become one of the most important techniques applied in plant molecular cytogenetics. However, the application of this technique in cotton has lagged behind because of difficulties in chromosome preparation. The focus of this article was FISH performed not only on cotton pachytene chromosomes, but also on cotton extended DNA fibers. The cotton pollen mother cells (PMCs) instead of buds or anthers were directly digested in enzyme to completely breakdown the cell wall. Before the routine acetic acid treatment, PMCs were incubated in acetic acid and enzyme mixture to remove the cytoplasm and clear the background. The method of ice-cold Carnoy's solution spreading chromosome was adopted instead of nitrogen removed method to avoid chromosomes losing and fully stretch chromosome. With the above-improved steps, the high quality well-differentiated pachytene chromosomes with clear background were obtained. FISH results demonstrated that a mature protocol of cotton pachytene chromosomes preparation was presented. Intact and no debris cotton nuclei were obtained by chopping from etiolation cotyledons instead of the conventional liquid nitrogen grinding method. After incubating the nuclei with nucleus lysis buffer on slide, the parallel and clear background DNA fibers were acquired along the slide. This method overcomes the twist, accumulation and fracture of DNA fibers compared with other methods. The entire process of DNA fibers preparation requires only 30 min, in contrast, it takes 3 h with routine nitrogen grinding method. The poisonous mercaptoethanol in nucleus lysis buffer is replaced by nonpoisonous dithiothreitol. PVP40 in nucleus isolation buffer is used to prevent oxidation. The probability of success in isolating nuclei for DNA fiber preparation is almost 100% tested with this method in cotton. So a rapid, safe, and efficient method for the preparation of cotton extended DNA fibers suitable for FISH was established. PMID- 22442729 TI - Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo. AB - Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A (VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway. PMID- 22442731 TI - Integrating spread dynamics and economics of timber production to manage Chinese tallow invasions in southern U.S. forestlands. AB - Economic costs associated with the invasion of nonnative species are of global concern. We estimated expected costs of Chinese tallow (Triadica sebifera (L.) Small) invasions related to timber production in southern U.S. forestlands under different management strategies. Expected costs were confined to the value of timber production losses plus costs for search and control. We simulated management strategies including (1) no control (NC), and control beginning as soon as the percentage of invaded forest land exceeded (2) 60 (Low Control), (3) 25 (Medium Control), or (4) 0 (High Control) using a spatially-explicit, stochastic, bioeconomic model. With NC, simulated invasions spread northward and westward into Arkansas and along the Gulf of Mexico to occupy ~1.2 million hectares within 20 years, with associated expected total costs increasing exponentially to ~$300 million. With LC, MC, and HC, invaded areas reached ~275, 34, and 2 thousand hectares after 20 years, respectively, with associated expected costs reaching ~$400, $230, and $200 million. Complete eradication would not be cost-effective; the minimum expected total cost was achieved when control began as soon as the percentage of invaded land exceeded 5%. These results suggest the importance of early detection and control of Chinese tallow, and emphasize the importance of integrating spread dynamics and economics to manage invasive species. PMID- 22442730 TI - Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. AB - BACKGROUND: Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding, and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is an indispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1. Although FGF19 can predominantly activate the responses of the liver and to a less extent the adipose tissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolic and endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted by the ablation of KLB or FGFR1. CONCLUSIONS: Our results indicate that unlike FGF19, FGF21 is unable to bind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiological concentration less likely to directly and significantly target the liver where FGFR4-KLB predominantly resides. However, both FGF21 and FGF19 have the potential to activate responses of primarily the adipose tissue where FGFR1-KLB resides. PMID- 22442732 TI - Galanin transgenic mice with elevated circulating galanin levels alleviate demyelination in a cuprizone-induced MS mouse model. AB - Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ) demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg), we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS. PMID- 22442733 TI - Interactivity and reward-related neural activation during a serious videogame. AB - This study sought to determine whether playing a "serious" interactive digital game (IDG)--the Re-Mission videogame for cancer patients--activates mesolimbic neural circuits associated with incentive motivation, and if so, whether such effects stem from the participatory aspects of interactive gameplay, or from the complex sensory/perceptual engagement generated by its dynamic event-stream. Healthy undergraduates were randomized to groups in which they were scanned with functional magnetic resonance imaging (FMRI) as they either actively played Re Mission or as they passively observed a gameplay audio-visual stream generated by a yoked active group subject. Onset of interactive game play robustly activated mesolimbic projection regions including the caudate nucleus and nucleus accumbens, as well as a subregion of the parahippocampal gyrus. During interactive gameplay, subjects showed extended activation of the thalamus, anterior insula, putamen, and motor-related regions, accompanied by decreased activation in parietal and medial prefrontal cortex. Offset of interactive gameplay activated the anterior insula and anterior cingulate. Between-group comparisons of within-subject contrasts confirmed that mesolimbic activation was significantly more pronounced in the active playgroup than in the passive exposure control group. Individual difference analyses also found the magnitude of parahippocampal activation following gameplay onset to correlate with positive attitudes toward chemotherapy assessed both at the end of the scanning session and at an unannounced one-month follow-up. These findings suggest that IDG induced activation of reward-related mesolimbic neural circuits stems primarily from participatory engagement in gameplay (interactivity), rather than from the effects of vivid and dynamic sensory stimulation. PMID- 22442734 TI - Conjunctiva-associated lymphoid tissue (CALT) reactions to antiglaucoma prostaglandins with or without BAK-preservative in rabbit acute toxicity study. AB - Conjunctiva-associated lymphoid tissue (CALT) is closely associated with ocular surface immunity. This study investigated the effects of antiglaucoma prostaglandin analogs with or without benzalkonium chloride (BAK) preservative on organized CALT using an acute toxic model. A total of 48 albino rabbits were used and seven groups of treatments were constituted. Solutions (50 ul) of PBS, 0.02%BAK, (0.02%BAK+)latanoprost, (0.015%BAK+)travoprost, (0.005%BAK+)bimatoprost, (BAK-free)travoprost preserved with the SofZia(r) system or (BAK-free)tafluprost were instilled 15 times at 5-min intervals in both eyes. CALT changes were analyzed using in vivo confocal microscopy (IVCM), immunohistology in cryosections for detecting MUC-5AC+ mucocytes and CD45+ hematopoietic cells. Antiglaucoma eye drops stimulated inflammatory cell infiltration in the CALT, and seemed to be primarily related to the concentration of their BAK content. The CALT reaction after instillation of BAK-containing eye drops was characterized by inflammatory cell infiltration in the dome and intrafollicular layers and by cell circulation inside the lymph vessels. CD45 was strongly expressed in the CALT after instillation of all BAK-containing solutions at 4 h and decreased at 24 h. The number of MUC-5AC+ mucocytes around the CALT structure decreased dramatically after instillation of BAK-containing solutions. This study showed for the first time the in vivo aspect of rabbit CALT after toxic stimuli, confirming the concentration-dependent toxic effects of BAK. IVCM CALT analysis could be a pertinent tool in the future for understanding the immunotoxicologic challenges in the ocular surface and would provide useful criteria for evaluating newly developed eye drops. PMID- 22442735 TI - Evidence of different thermoregulatory mechanisms between two sympatric Scarabaeus species using infrared thermography and micro-computer tomography. AB - In endotherms insects, the thermoregulatory mechanisms modulate heat transfer from the thorax to the abdomen to avoid overheating or cooling in order to obtain a prolonged flight performance. Scarabaeus sacer and S. cicatricosus, two sympatric species with the same habitat and food preferences, showed daily temporal segregation with S. cicatricosus being more active during warmer hours of the day in opposition to S. sacer who avoid it. In the case of S. sacer, their endothermy pattern suggested an adaptive capacity for thorax heat retention. In S. cicatricosus, an active 'heat exchanger' mechanism was suggested. However, no empirical evidence had been documented until now. Thermographic sequences recorded during flight performance showed evidence of the existence of both thermoregulatory mechanisms. In S. sacer, infrared sequences showed a possible heat insulator (passive thermal window), which prevents heat transfer from meso- and metathorax to the abdomen during flight. In S. cicatricosus, infrared sequences revealed clear and effective heat flow between the thorax and abdomen (abdominal heat transfer) that should be considered the main mechanism of thermoregulation. This was related to a subsequent increase in abdominal pumping (as a cooling mechanism) during flight. Computer microtomography scanning, anatomical dissections and internal air volume measurements showed two possible heat retention mechanisms for S. sacer; the abdominal air sacs and the development of the internal abdominal sternites that could explain the thermoregulation between thorax and abdomen. Our results suggest that interspecific interactions between sympatric species are regulated by very different mechanisms. These mechanisms create unique thermal niches for the different species, thereby preventing competition and modulating spatio-temporal distribution and the composition of dung beetle assemblages. PMID- 22442736 TI - Women with endometriosis are more likely to suffer from migraines: a population based study. AB - Previous research suggests that a co-morbid relationship exists between migraine and endometriosis; however, results have been inconsistent. In addition, female hormones, which are important in the pathogenesis and management of endometriosis, have been reported to precipitate migraine attacks and may confound the results. The aim of this population-based cohort study was to explore the relationship between migraine and endometriosis in women of reproductive age (18-51 years). Data were derived from the National Health Insurance Research Database of Taiwan, which contains outpatient and inpatient records from 2000 to 2007. Our study cohort included 20,220 endometriosis patients and 263,767 controls without endometriosis. We analyzed the prevalence of migraine in these women as recorded during the eight years of the database. Our results found that patients with endometriosis were more likely to suffer migraine headaches compared to controls (odds ratio [OR], 1.70; 95% confidence interval [CI] [1.59, 1.82]; p<0.001). In addition, the co-morbid association between migraine and endometriosis remained significant after the data were controlled for age and frequently utilized hormone therapies (OR, 1.37; 95% CI, [1.27, 1.47]; p<0.001). The results of this cohort study support the existence of a co-morbid relationship between migraine and endometriosis, even after adjusting for the possible effects of female hormone therapies on migraine attacks. PMID- 22442737 TI - Co-inoculation with rhizobia and AMF inhibited soybean red crown rot: from field study to plant defense-related gene expression analysis. AB - BACKGROUND: Soybean red crown rot is a major soil-borne disease all over the world, which severely affects soybean production. Efficient and sustainable methods are strongly desired to control the soil-borne diseases. PRINCIPAL FINDINGS: We firstly investigated the disease incidence and index of soybean red crown rot under different phosphorus (P) additions in field and found that the natural inoculation of rhizobia and arbuscular mycorrhizal fungi (AMF) could affect soybean red crown rot, particularly without P addition. Further studies in sand culture experiments showed that inoculation with rhizobia or AMF significantly decreased severity and incidence of soybean red crown rot, especially for co-inoculation with rhizobia and AMF at low P. The root colony forming unit (CFU) decreased over 50% when inoculated by rhizobia and/or AMF at low P. However, P addition only enhanced CFU when inoculated with AMF. Furthermore, root exudates of soybean inoculated with rhizobia and/or AMF significantly inhibited pathogen growth and reproduction. Quantitative RT-PCR results indicated that the transcripts of the most tested pathogen defense related (PR) genes in roots were significantly increased by rhizobium and/or AMF inoculation. Among them, PR2, PR3, PR4 and PR10 reached the highest level with co inoculation of rhizobium and AMF. CONCLUSIONS: Our results indicated that inoculation with rhizobia and AMF could directly inhibit pathogen growth and reproduction, and activate the plant overall defense system through increasing PR gene expressions. Combined with optimal P fertilization, inoculation with rhizobia and AMF could be considered as an efficient method to control soybean red crown rot in acid soils. PMID- 22442738 TI - Purified human pancreatic duct cell culture conditions defined by serum-free high content growth factor screening. AB - The proliferation of pancreatic duct-like CK19+ cells has implications for multiple disease states including pancreatic cancer and diabetes mellitus. The in vitro study of this important cell type has been hampered by their limited expansion compared to fibroblast-like vimentin+ cells that overgrow primary cultures. We aimed to develop a screening platform for duct cell mitogens after depletion of the vimentin+ population. The CD90 cell surface marker was used to remove the vimentin+ cells from islet-depleted human pancreas cell cultures by magnetic-activated cell sorting. Cell sorting decreased CD90+ cell contamination of the cultures from 34+/-20% to 1.3+/-0.6%, yielding purified CK19+ cultures with epithelial morphology. A full-factorial experimental design was then applied to test the mitogenic effects of bFGF, EGF, HGF, KGF and VEGF. After 6 days in test conditions, the cells were labelled with BrdU, stained and analyzed by high throughput imaging. This screening assay confirmed the expected mitogenic effects of bFGF, EGF, HGF and KGF on CK19+ cells and additionally revealed interactions between these factors and VEGF. A serum-free medium containing bFGF, EGF, HGF and KGF led to CK19+ cell expansion comparable to the addition of 10% serum. The methods developed in this work should advance pancreatic cancer and diabetes research by providing effective cell culture and high-throughput screening platforms to study purified primary pancreatic CK19+ cells. PMID- 22442739 TI - Tight junction-related barrier contributes to the electrophysiological asymmetry across vocal fold epithelium. AB - Electrophysiological homeostasis is indispensable to vocal fold hydration. We investigate tight junction (TJ)-associated components, occludin and ZO-1, and permeability with or without the challenge of a permeability-augmenting agent, histamine. Freshly excised ovine larynges are obtained from a local abattoir. TJ markers are explored via reverse transcriptase polymerase chain reaction (RT PCR). Paracellular permeabilities are measured in an Ussing system. The gene expression of both TJ markers is detected in native ovine vocal fold epithelium. Luminal histamine treatment significantly decreases transepithelial resistance (TER) (N = 72, p<0.01) and increases penetration of protein tracer (N = 35, p<0.001), respectively, in a time-, and dose-dependent fashion. The present study demonstrates that histamine compromises TJ-related paracellular barrier across vocal fold epithelium. The detection of TJ markers indicates the existence of typical TJ components in non-keratinized, stratified vocal fold epithelium. The responsiveness of paracellular permeabilities to histamine would highlight the functional significance of this TJ-equivalent system to the electrophysiological homeostasis, which, in turn, regulates the vocal fold superficial hydration. PMID- 22442740 TI - PLGA nanoparticles for peptide receptor radionuclide therapy of neuroendocrine tumors: a novel approach towards reduction of renal radiation dose. AB - BACKGROUND: Peptide receptor radionuclide therapy (PRRT), employed for treatment of neuroendocrine tumors (NETs) is based on over-expression of Somatostatin Receptors (SSTRs) on NETs. It is, however, limited by high uptake and retention of radiolabeled peptide in kidneys resulting in unnecessary radiation exposure thus causing nephrotoxicity. Employing a nanocarrier to deliver PRRT drugs specifically to the tumor can reduce the associated nephrotoxicity. Based on this, (177)Lu-DOTATATE loaded PLGA nanoparticles (NPs) were formulated in the present study, as a potential therapeutic model for NETs. METHODOLOGY AND FINDINGS: DOTATATE was labeled with Lutetium-177 ((177)Lu) (labeling efficiency 98%; R(f)~0.8). Polyethylene Glycol (PEG) coated (177)Lu-DOTATATE-PLGA NPs (50:50 and 75:25) formulated, were spherical with mean size of 304.5+/-80.8 and 733.4+/ 101.3 nm (uncoated) and 303.8+/-67.2 and 494.3+/-71.8 nm (coated) for PLGA(50:50) and PLGA(75:25) respectively. Encapsulation efficiency (EE) and In-vitro release kinetics for uncoated and coated NPs of PLGA (50:50 & 75:25) were assessed and compared. Mean EE was 77.375+/-4.98% & 67.885+/-5.12% (uncoated) and 65.385+/ 5.67% & 58.495+/-5.35% (coated). NPs showed initial burst release between 16.64 21.65% with total 42.83-44.79% over 21 days. The release increased with coating to 20.4-23.95% initially and 60.97-69.12% over 21 days. In-vivo studies were done in rats injected with (177)Lu-DOTATATE and (177)Lu-DOTATATE-NP (uncoated and PEG coated) by imaging and organ counting after sacrificing rats at different time points over 24 hr post-injection. With (177)Lu-DOTATATE, renal uptake of 37.89+/ 10.2%ID/g was observed, which reduced to 4.6+/-1.97% and 5.27+/-1.66%ID/g with uncoated and coated (177)Lu-DOTATATE-NP. The high liver uptake with uncoated (177)Lu-DOTATATE-NP (13.68+/-3.08% ID/g), reduced to 7.20+/-2.04%ID/g (p = 0.02) with PEG coating. CONCLUSION: PLGA NPs were easily formulated and modified for desired release properties. PLGA 50:50 NPs were a more suitable delivery vehicle for (177)Lu-DOTATATE than PLGA 75:25 because of higher EE and slower release rate. Reduced renal retention of (177)Lu-DOTATATE and reduced opsonisation strongly advocate the potential of (177)Lu-DOTATATE-PLGA-PEG NPs to reduce radiation dose in PRRT. PMID- 22442741 TI - Endoscopic and radiographic features of gastrointestinal involvement in vasculitis. AB - Vasculitis is an inflammation of vessel walls, followed by alteration of the blood flow and damage to the dependent organ. Vasculitis can cause local or diffuse pathologic changes in the gastrointestinal (GI) tract. The variety of GI lesions includes ulcer, submucosal edema, hemorrhage, paralytic ileus, mesenteric ischemia, bowel obstruction, and life-threatening perforation.The endoscopic and radiographic features of GI involvement in vasculitisare reviewed with the emphasis on small-vessel vasculitis by presenting our typical cases, including Churg-Strauss syndrome, Henoch-Schonlein purpura, systemic lupus erythematosus, and Behcet's disease. Important endoscopic features are ischemic enterocolitis and ulcer. Characteristic computed tomographic findings include bowel wall thickening with the target sign and engorgement of mesenteric vessels with comb sign. Knowledge of endoscopic and radiographic GI manifestations can help make an early diagnosis and establish treatment strategy. PMID- 22442742 TI - Recent advances in targeted endoscopic imaging: Early detection of gastrointestinal neoplasms. AB - Molecular imaging has emerged as a new discipline in gastrointestinal endoscopy. This technology encompasses modalities that can visualize disease-specific morphological or functional tissue changes based on the molecular signature of individual cells. Molecular imaging has several advantages including minimal damage to tissues, repetitive visualization, and utility for conducting quantitative analyses. Advancements in basic science coupled with endoscopy have made early detection of gastrointestinal cancer possible. Molecular imaging during gastrointestinal endoscopy requires the development of safe biomarkers and exogenous probes to detect molecular changes in cells with high specificity anda high signal-to-background ratio. Additionally, a high-resolution endoscope with an accurate wide-field viewing capability must be developed. Targeted endoscopic imaging is expected to improve early diagnosis and individual therapy of gastrointestinal cancer. PMID- 22442743 TI - Natural orifice translumenal endoscopic surgery applications in clinical practice. AB - To review natural orifice translumenal endoscopic surgery (NOTES) applications in clinical practice and assess the evidence base for each application as reported in the literature. An electronic literature search was performed. Inclusion criteria were publications relating to NOTES applications in humans. For each type of operation the highest level of evidence available for clinical NOTES publications was evaluated. Morbidity and short-term operative outcomes were compared with gold standard published evidence where available. Finally, registered trials recruiting patients for NOTES applications were identified. Human NOTES publications with the highest level of evidence in each application are identified. There were no RCTs in the literature to date. The strongest evidence came in the form of large, multi-centre trials with 300-500 patients. The results are encouraging, comparable with gold standard techniques on morbidity and mortality. While short-term operative outcomes were also similar when compared to the gold standard techniques, other than improved cosmesis little else can definitely be concluded as a clear benefit of a NOTES procedure. The most common procedures are cholecystectomy, appendicectomy and peritoneoscopy mainly performed via transvaginal access. It is evident that morbidity appears to be higher when the transgastric route is used. The safety profile of hybrid NOTES transvaginal procedures is beginning to be confirmed as is evident from the large number of procedures presented in this review. A number of authors have presented work on pure NOTES procedures but the results are inconsistent and thus the vast majority of NOTES procedures worldwide are performed in a hybrid fashion with a variable amount of laparoscopy. This review of the clinical applications of NOTES summarises the growing evidence behind this surgical discipline and highlights NOTES procedures with an acceptable safety profile. PMID- 22442744 TI - Diagnosis of boundary in early gastric cancer. AB - Endoscopic submucosal dissection (ESD) is an advanced therapeutic endoscopic technique, which allowsresection of larger superficial tumors in the esophagus, stomach, and colon. Precise diagnosis of the boundary between tumor and the non tumorous surrounding portion is especially important before starting ESD, because too much resection can potentially take more time and can induce a higher complication rate, while too little resection can result in a non-curative resection. The boundary diagnosis is often difficult for early gastric cancer, mainly because of the underlying condition of chronic gastritis. Due to recent developments in endoscopy, including magnified endoscopy and narrow band endoscopy, the boundary diagnosis is becoming easy and more accurate.We have also applied magnified endoscopy combined with narrow band imaging to fresh specimens immediately after resection using thetiling method and XY stage. PMID- 22442745 TI - Diazepam during endoscopic submucosal dissection of gastric epithelial neoplasias. AB - AIM: To investigate risk factors and adverse events related to high-dose diazepam administration during endoscopic submucosal dissection for gastric neoplasias. METHODS: Between February 2002 and December 2009, a total of 286 patients with gastric epithelial neoplasia underwent endoscopic submucosal dissection in our hospital. To achieve moderate sedation, 5-7.5 mg of diazepam was administered intravenously by non-anesthesiologists. Intermittent additional administration of 2.5-5 mg diazepam was performed if uncontrollable body movement of the patient was observed. All patients were classified into groups based on the required diazepam dose: low-dose (<= 17.5 mg, n = 252) and high-dose (> 17.5 mg, n = 79). RESULTS: Differences between the low- and high-dose diazepam groups were observed in lifetime alcohol consumption (0.30 +/- 0.48 vs 0.44 +/- 0.52 tons, P = 0.032), body weight (58.4 +/- 10.3 vs 62.0 +/- 9.9 kg, P = 0.006), tumor size (15 +/- 10 vs 23 +/- 18 mm, P < 0.001), lesion location (P < 0.001) and the presence of ulcerative findings (14/238 vs 18/61, P < 0.001). Multivariate analysis identified all five variables as independently related to required diazepam dosage. In terms of adverse reactions to diazepam administration, paradoxical excitement was significantly more frequent in the high-dose diazepam group (P < 0.001). CONCLUSION: Intermittent administration of diazepam enabled safe completion of gastric endoscopic submucosal dissection except in patients who were alcohol abusers or obese, or who showed complicated lesions. PMID- 22442746 TI - Small bowel capsule endoscopy in patients with cardiac pacemakers and implantable cardioverter defibrillators: Outcome analysis using telemetry review. AB - AIM: To determine if there were any interactions between cardiac devices and small bowel capsules secondary to electromagnetic interference (EMI) in patients who have undergone small bowel capsule endoscopy (SBCE). METHODS: Authors conducted a chart review of 20 patients with a cardiac pacemaker (CP) or implantable cardioverter defibrillator (ICD) who underwent continuous electrocardiographic monitoring during their SBCE from 2003-2008. authors searched for unexplained electrocardiogram (ECG) findings, changes in CP and ICD set parameters, any abnormality in transmitted capsule data, and adverse clinical events. RESULTS: There were no adverse events or hemodynamically significant arrhythmias reported. CP and ICD set parameters were preserved. The majority of ECG abnormalities were also found in pre- or post- SBCE ECG tracings and the CP behavior during arrhythmias appeared appropriate. Two patients seemed to have episodes of undersensing by the CP. However, similar findings were documented in ECGs taken outside the time frame of the SBCE. One patient was observed to have a low signal encountered from the capsule resulting in lack of localization, but no images were lost. CONCLUSION: Capsule-induced EMI remains a possibility but is unlikely to be clinically important. CP-induced interference of SBCE is also possible, but is infrequent and does not result in loss of images transmitted by the capsule. PMID- 22442747 TI - Acquired double pylorus, due to penetrating gastric ulcer, presenting with melena. AB - Acquired double pylorus (DP) is an uncommon condition consisting of two communicating channels between the gastric antrum and the first part of duodedum. Little is known about the origin of DP. As there is no specific gastrointestinal symptom due to DP, most often it is diagnosed by gastroscopy while performing for other indicationsFew data are also known about the clinical course of DP. In the patients with peptic ulcer symptoms, the pyloroplasty-like drainage effect, improving gastric emptying after the estabilishment of the fistula, could relieve these symptoms. This represents an unresolved issues about the necessity of repeating endoscopy to document in the patients with DP its final outcome, as the risk of ulcer recurrence. We describe a case of a 76-years-old woman admitted to our department for hyposideremic anemia associated to a recent history of melena. PMID- 22442748 TI - Typical gastroduodenal endoscopic findings in a Crohn's disease patient in remission stage. AB - A 39-year-old patient with Crohn's disease (CD) was referred to our hospital for maintenance treatment of CD. He was diagnosed as having CD of the small and large intestines at 32 years old. He underwent partial resection of the ileum at 35 years old because of ileal perforation. He had received enteral nutritional supplement (1200 kcal/d) and metronidazole preparation (500 mg/d), and was in remission Crohn's disease activity index 73. We performed a routine gastroduodenal endoscopic examination, which revealed the representative endoscopic findings of gastroduodenal lesions in CD, namely, bamboo-joint-like appearance of the gastric body and cardia and a notched sign in the duodenum. These findings were clearly observed by using indigo carmine dye spraying. In our patient, typical gastroduodenal findings were observed even in the remission stage, suggesting that these findings would contribute to the early diagnosis of CD not only in the active stage but also during remission. PMID- 22442749 TI - Leucine signaling in the pathogenesis of type 2 diabetes and obesity. AB - Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D). This paper presents a new concept and comprehensive review of leucine mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response to glucose, energy, growth factors and amino acids. Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of beta-cells. Moreover, leucine-mediated mTORC1 S6K1-signaling plays an important role in adipogenesis, thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased beta-cell growth and beta-cell proliferation promoting an early onset of replicative beta cell senescence with subsequent beta-cell apoptosis. Disturbances of beta-cell mass regulation with increased beta-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects. Furthermore, bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids. Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy proteins may offer a great chance for the prevention of T2D and obesity, as well as other epidemic diseases of civilization with increased mTORC1 signaling, especially cancer and neurodegenerative diseases, which are frequently associated with T2D. PMID- 22442750 TI - ApoE isoforms, treatment of diabetes and the risk of coronary heart disease. AB - AIM: To analyze the risk of coronary heart disease in patients with type 2 diabetes mellitus (T2DM) receiving standard medical treatment. METHODS: We performed a retrospective chart analysis of 269 middle-aged patients (age 45-64 years, mean age, 53.9 +/- 5.5 years) with T2DM and without atherosclerotic cardiovascular events who underwent typing to determine their apolipoprotein E (apoE) isoforms. The apoE isoforms were determined using isoelectric focusing, followed by immunoblotting. We retrospectively evaluated the charts of the 269 patients, recorded between their first visit to the hospital (the study's start point, between 1987 and 1992) and the occurrence of an atherosclerotic cardiovascular event (the study's endpoint) or January 2004, whichever came first. The age-adjusted mean values and the prevalences of covariates were calculated to compare the laboratory data among the apoE phenotypes. To investigate the association of risk factors with the incidence of coronary heart disease during the follow-up period, monovariate and multivariate Cox regression models were used. RESULTS: At enrollment, the mean serum low density lipoprotein (LDL) cholesterol levels were lowest (2.92 +/- 0.89 mmol/L) among the subjects with apoE2 (apoE2/2 or apoE2/3) and highest (3.52 +/- 0.77 mmol/L) among the subjects with apoE4 (apoE3/4 or apoE4/4). No significant differences in mean age or the percentage of smokers were observed among the three groups. Furthermore, no significant differences were observed in the systolic and diastolic blood pressures, body mass index, HbA1c level or serum triglyceride levels among the three groups. There were 47 cases of coronary heart disease over 3285 person years of follow-up. An age-adjusted multivariate Cox proportional model identified diabetic retinopathy (hazard ratio, 2.38, 95% CI: 1.28-4.43, P = 0.006), a high systolic blood pressure (hazard ratio, 1.04, 95% CI: 1.02-1.06, P < 0.001) and high HbA1c values (hazard ratio, 1.19, 95% CI: 1.02-1.38, P = 0.0029), but not the LDL cholesterol value at enrollment (hazard ratio, 1.01, 95% CI: 0.97-1.05, P = 0.77) nor the specific apoE isoform, as significant predictors of coronary heart disease. CONCLUSION: Under standard medical treatment of diabetes, including the control of LDL cholesterol levels, the apoE4 isoform was not associated with coronary heart disease among T2DM patients. PMID- 22442751 TI - Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A. AB - Previous structure-activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency at KOP receptors. However, the reason for this increase remains unclear. Here we report our efforts towards the synthesis and evaluation of C-2 constrained analogs of salvinorin A. These analogs were evaluated at opioid receptors in radioligand binding experiments as well as in the GTP-gamma-S functional assay. One compound, 5, was found to have affinity and potency at kappa opioid (KOP) receptors comparable to salvinorin A. In further studies, 5 was found to attenuate cocaine-induced drug seeking behavior in rats comparably to salvinorin A. This finding represents the first example of a salvinorin A analog that has demonstrated anti-addictive capabilities. PMID- 22442752 TI - A fast and flexible panoramic virtual reality system for behavioural and electrophysiological experiments. AB - Ideally, neuronal functions would be studied by performing experiments with unconstrained animals whilst they behave in their natural environment. Although this is not feasible currently for most animal models, one can mimic the natural environment in the laboratory by using a virtual reality (VR) environment. Here we present a novel VR system based upon a spherical projection of computer generated images using a modified commercial data projector with an add-on fish eye lens. This system provides equidistant visual stimulation with extensive coverage of the visual field, high spatio-temporal resolution and flexible stimulus generation using a standard computer. It also includes a track-ball system for closed-loop behavioural experiments with walking animals. We present a detailed description of the system and characterize it thoroughly. Finally, we demonstrate the VR system's performance whilst operating in closed-loop conditions by showing the movement trajectories of the cockroaches during exploratory behaviour in a VR forest. PMID- 22442753 TI - Parasite-insecticide interactions: a case study of Nosema ceranae and fipronil synergy on honeybee. AB - In ecosystems, a variety of biological, chemical and physical stressors may act in combination to induce illness in populations of living organisms. While recent surveys reported that parasite-insecticide interactions can synergistically and negatively affect honeybee survival, the importance of sequence in exposure to stressors has hardly received any attention. In this work, Western honeybees (Apis mellifera) were sequentially or simultaneously infected by the microsporidian parasite Nosema ceranae and chronically exposed to a sublethal dose of the insecticide fipronil, respectively chosen as biological and chemical stressors. Interestingly, every combination tested led to a synergistic effect on honeybee survival, with the most significant impacts when stressors were applied at the emergence of honeybees. Our study presents significant outcomes on beekeeping management but also points out the potential risks incurred by any living organism frequently exposed to both pathogens and insecticides in their habitat. PMID- 22442755 TI - Sub-optimal CD4 T-lymphocyte responses among HIV infected patients who develop TB during the first year of ART. AB - STUDY BACKGROUND: Poor CD4 T-lymphocyte responses to anti-retroviral treatment (ART) are associated with increased HIV disease progression and mortality. In sub Saharan Africa a substantial proportion of HIV infected patients are co-infected with TB. This study evaluated the effect of active TB presenting after ART initiation on immunological responses to ART. METHODS: A retrospective cohort study was conducted of patients initiated on ART in a South African academic hospital between 1 January 2004 and 15 May 2008. Changes in CD4 T-lymphocyte count, virological suppression and incident TB episodes occurring in the first year of ART were assessed. Sub-optimal CD4 responses were defined as 'failure to increase CD4 T-lymphocyte count by 50cells/MUl at 6 month on ART'. RESULTS: The cohort for analysis included 691 patients. 141 (20.4%) had sub-optimal CD4 responses at 6 months on ART. 49 patients (7.1%) developed incident TB within the first 12 months of ART. After adjustment for age, sex, baseline CD4 count and detectable viral load, patients with incident TB were found to have a 2.20 times greater odds of a sub-optimal CD4 response at 6 month of ART as compared to those who were TB free (95%CI: 1.14-4.23). CONCLUSION: Incident TB was associated with a poor CD4 response during early ART in this cohort. Although the direction of causality cannot be determined from these data, these findings provide additional support for the initiation of ART at higher CD4 counts. PMID- 22442754 TI - The Central Role of Glia in Pathological Pain and the Potential of Targeting the Cannabinoid 2 Receptor for Pain Relief. AB - Under normal conditions, acute pain processing consists of well-characterized neuronal signaling events. When dysfunctional pain signaling occurs, pathological pain ensues. Glial activation and their released factors participate in the mediation of pathological pain. The use of cannabinoid compounds for pain relief is currently an area of great interest for both basic scientists and physicians. These compounds, bind mainly either the cannabinoid receptor subtype 1 (CB(1)R) or cannabinoid receptor subtype 2 (CB(2)R) and are able to modulate pain. Although cannabinoids were initially only thought to modulate pain via neuronal mechanisms within the central nervous system, strong evidence now supports that CB(2)R cannabinoid compounds are capable of modulating glia, (e.g. astrocytes and microglia) for pain relief. However, the mechanisms underlying cannabinoid receptor-mediated pain relief remain largely unknown. An emerging body of evidence supports that CB(2)R agonist compounds may prove to be powerful novel therapeutic candidates for the treatment of chronic pain. PMID- 22442757 TI - Correlation between the proportion of breast volume involved by locally advanced tumors and invasion of the skin and posterior structures. AB - AIM: To evaluate any differences between the percentages of involved breast volume, pathologic attributes, and tumor marker expression of T3 and T4a-c tumors in locally advanced breast cancers (BC). METHODS: All patients with T3N > 0 and T4a-c BC without evidence of distant metastasis (M0), presenting to the Breast Clinic from 1980 to 2010, were examined to determine whether their BC's involved >= 50% of their breast volumes, defined by gross replacement of at least one hemisphere. Core needle biopsy or post-mastectomy specimens from tumors involving a known percent of breast volume were evaluated for: (1) pathological grades and lympho-vascular invasion (LVI); (2) hormone receptor (ER/PR) expression > 0; and (3) epidermoid growth factor 2 (her2) over-expression (3+) by immune histochemical staining or fluorescent in situ hybridization. RESULTS: The data base included 98 patients with T3N> 0 M0 and 120 with T4a-c, any N disease, M0 disease. T3 tumor masses involved 50% or more of the breast in 23/98 (24%), and T4a-c tumors 65/120 (54%) (P < 0.001). Only 1% of T3 tumors and 23% of T4a-c tumors presented with total breast replacement. There were no significant differences between the pathological attributes and marker expression of the T3 and T4a-c tumors. CONCLUSION: These data suggest that erosion of the overlying skin or underlying chest wall by some BC may be due to neglect and delay, rather than inherent biological aggressiveness. PMID- 22442756 TI - Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. AB - Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/beta-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3'-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-kappaB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas. PMID- 22442758 TI - Central pain states: a shift in thinking about chronic pain. PMID- 22442759 TI - Use of complementary therapies to treat the pain of osteoarthritis. PMID- 22442760 TI - The promise of telemedicine: providing curbside consults for chronic care, acute care, and pain. PMID- 22442761 TI - REMS; red tape, or a remedy for opioid abuse? PMID- 22442762 TI - Value added. PMID- 22442763 TI - Effects of laser irradiation on machined and anodized titanium disks. AB - PURPOSE: Although the laser has become one of the most commonly used tools for implant dentistry, research is lacking on whether or not the laser causes any changes on the surface of titanium (Ti) implants. The present study analyzed the morphology, composition, crystal structure, and surface roughness changes of machined and anodized Ti surfaces, irradiated with erbium chromium-doped yttrium scandium-gallium-garnet (Er,Cr:YSGG), erbium-doped yttrium-aluminum-garnet (Er:YAG), and carbon dioxide (CO2) lasers. MATERIALS AND METHODS: Seventy-two Ti disks were fabricated by machining commercially pure Ti (grade 3); 36 of them were anodized at 300 V. The disks were irradiated with Er,Cr:YSGG, Er:YAG, and CO2 lasers at five different powers (1, 2, 3, 4, and 5 W). The irradiated disks were examined with scanning electron microscopy, electron probe microanalysis, x ray diffractometry, and optical interferometry. RESULTS: Surface changes were observed on both types of Ti surfaces irradiated with the Er,Cr:YSGG laser when more than 3 W of power were applied. Surface changes were observed on both types of Ti surfaces when irradiated with the Er:YAG laser with more than 2 W of power. No change was observed when the disks were irradiated with the CO2 laser. The proportion of oxide in the machined Ti disk increased after the application of the Er,Cr:YSGG or Er:YAG laser. In the anodized Ti disk, the anatase peak intensity decreased and the rutile peak intensity increased after laser irradiation. The irradiated Ti disks were significantly rougher than the nonirradiated Ti disks. CONCLUSIONS: The Er:YAG and Er,Cr:YSGG laser resulted in surface changes on the Ti disks according to the power output. The CO2 laser did not affect the surface of the Ti disks, irrespective of the power output. PMID- 22442764 TI - Distribution of endosseous bony canals in the mandibular symphysis as detected with cone beam computed tomography. AB - PURPOSE: The purpose of this article was to investigate the distribution of endosseous bony canals in the anterior mandible using cone beam computed tomography (CBCT) technology. MATERIALS AND METHODS: Two hundred ninety-nine images based on CBCT of the anterior mandible were analyzed for the presence of endosseous canals. The bony canals were observed in relationship to the adjacent anatomical structures, and relationships between their topographic variability and patient age and gender were analyzed. RESULTS: Bony canals were found in the anterior mandible in almost 86% of the examined patients, independent of age and gender. The highest regional frequency was seen in the midline area, followed by the lateral incisor and canine regions. The length of the canals ranged from 5 to 15 mm (mean, 10.55 mm). Multiple (two or three) canals were also observed in approximately 9% of the scans. Varying appearances of these bony canals in the symphysis region were also demonstrated. CONCLUSIONS: Endosseous canals in the mandibular symphysis were found using CBCT scans. CBCT seems to be an important diagnostic technique for evaluation of the exact distribution of bony canals in the symphysis region that may help reduce the risk of surgical complications. PMID- 22442765 TI - Translucent titanium coating facilitates observation of osteoblast migration behavior on a titanium surface. AB - PURPOSE: The appropriate surface composition and topography are crucial for osseointegration of titanium dental implants, and surface properties are known to enhance cell adhesion and promote expression of specific osteoblastic genes. In this study, a translucent titanium coating on glass coverslip (TiGlass) was introduced as a potential tool for direct observation of cell behavior on a titanium surface. MATERIALS AND METHODS: Scanning electron microscopy, energy dispersive x-ray analysis, and atomic force microscopy were performed on TiGlass to provide information about its physical properties. Random migration, osteoblastic gene expression, and immunofluorescence cell staining on TiGlass were also examined and analyzed. RESULTS: The translucent titanium surface offered excellent optical characteristics that facilitated transmitted light observations under an optical microscope, transforming the opaque metal into an observable titanium matrix. Random migration analysis of the primary osteoblasts on TiGlass revealed that the titanium coating enhanced the migration speed of the osteoblasts and significantly shortened the time lag for the initial migration behavior. Further study of osteoblastic gene expression on this smooth titanium surface revealed no significant changes. Co-localization of actin filament and vinculin was found on TiGlass under epifluorescent microscopy. CONCLUSION: The application of a translucent titanium-coated coverslip in vitro altered the migration pattern of osteoblasts. Collectively, the results suggest that titanium promotes initial adhesion and accelerates osteoblast migration. PMID- 22442766 TI - Bilayer hydroxyapatite scaffolds for maxillofacial bone tissue engineering. AB - PURPOSE: The frequency of alveolar ridge resorption and crestal bone loss emphasizes the clinical need for bone graft substitutes to improve local bone quality prior to dental implant placement. Microcomputed tomography has been extensively employed to estimate bone quality more objectively (ie, quantitatively) by relating it to architectural parameters. In the present study, the mechanical properties of open cellular fully interconnected bilayer hydroxyapatite scaffolds, which mimicked the cortical shell/trabecular core architecture of human bone, were investigated for suitability as bone graft substitutes for maxillofacial reconstruction. MATERIALS AND METHODS: Hydroxyapatite scaffolds with different architectures were fabricated using polymeric template pore sizes of 450 or 340 MUm for the inner trabecular cores and 200 or 250 MUm for the outer cortical shells in three different core-to-shell volume ratios. The architectural and mechanical properties and fluid permeability of the scaffolds were compared to reported values for maxillofacial bone. RESULTS: Whereas the elastic moduli of the scaffolds were comparable, their compressive strength was observed to be in the lower range of human mandibular trabecular bone. The microcomputed tomography architectural indices for the scaffolds were comparable to those of human trabecular bone at different locations in the human body, including the maxilla and mandible. Scaffold compressive strength, elastic modulus, and fluid conductance were 0.3 to 2.3 MPa, 40.9 to 668.1 MPa, and 8.8 to 49.9 x 10-10 m3s-1Pa-1, respectively. CONCLUSION: Open-pore bilayer scaffolds can be fabricated to exhibit sufficient mechanical integrity for maxillofacial bone graft applications to match specific bone site architecture while providing sufficient permeability to sustain bone regeneration. PMID- 22442767 TI - Bone-implant interface with simulated insertion stress around an immediately loaded dental implant in the anterior maxilla: a three-dimensional finite element analysis. AB - PURPOSE: The purpose of the present study was to investigate the stress distribution around the bone-implant interface and the effect of the length of an immediately loaded implant in the anterior maxilla using a finite element model with simulated loading stresses. MATERIALS AND METHODS: Four-mm-diameter external hex implants with different lengths (8.5, 10.0, 11.5, 13.0, and 15.0 mm) were used in this study. The anterior maxilla was assumed to be D3 bone quality. All of the material was assumed to be homogenous, isotropic, and linearly elastic. Average bone deformation during implant placement was calculated through the simulation process, and using this, insertion stress was created. The bone implant interface was constructed using a contact element to simulate a nonosseointegrated condition. Then, 176 N of static force was applied at the middle of the palatoincisal line angle of the abutment at a 120-degree angle to the long axis of the abutment. The von Mises stresses were measured at intervals of 0.25 mm along the bone-implant interface. RESULTS: Prior to loading, the stresses were evenly distributed around the implant and highly concentrated in the cortical area. When the load was applied, von Mises stresses were concentrated in the cortical bone of the implant neck area. More favorable stress distribution was seen with increasing implant length. However, when the implant length reached 15.0 mm, the stresses increased. CONCLUSIONS: In the maxilla, when immediate loading is applied after implant placement, 11.5- and 13.0-mm-long single implants showed more favorable stress patterns than the others analyzed. If implants longer than 15.0 mm are used in immediate loading, sufficient bone volume in the recipient site should be considered an important factor. PMID- 22442768 TI - Influence of abutment screw preload on stress distribution in marginal bone. AB - Changes in an implant assembly after abutment connection might possibly cause deformation in the implant/abutment joint and even in the marginal bone. PURPOSE: The aim of this study was to evaluate the influence of abutment screw preload through the implant collar on marginal bone stress without external load application. MATERIALS AND METHODS: Models of three implant parts made of titanium (implant, abutment, and abutment screw) and cortical bone were built and positioned with computer-aided design software. Meshing and generation of boundary conditions, loads, and interactions were performed. Each part was meshed independently. The sole load applied to the model was a torque of 32 Ncm on the abutment screw about its axis of rotation. RESULTS: The implant collar was deformed axially after the screw was tightened (3 MUm). This deformation resulted in 60 MPa of stress in the marginal bone. Moreover, pressure on the marginal bone in a radial direction was observed. CONCLUSIONS: It can be concluded that, without any external load application, abutment screw preload exerts stresses on the implant collar and the marginal bone. These findings should help guide the development of new implant/abutment joint designs that exert less stress on the marginal bone. PMID- 22442769 TI - Effects of 10 cleaning instruments on four different implant surfaces. AB - PURPOSE: The aim of this study was to evaluate the effects of a variety of implant cleaning instruments on different implant surfaces, specifically surface roughness and cleaning efficacy. MATERIALS AND METHODS: Biofilm layers of Streptococcus mutans were cultivated on titanium disks with four different surface structures (polished, grit-blasted, acid-etched, and acid-etched/grit blasted). Five disks each were cleaned using nine mechanical implant cleaning instruments or an erbium:yttrium-aluminum-garnet laser. Surface roughness (average, Ra; maximum, Rz) and waviness (Lr) were evaluated by two-dimensional laser profilometry. Surface structure damage and cleaning scores were assessed by scanning electron microscopy. Statistical analyses of the results were performed with one- and two-way analyses of variance and Bonferroni-Dunn multiple comparison post hoc analysis (alpha = .05). RESULTS: Ra and Rz values for the acid-etched surfaces and Ra, Rz, and Lr values for the polished and the grit blasted surfaces showed no significant differences between the different cleaning methods or cleaning instruments compared to the control (not cultured, not cleaned) groups. Significantly lower Ra and Rz values on grit-blasted/acid-etched implant surfaces were found following use of the Sonic-Flex clean with prophylaxis brush and the plastic curette compared to Satelec ProphyMax with Periosoft curette. Ra and Rz values of the different implant structure surfaces before cleaning were significantly different between all implant surfaces except for the polished compared to the acid-etched surfaces. CONCLUSIONS: Cleaning effect and alterations of the implant surfaces were strongly dependent on the implant cleaning method used. PMID- 22442770 TI - In vitro validation of a novel diagnostic device for intraoperative determination of alveolar bone quality. AB - PURPOSE: Current methods for the evaluation of alveolar bone quality and dental implant stability have been shown to provide inconsistent results. The aim of this investigation was to validate a novel diagnostic device (BoneProbe) for the objective classification of alveolar bone during dental implant surgery. MATERIALS AND METHODS: A metal cylinder (diameter, 3.5 mm) split into six segments was used as a sensor that could be positioned in implant sockets and expanded while the force needed to expand the site was recorded. Simulating all surgical steps, implants were placed into polyurethane foam materials (n = 100 implants) and human cadaver bone (n = 110 implants). Bone quality (cortical bone thickness, trabecular bone density, drilling resistance, implant insertion torque, compressive testing) and primary implant stability (Osstell, Periotest) were evaluated as reference data. RESULTS: In polyurethane foam, significant correlations between all parameters (Pearson correlation coefficients) and a significant influence of the different polyurethane foam materials on all measurement results (multiple analysis of variance with Pillai trace) were found. In general, in human cadaver bone, weaker correlations between the different measurement techniques were seen (Pearson product-moment correlation). With the exception of compressive testing and radiographic assessment of trabecular bone density, all methods were able to differentiate between mandibular and maxillary bone. CONCLUSIONS: Based on these in vitro results, it appears that intraoperative testing of alveolar bone allows for a reproducible classification of bone quality. Because the proposed system is independent of any specific implant design, this device could be used for establishing a universally valid bone classification system. PMID- 22442771 TI - Distribution of occlusal forces during occlusal adjustment of dental implant prostheses: a nonlinear finite element analysis considering the capacity for displacement of opposing teeth and implants. AB - PURPOSE: The purpose of this study was to investigate the influence of occlusal forces (the contractile forces of the masticatory muscles) during occlusal adjustment on the distribution of forces on combinations of implants and teeth during intercuspal clenching by means of finite element analysis. MATERIALS AND METHODS: Three-dimensional finite element models of the mandible, one with two implants in the molar region and the other with four implants in the premolar and molar regions, were constructed. Linearly elastic material properties were defined for all elements except the periodontal ligament, which was defined as nonlinearly elastic. The temporomandibular joints and antagonists were simplified and replaced with nonlinear springs. Antagonists were assumed to be a natural tooth or an implant and had two- or three-stage displaceability (ie, very high displaceability under tension and when the displacement was smaller than the clearance assumed to be made by occlusal adjustment, but displaceability of the antagonists themselves when the displacement was greater than the clearance). The clearance by occlusal adjustment was decided beforehand with a trial-and-error method so that the occlusal forces were distributed symmetrically under a prescribed load. Each model was evaluated under loads of 100 N, 200 N, and 800 N for the distribution of occlusal forces on the teeth and implants. RESULTS: In the case of occlusal adjustment under the total occlusal force of 40 N, the stress was concentrated at the most posteriorly located implant in all models under all loading conditions. This concentration was reduced in the case of occlusal adjustment under the total occlusal force of 200 N, except under a load of 800 N. CONCLUSION: Hard biting appeared to be better for occlusal adjustment to avoid overloading of the most posterior implant. PMID- 22442772 TI - Bone regeneration with algae-derived hydroxyapatite: a pilot histologic and histomorphometric study in rabbit tibia defects. AB - PURPOSE: Algipore is a biologic hydroxyapatite derived from calcifying maritime algae. The present study evaluated this material histologically and histomorphometrically after implantation in rabbit tibia defects for 4 weeks. MATERIALS AND METHODS: Six New Zealand rabbits were used in this study. In each rabbit tibia, two 7-mm defects were prepared. Control defects were left empty, and test defects were filled with Algipore. Twenty-four specimens (12 test and 12 control) were retrieved and processed for histology. RESULTS: In control sites, newly formed trabecular bone with large marrow spaces was plentiful in the most peripheral areas of the defects but sparse elsewhere. In contrast, in test sites, a large quantity of newly formed bone around the biomaterial particles was detected in the central medullary portion of the defect. In addition, in several areas, the biomaterial particles were bridged by newly formed bone. The percentage of contact between newly formed bone and biomaterial particles was 71.2% +/- 9.8%. Inside the central portion of the biomaterial particles, it was possible to see newly formed bone (about 35.3% +/- 4.8% in each particle). In test sites, newly formed bone represented 31.1% +/- 1.9% of the material, with residual biomaterial particles occupying 33.4% +/- 2.8% and marrow spaces another 34.7% +/- 4.3%. In the control sites, the values were 30.2% +/- 2.2% for newly formed bone and 68.7% +/- 4.1% for marrow spaces. A statistically significant difference was found in the percentage of marrow space between the two groups, but no significant difference was observed in the percentage of newly formed bone. CONCLUSIONS: The present rabbit study confirmed the high osteoconductivity and resorbability of this biomaterial. PMID- 22442773 TI - A strain gauge analysis of microstrain induced by various splinting methods and acrylic resin types for implant impressions. AB - PURPOSE: The aim of this study was to investigate the level of microstrain that is exerted during polymerization of acrylic resins used for splinting during implant impressions. MATERIAL AND METHODS: Two acrylic resins (GC Pattern Resin, Duralay II) and square transfer coping splinting methods were evaluated by means of strain gauge analysis. Two implants were embedded in a polyurethane block, and the abutments were positioned. Sixty specimens were prepared using two square transfer copings that were rigidly connected to each other using the acrylic resins. The specimens were randomly divided into three groups of 20 each for the splinting methods: Method 1 was a one-piece method; in method 2, the splint was separated and reconnected after 17 minutes; and in method 3, the splint was separated and reconnected after 24 hours. In each group, half the specimens were splinted with GC Pattern Resin and the other half were splinted with Duralay II. Three microstrain measurements were performed by four strain gauges placed on the upper surface of the polyurethane blocks at 5 hours after resin polymerization for all groups. The data were analyzed statistically. RESULTS: Both resin type and splinting method significantly affected microstrain. Interaction terms were also significant. Method 1 in combination with Duralay II produced significantly higher microstrain (1,962.1 MUepsilon) than the other methods with this material (method 2: 241.1 MUepsilon; method 3: 181.5 MUepsilon). No significant difference was found between splinting methods in combination with GC Pattern Resin (method 1: 173.8 MUepsilon; method 2: 112.6 MUepsilon; method 3: 105.4 MUepsilon). CONCLUSIONS: Because of the high microstrain generated, Duralay II should not be used for one-piece acrylic resin splinting, and separation and reconnection are suggested. For GC Pattern Resin, variations in splinting methods did not significantly affect the microstrain created. PMID- 22442774 TI - Evaluation of implant-abutment microgap and bacterial leakage in five external hex implant systems: an in vitro study. AB - PURPOSE: The aim of the present study was to verify the presence of a microgap between implants and prosthetic abutments on their external surfaces in five different external-hex implant systems and to determine whether bacterial leakage occurs through the implant-abutment (I-A) interface. MATERIALS AND METHODS: Ten samples of each implant system were used. Eight samples of each implant system were inoculated with 0.3 MUL of a suspension of Escherichia coli for bacterial leakage evaluation. Two other samples were used as controls. Sample analysis was accomplished at 24 and 48 hours and on the 5th, 7th, and 14th day after inoculation. After microbiologic analysis, all samples were prepared for I-A interface evaluation by scanning electron microscopy. The mean of the microgap misfit was obtained from six points at x1,000 and x3,000 magnifications. RESULTS: The Neodent implant system (0.51 +/- 0.39 MUm) showed the closest adaptation, followed by Dentoflex (1.44 +/- 0.73 MUm), Titanium Fix (1.88 +/- 1.28 MUm), SIN (2.46 +/- 3.38 MUm), and Conexao (2.68 +/- 3.02 MUm). Twenty-five percent of the Dentoflex samples showed bacterial leakage through the I-A interface; no other implant system presented bacterial leakage. CONCLUSION: The width of the microgap at the I-A interface was less than 3 MUm in all systems. A direct correlation between bacterial leakage and I-A interface misfit was not observed. PMID- 22442775 TI - Osseointegration of zirconia implants with different surface characteristics: an evaluation in rabbits. AB - PURPOSE: Zirconia ceramics are a viable alternative to titanium for use as dental implants. However, the smooth surface of zirconia means that longer healing periods are needed to accomplish osseointegration compared to roughened titanium surfaces. Surface modifications can be used to increase the roughness of zirconia. The aim of this study was to assess histologically and compare the degree of early bone apposition around zirconia dental implants with sandblasted, sintered, or laser-modified surfaces to that seen around surface-modified titanium implants. Removal torque was also measured and compared. MATERIALS AND METHODS: Ninety-six implants--24 each of four types (sintered zirconia, laser modified zirconia, sandblasted zirconia, and acid-etched titanium)--were placed in 48 New Zealand White female rabbits. One implant was inserted in each distal femur. Half of the specimens were harvested at 6 or 12 weeks and processed for light microscopic analysis; the area of bone-to-implant contact was measured morphometrically. The other half were evaluated for removal torque at 6 and 12 weeks. RESULTS: No statistically significant differences existed in bone apposition between the different surfaces at either time point. Differences in removal torque were significantly different between titanium and sandblasted zirconia and between sintered zirconia and sandblasted zirconia, with the first mentioned demonstrating a higher torque value at 6 weeks. At 12 weeks, the only significant difference in removal torque was between titanium and sandblasted zirconia, with titanium demonstrating the higher value. CONCLUSION: Comparable rates of bone apposition in the zirconia and titanium implant surfaces at 6 and 12 weeks of healing were observed. Removal torque values were similar for all implants with a roughened surface. PMID- 22442776 TI - Sinus elevation with a cortical bone graft block: a patient-specific three dimensional finite element study. AB - PURPOSE: The aim of the present study was to perform a finite element (FE) analysis of a modified sinus elevation procedure involving additional implantation of a cortical bone graft block for stabilization of an implant. A secondary aim was to compare the modified sinus augmentation with the standard technique and to determine whether the FE model to replace a dental implant can be simplified into a cylinder without compromising the accuracy of the outcome. MATERIALS AND METHODS: Based on computed tomography data, three-dimensional FE models of half of a maxilla were created. A basic model was generated to analyze a conventional sinus elevation procedure and another was created for the modified version, which involved insertion of a cortical bone graft block. Two implant models were used in the premolar region: a typical threaded endosseous dental implant and a simplified 4 x 10-mm cylinder. Occlusal loads were applied in axial, mediotrusive, and laterotrusive directions, and perfect bonding was assumed to be present at all interfaces. RESULTS: The maximum von Mises stresses were significantly lower for the sinus graft models with added cortical bone than for the conventional sinus elevation under all types of loads. No significant difference was observed between the use of threaded implants and the simplified implant cylinders. CONCLUSION: The addition of a cortical bone graft may be a useful approach to decrease stresses around implants placed into the grafted sinus. PMID- 22442777 TI - Bone responses to simvastatin-loaded porous implant surfaces in an ovariectomized model. AB - PURPOSE: The purpose of this study was to investigate bone responses to simvastatin-loaded porous implant surfaces in an ovariectomized model. MATERIALS AND METHODS: Roughened implants were divided into a control group (n = 32), test group 1 (n = 32), and test group 2 (n = 32). Test implants were immersed into 10?7 mol/L (test group 1) or 10?6 mol/L (test group 2) simvastatin solutions for drug adsorption onto implant surfaces. Forty-eight ovariectomized rats randomly received an implant in each tibia. One, 2, 4, and 12 weeks later, the tibiae were retrieved and prepared for histomorphometric evaluation. Bone-to-implant contact and bone area around the implant were determined, and histologic observations were made. RESULTS: New bone formation on test implant surfaces was seen after 1 week, while it was seen on the control implant surface after 2 weeks. There was more bone tissue and bone-to-implant contact along the test implant surfaces than along the control implant surface. The test group 1 and test group 2 implants showed significantly greater bone area and bone-to-implant contact compared to the control implant at all observed time points (P < .05). No differences were found between the two types of test group implants after 1, 2, 4, and 12 weeks (P > .05). CONCLUSION: Simvastatin-loaded porous implant surfaces have the potential to improve implant osseointegration in an ovariectomized rat model. PMID- 22442778 TI - Utility of bispectral index monitoring during intravenous sedation in the dental office. AB - PURPOSE: This research sought to compare two different systems to monitor sedated patients undergoing implant surgery in the dental office: the bispectral index (BIS) and the Ramsay scale. This information was used to establish an optimal BIS range for surgery in these patients and to calculate differences in drug consumption in both groups. MATERIALS AND METHODS: Consecutive patients undergoing implant surgery were studied and randomly assigned to two groups. Patients were sedated using intravenous propofol, fentanyl, and midazolam. The sedation level in group A was measured using the Ramsay scale. In group B, the Ramsay scale and the BIS were used together. Heart rate, blood pressure, and peripheral oxygen saturation were monitored in all patients. The levels of anxiety, satisfaction, and drug consumption were compared between groups. RESULTS: Forty-three patients were included; 20 were placed in group A and 23 were included in group B. There were no differences in the hemodynamic and respiratory parameters monitored or in anxiety or satisfaction levels in both groups. In group B patients, the BIS values stabilized around 85; the Ramsay scale stabilized around 3 in both groups and remained at these levels until the end of the procedure. Drug consumption was significantly lower in the BIS group. CONCLUSION: The optimal BIS value during intravenous sedation in sedated ambulatory patients in dental surgery should be within the 80 to 85 range. BIS monitoring allows for reduced consumption of propofol, fentanyl, and midazolam. PMID- 22442779 TI - Dental implant thread pitch and its influence on the osseointegration process: an in vivo comparison study. AB - PURPOSE: The design of an implant plays a fundamental role in the osseointegration process, particularly in low-density bone. It has been postulated that design features that maximize the surface area available for contact may improve mechanical anchorage and primary stability in cancellous bone. Two different implant profiles were compared to evaluate the influence of thread pitch on the osseointegration process in bone of low density and limited height. MATERIALS AND METHODS: "Narrow-pitch" implants (NP) with a 0.5-mm pitch and "wide-pitch" implants (WP) with a 1.7-mm pitch were tested for osseointegration after 0 days and 4 and 8 weeks in a sheep iliac crest model. The two different implants were analyzed with biologic and biomechanical tests. RESULTS: The present findings showed that initial mechanical anchorage and subsequent early endosseous integration in low-density bone could be improved by a reduction of thread pitch. The greater surface area gained by decreasing thread pitch increased bone-implant contact and primary stability from the time of implant placement. This better performance of the NP profile could be appreciated even at an early healing time when the subsequent biologic integration was enhanced not only in terms of a higher quantity of newly deposited bone but also more regular and mature geometric distribution of bone tissue at the interface. CONCLUSION: These results confirmed that, when primary stability is a concern, as in cancellous bone, increasing the implant surface area by using implants with smaller pitch might be beneficial. PMID- 22442780 TI - Horizontal and vertical dimensional changes of peri-implant facial bone following immediate placement and provisionalization of maxillary anterior single implants: a 1-year cone beam computed tomography study. AB - PURPOSE: This cone beam computed tomography study (CBCT) evaluated horizontal and vertical dimensional changes to the facial bone following maxillary anterior single immediate implant placement and provisionalization. MATERIALS AND METHODS: CBCT scans taken immediately after (T1) and 1 year after surgery (T2) were evaluated. The midsagittal cut of each implant was identified, and measurements were made at predetermined levels. Horizontal facial bone thickness (HFBT) was measured at 0, 1, 2, 4, 6, 9, and 12 mm apical to the implant platform. Vertical facial bone level (VFBL) was the perpendicular distance from the implant platform (0) to the most coronal point of the facial bone. Measurements were recorded and changes between T1 and T2 were calculated. The data were analyzed statistically at a significance level of alpha = 0.05. RESULTS: CBCT scans of 21 patients were analyzed. At T2, the mean HFBT changes ranged from -1.23 to -0.08 mm at the seven different levels evaluated. The mean VFBL change was -0.82 mm. The HFBT changes at the 1- to 9-mm levels were not significantly different from one another, but they were significantly smaller than the change at the 0-mm level and significantly greater than the change at the 12-mm level. Significant positive correlations were observed only between horizontal and vertical changes and between horizontal change and initial VFBL at the implant platform. While the VFBL of eight implants (38%) was apical to the implant platform at T2, none was noted at T1. CONCLUSIONS: Dimensional changes to the peri-implant facial bone following maxillary anterior single immediate implant placement and provisionalization should be expected. The greatest HFBT change was noted at the implant platform level, in part because HFBT change is correlated to the initial VFBL and the change in VFBL at that level. PMID- 22442781 TI - Porous titanium granules in the surgical treatment of peri-implant osseous defects: a randomized clinical trial. AB - PURPOSE: Porous titanium granules (PTG) may have potential as an osteoconductive bone graft substitute to treat peri-implant osseous defects. The aim of this study was to analyze clinical and radiographic outcomes of peri-implant osseous defects after treatment with PTG. MATERIALS AND METHODS: This prospective, randomized, case-control, clinical 12-month study compared open-flap debridement and surface decontamination with titanium curettes and 24% ethylenediaminetetraacetic acid gel (n = 16) to the same protocol but with the addition of PTG (n = 16). One-, two-, and three-wall infrabony defects were included. Patients were given amoxicillin and metronidazole 3 days before surgery and for 7 days afterwards. Implants were submerged and allowed to heal for 6 months. Probing pocket depths, bleeding on probing, implant stability using resonance frequency analysis, and radiographic evaluation were performed at baseline and at 12 months. The threshold for significance was set at .05. RESULTS: Change in radiographic defect height and percent fill of the peri implant osseous defect significantly favored patients treated with PTG. Both treatment modalities demonstrated significant improvements in probing pocket depth, but significant differences between groups were not observed. The PTG treated implants showed an increase in implant stability quotient (ISQ) of 1.6 units, compared with a decrease of 0.7 ISQ for the control group. No adverse effects were associated with PTG treatment. CONCLUSIONS: Reconstruction with PTG resulted in significantly better radiographic peri-implant defect fill compared with controls; however, the results do not necessarily imply reosseointegration or osseointegration of PTG particles. Improvements in clinical parameters were seen in both groups, but no differences between groups were demonstrated. PMID- 22442782 TI - Implant site development by orthodontic forced extraction: a preliminary study. AB - PURPOSE: To evaluate the soft and hard tissue response to orthodontic implant site development (OISD) (ie, forced extraction), to measure the amount of tissue that was regenerated and its relationship to the amount of orthodontic vertical tooth movement, to evaluate the tissue response in teeth with different degrees of periodontal attachment loss, to understand the limits of OISD, and to evaluate the implant survival rate. MATERIALS AND METHODS: A total of 32 hopeless teeth were treated with OISD, and 27 implants were placed in 13 patients consecutively. The level of periodontal attachment on the teeth to be extracted, amount of augmented alveolar bone, changes in soft tissue volume, and the rate of orthodontic tooth movement were recorded. RESULTS: Mean values after OISD were as follows: orthodontic extrusive movement, 6.2 +/- 1.4 mm; bone augmentation, 4 +/- 1.4 mm; coronal movement of the gingival margin, 3.9 +/- 1.5 mm; coronal movement of the mucogingival junction, 2.1 +/- 1.3 mm; keratinized gingival augmentation, 1.8 +/- 1.1 mm; gingival thickness (buccolingual dimension) augmentation, 0.7 +/- 0.4 mm; recession, 1.8 +/- 1.2 mm; bone augmentation/orthodontic movement ratio (efficacy), 68.9% +/- 17.3%; gingival augmentation/orthodontic movement ratio (efficacy), 65.2% +/- 19.9%; and pocket depth reduction, 1.8 +/- 0.9 mm. The implant survival rate was 96.3%. CONCLUSIONS: OISD was a viable treatment for these hopeless teeth to regenerate hard and soft tissues. Its efficacy was about 70% for bone regeneration and 60% for gingival augmentation. The residual attachment level on the tooth was not a limitation. OISD might be a valuable treatment option to regenerate tissues for implant site development in patients in need of conventional orthodontic therapy. PMID- 22442783 TI - A retrospective comparison of 1,022 implants: immediate versus nonimmediate. AB - PURPOSE: The aim of this study was to compare the survival of implants placed in mature bone with the survival of implants placed in fresh extraction sockets in the same patients. MATERIALS AND METHODS: A retrospective study of patients treated simultaneously with at least one immediate and one nonimmediate implant was carried out for the period 2005 to 2008. Data were recorded for patient age and sex; implant length, diameter, and position; and, for postextraction implants, distance between the implant and the alveolar bone. RESULTS: One thousand twenty-two implants were placed in 150 patients; 480 were placed immediately and 542 were placed in mature bone. The mean implant survival rate was 93.4%; survival rates were 93.8% for immediate implants and 93.2% for nonimmediate implants. The failure rate in the maxilla was 5.2% and in the mandible it was 2.8%. The failure rate for immediate implants in the posterior maxilla was 8.5%, which was statistically significantly higher than for implants placed elsewhere. Of the failed implants, 72% were early failures. CONCLUSIONS: The survival rate of implants placed in fresh extraction sockets was similar to that of implants placed in mature bone. A statistically significantly higher failure rate was seen with immediate implants placed in the posterior maxilla. PMID- 22442784 TI - A clinical study of edentulous patients rehabilitated according to the "all on four" immediate function protocol. AB - PURPOSE: The aim of this study was to compare definitive acrylic resin prostheses with or without a cast metal framework that were immediately loaded and supported by axial and tilted implants in completely edentulous patients after 3 years of function. MATERIALS AND METHODS: Patients who were completely or partially edentulous in one or both arches with severe atrophy of the posterior regions were selected for this study. All patients immediately received prosthetic rehabilitations, each supported by four implants (two axial and two tilted). The patients were randomized to receive a definitive prosthesis with a cast metal framework or one made of acrylic resin only. Follow-up visits were performed up to 36 months after implant insertion and included radiographic assessments of bone levels around the implants. RESULTS: Thirty-six patients participated, and 44 complete-arch immediately loaded prostheses (24 maxillary and 20 mandibular), each supported by four implants (in total 176 implants), were placed. In all, 21 screw-retained full-arch acrylic resin prostheses and 23 cast-metal-framework prostheses were delivered to the patients. The 3-year overall implant survival rate was 100% for axially positioned implants and 96.59% for tilted implants. Implant survival rates were 98.96% in the maxilla and 97.5% in the mandible. None of the 44 fixed prostheses were lost during the observation period, representing a prosthetic survival rate of 100%. No statistically significant differences were seen in crestal bone loss between tilted and axial implants at 12, 24, and 36 months in either arch. CONCLUSIONS: The same clinical outcome was seen for patients treated with the so-called All on Four protocol, regardless of whether the acrylic resin restorations were reinforced with metal. PMID- 22442785 TI - A randomized, controlled clinical evaluation of a synthetic gel membrane for guided bone regeneration around dental implants: clinical and radiologic 1- and 3 year results. AB - PURPOSE: The objective of this study was to determine whether a synthetic bioresorbable polyethylene glycol (PEG) hydrogel membrane could provide similar clinical and radiographic outcomes as a standard collagen membrane, both in combination with a membrane-supporting material, during follow-up periods of 1 and 3 years. MATERIALS AND METHODS: This study enrolled patients requiring implant treatment with an expected osseous defect in the posterior maxilla or mandible. Defects around the implants were grafted with deproteinized bovine bone mineral and covered with either a collagen membrane or a PEG hydrogel membrane, which is applied as a liquid and becomes a solid gel in situ. Surgical re-entry was performed after 6 months, and fixed partial dentures were inserted subsequently. Patients were examined clinically and radiographically 1 and 3 years after loading. RESULTS: Thirty-six of the 37 included patients were reexamined in the third year. The implant survival rate at 3 years was 100%. The peri-implant tissues were healthy, with no differences between the two groups. Compared to the time of surgery, the mean changes in the distance between the first bone-to-implant contact to the transition point (ie, rough implant surface to polished neck portion) were 0.43 +/- 0.56 mm (PEG) and 0.21 +/- 0.36 mm (collagen) at 1 year and 0.61 +/- 0.89 mm (PEG) and 0.33 +/- 0.64 mm (collagen) at 3 years. The respective differences between groups were 0.13 mm (1 year) and 0.31 mm (3 years), which were not significant at either time point (analysis of covariance). CONCLUSION: The tested PEG hydrogel was as successful as a standard collagen membrane for the treatment of bony dehiscence defects around dental implants after follow-up periods of 1 and 3 years. PMID- 22442786 TI - The use of tapered implants in the maxillae of periodontally susceptible patients: 10-year outcomes. AB - PURPOSE: This study is a retrospective assessment of the long-term efficacy of dental implant therapy in periodontally susceptible patients. MATERIALS AND METHODS: A private-practice chart review was conducted to identify partially dentate subjects treated with implant-supported restorations that had been monitored annually for at least 9.5 years. Subjects were assigned to either a periodontal group or a control group according to their health histories. Data were entered into spreadsheets on a personal computer and analyzed statistically with dedicated software. RESULTS: Thirty periodontal subjects were treated with 138 implants and 45 prostheses, and 16 control subjects were treated with 35 implants and 21 prostheses. The mean follow-up was 130 months. One implant failed before loading in the periodontal group. Cumulative 10-year survival rates were 99.3% (n = 137/138) for periodontal implants and 100% (n = 35/35) for control implants. Most surviving implants had no bone loss (n = 109/172, 63.4%). Most of the surviving implants with bone loss (n = 63/172, 36.6%) were concentrated in the periodontal cohort (90%, n = 57/63) and among women (60%, n = 15/25) regardless of cohort. Prosthesis failure was 25.2% (n = 16/66), with 12 porcelain fractures, 2 cement failures, and 2 framework fractures. In all cases, failed prostheses were immediately replaced and patients continued to function. CONCLUSIONS: Periodontal susceptibility resulted in increased bone loss but did not affect implant survival. The cause of greater bone loss in women could not be determined from the data but may have been related to the postmenopausal status of the subject population (mean age = 54 years). PMID- 22442787 TI - Incidence, diagnosis, and treatment of sinus graft infection after sinus floor elevation: a clinical study. AB - PURPOSE: The aims of this clinical study were to evaluate the occurrence of sinus graft infection and the results of a planned surgical and pharmacologic treatment regimen to eliminate infections and preserve the graft. MATERIALS AND METHODS: Patients were consecutively treated with sinus floor elevations using the lateral window technique. If a clinical diagnosis of sinus graft infection was made for a patient, a postoperative computed tomographic scan was performed to diagnose involvement of the sinus cavity. RESULTS: Of 198 patients treated with 274 sinus grafts, 8 (2.3%) developed a sinus graft infection. These patients were treated with the same surgical and pharmacologic regimen. Symptoms of infection were recognized, the infected graft was removed, and the remaining graft material was cleansed. The remaining defect was not filled with new graft material; instead, it was left to heal for an extended healing period (average of 10.6 months), and residual bone defects were corrected during implant placement. Acute symptoms of infection disappeared within 48 hours of treatment and all patients healed uneventfully thereafter. All 24 implants placed have survived to date (with implant loading times ranging from 1 to 9 years), resulting in a 100% implant survival rate for these sites with postoperative infection. CONCLUSIONS: The overall clinical outcome, including patient satisfaction, achievement of optimal graft volume without subsequent sinus elevation, and long-term implant survival, confirmed the success of this treatment protocol. PMID- 22442788 TI - Three-year prospective multicenter study evaluating marginal bone levels and soft tissue health around a one-piece implant system. AB - PURPOSE: The aim of this clinical investigation was to evaluate marginal bone remodeling and soft tissue health surrounding a novel one-piece implant system over a 3-year study period. MATERIALS AND METHODS: Subjects missing at least one tooth in either arch were consecutively enrolled in this open prospective 3-year investigation. Five clinics were invited to participate. Strict inclusion and exclusion criteria were used. Marginal bone levels were evaluated using radiographs taken at implant insertion, 6 months, and annually thereafter. Plaque and bleeding indices were recorded at 3 and 6 months and 1 and 3 years following implant insertion. The shapes of papillae were evaluated at implant insertion with the provisional restoration in place, at the insertion of the definitive restoration, and at the 3-year follow-up, using Jemt's papilla index. Life tables and the Mann-Whitney U test were used for statistical analyses. RESULTS: Fifty six patients were restored with a total of 82 one-piece implants; 47 patients attended the 3-year appointment. One implant had to be removed 1 month postinsertion, giving a cumulative survival rate of 98.8% for the 3-year study period. Most bone resorption (mean, 1.19 +/- 1.38 mm; n = 61) occurred during the first year of function, while there was minimal change in mean marginal bone levels between 1 and 3 years (-0.07 +/- 1.07 mm; n = 58). Normal peri-implant mucosa was registered for more than 81% of the sites, and no visible plaque was registered for more than 54% of the sites. CONCLUSION: This prospective 3-year multicenter study showed stable marginal bone levels, good soft tissue health, and a high implant survival rate, supporting the hypothesis that the presented one-piece implant system has the capacity to maintain both hard and soft tissues after the first year of initial bone remodeling. PMID- 22442789 TI - Effect of laser irradiation on adrenoreactivity of pial arterial vessels in rats. AB - Experiments on WKY and SHR rats showed that low-intensity laser irradiation reduced the tone of pial arterial vessels thereby potentiating the subsequent constrictor effect of norepinephrine. Irradiation in the red region of the spectrum produced a more pronounced effect in the blue region. The observed effects were less pronounced in SHR rats compared to normotensive WKY rats. PMID- 22442790 TI - Mechanical properties of lymph node capsule. AB - We studied the relationship between the length and tension in isolated strips of the capsules of bovine mesenteric lymph nodes. The deformation-strain and radius pressure relationships were established in the lymph node. The capsule possesses high distensibility, modulus of elasticity at optimal tension was 0.09*10(5) N/m2. Smooth muscle activation produces a 6-fold increase of modulus of elasticity. Maximum active stress in the capsule was recorded at a length of 1.1 L0 and maximal active pressure (4.5 cm H2O) at 0.9 L0. PMID- 22442791 TI - Staging of hemodynamic parameters during development of experimental arterial hypertension in rabbits. AB - The study analyzed changes in parameters of the central and intracardiac hemodynamics during the development of experimental arterial hypertension, which were assessed as the adaptive in nature. The development of hypertension demonstrated staging of the adaptive processes. The development of the adaptive responses was characterized by changes in the magnitude and probabilistic distribution of the hemodynamic parameters. PMID- 22442792 TI - VCAM-1 expression on bone marrow stromal cells from patients with myelodysplastic syndromes. AB - We studied the expression of VCAM-1 adhesion molecules on stromal cells from the bone marrow of patients with myelodysplastic syndromes, healthy donors, and patients with chronic myeloproliferative diseases and acute leukemias. Expression of adhesion molecule on mesenchymal stromal cells from the bone marrow of patients and healthy donors was evaluated after 2-4 passages by the methods of immunoprecipitation and electrophoresis. VCAM-1 expression in the majority of patients with myelodysplastic syndromes was lower than in healthy donors. At the same time, VCAM-1 expression was not identified on mesenchymal cells from acute leukemia patients. VCAM-1 expression on cells from patients with chronic myeloproliferative diseases did not differ from that in healthy donors. We conclude that VCAM-1 synthesis in bone marrow stromal cells is impaired in patients with myelodysplastic syndromes and acute leukemias. These changes can be followed by the loss of relationships between hemopoietic cells and stromal microenvironment in bone marrow niches. Hemopoietic cells gain the ability for uncontrolled growth, which results in progression of the disease. PMID- 22442793 TI - Parameters of microcirculation in paired formations after single aspirin administration: laser Doppler flowmetry data. AB - Laser Doppler flowmetry showed that aspirin can induce blood flow reduction and transitory manifold increase or decrease in vascular tone in rat skin and kidneys. The dynamics is more illustrative when parameters of individual animals are evaluated and depends on the areas of blood flow recording. Deaths and reduction of narcotic sleep duration were noted in concomitant use of nembutal and aspirin. PMID- 22442794 TI - Content of total homocysteine and major aminothiols in rats with experimental renal ischemia. AB - The contents of total homocysteine, cysteine, and glutathione in blood plasma and tissue of rats with renal ischemia were measured by HPLC. Our study was performed on the "two-kidney, one-clip (0.13 mm)" model. The concentrations of homocysteine and cysteine in blood plasma from treated rats were higher than in sham-operated animals (control; by 36 and 14%, respectively). Homocysteine level in the intact and clipped kidneys of treated rats was 40% higher than in the control. However, no differences were found in homocysteine level in the ischemic and intact kidneys of treated animals. Cysteine concentration in the clipped kidney was lower than in the kidneys of intact and sham-operated animals (by 1.6 and 1.5 times, respectively). Glutathione concentration in the ischemic kidney did not differ from the control. No differences were revealed in the content of aminothiols in liver samples from rats of the treatment and control groups. Our results suggest that functional inactivation of one kidney is accompanied by impairment of homocysteine catabolism (trans-sulfonation). PMID- 22442795 TI - Activity of mitochondrial ATP-dependent potassium channel in animals with different resistance to hypoxia before and after the course of hypoxic training. AB - Activity of mitochondrial ATP-dependent potassium channel in rats with high genetically determined resistance to hypoxia was higher than in sensitive animals. Adaptation of low resistant rats to hypoxia was accompanied by activation of the channel, facilitation of potassium recycling in mitochondria, and a decrease in the rate of H2O2 formation. Our results indicate that mitochondrial ATP-dependent potassium channel plays an important role in the delayed mechanisms of animal's adaptation to hypoxia. PMID- 22442796 TI - In vitro effects of anandamide and prostamide e2 on normal and transformed nerve cells. AB - We studied the effects of endocannabinoid anandamide and its cyclooxygenase derivative prostamide E2 on cultured cerebellar granular cells and C6 glioma cells from rats. Prostamide E2 prevented apoptosis in cerebellar neurons induced by potassium deprivation of cultures, while anandamide had no neuroprotective properties. Prostamide E2 did not modulate the survival rate of glioma cells, while anandamide produced a cytotoxic effect. Our results indicate that cyclooxygenase transformation of anandamide is followed by the loss of antitumor activity of this agent. By contrast, prostamide E2 exhibited strong neuroprotective properties. PMID- 22442797 TI - Expression of P2X receptor subtypes on CD34+ cells and c-kit+ cells of human umbilical blood. AB - The presence of several subtypes of P2X receptors on early hemopoietic precursors (CD34+) from human umbilical blood was detected by flow cytometry. The expression of P2X receptors on umbilical blood lymphocytes was an order of magnitude higher than that on adult human blood cells. Our results attest to early involvement of P2X receptors in differentiation of human hemopoietic cells. PMID- 22442798 TI - Hematological and toxicogenomic effects of ferromagnetic screening of natural electromagnetic fields. AB - Aftereffects of ferromagnetic screening on the hematological and toxicogenomic parameters in rats were traced over 45 days. Two-day ferromagnetic screening of male and female rats (reducing permanent constituent of magnetic field induction by 4-10 MUT) led to leukopenia observed on day 14 of the experiment. Life-time evaluation of the toxicogenomic effects was carried out by rapid method for measurement of blood nucleotide DNA by fluorescent indication. In male blood leukocytes, increased aneuploidy and polyploidy were observed after 48 h of ferromagnetic screening and remained high on days 12 and 28 after screen removal. In contrast to males, leukocyte apoptosis in females was increased only 48 h after the start of ferromagnetic screening. PMID- 22442799 TI - Effects of afobazole on cognitive behavior of the offspring of rats exposed to tobacco smoke during gestation period. AB - Experiments on the model of foraging behavior formation under conditions of free choice (T-maze) revealed learning failure against the background of reduced motor activity in the offspring of rats exposed to tobacco smoke on gestation days 1 20. Afobazole administered to pregnant rats orally in doses of 1 or 10 mg/kg daily during the whole gestation and/or entering rat pup body with breast milk from mothers receiving 200 mg/kg to day 20 of their life normalized their learning capacity. The formation of short-term and long-term memory in animals receiving afobazole did not differ from the control. Hence, afobazole corrects cognitive disorders in rats exposed to tobacco smoke during prenatal development. PMID- 22442800 TI - Anxiety and predisposition to audiogenic epilepsy in rats of different genotypes. AB - We studied plus-maze behavior of inbred Krushinskii-Molodkina, Wistar, and black hooded rats (originating from the Long-Evans outbred strain) differing by predisposition to audiogenic seizures. The severity of audiogenic seizures partially correlated with anxiety and negatively correlated with the total level of locomotor activity in the elevated plus-maze. The anxiety parameters in Krushinskii-Molodkina rats were evaluated after injection of anticonvulsant levetiracetam and anxiolytic afobazol. Levetiracetam and afobazol somewhat stimulated locomotor activity. PMID- 22442801 TI - Psychoimmunomodulatory effect of phenotropil in animals with immune stress. AB - We studied the effect of phenotropil (25 mg/kg intraperitoneally, 5 days) on the immune and psychoemotional state of Wistar rats with LPS-induced immune stress. Hyperactivity of the immune system in animals after treatment with Pseudomonas aeruginosa LPS (100 MUg/kg intraperitoneally, 3 days) manifested in a significant increase in the delayed-type hypersensitivity index, antibody titer in the reaction of passive hemagglutination, and phagocytic activity of peripheral blood neutrophils. Locomotor, orientation, and exploratory activities were reduced, while anxiety increased in animals with immune stress. Phenotropil exhibited the psychoimmunomodulatory effect under these conditions, which manifested in prevention of anxiety and fear response, increase in horizontal locomotion and exploratory behavior, and improvement of immunoreactivity. PMID- 22442802 TI - Postvaccinal changes in the nitric oxide system after immunization with live dry tularemia vaccine. AB - Immunization of outbred male albino mice with live dry tularemia vaccine in a dose of 50 CFU/mouse was associated with stimulation of the NO system and accumulation of NO metabolites (nitrites and nitrates) in splenic and hepatic tissues. High levels of these metabolites persisted by day 14 after the initial and repeated immunization. These results suggest that the immunotropic effect of live dry tularemia vaccine manifested by not only modulation of the functions of immunocompetent T and B cells, NK and K cells, micro- and macrophages, but also by stimulation of intracellular anti-infection defense at the tissue level via intensification of NO synthesis. PMID- 22442803 TI - Experimental study of the effects of low-intensity monochromatic photodiode radiation and antitumor efficiency of cyclophosphamide injected with autoblood. AB - Experimental study of extracorporeal exposure of autoblood to red monochromatic photodiode radiation for improving antitumor efficiency of cyclophosphamide injected with autoblood was carried out on the model of sarcoma 45 cells ectopically transplanted to the lungs. Co-incubation of irradiated autoblood with cyclophosphamide and reinfusion of the blood to animals increased the antitumor efficiency of chemotherapy in animals with tumors. PMID- 22442804 TI - Effects of cisplatin on lymphocyte structure and functions in mice with ehrlich ascitic carcinoma. AB - The effects of cisplatin on [Ca2+]in, pHin, NAD(P)H level, and lymphocyte membrane microviscosity were studied in mice with Ehrlich ascitic carcinoma. The level of free [Ca2+]in in lymphocytes from mice with Ehrlich ascitic carcinoma was 4-fold reduced compared to that in intact animals on day 13 of tumor development, while [H+]in level was elevated. Cisplatin caused no changes in the level of free Ca2+, but reduced cytosol acidification. Lymphocyte membrane fluidity in mice with tumors was increased in the lipid bilayer and in the protein-lipid contact zone and did not depend on cisplatin treatment. The level of NAD(P)H was low in mice with tumors, but increased sharply after cisplatin treatment. It seems that functional activity of lymphocytes decreased at the stage of well-developed tumor, which promoted inhibition of the lymphocyte defense properties. Cisplatin did not modify the structure and functions of lymphocytes and presumably even improved their energy status. PMID- 22442805 TI - Site-specific binding of short peptides with DNA modulated eukaryotic endonuclease activity. AB - Short peptides (2-4 amino acid residues) inhibit or stimulate hydrolysis of lambda phage DNA by eukaryotic endonucleases WEN1 and WEN2 depending on DNA methylation status. Peptide modulation of endonucleases activity most likely appears as a result of their binding to DNA. Peptides discriminate (recognize) not only certain DNA sequences, but also their methylation status. Apart from intact DNA, the test peptides bind to single-stranded DNA structures (oligonucleotides) containing NG- and CG-sites methylated in eukaryotes. Peptides affect the set of hydrolyzed sites during endonuclease hydrolysis of double stranded structures. The effects of peptides with different primary structure on DNA hydrolysis by endonucleases are different and are modulated by histones (histone H1). Site-specific peptide interactions with DNA may epigenetically control genetic functions of the cell. These interactions probably played an important role at the very early stages of evolution. PMID- 22442806 TI - Age-specific peculiarities of formation of long-term posttetanic potentiation in OXYS rats. AB - OXYS rats with hereditary hyperproduction of active oxidative radicals and early disorders in the mitochondrial structure and functions are an interesting model for studies of age-specific features of synaptic plasticity. The formation of long-term posttetanic potentiation in the mossy fibers-CA3 pyramidal neuron system were studied in hippocampal slices from Wistar and OXYS rats aged 3 and 4.5 months (young), 11 (middle-aged), and 18 months (old). No appreciable age related differences were detected in the amplitudes and latencies of stimulatory postsynaptic summary potentials of the mossy synapses evoked by test stimuli in Wistar and OXYS rat groups of different age and between the two strains. The capacity to induction and formation of long-term posttetanic potentiation and its value decreased in 18-month-old Wistar rats, which attested to disorders in synaptic plasticity of old animals. The capacity to induction and formation of long-term posttetanic potentiation and its value in OXYS were lower than Wistar rats of the same age in all the studied groups. PMID- 22442807 TI - Mechanisms for hepatoprotective effects of hyaluronidase immobilized by the nanotechnology method of electron-beam synthesis. AB - Immobilized hyaluronidase (nanotechnology method of electron-beam synthesis) exhibited high hepatoprotective activity on the model of Cl4-induced hepatitis. This agent produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects were shown to accompany stimulation of multipotent bone marrow precursors, mobilization of these cells into the peripheral blood, and cell migration to the target organ increasing the number of parenchymal progenitor cells in the liver. The mechanisms for targeted migration of progenitor cells suggest a decrease in SDF-1 production by bone marrow stromal cells and increase in the synthesis of this factor by microenvironmental cells of the liver tissue. PMID- 22442808 TI - Effects of nanostructurized silicon on proliferation of stem and cancer cell. AB - In vitro experiments showed that stem and cancer cells retained their viability on the surface of porous silicon with 10-100 nm nanostructures, but their proliferation was inhibited. Silicon nanoparticles of 100 nm in size obtained by mechanical grinding of porous silicon films or crystal silicon plates in a concentration below 1 mg/ml in solution did not modify viability and proliferation of mouse fibroblast and human laryngeal cancer cells. Additional ultrasonic exposure of cancer cells in the presence of 1 mg/ml silicon nanoparticles added to nutrient medium led to complete destruction of cells or to the appearance of membrane defects blocking their proliferation and initiating their apoptotic death. PMID- 22442809 TI - Combined effects of blood serum as a source of endogenous beta-adrenoceptor sensitizing agent and its analogues histidine, tryptophan, tyrosine, mildronat, and preductal. AB - Human blood serum exhibiting beta-adrenoceptor-sensitizing activity does not prevent manifestation of similar activity of histidine, tryptophan, tyrosine, mildronat, and preductal. This opens prospects for the use of analogues of endogenous beta-adrenoceptor-sensitizing agent in clinical practice. PMID- 22442810 TI - Ultrastructure and stereology of cardiomyocytes in the development of regenerative and plastic myocardial insufficiency during ontogeny. AB - The age-related features of ultrastructural reorganization of cardiomyocytes were studied in rats with anthracycline-induced injury. The development of regenerative and plastic insufficiency of cardiomyocytes in animals of various age groups was accompanied by stereotypic ultrastructural reorganization. The major changes concerned the nucleus, myofibrillar compartment, and rough sarcoplasmic reticulum. Intracellular reorganization of cardiomyocytes in young animals was observed in the same period, but included a greater decrease in the volume density of myofibrils as compared to that in old rats. The recovery of cardiomyocyte ultrastructure in young animals occurred in the earlier period. Cardiomyocytes of old rats were characterized by greater structural modification of mitochondria and considerable area of lytic changes in myofibrillar bundles. Cardiotoxicity of doxorubicin in young animals was manifested in severe destruction of the capillary endothelium, which occurred in the early period after treatment. PMID- 22442811 TI - Morphological changes in the brain of mice with systemic candidiasis treated with composition of amphotericin B and oxidized dextran. AB - We observed morphological manifestation of encephalitis 3, 7, 10 and 28 days after intravenous infection of adult male CBA mice with Candida albicans. Compounds were administered intraperitoneally every other day starting from the next day postinfection. Untreated animals (100%) died over the period between days 18 and 20 postinfection; 60% animals receiving oxidized dextran alone survived by day 28 of observation. All animals treated with amphotericin B and composition of amphotericin B and oxidized dextran survived. On day 3 postinfection, the count of macrophage infiltrates and granulomas in the cerebral interstitium of mice treated with amphotericin B was equal to that in untreated mice, but was sufficiently lower in animals treated with the composition or oxidized dextran alone. On day 10, this index was similar in all groups and was approximately 5 times lower than in untreated animals on day 3. On day 28, macrophage infiltrates and granulomas were absent in the brain of all treated mice. These data suggest that oxidized dextran produced a therapeutic effect, which manifested earlier than the effect of amphotericin B and potentiated its effect, probably due to its competition with Candida albicans for mannose receptors on the brain-blood barrier endothelium. PMID- 22442812 TI - Morphofunctional characteristic of the immune system in BALB/c and C57BL/6 mice. AB - Inbred animals serve as an adequate model to study the role of genetic factors in adaptive, disadaptive, and pathological processes. Morphofunctional study of the immune system was performed on intact BALB/c and C57Bl/6 mice. The structural and functional parameters of the immune system in BALB/c and C57Bl/6 mice differ under physiological conditions. In BALB/c mice, volume density of T zone in the spleen and production of IL-2, IL-3, IL-4, IL-10, and TNF-alpha were much higher than in C57Bl/6 mice. However, IL-12 production in BALB/c mice was lower than in C57Bl/6 mice. C57Bl/6 mice were characterized by higher cytostatic activity of splenic NK cells. The observed interstrain differences are genetically determined and contribute to the type of adaptive processes and different sensitivity of these mice to pathogenic agents. PMID- 22442813 TI - Changes in neurons of medulla oblongata nuclei under conditions of chronic NO synthase inhibition. AB - Nucleus tractus solitarius and giant-cell and lateral reticular nuclei were studied using the reaction to NADPH-diaphorase in 7-, 10-, 14-, 30-, 45-, 60-day and 3- and 6-month-old rats receiving L-NAME (50 MUg/kg, 2 times a day) on days 1 6 of life. In 7-14-day-old rats, the compound reduced NO-synthase activity in the majority of NO-neurons and the total number and to a lesser degree the relative number of these neurons, while cell cross-section areas remained practically unchanged. The differences in the corresponding quantitative parameters between the control (D-NAME administration) and experimental groups decreased with time after the last L-NAME injection and became undetectable starting from the age of 30-45 days. In the nucleus tractus solitarius, the changes in metric parameters after exposure to NO-synthase inhibitor were more pronounced than in the reticular formation nuclei. PMID- 22442814 TI - Optimization of a method for preparation and repopulation of the tracheal matrix for allogenic transplantation. AB - A method for decellularization of the trachea for subsequent repopulation with allogenic MSC was optimized. Tracheas from C57BL/6 mice were devitalized and repopulated with MSC from BALB/c mice. The tracheal matrix with devitalized mucosa and intact cartilaginous structure, fit for repopulation with allogenic MSC, was obtained by chemical treatment with NaClO4. This approach seemed to be promising for transplantation of allogenic trachea. PMID- 22442815 TI - Isolation of insulin-producing cells from different populations of multipotent stromal cells of the umbilical cord and human adipose tissue. AB - Stromal cells of adipose tissue and human umbilical cord were isolated by the original method from general populations of multipotent subpopulation of multipotent stromal cells exhibiting perivascular phenotype (CD146+, CD31-). Effective directed differentiation of these cells into insulin-producing cells by transient transfection of the gene Pdx1 was demonstrated. Transfection multipotent stromal cells CD146-, CD31- derived from adipose tissue and umbilical cord and isolated by the standard method, did not result in activation of insulin gene transcription. It was shown that the expression of nestin was not necessary for effective pancreatic cell differentiation. PMID- 22442816 TI - Dynamics of elimination of plasmids and expression of VEGF121 gene transfected into human mesenchymal stem cells by different methods. AB - We compared two methods of transfection (lipofection and electroporation) with plasmid containing VEGF121 gene in four cultures of mesenchymal stem cells from the human adipose tissue. The efficacy of transfection after 1 day, the dynamics of plasmid elimination after 3, 6, 9 days, and expression of the target gene were evaluated. Transfection by both methods failed in one of 4 cultures. Analysis of the plasmid elimination dynamics showed that the content of plasmids introduced by both methods decreased by 30-69% in all cultures by day 3 and then remained unchanged from day 3 to day 9. The expression of the target gene did not correlate with the content of plasmids in cells and varied by 2-10 times in control cells and cells transfected by both methods. Fluctuation of VEGF121 expression was not related to methylation. PMID- 22442817 TI - Neurons and stromal stem cells as targets for polycation-mediated transfection. AB - Expression of transgenes in neurons and stromal/mesenchymal stem cells (MSC) can greatly enhance their therapeutic potential. In transfection experiments, we studied properties of linear and branched (dendrimers) polycations as transgene delivery vehicles. Linear polyethyleneimine transfected neurons, but was ineffective in MSC. Polyamidoamine dendrimers showed greater transfection efficiency and mean GFP fluorescence intensity compared to phosphorus dendrimers of the same (4th) generation. Expression of neurotrophic factor BDNF in MSC transfected with polyamidoamine dendrimers was also by more than 10 times higher. PMID- 22442818 TI - Mesenchymal stem cells restore orientation and exploratory behavior of rats after brain injury. AB - We studied the effects of intravenous and intracerebral transplantation of MSC on restoration of orientation and exploratory behavior of Wistar-Kyoto rats after removal of the left motor cortex. Removal of the motor cortex led to a significant reduction of the number of behavioral acts in the open field test. Two weeks after removal of the motor cortex and intravenous transplantation, the animals were as inhibited as the controls, but during the next 10 weeks, the behavioral status of these rats remained unchanged, while controls exhibited further behavioral degradation. After injection of MSC into the brain, the behavior of rats with trauma did not change in comparison with intact rats over 10 weeks. PMID- 22442819 TI - Multiplex analysis of cytokines, chemokines, growth factors, MMP-9 and TIMP-1 produced by human bone marrow, adipose tissue, and placental mesenchymal stromal cells. AB - Comparative analysis of mesenchymal stromal cells isolated from human BM, adipose tissue, and placenta was carried out. The cells were compared by the levels of constitutive, spontaneous, and LPS-induced production of Th1/proinflammatory (IFN gamma, IL-2, IL-1beta, TNF-alpha, IL-12, IL-17) and Th2/anti-inflammatory cytokines (IL-4, IL-5, IL-6, IL-10, IL-13), chemokines (IL-8, MCP-1, MIP-1beta), growth factors (IL-7, granulocytic CSF, granulocytic macrophageal CSF, erythropoietin, VEGF, EGF, IGF-1, main FGF), matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1. Mesenchymal stromal cells originating from different tissues were characterized by functional potential for hemopoiesis support (through production of granulocytic CSF, granulocytic macrophage CSF, erythropoietin), immunomodulation (through production of IFN-gamma, IL-2, IL-6, IL-1beta, TNF-alpha and chemokines IL-8, MCP-1, MIP-1beta), and stimulation of reparative processes (through production of VEGF, FGF, IGF-1, IL-6 tissue inhibitor of metalloproteinase-1, and matrix metalloproteinase-9). By the type and levels of spontaneous (basal) production of cytokines, the adipose tissue mesenchymal stromal cells more distinctly demonstrated the proinflammatory (IL 1beta TNF-alpha), immunoregulatory (IFN-gamma, IL-2, IL-4, IL-6, IL-8, MCP-1, MIP 1beta), and hemopoiesis-stimulating (granulocytic CSF, granulocytic macrophage CSF) phenotype and at the same time were characterized by lower sensitivity to lipopolysaccharide stimulation than BM and placental mesenchymal cells. PMID- 22442820 TI - Hepatogenic potential of human bone marrow and umbilical cord blood mesenchymal stem cells. AB - Conditions of human BM and umbilical cord blood MSC in vitro differentiation in the hepatogenic direction were studied. Changes in cell morphology, phenotype, acquisition of the capacity to produce albumin and accumulate glycogen, express cytokeratin, alkaline phosphatase, and albumin mRNA indicated that BM and umbilical cord blood MSC differentiated in vitro into immature hepatocyte-like cells. PMID- 22442821 TI - Effect of hyaluronidase immobilized using electron-beam synthesis nanotechnology on sensitivity of progenitor cells to regulatory factors. AB - In vitro experiments demonstrated increased colony-forming capacity of erythroid, granulomonocytic, and mesenchymal progenitors of the bone marrow and parenchymal progenitor elements of the liver after treatment with immobilized hyaluronidase. Increased sensitivity of these progenitor cells to erythropoietin, granulocyte colony-stimulating factor, fibroblast growth factor, and stem cell factor, respectively, was demonstrated. Immobilized hyaluronidase enhanced the formation of tissue-specific hepatic CFU against the background of reduced yield of stromal precursors in liver tissue culture containing insulin. PMID- 22442822 TI - Cell technology employing femtosecond laser pulses. AB - Practical advantages of using femtosecond laser pulses for manipulations in cell surgery were demonstrated. The use of femtosecond laser pulses enables precision punching of the zona pellucida of the embryo without damaging its cells. With the help of femtosecond laser tweezers/scalpel, auxillary laser hatching was performed and a technique of optical biopsy of mammalian embryo was developed, which enabled non-contact sampling of embryonic material for preimplantation diagnostics. Our findings suggest that about 90% embryos retained the ability to develop at least to the blastula stage after this manipulation. PMID- 22442823 TI - Regularities in the formation of structural and functional changes in the brain in technogenic stress. AB - Study of structural and functional changes in the brain under the influence of anthropogenic factors showed that limbic brain structures and especially the hippocampus undergo most pronounced reorganization. PMID- 22442824 TI - Synthesis of [(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines. AB - The reactions of 2-, 3- and 4-aminopyridines with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) 4 to give N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin X-amines 1a (X = 2), 1g (X = 3) and 1k (X = 4) were optimized with respect to base, temperature and reaction time. Based on these conditions a total of thirteen [(dithiazolylidene)amino]azines 1a-m were prepared and fully characterized. PMID- 22442825 TI - Mechanism-based population modelling of the effects of vildagliptin on GLP-1, glucose and insulin in patients with type 2 diabetes. AB - AIM: To build a mechanism-based population pharmacodynamic model to describe and predict the time course of active GLP-1, glucose and insulin in type 2 diabetic patients after treatment with various doses of vildagliptin. METHODS: Vildagliptin concentrations, DPP-4 activity, active GLP-1, glucose and insulin concentrations from 13 type 2 diabetic patients after oral vildagliptin doses of 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. The population PK/PD model was developed utilizing the MC-PEM algorithm in parallelized S-ADAPT version 1.56. RESULTS: In the PD model, active GLP-1 production was stimulated by gastrointestinal intake of nutrients. Active GLP-1 was primarily metabolized by DPP-4 and an additional non-saturable pathway. Increased plasma glucose stimulated secretion of insulin which stimulated utilization of glucose. Active GLP-1 stimulated both glucose-dependent insulin secretion and insulin-dependent glucose utilization. Complete inhibition of DPP-4 resulted in an approximately 2.5-fold increase of active GLP-1 half-life. CONCLUSIONS: The effects of vildagliptin in patients with type 2 diabetes on several PD endpoints were successfully described by the proposed model. The mechanisms of vildagliptin on glycaemic control could be evaluated from a variety of aspects such as effects of DPP-4 on GLP-1, effects of GLP-1 on insulin secretion and effects on hepatic and peripheral insulin sensitivity. The present model can be used to predict the effects of other dosage regimens of vildagliptin on DPP-4 inhibition, active GLP-1, glucose and insulin concentrations, or can be modified and applied to other incretin-related anti-diabetes therapies. PMID- 22442826 TI - Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV. AB - AIMS: To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology. METHODS: Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling. RESULTS: A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter individual coefficient of variation) were: non-saturable clearance 36 l h-1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%). CONCLUSIONS: Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties. PMID- 22442827 TI - Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects (pages. AB - AIMS: There is no consensus as to what extent the results of thorough QT interval/corrected QT interval (QT/QTc) studies need to be bridged. METHODS: The results of two studies using levofloxacin in Japanese and Caucasian subjects were compared in a post hoc analysis to investigate the similarity of dose-effect responses. RESULTS: Concentration-response analysis based on the change of QT interval corrected using Fridericia's formula (QTcF) from time-matched placebo was planned and performed in the combined data sets. At the geometric maximum mean concentration for the two doses in the Caucasian study, a predicted effect on QTcF comparable to the effects observed was found. For the Japanese study, the predicted effect was lower, but the difference was not statistically significant. CONCLUSIONS: No statistically significant differences in QTc-prolonging effect between Japanese and Caucasian subjects were observed following levofloxacin dosing. However, a trend suggests that Caucasian subjects may be more sensitive. Age and sex did not have an impact. PMID- 22442828 TI - Fracture of the cricoid as a potential pointer to homicide. A 6-year retrospective study of neck structures fractures in hanging victims. AB - The distinction of a suicidal hanging from a simulated hanging following a homicidal strangulation is highly challenging. The present study evaluates the fracture of the cricoid cartilage as a potential pointer toward homicide. Despite the numerous studies on neck structures fractures in hanging, this is the first study to concentrate on the cricoid cartilage. Neck structures fractures in all cases of suicidal hanging over a 6-year period were retrospectively reviewed (231 cases) and a comparison with homicidal hangings (4 cases) and homicidal no hanging strangulations cases (52 cases) was performed. Overall, neck structures fractures were found in 23.4% of suicidal cases (54 cases). The cricoid cartilage was intact in all suicidal hangings. The general incidence of fractures in homicidal no-hanging strangulation was 65.4% (34 cases),with an incidence of fracture of the cricoid cartilage of 20.6%. By compiling studies from the literature, only one cricoid cartilage over 2700 suidical hanging cases was found, whereas an incidence of 5 to 20% is found for homicidal strangulation. It is therefore proposed that the presence of a fracture of the cricoid in an apparent suicidal hanging should be considered highly suspicious. PMID- 22442829 TI - Proceedings of the VIII Barcelona International Congress on the Mediterranean Diet, 24-25th March, 2010, Barcelona, Spain. PMID- 22442830 TI - Death caused by cardioinhibitory reflex: what experts believe. AB - The danger of neck compression without restriction of the arterial flow remains unresolved in forensic medicine. There is an ongoing debate concerning life endangerment due to the cardioinhibitory reflex. The aim of this study was to determine what forensic medical experts believe and how they deal with this reflex. An anonymous electronic questionnaire was sent to 1429 forensic medical experts all over the world. We asked them about their opinion on the cardioinhibitory reflex, its role in causing death, and what their diagnostic criteria were.A total of 182 questionnaires were returned. The experts who answered were from 32 different countries. Our survey showed that 80.2% of experts believe that the cardioinhibitory reflex can theoretically cause death. In the practical application opinions diverge though. Apparently, the practical application mainly depends on the habit of the individual expert. We observed no consensus on the diagnostic criteria to be used. Given the potentially frequent use of the concept of the cardioinhibitory reflex in forensic practice and its judicial impact it would be important to reach a consensus. PMID- 22442831 TI - Proceedings of the 11th German Parkinson Expert Meeting, October 29-30, 2010, Dresden, Germany. PMID- 22442832 TI - Sexual assault documentation program. AB - Since 2001, the Los Angeles County Department of Coroner has collaborated with Los Angeles County-University of Southern California Medical Center Violence Intervention Program and their Sexual Assault Center. The partnership was established at the suggestion of the district attorney's office to enhance the clinical recognition of sexual assault in the medical examiner's office using the extensive experience of experts in the field of sexual assault. As of December 2008, over 5 dozen victims of sexual assault have been evaluated with this collaboration. The partnership relied on the expertise of 2 pediatricians who are established clinical experts in the field of sexual abuse and assault, in collaboration with the staff of the medical examiner's office. In cases of suspected sexual assault, a joint evaluation by the clinical experts and the medical examiner was made. The goal of the project was for the medical examiners to become more confident in their observations and documentation of crimes of sexual abuse. Even though they are still available upon request, consultations with the sexual assault experts have decreased as the skills of the medical examiner to evaluate sexual assault cases have increased. PMID- 22442833 TI - Sudden cardiac death: look closely at the coronaries for spontaneous dissection which can be missed. A study of 9 cases. AB - Spontaneous coronary artery dissection is a rare cause of death seen largely in young women, with many cases occurring in the early postpartum period. Nine cases with this condition were examined from our histopathology records comprising 6 women and 3 men with an age range of 26 to 47 years. All deaths were sudden, and only one patient complained of chest pain and she was 8 weeks postpartum. All cases showed dissection macroscopically, though 4 of the 6 cases, which were sent for a second opinion, were described as having normal coronaries by the referring pathologists. One heart seemed to have postmortem coronary artery thrombus and dissection was difficult to discern on gross examination. All cases were examined histologically and confirmed acute dissection of the coronary arteries, with more than 2 arteries affected in 2 cases. Histologic features of myocardial ischemia/infarction were noted in 4 cases so the explanation for the sudden death in the other 4 cases remains a possible fatal arrhythmia. The macroscopic changes in the heart of acute coronary artery dissection can be difficult to detect and can be easily mistaken for postmortem clot or a thrombus overlying an atheromatous plaque. All such cases with thrombus in the arteries, even the normal-looking coronary arteries, in young adults should be examined microscopically for dissection PMID- 22442834 TI - Huffing air conditioner fluid: a cool way to die? AB - "Huffing," the form of substance abuse involving inhalants, is growing in popularity because of the ease and availability of chemical inhalants in many household products. The purpose in huffing is to achieve euphoria when the chemicals in question interact with the central nervous system in combination with oxygen displacement. The abuser is lulled into a false sense of safety despite the well-documented potential for lethal cardiac arrhythmia and the effects of chronic inhalant abuse, including multisystem organ failure, and brain damage. Huffing air conditioner fluid is a growing problem given the accessibility to outdoor units and their fluid components, such as difluorochloromethane(chlorodifluoromethane, Freon), and we have classified multiple cases of accidental death due to the toxicity of difluorochloromethane. Given the ubiquity of these devices and the vast lack of gating or security devices, they make an inviting target for inhalant abusers. Acute huffing fatalities have distinct findings that are present at the scene, given the position of the decedent and proximity to the air conditioner unit. The purpose of the autopsy in these cases is to exclude other potential causes of death and to procure specimens for toxicological analysis. PMID- 22442835 TI - Proceedings of the International Conference on Hemoglobin Disorders, February 5 7th, 2011, Kuwait. In memoriam of T.H.J. Huisman. PMID- 22442836 TI - Case report of fatal complication in prostatic cryotherapy. First reported death due to argon gas emboli. AB - We present the first reported fatality from argon gas emboli during prostate cryosurgery. The decedent underwent cryotherapy for prostate carcinoma using cryoablation probes which were cooled with argon and nitrous oxide and warmed with helium. Minutes into the procedure he experienced sudden cardiovascular collapse and could not be resuscitated. Postmortem examination was performed at the request of family and healthcare providers. Collection of tissues and blood samples had to be conducted carefully to capture suspected noble gases,argon, and helium. Specimens were submitted to Saint Louis University Forensic Toxicology Laboratory for toxicological examination and for evaluation of the composition of the gas retrieved from the vascular system.Gas chromatography mass spectrometric analyses confirmed argon in blood, brain, liver, and gas retrieved from the aorta. These samples had significant argon compared with room air also sent for comparison. The manner of death was accident. To date, there have been no intraoperative surgical fatalities reported from prostatic cryotherapy. We report such an unfortunate death to raise awareness in the medical community. We also describe how to collect and handle blood and tissue samples to submit for toxicological analysis in cases of volatile gas emboli. PMID- 22442837 TI - Vehicle-assisted decapitation: a case report. AB - A rare case of vehicle-assisted suicide in a 40-year-old man is presented. The victim had tied a rope between his neck and a tree and then attempted to drive the vehicle away while seated in the driver's seat.The acceleration of the vehicle resulted in complete decapitation. Injuries to the organs of the man's neck bore vital signs. This, together with blood aspiration into his airways, confirmed that the victim's injuries took place when vital functions of his organism were still preserved. The degree of cervical trauma found in this case was far greater than that in characteristic ligature strangulation or hanging, except in cases where the body has fallen some distance. PMID- 22442838 TI - A mysterious parathyroid adenoma. PMID- 22442839 TI - A solid-supported organocatalyst for continuous-flow enantioselective aldol reactions. AB - Asymmetric aldol reactions catalyzed by a novel polystyrene-immobilized proline derivative occur in short reaction times with excellent diastereo- and enantioselectivity. The catalyst can be recovered by simple filtration and shows very high reusability. The high activity depicted by the supported catalyst and its chemical and mechanical stability have allowed its application in packed-bed reactors for continuous flow processing. This system can produce enantio- and diastereomerically pure aldol adducts under continuous flow conditions with a residence time of 26 min. Furthermore, the reactor allowed processing of four different aldol products in sequence without any decrease in both catalytic activity and optical purity. The effective catalyst loading could be reduced to 1.6% (six-fold reduction of catalyst loading compared to the corresponding batch process). PMID- 22442840 TI - Postdoc or not? PMID- 22442841 TI - Computer-assisted navigation systems for insertion of cannulated screws in femoral neck fractures: a comparison of bi-planar robot navigation with optoelectronic navigation in a Synbone hip model trial. AB - BACKGROUND: Computer-assisted procedures have recently been introduced for navigated femoral neck screw placement. Currently there is little information available regarding accuracy and efficiency of the different navigated procedures. The aim of this study was to compare two fluoroscopic navigation tracking technologies, a novel bi-planar robot navigation and standardized optoelectronic navigation, versus standard freehand fluoroscopic insertion in a Synbone hip model. METHODS: Eighteen fixed Synbone hip models were divided into 3 groups. C-arm navigated cannulated screws (AO-ASIF, diameter 7.3 mm) were inserted using freehand targeting (control group). A novel bi-planar robot system (TINAV, GD2000) and an optoelectronic system (Stryker OTS Navigation System) were used for the navigated procedures (robot group and optoelectronic group). Accuracy was measured using radiographic evaluation including the measurement of screw parallelism and decentralization, and joint penetration. To evaluate the efficiency, the number of guidewire passes, operative time and fluoroscopic images taken were noted. RESULTS: The two computer-assisted systems provided significantly improved accuracy compared to the freehand technique. Each of the parameters, including guidewire passes and number of fluoroscopy images, was significantly lower when using the computer-assisted systems than for freehand unguided insertion (P <0.05), but operative time was significantly shorter when using freehand-unguided insertion than for the computer-assisted systems (P <0.05). Accuracy, operative time and number of fluoroscopy images taken were similar among the two navigated groups (P >0.05), but guidewire passes in the robot group were significantly less than in the optoelectronic group (P <0.05). CONCLUSIONS: Both bi-planar robot navigation and optoelectronic navigation were similarly accurate and have the potential to improve accuracy and reduce radiation for freehand fluoroscopic targeting for insertion of cannulated screws in femoral neck fractures. Guidewire passes in the robot group were significantly less than in the optoelectronic group. However, both navigated procedures were associated with time-consuming registration and high rates of failed matching procedures. PMID- 22442842 TI - Framing the new midwifery: media narratives in Ontario and Quebec during the 1980s and 1990s. AB - After long periods of activism and policy debate, Ontario and Quebec were the first two provinces to integrate midwifery into their health-care services. Despite its success and growing popularity in the post-legislative era, midwifery was a highly contentious policy issue, with debates emerging at every level of policy development. In this essay, the authors explore how these debates played out in media. Specifically, the authors suggest that the frames produced by newspapers during this period served to align midwifery with broader provincial socio-political discourses, which in turn legitimized state intervention in the area of reproductive health. At the same time, however, the authors demonstrate that where Ontario media representations muted differences between midwives and physicians, representations in Quebec emphasized them. Thus, the authors show that in very different ways, media representations of midwifery in Ontario and Quebec both established a discursive context in which the state had to "act on" midwifery and midwives, and also challenged the potential of midwifery to transform women's birth experiences. PMID- 22442843 TI - Plague historians in lab coats. PMID- 22442844 TI - The paradox of planning: German agricultural policy in a European perspective, 1920s to 1970s. PMID- 22442845 TI - [Giving life a chance: health professionals' influence on mothers' decisions]. PMID- 22442846 TI - Salt effects on the denaturation of DNA. AB - When DNA's of differing GC:AT base ratios, e.g. synthetic poly dAT, T4 DNA,calf thymus DNA, E. coli DNA, and M. lysodeikticus DNA, are heat-denatured at neutral pH in increasing concentrations of N(a)(2)SO(4) or C(s)(2)SO(4) as supporting electrolytes,the variation of melting temperature with average base composition, dT(m)/dX(G)(C), changes from 45 degrees C (in 0.002M Na) to ll degrees C (in 4.5M Na) and from 42 degrees C (in 0.002M Cs) to 3 degrees C(in 4.5M Cs). The decrease of dT(m)/dX(G)(C) is a monotonic function of decreasing water activity in the salt solutions. We interpret this decreased composition dependence of the thermal stability of the various DNA's as being due to a destabilization of the GC base pairs relative to the AT base pairs by the concentrated salt media. A simple quantitative treatment shows that k = 8GC/SAT decreases from a value of 4.14 (in 0.01MN(a)) to 1.86 (in 3M Na) and from 4.18 (in 0.01M Cs) to 1.42 (in 3M Cs). SAT is the equilibrium constant for the formation of a hydrogen-bonded AT base pair from a pair of unbonded bases at the junction between a helical region and a denatured region and SGC is the like constant for the formation of a GC base pair. These results corroborate our previous findings of a strongly reduced composition dependence of the negative logarithm of the methylmercuric hydroxide concentration necessary to produce 50% denaturation when the helix-coil transition of DNA is studied in concentrated Cs(s)SO(4)(ultracentrifugation) instead of in dilute N(a)(2)SO(4) (ultraviolet spectrophotometry). PMID- 22442847 TI - High-frequency transformation of the fission yeast Schizosaccharomyces pombe. AB - The fission yeast, Schizosaccharomyces pombe, has been used extensively for genetic studies but until now it has not been utilized as a host organism for DNA cloning. Here we describe a method for high-frequency transformation fo a leu 1( ) strain of this yeast with hybrid plasmids containing the Saccharomyces cerevisiae LEu 2(+) gene, a bacterial plasmid and either the S. cerevisiae 2 MUm plasmid or autonomously replicating sequences (ars)(1) derived from S. pombe DNA. Some of the plasmids contain unique restriction sites which make them suitable for the isolation of S. pombe genes, and they can also be used for the exchange of DNA between S. pombe and S. cerevisiae. PMID- 22442848 TI - [Rhetorical articulation and boredom in Alfred de Musset's 'Confession d'un Enfant du Siecle]. PMID- 22442850 TI - [Ethnic conflicts, solidarity, and motivations in the Italian press]. PMID- 22442854 TI - [The transition of international mobility and contemporary Italian emigration to Germany]. PMID- 22442855 TI - [Migration in Europe: thoughts regarding the 1998 SOPEMI report]. PMID- 22442856 TI - [Mass media, ethnic conflicts, and Italian identity]. PMID- 22442857 TI - [My technique: reconstruction of the pulmonary artery in arterial switch operation]. PMID- 22442858 TI - [Mass media, immigration, and ethnic conflicts in Italy: quantitative analysis of information about immigration]. PMID- 22442859 TI - [Overlap method for ischemic myocardiopathy: my first case]. PMID- 22442860 TI - [Imaging diagnosis: Q & A. Cor triatriatum and ostium secundum atrial septal defect]. PMID- 22442861 TI - [How to write academic theses]. PMID- 22442862 TI - University of Buenos Aires: its 190th anniversary (1821-2011): A good opportunity to say something about bioengineering. PMID- 22442863 TI - DARPA Nest. PMID- 22442864 TI - [New development in the treatment of head and neck cancer--with special reference to non-surgical approach. Treatment of progressive head and neck cancers for functional preservation: simultaneous chemo-radiotherapy]. PMID- 22442865 TI - [EM900 and eosinophilic paranasal sinusitis]. PMID- 22442866 TI - [On the trends in the system of clinical residency]. PMID- 22442867 TI - [Hearing aids: their progress in the past 20 years]. PMID- 22442868 TI - [Future of thoracic surgery in the Czech Republic]. PMID- 22442869 TI - [Acute mediastinitis]. AB - The authors give an outline of the issue of acute mediastinitis. It is a severe infection of connective tissue of the mediastinum. Timing of recognition and accuracy of drainage are the most essential conditions of successful treatment. Acute mediastinitis may be divided in the postoperative sternal infections with infection of the mediastinum, mediastinitis due to perforation of the aero digestive tract and descending necrotizing mediastinitis. The authors describe etiopathogenesis, diagnostics and therapy in each particular type of mediastinitis. PMID- 22442870 TI - [Lung transplantation]. AB - Lung transplantation is an effective life-saving therapy for the treatment of a variety of end-stage lung diseases. However, the application of lung transplantation is hindered by multiple factors such as the shortage of organ donors, early graft failure, infection, and chronic graft dysfunction. A novel strategy for donor lung preservation--ex-vivo lung perfusion (EVLP)--that keeps the organ at physiological protective conditions, has shown great promise to increase lung utilization by reassessing, treating, and repairing injured donor lungs prior to transplantation. Infections are a major cause of early morbidity and mortality after lung transplantation. Because of the potential association of infections such as respiratory viral infections and gram-negative bacterial infections with bronchiolitis obliterans syndrome, prompt attention to these pathogens is critical. Despite marked improvements in early survival, long-term outcome after lung transplantation is still threatened by bronchiolitis obliterans syndrome. The program of lung transplantation in Czech Republic was started in University Hospital Motol in Prague in 1997. Nowadays in Czech Republic is performed about 20 transplants every year with results comparable to other advanced centers. Until September 2011, 175 transplants were carried out in Czech Republic. PMID- 22442871 TI - [Experimental use of the recipient's epithelial cells in tracheal allotransplantation--initial outcomes]. AB - The management of long tracheal lesions requires development of tracheal implants, which would enable resection combined with anastomosis. The authors' scientific study is based on tracheal allotransplantation on an animal model (sheep), using tracheal epithelial cells of the recipient. The project covers preparation of the graft, so that all components of the major histocompatibility complex (MHC), which participate in graft rejection, are removed. Histological examination of the allograft with cultivated epithelial cells showed its good healing with revasculatization and with no signs of graft rejection. PMID- 22442872 TI - [Are there any news in the management of spontaneous pneumothorax?]. AB - Although numerous medical associations publish various guidance recommendations in order to introduce common procedures and rules for the management of spontaneous pneumotorax (SPNO), no general consensus has been reached in this area. The major controversy remains in the treatment of the 1st episode of primary SPNO (PSPNO), there is a strong disagreement between advocates of a single, one-step aspiration method and advocates of pleural cavity drainage. Furthermore, some authors promote miniinvasive surgical revision. On the other hand, there is a relative concesus regarding the management of PSPNO relapses, i.e. indication for videothoracoscopic procedure, if feasible considering the patient's condition. Similarly, there is an agreement concerning individual indications for videothoracoscopy in PSPNO. There is a tendency to prefer least injuring of the organism, resulting in procedures which use a single incision, so called uniportal procedures, and in the use of thoracoscopes and instruments measuring from 2 mm to the maximum of 5 mm in a diameter in so called needlescopic videothoracoscopies. The videothoracoscopic procedure itself, as a standard, includes lung surgery - i.e. removal of the pathology causing pneumothorax, and preventive procedure on parietal pleura, and recently on visceral pleura, as well. Endostapler non-anatomical resection is the commonest lung procedure, while pleuroabrasion or its combination with partial apical pleurectomy are the commonest pleurodesis procedures. Talc pleurodesis features certain comeback after some time. Recently, some authors have turned their attention to, so called, tenting - i.e. strengthening of the endangered visceral pleura parts with absorbable polymers to prevent development of new subpleural blisters or emphysema bulae responsible for the disease recurrence. Drainage of the pleural cavity is the method of choice in the management of the first episode of the secondary SPNO (SSPNO). SSPNO relapses and complications are managed by surgical intervention and, contrary to that in PSPNO, with higher rates of thoracotomy procedures compared to VTS procedures, which is due to inability of these patients to undergo unilateral lung respiration. When this intervention is not feasible, chemical pleurodesis with introduction of a drain using talc, autologous blood or tetracycline derivates is performed. Catamenial pneumotorax with high relaps rates requires videothoracic revision already at its first occurence, accompanied by the causative factor removal, pleurodesis and induction of hormonal amenorrhea. PMID- 22442873 TI - [Is pneumonectomy justified in the management of lung metastases?]. AB - The authors discuss about questions of possibility pneumonectomy in concept of lung metastasis therapy. They analysed in detail indications, surgery, complications, survival and factors of survival. The authors also introduce case report of one patient with pneumonectomy in your group of patients. PMID- 22442874 TI - [Spontaneous pneumomediastinum--a case review]. AB - The authors present in the following case review a patient with spontaneous pneumomediastinum which can be on of the causes of acute chest pain and it is necessary to think about it in the differential diagnosis of this condition. PMID- 22442875 TI - [Principles of the thoracic wall injury management]. AB - The overview presents the current situation in the diagnostics and therapy of unstable thoracic wall injuries. The diagnostic spectrum is enlarged by multidetector computed tomography with 3D reconstruction imaging in rib fractures. The use of MDCT in routine examination of blunt thoracic injuries proved to bet the most sensitive imaging method in rib fractures detection, including their dislocations and assessment of the extent of thoracic wall deformity. MDCT improves visualization of the thoracic wall injuries, thus facilitating assessment of the potential respiratory disorder significance. Non surgical therapy is, as a standard, indicated in patients with thoracic wall injuries. The treatment includes respiratory tract hygiene, pain management and selective ventilatory support. Relative indications for surgical stabilization of fractures include block and serial rib fractures, thoracic deformities and defects and rib fractures healing disorders combined with other limiting criteria. Surgical stabilization is technically managed using metal or absorbable plasters. Surgery with open reduction and internal rib fixation, in particular in block or serial rib fractures, is associated with reduction of ventilation support time and reduction in the risk of infection. PMID- 22442876 TI - [Penetrating thoracic and abdominal injuries: diagnostic and therapeutic approach]. AB - INTRODUCTION: Penetrating thoracic or abdominal or combined injuries are associated with high risk of life-threatening intraabdominal or intrathoracic organ injury. Most patients require acute surgery. When miniinvasive technique is available, thoracoscopic or laparoscopic intervention is indicated in hemodynamically stable patients to evaluate severity of the injury, as well as to treat the condition. AIM OF THE STUDY: Retrospective analysis of incidence, diagnostics and treatment of penetrating thoracic and abdominal injuries and combined thoracoabdominal injuries in a Trauma centre. PATIENTS, METHODS AND RESULTS: A total of 195 patients with penetrating thoracic, abdominal or combined injuries, who were hospitalized in the FNKV (Krilovske Vinohrady Faculty Hospital) Trauma centre in Prague from 1999 to 2010, were included in the study. The study group included 177 (91%) males. Out of the total, 102 patients (53%) suffered from penetrating abdominal injuries, 71 (36%) from thoracic injuries and 22 (11%) from combined, thoracoabdominal injuries. The majority of injuries were stab injuries (173, i.e. 89% of the patients). 22 subjects, the penetrating injury was caused by shot injuries. In stable patients, MDCT has been lately used to establish the diagnosis. In 171 subjects, acute thoracotomy or thoracotomy was indicated. Patients with combined injuries of the both cavities were indicated either for thoracotomy and laparotomy or thoracophrenolaparotomy. Videothoracoscopy or laparoskopy was conducted in 21 (11%) of the subjects. During the surgical revision, two subjects exited due to ireversible hemorrhagic shock, further 2 subjects died because of septic complications following shot abdominal injuries. CONCLUSION: Incidence of penetrating thoracic, abdominal or combined thoracoabdominal injuries is fairly rare in our country. Subjects with unstable hemodynamic conditions are indicated for acute thoracotomy or laparotomy. Miniinvasive procedures have diagnostic and therapeutic benefit in stable patients. Diagnostic thoracoscopy and laparocopy provides evidence of some injuries (diaphragm, alimentary tract). Therapeutically, miniinvasive methods may be used to manage the source of bleeding and for targeted drainage. Nonsurgical procedure is the method of choice in a selected group of hemodynamically stable patients with stab injuries, with monitoring of the patient's condition, including the use of x-ray imaging. PMID- 22442877 TI - [Esophageal perforation]. AB - OBJECTIVE: Evaluation of patients with acute esophageal perforations with single institution experience. MATERIAL AND METHODS: The authors evaluate the set of 64 consecutive patients with esophageal perforation treated in our department between January 2000 and December 2010. In all patients were before decision making performed CT scans and X-ray examination with contrast agent administration. For selected patients was also accompanied upper endoscopy. Excluded were patients with malignant tracheoesophageal fistula and patients with perforation of malignant stenosis treated with palliative intent. RESULTS: The mean age was 62 years (range 24-90), of which one third (34.4%) were aged 70 years or more. We received the iatrogenic perforation in 45 (70%) patients, less than one quarter (n = 15; 23%) consisted of spontaneous perforation, in three patients we have failed to determine the cause of perforation (5%) and one patient experienced perforation during removal of foreign body. Perforation of the thoracic esophagus in 41 patients, in 20 (31%) cases in the upper and middle third and 21 (33%) in the distal third of the thoracic esophagus. Cervical perforation was noted in 14 patients (22%) and abdominal of the 9 patients (14%). 92% of patients were treated surgically (n = 59). 43% (n = 27) were treated by primary suture of the perforation, esophageal resection with primary reconstruction was performed in 4 patients, esophagectomy with terminal esophagostomy and nutritional jejunostomy in 7 patients, 4 patients were treated by surgical drainage and only 7 patients, we introduced endless lavage. In 9 cases we have resected affected portion of esophagus with stapler closure in the chest. Conservative management of esophageal perforation we proceeded in 5 patients in whom a stent was introduced and the perforation successfully healed. Overall mortality in our set of patients is 23.4%. CONCLUSION: Conservative procedure in carefully selected patients could be an alternative to radical and inherently surgical procedures. Published results and our little experience are encouraging, but this topic is still under study. PMID- 22442878 TI - [Rates of metastatic affections of mediastinal nodes during pulmonary metastasectomy]. AB - OBJECT: The aim is the evaluation of lymph node metastasis rate during pulmonary metastasectomy harvested by technique of systematic mediastinal lymphadenectomy in year 2009-2010. METHODS: We performed systematic mediastinal lymphadenectomy (the same technique as in non-small cell lung cancer) during pulmonary metastasectomy. RESULTS: There was found lymph node metastasis in four cases from 70 patients. The rate of metastatic involved mediastinal lymph node 5.7% harvested during lung metastasectomy is on lower limit of published interval. We expected higher lymph node involvement in lung metastasis of colorectal origin. PMID- 22442879 TI - [Right ventricular perforation by a rib fragment following blunt thoracic trauma]. AB - Blunt chest trauma produces a variety of injuries. Penetrating cardiac injuries from rib fractures are extremely rare. We report the unusual case of a patient with multiple rib fractures and penetrating cardiac injury from dislocated segment of fractured VIII left rib. We did find eight patients reported in the literature having penetrating cardiac injuries from rib fractures. The clinical finding and the diagnosis of this injuries are discussed. PMID- 22442880 TI - Adenovirus vectors: promise and possible pitfalls. PMID- 22442881 TI - The global fund's uncertain future. PMID- 22442882 TI - In pursuit of a cure. PMID- 22442883 TI - Trial evaluating DNA/Ad35 prime-boost regimen commences in Africa. PMID- 22442884 TI - Trial testing mucosal and systemic delivery of DNA vaccine candidate begins. PMID- 22442885 TI - Polio eradication: one step forward, one step back. PMID- 22442886 TI - Researchers analyze CD8+ T cell types in unprecedented detail. PMID- 22442887 TI - [150 years since the first issue of the Journal of Czech Physicians. Jubilee of the journal at its own pages]. PMID- 22442888 TI - [Methods for assessing the potential health risks of traces of pharmaceuticals in drinking water]. AB - Increasing consumption of pharmaceuticals leads also to higher release of its non metabolized residues into environment, mostly hydrosphere. Some of these substances may reach also processed drinking water. Although it is found in traces, it causes public concern as it can represent a non-targeted and unwanted medication. Toxicologists and public health authorities are appealed to assess potential health risks carefully and to communicate the risk adequately to public. As health risks assessment of environmental exposure to pharmaceuticals is a new field of expertise, its methodology has not been unified and standardized yet, but several different procedures have been proposed and used. The paper provides overview of these methods. PMID- 22442889 TI - [Endoscopy simulator for training in digestive endoscopy]. AB - This paper reports on a computer-based simulator (GI Mentor II) used for initial training in digestive endoscopy. The highly sophisticated apparatus employs real endoscopes and virtual accessories. The training programme starts with a group of exercises, specially designed to enhance eye-hand coordination. Interactive computerised simulator contains modules for training in gastroscopy, colonoscopy, endoscopic retrograde cholangio-pancreatography and endoscopic control of gastrointestinal bleeding. Virtual library contains 88 authentic cases of diagnostic and therapeutic procedures. Computer-based endoscopy simulators enable trainees to learn and gain technical endoscopic skills before operating on patients. It has the potential to shorten the learning process to competency in digestive endoscopy. PMID- 22442890 TI - [Catheter related blood stream infections--prevalence and interventions]. AB - BACKGROUND: Catheter related blood stream infections are a significant complication of intensive care with worldwide prevalence rate around 5 cases per 1000 catheter-days. Only scanty Czech data have been published. Our study monitored the occurrence of catheter-related blood stream infections in a high dependency unit of regional hospital. METHODS: In 2008 we commenced to monitor the occurrence rate of catheter-related blood stream infections in short-term central venous catheters without antimicrobial coating. We organized a training session for medical staff and started to strictly adhere to published guidelines. After two years of keeping a register we analysed individual cases as proven, possible, or not proven blood stream infections. RESULTS: From March 2008 to March 2010 we inserted 142 central venous catheters for total time of 1423 catheter days (median 9 days). Ten catheters were removed after median of 17 days due to unexplained pyrexia. Blood stream infection was proven in 4 cases and possible in 2 cases. We have noted total 2.81 proven cases, and 4.22 proven and/or possible cases of blood stream infection per 1000 catheter-days. CONCLUSION: The register of catheter related blood stream infections is an inexpensive and time-efficient tool that improves the quality of intensive PMID- 22442891 TI - [Statin-ezetimibe combination in hyperlipidemia treatment]. AB - BACKGROUND: Statin monotherapy for dyslipidemia only rarely achieves recommended target values of plasma lipids. Statin plus ezetimibe is a feasible treatment option. The aim of the present study was to test efficacy and safety of statin plus ezetimibe combination in the treatment of severe dyslipidemia in patients coming to an ordinary lipid and diabetology department. METHODS AND RESULTS: A retrospective evaluation of 3 months treatment in 82 dyslipidemia patients (25 male, 57 female) with unsatisfactory statin monotherapy results (average equivalent of 30 mg atorvastatin) was performed. Ezetimibe 10 mg per day was added to preceding treatment. The group included 26 diabetics type 2. The addition of ezetimibe resulted in statistically significant decrease of plasma total cholesterol (TC) (-21%), LDL-C (-28%), triacylglyceroles (TAG) (-26%) and HDL-C (-6%). The recommended values of LDL-C were achieved in 42% of patients. In the diabetic subgroup a significant decrease of TC (24%), LDL-C (33%) and TAG (18%) was observed. There was no significant decrease of HDL-C. The recommended value of LDL-C was achieved in 48% of diabetics. There were no unfavourable side effects. CONCLUSIONS: The addition of ezetimib in a dose of 10 mg in hyperlipidaemia patients who had not achieved the recommended target values of LDL-C resulted in a subsequent significant decrease of both TC and LDL-C. It also enabled to increase the number of patients achieving the recommended target plasma lipid values. The treatment was safe and was not associated with adverse effects. PMID- 22442892 TI - [Prediction in medicine--genome contra envirome]. AB - Human phenotype is governed by its genotype--a set of genetic information materialized in DNA. Using traditional terminology we speak about a little more than 20 thousands genes that differ in strength to become realized and their effect is modified by a large number of other genes. The result originates from firmly established programmes we obtained from our ancestors. Development and activity of such molecules selected for maintenance, copying and transfer of information i.e. nucleic acids can be followed back to the very origin of the life. Nevertheless the final result is achieved not only by confrontation of the original information with other genetic information but largely also by external influences--environment. Though we are relatively successful in understanding what we have inherited from our parents, our knowledge of environmental factors and their effects on formation of the phenotype is still limited. From this point of view medical prediction has always to be very cautious and interpretations at the probability level must be done by a very experienced and responsible professional. PMID- 22442893 TI - [The history of medicine in the ancient time]. AB - This article deals with the history of medicine in the ancient Greece; from the cult of the God Asklepios, to the founder of the scientific rational medicine, Hippokrates. The humoral theory of Hippokrates is explained (the human body consists from four liquids) and his ideal of a physician's approach to a patient is emphasized. In the Hellenistic period the medical development continued in the Alexandria Medical School (Herofilos and Erasistratos). At first, not much attention was given to medicine and scientific health prevention in ancient Rome. Only 293 AD have physicians from Greece first been invited to Rome--e.g. Asklepiades. During the reign of C. lulius Caesar, foreigners, who engaged in medical practice, were granted Roman citizenship and thanks to a number of benefits the medical condition in Roman Empire blossomed. Medical clinics (iatreia), infirmaries (valetudinaria) and, under the influence of Christianity, hospitals were established. In the 2nd century AD ancient medicine reached its climax with physician Galenos, who created the entire system of medical science and became the most significant, but also last medical figure of ancient Rome. PMID- 22442894 TI - [Nobel Prize laureates. Ulf Svante von Euler (1905-1983)]. PMID- 22442895 TI - Joining Forces Initiative. PMID- 22442896 TI - The Medicare shared savings program. PMID- 22442897 TI - Cultural competence: why surgeons should care. PMID- 22442898 TI - A crisis in the ED: liability protection needed STAT. PMID- 22442899 TI - Survey shows social media usage increasing among ACS fellow. PMID- 22442900 TI - The real history of Poland's syndrome. PMID- 22442902 TI - Resources for preventing hospital readmissions. PMID- 22442901 TI - Trends in the otolaryngology workforce in the U.S. PMID- 22442903 TI - Timing of carotid endarterectomy: a comprehensive review. AB - Some controversy exists on the best moment to treat symptomatic carotid artery disease. This controversy concerns mainly neurologically unstable patients and patients who suffered a minor stroke. The authors discuss recent literature data on the feasibility and the safety of performing urgent (within 24 to 72 hours) carotid endarterectomy (CEA) in patients presenting repetitive transient ischaemic attacks or progressing stroke. Neurologically unstable patients, suffering ischemic brain deficit caused by carotid artery stenosis, are defined according to the following criteria: two or more transient ischaemic attacks (crescendo TIAs) or a fluctuating neurological deficit evolving no longer than 24 hours (progressing stroke), no impairment of consciousness, cerebral infarct of limited size on diffusion-weighted magnetic resonance imaging of the brain and a carotid artery stenosis of 70% or more on the appropriate side. In the past, these patients were often considered at too high risk to undergo immediate carotid surgery. Many neurologists remain reluctant to confine these neurologically unstable patients for urgent carotid endarterectomy and prefer to stabilise the neurological status, arguing the increased stroke morbidity in the urgent setting. Nevertheless, the natural history of stroke- in-evolution or repetitive transient ischemic attacks is far from benign, exposing the patient to a high risk of subsequent spontaneous stroke, even under best medical treatment. Another controversy exists on the timing of surgery in patients who suffered a minor, non-disabling stroke. Is a waiting period of 6 weeks safe? Once more, the operative risk should be balanced against the anticipated natural history. Published series, and sub-analysis of the recent carotid surgery trials (NASCET, ECST) plaid for carotid surgery within two weeks of a minor stroke. CONCLUSIONS: Contemporary literature argues that neurologically unstable patients, presenting repetitive transient ischaemic attacks or progressing stroke, should be managed by urgent (within 24 to 72 hours) carotid endarterectomy, even if the peri operative stroke-death rate is slightly higher than in the elective setting. Despite an inherent increased operative morbidity-mortality, urgent carotid endarterectomy seems to us justified by the fact that waiting for the surgery may lead to the development of a more profound stroke in these neurologically unstable patients. Their only chance for neurological recovery (partial or complete) is in the early phase (12 to 60 hours after the acute onset of the neurological syndrome of crescendo-TIAs or stroke-in-evolution). For patients presenting a minor stroke, with limited brain infarction, carotid endarterectomy should preferentially be done in a semi-urgent fashion, within two weeks. PMID- 22442904 TI - Defunctioning stoma and anastomotic leak rate after total mesorectal excision with coloanal anastomosis in the context of PROCARE. AB - BACKGROUND: Anastomotic leakage (AL) after total mesorectal excision is a major adverse event. Construction of a defunctioning stoma (DS) reduces the morbidity of AL. This study aims to illustrate the AL rate and its related morbidity with and without primary stoma formation in the context of a Belgian project, PROCARE. METHODS: Between January 2006 and March 2011, 1912 patients who underwent elective TME with colo-anal anastomosis for invasive rectal adenocarcinoma up to 15 cm above the anal verge were registered. A primary DS was constructed in 1183 patients (62%). Early clinical AL rate, AL-related re-operation rate, length of stay (LoS), in-hospital mortality were analysed. RESULTS: In patients without leak, mortality was 1.1% and the mean LoS was 14.7 days. AL occurred in 6.5%, varying from 0%-25% between participating centres. In patients with AL, mortality was 4.8% (p < 0.001). In the presence of a primary DS, AL rate was 4.3%, requiring re-operation under narcosis in 78% with no mortality, resulting in a mean LoS of 30.4 days. In the absence of a primary DS, AL rate was 10.2%, requiring re-operation under narcosis in 93% with a mortality of 8.1% and a mean LoS of 33.4 days. Analysis per centre showed a weak relation between percentage of DS construction and AL rate. CONCLUSION: Construction of a primary DS significantly reduced the incidence of early AL, re-operation rate, and mortality. Although technical aspects of colo-anal anastomosis are of paramount importance, construction of a DS at primary surgery has to be considered by those teams with high early AL rate and/or high AL related mortality. PMID- 22442905 TI - Exploring limits for data registration in the context of PROCARE, a quality improvement project on rectal cancer. AB - BACKGROUND: A high burden of registration in the context of quality improvement projects may result in registration fatigue. METHODS: Time required for data collection and registration was measured. Quality of care indicators (QCI) were scored and factors for adjusted benchmarking were identified. The PROCARE data set was compared with 5 other European data sets. RESULTS: Time required for data collection varied per domain while time for registration was more uniform. On average, per item 33 seconds were needed for collection and registration. The number of data to be registered per patient was 48-276, depending on the stage of the disease, resulting in a minimum of 25 minutes and a maximum of 2 hours 4 minutes per patient, follow-up not included. Focusing on 43 clinically relevant QCIs would result in a 50% reduction, using aggregate scores for performance audit in a 71% reduction. The PROCARE data set was larger than comparable European data sets. Linkage of the PROCARE database with administrative databases provided confident data on the patients' survival status, but did not appear to be a practical option for other QCIs. CONCLUSIONS: Limiting the aim to performance audit could significantly reduce the burden of registration. In the context of a quality improvement project, the PROCARE Steering Group concluded that detailed clinical data from all centres are still required, which can be reconsidered in the future. Maintenance of a specific database remains of crucial value. Data collection and registration cannot be based on benevolence but should be compensated for. PMID- 22442906 TI - Cost-effectiveness analysis of postoperative surveillance protocols following radical surgery for colorectal cancer. AB - INTRODUCTION: Up to 30-50% of patients who undergo radical surgery for colorectal cancer (CRC) develop tumor relapse. The aim of this study was to assess various surveillance protocols utilized in a tertiary referral hospital in Northern Italy. METHODS: Data concerning 373 consecutive patients who underwent radical surgery for CRC between 1990 and 2006 and whose data had been entered into a prospective database were considered eligible for this study. The overall costs and the percentages of recurrence following the various surveillance protocols were calculated. RESULTS: One hundred two (27.35%) of the patients suffered a recurrence after a mean of 17.6 (95% CI 13.9-21.1) months. The combination of physical examination, colonoscopy, thorax-abdominal computed tomography (CT) scan, and serum carcinoembryonic antigen (CEA) dosage was found to be the most cost/effective one to monitor stages I and II colon cancer; while physical examination, rigid sigmoidoscopy, thorax-abdominal CT scan, and serum CEA dosage were found to be the most cost/effective surveillance to monitor stages III and IV of colon cancer and rectal cancer. CONCLUSIONS: Adherence to follow-up guidelines and early detection are vital factors affecting the curability of relapsed cancer in CRC patients who undergo surgery. The first five years after surgery was found to be the most risky period for recurrence. Cost/effectiveness analysis indicate that follow-up protocols should be tailored to the risk of recurrence with the aim of identifying relapse when the disease is at an asymptomatic, presumably more curable stage. PMID- 22442907 TI - Gastrointestinal stromal tumors (GIST): a single center experience. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal (GI) tract. They are believed to originate from the interstitial cells of Cajal (ICCs) or from the precursors of ICCs. Most GISTs show an activating mutation in either the c-kit or platelet derived growth factor receptor alpha (PDGFRA) gene. Tumor size, mitotic rate, and anatomic location correlate with potential malignancy and recurrence rate. PATIENTS AND METHODS: A total of 12 patients were diagnosed to have GIST based on histology or immunohistochemistry of a biopsy or resection specimen obtained from the GI tract in the 2004-2009 period. The material was obtained using retrospective data collection. RESULTS: The male to female ratio was 1:1; mean age 68.2 +/- 7.0 years. The stomach was involved in seven cases (58.3%), the small intestine in four (33.3%), and from a lymph node without the finding of a primary tumor was material obtained in one case (8.3%). The course was asymptomatic in four patients (incidental findings). All 12 patients had surgery; a curative procedure was undertaken in 11 patients. A spindle-cell pattern was present in 8/12 of the specimens examined, epithelioid in 2/12 and a mixed pattern in two cases. Ten specimens were CD117 positive (83.3%), two were negative; all 10 examined specimens exhibited CD34 positivity while two were not examined. The findings were classified as GISTs with a high risk of progressive disease in three patients, with a moderate risk in one patient, and a low or very low degree of malignancy in five patients. GISTs smaller than 2 cm in three patients were regarded as essentially benign. All patients with low and very low risk of progressive disease survive for 1 to 5 years free of signs. Of the three patients with high degree of malignancy, one died within one year for dissemination, the two remaining patients survive for over two years and six month postoperatively on therapy with tyrosine kinase inhibitors. CONCLUSION: Tumors classified as GISTs with low and very low risk of progression are associated with a very good prognosis, with virtually all patients surviving 5 years. In patients with high risk or progressive diseases, the prognosis of 5 year survival is much poorer. The main therapeutic option is surgical removal of the tumor (resection or broad excision). Agents showing promise for patients with malignant forms of GISTs are tyrosine kinase receptor inhibitors. Although imatinib is currently used as a first line treatment for all patients with metastatic or unresectable GISTs, it is likely that this treatment will change in the future based on the underlying mutational status. PMID- 22442908 TI - Completion thyroidectomy for differentiated thyroid cancer (results in a consecutive series of 68 patients). AB - INTRODUCTION: Completion thyroidectomy plays an important role in the management of patients with thyroid cancer. The aim of this study is to determine the indications for and timing of a second surgery, as well as surgical complications. MATERIAL AND METHODS: Operative reports, as well as the hospital and outpatient records of 686 consecutive patients, who had undergone surgery for differentiated thyroid cancer, were reviewed. Among these, 68 (9,9%) patient records of a completion thyroidectomy for cancer were analyzed. RESULTS: The mean time interval between the first and second operation was 3.6 months (range: 1-9). Post-operative complications occurred in 9 patients (12,9%). Among three patients with inferior laryngeal nerve palsy (4,4%) one had definitive palsy (1.4%). Hypoparathyroidism occurred in 6 patients (8,8%) being permanent in one of them (1.4%). No significant difference either for definitive inferior laryngeal nerve lesions (p = 0.9) or for definitive hypocalcemia (p = 1) was found between the groups of patients who had a completion thyroidectomy and those who had a one step total thyroidectomy for cancer. CONCLUSIONS: Correct indications for re operation, total lobectomy as a primary surgical procedure as well as lateral access to the residual thyroid gland could all reduce the high risks of complications related to this kind of surgery. PMID- 22442909 TI - Elective neck dissection in papillary thyroid carcinoma patients. AB - BACKGROUND: This study was designed to review the diagnostic performance of cervical lymph node metastases for assessment of elective neck dissection in papillary thyroid carcinoma patients and to determine the technique (using Methylene blue dye) that demonstrated the highest success rate with regard to the detection rate and sensitivity. METHODS: Preoperative 24 h, 1 mL of 1.0% methylene blue was injected into the parenchyma surrounding the primary tumor with ultrasound guidance by a 27-gauge needle. Intra-operative lymph nodes that were stained blue and/or having afferent lymphatic channels stained blue were also considered to be excised. All stained blue nodes were defined by levels, number, site and were sent for frozen and permanent section histologic analysis. RESULTS: For the 132 patients who underwent methylene blue dye, 1373 lymph nodes were removed. 7 lymph nodes had negative dye results but, in the end, had metastatic lymph nodes. 120 lymph nodes had both negative dye and lymph node results. The number of blue-dye lymph nodes was 1246 and the number of pathology metastatic nodes was 1079, so the pathological diagnose accordance rate was 87.8 percent. The nodal metastases often occur at level VI, IV, III, then in level II, and less in level I and V. CONCLUSIONS: This method using methylene blue dye is feasible technically and is safe, and the findings correlate with cervical lymph node status. According to the pattern of blue dye lymph nodes and frozen-section histologic analysis, performing elective neck dissection is a reliable, safe surgical procedure for PTC. PMID- 22442910 TI - Comparison of laparoscopic and open aortobifemoral bypass in the treatment of aortoiliac disease. Results of a contemporary series (2003-2009). AB - OBJECTIVES: The study objective was to describe and evaluate our single center (University Hospital Liege) experience with totally laparoscopic bypass surgery compared with conventional open surgery to treat aortoiliac occlusive disease. MATERIAL AND METHODS: A retrospective database review of all patients undergoing aortobifemoral bypass for aortoiliac occlusive disease in our center, between 2003 and 2009, was performed. During this period, a total of 251 consecutive patients were identified. Among these patients, 95 underwent totally laparoscopic aortobifemoral bypass (group I) and 156 conventional open surgery (group II). Demographic data, operative data, postoperative recovery data, complications, two year follow-up, morbidity and mortality were analysed according to the laparoscopic and conventional open group. RESULTS: Patients included 160 men and 91 women. The mean age was 61 years (range, 40 to 88 years) in both groups. Indications for surgery were invalidating claudication in 87%, rest pain in 7%, trophic disorders in 5%, impotence in 1.6% and digestive claudication in 1.2%. Prior to bypass surgery, 11 (11.6%) for the group I and 41 (26.3%) for the group II had undergone one or more abdominal surgical procedures. A transperitoneal and retrocolic approach was preferred in all laparoscopic procedures. Laparoscopic aortobifemoral bypass (LABF) required an operative time of 242 minutes (range, 129 to 465) and open aortobifemoral bypass (OABF), 200 minutes (range, 105 to 430). The mean aortic cross clamping time was 62 minutes in group I and 33 minutes in group II. Mean blood loss was more important in group II (1010 ml) than in group I (682 ml). The average length of hospital stay was 8.1 days for LABF compared with an average of 12 days for OABF. In 21 cases (20%) conversion to open surgery was necessary in the laparoscopic group. Systemic morbidity was significantly higher in the OABF group. Thirty-day postoperative mortality was 2% for group II. There was no hospital mortality in the laparoscopic group. Twenty nine patients were lost to follow-up and the mean follow-up was 23.5 months. CONCLUSION: Analysis of the results shows that laparoscopic aortobifemoral bypass for aortoiliac occlusive disease is a safe procedure. The statistically significant advantages observed in the majority of our patients were decreased blood loss, faster post-operative recovery and shorter hospital stay. In the two groups, late morbidity attributable to the bypass prosthesis was minimal compared with other causes. PMID- 22442911 TI - Prediction of surgical outcome after aortic valve replacement. AB - BACKGROUND: Aortic valve replacement has some major adverse outcomes. For these, the predictors need identification. METHODS: This was a retrospective file study of 1000 consecutive patients who underwent AVR for degenerative aortic valve disease. Twenty-five preoperative and 5 peroperative factors were screened by a univariate Fisher-exact analysis. The predictors were identified in a second step by logistic regression multivariate analysis. RESULTS: Five hundred thirty patients were male. The mean age was 75 (71-77) years and 610 also underwent CABG. For hospital mortality, need for urgent aortic valve replacement (p < 0.001) was the dominant predictor. Need for digitalis (p = 0.002) and age > 80 (p = 0.005) followed. For postoperative congestive heart failure, need for urgent aortic valve replacement was also dominant (p <0.001). Atrial fibrillation (p = 0.001,) and ejection fraction < 50% (p = 0.055) were less important. For ventricular arrhythmia, previous infarction (p = 0.025) and ejection fraction < 50% (p = 0.032) were identified. For bleeding, concomitant CABG (p = 0.046) and chronic obstructive pulmonary disease were identified. For thromboembolic events only an ejection fraction < 50% (p = 0.027) was identified. CONCLUSIONS: Need for urgent aortic valve replacement is the dominant predictor for postoperative mortality and congestive heart failure. Once a degenerative aortic valve disease becomes symptomatic, prompt referral could prevent the development for need for urgent surgery, with all its adverse postoperative consequences. PMID- 22442912 TI - Influence of respiratory cycle on proximal renal artery motion: an angiographic study in patients undergoing endovascular aneurysm repair. AB - BACKGROUND: The purpose of our study was to evaluate the influence of respiratory cycle on proximal renal artery (RA) motion in twenty consecutive patients with abdominal aneurysm and the potential impact on endograft deployment during endovascular aneurysm repair (EVAR). METHODS: Prior to the device introduction, a preoperative angiography to define the location of the RAs was performed by a calibrated pigtail catheter. A measuring tape on the table served as the reference point for all measurements. Images of RA levels were acquired during expiration (E) and inspiration (I) cycles. In order to have homogenous comparative values for each patient during inhalation, the anaesthesiologist maintained a controlled inspiration with a uniform pressure of 30 cm of water. Motion of the RAs was defined as the changes in distance between E and I measures, adjusted to the calibrated pigtail. RESULTS: The median right proximal RA motion was 3.0 mm (IQR 2.4 mm; range: 0 to 5.6 mm). The median left proximal RA motion was 3.1 mm (IQR 2.2 mm; range: 0.54 to 5.6 mm). The current results demonstrate the proximal RAs motion during breath with a median magnitude of 3 mm, without significant differences between both RA (P = .83). CONCLUSION: Our data confirm the RAs motion during respiratory cycle. More than the predictive absolute value of the RA motion between inspiratory and expiratory phases, it is the motion itself which is important. This unrecognized condition, even if it interests only a minority of patients, could potentially have clinical disastrous consequences : potential stenosis or covering of RAs. PMID- 22442913 TI - Acute appendicitis presenting as hyper-amylasemia and testicular pain. PMID- 22442914 TI - Arterioureteral fistula. An unusual cause of aortofemoral bypass infection. A case report. AB - We report a case of arterioureteral fistula after aortobifemoral bypass surgery and prolonged bilateral double J stents due to ureteral stenosis. A 70-year-old woman presented with a non-tender mass in the left groin and a single episode of haematuria 2 months earlier. A Computed Tomography (CT) revealed a pseudoaneurysm of the left distal suture of the graft. Surgical repair was performed. Because of suspicion of infection the entire aortobifemoral graft was removed and replaced by an autologous venous aortofemoral bypass to the right groin and femorofemoral crossover bypass from the right to the left. During surgery an arterioureteral fistula could be visualized. The urologists performed a left nephroureterectomy of the afunctional left kidney. The further postoperative course was uneventful during the 10 months of follow up. PMID- 22442915 TI - A rare histological presentation of a common lung tumor: adenoleiomyomatous hamartoma. AB - Hamartomas are the most common benign pulmonary tumors. They most often contain either chondromatous or lipomatous tissues. Thus, they show typical radiological findings which help to make a preoperative diagnosis of this benign tumor. We present a very rare case of a pulmonary hamartoma with atypical radiologic and histologic findings. Histological examination revealed the lesion to be an adenoleiomyomatous hamartoma. PMID- 22442916 TI - Small bowel obstruction by an anomalous congenital band. AB - We report a case of a 3-year-old boy who presented with symptoms and signs of intestinal obstruction. The patient reported no previous history of abdominal surgery or trauma while clinical and radiographic examinations were not diagnostic. An open laparotomy was subsequently performed and the intraoperative findings were consistent with a congenital band extending from the antimesenteric wall of the jejunum to the root of mesentery. The band was ligated and divided with an uneventful postoperative course. Congenital bands are extremely rare. Their exact incidence is still unknown. This case, therefore, represents an unusual surgical problem in a child in which the diagnosis was clinically unexpected. PMID- 22442917 TI - Aggressive angiomyxoma of the vulva: intra-operative pathological diagnosis is useful in deciding the scope of surgery and reducing recurrence. AB - Aggressive angiomyxoma (AA) is a rare, slow-growing myxoid neoplasm of the pelvi perineum. Because of its rarity, it is often initially misdiagnosed, frequently as a gynaecological malignancy. Surgical resection is the main treatment modality of AA, but, local recurrence rates are high. In order to reduce recurrence, the scope of surgical resection should be as broad as possible. Intra-operative pathological diagnosis is useful in deciding the scope of surgery, and wide excision may reduce recurrence. PMID- 22442918 TI - The Actis-gouge: a simple cutting tool for proper muscular resection in hypertrophic cardiomyopathy. AB - BACKGROUND: Surgical treatment of hypertrophic cardiomyopathy (HC) may be challenging for the risk of surgical complications or insufficient resection. We present our cutting tool to perform proper muscular resection in HC. MATERIAL AND METHODS: Ten patients (5 males, mean age 43,1 +/- 19,6 years, range 9-70 years) were operated on for HC using this semicircular cutting device. Combined procedures were : mitral valve repair (n = 1), mitral valve replacement (n = 2), right ventricular myectomy (n = 1), aortic valve replacement (n = 1), mitral and aortic replacement (n = 1). RESULTS: There was one early death. All the surviving patients are alive over a variable follow up from 2 to 8 years, with consistent reduction of symptoms: in fact, no patient had residual angina with significant reduction of the NYHA class from 3,2 +/- 0,6 to 1,3 +/- 0,5 postoperatively (p < 0,05). Muscular resection was effective with significant reduction of sub valvular gradient from 84.5 + 33,4 mmHg to 14,1 +/- 17,6 mmHg (p < 0,05) without complications such as complete atrio-ventricular block or ventricular septal defects. CONCLUSION: Our semicircular myotome is an effective tool to perform a safe myectomy and it avoids surgical complications such as atrio-ventricular blocks or sub-valvular injuries. Our experience suggests that this cutting tool offers a reproducible method for muscular resection and it shows appreciable effects in the reduction of sub-valvular gradient with promising results in terms of morbidity and mortality. PMID- 22442919 TI - Leuven: birthplace of modern skeletology, thanks to Andreas Vesalius, with the help of Gemma Frisius, his friend and fellow-physician. AB - The skeleton-making technique of Andreas Vesalius is described and is compared with that of others. An overview is added of the skeletons he constructed himself. The significance of his friend Gemma Frisius is discussed as well as the translations of the chapter of this technique in the De humani corporis fabrica. PMID- 22442920 TI - Caesarean section in the world: a new ecological approach. AB - INTRODUCTION: This study aimed to estimate the most recent caesarean section rates in the world and examine the association between these rates and old and new indicators of health care. METHODS: Authors analyzed the Caesarean Section (CS) rates, also in geo-economic and economic groups, and correlated them to maternal and neonatal mortality, to births attended by skilled health personnel and to births among adolescents. Analysis of covariance and piecewise regressions were used for the statistical analysis. RESULTS: In 47.2% of the countries, the CS rate exceeded 15%. Countries of Latin America and the Caribbean along with Europe, North America and Oceania had the highest values. The analysis showed an inverse association between CS rates and Maternal Mortality (MMR) and Neonatal Mortality (NMR) for all geographical areas except for Europe. The greatest association was observed in lower-middle-income countries. In developing countries only 50% of cases, occur in medical facilities and only half of these are seen by medical, nursing and obstetrical staff. Age of the mother appears to influence the outcome and choice of delivery type. Countries where an high ABR rate is present have low CS use. CONCLUSIONS: To best evaluate the consequences of the increasing rate of CS, it would be useful to identify the most sensitive outcome indicators. PMID- 22442921 TI - Physical activity and cancer prevention: a review of current evidence and biological mechanisms. AB - OBJECTIVE: The main aim of this paper is to review the evidence available from the date of PubMed's inception to May 2011 for a link between cancer and physical activity (PA) in both animal models and humans. METHODS: We decided to select studies that comply with the scheme proposed by the American College of Sports Medicine/American Heart Association (ACSM/AHA) that distinguish occupational physical activity (OPA) and leisure-time physical activity (LT-PA), further classified in three levels of intensity (low, moderate and heavy) based on the Metabolic Equivalent of Task (MET) index. RESULTS: Considering animal models, there was strong evidence for an inverse association between voluntary wheel exercise and the risk of colon and breast cancer. Regarding human studies, we identified the following main results: 1) colorectum: LT-PA provided an overall colon risk reduction of 13-14%; 2) breast: significant reduction in the frequency of post-menopausal (PMP) cancers in women that practiced heavy and moderate LT PA; 3) prostate: heavy OPA and LT-PA seemed to reduce the risk of advanced prostate cancers; 4) endometrium: strong protective effect of heavy/moderate LT PA among overweight/ obese women; 5) lung: inverse relationship between heavy LT PA and lung cancer in former or current smokers across all histologies. CONCLUSION: Increased LT-PA is associated with cancer prevention in several organs, but strong biases, such as body mass index (BMI), gender and age, make it difficult to assess which aspects of PA contribute most strongly to the reduced risk. Furthermore, we found few studies that indicated a protective role for OPA in cancer prevention when compared with LT-PA. PMID- 22442922 TI - BMI from nutritional surveillance of 8-9 years old children in Tuscany (Italy). AB - INTRODUCTION: The latest increase in childhood obesity focused attention on the important consequences that this phenomenon may have on public health in relationship to the increasing risk that an obese child may become an obese adult. To deal with this problem, there is necessary to assess systematically the distribution of childhood nutritional status at different levels: international, regional and local. In this paper are presented data on underweight, overweight and obesity prevalence in third grade primary school children, aged 8/9 years in Tuscany (2008) and its distribution in relationship to the demographic breadth of their place of residence. METHODS: Data from statistic sample of 2109 (1.091 males, 1.018 females), 8/9 years school-children were collected; weight and height were measured using standardised personnel and instruments. Exact month age was calculated between the data of measurement and that of birth. Body Mass Index (BMI) classes were calculated using Cole et al.'s epidemiologic cut-off for children and adolescents. Residence areas were divided into four classes based on the number of inhabitants (< 10.000; 10.000-50.000; > 50.000; > 50.000 metropolitan). RESULTS: The prevalence of underweight was 0.88% (0.76% in males and 1.01% in females), the prevalence of overweight was 23.43% (22.33% in males and 24.65% in females), the prevalence of obese was 7.95% (9.08% in males, 6.70% in females). The lowest prevalence of obese (6.46%) was found in towns with over 50.000 residents (metropolitan). CONCLUSION: The obesity prevalence in Tuscany children is still lower than that of the Italian National Survey, while the overweight prevalence it's the same. Obesity prevalence (10.71%) is higher in municipalities with low residents number (< 10.000). PMID- 22442923 TI - Knowledge of breast cancer and practice of breast self examination among female senior secondary school students in Abuja, Nigeria. AB - INTRODUCTION: Breast cancer is a public health problem that is increasing throughout the world especially in developing countries. The study was aimed at assessing the knowledge of breast cancer and practice of breast self examination (BSE) among female senior secondary school students in the municipal council area of Abuja, Nigeria. METHODS: This descriptive cross sectional study was carried out among female senior secondary school students from selected schools in the municipal area council of Abuja. The tool for data collection was a structured self administered questionnaire. Data were analysed using SPSS version 16.0. RESULTS: Two hundred and eighty-seven students participated in the study. Their mean age was 16.5 +/- 1.4 years. A greater proportion of respondents 163 (56.8%) had poor knowledge of breast cancer while 217 (75.6%) had poor knowledge of BSE. Only 114 (39.7%) of the respondents knew that being a female was a risk factor for breast cancer and the least known risk factors were obesity and aging. The major source of information for breast cancer and BSE among the respondents was the mass media. Only 29 (10.1%) of respondents had practiced BSE. Knowledge of BSE was significantly associated with BSE practice. CONCLUSION: This study revealed that female secondary school students have poor knowledge of breast cancer. A good proportion of them knew that BSE could be used as a screening method for breast cancer but only few had practiced BSE. There is need for adequate health education on breast cancer and BSE among adolescent females in Nigeria. PMID- 22442924 TI - A proposal for an evidence-based model of the screening for the colorectal carcinoma in an Italian setting. AB - INTRODUCTION: The aim of this paper is to improve the feasibility perception of policymakers, health care workers and target population about the cost effectiveness of the implementation of colorectal screening as Public Health strategy. METHODS: Retrospective study by application of a three-step model designed for a local setting in Sicily (Palermo and its Province) in order to distribute Fecal Occult Blood Tests (FOBTs), offer colonoscopy and surgery, by district allocation of pharmacies, public digestive endoscopic centres and oncologic and general surgery units. Mean adherence to consolidated colorectal screening programs in Italy was applied in order to evaluate the feasibility of an operative model in our area. RESULTS: Applying the model to the target population (269,368 individuals of both sexes), it can be expected a mean percentage of 79% delivered invitation and a mean participation rate of 46.3% accounting for a total of 213,070 invited individuals and 98,651 participating in the first round of the program. Furthermore, considering the national mean of 6% positive FOBT, 82% of colonscopy adhesion and 7% CRC detection rate, it can be scheduled a burden for health care structures involved in the program accounting for 49,325 FOBTs, 2,338 colonscopies and 141 surgeries for each year. DISCUSSION: This work demonstrates the feasibility of a colorectal screening project in our area, showing a sustainable impact for local health care involved structures. Furthermore, this program may be spread as an applicative model to other areas, adapting the project to the needs of the local setting in which the colorectal screening will be organized. PMID- 22442925 TI - Knowledge, attitude and practice of medical students towards self medication at Ain Shams University, Egypt. AB - INTRODUCTION: Self medication is usually defined as intake of any type of drugs for treating oneself without professional supervision to relieve an illness or a condition. Self medication is an issue with serious global implications. In this study it was aimed to determine the knowledge, attitudes and behavior of self medication by the near coming physicians. METHODS: A cross-sectional study was conducted on a sample of randomly selected medical students from Ain Shams University. Data was collected using self administered questionnaire. Verbal consent was ensured before applying the questionnaire. The Chi square was performed using SPSS 16 to identify associations and differences. RESULTS: The sample consisted of 300 students 67% females and 33% male students. Prevalence of self medication was 55%. Out of which 58.8%, 54.4%, 87.2%, 12%, 28% took antibiotic, vitamins, analgesics, sedatives, herbal products respectively without physician prescription. As regards the personal behavior towards following any prescription 14.4% always followed properly the prescription compared to 63.3% always discontinued the drug on feeling improvement, and 13.6% always repeated the prescription without seeking medical advice. Also 60% said that they increased the dose without medical advice. As regards the reported side effects 4.8%, 1.6%, 12% as a result of interaction between drugs, increase dose without medical advice and early stopping of treatment respectively. CONCLUSION: Self medication by medical students is an important issue to be avoided and need to be added to the curriculum of undergraduate students and raise the community awareness about these hazards and drawbacks. PMID- 22442926 TI - Prevalence and correlates for self-reported sleep problems among nursing students. AB - INTRODUCTION: University students report significantly worse sleep quality than the general population. Sleep problems are related to increased health concerns, irritability, depression, fatigue, attention and concentration difficulties, along with poor academic performance. The aim of this paper is to conduct a survey based on a questionnaire that would characterize night time and daytime habits in nursing students to estimate the prevalence of chronic insomnia, sleep disturbance and their correlates. METHODS: We conducted a cross-sectional survey among 364 nursing students of the University of L'Aquila, in Italy. Self-reported sleep data were derived from Sleep and Daytime Habits Questionnaire" (S&DHQ) that covered sleep and daytime habits and academic progress. Anxiety and depression symptoms were assessed by the Mental Health Inventory-5 (MHI-5) questionnaire. A supplement includes information about lifestyle, health status and physical activity. RESULTS: The overall prevalence of insomnia was 26.7%. It increased significantly from 10.3% for students aged < 20 years to 45.5% for those aged > 40 years. The prevalence of sleep problems were 9.4% for disorders of initiating sleep, 8.3% for disrupted sleep, 7.7% for early morning awakening and subjectively poor quality of sleep 22.3%. Multiple logistic regression analysis showed that greater age was significantly associated with an increased risk of insomnia. Other risk predictors of insomnia were headache, severe depression and self perception of poor quality of life. Daytime sleepiness and morning tiredness were significantly associated with current smoking habit and painful physical condition. The risk of unsatisfactory academic progress increased significantly in students reported poor sleep quality. DISCUSSION: Our study demonstrates that sleep problems are very common among students, and supports the need to assess sleep problems and identify students at risk regarding school achievement. PMID- 22442927 TI - Retrospective analysis of microorganisms isolated from cystic fibrosis patients in Southern Italy, 2002-2010. AB - OBJECTIVE: This study aim was to determine the prevalence of microorganisms in the respiratory tract of patients with cystic fibrosis (CF) admitted to the CF Reference Centre in Southern Italy between 2002-2010. METHODS: Microbiology assessment of samples (sputum and tracheal aspirates) collected from patients with pulmonary exacerbation admitted to hospital was carried out. All patients were registered in a database and clinical and microbiological data were retrospectively analysed. RESULTS: Overall, 188 patients were included and a total of 1217 samples were analysed. The most common microorganisms were Staphylococcus aureus (78.7% of the patients) and Pseudomonas aeruginosa (58%), followed by Candida albicans (19.1%), Haemophilus influenzae (13.3%) and Aspergillus fumigatus (9.6%). CONCLUSION: Compared to similar studies performed in other European countries, our microbiological data, especially the low occurrence of filamentous fungi, suggest a specific local epidemiology, probably related to some uncommon CFTR mutations, which are specific to Southern Italy. PMID- 22442928 TI - Evaluation of bacterial and fungal contamination in the health care workers' hands and rings in the intensive care unit. AB - INTRODUCTION: Nosocomial infections remain a major challenge to the health care system and result in significant mortality, morbidity, and economic burden. Intensive care unit (ICU) patients are at great risk of acquiring nosocomial infections. The objective of this study was to determine the contamination rate (bacterial and fungal) of the health care workers' (HCWs') hands and ring in ICU. METHODS: All health care workers were screened during the day shift in Emam hospital ICU. After obtaining informed consent, convenience samples of HCWs' hands and rings were cultured on specific media during their routine work hours, always after a patient care episode. The fungal and bacterial isolates were identified using standard microbiological procedures. RESULTS: A total of 40 subjects were selected in this study (28 females, 12 males). The rate of contamination of hands and rings was observed in 73.1%. Most of isolates are known to cause nosocomial infections which included: 23% staphylococci, 7.9% Klebsiella spp., 4.7% Enterobacter spp., 3.9% Escherichia coli, 3.1% Acinetobacter spp., 2.3% Pseudomonas spp., and 27.7% were colonized with fungi. The fungal isolates were 16.6% Candida spp., 3.9% Rhodotorula spp., 3.1% Aspergillus niger, and 3.9% Aspergillus flavus. CONCLUSION: According to these results HCWs' hands and their rings were contaminated with various types of microorganisms. Medical and hospital personals must follow careful hand-washing techniques to minimize transmission of disease and should remove rings, watches, and bracelets before washing their hands and entering the ICU. PMID- 22442929 TI - A study on the sexual and contraception behaviours of the pre-university students in Puglia (South-Italy). AB - INTRODUCTION: The aim of the present study is to determine attitude and associated factors towards the use of methods of protection/contraception. METHODS: In August 2008, a study was carried out using a self-administered standardised anonymous questionnaire. It was administered to school-leavers who were attending a study course at Bari University. RESULTS: The total number of questionnaires returned was 1091, the average age of the interviewed subjects was 19.6. Those declaring to have had sexual intercourse at least once was 88%. Of those sexually active, the average age at first intercourse was 16.8, and 75.2% stated that they had used some form of contraception on this occasion. The condom was the most popular method employed, followed by withdrawal and by contraceptive pills. Around 20% of the interviewees indicated that they used emergency post coital contraception. DISCUSSION: The study results emphasise the importance of an effective teaching of the aspects of sex and relationship education before puberty. PMID- 22442930 TI - Mercury emission and plant uptake of trace elements during early stage of soil amendment using flue gas desulfurization materials. AB - A pilot-scale field study was carried out to investigate the distribution of Hg and other selected elements (i.e., As, B, and Se), i.e., emission to ambient air, uptake by surface vegetation, and/or rainfall infiltration, after flue gas desulfurization (FGD) material is applied to soil. Three FGD materials collected from two power plants were used. Our results show Hg released into the air and uptake in grass from all FGD material-treated soils were all higher (P < 0.1) than the amounts observed from untreated soil. Hg in the soil amended with the FGD material collected from a natural oxidation wet scrubber (i.e., SNO) was more readily released to air compared to the other two FGD materials collected from the synthetic gypsum dewatering vacuum belt (i.e., AFO-gypsum) and the waste water treatment plant (i.e., AFO-CPS) of a forced oxidation FGD system. No Hg was detected in the leachates collected during the only 3-hour, 1-inch rainfall event that occurred throughout the 4-week testing period. For every kilogram of FGD material applied to soil, AFO-CPS released the highest amount of Hg, B, and Se, followed by SNO, and AFO gypsum. Based on the same energy production rate, the land application of SNO FGD material from Plant S released higher amounts of Hg and B into ambient air and/or grass than the amounts released when AFO-gypsum from Plant A was used. Using FGD material with lower concentration levels of Hg and other elements of concern does not necessary post a lower environmental risk. In addition, this study demonstrates that considering only the amounts of trace elements uptake in surface vegetation may under estimate the overall release of the trace elements from FGD material-amended soils. It also shows, under the same soil amendment conditions, the mobility of trace elements varies when FGD materials produced from different processes are used. PMID- 22442931 TI - Thermal inactivation of Bacillus anthracis surrogate spores in a bench-scale enclosed landfill gas flare. AB - A bench-scale landfill flare system was designed and built to test the potential for landfilled biological spores that migrate from the waste into the landfill gas to pass through the flare and exit into the environment as viable. The residence times and temperatures of the flare were characterized and compared to full-scale systems. Geobacillus stearothermophilus and Bacillus atrophaeus, nonpathogenic spores that may serve as surrogates for Bacillus anthracis, the causative agent for anthrax, were investigated to determine whether these organisms would be inactivated or remain viable after passing through a simulated landfill flare. High concentration spore solutions were aerosolized, dried, and sent through a bench-scale system to simulate the fate of biological weapon (BW) grade spores in a landfill gas flare. Sampling was conducted downstream of the flare using a bioaerosol collection device containing sterile white mineral oil. The samples were cultured, incubated for seven days, and assessed for viability. Results showed that the bench-scale system exhibited good similarity to the real world conditions of an enclosed standard combustor flare stack with a single orifice, forced-draft diffusion burner. All spores of G. stearothermophilus and B. atrophaeus were inactivated in the flare, indicating that spores that become re-entrained in landfill gas may not escape the landfill as viable, apparently becoming completely inactivated as they exit through a landfill flare. PMID- 22442932 TI - Reducing ammonia emissions from laying-hen houses through dietary manipulation. AB - Feed additives can change the microbiological environment of the animal digestive track, nutrient composition of feces, and its gaseous emissions. This 2-yr field study involving commercial laying-hen houses in central Iowa was conducted to assess the effects of feeding diets containing EcoCal and corn-dried distillers grain with solubles (DDGS) on ammonia (NH3), hydrogen sulfide (H2S), and greenhouse gas (CO2, CH4, and N2O) emissions. Three high-rise layer houses (256,600 W-36 hens per house) received standard industry diet (Control), a diet containing 7% EcoCal (EcoCal) or a diet containing 10% DDGS (DDGS). Gaseous emissions were continuously monitored during the period of December 2007 to December 2009, covering the full production cycle. The 24-month test results revealed that mean NH3 emission rates were 0.58 +/- 0.05, 0.82 +/- 0.04, and 0.96 +/- 0.05 g/hen/day for the EcoCal, DDGS, and Control diet, respectively. Namely, compared to the Control diet, the EcoCal and DDGS diets reduced NH3 emission by an average of 39.2% and 14.3%, respectively. The concurrent H2S emission rates were 5.39 +/- 0.46, 1.91 +/- 0.13, and 1.79 +/- 0.16 mg/ hen/day for the EcoCal, DDGS, and Control diet, respectively. CO2 emission rates were similar for the three diets, 87.3 +/- 1.37, 87.4 +/- 1.26, and 89.6 +/- 1.6 g/hen/day for EcoCal, DDGS, and Control, respectively (P = 0.45). The DDGS and EcoCal houses tended to emit less CH4 than the Control house (0.16 and 0.12 vs. 0.20 g/hen/day) during the monitored summer season. The efficacy of NH3 emission reduction by the EcoCal diet decreased with increasing outside temperature, varying from 72.2% in February 2009 to -7.10% in September 2008. Manure of the EcoCal diet contained 68% higher ammonia nitrogen (NH3-N) and 4.7 times higher sulfur content than that of the Control diet. Manure pH values were 8.0, 8.9, and 9.3 for EcoCal, DDGS, and Control diets, respectively. This extensive field study verifies that dietary manipulation provides a viable means to reduce NH3 emissions from modern laying hen houses. PMID- 22442933 TI - Full-scale biofilter reduction efficiencies assessed using portable 24-hour sampling units. AB - Portable 24-hr sampling units were used to collect air samples from eight biofilters on four animal feeding operations. The biofilters were located on a dairy, a swine nursery, and two swine finishing farms. Biofilter media characteristics (age, porosity, density, particle size, water absorption capacity, pressure drop) and ammonia (NH3), hydrogen sulfide (H2S), sulfur dioxide (SO2), methane (CH4), and nitrous oxide (N2O) reduction efficiencies of the biofilters were assessed. The deep bed biofilters at the dairy farm, which were in use for a few months, had the most porous media and lowest unit pressure drops. The average media porosity and density were 75% and 180 kg/m3, respectively. Reduction efficiencies of H2S and NH3 (biofilter 1: 64% NH3, 76% H2S; biofilter 2: 53% NH3, 85% H2S) were close to those reported for pilot-scale biofilters. No N2O production was measured at the dairy farm. The highest H2S, SO2, NH3, and CH4 reduction efficiencies were measured from a flat-bed biofilter at the swine nursery farm. However, the highest N2O generation (29.2%) was also measured from this biofilter. This flat-bed biofilter media was dense and had the lowest porosity. A garden sprinkler was used to add water to this biofilter, which may have filled media pores and caused N2O production under anaerobic conditions. Concentrations of H2S and NH3 were determined using the portable 24 hr sampling units and compared to ones measured with a semicontinuous gas sampling system at one farm. Flat-bed biofilters at the swine finishing farms also produced low amounts of N2O. The N2O production rate of the newer media (2 years old) with higher porosity was lower than that of older media (3 years old) (P = 0.042). PMID- 22442934 TI - Methane emissions from 20 landfills across the United States using vertical radial plume mapping. AB - Landfill fugitive methane emissions were quantified as a function of climate type and cover type at 20 landfills using US. Environmental Protection Agency (EPA) Other Test Method (OTM)-10 vertical radial plume mapping (VRPM) with tunable diode lasers (TDLs). The VRPM data were initially collected as g CH4/sec emission rates and subsequently converted to g CH4/m2/ day rates using two recently published approaches. The first was based upon field tracer releases of methane or acetylene and multiple linear regression analysis (MLRM). The second was a virtual computer model that was based upon the Industrial Source Complex (ISC3) and Pasquill plume stability class models (PSCMs). Calculated emission results in g CH4/m2/day for each measured VRPM with the two approaches agreed well (r2 = 0.93). The VRPM data were obtained from the working face, temporary soil, intermediate soil, and final soil or synthetic covers. The data show that methane emissions to the atmosphere are a function of climate and cover type. Humid subtropical climates exhibited the highest emissions for all cover types at 207, 127, 102, and 32 g CH4/m2/day, for working face (no cover), temporary, intermediate, and final cover, respectively. Humid continental warm summers showed 67, 51, and 27 g CH4/m2/day for temporary, intermediate, and final covers. Humid continental cool summers were 135, 40, and 26 g CH4/m2/day for the working face, intermediate, and final covers. Mediterranean climates were examined for intermediate and final covers only and found to be 11 and 6 g CH4/m2/day, respectively, whereas semiarid climates showed 85, 11, 3.7, and 2.7 g CH4/m2/day for working face, temporary, intermediate, and final covers. A closed, synthetically capped landfill covered with soil and vegetation with a gas collection system in a humid continental warm summer climate gave mostly background methane readings and average emission rates of only 0.09 g CH4/m2/day flux when measurable. PMID- 22442935 TI - An inexpensive active optical remote sensing instrument for assessing aerosol distributions. AB - Air quality studies on a broad variety of topics from health impacts to source/sink analyses, require information on the distributions of atmospheric aerosols over both altitude and time. An inexpensive, simple to implement, ground based optical remote sensing technique has been developed to assess aerosol distributions. The technique, called CLidar (Charge Coupled Device Camera Light Detection and Ranging), provides aerosol altitude profiles over time. In the CLidar technique a relatively low-power laser transmits light vertically into the atmosphere. The transmitted laser light scatters off of air molecules, clouds, and aerosols. The entire beam from ground to zenith is imaged using a CCD camera and wide-angle (100 degree) optics which are a few hundred meters from the laser. The CLidar technique is optimized for low altitude (boundary layer and lower troposphere) measurements where most aerosols are found and where many other profiling techniques face difficulties. Currently the technique is limited to nighttime measurements. Using the CLidar technique aerosols may be mapped over both altitude and time. The instrumentation required is portable and can easily be moved to locations of interest (e.g. downwind from factories or power plants, near highways). This paper describes the CLidar technique, implementation and data analysis and offers specifics for users wishing to apply the technique for aerosol profiles. PMID- 22442936 TI - Acid neutralization of precipitation in Northern China. AB - There is an increasing concern over the impact of human-related emissions on the acid precipitation in China. However, few measurements have been conducted so far to clarify the acid-neutralization of precipitation on a regional scale. Under a network of 10 sites across Northern China operated during a 3-year period from December 2007 to November 2010, a total of 1118 rain and snow samples were collected. Of this total, 28% was acid precipitation with pH < 5.6. Out of these acid samples, 53% were found heavily acidic with pH value below 5.0, indicating significantly high levels of acidification of precipitation. Most of the acidity of precipitation was caused by H2SO4 and HNO3, their relative contribution being 72% and 28%, respectively. However; the contribution of HNO3 to precipitation acidity will be enhanced due to the increasing NO(x) and stable SO2 emissions in future. Neutralization factors for K+, NH4+, Ca2+, Na+, and Mg2+ were estimated as 0.06, 0.71, 0.72, 0.15, and 0.13, respectively. The application of multiple regression analysis further quantified higher NH4+ and Ca2+ contribution to the neutralization process, but the dominant neutralizing agent varied from site to site. The neutralization was less pronounced in the rural than urban areas, probably due to different levels of alkaline species, which strongly buffered the acidity. Presence of high concentrations of basic ions was mainly responsible for high pH of precipitation with annual volume-weighted mean (VWM) values larger than 5.6 at several sites. It was estimated that in the absence of buffering ions, for the given concentration of SO4(2-) and NO3-, the annual VWM pH of precipitation would have been recorded around 3.5 across Northern China. This feature suggested that emissions of particles and gaseous NH3 played very important role in controlling the spatial variations of pH of precipitation in the target areas. PMID- 22442937 TI - Effect of solution pH on SO2, NO(x), and Hg removal from simulated coal combustion flue gas in an oxidant-enhanced wet scrubber. AB - This paper presents a study on the simultaneous removal of SO2, NO(x) and Hg (both Hg0 and Hg2+) from a simulated flue gas by oxidant injection in a bench simulated wet limestone scrubber for a wide range of slurry pH. The slurry pH strongly influenced the chemical mechanism in the scrubber and, therefore, affected pollutant removal. This paper also examines the potential ClO2(gas) reemission from a developed multipollutant scrubber at different slurry pHs. To better understand the chemical mechanisms at each slurry pH and to apply a mass balance to the process, detailed product ion analyses were performed for all experiments. Ion analysis covered three different chlorine species (chlorite, chloride, chlorate), sulfate, nitrite and nitrate. Different NO(x) removal efficiencies and mechanisms were found in acidic and alkaline pHs in the multipollutant scrubber. The acidic solution was favorable for NO and Hg0 oxidation, but increasing the slurry pH above 7.0 was disadvantageous for NO and Hg oxidation/removal. However the rate of NO(x) absorption (by percentage) was higher for the alkaline solution. PMID- 22442938 TI - Carbonyl emissions from vehicular exhausts sources in Hong Kong. AB - Vehicular emission (VE) is one of the important anthropogenic sources for airborne carbonyls in urban area. Six types of VE-dominated samples were collected at representative locations in Hong Kong where polluted by a particular fueled type of vehicles, including (i) a gas refilling taxis station (liquefied petroleum gas [LPG] emission); (ii) a light-duty passenger car park (gasoline emission); (iii) a minibus station (diesel emission); (iv) a single-deck-bus depot (diesel emission); (v) a double-deck-bus depot (diesel emission); and (vi) a whole-food market entrance for light- and heavy-duty vehicles (diesel emission). A total of 15 carbonyls in the samples were quantified. Formaldehyde was the most abundant carbonyl among the VE-dominated samples, and its contribution to the total quantified amount on a molar basis ranged from 54.8% to 60.8%. Acetaldehyde and acetone were the next two abundant carbonyls. The carbonyls were quantified at three roadside locations in Hong Kong. The highest concentrations of formaldehyde and acetaldehyde, 22.7 +/- 8.4 and 6.0 +/- 2.8 microg/m3, respectively, were determined in the samples collected at a main transportation gate for goods between Hong Kong and Mainland China. The total quantified carbonyl concentration, 37.9 +/- 9.3 microg/m3, was the highest at an entrance of a cross-harbor tunnel in downtown area. The theoretical carbonyls compositions of the three roadside locations were estimated according to the VE dominated sample profiles and the statistics on vehicle numbers and types during the sampling period. The measured compositions of formaldehyde were much higher than the theoretical compositions in summer, demonstrating that photochemical reactions significantly contributed to the formaldehyde production in the roadsides. PMID- 22442939 TI - Physicochemical properties of chars at different treatment temperatures. AB - In this study, the physicochemical properties of the char of Indonesian SM coal following heat treatment at various temperatures were evaluated using X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy (FT IR), scanning electron microscopy (SEM), and morphological and specific surface area analysis. Based on these analyses, heat treatment of coal was determined to be the most effective in increasing the coal rank. In the XPS analysis, the C-O and C-O-C groups and quaternary-N species were found to be of a lower grade coal when the pretreatment temperature decreased, meanwhile the C-C group and pyridinic species increased. In the FT-IR analysis, the collapse of the C-O and C O-C group was observed due to the collapse of the ether group. In SEM and Brunauer-Emmett-Teller (BET) analysis, a decrease in the ether group was shown to be accompanied with the formation of micropores. PMID- 22442940 TI - A novel methodology for determining low-cost fine particulate matter street sweeping routes. AB - This paper addresses the problem of low-cost PM10 (particulate matter with aerodynamic diameter < 10 microm) street sweeping route. In order to do so, only a subset of the streets of the urban area to be swept is selected for sweeping, based on their PM10 emission factor values. Subsequently, a low-cost route that visits each street in the set is computed. Unlike related problems of waste collection where streets must be visited once (Chinese or Rural Postman Problem, respectively), in this case, the sweeping vehicle route must visit each selected street exactly as many times as its number of street sides, since the vehicle can sweep only one street side at a time. Additionally, the route must comply with traffic flow and turn constraints. A novel transformation of the original arc routing problem into a node routing problem is proposed in this paper. This is accomplished by building a graph that represents the area to sweep in such a way that the problem can be solved by applying any known solution to the Traveling Salesman Problem (TSP). As a way of illustration, the proposed method was applied to the northeast area of the Municipality of Santiago (Chile). Results show that the proposed methodology achieved up to 37% savings in kilometers traveled by the sweeping vehicle when compared to the solution obtained by solving the TSP problem with Geographic Information Systems (GIS)--aware tools. PMID- 22442941 TI - Efficacy of recent state implementation plans for 8-hour ozone. AB - The development of state implementation plans (SIPs) for attainment of criteria pollutant standards is an integral component of air quality management in the United States. However, the content and efficacy of SIPs have rarely been examined systematically. Here, 20 SIPs developed in response to the 1997 8-hr ozone standard are reviewed as case studies of attainment efforts at the state level. Comparison of observed and model predicted ozone concentrations shows the US Environmental Protection Agency (EPA) recommended modeled attainment test to be a somewhat conservative predictor of attainment. Among 12 SIPs for regions that sought attainment by 2009, the test correctly predicted attainment and nonattainment in four and five regions, respectively; in the other three regions, attainment was observed despite predictions of nonattainment. However weight-of evidence determinations and deviations from the recommended modeled attainment test methodology led five of these SIPs to predict attainment that was not in fact observed by 2009; three of those regions achieved attainment in 2010. Ozone and NO2 concentrations declined across much of the United States during the period covered by the SIPs, with rates of improvement strongly correlated with the initial pollution levels and hence greatest in nonattainment regions. However at monitors with mid-range levels of ozone initially, rates of reduction were largely independent of the initial attainment status of the region. This is consistent with thefact that apart from California, the majority of ozone precursor reductions documented by SIPs resulted from federal measures rather than from state or local controls specific to the nonattainment regions. PMID- 22442942 TI - Resource recycling through artificial lightweight aggregates from sewage sludge and derived ash using boric acid flux to lower co-melting temperature. AB - This study focuses on artificial lightweight aggregates (ALWAs) formed from sewage sludge and ash at lowered co-melting temperatures using boric acid as the fluxing agent. The weight percentages of boric acid in the conditioned mixtures of sludge and ash were 13% and 22%, respectively. The ALWA derived from sewage sludge was synthesized under the following conditions: preheating at 400 degrees C 0.5 hr and a sintering temperature of 850 degrees C 1 hr. The analytical results of water adsorption, bulk density, apparent porosity, and compressive strength were 3.88%, 1.05 g/cm3, 3.93%, and 29.7 MPa, respectively. Scanning electron microscope (SEM) images of the ALWA show that the trends in water adsorption and apparent porosity were opposite to those of bulk density. This was due to the inner pores being sealed off by lower-melting-point material at the aggregates'surface. In the case of ash-derived aggregates, water adsorption, bulk density, apparent porosity, and compressive strength were 0.82%, 0.91 g/cm3, 0.82%, and 28.0 MPa, respectively. Both the sludge- and ash-derived aggregates meet the legal standards for ignition loss and soundness in Taiwan for construction or heat insulation materials. PMID- 22442943 TI - [A method of increasing the sensitivity and resolution of NMR spectroscopy]. PMID- 22442944 TI - [Estimation of the homeostatic activity of human body and its systems in treatment of the cancer of the uterine cervix]. PMID- 22442945 TI - [A stereotactic neurosurgery system NIZAN-M]. PMID- 22442946 TI - [Tomosynthesis of the human head phantom on the ProGraf-7000 apparatus]. PMID- 22442947 TI - [Determination of the practical peak voltage from the bremsstrahlung damping rate in a semiconductor detector]. PMID- 22442948 TI - [A subsystem for electroencephalographic diagnosis of epilepsy]. PMID- 22442949 TI - [Analysis of the effect of audiovisual stimulation on the parameters of encephalogram and the rate of pulse wave propagation in humans]. PMID- 22442950 TI - [Calibration testing of instruments for measurement of arterial pressure and heart rate using pulsating liquid streams]. PMID- 22442951 TI - [Implementation of tuning fork hearing tests using electronic devices]. PMID- 22442952 TI - [Automated estimation of the severity of walking disorders in patients after stroke]. PMID- 22442953 TI - [Artificial bladder sphincter implants for treating urge urinary incontinence]. PMID- 22442954 TI - [Electrophysiological study of the mechanism of mexidol action]. AB - It has been found that mexidol (5 mM) significantly (96 +/- 2%) depressed excitatory postsynaptic current caused by step depolarization in neurons of medial vestibular nucleus of medulla oblongata slices in young (aged 13 - 17 days) male albino rats. In addition, mexidol (2,5 - 5 mM) depressed by 94 +/- 3% excitatory postsynaptic current caused by Shaffer collaterals stimulation of CA1 pyramidal neurons of hippocampal slices in young rats. Complex MK-801 (non competitive antagonist of NMDA receptors), in contrast to CNQX (competitive AMPA receptor antagonist), considerably decreased the depressant effect of the drug in both brain structures. Therefore, the central favorable effect of mexidol can be mediated by ion mechanisms with glutamate- and GABA-ergic components, primarily by the inhibition of ion currents through NMDA receptor complex. PMID- 22442955 TI - [Effect of disulfiram on energy metabolism (redox potential shift) coupled to paradoxical sleep episodes in rat cerebral cortex]. AB - Disulfiram (DS) is widely used to treat patients with chronic alcoholism. DS treatment multiplies PS episodes. In this work, DS effect on the number of PS episodes and on the energy metabolism changes in the cerebral cortex (coupled to PS episodes) was investigated for the first time in rats. Polygraphic recording of the redox potential E (with platinum electrodes implanted in several cortical sites), electrocorticogram, neck electromyogram, and general motor activity were made in sleep-wake cycles. Rats received DS (100 mg/kg) with meals for two nights, after which the number of PS episodes increased almost twice during two subsequent sessions (prior to receiving DS). This was evidence of an increase in PS pressure coupled to a decrease of norepinephrine level in the brain. DS also evoked sharp decrease in the amount of the positive E shifts related to PS, which were replaced by the negative E shifts or by the two-phase E shifts (negative positive waves). The absolute mean amplitude decreased both for the positive E shifts and the negative E shifts. These findings demonstrate prevailing glycolytic compartment as a source of fuel supporting PS and the inhibition in all brain energetic compartments. The data presented well agree with the conception that glycolysis becomes the main source for the brain activity under pathology conditions. PMID- 22442956 TI - [Behavioral effects of ketanserine in prenatally stressed female rats]. AB - Comparative study of the effects of chronic administration of 5-HT(2A/2C) receptors agonist (m-CPP, 0.5 mg/kg, i.p.) and 5-HT(2A/2C)-receptors antagonist (ketanserine, 0.1 mg/kg, i.p.) for 14 days on the anxiety- and depression-like behavior in adult prenatally stressed female rats showed that prenatal stress increased the anxiety level in female rats. Chronic administration of ketanserine produced anxiolytic and antidepressant effects, which inhibited the negative action of prenatal stress on the emotional behavior, whereas chronic administration of m-CPP did not change the emotional behavior. PMID- 22442957 TI - [Hypolipidemic activity of trimethylglycine]. AB - Hypolipidemic properties of a native trimethyl derivative of glycine, trimethylglycine (TMGl), were studied in hyperlipidemic rats and guinea pigs. The administration of TMGl to the hyperlipidemic rats and guinea pigs produced a pronounced hypolipidemic effect. A positive action of TMGl on the lipid profile of blood serum of the experimental animals was observed as manifested by a decrease in the level of cholesterol of low density lipoproteins (LDL) and an increase in the cholesterol level of high density lipoproteins (HDL). PMID- 22442958 TI - [Effect of some vitamins on activity of immunocompetent cells]. AB - The content of vitamins A, E, B1, B2, B6 in lymphocytes and serum of blood was studied with simultaneous determination of CD3+, CD5+, CD4+, CD8+, CD16+, CD25+, CD71+, CD95+, and HLADR+ populations. According to cellular immunity response, patients were divided into two groups--with physiological norm and deficiency. It was established that, irrespective of the group, the content of vitamins A, E, B6 in blood serum does not change, while the concentration of B1 and B2 in the group with physiological norm is greater than that in the group with deficiency. In the group with deficiency of cellular immunity, increased level of endocellular vitamins A, E, B2 and B6 was revealed. Concentration of thiamine in both blood serum and lymphocytes in the group with physiological norm was greater than in the group with deficiency of cellular immunity. PMID- 22442959 TI - [Dose-dependent interferon-induction activity and pharmacokinetics of cycloferon in healthy humans]. AB - Dose-dependent interferonogenic activity and pharmacokinetics of cycloferon--a low-molecular inductor of interferon--have been studied in a group of 35 healthy volunteers. It is established that cycloferon induces the production of early alpha-IFN within 24 h from the moment of drug introduction. In a dose of 500 mg, the drug induces production of gamma-IFN by leukocytes in vitro within 24 h from the moment of introduction, with retention of the titer for 48 h. This proves the need for differentiated approach to a choice of the dose of cycloferon, depending on diseases in which complex treatment involving interferon inductors is required. After the introduction of cycloferon (500 mg) in healthy volunteers, the peak of drug concentration in the blood is observed in 40 min, with the subsequent considerable decrease within 2 h. Variation of the cycloferon concentration in the blood correlates with its content in urine, which is evidence for the drug elimination from organism through kidneys. PMID- 22442960 TI - [Studying toxicity caused by interaction of caffeine and ketorolac]. AB - Combined administration of caffeine and ketorolac (NSAID) is accompanied by all possible types of drug interaction. Side effects of the drug combination are mostly due to the action of ketorolac and manifested by decompensated renal failure and progressive endotoxemia within 3 - 7 days after single administration of drugs. Thus, the amplification of ketorolac effects by caffeine must be taken into consideration in prescribing NSAIDs. PMID- 22442961 TI - [Effects of granulocyte colony-stimulating factor on experimental bleomycin induced pulmonary fibrosis]. AB - The influence of granulocyte colony-stimulating factor (G-CSF) has been studied on a model of bleomycin-induced pulmonary fibrosis. It is established that G-CSF significantly increases infiltration of alveolar and alveolar duct interstitium by inflammation cells (lymphocytes, neutrophils, plasmocytes) and increases collagen deposition in lung under conditions of bleomycin introduction. Simultaneously with profibrotic and anti-inflammation effects, G-CSF increased the content of granulocyte cells in the bone marrow and peripheral blood, which was related to the stimulation of committed granulocyte precursors in the bone marrow. PMID- 22442962 TI - [Mechanism of neuroprotector action of metabolic antihypoxant reamberin in patients with toxicohypoxic encephalopathy]. AB - Based on investigation of a group of patients with heavy forms of sharp poisoning by neurotropic substances, it is established that inclusion if antihypoxant reamberin in intensive treatment of toxicohypoxic encephalopathy leads to a decrease in the depth of central nervous system depression. This is manifested by reduced duration of patient stay in coma and decreased total duration of resuscitation treatment. Improvement of the clinical picture is accompanied by a decrease in lipid peroxidation activity, increase in the level of antioxidant enzymes, and decrease in the level of NR2A auto-antibodies. That is objective evidence of the efficiency of neuroprotective therapy by reamberin. PMID- 22442963 TI - [Erythropoietin and blood oxygen transport: new sides of well-known problem]. AB - Original results and literature data on the erythropoietin effects and mechanisms of action are analyzed. The action of this substance on blood oxygen transport is not only manifested by direct change in hemoglobin concentration and, correspondingly, by increased oxygen capacity, but is also mediated by modulators of hemoglobinaffinity to oxygen, in particular, via nitric oxide effect on hemoglobin. PMID- 22442964 TI - [Taxonomic characteristics and mixed communities of wound infection agents in patients of reanimation and surgical departments of a hospital]. AB - AIM: Study of taxonomical structure ofwound infection agents, prevalence of mixes, and detection of character of their possible connection with the results of various microorganisms population interaction in septic wounds. MATERIALS AND METHODS: A microbiological study of material from patients with wound infection (WI), 582 of those were cured in reanimation and intensive therapy departments (RITD; group 1) and 1455 - in surgical departments (SD; group 2), was performed. Taxonomic membership and ability to coexist was determined in 4129 microorganisms strains. Etiological role of the agents was evaluated by using values of consistency rate (CR). Species that were present in more than 50% of samples were considered consistent, in 25 to 50%--additional, and in less than 25%--random. Frequency rates (FR) were also determined, that is the fraction of a certain species (genus) of the microorganism (in %) from all the isolated cultures that correspond to 100%. For the determination of the significance of individual species of the agent in the structure of mixed microorganism populations, FR - their fraction (%) in mixed population from the number of strains of this species that correspond to 100% - was calculated. RESULTS: A significant part of the microorganisms strains, more frequently in reanimation department (65.5%), caused wound suppuration in populations mixed with other species of the agents. In reanimation and surgical departments consistent species of wound infection agents were not detected. A leading etiological role of Staphylococcus aureus (FR 19.2% and 23.9%) was determined, and FR of S. aureus strains in mixes was 64.6% in RITD and 46.8% in SD. The parameters ofotheragents of WI in the comparison groups were similar. However FR among mixes in RITD were significantly higher for streptococci that do not belong to S. pyogenes species (72,5%), and also nonfermentative microorganisms (67,2%), and in SD - in Klebsiella pneumoniae mixes. For agents of wound infection especially in RITD, low species diversity was characteristic and the number of mixes variants is significantly higher. In RITD mixed infections develop more frequently, and the ecological community of microorganisms reaches higher values than in SD. CONCLUSION: During the analysis of microbiologi-cal data in RITD and SD general patterns and specific features of taxonomical structure, prevalence of mixed populations and character of their ecological community in wound infection was determined. PMID- 22442965 TI - [Neutrophil dependent breakdown of biofilms formed by Staphylococcus aureus]. AB - AIM: Study of effects during interaction of neutrophils with Staphylococcus aureus biofilms in vitro. MATERIALS AND METHODS: 2 day biofilms (BF) based on Staphylococcus aureus (strain 5983) were used as a model. Destruction of BF was evaluated at 5, 15, 30, 45 and 60 minutes of incubation with neutrophils. Quantitative evaluation of staphylococci was performed by using microfilming (Shangrao Optical Instruments) and a computer program described by I.V.Chebotaret al., 2010. Measurement of thickness of BF during reaction with neutrophils was evaluated by using laser scanning microscope LSM 510 Meta (Zeiss). RESULTS: Human neutrophils can influence the breakdown effect on BF formed by S. auerus. A pronounced breakdown was observed at 15 minutes of the reaction, by 45 minutes staphylococci content in the BF remained only around 2%. Breakdown of BF was accompanied by an increase of quantity of viable staphylococci in the supernatant. Around 80% of neutrophils perished at 30 minutes of interaction with BE Neutrophil lysate at 30 minutes caused 30% destruction of staphylococci BF. CONCLUSION: Adhesive staphylococci are more resistant to the effect of neutrophils than BE Neutrophil dependent destruction of staphylococci BF could be the result ofbreakdown of intracellular matrix by phagocyte secretion products and direct phagocytosis. PMID- 22442966 TI - [Molecular-biological characteristic of Yersinia enterocolitica circulating in various regions of Russian Federation]. AB - AIM: Complex characteristic by phenotype signs and main virulence genes of Yersinia enterocolitica strains circulating in various regions of Russian Federation. MATERIALS AND METHODS: 46 strains of Y. enterocolitica of 2 - 4 biotypes and 401 strains of Y. enterocolitica IA biotype isolated in 15 administrative territories of Russian Federation (Siberian, Far Eastern, Northwestern, Urals Federal Districts) from infected people, rodents, agricultural animals, birds, the environment were studied. Phagotyping was performed in the reference laboratory of the Pasteur Institute (Paris). All the Y. enterocolitica cultures were studied for the presence of ail, ystB and ystA genes by PCR method. Presence of virulence plasmid pYVwas determined by gel electrophoresis by T. Kieser method. RESULTS: 447 strains of Y. enterocolitica biotype 1A and 2 - 4 were studied. Most of the strains belonged to serotypes O:3; O:9; O: 5; O: 6,30; O:6,31; O:7,8. Phagotyping was performed for part of the strains. Phagotypes Xz and Xo were determined in biotype 1A strains. 2 - 4 biotype strains circulating in Siberia and the Far East were characterized by phagotype VIII, X3 that are present in other countries, and phagotype Xz that is spread only in Russia. Phagotypes IXa, IXb, II that are characteristic for strains from Canada, South Africa, Japan were not detected in Russian Federation. All the strains of 2 - 4 biotypes had ail and ystA genes. Most of the recently isolated strains had pYV. The only pathogenicity factor detected in 81.3% of biotype 1A strains including 14 strains from patients was ystB gene. These infections were accompanied by an expressed clinical symptomatology of enteritis and enterocolitis. CONCLUSION: Isolation of 1A biotype strains from patients necessitates execution of diagnostic studies of intestinal yersiniosis in patients with diagnosis "acute intestinal infection of undetermined etiology". PMID- 22442967 TI - [Monitoring of implementation of international programs of poliomyelitis eradication and measles and rubella elimination in the Republic of Belarus]. AB - AIM: Monitoring of implementation of international programs of poliomyelitis eradication, and measles and rubella elimination in the Republic of Belarus based on results of molecular-epidemiologic studies of 2009 - 2010. MATERIALS AND METHODS: 271 viral agents isolated from children with acute flaccid paralysis syndrome, other diseases, healthy children and from sewage water within the framework of poliomyelitis control implementation were identified by serological and molecular methods. Blood sera of 528 patients with fever and rash were examined for the presence of IgM to measles and rubella virus, 418 - for the presence of IgM to parvovirus B19 and parvovirus DNA. Blood sera of 33 pregnant women and 64 children with signs of intrauterine infection were studied for IgM and IgG antibodies to rubella virus. Measles virus was isolated, N-gene sequence and phylogenetic analysis carried out. RESULTS: The studies performed confirmed that indigenous wild polioviruses in the country do not circulate, imported wild or vaccine-related polioviruses were also not detected. Measles and rubella morbidity in the Republic of Belarus was less than 1 in 1 000 000. 2 cases of rubella (2009) and 1 case of measles (2010) was detected during adequate control level: the rate of detection of patients with fever and rash, in whom measles and rubella diagnosis was excluded by the results of laboratory examination, was more than 2 in 100 000 of the population. The etiologic agent in more than 20% of diseases with fever and rash was parvovirus B19. A single case of measles was caused by genotype D8 virus imported from India. CONCLUSION: The data obtained give evidence to conformance of the poliomyelitis, measles, rubella, innate rubella syndrome control implemented in the Republic of Belarus to WHO recommendations; maintenance of status of country as free from poliomyelitis and achievement of main criteria of elimination of both measles and rubella by 2010. PMID- 22442968 TI - [Dynamics of cytokine production in adults after administration of influenza vaccine from A/California/7/2009 (H1N1) strain]. AB - AIM: Study dynamics of IFNalpha, IFNgamma, TNFalpha cytokines in healthy adults after administration of inactivated subunit monovalent influenza vaccine, A/California/7/2009 (H1N1) strain. MATERIALS AND METHODS: Levels of IFNalpha, IFNgamma, TNFalpha cytokines were studied in blood sera of 58 mostly healthy adults aged 18 - 60 years. Kits for enzyme immunoassay determination of cytokine levels (Vector-Best, Novosibirsk) were used in the study. Antibody titers to A/California/7/2009 (H1N1) strain were determined at analogous time by using microneutralization reaction (MNR). RESULTS: Changes in the level of IFNalpha, IFNgamma, TNFalpha in healthy volunteers immunized by pandemic influenza vaccine were evaluated. Vaccine was safe. Two immunizations did not result in an increase of TNFalpha level that is an additional evidence of vaccine safety. IFNalpha level had a tendency to increase in vaccinated volunteers. IFNgamma levels in volunteers with normal level of this cytokine (below 10 pg/ml) were increased significantly after the second immunization (from 2.66 +/- 2.48 to 5.21 +/- 2.56). Correlation analysis showed that there is a strong negative association between IFNalpha, IFNgamma and seroconversion. PMID- 22442969 TI - [Evaluation of the interferon system and major cytokines in patients with bronchial asthma]. AB - AIM: Study of the interferon system (IFN) and the production of major cytokines in patients with bronchial asthma of various course severity. MATERIALS AND METHODS: 204 patients with atopic bronchial asthma (BA); 32 patients with allergic rhinitis (AR) and 93 mostly healthy volunteers were examined. Blood cells of patients with BA of various course severity were studied by biological method in HEP cell culture for the ability to produce IFN. Levels of cytokines in the blood sera were determined by EIA method with the corresponding commercial test systems: IL-4, IL-10, IL-13 and IFN-gamma according to user manual. RESULTS: Disorders in the ability ofleukocytes to produce IFN-alpha and IFN-gamma were detected in patients with bronchial asthma and allergic rhinitis. Misbalance in the production of pro- and anti-inflammatory cytokines depending on the level of disease severity was noted. The highest serum IFN-gamma was noticed in patients with mild persistence BA course, that is most probably determined by higher frequency of ARVI in this group of patients. Maximum level of IL-10 was detected in mild BA form and was nearly undetected in the severe course of the infection, which is characterized by higher content of IL-4 in blood sera. CONCLUSION: Increase of course severity of chronic (allergic) inflammation in bronchial tissue and higher frequency of ARVI among patients with persistent BA of medium and severe course is characterized by a lack of interferon link of the immune system and disorders of regulatory mechanisms, that is expressed by a change in the ratio of IFN-gamma/IL-4 parameters and decrease of IL-10 content in blood sera. PMID- 22442970 TI - [Antagonistic activity of lactobacilli of the colon]. AB - AIM: Study of antagonistic activity of lactobacilli of the colon against members of its autochthonous bacterial flora and agents of some acute infectious and chronic diseases of the gastrointestinal tract. MATERIALS AND METHODS: Antagonistic activity of 19 lactobacilli cultures against 28 cultures of bacteria belonging to various groups and fungi was evaluated within the framework of specially developed two-stage cultivation technique in the conditions of a combined system. The results of the study were evaluated according to a semi quantitative scale that allows to put one or the other value of the zone of growth delay of the studied strain culture in compliance with the one or the other (low, moderate, high) level of antagonistic activity of the lactobacillus culture. RESULTS: Lactobacilli of the colon showed selective antagonistic activity against pathogenic enterobacteriae: pronounced against Salmonella enterica Serovar Enteritidis, Shigella flexneri 2b, Yersinia spp., and trace against Salmonella enterica Serovar Typhimurium. The level of antagonistic activity of lactobacilli against a wide range of members of autochthonous bacterial flora varied in a wide range, without revealing connection neither to its belonging to species, nor to its population level, nor to the belonging to group of the antagonistic effect objects. On the other hand a connection was traced with beloriging to a certain microbiota: being quite active against members of its own microbiota, lactobacilli often showed significantly lower level of antagonistic activity against cultures with the same species name isolated from other microbiota. CONCLUSION: In light of the results obtained, level of lactobacilli population may hardly be viewed as the only criteria of their full participation in the process of stabilizing microecological welfare of the colon, that allows to make a complete representation of the level of dysbiotic disorder in the mentioned biotope. With in the framework of rational bacteriological diagnostics of the level of dysbiotic disorders in the colon, evaluation of population level of lactobacilli should be evaluated along with the degree of their antagonistic activity against other components of the same microbiota. PMID- 22442971 TI - [Study of the state of parietal microflora and wall of the large intestine of mice under the influence of anomalous magnetic field]. AB - AIM: Study the possible qualitative and quantitative changes of microbial community of the parietal mucin of the large intestine and the state of the wall of the large intestine in experimental animals underbackground and anomalous influence of geomagnetic field. MATERIALS AND METHODS: CBA mice were put under the influence of anomalous magnetic field comparable to its intensity in Zheleznogorsk (3 Oe) for 1 and 2 weeks. Quantitative and qualitative study of mucous microflora of the large intestine of the mice was performed by bacteriological method. Identification of the microorganisms was performed by microbiological analyzer "Multiskan-Ascent" and commercial test-systems "Lachema Czech Republic": ENTHEROtest-16, STAPHYtest-16, Streptotest-16, En-COCCUStest-16; for lactobacilli and bifidobacteria identification - API 50 CHL (bioMerieux). Bacteria content in 1 g of material was calculated by the number of microorganism colonies grown. RESULTS: A pattern of changes of mucous microflora of the intestine and the state of the wall of the large intestine of the experimental animals that had been put under the influence of anomalous magnetic field is shown. During evaluation of qualitative and quantitative diversity of microbial community of parietal mucin of the large intestine of the mice under the influence of magnetic field on the background and anomalous levels changes not only in quantity and frequency of detection of obligate, transitory flora but also cell elements of mucous membrane of the wall of the large intestine were established. CONCLUSION: The results of the study allow to make a conclusion about the presence of reactivity of the parietal microflora of the intestine of the mice to the influence of the anomalous magnetic field. This leads to changes in cell elements in the mucous membrane of the wall that manifest by infiltration of the connective tissue stroma by leucocytes and reconstruction of epithelium, that are features of dysbiosis. PMID- 22442972 TI - [Study of extracellular antigens by immunodiffusion methods in differentiation of pathogenic burkholderiae]. AB - AIM: Isolation and composition comparison of extracellular antigens (ECA) of pathogenic burkholderiae in SDS-PAGE electrophoresis and their use for differentiation of these microorganisms by immunodiffusion methods. MATERIALS AND METHODS: 60 Burkholderia pseudomallei strains, 14 B. mallei strains, 5 B. thailandensis strains, 4 B. cepacia strains were studied. ECA was obtained by Liu technique on F-agar covered with cellophane. SDS-PAGE electrophoresis was performed in 10% gel by Laemmli, immunodiffusion reaction (IDR) in 1% agarose gel, IDR with live cultures, immunoelectrophoresis (IEPH) was performed by the standard techniques. Sera was obtained by immunizing rabbits with a mixture of ECA and incomplete Freund adjuvant. RESULTS: ECA spectra of typical strains of the studied burkholderiae strains after the electrophoresis in SDS-PAGE stained by silver have 8 - 9 major fractions. ECA electrophoregrams of B. pseudomallei and B. thailandensis had a high similarity. ECA analysis by IDR with antisera against ECA revealed maximum number of cross-reactive ECA (3) between B. pseudomallei B. thailandensis. These strains had only a single crossreactive ECA to B. mallei strain. IDR with live culture and antisera to B. thailandensis ECA revealed ECA in all the B. pseudomallei, B. thailandensis strains and did not reveal those in B. mallei strains. Analysis of electrophoregram obtained with IEPH method of pathogenic burkholderiae ECA with antisera to ECA revealed differences of the composition sufficient for their differentiation. CONCLUSION: The differences of ECA composition revealed by immunodiffusion methods allowed to develop additional approaches of differentiation ofglanders and melioidosis pathogenic agents. PMID- 22442973 TI - [Detection of rubella virus RNA in clinical material by real time polymerase chain reaction method]. AB - AIM: Development of a reagent kit for detection of rubella virus RNA in clinical material by PCR-RT. MATERIALS AND METHODS: During development and determination of analytical specificity and sensitivity DNA and RNA of 33 different microorganisms including 4 rubella strains were used. Comparison of analytical sensitivity of virological and molecular-biological methods was performed by using rubella virus strains Wistar RA 27/3, M-33, "Orlov", Judith. Evaluation of diagnostic informativity of rubella virus RNAisolation in various clinical material by PCR-RT method was performed in comparison with determination of virus specific serum antibodies by enzyme immunoassay. RESULTS: A reagent kit for the detection of rubella virus RNA in clinical material by PCR-RT was developed. Analytical specificity was 100%, analytical sensitivity - 400 virus RNA copies per ml. Analytical sensitivity of the developed technique exceeds analytical sensitivity of the Vero E6 cell culture infection method in studies of rubella virus strains Wistar RA 27/3 and "Orlov" by 11g and 31g, and for M-33 and Judith strains is analogous. Diagnostic specificity is 100%. Diagnostic specificity for testing samples obtained within 5 days of rash onset: for peripheral blood sera - 20.9%, saliva - 92.5%, nasopharyngeal swabs - 70.1%, saliva and nasopharyngeal swabs - 97%. Positive and negative predictive values of the results were shown depending on the type of clinical material tested. CONCLUSION: Application of reagent kit will allow to increase rubella diagnostics effectiveness at the early stages of infectious process development, timely and qualitatively perform differential diagnostics of exanthema diseases, support tactics of anti-epidemic regime. PMID- 22442974 TI - [Heterogeneity of hepatitis B virus and diagnostic potential of modern test systems for the detection of HBsAg]. AB - AIM: Study heterogeneity ofhepatitis B virus in adult patients with chronic hepatitis B and determination of diagnostic potential of modern test systems with the detection of HBsAg with amino acid substitutions in the main hydrophilic region (MHR). MATERIALS AND METHODS: In 27 hepatitis B virus samples isolated from patients with chronic hepatitis B virus infection living in Vladimir, nucleotide sequence ofgenome region corresponding to preS1/preS2/S genes was determined. RESULTS: In all of the 27 isolates genotype D virus presented by 3 subgenotypes D1, D2, D3 was detected in 18%, 26% and 56% respectively. Based on the distribution of nucleotide substitutions in the compared functional regions of hepatitis B virus (virus entry into the cell coding site (2875 - 2991 n.b.), pre-S2/S promoter region (2994 - 3171 n.b.), 5'-end pre-S2 and S-genes sequences (3172 - 154 n.b. and 155-455 n.b.), MHR (455 - 635 n.b.) and 3'-end S-gene sequence (636 - 835 n.b.), substitutions are mostly concentrated in the promoter region of the S2/S-genes (30.8%). HBsAg serotypes were determined in 24 of 27 cases by using the predicted amino acid sequence, and in 17 cases HBsAg belonged to ayw2 (71%) serotype and in 7 cases - to ayw3 serotype (29%). Amino acid substitutions G145A, M133I, S132T localized in the main hydrophilic region and P217L, S207N, V184A localized in the C-end of the protein C that are connected with diagnostic and vaccine escape were identified in 5 isolates. CONCLUSION: Diagnostic potential of test systems with the detection of HBsAg with known amino acid sequence of the MHR region were studied. Approximately equal potential of 6 test systems to detect HBsAg with amino acid substitutions G145A, M133I and S132T localized in the MHR region were shown. PMID- 22442975 TI - [Morphometric characteristics of tularemia infectious process in the organism of immunized guinea pigs]. AB - AIM: Morphometric characteristic of organ and system state of guinea pigs immunized with live tularemia vaccine during infection with virulent culture of tularemia. MATERIALS AND METHODS: Morphometric study of histological material from immunized guinea pigs infected subcutaneously at day 30 with a culture of virulent tularemia strain was performed. A standard scheme of sampling and preparation of morphological material and staining of final semifine section with hematoxylin and eosin, impregnation with silver by Masson in Gamperl and Grimelius modificationwas used. Morphometric study was performed by using "Densitomorphometry" program. RESULTS: Morphometric parameters that characterize functional state of organs and systems in immunized, immunized with consequent infection and infected guinea pigs were established. Reactive processes that take place in the infected animal organism against the background of prior immunization fit into the range of adaptation-compensation reactions. CONCLUSION: The morphometric study carried out allowed to adequately evaluate the state of functionally important systems of the organism of experimental animals, this allows to consider perspective the wider use of morphometric analysis in experimental morphology. PMID- 22442976 TI - [Changes in expression level of TLR9 and BD-2 genes in cornea of mice with viral keratitis]. AB - AIM: Study of innate immunity genes expression (TLR9 and BD-2) in epithelial cells of mice cornea on the model of viral keratitis during the application of immunotherapy. MATERIALS AND METHODS: RNA isolation from cornea cells was performed by using RNeasy Mini Kit (Qiagen) and "RIBO-sorb" (ILS, Russia) reagent kits. "Kit for performing PCR-RT in the presence of intercalating dye SYBR Green I" (Syntol, Russia) was used for performing PCR. Data on gene expression is presented in decimal logarithms (relatively to 1 million of beta-actin gene copies). RESULTS: In C57B1/6 mice line at day 1 post infection the virus was detected in 33% of animals, at 3 days - in 90%, at 7 days the number of infected mice started to decline. In cornea of the mice infected with HSV-1 a significant decrease of TLR9 gene expression was observed. Administration of a complex of natural cytokines and antimicrobial peptides (Superlimf preparation) caused statistically significant increase of expression levels of the studied TLR9 and BD-2 genes. CONCLUSION: The model of viral keratitis and expression analysis of recognizing receptor TLR9 and defensin (BD-2) genes can be used to study mechanism of action of various preparations during infection in eye tissues and evaluation of possibility of their use in complex therapy of ophthalmic herpes. PMID- 22442977 TI - [Analysis of Helicobacter pylori infection prevalence in children in the contemporary period]. AB - AIM: Study of prevalence of Helicobacter pylori infection in one organized children community of St. Petersburg in the current period. MATERIALS AND METHODS: 390 children and adolescents of one of the general education schools of St. Petersburg were examined. Presence in blood sera of IgG to bacterial antigen of H. pylori and IgG to its CagA toxin by ELISA method was studied. In 222 children feces samples were studied. Determination of presence of H. pylori antigen in the feces was carried out by using Helicobacter pylori antigen ELISA Kit, Immundiagnostik test system. RESULTS: Comparison of H. pylori infection prevalence in children of various age revealed that infection is minimal in children aged 7 - 8 years (36.84%) and reaches maximum levels in students aged 14 years (66.67%). Screening result shows that there are 2 waves of H. pylori infection (the first peak was detected in 11 years, the second - in 14 years). Excess weight in H. pylori positive students is present less frequently (19.89% versus 30.13%). The difference is more notable in boys (20.25% and 38.75% respectively). CONCLUSION: A sufficiently high level of infectivity by H. pylori in the students of this school was detected. It was established, that seropositivity increases with student age and reaches maximum levels in upperclassmen. 2 waves of H. pylori infection curve are noticed. It was detected that excess weight occurs more frequently in children not infected by helicobater (p<0.05). Combination of various diagnostic methods gives more precise information on the presence of H. pylori infection. PMID- 22442978 TI - [Changes in oxidative stress and apoptosis parameters of neutrophils in rheumatoid diseases]. AB - AIM: Study parameters of oxidative stress and apoptosis of neutrophils in patients with ankylosing spondylitis, systemic lupus erythematosus, systemic scleroderma and rheumatoid heart disease. MATERIALS AND METHODS: 240 patients with rheumatoid diseases and 25 healthy control group volunteers were examined. Neutrophil isolation from peripheral blood was performed by using double density gradient of ficoll-urografin. Cell functional activity was studied by chemiluminescence method. Pro-apoptosis antigen bak expression by neutrophils was studied by using streptavidin-biotin method. Griss reagent was used for nitrogen oxide production analysis. RESULTS: An increase of oxygen dependent neutrophil metabolism processes was detected in patients with ankylosing spondylitis in comparison with systemic lupus erythematosus and systemic scleroderma patients. Systemic lupus erythematosus is characterized by higher biocidity of neutrophils in comparison with systemic scleroderma and rheumatoid heart disease. Increase of neutrophil granulocyte activity in ankylosing spondylitis is accompanied by an increase of superoxide-anion formation. In spite of high level of metabolic activity neutrophils in patients with ankylosing spondylitis have a low functional reserve, and neutrophils in patients with systemic scleroderma have the highest reserve potential. CONCLUSION: Differences in expression parameters of oxidative stress by neutrophils depend on nosological form, varying by production level and active oxygen form formation reserve. PMID- 22442979 TI - [Interspecies interaction of bacteria and the formation of mixed (polymicrobial) biofilm]. AB - Natural biofilms rarely exist as monocultures. Usually they are formed from various microorganism species that interact with each other, have shared metabolites, strengthen the attachment of each other to the support substrate, provide expression of "foreign" genes etc. Material on factors and mechanisms that determine the formation of mixed (polymicrobial) biofilms is analyzed in the review. The significance of interspecies interaction between bacteria based on QS system signal autoinductors is underlined. Examples of humoral and contact communications between bacteria and eukaryotes including host cells are provided. Study of polymicrobial processes and their interaction with innate and adaptive immune response seems important for further development of medical microbiology (especially regarding chronic infectious diseases). PMID- 22442980 TI - [Hantapulmonary syndrome]. AB - Features of hantavirus pulmonary syndrome are considered in the review - zoonosis natural focal polyetiological viral infection, that is characterized by lung injury. Etiology of the disease, main characteristics of the agents, epidemiology, contagiousness, pathogenesis, clinical presentation of this pathology are examined. Laboratory diagnostics, therapy and prophylaxis ofhantavirus pulmonary syndrome are described. PMID- 22442981 TI - [Ethical principles of management and planning during influenza pandemic]. AB - The article is dedicated to an actual problem of ethical component inclusion into the system of management and planning of epidemic control measures during threat emergence and in the course of influenza pandemic (epidemic) progress. Data regarding development of international ethical guidelines during influenza including WHO recommendations are presented and analysis of normative documents in Russian Federation is given. A necessity of comprehension and accounting of ethical values in pandemic preparedness is shown, main directions of action and responsibility are revealed. Key ethical positions of planning and implementation of measures during influenza pandemic are outlined, compliance with those determines the level of public support and thus provides the effectiveness of the implemented measures. PMID- 22442982 TI - [HIV infection of a medical worker during performance of official duties]. PMID- 22442983 TI - [Epidemiologic surveillance for anthrax foci by using standard case definition]. PMID- 22442984 TI - [Choroidal melanoma and maculopathy]. AB - Distant macular changes were revealed in 21 of 28 patients with intraocular melanoma. In 13 eyes maculopathy was very distant from choroidal melanoma (CM), in 4 cases the tumor was located preequatorially and in 9 patients in the posterior fundus beyond the macular zone. In 8 patients bilateral AMD was found along with CM. Revealed changes are considered to be tumor-associated sign of progressing CM. Association of AMD and CM should be considered as a combination of two distinct conditions, when CM disturbs hematoretinal barrier and thus leads to AMD progression. PMID- 22442985 TI - [Optic neuropathies of different etiology and normal tension glaucoma: the point of differential diagnosis]. AB - 62 patients (109 eyes) with glaucoma-like optic nerve head cupping and normal IOP indices (Po not more than 21 mm Hg) were examined to find the etiology of optic nerve changes. Regarding corneal biomechanics new-onset primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) were diagnosed in 27% and 3% of examined patients respectively. In 59% of patients optic neuropathy (ON) of different etiology was found to be the cause of glaucoma-like optic nerve changes including compression ON due to lesion of intracranial portion of optic nerve and chiasma in 6% of cases. In 11% physiologic large optic nerve head cupping with normal visual functions and absence of nerve fiber structural changes was found. PMID- 22442986 TI - [Biochemical, structural and biomechanical features of human scleral matrix in primary open-angle glaucoma]. AB - The goal of the investigation was to study the changes of scleral matrix collagen in progressing primary open-angle glaucoma (POAG). In scleral samples of 16 patients aged 52-81 years with different stages of POAG amino acid composition, collagen content and cross-linking ratio characterizing tissue rigidity were estimated. Collagen I was found to be the dominant type in sclera of glaucomatous and normal eyes, though as POAG progressing the content and cross-linking increase, that underlies the scleral rigidity increase and permeability decrease. Similar ratio of collagen cross-linking with age and glaucoma progression give evidence of specific pathologic changes of the dominant matrix component, that may be one of significant pathogenic factor of POAG. PMID- 22442987 TI - [Initial experience of threefocal diffractive/refractive intraocular lenses implantation]. AB - Due to original Russian technique of frontal photopolimerization of liquid oligomers in form the use of threefocal intraocular lense (IOL) with square relief of diffractive surface has become possible. The first 36 implantations of MIOL-Record showed good clinical and functional results. This lens provides high quality of intermediate vision without decrease of distant and near visual acuity. 94% of patients completely refused spectacle correction for all distances. The vast majority of patients are satisfied with their intermediate vision, 94% of them don't use spectacles for computer work. Incidence of disphotopsias is similar to that after other MIOLs implantation. PMID- 22442988 TI - [The results of presbyopia correction with multifocal and accommodating intraocular lenses]. AB - Clinical results of implantation of intraocular lenses (IOL) Restor +3D and Crystalens HD 500 for presbyopia correction were compared, indications for every IOL type were optimized. 40 patients were divided into 2 equal groups: the 1st included patients without concomitant ocular and somatic diseases, patients with these conditions were enrolled into the the 2nd group. Uncorrected visual acuity, optic phenomena and patient's satisfaction with the results of treatment were estimated in 6-12 months after surgery. Restor +3D and Crystalens implantation is effective in presbyopia correction. MIOLs provide high visual functions in all distances but reduce vision quality. In patients with concomitant diseases Crystalens HD implantation is preferable. PMID- 22442989 TI - [Objective accommodation parameters depending on accommodation task]. AB - 62 myopic patients were examined to study objective accommodation parameters in different conditions of accommodation stimulus presenting (use of convex lenses). Objective accommodation response (OAR) was studied using binocular open-field autorefractometer in different conditions of stimulus presenting: complete myopia correction and adding of convex lenses with increasing power from +1.0 till +3.0 D. In 88,5% of children and adolescents showed significant decrease of OAR for 1,5-2,75D in 3.0D stimulus. Additional correction with convex lenses with increasing power leads to further reduce of accommodation response. As a result induced dynamic refraction in eye-lens system is lower than accommodation task. Only addition of +2,5D lense approximates it to required index of -3.0D. PMID- 22442990 TI - [Macula structure and function in retinopathy of prematurity]. AB - Macula structure and function were studied in 64 patients with retinopathy of prematurity (RP) stage I-III aged 8-17 years old using optical coherence tomography (OCT) and electroretinography. Absence of foveolar depression associated with preservation of fovea layers and normal electroretinography indices were showed to be the evidence of differentiation damage and macula underdevelopment due to immaturity and to have no effect on visual acuity. Preserved or pathologic foveolar depression associated with abnormal OCT findings and central retina electrogenesis damage indicate dysfunction and morphological changes of macula due to not macula underdevelopment because of immaturity only but RP either that can lead to depression, visual function. PMID- 22442991 TI - [Congenital corneal staphylomas in children]. AB - Clinical manifestation, results and outcomes of surgical treatment were studied in children with very rare anomaly of cornea and anterior segment. Symptoms and signs, histological findings are described in details, results of ophthalmoscopy, ultrasound biomicroscopy and maternal ophthalmotrophic infections are studied in children with corneal staphylomas. PMID- 22442992 TI - [Plasmapheresis combined with cell mass ozonation in endogenous uveitis treatment]. AB - Authors propose a new method of uveitis treatment based on plasmapheresis in combination with cell mass ozonation. Analysis of treatment results of 3 patient groups (179 patients, 209 eyes) showed advantage of this original modification of plasmapheresis. In our opinion the effectiveness of proposed treatment option is associated with immunomodulatory effect of plasmapheresis and ozone therapy as well as bactericidal, antiviral and fungicidal effects of ozone therapy. Some sanogenetic mechanisms of the new treatment are disclosed in the study such as correction of T-cell immunodeficiency, decrease of circulating immune complexes and others. PMID- 22442993 TI - [Improvement and estimation of tearscopy potentials]. AB - New potentials of improved tearscopy technique based on photoregistration of colour interference phenomenon are presented. A new softwear "Lacrima" was developed in order to objectivate the results and to get more detailed data, it allows to reveal data on lipid layer thickness (LLT), estimate relative area of examined zone (in %) with certain LLT as well as regularity of lipids distribution. Digital images of interference picture of precorneal tear film of 13 healthy objects (26 eyes) and 20 patients with exogenous dry eye syndrome were analyzed. In eyes with dry eye syndrome compared to normal eyes increase of uncertainty zone and zone with minimal LLT were revealed for 13,2 and 12,8% respectively. Relative area of zones with increased LLT decreased for 16,7 and 56,3 % respectively. Computer analysis of interference picture of precorneal tear film using softwear "Lacrima" allows to extend capabilities of tearscopy and get additional data on lipid layer status. PMID- 22442994 TI - [Scanning electronic microscopy of lens after mechanical eye injury]. AB - The results of scanning electronic microscopy (SEM) of 12 lenses after mechanical eye injury with rupture of Zinn ligament fibers in elderly patients. SEM results are compared to those of lenses after senile cataract cryoextraction including pseudoexfoliation syndrome (PES). Characteristic features of lens capsule changes after mechanical eye injury are revealed including PES as a pathologic lens aging. PMID- 22442995 TI - [A case of rod monochromasia]. AB - A case of rare genetic disease rod monochromasia which is often called total congenital cone dysfunction (syn. congenital cone dystrophy, congenital achromatopsia) is presented. Symptoms and signs of the disease are described in details and methods for improvement of patient's condition are indicated. PMID- 22442996 TI - [Potential of implantation of soft supplementary intraocular lens with ciliary sulcus fixation in surgery of complicated cataract]. AB - A case of using of different surgical methods in bilateral cataract treatment in patient with extremely high myopia and previously implanted phakic lenses is presented. Phacoemulsification was performed as an initial procedure, after that supplementary toric lens sulcoflex was implanted and the final procedure was laser in situ keratomileusis. As a result of 3-staged surgery the maximal visual acuity was achieved. Characteristics of each stage are described. PMID- 22442997 TI - [Laser iris reconstruction in pupil deformities and dislocation in aphakia and pseudophakia]. AB - Up-to-date methods of laser iris reconstruction in pupil deformities and dislocation are presented (photomydriasis, corepraxia, synechiolysis). PMID- 22442998 TI - [Current potentials of endoscopic rhinosinusosurgery]. AB - Information on current potentials of endoscopic rhinosinusosurgery are presented in this review. Potentials of miniinvasive endoscopic procedures as an alternative or adjuvant treatment option in surgery of ophthalmologic patients are discussed. PMID- 22442999 TI - [Endovitreal surgery in children]. AB - As new technics in vitreoretinal surgery develop performance of miniinvasive procedures has become possible in children with ocular diseases associated with cataract (persistent hyperplastic primary vitreous, retinal detachment, vitreous synechia), retinopathy of prematurity, retinoblastoma, retinal detachment of different ethiology as well as for prevention of proliferative syndrome. Analysis of endovitreous surgical procedures in children allows to estimate advantages and falls of each technique, helps to find new techniques aimed to improve functional outcome and decrease unfavorable results of vitreoretinal surgery. PMID- 22443000 TI - [Laser treatment of central retina diseases]. AB - Review of literature is devoted to the most up-to-date retinal diseases such as diabetic macular edema and age macular degeneration affecting people of different age and leading to disability. Besides management of central serous retinopathy that affects younger patients is discussed. According to data of domestic and foreign studies common treatment options of central retina diseases along with therapeutic effect have adverse effects leading to damage of neurosensory retina. Thus despite of a great number of studies devoted to this problem a search of effective and safe treatment option of central retina diseases is still important. PMID- 22443001 TI - [Professor T. I. Yeroshevsky and his school]. PMID- 22443002 TI - Registrant opinion is key to regulator reform. PMID- 22443003 TI - Prospective nursing students tested for emotional intelligence. PMID- 22443004 TI - Lords hailed for insisting mental and physical health are on a par. PMID- 22443005 TI - Three-month NMC review aims to give regulator a fresh start. PMID- 22443006 TI - Nurses are in denial about poor care, warns ex-Mid Staffs chair. PMID- 22443007 TI - Population growth and funding cuts push services to their limit. PMID- 22443008 TI - Dignity in toileting. AB - Failure to meet the toileting needs of patients is one of the top causes of complaints about hospital care. As part of our series examining the four strands of fundamental care that are being highlighted by our Care campaign, we look at barriers to dignified toileting and identify examples of good practice. PMID- 22443009 TI - Breaking the fast. AB - A nurse-led study at a London hospital has found that many surgeons do not follow national guidance on perioperative fasting times. Excessive fasting can weaken patients and delay recovery. Surgical teams may be willing to introduce shorter fasts if the benefits to patients are made clear. PMID- 22443010 TI - A powerful legacy. AB - Community nurses, many of them inexperienced, face highly emotional situations when caring for dying patients at home, particularly when their wishes are at odds with family members'. The winning team of a one-off award from the Queen's Nursing Institute has developed a training course that increases nurses' confidence in their ability to manage sensitive discussions. PMID- 22443011 TI - An online training resource for clinical supervision. AB - This article describes the development and evaluation of an online clinical supervision resource. Technology-based learning is on the increase and is viewed as an excellent resource that offers flexibility to managers, educators and students. However, by creating a more flexible approach to training, nurses may feel under pressure to conduct and complete this training outside of their normal working hours. This article reports on the findings and explores the issues surrounding implementing an online training programme for registered nurses. PMID- 22443012 TI - Taking a patient history: the role of the nurse. AB - History taking is a key component of patient assessment, enabling the delivery of high-quality care. Understanding the complexity and processes involved in history taking allows nurses to gain a better understanding of patients' problems. Care priorities can be identified and the most appropriate interventions commenced to optimise patient outcomes. PMID- 22443013 TI - Dementia. PMID- 22443014 TI - Debridement of diabetic foot wounds. AB - The management of foot ulcers in patients with diabetes is a complex and increasingly common problem. This article outlines the core principles of best practice for these patients focusing, in particular, on debridement. The article defines debridement, looks in detail at the rationale and evidence for its use in wound bed preparation and examines the various debridement methods available. PMID- 22443015 TI - Management of minor burns in the emergency department. AB - Many patients with minor burns can be cared for in the emergency department or community setting, but clinicians must be confident in assessing and managing a burn injury to ensure the best possible outcome. This article defines a minor burn, reviews burn assessment and considers aspects of nursing management that optimise minor burn care. PMID- 22443016 TI - Award gives me authority. PMID- 22443017 TI - When a sense of duty calls. PMID- 22443018 TI - Power to gain knowledge. PMID- 22443019 TI - Attitudes about hypnosis: factor analyzing the VSABTH-C with an American sample. AB - In the present study, the authors factor-analyzed responses from 1,141 American undergraduate students to the Valencia Scale of Attitudes and Beliefs Toward Hypnosis-Client Version. They obtained an 8-factor solution accounting for 66% of the total variance in responses. A confirmatory factor analysis indicated acceptable fit of their model and those reported earlier by Carvalho et al. (2007) and Capafons, Mendoza, et al. (2008) using Portuguese and international samples, respectively. Unlike previous factor analyses of the scale, the authors obtained an independent clusters solution. Distinctions between the authors' model and those reported previously are discussed. PMID- 22443020 TI - Hypnosis to alleviate the symptoms of ciguatera toxicity: a case study. AB - Ciguatera toxicity is a poisoning from consuming reef fish that had fed on dinoflagellates such as Gambierdiscus toxicus found along coral reefs. The toxin is oil soluble, odorless, colorless, tasteless, heat stable, and is concentrated in larger carnivorous fish such as amberjack, barracuda, eel, grouper, red snapper, sea bass, and Spanish mackerel. Onset of symptoms is usually within 6-12 hours after ingestion. Gastrointestinal symptoms lasting 1-2 days include abdominal pain, nausea, vomiting, and diarrhea. Neurological symptoms may persist for weeks or several months or--rarely--years and include circumoral and extremity paresthesias, temperature sensation reversal, itching, weakness, ataxia, and others. A patient with burning hands and feet who had not found relief using other methods had diagnosis of ciguatera toxicity assisted by hypnotically refreshed memory followed by rapid relief with hypnotic suggestions in 1 session and remained free of symptoms. PMID- 22443021 TI - Virtual reality hypnosis pain control in the treatment of multiple fractures: a case series. AB - This case series evaluated the use of virtual reality hypnosis (VRH) for the treatment of pain associated with multiple fractures from traumatic injuries. VRH treatment was administered on 2 consecutive days, and pain and anxiety were assessed each day before and after VRH treatment as well as on Day 3, which was 24 hours after the second treatment session. Pain reduction from baseline to Day 3 was from 70% to 30%, despite opioid analgesic use remaining stable. The subjective pain reduction reported by patients was encouraging, and the results of this case series suggest the importance of further study of VRH with larger samples using randomized controlled trials. PMID- 22443022 TI - Hypnotic intervention in a 7-year-old thumbsucker: a case study. AB - Thumbsucking is a common habit among younger children. Usually, the child outgrows this habit by age 6. When a child over the age of 6 continues to suck his or her thumb, it can be a cause of potential harm due to peer pressure, ridicule, and shunning. It can also lead to malocclusions requiring eventual orthodontic interventions. In this case study, the author demonstrates a hypnotic intervention in a 7-year-old girl. Validation of her habit and imaging a role model sucking her thumb were employed in trance. Using this approach, the child was able to end her dependence on thumbsucking in 1 session. PMID- 22443023 TI - The Spanos Attitudes Toward Hypnosis Questionnaire: psychometric characteristics and normative data. AB - The Attitudes Toward Hypnosis Questionnaire (ATHQ) is a 14-item, self-report measure of positive versus negative attitudes about hypnosis. It is composed of three subscales identified via factor analysis: Positive Beliefs, Fearlessness, and Mental Stability. The purpose of this study was to evaluate the generalizability of the original factor structure of the ATHQ and to provide normative data based on a large sample of 925 introductory psychology students. Internal consistency analysis and factor analysis did not support the scale's original factor structure. Accordingly, it is recommended that the subscales be abandoned and that the 14 items of the ATHQ be utilized as a unidimensional scale. Although attitudes toward hypnosis have been described as an important determinant of hypnotic responding, there has been very little research evaluating this association. If employed as a unidimensional scale, the ATHQ could be a very useful tool in future studies on this topic. PMID- 22443024 TI - Issues in the detection of those suffering adverse effects in hypnosis training workshops. AB - Enhancing safety in hypnosis workshops is an issue of significant concern in the progress and promulgation of hypnosis as a facilitator of treatment. In general, hypnosis is a safe modality, but occasional adverse effects are encountered in its use in clinical, research, and professional workshop settings. To develop and implement modifications designed to reduce the number and/or severity of such unfortunate incidents in workshop settings, it is necessary to establish an awareness of the nature and implications of these adverse events. This article describes 9 categories of problem presentations known to have been generated in workshop settings. It also discusses a particular constellation of factors that- without imputing blame to either faculty or to workshop participants--creates powerful forces that minimize the likelihood that adverse effects will either be recognized by faculty or reported by workshop participants. PMID- 22443025 TI - Localization of acupuncture points on the Lung Meridian using Bi-Digital O-Ring Test electromagnetic field resonance phenomenon between 2 identical substances. AB - Using Bi-Digital O-Ring Test electromagnetic field resonance phenomenon between 2 identical substances, it is possible to draw on the surface of the human body several points similar to the acupuncture points of Traditional Chinese Medicine TCM with the help of histological slides of 12 organs of the main TCM Meridians, using the method first described by Yoshiaki Omura Sc.D. M.D. To determine the relationship of the Lung Meridian of TCM and the points drawn with a histological human Lung slide by BDORT, it was mapped the upper limb in 41 healthy individuals. There were almost identical matches in all points in 26 subjects (63.4%). In 15 subjects there were no identical matches at any point (36.5%). In all cases of no identical matches of the points, the new Lu1 point is displaced in the direction of midpoint of thorax below the clavicle. On the arm there was a medially deviation in comparison to the line obtained from the TCM points, for example the new Lu9 point was located on the midpoint of the wrist. PMID- 22443026 TI - The characteristics of acupuncture-like transcutaneous electrical nerve stimulation (acupuncture-like TENS): a literature review. AB - Acupuncture-like Transcutaneous Electrical Nerve Stimulation (TENS) is used for pain relief. This study aimed to review the descriptions of the characteristics of acupuncture-like TENS reported within the published literature up to June 2011. A total of 88 items of published literature were retrieved.. 35 authors or groups provided 1 publication (Single Contributions - SC) and 10 authors or groups provided more than 1 publication (Multiple Contributions - MC). In order to gain the acupuncture-like effects of TENS, authors often characterised acupuncture-like TENS using: an intensity that caused muscle contractions (6MC, 17SC), or a sensation to tolerance threshold (3MC, 4SC); a 1-4 pulses per second (pps) pulse rate (5MC, 16SC); a 100-200 micros pulse duration (2MC, 8SC); stimulation to acupuncture points (5MC, 4SC), or myotomes (3MC, 3SC), or over the painful area (3MC, 1SC). Critically, unlike many authors included in the present review, the International Association for the Study of Pain core curriculum does not mention the triggering of muscle contractions when acupuncture-like TENS is defined. This may be an area that that they should reconsider. PMID- 22443027 TI - Effects of electroacupuncture on depression in a rat model. AB - OBJECTIVE: To investigate the antidepressant-like effect of electroacupuncture (EA) in a validated rat model. METHODS: Wistar Kyoto rats, a valid animal model of depression, were randomly divided into two groups, EA (n = 7) and placebo control (n = 6). EA treatment was given once a day, 5 days a week, for 3 weeks. Two acupoints, GV14 (Dazhui) and GV20 (Baihui), respectively on the cervical spine and scalp, were selected. EA frequency was held constant at 2Hz (2 pulses/second), pulse width 0.3-ms, and intensity was adjusted to 3 mA. Forced swim tests (FST), open field tests (OFT; e.g., a. rearing and grooming, b. distance traveled within a central area, c. time spent in central area, and d. total distance traveled), and the Morris Water Maze test (MWM) were conducted 3 weeks after the initial treatment. RESULTS: In the FST, there was significant difference between EA and control (P < 0.05) in immobility. In the OFT, there were significant differences between EA and control (P < 0.05) in rearing and grooming (P < 0.05). In the MWM, there were significant differences between treatment and control in frequency of crossing the platform (P < 0.05) and its surrounding area (P < 0.05). CONCLUSION: Our data demonstrate that EA enhances memory and improves depression-related behaviors in a rat model of depression. This suggests that the modality may have therapeutic effects on depression in humans. Electroacupuncture may act on depression by protecting nerve cells in the hippocampus. PMID- 22443028 TI - Pain induced by intensive light beam pulse stimulation of acupuncture point GB34 of lower extremities and its associated changes in EEG's. AB - Pain perception and its EEG wave have been used to describe the body's neural systemic response with respect to a given stimulation. Pain artificially induced by non-coherent intensive light (wavelength of 500nm-1200nm) impulse has not been studied yet. In this study this technique was applied to statistically correlate the brain activity under induced pain while particular acupuncture points (yanlingchuan of both feet, GB34) were stimulated by intensive light impulses. The brain electrophysiological signals or electroencephalogram (EEG) at F(p1), F(p2) were recorded. The data of brain waves showed a distinguishable raising slope in this study. Intensive light beam impulse with beam diameter of 10 mm and intensity of 14 joule/cm2 was applied to the acupuncture points. In order to quantify the pain effects, a pain intensity function was defined based on the induced pain activities related to the collected data. The pain intensity function and its equations were used to analyze the changing rate of pain with respect to stimulated intensity and pain momentum transport activity. The results showed that the area of the brain wave evoked by pain could be used as pain perception indicator. The raising slope at one brain side was relatively higher when the acupuncture point GB34 at the contralateral side was stimulated. PMID- 22443029 TI - New clinical findings on the longevity gene in disease, health, & longevity: Sirtuin 1 often decreases with advanced age & serious diseases in most parts of the human body, while relatively high & constant Sirtuin 1 regardless of age was first found in the hippocampus of supercentenarians. AB - The expression of the longevity gene, Sirtuin 1, was non-invasively measured using Electro-Magnetic Field (EMF) resonance phenomenon between a known amount of polyclonal antibody of the C-terminal of Sirtuin 1 & Sirtuin 1 molecule inside of the body. Our measurement of over 100 human adult males and females, ranging between 20-122 years old, indicated that the majority of subjects had Sirtuin 1 levels of 5-10 pg BDORT units in most parts of the body. When Sirtuin 1 was less than 1 pg, the majority of the people had various degrees of tumors or other serious diseases. When Sirtuin 1 levels were less than 0.25 pg BDORT units, a high incidence of AIDS was also detected. Very few people had Sirtuin 1 levels of over 25 pg BDORT units in most parts of the body. We selected 7 internationally recognized supercentenarians who lived between 110-122 years old. To our surprise, most of their body Sirtuin 1 levels were between 2.5-10 pg BDORT units. However, by evaluating different parts of the brain, we found that both sides of the Hippocampus had a much higher amount of Sirtuin 1, between 25-100 pg BDORT units. With most subjects, Sirtuin 1 was found to be higher in the Hippocampus than in the rest of the body and remains relatively constant regardless of age. We found that Aspartame, plastic eye contact lenses, and asbestos in dental apparatuses, which reduce normal cell telomeres, also significantly reduce Sirtuin 1. In addition, we found that increasing normal cell telomere by electrical or mechanical stimulation of True ST-36 increases the expression of the Sirtuin 1 gene in people in which expression is low. This measurement of Sirtuin 1 in the Hippocampus has become a reliable indicator for detecting potential longevity of an individual. PMID- 22443030 TI - Lord of the castle. PMID- 22443031 TI - Summary of the 2010 Census: Pennsylvania. PMID- 22443032 TI - Advantages of practicing in rural Pennsylvania. PMID- 22443033 TI - Electronic health records (EHRs) and new technology. PMID- 22443034 TI - Disaster recovery planning--is your business at risk? PMID- 22443035 TI - Out of the woods: a tribute to the greatest generation. PMID- 22443036 TI - A view from the other side of the hill. PMID- 22443037 TI - The climb. PMID- 22443038 TI - Father & son's experiences show contrasting eras. PMID- 22443039 TI - A role model's influence. PMID- 22443040 TI - Three continuous generations in dentistry. PMID- 22443041 TI - A Punxsutawney legacy of helping those in need. PMID- 22443042 TI - Observations. PMID- 22443044 TI - Forty years in cancer nursing research: time flies when you're having fun! PMID- 22443043 TI - Mutual funds (part 1). PMID- 22443045 TI - Screening for distress: responding is a critical function for oncology nurses. AB - The practice of routine screening for distress in cancer populations has been gaining worldwide support over the past several years with the conceptualization of distress as the sixth vital sign. Across Canada, experience with screening for distress is growing, as cancer facilities implement screening programs. Early learning from these efforts has emphasized the need for a programmatic approach and the importance of oncology nurses in screening and providing the initial response to distress. To date, little has been written from the nursing perspective about the oncology nursing role in a program screening for distress and responding to the identified patient concerns. This article describes the current thinking about distress; explores how screening for and responding to distress is integral to oncology nursing practice; and shares the early learning and experiences of cancer nurses in implementing screening for distress initiatives. PMID- 22443046 TI - Mentoring advanced practice nurses in research: recommendations from a pilot program. AB - Advanced Practice Nurses (APNs) need research skills to develop and advance their practice and, yet, many have limited access to research training and support following completion of their advanced degree. In this paper we report on the development, delivery, and evaluation of an innovative pilot program that combined research training and one-to-one mentorship for nine APNs in conducting research relevant to their practice. The program was organized within an academic institution and its affiliated hospitals in Toronto, Canada. Our experience with this program may assist those in other organizations to plan and deliver a similar program for APN research mentorship. PMID- 22443047 TI - The Fatigue Pictogram: assessing the psychometrics of a new screening tool. AB - Fatigue is one of the most distressing side effects of cancer for patients, yet clinicians often do not focus on it during busy clinic appointments. The purpose of this project was to evaluate the psychometric properties of a new instrument designed to quickly identify patients experiencing difficulties with fatigue. The evaluation was conducted with a mixed group of 220 patients receiving chemotherapy. The two-item Fatigue Pictogram had good reliability for test-retest over a 24-hour period (Spearman Coefficient 0.69 for Question 1 and 0.72 for Question 2) and for equivalence of method (in person versus phone) (Spearman Coefficient 0.69 for Question 1 and 0.59 for Question 2). Validity was assessed by comparing results of the new tool against the Multidimensional Fatigue Inventory and the FACT-an. Overall, patients who indicated high fatigue levels did so on all respective scales. The new Fatigue Pictogram was easy to administer and score in a busy clinical setting. It provides a standardized reliable and valid instrument to screen patients experiencing difficulty with fatigue and set the stage for a conversation about this bothersome side effect. PMID- 22443048 TI - Lived experiences of nurses as family caregivers in advanced cancer. AB - Research regarding experiences of nurses caring for family members with a cancer diagnosis is limited. To address this gap, a hermeneutic phenomenology approach was used to explore lived experiences of five nurses caring for family members living with advanced cancer. Their experiences were fraught with tensions and conflicts as they balanced the roles of nurse and caregiver. At the heart of their experiences was a sense of being caught in a web of conflicting expectations. Their struggles of expectations stemmed from anticipating the illness trajectory, expectations from family, expectations from other health professionals, and expectations from the nurse caregivers of themselves. Conflict between their professional and personal lives was most challenging. Implications of this care-giving situation are described. PMID- 22443049 TI - [Effect of selenium on the protection of myocardial cells from injuries induced by overloaded reactive oxygen species, and on the expression of actin in myocardial cells]. AB - OBJECTIVE: To investigate the effect of selenium on the protection of myocardial cells from injuries induced by H2O2 and on the expression of alpha-actin and beta actin in myocardial cells. METHOD: Myocardial cells of suckling mice in the culture were divided into six groups: Controls group (without H2O2 or Se), H2O2 group, Se 0.05 micromol/ L group, Se 0.5 micromol/L group, Se 1.0 micromol/L group and Se 5.0 micromol/L group. The ultrastructure of myocardial cells was observed by transmission electron microscope (TEM), and the LDH and MDA contents in the culture media were determined by colorimetry. The expression of alpha actin and beta-actin in myocardial cells was detected by Western blot. RESULTS: The injury of myocardial cells observed under TEM was attenuated in the 0.5 micromol/L Se group. The LDH and MDA contents in the culture media of the Se groups was higher than the control group (P < 0.05), but lower than the H2O2 group (P < 0.05). The LDH and MDA contents in the 0.5 micromol/L Se group were the lowest in all Se groups. The expression level of alpha-actin and beta-actin in the 0.5 micromol/L Se group is higher than that in the H2O2 group, even higher than the control group. CONCLUSION: The protective effect of Se on myocardial cells damaged by H2O2 was better in the 0.5 micromol/ LSe group, which could maintain the expression of alpha-actin and beta-actin, even induce the remolding of cytoskeleton proteins. PMID- 22443050 TI - [Nutritional components and sub-chronic toxicity of genetically modified rice expressing human lactoferrin]. AB - OBJECTIVE: To compare the nutritional components of genetically modified rice expressing human lactoferrin (hLf) with its parental rice, and to observe the sub chronic toxicity of hLf rice. METHODS: The nutritional components of hLf rice and its parental rice were determined by the National Standard Methods. Eighty weanling Wistar rats were randomly divided into 4 groups based on their gender and body weight: group A (hLf rice high-dose group with 71.45% rice), group B (hLf rice medium-dose group with 35. 725% rice), group C (parental rice group with 71.01% rice) and group D (AIN-93G diet group), and the latter two groups were used as the control. Body weight, dietary intake, blood routine test, blood biochemical examination, organ coefficient, bone density and the pathology of organs were investigated at the end of a 90-day feeding experiment. RESULTS: Except for human lactoferrin and Fe, there was no difference of main nutritional components, minerals and vitamins between groups. The differences of some indicators of blood routine (WBC, HGB, RBC and MCH), blood biochemistry (AST and GLU), organ coefficient and bone density between group A and B (hLf rice) with group C (parental rice) or group D (AIN-93G) were significant, while no difference of other indicators. CONCLUSION: Although some differences were observed, all indicators were still in the normal reference range. Therefore, there was no sign of toxic and adverse effects for hLf rice on rats. PMID- 22443051 TI - [Effects of recombinant human lactoferrin on improving the iron status of IDA rats]. AB - OBJECTIVE: To investigate the effect of recombinant human lactoferrin (rhLf) separated and purified from milk of transgenic cows on improving the iron status of rats suffered from iron deficiency anemia (IDA). METHOD: The IDA model of female weaning Wistar rats was induced by iron deficient diet, and the rats were then randomly divided into 6 groups (12 rats in each group, based on their body weight and the concentration of hemoglobin) : group A (the model control ), group B, C and D (rhLf 0.375. 0.75 or 2.25 g/kg BW), group E (ferrous lactate 0.011 g/kg BW), and group F (ferrous lactate 0.011 g/kg BW + rhLf 0.375 g/kg BW). Test substances were administered by gavage daily for 8 weeks. Related indexes, including general health condition, body weight, hematological parameters, free erythrocyte protoporphyrin (FEP), serum iron (SI), total iron binding capacity (TIBC), serum ferritin (SF), serum Cu and serum Zn, were determined. RESULTS: After 8 weeks of supplementation, body weight, RBC, Hb, SI, TS and SF levels of rats in group E and F were improved and significantly higher than those in group A, while levels of FEP, TIBC and Zn were lower. Indexes of rats in group D were also significantly different from those in group A but with a less degree than those in group E or F. Compared with group A, there were no obvious difference in iron status for group B or C except for more RBC and lower levels of FEP and Zn in group C, as well as the lower level of Zn in group B. SI, TS and SF levels in group F were significantly higher but TIBC was lower than those in group E. CONCLUSION: The iron status of IDA rats could be improved to some degree by the supplementation of rhLf alone, but the effect was weaker than that of ferrous lactate. The effect of combining rhLf with ferrous lactate was more intensive than ferrous lactate or rhLf administered individually. PMID- 22443052 TI - [Relationship of plasma ghrelin, IGF-1 and insulin with the growth and development of 2 -7 year-old children with small for gestational age at birth]. AB - OBJECTIVE: To explore the relationship of Ghrelin, insulin-like growth factor-1 (IGF-1) and insulin with the growth and development of 2 -7 year-old children with small for gestational age (SGA) at birth. METHODS: The levels of ghrelin, IGF-1, IGFBP-3, insulin and glucose were measured in the children with preterm SGA and term SGA and compared with the children with preterm appropriate for gestational age (AGA) and term AGA. The correlation of ghrelin with IGF-1, IGFBP 3 and insulin was analyzed. RESULTS: Plasma ghrelin in preterm SGA was higher than that in term SGA (P < 0.05), and there was no significant difference between preterm SGA and preterm AGA (P > 0.05). Plasma ghrelin in preterm AGA and term SGA was higher than that in term AGA (P < 0.05, P < 0.01 respectively). Serum IGF 1 and IGFBP-3 in preterm SGA were lower than those in term SGA (P < 0.05 for all) and serum IGF-1 and IGFBP-3 in preterm AGA were much lower than those in term AGA (P < 0.0001 for all). The level of serum insulin was the highest in term SGA. The trend of insulin resistance index (IRI) was similar to insulin. There were negative correlations of ghrelin with other indexes (weight SDS, IGF-1, IGFBP-3, insulin and IRI) in preterm SGA and term SGA (in preterm SGA r = -0.683, P < 0.002; r = -0.749, P < 0.001; r = -0.828, P < 0.001; r = -0.694, P < 0.005; r = 0.822, P < 0.001; in term SGA r = -0.792, P < 0.001; r = -0.707, P < 0.002; r = 0.615, P < 0.01; r = -0.648, P < 0.005; r = -0.679, P < 0.005). CONCLUSION: Ghrelin is involved in the regulation of growth and development of preterm and SGA children, regardless of the magnitude of their catch up growth. As a re regulatory factor to insulin, ghrelin regulates the energy metabolism in a form of negative feedback. PMID- 22443053 TI - [Development of in vitro digestion model for assessing the bioaccessibility of deoxynivalenol derived from foods]. AB - OBJECTIVE: To develop and validate in vitro digestion model for assessing the bioaccessibility of deoxynivalenol (DON) derived from foods, and optimize the major parameters affecting the model. METHOD: To study the effect of digestion time, the fasting and feeding status, the volume and the pH of digestive juice, as well as other food components ingested with DON derived from mixed foodstuff on the bioaccessiblity of DON in a model simulating the process manner on gastrointestinal physiological digestion. To optimize some technical parameters of the model and validate it with both mycotoxin adsorbents and foods naturally contaminated by DON. RESULTS: The optimized conditions of which DON released from the ingested foods at the highest concentration in gastrointestinal tract are as follows: digestion of 6 min, 1.5h and 1.5h in mouth, stomach and duodenum, respectively. At pH value of 6.5, 0.9, 7.5 and 8.0 as well as digestive juice volume of 6 ml, 13 ml, 11 ml and 6 ml for saliva, gastric juice, intestinal juice and bile, respectively. The bioaccessibility of DON at fasting and different feeding status was in the range from 81.28% to 99.58%, and the bioaccessibility of DON was reduced with the increase of contents in stomach. No significant effect of food matrix type (corn or wheat) on the bioaccessibility of DON was observed. However, other food components consumed along with DON can reduce the bioaccessibility of DON in cereals. CONCLUSION: The in vitro digestion model developed for assessing the bioaccessibility of DON is stable and reproducible, which can meet the requirement of studies on the bioaccessibility of DON derived from foods. PMID- 22443054 TI - [Effects of CdTe QDs on oxidative stress and DNA damage of liver cells in mice]. AB - OBJECTIVE: To investigate the effects of CdTe QDs (cadmium telluride quantum dots) on oxidative stress and DNA damage of liver cells in mice. METHODS: Thirty ICR male mice were randomly divided into 5 groups: one negative control (normal saline) group. Three CdTe QDs groups (exposed by intravenous injection of 0.2 ml of CdTe QDs at the concentration of 3.75, 37.5 and 375 nmol/ml respectively) for electron paramagnetic resonance (EPR) test, and another positive control group (exposed by intravenous injection of 0.2 ml of cyclophosphamide 20 mg/ml) for single cell gel electrophoresis (SCGE) test. All mice were decapitated 24h after the injection, free radicals and DNA damage of liver cells were detected by EPR and SCGE. RESULTS: The levels of oxygen free radicals detected by EPR were increased with the increase of CdTe QDs. The tail length, olive tail moment, tail DNA (%) and the ratio of tail/head examined by SCGE were also increased with the increase of the dosage of CdTe QDs (P < 0.01). CONCLUSION: CdTe QDs could induce oxidative stress and DNA damage of liver cells in mice with a dose-effect relationship. PMID- 22443055 TI - [Investigation on the characteristics and space-time distribution of fine particles in the atmosphere of residential area in Shanghai City]. AB - OBJECTIVE: To observe the ambient fine particle pollution and the trend of its space-time distribution in residential areas in Shanghai, and to explore the effects of vehicle exhaust emission on the ambient fine particle pollution. METHODS: Two residential areas A and B were selected for monitoring the pollution of fine particles. Area A is a normal residential area and area B is closed to a main road with heavy traffic. Four monitoring sites were set in the distance of 0 m, 50 m, 100 m and 200 m to the roadside and on a place 1.5 - 1.8 m above the ground. The concentration of fine particles in the air were measured in April, July, October 2010 and Jan 2011 for 1l0 days in each month in both areas using SIDEPAK AM510 (TSI, USA) fine particle monitors. RESULTS: The pollution of fine particle was varied in different seasons (spring > winter > autumn > summer) and at different time (with two peaks at 8:00 AM and 19:00 PM, corresponding to the rush hours). The pollution of fine particles is higher in residential area B than that in area A. The concentration of fine particles was reduced with the increase of the distance to the roadside. CONCLUSION: The level of fine particles in residential areas is comparatively high in Shanghai, and the vehicle exhaust emissions have significant effects on the concentration of fine particles in the atmosphere of residential area. PMID- 22443056 TI - [Protection of HSF1/HSP70 pathway on UVA-induced HaCaT cells apoptosis via inhibiting the activation of c-Jun N-terminal kinase]. AB - OBJECTIVE: To investigate the protective effect of heat shock factor1 (HSF1) and heat shock protein70 (HSP70) on ultraviolet A (UVA)-induced HaCaT cells apoptosis and its mechanism. METHODS: The apoptotic HaCaT cell model was induced by UVA irradiation (8mJ/cm2). The cells were randomly divided into three groups, including a control group, a model group (8mJ/cm2 UVA) and a HSP70 transcription inhibitor group (50 micromol/L quercetin). The morphologic alteration of apoptotic cells was investigated by using Hoechst 33258 fluorescent staining. Western blotting was used to investigate protein expression levels of phosphorylated HSF1 and HSP70 at different time points, as well as c-Jun N terminal kinase (JNK) and phosphorylated JNK were investigated after incubating for 6 hours following UVA irradiation. HSP70 mRNA was detected by Real-Time PCR. RESULTS: Protein expression levels of both phosphorylated HSF1 and HSP70 were time-dependent, appearing an increase at first and then decreased. The increase of p-HSF1 begining at 1h, up to the peak at 3h; and the increase of HSP70 to the peak at 6h and then recovered to the original level at 24h. The pretreatment of HSP70 transcription inhibitor quercetin could significantly inhibit the expression of HSP70 mRNA., and increase the expression of phosphorylated JNK, while increase the apoptosis rate in comparison with UVA model group observed by using Hoechst 33258 fluorescent staining. CONCLUSION: 8mJ/cm2 UVA irradiation could stimulate the activation of HSF1 and increase HSP70 protein expression. HSF1/HSP70 pathway has a protective effect on UVA-induced HaCaT cells apoptosis and its mechanism is that a large number of HSP70 expression inhibited the activation of JNK. PMID- 22443057 TI - [Association of hOGG1 genotype with life style and oxidative DNA damage in five ethnic populations in China]. AB - OBJECTIVE: To assess the natural variation of hOGG1 gene and the gene environmental interactions. METHODS: The hOGG1 codon 326 polymorphism and urinary 8-OHdG levels were investigated in a large sample of healthy individuals (n = 953) from five ethnic populations in China by using PCR-RFLP and HPLC-ECD. Life style parameters were obtained through a questionnaire survey. RESULTS: The allelic frequencies of hOGG1 gene in whole subjects were 0.16 (Ser/Ser), 0.49 (Ser/Cys) and 0.35 (Cys/Cys). The frequency of Ser326Cys was significantly different among the five ethnic populations (P = 0.002). No association was found between the hOGG1 gene polymorphism and other life style parameters except for the association between Ser326Cys and smoking (P = 0.027). A significant increase of urinary 8-OHdG level was observed in Cys326Cys allelic healthy subjects (P = 0.033). CONCLUSION: There are natural variations of hOGG1 gene in different ethnic populations in China. Smoking is related to the frequencies of Cys/Cys polymorphism, and the repairing of oxidative DNA damage is lower in individuals with the hOGG1 Cys326Cys genotype. PMID- 22443058 TI - [Effect of iron supplementation on iron deficiency anemia of childbearing age women in Shanghai]. AB - OBJECTIVE: To investigate the effect of iron supplementation on iron deficiency anemia of childbearing age women, and to find out the optimal amount of iron intake for maintaining their health. METHODS: 74 childbearing age women aged 21 to 45 years with anemia were randomly assigned to intervention or control group by hemoglobin content, and a iron nutrition packet (mainly composed of ferric pyrophosphate and ferrous fumarate, containing iron 8 mg) or a placebo packet was given daily for six months, respectively. Hemoglobin, serum ferritin, food frequency and 24h dietary recall survey were performed before intervention and three and six months after intervention. RESULTS: Hemoglobin and serum ferritin of the intervention group were significantly higher (P < 0.01) than that in control group after six months. The number of women with hemoglobin > or = 120 g/L in intervention and control group was 15 (44.1%) and 5 (14.3%), respectively (P < 0.01). The number of women with serum ferritin > or = 15 micro g/L in intervention and control group was 11 (34.4%) and 4 (12.5%), respectively (P < 0.05). The average dietary iron intake was 14.0 mg/d, mainly from plant foods. There was a positive correlation of total iron intake (dietary iron plus iron supplements) with hemoglobin (r = 0.57, P < 0.01). More menstrual blood and dietary fiber were the risk factors for iron deficiency anemia (P < 0.05). CONCLUSION: The anemic status in childbearing age women could be improved by providing iron 8 mg daily for six months consecutively. Daily dietary intake of iron 23.2 mg can meet the requirement of maintaining normal iron storage for childbearing age women. PMID- 22443059 TI - [Analysis on the status and factors influencing the breastfeeding of children under 2 years of age in poverty stricken areas of China in 2007 - 2009]. AB - OBJECTIVE: To analyze the main factors influencing the breastfeeding of children within 6 months after birth in poor areas, to provide effective intervention measures for improving the unreasonable behavior in order to promote healthy development of children. METHODS: Using the data of nutrition and health monitoring of children under 2 years of age in poor areas of China in 2007 - 2009. Analyzing the factors which influencing the behavior of feeding children. RESULTS: Single factor analysis and multivariate analysis showed that the nationality, place of delivery, main caregiver, family per capita income were important influencing factors. CONCLUSION: Health education is to be strengthened for improving the breastfeeding of children within 6 months after birth in poor areas, especially in ethnic minority areas and families with lower per capita income. Measures on interventions of these influencing factors and scientific feeding patterns should be established. PMID- 22443060 TI - [Effects of multi-nutrients supplementation on the nutritional status and antioxidant capability of healthy adults]. AB - OBJECTIVE: To determine whether daily multivitamins/minerals supplement can improve nutrient status, plasma, antioxidant enzymes activity and total antioxidant capacity in healthy adults. METHODS: One hundred and fifty-one healthy adults living in a normal lifestyle with a mean age of 28 (20 - 50) years were recruited from Guangzhou. The subjects were divided into the supplement group and the control ineral supplements. METHODS: One hundred and fifty-one healthy adults living in a normal lifestyle with a mean age of 28 (20 - 50) years were recruited from Guangzhou. The subjects were divided into the supplement group and the control group carefully matched with age and gender. Supplement pellets (consisted of multivitamins/minerals, including VitA, VitC, VitE,Ca, Zn, Fe, Se, etc.) and placebo pellets (consisted of only dextrin with the same color, shape and size as the supplement pellets) were administrated in a double-blinded manner for 8 week. The nutrients intake data of the research subjects were collected daily by a 24-hour dietary recall method. Blood samples were collected at the beginning and the end of the intervention period for determining the nutritional status, the activities of antioxidant enzymes and the products of oxidative damage. RESULTS: The dietary intake of nutrients was insufficient in these subjects. The levels of plasma VitC, alpha-tocopherol, beta-carotene, Zn, Fe and Se in the supplement group were increased in comparison with the control group by 46%, 28%, 116%, 7%, 30% and 28% respectively (P < 0.05), indicating that the nutritional status regarding antioxidant nutrients had largely been improved. But levels of plasma gamma-tocopherol were decreased by 25% in comparison with the control group (P < 0.05). The activities of GPX, CAT and T-AOC were increased in comparison with the control group and before the supplementation (P < 0.05), while the activities of SOD and the level of 8-isoprostanes remained steady. CONCLUSION: Supplementation of multiple micronutrients could effectively increase the levels of plasma VitC, alpha-tocopherol, beta-carotene, Zn, Fe and Se and the activities of GPX, CAT and T-AOC. PMID- 22443061 TI - [Prevalence of anemia in pregnant women and its related factors in Jiangsu Province and zhejiang Province in China in 2001 - 2005]. AB - OBJECTIVE: To identify the demographic characteristics of anemia and its prevalent trend in pregnant women. METHODS: The data of hemoglobin of 276 895 pregnant women participating in a perinatal health care surveillance system and their babies were born on Jan 1st, 2001 to Dec 31st, 2005 from 14 cities or counties in Jiangsu and Zhejiang provinces in China were analyzed. RESULTS: The overall prevalence of anemia was 31.7% (95% CI 31.4% - 31.9%). The prevalence of anemia in the 1st, 2nd and 3rd trimesters during pregnancy was 15.0% (95% CI 14.9% - 15.2%), 24. 6% (95% CI 24.4% - 24.9%) and 50.8% (95% CI 50.5% -51.1%), respectively. Most of them were mild anemic. The overall prevalence of anemia during pregnancy decreased 26.6%, 39.4%, 32.6% and 23.4% in the years of 2002 to 2005. CONCLUSION: The prevalence of anemia was higher in pregnant women who were farmers and with less education, higher gravidity or parity. The prevalence of anemia during pregnancy remains a public health problem in China. PMID- 22443062 TI - [Relationship between adiposity indicators and blood pressure of urban and rural residents in China]. AB - OBJECTIVE: To explore the relationship between adiposity and blood pressure (BP)of urban and rural residents in China. METHODS: The data in the China Health and Nutrition survey (CHNS) in 2006 were utilized. Cross-sectional analysis was carried out on the relationship between blood pressure and body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) among 6433 adult inhabitants aged 18-60 from 9 provinces of China. A multiple regression equation was used for the prediction of blood pressure with these indicators. RESULTS: The average SBP and DBP were increased linearly with the increase of BMI, WC, WHR and WHtR. A statistically significant linear association was found between each adiposity indicator and BP level in separate regression models controlled by age. The regression coefficients were higher in women than that in men. A gain of 0.77 in BMI, 2.43 cm in WC, 2.66% in WHR and 1.54% in WHtR for men and a gain of 0.75, 2.12 cm, 2.54% and 1.53% respectively for women would have a corresponding elevation of 1 mmHg in SBP. Multiple stepwise regression analyses showed that DBP was related with WHtR. CONCLUSION: There was a stable linear relationship between adiposity indicators and BP. WHtR not a good predicator of SBP and DBP in Chinese adults. PMID- 22443063 TI - [Energy expenditure on different physical activities of rural adults in North China]. AB - To test the energy metabolism of healthy adults in rural north China and to obtain the data of energy expenditure on different physical activities, in order to provide the basis for the Dietary Reference Intakes for Chinese people and the prevention and treatment of diseases related to energy and nutrition imbalance. METHOD: The energy expenditures on different physical activities of 30 healthy adult men and women were investigated under strictly controlled experimental conditions by using portable cardiopulmonary function determinator k4b2 to examine the oxygen consumption (VO2) and carbon dioxide production (VCO2) during basal metabolic conditions and seven kinds of physical activities (walking, brisk walking, jogging, cycling, stair climbing, and watching TV). The content of 24 hour urine nitrogen was measured by micro Kjeldahl method. Combining with the change of body weight, the energy expenditures on different physical activities of normal adult men and women in north China were obtained. RESULTS: The average energy expenditure on physical activities (kJ x h(-1) x kg(-1)) were: walking 12.60 +/- 5.54 (11.46 +/- 2.19 for male and 15.47 +/- 6.97 for female), brisk walking 20.79 +/- 10.46 (15.95 +/- 3.59 for male and 25.33 +/- 12.70 for female), jogging 34.78 +/- 16.00 (30.45 +/- 5.07 for male and 38.84 +/- 21.58 for female) cycling 16.47 +/- 3.95 (14.77 +/- 2.57 for male and 18.74 +/- 4.85 for female), going up stairs 23.55 +/- 5.05 (23.61 +/- 3.43 for male and 23.49 +/- 6.41 for female) going down stairs 12.46 +/- 6.30 (10.43 +/- 1.27 for male and 14.49 +/- 8.48 for female) and watching TV 3.85 +/- 1.97 (3.56 +/- 0.86 for male and 4.16 +/- 2.79 for female). CONCLUSION: The average energy expenditure on physical activities of males was lower than that of females (P < 0.05), except of going up stairs, which was roughly equal in males and females. The average energy expenditure on various physical activities was different. Walking, watching TV and going downstairs are low-intensity physical activities; brisk walking, cycling and climbing upstairs are medium-intensity physical activities; and jogging is a high-intensity physical activity. PMID- 22443064 TI - [Investigation on the iodine nutritional status and the prevalence of thyroid carcinoma in Zhoushan Archipelago residents]. AB - OBJECTIVE: To investigate the nutritional status of iodine and the prevalence of thyroid carcinoma of residents in Zhoushan Archipelago, and to explore the related factors influencing the prevalence of thyroid carcinoma. METHODS: The residents in Zhoushan Archipelago were selected by cluster random sampling. The subjects were surveyed by questionnaire, their thyroids were examined by B ultrasonography, the thyroid function and the levels of urine iodine were analyzed. Pathological diagnosis was conducted to the patients suspected of thyroid carcinoma. RESULTS: The median levels of urine iodine in urban residents, famers, salt-makers, fishermen from Zhoushan and buddhists from Putuoshan were 320.7, 188.9, 122.2, 193.6 and 271.7 microg/L respectively, while the prevalence rates of thyroid carcinoma were 215/100 000, 398/100 000 0, 407/100 000, 829/100 000,340/100 000, respectively; The age or a higher level of hTSH of a person were risk factors for suffering from thyroid carcinoma. CONCLUSION: The iodine intake of residents in ZhouShan Archipelago is adequate and the prevalence rate of thyroid carcinoma is high. Serum hTSH could be used as a predictor for the risk of thyroid carcinoma. PMID- 22443065 TI - [Purine in common plant food in China]. AB - OBJECTIVE: To determine the content of purine in plant food in China with HPLC. METHOD: HPLC analysis was applied on Waters Atlantis T3 column (4.6mm x 250mm x 5 microm), using 10.0 mmol/L NH4COOH (pH 3.6) and CH3OH (99%/1%) as mobile phase and running at a flow rate of 1.0 ml/min. The column temperature was 30 degrees C, and the detection wavelength was at 254nm. RESULTS: The content of purine varied significantly in different kinds of plant food. The content of purine in dried fungi and dried legumes and legume products was higher than that in other food, the content of purine in vegetables and vegetable products and fruits and fruit products was low. As a whole, the content of purine was: dried fungi and algae > dried legumes and legume products > nuts and fresh > seeds fungi and algae > cereal and cereals products > vegetables and vegetable products > fruit and fruit products > tubers, starches and products. CONCLUSION: The content of purine of dried fungi and algae and dried legumes and legume products in plant food was high. The content of purine was varied significantly in different kinds of plant food. PMID- 22443066 TI - [Development of a xMAP liquid chip assay for the rapid identification of 7 common foodborne pathogens and its application]. AB - OBJECTIVE: To develop an assay for the simultaneous detection of 7 common foodborne pathogens with xMAP liquid chip in a single-tube reaction. METHODS: Seven specific primers and probes were designed and synthesized based on the target gene sequences from GenBank. Target bacterial sequences were amplified by asymmetric PCR. The biotinylated products were hybridized to seven probe beads in a multiplex reaction and analyzed by using streptavidin conjugated to a fluorescent reporter molecule. The developed liquid chip xMAP assay was used to test 140 strains of bacteria and then 56 food samples. RESULTS: No cross-reaction and false signals were observed. The detection limit was 1 - 100 pg and 10(5) - 10(6) cfu/ml. The results tested by xMAP were in accordance with the traditional culture method. CONCLUSION: The processing of xMAP liquid chip assay, including DNA preparation and sample detection, could be finished within 3.5 hours and could be applied to the classification and identification of foodborne pathogens in the food safety monitoring. PMID- 22443067 TI - [Lipid peroxidation in different tissues of rats treated with 2-amino-1-methyl-6 phenylimidazo [4,5-b] pyridine]. AB - OBJECTIVE: To study the effects of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) (a kind of heterocyclic amines) on lipid peroxidation in the heart, lung, liver and kidney of rats. METHODS: Rats were divided into a normal control group and three PhIP groups exposed to different doses of PhIP (5, 10 and 15 mg/kg body weight) by gavage. The indexes of lipid peroxidation were measured 24 hours after gavaging. RESULTS: In comparison with the control group, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were increased in hearts and lungs while were significantly inhibited in livers of rats in PhIP groups at the doses of 10 and 15 mg/kg body weight (P < 0.05 or P < 0.01). There was no significant change in kidneys. Moreover, malondialdehyde (MDA) levels in the tissues of rats increased with a dose-dependent manner for PhIP exposure. CONCLUSION: PhIP could cause lipid peroxidation in the heart, lung, liver and kidney of rats, and such effects were varied in different organs. PMID- 22443068 TI - [Effect of fluoride on the expression of StAR mRNA and P450scc mRNA in the progesterone synthesis of mouse Leydig tumor cells]. AB - OBJECTIVE: To observe the effect of sodium fluoride on the expression of steroidogenic acute regulatory protein (StAR) mRNA and cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) mRNA in the testosterone synthesis of mouse Leydig tumor cells (mLTC-1). and to explore the molecular mechanisms of fluoride on reproductive injury. METHODS: Using mLTC-1 cells as a model, progesterone in the supernatant of cell culture medium was measured by RIA. The expression of StAR mRNA and P450scc mRNA in mLTC-1 cells was determined by real-time PCR. RESULTS: In comparison with the control group, the expression of StAR mRNA and P450scc mRNA in mLTC-1 cells and the secretion of progesterone of mLTC-1 cells in the three fluoride groups with 12,16 and 20 microg/ml of NaF in their media respectively were obviously lower (P < 0.05). CONCLUSION: The expression of StAR mRNA and P450scc mRNA in mLTC-1 cells could be inhibited by NaF, and consequently the secretion of progesterone in mLTC-1 cells was affected. PMID- 22443069 TI - [Simultaneous determination of 11 phthalate metabolites in urine by liquid chromatography tandem mass spectrometry]. AB - OBJECTIVE: To develop a method for determining 11 kinds of phthalate metabolites in urine simultaneously. METHODS: The phthalate metabolites in human urine samples were hydrolyzed by glucuronidase, and then were concentrated by solid phase extraction and eluted by methanol/acetonitrile (1 : 1, V/V). After chromatographic separation on phenyl column, the analytes were analyzed qualitatively and quantitatively under MRM mode. RESULTS: The limits of detection (LOD) for the eleven kinds of phthalate metabolites were in the range of 0.13 - 2.27 ng/ml. The mean recoveries at the two spiked levels were 67% - 108%, with the relative standard deviation (RSD) of less than 12%. CONCLUSION: The method can be used to determine the residues of eleven kinds of phthalate metabolites in urine accurately and sensitively. PMID- 22443070 TI - [Research and development of a vehicle-mounted drinking water installation and its purification effect]. AB - OBJECTIVE: To provide a suitable vehicle-mounted installation to solve the problem of drinking water in the wild. METHODS: The vehicle-mounted drinking water installation, made up of pre-treatment unit, purification unit, box and VECU, was used to storage, transport and purify water in the wild. The effect of purification was detected by assembling the installation in the wild and observing the change of water turbidity, TDS, the number of total bacteria and coliform bacteria before and after the treatment of water sources. RESULTS: The wild water sources, such as river water, rainwater, well water and spring water could be purified, and the quality of the treated water could meet the requirement of Drinking Water Quality Standard of CJ94-2005. CONCLUSION: The vehicle-mounted drinking water installation is suitable for purifying water sources in the wild for drinking use. PMID- 22443071 TI - [Effects of organic selenium supplement on glutathione peroxidase activities: a meta-analysis of randomized controlled trials]. AB - OBJECTIVE: To study the effects of organic selenium supplementation on glutathione peroxidase (GPx) activities. METHODS: Randomized controlled trials (RCT) published from January 1988 to December 2010 on the relationship between organic selenium supplementation and GPx activities were collected. Meta-analysis was applied to estimate the combined standardized mean difference (SMD) and 95% confidence interval (95% CI). RESULTS: A total of 10 RCTs were included. The number of studies observing GPx activities in plasma, erythrocyte and platelet was 8, 5 and 5, respectively. Compared with the controls, the combined SMD (95% CI) of GPx activities in plasma, erythrocyte and platelet of subjects supplemented with organic selenium was 0.46 (0.09 - 0.83), 0.36 (0.02 - 0.69) and 0.56 (-0.02 - 1.15). CONCLUSION: Supplementation with organic selenium increases GPx activities in healthy adults. PMID- 22443072 TI - [Advances on studies related to the requirement of vitamin A for infants, young and preschool children]. AB - There are many factors that could affect the requirement of vitamin A including infections, parasites, protein-energy malnutrition, bioconversion efficiency of provitamin A, food matrix and so on. However, the toxicity of vitamin A should also be taken into account when establishing reference values for infants, young and preschool children. Serum and breast-milk retinol concentrations, retinol binding protein concentrations, the relative-dose-response test , the modified relative-dose-response and the deuterated retinol isotope dilution test are the common tools to assess vitamin A status. PMID- 22443073 TI - [Advances on the study of iron deficiency and mental development in children]. AB - Childhood is a critical period for mental development. Iron deficiency will affect the development of nerve system and depress the learning ability, memory and cognitive function of children. There are a large number of literatures focusing on the mechanism of iron deficiency on mental retardation and the effect of iron reinforcement on iron deficient children in recent years. More attention has been paid to the prevention of iron deficiency. It has been proposed that the prevention of iron deficiency during early life of infants is more important than the reinforcement of iron in childhood. Exploring the relationship between iron deficiency and mental development is very important to improve the intelligence of children and the quality of whole population. PMID- 22443074 TI - [Progress on the research of stem Leydig cell line in the testis of rodents]. AB - OBJECTIVE: Leydig cells are the primary source of generating testosterone, and the differentiation of Leydig cells in testes is a signature event of the ontogenesis of males. Many studies elucidating the molecular changes and the mechanisms involved in the progressive differentiation of stem Leydig cells into adult Leydig cells have been appeared recently. Herein, the hormonal regulation on the ontogenesis of fetal and mature Leydig cells was reviewed in this paper. PMID- 22443075 TI - Visual impairment in patients with leprosy in Adilabad District in the state of Andhra Pradesh, India. AB - The aim was to estimate the prevalence of eye problems in patients with leprosy and to assess the utilization rate of eye care services using cross-sectional case series design. All leprosy patients registered between April 2007 and June 2009 were included in the study. They were prospectively assessed by an internist for general health issues. An ophthalmic examination including assessment of visual acuity was conducted by an ophthalmologist. A total of 150 leprosy patients were examined, of which 78 (52%) suffered from pausi bacillary (PB) leprosy and majority were males (52%); 43 (29%) patients were literate. Nineteen (14%) patients had organ deformities and ocular lesions were seen in 12 (8%) patients, but 76 (51%) (95% CI 40.8-62.7) patients had earlier reported eye problems requiring intervention as assessed by the ophthalmic officer. Only 26 (17%) (95% CI 11.6-24.4) patients had sought eye care services earlier. Visual impairment was observed in 19 (12.6%) cases and blindness related to leprosy was seen in 5 (3.3%) patients. To conclude prevention of blindness among leprosy patients is possible only with strong coordination between the general health and eye care unit in the area with mandatory eye screening being made part of the treatment schedule for leprosy patients. PMID- 22443076 TI - Evaluation of national leprosy eradication programme in Satara District, Maharashtra. AB - The aim of this study was to evaluate the impact of national leprosy eradication programme (NLEP) in Satara District. A retrospective record based study was conducted in the district leprosy control unit with evaluation indicators like prevalence rate (PR), new case detection rate (NCDR), percentage of cases released from treatment, proportion of female cases among new cases, proportion of multi bacillary (MB) cases among new cases, proportion of grade-2 disability among new cases and proportion of child cases among new cases and trend was analyzed for statistical significance by using Chi-square test. During study period from year March 2003-04 to March 2007-08, there was decrease in PR of leprosy from 2.46/10000 population to 0.62/10000 population, NCDR decreased from 3.46/10000 population to 0.77/10000 population and trend was statistically significant (p<0.001*, P<0.001*) respectively. Declining trend of grade 2 disability among new cases was noted and this was statistically significant (p<0.01*). Proportion of female cases among new cases showed little fluctuation from 43.3% to 47.5% but trend was statistically significant (p<0.03*). Proportion of MB cases among new cases increased from 44.4% to 53.6% while proportion of child cases among new cases decreased from 16.5% to 12% and trend was statistically significant (p <0.001*, p<0.001*) respectively. The NLEP has a favorable impact towards elimination of leprosy in Satara District, Maharashtra. PMID- 22443077 TI - Medical and social concerns of leprosy cured after integration in India. AB - In order to understand nature of the medical and society related problems of leprosy cured individuals from various socio-cultural groups and develop proper system to address the current needs of leprosy cured, data have been collected from leprosy cured, employing qualitative methods such as FGDs, open ended interviews and participant observation and a quantitative survey method. The findings show that there has been not much change in the socio-cultural and economic situation of the leprosy cured especially the disabled ones, except a recognition in the health system that their anti-leprosy treatment is completed. In the present integrated health care system, disabled leprosy patients are also expected to seek their own health care by themselves along with general public, which is not happening because the leprosy cured are not yet perceived to be cured of leprosy by community as well as by themselves. Though some of the problems of leprosy cured seem to be poverty related, qualitative analysis shows, a vast gap between poverty problem of leprosy afflicted and non leprosy afflicted. Any special programme to bridge the gap between PHC and leprosy community is required and the new functionaries like ASHA in National Rural Health Mission (NRHM) and similar developments could be of vital use to make them cured in totality. PMID- 22443078 TI - Progression of cataracts following photodynamic therapy combined with intravitreous triamcinolone injection in cases of age-related macular degeneration. AB - BACKGROUND: To present long-term data on the progression of cataracts following photodynamic therapy (PDT) combined with 4 mg intravitreal triamcinolone acetonide (IVTA) for age-related macular degeneration (AMD). METHODS: Fifty-seven phakic eyes of 56 patients underwent the treatment between October 2004 and November 2006. The follow-up period ranged from 12 to 38 months with 3 months interval of observation and repeated treatment at recurrence. RESULTS: Cataract progression was noted in 40 eyes 5-21 months after treatment, consisting of 4 eyes between 3 and < 6 months after treatment, 22 eyes between 6 and < 12 months, 8 eyes between 12 and < 18 months, and 6 eyes between 18 and < 24 months. The percentage of the eyes with cataract progression began to decrease 5 months after treatment and, occurred most frequently during the period from 6 months to 12 months after treatment. There was no significant difference in age, follow-up period, or the frequency of the treatment between the cataract progression group and the non progression group. Twenty four eyes underwent surgery 10-31 months after treatment, showing significant improvement in visual acuity. CONCLUSIONS: This study showed high incidence of cataract during a long-term follow-up after PDT combined with IVTA and significant reduction of visual acuity due to cataract. PMID- 22443079 TI - Clinical outcome of amrubicin therapy according to the prior chemotherapy sensitivities of extensive small cell lung cancer. AB - BACKGROUND: Amrubicin (AMR) is an active agent for relapsed small cell lung cancer (SCLC). However, the activity of AMR in refractory relapsed patients is controversial. The objective of this retrospective analysis was to evaluate the efficacy and safety of AMR as second-line chemotherapy in SCLC, especially refractory relapsed SCLC. METHODS: Between July 2003 and February 2009, a total of 27 patients were treated with AMR at a dosage of 40 mg x m(-2) x day(-1) on days 1-3 every 3 weeks. Safety was assessable for all patients. Efficacy was evaluated in 26 patients (one patient was not assessable for response), in 12 patients with chemotherapy-sensitive relapse and 14 patients with chemotherapy refractory relapse. Sensitive relapse means that a first-line response lasted more than 90 days. Refractory relapse means that either did not respond to first line chemotherapy or responded initially but relapsed within 90 days. RESULTS: Thirteen patients (50%, 95% CI, 31% to 69%) had partial response, including 6 (50%) of the 12 patients with chemotherapy-sensitive relapse and 7 (50%) of 14 patients with chemotherapy-refractory relapse. Median survival times of patients with chemotherapy-sensitive and -refractory relapse were 9.7 months and 8.4 months, respectively, showing significant difference (p = 0.0337). Adverse events were observed in all 27 patients. Grade 3 and 4 neutropenia was seen in 8 patients (29.6%) and 15 patients (55.5%), respectively. Grade 3 and 4 thrombocytopenia occurred in 10 patients (37.0%) and 2 patients (7.4%). Non hematologic toxicities were generally mild, except for febrile neutropenia. Febrile neutropenia was seen in 6 patients (22.2%). No treatment-related deaths occurred. CONCLUSIONS: AMR is an active agent for the treatment of relapsed SCLC, especially chemotherapy-refractory relapse SCLC, with predictable and manageable toxicities. PMID- 22443080 TI - Lower skin temperature decreases maximal cycling performance. AB - BACKGROUND: It is known that external cooling of body regions involved in exercise, prior to exercise, decreases anaerobic performance. However, there have been no studies reporting the effects of whole body skin surface cooling before exercise on maximal anaerobic capacity. In order to clarify the effects, we compared power output during the Wingate anaerobic test between preconditioning by exposure to temperature 10 degrees C and 25 degrees C. METHODS: Eight healthy males carried out the Wingate test for 30 seconds, after pre-conditioning for 60 minutes using a perfusion suit with water at a temperature of 10 degrees C or 25 degrees C. We evaluated the peak power (PP) and peak power slope (PS) of the power output. RESULTS: Mean skin temperature (T(sk)) at 60 minutes of pre conditioning in the 10 degrees C trial was significantly lower than in the 25 degrees C trial (p < 0.05). PP and also PS were significantly lower in the 10 degrees C trial than in the 25 degrees C trial. Changes (Delta) in PP between the 10 degrees C trial and the 25 degrees C trial were strongly correlated with DeltaT(sk) and Delta in thigh and leg skin temperature (DeltaT(thigh) and DeltaT(leg), respectively), whereas DeltaPS was strongly correlated with DeltaT(sk), but not with DeltaT(thigh) and DeltaT(leg). CONCLUSIONS: Whole body skin surface cooling prior to exercise restricts anaerobic capacity, especially in the initial phase of exercise. PMID- 22443081 TI - Granulocyte colony-stimulating factor-producing ascending colon cancer as indicated by histopathological findings: report of a case. AB - Various types of granulocyte colony-stimulating factor (G-CSF)-producing malignant tumors have been reported. However, a G-CSF-producing colorectal cancer is rare. We present a case of G-CSF-producing ascending colon cancer. An 81-year old man was referred to our hospital with right lower abdominal pain. A colon fiberscopy revealed an ascending colon tumor, and histological examination revealed tubular adenocarcinoma. He was admitted due to worsening abdominal pain. Although laboratory data showed an elevated white blood cell (WBC) count of 17000/mm3 with 77.8% neutrophils, elevated C-reaction protein (CRP) was insignificant (1.06 mg/dL), and he was afebrile. Because computed tomography indicated that the tumor penetrated into surrounding tissue, a semi-urgent ileocecal resection was performed. An abscess was not located. The tumor was staged as T3N2aM0 and as stage IIB according to the TNM classification. Microscopically, significant neutrophil infiltration between cancer cells was observed, suggesting the presence of a G-CSF-producing tumor. Immunohistochemical staining using a G-CSF antibody revealed cytoplasmic staining in cancer cells. The serum concentration of G-CSF upon admission was 334 pg/mL. After surgical resection, the WBC count decreased to within a normal range. These findings confirmed the diagnosis of G-CSF-producing ascending colon cancer. The prognosis of G-CSF-producing tumors is considered to be poor. Early diagnosis and surgical treatment are needed for patients with G-CSF-producing tumors, and continuous careful follow-up is required. PMID- 22443082 TI - Cytotoxicity and cytoprotective effects of citrus flavonoids on insulin-secreting cells BRIN-BD11: beneficial synergic effects. AB - Flavonoids, in general, have potent antioxidant activity and they can be used in treating chronic diseases involving oxidative stress, such as diabetes mellitus. The purpose of this study was to evaluate the cytotoxicity and cytoprotective effects of citrus flavonoids on the functionality of BRIN-BD11 cells. The assessment of cytotoxic and cytoprotective flavonoid tested was performed using the MTT reduction assay. The flavonoids did not show cytotoxic effects in any of the tested concentrations (5-20 uM) and also negative insulinotropic effects were not observed. To cytoprotective assay, the IC50 of H2O2 in treatment of 2 h (acute oxidative stress) was measured (350 uM). Moreover, under acute oxidative stress, the isolated flavonoids (10 uM) had no cytoprotective effects. Besides an antioxidant role of the flavonoids was only observed when using in association. Thus future experiments are needed, varying the experimental condition, to better evaluate the possible mechanisms of action of these flavonoids. PMID- 22443083 TI - Morphologic patterns of lip prints in a Portuguese population: a preliminary analysis. AB - Lip prints are thought to have the ability to distinguish individuals and, hence, have a potential use in human identification purposes. However, questions remain regarding their utility for sex determination. This study aimed to classify lip prints for different individuals in a Portuguese population and to determine whether sex differences exist. Lip prints of 25 females and 25 males were obtained using dark-colored lipstick and cellophane tape. Lip prints were analyzed using a magnifying lens and classified according to the Suzuki and Tsuchihashi classification. A Type II pattern was found to be most common. A comparison of lip-print patterns between males and females showed results with a statistically significant difference: Type III pattern was most common in males, and a Type II pattern in females. This study corroborates the hypothesis that lip prints are able to distinguish individuals and may be useful in sex determination. PMID- 22443084 TI - The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. AB - INTRODUCTION: The RAS/RAF/MAP kinase-ERK kinase (MEK)/extracellular-signal regulated kinase (ERK) (MAPK) and the PI3K/AKT/mammalian target of rapamycin (mTOR) (PI3K) pathways are frequently deregulated in human cancer as a result of genetic alterations in their components or upstream activation of cell-surface receptors. These signalling cascades are regulated by complex feedback and cross talk mechanisms. AREAS COVERED: In this review the key components of the MAPK and AKT pathways and their molecular alterations are described. The complex interactions between these signalling cascades are also analysed. EXPERT OPINION: The observation that the MAPK and the PI3K pathways are often deregulated in human cancer makes the components of these signalling cascades interesting targets for therapeutic intervention. Recently, the presence of compensatory loops that activate one pathway following the blockade of the other signalling cascade has been demonstrated. Therefore, the blockade of both pathways with combinations of signalling inhibitors might result in a more efficient anti-tumor effect as compared with a single agent. In addition, the MAPK and PI3K pathways are activated by mutations that coexist or can be mutually exclusive. In this regard, a large-scale characterization of the cancer genome might offer personalized cancer genomic information, which may improve the anti-tumor efficacy of signalling inhibitors. PMID- 22443085 TI - Spatially resolved scattering correlation spectroscopy using a total internal reflection configuration. AB - In the paper, we present a novel single particle method, named spatially resolved scattering correlation spectroscopy (SRSCS), based on a total internal reflection (TIR) configuration and strong resonance light scattering (RLS) of silver nanoparticles (AgNPs). The principle of SRSCS is similar to fluorescence correlation spectroscopy (FCS), and it is based on measuring the RLS fluctuations in a small volume due to Brownian motion of single nanoparticles. We first established a highly sensitive SRSCS system. In the SRSCS system, a millimeter scale hole is employed to efficiently separate nanoparticle scattering light from the background reflected beam, and an electron multiplying charge-coupled device (EMCCD) is used as an array detector. The SRSCS system was successfully used for detection and imaging of single AgNPs in solution. Furthermore, we developed the model of SRSCS according to the FCS method and systematically investigated the effects of certain factors such as particle concentration, viscosity of the solution, hardware and software binning and accumulation time on SRSCS measurements using AgNPs as a model sample. A series of calibration experiments were conducted, and the experimental data obtained were in good agreement with the SRSCS model. This new method is multiplexing, spatially resolved, and free of photobleaching and may become a useful method for study on heterogeneous systems, such as the motion of proteins on the cell membrane. PMID- 22443086 TI - Tris[2-(acryloyloxy)ethyl]isocyanurate cross-linked low-molecular-weight polyethylenimine as gene delivery carriers in cell culture and dystrophic mdx mice. AB - Hyperbranched poly(ester amine)s (PEAs) were successfully synthesized by Michael addition reaction between tris[2-(acryloyloxy)ethyl]isocyanurate (TAEI) and low molecular-weight polyethylenimine (LPEI, M(w) 0.8k, 1.2k, and 2.0k) and evaluated in vitro and in vivo as gene carriers. PEAs effectively condensed plasmid DNA with particle sizes below 200 nm and surface charges between 11.5 and 33.5 mV under tested doses [at the ratios 2-10:1 of polymer/pDNA(w/w)]. The PEAs showed significantly lower cytotoxicities when compared with PEI 25k in two different cell lines. The PEAs (C series) composed of PEI 2k showed higher transgene expression compared to PEAs of PEI 0.8k (A series) or 1.2k (B series). Highest gene transfection efficiency in CHO, C2C12 myoblast, and human skeletal muscle (HSK) cell lines was obtained with TAEI/PEI-2K (C12) at a ratio of 1:2. Both C12, C14(TAEI/PEI-2K at a ratio of 1:4) demonstrated 5-8-fold higher gene expression as compared with PEI 25k in mdx mice in vivo through intramuscular administration. No obvious muscle damage was observed with these new polymers. Higher transfection efficiency and lower toxicity indicate the potential of the biodegradable PEAs as safe and efficient transgene delivery vectors. PMID- 22443087 TI - Influence of alkyl chain length and temperature on thermophysical properties of ammonium-based ionic liquids with molecular solvent. AB - Mixing of ionic liquids (ILs) with molecular solvent can expand the range of structural properties and the scope of molecular interactions between the molecules of the solvents. Exploiting of these phenomena essentially require a basic fundamental understanding of mixing behavior of ILs with molecular solvents. In this context, a series of protic ILs possessing tetra-alkyl ammonium cation [R(4)N](+) with commonly used anion hydroxide [OH](-) were synthesized and characterized by temperature dependent thermophysical properties. The ILs [R(4)N](+)[OH](-) are varying only in the length of alkyl chain (R is methyl, ethyl, propyl, or butyl) of tetra-alkyl ammonium on the cationic part. The ILs used for the present study included tetramethyl ammonium hydroxide [(CH(3))(4)N](+)[OH](-) (TMAH), tetraethyl ammonium hydroxide [(C(2)H(5))(4)N](+)[OH](-) (TEAH), tetrapropyl ammonium hydroxide [(C(3)H(7))(4)N](+)[OH](-) (TPAH) and tetrabutyl ammonium hydroxide [(C(4)H(9))(4)N](+)[OH](-) (TBAH). The alkyl chain length effect has been analyzed by precise measurements such as densities (rho), ultrasonic sound velocity (u), and viscosity (eta) of these ILs with polar solvent, N-methyl-2 pyrrolidone (NMP), over the full composition range as a function of temperature. The excess molar volume (V(E)), the deviation in isentropic compressibility (Deltakappa(s)) and deviation in viscosity (Deltaeta) were predicted using these properties as a function of the concentration of ILs. Redlich-Kister polynomial was used to correlate the results. A qualitative analysis of the results is discussed in terms of the ion-dipole, ion-pair interactions, and hydrogen bonding between ILs and NMP molecules. Later, the hydrogen bonding features between ILs and NMP were also analyzed using a molecular modeling program with the help of HyperChem 7. PMID- 22443088 TI - Extracellular polymeric substances from Bacillus subtilis associated with minerals modify the extent and rate of heavy metal sorption. AB - Extracellular polymeric substances (EPS) are an important source of organic matter in soil. Once released by microorganisms, a portion may be sorbed to mineral surfaces, thereby altering the minerals ability to immobilize heavy metals. EPS from Bacillus subtilis were reacted with Ca-saturated bentonite and ferrihydrite in 0.01 M KCl at pH 5.0 to follow the preferential uptake of EPS-C, N, and -P. The sorption kinetics of Pb(2+), Cu(2+), and Zn(2+) to the resulting EPS-mineral composites was studied in single and binary metal batch experiments ([metal](total) = 50 MUM, pH 5.0). Bentonite sorbed much more EPS-C (18.5 mg g( 1)) than ferrihydrite (7.9 mg g(-1)). During sorption, EPS were chemically and size fractionated with bentonite favoring the uptake of low-molecular weight components and EPS-N, and ferrihydrite selectively retaining high-molecular weight and P-rich components. Surface area and pore size measurements by N(2) gas adsorption at 77 K indicated that EPS altered the structure of mineral-EPS associations by inducing partial disaggregation of bentonite and aggregation of ferrihydrite. Whereas mineral-bound EPS increased the extent and rate of Pb(2+), Cu(2+), and Zn(2+) sorption for bentonite, either no effect or a decrease in metal uptake was observed for ferrihydrite. The extent of sorption always followed the order Pb(2+) > Cu(2+) > Zn(2+), which also prevailed in binary Pb(2+)/Cu(2+) systems. In consequence, sorption of EPS to different minerals may have contrasting consequences for the immobilization of heavy metals in natural environments by inducing mineral-specific alterations of the pore size distribution and, thus, of available sorption sites. PMID- 22443089 TI - 'Bubbles in my eye'. Perfluorocarbon liquid residue in the anterior chamber. PMID- 22443090 TI - The positive symptoms of acute schizophrenia and latent inhibition in humans and animals: underpinned by the same process(es)? AB - INTRODUCTION: It has been suggested that the positive symptoms of acute schizophrenia are a consequence of a disruption of the process that produces latent inhibition (slower acquisition of conditioned responding after preexposure to the conditioned stimulus) and that this effect can be modelled by pro- and antipsychotic compounds in healthy participants and in nonhuman animals. This idea assumes that latent inhibition in humans and animals is underpinned by the same process(es). METHOD: First, we question the equivalence of human and animal latent inhibition. Second, we review the studies that have examined latent inhibition in populations with schizophrenia and in healthy populations after administration of amphetamine or haloperidol. RESULTS: Theoretical analysis of the similarities and differences in latent inhibition effects, and the procedures used to generate them, in humans and animals renders the suggested equivalence between them unconvincing. The studies examining latent inhibition in populations with schizophrenia and in healthy populations after administration of amphetamine or haloperidol are marked by a number of methodological shortcomings and reveal discrepant results. CONCLUSIONS: The theoretical and empirical analyses provide little support for a common process underlying deficits of latent inhibition in patients exhibiting positive symptoms of acute schizophrenia, and such deficits in experimental models in healthy humans and infrahumans. PMID- 22443091 TI - Insulin resistance and risk of venous thromboembolism: results of a population based cohort study. AB - BACKGROUND: Obesity is an established risk factor for venous thromboembolism (VTE), but it is uncertain how this is mediated. Insulin resistance has a central role in the pathophysiology of the metabolic effects of obesity. OBJECTIVE: We aimed to investigate whether insulin resistance is a risk factor for VTE. METHODS: For this analysis we used the PREVEND prospective community-based observational cohort study. Insulin resistance was measured as HOMA-IR (homeostasis model assessment of insulin resistance) and fasting insulin. VTE was assessed using databases of the national registries of hospital discharge diagnoses, death certificates and the regional anticoagulation clinic. RESULTS: Out of 7393 subjects, 114 developed VTE during a median follow-up of 10.5 years. High HOMA-IR was associated with increased risk of VTE after adjustment for traditional cardiovascular risk factors, CRP and markers of endothelial dysfunction (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.09 1.75; P=0.007). When body mass index (BMI) was added to the model, BMI was a strong risk predictor for VTE (HR, 1.53; 95% CI, 1.24-1.88; P<0.001) whereas HOMA IR no longer showed such an association (HR, 1.11; 95% CI, 0.85-1.43; P=0.45). Results were similar for fasting insulin. CONCLUSION: Our population-based cohort study shows an increased risk of VTE in subjects with increasing insulin resistance but not independently of BMI. PMID- 22443092 TI - Evaluation of invertebrate infection models for pathogenic corynebacteria. AB - For several pathogenic bacteria, model systems for host-pathogen interactions were developed, which provide the possibility of quick and cost-effective high throughput screening of mutant bacteria for genes involved in pathogenesis. A number of different model systems, including amoeba, nematodes, insects, and fish, have been introduced, and it was observed that different bacteria respond in different ways to putative surrogate hosts, and distinct model systems might be more or less suitable for a certain pathogen. The aim of this study was to develop a suitable invertebrate model for the human and animal pathogens Corynebacterium diphtheriae, Corynebacterium pseudotuberculosis, and Corynebacterium ulcerans. The results obtained in this study indicate that Acanthamoeba polyphaga is not optimal as surrogate host, while both Caenorhabtitis elegans and Galleria larvae seem to offer tractable models for rapid assessment of virulence between strains. Caenorhabtitis elegans gives more differentiated results and might be the best model system for pathogenic corynebacteria, given the tractability of bacteria and the range of mutant nematodes available to investigate the host response in combination with bacterial virulence. Nevertheless, Galleria will also be useful in respect to innate immune responses to pathogens because insects offer a more complex cell based innate immune system compared with the simple innate immune system of C. elegans. PMID- 22443093 TI - Dunn's index for cluster tendency assessment of pharmacological data sets. AB - Cluster tendency assessment is an important stage in cluster analysis. In this sense, a group of promising techniques named visual assessment of tendency (VAT) has emerged in the literature. The presence of clusters can be detected easily through the direct observation of a dark blocks structure along the main diagonal of the intensity image. Alternatively, if the Dunn's index for a single linkage partition is greater than 1, then it is a good indication of the blocklike structure. In this report, the Dunn's index is applied as a novel measure of tendency on 8 pharmacological data sets, represented by machine-learning-selected molecular descriptors. In all cases, observed values are less than 1, thus indicating a weak tendency for data to form compact clusters. Other results suggest that there is an increasing relationship between the Dunn's index as a measure of cluster separability and the classification accuracy of various cluster algorithms tested on the same data sets. PMID- 22443094 TI - Molecular characterization of diverse CIMMYT maize inbred lines from eastern and southern Africa using single nucleotide polymorphic markers. AB - BACKGROUND: Knowledge of germplasm diversity and relationships among elite breeding materials is fundamentally important in crop improvement. We genotyped 450 maize inbred lines developed and/or widely used by CIMMYT breeding programs in both Kenya and Zimbabwe using 1065 SNP markers to (i) investigate population structure and patterns of relationship of the germplasm for better exploitation in breeding programs; (ii) assess the usefulness of SNPs for identifying heterotic groups commonly used by CIMMYT breeding programs; and (iii) identify a subset of highly informative SNP markers for routine and low cost genotyping of CIMMYT germplasm in the region using uniplex assays. RESULTS: Genetic distance for about 94% of the pairs of lines fell between 0.300 and 0.400. Eighty four percent of the pairs of lines also showed relative kinship values <= 0.500. Model based population structure analysis, principal component analysis, neighbor joining cluster analysis and discriminant analysis revealed the presence of 3 major groups and generally agree with pedigree information. The SNP markers did not show clear separation of heterotic groups A and B that were established based on combining ability tests through diallel and line x tester analyses. Our results demonstrated large differences among the SNP markers in terms of reproducibility, ease of scoring, polymorphism, minor allele frequency and polymorphic information content. About 40% of the SNPs in the multiplexed chip based GoldenGate assays were found to be uninformative in this study and we recommend 644 of the 1065 for low to medium density genotyping in tropical maize germplasm using uniplex assays. CONCLUSIONS: There were high genetic distance and low kinship coefficients among most pairs of lines, clearly indicating the uniqueness of the majority of the inbred lines in these maize breeding programs. The results from this study will be useful to breeders in selecting best parental combinations for new breeding crosses, mapping population development and marker assisted breeding. PMID- 22443095 TI - Patch testing with own cosmetics-- prospective study of testing and reporting of adverse effects to the Swedish Medical Products Agency. AB - BACKGROUND: The Swedish Medical Products Agency (MPA) provides a voluntary reporting system for adverse reactions to cosmetics. However, the reporting is sparse, and the products involved are sometimes difficult to identify. OBJECTIVES: To investigate how often patients referred for patch testing were tested with the cosmetic products that they had been using themselves, and to improve the reporting to the MPA by the use of photographic documentation of product labels. PATIENTS AND METHODS: Consecutive patients at five dermatology departments who were patch tested with their own cosmetics were included. Reports including protocols of positive patch test results for the patients' own cosmetics and photographs/photocopies of product labels were sent to the MPA. RESULTS: Three hundred and sixteen of 948 patients (33%) were tested with their own cosmetics, and 15% of these tested positive with one or more products. The number of reports was more than three times higher than in corresponding periods in earlier years. For 79% of the products, photographs/photocopies of the containers were submitted, and for 30%, batch numbers were submitted. CONCLUSIONS: For a substantial number of patients, their own cosmetics were suspected of causing adverse reactions and were therefore tested. During the study, the number of reports to the MPA tripled, and the relevant products were easier to identify. PMID- 22443096 TI - Conversation with Beny J. Primm. PMID- 22443097 TI - Trajectories and nuclear arrangement of PML bodies are influenced by A-type lamin deficiency. AB - BACKGROUND INFORMATION: Promyelocytic leukaemia (PML) bodies are specific nuclear structures with functional significance for acute promyelocytic leukaemia. In this study, we analysed the trajectories of PML bodies using single-particle tracking. RESULTS: We observed that the recovery of PML protein after photobleaching was ATP dependent in both wild-type (wt) and A-type lamin deficient cells. The movement of PML bodies was faster and the nuclear area occupied by particular PML bodies was larger in A-type lamin-deficient fibroblasts compared with their wt counterparts. Moreover, dysfunction of the LMNA gene increased the frequency of mutual interactions between individual PML bodies and influenced the morphology of these domains at the ultrastructural level. As a consequence of A-type lamin deficiency, PML protein accumulated in nuclear blebs and frequently appeared at the nuclear periphery. CONCLUSIONS: We suggest that the physiological function of lamin A proteins is important for events that occur in the compartment of PML bodies. This observation was confirmed in other experimental models characterised by lamin changes, including apoptosis or the differentiation of mouse embryonic stem cells. PMID- 22443098 TI - Volatile single-source molecular precursor for the lithium ion battery cathode. AB - The first single-source molecular precursor for a lithium-manganese cathode material is reported. Heterometallic beta-diketonate LiMn(2)(thd)(5) (1, thd = 2,2,6,6-tetramethyl-3,5-heptanedionate) was obtained in high yield by simple one step solid-state reactions employing commercially available reagents. Substantial scale-up preparation of 1 was achieved using a solution approach. The crystal structure of the precursor contains discrete Li:Mn = 1:2 trinuclear molecules held together by bridging diketonate ligands. The complex is relatively stable in open air, highly volatile, and soluble in all common solvents. It was confirmed to retain its heterometallic structure in solutions of non-coordinating solvents. The heterometallic diketonate 1 was shown to exhibit clean, low-temperature decomposition in air/oxygen that results in nanosized particles of spinel-type oxide LiMn(2)O(4), one of the leading cathode materials for lithium ion batteries. PMID- 22443099 TI - Connectedness, social support and internalising emotional and behavioural problems in adolescents displaced by the Chechen conflict. AB - The study investigated factors associated with internalising emotional and behavioural problems among adolescents displaced during the most recent Chechen conflict. A cross-sectional survey (N=183) examined relationships between social support and connectedness with family, peers and community in relation to internalising problems. Levels of internalising were higher in displaced Chechen youth compared to published norms among non-referred youth in the United States and among Russian children not affected by conflict. Girls demonstrated higher problem scores compared to boys. Significant inverse correlations were observed between family, peer and community connectedness and internalising problems. In multivariate analyses, family connectedness was indicated as a significant predictor of internalising problems, independent of age, gender, housing status and other forms of support evaluated. Sub-analyses by gender indicated stronger protective relationships between family connectedness and internalising problems in boys. Results indicate that family connectedness is an important protective factor requiring further exploration by gender in war-affected adolescents. PMID- 22443100 TI - Syntheses of 2-nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane N,N'-diacetic acid labeled with F-18 using an aluminum complex method for hypoxia imaging. AB - Hypoxia imaging is important for diagnosis of ischemic diseases, and thus various (18)F-labeled radiopharmaceuticals have been developed. However, (18)F-labeling requires multistep procedures including azeotropic distillation, which is complicated and difficult to automate. Recently, (18)F-labeling method using Al-F complex in aqueous solution was devised that offered a straightforward (18)F labeling procedure. We synthesized nitroimidazole derivatives conjugated with 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) that can be labeled with (18)F using Al-F complex and examined their radiochemistries, in vitro and in vivo biological properties, and animal PET imaging characteristics. We found that the synthesized derivatives have excellent (18)F-labeling efficiencies, high stabilities, specific uptakes in cultured hypoxic tumor cells, and high tumor to nontumor ratios in xenografted mice. Furthermore, the derivatives were labeled with (18)F in a straightforward manner within 15 min at high labeling efficiencies and radiochemical purities. In conclusion, (18)F-labeled NODA nitroimidazole conjugates were developed and proved to be promising hypoxia PET agents. PMID- 22443101 TI - Teacher response to ambulatory monitoring of voice. AB - Voice accumulation and dosimetry devices are used for unobtrusive monitoring of voice use. While numerous studies have used these devices to examine how individuals use their voices, little attention has been paid to how subjects respond to them. Therefore, the purpose of this short communication is to begin to explore two questions: 1) How do voice monitoring devices affect daily communication? and 2) How do participants feel about the physical design and function of these types of voice monitoring devices? One key finding is that most of the subjects remain aware of the dosimeter while wearing it, which may impact the data collected. Further, most subjects have difficulty with the accelerometer and/or the data storage device. PMID- 22443102 TI - Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis. AB - BACKGROUND: Epithelial mesenchymal transition (EMT) is a crucial event likely involved in dissemination of epithelial cancer cells. This process enables them to acquire migratory/invasive properties, contributing to tumor and metastatic spread. To know if this event is an early one in breast cancer, we developed a clinical trial. The aim of this protocol was to detect circulating tumor cells endowed with mesenchymal and/or stemness characteristics, at the time of initial diagnosis. Breast cancer patients (n = 61), without visceral or bone metastasis were enrolled and analysis of these dedifferentiated circulating tumor cells (ddCTC) was realized. METHODS: AdnaGen method was used for enrichment cell selection. Then, ddCTC were characterized by RT-PCR study of the following genes: PI3Kalpha, Akt-2, Twist1 (EMT markers) and ALDH1, Bmi1 and CD44 (stemness indicators). RESULTS: Among the studied primary breast cancer cohort, presence of ddCTC was detected in 39% of cases. This positivity is independant from tumor clinicopathological factors apart from the lymph node status. CONCLUSIONS: Our data uniquely demonstrated that in vivo EMT occurs in the primary tumors and is associated with an enhanced ability of tumor cells to intravasate in the early phase of cancer disease. These results suggest that analysis of circulating tumor cells focused on cells showing mesenchymal or stemness characteristics might facilitate assessment of new drugs in clinical trials. PMID- 22443103 TI - Spatial cluster detection using dynamic programming. AB - BACKGROUND: The task of spatial cluster detection involves finding spatial regions where some property deviates from the norm or the expected value. In a probabilistic setting this task can be expressed as finding a region where some event is significantly more likely than usual. Spatial cluster detection is of interest in fields such as biosurveillance, mining of astronomical data, military surveillance, and analysis of fMRI images. In almost all such applications we are interested both in the question of whether a cluster exists in the data, and if it exists, we are interested in finding the most accurate characterization of the cluster. METHODS: We present a general dynamic programming algorithm for grid based spatial cluster detection. The algorithm can be used for both Bayesian maximum a-posteriori (MAP) estimation of the most likely spatial distribution of clusters and Bayesian model averaging over a large space of spatial cluster distributions to compute the posterior probability of an unusual spatial clustering. The algorithm is explained and evaluated in the context of a biosurveillance application, specifically the detection and identification of Influenza outbreaks based on emergency department visits. A relatively simple underlying model is constructed for the purpose of evaluating the algorithm, and the algorithm is evaluated using the model and semi-synthetic test data. RESULTS: When compared to baseline methods, tests indicate that the new algorithm can improve MAP estimates under certain conditions: the greedy algorithm we compared our method to was found to be more sensitive to smaller outbreaks, while as the size of the outbreaks increases, in terms of area affected and proportion of individuals affected, our method overtakes the greedy algorithm in spatial precision and recall. The new algorithm performs on-par with baseline methods in the task of Bayesian model averaging. CONCLUSIONS: We conclude that the dynamic programming algorithm performs on-par with other available methods for spatial cluster detection and point to its low computational cost and extendability as advantages in favor of further research and use of the algorithm. PMID- 22443104 TI - SNAP-tag based proteomics approach for the study of the retrograde route. AB - Proteomics is a powerful technique for protein identification at large scales. A number of proteomics approaches have been developed to study the steady state composition of intracellular compartments. Here, we report a novel vectorial proteomics strategy to identify plasma membrane proteins that undergo retrograde transport to the trans-Golgi network (TGN). This strategy is based on the covalent modification of the plasma membrane proteome with a membrane impermeable benzylguanine derivative. Benzylguanine-tagged plasma membrane proteins that are subsequently targeted to the retrograde route are covalently captured by a TGN localized SNAP-tagged fusion protein, which allows for their identification. The approach was validated step-by-step using a well explored retrograde cargo protein, the B-subunit of Shiga toxin. It was then extended to the proteomics format. Among other hits we found one of the historically first identified cargo proteins that undergo retrograde transport, which further validated our approach. Most of the other hits were kinases, receptors or transporters. In conclusion, we have pioneered a vectorial proteomics approach that complements traditional methods for the study of retrograde protein trafficking. This approach is of generic nature and could in principle be extended to other endocytic pathways. PMID- 22443105 TI - A 3-month-old infant with upper extremity weakness. AB - A detailed history should be obtained for all pediatric patients presenting with acute neurological changes. A thorough physical exam can help narrow the possible etiologies. Prompt imaging can lead to a more precise understanding of the level of neuronal involvement. Neurenteric cysts and fistulas are extremely rare in the pediatric population, with most occurring in the lower cervical and upper thoracic region. Most patients will present with symptoms related to cord or brainstem compression; however, associated infections have been reported. Epidural abscesses are also rare, occurring in the mid-thoracic or lower lumbar region. When there is no communication between the gastrointestinal tract and spinal canal, S. aureus accounts for most of these infections. When gram-negative pathogens, such as E.coli and E. cloacae, are isolated, it is imperative to evaluate for the presence of neurenteric fistulas. Because of numerous anomalies associated with neurenteric cysts, the entire spinal canal should be evaluated completely. PMID- 22443106 TI - Youth Justice staff attitudes towards screening for self-harm. AB - Young offenders are recognised as a high-risk group for suicidal behaviour. It is essential that the screening used to identify those at risk and refer them to mental health services is effective, especially in community settings where service utilisation is low. Staff attitudes towards screening for suicide and self-harm are likely to influence how a young offender engages with the screening process. Our study is the first to explore community youth justice staff attitudes towards, and perceptions of, screening for self-harmful behaviour. Eight semi-structured interviews were conducted at an English Youth Offending Team in June 2006 with staff who had used the suicide screening tool with young offenders. Data were analysed using Interpretative Phenomenological Analysis. Staff attitudes towards working within the screening system varied along two dimensions. The first 'active/passive' dimension related to perceived confidence in dealing with self-harm. The second 'positive/negative' dimension related to perceptions of the benefits of screening and the effectiveness of mental health provision for young offenders. Results indicate that barriers to effective screening must be tackled at both individual and organisational levels. The model of attitudes presented here could be used to increase understanding of how staff can be supported to engage effectively with the screening system. PMID- 22443107 TI - Religiosity and adolescent substance use: evidence from the national survey on drug use and health. AB - Prior research indicates that religiosity is associated with lower levels of substance use in adolescence. The extant research, however, is limited by issues related to data quality and analytic strategy. The current research uses the National Survey on Drug Use and Health to further our understanding of the nature of the relationship between religiosity and substance use during adolescence. Results show that religiosity reduces the odds of tobacco use, heavy drinking, prescription drug misuse, marijuana use, and other illicit drug use. These associations are partially explained by respondent and peer attitudes toward substance use and, to a lesser extent, respondent psychological well-being. The influence of respondent substance use attitude is especially pronounced, explaining between 41% (marijuana) and 53% (tobacco) of the association between religiosity and substance use. In fully adjusted models, all mediators account for between 46% (marijuana) and 59% (tobacco) of the association between religiosity and substance use. PMID- 22443108 TI - Antinociceptive and anti-inflammatory effects of electroacupuncture on experimental arthritis of the rat temporomandibular joint. AB - This study investigated the antinociceptive and anti-inflammatory effects of electroacupuncture (EA) on zymosan-induced acute arthritis of the rat temporomandibular joint (TMJ). Male Wistar rats were injected with saline or zymosan (control group; 2 mg) into the left TMJ. Low frequency EA (10 Hz, 30 min) was performed at acupoints (LI4, LI11, ST36, ST44) or sham points 2 h after or 1 h before zymosan administration. Mechanical hypernociception was accessed by the electronic Von Frey method after zymosan administration. Rats were sacrificed 6 h after zymosan administration and the joint was removed for histopathological analysis, myeloperoxidase activity assessment, vascular permeability observations, and immunohistochemical verification of inflammatory mediators. The results showed that EA inhibited zymosan-induced hypernociception, compared with the control group and with the sham group (p < 0.05). The results showed that EA inhibited inflammatory parameters such as neutrophil migration, vascular permeability, and tumour necrosis factor alpha (TNF-alpha), cyclooxygenase-2 (COX 2), and inducible nitric oxide synthase (iNOS) expression in the TMJ compared with the sham group (p < 0.05). Histopathological analysis showed that EA significantly inhibited edema and periarticular infiltration (p < 0.05) compared with the control and sham groups. EA at acupoints produced antinociceptive and anti-inflammatory effects on zymosan-induced arthritis in the rat TMJ. PMID- 22443109 TI - Resource utilization and costs before and after total joint arthroplasty. AB - BACKGROUND: The purpose of this study was to compare pre- and post-surgical healthcare costs in commercially insured total joint arthroplasty (TJA) patients with osteoarthritis (OA) in the United States (U.S.). METHODS: Using a large healthcare claims database, we identified patients over age 39 with hip or knee OA who underwent unilateral primary TJA (hip or knee) between 1/1/2006 and 9/30/2007. Utilization of healthcare services and costs were aggregated into three periods: 12 months "pre-surgery," 91 days "peri-operative," and 3 to 15 month "follow-up," Mean total pre-surgery costs were compared with follow-up costs using Wilcoxon signed-rank test. RESULTS: 14,912 patients met inclusion criteria for the study. The mean total number of outpatient visits declined from pre-surgery to follow-up (18.0 visits vs 17.1), while the percentage of patients hospitalized increased (from 7.5% to 9.8%) (both p < 0.01). Mean total costs during the follow-up period were 18% higher than during pre-surgery ($11,043 vs. $9,632, p < 0.01), largely due to an increase in the costs of inpatient care associated with hospital readmissions ($3,300 vs. $1,817, p < 0.01). Pharmacotherapy costs were similar for both periods ($2013 [follow-up] vs. $1922 [pre-surgery], p = 0.33); outpatient care costs were slightly lower in the follow up period ($4338 vs. $4571, p < 0.01). Mean total costs for the peri-operative period were $36,553. CONCLUSIONS: Mean total utilization of outpatient healthcare services declined slightly in the first year following TJA (exclusive of the peri operative period), while mean total healthcare costs increased during the same time period, largely due to increased costs associated with hospital readmissions. Further study is necessary to determine whether healthcare costs decrease in subsequent years. PMID- 22443110 TI - Genomes-based phylogeny of the genus Xanthomonas. AB - BACKGROUND: The genus Xanthomonas comprises several plant pathogenic bacteria affecting a wide range of hosts. Despite the economic, industrial and biological importance of Xanthomonas, the classification and phylogenetic relationships within the genus are still under active debate. Some of the relationships between pathovars and species have not been thoroughly clarified, with old pathovars becoming new species. A change in the genus name has been recently suggested for Xanthomonas albilineans, an early branching species currently located in this genus, but a thorough phylogenomic reconstruction would aid in solving these and other discrepancies in this genus. RESULTS: Here we report the results of the genome-wide analysis of DNA sequences from 989 orthologous groups from 17 Xanthomonas spp. genomes available to date, representing all major lineages within the genus. The phylogenetic and computational analyses used in this study have been automated in a Perl package designated Unus, which provides a framework for phylogenomic analyses which can be applied to other datasets at the genomic level. Unus can also be easily incorporated into other phylogenomic pipelines. CONCLUSIONS: Our phylogeny agrees with previous phylogenetic topologies on the genus, but revealed that the genomes of Xanthomonas citri and Xanthomonas fuscans belong to the same species, and that of Xanthomonas albilineans is basal to the joint clade of Xanthomonas and Xylella fastidiosa. Genome reduction was identified in the species Xanthomonas vasicola in addition to the previously identified reduction in Xanthomonas albilineans. Lateral gene transfer was also observed in two gene clusters. PMID- 22443111 TI - Ring keratitis due to topical anaesthetic abuse in a contact lens wearer. AB - A 38-year-old woman wearing hydrogel coloured contact lenses presented to the clinic with a painful red eye and epiphora. On biomicroscopy, a large corneal epithelial defect and ring infiltrate were observed. She had been using topical anaesthetic drops for 10 days. After cessation of the anaesthetic drops, the corneal lesions resolved completely in two weeks. On evaluation of a contact lens user with atypical keratitis, misuse of topical anaesthetics should also be considered. PMID- 22443112 TI - Morphological and genetic evidence of contemporary intersectional hybridisation in Mediterranean Helichrysum (Asteraceae, Gnaphalieae). AB - Hybridisation is considered an important evolutionary phenomenon in Gnaphalieae, but contemporary hybridisation has been little explored within the tribe. Here, hybridisation between Helichrysum orientale and Helichrysum stoechas is studied at two different localities in the islands of Crete and Rhodes (Greece). Using three different types of molecular data (AFLP, nrDNA ITS sequences and cpDNA ndhF sequences) and morphological data, the aim is to provide simultaneous and direct comparisons between molecular and morphological variation among the parental species and the studied hybrid populations. AFLP profiles, ITS sequences and morphological data support the existence of hybrids at the two localities studied, shown as morphological and genetic intermediates between the parental species. Chloroplast DNA sequences show that both parental species can act either as pollen donor or as maternal parent. Fertility of hybrids is demonstrated by the viability of seeds produced by hybrids from both localities, and the detection of a backcross specimen to H. orientale. Although there is general congruence of morphological and molecular data, the analysis of morphology and ITS sequences can fail to detect backcross hybrids. PMID- 22443113 TI - The emerging role of ALK inhibitors in the treatment of advanced non-small cell lung cancer. AB - INTRODUCTION: Most NSCLC patients are diagnosed in the advanced stage of the disease. Recently, chemotherapeutic agents have reached a plateau of effectiveness. Increased understanding of cancer biology has revealed several potential therapeutic strategies that have led to marketing of new biologic agents. The echinoderm microtubule-associated protein like-4-anaplastic lymphoma kinase (EML4-ALK) fusion oncogene represents one of the newest molecular targets in NSCLC, identifying a subset of NSCLC patients characterized by distinct clinicopathological features. AREAS COVERED: The available results concerning ALK inhibitors for the treatment of advanced NSCLC patients. An electronic search was used to retrieve the articles addressing this topic. EXPERT OPINION: In a pivotal Phase I clinical trial, crizotinib (PF-02341066), a small-molecule ALK inhibitor, demonstrated impressive antitumor activity in the majority of NSCLC patients with ALK fusions. Phase III randomized trials investigating crizotinib in this subgroup of patients are ongoing. If the results from these large international trials confirm the efficacy of crizotinib in the subset of patients, the next few years could see the treatment of advanced NSCLC patients with ALK fusions. Specific inhibitors would realize the so called personalized medicine in subsets of this disease. PMID- 22443114 TI - Turbidostat culture of Saccharomyces cerevisiae W303-1A under selective pressure elicited by ethanol selects for mutations in SSD1 and UTH1. AB - We investigated the genetic causes of ethanol tolerance by characterizing mutations selected in Saccharomyces cerevisiae W303-1A under the selective pressure of ethanol. W303-1A was subjected to three rounds of turbidostat, in a medium supplemented with increasing amounts of ethanol. By the end of selection, the growth rate of the culture has increased from 0.029 to 0.32 h(-1) . Unlike the progenitor strain, all yeast cells isolated from this population were able to form colonies on medium supplemented with 7% ethanol within 6 days, our definition of ethanol tolerance. Several clones selected from all three stages of selection were able to form dense colonies within 2 days on solid medium supplemented with 9% ethanol. We sequenced the whole genomes of six clones and identified mutations responsible for ethanol tolerance. Thirteen additional clones were tested for the presence of similar mutations. In 15 of 19 tolerant clones, the stop codon in ssd1-d was replaced with an amino acid-encoding codon. Three other clones contained one of two mutations in UTH1, and one clone did not contain mutations in either SSD1 or UTH1. We showed that the mutations in SSD1 and UTH1 increased tolerance of the cell wall to zymolyase and conclude that stability of the cell wall is a major factor in increased tolerance to ethanol. PMID- 22443115 TI - In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: their action on acute and chronic phases of Chagas disease. AB - The in vitro and in vivo anti- Trypanosoma cruzi activity of the pyrazole containing macrobicyclic polyamine 1 and N-methyl- and N-benzyl-substituted monocyclic polyamines 2 and 3 was studied. Activity against both the acute and chronic phases of Chagas disease was considered. The compounds were more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, but 1 and 2 were especially effective, where cryptand 1 was the most active, particularly in the chronic phase. The activity results found for these compounds were complemented and discussed by considering their inhibitory effect on the iron superoxide dismutase enzyme of the parasite, the nature of the metabolites excreted after treatment, and the ultrastructural alterations produced. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug and that 1 and 2 exhibited lower levels of damage than 3. PMID- 22443116 TI - EMMPRIN/CD147 up-regulates urokinase-type plasminogen activator: implications in oral tumor progression. AB - BACKGROUNDS: An elevated level of EMMPRIN in cancer tissues have been correlated with tumor invasion in numerous cancers including oral cavity and larynx. Although EMMPRIN's effect has been generally attributed to its MMP inducing activity, we have previously demonstrated in breast cancer model that EMMPRIN can also enhance invasion by upregulating uPA. In this study, the role of EMMPRIN in regulating uPA and invasion was investigated in oral squamous cell carcinoma (OSCC) progression. METHODS: Precancerous and invasive oral tumoral tissues were used as well as the corresponding cell lines, DOK and SCC-9 respectively. The paracrine regulation of uPA by EMMPRIN was investigated by treating culture cells with EMMPRIN-enriched membrane vesicles. UPA expression was analyzed by qPCR and immunostaining and the consequence on the invasion capacity was studied using modified Boyden chamber assay, in the presence or absence of EMMPRIN blocking antibody, the uPA inhibitor amiloride or the MMP inhibitor marimastat. RESULTS: OSCC tumors were shown to express more EMMPRIN and uPA compared to dysplastic lesions. The corresponding cell models, SCC-9 and DOK cells, displayed similar expression pattern. In both cell types EMMPRIN upregulated the expression of uPA as well as that of MMP-2 and MMP-9. EMMPRIN treatment led to a significant increase in cell invasion both in the invasive SCC-9 and in the less invasive dysplastic DOK cells, in an MMP and uPA dependent manner. CONCLUSIONS: Our results suggest that the upregulation of uPA contributes to EMMPRIN's effect in promoting oral tumor invasion. PMID- 22443117 TI - High ion yields of carbohydrates from frozen solution by UV-MALDI. AB - An aqueous acetonitrile solution containing oligosaccharides (maltopentaose and polysaccharides) and a matrix (2,5-dihydroxybenzoic acid) was frozen at 100 K for mass analysis using ultraviolet matrix-assisted laser desorption/ionization (UV MALDI). Compared with conventional UV-MALDI (i.e., using a dry analyte/matrix mixture), a frozen solution generates more oligosaccharide ions and less fragments from postsource decay. Furthermore, the ion signal is long-lasting, and the analyte distribution features enhanced homogeneity. The ion generation efficiency for this procedure is 20-30 times greater than that for a conventional dried mixture. Interestingly, the percentages for maltopentaose fragmentation from postsource decay for the frozen samples are close to zero (<2%), as compared with the 17% and 40% values found for dried samples at low and high laser fluences, respectively. Comparisons with other UV matrixes (alpha-cyano-4 hydroxycinnamic acid and sinapinic acid) and ionic liquids (2,5-dihydroxybenzoic acid + pyridine and alpha-cyano-4-hydroxycinnamic acid + butylamine) were investigated, and possible mechanisms are discussed. PMID- 22443118 TI - Thiophenones inhibit Staphylococcus epidermidis biofilm formation at nontoxic concentrations. AB - Frequent use of medical implants has led Staphylococcus epidermidis to develop into an opportunistic pathogen. The virulence is mainly linked to biofilm formation. Infections associated with biofilms are difficult to treat owing to enhanced resistance to antibiotics. Therefore, new and alternative treatments are called for. Bacterial communication is one of the regulatory mechanisms suggested to be involved in coordinating biofilm formation. In this study, we compared three communication inhibitors for preventing in vitro biofilm formation: a synthetic furanone, and two synthetic thiophenones, which are sulphur analogues of furanones. Furanones naturally source from the red macro alga Delisea pulchra. We also investigated the effect of thiophenone on transcriptional levels of genes associated with biofilm formation. We found that thiophenones were more effective in inhibiting biofilm formation than furanone, also in presence of albumin. We furthermore found that the thiophenones inhibited biofilm formation and bacterial communication more than furanones, and were less cytotoxic. The expression of the icaC and the lrgB genes, which are associated with biofilm formation, were affected by the thiophenone. PMID- 22443119 TI - Accuracy of three age estimation methods in children by measurements of developing teeth and carpals and epiphyses of the ulna and radius. AB - The aim of this study was to compare the accuracy of three methods for age estimation in children: the measurements of open apices in tooth roots (T), the ratio between the total area of carpal bones and epiphyses of the ulna and radius (HW), and the combined method (THW). The sample consisted of 288 Caucasian Italian children (152 boys and 136 girls) aged between 5 and 15 years. Accuracy was determined as the difference between estimated age and chronological age, and accuracy was assessed by analyzing individuals' orthopantomograms and hand-wrist radiographs. Accuracies were 0.41 years for girls and 0.54 years for boys with the THW method; for the HW method, 1.00 years for girls and 0.92 years for boys; and for the T method, 0.62 years for girls and 0.71 years for boys. THW is the most accurate technique for age estimation in these children. PMID- 22443120 TI - Management of postmenopausal women with vaginal bleeding when the endometrium can not be visualized. AB - OBJECTIVE: To determine the risk of endometrial cancer when endometrial thickness is not visualized using ultrasonography. DESIGN: Cross-sectional study. SETTING: Gynecological oncology center in the United Kingdom. POPULATION: All postmenopausal women referred with vaginal bleeding. METHODS: All women were investigated using gray-scale transvaginal ultrasonography. Women were arbitrarily stratified into four groups according to the endometrial thickness measurement. Women with endometrial thickness that was not adequately visualized on ultrasonography were included in a separate group. MAIN OUTCOME MEASURES: Endometrial cancer diagnosis. RESULTS: Over a 50-month period, 4454 women were investigated for postmenopausal vaginal bleeding. A total of 259 (6%) of women were diagnosed with endometrial carcinoma. Endometrial thickness measured 5-9.9 mm in 1201 (27%), 10-14.9 mm in 468 (11%), 15-19.9 mm in 209 (5%), and equal to or greater than 20mm in 197 (4%) of women. In 174 (4%) of women, the endometrial thickness was not visualized on transvaginal ultrasonography. For women where the endometrial thickness was not adequately visualized, the final histology included benign endometrium (124), endometrial cancer (26), endometrial polyps (11), endometritis (7), and other pathology (7). The odds of endometrial cancer in women where the endometrial thickness was not visualized were found to be significantly higher than the odds of cancer for women with an endometrial thickness of 5-9.9 mm (OR = 5.23, 95%CI 3.10-8.85, p-value <0.0001). CONCLUSIONS: For women presenting with postmenopausal bleeding and where the endometrial thickness cannot be adequately visualized on ultrasonography, hysteroscopic evaluation is recommended. PMID- 22443121 TI - Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. AB - Tissue engineering has recently become available as a treatment procedure for bone augmentation. However, this procedure has several problems, such as high capital investment and expensive cell culture, complicated safety and quality management issues regarding cell handling, and patient problems with the invasive procedure of cell collection. Moreover, it was reported that stem cells secrete many growth factors and chemokines during their cultivation, which could affect cellular characteristics and behavior. This study investigated the effect of stem cell-cultured conditioned media on bone regeneration. Cultured conditioned media from human bone marrow-derived mesenchymal stem cells (MSC-CM) enhanced the migration, proliferation, and expression of osteogenic marker genes, such as osteocalcin and Runx2, of rat MSCs (rMSCs) in vitro. MSC-CM includes cytokines such as insulin-like growth factor-1 and vascular endothelial growth factor. In vivo, a prepared bone defect of a rat calvarial model was implanted in five different rat groups using one of the following graft materials: human MSCs/agarose (MSCs), MSC-CM/agarose (MSC-CM), Dulbecco's modified Eagle's medium without serum [DMEM(-)]/agarose [DMEM(-)], PBS/agarose (PBS), and defect only (Defect). After 4 and 8 weeks, implant sections were evaluated using microcomputed tomography (micro-CT) and histological analysis. Micro-CT analysis indicated that the MSC-CM group had a greater area of newly regenerated bone compared with the other groups (p<0.05) and histological analysis at 8 weeks indicated that the newly regenerated bone bridge almost covered the defect. Interestingly, the effects of MSC-CM were stronger than those of the MSC group. In vivo imaging and immunohistochemical staining of transgenic rats expressing green fluorescent protein also showed that migration of rMSCs to the bone defect in the MSC-CM group was greater than in the other groups. These results demonstrated that MSC-CM can regenerate bone through mobilization of endogenous stem cells. The use of stem-cell-cultured conditioned media for bone regeneration is a unique concept that utilizes paracrine factors of stem cells without cell transplantation. PMID- 22443122 TI - The effect of surface treatment of the interfacial surface on fatigue-related microtensile bond strength of milled zirconia to veneering porcelain. AB - PURPOSE: The success of zirconia-reinforced all-ceramic crowns depends on the formation of a stable bond between the zirconia core and the veneering porcelain. The purpose of this study was to test the effects of liner application and airborne particle abrasion of a postsintered Y-TZP core on the bond strength between the zirconia core and veneering porcelain with or without cyclic loading. MATERIALS AND METHODS: Kavo Everest(r) Y-TZP blank disks were sintered and divided into three treatment groups: airborne particle abrasion, IPS e.max(r) Ceram Zirliner application, or no surface treatment. The disks were then veneered with IPS e.max(r) ZirPress veneering porcelain. Half the veneered disks from each group were cyclically loaded. This created six experimental groups: three surface treatment groups cyclically loaded and three not loaded. The disks were then sectioned into microbars for microtensile bond strength (MTBS) testing (40 specimens per group). Specimens were luted to a fixture mount and loaded to failure using a universal testing machine (MTS Insight). The maximum force was measured and bond strength computed. Data were analyzed with a two-way ANOVA and Tukey's HSD test (alpha= 0.05). RESULTS: Airborne particle abrasion significantly decreased MTBS values (p= 0.043), and ZirLiner application did not have a significant effect on MTBS values compared to control. Cyclic loading did not have a significant effect on MTBS values. The predominant failure mode in all groups was mixed. CONCLUSIONS: Airborne particle abrasion of the interfacial surface of the Everest(r) Y-TZP core significantly decreased the MTBS to ZirPress veneering porcelain when compared to no interfacial surface treatment. Application of ZirLiner to the interfacial surface of the Everest(r) Y-TZP core did not significantly increase or decrease the MTBS to ZirPress veneering porcelain, compared to the other surface treatments. Cyclic loading did not affect bond strengths in any of the groups, regardless of surface treatment. Neither cyclic loading nor surface treatment affected the failure mode of the specimens. PMID- 22443123 TI - Herkogamy and mate diversity in the wild daffodil Narcissus longispathus: beyond the selfing-outcrossing paradigm in the evolution of mixed mating. AB - Spatial separation of male and female reproductive structures (herkogamy) is a widespread floral trait that has traditionally been viewed as an adaptation that reduces the likelihood of self-pollination. Here we propose that increased herkogamy may also influence another important aspect of plant mating: the diversity of pollen donors siring seeds within fruits. We test this hypothesis in Narcissus longispathus, a wild daffodil species with extensive variation in anther-stigma separation. To study the morphological basis of variation in herkogamy, floral measurements were undertaken in 16 populations of N. longispathus. We then quantified multilocus outcrossing rates and the correlation of outcrossed paternity in three of these populations sampled over several years. Mating system estimates were calculated for each population and year, and also separately for groups of plants that differed markedly in herkogamy within each population and year. In N. longispathus herkogamy was much more variable than other floral traits, and was more closely related to style length than to anther position. Averaged across populations and years, plants with high herkogamy had similar outcrossing rates (0.683) to plants with intermediate (0.648) or low herkogamy (0.590). However, a significant linear trend was found for correlation of outcrossed paternity, which increased monotonically from high herkogamy (0.221), through intermediate herkogamy (0.303) to low herkogamy (0.463) plants. The diversity of pollen donors siring seeds of high herkogamy Narcissus flowers was thus consistently greater than the diversity of pollen donors siring seeds of low herkogamy flowers. Results of this study contribute to the emerging consensus that floral traits can simultaneously influence several aspects of plant mating system in complex ways, thus extending the traditional focus centred exclusively on patterns and relative importance of self- and cross-fertilisation. PMID- 22443124 TI - Infraclavicular sensor site: a new promising site for transcutaneous capnography. AB - BACKGROUND: Transcutaneous measurement of carbon dioxide is routinely done at the earlobe site. In patients receiving non invasive ventilation or in the intensive care setting with necklines, an alternate measurement site would be useful. We started to use the infraclavicular site for transcutaneous measurements of carbon dioxide using a new digital sensor. AIM: Comparison of transcutaneous carbon dioxide with arterial carbon dioxide at the infraclavicular site. METHODS: We retrospectively compared transcutaneous carbon dioxide at the infraclavicular site with arterial carbon dioxide in 50 samples. The Sentec Digital Monitoring System (Sentec AG, Therwil, Switzerland) was used. The V-Sign digital sensor was placed on the infraclavicular site at the medial two third and one third point from the sternoclavicular joint and acromioclavicular joint. RESULTS: When comparing P(c)CO(2) with P(a)CO(2) values, the Bland-Altman analysis revealed a bias of 0.02 kPa (95% CI: [- 0.1; 0.14]) with a precision of 0.42 kPa. Linear regression analysis describes the relationship between the two methods. The slope of the linear model was 0.85 +/- 0.04 and the intercept was 0.77 +/- 0.21 (RSE = 0.37, R(2) = 0.91). CONCLUSION: The measurement of transcutaneous carbon dioxide at the infraclavicular site is feasible with a digital sensor and has a good correlation with the carbon dioxide values obtained from the arterial blood gas. The findings of the current study form the basis for further clinical studies for its regular application in clinical use. PMID- 22443125 TI - Conservation and the microbiome. PMID- 22443126 TI - Internalizing conservation through our own microbes. PMID- 22443127 TI - Considering extinction of dependent species during translocation, ex situ conservation, and assisted migration of threatened hosts. AB - Translocation, introduction, reintroduction, and assisted migrations are species conservation strategies that are attracting increasing attention, especially in the face of climate change. However, preventing the extinction of the suite of dependent species whose host species are threatened is seldom considered, and the effects on dependent species of moving threatened hosts are unclear. There is no published guidance on how to decide whether to move species, given this uncertainty. We examined the dependent-host system of 4 disparate taxonomic groups: insects on the feather-leaf banksia (Banksia brownii), montane banksia (B. montana), and Stirling Range beard heath (Leucopogon gnaphalioides); parasites of wild cats; mites and ticks on Duvaucel's gecko (Hoplodactylus duvaucelii) and tuatara (Sphenodon punctatus); and internal coccidian parasites of Cirl Bunting (Emberiza cirlus) and Hihi (Notiomystis cincta). We used these case studies to demonstrate a simple process for use in species- and community level assessments of efforts to conserve dependents with their hosts. The insects dependent on Stirling Range beard heath and parasites on tigers (Panthera tigris) appeared to represent assemblages that would not be conserved by ex situ host conservation. In contrast, for the cases of dependent species we examined involving a single dependent species (internal parasites of birds and the mite Geckobia naultina on Duvaucel's gecko), ex situ conservation of the host species would also conserve the dependent species. However, moving dependent species with their hosts may be insufficient to maintain viable populations of the dependent species, and additional conservation strategies such as supplementing populations may be needed. PMID- 22443128 TI - Feedbacks between conservation and social-ecological systems. AB - Robust ways to meet objectives of environmental conservation and social and economic development remain elusive. This struggle may in part be related to insufficient understanding of the feedbacks between conservation initiatives and social-ecological systems, specifically, the ways in which conservation initiatives result in social changes that have secondary effects on the environments targeted by conservation. To explore this idea, we sampled peer reviewed articles addressing the social and environmental dimensions of conservation and coded each paper according to its research focus and characterization of these feedbacks. The majority of articles in our sample focused either on the effect of conservation initiatives on people (e.g., relocation, employment) or the effect of people on the environment (e.g., fragmentation, conservation efficacy of traditional management systems). Few studies in our sample empirically addressed both the social dynamics resulting from conservation initiatives and subsequent environmental effects. In many cases, one was measured and the other was discussed anecdotally. Among the studies that describe feedbacks between social and environmental variables, there was more evidence of positive (amplifying) feedbacks between social and environmental outcomes (i.e., undesirable social outcomes yielded undesirable environmental effects and desirable social outcomes yielded desirable environmental effects). The major themes within the sampled literature include conflict between humans and wild animals, social movements, adaptive comanagement, loss of traditional management systems, traditional ecological knowledge, human displacement and risks to livelihoods, and conservation and development. The narratives associated with each theme can serve as hypotheses for facilitating further discussion about conservation issues and for catalyzing future studies of the feedbacks between conservation and social-ecological systems. PMID- 22443129 TI - Effects of matrix characteristics and interpatch distance on functional connectivity in fragmented temperate rainforests. AB - The connectivity of remnant patches of habitat may affect the persistence of species in fragmented landscapes. We evaluated the effects of the structural connectivity of forest patches (i.e., distance between patches) and matrix class (land-cover type) on the functional connectivity of 3 bird species (the White crested Elaenia [Elaenia albiceps], the Green-backed Firecrown Hummingbird [Sephanoides sephaniodes], and the Austral Thrush [Turdus falklandii]). We measured functional connectivity as the rate at which each species crossed from one patch to another. We also evaluated whether greater functional connectivity translated into greater ecological connectivity (dispersal of fruit and pollen) by comparing among forest patches fruit set of a plant pollinated by hummingbirds and abundance of seedlings and adults of 2 plants with bird- and wind-dispersed seeds. Interpatch distance was strongly associated with functional connectivity, but its effect was not independent of matrix class. For one of the bird-dispersed plants, greater functional connectivity for White-crested Elaenias and Austral Thrushes (both frugivores) was associated with higher densities of this plant. The lack of a similar association for the wind-dispersed species suggests this effect is linked to the dispersal vector. The abundance of the hummingbird pollinated species was not related to the presence of hummingbirds. Interpatch distance and matrix class affect animal movement in fragmented landscapes and may have a cascading effect on the distribution of some animal-dispersed species. On the basis of our results, we believe effort should be invested in optimizing patch configuration and modifying the matrix so as to mitigate the effects of patch isolation in fragmented landscapes. PMID- 22443130 TI - Ecological metrics of biomass removed by three methods of purse-seine fishing for tunas in the eastern tropical Pacific Ocean. AB - An ecosystem approach to fisheries management is a widely recognized goal, but describing and measuring the effects of a fishery on an ecosystem is difficult. Ecological information on the entire catch (all animals removed, whether retained or discarded) of both species targeted by the fishery and nontarget species (i.e., bycatch) is required. We used data from the well-documented purse-seine fishery for tunas (Thunnus albacares, T. obesus, and Katsuwonus pelamis) in the eastern tropical Pacific Ocean to examine the fishery's ecological effects. Purse seine fishing in the eastern tropical Pacific is conducted in 3 ways that differ in the amount and composition of target species and bycatch. The choice of method depends on whether the tunas are swimming alone (unassociated sets), associated with dolphins (dolphin sets), or associated with floating objects (floating object sets). Among the fishing methods, we compared catch on the basis of weight, number of individuals, trophic level, replacement time, and diversity. Floating-object sets removed 2-3 times as much biomass as the other 2 methods, depending on how removal was measured. Results of previous studies suggest the ecological effects of floating-object sets are thousands of times greater than the effects of other methods, but these results were derived from only numbers of discarded animals. Management of the fishery has been driven to a substantial extent by a focus on reducing bycatch, although discards are currently 4.8% of total catch by weight, compared with global averages of 7.5% for tuna longline fishing and 30.0% for midwater trawling. An ecosystem approach to fisheries management requires that ecological effects of fishing on all animals removed by a fishery, not just bycatch or discarded catch, be measured with a variety of metrics. PMID- 22443131 TI - Defining trade-offs among conservation, profitability, and food security in the California current bottom-trawl fishery. AB - Although it is recognized that marine wild-capture fisheries are an important source of food for much of the world, the cost of sustainable capture fisheries to species diversity is uncertain, and it is often questioned whether industrial fisheries can be managed sustainably. We evaluated the trade-off among sustainable food production, profitability, and conservation objectives in the groundfish bottom-trawl fishery off the U.S. West Coast, where depletion (i.e., reduction in abundance) of six rockfish species (Sebastes) is of particular concern. Trade-offs are inherent in this multispecies fishery because there is limited capacity to target species individually. From population models and catch of 34 stocks of bottom fish, we calculated the relation between harvest rate, long-term yield (i.e., total weight of fish caught), profit, and depletion of each species. In our models, annual ecosystem-wide yield from all 34 stocks was maximized with an overall 5.4% harvest rate, but profit was maximized at a 2.8% harvest rate. When we reduced harvest rates to the level (2.2% harvest rate) at which no stocks collapsed (<10% of unfished levels), biomass harvested was 76% of the maximum sustainable yield and profit 89% of maximum. A harvest rate under which no stocks fell below the biomass that produced maximum sustainable yield (1% harvest rate), resulted in 45% of potential yield and 67% of potential profit. Major reductions in catch in the late 1990s led to increase in the biomass of the most depleted stocks, but this rebuilding resulted in the loss of >30% of total sustainable yield, whereas yield lost from stock depletion was 3% of total sustainable yield. There are clear conservation benefits to lower harvest rates, but avoiding overfishing of all stocks in a multispecies fishery carries a substantial cost in terms of lost yield and profit. PMID- 22443132 TI - Species, functional groups, and thresholds in ecological resilience. AB - The cross-scale resilience model states that ecological resilience is generated in part from the distribution of functions within and across scales in a system. Resilience is a measure of a system's ability to remain organized around a particular set of mutually reinforcing processes and structures, known as a regime. We define scale as the geographic extent over which a process operates and the frequency with which a process occurs. Species can be categorized into functional groups that are a link between ecosystem processes and structures and ecological resilience. We applied the cross-scale resilience model to avian species in a grassland ecosystem. A species' morphology is shaped in part by its interaction with ecological structure and pattern, so animal body mass reflects the spatial and temporal distribution of resources. We used the log-transformed rank-ordered body masses of breeding birds associated with grasslands to identify aggregations and discontinuities in the distribution of those body masses. We assessed cross-scale resilience on the basis of 3 metrics: overall number of functional groups, number of functional groups within an aggregation, and the redundancy of functional groups across aggregations. We assessed how the loss of threatened species would affect cross-scale resilience by removing threatened species from the data set and recalculating values of the 3 metrics. We also determined whether more function was retained than expected after the loss of threatened species by comparing observed loss with simulated random loss in a Monte Carlo process. The observed distribution of function compared with the random simulated loss of function indicated that more functionality in the observed data set was retained than expected. On the basis of our results, we believe an ecosystem with a full complement of species can sustain considerable species losses without affecting the distribution of functions within and across aggregations, although ecological resilience is reduced. We propose that the mechanisms responsible for shaping discontinuous distributions of body mass and the nonrandom distribution of functions may also shape species losses such that local extinctions will be nonrandom with respect to the retention and distribution of functions and that the distribution of function within and across aggregations will be conserved despite extinctions. PMID- 22443133 TI - Stakeholder participation in management of invasive vertebrates. AB - Stakeholders are increasingly involved in species conservation. We sought to understand what features of a participatory conservation program are associated with its ecological and social outcomes. We conducted a case study of the management of invasive vertebrates in Australia. Invasive vertebrates are a substantial threat to Australia's native species, and stakeholder participation in their management is often necessary for their control. First, we identified potential influences on the ecological and social outcomes of species conservation programs from the literature. We used this information to devise an interview questionnaire, which we administered to managers of 34 participatory invasive-vertebrate programs. Effects of invasive species were related to program initiator (agency or citizen), reasons for use of a participatory approach, and stakeholder composition. Program initiator was also related to the participation methods used, level of governance (i.e., governed by an agency or citizens), changes in stakeholder interactions, and changes in abundance of invasive species. Ecological and social outcomes were related to changes in abundance of invasive species and stakeholder satisfaction. We identified relations between changes in the number of participants, stakeholder satisfaction, and occurrence of conflict. Potential ways to achieve ecological and social goals include provision of governmental support (e.g., funding) to stakeholders and minimization of gaps in representation of stakeholder groups or individuals to, for example, increase conflict mitigation. Our findings provide guidance for increasing the probability of achieving ecological and social objectives in management of invasive vertebrates and may be applicable to other participatory conservation programs. PMID- 22443134 TI - Metastatic melanoma: the new era of targeted therapy. AB - INTRODUCTION: Metastatic melanoma is one of the most resistant tumors to standard chemotherapy, with a median overall survival of 6 - 8 months. Previously approved drugs offer only marginal survival advantages. Advances in the understanding of melanoma biology and host immunity have recently opened the field to new therapeutic approaches. Thus, after many years of disappointing results, a new era in the treatment of melanoma is beginning. AREAS COVERED: This review discusses new advances in the treatment of metastatic melanoma. Current data regarding the new agents under clinical development are reviewed, including emerging data from recently completed clinical trials, as well as preliminary data from ongoing studies testing novel therapeutic strategies. EXPERT OPINION: The new agents specifically targeted against melanoma are changing the standard of care for this disease. The monoclonal antibody ipilimumab is the first new agent approved for first- and second-line treatment of metastatic melanoma, based on improved overall survival compared -with standard therapy. Other drugs, such as BRAF inhibitors, have demonstrated high activity in the advanced disease and will be reaching clinical approval. Researchers are already planning ways to combine some of these new drugs in order to render possible a longer control of tumor. PMID- 22443135 TI - How much can we gain from improved efficiency? An examination of performance of national HIV/AIDS programs and its determinants in low- and middle-income countries. AB - BACKGROUND: The economic downturn exacerbates the inadequacy of resources for combating the worldwide HIV/AIDS pandemic and amplifies the need to improve the efficiency of HIV/AIDS programs. METHODS: We used data envelopment analysis (DEA) to evaluate efficiency of national HIV/AIDS programs in transforming funding into services and implemented a Tobit model to identify determinants of the efficiency in 68 low- and middle-income countries. We considered the change from the lowest quartile to the average value of a variable a "notable" increase. RESULTS: Overall, the average efficiency in implementing HIV/AIDS programs was moderate (49.8%). Program efficiency varied enormously among countries with means by quartile of efficiency of 13.0%, 36.4%, 54.4% and 96.5%. A country's governance, financing mechanisms, and economic and demographic characteristics influence the program efficiency. For example, if countries achieved a notable increase in "voice and accountability" (e.g., greater participation of civil society in policy making), the efficiency of their HIV/AIDS programs would increase by 40.8%. For countries in the lowest quartile of per capita gross national income (GNI), a notable increase in per capita GNI would increase the efficiency of AIDS programs by 45.0%. CONCLUSIONS: There may be substantial opportunity for improving the efficiency of AIDS services, by providing more services with existing resources. Actions beyond the health sector could be important factors affecting HIV/AIDS service delivery. PMID- 22443136 TI - Activation of the RpoN-RpoS regulatory pathway during the enzootic life cycle of Borrelia burgdorferi. AB - BACKGROUND: The maintenance of Borrelia burgdorferi in its complex tick-mammalian enzootic life cycle is dependent on the organism's adaptation to its diverse niches. To this end, the RpoN-RpoS regulatory pathway in B. burgdorferi plays a central role in microbial survival and Lyme disease pathogenesis by up- or down regulating the expression of a number of virulence-associated outer membrane lipoproteins in response to key environmental stimuli. Whereas a number of studies have reported on the expression of RpoS and its target genes, a more comprehensive understanding of when activation of the RpoN-RpoS pathway occurs, and when induction of the pathway is most relevant to specific stage(s) in the life cycle of B. burgdorferi, has been lacking. RESULTS: Herein, we examined the expression of rpoS and key lipoprotein genes regulated by RpoS, including ospC, ospA, and dbpA, throughout the entire tick-mammal infectious cycle of B. burgdorferi. Our data revealed that transcription of rpoS, ospC, and dbpA is highly induced in nymphal ticks when taking a blood meal. The RpoN-RpoS pathway remains active during the mammalian infection phase, as indicated by the sustained transcription of rpoS and dbpA in B. burgdorferi within mouse tissues following borrelial dissemination. However, dbpA transcription levels in fed larvae and intermolt larvae suggested that an additional layer of control likely is involved in the expression of the dbpBA operon. Our results also provide further evidence for the downregulation of ospA expression during mammalian infection, and the repression of ospC at later phases of mammalian infection by B. burgdorferi. CONCLUSION: Our study demonstrates that the RpoN-RpoS regulatory pathway is initially activated during the tick transmission of B. burgdorferi to its mammalian host, and is sustained during mammalian infection. PMID- 22443137 TI - Antimicrobial susceptibility and genetic relatedness of bovine Stenotrophomonas maltophilia isolates from a mastitis outbreak. AB - AIMS: To evaluate the antimicrobial susceptibility and genetic relatedness of 11 Stenotrophomonas maltophilia isolates from an outbreak of bovine clinical mastitis in one herd and two isolates from two separate mastitis cases in two other herds. METHODS AND RESULTS: Thirteen S. maltophilia isolates were obtained from milk samples from 11 cows from three dairy herds in Japan during 2008. We tested their susceptibility to 14 antimicrobials by broth microdilution and identified their genotypes by enterobacterial repetitive intergenic consensus 2 (ERIC2)-PCR. Every cow had acute mild mastitis (slightly watery foremilk with flakes) without systemic symptoms and all resolved within 3-5 weeks of diagnosis. Eleven of the 13 isolates derived from nine cows in one herd over a 7-month period exhibited a closely related ERIC2 type (A). The remaining two isolates derived from two cows from two other herds exhibited two distinct ERIC2 types (B and C). Most of the 13 isolates exhibited susceptibility to trimethoprim sulfamethoxazole, chloramphenicol, minocycline and levofloxacin; however, they were resistant to four beta-lactams, kanamycin, gentamicin and oxytetracycline. They were intermediate to enrofloxacin. CONCLUSIONS: Eleven closely related S. maltophilia isolates were involved in a herd outbreak of mastitis to some extent. Bovine S. maltophilia isolates exhibited resistance to many classes of antimicrobials. SIGNIFICANCE AND IMPACT OF STUDY: This is a rare report of a herd outbreak of bovine mastitis involving closely related S. maltophilia isolates. PMID- 22443138 TI - The regulation of different metabolic pathways through the Pal/Rim pathway in Ustilago maydis. AB - One of the most important physicochemical factors that affect cell growth and development is pH, and living organisms have developed specific mechanisms to adapt to media with variable pH values. Most fungi posses a specific mechanism for such adaptation: the Pal/Rim pathway. To analyze the different metabolic processes regulated by this pathway, and its possible relationships with other physiological regulatory mechanisms, we analyzed the phenotype of a mutant in the PALB/RIM13 gene of the phytopathogenic fungus Ustilago maydis. The mutant displayed important alterations in the synthesis and organization of the cell wall and was affected in its response to stress, revealing its relationship with the MAPKC pathway involved in maintaining the integrity of the cell wall, and the stress response pathway, but not with the HOG pathway. An important observation was that the mutant, in contrast to the wild-type strain, was unable to maintain a constant intracellular pH, suggesting that probably the main function of the Pal/Rim pathway, in collaboration with other regulatory mechanisms, is to maintain a constant intracellular pH, despite the changes occurring in the environment. PMID- 22443139 TI - Nuclear expression of Rac1 in cervical premalignant lesions and cervical cancer cells. AB - BACKGROUND: Abnormal expression of Rho-GTPases has been reported in several human cancers. However, the expression of these proteins in cervical cancer has been poorly investigated. In this study we analyzed the expression of the GTPases Rac1, RhoA, Cdc42, and the Rho-GEFs, Tiam1 and beta-Pix, in cervical pre malignant lesions and cervical cancer cell lines. METHODS: Protein expression was analyzed by immunochemistry on 102 cervical paraffin-embedded biopsies: 20 without Squamous Intraepithelial Lesions (SIL), 51 Low- grade SIL, and 31 High grade SIL; and in cervical cancer cell lines C33A and SiHa, and non-tumorigenic HaCat cells. Nuclear localization of Rac1 in HaCat, C33A and SiHa cells was assessed by cellular fractionation and Western blotting, in the presence or not of a chemical Rac1 inhibitor (NSC23766). RESULTS: Immunoreacivity for Rac1, RhoA, Tiam1 and beta-Pix was stronger in L-SIL and H-SIL, compared to samples without SIL, and it was significantly associated with the histological diagnosis. Nuclear expression of Rac1 was observed in 52.9% L-SIL and 48.4% H-SIL, but not in samples without SIL. Rac1 was found in the nucleus of C33A and SiHa cells but not in HaCat cells. Chemical inhibition of Rac1 resulted in reduced cell proliferation in HaCat, C33A and SiHa cells. CONCLUSION: Rac1 is expressed in the nucleus of epithelial cells in SILs and cervical cancer cell lines, and chemical inhibition of Rac1 reduces cellular proliferation. Further studies are needed to better understand the role of Rho-GTPases in cervical cancer progression. PMID- 22443140 TI - Regulatory systems controlling motility and gene transfer agent production and release in Rhodobacter capsulatus. AB - Production of the gene transfer agent of Rhodobacter capsulatus, RcGTA, is dependent upon several cellular regulatory systems, including a putative phosphorelay involving the CtrA and CckA proteins. These proteins are also involved in flagellar motility in R. capsulatus. The interactions of proteins in this system are best understood in Caulobacter crescentus where CtrA is activated by phosphorylation by the CckA-ChpT phosphorelay. CtrA~P activity is further controlled by SciP, which represses ctrA transcription and CtrA activation of transcription. We show that R. capsulatus chpT and cckA mutants both have greatly reduced motility and RcGTA activity. Unlike the ctrA mutant where RcGTA gene transcription is absent, the decrease in RcGTA activity is because of reduced release of RcGTA from the cells. The sciP mutant is not affected for RcGTA production but our results support the C. crescentus model of SciP repression of flagellar motility genes. We show that both unphosphorylated and phosphorylated CtrA can activate RcGTA gene expression, while CtrA~P seems to be required for release of the particle and expression of motility genes. This has led us to a new model of how this regulatory system controls motility and production of RcGTA in R. capsulatus. PMID- 22443141 TI - Synthesis, structure-activity relationship studies, and X-ray crystallographic analysis of arylsulfonamides as potent carbonic anhydrase inhibitors. AB - A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (K(i) values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure-affinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (I and 2a) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site. PMID- 22443142 TI - Ultra-high-sensitive extraction-photometric determination of sodium ion using flow injection analysis with a chromogenic calix[4]arene derivative and a laser interferometric photothermal detector. AB - A novel flow injection analysis (FIA) system for ultra-high-sensitive determination of Na(+), which involves laser interferometric photothermal equipment as the detector, was designed using a proton-dissociable chromogenic calix[4]arene derivative with a dinitrophenol moiety as the extraction photometric reagent. The chromogenic calix[4]arene derivative showed an excellent extractability toward Na(+), which reflected the cation-complexing property of the tetraethyl ester derivative of calix[4]arene. As the calibration graph of the Na(+) concentration could be successfully obtained at the nanomolar level by this method, the proposed FIA system was found to be promising for highly sensitive determination of Na(+) in very dilute samples such as supply water and cooling water in power plants. PMID- 22443143 TI - Organ donation following fatal organophosphate poisoning. PMID- 22443144 TI - TDDFT studies on the electronic structures and chiroptical properties of mono-tin substituted Wells-Dawson polyoxotungstates. AB - The UV/CD spectra of tin-bearing acetonyl-substituted Wells-Dawson polyoxotungstates alpha(1)- and alpha(2)-[P(2)W(17)O(61){SnCH(2)CH(2)C(?O)}](6-) were systematically investigated using the time-dependent density functional theory (TDDFT) method. The electronic circular dichroism (ECD) spectra were produced over the range of 3.3-5.8 eV. The calculated ECD spectra of the alpha(1) R isomer were generally in agreement with the experimental spectra. The CAM-B3LYP hybrid functional was found to predict the excitation energies of tin-containing polyoxotungstates well. The fact that the UV/ECD spectra of alpha(1)-isomers are different from those of alpha(2)-isomers demonstrates the effect of the tin substitution site on the chiroptical properties of the studied isomers. The origins of the ECD bands are mainly ascribed to charge-transfer (CT) transitions from oxygen atoms to W atoms, from organic fragments to W atoms, or from the combination of two CT transitions. The results suggest that the organic fragment and polyoxometalate (POM) cage are chiroptical chromophores. PMID- 22443145 TI - Differential regulation of accumbal dopamine transmission in rats following cocaine, heroin and speedball self-administration. AB - Cocaine/heroin combinations (speedball) exert synergistic neurochemical and behavioral effects that are thought to contribute to the increased abuse potential and subjective effects reported by polydrug users. In vivo fast-scan cyclic voltammetry was used to examine the effects of chronic intravenous self administration (25 consecutive sessions) of cocaine (250 MUg/inf), heroin (4.95 MUg/inf) and speedball (250/4.95 MUg/inf cocaine/heroin) on changes in electrically evoked dopamine (DA) efflux, maximal rate of DA uptake (V(max)) and the apparent affinity (K(m)) of the DA transporter in the nucleus accumbens. The increase in electrically evoked DA was comparable following cocaine and speedball injection; however, heroin did not increase evoked DA. DA transporter K(m) values were similarly elevated following cocaine and speedball, but unaffected by heroin. However, speedball self-administration significantly increased baseline V(max), while heroin and cocaine did not change baseline V(max), compared with the baseline V(max) values of drug-naive animals. Overall, elevated DA clearance is a likely consequence of synergistic elevations of nucleus accumbens extracellular DA concentrations by chronic speedball self-administration, as reported previously in microdialysis studies. The present results indicate neuroadaptive processes that are unique to cocaine/heroin combinations and cannot be readily explained by simple additivity of changes observed with cocaine and heroin alone. PMID- 22443146 TI - What we don't talk about when we don't talk about sex: results of a national survey of U.S. obstetrician/gynecologists. AB - INTRODUCTION: Sexuality is a key aspect of women's physical and psychological health. Research shows both patients and physicians face barriers to communication about sexuality. Given their expertise and training in addressing conditions of the female genital tract across the female life course, obstetrician/gynecologists (ob/gyns) are well positioned among all physicians to address sexuality issues with female patients. New practice guidelines for management of female sexual dysfunction and the importance of female sexual behavior and function to virtually all aspects of ob/gyn care, and to women's health more broadly, warrant up-to-date information regarding ob/gyns' sexual history-taking routine. AIMS: To determine ob/gyns' practices of communication with patients about sexuality, and to examine the individual and practice-level correlates of such communication. METHOD: A population-based sample of 1,154 practicing U.S. ob/gyns (53% male; mean age 48 years) was surveyed regarding their practices of communication with patients about sex. MAIN OUTCOME MEASURES: Self-reported frequency measures of ob/gyns' communication practices with patients including whether or not ob/gyns discuss patients' sexual activities, sexual orientation, satisfaction with sexual life, pleasure with sexual activity, and sexual problems or dysfunction, as well as whether or not one ever expresses disapproval of or disagreement with patients' sexual practices. Multivariable analysis was used to correlate physicians' personal and practice characteristics with these communication practices. RESULTS: Survey response rate was 65.6%. Sixty-three percent of ob/gyns reported routinely assessing patients' sexual activities; 40% routinely asked about sexual problems. Fewer asked about sexual satisfaction (28.5%), sexual orientation/identity (27.7%), or pleasure with sexual activity (13.8%). A quarter of ob/gyns reported they had expressed disapproval of patients' sexual practices. Ob/gyns practicing predominately gynecology were significantly more likely than other ob/gyns to routinely ask about each of the five outcomes investigated. CONCLUSION: The majority of U.S. ob/gyns report routinely asking patients about their sexual activities, but most other areas of patients' sexuality are not routinely discussed. PMID- 22443147 TI - The role of environmental factors in regulating the development of cartilaginous grafts engineered using osteoarthritic human infrapatellar fat pad-derived stem cells. AB - Engineering functional cartilaginous grafts using stem cells isolated from osteoarthritic human tissue is of fundamental importance if autologous tissue engineering strategies are to be used in the treatment of diseased articular cartilage. It has previously been demonstrated that human infrapatellar fat pad (IFP)-derived stem cells undergo chondrogenesis in pellet culture; however, the ability of such cells to generate functional cartilaginous grafts has not been adequately addressed. The objective of this study was to explore how environmental conditions regulate the functional development of cartilaginous constructs engineered using diseased human IFP-derived stem cells (FPSCs). FPSCs were observed to display a diminished chondrogenic potential upon encapsulation in a three-dimensional hydrogel compared with pellet culture, synthesizing significantly lower levels of glycosaminoglycan and collagen on a per cell basis. To engineer more functional cartilaginous grafts, we next explored whether additional biochemical and biophysical stimulations would enhance chondrogenesis within the hydrogels. Serum stimulation was observed to partially recover the diminished chondrogenic potential within hydrogel culture. Over 42 days, stem cells that had first been expanded in a low-oxygen environment proliferated extensively on the outer surface of the hydrogel in response to serum stimulation, assembling a dense type II collagen-positive cartilaginous tissue resembling that formed in pellet culture. The application of hydrostatic pressure did not further enhance extracellular matrix synthesis within the hydrogels, but did appear to alter the spatial accumulation of extracellular matrix leading to the formation of a more compact tissue with superior mechanically functionality. Further work is required in order to recapitulate the environmental conditions present during pellet culture within scaffolds or hydrogels in order to engineer more functional cartilaginous grafts using human osteoarthritic FPSCs. PMID- 22443148 TI - Spread of herbicide-resistant weedy rice (red rice, Oryza sativa L.) after 5 years of Clearfield rice cultivation in Italy. AB - The weedy relative of cultivated rice, red rice, can invade and severely infest rice fields, as reported by rice farmers throughout the world. Because of its close genetic relationship to commercial rice, red rice has proven difficult to control. Clearfield (Cl) varieties, which are resistant to the inhibiting herbicides in the chemical group AHAS (acetohydroxyacid synthase), provide a highly efficient opportunity to control red rice infestations. In order to reduce the risk of herbicide resistance spreading from cultivated rice to red rice, stewardship guidelines are regularly released. In Italy, the cultivation of Cl cultivars started in 2006. In 2010, surveillance of the possible escape of herbicide resistance was carried out; 168 red rice plants were sampled in 16 fields from six locations containing Cl and traditional cultivars. A first subsample of 119 plants was analysed after herbicide treatment and the resistance was found in 62 plants. Of these 119 plants, 78 plants were randomly selected and analysed at the level of the AHAS gene to search for the Cl mutation determining the resistant genotype: the Cl mutation was present in all the resistant plants. Nuclear and chloroplast microsatellite markers revealed a high correlation between genetic similarity and herbicide resistance. The results clearly show that Cl herbicide-resistant red rice plants are present in the field, having genetic relationships with the Cl variety. Finding plants homozygous for the mutation suggests that the crossing event occurred relatively recently and that these plants are in the F2 or later generations. These observations raise the possibility that Cl red rice is already within the cultivated rice seed supply. PMID- 22443149 TI - Mitochondrial DNA sequence of yellow catfish (Pelteobagrus fulvidraco). AB - Yellow catfish (Pelteobagrus fulvidraco) belongs to the family Bagridae, which is one of the most important economic freshwater aquaculture species in China. In this study, we reported the complete sequence of the mitochondrial genome of P. fulvidraco. The complete mitochondrial genome is 16,527 bp in length, including the typical structure of 22 transfer RNA genes, 13 protein-coding genes, two ribosomal RNA genes, and the non-coding control region. Both the termination associated sequence and critical central conserved sequences (CSB-D, CSB-E, and CSB-F) was also detected. PMID- 22443150 TI - Fetal central nervous system development and alcohol--the evidence so far. AB - Currently in the UK, there is no absolute guidance about alcohol consumption in pregnancy. The guidance for drinking during pregnancy is one or two units of alcohol one or two times weekly, but conservative advice is to abstain as a cautionary measure. Despite the lack of consensus about the safe levels of alcohol consumption in pregnancy, there is increasing evidence of the impact of alcohol on the developing central nervous system. This article explores the evidence regarding alcohol consumption and its effects on the developing fetal central nervous system. PMID- 22443151 TI - Psychological gender of patients with polycystic ovary syndrome. AB - OBJECTIVE: We compared women with polycystic ovary syndrome (PCOS) to a control group with regard to intensity of hirsutism and psychological gender. DESIGN: Cohort study, 2005-2009. SETTING: Gynecological endocrinology clinic and gynecological practice, Silesian area, Poland. SAMPLE: 89 women aged 17-42 years with PCOS, in two groups (S1, S2) by age < or >=31 years, and age-stratified controls of 45 healthy women. METHODS: We used the General Health Questionnaire (GHQ 12), Ferriman-Gallwey score and Psychological Gender Inventory, to assess masculinity and femininity through self-reported possession of socially desirable, stereotypical personality traits (masculine, feminine, androgynous, undifferentiated), supplemented by questions concerning social status (education, profession) and gynecological history. All questionnaires were anonymous and independently answered during clinic visits. MAIN OUTCOME MEASURES: Influence of PCOS and concomitant hirsutism on psychological gender. RESULTS: Hirsutism (moderate or severe intensity) was observed in a considerably higher number of women from both PCOS groups compared with controls (S1: 49.0 vs. 20.0%, p < 0.05, S2: 41.9 vs. 16.7%, p < 0.05, respectively). Women >=31 years with PCOS more often viewed themselves as sexually undifferentiated compared with controls (31.8 vs. 6.7%, p < 0.01), less likely to identify with a female gender scheme (18.2 vs. 33.3%), and more likely to see themselves as androgynous (50.0 vs. 40.9%). CONCLUSIONS: Women with PCOS have, depending on age and severity of disease, problems with psychological gender identification. Duration and severity of PCOS can negatively affect the self-image of patients, lead to a disturbed identification with the female-gender scheme and, associated with it, social roles. PMID- 22443152 TI - Assessing citizen contributions to butterfly monitoring in two large cities. AB - Citizen science may be especially effective in urban landscapes due to the large pool of potential volunteers. However, there have been few evaluations of the contributions of citizen scientists to knowledge of biological communities in and around cities. To assess the effectiveness of citizen scientists' monitoring of species in urban areas, we compared butterfly data collected over 10 years in Chicago, Illinois (U.S.A.), and New York City, New York (U.S.A.). The dates, locations, and methods of data collection in Chicago were standardized, whereas data from New York were collected at any location at any time. For each city, we evaluated whether the number of observers, observation days (days on which observations were reported), and sampling locations were associated with the reported proportion of the estimated regional pool of butterfly species. We also compared the number of volunteers, duration of volunteer involvement, and consistency of sampling efforts at individual locations within each city over time. From 2001 to 2010, there were 73 volunteers in Chicago and 89 in New York. During this period, volunteers observed 86% and 89% of the estimated number of butterfly species present in Chicago and New York, respectively. Volunteers in New York reported a greater proportion of the estimated pool of butterfly species per year. In addition, more species were observed per volunteer and observation day in New York, largely due to the unrestricted sampling season in New York. Chicago volunteers were active for more years and monitored individual locations more consistently over time than volunteers in New York. Differences in monitoring protocol--especially length of sampling season and selection protocol for monitoring locations--influenced the relationship between species accrual and sampling effort, which suggests these factors are important in volunteer-based species-monitoring programs. PMID- 22443153 TI - Systematic review: antibodies and anti-TNF-alpha levels in inflammatory bowel disease. AB - BACKGROUND: The associations between clinical efficacy and infusion reactions with anti-TNF-alpha drug levels and the presence of antibodies against the drug have been described. However, the clinical utility of these tests in routine clinical practice remains unclear. AIMS: To examine the clinical significance of the development of antibodies against anti-TNF-alpha drugs and the relationship between the efficacy of these drugs and their serum levels. We also studied the clinical utility of testing for anti-TNF-alpha antibodies and measuring drug serum levels to optimise treatment of patients with inflammatory bowel disease (IBD) receiving these agents. METHODS: A systematic review was undertaken based on electronic searches of the PubMed database from the earliest record to February 2012. The reference lists of all relevant articles and abstracts from meetings were also consulted. RESULTS: We observed a close relationship between trough levels of anti-TNF-alpha drug and maintenance of response to these drugs. The role of antibodies in loss of response seems to be limited to their effect favouring the clearance of the drug. The risk of infusion reactions, but not of delayed hypersensitivity reactions, is higher in patients with antibodies against the anti-TNF-alpha drug. Testing anti-TNF-alpha drug and antibody levels, together with clinical and endoscopic or radiological assessment, seems useful when attempting to optimise therapy and prevent inappropriate management of IBD patients. CONCLUSION: Measurement of serum anti-TNF-alpha trough levels and antibody titres could prove useful in therapeutic drug monitoring in IBD patients treated with anti-TNF-alpha agents. PMID- 22443154 TI - Systematic review of efficacy and safety of buprenorphine versus fentanyl or morphine in patients with chronic moderate to severe pain. AB - OBJECTIVE: To systematically assess efficacy and safety of buprenorphine patch versus fentanyl patch in patients with chronic moderate to severe pain. METHODS: Fifteen databases were searched up to December 2010. Randomised and quasi randomised trials assessing the efficacy in patients with chronic pain were included. Quantitative methods for data synthesis were used and two network meta analyses were conducted. RESULTS: Fourteen unique trials (17 publications) were included. No head-to-head randomised trials of buprenorphine patch compared with fentanyl patch were identified. Therefore, less robust evidence from indirect comparisons was used. Results from a network meta-analysis of non-enriched designs (eight trials), using trials versus placebo and trials versus morphine for indirect comparisons, indicated that transdermal fentanyl, in comparison with transdermal buprenorphine, showed significantly more nausea (odds ratio [OR] 4.66, 95% confidence interval (CI) 1.07 to 20.39), a significantly higher number of treatment discontinuations due to adverse events (OR 5.94, 95% CI 1.78 to 19.87), and non-significant differences on all other outcomes, including pain measures. In comparison with morphine, transdermal buprenorphine had a significantly higher decrease of pain intensity (MD [mean difference] -16.20, 95% CI -28.92 to -3.48) while morphine caused more cases of constipation (OR 7.50, 95% CI 1.45 to 38.85) and a significantly higher number of treatment discontinuations due to adverse events (OR 5.80, 95% CI 1.68 to 20.11). All other outcomes showed non-significant differences between transdermal buprenorphine and morphine. The results were similar when also including six trials using enriched designs with the exception of more cases of vomiting for fentanyl (OR 17.32, 95% CI 4.43 to 67.71) and morphine (OR 15.85, 95% CI 3.92 to 64.13) compared to buprenorphine. CONCLUSIONS: The findings indicate comparability of transdermal buprenorphine and transdermal fentanyl for pain measures with significantly fewer adverse events (nausea and treatment discontinuation due to adverse events) caused by transdermal buprenorphine. PMID- 22443155 TI - Integration of radioembolisation into multimodal treatment of liver-dominant metastatic colorectal cancer. AB - INTRODUCTION: Radioembolisation (selective internal radiation therapy; SIRT), as part of a continuous strategy contributed to the improvement in response rates and median survival for unresectable metastatic colorectal cancer. Therefore, the role of SIRT in the different stages of treatment plan was investigated in this review. AREAS COVERED: After a brief description of the principles of SIRT, the review focused on the clinical evidences of published trials on the current experience of radioembolisation and its role in both salvage setting and earlier lines of chemotherapy. EXPERT OPINION: Evidence from Phase I studies and small Phase II/III randomised controlled trials has provided an early signal of the safety and improved overall survival, which can be achieved with radioembolisation and chemotherapy compared with chemotherapy (alone), due to an improved liver control. In the salvage setting, interesting results were observed in term of response, toxicity and median overall survival. Until the results of these early-line randomised trials will be available, radioembolisation could be considered either alone or combined with an appropriate chemotherapy regimen following failure of first- or second-line therapy. PMID- 22443156 TI - Surface-expressed enolase contributes to the adhesion of Paracoccidioides brasiliensis to host cells. AB - Paracoccidioidomycosis is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis. Understanding the interactions between P. brasiliensis and the host tissue depends on the study of the different steps of the process of colonization, especially adhesion, in which the pathogen recognizes ligands on the surface of host cells. This study aimed to verify the role of enolase in the host cell-fungus interaction and the ability of enolase to bind to extracellular matrix components, to determine its subcellular localization, and to study the P. brasiliensis enolase amino acid sequence. The data revealed that fibronectin is the major ligand of enolase. Evaluation of the location of enolase at an ultrastructural level revealed that it is distributed in various cellular compartments, but at a high level in the cell wall. The analysis of the amino acid sequence revealed an internal plasminogen-binding motif ((254)FYKADEKKY(262)), which is conserved in most organisms and described as an important interaction site of the enolase with the host cell surface. This suggests that enolase performs additional functions related to the glycolytic pathway and also plays a role of adhesion in P. brasiliensis. Therefore, this study increases the knowledge about the characteristics of enolase and its influence on the binding process of P. brasiliensis. PMID- 22443157 TI - Gene cluster analysis for the biosynthesis of elgicins, novel lantibiotics produced by Paenibacillus elgii B69. AB - BACKGROUND: The recent increase in bacterial resistance to antibiotics has promoted the exploration of novel antibacterial materials. As a result, many researchers are undertaking work to identify new lantibiotics because of their potent antimicrobial activities. The objective of this study was to provide details of a lantibiotic-like gene cluster in Paenibacillus elgii B69 and to produce the antibacterial substances coded by this gene cluster based on culture screening. RESULTS: Analysis of the P. elgii B69 genome sequence revealed the presence of a lantibiotic-like gene cluster composed of five open reading frames (elgT1, elgC, elgT2, elgB, and elgA). Screening of culture extracts for active substances possessing the predicted properties of the encoded product led to the isolation of four novel peptides (elgicins AI, AII, B, and C) with a broad inhibitory spectrum. The molecular weights of these peptides were 4536, 4593, 4706, and 4820 Da, respectively. The N-terminal sequence of elgicin B was Leu-Gly Asn-Tyr, [corrected] which corresponded to the partial sequence of the peptide ElgA encoded by elgA. Edman degradation suggested that the product elgicin B is derived from ElgA. By correlating the results of electrospray ionization-mass spectrometry analyses of elgicins AI, AII, and C, these peptides are deduced to have originated from the same precursor, ElgA. CONCLUSIONS: A novel lantibiotic like gene cluster was shown to be present in P. elgii B69. Four new lantibiotics with a broad inhibitory spectrum were isolated, and these appear to be promising antibacterial agents. PMID- 22443158 TI - Effects of long-term simulated RPD clasp attachment/detachment on retention loss and wear for two clasp types and three abutment material surfaces. AB - PURPOSE: The purpose of this in vitro study was to measure the loss of retention and wear of two clasp types (E-circlet, back action) against three abutment materials (enamel, composite, CAD/CAM ceramic) after 16,000 simulated cycles of attachment-detachment. MATERIALS AND METHODS: Forty-eight models were constructed by placing either an upper first premolar or a metal die inside a metal rectangular block. Models were divided according to the abutment teeth into three groups. Group E consisted of 16 unrestored human premolars with sound enamel. Group R had 16 premolars recontoured buccally using composite resin. Group C had 16 metal dies (duplicated from a human premolar) covered by CAD/CAM all-ceramic crowns. On the models, E-circlet (E) and back-action (B) clasps were constructed to engage the model's teeth. Withdrawal and insertion cycling of clasps was carried out for 16,000 cycles by using a chewing simulator. The retention force of each clasp was measured after cycling. An acrylic replica was made for each abutment retention surface before and after cycling. Each replica was examined by SEM, and the wear areas were measured. The data were analyzed statistically using one-way ANOVA, two-way ANOVA, and Mann-Whitney tests. RESULTS: There was no significant retention loss after 16,000 cycles (p>= 0.05) of both clasps (E, B) on the three abutment materials (E, R, C). The mean of wear areas in mm(2) were 1.83 +/- 0.36, 0.85 +/- 0.66, 2.37 +/- 1.88, 1.7 +/- 1.11, 0.6 +/- 0.2, and 0.06 +/- 0 for EE, BE, ER, BR, EC, and BC, respectively. There were significant differences among the wear areas of the abutment surface of the six subgroups (p<= 0.05). CONCLUSION: The composite resin contoured surfaces showed more wear than the enamel and ceramic surfaces. E-clasps caused more wear on the abutment materials than back-action clasps. PMID- 22443159 TI - Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees. AB - BACKGROUND: Esthesioneuroblastoma (ENB) is a rare, aggressive tumor with no established treatment in children. We analyzed a series of pediatric ENB patients with the aim of improving our knowledge of this disease. METHODS: 9 patients (6 males; age 0.9-18 years, median 9.9) were identified by searching the AIEOP (Italian Association of Pediatric Hematology and Oncology) registry and the national databases of rare tumors, soft tissue sarcomas (STS) and neuroblastomas. The data on the cases included in STS treatment protocols were collected prospectively and histology was centrally reviewed; the data and histology concerning the other children were reviewed for the purpose of this analysis. RESULTS: All tumors occurred in the sinonasal region with bone erosion (7 patients) and intracranial (4) or intraorbital (4) extension. Three patients were in Kadish stage B, and 6 in stage C. Complete tumor resection was very difficult to achieve, but adding chemotherapy and radiotherapy enabled tumor control in 8 patients. Response to chemotherapy was evident in 5/7 evaluable cases. Radiotherapy (48.5-60 Gy) was delivered in all children but one, due to early disease progression. With a median follow-up of 13.4 years (range 9.2-22.9), 7 patients are alive in 1st and one in 2nd complete remission. All surviving patients developed treatment-related sequelae, the most frequent being endocrine dysfunctions (4 patients) and craniofacial growth impairments (4 patients). CONCLUSIONS: Our findings confirm that ENB in children has an aggressive presentation, but multimodal therapy can cure most patients. Our results are encouraging but future strategies must optimize treatment in terms of survival and related morbidities. PMID- 22443160 TI - Differential Forster resonance energy transfer from the excimers of poly(N vinylcarbazole) to coumarin 153. AB - Photophysics of the nonconjugated vinyl polymer poly(N-vinylcarbazole) (PNVC) has been explored in the presence of coumarin 153 (C153) exploiting steady state and time-resolved fluorometric techniques. Dual emission from the two distinct excimers of PNVC adds importance to the study and makes it interesting. The study substantiates the occurrence of Forster resonance energy transfer (FRET) from PNVC to C153. The differential involvement of the two excimers in the energy transfer process has been established. Considering the fact that FRET is a long distance dipole induced phenomenon, this differential effect has been rationalized from a difference in the dipole moments of the two excimers. Determination of the quenching constants reveals an order of magnitude more quenching of the high energy excimer than the low energy one in the presence of the quencher C153. PMID- 22443161 TI - Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds. AB - The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a compound is dependent on physicochemical properties such as molecular size, lipophilicity, and ionization state. However, much less is known regarding the relationship between ADMET and the molecular topology. In this study two descriptors related to the molecular topology have been investigated, the fraction of the molecular framework (f(MF)) and the fraction of sp(3)-hybridized carbon atoms (Fsp(3)). f(MF) and Fsp(3), together with standard physicochemical properties (molecular size, ionization state, and lipophilicity), were analyzed for a set of ADMET assays. It is shown that aqueous solubility, Caco-2 permeability, plasma protein binding, human ether-a-go-go-related potassium channel protein inhibition, and CYP3A4 (CYP = cytochrome P450) inhibition are influenced by the molecular topology. These findings are in most cases independent of the already well-established relationships between the properties and molecular size, lipophilicity, and ionization state. PMID- 22443162 TI - An exploration of the enablers and barriers in access to the Dutch healthcare system among Ghanaians in Amsterdam. AB - BACKGROUND: Sub-Saharan African populations are growing in many European countries. Data on the health of these populations are rare. Additionally, many sub-Saharan African migrants are confronted with issues of low socio-economic status, acculturation and language difficulties, which may hamper their access to health care. Despite the identification of some of those barriers, little is known about the enabling factors. Knowledge about the enablers and barriers in access to healthcare experienced is important in addressing their health needs and promoting healthcare access. This study aimed to investigate the enabling factors as well as barriers in access to the Dutch healthcare system among the largest sub-Saharan African migrant group (Ghanaians) living in Amsterdam, the Netherlands. METHODS: Six focus groups were conducted from November 2009 to February 2010. A semi-structured interview guideline was used. Discussions were conducted in English or Twi (Ghanaian dialect), recorded and transcribed verbatim. Analysis was based on the Andersen model of healthcare utilisation using MAXQDA software. RESULTS: Knowledge and perceived quality of the health system, awareness of diseases, family and community support, community initiatives and availability of social support were the main enablers to the healthcare system. Difficulties with the Dutch language and mistrust in health care providers were major barriers in access to healthcare. CONCLUSIONS: Access to healthcare is facilitated mainly by knowledge of and the perceived efficiency and quality of the Dutch healthcare system. However, poor Dutch language proficiency and mistrust in health care providers appear to be important barriers in accessing healthcare. The enablers and barriers identified by this study provide useful information for promoting healthcare access among this and similar Sub-Saharan African communities. PMID- 22443163 TI - Adjuvant adenoidectomy in persistent bilateral otitis media with effusion: hearing and revision surgery outcomes through 2 years in the TARGET randomised trial. AB - OBJECTIVES: To determine the adjuvant effects of adenoidectomy with short-stay ventilation tubes to hearing and revision surgery in children over 3.5 years with persistent otitis media with effusion. DESIGN: Randomised controlled three armed trial: observation, short-stay ventilation tube or ventilation tubes with adjuvant adenoidectomy. Five follow-up visits over 2 years. SETTING: Eleven UK Otorhinolaryngology Departments. PARTICIPANTS: Children with bilateral otitis media with effusion and better ear hearing level (HL) >=20 dB persistent for 3 months. Of the 425 eligible children, 376 (88%) accepted randomisation. MAIN OUTCOME MEASURES: Pure-tone hearing thresholds, eligibility for and actual revision surgery rates, otoscopic sequelae and complications of adenoidectomy. RESULTS: Loss to follow-up at 3, 12 and 24 months was 2%, 6% and 5% respectively. Of the 376 randomised children, 253 (67%) had complete data for all five follow up visits. Adenoidectomy did not add to the benefit to hearing thresholds of ventilation tubes of 8.8 dB (CI: 7.1-10.5) averaged over 3-6 months postoperatively. Averaged over 12, 18 and 24 months, adenoidectomy provided 4.2 dB of benefit (CI: 2.6-5.7) whilst ventilation tubes gave no benefit. Standardised effect sizes through two years showed equal benefit from ventilation tubes (0.50 sd) and adenoidectomy (0.61 sd) which are additive (1.11 sd). Adenoidectomy halved the numbers meeting a 25 dB HL bilateral cut-off for eligibility for repeat tube surgery from 31% to 14% at 12 months and from 33% to 15% at 18 months. The actual reduction in re-insertion surgery (absolute risk difference) was 21%. In tubed ears, tympanosclerosis occurred in 27%, but otorrhoea in only <2% and permanent perforations in <1%. These events did not occur in control ears. In children that had adenoidectomy, one of 165 (0.6%) had haemorrhage that required return to theatre. CONCLUSIONS: Adjuvant adenoidectomy doubles benefit from short-stay ventilation tubes by extending better hearing through the second year in children aged 3.25-6.75 years with persistent otitis media with effusion with at least a 20 dB HL in both ears. The duration of benefit of adenoidectomy is related to the duration of function of the type of the ventilation tubes used. Adenoidectomy also substantially reduces eligibility for revision surgery. PMID- 22443164 TI - Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity. AB - Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/ mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis. PMID- 22443165 TI - No ocular involvement in familial amyloidotic polyneuropathy ATTR V30M domino liver recipients. AB - In many transplantation centers domino liver transplantation is an established procedure, increasing the number of available liver grafts. Increasingly, grafts from familial amyloidotic polyneuropathy (FAP) patients are used. Ocular involvement is a well known manifestation of FAP, and can be vision-threatening. The aim of this study was to evaluate the risk of development of familial amyloidotic polyneuropathy ocular manifestations in domino liver recipients. Forty-four cirrhotic patients submitted to liver transplantation were studied, with an average of 6 years of follow up after the procedure. Twenty two patients had received a liver from a FAP donor (Group 1) and 22 had received a liver from a non-FAP cadaveric donor (Group 2). Both groups were similar for mean age and gender. Routine ophthalmological examinations with particular attention to amyloid deposition in the anterior segment and vitreous, peripheral retina state, lacrimal functions tests (Schirmer and tear break-up time) and pupillometry (dynamic and static) were performed. No statistically significant differences were observed in all studied ophthalmic parameters between the two groups. No FAP related ophthalmic manifestations were detected after 6 years of domino liver transplantation, but further prospective regular ophthalmological examinations are necessary to detect the eventual development of late ocular manifestations. PMID- 22443166 TI - Effects of vulture declines on facultative scavengers and potential implications for mammalian disease transmission. AB - Vultures (Accipitridae and Cathartidae) are the only known obligate scavengers. They feed on rotting carcasses and are the most threatened avian functional group in the world. Possible effects of vulture declines include longer persistence of carcasses and increasing abundance of and contact between facultative scavengers at these carcasses. These changes could increase rates of transmission of infectious diseases, with carcasses serving as hubs of infection. To evaluate these possibilities, we conducted a series of observations and experimental tests of the effects of vulture extirpation on decomposition rates of livestock carcasses and mammalian scavengers in Kenya. We examined whether the absence of vultures changed carcass decomposition time, number of mammalian scavengers visiting carcasses, time spent by mammals at carcasses, and potential for disease transmission at carcasses (measured by changes in intraspecific contact rates). In the absence of vultures, mean carcass decomposition rates nearly tripled. Furthermore, the mean number of mammals at carcasses increased 3-fold (from 1.5 to 4.4 individuals/carcass), and the average time spent by mammals at carcasses increased almost 3-fold (from 55 min to 143 min). There was a nearly 3-fold increase in the mean number of contacts between mammalian scavengers at carcasses without vultures. These results highlight the role of vultures in carcass decomposition and level of contact among mammalian scavengers. In combination, our findings lead us to hypothesize that changes in vulture abundance may affect patterns of disease transmission among mammalian carnivores. PMID- 22443167 TI - Renal failure of the surviving fetus after intrauterine death of the co-twin. AB - Twin pregnancies are considered at a higher risk for fetal mortality than singleton pregnancies. The antenatal death of one of the twins is associated with an increasing rate of cerebral impairment and lesions in other organs in the surviving fetus, especially if the pregnancy is monochorionic. We describe a case of isolate renal failure becoming evident gradually after birth in a surviving twin after the antenatal death of the co-twin. Considering the deleterious effects of vascular disruption in a surviving twin, our findings suggest careful investigation of renal function, even if no intrauterine signs of diminished renal function were previously detected. PMID- 22443168 TI - The prevalence and correlates of intermittent explosive disorder in Iraq. AB - OBJECTIVE: Intermittent explosive disorder is common, begins early in life, and is associated with considerable impairment in the United States. The epidemiology of IED outside the United States is unknown. We examined the prevalence and correlates of IED in Iraq, where exposure to violence has been widespread during the last three decades. METHOD: Data were drawn from a national survey of the Iraq population, the Iraq Mental Health Survey (IMHS), conducted in 2006-2007. The WHO Composite International Diagnostic interview was used to assess DSM-IV disorders, including IED. The response rate was 95.2%. RESULTS: Lifetime and 12 month prevalence estimates of IED were 1.7% and 1.5%. Mean age of onset was 18.5. The mean number of lifetime attacks was 141.6 attacks, and IED-related injuries occurred 61 times per 100 lifetime cases. IED was significantly comorbid with mood and anxiety, but not substance, disorders. CONCLUSION: Although the prevalence of IED is lower in Iraq than in the United States, the disorder has an early age of onset, is highly persistent, and is associated with substantial comorbidity and functional impairment. Iraq lacks national policies or systematic programmes to reduce aggression, highlighting the importance of implementing violence prevention programmes to reduce the societal burden of violence in Iraq. PMID- 22443169 TI - Root fractures: the influence of type of healing and location of fracture on tooth survival rates - an analysis of 492 cases. AB - AIM: The purpose of this study was to analyze tooth loss after root fractures and to assess the influence of the type of healing and the location of the root fracture. Furthermore, the actual cause of tooth loss was analyzed. MATERIAL AND METHODS: Long-term survival rates were calculated using data from 492 root fractured teeth in 432 patients. The cause of tooth loss was assessed as being the result of either pulp necrosis (including endodontic failures), new traumas or excessive mobility. The statistics used were Kaplan-Meier and the log rank method. RESULTS AND CONCLUSIONS: The location of the root fracture had a strong significant effect on tooth survival (P = 0.0001). The 10-year tooth survival of apical root fractures was 89% [95% confidence interval (CI), 78-99%], of mid-root fractures 78% (CI, 64-92%), of cervical-mid-root fractures 67% (CI, 50-85%), and of cervical fractures 33% (CI, 17-49%). The fracture-healing type offered further prognostic information. No tooth loss was observed in teeth with hard tissue fracture healing regardless of the position of the fracture. For teeth with interposition of connective tissue, the location of the fracture had a significant influence on tooth loss (P = 0.0001). For teeth with connective tissue healing, the estimated 8-year survival of apical, mid-root, and cervical mid-root fractures were all more than 80%, whereas the estimated 8-year survival of cervical fractures was 25% (CI, 7-43%). For teeth with non-healing with interposition of granulation tissue, the location of the fracture showed a significant influence on tooth loss (P = 0.0001). The cause of tooth loss was found to be very dependent upon the location of the fracture. In conclusion, the long-term tooth survival of root fractures was strongly influenced by the type of healing and the location of the fracture. PMID- 22443170 TI - Pumpers, skypers, surfers and texters: technology to improve the management of diabetes in teenagers. AB - A variety of innovative technologies are available to assist with the management of diabetes in teenagers. Technologies include devices that assist with the direct day-to-day management of diabetes including insulin pumps and continuous glucose monitors. These devices are being used more and more with teenagers as a means of improving treatment adherence and glycaemic control. In addition, telehealth is being used to deliver care and support around diabetes management issues for teens with diabetes. Telehealth used in diabetes care for teens includes cell phones and video-conferencing. The goal of this telehealth technology is to support health behaviours and implement behavioural change strategies in a way that is more integrated into the everyday lives of patients and even in the context in which the behaviours occur in 'real time'. Finally, information and support via the Internet are gaining acceptance and use among teens with diabetes as an effective means of strategies for improved diabetes self-care. All three of these broad uses of technology in diabetes in teens represent flexible, innovative, and accessible approaches to improving both diabetes management and glycaemic control in this 'at risk' population. PMID- 22443171 TI - Poly (ADP-ribose) polymerase (PARP): rationale, preclinical and clinical evidences of its inhibition as breast cancer treatment. AB - INTRODUCTION: The chance to take advantage of genetic defects of cancer cells is a promising clinical tool in breast cancer therapy. Among the genetic aberrations, dysfunctions in DNA repair mechanisms are quite common and suitable for an attractive antitumor effect. Poly (ADP-ribose) polymerase I (PARP-1) is an enzyme with many functions in transcriptions and cell cycle regulation and in coordination of cellular response to DNA damage. Its involvement in tumorigenesis is witnessed by the overexpression found in different primary human tumors, where the increased enzymatic activity leads to cancer cell protection against DNA damage and instability. Therefore, activity of PARP and the opportunity to block it, mainly in cancer cells also deficient in other mechanisms of repair, are promising. AREAS COVERED: In this review, areas covered include the main DNA repair mechanisms, the role of PARP enzymatic activity in diverse cell pathways as well as the preclinical and clinical data with PARP inhibitors. EXPERT OPINION: Despite the theoretical role of PARP inhibitors as therapeutic strategy in specific subtypes of breast cancer (hereditary BRCA1/BRCA2 mutation-related cancers and sporadic triple-negative breast cancer), questions are still open. More exhaustive knowledge is needed about other important functions of PARPs in cellular homeostasis and about escape mechanisms of cancer cells to inhibitory effect of PARP inhibitors. PMID- 22443172 TI - Dynamic Ca(2+) signal modalities in the vascular endothelium. AB - The endothelium is vital to normal vasoregulation. Although acute vasodilation associated with broad endothelial Ca(2+) elevation is well known, the control and targeting of Ca(2+) -dependent signals in the endothelium are poorly understood. Recent studies have revealed localized IP(3) -motivated Ca(2+) events occurring basally along the intima that may provide the fundamental basis for various endothelial influences. Here, we provide an overview of dynamic endothelial Ca(2+) signals and discuss the potential role of these signals in constant endothelial control of arterial tone and the titration of functional responses in vivo. In particular, we focus on the functional architecture contributing to the properties and ultimate impact of these signals, and explore new avenues in evaluating their prevalence and specific modalities in intact tissue. Finally, we discuss spatial and temporal effector recruitment through modification of these inherent signals. It is suggested that endothelial Ca(2+) signaling is a continuum in which the specific framework of store-release components and cellular targets along the endothelium allows for differential modes of Ca(2+) signal expansion and distinctive profiles of effector recruitment. The precise composition and distribution of these inherent components may underlie dynamic endothelial control and specialized functions of different vascular beds. PMID- 22443173 TI - Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial. AB - BACKGROUND: Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post polypectomy patients. METHODS/DESIGN: This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. DISCUSSION: This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps. TRIAL REGISTRATION: This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254. PMID- 22443174 TI - Dutch healthcare reform: did it result in better patient experiences in hospitals? A comparison of the consumer quality index over time. AB - BACKGROUND: In 2006, the Dutch hospital market was reformed to create a more efficient delivery system through managed competition. To allow competition on quality, patient experiences were measured using the Consumer Quality index (CQI). We study whether public reporting and competition had an effect on the CQI between 2006 and 2009. METHODS: We analyzed 8,311 respondents covering 31 hospitals in 2006, 22,333 respondents covering 78 hospitals in 2007 and 24,246 respondents covering 94 hospitals in 2009. We describe CQI trends over the period 2006-2009. In addition we compare hospitals that varied in the level of competition they faced and hospitals that were forced to publish CQI results publicly and those that were not. We corrected for observable covariates between hospital respondents using a multi level linear regression. We used the Herfindahl Hirschman Index to indicate the level of competition. RESULTS: Between 2006 and 2009 hospitals showed a CQI improvement of 0.034 (p < 0.05) to 0.060 (p < 0.01) points on a scale between one and four. Hospitals that were forced to publish their scores showed a further improvement of 0.027 (p < 0.01) to 0.030 (p < 0.05). Furthermore, hospitals that faced more competition from geographically close competitors showed a more pronounced improvement of CQI-scores 0.004 to 0.05 than other hospitals (p < 0.001). CONCLUSION: Our results show that patients reported improved experiences measured by the CQI between 2006 and 2009. CQI levels improve at a faster rate in areas with higher levels of competition. Hospitals confronted with forced public publication of their CQI responded by enhancing the experiences of their patients. PMID- 22443176 TI - Hamman-Rich syndrome revisited: how to avoid misdiagnosis. PMID- 22443175 TI - The leukemia associated nuclear corepressor ETO homologue genes MTG16 and MTGR1 are regulated differently in hematopoietic cells. AB - BACKGROUND: MTG16, MTGR1 and ETO are nuclear transcriptional corepressors of the human ETO protein family. MTG16 is implicated in hematopoietic development and in controlling erythropoiesis/megakaryopoiesis. Furthermore, ETO homologue genes are 3'participants in leukemia fusions generated by chromosomal translocations responsible of hematopoietic dysregulation. We tried to identify structural and functional promoter elements of MTG16 and MTGR1 genes in order to find associations between their regulation and hematopoiesis. RESULTS: 5' deletion examinations and luciferase reporter gene studies indicated that a 492 bp sequence upstream of the transcription start site is essential for transcriptional activity by the MTG16 promoter. The TATA- and CCAAT-less promoter with a GC box close to the start site showed strong reporter activity when examined in erythroid/megakaryocytic cells. Mutation of an evolutionary conserved GATA -301 consensus binding site repressed promoter function. Furthermore, results from in vitro antibody-enhanced electrophoretic mobility shift assay and in vivo chromatin immunoprecipitation indicated binding of GATA-1 to the GATA 301 site. A role of GATA-1 was also supported by transfection of small interfering RNA, which diminished MTG16 expression. Furthermore, expression of the transcription factor HERP2, which represses GATA-1, produced strong inhibition of the MTG16 promoter reporter consistent with a role of GATA-1 in transcriptional activation. The TATA-less and CCAAT-less MTGR1 promoter retained most of the transcriptional activity within a -308 to -207 bp region with a GC box-rich sequence containing multiple SP1 binding sites reminiscent of a housekeeping gene with constitutive expression. However, mutations of individual SP1 binding sites did not repress promoter function; multiple active SP1 binding sites may be required to safeguard constitutive MTGR1 transcriptional activity. The observed repression of MTG16/MTGR1 promoters by the leukemia associated AML1 ETO fusion gene may have a role in hematopoietic dysfunction of leukemia. CONCLUSIONS: An evolutionary conserved GATA binding site is critical in transcriptional regulation of the MTG16 promoter. In contrast, the MTGR1 gene depends on a GC-box-rich sequence for transcriptional regulation and possible ubiquitous expression. Our results demonstrate that the ETO homologue promoters are regulated differently consistent with hematopoietic cell-type- specific expression and function. PMID- 22443177 TI - Single and double core-hole ionization energies in molecules. AB - The recently demonstrated ability to measure double-hole core-ionization energies in first-row elements has led to a renewed interest in the use of such energies to investigate the effects of initial-state charge distribution and final-state charge rearrangement on the energies of chemical processes that involve addition of charge to a molecule. With theoretical calculations for the molecules CH(4 n)X(n), X = F, Cl, and for C(CH(3))(4) as a basis, the relationships between one hole and two-hole ionization energies, on one hand, and initial-state and final state effects, on the other, are reviewed. It is shown that higher-order corrections to the traditionally used relationships are quantitatively significant but do not lead to qualitatively different conclusions. The role of the Wagner plot as a way to display the relationships among the various quantities of interest is discussed, and a generalized Wagner plot for displaying two-site double-hole ionization energies is presented. Some possible applications of measurements of double-hole ionization energies to the investigation of molecular conformation and molecular fragmentation are discussed. PMID- 22443178 TI - A broadly tuned mouse odorant receptor that detects nitrotoluenes. AB - Mammals employ large numbers of odorant receptors to sample and identify volatile chemicals in the environment. These receptors are thought to vary not only in specificity for particular odorants, but also in breadth of tuning. That is, some odorant receptors are narrowly focused on a few closely related structures, while other odorant receptors may be 'broadly tuned', responding to a wide variety of odorant structures. In this study, we have performed a detailed examination the mouse odorant receptor MOR256-17, demonstrating that this receptor is broadly tuned. This receptor responds to odorant structures that span a significant portion of a multi-dimensional odor space. However, we found that broad tuning was not a defining characteristic of other members the MOR256 subfamily. Two additional members of this odorant receptor subfamily (MOR256-8 and MOR256-22) were more narrowly focused on small sets of odorant structures. Interestingly, the receptive range of MOR256-17 encompassed a variety of nitrotoluenes, including various trinitrotoluene synthesis intermediates, degradation products and trinitrotoluene itself, suggesting the potential utility of odorant receptors in the development of sensing technologies for the detection of explosives and other forms of contraband. PMID- 22443179 TI - Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study. AB - BACKGROUND: Proton pump inhibitors (PPIs) may activate the immune system and cause asthma. AIM: To investigate the association of prenatal exposure to PPIs and histamine 2-receptor antagonists (H2RAs) with risk of asthma. METHODS: In this cohort study, 197,060 singletons born between 1996 and 2008 in northern Denmark were followed until the end of 2009. Data were obtained through Danish medical registries. Asthma in offspring was defined as at least two prescriptions of both a beta-agonist and an inhaled glucocorticoid and/or a hospital diagnosis of asthma during the follow-up. Cox proportional-hazard regression was used to compute incidence rate ratios, adjusting for covariates. RESULTS: A total of 2238 (1.1%) children were prenatally exposed to PPIs and 24,506 (12.4%) children developed asthma during follow-up (median follow-up = 6.8 years). The adjusted IRR (aIRR) of asthma associated with prenatal exposure to PPIs was 1.41 (95% confidence interval (CI): 1.27-1.56), compared with those unexposed. The association did not vary by trimester of exposure, and prenatal exposure to H2RAs was associated with similar increase in risk. The aIRR for maternal PPI and H2RA use in the year after, but not during pregnancy was 1.32 (95% CI: 1.20-1.46) and 1.13 (0.93-1.36), respectively, compared with non-use during and in the year after pregnancy. CONCLUSIONS: Prenatal exposure to both PPIs and H2RAs was associated with an increased risk of asthma in our study. Because the observed association is not drug specific and also observed for maternal postnatal use it may be explained by a 'class effect' or maternal underlying condition. PMID- 22443180 TI - Cost analysis: Mohs micrographic surgery. AB - BACKGROUND: With the continuing increase in the incidence of skin cancer, delivery of cost-efficient skin cancer treatment is a top priority. OBJECTIVE: To compare costs associated with removal of skin cancers using Mohs micrographic surgery (MMS) with that using standard surgical excision (SSE) with frozen or permanent margin control in the office or an ambulatory surgery center (ASC). METHODS AND MATERIALS: Costs for actual MMS and calculated costs for all SSE were recorded. The expense of treatment of incomplete excisions with subsequent reexcision and reconstruction and MMS on recurrent tumors were added to the final estimate. RESULTS: Four hundred six tumors were included in the study. An average tumor was cleared in 1.6 stages. MMS was the least expensive surgical procedure evaluated, at $805 per tumor. SSE with permanent margins ($1,026) was more expensive than MMS but less expensive than SSE with frozen margins ($1,200) and ASC-SSE with frozen margins ($2,507). Adjusted for inflation, the cost of MMS, inclusive of initial examination, biopsy, and 5-year follow-up, in 2009 ($1,376) was lower than in 1998 ($1,635). CONCLUSIONS: This study confirms MMS as the cornerstone of cost-effective treatment, regardless of place of service or type of margin control pathology. PMID- 22443181 TI - NF-kappaB as a target for pancreatic cancer therapy. AB - INTRODUCTION: Pancreatic cancer is the fourth leading cause of adult cancer mortality in the USA. It represents one of the greatest challenges in cancer treatment. The NF-kappaB transcriptional factors are constitutively activated in the majority of pancreatic cancers and are involved in the regulation of numerous aspects of tumor development and progression. NF-kappaB and the signaling cascades that regulate its activity have thus become attractive targets for novel therapeutic approaches for pancreatic cancer. AREAS COVERED: This review describes and discusses the most important advances in the comprehension of the complex molecular biology of NF-kappaB, as well as the development of novel NF kappaB-targeting strategies for the treatment of pancreatic cancer. EXPERT OPINION: Although the inhibition of NF-kappaB, especially when combined with more classic chemotherapeutic drugs, could be a promising therapeutic strategy, direct targeting NF-kappaB still faces important challenges. In the future, targeting nonredundant cytosolic mediators of the activation of NF-kappaB - such as TNF receptor associated factor family member-associated NF-kappaB activator -binding kinase 1 (TBK1) and TGF-beta activated kinase 1 (TAK1) - could represent a better approach to inhibit key processes in pancreatic tumor cells and make a difference for this devastating disease. PMID- 22443182 TI - Thermal generation of pentacenes from soluble 6,13-dihydro-6,13-ethenopentacene precursors by a Diels-Alder-retro-Diels-Alder sequence with 3,6-disubstituted tetrazines. AB - 3,6-Substituted tetrazines 2 (a: R(2) = 2-pyridyl or b: CO(2)Me) react with 2,3,9,10-(R(1))(4)-dihydro-6,13-ethenopentacene 3 in solution at elevated temperature to the corresponding pentacene 1 (a: R(1) = H, b: OBn, c: F). PMID- 22443183 TI - Comparison between sitagliptin as add-on therapy to insulin and insulin dose increase therapy in uncontrolled Korean type 2 diabetes: CSI study. AB - AIM: Individuals requiring insulin therapy for type 2 diabetes often require escalation of their regimen to achieve glycaemic control. Optimal management strategies for uncontrolled type 2 diabetes would improve glycaemic control without hypoglycaemia and weight gain. This study compared the efficacy and tolerability of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, and an up to 20% increase in insulin dose in patients with uncontrolled type 2 diabetes on insulin therapy. METHODS: We conducted a 24-week, randomized, active competitor, parallel-group study in subjects with uncontrolled type 2 diabetes [haemoglobin A1c (HbA1c) = 7.5-11%] currently using insulin therapy. Subjects were randomly assigned to either the sitagliptin adding (100 mg daily, n = 70) or an insulin-increasing arm (>= 10% at week 12 and >= 10% at week 24, n = 70) while continuing other medications. RESULTS: Average baseline HbA1c was 9.2% in both groups. HbA1c decreased more at 24 weeks in the sitagliptin adding than the insulin-increasing arm (-0.6 +/- 0.1% vs. -0.2 +/- 0.1%, p < 0.01). Insulin was increased by 25% at 24 weeks in the insulin-increasing group. Hypoglycaemic events were less common and less severe in sitagliptin adding arm than insulin increasing arm (7.0 vs. 14.3 events per patient-year, p < 0.05). Weight was stable in the sitagliptin adding subjects (68.6 +/- 11.6 vs. 68.1 +/- 11.4 kg) but increased in the insulin-increasing subjects (66.2 +/- 10.6 vs. 67.4 +/- 9.7 kg, p < 0.05). Other adverse events occurred at similar rates in both arms. CONCLUSIONS: Compared to a 25% increase in insulin dose, adding sitagliptin to an insulin-based regimen was more effective at lowering HbA1c and associated with less hypoglycaemia and weight gain over 24 weeks. CLINICAL TRIAL NUMBER: NCT01100125. PMID- 22443185 TI - Bioaugmentation of a historically contaminated soil by polychlorinated biphenyls with Lentinus tigrinus. AB - BACKGROUND: Several species belonging to the ecological group of white-rot basidiomycetes are able to bring about the remediation of matrices contaminated by a large variety of anthropic organic pollutants. Among them, polychlorobiphenyls (PCBs) are characterized by a high recalcitrance due to both their low bioavailability and the inability of natural microbial communities to degrade them at significant rates and extents. Objective of this study was to assess the impact of a maize stalk-immobilized Lentinus tigrinus CBS 577.79 inoculant combined with soybean oil (SO), as a possible PCB-mobilizing agent, on the bioremediation and resident microbiota of an actual Aroclor 1260 historically contaminated soil under unsaturated solid-phase conditions. RESULTS: Best overall PCB depletions (33.6 +/- 0.3%) and dechlorination (23.2 +/- 1.3%) were found after 60 d incubation in the absence of SO where, however, the fungus appeared to exert adverse effects on both the growth of biphenyl- and chlorobenzoate degrading bacteria and the abundance of genes coding for both biphenyl dioxygenase (bph) and catechol-2,3-dioxygenase. A significant (P < 0.001) linear inverse relationship between depletion yields and degree of chlorination was observed in both augmented and control microcosms in the absence of SO; conversely, this negative correlation was not evident in SO-amended microcosms where the additive inhibited the biodegradation of low chlorinated congeners. The presence of SO, in fact, resulted in lower abundances of both biphenyl-degrading bacteria and bph. CONCLUSIONS: The PCB depletion extents obtained in the presence of L. tigrinus are by far higher than those reported in other remediation studies conducted under unsaturated solid phase conditions on actual site soils historically contaminated by Aroclor 1260. These results suggest that the bioaugmentation strategy with the maize stalk-immobilized mycelium of this species might be promising in the reclamation of PCB-contaminated soils. The addition of SO to matrices contaminated by technical PCB mixtures, such as Aroclor 1242 and Delor 103 and characterized by a large preponderance of low chlorinated congeners, might not be advisable. PMID- 22443186 TI - Investigating geographic variation in mortality in the context of organ donation. AB - Organ procurement organizations (OPOs) report a nearly fourfold difference in donor availability as measured by eligible deaths per million population (PMP) based on hospital referrals. We analyzed whether mortality data help explain geographic variation in organ supply as measured by the number of eligible deaths for organ donation. Using the 2007 National Center for Health Statistics' mortality data, we analyzed deaths occurring in acute care hospitals, aged <= 70 years from cerebrovascular accidents and trauma. These deaths were mapped at the county level and compared to eligible deaths reported by OPOs. In 2007, there were 2 428 343 deaths reported in the United States with 42 339 in-hospital deaths <= 70 years from cerebrovascular accidents (CVA) or trauma that were correlated with eligible deaths PMP (r(2) = 0.79.) Analysis revealed a broad range in the death rate across OPOs: trauma deaths: 44-118 PMP; deaths from CVA: 34-118 PMP; and combined CVA and trauma: 91-229 PMP. Mortality data demonstrate that deaths by neurologic criteria of people who are likely to be suitable deceased donors are not evenly distributed across the nation. These deaths are correlated with eligible deaths for organ donation. Regional availability of organs is affected by deaths which should be accounted for in the organ allocation system. PMID- 22443187 TI - Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. AB - BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza) and exenatide (Byetta) are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R). Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. RESULTS: In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza) and lixisenatide (Lyxumia). We measured the kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip.) when measured 30 min post injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. CONCLUSIONS: Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of neurodegenerative diseases. PMID- 22443188 TI - Development of lung function in very low birth weight infants with or without bronchopulmonary dysplasia: longitudinal assessment during the first 15 months of corrected age. AB - BACKGROUND: Very low birth weight (VLBW) infants (< 1,500 g) with bronchopulmonary dysplasia (BPD) develop lung damage caused by mechanical ventilation and maturational arrest. We compared functional lung development after discharge from hospital between VLBW infants with and without BPD. METHODS: Comprehensive lung function assessment was performed at about 50, 70, and 100 weeks of postmenstrual age in 55 sedated VLBW infants (29 with former BPD [O2 supplementation was given at 36 weeks of gestational age] and 26 VLBW infants without BPD [controls]). Mean gestational age (26 vs. 29 weeks), birth weight (815 g vs. 1,125 g), and the proportion of infants requiring mechanical ventilation for >=7 d (55% vs. 8%), differed significantly between BPD infants and controls. RESULTS: Both body weight and length, determined over time, were persistently lower in former BPD infants compared to controls, but no significant between-group differences were noted in respiratory rate, respiratory or airway resistance, functional residual capacity as determined by body plethysmography (FRC(pleth)), maximal expiratory flow at the FRC (V'max (FRC)), or blood gas (pO2, pCO2) levels. Tidal volume, minute ventilation, respiratory compliance, and FRC determined by SF6 multiple breath washout (representing the lung volume in actual communication with the airways) were significantly lower in former BPD infants compared to controls. However, these differences became non-significant after normalization to body weight. CONCLUSIONS: Although somatic growth and the development of some lung functional parameters lag in former BPD infants, the lung function of such infants appears to develop in line with that of non-BPD infants when a body weight correction is applied. Longitudinal lung function testing of preterm infants after discharge from hospital may help to identify former BPD infants at risk of incomplete recovery of respiratory function; such infants are at risk of later respiratory problems. PMID- 22443189 TI - Impaired cytokine production and decreased TLR2-mediated signaling in mouse infant macrophages. AB - Infants are known to be more susceptible to pathogens. This might be due in part to the impaired function of macrophage. In the present study, we observed that macrophages from infant mice produced decreased levels of TNF-alpha and IL-6, but increased IL-10 after stimulation with toll-like receptor 2 (TLR2) agonist zymosan. Moreover, zymosan-stimulated activation of mitogen-activated protein kinase (MAPK) p38 and ERK1/2 was significantly reduced in mouse infant macrophages. These effects could be reversed by using MAPK modulators. The findings suggest that the impaired cytokine production and decreased TLR2 mediated signaling in infant macrophages may contribute to the susceptibility of infants to bacterial infection. PMID- 22443190 TI - Aspergillus fumigatus mitochondrial electron transport chain mediates oxidative stress homeostasis, hypoxia responses and fungal pathogenesis. AB - We previously observed that hypoxia is an important component of host microenvironments during pulmonary fungal infections. However, mechanisms of fungal growth in these in vivo hypoxic conditions are poorly understood. Here, we report that mitochondrial respiration is active in hypoxia (1% oxygen) and critical for fungal pathogenesis. We generated Aspergillus fumigatus alternative oxidase (aoxA) and cytochrome C (cycA) null mutants and assessed their ability to tolerate hypoxia, macrophage killing and virulence. In contrast to DeltaaoxA, DeltacycA was found to be significantly impaired in conidia germination, growth in normoxia and hypoxia, and displayed attenuated virulence. Intriguingly, loss of cycA results in increased levels of AoxA activity, which results in increased resistance to oxidative stress, macrophage killing and long-term persistence in murine lungs. Thus, our results demonstrate a previously unidentified role for fungal mitochondrial respiration in the pathogenesis of aspergillosis, and lay the foundation for future research into its role in hypoxia signalling and adaptation. PMID- 22443191 TI - Hospitalization of influenza-like illness patients recommended by general practitioners in France between 1997 and 2010. AB - BACKGROUND: The case-hospitalization ratio (CHR) is a key quantity for the management of emerging pathogens such as pandemic influenza. Yet, few running surveillance systems prospectively monitor the CHR during influenza epidemics. Here, we analyze the proportion of recommended hospitalizations (PRH) among influenza-like illness (ILI) patients attended in general practice in France and compare the PRH observed during the 2009-2010 A(H1N1) pandemic with the one of the twelve previous seasons. METHODS: ILI cases were recorded by general practitioners (GPs) involved in surveillance, who indicated for each case whether they recommended hospitalization. We stratify the analysis by age, sex, and viral subtype. We investigate the reasons why GPs recommended hospitalization and the presence of risk factors for pandemic A(H1N1) complications. RESULTS: The average PRH over the seasons 1997-1998 to 2008-2009 was 3.40/00 (3-3.9). It was three times higher during the 2009-2010 pandemic than during seasonal influenza epidemics (OR = 2.89, 95% CI: 2.28-3.64). The highest increase was among 20-39 year-old women: OR = 11.8 (5.04-29.59). Overall, the principal reasons for recommending hospitalization were "respiratory problems" and "bad general condition." However, during the pandemic, "age" (mainly associated with infants), "pregnancy," and "diagnostic" became more frequent than before (P < 0.001). Finally, pregnancy was the reported risk factor for pandemic A(H1N1) complications that had the largest impact on hospitalization recommendation during the pandemic (OR = 38.62, P < 0.001). CONCLUSION: Easily implemented in surveillance systems, this protocol has the potential to reveal changes in hospitalization recommendation by GPs. Moreover, if the right data are collected alongside, it could give timely insights into epidemic severity. PMID- 22443192 TI - Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling. AB - We have recently reported that Presenilin 1 (PS1), a causative gene of familial Alzheimer disease (AD), down-regulates the expression level of insulin receptor (IR) as well as its signaling through a gamma-secretase-independent pathway. PS1 is phosphorylated by glycogen synthase kinase 3 beta at the serine 353 and 357 residues. The main purpose of the present study was to clarify the effect of PS1 phosphorylation on IR/insulin signaling. Here, we demonstrate that the pseudo phosphorylation mutant of PS1 inhibited IR transcription and reduced IR expression compared with wild-type PS1. Importantly, there was a decrease in expression of IR in AD brains, and the phosphorylation ratio of PS1 was negatively correlated with IR level in human brain samples. In the data from mouse models of AD, IR reduction was not observed at the pre-Abeta deposition stage but became apparent in that of post-Abeta deposition. Together with our previous reports, these results suggest that phosphorylated PS1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling. As insulin resistance is reported to be a risk factor for sporadic AD, this PS1-mediated regulatory mechanism of brain insulin signaling may be causally associated with AD pathology. PMID- 22443193 TI - Theoretical spectroscopic study of europium tris(bipyridine) cryptates. AB - A series of europium cryptates are studied, using semiempirical methods to predict electronic and spectroscopic properties. The results are compared with theoretical (DFT) and experimental results published by Guillaumont and co workers (ChemPhysChem2007, 8, 480). Triplet energies calculated by semiempirical methods have errors similar to those obtained by TD-DFT methodology but hundreds of times faster. Moreover, the semiempirical results not only reproduce well the experimental values but also help explain the low values of quantum efficiency observed for these complexes. PMID- 22443194 TI - Considering the risk of infection by cryptosporidium via consumption of municipally treated drinking water from a surface water source in a Southwestern Ontario community. AB - Through the use of case-control analyses and quantitative microbial risk assessment (QMRA), relative risks of transmission of cryptosporidiosis have been evaluated (recreational water exposure vs. drinking water consumption) for a Canadian community with higher than national rates of cryptosporidiosis. A QMRA was developed to assess the risk of Cryptosporidium infection through the consumption of municipally treated drinking water. Simulations were based on site specific surface water contamination levels and drinking water treatment log10 reduction capacity for Cryptosporidium. Results suggested that the risk of Cryptosporidium infection via drinking water in the study community, assuming routine operation of the water treatment plant, was negligible (6 infections per 1013 persons per day--5th percentile: 2 infections per 1015 persons per day; 95th percentile: 3 infections per 1012 persons per day). The risk is essentially nonexistent during optimized, routine treatment operations. The study community achieves between 7 and 9 log10 Cryptosporidium oocyst reduction through routine water treatment processes. Although these results do not preclude the need for constant vigilance by both water treatment and public health professionals in this community, they suggest that the cause of higher rates of cryptosporidiosis are more likely due to recreational water contact, or perhaps direct animal contact. QMRA can be successfully applied at the community level to identify data gaps, rank relative public health risks, and forecast future risk scenarios. It is most useful when performed in a collaborative way with local stakeholders, from beginning to end of the risk analysis paradigm. PMID- 22443195 TI - The role of microRNAs in cancer: diagnostic and prognostic biomarkers and targets of therapies. AB - INTRODUCTION: miRNAs are noncoding RNAs that target specific mRNA with subsequent regulation of particular genes, implicated in various biological processes. In cancer, miRNAs could show a different expression from normal tissues. miRNAs have a role as oncogenes when they target tumor suppressor genes and similarly they are tumor suppressors when they target oncogenes. AREAS COVERED: In this review, areas covered include the role of miRNAs in cancer diagnosis, prognosis and research for achievement of therapeutic strategies implicating miRNAs in oncology. As biogenesis of miRNAs is fundamental to understand their usefulness, this has also been discussed. Both miRNA expression profiles in cancer tissues and miRNA levels in peripheral blood were studied for improvement in the management of cancer patients. EXPERT OPINION: miRNAs have the potential for better understanding of tumor biology, but could also provide clinical advancement in management and therapy of various malignancies. The possibility of miRNA detection in peripheral blood would allow an eager expansion of their application in various clinical settings for cancer. The applicability of miRNA expression profiles still needs to be defined. PMID- 22443196 TI - Cyclic intensive light exposure induces retinal lesions similar to age-related macular degeneration in APPswe/PS1 bigenic mice. AB - BACKGROUND: Intensive light exposure and beta-amyloid (Abeta) aggregates have been known as a risk factor for macular degeneration and an important component in the pathologic drusen structure involved in this disorder, respectively. However, it is unknown whether Abeta deposition mediates or exacerbates light exposure-induced pathogenesis of macular degeneration. Several studies including the one from us already showed accumulation of Abeta deposits in the retina in Alzheimer's transgenic mice. Using histopathological analysis combined with electroretinographic functional assessment, we investigated the effects of cyclic intensive light exposure (CILE) on the architecture of retina and related function in the APPswe/PS1bigenic mouse. RESULTS: Histopathological analysis has found significant loss of outer nuclear layer/photoreceptor outer segment and outer plexiform layer along with abnormal hypo- and hyper-pigmentation in the retinal pigment epithelium (RPE), remarkable choroidal neovascularization (CNV), and exaggerated neuroinflammatory responses in the outer retina of APPswe/PS1 bigenic mice following cyclic intensive light exposure (CILE), whereas controls remained little change contrasted with age-matched non-transgenic littermates. CILE-induced degenerative changes in RPE are further confirmed by transmission electron microcopy and manifest as formation of basal laminar deposits, irregular thickening of Bruch's membrane (BrM), deposition of outer collagenous layer (OCL) in the subretinal space, and vacuolation in the RPE. Immunofluorescence microscopy reveals drusenoid Abeta deposits in RPE as well as neovessels attached which are associated with disruption of RPE integrity and provoked neuroinflammatory response as indicated by markedly increased retinal infiltration of microglia. Moreover, both immunohistochemistry and Western blots detect an induction of vascular endothelial growth factor (VEGF) in RPE, which corroborates increased CNV in the outer retina in the bigenic mice challenged by CILE. CONCLUSIONS: Our findings demonstrate that degenerative changes in the outer retina in the APPswe/PS1 bigenic mouse induced by CILE are consistent with these in AMD. These results suggest that an Alzheimer's transgenic animal model with accumulation of Abeta deposits might be an alternative animal model for AMD, if combined with other confounding factors such as intensive light exposure for AMD. PMID- 22443197 TI - PPAR agonists for the treatment of cardiovascular disease in patients with diabetes. AB - Diabetes is a complex disease defined by hyperglycaemia; however, strong associations with abdominal obesity, hypertension and dyslipidaemia contribute to the high risk of cardiovascular disease. Although aggressive glycaemic control reduces microvascular complications, the evidence for macrovascular complications is less certain. The theoretical benefits of the mode of action of peroxisome proliferator-activated receptor (PPAR) agonists are clear. In clinical practice, PPAR-alpha agonists such as fibrates improve dyslipidaemia, while PPAR-gamma agonists such as thiazolidinediones improve insulin resistance and diabetes control. However, although these agents are traditionally classed according to their target, they have different and sometimes conflicting clinical benefit and adverse event profiles. It is speculated that this is because of differing properties and specificities for the PPAR receptors (each of which targets specific genes). This is most obvious in the impact on cardiovascular outcomes- in clinical trials pioglitazone appeared to reduce cardiovascular events, whereas rosiglitazone potentially increased the risk of myocardial infarction. The development of a dual PPAR-alpha/gamma agonist may prove beneficial in effectively managing glycaemic control and improving dyslipidaemia in patients with type 2 diabetes. Yet, development of agents such as muraglitazar and tesaglitazar has been hindered by various serious adverse events. Aleglitazar, a balanced dual PPAR-alpha/gamma agonist, is currently the most advanced in clinical development and has shown promising results in phase II clinical trials with beneficial effects on glucose and lipid variables. A phase III study, ALECARDIO, is ongoing and will establish whether improvements in laboratory test profiles translate into an improvement in cardiovascular outcomes. PMID- 22443199 TI - Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers. AB - Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers. PMID- 22443200 TI - Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the Ovarian Cancer Association Consortium (OCAC). AB - In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the Ovarian Cancer Association Consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work. PMID- 22443201 TI - Resolving the variable genome and epigenome in human disease. AB - The individual human genome and epigenome are being defined at unprecedented resolution by current advances in sequencing technologies with important implications for human disease. This review uses examples relevant to clinical practice to illustrate the functional consequences of genetic and epigenetic variation. The insights gained from genome-wide association studies are described together with current efforts to understand the role of rare variants in common disease, set in the context of recent successes in Mendelian traits through the application of whole exome sequencing. The application of functional genomics to interrogate the genome and epigenome, build up an integrated picture of the regulatory genomic landscape and inform disease association studies is discussed, together with the role of expression quantitative trait mapping and analysis of allele-specific gene expression. PMID- 22443202 TI - Folic acid supplementation increases survival and modulates high risk HPV-induced phenotypes in oral squamous cell carcinoma cells and correlates with p53 mRNA transcriptional down-regulation. AB - BACKGROUND: Although the primary risk factors for developing oral cancers are well understood, less is known about the relationship among the secondary factors that may modulate the progression of oral cancers, such as high-risk human papillomavirus (HPV) infection and folic acid (FA) supplementation. This study examined high-risk HPV and FA supplementation effects, both singly and in combination, to modulate the proliferative phenotypes of the oral cancer cell lines CAL27, SCC25 and SCC15. RESULTS: Using a comprehensive series of integrated in vitro assays, distinct effects of HPV infection and FA supplementation were observed. Both high-risk HPV strains 16 and 18 induced robust growth-stimulating effects in CAL27 and normal HGF-1 cells, although strain-specific responses were observed in SCC25 and SCC15 cells. Differential effects were also observed with FA administration, which significantly altered the growth rate of the oral cancer cell lines CAL27, SCC15, and SCC25, but not HGF-1 cells. Unlike HPV, FA administration induced broad, general increases in cell viability among all cell lines that were associated with p53 mRNA transcriptional down-regulation. None of these cell lines were found to harbor the common C677T mutation in methylenetetrahydrofolate reductase (MTHFR), which can reduce FA availability and may increase oral cancer risk. CONCLUSION: Increased FA utilization and DNA hypermethylation are common features of oral cancers, and in these cell lines, specifically. The results of this study provide further evidence that FA antimetabolites, such as Fluorouracil (f5U or 5-FU) and Raltitrexed, may be alternative therapies for tumors resistant to other therapies. Moreover, since the incidence of oral HPV infection has been increasing, and can influence oral cancer growth, the relationship between FA bioavailability and concomitant HPV infection must be elucidated. This study is among the first pre-clinical studies to evaluate FA- and HPV-induced effects in oral cancers, both separately and in combination, which provides additional rationale for clinical screening of HPV infection prior to treatment. PMID- 22443203 TI - Influence of cross-linked arabinoxylans on the postprandial blood glucose response in rats. AB - Viscous dietary fibers are well established to reduce the blood glucose response to a meal. In this study, arabinoxylans, the most abundant dietary fiber in most cereals, were extracted under alkaline conditions and cross-linked by using laccase. Cross-linking of the arabinoxylans led to gel formation and increased in vitro viscosity almost 100-fold after drying and rehydration. To determine the ability of these cross-linked arabinoxylans to blunt the postprandial blood glucose curve of a meal, arabinoxylans, either native or cross-linked, and either prehydrated or not, were fed to rats as part of a meal, and blood glucose was monitored at intervals after the meal. Cellulose, a nonviscous fiber, served as a control. Cross-linked, but not native, arabinoxylans significantly reduced the area under the blood glucose time curve 5-9% relative to cellulose, indicating that they remained viscous within the gastrointestinal tract, and thus likely provide the health benefits found with other viscous fibers. PMID- 22443204 TI - Acrania-anencephaly associated with hypospadias. Prenatal ultrasound and MRI diagnosis and molecular folate metabolism pathway analysis. AB - Acrania may occur as a single isolated malformation or associated with extracranial defects. Hypospadias is one of the most common congenital abnormalities of the genitalia frequently missed on prenatal sonograms. Second trimester two- and three-dimensional ultrasound and MRI diagnosis with necropsy and folate metabolism pathway analysis. The mechanisms leading to closure of both neural and urethral tubes, are far from being demonstrated, and molecular studies of this very rare association are lacking although it might be based on a common genetic mechanism, leading to a disturbed development pathway at the molecular level. PMID- 22443205 TI - A history of intraspinal analgesia, a small and personal journey. AB - INTRODUCTION: There is a large and robust literature on the spinal use of opioids and non-opioids alike, but unless one is my age and older, very few persons know how we got here. This small history offering tells us how we got to where we are today regarding the science, clinical uses, and management of intraspinal analgesia. METHODS: I have reviewed the literature bases of Google Scholar and the National Library of Medicine using the key words: history, opium, spinal analgesia, spinal morphine, intrathecal (IT), opioid receptors, endogenous opioids, IT delivery of opioids, and IT side-effects/complications. RESULTS: In this personal review of the history of intraspinal analgesia, I relate my own early and later experiences of the science and clinical uses of intraspinal morphine, other opioids, and non-opioids alike to a historical context. This review outlines a rather small history of opium, the historical use of opium and its various compounds, and the search for and answer to the question, "why was the poppy created for wondrous medicinal uses for mankind?" This search led to the discovery of endogenous opioid like chemicals, the discovery of opiate receptors for these endogenous opioids, the first uses of intraspinal opioids in animal models and man, and, finally, our understanding of the appropriate and inappropriate clinical uses of intraspinal analgesia. Within this paper, I acknowledge the works of my colleagues and the "heroes" who have laid the foundation for our understanding of intraspinal analgesia. CONCLUSIONS: The history of the use of intraspinal analgesia is rich and guides us to advance the science and clinical use of intraspinal analgesia without reinventing the wheel. PMID- 22443206 TI - Are people willing to buy natural disaster insurance in China? Risk awareness, insurance acceptance, and willingness to pay. AB - After the Wenchuan earthquake (magnitude 7.9, May 12, 2008), intensive debates on how China should establish a natural disaster insurance system were initiated among researchers, policymakers, and insurance professionals. Our focus was the social aspects of disaster insurance, explored in China through a nationwide survey. Our questionnaires investigated people's risk awareness, insurance acceptance, their opinions on governmental measures for disaster management, and their willingness to pay for disaster house insurance. We analyzed the results at both regional and individual scales. We found that the integrated hazard index and respondents' experience of insurance (considered objective factors), and their opinions on the importance of insurance and government responsibility (considered subjective factors) showed strong correlation with the regional overall acceptance of disaster insurance. An individual's decision to participate highly depended on his/her experience of both insurance and disaster and his/her opinion on the importance of insurance as a coping mechanism. Respondents from poverty-stricken or less-developed counties were not necessarily more reluctant to accept natural disaster insurance, though they exhibited relatively lower ability to afford insurance. In general, respondents had correct perceptions of natural disasters in their areas; however, people from regions with a greater multihazard threat showed less willingness to accept disaster insurance because they tended to expect the government to undertake to cover losses and considered insurance to be less important. People's willingness to pay for an assumed disaster house insurance was also investigated and analyzed. We consequently discuss the policy implications for developing a disaster insurance system in China. PMID- 22443208 TI - Synthesis and microwave spectrum of vinyl isoselenocyanate (H2C?CHNCSe), a compound with a quasilinear CNCSe chain. AB - The first alpha,beta-unsaturated isoselenocyanate, vinyl isoselenocyanate (H(2)C?CHNCSe), has been synthesized, and its microwave spectrum has been investigated in the 11.5-77.0 GHz spectral range. The microwave work was augmented by quantum chemical calculations using four different methods, namely, CCSD(T), CCSD, B3LYP, and M062X, with the cc-pVTZ basis set. It is generally assumed that two rotamers having the isoselenocyanide group in an antiperiplanar or a synperiplanar position can exist for this compound. However, these four methods all predict that there is only one rotameric form of the molecule, namely, the antiperiplanar form. The CNC angle of the antiperiplanar rotamer is calculated to vary from 151 degrees to 170 degrees depending on the quantum chemical methodology. CCSD(T) and B3LYP potential functions of the in-plane CNC bending vibrations were calculated. These functions have one shallow minimum corresponding to the antiperiplanar form. The spectra of the ground and one vibrationally excited state of this rotamer were assigned. Spectral searches for the synperiplanar form were performed but were not successful, so this form must have a relatively high energy, if it exists at all. The vibrationally excited state is presumably the lowest in-plane bending vibration of the CNC angle. Relative intensity measurements yielded a very low frequency of 18(25) cm(-1) for this vibration. The large-amplitude vibration of this mode suggests that this compound should rather be regarded as having a quasilinear CNCSe link of atoms than a rigid, bent antiperiplanar form. PMID- 22443207 TI - Collapsin response mediator protein-2 phosphorylation promotes the reversible retraction of oligodendrocyte processes in response to non-lethal oxidative stress. AB - The extension of processes of oligodendrocyte (OLG) and their precursor cells are crucial for migration, axonal contact and myelination. Here we show that a non lethal oxidative stress induced by 3-nitropropionic acid (3-NP) elicited a rapid shortening of processes (~24%) in primary OLGs and in oligodendroglial cell line (OLN-93) cells (~36%) as compared with vehicle-exposed cells. This was reversible and prevented by antioxidants. Proteomics of OLG lysates with and without 3-NP treatment yielded collapsin response mediator protein 2 (CRMP-2) as a candidate effector molecule. Inhibition of rho kinase was sufficient to prevent process retraction in both OLGs and OLN-93 cells. Oxidative stress increased phosphorylation of CRMP-2 at T555 that was completely prevented by Y27632. Moreover, transfection of OLN-93 cells with the mutant CRMP-2 T555A which cannot be phosphorylated by rho kinase, prevented process shortening induced by 3-NP as compared with wild-type CRMP-2. Our results suggest a role for endogenous reactive oxygen species in a pathway that regulates OLG process extension. The vulnerability of late myelinated neurons in the adult brain and the presence of white matter pathology in human dementias warrant the study of this oligodendroglial pathway in the early stages of neurodegenerative conditions characterized by oxidative stress. PMID- 22443209 TI - Efficient siRNA targeted delivery into cancer cells by gastrin-releasing peptides. AB - Small interfering RNAs (siRNAs) have displayed considerable promise for the treatment of cancer. However, their delivery to the desired cell population remains a challenging task. Here we have covalently conjugated a siRNA against survivin to gastrin-releasing peptides (GRPs) to direct siRNA molecules to cancer cells that express the GRP receptor. The cellular uptake of the peptide-siRNA conjugates was tested in breast MDA-MB 231 cancer cells, which express the GRP receptor. Fluorescein-tagged GRP-siRNA conjugates were taken up by cancer cells but not normal mammary epithelial cells or human blood monocytes. By 120 min of incubation, most of the cells have taken up the conjugates. Excess free peptide inhibited uptake, implying dependence of uptake on GRP receptor. Moreover, bitargeting of siRNA molecules by GR and luteinizing hormone-releasing peptides accelerated the uptake kinetics by MDA-MB 231 cells when compared to monotargeted siRNAs. Peptide-siRNA conjugates, but not free siRNAs, inhibited the expression of survivin, an endogenous gene involved in cancer cell survival. None of the peptide-siRNA conjugates induced the expression of inflammatory cytokines or interferon alpha in human blood leukocytes. Overall, the data demonstrate the feasibility of GRP receptor-mediated targeted delivery of siRNAs to cancer cells, an important step for RNA interference therapy in humans. PMID- 22443210 TI - Concise approach to benzisothiazol-3(2H)-one via copper-catalyzed tandem reaction of o-bromobenzamide and potassium thiocyanate in water. AB - A concise approach to various benzisothiazol-3(2H)-one derivatives has been developed by copper-catalyzed the reaction of o-bromobenzamide derivatives with potassium thiocyanate (KSCN) in water. The reaction proceeds via a tandem reaction with S-C bond and S-N bond formation. PMID- 22443211 TI - Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines. AB - INTRODUCTION: Chemotherapy-induced neutropenia, the depth and length of which are correlated to the risk of febrile neutropenia (FN) and neutropenia sepsis, remains a serious problem in medical oncology. Granulocyte colony-stimulating factors (G-CSF) stimulate the proliferation and survival of neutrophils and their precursors, thereby reducing the incidence, duration and severity of neutropenic events across a broad range of malignancies and regimens, often enabling the delivery of full chemotherapy dose intensity. AREAS COVERED: In this review, areas covered include the physiologic role of G-CSF in granulopoiesis, as well as a related biological model of bone marrow kinetics after chemotherapy. Information relating to the application of clinical guidelines for optimization of prophylaxis of FN in adult cancer patients was critically summarized. The literature and pharmacological data were obtained through an electronic search. EXPERT OPINION: There are relevant physiological and clinical evidences for the use of G-CSF to prevent FN and to ameliorate the myelotoxicities of cancer chemotherapy. In particular, biological models are in favor of the prophylactic rather than therapeutic use of G-CSF therapy. Use of a single dose of pegfilgrastim per cycle in appropriate patients provides a more convenient and potentially more effective strategy for assisting neutrophil recovery. While biosimilars may cost less, future developments in their regulation will need to address multiple issues. In the interim, physicians should remember that small differences in biochemical and biophysical characteristics might translate into differences in potency and immunogenic potential. PMID- 22443212 TI - Effective lifestyle interventions to improve type II diabetes self-management for those with schizophrenia or schizoaffective disorder: a systematic review. AB - BACKGROUND: The prevalence of type II diabetes among individuals suffering from schizophrenia or schizoaffective disorders is more than double that of the general population. By 2005, North American professional medical associations of Psychiatry, Diabetes, and Endocrinology responded by recommending continuous metabolic monitoring for this population to control complications from obesity and diabetes. However, these recommendations do not identify the types of effective treatment for people with schizophrenia who have type II diabetes. To fill this gap, this systematic evidence review identifies effective lifestyle interventions that enhance quality care in individuals who are suffering from type II diabetes and schizophrenia or other schizoaffective disorders. METHODS: A systematic search from Medline, CINAHL, PsycINFO, and ISI Web of Science was conducted. Of the 1810 unique papers that were retrieved, four met the inclusion/exclusion criteria and were analyzed. RESULTS: The results indicate that diabetes education is effective when it incorporates diet and exercise components, while using a design that addresses challenges such as cognition, motivation, and weight gain that may result from antipsychotics. CONCLUSIONS: This paper begins to point to effective interventions that will improve type II diabetes management for people with schizophrenia or other schizoaffective disorders. PMID- 22443213 TI - Study of Once Daily Levemir (SOLVETM): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice. AB - AIMS: The aim of this analysis is to determine the timing of insulin initiation in routine clinical practice, especially in relation to glycaemic control and use of oral antidiabetic drugs (OADs). METHODS: Study of Once Daily Levemir was a 24 week international observational study involving 10 countries which evaluated the safety and effectiveness of initiating once-daily insulin detemir in people with type 2 diabetes mellitus (T2DM) being treated with one or more OADs (clinical trial number NCT00825643 and NCT00740519). RESULTS: A total of 17 374 participants were enrolled in the study: aged 62 +/- 12 years, 53% male, T2DM duration 10 +/- 7 years, body mass index 29.3 +/- 5.4 kg/m(2) . Pre-insulin HbA1c was 8.9 +/- 1.6%. The proportion of patients with HbA1c >=9.0% ranged from 64% (UK) to 23% (Poland). Pre-insulin OAD treatment included metformin (81%), sulphonylureas (59%), glinides (16%), thiazolidinediones (TZD) (12%), alpha glucosidase inhibitors (12%) and dipeptidyl peptidase (DPP)-IV inhibitors (7%). The mean starting dose of insulin detemir for the total cohort was 0.16 +/- 0.09 U/kg. Differences in OAD use and insulin doses at initiation were evident among participating countries. The largest proportional changes in OAD prescribing at insulin initiation were seen with glinides (+15%), sulphonylureas (-19%), TZD ( 31%) and DPP-IV inhibitors (-28%). CONCLUSIONS: Despite well-documented benefits of timely glycaemic control and consensus guidelines encouraging earlier use of insulin, considerable clinical inertia exists with respect to initiating appropriate insulin therapy in people with T2DM. Considerable regional differences exist in the timing of insulin initiation and in the use of OADs. PMID- 22443214 TI - Identification of expressed resistance gene-like sequences by data mining in 454 derived transcriptomic sequences of common bean (Phaseolus vulgaris L.). AB - BACKGROUND: Common bean (Phaseolus vulgaris L.) is one of the most important legumes in the world. Several diseases severely reduce bean production and quality; therefore, it is very important to better understand disease resistance in common bean in order to prevent these losses. More than 70 resistance (R) genes which confer resistance against various pathogens have been cloned from diverse plant species. Most R genes share highly conserved domains which facilitates the identification of new candidate R genes from the same species or other species. The goals of this study were to isolate expressed R gene-like sequences (RGLs) from 454-derived transcriptomic sequences and expressed sequence tags (ESTs) of common bean, and to develop RGL-tagged molecular markers. RESULTS: A data-mining approach was used to identify tentative P. vulgaris R gene-like sequences from approximately 1.69 million 454-derived sequences and 116,716 ESTs deposited in GenBank. A total of 365 non-redundant sequences were identified and named as common bean (P. vulgaris = Pv) resistance gene-like sequences (PvRGLs). Among the identified PvRGLs, about 60% (218 PvRGLs) were from 454-derived sequences. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirmed that PvRGLs were actually expressed in the leaves of common bean. Upon comparison to P. vulgaris genomic sequences, 105 (28.77%) of the 365 tentative PvRGLs could be integrated into the existing common bean physical map. Based on the syntenic blocks between common bean and soybean, 237 (64.93%) PvRGLs were anchored on the P. vulgaris genetic map and will need to be mapped to determine order. In addition, 11 sequence-tagged-site (STS) and 19 cleaved amplified polymorphic sequence (CAPS) molecular markers were developed for 25 unique PvRGLs. CONCLUSIONS: In total, 365 PvRGLs were successfully identified from 454 derived transcriptomic sequences and ESTs available in GenBank and about 65% of PvRGLs were integrated into the common bean genetic map. A total of 30 RGL-tagged markers were developed for 25 unique PvRGLs, including 11 STS and 19 CAPS markers. The expressed PvRGLs identified in this study provide a large sequence resource for development of RGL-tagged markers that could be used further for genetic mapping of disease resistant candidate genes and quantitative trait locus/loci (QTLs). This work also represents an additional method for identifying expressed RGLs from next generation sequencing data. PMID- 22443215 TI - Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction. AB - Genetic factors are believed to account for 30-50% of the risk for cocaine and heroin addiction. Dynorphin peptides, derived from the prodynorphin (PDYN) precursor, bind to opioid receptors, preferentially the kappa-opioid receptor, and may mediate the aversive effects of drugs of abuse. Dynorphin peptides produce place aversion in animals and produce dysphoria in humans. Cocaine and heroin have both been shown to increase expression of PDYN in brain regions relevant for drug reward and use. Polymorphisms in PDYN are therefore hypothesized to increase risk for addiction to drugs of abuse. In this study, 3 polymorphisms in PDYN (rs1022563, rs910080 and rs1997794) were genotyped in opioid-addicted [248 African Americans (AAs) and 1040 European Americans (EAs)], cocaine-addicted (1248 AAs and 336 EAs) and control individuals (674 AAs and 656 EAs). Sex-specific analyses were also performed as a previous study identified PDYN polymorphisms to be more significantly associated with female opioid addicts. We found rs1022563 to be significantly associated with opioid addiction in EAs [P = 0.03, odds ratio (OR) = 1.31; false discovery rate (FDR) corrected q value]; however, when we performed female-specific association analyses, the OR increased from 1.31 to 1.51. Increased ORs were observed for rs910080 and rs199774 in female opioid addicts also in EAs. No statistically significant associations were observed with cocaine or opioid addiction in AAs. These data show that polymorphisms in PDYN are associated with opioid addiction in EAs and provide further evidence that these risk variants may be more relevant in females. PMID- 22443216 TI - Intraspecific chemical variability of essential oil from leaves of Cupressus atlantica Gaussen, an endemic and endangered coniferous species in Morocco. AB - The composition of essential oils isolated from leaves of 11 natural populations of Cupressus atlantica, an endemic and endangered coniferous species from Morocco, was investigated by GC-MS. In total, 42 essential oil components were identified, accounting for 73.1-97.7% of the total oil. Monoterpene (25.2-84.9%) and sesquiterpene hydrocarbons (12.2-46.8%) were the principal subclasses of compounds, with alpha-pinene (15-65.4%), germacrene D (5.9-30.5%), delta-3-carene (2-16.6%) and gamma-cadinene (1.3-9.8%) as the main constituents. The results of the oil composition were analysed by hierarchical cluster and principal component analysis that established three main groups of essential oils. These oils were differentiated by the content of the major constituents (alpha-pinene, germacrene D, delta-3-carene and gamma-cadinene), geographical location and climatic characteristics. PMID- 22443217 TI - Ovarian Sertoli-Leydig cell tumor in a 9-month-old infant with special histologic pattern. AB - A 9-month-old infant with left ovarian Sertoli Leydig cell tumors (SLCTs) was reported and the special histological pattern was that the main components of the tumor were leydig cells. She was the youngest reported case of the tumor. The patient had increased serum estradiol and A-Fetoprofein (AFP) and a left oophorectomy was performed. After surgery, the patient has not received any treatment. So far, the patient has been well and survived without recurrence for 40 months. PMID- 22443218 TI - Elevated cerebrospinal fluid kynurenic acid levels in patients with tick-borne encephalitis. AB - BACKGROUND: Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan that is thought to regulate cognitive functions. Previous studies have shown that levels of KYNA increase during virus infection and that this metabolite interacts with the immune system. OBJECTIVE: The aim of the study was to investigate whether patients with tick-borne encephalitis (TBE), a viral infectious disease associated with long-term cognitive impairment, have increased levels of KYNA in the cerebrospinal fluid (CSF). METHODS: CSF KYNA was analysed using high performance liquid chromatography in 108 patients with TBE and 52 age-matched controls. Patients were classified according to the severity of TBE: mild (47%), moderate (44%) or severe (9%). RESULTS: Concentrations of CSF KYNA were considerably higher in patients with TBE (5.3 nmol L(-1) ) than in control subjects (0.99 nmol L(-1) ). KYNA concentration in the CSF varied greatly amongst individuals with TBE and increased (P < 0.05) with the severity of disease. CONCLUSIONS: This is the first study to demonstrate increased levels of CSF KYNA in patients with TBE. The importance of brain KYNA in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in TBE might play a part in the pathophysiology of the disease. A detailed knowledge of endogenous brain KYNA during the course of CNS infection might yield further insights into the neuroimmunological role of the compound and may also provide new pharmacological approaches for the treatment of cognitive symptoms. PMID- 22443219 TI - Retinoic acid signalling in gastrointestinal parasite infections: lessons from mouse models. AB - Retinoic acid or vitamin A is important for an extensive range of biological processes, including immunomodulatory functions, however, its role in gastrointestinal parasite infections is not yet clear. Despite this, parasite infected individuals are often supplemented with vitamin A, given the co localised prevalence of parasitic infections and vitamin deficiencies. Therefore, it is important to understand the impact of this vitamin on the immune responses to gastrointestinal parasites. Here, we review data regarding the role of retinoic acid signalling in mouse models of intestinal nematode infection, with a view to understanding better the practice of giving vitamin A supplements to worm infected people. PMID- 22443220 TI - Transcript and protein expression profile of PF11_0394, a Plasmodium falciparum protein expressed in salivary gland sporozoites. AB - BACKGROUND: Plasmodium falciparum malaria is a significant problem around the world today, thus there is still a need for new control methods to be developed. Because the sporozoite displays dual infectivity for both the mosquito salivary glands and vertebrate host tissue, it is a good target for vaccine development. METHODS: The P. falciparum gene, PF11_0394, was chosen as a candidate for study due to its potential role in the invasion of host tissues. This gene, which was selected using a data mining approach from PlasmoDB, is expressed both at the transcriptional and protein levels in sporozoites and likely encodes a putative surface protein. Using reverse transcription-polymerase chain reaction (RT-PCR) and green fluorescent protein (GFP)-trafficking studies, a transcript and protein expression profile of PF11_0394 was determined. RESULTS: The PF11_0394 protein has orthologs in other Plasmodium species and Apicomplexans, but none outside of the group Apicomplexa. PF11_0394 transcript was found to be present during both the sporozoite and erythrocytic stages of the parasite life cycle, but no transcript was detected during axenic exoerythrocytic stages. Despite the presence of transcript throughout several life cycle stages, the PF11_0394 protein was only detected in salivary gland sporozoites. CONCLUSIONS: PF11_0394 appears to be a protein uniquely detected in salivary gland sporozoites. Even though a specific function of PF11_0394 has not been determined in P. falciparum biology, it could be another candidate for a new vaccine. PMID- 22443221 TI - Dietary fiber from Tunisian common date cultivars (Phoenix dactylifera L.): chemical composition, functional properties, and antioxidant capacity. AB - The dietary fibers (DF) of 10 date varieties from Tunisian oases have been investigated. Further knowledge on the content, composition, and technological applications of those fibers could support their genetic variability and promote the socioeconomical development of growing areas. The composition, water- and oil holding capacities, solubility, and antiradical activity have been determined. The DF content ranged from 4.7% (Matteta, Rochdi) to >7% (Degle Nour, Garen Gaze, Smeti). Composition varied significantly among cultivars, and the results evidenced that uronic acids and lignin determine to a great extent the organoleptic quality of dates. Many of the varieties that have been studied (Garen Gaze, Matteta, Kenta, Rochdi, Mermella, Korkobbi, Eguwa) were selected because of great interest from technological and functional points of view. Among their physicochemical characteristics, these samples presented water- and oil holding capacities of higher than 17 and 4 mL/g fiber, respectively, which make them suitable for use as additives in fiber-enriched foods. Also, DF of Garen Gaze, Smeti, Mermella, and Eguwa had a high antiradical capacity (>230 Trolox equiv/kg fiber). It was concluded that some of these varieties could be grown as potential sources of DF, which could be included in the formulation of fiber- and antioxidant-enriched foods. PMID- 22443222 TI - Microwave rotational spectra and structures of 2-fluoropyridine and 3 fluoropyridine. AB - The ground state rotational spectra of 2-fluoropyridine and 3-fluoropyridine have been investigated using both Fourier transform microwave (FTMW) and chirped pulse Fourier transform microwave (cp-FTMW) spectroscopies. In addition to the parent species, the spectra of the (13)C and (15)N singly substituted isotopologues were recorded in the 8-23 GHz region in natural abundance. The rotational constants determined for the seven isotopologues of each were used to calculate relevant geometric parameters including the bond distances and angles of the pyridine ring backbone. The derived structures show a more pronounced deviation from the pyridine ring geometry when the fluorine substituent is ortho to nitrogen which is consistent with ab initio predictions at various levels of theory. Analysis of the (14)N hyperfine structure provided an additional source of information about the electronic structure surrounding the nitrogen atom as a function of fluorine substitution. Together, the experimental results are consistent with a bonding model that involves hyperconjugation whereby fluorine donates electron density from its lone pair into the pi-system of pyridine. PMID- 22443223 TI - Construction and assembly of branched Y-shaped DNA: "click" chemistry performed on dendronized 8-aza-7-deazaguanine oligonucleotides. AB - Branched DNA was synthesized from tripropargylated oligonucleotides by the Huisgen-Meldal-Sharpless cycloaddition using "stepwise and double click" chemistry. Dendronized oligonucleotides decorated with 7-tripropargylamine side chains carrying two terminal triple bonds were further functionalized with bis azides to give derivatives with two terminal azido groups. Then, the branched side chains with two azido groups or two triple bonds were combined with DNA fragments providing the corresponding clickable function. Both concepts afforded branched (Y-shaped) three-armed DNA. Annealing of branched DNA with complementary oligonucleotides yielded supramolecular assemblies. The concept of "stepwise and double click" chemistry combined with selective hybridization represents a flexible tool to generate DNA nanostructures useful for various purposes in DNA diagnostics, delivery, and material science applications. PMID- 22443224 TI - A history of pediatric anesthesia: a tale of pioneers and equipment. AB - The history of pediatric anesthesia is fascinating in terms of how inventive anesthesiologists became over time to address the needs for advances in surgery. We have many pioneers and heroes. We hope you will enjoy this brief overview and that we have not left out any of the early contributors to our speciality. Obviously there is insufficient space to include everyone. PMID- 22443225 TI - Horseshoe tract of anal fistula: bad luck or an avoidable extension? Lessons from 82 cases. AB - AIM: The aim of this study was to analyse the characteristics of horseshoe tract formation in anal fistula. METHOD: We retrospectively analysed the data from all consecutive patients who underwent surgery for an anal fistula from November 2004 to March 2011. A horseshoe tract was defined as a circumferential extension connecting both sides of the anorectum. RESULTS: During the period of analysis, 1876 patients were operated on for a fistula. Of these, 82 (4.4%) had a horseshoe extension. The majority (72%) were male and the median age was 46 (17-84) years. The primary tract was high transsphincteric in 90% of cases and the primary opening was posterior in 65% of cases. The location of the horseshoe extension was posterior in 66% of cases with spread in the deep perianal space in 62%. In all, 71% were cryptoglandular and 24% were seen in Crohn's disease (20). Of the 62 non-Crohn's patients previous treatment was common and included surgery (42), antibiotics alone (41) and non-steroidal anti-inflammatory drugs (21). CONCLUSION: Horseshoe extension in anal fistula is uncommon. With Crohn's disease excepted, the majority had had previous treatment. PMID- 22443226 TI - Living alone and antidepressant medication use: a prospective study in a working age population. AB - BACKGROUND: An increasing proportion of the population lives in one-person households. The authors examined whether living alone predicts the use of antidepressant medication and whether socioeconomic, psychosocial, or behavioral factors explain this association. METHODS: The participants were a nationally representative sample of working-age Finns from the Health 2000 Study, totaling 1695 men and 1776 women with a mean age of 44.6 years. In the baseline survey in 2000, living arrangements (living alone vs. not) and potential explanatory factors, including psychosocial factors (social support, work climate, hostility), sociodemographic factors (occupational grade, education, income, unemployment, urbanicity, rental living, housing conditions), and health behaviors (smoking, alcohol use, physical activity, obesity), were measured. Antidepressant medication use was followed up from 2000 to 2008 through linkage to national prescription registers. RESULTS: Participants living alone had a 1.81 fold (CI = 1.46-2.23) higher purchase rate of antidepressants during the follow up period than those who did not live alone. Adjustment for sociodemographic factors attenuated this association by 21% (adjusted OR = 1.64, CI = 1.32-2.05). The corresponding attenuation was 12% after adjustment for psychosocial factors (adjusted OR = 1.71, CI = 1.38-2.11) and 9% after adjustment for health behaviors (adjusted OR = 1.74, CI = 1.41-2.14). Gender-stratified analyses showed that in women the greatest attenuation was related to sociodemographic factors and in men to psychosocial factors. CONCLUSIONS: These data suggest that people living alone may be at increased risk of developing mental health problems. The public health value is in recognizing that people who live alone are more likely to have material and psychosocial problems that may contribute to excess mental health problems in this population group. PMID- 22443227 TI - Adjuvant lithium improves the efficacy of radioactive iodine treatment in Graves' and toxic nodular disease. AB - CONTEXT: Lithium increases iodine retention in the thyroid gland and inhibits thyroid hormone release. Although lithium has been reported to improve the efficacy of radioactive iodine (RAI) treatment in Graves' disease, its role as an adjunct to RAI treatment of hyperthyroidism, particularly in toxic nodular disease, remains contentious. OBJECTIVE: To assess whether adjuvant lithium increases the efficacy of a fixed dose RAI regimen in Graves' and toxic nodular hyperthyroid patients. DESIGN AND SETTING: Retrospective cohort study in a tertiary referral centre. Two hundred and four hyperthyroid patients (163 Graves' disease, 26 toxic multinodular goitre and 15 solitary toxic thyroid adenoma). INTERVENTION: One hundred and three patients received RAI alone (median dose 558 MBq). One hundred and one patients received RAI (median dose 571 MBq) with adjuvant lithium (800 mg/day for 10 days). MAIN OUTCOME MEASURE: Proportion of patients cured at any time over a 1-year period following RAI treatment. Cure was defined as sustained (two or more sequential time points) biochemical euthyroidism or hypothyroidism during the follow-up period. RESULTS: The likelihood of cure at any time was 60% greater in all hyperthyroid patients (Graves' plus toxic nodular disease) receiving adjuvant lithium (n = 204, P = 0.003). In patients with Graves' disease receiving RAI + lithium, there was a similar occurrence in cure (n = 163, P = 0.006). Cure was twice as likely in patients with toxic nodular (non-Graves') disease receiving RAI + lithium compared with RAI alone (n = 41, P = 0.01). CONCLUSIONS: This study supports the use of adjuvant lithium to improve the efficacy of RAI in the treatment of Grave's disease and suggests a novel role in the management of toxic nodular (non Graves') disease. PMID- 22443228 TI - Current status of targeted therapies in advanced gastric cancer. AB - INTRODUCTION: In metastatic gastric cancer, chemotherapy is the standard treatment because it prolongs survival when compared to best supportive care alone. However, even after the use of more effective regimens, the overall survival remains disappointing, justifying the need for new treatment options. AREAS COVERED: Areas covered in this review include the most common molecular pathways, which have provided novel targets in gastric cancer therapy. These therapeutic strategies include EGFR inhibitors, anti-angiogenic agents, cell cycle inhibitors and apoptosis promoters. EXPERT OPINION: Several mAbs and kinase inhibitors, especially those targeting EGFR and VEGF/VEGFR, have already demonstrated promising activity in gastric cancer. The Phase III ToGA trial reported an increase in overall survival for patients with human EGF receptor (HER)2-positive gastric cancer treated with chemotherapy and trastuzumab compared to chemotherapy alone. This means that accurate HER2 testing in gastric cancer is necessary. Final data of ongoing trials with novel agents will be critical to further progress with this cancer. PMID- 22443229 TI - Application of collagen hydrogel/sponge scaffold facilitates periodontal wound healing in class II furcation defects in beagle dogs. AB - BACKGROUND AND OBJECTIVE: A three-dimensional scaffold may play an important role in periodontal tissue engineering. We prepared bio-safe collagen hydrogel, which exhibits properties similar to those of native extracellular matrix. The aim of this study was to examine the effect of implantation of collagen hydrogel/sponge scaffold on periodontal wound healing in class II furcation defects in dogs. MATERIAL AND METHODS: The collagen hydrogel/sponge scaffold was prepared by injecting collagen hydrogel, cross-linked to the ascorbate-copper ion system, into a collagen sponge. Class II furcation defects (of 5 mm depth and 3 mm width) were surgically created in beagle dogs. The exposed root surface was planed and demineralized with EDTA. In the experimental group, the defect was filled with collagen hydrogel/sponge scaffold. In the control group, no implantation was performed. Histometric parameters were evaluated 2 and 4 wk after surgery. RESULTS: At 2 wk, the collagen hydrogel/sponge scaffold displayed high biocompatibility and biodegradability with numerous cells infiltrating the scaffold. In the experimental group, reconstruction of alveolar bone and cementum was frequently observed 4 wk after surgery. Periodontal ligament tissue was also re-established between alveolar bone and cementum. Volumes of new bone, new cementum and new periodontal ligament were significantly greater in the experimental group than in the control group. In addition, epithelial down-growth was suppressed by application of collagen hydrogel. CONCLUSION: The collagen hydrogel/sponge scaffold possessed high tissue compatibility and degradability. Implantation of the scaffold facilitated periodontal wound healing in class II furcation defects in beagle dogs. PMID- 22443230 TI - Linking variability in brain chemistry and circuit function through multimodal human neuroimaging. AB - Identifying neurobiological mechanisms mediating the emergence of individual differences in behavior is critical for advancing our understanding of relative risk for psychopathology. Neuroreceptor positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) can be used to assay in vivo regional brain chemistry and function, respectively. Typically, these neuroimaging modalities are implemented independently despite the capacity for integrated data sets to offer unique insight into molecular mechanisms associated with brain function. Through examples from the serotonin and dopamine system and its effects on threat- and reward-related brain function, we review evidence for how such a multimodal neuroimaging strategy can be successfully implemented. Furthermore, we discuss how multimodal PET-fMRI can be integrated with techniques such as imaging genetics, pharmacological challenge paradigms and gene environment interaction models to more completely map biological pathways mediating individual differences in behavior and related risk for psychopathology and inform the development of novel therapeutic targets. PMID- 22443231 TI - The effect of initial local anesthetic dose with continuous interscalene analgesia on postoperative pain and diaphragmatic function in patients undergoing arthroscopic shoulder surgery: a double-blind, randomized controlled trial. AB - BACKGROUND: Interscalene block (ISB) is commonly performed using 20-40 mL of local anesthetic. Spread to adjacent structures and consequent adverse effects including paralysis of the ipsilateral hemidiaphragm are frequent. Pain ratings, analgesic requirements, adverse events, satisfaction, function and diaphragmatic excursion were compared following interscalene block (ISB) with reduced initial bolus volumes. METHODS: Subjects undergoing arthroscopic rotator cuff repair were randomized to receive 5, 10, or 20 mL ropivacaine 0.75% for ISB in a double-blind fashion (N = 36). Continuous infusion with ropivacaine 0.2% was maintained for 48 h. Pain and diaphragmatic excursion were assessed before block and in the recovery unit. RESULTS: Pain ratings in the recovery room were generally less than 4 (0-10 NRS) for all treatment groups, but a statistically significant difference was noted between the 5 and 20 mL groups (NRS: 2.67 vs. 0.62 respectively; p = 0.04). Pain ratings and supplemental analgesic use were similar among the groups at 24 h, 48 h and 12 weeks. There were no differences in the quality of block for surgical anesthesia. Dyspnea was significantly greater in the 20 mL group (p = 0.041). Subjects with dyspnea had significant diaphragmatic impairment more frequently (Relative risk: 2.5; 95%CI: 1.3-4.8; p = 0.042). Increased contralateral diaphragmatic motion was measured in 29 of the 36 subjects. Physical shoulder function at 12 weeks improved over baseline in all groups (baseline mean SST: 6.3, SEM: 0.6; 95%CI: 5.1-7.5; 12 week mean SST: 8.2, SEM: 0.46; 95%CI: 7.3-9.2; p = 0.0035). CONCLUSIONS: ISB provided reliable surgical analgesia with 5 mL, 10 mL or 20 mL ropivacaine (0.75%). The 20 mL volume was associated with increased complaints of dyspnea. The 5 mL volume was associated with statistically higher pain scores in the immediate postoperative period. Lower volumes resulted in a reduced incidence of dyspnea compared to 20 mL, however diaphragmatic impairment was not eliminated. Compensatory increases in contralateral diaphragmatic movement may explain tolerance for ipsilateral paresis. TRIAL REGISTRATION: clinicaltrials.gov. identifier: NCT00672100. PMID- 22443232 TI - Three-hindered quadrant phosphine ligands with an aromatic ring backbone for the rhodium-catalyzed asymmetric hydrogenation of functionalized alkenes. AB - The three-hindered quadrant phosphine ligands (R)-1-tert-butylmethylphosphino-2 (di-tert-butylphosphino)benzene ((R)-3H-BenzP*) and (R)-2-tert butylmethylphosphino-3-(di-tert-butylphosphino)quinoxaline ((R)-3H-QuinoxP*) exhibited good to excellent enantioselectivities in the rhodium-catalyzed asymmetric hydrogenation of selected dehydroamino acid derivatives, enamides, and ethenephosphonates. PMID- 22443233 TI - Effect of unialgal diets on the composition of fatty acids and sterols in juvenile ark shell Tegillarca granosa Linnaeus. AB - This study has investigated the effects of six different unialgal diets ( Chaetoceros calcitrans , Platymonas helgolandica , Chlorella sp., Isochrysis galbana , Nannochloropsis oculata , and Pavlova viridis ) on the composition of fatty acids and sterols in juvenile ark shell Tegillarca granosa Linnaeus. The best feeding effects on the growth of shellfish were found in C. calcitrans, followed by I. galbana and P. viridis, whereas Chlorella sp. and N. oculata exhibited relatively poor effects. The fatty acid and sterol compositions in the six microalgae and the juvenile ark shell after feeding were analyzed, and 39 fatty acids and 18 sterols were identified. Although the results demonstrate a close correlation between the sterol compositions in algal species and juvenile ark shell, a similar correlation was not observed between fatty acids. In the juvenile ark shell fed microalgae, the ratio of total saturated fatty acids (SFA) rapidly decreases, whereas the proportion of total polyunsaturated fatty acids (PUFAs) increases considerably. The abundances of AA, EPA, and DHA increase most significantly in shellfish with better growth (fed C. calcitrans, I. galbana, and P. viridis). The number of sterol species is reduced, but the total sterol content in groups fed corresponding microalgae increases, and abundant plant sterols, instead of cholesterol, are accumulated in juvenile ark shell fed appropriate microalgae I. galbana and P. viridis. Therefore, to be more conducive to human health, I. galbana and P. viridis, of the six experimental microalgae, are recommended for artificial ark shell culture. PMID- 22443234 TI - Chronic histiocytic intervillositis with cytomegalovirus placentitis in a case of hydrops fetalis. AB - Chronic histiocytic intervillositis (CHI) is an infrequent inflammatory placental disorder associated with unfavorable pregnancy outcomes and a high rate of recurrence. This disorder is thought to reflect a maternal delayed hypersensitivity response to fetal antigen(s) in placental tissue. We report a case of a 20-week-gestation hydropic fetus in which the placenta showed chronic histiocytic intervillositis with cytomegalovirus placentitis. Immunophenotyping studies supported a delayed hypersensitivity response. This is the first report of these two diseases co-occurring, raising the possibility of a relationship between chronic histiocytic intervillositis and infection. Chronic histiocytic intervillositis may represent an idiosyncratic immune response, in this case to cytomegalovirus. PMID- 22443235 TI - Defining and detecting malaria epidemics in south-east Iran. AB - BACKGROUND: A lack of consensus on how to define malaria epidemics has impeded the evaluation of early detection systems. This study aimed to develop local definitions of malaria epidemics in a known malarious area of Iran, and to use that definition to evaluate the validity of several epidemic alert thresholds. METHODS: Epidemic definition variables generated from surveillance data were plotted against weekly malaria counts to assess which most accurately labelled aberrations. Various alert thresholds were then generated from weekly counts or log counts. Finally, the best epidemic definition was used to calculate and compare sensitivities, specificities, detection delays, and areas under ROC curves of the alert thresholds. RESULTS: The best epidemic definition used a minimum duration of four weeks and week-specific and overall smoothed geometric means plus 1.0 standard deviation. It defined 13 epidemics. A modified C-SUM alert of untransformed weekly counts using a threshold of mean+0.25 SD had the highest combined sensitivity and specificity. Untransformed C-SUM alerts also had the highest area under the ROC curve. CONCLUSIONS: Defining local malaria epidemics using objective criteria facilitated the evaluation of alert thresholds. This approach needs further study to refine epidemic definitions and prospectively evaluate epidemic alerts. PMID- 22443236 TI - Photoionization-induced water migration in the hydrated trans-formanilide cluster cation revealed by gas-phase spectroscopy and ab initio molecular dynamics simulation. AB - Photoionization-induced water migration in the trans-formanilide-water 1:1 cluster, FA-(H(2)O)(1), has been investigated by using IR-dip spectroscopy, quantum chemical calculations, and ab initio molecular dynamics simulations. In the S(0) state, FA-(H(2)O)(1) has two structural isomers, FA(NH)-(H(2)O)(1) and FA(CO)-(H(2)O)(1), where a water molecule is hydrogen-bonded (H-bonded) to the NH group and the CO group, respectively. In addition, the S(1)-S(0) origin transition of FA(CO)-(H(2)O)(2), where a water dimer is H-bonded to the CO group, was observed only in the [FA-(H(2)O)(1)](+) mass channel, indicating that one of the water molecules evaporates completely in the D(0) state. These results are consistent with a previous report [Robertson, E. G. Chem. Phys. Lett., 2000, 325, 299]. In the D(0) state, however, [FA-(H(2)O)(1)](+) produced by photoionization via the S(1)-S(0) origin transitions of FA(NH)-(H(2)O)(1) and FA(CO)-(H(2)O)(1) shows essentially the same IR spectra. Compared with the theoretical calculations, [FA-(H(2)O)(1)](+) can be assigned to [FA(NH)-(H(2)O)(1)](+). This means that the water molecule in [FA-(H(2)O)(1)](+) migrates from the CO group to the NH group when [FA-(H(2)O)(1)](+) is produced by photoionization of FA(CO) (H(2)O)(1). [FA-(H(2)O)(1)](+) produced by photoionization of FA(CO)-(H(2)O)(2) also shows the IR spectrum corresponding to [FA(NH)-(H(2)O)(1)](+). In this case, the water migration from the CO group to the NH group occurs with the evaporation of a water molecule. Ab initio molecular dynamics simulations revealed the water migration pathway in [FA-(H(2)O)(1)](+). The calculations of classical electrostatic interactions show that charge-dipole interaction between FA(+) and H(2)O induces an initial structural change in [FA-(H(2)O)(1)](+). An exchange repulsion between the lone pairs of the CO group and H(2)O in [FA-(H(2)O)(1)](+) also affects the initial direction of the water migration. These two factors play important roles in determining the initial water migration pathway. PMID- 22443237 TI - Identification of Leishmania infantum chagasi proteins in urine of patients with visceral leishmaniasis: a promising antigen discovery approach of vaccine candidates. AB - Visceral leishmaniasis (VL) is a serious lethal parasitic disease caused by Leishmania donovani in Asia and by Leishmania infantum chagasi in southern Europe and South America. VL is endemic in 47 countries with an annual incidence estimated to be 500,000 cases. This high incidence is due in part to the lack of an efficacious vaccine. Here, we introduce an innovative approach to directly identify parasite vaccine candidate antigens that are abundantly produced in vivo in humans with VL. We combined RP-HPLC and mass spectrometry and categorized three L. infantum chagasi proteins, presumably produced in spleen, liver and bone marrow lesions and excreted in the patients' urine. Specifically, these proteins were the following: Li-isd1 (XP_001467866.1), Li-txn1 (XP_001466642.1) and Li ntf2 (XP_001463738.1). Initial vaccine validation studies were performed with the rLi-ntf2 protein produced in Escherichia coli mixed with the adjuvant BpMPLA-SE. This formulation stimulated potent Th1 response in BALB/c mice. Compared to control animals, mice immunized with Li-ntf2+ BpMPLA-SE had a marked parasite burden reduction in spleens at 40 days post-challenge with virulent L. infantum chagasi. These results strongly support the proposed antigen discovery strategy of vaccine candidates to VL and opens novel possibilities for vaccine development to other serious infectious diseases. PMID- 22443238 TI - Evaluation of end-capped DNA modules for pRNA capture and functionalization. AB - The ability of packaging RNA (pRNA) from the phi29 DNA packaging motor to form nanoassemblies and nanostructures has been exploited for the development of the nascent field of RNA nanotechnology and subsequent applications in nanomedicine. For applications in nanomedicine, it is necessary to modify the pRNA structure for the conjugation of active molecules. We have investigated end-capped double stranded DNA segments as reversible capture reagents for pRNA. These capture agents can be designed to allow the conjugation of any desired molecule for pRNA functionalization. The results of model studies presented in this report show that 5- to 7-nucleotide overhangs on a target RNA can provide efficient handles for the high-affinity association to capped double-stranded DNA. PMID- 22443239 TI - New anticoagulant drugs for treatment of venous thromboembolism and stroke prevention in atrial fibrillation. AB - Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) and atrial fibrillation are common conditions in Western countries. The mainstay of treatment and prevention for these diseases is fast-acting anticoagulant drugs such as heparins and vitamin K antagonists. The use of these drugs is, however, complex and demanding for both patients and physicians. Recently, new antithrombotic drugs that act directly by inhibiting activated coagulation factors such as factor X or thrombin have been developed and investigated in phase III clinical trials. The aim of this article is to review: (i) the need to develop new drugs; (ii) their efficacy/safety as demonstrated in clinical trials; (iii) the need for laboratory monitoring and (iv) the direction towards the use of these new drugs in the real-life clinical situation. PMID- 22443240 TI - Insight in schizophrenia: from conceptualization to neuroscience. AB - Lack of insight into illness is a prevalent and distinguishing feature of schizophrenia, which has a complex history and has been given a variety of definitions. Currently, insight is measured and treated as a multidimensional phenomenon, because it is believed to result from psychological, neuropsychological and organic factors. Thus, schizophrenia patients may display dramatic disorders including demoralization, depression and a higher risk of suicide, all of which are directly or indirectly related to a lack of insight into their illness, and make the treatment difficult. To improve the treatment of people with schizophrenia, it is thus crucial to advance research on insight into their illness. Insight is studied in a variety of ways. Studies may focus on the relationship between insight and psychopathology, may view behavioral outcomes or look discretely at the cognitive dysfunction versus anatomy level of insight. All have merit but they are dispersed across a wide body of literature and rarely are the findings integrated and synthesized in a meaningful way. The aim of this study was to synthesize findings across the large body of literature dealing with insight, to highlight its multidimensional nature, measurement, neuropsychology and social impact in schizophrenia. The extensive literature on the cognitive consequences of lack of insight and the contribution of neuroimaging techniques to elucidating neurological etiology of insight deficits, is also reviewed. PMID- 22443241 TI - Predictors of dropout among personality disorders in a specialist outpatients psychosocial treatment: a preliminary study. AB - AIM: The aim of this study was to identify factors that may affect treatment retention in a 1-year psychosocial program for adult personality disorders. METHODS: The sample consists of patients admitted to the Adult Personality Disorder Outpatient Programme of the Bologna Community Mental Health Centre in the period 2003-2008. At the beginning of the program, patients were evaluated through a comprehensive assessment including sociodemographic form, diagnostic interviews and self-report questionnaires. Patients who dropped out from treatment were retrospectively compared with patients who completed the program. RESULTS: Out of 39 patients enrolled in the program, 20 (51.3%) dropped out and 19 (48.7%) completed the treatment. Out of 20 patients who dropped out, 14 terminated the treatment within the first 2 months. The dropout group and the group which remained showed significant differences in diagnosis (borderline personality disorder [BPD]), demographic data (age, time from first contact with psychiatric services), clinical variable (impulsiveness) and subjective experience (motivation, treatment expectation, therapeutic relation perception and barriers to access). BPD and subjective evaluation were found to be predictors of premature termination in the sample. In detail, BPD patients who experienced a less satisfactory therapeutic relationship and reported many external problems were more likely to drop out of the program. CONCLUSION: Important factors contributing to dropout were identified, with potential implication for clinical practice. Further efforts need to be made to find ways to retain BPD patients who find the first subjective experience of the service more problematic. PMID- 22443242 TI - Influence of self-efficacy on the interpersonal behavior of schizophrenia patients undergoing rehabilitation in psychiatric day-care services. AB - AIM: The present study examined whether the self-efficacy of interpersonal behavior influenced the interpersonal behavior of schizophrenia patients using psychiatric day-care services. METHODS: Thirty-nine patients with schizophrenia were examined with the Interpersonal Relations subscale of the Life Assessment Scale for Mentally Ill, the Self-efficacy Scale of Interpersonal Behavior, the Brief Assessment of Cognition in Schizophrenia-Japanese version, and the Positive and Negative Syndrome Scale. RESULTS: The Life Assessment Scale for Mentally Ill score was significantly correlated with the self-efficacy of interpersonal behavior, and was also significantly correlated with neurocognitive functions and negative symptoms. However, the Self-efficacy Scale of Interpersonal Behavior score was not correlated with neurocognitive functions and negative symptoms. To examine the causal correlations between the above social, psychological and clinical factors, multiple regression analysis was performed with the self efficacy of interpersonal behavior, neurocognitive functions, and negative symptoms as the independent variables and interpersonal behavior as the dependent variable. The self-efficacy of interpersonal behavior was found to contribute to interpersonal behavior as well as neurocognitive functions. CONCLUSION: The self efficacy of interpersonal behavior contributed to the interpersonal behavior as well as the neurocognitive functions in the case of schizophrenia patients in the community. This suggested that interventions targeting the self-efficacy of interpersonal behavior, as well as those targeting neurocognitive functions, were important to improve the interpersonal behavior of schizophrenia patients undergoing psychiatric rehabilitation in the community. PMID- 22443243 TI - Psychological health and coping strategy among survivors in the year following the 2008 Wenchuan earthquake. AB - AIM: The powerful earthquake of 12 May 2008 wrought incalculable havoc on lives and properties in Wenchuan, Sichuan Province, China. The catastrophic earthquake not only created tremendous changes in the external environment, but also caused stress and difficulties for the people in the affected areas which were felt long after the event. In this study, we attempt to clarify the correlation between coping strategies and psychological well-being among survivors across sex and levels of exposure. METHOD: A total of 2080 survivors from 19 counties freely participated in the survey which used self-report psychological questionnaires, the Short Form-12, version 2 Scale and Coping Scales. We estimated regression models to identify the coping factors associated with the presence of mental symptoms after the disaster. RESULTS: Four main factors (middle-age, low educational level, low monthly income, and high exposure) were significantly related to poor health. Highly exposed survivors tended to problem-avoidance, fantasy, self-blame and seeking assistance, which was significantly different to those lowly exposed. Women tended to be more vulnerable than men and exhibited problem-avoidance and self-blame. Six coping styles were significant determinants and predicted 64.2% of health. CONCLUSION: Post-disaster mental health recovery intervention, including early identification, ongoing monitoring, sustained psychosocial support and more mental health services, are required for the high risk population, especially for women. PMID- 22443244 TI - Changes in oxidative stress and cellular immunity serum markers in attention deficit/hyperactivity disorder. AB - AIMS: Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder with an etiopathogeny not fully understood. According to the prevailing view, the main factors contributing to the disorder are prefrontal dopamine deficiency and central dopaminergic dysfunction, but the factors/mechanisms involved in the brain dysfunction and its consequences are not well known. We suggest that changes in oxidative metabolism and cellular immunity may be involved. In this study, we aimed to investigate whether there are associations between ADHD and changes in serum levels of nitric oxide synthase (NOS), xanthine oxidase (XO), glutathione S-transferase (GST) and paraoxonase-1 (PON-1) activities, which are important markers of oxidative stress, and adenosine deaminase (ADA) activity, marker of cellular immunity. METHODS: The study sample consisted of 35 child or adolescent patients diagnosed with ADHD according to DSM-IV-TR criteria. Thirty five healthy subjects were also included in the study as controls. Venous blood samples were collected, and NOS, XO, GST, PON-1 and ADA activities were measured. RESULTS: NOS, XO and ADA activities of the patients were significantly higher than those of the controls. GST and PON-1 activities of the patients were significantly lower than those of the controls. CONCLUSIONS: Changes in oxidative metabolism and cellular immunity may have a role in the etiopathogenesis of ADHD. PMID- 22443245 TI - Validation of apathy evaluation scale and assessment of severity of apathy in Alzheimer's disease. AB - AIM: Apathy is a well-recognized symptom of Alzheimer's disease (AD). The aim of the present study was to validate the Taiwanese version of the Apathy Evaluation Scale, clinician version (AES-C) and assess the severity of apathy in patients with AD. METHODS: Comprehensive evaluations were conducted in a total of 144 AD patients. This study used a cross-sectional comparative design. Data were collected from clinical interviews using the AES, the Mini-Mental Status Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the Clinical Dementia Rating Scale (CDR). RESULTS: Internal consistency was indicated by Cronbach's alphas of 0.85; test-retest reliability was 0.89 over a period of 3 days. Criterion-related validity was supported by the fact that AES-C significantly correlated with the apathy scores of the NPI. Factor analysis indicated a three-factor structure. Convergent validity was supported by a positive correlation between the AES-C score and the anxiety score of the NPI. Discriminant validity was supported by the fact that the AES-C scores did not correlate with the depression subscale of the NPI, and the correlation between the AES-C score and the euphoria score of the NPI score was negative. Known-group validity was supported by results showing that AD patients in a moderate stage of dementia (CDR = 2) had significantly higher scores on the AES-C than patients with mild-stage dementia (CDR = 1). CONCLUSION: The AES-C is a reliable and valid instrument for measuring symptoms of apathy among AD patients in Taiwan. PMID- 22443246 TI - Cognitive changes in topiramate-treated patients with alcoholism: a 12-week prospective study in patients recently detoxified. AB - AIMS: The aim of this study was to determine the 12-week cognitive changes in topiramate-treated patients recently detoxified from alcohol. METHODS: Participants were inpatients with DSM-IV alcohol dependence. All of them were discharged within 14 days after the initiation of topiramate treatment. The topiramate dose range was 50-300 mg/day. The Montreal Cognitive Assessment (MoCA) was used on day 0, day 29, day 57, and day 85. Differences of the MoCA total and seven subtest scores among four time-points were compared. RESULTS: Thirty-eight participants (36 men and two women) had a mean +/- SD age of 43.1 +/- 8.6 years old. At enrollment, they were abstinent for a mean +/- SD of 11.5 +/- 5.3 days. Five, one, and three patients dropped out of the study on day 29, day 57, and day 85, respectively. On day 85, the mean +/- SD dose of topiramate was 253.1 +/- 60.8 mg/day. Alcohol consumption decreased drastically during follow up. At each time-point, 75%-80% of the participants were continuous abstainers. The mean +/- SD MoCA total, language subtest, and delayed recall subtest scores increased significantly from day 0 to day 85, from 22.0 +/- 4.7 to 24.7 +/- 3.4 (P < 0.01), from 1.1 +/- 1.0 to 1.3 +/- 1.0 (P = 0.03), and from 2.7 +/- 1.7 to 4.1 +/- 1.0 (P < 0.01), respectively. CONCLUSION: Topiramate-treated patients recently detoxified from alcohol usually have an improvement of their cognitive function, especially in the language and delayed recall domains. This phenomenon may be caused by the greater influence of cognitive recovery associated with decreased drinking as compared with topiramate-induced cognitive impairment. PMID- 22443247 TI - Electroconvulsive therapy can improve psychotic symptoms in anti-NMDA-receptor encephalitis. PMID- 22443248 TI - Recognizing hypomania symptoms in the current expanses of depression in Japanese clinical practices. PMID- 22443249 TI - Depressive state due to isolated adrenocorticotropic hormone deficiency underlies school refusal. PMID- 22443250 TI - Improvement in QTc prolongation induced by zotepine following a switch to perospirone. PMID- 22443251 TI - Diphenhydramine overdose and serotonin syndrome. PMID- 22443252 TI - Hyperhidrosis under combination of zotepine and haloperidol alleviated by aripiprazole. PMID- 22443253 TI - Sulpiride-associated torsade de pointes in a woman with bipolar disorder. PMID- 22443254 TI - Large bowel obstruction due to colorectal carcinoma can be safely treated by colonic stent insertion--case series from a UK district general hospital. AB - AIM: The aim of this study is to audit our outcomes and experience of colonic stent insertion for malignant bowel obstruction. METHOD: Retrospective audit of all stent insertions in a single district general hospital between August 2003 and December 2009. All patients had presented with acute bowel obstruction caused by malignant colorectal disease and details were collected prospectively and contemporaneously onto a database. Stent insertion was a combined endoscopic and fluoroscopic procedure involving a colorectal surgeon and consultant radiologist. RESULTS: Stenting was attempted on 62 occasions in 54 patients. The technical success rate was 86% and the clinical success rate 84%. The indications for stenting were for relief of acute bowel obstruction, palliation and as a bridge to surgery. There were complications in 14 cases (22.5%) including three perforations and one perioperative mortality. There were three cases of stent migration, six cases of re-stenosis and two stents became impacted with stool. There were no incidents of acute or delayed haemorrhage in any patients. CONCLUSION: Our experience shows that stenting for obstructing colorectal cancer is a safe and effective method of alleviating acute and impending bowel obstruction and can be provided safely and effectively in a district general hospital. PMID- 22443256 TI - Heavy metals in toys and low-cost jewelry: critical review of U.S. and Canadian legislations and recommendations for testing. AB - High metal contamination in toys and low-cost jewelry is a widespread problem, and metals can become bioavailable, especially via oral pathway due to common child-specific behaviors of mouthing and pica. In this review, the U.S., Canadian, and European Union (EU) legislations on metals in toys and jewelry are evaluated. A literature review on content, bioavailability, children's exposure, and testing of metals in toys and low-cost jewelry is provided. A list of priority metals is presented, and research needs and legislative recommendations are addressed. While the U.S. and Canadian legislations put emphasis on lead exposure prevention, other toxic elements like arsenic and cadmium in toy materials are not regulated except in paint and coatings. The EU legislation is more comprehensive in terms of contaminants and scientific approach. Current toy testing procedures do not fully consider metal bioavailability. In vitro bioaccessibility tests developed and validated for toys and corresponding metal bioaccessibility data in different toy matrices are lacking. The U.S. and Canadian legislations should put more emphasis on metal bioavailability and on other metals in addition to lead. A two-step management approach with mandatory testing of toys for total metal concentrations followed by voluntary bioaccessibility testing could be implemented. PMID- 22443255 TI - Cervical cancer screening by visual inspection in Cote d'Ivoire, operational and clinical aspects according to HIV status. AB - BACKGROUND: Cervical cancer screening is not yet standard of care of women attending HIV care clinics in Africa and presents operational challenges that need to be addressed. METHODS: A cervical cancer screening program based on visual inspection methods was conducted in clinics providing antiretroviral treatment (ART) in Abidjan, Cote d'Ivoire. An itinerant team of midwives was in charge of proposing cervical cancer screening to all HIV-positive women enrolled in ART clinics as well as to HIV-negative women who were attending the Abidjan national blood donor clinic. Positively screened women were systematically referred to a colposcopic examination. A phone-based tracking procedure was implemented to reach positively screened women who did not attend the medical consultation. The association between HIV status and cervical cancer screening outcomes was estimated using a multivariate logistic model. RESULTS: The frequency of positive visual inspection was 9.0% (95% CI 8.0-10.0) in the 2,998 HIV-positive women and 3.9% (95% CI 2.7-5.1) in the 1,047 HIV-negative ones (p < 10-4). In multivariate analysis, HIV infection was associated with a higher risk of positive visual inspection [OR = 2.28 (95% CI 1.61-3.23)] as well as more extensive lesions involving the endocervical canal [OR = 2.42 (95% CI 1.15 5.08)]. The use of a phone-based tracking procedure enabled a significant reduction of women not attending medical consultation after initial positive screening from 36.5% to 19.8% (p < 10-4). CONCLUSION: The higher frequency of positive visual inspection among HIV-positive women supports the need to extend cervical cancer screening program to all HIV clinics in West Africa. Women loss to follow-up after being positively screened is a major concern in cervical screening programs but yet, partly amenable to a phone tracking procedure. PMID- 22443257 TI - Polycystic ovary syndrome is not associated with polymorphisms of the TCF7L2, CDKAL1, HHEX, KCNJ11, FTO and SLC30A8 genes. AB - OBJECTIVE: Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Recently, genome-wide association studies have reported a number of single-nucleotide polymorphisms (SNPs) with reproducible associations and susceptibilities to type 2 diabetes. We examined the potential association between the diabetogenic genes uncovered in the genome-wide association studies and PCOS in Korean women. DESIGN: Case-control study. PATIENTS: Women with or without PCOS. MEASUREMENTS: DNA samples from 377 patients with PCOS and 386 age matched controls were genotyped. RESULTS: None of the 12 SNPs in the six genes (KCNJ11, TCF7L2, SLC30A8, HHEX, FTO and CDKAL1) uncovered in the genome-wide association studies were associated with PCOS. For further analysis, the patients with PCOS were divided into two or three subgroups according to genotype, and the associations between the genotypes and insulin resistance or insulin secretory capacity were assessed. No SNPs were significantly associated with HOMA-IR, HOMA (betacell) (%), or 2-h 75-g oral glucose tolerance test insulin levels in the patients with PCOS; there were no significant associations with other serum hormonal and metabolic markers, such as androgen or glucose levels. CONCLUSIONS: Our results suggest that the six type 2 diabetes-associated genes identified in genome-wide association studies are not associated with PCOS. PMID- 22443258 TI - Oral tyrosine kinase inhibitors in the first-line treatment of advanced non-small cell lung cancer. AB - INTRODUCTION: In EGFR mutated advanced NSCLC, tyrosine kinase inhibitors are new valid options as first-line treatment. Gefitinib appears a valid alternative to chemotherapy as first-line therapy, in EGFR mutated elderly or unfit patients too, while erlotinib remains an option for subsequent lines of treatment. AREAS COVERED: Areas covered in this review include two international trials, which evaluated erlotinib in chemo-naive EGFR mutated patients both in an Asian and caucasian population, showing a dramatic advantage in terms of progression-free survival and overall response rate as well as gefitinib. Results showed a good safety profile, with side effects of mild to moderate intensity, usually manageable with temporary interruption of treatment. EXPERT OPINION: Investigating EGFR mutations is critical in order to obtain sufficient data. It has now become mandatory for molecular characterization, as part of baseline diagnostic procedures. This approach is also becoming increasingly important during progression of the disease as a sort of 'molecular follow up'. It plays a central role in the right choice of treatment, in an aim to give the best drug to the right patients, overcoming other well known prognostic factors. PMID- 22443259 TI - Is there a U-shaped curve of A1c versus mortality? PMID- 22443260 TI - Enantioselective conjugate addition of both aromatic ketones and acetone to nitroolefins catalyzed by chiral primary amines bearing multiple hydrogen-bonding donors. AB - A new class of chiral primary amine catalysts bearing multiple hydrogen-bonding donors have been designed and synthesized. The newly developed bifunctional organocatalysts efficiently catalyzed not only enantioselective conjugate addition of aromatic ketones to nitroolefins in good yields (up to 87%) with excellent enantioselectivities (97->99% ee) but also enantioselective conjugate addition of acetone to nitroolefins in excellent yields (90-96%) with high enantioselectivities (up to 97% ee). PMID- 22443261 TI - Standard guidelines for the chromosome-centric human proteome project. AB - The objective of the international Chromosome-Centric Human Proteome Project (C HPP) is to map and annotate all proteins encoded by the genes on each human chromosome. The C-HPP consortium was established to organize a collaborative network among the research teams responsible for protein mapping of individual chromosomes and to identify compelling biological and genetic mechanisms influencing colocated genes and their protein products. The C-HPP aims to foster the development of proteome analysis and integration of the findings from related molecular -omics technology platforms through collaborations among universities, industries, and private research groups. The C-HPP consortium leadership has elicited broad input for standard guidelines to manage these international efforts more efficiently by mobilizing existing resources and collaborative networks. The C-HPP guidelines set out the collaborative consensus of the C-HPP teams, introduce topics associated with experimental approaches, data production, quality control, treatment, and transparency of data, governance of the consortium, and collaborative benefits. A companion approach for the Biology and Disease-Driven HPP (B/D-HPP) component of the Human Proteome Project is currently being organized, building upon the Human Proteome Organization's organ-based and biofluid-based initiatives (www.hupo.org/research). The common application of these guidelines in the participating laboratories is expected to facilitate the goal of a comprehensive analysis of the human proteome. PMID- 22443262 TI - Synthesis and antifungal activities of carabrol ester derivatives. AB - Thirty-eight new ester derivatives of carabrol were designed, synthesized, and characterized by (1)H and (13)C NMR and HR-ESI-MS. Their antifungal activities against the fungal pathogen Colletotrichum lagenarium were evaluated using a spore germination assay. Of these 38 ester derivatives, 16 showed higher antifungal activity than that of carabrol and 7 showed higher antifungal activity than that of carabrone. It was found that the C-4 position of carabrol was a key position involving its antifungal activity, which showed the variation of 50% inhibition concentration (IC(50)) from 2.70 to 52.33 MUg/mL. When substituted by the phenyl ring, the ester derivatives with electron-attracting groups showed higher activity than those with electron-donating ones. Two ester derivatives, carabryl 4-cynaobenzoate (II-17, IC(50) 2.70 MUg/mL) and carabryl 4 isopropylbenzoate (II-27, IC(50) 2.82 MUg/mL), showed only slightly lower antifungal activity than that of the positive control chlorothalonil (IC(50) 0.87 MUg/mL) and have been identified as promising leads for development of new environmentally friendly fungicides. PMID- 22443263 TI - Phenotyping for abiotic stress tolerance in maize. AB - The ability to quickly develop germplasm having tolerance to several complex polygenic inherited abiotic and biotic stresses combined is critical to the resilience of cropping systems in the face of climate change. Molecular breeding offers the tools to accelerate cereal breeding; however, suitable phenotyping protocols are essential to ensure that the much-anticipated benefits of molecular breeding can be realized. To facilitate the full potential of molecular tools, greater emphasis needs to be given to reducing the within-experimental site variability, application of stress and characterization of the environment and appropriate phenotyping tools. Yield is a function of many processes throughout the plant cycle, and thus integrative traits that encompass crop performance over time or organization level (i.e. canopy level) will provide a better alternative to instantaneous measurements which provide only a snapshot of a given plant process. Many new phenotyping tools based on remote sensing are now available including non-destructive measurements of growth-related parameters based on spectral reflectance and infrared thermometry to estimate plant water status. Here we describe key field phenotyping protocols for maize with emphasis on tolerance to drought and low nitrogen. PMID- 22443264 TI - Apert syndrome with fused thalami. AB - Apert syndrome (Acrocephalosyndactyly type I; AS) is a rare but well-known autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, bony/cutaneous syndactyly of fingers and toes as well as a variety of associated congenital anomalies involving the brain, heart, limbs and other organ systems. We report the case of a fetus with molecularly confirmed Apert syndrome and additional fusion of the thalamic nuclei. Various central nervous system anomalies, have been reported in patients with AS. However, as far as we know cases of fused thalami in Apert syndrome have never been reported so far. PMID- 22443265 TI - Models of long-distance transport: how is carrier-dependent auxin transport regulated in the stem? AB - * This paper presents two models of carrier-dependent long-distance auxin transport in stems that represent the process at different scales. * A simple compartment model using a single constant auxin transfer rate produced similar data to those observed in biological experiments. The effects of different underlying biological assumptions were tested in a more detailed model representing cellular and intracellular processes that enabled discussion of different patterns of carrier-dependent auxin transport and signalling. * The output that best fits the biological data is produced by a model where polar auxin transport is not limited by the number of transporters/carriers and hence supports biological data showing that stems have considerable excess capacity to transport auxin. * All results support the conclusion that auxin depletion following apical decapitation in pea (Pisum sativum) occurs too slowly to be the initial cause of bud outgrowth. Consequently, changes in auxin content in the main stem and changes in polar auxin transport/carrier abundance in the main stem are not correlated with axillary bud outgrowth. PMID- 22443266 TI - Low coverage of intermittent preventive treatment for malaria in pregnancy in Nigeria: demand-side influences. AB - BACKGROUND: Nigeria instituted intermittent preventive treatment for malaria (IPTp) using sulphadoxine-pyrimethamine (SP) for pregnant women in 2001, but coverage remains low. This study examined the influence of demand side factors on IPTp coverage. METHODS: Data were collected using a household survey from 1307 women who were delivered of a live baby within the one-year period preceding the study and through an exit poll from 146 women attending antenatal clinics (ANC). Data analysis examined coverage based on the national and WHO guidelines for IPTp delivery which differ with regards to use of IPTp in the last month of pregnancy. Focus group discussions (FGDs) were undertaken to further explain demand side constraints to coverage. RESULTS: From the household survey, 96.1% of respondents attended ANC, with most having five or more visits. Overall IPTp coverage for the first and second doses was 13.7% and 7.3% respectively. The coverage was higher in the urban areas compared to rural areas (p < 0.01). Amongst women who could have received IPTp based on the timing of their attendance, only 14.1% and 14.3% were offered the first dose based on national and WHO guidelines, while 7.7% and 7.5% were offered the second dose respectively giving significant missed opportunities. Amongst ANC attendees offered first and second doses, 98.9% and 96.9% respectively took the medicine. Only 13.6% and 21.5% of these clients reported taking the drug under direct observation. The low level of coverage was confirmed by exit survey data, which found coverage of 11.6% and 3.0% for the first and second doses. The FGDs revealed that women do not have many concerns about side effects, but they take drugs providers give them because they believe such drugs must be safe. CONCLUSION: This study found low coverage of IPTp and high levels of missed opportunities supporting findings that high ANC attendance does not guarantee high IPTp coverage. Demand side factors such as ANC attendance, appropriate timing of attendance, and perceptions about side effects were not constraining factors to increased coverage, raising the need to examine supply side factors. PMID- 22443267 TI - Linear and non-linear QSAR modelling of juvenile hormone esterase inhibitors. AB - A tight control of juvenile hormone (JH) titre is crucial during the life cycle of a holometabolous insect. JH metabolism is made through the action of enzymes, particularly the juvenile hormone esterase (JHE). Trifluoromethylketones (TFKs) are able to inhibit this enzyme to disrupt the endocrine function of the targeted insect. In this context, a set of 96 TFKs, tested on Trichoplusia ni for their JHE inhibition, was split into a training set (n = 77) and a test set (n = 19) to derive a QSAR model. TFKs were initially described by 42 CODESSA (Comprehensive Descriptors for Structural and Statistical Analysis) descriptors, but a feature selection process allowed us to consider only five descriptors encoding the structural characteristics of the TFKs and their reactivity. A classical and spline regression analysis, a three-layer perceptron, a radial basis function network and a support vector regression were experienced as statistical tools. The best results were obtained with the support vector regression (r(2) and r(test)(2) = 0.91). The model provides information on the structural features and properties responsible for the high JHE inhibition activity of TFKs. PMID- 22443268 TI - Immigrant status and increased risk of heart failure: the role of hypertension and life-style risk factors. AB - BACKGROUND: Studies from Sweden have reported association between immigrant status and incidence of cardiovascular diseases. The nature of this relationship is unclear. We investigated the relationship between immigrant status and risk of heart failure (HF) hospitalization in a population-based cohort, and to what extent this is mediated by hypertension and life-style risk factors. We also explored whether immigrant status was related to case-fatality after HF. METHODS: 26,559 subjects without history of myocardial infarction (MI), stroke or HF from the community-based Malmo Diet and Cancer (MDC) cohort underwent a baseline examination during 1991-1996. Incidence of HF hospitalizations was monitored during a mean follow-up of 15 years. RESULTS: 3,129 (11.8%) subjects were born outside Sweden. During follow-up, 764 subjects were hospitalized with HF as primary diagnosis, of whom 166 had an MI before or concurrent with the HF. After adjustment for potential confounding factors, the hazard ratios (HR) for foreign born were 1.37 (95% CI: 1.08-1.73, p = 0.009) compared to native Swedes, for HF without previous MI. The results were similar in a secondary analysis without censoring at incident MI. There was a significant interaction (p < 0.001) between immigrant status and waist circumference (WC), and the increased HF risk was limited to immigrants with high WC. Although not significant foreign-born tended to have lower one-month and one-year mortality after HF. CONCLUSIONS: Immigrant status was associated with long-term risk of HF hospitalization, independently of hypertension and several life-style risk factors. A significant interaction between WC and immigrant status on incident HF was observed. PMID- 22443269 TI - Rice RNA-dependent RNA polymerase 6 acts in small RNA biogenesis and spikelet development. AB - Higher plants have evolved multiple RNA-dependent RNA polymerases (RDRs), which work with Dicer-like (DCL) proteins to produce different classes of small RNAs with specialized molecular functions. Here we report that OsRDR6, the rice (Oryza sativa L.) homolog of Arabidopsis RDR6, acts in the biogenesis of various types and sizes of small RNAs. We isolated a rice osrdr6-1 mutant, which was temperature sensitive and showed spikelet defects. This mutant displays reduced accumulation of tasiR-ARFs, the conserved trans-acting siRNAs (tasiRNAs) derived from the TAS3 locus, and ectopic expression of tasiR-ARF target genes, the Auxin Response Factors (including ARF2 and ARF3/ETTIN). The loss of tasiR-mediated repression of ARFs in osrdr6-1 can explain its morphological defects, as expression of two non-targeted ARF3 gene constructs (ARF3muts) in a wild-type background mimics the osrdr6 and osdcl4-1 mutant phenotypes. Small RNA high throughput sequencing also reveals that besides tasiRNAs, 21-nucleotide (nt) phased small RNAs are also largely dependent on OsRDR6. Unexpectedly, we found that osrdr6-1 has a strong impact on the accumulation of 24-nt phased small RNAs, but not on unphased ones. Our work uncovers the key roles of OsRDR6 in small RNA biogenesis and directly illustrates the crucial functions of tasiR-ARFs in rice development. PMID- 22443270 TI - Making sense of drinking: the role of techniques of neutralisation and counter neutralisation in negotiating alcohol consumption. AB - This article contributes to the understanding of how students neutralise potential feelings of guilt and stigmatisation regarding their alcohol consumption. We report findings from two qualitative studies with students at a UK university. The aim of the research was to uncover the range and ways in which neutralisation and counter-neutralisation techniques are used by drinkers and abstainers/near-abstainers in managing their alcohol position. Study 1 consisted of five focus groups with heavy drinkers and Study 2 comprised nine one-to-one interviews with abstainers and near-abstainers. Analysis highlights the importance of alcohol consumption in students' lifestyles, but also the potential identity conflicts experienced by all drinkers, regardless of the amount consumed. Heavy drinkers primarily employ neutralisation techniques as a means to rationalise the negative impacts of their actions, whereas abstainers and near abstainers mainly use counter-neutralisation techniques as a means to reinforce their commitment to lifestyles which run counter to mainstream student life expectations. However, regardless of the amount of alcohol consumed, all participants employed neutralising and counter-neutralising arguments in some social situations. The article discusses the usefulness of neutralisation theory to account for the adoption of risky health behaviours, such as excessive alcohol consumption, and the potential implications for public health interventions. PMID- 22443271 TI - Contemporary trends of in-hospital complications and mortality for radical cystectomy. AB - What's known on the subject? and What does the study add? Radical cystectomy (RC) carries significant risks of morbidity and mortality. Little is known whether in hospital outcomes are improving for RC. Using a contemporary population-based cohort, the present study suggests minimal improvement in postoperative complications and mortality overall or by hospital-volume category from 2001 to 2008. About 29% and 2% of patients undergoing RC will experience a postoperative complication or die during hospitalisation, respectively. OBJECTIVE: To characterise the contemporary trends of in-hospital complications and mortality for radical cystectomy (RC) from a contemporary population-based cohort, as patients undergoing RC for bladder cancer are at significant risk for complications and mortality and the degree to which in-hospital outcomes have changed over time is unknown. PATIENTS AND METHODS: We identified 50 625 individuals who underwent RC for bladder cancer between 2001 and 2008 from the Nationwide Inpatient Sample. Multivariable regression models were used to identify hospital and patient covariates associated with in-hospital complications and mortality and to estimate predicted probabilities of each outcome. Temporal trends of in-hospital mortality and complications were assessed by Wilcoxon rank-sum test. RESULTS: The proportion of patients with in-hospital complications remained stable at 28.3% in 2001-2002 compared with 28.0% in 2007 2008 (P = 0.81 for trend). In-hospital mortality was also unchanged from 2.4% in 2001-2002 compared with 2.3% in 2007-2008 (P = 0.87 for trend). While high-volume hospitals were associated with lower odds of in-hospital complications (odds ratio [OR] 0.77, P = 0.01) and mortality (OR 0.60, P = 0.02) compared with low volume hospitals, the predicted probabilities of in-hospital complications or mortality were unchanged within each volume category between 2001 and 2008. CONCLUSIONS: In-hospital complications and mortality for RC remain unchanged from 2001 to 2008. While high-volume hospitals continue to have better outcomes, there is little evidence that postoperative mortality and morbidity are improving among low-, medium- and high-volume hospitals. Increased attention is needed to identify the modifiable aspects of postoperative care to improve in-hospital outcomes and safety for patients undergoing RC. PMID- 22443272 TI - Inhibin B and luteinizing hormone levels in girls aged 6-11 years from NHANES III, 1988-1994. AB - OBJECTIVE: To evaluate inhibin B and luteinizing hormone (LH) levels in a large, representative cross-sectional sample of US girls and characterize the relationships of these laboratory values with age, clinical signs of puberty and other correlates. DESIGN: Cross-sectional analysis of LH and inhibin B in banked serum from 720 girls aged 6-11 years who participated in the Third National Health and Nutrition Examination Survey (NHANES III). MEASUREMENTS: Levels of inhibin B and LH, race, ethnicity and anthropometric measurements were compared for all girls. Visual assessment of pubertal stage was performed on girls aged 8 years and older. A two-part model was used to establish normative data and Tobit regression models were used to evaluate associations with participant characteristics. Receiver operating characteristic (ROC) analysis was performed to identify optimum cut points predictive of puberty onset. RESULTS: Mean hormone levels progressively increased with age. LH levels progressively increased with pubertal stage. Inhibin B levels increased gradually from breast stage I to II, then more sharply to peak at stage III, followed by a plateau at stages IV and V. ROC curves indicated that both hormones were consistent with pubertal onset as indicated by breast stage II. CONCLUSIONS: This study characterizes inhibin B and LH values in a large, representative cross-sectional sample of US girls. Inhibin B can be a useful tool in combination with other clinical and biochemical parameters to evaluate gonadal function as a reflection of pubertal progression in girls. PMID- 22443275 TI - Total synthesis of (-)-goniotrionin. AB - A stereoselective total synthesis of the reported structure of goniotrionin (4) has been accomplished. The key steps involved the opening of a chiral epoxide, a highly diastereoselective Mukaiyama aerobic oxidative cyclization, a selective 1,2-syn Mukaiyama aldol reaction, and a Noyori reduction. PMID- 22443276 TI - Nitryl chloride and molecular chlorine in the coastal marine boundary layer. AB - The magnitude and sources of chlorine atoms in marine air remain highly uncertain but have potentially important consequences for air quality in polluted coastal regions. We made continuous measurements of ambient ClNO(2) and Cl(2) concentrations from May 15 to June 8 aboard the Research Vessel Atlantis during the CalNex 2010 field study. In the Los Angeles region, ClNO(2) was more ubiquitous than Cl(2) during most nights of the study period. ClNO(2) and Cl(2) ranged from detection limits at midday to campaign maximum values at night reaching 2100 and 200 pptv, respectively. The maxima were observed in Santa Monica Bay when sampling the Los Angeles urban plume. Cl(2) at times appeared well correlated with ClNO(2), but at other times, there was little to no correlation implying distinct and varying sources. Well-confined Cl(2) plumes were observed, largely independent of ClNO(2), providing support for localized industrial emissions of reactive chlorine. Observations of ClNO(2), Cl(2), and HCl are used to constrain a simple box model that predicts their relative importance as chlorine atom sources in the polluted marine boundary layer. In contrast to the emphasis in previous studies, ClNO(2) and HCl are dominant primary chlorine atom sources for the Los Angeles basin. PMID- 22443277 TI - Premetastatic niche: ready for new therapeutic interventions? AB - INTRODUCTION: Bone marrow-derived cells (BMDC) localize in premetastatic niche through chemokines and integrins signals and establish clusters that precede the arrival of even single metastatic tumor cell at distant site. CSCs demonstrate an increased metastatic propensity and would seem likely candidates for the acquisition of migratory capabilities and propagation of heterogeneous tumor cell populations to different target organs. Sonic Hedgehog (SHH), FOXM1 and Notch pathways and signaling molecules such as integrin and chemokine could dictate their fate. AREAS COVERED: In this review, the molecular mechanisms of premetastatic niche onset are summarized. EXPERT OPINION: Premetastatic niche is defined as a fertile microenvironment that forms in metastatic target organ and facilitates the invasion, survival and/or proliferation of metastatic tumor cells, providing a novel mechanism for the promotion of metastasis. Drugs targeting premetastatic niche could represent a new promising therapeutic approach in the treatment of bone metastases. PMID- 22443278 TI - DNA-based analysis of regurgitates: a noninvasive approach to examine the diet of invertebrate consumers. AB - DNA-based gut content analysis has become an important tool for unravelling feeding interactions in invertebrate communities under natural conditions. It usually implies killing of the consumer and extracting the DNA from its food, using either the whole animal or its dissected gut. This post-mortem approach, however, is not suitable for investigating the diet of rare or protected species and also prohibits tracking individual dietary preferences as each consumer can provide trophic information only once. Moreover, removing large numbers of consumers from a habitat for analysis might critically change population densities and affect species interactions. Here, we present DNA-based analysis of invertebrate regurgitates, a novel approach to overcome these limitations. Conducting feeding experiments where adult Poecilus cupreus (Coleoptera: Carabidae) were fed with larvae of Amphimallon solstitiale (Coleoptera: Scarabaeidae), we show that detection success in regurgitates compared to samples prepared from whole beetles was similar or significantly enhanced for small/medium and large prey DNA fragments, respectively. Prey DNA detection success remained high in regurgitates stored in ethanol for 21 months at room temperature prior to DNA extraction. We conclude that in those invertebrates where regurgitates can be obtained, examination of food DNA in regurgitates offers many advantages over conventional post-mortem gut content analysis. PMID- 22443279 TI - Efficient fluorescence energy transfer system between CdTe-doped silica nanoparticles and gold nanoparticles for turn-on fluorescence detection of melamine. AB - We here report an efficient and enhanced fluorescence energy transfer system between confined quantum dots (QDs) by entrapping CdTe into the mesoporous silica shell (CdTe@SiO2) as donors and gold nanoparticles (AuNPs) as acceptors. At pH 6.50, the CdTe@SiO2-AuNPs assemblies coalesce to form larger clusters due to charge neutralization, leading to the fluorescence quenching of CdTe@SiO2 as a result of energy transfer. As compared with the energy transfer system between unconfined CdTe and AuNPs, the maximum fluorescence quenching efficiency of the proposed system is improved by about 27.0%, and the quenching constant, K(sv), is increased by about 2.4-fold. The enhanced quenching effect largely turns off the fluorescence of CdTe@SiO2 and provides an optimal "off-state" for sensitive "turn on" assay. In the present study, upon addition of melamine, the weak fluorescence system of CdTe@SiO2-AuNPs is enhanced due to the strong interactions between the amino group of melamine and the gold nanoparticles via covalent bond, leading to the release of AuNPs from the surfaces of CdTe@SiO2; thus, its fluorescence is restored. A "turn-on" fluorimetric method for the detection of melamine is proposed based on the restored fluorescence of the system. Under the optimal conditions, the fluorescence enhanced efficiency shows a linear function against the melamine concentrations ranging from 7.5 * 10-9 to 3.5 * 10-7 M (i.e., 1.0-44 ppb). The analytical sensitivity is improved by about 50%, and the detection limit is decreased by 5.0-fold, as compared with the analytical results using the CdTe-AuNPs system. Moreover, the proposed method was successfully applied to the determination of melamine in real samples with excellent recoveries in the range from 97.4 to 104.1%. Such a fluorescence energy transfer system between confined QDs and AuNPs may pave a new way for designing chemo/biosensing. PMID- 22443280 TI - Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection. AB - Hepatic fat export occurs by apolipoprotein B-100-containing lipoprotein production, whereas impaired production leads to liver steatosis. Hepatitis C virus (HCV) infection is associated to dysregulation of apoB-100 secretion and steatosis; however, the molecular mechanism by which HCV affects the apoB-100 secretion is not understood. Here, combining quantitative proteomics and computational biology, we propose ferritin heavy chain (Fth) as being the cellular determinant of apoB-100 production inhibition. By means of molecular analyses, we found that HCV nonstructural proteins and NS5A appear to be sufficient for inducing Fth up-regulation. Fth in turn was found to inhibit apoB 100 secretion leading to increased intracellular degradation via proteasome. Notably, intracellular Fth down-regulation by siRNA restores apoB-100 secretion. The inverse correlation between ferritin and plasma apoB-100 concentrations was also found in JFH-1 HCV cell culture systems (HCVcc) and HCV-infected patients. Finally, Fth expression was found to be required for robust HCV infection. These observations provide a further molecular explanation for the onset of liver steatosis and allow for hypothesizing on new therapeutic and antiviral strategies. PMID- 22443281 TI - The hemibiotrophic cacao pathogen Moniliophthora perniciosa depends on a mitochondrial alternative oxidase for biotrophic development. AB - The tropical pathogen Moniliophthora perniciosa causes witches' broom disease in cacao. As a hemibiotrophic fungus, it initially colonizes the living host tissues (biotrophic phase), and later grows over the dead plant (necrotrophic phase). Little is known about the mechanisms that promote these distinct fungal phases or mediate the transition between them. An alternative oxidase gene (Mp-aox) was identified in the M. perniciosa genome and its expression was analyzed througout the fungal life cycle. In addition, the effects of inhibitors of the cytochrome dependent respiratory chain (CRC) and alternative oxidase (AOX) were evaluated on the in vitro development of M. perniciosa. Larger numbers of Mp-aox transcripts were observed in the biotrophic hyphae, which accordingly showed elevated sensitivity to AOX inhibitors. More importantly, the inhibition of CRC prevented the transition from the biotrophic to the necrotrophic phase, and the combined use of a CRC and AOX inhibitor completely halted fungal growth. On the basis of these results, a novel mechanism is presented in which AOX plays a role in the biotrophic development of M. perniciosa and regulates the transition to its necrotrophic stage. Strikingly, this model correlates well with the infection strategy of animal pathogens, particularly Trypanosoma brucei, which uses AOX as a strategy for pathogenicity. PMID- 22443282 TI - Antiretroviral drug susceptibility among HIV-infected adults failing antiretroviral therapy in Rakai, Uganda. AB - We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART. PMID- 22443283 TI - The role of Corynebacterium glutamicum spiA gene in whcA-mediated oxidative stress gene regulation. AB - The Corynebacterium glutamicum WhcA protein, which inhibits the expression of oxidative stress response genes, is known to interact with the SpiA protein. In this study, we constructed and analyzed spiA mutant cells with the goal of better understanding the function of the spiA gene. A C. glutamicum strain overexpressing the spiA gene showed retarded cell growth, which was caused by an increased sensitivity to oxidants. Expression of the spiA and whcA genes was repressed by oxidant diamide, indicating coordinate regulation and dispensability of the genes in cells under oxidative stress. In the spiA-overexpressing cells, the trx gene, which encodes thioredoxin reductase, was severely repressed. Deletion of whcA in spiA-overexpressing cells (or vice versa) produced phenotypes similar to the wild-type strain. Collectively, these data demonstrate a negative regulatory role of the spiA gene in whcA-mediated oxidative stress response and provide additional clues on the mechanism by which the whcA gene is regulated. PMID- 22443284 TI - Latin American immigrants have limited access to health insurance in Japan: a cross sectional study. AB - BACKGROUND: Japan provides universal health insurance to all legal residents. Prior research has suggested that immigrants to Japan disproportionately lack health insurance coverage, but no prior study has used rigorous methodology to examine this issue among Latin American immigrants in Japan. The aim of our study, therefore, was to assess the pattern of health insurance coverage and predictors of uninsurance among documented Latin American immigrants in Japan. METHODS: We used a cross sectional, mixed method approach using a probability proportional to estimated size sampling procedure. Of 1052 eligible Latin American residents mapped through extensive fieldwork in selected clusters, 400 immigrant residents living in Nagahama City, Japan were randomly selected for our study. Data were collected through face-to-face interviews using a structured questionnaire developed from qualitative interviews. RESULTS: Our response rate was 70.5% (n = 282). Respondents were mainly from Brazil (69.9%), under 40 years of age (64.5%) and had lived in Japan for 9.45 years (SE 0.44; median, 8.00). We found a high prevalence of uninsurance (19.8%) among our sample compared with the estimated national average of 1.3% in the general population. Among the insured full time workers (n = 209), 55.5% were not covered by the Employee's Health Insurance. Many immigrants cited financial trade-offs as the main reasons for uninsurance. Lacking of knowledge that health insurance is mandatory in Japan, not having a chronic disease, and having one or no children were strong predictors of uninsurance. CONCLUSIONS: Lack of health insurance for immigrants in Japan is a serious concern for this population as well as for the Japanese health care system. Appropriate measures should be taken to facilitate access to health insurance for this vulnerable population. PMID- 22443285 TI - Role of cyclooxygenase 2 and endothelial nitric oxide synthetase in preclinical atherosclerosis. AB - Cyclooxygenase-2 and endothelial nitric oxide (NO) synthase enzymes may have a role in developing preclinical atherosclerosis. Designed groups were as follows: smoke exposed rats before and during pregnancy, only before pregnancy, and controls. Cross-sectional samples of abdominal aorta were examined immunohistochemically. Cyclooxygenase-2 and eNOS expression was evaluated semi quantitatively through staining extent (focal, diffuse) and staining intensity. Diffuse COX-2 expression was detected in study groups. Endothelial NO synthase expression was diffuse in study groups. COX-2 and eNOS may contribute to the formation of preatherosclerotic lesions in offspring of rats exposed to cigarette smoke through inflammatory response. PMID- 22443286 TI - Individual patient data meta-analysis of survival data using Poisson regression models. AB - BACKGROUND: An Individual Patient Data (IPD) meta-analysis is often considered the gold-standard for synthesising survival data from clinical trials. An IPD meta-analysis can be achieved by either a two-stage or a one-stage approach, depending on whether the trials are analysed separately or simultaneously. A range of one-stage hierarchical Cox models have been previously proposed, but these are known to be computationally intensive and are not currently available in all standard statistical software. We describe an alternative approach using Poisson based Generalised Linear Models (GLMs). METHODS: We illustrate, through application and simulation, the Poisson approach both classically and in a Bayesian framework, in two-stage and one-stage approaches. We outline the benefits of our one-stage approach through extension to modelling treatment covariate interactions and non-proportional hazards. Ten trials of hypertension treatment, with all-cause death the outcome of interest, are used to apply and assess the approach. RESULTS: We show that the Poisson approach obtains almost identical estimates to the Cox model, is additionally computationally efficient and directly estimates the baseline hazard. Some downward bias is observed in classical estimates of the heterogeneity in the treatment effect, with improved performance from the Bayesian approach. CONCLUSION: Our approach provides a highly flexible and computationally efficient framework, available in all standard statistical software, to the investigation of not only heterogeneity, but the presence of non-proportional hazards and treatment effect modifiers. PMID- 22443287 TI - Peptidoglycan plasticity in bacteria: stress-induced peptidoglycan editing by noncanonical D-amino acids. AB - It has been generally assumed that the role of D-amino acids in bacterial physiology is rather limited. However, recent new evidence demonstrated that millimolar concentrations of noncanonical D-amino acids are synthesized and released to the environment by bacteria from diverse phyla. These D-amino acids help bacteria adapt to environmental challenges by modulating the structure and composition of the peptidoglycan (PG). This regulation, which appears to be well conserved among bacterial species, occurs principally through the incorporation of the D-amino acids into the terminus of the peptide moiety of muropeptides. These findings revived interest in studies investigating D-amino acids as an exciting and trendy topic in current microbiology, which considers them as fundamental players in different aspects of bacterial physiology. In this article, we provide an overview of the origins of research on the effects of D amino acids in the biology of bacterial cell walls, including their recent implication as key factors for stress-associated PG remodeling. PMID- 22443288 TI - Exhausted women, tough men: a qualitative study on gender differences in health, vulnerability and coping with illness in Spain. AB - This study analyses different perceptions by women and men, from different social backgrounds and ages, regarding their health, vulnerability and coping with illness, and describes the main models provided by both sexes to explain determinants for gender inequalities in health. The qualitative study involved in depth interviews with women and men resident in Granada (Spain). The women rated their health worse than men, associating it with feelings of exhaustion. However, men tended to overrate their health, hiding their problems behind the 'tough guy' stereotype associated with masculinity. Both women and men shared the belief that women are more vulnerable, while men are weaker at coping with illness. The explanatory models offered for this paradox of 'weak but strong women' and 'tough but weak men' were different for each sex. Men used biological arguments more than women, centred on the female reproductive cycle. Women used more cultural models and identified determinants relating to social stratification, gender roles and power imbalances. In conclusion, gender constructions affect the health perceptions of both women and men at any social level or age. 'Exhausted' women and 'tough' men should form preferential target groups for intervention to reduce gender inequalities in health. PMID- 22443289 TI - MAP65-1 and MAP65-2 promote cell proliferation and axial growth in Arabidopsis roots. AB - We investigated the role of the Arabidopsis microtubule associated proteins 65-1 and 65-2 (MAP65-1 and MAP65-2) in the control of axial root growth. Transgenic plants expressing fluorescent fusion proteins from native promoters indicated exactly overlapping accumulation of MAP65-1 and MAP65-2 in the root tip and elongation zone. Nearly identical protein accumulation patterns were observed when MAP65-1 and MAP65-2 were expressed behind a constitutive CaMV 35S promoter, suggesting a level of post-transcriptional control that restricts these proteins to rapidly growing portions of the root. Co-expression of MAP65-1 and MAP65-2 fusion proteins showed precise co-localization to interphase and cytokinetic microtubule arrays. In interphase root tip cells, the fluorescent protein fusions labeled microtubules that were organized into a variety of different array patterns. In the rapidly growing cells of the root elongation zone, we found MAP65-1 and MAP65-2 co-localized exclusively to the lateral faces of cells that were axially extending. Genetic analysis showed that MAP65-1 and MAP65-2 are coordinately required for proper root elongation. Double map65-1-1 map65-2-2 mutant roots from dark-grown plants contained 50% fewer cells per file than wild type roots, but we found no evidence that cytokinesis was disrupted. We additionally discovered that cell length was significantly shorter in the mature regions of the root beyond the zone where MAP65-1 and MAP65-2 accumulated. Our data indicate that MAP65-1 and MAP65-2 play a critical role in root growth by promoting cell proliferation and axial extension. PMID- 22443290 TI - Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. AB - CONTEXT: Vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700) is a rare autosomal recessive disorder and is caused by mutations in the CYP27B1 gene. OBJECTIVES: We aim to investigate CYP27B1 mutation in seven patients from four separate families and characterize the genotype-phenotype correlation. METHODS: The entire coding region of the CYP27B1 gene was sequenced, and genotype phenotype correlation among patients was assessed. RESULTS: Sequencing analysis identified biallelic CYP27B1 mutations in all patients and monoallelic mutations in their parents. One patient from the first family was compound heterozygous for c.1166G>A (p.Arg389His) and a novel nonsense mutation c.1079 C>A (p.Ser360*). Two patients from the second family were homozygous for a novel splice donor site mutation in intron 1 (c.195 + 2 T>G), causing partial retention of the intron and a shift in the reading frame. Both novel mutations lead to the complete loss of vitamin D1alpha-hydroxylase activity. Four patients from families 3 and 4 were homozygous for a previously reported duplication mutation in exon 8 (1319 1325dupCCCACCC, Phe443Profs*24). Interestingly, one patient who was presented with severe hypocalcaemia and seizures at 4 months of age as a result of Phe443Profs*24 has improved spontaneously since 11 years of age and does not need regular treatment. Her laboratory tests showed normal serum calcium and 1,25(OH)(2) D after refusing to take medication for 12 months. CONCLUSIONS: There is a good genotype-phenotype correlation in VDDR-IA. However, some patients may recover from the loss of CYP27B1 function, probably due to 1alpha-hydroxylase activity exerted by a non-CYP27B1 enzyme. PMID- 22443291 TI - Do patients adhere to over-the-counter artemisinin combination therapy for malaria? evidence from an intervention study in Uganda. AB - BACKGROUND: Increasing affordability of artemisinin combination therapy (ACT) in the African retail sector could be critical to expanding access to effective malaria treatment, but must be balanced by efforts to protect the efficacy of these drugs. Previous research estimates ACT adherence rates among public sector patients, but adherence among retail sector purchasers could differ substantially. This study aimed to estimate adherence rates to subsidized, over the-counter ACT in rural Uganda. METHODS: An intervention study was conducted with four licensed drug shops in Eastern Uganda in December 2009. Artemether lumefantrine (AL) was made available for sale at a 95% subsidy over-the counter. Customers completed a brief survey at the time of purchase and then were randomly assigned to one of three study arms: no follow-up, follow-up after two days or follow-up after three days. Surveyors recorded the number of pills remaining through blister pack observation or through self-report if the pack was unavailable. The purpose of the three-day follow-up arm was to capture non adherence in the sense of an incomplete treatment course ("under-dosing"). The purpose of the two-day follow-up arm was to capture whether participants completed the full course too soon ("over-dosing"). RESULTS: Of the 106 patients in the two-day follow-up sample, 14 (13.2%) had finished the entire treatment course by the second day. Of the 152 patients in the three-day follow-up sample, 49 (32.2%) were definitely non-adherent, three (2%) were probably non-adherent and 100 (65.8%) were probably adherent. Among the 52 who were non-adherent, 31 (59.6%) had more than a full day of treatment remaining. CONCLUSIONS: Overall, adherence to subsidized ACT purchased over-the-counter was found to be moderate. Further, a non-trivial fraction of those who complete treatment are taking the full course too quickly. Strategies to increase adherence in the retail sector are needed in the context of increasing availability and affordability of ACT in this sector. PMID- 22443292 TI - Modeling of oxygen transport and cell killing in type-II photodynamic therapy. AB - Photodynamic therapy (PDT) provides an effective option for treatment of tumors and other diseases in superficial tissues and attracts attention for in vitro study with cells. In this study, we present a significantly improved model of in vitro cell killing through Type-II PDT for simulation of the molecular interactions and cell killing in time domain in the presence of oxygen transport within a spherical cell. The self-consistency of the approach is examined by determination of conditions for obtaining positive definitive solutions of molecular concentrations. Decay constants of photosensitizers and unoxidized receptors are extracted as the key indices of molecular kinetics with different oxygen diffusion constants and permeability at the cell membrane. By coupling the molecular kinetics to cell killing, we develop a modeling method of PDT cytotoxicity caused by singlet oxygen and obtain the cell survival ratio as a function of light fluence or initial photosensitizer concentration with different photon density or irradiance of incident light and other parameters of oxygen transport. The results show that the present model of Type-II PDT yields a powerful tool to quantitate various events underlying PDT at the molecular and cellular levels and to interpret experimental results of in vitro cell studies. PMID- 22443293 TI - Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study. AB - OBJECTIVE: This open-label, phase 3b study evaluated the effectiveness and tolerability of tapentadol prolonged release and tapentadol immediate release (for acute pain episodes) for severe, chronic low back pain with or without a neuropathic pain component that was inadequately managed in patients taking World Health Organization (WHO) Step I or II analgesics or who were not regularly treated with analgesics. RESEARCH DESIGN AND METHODS: Average baseline pain intensity was greater than 5 (11-point numerical rating scale-3 [NRS-3; 3-day average pain intensity]) with WHO Step I or II analgesics and greater than 6 with no regular analgesic regimen. WHO Step II analgesics were discontinued before starting study treatment; WHO Step I analgesics or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50-250 mg bid) during a 5-week titration and 7-week maintenance period. Tapentadol immediate release was permitted for acute pain episodes (tapentadol prolonged release and immediate release maximum combined dose, <=500 mg/day). The painDETECT questionnaire was used to define subsets of patients based on the probability of a neuropathic pain component to their low back pain as 'negative', 'unclear', or 'positive'. CLINICAL TRIAL REGISTRATION: NCT00983385. MAIN OUTCOME MEASURE: The primary endpoint was the change from baseline to week 6 in average pain intensity (NRS-3), using the last observation carried forward to impute missing scores. RESULTS: In the painDETECT negative (n = 49) and unclear/positive (n = 126) subsets, respectively, mean (SD) changes in pain intensity from baseline to week 6 were -2.4 (2.18) and -3.0 (2.07; both p < 0.0001). Among patients who had not received prior WHO Step II treatment, lower doses of tapentadol prolonged release were generally required with increasing likelihood of a neuropathic pain component. Based on the painDETECT questionnaire and the Neuropathic Pain Symptom Inventory (NPSI), tapentadol prolonged release treatment was also associated with significant improvements in neuropathic pain symptoms, with decreases in the number of pain attacks and the duration of spontaneous pain in the last 24 hours in patients with low back pain with a neuropathic pain component (painDETECT unclear or positive score at baseline or screening). The most common treatment emergent adverse events (incidence >=10%, n = 176) were nausea, dizziness, headache, dry mouth, fatigue, constipation, diarrhea, nasopharyngitis, and somnolence. CONCLUSIONS: Tapentadol prolonged release was well tolerated and effective for managing severe, chronic low back pain with or without a neuropathic pain component. PMID- 22443294 TI - Enzymatic synthesis of galacto-oligosaccharides in an organic-aqueous biphasic system by a novel beta-galactosidase from a metagenomic library. AB - Prebiotic galacto-oligosaccharides (GOS) were effectively synthesized from lactose in organic-aqueous biphasic media by a novel metagenome-derived beta galactosidase BgaP412. A maximum GOS yield of 46.6% (w/w) was achieved with 75.4% lactose conversion rate in the cyclohexane/buffer system [95:5 (v/v) cyclohexane/buffer] under the optimum reaction conditions (initial lactose concentration = 30% (w/v), T = 50 degrees C, pH 7.0, and t = 8 h). The corresponding productivity of GOS was approximately 17.5 g L(-1) h(-1). The GOS mixture consisted of tri-, tetra-, and pentasaccharides. Trisaccharides were the chief component of reaction products. These experimental results showed that a low water content, a high initial lactose concentration, and an elevated reaction temperature could significantly promote the transgalactosylation activity of beta galactosidase BgaP412; at the same time, the enhanced GOS yield in an organic aqueous biphasic system is because of the fact that thermodynamic equilibrium can be shifted to the synthetic direction by reversing the normal hydrolysis. PMID- 22443295 TI - Prediction of a deletion copy number variant by a dense SNP panel. AB - BACKGROUND: A newly recognized type of genetic variation, Copy Number Variation (CNV), is detected in mammalian genomes, e.g. the cattle genome. This form of variation can potentially cause phenotypic variation. Our objective was to determine whether dense SNP (single nucleotide polymorphisms) panels can capture the genetic variation due to a simple bi-allelic CNV, with the prospect of including the effect of such structural variations into genomic predictions. METHODS: A deletion type CNV on bovine chromosome 6 was predicted from its neighboring SNP with a multiple regression model. Our dataset consisted of CNV genotypes of 1,682 cows, along with 100 surrounding SNP genotypes. A prediction model was fitted considering 10 to 100 surrounding SNP and the accuracy obtained directly from the model was confirmed by cross-validation. RESULTS AND CONCLUSIONS: The accuracy of prediction increased with an increasing number of SNP in the model and the predicted accuracies were similar to those obtained by cross-validation. A substantial increase in accuracy was observed when the number of SNP increased from 10 to 50 but thereafter the increase was smaller, reaching the highest accuracy (0.94) with 100 surrounding SNP. Thus, we conclude that the genotype of a deletion type CNV and its putative QTL effect can be predicted with a maximum accuracy of 0.94 from surrounding SNP. This high prediction accuracy suggests that genetic variation due to simple deletion CNV is well captured by dense SNP panels. Since genomic selection relies on the availability of a dense marker panel with markers in close linkage disequilibrium to the QTL in order to predict their genetic values, we also discuss opportunities for genomic selection to predict the effects of CNV by dense SNP panels, when CNV cause variation in quantitative traits. PMID- 22443296 TI - Assessing the cost effectiveness of robotics in urological surgery - a systematic review. AB - OBJECTIVES: Although robotic technology is becoming increasingly popular for urological procedures, barriers to its widespread dissemination include cost and the lack of long term outcomes. This systematic review analyzed studies comparing the use of robotic with laparoscopic and open urological surgery. These three procedures were assessed for cost efficiency in the form of direct as well as indirect costs that could arise from length of surgery, hospital stay, complications, learning curve and postoperative outcomes. METHODS: A systematic review was performed searching Medline, Embase and Web of Science databases. Two reviewers identified abstracts using online databases and independently reviewed full length papers suitable for inclusion in the study. RESULTS: Laparoscopic and robot assisted radical prostatectomy are superior with respect to reduced hospital stay (range 1-1.76 days and 1-5.5 days, respectively) and blood loss (range 482-780 mL and 227-234 mL, respectively) when compared with the open approach (range 2-8 days and 1015 mL). Robot assisted radical prostatectomy remains more expensive (total cost ranging from US $2000-$39,215) than both laparoscopic (range US $740-$29,771) and open radical prostatectomy (range US $1870-$31,518). This difference is due to the cost of robot purchase, maintenance and instruments. The reduced length of stay in hospital (range 1-1.5 days) and length of surgery (range 102-360 min) are unable to compensate for the excess costs. Robotic surgery may require a smaller learning curve (20-40 cases) although the evidence is inconclusive. CONCLUSIONS: Robotic surgery provides similar postoperative outcomes to laparoscopic surgery but a reduced learning curve. Although costs are currently high, increased competition from manufacturers and wider dissemination of the technology could drive down costs. Further trials are needed to evaluate long term outcomes in order to evaluate fully the value of all three procedures in urological surgery. PMID- 22443297 TI - Is there something other than imatinib mesilate in therapeutic options for GIST? AB - INTRODUCTION: In the last decade, the introduction of imatinib mesilate into the clinical practice has resulted in a dramatic improvement in the treatment of gastrointestinal stromal tumor (GIST). Nowadays, the median overall survival in patients with advanced disease has increased to 5 years, while recent Phase III trials demonstrated that imatinib mesilate can be successfully employed as adjuvant therapy in patients at significant risk of recurrence. Despite these good results, the emergence of secondary resistance represents the main cause of treatment failure. In recent years, many efforts have been made in search of drugs to overcome imatinib mesilate resistance; some of these have been employed as second-line treatment or salvage therapy. AREAS COVERED: Summarized and investigated in this paper are the results obtained by imatinib mesilate in advanced and adjuvant setting, the role of sunitinib malate as second-line therapy in imatinib mesilate-resistant patients and the clinical results concerning new drugs, mainly tyrosine-kinase inhibitors. EXPERT OPINION: Current research on novel therapeutic agents, as third-line treatments in GIST, is ongoing. However, despite the promising results obtained with the new molecules, imatinib mesilate remains the cornerstone in the medical treatment of GIST and to date no other drugs can replace it. PMID- 22443298 TI - Synthesis of (+/-)-7-hydroxylycopodine. AB - A seven-step synthesis of (+/-)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether. The resulting product was converted to 7-hydroxydehydrolycopodine by heating with KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate the starting material so that we could adapt this synthesis to the preparation of (+/-)-7,8 dihydroxylycopodine (sauroine) we observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)(3) and to an amino phenol with KHMDS and oxygen. PMID- 22443299 TI - Inhibition of bacterial DD-peptidases (penicillin-binding proteins) in membranes and in vivo by peptidoglycan-mimetic boronic acids. AB - The DD-peptidases or penicillin-binding proteins (PBPs) catalyze the final steps of bacterial peptidoglycan biosynthesis and are inhibited by the beta-lactam antibiotics. There is at present a question of whether the active site structure and activity of these enzymes is the same in the solubilized (truncated) DD peptidase constructs employed in crystallographic and kinetics studies as in membrane-bound holoenzymes. Recent experiments with peptidoglycan-mimetic boronic acids have suggested that these transition state analogue-generating inhibitors may be able to induce reactive conformations of these enzymes and thus inhibit strongly. We have now, therefore, measured the dissociation constants of peptidoglycan-mimetic boronic acids from Escherichia coli and Bacillus subtilis PBPs in membrane preparations and, in the former case, in vivo, by means of competition experiments with the fluorescent penicillin Bocillin Fl. The experiments showed that the boronic acids bound measurably (K(i) < 1 mM) to the low-molecular mass PBPs but not to the high-molecular mass enzymes, both in membrane preparations and in whole cells. In two cases, E. coli PBP2 and PBP5, the dissociation constants obtained were very similar to those obtained with the pure enzymes in homogeneous solution. The boronic acids, therefore, are unable to induce tightly binding conformations of these enzymes in vivo. There is no evidence from these experiments that DD-peptidase inhibitors are more or less effective in vivo than in homogeneous solution. PMID- 22443300 TI - Mycobacterium tuberculosis-specific phagosome proteome and underlying signaling pathways. AB - The phagosome is very important to host immunity and tissue homeostasis maintenance. The destiny of the phagosome is closely associated with the outcome of the pathogen within. Most pathogens are successfully delivered to the lysosome and destroyed via the fusion of the phagosome with the lysosome. Mycobacterium tuberculosis has evolved multiple tactics to deflect the normal fusion process, such as delaying the phagosome maturation and acidification, thereby evading the immune recognition and subsequent elimination. Identification of the specific constituents of M. tuberculosis phagosome and the underlying signaling pathways are pivotal to define the key molecular features of this process and better targets to control this recalcitrant pathogen. Proteomic profiling is a comprehensive approach to define the protein inventory. In this review, currently available mycobacteria-containing phagosome proteome data were compiled. Ten putative evolutionarily conserved phagosome proteins were summarized. Unique proteins of the M. tuberculosis-containing phagosome proteome were compiled via comparison with other phagosomes, especially the inert latex bead phagosome. Signaling events associated with these unique proteins, such as Rab GTPase and PI3P, were also found and discussed. The data will facilitate better characterization of the M. tuberculosis specific phagosome constituents and involved signaling, and host-derived targets for better tuberculosis control. PMID- 22443301 TI - Aggregation kinetics and transport of single-walled carbon nanotubes at low surfactant concentrations. AB - Little is known about how low levels of surfactants can affect the colloidal stability of single-walled carbon nanotubes (SWNTs) and how surfactant-wrapping of SWNTs can impact ecological exposures in aqueous systems. In this study, SWNTs were suspended in water with sodium dodecylsulfate (SDS) as a surface-active dispersing agent. The effect of SDS concentration on SWNT suspension stability was investigated with time-resolved dynamic light scattering (TRDLS) initial aggregation studies utilizing both monovalent (Na(+)) and divalent (Ca(2+)) cations. The critical coagulation concentration (CCC) values increased with SDS concentration for the Na(+) treatments, but the Ca(2+) treatments were less sensitive to SDS concentration changes. Longer term stability studies with SDS concentrations orders of magnitude below the SDS critical micelle concentration demonstrated that SWNTs remained suspended for over six weeks in a surface water. Transport studies in a freshwater sediment similarly showed a SDS concentration dependent mobility of SDS-wrapped SWNTs in that SWNTs showed a relatively greater retention at lower SDS concentrations (0.001%-0.05% w/v) than at a higher SDS concentration (0.1%). It is hypothesized that the stability and mobility of SWNT suspensions is directly related to the surface coverage of SDS on the SWNT surface that simultaneously increases electrosteric repulsion and decreases surface chemical heterogeneity. Overall, these studies demonstrate that low levels of surfactant are effective in stabilizing and mobilizing SWNTs in environmental media. PMID- 22443302 TI - Interface engineering catalytic graphene for smart colorimetric biosensing. AB - Herein a hybrid catalyst consisting of "naked" Au-NPs in situ grown on graphene sheets is engineered, which exhibits a synergetic effect in mimicking peroxidase at its interface, although free Au-NPs or graphene alone has very little activity. What is more, one of the unique features of our synergetic catalyst is that its interface can be reversibly switched from "inactive" to "active" upon treatment with different ssDNA species in solution, thus providing a powerful and versatile basis for designing graphene/DNA-based label-free colorimetric biosensors. Compared with other signal transduction modes in traditional graphene/aptamer-based systems, our novel signaling strategy not only avoids any labeling or modification procedures but also reduces the background signal due to the "off-on" switching mode during the sensing. Furthermore, this facile and general approach can be applicable to the other extended graphene/aptamer-based systems for colorimetric detection of a wide range of analytes. We envision that the tunable graphene-based smart interface could find potential applications in the development of biocatalysis, bioassays, and smart material devices in the future. PMID- 22443303 TI - Effect of liver fibrosis on long-term mortality in HIV/hepatitis C virus coinfected individuals who are evaluated to receive interferon therapies in the highly active antiretroviral therapy era. AB - The factors associated with overall mortality and liver decompensation in HIV and hepatitis C virus (HCV)-coinfected patients who are evaluated to receive HCV antiviral therapy with a known liver histological fibrosis stage were evaluated in a prospective cohort study. A total of 387 consecutive HIV/HCV-coinfected patients attending an outpatient clinical unit between January 1997 and December 2007 who fulfilled criteria to be treated with interferon and to whom liver biopsy was performed were included and followed every 6 months from time of liver biopsy to death or to December 2008. The follow-up period was 6.2 years (IQR: 3.5 9.2). The median age at time of liver biopsy was 38 years. This included 73% men; 28% had advanced liver fibrosis (F3-F4) and a CD4 cell count of 556 cells/mm(3), 72% had HIV RNA <400 copies/ml and a mean CD4 nadir of 207 cell/mm(3), 21% had a previous diagnosis of AIDS, and 92% were on antiretroviral therapy. During follow up 48% underwent HCV antiviral therapy, with a sustained virological response in 33%. The overall mortality rate and the incidence of liver decompensation or liver-related death were 1.17 and 0.72 per 100 patients-year, respectively. End stage liver disease (9/28 patients) and non-AIDS-related cancer (6/28) were the main causes of death. F3-F4 (HR: 3.74, 95% CI: 1.69-8.26, p=0.001) and previous AIDS diagnosis (HR: 3.04, 95% CI: 1.36-6.81) were the factors independently associated with death. Mortality rates in patients who received and who did not receive HCV antiviral therapy were 0.44 and 2.04 per 100 patients-year, respectively (p=0.003). In addition to the low mortality rate observed, HIV/HCV coinfected patients with poor predictors of survival are candidates for intensive clinical management. PMID- 22443304 TI - Use of data on avian demographics and site persistence during overwintering to assess quality of restored riparian habitat. AB - Monitoring responses by birds to restoration of riparian vegetation is relatively cost-effective, but in most assessments species-specific abundances, not demography, are monitored. Data on birds collected during the nonbreeding season are particularly lacking. We captured birds in mist nets and resighted banded birds to estimate species richness and diversity, abundance, demographic indexes, and site-level persistence of permanent-resident and overwintering migrants in remnant and restored riparian sites in California. Species richness in riparian remnants was significantly higher than in restored sites because abundances of uncommon permanent residents were greater in remnants. Species richness of overwintering migrants did not differ between remnants and restored sites. Responses among overwintering migrants (but not permanent residents) to remnant and restored riparian sites differed. Capture rates were higher in remnant or restored riparian sites for 7 of 10 overwintering migratory species. For Lincoln's Sparrows (Melospiza lincolnii) and White-crowned Sparrows (Zonotrichia leucophrys) proportions of older birds were significantly higher in remnants, even though capture rates of these species were higher in restored sites. Overwinter persistence of 4 migrant species was significantly higher in remnant than in restored sites. A higher proportion of Hermit Thrushes (Catharus guttatus, 56.3%), older Fox Sparrows (Passerella iliaca, 57.1%), Lincoln's Sparrows (59.7%), and White-crowned Sparrows (67.8%) persisted in remnants than restored sites. Our results suggest restored riparian sites provide habitat for a wide variety of species in comparable abundances and diversity as occurs in remnant riparian sites. Our demographic and persistence data showed that remnants supported some species and age classes to a greater extent than restored sites. PMID- 22443305 TI - Asthma prevalence among 16- to 18-year-old adolescents in Saudi Arabia using the ISAAC questionnaire. AB - BACKGROUND: Most of the studies investigating the prevalence of asthma in various countries have focused on children below the age of 15 years or adults above the age of 18 years. There is limited knowledge concerning the prevalence of asthma in 16- to 18-year-old adolescents. Our objective was to study the prevalence of asthma and associated symptoms in 16- to 18-year-old adolescents in Saudi Arabia. METHODS: A cross-sectional study was conducted in secondary (high) schools in the city of Riyadh utilizing the International Study of Asthma and Allergies in Children (ISAAC) questionnaire tool. RESULTS: Out of 3073 students (1504 boys and 1569 girls), the prevalence of lifetime wheeze, wheeze during the past 12 months and physician-diagnosed asthma was 25.3%, 18.5% and 19.6%, respectively. The prevalence of exercise-induced wheezing and night coughing in the past 12 months was 20.2% and 25.7%, respectively. The prevalence of rhinitis symptoms in students with lifetime wheeze, physician-diagnosed asthma and exercise-induced wheeze was 61.1%, 59.9% and 57.4%, respectively. Rhinitis symptoms were significantly associated with lifetime wheeze (OR = 2.5, p value < 0.001), physician-diagnosed asthma (OR = 2.2, p < 0.001), and exercise-induced wheeze (OR = 1.9, p value < 0.001). CONCLUSIONS: The prevalence of asthma and associated symptoms in 16- to 18-year-old adolescents in Saudi Arabia is high, although it is within range of reported prevalence rates from various parts of the world. PMID- 22443306 TI - Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes. AB - For many years, the development of insulin resistance has been seen as the core defect responsible for the development of Type 2 diabetes. However, despite extensive research, the initial factors responsible for insulin resistance development have not been elucidated. If insulin resistance can be overcome by enhanced insulin secretion, then hyperglycaemia will never develop. Therefore, a beta-cell defect is clearly required for the development of diabetes. There is a wealth of evidence to suggest that disorders in insulin secretion can lead to the development of decreased insulin sensitivity. In this review, we describe the potential initiating defects in Type 2 diabetes, normal pulsatile insulin secretion and the effects that disordered secretion may have on both beta-cell function and hepatic insulin sensitivity. We go on to examine evidence from physiological and epidemiological studies describing beta-cell dysfunction in the development of insulin resistance. Finally, we describe how disordered insulin secretion may cause intracellular insulin resistance and the implications this concept has for diabetes therapy. In summary, disordered insulin secretion may contribute to development of insulin resistance and hence represent an initiating factor in the progression to Type 2 diabetes. PMID- 22443307 TI - Prevalence of malaria infection in Butajira area, south-central Ethiopia. AB - BACKGROUND: In 2005, the Ethiopian government launched a massive expansion of the malaria prevention and control programme. The programme was aimed mainly at the reduction of malaria in populations living below 2,000 m above sea level. Global warming has been implicated in the increase in the prevalence of malaria in the highlands. However, there is still a paucity of information on the occurrence of malaria at higher altitudes. The objective of this study was to estimate malaria prevalence in highland areas of south-central Ethiopia, designated as the Butajira area. METHODS: Using a multi-stage sampling technique, 750 households were selected. All consenting family members were examined for malaria parasites in thick and thin blood smears. The assessment was repeated six times for two years (October 2008 to June 2010). RESULTS: In total, 19,207 persons were examined in the six surveys. From those tested, 178 slides were positive for malaria, of which 154 (86.5%) were positive for Plasmodium vivax and 22 (12.4%) for Plasmodium falciparum; the remaining two (1.1%) showed mixed infections of Plasmodium falciparum and Plasmodium vivax. The incidence of malaria was higher after the main rainy season, both in lower lying and in highland areas. The incidence in the highlands was low and similar for all age groups, whereas in the lowlands, malaria occurred mostly in those of one to nine years of age. CONCLUSION: This study documented a low prevalence of malaria that varied with season and altitudinal zone in a highland-fringe area of Ethiopia. Most of the malaria infections were attributable to Plasmodium vivax. PMID- 22443308 TI - Defining hyperandrogenaemia according to the free androgen index in Chinese women: a cross-sectional study. AB - OBJECTIVE(S): To determine the normative cut-off value for the free androgen index (FAI) among reproductive-age women in China. DESIGN: Cross-sectional, population-based study. SETTING: A multistage systematic cluster random sampling among 16 communities from two rural and two city regions. PATIENT(S): A total of 1526 women were randomly selected from a representative sample of 3009 women aged 20-45 years from the general population of southern China. Among these women, 444 subjects without known factors affecting androgen levels were selected as the reference group. INTERVENTION(S): Subjects underwent physical examination, blood tests of hormone and metabolic profiles, and ultrasound evaluations. MEASUREMENT OF THE MAIN OUTCOMES: The FAI was calculated according to the following equation: FAI = 100 * total testosterone (nmol/l)/sex hormone-binding globulin (nmol/l). The normative cut-off value of the FAI was computed based on the 5th-95th percentiles and K-means cluster analysis (K = 2). RESULTS: A reference range of 0.7-6.4 of the FAI was indicated by the 5th and 95th percentiles. K-means cluster analysis identified 6.1 as the cut-off value for the FAI in the total population, which was close to the upper limit determined by the 95th percentile. Hyperandrogenic women present with elevated risk factors for metabolic disorders. The mean FAI values decreased with age among the total population, as evaluated by either K-means clustering or a percentile analysis. The FAI value was negatively correlated with age (r = -0.185, P < 0.0001) and positively correlated with body mass index after adjustment for age (r = 0.250, P < 0.0001). CONCLUSION: A reference range of 0.7-6.4 FAI was indicated by the 5th and 95th percentiles among the reference group, which excluded the subjects with factors known to affect androgen levels; 6.1 was identified by the K-means cluster analysis as the cut-off value of the FAI for the general population. Hyperandrogenic women present with higher risks for metabolic disorders. PMID- 22443309 TI - The effects of a psychosocial dimension of socioeconomic position on survival: occupational prestige and mortality among US working adults. AB - The association between education or income and mortality has been explored in great detail. These measures capture both the effects of material disadvantage on health and the psychosocial impacts of a low socioeconomic position on health. When explored independently of educational attainment and income, occupational prestige - a purely perceptual measure - serves as a measure of the impact of a psychosocial phenomenon on health. For instance, a fire-fighter, academician or schoolteacher may carry the social benefits of a higher social status without actually having the income (in all cases) or the educational credentials (in the case of the fire-fighter) to match. We explored the independent influence of occupational prestige on mortality. We applied Cox proportional hazards models to a nationally representative sample of over 380,000 US workers who had worked at any time between 1986 and 1994 with mortality follow up through 2002. We found that occupational prestige is associated with a decrease in the risk of all cause, cancer, cardiovascular and respiratory-related mortality after controlling for household income and educational attainment. We further investigated the question of whether the effects of prestige are moderated by sex and broader occupational groupings. Prestige effects operate in white-collar occupations for men only and within service occupations for all workers. PMID- 22443310 TI - Kerion celsi due to Arthroderma incurvatum infection in a Sri Lankan child: species identification and analysis of area-dependent genetic polymorphism. AB - A three-year-old Sri Lankan boy residing in Japan developed a nodule on his scalp after visiting Sri Lanka. Two months later, the lesion increased in size to 22 * 19 mm(2), and was identified as an erythematous nodule with alopecia. Direct examination of the infected hair shafts indicated fungal hyphae outside the shafts. The fungus was identified as Microsporum gypseum following mycological examination. The sequence of the internal transcribed spacer 1 region of ribosomal RNA gene (ITS1 rDNA) exhibited 95.7-100.0% homology with that of Arthroderma incurvatum. The patient was successfully treated with a 6-week itraconazole course. We also examined DNA samples from eight clinical isolates of A. incurvatum. Alignments of ITS1 sequences of these strains and our isolate, showed gaps in the 64-bp positions 140-142 and 141-143 of the 205-207-bp ITS1 alignment. We performed phylogenetic analysis using the neighbor-jointing (NJ) method based on the ITS1 sequences of the present isolate and twenty related strains. Fifteen A. incurvatum strains were divided into East Asia and non-East Asia clusters. The present isolate belonged to the non-East Asia cluster, suggesting that the patient was infected outside Japan. Moreover, the trees suggested area-dependent genetic polymorphism of A. incurvatum. PMID- 22443311 TI - Epidermal cell differentiation in cotton mediated by the homeodomain leucine zipper gene, GhHD-1. AB - Gossypium hirsutum L. (cotton) fibres are specialized trichomes a few centimetres in length that grow from the seed coat. Few genes directly involved in the differentiation of these epidermal cells have been identified. These include GhMYB25-like and GhMYB25, two related MYB transcription factors that regulate fibre cell initiation and expansion. We have also identified a putative homeodomain leucine zipper (HD-ZIP) transcription factor, GhHD-1, expressed in trichomes and early fibres that might play a role in cotton fibre initiation. Here, we characterize GhHD-1 homoeologues from tetraploid G. hirsutum and show, using reporter constructs and quantitative real-time PCR (qRT-PCR), that they are expressed predominantly in epidermal tissues during early fibre development, and in other tissues bearing epidermal trichomes. Silencing of GhHD-1 reduced trichome formation and delayed the timing of fibre initiation. Constitutive overexpression of GhHD-1 increased the number of fibres initiating on the seed, but did not affect leaf trichomes. Expression of GhHD-1 in cotton silenced for different fibre MYBs suggest that in ovules it acts downstream of GhMYB25-like, but is unaffected in GhMYB25- or GhMYB109-silenced plants. Microarray analysis of silencing and overexpression lines of GhHD-1 indicated that it potentially regulates the levels of ethylene and reactive oxidation species (ROS) through a WRKY transcription factor and calcium-signalling pathway genes to activate downstream genes necessary for cell expansion and elongation. PMID- 22443312 TI - Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: the randomized controlled trial of balloon kyphoplasty versus non surgical care for vertebral compression fracture (FREE). AB - BACKGROUND: Clinical trial participants may be temporarily absent or withdraw from trials, leading to missing data. In intention-to-treat (ITT) analyses, several approaches are used for handling the missing information - complete case (CC) analysis, mixed-effects model (MM) analysis, last observation carried forward (LOCF) and multiple imputation (MI). This report discusses the consequences of applying the CC, LOCF and MI for the ITT analysis of published data (analysed using the MM method) from the Fracture Reduction Evaluation (FREE) trial. METHODS: The FREE trial was a randomised, non-blinded study comparing balloon kyphoplasty with non-surgical care for the treatment of patients with acute painful vertebral fractures. Patients were randomised to treatment (1:1 ratio), and stratified for gender, fracture aetiology, use of bisphosphonates and use of systemic steroids at the time of enrolment. Six outcome measures - Short form 36 physical component summary (SF-36 PCS) scale, EuroQol 5-Dimension Questionnaire (EQ-5D), Roland-Morris Disability (RMD) score, back pain, number of days with restricted activity in last 2 weeks, and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC, LOCF, MM and MI analyses. RESULTS: There were no missing data in baseline covariates values, and only a few missing baseline values in outcome variables. The overall missing-response level increased during follow-up (1 month: 14.5%; 24 months: 28%), corresponding to a mean of 19% missing data during the entire period. Overall patterns of missing response across time were similar for each treatment group. Almost half of all randomised patients were not available for a CC analysis, a maximum of 4% were not included in the LOCF analysis, and all randomised patients were included in the MM and MI analyses. Improved estimates of treatment effect were observed with LOCF, MM and MI compared with CC; only MM provided improved estimates across all six outcomes considered. CONCLUSIONS: The FREE trial results are robust as the alternative methods used for substituting missing data produced similar results. The MM method showed the highest statistical precision suggesting it is the most appropriate method to use for analysing the FREE trial data. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (number NCT00211211). PMID- 22443313 TI - Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats. AB - BACKGROUND: Levodopa (L-dopa) is the most commonly used treatment for alleviating symptoms of Parkinson's disease. However, L-dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents L-dopa action on gastric emptying and enhances circulating L-dopa in rats. METHODS: Gastric emptying of non-nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) L dopa, or intravenous (i.v.) ghrelin 10 min before orogastric L-dopa. Plasma L dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 MUg kg(-1)) 10 min before i.p. L-dopa. KEY RESULTS: Levodopa (5 and 15 mg kg(-1)) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 MUg kg(-1), i.v.) completely prevented L-dopa's (15 mg kg(-1), orogastrically) inhibitory action on gastric emptying and enhanced plasma L-dopa and dopamine levels compared with vehicle 15 min after orogastric L-dopa. Levodopa (5 mg kg(-1)) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg( 1), i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. CONCLUSIONS & INFERENCES: Ghrelin counteracts L-dopa-induced delayed gastric emptying but not Fos induction in the brain and enhances circulating L dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson's disease patients treated with L-dopa remain to be investigated. PMID- 22443314 TI - Quantifying dehydration in the fire service using field methods and novel devices. AB - OBJECTIVE: This study reports measurements of hydration status among firefighters prior to training, documents changes in hydration status after prolonged firefighting training, and reports the utility of salivary measurements to assess changes in hydration in field environments. METHODS: Nude body mass measurements as well as urinary and salivary measurements of hydration status were taken before and after approximately three hours of firefighting training activities. Initial hydration status was assessed via urinary and salivary measures. Changes in body mass and total body water were measured following firefighting activity and correlated with changes in urinary and salivary measures of hydration. RESULTS: The most important findings of this study were that a high percentage of firefighters arrived at training in a significantly or seriously dehydrated state; that firefighters lost a significant amount of body mass because of firefighting operations; and that portable salivary osmolality measurements showed much stronger correlation with changes in hydration status after firefighting operations than standard urinary measurements did. CONCLUSIONS: Firefighters arriving in a dehydrated state are at risk for heat injuries and may be in a physically and/or psychologically compromised state at the outset of firefighter training. Even during cool autumn days with ample fluids available, firefighters experience dehydration during typical firefighting activities, so the ability to measure hydration status throughout such activities may be important. Our data suggest that quantification of changes in hydration status through salivary osmolality measurements may provide a viable field measurement tool for such activities. PMID- 22443315 TI - Development of an indirect stereolithography technology for scaffold fabrication with a wide range of biomaterial selectivity. AB - Tissue engineering, which is the study of generating biological substitutes to restore or replace tissues or organs, has the potential to meet current needs for organ transplantation and medical interventions. Various approaches have been attempted to apply three-dimensional (3D) solid freeform fabrication technologies to tissue engineering for scaffold fabrication. Among these, the stereolithography (SL) technology not only has the highest resolution, but also offers quick fabrication. However, a lack of suitable biomaterials is a barrier to applying the SL technology to tissue engineering. In this study, an indirect SL method that combines the SL technology and a sacrificial molding process was developed to address this challenge. A sacrificial mold with an inverse porous shape was fabricated from an alkali-soluble photopolymer by the SL technology. A sacrificial molding process was then developed for scaffold construction using a variety of biomaterials. The results indicated a wide range of biomaterial selectivity and a high resolution. Achievable minimum pore and strut sizes were as large as 50 and 65 MUm, respectively. This technology can also be used to fabricate three-dimensional organ shapes, and combined with traditional fabrication methods to construct a new type of scaffold with a dual-pore size. Cytotoxicity tests, as well as nuclear magnetic resonance and gel permeation chromatography analyses, showed that this technology has great potential for tissue engineering applications. PMID- 22443316 TI - Spatially resolving the secretome within the mycelium of the cell factory Aspergillus niger. AB - Aspergillus niger is an important cell factory for the industrial production of enzymes. These enzymes are released into the culture medium, from which they can be easily isolated. Here, we determined with stable isotope dimethyl labeling the secretome of five concentric zones of 7-day-old xylose-grown colonies of A. niger that had either or not been treated with cycloheximide. As expected, cycloheximide blocked secretion of proteins at the periphery of the colony. Unexpectedly, protein release was increased by cycloheximide in the intermediate and central zones of the mycelium when compared to nontreated colonies. Electron microscopy indicated that this is due to partial degradation of the cell wall. In total, 124 proteins were identified in cycloheximide-treated colonies, of which 19 secreted proteins had not been identified before. Within the pool of 124 proteins, 53 secreted proteins were absent in nontreated colonies, and additionally, 35 proteins were released >=4-fold in the central and subperipheral zones of cycloheximide-treated colonies when compared to nontreated colonies. The composition of the secretome in each of the five concentric zones differed. This study thus describes spatial release of proteins in A. niger, which is instrumental in understanding how fungi degrade complex substrates in nature. PMID- 22443317 TI - Photocatalysis for continuous air purification in wastewater treatment plants: from lab to reality. AB - The photocatalytic efficiency of TiO(2)-SiMgO(x) plates to oxidize H(2)S was first evaluated in a flat laboratory reactor with 50 mL min(-1) synthetic air containing 100 ppm H(2)S in the presence of humidity. The use of the photocatalyst-adsorbent hybrid material enhanced the photocatalytic activity in terms of pollutant conversion, selectivity, and catalyst lifetime compared to previous H(2)S tests with pure TiO(2) because total H(2)S elimination was maintained for more than 30 operating hours with SO(2) appearing in the outlet as reaction product only after 18 h. Subsequently, the hybrid material was successfully tested in a photoreactor prototype to treat real polluted air in a wastewater treatment plant. For this purpose, a new tubular photocatalytic reactor that may use solar radiation in combination with artificial radiation was designed; the lamp was turned on when solar UV-A irradiance was below 20 W m(-2), which was observed to be the minimum value to ensure 100% conversion. The efficient distribution of the opaque photocatalyst inside the tubular reactor was achieved by using especially designed star-shaped structures. These structures were employed for the arrangement of groups of eight TiO(2)-SiMgO(x) plates in easy-to-handle channelled units obtaining an adequate flow regime without shading. The prototype continuously removed during one month and under real conditions the H(2)S contained in a 1 L min(-1) air current with a variable inlet concentration in the range of tens of ppmv without release of SO(2). PMID- 22443318 TI - Triplex-directed recognition of a DNA nanostructure assembled by crossover strand exchange. AB - DNA has been widely exploited for the self-assembly of nanosized objects and arrays that offer the potential to act as scaffolds for the spatial positioning of molecular components with nanometer precision. Methods that allow the targeting of components to specific locations within these structures are therefore highly sought after. Here we report that the triplex approach to DNA recognition, which relies on the specific binding of an oligonucleotide within the major groove of double-helical DNA, can be exploited to recognize specific loci within a DNA double-crossover tile and array, a nanostructure assembled by crossover strand exchange. The oligonucleotide can be targeted to both crossover and non-crossover strands and, surprisingly, across the region spanning the crossover junction itself. Moreover, by attaching biotin to the end of the oligonucleotide, we show that streptavidin molecules can be recruited to precise locations within a DX array, with an average spacing of 31.9 (+/-1.3) nm. This is a promising approach that could be exploited to introduce other components compatible with oligonucleotide synthesis into the wide variety of DNA nanostructures assembled by crossover strand exchange, such as those generated by DNA origami. PMID- 22443319 TI - Methionine oxidation enhances kappa-casein amyloid fibril formation. AB - The effects of protein oxidation, for example of methionine residues, are linked to many diseases, including those of protein misfolding, such as Alzheimer's disease. Protein misfolding diseases are characterized by the accumulation of insoluble proteinaceous aggregates comprised mainly of amyloid fibrils. Amyloid containing bodies known as corpora amylacea (CA) are also found in mammary secretory tissue, where their presence slows milk flow. The major milk protein kappa-casein readily forms amyloid fibrils under physiological conditions. Milk exists in an extracellular oxidizing environment. Accordingly, the two methionine residues in kappa-casein (Met(95) and Met(106)) were selectively oxidized and the effects on the fibril-forming propensity, cellular toxicity, chaperone ability, and structure of kappa-casein were determined. Oxidation resulted in an increase in the rate of fibril formation and a greater level of cellular toxicity. beta Casein, which inhibits kappa-casein fibril formation in vitro, was less effective at suppressing fibril formation of oxidized kappa-casein. The ability of kappa casein to prevent the amorphous aggregation of target proteins was slightly enhanced upon methionine oxidation, which may arise from the protein's greater exposed surface hydrophobicity. No significant changes to kappa-casein's intrinsically disordered structure occurred upon oxidation. The enhanced rate of fibril formation of oxidized kappa-casein, coupled with the reduced chaperone ability of beta-casein to prevent this aggregation, may affect casein-casein interaction within the casein micelle and thereby promote kappa-casein aggregation and contribute to the formation of CA. PMID- 22443320 TI - Self-reported and behavioral sound avoidance in tinnitus and hyperacusis subjects, and association with anxiety ratings. AB - OBJECTIVE: The purpose of the study was to analyse the role of sound avoidance and anxiety in tinnitus subjects with hyperacusis, defined as hypersensitivity to low to moderate intensity sounds. DESIGN: A group of tinnitus subjects with hyperacusis was compared to tinnitus subjects without hyperacusis, and healthy controls. For assessing noise avoidance, a questionnaire was developed (noise avoidance questionnaire, NAQ) and the duration of self-exposure to a pure tone was assessed as a behavioral index. Different self-rating instruments concerning tinnitus (STI, TF-12), hyperacusis (GUF), and anxiety (BAI, STAI-T) were used, as well as a psychoacoustic indicator of hyperacusis (ULL). STUDY SAMPLE: Fifty-six tinnitus subjects with/without hyperacusis and 30 controls without tinnitus and hyperacusis participated in the experiment. RESULTS: The findings indicate that subjects with hyperacusis reported significantly more noise-related avoidance in daily life and show significantly shorter exposure to a pure tone than non hyperacusic subjects, while discomfort was at the same level for each individual. Self-reported avoidance behavior correlated significantly with distress attributed to hyperacusis (r =0.81), and with anxiety ratings. CONCLUSIONS: These results suggest that hyperacusis is associated with noise-related avoidance behavior and anxiety. Systematic exposure to sound could play a significant role in the treatment of hyperacusis. PMID- 22443321 TI - Assessing couples' preferences for postoperative sexual rehabilitation before radical prostatectomy. AB - OBJECTIVES: To evaluate the readiness of couples to engage in a sexual rehabilitation programme (SRP) before radical prostatectomy (RP) and to identify barriers to participation in an SRP after RP. To identify couples' current levels of sexual function and intimacy. PATIENTS AND METHODS: Patients completed the International Index of Erectile Function (IIEF) and their partners completed the Female Sexual Function Index (FSFI) to measure sexual function. Couples completed the Miller Social Intimacy Scale (MSIS) to measure intimacy in relationships. All participants were seen by a sexual health clinician after completing the measures to discuss barriers to participation in an SRP, and to receive an education session. RESULTS: Study participants comprised 143 patients and 104 partners. Patients <60 years old had significantly higher sexual function (P < 0.002) compared with those patients aged 60 years and older. Partners' sexual function scores were suggestive of need for further medical evaluation. Partners' participation was cited by patients as important to them enrolling in an SRP. Couples' intimacy levels were strongly correlated (P < 0.0001). CONCLUSIONS: Results suggest that less than 50% of patients are interested in receiving information about the impact of RP on sexual function before surgery. Female sexual function should be assessed as part of any SRP because they may require medical treatment if they are to support rehabilitation efforts for their spouses. Baseline assessment of a couple's sexual function and willingness to participate in an SRP should be performed preoperatively. PMID- 22443323 TI - Ratified Australian Veterinary Association policies January/February 2012. PMID- 22443325 TI - Financial effect of bovine Johne's disease in beef cattle herds in Australia. AB - OBJECTIVE: To assess the financial effect of programs for controlling bovine Johne's disease (BJD) in beef herds. DESIGN: A spreadsheet simulation model of a self-replacing beef herd in south-eastern Australia selling 400-kg steers at 15 months old. METHODS: The model calculated the monthly cash flow, and net present value (NPV) of cumulative cash flow, over 10 years. Four main control options were compared: (1) a base herd (no action to control the disease), (2) test and cull, and (3) partial and (4) total destocking. It was assumed that BJD was eradicated after 3 and 5 years with total and partial destocking, respectively, and not eradicated with a test and cull program. Scenarios were compared for both commercial and stud enterprises. RESULTS: If there was no discount on the sale price of cattle in commercial herds, deaths from BJD had to exceed 5% before the NPV of partial or total destocking was similar to taking no action to control the disease over a 10-year period. When cattle sales incurred a 10% discount, deaths had to exceed 1% before the destocking strategies would break even after 10 years. CONCLUSION: Control options for BJD should be carefully planned on an individual herd basis, as significant production and financial risks accompany destocking programs. Eradication will only be more profitable in the longer term, compared with living with the disease, when discounts on the sale of stock from infected herds are high. This can occur with the selling of store cattle or breeders. In stud herds, BJD will usually cause the total failure of the business. PMID- 22443326 TI - Comparison of three diagnostic techniques for detection of rotavirus and coronavirus in calf faeces in Australia. AB - OBJECTIVE: Compare real-time reverse transcription polymerase chain reaction (qRT PCR), a commercially available enzyme-linked immunosorbent assay (ELISA) and lateral flow immunochromatography assay (LAT) for the detection of rotavirus and coronavirus in faecal samples collected from diarrhoeic calves. DESIGN: Prospective survey. METHOD: Samples were tested at two separate facilities using a commercial ELISA and an in-house qRT-PCR. Simple logistic regression was performed to examine the relationship between the two tests. A subset of samples was screened using qRT-PCR, ELISA and a commercial LAT dipstick (132 faecal samples were tested for coronavirus and 122 samples for rotavirus). RESULTS: Of the 586 samples tested, 131 (22.39%) and 468 (79.86%) were positive for coronavirus and group A rotavirus, respectively, using qRT-PCR. The number of samples positive on ELISA for coronavirus and rotavirus was 73 (12.46%) and 225 (38.40%), respectively. Using LAT, 30 (22.73%) and 43 (35.35%) samples were positive for coronavirus and rotavirus, respectively. Simple linear regression revealed a statistically significant (P < 0.05) but weak (r(2) =-0.07 and -0.40) correlation between the rotavirus/coronavirus qRT-PCR and ELISA, respectively. There was also poor agreement between the LAT and qRT-PCR assays. CONCLUSION: The sensitivity and specificity of the commercial ELISA and LAT assays evaluated in this study were low compared with qRT-PCR. The low positive and negative predictive values of the assays suggests that they were of limited diagnostic benefit in the population sampled. PMID- 22443327 TI - Canine vector-borne disease pathogens in dogs from south-east Queensland and north-east Northern Territory. AB - OBJECTIVES: To determine the prevalence of canine vector-borne diseases (CVBD: Babesia spp., Anaplasma spp., Ehrlichia spp., haemotropic mycoplasmas and Hepatozoon) in Australian dogs; namely, dogs from pounds in south-east Queensland and an indigenous Aboriginal community in the north-east of the Northern Territory. DESIGN AND PROCEDURE: Blood samples were collected from 100 pound dogs and 130 Aboriginal community dogs and screened for the CVBD pathogens using polymerase chain reaction (PCR). All positive PCR products were sequenced for species confirmation. RESULTS: In total, 3 pound dogs and 64 Aboriginal community dogs were infected with at least one CVBD pathogen. Overall, B. vogeli was detected in 13 dogs, A. platys in 49, M. haemocanis in 23, Candidatus Mycoplasma haematoparvum in 3 and C. M. haemobos in 1 dog. Co-infections were detected in 22 Aboriginal community dogs. CONCLUSIONS: This study found B. vogeli, A. platys and haemotropic mycoplasma infections to be common in dogs in subtropical and tropical areas of Australia. This study also reports for the first time the prevalence and genetic characterisation of haemotropic mycoplasmas in dogs in Australia. PMID- 22443328 TI - Identification of parvovirus in the bone marrow of eight cats. AB - OBJECTIVE: To determine if canine parvovirus (CPV) or feline panleucopenia virus (FPV) genomic sequences are present in adult feline bone marrow samples. DESIGN: Bone marrow samples were obtained from 32 semi-feral cats that were euthanased at an animal shelter. DNA was extracted and subjected to conventional polymerase chain reaction (PCR) designed to determine if CPV or FPV DNA was present. Positive PCR products were purified, cloned and sequenced to differentiate between CPV and FPV. RESULTS: Eight of the bone marrow samples contained parvoviral DNA (7 CPV, 1 FPV). CONCLUSION: CPV and FPV DNA can be found in the bone marrow of healthy adult cats. PMID- 22443329 TI - Systemic toxoplasmosis in captive flying-foxes. AB - Systemic toxoplasmosis caused by Toxoplasma gondii was diagnosed in two juvenile, captive flying-foxes (Pteropus conspicillatus and P. scapulatus), which died following respiratory distress. One animal displayed clinical signs suggestive of neurological disease. This is the first report of this disease in megachiropteran bats and adds to the list of differential diagnoses for both systemic and neurological disease in these animals. The role of captivity in the exposure and development of the disease is discussed. PMID- 22443330 TI - Poxvirus infection outbreak in common ringtails (Pseudocheirus peregrinus). AB - Viruses belonging to the Poxviridae family have long been recognised as pathogens of invertebrates and vertebrates alike. Poxvirus infection in Australian macropodids is well described, but few cases have been documented in marsupial species beyond this family. Only one instance has been previously reported in the common ringtail (Pseudocheirus peregrinus). This case report describes a poxvirus infection outbreak in a group of common ringtails held within a zoological collection in eastern Australia. PMID- 22443331 TI - Comparison of two approaches to performing an inferior alveolar nerve block in the horse. AB - OBJECTIVES: To compare two approaches to performing the inferior alveolar nerve block in the horse and to evaluate the consistency of described topographical landmarks. DESIGN: Experimental cadaver model. METHODS: Eleven cadaver heads were positioned to mimic a standing sedated horse and the position of the mandibular foramen approximated. The vertical approach to the approximate location of the mandibular foramen was undertaken and red dye was deposited. The angled approach was then undertaken and blue ink was used to identify it. The heads were then dissected to determine the location of the dye. Placement was categorised as a hit or a miss for each technique for each side of the head. The distance of the dye from the nerve was recorded. Straight lateral radiographs of the sectioned heads were taken to evaluate the topographical landmarks for performing this nerve block. RESULTS: Each method was performed 22 times. A hit was achieved 16 times (73%) for the angled approach and 13 times (59%) for the vertical approach. There was no significant difference between the two approaches (P = 0.34). Radiographs revealed that the topographical landmarks used to approximate the mandibular foramen were relatively accurate. CONCLUSION: Both methods were found to be equivalently accurate. The previously reported topographic landmarks for locating the approximate position of the mandibular foramen on the medial aspect of the mandible were found to be accurate, but currently recommended doses of local anaesthetic may be excessive. PMID- 22443332 TI - Nigropallidal encephalomalacia in horses grazing Rhaponticum repens (creeping knapweed). AB - Nigropallidal encephalomalacia was diagnosed in two horses in northern Victoria that had a history of long-term pasture access to a dense growth of Rhaponticum repens. The region in which the affected horses lived had received well above average rainfall for several months preceding the poisoning. Affected horses had sudden onset of subcutaneous oedema of the head, impaired prehension and mastication, dullness, lethargy and repeated chewing-like jaw movements. Diagnosis was confirmed at necropsy, with characteristic malacic lesions in the substantia nigra and globus pallidus of the brain. This is the first documented case of nigropallidal encephalomalacia in Australian horses associated with R. repens. PMID- 22443333 TI - Bone loss in premenopausal, perimenopausal and postmenopausal women: results of a prospective observational study over 9 years. AB - INTRODUCTION: Few longitudinal data about rates of bone loss in women in midlife exist. Fewer still with their reproductive states having been carefully assessed and sequentially followed-up. METHODS: Complete data from 50 women younger than 60 years (mean age at baseline 48.3 +/- 5.4 years) were prospectively collected over 9 years. This was done by standardized interviews, measurement of endocrinological parameters as well as bone markers and repeated bone mineral density (BMD) measurements using quantitative computer tomography (QCT). Women were classified in three groups according to their reproductive characteristics over 9 years. RESULTS: Significant BMD loss was found in women going through the menopausal transition. In perimenopause, there was a correlation (multiple regression results, r = -0.396 and r = -0.527) between accelerated bone density loss and increased gonadotropin levels (follicle stimulating hormone, luteinizing hormone). Although significantly higher levels of bone markers (osteocalcin, bone specific alkaline phosphatase, c-terminal telopeptide cross-linked collagen type I) were measured in postmenopause, the greatest increase in these markers was seen during the menopausal transition. No individual marker's increase, however, was predictive for perimenopausal bone density loss. The major risk factors for rapid bone loss were a lower initial body weight (< 57 kg), a body mass index < 20 kg/m(2) as well as a positive family history of fragility fractures. CONCLUSIONS: Women in the menopausal transition lose trabecular bone at a rapid rate despite intermittently high and usually normal estrogen levels. This is the only prospective study to date that documents trabecular bone changes in women through the entire perimenopause, which may last up to 10 years. PMID- 22443334 TI - Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies. AB - BACKGROUND: Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration. METHODS: We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers. RESULTS: We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene. CONCLUSIONS: Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes. PMID- 22443335 TI - Effect of substitution of proline-77 to aspartate on the light-driven proton release of bacteriorhodopsin. AB - Wild-type bacteriorhodopsin (BR) and another retinal protein archaerhodopsin 4 (AR4) are both light-driven proton pumps, but exhibit opposite temporal orders of proton release and uptake upon a flash illumination at neutral pH due to a higher pK(a) of proton release complex (PRC) in AR4. Since the 77th residue in the extracellular side is proline (P) in BR, but aspartic acid (D) in AR4, we have mutated P77 in BR by D in this study. The new point mutation was found to affect the kinetics of proton release and the pH dependence significantly. Upon a flash excitation, three components "fast proton release,""proton uptake" and "slow proton release" were observed at neutral pH in P77D. The pK(a) of PRC in the M intermediate was increased from 5.6 in the wild-type to 7.0, and became closer to that in AR4, which is 8.4. The coupling strength between D85 and PRC were also weakened, as expected. These data indicate that the 77th residue in AR4 greatly account for the difference between the two proton pumps. PMID- 22443336 TI - Combined modality treatments in pancreatic cancer. AB - INTRODUCTION: Of all the carcinomas, pancreatic carcinoma (PC) has the highest mortality rate, with a 1- and 5-year survival rate of 25% and less than 5% respectively. This is regardless of the stage at diagnosis. AREAS COVERED: In this review relevant literature assessing the evidence regarding preoperative and adjuvant chemoradiotherapy (CRT) is discussed. Furthermore, new therapeutic approaches are summarized, while the future direction regarding the multimodality approach to PC is also discussed. EXPERT OPINION: The role of combined-modality therapy for PC is continuously evolving. There have been several recent developments, as well as the completion of major, multi-institutional clinical trials. One of the challenges for the busy clinician is to appreciate the variation in staging, surgical expertise, and application of either definitive CRT or neo-adjuvant CRT for local and/or borderline disease. PMID- 22443337 TI - Transient receptor potential genes, smoking, occupational exposures and cough in adults. AB - BACKGROUND: Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough. METHODS: Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model. RESULTS: Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 * 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 * 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05). CONCLUSIONS: TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures. PMID- 22443338 TI - Pyrene-fluorene hybrids containing acetylene linkage as color-tunable emitting materials for organic light-emitting diodes. AB - New blue- to yellow-emitting materials have been developed by incorporating fluorene-based chromophores on pyrene core with acetylene linkage and using multifold palladium-catalyzed cross-coupling reactions. Both mono- and tetrasubstituted derivatives have been synthesized and characterized. The tetrasubstituted derivatives displayed red-shifted emission when compared to the monosubstituted derivative indicative of an extended conjugation in the former. End-capping with a diphenylamine unit further red-shifted the absorption and emission profiles and imparted a weak dipolar character to the molecules. Amine containing derivatives displayed positive solvatochromism in the fluorescence spectra indicating a more polar excited state due to an efficient charge migration from the diphenylamine donor to the pyrene pi-acceptor. All of the derivatives were tested as emitting dopants with host material 4,4'-bis(9H carbazol-9-yl)biphenyl (CBP) in a multilayered OLED and found to exhibit bright blue or yellow electroluminescence. The device utilizing 1,3,6,8-tetrasubstituted pyrene derivative as a dopant emitter displayed highest maximum luminescence 4630 cd/m(2) with power efficiency 3.8 lm/W and current efficiency 7.1 cd/A at 100 cd/m(2) attributable to the proper alignment of energy levels that led to the efficient harvesting of excitons. All of the devices exhibited color purity over a wide range of operating voltages. PMID- 22443339 TI - Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression. AB - Mutations of the CD40 gene have been found in patients with autosomal recessive hyper-immunoglobulin M (HIGM) syndrome type 3. Five patients from four unrelated families with CD40 mutation have been reported so far. Clinical manifestations include recurrent sinopulmonary infections, Pneumocystis carinii pneumonia and Cryptosporidium parvum infection. Affected patients typically have very low levels of IgG and IgA and normal or high levels of IgM. Flow cytometry analysis of these five patients demonstrated that peripheral blood B lymphocytes lacked expression of surface CD40. Herein, we present two siblings from second-degree consanguineous Turkish parents with homozygous CD40 deletion of four nucleotides including the stop codon resulting presumably to a longer protein. Clinical and immunological profile of these patients is similar to the already reported HIGM3 patients except normal CD40 expression on B lymphocytes. This observation emphasizes the requirement of CD40 mutation analysis for definite diagnosis of HIGM3 despite normal flow cytometric expression of CD40, particularly if the immunological and clinical profile is suggestive for HIGM3. PMID- 22443340 TI - Impact of body mass index on the predictive ability of body fat distribution for type 2 diabetes risk in Koreans. AB - AIMS: The optimal anthropometric measure of obesity or body fat distribution that best predicts the risk of Type 2 diabetes in Asians is unclear. Moreover, it has not been determined whether BMI modifies the effect of body fat distribution on diabetes risk in Asians. METHODS: We analysed the anthropometric and laboratory data of 7658 non-diabetic Korean adults (5061 men and 2597 women, aged 20-79 years) who underwent routine medical check-ups at 5-year intervals. BMI, waist circumference, waist-to-height ratio, and bioelectrical impedance (to calculate fat mass and per cent body fat) were measured at baseline. RESULTS: Of the 7658 participants, 278 subjects (3.6%) developed diabetes over 5 years. Each of the anthropometric measures of general obesity (BMI, fat mass, per cent body fat) and central body fat distribution (waist circumference and waist-to-height ratio) was a good predictor of Type 2 diabetes. However, when the areas under the receiver operating characteristic curves were compared, BMI (0.697; 95% CI, 0.669-0.725), waist circumference (0.709, 0.682-0.736) and waist-to-height ratio (0.718, 0.692 0.743) were better predictors of diabetes risk than fat mass (0.672, 0.643-0.700) or per cent body fat (0.657, 0.628-0.686). In the low- (< 23 kg/m(2)) and mid- (23-27 kg/m(2)) BMI groups, the addition of waist-to-height ratio or waist circumference to BMI could improve the prediction of diabetes risk. CONCLUSIONS: BMI, waist circumference and waist-to-height ratio were good predictors of Type 2 diabetes risk in Koreans. In non-obese or less obese subjects, measures of central body fat distribution can help improve the prediction of Type 2 diabetes risk when added to measures of general obesity. PMID- 22443341 TI - Comparative echocardiographic and clinical features of hypertrophic cardiomyopathy in 5 breeds of cats: a retrospective analysis of 344 cases (2001 2011). AB - BACKGROUND: Primary hypertrophic cardiomyopathy (HCM) is the most common feline heart disease and has been demonstrated to be inherited in some breeds. However, few studies have compared HCM phenotypes and survival according to breed. OBJECTIVES: To compare epidemiological characteristics, clinical findings, left ventricular (LV) geometric patterns, and survival in several breeds of cats with HCM. ANIMALS: Three hundred and forty-four cats from 5 different breeds (Persian, Domestic Shorthair [DS], Sphynx, Maine coon [MC], and Chartreux) with primary HCM diagnosed by conventional echocardiography. METHODS: Retrospective study. Cats were classified according to breed and clinical status. RESULTS: Age at the time of diagnosis was lower (P < .001) in MC (median age, 2.5 years) and Sphynx (3.5 years) than in other breeds (OB), ie, 8.0, 8.0, and 11.0 years for DS, Chartreux, and Persians, respectively. The prevalence of LV outflow tract obstruction was higher (P < .001) in Persians (23/41; 56%) than in OB (115/303; 38%). Age at the first cardiac event was lower (P < .01) in MC (median age, 2.5 years) than in OB (7.0 years). All cats surviving > 15 years of age were DS, Persians, or Chartreux. Sudden death (representing 24% of all cardiac deaths) was observed only in 3 breeds (DS, MC, and Sphynx). CONCLUSION AND CLINICAL IMPORTANCE: As in humans, feline HCM is characterized by marked phenotypic variability with several breed-dependent features regarding epidemiology, LV geometric patterns, and clinical course (ie, age at diagnosis, 1st cardiac event, and cause of death). PMID- 22443342 TI - Benefits and limitations of errorless learning after surviving pediatric brain tumors: a case study. AB - Survivors of childhood brain tumors often acquire complex cognitive difficulties including impairments in attention, processing speed, and different aspects of memory function. These impairments can affect their learning in the real world and in the classroom. However, the efficacy of memory rehabilitation techniques post treatment has not yet been assessed in these patients. We present the case of a 15-year-old boy, C.J., who acquired a profound episodic memory impairment due to a metastatic germ cell tumor and subsequent treatment. The focus of this study was the application of an errorless learning technique to a verbal learning task. We were interested to test whether C.J. would benefit from errorless learning as compared to errorful learning. Results of an experiment and a follow up study indicated that C.J.'s learning was more efficient under errorless conditions, although access to the information from long-term memory remained cue dependent. Implications for learning with or without the support of episodic memory are discussed, and future directions for memory rehabilitation of brain tumor survivors are outlined. PMID- 22443343 TI - Biomedicine inside out: an ethnography of brain surgery. AB - The article discusses patient objectification from the viewpoint of the objectifying, rather than the objectified party. Resisting a dichotomy between physician-objectifying and ethnographer-humanising, the author portrays objectification not as an essential by-product of professional tendencies, epistemological bases, practical necessities and processes of socialisation but as highly dependent upon context. A further look is given to the settings within which the discursive dynamics of 'objectivity' and 'experience' come about through artefacts, space, symbols, bodily appearances and so on. The author portrays her relationship with Omer, a brain cancer patient whom she has followed over a period of 18 months and then focuses on her observations of his brain surgery. The fluctuations in the author's relationship with Omer (as a subject and as a body, alternately) are brought within their immediate contextual elements. PMID- 22443344 TI - Management of uncomplicated malaria in febrile under five-year-old children by community health workers in Madagascar: reliability of malaria rapid diagnostic tests. AB - BACKGROUND: Early diagnosis, as well as prompt and effective treatment of uncomplicated malaria, are essential components of the anti-malaria strategy in Madagascar to prevent severe malaria, reduce mortality and limit malaria transmission. The purpose of this study was to assess the performance of the malaria rapid diagnostic tests (RDTs) used by community health workers (CHWs) by comparing RDT results with two reference methods (microscopy and Polymerase Chain Reaction, PCR). METHODS: Eight CHWs in two districts, each with a different level of endemic malaria transmission, were trained to use RDTs in the management of febrile children under five years of age. RDTs were performed by CHWs in all febrile children who consulted for fever. In parallel, retrospective parasitological diagnoses were made by microscopy and PCR. The results of these different diagnostic methods were analysed to evaluate the diagnostic performance of the RDTs administered by the CHWs. The stability of the RDTs stored by CHWs was also evaluated. RESULTS: Among 190 febrile children with suspected malaria who visited CHWs between February 2009 and February 2010, 89.5% were found to be positive for malaria parasites by PCR, 51.6% were positive by microscopy and 55.8% were positive by RDT. The performance accuracy of the RDTs used by CHWs in terms of sensitivity, specificity, positive and negative predictive values was greater than 85%. Concordance between microscopy and RDT, estimated by the Kappa value was 0.83 (95% CI: 0.75-0.91). RDTs stored by CHWs for 24 months were capable of detecting Plasmodium falciparum in blood at a level of 200 parasites/MUl. CONCLUSION: Introduction of easy-to-use diagnostic tools, such as RDTs, at the community level appears to be an effective strategy for improving febrile patient management and for reducing excessive use of anti-malarial drugs. PMID- 22443346 TI - Nanotube-bridged wires with sub-10 nm gaps. AB - We report a simple but efficient method to synthesize carbon nanotube-bridged wires (NBWs) with gaps as small as 5 nm. In this method, we have combined a strategy for assembling carbon nanotubes (CNTs) inside anodized aluminum oxide pores and the on-wire lithography technique to fabricate CNT-bridged wires with gap sizes deliberately tailored over the 5-600 nm range. As a proof-of-concept demonstration of the utility of this architecture, we have prepared NBW-based chemical and biosensors which exhibit higher analyte sensitivity (lower limits of detection) than those based on planar CNT networks. This observation is attributed to a greater surface-to-volume ratio of CNTs in the NBWs than those in the planar CNT devices. Because of the ease of synthesis and high yield of NBWs, this technique may enable the further incorporation of CNT-based architectures into various nanoelectronic and sensor platforms. PMID- 22443345 TI - Comparative transcriptomics of three Poaceae species reveals patterns of gene expression evolution. AB - The Poaceae family, also known as the grasses, includes agronomically important cereal crops such as rice, maize, sorghum, and wheat. Previous comparative studies have shown that much of the gene content is shared among the grasses; however, functional conservation of orthologous genes has yet to be explored. To gain an understanding of the genome-wide patterns of evolution of gene expression across reproductive tissues, we employed a sequence-based approach to compare analogous transcriptomes in species representing three Poaceae subgroups including the Pooideae (Brachypodium distachyon), the Panicoideae (sorghum), and the Ehrhartoideae (rice). Our transcriptome analyses reveal that only a fraction of orthologous genes exhibit conserved expression patterns. A high proportion of conserved orthologs include genes that are upregulated in physiologically similar tissues such as leaves, anther, pistil, and embryo, while orthologs that are highly expressed in seeds show the most diverged expression patterns. More generally, we show that evolution of gene expression profiles and coding sequences in the grasses may be linked. Genes that are highly and broadly expressed tend to be conserved at the coding sequence level while genes with narrow expression patterns show accelerated rates of sequence evolution. We further show that orthologs in syntenic genomic blocks are more likely to share correlated expression patterns compared with non-syntenic orthologs. These findings are important for agricultural improvement because sequence information is transferred from model species, such as Brachypodium, rice, and sorghum to crop plants without sequenced genomes. PMID- 22443347 TI - Molecular profiling of oral microbiota in jawbone samples of bisphosphonate related osteonecrosis of the jaw. AB - OBJECTIVE: Infection has been hypothesized as a contributing factor to bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ). The objective of this study was to determine the bacterial colonization of jawbone and identify the bacterial phylotypes associated with BRONJ. MATERIALS AND METHODS: Culture independent 16S rRNA gene-based molecular techniques were used to determine and compare the total bacterial diversity in bone samples collected from 12 patients with cancer (six, BRONJ with history of BP; six, controls without BRONJ, no history of BP but have infection). RESULTS: Denaturing gradient gel electrophoresis profile and Dice coefficient displayed a statistically significant clustering of profiles, indicating different bacterial population in BRONJ subjects and control. The top three genera ranked among the BRONJ group were Streptococcus (29%), Eubacterium (9%), and Pseudoramibacter (8%), while in the control group were Parvimonas (17%), Streptococcus (15%), and Fusobacterium (15%). H&E sections of BRONJ bone revealed layers of bacteria along the surfaces and often are packed into the scalloped edges of the bone. CONCLUSION: This study using limited sample size indicated that the jawbone associated with BRONJ was heavily colonized by specific oral bacteria and there were apparent differences between the microbiota of BRONJ and controls. PMID- 22443348 TI - Bias and imprecision in posture percentile variables estimated from short exposure samples. AB - BACKGROUND: Upper arm postures are believed to be an important risk determinant for musculoskeletal disorder development in the neck and shoulders. The 10th and 90th percentiles of the angular elevation distribution have been reported in many studies as measures of neutral and extreme postural exposures, and variation has been quantified by the 10th-90th percentile range. Further, the 50th percentile is commonly reported as a measure of "average" exposure. These four variables have been estimated using samples of observed or directly measured postures, typically using sampling durations between 5 and 120 min. METHODS: The present study examined the statistical properties of estimated full-shift values of the 10th, 50th and 90th percentile and the 10th-90th percentile range of right upper arm elevation obtained from samples of seven different durations, ranging from 5 to 240 min. The sampling strategies were realized by simulation, using a parent data set of 73 full-shift, continuous inclinometer recordings among hairdressers. For each shift, sampling duration and exposure variable, the mean, standard deviation and sample dispersion limits (2.5% and 97.5%) of all possible sample estimates obtained at one minute intervals were calculated and compared to the true full-shift exposure value. RESULTS: Estimates of the 10th percentile proved to be upward biased with limited sampling, and those of the 90th percentile and the percentile range, downward biased. The 50th percentile was also slightly upwards biased. For all variables, bias was more severe with shorter sampling durations, and it correlated significantly with the true full-shift value for the 10th and 90th percentiles and the percentile range. As expected, shorter samples led to decreased precision of the estimate; sample standard deviations correlated strongly with true full-shift exposure values. CONCLUSIONS: The documented risk of pronounced bias and low precision of percentile estimates obtained from short posture samples presents a concern in ergonomics research and practice, and suggests that alternative, unbiased exposure variables should be considered if data collection resources are restricted. PMID- 22443349 TI - Long-term cryopreservation model of rat salivary gland stem cells for future therapy in irradiated head and neck cancer patients. AB - Irradiated head and neck cancer patients suffer from irreversible loss of salivary gland (SG) function, along with significant morbidity and compromised quality of life. To date there is no biologically-based treatment for this distress. Adult salivary gland stem cells are promising candidates for autologous transplantation therapy in the context of tissue-engineered artificial SGs or direct cell therapy. The major restrictions in handling such cells are their limited lifespan during in vitro cultivation, resulting in a narrow time-window for implantation and a risk of tumorigenic changes during culture. To overcome these difficulties, we tested in a rat model the possibility of establishing a personal/autologous SG stem cell bank. SG's integrin-alpha6beta1-expressing cells were shown to hold a subpopulation of SG-specific progenitor-cells. Explanted and cultured single cell-originated clones were cryopreserved for up to 3 years and shown to exhibit genetic and functional stability similar to noncryopreserved cells, as was emphasized by soft agar assay, division potential assessment, flow cytometric analysis, real-time reverse transcriptase-polymerase chain reaction, in vitro three-dimensional differentiation assay, and immunofluorescence confocal microscopy. Future integration of the novel strategies presented herein to a clinical therapeutic model will allow safe preservation until transplantation and repeated transplantation if needed. These tools open a new venue for adult autologous stem-cell transplantation-based SG regeneration. PMID- 22443350 TI - Transport disposition using the Transport Risk Assessment in Pediatrics (TRAP) score. AB - BACKGROUND: Determining appropriate disposition for referred pediatric patients is difficult, since it relies primarily on a telephone description of the patient. In this study, we evaluate the Transport Risk Assessment in Pediatrics (TRAP) score's ability to assist in appropriate placement of these patients. This novel tool is derived from physiologic variables. OBJECTIVES: To determine the feasibility of calculating a TRAP score and whether a higher score correlates with pediatric intensive care unit (PICU) admission. METHODS: We performed an observational study of pediatric patients transported by a specialized team to a tertiary care center and the feasibility of implementing the TRAP tool. Patients were eligible if transported by the pediatric specialty transport team for direct admission to the children's hospital. The TRAP score was obtained either through chart review of the transport team's initial assessment or in real time by the transport team. RESULTS: A total of 269 patients were identified, with 238 patients included in the study. Using logistic regression, higher TRAP scores were associated with PICU admission (odds ratio [OR] 1.40, p < 0.001). Patients with a higher score were also less likely to leave the PICU within 24 hours (OR 0.79, p < 0.001). CONCLUSION: The TRAP score is a novel objective pediatric transport assessment tool where an elevated score is associated with PICU admission for more than 24 hours. This score may assist with the triage decisions for transported pediatric patients. PMID- 22443351 TI - Evaluating the effects of bioremediation on genotoxicity of polycyclic aromatic hydrocarbon-contaminated soil using genetically engineered, higher eukaryotic cell lines. AB - Bioremediation is one of the commonly applied remediation strategies at sites contaminated with polycyclic aromatic hydrocarbons (PAHs). However, remediation goals are typically based on removal of the target contaminants rather than on broader measures related to health risks. We investigated changes in the toxicity and genotoxicity of PAH-contaminated soil from a former manufactured-gas plant site before and after two simulated bioremediation processes: a sequencing batch bioreactor system and a continuous-flow column system. Toxicity and genotoxicity of the residues from solvent extracts of the soil were determined by the chicken DT40 B-lymphocyte isogenic cell line and its DNA-repair-deficient mutants. Although both bioremediation processes significantly removed PAHs from the contaminated soil (bioreactor 69% removal, column 84% removal), bioreactor treatment resulted in an increase in toxicity and genotoxicity over the course of a treatment cycle, whereas long-term column treatment resulted in a decrease in toxicity and genotoxicity. However, when screening with a battery of DT40 mutants for genotoxicity profiling, we found that column treatment induced DNA damage types that were not observed in untreated soil. Toxicity and genotoxicity bioassays can supplement chemical analysis-based risk assessment for contaminated soil when evaluating the efficacy of bioremediation. PMID- 22443352 TI - Synthesis and characterizations of ternary InGaAs nanowires by a two-step growth method for high-performance electronic devices. AB - InAs nanowires have been extensively studied for high-speed and high-frequency electronics due to the low effective electron mass and corresponding high carrier mobility. However, further applications still suffer from the significant leakage current in InAs nanowire devices arising from the small electronic band gap. Here, we demonstrate the successful synthesis of ternary InGaAs nanowires in order to tackle this leakage issue utilizing the larger band gap material but at the same time not sacrificing the high electron mobility. In this work, we adapt a two-step growth method on amorphous SiO(2)/Si substrates which significantly reduces the kinked morphology and surface coating along the nanowires. The grown nanowires exhibit excellent crystallinity and uniform stoichiometric composition along the entire length of the nanowires. More importantly, the electrical properties of those nanowires are found to be remarkably impressive with I(ON)/I(OFF) ratio >10(5), field-effect mobility of ~2700 cm(2)/(V.s), and ON current density of ~0.9 mA/MUm. These nanowires are then employed in the contact printing and achieve large-scale assembly of nanowire parallel arrays which further illustrate the potential for utilizing these high-performance nanowires on substrates for the fabrication of future integrated circuits. PMID- 22443353 TI - Common variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/2), adiponectin concentrations, and diabetes incidence in the Diabetes Prevention Program. AB - AIMS: Baseline adiponectin concentrations predict incident Type 2 diabetes mellitus in the Diabetes Prevention Program. We tested the hypothesis that common variants in the genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1, ADIPOR2) would associate with circulating adiponectin concentrations and/or with diabetes incidence in the Diabetes Prevention Program population. METHODS: Seventy-seven tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ (24), ADIPOR1 (22) and ADIPOR2 (31) were genotyped. Associations of SNPs with baseline adiponectin concentrations were evaluated using linear modelling. Associations of SNPs with diabetes incidence were evaluated using Cox proportional hazards modelling. RESULTS: Thirteen of 24 ADIPOQ SNPs were significantly associated with baseline adiponectin concentrations. Multivariable analysis including these 13 SNPs revealed strong independent contributions of rs17366568, rs1648707, rs17373414 and rs1403696 with adiponectin concentrations. However, no ADIPOQ SNPs were directly associated with diabetes incidence. Two ADIPOR1 SNPs (rs1342387 and rs12733285) were associated with ~18% increased diabetes incidence for carriers of the minor allele without differences across treatment groups, and without any relationship with adiponectin concentrations. CONCLUSIONS: ADIPOQ SNPs are significantly associated with adiponectin concentrations in the Diabetes Prevention Program cohort. This observation extends prior observations from unselected populations of European descent into a broader multi-ethnic population, and confirms the relevance of these variants in an obese/dysglycaemic population. Despite the robust relationship between adiponectin concentrations and diabetes risk in this cohort, variants in ADIPOQ that relate to adiponectin concentrations do not relate to diabetes risk in this population. ADIPOR1 variants exerted significant effects on diabetes risk distinct from any effect of adiponectin concentrations. PMID- 22443354 TI - Inverse Batschelet distributions for circular data. AB - We provide four-parameter families of distributions on the circle which are unimodal and display the widest ranges of both skewness and peakedness yet available. Our approach is to transform the scale of a generating distribution, such as the von Mises, using various nontrivial extensions of an approach first used in Batschelet's (1981, Circular Statistics in Biology) book. The key is to employ inverses of Batschelet-type transformations in certain ways; these exhibit considerable advantages over direct Batschelet transformations. The skewness transformation is especially appealing as it has no effect on the normalizing constant. As well as a variety of interesting theoretical properties, when likelihood inference is explored these distributions display orthogonality between elements of a pairing of parameters into (location, skewness) and (concentration, peakedness). Further, the location parameter can sometimes be made approximately orthogonal to all the other parameters. Profile likelihoods come to the fore in practice. Two illustrative applications, one concerning the locomotion of a Drosophila fly larva, the other analyzing a large set of sudden infant death syndrome data, are investigated. PMID- 22443361 TI - Biometrics. Report of the editors--2011. PMID- 22443362 TI - Impregnation of bone chips with alendronate and cefazolin, combined with demineralized bone matrix: a bone chamber study in goats. AB - BACKGROUND: Bone grafts from bone banks might be mixed with bisphosphonates to inhibit the osteoclastic response. This inhibition prevents the osteoclasts to resorb the allograft bone before new bone has been formed by the osteoblasts, which might prevent instability. Since bisphosphonates may not only inhibit osteoclasts, but also osteoblasts and thus bone formation, we studied different bisphosphonate concentrations combined with allograft bone. We investigated whether locally applied alendronate has an optimum dose with respect to bone resorption and formation. Further, we questioned whether the addition of demineralized bone matrix (DBM), would stimulate bone formation. Finally, we studied the effect of high levels of antibiotics on bone allograft healing, since mixing allograft bone with antibiotics might reduce the infection risk. METHODS: 25 goats received eight bone conduction chambers in the cortical bone of the proximal medial tibia. Five concentrations of alendronate (0, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, and 10 mg/mL) were tested in combination with allograft bone and supplemented with cefazolin (200 MUg/mL). Allograft not supplemented with alendronate and cefazolin served as control. In addition, allograft mixed with demineralized bone matrix, with and without alendronate, was tested. After 12 weeks, graft bone area and new bone area were determined with manual point counting. RESULTS: Graft resorption decreased significantly (p < 0.001) with increasing alendronate concentration. The area of new bone in the 1 mg/mL alendronate group was significantly (p = 0.002) higher when compared to the 10 mg/mL group. No differences could be observed between the group without alendronate, but with demineralized bone, and the control groups. CONCLUSIONS: A dose-response relationship for local application of alendronate has been shown in this study. Most new bone was present at 1 mg/mL alendronate. Local application of cefazolin had no effect on bone remodelling. PMID- 22443363 TI - OsWRKY22, a monocot WRKY gene, plays a role in the resistance response to blast. AB - With the aim of identifying novel regulators of host and nonhost resistance to fungi in rice, we carried out a systematic mutant screen of mutagenized lines. Two mutant wrky22 knockout lines revealed clear-cut enhanced susceptibility to both virulent and avirulent Magnaporthe oryzae strains and altered cellular responses to nonhost Magnaporthe grisea and Blumeria graminis fungi. In addition, the analysis of the pathogen responses of 24 overexpressor OsWRKY22 lines revealed enhanced resistance phenotypes on infection with virulent M. oryzae strain, confirming that OsWRKY22 is involved in rice resistance to blast. Bioinformatic analyses determined that the OsWRKY22 gene belongs to a well defined cluster of monocot-specific WRKYs. The co-regulatory analysis revealed no significant co-regulation of OsWRKY22 with a representative panel of OsWRKYs, supporting its unique role in a series of transcriptional responses. In contrast, inquiring a subset of biotic stress-related Affymetrix data, a large number of resistance and defence-related genes were found to be putatively co-expressed with OsWRKY22. Taken together, all gathered experimental evidence places the monocot-specific OsWRKY22 gene at the convergence point of signal transduction circuits in response to both host and nonhost fungi encountering rice plants. PMID- 22443364 TI - Tedarenes A and B: structural and stereochemical analysis of two new strained cyclic diarylheptanoids from the marine sponge Tedania ignis. AB - Ring strain causes planar chirality in tedarenes A and B, two cyclic diarylheptanoids isolated from the marine sponge Tedania ignis. In both molecules, the chiral plane is an olefinic system, which is very rare among natural products. In tedarene A (1), interconversion is too fast to allow isolation of the enantiomeric atropisomers but still slow enough to cause coalescence of some (1)H and (13)C NMR signals at room temperature. In tedarene B (2), which also shows stable central and axial chirality, the two planar diastereomers are in slow equilibrium. Tedarene B is the smallest natural product with central, axial, and planar chirality in the same simple molecule. The identification of planar chirality as the difference between its conformational isomers allowed the use of theoretical prediction of the CD spectrum to determine the absolute configuration of the stereogenic carbon C-9 as well as of the biphenyl chiral axis. PMID- 22443366 TI - The brain as a target for development of new class of drugs for the treatment of somatic diseases. AB - Usually, drugs are designed to modulate at cellular level the activity of peripheral tissues and organs affected by pathological processes. Despite unprecedented investment, the number of newly developed drugs remains low. Therefore, potent new drugs that directly influence and restore activity of peripheral tissues and organs altered by somatic diseases are being released into clinical use at the same rate as seen in the past. The brain has long been known to regulate the function of all tissues and organs in the body. This regulatory influence has also been shown to play an important role during pathological conditions, when the brain triggers protective and adaptive reactions modulating the development and progression of somatic diseases affecting peripheral tissues and organs. Importantly, several drugs recently used for the treatment of somatic diseases (e.g., beta-blockers, sartans, statins) also act at the level of the CNS, where they modulate the protective and adaptive reactions of the brain. Pharmacological modulation of brain structures activities may represent the basis for a new approach towards the treatment of various somatic diseases (e.g., cardiovascular and gastrointestinal diseases). Therefore, brain-targeted therapy of somatic diseases may significantly extend the area for development of new drugs. PMID- 22443365 TI - Role of mitochondrial Ca2+ in the regulation of cellular energetics. AB - Calcium is an important signaling molecule involved in the regulation of many cellular functions. The large free energy in the Ca(2+) ion membrane gradients makes Ca(2+) signaling inherently sensitive to the available cellular free energy, primarily in the form of ATP. In addition, Ca(2+) regulates many cellular ATP-consuming reactions such as muscle contraction, exocytosis, biosynthesis, and neuronal signaling. Thus, Ca(2+) becomes a logical candidate as a signaling molecule for modulating ATP hydrolysis and synthesis during changes in numerous forms of cellular work. Mitochondria are the primary source of aerobic energy production in mammalian cells and also maintain a large Ca(2+) gradient across their inner membrane, providing a signaling potential for this molecule. The demonstrated link between cytosolic and mitochondrial Ca(2+) concentrations, identification of transport mechanisms, and the proximity of mitochondria to Ca(2+) release sites further supports the notion that Ca(2+) can be an important signaling molecule in the energy metabolism interplay of the cytosol with the mitochondria. Here we review sites within the mitochondria where Ca(2+) plays a role in the regulation of ATP generation and potentially contributes to the orchestration of cellular metabolic homeostasis. Early work on isolated enzymes pointed to several matrix dehydrogenases that are stimulated by Ca(2+), which were confirmed in the intact mitochondrion as well as cellular and in vivo systems. However, studies in these intact systems suggested a more expansive influence of Ca(2+) on mitochondrial energy conversion. Numerous noninvasive approaches monitoring NADH, mitochondrial membrane potential, oxygen consumption, and workloads suggest significant effects of Ca(2+) on other elements of NADH generation as well as downstream elements of oxidative phosphorylation, including the F(1)F(O)-ATPase and the cytochrome chain. These other potential elements of Ca(2+) modification of mitochondrial energy conversion will be the focus of this review. Though most specific molecular mechanisms have yet to be elucidated, it is clear that Ca(2+) provides a balanced activation of mitochondrial energy metabolism that exceeds the alteration of dehydrogenases alone. PMID- 22443367 TI - Comparative potential therapeutic effect of sesame oil and peanut oil against acute monocrotaline (Crotalaria) poisoning in a rat model. AB - BACKGROUND: Many Crotalaria plant species contain hepatotoxic pyrrolizidine alkaloids (such as monocrotaline) that can cause acute and chronic poisoning in cattle and other animals. HYPOTHESIS: Peanut oil, atropine sulfate, and antidiarrheal agents are used to treat acute monocrotaline poisoning. The effect of sesame on acute monocrotaline poisoning has never been investigated. ANIMALS: Fifty male Sprague-Dawley rats were used for toxicity studies. METHODS: Experiment 1: Group I, control. Groups II-IV were given monocrotaline (205.2 mg/kg) and euthanized 6, 12, and 24 hours later. Experiment 2: Group I, control. Group II monocrotaline alone (205.2 mg/kg). Groups III-VI were given monocrotaline (205.2 mg/kg) and 1 hour later, Groups III and IV were given sesame oil (1 and 2 mL/kg) and Groups V and VI were given peanut oil (1 and 2 mL/kg). RESULTS: Monocrotaline significantly decreased (P < .05) serum amylase activity, but, over time, increased (P < .05) pancreatic and lung injury. AST and ALT activity and liver injury peaked at 24 hours. Sesame oil and peanut oil (P < .05) inhibited the changes in all tested parameters in acute monocrotaline poisoning. Although peanut oil inhibited acute monocrotaline poisoning, it induced steatosis, but sesame oil did not. CONCLUSION AND CLINICAL IMPORTANCE: We hypothesize that early pancreatic and lung injury and late liver injury contribute to acute monocrotaline poisoning and that sesame oil is more efficacious than peanut oil against acute monocrotaline poisoning in rats. However, additional studies are needed to confirm that these oils have the same effects in cattle and other animals. PMID- 22443368 TI - The health status of postpartum immigrant women in Taiwan. AB - AIMS: This study aims to contribute to the current body of literature by examining immigrant women's postpartum health in the context of Taiwan, in particular, their experience with postpartum stress and depression as well as the levels of social support available to them. This study also aims to identify predictors of their postpartum health status. BACKGROUND: While there has been considerable research on the risk factors for poor postpartum health in the general population, research on the factors influencing immigrant women's postpartum health has been limited. DESIGN: A non-experimental research design. METHODS: We collected data from a sample of 340 immigrant postpartum women who could speak Mandarin Chinese, recruited from 10 general hospitals and one obstetric clinic in Taiwan from March 2005-September 2006. The Hung Postpartum Stress Scale, Beck Depression Inventory-II, Social Support Scale and Chinese Health Questionnaire were used in this study. RESULTS: We found that immigrant women's postpartum health status differed significantly in relation to their key helpers, depression status, levels of postpartum stress and social support. The logistic regression analysis showed that a one-point increase in immigrant women's postpartum stress increased the probability of suffering from minor psychiatric morbidity by 1.04 times. CONCLUSIONS: These findings suggest that health care professionals should pay attention not only to immigrant postpartum women's basic financial and support needs but also to their postpartum stress and stressors. RELEVANCE TO CLINICAL PRACTICE: The use of trained community health advocates in partnership with registered nurses can help meet the needs of postpartum women and improve maternal and infant health through their home visits. These nursing interventions should be tailored specifically to decrease immigrant Asian women's postpartum stress and improve their overall health status and well-being. PMID- 22443369 TI - Ageing-associated changes in cellular immunity based on the SENIEUR protocol. AB - To investigate ageing-associated changes in cellular immunity, we recruited three groups of healthy subjects based on SENIEUR protocol criteria. In addition, 10 subjects were randomly selected from each group to isolate their T cells from peripheral blood mononuclear cells; T cell proliferation after phytohemagglutinin (PHA) stimulation was determined by methyl thiazolyl tetrazolium assays. There were no marked differences in the absolute numbers of peripheral blood T cells, NK cells or B cells among the three groups (P > 0.05). Also, no significant differences were noted in the numbers of CD4+ cells, CD8+ cells, or the CD4+/CD8+ ratios (P > 0.05). After PHA stimulation, T cell proliferation was markedly increased, with the highest level in group C and the lowest level in group A (P < 0.05). Cytokine-induced killer tumouricidal activities were also dramatically increased, with the highest activity in group C and the lowest activity in group A (P < 0.05). Our findings suggest that the number of immune cells remains unchanged with advanced age. However, there is a trend for decreased cellular immunity with an increase in age. PMID- 22443370 TI - Flexibility in children with autism spectrum disorders (ASD): inconsistency between neuropsychological tests and parent-based rating scales. AB - In this study, we compared neuropsychological tests and parent-based ratings of flexibility in a sample of children with autism spectrum disorders (ASD). We investigated the discriminant validity of the domain-specific flexibility measures by comparison with the domain general measures, general behavioral problems, general ASD-related traits, and general intelligence. Tests and parent based ratings of flexibility were not significantly correlated. Parent-based ratings were strongly related with the three broadband measures, whereas the discriminant validity indices of the neuropsychological tests were satisfactory. These findings suggest that parent-based ratings do not reflect the specific executive construct of flexibility, but instead reflect a broad spectrum of general child characteristics. PMID- 22443371 TI - Is podoplanin expression associated with the proliferative activity of ameloblastomas? AB - OBJECTIVES: The aim of this study was to investigate the relationship between podoplanin expression and proliferative activity of ameloblastomas and remnants of the odontogenic epithelium from dental follicles (DF) of unerupted teeth. SUBJECTS AND METHODS: Thirty-three paraffin-embedded ameloblastomas and thirty two DF obtained of unerupted teeth were analyzed by immunohistochemistry using anti-human podoplanin and anti-Ki-67 antibodies. Podoplanin expression in odontogenic epithelial cells was evaluated using a scoring method, and the Ki-67 labeling index was determined by the percentage of positive odontogenic cells. RESULTS: All ameloblastomas displayed podoplanin expression in ameloblast-like cells of the epithelial islands. Membranous expression of podoplanin in ameloblastomas was stronger than in the remnants of odontogenic epithelium (P = 0.001). Statistically significant difference was observed between the cytoplasmic and membranous expression of podoplanin in the remnants of odontogenic epithelium (P = 0.001). The index of epithelial odontogenic proliferative activity, verified by Ki-67 expression, was higher in ameloblastomas vs remnants of odontogenic epithelium (P < 0.001). No statistically significant correlation was identified between podoplanin and the cellular odontogenic proliferative activity in meloblastomas and DF (P > 0.05). CONCLUSIONS: These results provide evidence that there is no connection between podoplanin immunostaining and odontogenic cellular proliferative activity and suggest a role for membranous podoplanin expression in the local invasion of ameloblastomas. PMID- 22443372 TI - Metachronous metastasis- and survival-analysis show prognostic importance of lymphadenectomy for colon carcinomas. AB - BACKGROUND: Lymphadenectomy is performed to assess patient prognosis and to prevent metastasizing. Recently, it was questioned whether lymph node metastases were capable of metastasizing and therefore, if lymphadenectomy was still adequate. We evaluated whether the nodal status impacts on the occurrence of distant metastases by analyzing a highly selected cohort of colon cancer patients. METHODS: 1,395 patients underwent surgery exclusively for colon cancer at the University of Lubeck between 01/1993 and 12/2008. The following exclusion criteria were applied: synchronous metastasis, R1-resection, prior/synchronous second carcinoma, age < 50 years, positive family history, inflammatory bowel disease, FAP, HNPCC, and follow-up < 5 years. The remaining 421 patients were divided into groups with (TM+, n = 75) or without (TM-, n = 346) the occurrence of metastasis throughout a 5-year follow-up. RESULTS: Five-year survival rates for TM + and TM- were 21% and 73%, respectively (p < 0.0001). Survival rates differed significantly for N0 vs. N2, grading 2 vs. 3, UICC-I vs. -II and UICC-I vs. -III (p < 0.05). Regression analysis revealed higher age upon diagnosis, increasing N- and increasing T-category to significantly impact on recurrence free survival while increasing N-and T-category were significant parameters for the risk to develop metastases within 5-years after surgery (HR 1.97 and 1.78; p < 0.0001). CONCLUSIONS: Besides a higher T-category, a positive N-stage independently implies a higher probability to develop distant metastases and correlates with poor survival. Our data thus show a prognostic relevance of lymphadenectomy which should therefore be retained until conclusive studies suggest the unimportance of lmyphadenectomy. PMID- 22443373 TI - Photostability and skin penetration of different E-resveratrol-loaded supramolecular structures. AB - It is desirable and challenging to prevent E-resveratrol (E-RSV) from photoisomerizing to its Z-configuration to preserve its biological and pharmacological activities. The aim of this research was to evaluate the photostability of E-RSV-loaded supramolecular structures and the skin penetration profile of chemically and physically stable nanoestructured formulations. Different supramolecular structures were developed to act as carriers for E-RSV, that is, liposomes, polymeric lipid-core nanocapsules and nanospheres and solid lipid nanoparticles. The degrees of photostability of these formulations were compared with that of an ethanolic solution of E-RSV. The skin penetration profiles of the stable formulations were obtained using vertical diffusion cells (protected from light and under UVA radiation) with porcine skin as the membrane, followed by tape stripping and separation of the viable epidermis and dermis in a heated water bath. Photoisomerization was significantly delayed by the association of resveratrol with the nanocarriers independently of the supramolecular structure. Liposomes were the particles capable of maintaining E RSV concentration for the longest time. On the other hand, E-RSV-loaded liposomes reduced in size showing low physical stability under UVA radiation. In the dark, the skin penetration profiles were very similar, but under UVA radiation the E RSV-loaded nanocarriers showed increasing amounts in the total epidermis. PMID- 22443374 TI - Expeditious stochastic calculation of multiexciton generation rates in semiconductor nanocrystals. AB - A stochastic method is developed to calculate the multiexciton generation (MEG) rates in semiconductor nanocrystals (NCs). The numerical effort scales near linearly with system size allowing the study of MEG rates up to diameters and exciton energies previously unattainable using atomistic calculations. Illustrations are given for CdSe NCs of sizes and energies relevant to current experimental setups, where direct methods require treatment of over 10(11) states. The approach is not limited to the study of MEG and can be applied to calculate other correlated electronic processes. PMID- 22443375 TI - Sero-epidemiological evaluation of changes in Plasmodium falciparum and Plasmodium vivax transmission patterns over the rainy season in Cambodia. AB - BACKGROUND: In Cambodia, malaria transmission is low and most cases occur in forested areas. Sero-epidemiological techniques can be used to identify both areas of ongoing transmission and high-risk groups to be targeted by control interventions. This study utilizes repeated cross-sectional data to assess the risk of being malaria sero-positive at two consecutive time points during the rainy season and investigates who is most likely to sero-convert over the transmission season. METHODS: In 2005, two cross-sectional surveys, one in the middle and the other at the end of the malaria transmission season, were carried out in two ecologically distinct regions in Cambodia. Parasitological and serological data were collected in four districts. Antibodies to Plasmodium falciparum Glutamate Rich Protein (GLURP) and Plasmodium vivax Merozoite Surface Protein-1(19) (MSP-1(19)) were detected using Enzyme Linked Immunosorbent Assay (ELISA). The force of infection was estimated using a simple catalytic model fitted using maximum likelihood methods. Risks for sero-converting during the rainy season were analysed using the Classification and Regression Tree (CART) method. RESULTS: A total of 804 individuals participating in both surveys were analysed. The overall parasite prevalence was low (4.6% and 2.0% for P. falciparum and 7.9% and 6.0% for P. vivax in August and November respectively). P. falciparum force of infection was higher in the eastern region and increased between August and November, whilst P. vivax force of infection was higher in the western region and remained similar in both surveys. In the western region, malaria transmission changed very little across the season (for both species). CART analysis for P. falciparum in the east highlighted age, ethnicity, village of residence and forest work as important predictors for malaria exposure during the rainy season. Adults were more likely to increase their antibody responses to P. falciparum during the transmission season than children, whilst members of the Charay ethnic group demonstrated the largest increases. DISCUSSION: In areas of low transmission intensity, such as in Cambodia, the analysis of longitudinal serological data enables a sensitive evaluation of transmission dynamics. Consecutive serological surveys allow an insight into spatio-temporal patterns of malaria transmission. The use of CART enabled multiple interactions to be accounted for simultaneously and permitted risk factors for exposure to be clearly identified. PMID- 22443376 TI - Accuracy of paramedic Broselow tape use in the prehospital setting. AB - BACKGROUND: The Broselow tape is widely used to rapidly estimate weight and facilitate proper medication dosing in pediatric patients. OBJECTIVE: We aimed to determine the accuracy of prehospital use of the Broselow tape. METHODS: We prospectively enrolled a consecutive sample of pediatric patients transported to the emergency department (ED) at Harbor-UCLA Medical Center from February 2008 to January 2009. Eligible subjects arrived via ambulance and were less than 145 cm tall, the upper limit of height for Broselow measurements. Subjects were excluded if they had a medical condition preventing proper measurement (e.g., contractures). Per Los Angeles County protocol, paramedics obtained a Broselow weight on all pediatric patients. The paramedic Broselow weight was compared with the ED Broselow weight and the ED scale weight, which was obtained unless mobilization was contraindicated. Accuracy was determined by assessing Bland Altman plots and the Pearson correlation coefficient. As part of a sensitivity analysis, multiple imputation was used to account for missing data. RESULTS: There were 572 subjects enrolled. The median age was 24 months (interquartile range [IQR] 10 to 49 months); 316 (55%) of the subjects were male. The weighted Cohen's kappa assessing agreement between the paramedic and ED Broselow colors was 0.74 (95% confidence interval [CI] 0.68 to 0.79). The median difference between the paramedic Broselow weight and the scale weight was -0.10 kg (IQR -1.7 to 0.7). The accuracy of the paramedic Broselow weight when compared with the ED scale weight and the ED Broselow weight as defined by Pearson's correlation coefficient was 0.92 (95% CI 0.90 to 0.93) and 0.97 (95% CI 0.97 to 0.98), respectively. Multiple imputation for missing data did not alter the results. CONCLUSION: Paramedic Broselow weight correlates well with scale weight and ED Broselow weight. Paramedics can use the Broselow tape to accurately determine weight for pediatric patients in the prehospital setting. PMID- 22443378 TI - Risk, ritual and health responsibilisation: Japan's 'safety blanket' of surgical face mask-wearing. AB - This article begins to develop an understanding of surgical mask-wearing in Japan, now a routine practice against a range of health threats. Their usage and associated meanings are explored through surveys conducted in Tokyo with both mask wearers and non-mask wearers. It contests commonly held cultural views of the practice as a fixed and distinctively Japanese collective courtesy to others. A historical analysis suggests that an originally collective, targeted and science-based response to public health threats has dispersed into a generalised practice lacking a clear end or purpose. Developed as part of the biomedical response to the Spanish flu of 1919, the practice resonated with folk assumptions as making a barrier between purity and pollution. But mask-wearing became socially embedded as a general protective practice only from the 1990s through a combination of commercial, corporate and political pressures that responsibilised individual health protection. These developments are usefully understood amidst the uncertainty created by Japan's 'second modernity' and the fracturing of her post-war order. Mask-wearing is only one form of a wider culture of risk; a self protective risk ritual rather than a selfless collective practice. PMID- 22443377 TI - Correlation set analysis: detecting active regulators in disease populations using prior causal knowledge. AB - BACKGROUND: Identification of active causal regulators is a crucial problem in understanding mechanism of diseases or finding drug targets. Methods that infer causal regulators directly from primary data have been proposed and successfully validated in some cases. These methods necessarily require very large sample sizes or a mix of different data types. Recent studies have shown that prior biological knowledge can successfully boost a method's ability to find regulators. RESULTS: We present a simple data-driven method, Correlation Set Analysis (CSA), for comprehensively detecting active regulators in disease populations by integrating co-expression analysis and a specific type of literature-derived causal relationships. Instead of investigating the co expression level between regulators and their regulatees, we focus on coherence of regulatees of a regulator. Using simulated datasets we show that our method performs very well at recovering even weak regulatory relationships with a low false discovery rate. Using three separate real biological datasets we were able to recover well known and as yet undescribed, active regulators for each disease population. The results are represented as a rank-ordered list of regulators, and reveals both single and higher-order regulatory relationships. CONCLUSIONS: CSA is an intuitive data-driven way of selecting directed perturbation experiments that are relevant to a disease population of interest and represent a starting point for further investigation. Our findings demonstrate that combining co expression analysis on regulatee sets with a literature-derived network can successfully identify causal regulators and help develop possible hypothesis to explain disease progression. PMID- 22443379 TI - The evaluation of nail heath conditions with skin ultrasound. AB - BACKGROUND/PURPOSE: Skin ultrasound is a non-invasive technique widely used in the dermatological fields. Previous studies have indicated that ultrasound was able to measure nails depth. The use of ultrasound is particularly appropriate for the study of nail morphology because of the differences in tissue density. The objective of this present study was to understand the characteristics and changes of adult nail texture associated with mild irritation. METHODS: The skin ultrasound measurement and clinical grading scales were used to evaluate nail texture and other important objective parameters relating to nail health in subjects with and without mild irritant hand eczema (IHE). RESULTS: There was no difference in the objective parameters between the left and right hands of subjects within each group (P > 0.05). There were significant differences between the groups for the objective parameters (P < 0.05), and the left hand was more obviously damaged than the right one. CONCLUSIONS: The surface texture of nails with IHE was different from the normal group. The nails of the IHE group were much more uneven and thicker, although there was no noticeable change in density. PMID- 22443380 TI - Activation energy paths for graphene nucleation and growth on Cu. AB - The synthesis of wafer-scale single crystal graphene remains a challenge toward the utilization of its intrinsic properties in electronics. Until now, the large area chemical vapor deposition of graphene has yielded a polycrystalline material, where grain boundaries are detrimental to its electrical properties. Here, we study the physicochemical mechanisms underlying the nucleation and growth kinetics of graphene on copper, providing new insights necessary for the engineering synthesis of wafer-scale single crystals. Graphene arises from the crystallization of a supersaturated fraction of carbon-adatom species, and its nucleation density is the result of competition between the mobility of the carbon-adatom species and their desorption rate. As the energetics of these phenomena varies with temperature, the nucleation activation energies can span over a wide range (1-3 eV) leading to a rational prediction of the individual nuclei size and density distribution. The growth-limiting step was found to be the attachment of carbon-adatom species to the graphene edges, which was independent of the Cu crystalline orientation. PMID- 22443381 TI - Simplest homoleptic metal-centered tetrahedrons, [M(OH2)4]2+, in 1-ethyl-3 methylimidazolium tetrafluoroborate ionic liquid (M = Co, Ni, Cu). AB - Dissolution of a tetrafluoroborate or perchlorate salt of [M(OH(2))(6)](2+) (M = Co, Ni, Cu) in 1-ethyl-3-methylimidazolium tetraluforoborate ionic liquid ([emim]BF(4)) results in significant solvatochromism and increasing intensity of color. These observations arise from partial dehydration from the octahedral [M(OH(2))(6)](2+) and formation of the tetrahedral [M(OH(2))(4)](2+). This reaction was monitored by the intense absorption band due to the d-d transition in the UV-vis absorption spectrum. The EXAFS investigation clarified the coordination structures around M(2+) {[Co(OH(2))(4)](2+), R(Co-O) = 2.17 A, N = 4.2; [Cu(OH(2))(4)](2+), R(Cu-O) = 2.09 A, N = 3.8}. (1)H and (19)F NMR study suggested that both [emim](+) and BF(4)(-) are randomly arranged in the second coordination sphere of [M(OH(2))(4)](2+). PMID- 22443382 TI - Bacteria interface pickering emulsions stabilized by self-assembled bacteria chitosan network. AB - An oil-in-water Pickering emulsion stabilized by biobased material based on a bacteria-chitosan network (BCN) was developed for the first time in this study. The formation of self-assembled BCN was possible due to the electrostatic interaction between negatively charged bacterial cells and polycationic chitosan. The BCN was proven to stabilize the tetradecane/water interface, promoting formation of highly stable oil-in-water emulsion (o/w emulsion). We characterized and visualized the BCN stabilized o/w emulsions by scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM). Due to the sustainability and low environmental impact of chitosan, the BCN-based emulsions open up opportunities for the development of an environmental friendly new interface material as well as the novel type of microreactor utilizing bacterial cells network. PMID- 22443383 TI - Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project. AB - Deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P = 1.19 * 10(-31)) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P < 10(-10)) of agkistrodon contortrix venom (ACV) (exploring the PC pathway) variability which was under the main control of the F5 and F2 loci that further explained about 40% and 10%, respectively. We presented here the first GWAS for plasma AT and free-PS levels and ACV in Caucasian samples. We identified three independent loci associated with ACV (F2, F5 and PROCR) and replicated two independent effects on plasma PC levels at the PROCR locus. PMID- 22443384 TI - Experimentally induced incomplete burst fractures - a novel technique for calf and human specimens. AB - BACKGROUND: Fracture morphology is crucial for the clinical decision-making process preceding spinal fracture treatment. The presented experimental approach was designed in order to ensure reproducibility of induced fracture morphology. RESULTS: The presented method resulted in fracture morphology, found in clinical classification systems like the Magerl classification. In the calf spine samples, 70% displayed incomplete burst fractures corresponding to type A3.1 and A3.2 fractures. In all human samples, superior incomplete burst fractures (Magerl A3.1) were identified by an independent radiologist and spine surgeon. CONCLUSIONS: The presented set up enables the first experimental means to reliably model and study distinct incomplete burst fracture patterns in an in vitro setting. Thus, we envisage this protocol to facilitate further studies on spine fracture treatment of incomplete burst fractures. PMID- 22443385 TI - Association of adrenocorticotrophin and cortisol concentrations with peripheral blood leukocyte cytokine gene expression in septic and nonseptic neonatal foals. AB - BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) is influenced by the proinflammatory cytokines IL-6, IL-1beta, and TNF-alpha in critically ill humans. Information about the association of cytokines with the HPA axis in neonatal foals is lacking. HYPOTHESIS/OBJECTIVES: The objectives were to describe for hospitalized septic and nonseptic foals (1) temporal changes in blood concentrations of ACTH, and cortisol, and leukocyte cytokine gene expression, and (2) coassociation of these HPA axis hormones with blood leukocyte cytokine gene expression. ANIMALS: Hospitalized septic foals (N = 15) and hospitalized nonseptic foals (N = 11). METHODS: Blood samples, obtained from study foals at admission (T = 0), and 24 (T = 1), 48 (T = 2), 72 (T = 3), and 96 (T = 4) hours after admission, were processed to isolate RNA from leukocytes and to harvest plasma and serum for hormone assays. Plasma ACTH and serum cortisol concentrations were determined by radioimmunoassay. Leukocyte mRNA expression of IL-1beta IL-6, IL-8, IL-10, and TNF-alpha was determined using RT-PCR. RESULTS: Cortisol concentrations were greater (P < .05) in foals at admission than at other time points. The expressions of IL-8 and IL-10 mRNA were lower (P < .05) at each time point in septic than in nonseptic foals. Among septic foals, ACTH was positively associated (P = .0026) with IL-6 mRNA expression. CONCLUSIONS: Sepsis influences secretion of the HPA axis hormones and expression of cytokines in foals. A positive association with the HPA axis and IL-6 expression was detected. The clinical importance of these findings requires additional study. PMID- 22443386 TI - Inter-field variability in the microbial communities of hydrothermal vent deposits from a back-arc basin. AB - Diverse microbial communities thrive on and in deep-sea hydrothermal vent mineral deposits. However, our understanding of the inter-field variability in these communities is poor, as limited sampling and sequencing efforts have hampered most previous studies. To explore the inter-field variability in these communities, we used barcoded pyrosequencing of the variable region 4 (V4) of the 16S rRNA gene to characterize the archaeal and bacterial communities of over 30 hydrothermal deposit samples from six vent fields located along the Eastern Lau Spreading Center. Overall, the bacterial and archaeal communities of the Eastern Lau Spreading Center are similar to other active vent deposits, with a high diversity of Epsilonproteobacteria and thermophilic Archaea. However, the archaeal and bacterial communities from the southernmost vent field, Mariner, were significantly different from the other vent fields. At Mariner, the epsilonproteobacterial genus Nautilia and the archaeal family Thermococcaceae were prevalent in most samples, while Lebetimonas and Thermofilaceae were more abundant at the other vent fields. These differences appear to be influenced in part by the unique geochemistry of the Mariner fluids resulting from active degassing of a subsurface magma chamber. These results show that microbial communities associated with hydrothermal vent deposits in back-arc basins are taxonomically similar to those from mid-ocean ridge systems, but differences in geologic processes between vent fields in a back-arc basin can influence microbial community structure. PMID- 22443387 TI - Rhodium-catalyzed asymmetric conjugate addition of arylboronic acids to nitroalkenes using olefin-sulfoxide ligands. AB - An efficient rhodium/olefin-sulfoxide catalyzed asymmetric conjugate addition of organoboronic acids to a variety of nitroalkenes has been developed, where 2 methoxy-1-naphthyl sulfinyl functionalized olefin ligands have shown to be highly effective and are applicable to a broad scope of aryl, alkyl, and heteroaryl nitroalkenes. PMID- 22443388 TI - Sex ratio variations among the offspring of women with diabetes in pregnancy. AB - AIMS: It has long been hypothesized that natural selection would favour a reproductive strategy biased towards females under adverse circumstances in order to maximize the number of surviving grandchildren. An excess of daughters in women with Type 1 diabetes and a greater likelihood of gestational diabetes in women carrying male fetuses have also been reported. This study aims to compare the sex ratio across categories of maternal glycaemia. METHODS: Among 288,009 mother-infant pairs delivering at Kaiser Permanente Northern California in 1996 2008, sex ratios were calculated for the following categories: pregravid diabetes, gestational diabetes, mild pregnancy hyperglycaemia (defined as an abnormal screening but normal diagnostic test for gestational diabetes) and normoglycaemia. Odds ratios for delivering a male were estimated with logistic regression; normoglycaemic pregnancies comprised the reference. RESULTS: Women with pregravid diabetes delivered the fewest males (ratio male/female = 1.01), followed by women with normoglycaemic pregnancies and those with an abnormal screening only (both sex ratios = 1.05); women with gestational diabetes delivered the most males (sex ratio = 1.07). Odds ratio estimates suggested the same pattern, but none attained statistical significance. CONCLUSIONS: The crude sex ratios in this cohort suggest a possible gradient by category of maternal glycaemia. Women with gestational diabetes, a condition characterized by excessive fuel substrates, appear to deliver more males. Women with pregravid diabetes delivered the fewest males, possibly reflecting the unfavourable state of chronic disease. PMID- 22443389 TI - Glomeruloid hemangiomas in the absence of POEMS syndrome. PMID- 22443390 TI - Glomeruloid hemangiomas in the absence of POEMS syndrome. PMID- 22443391 TI - The cure for boredom. PMID- 22443392 TI - Transepidermal elimination in cutaneous leishmaniasis: a multiregional study. AB - BACKGROUND: Transepidermal elimination has been documented in a myriad of infectious diseases; however, its occurrence in cutaneous leishmaniasis has not been evaluated. METHODS: Skin biopsies (n = 212) with cutaneous leishmaniasis in Lebanon (n = 46), Syria (n = 53), Saudi Arabia (n = 45) and Pakistan (n = 68) were evaluated. Clinical data collected included age, gender, eruption type (papule, nodule, verrucous or scar), duration and anatomic location. Histopathologically, multiple parameters were recorded including Ridley's parasitic index and pattern, transepidermal elimination, interface changes, ulceration and necrosis. Transepidermal elimination was defined as the presence of amastigotes in the epidermis in all layers, limited to the basal layer or present in a perforating plug. All cases were confirmed by polymerase chain reaction (PCR) analysis followed by restriction fragment length polymorphism analysis for molecular subspeciation. RESULTS: Leishmania tropica was identified in 88.2% and Leishmania major in 11.8% of all cases. Transepidermal elimination was observed in 28.3% of cases (29 perforating plug, 19 all layers and 12 basal layer) with a significant prevalence of L. major in this group (35 vs. 2%, p < 0.001). Cases with transepidermal elimination were associated with interface changes and higher parasitic index (p < 0.001) but not with an increased ulceration rate (p > 0.05). Multivariate analysis showed that transepidermal elimination was independently predicted by L. major [OR (95% confidence interval) = 80 (9-712); p < 0.001], parasitic index [OR = 3.4 (2.1-5.3); p < 0.001], interface changes [OR = 6.24 (2.2-17.8); p < 0.001] and necrosis [OR = 0.2 (0.1 0.8);p = 0.026]. CONCLUSIONS: We report the largest multiregional cutaneous leishmaniasis series with a 28.3% documented transepidermal elimination incidence of which 48% were perforating plug; a significant prevalence of L. major was also identified in the transepidermal elimination group. The association of transepidermal elimination with interface changes and a higher parasitic index, without an increased ulceration rate, may reflect a unique biologic alteration in the epidermis, serving to facilitate the extrusion of the parasites through the skin. PMID- 22443393 TI - Assessment of the 'no eosinophils' rule: are eosinophils truly absent in pityriasis lichenoides, connective tissue disease, and graft-vs.-host disease? AB - Eosinophils are often present in the inflammatory infiltrate of an interface dermatitis, but the diagnostic specificity of eosinophils in interface dermatitis has not been formally evaluated. We retrospectively identified 97 examples of interface dermatitis with clinically confirmed diagnoses, including lupus erythematosus (LE), lichen planus, pityriasis lichenoides (PL), graft-vs.-host disease (GVHD), dermatomyositis (DM) and drug reaction. Diagnoses were clinically confirmed by at least two dermatologists. Slides were reviewed in a blinded fashion by at least two dermatopathologists. The average eosinophil count per 10 *200 (*20 objective) fields was lowest for PL (0.2), DM (0.3), GVHD (0.4), and LE (0.5) [defined as Group 1] and was higher for lichen planus, drug reactions, erythema multiforme (major and minor) and viral exanthems [defined as Group 2]. Distinction between Group 1 and Group 2 was maximized using an eosinophil count cutoff of 1.1. In conclusion, eosinophils are usually rare to absent in PL, DM, most forms of LE and GVHD. While final interpretation requires a composite assessment of all features, our results suggest that the presence of even a single eosinophil within nine or ten *20 fields argues against a diagnosis of PL, DM or LE. PMID- 22443394 TI - Hereditary mucoepithelial dysplasia: unique histopathological findings in skin lesions. AB - Hereditary mucoepithelial dysplasia (HMD) is a rare, autosomal dominantly inherited, multisystem disease thought to be caused by abnormalities in desmosomes and gap junctions. HMD affects the skin, mucosae, hair, eyes and lungs. Nearly all patients clinically display the triad of non-scarring alopecia, well-demarcated mucosal erythema and erythematous intertriginous plaques. Although histopathological findings of mucous membrane epithelium have been well characterized, only three reports have described histopathologic findings in the skin. We report a case with unique histopathological findings not previously reported in HMD. PMID- 22443395 TI - Eruptive tumors of the follicular infundibulum presenting as hypopigmented macules on the buttocks of two Black African males. AB - We report two cases of eruptive tumors of the follicular infundibulum (TFI) with an unusual clinical presentation which has not been described previously in literature. In both cases, the appearance was strikingly similar, consisting of multiple asymptomatic hypopigmented macules on the buttocks of two Black African males, aged 38 and 55 years old. In both cases, the eruption had evolved over several months. The individual lesions were of similar size, approximately 1 cm, with irregular and ill-defined borders. Histopathological examination revealed a superficial and horizontal plate-like proliferation of keratinocytes emanating from the epidermis with multiple slender attachments. Pale keratinocytes were present within the epithelial plates. A Fontana stain showed a loss of melanin pigment from the epithelial plates. Orcein (elastic) stain highlighted an increase of the number of the elastic fibers surrounding the tumor. On the basis of these findings, a diagnosis of eruptive TFI was established for both cases. Among the various presentations of TFI, only the eruptive variant appears to be clinically distinctive, with asymptomatic hypopigmented macules usually located on the face, neck and upper trunk. Eruptive TFI should also be added to the clinical differential diagnosis of multiple hypopigmented macules on the buttocks of Black patients. PMID- 22443397 TI - Development of a new CARD-FISH protocol for quantification of Legionella pneumophila and its application in two hospital cooling towers. AB - AIMS: Open cooling towers are frequent sources of infections with Legionella pneumophila. The gold standard for the detection of Leg. pneumophila is based on cultivation lasting up to 10 days and detecting only culturable cells. Alternative fluorescence in situ hybridization (FISH) protocols have been proposed, but they result in faint fluorescence signals and lack specificity because of cross-hybridization with other Legionella species. Our aim was thus to develop a new FISH protocol for rapid and specific detection of Leg. pneumophila in water samples. METHODS AND RESULTS: A novel catalysed reporter deposition FISH (CARD-FISH) protocol for the detection of Leg. pneumophila was developed, which significantly enhanced signal intensity as well as specificity of the probe through the use of a novel competitor probe. The developed protocol was compared with the culture method for monitoring the seasonal development of culturable and nonculturable Leg. pneumophila in two hospital cooling tower systems. Seasonal fluctuations of Leg. pneumophila concentrations detected via CARD-FISH were related to the development of the total bacterial community in both cooling towers, with temperature and biocide as the main factors controlling this development. CONCLUSIONS: Our results clearly showed that the majority of the Leg. pneumophila cells were in a nonculturable state. Thus, detection of Leg. pneumophila with culture methods may underestimate the total numbers of Leg. pneumophila present. SIGNIFICANCE AND IMPACT OF THE STUDY: Rapid, sensitive and specific detection and quantification of Leg. pneumophila in water systems is prerequisite for reliable risk estimation. The new protocol significantly improves current methodology and can be used to monitor and screen for Leg. pneumophila concentrations in cooling towers or other water systems. PMID- 22443398 TI - Catalytic mechanism of perosamine N-acetyltransferase revealed by high-resolution X-ray crystallographic studies and kinetic analyses. AB - N-Acetylperosamine is an unusual dideoxysugar found in the O-antigens of some Gram-negative bacteria, including the pathogenic Escherichia coli strain O157:H7. The last step in its biosynthesis is catalyzed by PerB, an N-acetyltransferase belonging to the left-handed beta-helix superfamily of proteins. Here we describe a combined structural and functional investigation of PerB from Caulobacter crescentus. For this study, three structures were determined to 1.0 A resolution or better: the enzyme in complex with CoA and GDP-perosamine, the protein with bound CoA and GDP-N-acetylperosamine, and the enzyme containing a tetrahedral transition state mimic bound in the active site. Each subunit of the trimeric enzyme folds into two distinct regions. The N-terminal domain is globular and dominated by a six-stranded mainly parallel beta-sheet. It provides most of the interactions between the protein and GDP-perosamine. The C-terminal domain consists of a left-handed beta-helix, which has nearly seven turns. This region provides the scaffold for CoA binding. On the basis of these high-resolution structures, site-directed mutant proteins were constructed to test the roles of His 141 and Asp 142 in the catalytic mechanism. Kinetic data and pH-rate profiles are indicative of His 141 serving as a general base. In addition, the backbone amide group of Gly 159 provides an oxyanion hole for stabilization of the tetrahedral transition state. The pH-rate profiles are also consistent with the GDP-linked amino sugar substrate entering the active site in its unprotonated form. Finally, for this investigation, we show that PerB can accept GDP-3 deoxyperosamine as an alternative substrate, thus representing the production of a novel trideoxysugar. PMID- 22443399 TI - Letter to the editor: response to "What women want from abortion counseling in the United States: a qualitative study of abortion patients in 2008". PMID- 22443401 TI - Individual and community predictors of maternal smoking in the city of Baltimore: what can be learned from a predominantly minority case controlled study? AB - This case control study of 1,000 birth certificates examined what individual and community factors predicted maternal smoking in Baltimore, Maryland. Conditional multinomial logistic regression results indicated women who were White were more likely to start smoking at a young age, but as they got older, they were less likely to smoke. Minority women were more likely to start smoking at a later age. Also, White women were more likely to smoke as the rate of poverty increased, while for minority women, smoking was unrelated to whether they lived in higher or lower poverty areas. Medical assistance status, community education level, and crime rate were not found to be related to smoking status. PMID- 22443402 TI - Understanding and addressing stigma and attachment insecurity in HIV-positive women who experience intimate partner violence: a model of medical and psychosocial care. AB - Low-income women of color who are HIV positive and living in violent relationships are at significant risk for stigma and problems with attachment security. This article explores the ways in which these women may experience internalized stigma from incorporating society's negative views of HIV and domestic violence. It also addresses the ways in which insecure attachment may develop or intensify in this population through violence in their adult intimate relationships and/or living with a life threatening illness. A model of medical and psychosocial care utilized at the Women's HIV Program at the University of California San Francisco is offered as an intervention to reduce stigma and enhance healthy attachment. Clinical examples demonstrate how this system of medical and psychosocial care can help women in this situation establish stability and improve their lives despite the intense challenges they face. PMID- 22443403 TI - Evaluation of an online peer support network for fathers of a child with a brain tumor. AB - This study explored impacts of an online support network for fathers of a child with a brain tumor. Evaluation comprised pre/post-intervention questionnaires, content analysis of online network postings, and post-intervention qualitative interviews. Findings suggest that this intervention was beneficial to fathers. Positive effects on paternal coping were demonstrated, as were opportunities to grapple with difficult issues related to having a child with a brain tumor. Fathers recommended a combined resource of online and face-to-support, including the development of a support network with a larger participant base. Implications for practice are examined. PMID- 22443404 TI - The Writing Series Project: a model for supporting social work clinicians in health settings to disseminate practice knowledge. AB - Social work clinicians across health care settings are uniquely positioned to disseminate valuable practice experience, thereby contributing to knowledge development within their field of practice and across disciplines. Unfortunately, practitioners tend to shy away from writing and research, and are often reluctant to publicly disseminate their expertise through peer-reviewed journals and conference presentations. To better support health social workers in scholarly endeavors, we developed and implemented The Writing Series Project in southeast Queensland, Australia. This article reports on the development, programmatic challenges and practitioner feedback that offer insight into the benefits and pitfalls that we encountered. PMID- 22443407 TI - Temporal changes of smoking status and motivation in Chinese patients with hepatitis B: relationship with anxiety and depression. AB - AIMS AND OBJECTIVES: The present study provided the first examination of cigarette smoking status and motivation before and after the diagnosis of hepatitis B in Chinese hepatitis B smokers. BACKGROUND: Cigarette smoking is known to contribute to the severity of chronic liver diseases. However, the rates of cigarette smoking remain high in Chinese patients with hepatitis B. DESIGN: We used individual interviews and brief questionnaires to collect smoking status and motivation before and after the diagnosis of hepatitis B in hepatitis B smokers. We also evaluated the relationships between anxiety and depression and cigarette smoking in Chinese hepatitis B smokers. METHOD: Patients with hepatitis B (54 smokers and 127 non-smokers) were enrolled consecutively. A battery of self report questionnaires was used to assess smoking status and motivation before and after the diagnosis of hepatitis B. All participants also were asked to complete the Hospital Anxiety and Depression Scale. RESULTS: We found that the number of cigarettes per day after the diagnosis of hepatitis B was higher than that before the diagnosis of hepatitis B in hepatitis B smokers. A wide range of smoking motivation was found before and after the diagnosis of hepatitis B. 'Nicotine pleasure' was the primary motivation before the diagnosis of hepatitis B, whereas 'anxiety' and 'depression' were the primary motivation for the increase in cigarette consumption after the diagnosis of hepatitis B. Anxiety and depression were more frequently observed in hepatitis B smokers than in hepatitis B non smokers. Anxiety and depression were associated with continued smoking after hepatitis B diagnosis. CONCLUSIONS: The present study first demonstrated that cigarette smoking status and motivation were different before and after the diagnosis of hepatitis B. Anxiety and depression play an important role in temporal changes of smoking status and motivation. RELEVANCE TO CLINICAL PRACTICE: These findings highlight the need for individual anxiety and depression screening and assessment in conjunction with smoking cessation efforts in hepatitis B smokers. PMID- 22443408 TI - Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches. AB - OBJECTIVE: The efficacy of omalizumab in severe asthma has been widely demonstrated. The main objective of this study was to evaluate the efficacy and tolerability of omalizumab in a real-life setting in Spain, particularly in those patients with immunoglobulin E (IgE) levels out of range. METHODS: Totally 266 uncontrolled severe asthma patients receiving high-dose inhaled corticosteroids (ICSs) plus long-acting beta2-agonist (LABA) were recruited. Main efficacy outcomes were asthma exacerbation rate (AER), asthma control test (ACT), and global evaluation of treatment effectiveness (GETE). RESULTS: AER was reduced from 3.6 (3.6) in previous year to 0.67 (1.2) at 4 months (p < .05) and to 1.04 (1.8) at 2 years (p < .05). ACT increased significantly from 14.3 (4.7) at baseline to 18.4 (4.4) at 4 months (p < .05) and to 20.3 (4.0) (p < .05) at 2 years. After 4 months, 74.6% of patients had reached a good or excellent rate on the GETE scale (p < .05). This rate continued increasing up to 81.6% at 2 years. These efficacy results were similar for patients with "off-label" IgE > 700 IU/ml. At follow-up, maintenance treatment with oral steroids was discontinued in a considerable number of patients: from 89 to 19 (p < .05). Omalizumab was discontinued because of lack of efficacy only in 28/266 (10.5%) patients. Overall, 30 patients (11.4%) reported adverse events. Severe adverse events were not observed. CONCLUSION: This real-life study confirms that omalizumab is very efficacious and very well tolerated in patients with uncontrolled severe asthma. Results did not vary in the subgroup of patients with IgE levels >700 IU/ml. PMID- 22443409 TI - New directing groups for metal-catalyzed asymmetric carbon-carbon bond-forming processes: stereoconvergent alkyl-alkyl Suzuki cross-couplings of unactivated electrophiles. AB - The ability of two common protected forms of amines (carbamates and sulfonamides) to serve as directing groups in Ni-catalyzed Suzuki reactions has been exploited in the development of catalytic asymmetric methods for cross-coupling unactivated alkyl electrophiles. Racemic secondary bromides and chlorides undergo C-C bond formation in a stereoconvergent process in good ee at room temperature in the presence of a commercially available Ni complex and chiral ligand. Structure enantioselectivity studies designed to elucidate the site of binding to Ni (the oxygen of the carbamate and of the sulfonamide) led to the discovery that sulfones also serve as useful directing groups for asymmetric Suzuki cross couplings of racemic alkyl halides. To our knowledge, this investigation provides the first examples of the use of sulfonamides or sulfones as effective directing groups in metal-catalyzed asymmetric C-C bond-forming reactions. A mechanistic study established that transmetalation occurs with retention of stereochemistry and that the resulting Ni-C bond does not undergo homolysis in subsequent stages of the catalytic cycle. PMID- 22443410 TI - Substrate variations that affect the nucleic acid clamp activity of reverse transcriptases. AB - We have recently shown that reverse transcriptases (RTs) perform template switches when there is a very short (two-nucleotide) complementarity between the 3' ends of the primer (donor) strand and the DNA or RNA template acceptor strands [Oz-Gleenberg et al. (2011) Nucleic Acids Res 39, 1042-1053]. These dinucleotide pairs are stabilized by RTs that are capable of 'clamping' together the otherwise unstable duplexes. This RT-driven stabilization of the micro-homology sequence promotes efficient DNA synthesis. In the present study, we have examined several factors associated with the sequence and structure of the DNA substrate that are critical for the clamp activity of RTs from human immunodeficiency virus type 1 (HIV-1), murine leukemia virus (MLV), bovine immunodeficiency virus (BIV) and the long terminal repeat retrotransposon Tf1. The parameters studied were the minimal complementarity length between the primer and functional template termini that sustains stable clamps, the effects of gaps between the two template strands on the clamp activity of the tested RTs, the effects of template end phosphorylations on the RT-associated clamp activities, and clamp activity with a long 'hairpin' double-stranded primer comprising both the primer and the complementary non-functional template strands. The results show that the substrate conditions for clamp activity of HIV-1 and MLV RTs are more stringent, while Tf1 and BIV RTs show clamp activity under less rigorous substrate conditions. These differences shed light on the dissimilarities in catalytic activities of RTs, and suggest that clamp activity may be a potential new target for anti-retroviral drugs. PMID- 22443411 TI - Potential dual role of KGF/KGFR as a target option in novel therapeutic strategies for the treatment of cancers and mucosal damages. AB - INTRODUCTION: Keratinocyte growth factor (KGF) and its receptor KGFR play a pivotal role in regulating cell proliferation, migration, differentiation and survival, in response to injury and tissue repair. Altered expression of this pathway in cancer opened the way to the development of targeted therapy to achieve KGFR inhibition. Nevertheless, KGF administration has been demonstrated to ameliorate oral mucositis resulting from chemoradiotherapy, besides protecting epithelial cells against radiation-induced damage. AREAS COVERED: This review focuses on the potential therapeutic interest of KGF/KGFR in two different areas: selective inhibition of KGFR signaling for the treatment of cancers characterized by upregulation of this pathway and administration of KGF to protect epithelial cells from induced damage. The review presents an overview of therapeutic strategies in both directions. EXPERT OPINION: KGF/KGFR signaling can contribute to enhancing the malignant potential of epithelial cells and to promoting tumorigenesis. On the other hand, the therapeutic use of KGF in cancer patients provides epithelial protection, reducing chemotherapy side effects. FGFRs have become attractive antitumor targets and various inhibitors have been used to contrast tumor cell growth. The identification of KGFR-specific molecules might represent a promising therapeutic strategy that could increase the window of available agents and treatment methods. PMID- 22443412 TI - Acts of generating and their sources: predicting the effects of imagery encoding on false recognition errors. AB - In the two experiments reported here the basis of the beneficial effects of generating images on false recognition errors is investigated. Acts of generating (descriptions, images, or both) were manipulated while examining the effects of the source of descriptions guiding imagery generations (participant vs peer). False recognition errors were relatively high across encoding conditions except when imagery generations were based on participants' own descriptions (Experiments 1 and 2). These differences in the acts of generating were not attributable to differences in the cohesiveness of descriptions themselves. Acts of generating led to greater "remember" responses than "know" responses only when participants were not the source of the descriptions used to generate images (Experiment 2). Results highlight the importance of examining the effects of the source of descriptions for guiding imagery (participant or peer) when testing predictions about the effects of imagery encoding on false recognition errors. PMID- 22443413 TI - Analysis of high-depth sequence data for studying viral diversity: a comparison of next generation sequencing platforms using Segminator II. AB - BACKGROUND: Next generation sequencing provides detailed insight into the variation present within viral populations, introducing the possibility of treatment strategies that are both reactive and predictive. Current software tools, however, need to be scaled up to accommodate for high-depth viral data sets, which are often temporally or spatially linked. In addition, due to the development of novel sequencing platforms and chemistries, each with implicit strengths and weaknesses, it will be helpful for researchers to be able to routinely compare and combine data sets from different platforms/chemistries. In particular, error associated with a specific sequencing process must be quantified so that true biological variation may be identified. RESULTS: Segminator II was developed to allow for the efficient comparison of data sets derived from different sources. We demonstrate its usage by comparing large data sets from 12 influenza H1N1 samples sequenced on both the 454 Life Sciences and Illumina platforms, permitting quantification of platform error. For mismatches median error rates at 0.10 and 0.12%, respectively, suggested that both platforms performed similarly. For insertions and deletions median error rates within the 454 data (at 0.3 and 0.2%, respectively) were significantly higher than those within the Illumina data (0.004 and 0.006%, respectively). In agreement with previous observations these higher rates were strongly associated with homopolymeric stretches on the 454 platform. Outside of such regions both platforms had similar indel error profiles. Additionally, we apply our software to the identification of low frequency variants. CONCLUSION: We have demonstrated, using Segminator II, that it is possible to distinguish platform specific error from biological variation using data derived from two different platforms. We have used this approach to quantify the amount of error present within the 454 and Illumina platforms in relation to genomic location as well as location on the read. Given that next generation data is increasingly important in the analysis of drug-resistance and vaccine trials, this software will be useful to the pathogen research community. A zip file containing the source code and jar file is freely available for download from http://www.bioinf.manchester.ac.uk/segminator/. PMID- 22443414 TI - Associations of pre-transplant anemia management with post-transplant delayed graft function in kidney transplant recipients. AB - BACKGROUND: Delayed graft function (DGF) complicates kidney allograft outcomes in the immediate post-transplantation period. We hypothesized that in hemodialysis patients more severe anemia, iron deficiency, the requirement for higher doses of erythropoietin-stimulating agents (ESA), or blood transfusions prior to transplantation are associated with higher risk of DGF. METHODS: Linking five-yr hemodialysis patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, we identified 11 836 hemodialysis patients. Using logistic regression analyses we examined the association between pre transplant parameters and post-transplant DGF. RESULTS: Patients were 49 +/- 14 (mean +/- SD) yr old and included 38% women, 27% blacks, and 26% diabetics. After adjusting for relevant covariates, pre-transplant blood transfusion was associated with 33% higher DGF risk (odds ratio [OR] = 1.33; 95% confidence interval [CI]: 1.19-1.48); and each 5000 U/wk increase of pre-transplant ESA dose with 5% higher DGF (OR = 1.05; 95% CI: 1.02-1.09). Compared to pre-transplant blood hemoglobin of 12-12.99 g/dL, there was 25% higher risk of DGF with blood hemoglobin 10-10.99 g/dL (OR = 1.25; 95% CI: 1.01-1.55), whereas blood hemoglobin >=13 g/dL exhibited 15% higher risk of DGF (OR = 1.15; 95% CI: 0.98-1.34). CONCLUSIONS: Pre-transplant blood transfusion, higher ESA dose, and either high or low blood hemoglobin but not iron markers are associated with higher risk of DGF. PMID- 22443415 TI - Hemoglobin E syndromes in Pakistani population. AB - BACKGROUND: Hemoglobin E is an important hemoglobin variant with a worldwide distribution. A number of hemoglobinopathies have been reported from Pakistan. However a comprehensive description of hemoglobin E syndromes for the country was never made. This study aimed to describe various hemoglobin E disorders based on hematological parameters and chromatography. The sub-aim was to characterize hemoglobin E at molecular level. METHODS: This was a hospital based study conducted prospectively for a period of one year extending from January 1 to December 31, 2008. EDTA blood samples were analyzed for completed blood counts and hemoglobin variants through automated hematology analyzer and Bio-Rad beta thalassaemia short program respectively. Six samples were randomly selected to characterize HbE at molecular level through RFLP-PCR utilizing MnlI restriction enzyme. RESULTS: During the study period, 11403 chromatograms were analyzed and Hb E was detected in 41 (or 0.36%) samples. Different hemoglobin E syndromes identified were HbEA (n = 20 or 49%), HbE/beta-thalassemia (n = 14 or 34%), HbEE (n = 6 or 15%) and HbE/HbS (n = 1 or 2%). Compound heterozygosity for HbE and beta thalassaemia was found to be the most severely affected phenotype. RFLP-PCR utilizing MnlI successfully characterized HbE at molecular level in six randomly selected samples. CONCLUSIONS: Various HbE phenotypes are prevalent in Pakistan with HbEA and HbE/beta thalassaemia representing the most common syndromes. Chromatography cannot only successfully identify hemoglobin E but also assist in further characterization into its phenotype including compound heterozygosity. Definitive diagnosis of HbE can easily be achieved through RFLP-PCR. PMID- 22443416 TI - Pressure transduction and fluid evacuation during conventional negative pressure wound therapy of the open abdomen and NPWT using a protective disc over the intestines. AB - BACKGROUND: Negative pressure wound therapy (NPWT) has gained acceptance among surgeons, for the treatment of open abdomen, since very high closure rates have been reported with this method, compared to other kinds of wound management for the open abdomen. However, the method has occasionally been associated with increased development of fistulae. We have previously shown that NPWT induces ischemia in the underlying small intestines close to the vacuum source, and that a protective disc placed between the intestines and the vacuum source prevents the induction of ischemia. In this study we compare pressure transduction and fluid evacuation of the open abdomen with conventional NPWT and NPWT with a protective disc. METHODS: Six pigs underwent midline incision and the application of conventional NPWT and NPWT with a protective disc between the intestines and the vacuum source. The pressure transduction was measured centrally beneath the dressing, and at the anterior abdominal wall, before and after the application of topical negative pressures of -50, -70 and -120 mmHg. The drainage of fluid from the abdomen was measured, with and without the protective disc. RESULTS: Abdominal drainage was significantly better (p < 0. 001) using NPWT with the protective disc at -120 mmHg (439 +/- 25 ml vs. 239 +/- 31 ml), at -70 mmHg (341 +/- 27 ml vs. 166 +/- 9 ml) and at -50 mmHg (350 +/- 50 ml vs. 151 +/- 21 ml) than with conventional NPWT. The pressure transduction was more even at all pressure levels using NPWT with the protective disc than with conventional NPWT. CONCLUSIONS: The drainage of the open abdomen was significantly more effective when using NWPT with the protective disc than with conventional NWPT. This is believed to be due to the more even and effective pressure transduction in the open abdomen using a protective disc in combination with NPWT. PMID- 22443417 TI - Cannabinoid research in the 2010s. PMID- 22443418 TI - Synthesis and properties of cycloparaphenylene-2,5-pyridylidene: a nitrogen containing carbon nanoring. AB - The first synthesis of a nitrogen-containing cycloparaphenylene, cyclo[14]paraphenylene[4]2,5-pyridylidene ([14,4]CPPy), has been achieved. A palladium-catalyzed stepwise assembly of 2,2'-bipyridine, benzene, and L-shaped cyclohexane units, followed by NaHSO(4)/o-chloranil-mediated aromatization, successfully provided [14,4]CPPy. While the absorption and fluorescence properties of [14,4]CPPy were somewhat similar to those of cycloparaphenylenes (lambda(abs) = 344 nm, epsilon = 7.3 * 10(4) cm(-1) M(-1), lambda(em) = 427 nm, Phi(F) = 0.80), it was found that [14,4]CPPy possesses an interesting halochromic property. PMID- 22443419 TI - Eggs, ethics and exploitation? Investigating women's experiences of an egg sharing scheme. AB - There is a growing global demand for human eggs for the treatment of sub-fertile women and for stem cell-related research. This demand provokes concerns for the women providing the eggs, including their possible exploitation, whether they should be paid, whether they can give properly informed consent and whether their eggs and bodies are becoming commodified. However, few of the debates have benefitted from insights from the women themselves. We address this gap in knowledge by reporting on a study investigating women's views and experiences of a scheme in which they can volunteer, in their capacity as fertility patients, to 'share' their eggs with researchers and receive a reduction in in vitro fertilisation fees. We focus our discussion on the question of exploitation, a concept central to many sociological and ethical interests. In brief, our analysis suggests that while interviewees acknowledge the potential of this scheme to be exploitative, they argue that this is not the case, emphasising their ability to act autonomously in deciding to volunteer. Nonetheless, these freely made decisions do not necessarily take place under circumstances of their choosing. We discuss the implications of this for egg provision in general and for understandings of exploitation. PMID- 22443420 TI - Quantum dot-fluorescent protein FRET probes for sensing intracellular pH. AB - Intracellular pH (pH(i)) plays a critical role in the physiological and pathophysiological processes of cells, and fluorescence imaging using pH sensitive indicators provides a powerful tool to assess the pH(i) of intact cells and subcellular compartments. Here we describe a nanoparticle-based ratiometric pH sensor, comprising a bright and photostable semiconductor quantum dot (QD) and pH-sensitive fluorescent proteins (FPs), exhibiting dramatically improved sensitivity and photostability compared to BCECF, the most widely used fluorescent dye for pH imaging. We found that Forster resonance energy transfer between the QD and multiple FPs modulates the FP/QD emission ratio, exhibiting a >12-fold change between pH 6 and 8. The modularity of the probe enables customization to specific biological applications through genetic engineering of the FPs, as illustrated by the altered pH range of the probe through mutagenesis of the fluorescent protein. The QD-FP probes facilitate visualization of the acidification of endosomes in living cells following polyarginine-mediated uptake. These probes have the potential to enjoy a wide range of intracellular pH imaging applications that may not be feasible with fluorescent proteins or organic fluorophores alone. PMID- 22443421 TI - Relationship between cultivar difference in the sensitivity of net photosynthesis to ozone and reactive oxygen species scavenging system in Japanese winter wheat (Triticum aestivum). AB - To clarify the relationship between cultivar difference in the sensitivity of net photosynthesis to ozone (O(3)) and the reactive oxygen species (ROS) scavenging system in wheat (Triticum aestivum), we investigated the effects of chronic exposure to ambient levels of O(3) on gas exchange rates, activity and concentration of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco), activity of ROS scavenging enzymes and concentration of antioxidants of the flag leaf in two Japanese winter wheat cultivars (Norin 61 and Shirogane-komugi). Although the net photosynthetic rate of the flag leaf in Norin 61 was not significantly reduced by exposure to O(3), that in Shirogane-komugi was significantly reduced by the exposure to O(3) during the anthesis and early grain filling stages. In the two cultivars, stomatal diffusive conductance to H(2) O of the flag leaf was not significantly affected by the exposure to O(3). The exposure to O(3) induced significant reductions in the activity and concentration of Rubisco, activities of catalase (CAT) and monodehydroascorbate reductase (MDAR) and concentrations of reduced form of ascorbate and total glutathione of the flag leaf in Shirogane-komugi. It was concluded that the sensitivity of net photosynthesis of flag leaf to O(3) is higher in Shirogane-komugi than in Norin 61, and the difference in the sensitivity to O(3) between the two cultivars is mainly due to that in the effects of O(3) on the detoxification ability of ROS, mainly determined by the activity of ROS scavenging enzymes, such as CAT and MDAR. PMID- 22443422 TI - Atypical fibroxanthoma. PMID- 22443423 TI - Fine-scale spatial variability of heat-related mortality in Philadelphia County, USA, from 1983-2008: a case-series analysis. AB - BACKGROUND: High temperature and humidity conditions are associated with short term elevations in the mortality rate in many United States cities. Previous research has quantified this relationship in an aggregate manner over large metropolitan areas, but within these areas the response may differ based on local scale variability in climate, population characteristics, and socio-economic factors. METHODS: We compared the mortality response for 48 Zip Code Tabulation Areas (ZCTAs) comprising Philadelphia County, PA to determine if certain areas are associated with elevated risk during high heat stress conditions. A randomization test was used to identify mortality exceedances for various apparent temperature thresholds at both the city and local scale. We then sought to identify the environmental, demographic, and social factors associated with high-risk areas via principal components regression. RESULTS: Citywide mortality increases by 9.3% on days following those with apparent temperatures over 34 degrees C observed at 7:00 p.m. local time. During these conditions, elevated mortality rates were found for 10 of the 48 ZCTAs concentrated in the west central portion of the County. Factors related to high heat mortality risk included proximity to locally high surface temperatures, low socioeconomic status, high density residential zoning, and age. CONCLUSIONS: Within the larger Philadelphia metropolitan area, there exists statistically significant fine-scale spatial variability in the mortality response to high apparent temperatures. Future heat warning systems and mitigation and intervention measures could target these high risk areas to reduce the burden of extreme weather on summertime morbidity and mortality. PMID- 22443424 TI - The memory remains: application of historical DNA for scaling biodiversity loss. AB - Few species worldwide have attracted as much attention in relation to conservation and sustainable management as Pacific salmon. Most populations have suffered significant reductions, many have disappeared, and even entire evolutionary significant units (ESUs) are believed to have been lost. Until now, no 'smoking gun' in terms of direct genetic evidence of the loss of a salmon ESU has been produced. In this issue of Molecular Ecology, Iwamoto et al. (2012) use microsatellite analysis of historical scale samples of Columbia River sockeye salmon (Oncorhynchus nerka) from 1924 (Fig. 1) to ask the pertinent question: Do the historical samples contain salmon from extirpated populations or ESUs? They identified four genetic groups in the historical samples of which two were almost genetically identical to contemporary ESUs in the river, one showed genetic relationship with a third ESU, but one group was not related to any of the contemporary populations. In association with ecological data, the genetic results suggest that an early migrating Columbia River headwater sockeye salmon ESU has been extirpated. The study has significant importance for conservation and reestablishment of sockeye populations in the Columbia River, but also underpins the general significance of shifting baselines in conservation biology, and how to assess loss of genetic biodiversity. The results clearly illustrate the huge and versatile potential of using historical DNA in population and conservation genetics. Because of the extraordinarily plentiful historical samples and rapid advances in fish genomics, fishes are likely to spearhead future studies of temporal ecological and population genomics in non-model organisms. [Figure: see text]. PMID- 22443425 TI - Population genomics as a new tool for wildlife management. AB - Admixture and introgression have varied effects on population viability and fitness. Admixture might be an important source of new alleles, particularly for small, geographically isolated populations. However, admixture might also cause outbreeding depression if populations are adapted to different ecological or climatic conditions. Because of the emerging use of translocation and admixture as a conservation and wildlife management strategy to reduce genetic load (termed genetic rescue), the possible effects of admixture have practical consequences (Bouzat et al. 2009; Hedrick & Fredrickson 2010). Importantly, genetic load and local adaptation are properties of individual loci and epistatic interactions among loci rather than properties of genomes. Likewise, the outcome and consequences of genetic rescue depend on the fitness effects of individual introduced alleles. In this issue of Molecular Ecology, Miller et al. (2012) use model-based, population genomic analyses to document locus-specific effects of a recent genetic rescue in the bighorn sheep population within the National Bison Range wildlife refuge (NBR; Montana, USA). They find a subset of introduced alleles associated with increased fitness in NBR bighorn sheep, some of which experienced accelerated introgression following their introduction. These loci mark regions of the genome that could constitute the genetic basis of the successful NBR bighorn sheep genetic rescue. Although population genomic analyses are frequently used to study local adaptation and selection (e.g. Hohenlohe et al. 2010; Lawniczak et al. 2010), this study constitutes a novel application of this analytical framework for wildlife management. Moreover, the detailed demographic data available for the NBR bighorn sheep population provide a rare and powerful source of information and allow more robust population genomic inference than is often possible. PMID- 22443426 TI - Bacterial biofilms in a 'genes-to-ecosystems' context. AB - In ecology, there is an increasing amount of research dedicated to understanding how intraspecific genetic diversity can extend beyond the population level to influence the assembly of communities and the functioning of ecosystems. In this issue of Molecular Ecology, Koh et al. (2012) take this exploration to a new level using bacterial biofilms and protozoan grazers. They show that there is heritable variation in the phenotypes of different variants of biofilms of Serratia marcescens and that these strains display complementarity when combined in a diverse assemblage. Mixtures of variants were significantly more resistant to protozoan grazing than either wild-type or variant biofilms grown in monocultures. While similar biodiversity effects of genotype mixtures have been observed in other systems, Koh et al. (2012) link phenotype variation of the biofilms to a single nucleotide polymorphism in one regulatory gene. Importantly, the authors demonstrate that minimal changes in a genotype can result in substantial shifts in interspecific ecological interactions. PMID- 22443428 TI - Feasibility of the FINDRISC questionnaire to identify individuals with impaired glucose tolerance in Swedish primary care. A cross-sectional population-based study. AB - AIM: To evaluate the performance of the FINDRISC questionnaire as a tool to recruit individuals with impaired glucose tolerance for lifestyle intervention programmes. METHODS: A cross-sectional population-based study in primary Health Care Centres in a middle-sized Swedish town. All 9734 individuals, aged 35-75 years, living within a defined area, were invited by mail to fill in and return the FINDRISC questionnaire. Participants with a risk score >= 15 (n = 525) were invited to perform an oral glucose tolerance test while those with known diabetes were excluded. RESULTS: In total, 5452 questionnaires (58%) were returned and revealed a mean risk-score of 8.5 +/- 4.5 (mean +/- SD). We found that 525 participants had a risk-score >= 15 and 302 (58%) were further examined with an oral glucose tolerance testing (OGTT). Among them we detected 11% with previously undiagnosed Type 2 diabetes, 16% with impaired glucose tolerance and 29% with impaired fasting glucose. A FINDRISC score >= 15 was associated with a positive predictive value of 55% for impaired glucose metabolism (impaired fasting glucose + impaired glucose tolerance + Type 2 diabetes) and of 16% for impaired glucose tolerance, respectively. The positive predictive value for impaired glucose tolerance did not increase to more than 17% when choosing the cut-point 17, while there was a significant increase in the positive predictive value for impaired glucose metabolism (70%). CONCLUSIONS: The FINDRISC questionnaire is a useful instrument for identification of individuals with impaired glucose metabolism but seems less effective for detection of individuals with impaired glucose tolerance. Strategies to find individuals with impaired glucose tolerance for implementation of lifestyle changes in primary care should therefore be developed further. PMID- 22443430 TI - How big is Florida's python problem? PMID- 22443431 TI - Ultrasound-guided endoscopic diode laser ablation in dogs with transitional cell carcinoma. PMID- 22443432 TI - Veterinary college accreditation: setting the record straight. PMID- 22443433 TI - What is your diagnosis? Extraskeletal osteosarcoma. PMID- 22443434 TI - What is your diagnosis? Histiocytic sarcoma. PMID- 22443435 TI - Pathology in practice. Benign peripheral nerve sheath tumor. PMID- 22443436 TI - Veterinarian satisfaction with companion animal visits. AB - OBJECTIVE: To measure veterinarian satisfaction with companion animal visits through an adaptation of a previously validated physician visit satisfaction scale and to identify demographic, personality, appointment, and communication factors that contribute to veterinarian visit satisfaction. DESIGN: Cross sectional descriptive study. SAMPLE: Random sample of 50 companion animal practitioners in southern Ontario, Canada, and convenience sample of 300 clients and their pets. PROCEDURES: For each practitioner, 6 clinical appointments were videotaped, and the resulting 300 videotapes were analyzed by use of the Roter interaction analysis system. The physician satisfaction scale, Rosenberg self esteem scale, and interpersonal reactivity index were used to measure veterinarian visit satisfaction, self-esteem, and empathy, respectively. Linear regression analysis was conducted to study the relationship between factors and veterinarian visit satisfaction. RESULTS: Veterinarian visit satisfaction ranged from 1 to 5 (mean +/- SD, 3.97 +/- 0.99) and differed significantly between wellness appointments (mean scale score, 4.13) and problem appointments (mean scale score, 3.81). Various elements of client and veterinarian communication as well as personality measures of veterinarian self-esteem and empathy were associated with veterinarian satisfaction. The specific factors differed depending on the nature of the appointment. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that veterinarian visit-specific satisfaction is enhanced through the use of communication that builds relationships with clients and is associated with degrees of veterinarian empathetic concern and veterinarian self esteem. The implications extend to overall job satisfaction and its potential link to the health and well-being of individual veterinarians. PMID- 22443437 TI - Risk factors for urate uroliths in cats. AB - OBJECTIVE: To identify demographic factors associated with urate urolithiasis in cats and determine whether the rate of urolith submission to a laboratory had changed over time. DESIGN: Case series and case-control study. ANIMALS: Cases consisted of 5,072 cats with urate uroliths submitted to the Minnesota Urolith Center between January 1, 1981, and December 31, 2008. Controls consisted of 437,228 cats without urinary tract diseases identified in records of the Veterinary Medical Database during the same period. PROCEDURES: Information on cat breed, age, sex, reproductive status, and location of uroliths was used to identify risk factors. Changes in annual urolith submission rates were evaluated. RESULTS: Purebred cats had significantly higher odds of developing urate uroliths than did cats of mixed breeding (reference group). On the other hand, cats of the Abyssinian, American Shorthair, Himalayan, Manx, and Persian breeds had significantly lower odds of developing urate uroliths than did mixed breeds. Neutered cats were 12 times as likely to develop urate uroliths as were sexually intact cats. Cats in all age groups had significantly increased odds of developing urate uroliths, compared with cats < 1 year of age (reference group). Cats >= 4 but < 7 years of age had the highest odds of all groups and were 51 times as likely to develop urate uroliths as were cats < 1 year of age. Urolith submission rates did not change significantly with time. CONCLUSIONS AND CLINICAL RELEVANCE: Findings of this study suggested that the typical cat with urate uroliths was a purebred neutered cat, 4 to 7 years old, with uroliths in the bladder or urethra. This information may be helpful in predicting mineral composition of uroliths in vivo. However, no conclusions can be made regarding cause-and-effect relationships. PMID- 22443438 TI - Evolution of clinical signs and predictors of outcome after conservative medical treatment for disk-associated cervical spondylomyelopathy in dogs. AB - OBJECTIVE: To evaluate the evolution of clinical signs and their correlation with results of magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS) and to assess potential prognostic variables after conservative medical treatment for disk-associated cervical spondylomyelopathy (DA-CSM) in dogs. DESIGN: Prospective cohort study. ANIMALS: 21 client-owned dogs with DA-CSM. PROCEDURES: After neurologic grading, dogs underwent low-field MRI and TMS with measurement of onset latencies and peak-to-peak amplitudes from the extensor carpi radialis and cranial tibial muscles. Dimensions calculated from MRI images were remaining spinal cord area, spinal cord compression ratio, vertebral occupying ratio, vertebral canal height-to-body height ratio, vertebral canal height-to-body length ratio, and vertebral canal compromise ratio. Intraparenchymal signal intensity changes were graded. Dogs were reevaluated 1, 3, 6, 12, and 24 months after initial diagnosis. RESULTS: Outcome was successful in 8 of 21 dogs. Negative outcomes were characterized by rapid progression of clinical signs. All dogs with more severe clinical signs of DA-CSM 1 month after diagnosis had unsuccessful outcomes. Outcome was associated with the remaining spinal cord area and vertebral canal compromise ratio. Prognosis was not associated with severity of clinical signs or results of TMS. There were no significant correlations among clinical signs, MRI findings, and TMS results. CONCLUSIONS AND CLINICAL RELEVANCE: Conservative medical treatment of DA-CSM was associated with a guarded prognosis. Selected MRI variables and clinical evolution 1 month after diagnosis can be considered prognostic indicators. The lack of correlation among clinical signs, results of diagnostic imaging, and results of electrophysiologic evaluation in dogs with DA-CSM warrants further investigation. PMID- 22443439 TI - Surgical treatment of a pulmonary artery vascular hamartoma in a dog. AB - CASE DESCRIPTION: A 6-year-old Siberian Husky-mix dog was examined for episodes of collapse. CLINICAL FINDINGS: Physical examination, echocardiography, abdominal ultrasonography, ECG, and thoracic computed tomography with contrast were performed and revealed a 2.5 * 2.3 * 2.0-cm mass over the pulmonic valve leaflets, resulting in moderate pulmonic stenosis. Other abnormal findings included systemic hypertension, right bundle branch block, proteinuria, and a urinary bladder mass. TREATMENT AND OUTCOME: Pulmonary arteriotomy was performed under inflow occlusion, and the mass was resected with transesophageal echocardiographic guidance and direct visualization. Results of histologic examination of the mass revealed a vascular hamartoma. Sequential follow-up examinations and telephone contacts (at 0.5, 5, and 15 months after surgery) revealed that the patient had been free from episodes of collapse since surgery. No regrowth of the mass was noted on follow-up echocardiograms, and the pulmonic stenosis had resolved, although mild to moderate pulmonary insufficiency later developed. The bladder mass was excised 15 months after the first surgery when hematuria developed, and results of histologic examination of this mass revealed a vascular hamartoma. The dog was eventually euthanized 31 months after the initial surgery for reasons that could not be directly linked to any recurrence of the pulmonary artery mass. CLINICAL RELEVANCE: Hamartomas are benign tumors that can be located in various tissues, including large arteries. Computed tomography was helpful in predicting the resectability of the intracardiac mass in this dog. Treatment with arteriotomy under inflow occlusion and mild hypothermia resulted in a favorable outcome. PMID- 22443440 TI - Lateral approach to nephrotomy in the management of unilateral renal calculi in a rabbit (Oryctolagus cuniculus). AB - CASE DESCRIPTION: A 5-year-old 2.23-kg (4.91-lb) spayed female Lop rabbit (Oryctolagus cuniculus) was evaluated because of a history of lethargy, polyuria, and polydipsia of 1 month's duration. The referring veterinarian made a presumptive diagnosis of hypercalcemia of unknown etiology on the basis of a plasma total calcium concentration of 14.0 mg/dL. CLINICAL FINDINGS: Physical examination findings were unremarkable. Hematologic and plasma biochemical analysis revealed nonregenerative, normocytic, normochromic anemia (PCV, 28%) with heteropenia (23%; 1,334 heterophils/mL) and a total plasma calcium concentration of 16 mg/dL. Radiographic and ultrasonographic examination revealed radiodense and hyperechoic structures in both renal pelves and right unilateral nephrolithiasis. TREATMENT AND OUTCOME: Nephrotomy was performed via laparotomy with a right lateral approach. A nephrolith composed of calcium carbonate and carbonate apatite was removed from the right renal pelvis. The rabbit's plasma tested positive for antibodies against Encephalitozoon cuniculi by means of an indirect immunofluorescence assay, and fenbendazole (20 mg/kg [9.1 mg/lb], p.o., q 24 h) was administered for 28 days. Although plasma calcium concentration was not substantially decreased after treatment (values were 14.1 and 15.1 mg/dL 1 week and 3 months after surgery, respectively), the patient did not have clinical signs of hypercalcemia and died of unrelated causes approximately 1 year after surgery. CLINICAL RELEVANCE: To the authors' knowledge, this is the first report of a nephrotomy performed in a rabbit via a lateral abdominal approach. This approach allowed easy location of the kidney and also reduced manipulation, thus decreasing the risk of damaging the abdominal viscera and potentially decreasing postoperative pain. PMID- 22443442 TI - Endoscopically guided removal of cloacal calculi in three African spurred tortoises (Geochelone sulcata). AB - CASE DESCRIPTION: 3 female African spurred tortoises (Geochelone sulcata) of various body weights (0.22, 0.77, and 2.86 kg [0.48, 1.69, and 6.29 lb]) were examined because of reduced food intake and lack of fecal output. Owners reported intermittent tenesmus in 2 of the tortoises. CLINICAL FINDINGS: Physical examinations revealed no clinically important abnormalities in the tortoises. Cloacal calculi were diagnosed on the basis of radiography and cloacoscopy in all 3 tortoises. One tortoise had another calculus in the urinary bladder. TREATMENT AND OUTCOME: Tortoises were anesthetized, and cloacal calculi were removed by use of a cutting burr (plain-fissure cutting burr and a soft tissue protector mounted to a dental handpiece that had a low-speed motor and a straight nose cone) and warm water irrigation with endoscopic guidance. Complete removal of calculus fragments was achieved by use of forceps and irrigation. In 1 tortoise, removal of the cloacal calculus was staged (2 separate procedures). In another tortoise, a second cloacal calculus (which had been located in the urinary bladder during the first examination) was successfully removed 25 days after removal of the first calculus. All 3 tortoises recovered uneventfully, and serious complications secondary to removal of the cloacal calculi were not detected. CLINICAL RELEVANCE: Cloacoscopy combined with the use of a low-speed dental drill and warm water irrigation should be considered a simple, safe, and nontraumatic treatment option for removal of obstructive cloacal calculi in tortoises. PMID- 22443443 TI - Potential role of noncommercial swine populations in the epidemiology and control of porcine reproductive and respiratory syndrome virus. AB - OBJECTIVE: To assess the role of noncommercial pigs in the epidemiology of porcine reproductive and respiratory syndrome (PRRS) virus. DESIGN: Seroepidemiologic study and survey study. ANIMALS: 661 pigs from which blood samples were collected at slaughter and 32 pigs from which blood samples were collected longitudinally. PROCEDURES: Spatial databases of commercial farms and 4 H participation were evaluated by use of commercial geographic information systems software. Information on disease knowledge and management methods of 4-H participants was obtained by mail survey and personal interview. Serum samples for antibody testing by PRRS ELISA were obtained from pigs at slaughter or at county fairs and on farms. RESULTS: Participation in 4-H swine programs was geographically associated with commercial swine production in Minnesota, and 39% of 4-H participants reared pigs at locations with commercial pigs. High seroprevalence at fairs (49%; range, 29% to 76%) and seroconversion after fairs indicated that PRRS virus exposure was common in pigs shown by 4-H participants and that transmission could occur at fairs. CONCLUSIONS AND CLINICAL RELEVANCE: The small swine population shown by 4-H members (estimated 12,000 pigs) relative to the population of commercial swine in Minnesota (estimated 6.5 million pigs) suggested the former overall was likely of minor importance to PRRS virus epidemiology at present. However, the relative frailty of knowledge of biosecurity practices, evidence that PRRS virus exposure was frequent, common intentions to show pigs at multiple events, and often close interactions with commercial herds suggested that the 4-H community should be involved in regional efforts to control PRRS. PMID- 22443444 TI - Detection of class 1 integrons in Salmonella Weltevreden and silent antibiotic resistance genes in some seafood-associated nontyphoidal isolates of Salmonella in south-west coast of India. AB - AIMS: To study the antibiogram of 40 seafood isolates of Salmonella and use of PCR to detect the presence of integrons and genes coding for antibiotic resistance. METHODS AND RESULTS: In this study, 40 isolates of Salmonella were used for antibiogram analysis. The multidrug-resistant isolates were analyzed for the presence of integron using integron-specific primers. Twenty-five percentage of the isolates were multidrug resistant while 67.50% were resistant to at least two antibiotics. Antibiotic resistance genes catA1 and tetA were present in 57.52 and 60%, respectively. Although widespread presence of genes was observed, only 26.08% of the catA1-carrying isolates exhibited phenotypic resistance against the respective antibiotic. Integrons present in representative isolates of Salmonella Weltevreden and Salmonella Newport were sequenced. The former contained class 1 integron with a single gene dfrA7 in the integron cassette and an adjacent dihydropteroate synthetase gene along with the usual quaternary ammonium compound resistance gene, while the later contained class 1 integron with dhfrA1, OrfC, in the integron cassette and an adjacent dihydropteroate synthetase gene along with the usual quaternary ammonium compound resistance gene. CONCLUSIONS: This study demonstrates the presence of silent antibiotic resistance genes and class I integrons in seafood-associated Salmonella strains. The study also demonstrates the first report of class I integron in Salm. Weltevreden. Detection of catA1 genes in phenotypically sensitive bacteria suggests that these could be reservoirs in the environment. SIGNIFICANCE AND IMPACT OF THE STUDY: The manuscript provides novel results describing the existence of a high rate of antibiotic resistance in the Salmonella populations prevailing in environmental sources as well as an absence of correspondence between the presence of antibiotic resistance genes, and the exhibition of a the corresponding phenotypic trait of resistance against the respective antibiotic compound was observed. In addition, the manuscript reports the presence of the class I integron in Salm. Weltevreden. PMID- 22443445 TI - The dimanganese(II) site of Bacillus subtilis class Ib ribonucleotide reductase. AB - Class Ib ribonucleotide reductases (RNRs) use a dimanganese-tyrosyl radical cofactor, Mn(III)(2)-Y(*), in their homodimeric NrdF (beta2) subunit to initiate reduction of ribonucleotides to deoxyribonucleotides. The structure of the Mn(II)(2) form of NrdF is an important component in understanding O(2)-mediated formation of the active metallocofactor, a subject of much interest because a unique flavodoxin, NrdI, is required for cofactor assembly. Biochemical studies and sequence alignments suggest that NrdF and NrdI proteins diverge into three phylogenetically distinct groups. The only crystal structure to date of a NrdF with a fully ordered and occupied dimanganese site is that of Escherichia coli Mn(II)(2)-NrdF, prototypical of the enzymes from actinobacteria and proteobacteria. Here we report the 1.9 A resolution crystal structure of Bacillus subtilis Mn(II)(2)-NrdF, representative of the enzymes from a second group, from Bacillus and Staphylococcus. The structures of the metal clusters in the beta2 dimer are distinct from those observed in E. coli Mn(II)(2)-NrdF. These differences illustrate the key role that solvent molecules and protein residues in the second coordination sphere of the Mn(II)(2) cluster play in determining conformations of carboxylate residues at the metal sites and demonstrate that diverse coordination geometries are capable of serving as starting points for Mn(III)(2)-Y(*) cofactor assembly in class Ib RNRs. PMID- 22443446 TI - Environmentally friendly, one-pot synthesis of Ag nanoparticle-decorated reduced graphene oxide composites and their application to photocurrent generation. AB - In this paper, we develop an environmentally friendly, one-pot strategy toward rapid preparation of Ag nanoparticle-decorated reducd graphene oxide (AgNPs/rGO) composites by heating the mixture of GO and AgNO(3) aqueous solution in the presence of sodium hydroxide at 80 degrees C under stirring. The reaction was accomplished within a short period of 10 min without extra reducing agent. As synthesized AgNPs/rGO composites have been successfully applied in photocurrent generation in the visible spectral region. PMID- 22443447 TI - Neural correlates of fair behavior in interpersonal bargaining. AB - Research findings show that proposers make surprisingly fair offers in the ultimatum and dictator games, an observation that contradicts predictions of classical game theory. The present functional magnetic resonance imaging (fMRI) study examines brain activities of proposers that contribute to fair and unfair behaviors. We hypothesized that egoistic and altruistic motives of proposers affect fairness differentially in the two games. fMRI analysis revealed that the 28% of fair offers in the present ultimatum game were related to enhanced activity in prefrontal areas, in particular, in regions involved in reward and theory of mind. This corroborates the idea that egoistic motives are primarily responsible for fair offers in this game, which we denote as strategic fairness. Fair offers in the dictator game, however, were related to increased activity in the dorsal anterior cingulate cortex and the posterior cingulate cortex. This supports the idea that altruistic motives primarily drive fair offers in the dictator game, denoted here as altruistic fairness. PMID- 22443448 TI - Dental erosive wear and salivary flow rate in physically active young adults. AB - BACKGROUND: Little attention has been directed towards identifying the relationship between physical exercise, dental erosive wear and salivary secretion. The study aimed i) to describe the prevalence and severity of dental erosive wear among a group of physically active young adults, ii) to describe the patterns of dietary consumption and lifestyle among these individuals and iii) to study possible effect of exercise on salivary flow rate. METHODS: Young members (age range 18-32 years) of a fitness-centre were invited to participate in the study. Inclusion criteria were healthy young adults training hard at least twice a week. A non-exercising comparison group was selected from an ongoing study among 18-year-olds. Two hundred and twenty participants accepted an intraoral examination and completed a questionnaire. Seventy of the exercising participants provided saliva samples. The examination was performed at the fitness-centre or at a dental clinic (comparison group), using tested erosive wear system (VEDE). Saliva sampling (unstimulated and stimulated) was performed before and after exercise. Occlusal surfaces of the first molars in both jaws and the labial and palatal surfaces of the upper incisors and canines were selected as index teeth. RESULTS: Dental erosive wear was registered in 64% of the exercising participants, more often in the older age group, and in 20% of the comparison group. Enamel lesions were most observed in the upper central incisors (33%); dentine lesions in lower first molar (27%). One fourth of the participants had erosive wear into dentine, significantly more in males than in females (p = 0.047). More participants with erosive wear had decreased salivary flow during exercise compared with the non-erosion group (p < 0.01). The stimulated salivary flow rate was in the lower rage (<= 1 ml/min) among more than one third of the participants, and more erosive lesions were registered than in subjects with higher flow rates (p < 0.01). CONCLUSION: The study showed that a high proportion of physically active young adults have erosive lesions and indicate that hard exercise and decreased stimulated salivary flow rate may be associated with such wear. PMID- 22443449 TI - Mapsembler, targeted and micro assembly of large NGS datasets on a desktop computer. AB - BACKGROUND: The analysis of next-generation sequencing data from large genomes is a timely research topic. Sequencers are producing billions of short sequence fragments from newly sequenced organisms. Computational methods for reconstructing whole genomes/transcriptomes (de novo assemblers) are typically employed to process such data. However, these methods require large memory resources and computation time. Many basic biological questions could be answered targeting specific information in the reads, thus avoiding complete assembly. RESULTS: We present Mapsembler, an iterative micro and targeted assembler which processes large datasets of reads on commodity hardware. Mapsembler checks for the presence of given regions of interest that can be constructed from reads and builds a short assembly around it, either as a plain sequence or as a graph, showing contextual structure. We introduce new algorithms to retrieve approximate occurrences of a sequence from reads and construct an extension graph. Among other results presented in this paper, Mapsembler enabled to retrieve previously described human breast cancer candidate fusion genes, and to detect new ones not previously known. CONCLUSIONS: Mapsembler is the first software that enables de novo discovery around a region of interest of repeats, SNPs, exon skipping, gene fusion, as well as other structural events, directly from raw sequencing reads. As indexing is localized, the memory footprint of Mapsembler is negligible. Mapsembler is released under the CeCILL license and can be freely downloaded from http://alcovna.genouest.org/mapsembler/. PMID- 22443450 TI - Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis. AB - BACKGROUND: Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model. METHODS: ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups. RESULTS: The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation. CONCLUSIONS: These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model. PMID- 22443451 TI - An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes. AB - During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor alpha, interleukin 6, insulin and transforming growth factor beta orchestrate these responses and are integrated during the G(1) phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels. PMID- 22443452 TI - Utilization of combined remote sensing techniques to detect environmental variables influencing malaria vector densities in rural West Africa. AB - INTRODUCTION: The use of remote sensing has found its way into the field of epidemiology within the last decades. With the increased sensor resolution of recent and future satellites new possibilities emerge for high resolution risk modeling and risk mapping. METHODS: A SPOT 5 satellite image, taken during the rainy season 2009 was used for calculating indices by combining the image's spectral bands. Besides the widely used Normalized Difference Vegetation Index (NDVI) other indices were tested for significant correlation against field observations. Multiple steps, including the detection of surface water, its breeding appropriateness for Anopheles and modeling of vector imagines abundance, were performed. Data collection on larvae, adult vectors and geographic parameters in the field, was amended by using remote sensing techniques to gather data on altitude (Digital Elevation Model = DEM), precipitation (Tropical Rainfall Measurement Mission = TRMM), land surface temperatures (LST). RESULTS: The DEM derived altitude as well as indices calculations combining the satellite's spectral bands (NDTI = Normalized Difference Turbidity Index, NDWI Mac Feeters = Normalized Difference Water Index) turned out to be reliable indicators for surface water in the local geographic setting. While Anopheles larvae abundance in habitats is driven by multiple, interconnected factors - amongst which the NDVI - and precipitation events, the presence of vector imagines was found to be correlated negatively to remotely sensed LST and positively to the cumulated amount of rainfall in the preceding 15 days and to the Normalized Difference Pond Index (NDPI) within the 500 m buffer zone around capture points. CONCLUSIONS: Remotely sensed geographical and meteorological factors, including precipitations, temperature, as well as vegetation, humidity and land cover indicators could be used as explanatory variables for surface water presence, larval development and imagines densities. This modeling approach based on remotely sensed information is potentially useful for counter measures that are putting on at the environmental side, namely vector larvae control via larviciding and water body reforming. PMID- 22443453 TI - Geometry control and optical tunability of metal-cuprous oxide core-shell nanoparticles. AB - Metal-semiconductor hybrid heteronanostructures may exhibit synergistically reinforced optical responses and significantly enhanced optical tunability that essentially arise from the unique nanoscale interactions between the metal and semiconductor components. Elaboration of multi-component hybrid nanoparticles allows us to achieve optimized or diversified material functionalities through precise control over the dimension and morphology of the constituent building units, on one hand, and through engineering their relative geometrical arrangement and interfacial structures, on the other hand. Here we study the geometry-dependent optical characteristics of metal-cuprous oxide (Cu(2)O) core shell hybrid nanoparticles in great detail through combined experimental and theoretical efforts. We demonstrate that several important geometrical parameters, such as shell thickness, shell crystallinity, shell porosity, and core composition, of the hybrid nanoparticles can be tailored in a highly precise and controllable manner through robust wet chemistry approaches. The tight control over the particle geometries provides unique opportunities for us to develop quantitative understanding of how the dimensions, morphologies, and electronic properties of the semiconducting shells and the geometry and compositions of the metallic cores affect the plasmon resonance frequencies, the light scattering and absorption cross sections, and the overall extinction spectral line shapes of the hybrid nanoparticles. Mie scattering theory calculations provide further insights into the origin of the geometrically tunable optical responses and the interesting extinction spectral line shapes of the hybrid nanoparticles that we have experimentally observed. PMID- 22443454 TI - Chimeric platinum-polyamines and DNA binding. Kinetics of DNA interstrand cross link formation by dinuclear platinum complexes with polyamine linkers. AB - The first observation of a polyamine-DNA interaction using 2D [(1)H, (15)N] HSQC NMR spectroscopy allows study of the role of the linker in polynuclear platinum DNA interactions and a novel "anchoring" of the polyamine by Pt-DNA bond formation allows examination of the details of conformational B -> Z transitions induced by the polyamine. The kinetics and mechanism of the stepwise formation of 5'-5' 1,4-GG interstrand cross-links (IXLs) by fully (15)N-labeled [{trans PtCl((15)NH(3))(2)}(2){MU-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(6)(15)NH(2))}](3+) (1,1/t,t-6,6, 1) and [{trans-PtCl((15)NH(3))(2)}(2){MU ((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(2)(15)NH(2)(CH(2))(6)(15)NH(2))}](4+) (1,1/t,t-6,2,6, 1') with the self-complementary oligonucleotide 5' {d(ATATGTACATAT)(2)} (duplex I) are compared to the analogous reaction with 1,0,1/t,t,t (BBR3464) under identical conditions (pH 5.4, 298 K). Initial electrostatic interactions with the DNA are delocalized and followed by aquation to form the monoaqua monochloro species. The rate constant for monofunctional adduct formation, k(MF), for 1 (0.87 M(-1) s(-1)) is 3.5 fold higher than for 1,0,1/t,t,t (0.25 M(-1) s(-1); the value could not be calculated for 1' due to peak overlap). The evidence suggests that several conformers of the bifunctional adduct form, whereas for 1,0,1/t,t,t only two discrete conformers were observed. The combined effect of the conformers observed for 1 and 1' may play a crucial role in the increased potency of these novel complexes compared to 1,0,1/t,t,t. Treated as a single final product, the rate of formation of the 5'-5' 1,4-GG IXL, k(CH), for 1 (k(CH) = 4.37 * 10(-5) s(-1)) is similar to that of 1,0,1/t,t,t, whereas the value for 1' is marginally higher (k(CH) = 5.4 * 10(-5) s(-1)). PMID- 22443455 TI - Aqueous solvation of methane from first principles. AB - Structural, dynamical, bonding, and electronic properties of water molecules around a soluted methane molecule are studied from first principles. The results are compatible with experiments and qualitatively support the conclusions of recent classical molecular dynamics simulations concerning the controversial issue on the presence of "immobilized" water molecules around hydrophobic groups: the hydrophobic solute slightly reduces (by a less than 2 factor) the mobility of many surrounding water molecules rather than immobilizing just the few ones which are closest to methane, similarly to what was obtained by previous first principles simulations of soluted methanol. Moreover, the rotational slowing down is compatible with the one predicted on the basis of the excluded volume fraction, which leads to a slower hydrogen bond exchange rate. The analysis of simulations performed at different temperatures suggests that the target temperature of the soluted system must be carefully chosen, in order to avoid artificial slowing-down effects. By generating maximally localized Wannier functions, a detailed description of the polarization effects in both solute and solvent molecules is obtained, which better characterizes the solvation process. PMID- 22443456 TI - Do informed consent documents for cancer trials do what they should? A study of manifest and latent functions. AB - Though patient information leaflets (PILs) are provided to those invited to take part in medical research, they usually fall short in facilitating informed decisions about participation. We aimed to explore why there is an enduring requirement for a process that seems not to 'work', and to explain why the problems have proven resistant to correction. We analysed applications for ethical approval for 13 oncology trials and related official guidance. We interviewed 26 patients invited to participate in the trials. Data analysis was based on the constant comparative method. We show that PILs function latently to satisfy purposes other than their manifest function as a decision-facilitating tool. PILs are the outcome of a process of institutional scripting that is strongly shaped by the accountability demands inherent in the ethical review process. This results in the PIL being made to serve purposes both as a prospectus and as a contract. Though PILs have value for some patients, most do not recognise these documents as operating primarily in their interests. Patients make decisions in ways that deviate from official ideals. This analysis is important in recognising that no simple technical fix is available, and in enhancing sociological understanding of the institutional role of documents. PMID- 22443457 TI - Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. AB - AIMS: Mice and nonhuman primates administered with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. METHODS: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell specific markers and analysed by confocal microscopy. RESULTS: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. CONCLUSIONS: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism. PMID- 22443458 TI - Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease. AB - SIGNIFICANCE: The role of reactive oxygen species (ROS) in angiotensin II (AngII) induced endothelial dysfunction, cardiovascular and renal remodeling, inflammation, and fibrosis has been well documented. The molecular mechanisms of AngII pathophysiological activity involve the stimulation of NADPH oxidases, which produce superoxide and hydrogen peroxide. AngII also increases the production of mitochondrial ROS, while the inhibition of AngII improves mitochondrial function; however, the specific molecular mechanisms of the stimulation of mitochondrial ROS is not clear. RECENT ADVANCES: Interestingly, the overexpression of mitochondrial thioredoxin 2 or mitochondrial superoxide dismutase attenuates AngII-induced hypertension, which demonstrates the importance of mitochondrial ROS in AngII-mediated cardiovascular diseases. CRITICAL ISSUES: Although mitochondrial ROS plays an important role in normal physiological cell signaling, AngII, high glucose, high fat, or hypoxia may cause the overproduction of mitochondrial ROS, leading to the feed-forward redox stimulation of NADPH oxidases. This vicious cycle may contribute to the development of pathological conditions and facilitate organ damage in hypertension, atherosclerosis, and diabetes. FUTURE DIRECTIONS: The development of antioxidant strategies specifically targeting mitochondria could be therapeutically beneficial in these disease conditions. PMID- 22443459 TI - Microsatellite genotyping reveals end-Pleistocene decline in mammoth autosomal genetic variation. AB - The last glaciation was a dynamic period with strong impact on the demography of many species and populations. In recent years, mitochondrial DNA sequences retrieved from radiocarbon-dated remains have provided novel insights into the history of Late Pleistocene populations. However, genotyping of loci from the nuclear genome may provide enhanced resolution of population-level changes. Here, we use four autosomal microsatellite DNA markers to investigate the demographic history of woolly mammoths (Mammuthus primigenius) in north-eastern Siberia from before 60 000 years ago up until the species' final disappearance c.4000 years ago. We identified two genetic groups, implying a marked temporal genetic differentiation between samples with radiocarbon ages older than 12 thousand radiocarbon years before present (ka) and those younger than 9ka. Simulation based analysis indicates that this dramatic change in genetic composition, which included a decrease in individual heterozygosity of approximately 30%, was due to a multifold reduction in effective population size. A corresponding reduction in genetic variation was also detected in the mitochondrial DNA, where about 65% of the diversity was lost. We observed no further loss in genetic variation during the Holocene, which suggests a rapid final extinction event. PMID- 22443460 TI - Outcomes of PCI at hospitals with or without on-site cardiac surgery. AB - BACKGROUND: Performance of percutaneous coronary intervention (PCI) is usually restricted to hospitals with cardiac surgery on site. We conducted a noninferiority trial to compare the outcomes of PCI performed at hospitals without and those with on-site cardiac surgery. METHODS: We randomly assigned participants to undergo PCI at a hospital with or without on-site cardiac surgery. Patients requiring primary PCI were excluded. The trial had two primary end points: 6-week mortality and 9-month incidence of major adverse cardiac events (the composite of death, Q-wave myocardial infarction, or target-vessel revascularization). Noninferiority margins for the risk difference were 0.4 percentage points for mortality at 6 weeks and 1.8 percentage points for major adverse cardiac events at 9 months. RESULTS: A total of 18,867 patients were randomly assigned in a 3:1 ratio to undergo PCI at a hospital without on-site cardiac surgery (14,149 patients) or with on-site cardiac surgery (4718 patients). The 6-week mortality rate was 0.9% at hospitals without on-site surgery versus 1.0% at those with on-site surgery (difference, -0.04 percentage points; 95% confidence interval [CI], -0.31 to 0.23; P=0.004 for noninferiority). The 9-month rates of major adverse cardiac events were 12.1% and 11.2% at hospitals without and those with on-site surgery, respectively (difference, 0.92 percentage points; 95% CI, 0.04 to 1.80; P=0.05 for noninferiority). The rate of target-vessel revascularization was higher in hospitals without on-site surgery (6.5% vs. 5.4%, P=0.01). CONCLUSIONS: We found that PCI performed at hospitals without on-site cardiac surgery was noninferior to PCI performed at hospitals with on-site cardiac surgery with respect to mortality at 6 weeks and major adverse cardiac events at 9 months. (Funded by the Cardiovascular Patient Outcomes Research Team [C-PORT] participating sites; ClinicalTrials.gov number, NCT00549796.). PMID- 22443461 TI - Improving xylem hydraulic conductivity measurements by correcting the error caused by passive water uptake. AB - Xylem hydraulic conductivity (K) is typically defined as K = F/(P/L), where F is the flow rate through a xylem segment associated with an applied pressure gradient (P/L) along the segment. This definition assumes a linear flow-pressure relationship with a flow intercept (F(0)) of zero. While linearity is typically the case, there is often a non-zero F(0) that persists in the absence of leaks or evaporation and is caused by passive uptake of water by the sample. In this study, we determined the consequences of failing to account for non-zero F(0) for both K measurements and the use of K to estimate the vulnerability to xylem cavitation. We generated vulnerability curves for olive root samples (Olea europaea) by the centrifuge technique, measuring a maximally accurate reference K(ref) as the slope of a four-point F vs P/L relationship. The K(ref) was compared with three more rapid ways of estimating K. When F(0) was assumed to be zero, K was significantly under-estimated (average of -81.4 +/- 4.7%), especially when K(ref) was low. Vulnerability curves derived from these under-estimated K values overestimated the vulnerability to cavitation. When non-zero F(0) was taken into account, whether it was measured or estimated, more accurate K values (relative to K(ref)) were obtained, and vulnerability curves indicated greater resistance to cavitation. We recommend accounting for non-zero F(0) for obtaining accurate estimates of K and cavitation resistance in hydraulic studies. PMID- 22443463 TI - Exenatide BID and liraglutide QD treatment patterns among type 2 diabetes patients in Germany. AB - OBJECTIVES: This study evaluated patient and prescriber characteristics, treatment patterns, average daily dose (ADD), and glycemic control of patients initiating glucagon-like peptide 1 (GLP-1) receptor agonists in Germany. METHODS: The LifeLinkTM EMR-EU database was searched to identify patients initiating exenatide twice daily (BID) or liraglutide once daily (QD) during the index period (January 1, 2009-April 4, 2010). Eligible patients had >= 180 days pre index history, >= 90 days post-index follow-up, and a pre-index type 2 diabetes diagnosis. Univariate tests were conducted at alpha=0.05. RESULTS: Six hundred and ninety-two patients were included (exenatide BID 292, liraglutide QD 400): mean (SD) age 59 (10) years, 59% male. Diabetologists prescribed liraglutide QD to a larger share of patients (65% vs 35% exenatide BID) than non-diabetologists (51% vs 49%). GLP-1 receptor agonist choice was not associated with age (p=0.282), gender (p=0.960), number of pre-index glucose-lowering medications (2.0 [0.9], p=0.159), pre-index HbA1c (8.2 [1.5%], p=0.231) or Charlson Comorbidity Index score (0.45 [0.78], p=0.547). Mean (SD) ADD was 16.7 mcg (9.2, label range 10-20 mcg) for exenatide BID and 1.4 mg (0.7, label range 0.6-1.8 mg) for liraglutide QD. Among patients with post-index HbA1c tests, mean unadjusted values did not differ between cohorts. Exenatide BID patients were more likely than liraglutide QD patients to continue pre-index glucose-lowering medications (67.1% vs 60.3%, p=0.027) or to start concomitant glucose-lowering medications at index (32.2% vs 25.0%, p=0.013); exenatide BID patients were less likely to augment treatment with another drug post-index (15.8% vs 22.5%, p=0.027). LIMITATIONS: Results may not be generalizable. Lab measures for clinical outcomes were available only for a sub-set of patients. CONCLUSIONS: Results suggested that some differences exist between patients initiating exenatide BID or liraglutide QD, with respect to prescribing physician specialty and pre- and post index treatment patterns. Both GLP-1 receptor agonists showed comparable post index HbA1c values in a sub-set of patients. PMID- 22443427 TI - Vorapaxar in the secondary prevention of atherothrombotic events. AB - BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.). PMID- 22443464 TI - Multimodal therapeutic approach and interdisciplinary challenge for the treatment of unresectable head and neck squamous cell carcinoma in six cats: a pilot study. AB - Feline head and neck squamous cell carcinoma (SCC) is a loco-regional disease harbouring a poor prognosis. The complex anatomic location precludes aggressive surgical resection and tumours recur within weeks to few months. Response to chemotherapy and local control after radiation therapy has been disappointing. In this study, a multimodal approach including medical treatment (thalidomide, piroxicam and bleomycin), radiation therapy (accelerated, hypofractionated protocol) and surgery was attempted in six cats. Treatment was well tolerated. Three cats with sublingual SCC were alive and in complete remission at data analysis closure after 759, 458 and 362 days. One cat with laryngeal SCC died of renal lymphoma after 51 days and the other with maxillary SCC died of a primary lung tumour 82 days after diagnosis. In both cats, the SCC was in complete remission. Only one cat developed metastases after 144 days. These encouraging preliminary results merit further evaluation in future trials. PMID- 22443465 TI - Migration of iron-labeled KHYG-1 natural killer cells to subcutaneous tumors in nude mice, as detected by magnetic resonance imaging. AB - BACKGROUND AIMS: A novel cell line of cytotoxic natural killer (NK) cells, KHYG 1, was examined in vivo for immunotherapy against prostate cancer. The feasibility of using magnetic resonance imaging (MRI) tracking to monitor the fate of injected NK cells following intravenous (i.v.), intraperitoneal (i.p.) and subcutaneous (s.c.) administration was assessed. METHODS: PC-3M human prostate cancer cells were injected s.c. into the flank of nude mice (day 0). KHYG-1 NK cells were labeled with an iron oxide contrast agent and injected s.c., i.v. or i.p. on day 8. Mice were imaged by MRI on days 7, 9 and 12. Tumor sections were examined with fluorescence microscopy and immunohistologic staining for NK cells. RESULTS: NK cells were detected in the tumors by histology after all three administration routes. NK cells and fluorescence from the iron label were co-localized. Signal loss was seen in the areas around the tumors and between the tumor lobes in the s.c. group. CONCLUSIONS: We are the first to label this cell line of NK cells with an iron oxide contrast agent. Accumulation of NK cells was visualized by MRI after s.c. injection but not after i.v. and i.p. injection. PMID- 22443466 TI - Use of biosimilar epoetin to increase hemoglobin levels in patients with chemotherapy-induced anemia: real-life clinical experience. AB - AIM: To evaluate the effectiveness of a biosimilar erythropoiesis-stimulating agent (Binocrit) for the treatment of patients with cancer and chemotherapy induced anemia in real-life clinical practice. MATERIALS & METHODS: Data were collected retrospectively from patients at five European centers (in France, Italy, The Netherlands, Romania and Spain) who received treatment with Binocrit. Hemoglobin (Hb) levels were recorded at regular intervals during Binocrit therapy for up to 26 weeks. Hb response (an increase of >= 1 g/dl in 4 weeks or a Hb level in the range 10-12 g/dl during the study) was assessed in patients with a Hb level >= 8.5 g/dl at the start of therapy who received treatment for at least 6 weeks. Hb response rates in patients who did and did not receive intravenous (iv.) iron were also assessed, and data on any serious unexpected adverse events were collected. RESULTS: Among evaluable patients (n = 113), 79% achieved a Hb response. Response rates were similar among evaluable patients who received an initial Binocrit dose of 30,000 or 40,000 IU/week (81 vs 78%; p = not significant). The Hb response rate was significantly greater in patients who received iv. iron than in patients who did not receive iv. iron (93 vs 77%; p < 0.05). No serious unexpected adverse events were reported. CONCLUSION: Use of the biosimilar erythropoiesis-stimulating agent Binocrit is effective and safe for the treatment of patients with cancer and chemotherapy-induced anemia. Supplementation with iv. iron increases the response rate compared with oral or no iron supplementation. PMID- 22443467 TI - Lanthanide coordination polymers with tetrafluoroterephthalate as a bridging ligand: thermal and optical properties. AB - By slow diffusion of triethylamine into a solution of 2,3,5,6 tetrafluoroterephthalic acid (H2tfBDC) and the respective lanthanide salt in EtOH/DMF single crystals of seven nonporous coordination polymers, (infinity)(2)[Ln(tfBDC)(NO(3))(DMF)(2)].DMF (Ln(3+) = Ce, Pr, Nd, Sm, Dy, Er, Yb; C2/c, Z = 8) have been obtained. In the crystal structures, two-dimensional square grids are found, which are composed of binuclear lanthanide nodes connected by tfBDC(2-) as a linking ligand. The coordination sphere of each lanthanide cation is completed by a nitrate anion and two DMF molecules (CN = 9). This crystal structure is unprecedented in the crystal chemistry of coordination polymers based on nonfluorinated terephthalate (BDC(2-)) as a bridging ligand; as for tfBDC(2-), a nonplanar conformation of the ligand is energetically more favorable, whereas for BDC(2-), a planar conformation is preferred. Differential thermal analysis/thermogravimetric analysis (DTA/TGA) investigations reveal that the noncoordinating DMF molecule is released first at temperatures of 100-200 degrees C. Subsequent endothermal weight losses correspond to the release of the coordinating DMF molecules. Between 350 and 400 degrees C, a strong exothermal weight loss is found, which is probably due to a decomposition of the tfBDC(2-) ligand. The residues could not be identified. The emission spectra of the (infinity)(2)[Ln(tfBDC)(NO(3))(DMF)(2)].DMF compounds reveal intense emission in the visible region of light for Pr, Sm, and Dy with colors from orange, orange red, to warm white. PMID- 22443468 TI - Aurora kinase-C-T191D is constitutively active mutant. AB - BACKGROUND: Aurora kinases (Aurora-A, B and C) belong to a family of conserved serine/threonine kinases which are key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved in cell cycle regulation while aurora-C is meiotic chromosome passenger protein. As Aurora kinase C is rarely expressed in normal somatic cells and has been found over expressed in many cancer lines. It is suggested that Aurora-C-T191D is not hyperactive mutant. RESULT: Aurora-C-T191D variant form was investigated and compared with wild type. The overexpression of Aurora-C-T191D was observed that it behaves like Aurora-C wild type (aurC-WT). Both Aurora-C-T191D and aurC-WT induce abnormal cell division resulting in centrosome amplification and multinucleation in transiently transfected cells as well as in stable cell lines. Similarly, Aurora-C-T191D and aurC-WT formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3 T3 stable cell lines overexpressing Aurora-C-T191D and its wild type partner induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumour aggressiveness was positively correlated with the rate of kinase activity, making Aurora-C a potential anti cancer therapeutic target. CONCLUSION: These findings proved that Aurora C-T191D is not hyperactive but is constitutively active mutant. PMID- 22443469 TI - Many of the functional differences between acetohydroxyacid synthase (AHAS) isozyme I and other AHASs are a result of the rapid formation and breakdown of the covalent acetolactate-thiamin diphosphate adduct in AHAS I. AB - Acetohydroxy acid synthase (AHAS; EC 2.2.1.6) is a thiamin diphosphate (ThDP) dependent decarboxylase-ligase that catalyzes the first common step in the biosynthesis of branched-chain amino acids. In the first stage of the reaction, pyruvate is decarboxylated and the reactive intermediate hydroxyethyl-ThDP carbanion/enamine is formed. In the second stage, the intermediate is ligated to another 2-ketoacid to form either acetolactate or acetohydroxybutyrate. AHAS isozyme I from Escherichia coli is unique among the AHAS isozymes in that it is not specific for 2-ketobutyrate (2-KB) over pyruvate as an acceptor substrate. It also appears to have a different mechanism for inhibition by valine than does AHAS III from E. coli. An investigation of this enzyme by directed mutagenesis and knowledge of detailed kinetics using the rapid mixing-quench NMR method or stopped-flow spectroscopy, as well as the use of alternative substrates, suggests that two residues determine most of the unique properties of AHAS I. Gln480 and Met476 in AHAS I replace the Trp and Leu residues conserved in other AHASs and lead to accelerated ligation and product release steps. This difference in kinetics accounts for the unique specificity, reversibility and allosteric response of AHAS I. The rate of decarboxylation of the initially formed 2-lactyl ThDP intermediate is, in some AHAS I mutants, different for the alternative acceptors pyruvate and 2-KB, putting into question whether AHAS operates via a pure ping-pong mechanism. This finding might be compatible with a concerted mechanism (i.e. the formation of a ternary donor-acceptor:enzyme complex followed by covalent, ThDP-promoted catalysis with concerted decarboxylation carboligation). It might alternatively be explained by an allosteric interaction between the multiple catalytic sites in AHAS. PMID- 22443470 TI - The role of obesity-related genetic loci in insulin sensitivity. AB - AIMS: Despite rapid advancements and many new diabetes susceptibility loci found in the past few years, few genetic variants associated with insulin sensitivity have been described, potentially attributable to the lack of larger cohorts examined with gold standard methods for insulin sensitivity assessment. There is a strong link between obesity and insulin sensitivity, and we hypothesized that known obesity susceptibility loci may act via effects on insulin sensitivity. METHODS: A cohort of 71-year-old men without diabetes (Uppsala Longitudinal Study of Adult Men) underwent a euglycaemic-hyperinsulinaemic clamp and genotyping for genetic variants representing 32 loci recently reported to be associated with BMI (n = 926). The effect of these loci on the insulin sensitivity index (M/I ratio) was examined using linear regression. An in silico replication was performed in publically available data for the three top single-nucleotide polymorphisms from the Meta-Analyses of Glucose and Insulin-related traits Consortium analyses of homeostasis model assessment of insulin resistance (n = 37,037). RESULTS: Three loci (SH2B1, MTCH2 and NEGR1) were associated with decreased insulin sensitivity at a nominal significance (P <= 0.05) after adjustment for BMI, but did not hold for multiple comparison correction. SH2B1 rs7359397 was also associated with homeostasis model assessment of insulin resistance in the Meta-Analyses of Glucose and Insulin-related traits Consortium data set (P = 3.9 * 10(-3)). CONCLUSIONS: Our study supports earlier reports of SH2B1 to be of importance in insulin sensitivity and, in addition, suggests potential roles of NEGR1 and MTCH2. PMID- 22443471 TI - Changes in protein dynamics of the DNA repair dioxygenase AlkB upon binding of Fe(2+) and 2-oxoglutarate. AB - The Escherichia coli DNA repair enzyme AlkB is a 2-oxoglutarate (2OG)-dependent Fe(2+) binding dioxygenase that removes methyl lesions from DNA and RNA. To date, nine human AlkB homologues are known: ABH1 to ABH8 and the obesity-related FTO. Similar to AlkB, these homologues exert their activity on nucleic acids, although for some homologues the biological substrate remains to be identified. 2OG dioxygenases require binding of the cofactors Fe(2+) and 2OG in the active site to form a catalytically competent complex. We present a structural analysis of AlkB using NMR, fluorescence, and CD spectroscopy to show that AlkB is a dynamic protein exhibiting different folding states. In the absence of the cofactors Fe(2+) and 2OG, apoAlkB is a highly dynamic protein. Binding of either Fe(2+) or 2OG alone does not significantly affect the protein dynamics. Formation of a fully folded and catalytically competent holoAlkB complex only occurs when both 2OG and Fe(2+) are bound. These findings provide the first insights into protein folding of 2OG-dependent dioxygenases. A role for protein dynamics in the incorporation of the metal cofactor is discussed. PMID- 22443472 TI - Potential impact of CO2 leakage from carbon capture and storage systems on field bean (Vicia faba). AB - Capture and geological storage of carbon dioxide (CO(2)) has been suggested to be essential to reduce emissions to the atmosphere and aid mitigation of global climate change. However, leakage from transport pipelines or carbon capture and storage (CCS) reservoirs may pose risks to vegetation and contribute to rising atmospheric concentrations [CO(2)]. This study examined effects on seedling emergence and growth when field bean plants (Vicia faba cv. Wizard) grown under field conditions were subjected to elevated soil [CO(2)] for 39 days after planting. The strong negative correlation between soil [CO(2)] and [O(2)] during the injection period created a hypoxic soil environment under conditions of elevated soil [CO(2)]. The damaging impact of this treatment became apparent early in the experiment as no seeds exposed to soil [CO(2)] >50% emerged, even after injection was discontinued. Some seeds exposed to soil [CO(2)] <50% produced seedlings, but many did not survive. Seedling emergence and survival in the gassed plots was greatest at [CO(2)] of 5-20%, but root and shoot growth was reduced relative to control plants. Seedling emergence and growth were negatively related to soil [CO(2)] and positively related to [O(2)], although it is not known which was more important in inducing the observed effects. These findings suggest that leakage of CO(2) from transport pipelines or CCS sites may greatly reduce seedling emergence and crop establishment in the vicinity of such infrastructures. PMID- 22443473 TI - RhoA: a therapeutic target for chronic myeloid leukemia. AB - BACKGROUND: Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. METHODS: To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. RESULTS: In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. CONCLUSIONS: RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML. PMID- 22443474 TI - Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib. AB - Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin-converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib. Rats were administered sorafenib (20 mg/kg per day) alone or in combination with captopril (40 mg/kg per day) for 4 weeks. Sorafenib administration increased blood pressure, which plateaued by day 10. Concurrent treatment with captopril for 4 weeks resulted in a 30 mmHg decrease in blood pressure compared with sorafenib alone (155 +/- 5 vs 182 +/- 6 mmHg, respectively; P < 0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20 +/- 8 vs 42 +/- 9 mg/day, respectively; P < 0.05) and reduced nephrinuria by eightfold (280 +/- 96 vs 2305 +/- 665 MUg/day, respectively; P < 0.05). Glomerular injury, thrombotic microangiopathy and tubular cast formation were also decreased in captopril treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity. In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side-effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib. PMID- 22443475 TI - Addiction research centres and the nurturing of creativity: Center for Alcohol Studies (CAS), Thailand. AB - The Center for Alcohol Studies of Thailand (CAS) is a newly established research agency in Thailand. With support from the Thai Health Promotion Foundation, CAS was established as the national research and knowledge management institute for addressing alcohol-related harms. CAS possesses some rare qualities. First, it is one of a few alcohol-specific research centres in low- and middle-income countries, and the only one in the Southeast Asia region. Secondly, CAS both conducts research and grants research funding, allowing it to influence to some extent the direction of Thai alcohol research. Furthermore, CAS researchers engage in all components of the research and policy process. In line with the concept of 'the Triangle that Moves the Mountain', CAS interacts closely with partners from all sectors, prioritizes capacity development and frequently operates beyond conventional academic function. PMID- 22443476 TI - Rate of preterm birth in pregnant women with vitamin E treatment: a population based study. AB - OBJECTIVE: Vitamin E is frequently used for prevention/treatment of repeated or threatened abortion and threatened preterm delivery in Hungarian pregnant women, though, internationally this old-fashion method is not recommended. METHODS: The rate of preterm birth of newborns in pregnant women with high dose (estimated daily dose 450 mg) vitamin E treatment or without this treatment was compared in the population-based large data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS: Of 38,151 newborns with any defect, 2,287 (6.0%) had mothers with vitamin E treatment. Pregnant women with vitamin E treatment had very high rate of threatened abortion (43.6% vs. 15.4%) and high rate of threatened preterm delivery (27.5% vs. 13.4%) compared to pregnant women without vitamin E treatment. Nevertheless, the gestational age at delivery was 0.2 week longer and rate of preterm births was lower in the newborns of pregnant women with vitamin E treatment (6.6% vs. 9.3%; adjusted OR with 95% CI: 0.71, 0.63-0.84). This preterm preventive effect of vitamin E treatment could not be explained by known confounders, though folic acid/multivitamins also reduced the rate of preterm birth. CONCLUSION: The study showed nearly 30% reduction in preterm births of pregnant women with vitamin E treatment. PMID- 22443478 TI - Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. AB - BACKGROUND: Transcatheter aortic-valve replacement (TAVR) is the recommended therapy for patients with severe aortic stenosis who are not suitable candidates for surgery. The outcomes beyond 1 year in such patients are not known. METHODS: We randomly assigned patients to transfemoral TAVR or to standard therapy (which often included balloon aortic valvuloplasty). Data on 2-year outcomes were analyzed. RESULTS: A total of 358 patients underwent randomization at 21 centers. The rates of death at 2 years were 43.3% in the TAVR group and 68.0% in the standard-therapy group (P<0.001), and the corresponding rates of cardiac death were 31.0% and 62.4% (P<0.001). The survival advantage associated with TAVR that was seen at 1 year remained significant among patients who survived beyond the first year (hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.92; P=0.02 with the use of the log-rank test). The rate of stroke was higher after TAVR than with standard therapy (13.8% vs. 5.5%, P=0.01), owing, in the first 30 days, to the occurrence of more ischemic events in the TAVR group (6.7% vs. 1.7%, P=0.02) and, beyond 30 days, to the occurrence of more hemorrhagic strokes in the TAVR group (2.2% vs. 0.6%, P=0.16). At 2 years, the rate of rehospitalization was 35.0% in the TAVR group and 72.5% in the standard-therapy group (P<0.001). TAVR, as compared with standard therapy, was also associated with improved functional status (P<0.001). The data suggest that the mortality benefit after TAVR may be limited to patients who do not have extensive coexisting conditions. Echocardiographic analysis showed a sustained increase in aortic-valve area and a decrease in aortic-valve gradient, with no worsening of paravalvular aortic regurgitation. CONCLUSIONS: Among appropriately selected patients with severe aortic stenosis who were not suitable candidates for surgery, TAVR reduced the rates of death and hospitalization, with a decrease in symptoms and an improvement in valve hemodynamics that were sustained at 2 years of follow-up. The presence of extensive coexisting conditions may attenuate the survival benefit of TAVR. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.). PMID- 22443480 TI - Enhancing the intestinal absorption of poorly water-soluble weak-acidic compound by controlling local pH. AB - Recently, the number of poorly water-soluble drug candidates has increased and has hindered the rapid improvement of new drugs with low intestinal absorption; however, the intestinal absorption of pH-dependent poorly water-soluble compounds is expected to be markedly improved by changing the pH in the vicinity of the absorption site. The aim of this study is to clarify the effect of local pH change in the intestinal tract by magnesium oxide on the intestinal absorption of hydrochlorothiazide, a model poorly water-soluble weak-acid compound. The application of hydrochlorothiazide granule containing magnesium oxide to the rat intestinal loop increased the pH in the vicinity of the dosing site to more than 8.5 for 90 min without any mucosal damage. As a result, absorption of hydrochlorothiazide increased by the addition of magnesium oxide to the granule. Intraintestinal administration of a suspension prepared from hydrochlorothiazide granules with magnesium oxide increased the intestinal absorption and the AUC value was 3-fold higher than that without magnesium oxide. To further increase the intestinal absorption of hydrochlorothiazide, we prepared granules containing magnesium oxide and chitosan as a mucoadhesive and tight junction opening material. Chitosan showed a marked increase of intestinal absorption, and the AUC value after the administration of suspensions of chitosan granules was more than 5-fold higher than that of granules containing hydrochlorothiazide alone, respectively. In summary, it has been clarified that the intestinal absorption of weak-acidic poorly water-soluble compound can be enhanced by increasing local pH, mucoadhesion and opening tight junction. PMID- 22443479 TI - Two-year outcomes after transcatheter or surgical aortic-valve replacement. AB - BACKGROUND: The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits. METHODS: At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation. RESULTS: The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001). CONCLUSIONS: A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.). PMID- 22443481 TI - Case-control studies of sporadic enteric infections: a review and discussion of studies conducted internationally from 1990 to 2009. AB - Epidemiologists have used case-control studies to investigate enteric disease outbreaks for many decades. Increasingly, case-control studies are also used to investigate risk factors for sporadic (not outbreak-associated) disease. While the same basic approach is used, there are important differences between outbreak and sporadic disease settings that need to be considered in the design and implementation of the case-control study for sporadic disease. Through the International Collaboration on Enteric Disease "Burden of Illness" Studies (the International Collaboration), we reviewed 79 case-control studies of sporadic enteric infections caused by nine pathogens that were conducted in 22 countries and published from 1990 through to 2009. We highlight important methodological and study design issues (including case definition, control selection, and exposure assessment) and discuss how approaches to the study of sporadic enteric disease have changed over the last 20 years (e.g., making use of more sensitive case definitions, databases of controls, and computer-assisted interviewing). As our understanding of sporadic enteric infections grows, methods and topics for case-control studies are expected to continue to evolve; for example, advances in understanding of the role of immunity can be used to improve control selection, the apparent protective effects of certain foods can be further explored, and case-control studies can be used to provide population-based measures of the burden of disease. PMID- 22443482 TI - Optimization of pulsed-field gel electrophoresis protocols for Salmonella Paratyphi A subtyping. AB - Salmonella enterica serovar Paratyphi A infection has caused public health problems in some countries in recent years. Pulsed-field gel electrophoresis (PFGE) has been used for the subtyping and epidemiological investigations of some serotypes of Salmonella, mainly in outbreaks caused by non-typhoidal Salmonella. In this study, different restriction endonucleases and electrophoresis parameters were compared for the PFGE subtyping by using Salmonella Paratyphi A strain panels. Two protocols for the enzymes SpeI and XbaI showed higher discriminatory power, which may facilitate epidemiological analysis for more accurate case definition, and clonality study of Salmonella Paratyphi A. PMID- 22443484 TI - Morphology-controlled synthesis of W18O49 nanostructures and their near-infrared absorption properties. AB - The morphology-controlled synthesis and near-infrared (NIR) absorption properties of W(18)O(49) were systematically investigated for the application of innovative energy-saving windows. Various morphologies of W(18)O(49), such as nanorods, nanofibers, nanograins, nanoassembles, nanoplates, and nanoparticles, with various sizes were successfully synthesized by solvothermal reactions using organic alcohols as reaction media and WCl(6), W(EtO)(6), and WO(3) solids as the tungsten source. W(18)O(49) nanorods of less than 50 nm in length showed the best optical performance as an effective solar filter, which realized high transmittance in the visible region as well as excellent shielding properties of NIR light. Meanwhile, the W(18)O(49) nanorods also exhibited strong absorption of NIR light and instantaneous conversion of the absorbed photoenergy to the local heat. PMID- 22443485 TI - Adaptive evolution and functional constraint at TLR4 during the secondary aquatic adaptation and diversification of cetaceans. AB - BACKGROUND: Cetaceans (whales, dolphins and porpoises) are a group of adapted marine mammals with an enigmatic history of transition from terrestrial to full aquatic habitat and rapid radiation in waters around the world. Throughout this evolution, the pathogen stress-response proteins must have faced challenges from the dramatic change of environmental pathogens in the completely different ecological niches cetaceans occupied. For this reason, cetaceans could be one of the most ideal candidate taxa for studying evolutionary process and associated driving mechanism of vertebrate innate immune systems such as Toll-like receptors (TLRs), which are located at the direct interface between the host and the microbial environment, act at the first line in recognizing specific conserved components of microorganisms, and translate them rapidly into a defense reaction. RESULTS: We used TLR4 as an example to test whether this traditionally regarded pattern recognition receptor molecule was driven by positive selection across cetacean evolutionary history. Overall, the lineage-specific selection test showed that the dN/dS (omega) values along most (30 out of 33) examined cetartiodactylan lineages were less than 1, suggesting a common effect of functional constraint. However, some specific codons made radical changes, fell adjacent to the residues interacting with lipopolysaccharides (LPS), and showed parallel evolution between independent lineages, suggesting that TLR4 was under positive selection. Especially, strong signatures of adaptive evolution on TLR4 were identified in two periods, one corresponding to the early evolutionary transition of the terrestrial ancestors of cetaceans from land to semi-aquatic (represented by the branch leading to whale + hippo) and from semi-aquatic to full aquatic (represented by the ancestral branch leading to cetaceans) habitat, and the other to the rapid diversification and radiation of oceanic dolphins. CONCLUSIONS: This is the first study thus far to characterize the TLR gene in cetaceans. Our data present evidences that cetacean TLR4 has undergone adaptive evolution against the background of purifying selection in response to the secondary aquatic adaptation and rapid diversification in the sea. It is suggested that microbial pathogens in different environments are important factors that promote adaptive changes at cetacean TLR4 and new functions of some amino acid sites specialized for recognizing pathogens in dramatically contrasted environments to enhance the fitness for the adaptation and survival of cetaceans. PMID- 22443486 TI - Physiological aspects of the determination of comprehensive arterial inflows in the lower abdomen assessed by Doppler ultrasound. AB - Non-invasive measurement of splanchnic hemodynamics has been utilized in the clinical setting for diagnosis of gastro-intestinal disease, and for determining reserve blood flow (BF) distribution. However, previous studies that measured BF in a "single vessel with small size volume", such as the superior mesenteric and coeliac arteries, were concerned solely with the target organ in the gastrointestinal area, and therefore evaluation of alterations in these single arterial BFs under various states was sometimes limited to "small blood volumes", even though there was a relatively large change in flow. BF in the lower abdomen (BF(Ab)) is potentially a useful indicator of the influence of comprehensive BF redistribution in cardiovascular and hepato-gastrointestinal disease, in the postprandial period, and in relation to physical exercise. BF(Ab) can be determined theoretically using Doppler ultrasound by subtracting BF in the bilateral proximal femoral arteries (FAs) from BF in the upper abdominal aorta (Ao) above the coeliac trunk. Prior to acceptance of this method of determining a true BF(Ab) value, it is necessary to obtain validated normal physiological data that represent the hemodynamic relationship between the three arteries. In determining BF(Ab), relative reliability was acceptably high (range in intra class correlation coefficient: 0.85-0.97) for three arterial hemodynamic parameters (blood velocity, vessel diameter, and BF) in three repeated measurements obtained over three different days. Bland-Altman analysis of the three repeated measurements revealed that day-to-day physiological variation (potentially including measurement error) was within the acceptable minimum range (95% of confidence interval), calculated as the difference in hemodynamics between two measurements. Mean BF (ml/min) was 2951 +/- 767 in Ao, 316 +/- 97 in left FA, 313 +/- 83 in right FA, and 2323 +/- 703 in BF(Ab), which is in agreement with a previous study that measured the sum of BF in the major part of the coeliac, mesenteric, and renal arteries. This review presents the methodological concept that underlies BF(Ab), and aspects of its day-to-day relative reliability in terms of the hemodynamics of the three target arteries, relationship with body surface area, respiratory effects, and potential clinical usefulness and application, in relation to data previously reported in original dedicated research. PMID- 22443489 TI - Mist separation and sonochemiluminescence under pulsed ultrasound. AB - Differences in the amount of water-mist separation and the intensity of luminol chemiluminescence for pulsed and continuous-wave (CW) ultrasound at 135 kHz have been investigated. The amount of mist generated is estimated using the cooling rate of a copper plate sprayed with the mist. For pulsed operation with an appropriate duty cycle, the cooling rate and the cooling rate per input power to the transducer are higher by 4 and 12 times compared to CW operation, respectively. This is due to the amplitude of the pulsed ultrasound being higher than that for CW ultrasound. Relatively low power pulsed operation can successfully produce both a higher sonochemiluminescence (SCL) intensity and cooling rate than those for CW ultrasound. The sonochemical reaction for pulsed ultrasound occurs at the same input power threshold as that for mist separation, whereas for CW ultrasound, the former threshold is lower than the latter. A higher number of large bubbles is produced with CW ultrasound than that with pulsed ultrasound. To achieve a sound pressure amplitude sufficient for mist separation near the surface of a liquid, it is necessary to expel these bubbles by changing the sound field from resonant standing waves to progressive waves that give rise to capillary waves on the liquid surface. PMID- 22443490 TI - Transvaginal ultrasonography to predict preterm birth in women with bicornuate or didelphus uterus. AB - OBJECTIVE: To estimate whether cervical length measured by transvaginal ultrasonography (TVUS) in women with uterine anomalies predicts spontaneous preterm birth (SPTB). METHODS: This retrospective cohort study compared women with a uterine anomaly who were pregnant with singleton gestations and delivered August 2000 to April 2008 to a low risk control group. Transvaginal ultrasonographic cervical lengths were measured 16-30 weeks gestation. Primary outcome was cervical length and SPTB less than 35 weeks and the primary exposure variable of interest was cervical length. Secondary outcomes were SPTB less than 37 weeks, less than 32 weeks, low birth weight, maternal and neonatal outcomes. Receiver operating characteristic curves were generated to identify the best cervical length cutoff. RESULTS: Women with a bicornuate uterus (N = 35) had shorter cervical length (3.46 cm) than the low risk control group (N = 122, 4.32 cm, p < 0.0001). Women with a bicornuate or didelphus uterus, compared with low risk women, had higher rates of SPTB less than 35 weeks (8.6% and 30.8% versus 0.8%, p = 0.0007), neonatal intensive care unit admission more than 24 h (26.5% and 41.7% versus 7.5%, p = 0.0021) and composite perinatal morbidity (32.4% and 69.2% versus 8.3%, p < 0.0001). Using a cutoff of 3.0 cm, TVUS cervical length in women with a bicornuate uterus predicted SPTB less than 35 weeks (positive predictive value [PPV] = 37.5% and negative predictive value [NPV] = 100%), birth weight less than 2500 g (PPV = 50.0% and NPV = 96.3%) and respiratory distress syndrome (PPV = 37.5% and NPV = 100%). CONCLUSION Women with a bicornuate uterus have shorter cervical lengths than low risk controls, and are at higher risk of SPTB less than 35 weeks. Transvaginal ultrasonographic cervical length predicts SPTB less than 35 weeks, low birth weight and perinatal morbidity in these women. PMID- 22443491 TI - Sodium-potassium synergism in Theobroma cacao: stimulation of photosynthesis, water-use efficiency and mineral nutrition. AB - In ecological setting, sodium (Na(+)) can be beneficial or toxic, depending on plant species and the Na(+) level in the soil. While its effects are more frequently studied at high saline levels, Na(+) has also been shown to be of potential benefit to some species at lower levels of supply, especially in C4 species. Here, clonal plants of the major tropical C3 crop Theobroma cacao (cacao) were grown in soil where potassium (K(+)) was partially replaced (at six levels, up to 50% replacement) by Na(+), at two concentrations (2.5 and 4.0 mmol(c) dm(-3)). At both concentrations, net photosynthesis per unit leaf area (A) increased more than twofold with increasing substitution of K(+) by Na(+). Concomitantly, instantaneous (A/E) and intrinsic (A/g(s)) water-use efficiency (WUE) more than doubled. Stomatal conductance (g(s)) and transpiration rate (E) exhibited a decline at 2.5 mmol dm(-3), but remained unchanged at 4 mmol dm(-3). Leaf nitrogen content was not impacted by Na(+) supplementation, whereas sulfur (S), calcium (Ca(2+)), magnesium (Mg(2+)) and zinc (Zn(2+)) contents were maximized at 2.5 mmol dm(-3) and intermediate (30-40%) replacement levels. Leaf K(+) did not decline significantly. In contrast, leaf Na(+) content increased steadily. The resultant elevated Na(+)/K(+) ratios in tissue correlated with increased, not decreased, plant performance. The results show that Na(+) can partially replace K(+) in the nutrition of clonal cacao, with significant beneficial effects on photosynthesis, WUE and mineral nutrition in this major perennial C3 crop. PMID- 22443492 TI - Anticancer drug vinblastine sulphate induces transient morphological changes on the olfactory mucosa of the rabbit. AB - Vinblastine sulphate (VBS) is an anticancer drug that acts by disrupting microtubule dynamics of highly mitotic tissue cells. The consequences of VBS on the olfactory mucosa (OM), a tissue with high mitotic numbers, are not clearly understood. We used qualitative and quantitative methods to determine the structural changes that may be produced on the rabbit OM by VBS. Following a single dose (0.31 mg/kg) of this drug, the structure of the mucosa was greatly altered on the first 3-5 days. The alteration was characterized by disarrangement of the normal layering of nuclei of the epithelia, degeneration of axonal bundles, occurrence of blood vessels within the bundles, localized death of cells of Bowman's glands and glandular degeneration. Surprisingly on or after day 7 and progressively to day 15 post-exposure, the OM was observed to regenerate and acquire normal morphology, and the vessels disappeared from the bundles. Relative to control values, bundle diameters, olfactory cell densities and cilia numbers decreased to as low as 53.1, 75.2 and 71.4%, respectively, on day 5. Volume density for the bundles, which was 28.6% in controls, decreased to a lowest value of 16.8% on day 5. In contrast, the volume density for the blood vessels was significantly lower in controls (19.9%) than in treated animals at day 2 (25.8%), day 3 (34.3%) and day 5 (31.5%). These findings suggest that the changes induced on the rabbit OM by VBS are transient and that regenerative recovery leads to the restoration of the normal structure of the mucosa. PMID- 22443493 TI - Impact of plaques in the left coronary artery on wall shear stress and pressure gradient in coronary side branches. AB - In this study, we investigate plaques located at the left coronary bifurcation. We focus on the effect that the resulting changes in wall shear stress (WSS) and wall pressure stress gradient (WPSG) have on atherosclerotic progress in coronary artery disease. Coronary plaques were simulated and placed at the left main stem and the left anterior descending to produce >50% narrowing of the coronary lumen. Computational fluid dynamics analysis was carried out, simulating realistic physiological conditions that show the in vivo cardiac haemodynamic. WSS and WPSG in the left coronary artery were calculated and compared in the left coronary models, with and without the presence of plaques during cardiac cycles. Our results showed that WSS decreased while WPSG was increased in coronary side branches due to the presence of plaques. There is a direct correlation between coronary plaques and subsequent WSS and WPSG variations based on the bifurcation plaques simulated in the realistic coronary models. PMID- 22443494 TI - Effective gene delivery using stimulus-responsive catiomer designed with redox sensitive disulfide and acid-labile imine linkers. AB - A dual stimulus-responsive mPEG-SS-PLL(15)-glutaraldehyde star (mPEG-SS-PLL(15) star) catiomer is developed and biologically evaluated. The catiomer system combines redox-sensitive removal of an external PEG shell with acid-induced escape from the endosomal compartment. The design rationale for PEG shell removal is to augment intracellular uptake of mPEG-SS-PLL(15)-star/DNA complexes in the presence of tumor-relevant glutathione (GSH) concentration, while the acid induced dissociation is to accelerate the release of genetic payload following successful internalization into targeted cells. Size alterations of complexes in the presence of 10 mM GSH suggest stimulus-induced shedding of external PEG layers under redox conditions that intracellularly present in the tumor microenvironment. Dynamic laser light scattering experiments under endosomal pH conditions show rapid destabilization of mPEG-SS-PLL(15)-star/DNA complexes that is followed by facilitating efficient release of encapsulated DNA, as demonstrated by agarose gel electrophoresis. Biological efficacy assessment using pEGFP-C1 plasmid DNA encoding green fluorescence protein and pGL-3 plasmid DNA encoding luciferase as reporter genes indicate comparable transfection efficiency of 293T cells of the catiomer with a conventional polyethyleneimine (bPEI-25k) based gene delivery system. These experimental results show that mPEG-SS-PLL(15) star represents a promising design for future nonviral gene delivery applications with high DNA binding ability, low cytotoxicity, and high transfection efficiency. PMID- 22443495 TI - Characteristics of atrial substrates for atrial tachyarrhythmias induced in aged and hypercholesterolemic rabbits. AB - BACKGROUND: Old age and dyslipidemia increase the occurrence of atrial tachyarrhythmias (ATR). This study investigated the effect of age and hypercholesterolemia on the atrial substrates for ATR. METHODS: Five 3-year-old rabbits fed standard chow were categorized into an old-age group, five 3-month old rabbits fed high cholesterol chow were used as a hypercholesterolemia group, and five 3-month-old rabbits fed standard chow were controls. Effective refractory period, atrial vulnerability to ATR, expressions of connexin40 (Cx40) and connexin43 (Cx43), phosphorylated c-Jun N-terminal Kinase (P-JNK), and degree of fibrosis in the right (RA) and left (LA) atria were compared. RESULTS: Old-age and hypercholesterolemia rabbits were more vulnerable to ATR than the controls (18,628 +/- 13,981 ms and 30,157 +/- 39,548 ms vs 639 +/- 325 ms, P < 0.05). Old age rabbits had significantly decreased Cx40 expression in both atria (3.9-fold decrease in RA, P < 0.01 and 4.8-fold in LA, P < 0.01) and significantly decreased Cx43 in RA (14-fold, P < 0.01). Hypercholesterolemia rabbits had significantly decreased Cx40 expression in both atrial (18-fold decrease in RA, P < 0.01 and 17-fold in LA, P < 0.01) and significantly increased Cx43 expression in LA (five-fold increase, P < 0.01). Hypercholesterolemia, but not old-age rabbits, had greater expression of P-JNK in both atria (1.8-fold in RA and 2.3 fold in LA, P < 0.01). There were no significant group differences in ERP or degree of atrial fibrosis in both atria. CONCLUSIONS: ATR is more easily induced in the atria of old-age and hypercholesterolemia rabbits than younger rabbits with normal cholesterol levels. The age and hypercholesterolemia induced changes in gap junctions expression may have partially contributed to the higher atrial vulnerability to ATR. PMID- 22443496 TI - Genetic mapping of complex traits by minimizing integrated square errors. AB - BACKGROUND: Genetic mapping has been used as a tool to study the genetic architecture of complex traits by localizing their underlying quantitative trait loci (QTLs). Statistical methods for genetic mapping rely on a key assumption, that is, traits obey a parametric distribution. However, in practice real data may not perfectly follow the specified distribution. RESULTS: Here, we derive a robust statistical approach for QTL mapping that accommodates a certain degree of misspecification of the true model by incorporating integrated square errors into the genetic mapping framework. A hypothesis testing is formulated by defining a new test statistics--energy difference. CONCLUSIONS: Simulation studies were performed to investigate the statistical properties of this approach and compare these properties with those from traditional maximum likelihood and non parametric QTL mapping approaches. Lastly, analyses of real examples were conducted to demonstrate the usefulness and utilization of the new approach in a practical genetic setting. PMID- 22443497 TI - The reliability and validity of the Visual Analog Mood Scales in non-English speaking pain patients. AB - OBJECTIVES: This study assessed the validity and reliability of the Visual Analog Mood Scales (VAMS) when administered to a non-English-speaking, headache population. METHODS: The VAMS and another frequently administered measure of mood, the Profile of Mood States (POMS), were administered to sixty patients at a headache clinic in Milan, Italy. The VAMS and POMS were both administered before and after a regularly scheduled appointment at the clinic. Multitrait-multimethod analyses were conducted to assess the validity of each subscale comprising the VAMS. RESULTS: All subscales comprising the VAMS possessed high test-retest reliability, and the "confused,""sad,""angry,""energetic," and "tired" subscales of the VAMS were shown to be valid when administered to a non-English-speaking pain population. Further, compared to age-matched controls (from available normative data), pain patients reported being significantly more confused, sad, and tense on the VAMS and significantly more tired, confused, depressed, and tense on the POMS. DISCUSSION: Given the evidence of strong reliability and validity, the VAMS may be useful as a clinical diagnostic tool when administered to non-English-speaking pain populations. PMID- 22443498 TI - Histone deacetylase activity is decreased in peripheral blood monocytes in patients with COPD. AB - BACKGROUND: Histone deacetylase (HDAC) is an enzyme that regulates chromatin structure and inflammatory gene expression. In patients with chronic obstructive pulmonary disease (COPD), while accumulating evidence indicates that the activity of HDAC is decreased in lung tissue alveolar macrophages, HDAC activity in peripheral inflammatory cells has not yet been evaluated in detail. METHODS: HDAC activities in peripheral blood mononuclear cells (PBMC) were investigated in patients with stable COPD (n = 26), non-smoking controls (n = 13), and smoking controls (n = 10), respectively. HDAC activity was measured using an HDAC Activity/Inhibitor Screening Assay Kit. Serum interleukine-8 (CXCL8) levels were determined by ELISA techniques. Lung function test was carried out according to the ATS/ERS guidelines. RESULTS: Compared with healthy non-smokers, HDAC activity in the PBMCs of COPD patients was decreased by 40% (13.06 +/- 5.95 vs. 21.39 +/- 4.92 (MUM/MUg), p < 0.001). In patients with COPD, HDAC activity was negatively correlated to smoke intensity (r = -0.867, p < 0.001). In COPD patients who had smoked for more than 40 pack-years, HDAC activity in PBMC was 40% lower than that in COPD patients who had smoked fewer than 40 pack-years.Moreover, serum CXCL8 levels in patients with COPD were significantly higher than that in controls and were negatively correlated to HDAC activities. CONCLUSION: In patients with COPD, HDAC activity in the PBMCs is lower than that in healthy controls. The reduction of HDAC activity may be associated with smoking exposure through inflammatory pathways. PMID- 22443499 TI - Early subarachnoid hemorrhage. PMID- 22443500 TI - Delayed complication after Gamma Knife surgery for mesial temporal lobe epilepsy. AB - OBJECT: Despite the controversy over the clinical significance of Gamma Knife surgery (GKS) for refractory mesial temporal lobe epilepsy (MTLE), the modality has attracted attention because it is less invasive than resection. The authors report long-term outcomes for 7 patients, focusing in particular on the long-term complications. METHODS: Between 1996 and 1999, 7 patients with MTLE underwent GKS. The 50% marginal dose covering the medial temporal structures was 18 Gy in 2 patients and 25 Gy in the remaining 5 patients. RESULTS: High-dose treatment abolished the seizures in 2 patients and significantly reduced them in 2 others. One patient in this group was lost to follow-up. However, 2 patients presented with symptomatic radiation necrosis (SRN) necessitating resection after 5 and 10 years. One patient who did not need necrotomy continued to show radiation necrosis on MRI after 10 years. One patient died of drowning while swimming in the sea 1 year after GKS, before seizures had disappeared completely. CONCLUSIONS: High-dose treatment resulted in sufficient seizure control but carried a significant risk of SRN after several years. Excessive target volume was considered as a reason for delayed necrosis. Drawbacks such as a delay in seizure control and the risk of SRN should be considered when the clinical significance of this treatment is evaluated. PMID- 22443501 TI - Epilepsy and radiosurgery. PMID- 22443502 TI - Elevated body mass index and risk of postoperative CSF leak following transsphenoidal surgery. AB - OBJECT: Postoperative CSF leakage can be a serious complication after a transsphenoidal surgical approach. An elevated body mass index (BMI) is a significant risk factor for spontaneous CSF leaks. However, there is no evidence correlating BMI with postoperative CSF leak after transsphenoidal surgery. The authors hypothesized that patients with elevated BMI would have a higher incidence of CSF leakage complications following transsphenoidal surgery. METHODS: The authors conducted a retrospective review of 121 patients who, between August 2005 and March 2010, underwent endoscopic endonasal transsphenoidal surgeries for resection of primarily sellar masses. Patients requiring extended transsphenoidal approaches were excluded. A multivariate statistical analysis was performed to investigate the association of BMI and other risk factors with postoperative CSF leakage. RESULTS: In 92 patients, 96 endonasal endoscopic transsphenoidal surgeries were performed that met inclusion criteria. Thirteen postoperative leaks occurred and required subsequent treatment, including lumbar drainage and/or reoperation. The average BMI of patients with a postoperative CSF leak was significantly greater than that in patients with no postoperative CSF leak (39.2 vs 32.9 kg/m(2), p = 0.006). Multivariate analyses indicate that for every 5-kg/m(2) increase in BMI, patients undergoing a transsphenoidal approach for a primarily sellar mass have 1.61 times the odds (95% CI 1.10-2.29, p = 0.016, by multivariate logistic regression) of having a postoperative CSF leak. CONCLUSIONS: Elevated BMI is an independent predictor of postoperative CSF leak after an endonasal endoscopic transsphenoidal approach. The authors recommend that patients with BMI greater than 30 kg/m(2) have meticulous sellar reconstruction at surgery and close monitoring postoperatively. PMID- 22443503 TI - Novel strategy to treat a case of recurrent lymphocytic hypophysitis using rituximab. AB - Lymphocytic hypophysitis is an uncommon autoimmune condition that often results in significant morbidity. Although most cases resolve spontaneously or after a short course of steroids, rarely, refractory cases can cause persistent neurological deficits despite aggressive medical and surgical management. A 41 year-old woman presented with progressive visual loss in the left eye and was found to have a sellar mass. She underwent transsphenoidal surgery because of lesion enlargement. Histopathology was consistent with adenohypophysitis with B cell predominance. Despite steroid treatment, her neurological condition worsened and she experienced loss of vision in the right eye. Craniotomy with decompression of the right optic nerve was performed. Her condition improved initially, but she continued to have progressive visual compromise over the following months. She was therefore treated with rituximab, a monoclonal antibody against B cells. Her vision improved significantly within a few weeks. There was no clinical or radiographic exacerbation 2 years after starting immunotherapy. Rituximab, an anti-CD20 antibody that specifically depletes B lymphocytes, can be an effective treatment strategy for patients with steroid-refractory, B cell predominant lymphocytic hypophysitis. PMID- 22443504 TI - Morbidity profile following aggressive resection of parietal lobe gliomas. AB - OBJECT: The impact of parietal lobe gliomas is typically studied in the context of parietal lobe syndromes. However, critical language pathways traverse the parietal lobe and are susceptible during tumor resection. The authors of this study reviewed their experience with parietal gliomas to characterize the impact of resection and the morbidity associated with language. METHODS: The study population included adults who had undergone resection of parietal gliomas of all grades. Tumor location was identified according to a proposed classification system for parietal region gliomas. Low- and high-grade tumors were volumetrically analyzed using FLAIR and T1-weighted contrast-enhanced MR imaging. RESULTS: One hundred nineteen patients with parietal gliomas were identified--34 with low-grade gliomas and 85 with high-grade gliomas. The median patient age was 45 years, and most patients (53) presented with seizures, whereas only 4 patients had an appreciable parietal lobe syndrome. The median preoperative tumor volume was 31.3 cm(3), the median extent of resection was 96%, and the median postoperative tumor volume was 0.9 cm(3). Surprisingly, the most common early postoperative neurological deficit was dysphasia (16 patients), not weakness (12 patients), sensory deficits (14 patients), or parietal lobe syndrome (10 patients). A proposed parietal glioma classification system, based on surgical anatomy, was predictive of language deficits. CONCLUSIONS: This is the largest reported experience with parietal lobe gliomas. The findings suggested that parietal language pathways are compromised at a surprisingly high rate. The proposed parietal glioma classification system is predictive of postoperative morbidity associated with language and can assist with preoperative planning. Taken together, these data emphasize the value of identifying language pathways when operating within the parietal lobe. PMID- 22443505 TI - Hyperacute cerebral aneurysm rerupture during CT angiography. AB - OBJECT: The object of this study was to identify the clinical features and outcomes of a subgroup of patients with aneurysmal subarachnoid hemorrhage (SAH) who had active contrast extravasation from a ruptured aneurysm during initial cerebral CT angiography (CTA). METHODS: The authors performed a retrospective study of spontaneous SAH cases involving patients treated at their institute. They identified 9 cases in which active contrast extravasation was evident on the initial CT angiogram. Another 12 similar cases were also identified in a literature review and data was gathered from these cases to evaluate the outcomes. RESULTS: Analysis of all 21 cases revealed that the overall outcomes in cases characterized by active aneurysmal bleeding during CTA were poor. Seventy six percent of patients had unfavorable results. Patients who showed poor neurological status at presentation died no matter what kind of treatment they received. In contrast, patients who presented with good neurological status initially had a chance of favorable outcome. Among the patients with good initial neurological status, most demonstrated rapid deterioration of their condition during the CTA examination; only those who received immediate and effective decompressive surgery and aneurysm obliteration had good results. CONCLUSIONS: Active aneurysmal rebleeding during CTA is an uncommon but devastating event. Though the mortality of this distinct group of patients remains high, a clinical subgroup may benefit from immediate surgery. Patients with good initial neurological status who show rapid neurological deterioration may still have a favorable outcome if they undergo timely and successful decompressive surgery and proper aneurysm obliteration. Patients who present with poor neurological status do badly, and there is no effective treatment for such patients. PMID- 22443506 TI - Knowledge, attitudes and practices surveys of blood donation in developing countries. AB - BACKGROUND AND OBJECTIVES: Knowledge, attitude and practice (KAP) surveys have been used in many countries to understand factors that influence blood donation and as the basis for communication and donor mobilization strategies. MATERIALS AND METHODS: A search was conducted of publically available databases, and studies with the following characteristics were selected: (1) the study was a knowledge, attitude and practice or KAP plus behaviour survey; (2) the subject of the survey was blood donation; (3) the survey was performed between 1995 and 2011; and (4) the survey was performed in countries classified as emerging and developing by the International Monetary Fund. RESULTS: Eighteen KAP studies conducted in seventeen developing countries were identified. There was considerable difference in the structure, population surveyed and conduct of the KAP studies. The common following themes emerged: misinformation about blood donation, fear of blood donation, willingness to donate for family and friends, concern about selling blood and a failure to transfer positive attitudes into actual blood donation. CONCLUSION: Despite considerable differences in the culture and demographics of developing countries, several common themes emerged from different KAP surveys. PMID- 22443507 TI - The physiology of the axon initial segment. AB - The action potential generally begins in the axon initial segment (AIS), a principle confirmed by 60 years of research; however, the most recent advances have shown that a very rich biology underlies this simple observation. The AIS has a remarkably complex molecular composition, with a wide variety of ion channels and attendant mechanisms for channel localization, and may feature membrane domains each with distinct roles in excitation. Its function may be regulated in the short term through the action of neurotransmitters, in the long term through activity- and Ca(2+)-dependent processes. Thus, the AIS is not merely the beginning of the axon, but rather a key site in the control of neuronal excitability. PMID- 22443508 TI - The restless engram: consolidations never end. AB - Memory consolidation is the hypothetical process in which an item in memory is transformed into a long-term form. It is commonly addressed at two complementary levels of description and analysis: the cellular/synaptic level (synaptic consolidation) and the brain systems level (systems consolidation). This article focuses on selected recent advances in consolidation research, including the reconsolidation of long-term memory items, the brain mechanisms of transformation of the content and of cue-dependency of memory items over time, as well as the role of rest and sleep in consolidating and shaping memories. Taken together, the picture that emerges is of dynamic engrams that are formed, modified, and remodified over time at the systems level by using synaptic consolidation mechanisms as subroutines. This implies that, contrary to interpretations that have dominated neuroscience for a while, but similar to long-standing cognitive concepts, consolidation of at least some items in long-term memory may never really come to an end. PMID- 22443509 TI - Mechanisms of gamma oscillations. AB - Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease. PMID- 22443510 TI - An updated doubled haploid oat linkage map and QTL mapping of agronomic and grain quality traits from Canadian field trials. AB - The first doubled haploid oat linkage map constructed at MTT Agrifood Research Finland was supplemented with additional microsatellites and Diversity Array Technology (DArT) markers to produce a map containing 1058 DNA markers and 34 linkage groups. The map was used to locate quantitative trait loci (QTLs) for 11 important breeding traits analyzed from Finnish and Canadian field trials. The new markers enabled most of the linkage groups to be anchored to the 'Kanota' * 'Ogle' oat ( Avena sativa L.) reference map and allowed comparison of the QTLs located in this study with those found previously. Two to 12 QTLs for each trait were discovered, of which several were expressed consistently across several environments. PMID- 22443511 TI - Direct synthesis of aqueous quantum dots through 4,4'-bipyridine-based twin ligand strategy. AB - We report a new class of derivatized 4,4'-bipyridinium ligands for use in synthesizing highly fluorescent, extremely stable, water-soluble CdSe and CdTe quantum dots (QDs) for bioconjugation. We employed an evaporation-condensation technique, also known as solvated metal atom dispersion (SMAD), followed by a digestive ripening procedure. This method has been used to synthesize both metal nanoparticles and semiconductors in the gram scale with several stabilizing ligands in various solvents. The SMAD technique comprised evaporation condensation and stabilization of CdSe or CdTe in tetrahydrofuran. The as prepared product was then digestively ripened in both water and dimethyl formamide, leading to narrowing of the particle size distributions. The ligands were synthesized by nucleophilic substitution (S(N)2) reactions using 4,4' bipyridine as a nucleophile. Confocal microscopy images revealed the orange color of the nanocrystalline QDs with diameters of ~5 nm. The size has been confirmed by using transmission electron microscopy. As a part of our strategy, 85% of the 4,4'-bipyridinium salt was synthesized as propionic acid derivative and used to both stabilize the QDs in water and label basic amino acids and different biomarkers utilizing the carboxylic acid functional group. Fifteen percent of the 4,4'-bipyridinium salt was synthesized as N-propyl maleimide and used as a second ligand to label any protein containing the amino acid cysteine by means of a 1,4 Michael addition. PMID- 22443512 TI - Occurrence and impact of the root-rot biocontrol agent Phlebiopsis gigantea on soil fungal communities in Picea abies forests of northern Europe. AB - The aim of this study was to assess belowground occurrence, persistence and possible impact of the biocontrol agent Phlebiopsis gigantea (Fr.) Julich on soil fungi. Sampling of soil and roots of Picea abies (L.) H. Karst. was carried out at 12 P. gigantea-treated and five nontreated control sites representing 1- to 60 month-old clear-cuts and thinned forest sites in Finland and Latvia. The 454 sequencing of ITS rRNA from fine roots, humus and mineral soil resulted in 8626 high-quality fungal sequences. Phlebiopsis gigantea represented 1.3% of all fungal sequences and was found in 14 treated and nontreated sites and in all three substrates. In different substrates, the relative abundance of P. gigantea at stump treatment sites either did not differ significantly or was significantly lower than in nontreated controls. No significant correlation was found between the time elapsed since the tree harvesting and/or application of the biocontrol and abundance of P. gigantea in different substrates. In conclusion, the results demonstrate that P. gigantea occasionally occurs belowground in forest ecosystems but that stump treatment with the biocontrol agent has little or no impact on occurrence and persistence of P. gigantea belowground, and consequently no significant impact on soil fungi. PMID- 22443513 TI - Criteria for determining the need for surgical treatment of tricuspid regurgitation during mitral valve replacement. AB - BACKGROUND: Tricuspid regurgitation (TR) is common in patients with mitral valve disease; however, there are no straightforward, rapidly determinably criteria available for deciding whether TR repair should be performed during mitral valve replacement. The aim of our retrospective study was to identify a simple and fast criterion for determining whether TR repair should be performed in patients undergoing mitral valve replacement. METHODS: We reviewed the records of patients who underwent mitral valve replacement with or without (control) TR repair (DeVega or Kay procedure) from January 2005 to December 2008. Preoperative and 2 year postoperative echocardiographic measurements included right ventricular and atrial diameter, interventricular septum size, TR severity, ejection fraction, and pulmonary artery pressure. RESULTS: A total of 89 patients were included (control, n = 50; DeVega, n = 27; Kay, n = 12). Demographic and clinical characteristics were similar between groups. Cardiac variables were similar between the DeVega and Kay groups. Right atrium and ventricular diameter and ejection fraction were significantly decreased postoperatively both in the control and operation (DeVega + Kay) group (P < 0.05). Pulmonary artery pressure was significantly decreased postoperatively in-operation groups (P < 0.05). Our findings indicate that surgical intervention for TR should be considered during mitral valve replacement if any of the following preoperative criteria are met: right atrial transverse diameter > 57 mm; right ventricular end-diastolic diameter > 55 mm; pulmonary artery pressure > 58 mmHg. CONCLUSIONS: Our findings suggest echocardiography may be used as a rapid and simple means of determining which patients require TR repair during mitral valve replacement. PMID- 22443514 TI - Proteomic analysis of effluents from perfused human heart for transplantation: identification of potential biomarkers for ischemic heart damage. AB - BACKGROUND: Biomarkers released from the heart at early stage of ischemia are very important to diagnosis of ischemic heart disease and salvage myocytes from death. Known specific markers for blood tests including CK-MB, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are released after the onset of significant necrosis instead of early ischemia. Thus, they are not good biomarkers to diagnose myocardial injury before necrosis happens. Therefore, in this study, we performed proteomic analysis on effluents from perfused human hearts of donors at different ischemic time. RESULTS: After global ischemia for 0 min, 30 min and 60 min at 4 degrees C, effluents from five perfused hearts were analyzed respectively, by High performance liquid chromatography-Chip-Mass spectrometry (HPLC-Chip-MS) system. Total 196 highly reliable proteins were identified. 107 proteins were identified at the beginning of ischemia, 174 and 175 proteins at ischemic 30 min and ischemic 60 min, respectively. With the exception of cardiac troponin I and T, all known biomarkers for myocardial ischemia were detected in our study. However, there were four glycolytic enzymes and two targets of matrix metalloproteinase released significantly from the heart when ischemic time was increasing. These proteins were L-lactate dehydrogenase B(LDHB), glyceraldehyde-3 phosphate dehydrogenase, glucose-6-phosphate isomerase (GPI), phosphoglycerate mutase 2 (PGAM2), gelsolin and isoform 8 of titin. PGAM2, LDHB and titin were measured with enzyme-linked immunosorbent assays kits. The mean concentrations of LDHB and PGAM2 in samples showed an increasing trend when ischemic time was extending. In addition, 33% identified proteins are involved in metabolism. Protein to protein interaction network analysis showed glycolytic enzymes, such as isoform alpha-enolase of alpha-enolase, isoform 1 of triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase, had more connections than other proteins in myocardial metabolism during ischemia. CONCLUSION: It is the first time to use effluents of human perfused heart to study the proteins released during myocardial ischemia by HPLC-Chip-MS system. There might be many potential biomarkers for mild ischemic injury in myocardium, especially isoform 8 of titin and M-type of PGAM2 that are more specific in the cardiac tissue than in the others. Furthermore, glycolysis is one of the important conversions during early ischemia in myocardium. This finding may provide new insight into pathology and biology of myocardial ischemia, and potential diagnostic and therapeutic biomarkers. PMID- 22443515 TI - Variation in genomic islands contribute to genome plasticity in Cupriavidus metallidurans. AB - BACKGROUND: Different Cupriavidus metallidurans strains isolated from metal contaminated and other anthropogenic environments were genotypically and phenotypically compared with C. metallidurans type strain CH34. The latter is well-studied for its resistance to a wide range of metals, which is carried for a substantial part by its two megaplasmids pMOL28 and pMOL30. RESULTS: Comparative genomic hybridization (CGH) indicated that the extensive arsenal of determinants involved in metal resistance was well conserved among the different C. metallidurans strains. Contrary, the mobile genetic elements identified in type strain CH34 were not present in all strains but clearly showed a pattern, although, not directly related to a particular biotope nor location (geographical). One group of strains carried almost all mobile genetic elements, while these were much less abundant in the second group. This occurrence was also reflected in their ability to degrade toluene and grow autotrophically on hydrogen gas and carbon dioxide, which are two traits linked to separate genomic islands of the Tn4371-family. In addition, the clear pattern of genomic islands distribution allowed to identify new putative genomic islands on chromosome 1 and 2 of C. metallidurans CH34. CONCLUSIONS: Metal resistance determinants are shared by all C. metallidurans strains and their occurrence is apparently irrespective of the strain's isolation type and place. Cupriavidus metallidurans strains do display substantial differences in the diversity and size of their mobile gene pool, which may be extensive in some (including the type strain) while marginal in others. PMID- 22443516 TI - Influence of LC retention data on antitumor acridinones' classification evaluated by factor analysis method. AB - The application of factor analysis (FA) method in classification of the antitumor acridinones based on high-performance liquid chromatography (HPLC) retention data and calculated parameters of lipophilicity as well as some nonempirical structural parameters was studied. First, a group of 19 acridinone (imidazoacridinone and triazoloacridinone) derivatives was chromatographed in six RP-HPLC systems, and the values of their HPLC retention data as retention' times determined in both 10 min and 30 min gradient times were obtained as well as log kw (retention factor log k extrapolated to 0% organic modifier) parameters using DryLab program were calculated. Additionally, molecular modeling studies were performed based on the structural formula of considered acridinones and structural descriptors were derived as well as log P parameters using some commonly available software were calculated and subsequently used. A matrix of 19 x 32 HPLC data together with log P data and molecular properties parameters was subjected to factor analysis and led to extract three main factors with eigenvalues higher than 1. The first principal component (factor 1) accounted for, by 80.87% of the variance in data, the second principal component (factor 2) explained 7.77% and the third principal component (factor 3) was responsible by 4.46% of data variance. The total data variance was at the level 93.09% and was explained by the first three principal components. Moreover, one of the most significant influences on the values of factor 1 and factor 2 possessed HPLC retention data and calculated parameters describing lipophilicity, respectively. More importantly, distribution of individual drugs on the plane determined by two principal components produced patterns in good agreement with their chemical structures as well as with their antitumor activity. PMID- 22443517 TI - A comprehensive history of arynes in natural product total synthesis. PMID- 22443519 TI - Human neutrophil defensins and their effect on epithelial cells. AB - BACKGROUND: The aims of the present study include: 1) to localize human neutrophil defensin-1 (HNP-1) through HNP-3 in gingiva and in neutrophil extract treated epithelial cell monolayers; 2) to determine the effects of HNP-1 on the epithelial cell viability, attachment, and spreading; and 3) to analyze the effect of HNP-1 on the bacterial adherence to epithelial cells. METHODS: For localization of HNP-1 through HNP-3 in gingival tissue and in preincubated cell monolayers, immunohistochemical and immunocytochemical methods were used. Viability and proliferation of epithelial cells were determined with commercial kits after incubating the keratinocytes with different HNP-1 concentrations (low, 1 to 5 MUg/mL; moderate, 10 MUg/mL; high, 20 to 50 MUg/mL). Attachment and spreading of keratinocytes on fibronectin-coated surfaces in the presence of HNP 1 were evaluated under microscope. Attachment of Fusobacterium nucleatum ATCC25586 and Prevotella intermedia ATCC25611 on keratinocytes preincubated with HNP-1 were determined with a standard antibiotic test. RESULTS: HNP-1 through HNP 3 localized in the junctional epithelium of clinically healthy gingiva and in the pocket epithelium of gingiva with periodontitis. When keratinocyte monolayers were incubated with neutrophil extracts, HNP-1 through HNP-3 were bound to the periphery of the growing cell colonies. In low HNP-1 concentrations, the keratinocyte proliferation enhanced. Moderate and high concentrations of HNP-1 increased the cellular death significantly. HNP-1 increased the attachment and spreading of keratinocytes on fibronectin-coated surfaces and bacterial attachment to keratinocytes in a concentration-dependent manner. CONCLUSION: HNP 1 plays a role in the integrity of keratinocytes by stimulating their proliferation, attachment, and spreading, whereas higher doses increase the bacterial attachment and keratinocyte death. PMID- 22443520 TI - Individual composition of human leukocyte antigens and periodontopathogens in the background of periodontitis. AB - BACKGROUND: Human leukocyte antigens (HLAs) are a basic precondition to induce the immune response to pathogens. Therefore, this study evaluates associations among periodontitis, five key periodontopathic bacteria, and HLAs to test their impact together with additional risk factors in multivariate analyses. METHODS: Eighty-five patients with generalized aggressive periodontitis (GAgP) and 71 patients with generalized chronic periodontitis (CP) were compared to 88 periodontitis-free controls. HLA Class I and II typing was performed by polymerase chain reaction (PCR) with sequence-specific primers. Subgingival plaque specimens were detected by PCR with sequence-specific oligonucleotides. Risk-factor analyses were performed with respect to the cofactors age, sex, smoking, and plaque level by logistic regression. RESULTS: In the total patient group (GAgP + CP), the adjusted odds ratio (OR) of periodontitis was decreased in cases who were carriers of HLA-B*57 (OR = 0.259, 95% confidence interval [CI] = 0.086 to 0.782), HLA-DQB1*08 (OR = 0.404, 95% CI = 0.187 to 0.871), or the combination HLA-DRB1*04;DRB4*;DQB1*0302 (OR = 0.407, 95% CI = 0.185 to 0.895). Moreover, individuals who expressed HLA-DRB1*04 (OR = 0.36, 95% CI = 0.148 to 0.886) or HLA-DRB1*04;DRB4*;DQB1*0302 (OR = 0.29, 95% CI = 0.092 to 0.884) had a decreased colonization risk with Aggregatibacter actinomycetemcomitans. CONCLUSIONS: Certain HLA markers were negatively associated to the manifestation of a generalized periodontitis and/or the individual colonization of A. actinomycetemcomitans. The underlying mechanisms have to be investigated in future studies. PMID- 22443521 TI - Specificity of antimicrobial peptide LL-37 to neutralize periodontopathogenic lipopolysaccharide activity in human oral fibroblasts. AB - BACKGROUND: The antimicrobial peptide LL-37 is known to have a potent lipopolysaccharide (LPS)-neutralizing activity in various cell types. Because of observed heterogeneity within periodontopathogenic LPS, the authors hypothesized that LL-37 had specificity to neutralize such LPS activity. The present study, therefore, aims to investigate the LPS-neutralizing activity of LL-37 to various periodontopathogenic LPS in interleukin-8 (IL-8) production after challenging them in human oral fibroblasts. METHODS: Human periodontal ligament fibroblasts (PDLF) and gingival fibroblasts (GF) were cultured from biopsies of periodontal ligament and gingival tissues. After cell confluence in 24-well plates, LPS (10 MUg/mL) from Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans were added with or without LL-37 (10 MUg/mL). After 18 hours, the supernatant was collected and analyzed in IL-8 production by enzyme-linked immunosorbent assay. RESULTS: All periodontopathogenic LPS statistically significantly induced IL-8 production in both PDLF and GF (P <0.01). After neutralization with LL-37, both PDLF and GF showed a statistically significant reduction in IL-8 production compared with LPS treated groups without LL-37 (P <0.01), and the percentage of reduction in IL-8 production in PDLF appeared to be higher than in GF. In addition, the percentage of reduction in IL-8 production varied considerably according to each periodontopathogenic LPS. CONCLUSIONS: The antimicrobial peptide LL-37 had an ability to suppress periodontopathogenic LPS-induced IL-8 production in both PDLF and GF. Its LPS-neutralizing activity revealed specificity to periodontopathogenic LPS and seemed to be dependent on the heterogeneity within LPS between different genera. PMID- 22443522 TI - Study of compliance with a new, targeted antenatal D immunization prevention programme in Denmark. AB - BACKGROUND AND OBJECTIVES: A targeted routine antenatal anti-D prophylaxis programme was implemented in Denmark where anti-D immunoglobulin is given based on the result from noninvasive antenatal screening for fetal RHD. Our objective was to evaluate compliance with this new programme right after its initiation. MATERIALS AND METHODS: We examined the treatment outcome of 239 D-negative pregnant women who gave birth at our hospital between June and September 2010. RESULTS: The majority of these women (90%) underwent antenatal RHD screening, 86% of the women who were recommended antenatal prophylaxis received anti-D, and 99% of the women who delivered RhD-positive infants received postnatal anti-D. CONCLUSION: These compliance results are acceptable as they were obtained only a few months after the initiation of the new prophylaxis regime. However, suggestions to further improve compliance are presented. PMID- 22443524 TI - An investigation of Taiwanese norms for the Stanford Hypnotic Susceptibility Scale: Form C (Mandarin Chinese Translation). AB - This study establishes normative data for the Mandarin Chinese Translation of the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C-MCT). Fourteen administrators gave the SHSS:C-MCT as well as demographic and meditation questionnaires to 322 participants of Taiwanese nationality. Score distributions, normality, internal consistency, item difficulty, and comparisons with other SHSS:C samples are presented. Scores on the SHSS:C-MCT were compared to both demographic and meditation practice data. The psychometric properties of the SHSS:C-MCT were found to be similar to those of other samples, and the Taiwanese mean score was found to be higher than most other samples, providing support for continued and expanded use of hypnosis in relative treatment applications in Taiwan. PMID- 22443523 TI - Hypnosis for symptom management in women with breast cancer: a pilot study. AB - Eight women who were in treatment for breast cancer (n = 4) or breast cancer survivors (n = 4), presenting with 1 or more of 4 symptoms (chronic pain, fatigue, hot flashes, and sleep difficulties), were given 4 to 5 sessions of self hypnosis training for symptom management. Analyses revealed (a) significant pre- to posttreatment decreases in pain intensity, fatigue, and sleep problems and (b) that pain intensity continued to decrease from posttreatment to 6-month follow up. Although there was a slight increase in fatigue severity and sleep problems from posttreatment to 6-month follow-up, the follow-up scores did not return to pretreatment levels. The findings provide initial support for using hypnosis to manage symptoms in women who are breast cancer survivors. Clinical trials evaluating hypnosis efficacy over and above other treatments are warranted. PMID- 22443525 TI - Hypnotically assisted diaphragmatic exercises in the treatment of stuttering: a preliminary investigation. AB - This preliminary study investigates the combined effect of intensive hypnotherapy and diaphragmatic exercises in the management of stuttering. Fifty-nine clients with stuttering were trained to practice abdominal weightlifting to strengthen their respiratory muscles and to improve their diaphragmatic movements. The weightlifting exercises involved lifting a dumbbell (2.0-4.0 kg) with the abdomen for 2 hours daily for 8 consecutive days. Hypnotherapy was utilized to alleviate anxiety, to boost self-confidence, and to increase motivation for weightlifting exercise. The pre- and postmeasures were statistically significant (p < .001). Results of the study provide support for the effectiveness of hypnotically assisted diaphragmatic training in the management of stuttering but should be further studied in controlled trials. PMID- 22443526 TI - Modulating the default mode network using hypnosis. AB - Debate regarding the neural basis of the hypnotic state continues, but a recent hypothesis suggests that it may produce alterations in the default mode network (DMN). DMN describes a network of brain regions more active during low-demand compared to high-demand task conditions and has been linked to processes such as task-independent thinking, episodic memory, semantic processing, and self awareness. However, the experiential and cognitive correlates of DMN remain difficult to investigate directly. Using hypnosis as a means of altering the resting ("default") state in conjunction with subjective measures and brain imaging, the authors found that the state of attentional absorption following a hypnotic induction was associated with reduced activity in DMN and increased activity in prefrontal attentional systems, under invariant conditions of passive visual stimulation. The findings that hypnosis and spontaneous conceptual thought at rest were subjectively and neurally distinctive are also relevant to understanding hypnosis itself. PMID- 22443527 TI - The Valencia Scale of Attitudes and Beliefs Toward Hypnosis-Client version and hypnotizability. AB - Abstract The present study examined responses on the Valencia Scale of Attitudes and Beliefs Toward Hypnosis-Client (VSABTH-C) version among a sample of American college students (N = 448) and explored the relationship between VSABTH C factor scores and measures of hypnotizability, fantasy proneness, and absorption. Scores across three factors (i.e., help, interest, and marginal factors) accounted for 12% of the variance in responsiveness to suggestions administered from the Harvard Group Scale of Hypnotic Susceptibility, Form A. Normative data on the VSABTH-C factors by hypnotizability level and individual VSABTH-C item factor loadings are provided. PMID- 22443528 TI - Measured outcomes with hypnosis as an experimental tool in a cardiovascular physiology laboratory. AB - The authors detail their multidisciplinary collaboration of cardiologists, physiologists, neurologists, psychologists, engineers, and statisticians in researching the effects of hypnosis on the cardiovascular system and their additions to that incomplete literature. The article details their results and provides guidelines for researchers interested in replicating their research on hypnosis' effect on the cardiovascular system. PMID- 22443529 TI - A proteome map of primary cultured rat Schwann cells. AB - BACKGROUND: Schwann cells (SCs) are the principal glial cells of the peripheral nervous system with a wide range of biological functions. SCs play a key role in peripheral nerve regeneration and are involved in several hereditary peripheral neuropathies. The objective of this study was to gain new insight into the whole protein composition of SCs. RESULTS: Two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D LC-MS/MS) was performed to identify the protein expressions in primary cultured SCs of rats. We identified a total of 1,232 proteins, which were categorized into 20 functional classes. We also used quantitative real time RT-PCR and Western blot analysis to validate some of proteomics-identified proteins. CONCLUSION: We showed for the first time the proteome map of SCs. Our data could serve as a reference library to provide basic information for understanding SC biology. PMID- 22443530 TI - Site-selective X-ray spectroscopy on an asymmetric model complex of the [FeFe] hydrogenase active site. AB - The active site for hydrogen production in [FeFe] hydrogenase comprises a diiron unit. Bioinorganic chemistry has modeled important features of this center, aiming at mechanistic understanding and the development of novel catalysts. However, new assays are required for analyzing the effects of ligand variations at the metal ions. By high-resolution X-ray absorption spectroscopy with narrow band X-ray emission detection (XAS/XES = XAES) and density functional theory (DFT), we studied an asymmetrically coordinated [FeFe] model complex, [(CO)(3)Fe(I)1-(bdtCl(2))-Fe(I)2(CO)(Ph(2)P-CH(2)-NCH(3)-CH(2)-PPh(2))] (1, bdt = benzene-1,2-dithiolate), in comparison to iron-carbonyl references. Kbeta emission spectra (Kbeta(1,3), Kbeta') revealed the absence of unpaired spins and the low-spin character for both Fe ions in 1. In a series of low-spin iron compounds, the Kbeta(1,3) energy did not reflect the formal iron oxidation state, but it decreases with increasing ligand field strength due to shorter iron-ligand bonds, following the spectrochemical series. The intensity of the valence-to-core transitions (Kbeta(2,5)) decreases for increasing Fe-ligand bond length, certain emission peaks allow counting of Fe-CO bonds, and even molecular orbitals (MOs) located on the metal-bridging bdt group of 1 contribute to the spectra. As deduced from 3d -> 1s emission and 1s -> 3d absorption spectra and supported by DFT, the HOMO-LUMO gap of 1 is about 2.8 eV. Kbeta-detected XANES spectra in agreement with DFT revealed considerable electronic asymmetry in 1; the energies and occupancies of Fe-d dominated MOs resemble a square-pyramidal Fe(0) for Fe1 and an octahedral Fe(II) for Fe2. EXAFS spectra for various Kbeta emission energies showed considerable site-selectivity; approximate structural parameters similar to the crystal structure could be determined for the two individual iron atoms of 1 in powder samples. These results suggest that metal site- and spin selective XAES on [FeFe] hydrogenase protein and active site models may provide a powerful tool to study intermediates under reaction conditions. PMID- 22443531 TI - Pharmacokinetics and disposition of nanomedicine using biodegradable PEG/PCL polymers as drug carriers. AB - Micelles assembled from amphiphilic poly(ethylene glycol)/poly(-caprolactone) (PEG/PCL) copolymers are promised as safe and effective drug delivery systems. They offer the potential to achieve high solubility of hydrophobic drugs, long blood circulation time and effective delivery to target organs. These advantages contribute to their application as vehicles of a broad variation of therapeutic compounds. In this review, we discussed the safety of the copolymers, release behavior of PEG/PCL micelles in vitro, and pharmacokinetic profiles referring to the optimized fate in vascular system and targeting biodistribution. PMID- 22443532 TI - Current methods and research progress in nanomaterials risk assessment. AB - Nanomaterials have unique physicochemical properties compared with those bulk materials of the same composition. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. A number of studies on the effects of Nanomaterials in vitro and in vivo systems have been published. However, while the number of nanomaterials types and applications continues to increase, studies to characterize their effects after exposure and to address their potential toxicity are few in comparison, there is still a need for further studies that conclusively establish their safety/toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable. The major goal of this review is to summarize 1) analytical techniques applied for characterization of nanomaterials, 2) current analytical methods to assess nanomaterials toxicity in vitro and in vivo; 3) research progress of polymeric nanomaterials toxicity; 4) outlook. PMID- 22443533 TI - Pharmacokinetics and in vivo fate of drug loaded chitosan nanoparticles. AB - Chitosan is a natural polysaccharide which is generally biodegradable, biocompatible and mucoadhesive, thus, attracting considerable interest of scientific researchers. The application of chitosan as nanocarriers for drug delivery thrived. And some of their pharmacokinetics and biodistribution profiles were studied, which are crucial to develop a promising drug delivery system. In this article, we will first give an introduction for the chitosan as drug delivery system, especially as nanoparticles. Then, we focus on pharmacokinetics studies of various chitosan nanoparticles both in vitro and in vivo. In a following part, we refer to researches on biodistribution properties of chitosan nanoparticles. Here we crucially discuss the in vivo fate of chitosan nanoparticles. And finally, toxicity issue is discussed and conclusions are drawn. PMID- 22443534 TI - Pharmacokinetics and disposition of various drug loaded liposomes. AB - Due to great efforts in past 45 years, several liposomal products including two liposomal vaccine products have been commercialized and many more potential products are now under clinical trial stage. Although liposome has significantly reduced the toxicity of the drugs with improved or maintained the efficacy, its further development has been limited by its instabilities during preparation and storage, incompatibility with certain drugs, relative high cost of production and quality control as well as unspecified drug release time and sites in vivo. In vivo behaviors of liposomal drugs highly depend on their physiochemical properties including lipid composition, particle size, surface charge, surface modifications and the administrated dose as well as the route of administration. Based on the literature reports from the past two decades, the current review provided an updated summary of the key factors in liposomal preparations for clinical usage and its impact on the alternation of pharmacokinetic and disposition behaviors of drugs encapsulated in the liposome formulations. Clinical applications of liposomal preparation in anti-tumor agents, anti infective agents as well as the macromolecules have been highlighted. PMID- 22443535 TI - Absorption, disposition and pharmacokinetics of nanoemulsions. AB - Nanoemulsions are composed of nanoscale droplets of one immiscible liquid dispersed within another, which have been the focus of extensive research worldwide due to their solubilization and transportation capacity of both hydrophobic and hydrophilic active compounds with unique physical properties. In a broad sense, submicron-emulsion, microemulsion, self-microemulsifing drug delivery system, lipid emulsion and cholesterol-rich microemulsion (LDE) all belong to nanoemulsions. The review starts with a brief introduction to the definition, formulation rationale, and types of nanoemulaions, and focused on, by different administration routes such as the oral, intravenous, transdermal, ocular nasal and rectal routes, the absorption, disposition, pharmacokinetics properties of nanoemulsions. PMID- 22443536 TI - Absorption, disposition and pharmacokinetics of solid lipid nanoparticles. AB - Solid lipid nanoparticles (SLNs) are primarily composed of solid lipids, which thus impart to them some of the fundamental properties of these lipids, including biocompatibility, biodegradability and low-toxicity. SLNs represent a unique class of colloidal drug delivery systems that possess the advantages of both the "soft" drug carriers such as emulsions and liposomes and polymeric nanoparticles. In this review, we will provide an overview on the absorption, disposition and pharmacokinetics of SLNs. The lipidic nature, as well as the relatively small particle size, of SLNs ensures sufficient affinity with the biomembranes, and results in improved absorption by either of the oral, transdermal, pulmonary, nasal, ocular, rectal or buccal route. One special aspect of oral SLNs is the enhanced lymphatic absorption by either the chylomicron-association pathway or the M cell uptaking pathway. Intravenous SLNs are predominantly uptaken by the liver or spleen following opsonization by the complementary system. Modification of SLN surface with PEGs chains will mask the hydrophobic surface and divert SLNs to non-hepatic and non-splenic organs, while ligand-modification will achieve active targeting to specific tissues or organs. Degradation of SLNs is primarily based on the degradation of the lipids themselves by lipase. Pharmacokinetics reflects the effect of the lipidic vehicles of SLNs on in vivo disposition of the loaded drugs. PMID- 22443537 TI - Absorption, pharmacokinetics and disposition of biodegradable nanoscale preparations. AB - Nowadays, biodegradable nanoscale preparations such as liposomes, micelles, nanoparticles (NPs), and solid lipid nanoparticles (SLN) have attracted increasing attention from major researchers. This article aims to review the absorption, pharmacokinetics, distribution properties and toxicity of the above mentioned nanoscale preparations and the relative methodology. It may be significant for successful use of more nanoscale preparations in clinical practice. PMID- 22443538 TI - Toxicity of biodegradable nanoscale preparations. AB - Nowadays, biodegradable nanoscale preparations such as liposomes, micelles, nanoparticles (NPs), and solid lipid nanoparticles (SLN) have attracted increasing attention from major researchers. Meanwhile the biosafety of the nanomaterials brings more and more attention. Toxicity of the biodegradable nanoscale preparations varies depending on their particle size, shape, surface structure, etc. This article aims to review the toxicity of the above-mentioned nanoscale preparations and the relative methodology. It may be significant for successful use of more nanoscale preparations in clinical practice. PMID- 22443539 TI - Absorption, pharmacokinetics and disposition properties of solid lipid nanoparticles (SLNs). AB - In recent years, many researchers have paid more and more attentions on the use of Nanotechnology. Solid lipid nanoparticles (SLNs) are emerged as a promising alternation herein to emulsions, liposomes, microparticles and polymeric nanoparticles for their advantages. As promising drug carrier systems, SLNs are valuable for nanomedicine and have been widely used as delivery systems mostly for drugs and macromolecules like proteins, oligonucleotides and DNA by various application routes, such as intravenous, oral, duodenalous, intramuscular, pulmonary, intranasal, ocular, rectal and intraperitoneal administrations. It has been shown that SLNs can increase bioavailability, alter pharmacokinetic parameters and tissue distribution of the drug loaded. In this review, we will primarily focus on the absorption, pharmacokinetics and disposition properties of SLNs for their possible applications in drug delivery. PMID- 22443540 TI - Microbial diversity and biomineralization in low-temperature hydrothermal iron silica-rich precipitates of the Lau Basin hydrothermal field. AB - Iron-silica-rich low-temperature hydrothermal precipitates were collected from the CDE hydrothermal field located at the East Lau Spreading Center. Phylogenetic analysis showed that the precipitates were dominated by the members of alpha proteobacteria and marine group I archaea. Ultrastructural analysis suggested the bacteriogenic origin of the iron-silica-rich deposits. Distinctive biosignatures detected included straight filaments, helical stalks and curved irregular filaments, which were similar in appearance to those structures excreted by the known iron-oxidizing genera Leptothrix spp., Gallionella spp. and Mariprofundus spp. 16S rRNA gene analysis confirmed the presence of neutrophilic iron-oxidizing bacteria with the detection of phylotypes clustering with Gallionella spp. and the proposed zeta-proteobacteria class. Mineralogy and bulk geochemical analyses showed that the precipitates were dominated by amorphous silica with low amounts of iron. Based on microbiological, geochemical and mineralogical analyses, we conclude that silicification was a common process and microbial cells and related ultrastructures likely acted as nucleation templates for silica precipitation in the CDE hydrothermal field. PMID- 22443541 TI - Production and proteomic characterisation of purified protein derivative from Mycobacterium avium subsp. paratuberculosis. AB - BACKGROUND: Effective diagnosis of Johne's disease (JD), particularly at the stage of early subclinical infection, remains one of the greatest challenges for the control of JD worldwide. The IFN-gamma test of cell mediated immunity is currently one of the most suitable diagnostics for subclinical infections, however a major limitation of this test is the lack of a standardised purified protein derivative (PPD) antigen (also referred to as Johnin PPD or PPDj). While attempting to replace PPDj with more specific individual antigens is an attractive proposition, bacterial culture derived PPDj remains the most effective antigen preparation for the diagnosis of subclinical JD. It may be possible to increase the reproducibility and specificity of PPDj preparations by further characterising and standardising the PPDj production. RESULTS: Using a standardised protocol, five in-house preparations of PPDj were prepared from cultures of Mycobacterium avium subsp. paratuberculosis (MAP). Compared to PPDs obtained from other institutes/laboratories, these preparations appeared to perform similarly well in the IFN-gamma test. Although the broad proteomic composition of all PPDj preparations was remarkably similar, the absolute abundance of individual proteins varied markedly between preparations. All PPDj preparations contained common immunogenic proteins which were also observed in PPD preparations from Mycobacterium avium subsp. avium (PPDa) and Mycobacterium bovis (PPDb). Temporal difference in protein secretion of in vitro cultured MAP was observed between 20 and 34 weeks suggesting that the age of MAP culture used for PPDj preparations may markedly influence PPDj composition. CONCLUSIONS: This study describes a protocol for the production of PPDj and its subsequent proteomic characterisation. The broad proteomic composition of different preparations of PPDj was, for the most part, highly similar. Compositional differences between PPDj preparations were found to be a direct reflection of genetic differences between the MAP strain types used to produce these preparations and the age of MAP cultures they were derived from. A number of conserved immunogenic proteins, such as members of the cutinase-like protein family, were found to be more abundant in PPDj compared to PPDa and should be considered as possible diagnostic antigens for the future. PMID- 22443542 TI - Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants. RESULTS: Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death. CONCLUSIONS: These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different. PMID- 22443543 TI - Comparison of microbial changes in early redeveloping biofilms on natural teeth and dentures. AB - BACKGROUND: Surfaces and fluids can affect oral bacterial colonization. The aim of this study is to compare redeveloping biofilms on natural teeth and dentures. METHODS: Supragingival plaque samples were taken from 55 dentate individuals and the denture teeth of 62 edentulous individuals before and after professional cleaning. Also, samples from seven "teeth" (samples included dentures) in randomly selected quadrants were collected after 1, 2, 4, and 7 days of no oral hygiene. Samples were analyzed using checkerboard DNA-DNA hybridization. Counts and proportions of 41 bacterial taxa were determined at each time point, and significant differences were determined using the Mann-Whitney U test. Ecological succession was determined using a modified moving window analysis. RESULTS: Mean total DNA probe counts were similar precleaning but were higher in dentate individuals at all post-cleaning visits (P <0.01). Precleaning edentate biofilms had higher counts and proportions of Streptococcus mitis, Streptococcus oralis, and Streptococcus mutans, whereas dentate individuals had higher proportions of Tannerella forsythia, Selenomonas noxia, and Neisseria mucosa. By day 2, mean counts of all taxa were higher in natural teeth, and most remained higher at day 7 (P <0.01). Succession was more rapid and complex in dentate individuals. Both groups demonstrated increased proportions of S. mitis and S. oralis by day 1. N. mucosa, Veillonella parvula, and Eikenella corrodens increased in both groups, but later in samples from edentate individuals. CONCLUSIONS: "Mature" natural and denture teeth biofilms have similar total numbers of bacteria but different species proportions. Post-cleaning biofilm redevelopment is more rapid and more complex on natural teeth than on denture teeth. PMID- 22443544 TI - Pain related-visual imagery is associated with distress in chronic pain sufferers. AB - BACKGROUND: Chronic pain patients often describe their pain in ways that suggest vivid mental images, with some reporting images relating to their pain. Despite these clinical observations, there are few studies describing the nature and consequences of these images. This study examined whether mental imagery of pain is associated with levels of reported distress, cognitions, disability or pain severity. METHOD: In a postal survey, 83 adult chronic pain patients indicated whether or not they experienced mental images of their pain. They also completed standardized measures of depression, anxiety, cognitions, disability and pain severity. Those reporting images were compared to those not reporting images on their responses to the other variables. RESULTS: People with pain imagery reported significantly higher levels of anxiety, depression and catastrophizing than patients who did not report such images. No differences were found on measures of physical disability. DISCUSSION: Mental images of pain appear to be associated with higher levels of anxiety, depression and catastrophizing. It is possible that these images play a role in maintaining such difficulties. For these patients, imagery may provide a route via which clinicians can work with patients to help them reinterpret or respond more flexibly to their pain. PMID- 22443546 TI - Impact of spinopelvic alignment on decision making in deformity surgery in adults: A review. AB - Sagittal spinal misalignment (SSM) is an established cause of pain and disability. Treating physicians must be familiar with the radiographic findings consistent with SSM. Additionally, the restoration or maintenance of physiological sagittal spinal alignment after reconstructive spinal procedures is imperative to achieve good clinical outcomes. The C-7 plumb line (sagittal vertical axis) has traditionally been used to evaluate sagittal spinal alignment; however, recent data indicate that the measurement of spinopelvic parameters provides a more comprehensive assessment of sagittal spinal alignment. In this review the authors describe the proper analysis of spinopelvic alignment for surgical planning. Online videos supplement the text to better illustrate the key concepts. PMID- 22443545 TI - The complete genome sequence of the acarbose producer Actinoplanes sp. SE50/110. AB - BACKGROUND: Actinoplanes sp. SE50/110 is known as the wild type producer of the alpha-glucosidase inhibitor acarbose, a potent drug used worldwide in the treatment of type-2 diabetes mellitus. As the incidence of diabetes is rapidly rising worldwide, an ever increasing demand for diabetes drugs, such as acarbose, needs to be anticipated. Consequently, derived Actinoplanes strains with increased acarbose yields are being used in large scale industrial batch fermentation since 1990 and were continuously optimized by conventional mutagenesis and screening experiments. This strategy reached its limits and is generally superseded by modern genetic engineering approaches. As a prerequisite for targeted genetic modifications, the complete genome sequence of the organism has to be known. RESULTS: Here, we present the complete genome sequence of Actinoplanes sp. SE50/110 [GenBank:CP003170], the first publicly available genome of the genus Actinoplanes, comprising various producers of pharmaceutically and economically important secondary metabolites. The genome features a high mean G + C content of 71.32% and consists of one circular chromosome with a size of 9,239,851 bp hosting 8,270 predicted protein coding sequences. Phylogenetic analysis of the core genome revealed a rather distant relation to other sequenced species of the family Micromonosporaceae whereas Actinoplanes utahensis was found to be the closest species based on 16S rRNA gene sequence comparison. Besides the already published acarbose biosynthetic gene cluster sequence, several new non ribosomal peptide synthetase-, polyketide synthase- and hybrid-clusters were identified on the Actinoplanes genome. Another key feature of the genome represents the discovery of a functional actinomycete integrative and conjugative element. CONCLUSIONS: The complete genome sequence of Actinoplanes sp. SE50/110 marks an important step towards the rational genetic optimization of the acarbose production. In this regard, the identified actinomycete integrative and conjugative element could play a central role by providing the basis for the development of a genetic transformation system for Actinoplanes sp. SE50/110 and other Actinoplanes spp. Furthermore, the identified non-ribosomal peptide synthetase- and polyketide synthase-clusters potentially encode new antibiotics and/or other bioactive compounds, which might be of pharmacologic interest. PMID- 22443547 TI - Differences between 1- and 2-level cervical arthroplasty: more heterotopic ossification in 2-level disc replacement: Clinical article. AB - OBJECT: The most currently accepted indication for cervical arthroplasty is 1- or 2-level degenerative disc disease (DDD) refractory to medical treatment. However, the randomized and controlled clinical trials by the US FDA investigational device exemption studies only compared cervical arthroplasty with anterior cervical discectomy and fusion for 1-level disease. Theoretically, 2-level cervical spondylosis usually implicates more advanced degeneration, whereas the 1 level DDD can be caused by merely a soft-disc herniation. This study aimed to investigate the differences between 1- and 2-level cervical arthroplasty. METHODS: The authors analyzed data obtained in 87 consecutive patients who underwent 1- or 2-level cervical arthroplasty with Bryan disc. The patients were divided into the 1-level and the 2-level treatment groups. Clinical outcomes were measured using the visual analog scale (VAS) for the neck and arm pain and the Neck Disability Index (NDI), with a minimum follow-up of 30 months. Radiographic outcomes were evaluated on both radiographs and CT scans. RESULTS: The study analyzed 98 levels of Bryan cervical arthroplasty in 70 patients (80.5%) who completed the evaluations in a mean follow-up period of 46.21 +/- 9.85 months. There were 22 females (31.4%) and 48 males (68.6%), whose mean age was 46.57 +/- 10.07 years at the time of surgery. The 1-level group had 42 patients (60.0%), while the 2-level group had 28 patients (40.0%). Patients in the 1-level group were younger than those in the 2-level group (mean 45.00 vs 48.93 years, p = 0.111 [not significant]). Proportional sex compositions and perioperative prescription of nonsteroidal antiinflammatory drugs were also similar in both groups (p = 0.227 and p = 1.000). The 2-level group had significantly greater EBL during surgery than the 1-level group (220.80 vs 111.89 ml, p = 0.024). Heterotopic ossification was identified more frequently in the 2-level group than the 1-level group (75.0% vs 40.5%, p = 0.009). Although most of the artificial discs remained mobile during the follow up, the 2-level group had fewer mobile discs (100% and 85.7%, p = 0.022) than the 1-level group. However, in both groups, the clinical outcomes measured by VAS for neck pain, VAS for arm pain, and NDI all significantly improved after surgery compared with that preoperatively, and there were no significant differences between the groups at any point of evaluation (that is, at 3, 6, 12, and 24 months after surgery). CONCLUSIONS: Clinical outcomes of 1- and 2-level cervical arthroplasty were similar at 46 months after surgery, and patients in both groups had significantly improved compared with preoperative status. However, there was a significantly higher rate of heterotopic ossification formation and less mobility of the Bryan disc in patients who underwent 2-level arthroplasty. Although mobility to date has been maintained in the vast majority (94.3%) of patients, the long-term effects of heterotopic ossification warrant further investigation. PMID- 22443548 TI - Impact of bioactive substances on the gastrointestinal tract and performance of weaned piglets: a review. AB - The EU ban on in-feed antibiotics has stimulated research on weaning diets as a way of reducing post-weaning gut disorders and growth check in pigs. Many bioactive components have been investigated but only few have shown to be effective. Amongst these, organic acids (OA) have been shown to exert a bactericidal action mediated by non-dissociated OA, by lowering gastric pH, increasing gut and pancreas enzyme secretion and improving gut wall morphology. It has been postulated that they may also enhance non-specific immune responses and improve disease resistance. In contrast, relatively little attention has been paid to the impact of OA on the stomach but recent data show they can differently affect gastric histology, acid secretion and gastric emptying. Butyrate and precursors of butyric acid have received special attention and although promising results have been obtained, their effects are dependent upon the dose, treatment duration, initial age of piglets, gastrointestinal site and other factors. The amino acids (AA) like glutamine, tryptophan and arginine are supportive in improving digestion, absorption and retention of nutrients by affecting tissue anabolism, stress and (or) immunity. Glutamine, cysteine and threonine are important for maintaining mucin and permeability of intestinal barrier function. Spray-dried plasma (SDP) positively affects gut morphology, inflammation and reduces acquired specific immune responses via specific and a-specific influences of immunoglobulins and other bioactive components. Effects are more pronounced in early-weaned piglets and under poorer health conditions. Little interaction between plasma protein and antibiotics has been found, suggesting distinct modes of action and additive effects. Bovine colostrum may act more or less similarly to SDP. The composition of essential oils is highly variable, depending on environmental and climatic conditions and distillation methods. These oils differ widely in their antimicrobial activity in vitro and some components of weaning diets may decrease their activity. Results in young pigs are highly variable depending upon the product and doses used. These studies suggest that relatively high concentrations of essential oils are needed for beneficial effects to be observed and it has been assumed that these plant extracts mimic most of the effects of antibiotics active on gut physiology, microbiology and immunology. Often, bioactive substances protective to the gut also stimulate feed intake and growth performance. New insights on the effects of selected OA and AA, protein sources (especially SDP, bovine colostrum) and plant extracts with anti-bacterial activities on the gut are reported in this review. PMID- 22443549 TI - Natural alternatives to in-feed antibiotics in pig production: can immunomodulators play a role? AB - As a result of the European ban of in-feed growth-promoting antibiotics, new strategies are being developed to increase the resistance to disease in farm animals. In pig production, this is of particular importance during the weaning transition when piglets are subjected to major stressful events, making them highly sensitive to digestive disorders. At this time, the development of both innate and adaptive immunity at the mucosal surface is critical in preventing the potential harmful effects of intestinal pathogenic agents. Strategies aiming at stimulating natural host defences through the use of substances able to modulate immune functions have gained increasing interest in animal research, and different bioactive components a priori sharing those properties have been the subject of in vivo nutritional investigations in pig. Among these, yeast derivates (beta-glucans and mannans) are able to interact with immune cells, particularly phagocytic cells. However, studies where they have been fed to pigs have shown inconsistent results, suggesting that their ability to target the sensitive immune cells through the oral route is questionable. The plant extracts, which would benefit from a positive image in the public opinion, have also been tested. However, due to a lack of data on the bioactive components of particular plants and the large diversity of species, it has proved difficult to prepare extracts of equivalent potency and thus, the literature on their influence on pig immunity remains inconclusive. In considering piglet immunity and health benefits, the most promising results to date have been obtained with spray-dried animal plasma, whose positive effects would be provided by specific antibodies and non-specific competition of some plasma components with bacteria for intestinal receptors. The major positive effect of spray-dried animal plasma is in reducing the infiltration of gut-associated lymphoid tissue by immune cells, which is likely to be the result of a decreased colonisation by potentially harmful bacteria. This review also highlights the limitations of some of the published in vivo studies on the immunomodulatory activity of certain feed additives. Among those, the lack of standardisation of extracts and the heterogeneity of piglet-rearing conditions (e.g. exposure to pathogens) are likely the most limiting. PMID- 22443550 TI - Effects of inbreeding and other genetic components on equine fertility. AB - The Finnish mating records of Standardbred trotters (SB; n = 33 679) and Finnhorses (FH; n = 32 731) were analysed to study the effect of the level of inbreeding on foaling rates and to estimate the heritability of foaling rate. A linear mixed model was assumed, with the outcome of the foaling (foal or no foal) as the trait of the study. A restricted maximum likelihood-based method was used to calculate the estimates of the variance components. Predictions of breeding values and estimates of fixed effects were also calculated. The average level of inbreeding was 9.9% in the SB and 3.6% in the FH. The average foaling rates were better in the SB (72.6%) than in the FH (66.3%), but within each breed intense inbreeding had a statistically significant negative effect on foaling rate (P < 0.05). Also, the mating type, the age and breeding type of the mare, and the age of the stallion had statistically significant effects on foaling rate (P < 0.001). The heritability of foaling rate was between 3.4% and 3.7% in SBs and between 5.5% and 9.8% in FHs, when the outcome of the foaling was considered to be a trait of the expected foal. With the same model, the estimates of maternal genetic effect were 4.7% for SBs and 3.2% for FHs, and the estimates of the permanent environmental effects of the stallion were between 1.3% and 1.7%. Avoiding matings with very high inbreeding coefficients would improve foaling rates. It would also be possible to devise a breeding program for better equine fertility, but because the heritability is low, improvement of environmental factors deserves special attention. PMID- 22443551 TI - Estimation of genetic variation in residual variance in female and male broiler chickens. AB - In breeding programs, robustness of animals and uniformity of end product can be improved by exploiting genetic variation in residual variance. Residual variance can be defined as environmental variance after accounting for all identifiable effects. The aims of this study were to estimate genetic variance in residual variance of body weight, and to estimate genetic correlations between body weight itself and its residual variance and between female and male residual variance for broilers. The data sets comprised 26 972 female and 24 407 male body weight records. Variance components were estimated with ASREML. Estimates of the heritability of residual variance were in the range 0.029 (s.e. = 0.003) to 0.047 (s.e. = 0.004). The genetic coefficients of variation were high, between 0.35 and 0.57. Heritabilities were higher in females than in males. Accounting for heterogeneous residual variance increased the heritabilities for body weight as well. Genetic correlations between body weight and its residual variance were 0.41 (s.e. = 0.032) and -0.45 (s.e. = 0.040), respectively, in females and males. The genetic correlation between female and male residual variance was 0.11 (s.e. = 0.089), indicating that female and male residual variance are different traits. Results indicate good opportunities to simultaneously increase the mean and improve uniformity of body weight of broilers by selection. PMID- 22443552 TI - Estimation of genetic trends from 1977 to 2000 for stress-responsive systems in French Large White and Landrace pig populations using frozen semen. AB - An experimental design aiming at analysing the consequences of genetic selection from 1977 to 1998-2000 on the evolution of stress-responsive systems in the French Large White (LW) and Landrace (LR) pig populations was conducted by INRA and IFIP-Institut du Porc. Large White sows were inseminated with semen from LW boars born in 1977 (frozen semen) or in 1998 and their second-generation offspring were station-tested. Landrace sows were inseminated with semen from LR boars born in 1977 (frozen semen) or in 1999 to 2000, and their progeny was station-tested. Urinary concentration of stress hormones (cortisol and catecholamines) and traits related to carcass composition (estimated carcass lean content (ECLC) and global adiposity) and meat quality (pH 24 h) were measured. For the two populations, selection carried out since 1977 led to an increase in ECLC and a decrease in carcass adiposity. Between 1977 and 1998 to 2000, urinary concentrations of stress hormones were unchanged in the LR breed, but were decreased in the LW breed. Moreover, for the animals generated from LW boars born in 1977 and in 1998, urinary cortisol levels were negatively correlated with ECLC. Therefore, in the LW breed, selection carried out for higher ECLC resulted in a decrease in cortisol production, as well as a reduction of catecholamine production that may be responsible for the lower ultimate pH of meat. Therefore, selection carried out for increased carcass lean content led, in this breed, to large modifications in the functioning of the stress-responsive systems, thereby influencing a large range of physiological regulations and technical properties such as carcass composition and meat pH, which remained however in the normal range for acceptable meat quality. PMID- 22443553 TI - Associations of PrP genotype with lamb production traits in three commercial breeds of British lowland sheep. AB - The Ram Genotyping Scheme was launched in Great Britain in 2001 as part of the National Scrapie Plan and was devised to reduce and eventually eradicate classical scrapie susceptible genotypes from the national pedigree flock. Anecdotal claims from breeders suggest that sheep with more resistant PrP genotypes may have inferior phenotypes. In this study, we test this possibility for lamb production traits in three breeds of lowland sheep: Charollais (22 752 lambs), Poll Dorset (22 589 lambs) and Texel (23 492 lambs). Data were received from 50 breeders and comprised weights at birth, 8 weeks and scanning (from which average daily weight gain was derived), and ultrasonic muscle and fat depths. Animal (direct) genetic effects and up to three maternal effects were fitted in linear mixed models for each trait. Fitting either PrP genotype or number of copies of individual alleles carried as fixed effects allowed potential associations with the PrP gene to be assessed. There were no significant associations seen in the Poll Dorset breed; however, significant associations were found with the number of allele copies carried in the other two breeds included in this study. Charollais lambs carrying one copy of the VRQ allele had significantly (P < 0.01) greater ultrasonic muscle depth (0.58 mm) and fat depth (0.2 mm) than non-carriers. In the Texel breed, lambs with one ARR allele were significantly heavier than those with two or zero ARR alleles; heterozygous ARR lambs were 0.07 kg heavier at birth (P < 0.05), 0.42 kg heavier at 8 weeks (P < 0.01) and 0.17 kg heavier at scan weight (P < 0.01), than non-carriers. After Bonferroni corrections to adjust significance thresholds to account for the large number of independent comparisons made, all significant results remained so at P < 0.05 or greater, except for the ARR allele effect on birth weight in the Texel breed, which was no longer significant. These results compare favourably with others from studies on many continental breeds of sheep, published in recent years, and add credence to the conclusion that selection on PrP genotype is unlikely to have any noticeable impact on the measured growth and carcass traits in sheep. PMID- 22443554 TI - Determination of standardized ileal crude protein and amino acid digestibilities in protein supplements for piglets. AB - The objective of the study was to determine standardized ileal digestibilities (SID) of crude protein (CP) and amino acids (AA) in six ingredients commonly used in weanling pigs diets. The ingredients consisted of extruded soybeans (SBe), high-protein soybean meal (SBMhp), soy protein concentrate (SPC), hydrolyzed wheat gluten (WGh), conventional fish meal 1 (FM1) and extracted fish meal 2 (FM2e). Each assay feed ingredient was added to a purified cornstarch-based basal diet supplemented with casein and crystalline AA, and SID of CP and AA of assay ingredients were estimated using the difference method. A total of 12 3-week-old barrows were surgically fitted with T-cannulas at the distal ileum. The piglets were allocated to four simultaneous 3 * 3 Latin-square designs with three animals and three periods each, resulting in six observations per assay diet. After 3 to 5 days recovery from surgery, each assay diet was fed at a level of 30 g/kg body weight. Each experimental period consisted of 5 days for adaptation to the assay diets and 2 days for ileal digesta collection. The SID of CP, Lys, Met, Thr and Trp were 73%, 78%, 76%, 66% and 71% in SBe; 80%, 84%, 87%, 75% and 81% in SBMhp; 86%, 89%, 89%, 78% and 83% in SPC; 87%, 60%, 88%, 76% and 79% in WGh; 87%, 92%, 94%, 86% and 86% in FM1; and 79%, 86%, 89%, 80% and 74% in FM2e, respectively. The greatest SID of indispensable AA were observed for FM1 and SPC (SID 85% for most indispensable AA), followed by WGh, FM2e and SBMhp (SID 80% for most indispensable AA) and the smallest SID were obtained for SBe (SID < 80% for most indispensable AA). The SID of CP and indispensable AA in both types of fish meal, SBMhp and WGh were similar to SPC (P = 0.063 to 0.855), except for Arg (P = 0.010) and Lys (P = 0.001) in WGh, and Phe (P = 0.044) and Trp (P = 0.037) in FM2e. The SID of CP and indispensable AA were smaller in SBe compared with SPC (P < 0.001 to P = 0.017), except for Lys (P = 0.136). The SID of CP and indispensable AA were consistently smaller in FM2e compared with FM1 with significant differences for CP (P = 0.035), Phe (P = 0.028) and Trp (P = 0.008). Digestibility values measured in the present study can be used to formulate diets for piglets based on standardized ileal digestible contents of CP and AA. PMID- 22443555 TI - Effect of rumen fill on intake of fresh perennial ryegrass in young and mature dairy cows grazing or zero-grazing fresh perennial ryegrass. AB - Rumen fill may be a strong intake constraint for dairy cows fed on pasture, even though pasture is highly digestible in the grasslands of temperate climates. This constraint may also depend on the cows' maturity. Moreover, indoor feeding of fresh herbage may not always be a good model for the study of intake regulation at grazing. To test these hypotheses, four mature (6.3 +/- 0.72 year old) and four young (3.8 +/- 0.20 year old) dairy cows were offered fresh perennial ryegrass indoors or at grazing. The impact of rumen fill on intake was evaluated by addition of rumen inert bulk (RIB; coconut fiber, 15 l) compared to a control. The experimental design was a double 4 * 4 Latin square with four 14-day periods and a 2 * 2 factorial arrangement of two feeding methods (indoor feeding v. grazing), combined with the addition, or not, of RIB (RIB v. control), repeated for four mature and four young cows. Digestibility of offered herbage was 0.81. The average ytterbium measured dry matter intake (Yb DMI) was 19.0 and 15.5 kg/day for mature and young cows respectively (P = 0.019). The effect of RIB on predicted Yb DMI interacted with feeding method and cow age (P = 0.043). The presence of RIB decreased Yb DMI by 4.4 kg/day in mature cows at grazing and by 3.4 kg/day in young cows indoors, whereas it did not affect the Yb DMI of mature cows indoors or grazing young cows. Both grazing and young age constituted a clear constraint on the feeding behavior of the cows. Grazing cows had fewer ingestion and rumination sequences, which were longer and less evenly distributed throughout the day and night. Young cows had lower intake rates that were less adaptable to the feeding method and the presence of RIB. Mature cows clearly decreased their daily intake rate at grazing compared to indoor feeding, and with RIB compared to control, whereas the intake rate of young cows did not vary. These results indicate that rumen fill can represent a constraint on intake in grazing cows, even when highly digestible perennial ryegrass is offered. The study also shows that the impact of RIB on intake is highly dependent upon other constraints applied to the chewing behavior, which in this experiment were methods of offering herbage and cow age. PMID- 22443556 TI - Effects of silage digestibility on intake and body reserves of dry cows and performance in the first part of the next lactation. AB - This experiment evaluated different strategies for allocating first-cut grass silages to dry dairy cows that had low body-condition score (BCS) at drying off. A total of 48 moderately yielding Holstein-Friesian cows were used, receiving one of three dietary treatments in the dry period and a single lactation diet based on a flat-rate of concentrates and grass silage ad libitum. Throughout the dry period, one group received a low-digestibility silage (harvested 15 June 1998; LL; metabolisable energy (ME) = 10.3 MJ/kg dry matter (DM)) and a second group received a high-digestibility silage (harvested 9 May 1998, HH; ME = 11.7 MJ/kg DM). A third strategy (LH) offered the low-digestibility silage in the early dry period and the high-digestibility silage in the final 3 weeks before calving. The silages had very different crude protein concentrations (144 and 201 g/kg DM) and intakes were widely divergent (10.1 v. 13.5 kg DM/day) across the dry period. No concentrates were fed during the dry period. Silage quality had a very large effect on liveweight change, with treatment means of 0.32 and 1.75 kg/day for LL and HH, respectively. BCS changes followed a similar pattern, though no cows became over-conditioned and blood metabolites were within normal ranges. Increased silage digestibility in the late dry period led to a substantial increase in milk fat concentration and a smaller increase in milk protein concentration, the latter confined to the first full week of lactation. Depression of milk fat appears related to low blood glucose when dry cows in low body condition are fed at a low level. The LH strategy avoided the tendency for lower milk yields and fat concentration that resulted from feeding the low digestibility silage until calving. This strategy also avoided the higher calf weights that resulted from feeding the high-digestibility silage in the early dry period. PMID- 22443557 TI - A comparison between the 2N and 4N HCl acid-insoluble ash methods for digestibility trials in horses. AB - The digestibility of horse feeds and rations can be determined using different techniques such as calculations based on the chemical composition, in vivo or in vitro methods. The marker methods overcome difficulties like discomfort for the animals and longer experimental times encountered using the ingesta/egesta method. In field conditions, a natural indigestible marker like acid-insoluble ash (AIA), with no changes in the normal ration, could be a very useful tool for digestibility trials. A group of six standardbred horses was used in a set of seven apparent digestibility trials. The diets were based on a first-cut meadow hay added to three different cereals (barley for trials 1 and 2; oats for trials 3 and 5 and corn for trials 6 and 7), the hay : concentrate ratio being 60 : 40 or 70 : 30 on a dry matter basis. Feedstuffs and faeces were analysed to determine the AIA content, using 2N HCl or 4N HCl technique. No differences about AIA concentration were found between the two methods for means and accuracy in each diet. Digestion coefficients for each diet did not differ with AIA method, even if in some trials interfering factors consistently lowered the overall values. Consequently, the AIA 2N HCl can be considered the easier and cheaper method to state apparent digestibility in field conditions, and a good tool for digestibility trials in horses fed hay-based diets. PMID- 22443558 TI - Mammary gland secretion: hormonal coordination of endocytosis and exocytosis. AB - The mammary epithelium coordinates the uptake of milk precursors and the transport of milk components in order to produce milk of relatively constant composition at a particular stage of lactation, as long as the mammary gland is healthy. The mammary epithelial cell controls the uptake of blood-borne molecules at its basal side and the release of products into milk at its apical side, through mechanisms of internalization (endocytosis) and mechanisms of release (exocytosis). These events are strictly dependent on the physiological stage of the mammary gland. This review addresses the mechanisms responsible for these processes and points out new questions that remain to be answered concerning possible interconnections between them, for an optimal milk secretion. PMID- 22443559 TI - Interactions of the bovine placental lactogen and prolactin receptor genes are associated with fertility traits in cattle. AB - Decline in fertility of high-producing dairy cattle has become a global challenge to the dairy industry. Because of low heritability and complexity, it is difficult to find genetic markers for fertility traits in cattle. Here, we report the use of an in vitro fertilization (IVF) system and candidate gene approach to test genetic associations of a single-nucleotide polymorphism (SNP) in bovine placental lactogen (bPL), and its interactions with SNPs in the prolactin receptor (PRLR) and growth hormone receptor genes with fertility traits in an IVF system. The associations suggest a possible involvement of genetic interactions between bPL and PRLR in the fertilization and embryonic development processes, and the potential for application in a marker-assisted selection program. PMID- 22443560 TI - Measurement of spatial gait parameters from footprints of dairy cows. AB - The variability in dairy cow gait characteristics, determined by measurements of footprints (trackway measurements), was analysed. Seven gait parameters were determined from 32 non-lame dairy cows during free-speed walking on a slatted concrete walkway. The footprints were revealed by application of a thin lime powder-slurry layer to the walkway surface. The cows were observed on two test occasions with a 3-week interval, with measurements from four consecutive strides used within each test session. The variance components for cow, test and cow-test interaction were estimated by a residual (restricted) maximum likelihood method. The percentage of each variance component was calculated to assess the relative impact of each factor on total variance. Between-test variation was generally low, suggesting that cows maintain the same average gait pattern, at least over a 3-week period. The proportion of within-test variation was considerable for most trackway measurements. Stride length, step angle, step width and tracking (overlap) showed low to moderate within-test variation (12% to 27%), whereas for mediolateral displacement of rear feet and step length it was rather high (54% and 62%, respectively). Within-test variation in step asymmetry was very high (77%), suggesting the occurrence of natural, non-systematic changes in inter-limb coordination in non-lame cows. For better understanding the gait pattern in non lame cows, linear associations between the trackway measurements and with body size were assessed. It was concluded that trackway measurements were able to describe the gait pattern in walking cows under dairy farm conditions. However, considering the relatively high within-test variation in gait, several strides should be used to obtain a representative gait pattern. PMID- 22443561 TI - Effect of replacing calcium salts of palm oil distillate with extruded linseeds on milk fatty acid composition in Jersey and Holstein cows. AB - Clinical and biomedical studies have provided evidence for the critical role of n 3 fatty acids on the reduction of chronic disease risk in humans, including cardiovascular disease. In the current experiment, the potential to enhance milk n-3 content in two breeds with inherent genetic differences in mammary lipogenesis and de novo fatty acid synthesis was examined using extruded linseeds. Six lactating cows (three Holstein and three Jersey) were used in a two treatment switchback design with 3 * 21-day experimental periods to evaluate the effect of iso-energetic replacement of calcium salts of palm oil distillate (CPO) in the diet (34 g/kg dry matter (DM)) with 100 g/kg DM extruded linseeds (LIN). For both breeds, replacing CPO with LIN had no effect (P > 0.05) on DM intake or milk yield, but reduced (P < 0.05) milk fat and protein yield (on average, from 760 to 706 and 573 to 552 g/day, respectively). Relative to CPO, the LIN treatment reduced (P < 0.01) total saturated fatty acid content and enhanced (P < 0.001) 18:3n-3 in milk, whereas breed by diet interactions were significant for milk fat 16:0, total trans fatty acid and conjugated linoleic acid concentrations. Increases in 18:3n-3 intake derived from LIN in the diet were transferred into milk with a mean marginal transfer efficiency of 1.8%. Proportionate changes in milk fatty acid composition were greater in the Jersey, highlighting the importance of diet-genotype interactions on mammary lipogenesis. More extensive studies are required to determine the role of genotype on milk fat composition responses to oilseeds in the diet. PMID- 22443562 TI - Light lamb meat quality packed under modified atmospheres: effect of stunning systems (electrically v. gas). AB - In the present study, the effect of type of stunning (electrical v. gas) and the gas mixtures in a modified atmosphere (MA) packing system (MA-A: 30% CO2 + 70% O2; MA-B: 30% CO2 + 69.3% N2 + 0.7% CO; MA-C: 40% CO2 + 60% N2) on light lamb meat quality, obtained by 20 males of Manchego Spanish breed, was evaluated at 7, 14 and 21 days post packing. For all ageing times, gas-stunned groups reached the highest pH (P < 0.001) and shear force (SF) values (P < 0.05), and at 21 days, water losses were highest; in contrast, meat colour coordinates were lower (P < 0.001). In general, MA-B showed the highest stability for colour coordinates whereas the lowest tenderness (high SF) was found on MA-A. In this study, the gas mixture with a low carbon monoxide level (MA-B) promoted a higher colour stability and good tenderness, in comparison to the other two blends. In contrast, the conventional packaging system (type A, high oxygen levels) had a reduced tenderness and major colour instability. PMID- 22443563 TI - Lipid-deprived diet perturbs O-glycosylation of secretory proteins in rat mammary epithelial cells. AB - Nutrition modulates both production and composition of milk. Milk composition was studied in rats chronically fed a diet without additional lipids, and therefore eating only traces of the recommended supply of essential polyunsaturated fatty acid. Despite a large decrease in milk-protein synthesis, only protein composition, but not protein concentration, was found to change in the milk of rats following a lipid-deprived diet. Correlatively, we observed a substantial increase in the lactose concentration of milk. Analysis of milk proteins by two dimensional electrophoresis demonstrated that the relative proportion of the various molecular forms of kappa-casein, an O-glycosylated protein, was modified in the milk of rats receiving the lipid-deprived diet. In tissues, differences in the two-dimensional pattern of kappa-casein between control and lipid-deprived rats were similar, if not identical. In contrast to kappa-casein, the molecular forms of alpha-lactalbumin, an N-glycosylated protein, were not affected by the diet. These data provide evidence that O-glycosylation of milk proteins in the secretory pathway of mammary epithelial cells is modulated by the lipid content of experimental diets. PMID- 22443564 TI - Urea and short-chain fatty acids metabolism in Holstein cows fed a low-nitrogen grass-based diet. AB - Three ruminally cannulated and multicatheterised lactating dairy cows were used to investigate the effect of different supplement strategies to fresh clover grass on urea and short-chain fatty acid (SCFA) metabolism in a zero-grazing experiment with 24-h blood and ruminal samplings. Fresh clover grass was cut every morning and offered from 0800 to 1500 h. Maize silage was fed at 1530 h. The three treatments, arranged in a Latin square, differed by timing of feeding rolled barley and soya-bean hulls relative to fresh clover grass. All diets had the same overall composition. Treatments were soya-bean hulls fed at 0700 h and barley fed at 1530 h (SAM), barley fed at 0700 h and soya-bean hulls fed at 1530 h (BAM), and both soya-bean hulls and barley fed at 1530 h (SBPM). The grass had an unexpectedly low content of crude protein (12.7%) and the cows were severely undersupplied with rumen degradable protein. The treatment effects were numerically small; greater arterial ammonia concentration, net portal flux of ammonia and net hepatic flux of urea during part of the day were observed when no supplementary carbohydrate was fed before grass feeding. A marked diurnal variation in ruminal fermentation was observed and grass feeding increased ruminal concentrations of propionate and butyrate. The net portal fluxes of propionate, butyrate, isovalerate and valerate as well as the net hepatic uptake of propionate, butyrate, valerate and caproate increased after feeding at 0700 h. The hepatic extraction of butyrate showed a relatively large depression with grass feeding with nadir at 1200 to 1330 h. The increased net portal absorption and the decreased hepatic extraction resulted in an approximately six-fold increase in the arterial blood concentration of butyrate. The gut entry rate of urea accounted for 70 +/- 10% of the net hepatic production of urea. Saliva contributed to 14% of the total amount of urea recycled to the gut. Urea recycling to the gut was equivalent to 58% of the dietary nitrogen intake. Despite the severe undersupply of rumen degradable protein, the portal-drained viscera did not extract more than 4.3% of the urea supplied with arterial blood. This value is in line with the literature values for cows fed diets only moderately deficient in rumen degradable protein and indicates that cows maximise urea transfer across gut epithelia even when the diet is moderately deficient in rumen degradable protein. PMID- 22443565 TI - The potential for improving physiological, behavioural and immunological responses in the neonatal lamb by trace element and vitamin supplementation of the ewe. AB - Neonatal lamb mortality represents both a welfare issue (due to the considerable suffering and distress) and an important production inefficiency. In lambs, approximately 80% of mortality can be attributed to the starvation-mismothering exposure complex and occurs in the first 3 days after birth. It was the object of this review to determine the micronutrient(s) most likely to have a positive effect on neonatal lamb survival when included above the requirement for that micronutrient. Micronutrients discussed were Co, Cu, I, Fe, Mn, Se, Zn, vitamins A and E and n-3 fatty acids. For Co, Fe, Mn and Zn, there was no evidence of positive responses to supplementation. Cu and I had toxicity thresholds that were sufficiently close to requirement that supplementing above requirement presented a risk of inducing toxicity. In the case of vitamin A, while serum concentrations indicated that sub-optimal status did exist, long-term buffering from liver stores (from grazing) makes experimentation difficult and practical benefits to supplementation unlikely. Therefore, the most likely candidates for supplementation were Se, vitamin E and fatty acids. Fatty acid supplementation with fish oils or docosahexaenoic acid-containing algal biomass consistently improved lamb vigour but it is unlikely that supplementation will be economic. Positive responses to Se supplementation throughout gestation were recorded. However, in many studies the Se status of control ewes was marginal and there is a need for more studies where control ewes are clearly adequate in Se. Positive responses to vitamin E supplementation above requirement in the last-third of gestation were observed but the optimum dietary inclusion of vitamin E and period of feeding during pregnancy still require clarification. PMID- 22443566 TI - Adaptability of the digestive function according to age at weaning in the rabbit: I. Effect on feed intake and digestive functionality. AB - The functional adaptability of the digestive system to the level of feed intake was investigated in the young rabbits by comparing two groups of 12 litters each, weaned at 21 (W21) or 35 (W35) days of age. From 14 days onwards, rabbits were fed a pelleted feed (NDF: 332 g/kg, CP: 177 g/kg, starch: 98 g/kg, as-fed basis). Until 49 days of age, the profile of digestive enzymes was weekly determined in the small intestinal content and mucosa, as well as caecal fermentation traits and fibrolytic activities. In the W21 group, the solid feed intake was increased by 57% between 21 and 35 days (P < 0.01), while the daily body growth was lower from 21 till 42 days (-17%, P < 0.05) when compared with the W35 group. Activities of enzymes of pancreatic origin were only scarcely influenced by the weaning age. In the W21 group, amylase activity tended to be lower at 28 days of age (-36%, P = 0.064), and trypsin activity was decreased by 31% at 49 days of age (P < 0.01). Lipase activity was similar in both weaning groups. Duodenal and jejunal activities of maltase and aminopeptidase N (APN) were higher on day 28 in the W21 group as compared with the W35 group (*1.4 to *2.4, respectively, P < 0.05). On day 35, duodenal APN activity was twice as higher in the W21 group than in the W35 group (P < 0.01). In caecum, major differences between both weaning groups were observed at 28 days of age with a decrease in ammonia concentration ( 43%, P < 0.01) in W21 compared with W35 rabbits. Conversely, the acetate proportion was 5% higher in the W21 group (P < 0.01) on day 28. In conclusion, the digestive tract of early-weaned rabbits showed some adaptative properties in response to nutritional environment changes, but they were insufficient to maintain their growth rate. PMID- 22443567 TI - Adaptability of the digestive function according to age at weaning in the rabbit: II. Effect on nutrient digestion in the small intestine and in the whole digestive tract. AB - The ability of young rabbits to digest a solid diet was evaluated according to the weaning age: 21 (W21, 12 litters) or 35 (W35, 12 litters) days of age. From 14 days onwards, the rabbits were fed the same pelleted feed. Three methods were compared to estimate the faecal digestibility in the young rabbits, between 24 to 28 and 38 to 42 days. Digestive balance at ileal and faecal levels was determined for the main nutrients provided by milk and solid feed. The W21 rabbits increased their solid feed intake only 2 days after their weaning, when compared with suckling rabbits. Thus, their crude protein (CP) intake remained lower until 26 days compared with the W35 rabbits (from 41%, P < 0.01), as well as their crude fat intake until 28 days (from 72%, P < 0.001). On the contrary, the W35 rabbits increased their solid feed intake without a delay after weaning, quickly reaching the intake level of the W21 rabbits. The amounts of organic matter (OM) and CP reaching the caecum were increased on day 28 by 56% and 42% in the W21 rabbits compared with the W35 rabbits, respectively (P < 0.05), and were similar between groups on day 42. Starch ileal digestibility coefficients were 94.2% and 95.4% in 28- and 42-day-old rabbits, respectively, irrespective of the weaning age. The amount of starch flowing through the ileo-caecal junction was low and only tended to be higher on day 28 in the W21 group (0.20 v. 0.15 g/day in the W35 group, P = 0.10). The digestive balance pointed out that the digestible energy intake was similar between weaned and suckling rabbits from 23 to 27 days, a phenomenon partly explained by a high ability of the W21 rabbits to digest starch (98%) and NDF (36%). Indeed, the amounts of starch and NDF digested by the W21 group were 2.0- and 2.4-fold higher than those of the W35 rabbits at this period (P < 0.001). However, they ate 20% less digestible proteins than still-suckling rabbits (P < 0.001). From 38 till 42 days, only a lower ability of the W21 rabbits to digest lipids was detected (P < 0.05). In conclusion, early-weaned rabbits were able to adapt quickly to digest large amounts of starch and fibres. PMID- 22443568 TI - Effects of osmotic pressure on motility, plasma membrane integrity and viability in fresh and frozen-thawed buffalo spermatozoa. AB - In the first experiment, osmotic pressure of semen and seminal plasma in a semen sample from each of the 20 mature Nili-Ravi buffalo bulls was determined. In the second experiment, effects of osmotic pressure on motility (%), plasma membrane integrity (%) and viability (%) in fresh and frozen-thawed semen samples from each of the seven mature Nili-Ravi buffalo bulls was determined. In the first experiment, seminal plasma was harvested by centrifuging semen at 400 * g for 10 min at 37 degrees C and osmotic pressure was determined using an osmometer. In the second experiment, motility (%) was assessed in fresh and frozen-thawed (37 degrees C for 30 s) semen samples using a phase-contrast microscope (*400). Plasma membrane integrity (%) was determined by mixing 50 MUl each of fresh and frozen-thawed semen with 500 MUl of solution having an osmotic pressure of 50, 100, 150, 190 or 250 mOsm/l (hypotonic treatments of fructose + sodium citrate) and incubating at 37 degrees C for 1 h. Viability (%) of fresh and frozen-thawed spermatozoa before and after challenging them to osmotic pressure (hypotonic treatments) was assessed using supravital stain under a phase-contrast microscope (*400). In the first experiment, the mean +/- s.e. osmotic pressures of the buffalo semen and seminal plasma were 268.8 +/- 1.17 and 256.0 +/- 1.53 mOsm/l, respectively. In the second experiment, motility (%) decreased (P < 0.05) in frozen-thawed semen samples as compared with fresh semen (60.1 +/- 1.34 v. 81 +/- 1.57, respectively). The plasma membrane integrity (%) and magnitude of osmotic stress in fresh and frozen-thawed semen samples was higher (P < 0.05) at 50, 100, 150 and 190 mOsm/l as compared with 250 mOsm/l. Loss of viability (%) in fresh and frozen-thawed semen samples was higher (P < 0.05) at 50 mOsm/l (59% in fresh, 70% frozen thawed) as compared with other osmotic pressures, while it was lowest at 250 mOsm/l (4.1% for fresh, 9.7% frozen thawed). In conclusion, osmotic pressure of Nili-Ravi buffalo semen and seminal plasma is determined. Furthermore, variation in osmotic pressure below 250 mOsm/l is not favorable to fresh and frozen-thawed buffalo spermatozoa. PMID- 22443569 TI - Effect of season on luteal activity during the post partum period of dairy cows in temperate areas. AB - Seasonal effects on luteal activity during post partum were evaluated in two consecutive studies in 253 dairy cows in Northern Italy. In study 1, plasma progesterone concentrations were determined on days 14, 21, 28, 35, 42, 49 and 56 post partum and in study 2 cows were synchronized and inseminated at a fixed time using two regimes based on the 'Ovsynch' protocol. Study 1: Animals were classified as luteal (progesterone >1.5 ng/ml in at least two consecutive samples) or non-luteal (progesterone <1.5 ng/ml in all samples). The proportion of cows without luteal activity from calving to day 56 post partum was 47/253 (18.5%). Of the 47 cows without luteal activity, 42 (89%) were detected during the warm months of the year and five were detected during the cold months of the year, and the effect of season was highly significant (P < 0.001). Study 2: Three study groups were established; control (CONT, untreated cows, n = 92), GPG (cows receiving gonadotropin-releasing hormone (GnRH) on day 0, PGF2alpha on day 7 followed by a second dose of GnRH 24 h later, n = 80); and HPH (the same as the GPG group, but with human chorionic gonadotropin (hCG) substituted for GnRH, n = 81). In the GPG and HPH groups, cows were inseminated 16 to 22 h after the second GnRH or hCG injection. Untreated cows were inseminated at first estrus after a voluntary weaning period. Because the effects of the GPG and HPH regimes on pregnancy rate were not significantly different, data were pooled into a single treatment group (TREAT). Pregnancy rates during the warm months of the year were 16% and 15% at first service and 65% and 66% at day 135 post partum for CONT and TREAT groups, respectively. Pregnancy rates during the cold months of the year were 36% and 38% at first service and 72% and 76% at day 135 post partum for CONT and TREAT groups, respectively. There was an effect of season (P < 0.05) but not of treatment on pregnancy rate. Treatment reduced the number of days from calving to conception during both the cold (101 +/- 3.2 v. 121 +/- 3.1 days; P < 0.001) and warm seasons (122 +/- 3.2 v. 145 +/- 3.1 days; P < 0.001). In conclusion, the present study shows that (i) heat stress during the warm season can compromise luteal activity and (ii) that regimes based on the Ovsynch protocol did not improve pregnancy rate at first service or by 135 post partum, but they had a positive effect on the calving-to-conception interval. PMID- 22443570 TI - Use of linear and non-linear functions to describe the growth of young sport- and race-horses born in Normandy. AB - The objectives of this study were to establish standards for growth and to model the evolution of wither height (WH) between birth and adult age in different breeds of sport- and race-horses. Therefore, 398 foals, then yearlings of three different breeds, were measured regularly between birth and 18 months of age. Linear and non-linear functions were compared for describing the growth in each breed group. The monomolecular, Gompertz, logistic and cubic models correctly estimated WH in the three breeds during the first 2 years (R2 = 0.99, s.e. 3.9 to 4.5) and better than the cubic and quadratic models (R2 = 0.93, s.e. = 4.7 to 5.3). The logarithmic and power model seemed better in the last part of the growth period (2 to 6 years, R2 = 0.85, s.e. = 5.6 to 5.9). The linear model did not fit with data on most of the growth period. Comparison of the growth in the three breeds using these models confirmed that race-horses had an intense growth in their first months whereas sport-horses had a more regular growth prolonged in their first years of life. PMID- 22443571 TI - Goat's alphaS1-casein polymorphism affects gene expression profile of lactating mammary gland. AB - Goat's alphaS1-casein (CSN1S1) polymorphism has a significant effect on milk protein and lipid composition, which affects the nutritional quality and technological properties of milk. Moreover, this polymorphism has a large impact on the morphology of mammary epithelial cells. To explore the metabolic pathways modulated in relation to this polymorphism, we compared the mammary gene expression profiles of two groups of lactating goats carrying either two reference or two defective alleles, using a bovine oligonucleotide microarray representing 8379 genes. We identified 41 differentially expressed genes between the two genotype groups. In particular, we showed a downregulation of two key lipogenic genes encoding fatty acid synthase and glycerol-3-phosphate acyltransferase in agreement with the low fat concentration associated with CSN1S1 deficiency. In addition, this study highlights changes in the expression level of several genes known to influence membrane fluidity, cell-cell interaction or chromatin organization. Our results open up new fields of investigation on structural modifications associated with CSN1S1 deficiency that could affect mammary gland function. PMID- 22443572 TI - Late foetal life nutrient restriction and sire genotype affect postnatal performance of lambs. AB - This experiment investigates the effects of maternal nutrient restriction in late gestation on the offsprings' postnatal metabolism and performance. Forty purebred Shropshire twin lambs born to ewes fed either a high-nutrition diet (H) (according to standard) or a low-nutrition (L) diet (50% during the last 6 weeks of gestation) were studied from birth until 145 days of age. In each feeding group, two different sires were represented, 'growth' (G) and 'meat' (M), having different breeding indices for the lean : fat ratio. Post partum all ewes were fed the same diet. Lambs born to L-ewes had significantly lower birth weights and pre-weaning growth rates. This was especially pronounced in L-lambs born to the M ram, which also had markedly lower pre-weaning glucose concentrations than the other three groups of lambs. L-lambs converted milk to live weight with an increased efficiency in week 3 of life. Their glucose concentrations and growth rates were both increased. Plasma glucose concentrations in LM-lambs became similar to those observed in H-lambs post-weaning. However, LM-lambs continued to be lighter than the other groups throughout the experimental period and were unable to compensate for the reduced weight at birth despite having the highest daily fractional growth rates. LG-lambs had the highest plasma glucose concentrations of all four groups of lambs, and they indeed reached body weights comparable to those of the H-lambs by 145 days of age. The increased growth rate post-weaning in L-lambs was not reflected in fat deposition, as L-lambs had lower fat deposition than H-lambs. This may relate to the lower plasma insulin levels found in the L-lambs than in the H-lambs. In conclusion, a 50% reduction of maternal nutrient supply in the last 6 weeks of gestation reduces the birth weight and pre-weaning growth of the offspring due to lower milk intake. Growth rates can be restored when an adequate post-weaning diet is provided, but the prenatal nutrition may programme postnatal metabolism differentially depending on genotype, thus affecting the ability of the ad libitum-fed lamb to achieve a given body weight by a certain age. PMID- 22443573 TI - Plasma concentration of leptin and ghrelin in Standardbred foals as related to the age, sex, exercise and training. AB - The effect of acute exercise was studied in a group of 42 clinically healthy young Standardbred trotters. These trotters had been divided into four groups according to their age. Their ages were from 1.5 to 3 years. Three jugular venous blood samples were collected via venipuncture from each horse. These samples were collected while (1) at rest, (2) after the end of the exercise and (3) 30 min after the end of the exercise. Exercise showed a significant increase in plasma leptin concentration (3.8 +/- 0.31 at rest v. 4.3 +/- 0.37 just after exercise and 4.4 +/- 0.47 ng/ml after a 30-min rest; ANOVA P < 0.05). The difference between values obtained 30 min after exercise and at rest was significantly greater in 1.5-year-old horses than in those aged 2.5 years (+1.3 +/- 0.43 v. +0.1 +/- 0.15 ng/ml; ANOVA P < 0.05). The mean plasma leptin concentration was higher in fillies than in colts (4.9 +/- 0.47 v. 3.5 +/- 0.36 ng/ml; ANOVA P < 0.05). A positive correlation between the plasma concentrations of leptin and triacylglycerides measured just after exercise was detected (r = 0.65). The acute exercise significantly increased the plasma concentration of ghrelin that was measured just after exercise (1255 +/- 55.9 v. 1127 +/- 54.2 pg/ml; ANOVA P < 0.05). The exercise-induced age-related changes in the plasma ghrelin concentration were significantly lower in 2.5-year-old trotters than in 1.5-year olds. To sum up, the changes in plasma leptin and ghrelin concentrations during bouts of exertion tend to decrease with age and/or training of Standardbred foals. PMID- 22443574 TI - Effect of pregnancy and feeding level on cell turnover and expression of related genes in the mammary tissue of lactating dairy cows. AB - Milk yield is reduced by pregnancy, and the present experiment was conducted to study the biological basis for the negative effect of pregnancy on milk yield. A total of 16 dairy cows were fed at either a normal or a low feeding level (eight cows per treatment), and half of them were inseminated after approximately 3 months of lactation and the other half were not inseminated. Mammary biopsies were taken at approximately 9 months of lactation. The milk yield of pregnant cows was reduced by 2.6 kg/day, and lactation persistency was reduced already from the time of insemination. Low feeding level reduced the milk yield by 9.8 kg/day from week 8 to week 39 of lactation, whereas no interaction between pregnancy and feeding level was found. Cell proliferation (Ki-67) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) were unaffected by feeding level, and pregnancy tended to reduce cell proliferation but had no effect on apoptosis. Reduced cell proliferation may explain the reduced lactation persistency in pregnant cows. Transcription of oestrogen receptor alpha, progesterone receptor A and B, and long and short isoforms of the prolactin receptor were higher in pregnant cows compared with non-pregnant cows. Feeding level did not mediate changes in transcription of genes. Transcription of other cell-turnover-related genes (IGF-I, IGF binding protein-5, caspase-3) as well as genes related to the secretory activity of the cells (alpha-lactalbumin and acetyl CoA carboxylase alpha) was not affected by pregnancy or by feeding level. PMID- 22443575 TI - Osmolarity and composition of cell culture media affect further development and survival in zebrafish embryos. AB - With the aim of carrying out chimaerism and somatic cell-midblastula transition (MBT) embryos co-culture experiments in freshwater fish species, we evaluated the effect of osmolarity and composition of two media commonly used in cell fish culture on MBT zebrafish embryos and their further development and survival. To this end, wild zebrafish dechorionated embryos in midblastula stage were cultured for 6 days (Experiment 1: 189 embryos) or 1 h (Experiment 2: 150 embryos) in three different media: Hanks' 10% (H-10), 35 mOsm; Hanks' 100% (CH), 315 mOsm; and L-15 with serum (L-15: 315 mOsm). High osmolarity affected the survival rate (6 days: L-15: 45.1% v. CH: 72.34% v. H-10: 100%, P < 0.05; after 6 days: 0% both in L-15 and CH) and slowed their developmental timing. Embryos showed tail deformation (curly) as well as body paralysis at 48 h when they showed tail movements at 28 h. Differences in tail deformation were observed between high osmolarity groups (CH: 85.10% v. L-15: 98.04%; P < 0.05). In Experiment 2, no effects on survival rate were observed. Teratogenic effects were only observed in L-15 (L-15: 12.98% v. CH: 0%; P< 0.05). Loss of motility was not detected in any group at 48 h. Optimum osmolar condition for cultured cells and also embryonic cells is around 315 mOsm and so, during chimaerism experiments (usually practised at MBT stage), present results indicate that midblastula embryos can acceptably bear the effects caused by 315 mOsm (CH) for 1 h, even though this involves a certain delay in developmental timing. PMID- 22443576 TI - Modelling feeding behaviour, rate of feed passage and daily feeding cycles, as possible causes of fatigued pigs. AB - This study was initiated to understand whether feeding behaviour and physiology may contribute to the rate of fatigued pigs at processing plants. Specifically, this study sought to determine: (1) how often pigs eat during the day, (2) the times of the day they eat and (3) a first approximation of the time from feed consumption to excretion (rate of passage) when housed in a group in conventional finishing facilities. Finally, models were constructed to try to predict the percentage of pigs with empty/diminished gastrointestinal (GI) tracts depending on the time of day of truck loading and transport durations. Pigs were randomly selected, weighed and selected for behavioural observations. From video records and live observations, the number of meals (feeding bouts) per day and the time of the day meals took place were recorded. Feed containing chromic oxide was fed to determine when a given meal was excreted. With the feeding times of day determined, models were constructed of the percentage of pigs that would have empty stomachs depending on the time of day pigs were removed from the barn and the length of transport/lairage. Finishing pigs housed in groups ate 5.6 +/- 0.6 meals per day with an average feeding bout (meal) length of 11.3 +/- 1.1 min. Many pigs fed ad libitum ate most of their meals during the afternoon and evening. The rate of passage of feed was 20.5 h (range = 18 to 24 h). Because fewer pigs ate in the late evening through morning, if pigs were shipped at these times they would have an increased risk of arriving at the stun at a plant with an empty GI tract. Some of the variation in rates of fatigued pigs and pork quality may be explained by times of day taken off feed and transport duration. Shipping in the afternoon or early evening may result in fewer pigs with empty/diminished GI tracts at processing which may influence the rate of fatigued pigs and pork quality. PMID- 22443577 TI - The effect of shearing procedures on blood levels of growth hormone, cortisol and other stress haematochemical parameters in Sarda sheep. AB - The aim of this research was to investigate how growth hormone (GH) cortisol and some haematochemical parameters could be modified by the stress caused by the stages of shearing in Sarda breed sheep. Five groups of 10 sheep each were formed. Group A, only separated from the flock; Group B, only tied; Group C, both tied and shorn (animals in these three groups were ewe lambs shorn for the first time); Group D, adult females both tied and shorn; and Group E, adult entire males both tied and shorn (animals in these two groups had been shorn previously). Five blood samples were taken from each animal: the day before treatment (first sample); at the start of the treatment (second sample); in the middle of shearing for Groups C, D and E, 10 min after separation in Group A and 10 min after tying in Group B (third sample); at the end of treatment (fourth sample); and on the day after treatment (fifth sample). Plasma GH levels showed a decrease (P < 0.01) in Groups A, B, C and D during treatment (third and fourth samples), while Group E only at the end of shearing (fourth sample). In the third sample, the highest GH levels were recorded for Group E (P < 0.05), while it was recorded in the fourth sample for Groups A and E (P < 0.05). Cortisol levels showed a clear increase (P < 0.01) in all groups during treatment, but Group A showed a decrease in the fourth sample in comparison to the third sample. Males in the second, third and fourth sample and Group A only in the fourth sample showed lower cortisol levels when compared with the other groups (P < 0.05). Plasma glucose levels showed an increase (P < 0.01) in all groups during treatment but Groups B, C and E showed the highest values (P < 0.05). Magnesium (Mg) showed an increase in all groups in the third and fourth sample, while sodium (Na), in the same samples, only in Groups B, C and D. Potassium (K) values showed a significant decrease (P < 0.05) only in Groups C and D at the end of shearing. These results show that GH secretion is influenced by all the stress procedure: separation, tying and shearing. Shearing, even if necessary for animals, causes a significant change of the blood parameters involved in the stress response. PMID- 22443578 TI - Prevalence of, and risk factors associated with, perinatal calf mortality in pasture-based Holstein-Friesian cows. AB - Recent publications indicate that the prevalence of perinatal mortality has increased in some dairy industries and an increased proportion of this loss is not associated with the traditional risk factors for perinatal mortality. The objectives of this study were to establish the prevalence of perinatal mortality (calf death within 24 h of calving) in Irish dairy herds and to determine the current significance of putative risk factors in pasture-based management systems. A total of 182 026 records of full-term calvings from Holstein-Friesian dams served by artificial insemination (AI) sires of seven breeds in herds of 20 calvings or more per year were available from the Irish national breeding database over 4 years (2002 to 2005). The prevalence of perinatal mortality was 4.29% (7.7% in primiparae and 3.5% in pluriparae). The likelihood of perinatal mortality increased between 2002 and 2005 and was greatest in June and in winter. There was an interaction (P < 0.001) between the effect of calving assistance and parity with the effect of dystocia on perinatal mortality being greater in primiparae. The odds of perinatal mortality were greater in male (OR = 1.12; P < 0.001) and in twin calves (OR = 5.70-13.36; P < 0.001) and in dams that had perinatal mortality at the previous calving (OR = 4.21; P < 0.001). The logit of the probability of perinatal mortality increased by 0.099 per unit increase in sire predicted transmitting ability (PTA) for direct perinatal mortality. The probability of perinatal mortality increased at an increasing rate in primiparae as animals calved at a younger age relative to the median age at first calving. The only herd-level factor examined, herd size did not affect the odds of perinatal mortality. These data indicate that the prevalence of perinatal mortality in this cattle population is similar to that in other pasture-based dairy systems worldwide. The putative exposures and attributes traditionally associated with perinatal mortality were associated with perinatal mortality in this pasture-based dairy cow population. The practical implication of these results is that as many of the significant risk factors are largely not under management control (year of calving, month of calving, twin calving, primiparity, previous perinatal mortality and foetal gender), herd owners must focus on the significant determinants under their control (age at first calving, sire genetic merit for direct perinatal mortality and both the extent of calving supervision and the degree of assistance), in order to reduce the prevalence of perinatal mortality and improve perinatal welfare. PMID- 22443579 TI - Chemical composition and oxidative status of tissues from Iberian pigs as affected by diets: extensive feeding v. oleic acid- and tocopherol-enriched mixed diets. AB - The present work was intended to analyse the chemical composition and oxidative stability of the muscle biceps femoris and adipose tissues from Iberian pigs fed different finishing diets: free-range feeding on grass and acorns in a 'Montanera' traditional system (MON), fed in confinement with a mixed diet containing high-oleic sunflower oil (115 g/kg of diet) and supplemented with 250 mg/kg alpha-tocopherol (HOVE), and fed in confinement with a tocopherol-non supplemented control mixed diet (CON). Muscles from MON pigs contained significantly (P < 0.05) higher amounts of intramuscular fat than those from HOVE and CON pigs. Muscles from MON and HOVE pigs had significantly higher levels of alpha-tocopherol than muscles from CON pigs whereas free-range feeding provided significantly higher levels of gamma-tocopherol to muscles from MON pigs than the experimental diets did to CON and HOVE pigs. Adipose tissues from MON and HOVE pigs contained significantly lower proportions of saturated fatty acids and significantly higher levels of oleic acid and monounsaturated fatty acids than those from CON pigs. Tissues from MON pigs contained significantly smaller levels of polyunsaturated fatty acids than those from CON and HOVE pigs. To a higher extent, feeding background affected the fatty acid composition of polar lipids from the muscle biceps femoris than that of neutral lipids. Tissues from MON pigs contained significantly smaller omega-6/omega-3 values than those from pigs fed mixed diets. Compared to tissues from CON pigs, those from MON and HOVE pigs exhibited a higher oxidative stability as a likely result of a most favourable fatty acid composition and the presence of higher tocopherol levels. PMID- 22443580 TI - Influence of a preen gland secretion on growth and meat quality of heavy broilers. AB - Preen gland secretions were obtained from several hens that were rearing their chicks and the content of these secretions was analysed. From these results, a synthetic analogue of the secretions was created (given the title Mother Hen Uropygial Secretion Analogue, or MHUSA, in this study). According to a blinded, controlled experimental design, heavy broilers (strain SASSO T56N) were reared from 1 day of age in an environment treated with either MHUSA or control. At 80 days the birds were slaughtered. Post mortemcarcass weight, abdominal fat and fillet weights were then measured. Colour, pH and yield were also measured as indicators of meat quality. Broilers exposed to MHUSA had both higher carcass weights and higher fillet weights compared with control-treated birds (P < 0.05). Abdominal fat, pH, water loss and colorimetry results were similar between the treatment groups at all time points (24 h and 6 days post mortem) and also after a cooking procedure. The meat from the MHUSA birds was less yellow compared with control. It is concluded that constant exposure to MHUSA from rearing until slaughter improves growth rate in broilers without significantly affecting meat quality. PMID- 22443581 TI - Substitution of dietary oleic acid for myristic acid increases the tissue storage of alpha-linolenic acid and the concentration of docosahexaenoic acid in the brain, red blood cells and plasma in the rat. AB - Various strategies have been developed to increase the cellular level of (n-3) polyunsaturated fatty acids in animals and humans. In the present study, we investigated the effect of dietary myristic acid, which represents 9% to 12% of fatty acids in milk fat, on the storage of alpha-linolenic acid and its conversion to highly unsaturated (n-3) fatty acid derivatives. Five isocaloric diets were designed, containing equal amounts of alpha-linolenic acid (1.3% of dietary fatty acids, i.e. 0.3% of dietary energy) and linoleic acid (7.0% of fatty acids, i.e. 1.5% of energy). Myristic acid was supplied from traces to high levels (0%, 5%, 10%, 20% and 30% of fatty acids, i.e. 0% to 6.6% of energy). To keep the intake of total fat and other saturated fatty acids constant, substitution was made with decreasing levels of oleic acid (76.1% to 35.5% of fatty acids, i.e. 16.7% to 7.8% of energy) that is considered to be neutral in lipid metabolism. After 8 weeks, results on physiological parameters showed that total cholesterol and low-density lipoprotein-cholesterol did not differ in the diets containing 0%, 5% and 10% myristic acid, but were significantly higher in the diet containing 30% myristic acid. In all the tissues, a significant increasing effect of the substitution of oleic acid for myristic acid was shown on the level of both alpha-linolenic and linoleic acids. Compared with the rats fed the diet containing no myristic acid, docosahexaenoic acid significantly increased in the brain and red blood cells of the rats fed the diet with 30% myristic acid and in the plasma of the rats fed the diet with 20% myristic acid. Arachidonic acid also increased in the brain of the rats fed the diet with 30% myristic acid. By measuring Delta6-desaturase activity, we found a significant increase in the liver of the rats fed the diet containing 10% of myristic acid but no effect at higher levels of myristic acid. These results suggest that an increase in dietary myristic acid may contribute in increasing significantly the tissue storage of alpha-linolenic acid and the overall bioavailability of (n-3) polyunsaturated fatty acids in the brain, red blood cells and plasma, and that mechanisms other than the single Delta6-desaturase activity are involved in this effect. PMID- 22443582 TI - 9 cis,11 trans conjugated linoleic acid (CLA) is synthesised and desaturated into conjugated 18:3 in bovine adipose tissues. AB - Although endogenous synthesis of conjugated linoleic acid (CLA) in the mammary gland of lactating cows has been already well documented, no study has determined so far as to which tissue and/or organ is involved in CLA synthesis in the growing ruminant except one study showing that CLA synthesis does not occur in ruminant liver. In this context, adipose tissue appears to be a good candidate for endogenous synthesis of CLA in the growing ruminant. The aim of this study was to compare the respective metabolisms of 11trans 18:1 (vaccenic acid, VA) and 9cis,11trans 18:2 (rumenic acid) to that of stearic acid (the preferential substrate of Delta9 desaturase) in adipose tissues (subcutaneous, SC and intermuscular, IM) of six Charolais steers by using the in vitromethod of incubated tissue slices. Samples of SC and IM adipose tissues were incubated at 37 degrees C for 16 h under an atmosphere of 95% O2/5% CO2 in a medium supplemented with 0.75 mM of fatty acid (FA) mixture (representative of circulating non-esterified FA) and 186 MUM [1-14C]-18:0 or 58.6 MUM [1-14C]-VA or 56 MUM [1-14C]-9cis,11trans CLA. Viability of explants was verified by measuring metabolic functions (glucose uptake and glucose-6-phosphate dehydrogenase activity). After 16 h of incubation, FA uptake was similar for all FA (18:0, VA and 9cis,11trans 18:2) in both SC and IM adipose tissues (around 40%). Once in adipose tissue, all FA were preferentially esterified (>80% of cell FA) favouring neutral lipid synthesis (around 90% of esterified FA). Stearic acid was highly (27%) desaturated into oleic acid in SC adipose tissue whereas this desaturation was much lower (6.8%) in IM adipose tissue (P < 0.0001). VA was desaturated into 9cis,11trans CLA at a low extent of about 2.5% to 4.4% in both adipose tissues probably because of a limited affinity of Delta9 desaturase for VA. 9cis,11trans CLA was itself converted by desaturation into 6cis, 9cis,11trans 18:3 at the intensity of 10.8% and 14.5% of cell 9cis,11trans CLA in SC and IM adipose tissues, respectively. In conclusion, bovine adipose tissues of the growing ruminant were especially involved in the endogenous synthesis of CLA from VA and in its desaturation into conjugated derivative, mainly 6cis, 9cis,11trans 18:3, of which biological properties need to be elucidated. PMID- 22443584 TI - Molecular targeting regulation of proliferation and differentiation of the bone marrow-derived mesenchymal stem cells or mesenchymal stromal cells. AB - The bone marrow-derived mesenchymal stem cells or mesenchymal stromal cells (MSCs), with pluripotent differentiation capacity, present an ideal source for cell transplantation or tissue engineering therapies, but exact understanding of regulating mechanism underling MSC proliferation and differentiation remains a critical issue in securing their safe and efficient clinical application. This review outlines current knowledge regarding MSC cell surface biomarkers and molecular mechanisms of MSC differentiation and proliferation with emphasis on Wnt/beta-catenin signaling, Notch signaling pathway, bone morphogenesis proteins and various growth factors functioning in regulation of differentiation and proliferation of MSCs. Possible relation of oncogene and immunosuppressive activities of MSCs with tumorigenicity or tumor generation is also addressed for safe translational clinical application. Fast increase of MSC knowledge and techniques has led to some successful clinical trials and helped devising new tissue engineering therapies for bone and cartilage diseases that severely afflict human health. Production of adult MSC-derived functional neurons can further extend their therapeutic application in nerve injury and neurodegenerative diseases. It is promising that MSCs shall overcome ethical and immunorejection problems appeared in human embryonic stem cells, and specific molecular targeting manipulation may result in practical MSC therapy for personalized treatment of various diseases in the regeneration medicine. PMID- 22443585 TI - A new fluorometric turn-on detection of L-lactic acid based on the cascade enzymatic and chemical reactions and the abnormal fluorescent behavior of silole. AB - By making use of the aggregation-induced emission feature of silole 1 and the cascade reactions among l-lactic acid (LA), lactate oxidase (LOD), and dodecanoic hydrazine (DH), a new fluorometric "turn-on" method is developed for the detection of LA. PMID- 22443586 TI - 7-Ethynylcoumarins: selective inhibitors of human cytochrome P450s 1A1 and 1A2. AB - To discover new selective mechanism-based P450 inhibitors, eight 7 ethynylcoumarin derivatives were prepared through a facile two-step synthetic route. Cytochrome P450 activity assays indicated that introduction of functional groups in the backbone of coumarin could enhance the inhibition activities toward P450s 1A1 and 1A2, providing good selectivity against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin (7ETMC) showed IC(50) values of 0.46 MUM and 0.50 MUM for P450s 1A1 and 1A2 in the first six minutes, respectively, and did not show any inhibition activity for P450s 2A6 and 2B1 even at the dose of 50 MUM. All of the inhibitors except 7-ethynyl-3-methyl-4 phenylcoumarin (7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2. In order to explain this mechanistic difference in inhibitory activities, X-ray crystallography data were used to study the difference in conformation between 7E3M4PC and the other compounds studied. Docking simulations indicated that the binding orientations and affinities resulted in different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC with its two-plane structure fits into the P450 1A2's active site cavity with an orientation leading to no reactive binding, causing it to act as a competitive inhibitor. PMID- 22443587 TI - Two-dose exposure of intra-arterial chemotherapy for group D retinoblastoma. AB - The authors present a case of group D unilateral sporadic retinoblastoma treated with only two intra-arterial chemotherapy cycles using melphalan, which resulted in tumor regression, resolution of subretinal fluid, and, most importantly, salvage of the life, and the eye. PMID- 22443588 TI - Laparoscopic extravesical ureteral reimplantation with diverticulectomy for refluxing ureters associated with paraureteral diverticula. PMID- 22443589 TI - Overexpression of mltA in Edwardsiella tarda reduces resistance to antibiotics and enhances lethality in zebra fish. AB - AIMS: The aim of this study was to investigate the role of membrane-bound lytic murein transglycosylase A (MltA) in a bacterial fish pathogen Edwardsiella tarda. METHODS AND RESULTS: An mltA in-frame deletion mutant (DeltamltA) and an mltA overexpression strain (mltA(+)) of Edw. tarda were constructed through double crossover allelic exchange and by transformation of a low-copy plasmid carrying the intact mltA into the DeltamltA mutant, respectively. Either inactivation or overexpression of MltA in Edw. tarda resulted in elevated sensitivity to beta lactam antibiotics and lower viability in oligotrophic or high osmotic environment than wild-type strain. Autolysis induced by EDTA was reduced in DeltamltA strain, while mltA(+) strain was virtually flimsy, indicating that MltA is responsible for the lysis effect. Moreover, mltA(+) strain exhibited significant increases in lipopolysaccharide (LPS) biosynthesis and virulence to zebra fish compared with wild-type strain. CONCLUSIONS: The results indicated that MltA plays essential roles in beta-lactam antibiotics and environmental stresses resistance, autolysis, LPS biosynthesis and pathogenicity of Edw. tarda. This is the first report that MltA has a virulence-related function in Edw. tarda. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provided useful information for further studies on pathogenesis of Edw. tarda. PMID- 22443590 TI - Advances in microbial ecosystem concepts and their consequences for ruminant agriculture. AB - Microbial transformations in the rumen ecosystem have a major impact on our ability to meet the challenge of reducing the environmental footprint of ruminant livestock agriculture, as well as enhancing product quality. Current understanding of the rumen microbial ecosystem is limited, and affects our ability to manipulate rumen output. The view of ruminal fermentation as the sum of activities of the dominant rumen microbiota is no longer adequate, with a more holistic approach required. This paper reviews rumen functionality in the context of the microbiota of the rumen ecosystem, addressing ruminal fermentation as the product of an ecosystem while highlighting the consequences of this for ruminant agriculture. Microbial diversity in the rumen ecosystem enhances the resistance of the network of metabolic pathways present, as well as increasing the potential number of new pathways available. The resulting stability of rumen function is further promoted by the existence of rumen microbiota within biofilms. These protected, structured communities offer potential advantages, but very little is currently known about how ruminal microorganisms interact on feed-surfaces and how these communities develop. The temporal and spatial development of biofilms is strongly linked to the availability of dietary nutrients, the dynamics of which must also be given consideration, particularly in fresh-forage-based production systems. Nutrient dynamics, however, impact not only on pathway inputs but also the turnover and output of the whole ecosystem. Knowledge of the optimal balance of metabolic processes and the corresponding microbial taxa required to provide a stable, balanced ecosystem will enable a more holistic understanding of the rumen. Future studies should aim to identify key ecosystem processes and components within the rumen, including microbial taxa, metabolites and plant based traits amenable to breeding-based modification. As well as gaining valuable insights into the biology of the rumen ecosystem, this will deliver realistic and appropriate novel targets for beneficial manipulation of rumen function. PMID- 22443591 TI - Gut microbiology - broad genetic diversity, yet specific metabolic niches. AB - Analysis of 16S ribosomal RNA (rRNA)-encoding gene sequences from gut microbial ecosystems reveals bewildering genetic diversity. Some metabolic functions, such as glucose utilisation, are fairly widespread throughout the genetic spectrum. Others, however, are not. Despite so many phylotypes being present, single species or perhaps only two or three species often carry out key functions. Among ruminal bacteria, only three species can break down highly structured cellulose, despite the prevalence and importance of cellulose in ruminant diets, and one of those species, Fibrobacter succinogenes, is distantly related to the most abundant ruminal species. Fatty acid biohydrogenation in the rumen, particularly the final step of biohydrogenation of C18 fatty acids, stearate formation, is achieved only by a small sub-group of bacteria related to Butyrivibrio fibrisolvens. Individuals who lack Oxalobacter formigenes fail to metabolise oxalate and suffer kidney stones composed of calcium oxalate. Perhaps the most celebrated example of the difference a single species can make is the 'mimosine story' in ruminants. Mimosine is a toxic amino acid found in the leguminous plant, Leucaena leucocephala. Mimosine can cause thyroid problems by being converted to the goitrogen, 3-hydroxy-4(1H)-pyridone, in the rumen. Observations that mimosine-containing plants were toxic to ruminants in some countries but not others led to the discovery of Synergistes jonesii, which metabolises 3-hydroxy 4(1H)-pyridone and protects animals from toxicity. Thus, despite the complexities indicated by molecular microbial ecology and genomics, it should never be forgotten that gut communities contain important metabolic niches inhabited by species with highly specific metabolic capability. PMID- 22443592 TI - Effects of feed additives on the development on the ileal bacterial community of the broiler chicken. AB - Intensifying concerns about the use of antimicrobials in meat and poultry production has enhanced interest in the application of prebiotics, probiotics and enzymes to enhance growth and prevent disease in food animals. Growth-promoting antibiotics enhance growth of animals by reducing the load of bacteria in the intestine, by reducing colonization by intestinal pathogens or by enhancing the growth and/or metabolism of beneficial bacteria in the intestine. Recently, molecular ecology, utilizing DNA-sequence heterogeneity of the 16S rRNA gene, has revealed a surprising diversity of uncharacterized bacteria inhabiting this ecosystem. We used this approach to determine the effect of growth-promoting antibiotics on the development and composition of the ileal bacterial community. Pairwise comparisons, correspondence analysis and community diversity indices revealed significant differences among the treatments (bacitracin/virginiamycin or monensin) and controls. Antibiotics reduced the diversity of the ileal bacterial community and induced communities rich in Clostridia throughout the life of the broiler chicken. These results indicate that some bacterial species, such as lactobacilli, were suppressed and also suggest that many intestinal Clostridia may be non-pathogenic. Future studies should focus on characterizing the important bacterial species needed to stabilize the intestinal microbiota and identifying those commensals that stimulate and enhance development of intestinal function. PMID- 22443593 TI - Digestion of fatty acids in ruminants: a meta-analysis of flows and variation factors. 1. Total fatty acids. AB - A database built from 95 experiments with 303 treatments was used to quantify the ruminal biohydrogenation (BH) of fatty acids (FA), efficiency of microbial protein synthesis (EMPS), duodenal flow and intestinal absorption of total FA and of FA with 12 to 18 C units, in response to variations in dietary FA content, source or technological treatment of fat supplement. Flows of FA were expressed relative to dry matter intake (DMI) to compile data from bovine and ovine species. BH tended to increase curvilinearly with FA intake, whereas dietary FA did not affect EMPS. A linear relationship between FA intake and duodenal flow of total FA was obtained, with a coefficient of 0.75 +/- 0.06 g duodenal FA/kg DMI for each g FA intake/kg DMI. Between experiments, positive balances of total FA (intake - duodenum) were related to low EMPS. Relationships between duodenal flows of FA with 12 to 18 C units and their respective intakes were linear, with a coefficient that increased with the number of C units. Duodenal flow of bacterial FA was linearly related to FA intake (coefficient 0.33 +/- 0.13), whereas contribution of bacterial lipid to duodenal flow decreased as FA intake increased. For each FA with 12 to 16 C units, prediction of FA absorption from its respective duodenal flow was linear. For total FA and FA with 18 C units, apparent absorption levelled off at high duodenal flows. All these relationships were discussed according to current knowledge on microbial metabolism in the rumen and on the intestinal digestibility of FA in the intestine. PMID- 22443594 TI - Digestion of fatty acids in ruminants: a meta-analysis of flows and variation factors: 2. C18 fatty acids. AB - In ruminants, dietary lipids are extensively hydrogenated by rumen micro organisms, and the extent of this biohydrogenation is a major determinant of long chain fatty acid profiles of animal products (milk, meat). This paper reports on the duodenal flows of C18 fatty acids and their absorption in the small intestine, using a meta-analysis of a database of 77 experiments (294 treatments). We established equations for the prediction of duodenal flows of various 18-carbon (C18) fatty acids as a function of the intakes of their precursors and other dietary factors (source and/or technological treatment of dietary lipids). We also quantified the influence of several factors modifying rumen metabolism (pH, forage : concentrate ratio, level of intake, fish oil supplementation). We established equations for the apparent absorption of these fatty acids in the small intestine as a function of their duodenal flows. For all C18 unsaturated fatty acids, apparent absorption was a linear function of duodenal flow. For 18:0, apparent absorption levelled off for high duodenal flows. From this database, with fatty acid flows expressed in g/kg dry matter intake, we could not find any significant differences between animal categories (lactating cows, other cattle or sheep) in terms of rumen metabolism or intestinal absorption of C18 fatty acids. PMID- 22443595 TI - Increasing sodium bicarbonate level in high-concentrate diets for heifers. I. Effects on intake, water consumption and ruminal fermentation. AB - Four ruminally fistulated Holstein heifers (BW = 264 +/- 12 kg) were used in a 4 * 4 Latin square design experiment to determine the effect of increasing levels of sodium bicarbonate (BICARB; 0%, 1.25%, 2.50% and 5%, on concentrate dry matter (DM) basis) on DM intake (DMI), water consumption and ruminal fermentation. Sampling was carried out in the last week of each four 21-day experimental periods. Heifers were offered concentrate (13.4 +/- 0.04% crude protein (CP), 13.3 +/- 0.44% NDF, 51.7 +/- 0.97% starch) and barley straw once daily at 0830 h ad libitum. There was a linear decrease in concentrate DMI and a linear increase in straw DMI with increasing buffer level in the diet, resulting in a tendency towards a linear decrease in total DMI. Intake of concentrate was 6.89, 7.66, 6.72 and 5.72 +/- 0.83 kg/day, whereas straw intakes were 0.73, 0.84, 0.94 and 1.06 +/- 0.14 kg/day, for the 0%, 1.25%, 2.5% and 5% BICARB, respectively. Water consumption was not affected by treatments when expressed as l/day or percentage of BW, but increased linearly when expressed as l/kg of DMI. The percentage of total daily water drunk in the morning (from 0830 to 1230 h) increased linearly with the level of buffer. Mean ruminal pH and total area under the pH curve were not affected with increasing buffer level. The lowest daily pH (5.65 +/- 0.09) was not affected by treatments. A quadratic tendency (P 0.10) was observed in the number of hours and the area under the pH curve in which ruminal pH was below 5.8, with high values only at the 0% BICARB. Additionally, increasing bicarbonate level caused a linear increase in the ruminal pH at 2 and 4 h after feeding. Daily average NH3 N (2.4 +/- 0.9 mg N/100 ml) and total volatile fatty acids (VFA) (143 +/- 12 mM) concentrations were not affected by treatments. Daily average molar proportion of propionate decreased linearly, and acetate proportion and the acetate-to-propionate ratio were increased with increasing buffer level in the diet. Molar percentage of butyrate, isobutyrate and isovalerate, and branched-chain VFA concentration increased linearly as the level of bicarbonate increased in the diet. Results indicate that high levels of BICARB to finishing heifers fed high-concentrate diets may result in a decreased DMI without significant effects on mean ruminal pH, which may affect animal performance. All individual VFA proportions, except valerate, were changed by the addition of bicarbonate. PMID- 22443596 TI - Increasing sodium bicarbonate level in high-concentrate diets for heifers. II. Effects on chewing and feeding behaviors. AB - Four Holstein heifers (264 +/- 12 kg initial BW) were used in a 4 * 4 Latin square design with 21-day experimental periods to determine the effect of increasing levels of sodium bicarbonate (BICARB) (0%, 1.25%, 2.5% and 5%, of concentrate dry matter (DM) basis) on chewing and feed intake behavior when fed high-concentrate diets. Concentrate (13.41% CP, 13.35% NDF) and barley straw were fed once a day at 0830 h ad libitum. Feed bunks placed on scales and video recording were used to measure 24-h feed intake and chewing behavior, respectively. The patterns of feeding behavior (feed intake, meal size and length) and chewing behavior (eating, ruminating and total chewing) were studied by dividing the day into 12 intervals of 2-h each, beginning at feeding (interval 1 through 12). Number of meals per day and eating rate decreased linearly with increasing buffer level, but meal length increased linearly. No treatment effects were observed in sum of daily meal lengths or average meal size. The treatment * interval interaction was significant on meal size, length and feed intake. The size and length of those meals occurring during the 4 h post-feeding increased linearly. However, meal size tended to decrease in the evening between 8 and 12 h, whereas feed intake decreased linearly from 6 to 10 h and from 12 to 14 h post feeding. Buffer concentration did not affect the percentage of time spent ruminating, eating or drinking per day but the buffer level * interval interaction was significant. Time spent eating expressed as min per kg of DM or organic matter (OM) intake increased linearly with buffer levels. Proportion of time spent eating increased linearly during the intervals between 0 and 4 h post feeding. Time spent ruminating decreased linearly during the 2 h post-feeding, and also in the evening from 12 to 14 h, and at night from 18 to 22 h post feeding, but the effect was quadratic between 8 and 10 h when intermediate buffer levels showed the greatest ruminating time. Time spent drinking decreased linearly from 6 to 8 h but increased during the 2 h following feeding and from 10 to 12 h post-feeding. Daily eating rate and meal frequency decreased linearly as the buffer level increased, but average meal size and daily chewing times were not affected. However, significant time of the day * buffer level interactions were observed for feed intake, meal size and length and chewing behavior. PMID- 22443597 TI - Dietary starch sources affect net portal appearance of amino acids and glucose in growing pigs. AB - Four male pigs (Duroc * Landrace * Yorkshire; average initial (mean +/- SEM) BW = 22.5 +/- 1.1 kg), fitted with permanent catheters in the portal vein, ileal vein and carotid artery, were used in a 4 * 4 Latin square experimental design to measure the effect of dietary starch sources on the net portal appearance of glucose and amino acids. Dietary starch sources were resistant starch (RS), maize, sticky rice and brown rice. Diets were provided at 0730, 1530 and 2330 h during a 6-day adjustment period and 1-day collection period. On day 7 of each period, blood samples were collected from the portal vein and carotid artery at 0730 h (prior to feeding) and hourly up to 8 h after meal. Blood samples were used to determine glucose, amino acid, packed cell volume and partial pressure of oxygen (pO2). When calculated per 100 g feed intake, cumulative portal glucose appearance was lower (P < 0.05) for resistant starch than for maize, sticky rice or brown rice up to 8 h after the meal. Cumulative portal glucose appearance was higher (P < 0.05) for sticky rice and brown rice than for other diets until 4 h after the meal, but maize had higher cumulative glucose appearance after 4 h. Net cumulative portal concentrations of most amino acids for resistant starch were also reduced (P < 0.05) than for the other starch sources. Cumulative portal appearance of amino acid represented 48.39%, 63.76%, 61.80% and 59.18% of dietary intake for resistant starch, maize, sticky rice and brown rice, respectively. Collectively, our results indicate that dietary starch sources substantially affect the appearance of amino acids and glucose in the portal circulation. PMID- 22443598 TI - Effect of a bovine colostrum whey supplementation on growth performance, faecal Escherichia coli population and systemic immune response of piglets at weaning. AB - This study examined the effect of a bovine colostrum whey supplementation on growth performance, feed intake, faecal Escherichia coli population and systemic immune response of piglets at weaning. A total of 96 piglets weaned at 26 +/- 2 days of age were assigned for 4 weeks to one of the two treatments: (1) the control (commercial diet with bovine milk whey powder) and (2) the colostrum (commercial diet with freeze-dried bovine colostrum whey) treatments. The two supplements were incorporated in the diet at a level of 20 g/kg during the first 2 weeks after weaning and lowered to a level of 10 g/kg for the next 2 weeks. BW and feed intake were measured weekly. Faecal E. coli counts were determined weekly on specific culture media. Blood samples were collected weekly and submitted to a cell counter analyser for their main components (red and white blood cells, platelets) and flow cytometry was used to determine the lymphocyte population (B, T, Th and Tc). Finally, total seric immunoglobulin (IgM, IgG and IgA) concentrations were determined by the ELISA method. During the first week of the trial, the piglets from the colostrum treatment had improved average daily gain (170 g/day v. 81 g/day, P < 0.001), average daily feed intake (346 g/day v. 256 g/day, P = 0.03) and feed efficiency (BW gain/feed intake) (0.48 v. 0.31, P = 0.04). The pigs fed the colostrum treatment had also a 25% increase in circulating IgA (P = 0.03) compared with the control treatment the first week. It is concluded that a distribution of bovine colostrum whey (20 g/kg diet) during the first week post-weaning induces a systemic IgA response and has a beneficial action on growth performances and feed efficiency. PMID- 22443599 TI - Food restriction and refeeding in lambs influence muscle antioxidant status. AB - Compensatory growth, a frequent phenomenon observed in ruminants due to seasonal variation in food availability, affects protein metabolism including protein oxidation. These oxidation processes may have an impact on animal health as well as on meat protein degradation during post mortem aging (ie meat maturation). Sixteen male lambs were randomly divided into four groups. One group was fed ad libitum (C) and one group was food-restricted to 60% of the intake of the C group (R). The last two groups were restricted similarly to the R group and refed either ad libitum (RAL) or similarly to the C group (pair-feeding) (RPF). Muscles samples were taken immediately after slaughter. The present study showed that the restriction/refeeding pattern had no effect on protein oxidation in the muscles studied (longissimus dorsi (LD), semitendinosus (ST) and supraspinatus (SP)). However, total antioxidant capacity decreased after food restriction (-51%, -43%, P < 0.01 for ST and LD muscles, respectively) and re-increased only after ad libitum refeeding. This alteration in the total antioxidant status can partially be explained by the similar pattern of change observed in the glutathione concentration of the muscles (-25%, P < 0.05 for ST muscle and NS for the other muscles). However, none of the concentrations of other water-soluble antioxidants studied (carnosine, anserine, glutathione peroxidase and superoxide dismutase) were altered during compensatory growth. This study showed that an inappropriate feeding level following a nutritional stress induced alterations in the total antioxidant status (particularly that of glutathione), which may have consequences on animal health. Other consequences of a decrease of the animal antioxidant status in vivo could be an alteration of the protein oxidation processes during meat maturation. PMID- 22443600 TI - Evolution of anti-eCG antibodies in response to eCG doses and number of injections. Relationship with productivity of rabbit does. AB - The aim of this experiment was to study the kinetics of anti-eCG (equine chorionic gonadotrophin) antibodies in relation to eCG dose (8 or 25 IU) and number of injections (n = 11) in comparison with a control group (no injection), and to relate antibody production to sexual receptivity and productivity of rabbit does. In all, 124 lactating primiparous rabbit does were inseminated every 35 days for a year. Just before eCG injection (48 h before insemination), blood samples were collected from all the does to assay anti-eCG antibodies. The anti eCG antibody binding rate, regardless of the injected dose, shows that none of the does developed detectable anti-eCG antibodies before the 7th injection. The level of detectable anti-eCG antibodies began to show an increase at the 7th injection and was significant only for the 25 IU dose at the 11th injection. At the end of the experiment, 15% and 39% of does treated with 8 and 25 IU, respectively, developed immunity to eCG (binding rate >6%: higher binding rate of the control group). Consequently, the immune response depends on the eCG dose and on the number of injections. Moreover, productivity of does estimated from the number of weaned rabbits produced per insemination is not influenced by the level of eCG antibodies (7.0 and 6.9 for binding rate <6% and binding rate 6%, respectively). Only 19 inseminations (n = 6 and n = 13 for 8 and 25 IU, respectively) were made on hyperimmune does. Consequently, the immune response to eCG seems to be marginal for rabbit does. Moreover, under the described experimental conditions, reproductive performances of hyperimmune does were not affected. PMID- 22443601 TI - The value of muscular and skeletal scores in the live animal and carcass classification scores as indicators of carcass composition in cattle. AB - The objective was to determine the relationship of muscular and skeletal scores taken on the live animal and carcass conformation and fat scores with carcass composition and value. Bulls (n = 48) and heifers (n = 37) of 0.75 to 1.0 late maturing breed genotypes slaughtered at 16 and 20 months of age, respectively, were used. At 8 months of age (weaning) and immediately pre-slaughter, visual muscular scores were recorded for each animal and additionally skeletal scores were recorded pre-slaughter. Carcass weight, kidney and channel fat weight, carcass conformation and fat scores, fat depth over the longissimus dorsi muscle at the 12th (bulls) or 10th (heifers) rib and carcass length were recorded post slaughter. Each carcass was subsequently dissected into meat, fat and bone using a commercial dissection procedure. Muscular scores taken pre-slaughter showed positive correlations with killing-out rate (r ~ 0.65), carcass meat proportion (r ~ 0.60), value (r ~ 0.55) and conformation score (r ~ 0.70), and negative correlations with carcass bone (r ~ -0.60) and fat (r ~ -0.4) proportions. Corresponding correlations with muscular scores at weaning were lower. Correlations of skeletal scores taken pre-slaughter, carcass length and carcass weight with killing-out rate and the various carcass traits were mainly not significant. Carcass fat depth and kidney and channel fat weight were negatively correlated with carcass meat proportion and value, and positively correlated with fat proportion. Correlations of carcass conformation score were positive (r = 0.50 to 0.68) with killing-out rate, carcass meat proportion and carcass value and negative with bone (r ~ -0.56) and fat (r ~ -0.40) proportions. Corresponding correlations with carcass fat score were mainly negative except for carcass fat proportion (r ~ 0.79). A one-unit (scale 1 to 15) increase in carcass conformation score increased carcass meat proportion by 8.9 and 8.1 g/kg, decreased fat proportion by 4.0 and 2.9 g/kg and decreased bone proportion by 4.9 and 5.2 g/kg in bulls and heifers, respectively. Corresponding values per unit increase in carcass fat score were -11.9 and -9.7 g/kg, 12.4 and 9.9 g/kg, and 0.5 and -0.2 g/kg. Carcass conformation and fat scores explained 0.70 and 0.55 of the total variation in meat yield for bulls and heifers, respectively. It is concluded that live animal muscular scores, and carcass conformation and fat scores, are useful indicators of carcass meat proportion and value. PMID- 22443602 TI - Time of ovulation in nulliparous and multiparous goats. AB - Fifteen nulliparous and nine multiparous Serrana goats were used, through two successive oestrous cycles, in order to characterize their ovulation time with regard to the number of ovulations after induced and natural oestrus during the breeding season. The onset of oestrus was detected by the amount of vasectomized bucks after oestrus synchronization with prostaglandin, given 10 days apart, and in the following two expected natural oestrus. The preovulatory LH peak was determined from blood samples collected 0, 4, 8, 12, 16, 20 and 24 h after onset of oestrus. A transrectal ovarian ultrasound scanning was performed 20, 24, 28, 32, 36, 40, 44 and 60 h after onset of oestrus, for the detection of ovulations by means of the disappearance of large follicles (>4 to 5 mm). Single ovulations were observed in 76% of oestrous periods in nulliparous goats and in 18% of nulliparous goats. The onset of oestrus to LH peak interval was lower in nulliparous (12.1 +/- 0.9 h, n = 38) than in multiparous (15.6 +/- 1.0 h, n = 22, P < 0.05) goats with no oestrus interaction effects (P > 0.05). The LH peak to first ovulation interval was higher after natural (18.9 +/- 0.7 h, n = 36) than after induced (15.8 +/- 1.2 h, n = 24, P < 0.05) oestrus. The onset of oestrus to total ovulation interval was influenced by parity (P < 0.01) and oestrus type (P < 0.05) with a length of 30.1 +/- 1.1 h (n = 15) and 33.4 +/- 1.5 h (n = 9) for induced oestrus of nulliparous and multiparous goats, respectively, and 32.5 +/- 1.0 h (n = 23) and 36.5 +/- 1.1 h (n = 13) for natural oestrus of nulliparous and multiparous goats, respectively. The onset of oestrus to first ovulation interval was not influenced by parity, but an interval of 8.0 +/- 1.6 h was observed between the first and second ovulations in polyovulatory oestrus. Consequently, nulliparous goats that are predominantly monovular ovulate earlier than multiparous goats that are predominantly polyovulatory. In conclusion, significant differences occurred in the number and time of ovulations between nulliparous and multiparous goats. More research is necessary for a deeper understanding of the mechanisms regulating monovularory and polyovulatory oestrous cycles regarding the parity of goats. PMID- 22443603 TI - Welfare and performance of yearling dairy heifers out-wintered on a wood-chip pad or housed indoors on two levels of nutrition. AB - Wood-chip pads represent a low-cost alternative to housing for cattle during the winter. Considering the negative welfare implications associated with housing indoors on concrete, they may also offer welfare benefits to replacement dairy heifers. However, these animals may not be able to withstand winter weather conditions on a grass silage diet. The aim of this experiment was to evaluate behaviour, limb injuries, dirtiness scores, performance and climatic energy demand (CED) of yearling dairy heifers on two levels of nutrition kept outdoors on a wood-chip pad or indoors in cubicles during the winter. Ninety-six 10-month old heifers were blocked and assigned in groups of eight, to one of the following four treatments in a 2 * 2 factorial design: (a) indoors, silage only; (b) indoors, silage plus concentrate; (c) outdoors, silage only; and (d) outdoors, silage plus concentrate. There were three replicate groups per treatment. All animals were inspected for skin lesions and were weighed and body condition scored (BCS) at the beginning and end of the trial. Instantaneous scan sampling and continuous all-occurrence behaviour sampling were used to collect behaviour data during two 24-h periods. Animals were also dirtiness scored and group feed intakes were recorded during the trial. Significantly more comfort, social and play behaviours were recorded outdoors (P < 0.05) while trips, slips and falls were only recorded indoors (P < 0.001). Groups outdoors had significantly lower limb lesion scores at the end of the experiment (P < 0.05) and fewer groups outdoors were affected by all categories of limb lesions. However, they were consistently dirtier than animals indoors (P < 0.001). Low-nutrition animals had lower feed intakes, smaller BCS changes and lower average daily weight gains than high-nutrition animals (P < 0.01). Heifers outdoors had significantly lower average daily weight gains and BCS changes (P < 0.05) explained by lower feed intakes (P < 0.01). However, outdoor heifers on both the high- and low-nutrition diets and indoor animals on the low-nutrition diet had lower UFL (feed unit for maintenance and lactation (Irish Republic)) intakes (-0.36, -0.35 and -0.22, respectively) than that required to meet the daily live-weight gains they achieved. Heifers indoors on the high-nutrition diet gained 0.98 kg per day but consumed 0.17 UFL more than what would be recommended to achieve a daily weight gain of 1.0 kg. The CED for outdoor heifers was higher than that of indoor heifers (6.18 v. 5.47 MJ/day per m2 body surface area; P < 0.001, s.e.d. 0.044). However, CED did not exceed heat production in any treatment. Although animal performance was reduced outdoors, the wood-chip pad was associated with welfare benefits compared with cubicle housing. PMID- 22443604 TI - Effects of pre-weaning concentrate feeding on calf performance, carcass and meat quality of autumn-born bull calves weaned at 90 or 150 days of age. AB - A study was conducted to evaluate the effect of pre-weaning concentrate feeding in early-weaned (EW, day 90) or traditionally weaned (TW, day 150) autumn-born beef calves on growth, feed intake and feed efficiency, and carcass and meat quality. Twenty-eight male calves were either EW or TW, and offered a starter concentrate (S) or no additional feed (NS) during the pre-weaning period. Therefore, four management strategies were tested: EWS, EWNS, TWS and TWNS. Growth patterns were affected by management strategy. From day 90 to 150, TWNS calves presented a substantially lower average daily gain (ADG) than their counterparts, which had similar performance. During the finishing phase (from day 150 to slaughter at 450 kg live weight), EWS calves had the lowest ADG. Daily feed intake or efficiency in the finishing phase was unaffected by previous management. Serum IGF-I concentrations at day 90 and slaughter did not differ with management strategy, but early weaning and pre-weaning concentrate feeding increased IGF-I concentrations at day 150. Circulating leptin concentrations were unaffected by age at weaning and pre-weaning concentrate feeding, except for leptin concentrations at slaughter, which were higher in S calves than in NS calves. Total concentrate intake from birth to slaughter and the concomitant feed costs were higher for EWS and EWNS calves than for TWNS and TWS ones. However, cow feed costs were lower for cows whose calves had been early weaned. Concerning carcass quality, early weaning improved dressing percentage and increased fatness score, and particularly TWNS calves presented a poorer conformation. Meat quality was not affected by management strategy. Considering the economic performance, TWS, EWNS and EWS strategies yielded a similar economic margin, whereas TWNS would be the least advisable strategy when calves are fattened in the farm until slaughter. PMID- 22443605 TI - Effect of the tropical tannin-rich shrub legumes Calliandra calothyrsus and Flemingia macrophylla on methane emission and nitrogen and energy balance in growing lambs. AB - The objective of this study was to test whether the use of tannin-rich shrub legume forage is advantageous for methane mitigation and metabolic protein supply at unchanged energy supply when supplemented in combination with tannin-free legumes to sheep. In a 6 * 6 Latin-square design, foliage of two tannin-rich shrub legume species (Calliandra calothyrsus and Flemingia macrophylla) were used to replace either 1/3 or 2/3, respectively, of a herbaceous high-quality legume (Vigna unguiculata) in a diet composed of the tropical grass Brachiaria brizantha and Vigna in a ratio of 0.55 : 0.45. A Brachiaria-only diet served as the negative control. Each experimental period lasted for 28 days, with week 3 serving for balance measurement and data collection inclusive of a 2-day stay of the sheep in open-circuit respiration chambers for measurement of gaseous exchange. While Vigna supplementation improved protein and energy utilisation, the response to the partial replacement with tannin-rich legumes was less clear. The apparent total tract digestibilities of organic matter, NDF and ADF were reduced when the tannin-rich plants partially replaced Vigna, and the dose response relationships were mainly linear. The tannin-rich plants caused the expected redistribution of more faecal N in relation to urinary N. While Flemingia addition still led to a net body N retention, even when fed at the higher proportion, adding higher amounts of Calliandra resulted in body protein mobilisation in the growing lambs. With respect to energy, supplementation of Vigna alone improved utilisation, while this effect was absent when a tannin-rich plant was added. The inclusion of the tannin-rich plants reduced methane emission per day and per unit of feed and energy intake by up to 24% relative to the Vigna only-supplemented diet, but this seems to have been mostly the result of a reduced organic matter and fibre digestion. In conclusion, Calliandra seems less apt as protein supplement for ruminants while Flemingia could partially replace a high-quality legume in tropical livestock systems. However, methane mitigation would be small due to associated reductions in N and energy retention. PMID- 22443606 TI - Effects of two supplementation levels of linseed combined with CLA or tallow on meat quality traits and fatty acid profile of adipose and different muscle tissues in slaughter pigs. AB - Dietary linseed supply efficiently elevates the linolenic acid concentration of pork. The main problem of increasing the n-3 fatty acid tissue levels arises from a higher susceptibility to lipid oxidation. Increasing the saturation level of tissue lipids by the dietary inclusion of conjugated linoleic acids (CLA) or tallow might prevent oxidation. Thus, the aim of the study was to evaluate the impact of dietary CLA or tallow supplementation combined with extruded linseed on the growth performance, carcass characteristics and fatty acid profile of muscles (longissimus, semimembranosus, biceps femoris) and subcutaneous fat (SF). The enzyme activity of the de novo lipogenesis and stearoyl-CoA desaturase in the SF was also assessed. From 18 to 104 kg BW, 32 Swiss Large White barrows were fed a diet supplemented with either: (1) 2% linseed (L2); (2) 3% linseed (L3); (3) 2% linseed + 1% CLA (L2-C) or (4) 2% linseed + 1% tallow (L2-T). The linolenic and eicosatrienoic acid concentrations were higher (P < 0.01) and the ?n-6/?n-3 ratio was lower (P < 0.01) in all tissues of L3 than L2 and L2-T barrows. Only in the SF the docosapentaenoic acid concentration was increased (P < 0.01) in L3 barrows. Compared with the other three diets, feeding the L2-C diets increased (P < 0.01) the amount of myristic, palmitic, stearic and palmitoleic acid at the expense of the oleic and eicosenoic acid content in the intramuscular and SF lipids. Except for the lower (P < 0.05) eicosadienoic acid concentration in the muscles, feeding the L2-C treatment resulted in similar polyunsaturated fatty acid concentrations and ?n-6/?n-3 ratio than feeding L2 or L2-T diets. Both the c9,t11- and t10,c12-CLA isomers found in the CLA-supplemented diet were also detected in the tissues, but the c9,t11-isomer was more abundant than the t10,c12 isomer. De novo lipogenesis was not (P > 0.05) affected by the dietary fats, whereas Delta9-desaturase activity was depressed (P < 0.05) by CLA inclusion (L2 C). Only when oxidation was challenged by cooking and subsequent storage for 4 days at 4 degrees C values of thiobarbituric acid-reactive substances were lower (P < 0.05) in longissimus muscle chops of L2-C compared with L2, L3 and L2-T barrows. The present findings revealed that CLA, but not tallow, combined with extruded linseed enhanced the oxidative stability of pork probably by lowering the degree of unsaturation of the lipids without affecting the improved ?n-6/?n-3 ratio. PMID- 22443607 TI - Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier. AB - A brain delivery probe was prepared by covalently conjugating lactoferrin (Lf) to a poly(ethylene glycol) (PEG)-coated Fe(3)O(4) nanoparticle in order to facilitate the transport of the nanoparticles across the blood-brain barrier (BBB) by receptor-mediated transcytosis via the Lf receptor present on cerebral endothelial cells. The efficacy of the Fe(3)O(4)-Lf conjugate to cross the BBB was evaluated in vitro using a cell culture model for the blood-brain barrier as well as in vivo in SD rats. For an in vitro experiment, a well-established porcine BBB model was used based on the primary culture of cerebral capillary endothelial cells grown on filter supports, thus allowing one to follow the transfer of nanoparticles from the apical (blood) to the basolateral (brain) side. For in vivo experiments, SD rats were used as animal model to detect the passage of the nanoparticles through the BBB by MRI techniques. The results of both in vitro and in vivo experiments revealed that the Fe(3)O(4)-Lf probe exhibited an enhanced ability to cross the BBB in comparison to the PEG-coated Fe(3)O(4) nanoparticles and further suggested that the Lf-receptor-mediated transcytosis was an effective measure for delivering the nanoparticles across the BBB. PMID- 22443608 TI - Daily follow-up of bacterial communities in the human gut reveals stable composition and host-specific patterns of interaction. AB - In the last decade, an extensive effort has been made to characterize the human intestinal microbiota by means of SSU rRNA gene sequence and metagenomic analysis. Relatively few studies have followed intestinal bacterial communities over time to assess their stability in the absence of perturbation. In this study, we have monitored the faecal bacteria of three healthy subjects during 15 consecutive days. The global community structure was analysed through SSU rRNA gene sequencing. In agreement with previous studies, we found that the between subject variation in community structure was larger than within. The composition was fairly stable throughout, although daily fluctuations were detected for all genera and phylotypes at 97% of sequence identity. While the core shared between subjects was very small, each subject harboured a stable high-abundance core composed of a small number of bacterial groups (9% of the phylotypes accounted for between 74% and 93% of the sequences). This may suggest that studies aimed at linking the microbiota composition with disease risk should be limited to the numerically most dominant phylotypes, as the rest appears transient. Networks of potential interactions between co-occurring genera were also subject-specific, even for the same bacterial genus, which might be reflecting host-specific selective pressures and historic events. PMID- 22443609 TI - Re: Arginine-nitric oxide-polyamine metabolism in periodontal disease. Ozer L, Elgun S, Ozdemir B, Pervane B, Ozmeric N. (J Periodontol 2011;82:320-328.). PMID- 22443610 TI - Evaluation of the uptake of the Australian standardized terminology and definitions for texture modified foods and fluids. AB - This paper discusses the uptake of standardized terminology and definitions for texture modified foods and fluids. The Australian dietetic and speech-language pathology associations endorsed national standards in 2007. This project sought to determine the barriers and enablers for use of the national standards in clinical practice. Cross-sectional online surveys were developed, including open- and closed-response questions. The surveys targeted different professional groups in Australia including speech-language pathologists, dietitians, nurses, and food service personnel. Australian accredited universities were contacted to determine penetration of the standards. A total of 574 surveys were received. Sixty-five per cent of respondents indicated full implementation, 23% partial implementation, and 10% no implementation of the standards in their workplace. Speech-language pathologists and dietitians were most likely to have championed implementation of the standards. Barriers to implementation included: lack of knowledge about the standards, time, and resistance to change. Enablers included: encouragement to use the standards and 'buy-in' from stakeholders. Benefits of implementation included: consistent terminology and perceived improvements in patient safety. It was concluded that the standards have been successfully implemented in a majority of facilities and Australian universities. This study provides insight into the complexity of introducing and managing change in healthcare environments. PMID- 22443611 TI - "Hiding the story": indigenous consumer concerns about communication related to chronic disease in one remote region of Australia. AB - This paper reports on a collaborative qualitative study which explored education and communication practice related to chronic disease from the perspectives of Aboriginal people in a remote region of the Northern Territory, Australia, where the prevalence of chronic disease is extremely high. Most Yolngu (Aboriginal people of Northeast Arnhem Land) do not speak English as their first language and few health staff share the language and cultural background of their clients. Semi-structured interviews were conducted with Yolngu community members and health staff in their preferred language in small groups or individually, in an approach that was flexible and responsive to the concerns and priorities of Yolngu researchers and participants. As well, health education interactions were videotaped to facilitate more in-depth understanding of the strengths and challenges in communication (one video can be viewed at http://informahealthcare.com/doi/abs/10.3109/17549507.2012.663791). An iterative and collaborative process of analysis, interpretation, and verification revealed that communication and education related to chronic disease is highly ineffective, restricting the extent to which Yolngu can make informed decisions in managing their health. Yolngu participants consistently stated that they wanted a detailed and direct explanation about causes and management of chronic disease from health staff, and rarely believed this had been provided, sometimes assuming that information about their health is deliberately withheld. These serious limitations in communication and education have extensive negative consequences for individuals, their families, and health services. These findings also have broader relevance to all areas of healthcare, including allied health services, which share similar challenges in achieving effective communication. Without addressing the profound and pervasive inadequacies in communication, other interventions designed to close the gap in Indigenous health are unlikely to succeed. PMID- 22443612 TI - Consistency statistics and genetic parameters for taste panel assessed meat quality traits and their relationship with carcass quality traits in a commercial population of Angus-sired beef cattle. AB - Sensory traits, such as juiciness and tenderness, are known to be important to the consumer and thus will influence their consumption of meat, specifically beef. These traits are difficult to measure and often require the use of taste panels to assess the complex parameters involved in the eating experience. Such panels are potentially a large source of measurement error, which may reduce the effectiveness of breeding programmes based on the data they generate. The aim of this study was to assess the quality of such taste panel-derived sensory traits as well as calculating genetic parameters and residual correlations for these traits along with a further set of traditional carcass quality traits. The study examined a sample of 443 Aberdeen Angus-cross animals collected from 14 breeder finisher farms throughout Scotland. To assess the quality of the taste panel measurements, three consistency statistics were calculated: (i) panel-member consistency, i.e. the extent to which an individual panel member varied in their scoring for a given trait over the period of the experiment; (ii) repeatability, i.e. the consistency with which an individual panel member was able to score a trait on repeated samples from the same animal; and (iii) reproducibility, i.e. the extent to which taste panel members agreed with each other when scoring a trait. These consistency statistics were moderately high, particularly for panel member consistency and reproducibility, with values ranging from 0.48 to 0.81 and 0.43 to 0.73 respectively. Estimated heritabilities were low for most of the sensory taste-panel-evaluated traits where the maximum value was 0.16 for overall liking. Residual correlations were high between many of the closely related sensory traits, although few significant correlations were found between the carcass quality data and meat quality traits. PMID- 22443613 TI - The effect of missing marker genotypes on the accuracy of gene-assisted breeding value estimation: a comparison of methods. AB - In livestock populations, missing genotypes on a large proportion of the animals is a major problem when implementing gene-assisted breeding value estimation for genes with known effect. The objective of this study was to compare different methods to deal with missing genotypes on accuracy of gene-assisted breeding value estimation for identified bi-allelic genes using Monte Carlo simulation. A nested full-sib half-sib structure was simulated with a mixed inheritance model with one bi-allelic quantitative trait loci (QTL) and a polygenic effect due to infinite number of polygenes. The effect of the QTL was included in gene-assisted BLUP either by random regression on predicted gene content, i.e. the number of positive alleles, or including haplotype effects in the model with an inverse IBD matrix to account for identity-by-descent relationships between haplotypes using linkage analysis information (IBD-LA). The inverse IBD matrix was constructed using segregation indicator probabilities obtained from multiple marker iterative peeling. Gene contents for unknown genotypes were predicted using either multiple marker iterative peeling or mixed model methodology. For both methods, gene assisted breeding value estimation increased accuracies of total estimated breeding value (EBV) with 0% to 22% for genotyped animals in comparison to conventional breeding value estimation. For animals that were not genotyped, the increase in accuracy was much lower (0% to 5%), but still substantial when the heritability was 0.1 and when the QTL explained at least 15% of the genetic variance. Regression on predicted gene content yielded higher accuracies than IBD LA. Allele substitution effects were, however, overestimated, especially when only sires and males in the last generation were genotyped. For juveniles without phenotypic records and traits measured only on females, the superiority of regression on gene content over IBD-LA was larger than when all animals had phenotypes. Missing gene contents were predicted with higher accuracy using multiple-marker iterative peeling than with using mixed model methodology, but the difference in accuracy of total EBV was negligible and mixed model methodology was computationally much faster than multiple iterative peeling. For large livestock populations it can be concluded that gene-assisted breeding value estimation can be practically best performed by regression on gene contents, using mixed model methodology to predict missing marker genotypes, combining phenotypic information of genotyped and ungenotyped animals in one evaluation. This technique would be, in principle, also feasible for genomic selection. It is expected that genomic selection for ungenotyped animals using predicted single nucleotide polymorphism gene contents might be beneficial especially for low heritable traits. PMID- 22443614 TI - Diversity, abundance and novel 16S rRNA gene sequences of methanogens in rumen liquid, solid and epithelium fractions of Jinnan cattle. AB - Three methanogen 16S rRNA gene clone libraries were constructed from liquid (LM), solid (SM) and epithelium (EM) fractions taken from the rumen of Jinnan cattle in China. After the amplification by PCR using methanogen-specific primers Met86F and Met1340R, equal quantities of PCR products from the same fractions from each of the four cattle were mixed together and used to construct the three libraries. Sequence analysis showed that the 268 LM clones were divided into 35 phylotypes with 18 sequences of phylotypes affiliated with the genus Methanobrevibacter (84.3% of clones). The 135 SM clones were divided into 19 phylotypes with 11 phylotypes affiliated with the genus Methanobrevibacter (77.8%). The 267 EM clones were divided into 33 phylotypes with 15 phylotypes affiliated with the genus Methanobrevibacter (77.2%). Clones closely related to Methanomicrobium mobile and Methanobrevibacter wolinii were only found in the LM library, and those to Methanobrevibacter ruminantium and Methanobrevibacter gottschalkii only in the SM library. LM library comprised 12.4% unidentified euryarchaeal clones, SM library 23.7% and EM library 25.5%, respectively. Five phylotypes (accession number: EF055528 and EF055531-EF055534) did not belong to the Euryarchaeota sequences we had known. One possible new genus (represented by phylotype E17, accession number EF055528) belonging to Methanobacteriaceae was identified from EM library. Quantitative real-time PCR for the first time revealed that epithelium fraction had significantly higher density of methanogens, with methanogenic mcrA gene copies (9.95 log 10 (copies per gram of wet weight)) than solid (9.26, P < 0.01) and the liquid (8.44, P < 0.001). The three clone libraries also appeared different in Shannon index (EM library 2.12, LM library 2.05 and SM library 1.73). Our results showed that there were apparent differences in the methanogenic diversity and abundance in the three different fractions within the rumen of Jinnan cattle, with Methanobrevibacter species predominant in all the three libraries and with epithelium fraction having more unknown species and higher density of methanogens. PMID- 22443615 TI - Effects of pressed beet pulp silage inclusion in maize-based rations on performance of high-yielding dairy cows and parameters of rumen fermentation. AB - Beet pulp contains high amounts of pectins that can reduce the risk of rumen disorders compared to using feedstuffs high in starch. The objective was to study the effects of inclusion of ensiled pressed beet pulp in total mixed rations (TMR) for high-yielding dairy cows. Two TMR containing no or about 20% (on dry matter (DM) basis) beet pulp silage were used. The beet pulp silage mainly replaced maize silage and corn cob silage. The TMR were intentionally equal in the concentrations of energy and utilisable crude protein (CP) at the duodenum. TMR were fed to 39 and 40 dairy cows, respectively, for 118 days. The average daily milk yield was about 43 kg/day. No significant differences in milk yield and milk fat or milk protein content were detected. DM intake of cows was significantly reduced by the inclusion of beet pulp silage (23.0 v. 24.5 kg/day). However, a digestibility study, separately conducted with sheep, showed a significantly higher organic matter digestibility and metabolisable energy concentration for the TMR that contained beet pulp silage. In vitro gas production kinetics indicated that the intensity of fermentation was lower in the TMR that contained beet pulp silage. In vitro production of short-chain fatty acids, studied using a Rusitec, did not differ between the TMR. However, the inclusion of beet pulp silage in the ration caused a significant reduction in the efficiency of microbial CP synthesis in vitro. The amino acid profile of microbial protein remained unchanged. It was concluded that beet pulp silage has specific effects on ruminal fermentation that may depress feed intake of cows but improve digestibility. An inclusion of beet pulp silage of up to 20% of DM in rations for high-yielding dairy cows is possible without significant effects on milk yield and milk protein or milk fat. PMID- 22443616 TI - Effects of prefermented cereals or the end products of fermentation on growth and metabolism of enterocyte-like Caco-2 cells and on intestinal health of restrictedly fed weanling pigs. AB - To unravel the underlying mechanisms that explain the positive effects of prefermented cereals on in vivo gastrointestinal (GI) architecture and function, an in vitro experiment using a human small intestinal epithelial cell model (Caco 2) was performed. A range of dilutions (0% to 10%) of the supernatants of three liquid experimental diets, as well as Na-lactate were used in an in vitro experiment to assess their effect on cellular growth, metabolism, differentiation and mucosal integrity using Caco-2. The experimental diets contained, in addition to a protein rich basal diet (60%), (1) a liquid control diet (C) containing 40% of a mixture of barley and wheat (ratio 3 : 1) or (2) a liquid diet (F) containing 40% prefermented barley and wheat or (3) C with the addition of the fermentation end-products (organic acids and ethanol) in concentrations similar to those in the fermented diet (FP). For F, the mixture of barley and wheat was fermented at 35 degrees C for 48 h. Parallel to the in vitro experiment, 18 groups of eight weanling pigs were assigned to one of the experimental diets during a 14-day in vivo experiment. Each group was fed restrictively. The results of the in vitro experiment showed that the lowest dose of both F- and FP supernatants had no clear effects on the cell proliferation, but incubation with 5% and 10% of the F- and FP-supernatants decreased the cell numbers at day 19. DNA, RNA, protein and glycoprotein synthesis in differentiated Caco-2 cells were stimulated by incubation with the lower concentrations (0.5% to 2.5%) of F- and FP-supernatants whereas the higher concentrations (5% and 10%) had no effect. Both the F- and FP-supernatants decreased the specific sucrase-isomaltase activity in a dose-dependent manner, but the effects on the specific aminopeptidase activities were less clear. Mucosal integrity initially decreased after incubation with the highest F- and FP-supernatants and started to recover between 24 and 48 h. The results of the in vivo experiment showed no dietary effects (P > 0.1) on GI morphology and brush-border enzyme activities at day 5 or at day 14. Time related changes in GI characteristics followed a normal pattern. In conclusion, the supernatants of diets containing either prefermented cereals or their fermentation end-products clearly modulate cellular growth, metabolism, differentiation and mucosal integrity in an in vitro model, although these effects were not observed in the in vivo characteristics measured in weanling pigs. PMID- 22443617 TI - Energy intake in late gestation affects blood metabolites in early lactation independently of milk production in dairy cows. AB - The present experiment examined the effect of offering either a high- (H) or low- (L) energy-density diet in late gestation and early lactation on physiological parameters, body condition score (BCS) and milk production in early lactation. In all, 40 multiparous Holstein cows were randomly allocated to one of four treatments in a 2 * 2 factorial design, where the factors were H- or L-energy density in a total mixed ration (TMR) both pre- and post-calving. Consequently, there were four treatment groups: HH, HL, LL and LH. The pre-calving treatment was initiated 100 days prior to expected calving; the H TMR was fed ad libitum whereas the L TMR was restricted to 10 kg dry matter/day during late lactation, and to approximately 75% of energy requirements from drying off until calving. Both diets were offered ad libitum post-calving. Feeding diet H compared to L pre calving led to higher BCS at calving (2.68 v. 2.34, P < 0.01). Energy corrected milk yield and energy-intake post-calving were not affected by pre-calving diets. Changes in BCS and blood concentrations of non-esterified fatty acids, beta hydroxybutyrate and glucose in early lactation showed that cows offered diet H pre-calving generally mobilised more body reserves compared to cows offered diet L pre-calving. An interaction between pre- and post-calving diets showed that cows offered diet H pre-calving had lower body tissue mobilisation when offered diet H post-calving compared to diet L. Cows offered diet L pre-calving, did not mobilise differently whether they were offered diet H or L post-calving. The pre- and post-calving diets had no effect on liver triacylglycerol, whereas liver glycogen was higher in cows on treatment HH compared to the other three treatments. Collectively, these results indicate that overfeeding should be avoided in late gestation and that a high-energy-density diet is desirable in early lactation in order to obtain a more favourable metabolic profile. PMID- 22443618 TI - Methionine-hydroxy analogue was found to be significantly less bioavailable compared to dl-methionine for protein deposition in growing pigs. AB - When methionine (Met) is limiting in swine diets, it is commonly supplemented by using anhydrous dl-methionine (DLM, 99% purity) or liquid dl-methionine-hydroxy analogue free acid (MHA-FA, 88% purity). The objective of this experiment was to test the null hypothesis that the bioavailability of DLM and MHA-FA were not different for growing pigs, using the indicator amino acid (AA) (phenylalanine, Phe) oxidation (IAAO) method in a slope-ratio assay. Six barrows (mean BW during study: 21.1 kg) received seven dietary treatments with all pigs receiving all diets in random order at an intake of 95 g/kg BW0.75. The basal diet (BD) contained analyzed content of 15.1% CP, 0.20% Met, 0.73% Phe and all other AA in excess of requirement. The BD was supplemented with three graded levels of DLM or MHA-FA on an equimolar basis. Dietary treatments only varied in Met content and included: (i) BD, (ii) BD + 0.034% DLM, (iii) BD + 0.054% DLM, (iv) BD + 0.086% DLM, (v) BD + 0.029% MHA-FA, (vi) BD + 0.078% MHA-FA and (vii) BD + 0.107% MHA FA, as analyzed. Indicator AA oxidation was determined during 4 h studies, where pigs were fed half-hourly meals each equal to 1/32 of their daily feed allowance. Each meal was mixed with 258.7 kBq (s.e. 2.6) of l-[1-14C]Phe with a prime of 3.5 times the half-hourly dose added to the first meal. The slope of the decrease in IAAO calculated by linear regression analysis was greater (P = 0.012) for DLM supplementation (9.87 +/- 1.450 per g, 1.488 +/- 0.215% per mmol) than for MHA-FA (6.48 +/- 0.89 per g, 1.107 +/- 0.152% per mmol). The ratio of slopes indicated a bioavailability of MHA-FA on a product basis, relative to DLM, of 65.7%. Bioavailability on an equimolar Met basis, calculated from the ratio of the slopes was 74.4% for MHA-FA, relative to DLM. In conclusion, these results indicate that the metabolic bioavailability of MHA-FA for growing pigs is appreciably lower than that of DLM on both an equimolar and a product basis. PMID- 22443619 TI - Effects of physical form and stage of maturity at harvest of whole-crop barley silage on intake, chewing activity, diet selection and faecal particle size of dairy steers. AB - This study examined the effects of physical form and stage of maturity at harvest of whole-crop barley silage (WCBS) on feed intake, eating and rumination activity, diet selection and faecal particle size in dairy steers. Whole-crop barley was harvested and ensiled in round bales. Eight dairy steers (live weight (LW): 350 +/- 10 kg) in a duplicated 4 * 4 Latin square design were fed WCBS harvested at heading or dough stage of maturity in long form or chopped in a 2 * 2 factorial treatment arrangement. The WCBS was supplemented with soybean meal. Daily dry matter (DM) intake increased by 7% (P < 0.05) due to chopping of dough stage silage but was unaffected by chopping of heading-stage silage. The steers fed chopped, but not those fed long dough-stage silage, selected for starch in the WCBS (P < 0.001). The neutral detergent fibre (NDF) intake was 5% higher (P < 0.01) for heading than for dough-stage silage and was associated with lower concentration of indigestible NDF (96 v. 170 g/kg DM). Rate of intake of DM and NDF was 37% higher (P < 0.001), daily eating time was 24% shorter (P < 0.001) and daily chewing time was 8% shorter (P < 0.05) for chopped silage compared with long silage but there was no effect of maturity. Daily rumination time was not affected by treatments, whereas rumination and chewing times per kg NDF intake were 15% and 13% higher (P < 0.05), respectively, for dough-stage than for heading-stage silage. The proportion of faecal particles retained on a 1 mm screen was 30% higher (P < 0.001) due to chopping and 45% higher (P < 0.001) due to delayed harvest. Chopping the dough-stage silage reduced the proportion of grain in faeces from 97 to 43 g/kg DM (P < 0.05) indicating higher starch digestibility. In conclusion, chopping increased DM intake of WCBS when harvested at dough stage but not at heading stage of maturity. PMID- 22443620 TI - Effects of forage NDF content and body condition score on forage intake by Holstein-Friesian dairy cows in the dry period. AB - This study used individual weekly results for 160 non-lactating Holstein-Friesian dairy cows in the last 5 weeks of gestation to develop regression equations based on forage NDF content and individual body condition score (BCS) for predicting dry matter (DM) intake. Results were used from treatments in which cows received the same forage and no concentrates throughout the dry period. Ten different conserved forages, either grass silages or mixtures of grass silage and barley straw, were fed in six different experiments and forage NDF ranged from 452 to 689 g/kg DM. On average cows gained 390 g live weight per day, which is less than conceptus growth at this stage - suggesting some mobilisation of maternal tissues to support conceptus growth. BCS remained unchanged at 2.5 over the dry period. DM intake declined from 10.79 kg/day 5 weeks before calving to 9.32 kg/day in the week before calving, with half of this decline occurring in the final week before calving. Intake as a percentage of live weight was moderately predicted (R2 = 0.61 for the entire period) from measures of diet composition (NDF) and cow state (BCS). There were highly significant negative effects of forage NDF and increased BCS on DM intake. The effect of BCS on DM intake was greatly reduced in the week before calving, possibly as a result of a change in metabolic priorities from gaining to losing body reserves. PMID- 22443621 TI - Offspring born to ewes fed high salt during pregnancy have altered responses to oral salt loads. AB - Prenatal growth is sensitive to the direct and indirect effects of maternal dietary intake; manipulation can lead to behavioural and physiological changes of the offspring later in life. Here, we report on three aspects of how a high-salt diet during pregnancy (conception to parturition) may affect the offspring's response to high oral salt loads: (i) dietary preferences for salt; (ii) response to salt and water balance and aldosterone and arginine vasopressin (AVP) concentrations after an oral salt challenge; (iii) concentrations of insulin and leptin after an oral salt challenge. We used two groups of lambs born to ewes fed either a high-salt (13% NaCl) diet during pregnancy (S lambs; n = 12) or control animals born to ewes fed a conventional (0.5% NaCl) diet during pregnancy (C lambs; n = 12). Lambs were subjected to short- (5 min) and long-term (24 h) preference tests for a high-salt (13% NaCl) or control diet, and the response to an oral challenge with either water or 25% NaCl solution were also carried out. Weaned lambs born to ewes fed high salt during pregnancy did not differ in their preference for dietary salt, but they did differ in their physiological responses to an oral salt challenge. Results indicate that these differences reflect an alteration in the regulation of water and salt balance as the metabolic hormones, insulin and leptin, were not affected. During the first 2 h after a single salt dose, S lambs had a 25% lower water intake compared to the C lambs. S lambs had, on average, a 13% lower AVP concentration than the C lambs (P = 0.014). The plasma concentration of aldosterone was higher in the S lambs than in the C lambs (P = 0.013). Results suggest that lambs born to ewes that ingest high amounts of salt during pregnancy are programmed to have an altered thirst threshold, and blunted response in aldosterone to oral salt loads. PMID- 22443622 TI - Regulation of glucose and protein metabolism in growing steers by long-chain n-3 fatty acids in muscle membrane phospholipids is dose-dependent. AB - A previous study showed that long-chain n-3 polyunsaturated fatty acids (LCn 3PUFA; >18 carbons n-3) exert an anabolic effect on protein metabolism through the upregulation of insulin sensitivity and activation of the insulin signaling pathway. This study further delineates for the first time whether the anabolic effect of LCn-3PUFA on metabolism is dose responsive. Six steers were used to test three graded amounts of menhaden oil rich in LCn-3PUFA (0%, 2% and 4%; enteral infusions) according to a double 3 * 3 Latin square design. Treatment comparisons were made using iso-energetic substitutions of control oil for menhaden oil and using 6-week experimental periods. The LCn-3PUFA in muscle total membrane phospholipids increased from 8%, 14% to 20% as dietary menhaden oil increased. Feeding graded amounts of menhaden oil linearly decreased plasma insulin concentration (49, 35 and 25 MUU/ml, P = 0.01). The insulin-stimulated amino acid disposal rates as assessed using hyperinsulinemic-euglycemic euaminoacidemic clamps (20, 40 and 80 mU/kg per h) were linearly increased by the incremental administrations of menhaden oil from 169, 238 to 375 MUmol/kg per h (P = 0.005) during the 40 mU/kg per h clamp, and from 295, 360 and 590 MUmol/kg per h (P = 0.02) during the 80 mU/kg per h clamp. Glucose disposal rate responded according to a quadratic relationship with the incremental menhaden oil amounts (P < 0.05). A regression analysis showed that 47% of the amino acid disposal rates elicited during the hyperinsulinemic clamp was related to muscle membrane LCn-3PUFA content (P = 0.003). These results show for the first time that both protein and glucose metabolism respond in a dose-dependent manner to menhaden oil and to muscle membrane LCn-3PUFA. PMID- 22443623 TI - Short-term behavioural effects of weaning age in outdoor-reared piglets. AB - Age at weaning affects the behaviour of piglets weaned in conventional confined environments. The adaptation of piglets to this event, which exposes piglets to important stressors, has not been examined in detail in outdoor systems. The aim of this study was to compare the behaviour of piglets weaned at 3 or 4 weeks of age in an outdoor production system. Six replicates of four piglets born and raised outdoors, originated from different litters but previously acquainted, were weaned at the age of approximately 20 (D20) or 30 (D30) days in 36 m2 outdoor pens and offered high-quality diets. Their behaviour was recorded by direct visual observation during four consecutive days after weaning (days 1 to 4). Data were analysed by repeated measures ANOVA. An effect of weaning age was observed on feeding and rooting ( P < 0.01), and a day-by-weaning age interaction for escape attempts, vocalizing, walking and fighting ( P < 0.01), and playing ( P < 0.03). Compared to D30 piglets, D20 piglets showed a higher frequency of escape attempts on day 1, vocalized more during days 1 and 2, and walked more during days 1 to 3 ( P < 0.05). Feeding behaviour, on the other hand, was higher in D30 piglets on days 1 to 3 ( P < 0.05). On days 3 and 4, D30 piglets spent more time interacting with peers (playing and fighting; P < 0.05) and on day 4 were more active than D20 piglets ( P < 0.05). As previously reported in confined environments, age at weaning affected the behaviour of piglets raised on the outdoors system. Weaning appeared to be more stressful for the piglets at 3 than at 4 weeks of age. The impact of weaning age on welfare cannot be ignored, especially when outdoor breeding of pigs is proposed to address welfare concerns of the public. PMID- 22443624 TI - The effects of pasture availability for twin- and triplet-bearing ewes in mid and late pregnancy on ewe and lamb behaviour 12 to 24 h after birth. AB - This experiment was conducted to evaluate the effect of offering ewes two different feeding levels, during mid and late pregnancy, on ewe and lamb behaviour 12 to 24 h after birth. Romney ewes, bearing twin (n = 80) or triplet foetuses (n = 56), were allocated to a pasture sward height of 2 or 4 cm between 70 and 107 days of pregnancy. In late pregnancy (day 107 to 147), half of the ewes were reallocated the alternate sward height, which produced four treatments: 2-2, 2-4, 4-2 and 4-4. Ewes were weighed on days 65, 92, 107 and 130 of pregnancy and lamb live weights were recorded 12 to 24 h after birth. Twelve to 24 h after birth the maternal behaviour score (MBS) of the ewes were determined, whilst their lambs were tagged. After the lambs were released, the behaviour of each ewe and her lambs was observed for 5 min. Ewe treatment and litter size had no effect on ewe MBS. However, as MBS increased (ewes stayed closer to lambs during tagging), ewes bleated less in a high-pitch and were quicker to make contact with their lamb. During the observation period, ewes in the 4-4 treatment had a greater percentage of their bleats in a low pitch (P < 0.05) than ewes in the 2-2 and 4-2 treatment (61.3% v. 41.3% and 38.8% low bleats, respectively) and more lambs born to 4-4 ewes (95%) bleated than lambs born to 2-2 ewes (84%; P < 0.05). However, lambs born to ewes in the 2-2 treatment bleated earlier than lambs in all other treatments (P < 0.05). Lambs born to 4-4 ewes were less likely (P < 0.05) to move towards their dam in order to make contact than lambs born to 2-2 or 4-2 ewes (3.1% v. 16.9% and 16.7%, respectively). These findings suggest that under the conditions of the present study, ewe nutrition had little effect on maternal behaviour. However, lambs born to ewes offered 2 cm pasture sward heights during mid and/or late pregnancy (2-2, 2-4 and 4-2 treatments) displayed behaviour that demonstrated greater 'need' whereas lambs born to ewes offered 4 cm during mid and late pregnancy sought less attention from their dam. PMID- 22443625 TI - Effect of water trough type on the drinking behaviour of pasture-based beef heifers. AB - The objective of this study was to investigate the effects of different trough types on the water consumption and drinking behaviour of pasture-based beef heifers. Two trials were implemented with 32 beef heifers to test two different types of water troughs, namely a rectangular concrete trough (RC) and a round polyvinyl chloride water tank (PVC). In Trial 1, both troughs were simultaneously available to groups of four animals within eight paddocks. In Trial 2, the animals were distributed in pairs throughout 16 paddocks and, in a crossover design, were exposed to one type of trough at a time. In both trials, estimated water intake was per four animals. Number of drinking bouts, time spent drinking and amount of water intake from the RC and PVC trough were recorded in both trials. Data were statistically analysed by analysis of variance. In Trial 1, group and trough effect were in the model. In Trial 2, stage, pair and trough were tested. In Trial 1, where both types of troughs were available, animals had a higher number of drinking bouts (3.32 v. 0.57 +/- 0.09; P < 0.01), longer drinking periods (144.21 v. 22.81 +/- 7.3 s; P < 0.01) and greater intake (160.21 v. 23.76 +/- 13.06 l; P < 0.01) from the PVC water tank, compared to the RC trough. In Trial 2, all groups drank more often (5.10 v. 3.28 +/- 0.32; P < 0.001), for longer periods (167.23 v. 115.23 +/- 15.61 s; P < 0.02) and with higher intake (141.36 v. 118.47 +/- 5.01 l; P < 0.02) from the PVC than from the RC trough. Thus, heifers not only prefer, but also drink more from a PVC water tank in comparison to a RC trough. PMID- 22443626 TI - Merino ewes bred for parasite resistance reduce larval contamination onto pasture during the peri-parturient period. AB - The peri-parturient period is crucial for controlling worms as the acquired immunity of ewes is disrupted, resulting in an increase in faecal worm egg counts. Two hypotheses were tested in this experiment - that ewes bred for worm resistance would have lower faecal worm egg counts than unselected control ewes, during late pregnancy and lactation, under similar but separate grazing areas; and also that numbers of infective nematode larvae would be lower on pastures grazed by resistant ewes than pastures grazed by unselected control ewes. Faecal samples were collected from resistant and unselected ewes in late pregnancy and early lactation, during the winter rainfall season, and analysed for numbers of Trichostrongylus colubriformis and Teladorsagia circumcincta. Pasture samples were taken 1 week before and 7 weeks after lambing started and analysed for infective larvae. In all sheep, worm egg counts rose 2 weeks prior to lambing and continued into lactation. Worm egg counts were significantly lower in the resistant ewes from 1 week before lambing to 2 weeks after lambing. There were no differences in egg counts between single- and twin-bearing ewes in the resistant line. However, twin-bearing control ewes had significantly higher egg counts than single-bearing control ewes. Following lactation, plots grazed by resistant ewes had substantially less contamination with T. colubriformis larvae, but there were no differences in numbers of T. circumcincta larvae. Our results demonstrate that sheep bred for worm resistance has lower worm burdens during the peri-parturient phase and that lambs born to resistant ewes face a lower larval challenge during their introduction to grazing. In our environment, selection for low worm egg counts has produced sheep highly resistant to T. colubriformis, but has had less impact on resistance towards T. circumcincta. PMID- 22443627 TI - The effects of stunning methods on product qualities in force-fed ducks and geese. 1. Carcass downgrading and meat quality. AB - This study investigated the effects of various stunning methods on the quality of carcass and meat in ducks and geese force-fed for the production of French 'foie gras'. The ducks (n = 30 per group) were stunned with one of the following techniques: electrical stunning in a water bath (50 Hz AC, 130 mA, 4 s), head only electrical stunning (50 Hz AC, 600 mA, 4 s), mechanical stunning (captive bolt) and controlled atmosphere stunning (CAS: phase 1, CO2 (40%)-O2 (30%)-N2 (30%), for 2 min followed by phase 2, CO2 > 85% in air, for 2 min). The same methods (except head-only stunning which was not applied) were used in geese (n = 40 per group). During the first 5 min after slaughter, the stunning techniques that did not kill the animals were associated with a high incidence of head movements (mechanical and electrical head-only stunning), convulsions and convulsive wing flapping (mechanical stunning), in both species. Consequently, the rate of post-mortem pH fall in breast muscle was enhanced and the meat was paler when measured at 24 h or 6 days post mortem (L*, a*, b* coordinates). In ducks, the animals stunned in the water bath showed the lowest bleeding efficiency, compared to the three other procedures. In geese, the mechanical stunning allowed the highest recovery of blood compared to the CAS and the water bath methods. Meat texture assessed instrumentally and fluid losses during storage and processing were not affected by the stunning method in any species. Sensory analysis showed a higher score for bloody appearance of raw meat in ducks stunned with the methods that kill before neck cutting (water-bath and CAS). This effect was, however, not linked to the rate of bleeding. The sensory properties of cooked meat were not affected by the stunning method. In both ducks and geese, CAS was associated with the lowest rate of fractures of humeral bone but CAS stunned geese showed the most engorged wing veins. Overall, these results show the positive effect of CAS on the appearance defects of carcass and meat of ducks and geese, and, on the contrary, they confirm the detrimental effects of water bath stunning on these criteria. However, the incidences on meat sensory qualities were scarce. PMID- 22443628 TI - The effects of stunning methods on product qualities in force-fed ducks and geese. 2. Fatty liver quality. AB - This study investigated the effects of various stunning methods on the quality of French 'foie gras' in ducks and geese. The ducks (n = 30 per group) were stunned with one of the following techniques: electrical stunning in a water bath (50 Hz AC, 130 mA, 4 s), head-only electrical stunning (50 Hz AC, 600 mA, 4 s), mechanical stunning (captive bolt) and controlled atmosphere stunning (CAS: phase 1, CO2 (40%)-O2 (30%)-N2 (30%), for 2 min followed by phase 2, CO2 >85% in air, for 2 min). The same methods (except head-only stunning which was not applied) were used in geese (n = 40 per group). The weight of the liver at slaughter was not affected by the stunning techniques, neither was its colour (L*, a*, b* coordinates), despite the differences in bleeding rate between the stunning treatments. The loss of fat during the cooking of canned fatty liver did not depend upon stunning treatment. Some appearance defects of raw fatty livers were significantly affected by the treatment: mechanical and head-only stunning induced higher incidence of petechial haemorrhages in duck liver, whereas in geese, incidence of superficial haemorrhages was significantly higher after CAS and water-bath stunning. The calculation of an overall score based on the incidence and severity of the different appearance defects observed in the present experiment showed that CAS was associated with the least favourable position in ducks as well as in geese, compared to the other treatments. The commercial grading of ducks and geese fatty livers, carried out by an expert from the industry, clearly showed the detrimental effect of CAS on the commercial value of raw livers. CAS, under the conditions applied in the present work cannot be recommended, because of its drastic effect on liver quality. The underlying mechanisms deserve further investigations. PMID- 22443629 TI - Iodine and selenium carry over in milk and cheese in dairy cows: effect of diet supplementation and milk yield. AB - Iodine and selenium are essential trace elements involved in the regulation of thyroid metabolism and antioxidant status. Two experiments were undertaken on lactating cows to determine the milk concentrations of iodine and selenium, carry over (CO) in milk, the fraction in curdle portion and how milk yield affects the milk iodine and selenium concentrations and CO. Sources of elements were potassium iodide and sodium selenite. In Experiment 1, 12 cows were randomly allotted to three diet groups in a completely randomized design: control group (CTR) - total mixed ration (TMR) containing 1.71 and 0.08 mg/kg dry matter (DM); Group 1 (T1) - TMR plus 23.8 and 2.2 mg; Group 2 (T2) - TMR plus 45.5 and 4.3 mg, respectively, for iodine and selenium. In Experiment 2, 30 cows were allotted to three groups according to milk yield: high (H), average (A) and low (L). Within each group, cows were randomly assigned two levels of iodine and selenium: Level 1: TMR containing 1.55 and 0.15 mg/kg DM; Level 2: TMR plus 47.2 mg and 8.0 mg, respectively, iodine and selenium. In both experiments, individual milk samples were collected and analyzed for iodine and selenium contents. In Experiment 1, Grana Padano cheese was obtained at lab scale and the iodine and selenium fractions in the curd were measured. In Experiment 1, the iodine intake increased (P < 0.001) the concentration and total excretion in milk. The CO increased (P < 0.05) from 16 (CTR) to 27 (T1) and 26% (T2); the sampling time was significant (P < 0.05) with no interaction with treatments. Concentration of selenium in milk was increased (P < 0.05) by treatment and CO decreased (P < 0.01) from 26 (CTR) to 12 (T1) and 9% (T2). The iodine showed a mild enrichment factor in the curdle (about 1.7-fold), whereas selenium enriched five- to sevenfold. In Experiment 2, the level of iodine supplementation affected (P < 0.05) the concentration and total excretion in milk. No effects on milk iodine concentration were related to milk yield or milk yield * treatment interaction; however, the iodine excretion in milk was major (P < 0.05) in higher yielding groups. The iodine CO was affected (P < 0.05) by the milk yield in supplemented groups. The selenium milk concentration and excretion were affected (P < 0.01) by the milk yield, whereas the CO was affected (P < 0.05) by the milk yield and selenium supplementation. Results highlight the possibility of fortification with iodine in milk and selenium in cheese through animal feeding. PMID- 22443630 TI - The mechanism of carvedilol in experimental viral myocarditis. AB - Carvedilol is a nonselective beta-blocker with alpha1-adrenergic blocking and antioxidant properties. A number of preclinical experiments and clinical trials have demonstrated that carvedilol provides prominent benefit in heart failure. However, less research has been done in the area of animal models of viral myocarditis. This paper reviews the use of carvedilol in animal models of viral myocarditis. The experimental evidence strongly suggests that carvedilol, but not metoprolol (a selective beta1-adrenergic blocking agent), protects against viral myocarditis and the superior cardioprotection effect of carvedilol to metoprolol may be due to its upregulating the production of antiinflammatory cytokines, downregulating the production of proinflammatory cytokines, antioxidative effects, the suppression of matrix metalloproteinases production, and positive hemodynamic effects. PMID- 22443631 TI - Cucurbitacins as inducers of cell death and a rich source of potential anticancer compounds. AB - Triterpenes have been reported to induce cell death. One relevant group of this family of compounds is cucurbitacins, which have been studied as inducers of apoptosis in various cancer cell lines. The most significant mechanisms with regard to the apoptotic effects of cucurbitacins are their ability to modify transcriptional activities via nuclear factors or genes and their capability to activate or inhibit pro- or anti-apoptotic proteins. Still, while the majority of studies on these compounds have dealt with their apoptotic effects on cancer cell lines, several research groups have also explored their anti-inflammatory activities. In general, cucurbitacins are considered to be selective inhibitors of the JAK/STAT pathways; however, other mechanisms may be implicated in their apoptotic effects, including the MAPK pathway (known to be important for cancer cell proliferation and survival), PARP cleavage, expression of active caspase-3, decreased pSTAT3 and JAK3 levels, as well as decreases in various downstream STAT3 targets such as Mcl-1, Bcl-2, Bcl-xL, and cyclin D3, all of which are implicated in apoptosis and the cell cycle. Taking all these effects into account, cucurbitacins may prove useful in the treatment of different kinds of cancers, especially when used with other cytostatic agents. PMID- 22443632 TI - Organocatalysis as a safe practical method for the stereospecific dibromination of unsaturated compounds. AB - Organocatalytic stereospecific dibromination of a wide variety of functionalized alkenes was achieved using a stable, inexpensive halogen source, 1,3-dibromo 5,5 dimethylhydantoin, and a simple thiourea catalyst at room temperature. The presence of a tertiary amine enhanced the rate of the dibromination reaction, and yields were good in various solvents, including aqueous solvents. The procedure was extended to alkynes and aromatic rings and to dichlorination reactions by using the 1,3-dichloro hydantoin derivative. PMID- 22443634 TI - Special issue: Cytochrome P450 structure and function: introduction. AB - The 17th International Conference on Cytochrome P450 Biochemistry, Biophysics and Structure was held in Manchester, UK from 26-30 June 2011. This issue of FEBS J. contains review and primary research articles reflecting the breadth of science covered at this conference, and reflecting the impact of P450-related research in fields as diverse as steroid metabolism, plant biochemistry, structural biology and biotechnology. PMID- 22443633 TI - Harmful effects of carbamazepine on the postnatal development of the rat ventral prostate. AB - BACKGROUND: Carbamazepine (CBZ) is a first-line antiepileptic drug (AED), although it is also used for the treatments of psychiatric disorders and neuropathic pain. The CBZ utilization has been associated with male reproductive damage, including hormonal alterations, sexual dysfunction and reduction of sperm quality. The wide and long-term use of the CBZ is a common schedule in children and adolescents and alters the testosterone level in adult rats and humans. The objective of this work was to evaluate the CBZ side effects on the ventral prostate of rats from pre-puberty to sexual maturation, since the prostate is an androgen-dependent organ. METHODS: Twenty three day-old male albino Wistar rats received CBZ diluted in propylene glycol (20 mg/Kg/i.p via). The treatment lasted 20, 40 and 70 days, according to the different stages of the rat sexual maturation. At the end of each treatment period, ventral prostates were removed and histologically processed. The prostate sections were submitted to the histopathological, morphological and stereological analyses using image analysis system. RESULTS: Reductions of the glandular epithelium, glandular lumen and fibromuscular stroma volume of the ventral prostate were observed in adult rats treated with CBZ since the weaning. Triggering and degranulation of mast cells were observed in the fibromuscular stroma of prepubertal and pubertal CBZ treated rats. CONCLUSIONS: The results suggest a direct effect of the CBZ on rat ventral prostate, evidenced by increase of mast cell and macrophage populations during pre-puberty and puberty causing a ventral prostate accentuated damage in the adult phase. PMID- 22443635 TI - Optimizing solute-water van der Waals interactions to reproduce solvation free energies. AB - An accurate representation of solute-water interactions is necessary for molecular dynamics simulations of biomolecules that reside in aqueous environments. Modern force fields and advanced water models describe solute solute and water-water interactions reasonably accurately but have known shortcomings in describing solute-water interactions, demonstrated by the large differences between calculated and experimental solvation free energies across a range of peptide and drug chemistries. In this work, we introduce a method for optimizing solute-water van der Waals interactions to reproduce experimental solvation free energy data and apply it to the optimization of a fixed charge force field (AMBER ff99SB/GAFF) and advanced water model (TIP4P-Ew). We show that, with these optimizations, the combination of AMBER ff99SB/GAFF and TIP4P-Ew is able to reproduce the solvation free energies of a variety of biologically relevant small molecules to within 1.0 k(B)T. We further validate these optimizations by examining the aggregation propensities of dipeptide-water solutions, the conformational preferences of short disordered peptides, and the native state stability and dynamics of a folded protein. PMID- 22443637 TI - Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution's experience and summary of the literature. AB - AIM: To determine the efficacy of the ketogenic diet for children with Lennox Gastaut syndrome (LGS) at our institution and in the literature. METHOD: The records of children with LGS initiated on the ketogenic diet at our institution from 1994 to 2010 were reviewed. Inclusion criteria included the presence of <=2.5Hz spike-and-wave complexes on electroencephalogram, multiple seizure types including tonic, atonic, or atypical absence, developmental delay, and age under 1 year. We additionally reviewed the literature for cases of LGS treated with the ketogenic diet and their outcomes. RESULTS: Seventy-one children (41 males, 30 females, median age 3y 6mo, range 18mo-18y), with LGS were initiated on the ketogenic diet. Using an intent-to-treat analysis, after 6 months, 36 (51%) achieved more than 50% seizure reduction, 16 (23%) experienced more than 90% seizure reduction, and 1 (1%) achieved seizure freedom. Results were similar after 12 months. Age, sex, side effects, valproate use, and history of infantile spasms were not predictive of more than 90% seizure reduction. In the literature, 88 of 189 (47%) children with LGS had more than 50% seizure reduction after 3 to 36 months of ketogenic diet treatment. INTERPRETATION: The ketogenic diet is efficacious in the treatment of LGS, with approximately one-half of children responding at 12 months. PMID- 22443638 TI - Virulence genes of Porphyromonas gingivalis W83 in chronic periodontitis. AB - OBJECTIVE: To identify virulence genes found in highly virulent strains of Porphyromonas gingivalis (P. gingivalis) among Chinese patients with chronic periodontitis and to evaluate the association of these virulence genes with clinical parameters and with periodontal tissue destruction. MATERIAL AND METHODS: Suppression subtractive hybridization was applied to acquire short gene fragments harbored only in virulent strains of P. gingivalis W83. Eighteen genes, which were present in P. gingivalis W83 but absent from P. gingivalis ATCC 33277, were labeled with Cy5 and used as probes in DNA microarray hybridization to analyze DNA of P. gingivalis isolated from chronic periodontitis patients. RESULTS: Spearman correlation analysis revealed 10 genes correlated with probing depth, clinical attachment loss, and tooth mobility (p<0.05). CONCLUSION: These genes may provide an important clue towards our understanding the mechanism of occurrence and the development of periodontal disease. PMID- 22443639 TI - Intrapleural therapy in empyema thoracis: a contemporary solution to an age-old problem? PMID- 22443640 TI - Human lung stem cells: has the future arrived? AB - An intriguing paper was recently published that describes c-kit-positive human lung stem cells that self-renew and differentiate into multiple lineages. While these findings are potentially therapeutically exciting, several questions remain to be answered. We review the paper and the issues that have arisen. PMID- 22443641 TI - Barrett's esophagus and cancer risk: a more realistic estimate. AB - The cancer risk in patients with Barrett's esophagus is important because it determines screening, surveillance, and treatment considerations. Previously, the risk of progression to esophageal adenocarcinoma in patients with Barrett's esophagus was thought to be approximately 1%. Recently, 2 very large population based studies have significantly reduced this risk estimate of cancer. Paradoxically, esophageal adenocarcinoma continues to rise exponentially in the United States. Screening and surveillance programs based on endoscopic, histopathological, and molecular criteria need to be improved to identify a high risk population of progressors. PMID- 22443642 TI - Airway stenting for emphysema: back to the drawing board. AB - In a recent report, authors describe their findings from the Exhale Airway Stents for Emphysema (EASE) trial. In this study, investigators follow patients with emphysema and severe hyperinflation after a novel bronchoscopic lung-volume reduction procedure utilizing paclitaxel-eluting stents. Despite the merits of this randomized, sham-controlled, multi-institutional study, the authors were unable to demonstrate any sustainable benefit for the treatment group upon follow up. Nonetheless, important lessons can be learned from this trial, which has set a foundation for future investigations. PMID- 22443643 TI - Partner IA: what it means for surgeons. PMID- 22443644 TI - Percutaneous treatment of mitral regurgitation: current status and future directions. AB - The burgeoning field of catheter-based, percutaneous valve intervention takes an interdisciplinary approach to mitral valve regurgitation with the goal of maximizing clinical outcomes and minimizing procedure-associated morbidity. This exciting field continues to push the boundaries of technological innovation as it expands the armamentarium available to treat valvular disease. Around the world teams are working to create a catheter-based approach that is practical and durable. Several technologies are in various stages of development and clinical application. PMID- 22443645 TI - Innovative clinical trial design in cardiac surgery. PMID- 22443646 TI - Hybrid options for treating cardiac disease. AB - The options for treating heart disease have greatly expanded during the course of the last 2 1/2 decades with the advent of hybrid technology. The hybrid option for treating cardiac disease implies using the technology of both interventional cardiology and cardiac surgery to treat cardiac disease. This rapidly developing technology has given rise to new and creative techniques to treat cardiac disease involving coronary artery disease, coronary artery disease and cardiac valve disease, and atrial fibrillation. It has also led to the establishment of new procedural suites called hybrid operating rooms that facilitate the integration of technologies of interventional cardiology catheterization laboratories with those of cardiac surgery operating rooms. The development of hybrid options for treating cardiac disease has also greatly augmented teamwork and collaboration between interventional cardiologists and cardiac surgeons. PMID- 22443647 TI - Personalized therapy for non-small cell lung cancer: which drug for which patient? AB - The elucidation of the molecular alterations in non-small cell lung cancer (NSCLC) and the development of molecularly targeted agents have permanently shifted NSCLC therapy to a personalized approach. In the metastatic setting, the addition of the anti-vascular endothelial growth factor monoclonal antibody, bevacizumab, to chemotherapy improves overall survival. The oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, prolong progression-free survival in patients selected for the presence of an EGFR activating mutation. The monoclonal antibody to EGFR, cetuximab, improves survival in patients with metastatic NSCLC, and the inhibitor of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein, crizotinib, has resulted in an unprecedented overall survival advantage in patients harboring the EML4-ALK translocation. In the adjuvant setting, gefitinib has not been shown to improve patient survival outcomes; however, there are several ongoing clinical trials in the adjuvant setting evaluating the role of erlotinib, bevacizumab, and the MAGE-A3 and MUC1 vaccines. The realm of personalized lung cancer therapy also includes the study of chemotherapy selected on the basis of the pharmacogenetic profile of a patient's tumor. Several ongoing clinical trials in both the metastatic and adjuvant settings are studying the excision repair cross-complementing group 1 (ERCC1) protein, the ribonucleotide reductase subunit 1 (RRM1) protein, thymidylate synthase, and BRCA1 as predictors of chemotherapy response. This review will outline the current state of the art of personalized NSCLC therapy. PMID- 22443648 TI - Current surgical therapy for stage IIIA (N2) non-small cell lung cancer. AB - Local therapy alone (surgery or radiation) leads to poor overall survival in patients with stage III non-small cell lung cancer because most of these patients die of distant metastases. During the past 20 years, studies have focused on developing effective chemotherapy regimens that can be combined with local therapies (surgery and/or radiation). The role of surgery has been evaluated, and the selection criteria for resection have been defined. PMID- 22443649 TI - Chest physiotherapy in lung resection patients: state of the art. AB - The role of chest physiotherapy in limiting postoperative pulmonary complications and in the recovery of pulmonary function and exercise capacity after lung surgery is still unclear because of the lack of conclusive, well-designed clinical trials. In this article the available literature on these topics is reviewed, and the effects of respiratory physiotherapy, instituted preoperatively or administered after surgery to patients undergoing lung resection, are commented on. The authors conclude that chest physiotherapy improves preoperative exercise capacity; this is a parameter highly predictive of postoperative pulmonary complications. Also physiotherapy administered during the immediate period after lung resection probably decreases frequency of pulmonary complications. Finally, further investigation is required for a better understanding of the effects of long-term chest physiotherapy after hospital discharge in lung resection patients. PMID- 22443650 TI - Chest wall resection and reconstruction according to the principles of biomimesis. AB - Biomimesis has become the objective of the reconstructive strategies after chest wall resections for primary or secondary tumors. Biomimesis is pursued by respecting the anatomy, preserving function, selecting adequate reconstructive materials, and integrating multidisciplinary efforts for complex reconstructions. Elements of novelty in the clinical practice are represented by the introduction of the principles of video-assisted thoracic surgery to resect chest wall tumors and the increasingly frequent resort to either new materials or revised concepts of time-honored ones for chest wall reconstruction. Experimental investigation seems to outline interesting perspectives for materials destined to reconstruction after either partial or full-thickness resections for recurrent chest wall tumors. PMID- 22443651 TI - Myocardial preservation: beating heart techniques. PMID- 22443652 TI - Myocardial preservation: controlled reperfusion. AB - Reperfusion injury after reestablishing coronary flow by releasing the aortic cross clamp after cardiac surgery with cardioplegic arrest causes myocardial damage and even death. Attenuation of this reperfusion response by controlling the biochemical and physical environment can avoid morbidity and mortality. Use of a warm reperfusate with addition of drugs that are known to decrease reperfusion injury with manipulation of coronary vascular resistance and the physical parameters of the reperfusion environment helps the heart to reestablish coronary perfusion while decreasing the harm produced by the period of ischemia that occurs during cardiac surgery with intermittent cardioplegic arrest. PMID- 22443653 TI - Introduction: superior vena cava and innominate vein reconstruction in thoracic malignancies. PMID- 22443654 TI - Superior vena cava and innominate vein reconstruction in thoracic malignancies: single-vein reconstruction. AB - Benign or malignant disease processes involving the superior vena cava can be resected and reconstructed with excellent perioperative results and sustained durability. PMID- 22443655 TI - Superior vena cava and innominate vein reconstruction in thoracic malignancies: double-vein reconstruction. PMID- 22443656 TI - Superior vena cava and innominate vein reconstruction in thoracic malignancies: cryopreserved graft reconstruction. PMID- 22443657 TI - Managing extreme airway size mismatch in lung transplantation: the "upper lobectomy" technique. PMID- 22443658 TI - Nonanatomical mitral valve replacement in the pulmonary venous confluence for heavily calcified aortic or mitral annulus. AB - Mitral valve replacement surgery after previous aortic valve surgery can be extremely challenging. The presence of heavy calcification and scarring in the aortic and/or mitral annulus can make suture placement nearly impossible. Although novel techniques have been described, even these alternatives might not be feasible. We present a case of nonanatomical mitral valve replacement in the pulmonary venous confluence as a salvage operation. This can provide adequate hemodynamics and survival until a subsequent care plan can be established. PMID- 22443659 TI - Detection of quantitative trait loci for teat number and female reproductive traits in Meishan * Large White F2 pigs. AB - A quantitative trait locus (QTL) analysis of female reproductive data from a three-generation experimental cross between Meishan (MS) and Large White (LW) pig breeds is presented. Six F1 boars and 23 F1 sows, progeny of six LW boars and six MS sows, produced 573 F2 females and 530 F2 males. Six traits, i.e. teat number (TN), age at puberty (AP), ovulation rate (OR), weight at mating (WTM), number of viable embryos (NVE) and embryo survival (ES) at 30 days of gestation were analysed. Animals were genotyped for a total of 137 markers covering the entire porcine genome. Analyses were carried out based on interval mapping methods, using a line-cross (LC) regression and a half-full sib (HFS) maximum likelihood test. Genome-wide (GW) highly significant (P < 0.001) QTL were detected for WTM on SSC 7 and for AP on SSC 13. They explained, respectively, 14.5% and 8.9% of the trait phenotypic variance. Other GW significant (P < 0.05) QTL were detected for TN on SSC 3, 7, 8, 16 and 17, for OR on SSC 4 and 5, and for ES on SSC 9. Two additional chromosome-wide significant (P < 0.05) QTL were detected for TN, three for WTM, four for AP, three for OR, three for NVE and two for ES. With the exception of the two above-mentioned loci, the QTL explained from 1.2% to 4.6% of trait phenotypic variance. QTL alleles were in most cases not fixed in the grand parental populations and Meishan alleles were not systematically associated with higher reproductive performance. PMID- 22443660 TI - Partition of the genetic trend to validate multiple selection decisions. AB - In this note, a procedure to partition the genetic trend of a selected population is presented. Each part of the genetic gain accounts for the Mendelian sampling terms of different groups of animals, which can be sometimes assigned to different selection policies. The method is based on a simple transformation of the predicted breeding values. The procedure was illustrated with two simulated examples. In the first example, the genetic trend is partitioned into two pieces, one coming from the selection on sires and the other coming from the selection on dams. The second example shows how the impact of an artificial insemination center in the genetic gain of the whole population can be evaluated. PMID- 22443661 TI - Effects of dietary protein supply, weaning age and experimental enterotoxigenic Escherichia coli infection on newly weaned pigs: performance. AB - An experiment was conducted to investigate the effects of post-weaning dietary protein supply and weaning age on the performance of pigs in the absence of in feed antimicrobial growth promoters (AGP) when artificially challenged with enterotoxigenic Escherichia coli (ETEC), a pathogen associated with post-weaning colibacillosis (PWC). The experiment consisted of a complete 2 * 2 * 2 factorial combination of two weaning ages (4 v. 6 week), two levels of dietary protein (H, 230 g CP/kg v. L, 130 g CP/kg) and challenge with ETEC (+ v. -). An additional four treatments were added to test for the effects of protein source (DSMP, dried skimmed milk powder v. SOYA, soybean meal) and AGP inclusion (yes v. no) on challenged pigs of both weaning ages. At weaning (day 0), pigs were assigned to one of the experimental treatments for 2 weeks. On day 14 post-weaning, the same standard grower ration was fed to all animals until 10 weeks of age. On day 3 post weaning, challenged pigs were administered per os with 109 cfu ETEC. The ETEC challenge had a detrimental short-term effect on performance, decreasing average daily gain (ADG) (days 3 to 6; P = 0.014) in both 4- and 6-week weaned animals. Compared with their non-infected counterparts, challenged 4-week weaned pigs on the H diet demonstrated a larger decrease in ADG immediately post infection than those on the L diet, -42% and -25%, respectively (P = 0.088). This effect was smaller in the 6-week weaned pigs, -26% and -19% for the H and L diets, respectively. Pigs fed SOYA had lower (P < 0.001) daily intake and ADG (day 0 to 14) than those fed DSMP, with 6-week weaned pigs being affected to a greater extent than 4-week weaned pigs. In the absence of AGP, increasing weaning age and decreasing dietary protein level, especially in earlier weaned pigs, may help to minimise the effects of PWC on performance, particularly in sub-optimal environments. PMID- 22443662 TI - Effects of dietary protein supply, weaning age and experimental enterotoxigenic Escherichia coli infection on newly weaned pigs: health. AB - Weaning is often associated with post-weaning colibacillosis (PWC), caused by enterotoxigenic Escherichia coli (ETEC). The objective was to investigate the effects of manipulating dietary protein supply and increasing weaning age on enteric health and ETEC shedding of newly weaned pigs exposed to an experimental ETEC challenge. The experiment consisted of a complete 2 * 2 * 2 factorial combination of weaning age (4 v. 6 weeks), dietary protein content (H, 230 g crude protein (CP)/kg v. L, 130 g CP/kg) and experimental ETEC challenge (+ v. ); all foods were free from in-feed antimicrobial growth promoters (AGP). An additional four treatments were added to allow the effect of protein source (DSMP, dried skimmed milk powder v. SOYA, soybean meal) and AGP inclusion (yes v. no) to be investigated in challenged pigs of both weaning ages. On day 3 post weaning challenged pigs were administered per os with 109 cfu ETEC O149. A subset of pigs was euthanased on days 0 and 6 post weaning to assess enteric health and small intestine morphology. Both weaning age and dietary protein content affected the consequences of ETEC challenge. ETEC excretion persisted longer in the 4-week weaned pigs than those weaned at 6 weeks. Although not significant, the numbers of ETEC shed in the faeces post infection (days 4 to 14) were higher on the H than L diet, especially in the 4-week-weaned pigs (P = 0.093). Lowering CP level led to significantly firmer faeces post challenge (days 3 to 6) and decreased colonic digesta pH. Protein level had no effect on small intestine villous heights or crypt depths. There was no significant effect of protein source on ETEC excretion or enteric health. Results suggest that increasing weaning age and decreasing the level of dietary protein, especially in earlier weaned pigs, may help to maintain enteric health and minimise the effects of PWC. PMID- 22443663 TI - Heat production and retained energy in lactating cows held under hot summer conditions with evaporative cooling and fed two rations differing in roughage content and in vitro digestibility. AB - The objective of this study was to measure the effect of feeding two total mixed rations (TMRs), differing in their roughage content and in vitro dry matter (DM) digestibility, on the physiological response and energy balance of lactating cows. The partitioning of metabolizable energy intake (MEI) between heat production (HP) and retained energy (RE) of cows held under hot weather conditions and external evaporative cooling was measured. In all, 42 lactating cows were divided into two similar sub-groups, each of 21 animals, and were fed either a control (CON) ration containing 18% roughage neutral detergent fiber (NDF) or an experimental (EXP) TMR containing 12% roughage NDF and used soy hulls as partial wheat silage replacer. The in vitro DM digestibility of the CON and EXP TMR was 75.3% and 78.6%, respectively (P < 0.05). All cows were cooled by evaporative cooling for 2 adaptation weeks plus 6 experimental weeks under hot weather conditions. The EXP diet reduced rectal temperature and respiratory rate of the cows while increasing their DM intake (DMI) from 23.1 to 24.7 kg/cow per day, milk yield from 41.9 to 44.2 kg and yield of energy-corrected milk from 38.7 to 39.7 kg, as compared with the CON group. Cows fed the EXP TMR had increased RE in milk and body tissue, as compared with the CON group, but the diets had no effect on the measured HP that was maintained constant (130.4 v. 130.8 MJ/cow per day) in the two groups. The measured MEI (MEI = RE + HP) and the efficiency of MEI utilization for RE production were also similar in the two dietary groups. PMID- 22443664 TI - Digestion, rumen fermentation and circulating concentrations of insulin, growth hormone and IGF-1 in steers fed diets based on different proportions of maize silage and grass silage. AB - Replacing grass silage with maize silage results in a fundamental change in the ratio of structural to non-structural carbohydrates with commensurate changes in rumen fermentation patterns and nutrient utilisation. This study investigated the effects of feeding four forage mixtures, namely grass silage (G); 67 g/100 g grass silage + 33 g/100 g maize silage (GGM); 67 g/100 g maize silage + 33/100 g grass silage (MMG); maize silage (M) to four ruminally and duodenally canulated Holstein Friesian steers. All diets were formulated to be isonitrogenous (22.4 g N/kg DM) using a concentrate mixture. Dietary dry matter (DM) and organic matter (OM) digestibility increased with ascending maize silage inclusion (P < 0.1) whereas starch and neutral detergent fibre digestibility declined (P < 0.05). Ratio of non-glucogenic to glucogenic precursors in the rumen fluid increased with maize silage inclusion (P < 0.01) with a commensurate reduction in rumen pH (P < 0.05). Mean circulating concentrations of insulin were greatest and similar in diets MMG and GGM, lower in diet M and lowest in diet G (P < 0.01). There were no effects of diet on the mean circulating concentration of growth hormone (GH), or the frequency, amplitude and duration of GH pulses, or the mean circulating concentrations of IGF-1. Increasing levels of DM, OM and starch intakes with the substitution of grass silage with maize silage affected overall digestion, nutrient partitioning and subsequent circulating concentrations of insulin. PMID- 22443665 TI - Effect of organic and inorganic selenium sources in sow diets on colostrum production and piglet response to a poor sanitary environment after weaning. AB - The objectives of this study were to determine the effect of the chemical form of selenium (Se) fed to sows (1) on production and immune quality of colostrum and (2) on piglet response to a deterioration of sanitary conditions after weaning. Twenty-two pregnant sows were assigned to receive a diet supplemented with 0.3 ppm Se from either sodium selenite (inorganic Se) or Se-enriched yeast (organic Se as Sel-Plex(r); Alltech Inc., Nicholasville, KY, USA). Dietary treatments were applied during the last month of pregnancy and lactation. Blood samples were collected on sows before dietary treatment, on the day of weaning and 6 weeks later, and on three to five piglets within litters at birth, at weaning and 6 weeks post weaning. Whole blood was analysed for Se concentration. Colostrum samples were collected at 0, 3, 6 and 24 h post partum and milk samples on days 14 and 27 of lactation. Colostrum and milk were analysed for Se and immunoglobulin G (IgG) concentrations. At weaning, 40 pairs of littermate piglets were moved to rooms where sanitary conditions were good or purposely deteriorated. Piglets were reared individually and fed ad libitum. After 15 days, piglets and feed refusals were weighed and a blood sample was collected to measure plasma haptoglobin concentration. When sows were fed organic Se, Se concentrations were increased by 33% in colostrum (P < 0.05), 89% in milk (P < 0.001) and by 28% in whole blood of piglets at weaning (P < 0.001). Colostrum production during the 24 h after the onset of farrowing and IgG concentrations in colostrum and milk did not significantly differ between the two groups of sows. Weaned piglets reared in good sanitary conditions grew faster (P < 0.001) than piglets housed in poor conditions. Sanitary conditions did not influence mean plasma haptoglobin concentrations of piglets (P > 0.1). The source of Se fed to the dams did not influence piglet performance or haptoglobin concentrations after weaning. These findings confirm that, compared with inorganic Se, organic Se fed to the dam is better transferred to colostrum and milk, and consequently to piglets. They indicate that the Se source influences neither colostrum production nor IgG concentrations in colostrum, and that the higher Se contents of piglets does not limit the reduction of growth performance when weaning occurs in experimentally deteriorated sanitary conditions. PMID- 22443666 TI - Physicochemical properties and nutritional quality of raw cereals for newly weaned piglets. AB - The digestibility of the starch component of raw cereals in newly weaned piglets is highly variable. Reasons for this must be elucidated if the most suitable cereals are to be used. A novel approach was employed, which consisted of assessing the physicochemical properties (rapid visco analysis, water absorption and solubility indices, particle size distribution and in vitro amylolytic digestion) of eight raw cereals contained within piglet diets and subsequently relating this in vitro data to the biological responses of weaned piglets. Trial 1 examined soft and hard wheat, trial 2 - soft wheat, barley, rye and triticale, and trial 3 - soft wheat, naked oats, whole oats and maize. The initial observation was that in vitro testing prior to animal trials is recommended in nutritional evaluation since it indicated fundamental differences between raw cereals, such as for example the levels of endogenous amylase in wheat. Starch and nitrogen digestibility differed between cereals (apparent digestibility coefficients at the 0.5 site of the small intestine ranged from 0.10 to 0.69 for starch and from 0.17 to 0.68 for nitrogen). There is also a probable relationship between the coefficients of ileal apparent starch digestibility, at approximately halfway from the gastric pylorus to the ileocaecal valve, and the presence of endogenous amylase (mean values of 0.53 and 0.62 in trials 2 and 3, respectively, for the higher amylase wheat; 0.38 for the low-amylase wheat used in trial 1). This additional variable (i.e. the unforeseen presence of endogenous amylase) in wheat made it more difficult to draw a firm conclusion about the nutritional suitability of the different cereals. All raw-cereal diets caused atrophy of the villi during the initial week following weaning, but the soft wheat was associated with the highest comparative villi height and might therefore be considered the best of all raw cereals in minimising the post-weaning growth check. For wheat, this might also suggest a possible interaction between villus architecture and endosperm texture in the immediate post-weaning period. PMID- 22443667 TI - Birth of the first mithun ( Bos frontalis) calf through artificial insemination. AB - The study describes the standardization of a suitable semen cryopreservation protocol for the first time in mithun (Bos frontalis) and birth of the first mithun calf through artificial insemination. The semen samples were collected from adult bulls through the rectal massage method and cryopreserved in liquid nitrogen using tris-egg yolk-glycerol diluent. The diluted semen samples were packaged in 0.50 ml straws and kept at 5 degrees C for 4 h for equilibration. Following the equilibration, the straws were frozen into liquid nitrogen vapour for 10 min and then plunged into liquid nitrogen for storage. It was observed that the progressive motility (%) decreased significantly (P < 0.01) in cryopreserved semen (43.3 +/- 4.1) compared with fresh samples (76.6 +/- 3.3). The percentages of live spermatozoa (P < 0.01) and spermatozoa with intact acrosome (P < 0.05) also decreased significantly in cryopreserved semen (54.0 +/- 3.3 and 64.6 +/- 5.3) compared with fresh samples (79.3 +/- 2.6 and 85.3 +/- 1.8). Simultaneously, the total morphological abnormality (%) was found to be significantly (P < 0.01) higher in cryopreserved samples (15.46 +/- 2.68) than in fresh semen (3.85 +/- 0.63). A total of three mithun cows were inseminated using the cryopreserved semen. All the cows conceived following insemination and gave birth to healthy calves. The study revealed that mithun semen can be cryopreserved efficiently using tris-egg yolk-glycerol diluent, which can be further used for artificial insemination. PMID- 22443668 TI - Effect of dietary enrichment with either n-3 or n-6 fatty acids on systemic metabolite and hormone concentration and ovarian function in heifers. AB - The objective of this experiment was to examine the effects of dietary n-3 or n-6 fatty acid (FA) supplementation on blood FA, metabolite and hormone concentrations, follicle size and dynamics and corpus luteum (CL) size. Reproductively normal heifers (n = 24) were individually fed diets of chopped straw and concentrate containing either (i) no added lipid (CON; n = 8); (ii) 2% added fat as whole raw soya beans (WSB, n-6; n = 8); or (iii) 2% added fat as fish oil (FO, n-3; n = 8). Following oestrous cycle synchronisation, blood samples were collected at appropriate times and intervals for the measurement of hormones, FAs and metabolites. On days 15 and 16 of the cycle, animals were subjected to an intravenous oxytocin challenge and prostaglandin F2alpha (PGF2alpha) response, measured as venous concentrations of 13,14-dihydro-15-keto PGF2alpha (PGFM). Dry matter intake and average daily gain were similar among treatments (P > 0.05). Plasma concentration of linoleic acid was highest on WSB (P < 0.05), while eicosapentaenoic (EPA, n-3; P < 0.0001) and docosahexaenoic acid (DHA, n-3; P < 0.0001) were greatest in the FO group. Plasma concentrations of arachidonic acid were higher on FO (P < 0.05) compared with CON and WSB. Plasma triglyceride concentrations increased, while beta-hydroxybutyrate (BHBA) decreased with time on all diets (P < 0.05). There was a diet * time interaction (P < 0.01) for non-esterified fatty acid (NEFA) concentrations. Plasma cholesterol was higher on WSB and FO (P < 0.01) compared with CON. Progesterone (P4) and oestradiol (E2) concentrations, as well as follicle growth rate and CL diameter were similar across diets (P > 0.05). There was a diet * day interaction for PGFM (P < 0.01). When corrected for systemic E2 : P4 ratio, day 15 concentrations of PGFM were higher in the WSB group at 15 and 30 min (P < 0.01) post oxytocin administration compared with CON and FO, which were similar (P > 0.05). Concentrations of PGFM on day 16 were similar for WSB and FO and were greater than CON at 15 (P < 0.01) and 45 min (P < 0.05) post oxytocin administration, and at 30 min for FO (P < 0.05). With the exception of PGFM, dietary lipid source did not affect the reproductive variables measured. PMID- 22443669 TI - Positive attitudes of farmers and pen-group conservation reduce adverse reactions of bulls during transfer for slaughter. AB - Transfer to slaughter may be very stressful for cattle and negatively affect their ultimate carcass pH. A potential link between farmers' attitudes, farmers' behaviour, responses of animals to handling and carcass pH in beef bull production was questioned. Whether carcass pH depends on experiences in handling and social mixing was analysed. We conducted a survey on commercial farms where we questioned farmers on their work and beliefs about bulls. Farmers' behaviour with bulls during a test and bulls' behaviour during loading in the truck for transport to the slaughterhouse were observed. The ultimate carcass pH was measured. Farmers tended to behave more gently with their bulls when they had positive attitudes towards gentle contacts with bulls (P = 0.07). The loading of bulls in the truck tended to be more difficult when the farmer was more ready to approach his bulls (P = 0.07). Carcass pH was higher for bulls that had not been transferred from a breeding to a finishing unit (P = 0.03). It tended to be higher when the farmer did not display a gentle behaviour (P = 0.09). The link between farmers' attitudes and farmers' behaviour and the lower meat pH resulting from a gentle farmers' behaviour during finishing are consistent with previous findings in pig, veal or dairy productions. However, the present links were weaker than in the other productions, probably due to the low frequency of close contacts between farmers and beef bulls. When loading bulls into a truck, handlers use the tendency of animals to avoid people, hence overly positive behaviour with the animals during finishing may result in more difficulties at loading. In that case, use of alternative driving aids should be recommended. Our results on carcass pH suggest some habituation to transport among bulls transferred between breeding and finishing, even though the two experiences are several months apart. In view of our results, it seems that contacts with bulls, when they are needed, should be gentle. PMID- 22443670 TI - Effect of rearing system and mixing at loading on transport and lairage behaviour and meat quality: comparison of outdoor and conventionally raised pigs. AB - The effect of raising pigs outdoors or conventionally in a barren environment was investigated with respect to behaviour during a 3 to 4 h journey and a 2 h lairage, blood chemistry at slaughter and meat quality characteristics. Pigs were either kept in farm pen groups or were mixed at loading and kept in the groups, so formed, until slaughter. Non-mixed outdoor pigs settled more quickly during transport and lay down to a greater extent at the end of the journey and lairage period compared with conventionally raised pigs. Mixing led to fewer pigs sitting and lying during transport for conventionally raised pigs, where nearly 80% were still standing at the end of the journey. Mixing had no effect on pig posture in the lairage. Outdoor pigs were less aggressive than conventionally raised pigs especially during lairage and had a lower frequency of unacceptable skin damage in the rear and shoulder area. Aggressive interactions were almost exclusively confined to mixed groups and occurred mainly between pigs from different farm pens, i.e. between unfamiliar animals. Mixing at loading led therefore to higher levels of unacceptable skin damage. Cortisol concentrations in slaughter blood were not affected by rearing system or mixing, but mixed, conventionally raised pigs had higher plasma creatine kinase (CK) activities than non-mixed ones (1132 v. 761 U/l, respectively, P < 0.05). Outdoor pigs had similar CK activities, irrespective of mixing (682 and 771 U/l for mixed and non-mixed, respectively). Muscle pH early post mortem was highest in outdoor pigs and muscle temperature lower, but no pig showed pH values below 6.0. Ultimate pH values were both higher (Semimembranosus (S)) and lower (Semispinalis capitis (SC)) than in conventionally raised pigs, and outdoor pigs tended to have a lower frequency of higher than normal pH values. Internal reflectance (MQM) values in Biceps femoris (BF) were highest in outdoor pigs but the incidence of pale, soft and exudative (PSE) meat was low, varying between 0% and 1% for experimental groups. In general, the effects of rearing system and mixing on meat quality measurements taken early post mortem or the day after slaughter were slight, but the trends seen support the CK results, and show that conventionally raised pigs may have found mixing pre-slaughter to be more physically stressful than outdoor pigs did. PMID- 22443671 TI - The effect of out-wintering pad design on dirtiness score, somatic cell score and mastitis incidence in dairy cows. AB - This study aimed to compare three woodchip out-wintering pad (OWP) designs, and indoor cubicle housing with regard to cow dirtiness scores during the winter housing period, and udder health during both the winter period and the following lactation, for spring-calving dairy cows. The treatments were: an uncovered (UP) and covered (CP) OWP with a concrete feed apron; an uncovered OWP with self-feed silage pit provided directly on the woodchips (SP); and indoor cubicle housing (IC). Data were compared during 2 years: year 1 was a case study while year 2 was an experimental study. In year 1, treatments were UP (space allowance = 12 m2/cow), CP (6 m2/cow) and IC. In year 2, all three OWP designs (12 m2/cow) were compared with IC. Animals were assigned to treatments at the end of lactation in the autumn, and remained there while dry until calving the following spring. Subsequently, all cows were at pasture during lactation. Outcome measures for analysis were cow dirtiness score, somatic cell score (SCS) and incidence of clinical mastitis during the dry period and during lactation. Quarter milk samples were also taken at drying off, calving and 3 weeks post partum both years, and at approximately 113 days in milk in year 2. Samples were analysed for presence of mastitis-causing agents and SCS was determined. Sub-clinical mastitis was diagnosed when cows had an SCS greater than 200 000, or California mastitis test greater than 1 in at least one quarter. In year 1, cows in CP were dirtier than cows in the other two treatments. These animals also had the highest SCS during lactation and tended to have more mastitis-causing agents isolated from quarter milk samples. In year 2, when all cows were stocked at the same density, cows in the sheltered OWP (i.e. CP) had similar dirtiness scores to cows in cubicles and significantly lower dirtiness scores than cows in the unsheltered OWP designs, i.e. UP and SP. However, there were no effects on SCS or quarter sample results. Cleaning of OWP's stocked at 12 m2/cow reduced cow dirtiness scores. However, cleaning of CP in year 1 when cows were stocked at 6 m2/cow had no effect on dirtiness scores. We conclude that dry cows stocked at 12 m2/cow on OWP's are unlikely to have udder health problems in the subsequent lactation. Furthermore, provision of shelter and cleaning of the woodchips are management factors that help to keep cows clean on OWP's. PMID- 22443672 TI - Calculating luminous flux and lighting levels for domesticated mammals and birds. AB - This paper considers whether photometric calculations using standard human spectral sensitivity data are satisfactory for applications with other species or whether it would be worthwhile to use bespoke spectral sensitivity functions for each species or group of species. Applications include the lighting of interior areas and the design of photometers. Published spectral sensitivity data for a number of domesticated animals (human, turkey, duck, chicken, cat, rat and mouse) were used to calculate lighting levels for each species and compared with those derived from standard CIE human photopic and scotopic functions. Calculations were made for spectral power distributions of daylight, incandescent light and 12 fluorescent sources commonly used to light interiors. The calculated lighting levels showed clear differences between species and the standard human. Assuming that the resulting effects on retinal illuminance determine the overall perception of the level of light, there may be applications where these differences are important. However, evidence is also presented that the magnitude of these inter-species effects are similar to, or smaller than, those arising from other optical, physiological and psychological factors, which are also likely to influence the resulting perception. It is also important to recognise that lighting-related parameters such as the good colour rendering of surfaces, the avoidance of glare from lamps and other factors that may be species related are sometimes of greater importance than the lighting levels. Our results suggest that a judicial choice of three spectral sensitivity functions would satisfy most circumstances. Firstly, where the overall sensitivity is maximal in the medium to long wavelengths, the standard CIE photopic function will suffice, chicken, turkey and duck fall in this category. Secondly, in a small number of cases where the sensitivity centres on the short to medium wavelengths, the CIE scotopic function should be used, e.g. for the scotopic cat, photopic rat and photopic mouse. Finally, where an animal is also sensitive to the UV region of the spectrum and there is a significant component of UV radiation, then an additional measure of the UV response should be included, as for the photopic rat and photopic mouse. PMID- 22443673 TI - Effect of the rate of increase in concentrate allowance with concentrates high or low in starch on the performance of dairy cows in early lactation. AB - The effect of the rate of increase in concentrate allowance after calving with two concentrate mixes (A and B) differing in composition was evaluated using 64 Finnish Ayrshire cows during the first 100 days of lactation. After calving, the concentrate allowance of multiparous cows was increased stepwise from 4 to 17 kg/day, and of primiparous cows from 3 to 13.5 kg/day over 12 days (F rate of increase; multiparous 1.08 kg/day, primiparous 0.88 kg/day) or 24 days (S rate of increase; mutiparous 0.54 kg/day, primiparous 0.44 kg/day). The concentrates were formulated to have similar crude protein and metabolizable energy concentrations but differing starch and NDF concentrations. For concentrate A the starch and NDF concentrations were 421 and 167 g/kg dry matter (DM) and for concentrate B 258 and 251 g/kg DM. All cows received grass silage ad libitum. The higher concentrate intake during weeks 1 to 4 of lactation with F compared with the S rate of increase caused higher DM, energy and protein intake. The higher concentrate intake for F than for S treatment in early lactation did not cause a large decrease in silage intake (8.8 v. 8.3 kg DM/day). The intake of concentrate A and B after calving did not differ for S treatment. However, for F treatment the intake of fibrous concentrate B increased faster than starch-rich concentrate A during weeks 1 to 4 of lactation. The concentrate composition had no effect on energy-corrected milk (ECM) yield during weeks 1 to 4 of lactation for S treatments, but with F treatments the cows fed B concentrate produced more milk. The F rate of increase in concentrate allowance compared with the S rate increased the calculated energy balance after calving. The rate of increase in concentrate feeding post partum or concentrate composition had no effect on DM, energy or protein intake during the whole 100-day experiment. The average ECM yield over days 1 to 100 of lactation was higher for S than for F treatments and tended to be higher with concentrate B than A. Results of this study showed that by the fast rate of increase in concentrate allowance after calving on a grass silage diet, it was possible to improve the energy status of the cows in early lactation. This had, however, no effect on production later in lactation. PMID- 22443674 TI - Evaluation of concentrate factors affecting silage intake of dairy cows: a development of the relative total diet intake index. AB - The aim of this work was to develop an index describing the relative intake of the total diet by dairy cows, and hence the ability to predict intake responses to changes in both forage and concentrate variables. An evaluation of concentrate factors affecting silage dry matter (DM) intake of dairy cows was conducted based on dietary treatment means from milk production experiments. The data were divided into four subsets according to concentrate treatments used within the experiments: the amount of concentrate supplementation (n = 217), protein supplementation (n = 336), carbohydrate composition (n = 114) and fat concentration of the concentrate (n = 29). The data were subjected to mixed-model regression analysis. Increased concentrate DM intake (CDMI) decreased silage DM intake (SDMI) quadratically. The substitution rate (substitution of silage DM for concentrate DM) increased with improved silage intake potential. SDMI increased quadratically with concentrate protein intake, the response being negatively related to the effective protein degradability (EPD) of concentrates. Replacement of starchy concentrate ingredients with fibrous supplements had a small positive effect on silage intake, whereas increased concentrate fat concentration slightly decreased SDMI. The outcome of concentrate factors influencing total DM intake (TDMI) was used to create a relative CDMI index as follows: CDMI index = 100 + 10 * [(CDMI - 0.1629 * CDMI - 0.01882 * CDMI2 - 5.49) + ((0.9474 * CCPI - 0.4965 * CCPI2) - 2.017 * (CEPD - 0.74)) + 0.00225 * (CNDF - 250) - 0.0103 * (40 - Cfat) - 0.00058 * (CDMI - 8.0) * (SDMI index - 100)], where CDMI = concentrate DM intake (kg/day), CCPI = supplementary concentrate CP intake (kg/day; CP>170 g/kg DM), CEPD = concentrate EPD (g/g), CNDF = concentrate NDF concentration (g/kg DM), Cfat = concentrate fat concentration (g/kg DM) and SDMI index is the relative intake potential of silage (Huhtanen, Rinne and Nousiainen 2007. Animal 1, 758 770). TDMI index was calculated as SDMI index + CDMI index - 100 to describe the relative intake potential of the total diet. For the whole data set (n = 943), one TDMI index unit was equivalent to 0.095 kg/day DM intake, i.e. close to the default value of 0.100 kg. The CDMI index explained proportionally 0.88 of the variation in TDMI within a study with a 0.27 kg/day residual mean-square error (n = 616). The corresponding values for the TDMI index were 0.81 and 0.37 kg/day (n = 943), respectively. The residual mean-square errors in cross-validation were marginally higher. The developed TDMI index can be used to estimate the intake responses to diet changes. It provides an improved basis for practical dairy cow ration formulation and economic evaluation. PMID- 22443675 TI - The effect of supplementing maize stover with cowpea ( Vigna unguiculata) haulms on the intake and growth performance of Ethiopian sheep. AB - This study compared the effect of supplementing maize stover (MS) with cowpea (Vigna unguiculata) haulms or commercial concentrate (CC) on feed intake, nutrient digestibility, live weight gain and carcass yield of male Ethiopian Highland sheep. Two cowpea genotypes, 12688 (forage) and IT96D-774 (dual purpose), were used. A randomised block design was applied with groups of eight sheep, blocked by weight, allocated to one of six treatments; MS ad libitum either unsupplemented or supplemented daily with 150 or 300 g dry matter (DM) of either cowpea or CC. MS contained more neutral detergent fibre (NDF), acid detergent fibre (ADF) and lignin than either cowpeas or CC. Crude protein (CP) content of the forage-type cowpeas was higher than either dual-purpose or CC, while MS had the lowest CP content. Relative to the negative control group, cowpea at either level significantly (P < 0.01) increased both MS intake and total NDF and lignin. Supplementation significantly (P < 0.01) increased nitrogen (N) intakes relative to the negative control, with N intake for CC and dual purpose cowpea (high level) being similar to the intakes for cowpeas at 150 g. N intake with the forage-type cowpea offered at higher levels was significantly (P < 0.01) greater than the other groups. No significant differences (P > 0.01) in MS intake were identified between cowpeas at either level or CC and, although intake level of CC increased, it did not differ significantly from the negative control group. Supplementation significantly (P < 0.01) improved average daily gain, with the negative control group losing weight over the experimental period, and increased final live weight, carcass cold weight and dressing percentage. Supplementation significantly improved the apparent digestibility of DM, organic matter and NDF, with no significant difference found between cowpeas at either level. N retention was negative for sheep offered only MS, but positive with all supplements, with cowpeas improving N retention to a greater extent than CC. Interestingly, N retention/N intake was higher with cowpeas offered at the lower level suggesting an improvement in utilisation efficiency. The results indicate that the supplementation of MS with cowpea enhanced ruminant production through improvements in digestibility and intake. Further, as production improvements associated with the two levels of supplementation did not differ significantly, it is suggested that where limited quantities of cowpea are available, it may be of greater nutritional benefit to offer smaller quantities over an increased number of animal days. PMID- 22443676 TI - Performance of dairy ewes fed diets with a fibrolytic enzyme product included in the concentrate during the suckling period. AB - Seventy-two multiparous ewes from two dairy breeds (Manchega, n = 36 and Lacaune, n = 36) were used in a replicated 2 * 2 factorial design to evaluate the effects of diet supplementation with an exogenous fibrolytic enzyme product on lactation performance and feed intake during the suckling period (weeks 1 to 4) according to breed. Ewes were blocked in groups of nine and fed ad libitum after lambing a diet based on 70% forage and 30% concentrate to which the enzyme was added after pelleting. Experimental concentrates were: control (without enzyme) and enzyme (fibrolytic enzyme complex, included at 0.47% volume to weight of concentrate). Twenty-four dry and open ewes (Manchega, n = 12 and Lacaune, n = 12) were also grouped by breed and used to measure the fill value of the ration used. During the suckling period, milk yield, milk composition, dry matter intake, lamb growth, as well as body weight change and body condition score change were not affected by enzyme supplementation. Breed effect was significant for milk yield, the Manchega ewes yielding less milk with a higher content of milk components than the Lacaune ewes. The opposite was observed for dry matter intake. Enzyme supplementation reduced intake by 9% in the dry ewes, resulting in a greater fill value of the diet. In conclusion, no lactational effects were detected when the fibrolytic enzyme product was added to the concentrate fed to dairy ewes. PMID- 22443677 TI - A comparison of energy balance and metabolic profiles of the New Zealand and North American strains of Holstein Friesian dairy cow. AB - The milk production, energy balance (EB), endocrine and metabolite profiles of 10 New Zealand Holstein Friesian (NZ) cows and 10 North American Holstein Friesian (NA) cows were compared. The NA cows had greater peak milk yields and total lactation milk yields (7387 v. 6208 kg; s.e.d. = 359), lower milk fat and similar protein concentrations compared with the NZ cows. Body weight (BW) was greater for NA cows compared with NZ cows throughout lactation (596 v. 544 kg; s.e.d. = 15.5), while body condition score (BCS) tended to be lower. The NA strain tended to have greater dry matter intake (DMI) (17.2 v. 15.7 kg/day; s.e.d. = 0.78) for week 1 to 20 of lactation, though DMI as a proportion of metabolic BW was similar for both strains. No differences were observed between the strains in the timing and magnitude of the EB nadir, interval to neutral EB, or mean daily EB for week 1 to 20 of lactation. Plasma concentrations of glucose and insulin were greater for NA cows during the transition period (day 14 pre partum to day 28 post partum). Plasma IGF-I concentrations were similar for the strains at this time, but NZ cows had greater plasma IGF-I concentration from day 29 to day 100 of lactation, despite similar calculated EB. In conclusion, the results of this study do not support the premise that the NZ strain has a more favourable metabolic status during the transition period. The results, however, indicate that NZ cows begin to partition nutrients towards body reserves during mid lactation, whereas NA cows continue to partition nutrients to milk production. PMID- 22443678 TI - Fruit juice consumption is associated with improved nutrient adequacy in children and adolescents: the National Health and Nutrition Examination Survey (NHANES) 2003-2006. AB - OBJECTIVE: To examine the contribution of 100 % fruit juice (FJ) consumption to dietary adequacy of shortfall nutrients by children and adolescents. DESIGN: Cross-sectional. SETTING: Secondary analysis of data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES). SUBJECTS: Children and adolescents aged 2-18 years (n 7250). Usual intake, determined from two 24 h dietary recalls, was calculated using the National Cancer Institute method. The population was dichotomized into consumers or non-consumers of 100 % FJ. The age/gender-specific percentage of the two consumption groups with intakes less than the Estimated Average Requirement or that exceeded the Adequate Intake for selected nutrients was determined. A Z-statistic for differences in population proportions was used to determine significance (P < 0.05). RESULTS: Children aged 2-5 years had the highest percentage of 100 % FJ consumers (71.1 %), followed by children aged 6-12 years (57.0 %) and adolescents aged 13-18 years (44.5 %). Compared with 100 % FJ consumers, a significantly higher percentage of non consumers had intakes below the Estimated Average Requirement for vitamin A (24.4 (SE 2.5) % v. 42.2 (SE 2.5) %), vitamin C (0.1 (SE 0.2) % v. 38.9 (SE 4.1) %), folate (8.8 (SE 1.5) % v. 22.1 (SE 2.4) %), P (11.6 (SE 2.1) % v. 21.3 (SE 2.6) %) and Mg (25.8 (SE 1.7) % v. 46.1 (SE 2.0) %). A greater percentage of 100 % FJ consumers exceeded the Adequate Intake for K (2.4 (SE 0.5) v. 0.5 (SE 0.2) %) compared with non-consumers. CONCLUSIONS: Consumption of 100 % FJ is associated with improved nutrient adequacy and can contribute to a healthy diet. PMID- 22443679 TI - A stable two-coordinate acyclic silylene. AB - Simple two-coordinate acyclic silylenes, SiR(2), have hitherto been identified only as transient intermediates or thermally labile species. By making use of the strong sigma-donor properties and high steric loading of the B(NDippCH)(2) substituent (Dipp = 2,6-(i)Pr(2)C(6)H(3)), an isolable monomeric species, Si{B(NDippCH)(2)}{N(SiMe(3))Dipp}, can be synthesized which is stable in the solid state up to 130 degrees C. This silylene species undergoes facile oxidative addition reactions with dihydrogen (at sub-ambient temperatures) and with alkyl C-H bonds, consistent with a low singlet-triplet gap (103.9 kJ mol( 1)), thus demonstrating fundamental modes of reactivity more characteristic of transition metal systems. PMID- 22443680 TI - Daming capsule restores endothelial dysfunction induced by high-fat diet. AB - BACKGROUND: Daming capsule (DMC), a traditional Chinese formula, has a lipid modulating action with reduced adverse side effects as compared with other lipid lowering compounds. Since endothelial dysfunction often accompanies the hyperlipidemic state, we hypothesize that DMC might restore endothelial dysfunction produced by a high-fat (HF) diet. Importantly, we also investigate possible mechanisms involved in mediating the effects of DMC on vascular reactivity. METHODS: Rats were divided into four groups: control, HF diet, HF mixed DMC diet, HF mixed atorvastatin (ATV) diet. After 30 days, the thoracic cavity was exposed to remove the thoracic aorta for (i) histological examination; (ii) measurement of endothelial nitric oxide synthase (eNOS) by western blot; and (iii) tension study of thoracic aortic ring. RESULTS: HF diet induced significant attenuation in the contraction and relaxation of rat aortic rings. Treatment with DMC significantly improved the relaxation of the aortic rings as compared with those from HF rats (P < 0.05), which was abolished by a nonspecific NOS inhibitor L-NAME. Moreover DMC significantly restored the decrease in eNOS expression induced by HF diet. Similar results were found in histopathologic changes. DMC failed to restore the loss of vasocontraction of aorta explained by an impairment of ATP-sensitive K+ channels (KATP) on the structure and/or function. DMC exerted the same protective effect as ATV, a positive control drug, on vascular injury produced by HF diet. CONCLUSION: DMC partially protects the aorta from HF-induced endothelial dysfunction via upregulation of the expression of eNOS. PMID- 22443681 TI - Factors associated with discharge destination from acute care after acquired brain injury in Ontario, Canada. AB - BACKGROUND: The aim of this paper is to examine factors associated with discharge destination after acquired brain injury in a publicly insured population using the Anderson Behavioral Model as a framework. METHODS: We utilized a retrospective cohort design. Inpatient data from provincial acute care records from fiscal years 2003/4 to 2006/7 with a diagnostic code of traumatic brain injury (TBI) and non-traumatic brain injury (nTBI) in Ontario, Canada were obtained for the study. Using multinomial logistic regression models, we examined predisposing, need and enabling factors from inpatient records in relation to major discharge outcomes such as discharge to home, inpatient rehabilitation and other institutionalized care. RESULTS: Multinomial logistic regression revealed that need factors were strongly correlated with discharge destinations overall. Higher scores on the Charlson Comorbidity Index were associated with discharge to other institutionalized care in the nTBI population. Length of stay and special care days were identified as markers for severity and were both strongly positively correlated with discharge to other institutionalized care and inpatient rehabilitation, compared to discharge home, in both nTBI and TBI populations. Injury by motor vehicle collisions was found to be positively correlated with discharge to inpatient rehabilitation and other institutionalized care for patients with TBI. Controlling for need factors, rural location was associated with discharge to home versus inpatient rehabilitation. CONCLUSIONS: These findings show that need factors (Charlson Comorbidity Index, length of stay, and number of special care days) are most significant in terms of discharge destination. However, there is evidence that other factors such as rural location and access to supplemental insurance (e.g., through motor vehicle insurance) may influence discharge destination outcomes as well. These findings should be considered in creating more equitable access to healthcare services across the continuum of care. PMID- 22443682 TI - Occurrence of Cronobacter spp. in retail foods. AB - AIMS: To study the occurrence of Cronobacter spp. in foods and to investigate the phenotypic properties of the strains isolated. METHODS AND RESULTS: A total of 53 strains of Cronobacter spp. isolated from 399 food samples were identified using conventional biochemical methods and MALDI-TOF mass spectrometry. Foods of plant origin were the most frequently contaminated samples. No Cronobacter spp. were found in infant milk formula, wheat-based infant food, pasteurized and raw cow milk, mincemeat, chicken, chickpea and potato dumpling powder. The individual species were identified as Cronobacter sakazakii (54.7%), Cronobacter malonaticus (28.4%), Cronobacter dublinensis (7.5%), Cronobacter muytjensii (7.5%) and Cronobacter turicensis (1.9%). Cronobacter sakazakii and C. malonaticus belong to biotype 1, 2, 2a, 3, 4 and 5, 5a, respectively. Cronobacter dublinensis strains were subdivided into biotypes 6 and 12. All strains were resistant to erythromycin and two of them were resistant to both erythromycin and tetracycline. CONCLUSIONS: Cronobacter spp. were isolated from various food samples pre-eminently of plant origin and dried food ingredients. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings will increase and detail our knowledge of the presence and diversity of Cronobacter spp. in foods. PMID- 22443683 TI - The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. AB - Protein phosphatase type 2A (PP2A) enzymes constitute a large family of Ser/Thr phosphatases with multiple functions in cellular signaling and physiology. The composition of heterotrimeric PP2A holoenzymes, resulting from the combinatorial assembly of a catalytic C subunit, a structural A subunit, and regulatory B-type subunit, provides the essential determinants for substrate specificity, subcellular targeting, and fine-tuning of phosphatase activity, largely explaining why PP2A is functionally involved in so many diverse physiological processes, sometimes in seemingly opposing ways. In this review, we highlight how PP2A holoenzyme biogenesis and enzymatic activity are controlled by a sophisticatedly coordinated network of five PP2A modulators, consisting of alpha4, phosphatase 2A phosphatase activator (PTPA), leucine carboxyl methyl transferase 1 (LCMT1), PP2A methyl esterase 1 (PME-1) and, potentially, target of rapamycin signaling pathway regulator-like 1 (TIPRL1), which serve to prevent promiscuous phosphatase activity until the holoenzyme is completely assembled. Likewise, these modulators may come into play when PP2A holoenzymes are disassembled following particular cellular stresses. Malfunctioning of these cellular control mechanisms contributes to human disease. The potential therapeutic benefits or pitfalls of interfering with these regulatory mechanisms will be briefly discussed. PMID- 22443684 TI - Influence of lipid composition on the phase transition temperature of liposomes composed of both DPPC and HSPC. AB - OBJECTIVE: Phase transition of the lipid membrane is one of the most important properties of liposomes. The objective of this study was to investigate the influence of molar ratio of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and hydrogenated soy phosphatidylcholine (HSPC) on the phase transition temperature (T(m)) of the liposomes. MATERIALS AND METHODS: The T(m)s of the liposomes with different phosphatidylcholine (PC) composition were determined by calcein release test and differential scanning calorimetry (DSC). RESULTS: Only one phase transition was observed for liposomes composed of both DPPC and HSPC, indicating that DPPC and HSPC might combine into one phase with single phase transition. The T(m) of the liposomes composed of both DPPC and HSPC was directly dependent on the molar ratio of the two PCs. Moreover, DPPC percentage and T(m) relationship could be fitted with a linear equation (r(2) > 0.98). In addition, the serum stability of the liposomes at 37 degrees C was directly increased with the increase of DPPC percentage. When 10% DSPE-PEG2000 was added, the significant increase of calcein release at T(m) and decrease at 37 degrees C were observed. DISCUSSION: It is easy to obtain liposomes with a T(m) in between that of DPPC and HSPC by modifying the molar ratio of DPPC and HSPC. CONCLUSION: With the modification of T(m), the liposomes containing various ratios of DPPC and HSPC may have promising application potential in the field of thermosensitive liposomes (TSLs). After 10% DSPE-PEG2000 is added, a formulation of sterically stabilized liposomes with the proper thermal sensitivity can be obtained. PMID- 22443685 TI - Redox balance is key to explaining full vs. partial switching to low-yield metabolism. AB - BACKGROUND: Low-yield metabolism is a puzzling phenomenon in many unicellular and multicellular organisms. In abundance of glucose, many cells use a highly wasteful fermentation pathway despite the availability of a high-yield pathway, producing many ATP molecules per glucose, e.g., oxidative phosphorylation. Some of these organisms, including the lactic acid bacterium Lactococcus lactis, downregulate their high-yield pathway in favor of the low-yield pathway. Other organisms, including Escherichia coli do not reduce the flux through the high yield pathway, employing the low-yield pathway in parallel with a fully active high-yield pathway. For what reasons do some species use the high-yield and low yield pathways concurrently and what makes others downregulate the high-yield pathway? A classic rationale for metabolic fermentation is overflow metabolism. Because the throughput of metabolic pathways is limited, influx of glucose exceeding the pathway's throughput capacity is thought to be redirected into an alternative, low-yield pathway. This overflow metabolism rationale suggests that cells would only use fermentation once the high-yield pathway runs at maximum rate, but it cannot explain why cells would decrease the flux through the high yield pathway. RESULTS: Using flux balance analysis with molecular crowding (FBAwMC), a recent extension to flux balance analysis (FBA) that assumes that the total flux through the metabolic network is limited, we investigate the differences between Saccharomyces cerevisiae and L. lactis that downregulate the high-yield pathway at increasing glucose concentrations, and E. coli, which keeps the high-yield pathway functioning at maximal rate. FBAwMC correctly predicts the metabolic switching mode in these three organisms, suggesting that metabolic network architecture is responsible for differences in metabolic switching mode. Based on our analysis, we expect gradual, "overflow-like" switching behavior in organisms that have an additional energy-yielding pathway that does not consume NADH (e.g., acetate production in E. coli). Flux decrease through the high-yield pathway is expected in organisms in which the high-yield and low-yield pathways compete for NADH. In support of this analysis, a simplified model of metabolic switching suggests that the extra energy generated during acetate production produces an additional optimal growth mode that smoothens the metabolic switch in E. coli. CONCLUSIONS: Maintaining redox balance is key to explaining why some microbes decrease the flux through the high-yield pathway, while other microbes use "overflow-like" low-yield metabolism. PMID- 22443686 TI - Calculation of total free energy yield as an alternative approach for predicting the importance of potential chemolithotrophic reactions in geothermal springs. AB - To inform hypotheses regarding the relative importance of chemolithotrophic metabolisms in geothermal environments, we calculated free energy yields of 26 chemical reactions potentially supporting chemolithotrophy in two US Great Basin hot springs, taking into account the effects of changing reactant and product activities on the Gibbs free energy as each reaction progressed. Results ranged from 1.2 * 10(-5) to 3.6 J kg(-1) spring water, or 3.7 * 10(-5) to 11.5 J s(-1) based on measured flow rates, with aerobic oxidation of CH(4) or NH4 + giving the highest average yields. Energy yields calculated without constraining pH were similar to those at constant pH except for reactions where H(+) was consumed, which often had significantly lower yields when pH was unconstrained. In contrast to the commonly used normalization of reaction chemical affinities per mole of electrons transferred, reaction energy yields for a given oxidant varied by several orders of magnitude and were more sensitive to differences in the activities of products and reactants. The high energy yield of aerobic ammonia oxidation is consistent with previous observations of significant ammonia oxidation rates and abundant ammonia-oxidizing archaea in sediments of these springs. This approach offers an additional lens through which to view the thermodynamic landscape of geothermal springs. PMID- 22443687 TI - Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK pathways. AB - BACKGROUND: Curcumin is a principal compound of turmeric, commonly used to treat tumors and other diseases. However, its anti-cancer activity in human acute monocytic leukemia THP-1 cells is not clear. This study aimed to study the anti cancer effect and action of curcumin on THP-1 cells. METHODS: THP-1 parental cells and PMA-treated THP-1 cells, were used as in vitro models to evaluate the anti-cancer effect and mechanism of curcumin. Apoptosis and its mechanism were evaluated by WST-1, flow cytometry and Western blotting. MAPK inhibitors were used to further confirm the molecular mechanism of curcumin-induced THP-1 cell apoptosis. RESULTS: Curcumin induced cell apoptosis of THP-1 cells as shown by cell viability, cell cycle analysis and caspase activity. Curcumin significantly increased the phosphorylation of ERK, JNK and their downstream molecules (c-Jun and Jun B). Inhibitor of JNK and ERK reduced the pro-apoptotic effect of curcumin on THP-1 cells as evidenced by caspase activity and the activation of ERK/JNK/Jun cascades. On the contrary, the pro-apoptotic effect of curcumin was abolished in the differentiated THP-1 cells mediated by PMA. CONCLUSIONS: This study demonstrates that curcumin can induce the THP-1 cell apoptosis through the activation of JNK/ERK/AP1 pathways. Besides, our data suggest its novel use as an anti-tumor agent in acute monocytic leukemia. PMID- 22443688 TI - The ketogenic diet in the treatment of Lennox-Gastaut syndrome. PMID- 22443689 TI - Palladium-catalyzed direct arylation of imidazolone N-oxides with aryl bromides and its application in the synthesis of GSK2137305. AB - The palladium-catalyzed direct arylation of imidazolone N-oxides with aryl bromides to afford the corresponding 4-aryl imidazolone N-oxides is described. This method has been successfully used for the synthesis of GSK2137305. PMID- 22443690 TI - On Ni catalysts for catalytic, asymmetric Ni/Cr-mediated coupling reactions. AB - The importance of the Ni catalyst in achieving catalytic asymmetric Ni/Cr mediated coupling reactions effectively is demonstrated. Six phenanthroline NiCl(2) complexes 1a-c and 2a-c and five types of alkenyl iodides A-E were chosen for the study, thereby demonstrating that these Ni catalysts display a wide range of overall reactivity profiles in terms of the degree of asymmetric induction, geometrical isomerization, and coupling rate. For three types of alkenyl iodides A-C, a satisfactory Ni catalyst(s) was found within 1a-c and 2a-c. For disubstituted (Z)-alkenyl iodide D, 2c was identified as an acceptable Ni catalyst in terms of the absence of Z -> E isomerization and the degree of asymmetric induction but not in terms of the coupling rate. Two phosphine-based Ni catalysts, [(Me)(3)P](2).NiCl(2) and [(cy)(3)P](2).NiCl(2), were found to meet all three criteria for D. The bond-forming reaction at the C16-C17 position of palytoxin was used to demonstrate the usefulness of the Ni catalysts thus identified. PMID- 22443692 TI - c-Jun NH(2) -terminal kinase may predict hepatocellular carcinoma recurrence. PMID- 22443691 TI - Pathogenic and regulatory roles for B cells in experimental autoimmune encephalomyelitis. AB - A dual role of B cells in experimental autoimmune encephalomyelitis (EAE), the animal model of the human autoimmune disease multiple sclerosis (MS), has been established. In the first role, B cells contribute to the pathogenesis of EAE through the production of anti-myelin antibodies that contribute to demyelination. On the contrary, B cells have also been shown to have protective functions in that they play an essential role in the spontaneous recovery from EAE. In this review, we summarize studies conducted in a number of species demonstrating the conditions under which B cells are pathogenic in EAE. We also discuss the phenotype and anti-inflammatory mechanisms of regulatory B cells. PMID- 22443693 TI - Antimitochondrial antibody -M2 positive autoimmune hepatitis during standard of care for chronic hepatitis C. AB - The current standard of care (SoC) for chronic hepatitis C, i.e. the combination of a pegylated-interferon (PEG-IFN) with ribavirin (RBV), may activate underlying autoimmune conditions. Particularly, interferon (IFN) has been known to induce or exacerbate autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) in hepatitis C virus patients. We describe a severe, acute-onset antimitochondrial antibody (AMA)-M2 positive AIH appearing during the last weeks of SoC in a woman with chronic hepatitis C and no previous history of autoimmunity, and resolving on protracted steroids. In this context, the relevance of the characterization of the immunoglobulin isotype of portal plasma cells for a more appropriate diagnosis of autoimmune liver diseases can be emphasized. PMID- 22443694 TI - Pulmonary embolism and deep venous thrombosis in hospitalized patients with liver cirrhosis. PMID- 22443695 TI - A novel allele HLA-DRB1*11:119 was identified by polymerase chain reaction sequence-based typing in a Chinese individual. AB - HLA-DRB1*11:119 has one nucleotide difference from HLA-DRB1*11:25 at position 286 T>A in exon 2. PMID- 22443696 TI - Environmental and genetic variation factors of artificial insemination success in French dairy sheep. AB - Artificial inseminations (n = 678 168) recorded during 5 years in five French artificial insemination (AI) centres (2 'Lacaune', 1 'Manech tete rousse', 1 'Manech tete noire' and 1 'Basco bearnaise') were analysed to determine environmental and genetic factors affecting the insemination results. Analyses within centre-breed were performed using a linear model, which jointly estimates male and female fertility. This model combined four categories of data: the environmental effects related to the female, those related to the male, the non sex-specific effects and finally the pedigree data of these males and females. After selection, the environmental female effects considered were age, synchronisation (0/1) on the previous year, total number of synchronisations during the female reproductive life, time interval between previous lambing and insemination, already dry or still lactating (0/1) when inseminated, and milk quantity produced during the previous year expressed as quartiles intra herd * year. The environmental male effects were motility and concentration of the semen. The non-sex-specific effects were the inseminator, the interaction herd * year nested within the inseminator, considered as random effects and the interaction year * season considered as a fixed effect. The main variation factors of AI success were relative to non-sex-specific effects and to female effects. Heritability estimates varied from 0.001 to 0.005 for male fertility and from 0.040 to 0.078 for female fertility. Repeatability estimates varied from 0.007 to 0.015 for male fertility and from 0.104 to 0.136 for female fertility. These parameters indicate that genetic improvement of AI results through a classical polygenic selection would be difficult. Moreover, in spite of the large quantity of variation factors fitted by the joint model, a very large residual variance remained unexplained. PMID- 22443697 TI - Characterization of Osteopontin gene of Bubalus bubalis. AB - Osteopontin, a glycoprotein, is expressed in several tissues including the mammary gland. The gene has been reported to be associated with milk and its constituents in various livestock species. This gene was sequenced in buffalo and it coded for the protein of 280 amino acids with the conserved GRGDS domain. The sequence was confirmed from the cDNA sequence derived from the mammary gland of buffalo. The earlier-reported 9T/10T variation in the upstream region of the gene was investigated for its effect on milk in buffalo and it was found to be non significant. PMID- 22443698 TI - Genetic diversity and admixture analysis of Sanfratellano and three other Italian horse breeds assessed by microsatellite markers. AB - Sanfratellano is a native Sicilian horse breed, mainly reared in the north east of the Island, developed in the 19th century from local dams and sires with a restricted introgression of Oriental, African and, more recently, Maremmano stallions. In this study, the genetic relationships and admixture among Sanfratellano, the other two Sicilian autochthonous breeds and Maremmano breed were assessed using a set of microsatellites. The main goals were to infer the impact of Maremmano breed in the current Sanfratellano horse and to provide genetic information useful to improve the selection strategies of the Sanfratellano horse. The whole sample included 384 horses (238 Sanfratellano, 50 Sicilian Oriental Purebred, 30 Sicilian Indigenous and 66 Maremmano), chosen avoiding closely related animals. A total of 111 alleles from 11 microsatellite loci were detected, from four at HTG7 to 15 at ASB2 locus. The mean number of alleles was the lowest in Oriental Purebred (6.7), the highest in Sanfratellano (8.3). All the breeds showed a high level of gene diversity (He) ranging from 0.71 +/- 0.04 in Sicilian Oriental Purebred to 0.81 +/- 0.02 in Sicilian Indigenous. The genetic differentiation index was low; only about 6% of the diversity was found among breeds. Nei's standards (DS) and Reynolds' (DR) genetic distances reproduced the same population ranking. Individual genetic distances and admixture analysis revealed that: (a) nowadays Maremmano breed does not significantly influence the current Sanfratellano breed; (b) within Sanfratellano breed, it is possible to distinguish two well-defined groups with different proportions of Indigenous blood. PMID- 22443699 TI - Effect of leptin gene polymorphism on the breeding value of milk production traits in Iranian Holstein. AB - New molecular techniques focused on genome analysis, open new possibilities for more accurate evaluation of economiclly important traits in farm animals. Milk production traits are typical quantitative characteristics controlled by a number of genes. Mutations in their sequences may alter animal performance as well as their breeding values. In this study, we investigated the effect of Kpn2I restriction fragment length polymorphisms in the leptin gene, on bull breeding values for milk yield, fat, and protein yield, and their percentage. In order to test for an association between the leptin single-nucleotide polymorphism in exon 2 and milk productivity, we genotyped 134 Iranian Holstein bulls. Breeding values for milk-related traits (milk yield, fat, and protein yield and percentage) were estimated using the BLUP based on an animal model. The effect of the genotypes of Kpn2I polymorphism on the breeding values for milk-related traits was examined using least square methods. The T allele frequency was 0.425. Genotypes were distributed according to the Hardy-Weinberg equilibrium. Bulls with TT genotype had higher milk, fat and protein yield compared with TC and CC bulls (P < 0.05). Bulls with CC genotype had higher protein percentage compared with TT and TC bulls (P < 0.05). The association between leptin polymorphism with milk production traits suggests that this marker may be useful for selection based on molecular information. PMID- 22443700 TI - Comparison of non-linear growth models to describe the growth curve in West African Dwarf sheep. AB - The objectives of this study were to compare the goodness of fit of four non linear growth models, i.e. Brody, Gompertz, Logistic and Von Bertalanffy, in West African Dwarf (WAD) sheep. A total of 5274 monthly weight records from birth up to 180 days of age from 889 lambs, collected during 2001 to 2004 in Betecoucou breeding farm in Benin were used. In the preliminary analysis, the General Linear Model Procedure of the Statistical Analysis Systems Institute was applied to the dataset to identify the significant effects of the sex of lamb (male and female), type of birth (single and twin), season of birth (rainy season and dry season), parity of dam (1, 2 and 3) and year of birth (2001, 2002, 2003 and 2004) on the observed birth weight and monthly weight up to 6 months of age. The models parameters (A, B and k), coefficient of determination (R2), mean square error (MSE) were calculated using language of technical computing package Matlab(r), 2006. The mean values of A, B and k were substituted into each model to calculate the corresponding Akaike's Information Criterion (AIC). Among the four growth functions, the Brody model has been selected for its accuracy of fit according to the higher R2, lower MSE and AIC. Finally, the parameters A, B and k were adjusted in Matlab(r), 2006 for the sex of lamb, year of birth, season of birth, birth type and the parity of ewe, providing a specific slope of the Brody growth curve. The results of this study suggest that Brody model can be useful for WAD sheep breeding in Betecoucou farm conditions through growth monitoring. PMID- 22443701 TI - Economic implications of using Japanese Black sires carrying recessive genes associated with genetic defects. AB - The objective of this study was to calculate cumulative discounted expressions (CDE) for Japanese Black sires carrying a single defective allele in a herd by applying the gene-flow method to investigate the expression pattern of homozygous recessive genotype and to evaluate the monetary loss of using these sires. A single biallelic locus was considered with A representing the dominant allele and a representing the recessive allele. The gene-flow method was modified to consider the fitness of homozygous recessive genotype. Input parameters representing a typical situation in a Japanese Black cattle herd were used to calculate the CDE and the loss of using carrier sires. The effects of initial allele frequency and fitness on the CDE were determined for Aa and AA sires. The CDE of Aa sires were larger than those of AA sires under all initial allele frequencies and fitness. The difference in the CDE between using Aa and AA sires was largest when fitness was 0 (lethal recessive condition). The differences in the loss between Aa and AA sires were larger with increasing initial allele frequencies in lethal recessive condition. Applying the method used in this study to defects reported in Japanese Black cattle and with a population size of 628 000, the difference in the loss between using Aa and AA sires was US$48 575 800 and US$74 418 000 in the case of Band-3 and Claudin-16 deficiencies, respectively. The approach used in this study could be applied to other genetic defects in different breeds and species. PMID- 22443702 TI - Rumen-protected choline and vitamin E supplementation in periparturient dairy goats: effects on milk production and folate, vitamin B12 and vitamin E status. AB - We investigated the effects of rumen-protected choline (RPC) and vitamin E (VITE) administration on milk production and status of folate, vitamin B12 and vitamin E during the periparturient period of dairy goats. Forty-eight Saanen multiparous goats were selected for the 72-day experiment, being moved to a maternity pen 30 days before expected parturition and assigned to one of the four experimental groups: control (CTR), no choline or vitamin E supplementation; choline (RPC), supplemented with 4 g/day choline chloride in rumen-protected form; vitamin E (VITE), supplemented with 200 IU/day vitamin E in rumen-protected form; and choline and vitamin E (RPCE), supplemented with 4 g/day RPC chloride and 200 IU/day vitamin E. Supplements were administered individually before the morning feed to ensure complete consumption, starting 30 days before kidding and continuing for 35 days after. During the experiment, milk yield and 4% fat corrected milk (FCM) yield were, respectively, 210 and 350 g/day higher in RPC supplemented goats than in non-supplemented goats. Milk fat concentration and fat yield were also increased by RPC treatment. Milk yield and composition were unaffected by vitamin E supplementation. There were no significant interactions between RPC and VITE for any of the variables measured. Plasma metabolites did not differ between treatments before and after kidding except that plasma folate at parturition was higher in RPC-supplemented goats. Neither choline nor vitamin E affected vitamin B12 plasma concentrations, while a time effect was evident after the second week of lactation, when B12 levels in each treatment group started to increase. Vitamin E administration resulted in plasma alpha-tocopherol levels that were 2 to 2.5 times higher than in non-supplemented goats. Overall, these results suggest that greater choline availability can improve milk production and methyl group metabolism in transition dairy goats. PMID- 22443703 TI - Effects of fermentable starch and straw-enriched housing on energy partitioning of growing pigs. AB - Both dietary fermentable carbohydrates and the availability of straw bedding potentially affect activity patterns and energy utilisation in pigs. The present study aimed to investigate the combined effects of straw bedding and fermentable carbohydrates (native potato starch) on energy partitioning in growing pigs. In a 2 * 2 factorial arrangement, 16 groups of 12 pigs (approximately 25 kg) were assigned to either barren housing or housing on straw bedding, and to native or pregelatinised potato starch included in the diet. Pigs were fed at approximately 2.5 times maintenance. Nitrogen and energy balances were measured per group during a 7-day experimental period, which was preceded by a 30-day adaptation period. Heat production and physical activity were measured during 9-min intervals. The availability of straw bedding increased both metabolisable energy (ME) intake and total heat production (P < 0.001). Housing conditions did not affect total energy retention, but pigs on straw bedding retained more energy as protein (P < 0.01) and less as fat (P < 0.05) than barren-housed pigs. Average daily gain (P < 0.001), ME intake (P < 0.001) and energy retention (P < 0.01) were lower in pigs on the native potato starch diet compared to those on the pregelatinised potato starch diet. Pigs on the pregelatinised potato starch diet showed larger fluctuations in heat production and respiration quotient over the 24-h cycle than pigs on the native potato starch diet, and a higher activity related energy expenditure. The effect of dietary starch type on activity-related heat production depended, however, on housing type (P < 0.05). In barren housing, activity-related heat production was less affected by starch type (16.1% and 13.7% of total heat production on the pregelatinised and native potato starch diet, respectively) than in straw-enriched housing (21.1% and 15.0% of the total heat production on the pregelatinised and native potato starch diet, respectively). In conclusion, the present study shows that the availability both of straw bedding and of dietary starch type, fermentable or digestible, affects energy utilisation and physical activity of pigs. The effects of housing condition on protein and fat deposition suggest that environmental enrichment with long straw may result in leaner pigs. The lower energy expenditure on the physical activity of pigs on the native potato starch diet, which was the most obvious in straw-housed pigs, likely reflects a decrease in foraging behaviour related to a more gradual supply of energy from fermentation processes. PMID- 22443704 TI - Intestinal amino acid absorption in lambs fed fresh Lucerne ( Medicago sativa) during an established Trichostrongylus colubriformis infection. AB - The effects of an established Trichostrongylus colubriformis infection on amino acid (AA) absorption from the small intestine and their availability to other tissues were determined in lambs 48 days post infection. The lambs were fed fresh Lucerne (Medicago sativa; 800 g dry matter (DM)/day) and dosed with 6000 L3 T. colubriformis larvae for 6 days (n = 5) or kept as parasite free controls (n = 6). Faecal egg production was monitored every second day from day 22 to day 48. A nitrogen (N) balance was conducted on days 35 to 43 after infection, and digesta flow and AA concentration measurements were made on day 44. On day 48 after infection, blood was continuously collected from the mesenteric artery and vein, plasma harvested and AA concentrations measured. Faecal egg production peaked on the 26th day after infection (P < 0.001) and intestinal worm burdens on day 48 were greater (P < 0.001) in the infected lambs. Feed intake and liveweight gain were similar (P > 0.10) between control and infected lambs. Digestibility and flow of DM and N through the digestive tract were also unaffected (P > 0.10) by parasite infection. Despite a trend towards higher abomasal AA flux in the parasitised lambs (P < 0.10), apparent AA absorption from the small intestine and AA availability to other tissues were unaffected (P > 0.10) by infection. These results suggest that an established parasite infection had little effect on the intestinal absorption and availability of AA to other tissues in lambs fed fresh Lucerne. PMID- 22443705 TI - Effect of dietary supplementation of different oils during the first or second half of pregnancy on the glucose tolerance of the sow. AB - Poor glucose tolerance may be an under-researched contributory factor in the high (10% to 20%) pre-weaning mortality rate observed in pigs. Insulin resistance commences at around week 12 of gestation in the sow, although there are conflicting reports in the literature about the extent to which insulin resistance is modulated by maternal diet. The aim of the study was to determine the effects of supplementing the maternal diet with different dietary oils during either the first half or the second half of gestation on the glucose tolerance of the sow. Sows were offered the control (C: n = 5) diet as pellets or the C diet plus 10% extra energy (n = 16 per group) derived from either: (i) extra pellets; (ii) palm oil; (iii) olive oil; (iv) sunflower oil; or (v) fish oil. Experimental diets were fed during either the first (G1) or second (G2) half of gestation. A glucose tolerance test (GTT) was conducted on day 108 of gestation by administering 0.5 g/kg glucose i.v. Blood samples were taken every 5 to 10 min for 90 min post administration. The change in body weight and backfat thickness during gestation was similar but both type and timing of dietary supplementation influenced litter size and weight. With the exception of the sunflower oil group, supplementing the maternal diet in G1 resulted in larger and heavier litters, particularly in mothers offered palm oil. Basal blood glucose concentrations tended to be more elevated in G1 than G2 groups, whilst plasma insulin concentrations were similar. Following a GTT, the adjusted area under the curve was greater in G1 compared to G2 sows, despite no differences in glucose clearance. Maternal diet appeared to influence the relationship between glucose curve characteristics following a GTT and litter outcome. In conclusion, the degree of insulin sensitivity can be altered by both the period during which maternal nutritional supplementation is offered and the fatty acid profile of the diet. PMID- 22443706 TI - Seasonal variations in daily rhythms of activity in athletic horses. AB - Circadian rhythms reflect extensive programming of biological activity that meets and exploits the challenges and opportunities offered by the periodic nature of the environment. In the present investigation, we recorded the total activity of athletic horses kept at four different times of the year (vernal equinox, summer solstice, autumn equinox and winter solstice), to evaluate the presence of seasonal variations of daily activity rhythms. Athletic Thoroughbred horses were kept in individual boxes with paddock. Digitally integrated measure of total activity of each mare was continuously recorded by actigraphy-based data loggers. Horse total activities were not evenly distributed over the day, but they were mainly diurnal during the year. Daily activity rhythms showed clear seasonal variations, with the highest daily amount of activity during the vernal equinox and the lowest during the winter solstice. Interestingly, the amount of activity during either photophase or scotophase changed significantly throughout the year. Circadian analysis of horse activities showed that the acrophase, the estimated time at which the peak of the rhythm occurs, did not change during the year, it always occurred in the middle of the photoperiod. Analysing the time structure of long-term and continuously measured activity and feeding could be a useful method to critically evaluate athletic horse management systems in which spontaneous locomotor activity and feeding are severely limited. Circadian rhythms are present in several elements of sensory motor and psychomotor functions and these would be taken into consideration to plan the training schedules and competitions in athletic horses. PMID- 22443707 TI - Synthesis of semantic modelling and risk analysis methodology applied to animal welfare. AB - Decision-making on animal welfare issues requires a synthesis of information. For the assessment of farm animal welfare based on scientific information collected in a database, a methodology called 'semantic modelling' has been developed. To date, however, this methodology has not been generally applied. Recently, a qualitative Risk Assessment approach has been published by the European Food Safety Authority (EFSA) for the first time, concerning the welfare of intensively reared calves. This paper reports on a critical analysis of this Risk Assessment (RA) approach from a semantic-modelling (SM) perspective, emphasizing the importance of several seemingly self-evident principles, including the definition of concepts, application of explicit methodological procedures and specification of how underlying values and scientific information lead to the RA output. In addition, the need to include positive aspects of welfare and overall welfare assessments are emphasized. The analysis shows that the RA approach for animal welfare could benefit from SM methodology to support transparent and science based decision-making. PMID- 22443708 TI - Administration of dexamethasone per os in finishing bulls. I. Effects on productive traits, meat quality and cattle behaviour as indicator of welfare. AB - The study investigated the effects of prolonged oral administration of dexamethasone at a low daily dosage of 0.75 mg/head per day (Dexa) on beef cattle productive traits, behaviour and meat quality. In all, 14 finishing Marchigiana bulls were used in a trial that begun 56 days prior to slaughter, of which six bulls received treatment from day 5 to day 53, whereas the remaining animals were used for Control. The animals treated showed an increased average daily gain (1515 v. 1177 g/head per day; P < 0.05; s.e.d. = 48.54) and improved warm carcass dressing percentage (60.8% v. 59.7%; P < 0.05; s.e.d. = 0.32). Behavioural observation did not permit a clear distinction between treated and Control animals since feeding and social behaviour were similar in both groups. The bulls treated spent less time lying (16.5% v. 34.6%; P < 0.05; s.e.d. = 4.38) and grooming (6.7% v. 11.9%; P < 0.05; s.e.d. = 1.23), and this may indicate poorer welfare. No evidence of treatment was observed in other carcass traits, and redness was the only meat quality parameter slightly affected by corticosteroid administration. PMID- 22443709 TI - Administration of dexamethasone per os in finishing bulls. II. Effects on blood parameters used as indicators of animal welfare. AB - A set of hormonal, haematological and biochemical parameters was used to evaluate the physiological response and welfare status of 14 finishing Marchigiana bulls treated for 49 days with a low daily dosage (0.75 mg/head per day) of dexamethasone per os. Compared to the Control group, dexamethasone decreased cortisol concentrations (42.3 v. 5.7 nmol/l; s.e.d. = 4.17; P < 0.001), and led to the reversal of the leukocyte formula in the animals treated (P < 0.05). Total serum proteins (70.2 v. 73.9 g/l; s.e.d. = 1.55; P < 0.05), in particular beta1 globulins (7.5 v. 9.1 g/l; s.e.d. = 0.24; P < 0.01) and fibrinogen (199 v. 258 mg/dl; s.e.d. = 32.70; P < 0.05), increased as a consequence of treatment. Prolonged dexamethasone administration led the bulls to an apparently chronic stress condition. Moreover, the study indicated various blood parameters that might be used by health officials as effective tools in identifying beef cattle suspected of being illegally treated with dexamethasone. PMID- 22443710 TI - Substitution of crude cell wall for neutral detergent fibre in the equations of the Cornell Net Carbohydrate and Protein System that predict carbohydrate fractions: application to sunflower ( Helianthus annuus L.). AB - Prediction of carbohydrate fractions using equations from the Cornell Net Carbohydrate and Protein System (CNCPS) is a valuable tool to assess the nutritional value of forages. In this paper, these carbohydrate fractions were predicted using data from three sunflower (Helianthus annuus L.) cultivars, fresh or as silage. The CNCPS equations for fractions B2 and C include measurement of ash and protein-free neutral detergent fibre (NDF) as one of their components. However, NDF lacks pectin and other non-starch polysaccharides that are found in the cell wall (CW) matrix, so this work compared the use of a crude CW preparation instead of NDF in the CNCPS equations. There were no differences in the estimates of fractions B1 and C when CW replaced NDF; however, there were differences in fractions A and B2. Some of the CNCPS equations could be simplified when using CW instead of NDF. Notably, lignin could be expressed as a proportion of DM, rather than on the basis of ash and protein-free NDF, when predicting CNCPS fraction C. The CNCPS fraction B1 (starch + pectin) values were lower than pectin determined through wet chemistry. This finding, along with the results obtained by the substitution of CW for NDF in the CNCPS equations, suggests that pectin was not part of fraction B1 but present in fraction A. We suggest that pectin and other non-starch polysaccharides that are dissolved by the neutral detergent solution be allocated to a specific fraction (B2) and that another fraction (B3) be adopted for the digestible cell wall carbohydrates. PMID- 22443711 TI - Colour differences among carcasses graded with similar score for conformation and fatness. AB - In a population of 268 yearling bulls, those carcasses graded as U-, U0 or U+ for beef carcass conformation (n = 240) and those graded as 2-, 20 or 2+ for beef carcass fatness (n = 213) were selected to study the efficiency of carcass weight, carcass dimensions and instrumental colour of latissimus dorsi, rectus abdominis and subcutaneous fat, to discriminate among these carcass grades, in a population of high-muscled and very lean carcasses from young bulls. The increase in conformation grade meant an increase in carcass weight and perimeter of the leg. Classifiers use attributes characterizing muscular development and carcass profiles from a general impression of the whole carcass. There were no significant differences for carcass weight or carcass dimensions, among the carcasses classified according to the three fat classes. The a* and b* coordinate values for the latissimus dorsi muscle were observed to decrease significantly as the carcass conformation score increased (P < 0.05). However, muscle and subcutaneous fat of fatter carcasses showed higher a*, b* colour coordinates and chroma (C*) values than leaner carcasses. The CIE (Commission International de l'Eclairage) L*, a* and b* colour coordinate measurements taken on the carcasses 45 min post mortem varied significantly from the readings taken after hanging for 24 h (P < 0,001). The higher a* and b* values on the carcasses chilled for 24 h could be caused by oxygenation of both subcutaneous fat, and latissimus dorsi and rectus abdominis muscles in the time elapsing after slaughter and after carcass exposition to circulating air in the cooler for 24 h. Lightness of the latissimus dorsi muscle underwent a decrease, compared with an increase in the rectus abdominis muscle. Hardening of the subcutaneous fat during cold storage may exert an influence on the decrease in lightness observed. These differences in carcass colour during chilling storage would suggest that the relationship between carcass colour and conformation grades was higher shortly after slaughter. Both L* colour coordinate of fat colour (P < 0.01) and a*, b* and C* colour coordinates of latissimus dorsi muscle (P < 0.05) were related to conformation classification. Colour was more efficient to differentiate conformation than fat cover classes. Sixty-two percent of carcasses were correctly classified for conformation by colour differences but only 37% of carcasses were correctly classified for fatness by colour. PMID- 22443712 TI - Clinical decision-making: midwifery students' recognition of, and response to, post partum haemorrhage in the simulation environment. AB - BACKGROUND: This paper reports the findings of a study of how midwifery students responded to a simulated post partum haemorrhage (PPH). Internationally, 25% of maternal deaths are attributed to severe haemorrhage. Although this figure is far higher in developing countries, the risk to maternal wellbeing and child health problem means that all midwives need to remain vigilant and respond appropriately to early signs of maternal deterioration. METHODS: Simulation using a patient actress enabled the research team to investigate the way in which 35 midwifery students made decisions in a dynamic high fidelity PPH scenario. The actress wore a birthing suit that simulated blood loss and a flaccid uterus on palpation. The scenario provided low levels of uncertainty and high levels of relevant information. The student's response to the scenario was videoed. Immediately after, they were invited to review the video, reflect on their performance and give a commentary as to what affected their decisions. The data were analysed using Dimensional Analysis. RESULTS: The students' clinical management of the situation varied considerably. Students struggled to prioritize their actions where more than one response was required to a clinical cue and did not necessarily use mnemonics as heuristic devices to guide their actions. Driven by a response to single cues they also showed a reluctance to formulate a diagnosis based on inductive and deductive reasoning cycles. This meant they did not necessarily introduce new hypothetical ideas against which they might refute or confirm a diagnosis and thereby eliminate fixation error. CONCLUSIONS: The students response demonstrated that a number of clinical skills require updating on a regular basis including: fundal massage technique, the use of emergency standing order drugs, communication and delegation of tasks to others in an emergency and working independently until help arrives. Heuristic devices helped the students to evaluate their interventions to illuminate what else could be done whilst they awaited the emergency team. They did not necessarily serve to prompt the students' or help them plan care prospectively. The limitations of the study are critically explored along with the pedagogic implications for initial training and continuing professional development. PMID- 22443713 TI - A model of dirigent proteins derived from structural and functional similarities with allene oxide cyclase and lipocalins. AB - Dirigent proteins impart stereoselectivity on the phenoxy radical-coupling reaction, yielding optically active lignans from two molecules of coniferyl alcohol. By an unknown mechanism, they direct the coupling of two phenoxy radicals toward the formation of optically active (+)- or (-)-pinoresinol. We show here that the dirigent protein AtDIR6 from Arabidopsis thaliana is a homodimeric all-beta protein in the superfamily of calycins. Based on its homology with calycins, the structure of AtDIR6 was modeled using allene oxide cyclase as template. The structural model of AtDIR6 was supported experimentally by confirmation of a predicted disulfide bridge and by the characterization of two N-linked glycans at the solvent-exposed protein surface. The model shows AtDIR6 as an eight-stranded antiparallel beta-barrel with a central hydrophobic cavity for substrate binding, suggesting that dirigent proteins evolved from hydrophobic ligand-binding proteins. The data are fully consistent with the current view of the dirigent protein mode of action, according to which each subunit of the homodimer captures one of the substrate radicals and orients them in a way that precludes undesired reaction channels, thus favoring the formation of the optically pure coupling product. PMID- 22443714 TI - Barriers and attitudes influencing non-engagement in a peer feedback model to inform evidence for GP appraisal. AB - BACKGROUND: The UK general practitioner (GP) appraisal system is deemed to be an inadequate source of performance evidence to inform a future medical revalidation process. A long-running voluntary model of external peer review in the west of Scotland provides feedback by trained peers on the standard of GP colleagues' core appraisal activities and may 'add value' in strengthening the robustness of the current system in support of revalidation. A significant minority of GPs has participated in the peer feedback model, but a clear majority has yet to engage with it. We aimed to explore the views of non-participants to identify barriers to engagement and attitudes to external peer review as a means to inform the current appraisal system. METHODS: We conducted semi-structured interviews with a sample of west of Scotland GPs who had yet to participate in the peer review model. A thematic analysis of the interview transcriptions was conducted using a constant comparative approach. RESULTS: 13 GPs were interviewed of whom nine were males. Four core themes were identified in relation to the perceived and experienced 'value' placed on the topics discussed and their relevance to routine clinical practice and professional appraisal: 1. Value of the appraisal improvement activity. 2. Value of external peer review. 3. Value of the external peer review model and host organisation and 4. Attitudes to external peer review. CONCLUSIONS: GPs in this study questioned the 'value' of participation in the external peer review model and the national appraisal system over the standard of internal feedback received from immediate work colleagues. There was a limited understanding of the concept, context and purpose of external peer review and some distrust of the host educational provider. Future engagement with the model by these GPs is likely to be influenced by policy to improve the standard of appraisal and contractual related activities, rather than a self-directed recognition of learning needs. PMID- 22443716 TI - Immunomodulation of T-cell responses with Vibrio cholerae O135 capsular polysaccharide and its protein conjugate, novel cholera vaccine study models. AB - We studied T-cell immune responses to surface capsular polysaccharide (CPS) of Vibrio cholerae O135 and its protein conjugate. CPS and CPS-bovine serum albumin (BSA) activation and presentation are characterized with induced alterations in expression and upregulation of membrane antigens CD25, CD11b, CD16/32, MHCII and CD45 on blood- and spleen-derived T cells. Expression of the early activation marker CD25 revealed efficient CPS-BSA conjugate activation especially of CD4(+) CD3(+) and CD8(+) CD3(+) cells. Specific CPS-BSA-induced CD25(+) T-cell subsets in blood were observed after the first application, i.e. a 4.2-fold increase of CD4(+) CD25(+) and 7.6-fold increase of CD8(+) CD25(+) vs. preimmune levels was determined. The upregulation of surface antigens MHCII and CD45 involved in antigen presentation and cell activation of CD3(+) cells and their significant reciprocal correlation (R(2) = 0.92) observed only with CPS BSA conjugate suggested efficient T-cell dependency and presentation. The pattern of accelerated T-cell activation and engagement of T cells as antigen-presenting cells throughout CPS-BSA immunization contrary to CPS alone was also confirmed in CD4(+) /CD8(+) /CD3(+) splenic cells. The results revealed different T-cell antigen presentation and activation following administration of CPS and CPS-BSA conjugates, as supported also by evaluation of CD45, MHCII and CD25 expression on CD19(+) B cells. PMID- 22443717 TI - One-pot surfactantless route to polyaniline hollow nanospheres with incontinuous multicavities and application for the removal of lead ions from water. AB - Polyaniline (PANI) hollow nanospheres with controllable incontinuous nanocavities ranging in size from 10 to 50 nm as a novel hollow nanostructure have been successfully fabricated by chemical polymerization of aniline with chloroaurate acid as the oxidant and citric acid as the doping acid. Experimental factors, such as concentration and kind of oxidant and doping acid, were investigated to illustrate their effect on morphology of PANI. According to experimental results and time-dependent investigations, a possible formation mechanism involved was then proposed. The adaptability of this route to hollow nanostructures with multicavities of other conducting polymer was also revealed. Furthermore, the adsorption properties of PANI hollow nanospheres toward lead ions in water were investigated. PMID- 22443718 TI - Paecilomyces lilacinus causing debilitating sinusitis in an immunocompetent patient: a case report. AB - INTRODUCTION: Since the discovery of the first documented case of Paecilomyces in 1963, only five cases of Paecilomyces sinusitis have been described to date and all of them have predisposing factors such as immunocompromised status or prior nasal surgery. We present the first case of Paecilomyces lilacinus sinusitis in a fit young woman with no identified predisposing factors. To the best of our knowledge, this is the first known case in the UK and in Europe. CASE PRESENTATION: A 20-year-old Iraqi woman who has lived in the UK for the past five years presented with rhinorrhea, hyposmia, and nasal obstruction. She was previously fit and well and had no significant medical history. Imaging revealed a fungal infection that was eventually revealed on cytological examination to be P. lilacinus. CONCLUSIONS: P. lilacinus is both a difficult and important organism to identify because it has intrinsic anti-fungal resistance. In our case, the infection was severe and recurrent, and the organism demonstrated resistance to common oral anti-fungal agents. There was a delay in its diagnosis, owing to its similarity in appearance to Penicillium and a difficulty in distinguishing between the two without specialized knowledge of fungal taxonomy. In the field of otolaryngology, Paecilomyces is relatively unknown. Our intention is to raise awareness of this organism as well as to describe the challenges in its management. PMID- 22443720 TI - Subextensive entropies and open order in perovskite oxynitrides. AB - Unusual subextensive configurational entropies that vary with particle size and tend to zero per atom in macroscopic samples are predicted for AMO(3-z)N(z) oxynitrides with perovskite type crystal structures. These materials are crystallographically disordered on the atomic scale, but local anion order produces chains of M-N-M bonds that undergo a 90 degrees turn at each M cation, giving rise to subextensive entropies in materials such as SrTaO(2)N, LaNbON(2), and EuWO(1.5)N(1.5). A general Pauling ice-rules formula is used to calculate the extensive molar entropies for other cases such as SrMoO(2.5)N(0.5) and BaTaO(2)N. The subextensive oxynitrides are usefully classified as showing an "open order", related to the correlated order of displacements in ferroelectric perovskites such as BaTiO(3). This raises the possibility that further open-ordered oxynitride or molecular structures may be accessible, and other states such as spins and charges may also show novel open orders. PMID- 22443721 TI - Fertility in dairy cows: bridging the gaps. PMID- 22443722 TI - Effect of progesterone on embryo survival. AB - Increased genetic selection over the past 40 years has resulted in a dairy cow with an improved biological efficiency for producing milk but with an associated reduced fertility. Embryo loss is the greatest factor contributing to the failure of a cow to conceive. The extent and timing of embryo loss indicates that 70% to 80% of this loss occurs in the first 2 weeks after artificial insemination (AI). This is the period when a number of critical phases in embryo development occur and where protein accretion, substrate utilization and embryo metabolism increase dramatically. During this time the early embryo is completely dependent on the oviduct and uterine environment for its survival and it is likely that the embryo requires an optimal uterine environment to ensure normal growth and viability. There is increasing evidence of an association between the concentration of systemic progesterone and early embryo loss and that progesterone supplementation of cows, particularly those with low progesterone, can reduce this loss. While progesterone is known to affect uterine function and embryo growth, little is known about the uterus during the period of early embryo loss and how this is affected by changes in the concentration of systemic progesterone. The expression of uterine genes encoding the transport protein retinol binding protein (RBP) and the gene for folate binding protein (FBP) appear to be sensitive to changes in systemic progesterone, particularly during the early luteal phase of the cycle. Uterine concentrations of proteins also seem to be regulated by stage of cycle; however, their relationship with the systemic concentration of progesterone is unclear. There is an urgent need to characterize the uterine environment from a functional perspective during the early part of the luteal phase of the cycle, particularly in the high-producing cow, in order to understand the factors contributing to early embryo loss and in order to devise strategies to minimize or reduce this loss. PMID- 22443723 TI - The consequences of metabolic changes in high-yielding dairy cows on oocyte and embryo quality. AB - Unsatisfactory reproductive performance in dairy cows, such as reduced conception rates, in addition to an increased incidence of early embryonic mortality, is reported worldwide and has been associated with a period of negative energy balance (NEB) early post partum. Typically, NEB is associated with biochemical changes such as high non-esterified fatty acid (NEFA), high beta-hydroxybutyrate (beta-OHB) and low glucose concentrations. The concentrations of these and other metabolites in the follicular fluid (FF) of high-yielding dairy cows during NEB were determined and extensively analyzed, and then were replicated in in vitro maturation models to investigate their effect on oocyte quality. The results showed that typical metabolic changes during NEB are well reflected in the FF of the dominant follicle. However, the oocyte seems to be relatively isolated from extremely elevated NEFA or very low glucose concentrations in the blood. Nevertheless, the in vitro maturation models revealed that NEB-associated high NEFA and low glucose levels in the FF are indeed toxic to the oocyte, resulting in deficient oocyte maturation and developmental competence. Induced apoptosis and necrosis in the cumulus cells was particularly obvious. Furthermore, maturation in saturated free fatty acid-rich media had a carry-over effect on embryo quality, leading to reduced cryotolerance of day 7 embryos. Only beta-OHB showed an additive toxic effect in moderately hypoglycemic maturation conditions. These in vitro maturation models, based on in vivo observations, suggest that a period of NEB may hamper the fertility of high-yielding dairy cows through increased NEFA and decreased glucose concentrations in the FF directly affecting oocyte quality. In addition to oocyte quality, these results also demonstrate that embryo quality is reduced following an NEB episode. This important observation may be linked to the typical diet provided to stimulate milk yield, or to physiological adaptations sustaining the high milk production. Research into this phenomenon is ongoing. PMID- 22443724 TI - Developmental programming of reproduction and fertility: what is the evidence? AB - The concept of the foetal/developmental origins of adult disease has been around for ~20 years and from the original epidemiological studies in human populations much more evidence has accumulated from the many studies in animal models. The majority of these have focused upon the role of early dietary intake before conception, through gestation and/or lactation and subsequent interactions with the postnatal environment, e.g. dietary and physical activity exposures. Whilst a number of theoretical models have been proposed to place the experimental data into a biological context, the underlying phenomena remain the same; developmental deficits (of single (micro) nutrients) during critical or sensitive periods of tissue growth alter the developmental pathway to ultimately constrain later functional capacity when the individual is adult. Ageing, without exception, exacerbates any programmed sequelae. Thus, adult phenotypes that have been relatively easy to characterise (e.g. blood pressure, insulin sensitivity, body fat mass) have received most attention in the literature. To date, relatively few studies have considered the effect of differential early environmental exposures on reproductive function and fecundity in predominantly mono-ovular species such as the sheep, cow and human. The available evidence suggests that prenatal insults, undernutrition for example, have little effect on lifetime reproductive capacity despite subtle effects on the hypothalamic pituitary-gonadal axis and gonadal progenitor cell complement. The postnatal environment is clearly important, however, since neonatal/adolescent growth acceleration (itself not independent from prenatal experience) has been shown to significantly influence fecundity in farm animals. The present paper will expand these interesting areas of investigation and review the available evidence regarding developmental programming of reproduction and fertility. However, it appears there is little strong evidence to indicate that offspring fertility and reproductive senescence in the human and in farm animal species are overtly affected by prenatal nutrient exposure. Nevertheless, it is clear that the developing gonad is sensitive to its immediate environment but more detailed investigation is required to specifically test the long-term consequences of nutritional perturbations during pregnancy on adult reproductive well-being. PMID- 22443725 TI - Factors influencing heifer survival and fertility on commercial dairy farms. AB - The average dairy cow survives only three lactations, reducing the availability of replacement heifers. Prenatal losses occur due to early embryonic mortality (about 40%), later embryo loss (up to 20% in high-yielding herds) or abortion (about 5%). A recent survey of 19 UK herds showed that 7.9% of calves were born dead and 3.4% died within 1 month. During the rearing phase, 6.7% of animals were lost before reaching first service at 15 months due to disease or accident and another 2.3% failed to conceive. Many potential replacements therefore never enter the milking herd. This severely limits opportunities for on-farm selection of breeding cows in addition to presenting a welfare issue and causing economic loss. The most profitable animals once lactation is reached combine good milk production with a regular calving pattern. Some aspects of performance are related to age at first calving (AFC), which in turn is influenced by heifer growth rates. Poorly growing animals required more services to conceive, calved later and subsequently performed badly. Optimum fertility and maximum yield in the first lactation were associated with an AFC of 24 to 25 months. However, heifers calving at 22 to 23 months performed best in terms of total milk yield and survival over the first 5 years, partly because good heifer fertility was associated with better fertility later. We have investigated some possible juvenile predictors of future performance. Low-birth-weight calves were more likely to come from either primiparous mothers or older dams (3+ lactations) with higher peak milk yields, suggesting that the uterine environment may limit prenatal calf growth due to competition for nutrients with maternal growth or milk production. Linear trait classification scores for frame size show genetic correlations with longevity. The skeletal measures of height and crown rump length in 1-month-old calves was correlated to subsequent stature, and frame size was correlated to weight at 15 months. It may thus be possible to predict performance from simple size measurements as juveniles. Neither endogenous nor stimulated growth hormone (GH) release in 6-month-old calves were related to milk yield in the first three lactations, but size of a stimulated GH peak was positively related to milk energy values in the first lactation. Cows with delayed ovulation (>45 days) in the first lactation had a higher GH pulse amplitude and lower IGF-I as a juvenile. Cows that partition excess energy into milk in their first lactation may suffer reduced longevity. PMID- 22443726 TI - Integration of physiological mechanisms that influence fertility in dairy cows. AB - Fertility in dairy cows has been declining for the past three decades. Genetic selection for increased milk production has been associated with changes in key metabolic hormones (growth hormone, insulin, IGF and leptin) that regulate metabolism by homoeostasis and homeorhesis. These metabolic hormones, particularly insulin, provide signals to the reproductive system so that regulation of ovarian function is coordinated with changes in metabolic status. Studies have shown, for example, that increasing circulating insulin concentrations during the early post partum period can advance the resumption of oestrous cycles by enhancing follicular growth. However, high concentrations of insulin can be detrimental to the developmental competence of oocytes, which is also influenced by the supply of fatty acids at the systemic level and at the ovarian level. Insulin status is also associated with the incidence and characteristics of abnormal ovarian cycles. These changes can occur without significant variation in circulating gonadotrophin concentrations. This suggests that additional factors, such as peripheral metabolites, metabolic hormones and locally produced growth factors, may have a modulating role. Recent evidence has demonstrated that ovarian responses to metabolic signals and nutrient profile vary according to the stage of the reproductive cycle. Improved understanding of this multifactorial process enables nutrition to be matched to genotype and milk production, with a positive impact on pregnancy rate. PMID- 22443727 TI - Effect of Escherichia coli infection of the bovine uterus from the whole animal to the cell. AB - Following parturition, contamination of the uterine lumen by bacteria is ubiquitous, and uterine health is impaired in cattle because infection persists in 10% to 15% of animals as endometritis. Endometritis causes infertility for the duration of infection, and subfertility persists even after apparent successful resolution of the disease. Escherichia coli is the pathogenic bacterium most frequently isolated from the post partum uterus, and is associated with increased concentrations of peripheral plasma acute phase proteins and fetid vaginal mucus. The presence of E. coli is also associated with slower growth of the first post partum dominant follicle and perturbed oestradiol secretion. Furthermore, in animals that ovulate the first dominant follicle, the corpus luteum is smaller and secretes less progesterone. The endotoxin lipopolysaccharide (LPS), which is released from E.coli, can pass from the uterine lumen to the peripheral circulation and LPS concentrations are increased in cows with uterine infection. Infusion of E. coli LPS into the uterine lumen suppresses the pre-ovulatory luteinising hormone surge and disrupts ovulation in heifers. In vitro, endometrial explants produce prostaglandins in response to LPS. Addition of LPS or E. coli to stromal or epithelial cells increases cyclooxygenase-2 mRNA expression, and stimulates the production of prostaglandin E2 and prostaglandin F2alpha . Furthermore, uterine and ovarian cells express mRNA of the molecules required for recognition of LPS, Toll-like receptor-4 and CD14. In summary, E. coli is a common cause of infertility involving the perturbation of the hypothalamus, pituitary and ovary in dairy cows. PMID- 22443728 TI - Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities. AB - Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management. Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics, are discussed including their promising future value for dairy cow fertility. PMID- 22443729 TI - Sire breed comparisons for meat and eating quality traits in Australian pig populations. AB - Sire breed comparisons for carcase (n = 1169), meat and eating quality (n = 686) traits were obtained using data recorded on progeny of known pedigree sired by Duroc (DU), Large White (LW), Landrace (LR) and Duroc Synthetic (DS) boars from crossbred (LW/LR) sows. Animals were reared in eco-shelters in large single-sex contemporary groups and slaughtered on an age constant basis at 22 weeks of age. Compared to progeny from other sire groups, animals sired by purebred Duroc boars tended to have improved eating quality traits (higher intramuscular fat and lower shear force) at the expense of poorer carcase characteristics (higher subcutaneous and belly fat). Animals sired by DS boars tended to be heavier and leaner than those sired by LW, LR or DU boars; intramuscular fat but not belly fat was correspondingly lower, while tenderness was generally consistent with that of the DU progeny. Significant variability of sire progeny groups within sire breed suggests that sire breed selection, potentially used for improving traits such as meat quality in commercial progeny, will be less accurate in the absence of sire-specific information, which is typically poorly recorded in this class of traits. PMID- 22443730 TI - Genetic relationships between composition of pork bellies and performance, carcase and meat quality traits. AB - Belly traits including predicted fat percentage of the belly (FATPC), combined area of the rib bone and muscle (RBMA), intermuscular fat area (IMFA) and subcutaneous fat area (SFA) were recorded on 2403 pigs along with carcase fat depth at the P2 site (P2). Belly traits were derived from image analysis of the anterior side of pork bellies. Further data available for pigs with belly data and their contemporaries included lifetime growth rate, ultrasound backfat and loin muscle depth (35 406 records), along with meat quality traits (3935 records). There were 4586 feed intake records and 18 398 juvenile insulin-like growth factor-I (IGF-I) records available, which included the majority of pigs with belly data. Genetic parameters were estimated based on an animal model using Residual Maximum Likelihood procedures. Heritability estimates for belly traits ranged from 0.23 to 0.34 (+/-0.05 to 0.06) while the common litter effect varied from 0.04 to 0.07 (+/-0.03). Genetic correlations between FATPC, individual belly fat measurements and carcase P2 fat depth differed significantly from unity, ranging from 0.71 to 0.85 (+/-0.05 to 0.08). Genetic correlations between IMFA and subcutaneous fat measurements varied from 0.47 to 0.63 (+/-0.08 to 0.13). Genetic correlations between belly and performance traits show that selection for reduced juvenile-IGF-I, reduced feed intake and reduced backfat along with increased loin muscle depth will reduce overall fat levels in the belly. Only loin muscle depth had a significant genetic correlation with RBMA (0.32 +/- 0.10), thereby assisting selection for improved lean meat content of the belly. Ultimately, genetic improvement of belly muscles requires specific measurements of lean meat content of the belly. For this to be effective, measurements are required that can be routinely recorded on the slaughter line, or preferably on the live animal. PMID- 22443731 TI - Neonatal lamb vigour is improved by feeding docosahexaenoic acid in the form of algal biomass during late gestation. AB - To determine whether feeding a sustainable, algal source of docosahexaenoic acid (DHA) to sheep during late pregnancy would improve neonatal lamb vigour, 48 English mule ewes, of known conception date, were divided into four treatment groups. For the last 9 weeks of gestation, ewes received one of two dietary supplements: either a DHA-rich algal biomass providing 12 g DHA/ewe per day, or a control supplement based on vegetable oil. The four dietary treatment groups (n = 12) were: control supplement for the duration of the trial (C), DHA supplement from 9 to 6 weeks before parturition (3 week), DHA supplement from 9 to 3 weeks before parturition (6 week) and DHA supplement for the duration of the trial (9 week). Dietary supplements were fed alongside grass silage and commercial concentrate. There was a tendency for gestation length to be extended with increased duration of DHA supplementation (P = 0.08). After parturition, the concentrations of eicosapentaenoic acid (EPA) and DHA in ewe and lamb plasma and colostrum were elevated in line with increased periods of DHA supplementation. Lambs from the 6-week and 9-week groups stood significantly sooner after birth than lambs from the C group (P < 0.05). These data show that neonatal vigour may be improved by the supplementation of maternal diets with DHA-rich algal biomass and that this beneficial effect depends upon the timing and/or duration of DHA allocation. PMID- 22443732 TI - The efficiency of conversion of metabolisable protein into milk true protein over a range of metabolisable protein intakes. AB - The aim of this work was to test the robustness of the 0.68 estimate of the efficiency of conversion of metabolisable protein into true milk protein (Agriculture and Food Research Council (AFRC), 1993) for protein-limiting diets and to determine whether a different value is appropriate for practical rationing. Seventy-two multiparous cows were blocked on the basis of milk energy output per unit of dry matter intake (DMI), and allocated at random to one of four treatments. Treatments supplied metabolisable energy (ME) at a fixed level to individuals within a block, but varied metabolisable protein (MP) supply from 25% below the estimated requirements, through -12.5% and +12.5% up to 25% above requirements for the average performance of animals within blocks at the start of the study. Cows were offered diets to meet their predicted ME requirements for each 3-week period with measurements performed in the last week of each period. Milk protein output was regressed against the estimated MP available for production for each cow and the efficiency of conversion of MP into milk true protein was calculated, assuming a maintenance requirement according to the MP system. The efficiency of conversion of MP into milk true protein decreased with the increasing supply of MP from 0.77 to 0.50. Using an iterative approach to determine the best fit of the data when supply matched requirement resulted in a range of efficiency values between 0.62 and 0.64 g of true milk protein per g of MP. PMID- 22443733 TI - Meta-analyses of experimental data in animal nutrition. AB - Research in animal sciences, especially nutrition, increasingly requires processing and modeling of databases. In certain areas of research, the number of publications and results per publications is increasing, thus periodically requiring quantitative summarizations of literature data. In such instances, statistical methods dealing with the analysis of summary (literature) data, known as meta-analyses, must be used. The implementation of a meta-analysis is done in several phases. The first phase concerns the definition of the study objectives and the identification of the criteria to be used in the selection of prior publications to be used in the construction of the database. Publications must be scrupulously evaluated before being entered into the database. During this phase, it is important to carefully encode each record with pertinent descriptive attributes (experiments, treatments, etc.) to serve as important reference points for the rest of the analysis. Databases from literature data are inherently unbalanced statistically, leading to considerable analytical and interpretation difficulties; missing data are frequent, and data structures are not the outcomes of a classical experimental system. An initial graphical examination of the data is recommended to enhance a global view as well as to identify specific relationships to be investigated. This phase is followed by a study of the meta system made up of the database to be interpreted. These steps condition the definition of the applied statistical model. Variance decomposition must account for inter- and intrastudy sources; dependent and independent variables must be identified either as discrete (qualitative) or continuous (quantitative). Effects must be defined as either fixed or random. Often, observations must be weighed to account for differences in the precision of the reported means. Once model parameters are estimated, extensive analyses of residual variations must be performed. The roles of the different treatments and studies in the results obtained must be identified. Often, this requires returning to an earlier step in the process. Thus, meta-analyses have inherent heuristic qualities. PMID- 22443734 TI - Effects of immunization against GnRH on gonadotropins, the GH-IGF-I-axis and metabolic parameters in barrows. AB - Surgically castrated male piglets (barrows) reveal an increase in LH and a decrease in GH compared to untreated boars. Boars that were castrated by immunization against gonadotropin releasing hormone (GnRH) have decreased LH but maintain GH. The difference in GH levels between barrows and immunological castrated boars cannot be explained by testicular steroids because they are low in surgical and immunocastrated boars as well. Therefore, differences in GH concentrations might be due to an interaction between GnRH and growth hormone releasing hormone (GRH) in the hypothalamus or the pituitary. This hypothesis was tested with twelve male piglets that had been castrated within 1 week postnatally and fitted with indwelling cephalic vein catheters at 17 weeks of age. They were split into a control group and an immunized group (each n = 6). Vaccination with Improvac(r) was performed at 18 and 22 weeks of age. Specific radioimmunoassays were used for hormone determinations (GH, LH, FSH, testosterone and IGF-I). Additionally, metabolic responses were evaluated by measuring analytical parameters that characterize protein synthesis and breakdown, and body fat content. The second vaccination led to a rapid decrease of LH below the limit of detection whereas FSH decreased more slowly, over a period of 5 weeks, from 2.2 to 0.5 ng/ml. This level of FSH, which corresponds to boar-specific concentrations, was maintained thereafter. GH decreased with increasing age but was not influenced by vaccination and remained at a low concentration typical for barrows. Similarly, IGF-I was not altered by vaccination. Consequently, metabolic status was not changed by immunization. It is concluded that the difference in GH levels between surgical and immunocastrated boars is not explained by an interaction between GnRH and GRH. PMID- 22443735 TI - Concomitant changes in progesterone catabolic enzymes, cytochrome P450 2C and 3A, with plasma insulin concentrations in ewes supplemented with sodium acetate or sodium propionate. AB - Progesterone is essential for maintaining pregnancy, and several authors have suggested that low peripheral concentrations of progesterone may be responsible for high rates of embryonic loss. The primary organ involved in the catabolism of progesterone is the liver, and cytochrome P450 2C and 3A sub-families account for a large proportion of this catabolism. Elucidating a mechanism to decrease progesterone catabolism, thereby increasing embryonic and uterine exposure to progesterone, seems a logical approach to ameliorate high rates of embryonic loss. The objectives of the current experiment were to determine the pattern of insulin secretion after supplementing feed with either sodium acetate or sodium propionate and to determine any association between the differential patterns of insulin secretion with the hepatic activity of cytochrome P450 2C and 3A and progesterone clearance. Sixteen ovariectomized ewes were fed 3 kg/day for 10 days of a diet consisting of 50% corn silage, 38% triticale haylage, 12% soybean meal and 600 ml of 3.5 M sodium acetate (energy control; n = 8) or 2.0 M sodium propionate (gluconeogenic substrate; n = 8). Equal portions of the ration (1 kg as-fed basis along with 200 ml of 3.5 M sodium acetate or 2.0 M sodium propionate) were offered three times daily at 0600, 1400 and 2200 h. Concentrations of insulin in plasma were determined immediately before feeding and at 15, 30, 60, 90, 120, 180, 240 and 300 min after feeding. Progesterone clearance from peripheral circulation (ng/ml per min) was measured by giving a 5 mg injection of progesterone into the left jugular vein and collecting blood via the right jugular vein at 0, 2, 4, 6, 8, 10, 15, 20 and 30 min afterwards. Liver biopsies were taken 1 h after feeding to determine cytochrome P450 2C and 3A activities. Insulin concentrations in ewes supplemented with sodium propionate were elevated at 15, 30 and 60 min after feeding compared to the sodium acetate group. Cytochrome P450 2C and 3A activities were decreased 1 h after feeding in the sodium propionate-treated ewes relative to sodium acetate. Insulin appears to down-regulate cytochrome P450 activity, which could be used to decrease the catabolism of progesterone during early gestation, thereby increasing peripheral concentrations of progesterone and, consequently, embryonic exposure to progesterone. PMID- 22443736 TI - Risk factors and milk yield losses associated with lameness in Holstein-Friesian dairy cattle. AB - Weekly locomotion scores on a scale of 1 to 5 were used to investigate the relationship between cattle lameness, management systems and the impact of lameness on milk production. The data were 14026 locomotion scores from 248 Holstein-Friesian cows. Cows were managed in two groups, XE (high-concentrate feed and housed indoors all year) and XM (low-concentrate feed and outdoors in summer). Analysis was performed using residual maximum likelihood. Results indicated that the most significant variables affecting locomotion were time of year when the animal was locomotion scored and management group. Cows scored during February and August had increased locomotion problems. Cows in the more intensively managed group had significantly poorer locomotion compared with those in the more extensive group. Older animals were more susceptible to lameness than heifers. Body weight, body condition score and days in milk (DIM) also accounted for significant variation in locomotion score. Poor locomotion was associated with a significant reduction in the milk yield of later lactation cows. There was a significant difference in the shape of the lactation curve depending on whether or not the cow was lame during lactation. Average persistency was greater for the group of cows never lame throughout lactation compared with those lame before 60 DIM. PMID- 22443737 TI - Effect of rearing system and mixing at loading on transport and lairage behaviour and meat quality: comparison of free range and conventionally raised pigs. AB - Free range pigs, born outdoors and reared after weaning in enriched indoor accommodation, were compared with conventionally raised pigs from a farm, matched for effects on meat quality, with respect to behaviour during transport and lairage, blood chemistry at slaughter and meat quality characteristics. Pigs were either kept in farm pen groups or were mixed at loading and kept in the groups, so formed, until slaughter. Free range pigs tended to settle faster during the 21/2 h transport and 2 h lairage than conventionally raised pigs and were more likely to lie as resting posture during transport. Mixing at loading had no effect on posture during transport or during lairage for free range pigs but mixed conventionally raised pigs showed a greater variability in posture during lairage compared to non-mixed conventionally raised pigs, presumably as a result of disturbance from fighting conspecifics. Conventionally raised and free range pigs showed similar levels of aggression during transport but conventionally raised pigs were more aggressive during the lairage (average for mixed groups 12 v. 2 fights, P < 0.001). Aggressive interactions, such as one-way bites, were almost exclusively confined to mixed groups and all fights with mutual biting in mixed groups occurred solely between unfamiliar animals. The frequency of unacceptable skin damage in the middle and shoulder was highest in conventionally raised pigs and in mixed groups. Cortisol concentration and creatine kinase (CK) activity in slaughter blood were not affected by the rearing system. Mixing did not affect cortisol concentrations but led to higher CK activities compared to non-mixing (957 v. 588 U/l, respectively, P < 0.05). The rate of pH fall after slaughter was not affected by the rearing system but muscle temperatures early post mortem were highest in free range pigs. Mixing did not affect pH or temperature early post mortem. Neither rearing system nor mixing at loading affected ultimate pH or internal reflectance (meat quality marbling values). PMID- 22443738 TI - Estimation of the methane emission factor for the Italian Mediterranean buffalo. AB - In order to contribute to the improvement of the national greenhouse gas emission inventory, this work aimed at estimating a country-specific enteric methane (CH4) emission factor for the Italian Mediterranean buffalo. For this purpose, national agriculture statistics, and information on animal production and farming conditions were analysed, and the emission factor was estimated using the Tier 2 model of the Intergovernmental Panel on Climate Change. Country-specific CH4 emission factors for buffalo cows (630 kg body weight, BW) and other buffalo (313 kg BW) categories were estimated for the period 1990-2004. In 2004, the estimated enteric CH4 emission factor for the buffalo cows was 73 kg/head per year, whereas that for other buffalo categories it was 56 kg/head per year. Research in order to determine specific CH4 conversion rates at the predominant production system is suggested. PMID- 22443739 TI - The effect of recombinant caspase 3 on myofibrillar proteins in porcine skeletal muscle. AB - The objective of this study was to investigate the potential role of the caspase protease family in meat tenderisation by examining if caspase 3 was capable of causing myofibril protein degradation. Full-length human recombinant caspase 3 (rC3) was expressed in Escherichia coli and purified. The rC3 was active in the presence of myofibrils isolated from porcine longissimus dorsi muscle (LD) and retained activity in a buffer system closely mimicking post mortem conditions. The effect of increasing concentrations of rC3, incubation temperature, as well as incubation time on the degradation of isolated myofibril proteins were all investigated in this study. Myofibril protein degradation was determined by SDS PAGE and Western blotting. There was a visible increase in myofibril degradation with a decrease in proteins identified as desmin and troponin I and the detection of protein degradation products at approximately 32, 28 and 18 kDa with increasing concentrations of rC3. These degradation products were analysed using MALDI-TOF mass spectrometry and identified to occur from the proteolysis of actin, troponin T and myosin light chain, respectively. The production of these degradation products was not inhibited by 5 mM EDTA or semi-purified calpastatin but was inhibited by the caspase-specific inhibitor Ac-DEVD-CHO. The temperature at which isolated myofibrils were incubated with rC3 was also found to affect degradation, with increasing incubation temperatures causing increased desmin degradation and cleavage of pro-caspase 3 into its active isoform. Incubation of isolated myofibrils at 4 degrees C for 5 days with rC3 resulted in the visible degradation of a number of myofibril proteins including desmin and troponin I. This study has shown that rC3 is capable of causing myofibril degradation, hydrolysing myofibril proteins under conditions that are similar to those found in muscle in the post mortem conditioning period. PMID- 22443740 TI - Communication: hybrid femtosecond/picosecond rotational coherent anti-Stokes Raman scattering thermometry using a narrowband time-asymmetric probe pulse. AB - A narrowband, time-asymmetric probe pulse is introduced into the hybrid femtosecond/picosecond rotational coherent anti-Stokes Raman scattering (fs/ps RCARS) technique to provide accurate and precise single-shot, high-repetition rate gas-phase thermometric measurements. This narrowband pulse-generated by inserting a Fabry-Perot etalon into the probe-pulse beam path-enables frequency domain detection of pure-rotational transitions. The unique time-asymmetric nature of this pulse, in turn, allows for detection of resonant Raman-active rotational transitions free of signal contamination by nonresonant four-wave mixing processes while still allowing detection at short probe-pulse delays, where collisional dephasing processes are negligible. We demonstrate that this approach provides excellent single-shot thermometric accuracy (<1% error) and precision (~2.5%) in gas-phase environments. PMID- 22443741 TI - Communication: impact of inertia on biased Brownian transport in confined geometries. AB - We consider the impact of inertia on biased Brownian motion of point-size particles in a two-dimensional channel with sinusoidally varying width. If the time scales of the problem separate, the adiabatic elimination of the transverse degrees of freedom leads to an effective description for the motion along the channel given by the potential of mean force. The possibility of such description is intimately connected with equipartition. Numerical simulations show that in the presence of external bias the equipartition may break down leading to non monotonic dependence of mobility on external force and several other interesting effects. PMID- 22443742 TI - Communication: spin-orbit splittings in degenerate open-shell states via Mukherjee's multireference coupled-cluster theory: a measure for the coupling contribution. AB - We propose a generally applicable scheme for the computation of spin-orbit (SO) splittings in degenerate open-shell systems using multireference coupled-cluster (MRCC) theory. As a specific method, Mukherjee's version of MRCC (Mk-MRCC) in conjunction with an effective mean-field SO operator is adapted for this purpose. An expression for the SO splittings is derived and implemented using Mk-MRCC analytic derivative techniques. The computed SO splittings are found to be in satisfactory agreement with experimental data. Due to the symmetry properties of the SO operator, SO splittings can be considered a quality measure for the coupling between reference determinants in Jeziorski-Monkhorst based MRCC methods. We thus provide numerical insights into the coupling problem of Mk-MRCC theory. PMID- 22443743 TI - Calculation of longitudinal polarizability and second hyperpolarizability of polyacetylene with the coupled perturbed Hartree-Fock/Kohn-Sham scheme: where it is shown how finite oligomer chains tend to the infinite periodic polymer. AB - The longitudinal polarizability, alpha(xx), and second hyperpolarizability, gamma(xxxx), of polyacetylene are evaluated by using the coupled perturbed Hartree-Fock/Kohn-Sham (HF/KS) scheme as implemented in the periodic CRYSTAL code and a split valence type basis set. Four different density functionals, namely local density approximation (LDA) (pure local), Perdew-Becke-Ernzerhof (PBE) (gradient corrected), PBE0, and B3LYP (hybrid), and the Hartree-Fock Hamiltonian are compared. It is shown that very tight computational conditions must be used to obtain well converged results, especially for gamma(xxxx), that is, very sensitive to the number of k(->) points in reciprocal space when the band gap is small (as for LDA and PBE), and to the extension of summations of the exact exchange series (HF and hybrids). The band gap in LDA is only 0.01 eV: at least 300 k(->) points are required to obtain well converged total energy and equilibrium geometry, and 1200 for well converged optical properties. Also, the exchange series convergence is related to the band gap. The PBE0 band gap is as small as 1.4 eV and the exchange summation must extend to about 130 A from the origin cell. Total energy, band gap, equilibrium geometry, polarizability, and second hyperpolarizability of oligomers -(C(2)H(2))(m)-, with m up to 50 (202 atoms), and of the polymer have been compared. It turns out that oligomers of that length provide an extremely poor representation of the infinite chain polarizability and hyperpolarizability when the gap is smaller than 0.2 eV (that is, for LDA and PBE). Huge differences are observed on alpha(xx) and gamma(xxxx) of the polymer when different functionals are used, that is in connection to the well-known density functional theory (DFT) overshoot, reported in the literature about short oligomers: for the infinite model the ratio between LDA (or PBE) and HF becomes even more dramatic (about 500 for alpha(xx) and 10(10) for gamma(xxxx)). On the basis of previous systematic comparisons of results obtained with various approaches including DFT, HF, Moller-Plesset (MP2) and coupled cluster for finite chains, we can argue that, for the infinite chain, the present HF results are the most reliable. PMID- 22443744 TI - Effect of discontinuities in Kohn-Sham-based chemical reactivity theory. AB - We provide a new derivation of a formula for the Fukui function of density functional chemical reactivity theory which incorporates the discontinuities in the Kohn-Sham reference system. Orbital relaxations are described in terms of the exchange-correlation (XC) kernel, i.e., the derivative of the XC potential with respect to the density and it is shown that in order to correctly measure the reactivity toward a nucleophilic reagent a discontinuity of the XC kernel has to be taken into account. The importance of this finding is illustrated in model molecular systems. PMID- 22443745 TI - Diffusion in one-dimensional channels with zero-mean time-periodic tilting forces. AB - We investigate the motion of overdamped Brownian particles in a one-dimensional channel under a zero-mean time-periodic tilting force F(t). By introducing a simple harmonic signal, strong enhancement of diffusion is possible for relatively large values of the Peclet number. Direct numerical simulations over the corresponding Fokker-Planck equation show that the diffusion enhancement is induced by a type of nonlinear resonance effect involving the tilting force and the density gradient. PMID- 22443746 TI - Shape fluctuation-induced dynamic hysteresis. AB - We consider a system of Brownian particles confined in a two-dimensional bilobal enclosure whose walls are driven in time periodically by an external perturbation. The response of the particles under shape modulation is characterized by a relaxational delay which results in a non-vanishing area of the response function-field loop, response function being the integrated probability of residence of the particles in any of the lobes. This phenomenon is an entropic analogue of dynamical hysteresis, which vanishes in the quasi-static limit. The hysteresis loop area depends on temperature, strength of modulating field, and the geometrical parameters of the enclosure and exhibits a turnover as a function of frequency of the field. PMID- 22443747 TI - Efficient evaluation of Coulomb integrals in a mixed Gaussian and plane-wave basis using the density fitting and Cholesky decomposition. AB - The objective of this paper is to show that the density fitting (resolution of the identity approximation) can also be applied to Coulomb integrals of the type (k(1)(1)k(2)(1)|g(1)(2)g(2)(2)), where k and g symbols refer to plane-wave functions and gaussians, respectively. We have shown how to achieve the accuracy of these integrals that is needed in wave-function MO and density functional theory-type calculations using mixed Gaussian and plane-wave basis sets. The crucial issues for achieving such a high accuracy are application of constraints for conservation of the number electrons and components of the dipole moment, optimization of the auxiliary basis set, and elimination of round-off errors in the matrix inversion. PMID- 22443748 TI - Application of efficient algorithm for solving six-dimensional molecular Ornstein Zernike equation. AB - In this article, we propose an efficient algorithm for solving six-dimensional molecular Ornstein-Zernike (MOZ) equation. In this algorithm, the modified direct inversion in iterative subspace, which is known as the fast convergent method for solving the integral equation theory of liquids, is adopted. This method is found to be effective for the convergence of the MOZ equation with a simple initial guess. For the accurate averaging of the correlation functions over the molecular orientations, we use the Lebedev-Laikov quadrature. The appropriate number of grid points for the quadrature is decided by the analysis of the dielectric constant. We also analyze the excess chemical potential of aqueous ions and compare the results of the MOZ with those of the reference interaction site model. PMID- 22443749 TI - Dynamical mean-field theory for molecules and nanostructures. AB - Dynamical mean-field theory (DMFT) has established itself as a reliable and well controlled approximation to study correlation effects in bulk solids and also two dimensional systems. In combination with standard density-functional theory (DFT), it has been successfully applied to study materials in which localized electronic states play an important role. It was recently shown that this approach can also be successfully applied to study correlation effects in nanostructures. Here, we provide some details on our recently proposed DFT+DMFT approach to study the magnetic properties of nanosystems [V. Turkowski, A. Kabir, N. Nayyar, and T. S. Rahman, J. Phys.: Condens. Matter 22, 462202 (2010)] and apply it to examine the magnetic properties of small FePt clusters. We demonstrate that DMFT produces meaningful results even for such small systems. For benchmarking and better comparison with results obtained using DFT+U, we also include the case of small Fe clusters. As in the case of bulk systems, the latter approach tends to overestimate correlation effects in nanostructures. Finally, we discuss possible ways to further improve the nano-DFT+DMFT approximation and to extend its application to molecules and nanoparticles on substrates and to nonequilibrium phenomena. PMID- 22443750 TI - Pattern formation from consistent dynamical closures of uniaxial nematic liquid crystals. AB - Pattern formation in uniaxial polymeric liquid crystals is studied for different dynamic closure approximations. Using the principles of mesoscopic non equilibrium thermodynamics in a mean-field approach, we derive a Fokker-Planck equation for the single-particle non-homogeneous distribution function of particle orientations and the evolution equations for the second and fourth order orientational tensor parameters. Afterwards, two dynamic closure approximations are discussed, one of them considering the relaxation of the fourth order orientational parameter and leading to a novel expression for the free-energy like function in terms of the scalar order parameter. Considering the evolution equation of the density of the system and values of the interaction parameter for which isotropic and nematic phases coexist, our analysis predicts that patterns and traveling waves can be produced in lyotropic uniaxial nematics even in the absence of external driving. PMID- 22443751 TI - On the use of effective core potentials in the calculation of magnetic properties, such as magnetizabilites and magnetic shieldings. AB - State-of-the art effective core potentials (ECPs) that replace electrons of inner atomic cores involve non-local potentials. If such an effective core potential is added to the Hamiltonian of a system in a magnetic field, the resulting Hamiltonian is not gauge invariant. This means, magnetic properties such as magnetisabilities and magnetic shieldings (or magnetic susceptibilities and nuclear magnetic resonance chemical shifts) calculated with different gauge origins are different even for exact solutions of the Schrodinger equation. It is possible to restore gauge invariance of the Hamiltonian by adding magnetic field dependent terms arising from the effective core potential. Numerical calculations on atomic and diatomic model systems (potassium mono-cation and potassium dimer) clearly demonstrate that the standard effective core potential Hamiltonian violates gauge invariance, and this affects the calculation of magnetisabilities more strongly than the calculation of magnetic shieldings. The modified magnetic field dependent effective core potential Hamiltonian is gauge invariant, and therefore it is the correct starting point for distributed gauge origin methods. The formalism for gauge including atomic orbitals (GIAO) and individual gauge for localized orbitals methods is worked out. ECP GIAO results for the potassium dimer are presented. The new method performs much better than a previous ECP GIAO implementation that did not account for the non-locality of the potential. For magnetic shieldings, deviations are clearly seen, but they amount to few ppm only. For magnetisabilities, our new ECP GIAO implementation is a major improvement, as demonstrated by the comparison of all-electron and ECP results. PMID- 22443752 TI - Kinetic energy release in fragmentation processes following electron emission: a time-dependent approach. AB - A time-dependent approach for the kinetic energy release (KER) spectrum is developed for a fragmentation of a diatomic molecule after an electronic decay process, e.g., Auger process. It allows one to simulate the time-resolved spectra and provides more insight into the molecular dynamics than the time-independent approach. Detailed analysis of the time-resolved emitted electron and KER spectra sheds light on the interrelation between wave packet dynamics and spectra. PMID- 22443753 TI - Ewald mesh method for quantum mechanical calculations. AB - The Fourier transform Coulomb (FTC) method has been shown to be effective for the fast and accurate calculation of long-range Coulomb interactions between diffuse (low-energy cutoff) densities in quantum mechanical (QM) systems. In this work, we split the potential of a compact (high-energy cutoff) density into short-range and long-range components, similarly to how point charges are handled in the Ewald mesh methods in molecular mechanics simulations. With this linear scaling QM Ewald mesh method, the long-range potential of compact densities can be represented on the same grid as the diffuse densities that are treated by the FTC method. The new method is accurate and significantly reduces the amount of computational time on short-range interactions, especially when it is compared to the continuous fast multipole method. PMID- 22443754 TI - Observable quasi-bound states of the H2 molecule. AB - Characteristic parameters (energetic positions, widths, etc.) of the 23 spectroscopically observed (or potentially observable) quasi-bound energy levels for the ground state H(2) molecule are determined with high accuracy. The recent advances concerning nonadiabatic, relativistic, and quantum electrodynamical corrections have been taken into consideration. Theoretical approach is based on the careful investigation of the energy dependences of the real stationary scattering-state wave functions (their phase shifts and amplitudes). These energy dependences can be very accurately fitted to simple analytic formulas resulting from the quantum scattering theory. General criteria for the assignment of quasi bound states are discussed and a new criterion is proposed, which excludes too broad and ambiguous resonances. To implement the proposed approach, a special high-precision computational method was used, which is described in full detail. PMID- 22443755 TI - Enhanced Wang Landau sampling of adsorbed protein conformations. AB - Using computer simulations to model the folding of proteins into their native states is computationally expensive due to the extraordinarily low degeneracy of the ground state. In this paper, we develop an efficient way to sample these folded conformations using Wang Landau sampling coupled with the configurational bias method (which uses an unphysical "temperature" that lies between the collapse and folding transition temperatures of the protein). This method speeds up the folding process by roughly an order of magnitude over existing algorithms for the sequences studied. We apply this method to study the adsorption of intrinsically disordered hydrophobic polar protein fragments on a hydrophobic surface. We find that these fragments, which are unstructured in the bulk, acquire secondary structure upon adsorption onto a strong hydrophobic surface. Apparently, the presence of a hydrophobic surface allows these random coil fragments to fold by providing hydrophobic contacts that were lost in protein fragmentation. PMID- 22443756 TI - Employing a cylindrical single crystal in gas-surface dynamics. AB - We describe the use of a polished, hollow cylindrical nickel single crystal to study effects of step edges on adsorption and desorption of gas phase molecules. The crystal is held in an ultra-high vacuum apparatus by a crystal holder that provides axial rotation about a [100] direction, and a crystal temperature range of 89 to 1100 K. A microchannel plate-based low energy electron diffraction/retarding field Auger electron spectrometer (AES) apparatus identifies surface structures present on the outer surface of the cylinder, while a separate double pass cylindrical mirror analyzer AES verifies surface cleanliness. A supersonic molecular beam, skimmed by a rectangular slot, impinges molecules on a narrow longitudinal strip of the surface. Here, we use the King and Wells technique to demonstrate how surface structure influences the dissociation probability of deuterium at various kinetic energies. Finally, we introduce spatially-resolved temperature programmed desorption from areas exposed to the supersonic molecular beam to show how surface structures influence desorption features. PMID- 22443757 TI - Infrared/ultraviolet quadruple resonance spectroscopy to investigate structures of electronically excited states. AB - Molecular beam investigations in combination with IR/UV spectroscopy offer the possibility to obtain structural information on isolated molecules and clusters. One of the demanding tasks is the discrimination of different isomers, e.g., by the use of isomer specific UV excitations. If this discrimination fails due to overlaying UV spectra of different isomers, IR/IR methods offer another possibility. Here, we present a new IR/UV/IR/UV quadruple resonance technique to distinguish between different isomers especially in the electronically excited state. Due to the IR spectra, structural changes and photochemical pathways in excited states can be assigned and identified. The method is applied to the dihydrated cluster of 3-hydroxyflavone which has been investigated as photochemically relevant system and proton wire model in the S(1) state. By applying the new IR/UV/IR/UV technique, we are able to show experimentally that both in the electronic ground (S(0)) and the electronically excited state (S(1)) two isomers have to be assigned. PMID- 22443758 TI - Multipodal coordination of a tetracarboxylic crown ether with NH4(+): a vibrational spectroscopy and computational study. AB - The elucidation of the structural requirements for molecular recognition by the crown ether (18-crown-6)-2,3,11,12-tetracarboxylic acid (18c6H(4)) and its cationic complexes constitutes a topic of current fundamental and practical interest in catalysis and analytical sciences. The flexibility of the central ether ring and its four carboxyl side arms poses important challenges to experimental and theoretical approaches. In this study, infrared action vibrational spectroscopy and quantum mechanical computations are employed to characterize the conformational structure of the isolated gas phase complex formed by the 18c6H(4) host with NH(4)(+) as guest. The results show that the most stable gas-phase structure is a barrel-like conformation sustained by tetrapodal H-bonding of the ammonia cation with two C=O side groups and with four oxygen atoms of the ether ring in a bifurcated arrangement. Interestingly, a similar structure had been proposed in previous crystallographic studies. The experiment also provides evidence for a significant contribution of a higher energy bowl-like conformer with features resembling those adopted by 18c6H(4) in the analogous complexes with secondary amines. Such a conformation displays H bonding between confronted side carboxyl groups and tetrapodal binding of the NH(4)(+) with the ether ring and with one C=O group. Structures involving even more extensive intramolecular H-bonding in the 18c6H(4) substrate are found to lie higher in energy and are ruled out by the experiment. PMID- 22443759 TI - Transition dipole moments between the low-lying Omega(g,u)(+/-) states of the Rb2 and Cs2 molecules. AB - For the Rb(2) and Cs(2) molecules, the adiabatic potential-energy curves and the transition dipole moments of the 43 Omega((+/-)) (g,u) low-lying states dissociating adiabatically to the limits up to ns+(n-1)d (n = 5,6 for Rb(2) and Cs(2), respectively), have been computed as a function of the internuclear distance R for a large and dense grid. Each molecule was treated as a two electron system. We used an ab initio approach involving a relativistic non empirical pseudo-potential for Rb and Cs cores, core-valence polarization potentials, and full valence configuration interaction calculations for the two valence electrons. Spin-orbit effects were taken into account through semi empirical spin-orbit pseudopotentials. Equilibrium distances, transition energies, rotational constants, and harmonic frequencies as well as depths of wells and heights of barriers are reported for all the molecular states investigated in Hund's cases (a) and (c). Extensive tables of energy values and transition dipole moments are given in an auxiliary (EPAPS) files as a database for future studies on Rb(2) and Cs(2). PMID- 22443760 TI - Inter-channel effects in monosolvated atomic iodide cluster anion detachment: correlation of the anisotropy parameter with solvent dipole moment. AB - Photoelectron imaging results are presented for I(-)[middle dot]X cluster anions (X = CO(2), C(4)H(5)N [pyrrole], (CH(3))(2)CO, CH(3)NO(2)). The available detachment channels are labeled according to the neutral iodine atom states produced (channel I = (2)P(3/2) and channel II = (2)P(1/2)). At photon energies in the vicinity of the channel II threshold these data are compared to previously reported results for I(-)[middle dot]X (X = CH(3)CN, CH(3)Cl, CH(3)Br, and H(2)O). In particular, these results show a strong connection between the dipole moment of the solvent molecule and the behavior of the channel I photoelectron angular distributions in this region, which is consistent with an electronic autodetachment process. The evolution of the channel II:channel I branching ratios in this excitation regime supports this contention. PMID- 22443761 TI - Excited states and electronic spectra of annulated dinuclear free-base phthalocyanines: a theoretical study on near-infrared-absorbing dyes. AB - The electronic excited states and electronic absorption spectra of annulated dinuclear free-base phthalocyanine (C(58)H(30)N(16)) are studied through quantum chemical calculations using the symmetry-adapted cluster-configuration interaction (SAC-CI) method. Three tautomers are possible with respect to the position of the pyrrole protons; therefore, the SAC-CI calculations for these tautomers were performed. The structures of the Q-band states are discussed based on the character of their molecular orbitals. The lower energy shift of the Q bands because of dimerization is explained by the decrease in the HOMO-LUMO gaps resulting from the bonding and antibonding interactions between the monomer units. The electronic dipole moments of the nonsymmetric tautomer were calculated, and the possibility of charge-separated excited states is discussed. The relative energies of these tautomers are examined using density functional theory (DFT) calculations for several peripheral substituents. The relative energies of these tautomers significantly depend on the substituents, and therefore, the abundance ratios of the three tautomers were affected by the substituents. The absorption spectra were simulated from the SAC-CI results weighted by the Boltzmann factors obtained from the DFT calculations. The SAC-CI spectra reproduce the experimental findings well. The thermal-averaged SAC-CI spectra could explain the observed substituent effect on the structure of the Q bands in terms of the relative stabilities and the abundance ratios of the tautomers. The SAC-CI and time-dependent density functional theory calculations are also compared. The CAM-B3LYP results agreed with the trends of the SAC-CI results; however, the CAM-B3LYP calculation overestimated the excitation energies in comparison with the SAC-CI and experimental results. PMID- 22443762 TI - Theoretical studies on absorption, emission, and resonance Raman spectra of Coumarin 343 isomers. AB - The vibrationally resolved spectral method and quantum chemical calculations are employed to reveal the structural and spectral properties of Coumarin 343 (C343), an ideal candidate for organic dye photosensitizers, in vacuum and solution. The results manifest that the ground-state energies are dominantly determined by different placements of hydrogen atom in carboxylic group of C343 conformations. Compared to those in vacuum, the electronic absorption spectra in methanol solvent show a hyperchromic property together with the redshift and blueshift for the neutral C343 isomers and their deprotonated anions, respectively. From the absorption, emission, and resonance Raman spectra, it is found that the maximal absorption and emission come from low-frequency modes whereas the high-frequency modes have high Raman activities. The detailed spectra are further analyzed for the identification of the conformers and understanding the potential charge transfer mechanism in their photovoltaic applications. PMID- 22443763 TI - Shell models of two-dimensional Coulomb crystals: assessment and comparison with the three-dimensional case. AB - Three shell models, differing in accuracy and computational cost, are formulated for two-dimensional Coulomb crystals. Offering a new means of predicting and analyzing properties of these species, the new models also provide new insights into their previously derived three-dimensional counterparts. In particular, analysis of the individual components of the energy error points out to the neglect of the positional relaxation as the main source of the differences between the approximate and exact energies. Within the realm of shell models, the two-dimensional case turns out to be somewhat more challenging than the three dimensional one. Due to the lack of exact closed-form expressions for the optimal shell radii, it is computationally more expensive and the energy predictions at the same level of approximation are less accurate (as indicated by the maximum relative energy error of 0.15% vs. that of 0.03% found for spherical Coulomb crystals). PMID- 22443764 TI - Fully converged integral cross sections of collision induced dissociation, four center, and single exchange reactions, and accuracy of the centrifugal sudden approximation in H2 + D2 reaction. AB - The initial state selected time-dependent wave packet method was employed to calculate the integral cross sections for the H(2) + D(2) reaction with and without the centrifugal sudden (CS) approximation by including all important K (the projection of the total angular momentum on the body-fixed axis) blocks. With a full-dimensional model, the first fully converged coupled-channel (CC) cross sections for different competitive processes from the ground rotational state were obtained: collision induced dissociation (CID), four-center (4C) reaction and single exchange (SE) reaction. The effect of the total angular momentum J on the reaction dynamics of H(2) + D(2) and the accuracy of the CS approximation have also been studied. It was found that the CID and SE processes occur in a wide range of J values while the 4C process can only take place in a narrow window of J values. For this reason, the CC cross section for the 4C channel is merely comparable to the SE channel. A comparison of the integral cross sections from CC and CS calculations showed that the CS approximation works well for the CID process but not for the 4C and SE processes, and the discrepancy between the CC and CS cross sections grows larger as the translational energy and/or the vibrational energy increase(s). PMID- 22443765 TI - Excited Li and Na in He(n): influence of the dimer potential energy curves. AB - The X(2)Sigma ground and the A(2)Pi and B(2)Sigma first two excited states of Li He and Na-He are determined using high level complete active space self consistent field-multireference configuration interaction ab initio method. The obtained potentials differ from the ones proposed by Pascale [Phys. Rev. A 28, 632 (1983)], more strongly for the ground than for the excited states. Quantum diffusion Monte Carlo studies of small Li(*)He(n) and Na(*)He(n) with n <= 5 are performed using a diatomics-in-molecule approach to model the non-pair additive interaction potential. The sensitivity of our results to the A(2)Pi and B(2)Sigma potentials used is assessed by an analysis of the structure and of the energetics of the clusters. For these small clusters, the physical conclusions are essentially independent of the diatomic curves employed. PMID- 22443766 TI - Optical Stark spectroscopy of the 2(0)(6) A1A''-X1A' band of chloro-methylene, HCCl. AB - The laser induced fluorescence spectra of the 2(0)(6)A(1)A('')-X(1)A(') band of a rotationally cold (<20 K) molecular beam sample of chloro-methylene, HCCl, has been recorded, field-free and in the presence of a static electric field. The field-free spectrum has been analyzed to produce an improved set of spectroscopic parameters for the A(1)A('') (060) vibronic state. The magnitude of the a component of the permanent electric dipole moment, MU(a), for the X(1)A(') (000) vibronic state has been determined to be 0.501(1) D from the analysis of the observed electric field induced shifts. Comparisons with theoretical predictions and flouro-methylene, HCF, are presented. PMID- 22443767 TI - Quantum state-to-state dynamics for the quenching process of Br(2P1/2) + H2(v(i) = 0, 1, j(i) = 0). AB - Quantum state-to-state dynamics for the quenching process Br((2)P(1/2)) + H(2)(v(i) = 0, 1, j(i) = 0) -> Br((2)P(3/2)) + H(2)(v(f), j(f)) has been studied based on two-state model on the recent coupled potential energy surfaces. It was found that the quenching probabilities have some oscillatory structures due to the interference of reflected flux in the Br((2)P(1/2)) + H(2) and Br((2)P(3/2)) + H(2) channels by repulsive potential in the near-resonant electronic-to vibrational energy transfer process. The final vibrational state resolved integral cross sections were found to be dominated by the quenching process Br((2)P(1/2)) + H(2)(v) -> Br((2)P(3/2)) + H(2)(v+1) and the nonadiabatic reaction probabilities for Br((2)P(1/2)) + H(2)(v = 0, 1, j(i) = 0) are quite small, which are consistent with previous theoretical and experimental results. Our calculated total quenching rate constant for Br((2)P(1/2)) + H(2)(v(i) = 0, j(i) = 0) at room temperature is in good agreement with the available experimental data. PMID- 22443768 TI - Electron scattering by methanol and ethanol: a joint theoretical-experimental investigation. AB - We present a joint theoretical-experimental study on electron scattering by methanol (CH(3)OH) and ethanol (C(2)H(5)OH) in a wide energy range. Experimental differential, integral and momentum-transfer cross sections for elastic electron scattering by ethanol are reported in the 100-1000 eV energy range. The experimental angular distributions of the energy-selected electrons are measured and converted to absolute cross sections using the relative flow technique. Moreover, elastic, total, and total absorption cross sections for both alcohols are calculated in the 1-500 eV energy range. A complex optical potential is used to represent the dynamics of the electron-alcohol interaction, whereas the scattering equations are solved iteratively using the Pade's approximant technique. Our calculated data agree well with those obtained using the Schwinger multichannel method at energies up to 20 eV. Discrepancies at high energies indicate the importance of absorption effects, included in our calculations. In general, the comparison between our theoretical and experimental results, as well as with other experimental data available in the literature, also show good agreement. Nevertheless, the discrepancy between the theoretical and experimental total cross sections at low incident energies suggests that the experimental cross sections measured using the transmission technique for polar targets should be reviewed. PMID- 22443769 TI - A detailed test study of barrier heights for the HO2 + H2O + O3 reaction with various forms of multireference perturbation theory. AB - We report an ab initio multireference perturbation theory investigation of the HO(2) + H(2)O + O(3) reaction, with particular emphasis on the barrier heights for two possible reaction mechanisms: oxygen abstraction and hydrogen abstraction, which are identified by two distinct saddle points. These saddle points and the corresponding pre-reactive complexes were optimized at the CASSCF(11,11) level while the single point energies were calculated with three different MRPT2 theories: MRMP, CASPT2, and SC-NEVPT2. Special attention has been drawn on the "intruder state" problem and the effect of its corrections on the relative energies. The results were then compared with single reference coupled cluster methods and also with our recently obtained Kohn-Sham density functional theory (KS-DFT) calculations [L. P. Viegas and A. J. C. Varandas, Chem. Phys., (2011)]. It is found that the relative energies of the pre-reactive complexes have a very good agreement while the MRPT2 classical barrier heights are considerably higher than the KS-DFT ones, with the SC-NEVPT2 calculations having the highest energies between the MRPT2 methods. Possible explanations have been given to account for these differences. PMID- 22443770 TI - Experimental studies of the NaCs 5(3)Pi0 and 1(a)3Sigma+ states. AB - We report high resolution measurements of 372 NaCs 5(3)Pi(0)(v, J) ro-vibrational level energies in the range 0 <= v <= 22. The data have been used to construct NaCs 5(3)Pi(0) potential energy curves using the Rydberg-Klein-Rees and inverted perturbation approximation methods. Bound-free 5(3)Pi(0)(v, J) -> 1(a)(3)Sigma(+) emission has also been measured, and is used to determine the repulsive wall of the 1(a)(3)Sigma(+) state and the 5(3)Pi(0) -> 1(a)(3)Sigma(+) relative transition dipole moment function. Hyperfine structure in the 5(3)Pi(0) state has not been observed in this experiment. This null result is explained using a simple vector coupling model. PMID- 22443771 TI - Fourier transform infrared isotopic study of ZnC3: identification of the nu1(a') mode. AB - An isomer of ZnC(3) with bent structure in its (1)A(') electronic state has been detected in the products from the dual laser ablation of carbon and zinc rods that were trapped in solid Ar at ~12 K. Measurements of (13)C isotopic shifts have enabled the identification of the nu(1)(a(')) asymmetric carbon stretching fundamental at 1858.9 cm(-1). The experimental results are in good agreement with the predictions of DFT-B3LYP/6-311G(d) calculations that indicate a singlet bent isomer ground state structure with triplet linear and singlet cyclic isomers lying slightly higher in energy. This is the first optical detection of any isomer of ZnC(3). PMID- 22443772 TI - Dielectric spectra broadening as the signature of dipole-matrix interaction. I. Water in nonionic solutions. AB - Whenever water interacts with another dipolar entity, a broadening of its dielectric relaxation occurs. Often this broadening can be described by the Cole Cole (CC) spectral function. A new phenomenological approach has been recently presented [A. Puzenko, P. Ben Ishai, and Y. Feldman, Phys. Rev. Lett. 105, 037601 (2010)] that illustrates a physical mechanism of the dipole-matrix interaction underlying the CC behavior in complex systems. By considering the relaxation amplitude Deltaepsilon, the relaxation time tau, and the broadening parameter alpha, one can construct a set of 3D trajectories, representing the dynamic behavior of different systems under diverse conditions. Our hypothesis is that these trajectories will contribute to a deeper understanding of the dielectric properties of complex systems. The paper demonstrates how the model describes the state of water in aqueous solutions of non-ionic solutes. For this purpose complex dielectric spectra for aqueous solutions of D-glucose and D-fructose are analyzed. PMID- 22443773 TI - Dielectric spectra broadening as the signature of dipole-matrix interaction. II. Water in ionic solutions. AB - In this, the second part of our series on the dielectric spectrum symmetrical broadening of water, we consider ionic aqueous solutions. If in Part I, dipole dipole interaction was the dominant feature, now ion-dipole interplay is shown to be the critical element in the dipole-matrix interaction. We present the results of high-frequency dielectric measurements of different concentrations of NaCl/KCl aqueous solutions. We observed Cole-Cole broadening of the main relaxation peak of the solvent in the both electrolytes. The 3D trajectory approach (described in detail in Part I) is applied in order to highlight the differences between the dynamics and structure of solutions of salts on one hand and dipolar solutes on the other hand. PMID- 22443774 TI - 1H NMR relaxation in glycerol solutions of nitroxide radicals: effects of translational and rotational dynamics. AB - (1)H spin-lattice relaxation rates in glycerol solutions of selected nitroxide radicals at temperatures between 200 K and 400 K were measured at 15 MHz and 25 MHz. The frequency and temperature conditions were chosen in such a way that the relaxation rates go through their maximum values and are affected by neither the electron spin relaxation nor the electron-nitrogen nucleus hyperfine coupling, so that the focus could be put on the mechanisms of motion. By comparison with (1)H spin-lattice relaxation results for pure glycerol, it has been demonstrated that the inter-molecular electron spin-proton spin dipole-dipole interactions are affected not only by relative translational motion of the solvent and solute molecules, but also by their rotational dynamics as the interacting spins are displaced from the molecular centers; the eccentricity effects are usually not taken into account. The (1)H relaxation data have been decomposed into translational and rotational contributions and their relative importance as a function of frequency and temperature discussed in detail. It has been demonstrated that neglecting the rotational effects on the inter-molecular interactions leads to non-realistic conclusions regarding the translational dynamics of the paramagnetic molecules. PMID- 22443775 TI - Structural changes of Pd13 upon charging and oxidation/reduction. AB - First-principle generalized gradient corrected density functional calculations have been performed to study the stability of cationic and anionic Pd(13) (+/-), and neutral Pd(13)O(2) clusters. It is found that while cationic Pd(13) (+) favors a C(s) geometry similar to the neutral Pd(13), both anionic Pd(13)(-) and neutral Pd(13)O(2) favor a compact ~I(h) structure. A detailed analysis of the electronic structure shows that the stabilization of the delocalized 1P and 2P cluster orbitals, and the hybridization of the 1D orbitals with the oxygen atomic p orbitals play an important role in the energetic ordering of C(s) and ~I(h) isomers. A structural oscillation is predicted during an oxidation/reduction cycle of Pd(13) in which small energy barriers between 0.3 and 0.4 eV are involved. PMID- 22443776 TI - Fluid transport in nanochannels induced by temperature gradients. AB - We investigate the mechanisms of fluid transport driven by temperature gradients in nanochannels through molecular dynamics simulations. It is found that the fluid-wall interaction is critical in determining the flow direction. In channels of very low surface energy, where the fluid-wall binding energy epsilon(fw) is small, the fluid moves from high to low temperature and the flow is induced by a potential ratchet near the wall. In high surface energy channels, however, the fluid is pumped from low to high temperature and the pressure drop caused by the temperature gradient is the major driving force. In addition, as the fluid-wall interaction is strengthened, the flow flux assumes a maximum, where epsilon(fw) is close to the lower temperature T(L) of the channel and epsilon(fw)/kT(L) ~ 1 is roughly satisfied. PMID- 22443777 TI - A transferable ab initio based force field for aqueous ions. AB - We present a new polarizable force field for aqueous ions (Li(+), Na(+), K(+), Rb(+), Cs(+), Mg(2 +), Ca(2 +), Sr(2 +), and Cl(-)) derived from condensed phase ab initio calculations. We use maximally localized Wannier functions together with a generalized force and dipole-matching procedure to determine the whole set of parameters. Experimental data are then used only for validation purposes and a good agreement is obtained for structural, dynamic, and thermodynamic properties. The same procedure applied to crystalline phases allows to parametrize the interaction between cations and the chloride anion. Finally, we illustrate the good transferability of the force field to other thermodynamic conditions by investigating concentrated solutions. PMID- 22443778 TI - The dispersive behavior of collective excitations in fluids: an experimental test for the generalized collective modes theory. AB - The predictions of the generalized collective modes (GCM) theory on the non hydrodynamic dispersion of collective excitations of liquids and supercritical fluids have been tested against previous inelastic x-ray scattering measurements on samples of increasing complexity. We observed a good agreement between experimental results and theoretical predictions within the hypothesis that sound propagation is adiabatic. Overall, the performed comparison provides an experimental validation of GCM predictions and shows that, even in the transition region between the hydrodynamic and the mesoscopic regimes, thermal fluctuations have a minor influence on the dispersion, whose non-hydrodynamic effects are mostly driven by viscoelastic phenomena. PMID- 22443779 TI - A first principles molecular dynamics study of the solvation structure and migration kinetics of an excess proton and a hydroxide ion in binary water ammonia mixtures. AB - We have investigated the solvation structure and migration kinetics of an excess proton and a hydroxide ion in water-ammonia mixed liquids of varying composition by means of ab initio molecular dynamics simulations. The excess proton is always found to be attached to an ammonia molecule to form the ammonium ion. Migration of the excess proton is found to occur very occasionally from one ammonia to the other but no proton transfer to a water molecule is observed during the entire simulations. Also, when the ammonium ion is solvated in water only, its hydrogen bond dynamics and rotation are found to occur at a faster rate than those in water-ammonia mixtures. For water-ammonia mixtures containing a proton less, the defect is found to stay like the hydroxide ion. For these systems, occasional proton transfer is found to occur only through the hydrogen bonded chains of water molecules in these water-ammonia mixtures. No proton transfer is found to take place from an ammonia molecule. The presence of ammonia molecules makes the realization of proper presolvated state of the hydroxide ion to accept a proton a more difficult process and, as a result, the rate of proton transfer and migration kinetics of the hydroxide ion in water-ammonia mixtures are found to be slower than that in liquid water and these rates are found to slow down further with increase of ammonia concentration. PMID- 22443780 TI - The effect of pressure on the hydration structure around hydrophobic solute: a molecular dynamics simulation study. AB - Molecular dynamics simulations are performed to study the effects of pressure on the hydrophobic interactions between neopentane molecules immersed in water. Simulations are carried out for five different pressure values ranging from 1 atm to 8000 atm. From potential of mean force calculations, we find that with enhancement of pressure, there is decrease in the well depth of contact minimum (CM) and the relative stability of solvent separated minimum over CM increases. Lower clustering of neopentane at high pressure is also observed in association constant and cluster-structure analysis. Selected site-site radial distribution functions suggest efficient packing of water molecules around neopentane molecules at elevated pressure. The orientational profile calculations of water molecules show that the orientation of water molecules in the vicinity of solute molecule is anisotropic and this distribution becomes flatter as we move away from the solute. Increasing pressure slightly changes the water distribution. Our hydrogen bond properties and dynamics calculations reveal pressure-induced formation of more and more number of water molecules with five and four hydrogen bond at the expense of breaking of two and three hydrogen bonded water molecules. We also find lowering of water-water continuous hydrogen bond lifetime on application of pressure. Implication of these results for relative dispersion of hydrophobic molecules at high pressure are discussed. PMID- 22443781 TI - Ab initio parameterization of an all-atom polarizable and dissociable force field for water. AB - A novel all-atom, dissociative, and polarizable force field for water is presented. The force field is parameterized based on forces, stresses, and energies obtained form ab initio calculations of liquid water at ambient conditions. The accuracy of the force field is tested by calculating structural and dynamical properties of liquid water and the energetics of small water clusters. The transferability of the force field to dissociated states is studied by considering the solvation of a proton and the ionization of water at extreme conditions of pressure and temperature. In the case of the solvated proton, the force field properly describes the presence of both Eigen and Zundel configurations. In the case of the pressure-induced ice VIII/ice X transition and the temperature-induced transition to a superionic phase, the force field is found to describe accurately the proton symmetrization and the melting of the proton sublattice, respectively. PMID- 22443782 TI - The optical activity of carvone: a theoretical and experimental investigation. AB - The optical rotatory dispersion (ORD) and circular dichroism of the conformationally flexible carvone molecule has been investigated in 17 solvents and compared with results from calculations for the "free" (gas phase) molecule. The G3 method was used to determine the relative energies of the six conformers. The optical rotation of (R)-(-)-carvone at 589 nm was calculated using coupled cluster and density functional methods, including temperature-dependent vibrational corrections. Vibrational corrections are significant and are primarily associated with normal modes involving the stereogenic carbon atom and the carbonyl group, whose n -> pi* excitation plays a significant role in the chiroptical response of carvone. Without the inclusion of vibrational corrections the optical rotation calculated with CCSD and DFT has the opposite sign of experimental data. Calculations of optical rotation performed in solution using the polarizable continuum model were also opposite in sign when compared to that of the experiment. PMID- 22443783 TI - Formation and phase transitions of methane hydrates under dynamic loadings: compression rate dependent kinetics. AB - We describe high-pressure kinetic studies of the formation and phase transitions of methane hydrates (MH) under dynamic loading conditions, using a dynamic diamond anvil cell (d-DAC) coupled with time-resolved confocal micro-Raman spectroscopy and high-speed microphotography. The time-resolved spectra and dynamic pressure responses exhibit profound compression-rate dependences associated with both the formation and the solid-solid phase transitions of MH-I to II and MH-II to III. Under dynamic loading conditions, MH forms only from super-compressed water and liquid methane in a narrow pressure range between 0.9 and 1.6 GPa at the one-dimensional (1D) growth rate of 42 MUm/s. MH-I to II phase transition occurs at the onset of water solidification 0.9 GPa, following a diffusion controlled mechanism. We estimated the activation volume to be -109+/ 29 A(3), primarily associated with relatively slow methane diffusion which follows the rapid interfacial reconstruction, or martensitic displacements of atomic positions and hydrogen bonds, of 5(12)6(2) water cages in MH-I to 4(3)5(12)6(3) cages in MH-II. MH-II to III transition, on the other hand, occurs over a broad pressure range between 1.5 and 2.2 GPa, following a reconstructive mechanism from super-compressed MH-II clathrates to a broken ice-filled viscoelastic solid of MH-III. It is found that the profound dynamic effects observed in the MH formation and phase transitions are primarily governed by the stability of water and ice phases at the relevant pressures. PMID- 22443784 TI - Hydrogen fluoride adsorption and reaction on the alpha-Al2O3(0001) surface: a density functional theory study. AB - The adsorption and reaction behaviors of HF on the alpha-Al(2)O(3)(0001) surface are systematically investigated using density functional theory method. By increasing the number of HF molecules in a p(2 * 1) alpha-Al(2)O(3)(0001) slab, we find that HF is chemically dissociated at low coverage; while both physical and dissociative adsorption occurs at a 3/2 monolayer (ML) coverage. At the same coverage (1.0 ML), diverse configurations of the dissociated HF are obtained in the p(2 * 1) model; while only one is observed in the p(1 * 1) slab due to its smaller surface area compared with the former one. Preliminary fluorination reaction study suggests that the total energy of two dissociated HF in the p(2 * 1) slab increases by 1.00 and 0.72 eV for the formation and desorption of water intermediate, respectively. The coadsorption behaviors of HF and H(2)O indicate that the pre-adsorbed water is unfavorable for the fluorination of Al(2)O(3), which is well consistent with the experimental results. The calculated density of states show that the peak of sigma(H-F) disappears, while the peaks of sigma(H-O) and sigma(Al-F) are observed at -8.4 and -5 to -3 eV for the dissociated HF. Charge density difference analysis indicates that the dissociated F atom attracts electrons, while no obvious changes on electrons are observed for the surface Al atoms. PMID- 22443785 TI - Explicit all-atom modeling of realistically sized ligand-capped nanocrystals. AB - We present a study of an explicit all-atom representation of nanocrystals of experimentally relevant sizes (up to 6 nm), "capped" with alkyl chain ligands, in vacuum. We employ all-atom molecular dynamics simulation methods in concert with a well-tested intermolecular potential model, MM3 (molecular mechanics 3), for the studies presented here. These studies include determining the preferred conformation of an isolated single nanocrystal (NC), pairs of isolated NCs, and (presaging studies of superlattice arrays) unit cells of NC superlattices. We observe that very small NCs (3 nm) behave differently in a superlattice as compared to larger NCs (6 nm and above) due to the conformations adopted by the capping ligands on the NC surface. Short ligands adopt a uniform distribution of orientational preferences, including some that lie against the face of the nanocrystal. In contrast, longer ligands prefer to interdigitate. We also study the effect of changing ligand length and ligand coverage on the NCs on the preferred ligand configurations. Since explicit all-atom modeling constrains the maximum system size that can be studied, we discuss issues related to coarse graining the representation of the ligands, including a comparison of two commonly used coarse-grained models. We find that care has to be exercised in the choice of coarse-grained model. The data provided by these realistically sized ligand-capped NCs, determined using explicit all-atom models, should serve as a reference standard for future models of coarse-graining ligands using united atom models, especially for self-assembly processes. PMID- 22443786 TI - Ethanol adsorption on the Si (111) surface: first principles study. AB - Equilibrium atomic configurations and electron energy structure of ethanol adsorbed on the Si (111) surface are studied by the first principles density functional theory. Geometry optimization is performed by the total energy minimization method. Equilibrium atomic geometries of ethanol, both undissociated and dissociated, on the Si (111) surface are found and analysed. Reaction pathways and predicted transition states are discussed in comparison with available experimental data in terms of the feasibility of the reactions occurring. Analysis of atom and orbital resolved projected density of states indicates substantial modifications of the Si surface valence and conduction electron bands due to the adsorption of ethanol affecting the electronic properties of the surface. PMID- 22443787 TI - Casimir amplitudes and capillary condensation of near-critical fluids between parallel plates: renormalized local functional theory. AB - We investigate the critical behavior of a near-critical fluid confined between two parallel plates in contact with a reservoir by calculating the order parameter profile and the Casimir amplitudes (for the force density and for the grand potential). Our results are applicable to one-component fluids and binary mixtures. We assume that the walls absorb one of the fluid components selectively for binary mixtures. We propose a renormalized local functional theory accounting for the fluctuation effects. Analysis is performed in the plane of the temperature T and the order parameter in the reservoir psi(infinity). Our theory is universal if the physical quantities are scaled appropriately. If the component favored by the walls is slightly poor in the reservoir, there appears a line of first-order phase transition of capillary condensation outside the bulk coexistence curve. The excess adsorption changes discontinuously between condensed and noncondensed states at the transition. With increasing T, the transition line ends at a capillary critical point T=T(c) (ca) slightly lower than the bulk critical temperature T(c) for the upper critical solution temperature. The Casimir amplitudes are larger than their critical point values by 10-100 times at off-critical compositions near the capillary condensation line. PMID- 22443788 TI - On simulations of complex interfaces: molecular dynamics simulations of stationary phases. AB - Methodological considerations for molecular dynamics simulations of complex interfaces are presented in this article. A slab geometry is examined in the context of stationary phases where selectivity occurs predominantly in pores within silica beads. Specifically, we examine the Whelk-O1 interface with n hexane/2-propanol, the TMA-(Pro)(2)-N(CH(3))-tether interface with n-hexane/2 propanol, and the C(18)H(37)Si interface with water/methanol. The following methodological issues are considered in detail: The assessment of solvent density within the confined region and excluded volume of the interface; the structural equilibration of surface-bound moieties; solvent equilibration for binary mixtures; surface size effects, and periodic boundary conditions; the treatment of electrostatic interactions; and the impact of pore size. PMID- 22443789 TI - Surface properties of the polarizable Baranyai-Kiss water model. AB - The water surface properties using the Baranyai-Kiss (BK) model [A. Baranyai and P. T. Kiss, J. Chem. Phys. 133, 144109 (2010)] are studied by molecular dynamics simulation, and compared to popular rigid water potentials, namely to the extended simple point charge (SPC/E) and the transferable interaction potential with 4 points (TIP4P) models. The BK potential is a polarizable model of water with three Gaussian charges. The negative charge is connected to its field-free position by a classical harmonic spring, and mechanical equilibrium is established between this spring force and the force due to the charge distribution of the system. The aim of this study is, on the one hand, to test the surface properties of the new model, and on the other hand, to identify differences between the models listed above. The obtained results reveal that the BK model reproduces very well a number of properties corresponding to liquid vapor equilibrium, such as the coexisting liquid and vapor densities, saturated vapor pressure or surface tension. Further, this model reproduces excellently the critical point of water even in comparison with a large number of widely used polarizable and nonpolarizable models. The structural properties of the liquid surface of BK water turns out to be very similar to that of the SPC/E model, while the surface of TIP4P water is found to be somewhat less ordered. This finding is related to the fact that the critical temperature of the TIP4P model is lower than that of either SPC/E or BK. PMID- 22443790 TI - On interfacial tension calculation from the test-area methodology in the grand canonical ensemble. AB - We propose the extension of the test-area methodology, originally proposed to evaluate the surface tension of planar fluid-fluid interfaces along a computer simulation in the canonical ensemble, to deal with the solid-fluid interfacial tension of systems adsorbed on slitlike pores using the grand canonical ensemble. In order to check the adequacy of the proposed extension, we apply the method for determining the density profiles and interfacial tension of spherical molecules adsorbed in slitlike pore with different pore sizes and solid-fluid dispersive energy parameters along the same simulation. We also calculate the solid-fluid interfacial tension using the original test-area method in the canonical ensemble. Agreement between the results obtained from both methods indicate that both methods are fully equivalent. The advantage of the new methodology is that allows to calculate simultaneously the density profiles and the amount of molecules adsorbed onto a slitlike pore, as well as the solid-fluid interfacial tension. This ensures that the chemical potential at which all properties are evaluated during the simulation is exactly the same since simulations can be performed in the grand canonical ensemble, mimicking the conditions at which the adsorption experiments are most usually carried out in the laboratory. PMID- 22443791 TI - Desorption of C60 upon thermal decomposition of cesium C58 fullerides. AB - A monodispersed fullerene material comprising exclusively C(58) cages was doped with Cs to generate Cs(x)C(58) films of various compositions. The resulting modified properties have been studied using a variety of surface analysis methods with emphasis on thermal desorption and ultraviolet photoelectron spectroscopies. Cs doping raises the thermal stability of C(58) films which are characterized by quasi-covalent cage-cage bonds between annelated pentagon sites. Desorption mass spectra show emission of significant amounts of C(60) at elevated temperatures implying that Cs doping can activate C(58)->C(60) conversion in the condensed phase. In the case of saturated Cs(x)C(58) films, up to 4.5% of the initially deposited C(58) can be desorbed as C(60). From the spectroscopic data, we infer that Cs insertion and transport into the interstitial sites of the C(58) solid is accompanied by spontaneous electron transfer to the electronegative fullerene framework-leading to a weakening of intercage carbon-carbon bonds. At the same time, the overall cohesion of the solid film is enhanced by the formation of multiple ionic Cs(+) (beta)C(58) (-) (delta) interactions. Near 800 K, Cs(+) activates/catalyzes concerted disproportionation reactions resulting in the transfer of C(2) from C(58) (-) (delta) to neighbouring cages to yield C(60) (and C(56)). Heating Cs(x)C(58) films to beyond this temperature range yields a (high temperature) stable reaction product with a significantly modified UP spectrum and a finite density of states at the Fermi level. PMID- 22443792 TI - Hydration strongly affects the molecular and electronic structure of membrane phospholipids. AB - We investigate the structure and electronic properties of phosphatidylcholine (PC) under different degrees of hydration at the single-molecule and monolayer type level by linear scaling ab initio calculations. Upon hydration, the phospholipid undergoes drastic long-range conformational rearrangements which lead to a sickle-like ground-state shape. The structural unit of the tilted gel phase PC appears to be a water-bridged PC dimer. We find that hydration dramatically alters the surface potential, dipole and quadrupole moments of the lipids and consequently guides the interactions of the lipids with other molecules and the communication between cells. PMID- 22443793 TI - Evidence of stable high-temperature D(x)-CO intermediates on the Ru(0001) surface. AB - We demonstrate the formation of complexes involving attractive interactions between D and CO on Ru(0001) that are stable at significantly higher temperatures than have previously been reported for such intermediate species on this surface. These complexes are evident by the appearance of new desorption features upon heating of the sample. They decompose in stages as the sample temperature is increased, with the most stable component desorbing at >500 K. The D:CO ratio remaining on the surface during the final stages of desorption tends towards 1:1. The new features are populated during normally incident molecular beam dosing of D(2) on to CO pre-covered Ru(0001) surfaces (180 K) when the CO coverage exceeds 50% of the saturation value. The amount of complex formed decreases somewhat with increasing CO pre-coverage. It is almost absent in the case of dosing on to the fully saturated surface. The results are interpreted in terms of both local and long-range rearrangements of the overlayer that give rise to the observed CO coverage dependence and limit the amount of complex that can be formed. PMID- 22443794 TI - Hybrid molecular dynamics simulations of living filaments. AB - We propose a hybrid molecular dynamics/multi-particle collision dynamics model to simulate a set of self-assembled semiflexible filaments and free monomers. Further, we introduce a Monte Carlo scheme to deal with single monomer addition (polymerization) or removal (depolymerization), satisfying the detailed balance condition within a proper statistical mechanical framework. This model of filaments, based on the wormlike chain, aims to represent equilibrium polymers with distinct reaction rates at both ends, such as self-assembled adenosine diphosphate-actin filaments in the absence of adenosine triphosphate (ATP) hydrolysis and other proteins. We report the distribution of filament lengths and the corresponding dynamical fluctuations on an equilibrium trajectory. Potential generalizations of this method to include irreversible steps like ATP-actin hydrolysis are discussed. PMID- 22443795 TI - From protein denaturant to protectant: comparative molecular dynamics study of alcohol/protein interactions. AB - It is well known that alcohols can have strong effects on protein structures. For example, monohydric methanol and ethanol normally denature, whereas polyhydric glycol and glycerol protect, protein structures. In a recent combined theoretical and NMR experimental study, we showed that molecular dynamics simulations can be effectively used to understand the molecular mechanism of methanol denaturing protein. In this study, we used molecular dynamics simulations to investigate how alcohols with varied hydrophobicity and different numbers of hydrophilic groups (hydroxyl groups) exert effects on the structure of the model polypeptide, BBA5. First, we showed that methanol and trifluoroethanol (TFE) but not glycol or glycerol disrupt hydrophobic interactions. The latter two alcohols instead protect the assembly of the alpha- and beta-domains of the polypeptide. Second, all four alcohols were shown to generally increase the stability of secondary structures, as revealed by the increased number of backbone hydrogen bonds formed in alcohol/water solutions compared to that in pure water, although individual hydrogen bonds can be weakened by certain alcohols, such as TFE. The two monohydric alcohols, methanol and TFE, display apparently different sequence dependence in affecting the backbone hydrogen bond stability: methanol tends to enhance the stability of backbone hydrogen bonds of which the carbonyl groups are from polar residues, whereas TFE tends to stabilize those involving non-polar residues. These results demonstrated that subtle differences in the solution environment could have distinct consequences on protein structures. PMID- 22443796 TI - Influence of environment induced correlated fluctuations in electronic coupling on coherent excitation energy transfer dynamics in model photosynthetic systems. AB - Two-dimensional photon-echo experiments indicate that excitation energy transfer between chromophores near the reaction center of the photosynthetic purple bacterium Rhodobacter sphaeroides occurs coherently with decoherence times of hundreds of femtoseconds, comparable to the energy transfer time scale in these systems. The original explanation of this observation suggested that correlated fluctuations in chromophore excitation energies, driven by large scale protein motions could result in long lived coherent energy transfer dynamics. However, no significant site energy correlation has been found in recent molecular dynamics simulations of several model light harvesting systems. Instead, there is evidence of correlated fluctuations in site energy-electronic coupling and electronic coupling-electronic coupling. The roles of these different types of correlations in excitation energy transfer dynamics are not yet thoroughly understood, though the effects of site energy correlations have been well studied. In this paper, we introduce several general models that can realistically describe the effects of various types of correlated fluctuations in chromophore properties and systematically study the behavior of these models using general methods for treating dissipative quantum dynamics in complex multi-chromophore systems. The effects of correlation between site energy and inter-site electronic couplings are explored in a two state model of excitation energy transfer between the accessory bacteriochlorophyll and bacteriopheophytin in a reaction center system and we find that these types of correlated fluctuations can enhance or suppress coherence and transfer rate simultaneously. In contrast, models for correlated fluctuations in chromophore excitation energies show enhanced coherent dynamics but necessarily show decrease in excitation energy transfer rate accompanying such coherence enhancement. Finally, for a three state model of the Fenna Matthews-Olsen light harvesting complex, we explore the influence of including correlations in inter-chromophore couplings between different chromophore dimers that share a common chromophore. We find that the relative sign of the different correlations can have profound influence on decoherence time and energy transfer rate and can provide sensitive control of relaxation in these complex quantum dynamical open systems. PMID- 22443797 TI - Dimethyl sulfoxide induced structural transformations and non-monotonic concentration dependence of conformational fluctuation around active site of lysozyme. AB - Experimental studies have observed significant changes in both structure and function of lysozyme (and other proteins) on addition of a small amount of dimethyl sulfoxide (DMSO) in aqueous solution. Our atomistic molecular dynamic simulations of lysozyme in water-DMSO reveal the following sequence of changes on increasing DMSO concentration. (i) At the initial stage (around 5% DMSO concentration) protein's conformational flexibility gets markedly suppressed. From study of radial distribution functions, we attribute this to the preferential solvation of exposed protein hydrophobic residues by the methyl groups of DMSO. (ii) In the next stage (10-15% DMSO concentration range), lysozome partially unfolds accompanied by an increase both in fluctuation and in exposed protein surface area. (iii) Between 15-20% concentration ranges, both conformational fluctuation and solvent accessible protein surface area suddenly decrease again indicating the formation of an intermediate collapse state. These results are in good agreement with near-UV circular dichroism (CD) and fluorescence studies. We explain this apparently surprising behavior in terms of a structural transformation which involves clustering among the methyl groups of DMSO. (iv) Beyond 20% concentration of DMSO, the protein starts its final sojourn towards the unfolding state with further increase in conformational fluctuation and loss in native contacts. Most importantly, analysis of contact map and fluctuation near the active site reveal that both partial unfolding and conformational fluctuations are centered mostly on the hydrophobic core of active site of lysozyme. Our results could offer a general explanation and universal picture of the anomalous behavior of protein structure-function observed in the presence of cosolvents (DMSO, ethanol, tertiary butyl alcohol, dioxane) at their low concentrations. PMID- 22443798 TI - Note: particle transport through deformable pore geometries. PMID- 22443799 TI - Note: volume errors and equimolar surfaces. PMID- 22443800 TI - Association of ANCA-associated vasculitis-rheumatoid arthritis overlap syndrome in four patients: rituximab may be the right choice? AB - OBJECTIVES: There have been few reports on the association of rheumatoid arthritis (RA) with anti-neutrophil cytoplasmic antigen (ANCA)-associated systemic vasculitides. METHODS: Here we present four cases of RA overlapping with Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). All these cases had both the diagnosis of RA and that of ANCA associated vasculitis. RESULTS: After we tried corticosteroids, multiple immunosuppressive drugs, sometimes plasmapheresis, rituximab was introduced to 3 out of 4 cases. Rituximab therapy was found to be effective in these three overlap cases. In the fourth case, rituximab was and will be considered; however, the patient has not given consent. CONCLUSION: To our knowledge, this is the first report on RA+CSS association. Common pathogenic background, such as genetic predisposition and ANCA may account for the development of RA+vasculitis overlaps. In DMARD-refractory cases, such as the ones presented here, biologics, especially rituximab may be highly effective. PMID- 22443801 TI - Characterization of the novel HLA-C*07:195 allele in an Italian hematopoietic stem cell volunteer donor, detected by sequence-based typing. AB - The new allele shows one nucleotide change from C*07:02:01:01 at 351 nt from C to A, resulting in an amino acid change at codon 93 of exon 3 from H to Q. PMID- 22443802 TI - Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5 * 5 Gy) and intraoperative radiation therapy (15 Gy) in patients with primarily resectable pancreatic cancer - NEOPANC. AB - BACKGROUND: The current standard treatment, at least in Europe, for patients with primarily resectable tumors, consists of surgery followed by adjuvant chemotherapy. But even in this prognostic favourable group, long term survival is disappointing because of high local and distant failure rates. Postoperative chemoradiation has shown improved local control and overalls survival compared to surgery alone but the value of additional radiation has been questioned in case of adjuvant chemotherapy. However, there remains a strong rationale for the addition of radiation therapy considering the high rates of microscopically incomplete resections after surgery. As postoperative administration of radiation therapy has some general disadvantages, neoadjuvant and intraoperative approaches theoretically offer benefits in terms of dose escalation, reduction of toxicity and patients comfort especially if hypofractionated regimens with highly conformal techniques like intensity-modulated radiation therapy are considered. METHODS/DESIGN: The NEOPANC trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant short course intensity-modulated radiation therapy (5 * 5 Gy) in combination with surgery and intraoperative radiation therapy (15 Gy), followed by adjuvant chemotherapy according to the german treatment guidelines, in patients with primarily resectable pancreatic cancer. The aim of accrual is 46 patients. DISCUSSION: The primary objectives of the NEOPANC trial are to evaluate the general feasibility of this approach and the local recurrence rate after one year. Secondary endpoints are progression-free survival, overall survival, acute and late toxicity, postoperative morbidity and mortality and quality of life. TRIAL REGISTRATION: NCT01372735. PMID- 22443803 TI - Micropatterning of functional conductive polymers with multiple surface chemistries in register. AB - A versatile procedure is presented for fast and efficient micropatterning of multiple types of covalently bound surface chemistry in perfect register on and between conductive polymer microcircuits. The micropatterning principle is applied to several types of native and functionalized PEDOT (poly(3,4 ethylenedioxythiophene)) thin films. The method is based on contacting PEDOT-type thin films with a micropatterned agarose stamp containing an oxidant (aqueous hypochlorite) and applying a nonionic detergent. Where contacted, PEDOT not only loses its conductance but is entirely removed, thereby locally revealing the underlying substrate. Surface analysis showed that the substrate surface chemistry was fully exposed and not affected by the treatment. Click chemistry could thus be applied to selectively modify re-exposed alkyne and azide functional groups of functionalized polystyrene substrates. The versatility of the method is illustrated by micropatterning cell-binding RGD-functionalized PEDOT on low cell-binding PMOXA (poly(2-methyl-2-oxazoline)) to produce cell capturing microelectrodes on a cell nonadhesive background in a few simple steps. The method should be applicable to a wide range of native and chemically functionalized conjugated polymer systems. PMID- 22443804 TI - Safety and efficacy of simultaneous corneal collagen cross-linking with topography-guided PRK in managing low-grade keratoconus: 1-year follow-up. AB - PURPOSE: To evaluate 1-year visual and topographic outcomes and safety and efficacy of corneal collagen cross-linking (CXL) combined with topography-guided photorefractive keratectomy (TG-PRK) to achieve near emmetropia in eyes with low grade keratoconus. METHODS: Twenty-two eyes from 15 patients (11 women, 4 men) were included in a prospective, nonrandomized, noncontrolled clinical study. Mean patient age was 26.6+/-6.07 years (range: 19 to 40 years). Inclusion criteria were low-grade keratoconus with evidence of progression, transparent cornea, corrected distance visual acuity (CDVA) 0.8 (decimal) or better, corneal thickness >440 MUm, and maximum keratometry readings (K-max) <51.00 diopters (D). All patients underwent simultaneous TG-PRK with CXL. Study parameters were uncorrected distance visual acuity, CDVA, manifest refractive error, manifest and topographic (corneal) astigmatism, patient satisfaction, and efficacy and safety of the treatment. Follow-up was 1 year. RESULTS: After 1 year, statistically significant improvement was noted in all study parameters (P<.01). The safety and efficacy indices were 1.6 and 0.4, respectively. Patient satisfaction questionnaire showed that 91% were satisfied, 9% were not completely satisfied but believed they improved, and none were dissatisfied. Corneal topography demonstrated significant improvement in 55%, improvement in 36%, and minor improvement in 9% of cases. No cases progressed as evidenced by keratometry readings. CONCLUSIONS: Simultaneous TG-PRK with CXL is an effective and safe treatment with remarkable visual and topographic outcomes in patients with low grade keratoconus who meet the recommended inclusion criteria. PMID- 22443805 TI - Modulation transfer function of a toric intraocular lens: evaluation of the changes produced by rotation and tilt. AB - PURPOSE: To evaluate the changes in optical quality when toric intraocular lenses (IOL) are rotated or tilted and to demonstrate that IOL rotation produces an increasing effect of aberrations. METHODS: Modulation transfer function (MTF) and average modulation were used to analyze the image quality of a toric IOL. The axis of the toric IOL was rotated 5 degrees , 10 degrees , 15 degrees , 20 degrees , 25 degrees , and 30 degrees in successive MTF measurements. The tilt values were 0 degrees to 5 degrees , in increments of 1 degrees , plus a tilt of 15 degrees . Pupil diameters of 3 and 5 mm were used. RESULTS: The MTF decay due to aberrations was more sensitive to rotation than tilt. The main decrement in the average modulation, of approximately 50% in both pupils, occurs when the IOL rotates from 0 degrees to 5 degrees . Between 0 degrees and 1 degrees tilt, the average modulation decreases approximately 25% for both pupils; with tilt >1 degrees , the average modulation remains virtually unchanged. The points representing average modulation versus rotation angle are satisfactorily fitted by an exponential function, R=0.98. Average modulation versus tilt angle provides lower correlation degrees, R=0.91 and R=0.79, for 3- and 5-mm pupils, respectively. CONCLUSIONS: The MTF of the toric IOL decays with rotation and tilt, with greater decrement occurring in rotation from 0 degrees to 5 degrees . An asymptotic value exists in the average modulation decay, meaning that for angles higher than 15 degrees , the average modulation of the toric IOL remains virtually constant. PMID- 22443806 TI - An equilibrium model for chiral amplification in supramolecular polymers. AB - We describe a model that rationalizes amplification of chirality in cooperative supramolecular copolymerization. The model extends nucleation-elongation based equilibrium models for growth of supramolecular homopolymers to the case of two monomer and aggregate types. Using the principle of mass-balance for the two monomer types, we derive a set of two nonlinear equations, describing the thermodynamic equilibrium state of the system. These equations can be solved by numerical methods, but also analytical approximations are derived. The equilibrium model allows two-sided growth of the aggregates and can be applied to symmetric supramolecular copolymerizations, corresponding to the situation in which the monomers are enantiomerically related, as well as to the more general case of nonsymmetric supramolecular copolymerizations. In detail, so-called majority-rules phenomena in supramolecular systems with isodesmic as well as cooperative growth are analyzed. Comparison of model predictions with experimental data shows that the model gives a very good description of both titration and melting curves. When the system shows cooperative growth, the model leads to a phase diagram in which the presence of the various aggregate types is given as a function of composition and temperature. PMID- 22443807 TI - Enhancing medical students' communication skills: development and evaluation of an undergraduate training program. AB - BACKGROUND: There is a relative lack of current research on the effects of specific communication training offered at the beginning of the medical degree program. The newly developed communication training "Basics and Practice in Communication Skills" was pilot tested in 2008 and expanded in the following year at the University Medical Centre Hamburg-Eppendorf in Germany. The goal was to promote and improve the communicative skills of participants and show the usefulness of an early offered intervention on patient-physician communication within the medical curriculum. METHODS: The students participating in the project and a comparison group of students from the standard degree program were surveyed at the beginning and end of the courses. The survey consisted of a self assessment of their skills as well as a standardised expert rating and an evaluation of the modules by means of a questionnaire. RESULTS: Students who attended the communication skills course exhibited a considerable increase of communication skills in this newly developed training. It was also observed that students in the intervention group had a greater degree of self-assessed competence following training than the medical students in the comparison group. This finding is also reflected in the results from a standardised objective measure. CONCLUSIONS: The empirical results of the study showed that the training enabled students to acquire specialised competence in communication through the course of a newly developed training program. These findings will be used to establish new communication training at the University Medical Centre Hamburg Eppendorf. PMID- 22443808 TI - Editorial comment: oxytocin, vasopressin and social behavior. PMID- 22443809 TI - Staphylococcus aureus isolates belonging to different multilocus sequence types present specific virulence gene profiles. AB - To characterize 73 Staphylococcus aureus isolates from infections in an orthopedic hospital in Rio de Janeiro, we investigated the SCCmec types, the clonality by pulsed field gel electrophoresis and multilocus sequence typing, and the presence of virulence genes. Twenty-eight (38.3%) methicillin-resistant (16 SCCmec type IV and 12 type III) isolates were detected. Most (83.5%) of the isolates were included in five lineages: sequence type (ST) 239 (SCCmecIII), 1, 5, 30, and 1462 (SCCmecIV and/or methicillin-susceptible isolates). Virulence genes fnbB, bbp, and pvl were related to STs 239, 30, and 30/1462, respectively. Isolates from STs 1, 5, and 30 presented specific virulence profiles, irrespective of methicillin resistance. PMID- 22443810 TI - Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. AB - BACKGROUNDS: We conducted a pilot study of the infusion of intravenous autologous cord blood (CB) in children with cerebral palsy (CP) to assess the safety and feasibility of the procedure as well as its potential efficacy in countering neurological impairment. METHODS: Patients diagnosed with CP were enrolled in this study if their parents had elected to bank their CB at birth. Cryopreserved CB units were thawed and infused intravenously over 10~20 minutes. We assessed potential efficacy over 6 months by brain magnetic resonance imaging (MRI) diffusion tensor imaging (DTI), brain perfusion single-photon emission computed tomography (SPECT), and various evaluation tools for motor and cognitive functions. RESULTS: Twenty patients received autologous CB infusion and were evaluated. The types of CP were as follows: 11 quadriplegics, 6 hemiplegics, and 3 diplegics. Infusion was generally well-tolerated, although 5 patients experienced temporary nausea, hemoglobinuria, or urticaria during intravenous infusion. Diverse neurological domains improved in 5 patients (25%) as assessed with developmental evaluation tools as well as by fractional anisotropy values in brain MRI-DTI. The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. CONCLUSIONS: Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP. PMID- 22443811 TI - RVG peptide as transfection reagent for specific cdk4 gene silencing in vitro and in vivo. AB - The rabies virus glycoprotein (RVG) peptide is known as a transfection reagent for systemic delivery of small interfering RNA (siRNA) into the brain. However, selective transfection of neuronal cells or specific brain regions remains a problem. In the present study, we show that the RVG peptide can efficiently be used as shuttle system to transfect neuronal cells with cdk4 siRNA leading to selective knockdown of cdk4 expression in vitro and in vivo. After transfection, cdk4 expression was reduced up to 75% in Neuro2A cells. Stereotactically injected RVG peptide delivered cdk4 siRNA specifically to neurons in the hippocampus, resulting in a specific knockdown of cdk4 expression up to 400 um from the injection site. Further complexation studies of RVG peptide with larger molecules such as plasmid vectors or DNA fragments were also successfully performed and improved in vitro. Therefore, the peptide is not only a highly promising drug delivery system for siRNA and potentially other therapeutic molecules, but also a powerful tool to systematically analyze gene function in the brain under experimental settings in correlation to neurodegenerative disorders. PMID- 22443812 TI - The dangers of damage control orthopedics: a case report of vascular injury after femoral fracture external fixation. AB - BACKGROUND: Placement of external fixation frames is an expedient and minimally invasive method of achieving bone and joint stability in the setting of severe trauma. Although anatomic safe zones are established for placement of external fixation pins, neurovascular structures may be at risk in the setting of severe trauma. CASE REPORT: We present a case of a 21-year-old female involved in a high speed motorcycle accident who sustained a Type IIIB open segmental femur fracture with significant thigh soft tissue injury. Damage control orthopedic principals were applied and a spanning external fixator placed for provisional femoral stabilization. Intraoperative vascular examination noted absent distal pulses, however an intraoperative angiogram showed arterial flow distal to the trifurcation. Immediately postoperatively the dorsalis pedis pulse was detected using Doppler ultrasound but was then non-detectable over the preceding 12-hours. Femoral artery CT angiogram revealed iatrogenic superficial femoral artery occlusion due to kinking of the artery around an external fixator pin. Although the pin causing occlusion was placed under direct visualization, the degree of soft tissue injury altered the appearance of the local anatomy. The pin was subsequently revised allowing the artery to travel in its anatomic position, restoring perfusion. CONCLUSION: This case highlights the dangers associated with damage control orthopedics, especially when severe trauma alters normal local anatomy. Careful assessment of external fixator pin placement is crucial to avoiding iatrogenic injury. We recommend a thorough vascular examination pre operatively and prior to leaving the operating room, which allows any abnormalities to be further evaluated while the patient remains in a controlled environment. When an unrecognized iatrogenic injury occurs, serial postoperative neurovascular examinations allow early recognition and corrective actions. PMID- 22443813 TI - Isolation of a stable, acyclic, two-coordinate silylene. AB - The synthesis and characterization of a stable, acyclic two-coordinate silylene, Si(SAr(Me(6)))(2) [Ar(Me(6)) = C(6)H(3)-2,6(C(6)H(2)-2,4,6-Me(3))(2)], by reduction of Br(2)Si(SAr(Me(6)))(2) with a magnesium(I) reductant is described. It features a V-shaped silicon coordination with a S-Si-S angle of 90.52(2) degrees and an average Si-S distance of 2.158(3) A. Although it reacts readily with an alkyl halide, it does not react with hydrogen under ambient conditions, probably as a result of the ca. 4.3 eV energy difference between the frontier silicon lone pair and 3p orbitals. PMID- 22443814 TI - Hereditary hydrocephalus internus in a laboratory strain of golden hamsters ( Mesocricetus auratus). AB - Golden hamsters of one common laboratory strain had a high incidence of hydrocephalus internus. When a severity score of hydrocephalus was used, a major autosomal recessive locus could be identified. However, when a binary score (hydrocephalus, no hydrocephalus) was used, no such major locus could be detected and results of test matings were not consistent with Mendelian inheritance. Golden hamsters with severe forms of hydrocephalus had a dorsally compressed and ventrally intact hippocampus. Implications for the behavior and well-being of affected hamsters are unknown but researchers using this strain should be aware of the likely presence of hydrocephalus. PMID- 22443815 TI - Genetic aspects regarding piglet losses and the maternal behaviour of sows. Part 1. Genetic analysis of piglet mortality and fertility traits in pigs. AB - In spite of the improvement in management and the breeding goal of increasing the number of piglets born alive, piglet mortality is still a substantial problem in pig breeding. The objective of the first part of the study was to estimate genetic parameters for different causes of piglet losses and to investigate the relationship to litter-size traits. Data were collected on a nucleus herd from January till December 2004. Records from 943 German Landrace sows with 1538 pure bred litters and 13 971 individually weighted piglets were included. Four different causes of piglet losses (LOSS) were evaluated. Additional analysed traits were underweight and runting. Furthermore, the fertility traits number of piglets born alive, born in total and stillborn piglets as well as the individual birth and weaning weights were analysed. The different LOSS were treated as a binary trait and subsequently the heritabilities were estimated using a threshold model. The most important LOSS was crushing under the sow (12.4%). The survival rate and crushing had a heritability of h2 = 0.03. The fertility traits piglets born alive, born in total and stillborn piglets were analysed with a linear model and heritabilities rank from h2 = 0.05 (stillborn) to h2 = 0.10 (born alive). The estimated heritabilities for birth- and weaning weight were both h2 = 0.10. The genetic correlations between number of piglets born alive and each LOSS trait were analysed bivariately. Of all piglets born alive 84.3% survive the lactation period. Survival decreased with increasing litter size (rg = -0.54 up to -0.78) and the probability of being crushed under the sow increased. PMID- 22443816 TI - Genetic aspects regarding piglet losses and the maternal behaviour of sows. Part 2. Genetic relationship between maternal behaviour in sows and piglet mortality. AB - The aim of the study was to analyse the genetic background of different traits to characterise the maternal behaviour of sows and to evaluate the relationship to different causes of piglet losses - increasing piglet survival due to higher maternal abilities of the sow. A total of 1538 purebred litters from 943 German Landrace sows in the year 2004 were available for data analysis. Around 13 971 individually earmarked piglets were included in the analyses. Maternal abilities were characterised through the sow's reaction to the separation from her litter during the first 24 h after farrowing, and on day 21 of lactation, the reaction towards the playback of a piglet's distress call and the reaction towards an unknown noise (music). In 1220 of these litters, the sows were also scored for aggressiveness in the group when regrouped before entering the farrowing crates. To describe fertility, the number of piglets born alive, stillborn piglets, number of piglets born in total and the individual birth weight were utilised. Different causes of piglet losses were evaluated as binary traits of the dam with survival rate, different definitions for crushing by the sow, being underweight and runts. The heritability for being aggressive in the group was h2 = 0.32 and for the behaviour traits during lactation, the heritabilities ranged from h2 = 0.06 to 0.14. The genetic correlations showed that more-reactive sows had fewer piglet losses. PMID- 22443817 TI - Genetic and phenotypic aspects of foot lesion scores in sheep of different breeds and ages. AB - Footrot is a costly endemic disease of sheep. This study investigates the potential to decrease its prevalence through selective breeding for decreased lesion score. Pedigreed mule and Scottish Blackface (SBF) ewes were scored for lesions on each hoof on a 0 to 4 scale for up to 2 (SBF ewes) or 4 (mules) times over 2 years. One score was obtained for SBF lambs. An animal was deemed to have lesions (severe lesions) if at least one hoof had a score of at least 1 (2). The prevalence of lesions was 34% in lambs, 17% in SBF ewes and 51% in mules. The heritability of lesions (severe lesions) analysed as repeated measurements of the same trait in a threshold model was 0.19 (0.26) in SBF ewes and 0.12 (0.19) in mules. Estimates for the sum and maximum of scores as well as the number of feet affected were much lower, as were estimates for permanent animal effects (i.e. non-genetic effects associated with an animal). When successive scores on the same animal were analysed as correlated traits, heritability estimates for most traits tended to be higher, except for severe footrot in mules where estimates varied greatly over time. The phenotypic correlations between successive scores in SBF ewes were close to 0, genetic correlations were moderately positive (0.18 to 0.55). Correlations in mules were generally of a similar size, but some genetic correlations were higher (up to 0.92). There was a clear trend for heritabilities for lesions and severe lesions to increase with higher prevalence of lesions, even when analysed in a threshold model. Heritability estimates for traits that combine scores over several events in mules, identifying the more persistently affected animals, ranged from 0.12 to 0.23 with the highest estimates for the average number of feet that were (severely) affected in animals scored for a minimum at two events. The heritability of all lesion traits in lambs was estimated as 0. It is concluded that selection for lower lesions is possible in ewes but not lambs, and that a simple binary score at an animal level is at least as effective as a comprehensive score at hoof level. Given the low repeatability of lesion scores, repeated measures over time will improve effectiveness of selection. Selection across environments (flocks, seasons) with different prevalences of lesions scores will need to take account of variation in the heritability. PMID- 22443818 TI - Effect of liquid feeding at different water-to-feed ratios on the growth performance of growing-finishing pigs. AB - The study examined the growth performance of pigs offered liquid feed or dry feed on either a restricted or an ad libitum basis, and whether their growth performance was further influenced by the water-to-feed ratio. The study was split into two parts to enable unrestricted (trial 1; n = 64) and restricted (trial 2; n = 48) feeding to be compared. Male pigs were randomly allocated to six dietary treatment groups. A standard dry pellets diet (D) was offered either as: (i) unrestricted ration (UR); (ii) restricted ration (R); or D soaked in water at a feed-to-water ratio of (iii) 1 : 1.5 restricted (1 : 1.5 R); (iv) 1 : 3 unrestricted (1 : 3 UR); (v) 1 : 3 restricted (1 : 3 R); or (vi) 1 : 3 restricted with the addition of lactic acid to adjust the feed to pH 4 (1 : 3(4) R). Liquid feeding improved (P < 0.05) average daily live-weight gain (ADG) and lean tissue growth rate (LTGR) in the 1 : 3 UR compared with DUR but did not alter feed conversion ratio (FCR). Within the R groups, ADG were greater in all of the 1 : 3 diets, whereas feed intake, and hence FCR, was lower (P < 0.001) in these groups when offered the R ration. In conclusion, liquid feeding has a beneficial influence on the performance of modern porcine genotypes during the growth/finishing phase and this is further modulated by the water-to-feed ratio. PMID- 22443819 TI - Response of piglets weaned from sows fed diets supplemented with conjugated linoleic acid (CLA) to an Escherichia coli K88+ oral challenge. AB - Seventy-eight Cotswold piglets weaned from sows receiving 0% or 2% conjugated linoleic acid (CLA)-supplemented rations from day 85 of gestation through lactation were allocated to nursery diets (ND) according to their dam's lactation ration (LR) as follows (1) 0%-0% (0% CLA LR: 0% CLA ND, n = 17); (2) 0%-2% (0% CLA LR: 2% CLA ND, n = 17); (3) 2%-0% (2% CLA LR: 0% CLA ND, n = 23); and (4) 2% 2% (2% CLA LR: 2% CLA ND, n = 21). At 28 +/- 2 days of age all piglets received an oral Escherichia coli K88+ (enterotoxigenic Escherichia coli, ETEC) challenge and were subsequently monitored for scour development and overall health until 36 +/- 2 days of age, after which blood and tissue samples were collected. Piglet BW was not affected by dietary CLA supplementation to LR (P > 0.05). However, by day 36 piglets receiving 2% CLA-supplemented ND were significantly lighter (P < 0.05) than piglets receiving control diets. Average daily gain and feed efficiency were not affected by CLA supplementation. Average daily feed intake (ADFI) was greater for piglets weaned from 2% CLA-supplemented sows from day 17 to 28 (P < 0.05), otherwise ADFI was unaffected by dietary CLA supplementation (P > 0.05). The development of scours was less severe in piglets weaned from 2% CLA-supplemented sows at 8, 24, 48 and 56 h after ETEC challenge (P < 0.05). Intestinal coliform and lactic acid bacteria populations post challenge were not affected by CLA supplementation. However, cecal ammonia-N was numerically greatest in 0%-0% piglets compared to the other treatment groups, and the total volatile fatty acid production was numerically lower in 0%-0% and 0%-2% piglets compared to 2%-0% and 2%-2% piglets. In addition, piglets weaned from 2% CLA-supplemented sows had increased serum immunoglobulin A (P < 0.001) and G (P < 0.05) levels and reduced (P < 0.05) intestinal mucosal inflammation compared to piglets weaned from control sows. Although there were no obvious additional health effects observed when CLA was provided in ND, supplementing sow rations with 2% CLA from mid gestation through weaning appears to have immune-stimulating carry-over effects post weaning. Thus, supplementing sow rations with CLA may be a practical strategy for enhancing passive immune transfer and improving the immune status and overall gut health of nursery piglets. PMID- 22443820 TI - Physicochemical changes to starch granules during micronisation and extrusion processing of wheat, and their implications for starch digestibility in the newly weaned piglet. AB - Two trials were performed to assess changes in the physicochemical properties of precisely processed (micronised v. extruded) wheats, prior to inclusion in piglet diets. The in vitro data obtained were subsequently related to biological responses of newly weaned piglets over 14 days. The effects of the severity of micronisation (Trial 1) or extrusion (Trial 2) on the nutritional value of two wheats (varying in endosperm texture) were examined. Extrusion, in contrast to micronisation, drastically disrupted the structural properties of wheat starch granules through melting of crystallites and macromolecular degradation of starch polysaccharides. These structural changes strongly improved the hydration characteristics of starch and its digestibility. The amount of starch digested in vitro was approximately 0.20, 0.70 and 0.90 for the unprocessed, micronised and extruded samples, respectively. This enhanced in vitro digestibility correlated well with, and helped to explain, the significant improvement in the apparent digestibility of starch at both the 0.5 region (mean coefficients for extruded wheat were 0.869 and 0.959 v. raw 0.392; P = 0.017) and 0.75 region (extruded 0.973 v. raw 0.809; P = 0.009) of the small intestine, when compared with piglets fed an unprocessed wheat diet. Extrusion and, to a lesser extent, micronisation lessened the reduction in apparent starch digestibility on day 4 post-weaning, typically seen at the 0.5 intestinal region in piglets fed an unprocessed wheat diet. Processing variables influenced both in vitro and in vivo data, with for instance, a positive relationship between specific mechanical energy (SME) input during extrusion and starch digestibility at the 0.5 region. The higher digestibility coefficient observed at the 0.5 region for the high SME diet suggests enhanced digestion and more rapid release of starch. However, it remains to be seen whether a diet containing rapidly digestible, as opposed to slowly digestible, starch is more beneficial for piglets. This rate of starch breakdown in the piglet is an important finding, which may have implications in helping to alleviate the post-weaning growth check, particularly in the absence of in-feed antibiotic growth promoters. Processing did not appear to offer any benefit over unprocessed wheat with regard to daily live-weight gain or the apparent digestibility of nitrogen in the small intestine over the 14-day period. Based on the enhanced in vivo starch digestibility, performance might be improved over a longer period, although future studies are required to confirm this. Precise processing variables for raw materials must be stated in all animal trials. PMID- 22443821 TI - Effects of meal-time feeding and protein restriction on walking ability and some bone and carcass properties in broilers. AB - This experiment was designed to investigate the effects of meal-time feeding and protein restriction on performance, gait score (GS) and carcass and bone traits in broilers. A total of 420 1-day-old chicks were wing banded and randomly distributed into 21 pens with 20 chicks each. At 7 days of age, chicks were weighed and randomly assigned to one of the three treatments: (1) control (C) feed (23.02% crude protein (CP)) was available ad libitum; (2) meal-time feeding (MF); control feed was available from 0100 to 0900 h and from 1500 to 2300 h. Food was withdrawn from 0900 to 1500 h and whole wheat (10 g/bird per day) was dispersed on the floor from 7 to 21 days; and (3) low-protein (LP) diet (19.71% CP) was fed to the chicks from 7 to 21 days. All of the groups were fed ad libitum from 1 to 7 days of age and from 21 to 45 days of age with a standard commercial diet. Individual body weight was measured on days 7, 21 and 45. Feed consumption was measured from 7 to 21 days and from 21 to 45 days. Forty-two chicks were humanly slaughtered and eviscerated for bone evaluation, on days 21 and 45. Also carcass characteristics were determined on day 45. Control group body weight was significantly higher (P < 0.05) at 21 and 45 days of age than the MF and LP groups, which did not differ. Feed intake was reduced by meal-time feeding and LP diet (P < 0.01). Feed efficiency was the best in the MF group during the period of 21 to 45 days of age (P < 0.01). In the control group, shank was significantly longer than that of the LP group and tibia breaking strength was higher than that of the MF group at 21 days (P < 0.05). However, shank width, tibia wet weight and tibia mid-diaphysis ash percentage of the MF group were significantly lower than those of the C and LP groups at 21 days of age (P < 0.05). GS, shank and carcass and tibia bone traits on day 45 were not significant among groups. No compensatory growth and walking ability improvement were observed at 45 days of age for broilers fed with MF and LP between 7 and 21 days of age. PMID- 22443822 TI - In vivo and in situ measurements of the digestive characteristics of sainfoin in comparison with lucerne fed to sheep as fresh forages at two growth stages and as hay. AB - In vivo and in situ digestive characteristics of sainfoin (Onobrychis viciifolia L., a tannin-rich forage) and lucerne (Medicago sativa L., a tannin-free forage) were compared to evaluate the effects of condensed tannins (CT) and growth stage (vegetative v. early flowering) in experiment 1. In experiment 2, the hays of the two forages, harvested at early flowering, were compared. Ingestibility, organic matter digestibility (OMD) and nitrogen (N) retention were measured in sheep fed sainfoin and lucerne fresh forages and hays. The loss of dry matter (DM) and N from polyester bags suspended in the rumen, abomasum and small intestine was also measured using rumen fistulated sheep and other intestine fistulated sheep. Nitrogen content was lower in sainfoin than in lucerne. Content of CT in sainfoin decreased with growth stage (3.5 to 2.5 g CT/kg DM) and was lower for sainfoin hay (0.6 g CT/kg DM). Ingestibility and OMD did not differ between fresh-fed forage species. Total N tract digestibility in vivo was much lower for sainfoin than for lucerne fresh forages (mean value 0.540 v. 0.721, P < 0.001) and for sainfoin hay than lucerne hay (0.464 v. 0.683, P < 0.001). In both species, N digestibility was not altered by growth stage. The rumen degradation of N was lower in sainfoin than in lucerne, resulting in a lower proportion of N intake excreted in urine. The intestinal digestibility of sainfoin was also lower than that of lucerne, resulting in a higher N excretion in faeces. Hence the efficiency of N utilisation by sheep (ENr) was similar (mean value 0.205 and 0.199 g N retained/g N intake for fresh sainfoin and lucerne, respectively). The coefficient of N retention by the animal was higher for sainfoin at the vegetative stage than for all the other forages. Nitrogen degradability in the rumen determined by the nylon bag technique (DegN) was lower for sainfoin than for lucerne when forages were studied both fresh (mean value 0.608 and 0.818, respectively) and as hays (0.631 and 0.767). The efficiency of forage N digestion (ENd) was higher for sainfoin at the vegetative stage. Compared with lucerne, sainfoin greatly increased the in situ estimate of forage N escaping the rumen but decreased its intestinal digestibility. PMID- 22443823 TI - Bioelectrical impedance analysis for the prediction of fat-free mass in buffalo calf. AB - The objective of this study has been to develop a prediction equation of fat-free mass (FFM) from buffalo calves. Twenty buffaloes were fed ad libitum access at unifeed, with vitamin-mineral integration, for 14 months. Seven days before slaughtering, the animals were weighed and bioelectrical impedance measurements were collected. The data were analyzed by multiple linear regressions to evaluate the relationship between FFM and various predictor variables. Stepwise regression was used to eliminate variables that did not influence variation in the model. The value of resistance collected showed a decrease when the electrical frequency increases, while the values of reactance (Xc) increase. When using live weight (LW) and reactance at 500 and at 1000 kHz as independent variables, we obtained the best R2 Adj (0.967) and Durbin Watson statistic (2.596) that explain the prediction model (FFM = - 30.59 + 0.993LW + 0.150Xc500 - 0.123Xc1000 + 9.11). These results indicate that the use of bioelectrical impedance analysis has excellent potential as a rapid method, with minimal perturbation for the animal, to predict FFM in buffalo. PMID- 22443824 TI - Molecular approach of gossypol-induced reproductive toxicity in male rabbits. Changes in seminal plasma amino acids and fatty acids. AB - This study was done to evaluate the effects of two sublethal doses of gossypol (4 and 20 mg/kg of BW, every other day) on some amino and fatty acid concentrations in male rabbit seminal plasma. Rabbits were chosen as an experimental animal owing to the fact that they are excellent model for reproductive toxicological effects. The experiment lasted 16 weeks and included two periods: a treatment period (first 8 weeks) where the animals were given the tested product, and a recovery period (second 8 weeks) where all drugs were withdrawn. Results showed that total amino acids (TAA), total essential amino acids (EAA), total non essential amino acids (non-EAA) and EAA/non-EAA ratio were decreased in a dose dependent manner during gossypol treatment. The deleterious effect on TAA concentrations was mainly due to the reduction in total EAA. However, these concentrations regained their normal values after gossypol cessation. Basic, acidic, neutral amino acids and basic/acidic amino acids ratio decreased in a dose-dependent manner by gossypol treatment. Additionally, gossypol administration caused decreases in total unsaturated fatty acids (USFA) and increases in total saturated fatty acids (SFA) and the SFA/USFA ratio in a dose dependent manner. During the recovery period, total SFA and USFA showed significant reduction and significant increase, respectively, after gossypol withdrawal. In conclusion, gossypol administration affected rabbit seminal plasma concentrations of amino and fatty acids in a dose-dependant manner. Gossypol reduced TAA, total EAA and total non-EAA. Additionally, gossypol caused decreases in total USFA and increases in total SFA. These deleterious effects were associated with poor-quality semen observed in our previous studies. PMID- 22443825 TI - Reproductive capacity of Merino ewes fed a high-salt diet. AB - An option to increase the productivity of saline land is to graze sheep on salt tolerant plants, which, during the summer/autumn period, can contain 20% to 25% of their dry matter as salt. This study assessed the impact of coping with high dietary salt loads on the reproductive performance of grazing ewes. From the time of artificial insemination until parturition, 2-year-old maiden Merino ewes were fed either a high-salt diet (NaCl 13% of dry matter) or control diet (NaCl 0.5% of dry matter). Pregnancy rates, lamb birth weights, milk composition and the plasma concentrations of hormones related to salt and water balance, and energy metabolism were measured. Leptin and insulin concentrations were lower (1.4 +/- 0.09 v. 1.5 +/- 0.12 ng/ml; (P < 0.05) and 7.2 +/- 0.55 v. 8.2 +/- 0.83 ng/ml; P < 0.02) in response to high-salt ingestion as was aldosterone concentration (27 +/- 2.7 v. 49 +/- 5.4 pg/ml; P < 0.05), presumably to achieve salt and water homeostasis. Arginine vasopressin concentration was not significantly affected by the diets, but plasma concentration of T3 differed during gestation (P < 0.02), resulting in lower concentrations in the high-salt group in the first third of gestation (1.2 +/- 0.18 v. 1.3 +/- 0.14 pmol/ml) and higher concentrations in the final third of gestation (0.8 +/- 0.16 v. 0.6 +/- 0.06 pmol/ml). T4 concentration was lower in ewes ingesting high salt for the first two-thirds of pregnancy (162 +/- 8.6 v. 212 +/- 13 ng/ml; P < 0.001). No substantial effects of high salt ingestion on pregnancy rates, lamb birth weights or milk composition were detected. PMID- 22443826 TI - Feeding frequency has diet-dependent effects on plasma hormone concentrations but does not affect oocyte quality in dairy heifers fed fibre- or starch-based diets. AB - The post-fertilisation developmental capacity of bovine oocytes recovered by ultrasound guided transvaginal follicular aspiration (ovum pick-up, OPU) is influenced by diet-induced changes in hormone and metabolite concentrations. The objectives of this experiment were first to determine whether post-prandial changes in hormone concentrations, induced by changing the frequency of feeding, influenced oocyte quality and second whether changes in plasma glucagon concentration were associated with oocyte quality. Using a 2 * 2 factorial design, Holstein heifers (six per treatment) were fed either fibre- or starch based diets containing either 189 or 478 g starch/kg dry matter. The diets were offered in either two or four equal meals per day and supplied twice the maintenance energy requirement. Blood samples were obtained both at weekly intervals (three samples per heifer, collected before feeding) during the experiment and throughout an entire 24-h period (15 or 17 samples per heifer for twice or four times daily-fed heifers, respectively). Each heifer underwent six sessions of OPU (twice weekly) beginning 25 days after introduction of the diets. Oocyte quality was assessed by development to the blastocyst stage in synthetic oviductal fluid following in vitro fertilisation. Mean weekly plasma insulin concentrations did not differ between diets, but plasma glucagon concentrations were greatest when heifers were fed the starch-based diet twice daily compared with the other diets. When heifers were offered four meals per day, there were no meal-related changes in hormone concentrations. However, when heifers were offered two meals per day, plasma insulin concentration increased after feeding the starch-based, but not the fibre-based diet. Plasma glucagon concentration increased after meals when heifers were fed twice daily and the increase was substantially greater when the starch-based diet was fed. Treatments did not influence (overall mean with mean +/- s.e.) ovarian follicle size distribution or oocyte recovery by OPU (6.2 +/- 0.4 per heifer), the proportion of oocytes that cleaved following insemination (0.57 +/- 0.030) or blastocyst yield (0.27 +/- 0.027 of oocytes cleaved). In conclusion, by feeding diets differing in carbohydrate source at different frequencies of feeding, meal-related changes in plasma hormone profiles were altered significantly, but oocyte quality was not affected. Therefore effects of diet on oocyte quality appear not to be mediated by meal-related fluctuations in hormone concentrations. PMID- 22443827 TI - Developmental potential of oocytes fertilized by conventional in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) after cryopreservation and mesometrial autotransplantation of rabbit ovarian tissue. AB - OBJECTIVE: To evaluate mesometrial transplantation of frozen-thawed ovarian tissue in rabbit and to choose the optimized fertilization method for oocytes retrieved from grafts by investigating the capability of oocyte fertilization and further development. Forty rabbits were divided into three groups randomly: control group, fresh tissues transplantation group and frozen-thawed tissues transplantation group. Three months after the transplantation, rabbits were stimulated with FSH and oocytes were retrieved 13 h after human chorionic gonadotropin (HCG) injection. Oocytes matured in vivo or in vitro were then fertilized by conventional in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), followed by observation and evaluation of fertilization rate and blastocyst formation rate. Blastocytes embryos were transferred to pseudopregnancy rabbits to observe pregnancy rate and birth rate. There were no significant differences in the percentage of oocytes matured either in vivo or in vitro among the three groups. The fertilization rate, cleavage rate and blastocyst formation rate of in vivo-matured oocytes had no difference among the three groups, whether they were fertilized by IVF or ICSI. Significantly higher fertilization rates of in vitro-matured oocytes were observed with ICSI compared with IVF in each group. The blastocyst formation rate of in vitro-matured oocytes was significantly lower than that of in vivo-matured oocytes in each group. The birth rate of in vivo-matured oocytes was significantly higher than that of in vitro-matured oocytes, although the pregnancy rate was similar between them. Mesometrial transplantation of frozen-thawed ovarian tissue may provide favorable conditions for follicle development. Oocytes retrieved from mesometrial grafts can develop to the blastocyst stage and produce live offspring. ICSI can optimize the fertilization rate of in vitro-matured oocytes retrieved from grafts. PMID- 22443828 TI - Analysis of expressed sequence tags from abdominal muscle cDNA library of the pacific white shrimp Litopenaeus vannamei. AB - The pacific white shrimp, Litopenaeus vannamei, is a popular species in aquaculture. Abdominal muscle accounts for 90% of shrimp flesh. Its growth and related genes, particularly the regulatory genes, is not well known. A cDNA library of shrimp juvenile abdominal muscle was established by PCR-based SMARTTM cDNA technology. Library size was 5.0 * 106 pfu (plaque-forming unit) independent clones per microgram of starting RNA with the percentage of recombinant clones >95%. Sequence analysis of 311 randomly picked positive clones revealed 197 expressed sequence tags with average insert size of 745 nucleotides, 56% (110 of 197) clones having 5'-end sequence and 44% (87 of 197) clones having 3'-end sequence. Queries of the sequences by Blast identified 37 unknown sequences, and 160 unique clones, including 67 sequences of 100% identity matches, 28 high homologies (80% to 90% sequence match, >100 bits hit score in Blastn), 65 medium homologies (>100 bits hit score in Blastp) to the known EST sequences in the database. Among the high identity-matched ESTs, 12S ribosomal RNA, actin 1, actin 2, arginine kinase and beta-actin were the most abundant transcripts with 5 to 20 times of hit. Primary hit sequences originate from shrimp, insects, lobsters, crabs and crayfish. The EST sequences were categorized as muscle structural proteins (25%), rRNA and protein synthesis (25%), followed by mitochondrial functions (22%), exoskeleton (14%), enzymes (6%) and RNA splicing (2%), suggesting abundant and diverse transcripts present in the shrimp abdominal muscle cDNA library. PMID- 22443829 TI - Herbage intake and behavioural adaptation of grazing dairy cows by restricting time at pasture under two feeding regimes. AB - The time at pasture of dairy cows is often restricted in the context of extending the grazing season in autumn or at the end of winter. The objective of our study was to evaluate the effects of a restriction of time at pasture on milk production, herbage intake and feeding behaviour in dairy cows according to feeding regime. The four treatments consisted of 4 h or 8 h of time at pasture per day tested under two feeding regimes combining rate of supplementation and herbage allowance: either a high rate of supplementation (10 kg dry matter (DM) of a maize silage-soya bean meal mixture in the ratio 87 : 13 on a % DM basis) with a low herbage allowance (6 kg DM/cow per day above 5 cm), or a low rate of supplementation (5 kg DM of the same supplement) with a high herbage allowance (11 kg DM/cow per day). The study was carried out according to a 4 * 4 Latin square design with four 2-week periods, with 48 mid-lactation Holstein cows. The cows in the 4-h treatment had access to pasture from 0900 h to 1300 h and those in the 8-h treatment from 0900 h to 1700 h. The supplement was given at 1830 h. When time at pasture was reduced from 8 h to 4 h per day, herbage intake decreased (9.9 v. 8.1 kg DM, P < 0.001), along with a fall in milk production (22.3 v. 21.2 kg, P < 0.001) and milk protein concentration (30.1 v. 29.6 g/kg, P < 0.001), while milk fat concentration increased (39.4 v. 39.9 g/kg, P < 0.05). The effect of time at pasture on milk production was slightly more marked on the low-supplement feeding regime (interaction P < 0.06). Reducing time at pasture by 4 h led to a sharp decrease in grazing time (327 v. 209 min, P < 0.001), but strongly increased the pasture intake rate (31 v. 39 g DM/min, P < 0.001) and the proportion of time spent grazing (0.68 v. 0.87, P < 0.001). Cows showed a stronger motivation for grazing when receiving the low-supplement feeding regime. In conclusion, we showed that reducing time at pasture from 8 to 4 h for cows receiving 5 to 10 kg DM of a maize silage-based supplement decreased moderately milk production and herbage intake, because of the capacity for behavioural adaptation by the grazing dairy cows. PMID- 22443830 TI - Rearing strategy and optimizing first-calving targets in dairy heifers: a review. AB - Much research has been carried out and published on dairy replacement management, in order to rear heifers as efficiently as possible, from both a technical and economical point of view. In most cases, the aim is to rear the heifers at the lowest cost possible without any deleterious effects on future performances. However, the importance of dairy heifer husbandry is not sufficiently well recognized and probably mishandled by most farmers. The present review aims to give an actual overview of rearing procedures in dairy heifers and possible ways to achieve optimal goals. For many years, it has been well known that rapid rearing lowers the age of sexual maturity and consequently may be an efficient way to reduce the non-producing period prior to conception. But this may impair mammary development and consequently future milk production, at least during first lactation. In addition, a growth rate that is too low may not only be costly but also result in animals that are too fat at first calving, creating problems such as calving difficulties, dystocia, etc. Genetic considerations must also be factored, i.e. frame, size, body weight, etc. have changed during the last 20 years and there are differences between breeds. As a result, some time honoured recommendations may not be appropriate. The present paper reviews factors and management practices that may affect rearing and subsequent performance of dairy heifers. PMID- 22443831 TI - Estimation of alpha-tocopherol concentration necessary to optimise lamb meat quality stability during storage in high-oxygen modified atmosphere using broken line regression analysis. AB - The research was carried out to evaluate the effect of different alpha-tocopherol concentrations in lamb meat on oxidative stability during storage in high-oxygen atmosphere. Thirty-six lambs were randomly distributed to four groups and given diets containing four levels of vitamin E (20, 270, 520 and 1020 mg vitamin E/kg feed) from an initial weight of 13.2 +/- 0.5 kg to a slaughter weight of 26.2 +/- 0.3 kg. Supplementation of the diet with vitamin E increased (P < 0.001) the concentration of alpha-tocopherol in the meat and concentrations were obtained in the 0.46 to 4.14 mg/kg meat range. Broken-line analysis of data indicated a target dietary vitamin E supplementation of 287 mg/kg feed, which corresponded with a concentration of 2.26 mg alpha-tocopherol/kg meat. alpha-Tocopherol in meat was highly correlated with the oxidation of lipids and pigments. Broken-line analysis of data indicated the target alpha-tocopherol concentration in lamb for improved protection against lipid and pigment oxidation during 14, 21 and 28 days of storage in high-oxygen atmosphere was in the range 1.87 to 2.37 mg/kg meat. These concentrations of alpha-tocopherol in the meat made it possible to maintain the indicator values of lipid and pigment oxidation below the values considered in the bibliography as unacceptable to the consumer. PMID- 22443832 TI - Pro-tobacco content in social media: the devil does not have all the best tunes. PMID- 22443833 TI - Using hemoglobin A1c for prediabetes and diabetes diagnosis in adolescents: can adult recommendations be upheld for pediatric use? AB - The obesity epidemic has resulted in more young people having high-risk profiles for the development of type 2 diabetes. Screening to promote earlier diagnosis and treatment of type 2 diabetes is of significant importance, as untreated disease leads to metabolic, microvascular, and macrovascular complications. However, the choice of screening methodology in adolescents is controversial, and implementation of screening protocols is not uniform. Expert panels have recommended the use of glycated hemoglobin (A1c) for the diagnosis of prediabetes and diabetes, based on the facts that the A1c assay has technical advantages and correlates well with the risk of microvascular diabetes. However, these recommendations are based strictly on data from adult studies and lack any input based on pediatric research. The pediatric research that has been published on the topic indicates that using adult cutoff points for A1c values to predict prediabetes or diabetes significantly underestimates the prevalence of these conditions in the pediatric and adolescent population. Therefore, we call for further investigation of the role of A1c for the diagnosis of prediabetes and diabetes in adolescents before its adoption as a principal diagnostic method in pediatric populations. We contend that a more comprehensive diabetes evaluation, along with A1c, remains necessary for screening adolescents at high risk for prediabetes and type 2 diabetes. Collaborative multicentered studies of prediabetes and type 2 diabetes in the obese pediatric population are especially needed to determine the A1c cutoff points, as well as other diagnostic measures, that best predict diabetes-related comorbid conditions later in life. PMID- 22443834 TI - Interventions for weight gain prevention during the transition to young adulthood: a review of the literature. AB - PURPOSE: To review studies examining weight gain prevention interventions among young adults. METHODS: A snowball strategy was used to identify relevant studies, beginning with systematic PubMed, MEDLINE, PsychINFO, Education Resources Information Center (ERIC), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) searches. INCLUDED STUDIES: (a) were published from 1985 to 2011; (b) were completed in the United States or Canada; (c) focused on weight gain prevention among young adults aged 18-35 years, assessing weight, body mass index, body composition, diet, or physical activity as an outcome; and (d) comprised pre- and postintervention assessments. RESULTS: Thirty-seven interventions were identified. Ten interventions assessed weight, body mass index, or body composition; 27 addressed other relevant outcomes (e.g., diet, physical activity). Of the studies examining weight or body composition, six evaluated university courses or seminar-based interventions. Overall, many studies focused on individual-level intervention delivery and changes in weight related knowledge and/or skills, although some incorporated relatively unique aspects (e.g., focusing on eating disorders and obesity simultaneously, using online technology, providing personalized feedback on weight change). Most showed promising results as small-scale pilot studies but lacked data from fully powered randomized trials. CONCLUSIONS: There is an urgent need to develop effective young adult-focused weight gain prevention strategies. This review identified promising areas for future work, although much additional research is needed. PMID- 22443835 TI - Youth access, creation, and content of smokeless tobacco ("dip") videos in social media. AB - BACKGROUND: Smokeless tobacco (SLT) use among white adolescent males has increased in recent years, and prevalence of SLT use among adolescent males exceeds that for smoking in several U.S. states. Recent reports have described the presence of cigarette-related content on social media Web sites popular among youth; however, little has been reported on SLT content. METHODS: The YouTube video search engine was searched for the popular SLT brand Skoal, and the first 50 search results were downloaded. Video statistics data were collected for and content analysis was performed on all videos featuring smokeless use (82%). Access to SLT YouTube videos by youth was also determined by assessing whether YouTube permits youth viewing and creation of SLT videos. RESULTS: Mean number of views for videos analyzed was 15,422, and the most watched video had 124,276 views. Descriptions of SLT flavor/smell and social references/interactions were found in 48.8% and 63.4% of videos, respectively. By contrast, references to drug (nicotine) effects (12.2%) and public health messaging (9.8%) were less common. None of the SLT videos in the sample had restrictions that would block youth viewing. In addition, evidence of self-identified youth creating SLT videos was found for 13% of unique users in the sample. CONCLUSIONS: YouTube does not restrict youth from creating or viewing "dip videos." Proactive efforts are needed to ensure that YouTube and other online media do not become influential vehicles for tobacco promotion to youth. PMID- 22443836 TI - Just one click: a content analysis of advertisements on teen web sites. AB - PURPOSE: The current study provides a comprehensive analysis of the content of advertisements on Web sites targeted at adolescents, with a particular focus on the female beauty ideal. METHODS: Advertisements (N = 631) from 14 Web sites popular with adolescents were analyzed with respect to product advertised, characteristics of people presented, and emphasis on appearance and the thin beauty ideal. RESULTS: Although a wide variety of products were featured, advertisements for cosmetics and beauty products were the most frequent. Further, many of the products advertised (e.g., dating services, weight loss products, gambling games) might be considered inappropriate for the intended audience (i.e., teenagers) of the Web site. People who were a part of advertisements were generally female, young, thin, and attractive. Advertisements for games, weight loss products, and cosmetic and beauty products strongly focused on appearance and laid emphasis on the thin ideal. CONCLUSIONS: Like advertisements in mainstream media, advertising on the Internet perpetuates the stereotypical ideal of feminine beauty. Adolescents using the Internet are likely to be exposed to numerous advertisements that reinforce the importance of beauty and thinness, which could have a detrimental impact on how they feel about their bodies. PMID- 22443837 TI - The impact of a comprehensive microfinance intervention on depression levels of AIDS-orphaned children in Uganda. AB - PURPOSE: By adversely affecting family functioning and stability, poverty constitutes an important risk factor for children's poor mental health functioning. This study examines the impact of a comprehensive microfinance intervention, designed to reduce the risk of poverty, on depression among AIDS orphaned youth. METHODS: Children from 15 comparable primary schools in Rakai District of Uganda, one of those hardest hit by HIV/AIDS in the country, were randomly assigned to control (n = 148) or treatment (n = 138) conditions. Children in the treatment condition received a comprehensive microfinance intervention comprising matched savings accounts, financial management workshops, and mentorship. This was in addition to traditional services provided for all school-going orphaned adolescents (counseling and school supplies). Data were collected at wave 1 (baseline), wave 2 (10 months after intervention), and wave 3 (20 months after intervention). We used multilevel growth models to examine the trajectory of depression in treatment and control conditions, measured using Children's Depression Inventory (Kovacs). RESULTS: Children in the treatment group exhibited a significant decrease in depression, whereas their control group counterparts showed no change in depression. CONCLUSIONS: The findings indicate that over and above traditional psychosocial approaches used to address mental health functioning among orphaned children in sub-Saharan Africa, incorporating poverty alleviation-focused approaches, such as this comprehensive microfinance intervention, has the potential to improve psychosocial functioning of these children. PMID- 22443838 TI - The impact of role models on health outcomes for lesbian, gay, bisexual, and transgender youth. AB - PURPOSE: There is little research on the impact of role models on health outcomes for lesbian, gay, bisexual, and transgender (LGBT) youth. This exploratory study describes the presence and availability of LGBT-affirming role models, and examines the relationship between the accessibility of role models and health outcomes among a community-based sample of LGBT youth. METHODS: A convenience sample of 496 ethnically diverse, 16-24-year-old LGBT youth was recruited to complete a computer-assisted interview, using standardized instruments validated with adolescents. The prevalence and characteristics of role models were described. Differences in subgroup distribution were assessed using Pearson chi(2) test (p < .05). Differences in health outcomes for those with and without role models and the nature of those role models were determined using analysis of covariance models, with post hoc Bonferroni tests to probe significant global findings. RESULTS: Sixty percent of the participants reported having a role model, with younger participants significantly more likely to report having a role model. A majority of the participants reported having inaccessible role models, especially among younger participants. The presence and accessibility of a role model did not have a significant relationship to binge drinking, drug use, or sexually transmitted infection diagnoses; however, participants with inaccessible role models showed increased psychological distress versus those with accessible or no role models. CONCLUSIONS: Inaccessible role models may not be sufficient for protecting youth from negative outcomes, and formal mechanisms for connecting LGBT youth with caring adults who can serve as role models, such as mentoring programs, are critical. PMID- 22443839 TI - A family intervention to reduce sexual risk behavior, substance use, and delinquency among newly homeless youth. AB - PURPOSE: We evaluate the efficacy of a short family intervention in reducing sexual risk behavior, drug use, and delinquent behaviors among homeless youth. METHODS: A randomized controlled trial of 151 families with a homeless adolescent aged 12 to 17 years. Between March 2006 and June 2009, adolescents were recruited from diverse sites in Southern California and were assessed at recruitment (baseline), and at 3, 6, and 12 months later. Families were randomly assigned to an intervention condition with five weekly home-based intervention sessions or a control condition (standard care). Main outcome measures reflect self-reported sexual risk behavior, substance use, and delinquent behaviors over the past 90 days. RESULTS: Sexual risk behavior (e.g., mean number of partners; p < .001), alcohol use (p = .003), hard drug use (p < .001), and delinquent behaviors (p = .001) decreased significantly more during 12 months in the intervention condition compared with the control condition. Marijuana use, however, significantly increased in the intervention condition compared with the control condition (p < .001). CONCLUSIONS: An intervention to reengage families of homeless youth has significant benefits in reducing risk over 12 months. PMID- 22443840 TI - The consequences of juvenile detention reform for mental health and sexually transmitted infection screening among detained youth. AB - PURPOSE: To understand how diversion of low-risk youth from juvenile detention affected screening practices for detained youth. METHODS: In a 22-month cross sectional study of 2,532 detainees (age, 13-18 years), mental health and sexually transmitted infection (STI) screening data were compared before and after the beginning of diversion efforts through implementation of a Risk Assessment Instrument (RAI). RESULTS: Detention diversion resulted in a 30% census reduction. In a logistic regression, younger age (odds ratio [OR] = 1.10 for a 1 year increase; confidence interval [CI]: 1.03, 1.17), Hispanic versus white race/ethnicity (OR = .53; CI: .35, .82), and less severe crime (OR = .90 per 1 point; CI: .89, .91) predicted reduced likelihood of detention. Mental health and STI screening increased significantly after implementation of the RAI. Additionally, the rate of positive STI tests increased among detained males (9% pre-RAI to 14% after implementation of the RAI, p = .01). However, implementation of the RAI did not result in a significant increase in the number of positive mental health screens. CONCLUSIONS: Universal mental health and STI screening are increasingly common public health practices in detention centers. The results of this study indicate that juvenile justice diversion programming affects public health screening rates among detained youth in our population. Future study of the possible unintended consequences of criminal justice initiatives on public health outcomes is recommended. PMID- 22443841 TI - Testing three explanations of the emergence of weapon carrying in peer context: the roles of aggression, victimization, and the social network. AB - PURPOSE: To examine the relative contribution of weapon carrying of peers, aggression, and victimization to weapon carrying of male and female adolescents over time. METHODS: Data were derived from a population-based sample of male (N = 224) and female (N = 244) adolescents followed from grade 10 (M age = 15.5) to grade 11 (M age = 16.5). Peer networks were derived from best friend nominations. Self-reports were used to assess weapon carrying. Aggression and victimization were assessed using both self- and peer-reports. Use of dynamic social network modeling (SIENA) allowed prediction of weapon carrying in grade 11 as a function of weapon carrying of befriended peers, aggression, and victimization in grade 10, while selection processes and structural network effects (reciprocity and transitivity) were controlled for. RESULTS: Peer influence processes accounted for changes in weapon carrying over time. Self-reported victimization decreased weapon carrying 1 year later. Peer-reported victimization increased the likelihood of weapon carrying, particularly for highly aggressive adolescents. Boys were more likely to carry weapons than girls, but the processes associated with weapon carrying did not differ for boys and girls. CONCLUSIONS: These findings revealed that, in this population-based sample, weapon carrying of best friends, as well as aggression, contributed to the proliferation of weapons in friendship networks, suggesting processes of peer contagion as well as individual vulnerability to weapon carrying. PMID- 22443842 TI - Characteristics of African American adolescent females who perceive their current boyfriends have concurrent sexual partners. AB - PURPOSE: Perceived partner concurrency, reporting that a current sexual partner has other sexual partners, may pose sexual health risks to adolescents. We examined the contextual characteristics of African American female adolescents who reported their current boyfriend was having concurrent sexual relationships. METHODS: Participants were African American adolescent females (N = 511; mean age = 17.6) recruited from sexual health clinics. Before participating in an STD/HIV prevention trial, the participants completed audio computer-assisted self interviews with measures of perceived partner concurrency and individual- (e.g., depression, substance use), interpersonal- (e.g., social support, interpersonal stress), and community-level factors (i.e., neighborhood quality). RESULTS: Twenty-seven percent of participants reported their belief that their current boyfriend had concurrent sexual partners during their relationship. In a logistic regression analysis, participants endorsing perceived partner concurrency reported less relational power (adjusted odds ratio [AOR] = .94, 95% confidence interval [CI] = .89-.98, p < .01), decreased relationship commitment (AOR = .88, 95% CI = .80-.96, p < .01), elevated perceived interpersonal stress (AOR = 1.02, 95% CI = 1.003-1.04, p < .05), and previous STD diagnoses (AOR = 2.07, 95% CI = 1.31-3.28, p < .01; overall model: chi(2) = 67.25; p < .001). CONCLUSIONS: Results suggest that the efficacy of sexual risk reduction interventions may be improved by emphasizing the increased HIV/STD risks associated with having a boyfriend with concurrent sex partners. In addition, interventions may benefit from incorporating stress management training and addressing key relationship dynamics, particularly among adolescents with a history of STDs. PMID- 22443843 TI - Knowledge of medication abortion among adolescent medicine providers. AB - PURPOSE: Adolescents are at high risk for unintended pregnancy and abortion. The purpose of this study was to understand whether providers caring for adolescents have the knowledge to counsel accurately on medication abortion, a suitable option for many teenagers seeking to terminate a pregnancy. METHODS: Using an online questionnaire, a survey related to medication abortion was administered to U.S. providers in the Society for Adolescent Health and Medicine. We conducted chi(2) analyses to evaluate the knowledge of medication abortion by reported adolescent medicine fellowship training, and to compare responses to specific knowledge questions by medication abortion counseling. Furthermore, we examined the relationship between providers' self-assessed and actual knowledge using ANOVA. RESULTS: We surveyed 797 providers, with a 54% response rate. Almost 25% of respondents incorrectly believed that medication abortion was not very safe, 40% misidentified that it was < 95% effective, and 32% did not select the correct maximum recommended gestational age (7-9 weeks). Providers had difficulty identifying that serious complications of medication abortion are rare. Those who counseled on medication abortion had more accurate information in all knowledge categories, except for expected outcomes. Medication abortion knowledge did not differ by adolescent medicine fellowship completion. Only 32% of respondents had very good knowledge, and self-assessed knowledge minimally predicted actual knowledge (r(2) = .08). CONCLUSIONS: Knowledge regarding medication abortion safety, effectiveness, expected outcomes, and complications is suboptimal even among adolescent medicine fellowship trained physicians, and self-assessment poorly predicts actual knowledge. To ensure pregnant teenagers receive accurate counseling on all options, adolescent medicine providers need better education on medication abortion. PMID- 22443844 TI - Contraceptive paths of adolescent women undergoing an abortion in France. AB - PURPOSE: Although more than 30,000 teenagers had an induced abortion in France in 2007 (14.3% of all abortions), little is known about their abortion experience. We explore young women's decisions related to their abortion and the patterns of abortion care among teenagers in France, and draw particular attention to the contraceptive circumstances surrounding the abortion. METHODS: The data are drawn from the French National Survey of Abortion Patients conducted in 2007, comprising 1,525 women aged 13-19 years. RESULTS: A majority of French teens (82%) reported their pregnancy was unplanned and took on the responsibility of having an abortion: 45% made the decision alone, 46% shared the decision with their family or partner, and 9% reported the decision was made on their family's or partner's request alone. Sixty-nine percent of teenagers were eligible for both medical and surgical abortions, but only 43% thought they were given a choice of methods. Two-thirds of pregnancies were caused by contraceptive misuse or failure, mostly due to condom slippage or breakage (26%) or inconsistent pill use (20%). In 68% of cases, teenagers were prescribed a more effective method than the one they were using before, although only 11% received a prescription for a long-acting method. One in five teenagers reported not receiving a prescription for contraception. CONCLUSIONS: Our results reveal varying degrees of young women's autonomy in the decisions regarding their abortion. Although most teens switch to more effective methods of contraception after an abortion, only a minority receives a prescription for a long-acting method. PMID- 22443845 TI - The influence of socioeconomic status on cannabis use among French adolescents. AB - PURPOSE: To investigate the influence of the family socioeconomic status (F-SES) on various intensities and frequencies of cannabis use in late adolescence. DESIGN/SETTINGS/PARTICIPANTS: Data were obtained from a cross-sectional survey conducted in 2008, which was representative of French youth aged 17(n = 39,542). Outcomes were overall use (abstinence, lifetime use, 1-9, and 10+ uses in the past year) for all adolescents, and frequent use for those who smoked cannabis at least 10 times in the past year (<=9, 10-19, 20+ uses in the past month). Additionally, cannabis use disorders and heavy use (having smoked at least 4 joints last time) were studied among previous-year users. F-SES was the highest occupational category of both parents (in 7 categories, from managers/professionals [used as the reference category] to inactive/unemployed). Multinomial logistic regressions were computed controlling for gender; other substances use; parental separation; parental use of alcohol, tobacco, and cannabis; housing, being out of school, and sociability. FINDINGS: For overall use, we found a strong positive social gradient: the lower the F-SES or the higher the frequency of use, the lower the odds ratio (OR) (from .85 to .52 for 10+ uses in the past year among farmers). For frequent use, we found a strong negative gradient: the lower the F-SES category, the higher the OR (from 1.02 to 2.05 among inactive/unemployed), and likewise for cannabis use disorder and heavy use (OR = 1.85 and 2.03 among inactive/unemployed). CONCLUSIONS: Adolescents from affluent families are more prone to experimentation with cannabis and to use it at low levels but present lower levels of frequent, heavy, or problematic use than those from other SES categories. Mechanisms that hinder transition to intensive use should be investigated. PMID- 22443846 TI - Eating habits and total and abdominal fat in Spanish adolescents: influence of physical activity. The AVENA study. AB - OBJECTIVE: To evaluate the association between specific dietary habits and body fatness in Spanish adolescents, and to analyze the role of leisure-time physical activity (LTPA) in this association. METHODS: In this cross-sectional study, 1,978 adolescents (1,017 girls) aged 13.0-18.5 years from the AVENA (Alimentacion y Valoracion del Estado Nutricional en Adolescentes) study were included. Particular dietary habits (breakfast, mid-morning snack, lunch, afternoon snack, dinner, and nighttime snack, as well as time spent eating, number of meals, consumption of soft drinks, and ready-to-eat foods) and LTPA were self-reported and analyzed as dichotomic variables (yes/no). The sum of six skinfold thicknesses and waist circumference (WC) values were the main body fatness variables. RESULT: Skinfolds and WC values were lower in adolescents who reported consumption of mid-morning snack, afternoon snack, more than four meals per day, and an adequate speed of eating, independently of participation in LTPA. Moreover, a beneficial influence of breakfast consumption on skinfolds and WC values was observed in those adolescent boys who did not participate in LTPA (p for interactions = .044 and .040, respectively). CONCLUSIONS: In Spanish adolescents, certain healthy dietary habits (i.e., mid-morning snack, afternoon snack, > 4 meals per day, adequate eating speed) are associated with lower body fatness, independently of engaging in LTPA. In addition, among boys with non LTPA, those who skipped breakfast showed the highest body fatness values, indicating a beneficial influence of daily breakfast on body fat in this particular group. PMID- 22443847 TI - Patterns and correlates of parental and formal sexual and reproductive health communication for adolescent women in the United States, 2002-2008. AB - PURPOSE: To investigate patterns and correlates of sexual and reproductive health (SRH) communication among adolescent women in the United States between 2002 and 2008. METHODS: We used data with regard to adolescent women (aged 15-19 years) from the National Survey of Family Growth (between 2002 and 2006-2008, n = 2,326). Multivariate analyses focused on sociodemographic characteristics and SRH communication from parental and formal sources. RESULTS: Seventy-five percent of adolescent women had received parental communication on abstinence (60%), contraception (56%), sexually transmitted infections (53%), and condoms (29%); 9% received abstinence-only communication. Formal communication (92%) included abstinence (87%) and contraceptive (71%) information; 66% received both, whereas 21% received abstinence-only. Between 2002 and 2006-2008, parental (not formal) communication increased (7%, p < .001), including the abstinence communication (4%, p = .03). Age, sexual experience, education, mother's education, and poverty were positively associated with SRH communication. CONCLUSIONS: Between 2002 and 2008, receipt of parental SRH communication, especially abstinence, was increasingly common among United States adolescents. Strategies to promote comprehensive communication may improve adolescents' SRH outcomes. PMID- 22443848 TI - Benefits of universal intervention effects on a youth protective shield 10 years after baseline. AB - PURPOSE: An earlier randomized controlled study found that a universal, family focused preventive intervention produced protective shield effects-reduced adolescent exposures to illicit substance opportunities-among adolescents in grade 12. This study examined a follow-up assessment of the sample during young adulthood. METHODS: A randomized controlled trial evaluated the Iowa Strengthening Families Program that was implemented in 22 rural schools (N = 446 families) when the participants were in grade six. Measures included adolescent exposure to illicit substance use and young adult lifetime substance use (age 21; N = 331). Growth curve modeling examined indirect intervention effects through growth factors of adolescent exposure. RESULTS: Findings from this study confirm protective shield effects that mediate long-term reduction of illicit substance use (beta = -.14, p = .02, Relative Reduction Rate = 28.2%). CONCLUSIONS: The benefits of decreasing exposure to substance use during adolescence through universal interventions were supported, with positive effects extending into young adulthood. PMID- 22443849 TI - Impact of victimization on risk of suicide among lesbian, gay, and bisexual high school students in San Francisco. AB - PURPOSE: This study investigated the association between sexual orientation, victimization, and suicide risk-related outcomes among youth attending public high schools in San Francisco. METHODS: Data from the 2009 Youth Risk Behavior Survey were analyzed using bivariate and logistic regression methods for complex samples to examine the relationship between sexual orientation, victimization, and three suicide risk-related outcomes (sadness/depression, suicide planning, and attempting suicide) while controlling for demographics and substance use. RESULTS: Lesbian, gay, or bisexual (LGB) youth reported significantly higher rates of substance use, victimization, and suicide risk-related outcomes than heterosexual youth. However, in the controlled regression models, victimization was a significant predictor of sadness/depression and suicide attempts, regardless of sexual orientation. There was a significant interaction effect between sexual orientation and victimization on suicide planning, with heterosexual youth more affected than LGB youth. CONCLUSIONS: Results underscore the deleterious effect of victimization on suicide risk-related outcomes, regardless of sexual orientation. As LGB youth continue to report higher rates of victimization, effective violence prevention approaches must focus on reducing violence among youth, specifically LGB youth. Additional research should focus on identification of other factors that may help further explain elevated suicide risk among LGB youth. PMID- 22443850 TI - Follow-up analysis of adolescents partially vaccinated against human papillomavirus. AB - PURPOSE: To evaluate factors associated with human papillomavirus vaccination among a cohort of female adolescents previously identified as receiving only one or two doses of vaccine. METHODS: This was a 15-month follow-up analysis of a previously identified cohort of 9-18-year-old female adolescents seen in primary clinics within a university-based health system. Vaccine receipt and associated factors were identified by review of administrative records. RESULTS: Among the 1,714 partially vaccinated female adolescents, 53% eventually completed the vaccination series. There was a wide range of dosing intervals ranging from 31 to 840 days between first and second doses and from 85 to 666 days between second and third doses. Race and insurance type were associated with lower rates of series completion, but not with receiving second doses. CONCLUSIONS: Approximately half of the partially vaccinated girls in our cohort eventually completed the series, albeit often over a longer than recommended interval. There were important disparities in human papillomavirus vaccination. PMID- 22443851 TI - The male genital examination: a position paper of the Society for Adolescent Health and Medicine. AB - The male genital examination is a simple and quick clinical assessment and is important for screening and diagnostic purposes beyond the need to screen for testicular cancer. Despite the lack of evidence supporting screening for testicular cancer, the genital examination should be included as part of a male's routine physical examination, as well as when a male patient presents with genital complaints. PMID- 22443853 TI - Patients with CDH23 mutations and the 1555A>G mitochondrial mutation are good candidates for electric acoustic stimulation (EAS). AB - CONCLUSIONS: CDH23 mutations and the 1555A>G mitochondrial mutation were identified among our series of electric acoustic stimulation (EAS) patients, confirming that these genes were important in hearing loss with involvement of high frequency. Successful hearing preservation as well as good outcomes from EAS indicated that patients with this combination of mutations are good candidates for EAS. OBJECTIVES: Screening for gene mutations that possibly cause hearing loss involving high frequency was performed to identify the responsible genes in patients with EAS. In addition to a review of the genetic background of the patients with residual hearing loss, the benefit of EAS for patients with particular gene mutations was evaluated. METHODS: Eighteen patients (15 late onset, 3 early-onset) with residual hearing who had received EAS were included in this study. Genetic analysis was performed to identify GJB2, CDH23, SLC26A4, and the 1555 mitochondrial mutations. RESULTS: Three early-onset patients had CDH23 mutations. One late-onset patient had the 1555 A>G mitochondrial mutation. PMID- 22443854 TI - Efficacy of different routes of administration for Coenzyme Q10 formulation in noise-induced hearing loss: systemic versus transtympanic modality. AB - CONCLUSION: The effectiveness of a coenzyme Q10 formulation, Q-ter, given via transtympanic injection is interesting for the future application of this minimally invasive procedure in the treatment of reactive oxygen species (ROS) induced hearing loss. OBJECTIVE: We focused on antioxidant therapy in noise induced hearing loss (NIHL). Our study was designed to evaluate the effectiveness of Q-ter for different schedules of drug administration to establish the best modality for treatment. METHODS: Rats were exposed to acoustic trauma (10 kHz at 120 dB for 60 min) and received Q-ter according to two modalities: systemic (Q ter 100 mg/kg for 4 days 1 h before and 3 days post noise exposure) and transtympanic (Q-ter 20 and 40% concentration 1 h before noise exposure). Auditory brainstem response (ABR), immunohistochemical and morphological studies were performed. RESULTS: Q-ter administration significantly decreased NIHL at day 21 from noise exposure. The improvement of auditory function by Q-ter was paralleled by a significant reduction in oxidative stress. The transtympanic and systemic routes of drug administration showed a similar degree of protection. PMID- 22443855 TI - Cochlear implantation in children with congenital cytomegalovirus infection accompanied by psycho-neurological disorders. AB - CONCLUSION: Cochlear implantation was effective for deaf children with congenital cytomegalovirus (CMV) infection, but their cochlear implant (CI) outcomes were often impaired, depending on the types of CMV-associated psycho-neurological disorders. Evaluation of cognitive development and autistic tendency of implantees might be useful to predict their CI outcomes. OBJECTIVES: To reveal the influence of CMV-associated psycho-neurological disorders on CI outcomes. METHODS: This was a retrospective evaluation of 11 implantees with congenital CMV infection (CMV-CIs) and 14 implantees with autosomal recessive hearing loss (genetic-CIs). RESULTS: Nine of 11 CMV-CIs suffered from psycho-neurological disorders; one from attention deficit hyperactivity disorder, two from pervasive developmental disorder, and six from mental retardation. Aided hearing thresholds with CIs in the two groups did not differ, but two autistic and two mentally retarded CMV-CIs showed significantly low scores in speech discrimination tests. Language-Social (L-S) developmental quotients (DQs) evaluated by the Kyoto Scale of Psychological development were improved after the implantation in both groups, but the postoperative increase of L-S DQs was significantly smaller in the CMV CIs than that of genetic-CIs. Interestingly, the postoperative L-S and Cognitive Adaptive (C-A) DQs showed statistically significant correlation in all cases except for two autistic CMV-CIs whose L-S DQs were much lower than those expected from their C-A DQs. PMID- 22443856 TI - Collagen vitrigel scaffold for regenerative medicine of the trachea: experimental study and quantitative evaluation. AB - CONCLUSION: Our technique for tracheal regeneration using a collagen vitrigel scaffold affords a feasible approach for accelerating epithelial regeneration on the intraluminal surface of the host tracheal defect. OBJECTIVES: The purpose of the study was to quantitatively evaluate the effectiveness of a collagen vitrigel scaffold for the regeneration of the tracheal epithelium. METHODS: The collagen vitrigel scaffold was developed by conjugating a collagen vitrigel membrane to a collagen sponge to promote both epithelial cell growth and mesenchymal cell infiltration. The collagen vitrigel scaffold was implanted into tracheal defects in rats as the vitrigel model, and a conventional collagen sponge was implanted as a control model. The structure of the regenerated tissue was observed and thickness of the epithelium was quantitatively evaluated by histological examination. RESULTS: Histological findings showed the surface of the collagen vitrigel scaffold to be flat in comparison with that of the conventional collagen sponge. At 7, 14, and 28 days post-implantation, the average thickness of the regenerated epithelial layer in the vitrigel model group was greater than that in the control group. PMID- 22443857 TI - Color picture drawings without form and eye movements: a case report of visual form agnosia in a girl. AB - The case of an 8-year-old girl who manifested cortical blindness and whose color drawings of faces and objects were without outlines is reported. Her birth was uneventful. When she was 10 months old, she fell down to the floor from a chair, resulting in a subarachnoidal hemorrhage. A repeat brain MRI revealed localized lesions in the visual cortices in the right and left hemispheres. As she grew older she was found to have visual imperceptions. She was found to have difficulties in learning visually the names of objects with form and letters, and in recognizing faces of her family. However, she was able to discriminate well the colors of faces and objects and learn easily the names of the objects with form by touching. She seemed to utilize subcortical vision for seeing colors of faces and objects. PMID- 22443858 TI - Eating in response to hunger and satiety signals is related to BMI in a nationwide sample of 1601 mid-age New Zealand women. AB - OBJECTIVE: To examine the association between eating in response to hunger and satiety signals (intuitive eating) and BMI. A second objective was to determine whether the hypothesized higher BMI in less intuitive eaters could be explained by the intake of specific foods, speed of eating or binge eating. DESIGN: Cross sectional survey. Participants were randomly selected from a nationally representative sampling frame. Eating in response to hunger and satiety signals (termed 'intuitive eating'), self-reported height and weight, frequency of binge eating, speed of eating and usual intakes of fruits, vegetables and selected high fat and/or high-sugar foods were measured. SETTING: Nationwide study, New Zealand. SUBJECTS: Women (n 2500) aged 40-50 years randomly selected from New Zealand electoral rolls, including Maori rolls (66 % response rate; n 1601). RESULTS: Intuitive Eating Scale (IES) scores were significantly associated with BMI in an inverse direction, after adjusting for potential confounding variables. When controlling for confounding variables, as well as potential mediators, the inverse association between intuitive eating (potential range of IES score: 21 105) and BMI was only slightly attenuated and remained statistically significant (5.1 % decrease in BMI for every 10-unit increase in intuitive eating; 95 % CI 4.2, 6.1 %; P < 0.001). The relationship between intuitive eating and BMI was partially mediated by frequency of binge eating. CONCLUSIONS: Eating in response to hunger and satiety signals is strongly associated with lower BMI in mid-age women. The direction of causality needs to be investigated in longitudinal studies and randomized controlled trials. PMID- 22443859 TI - Theoretical study of Raman spectra of methanol in aqueous solutions: non coincident effect of the CO stretch. AB - Raman spectra of the CO stretch for liquid methanol and its aqueous solutions were simulated using the combined electronic structure and molecular dynamics simulation method. The instantaneous vibrational frequencies were obtained from an empirical mapping to the electrostatic potentials, while vibrational couplings between different molecules were calculated using the transition dipole coupling model. It is found that noncoincident effects (NCEs) at high concentrations are dominated by the intermolecular couplings of CO stretch and decrease monotonically as the methanol concentration decreases. This behavior is explained as the effect of reduced methanol-methanol hydrogen bonding with the addition of water. A non-monotonic change of the NCEs defined by the peak position of the CO stretch as a function of methanol mole fraction is found, which is ascribed to band asymmetry caused by reorientational dynamics. PMID- 22443860 TI - Effects of cognitive impairment on substance abuse treatment attendance: predictive validation of a brief cognitive screening measure. AB - BACKGROUND AND OBJECTIVES: Neuropsychological impairment among patients with substance use disorders (SUDs) contributes to poorer treatment processes and outcomes. However, neuropsychological assessment is typically not an aspect of patient evaluation in SUD treatment programs because it is prohibitively time and resource consuming. In a previous study, we examined the concurrent validity, classification accuracy, and clinical utility of a brief screening measure, the Montreal Cognitive Assessment (MoCA), in identifying cognitive impairment among SUD patients. To provide further evidence of criterion-related validity, MoCA classification should optimally predict a clinically relevant behavior or outcome among SUD patients. The purpose of this study was to examine the validity of the MoCA in predicting treatment attendance. METHODS: We compared previously collected clinical assessment data on 60 SUD patients receiving treatment in a program of short duration and high intensity to attendance data obtained via medical chart review. RESULTS: Though the proportion of therapy sessions attended did not differ between groups, cognitively impaired subjects were significantly less likely than unimpaired subjects to attend all of their group therapy sessions. CONCLUSION: These results complement our previous findings by providing further evidence of criterion-related validity of the MoCA in predicting a clinically relevant behavior (i.e., perfect attendance) among SUD patients. SCIENTIFIC SIGNIFICANCE: The capacity of the MoCA to predict a clinically relevant behavior provides support for its validity as a brief cognitive screening measure. PMID- 22443861 TI - R-SNARE ykt6 resides in membrane-associated protease-resistant protein particles and modulates cell cycle progression when over-expressed. AB - BACKGROUND INFORMATION: The arginine-type soluble N-ethylmaleimide-sensitive factor attachment protein receptor (R-SNARE) ykt6 possesses several atypical properties including selective high expression in neurons, a lipidated C terminus, localization to punctae that do not correspond with known endomembrane markers, a potent ability to protect the secretory pathway from alpha-synuclein over-expression and specific up-regulation in tumors. We have followed up on several of these features that together suggest nontraditional SNARE structures and functions. RESULTS: A significant portion of ykt6 in PC12 cells was found in a protease-resistant state suggestive of a large complex or aggregate. Other endoplasmic reticulum/Golgi SNAREs were not protease resistant, demonstrating that SNARE complexes per se did not cause protease resistance. Mutagenesis indicated that lipidation of the ykt6 C-terminus was also not involved, implicating its longin domain in particle formation. Immunogold electron microscopy revealed ykt6 labeling of ~100 nm electron densities associated with diverse membranes. Density gradient analysis of the protease-resistant structures confirmed their tight association with membranes. Since excess ykt6 has been correlated with tumorigenesis, we tested whether ykt6 over-expression in normal rat kidney cells that normally express little ykt6 affected the cell cycle. Ykt6 over-expression was found to result in altered cell division cycles as evidenced by significantly smaller cells, a higher mitotic index and increased DNA synthesis. Mutagenesis studies dis-correlated SNARE function with the cell cycle effects; instead, the cell cycle effects correlated better with ykt6 properties related to the longin domain or particle formation. CONCLUSIONS: The ykt6 particles/aggregates may represent ykt6 engaged in a non-SNARE function(s) or else nonfunctional, stored and/or excess ykt6. Whether the particulate ykt6 structures represent a means of buffering the apparent proliferative activity or are in fact mechanistically related to this activity will be of future interest in neuroscience and cancer biology. PMID- 22443862 TI - The mediterranean dietary pattern and breast cancer risk in Greek-Cypriot women: a case-control study. AB - BACKGROUND: Diet has long been suspected to impact on breast cancer risk. In this study we evaluated whether the degree of adherence to a Mediterranean diet pattern modifies breast cancer risk amongst Greek-Cypriot women. METHODS: Subjects included 935 cases and 817 controls, all participating in the MASTOS case-control study in Cyprus. The study was approved by the Cyprus National Bioethics Committee. Information on dietary intakes was collected using an interviewer administered 32-item Food Frequency Questionnaire. Information on demographic, anthropometric, lifestyle, and other confounding factors was also collected. Adherence to the Mediterranean Diet pattern was assessed using two a priory defined diet scores. In addition, dietary patterns specific to our population were derived using Principal Component Analysis (PCA). Logistic regression models were used to assess the association between the dietary patters and breast cancer risk. RESULTS: There was no association with breast cancer risk for either score, however, higher consumptions of vegetables, fish and olive oil, were independently associated with decreased risk. In addition, the PCA derived component which included vegetables, fruit, fish and legumes was shown to significantly reduce risk of breast cancer (ORs across quartiles of increasing levels of consumption: 0.89 95%CI: 0.65-1.22, 0.64 95%CI: 0.47-0.88, 0.67 95%CI: 0.49-0.92, P trend < 0.0001), even after adjustment for relevant confounders. CONCLUSIONS: Our results suggest that adherence to a diet pattern rich in vegetables, fish, legumes and olive oil may favorably influence the risk of breast cancer. This study is the first investigation of dietary effects on breast cancer risk in Cyprus, a country whose population has traditionally adhered to the Mediterranean diet. PMID- 22443863 TI - Prolonged hybridization with a cRNA probe improves the signal to noise ratio for in-tube in situ hybridization for quantification of mRNA after fluorescence activated cell sorting. AB - We developed an in-tube in situ hybridization method for mRNA quantification after fluorescence-activated cell sorting (FACS-mQ). A specific RNA in a particular cell type is stained with a cRNA probe and a fluorescent dye, which allows the stained cells to be selected by FACS without excessive RNA degradation. Our previous protocol required 4 h for hybridization with a cRNA probe, which might not produce enough fluorescence signal for sorting genes with low expressions. We determined the effect of prolonged hybridization for in-tube in situ hybridization on quantitative measurement of intracellular RNAs. During the hybridization step, the quantity of ACTB mRNA decreased gradually until 4 h, but remained constant from 4 to 16 h below 63.6 degrees C. For flow cytometry, cells hybridization with cRNA probes for TG mRNA at 60 degrees C for 16 h showed both increased signal and decreased background fluorescence compared to those hybridized for 4 h. These results indicate that when performing in-tube in situ hybridization, hybridization temperature can be raised to 63.6 degrees C and the hybridization step can be extended up to 16 h without excessive intracellular RNA degradation. PMID- 22443864 TI - Total arch replacement with stented elephant trunk technique for acute type B aortic dissection involving the aortic arch. AB - BACKGROUND: Optimal management of patients with acute type aortic dissection is not clear. The clinical experience with total arch replacement combined with stented elephant trunk technique in the treatment of acute type B aortic dissection involving the aortic arch was analyzed. METHODS: From January 2006 to April 2011, 24 consecutive patients with acute type B aortic dissection involving the aortic arch underwent total aortic arch replacement with stented elephant trunk implantation. Concomitant procedures included the Bentall procedure in 3 patients, David procedure in 1 patient, and ascending aortic replacement in 7 patients. RESULTS: The times of cardiopulmonary bypass and selective cerebral perfusion averaged 168+/-41 and 21+/-4 minutes, respectively. One patient died of multiorgan failure 3 days after surgery. Complications occurred in 3 patients (3 of 24; 12.5%), including hoarseness and mediastinal bleeding requiring reoperation, each in 1 patient. One patient experienced transient consciousness dysfunction. The in-hospital mortality was 4.1% (1 of 24). No paraplegia occurred postoperatively. Follow-up was available in 22 patients (22 of 23; 95.7%). During the follow-up, 1 patient died of massive gastrointestinal bleeding 2 months after surgery. Type II endoleak occurred in 1 patient. One patient underwent thoracoabdominal aortic replacement 14 months after surgery. The complete thrombosis ratio of the false lumen was 86.4% (19 of 22) 6 months after surgery. The 5-year survival was 91.7%. CONCLUSIONS: Total arch replacement combined with stented elephant trunk technique was safe and feasible for acute type B aortic dissection involving the aortic arch. A low rate of morbidity and mortality and a satisfactory 5-year survival rate were achieved, as well as improved thrombosis of the false lumen. PMID- 22443865 TI - Frequency of reoperations in patients with Marfan syndrome. AB - BACKGROUND: We undertook a retrospective study of the pattern of reoperations in surgical patients with Marfan disease. METHODS: Between 1985 and 2008, 83 Marfan patients (60 males, 23 females) underwent 155 aortic operations in our institution. Twenty-eight patients had acute dissection (22 type A, 6 type B), and two had aortic rupture. Mean age at initial operation was 32+/-13 years. Operations included valve-sparing or Bentall aortic root repair, and ascending aorta, arch, descending thoracic, thoracoabdominal aorta, and infrarenal aortic replacement. Sixty-one patients whose initial operation was elective (Group I) were compared with 22 patients with initial emergency surgery (Group II). RESULTS: Overall, 81/83 patients ultimately underwent root/ascending repair: 64% initially and 36% at reoperation. Operative mortality in Group I was 1.6% for both initial operations and reoperations vs 9.0% and 0% in Group II. Significant differences between Group I and Group II patients included: total reoperations (1 vs 3, p=0.05); arch operations (0 vs 1, p=0.003); descending thoracic aortic operations (0 vs 0.5, p=0.003); and total aortic segments replaced (1.6+/-1.0 vs 2.4+/-1.1, p=0.001). Survival at 5 and 10 years did not differ between Group I and II patients (87% and 71% vs 82% and 56%, p=0.19). CONCLUSIONS: Although reoperation occurs in about half of surgical Marfan patients, reoperative mortality is low. Patients with initial elective procedures fare better than those with initial emergency surgery: they have fewer subsequent operations, fewer aortic segments replaced, and trend toward improved survival. Elective root replacement should be seriously considered in any Marfan patient with significant root dilatation. PMID- 22443866 TI - Limitations of carbon footprint as indicator of environmental sustainability. AB - Greenhouse gas accountings, commonly referred to with the popular term carbon footprints (CFP), are a widely used metric of climate change impacts and the main focus of many sustainability policies among companies and authorities. However, environmental sustainability concerns not just climate change but also other environmental problems, like chemical pollution or depletion of natural resources, and the focus on CFP brings the risk of problem shifting when reductions in CFP are obtained at the expense of increase in other environmental impacts. But how real is this risk? Here, we model and analyze the life cycle impacts from about 4000 different products, technologies, and services taken from several sectors, including energy generation, transportation, material production, infrastructure, and waste management. By investigating the correlations between the CFP and 13 other impact scores, we show that some environmental impacts, notably those related to emissions of toxic substances, often do not covary with climate change impacts. In such situations, carbon footprint is a poor representative of the environmental burden of products, and environmental management focused exclusively on CFP runs the risk of inadvertently shifting the problem to other environmental impacts when products are optimized to become more "green". These findings call for the use of more broadly encompassing tools to assess and manage environmental sustainability. PMID- 22443867 TI - Pressure tuning of the optical properties of GaAs nanowires. AB - The tuning of the optical and electronic properties of semiconductor nanowires can be achieved by crystal phase engineering. Zinc-blende and diamond semiconductors exhibit pressure-induced structural transitions as well as a strong pressure dependence of the band gaps. When reduced to nanoscale dimensions, new phenomena may appear. We demonstrate the tuning of the optical properties of GaAs nanowires and the induction of a phase transition by applying an external pressure. The dependence of the E(0) gap on the applied pressure was measured, and a direct-to-indirect transition was found. Resonant Raman scattering was obtained by pressure tuning of the E(0) and the E(0) + Delta(SO) gaps with respect to the excitation energy. The resonances of the longitudinal optical modes LO and 2LO indicate the presence of electron-phonon Frohlich interactions. These measurements show for the first time a variation of ionicity in GaAs when in nanowire form. Furthermore, the dependence of the lattice constant on applied pressure was estimated. Finally, we found a clear indication of a structural transition above 16 GPa. PMID- 22443868 TI - Genomic breeding value prediction: methods and procedures. AB - Animal breeding faces one of the most significant changes of the past decades - the implementation of genomic selection. Genomic selection uses dense marker maps to predict the breeding value of animals with reported accuracies that are up to 0.31 higher than those of pedigree indexes, without the need to phenotype the animals themselves, or close relatives thereof. The basic principle is that because of the high marker density, each quantitative trait loci (QTL) is in linkage disequilibrium (LD) with at least one nearby marker. The process involves putting a reference population together of animals with known phenotypes and genotypes to estimate the marker effects. Marker effects have been estimated with several different methods that generally aim at reducing the dimensions of the marker data. Nearly all reported models only included additive effects. Once the marker effects are estimated, breeding values of young selection candidates can be predicted with reported accuracies up to 0.85. Although results from simulation studies suggest that different models may yield more accurate genomic estimated breeding values (GEBVs) for different traits, depending on the underlying QTL distribution of the trait, there is so far only little evidence from studies based on real data to support this. The accuracy of genomic predictions strongly depends on characteristics of the reference populations, such as number of animals, number of markers, and the heritability of the recorded phenotype. Another important factor is the relationship between animals in the reference population and the evaluated animals. The breakup of LD between markers and QTL across generations advocates frequent re-estimation of marker effects to maintain the accuracy of GEBVs at an acceptable level. Therefore, at low frequencies of re-estimating marker effects, it becomes more important that the model that estimates the marker effects capitalizes on LD information that is persistent across generations. PMID- 22443869 TI - Integrating biological information into the statistical analysis and design of microarray experiments. AB - Microarray technology is a powerful tool for animal functional genomics studies, with applications spanning from gene identification and mapping, to function and control of gene expression. Microarray assays, however, are complex and costly, and hence generally performed with relatively small number of animals. Nevertheless, they generate data sets of unprecedented complexity and dimensionality. Therefore, such trials require careful planning and experimental design, in addition to tailored statistical and computational tools for their appropriate data mining. In this review, we discuss experimental design and data analysis strategies, which incorporate prior genomic and biological knowledge, such as genotypes and gene function and pathway membership. We focus the discussion on the design of genetical genomics studies, and on significance testing for detection of differential expression. It is shown that the use of prior biological information can improve the efficiency of microarray experiments. PMID- 22443870 TI - Genetic analysis of return over feed in Canadian Holsteins. AB - The objective of this study was to investigate genetic merit of return over feed (ROF), which is a herd profit index defined by CanWest Dairy Herd Improvement as a difference between milk income and feed cost. A multiple-trait (MT) model and random regression model (RRM) were used. The traits analyzed in MT were rearing cost and ROF of the first three lactations. In RRM, a cumulative ROF was fitted as function of age and rearing cost was treated as a correlated trait. Variance components were estimated within a Bayesian framework by Gibbs sampling using a subsample of data. Breeding values were then estimated for 3 041 078 animals using records of 1 951 893 cows. Estimates of heritability for rearing cost from MT and RRM were 0.23 and 0.22, respectively. ROF per lactation and cumulative ROF were negatively correlated with rearing cost. Estimates of heritability of ROF through the first, second and third lactation from MT were 0.27, 0.10 and 0.08, respectively. Estimates of heritability of ROF from RRM increased with age and ranged from 0.08 through 0.31. Estimated breeding values (EBVs) for ROF from MT and RRM were moderately correlated with official EBV for production traits and the Canadian selection index (Lifetime Profit Index). Herd life EBV had -0.07 and 0.19 correlations with EBVs for ROF from MT and RRM, respectively. From both MT and RRM, small favorable correlations were reported between EBVs for ROF and for bone quality and angularity, whereas low unfavorable correlations were reported with EBV for udder depth, front end and chest width. Majority of correlations between EBVs for ROF and for reproduction traits were near 0, with the exception of EBV for gestation length, calf size and calving ease, where small favorable correlations were reported. The ROF is a good indicator of cow profitability despite the fact that it is a simplified profit index that does not account for animal-specific health and reproductive cost. However, because ROF does not account for differences in heritabilities between components of profit, ROF is not recommended to be used for direct selection for profit. PMID- 22443871 TI - Genetic and phenotypic parameters of age at first mating, litter size and animal size in Finnish mink. AB - Mink skin size in Finland, as well as in other countries, has increased considerably during last decade. However, there are signs that selection for large body size has a negative impact on litter size (LS) and also for survival of kits. Therefore, it is important to study the genetic relationships among fertility traits and animal size (AS). The variance components for age at first mating (AFM) and first three parity LS and AS were estimated using multi-trait restricted maximum likelihood animal model. Data included 82 945 animals born during 1990 to 2004, originating from nine farms. Heritability estimates for the fertility traits were from 0.10 to 0.15. For AS, heritability was estimated to be 0.18. Genetic correlation between AS and all fertility traits was estimated to be negative (varying from -0.004 to -0.38). It is important to recognize this antagonistic relationship and include the reproductive traits into breeding goals to maintain good reproductive performance when selecting for increased body size and hence larger pelts in fur animals. Genetic correlations between the traits should be accounted in breeding value evaluations by using a multi-trait model. Including AFM into breeding value estimation would also improve the accuracy of breeding value estimation for fertility, because females missing the first LS still have record on AFM. PMID- 22443872 TI - Genetic association between body energy measured throughout lactation and fertility in dairy cattle. AB - The objective of this study was to quantify the genetic association of body energy assessed throughout lactation with a cow's fertility. Nine direct and indirect body energy traits were defined at different stages of lactation. Four were daily records of energy balance, energy content, cumulative effective energy (CEE) and body condition score (BCS) calculated between lactation days 4 and 311. The other five traits included duration of negative energy balance (DNEB), rate of recovery during DNEB (RNEB), sum of negative energy balance (SNEB), nadir of energy content (NEC) and number of days from calving to NEC. Of these traits, energy balance, DNEB, RNEB and SNEB were primarily based on individual cow feed intake and milk yield, and considered direct measures of body energy. The other traits were calculated from body lipid and protein changes, predicted from BCS and live weight profiles, and were considered indirect measures of body energy. Fertility was defined by number of days between calving and commencement of luteal activity (DLA), first observed oestrus (DH) and conception (DC), and number of services per conception. A total of 957 cows in their first four lactations were considered in the study. Genetic models fitted cubic splines to define longitudinal traits (energy balance, energy content, CEE and BCS) and calculate heritability and genetic correlation with fertility. Daily heritability estimate ranges were 0.10 to 0.34, 0.35 to 0.61, 0.32 to 0.53 and 0.24 to 0.56 for energy balance, energy content, CEE and BCS, respectively, and, in most cases, tended to increase towards the middle of lactation and remain relatively stable thereafter. Of the other body energy traits, heritability of NEC (0.44) was the most notable. Statistically significant (P < 0.05) genetic correlations of DH with daily energy balance, energy content, CEE and BCS ranged from -0.16 to -0.28, -0.35 to -0.48, -0.16 to -0.26 and -0.37 to -0.44, respectively. For DC, respective estimates were -0.28 to -0.64, -0.37 to -0.60, -0.30 to -0.48 and 0.29 to -0.53. For DLA, they ranged from -0.47 to -0.56 with energy content and from -0.50 to -0.74 with BCS. Of special interest was the genetic correlation of NEC with DH (-0.54) and DC (-0.48). Results suggest that indirect measures of body energy have the strongest genetic association with cow fertility. NEC and early lactation (circa day 50) BCS and energy content are the most useful traits for selection in terms of the correlated improvement in a cow's capacity to resume her reproductive activity post partum. PMID- 22443873 TI - Zinc availability and digestive zinc solubility in piglets and broilers fed diets varying in their phytate contents, phytase activity and supplemented zinc source. AB - The study was conducted to evaluate the effects of dietary zinc addition (0 or 15 mg/kg of Zn as inorganic or organic zinc) to three maize-soybean meal basal diets varying in their native Zn, phytic P contents and phytase activity (expressed in kg of feed: P- with 25 mg Zn and 1.3 g phytic P, P+ with 38 mg Zn and 2.3 g phytic P or P+/ENZ being P+ including 500 units (FTU) of microbial phytase per kg) in two monogastric species (piglets, broilers). Measured parameters were growth performance, zinc status (plasma, and bone zinc) and soluble zinc in digesta (stomach, gizzard and intestine). The nine experimental diets were fed for 20 days either to weaned piglets (six replicates per treatment) or to 1-day old broilers (10 replicates per treatment). Animal performance was not affected by dietary treatments (P > 0.05) except that all P- diets improved body weight gain and feed conversion ratio in piglets (P < 0.05). Piglets fed P- diets had a better Zn status than those fed P+ diets (P < 0.05). In both species, Zn status was improved with supplemental Zn (P < 0.05), irrespective of Zn source. Phytase supplementation improved piglet Zn status to a higher extent than adding dietary Zn, whereas in broilers, phytase was less efficient than supplemental Zn. Digestive Zn concentrations reflected the quantity of ingested Zn. Soluble Zn (mg/kg dry matter) and Zn solubility (% of total Zn content) were highest in gizzard contents, which also presented lower pH values than stomach or intestines. The intestinal Zn solubility was higher in piglet fed organic Zn than those fed inorganic Zn (P < 0.01). Phytase increased soluble Zn in piglet stomach (P < 0.001) and intestine (P = 0.1), but not in broiler gizzard and intestinal contents. These results demonstrate (i) that dietary zinc was used more efficiently by broilers than by piglets, most probably due to the lower gizzard pH and its related higher zinc solubility; (ii) that zinc supplementation, irrespective of zinc source, was successful in improving animal's zinc status; and (iii) suggest that supplemented Zn availability was independent from the diet formulation. Finally, the present data confirm that phytase was efficient in increasing digestive soluble Zn and improving zinc status in piglets. However, the magnitude of these effects was lower in broilers probably due to the naturally higher Zn availability in poultry than in swine. PMID- 22443874 TI - Rumen chemical and bacterial changes during stepwise adaptation to a high concentrate diet in goats. AB - The correlation between rumen chemical and bacterial changes was investigated during a four periodical stepwise adaptation to a high-concentrate diet (concentrate level at 0%, 30%, 50% and 70% for diet I to IV, respectively) in goats. The results showed that ruminal pH decreased from 6.7 to 5.5 after switching from diet I to II, and was maintained at about 5.5 on diet III. Denaturing gradient gel electrophoresis results showed that the rumen bacterial community was relatively stable during the initial three feeding periods, except for the appearance of three bands when diet changed from I to II, suggesting that an appropriate concentrate level can promote the proliferation of some bacteria. After 12 days of feeding diet III, total volatile fatty acid (VFA) concentration and butyrate proportion decreased. At days 2 and 3 of feeding diet IV, ruminal pH declined sharply to 5.3 and 4.7, respectively, and total VFA concentration decreased further while lactic acid concentration increased markedly, suggesting a relation between lactic acid accumulation and ruminal pH decline. At the same time, many bacteria disappeared, including most fibrolytic-related bacteria while Streptococcus bovis and Prevotella-like species dominated. Interestingly, Succinivibrio dextrinosolvens-like species maintained throughout the experiment, suggesting its tolerance to low pH. In conclusion, rumen bacterial community was relatively stable feeding 0% to 50% concentrate diets, and it was observed that appropriate concentrate levels in the diet could increase the diversity of rumen bacteria. However, concentrate-rich diets caused lactic acid accumulation and low ruminal pH that caused the disappearance of most fibrolytic-related bacteria sensitive to low pH while S. bovis and genus Prevotella persisted. PMID- 22443875 TI - Effects of cloned-cattle meat on reproductive physiology in rats. AB - The influence of the cloned-cattle meat diets upon reproduction in mammals was rarely studied. This study was performed to analyze the effects of the diets containing cloned-cattle (Korean native beef, Hanwoo) meat on the reproductive physiology in rats. The male and female rats were fed with the diets containing 5% or 10% of normal- (N-5 or N-10) or cloned- (C-5 or C-10) cattle meat during test periods. The rats fed with commercial pellets were used as control. Lower food consumption in normal- and cloned-cattle meat diet groups is detected in both male and female rats compared with that of control (P < 0.05, 0.01 and 0.001). No signs of cloned-cattle meat diets on male reproductive parameters are found in all groups, except for lower sperm deformity in C-5 group (P < 0.05) and higher testosterone concentration in C-10 group (P < 0.05), respectively. There are no significant test substance-related differences of Caesarean section and delivery in dams and external examination and physiological development test in neonate compared with control and normal meat groups. Based on these results, it can be postulated that there are no obvious negative effects on the reproductive physiology in rats fed with cloned-cattle meat diets compared to their comparators. PMID- 22443876 TI - Functional and association studies on the pig HMGCR gene, a cholesterol synthesis limiting enzyme. AB - The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the rate-limiting enzyme in the biosynthesis of cholesterol. We have studied the role of the HMGCR gene in pig lipid metabolism by means of expression and structural analysis. We describe here the complete coding region of this gene in pigs and report two synonymous single nucleotide polymorphisms in the coding region. We have, additionally, studied the association of one of these polymorphisms (HMGCR:c.807A>C) with several lipid deposition- and cholesterol-related traits in a half-sib population generated from a commercial Duroc line, showing in some families a positive relationship of HMGCR:c.807A allele with serum low-density lipoprotein (LDL) bound cholesterol and triglyceride levels, and also with intramuscular fat (IMF) content of gluteus medius muscle. We have also assessed the expression levels in muscle and in liver from 68 Duroc individuals corresponding to the most extreme animals for the analysed traits. Liver HMGCR expression correlated negatively with the serum high-density lipoprotein (HDL) levels, carcass lean percentage and stearic acid content, while muscle expression correlated also negatively with the carcass lean percentage, stearic and linoleic acids content, but showed a positive correlation with the serum lipid cholesterol (HDL, LDL and total cholesterol), IMF and muscle oleic and palmitic fatty acid content. With this information, we have performed an association analysis of expression data with lipid metabolism phenotypic levels and the HMGCR genotype. The results indicate that HMGCR expression levels in muscle are different in the two groups of pigs with extreme values for fat deposition and total cholesterol levels, and also between animals with the different HMGCR genotypes. PMID- 22443877 TI - Predicting beef carcass meat, fat and bone proportions from carcass conformation and fat scores or hindquarter dissection. AB - Equations for predicting the meat, fat and bone proportions in beef carcasses using the European Union carcass classification scores for conformation and fatness, and hindquarter composition were developed and their accuracy was tested using data from 662 cattle. The animals included bulls, steers and heifers, and comprised of Holstein-Friesian, early- and late-maturing breeds * Holstein Friesian, early-maturing * early-maturing, late-maturing * early-maturing and genotypes with 0.75 or greater late-maturing ancestry. Bulls, heifers and steers were slaughtered at 15, 20 and 24 months of age, respectively. The diet offered before slaughter includes grass silage only, grass or maize silage plus supplementary concentrates, or concentrates offered ad libitum plus 1 kg of roughage dry matter per head daily. Following the slaughter, carcasses were classified mechanically for conformation and fatness (scale 1 to 15), and the right side of each carcass was dissected into meat, fat and bone. Carcass conformation score ranged from 4.7 to 14.4, 5.4 to 10.9 and 2.0 to 12.0 for bulls, heifers and steers, respectively; the corresponding ranges for fat score were 2.7 to 11.5, 3.2 to 11.3 and 2.8 to 13.3. Prediction equations for carcass meat, fat and bone proportions were developed using multiple regression, with carcass conformation and fat score both included as continuous independent variables. In a separate series of analyses, the independent variable in the model was the proportion of the trait under investigation (meat, fat or bone) in the hindquarter. In both analyses, interactions between the independent variables and gender were tested. The predictive ability of the developed equations was assed using cross-validation on all 662 animals. Carcass classification scores accounted for 0.73, 0.67 and 0.71 of the total variation in carcass meat, fat and bone proportions, respectively, across all 662 animals. The corresponding values using hindquarter meat, fat and bone in the model were 0.93, 0.87 and 0.89, respectively. The bias of the prediction equations when applied across all animals was not different from zero, but bias did exist among some of the genotypes of animals present. In conclusion, carcass classification scores and hindquarter composition are accurate and efficient predictors of carcass meat, fat and bone proportions. PMID- 22443878 TI - Environmental enrichment in early life affects cortisol patterns in growing pigs. AB - Effects of environmental enrichment at different stages of life on stress physiology of pigs were investigated in a trial with 63 groups, each of four siblings. In each of the three growing phases (suckling 0 to 4 weeks of age, nursery 5 to 9 weeks, fattening 10 to 24 weeks) pens either were (=E) or were not (=0) enriched. Accordingly, the treatments were (i) 000, (ii) E00, (iii) EE0, (iv) 00E, (v) 0EE and (vi) EEE. The enrichment material, renewed twice daily to leave a thin layer, consisted of wood shavings and chopped straw. Salivary cortisol was sampled hourly from 0700 to 1900 h at the age of 9 and 21 weeks. The presence of a circadian secretion rhythm was evaluated by an intra-assay coefficient of variation-based method. An adrenocorticotropic hormone test was performed at 21 weeks. Treatment effects on the odds of a physiological cortisol rhythm were assessed by logistic regression, and effects on cortisol concentrations with a repeated measures GLM. Substrate-enrichment from 0 to 9 weeks of age increased the odds of a rhythm as compared to barren housing (odds ratio (OR) = 30.0, P < 0.01). A flat cortisol secretion pattern may indicate chronic stress and/or delayed maturation of the rhythm. Barren as compared to enriched rearing (0 to 4 weeks of age) seemed to cause a blunted secretion rhythm at 21 weeks of age. Although behavioural and tail lesion observations provided support to the assumption that a blunted rhythm indicates chronic stress, the biological significance of these cortisol results needs confirmation in future studies. PMID- 22443879 TI - Physiological response and carcass and meat quality of suckling lambs in relation to transport time and stocking density during transport by road. AB - To evaluate the effect of stocking density and transport time on physiological responses and meat quality, 72 male suckling lambs were transported by road to the slaughterhouse at three different stocking densities (0.12, 0.20 or 0.25 m2/lamb) and two transport times (5 h or 30 min). Blood samples were collected pre-transport at the farm and after unloading in the slaughterhouse to measure levels of cortisol, creatine kinase (CK) and lactate dehydrogenase (LDH). After slaughter, the weights of the hot carcass, liver and spleen were recorded and pH in Musculus longisimus thoracis et lumborum (L), Musculus semitendinosus (ST) and Musculus psoas major (PM) were determined. Colour, water-holding capacity (WHC), texture and thiobarbituric acid-reactive substances (TBARS) values were measured in samples of L, at 24 h post mortem and after 5 days of ageing. Cortisol and LDH were higher in suckling lambs transported for 30 min than those transported for 5 h. Stocking density did not affect blood parameters studied. Transport time significantly affected some carcass quality parameters, but stocking density had no significant effect. Suckling lambs transported for 5 h had lower liver weights and dressing percentages than those transported for 30 min. Transport time influenced pH values, with lambs subjected to the longer journey showing the lowest pH at 0 h in the three muscles studied, with the lowest final pH in L and PM. The PM lambs transported at high density (0.12 m2/lamb) had the lowest pH at 24 h. Transport time and stocking density did not greatly affect colour and texture parameters. The meat from lambs transported for 30 min had higher WHC than meat from lambs transported for 5 h. Animals transported for longer journeys showed higher lipid oxidation after 5 days of ageing than those transported for 30 min. Loading and initial transport caused significant stress response in suckling lambs, that stress response was reduced over the time course of the journey. PMID- 22443880 TI - Aligning health and welfare principles and practice in organic dairy systems: a review. AB - This review provides an assessment of research findings into the current practices and standards and the principles and aspirations for organic dairy production, with respect to the health and welfare of the dairy cow. The relationships between the four main factors: management, environment, genetics and nutrition and their impact on the health and welfare status of organic dairy cows are considered. The concept that good animal health and welfare is more than merely the absence of disease, with behavioural aspects of health and welfare such as physiological and psychological needs, is also discussed. These factors are inter-related and important in all dairy systems, irrespective of whether the system is organic, low-input or intensive. Incidences of individual clinical and sub-clinical diseases that are recorded in conventional dairy systems also occur in organic dairy systems, with infertility, lameness and mastitis being the major problems. However, the magnitude of the incidence of many of these diseases may be either lower or higher in organic systems due to different management practices and the standards defined for organic milk production that, for example, prohibit the routine use of conventional medicines and require the feeding of high-forage diets. In relation to different systems, it is important to note that contrary to a common assumption, good welfare does not necessarily occur with more extensive systems. The type of organic system (self-sufficient, purchased-feed) also has the potential to have a major influence on the incidence of health problems and the reproductive status of organic dairy herds. Health status is also influenced by environmental and welfare factors, including the method of rearing replacement animals, type of housing and the geographical and climatic conditions of individual farms. Overall, this review identifies where conflicts arise between current practice and the organic principles and standards, and aims to provide suggestions to bring about further improvement in organic dairy health and welfare. PMID- 22443881 TI - The effect of dry cow winter management system on feed intake, performance and estimated energy demand. AB - This research compared three wood-chip out-wintering pad (OWP; an unsheltered OWP; a sheltered OWP (both with a concrete feed apron); and an unsheltered OWP with silage provided directly on top of the wood-chip bedding (self-feed OWP)) designs and cubicle housing with regard to dairy cow performance during the pre partum period, and for 8 weeks post partum. Data were compared during 2 years. In Year 1, the unsheltered (space allowance = 12 m2 per cow) and sheltered (6 m2 per cow) OWPs were compared with cubicle housing (n = 49 cows per treatment). In Year 2, all three OWP designs (12 m2 per cow) were compared with cubicle housing (n = 24 cows per treatment, split into two replicates). Animals were dried off and assigned to treatment in the autumn, and remained there until calving in spring. Subsequently, they were managed at pasture during lactation. Outcome measures for analysis during the pre-partum period were feed intake, live weight, body condition score (BCS), heat production and heat loss, and post-partum were live weight, BCS, milk yield and milk composition. In Year 1, all cows had a similar live weight, but both pre-partum and at calving cows on the unsheltered OWP had a lower BCS than cows in cubicles (P < 0.05). However, in Year 2, there were no differences in either live weight or BCS. In Year 1, cows in the unsheltered OWP produced less heat than in cubicles (P < 0.05), but in Year 2, there was no treatment effect. In both years, cows in unsheltered OWPs lost more heat than cows in the sheltered OWP (P < 0.001). Treatment had no effect on milk composition either year. However, in Year 2, cows in the self-feed OWP had higher milk yields than the other treatments (P < 0.05). The lower BCS and heat production values in unsheltered treatments during Year 1 were probably because of higher rainfall and wind-speed values of that year. However, in both years, live weight in all treatments increased pre partum, and BCS did not decrease, indicating that unsheltered cows did not need to mobilise body reserves. Thus, OWPs could be a suitable pre-partum alternative to cubicle housing for dry dairy cows with regard to some aspects of dairy cow productive performance. However, further research should be carried out to investigate longer-term effects. PMID- 22443882 TI - Using faecal DNA to determine consumption by kangaroos of plants considered palatable to sheep. AB - Disagreement exists within the scientific community with regards to the level of competition for feed between sheep and kangaroos in the Australian rangelands. The greatest challenge to solving this debate is finding effective means of determining the composition of the diets of these potential grazing competitors. An option is to adopt a non-invasive approach that combines faecal collection and molecular techniques that focus on faecal DNA as the primary source of dietary information. As proof-of-concept, we show that a DNA reference data bank on plant species can be established. This DNA reference data bank was then used as a library to identify plant species in kangaroo faeces collected in the southern rangelands of Western Australia. To enhance the method development and to begin the investigation of competitive grazing between sheep and kangaroos, 16 plant species known to be palatable to sheep were initially targeted for collection. To ensure that only plant sequences were studied, PCR amplification was performed using a universal primer pair previously shown to be specific to the chloroplast transfer RNA leucine (trnL) UAA gene intron. Overall, genus-specific, single and differently sized amplicons were reliably and reproducibly generated; enabling the differentiation of reference plants by PCR product length heterogeneity. However, there were a few plants that could not be clearly differentiated on the basis of size alone. This prompted the adoption of a post-PCR step that enabled further differentiation according to base sequence variation. Restriction endonucleases make sequence-specific cleavages on DNA to produce discrete and reproducible fragments having unique sizes and base compositions. Their availability, affordability and simplicity-of-use put restriction enzyme sequence (RES) profiling as a logical post-PCR step for confirming plant species identity. We demonstrate that PCR-RES profiling of plant and faecal matter is useful for the identification of plants included in the diet of kangaroos. The limitations, potential and the opportunities created for researchers interested in investigating the diet of competing herbivores in the rangelands are discussed. PMID- 22443883 TI - The influence of age at the beginning of Montanera period on meat characteristics and fat quality of outdoor Iberian pigs. AB - A total of 120 Iberian pigs of the Lampina line that grew under outdoor conditions were used to study the effect of the age at the beginning of Montanera period (AM) on meat characteristics and fatty acid (FA) profile of subcutaneous fat. AM period is a free-range fattening phase from November to February in which pigs ate mainly acorns and grass. There were two treatments with two AM (20 pigs per treatment); 18 (P18) and 12 months (P12). Barrows and gilts were in the same proportion within each treatment. All the animals were slaughtered at the same time (at the end of Montanera period) reaching an average 160 kg of body weight. Meat from P18 had less protein and was more red (a*) (P < 0.05), but tended to show higher intramuscular fat content (P < 0.10) than meat from P12. Loin from P18 had lower thawing (P < 0.001) and cooking losses (P < 0.10) than loin from P12. The fat from P18 had higher monounsaturated FA content than fat from P12 pigs (P < 0.01) due to the higher level of C18:1 (P < 0.01) and C20:1 (P < 0.001). However, fat from P12 had higher polyunsaturated FA content than fat from P18 pigs (P < 0.01) because of the higher level of C18:2 (P < 0.001). It is concluded that both 12 and 18 months are adequate AM for purebred Iberian pigs from the commercial point of view. However, if the aim is to produce high-quality dry-cured Iberian products, the P18 pigs would be more advisable because had better meat and fat characteristics than the P12 pigs. PMID- 22443884 TI - Influence of cage or pen housing on carcass traits and meat quality of rabbit. AB - Carcass traits and meat quality of rabbits reared in conventional cages (0.385 m2), small pens (0.662 m2) or large pens (4.052 m2) at a similar stock density of 15 rabbits/m2 were compared (n = 30 per group). Pens contained an elevated platform. Slaughter weight (SW; P < 0.01) and cold carcass weight (P < 0.05) decreased in the order of Cage < Small pen < Large pen groups. SW and cold carcass weight were 7% lower in rabbits housed in large pens than in cages. Dressing out and meat-to-bone ratio were not influenced by the housing system. Percentage of fat deposits was highest in caged rabbits (+0.15 point for scapular fat and +0.26 point for perirenal fat compared to rabbits reared in large pens P < 0.05). Rabbits housed in large pens had a bigger proportion of hind part (+1 point), and meat colour was shifted towards greater a* values (P < 0.01) compared to caged rabbits. Water holding capacity and shear test parameters in longissimus lumborum muscle, lipid content and shear test parameters of abductor cruralis cranialis, biceps femoris and semitendinosus muscles were not affected by the housing system. Tibia and femur bone moment of inertia increased in the order of Cage < Small pen < Large pen groups (P < 0.05), whereas elastic modulus, which is a measure of intrinsic stiffness, was highest in caged rabbits. This study showed that large pen housing altered carcass traits independently and increased meat redness and fracture resistance of tibia and femur. PMID- 22443885 TI - Intramuscular fat content in meat-producing animals: development, genetic and nutritional control, and identification of putative markers. AB - Intramuscular fat (IMF) content plays a key role in various quality traits of meat. IMF content varies between species, between breeds and between muscle types in the same breed. Other factors are involved in the variation of IMF content in animals, including gender, age and feeding. Variability in IMF content is mainly linked to the number and size of intramuscular adipocytes. The accretion rate of IMF depends on the muscle growth rate. For instance, animals having a high muscularity with a high glycolytic activity display a reduced development of IMF. This suggests that muscle cells and adipocytes interplay during growth. In addition, early events that influence adipogenesis inside the muscle (i.e proliferation and differentiation of adipose cells, the connective structure embedding adipocytes) might be involved in interindividual differences in IMF content. Increasing muscularity will also dilute the final fat content of muscle. At the metabolic level, IMF content results from the balance between uptake, synthesis and degradation of triacylglycerols, which involve many metabolic pathways in both adipocytes and myofibres. Various experiments revealed an association between IMF level and the muscle content in adipocyte-type fatty acid binding protein, the activities of oxidative enzymes, or the delta-6-desaturase level; however, other studies failed to confirm such relationships. This might be due to the importance of fatty acid fluxes that is likely to be responsible for variability in IMF content during the postnatal period rather than the control of one single pathway. This is evident in the muscle of most fish species in which triacylglycerol synthesis is almost zero. Genetic approaches for increasing IMF have been focused on live animal ultrasound to derive estimated breeding values. More recently, efforts have concentrated on discovering DNA markers that change the distribution of fat in the body (i.e. towards IMF at the expense of the carcass fatness). Thanks to the exhaustive nature of genomics (transcriptomics and proteomics), our knowledge on fat accumulation in muscles is now being underpinned. Metabolic specificities of intramuscular adipocytes have also been demonstrated, as compared to other depots. Nutritional manipulation of IMF independently from body fat depots has proved to be more difficult to achieve than genetic strategies to have lipid deposition dependent of adipose tissue location. In addition, the biological mechanisms that explain the variability of IMF content differ between genetic and nutritional factors. The nutritional regulation of IMF also differs between ruminants, monogastrics and fish due to their digestive and nutritional particularities. PMID- 22443886 TI - The racial disparity in breast cancer mortality in the 25 largest cities in the United States. AB - INTRODUCTION: Although the racial disparity in breast cancer mortality is widely discussed there are no studies that analyze this phenomenon at the city level. METHODS: We used national death files, abstracting those cases for which the cause was malignant neoplasm of the breast (ICD-10=C50) for the numerators and American Community Survey data for the denominators. The 25 largest cities in the US were the units of analysis. Non-Hispanic Black:non-Hispanic White rate ratios (RRs) were calculated, along with their confidence intervals, as measures of the racial disparity. Seven ecological (city-level) variables were examined as possible correlates. RESULTS: Almost all the NHB rates were greater than almost all the NHW rates. All but 3 of the RRs (range 0.78-2.09; median=1.44) were >1, 13 of them significantly so. None of the RRs<1 were significant. From among the 7 potential correlates, only median household income (r=-0.43, p=0.037) and a measure of segregation (r=0.42, r=0.039) were significantly related to the RR. CONCLUSION: This is the first study that we have been able to locate which examines city-level racial disparities in breast cancer mortality. The results are of concern for several cities and for the field in general. A strategy for reducing this disparity in Chicago is in place and may serve as a model for other cities wanting to initiate a similar process. Clearly it is time to take action. PMID- 22443887 TI - AFM-based force-clamp monitors lipid bilayer failure kinetics. AB - The lipid bilayer rupture phenomenon is here explored by means of atomic force microscopy (AFM)-based force clamp, for the first time to our knowledge, to evaluate how lipid membranes respond when compressed under an external constant force, in the range of nanonewtons. Using this method, we were able to directly quantify the kinetics of the membrane rupture event and the associated energy barriers, for both single supported bilayers and multibilayers, in contradistinction to the classic studies performed at constant velocity. Moreover, the affected area of the membrane during the rupture process was calculated using an elastic deformation model. The elucidated information not only contributes to a better understanding of such relevant process, but also proves the suitability of AFM-based force clamp to study model structures as lipid bilayers. These findings on the kinetics of lipid bilayers rupture could be extended and applied to the study of other molecular thin films. Furthermore, systems of higher complexity such as models mimicking cell membranes could be studied by means of AFM-based force-clamp technique. PMID- 22443888 TI - Simultaneous determination of jasmonic acid epimers as phytohormones by chiral liquid chromatography-quadrupole time-of-flight mass spectrometry and their epimerization study. AB - Jasmonic acid (JA) is an essential plant hormone involved in plant development and defense system. There are four stereoisomeric forms of JA and they act quite differently in vivo. In this work, a normal phase liquid chromatography quadrupole time-of-flight mass spectrometry (NPLC-QTOF-MS) method using cellulose tris (4-methylbenzoate) coated silica gel as the chiral stationary phase was first established for the simultaneous discrimination and direct analysis of all the four JA stereoisomers without need of derivatization. A non-endogenous JA stereoisomer was introduced as the internal standard to ensure the reliability of the developed method. Satisfactory results were obtained in terms of sensitivity (limit of detection, 0.5 ng mL(-1) or 2.4 fmol), linearity (R(2)=0.9996) and repeatability (run-to-run RSD of migration time and peak area, 0.37% and 5.9%, respectively, n=6). Endogenous rise of two natural JA stereoisomers was detected in tobacco leaves and their variations in response to mechanical wounding were monitored. In addition, the configurational stability of JA stereoisomers was investigated using the stereoisomerically pure forms which were not commercially available but easily obtained by our semi-preparative chiral LC method. Experimental evidence indicated that both of the two naturally existing JA stereoisomers were putative signals for wounding response, and the epimerization between them was not a spontaneous process simply promoted by the thermodynamical instability as expected before. PMID- 22443889 TI - Sequential determination of anionic-type detergents by complexation with methylene blue using dual high speed counter-current chromatography. AB - A new dual high-speed counter-current chromatographic system using organic extraction phase and aqueous mobile phase containing methylene blue was applied to the analysis of anionic-type detergents. After selecting appropriate conditions such as flow rate of each mobile phase and sample volume, the new system was successfully applied to the analysis of anionic detergent in river water. As all the analytical procedures can be made in a closed system, the method has no health hazard. The present method is safe, precise, and highly sensitive, and can be applied for sequential determination of multiple samples in a short analysis time. PMID- 22443890 TI - Quantifying injection solvent effects in reversed-phase liquid chromatography. AB - Peak distortion due to the injection was measured as a function of injection solvent strength, volume, mass, retention factor, and column selectivity. The concept of a method's sensitivity (s) to injection solvent strength was mathematically defined as a vector of theoretical plate counts compared to an ideal vector that does not change with injection solvent strength. Near ideal sensitivity (s>0.90) was measured on all columns with all analytes in low volume injections of 1.25 MUL. Increasing the injection volume reduces the measured sensitivity from ideality to a greater extent than increasing the injection mass, with differing values for each column. Using column parameters measured from the hydrophobic-subtraction model and fitting parameters from the acetonitrile excess adsorption isotherm, differences among the columns studied are explained. Decreased ligand density and increased silanol activity provide a consistent peak shape with changes in injection volume or solvent strength. For method development, a quick test is suggested with the ratio of hydrophobic-subtraction column parameters, H/A, to predict the injection solvent sensitivity of a column. As H/A decreases, the sensitivity to injection solvent worsens. Sensitivity to organic modifiers other than acetonitrile are predicted with cited sorbed layer thickness, such that MeOH>EtOH>IPA~THF~MeCN, i.e., a strong MeOH diluent is more ideal (better) than a strong MeCN diluent. PMID- 22443891 TI - On the chromatographic efficiency of analytical scale column format porous polymer monoliths: interplay of morphology and nanoscale gel porosity. AB - Porous monolithic poly(styrene-co-divinylbenzene) stationary phases in 4.6 mm I.D. analytical-scale column format with varying porosity, globule scale polymer morphology and flow-through pore structure have been investigated with respect to their transport properties toward small retained solutes in isocratic elution, reversed-phase liquid chromatography. The current study was performed under kinetically and thermodynamically relevant conditions comprising retention factors from close to zero up to the order of 50-100 under most extreme conditions, while a linear chromatographic flow velocity up to 4mm/s, in some instances up to 7 mm/s, was realized. Carefully designed experiments aimed at resolving issues associated with the monoliths performance, while a particular focus is given on gel porosity, chromatographic retention and band dispersion. Elucidation of three important metric properties gave orthogonal insight. These are: (i) the columns dry-state morphology and surface area, (ii) the gel porosity with tetrahydrofuran as solvent determined by size exclusion chromatography using a range of small subnanometer-sized molecules and polystyrene standards, as well as (iii) the isocratic reversed-phase performance of small molecules at varying binary acetonitrile/water mobile phase solvent compositions, modulating gel porosity. Consistently throughout the study, the adjustable and general retention factor-dependence of the performance of these monolithic materials is shown. It can also be correlated to the analytes molecular weight and consequently size. Isocratic performance strongly depends on the amount of gel porosity of the scaffold, which can be changed by varying the percentage of organic modifier in the mobile phase and indicates the adjustable chromatographic nature of porous polymer monoliths. This gel porosity which is absent in the dry-state of the polymer monoliths and is characterized by sub-nanometer to nanometer-sized pore space induces, additionally to permanent porosity, stagnant mass transfer zones. The displayed major reason for mass transfer resistance implied by the use of polymeric monolithic columns determines dispersion behavior of small molecules and its varying importance with respect to morphology and size of the globular features containing stagnant mass transfer zones is addressed. This leads to the conclusion, that a reduction in polymer feature size and increase in number of flow-through pores per unit cross-section of the monolith with an improved homogeneity may be an interesting option of tailoring column performance. It is further concluded that dry-state methods (such as nitrogen adsorption analysis and scanning electron microscopy) or solvated-state methods (such as size exclusion chromatography in tetrahydrofuran) by itself are insufficient measures to explain the adjustable chromatographic performance of porous polymer monoliths. PMID- 22443892 TI - Liquid chromatography/quadrupole-time-of-flight mass spectrometry with metabolic profiling of human urine as a tool for environmental analysis of dextromethorphan. AB - We use the combination of liquid chromatography/quadrupole-time-of-flight mass spectrometry (LC/Q-TOF-MS) and urine metabolic profiling to find and identify the metabolites of dextromethorphan, a common over-the-counter (OTC) cough suppressant. Next, we use the combination of ion masses, their MS/MS fragmentation, and retention times to determine dextromethorphan and its metabolites in surface water impacted by wastewater. Prior to this study, neither dextromethorphan nor its metabolites have been reported in surface water; in spite of its common use in over 100 various OTC medications. We found that the concentration of the dextrorphan metabolite in surface water greatly exceeded the parent compound by factors of 5-10 times, which reflects the urine profile, where parent compound is approximately <2% of the total excreted drug based on ion intensities. Urine profiling also indicated that glucuronide metabolites are major phase 2 products (92% of the total) in urine and then are completely hydrolyzed in wastewater to dextrorphan and N-demethyldextrorphan, which are phase 1 metabolites-a "kind of reversal" of human metabolism. PMID- 22443893 TI - Evaluation of a new wide pore core-shell material (Aeris WIDEPORE) and comparison with other existing stationary phases for the analysis of intact proteins. AB - The separation of large biomolecules such as proteins or monoclonal antibodies (mAbs) by RPLC can be drastically enhanced thanks to the use of columns packed with wide-pore porous sub-2 MUm particles or shell particles. In this context, a new wide-pore core-shell material has been recently released under the trademark Aeris WIDEPORE. It is made of a 3.2 MUm solid inner core surrounded by a 0.2 MUm porous layer (total particle size of 3.6 MUm). The aim of this study was to evaluate the performance of this new material, compare it to other recently developed and older conventional wide-pore columns and demonstrate its applicability to real-life separations of proteins and mAbs. At first, the traditional h(min) values of the Aeris WIDEPORE column were determined for small model compounds. The h(min) values were equal to 1.7-1.8 and 1.4 for the 2.1 and 4.6 mm I.D. columns, respectively, which are in agreement with the values reported for other core-shell materials. In the case of a small protein Insulin (5.7 kDa), the achievable lowest h value was below 2 and this impressive result confirms that the Aeris WIDEPORE material should be dedicated to protein analysis. This column was then compared with five other commercially available wide-pore and medium-pore stationary phases, in the gradient elution mode, using various flow rates, gradient steepness and model proteins of MW=5.7-66.8 kDa. The Aeris WIDEPORE material often provided the best performance, in terms of peak capacity, peak capacity per time and pressure unit (PPT) and also based on the gradient kinetic plot representation. Finally, real separations of filgrastim (18.8 kDa) and its oxidized and reduced forms were performed on the different columns and the Aeris WIDEPORE material provided the most impressive performance (peak capacity>100 for t(grad)<6 min). Last but not least, this new material was also evaluated on digested and reduced mAb and powerful, high-throughput separations were also attained. PMID- 22443894 TI - Programmed elution in comprehensive two-dimensional liquid chromatography. AB - Recent advances in applications of gradient elution in two-dimensional liquid chromatography are reviewed. Benefits of simultaneous programmed elution in two dimensional liquid chromatography are shown, with emphasis on fast gradient elution in second dimension using various gradient types and profiles. The theory of gradient elution is shortly overviewed with attention to its impacts on two dimensional separations. Various two-dimensional gradient systems are compared in terms of peak capacity and peak production rate: off-line, stop-and-go and real time comprehensive approaches. Selection of stationary phases in combination with gradient elution and the effects of gradient elution on improved regularity of two-dimensional space coverage, orthogonality and peak capacity are discussed. Not only two-dimensional reversed-phase systems, but also other HPLC modes such as HILIC, ion-exchange or normal-phase chromatography with organic mobile phases are included. Fraction modulation in gradient elution setups, mobile phase compatibility and solvent effects in the fraction transfer between the first and the second dimension are addressed. Design and optimization of two-dimensional gradient separation systems for particular ordered and non-ordered samples are dealt with in detail. The discussed principles are illustrated by practical examples. PMID- 22443895 TI - Emerging trends in regenerative medicine: a scientometric analysis in CiteSpace. AB - INTRODUCTION: Regenerative medicine involves research in a number of fields and disciplines such as stem cell research, tissue engineering and biological therapy in general. As research in these areas advances rapidly, it is critical to keep abreast of emerging trends and critical turns of the development of the collective knowledge. AREAS COVERED: A progressively synthesized network is derived from 35,963 original research and review articles that cite 3875 articles obtained from an initial topic search on regenerative medicine between 2000 and 2011. CiteSpace is used to facilitate the analysis of the intellectual structure and emerging trends. EXPERT OPINION: A major ongoing research trend is concerned with finding alternative reprogramming techniques as well as refining existing ones for induced pluripotent stem cells (iPSCs). A more recent emerging trend focuses on the structural and functional equivalence between iPSCs and human embryonic stem cells and potential clinical and therapeutic implications on regenerative medicine in a long run. The two trends overlap in terms of what they cite, but they are distinct and have different implications on future research. Visual analytics of the literature provides a valuable, timely, repeatable and flexible approach in addition to traditional systematic reviews so as to track the development of new emerging trends and identify critical evidence. PMID- 22443896 TI - Intraocular pressure change after myopic laser in situ keratomileusis as measured on the central and peripheral cornea. AB - BACKGROUND: Laser in situ keratomileusis (LASIK) leads to inaccurate measurement of intraocular pressure (IOP). This study aimed to determine the efficacy and reliability of IOP measurement on the peripheral cornea after LASIK. METHODS: The IOP was measured in 52 eyes of 26 subjects before LASIK and one week and one month after LASIK using non-contact tonometry. The measurements were made on the central and peripheral cornea and the results were subjected to statistical analysis. RESULTS: The mean measured IOP on the central cornea was decreased by 6.425 +/- 2.544 mmHg at one week and 5.752 +/- 3.863 mmHg at one month post operatively. The mean IOP measured on the peripheral cornea was decreased by only 0.921 +/- 2.054 mmHg at one week post-operatively. Most notably, the mean IOP measured on the peripheral cornea was increased by only 0.158 +/- 2.979 mmHg at one month post-operatively with no statistical significance (p > 0.05). Furthermore, a linear regression of ablation depth versus change in IOP measured on the central cornea was demonstrated, but the peripheral IOP did not display such a statistically significant correlation with the depth of ablation at both one week and one month after operation. CONCLUSION: The IOP measured on the peripheral cornea is closer to the actual IOP. Therefore, it is more accurate and reliable to measure IOP on the peripheral cornea than on the centre after LASIK. PMID- 22443897 TI - Pandemic 2009 H1N1 virus infection in children and adults: A cohort study at a single hospital throughout the epidemic. AB - BACKGROUND: In 2009, there was an influenza pandemic in South Korea. The aim of this study was to evaluate the epidemiological, clinical and laboratory characteristics of this infection in children and adults. METHODS: We evaluated the epidemiologic characteristics of patients infected with the 2009 H1N1 influenza A virus (4,463 patients, age range from 2 mo to 86 y), and the clinical and laboratory findings of 373 inpatients (80/217 children, <= 15 y, had pneumonia and 36/156 adults, > 16 y, had pneumonia) in a single hospital during the epidemic. RESULTS: The majority of infected patients (94%) were less than 40 y, and greater than 90% of cases occurred during a two-month period. The rates of admission and pneumonia were 8.4% (373/4,463) and 2.5% (116/4,463), respectively. The rates of admission and pneumonia, total duration of fever, the frequency of underlying diseases, and the values of C-reactive protein and erythrocyte sedimentation rate tended to increase as age increased; highest rates were found in the >= 65 y group. Pneumonia was founded more boys than girls in children, but more female than male in adults. The adult patients with pneumonia had higher leukocyte counts with lower lymphocyte differentials than the group without pneumonia, as shown in children group. CONCLUSION: Our results suggest that the immunologic reaction to viral insults may be associated with age, sex and underlying diseases, and that unknown herd immunity may affect populations. The patients with underlying diseases, especially in older patients may have immunologic insufficiency that is associated with immunologic consumption by the underlying diseases. PMID- 22443898 TI - Use of gene expression data for predicting continuous phenotypes for animal production and breeding. AB - Traits such as disease resistance are costly to evaluate and slow to improve using current methods. Analysis of gene expression profiles (e.g. DNA microarrays) has potential for predicting such phenotypes and has been used in an analogous way to classify cancer types in human patients. However, doubts have been raised regarding the use of classification methods with microarray data for this purpose. Here we propose a method using random regression with cross validation, which accounts for the distribution of variation in the trait and utilises different subsets of patients or animals to perform a complete validation of predictive ability. Published breast tumour data were used to test the method. Despite the small dataset (n < 100), the new approach resulted in a moderate but significant correlation between the predicted and actual phenotypes (0.32). Binary classification of the predicted phenotypes yielded similar classification error rates to those found by other authors (35%). Unlike other methods, the new method gave a quantitative estimate of phenotype that could be used to rank animals and select those with extreme phenotypic performance. Use of the method in an optimal way using larger sample sizes, and combining DNA microarrays and other testing platforms, is recommended. PMID- 22443899 TI - Association between PrP genotypes and performance traits in a Welsh Mountain flock. AB - The UK national scrapie plan (NSP) for sheep is based on selection for the resistant ARR/ARR genotype and elimination of susceptible types of the ovine prion protein (PrP) gene. The aim of this study was to estimate the possible association of the PrP genotype and performance traits by using data from the CAMDA Welsh Mountain flock. Four alleles (ARH, ARQ, ARR and VRQ) and 10 genotypes covering all five NSP risk groups were present in the CAMDA flock. Overall, the most common allele was ARR (35.2%), and VRQ was the least common (5.4%). The commonest genotypes were ARR/ARQ (23.7%) and ARR/AHQ (23.1%). The most resistant genotype, ARR/ARR, and the most susceptible genotype, VRQ/VRQ, were found in 10.2% and 0.3%, respectively, of the population tested. The associations of PrP genotypes with weight and ultrasonically scanned traits were investigated in three analyses, the first using genotypes, the second using risk categories and the third using number of alleles. These associations were evaluated by univariate analysis of each trait using an animal model with maternal effects where appropriate, and PrP was included as a fixed effect. Selection for scrapie resistance will not adversely affect progress in the traits considered and is consistent with improvements in muscle depth. PMID- 22443900 TI - The effect of footrot on weight gain in sheep. AB - Footrot is a highly contagious bacterial disease of sheep affecting the interdigital skin and surrounding soft and hard horn of a hoof, often resulting in severe lameness. This study was aimed at estimating the effect of footrot on weight gain of affected animals, and characterising the variation between animals in terms of phenotypic, environmental and genetic components. A general approach was developed describing the relationship between the disease and weight gain, defining new traits such as the maximum weight loss as a result of disease and the time after infection that this occurs. In two trials, 1267 Merino sheep were artificially challenged with footrot when 10 months old and re-infected through exposure to footrot on pasture 33 weeks later. Their feet were scored for footrot and live weights were measured approximately every 3 weeks. From data on animals that were not affected by footrot throughout each trial, normal growth curves were calculated and applied to affected animals to predict their growth had they remained healthy, so that weight loss as a result of footrot could be predicted. Animals with average footrot severity in the two trials suffered weight losses of 0.5 to 2.5 kg live weight, but most animals regained lost live weight later in the trials as footrot healed following vaccination. The estimates of the heritabilities of weight loss, adjusted for the severity of footrot, were about 0.30 and 0.15 in the experimental and natural challenge groups, respectively. Animals with higher genotypic values for weights at the start of each trial appeared to cope better with infections, in terms of lower weight losses. The time of highest footrot score and the time of maximum weight loss after infection had only very small genetic components. PMID- 22443901 TI - Meta-analysis of 0 to 8 h post-prandial evolution of ruminal pH. AB - The objective of this study was to identify relevant descriptors of ruminal pH post-prandial evolution that can replace the mean pH (considered unsatisfactory). These descriptors are to be used in the attempts to predict ruminal pH from dietary characteristics, in order to quantify the potential of a diet to induce subacute ruminal acidosis from its intrinsic characteristics. A total of 219 pH curves, reported as graphics in 48 published articles describing the post prandial evolution of ruminal pH (first 8 h), were digitized by image analysis then summarized in 15 pH variables. Relationships among pH variables and the principal components (PCs) of pH variability were analyzed in order to identify possible alternatives to mean pH, as the average value of all pH data the curve is composed of. Two groups of pH variables were identified according to their relationship with the most important principal components. A first group, including mean pH, was closely related to PC1, which accounted for 78% of data variability; hence, correlations between variables of this group were generally high. Of these, threshold-related variables were distinct as their within-study correlations with mean pH were rather moderate (0.69 on average). This suggests they might carry supplementary information that could explain the variation in ruminal pH induced by within-study factors, e.g. diet characteristics. However, caution should be taken in their use because of their truncation at 0 h and their non-normal distribution. Variables from the second group were independent of the PC1, and thus of the first group of variables, whereas they were mostly related to PC2 and PC3. This implies they are complementary to mean pH. Of this second group, the rate of pH decreases or the time period when pH reaches its minimum might be useful to better describe the ruminal status, from the point of view of the risk of subacute ruminal acidosis. PMID- 22443902 TI - Is the anthelmintic effect of heather supplementation to grazing goats always accompanied by anti-nutritional effects? AB - To test the hypothesis that the beneficial anthelmintic effect of consuming moderate amounts of tannins may not always be accompanied by anti-nutritional effects in goats, two experiments were conducted. In the first, 48 Cashmere goats were randomly assigned to two treatments: supplementation with tannin-containing heather (6.4% total tannins) and non-supplementation. All goats grazed continuously from May to September under farm conditions in a mountainous area of northern Spain. The mean percentage of heather incorporated into the diet of the supplemented animals was 29.1%. Supplementation reduced the mean number of nematode eggs in faeces (P < 0.001) and the goat mortality rate (P < 0.05). The rumen ammonia concentration was markedly reduced in the goats receiving the heather supplement (160 v. 209 mg/l; P < 0.01), while volatile fatty acid (VFA) concentrations were significantly greater (63.0 v. 53.6 mmol total VFA/l; P < 0.05). The heather-supplemented goats also showed a lower loss of live weight (P < 0.01) and body condition score (P < 0.001). In the second experiment, batch cultures of rumen microorganisms with rumen fluid from nine goats whose diet included 29% heather - or not, were used to incubate three substrates (pasture, pasture + heather and pasture + heather + polyethylene glycol) to investigate in vitro ruminal fermentation. Differences (P < 0.01) among substrates were observed in terms of dry matter disappearance (DMD), in vitro true substrate digestibility (ivTSD), gas production and ammonia concentration, the greatest values always associated with the pasture substrate. Cultures involving rumen inoculum derived from goats receiving the heather-containing diet showed slightly lower DMD (46.9 v. 48.5 g/100 g; P < 0.05), ivTSD (64.6 v. 65.9 g/100 g; P < 0.10) and gas production (105 v. 118 ml/g; P < 0.001) values, but much greater total VFA concentrations (48.5 v. 39.3 mmol/l; P < 0.05), and suggest that the efficiency of ruminal fermentation in these animals was probably improved. Together, the results support the absence of a clear nutritional cost counteracting the beneficial anthelmintic effect of supplementing the diet of grazing goats with tannin-containing heather. PMID- 22443903 TI - Effect of low-protein amino acid-supplemented diets on the growth performance, gut morphology, organ weights and digesta characteristics of weaned pigs. AB - A 21-day study was conducted to determine whether isoleucine might limit the performance of piglets fed low-crude protein (CP), amino acid (AA)-supplemented diets and to investigate the potential benefits of low-CP diets on gastrointestinal health in weaned pigs. Ninety-six piglets (initial BW = 6.44 +/- 0.14 kg), housed four per pen, were randomly assigned to one of four diets, resulting in six replicate pens per diet. Dietary treatments were as follows: (1) 210 g/kg CP diet, (2) 190 g/kg CP diet deficient in isoleucine, (3) 190 g/kg CP diet supplemented with crystalline isoleucine up to the level in the 210 g/kg CP diet and (4) 170 g/kg CP diet supplemented with isoleucine and valine on the ideal protein ratio basis (60% and 70% relative to lysine, respectively). Pigs were allowed to adapt to the new environment for 4 days before the experiment commenced. Overall, pigs fed the 210 g/kg CP diet had higher (P < 0.05) average daily gain and lower (P < 0.05) feed : gain ratio compared with those fed the other diets. The faecal consistency score of pigs fed the 210 g/kg CP diet was higher (P < 0.05) than those fed the other diets. Pigs fed the 170 g/kg diet had lower (P=0.02) small intestine weight than those fed the 210 g/kg CP diet. Pigs fed the 210 g/kg CP diet had deeper (P < 0.05) crypt in the duodenum and ileum and higher (P < 0.05) ammonia N concentration in caecal digesta than those fed the other diets. There were no effects of diet on microbial population and volatile fatty acid concentration in the caecal digesta except for propionic acid whose concentration was higher (P < 0.05) for pigs fed the 170 g/kg diet than those fed the 190+isoleucine and the 210 g/kg CP diets. The results indicate that the low-CP, AA-supplemented diet reduced crypt hypertrophy, ammonia N concentration in the caecal digesta, small intestine weight and the performance of piglets. Also, the results of the current study were inconclusive with respect to whether isoleucine may limit the performance of pigs fed a low-CP, AA supplemented diet. PMID- 22443904 TI - The effects of seaweed extract inclusion on gut morphology, selected intestinal microbiota, nutrient digestibility, volatile fatty acid concentrations and the immune status of the weaned pig. AB - An experiment (complete randomised design) was conducted to investigate the effects of Laminaria hyperborea and Laminaria digitata seaweed extract inclusion on gut morphology, selected intestinal microbiota populations, volatile fatty acid concentrations and the immune status of the weaned pig. Twenty-eight piglets (24 days of age, 6.5 +/- 1.4 kg live weight) were assigned to one of four dietary treatments for 7 days and then sacrificed: (T1) basal diet (control); (T2) basal diet and 1.5 g/kg L. hyperborea seaweed extract; (T3) basal diet and 1.5 g/kg L. digitata seaweed extract; and (T4) basal diet and 1.5 g/kg of a combination of L. hyperborea and L. digitata seaweed extract. The seaweed extract contained both laminarin and fucoidan. Digesta samples were taken from the caecum and colon to measure the enterobacteria, bifidobacteria and lactobacilli populations and for volatile fatty acid analysis. Tissue samples were taken from the duodenum, jejunum and ileum for morphological examination. Blood samples were taken to determine the cytokine gene expression profile and to measure the phagocytotic capacity of the blood. Pigs offered diets containing L. hyperborea seaweed extract had less bifidobacteria in the colon (P < 0.05) and lactobacilli in the caecum (P < 0.05) and colon (P < 0.001). The inclusion of L. digitata seaweed extract resulted in lower populations of enterobacteria in the caecum and colon (P < 0.01), bifidobacteria in the caecum (P < 0.05), and lactobacilli in the caecum (P < 0.05) and colon (P < 0.001). Pigs offered the combination of L. hyperborea and L. digitata seaweed extracts had less enterobacteria (P < 0.05) and lactobacilli (P < 0.01) in the caecum and colon. Pigs offered the L. digitata supplemented diet had a reduced villous height in the duodenum and jejunum (P < 0.05). The inclusion of the L. digitata seaweed extract increased the molar proportion of butyric acid in the colon (P < 0.05). There was a significant reduction in the ammonia concentration in the colon with the inclusion of L. hyperborea (P < 0.01) and L. digitata (P < 0.05) seaweed extracts. An increase in the expression of the Interleukin-8 mRNA was observed on day 6 with the supplementation of the combination of L. hyperborea and L. digitata seaweed extract (P < 0.05). The inclusion of L. hyperborea seaweed extract resulted in an increase in total monocyte number (P < 0.05). In conclusion, the supplementation of L. hyperborea and L. digitata seaweed extract alone and in combination reduced the enterobacteria, bifidobacteria and lactobacilli populations in the caecum and colon, while only marginal effects on the immune response was observed. PMID- 22443905 TI - Using the alkanes and long-chain alcohols of plant cuticular wax to estimate diet composition and the intakes of mixed forages in sheep consuming a known amount of alkane-labelled supplement. AB - In a feeding trial with 24 sheep, we used the alkanes, long-chain alcohols (LCOH) or both of these plant wax markers, to estimate the diet composition of animals offered diets comprising alkane-labelled cottonseed meal (CSM) together with up to four forages. The diets used were: Diet 1 subterranean clover (Trifolium subterraneum); Diet 2 subterranean clover + phalaris (Phalaris aquatica); Diet 3 subterranean clover, phalaris + annual ryegrass (Lolium rigidum); and Diet 4 subterranean clover, phalaris, annual ryegrass + wheat straw (Triticum aestivum). Estimates of diet composition were made following correction of faecal alkane or LCOH concentrations for incomplete faecal recovery, using recovery estimates derived from individual animals, mean recoveries for a given dietary treatment or grand mean recoveries. Estimated dietary proportions of CSM and known intakes of CSM were used to estimate forage intake. The LCOH concentrations of the diet components were much higher than their alkane concentrations, especially for phalaris. Multivariate analyses showed that the discriminatory information provided by the LCOH was additional to that provided by the alkanes, and that a combination of (LCOH + alkanes) discriminated better between diet components than either class of marker alone. Faecal recoveries of LCOH increased with increasing carbon-chain length; there were no differences in recovery attributable to diet. The most accurate estimates of diet composition were obtained with the combination of (LCOH + alkanes). Estimates of diet composition based on LCOH alone were not as good as alkanes alone, due to the high correlation between the LCOH profiles of phalaris and ryegrass. Total grass content of the diet was very accurately estimated using LCOH. Diet composition estimates provided estimates of whole-diet digestibility, which did not differ from the measured values. Trends in the accuracy of forage intake estimates reflected those found with diet composition and almost two-thirds of estimates based on (LCOH + alkanes) had lower error than those found with alkanes alone. The results confirm that supplements labelled with plant wax components can be used to estimate forage intake, and also show that the LCOH are useful markers for estimating diet composition. Intakes were also computed using a combination of natural LCOH concentrations in the diet and the daily dose rate of even-chain alkanes administered by intra-ruminal device. Differences between intakes so estimated and the measured intakes were closely related to the difference in faecal recovery between the LCOH/alkane pair used to estimate intake, by an amount close to that expected on theoretical grounds. It is concluded that the use of plant wax LCOH, especially in combination with alkanes, will result in improved estimates of diet composition and intake in grazing animals. PMID- 22443906 TI - alpha-Tocopherol and l-ascorbic acid increase the in vitro development of IVM/IVF swamp buffalo ( Bubalus bubalis) embryos. AB - This study was conducted to investigate the effects of capacitating agents added at in vitro fertilization (IVF) and antioxidants supplemented during in vitro culture (IVC) on the development of buffalo embryos. In experiment I, in vitro embryo development of buffalo embryos was compared when the IVF medium was supplemented with heparin, caffeine and calcium ionophore A23187 either alone or in combination. There was no significant difference (P > 0.05) in the cleavage rates of oocytes among the treatment groups but the development rate to the blastocyst stage and the cell numbers of blastocyst in the heparin-treated group were significantly higher (P < 0.05) than that of other treatments. In experiment II, in vitro embryo development of buffalo embryos was compared when IVC medium was supplemented with either alpha-tocopherol (250 and 500 MUM) or l-ascorbic acid (250 and 500 MUM). The rate of development to the blastocyst stage of embryos cultured in medium supplemented with 250 MUM alpha-tocopherol (33%, 41/123) and 250 MUM l-ascorbic acid (31%, 38/123) was significantly higher (P < 0.05) than that of those cultured in medium alone (19%, 20/108) but not significantly different (P < 0.05) from medium supplemented with either 500 MUM alpha-tocopherol (24%, 30/123) or 500 MUM l-ascorbic acid (25%, 33/133). These results suggest that buffalo spermatozoa treated with heparin were suitable for IVF and that alpha-tocopherol and l-ascorbic acid added during IVC increased the rate of buffalo embryo development. PMID- 22443907 TI - Jennet milk production during the lactation in a Sicilian farming system. AB - In Italy, the interest for jennet milk production has recently developed. An 18 month-long experiment was carried out on a jennet farm near Milo (CT), where 24 jennets, which derived from the Ragusana breed, were tested for milk yield and composition over an entire lactation period. The jennets were fed with hay and concentrate in a large paddock. From the 28th post-foaling day to the end of the lactation, the jennets were machine-milked twice a day with an in-between milking interval of 5 h. The milk amount from each jennet was recorded every 3 weeks and individual samples were collected and analyzed for fat, protein, casein, non proteic nitrogen, lactose and somatic cell count. This study showed that jennets at Sicilian latitudes are not seasonal polyestrous. The daily milk yield, the length of lactation and the milk characteristics varied depending on the foaling season. The total average milk production was 490 +/- 36 kg in 295 +/- 12 post foaling days, considering two milking records per day. During the lactation, milk yield decreased constantly from 1.98 to 1.28 kg/jennet per day. When looking at the jennet milk quality during lactation, the percentage of fat and protein decreased, while the lactose percentage increased, according to a tendency apparently unique for equines when compared to the ruminants. When looking at the productive season, spring generally gave the best qualitative and quantitative results. Based on these results, jennet milk yield and quality could be improved; furthermore, jennet milk production may turn out to be a profitable business. PMID- 22443908 TI - Short-duration insemination with frozen semen increases fertility rate in nulliparous dairy goats. AB - Standard artificial insemination (AI) using a speculum in dairy goats does not result in acceptable fertility rates in nulliparous does. An explanation might be the difficulties to pass the cervical canal in nulliparous females with the insemination gun, increasing the time needed for semen deposition. Nulliparous Alpine dairy goats were used to evaluate whether time interval from insertion to withdrawal of the speculum is a factor influencing pregnancy rates to first AI with frozenthawed semen. Oestrus was synchronized using fluorogestone acetate intravaginal sponges (FGA, 40 mg) for 11 days, associated with 50 mg i.m. of cloprostenol and 250 IU i.m. eCG 48 +/- 2 h before sponge removal. In the first experiment (n = 52; 3 herds), the average duration of the AI procedure was 42 +/- 10 s, with a median of 39 s. AI performed in less than 39 s resulted in higher pregnancy rates (75%, n = 28) than AI lasting for more than 39 s (46%, n = 24). In the second experiment, does (n = 325; 5 herds) were randomly assigned into two treatment groups according to a short (20 s) or long (60 s) AI procedure. We showed that the duration of AI affected fertility after a first insemination, and that pregnancy rate was significantly improved using a short-duration AI (61.2%; n = 169) compared with a long-duration AI (44.2%; n = 156). We have previously shown in the ewe that genital stimulation during AI enhanced uterine motility. Other authors reported a negative correlation between increased uterine motility at the time of AI and fertility rates in small ruminants. The results of this study suggest that rapid semen deposition may limit the reflex activation of uterine contractions provoked by the speculum and the movement of the insemination gun, and thus ameliorates reproductive performance to first AI in nulliparous goats. PMID- 22443909 TI - Pre-slaughter conditions, animal stress and welfare: current status and possible future research. AB - The present paper describes the main procedures used to slaughter fowl, pigs, calves and adult cattle, sheep, and farmed fish, starting on the farm and ending with the death of the animal at the abattoir. It reviews the currently known causes of stress, indicated by behavioural and physiological measurements on the animal level, and by post-mortem muscle metabolism. During the pre-slaughter period, psychological stress is due to changes of environment, social disturbances and handling, and physical stress is due to food deprivation, climatic conditions, fatigue, and sometimes pain. The exact causes of stress depend, however, on the characteristics of each species, including the rearing system. For fowl, bird catching and crating, duration and climatic conditions of transport and of lairage and shackling are the main known pre-slaughter stress factors. For pigs, stress is caused by fighting during mixing of pens, loading and unloading conditions, and introduction in the restrainer. Handling and novelty of the situation contribute to the stress reactions. For veal calves and adult cattle, disruption of the social group, handling, loading and sometimes unloading conditions, fatigue, novelty of the situation and for calves mixing with unfamiliar animals are known stress factors. Gathering and yarding of extensively reared lambs and sheep causes stress, particularly when shepherd dogs are used. Subsequent transport may induce fatigue, especially if sheep are commercialised through auctions or markets. In farmed fish, stress is predominantly related to environmental aspects such as temperature, oxygen, cleanliness of the water and, to a certain extent, stocking density and removal of the fish from the water. If transport and lairage conditions are good and their durations not too long, they may allow pigs, calves and adult cattle, sheep, and fish to rest. For certain species, it was shown that genetic origin and earlier experience influence reactions to the slaughter procedure. Stunning techniques used depend on the species. Pigs and fowl are mostly electrically or gas-stunned, while most adult cattle are stunned with a captive bolt pistol. Calves and sheep may be electrically stunned or with a captive bolt pistol. Various stunning methods exist for the different farmed fish species. Potential causes of stress associated with the different stunning procedures are discussed. The paper addresses further consequences for meat quality and possible itineraries for future research. For all species, and most urgently for fish, more knowledge is needed on stunning and killing techniques, including gas stunning techniques, to protect welfare. PMID- 22443910 TI - Behavioural and physiological fear responses in ducks: genetic cross effects. AB - Mule duck, a cross between a Muscovy drake and a Pekin female, is reported by the farmers to frequently express fear behaviours, such as man avoidance. The genetic basis of fear responses in mule ducks was therefore investigated in this study. According to a previous experiment, the dominant effect of Pekin genotype was hypothesised; however, due to the absence of birds from the reciprocal cross, a superiority of the Pekin in additive effect could not be distinguished from a direct maternal additive effect. In order to clarify this, ducks from the mule genotype, the two parental genotypes (Pekin and Muscovy) and the reciprocal intercross (hinny) underwent a set of physiological and individual behavioural tests of fear. Both parental genotypes were highly fearful but exhibited responses of different patterns: Pekin ducks manifested a higher locomotor activity, whereas the Muscovy ducks showed a higher avoidance to man. Hybrids expressed higher panic responses and specific fear of man than the two parent breeds. Both hybrids expressed similar patterns and the maternal effects were not significant. Significant heterosis effects were found for most of the behavioural responses, in agreement with the fact that higher fear responses were expressed by the hybrids compared to the parental genotypes. A significant heterosis effect was also found for basal adrenal activity; hybrids having higher basal level than parental genotypes. Maximum capacity of adrenal response appeared to be determined by direct additive effects with a superiority of the Pekin genotype. PMID- 22443911 TI - Voluntary intake and digestibility in horses: effect of forage quality with emphasis on individual variability. AB - Food intake is a key biological process in animals, as it determines the energy and nutrients available for the physiological and behavioural processes. In herbivores, the abundance, structure and quality of plant resources are known to influence intake strongly. In ruminants, as the forage quality declines, digestibility and total intake decline. Equids are believed to be adapted to consume high-fibre low-quality forages. As hindgut fermenters, it has been suggested that their response to a reduction in food quality is to increase intake to maintain rates of energy and nutrient absorption. All reviews of horse nutrition show that digestibility declines with forage quality; for intake, however, most studies have found no significant relationship with forage quality, and it has even been suggested that horses may eat less with declining forage quality similarly to ruminants. A weakness of these reviews is to combine data from different studies in meta-analyses without allowing the differences between animals and diets to be controlled for. In this study, we analysed a set of 45 trials where intake and digestibility were measured in 21 saddle horses. The dataset was analysed both at the group (to allow comparisons with the literature) and at the individual levels (to control for individual variability). As expected, dry matter digestibility declined with forage quality in both analyses. Intake declined slightly with increasing fibre contents at the group level, and there were no effects of crude protein or dry matter digestibility on intake. Overall, the analysis for individual horses showed a different pattern: intake increased as digestibility and crude protein declined, and increased with increasing fibre. Our analysis at the group level confirms previous reviews and shows that forage quality explains little of the variance in food intake in horses. For the first time, using mixed models, we show that the variable 'individual' clarifies the picture, as the horses showed different responses to a decrease in forage quality: some compensated for the low nutritional value of the forages by increasing intake, few others responded by decreasing intake with declining forage quality, but not enough to cause any deficit in their energy and protein supplies. On the whole, all the animals managed to meet their maintenance requirements. The individual variability may be a by-product of artificial selection for performance in competition in saddle horses. PMID- 22443912 TI - Dietary cyclic fatty acids derived from linolenic acid do not exhibit intrinsic toxicity in the rat during gestation. AB - Heating oils and fats may lead to cyclization of polyunsaturated fatty acids, especially those showing multiple double bonds like linolenic acid. Cyclohexenyl and cyclopentenyl fatty acids are subsequently present in some edible oils and these were suspected to induce metabolic disorders. When fed during gestation in the rat, cyclic fatty acids were historically reported to induce high mortality of the neonates. Nevertheless, none of these studies have been performed with cyclic fatty acids fed as triacylglycerols, limiting the nutritional value of the conclusions. Therefore, we assessed the toxicity of a diet containing 0.7% of cyclic fatty acids fed as triacylglycerols during gestation and the first days of life in the rat. In this work, we report no deleterious effect of cyclic fatty acids in the mothers and neonates. However, cyclic fatty acids induced a tremendous insulinopenia in the mothers and pups that was associated with the reduction of food intake in the gestating females. Such a finding may be a plausible explanation for the adverse effects of cyclic fatty acids observed previously with higher doses of cyclic fatty acids. Based on present data, on previous ones showing elimination of cyclic fatty acids, and considering their low amounts in the diet, we suggest that cyclic fatty acids formed from cyclization of linolenic acid are not a major concern for human safety. PMID- 22443913 TI - Influence of an increase in diet structure on milk conjugated linoleic acid content of cows fed extruded linseed. AB - This experiment studied the effect of a modest difference in diet structure value (SV) on milk conjugated linoleic acid (CLA) contents of cows fed diets supplemented with extruded linseed, in situations where the diets provided enough SV and therefore did not induce milk fat depression. Six lactating Holstein cows were used in a crossover design with two treatments ('SV 1.50' and 'SV 1.73') and two periods of 21 days. The 'SV 1.50' diet contained 59% maize silage, 13% soya bean meal, 13% sugar beet pulp and 14% Nutex Compact (containing 56% extruded linseed) (dry matter (DM) basis) and was offered as a restricted total mixed ration. For the 'SV 1.73' diet, 8% wheat straw (DM basis) was added to the 'SV 1.50' diet as an additional structure source. The two diets had a forage-to concentrate ratio of 59 : 41 and 62 : 38. The inclusion of straw in the diet resulted in an additional intake of NDF (+1110 g/day), which accounted for 90% of the additional intake of OM, whereas additional intakes of the other nutrients were minor. Milk yield and composition did not differ among treatments. The inclusion of straw in the diet did not affect the milk levels of t10-18:1, 18:2n 6, c9-16:1, c9-18:1, c11-18:1, 6:0, 8:0, 20:4 and 20:5. It decreased the milk levels of c9,t11-CLA (2.13% v. 3.03% of fatty acids (FA) reported, P < 0.001), t11-18:1 (4.99% v. 7.10% of FA reported, P < 0.001), 18:3n-3, t9-16:1 and t9 18:1, while it increased the milk levels of 6:0-14:0 (20.90% v. 19.69% of FA reported, P < 0.01), 16:0 (26.55% v. 25.25% of FA reported, P < 0.01), 18:0 (13.54% v. 12.59% of FA reported, P < 0.001), 17:0, 20:0 and 22:5. Regarding the ratio between FA, the inclusion of straw increased the 18:0/total C18 FA ratio (37.74% v. 32.07%, P < 0.001), whereas it decreased the total trans-C18 FA/total C18 FA ratio (15.46% v. 20.34%, P < 0.001), the t11-18:1/total C18 FA ratio (13.70% v. 17.95%, P < 0.01) and the c9,t11-CLA/total C18 FA ratio (5.82% v. 7.64%, P < 0.001). We conclude from this experiment that even a modest increase in SV to a diet supplemented with extruded linseed, yet already providing enough SV, alters the rumen lipid metabolism and, hence, CLA levels in milk fat. PMID- 22443914 TI - Effects of feeding and rearing systems on growth, carcass composition and meat quality in pigs. AB - Animal growth performance and quality of pork depend on the interactive effects of pig genotype, rearing conditions, pre-slaughter handling, and carcass and meat processing. This paper focuses on the effects of feeding and rearing systems (feeding level and diet composition, housing, production system, etc.) on growth performance, carcass composition, and eating and technological qualities of pork. The feeding level and protein : energy ratio can be used to manipulate growth rate or composition of weight gain. Restricted feed allowance strongly reduces growth rate and carcass fatness and also intramuscular fat (IMF) level, resulting in decreased meat tenderness or juiciness. Expression of compensatory growth due to restricted followed by ad libitum feeding modifies the composition of weight gain at both carcass and muscle levels, and may improve meat tenderness due to higher in vivo protein turnover. Decreasing the protein : energy ratio of the diet actually increases IMF and improves eating quality, but gives fatter carcasses. In contrast, a progressive reduction in the protein : energy ratio leads to similar carcass composition at slaughter but with higher IMF. Technological meat traits (pH1, pHu, colour, drip loss) are generally not affected by the level or protein : energy in feed. Modification of fatty acid composition and antioxidant level in meat can be obtained through diet supplementations (e.g. vegetable sources with high n-3 fatty acids), thereby improving the nutritional quality of pork. Influences of pig rearing system on animal performance, carcass and meat traits result from interactive effects of housing (floor type, space allowance, ambient temperature, physical activity), feeding level and genotype in specific production systems. Indoor enrichment (more space, straw bedding) generally increases growth rate and carcass fatness, and may improve meat juiciness or flavour through higher IMF. Outdoor rearing and organic production system have various effects on growth rate and carcass fatness, depending on climatic conditions and feed allowance. Influence on meat quality is also controversial: higher drip and lower pHu and tenderness have been reported, whereas some studies show improved meat juiciness with outdoor rearing. Discrepancies are likely due to differences between studies in rearing conditions and physiological responses of pigs to pre-slaughter handling. Specific production systems of the Mediterranean area based on local breeds (low growth rate, high adiposity) and free-range finishing (pasture, forests), which allows pig to express their genetic potential for IMF deposition, clearly demonstrate the positive effects of genotype * rearing system interactions on the quality of pork and pork products. PMID- 22443915 TI - Substance use disorder prevalence among female state prison inmates. AB - BACKGROUND: Substance use disorders (SUDs) are prevalent among female inmates. As the female state prison population continues to increase, describing the specific clinical and demographic characteristics of female prisoners remains of paramount importance to better define women's needs in the state prison system. OBJECTIVES: To determine the prevalence and patterns of current DSM-IV SUDs and explore whether particular demographic characteristics are more strongly associated with specific SUD categories. METHODS: Data were derived from routine clinical assessments of 801 female inmates incarcerated in the Minnesota Department of Corrections state prison system. The Substance Use Disorder Diagnostic Schedule IV (Hoffmann NG, Harrison PA. SUDDS-IV: Substance Use Disorder Diagnostic Schedule-IV. Smithfield, RI: Evince Clinical Assessments, 1995) was administered to all inmates as a computer-prompted interview on admission to the prison. RESULTS: Of the inmates, 70.0% were dependent on at least one substance, and 7.9% met criteria for substance abuse. Alcohol dependence (30.2%) and cocaine dependence (30.1%) were the two most prevalent SUDs. The remaining substance dependence diagnoses that predominated were as follows: stimulant dependence, 24.1%; marijuana dependence, 15.6%; and heroin dependence, 9.6%. Over half (56.9%) were dependent on a substance other than alcohol. Prevalence of cocaine dependence [odds ratio (OR) = 2.83, 95% confidence interval (CI) = 1.92-4.16] was significantly higher among African Americans, whereas prevalence of stimulant dependence (OR = 9.24, 95% CI = 5.40-15.80) was significantly higher among Caucasians. Prevalence of alcohol (OR = 2.12, 95% CI = 1.38-3.25) and heroin (OR = 2.67, 95% CI = 1.50-4.77) dependence was significantly higher among Native Americans. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: SUDs in general, and illicit drug use disorders in particular, are prevalent among female inmates entering a state prison system. Membership to a particular ethnic group may identify a set of inmates at elevated risk for the presence of substance-specific dependence diagnoses. PMID- 22443917 TI - Another look at the future of nursing. PMID- 22443916 TI - Variety in fruit and vegetable consumption and 10-year incidence of CHD and stroke. AB - OBJECTIVE: Consuming a variety of fruit and vegetables provides many different micronutrients and bioactive compounds. Whether this contributes to the beneficial association between fruit and vegetables and incident CHD and stroke is unknown. DESIGN: Prospective population-based cohort study. SETTING: The Netherlands. SUBJECTS: Men and women (n 20 069) aged 20-65 years. Participants completed a validated 178-item FFQ, including nine fruit and thirteen vegetable items. Variety in fruit and vegetables was defined as the sum of different items consumed at least once per 2 weeks over the previous year. Hazard ratios (HR) for variety in relation to incident CHD and stroke were calculated using multivariable Cox proportional hazards models additionally adjusted for quantity of fruit and vegetables. RESULTS: Variety and quantity in fruit and vegetables were highly correlated (r = 0.81). Variety was not associated with total energy intake (r = -0.01) and positively associated with nutrient intakes, particularly vitamin C (r = 0.70). During 10 years of follow-up, 245 cases of CHD and 233 cases of stroke occurred. Variety in vegetables (HR per 2 items = 1.05; 95 % CI 0.94, 1.17) and in fruit (HR per 2 items = 1.00; 95 % CI 0.87, 1.15) were not related to incident CHD. Variety in vegetables (HR per 2 items = 0.93; 95 % CI 0.83, 1.04) and in fruit (HR per 2 items = 1.03; 95 % CI 0.89, 1.18) were also not related to incident stroke. CONCLUSIONS: More variety in fruit and vegetable consumption was associated with higher intakes of fruit and vegetables and micronutrients. Independently of quantity, variety in fruit and vegetables was related neither to incident CHD nor to incident stroke. PMID- 22443918 TI - The nurse education imperative. PMID- 22443919 TI - Reduction of preoperative anxiety in pediatric surgery patients using age appropriate teaching interventions. AB - More than 5 million children in the United States undergo surgery annually. Of those 5 million children, 50% to 75% experience considerable fear and anxiety preoperatively. Preoperative anxiety in children is associated with a number of adverse postoperative outcomes, such as increased distress in the recovery phase, and postoperative regressive behavioral disturbances, such as nightmares, separation anxiety, eating disorders, and bedwetting. Preparing the pediatric patient adequately for surgery can prevent many behavioral and physiological manifestations of anxiety. Children are most susceptible to the stress of surgery owing to their limited cognitive capabilities, greater dependence on others, lack of self-control, limited life experience, and poor understanding of the health care system. This article will review the literature on preoperative interventional teaching strategies to reduce preoperative anxiety in children and discuss the methods available for evidence-based preparation of children undergoing surgery. PMID- 22443920 TI - Stethoscopes as a source of hospital-acquired methicillin-resistant Staphylococcus aureus. AB - Stethoscopes are potential vectors of methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this project was to determine the presence of MRSA on the diaphragms of personal and unit stethoscopes within a hospital setting before and after cleaning with alcohol prep pads. The sample consisted of 141 personal and unit stethoscopes in adult medical-surgical and intensive care units of a large university hospital in the Southeast. Each stethoscope was cultured once before cleaning and once after cleaning. Cultures were obtained using sterile swabs and inoculated on a selective medium for MRSA. Bacterial growth was noted in the precleaning group, but no MRSA colonies were detected. The postcleaning group had no bacterial growth. There was not enough data to statistically support that isopropyl alcohol is effective in decreasing bacterial counts; however, these findings suggest that current disinfection guidelines are effective in preventing MRSA colonization on stethoscopes in this setting. PMID- 22443921 TI - Comparison of manual compression alone versus with hemostatic patch in achieving hemostasis after femoral catheter removal. AB - This quasi-experimental study compares manual compression and use of hemostatic patch in achieving hemostasis after femoral sheath removal. Patients who agreed to participate were randomly assigned to either control group or study. A majority of the patients (75.3%, n=67) had a diagnostic procedure, and 24.7%, (n=22) had an interventional procedure. The mean compression time for the control group (mean=13.87, standard deviation [SD]=5.6) was 2.5 minutes longer compared with the mean compression time for the study group (mean=11.42, SD=3.17). A statistically significant difference was found between groups, t=2.782, (86, P<.001). No patients developed bleeding or hematoma during their stay or within 48 to 72 hours after discharge. No significant difference was found in pain scores between groups. There was no relationship between body mass index, abdominal girth, or pelvic girth to pressure time. PMID- 22443922 TI - Nursing care of patients undergoing isolated limb procedures for recurrent melanoma of the extremity. AB - Isolated limb perfusion and isolated limb infusion are surgical interventions that provide high-dose regional chemotherapy to patients experiencing a recurrence of melanoma in an extremity. Nurses may be unfamiliar with these treatment options, as they are not available in all hospitals; however, the number of people diagnosed with melanoma is increasing. It is important for nurses to understand these surgical procedures to provide safe high-quality care before and after the surgery. Currently, there are several gaps in our knowledge about patients' experiences or nurse-sensitive outcomes. There are abundant opportunities for nurses to improve the care of patients who undergo surgical interventions to manage melanoma in the extremity. PMID- 22443923 TI - Speak up and advocate! PMID- 22443924 TI - Hypertonic saline for perioperative fluid management. PMID- 22443925 TI - Obstructive sleep apnea and coronary artery disease: are they connected? PMID- 22443926 TI - Rivaroxaban: a new oral anticoagulant. PMID- 22443927 TI - Pediatric vital signs. PMID- 22443928 TI - The IOM report one year later: have you evaluated your options? PMID- 22443929 TI - Carbamazepine, carbamazepine epoxide and dihydroxycarbamazepine sorption to soil and occurrence in a wastewater reuse site in Tunisia. AB - Treated wastewater is being increasingly used for irrigation and aquifer replenishment through artificial recharge. However, wastewater reuse can result in contamination of exposed soil and groundwater by chemicals such as some pharmaceuticals and their metabolites. The fate of these molecules depends largely on their capacity to sorb onto soil and aquifer materials during infiltration. In this study, the sorption isotherm of carbamazepine (CBZ), an anti-seizure medication, and two of its metabolites, i.e. carbamazepine-10,11 epoxide (CBZ-EP) and 10,11-dihydro-10,11-dihydroxycarbamazepine (DiOH-CBZ), were determined in two soils in laboratory assays. In the field, the presence of CBZ and its metabolites were investigated in soil and in groundwater underlying an irrigated area with treated wastewater. The results showed that CBZ had the highest carbon normalised sorption coefficients in the two tested soils (irrigated soil and a Lufa SP2.4 reference soil) followed by CBZ-EP and DiOH-CBZ, indicating the relatively higher mobility of CBZ metabolites compared to CBZ. The chromatographic analysis revealed that CBZ and its two metabolites were present in treated wastewater used for irrigation and in groundwater. In soil samples, CBZ concentrations showed a build-up taking place with irrigation. The mobility of metabolites in soil and their potential biodegradation require further investigation. PMID- 22443931 TI - Pluripotency and nuclear reprogramming. AB - Pluripotency is a "blank" cellular state characteristic of specific cells within the early embryo (e.g., epiblast cells) and of certain cells propagated in vitro (e.g., embryonic stem cells, ESCs). The terms pluripotent cell and stem cell are often used interchangeably to describe cells capable of differentiating into multiple cell types. In this review, we discuss the prevailing molecular and functional definitions of pluripotency and the working parameters employed to describe this state, both in the context of cells residing within the early embryo and cells propagated in vitro. PMID- 22443930 TI - Endoplasmic reticulum stress and type 2 diabetes. AB - Given the functional importance of the endoplasmic reticulum (ER), an organelle that performs folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, the maintenance of ER homeostasis in insulin secreting beta-cells is very important. When ER homeostasis is disrupted, the ER generates adaptive signaling pathways, called the unfolded protein response (UPR), to maintain homeostasis of this organelle. However, if homeostasis fails to be restored, the ER initiates death signaling pathways. New observations suggest that both chronic hyperglycemia and hyperlipidemia, known as important causative factors of type 2 diabetes (T2D), disrupt ER homeostasis to induce unresolvable UPR activation and beta-cell death. This review examines how the UPR pathways, induced by high glucose and free fatty acids (FFAs), interact to disrupt ER function and cause beta-cell dysfunction and death. PMID- 22443932 TI - Toward the single-hour high-quality genome. AB - Today, resequencing of a human genome can be performed in approximately a week using a single instrument. Thanks to a steady logarithmic rate of increase in performance for DNA sequencing platforms over the past seven years, DNA sequencing is one of the fastest developing technology fields. As the process becomes faster, it opens up possibilities within health care, diagnostics, and entirely new fields of research. Immediate genetic characterization of contagious outbreaks has been exemplified, and with such applications for the direct benefit of human health, expectations of future sensitive, rapid, high-throughput, and cost-effective technologies are steadily growing. Simultaneously, some of the limitations of a rapidly growing field have become apparent, and questions regarding the quality of some of the data deposited into databases have been raised. A human genome sequenced in only an hour is likely to become a reality in the future, but its definition may not be as certain. PMID- 22443933 TI - Measurements and implications of the membrane dipole potential. AB - There are three kinds of membrane potentials: the surface potentials, resulting from the accumulation of charges at the membrane surfaces; the transmembrane potential, determined by imbalance of charge in the aqueous solutions; and the dipole potential, a membrane-internal potential from the dipolar components of the phospholipids and interface water. The absolute value of the dipole potential has been very difficult to measure, although its value has been estimated to be in the range of 200-1,000 mV from ion translocation rates (determined by the planar lipid bilayer method), the surface potential of lipid monolayers (determined by the lipid monolayer method), molecular-dynamics calculations, and electron scattering using cryoelectron microscopy (cryo-EM). Spectroscopy methods have also been used to monitor the dipole potential changes on the basis of the observed fluorescence changes of voltage-sensitive probes. The dipole potential accounts for the much larger permeability of a bare phospholipid membrane to anions than cations and affects the conformation and function of membrane proteins. PMID- 22443934 TI - Small-molecule inhibitors of bacterial AddAB and RecBCD helicase-nuclease DNA repair enzymes. AB - The AddAB and RecBCD helicase-nucleases are related enzymes prevalent among bacteria but not eukaryotes and are instrumental in the repair of DNA double strand breaks and in genetic recombination. Although these enzymes have been extensively studied both genetically and biochemically, inhibitors specific for this class of enzymes have not been reported. We developed a high-throughput screen based on the ability of phage T4 gene 2 mutants to grow in Escherichia coli only if the host RecBCD enzyme, or a related helicase-nuclease, is inhibited or genetically inactivated. We optimized this screen for use in 1536-well plates and screened 326,100 small molecules in the NIH molecular libraries sample collection for inhibitors of the Helicobacter pylori AddAB enzyme expressed in an E. coli recBCD deletion strain. Secondary screening used assays with cells expressing AddAB or RecBCD and a viability assay that measured the effect of compounds on cell growth without phage infection. From this screening campaign, 12 compounds exhibiting efficacy and selectivity were tested for inhibition of purified AddAB and RecBCD helicase and nuclease activities and in cell-based assays for recombination; seven were active in the 0.1-50 MUM range in one or another assay. Compounds structurally related to two of these were similarly tested, and three were active in the 0.1-50 MUM range. These compounds should be useful in further enzymatic, genetic, and physiological studies of these enzymes, both purified and in cells. They may also lead to useful antibacterial agents, since this class of enzymes is needed for successful bacterial infection of mammals. PMID- 22443935 TI - Once initiated, how does toxic tissue injury expand? AB - Once initiated, how tissue injury expands after high toxicant doses, even after their complete elimination, is not understood. Free-radical generation was initially proposed to mediate progression of injury. However, mechanisms proposed thus far have remained unsubstantiated. Necrotic injury is characterized by loss of osmoregulation, cell swelling, blebbing, and cell rupture. This exposes cytosolic enzymes, including proteases, phospholipases, and lysosomal Ca(2+) dependent enzymes, to high extracellular calcium (Ca(2+)). Activated hydrolytic enzymes, termed 'death proteins,' hydrolyze their substrates in the plasma membrane of neighboring cells, commencing self-perpetuated injury progression. Likewise, ischemia-reperfusion injury exposes the hydrolytic enzymes to high Ca(2+), fuelling the progression of tissue injury. This mechanism is independent of the offending toxicant that initiates the injury. I present here a case for therapeutic intervention with inhibitors directed against death proteins as a means to avert organ failure and death well after the poisoning event. PMID- 22443936 TI - Puerpera with dyspnoea and epileptic seizure. PMID- 22443937 TI - Guest editorial: Livestock and global climate change. PMID- 22443938 TI - Mitigating climate change: the role of domestic livestock. AB - Livestock contribute directly (i.e. as methane and nitrous oxide (N2O)) to about 9% of global anthropogenic greenhouse gas (GHG) emissions and around 3% of UK emissions. If all parts of the livestock production lifecycle are included (fossil fuels used to produce mineral fertilizers used in feed production and N2O emissions from fertilizer use; methane release from the breakdown of fertilizers and from animal manure; land-use changes for feed production and for grazing; land degradation; fossil fuel use during feed and animal production; fossil fuel use in production and transport of processed and refrigerated animal products), livestock are estimated to account for 18% of global anthropogenic emissions, but less than 8% in the UK. In terms of GHG emissions per unit of livestock product, monogastric livestock are more efficient than ruminants; thus in the UK, while sheep and cattle accounted for 32% of meat production in 2006, they accounted for 48% of GHG emissions associated with meat production. More efficient management of grazing lands and of manure can have a direct impact in decreasing emissions. Improving efficiency of livestock production through better breeding, health interventions or improving fertility can also decrease GHG emissions through decreasing the number of livestock required per unit product. Increasing the energy density of the diet has a dual effect, decreasing both direct emissions and the numbers of livestock per unit product, but, as the demands for food increase in response to increasing human population and a better diet in some developing countries, there is increasing competition for land for food v. energy dense feed crops. Recalculating efficiencies of energy and protein production on the basis of human-edible food produced per unit of human-edible feed consumed gave higher efficiencies for ruminants than for monogastric animals. The policy community thus have difficult decisions to make in balancing the negative contribution of livestock to the environment against the positive benefit in terms of food security. The animal science community have a responsibility to provide an evidence base which is objective and holistic with respect to these two competing challenges. PMID- 22443939 TI - Mitigating the greenhouse gas balance of ruminant production systems through carbon sequestration in grasslands. AB - Soil carbon sequestration (enhanced sinks) is the mechanism responsible for most of the greenhouse gas (GHG) mitigation potential in the agriculture sector. Carbon sequestration in grasslands can be determined directly by measuring changes in soil organic carbon (SOC) stocks and indirectly by measuring the net balance of C fluxes. A literature search shows that grassland C sequestration reaches on average 5 +/- 30 g C/m2 per year according to inventories of SOC stocks and -231 and 77 g C/m2 per year for drained organic and mineral soils, respectively, according to C flux balance. Off-site C sequestration occurs whenever more manure C is produced by than returned to a grassland plot. The sum of on- and off-site C sequestration reaches 129, 98 and 71 g C/m2 per year for grazed, cut and mixed European grasslands on mineral soils, respectively, however with high uncertainty. A range of management practices reduce C losses and increase C sequestration: (i) avoiding soil tillage and the conversion of grasslands to arable use, (ii) moderately intensifying nutrient-poor permanent grasslands, (iii) using light grazing instead of heavy grazing, (iv) increasing the duration of grass leys; (v) converting grass leys to grass-legume mixtures or to permanent grasslands. With nine European sites, direct emissions of N2O from soil and of CH4 from enteric fermentation at grazing, expressed in CO2 equivalents, compensated 10% and 34% of the on-site grassland C sequestration, respectively. Digestion inside the barn of the harvested herbage leads to further emissions of CH4 and N2O by the production systems, which were estimated at 130 g CO2 equivalents/m2 per year. The net balance of on- and off-site C sequestration, CH4 and N2O emissions reached 38 g CO2 equivalents/m2 per year, indicating a non significant net sink activity. This net balance was, however, negative for intensively managed cut sites indicating a source to the atmosphere. In conclusion, this review confirms that grassland C sequestration has a strong potential to partly mitigate the GHG balance of ruminant production systems. However, as soil C sequestration is both reversible and vulnerable to disturbance, biodiversity loss and climate change, CH4 and N2O emissions from the livestock sector need to be reduced and current SOC stocks preserved. PMID- 22443940 TI - Methane mitigation in ruminants: from microbe to the farm scale. AB - Decreasing enteric methane (CH4) emissions from ruminants without altering animal production is desirable both as a strategy to reduce global greenhouse gas (GHG) emissions and as a means of improving feed conversion efficiency. The aim of this paper is to provide an update on a selection of proved and potential strategies to mitigate enteric CH4 production by ruminants. Various biotechnologies are currently being explored with mixed results. Approaches to control methanogens through vaccination or the use of bacteriocins highlight the difficulty to modulate the rumen microbial ecosystem durably. The use of probiotics, i.e. acetogens and live yeasts, remains a potentially interesting approach, but results have been either unsatisfactory, not conclusive, or have yet to be confirmed in vivo. Elimination of the rumen protozoa to mitigate methanogenesis is promising, but this option should be carefully evaluated in terms of livestock performances. In addition, on-farm defaunation techniques are not available up to now. Several feed additives such as ionophores, organic acids and plant extracts have also been assayed. The potential use of plant extracts to reduce CH4 is receiving a renewed interest as they are seen as a natural alternative to chemical additives and are well perceived by consumers. The response to tannin- and saponin-containing plant extracts is highly variable and more research is needed to assess the effectiveness and eventual presence of undesirable residues in animal products. Nutritional strategies to mitigate CH4 emissions from ruminants are, without doubt, the most developed and ready to be applied in the field. Approaches presented in this paper involve interventions on the nature and amount of energy-based concentrates and forages, which constitute the main component of diets as well as the use of lipid supplements. The possible selection of animals based on low CH4 production and more likely on their high efficiency of digestive processes is also addressed. Whatever the approach proposed, however, before practical solutions are applied in the field, the sustainability of CH4 suppressing strategies is an important issue that has to be considered. The evaluation of different strategies, in terms of total GHG emissions for a given production system, is discussed. PMID- 22443941 TI - Developing breeding schemes to assist mitigation of greenhouse gas emissions. AB - Genetic improvement of livestock is a particularly effective technology, producing permanent and cumulative changes in performance. This paper highlights some of the options for including mitigation in livestock breeding schemes, focusing on ruminant species, and details three routes through which genetic improvement can help to reduce emissions per kg product via: (i) improving productivity and efficiency, (ii) reducing wastage in the farming system and (iii) directly selecting on emissions, if or when these are measurable. Selecting on traits that improve the efficiency of the system (e.g. residual feed intake, longevity) will have a favourable effect on the overall emissions from the system. Specific examples of how genetic selection will have a favourable effect on emissions for UK dairy systems are described. The development of breeding schemes that incorporate environmental concerns is both desirable and possible. An example of how economic valuation of public good outcomes can be incorporated into UK dairy selection indices is given. This paper focuses on genetic selection tools using, on the whole, currently available traits and tools. However, new direct and indirect measurement techniques for emissions will improve the potential to reduce emissions by genetic selection. The complexities of global forces on defining selection objectives are also highlighted. PMID- 22443942 TI - Climate change and infectious disease: helminthological challenges to farmed ruminants in temperate regions. AB - In the UK, recent mean temperatures have consistently increased by between 1 degrees C and 4 degrees C compared to the 30-year monthly averages. Furthermore, all available predictive models for the UK indicate that the climate is likely to change further and feature more extreme weather events and a trend towards wetter, milder winters and hotter, drier summers. These changes will alter the prevalence of endemic diseases spatially and/or temporally and impact on animal health and welfare. Most notable among these endemic parasites are the helminths, which have been shown to be very strongly influenced by both the short-term weather and climate through effects on their free-living larval stages on pasture. In this review, we examine recent trends in prevalence and epidemiology of key helminth species and consider whether these could be climate-related. We identify likely effects of temperature and rainfall on the free-living stages and some key parasite traits likely to determine parasite abundance under changed climatic conditions. We find clear evidence that climate change, especially elevated temperature, has already changed the overall abundance, seasonality and spatial spread of endemic helminths in the UK. We explore some confounders and alternative explanations for the observed patterns. Finally, we explore the implications of these findings for policy makers and the livestock industry and make some recommendations for future research priorities. PMID- 22443943 TI - Policy options in addressing livestock's contribution to climate change. AB - There is a great potential to reduce greenhouse gas (GHG) emissions related to livestock production. For achieving this potential will require new initiatives at national and international levels that include promoting research and development on new mitigation technologies; deploying, diffusing and transferring technologies to mitigate emissions; and enhancing capacities to monitor, report and verify emissions from livestock production. This study describes the sources of livestock-related GHG emissions and reviews available mitigation technologies and practices. We assess the main policy instruments available to curb emissions and promote carbon sinks, and discuss the relative merits of alternative approaches. We discuss recent experiences in countries that have enacted mitigation strategies for the livestock sector to illustrate some of the key issues and constraints in policy implementation. Finally, we explore the main issues and challenges surrounding international efforts to mitigate GHG emissions and discuss some possible ways to address these challenges in future climate agreements. PMID- 22443944 TI - The effects of a loin muscling quantitative trait locus (LoinMAXTM) on carcass and VIA-based traits in crossbred lambs. AB - LoinMAX (LM) is a quantitative trait locus (QTL), which was found to be segregated in Australian Poll Dorset sheep, and maps to the distal end of sheep chromosome 18. LM-QTL was reported to increase Musculus longissimus dorsi area and weight by 11% and 8%, respectively. The aim of this study was to comprehensively evaluate the direct effects of LM-QTL in a genetic background typical of the stratified structure of the UK sheep industry, before it can be recommended for use in the United Kingdom. Crossbred lambs, either non-carriers or carrying a single copy of LM-QTL, were produced out of Scottish Mule ewes (Bluefaced Leicester * Scottish Blackface) artificially inseminated with semen from two Poll Dorset rams that were heterozygous for LM-QTL. Unexpectedly, one of these rams was also heterozygous for a QTL that affects the overall carcass muscling (MyoMAXTM). This was accounted for by nesting MyoMAXTM status (carrier or non-carrier) within sire in the statistical analysis. Lambs were weighed and scanned by using X-ray computed tomography (CT) at an average age of 113 days. Ultrasound scan measurements, along with lamb weights, were taken at an average age of 140 days and lambs were then slaughtered. Carcasses were weighed and classified for fat cover and conformation scores, based on the Meat and Livestock Commission (MLC) carcass classification scheme, and then scanned by using a video image analysis (VIA) system. M. longissimus lumborum (MLL) width, as measured by CT scanning, was greater (P < 0.05) in lambs heterozygous for LM-QTL compared with non-carriers. MLL in LM-QTL carrier lambs was also significantly deeper, as measured by both ultrasound muscle depth at the third lumbar vertebrae (+3.7%; P < 0.05) and CT scanning at the fifth lumbar vertebrae (+3.4%; P < 0.01). Consequently, MLL area, was measured by using CT scanning, was significantly higher (+4.5%; P < 0.01) in lambs carrying a single copy of LM-QTL compared with non-carriers. Additional traits measured by CT, such as leg muscle dimensions, average muscle density and tissue proportions, were not significantly affected by LM-QTL. LM-QTL did not significantly affect total carcass lean or fat weights or MLC conformation and fat score classifications. Using previously derived algorithms, VIA could detect a significant effect of the LM-QTL on the predicted weight of saleable meat yield in the loin primal cut (+2.2%; P < 0.05), but not in the other primal cuts, or the total carcass. PMID- 22443945 TI - Quantitative trait loci analysis of osteochondrosis traits in the elbow joint of pigs. AB - Osteochondrosis is a growth disorder in the cartilage of young animals and is characterised by lesions found in the cartilage and bone. This study identified quantitative trait loci (QTLs) associated with six osteochondrosis lesion traits in the elbow joint of finishing pigs. The traits were: thickening of the cartilage, lesion in the subchondral bone, irregular cartilage surface, fissure under the cartilage, an irregular sagittal central groove and depression of the proximal edge of the radius. The study comprised 7172 finishing pigs from crossing 12 Duroc boars with 600 crossbred Landrace * Large White sows and included 462 single nucleotide polymorphism markers. The results showed 18 QTLs exceeding the 5% genome-wide threshold. The QTLs associated with lesions in the medial part of the condylus humeri (assumed to be the four main osteochondrosis traits) were, in most cases, at common locations, whereas the QTLs associated with depression of the proximal edge of the radius in general were on the same chromosomes but at separate locations. The detected QTLs explain a large part of the genetic variation, which is promising for incorporating osteochondrosis into a breeding programme using marker-assisted selection. PMID- 22443946 TI - Estimates of (co)variance components and genetic parameters for body weights and first greasy fleece weight in Bharat Merino sheep. AB - (Co)variance components and genetic parameters of weight at birth (BWT), weaning (3WT), 6, 9 and 12 months of age (6WT, 9WT and 12WT, respectively) and first greasy fleece weight (GFW) of Bharat Merino sheep, maintained at Central Sheep and Wool Research Institute, Avikanagar, Rajasthan, India, were estimated by restricted maximum likelihood, fitting six animal models with various combinations of direct and maternal effects. Data were collected over a period of 10 years (1998 to 2007). A log-likelihood ratio test was used to select the most appropriate univariate model for each trait, which was subsequently used in bivariate analysis. Heritability estimates for BWT, 3WT, 6WT, 9WT and 12WT and first GFW were 0.05 +/- 0.03, 0.04 +/- 0.02, 0.00, 0.03 +/- 0.03, 0.09 +/- 0.05 and 0.05 +/- 0.03, respectively. There was no evidence for the maternal genetic effect on the traits under study. Maternal permanent environmental effect contributed 19% for BWT and 6% to 11% from 3WT to 9WT and 11% for first GFW. Maternal permanent environmental effect on the post-3WT was a carryover effect of maternal influences during pre-weaning age. A low rate of genetic progress seems possible in the flock through selection. Direct genetic correlations between body weight traits were positive and ranged from 0.36 between BWT and 6WT to 0.94 between 3WT and 6WT and between 6WT and 12WT. Genetic correlations of 3WT with 6WT, 9WT and 12WT were high and positive (0.94, 0.93 and 0.93, respectively), suggesting that genetic gain in post-3WT will be maintained if selection age is reduced to 3 months. The genetic correlations of GFW with live weights were 0.01, 0.16, 0.18, 0.40 and 0.32 for BWT, 3WT, 6WT, 9WT and 12WT, respectively. Correlations of permanent environmental effects of the dam across different traits were high and positive for all the traits (0.45 to 0.98). PMID- 22443947 TI - Digestibility of whole-crop barley and oat silages in dairy heifers. AB - This study evaluated the digestibility of whole-crop cereal silage (WCCS) made from oats and six-rowed barley harvested at the heading, early milk and early dough stages, and two-rowed barley harvested at the early milk and early dough stages of maturity. The eight WCCSs were fed to 32 Swedish Red heifers in a changeover design over three periods of 28 days each. The heifers were first fed ad libitum for 17 days and then at 0.95 of ad libitum for 11 days of each period. During the last 5 days all faeces and orts were collected to determine the digestibility of the silages. Only the maturity stage effect was significant for the WCCS organic matter (OM) digestibility and the average OM digestibility was higher at the heading stage (698 g/kg) than at early milk (647 g/kg) and early dough (652 g/kg) stages of maturity. For neutral detergent fibre (NDF) digestibility the crop * maturity stage effect was significant. The NDF digestibility decreased from the heading to the early milk stage for both six rowed barley (746 to 607 g/kg) and oats (698 to 596 g/kg). There was no further significant decrease in NDF digestibility for six-rowed barley at the early dough stage (577 g/kg), but for two-rowed barley it decreased from the early milk (682 g/kg) to the early dough (573 g/kg) stage, and also for oats the NDF digestibility was lowest at the early dough stage (507 g/kg). The decrease in NDF digestibility during maturation was to a large extent compensated by an increase in starch concentration in the crops. The starch digestibility was lower for six rowed barley at early dough stage (948 g/kg) than at early milk stage (977 g/kg), and was also lower compared with oats (979 g/kg) at early dough stage. The average crude protein (CP) digestibility was higher at the heading (646 g/kg) and the early milk (642 g/kg) stages than at the early dough stage (599 g/kg), and oats had higher average CP digestibility (650 g/kg) than six-rowed (613 g/kg) and two-rowed (624 g/kg) barley. Delaying the harvest of WCCS from the heading to the early milk and dough stage of maturity will decrease the OM digestibility; as a result there is a decreased NDF digestibility. PMID- 22443948 TI - Effects of defaunation on digestion of fresh Digitaria decumbens grass and growth of lambs. AB - The effects of defaunation on growth and digestion were measured in sheep fed fresh Digitaria decumbens grass cut at four stages of regrowth 14, 28, 42, and 56 days, and with different protein to energy (P/E) ratios. Two completely randomized designs trials (growth and digestion) were conducted using faunated animals, defaunated rams and protozoa free lambs. The digestion trial: eight faunated and eight defaunated rams fitted with ruminal and duodenal cannulas were fed 4 diets (diets D1 to D4) to measure digestion parameters. The dietary P/E ratios were 120 (D1), 130 (D2), 130 (D3), and 140 (D4) g PDIN/UFL (Protein Digested in the small Intestine supplied by microbial protein from rumen-degraded protein/Feed Unit for Lactation) and the grass stages of regrowth were 56, 42, 28, and 14 days, respectively. Increasing the dietary P/E ratios increased dry matter intake (DMI) and the total tract digestibility of organic matter (OM), NDF and CP. Defaunation decreased DMI, except for rams fed D4 diet. Defaunation also decreased total tract digestibility of OM except for rams fed D1 diet and that of NDF except for rams fed D1 and D4 diets. Increasing the dietary P/E ratios also increased nitrogen intake and ammonia (NH3) concentration in the rumen, whereas defaunation decreased them. The dietary P/E ratio increased non-NH3 nitrogen and microbial nitrogen duodenal flows and microbial efficiency. Defaunation did not affect duodenal flows of neither non-NH3 nitrogen and microbial nitrogen or microbial efficiency. The growth trial: 20 faunated and 20 protozoa free lambs were fed four diets (diets D5 to D8) to measure their average daily gain (ADG). The dietary P/E ratios were 60 (D5), 70 (D6), 80 (D7) and 100 (D8) g PDIN/UFL and the stages of regrowth were 56, 42, 28, and 14 days, respectively. DMI of lambs increased with P/E ratio. Protozoa free lambs had greater DMI than faunated ones when fed D7 diet (80.8 v. 74.9 g/kg LW0.75, respectively). The ADG of the lambs increased with P/E ratio. Fed on the same D5 diet, protozoa free lambs had greater ADG than faunated lambs (29.8 v. 11.6 g/day, respectively). In conclusion, animal response to defaunation was modulated by the P/E ratio of the D. decumbens grass diets. Defaunation increased ADG of lambs fed forage with the lowest P/E ratio, while digestion and nitrogen duodenal flows of rams fed the lowest P/E ratio were not affected. PMID- 22443949 TI - Estrous behavior in dairy cows: identification of underlying mechanisms and gene functions. AB - Selection in dairy cattle for a higher milk yield has coincided with declined fertility. One of the factors is reduced expression of estrous behavior. Changes in systems that regulate the estrous behavior could be manifested by altered gene expression. This literature review describes the current knowledge on mechanisms and genes involved in the regulation of estrous behavior. The endocrinological regulation of the estrous cycle in dairy cows is well described. Estradiol (E2) is assumed to be the key regulator that synchronizes endocrine and behavioral events. Other pivotal hormones are, for example, progesterone, gonadotropin releasing hormone and insulin-like growth factor-1. Interactions between the latter and E2 may play a role in the unfavorable effects of milk yield-related metabolic stress on fertility in high milk-producing dairy cows. However, a clear understanding of how endocrine mechanisms are tied to estrous behavior in cows is only starting to emerge. Recent studies on gene expression and signaling pathways in rodents and other animals contribute to our understanding of genes and mechanisms involved in estrous behavior. Studies in rodents, for example, show that estrogen-induced gene expression in specific brain areas such as the hypothalamus play an important role. Through these estrogen-induced gene expressions, E2 alters the functioning of neuronal networks that underlie estrous behavior, by affecting dendritic connections between cells, receptor populations and neurotransmitter releases. To improve the understanding of complex biological networks, like estrus regulation, and to deal with the increasing amount of genomic information that becomes available, mathematical models can be helpful. Systems biology combines physiological and genomic data with mathematical modeling. Possible applications of systems biology approaches in the field of female fertility and estrous behavior are discussed. PMID- 22443950 TI - Dietary genistein stimulates mammary hyperplasia in gilts. AB - The possible role of the phytoestrogen genistein on prepubertal development of mammary glands, hormonal status and bone resorption was investigated in gilts. Forty-five gilts were fed a control diet containing soya (CTLS, n = 15), a control diet without soya (CTL0, n = 15) or the CTLS diet supplemented with 2.3 g of genistein daily (GEN, n = 15) from 90 days of age until slaughter (day 183 +/- 1). Both basal diets were isonitrogenous and isocaloric. Jugular blood samples were obtained on days 89 and 176 to determine concentrations of isoflavone metabolites (on day 176 only), prolactin, estradiol, progesterone, insulin-like growth factor 1 (IGF1), and N-telopeptide of type I collagen (NTx; on day 176 only). At slaughter, mammary glands were excised, parenchymal and extraparenchymal tissues were dissected, and composition of parenchymal tissue (protein, fat, dry matter (DM), DNA) was determined. Histochemical analyses of mammary parenchyma were performed. Dietary genistein increased parenchymal protein (P < 0.05) while decreasing DM (P < 0.05) and tending to lower fat content compared with the CTLS, but not the CTL0, diet. There was more parenchymal DNA (1.26 v. 0.92 mg/g, P < 0.05) in GEN than CTLS gilts, likely reflecting an increase in the quantity of mammary epithelial cells. Circulating concentrations of genistein were increased in GEN gilts (P < 0.001) but concentrations of hormones or NTx (indicator of bone collagen resorption) were not affected by GEN (P > 0.1). Percentage of estradiol receptor alpha (ERalpha) positive epithelial cells was lower (P < 0.05) in GEN than CTLS gilts, whereas 5 bromo-2'-deoxyuridine labeling index was unaltered (P > 0.1). Transcript levels for ERalpha, ERbeta, IGF1, epidermal growth factor (EGF), epidermal growth factor receptor and transforming growth factor alpha were not altered by treatments. Supplementation of the diet with genistein during the growing phase in gilts, therefore, led to hyperplasia of mammary parenchymal tissue after puberty; yet, even though circulating genistein was increased, this was not accompanied by changes in mammary expression of selected genes or circulating hormone levels. PMID- 22443951 TI - The myostatin null mutation and clenbuterol administration elicit additive effects in mice. AB - In mice, the myostatin (Mstn) null mutation and treatment with clenbuterol both increase muscle growth and decrease fat mass. Our objective was to determine whether mechanistic overlap exists by administering clenbuterol to Mstn null mice. Male Mstn null and wild-type mice of similar genetic backgrounds received either 0 (control) or 20 p.p.m. clenbuterol in tap water free choice for 14 days. Several traits were measured to estimate muscle and fat growth. The Mstn null mutation resulted in increased body and empty carcass weight, increased muscle weights and decreased fat pad weights. Fat content was reduced and protein content was increased in the empty carcasses of Mstn null mice. Similarly, treatment with clenbuterol resulted in increased body and empty carcass weight, increased muscle weights and reduced fat pad weights. Fat content of empty carcasses and viscera was reduced and protein content of empty carcasses was increased with clenbuterol treatment. A significant interaction of genotype and clenbuterol treatment would indicate an altered responsiveness of Mstn null mice to clenbuterol. However, only the weight of gastrocnemius muscles exhibited a significant (P = 0.01) interaction of genotype and clenbuterol treatment, indicating that Mstn null mice were less responsive to clenbuterol compared with wild-type mice. Thus, for all other traits, the impact of Mstn null mutation and clenbuterol treatment was completely additive. These data suggest that disruption of Mstn function does not alter the response of mice to beta-adrenergic agonists. PMID- 22443952 TI - Ram-induced oestrus and ovulation in lactating and weaned Corriedale ewes. AB - Two experiments were conducted in consecutive years in which recently (Experiment 1) or temporarily (Experiment 2) weaned ewes and matched post-partum non lactating flockmates (DRY) were exposed to a stimulus group of rams and oestrous ewes (10 and 20 in Experiment 1, 20 and 20 in Experiment 2) for 28 days in spring. Lactating ewes (n = 130) in Experiment 1 were isolated from their lambs 4 (W-4), 2 (W-2), 1 (W-1) or 0 (W-0) days in advance and exposed along with a group of 32 DRY flockmates. Lactating ewes in Experiment 2 (n = 230) were allocated to an unreplicated factorial of two levels of temporary weaning before stimulation (B0: control; B24: lambs removed 24 h before stimulation) by four levels of ewe lamb contact imposed at the start of the stimulation (A0: control; A12, A24 and A36: lamb-ewe separation during the initial 12, 24 or 36 h of exposure); DRY ewes (n = 54) acted as an augmented factorial control. Oestrus (rump marks) and ovulation (laparoscopy on day 5 and on day 28 (Experiment 1) or day 32 (Experiment 2)) were recorded. Ovulation and oestrous responses in Experiment 1 were similar for DRY (90.6% and 55.2%, respectively) and recently weaned ewes (83.8% and 53.7%, respectively). Amongst recently weaned ewes, the immediate ovulation response to the rams and the proportion of ewes still cycling by day 28 tended to be lower (P = 0.065 and P = 0.011) in ewes weaned on the day of ram exposure (71.9% and 54.8% v. 87.8% and 80.0%, respectively). Ovulation rate was lower (P < 0.003) in W-2 ewes (1.3 +/- 0.10) than in the other recently weaned groups. In Experiment 2, ovulation (83.3%) and oestrous (68.9%) responses in DRY ewes were higher (P = 0.022 and P = 0.053, respectively) than in lactating ewes (66.2% and 51.0%, respectively). More ewes ovulated (P = 0.036) in B24 (70.5%) than in B0 (61.8%). Ewes having their lambs returned 12 h after the onset of stimulation (A12) had poorer ovulation responses (54.9%) than control ewes (A0, 72.9%, P < 0.05); this was probably associated to lamb restitution after the sunset. Main conclusions were that (i) the presence of the lambs is a depressing factor of both ovulation and oestrous responses to the ram effect in lactating ewes, (ii) the ovulation response of lactating ewes will probably benefit from removing lambs for a period of 24 h before the onset of stimulation, (iii) until additional information becomes available, temporary weaning protocols should be designed avoiding lamb restitution during the night. PMID- 22443953 TI - Influence of sward structure on daily intake and foraging behaviour by horses. AB - The spatial heterogeneity of grasslands determines the abundance and quality of food resources for grazing animals. As plants mature, they increase in mass, which allows greater instantaneous intake rates, but the cell wall concentrations increase too, reducing diet quality. In ruminants, daily intake rates are often constrained by the time needed for the ingesta to pass through the rumen, which is influenced by the rate of digestion. It has been suggested that the digestive constraint should have much less effect on hindgut fermenters such as equids. Horses play an increasing role in the management of grasslands in Europe, but the data on the influence of the heterogeneity of the vegetation on their daily intake and foraging behaviour are sparse. We report here the results of a preliminary study concerning the effects of sward structure on nutrient assimilation and the use of patches of different heights by horses grazing successively a short immature, a tall mature and a heterogeneous pastures (with short and tall swards). Daily nutrient assimilation was higher in the heterogeneous pasture compared to the short (+35%) and the tall (+55%) ones. The digestive constraints may have limited voluntary intake by horses on the tall swards. In the heterogeneous pasture, the mean height used for feeding (6 to 7 cm) by horses was intermediate between the heights used in the short (4 to 5 cm) and tall pastures (22 to 23 cm), and the animals may thus have benefited from both short swards of high quality and tall swards offering a higher instantaneous intake rate. PMID- 22443954 TI - Effects of sire breed on ewe dystocia, lamb survival and weaned lamb output in hill sheep systems. AB - A study was carried out on six hill farms, located in the main hill regions of Northern Ireland, over three breeding seasons to investigate the effect of sire breed on ewe dystocia, lamb survival and weaned lamb output. On each farm, groups of 26 to 40 purebred Scottish Blackface ewes (n = 3174) were crossed with Blackface, Swaledale, North Country Cheviot, Lleyn and Texel sires by natural service (year 1) and artificial insemination (years 2 and 3). Each of the mating groups was initially balanced for ewe age, live weight and condition score, and a total of 15 sires of each breed were used over the 3 years. In total, 2272 ewes were recorded at lambing, producing 3451 lambs, over the 3 years. Sire breed had a significant effect (P < 0.001) on lamb birth weight with Blackface and Swaledale the lowest and Texel the highest. The proportion of ewes with dystocia was higher with Texel sires compared with Lleyn, Swaledale and Blackface sires (P < 0.05). Ewes mated to Cheviot sires had more dystocia than those mated to Blackface and Swaledale sires (P < 0.05), while ewes mated to Lleyn sire breed had more dystocia (P < 0.05) than those mated to Blackface sire breed. Most of the incidence of dystocia was attributable to increased lamb birth weight (P < 0.001), and some to litter size (P < 0.05). Swaledale, Cheviot, Lleyn and Texel sire breeds increased the incidence of malpresentations (P < 0.05). Lamb live weight at weaning was higher with Texel- and Cheviot- and Lleyn-sired lambs compared with Blackface- and Swaledale-sired lambs (P < 0.01). The level of lamb mortality at birth was not affected by sire breed. However, lamb mortality at weaning was lower for Lleyn-sired lambs compared with the other lamb genotypes (P < 0.05). These results indicate that the use of sires from larger breeds, such as Lleyn and Texel, within the Blackface ewe flocks can increase lamb output, with no apparent detrimental effects on lamb mortality or ewe survival, but increased assistance at lambing will be required. PMID- 22443955 TI - Optically induced tunable magnetization dynamics in nanoscale co antidot lattices. AB - We report the time-domain measurements of optically induced precessional dynamics in a series of Co antidot lattices with fixed antidot diameter of 100 nm and with varying lattice constants (S) between 200 and 500 nm. For the sparsest lattice, we observe two bands of precessional modes with a band gap, which increases substantially with the decrease in S down to 300 nm. At S = 200 nm, four distinct bands with significant band gaps appear. The numerically calculated mode profiles show various localized and extended modes with the propagation direction perpendicular to the bias magnetic field. We numerically demonstrate some composite antidot structures with very rich magnonic spectra spreading between 3 and 27 GHz based upon the above experimental observation. PMID- 22443956 TI - "Switching adalimumab from syringe to pen. Expected outcomes". PMID- 22443957 TI - What is on the horizon: the physiatrist's role in injury prevention. PMID- 22443958 TI - Polypharmacy and the role of physical medicine and rehabilitation. AB - Polypharmacy and inappropriate prescribing practices lead to higher rates of mortality and morbidity, particularly in vulnerable populations, such as the elderly and those with complex medical conditions. Physical medicine and physiatrists face particular challenges given the array of symptoms treated across a spectrum of conditions. This clinical review focuses on polypharmacy and the associated issue of potentially inappropriate prescribing. The article begins with a review of polypharmacy along with relevant aspects of pharmacokinetics and pharmacodynamics in the elderly. The adverse effects and potential hazards of selected medications commonly initiated and managed by rehabilitation specialists are then discussed with specific attention to pain medications, neurostimulants, antipsychotics, antidepressants, antispasmodics, sleep medications, and antiepileptics. Of particular concern is the notion that an adverse effect of one medication can mimic an indication for another and lead to a prescribing cascade and further adverse medication events. Appropriate prescribing practices mandate an accurate, current medication list, yet errors and inaccuracies often plague such lists. The evidence to support explicit (medications to avoid) and implicit (how to evaluate) criteria is presented along with the role of physicians and patients in prescribing medications. A brief discussion of "medication debridement" or de-prescribing strategies follows. In the last section, we draw on the essence of physiatry as a team-based endeavor to discuss the potential benefits of collaboration. In working to optimize medication prescribing, efforts should be made to collaborate not only with pharmacists and other medical specialties but with members of inpatient rehabilitation teams as well. PMID- 22443959 TI - Communicating risks clearly: absolute risk and number needed to treat. PMID- 22443960 TI - Electrodiagnostic testing before epidural steroid injections. PMID- 22443961 TI - Hypothermia-induced peripheral polyneuropathy after an episode of drowning. PMID- 22443962 TI - Iatrogenic Cushing syndrome after epidural steroid injections for lumbar radiculopathy in an HIV-infected patient treated with ritonavir: a case report highlighting drug interactions for spine interventionalists. PMID- 22443963 TI - Electrodiagnostic findings heralding neoplastic brachial plexopathy. PMID- 22443964 TI - Porosity control of Pd@SiO2 yolk-shell nanocatalysts by the formation of nickel phyllosilicate and its influence on Suzuki coupling reactions. AB - The surface of Pd@SiO(2) core-shell nanoparticles (1) was simply modified by the formation of nickel phyllosilicate. The addition of nickel salts formed branched nickel phyllosilicates and generated pores in the silica shells, yielding Pd@SiO(2)-Niphy nanoparticles (Niphy = nickel phyllosilicate; 2, 3). By removal of the silica residue, Pd@Niphy yolk-shell nanoparticles (4) was uniformly obtained. The four distinct nanostructures (1-4) were employed as catalysts for Suzuki coupling reactions with aryl bromide and phenylboronic acid, and the conversion yields were in the order of 1 < 2 < 3 < 4 as the pore volume and surface area of the catalysts increased. The reaction rates were strongly correlated with shell porosity and surface exposure of the metal cores. The chemical inertness of nickel phyllosilicate under the basic conditions rendered the catalysts reusable for more than five times without loss of activity. PMID- 22443965 TI - Synthesis of platinum-based binary and ternary alloy nanoparticles in an intense laser field. AB - Gold-platinum-silver (Au-Pt-Ag) ion mixtures produced nanoparticle alloys with an average particle size of 5 nm after co-reduction of metal ions by femtosecond laser irradiation of aqueous solutions in the presence of ammonia and polyvinylpyrrolidone, which was used as a stabilizer. Alloy formation was confirmed by analyzing the interplanar spacings measured by diffraction techniques; the interplanar spacings obtained showed good agreement with those derived from Vegard's law. The nanoparticles had elemental composition ratios close to the molar ratios of ions in the mixed solutions, implying a high reduction yield. High-resolution transmission electron microscopy images of nanoparticles revealed that the particles were crystalline and were not phase segregated. Binary nanoparticles from Au-Pt and Ag-Pt immiscible systems were also synthesized to confirm the applicability of this method to ternary systems. The formation of nanoalloys by intense femtosecond laser irradiation was possible due to the fast reduction of the mixed ions by solvated electrons and hydrogen radicals generated in situ during irradiation. PMID- 22443966 TI - Influence of interfacial water layer on surface properties of silver halides: effect of pH on the isoelectric point. AB - The hypothesis that pH dependent charge of interfacial water affects electrokinetic charge and electrokinetic potential of hydrophobic colloids, but not the (inner) surface potential was tested. It was found that isoelectric points of silver chloride, bromide and iodide shift to the higher pAg values in the acidic solutions, but that surface potential did not depend on pH. Isoelectric points of water at inert surfaces lie in the range 2400 ml Fe-fortified formula or 8 mg Fe/d) is associated with more favourable levels of Fe status indicators compared to those not following the recommendation. A random sample of 9-month-old infants living in Copenhagen was established and 312 healthy term infants were examined at 9.1 (sd 0.3) months of age. Blood samples were available from 278 infants. Overall, twenty infants (7.8 %) had Fe deficiency (serum ferritin < 12 MUg/l) and < 1 % had Fe deficiency anaemia (serum ferritin < 12 MUg/l and Hb < 100 g/l). Serum ferritin was positively associated with birth weight (P < 0.001), intake of fortified formula and follow-on formula (P = 0.001), and female sex (P < 0.001). Cow's milk intake and length of exclusive breast-feeding were negatively associated with Hb levels (P = 0.013 and P < 0.001). Serum ferritin levels were significantly higher (P < 0.0001) and transferrin receptor (TfR) was significantly lower (P = 0.003) among infants (n 188) meeting the Fe supplementation recommendation compared to those (n 67) not meeting the recommendation. No significant difference between these two groups was found for Hb. In conclusion, this study confirmed that Fe status of infants following the Danish Fe supplementation recommendation was significantly associated with increased serum ferritin and decreased levels of TfR indicating more favourable Fe status, compared to infants not following the recommendation. PMID- 22443991 TI - Footwear and orthopaedics. AB - Footwear is the oldest known fashion accessory in use. Footwear is often implicated in orthopaedic problems affecting lower limbs and back. Hence footwear modifications have a major role in management of these pathologies as well. This review explores footwear and its role in causation and management of orthopaedic problems. Based on our observations we recommend that children with flexible flatfeet should be encouraged to walk barefoot to help in developing their arches. Women with risk factors for secondary arthritis of knee or back pain may be advised to avoid heels. Commercial shoes which decrease hind foot loading may be used in symptomatic management of hindfoot and mid foot problems. Similarly shoes which decrease forefoot loading may be useful in managing forefoot pathology. Flip-flops should be avoided by diabetics as they do not protect from injuries. PMID- 22443992 TI - The primary arthrodesis for severely comminuted intra-articular fractures of the calcaneus: a systematic review. AB - BACKGROUND: Although open reduction and internal fixation via the extended lateral approach is currently considered gold-standard, severely comminuted calcaneal fractures might not be amendable for reconstruction. The primary aim of the current review study was to assess the functional outcome of the primary arthrodesis in the management of comminuted displaced intra-articular calcaneal fractures. METHODS: The literature was searched for studies published between January 1st 1990 and December 1st 2010, to identify studies in which a primary arthrodesis was utilized for the treatment of displaced intra-articular calcaneal fractures between. The methodological quality of the included studies was assessed using the Coleman Methodology Score. RESULTS: Seven case series and one abstract were identified, reporting on 120 patients with 128 severely comminuted calcaneal fractures. Average follow-up time was 28 months and union rate 97%. Functional outcome was assessed using the modified AOFAS score in seven studies; with a weighted average of 77.4 (range 72.4-88). One study reported a 75% good to excellent outcome on the Paley score. Three studies reported on return to work, ranging from 75 to 100%. Overall reported wound complications occurred in 19.4%. The average Coleman Methodology Score was 56 (range 38-68) points. CONCLUSIONS: The primary arthrodesis for the treatment of Sanders type-IV comminuted displaced intra-articular calcaneal fractures provides overall good results considering the severe nature of the injury. Therefore, in the process of choosing the best treatment modality for a severely comminuted calcaneal fracture, the primary arthrodesis should receive full consideration. PMID- 22443993 TI - Glomus tumor of the hallux. Review of the literature and report of two cases. AB - A glomus tumor is a rare and benign vascular tumor. It can originate in multiple locations on the body, although it has most frequently been found in subungeal areas of the hand. This two cases report describes a glomus tumor of the hallux, including a recurrence and a review of the related literature. We believe this case study might be of interest due to the unusual location of this tumor. PMID- 22443994 TI - The rheumatoid foot and ankle: current evidence. AB - The management of rheumatoid patients is a complex process due to the chronic, systemic, multi-joint and extra-articular nature of the disease. In comparison, osteoarthritis and post-traumatic arthritis usually involve a single joint and are hence not comparable to rheumatoid pathology. This review sets out to specifically look at studies on rheumatoid patients with interventions for foot or ankle disease. MEDLINE, EMBASE, the Cochrane databases, Current Controlled Trials and the WHO International Clinical Trials Registry Platform are all searched for relevant studies. PMID- 22443995 TI - Complications after open reduction and internal fixation of ankle fractures in the elderly. AB - BACKGROUND: Open reduction with internal fixation for unstable ankle fractures is relatively predictable with excellent outcomes. However, the management of ankle fractures in the elderly remains less predictable secondary to the various co morbidities associated with advanced age. METHODS: A retrospective chart review of 216 patients over the age of 60 that sustained an ankle fracture, was performed to determine the incidence of complications after ORIF of ankle fractures in an elderly population in the perioperative course. Secondly, the incidence of complications in patients that had locking plate fixation compared to those that had non-locking plate fixation was determined. Lastly, the effect of early weight bearing on the incidence of complications was analyzed. RESULTS: There was not a statistically significant difference in the complication rates between the group with co-morbidities (19.01%) and those without (11.96%). The postoperative complication with the highest incidence was wound dehiscence (9.7%), and only diabetes significantly predicted wound dehiscence. The fixation construct and weight-bearing protocol failed to significantly predict any of the indexed complications. CONCLUSIONS: Overall, the results suggest that surgical treatment of unstable ankle fractures in the elderly is fairly predictable with an acceptable complication rate. The complication rates are higher with increased age and diabetes, but they failed to reach statistical significance. Conventional plating appears to provide adequate stability without increased risk of hardware failure. In addition patients that were allowed to walk within the first 2 weeks postoperatively did not experience a higher rate of hardware failure. PMID- 22443996 TI - A comparison of two night ankle-foot orthoses used in the treatment of inferior heel pain: a preliminary investigation. AB - BACKGROUND: Non-operative treatment for plantar fasciitis varies widely and includes the use of night ankle-foot orthoses (AFOs). This study compares the effectiveness of a posterior AFO, which dorsiflexes the foot, with an anterior AFO, which maintains the foot in a plantigrade position. METHOD: Each participant was given a questionnaire to fill in to evaluate how satisfied the participants were with the orthosis with regards to comfort, ease of use and appearance, and whether the pain in the foot was reduced and at what stage was the pain decreased. RESULTS: Two-thirds of all participants confirmed that morning pain and stiffness was less after wearing the AFO; both types were relatively easy to don and doff, but the posterior orthosis was more uncomfortable and disrupted sleep. On average, the anterior AFO reduced heel pain more significantly than the posterior orthosis. CONCLUSION: Plantar fasciitis night AFOs are poorly tolerated orthoses but their use can be justified in that the pain levels are reduced. The anterior AFOs are more comfortable and more effective than posterior AFOs. PMID- 22443997 TI - Headless compression screw fixation prevents symptomatic metalwork in arthroscopic ankle arthrodesis. AB - BACKGROUND: Arthroscopic ankle arthrodesis (AAA) is a recognised salvage procedure for end-stage arthritis. Its reported disadvantages include a high rate of re-operation for symptomatic prominence of metalwork. We propose that the use of a headless screw would reduce this re-operation rate. METHODS: We reviewed 32 AAAs, using the AcutrakTM6/7 mm headless screw fixation system, to determine peri operative parameters and complication rates. RESULTS: At an average of 22 months follow-up, 28 (88%) had united radiologically. There were 2 stable fibrous non unions not requiring further intervention. Of the other 2, one was successfully revised using an open technique, and the other patient died of unrelated causes. There were no other complications in this series, with no cases of metalwork removal for prominence or pain. CONCLUSIONS: Using a headless screw fixation for arthroscopic ankle arthrodesis prevents symptomatic metalwork prominence and the requirement for removal. PMID- 22443998 TI - Synthetic osteochondral grafting of ankle osteochondral lesions. AB - BACKGROUND: The treatment of osteochondral lesions, especially those with a cystic component or those that have failed the standard arthroscopic procedures can be challenging. Synthetic grafts have several potential advantages over other second line treatments including the fact that only one operation is required and no other joint is violated. METHOD: We report the results of the first series of synthetic grafts used in the treatment of osteochondral lesions of the ankle with a minimum of one year follow up. RESULTS: There was significant improvement in the American Orthopaedic Foot & Ankle Society (AOFAS) Hindfoot and Ankle Osteoarthritis Scale (AOS) scores and all patients were satisfied with the results of surgery. Magnetic Resonance Imaging (MRI) scans at one year have demonstrated resolution of the bony cysts and surrounding bone marrow oedema but, worryingly, continued to show high signal on the T2 weighted images within the plugs themselves. Qualitative T2 mapping has suggested a fibrous rather than hyaline appearance of the cartilage portions of the plugs. CONCLUSIONS: The clinical results have been encouraging but more patients and longer follow up are required before firm conclusions can be drawn. PMID- 22443999 TI - Epidemiologic investigation of 1394 feet: coincidence of hindfoot malalignment and Achilles tendon disorders. AB - BACKGROUND: The aim of this epidemiologic study was to evaluate the incidence of the Achilles tendinopathy in non athletes and the coincidence with varus alignment of the hindfoot. METHODS: Six hundred ninety-seven patients (1394 feet) have been analysed. The tibiocalcaneal axis was goniometrically measured. The presence of a non insertional and insertional Achilles tendinopathy was clinically determined. RESULTS: Achilles tendinopathy was found in 5.6% of the patients (4% insertional, 3.6% non insertional, 1.9% both forms). The average tibiocalcaneal angle was calculated with -0.76 degrees for the tendinopathy group and -0.96 degrees for the insertional tendinopathy whereas the control group showed an average angle of 1.77 degrees . For the total group the average tibiocalcaneal axis was calculated with 1.62 degrees . Out of 1394 feet 38.3% showed a varus axis of the hindfoot and 61.7% a valgus alignment. CONCLUSIONS: The coincidence of varus alignment and Achilles tendinopathy could be validated. PMID- 22444000 TI - Achilles tendinoscopy and plantaris tendon release and division in the treatment of non-insertional Achilles tendinopathy. AB - BACKGROUND: The mainstay of treatment for non-insertional Achilles tendinopathy is non-operative, however a proportion of patients will fail conservative measures. We describe the results of Achilles tendinoscopy with plantaris tendon release in patients who have failed first line conservative treatment for at least 6 months. METHODS: A consecutive series of 11 patients with a minimum of 2 years follow up. RESULTS: The mean AOFAS scores significantly improved from 68 pre-op to 92 post op (p=0.0002) as did the AOS scores for both pain (28% pre-op to 8% post op (p=0.0004)) and disability (38% pre-op to 10% post op (p=0.0005). The mean SF-36 scores also improved but were not statistically significant (pre op 76, post op 87 (p=0.059). There were no complications. 8 of the 11 patients were satisfied, the other 3 somewhat satisfied. CONCLUSIONS: The results of Achilles tendinoscopy and division of the plantaris tendon are encouraging but further studies are required to compare it to other treatments. It is minimally invasive and low risk so should not affect the ability to perform a formal open procedure if unsuccessful. PMID- 22444001 TI - The safety profile of a retrospective Accessory Postero-Lateral hind foot portal: the risk of sural nerve damage during visualisation of the Achilles tendon insertion. AB - INTRODUCTION: The Accessory Postero-Lateral (AccPL) portal has recently been described to improve the visualisation for the endoscopic debridement of Haglund's tubercle. The safety of using this portal has been considered previously for posterior ankle arthroscopy. We performed a study to determine the proximity of the AccPL portal to the sural nerve. METHODS: We compared the distances between AccPL and PL portals to the sural nerve in 17 cadaveric specimens. RESULTS: The AccPL portal was significantly closer (mean 12.0mm, range 6-19 mm, SD=3.64) to the sural nerve than the PL portal (mean 14.1mm, range 11-18 mm, SD=2.34) (t(16)=-2.34, p=0.03). In two cases the sural nerve was in contact with the clip but on close inspection, the nerve had not been damaged in any of the specimens. CONCLUSIONS: We conclude that the AccPL portal is a safe method to allow visualisation during endoscopic debridement of the Achilles tendon insertion. We also recommend that the portal is used for visualisation rather than instrumentation. PMID- 22444002 TI - Molded arthrodesis of the hallux metatarsophalangeal joint using the crossed screw technique: surgical technique, results and functional outcomes. AB - BACKGROUND: We describe the surgical technique, results and functional outcomes of molded arthrodesis of hallux metatarsophalangeal (MTP) joint using crossed screw fixation. METHODS: 23 Toes in 21 consecutive patients operated between September 2007 and January 2010 were included for the retrospective study. Average age was 60.0 years (range 31-84 years) with male female ratio being 3:4. Differential pitch cannulated crossed screw technique was used in all cases. At the latest follow-up, the radiological findings, the hallux-forefoot AOFAS scores and patient satisfaction questionnaires were used to assess outcomes. RESULTS: Overall fusion rate was 91% with a mean hallux valgus angle of 13.6 degrees (range 8-22 degrees ) and a mean dorsi-flexion angle of 25 degrees (range 18-30 degrees ). Complication rate was 13% that included two superficial wound infections and one failed fusion that underwent a successful fusion after revision surgery. At a mean follow-up of 17 months (range 6-34 months), the mean AOFAS score was 79 (out of a maximum of 90). 92% of the patients were satisfied with the final outcome and 83% mentioned that they would have the procedure again. CONCLUSIONS: Crossed-screw technique of arthrodesis of the first MTP joint is successful for relief of pain, allowing a high level of function and good patient satisfaction. PMID- 22444003 TI - Prospective analysis of a first MTP total joint replacement. Evaluation by bone mineral densitometry, pedobarography, and visual analogue score for pain. AB - BACKGROUND: We hypothesized that a total replacement of the first metatarsophalangeal joint (MTP-1) would alter the walking pattern with medialisation of the ground reaction force (GRF) of the foot and subsequently cause an increase in bone mineral density (BMD) in the medial metatarsal bones and a decline of BMD in the lateral metatarsal bones. METHODS: Twelve patients receiving total joint replacements (Roto-Glide((r))) of MTP-1 were enrolled in a prospective cohort. BMD and pedobarography of the heel bone and the metatarsal heads were performed preoperatively and at least 12 months postoperatively. RESULTS: BMD in the lateral metatarsals and GRF under the lateral column of the operated feet decreased significantly on the operated feet. CONCLUSIONS: Total joint replacement of MTP-1 tends to reduce GRF under the lateral column of the foot causing a corresponding decline in BMD and pedobarographic measures. Our findings support the further use of the Roto-Glide((r)) prosthesis for osteoarthritis of the first metatarsophalangeal joint. PMID- 22444004 TI - Surgeon administered regional blocks for day case forefoot surgery. AB - INTRODUCTION: The aim was to see if as surgeons we were providing safe, efficient and effective, regional blocks for patients undergoing day case, forefoot surgery. We also assessed the costs of, providing this service. METHODS: 63 consecutive patients were recruited prospectively for local anaesthetic block. Blocks were, performed by the orthopaedic team. Efficacy of block was assessed intra-operatively with a visual, analogue score (VAS) of 0-10. Satisfaction with the anaesthetic procedure was also assessed. RESULTS: Average time to perform the block was 6 min. Mean VAS for knife to skin was 0.44 (95%, confidence 0.07-0.81) and for ankle tourniquet was 1.39 (95% confidence 0.85-1.39). Patients were, highly satisfied with the blocks. No complications were reported. CONCLUSIONS: These blocks are quick and easy to perform by orthopaedic surgeons. They are well, tolerated and effective. They result in considerable cost savings to the Hospital. PMID- 22444005 TI - Fibula lengthening osteotomy to correct valgus mal-alignment following total ankle arthroplasty. AB - Total Ankle Arthroplasty (TAA) is increasing in popularity following the development of the, next generation of implants and improved surgical technique giving better long-term results. Significant mal-alignment of the ankle pre operatively has always provided a challenge to the surgeon, to regain anatomical alignment to reduce subsequent wear. We present a series of two cases of TAA, who developed post-operative valgus deformity requiring salvage procedure in the form of a fibula, lengthening osteotomy. PMID- 22444006 TI - Comparison of statistical models to analyse the genetic effect on within-litter variance in pigs. AB - Genetics affects not only the weight of piglets at birth but also the variability of birth weight within litter. Previous studies on this topic assigned the sample standard deviation of piglet birth weights within litter as an observation to the sow. However, the contribution of the difference in mean birth weight per sex on the within-litter variance has been neglected so far. This work deals with the genetic effect on within-litter variance when different statistical models with different distributional assumptions are used and considers the sex effect and appropriate weights per trait. Traits were formed from the pooled sample variance of male and female birth weights within litter. A linear model approach was fitted to the logarithmized within-litter variance and the sample standard deviation. A generalized linear model with gamma-distributed residuals and log link function was applied to the untransformed sample variance. Models were compared by analysing data from 9439 litters from Landrace and Large White of a commercial breeding programme. The estimates of heritability for different traits ranged from 7% to 11%. Although the generalized linear mixed model is preferred from a mathematical view, the rank correlations between breeding values of the linear mixed models and the generalized linear mixed model were relatively high, i.e. 94% to 98%. By residual diagnostics, a linear mixed model using the weighted and pooled within-litter standard deviation was identified as most suitable. PMID- 22444007 TI - Evaluation of the VP22 gene adjuvant for enhancement of DNA vaccine against somatostatin in mice. AB - Somatostatin (SS) is a hormone that inhibits the secretion of growth hormone. Immunization against SS can promote the growth of animals. A novel SS-VP22 fused vaccine, pEGS2SS-V, was constructed from pEGS2SS plasmid with a VP22 gene fragment. Two times of immunization with pEGS2SS-V-induced anti-SS antibodies in mice. Compared with mice immunized with pEGS2SS and 0.85% saline, the growth performance of mice immunized with pEGS2SS-V was increased by 14.1% (P < 0.05) and 48.4% (P < 0.01) on the 2nd week after the first vaccination, respectively. The results indicated that the effects of the somatostatin DNA vaccine could be improved effectively by VP22 gene adjuvant. PMID- 22444008 TI - Pig peripheral blood mononuclear leucocyte subsets are heritable and genetically correlated with performance. AB - Indicator traits used to select pigs for increased resistance to infection or improved health must be heritable and, preferably, be associated with improved performance. We estimated the heritability of a range of immune traits and their genetic and phenotypic correlations with growth performance. We measured immune traits on 589 pigs and performance on 1941 pigs from six farms, three of which were classified as 'high health status' (i.e. specific pathogen-free) and three were of lower health status. All pigs were apparently healthy. Immune traits were total white blood cells (WBC), and peripheral blood mononuclear leucocyte (PBML) subsets positive for CD4, CD8alpha, gamma delta (gammadelta) T cell receptor, CD11R1 (natural killer cell marker), B cell and monocyte markers at the start and the end of standard growth performance tests. At both time points, all immune traits were moderately to highly heritable except for CD8alpha+ cells. At end of test, heritability estimates (h2) (+/-s.e.) were 0.18 (+/-0.11) for total WBC count. For PBML subset proportions, the heritabilities were 0.52 (+/-0.14) for gammadelta TCR+ cells, 0.62 (+/-0.14) for CD4+ cells, 0.44 (+/-0.14) for CD11R1+ cells, 0.58 (+/-0.14) for B cells and 0.59 (+/-0.14) for monocytes. Farm health status affected the heritabilities for WBC, being substantially higher on lower health status farms, but did not have consistent effects on heritabilities for the PBML subsets. There were significant negative genetic correlations between numbers and proportions of various PBML subsets and performance, at both start and end of test. In particular, the proportion of PBML cells that were CD11R1+ cells, at end of test, was strongly correlated with daily gain (rg = -0.72; P < 0.01). There were also weaker but significant negative phenotypic correlations between PBML subsets measured at end of test and performance, for gammadelta+ T cells, CD8alpha+, CD11R1+ cells, B cells or monocytes. Phenotypic correlations with daily gain were generally lower at the start of test than at the end of test. These results show that most of the major pig PBML subsets are heritable, and that systemic levels of several of these PBML subsets are genetically negatively correlated with performance. This approach provides a basis for using immune trait markers when selecting boars that can produce higher-performing progeny. PMID- 22444009 TI - Analysis of water intake, dry matter intake and daily milk yield using different error covariance structures. AB - The aim of the present study was to investigate the daily measured traits milk yield, water intake and dry matter intake with fixed and random regression models added with different error covariance structures. It was analysed whether these models deliver better model fitting in contrast to conventional fixed and random regression models. Furthermore, possible autocorrelation between repeated measures was investigated. The effect of model choice on statistical inference was also tested. Data recording was performed on the Futterkamp dairy research farm of the Chamber of Agriculture of Schleswig-Holstein. A dataset of about 21 000 observations from 178 Holstein cows was used. Average milk yield, water intake and dry matter intake were 34.9, 82.4 and 19.8 kg, respectively. Statistical analysis was performed using different linear mixed models. Lactation number, test day and the parameters to model the function of lactation day were included as fixed effects. Different structures were tested for the residuals; they were compared for their ability to fit the model using the likelihood ratio test, and Akaike's and Bayesian's information criteria. Different autocorrelation patterns were found. Adjacent repeated measures of daily milk yield were highest correlated (p1 = 0.32) in contrast to measures further apart, while for water intake and dry matter intake, the measurements with a lag of two units had the highest correlations with p2 = 0.11 and 0.12. The covariance structure of TOEPLITZ was most suitable to indicate the dependencies of the repeated measures for all traits. Generally, the most complex model, random regression with the additional covariance structure TOEPLITZ(4), provided the lowest information criteria. Furthermore, the model choice influenced the significance values of one fixed effect and therefore the general inference of the data analysis. Thus, the random regression + TOEPLITZ(4) model is recommended for use for the analysis of equally spaced datasets of milk yield, water intake and dry matter intake. PMID- 22444010 TI - Effects of rumen-protected choline supplementation on milk production and choline supply of periparturient dairy cows. AB - The objective of the present study was to determine the effects of rumen protected choline (RPC) supplementation on body condition, milk production and milk choline content during the periparturient period. Thirty-two Holstein cows were allocated into two groups (RPC group - with RPC supplementation, and control group - without RPC supplementation) 28 days before the expected calving. Cows were fed the experimental diet from 21 days before expected calving until 60 days of lactation. The daily diet of the RPC group contained 100 g of RPC from 21 days before calving until calving and 200 g RPC after calving for 60 days of lactation, which provided 25 g and 50 g per day choline, respectively. Body condition was scored on days -21, 7, 35 and 60 relative to calving. Milk production was measured at every milking; milk fat, protein and choline content were determined on days 7, 35 and 60 of lactation. Body condition was not affected by RPC supplementation. Milk yield was 4.4 kg higher for the group of cows receiving supplementary choline during the 60 days experimental period and 4% fat-corrected milk production was also increased by 2.5 kg/day. Milk fat content was not altered by treatment, but fat yield was increased by 0.10 kg/day as a consequence of higher milk yield in the RPC-treated group. Milk protein content tended to increase by RPC supplementation and a 0.18 kg/day significant improvement of protein yield was detected. Milk choline content increased in both groups after calving as the lactating period advanced. However, milk choline content and choline yield were significantly higher in the RPC group than in the control group. The improved milk choline and choline yield provide evidence that some of the applied RPC escaped ruminal degradation, was absorbed from the small intestine and improved the choline supply of the cows and contributed to the changes of production variables. PMID- 22444011 TI - Performance of growing-finishing pigs fed diets containing Roundup Ready wheat (MON 71800), a non-transgenic genetically similar wheat, or conventional wheat varieties. AB - The objective of this study was to compare growth performance and carcass and meat quality characteristics of growing-finishing pigs fed diets containing Roundup Ready wheat (MON 71800), compared with the non-transgenic genetically similar parental control wheat (MON 71900), and four commercial varieties of non transgenic wheat (HANK, Westbred 926, Express and Zeke). The study was carried out as a split-plot design with a 2 * 6 factorial arrangement of treatments (two genders and six wheat varieties). A three-phase dietary program was used; all diets were formulated with a fixed level of wheat inclusion (70%, 80% and 85% for the Grower, Finisher I and Finisher II phases, respectively). A total of 240 commercial hybrid pigs (equal numbers of barrows and gilts) were grown from 29.5 +/- 0.29 to 114.5 +/- 2.23 kg live weight in single-gender pens (barrows or gilts) of five pigs (eight pens per dietary treatment) with ad libitum access to feed and water throughout the study. At the end of each dietary phase and of the test period, ultrasound measurements were taken at the 10th rib. Animals from the transgenic (MON 71800) and non-transgenic (MON 71900) treatments were harvested at the end of the study and carcass and meat quality measurements were taken. Pigs fed the six wheat varieties had similar (P > 0.05) feed intake, live weight gain, gain : feed ratio and ultrasound measures of backfat thickness and longissimus muscle area. There was a wheat variety * gender interaction (P < 0.05) for longissimus fat content. Gilts fed the transgenic wheat had higher (P < 0.05) longissimus fat content than those fed the non-transgenic control wheat; however, for barrows there was no effect (P > 0.05) of wheat variety on longissimus fat content. However, there was no effect (P > 0.05) of wheat variety on other longissimus muscle quality or composition measures. Gilts had lower (P < 0.01) feed intake, growth rate and backfat thickness, and similar gain : feed ratio (P > 0.05) compared to barrows. This study, with growing-finishing swine, suggests that the Roundup Ready wheat (MON 71800) resulted in equivalent animal performance to conventional wheat. PMID- 22444012 TI - Selenium supplementation of lactating dairy cows: effects on milk production and total selenium content and speciation in blood, milk and cheese. AB - Forty multiparous Holstein cows were used in a 16-week continuous design study to determine the effects of either selenium (Se) source, selenised yeast (SY) (derived from a specific strain of Saccharomyces cerevisiae CNCM I-3060) or sodium selenite (SS), or Se inclusion rate in the form of SY in the diets of lactating dairy cows on the Se concentration and speciation in blood, milk and cheese. Cows received ad libitum a total mixed ration (TMR) with a 1 : 1 forage : concentrate ratio on a dry matter (DM) basis. There were four diets (T1 to T4), which differed only in either source or dose of Se additive. Estimated total dietary Se for T1 (no supplement), T2 (SS), T3 (SY) and T4 (SY) was 0.16, 0.30, 0.30 and 0.45 mg/kg DM, respectively. Blood and milk samples were taken at 28-day intervals and at each time point there were positive linear effects of Se in the form of SY on the Se concentration in blood and milk. At day 112, blood and milk Se values for T1 to T4 were 177, 208, 248 and 279 +/- 6.6 and 24, 38, 57 and 72 +/- 3.7 ng/g fresh material, respectively, and indicate improved uptake and incorporation of Se from SY. In whole blood, selenocysteine (SeCys) was the main selenised amino acid and the concentration of selenomethionine (SeMet) increased with the increasing inclusion rate of SY. In milk, there were no marked treatment effects on the SeCys content, but Se source had a marked effect on the concentration of SeMet. At day 112, replacing SS (T2) with SY (T3) increased the SeMet concentration of milk from 36 to 111 ng Se/g and its concentration increased further to 157 ng Se/g dried sample as the inclusion rate of SY increased further (T4) to provide 0.45 mg Se/kg TMR. Neither Se source nor inclusion rate affected the keeping quality of milk. At day 112, milk from T1, T2 and T3 was made into a hard cheese and Se source had a marked effect on total Se and the concentration of total Se comprised as either SeMet or SeCys. Replacing SS (T2) with SY (T3) increased total Se, SeMet and SeCys content in cheese from 180 to 340 ng Se/g, 57 to 153 ng Se/g and 52 to 92 ng Se/g dried sample, respectively. The use of SY to produce food products with enhanced Se content as a means of meeting the Se requirements is discussed. PMID- 22444013 TI - Effect of temperature level on thermal acclimation in Large White growing pigs. AB - The effect of temperature level (24 degrees C, 28 degrees C, 32 degrees C or 36 degrees C) on performance and thermoregulatory response in growing pigs during acclimation to high ambient temperature was studied on a total of 96 Large White barrows. Pigs were exposed to 24 degrees C for 10 days (days -10 to -1, P0) and thereafter to a constant temperature of 24 degrees C, 28 degrees C, 32 degrees C or 36 degrees C for 20 days. Pigs were housed in individual metal slatted pens, allowing a separate collection of faeces and urine and given ad libitum access to feed. Rectal (RT) and cutaneous (CT) temperatures and respiration rate (RR) were measured three times daily (0700, 1200 and 1800 h) every 2 to 3 days during the experiment. From day 1 to 20, the effect of temperature on average daily feed intake (ADFI) and BW gain (average daily gain, ADG) was curvilinear. The decrease of ADFI averaged 90 g/day per degrees C between 24 degrees C and 32 degrees C and 128 g/day per degrees C between 32 degrees C and 36 degrees C. The corresponding values for ADG were 50 and 72 g/day per degrees C, respectively. The 20 days exposure to the experimental temperature was divided in two sub periods (P1 and P2, from day 1 to 10 and from day 11 to 20, respectively). ADFI was not affected by duration of high-temperature exposure (i.e. P2 v. P1). The ADG was not influenced by the duration of exposure at 24 degrees C and 28 degrees C groups. However, ADG was higher at P2 than at P1 and this effect was temperature dependent (+130 and +458 g/day at 32 degrees C and 36 degrees C, respectively). In P2 at 36 degrees C, dry matter digestibility significantly increased (+2.1%, P < 0.01); however, there was no effect of either duration or temperature on the digestibility of dry matter at group 24 degrees C and 32 degrees C. RT, CT and RR were measured three times daily (0700, 1200 and 1800 h) every 2 to 3 days during the experiment. Between 28 degrees C and 36 degrees C, RT and CT were lower during P2 than during P1 (-0.20 degrees C and -0.23 degrees C; P < 0.05), whereas RR response was not affected by the duration of exposure whatever the temperature level. In conclusion, this study suggests that the effect of elevated temperatures on performance and thermoregulatory responses is dependent on the magnitude and the duration of heat stress. PMID- 22444014 TI - Age-related changes in muscle fiber type frequencies and cross-sectional areas in straightbred and crossbred rabbits. AB - This study was designed to investigate the effects of the interaction among genetic group, sex and age on the frequencies and cross-sectional areas of myofiber types in rabbits. A total of 48 straightbred and crossbred Botucatu rabbits, males and females, were involved in a split plot design with a 2 * 2 (genetic groups * genders) factorial arrangement. Young rabbits were weaned at 35 days of age and sequentially slaughtered, four per genetic group * sex combination, at 42, 63 and 84 days of age. The flexor carpi radialis muscle was dissected, histological sections (10 MUm) were obtained and the frequencies and cross-sectional areas of myofiber types: I, IIA and IIB/X were determined. An effect of the genetic group * sex * slaughter age interaction was found on the frequency distribution of myofiber types. A transition from type IIA to type IIB/X fibers was observed (P < 0.01) with advancing age, except in crossbred females, but the frequency of IIA fibers was already lower (57.3%) and of IIB/X fibers numerically higher (33.7%) in this group at 42 days. The proportions of IIA fibers in straightbred males, crossbred males and straightbred females decreased from 80.1%, 89.4% and 68.8% at 42 days to 43.9%, 52.3% and 40.1% at 63 days, respectively, whereas the proportions of type IIB/X fibers, in the same groups, increased from 10.3%, 1.6% and 22.3% at 42 days to 42.2%, 37.0% and 49.8% at 63 days, respectively. In all three age points, type IIA fibers showed the largest cross-sectional areas, followed by type I and IIB/X fibers. The cross sectional areas of IIB/X fibers were larger in crossbreds, but no differences were found between genetic groups concerning fiber types IIA and I. All three types of fibers showed positive linear association with age, but relative to the initial area type IIB/X fibers presented a higher degree of hypertrophy (144% up to 84 days) than type IIA and I fibers (86% and 85%, respectively). The flexor carpi radialis muscle was, on average, heavier in crossbred than in straightbred females, but no difference was observed between crossbred and straightbred males. Differences in the weight of flexor carpi radialis muscle were attributed to the hypertrophy of type IIB/X fibers in the crossbreds. PMID- 22444015 TI - Effect of dietary fat or starch supply during gestation and/or lactation on the performance of sows, piglets' survival and on the performance of progeny after weaning. AB - Two trials were carried out to compare the effects of fat or starch inclusion in sow's diet on sow and litter performance. In each trial, sows were assigned to one of two treatments. In trial 1, the sows were fed diets containing either soybean oil (5%, treatment GL5) or cornstarch (11.3%, GL0) from day 35 of gestation to weaning. Daily net energy and nutrient allowance were equalised during gestation. In trial 2, the same treatments were applied only after farrowing (treatments L5 and L0, respectively). Within each trial, a batch of piglets was studied until slaughter. In trial 1, adipose cell development and total lipid content were determined on some pigs at weaning (n = 6/treatment) and at slaughter in dorsal subcutaneous adipose tissue (n = 13/group at least) and in muscle (n = 46/group at least). Piglets' birth weight was not affected by treatment in trial 1. Survival rates at birth and after 24 h of life were higher in treatment GL5 (4.0% v. 7.5% stillborn piglets in GL0 treatment, P < 0.05; 8.7% v. 12.6% of piglets alive at 24 h of age died in treatment GL0, P = 0.06). Subsequently, overall survival rate until weaning was higher in treatment GL5 (81.4% v. 75.7% of total born piglets, P = 0.03), but litter size at weaning was not significantly affected (11.3). Litter growth rate before weaning was increased when a fat-enriched diet was provided during gestation and lactation (+140 g/day per litter; P < 0.01) and to a lower extent when provided only after farrowing (+90 g/day; P < 0.05). Energy supply through fat did not decrease the mobilisation of the sow's body reserve and backfat thickness loss was even higher with treatment GL5 (P < 0.05). After weaning, pigs' average daily gain, feed : gain ratio and carcass lean content were not affected by the energy source supplied before and/or after farrowing. At weaning, the number of adipose cells in the dorsal subcutaneous adipose tissue and in the Longissimus dorsi muscle was higher in the GL5 pigs. Muscle lipid content at weaning did not differ between treatments, but it was higher at slaughter, around 110 kg, in the GL5 pigs (3.46% v. 2.58%, P < 0.001). PMID- 22444016 TI - Horses do not exhibit motor bias when their balance is challenged. AB - In many equestrian pursuits such as dressage and show-jumping, it is important that the horse exhibits the same level of balance when ridden to the left as when ridden to the right in canter - that is, to show no motor bias. It is a long-held belief within such disciplines that to reduce bias that exists in horses and thus to enhance symmetry of performance to the left and right, the horse needs to be worked equally in both directions, although there is a lack of scientific evidence of this influencing bias. There also is little compelling evidence for either the existence or absence of motor bias in unridden (and therefore younger) or ridden (and therefore older) horses. In this study, we tested whether there was a difference in motor bias between unridden (n = 15) and ridden (n = 15) horses when their balance was challenged by cantering them in circles both to the left and to the right on the lunge. As indicators of a difference in balance between the left and right and thus as indicators of motor bias, we conducted three lunging tests - time spent in canter, whether the horse cantered on the correct lead and whether it became disunited. A grazing stance test, where the extended foreleg during grazing was recorded as the preferred forelimb, was also used to compare responses in a test where balance was not actively challenged, to the three lunging tests where balance was actively challenged. No bias was found in either the unridden or ridden groups when their balance was challenged, but ridden horses exhibited a motor bias in grazing stance - when their balance was not challenged. There was also a correlation between the responses in all three lunging tests, but none between the grazing stance test and any of the three lunging tests. We therefore conclude that neither ridden nor unridden horses are biased when their balance is challenged; thus it cannot be concluded that ambidextrous training affects an inherent bias, and that estimation of motor bias in horses is affected by the test conditions. Finally, if ridden horses are truly unbiased, strong human motor bias might be responsible for the common perception amongst riders that horses are biased. PMID- 22444017 TI - Young horse response on changing distance in free jumping combination. AB - The aim of the present study was to verify the influence of distance between obstacles in combination for free jumping test on linear and temporal kinematic parameters of the jump. Investigated groups of halfbred stallions being prepared for 100 days performance test (two groups, 36 horses in total) were filmed on different distances between main doublebarre obstacle and last cross-pole in the jumping lane. Both groups of horses were filmed during their regular work in the same training centre 1 week before performance test. Jumping parameters were obtained on the same size of the obstacle. Data were analysed separately for both groups by analysis of variance. On the basis of the conducted study, it is possible to conclude that in the range of the most popular free jumping distance horses may use different jumping techniques to clear the jump. The shorter distances between last two obstacles in the jumping lane in the range of 6.8 to 7.1 m stimulate higher jumps; however, the reaction of horses was not exactly the same for all measured jumping parameters. PMID- 22444018 TI - Sequential feeding with variations in energy and protein levels improves gait score in meat-type chickens. AB - Feeding broilers by alternating different diets for 1 or 2 days is known as sequential feeding, and it possibly reduces leg problems since it slows down early growth and may enhance general activity. The present study compared continuous feeding with a standard diet (C: metabolisable energy = 12.55 MJ/kg, crude protein = 190 g/kg) with alternations of a high-energy/low-protein diet (E+P-:+7% ME; -20% CP) and a low-energy/high-protein diet (E-P+: -7% ME,+20% CP) and investigated its effects on growth, behaviour and gait score in 352 male Ross broiler chickens. Sequential feeding was carried out during ten 48-h sequential feeding cycles from 8 to 28 days of age. Three treatments were compared: complete diet (C) and two alternations of diets varying in protein and energy contents (S1: E+P- followed by E-P+; and S2: E-P+ followed by E+P-). Chickens received the same feed during the starter and finisher periods (0 to 7 and 29 to 38 days of age). Body weight (BW), feed intake, general activity and gait score, bone quality and carcass conformation were measured to evaluate leg condition and general performance. Sequential feeding significantly reduced BW at 28 days of age (S1: -9.1%; S2: -3.7%/C group; P < 0.05) and S1 were lighter than S2. In both sequential groups, time spent standing increased (C: 28%; S1:33%; S2: 35%; P < 0.05) and leg abnormalities decreased (mean gait score: C: 2.61; S1: 2.45; S2: 2.38; P < 0.02). This improvement was not related to changes in bone quality. BW at slaughter was impaired in Group S1 only, and the feed conversion ratio throughout the rearing period was not significantly impaired by sequential feeding. However, abdominal fat was higher in the S2 group. Sequential feeding using diets varying in energy and crude protein can be a useful method of reducing leg problems in broilers since it improves gait score without impairing growth performance when used as early as 8 days of age and up to not less than 8 days before slaughter in order to compensate for reduced growth. This improvement can be explained by reduced early growth and enhanced motor activity. However, it appears that the low-energy diet should be given first in order to avoid a reduction in BW at slaughter. PMID- 22444019 TI - Castration of piglets under CO2-gas anaesthesia. AB - It has become common practice in pig fattening production systems to castrate young boar piglets without the use of anaesthesia. In this study, we examined whether or not CO2 gas is capable of inducing an acceptable anaesthetic state during which castration can be performed. The first step was to identify the most promising CO2/O2 mixture. Based on the results from this first experiment, a mixture of 70% CO2 + 30% O2 was chosen for further investigation as a potential anaesthetic during the castration of young piglets. Thereby, it was established whether the duration and depth of anaesthesia were acceptable for castration where the animal has to be insensible and unconscious. Physiological effects were assessed based on electroencephalogram (EEG) and electrocardiogram (ECG) measurements, blood gas values and behavioural responses. During the induction phase, the only typical behaviour the piglets exhibited when exposed to the 70/30 gas mixture was heavy breathing. All piglets (n = 25) lost consciousness after approximately 30 s according to the EEG. Heart rate decreased slowly during the induction phase, a serious drop occurred when piglets lost their posture. Immediately after this drop, the heart rate neared zero or showed a very irregular pattern. Shortly after loss of posture, most animals showed a few convulsions. None of the animals showed any reaction to castration in behaviour and/or on the EEG and ECG. On average, the piglets recovered within 59 s, i.e. EEG returned to its pre-induction pattern and piglets were able to regain a standing position. After 120 s, heart rate returned to pre-induction levels. In order to explore the usage range of CO2 concentration, 24 piglets were exposed to 60% CO2 + 20% O2 + 20% N2 for up to 30 s after loss of consciousness (as registered on EEG), and castrated after removal from the chamber. Sixteen of the 24 animals showed a reaction to the castration on the EEG. To establish the maximum time piglets survive in 70% CO2 + 30% O2, five piglets were placed in this mixture for 3 min. Two of them died. After that, four piglets were placed in this mixture for 2 min after unconsciousness, one died after 2 min. It was concluded from this study that it is possible to anaesthetise piglets with a mixture of 70% CO2 + 30% O2, but that there are limits to its safety in terms of CO2 concentration and duration of exposure. Before implementation for practical use, further research is essential to assess the limits of gas concentration and exposure times. PMID- 22444020 TI - Effects of various energy and protein levels during sequential feeding on feed preferences in meat-type chickens. AB - Short-term feed preferences were studied in individually caged chickens fed sequentially in order to understand a previously described imbalance in the intake of diets offered. Sequential feeding (SF) was carried out for four 48 h cycles in male broiler chickens. The diets varied in energy (2800 (E-) and 3200 kcal/kg (E+)) and protein (230 (P+) and 150 g/kg (P-)) contents. SF was compared to standard feeding (C) (3000 kcal/kg ME and CP = 190 g/kg). In experiment 1, three treatments were used: C, SE (E- followed by E+) and SE' (E+ followed by E ). Four treatments were used in experiment 2: C, SP (P+ followed by P-), SE and SEP (P+E- followed by P-E+). Total feed intake was measured during the SF period. After this, short-term preferences were evaluated with a choice test on chickens previously fed with the same feeds during the SF period (experienced birds) and in C chickens (naive birds). In both experiments, total feed intake was similar among treatments and the percentage of each feed consumed was not significantly different from controls (50%). In experiment 1, SE and SE' chickens over-consumed E+ and under-consumed E- diets only during the first 15 min of the fourth cycle. The choice test indicated that experienced chickens preferred E+, while naive chickens preferred E-. Similarly, in experiment 2, chickens over-consumed E+ and E+P- during the first 15 min of the fourth cycle, but the intake of diets varying in protein content was not different from controls. During the choice test, as in experiment 1, experienced chickens preferred E+, while naive chickens preferred E . There was a slight preference for the protein-poor diet in naive birds and there was no preference in the diet varying in both protein and energy contents. Experience modified choice between feeds varying in energy content but not in protein. When feeds were known, preference for energy affected the feed intake immediately after switching from one diet to the other, although lower with the diet also varying in protein, it did not influence the total intake of each diet. Interactions between the nutritional properties and sensorial cues of feed could explain these results. PMID- 22444021 TI - Effects of the forage-to-concentrate ratio of the diet on feeding behaviour in young Blond d'Aquitaine bulls. AB - The activities of bulls, their feeding behaviour and their ruminal pH were examined at several stages during the finishing period, according to the forage to-concentrate ratio of their diet. Twenty-four bulls of the Blond d'Aquitaine breed (initial body weight = 326 +/- 21 kg) were assigned to six balanced pens with a space allowance of 9.4 m2 per bull during the finishing period. They were fed three different diets with achieved forage-to-concentrate ratios of (i) 8% straw and 92% concentrate, (ii) 44% hay and 56% concentrate and (iii) 57% maize silage and 43% concentrate. Bulls had ad libitum access to feed dispensed once daily. Offered and refusals were weighed on 5 consecutive days per week. The bulls were slaughtered at the common final live weight of 650 kg and the finishing period lasted 138, 181 and 155 days for straw-concentrate, hay concentrate and maize silage-concentrate diets, respectively. The time budget was estimated four times by scan sampling with a 10-min interval. Feeding behaviour was appraised using data from electronic feeding gates. Ruminal pH was measured from a ruminal fluid sample collected by rumenocentesis. On average, the bulls spent 78% of the time lying or standing still, and 11% of the time eating. The forage-to-concentrate ratio of the diet influenced only those activities directly linked to feeding, i.e. eating and drinking. Bulls fed a high-concentrate diet spent less time eating than the other bulls (47 min v. >2 h) and took shorter meals (7 min v. 17 min). The bulls fed the straw-concentrate diet spread their meals over the entire day, whereas the others maintained two major peaks of eating activity, the main one in the morning after feed dispensing, the other one at the end of the diurnal period. Intake rate ranged widely between diets, from 58 g/min on average for the diets based on hay or maize silage up to 173 g/min for the high-concentrate diet. The concentrate-diet bulls also had a lower ruminal pH during the first 2 months of the finishing period. The dispersion of meals based on a high-acidosis-risk diet may be a way to limit the decrease in ruminal pH. PMID- 22444022 TI - Biosecurity risks associated with current identification practices of producers trading live pigs at livestock sales. AB - Approximately 5% of pigs produced in Australia is believed to be traded at livestock sales. Interviews and focus group discussions were conducted with producers (106 and 30 producers, respectively), who traded pigs at livestock sales. The purpose of the study was to gather information on how producers identified their pigs in order to evaluate how these practices may impact the ability to trace pig movements in the event of an emergency animal disease outbreak or food safety hazard. Results were analyzed according to herd size (0 to 150 sows, 150+ sows) and location (peri-urban, regional) as prior studies suggested a higher biosecurity risk among smaller farms and due to perceptions that peri-urban farms pose additional risk. Most producers (91.5%) had less than 150 sows and a high proportion (70.8%) resided in regional areas compared with only 29.2% residing in peri-urban areas. A higher proportion of large-scale producers identified their pigs than small-scale producers. A third of small scale producers reported not identifying breeding stock and most did not identify progeny. The most common forms of on-farm identification used were ear tags for breeding stock and ear notches for progeny. Producers identified breeding stock to assist with mating management and genetic improvement. Ear notches were used to determine the litter of origin of progeny. All large-scale producers owned a registered swine brand and used the official body tattoo for post-farm-gate identification. However, approximately 15% of small-scale producers did not own a registered swine brand, and an additional 8% did not identify their pigs post farm-gate. Producers were satisfied with tattoos as a methodology for post-farm gate identification of pigs and considered other methodologies cost-prohibitive. However, variations in the maintenance of the branding equipment, the type of ink used and the time of tattoo application in relation to the animal sale were highlighted during focus group discussions. These results suggest that there is a need for education and extension activities, especially among small-scale pig producers, regarding the benefits of identifying animals on-farm. In addition, increased awareness of the traceability legislation that exists in Australia to meet the National Performance Standards for Livestock Traceability in this country is required. PMID- 22444023 TI - Sensory evaluation and its relationship to physical meat quality attributes of beef from Nguni and Bonsmara steers raised on natural pasture. AB - The current study compared sensory characteristics and their relationships with physical meat characteristics of beef from Nguni and Bonsmara steers. Nguni beef was more (P < 0.05) tender than Bonsmara beef after ageing for 2 and 21 days, and had higher (P < 0.05) intramuscular fat (IMF; 1.12%) than Bonsmara beef (1.07%). Nguni beef had higher (P < 0.05) sensory scores than Bonsmara beef after ageing for 2 days. There were no (P > 0.05) relationships between IMF and sensory characteristics. Aroma intensity, impression on juiciness and tenderness-related scores were affected (P < 0.05) by pH. There were significant (P < 0.05) correlations between most physical meat characteristics and sensory characteristics. Nguni beef had better sensory scores than Bonsmara beef for beef aged for 2 days. While most physical meat characteristics were correlated to sensory scores, all sensory scores were not significantly correlated to IMF. PMID- 22444024 TI - Performances, meat quality and boar taint of castrates and entire male pigs fed a standard and a raw potato starch-enriched diet. AB - In Europe there is increasing concern about the common practice of surgical castration of piglets without anaesthesia. One possible alternative to completely avoid castration is entire male pig production. Thus, the objective of the study was to compare the growth performance, carcass characteristics, organ weights, meat quality traits, fat score and boar taint compounds in the adipose tissue of group-penned entire male pigs and castrates. Furthermore, the effect of raw potato starch (RPS) fed for 7 days prior to slaughter was determined. Pigs (n = 36) were blocked by BW into 12 blocks (3 littermates/block) and assigned to three experimental groups: surgical castrates (C); entire males (EM); and entire males offered RPS (30 g RPS/100 g diet) for 7 days prior to slaughter (EM+). Pigs had ad libitum access to the feed from 22 to 107 kg, individual feed intake was recorded daily and BW once a week. Entire males grew slower (EM: 771, EM+: 776 v. C: 830 g/day; P < 0.01), consumed less feed (EM: 1.87, EM+: 1.89 v. C: 2.23 kg/day; P < 0.01) and were more efficient (feed conversion ratio: EM: 2.42, EM+: 2.44 v. C: 2.69 kg/kg; P < 0.01) than C. Compared to C, carcass dressing percentage was lower (EM: 79.4, EM+: 79.4 v. C: 81.6%; P < 0.01) and percentage of valuable cuts was higher (EM: 57.3, EM+: 56.5 v. 52.6%; P < 0.01) in entire males. The hearts (EM: 426, EM+: 425 v. C: 378 g), kidneys (EM: 387, EM+: 378 v. C: 311 g), bulbourethral (EM: 200, EM+: 195 v. C: 7 g) and salivary glands (EM: 99, EM+: 94 v. C: 42 g) were heavier (P < 0.001) in entire males than in C. Meat quality traits did not (P > 0.05) differ among experimental groups but the adipose tissue was more unsaturated in entire males than in C as indicated by the higher fat scores (EM: 69.1, EM+: 67.2 v. C: 63.6; P < 0.01). Feeding RPS reduced (P = 0.04) the skatole tissue concentrations (expressed in MUg/g lipid) in EM+ (0.22) compared to EM (0.85), whereas androstenone and indole levels were not (P 0.60) affected (EM: 1.7 and 0.10, EM+: 2.0 and 0.09, respectively). Although the current results confirmed the high efficiency of entire males compared to castrates, the observed high androstenone levels represent a major challenge to implement entire males production. PMID- 22444025 TI - Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation. AB - A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti inflammatory activity and capable of inhibiting polyarthritis. PMID- 22444026 TI - Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies. AB - The combination of antagonism at histamine H(3) receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H(3) receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1 ylpropoxy)benzene)]sulfonylurea exhibited the best H(3) antagonism affinity. However, since all these derivatives failed to block K(ATP) channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H(3) antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype. PMID- 22444027 TI - Increased aerobic fitness after neuromuscular electrical stimulation training in adults with spinal cord injury. AB - OBJECTIVES: To evaluate the efficacy of a novel neuromuscular electrical stimulation (NMES) system for improving aerobic fitness in individuals with spinal cord injury (SCI). It was hypothesized that training with this NMES system would increase peak oxygen consumption (Vo(2)peak) and peak heart rate (HRpeak) in a sedentary adult SCI population. DESIGN: Prospective cohort study. SETTING: All testing took place at a university human performance laboratory. PARTICIPANTS: Volunteer participants with SCI (N=16; T4-11 American Spinal Injury Association Impairment Scale grades A and B) were recruited from the national SCI outpatient and outreach service databases. All completed the training program, but results from 2 participants were excluded because posttraining tests were invalid. Therefore, 14 participants (11 men, 3 women) completed the program and testing. INTERVENTIONS: Four electrodes (175cm(2)) were placed bilaterally on the quadriceps and hamstrings muscle groups, and subtetanic contractions were elicited using an NMES device. Training was undertaken unsupervised at home for 1 hour, 5d/wk for 8 weeks. MAIN OUTCOME MEASURES: An incremental treadmill wheelchair propulsion exercise test with simultaneous cardiopulmonary gas exchange analysis was used to determine Vo(2)peak and HRpeak. RESULTS: A statistically significant increase in Vo(2)peak (P=.001) and HRpeak (P=.032) between baseline and follow-up was observed. CONCLUSIONS: This novel form of NMES is an effective method of improving aerobic fitness in an SCI population. Results are comparable to those with current functional electrical stimulation exercise systems. PMID- 22444028 TI - Standardized measurement of recovery from nonspecific back pain. AB - OBJECTIVE: To propose standardized, patient-centered measures of recovery from nonspecific low back pain (LBP) in research, underpinned by an empirically derived concept of recovery and informed by expert opinion. DESIGN: Synthesis of literature reviews and expert panel opinion. SETTING: Primary care centers for the management of nonspecific LBP. PARTICIPANTS: Persons with nonspecific LBP. INTERVENTIONS: Conservative treatments for nonspecific LBP. MAIN OUTCOME MEASURES: Three phases of research were conducted. First, qualitative research that explored patients' perspectives of recovery from nonspecific LBP was reviewed. Second, measures of recovery used in LBP clinical trials during the past decade were investigated in a systematic review. Third, opinion was sought from an expert panel of clinicians and researchers about how to measure recovery from nonspecific LBP, in a workshop at the 10th International Forum for Primary Care Research in Low Back Pain. RESULTS: An empirically derived and patient centered concept of recovery from nonspecific LBP was developed from the qualitative research phase. The systematic review conducted in the second study phase revealed that researchers have used vastly heterogeneous measures of LBP recovery in clinical trials during the past decade. Finally, the key conclusions of the LBP Forum workshop were (1) that appropriate patient-centered instruments to measure recovery include global measures and patient-specific measures; and (2) that the benefits of implementing the same recovery measures for acute and chronic LBP outweigh the disadvantages of using different measures. CONCLUSIONS: The results were synthesized to inform our recommendation that researchers consider adopting 2 instruments as standardized measures of recovery from nonspecific LBP, as an adjunct to the existing core set of LBP outcome measures. These instruments are an 11-point Global Back Recovery Scale, for a simple measure of global recovery, and the Patient-Generated Index of Quality of Life Back Pain, to evaluate specific relevant dimensions of recovery. This recommendation has majority endorsement by members of the Australian National Health and Medical Research Council Acute Low Back Pain Review Group. PMID- 22444029 TI - Long-term safety of granulocyte colony-stimulating factor in normal donors: is it all clear? AB - INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that stimulates the proliferation and differentiation of neutrophil precursor cells. G-CSF-mobilized peripheral blood (PB) hematopoietic progenitor stem cells (HPSCs) collected by apheresis are being increasingly employed for allogeneic transplantation in patients with malignancies as an alternative to bone marrow (BM) transplant. Documenting the safety of G-CSF as a mobilizing agent for HPSC donation has long been a matter of importance for physicians, particularly when volunteer, unrelated adult donors are involved. AREAS COVERED: We review publications in the field with the goal of providing an overview of these approaches. EXPERT OPINION: Trials and international donor registries have not shown any long-term effects associated with G-CSF therapy and a threefold-or greater increased risk of leukemia or other malignancies through PB HPSC donation can be excluded. Our conclusions are that the administration of G-CSF to healthy donors has a favorable long-term risk-benefit profile, although it is essential to encourage the enrolment of donors in carefully designed programs for follow-up monitoring. PMID- 22444030 TI - Excitation polarization sensitivity of plasmon-mediated silver nanotriangle growth on a surface. AB - In this contribution, we report an effective and relatively simple route to grow triangular flat-top silver nanoparticles (NPs) directly on a solid substrate from smaller NPs through a wet photochemical synthesis. The method consists of fixing small, preformed nanotriangles (NTs) on a substrate and subsequently irradiating them with light in a silver seed solution. Furthermore, the use of linearly polarized light allows for exerting control on the growth direction of the silver nanotriangles on the substrate. Evidence for the role of surface plasmon resonances in governing the growth of the NTs is obtained by employing linear polarized light. Thus, this study demonstrates that light-induced, directional synthesis of nanoparticles on solid substrates is in reach, which is of utmost importance for plasmonic applications. PMID- 22444031 TI - Directory of residency and fellowship programs in Women's Health, 2012 Association of Academic Women's Health Programs. PMID- 22444033 TI - Object processing in visual perception and action in children and adults. AB - We investigated whether 6- and 7-year-olds and 9- and 10-year-olds, as well as adults, process object dimensions independent of or in interaction with one another in a perception and action task by adapting Ganel and Goodale's method for testing adults (Nature, 2003, Vol. 426, pp. 664-667). In addition, we aimed to confirm Ganel and Goodale's results in adults to reliably compare their processing strategies with those of children. Specifically, we tested the abilities of children and adults to perceptually classify (perception task) or grasp (action task) the width of a rectangular object while ignoring its length. We found that adults process object dimensions in interaction with one another in visual perception but independent of each other in action, thereby replicating Ganel and Goodale's results. Children processed object dimensions interactively in visual perception, and there was also some evidence for interactive processing in action. Possible reasons for these differences in object processing between children and adults are discussed. PMID- 22444032 TI - Random repeated cross sectional study on breeding site characterization of Anopheles sinensis larvae in distinct villages of Yongcheng City, People's Republic of China. AB - BACKGROUND: Characterizing the breeding site of Anopheles sinensis is of major importance for the transition from malaria control to elimination in China. However, little information is available especially regarding the characteristics and influencing factors of breeding sites of An. sinensis in Yongcheng City, a representative region of unstable malaria transmission in the Huang-Huai River region of central China. The aims of this study were to determine the breeding site characteristics of An. sinensis and related environmental and physicochemical parameters, to find out which breeding site characteristics could best explain the presence of An. sinensis larvae, and to determine whether the breeding habit of An. sinensis has changed or not. METHODS: Random repeated cross sectional study was undertaken in six villages of the Yongcheng city characterized by different levels of the historical incidence of P. vivax malaria. The potential breeding sites of An. sinensis larvae in each village were examined twice per month both in the household courtyards and the village surroundings. The larval sampling was done by the standard dipping method. Some important breeding site characterizations were recorded and characterized. The anopheline mosquito larvae and emerged adults were identified to the species level morphologically and to sub-species by the ribosomal DNA PCR technique. Chi square analysis and logistic regression analysis were applied to determine the importance of factors for explaining the presence or absence of An. sinensis larvae. RESULTS: According to the ribosomal DNA PCR assay, all sampled anopheline mosquito larvae and emerged adults belonged to An. sinensis. Only 3 containers that were sampled from the household courtyards were found to contain An. sinensis larvae. There were no differences in the species composition of mosquito larvae among containers that contained water in the household courtyards (P > 0.05). An. sinensis larvae were shown to be present in a total of 60 breeding sites in the village surroundings, this included 8 (13.3%) river fringes, 26 (43.3%) ponds, 23 (38.3%) puddles, and 3 (5.0%) irrigation/drainage ditches. Logistic regression analysis revealed that the breeding site type, water depth, chemical oxygen demand (COD), ammonia nitrogen, and sulphate were found to be the key factors determining the presence of An. sinensis larvae. Approximately 94.9% of An. sinensis larvae inhabited relatively large and medium-sized water bodies, with depths between 0.5 m and 1.0 m (73.3%), COD lower than 2 mg/L (75%), ammonia nitrogen lower than 0.4 mg/L (86.7%), and sulphate lower than 150 mg/L (58.3%), respectively. CONCLUSION: These results indicate that the majority of An. sinensis larval breeding sites were relatively large and medium-sized water bodies with depths between 0.5 m and 1.0 m, and containing low levels of COD, ammonia nitrogen, and sulphate, respectively. For effective An. sinensis larval control, the type of breeding site, water depth, COD, ammonia nitrogen, and sulphate should be given higher priority over other factors in areas where it is the primary vector. PMID- 22444034 TI - Investigation of the adsorption characteristics of natural organic matter from typical Chinese surface waters onto alumina using quartz crystal microbalance with dissipation. AB - The adsorption of natural organic matter (NOM) from eight typical Chinese surface waters onto alumina was investigated using quartz crystal microbalance with dissipation monitoring (QCM-D). The adsorbed masses of NOM varied between 25ngcm( 2) and 64ngcm(-2), and these showed significant correlation with geographical location, and NOM character and concentrations. Adsorbed mass correlated with DOC concentration (slope k=0.0676, R(2)=0.61) and hydrophobic acid (HoA) and weakly hydrophobic acid (WHoA) (k=0.0342 and 0.0183; R(2)=0.49 and 0.52 for HoA and WHoA, respectively) constituents present in the water samples. The process of adsorbed layer formation was investigated from changes in the DeltaD/Deltaf ratio and viscosity of adsorbed layer with injected time. The adsorbed layer viscosity increased exponentially with injected time (R(2)>0.99) for most samples. Samples with low DOC concentration (k=-1091.8, R(2)=0.55) and low content of HoA and WHoA (k=-524.33 and -322.76; R(2)=0.41 and 0.64 for HoA and WHoA, respectively), the slope of logarithm viscosity value is steeper, the property of adsorbed layer and NOM is more inconsistent. The QCM-D technique provides a method to view the process of complexation between NOM and coagulant, and can provide useful information to establish a quantitative calculation model of the coagulation process. PMID- 22444035 TI - Surface modified magnetic Fe3O4 nanoparticles as a selective sorbent for solid phase extraction of uranyl ions from water samples. AB - In this study, silica-coated magnetic nanoparticles modified with quercetin were synthesized by a sol-gel method. These magnetic nanoparticles were assessed as a new solid phase sorbent for extraction of uranyl ions from aqueous solutions. The crystal and chemical structures and magnetic property of the new sorbent were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectrophotometer (FT-IR), and vibration sample magnetometer (VSM). The experimental parameters affecting the extraction efficiency of uranyl ions from aqueous solutions using the synthesized sorbent were optimized by means of the response surface methodology. The adsorption equilibrium of uranyl ions onto the sorbent was explained by Langmuir isotherm and maximum monolayer adsorption capacity was found 12.33mg/g. The synthesized sorbent was applied to extraction of uranyl ions from different water samples. PMID- 22444036 TI - Genetic parameters for tissue and fatty acid composition of backfat, perirenal fat and longissimus muscle in Large White and Landrace pigs. AB - Genetic parameters pertaining to the same chemical characteristics of three porcine tissues, that is backfat (BF), perirenal fat (PF) and longissimus muscle (LM), were estimated in centrally tested Large White and Landrace pigs. Animals were fed ad libitum. They were slaughtered at an average BW of 99.6 kg, and samples of BF (both inner and outer layers) and LM were removed at the 13th to 14th rib level of the carcass on the day after slaughter. The data set included 2483 animals recorded for average daily gain (ADG; 35 to 100 kg), estimated carcass lean percentage (LEAN) and lean tissue growth rate (LTGR). Among these animals, around 950 pigs were recorded for lipid content (L%) and water content (W%) of BF and LM and for fatty acid composition (FAC) of BF, whereas FAC of LM was measured on 297 pigs and L%, W%, and FAC of PF on around 210 pigs. Heritabilities (h2) and genetic correlations (ra) were estimated using REML animal model methodology. Estimates of h2 for L%, W% and FAC of BF, PF and LM were of moderate-to-high magnitude: for example 0.47 +/- 0.09 for L% of LM, 0.59 +/- 0.11 for W% of BF, 0.45 +/- 0.08 for the ratio of polyunsaturated to saturated fatty acids (P/S) of BF, 0.61 +/- 0.15 and 0.29 +/- 0.10 for the coefficient of unsaturation of lipids (UNSAT, average number of double bonds of unsaturated fatty acids) of PF and LM, respectively. Genetic correlations of L% with P/S or UNSAT were strongly negative (from -0.4 to -0.9) in BF and LM, but not in PF. The 'between-tissue' genetic correlations for homologous compositional traits were far from being unity (e.g. ra = 0.57 +/- 0.05 'between' BF and PF for UNSAT). Genetic relationships between ADG and tissue compositional traits were globally weak. By contrast, genetic correlations were moderate-to-high between carcass leanness and tissue compositional traits, especially those of fat depots: for example -0.66 +/- 0.14 between LEAN and L% of BF, 0.50 +/- 0.07 between LEAN and UNSAT of PF, -0.44 +/- 0.08 between LEAN and L% of LM, and 0.27 +/- 0.03 between LEAN and UNSAT of LM. On the basis of the parameter estimates found here, breeding for higher LTGR is expected to increase the ratio of water to lipids and the unsaturation degree of lipids in subcutaneous BF and, to a lesser extent, in PF. Tissue composition and FAC of LM would be less affected. PMID- 22444037 TI - Genetic parameters for resistance to trichostrongylid infection in dairy sheep. AB - In sheep, the traditional chemical control of gastrointestinal nematode (GIN) parasites with anthelmintics has led to the widespread development of anthelmintic resistance. The selection of sheep with enhanced resistance to GIN parasites has been suggested as an alternative strategy to develop sustainable control of parasite infections. Most of the estimations of the genetic parameters for sheep resistance to GIN parasites have been obtained from young animals belonging to meat- and/or wool-specialised breeds. We present here the estimated genetic parameters for four parasite resistance traits studied in a commercial population of adult Spanish Churra dairy ewes. These involved two faecal egg counts (FECs) (LFEC0 and LFEC1) and two serum indicator traits, the anti Teladorsagia circumcincta fourth stage larvae IgA (IgA) and the pepsinogen (Peps) levels. In addition, this study has allowed us to identify the environmental factors influencing parasite resistance in naturally infected Spanish Churra sheep and to quantify the genetic component of this complex phenotype. The heritabilities estimated for the two FECs analysed (0.12 for LFEC0 and 0.09 for LFEC1) were lower than those obtained for the examined serum indicators (0.19 for IgA and 0.21 for Peps). The genetic correlations between the traits ranged from 0.43 (Peps-IgA) to 0.82 (LFEC0-LFEC1) and were higher than their phenotypic counterparts, which ranged between 0.07 and 0.10. The heritabilities estimated for the studied traits were lower than previously reported in lambs. This may be due to the differences in the immune mechanisms controlling the infection in young (antibody reactions) and adult (hypersensitivity reactions) animals/sheep. In summary, this study demonstrates the presence of heritable variation in parasite resistance indicator traits in the Churra population studied, which suggests that genetic improvement is feasible for this complex trait in this population. However, further studies in which the experimental variables are controlled as much as possible are needed to identify the best trait that could be measured routinely in adult sheep as an indicator of parasite resistance. PMID- 22444038 TI - Microarray analysis of genes differentially expressed in the liver of lean and fat chickens. AB - Excessive accumulation of lipids in the adipose tissue is one of the main problems faced by the broiler industry nowadays. In chicken, lipogenesis occurs essentially in the liver, in which much of the triglycerides that accumulate in avian adipose tissue are synthesized. In order to better understand the gene expression and its regulation in chicken liver, the gene expression profiles of liver at developmental stages of chicken (1 week, 4 weeks and 7 weeks of age) were investigated and differentially expressed genes between lean and fat chicken lines divergently selected for abdominal fat content for eight generations were screened. Our data indicated that 4 weeks of age was a very important stage on chicken liver lipogenesis compared to 1 week and 7 weeks of age, and the glycometabolism in chicken liver could be related to lipid metabolism and the difference of glycometabolism could be another potential reason for the fat and lean phenotype occurrence besides the difference of lipogenesis in chicken liver. Our result have established groundwork for further study of the basic genetic control of chicken obesity and will benefit chicken research communities as well as researches that use chicken as a model organism for developmental biology and human therapeutics. PMID- 22444039 TI - Molecular cloning, expression and polymorphism of the porcine apolipoprotein A5 gene in a Jinhua * Pietrain F2 reference population. AB - As a newly described member of the apolipoprotein gene family, apolipoprotein A5 (APOA5) has been suggested to play a key role in the triglyceride metabolism in both human and mice. The aim of this study was to identify the porcine (Sus scrofa) APOA5 gene, determine its mRNA and its mutations that are associated with lipid accumulation. The porcine APOA5 cDNA was amplified by reverse transcriptase polymerase chain reaction using the information of the mouse or other mammals. It had been determined that the open reading frame of the porcine APOA5 gene consists of 1092 bp, which encodes a predicted protein composed of 363 amino acids with a similarity to bovine (80.43%) and to human (78.47%). The expression analysis indicated that the porcine APOA5 gene was expressed in hypophysis, fat and liver. Twelve single nucleotide polymorphisms (SNPs), including 4 SNPs in the 5' end, 1 SNP in second intron, 1 SNP in third exon and 6 SNPs in the 3' end, were identified in the porcine APOA5 gene and genotyped on the Jinhua * Pietrain F2 reference population, it had revealed that the SNP of C1834T was significantly associated with average backfat thickness and leaf fat weight (P < 0.01 and P < 0.05, respectively). In conclusion, this study has got basic information of the porcine APOA5 gene and provides evidence that the APOA5 gene could be a potential candidate gene for fat deposition. PMID- 22444040 TI - Real-time PCR genotyping and frequency of the myostatin F94L mutation in beef cattle breeds. AB - This research developed two real-time PCR assays, employing high-resolution melt and allele-specific analysis to accurately genotype the F94L mutation in cattle. This mutation (g.433C > A) in the growth differentiation factor 8 or myostatin gene has recently been shown to be functionally associated with increased muscle mass and carcass yield in cattle. The F94L mutation is not, like other myostatin mutations, associated with reduced fertility and dystocia. It is therefore a candidate for introgression into other breeds to improve retail beef yield and the development of a simple and accurate test to genotype this specific mutation is warranted. Variations in the efficiency of enzyme cleavage compromised the accuracy of genotyping by published methods, potentially resulting in an overestimation of the frequency of the mutant allele. The frequency of the F94L mutation was determined by real-time PCR in 1140 animals from 15 breeds of cattle in Australia. The mutation was present in Simmental (0.8%), Piedmontese (2%), Droughtmaster (4%) and Limousin (94.2%) but not found in Salers, Angus, Poll Hereford, Hereford, Gelbvieh, Charolais, Jersey, Brahman, Holstein, Shorthorn or Maine Anjou. The low prevalence of F94L in all beef breeds except Limousin indicates the significant potential for this mutation to improve retail yield in Australian beef cattle. PMID- 22444041 TI - Genotype-environment interactions for growth and carcass traits in different pig breeds kept under conventional and organic production systems. AB - The demand for special breeding programmes for organic pig meat production is based on the assumption that pigs kept under organic conditions need different biological properties compared with conventionally kept pigs in order to achieve a good performance. This would mean that genotype-environment interactions exist. Therefore, 682 pigs of seven different genotypes were tested for growth performance and carcass quality under conventional and organic environments at two testing stations to verify genotype-environment interactions. All genotypes achieved significantly better results within the conventional environment and there were significant interactions between genotype and environment for all the criteria of growth performance and carcass quality. The interactions are mainly caused by varying differences between organic and conventional systems within genotypes, but for all traits, except weight gain, no major shift of the ranking order within environment between genotypes. Although statistically significant genotype-environment interactions exist, the modern genotypes selected under conventional conditions are also superior to indigenous breeds under organic conditions in economically important traits. Hence, it can be concluded from these results that no special breeding programme is necessary for organic production systems. PMID- 22444042 TI - Effect of offering dairy cows diets differing in phosphorus concentration over four successive lactations: 1. Food intake, milk production, tissue changes and blood metabolites. AB - The loss of phosphates from dairy farms contributes to the eutrophication of waterways. Whilst reducing the phosphorus (P) content of dairy cow diets has the potential to help reduce phosphate losses, diets containing inadequate dietary P may have a negative effect on cow health and performance. To address this issue, 100 winter-calving Holstein-Friesian dairy cows were offered diets containing either 'high' or 'low' levels of dietary P. The experiment was conducted over a 4 year period, with 80 primiparous cows commencing the study in year 1, while a further 20 primiparous cows commenced the study in year 2. Rations offered during the winter comprised grass silage, maize silage (70 : 30 dry matter (DM) basis, approximately) and concentrates (10.0 to 12.0 kg/cow per day). During the summer periods in years 1 and 2, half of the cows grazed both day and night, while the remaining cows grazed by day, and were housed by night and offered grass silage. During years 3 and 4, all cows grazed both day and night during the summer period. Concentrate feed levels during the summer periods were 3.0 to 4.0 kg/cow per day. Different dietary P levels were achieved by offering concentrates containing either high or low P levels during the winter period (approximately 7.0 or 4.4 g P/kg DM respectively), and during the summer period (approximately 6.8 or 3.6 g P/kg DM, respectively). Total ration P levels averaged 4.9 and 3.6 g P/kg DM for the 'high' and 'low' P winter diets respectively, and 4.2 and 3.6 g P/kg DM for the 'high' and 'low' P summer diets respectively. A total of 95, 70, 50 and 22 cows completed each of lactations 1 to 4 respectively. Dietary P level had no significant effect on food intake, milk output or milk composition (P > 0.05). Plasma P concentrations were significantly lower with cows offered the 'low' P diet in each of lactations 1 to 4 (P < 0.05). In each of lactations 3 and 4, cows offered the 'low' P diet tended to have lower condition scores and live weights than those offered the 'high' P diet. The results of this experiment highlight that the P content of dairy cow diets can be substantially reduced with no detrimental effect on dairy cow performance. PMID- 22444043 TI - Effect of offering dairy cows diets differing in phosphorus concentration over four successive lactations: 2. Health, fertility, bone phosphorus reserves and nutrient utilisation. AB - This experiment examined the long-term effects of offering diets containing low levels of dietary phosphorus (P) on dairy cow health, fertility and bone composition, and the effect of dietary P level on nutrient utilisation. One hundred winter-calving Holstein-Friesian dairy cows were offered diets containing either 'high' or 'low' levels of dietary P over a 4-year period. Rations offered during the winter included grass silage, maize silage (70 : 30 dry matter (DM) basis, approximately) and concentrates (10.0 to 12.0 kg/cow per day). During the summer periods in years 1 and 2, half of the cows grazed both day and night, while the remaining cows grazed by day, and were housed by night and offered grass silage. During years 3 and 4, all cows grazed both day and night during the summer period. Concentrate feed levels during the summer periods were 3.0 to 4.0 kg/cow per day. Different dietary P levels were achieved by offering concentrates containing either high or low P levels during the winter period (approximately 7.0 or 4.4 g P/kg DM, respectively) and during the summer period (approximately 6.8 or 3.6 g P/kg DM, respectively). Total ration P levels averaged 4.9 and 3.6 g P/kg DM for the high and low P winter diets, respectively, and 4.2 and 3.6 g P/kg DM for the high and low P summer diets, respectively. A total of 95, 70, 50 and 22 cows completed each of lactations from 1 to 4, respectively. Neither the incidence of lameness or mastitis, or milk somatic cell count, were affected by dietary P level (P > 0.05), while none of the fertility parameters recorded in any of lactations from 1 to 4 was affected by the dietary P level (P > 0.05). Dietary P level had no effect on the specific gravity, ash or calcium content of rib cortical bone cores (n = 78 cows), while the P content of cortical bone (g/kg fresh, g/kg DM and mg/ml fresh bone) was lower with cows offered low P diets (P < 0.05). Dietary P level had no significant effect on the digestibility of either the DM, nitrogen, energy or acid detergent fibre fraction of the diet (P > 0.05), while faecal P excretions were reduced by a mean of 27 g/cow per day with cows offered the low P diets during the winter period. The results of this study indicate that dietary P levels can be reduced to proportionately 0.8 (approximately) of current UK feeding standards (Agricultural and Food Research Council, 1991), with no detrimental effect on dairy cow health or fertility, while having only minor effects on bone composition. PMID- 22444044 TI - The effect of vitamin E and plant extract mixture composed of carvacrol, cinnamaldehyde and capsaicin on oxidative stress induced by high PUFA load in young pigs. AB - The objective of our study was to determine the antioxidative potential of a plant extract (PE) mixture composed of carvacrol, capsicum oleoresin and cinnamaldehyde against high n-3 polyunsaturated fatty acid (PUFA)-induced oxidative stress in young pigs. Thirty-two weaned castrated male crossbred pigs (BW 10.9 kg; n = 32) were randomly assigned to four dietary treatments (n = 8). The negative control diet (Cont) contained 17.2% energy from fat. Oxidative stress was induced in three of the four experimental groups with the inclusion of n-3 PUFA rich linseed oil. Linseed oil substituted wheat starch in the diet to elevate the amount of energy from fat to 34.1%. One of these diets served as a positive control (Oil), one was additionally supplemented with 271.2 mg/kg of PE mixture and one with 90.4 mg/kg alpha-tocopheryl acetate (Vit E). After 14 days of treatment, blood and urine were collected for the determination of lipid peroxidation and DNA damage. Lipid peroxidation was studied by plasma malondialdehyde (MDA) concentrations, 24 h urinary MDA and F2-isoprostane (iPF2alpha-VI) excretion, total antioxidant status of plasma and glutathione peroxidase assays. Lymphocyte DNA fragmentation and 24 h urinary 8-hydroxy-2' deoxyguanosine excretion were measured to determine DNA damage. Consumption of n 3 PUFA rich linseed oil increased the amount of MDA in plasma and urine, and induced DNA damage in lymphocytes, but did not elevate the amount of iPF2alpha-VI excreted in the urine. The supplementation with PE and with Vit E did not reduce MDA levels in plasma and urine, but it decreased the percentage of DNA damage in lymphocytes (P < 0.001). The PE reduced the urinary iPF2alpha-VI excretion in comparison to the Cont diet. The results show that PE and Vit E supplemented to pigs in concentrations of 271.2 mg/kg and 90.4 mg/kg, respectively, can effectively protect pig's blood lymphocytes against oxidative DNA damage, thus suggesting their potentially beneficial effects on the immune system under dietary-induced oxidative stress. PMID- 22444045 TI - The effect of dietary laminarin and fucoidan in the diet of the weanling piglet on performance, selected faecal microbial populations and volatile fatty acid concentrations. AB - A 2 * 2 factorial experiment (n = 12 replicates per treatment, 4 pigs per replicate) was performed to investigate the effects of seaweed extracts, laminarin (derived beta-glucans) and fucoidan (sulphated polysaccharides), independently or in combination on post-weaning piglet performance and selected microbial populations. At weaning, the piglets (24 days of age, 6.4 kg live weight) were assigned to one of the four dietary treatments: (T1) basal diet, (T2) basal diet with 300 p.p.m. laminarin, (T3) basal diet with 240 p.p.m. fucoidan, (T4) basal diet with 300 p.p.m. laminarin and 240 p.p.m. fucoidan. Pigs offered diets supplemented with laminarin had an increased daily gain (P < 0.01), and gain-to-feed ratio (P < 0.05) compared to pigs offered diets without laminarin supplementation during the experimental period (days 0 to 21). Pigs offered laminarin-supplemented diets had an increased faecal dry matter and reduced diarrhoea (P < 0.05) during the critical 7 to 14 day period. Pigs offered diets containing laminarin had reduced faecal Escherichia coli populations. There was a significant interaction (P < 0.01) on faecal Lactobacilli populations between laminarin and fucoidan. Pigs offered the fucoidan diet had an increased Lactobacilli population compared to pigs offered the basal diet. However, there was no effect of fucoidan on faecal Lactobacilli populations when laminarin was added. Overall, the reduction in E. coli population and the increase in daily gain suggest that laminarin may provide a dietary means to improve gut health after weaning. PMID- 22444046 TI - Impact of diet composition on ileal digestibility and small intestinal morphology in early-weaned pigs fitted with a T-cannula. AB - Piglets, separated from their dam at 12 days of age and fed a milk substitute hourly, were used as a model for suckling. Animals were fitted with a terminal ileal T-cannula and a jugular vein catheter. At 28 days of age, half of the pigs had a dietary change to a cereal-based weaner diet fed as slurry, and the others remained on milk substitute. Animals were labelled by oral administration of 15N labelled yeast for 10 days (days 15 to 25). Blood samples were taken twice a day to monitor 15N enrichment of the blood plasma. Diets included polyethylenglycol (PEG 4000) to allow calculation of apparent ileal digestibility of nitrogen and individual amino acids. Ileal bacterial nitrogen was calculated from D-alanine content of the digesta. Furthermore, small intestinal (SI) villus height and crypt depth were measured. Feed intake was increased by the dietary change. The total nitrogen flow was 3.2 +/- 0.4 g/day and 5.9 +/- 0.4 for the milk and weaner diet, respectively. Endogenous nitrogen flow at the terminal ileum was similar for both groups (milk diet 2.4 +/- 0.4 v. weaner diet 2.2 +/- 0.3 g/day), whereas the bacterial nitrogen content (0.08 +/- 0.01 g/day milk diet v. 0.15 +/- 0.01 g/day weaner diet, P < 0.01) and exogenous nitrogen flow (0.94 +/- 0.16 g/day milk diet v. 3.29 +/- 0.12 g/day weaner diet, P < 0.001) increased significantly in the weaner-diet group. The ileal apparent digestibility coefficient of protein was 0.81 +/- 0.06 and 0.68 +/- 0.01 for the milk replacer and the weaner diet, respectively. Morphology measurements made along the SI at 25%, 50% and 75% were similar between piglets fed milk replacer and those fed a cereal-based weaner diet. The only statistical effect (P < 0.01) of dietary change was an increase in crypt depth in the weaner-diet group. In conclusion, pigs, following a dietary change analogous to weaning, lack the capacity to fully digest a standard weaner diet. This may result in an increased nutrient content entering the large intestine and an altered microbiota. In the absence of a period of anorexia, often associated with traditional weaning, we saw no evidence of villous atrophy, but report here a significant crypt hyperplasia, especially at the 75% level, as a result of dietary change. PMID- 22444047 TI - Effect of age on spermiogram of Holstein Friesian * Sahiwal crossbred bulls. AB - This study was conducted on 94 Frieswal (5/8 Holstein Friesian 3/8 Sahiwal) crossbred bulls of three different grades, categorized based on their semen freezability visualising Group 1 (consistently freezable semen producer bulls, N = 11), Group 2 (inconsistent freezable, N = 16) and Group 3 (Non freezable, N = 67). Each group was further divided into two classes that is young (up to 30 months) and adult (31 to 70 months) bulls depending upon their age. Sperm morphology was studied by using the eosin-nigrosin staining technique. Bulls age significantly (P < 0.01) affected semen quality and sperm morphology. In adult bulls, semen volume, mass activity and sperm concentration were 36%, 17.56% and 19.6%, respectively, higher than young. Initial progressive motility (%) and livability showed significant (P < 0.01) improvement with the advancement of age (43.37 +/- 1.21 and 67.71 +/- 1.11, respectively, in young; 53.02 +/- 1.11 and 74.17 +/- 1.03, respectively, in adult). In young bulls, sperm head, mid piece, tail abnormality and total abnormal sperm percent (12.38 +/- 0.92, 4.87 +/- 0.24, 11.01 +/- 0.60 and 28.26 +/- 1.34, respectively) were 1.85, 1.27, 1.20 and 1.44 folds higher than that of their mature stage (6.69 +/- 0.64, 3.82 +/- 0.32, 9.14 +/- 0.64 and 19.66 +/- 1.31, respectively). Significant reduction (P < 0.01) in micro cephalic sperm, free heads, bent mid piece, looped mid piece and proximal protoplasmic droplets were observed at mature age as compared with their younger stage. In bulls of consistent freezing category, abnormal sperm heads significantly decreased from 4.40 +/- 0.31% to 3.28 +/- 0.02% on maturity. Similarly, in inconsistent freezing grade bulls sperm head abnormality (9.28 +/- 0.75% to 5.13 +/- 1.20%) and total abnormal sperm percent (24.89 +/- 1.43 to 18.73 +/- 3.40) was decreased over the age. On the contrary, in non-freezing category bulls' sperm morphology did not show significant (P > 0.05) improvement with age advancement, rather some abnormalities like long slender head, under developed/deformed head, abaxial implantation of mid piece, double mid piece, stump tail and distal protoplasmic droplets tend to increased significantly (P < 0.05) with age of bulls. Results indicated that in potential Frieswal bulls semen quality and sperm morphology were improved from young to mature stage, where as, in poor quality (non-freezing) semen producer bulls neither the morphology nor the semen quality showed any improvement with maturity. It was recommended that crossbred bulls producing more than 25% morphologically abnormal sperms in young age (below 30 months) along with poor progressive motility (<50%) and low sperm concentration (<1000 million/ml) need immediate culling with out any expectation of further improvement in semen quality with age advancement. PMID- 22444048 TI - Pigs' aggressive temperament affects pre-slaughter mixing aggression, stress and meat quality. AB - Pre-slaughter stress has a negative impact on animal welfare and on meat quality. Aggressive behaviour when pigs are mixed together for transportation to, or on arrival at, the abattoir is an important factor in pre-slaughter stress. Aggressiveness of pigs varies between individuals in the population, and this study investigated its effects on stress and meat quality at slaughter. We mixed pigs at a young age to identify individuals of high (H) or low (L) aggressive temperament using the previously validated approach of lesion scoring. To contrast extremes of social stress single-sex groups of eight pigs were mixed according to their aggressiveness in HH, HL or LL combinations or left unmixed (U) prior to transport and slaughter (n = 271). Each treatment was replicated in at least two groups in each of four slaughter batches. Mixing per se had little effect, but mixed groups composed of aggressive pigs (HH) had more carcass skin lesions and higher levels of plasma cortisol at slaughter and had loin muscle samples with higher pH at 24 h, and lower redness (a*) and yellowness (b*) compared to the other treatments. Females had higher levels of plasma cortisol at slaughter, a more rapid decline in pH post-slaughter and greater lean content of meat. Lactate and creatine kinase (CK) levels and meat pH were affected by the interaction of sex and treatment. Genetic factors, dam and sire line composition, and halothane locus (ryanodine receptor 1, RYR1) genotype, also affected a number of production and meat quality parameters as expected. Additionally, 'commercially normal' levels of social stress were studied in four further slaughter batches with no manipulation of group composition (n = 313). In these pigs, the proportion of unfamiliar pigs and group size of lairage groups explained limited variation in lesion scores at slaughter, but earlier aggressiveness did not. High numbers of skin lesions on the carcass were associated with high levels of cortisol and lactate and low glucose at slaughter, but not with meat quality measures. When stress and meat quality measures were compared for all pigs, high lactate was associated with low early pH and high drip loss, while high cortisol and CK were associated with high pH at 24 h and changes in meat colour. In conclusion, mixing pigs of above average aggressiveness resulted in greater aggression and stress, and changes in meat quality parameters, consistent with the effects of pre-slaughter stress on muscle chemistry. PMID- 22444049 TI - Evaluation of quality changes in udder quarter milk from cows with low-to moderate somatic cell counts. AB - Much emphasis has been put on evaluating alterations in milk composition caused by clinical and subclinical mastitis. However, little is known about changes in milk composition during subclinical mastitis in individual udder quarters with a low-to-moderate increase in milk somatic cell count (SCC). This information is needed to decide whether milk from individual udder quarters with a moderate-to high increase in milk SCC should be separated or not. The aim of this study was to determine how milk composition in separate udder quarters is affected when cow composite milk has low or moderately increased SCC levels. Udder quarter and cow composite milk samples were collected from 17 cows on one occasion. Milk yield was registered and samples were analyzed for SCC, fat, total protein, whey proteins, lactose, citric acid, non-protein nitrogen (NPN), lactoferrin, protein profile, free fatty acids (FFAs), lactate dehydrogenase (LDH), proteolysis, sodium and potassium. Bacteriological samples were collected twice from all four quarters of all cows. The cows were divided into three groups depending on their SCC at udder quarter level. The first group comprised healthy cows with four udder quarters with low SCC, <50 000 cells/ml; composition was equal when opposite rear and front quarters were compared. In the second and the third groups, cows had one udder quarter with 101 000 cells/ml < SCC < 600 000 cells/ml and SCC > 700 000 cells/ml, respectively. The remaining udder quarters of these cows had low SCC (<100 000 cells/ml). Despite the relatively low average cow composite SCC = 100 000 cells/ml of Group 2, milk from affected udder quarters exhibited lower casein number, content of lactose and beta-casein (beta-CN), while the content of whey protein, sodium, LDH and alpha-lactoalbumin (alpha-la) were higher compared to healthy opposite quarters. In addition to these changes, milk from affected udder quarters in Group 3 also exhibited lower values of potassium and alphas1-casein (alphas1-CN) and higher values of lactoferrin when compared to milk from opposite healthy quarters. This indicates that even when the SCC in cow composite milk is low, there might exist individual quarters for which milk composition is changed and milk quality impaired. PMID- 22444050 TI - Effects of supplementation of maize silage diets with extruded linseed, vitamin E and plant extracts rich in polyphenols, and morning v. evening milking on milk fatty acid profiles in Holstein and Montbeliarde cows. AB - The aim of this study was to evaluate the effects on dairy performance and milk fatty acid (FA) composition of (i) supplementation with extruded linseed (EL), (ii) supplementation with synthetic or natural antioxidants, namely vitamin E and plant extracts rich in polyphenols (PERP), (iii) cow breed (Holstein v. Montbeliarde) and (iv) time of milking (morning v. evening). After a 3-week pre experimental period 24 lactating cows (12 Holstein and 12 Montbeliarde) were divided up into four groups of six cows: the first group received a daily control diet (diet C) based on maize silage. The second group received the same diet supplemented with EL (diet EL, fat level approximately 5% of dietary dry matter (DM)). The third group received the EL diet plus 375 IU/kg diet DM of vitamin E (diet ELE). The fourth group received the ELE diet plus 10 g/kg diet DM of a PERP mixture (diet ELEP). Compared with the diet C, feeding EL-rich diets led to lower concentrations of total saturated FA (SFA) and higher concentrations of stearic and oleic acids, each trans and cis isomer of 18:1 (except c12-18:1), non conjugated isomers of 18:2, some isomers (c9t11-, c9c11- and t11t13-) of conjugated linoleic acid (CLA), and 18:3n-3. The vitamin E supplementation had no effect on milk yield, milk fat or protein percentage and only moderate effects on milk concentrations of FA (increase in 16:0, decreases in 18:0 and t6/7/8-18:1). The addition of PERP to vitamin E did not modify milk yield or composition and slightly altered milk FA composition (decrease in total saturated FA (SFA) and increase in monounsaturated FA (MUFA)). The minor effects of vitamin E may be partly linked to the fact that no milk fat depression occurred with the EL diet. During both periods the Holstein cows had higher milk production, milk fat and protein yields, and milk percentages of 4:0 and 18:3n-3, and lower percentages of odd-branched chain FA (OBCFA) than the Montbeliarde cows. During the experimental period the Holstein cows had lower percentages of total cis 18:1, and c9,c11-CLA, and higher percentages of 6:0, 8:0, t12-, t16/c14- and t13/14-18:1, and 18:2n-6 than Montbeliarde cows because of several significant interactions between breed and diet. Also, the total SFA percentage was higher for morning than for evening milkings, whereas those of MUFA, total cis 18:1, OBCFA and 18:2n-6 were lower. Extruded linseed supplementation had higher effect on milk FA composition than antioxidants, breed or time of milking. PMID- 22444051 TI - Production performance and pattern of milk fat depression of high-yielding dairy cows supplemented with encapsulated conjugated linoleic acid. AB - Several processes have been suggested to protect lipids from bioactivity of the rumen microorganisms. The majority of experiments with conjugated linoleic acid (CLA) were conducted using calcium salts of CLA. The objectives of this study were to determine the effects of encapsulated CLA (E-CLA) that was supplemented during days 21 to 100 post partum (PP), on milk fat depression, recovery rate and performance parameters. Forty-two multiparous Israeli-Holstein cows were divided at day 21 PP into two treatment groups: (i) control - supplemented with 43 g/day per cow of calcium salts of fatty acids (FAs). (ii) E-CLA - supplemented with 50 g/day per cow of encapsulated lipid supplement providing 4.7 g/day per cow of trans-10, cis-12 CLA. Post-treatment cows were followed for recovery rate until 140 days PP. Dry matter intake (DMI) during the treatment period was reduced by 2.5%, and milk yield was enhanced by 4.5% in the E-CLA cows. Milk fat percentage and yield were reduced by 13% and 9%, respectively, in the E-CLA treatment as compared with the control. The energy-corrected milk output was 3.6% higher in the control group than in the E-CLA group. Yields of trans-10, cis-12 CLA isomer in milk was 2.13-fold higher in the E-CLA cows than in the controls. Full recovery to milk fat percentage of the control group occurred 4 to 5 weeks after cessation of the E-CLA supplementation. No differences between groups were observed in any fertility parameter that was tested. In conclusion, the E-CLA supplement decreased DMI, enhanced milk yield, and decreased energy output in milk, and was effective in depressing milk fat. Full recovery to the milk fat content, but not yield, of the control group in the E-CLA group was relatively slow and occurred 4 to 5 weeks after termination of the supplementation. PMID- 22444052 TI - Effects of duration of zilpaterol hydrochloride supplementation on growth performance, carcass traits and meat quality of grain-fed cull cows. AB - Several studies have shown that feeding of an energy-dense diet over short periods to cull cows could be profitable in terms of increased saleable yield and improved carcass conditions. Although the application of growth promoters, such as anabolic implants and beta agonists, in finishing of cull cows have been recorded, there is no conclusive evidence as to the timing and duration of beta agonists in cull cow production. In this study, 288 cull cows with four or more permanent incisors and varying weights and body conditions were divided into four treatment groups so that variation in age, weight and body condition were equally distributed among groups. One group received concentrate feed without any beta agonist (C), whereas the other three groups also received concentrate feed with zilpaterol hydrochloride (6 p.p.m.) for 20 (Z20), 30 (Z30) or 40 (Z40) days, respectively, followed by a 2-day withdrawal. Animals were adapted for 10 days on a grain-based diet and fed an additional 40 days before slaughter. Growth rate and efficiency (live and carcass), trimmed meat yield and meat tenderness (Warner Bratzler shear force and sensory) of the aged (10 days) m. longissimus thoracis (LT) and m. semitendinosus (ST) were recorded. In general, Z cows had higher carcass gains and efficiency of gain than C cows (P < 0.05). In addition, Z carcasses showed higher proportional trimmed meat yields than C carcasses (P < 0.05). No significant differences in tenderness measurements were recorded for LT or ST. In general, supplementation of zilpaterol for 30 days showed better growth performance and higher trimmed meat yield than 20 and 40 days supplementation. PMID- 22444053 TI - Natural versus anthropogenic inhalable aerosol chemistry of transboundary East Asian atmospheric outflows into western Japan. AB - The eastward transport of aerosols exported from mainland Asia strongly influences air quality in the Japanese archipelago. The bulk of the inhalable particulate matter (PM(10)) in these intrusions comprises either natural, desert derived minerals (mostly supermicron silicates) or anthropogenic pollutants (mostly submicron sulphates), in various states of mixing. We analyse PM(10) collected in Kumamoto, SW Japan, during three contrasting types of aerosol intrusions, the first being dominated by desert PM which became increasingly mixed with anthropogenic components as time progressed, the second being a relatively minor event mixing fine, distal desert PM with anthropogenic materials, and the third being dominated by anthropogenic pollutants. Whereas the chemistry of the natural mineral component is characterised by "crustal" elements (Si, Al, Fe, Mg, K, Li, P, Sc, V, Rb, Sr, Zr, Th, lanthanoids), the anthropogenic component is rich in secondary inorganic compounds and more toxic metallic elements (NH(4)(+), SO(4)(2-), As, Pb, Cd, Cu, Zn, Sn, Bi, Sb, and Ge). Some desert-dust (Kosa) intrusions are more calcareous than others, implicating geologically different source areas, and contain enhanced levels of NO(3)(-), probably as supermicron Ca(NO(3))(2) particles produced by chemical reaction between NOx pollutants (mostly from industry and traffic) and carbonate during atmospheric transport. The overall trace element chemistry of aerosol intrusions into Kumamoto shows low V/Rb, low NO(3)(-)/SO(4)(2-), enhanced As levels, and unfractionated La/Ce values, which are all consistent with anthropogenic sources including coal emissions rather than those derived from the refining and combustion of oil fractionates. Geographically dispersed, residual sulphatic plumes of this nature mix with local traffic (revealed by OC and EC concentrations) and industrial emissions and dissipate only slowly, due to the dominance of submicron accumulation mode PM which is atmospherically persistent, and raise questions over the chronic health effects of breathing finely respirable sulphatic aerosol containing enhanced amounts of toxic metals. PMID- 22444054 TI - Stabilization of carbon in composts and biochars in relation to carbon sequestration and soil fertility. AB - There have been increasing interests in the conversion of organic residues into biochars in order to reduce the rate of decomposition, thereby enhancing carbon (C) sequestration in soils. However energy is required to initiate the pyrolysis process during biochar production which can also lead to the release of greenhouse gasses. Alternative methods can be used to stabilize C in composts and other organic residues without impacting their quality. The objectives of this study include: (i) to compare the rate of decomposition among various organic amendments and (ii) to examine the effect of clay materials on the stabilization of C in organic amendments. The decomposition of a number of organic amendments (composts and biochars) was examined by monitoring the release of carbon-dioxide using respiration experiments. The results indicated that the rate of decomposition as measured by half life (t(1/2)) varied between the organic amendments and was higher in sandy soil than in clay soil. The half life value ranged from 139 days in the sandy soil and 187 days in the clay soil for poultry manure compost to 9989 days for green waste biochar. Addition of clay materials to compost decreased the rate of decomposition, thereby increasing the stabilization of C. The half life value for poultry manure compost increased from 139 days to 620, 806 and 474 days with the addition of goethite, gibbsite and allophane, respectively. The increase in the stabilization of C with the addition of clay materials may be attributed to the immobilization of C, thereby preventing it from microbial decomposition. Stabilization of C in compost using clay materials did not impact negatively the value of composts in improving soil quality as measured by potentially mineralizable nitrogen and microbial biomass carbon in soil. PMID- 22444055 TI - The application of an analytical probabilistic model for estimating the rainfall runoff reductions achieved using a rainwater harvesting system. AB - Rainwater harvesting systems cannot only supplement on-site water needs, but also reduce water runoff and lessen downstream flooding. In this study, an existing analytic model for estimating the runoff in urban areas is modified to provide a more economical and effective model that can be used for describing rainwater harvesting. This model calculates the rainfall-runoff reduction by taking into account the catchment, storage tank, and infiltration facility of a water harvesting system; this calculation is based on the water balance equation, and the cumulative distribution, probability density, and average rainfall-runoff functions. This model was applied to a water harvesting system at the Seoul National University in order to verify its practicality. The derived model was useful for evaluating runoff reduction and for designing the storage tank capacity. PMID- 22444056 TI - Testing the use of passive sampling systems for understanding air mercury concentrations and dry deposition across Florida, USA. AB - This paper describes the use of passive sampling systems and surrogate surfaces for monitoring atmospheric mercury (Hg) concentrations and dry deposition, respectively, in Florida,USA. Although this area has been reported to have low air concentrations, wet deposition values, reported by the Mercury Deposition Network, are some of the highest in the United States, and little is known about the magnitude of dry deposition to the region. To address this uncertainty, dry deposition of gaseous oxidized mercury (GOM) was estimated based on data collected using surrogate surfaces and through the application of a dry deposition model that utilized Tekran(r) Mercury Analyzer data for three sites (Davie near Fort Lauderdale, Tampa and Pensacola) over a year (July 2009-July 2010). Passive sampler systems for monitoring GOM and total gaseous mercury (TGM) concentrations were also deployed. In general, higher surrogate surface deposition, and GOM and TGM passive sampler uptake were observed at the DVE location. Across all sites, empirically derived dry deposition was higher than that determined using modeled values. Tekran(r) Instrument derived GOM concentrations, as well as modeled deposition rates, followed the same seasonal and spatial patterns as that measured by the samplers, however there were some spatial and temporal trends captured by the samplers that were not seen in the Tekran(r) derived data. Results indicate that these samplers may be applied to identify spatial and temporal trends in air Hg concentrations and potential deposition at sites with low and fairly constant GOM concentrations as reported by the Tekran(r) system (2-8 pg m(-3)). When viewed collectively, trends in sampler and Tekran(r) derived data also suggest the potential for different forms of GOM in air. Using empirical and modeled values, dry deposition in Florida during the year of this study could account for 1.5 to 14% of total annual Hg deposition (wet+dry). PMID- 22444057 TI - Incorporating bioaccessibility into human health risk assessments of heavy metals in urban park soils. AB - Contaminants in urban soils can directly pose significant human health risks through oral ingestion, particle inhalation, and dermal contact, especially for children in public parks. Both non-carcinogenic and carcinogenic risks of heavy metals (Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) were characterized in 40 surface soils (exposed lawns) from 14 urban parks in Xiamen, China. Results based on total metal concentrations may overestimate the actual risks in comparison with oral bioaccessibility assessment that were estimated by a simplified physiologically based extraction test (SBET). After considering the soil-specific bioaccessibility (Cd>Cu>Pb>Mn>Zn>Co~Ni>Cr), the non-cancer hazard of Pb to children via oral ingestion should be a consideration though its Hazard Index (HI) was below one. The overall cancer risks to adults still exceeded the target value 10(-6), mainly contributed by Cr (93.8%) and Pb (6.19%) via dermal contact (68.3%) and oral ingestion (30.4%). To produce a more realistic estimation for human health risks of metal contamination in urban soils, a framework combining land use type and bioaccessibility is recommended and thereby should be applied for the derivation of risk-based, site-specific soil guidelines. PMID- 22444058 TI - Human health risk assessment of air emissions from development of unconventional natural gas resources. AB - BACKGROUND: Technological advances (e.g. directional drilling, hydraulic fracturing), have led to increases in unconventional natural gas development (NGD), raising questions about health impacts. OBJECTIVES: We estimated health risks for exposures to air emissions from a NGD project in Garfield County, Colorado with the objective of supporting risk prevention recommendations in a health impact assessment (HIA). METHODS: We used EPA guidance to estimate chronic and subchronic non-cancer hazard indices and cancer risks from exposure to hydrocarbons for two populations: (1) residents living >1/2 mile from wells and (2) residents living <= 1/2 mile from wells. RESULTS: Residents living <= 1/2 mile from wells are at greater risk for health effects from NGD than are residents living >1/2 mile from wells. Subchronic exposures to air pollutants during well completion activities present the greatest potential for health effects. The subchronic non-cancer hazard index (HI) of 5 for residents <= 1/2 mile from wells was driven primarily by exposure to trimethylbenzenes, xylenes, and aliphatic hydrocarbons. Chronic HIs were 1 and 0.4. for residents <= 1/2 mile from wells and >1/2 mile from wells, respectively. Cumulative cancer risks were 10 in a million and 6 in a million for residents living <= 1/2 mile and >1/2 mile from wells, respectively, with benzene as the major contributor to the risk. CONCLUSIONS: Risk assessment can be used in HIAs to direct health risk prevention strategies. Risk management approaches should focus on reducing exposures to emissions during well completions. These preliminary results indicate that health effects resulting from air emissions during unconventional NGD warrant further study. Prospective studies should focus on health effects associated with air pollution. PMID- 22444059 TI - Effects of sulfate reducing bacteria and sulfate concentrations on mercury methylation in freshwater sediments. AB - Methylmercury (MeHg) is the most poisonous form of mercury (Hg) and it enters the human body primarily through consumption of Hg contaminated fish. Sulfate reducing bacteria (SRB) are major producers of MeHg in anoxic sediments. The dsrAB gene was isolated from freshwater fish pond sediments. Sequence analyses showed that the SRB in sediments was mainly composed of Desulfobulbus propionicus and Desulfovibrio vulgaris. The two species of SRB were cultured from freshwater sediments. The addition of inorganic Hg to these freshwater sediments caused an increase in MeHg concentrations at 30 days incubation. MeHg levels were sensitive to sulfate concentrations; a medium sulfate level (0.11 mg/g) produced higher levels than treatments lacking sulfate addition or when amended with 0.55 mg/g. Assessment of bacterial levels by PCR measurements of microbial DNA indicated that the MeHg levels were correlated with cell growth. PMID- 22444061 TI - Historical lead isotope record of a sediment core from the Derwent River (Tasmania, Australia): a multiple source environment. AB - A 105 cm sediment core from the Derwent River (Tasmania, Australia) was collected in 2004 and was characterised considering both physical (loss on ignition at 550 degrees C and grain size) and chemical (Fe, Cu, Zn, Cd and Pb concentrations, Pb isotope ratios and (210)Pb dating) properties. The core was analysed to (i) investigate the historical profiles of some important elements associated with the Risdon zinc refinery adjacent to the Derwent River, (ii) determine Pb isotopic signatures of sediment samples, and (iii) assess the veracity of Pb isotope ratios as indicators of contaminant Pb input. Extractable metal concentrations were (all values as mgkg(-1), non-normalised for grain size) Fe: 20,000-35,000, Zn: 42-4500, Pb: 5-1090, Cu: 13-141, and Cd: 1-31; with a close correlation between Cu, Zn, Cd and Pb. Metal enrichment factors (normalised to Al) were Pb: 0.9-144, Zn: 0.8-93, Cd: 0.8-30, Cu: 0.8-8.9 and Fe: 0.9-1.3, confirming anthropogenic contributions of Cu, Zn, Pb and Cd to the sediments. The onset of metal contamination above background levels occurred at a depth between 43 and 49 cm, with maximum concentrations noted near 20 cm for Cu, Zn, Cd and Pb. Lead isotope ratios were determined in sediments using sector field ICP-MS, and were found to be 36.5-38.8, 16.5-18.7 and 1.07-1.20 for (208)Pb/(204)Pb, (206)Pb/(204)Pb and (206)Pb/(207)Pb ratios, respectively. Major Australian ores processed at the refinery over the previous ~90 years include those from Broken Hill, Rosebery, Mt Isa, Elura, Hellyer and Century deposits. Anthropogenic impact by Pb with Broken Hill type isotopic ratio was initially evident in the core at 43-49 cm. The introduction of Rosebery and Elura ores to the refinery was also clearly noted. Pb isotope ratios further highlight that the Derwent River has been exposed to a greater impact by anthropogenic Pb in comparison to other major Tasmanian rivers, namely the Huon and Tamar. PMID- 22444062 TI - Factors influencing blood mercury levels of inhabitants living near fishing areas. AB - Methylmercury (MeHg), a well-known neuro-toxicant, is usually emitted by industrial and other man-made activities; it is ingested with seafood and shellfish, and accumulates in the human body. The aim of this study was to compare the differences in blood levels of total mercury (T-Hg) and MeHg in residents of 4 coastal sites and 4 inland sites around Taiwan. Meanwhile, the potential question is warranted to find out the association between dietary intake and MeHg accumulation. We found that coastal residents had significantly higher mean blood T-Hg levels (mean: 16.1 MUg/L, range: 0.9-184.9 MUg/L) than inland residents (mean: 11.8 MUg/L, range: 0.8-146.6 MUg/L). The same was for blood MeHg levels: coastal residents (mean: 16.5 MUg/L, range: 0.9-184.9 MUg/L), inland residents (mean: 11.8 MUg/L, range: 2.1-133.4 MUg/L). These elevated levels were positively associated with seafood and shellfish consumption. However, the nature of their residential area may also be an important factor, because the highest T-Hg and MeHg levels were found in residents of a relatively non-industrialized area. To protect vulnerable population-especially children and pregnant women-it is important to know whether locally caught or raised and consumed fish has any source of Hg and MeHg pollution. PMID- 22444063 TI - Effects of in vivo chronic exposure to pendimethalin/Prowl 400(r) on sanitary status and the immune system in rainbow trout (Oncorhynchus mykiss). AB - The in vivo effects of the herbicide active substance (AS) pendimethalin (alone and with Prowl 400(r) adjuvant) were evaluated on sanitary status i.e. the health status with regard to chemical pollution and on the physiological state via the immune system in rainbow trout, Oncorhynchus mykiss. Four nominal exposure conditions were tested: i) control (C), ii) AS at 500 ng L(-1) (P500), iii) AS at 800 ng L(-1) (P800) and iv) Prowl 400(r) at 500 ng L(-1) (Pw). After a 28 day exposure period (D28), 10 fish were sampled for each condition and 10 other after a 15 day recovery period in clean fresh water (D43). Pendimethalin concentrations in the exposure water and muscles were followed. White blood cell counts, differential leucocyte counts, cell mortality and phagocytosis activity were measured. Haemolytic alternative complement activity, lysozyme concentration and stress parameters were analyzed. The resulting concentration of pendimethalin in the exposure water was lower than the expected concentration. At D28, the concentration quantified in the contaminated fish was negligible in comparison with the Reference Dose for Oral Exposure estimated by US-EPA's Integrated Risk Information System. Leucopenia was noted in all contaminated fish. A decrease in phagocytosis activity and ACH(50) was also observed in contaminated fish by P800 and Pw. Disturbed lysozyme activity was noted only in fish exposed to Pw. Furthermore, during exposure to a similar concentration of pendimethalin, the commercial product seemed to be more immunotoxic than the AS alone. Finally, at D43, the effects proved reversible for sanitary status while immunity was still disturbed in contaminated fish by P800 and Pw. PMID- 22444064 TI - Industrial pollution and pleural cancer mortality in Spain. AB - Pleural cancer mortality is an acknowledged indicator of exposure to asbestos and mesothelioma mortality but in 15%-20% of cases no exposure can be recalled. In the past, asbestos was used in many industries and it is still found in many installations. Our objective was to ascertain whether there might be excess pleural cancer mortality among populations residing in the vicinity of Spanish industrial installations that are governed by the Integrated Pollution Prevention and Control (IPPC) Directive and the European Pollutant Release and Transfer Register Regulation and report their emissions to air. An ecological study was designed to examine pleural cancer mortality at a municipal level (8098 Spanish towns) over the period 1997-2006, during which 2146 deaths were registered. We conducted an exploratory "near vs. far" analysis to estimate the relative risks (RRs) of towns situated at a distance of <2 km from installations. This analysis was repeated for each of the 24 industrial groups. RR and their 95% credible intervals (95% CIs) were estimated on the basis of a Poisson conditional autoregressive Bayesian model with explanatory variables. Integrated nested Laplace approximations were used as a Bayesian inference tool. Analysis showed statistically significant RRs in both sexes in the vicinity of 7 of the 24 industrial groups studied (RR, 95% CI), namely, biocide facilities (2.595, 1.459 4.621), ship-building (2.321, 1.379-3.918), glass and mineral fibre production (1.667, 1.041-2.665), non-hazardous waste treatment (1.737, 1.077-2.799), galvanising (1.637, 1.139-2.347), organic chemical plants (1.386, 1.075-1.782) and the food and beverage sector (1.255, 1.006-1.562). In the proximity of sources pertaining to the biocide, organic chemical and galvanising sectors, the risk was seen to be rising among men and women, a finding that could indicate airborne environmental exposure. These results support that residing in the vicinity of IPPC-registered industries that release pollutants to the air constitutes a risk factor for pleural cancer. PMID- 22444065 TI - Some insights into the relationship between urban air pollution and noise levels. AB - The relationship between noise and air pollution was investigated in eight different districts across Seoul, Korea, between September and November 2010. The noise levels in each district were measured at both roadside and non-roadside locations. It was found that the maximum levels of noise were generally at frequencies of around 1000 Hz. The equivalent noise levels (L(eq)), over all districts, averaged 61.4 +/- 7.36 dB which is slightly lower than the noise guidelines set by the World Health Organization (WHO) of 70 dB for industrial, commercial, traffic, and outdoor areas. Comparison of L(eq) levels in each district consistently indicates that noise levels are higher at roadside sites than non-roadside sites. In addition the relative dominance of noise during daytime as compared to nighttime was also apparent. Moreover, the results of an analysis relating sound levels with air pollutant levels indicate strongly that the correlation between these two parameters is the strongest at roadside sites (relative to non-roadside sites) and during nighttime (relative to daytime). The results of our data analysis point to a positive, but complex, correlation between noise levels and air pollution. PMID- 22444066 TI - Using the INCA-Hg model of mercury cycling to simulate total and methyl mercury concentrations in forest streams and catchments. AB - We present a new, catchment-scale, process-based dynamic model for simulating mercury (Hg) in soils and surface waters. The Integrated Catchments Model for Mercury (INCA-Hg) simulates transport of gaseous, dissolved and solid Hg and transformations between elemental (Hg(0)), ionic (Hg(II)) and methyl (MeHg) Hg in natural and semi-natural landscapes. The mathematical description represents the model as a series of linked, first-order differential equations describing chemical and hydrological processes in catchment soils and waters which we believe control surface water Hg dynamics. The model simulates daily time series between one and 100 years long and can be applied to catchments ranging in size from <1 to ~10,000 km(2). Here we present applications of the model to two boreal forest headwater catchments in central Canada where we were able to reproduce observed patterns of stream water total mercury (THg) and MeHg fluxes and concentrations. Model performance was assessed using Monte Carlo techniques. Simulated in-stream THg and MeHg concentrations were sensitive to hydrologic controls and terrestrial and aquatic process rates. PMID- 22444067 TI - Acid-base accounting assessment of mine wastes using the chromium reducible sulfur method. AB - The acid base account (ABA), commonly used in assessment of mine waste materials, relies in part on calculation of potential acidity from total sulfur measurements. However, potential acidity is overestimated where organic sulfur, sulfate sulfur and some sulfide compounds make up a substantial portion of the sulfur content. The chromium reducible sulfur (CRS) method has been widely applied to assess reduced inorganic sulfur forms in sediments and acid sulfate soils, but not in ABA assessment of mine wastes. This paper reports the application of the CRS method to measuring forms of sulfur commonly found in mine waste materials. A number of individual sulfur containing minerals and real waste materials were analyzed using both CRS and total S and the potential acidity estimates were compared with actual acidity measured from net acid generation tests and column leach tests. The results of the CRS analysis made on individual minerals demonstrate good assessment of sulfur from a range of sulfides. No sulfur was measured using the CRS method in a number of sulfate salts, including jarosite and melanterite typically found in weathered waste rocks, or from dibenzothiophene characteristic of organic sulfur compounds common to coal wastes. Comparison of ABA values for a number of coal waste samples demonstrated much better agreement of acidity predicted from CRS analysis than total S analysis with actual acidity. It also resulted in reclassification of most samples tested from PAF to NAF. Similar comparisons on base metal sulfide wastes generally resulted in overestimation of the acid potential by total S and underestimation of the acid potential by CRS in comparison to acidity measured during NAG tests, but did not generally result in reclassification. In all the cases examined, the best estimate of potential acidity included acidity calculated from both CRS and jarositic S. PMID- 22444068 TI - Fate of cyanobacteria and their metabolites during water treatment sludge management processes. AB - Cyanobacteria and their metabolites are an issue for water authorities; however, little is known as to the fate of coagulated cyanobacterial-laden sludge during waste management processes in water treatment plants (WTPs). This paper provides information on the cell integrity of Anabaena circinalis and Cylindrospermopsis raciborskii during: laboratory-scale coagulation/sedimentation processes; direct filtration and backwashing procedures; and cyanobacterial-laden sludge management practices. In addition, the metabolites produced by A. circinalis (geosmin and saxitoxins) and C. raciborskii (cylindrospermopsin) were investigated with respect to their release (and possible degradation) during each of the studied processes. Where sedimentation was used, coagulation effectively removed cyanobacteria (and intracellular metabolites) without any considerable exertion on coagulant demand. During direct filtration experiments, cyanobacteria released intracellular metabolites through a stagnation period, suggesting that more frequent backwashing of filters may be required to prevent floc build-up and metabolite release. Cyanobacteria appeared to be protected within the flocs, with minimal damage during backwashing of the filters. Within coagulant sludge, cyanobacteria released intracellular metabolites into the supernatant after 3d, even though cells remained viable up to 7d. This work has improved the understanding of cyanobacterial metabolite risks associated with management of backwash water and sludge and is likely to facilitate improvements at WTPs, including increased monitoring and the application of treatment strategies and operational practices, with respect to cyanobacterial-laden sludge and/or supernatant recycle management. PMID- 22444069 TI - Examining nocturnal railway noise and aircraft noise in the field: sleep, psychomotor performance, and annoyance. AB - BACKGROUND: Traffic noise is interfering during day- and nighttime causing distress and adverse physiological reactions in large parts of the population. Railway noise proved less annoying than aircraft noise in surveys which were the bases for a so called 5 dB railway bonus regarding noise protection in many European countries. OBJECTIVES: The present field study investigated railway noise-induced awakenings during sleep, nighttime annoyance and the impact on performance the following day. Comparing these results with those from a field study on aircraft noise allowed for a ranking of traffic modes concerning physiological and psychological reactions. METHODS: 33 participants (mean age 36.2 years +/- 10.3 (SD); 22 females) living alongside railway tracks around Cologne/Bonn (Germany) were polysomnographically investigated. These data were pooled with data from a field study on aircraft noise (61 subjects) directly comparing the effects of railway and aircraft noise in one random subject effects logistic regression model. Annoyance was rated in the morning evaluating the previous night. RESULTS: Probability of sleep stage changes to wake/S1 from railway noise increased significantly from 6.5% at 35 dB(A) to 20.5% at 80 dB(A) LAFmax. Rise time of noise events had a significant impact on awakening probability. Nocturnal railway noise led to significantly higher awakening probabilities than aircraft noise, partly explained by the different rise times, whereas the order was inversed for annoyance. Freight train noise compared to passenger train noise proved to have the most impact on awakening probability. Nocturnal railway noise had no effect on psychomotor vigilance. CONCLUSIONS: Nocturnal freight train noise exposure in Germany was associated with increased awakening probabilities exceeding those for aircraft noise and contrasting the findings of many annoyance surveys and annoyance ratings of our study. During nighttime a bonus for railway noise seems not appropriate. PMID- 22444070 TI - Tolerance of cultivated and wild plants of different taxonomy to soil contamination by kerosene. AB - In laboratory experiments on leached chernozem contaminated by kerosene (1-15 wt.%), germination of 50 plants from 21 families (cultivated and wild, annual and perennial, mono- and dicotyledonous) as affected by kerosene type and concentration and plant features was determined. Tested plants formed three groups: more tolerant, less tolerant, and intolerant, in which relative germination was more than 70%, 30-70% and less than 30%, respectively. As parameters of soil phytotoxicity, effective kerosene concentrations (EC) causing germination depression of 10%, 25% and 50% were determined. EC values depended on the plant species and varied in a wide range of kerosene concentrations: 0.02 7.3% (EC(10)), 0.05-8.1% (EC(25)), and 0.2-12.7% (EC(50)). The reported data on germination in soils contaminated by oil and petrochemicals were generalized. The comparison showed that at very high contamination levels (10 and 15%) kerosene was 1.3-1.6 times more phytotoxic than diesel fuel and 1.3-1.4 times more toxic than crude oil, and at low (1 and 2%) and medium (3 and 5%) levels the toxicity of these contaminants was close differing by a factor of 1.1-1.2. Tolerance of plants to soil contamination had a species-specific nature and, on the average, decreased in the following range of families: Fabaceae (germination decrease of 10-60% as compared to an uncontaminated control)>Brassicaceae (5-70%)>Asteraceae (25-95%)>Poaceae (10-100%). The monocotyledonous species tested were characterized as medium- and low-stable to contamination, whereas representatives of dicotyledonous plants were met in all groups of tolerance. Tested wild plants, contrary to reference data on oil toxicity, were more sensitive to kerosene than cultivated. No correlation was observed between degree of plant tolerance to kerosene and mass of seeds. The evidence indicates factors as structure and properties of testa, structure of germ, type of storage compounds, and type of seed germination (underground or aboveground) are more important. PMID- 22444071 TI - Genetic parameters for test-day yield of milk, fat and protein in buffaloes estimated by random regression models. AB - The test-day yields of milk, fat and protein were analysed from 1433 first lactations of buffaloes of the Murrah breed, daughters of 113 sires from 12 herds in the state of Sao Paulo, Brazil, born between 1985 and 2007. For the test-day yields, 10 monthly classes of lactation days were considered. The contemporary groups were defined as the herd-year-month of the test day. Random additive genetic, permanent environmental and residual effects were included in the model. The fixed effects considered were the contemporary group, number of milkings (1 or 2 milkings), linear and quadratic effects of the covariable cow age at calving and the mean lactation curve of the population (modelled by third-order Legendre orthogonal polynomials). The random additive genetic and permanent environmental effects were estimated by means of regression on third- to sixth-order Legendre orthogonal polynomials. The residual variances were modelled with a homogenous structure and various heterogeneous classes. According to the likelihood-ratio test, the best model for milk and fat production was that with four residual variance classes, while a third-order Legendre polynomial was best for the additive genetic effect for milk and fat yield, a fourth-order polynomial was best for the permanent environmental effect for milk production and a fifth-order polynomial was best for fat production. For protein yield, the best model was that with three residual variance classes and third- and fourth-order Legendre polynomials were best for the additive genetic and permanent environmental effects, respectively. The heritability estimates for the characteristics analysed were moderate, varying from 0.16+/-0.05 to 0.29+/-0.05 for milk yield, 0.20+/-0.05 to 0.30+/-0.08 for fat yield and 0.18+/-0.06 to 0.27+/-0.08 for protein yield. The estimates of the genetic correlations between the tests varied from 0.18+/-0.120 to 0.99+/-0.002; from 0.44+/-0.080 to 0.99+/-0.004; and from 0.41+/-0.080 to 0.99+/-0.004, for milk, fat and protein production, respectively, indicating that whatever the selection criterion used, indirect genetic gains can be expected throughout the lactation curve. PMID- 22444072 TI - Variations in estimates of underweight, stunting, wasting, overweight and obesity in children from Argentina comparing three growth charts. AB - OBJECTIVE: To compare estimates of underweight, stunting, wasting, overweight and obesity based on three growth charts. DESIGN: Cross-sectional study to estimate weight-for-age, length/height-for-age and weight-for-height comparing the 2006 WHO Child Growth Standards ('the WHO standards'), the 1977 National Center for Health Statistics (NCHS) international growth reference ('the NCHS reference') and the 1987 Argentine Pediatric Society Committee of Growth and Development reference ('the APS reference'). Cut-off points were defined as mean values +/-2 s d. Epi-Info software version 6.0 (Centers for Disease Control and Prevention) was used for statistical evaluations (chi 2, P <= 0.05). SETTING: Greater La Plata conurbation, Buenos Aires, Argentina. SUBJECTS: A total of 2644 healthy, full-term children from 0 to 5 years of age. RESULTS: Prevalence of underweight was higher with the WHO standards than with the other references up to the first 6 months. For the rest of the ages, prevalence was lower with the WHO standards. Stunting prevalence was higher with the WHO standards at all ages. Prevalence of wasting was higher with the WHO standards compared with the NCHS reference up to the first 6 months and lower at 2-5 years of age. Overweight and obesity prevalences were higher with the WHO standards at all ages. CONCLUSIONS: The new WHO standards appear to be a solid and reliable tool for diagnosis and treatment of nutritional diseases, also being the only one built with infants fed according to WHO recommendations. Therefore, our results support the decision of the National Ministry of Health about the utilization of the new WHO standards to monitor the nutritional status of Argentinean children aged less than 5 years. PMID- 22444073 TI - A novel ascaroside controls the parasitic life cycle of the entomopathogenic nematode Heterorhabditis bacteriophora. AB - Entomopathogenic nematodes survive in the soil as stress-resistant infective juveniles that seek out and infect insect hosts. Upon sensing internal host cues, the infective juveniles regurgitate bacterial pathogens from their gut that ultimately kill the host. Inside the host, the nematode develops into a reproductive adult and multiplies until unknown cues trigger the accumulation of infective juveniles. Here, we show that the entomopathogenic nematode Heterorhabditis bacteriophora uses a small-molecule pheromone to control infective juvenile development. The pheromone is structurally related to the dauer pheromone ascarosides that the free-living nematode Caenorhabditis elegans uses to control its development. However, none of the C. elegans ascarosides are effective in H. bacteriophora, suggesting that there is a high degree of species specificity. Our report is the first to show that ascarosides are important regulators of development in a parasitic nematode species. An understanding of chemical signaling in parasitic nematodes may enable the development of chemical tools to control these species. PMID- 22444074 TI - Global and system-specific resting-state fMRI fluctuations are uncorrelated: principal component analysis reveals anti-correlated networks. AB - The influence of the global average signal (GAS) on functional-magnetic resonance imaging (fMRI)-based resting-state functional connectivity is a matter of ongoing debate. The global average fluctuations increase the correlation between functional systems beyond the correlation that reflects their specific functional connectivity. Hence, removal of the GAS is a common practice for facilitating the observation of network-specific functional connectivity. This strategy relies on the implicit assumption of a linear-additive model according to which global fluctuations, irrespective of their origin, and network-specific fluctuations are super-positioned. However, removal of the GAS introduces spurious negative correlations between functional systems, bringing into question the validity of previous findings of negative correlations between fluctuations in the default mode and the task-positive networks. Here we present an alternative method for estimating global fluctuations, immune to the complications associated with the GAS. Principal components analysis was applied to resting-state fMRI time-series. A global-signal effect estimator was defined as the principal component (PC) that correlated best with the GAS. The mean correlation coefficient between our proposed PC-based global effect estimator and the GAS was 0.97+/-0.05, demonstrating that our estimator successfully approximated the GAS. In 66 out of 68 runs, the PC that showed the highest correlation with the GAS was the first PC. Since PCs are orthogonal, our method provides an estimator of the global fluctuations, which is uncorrelated to the remaining, network-specific fluctuations. Moreover, unlike the regression of the GAS, the regression of the PC-based global effect estimator does not introduce spurious anti-correlations beyond the decrease in seed-based correlation values allowed by the assumed additive model. After regressing this PC-based estimator out of the original time series, we observed robust anti-correlations between resting-state fluctuations in the default-mode and the task-positive networks. We conclude that resting state global fluctuations and network-specific fluctuations are uncorrelated, supporting a Resting-State Linear-Additive Model. In addition, we conclude that the network-specific resting-state fluctuations of the default-mode and task positive networks show artifact-free anti-correlations. PMID- 22444075 TI - New adoptive immunotherapy strategies for solid tumours with CIK cells. AB - INTRODUCTION: Despite development and introduction of new and innovative drugs, a large number of malignant diseases are associated with unfavourable prognosis. In recent years, considerable progress in cancer treatment has been obtained by the application of cytokine-induced killer (CIK) cells. AREAS COVERED: This review provides an overview and summary of recent advances in adoptive immunotherapy strategies in cancer treatment using CIK cells. A selective literature search has been performed. EXPERT OPINION: The application of CIK cells as adoptive immunotherapy plays an important role in cancer treatment. Combining CIK cells with other conventional and established therapy options represents an innovative approach and will hopefully provide new insight for the future. PMID- 22444076 TI - Genetic analysis of the growth rate of Israeli Holstein calves. AB - Weight of male and female Israeli Holstein calves and yearling gain were analyzed on 285 800 records from 105 935 animals from 458 herds recorded between 1994 and 2007. The difference between the sexes increased until around 400 days, at which point the difference between males and females was 110 kg. Yearling gain, defined as 365 * (weight - 35)/age + 35, was greatest for males at approximately 300 days and for females at 225 days. Yearling gain of male and female calves were highly correlated genetically; thus records from both sexes were combined into a joint genetic analysis. Heritability and repeatability were 0.33 and 0.73 in the analysis of both sexes, and similar in the single-sex analyses. Yearling gain is also highly correlated genetically with various measures of mature cow size. Yearling gain was positively correlated with milk, fat, protein production and somatic cell score, but negatively correlated with fertility and cow survival. Yearling gain was also positively correlated with both the sire and maternal grandsire effects on dystocia, but not with calf mortality. The genetic trend for yearling gain was 0.16 kg/year, while phenotypic trends for first and last weighings were both negative. PMID- 22444077 TI - Multiple-trait selection for radiographic health of the limbs, conformation and performance in Warmblood riding horses. AB - Information on 26 434 German Warmblood horses born between 1992 and 2001 was used for multivariate genetic analyses of radiographic health, conformation and performance traits to compare different modes of single- and multiple-trait selection of sires. Results of standardized radiological examinations of 5155 Hanoverian Warmblood horses, conformation evaluations from studbook inspections of 20 603 mares, and performance evaluations from mare performance tests and auction horse inspections of 16 098 horses were used for multivariate genetic analyses. Genetic parameters were estimated with restricted maximum likelihood (REML), and relative breeding values (RBV) were predicted with best linear unbiased prediction (BLUP) in multivariate linear animal models for four radiographic health traits, three conformation traits and five performance traits. Heritability estimates for osseous fragments in fetlock joints (OFF), osseous fragments in hock joints (OFH), deforming arthropathy in hock joints (DAH) and distinct radiographic findings in the navicular bones (DNB) ranged between 0.15 and 0.35 after transformation to the liability scale. Front limb conformation, hind limb conformation, withers height, walk, trot, canter, rideability and free jumping showed heritabilities between 0.09 and 0.49 and additive genetic correlations with OFF, OFH, DAH and DNB ranging between -0.53 and +0.52. Selection of sires was based on RBV or combinations of RBV, with selection for individual traits or traits from one of the three considered trait groups being considered as single-trait selection, and selection for traits from more than one trait group being considered as multiple-trait selection. The selection modes were compared by means of the expected selection response after one generation, calculated as the relative change in the prevalences of the radiographic findings or the mean conformation or performance scores in the offspring of the selected sires when compared with the offspring of all sires. The prevalences of OFF, OFH, DAH and DNB decreased by 30% to 57% after single trait selection and 14% to 29% after multiple-trait selection, while mean conformation and performance scores increased by up to 4%. The results indicated that it is possible to simultaneously improve the radiographic health of the limbs, limb conformation, quality of gaits and rideability. However, genetic progress in free jumping ability and style could only be achieved by single- or multiple-trait selection with focus on jumping performance. PMID- 22444078 TI - An effective rotational mating scheme for inbreeding reduction in captive populations illustrated by the rare sheep breed Kempisch Heideschaap. AB - Within breeds and other captive populations, the risk of high inbreeding rates and loss of diversity can be high within (small) herds or subpopulations. When exchange of animals between different subpopulations is organised according to a rotational mating scheme, inbreeding rates can be restricted. Two such schemes, a breeding circle and a maximum avoidance of inbreeding scheme, are compared. In a breeding circle, flocks are organised in a circle where each flock serves as a donor flock for another flock, and the same donor-recipient combination is used in each breeding season. In the maximum inbreeding avoidance scheme, donor recipient combinations change each year so that the use of the same combination is postponed as long as possible. Data from the Kempisch Heideschaap were used with computer simulations to determine the long-term effects of different breeding schemes. Without exchanging rams between flocks, high inbreeding rates (>1.5% per year) occurred. Both rotational mating schemes reduced inbreeding rates to on average 0.16% per year and variation across flocks in inbreeding rates, caused by differences in flock size, almost disappeared. Inbreeding rates with maximum inbreeding avoidance were more variable than with a breeding circle. Moreover, a breeding circle is easier to implement and operate. Breeding circles are thus efficient and flexible and can also be efficient for other captive populations, such as zoo populations of endangered wild species. PMID- 22444079 TI - Genotype by environment interaction for litter size in pigs as quantified by reaction norms analysis. AB - A Bayesian procedure was used to estimate linear reaction norms (i.e. individual G * E plots) on 297 518 litter size records of 121 104 sows, daughters of 2040 sires, recorded on 144 farms in North and Latin America, Europe, Asia and Australia. The method allowed for simultaneous estimation of all parameters involved. The analysis was carried out on three subsets, comprising (i) parity 1 records of 33 641 sows of line B, (ii) all parity records of 52 120 sows of line B and (iii) all parity records of 121 104 sows of lines A, B and A * B. Estimated heritabilities ranged from 0.09 to 0.10 (smallest to largest subset) for the intercept of the reaction norms, and were 0.15, 0.08 and 0.02 (ditto) for the slope. Estimated genetic correlations between intercept and slope were -0.09, +0.26 and +0.69 (ditto). The three subsets therefore showed a progressively lower genetic component to environmental sensitivity, and progressively less re-ranking of genotypes across the environmental (herd-year-season) range. In a genetic evaluation that does not include reaction norms in the statistical model, part of the G * E effect remains confounded with the additive genetic effect, which may lead to errors in the estimates of the additive genetic effect; the reaction norms model removes this confounding. The intercept estimates from the largest data subset show correlations with litter size estimated breeding values (EBV) from routine genetic evaluation (without reaction norms included) of 0.78 to 0.85 for sows with one to seven litter records, and 0.75 for sires. Hence, including reaction norms in genetic evaluation would increase the reliability of the EBV of young selection candidates without own performance or progeny data by considerably more than 100 * (1/0.75-1) = 33%. Reaction norm slope estimates turn out to be very demanding statistics; environmental sensitivity must therefore be classified as a 'hard-to-measure' trait. PMID- 22444080 TI - In vitro studies of the metabolism of [14C]- n-alkanes using ruminal fluid of sheep as substrate. AB - Whether the rumen microbes are able to synthesize and/or degrade long-chain alkanes in anaerobic conditions remains a question to be answered before these hydrocarbons can be confidently used as duodenal flow or rumen transit markers. In this context, an experiment in vitro was carried out to establish whether within a rumen liquor fermentation system, n-alkanes can be derived from de-waxed structures of the plant or from non-alkane wax components (long-chain fatty alcohols, long-chain fatty acids and esters), or may be metabolized by bacteria to other components or to shorter-chain hydrocarbons. Ryegrass was labelled with 14C in growth chambers under controlled conditions in order to use it as a substrate. The labelled material obtained was separated in three fractions: labelled alkanes, labelled de-waxed plant and labelled wax components without the alkanes. These fractions were used for three different incubations in vitro, which objectives were as follows: 1. To check whether rumen bacteria can synthesize alkanes from carbon structures other than waxes (e.g. sugars). 2. To verify whether rumen bacteria can metabolize the n-alkanes to other compounds. 3. To check whether rumen bacteria can synthesize n-alkanes from other carbon compounds from waxes. The results showed that there was neither bacterial synthesis nor metabolism of the n-alkanes in in vitro conditions. PMID- 22444081 TI - Tissue fatty acid composition of pigs fed different fat sources. AB - Dietary fat influences the physico-chemical properties of meat, and fatty acid (FA) composition may have implications on human health. The objectives of the experiment were to study tissue FA partitioning and the effect of dietary fat source on tissue FA composition. Seventy crossbred gilts (61.8 +/- 5.2 kg BW average) were fed one of seven treatments: a diet containing a very low level of fat (no fat (NF)) and six fat-supplemented diets (10%: tallow (T), high-oleic sunflower oil (HOSF), sunflower oil (SFO), linseed oil (LO), fat blend (FB: 55% tallow, 35% SFO, 10% LO) and fish oil blend (FO: 40% fish oil, 60% LO). Differential tissue FA depositions were observed, with flare fat being the most saturated, followed by intermuscular, and subcutaneous being the least saturated. Monounsaturated fatty acid (MUFA) deposition showed an opposite tissue pattern. Subcutaneous fat showed the highest MUFAs, intermuscular fat showed intermediate values and flare fat showed the lowest MUFAs. Intramuscular polyunsaturated fatty acid (PUFA) content was less susceptible to dietary treatment modifications compared with other depots. Significant tissue FA modifications were observed due to dietary treatments, mainly in diets rich in PUFA. The saturated fatty acids (SFA) were high in NF-fed and low in HOSF-fed animals, MUFA were high in HOSF-fed and low in SFO-, LO- and FO-fed animals, while PUFA were high in SFO- and LO-fed and low in HOSF-, T- and NF-fed animals. Pigs fed LO and FB showed detectable levels of EPA, which depended on the linolenic content of the diet. The only effective way to increase tissue DHA contents was to add DHA in the diet through FO feeding. Araquidonic acid was high in SFO diets and low in LO and FB diets, and also high in intramuscular fat compared with other tissues. EPA and DHA were also high in intramuscular fat compared with other fat depots. The deposition of oleic and linoleic acids depended on the composition of dietary fat, as their deposition varied between diets, even at similar levels of intake of each FA. The NF diet resulted in the greatest proportion of SFAs (palmitic and stearic) of all treatments tested. SFAs were less susceptible to modification than MUFA in response to the different PUFA levels supplemented in the diet. T resulted in less fat deposition in some of the fat depots and more in others, suggesting that T could partition fat differently among fat depots. PMID- 22444082 TI - Levels of copper and zinc in diets for growing and finishing pigs can be reduced without detrimental effects on production and mineral status. AB - One hundred and sixty pigs were used to evaluate dietary copper (Cu) and zinc (Zn) supplementation on performance, fecal mineral levels, body mineral status and carcass and meat quality. Diets differed in mineral form (MF) (Cu and Zn in the form of proteinate amino acid chelate (organic) or sulfate (inorganic)) and inclusion level (IL) (27 mg/kg of total Cu and 65 mg/kg of total Zn ('low') or 156 mg/kg of total Cu and 170 mg/kg of total Zn ('high')) according to a 2 * 2 factorial arrangement of treatments. Pigs were used from 25 to 107 kg body weight (BW) and fed their respective diets ad libitum. Blood and fecal samples were collected on days 14 and 77 of the experiment. Blood was analyzed for concentration of Cu and Zn, hemoglobin (Hb), Cu content of red blood cells (RBC Cu) and alkaline phosphatase (ALP) and feces for Cu and Zn concentration. Hot carcass weight (HCW) and backfat depth were measured at slaughter and indices of meat quality were assessed on a section of longissimus thoracis. Liver, kidney and bone samples were collected immediately after slaughter and liver and kidney were tested for Cu and Zn content, while bone was only tested for Zn. Over the entire experimental period (25 to 107 kg BW) no significant treatment differences in average daily gain (ADG) or average daily feed intake (ADFI) occurred; however, feed conversion ratio (FCR) was improved by the inclusion of proteinate amino acid chelate (P = 0.012). Copper and Zn concentrations in feces were in direct proportion to the IL in the diet. Blood mineral levels were within normal physiological ranges in all treatments and tissue Cu and Zn concentrations increased with dietary IL (P < 0.05). Results indicate that Cu and Zn fecal concentrations were reduced by approximately 6-fold for Cu and by 2.5-fold for Zn by feeding 27 mg/kg Cu and 65 mg/kg Zn, in either the proteinate amino acid chelate or the sulfate form, compared with a diet containing 156 mg/kg Cu and 170 mg/kg Zn. This decrease in total dietary Cu and Zn did not reduce performance or mineral status of pigs. PMID- 22444083 TI - Morphological fractions, chemical composition and in vitro fermentation characteristics of maize stover of five genotypes. AB - Five morphological fractions (leaf blade, leaf sheath, stem, husk and cob) of stover of five maize genotypes, namely waxy, conventional, fodder, sweet and high oil maize, respectively, were used to test the effects of genotype and morphological fractions on chemical composition and in vitro fermentation characteristics. The waxy maize had a higher (P < 0.05) stem but lower (P < 0.05) leaf blade proportion and fodder maize had a higher (P < 0.05) leaf blade but lower (P < 0.05) leaf sheath proportion than other genotypes, respectively. Maize genotype had a significant effect (P < 0.001) on the chemical composition of stover parts except for organic matter (OM) concentration. Chemical composition of stover parts was affected (P < 0.001) by morphological fractions. The interaction effects between genotype and morphological fraction on the fiber content of stover parts were significant. Over 0.40 and 0.50 of phosphorus (P) and crude protein (CP) of whole-plant maize stover were averagely contributed by leaf blade. Leaf blade, stem and cob contributed over 0.75 of OM, CP, P and fiber in the whole plant. There were significant effects of genotype and morphological fraction on both in vitro gas production parameters and in vitro organic matter disappearance of maize stovers. The genotype and morphological fraction of maize stover and their interaction had significant effects on NH3-N and total volatile fatty acid concentration and the molar proportion of volatile fatty acid in the supernatant after 72 h of incubation except for valeric acid. The present data indicated that the genotype and morphological fraction of maize resulted in variation in the nutritive value of maize stover. PMID- 22444084 TI - Effects of the usage of dried brewing yeast in the diets on the performance, egg traits and blood parameters in quails. AB - This experiment was carried out to determine the effects of the usage of dried brewing yeast in quail diets on laying performance, egg traits and blood parameters. A total of 240 Japanese quails (Coturnix coturnix japonica) aged 10 weeks were randomly allocated into one control group and three treatment groups. Each group was divided into five replicates as subgroups, comprising 12 quails each. Dried brewing yeast (Saccharomyces cerevisiae) was used at the levels of 1.5%, 3.0% and 4.5% in the diets of the first, second and third treatment groups, respectively. Soyabean meal was replaced with dried brewing yeast. The diets were formulated to be isocaloric and isonitrogenous. The experimental period lasted 18 weeks. Dietary treatments did not significantly affect body weight, daily feed intake, daily protein intake, egg production, egg weight, feed efficiency, mortality, egg shell thickness, egg albumen index, egg yolk index, egg Haugh unit, the percentages of egg shell, albumen and yolk, excreta moisture and small intestinal pH. Inclusion of 3% and 4.5% dried brewing yeast in diets reduced egg yolk cholesterol concentration as mg per yolk and mg per g yolk (P < 0.01). Blood serum cholesterol of groups fed diets with dried brewing yeast was significantly lower (P < 0.01) than that of the control group. Feeding diets containing 3.0% and 4.5% dried brewing yeast resulted in significant increases (P < 0.01) in blood serum levels of total protein, alanine aminotransferase at the end of the experiment. Blood serum levels of uric acid, triglyceride, aspartate aminotransferase and alkaline phosphatase were not affected by dietary dried brewing yeast. It is concluded that dried brewing yeast can be used up to 4.5% in the diets of laying quails without adverse effects on the measured parameters. PMID- 22444085 TI - The mRNA expression of brain-derived neurotrophic factor in oocytes and embryos and its effects on the development of early embryos in cattle. AB - The aims of the study were to measure the mRNA expression of brain-derived neurotrophic factor (BDNF) in bovine oocytes and early embryos derived from in vitro fertilization (IVF), parthenogenetic activation (PA) and nuclear transfer (NT), and to investigate the effects of BDNF on the development of IVF and parthenogenetic embryos. Bovine oocytes matured in vitro for 22 h were in vitro fertilized or parthenogenetic activated. By reverse transcription-PCR and quantitative real-time PCR, we found that germinal vesicle (GV) oocytes, metaphase II (MII) oocytes, 4-cell and 8-cell embryos, morulae, and blastocysts were all shown to express mRNA for BDNF. The mRNA levels for BDNF gene were different in bovine oocytes and IVF embryos at different stages (P < 0.01), with the highest expression in MII oocytes and the lowest expression in 8-cell embryos. The mRNA for BDNF was highly expressed in the PA and IVF blastocysts compared to the NT blastocysts (P < 0.01). Supplementation of culture media with BDNF at the concentration of 40 MUg/l caused a significant increase in the rates of in vitro-fertilized blastocyst formation (P < 0.05) and parthenogenetic blastocyst formation (P < 0.05). However, the rate of oocyte cleavage in BDNF groups was not significantly different from that in the BDNF-free control (P > 0.05) after IVF or PA. We have also investigated the effects of BDNF on the growth of granulosa cells, which were used for co-culture of bovine early embryos. The results revealed that supplementation of culture media with 20 MUg/l BDNF promoted the growth of granulosa cells (P < 0.01). Taken together, these results provided evidence for the role of neurotrophins in promoting early embryonic development as well as in the growth of granulosa cells by the co culture system, indicating that BDNF can directly or indirectly promote bovine early embryo development. PMID- 22444086 TI - Percentile growth charts for biomedical studies using a porcine model. AB - Increasing rates of obesity and heart disease are compromising quality of life for a growing number of people. There is much research linking adult disease with the growth and development both in utero and during the first year of life. The pig is an ideal model for studying the origins of developmental programming. The objective of this paper was to construct percentile growth curves for the pig for use in biomedical studies. The body weight (BW) of pigs was recorded from birth to 150 days of age and their crown-to-rump length was measured over the neonatal period to enable the ponderal index (PI; kg/m3) to be calculated. Data were normalised and percentile curves were constructed using Cole's lambda-mu-sigma (LMS) method for BW and PI. The construction of these percentile charts for use in biomedical research will allow a more detailed and precise tracking of growth and development of individual pigs under experimental conditions. PMID- 22444087 TI - Effect of concentrate percentage on ruminal pH and time-budget in dairy goats. AB - The aim of this study was to compare rumen pH and time-budget in eight mid lactation goats receiving two diets in a cross-over design (low-concentrate diet (L): 30% and high-concentrate diet (H): 60% concentrate). Feeding H increased daily intake (4.3 +/- 0.08% v. 4.7 +/- 0.08% of body weight for L and H, respectively) and daily milk production (3.01 +/- 0.130 v. 3.50 +/- 0.130 kg/day of 3.5% fat-corrected milk for L and H, respectively). It decreased milk fat and inverted the fat-to-protein ratio (1.07 +/- 0.054 v. 0.94 +/- 0.054 for L and H, respectively). As suggested by the percentage of time spent with rumen pH below 6.0 (23.4 +/- 6.60% v. 39.9 +/- 5.88% for L and H, respectively), H was more acidogenic than L. When offered H instead of L, goats spent less time eating (298 +/- 17.5 v. 265 +/- 17.5 min for L and H, respectively) and ruminating (521 +/- 21.0 v. 421 +/- 21.0 min for L and H, respectively) but more time resting (352 +/ 27.1 v. 459 +/- 21.1 min for L and H, respectively) over a 24-h period. They also tended to spend more time drinking (20 +/- 2.9 v. 25 +/- 2.9 min for L and H, respectively; P = 0.08) when offered H rather than L. These differences in activities were mainly observed during the first hours following feeding. When offered H, goats adapted their feeding behaviour around the feedings, which allowed them to limit the physiological disturbances potentially inducible by H and to increase milk production, without experiencing too much acidosis. PMID- 22444088 TI - Group housing in row cages: an alternative housing system for juvenile mink. AB - We studied a group housing system as an alternative to the traditional pair housing of juvenile mink. The focus was on both the welfare and production of mink. The pairs were housed in standard mink cages, whereas the groups were in row cage systems consisting of three standard mink cages connected to each other. The welfare of the mink was evaluated by behavioural observations (stereotypies and social contacts), evaluation of the incidence of scars assumed to be caused by biting, and adrenal function (serum cortisol level after adrenocorticotropic hormone (ACTH) administration and adrenal mass). Feed consumption, pelt length, quality and price were used for comparing the two housing systems from the economic point of view. Although the incidence of scars showed that there might have been more aggressive behaviour among the group-housed than among the pair housed mink, this was not observed unambiguously in behavioural observations, and, at least, aggression did not cause mortality or serious injuries to the animals as has been observed in some earlier studies. In addition, the housing system did not affect pelt size, and, although the quality of the pelts was slightly lower in the group than in pair-housed mink, there was only a tendency for lower pelt prices. The lower pelt prices in the group-housed mink might even be partially compensated for by the group-housed mink eating 10% to 20% less in the late autumn, due to thermoregulatory benefits, than their pair-housed conspecifics. The results on the frequency of stereotypic behaviour (but not adrenal function) suggest that the group-housed animals were possibly less stressed than the pair-housed animals. Group housing of juvenile farmed mink in a row cage system cannot be recommended before the effects on welfare and production are clarified in further studies. PMID- 22444089 TI - Grazing behaviour and performance of lactating suckler cows, ewes and goats on partially improved heathlands. AB - The foraging behaviour (grazing time and diet composition), live-weight (LW) changes and parasitic infection (faecal egg counts of gastrointestinal nematodes) of 12 beef cows, 84 ewes and 84 goats suckling their offspring, managed in mixed grazing on heathlands with 24% of improved pasture of perennial ryegrass-white clover, were studied during the years 2003 and 2006. The results showed that goats tended to graze for a longer time, and utilised significantly more heathland vegetation than cattle and sheep, including in their diet in an average of 0.39 herbaceous plants, 0.11 gorse and 0.51 heather over the grazing season, comparing with respective mean values of 0.85, 0.02 and 0.13 in cattle and sheep. Dietary overlap was higher between cattle and sheep (0.76) than between sheep and goats (0.53) or between cattle and goats (0.47). Despite the high performance of autumn-calving cows in spring, sheep had the best LW changes per livestock unit (LU) during the whole grazing season. Goats' performance per LU was lower than in sheep but higher than in spring-calving cows. Regarding offspring production, lambs had higher LW gains per LU than calves and kids. Mean nematode eggs/g fresh faeces (epg) during the grazing season were higher in goats (91 epg) compared with sheep (34 epg) and cattle (14 epg), particularly from September to December. In conclusion, sheep performed best on these heathlands with improved pasture areas if the entire grazing season was considered, despite the good level of production in spring from autumn-calving cows. The results suggested the complementary use of goats in order to increase the effective utilisation of the available vegetation, achieving production levels similar to those from spring calving cows. Therefore, mixed flocks of sheep and goats would be the most appropriate sustainable systems from the animal production and vegetation use points of view. PMID- 22444090 TI - Genetic parameters for traits evaluated at field tests of 3- and 4-year-old Swedish Warmblood horses. AB - There are two types of 1-day field tests available for young Swedish Warmblood sport horses; one test for 3-year olds and one more advanced test for 4-year olds. Conformation, gaits and jumping ability are evaluated at both tests. Studies on various genetic parameters were based on about 20 000 tested horses. The data for 4-year olds consisted of 30 years of testing. The aims of the study were to estimate genetic parameters for results from different time periods, and to estimate heritabilities for, and genetic correlations between, traits scored in the two tests. The judgement of traits was shown to have been changed during the 30 years of testing, resulting in changes in higher heritabilities in, and stronger genetic correlations between, later time periods. In the first time period, records showed higher residual and lower genetic variances than in the subsequent time periods. Genetic correlations between traits recorded in the first and last time period deviated considerably from unity. Further studies are needed to investigate how to treat data from the early period in genetic evaluations. Heritabilities were moderate to high for conformation traits (0.24 to 0.58) at both types of tests, except for correctness of legs (0.08). The heritabilities for gait traits were also moderate to high (0.37 to 0.53). For jumping traits, the heritabilities ranged between 0.17 and 0.33. The highly positive genetic correlations (0.82 to 0.99) between corresponding traits tested at the simpler test for 3-year olds and at the ridden test of 4-year olds implied that it would be desirable to include the test results of 3-year olds into the genetic evaluation as breeding values for Swedish Warmbloods for many years has only been based on results from 4-year olds. PMID- 22444091 TI - Influence of some sow characteristics on within-litter variation of piglet birth weight. AB - Within-litter variation of piglet birth weight (BW0) is associated with an increased piglet mortality and a high variability in pig weight at weaning and weight or age at slaughter. Data collected in two experimental herds were used to quantify within-litter variability in BW0 and to assess the influence of factors mainly related to the sow. Within 24 h after birth, piglets born alive were individually weighed and stillborn piglets were collectively (first data set) or individually (second data set) weighed. The first data set was restricted to litters with no or only one stillborn piglet (3338 litters). It was used to assess the influence of genetic selection on BW0 variation by comparing litter characteristics before (1994 to 1996) and after (2001 to 2004) the development of hyperprolific sows in this herd. The second data set included all litters (n = 1596) from sows born between 2000 and 2004. For each litter, mean BW0 (mBW0) and its coefficient of variation (CVBW0) were calculated. Then, variance analyses were performed to test the influence of litter size, parity, year of sow birth and season at conception. Prolificacy improvement was associated with an increased CVBW0 in litters from pure Large White (LW) and Landrace * Large White (LR * LW) crossbred sows. The CVBW0 averaged 21% and was significantly influenced by litter size and parity. It increased from 15% to 24% when litter size varied from less than 10 piglets to more than 15 piglets. The proportion of small piglets (i.e. weighing less than 1 kg) increased concomitantly. The CVBW0 was not repeatable from a parity to the following. It was lowest for first and second parities (20%) and thereafter increased progressively. The CVBW0 was positively related to sow's backfat thickness gain during gestation. Taking into account litter size, parity, year of sow birth and season at conception explained 20% of BW0 variation. Thus, major part of heterogeneity is due to other factors, presumably including embryo genotype, on the one hand, and factors that influence embryo and foetus development, such as epigenetic factors, on the other hand. PMID- 22444092 TI - Effect of replacing grass silage with maize silage in the diet on bovine milk fatty acid composition. AB - Even though extensive research has examined the role of nutrition on milk fat composition, there is less information on the impact of forages on milk fatty acid (FA) composition. In the current study, the effect of replacing grass silage (GS) with maize silage (MS) as part of a total mixed ration on animal performance and milk FA composition was examined using eight multiparous mid-lactation cows in a replicated 4 * 4 Latin square with 28-day experimental periods. Four treatments comprised the stepwise replacement of GS with MS (0, 160, 334 and 500 g/kg dry matter (DM)) in diets containing a 54 : 46 forage : concentrate ratio on a DM basis. Replacing GS with MS increased (P < 0.001) the DM intake, milk yield and milk protein content. Incremental replacement of GS with MS in the diet enhanced linearly (P < 0.001) the proportions of 6:0-14:0, decreased (P < 0.01) the 16:0 concentrations, but had no effect on the total milk fat saturated fatty acid content. Inclusion of MS altered the distribution of trans-18:1 isomers and enhanced (P < 0.05) total trans monounsaturated fatty acid and total conjugated linoleic acid content. Milk total n-3 polyunsaturated fatty acid (PUFA) content decreased with higher amounts of MS in the diet and n-6 PUFA concentration increased, leading to an elevated n-6 : n-3 PUFA ratio. Despite some beneficial changes associated with the replacement of GS with MS, the overall effects on milk FA composition would not be expected to substantially improve long-term human health. However, the role of forages on milk fat composition must also be balanced against the increases in total milk and protein yield on diets containing higher proportions of MS. PMID- 22444093 TI - Effect of fish oil on ruminal biohydrogenation of C18 unsaturated fatty acids in steers fed grass or red clover silages. AB - Red clover and fish oil (FO) are known to alter ruminal lipid biohydrogenation leading to an increase in the polyunsaturated fatty acid (PUFA) and conjugated linoleic acid (CLA) content of ruminant-derived foods, respectively. The potential to exploit these beneficial effects were examined using eight Hereford * Friesian steers fitted with rumen and duodenal cannulae. Treatments consisted of grass silage or red clover silage fed at 90% of ad libitum intake and FO supplementation at 0, 10, 20 or 30 g/kg diet dry matter (DM). The experiment was conducted with two animals per FO level and treatments formed extra-period Latin squares. Flows of fatty acids at the duodenum were assessed using ytterbium acetate and chromium ethylene diamine tetra-acetic acid as indigestible markers. Intakes of DM were higher (P < 0.001) for red clover silage than grass silage (5.98 v. 5.09 kg/day). There was a linear interaction effect (P = 0.004) to FO with a reduction in DM intake in steers fed red clover silage supplemented with 30 g FO/kg diet DM. Apparent ruminal biohydrogenation of C18:2n-6 and C18:3n-3 were lower (P < 0.001) for red clover silage than grass silage (0.83 and 0.79 v. 0.87 and 0.87, respectively), whilst FO increased the extent of biohydrogenation on both diets. Ruminal biohydrogenation of C20:5n-3 and C22:6n-3 was extensive on both silage diets, averaging 0.94 and 0.97, respectively. Inclusion of FO in the diet enhanced the flow of total CLA leaving the rumen with an average across silages of 0.22, 0.31, 0.41 and 0.44 g/day for 0, 10, 20 or 30 g FO/kg, respectively, with a linear interaction effect between the two silages (P = 0.03). FO also showed a dose-dependent increase in the flow of trans-C18:1 intermediates at the duodenum from 4.6 to 15.0 g/day on grass silage and from 9.4 to 22.5 g/day for red clover silage. Concentrations of trans-C18:1 with double bonds from Delta4-16 in duodenal digesta were all elevated in response to FO in both diets, with trans-11 being the predominant isomer. FO inhibited the complete biohydrogenation of dietary PUFA on both diets, whilst red clover increased the flow of C18:2n-6 and C18:3n-3 compared with grass silage. In conclusion, supplementing red clover silage-based diets with FO represents a novel nutritional strategy for enhancing the concentrations of beneficial fatty acids in ruminant milk and meat. PMID- 22444094 TI - Imaging utilization and the obsessive-compulsive physician. PMID- 22444095 TI - A new disease: bicuspid aortic valve aortopathy syndrome. PMID- 22444096 TI - B-cell-depleting therapy in systemic lupus erythematosus. AB - The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus. PMID- 22444097 TI - Digitalis toxicity: a fading but crucial complication to recognize. AB - Digoxin usage has decreased in the treatment of congestive heart failure and atrial fibrillation as a result of its inferiority to beta-adrenergic inhibitors and agents that interfere with the deleterious effects of the activated renin angiotensin-aldosterone system. As a result of reduction of usage and dosage, glycoside toxicity has become an uncommon occurrence but may be overlooked when it does occur. Older age, female sex, low lean body mass, and renal insufficiency contribute to higher serum levels and enhanced risk for toxicity. Arrhythmias suggesting digoxin toxicity led to its recognition in the case presented here. PMID- 22444098 TI - Medical management and prevention of nephrolithiasis. AB - Kidney stones have increased in prevalence and pose a significant burden on the US health care expenditure. This article is intended to help primary care physicians in their office management of stone disease by providing an update on the recent advances made in this field. PMID- 22444099 TI - Golden ring in eyes: all that glitters is not gold! PMID- 22444100 TI - A vicious cycle. PMID- 22444101 TI - Rash of a different kind. PMID- 22444102 TI - Quality of care for myocardial infarction at academic and nonacademic hospitals. AB - BACKGROUND: Whether academic hospitals provide better quality of care for patients with acute myocardial infarction is widely debated. The aim of this study was to compare processes of care and mortality between academic and nonacademic hospitals in the contemporary era of acute myocardial infarction management. METHODS: We analyzed the original data from a prospective cohort study of 3059 patients, including 1714 with ST-segment elevation and 1345 with non-ST-segment elevation myocardial infarction, enrolled at 39 and 183 academic and nonacademic hospitals, respectively, in France. RESULTS: Unadjusted 1-year mortality for academic and nonacademic hospitals was 10% versus 15% for patients with ST-segment elevation myocardial infarction (P=.01) and 13% versus 14% for patients with non-ST-segment elevation myocardial infarction (P=.75). Patients treated in academic or nonacademic hospitals with percutaneous coronary intervention capability were more likely to receive reperfusion and recommended drug therapies than those treated in nonacademic hospitals without percutaneous coronary intervention capability. After adjusting for baseline characteristics, the hazards of death associated with admission to nonacademic hospitals with and without percutaneous coronary intervention capability relative to academic hospitals were 1.13 (95% confidence interval [CI], 0.79-1.62) and 1.65 (95% CI, 1.09-2.49) for those with ST-segment elevation myocardial infarction and 0.95 (95% CI, 0.66-1.36) and 1.06 (95% CI, 0.72-1.58) for those with non-ST-segment elevation myocardial infarction, respectively. Further adjustment for receipt of acute reperfusion and recommended drug therapies eliminated all differences in mortality between the study groups. CONCLUSION: Admission to academic hospitals was associated with a more frequent use of recommended therapies, conveying a survival advantage for patients with ST-segment elevation myocardial infarction. PMID- 22444103 TI - Sleep apnea and risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. AB - BACKGROUND: Patients with sleep apnea have been reported to be associated with increased prevalence of deep vein thrombosis (DVT) in some papers, which were criticized for either a small sample size or lack of a prospective control. Our study strived to explore the relationship of sleep apnea and the subsequent development of DVT using a nationwide, population-based database. METHODS: From 2000 to 2007, we identified a study cohort consisting of newly diagnosed sleep apnea cases in the National Health Insurance Research Database. A control cohort without sleep apnea, matched for age, sex, comorbidities, major operation, and fractures, was selected for comparison. The 2 cohorts were followed-up, and we observed the occurrence of DVT by registry of DVT diagnosis. RESULTS: Of the 10,185 sampled patients (5680 sleep apnea patients vs. 4505 control), 40 (0.39%) cases developed DVT during a mean follow-up period of 3.56 years, including 30 (0.53%) from the sleep apnea cohort and 10 (0.22 %) from the control group. Subjects with sleep apnea experienced a 3.113-fold (95% confidence interval, 1.516-6.390; P=.002) increase in incident DVT, which was independent of age, sex, and comorbidities. Kaplan-Meier analysis also revealed the tendency of sleep apnea patients toward DVT development (log-rank test, P=.001). The risk of DVT was even higher in sleep apnea cases who needed continuous positive airway pressure treatment (hazard ratio 9.575; 95% confidence interval, 3.181-28.818; P <.001). CONCLUSION: Sleep apnea may be an independent risk factor for DVT. PMID- 22444104 TI - Evaluation of harm in the pharmacotherapy of irritable bowel syndrome. AB - OBJECTIVE: Current treatment options for irritable bowel syndrome are limited and often poorly studied. A select few drugs have been studied in irritable bowel syndrome, and the number needed to treat is frequently used to assess the relative efficacy of these treatments. However, side effects are an important consideration in the clinical decision on which particular treatment to use. This study examines trials of subjects with irritable bowel syndrome with diarrhea and constipation who are receiving a drug intervention deemed of merit by the American College of Gastroenterology task force and compares these therapies to examine the number needed to harm using a systematic review and meta-analysis approach. METHODS: Potential studies of irritable bowel syndrome treatments were identified through a search of MEDLINE (1950 to April 2011), EMBASE (1980 to April 2011), the Cochrane central register of controlled trials, and the bibliography of recent meta-analyses. Clinical trials of pharmacotherapy for irritable bowel syndrome were eligible for inclusion only if a description of adverse events and the number of patients who discontinued treatment because of adverse events were reported. The relative risk of experiencing an adverse event requiring discontinuation of treatment was used to determine the number needed to harm. In addition, the number and severity of adverse events were summarized. RESULTS: Twenty-six clinical trials (4 with selective serotonin reuptake inhibitors, 3 with lubiprostone, 6 with tricyclic antidepressants, 8 with alosetron, and 5 with rifaximin) were included. Lubiprostone was safe with insignificant harm in one combined phase III trial. Selective serotonin reuptake inhibitors did not have enough data for a reliable meta-analysis of harm but seemed to be safe. More rigorous data were available for tricyclic antidepressants, alosetron, and rifaximin; the numbers needed to harm were 18.3, 19.4, and 8971, respectively, and the numbers needed to treat were 8, 7.5, and 10.6, respectively. For tricyclic antidepressant and alosetron, an adverse event resulting in discontinuation of the study medication occurred for every 2.3 and 2.6 patients who benefited from a drug, respectively. For rifaximin, this number was 846 patients. In addition, adverse events were more common with tricyclic antidepressants and alosetron. CONCLUSION: In irritable bowel syndrome with diarrhea, tricyclic antidepressants and alosetron are associated with a significant number needed to harm compared with rifaximin. Apart from lubiprostone, treatment of irritable bowel syndrome with constipation is limited to small studies (with poor descriptions of side effects), although lubiprostone and selective serotonin reuptake inhibitors appear safe. PMID- 22444105 TI - The association between peripheral artery and lumbar spine disease: a single center study. AB - BACKGROUND: While intermittent claudication is the hallmark of symptomatic peripheral artery disease, most patients with peripheral artery disease have atypical symptoms. The presence of lumbosacral spine disease, a common cause of nonvascular lower extremity pain, may confound the diagnosis of peripheral artery disease. The goal of this study was to quantify the prevalence of severe lumbar spine degenerative disease in patients referred for lower extremity arterial studies. METHODS: All patients over age 18 years referred for segmental limb pressures and pulse volume recordings at rest and following treadmill exercise testing at a tertiary medical center accredited vascular diagnostic laboratory, who also underwent magnetic resonance imaging or computed tomography of the lumbar spine within 6 months of the arterial studies, were included in the analysis. Frequencies of peripheral artery disease and lumbar spine degenerative disease were determined, and medical records were reviewed for cardiovascular risk factors and prior vascular and spinal interventions. RESULTS: One hundred seven subjects (63 men) with a mean age of 70 years (range 35-88 years) were included in the analysis. Lumbar spine disease was present in 81 (75.7%) of the patients referred for vascular testing. The percentage of lumbar spine disease was equivalent in both patients with exercise-induced deterioration in arterial pressure and in those with a physiologic response to exercise. Compared with patients with a normal response to exercise, patients with exercise-induced peripheral artery disease had a lower resting ankle-brachial index (mean 0.79 vs 1.09, P <.001), abnormal pulse volume recordings, and were less likely to use opiate analgesics and more likely to have undergone lower extremity revascularization. CONCLUSIONS: Severe lumbar spine degenerative disease is widely prevalent in patients referred for lower extremity arterial studies. Our findings may help explain the high prevalence of atypical limb symptoms among peripheral artery disease patients. PMID- 22444106 TI - "Problem residents": prevalence, problems and remediation in the era of core competencies. PMID- 22444107 TI - Routine physical examination and the squatting maneuver. PMID- 22444109 TI - Calcium supplements and risk of myocardial infarction: an hypothesis twice tested. PMID- 22444111 TI - NT-proBNP in acute coronary syndrome: is it really there yet? PMID- 22444113 TI - Congenital bicuspid aortic valve first presenting as an aortic aneurysm. PMID- 22444114 TI - A gut feeling. PMID- 22444115 TI - [Management of immune thrombocytopenia in France before the era of thrombopoietin receptor agonists]. AB - PURPOSE: Adult immune thrombocytopenia (ITP) is an auto-immune disease with most often a chronic course for which a consensual therapeutic strategy is missing. The objective of this study was to describe treatment practices in adult ITP in France before the era of thrombopoietin receptor (TpoR) agonists. METHODS: A retrospective observational study was conducted in eight hospitals in France. All eligible patients were at least 18 years of age and were seen for a chronic ITP between January 2004 and March 2006 in one of the participating centers. Data were collected retrospectively from clinical charts. ITP treatment from disease onset was analyzed for every patient according to the time of diagnosis. RESULTS: The study included 122 patients (73% of women) with a mean age of 52.6 years. Patients in whom ITP had been diagnosed less than 4 years earlier (n=71) received on average 2.9 treatment lines. Corticosteroids possibly combined with intravenous immunoglobulins were most often used as a first-line. From the second line, up to 12 different regimens were identified. As a third line, rituximab and splenectomy were the most common therapeutic procedures. The number of splenectomy tended to decrease over time. CONCLUSION: This analysis reflects the great heterogeneity into the management of chronic ITP. Whether such heterogeneity has declined after national guidelines have been produced remains to be assessed as well as the place of the newly develop TpoR agonists. PMID- 22444116 TI - [Patients' beliefs about long-term glucocorticoid therapy and their association to treatment adherence]. AB - BACKGROUND: In patients treated with systemic glucocorticoids (GCs), it is unknown if beliefs about the treatment are associated with level of reported adherence. PATIENTS AND METHODS: Cross-sectional study conducted in two departments of internal medicine during a six-month period. All patients receiving long-term GCs therapy were asked to fill in a questionnaire regarding their beliefs about (specific scale of the Beliefs about Medicines Questionnaire) and their adherence to (four-item Morisky-Green scale) GCs. Logistic regression analysis was used to assess association between beliefs about GCs and adherence to treatment. RESULTS: One hundred and eighty one questionnaires were analysed (women: 79%, median age [IQR]: 47 [33-61] years, median duration of treatment: 18 [7-72] months, median daily dosage of prednisone equivalent: 10 [6-20] mg). Among these 181 patients, 83 (46%) reported a "concern" score equal to or higher than the "necessity" score. Nineteen percent of patients reported a low adherence level. In multivariate analysis, these patients were significantly younger (OR: 0.96 [0.93-0.98] per increasing year of age, P=0.002) and reported more frequently a "concern" score higher than a "necessity" score (OR: 3.08 [1.27 7.46], P=0.01) as compared to patients reporting a high adherence level. CONCLUSION: Informing patients about the "necessity" of GCs and taking into account their "concerns" about adverse events or their fear of becoming dependent on the medication may improve their adherence to treatment. PMID- 22444117 TI - Porphyrin assemblies through the air/water interface: effect of hydrogen bond, thermal annealing, and amplification of supramolecular chirality. AB - Molecular assemblies of two achiral porphyrins with different substituents, 5-(4 methoxycarbonylphenyl)-10,15,20-triphenyl-21H,23H-porphine (TPPCOOMe) and 5-(4 carboxyphenyl)-10,15,20-triphenyl-21H,23H-porphine (TPPCOOH), have been fabricated by the Langmuir-Blodgett (LB) technique. It is disclosed that although only slight differences exist in the molecular skeleton of these two compounds, their interfacial assemblies display distinct chiroptical properties. It is found that weak circular dichroism (CD) signals are observed from the TPPCOOH assemblies, while in the case of the TPPCOOMe assemblies, only negligible CD signals could be detected. Interestingly, after the assemblies are subjected to a thermal annealing treatment, TPPCOOH assemblies show a distinct amplification of CD signals, while those of TPPCOOMe do not. An explanation in terms of the effect of substituents on the spreading properties of the compounds and the effect of intermolecular hydrogen bonds on the cooperative stacking of the building blocks is proposed to explain these new findings. The investigation suggests that in the present porphyrin systems, besides a nice spreading property, the cooperative interaction of various noncovalent interactions, including hydrogen bonding, pi pi stacking, and hydrophobic interactions, is essentially required for the occurrence of symmetry breaking at the air/water interface. PMID- 22444118 TI - Analysis of body measurements of newborn purebred Belgian Blue calves. AB - At calving, purebred animals of the Belgian Blue (BB) breed are compromised by the incompatibility in size and shape of the dam and her calf, resulting in a very high incidence of dystocia problems. To clarify which body parts of the calf are of decisive importance to allow natural delivery and to investigate both the mean value as well as the variation among these body sizes within this breed (variation being an important condition for selection), measurements of nine body parts (body weight at birth (BW), body length (BL), length of the head (LH), shoulder width (SW), hip width (HW), heart girth (HG), withers height (WH) and the circumference of the fetlock of both the front (CFF) and the hind leg (CFH)) were assessed in 147 newborn purebred BB calves on 17 farms. Simple and partial correlations were assessed and we examined whether environmental factors (gender of the calf, parity of the cow, type of calving, season of birth and time of measurement after birth) were significantly associated with these specific calf measurements. The mean BW was 49.2 +/- 7.1 kg. The average BL was 56.4 +/- 4.5 cm and the mean LH was 24.4 +/- 2.3 cm. Measurements obtained for SW and HW were 22.4 +/- 2.2 and 22.9 +/- 2.1 cm, respectively, whereas the mean WH was 71.1 +/- 4.7 cm. Measurements of circumferences revealed a CFF of 17.9 +/- 1.1 cm, a CFH of 18.0 +/- 1.0 cm and a mean HG of 78.0 +/- 5.4 cm. Partial correlations of the BW with eight body measurements were significant (P < 0.01) and ranged between 0.17 and 0.85; 0.42 and 0.88; and 0.24 and 0.88 when corrected for gender, parity and type of calving, respectively. BL (P < 0.01) and the CFF and CFH (P < 0.001) are larger in bull calves than in heifer calves. Calves born through caesarean section had broader SW (P < 0.01) and HW (P < 0.01) when compared with calves born after natural calving (defined as born per vaginam without assistance or with slight traction). Sizes of calves born out of multiparous cows were generally larger than of calves born out of heifers (SW: P < 0.001; HW: P < 0.05). As SW and HW are the broadest points of a BB calf, they are both candidates for being the limiting measures for calving ease, but the difference between HW and SW for the total data set was not different from zero (P > 0.05). In contrast to male calves in which no significant difference (between HW and SW) could be found, female calves show the difference between HW and SW that was significantly different from zero (P < 0.001); thus, in female calves, the HW is the most limiting factor of the calf's body. The significant variation in some body measures between the calves and the strong correlation within these sizes raises the possibility of selection towards smaller calves aiming to limit the dystocia problem in the BB breed. Furthermore, on the basis of our results, we were able to build equations for the farmer to use at the moment of calving containing the LH, the CF and the calf's gender to estimate SW and HW, the limiting body parts of the calf to be born naturally. Together with the knowledge of the pelvic size of the dam, this information gives the obstetrician or the farmer a more accurate prediction of the probability of natural calving at parturition. PMID- 22444119 TI - Parent-of-origin effects cause genetic variation in pig performance traits. AB - In order to assess the relative importance of genomic imprinting for the genetic variation of traits economically relevant for pork production, a data set containing 21 209 records from Large White pigs was analysed. A total of 33 traits for growth, carcass composition and meat quality were investigated. All traits were recorded between 1997 and 2006 at a test station in Switzerland and the pedigree included 15 747 ancestors. A model with two genetic effects for each animal was applied: the first corresponds to a paternal and the second to a maternal expression pattern of imprinted genes. The imprinting variance was estimated as the sum of both corresponding genetic variances per animal minus twice the covariance. The null hypothesis of no imprinting was tested by a restricted maximum likelihood ratio test with two degrees of freedom. Genomic imprinting significantly contributed to the genetic variance of 19 traits. The proportion of the total additive genetic variance that could be attributed to genomic imprinting was of the order between 5% and 19%. PMID- 22444120 TI - Genetic variation in competition traits at different ages and time periods and correlations with traits at field tests of 4-year-old Swedish Warmblood horses. AB - For many years, the breeding value estimation for Swedish riding horses has been based on results from Riding Horse Quality Tests (RHQTs) of 4-year-olds only. Traits tested are conformation, gaits and jumping ability. An integrated index including competition results is under development to both get as reliable proofs as possible and increases the credibility of the indexes among breeders, trainers and riders. The objectives of this study were to investigate the suitability of competition data for use in genetic evaluations of horses and to examine how well young horse performance agrees with performance later in life. Competition results in dressage and show jumping for almost 40 000 horses from the beginning of the 1960s until 2006 were available. For RHQT data of 14 000 horses judged between 1988 and 2007 were used. Genetic parameters were estimated for accumulated competition results defined for different age groups (4 to 6 years of age, 4 to 9 years of age and lifetime), and for different birth year groups. Genetic correlations were estimated between results at RHQT and competitions with a multi-trait animal model. Heritabilities were higher for show jumping than dressage and increased with increasing age of the horse and amount of information. For dressage, heritabilities increased from 0.11 for the youngest group to 0.16 for lifetime results. For show jumping corresponding values increased from 0.24 to 0.28. Genetic correlations between competition results for the different age groups were highly positive (0.84 to 1.00), as were those between jumping traits at RHQT and competition results in show jumping (0.87 to 0.89). For dressage-related traits as 4-year-old and dressage competition results the estimated genetic correlations were between 0.47 and 0.77. We suggest that lifetime results from competitions should be integrated into the genetic evaluation system. However, genetic parameters showed that traits had changed during the over 35-year period covered due to the development of the sport, which needs to be considered in future genetic evaluations. PMID- 22444121 TI - Assessing feed efficiency in beef steers through feeding behavior, infrared thermography and glucocorticoids. AB - A better understanding of the factors regulating feed efficiency and their potential as predictors of feed efficiency in cattle is needed. Therefore, the potential of three classes of traits, namely, feeding behavior characteristics: daily time at feeder (TF; min/day), time per meal (TM; min), meal size (MS; g DM), eating rate (ER; g DM/min), number of daily meals (NM) and daily visits to the feeder (VF); infrared (IR) thermography traits ( degrees C): eye (EY), cheek (CK), snout (SN), ribs (RB) and hind area (HA); and glucocorticoid levels: fecal cortisol metabolites (FCM; ng/g) and plasma cortisol (PC; ng/ml) as predictors of efficiency were evaluated in 91 steers (436 +/- 37 kg) over 2 years (Y1 = 46; Y2 = 45). Additionally, the individual traits of each of these three classes were combined to define three single traits. Individual daily feed intake of a corn silage and high-moisture corn-based diet was measured using an automated feeding system. Body weight and thermographs were taken every 28 days over a period of 140 days. Four productive performance traits were calculated: daily dry matter intake (DMI), average daily gain (ADG), feed to gain ratio (F : G) and residual feed intake (RFI). Steers were also classified into three RFI categories (low-, medium- and high-RFI). Among the feeding behavior characteristics, MS and ER were correlated with all efficiency traits (range: 0.26 to 0.75). Low-RFI (more efficient steers) had smaller MS, lower ER and fewer VF in comparison to high-RFI steers. Less efficient steers (high-RFI) performed more VF during the nocturnal period than more efficient steers. More efficient steers had lower CK and SN temperatures than less efficient steers (28.1 degrees C v. 29.2 degrees C and 30.0 degrees C v. 31.2 degrees C), indicating greater energetic efficiency for low-RFI steers. In terms of glucocorticoids, PC was not correlated with efficiency traits. In contrast, more efficient steers had higher FCM in comparison to less efficient steers (51.1 v. 31.2 ng/g), indicating that a higher cortisol baseline is related to better feed efficiency. The overall evaluation of the three classes of traits revealed that feeding behavior, IR thermography and glucocorticoids accounted for 18%, 59% and 7% of the total variation associated with RFI, respectively. These classes of traits have usefulness in the indirect assessment of feed efficiency in cattle. Among them, IR thermography was the most promising alternative to screen cattle for this feed efficiency. These findings might have application in selection programs and in the better understanding of the biological basis associated with productive performance. PMID- 22444122 TI - Effect of subacute dietary nitrate on production traits and plasma analytes in Suffolk ewes. AB - Elevated dietary nitrate (NO3-) is associated with production losses in ruminant livestock, resulting in substantial economic losses incurred by producers. Severe drought, fertilization practices and poorly maintained pastures increase the risk of elevated NO3- intake among cattle and sheep. Nitrate is metabolized to nitrite (NO2-) in the rumen and further reduced to ammonia. Ruminants consuming high dietary NO3- vary in ability to efficiently reduce excess NO2- to ammonia. This leads to methemoglobin formation and ultimately NO3- toxicity signs. Variation in individual tolerance to elevated dietary NO3- can be partially attributed to rate and duration of exposure, rate of elimination, metabolism, species and dose. Our objectives were to confirm and quantify variation in individual tolerance to subacute levels of dietary NO3-, and determine if individuals could be identified as highly or lowly tolerant to elevated dietary NO3- based on production traits, plasma analytes and(or) signs of subacute NO3- toxicity. Purebred Suffolk ewes were administered supplement mixed with tap water (control; n = 8) or potassium nitrate (NO3- treated; 300 mg NO3-/kg BW daily; n = 47) for 8 days. Coefficients of variation (CV) indicated that supplement intake was more variable in NO3- treated ewes (CV = 59.3%) than in control ewes (CV = 13.6%). Among NO3- treated ewes, six ewes highly tolerant and six ewes lowly tolerant to elevated dietary NO3- were identified based on individual performance, NO3- treated supplement intake, and signs of toxicity. Supplement intake was lower (P < 0.0001) in NO3- treated ewes than in control ewes, indicating elevated dietary NO3- influences feed intake. Supplement intake differed (P < 0.0001) between control, highly tolerant and lowly tolerant ewes. Supplement intake of highly and lowly tolerant ewes was 82% and 23%, respectively, of the control ewes' intake. Weight change and plasma concentrations of NO2-, cortisol, glucose and retinol were not different (P 0.38) among control, highly tolerant and lowly tolerant ewes. Plasma urea nitrogen (PUN) levels were not different (P = 0.25) between control and lowly tolerant ewes, but were lower (P = 0.02) in highly tolerant ewes than in control ewes. Furthermore, PUN and NO3- treated supplement intake were highly correlated (0.71; P < 0.0001) in lowly tolerant ewes. These results confirm and quantify variation in response to subacute levels of dietary NO3- and indicate that individuals can be identified as highly or lowly tolerant to elevated dietary NO3- based on their performance and NO3- toxicity signs. PMID- 22444123 TI - Fasting and sampling time affect liver gene expression of high-fat diet-fed mice. AB - Several physiological and biological variables are known to affect peroxisome proliferator-activated receptor (PPAR)-alpha-dependent signaling pathway and plasma biochemical profiles. However, less is known about the effect of these variables on high-fat diet-fed mice. In a 5-week study, C57BL/6 mice were divided into control (C) and high-fat diet-fed (H) groups, whereby before dissection, each group was subdivided into non-fasted (nC and nH) and a 15-h fasted mice (fC and fH) killed in the early light cycle, and a 15-h fasted mice (eC and eH) killed in the late phase of the light cycle. Liver and blood from the vena cava were collected. Non-fasted nC and nH mice have a marginal difference in their body weight gain, whereas significant differences were found for fasted mice. In nH mice, PPAR-alpha, acyl-CoA oxidase and insulin-like growth factor-binding protein expressions were significantly elevated, in contrast to fatty acid synthase (Fasn), stearoyl CoA-desaturase (SCD)-1, and elongase (ELOVL)-6 expressions. Fasn was profoundly induced in fH mice, while decreased sterol regulatory-binding protein-1 and SCD-1 were found only in eH mice. Different from the gene expression profiles, plasma total cholesterol level of the eH mice was higher than controls, whereas nH mice have increased plasma non-esterified fatty acids. Only glucose level of the fH mice was higher than that observed for controls. Results showed that fasting and sampling time have significantly affected liver gene expression and plasma biochemical indices of the high-fat diet-treated mice. An overlook in these aspects can cause serious discrepancies in the experimental data and their interpretations. PMID- 22444124 TI - Systematic comparison of the empirical and factorial methods used to estimate the nutrient requirements of growing pigs. AB - Empirical and factorial methods are currently used to estimate nutrient requirements for domestic animals. The purpose of this study was to estimate the nutrient requirements of a given pig population using the empirical and factorial methods; to establish the relationship between the requirements estimated with these two methods; and to study the limitations of the methods when used to determine the level of a nutrient needed to optimize individual and population responses of growing pigs. A systematic analysis was carried out on optimal lysine-to-net-energy (Lys : NE) ratios estimated by the empirical and factorial methods using a modified InraPorc(r) growth model. Sixty-eight pigs were individually simulated based on detailed experimental data. In the empirical method, population responses were estimated by feeding pigs with 11 diets of different Lys : NE ratios. Average daily gain and feed conversion ratio were the chosen performance criteria. These variables were combined with economic information to estimate the economic responses. In the factorial method, the Lys : NE ratio for each animal was estimated by model inversion. Optimal Lys : NE ratios estimated for growing pigs (25 to 105 kg) differed between the empirical and the factorial method. When the average pig is taken to represent a population, the factorial method does not permit estimation of the Lys : NE ratio that maximizes the response of heterogeneous populations in a given time or weight interval. Although optimal population responses are obtained by the empirical method, the estimated requirements are fixed and cannot be used for other growth periods or populations. This study demonstrates that the two methods commonly used to estimate nutrient requirements provide different nutrient recommendations and have important limitations that should be considered when the goal is to optimize the response of individuals or pig populations. PMID- 22444125 TI - Barley and oat cultivars with diverse carbohydrate composition alter ileal and total tract nutrient digestibility and fermentation metabolites in weaned piglets. AB - An experiment was conducted to evaluate the effects of cereal carbohydrate form (isolated v. cereal matrix) and level, especially mixed-linked beta-glucan (hereafter referred to as beta-glucan) and starch amylase/amylopectin ratio on nutrient digestibility and fermentation parameters in the intestines of weaned pigs. Four hulless barley cultivars containing varying beta-glucan levels (41 to 84 g/kg) were compared with hulled barley, supplemented or not with a beta-glucan concentrate (BBG; 270 g/kg beta-glucan) and two oat cultivars for digestibility and fermentation metabolites. Seventy-two weaned piglets (BW = 12.8 +/- 1.9 kg) were assigned to one of nine diets composed of 815 g/kg cereal, 60 g/kg whey, 90 g/kg soy protein isolate and 35 g/kg minerals. After 15 days, the pigs were killed, and digesta collected from ileum and colon were analyzed for proximate nutrients, short-chain fatty acids (SCFAs), lactic acid (LA) and ammonia. Ileal and total tract digestibility of proximate nutrients and non-starch polysaccharides (NSPs) were determined using HCl-insoluble ash as a marker. Organic matter (OM) ileal digestibility was greater (P < 0.05) for diets based on hulless barley (77% +/- 1.1% on average), as compared with hulled barley (64% +/- 1.4%) and oat (58% +/- 1.5%). Similar trends were found for total tract OM digestibility, varying from 90% +/- 0.3% for hulless barley to 67% +/- 0.4% for oat, on average. NSP digestibility differed (P < 0.05) within and between cereal types, ranging from 20% (hulled barley plus 163 g/kg BBG or 40 g/kg beta-glucan) to 51% (SB94893 hulless barley cultivar with high beta-glucan and high amylose ratio) at the ileum and from 44% (hulled barley) to 84% (SB94893 cultivar) at the total tract level. No dietary effect (P > 0.05) was found for SCFA concentration in ileal contents, whereas in colonic contents, SCFA was lower in pigs fed oat (P < 0.001). LA concentration was greater (P < 0.001) in the colon of pigs fed hulless barley than in pigs fed hulled barley and oat. Expressed per kg carbohydrate (NSP + starch) fermented, the ammonia concentration at the colon was lowest for hulled barley diets (supplemented with beta-glucan) and the highest for oat diets. In conclusion, the interaction of both form and level of beta glucan impacted nutrient digestibility and fermentation. Hulless barleys with high soluble NSP such as beta-glucan and resistant starch yielded, in general higher SCFA and LA and lower ammonia. Hulless barleys may, therefore, have potential for use in feeding strategies designed to improve gut health in pigs. PMID- 22444126 TI - Effects of mixtures of red clover and maize silages on the partitioning of dietary nitrogen between milk and urine by dairy cows. AB - Eight multiparous lactating Holstein-Friesian cows were used to evaluate the partitioning of dietary nitrogen (N) from diets based on mixtures of red clover and maize silages in comparison with diets based on ryegrass silage. All cows received 4 kg/day of a standard dairy concentrate with one of four forage treatments in an incomplete changeover design with three 4-week periods. Three treatments were based on mixtures of red clover and maize silage. N intake was altered both by varying the ratio of these silages (40/60 and 25/75 on a dry matter (DM) basis) and by an additional treatment for which the DM intake of the 40/60 mixture was restricted to the level achieved with grass silage. Rumen passage rates were estimated from faecal excretion curves following a pulse oral dose of Dysprosium-labeled silage and urinary excretion of purine derivatives (PD) was used as an index of rumen microbial protein synthesis. Red clover silage mixtures led to significantly increased feed intake (21.5, 20.7 and 15.2 kg DM/day for 40/60 and 25/75 red clover/maize silage mixtures and grass silage, respectively), milk production (25.8, 27.8 and 20.0 kg/day for the same treatments, respectively) and milk component yields, but were without effect on milk fat and protein concentrations. The large increase in the yield of milk (24.5 kg/day) and milk components for the restricted red clover/maize silage treatment, in comparison with the grass silage treatment, was proportionately greater than the increase in DM intake (16.6 kg DM/day). There were no significant treatment effects on diet digestibility, while the higher intakes of red clover silage mixtures were associated with higher rumen passage rates (5.82%, 6.24% and 4.55%/h, respectively). There were significant effects of both N intake and forage source on the partitioning of dietary N between milk and urine. When dietary protein was diluted by the inclusion of maize silage, red clover silage led to increased milk N and reduced urinary N in comparison with grass silage. Improvements in N utilisation may be related to increased dietary starch and/or rumen passage rates leading to increased microbial protein synthesis for these treatments. Urinary excretion of PD was significantly higher for all diets based on mixtures of red clover and maize silages, in comparison with grass silage. Urinary N output was close to literature predictions based on N intake for the diet based on ryegrass silage, but 40 to 80 g/day (25% to 30%) less than predicted for the diets based on the mixtures of red clover and maize silages. PMID- 22444127 TI - Effects of inulin and lactulose on the intestinal morphology of calves. AB - For some time now prebiotics have been proposed to improve health by stimulation of beneficial bacteria in the intestine of humans and animals. The current study is aiming to show effects of feeding of either 2% inulin or 2% lactulose in milk replacer on performance and intestinal morphology of male Holstein-Friesian calves. After 20 weeks of feeding inulin led to significantly higher daily weight gains than lactulose while control animals ranged between the experimental feedings. Ingestion of milk replacer was reduced in lactulose treated animals. Additionally differences of villus height in jejunum (P = 0.07) and ileum (P = 0.03) could be found with an increase for lactulose treated animals and a decrease for inulin treated animals. In ileum the density of proliferative epithelial cells tended to be lower in inulin treated and higher in lactulose treated animals (P = 0.08). Both inulin and lactulose tended to decrease the quantity of goblet cells in the tips of ileal villi (P = 0.07). Both prebiotics can affect performance and intestinal morphology of calves and may as such affect animal health. But effects differ between substances. PMID- 22444128 TI - Nutritional values of sugarcane products in local Caribbean growing pigs. AB - A total of 24 castrated male Creole were used for digestibility studies on three sugarcane (SC) products: final molasses, SC juice and ground SC. Digestibility of macronutrients were determined in three consecutive experimental trials between 35 and 60 kg BW. The first trial measured the effect of a constant rate of incorporation of those SC products in a control diet (23% on a dry matter (DM) basis) on digestibility of energy and nutrients. The second and the third trials were designed to determine the effects of increasing rates of inclusion of SC juice and ground SC in the control diet on the digestibility of nutrients and energy. The DM content of molasses, SC juice and ground SC were 74.3%, 19.3% and 25.8%, respectively. Free sugar contents were 73.8%, 81.6% and 51.5% of DM for molasses, SC juice and ground SC, respectively. In contrast with molasses and SC juice, NDF content of ground SC was very high (40.3% DM). Energy digestibility coefficients (DC) were 99.0% and 83.6% for SC juice and molasses, respectively. For ground SC, amounts and composition of intakes differed from feed allowance as a consequence of chewing-then-spitting out most of the fibrous contents of ground SC. Expressed as a percentage of energy intake and energy allowance, DC of energy for ground SC were 68.6% and 31.9%, respectively. On an intake basis, digestible energy (DE) and metabolisable energy (ME) values were higher for SC juice (17.3 and 17.2 MJ/kg DM, respectively) than for molasses (13.1 and 12.6 MJ/kg DM, respectively) or ground SC (12.3 and 11.8 MJ/kg DM, respectively). On an allowance basis, the corresponding values for ground SC were only 5.7 and 5.6 MJ/kg DM, respectively. The gradual inclusion rate of SC juice in the diet up to 66% resulted in a linear increase of the DC of the diet organic matter and energy (P < 0.001) by 0.10% per 1% in SC juice DM. On the other hand, the partial substitution of the control diet by ground SC up to 74% resulted in a linear (P < 0.05) reduction of digestibility of nutrients and energy. Each 1% increase of ground SC incorporation rate resulted in a 0.13% and 0.61% linear decrease of DC of the energy, expressed as a percentage of energy intake or energy allowance, respectively. In conclusion, our study provides updated energy values of SC products usable as energy sources for feeding pigs. PMID- 22444129 TI - Effect of dietary fatty acids on expression of lipogenic enzymes and fatty acid profile in tissues of bulls. AB - This study investigated the effects of dietary linolenic acid (C18:3n-3) v. linoleic acid (C18:2n-6) on fatty acid composition and protein expression of key lipogenic enzymes, acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase (SCD) and delta 6 desaturase (Delta6d) in longissimus muscle and subcutaneous adipose tissue of bulls. Supplementation of the diet with C18:3n-3 was accompanied by an increased level of n-3 fatty acids in muscle which resulted in decrease of n-6/n 3 ratio. The diet enriched with n-3 polyunsaturated fatty acids (PUFAs) significantly inhibited SCD protein expression in muscle and subcutaneous adipose tissue, and reduced the Delta6d expression in muscle. There was no significant effect of the diet on ACC protein expression. Inhibition of the Delta6d expression was associated with a decrease in n-6 PUFA level in muscles, whereas repression of SCD protein was related to a lower oleic acid (C18:1 cis-9) content in the adipose tissue. Expression of ACC, SCD and Delta6d proteins was found to be relatively higher in subcutaneous adipose tissue when compared with longissimus muscle. It is suggested that dietary manipulation of fatty acid composition in ruminants is mediated, at least partially, through the regulation of lipogenic enzymes expression and that regulation of the bovine lipogenic enzymes expression is tissue specific. PMID- 22444130 TI - Effect of n-3 and n-6 polyunsaturated fatty acids on hare reproductive performances. AB - The study was carried out on 42 breeder couples (42 males and 42 females) of European brown hare (Lepus europaeus), divided into three groups fed three different experimental diets (14 couples/treatment). Two diets were supplemented with n-3 and n-6 polyunsaturated fatty acids (PUFAs; 2% of linseed oil and soybean oil, respectively) and were compared with a control diet supplemented with a monounsaturated fatty acids (2% of olive oil). During the experimental period (from 15 April to 30 September), the following parameters were recorded: days from the beginning of trial to the first parturition, parturition interval, number of parturitions, number of leverets born (alive and dead), dead during suckling, the total number of leverets weaned and feed intake per cage (of males, females and leverets until weaning). Feed intake was not influenced by treatments. In hares fed n-3 and n-6 diets, the days from the beginning of the trial to the first parturition and the parturition interval were similar and were lower compared with control group (63.1 v. 70.6 days, and 37.8 v. 40.9 days, respectively; P < 0.05). Hares from n-6 group had a higher (P < 0.05) number of parturitions per cage during the experimental period than the n-3 and control group that showed a similar value (3.00 v. 2.36, respectively). The total number of leverets born per cage and parturition in n-6 and n-3 groups increased with respect to those fed control diet (P < 0.05). The leverets' mortality rate at birth was higher in n-6 than in n-3 and control group (3.50 v. 2.17, respectively; P < 0.05). In control group, leverets' mortality rate during suckling was lower with respect to n-3 (P < 0.05) and n-6 (P < 0.05), showing the highest value for the latter (P < 0.05). In spite of this higher mortality, the number of leverets weaned per cage and parturition was higher (P < 0.05) in n-6 compared with n-3 group, being the latter higher than the control group (3.12, 2.79 and 2.43, respectively). Our results show that the dietary PUFAs, particularly n-6 supplementation, have a positive influence on the reproductive performances of the European brown hare. PMID- 22444131 TI - Construction of transgenic swine with induced expression of Cre recombinase. AB - Miniature pigs have been recognized as valuable experimental animals in medical research. However, porcine models related to gene knockout of human diseases are not widely available. The objective of this study was to establish Mx1-Cre pigs using somatic cell nuclear transfer. In this study, we created transgenic pigs using somatic cell nuclear transfer (SCNT). Transfer of 210, 230, 250 and 215 zygotes to four surrogates produced 10 piglets. The Cre recombinase expression in transgenic pigs was studied using reverse transcriptase (RT)-PCR and immunohistochemistry. Mx1-Cre swine were shown to harbor the Cre gene in their genomic DNA using the PCR. In conclusion, Mx1-Cre transgenic piglets were successfully produced by SCNT. These transgenic swine, in conjunction with inducible systems for controlling Cre expression and function, are likely to have a profound impact on the study of human diseases. PMID- 22444132 TI - Effect of Bromocryptine on hormones and milk secretion in Murrah buffaloes ( Bubalus bubalis). AB - An experiment was carried out on 10 advance pregnant Murrah buffaloes to determine the role of hormones in milk secretion around parturition. Experimental animals were administered with a single injection of bromocryptine, @ 100 MUg/kg BW, for 5 days before expected calving, whereas control group buffaloes were injected with placebo injections. Blood samples collected before parturition (-5, 4,-3,-2,-1 days), on day of parturition (day-0) and on day 1, 2, 3, 4, 5, 10 and 15 post partum were analyzed for growth hormone (GH), insulin like growth factor I (IGF-I) and prolactin (PRL) by radioimmunassay methods. Milk samples were collected daily for 5 days and on day 10 and 15 after parturition. Milk fat, protein, lactose, citric acid, non-esterified fatty acids (NEFAs) and somatic cell counts (SCCs) were determined in milk samples. Bromocryptine treatment significantly (P < 0.01) decreased pre partum PRL and increased GH levels (P < 0.01) on day of parturition in experimental buffaloes without influencing plasma IGF-I level. Milk yield was significantly lower (P < 0.01) in experimental than in control group. Further, effect of bromocryptine on milk yield was only for a week. Milk yield increased (P < 0.01) gradually and was similar to control group on day 15 post partum. Bromocryptine treatment significantly increased milk SCC (P < 0.01) and protein content (P < 0.01) but there was no effect of treatment on fat, lactose, citric acid, glucose, milk and plasma NEFA concentration. It was concluded that prepartum suppression of PRL by bromocryptine impairs milk secretion temporarily in ensuing lactation. The significant rise in GH level before parturition and on day of parturition suggests a role of it in milk secretion of buffaloes. PMID- 22444133 TI - Quantitative assessment of the effects of space allowance, group size and floor characteristics on the lying behaviour of growing-finishing pigs. AB - To obtain quantitative information that can be later used in animal welfare modelling, the relationship between the lying behaviour of growing-finishing pigs (initial body weight (BW) between 19 and 87 kg) and different factors related to the housing conditions, with a potential negative effect on their welfare, was studied by means of a meta-analytical approach. Data from 22 experiments reported in 21 scientific publications were collected. The space allowance, expressed on an allometric basis by means of a k-value (m2/BW0.667), the group size (n) and the floor characteristics (fully and partly slatted v. non-slatted floor), as well as their significant two-way interactions were used as fixed effects, and the experiment was used as a random factor to take into account the interexperiment effect. Further regression analyses were performed on the predicted values of observations in order to improve the adjustment of data. A significant quadratic relationship was established between space allowance (k value, P < 0.05; squared k-value, P < 0.01) and the percentage of time spent lying. A significant interaction between the k-value and the floor type was also found (P < 0.05), showing that the relationship between space allowance and lying behaviour is affected by the presence or absence of slats. Threshold k-values were obtained using broken-line analyses, being about 0.039 for slatted floors and almost double for non-slatted floors. Compared to other studies, these values suggest that the ability to rest as space availability decreases may be compromised before a reduced performance becomes apparent. Group size did not show a significant effect. Additional information should be added to the model, as further data become available, to adjust the proposed parameters as well as to try to include the effect of other important aspects such as that of ambient temperature. PMID- 22444134 TI - Role of early experience in the development of preference for low-quality food in sheep. AB - Domestic ruminant selectivity induces floristic changes in pasturelands, risking sustainability and limiting the subsequent availability of susceptible plant species. Development of preferences for species of lower nutritional quality may help to overcome those problems. In this study, we tested the hypothesis that early experience of sheep with a low-quality food (LQF) in a nutritional enriched context increases preference for LQF in adulthood. We predicted a higher proportional consumption of LQF in experienced lambs (EL) than in inexperienced lambs (IL) in choice situations involving LQF and alternative foods. Additionally, we determined intake of LQF by EL and IL at different levels of high-quality food (HQF) availability. From 60 to 210 days of age, EL were fed in separated feed bunks mature oat hay (LQF) simultaneously with sunflower meal (SM) and corn grain (CG), whereas IL were fed alfalfa hay (HQF) simultaneously with SM and CG. After exposure, EL and IL were offered LQF in free choice situations involving alternative foods, and also at five levels of HQF availability (100%, 75%, 50%, 25% and 0% of ad libitum intake). Proportional consumption of LQF was lower or similar in EL than IL. Intake of LQF was also lower or similar in EL than IL at all levels of HQF availability, except when the LQF was the only food available. Our results did not support the hypothesis that early experience with a LQF in a nutritional enriched context increases preference for LQF in adulthood. On the contrary, experience with LQF diminished subsequent preference for LQF in adulthood. It is proposed that, in the conditions of our study, continuous comparison between the LQF and the high-quality supplements (CG and SM) during the early exposure period lead to devaluation of LQF by EL through a simultaneous negative contrast effect. PMID- 22444135 TI - Effect of housing conditions on activity and lying behaviour of horses. AB - Housing conditions for horses impose various levels of confinement, which may compromise welfare. Lying behaviour and activity can be used as welfare indicators for domestic animals and rebound behaviour suggests a build-up of motivation resulting from deprivation. The objective of this study was to determine if activity and lying behaviour of horses are affected by housing conditions and to investigate the occurrence of rebound behaviour after release from confinement. Eight horses were subjected, in pairs, to each of four experimental treatments; paddock (P), fully stabled (FS), partly stabled (PS) and yard (Y). Each horse received 6 days acclimatisation prior to the 24 h recording period. Time spent in lying and activity were electronically recorded using a tilt switch and motion sensor connected to a data logger worn on the horse's left foreleg. Time spent active during the first 5 min of release from stable to paddock in the PS treatment (days 1 and 5) and at the same time of day in the P treatment was used as a measure of rebound behaviour. Effect of housing conditions on total time spent active was highly significant (FS = 123 s, PS = 158 s, Y = 377 s, P = 779 s, P < 0.001). Housing conditions did not significantly affect total time spent lying (P = 0.646). Horses were significantly more active, compared with baseline paddock behaviour, on release from stabling on both days 1 (P = 0.006) and 5 (P = 0.025) of PS treatment. These results suggest that activity patterns of horses, but not lying behaviour, are affected by the housing conditions tested and that rebound activity occurs in horses after a period of confinement. PMID- 22444136 TI - Ewe and lamb contact at lambing is influenced by both shelter type and birth number. AB - A significant number of lambs born each year in Australia die within 72 h of birth. Periods of high wind, combined with rain and low temperatures can lead to marked increases in the mortality level. Under these climatic conditions mortality levels may be reduced with the provision of shelter. This study used contact loggers to compare interactions between ewes with twin lambs across two shelter types (Hessian and shrubs), while also comparing ewes with single and twin lambs in a single shelter type (Hessian). The contact loggers record the time of the initial contact (within approximately 4 to 5 m) between collared animals and the duration of each contact. Contact levels between ewes immediately after lambing were only 10% of the initial levels (1 h/day). For single-born lambs, lambs averaged 11 h contact per day with their mother, while for twinborn lambs, each lamb averaged 9.25 h/day with its mother and 14.7 h/day with its sibling. The level of contact between ewes and each of their offspring in the Hessian was 24% lower (P < 0.05) for ewes with twin lambs than with singles. For ewes with twin lambs the level of contact was 17% lower (P < 0.05) in the Hessian shelter compared with shrub shelter. We conclude that shelter type and birth number can affect the level of contact between ewes and their offspring. PMID- 22444137 TI - Repeatability of lameness, fear and slipping scores to assess animal welfare upon arrival in pig slaughterhouses. AB - The EU project Welfare Quality(r) proposes an overall assessment system for animal welfare based on animal outcomes. The objective of this study was to test inter-observer reliability (IOR) when assessing lameness, fear and slipping and falling scores as parameters for monitoring the welfare of killing pigs during arrival at the slaughterhouse. Two Belgian and two Spanish slaughterhouses were visited by six to seven observers. Lameness, slipping and falling were assessed twice; during unloading and in the passageway to the lairage zone (lairage). Fear, which was assessed in the unloading area, was based on four indicators: reluctance to move, retreat attempts, turning back and vocalisations. Lameness had low-to-moderate IOR when observed in the passageway to lairage (r = 0.46), but the IOR was low during unloading (r = 0.25). IOR for slipping and falling was moderate to high (r = 0.71 and r = 0.50, respectively), when assessed in the unloading area, but low for observations in the passageway (r = 0.13). Fear indicators had only moderate or low IOR. Turning back was the measure with the highest IOR (r = 0.43) and retreat attempts had the lowest IOR (r = 0.25). Based on these results, we concluded that scoring lameness could be reliable when assessed from the unloading bay to lairage, whereas slipping and falling should be scored in the unloading area of the slaughterhouse. We suggest scoring a maximum of two measures of fear on the same animals at the unloading area, with the most reliable parameters being turning back and reluctance to move. The three indicators of animal welfare (lameness, fear and slipping and falling) should be measured in a way to reduce overtax of the observers in order to achieve accurate results. PMID- 22444138 TI - Increasing the incubation temperature between embryonic day 7 and 10 has no influence on the growth and slaughter characteristics as well as meat quality of broilers. AB - Avian embryogenesis can be manipulated by alteration of the temperature during incubation of the brooding egg. Investigations in turkeys showed that a higher temperature during early embryogenesis positively affects the myogenesis accompanied with a higher muscle fibre number (MFN). The aim of this study was to transfer this result to broiler and to investigate if an alteration of the temperature also affects the meat quality after slaughter of the birds. Therefore brooding eggs of the Cobb 500 broiler genetic were either incubated at 37.5 degrees C during the whole incubation period (at normal temperature (NT)), or at 38.5 degrees C during embryonic day (ED) 7 to 10 (at high temperature (HT)). After hatch the chicks were sexed and reared up to an age of 36 days in an experimental stable. Growth and feed conversion properties were determined during this period. After slaughter different meat quality characteristics as well as the muscle microstructure were analysed. The hatch rate and chick weight did not differ between the broiler of the NT and HT group. After 36 days the final body weights and the cumulative feed conversion rates were not different in the NT and HT groups. No differing results were obtained with regard to the slaughter, breast and leg weights of the NT and HT animals. Considering the gender of the animals no differences in the slaughter characteristics could be determined although the carcass and breast weights of the HT cocks were tendentially higher. The muscle fibre areas and MFNs in the breast muscles of the NT and HT cocks did not differ significantly and were in the range of the HT hens. Only the NT hens had significantly larger muscle fibres and less MFN than the other animals. With regard to the meat quality characteristics no clear differences of the pH, electrical conductivity (EC) and colour (L*a*b*) values were found. The L*a*b* values in the investigated breast muscles of all broilers usually increased during ageing. The increase of the incubation temperature had no impact on the hatch, growth, slaughter and meat quality characteristics of the broiler except for the tendentially higher carcass and breast weights of the HT cocks. However, the decrease of the fibre areas in the HT hens is an interesting effect of using a higher incubation temperature, which needs to be considered when implicating further investigations. PMID- 22444139 TI - Gray level co-occurrence matrix texture analysis of germinal center light zone lymphocyte nuclei: physiology viewpoint with focus on apoptosis. AB - In our study we investigated the relationship between conventional morphometric indicators of nuclear size and shape (area and circularity) and the parameters of gray level co-occurrence matrix texture analysis (entropy, homogeneity, and angular second moment) in cells committed to apoptosis. A total of 432 lymphocyte nuclei images from the spleen germinal center light zones (cells in early stages of apoptosis) were obtained from eight healthy male guinea pigs previously immunized with sheep red blood cells (antigen). For each nucleus, area, circularity, entropy, homogeneity, and angular second moment were determined. All measured parameters of gray level co-occurrence matrix (GLCM) were significantly correlated with morphometric indicators of nuclear size and shape. The strongest correlation was observed between GLCM homogeneity and nuclear area (p < 0.0001, r(s) = 0.61). Angular second moment values were also highly significantly correlated with nuclear area (r(s)= 0.39, p < 0.0001). These results indicate that the GLCM method may be a powerful tool in evaluation of ultrastructural nuclear changes during early stages of the apoptotic process. PMID- 22444140 TI - Perspectives on the ciliated protozoan Tetrahymena thermophila. AB - In biology, scientific discoveries are often linked to technical innovations made possible by an inspired choice of model organism. Ciliate species, especially Tetrahymena thermophila, have had historically significant roles as uniquely enabling experimental systems. More importantly, as the chapters in this volume attest, ongoing efforts of the T. thermophila model organism community have created a knowledge and resource infrastructure for systems-level studies across a whole genome or proteome, setting the stage for understanding the fundamental biology underlying the sophisticated life cycle and environmentally responsive behaviors of this free-living, single-celled eukaryote. One hope is that these developments will stimulate the integration of ciliates into phylogenomic comparative analyses and also encourage the experimental use of T. thermophila by a broader scientific community. This early branching yet highly gene-rich eukaryote has much to offer for future studies of human-relevant basic biology. PMID- 22444141 TI - The life and times of Tetrahymena. AB - The genus Tetrahymena is defined on the basis of a four-part oral structure composed of an undulating membrane and three membranelles. It is a monophyletic genus with 41 named species and numerous unnamed species, many of which are morphologically indistinguishable. Nuclear small subunit rRNA and mitochondrial cytochrome c oxidase subunit 1 sequences indicate two major clades, a "borealis" clade of less closely related species and an "australis" clade of more closely related species that correlate to differences in mating-type determination and frequency of amicronucleates. Members of both clades show convergence for histophagy (primarily facultative), macrostome transformation, and (rare) cyst formation. Life cycle parameters of species are presented and problematic species discussed. PMID- 22444142 TI - Nuclear dualism. AB - Nuclear dualism is a characteristic feature of the ciliated protozoa. Tetrahymena have two different nuclei in each cell. The larger, polyploid, somatic macronucleus (MAC) is the site of transcriptional activity in the vegetatively growing cell. The smaller, diploid micronucleus (MIC) is transcriptionally inactive in vegetative cells, but is transcriptionally active in mating cells and responsible for the genetic continuity during sexual reproduction. Although the MICs and MACs develop from mitotic products of a common progenitor and reside in a common cytoplasm, they are different from one another in almost every respect. PMID- 22444143 TI - Whole genome studies of Tetrahymena. AB - Within the past decade, genomic studies have emerged as essential and highly productive tools to explore the biology of Tetrahymena thermophila. The current major resources, which have been extensively mined by the research community, are the annotated macronuclear genome assembly, transcriptomic data and the databases that house this information. Efforts in progress will soon improve these data sources and expand their scope, including providing annotated micronuclear and comparative genomic sequences. Future studies of Tetrahymena cell and molecular biology, development, physiology, evolution and ecology will benefit greatly from these resources and the advanced genomic technologies they enable. PMID- 22444144 TI - From molecules to morphology: cellular organization of Tetrahymena thermophila. AB - Tetrahymena thermophila is both a cell and an organism, which combines great intracellular complexity with a remarkable accessibility to investigation using many different approaches. In this review, we start with a description of the elaborate cortical organization of the Tetrahymena cell, and then proceed inward to consider the mitochondria and then the nuclei. For each of these cellular organelles and organelle-systems, first we familiarize the reader with its location in the cell and its structure and ultrastructure, and then we analyze the molecular mechanisms associated with organelle assembly, function, and subdivision. This analysis includes a molecular inventory of the organelle or organelle system, as well as a review of the consequences of modification, disruption or overexpression of important molecular components of each structure or system. Relevant comparisons to results obtained with other well-studied organisms, from Paramecium to Homo sapiens, are also included. Our goal is to provide investigators, in particular those who are new to this organism, both the background and the motivation to work with this model system and achieve further insight into its organization and dynamics. PMID- 22444146 TI - Developmental progression of Tetrahymena through the cell cycle and conjugation. AB - The ciliate Tetrahymena thermophila can be said to undergo a variety of developmental programs. During vegetative growth, cells coordinate a variety of cell-cycle operations including macronuclear DNA synthesis and a-mitotic fission, micronuclear DNA synthesis and mitosis, cytokinesis and an elaborate program of cortical morphogenesis that replicates the cortical organelles. When starved, cells undergo oral replacement, transformation into fast-swimming dispersal forms or, when encountering cells of a complementary mating type, conjugation. Conjugation involves a 12 hour program of meiosis, mitosis, nuclear exchange and karyogamy, and two postzygotic divisions of the fertilization nucleus. This chapter reviews experimental data exploring the developmental dependencies associated with both vegetative and conjugal development. PMID- 22444145 TI - Conservation and innovation in Tetrahymena membrane traffic: proteins, lipids, and compartments. AB - The past decade has seen a significant expansion in our understanding of membrane traffic in Tetrahymena thermophila, facilitated by the development of new experimental tools and by the availability of the macronuclear genome sequence. Here we review studies on multiple pathways of uptake and secretion, as well as work on metabolism of membrane lipids. We discuss evidence for conservation versus innovation in the mechanisms used in ciliates compared with those in other eukaryotic lineages, and raise the possibility that existing gene expression databases can be exploited to analyze specific pathways of membrane traffic in these cells. PMID- 22444148 TI - Natural populations and inbred strains of Tetrahymena. AB - Tetrahymena typically is found in freshwater lakes, ponds, and streams in association with submerged or emergent vegetation. The genus consists of numerous breeding species with micronuclei and many asexual species without micronuclei. In summer months when most populations are at their peak, 30-50% of water samples may yield one or more species of Tetrahymena. This chapter describes both bulk and trapping procedures for collecting Tetrahymena and also evaluates barcode methods for species identification. The history and inbreeding of the laboratory model Tetrahymena thermophila is also discussed. There are numerous unresolved questions about Tetrahymena evolution and biogeography that may be solved by additional collecting. PMID- 22444147 TI - Tetrahymena in the laboratory: strain resources, methods for culture, maintenance, and storage. AB - The ciliated protozoan Tetrahymena thermophila has been an important model system for biological research for many years. During that time, a variety of useful strains, including highly inbred stocks, a collection of diverse mutant strains, and wild cultivars from a variety of geographical locations have been identified. In addition, thanks to the efforts of many different laboratories, optimal conditions for growth, maintenance, and storage of Tetrahymena have been worked out. To facilitate the efficient use of Tetrahymena, especially by those new to the system, this chapter presents a brief description of many available Tetrahymena strains and lists possible resources for obtaining viable cultures of T. thermophila and other Tetrahymena species. Descriptions of commonly used media, methods for cell culture and maintenance, and protocols for short- and long-term storage are also presented. PMID- 22444149 TI - Tetrahymena thermophila genetics: concepts and applications. AB - The differentiation of germline and somatic genomes in Tetrahymena thermophila results in two independent systems of genetic transmission. One is the conserved, sexual Mendelian genetics system of the germline genome. The other is a random genetic assortment mechanism, which operates in the somatic genome during asexual propagation. This chapter describes both systems, their interplay, and how they are exploited to construct useful biological reagents and powerful tools, which can be used to answer a variety of experimental questions. PMID- 22444150 TI - Transformation and strain engineering of Tetrahymena. AB - Transformation of Tetrahymena by microinjection of DNA was established 25 years ago. This rather labor-intensive technique has since been shelved, replaced by less time consuming and more efficient methods, electroporation and biolistics. Conjugative electroporation is the method of choice for introducing autonomously replicating, rDNA-based vectors into Tetrahymena. These are maintained as high copy linear mini-chromosomes. Versatile expression cassettes in these vectors facilitate expression of most genes. Transformation efficiencies are sufficiently high to permit screens using expression libraries. Biolistic transformation is primarily used to introduce DNA for integration into the genome by homologous recombination. This technique has greatly enhanced strain engineering of Tetrahymena through facilitating the disruption of genes (creating targeted knockout cell lines) or epitope-tagging coding regions, allowing researchers to take full advantage of the sequenced genome. The presence of both germline and somatic nuclei in these cells requires different strategies to target DNA to the desired compartment. This presents challenges, including the need to engineer the polygenic macronuclear genome, which has nearly 50 copies of each gene. However, separate manipulation of functionally distinct genomes provides experimental opportunities, especially for the analysis of essential genes, by modifying the silent micronucleus then subsequently examining phenotypes in the next sexual generation. The flexibility to engineer strains as needed makes Tetrahymena a facile system with which to answer many biological questions. PMID- 22444151 TI - Biochemical approaches including the design and use of strains expressing epitope tagged proteins. AB - Epitope tagging is a powerful approach used to enable investigations of a cellular component by elucidating its localization, interaction partners, and/or activity targets. Successful tag-based affinity purification yields a mixture of the molecule of interest, associated proteins and nucleic acids, and nonspecific background proteins and nucleic acids, many of which can depend on details of the protocol for enrichment. This chapter provides guidelines and considerations for designing an affinity purification experiment, beginning with construction of a strain expressing a tagged subunit. Common biochemical methods for detecting protein, RNA, and DNA in Tetrahymena thermophila are also discussed. PMID- 22444152 TI - Cytological analysis of Tetrahymena thermophila. AB - Since their first detection in pond water, large ciliates such as Tetrahymena thermophila, have captivated school children and scientists alike with the elegance of their swimming and the beauty of their cortical organization. Indeed, cytology - simply looking at cells - is an important component of most areas of study in cell biology and is particularly intriguing in the large, complex Tetrahymena cell. Cytological analysis of Tetrahymena is critical for the study of the microtubule cytoskeleton, membrane trafficking, complex nuclear movements and interactions, and the cellular remodeling during conjugation, to name a few topics. We briefly review previously reported cytological techniques for both light and electron microscopy, and point the reader to resources to learn about those protocols. We go on to present new and emerging technologies for the study of these marvelous cells. These include the use of fluorescent-protein tagging to localize cellular components in live cells, as well as for tracking the dynamic behavior of proteins using pulse labeling and fluorescence recovery after photobleaching. For electron microscopy, cellular and antigenic preservation has been improved with the use of cryofixation and freeze-substitution. The technologies described here advance Tetrahymena cell biology to the cutting-edge of cytological analysis. PMID- 22444153 TI - Purification of Tetrahymena cytoskeletal proteins. AB - Like all eukaryotic cells, Tetrahymena thermophila contains a rich array of cytoskeletal proteins, some familiar and some novel. A detailed analysis of the structure, function, and interactions of these proteins requires procedures for purifying the individual protein components. Procedures for the purification of actin and tubulin from Tetrahymena are reviewed, followed by a description of a procedure that yields proteins from the epiplasmic layer and associated structures, including the tetrins. Finally, the challenges and opportunities for future advances are assessed. PMID- 22444154 TI - Behavioral bioassays and their uses in Tetrahymena. AB - The swimming behaviors of Tetrahymena can be used in sensitive behavioral bioassays for estimating the effects of drugs, mutations, and other conditions on the physiological state of the cell. These assays can be used in both forward and reverse genetic approaches to help understand cellular functions from genotype to phenotype. PMID- 22444155 TI - Tetrahymena in the classroom. AB - Tetrahymena has been a useful model in basic research in part due to the fact it is easy to grow in culture and exhibits a range of complex processes, all within a single cell. For these same reasons Tetrahymena has shown enormous potential as a teaching tool for fundamental principles of biology at multiple science education levels that can be integrated into K-12 classrooms and undergraduate and graduate college laboratory courses. These Tetrahymena-based teaching modules are inquiry-based experiences that are also effective at teaching scientific concepts, retaining students in science, and exciting students about the scientific process. Two learning communities have been developed that utilize Tetrahymena-based teaching modules. Advancing Secondary Science Education with Tetrahymena (ASSET) and the Ciliate Genomics Consortium (CGC) have developed modules for K-12 students and college-level curriculums, respectively. These modules range from addressing topics in ecology, taxonomy, and environmental toxicity to more advanced concepts in biochemistry, proteomics, bioinformatics, cell biology, and molecular biology. An overview of the current modules and their learning outcomes are discussed, as are assessment, dissemination, and sustainability strategies for K-12 and college-level curriculum. PMID- 22444156 TI - Factor VIIa-antithrombin complexes plasma levels in cancer patients with and without thrombosis. PMID- 22444157 TI - Incidence and predictive factors of symptomatic thrombosis related to peripherally inserted central catheters in chemotherapy patients. AB - INTRODUCTION: The incidence of symptomatic catheter-related deep vein thrombosis (DVT) in cancer patients remains unclear and there is a lack of reliable data on the risk factors of PICC-related DVT. MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive cancer patients who received an ultrasound guided PICC line for the administration of chemotherapy. Univariable and multivariable logistic regression analyses were performed to identify risk factors for symptomatic PICC-related DVT. RESULTS: In total, 340 cancer patients obtained PICC lines for the administration of chemotherapy. Of these patients, 19 (5.6%; 95% CI: 3.6-8.6) developed symptomatic PICC-related DVT. Factors previously associated with catheter-related DVT, including side of catheter placement, lumen size, tip location, need for repositioning, and number of insertion attempts, were not significant determinants in our analysis. Patients with diabetes were three times more likely to develop PICC-related DVT (OR 3.0, p=0.039), while the presence of COPD and metastatic cancer also increased the odds (OR 3.3, p=0.078 and OR 2.3, p=0.083 respectively). Diabetes remained a significant risk factor after adjustment for effect of metastases and COPD (OR 3.175, p=0.039). Further, the presence of metastases was a significant predictor (OR 3.34, p=0.024) in our multivariable model. CONCLUSIONS: Symptomatic PICC related DVT are frequent in cancer patients receiving chemotherapy. Previously described factors associated with catheter-related thrombosis were not predictive of PICC-related DVT in our study. Diabetes, advanced disease and COPD appear to increase the risk of developing PICC-related DVT in chemotherapy patients. PMID- 22444158 TI - Sources of tissue factor that contribute to thrombosis after rupture of an atherosclerotic plaque. AB - Hyperlipidemia leads to the formation of oxidized LDL (oxLDL), vessel dysfunction, atherosclerotic disease, and ultimately to plaque rupture and thrombosis. OxLDL induces tissue factor (TF) expression in various cell types, including monocytes and macrophages. High levels of TF are present in atherosclerotic plaques and this represents that major source of TF that triggers thrombosis after plaque rupture. In addition, increased levels of "circulating TF" are observed in hyperlipidemic animals and patients. This is due to induced TF expression in monocytes and release of monocyte-derived, TF(+) microparticles, which represents a minor source of TF that likely contributes to thrombosis after plaques rupture. This review will summarize the connections between hyperlipidemia and TF expression within atherosclerotic plaques and circulating monocytes, as well as its inhibition by statins. PMID- 22444159 TI - Osteopontin induces growth of metastatic tumors in a preclinical model of non small lung cancer. AB - Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin alphavbeta3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (alphavbeta3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and alphavbeta3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a Kras(G12D LSL)p53(fl/fl) subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression. PMID- 22444160 TI - Cryptostatin, a chagasin-family cysteine protease inhibitor of Cryptosporidium parvum. AB - Cysteine proteases of pathogenic protozoan parasites play pivotal roles in the life cycle of parasites, but strict regulation of their activities is also essential for maintenance of parasite physiology and interaction with hosts. In this study, we identified and characterized cryptostatin, a novel inhibitor of cysteine protease (ICP) of Cryptosporidium parvum. Cryptostatin showed low sequence identity to other chagasin-family ICPs, but 3 motifs (NPTTG, GXGG, and RPW/F motifs), which are evolutionarily conserved in chagasin-family ICPs, were found in the sequence. The overall structure of cryptostatin consisted of 8 beta strands that progressed in parallel and closely resembled the immunoglobulin fold. Recombinant cryptostatin inhibited various cysteine proteases, including papain, human cathepsin B, human cathepsin L, and cryptopain-1, with K i's in the picomolar range. Cryptostatin was active over a wide pH range and was highly stable under physiological conditions. The protein was thermostable and retained its inhibitory activity even after incubation at 95 degrees C. Cryptostatin formed tight complexes with cysteine proteases, so the complexes remained intact in the presence of sodium dodecyl sulfate and beta-mercaptoethanol, but they were disassembled by boiling. An immunogold electron microscopy analysis demonstrated diffused localization of cryptostatin within oocystes and meronts, but not within trophozoites, which suggests a possible role for cryptostatin in host cell invasion by C. parvum. PMID- 22444161 TI - Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment. AB - The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack. PMID- 22444162 TI - Constructing the electricity-carbohydrate-hydrogen cycle for a sustainability revolution. AB - In this opinion, we suggest the electricity-carbohydrate-hydrogen (ECHo) cycle which bridges primary energies and secondary energies. Carbohydrates are sources of food, feed, liquid biofuels, and renewable materials and are a high-density hydrogen carrier and electricity storage compounds (e.g. >3000 Wh/kg). One element of this ECHo cycle can be converted to another reversibly and efficiently depending on resource availability, needs and costs. This cycle not only supplements current and future primary energy utilization systems for facilitating electricity and hydrogen storage and enhancing secondary energy conversion efficiencies, but also addresses such sustainability challenges as transportation fuel production, CO(2) utilization, fresh water conservation, and maintenance of a small closed ecosystem in emergency situations. PMID- 22444163 TI - Insulin degludec--a new-generation basal insulin. AB - Insulin degludec may provide dosing options for patients who, because of their lifestyle, require some flexibility in adhering to an insulin regimen, and it may also reduce the risk of hypoglycemia compared with the basal insulins that are currently available. PMID- 22444164 TI - Enhancement of anticancer efficacy of chemotherapeutics by gambogic acid against gastric cancer cells. AB - Gambogic acid (GA), the main active component of gamboge, is well known for its marked antitumor effect in vitro and in vivo. The aim of this study was to assess the natural interaction between GA and chemotherapeutic agents, 5-fluorouracil (5 FU), oxaliplatin (Oxa), and docetaxel (Doc), which are widely used in gastric cancer treatment. This study also investigated the effect of GA on cell apoptosis and drug-associated gene expression for further mechanism research. Synergistic interaction on human gastric cancer BGC-823 cells and MKN-28 cells was evaluated using the combination index (CI) method. The double staining method with Annexin V-FITC and PI was employed to distinguish the apoptotic cells from others. Expression of drug-associated genes, that is, thymidylate synthase (TS), excision repair cross-complementing (ERCC1), BRCA1, tau, and beta-tubulin III, was measured by real-time quantitative RT-PCR. This study found that GA had a synergistic effect on the cytotoxity of chemotherapeutic agents against both cell lines. The combination of GA and chemotherapeutic agents could also induce apoptosis in a synergistic manner. The mRNA levels of TS, ERCC1, BRCA1, tau, and beta-tubulin III were suppressed at 0.009, 0.075, 0.140, 0.267, and 0.624-fold, respectively, when cells were exposed to GA at the concentration of 0.25 MUM. These data suggest that GA has a promising role in enhancing the efficacy of 5 FU, Oxa, and Doc in the treatment of gastric cancer. The potential mechanism would be their synergistic effects on apoptosis induction and the downregulation of chemotherapeutic agent-associated genes. PMID- 22444165 TI - Pneumococcal infections: association with asthma and COPD. AB - Pneumococci are responsible for lower respiratory tract infections (bronchitis and pneumonia) and invasive infections (bacteremia and meningitis). Pneumococcal vaccination is recommended for adults at high risk of pneumococcal infection. Asthma is not currently considered as an indication for pneumococcal vaccination and this vaccination is indicated only in case of respiratory insufficiency. Indeed, asthma is not usually considered as a risk factor for pneumococcal infection and pneumococcal polysaccharide vaccine does not decrease mortality in patients presenting with COPD. According to several recent epidemiological studies, asthma is associated with a doubled risk of pneumonia and invasive infections. This epidemiological association is supported by biological data suggesting increased susceptibility to pneumococcal infection in asthmatic patients. Pneumococci are responsible for 10 to 15% of acute exacerbations and onset of often-severe pneumonia in patients presenting with COPD. The recent availability of pneumococcal conjugate vaccines could be interesting for these patients, but their clinical and cost effectiveness will have to be demonstrated before they can be recommended for these conditions. PMID- 22444166 TI - Polymorphism identification, RH mapping and association of placental lactogen gene with milk production traits of dairy cows. AB - Bovine placental lactogen (bPL) is structurally related to prolactin (PRL) and growth hormone (GH). In synergism with steroid and thyroid hormones, bPL is crucial in stimulating the development of the mammary gland, mammary cell differentiation and function. To further explore whether bPL gene is associated with milk production traits, we herein analyzed single-nucleotide polymorphisms (SNPs) within eight regions of bPL gene, which are potentially associated with five milk production traits on 1028 Chinese Holstein cows. Among these, two SNPs, NT7409(T-C) and Nt11246(G-A), were identified. The former is within exon 2; it induces an alteration of amino acid from Val to Ala. The later is within exon 4. It is a synonymous mutation. We found that there were significant associations between NT7409(T-C) and milk and protein yield. Cows of the AA genotype yielded less milk (P = 0.001) and less protein (P = 0.003) than those of genotypes AB and BB. However, on the NT11246(G-A) locus, no significant association was observed in the five milk production traits studied. In addition, bPL has been localized near markers RM185 and CC549051 with a distance of 23.2 cR on BTA 23. It is at the same position as the region including quantitative trait loci (QTLs) affecting milk and protein yields by previous linkage analysis. In summary, our findings demonstrated that the SNP within exon 2 of bPL (NT7409(T-C)) is associated with two milk production traits, and this provided further evidence that bPL could be a major gene-controlling milk production trait in Holstein dairy cattle. PMID- 22444167 TI - Population structure of the Trakehner Horse breed. AB - The objective of this study was to examine the population structure of the Trakehner Horse breed. A total of 13 793 pedigree records were used for analysing the active breeding population and their ancestors dating back to 1950. Ancestors that were born before 1950 were called as base animals. The average generation interval was calculated as 10.2 years. The effective population size (Ne) was estimated by the increase in average year-wise inbreeding coefficient and average coancestry, respectively. Two methods were applied to estimate the effective population size: 1. Numerator-relationship-matrix (NRM), which did not consider missing ancestries. 2. Uncertain-parentage-matrix (UPM), which considered a probabilistic correction for unknown ancestors. There were no major differences between these two methods with respect to the rate of increase in inbreeding although the global levels using the UPM method were observed to be higher. Estimates for the inbreeding coefficients and the average coancestries varied little between both methods. The estimates of the effective population size per generation based on the rate of inbreeding ranged from 169 (NRM) to 150 (UPM) and 158 (NRM) to 144 (UPM) calculated by the average coancestry. From the early 1990s onwards, a strong increase in the rate of inbreeding was observed. This may be due to an increasing variance of the family size of sires and may be interpreted as a consequence of the growing use of artificial insemination. Analysing coancestries within and between the centrally managed regional breeding societies in Germany further revealed the Trakehner horse breed to be a genetically fragmented population with a main partition corresponding to formerly divided East and West Germany. The average rate of gene contributions (Thoroughbred (xx), Arab Horse breed (ox)) to the defined actual breeding population was calculated to be 22.3% xx-genes and 11.7% ox-genes. PMID- 22444168 TI - Incorporation of genotype effects into animal model evaluations when only a small fraction of the population has been genotyped. AB - The method of Israel and Weller (Estimation of candidate gene effects in dairy cattle populations. Journal of Dairy Science 1998, 81, 1653-1662) to estimate quantitative trait locus (QTL) effects when only a small fraction of the population was genotyped was investigated by simulation. The QTL effect was underestimated in all cases, but bias was greater for extreme allelic frequencies, and increased with the number of generations included in the simulations. Apparently, as the fraction of animals with inferred genotypes increases, the genotype probabilities tend to 'mimic' the effect of relationships. Unbiased estimates of QTL effects were derived by a modified 'cow model' without the inclusion of the relationship matrix on simulated data, even though only a small fraction of the population was genotyped. This method yielded empirically unbiased estimates for the effects of the genes DGAT1 and ABCG2 on milk production traits in the Israeli Holstein population. Based on these results, an efficient algorithm for marker-assisted selection in dairy cattle was proposed. Quantitative trait loci effects are estimated and subtracted from the cows' records. Genetic evaluations are then computed for the adjusted records. Animals are then selected based on the sum of their polygenic genetic evaluations and QTL effects. This scheme differs from a traditional dairy cattle breeding scheme in that all bull calves were considered candidates for selection. At year 10, total genetic gain was 20% greater by the proposed algorithm as compared to the selection based on a standard animal model for a locus with a substitution effect of 0.5 phenotypic standard deviations. The proposed method is easy to apply, and all required software are 'on the shelf.' It is only necessary to genotype breeding males, which are a very small fraction of the entire population. The method is flexible with respect to the model used for routine genetic evaluation. Any number of genetic markers can be easily incorporated into the algorithm, and the reduction in genetic gain due to incorrect QTL determination is minimal. PMID- 22444169 TI - Performance of weanling piglets offered low-, medium- or high-lactose diets supplemented with a seaweed extract from Laminaria spp. AB - An experiment (3 * 4 factorial arrangement) was conducted to investigate the interaction between different levels of lactose (60 v. 150 v. 250 g/kg) and seaweed extract (0 v. 1 v. 2 v. 4 g/kg) containing both laminarin and fucoidan derived from Laminaria spp. on growth performance and nutrient digestibility of weanling pigs. In all, 384 piglets (24 days of age, 7.5 kg (s.d. 1 kg) live weight) were blocked on the basis of live weight and were assigned to one of 12 dietary treatments (eight replicates per treatment). Piglets were offered diets containing either low (60 g/kg), medium (150 g/kg) or high (250 g/kg) lactose levels with one of the following levels of seaweed extract additive: (1) 0 g/kg, (2) 1 g/kg, (3) 2 g/kg or (4) 4 g/kg seaweed extract. The pigs were offered the diets ad libitum for 21 days post weaning. There was a significant lactose * seaweed extract interaction (P < 0.05) in average daily gain (ADG) during the experimental period (days 0 to 21). At the low and medium levels of lactose, there was an increase in ADG as the level of seaweed extract increased to 2 g/kg (P < 0.05). However, at the high level of lactose there was no further response in ADG as the level of seaweed extract increased above 1 g/kg. There was a significant lactose * seaweed extract interaction during the experimental period (days 0 to 21) (P < 0.05) on the food conversion ratio (FCR). At the low level of lactose, there was a significant improvement in FCR as the levels of seaweed extract increased to 4 g/kg (P < 0.01). At the medium level of lactose, there was a significant improvement in FCR as seaweed extract increased to 2 g/kg. However, there was no significant effect of seaweed extract on FCR at the high levels of lactose (P > 0.05). There was a linear increase in average daily feed intake (ADFI) during the experimental period (days 0 to 21) (P < 0.05) as levels of seaweed extract increased. There was a linear increase in ash digestibility (P < 0.01) during the experimental period (days 0 to 21) as the level of lactose increased. There was a quadratic decrease (P < 0.01) in nitrogen (N) and neutral detergent fibre digestibility as the levels of lactose increased. In conclusion, pigs responded differently to the inclusion levels of seaweed extract at each level of lactose supplementation. The inclusion of a laminarin-fucoidan extract in piglet diets may alleviate the use for high-lactose diets (>60 g/kg) and would also alleviate some of the common problems that occur post weaning. PMID- 22444170 TI - Effects of malic acid on rumen fermentation, urinary excretion of purine derivatives and feed digestibility in steers. AB - The objective of this study was to evaluate the effects of malic acid (MA) supplementation on rumen fermentation, urinary excretion of purine derivatives (PDs) and whole gastro-intestinal tract feed digestibility in steers. Eight ruminally cannulated Simmental steers (465 +/- 13 kg) were used in a replicated 4 * 4 Latin square design. The treatments were: control (without MA), LMA (MA-low), MMA (MA-medium) and HMA (MA-high) with 0.0, 7.8, 15.6 and 23.4 g MA per kg dry matter (DM), respectively. Diets consisted of corn stover and concentrate (60/40, DM basis). DM intake was approximately 9 kg per day, which was 90% of ad libitum intake including 5.4 kg corn stover and 3.6 kg concentrate. Ruminal pH (range of 6.91 to 6.56), ratio of acetate to propionate (range of 3.88 to 3.25), ammonia N (range of 9.03 to 6.42 mg/100 ml) and lactate (range of 91.25 to 76.31 mg/100 ml) decreased linearly as MA supplementation increased, whereas total volatile fatty acid (VFA) concentration (range of 55.68 to 61.49 mM) linearly (P < 0.05) increased with increase in MA supplementation. In situ ruminal neutral detergent fiber (aNDF) degradation of corn stover was improved but the crude protein (CP) degradability of concentrate mix was decreased with increasing the dose of MA. Urinary excretion of PDs was quadratically (P < 0.01) changed with altering MA supplementation (67.88, 72.74, 75.81 and 73.78 mmol/day for control, LMA, MMA and HMA, respectively). Similarly, digestibilities of DM, organic matter (OM), NDF and acid detergent fiber (ADF) in the total tract were also quadratically increased with increasing MA, and no differences in terms of CP and ether extract digestibility were observed. The results indicate that MA supplementation has the potential to improve rumen fermentation and feed digestion in beef cattle. The MA stimulates the digestive microorganisms or enzymes in a quadratic response. In the experimental conditions of this trial, the optimum MA dose was 15.6 g MA per kg DM. PMID- 22444171 TI - Recent advances in the regulation of milk fat synthesis. AB - In addition to its economic value, milk fat is responsible for many of milk's characteristics and can be markedly affected by diet. Diet-induced milk fat depression (MFD) was first described over a century ago and remains a common problem observed under both intensive and extensive management. The biohydrogenation theory established that MFD is caused by an inhibition of mammary synthesis of milk fat by specific fatty acids (FA) produced as intermediates in ruminal biohydrogenation. During MFD, lipogenic capacity and transcription of key lipid synthesis genes in the mammary gland are down regulated in a coordinated manner. Our investigations have established that expressions of sterol response element-binding protein 1 (SREBP1) and SREBP activation proteins are down-regulated during MFD. Importantly, key lipogenic enzymes are transcriptionally regulated via SREBP1. Collectively, these results provide strong evidence for SREBP1 as a central signaling pathway in the regulation of mammary FA synthesis. Spot 14 is also down-regulated during MFD, consistent with a lipogenic role for this novel nuclear protein. In addition, SREBP1c and Spot 14 knock-out mice exhibit reduced milk fat similar to the magnitude and pattern of MFD in the cow. Application of molecular biology approaches has provided the latest chapter in the regulation of milk fat synthesis and is reviewed along with a brief background in nutritional regulation of milk fat synthesis in ruminants. PMID- 22444172 TI - Mouse models for identifying genes modulating fertility parameters. AB - Fertility can be defined as the natural capability of giving life. It is an important factor both for human medicine, where ~10% of the couples call for the services of assisted reproductive technologies, and for species of economic interest. In particular, in dairy cows, the recent years have seen a kind of competition between milk production and fertility, and genes improving fertility are now considered as parameters to be selected for. The study of fertility pathways is nevertheless made difficult by the strong impact of environmental factors on this parameter, as well as by the number of genes potentially involved (as shown by systematic transcriptome analysis studies in the recent years). One additional level of complexity is given by the fact that factors modulating fertility will probably be sex specific. The usage of mouse models has been one of the solutions exploited for tackling with these difficulties. Here, we review three different approaches using mice for identifying genes modulating fertility in mammals: gene invalidation, positional cloning and in vitro mutagenesis. These three approaches exploit specific characteristics of the mouse, such as the possibility of controlling precisely the environment, an excellent genetic characterization and the existence of genomic and molecular tools equalled only in humans. Many indications suggest that at least some of the results obtained in mice could be easily transposed to the species of interest. PMID- 22444173 TI - Differential adaptations during growth spurt and in young adult rat muscles. AB - During the post-weaning growth and maturation period (25/90 days after birth), rat limb muscles are submitted to specific adaptations. Our aim was to characterize the mechanical properties of two muscles that are opposite in terms of fibre-type distribution, the soleus and the extensor digitorum longus (EDL) muscles of male Wistar rats. Results showed a fast-to-slow fibre-type transition in soleus while no modification in fibre-type distribution was observed in EDL. A growth-induced increase in muscle force was observed. Soleus underwent an increase in twitch kinetics, but EDL showed no modification. Resistance to fatigue was higher in 90-day-old soleus but not modified in the EDL. Surprisingly, analysis of maximal shortening velocity showed a decrease in both soleus and EDL. Finally, tension/extension curves indicated a growth-induced increase in series elastic stiffness in the two muscles. These results suggest that during this growth period, skeletal muscles are submitted to differential adaptations. Moreover, whereas adaptation of biomechanical properties observed can be explained partly by an adaptation of fibre profile in soleus, this is not the case for EDL. It is suggested that changes in muscle architecture, which are often disregarded, could explain some variations in mechanical properties, especially when muscles undergo an increase in both mass and length. PMID- 22444174 TI - Nutrition level and season of birth do not modify puberty of Payoya goat kids. AB - This study analysed the effect of level of nutrition and date of birth (age) on the onset of puberty in Payoya she-kids born in autumn (November) or in winter (February). Two experiments were conducted to examine pubertal events at the onset of puberty. For each date of birth (age), two experimental groups were used, differing on the level of nutrition. Groups were balanced for live weight (LW) and body condition score (BCS). For the first experiment (goat kids born in autumn), 27 Payoya she-kids were used: high-nutrition group (H1, n = 13) and control group (C1, n = 14). For the second experiment (goat kids born in winter), 25 Payoya she-kids were used: high-nutrition group (H2, n = 13) and control group (C2, n = 12). In both experiments, the level of feeding was adjusted weekly according to LW so that the animals would gain about 50 and 100 g per day for C and H groups, respectively. Oestrus was tested daily using young aproned bucks. Ovulation rate was assessed by laparoscopy 7 days after identification of oestrus. Plasma samples were obtained weekly for progesterone assay. LW and BCS were recorded weekly. No effect of nutrition level or birth date (Experiment 1 v. 2) on the date of the first ovarian activity or the first detected oestrus was observed. No effect of nutrition on LW or BCS at the first detected oestrus was observed. Birth date influenced significantly the LW of the animals at the onset of ovarian activity or first oestrus (P < 0.001). Irregular sexual activity was frequently observed before the first oestrus (74.7% and 48.0% of the first reproductive activity was irregular for Experiments 1 and 2, respectively). No effect of nutrition level or birth date on ovulation rate was observed. Ovulation rate at first oestrus was influenced by LW in November-born goat kids (1.06 +/- 0.06 v. 1.67 +/- 0.21 corpora lutea for LW < 30 and 30 kg, respectively, P < 0.01). These results demonstrate that the age at puberty was very dependent upon the season of birth in Payoya goat kids, and that there could be some benefit in breeding November-born goat kids at a higher LW to obtain a higher prolificacy at the first kidding as a consequence of a higher ovulation rate at puberty. PMID- 22444175 TI - Gait assessment in dairy cattle. AB - Lameness is one of the most important dairy cow welfare issues and has inspired a growing body of literature on gait assessment. Validation studies have shown that several methods of gait assessment are able to successfully distinguish cows with and without painful pathologies. While subjective methods provide an immediate, on-site assessment and require no technical equipment, they show variation in observer reliability. On the other hand, objective methods of gait assessment provide accurate and reliable data, but typically require sophisticated technology, limiting their use on farms. In this critical review, we evaluate gait assessment methods, discuss the reliability and validity of measures used to date, and point to areas where new research is needed. We show how gait can be affected by hoof and leg pathologies, treatment of these ailments and the pain associated with lameness. We also discuss how cow (e.g. conformation, size and udder fill) and environmental features (e.g. flooring) contribute to variation in the way cows walk. An understanding of all these factors is important to avoid misclassifying of cows and confounding comparisons between herds. PMID- 22444176 TI - Effect of genetic group and feed system on locomotion score, clinical lameness and hoof disorders of pasture-based Holstein-Friesian cows. AB - The aim of the present study was to determine the effect of the genetic group of the Holstein-Friesian (HF) and pasture-based feeding system (3 * 2 factorial arrangement) on locomotion score (six gait aspects scored from one to five), clinical lameness and hoof disorders within a seasonal calving milk production system. The three genetic groups compared had an average Economic Breeding Index (EBI) value of 40, 70 and 80: representing the Irish national average genetic merit (LOW-NA), high EBI genetic merit of North American ancestry (HIGH-NA) and high EBI genetic merit of New Zealand ancestry (HIGH-NZ), respectively. Two feed systems were compared: a high grass allowance, low-concentrate system typical of spring-calving herds in Ireland (control) and a high-concentrate system. Data from 126 cows collected across a complete lactation period were analysed using generalised estimating equations and survival analysis. Genetic group of HF had a significant effect on locomotion score, clinical lameness and hoof disorders. Higher EBI cows (HIGH-NA and HIGH-NZ) had lower hazard of poor locomotion score in some gait aspects (e.g. spine curvature) and lower odds of clinical lameness in the first 200 days post-calving (Odds ratios 0.08 and 0.24, respectively, relative to the LOW-NA) and some hoof disorders (e.g. traumatic lesions) compared with LOW-NA cows. The high-concentrate feed system showed a higher incidence and severity of digital dermatitis (P < 0.01). Thus, high EBI cows have better locomotion, fewer cases of clinical lameness and less-severe hoof disorders (i.e. digital dermatitis, white line disease and traumatic lesions) than low EBI cows. These findings have important implications for cow welfare and productivity. PMID- 22444177 TI - Effect of age at weaning on the physiological stress response and temperament of two beef cattle breeds. AB - The study was conducted to evaluate the effect of age at weaning and breed on the stress response of calves to weaning and their temperament. At calving, 14 Parda de Montana calves and 14 Pirenaica calves were randomly assigned to either early weaning (at 90 days) or traditional weaning (at 150 days) treatment. During nursing, calves were allowed to suckle their dams twice a day for 30 min. After weaning, calves were placed in an adjacent barn without access to their dams, where they remained for 7 days. On day 8 after weaning, they were transported to a feedlot where they received an intensive diet. Blood samples were taken 168 h before weaning (baseline) and 6, 24, 48 and 168 h after weaning for cortisol, fibrinogen and haematology analyses, and temperament was measured 90 and 180 days after weaning with the flight speed test. Cortisol concentration increased after weaning, irrespective of age at weaning. Early-weaned calves had a lower fibrinogen baseline and a greater increase in fibrinogen concentrations 48 h after weaning than traditionally weaned calves. Moreover, fibrinogen concentration returned to baseline values 168 h after weaning in traditionally weaned calves, whereas it remained high in early-weaned calves. Concerning breed effects, Pirenaica calves had higher cortisol concentration and fibrinogen increments after weaning than Parda de Montana calves. Slight alterations occurred after weaning in haematology, but all parameters returned to baseline values 168 h after weaning, with no significant effects of age at weaning or breed. Despite the absence of clinical signs, early-weaned calves of both breeds suffered marginal anaemia, according to haemoglobin values. Regardless of age at weaning, Pirenaica calves had greater reactivity to human presence than Parda de Montana calves, according to their higher flight speed values measured. Finally, early-weaned calves were lighter than traditionally weaned calves at weaning, but had similar weight gains in the feedlot. Consequently, they needed an additional 40 days to reach the target weight, irrespective of breed. Therefore, age at weaning had no major effects on the stress response to weaning or temperament, but early weaning increased the length of the feedlot period. On the other hand, Pirenaica calves were more reactive than Parda de Montana calves to the stress of weaning and human presence. PMID- 22444178 TI - Behavioural, endocrine and immune responses to repeated social stress in pregnant gilts. AB - Pregnant sows are exposed to various stressors in intensive pig husbandry that may have negative consequences on their health, reproductive performances and welfare. Social stress is one of these challenges, because gestating sows have to be housed in groups according to EU guidelines (2001/88/CE). The purpose of this study was to determine the consequences of repeated social stress in pregnant female pigs on their behavioural, endocrine and immunological responses and on pregnancy outcome. Pregnant gilts were submitted to a repeated social stress procedure induced by housing unfamiliar gilts in pairs changed twice a week between days 77 and 105 of gestation (S group, n = 18). Control gilts were housed in stable pairs during the same period (C group, n = 18). Agonistic behaviour was observed during the first 3 h after each grouping. Skin lesions were numbered 2 h after each grouping. Salivary cortisol was measured before and repeatedly during the 4 weeks of grouping. Gilts were immunized against keyhole limpet haemocyanin (KLH) on days 81 and 95 of gestation. Immunoglobulins G against KLH, proliferative responses to concanavalin A, lipopolysaccharide, pokeweed mitogen and KLH and peripheral blood leukocyte numbers were evaluated 1 week before the first grouping and 3 days after the last one. Agonistic interactions and skin lesions were observed in S gilts at each grouping, although there was a decline between the first and the last grouping (P < 0.05). The repeated social stress induced a sustained endocrine response as shown by elevated salivary cortisol levels from 1 to 48 h after grouping in S gilts compared to C gilts. The cellular as well as the humoral immunity and the leukocyte numbers were not influenced by social stress. Gestation length tended to be shorter in S gilts (P = 0.09), but litter size, piglet weight or mortality at birth were not affected. Variability of the response of S gilts to groupings was partly explained by their average success value determined according to the outcome (defeat or win) of all the groupings. In conclusion, our study demonstrates that the application of repeated social stress to pregnant gilts during the last third of their gestation repeatedly activates their hypothalamo-pituitary-adrenal axis but does not impair their immune function and pregnancy outcome. PMID- 22444179 TI - Relationship between the behaviour of sows at 6 months old and the behaviour and performance at farrowing. AB - Piglet crushing remains a major problem in pig production. Reduced crushing might be obtained through genetic selection on sow behavioural traits. The aim of the study was to assess the relationship between behavioural responses at 6 months of age, around farrowing, and sows' reproductive performance including crushing levels. At 6 months of age, behavioural responses of 75 nulliparous sows were observed both during behavioural tests to human presence and to the presence of a novel object in their home pen, and their responses when placed in a weighing device. At first farrowing, nervousness of the sows was observed when placed in the farrowing crate 1 week before and the day of farrowing, as well as their fear responses when approached by a human from behind or at the front of the farrowing crate. At 6 months of age, escape from a human tended to be correlated with the reactivity in the weighing device (rs = 0.21, P = 0.09). Around first farrowing, the withdrawal reaction when a human approached at the front was correlated with the fear response when approached from behind and the nervousness of the sow in the crate (rs = 0.29, P < 0.05; rs = 0.37, P < 0.01). The fear response when approached from behind was correlated with nervousness in the crate and around farrowing (rs = 0.70, P < 0.001; rs = 0.25, P < 0.05), and nervousness in the crate was significantly correlated with the nervousness around farrowing (rs = 0.34, P < 0.01). The escape from a human at 6 months was correlated with withdrawal when approached from the front before farrowing (rs = 0.38, P < 0.01) and with nervousness of the sow in the crate (rs = 0.24, P < 0.05). The number of piglets crushed at first farrowing was correlated with the latency to approach a novel object at 6 months and nervousness around farrowing (rs = -0.27, P < 0.05; rs = 0.28, P < 0.05), and tended to be correlated with the escape behaviour from human at 6 months and withdrawal away from human presence before farrowing (rs = 0.21, P = 0.09; rs = 0.22, P = 0.08). These results suggest that behavioural responses to humans and during management practices of nulliparous sows at 6 months of age are, to some extent, related with their behaviour around farrowing and crushing levels of piglets at farrowing. PMID- 22444180 TI - Diet learning through post-ingestive consequences in sheep: the case of starch and casein variously combined in the same foods. AB - Ruminants generally succeed in selecting an appropriate diet relative to their nutrient requirements, and macronutrients such as energy and protein are considered as playing a primary role in their food preferences. Diet learning through post-ingestive consequences, evidenced by many studies that involved situations with simple discrimination tasks, may explain this ability to select a suitable diet. However, in more complex feeding environments where animals are faced with many plants varying both in their energy and protein contents, the extent to which such a mechanism operates is still uncertain. Our objective was to investigate a more complex feeding situation than previously tested and to determine whether lambs were able to associate three forages with both energy based and protein-based post-ingestive consequences of various intensities. The doses of starch and casein used to elicit these post-ingestive consequences were chosen so that the apparent metabolisable energy and crude protein values of hays were within the range found in plants normally encountered under field conditions. We applied five treatments: EmPm, EhPm, EmPh, EhPh, where medium (m) or high (h) levels of nutrients (E = energy and P = protein) were associated with different hays, and E0N0 where no stimuli were associated. Each animal experienced only three treatments: E0N0-EmPm-EhPm or E0N0-EmPh-EhPh, each one being associated with one hay during conditioning, on the basis of one treatment per day over three consecutive days. Animals then had a choice between the hay associated with E0N0 and one of the two others, successively on the two following days. This procedure was repeated through five 1-week-long periods, and applied to two groups of lambs (n = 12) maintained at feeding levels sufficient for maintenance or for a 150 g/day growth rate. This experiment was complemented by a methodological trial that aimed to estimate the doses of starch and casein eliciting preferences and a post-trial that aimed to evaluate the effect of our treatments on sheep ruminal environment. The methodological trial showed that lambs perceived the stimuli and the doses, and the post-trial showed that treatments affected the ruminal environment. In the main experiment, the lambs preferred the rewarded hays but did not discriminate in their choices the variation of post-ingestive consequences due to energy and protein. This suggests that in situations closer to reality where animals experience many foods varying in nutrient contents, the learning process may be impaired. The lambs do not seem to have strictly relied on it for shaping their diet choices. PMID- 22444181 TI - Effects of shearing at housing, grass silage feed value and extended grazing herbage allowance on ewe and subsequent lamb performance. AB - The study involved 120 crossbred ewes (sixty 1.5 years old animals and sixty 2.5 years old animals; initial liveweight 67.6 kg, condition score 3.7), that were mated in October. They were assigned to six treatments (two shearing treatments (shorn and unshorn) * two silage feed values (low and medium) and two extended grazed herbage allowances (1.0 and 1.8 kg dry matter (DM)/day)) designed to evaluate the effects of shearing at housing, grass silage feed value and extended grazed herbage allowance on their performance and the performance of their progeny. Swards, which had silage harvested on 6 September, received fertiliser N (34 kg/ha) for extended (deferred) grazing between 19 December and lambing in mid March. The herbage was allocated at DM allowances of 1.0 or 1.8 kg/ewe daily until 1 February. For the final 6 weeks of pregnancy, daily herbage DM allowances were 1.5, 1.6, 2.0, 2.0 and 2.0 kg for weeks 6, 5, 4, 3 and 2 to parturition, respectively. Two grass silages (low and medium feed value) were offered from housing on 19 December to lambing in mid-March. At housing, half the ewes were shorn whilst the remainder remained unshorn. Each ewe received 23.4 kg concentrate prior to lambing. For the extended-grazed herbage and the low and medium feed-value silages, DM concentrations were 132, 225 and 265 g/kg, and metabolisable energy (ME) concentrations were 10.0, 10.0 and 10.7 MJ/kg DM, respectively. Treatment did not alter (P > 0.05) litter size or number reared. Grass silage feed value did not significantly alter silage DM intake, or ewe and subsequent lamb performance. Increasing herbage allowance in mid-pregnancy decreased herbage utilisation (P < 0.05) and increased herbage intake (P < 0.05). Shearing increased silage intake (P < 0.05), lamb birth weight (P < 0.01) and tended to increase lamb weaning weight (P = 0.07). Relative to the housed shorn ewes, extended grazing did not alter (P > 0.05) ewe or subsequent lamb performance. It is concluded that shearing ewes at housing increased lamb birth weight due to increased silage intake probably associated with cold stress immediately post shearing and reduced heat stress in late pregnancy. Based on differences in lamb weight at weaning 0.8 kg of grass silage DM intake had the same feed value as a daily extended herbage DM allowance of 1.8 kg per ewe throughout the study. Neither silage feed value nor herbage allowance in mid pregnancy affected lamb birth weight or subsequent growth rate. PMID- 22444182 TI - Trajectories of evolution and drivers of change in European mountain cattle farming systems. AB - In the last few decades, significant changes in livestock farming systems and land use were observed in European mountain areas with large implications for the sustainability of grazing agro-ecosystems. System dynamic studies become essential to understand these changes, identify the drivers involved and trying to anticipate what might happen in the future. The objectives of this study were as follows: (i) to analyse the main recent changes that occurred in mountain cattle farming in the Spanish Pyrenees; (ii) to typify diverse trajectories of evolution of these systems; and (iii) to establish drivers of change that might help understand the evolution of mountain agriculture. A constant sample of mountain cattle farms was analysed for the period 1990 to 2004. In total, 30% of farms have disappeared during this time interval. For the remaining farms, the most important general changes observed were as follows: increment of size; change of productive orientation from mixed beef-dairy to pure beef production; extensification of grazing management; reduction of family labour and increase of pluriactivity; reduction of unitary variable costs; and increase of labour productivity. After the elimination of common temporal effects between dates, multivariate techniques allowed for the identification of three patterns and six specific trajectories of evolution that are profiled in the text. Relationships between the patterns of evolution and other variables referring the farm, the household and the socio-economic environment were identified as drivers of change: (i) the specific location of the farm in relation to the capital village of the municipality and the evolution other sectors of the economy, in particular tourism; (ii) the size of the family labour, presence of successors and degree of dynamism of the farmer; and (iii) the initial orientation of production. PMID- 22444183 TI - Variability of selected trace elements of different meat cuts determined by ICP MS and DRC-ICPMS. AB - The aim of this study was to determine the levels of cadmium, lead, iron, zinc, selenium, manganese, copper and molybdenum in different cuts of beef, pork, lamb, chicken and foal collected from supermarkets and butcheries in Switzerland. The concentrations of manganese, copper, molybdenum, zinc, iron, selenium, cadmium and lead were determined by inductively coupled plasma mass spectrometry (ICP-MS) after microwave digestion. Mean values and their respective coefficients of variation were calculated from the measured concentrations. The concentrations found for cadmium and lead ranged from 0.6 to 3.9 MUg/100 g and 1.0 to 2.1 MUg/100 g, respectively. Concentrations ranged between 0.5 and 3.3 mg/100 g for iron, 0.7 and 5.1 mg/100 g for zinc, 9 and 44 MUg/100 g for selenium, 3.1 and 16.7 MUg/100 g for manganese, 0.3 and 132 MUg/100 g for copper and 0.9 and 3.2 MUg/100 g for molybdenum. Differences found for the concentrations in meat from different species as well as between the individual meat cuts were notable for iron, zinc, selenium and copper. Manganese concentrations were found to vary unsystematically within muscles and species. Molybdenum concentrations were higher in chicken meat in comparison with the mammalian meats. The highest coefficients of variation were found for manganese (13% to 142%) and copper (13% to 224%), while the lowest was found for zinc (4% to 45%). In conclusion, in order to provide an accurate overview and to be able to calculate reliable dietary intakes, it is important to include the variability in food composition data. PMID- 22444184 TI - Effect or ractopamine on growth and body composition of pigs during compensatory growth. AB - The purpose of this study was to measure the growth and body composition of pigs during normal or compensatory growth from 60 to 100 kg, without (cont) or with ractopamine (rac) supplementation (20 mg/kg of diet). Thirty-four pigs were scanned by dual X-ray absorptiometry (DXA) for body composition analysis at a starting weight of 61.4 +/- 0.3 kg and at a final weight of 100.4 +/- 0.5 kg. Half the pigs were fed ad libitum throughout (8 cont and 9 rac). The other half were fed at maintenance for 8 weeks and then scanned again by DXA. Following the maintenance feeding, the pigs were fed ad libitum (9 cont and 8 rac) to the final weight. Compensatory growth resulted in a 30% increase in the rate of weight gain (1.23 v. 0.94 kg/day, P < 0.05), including a 44% increase in the rate of lean tissue deposition (0.90 v. 0.62 kg/day, P < 0.05), but no change in the rate of fat deposition (0.31 v. 0.30 kg/day, P > 0.05). Feeding rac resulted in a 13% increase in the rate of weight gain (1.15 v. 1.02 kg/day, P < 0.05), consisting of a 29% increase in the rate of lean tissue deposition (0.86 v. 0.67 kg/day, P < 0.05) and an 18% reduction in the rate of fat deposition (0.27 v. 0.33 kg/day, P < 0.05). The effects of ractopamine on the rates of fat and lean tissue deposition were similar for pigs continuously fed ad libitum and those experiencing compensatory growth. Both compensatory growth and the addition of ractopamine to the diet resulted in an improvement in efficiency of protein deposition; however, ractopamine also resulted in a reduction in the efficiency of energy deposition. For both growth rate and lean tissue deposition, there was an additive effect for ractopamine and compensatory growth. Thus, feeding ractopamine will enhance the growth and body composition during compensatory growth in swine. PMID- 22444185 TI - What are reasonable expectations? Healthcare student perceptions of their programmes in the North West of England. AB - BACKGROUND: Concerns about current levels of attrition from some healthcare programmes have emphasised the need to gain a greater insight into students' expectations and experiences. OBJECTIVES: The aim of this study was to determine how students in the North West of England perceived their studies and to identify the factors that could contribute to students' dissatisfaction. DESIGN: A mixed methods sequential exploratory study. SETTINGS: Nine universities in the North West of England. METHODS: Phase one used narrative interviews with a purposive sample of 24 students to investigate their expectations and experiences. Data from these interviews were analysed using a thematic framework and direct quotes from key themes were incorporated into online survey for phase 2. Survey respondents were asked to rate their agreement to statements on a four-point Likert-type response format. There was also an opportunity to leave comments through open questions relating to each theme. RESULTS: A total of 1080 respondents completed the online survey in phase 2. The majority of students reported positive experiences of their course. There was strong agreement in the importance of the role of the personal tutor and of a supportive placement mentor. Some students indicated that the workload and academic level were a shock at first. Students identified difficulties around the cost of placement travel and the impact of placements on family life. Financial hardship was a frequently cited issue that students attributed to thoughts of discontinuation. CONCLUSIONS: Most students had positive learning experiences which meet their expectations. Students who have unmet expectations report poor placement experiences, lack of support, unexpectedly high workloads and financial difficulties. Clear guidance on the role of personal tutor and placement mentor is recommended. PMID- 22444186 TI - Different underlying pain mechanisms despite identical pain characteristics: a case report of a patient with spinal cord injury. AB - Pain following spinal cord injury has been classified as nociceptive (musculoskeletal, visceral) or neuropathic (above, at, below level). There is no clear relation between the etiology and reported symptoms. Thus, due to different underlying mechanisms, the treatment is often ineffective. We report on a patient with spinal cord injury with neurological level of injury at T8 suffering from bilateral burning and prickling pain in the T9-11 dermatomes bilaterally (at level pain), as well as diffusely in both legs from below the torso (below-level pain), accompanied by musculoskeletal low back pain. Bilateral comparison of quantitative sensory testing (QST) and skin biopsy revealed completely different findings in the dermatome T9 despite identical at-level pain characteristics. On the right side, QST revealed a normal sensory profile; the intraepidermal nerve fiber density (IENFD) was reduced, but not as severe as the contralateral side. On the left side there was a severe sensory loss with a stronger reduction of the IENDF, similar to the areas below the neurological level. These findings were significantly related to the treatment results. Pregabalin induced unilateral pain relief only in the area with remaining sensory function, whereas the left sided at-level pain was unchanged. Thus, 2 different underlying mechanisms leading to bilaterally neuropathic pain with identical symptoms and with different treatment success were demonstrated in a single patient. The at-level pain in areas with remaining sensory function despite IENFD reduction could be relieved by pregabalin. Thus, in an individual case, QST may be helpful to better understand pain-generating mechanisms and to initiate successful treatment. PMID- 22444187 TI - Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-induced analgesia. AB - The concurrent rise of undertreated pain and opiate abuse poses a unique challenge to physicians and researchers alike. A focal, noninvasive form of brain stimulation called repetitive transcranial magnetic stimulation (rTMS) has been shown to produce acute and chronic analgesic effects when applied to dorsolateral prefrontal cortex (DLPFC), but the anatomical and pharmacological mechanisms by which prefrontal rTMS induces analgesia remain unclear. Data suggest that DLPFC mediates top-down analgesia via gain modulation of the supraspinal opioidergic circuit. This potential pathway might explain how prefrontal rTMS reduces pain. The purpose of this sham-controlled, double-blind, crossover study was to determine whether left DLPFC rTMS-induced analgesia was sensitive to MU-opioid blockade. Twenty-four healthy volunteers were randomized to receive real or sham TMS after either intravenous saline or naloxone pretreatment. Acute hot and cold pain via quantitative sensory testing and hot allodynia via block testing on capsaicin-treated skin were assessed at baseline and at 0, 20, and 40 minutes after TMS treatment. When compared to sham, real rTMS reduced hot pain and hot allodynia. Naloxone pretreatment significantly reduced the analgesic effects of real rTMS. These results demonstrate that left DLPFC rTMS-induced analgesia requires opioid activity and suggest that rTMS drives endogenous opioidergic pain relief in the human brain. Further studies with chronic dosing regimens of drugs that block or augment the actions of opiates are needed to determine whether TMS can augment opiates in chronic or postoperative pain management. PMID- 22444188 TI - Pain sensitivity and opioid analgesia: a pharmacogenomic twin study. AB - Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the MU-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype. PMID- 22444189 TI - Psychological symptoms in children of parents with chronic pain-the HUNT study. AB - The aim of the present study was to investigate the associations between parental chronic pain and anxiety, depression, and conduct problems in adolescents. The current study was based on cross-sectional surveys performed during 2006 to 2008 from the Nord Trondelag Health Study (HUNT 3 and Young-HUNT 3). The sample consisted of 3227 adolescents aged 13 to 18 years for whom information was available on parental chronic pain and health statuses. Separate analyses were conducted for girls and boys. The results indicated that if both parents experienced chronic pain, there was an increased risk of symptoms of anxiety and depression in girls (OR=2.17, CI=1.36-3.45, P=.001) and boys (OR=2.33, CI=1.17 4.63, P=.016) compared with children for whom neither parent had chronic pain. Girls had an increased risk of conduct problems in school if their mothers had chronic pain (OR=1.33, CI=1.02-1.74, P=.034). These results remained after adjusting for the possible effects of confounding factors and parental mental health. The results suggest that the presence of both maternal and paternal chronic pain is a high risk factor for internalizing symptoms in both girls and boys. The present study offers insights that should prove useful in clinical work and further large-scale research. PMID- 22444190 TI - A 2'-deoxy-2'-fluoro-2'-C-methyl uridine cyclopentyl carbocyclic analog and its phosphoramidate prodrug as inhibitors of HCV NS5B polymerase. AB - The 2 '-deoxy-2 '-fluoro-2 '-C-methyluridine nucleotide prodrug, PSI-7851 and its single diastereomer PSI-7977 have displayed potent antiviral activity against hepatitis C virus in clinical trials, and PSI-7977 is currently in Phase III studies. As part of our SAR study of the 2 '-deoxy-2 '-fluoro-2 '- C-methyl class of nucleosides, we prepared the cyclopentyl carbocyclic uridine analog 11 and its phosphoramidate prodrug 15. Both 11 and 15 were shown not to inhibit HCV replication. This lack of activity might be attributed to the inability of the monophosphate to be converted to the corresponding diphosphate or triphosphate or the inactivity of triphosphate of 11 as an inhibitor of the polymerase. PMID- 22444191 TI - Synthesis and biological evaluation of (3'S)-3'-deoxy-3'-fluoro-3'-C ethynylcytidine. AB - The novel pyrimidine nucleoside, (3'S)-3'-deoxy-3'-fluoro-3'-C-ethynylcytidine (1) was synthesized from cytidine in seven steps. The key step in the synthesis was the introduction of the tertiary fluorine at the 3'-position. Compound 1 was evaluated in vitro against several RNA viruses. PMID- 22444192 TI - Design, synthesis, antiviral, and cytotoxic evaluation of novel phosphonylated 1,2,3-triazoles as acyclic nucleotide analogues. AB - The 1,3-dipolar cycloaddition of diethyl 2-azidoethyl-, 3-azidopropyl-, 2-azido-1 hydroxyethyl-, 3-azido-2-hydroxypropylphosphonates with selected N-propargyl nucleobases gave a series of the phosphonylated 1,2,3-triazole acyclonucleosides in which the phosphonate residue and nucleobases were linked by three- and four carbon chains. Under standard conditions (TMSBr, ethanol), all synthesized O,O diethylphosphonates were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses. Unfortunately, no antiviral activity was observed at 100 MUM. PMID- 22444193 TI - Modified synthesis of 3'-O-TBDPS-protected furanoid glycal. AB - Thermolytic cleavage of 3'-OH protected thymidine is the most common method of preparing furanoid glycals. We have observed that glycosidic bond cleavage is more facile when the 5'-OH of thymidine was also protected with a silyl group. Addition of trimethylsilyl chloride facilitated cleavage of the glycosidic bond; thus, both modifications are required for the formation of the furanoid glycal. Investigations into the selective deprotection of 5'-silyl versus 3'-silyl and subsequent glycosidic bond cleavage are reported herein. PMID- 22444194 TI - Convenient and efficient syntheses of oligodeoxyribonucleotides containing O(6) (carboxymethyl)guanine and O(6)-(4-oxo-4-(3-pyridyl)butyl)guanine. AB - O(6)-(carboxymethyl)guanine (O(6)-CMG) and O(6)-(4-oxo-4-(3-pyridyl)butyl)guanine (O(6)-pobG) are toxic lesions formed in DNA following exposure to alkylating agents. O(6)-CMG results from exposure to nitrosated glycine or nitrosated bile acid conjugates and may be associated with diets rich in red meat. O(6)-pobG lesions are derived from alkylating agents found in tobacco smoke. Efficient syntheses of oligodeoxyribonucleotides (ODNs) containing O(6)-CMG and O(6)-pobG are described that involve nucleophilic displacement by the appropriate alcohol on a common synthetic ODN containing the reactive base 2-amino-6 methylsulfonylpurine. ODNs containing O(6)-pobG and O (6)-CMG were found to be good substrates for the S. pombe alkyltransferase-like protein Atl1. PMID- 22444195 TI - Ten paths to the discovery of antivirally active nucleoside and nucleotide analogues. AB - Nucleoside and nucleotide analogues have proven to be an effective approach toward the development of antiviral compounds. This approach has so far yielded a number of clinically useful antiviral drugs, such as BVDU (brivudin), (val)aciclovir, cidofovir, adefovir dipivoxil, and tenofovir disoproxil fumarate, and current perspectives justify the further development of other nucleoside analogues, such as FV-100, and that of the DAPy-based nucleotide analogues, the 5 aza analogue of cidofovir, and prodrug derivatives thereof. PMID- 22444196 TI - Effect of lovastatin therapy and withdrawal on serum uric acid level in people with type 2 diabetic nephropathy. AB - BACKGROUND/AIM: A high uric acid (UA) level is demonstrated as a major risk factor of nephropathy and cardiovascular events in people with type 2 diabetes (T2D). This study aimed to evaluate the lovastatin effect on serum UA levels in people with type 2 diabetic nephropathy (T2DN). METHODS: Thirty patients completed the study course, out of 38 adult male patients with T2DN who were initially enrolled. Lovastatin, 20 mg/d, was administered for 90 days. Afterwards, lovastatin was withdrawn for the next 30 days. Blood samples were obtained at baseline, after 45 and 90 days of intervention, and 30 days after the withdrawal of lovastatin. The serum level of UA was assessed by the uricase/PAP method. The lipid profile and high-sensitivity C-reactive protein (hs-CRP) were determined using commercial reagents and the ELISA method. RESULTS: After 90 days of lovastatin intervention, cholesterol (Chol) and low-density lipoprotein cholesterol (LDL-C) levels significantly decreased and the high-density lipoprotein cholesterol (HDL-C) level increased significantly, despite the unchanged level of triglyceride (TG). After withdrawal, Chol, TG, and LDL-C levels were significantly increased, without any change in the HDL-C level. The baseline serum UA level was 5.94 +/- 2.02 mg/dL and not changed after the intervention (5.95 +/- 2.21 mg/dL; p = 0.969) and withdrawal period (5.80 +/- 1.51 mg/dL; p = 0.647). The changes of serum UA levels were not correlated with the changes of serum hs-CRP levels, both after intervention and withdrawal (p = 0.963 & p = 0.835). CONCLUSIONS: Lovastatin does not have any effect on the serum UA level in people with T2DN. There is no correlation between the anti-lipidemic and anti-inflammatory effects of lovastatin and its effect on serum UA. PMID- 22444197 TI - Synthesis, molecular conformation and activity against herpes simplex virus of (E)-5-(2-bromovinyl)-2'-deoxycytidine analogs. AB - Analogs of (E)-5-(2-bromovinyl)-2'-deoxycytidine (BrVdCyd) (1) by substitution at N(4) were synthesized to impart resistance against deamination. The anti-HSV-1 activity and solution conformation of these analogs were determined. N(4)-Acetyl BrVdCyd (2) was a potent inhibitor of HSV-1 replication whereas N(4)-propanoyl BrVdCyd (3) had good activity and N(4)-Butanoyl-BrVdCyd (4) had only low activity against HSV-1 replication. N(4)-Methyl-BrVdCyd (5) was devoid of activity against HSV-1. PMID- 22444198 TI - Analysis of human DNA-arginine photoadduct modified with peroxynitrite. AB - The aim of the study is the biochemical characterization of human DNA modified with arginine and peroxynitrite. In the present study, DNA was isolated from human blood cells and its adduct was formed with one of the amino acid, arginine. The DNA-arginine adduct was then modified with peroxynitrite, a reactive nitrogen species. The modified DNA adduct was characterized by ultraviolet (UV) absorption spectroscopy, thermal melting profile, and electrophoresis studies. UV spectroscopic analysis of the photoadduct showed hyperchromicity, indicating the formation of single-strand breaks and photomodification. Thermal denaturation studies of DNA-arginine adduct and peroxynitrite-modified adduct showed a decrease in the temperature (T(m)) value by 4.5 degrees C and an increase in the T(m) of 8 degrees C, respectively. Peroxynitrite modification is evident by an increase in the T(m) value and a change in the migration pattern of native and modified photoadducts on agarose gel electrophoresis. The DNA-arginine and peroxynitrite-modified photoadducts could have important implications in various pathophysiological and immunopathological conditions. PMID- 22444199 TI - Synthesis and characterization of colloidal fluorescent silver nanoclusters. AB - Ultrasmall water-soluble silver nanoclusters are synthesized, and their properties are investigated. The silver nanoclusters have high colloidal stability and show fluorescence in the red. This demonstrates that like gold nanoclusters also silver nanoclusters can be fluorescent. PMID- 22444200 TI - Chitosan-based gastroretentive floating drug delivery technology: an updated review. AB - INTRODUCTION: Gastroretentive floating drug delivery systems have emerged as efficient approaches for enhancing the bioavailability and controlled delivery of various therapeutic agents. Significant advancements exploiting chitosan have been made worldwide, in order to investigate these systems according to patient requirements, both in terms of therapeutic efficacy as well as patient compliance. Such systems precisely control the release rate of the target drug to a specific site, which facilitates an enormous impact on health care. AREAS COVERED: Different novel strategies have been undertaken for the development of various gastric floating dosage forms utilizing chitosan as a promising excipient. The present paper is an earnest attempt to provide new insights on various physicochemical and biological characteristics of chitosan, along with its potential applications in a wide array of biomedical approaches. Numerous and significant research findings in the vistas of chitosan-based gastroretentive floating drug delivery technology are also discussed. EXPERT OPINION: Chitosan has been considered as a unique and efficacious agent possessing a myriad spectrum of desired characteristics. It is emphasized that recent scientific advancements in the use of this excipient as a carrier will yield new generation gastroretentive drug delivery systems, with better pharmacotherapeutic interventions. Further studies are required to unveil the hidden beneficial properties of chitosan and its derivatives, to obtain newer delivery systems which may hold tremendous prospects in the near future. PMID- 22444201 TI - Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. AB - BACKGROUND: Childhood abuse alters hypothalamic-pituitary-adrenal (HPA) function and increases the risk of suicide. Hippocampal glucocorticoid receptor (GR) activation regulates HPA activity, and human GR expression (hGR) is reduced in the hippocampus of suicide completers with a history of childhood abuse compared with controls. The abuse-related decrease in hGR expression associates with increased DNA methylation of the promoter of the hGR(1F) variant in the hippocampus. METHODS: In this study, we investigated the expression and methylation levels of other hGR splice variants in the hippocampus and anterior cingulate gyrus in suicide completers with and without a history of childhood abuse and in controls. Expression levels were quantified using quantitative reverse-transcriptase polymerase chain reaction and promoter methylation was assessed by pyrosequencing. RESULTS: In the hippocampus, the expression of total hGR and variants 1(B), 1(C), and 1(H) was decreased in suicide completers with histories of abuse compared with suicides with no histories of abuse and with control subjects. In the anterior cingulate gyrus, however, no group differences in hGR total or variant expression were found. Site-specific methylation in hGR1(B) and 1(C) promoter sequences were negatively correlated with total hGR messenger RNA, as well as with hGR1(B) and 1(C) expression. Luciferase assay showed that methylation in hGR promoter decreases transcriptional activity. In contrast, total and site-specific methylation in the hGR1(H) promoter was positively correlated with total hGR messenger RNA and hGR1(H) expression. CONCLUSION: These findings suggest that early-life events alter the expression of several hGR variants in the hippocampus of suicide completers through effects on promoter DNA methylation. PMID- 22444203 TI - Editorial: first issue. PMID- 22444202 TI - Gastric bypass surgery attenuates ethanol consumption in ethanol-preferring rats. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective weight loss strategy employed to treat obesity and associated complications. Importantly, the RYGB procedure has been reported to attenuate reward-related consummatory behaviors. The present work examined the hypothesis that RYGB surgery attenuates ethanol intake and reward in the context of frequent ethanol consumption. METHODS: To do this, self-report of ethanol intake was examined in human bariatric patients (n = 6165) before and following the RYGB procedure. In addition, we utilized a rodent model of RYGB and examined ethanol consumption and ethanol reward in male ethanol-preferring (P) rats, which are selectively bred to consume large volumes of ethanol. RESULTS: Patients that reported frequent consumption of ethanol before RYGB reported decreased consumption following RYGB surgery. Moreover, the RYGB procedure decreased ethanol intake and the reinforcing properties of ethanol in P rats. Notably, the attenuating effect of RYGB surgery on ethanol consumption was associated with ethanol-induced increases in the gut hormone glucagon-like peptide-1 (GLP-1). Pharmacologic administration of GLP-1 agonists attenuated ethanol consumption in sham P rats. In addition, pharmacologic replacement of the gut hormone ghrelin restored drinking behavior in P rats following RYGB. CONCLUSIONS: Collectively, these findings unveil the potential of RYGB surgery to attenuate ethanol consumption in some humans and rats. Furthermore, our data indicate that this regulation is achieved, in part, through reduction of reward and is modified by the gut hormones GLP-1 and ghrelin. PMID- 22444204 TI - Selection for carcass quality in hill sheep measured by X-ray computer tomography. AB - This paper describes an investigation of the use of computer tomography (CT) to genetically improve carcass composition and conformation in Scottish Blackface sheep. After 5 years of selection on an index designed to improve both composition and conformation (the 'CT index'), a large response was observed in the CT index, with genetic progress equivalent to 0.11 phenotypic standard deviations per year. Heritabilities for the index and for the component traits of average CT-assessed muscle area, ultrasonic muscle depth and ultrasonic fat depth were 0.41 (s.e. 0.08), 0.38 (s.e. 0.07), 0.41 (s.e. 0.05) and 0.30 (s.e. 0.05), respectively. The index was positively genetically correlated with ultrasonic muscle depth and carcass weight and negatively genetically correlated with fat class. The genetic and phenotypic correlations among ultrasonic measurements were positive and moderate. However, many of the genetic correlations tended to have large standard errors. Selection on the CT index moderately improved conformation and was successful at decreasing fat class of the carcass. Equivalent selection on live weight at ultrasound scanning would improve carcass and slaughter weight, and total price received, but would have a slightly deleterious impact on conformation score. The results of this study demonstrate that genetic improvement of carcass quality can be achieved in hill sheep using CT assessed traits. PMID- 22444205 TI - Breed variation and genetic parameters for growth and body development in diverse beef cattle genotypes. AB - Conformation scores can account for more than 20% of cattle price variation at Australian livestock sales. However, there are limited available references which define genetic factors relating objective live developmental traits to carcass composition. Weaning and post-weaning weight, height, length, girth, muscle (ratio of stifle to hip width) and fat depth of 1202 progeny from mature Hereford cows (637) mated to seven sire breeds (Jersey, Wagyu, Angus, Hereford, South Devon, Limousin and Belgian Blue) were examined for growth and development across ages. Crossbred Wagyu and Jersey were both lighter in weight and smaller in size (height, length and girth) than purebred Hereford and crossbred Angus, South Devon, Limousin and Belgian Blue. Within the five larger crossbreds, there were significant changes in relative weight from weaning to 600 days. Sire breeds differed in fat depth, with Angus being the fattest (9% on average fatter than Hereford and Wagyu), and Jersey 5% less fat than Hereford, followed by South Devon and Limousin (19% lower than Hereford) and Belgian Blue (39% lower than Hereford). Direct heritability ranged from 19 to 42% and was higher than the proportion of total phenotypic variance accounted for by maternal effects (which ranged from 0 to 17%) for most body measurement traits except for weight (38 v. 18%) and girth (36 v. 9%) traits at weaning, an indication of maternal effect on some body conformation traits at early ages. Muscularity (19 to 44%) and fat depth (26 to 43%) were moderately to highly heritable across ages. There were large differences for growth and the objective measures of body development between crossbreds with a degree of overlap among the progeny of the seven sire breeds. The variation between genetic (positive) and environmental (negative) correlations for dry versus wet season average daily gains in weight and fat, suggested the potential use of live-animal conformation traits for within breed selection of genetically superior animal in these traits across seasons. PMID- 22444206 TI - A simple method to approximate gene content in large pedigree populations: application to the myostatin gene in dual-purpose Belgian Blue cattle. AB - Gene content is the number of copies of a particular allele in a genotype of an animal. Gene content can be used to study additive gene action of candidate gene. Usually genotype data are available only for a part of population and for the rest gene contents have to be calculated based on typed relatives. Methods to calculate expected gene content for animals on large complex pedigrees are relatively complex. In this paper we proposed a practical method to calculate gene content using a linear regression. The method does not estimate genotype probabilities but these can be approximated from gene content assuming Hardy Weinberg proportions. The approach was compared with other methods on multiple simulated data sets for real bovine pedigrees of 1 082 and 907 903 animals. Different allelic frequencies (0.4 and 0.2) and proportions of the missing genotypes (90, 70, and 50%) were considered in simulation. The simulation showed that the proposed method has similar capability to predict gene content as the iterative peeling method, however it requires less time and can be more practical for large pedigrees. The method was also applied to real data on the bovine myostatin locus on a large dual-purpose Belgian Blue pedigree of 235 133 animals. It was demonstrated that the proposed method can be easily adapted for particular pedigrees. PMID- 22444207 TI - Associations between genetic merit for milk production and animal parameters and the fertility performance of dairy cows. AB - Relationships between genetic merit for milk production and animal parameters and various parameters of reproductive performance were examined using multilevel binary response analysis in a study of 19 dairy herds for three successive years, representing approximately 2500 cows per year. The proportion of cows intended for rebreeding that were back in-calf again within 100 days of calving (ICR-100) and the proportion of cows that reappeared again with 365 (RR-365) and 400 days (RR-400) of a previous calving were considered in addition to the traditional measures of reproductive performance. Each 100-kg increase in genetic merit for milk yield was associated with an increased interval to first service (IFS) and calving index (CI) of 1.4 ( P < 0.001) and 1.8 days ( P < 0.001), respectively, a 0.5% increase ( P < 0.05) in calving rate to first insemination (CR-1) and 0.8% increase in RR-400. Each L10 increase in LPIN (the economically weighted yield selection index used in the UK that takes account of butterfat and protein yields) was associated with an increased IFS and CI of 1.5 ( P < 0.001) and 3.0 days ( P < 0.001), respectively. Cows with increased genetic merit for milk yield and LPIN were more likely to re-calve (RR-overall; P < 0.001). Each 1000-kg increase in 305-day milk yield was associated with an increased IFS and CI of 3.2 ( P < 0.001) and 7.8 days ( P < 0.001), respectively, and a 13.6 ( P < 0.001), 22.4 ( P < 0.001), 19.9 ( P < 0.001) and 19.0% ( P < 0.001) decrease in CR-1, ICR 100, RR-365 and RR-400, respectively. A 10-kg increase in maximum yield was associated with a 6.6-day increase in CI ( P < 0.001) and a 14.9 ( P < 0.001), 18.3 ( P < 0.001), 9.6 ( P < 0.05) and 14.2% ( P < 0.001) decrease in CR-1, ICR 100, RR-365 and RR-400, respectively. Fertility performance was also associated with season of calving, lactation number and dystocia score. Level of production had a larger effect on fertility performance than genetic merit for milk production suggesting that infertility at an individual cow level is more likely to be associated with increased production and an inability to meet the nutritional requirements of the cow. PMID- 22444209 TI - Foreword: Predicting the responses of animals to their nutrients - quo vadimus? PMID- 22444208 TI - Bacterial protein meal in diets for growing pigs: effects on protein and energy metabolism. AB - This experiment investigated the effects of increasing the dietary content of bacterial protein meal (BPM) on the protein and energy metabolism of pigs from weaning to a live weight of 80 kg. Four litters with four castrated male pigs in each litter were used. The litters were divided into two blocks according to age. One pig from each litter was fed one of the four experimental diets. Soya-bean meal was replaced with BPM on the basis of digestible protein, and the BPM contents in the four diets were 0% (BP0), 5% (BP5), 10% (BP10) and 15% (BP15), corresponding to 0%, 17%, 35% and 52% of the digestible nitrogen (N), respectively. Four balance periods were performed, at the start of which the pigs weighed 9.5 kg, 20.7 kg, 45.3 kg and 77.2 kg, respectively. Once during each balance period, 22-h respiration experiments were performed using indirect calorimetry. Daily weight gain, feed intake and feed conversion rate were the same for all diets. The apparent digestibility of N was lower on diet BP10 than on BP0 (P = 0.002), whereas the apparent digestibility of energy was similar on all diets. The retention of nitrogen did not differ between diets and was 1.50, 1.53, 1.33 and 1.46 g N per kg0.75 per day on BP0, BP5, BP10 and BP15, respectively. Neither metabolisable energy intake nor heat production were affected by inclusion level of BPM. Retention of energy was 620 (BP0), 696 (BP5), 613 (BP10) and 664 kJ/kg0.75 per day (BP15), the differences among diets being non-significant. The N-free respiratory quotient was similar on all diets. It was concluded that the overall protein and energy metabolism in growing pigs were not affected when up to 50% of dietary N was derived from BPM. PMID- 22444210 TI - Predicting nutrient responses in poultry: future challenges. AB - Predicting the response of poultry to nutrients has progressed to a stage where it is now not only possible to predict voluntary feed intake accurately, but broiler feeds and feeding programmes may now be optimised using the more advanced simulation models. Development of such prediction models has stimulated useful and purposeful research targeted at filling the gaps in our knowledge of critical aspects of the theory incorporated into these models. The aim of this paper was to review some of these past developments, discuss the controversy that exists in designing and interpreting response experiments, and highlight some of the most recent challenges related to the prediction of responses to nutrients by poultry. These latter include differences, brought about by selection for diverse goals, that have become apparent between modern broiler strains in their responses in feed intake and mortality, which are not independent of level of feeding or strain of broiler, as was previously believed. Uniformity, an important quality criterion in broiler processing, is also not independent of level of feeding, and the effect may now be predicted using stochastic models. It is not yet clear whether breast meat yield, the carcass component of broilers yielding the highest returns, is a function of the strain of broiler or simply that of the protein weight of the bird when processed. An important aspect of response prediction is dealing with constraints to performance: whereas it is relatively straightforward to simulate the potential performance of a broiler, such performance is often constrained by the physical, social and infectious environment, among others, providing a challenge to modellers attempting to predict actual performance. Some of these constraints to potential performance have not yet been adequately described, but are now receiving attention, suggesting that nutrient responses in poultry have the potential to be more accurately predicted in the future. PMID- 22444211 TI - The effects of pathogen challenges on the performance of naive and immune animals: the problem of prediction. AB - Predictive frameworks for performance under both physical and social stressors are available, but no general framework yet exists for predicting the performance of animals exposed to pathogens. The aim of this paper was to identify the key problems that would need to be solved to achieve this. Challenges of a range of hosts by a range of pathogens were reviewed to consider reductions in growth beyond those associated with reductions in voluntary food intake (VFI). Pair feeding and marginal response studies identified the extent and mechanisms of how further reductions in growth occur beyond those caused by reduced VFI. Further reductions in growth depended on the pathogen, the host and the dose and were time dependent. In some instances the reduction in VFI fully explained the reduction in growth. Marginal response experiments showed increased maintenance requirements during exposure to pathogens, but these were different for specific amino acids. There were no clear effects on marginal efficiency. Innate immune functions, repair of damaged tissue and expression of acquired immunity caused significant but variable increases in protein (amino acid) requirements. More resistant genotypes had greater requirements for mounting immune responses. The partitioning of protein (amino acids) was found to be different during pathogen challenges. Prediction of the requirements and partitioning of amino acids between growth and immune functions appears to be a crucial problem to solve in order to predict performance during pathogen challenges of different kinds and doses. The problems of accounting for reductions in performance during pathogen challenges that are described here provide a useful starting point for future modelling and experimental solutions. PMID- 22444212 TI - Towards a biological basis for predicting nutrient partitioning: the dairy cow as an example. AB - Prediction of nutrient partitioning is a long-standing problem of animal nutrition that has still not been solved. Another substantial problem for nutritional science is how to incorporate genetic differences into nutritional models. These two problems are linked as their biological basis lies in the relative priorities of different life functions (growth, reproduction, health, etc.) and how they change both through time and in response to genetic selection. This paper presents recent developments in describing this biological basis and evidence in support of the concepts involved as they relate to nutrient partitioning. There is ample evidence that at different stages of the reproductive cycle various metabolic pathways, such as lipolysis and lipogenesis, are up or down regulated. The net result of such changes is that nutrients are channelled to differing extents to different organs, life functions and end products. This occurs not as a homeostatic function of changing nutritional environment but rather as a homeorhetic function caused by the changing expression of genes for processes such as milk production through time. In other words, the animal has genetic drives and there is an aspect of nutrient partitioning that is genetically driven. Evidence for genetic drives other than milk production is available and is discussed. Genetic drives for other life functions than just milk imply that nutrient partitioning will change through lactation and according to genotype - i.e. it cannot be predicted from feed properties alone. Progress in describing genetic drives and homeorhetic controls is reviewed. There is currently a lack of good genetic measures of physiological parameters. The unprecedented level of detail and amounts of data generated by the advent of microarray biotechnology and the fields of genomics, proteomics, etc. should in the long-term provide the necessary information to make the link between genetic drives and metabolism. However, gene expression, protein synthesis etc, have all been shown to be environmentally sensitive. Thus, a major challenge in realising the potential afforded by this new technology is to be able to be able to distinguish genetically driven and environmentally driven effects on expression. To do this we need a better understanding of the basis for the interactions between genotypes and environments. The biological limitations of traditional evaluation of genotype * environment interactions and plasticity are discussed and the benefits of considering these in terms of trade-offs between life functions is put forward. Trade-offs place partitioning explicitly at the centre of the resource allocation problem and allow consideration of the effects of management and selection on multiple traits and on nutrient partitioning. PMID- 22444213 TI - Predicting the profile of nutrients available for absorption: from nutrient requirement to animal response and environmental impact. AB - Current feed evaluation systems for dairy cattle aim to match nutrient requirements with nutrient intake at pre-defined production levels. These systems were not developed to address, and are not suitable to predict, the responses to dietary changes in terms of production level and product composition, excretion of nutrients to the environment, and nutrition related disorders. The change from a requirement to a response system to meet the needs of various stakeholders requires prediction of the profile of absorbed nutrients and its subsequent utilisation for various purposes. This contribution examines the challenges to predicting the profile of nutrients available for absorption in dairy cattle and provides guidelines for further improved prediction with regard to animal production responses and environmental pollution.The profile of nutrients available for absorption comprises volatile fatty acids, long-chain fatty acids, amino acids and glucose. Thus the importance of processes in the reticulo-rumen is obvious. Much research into rumen fermentation is aimed at determination of substrate degradation rates. Quantitative knowledge on rates of passage of nutrients out of the rumen is rather limited compared with that on degradation rates, and thus should be an important theme in future research. Current systems largely ignore microbial metabolic variation, and extant mechanistic models of rumen fermentation give only limited attention to explicit representation of microbial metabolic activity. Recent molecular techniques indicate that knowledge on the presence and activity of various microbial species is far from complete. Such techniques may give a wealth of information, but to include such findings in systems predicting the nutrient profile requires close collaboration between molecular scientists and mathematical modellers on interpreting and evaluating quantitative data. Protozoal metabolism is of particular interest here given the paucity of quantitative data.Empirical models lack the biological basis necessary to evaluate mitigation strategies to reduce excretion of waste, including nitrogen, phosphorus and methane. Such models may have little predictive value when comparing various feeding strategies. Examples include the Intergovernmental Panel on Climate Change (IPCC) Tier II models to quantify methane emissions and current protein evaluation systems to evaluate low protein diets to reduce nitrogen losses to the environment. Nutrient based mechanistic models can address such issues. Since environmental issues generally attract more funding from governmental offices, further development of nutrient based models may well take place within an environmental framework. PMID- 22444214 TI - Do age and feeding levels have comparable effects on fat deposition in breast muscle of mule ducks? AB - The effects of age (from 1 day post-hatch to 98 days of age) and feeding levels (feed restriction followed by overfeeding v. ad libitum feeding) on lipid deposition in breast muscle (quantity and quality, localisation) of mule ducks were determined in relation to muscle energy metabolism (glycolytic and oxidative), plasma levels of lipids, glucose and insulin, and muscle capacity for lipid uptake (characterised by lipoprotein lipase (LPL) activity). Two periods were defined for age effects on intramuscular lipids in breast muscle: - 1 to 42 days of age when lipids (mainly phospholipids and cholesterol provided by egg yolk) stored in the adipocytes during embryonic life were transferred to the muscle fibres and used for growth and energy requirements, - 42 to 98 days of age when the muscle again stored lipids (mainly triglycerides provided by liver lipogenesis), first in fibres and then in adipocytes.Plasma glucose and insulin levels were not affected by age. Plasma levels of lipids and LPL activity in breast muscle were high at 1 and 14 days of age and then decreased, remaining stable until 98 days of age. Energy metabolism activity in the breast muscle (mainly glycolytic activity) increased with age.Feed restriction, corresponding to 79% of ad libitum intake, applied between 42 and 75 days of age only resulted in decreases in plasma insulin concentration and total lipid content of breast muscle, mainly affecting triglyceride and mono-unsaturated fatty acid (MUFA) levels. Overfeeding increased plasma levels of insulin and lipids while glycaemia remained stable. LPL activity and total lipid levels increased in breast muscle, mainly induced by deposition of triglycerides and MUFA occurring particularly during the 2nd week of this period. Glycolytic energy metabolism decreased.In response to age or feeding levels, muscle lipid levels and composition reflect plasma lipid levels and composition and high muscle lipid levels stimulate oxidative energy metabolism. PMID- 22444215 TI - Effect of milking frequency and nutritional level on aspects of the health and welfare of dairy cows. AB - The objective of this experiment was to investigate the effect of milking frequency and nutritional level on some aspects of animal health. Holstein Friesian cows (n = 60) were assigned post calving to a factorial arrangement of treatments; twice a day (TAD) milking on a high or low nutritional level; once a day (OAD) milking on a high or low nutritional level. Milking characteristics were recorded daily. Blood samples to evaluate changes in the composition of the blood cells, milk leakage, udder tension and locomotory ability were measured on four occasions. Teat-ends were classified for hyperkeratosis (HK) monthly post partum. TAD had longer daily milking times (P < 0.001) compared with OAD cows. There was no effect of milking frequency or nutritional level on morning milking time, time to milk letdown or peak milk flow rate (P>0.05). High nutritional level cows had higher average flow-rates (P < 0.05) than low nutritional level cows. Neither milking frequency nor nutritional level affected HK (P>0.05). However, HK values were positively correlated with daily milking time for OAD cows for 6 months of lactation (P < 0.05). This correlation was significant (P < 0.01) for cows milked OAD on high nutrition during the peak lactation period. OAD cows had higher levels of milk leakage compared with TAD cows during the month of May (P < 0.01). Cows on high nutrition milked OAD showed higher udder firmness scores than cows milked once or twice daily at the low nutrition level in June and July (P < 0.05). OAD cows had higher locomotion scores compared with TAD cows (P < 0.001). Locomotion and udder firmness scores were significantly correlated for OAD in June (P < 0.05). OAD cows had lower blood lymphocyte counts, numerically higher counts of neutrophil and a higher monocyte count at peak lactation compared with TAD cows suggesting that OAD cows had altered immune responses. The increase in milk leakage, higher udder firmness and locomotion scores in conjunction with changes in blood cells, suggests that OAD milking may have caused some discomfort to the cows during peak lactation. A reduction in the concentrate input to OAD cows during this period could ameliorate this problem. PMID- 22444216 TI - Pig acute-phase protein levels after stress induced by changes in the pattern of food administration. AB - A total of 240 pigs, 74 days old, half boars and half females, were included in a trial designed to assess the effect of the stress caused by changes in the pattern of food administration on the concentration of acute phase proteins (APP) and productive performance parameters. Half of the animals (pigs fed ad libitum, AL group) had free access to feed, while the rest were fed following a disorderly pattern (DIS group), in which animals had alternating periods of free access to feed and periods of no feeding, when food was removed from the feeder. The periods of free access to feed (two daily periods of 2-h duration) were randomly assigned, and varied from day to day. Total feed supplied per day was identical in both groups, and exceeded the minimal amount required for animals of these ages. Pen feed intake, individual body weights and the main positive pig APP pig major acute phase protein (Pig-MAP), haptoglobin, serum amyloid A (SAA), C reactive protein (CRP), and the negative APP apolipoprotein A-I (ApoA-I) and transtherytin were determined every 2 weeks during the period 76 to 116 days of age. Animals fed ad libitum had better average daily gain (ADG) than DIS animals in the whole experimental period (P < 0.01) but the differences in ADG were only produced in the two first experimental sub-periods (60 to 74 and 74 to 116 days of age), suggesting that the stress diminished when the animals get used to the DIS feeding. Interestingly differences in ADG between DIS and AL pigs were due to males, whereas no differences were observed between females. The same differences observed for ADG were found for APP. DIS males had higher Pig-MAP concentration than AL males at 74 and 116 days of age, lower ApoA-I concentration at 74 days of age and higher haptoglobin and CRP concentration at 116 days of age (P < 0.05). The results obtained in this trial show an inverse relationship between weight gain and APP levels, and suggest that APP may be biomarkers for the evaluation of distress and welfare in pigs. PMID- 22444217 TI - Using n-alkanes to estimate diet composition of herbivores: a novel mathematical approach. AB - N-alkanes are long-chain saturated hydrocarbons occurring in plant cuticles that can be used as chemical markers for estimating the diet composition of herbivores. An important constraint of using n-alkanes to estimate diet composition with currently employed mathematical procedures is that the number of markers must be equal or larger than the number of diet components. This is a considerable limitation when dealing with free-ranging herbivores feeding on complex plant communities. We present a novel approach for the estimation of diet composition using n-alkanes which applies equally to cases where the number of markers is lower, equal or greater than the number of plant species in the diet. The model uses linear programming to estimate the minimum and maximum proportions of each plant in the diet, and avoids the need for grouping species in order to reduce the number of estimated dietary components. We illustrate the model with two data sets of n-alkane content of plants and faeces obtained from a sheep grazing experiment conducted in Australia and a red deer study in Portugal. Our results are consistent with previous studies on those data sets and provide additional information on the proportions of individual species in the diet. Results show that sheep included in the diet high proportions of white clover (from 0.25 to 0.37), and relatively high proportions of grasses (e.g. brome from 0.14 to 0.26) but tended to avoid Lotus spp. (always less than 0.04 of the diet). For red deer we found high proportions of legumes (e.g. Trifolium angustifolium and Vicia sativa reaching maximum proportions of 0.42 and 0.30 of the diet, respectively) with grasses being less important and Cistus ladanifer, a browse, also having relevance (from 0.21 to 0.42 of the diet). PMID- 22444218 TI - Analyses of lamb survival of Scottish Blackface sheep. AB - Scottish Blackface lamb viability records at birth, and postnatal survival from 1 day to 14 days, from 15 days to 120 days and from 121 days to 180 days were used to determine influential factors and to estimate variance components of lamb survival traits. The binary trait viability at birth was analysed using a linear model whereas the postnatal survival traits were analysed as continuous traits using a Weibull model. The data consisted of about 15 000 survival records of lambs born from 1996 to 2005 on two farms in Scotland. The models included fixed factors that had significant effects and random direct and maternal additive genetic effects and maternal litter effects for viability at birth, and sire and maternal litter effects for the postnatal survival traits. The possible effect of maternal behaviour measured around lambing on lamb survival was investigated in separate analyses. Male lambs were found to be at a higher risk of mortality than females during all periods considered. The effect of type of birth and age of dam was more important during the preweaning period than at later ages. The postnatal hazard rate was not significantly affected by the behaviour score of the dams. The genetic merit of dams had more influence on viability at birth than the genetic merit of lambs themselves. Estimates of heritability for postnatal survival traits were in the range of 0.18 to 0.33 and were significantly greater than zero. These results indicate that lamb survival can be improved through farm management practices and genetic selection. Both animal and maternal genetic effects should be considered in breeding programmes for improving viability at birth. PMID- 22444219 TI - Recent advances in cattle functional genomics and their application to beef quality. AB - The advent of high-throughput DNA sequencing techniques, array technology and protein analysis has increased the efficiency of research in bovine muscle physiology, with the ultimate objective of improving beef quality either by breeding or rearing factors. For genetic purposes, polymorphisms in some key genes have been reported for their association with beef quality traits. The sequencing of the bovine genome has dramatically increased the number of available gene polymorphisms. The association of these new polymorphisms with the variability in beef quality (e.g. tenderness, marbling) for different breeds in different rearing systems will be a very important issue. For rearing purposes, global gene expression profiling at the mRNA or protein level has already shown that previously unsuspected genes may be associated either with muscle development or growth, and may lead to the development of new molecular indicators of tenderness or marbling. Some of these genes are specifically regulated by genetic and nutritional factors or differ between different beef cuts. In recognition of the potential economic benefits of genomics, public institutions in association with the beef industry are developing livestock genomics projects around the world. From the scientific, technical and economical points of view, genomics is thus reshaping research on beef quality. PMID- 22444220 TI - Analysis of feed intake and energy balance of high-yielding first lactating Holstein cows with fixed and random regression models. AB - At the dairy research farm Karkendamm, the individual roughage intake was measured since 1 September 2005 using a computerised scale system to estimate daily energy balances as the difference between energy intake and calculated energy requirements for lactation and maintenance. Data of 289 heifers with observations between the 11th and 180th day of lactation over a period of 487 days were analysed. Average energy-corrected milk yield, feed intake, live weight and energy balance were 31.8kg, 20.6kg, 584 kg and 13.6 MJ NEL (net energy lactation), respectively, per day. Fixed and random regression models were used to estimate repeatabilities, correlations between cow effects and genetic parameters. The resulting genetic correlations in different lactation stages demonstrate that feed intake and energy balance at the beginning and the middle of lactation are genetically different traits. Heritability of feed intake is low with h2=0.06 during the first days after parturition and increases in the middle of lactation, whereas the energy balance shows the highest heritability with h2=0.34 in the first 30 days of lactation. Genetic correlations between energy balance and feed intake and milk yield, respectively, illustrate that energy balance depends more on feed intake than on milk yield. Genetic correlation between body condition score and energy balance decreases rapidly within the first 100 days of lactation. Hence, to avoid negative effects on health and reproduction as consequences of strong energy deficits at the beginning of lactation, the energy balance itself should be measured and used as a selection criterion in this lactation stage. Since the number of animals is rather small for a genetic analysis, the genetic parameters have to be evaluated on a more comprehensive dataset. PMID- 22444221 TI - Effects of the Texel muscling quantitative trait locus on carcass traits in crossbred lambs. AB - Texel muscling quantitative trait locus (TM-QTL) is a QTL on chromosome 18, originally identified in purebred UK Texel sheep, which was reported to increase ultrasonically measured muscle depth at the third lumbar vertebra by around 4% to 7%. The objective of the present study was to comprehensively evaluate the TM-QTL and to determine whether it could provide benefits to the UK sheep industry through increased carcass meat yield in crossbred slaughter lambs. Effects of this QTL on a range of carcass traits, including those measured in vivo and by dissection, were evaluated in heterozygous carrier and non-carrier lambs produced by crossing heterozygous carrier Texel rams with non-carrier Mule (Bluefaced Leicester * Scottish Blackface) ewes from a lowland flock. The TM-QTL was found to increase loin muscling in crossbred lambs at a given live weight or carcass weight, as measured by ultrasound, X-ray computed tomography (CT) and carcass dissection. Depth of M. longissimus lumborum (MLL) was greater in TM-QTL carrier lambs compared to non-carriers as measured by both ultrasound at the third lumbar vertebra (+4.5%; P = 0.033) and CT scanning at the fifth lumbar vertebra (+6.7%; P = 0.004). Width and area of MLL measured using CT were also greater in TM-QTL carrier lambs compared to non-carriers (+3.0%; P = 0.013 and +5.1%; P = 0.047, respectively). Loin muscle volume measured using CT was greater in TM-QTL carriers than in non-carriers (+5.9%; P = 0.005) and the dissected weight of the MLL was +7.1% greater in TM-QTL carriers compared to non-carriers (P < 0.001). The proportion of the total carcass lean meat yield (LMY) that was contained within the loin region was slightly higher in TM-QTL carriers than in non carriers (0.154 v. 0.145; P = 0.006). However, TM-QTL was found to have no significant effect on the total weight or proportion of LMY or of saleable meat yield in the carcass measured by dissection, or on muscling in the hind leg measured by CT or dissection. This work has verified that the inheritance of TM QTL is associated with increased loin muscling in crossbred lambs, as has previously been reported for purebred Texel lambs. PMID- 22444222 TI - Nutritional properties of potato protein concentrate compared with soybean meal as the main protein source in feed for the double-muscled Belgian Blue bull. AB - The objective of this experiment was to compare the nutritional properties of potato protein concentrate, a by-product of the starch industry produced entirely in Europe, with that of soybean meal (SBM), for growing cattle. The experiment was conducted on double-muscled Belgian Blue bulls, fitted with rumen, duodenal and ileal cannulas, according to a 4 * 4 Latin square design. They were fed three different iso-N and iso-net energy diets formulated according to the Dutch feed evaluation system, differing in the nature of the main protein source, which was either SBM ('SBM' treatment), potato protein concentrate (PPC, 'PPC' treatment) or an iso-N mixture of these two protein sources ('mixed' treatment). A fourth treatment consisted of 'PPC' supplemented by 9.5% digestible proteins supplied by duodenal perfusion of sodium caseinate (CAS, 'PPC + CAS' treatment). No significant difference was observed in the ruminal fluid pH, whereas both 'PPC' and 'PPC + CAS' had the effect of reducing the ruminal ammonia nitrogen (N-NH3) concentration. No significant difference was observed in the apparent intestinal digestibility of the dry matter (DM), organic matter (OM) or N. Outflows of non NH3-N, microbial proteins and dietary proteins from the rumen were similar for 'PPC', 'SBM' and 'mixed', and increased with CAS infusion by 20%, 17% and 27%, respectively. On the basis of in vivo observations, the degradability of SBM and PPC proteins was estimated at 0.60 and 0.43, respectively, corresponding to the values quoted in the literature. The supply of digestible essential amino acids (EAA) was significantly greater with 'PPC + CAS' and did not differ among 'SBM', 'mixed' and 'PPC'. This illustrates the difficulty of altering the amino acid (AA) pattern of digestible protein by the nature of the protein of dietary origin when an animal is fed a high nutritional value diet. N retention was not affected by replacing SBM with PPC, but increased by 10% with CAS infusion. On the basis of the plasma AA pattern, the supply of digestible Met was probably limiting with 'SBM', 'mixed' and 'PPC'. The CAS perfusion supplemented all AA, including Met, leading to increased N retention. This improvement was limited, however, and N utilisation remained unchanged between treatments. In conclusion, despite a more favourable EAA pattern, PPC offered no advantage compared with SBM for growing bulls when diets were formulated according to the Dutch feed evaluation system. PMID- 22444223 TI - Effects of dietary chromium supplementation on glucose tolerance and primary antibody response against peste des petits ruminants in dwarf Bengal goats ( Capra hircus). AB - An experiment was conducted to exploit the immune-modulation effect of trivalent chromium (Cr) for augmenting immunity against peste des petits ruminants (PPR) in dwarf black Bengal goats (Capra hircus). The goats (n = 6 per treatment group) either received a basal diet devoid of supplemental Cr (control) or were supplemented with 0.5 mg Cr as chromic chloride (+Cr) for 60 days. Live weight gain and feed conversion efficiency improved (P < 0.05) in the +Cr dietary group. Supplemental Cr did not affect the total number of monocytes, eosinophils and basophils (P > 0.1) although total leukocytes increased (P < 0.05) and the ratio of neutrophils to lymphocytes narrowed down (P < 0.05) in the +Cr dietary group. The effect of Cr supplementation on variables of the intravenous glucose tolerance test (IVGTT) was inconclusive. Compared to the control group, the basal concentration of glucose (P < 0.05) and insulin (P < 0.001) was higher, clearance rate was slower (P < 0.05) and serum half-life was greater (P < 0.05) in the +Cr dietary group during the IVGTT. Over the duration of the experiment, serum concentration of insulin increased (P < 0.001) and that of cortisol decreased (P < 0.01) in the +Cr group, which also showed a relatively higher primary antibody (Ab) response against PPR on days 10 (P < 0.01) and 20 (P < 0.05) post vaccination. In conclusion, the experiment indicated that supplementation of Cr as CrCl3, in the diet of non-stressed goats, may improve primary Ab response against PPR and help confer an augmented immunity to the disease besides promoting growth and feed conversion. PMID- 22444224 TI - Effect of particle size of alfalfa hay and reconstitution with water on intake, digestion and milk production in Holstein dairy cows. AB - Twenty-four lactating Holstein dairy cows (12 first lactation and 12 multiparous; day in milk = 11 +/- 5 days) were allotted to a randomised complete block design in a 2 * 3 factorial with four replicates per treatment to evaluate the effects of two methods of alfalfa feeding (dry and reconstituted to achieve a theoretical dry matter (DM) content of 350 g/kg) and three geometric mean (GM) particle sizes of alfalfa (9.13, 4.51 and 1.20 mm) on performance of dairy cows for a period of 28 days. Diets were offered for ad libitum intake as total mixed rations (TMR). The GM particle size, its standard deviation, and the values of physical effectiveness factor of alfalfa and TMR decreased as alfalfa particle size decreased. Reduction of particle size and reconstitution of alfalfa increased the bulk density and the functional specific gravity of alfalfa and rations. Reduction of particle size decreased insoluble dry matter, water-holding capacity, and hydration rate of alfalfa. As particle size decreased, the amount of physically effective NDF in the ration (g/kg) decreased but the daily intake of physically effective NDF (kg/day) increased. Reduction of particle size and reconstitution increased dry matter intake (DMI) and ruminal passage rate, but reduced NDF and ash digestibilities, ruminal pH, N-NH3, milk fat, total chewing activity, rumination and eating time, total and ruminal mean retention time, and time delay of marker. Increased functional specific gravity, from reduced forage particle size and the reconstitution of alfalfa, was the most important factor influencing DMI, milk composition, and chewing activity. PMID- 22444225 TI - Nutrition-induced differences in body composition, compensatory growth and endocrine status in growing pigs. AB - In this experiment, we assessed the effect of amino acid (AA) intake restriction in entire male Yorkshire pigs between 15 and 38 kg BW (restriction phase) on BW gain, body composition and plasma levels of blood urea nitrogen (BUN), cortisol, insulin-like growth factor I (IGF-I), growth hormone (GH) and leptin during the subsequent re-alimentation phase. During the restriction phase, 36 pigs were allotted to one of two dietary treatments: adequate AA intake (control) or AA limiting diets (AA-30%). Thereafter, pigs were fed common non-limiting diets up to 110 kg BW. Throughout the experiment, pigs were scale-fed at 90% of the estimated voluntary daily digestible energy intake. At the end of the restriction phase, pigs on AA-30% had lesser BW gain (650 v. 784 g/day; P < 0.001), loin area (LA; 12.2 v. 14.2 cm2; P < 0.001), BUN (4.6 v. 6.3 mg/dl; P < 0.02), lesser plasma levels of IGF-I (440 v. 640 ng/m; P < 0.001) and cortisol (8.2 v. 19.2 MUg/dl; P < 0.001), greater backfat thickness (BF; 7.56 v. 6.56 mm; P < 0.02), and greater plasma levels of leptin (2.7 v. 1.8 ng/ml; P = 0.027) and GH (3.3 v. 2.0 ng/ml; P = 0.05) than pigs on control. During the re-alimentation phase, previously restricted pigs showed full compensatory growth (CG) in terms of BW gain (1170 v. 1077 g/day; P < 0.002), whole-body protein deposition (Pd) (179 v. 163 g/day; P < 0.001) as well as physical and chemical body composition (whole body lipid to body protein mass ratio, LB/PB; 1.14 v. 1.15; P > 0.10). Besides GH at 45 kg BW (4.2 v. 2.4 ng/ml; P = 0.066), there were no effects of previous AA intake restriction on leptin, IGF-I and BUN during the re-alimentation phase (P > 0.10). Plasma cortisol and IGF-I levels may act as an indicator of AA-induced restriction in Pd in growing pigs. Plasma BUN level does not appear as a sensitive indicator for compensatory Pd. Plasma leptin and GH levels allow for the involvement of the brain in controlling chemical body composition. Full CG was observed during the energy-dependent phase of Pd in growing pigs and might be driven by a target LB/PB, possibly mediated via plasma leptin, IGF-I and GH levels. PMID- 22444226 TI - Different rates of glycolysis affect glycolytic activities and protein properties in turkey breast muscle. AB - Protein alterations of turkey breast muscles (Pectoralis major) were investigated at 20 min and 24 h post mortem. Specific activities, quantities and kinetic parameters of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and aldolase A were also determined at 20 min post mortem. Based on the pH values at 20 min post mortem, two groups of samples were classified as rapid glycolysis group (RG; pH20 min = 5.80 +/- 0.07, n = 20) and normal glycolysis group (NG; pH20 min = 6.21 +/- 0.01, n = 20). RG had lower specific activities of GAPDH and aldolase A than NG while Vm and Km values of both enzymes were not different between groups. RG showed lower high ionic strength (HIS) and pellet protein extractabilities at 20 min post mortem. It also had lower low ionic strength (LIS) and HIS protein extractabilities at 24 h post mortem. Besides pellet protein, muscular protein extractabilities at 24 h post mortem were higher than at 20 min post mortem. From SDS-PAGE of samples at 24 h post mortem, RG exhibited lower band intensities at 45 and 200 kDa, which were further identified as actin and myosin heavy chain (MHC), respectively. Western blots revealed that relative amounts of actin and MHC at 20 min post mortem were not different between groups. However, RG muscles had less relative amount of actin at 24 h post mortem. It also indicated that amounts of actin and MHC increased with regard to post mortem time. PMID- 22444227 TI - Comparison of cloned and non-cloned Holstein heifers in muscle contractile and metabolic characteristics. AB - Muscle contractile and metabolic characteristics were studied on nine cloned and eight non-cloned (control) heifers. The animals were submitted to repeated biopsies of the semitendinosus (ST) muscle at the ages of 8, 12, 18 and 24 months. The contractile type was determined from the proportion of the different myosin heavy chain (MyHC) isoforms separated by electrophoresis. Glycolytic metabolism was assessed by lactate dehydrogenase (LDH) activity, and oxidative metabolism was assessed by isocitrate dehydrogenase (ICDH), cytochrome-c oxidase (COX) and beta-hydroxyacyl-CoA dehydrogenase (HAD) activities. In cloned heifers at 8 months of age, there was a greater proportion of MyHC I (slow oxidative isoform) and MyHC IIa (fast oxido-glycolytic isoform), a lower proportion of MyHC IIx (fast glycolytic isoform), greater COX and HAD activity and a lower LDH/ICDH ratio compared with control heifers. Thus, young cloned heifers had slower muscle types associated with a more oxidative muscular metabolism than control heifers. From 12 months of age onwards, no significant differences were observed between cloned and control heifers. A delay in muscle differentiation and maturation in cloned heifers is hypothesised and discussed. PMID- 22444228 TI - Responses of North American and New Zealand strains of Holstein-Friesian dairy cattle to homeostatic challenges during early and mid-lactation. AB - This study investigated the physiological basis of differences in nutrient partitioning between the North American (NA) and New Zealand (NZ) strains of Holstein-Friesian cattle by determining the responses to homeostatic challenges at two stages of lactation. Glucose tolerance tests, epinephrine challenges and insulin challenges were carried out on consecutive days commencing on day 32 +/- 0.48 (mean +/- s.e.) of lactation (T1) and again commencing on day 137 +/- 2.44 of lactation (T2). The insulin and non-esterified fatty acid (NEFA) responses to glucose infusion did not differ between the strains. The NZ strain had a greater clearance rate (CR) of glucose (2.04% v. 1.66%/min) and tended to have a shorter (34.4 v. 41.1 min) glucose half-life (t1/2) at T2 when infused with glucose. The NA cows had a greater glucose response to epinephrine infusion across T1 and T2, and tended to have a greater insulin response to epinephrine infusion. Plasma NEFA concentration declined to similar nadir concentrations for both strains at T1 in response to insulin, though from a higher basal concentration in NA cows, resulting in a greater (-2.29 v. -1.38) NEFA area under the response curve for NA cows. Glucose response to insulin varied with time, tending to be greater for NA at T1, but tending to be lower for NA at T2. The results indicated that NA cows had a greater glycogenolytic response to epinephrine, but both strains had similar lipolytic responses. The results also imply that higher basal circulating NEFA concentrations in the NA strain in early lactation were not due to diminished adipose tissue responsiveness to insulin. There were indications that glucose CR was greater in NZ cows in mid-lactation, and may form the basis of increased body tissue accretion during mid- to late-lactation in this strain. PMID- 22444229 TI - Mucuna pruriens seed powder feeding influences reproductive conditions and development in Japanese quail Coturnix coturnix japonica. AB - This study was designed to test whether Mucuna pruriens, a natural source of l dihydroxyphenylalanine (l-DOPA, a dopamine precursor) feeding, can influence development and reproductive conditions in the high food value bird, Japanese quail, Coturnix coturnix japonica. Experiments were performed in both male and female Japanese quail. One-week-old quail chicks were divided into three groups of 36 birds each. Group I was provided with normal diet and served as control. Group II was provided with food mixed with l-DOPA (50 mg/15 g food) and Group III was provided with food mixed with M. pruriens seed powder (480 g/kg food). At the age of 3 weeks (when birds were sexually distinguished) Group I was divided into two sub-groups IA (male) and IB (female) of six birds each. Similarly, Groups II and III were sub-divided into IIA (male), IIB (female) and IIIA (male), IIIB (female), respectively, of six birds each. Observations were made up to the age of 5 weeks. Male experimental groups (IIA and IIIA) showed significantly increased testicular activity, cloacal gland volume, body weight (BW), plasma testosterone and LH level in comparison to control (IA). Similarly female experimental groups (IIB and IIIB) showed significantly greater weight of reproductive organs (uterus, ovary, oviduct and ovarian follicle), BW, egg weight and size and number of follicles. On the other hand, plasma prolactin level was significantly low in comparison to control (IB). Results suggest that M. pruriens is a rich natural source of l-DOPA and the development and reproduction in Japanese quail might be associated with the dopaminergic system of the brain. PMID- 22444230 TI - Evaluation of swine fertilisation medium (SFM) efficiency in preserving spermatozoa quality during long-term storage in comparison to four commercial swine extenders. AB - In pig production, artificial insemination is widely carried out and the use of fresh diluted semen is predominant. For this reason, there are increasing interests in developing new extenders and in establishing the optimal storage conditions for diluted spermatozoa. In the last few decades, we utilised a homemade diluent (swine fertilisation medium (SFM)) for spermatozoa manipulation and biotechnological application as the production of transgenic pigs utilising the sperm-mediated gene transfer technique. The purpose of the present study is therefore to analyse the ability of SFM, in comparison to four commercial extenders, in preserving the quality of diluted boar semen stored at 16.5 degrees C till 15 days. We utilised some of the main predictive tests as objectively measured motility, acrosome and sperm membrane integrity, high mitochondrial membrane potential and pH. Based on our in vitro study, SFM could be declared as a good long-term extender, able to preserve spermatozoa quality as well as Androhep Enduraguard for up to 6 to 9 days and more. PMID- 22444231 TI - Cholecystokinin-dependent selective inhibitory effect on 'minute rhythm' in the ovine small intestine. AB - Cholecystokinin (CCK) can exert multiple actions on intestinal motility but its effect on the small-intestinal 'minute rhythm' (MR) is virtually unknown. Therefore, the electrical activity from the abomasal antrum, duodenal bulb, duodenum, jejunum and ileum was continuously recorded in six sheep before, during and after slow intravenous administration, of three doses each, of cholecystokinin-octapeptide (CCK-OP) and cerulein. In four of these sheep, two additional electrodes and the strain gauge force transducer were also inserted in the duodenum. Chronic experiments were performed in the fasted and non-fasted animals and saline or CCK peptides were injected during phases 1, 2a or 2b of the duodenal migrating myoelectric complex (MMC). The administration of both CCK peptides in various doses evoked an inhibitory effect mostly in the duodenal bulb, except for the lowest dose of cerulein. The effects of 20 times greater doses of CCK-OP than that of cerulein were more pronounced. The introduction of both CCK peptides during phase 1 of the MMC produced no marked or significant response. In non-fasted animals, the effects of both hormonal peptides, given during phase 2b of the MMC, were often stronger than those given during phase 2a, while in fasted animals the effects of CCK peptides, administered in the course of phases 2a and 2b of the MMC, were similar. Both higher doses of CCK peptides increased the number of spike bursts within the given MR pattern in the duodenum and decreased the incidence of MR mostly in the duodenal bulb. The inhibitory effects of both CCK peptides on the bulbar MR exhibited a dose-response character, though the lowest dose often evoked the slight stimulatory response. It is concluded that CCK principally exerts an inhibitory effect upon the MR in the duodenal bulb and modifies the MR in the duodenum by increasing the spike burst number in a given MR pattern. Both these actions of CCK peptides seem to be physiological. There is a positive relationship between the intensity of the refractory period and the demonstrated effect of CCK in the duodenum. PMID- 22444232 TI - Necropsy survey of gastric ulcers in a population of aged donkeys: prevalence, lesion description and risk factors. AB - There is no information about the prevalence of gastric ulceration in donkeys or potential risk factors for its presence in donkeys. The donkey is a stoic, hardy animal that has not previously been thought to suffer from this disease. However, gastric ulceration was found to be a problem in a population of non-working UK donkeys resident at the Donkey Sanctuary and its prevalence was estimated by examining necropsy data over a 2-year period during 2005 to 2006. Associations with clinical and management factors were determined. In total, 426 donkeys were examined at necropsy to determine the presence of gastric ulceration. Lesions were described and scored according to a four-point scale. Management and clinical data from these donkeys were analysed to identify potential risk factors for the presence of gastric ulceration. Terminal blood samples were also studied to determine whether animals were exhibiting hyperlipaemia prior to death. Results showed that 41% (n = 174) of the donkeys studied had evidence of gastric ulceration at necropsy. Most (49%) of the ulcers were of a medium size (area of 2 cm2 - <10 cm2) and the most common site for ulcers was the margo plicatus. Of the donkeys examined, 18% had hyperlipaemia prior to or death or euthanasia and this was a risk factor for donkeys developing gastric ulceration; 62% of hyperlipaemia cases also displayed gastric ulceration (P < 0.001). Kidney disease was a potential risk factor (P = 0.02), with 74% of these animals having gastric ulceration. Donkeys that died or were euthanased due to respiratory disease were at a decreased risk of developing ulceration (P = 0.01) Donkeys fed a carbohydrate-based diet were more likely (P < 0.001) to have gastric ulceration than those fed a fibre-only diet, with 55% having gastric ulceration compared with 33% in the fibre-only group. This study has shown that gastric ulceration is commonly observed in donkeys at necropsy and may be extensive. PMID- 22444233 TI - Differential effects of undernutrition during pregnancy on the behaviour of does and their kids at parturition and on the establishment of mutual recognition. AB - We investigated whether undernutrition during the second half of pregnancy impaired the behaviour of does and their kids at parturition and early mutual recognition. Twenty-two control and 22 underfed mixed-breed, multiparous dairy goats were used, together with their respective kids (control, n = 31: nine singles, 16 twins and six triplets; underfed, n = 32: 11 singles, 18 twins and three triplets). Undernutrition involved limiting protein and energy intake at 70% of the nutritional requirements for maintenance and foetal growth from day 70 of pregnancy until birth. The behaviour of mothers and their two first-born kids was observed for 90 min from the birth of each kid. Maternal olfactory recognition of the kid was assessed at 4 h post partum by testing selective nursing behaviour. Non-olfactory recognition was assessed at 8 h in a two-choice test excluding olfactory cues. In kids, preference for the mother was assessed in a two-choice test at either 12 or 24 h post partum. Bodyweight of does and kids were lower in the underfed group up to 2 weeks post partum. At parturition, licking, maternal bleating frequency and latency to nursing did not differ between nutritional groups. Control kids were faster than underfed kids to stand, search for and reach the udder, but underfed kids bleated more and tended to spend more time at the udder. Both control and underfed does accepted their own kid and rejected the alien in the selectivity test at 4 h. In contrast, at 8 h post partum, only control goats showed a significant preference for their own kid in the non-olfactory recognition test. Both control and underfed kids showed a preference for their own mother at 12 and 24 h and undernutrition during pregnancy had little influence on the performance of kids. However, 12 h-old underfed kids tended to be less active than control kids and visited their own mothers less than control kids. There were no significant correlations between the behaviour of the mother or of the kid at parturition and their performance in the discrimination tests. Overall, undernutrition in the second half of pregnancy appears to be more detrimental for the behaviour of the mother than for the kid. Furthermore, it has more impact on the establishment of maternal non-olfactory recognition than on maternal care at parturition or the establishment of maternal selectivity. PMID- 22444234 TI - Toward a new practical energy evaluation system for dairy cows. AB - Energy evaluation systems translate an animal's net energy (NE) requirements into feed metabolisable energy requirements (MER). The Feed into Milk (FiM) project (Agnew RE, Yan T, France J, Kebreab E and Thomas C 2004. Energy requirement and supply. In Feed into Milk. A new applied feeding system for dairy cows (ed. C Thomas), pp. 11-20. Nottingham University Press, Nottingham, UK) proposed a new system to predict MER of dairy cows that is, in contrast to previous energy evaluation systems for cattle, independent of feed quality. The FiM system shares this characteristic with an energy evaluation system for ad libitum-fed cattle proposed in 1994 by Tolkamp and Ketelaars (T&K). The FiM system requires nine parameters to translate requirements for NE into MER for dairy cows, while the T&K system for cattle requires only two for the same purpose. This paper analyses the contribution of each of the parameters to the final MER predictions, the differences in MER prediction between the two systems and the underlying causes of these differences. The systems differ considerably in their estimates of the NE that is required for maintenance and in their (implicit) assumptions about the partial efficiency of ME utilisation for lactation. The T&K system is based on a constant partial efficiency of ME utilisation, but in the FiM system this efficiency changes with milk yield (MY) and shows a sharp discontinuity that is at odds with the underlying biology. These are the two main causes of the differences in MER predictions. Nevertheless, over a range of MYs between 10 and 40 kg, and for cows maintaining, gaining or losing weight, the MER predictions of the two systems are very similar with maximum differences of up to +/-2% only. FiM predictions of MER are systematically higher than T&K predictions for cows with very low and very high MY. It is concluded that the FiM system could reduce parameter requirements with negligible effects on MER predictions. The combination of a very high maintenance NE parameter and a curvilinear model with two subsequent corrections leads to internal inconsistencies in the FiM system. The T&K system is much simpler but it might benefit from including more recent information for the estimation of its parameters. PMID- 22444235 TI - Economic impact of clinical mastitis in a dairy herd assessed by stochastic simulation using different methods to model yield losses. AB - The main aim of the present study was to examine the economic consequences of a reduction in the incidence of clinical mastitis (CM) at herd level under current Swedish farming conditions. A second objective was to ask whether the estimated cost of CM alters depending upon whether the model reflects the fact that in different stages of lactation, CM gives rise to different yield-loss patterns or postulates just one type of yield-loss pattern irrespective of when, during lactation, CM occurs. A dynamic and stochastic simulation model, SimHerd, was used to study the effects of CM in a herd with 150 cows (9000 kg of energy corrected milk per cow-year). Four herd types, defined by production level and reproductive performance, were modelled to investigate possible interactions between herd type and response to a reduction in the risk of CM. Technical and economic results, given the initial incidence of CM (25.6 per 100 cow-years), were studied together with the consequences of reducing the initial risk of CM by 50% and 90% throughout lactation and the consequences of reducing the initial risk by 50% and 90% before peak yield. A conventional way of modelling yield losses - i.e. one employing a single yield-loss pattern irrespective of when, during the lactation period, the cow develops CM - was compared with a new modelling strategy in which CM was assumed to affect production differently depending on its lactational timing. The effect of the choice of reference level when estimating yield losses was investigated by comparing the results obtained using the potential yield of mastitic cows, had they not developed CM, with those obtained using the yield of non-mastitic cows. The yearly maximum avoidable cost of CM at herd level was estimated at ?14 504, corresponding to 6.9% of the net return given the initial incidence of CM. Expressed per cow-year, the maximum avoidable cost was ?97. The cost per case of CM was estimated at ?428. Herd types all responded in a similar manner to the reduced relative risk of CM. There were no major differences in the results obtained using the new and the conventional modelling strategy, with the exception of the cost per case of CM. Similarities between the results obtained using the two methods were particularly evident when the mastitic cows' own yield level, had they not developed CM, was used as the reference for production in healthy cows when yield losses were estimated. It was concluded that the conventional way of modelling yield losses is adequate and should, for the foreseeable future, be used in decision support systems. PMID- 22444236 TI - Intestinal permeability parameters in obese patients are correlated with metabolic syndrome risk factors. AB - BACKGROUND & AIMS: Altered intestinal permeability has been shown to be associated with metabolic alterations in animal models of obesity, but not in humans. The aim of this study was to assess intestinal permeability in obese women and verify if there is any association with anthropometric measurements, body composition or biochemical variables. METHODS: Twenty lean and twenty obese females participated in the study. Anthropometric measurements, body composition and blood pressure were assessed and biochemical analyses were performed. Administration of lactulose and mannitol followed by their quantification in urine was used to assess the intestinal permeability of volunteers. RESULTS: The obese group showed lower HDL (p < 0.05), higher fasting glucose, insulin, HOMA index and lactulose excretion than the lean group (p < 0.05), suggesting increased paracellular permeability. Lactulose excretion showed positive correlation (p < 0.05) with waist and abdominal circumference. Blood insulin and the HOMA index also increased with the increase in mannitol and lactulose excretion and in the L/M ratio (p < 0.05). L/M ratio presented a negative correlation with HDL concentration (p < 0.05). CONCLUSIONS: We demonstrated that intestinal permeability parameters in obese women are positively correlated with anthropometric measurements and metabolic variables. Therapeutic interventions focused on intestine health and the modulation of intestinal permeability should be explored in the context of obesity. PMID- 22444237 TI - Perioperative perturbations in carnitine metabolism are attenuated by preoperative carbohydrate treatment: Another mechanism by which preoperative feeding may attenuate development of postoperative insulin resistance. AB - BACKGROUND & AIMS: Fasting increases lipid flux into mitochondria causing excessive beta-oxidation, carnitine acylation and impaired cellular glucose uptake. Preoperative carbohydrate treatment (PCT) attenuates postoperative insulin resistance, but mechanisms underlying this and the effects on carnitine metabolism remain largely unknown. METHODS: Pre-, intra- and-postoperative (day 1) plasma, and intraoperative rectus muscle mitochondrial free (FC), acyl (AC) and total (TC) carnitine concentrations were determined radioenzymatically in non diabetic patients undergoing laparoscopic cholecystectomy in a post hoc analysis of a randomised double-blind study (NCT00662376). Patients received 600 ml of a carbohydrate-based drink (ONS, Fresenuis Kabi, N = 15, 50 g carbohydrate, 15 g glutamine and antioxidants/300 ml) or placebo (N = 15, 0 g carbohydrate) the evening before surgery, and 300 ml 3-4 h pre-anaesthesia. RESULTS: No intra- or intergroup differences occurred in pre- or intraoperative plasma FC, TC or AC concentrations. Postoperatively, plasma TC and FC concentrations increased in the placebo group (p = 0.005 and p = 0.013). In the ONS group, postoperative increases occurred in plasma TC (p = 0.048). Increases in postoperative plasma TC and FC concentrations were attenuated in the ONS group (p = 0.013 and p = 0.044, respectively). No intergroup differences occurred in intraoperative mitochondrial carnitine concentrations. CONCLUSIONS: Preventing excessive/incomplete mitochondrial beta-oxidation, characterised by perturbed carnitine metabolism, may be a mechanism by which PCT attenuates the reduction in postoperative insulin sensitivity. PMID- 22444238 TI - 68Ga-NODAGA-RGD is a suitable substitute for (18)F-Galacto-RGD and can be produced with high specific activity in a cGMP/GRP compliant automated process. AB - INTRODUCTION: (18)F-Galacto-cyclo(RGDfK) is a well investigated tracer for imaging of alphanubeta3 expression in vivo, but suffers from the drawback of a time consuming multistep synthesis that can hardly be established under GMP conditions. In this study, we present a direct comparison of the pharmacokinetic properties of this tracer with (68)Ga-NODAGA-cyclo(RGDyK), in order to assess its potential as an alternative for (18)F-Galacto-cyclo(RGDfK). METHODS: (68)Ga labeling of NODAGA-cyclo(RGDyK) was done in full automation using HEPES-buffered eluate of an SnO(2) based (68)Ga-generator. Using M21 (human melanoma) xenografted BALB/c nude mice, biodistribution studies and micro-PET scans were performed for both (18)F-Galacto-cyclo(RGDfK) and (68)Ga-NODAGA-cyclo(RGDyK), and for the latter, in vivo stability was assessed. IC(50) was determined in a displacement assay on M21 cells against (125)I-echistatin. RESULTS: (68)Ga-NODAGA cyclo(RGDyK) was produced with high specific activity (routinely ca. 500 GBq/MUmol) within 15 min. IC(50) values are similar for both substances. Tracer uptake was similar in alphanubeta3 positive tumors (1.45%+/-0.11% ID/g and 1.35%+/-0.53% ID/g for (68)Ga-NODAGA-RGD and (18)F-Galacto-RGD, respectively) as well as for all other organs and tissues, with the exception of gall bladder and intestines, where (18)F-Galacto-cyclo(RGDfK) uptake was significantly higher, which can be explained by the higher hydrophilicity of (68)Ga-NODAGA-cyclo(RGDyK) (logP=-4.0 vs. -3.2 for (18)F-Galacto-RGD). Only intact tracer was detected 30 min p.i. in organs and tumor; however, minor amounts of metabolites were found in the urine (6% of total urine activity). CONCLUSION: (68)Ga-labeling of NODAGA-RGD can be performed rapidly and efficiently within 15 min in a GMP compliant process. Similar preclinical results were obtained in comparison with (18)F Galacto-RGD. Therefore, (68)Ga-NODAGA-cyclo(RGDyK) is a suitable replacement for (18)F-Galacto-cyclo(RGDfK). PMID- 22444239 TI - Tryptophan metabolism in breast cancers: molecular imaging and immunohistochemistry studies. AB - INTRODUCTION: Tryptophan oxidation via the kynurenine pathway is an important mechanism of tumoral immunoresistance. Increased tryptophan metabolism via the serotonin pathway has been linked to malignant progression in breast cancer. In this study, we combined quantitative positron emission tomography (PET) with tumor immunohistochemistry to analyze tryptophan transport and metabolism in breast cancer. METHODS: Dynamic alpha-[(11)C]methyl-l-tryptophan (AMT) PET was performed in nine women with stage II-IV breast cancer. PET tracer kinetic modeling was performed in all tumors. Expression of L-type amino acid transporter 1 (LAT1), indoleamine 2,3-dioxygenase (IDO; the initial and rate-limiting enzyme of the kynurenine pathway) and tryptophan hydroxylase 1 (TPH1; the initial enzyme of the serotonin pathway) was assessed by immunostaining of resected tumor specimens. RESULTS: Tumor AMT uptake peaked at 5-20 min postinjection in seven tumors; the other two cases showed protracted tracer accumulation. Tumor standardized uptake values (SUVs) varied widely (2.6-9.8) and showed a strong positive correlation with volume of distribution values derived from kinetic analysis (P<.01). Invasive ductal carcinomas (n=6) showed particularly high AMT SUVs (range, 4.7-9.8). Moderate to strong immunostaining for LAT1, IDO and TPH1 was detected in most tumor cells. CONCLUSIONS: Breast cancers show differential tryptophan kinetics on dynamic PET. SUVs measured 5-20 min postinjection reflect reasonably the tracer's volume of distribution. Further studies are warranted to determine if in vivo AMT accumulation in these tumors is related to tryptophan metabolism via the kynurenine and serotonin pathways. PMID- 22444241 TI - Tumour microenvironment heterogeneity affects the perceived spatial concordance between the intratumoural patterns of cell proliferation and 18F-fluorothymidine uptake. AB - BACKGROUND AND PURPOSE: PET imaging with (18)F-fluorothymidine ((18)F-FLT) can potentially be used to identify tumour subvolumes for selective dose escalation in radiation therapy. The purpose of this study is to analyse the co-localization of intratumoural patterns of cell proliferation with (18)F-FLT tracer uptake. MATERIALS AND METHODS: Mice bearing FaDu or SQ20B xenograft tumours were injected with (18)F-FLT, and bromodeoxyuridine (proliferation marker). Ex vivo images of the spatial pattern of intratumoural (18)F-FLT uptake and that of bromodeoxyuridine DNA incorporation were obtained from thin tumour tissue sections. These images were segmented by thresholding and Relative Operating Characteristic (ROC) curves and Dice similarity indices were evaluated. RESULTS: The thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation were significantly different for the two xenograft tumour models, whereas the median Dice values were not. However, ROC analysis indicated that segmented FLT images were more specific at detecting the proliferation pattern in FaDu tumours than in SQ20B tumours. CONCLUSION: Highly dispersed patterns of cell proliferation observed in certain tumours can affect the perceived spatial concordance between the spatial pattern of (18)F-FLT uptake and that of cell proliferation even when high-resolution ex vivo autoradiography imaging is used for (18)F-FLT imaging. PMID- 22444240 TI - Regulation of B-cell responses by Toll-like receptors. AB - The discovery of host-encoded gene products that sense molecular patterns in infectious microbes, and the demonstration of their role in triggering innate and adaptive immune responses, has been a key milestone in our understanding of immunology. Twenty-three years after Janeway first outlined the fundamental concepts of the 'pattern recognition' model, and 15 years since the identification of Toll-like receptors (TLRs) as pattern recognition receptors (PRRs), new insights continue to be revealed, and questions remain. For example, innate immune responses to microbes that are mediated by PRRs have historically been viewed as the domain of innate immune cell populations such as dendritic cells and macrophages. New evidence, however, has pointed to the role of B-cell intrinsic TLR activation in shaping antibody responses. These studies have revealed that TLRs regulate a complex transcriptional network that controls multiple steps in the development of antigen-specific antibodies. This review covers these recent developments regarding the role of TLRs in B-cell gene expression and function in vitro and in vivo, and highlights the remaining challenges in the field, with particular emphasis on the role of TLRs in antibody responses to viral infection. A more complete understanding of how TLRs regulate antibody responses will lead to improved vaccine design. PMID- 22444242 TI - Novel approaches to improve the therapeutic index of head and neck radiotherapy: an analysis of data from the PARSPORT randomised phase III trial. AB - PURPOSE: Subjective xerostomia is a common side-effect following radiotherapy for the treatment of head-and-neck cancer. Standard mean dose models previously used to model xerostomia only that partially predict the occurrence of xerostomia. Studies in animal models have suggested that there are regional variations in the radiosensitivity of the parotid glands. In this work we tested the hypothesis that this is also true for the human parotid gland. METHODS: We present novel dose-response models explicitly taking the spatial distribution of the radiation dose into account. We considered dose to the submandibular gland and other clinical factors and used a variable-selection algorithm to select the best dose response model. This methodology was applied to 63 head and neck cancer patients and validated using two independent patient cohorts of 19 and 29 patients, respectively. RESULTS: The predictive accuracy of dose-response models improved significantly when including regional variations of radiosensitivity of the parotid glands compared to standard mean-dose models (p = 0.001, t-test). Beneficial dose-pattern analysis demonstrated the importance of minimising dose to the lateral and cranial component of the human parotid gland in order to avoid xerostomia. Furthermore we found an evidence that surgical removal of the sub mandibular gland significantly increases the risk of radiation-induced xerostomia. CONCLUSION: Dose-response models which take the shape of the dose distribution into account predicted xerostomia significantly better than standard mean-dose models. Our novel model could be used to rank potential treatment plans more reliably according to their therapeutic index and may be useful to generate better treatment plans. PMID- 22444243 TI - The updated ESTRO core curricula 2011 for clinicians, medical physicists and RTTs in radiotherapy/radiation oncology. AB - INTRODUCTION: In 2007 ESTRO proposed a revision and harmonisation of the core curricula for radiation oncologists, medical physicists and RTTs to encourage harmonised education programmes for the professional disciplines, to facilitate mobility between EU member states, to reflect the rapid development of the professions and to secure the best evidence-based education across Europe. MATERIAL AND METHODS: Working parties for each core curriculum were established and included a broad representation with geographic spread and different experience with education from the ESTRO Educational Committee, local representatives appointed by the National Societies and support from ESTRO staff. RESULTS: The revised curricula have been presented for the ESTRO community and endorsement is ongoing. All three curricula have been changed to competency based education and training, teaching methodology and assessment and include the recent introduction of the new dose planning and delivery techniques and the integration of drugs and radiation. The curricula can be downloaded at http://www.estro-education.org/europeantraining/Pages/EuropeanCurricula.aspx. CONCLUSION: The main objective of the ESTRO core curricula is to update and harmonise training of the radiation oncologists, medical physicists and RTTs in Europe. It is recommended that the authorities in charge of the respective training programmes throughout Europe harmonise their own curricula according to the common framework. PMID- 22444244 TI - Adaptive radiotherapy for long course neo-adjuvant treatment of rectal cancer. AB - PURPOSE: To quantify the potential margin reduction with adaptive radiotherapy (ART) during neo-adjuvant treatment of locally-advanced rectal cancer. METHODS AND MATERIALS: Repeat CT scans were acquired for 28 patients treated with 25*2 Gy, daily during the first week, and followed by weekly scans. The CTV was delineated on all scans, and shape variation was estimated. Five ART strategies were tested, consisting of an average CTV over the planning CT and one to five repeat CTs. Required PTV margins were calculated for adapted and non-adapted treatment. The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated. RESULTS: Substantial systematic and random shape variation demanded for a PTV margin up to 2.4 cm at the upper-anterior part of the CTV. Plan adaptation after fraction 4 resulted in a maximum 0.7 cm margin reduction and a significant PTV reduction from 1185 to 1023 cc (p<0.0001). The bowel area volume receiving 15, 45, and 50 Gy was reduced from 436 to 402 cc, 111 to 81 cc, and 49 to 29 cc, respectively (p<0.0001). CONCLUSIONS: With adaptive radiotherapy, maximum required PTV margins can be reduced from 2.4 to 1.7 cm, resulting in significantly less dose to the bowel area. PMID- 22444245 TI - Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy. AB - To identify the upstream signals of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy (TLE), we evaluated by immunohistochemistry and confocal microscopy brain tissues of 13 TLE patients and 5 control patients regarding expression of chemokines and cell-cycle proteins. The chemokine RANTES (CCR5) and other CC-chemokines and apoptotic markers (caspase-3, -8, -9) were expressed in lateral temporal cortical and hippocampal neurons of TLE patients, but not in neurons of control cases. The chemokine RANTES is usually found in cytoplasmic and extracellular locations. However, in TLE neurons, RANTES was displayed in an unusual location, the neuronal nuclei. In addition, the cell cycle regulatory transcription factor E2F1 was found in an abnormal location in neuronal cytoplasm. The pro-inflammatory enzyme cyclooxygenase-2 and cytokine interleukin-1beta were expressed both in neurons of patients suffering from temporal lobe epilepsy and from cerebral trauma. The vessels showed fibrin leakage, perivascular macrophages and expression of IL-6 on endothelial cells. In conclusion, the cytoplasmic effects of E2F1 and nuclear effects of RANTES might have novel roles in neuronal apoptosis of TLE neurons and indicate a need to develop new medical and/or surgical neuroprotective strategies against apoptotic signaling by these molecules. Both RANTES and E2F1 signaling are upstream from caspase activation, thus the antagonists of RANTES and/or E2F1 blockade might be neuroprotective for patients with medically intractable temporal lobe epilepsy. The results have implications for the development of new medical and surgical therapies based on inhibition of chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy. PMID- 22444246 TI - A Rehabilomics focused perspective on molecular mechanisms underlying neurological injury, complications, and recovery after severe TBI. AB - The molecular mechanisms underlying TBI pathophysiology and recovery are both complex and varied. Further, the pathology underlying many of the clinical sequelae observed in this population evolve over the acute injury period and encompass the subacute and chronic phases of recovery, supporting the contemporary concept that TBI is a chronic disease rather than a static insult from which limited recovery occurs. TBI related complications can also span from acute care to the very chronic stages of recovery that occur years after the initial trauma. Despite ongoing neurodegeneration, the TBI recovery period is also characterized by a propensity for neuroplasticity and rewiring through multiple mechanisms. This review summarizes key elements of acute pathophysiology, how they link to structural damage and ongoing degeneration, and how this process coincides with a permissive neuroplastic environment. The pathophysiology of selected TBI related complications is also discussed. Each of these concepts is studied through the lens of Rehabilomics, wherein an emphasis is placed on biomarker studies characterizing these pathophysiological mechanisms, and biomarker profiles are assessed in relation to multi-modal outcomes and susceptibility to rehabilitation relevant complications. In reviewing these concepts, implications for future research and theranostic principles for patient care are presented. PMID- 22444247 TI - Reduced tonsillar expression of human beta-defensin 1, 2 and 3 in allergic rhinitis. AB - Airway infections are known to cause exacerbations of allergy and asthma. Tonsils constitute a primary site for microbial recognition and triggering of the immune system in the airways. Human beta-defensins (HBDs) are antimicrobial peptides with an important role in this defense. Our aim was to investigate HBD1-3 in tonsillar tissue and their potential role in allergic rhinitis (AR). Tonsils, obtained from patients with AR and non-allergic controls, and isolated tonsillar CD4(+), CD8(+) and CD19(+) lymphocytes were analyzed for HBD1-3 expression using real-time RT-PCR and/or immunohistochemistry. Tonsillar tissue, mixed tonsillar lymphocytes and airway epithelial cells (AECs) were cultured with or without IL 4, IL-5, IL-13 or histamine followed by measurements of HBD1-3 release using ELISA. HBD1-3 were present in tonsillar tissue, including epithelial, CD4(+), CD8(+) and CD19(+) cells. The expression was reduced in allergic compared to healthy tonsils. Stimulation of AECs with IL-4, IL-5 and histamine down-regulated the HBD release, whereas no effects were seen in cultured tonsils or lymphocytes. This study demonstrates presence of HBD1-3 in tonsils and that the levels are reduced in patients with AR. Together with the down-regulation of HBDs in epithelial cells in the presence of allergic mediators suggest that AR patients have an impaired antimicrobial defense that might make them more susceptible to respiratory tract infections. PMID- 22444248 TI - Interrogation of MDM2 phosphorylation in p53 activation using native chemical ligation: the functional role of Ser17 phosphorylation in MDM2 reexamined. AB - The E3 ubiquitin ligase MDM2 functions as a crucial negative regulator of the p53 tumor suppressor protein by antagonizing p53 transactivation activity and targeting p53 for degradation. Cellular stress activates p53 by alleviating MDM2 mediated functional inhibition, even though the molecular mechanisms of stress induced p53 activation still remain poorly understood. Two opposing models have been proposed to describe the functional and structural role in p53 activation of Ser17 phosphorylation in the N-terminal "lid" (residues 1-24) of MDM2. Using the native chemical ligation technique, we synthesized the p53-binding domain (1 109)MDM2 and its Ser17-phosphorylated analogue (1-109)MDM2 pS17 as well as (1 109)MDM2 S17D and (25-109)MDM2, and comparatively characterized their interactions with a panel of p53-derived peptide ligands using surface plasmon resonance, fluorescence polarization, and NMR and CD spectroscopic techniques. We found that the lid is partially structured in apo-MDM2 and occludes p53 peptide binding in a ligand size-dependent manner. Binding of (1-109)MDM2 by the (15 29)p53 peptide fully displaces the lid and renders it completely disordered in the peptide-protein complex. Importantly, neither Ser17 phosphorylation nor the phospho-mimetic mutation S17D has any functional impact on p53 peptide binding to MDM2. Although Ser17 phosphorylation or its mutation to Asp contributes marginally to the stability of the lid conformation in apo-MDM2, neither modification stabilizes apo-MDM2 globally or the displaced lid locally. Our findings demonstrate that Ser17 phosphorylation is functionally neutral with respect to p53 binding, suggesting that MDM2 phosphorylation at a single site is unlikely to play a dominant role in stress-induced p53 activation. PMID- 22444249 TI - Estimation of the electron beam-induced specimen heating and the emitted X-rays spatial resolution by Kossel microdiffraction in a scanning electron microscope. AB - A Kossel microdiffraction experimental setup has been developed inside a Scanning Electron Microscope for crystallographic orientation, strain and stress determination at a micrometer scale. This paper reports an estimation of copper and germanium specimens heating due to the electron beam bombardment. The temperature rise is calculated from precise lattice parameters measurement considering different currents induced in the specimens. The spatial resolution of the technique is then deduced. PMID- 22444250 TI - Effects of facial expression and gaze direction on approach-avoidance behaviour. AB - Humans must coordinate approach-avoidance behaviours with the social cues that elicit them, such as facial expressions and gaze direction. We hypothesised that when someone is observed looking in a particular direction with a happy expression, the observer would tend to approach that direction, but that when someone is observed looking in a particular direction with a fearful expression, the observer would tend to avoid that direction. Twenty-eight participants viewed stimulus faces with averted gazes and happy or fearful expressions on a computer screen. Participants were asked to grasp (approach) or withdraw from (avoid) a left- or right-hand button depending on the stimulus face's expression. The results were consistent with our hypotheses about avoidance responses, but not with respect to approach responses. Links between social cues and adaptive behaviour are discussed. PMID- 22444251 TI - Identification of genes affecting expression of phosphoglycerate kinase on the surface of group B streptococcus. AB - Group B streptococcal phosphoglycerate kinase (GBS-PGK), a glycolytic enzyme, has previously been identified on the surface of group B streptococcus (GBS). To identify genes involved in surface expression of GBS-PGK, we performed Tn917 mutagenesis followed by quantification of PGK expressed on the GBS surface. Tn917 mutagenesis identified 4 genes (sag0966, sag0979, sag0980, and sag1003) that when disrupted, alter expression of GBS-PGK on the bacterial surface. Three of the identified genes were localized to a region of the GBS genome containing genes (sag0973-sag0977) predicted to be involved in resistance to antimicrobial peptides. One mutant isolate, designated NCS13sag1003::Tn917, was found to have increased sensitivity to the antimicrobial peptides bacitracin and nisin. In addition, all of the mutant strains assayed were found to have decreased beta hemolysis. In conclusion, we have identified genes involved in surface expression of GBS-PGK. These genes also appear to be involved in antimicrobial peptide resistance and regulate expression of the beta-hemolysin. PMID- 22444252 TI - Complications of high grade liver injuries: management and outcomewith focus on bile leaks. AB - BACKGROUND: Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to expect an increased risk of hepatic complications following trauma. The aim of the current study was to define hepatic related morbidity in patients sustaining high-grade hepatic injuries that could be safely managed non-operatively. PATIENTS AND METHODS: This is a retrospective study of patients with liver injury admitted to Hadassah-Hebrew University Medical Centre over a 10-year period. Grade 3-5 injuries were considered to be high grade. Collected data included the number and types of liver-related complications. Interventions which were required for these complications in patients who survived longer than 24 hours were analysed. RESULTS: Of 398 patients with liver trauma, 64 (16%) were found to have high-grade liver injuries. Mechanism of injury was blunt trauma in 43 cases, and penetrating in 21. Forty patients (62%) required operative treatment. Among survivors 22 patients (47.8%) developed liver-related complications which required additional interventional treatment. Bilomas and bile leaks were diagnosed in 16 cases post-injury. The diagnosis of bile leaks was suspected with abdominal CT scan, which revealed intraabdominal collections (n = 6), and ascites (n = 2). Three patients had continuous biliary leak from intraabdominal drains left after laparotomy. Nine patients required ERCP with biliary stent placement, and 2 required percutaneous transhepatic biliary drainage. ERCP failed in one case. Four angioembolizations (AE) were performed in 3 patients for rebleeding. Surgical treatment was found to be associated with higher complication rate. AE at admission was associated with a significantly higher rate of biliary complications. There were 24 deaths (37%), the majority from uncontrolled haemorrhage (18 patients). There were only 2 hepatic-related mortalities due to liver failure. CONCLUSIONS: A high complication rate following high-grade liver injuries should be anticipated. In patients with clinical evidence of biliary complications, CT scan is a useful diagnostic and therapeutic tool. AE, ERCP and temporary internal stenting, together with percutaneous drainage of intra abdominal or intrahepatic bile collections, represents a safe and effective strategy for the management of complications following both blunt and penetrating hepatic trauma. PMID- 22444253 TI - Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa. AB - BACKGROUND: RhoA-Rho kinase complex contributes to keep the cavernosus smooth muscle contracted and its inhibition is considered a potential strategy for the therapy of erectile dysfunction (ED). METHODS: We compared the effects of SAR407899, the Rho-kinase inhibitor Y-27632 and the PDE5 inhibitor sildenafil for their ability to relax corpus cavernosum strips contracted with phenylephrine in healthy and diabetic animals. Strips were obtained from WKY, spontaneous hypertensive (SHR), control CD, and diabetic CD rats, humans, control and diabetic rabbits. Diabetes was induced by streptozotocin or alloxan injection. In vivo penile erection (length) induced by drugs was measured in conscious rabbits. RESULTS: SAR407899 dose-dependently relaxed the pre-contracted corpora cavernosa in all species, with similar potency and efficacy in healthy vs diabetic rats, WKY vs SHR rats, healthy vs diabetic rabbits (IC(50) range from 0.05 to 0.29 MUM, Emax range 89 to 97%). In the presence of the NO-synthase (NOS) inhibitor, L NAME, the SAR407899 response did not decrease in any of the species or experimental conditions. The effect was confirmed in human strips where sildenafil was significantly less potent and effective, with IC50 respectively 0.13 and 0.51 MUM; Emax 92 and 43%. Unlike SAR407899, the potency and efficacy of sildenafil and Y27632 were significantly reduced by diabetes and L-NAME. In vivo, SAR407899 dose-dependently induced rabbit penile erection, with greater potency and longer duration of action than sildenafil. Sildenafil, but not SAR407899, was less effective in alloxan-induced diabetes. CONCLUSION: The induction of penile erection by SAR407899, unlike that by sildenafil, is largely independent of e-NO activity. This suggests its use in erectile dysfunction for diabetic and hypertensive patients where e-NO activity is impaired. PMID- 22444254 TI - A methodological approach to identify cheap and accurate indicators for biodiversity assessment: application to grazing management and two grassland bird species. AB - In response to environmental threats, numerous indicators have been developed to assess the impact of livestock farming systems on the environment. Some of them, notably those based on management practices have been reported to have low accuracy. This paper reports the results of a study aimed at assessing whether accuracy can be increased at a reasonable cost by mixing individual indicators into models. We focused on proxy indicators representing an alternative to the direct impact measurement on two grassland bird species, the lapwing Vanellus vanellus and the redshank Tringa totanus. Models were developed using stepwise selection procedures or Bayesian model averaging (BMA). Sensitivity, specificity, and probability of correctly ranking fields (area under the curve, AUC) were estimated for each individual indicator or model from observational data measured on 252 grazed plots during 2 years. The cost of implementation of each model was computed as a function of the number and types of input variables. Among all management indicators, 50% had an AUC lower than or equal to 0.50 and thus were not better than a random decision. Independently of the statistical procedure, models combining management indicators were always more accurate than individual indicators for lapwings only. In redshanks, models based either on BMA or some selection procedures were non-informative. Higher accuracy could be reached, for both species, with model mixing management and habitat indicators. However, this increase in accuracy was also associated with an increase in model cost. Models derived by BMA were more expensive and slightly less accurate than those derived with selection procedures. Analysing trade-offs between accuracy and cost of indicators opens promising application perspectives as time consuming and expensive indicators are likely to be of low practical utility. PMID- 22444255 TI - Understanding the reproductive performance of a dairy cattle herd by using both analytical and systemic approaches: a case study based on a system experiment. AB - Reproductive performance has recently been a growing concern in cattle dairy systems, but few research methodologies are available to address it as a complex problem in a livestock farming system. The aim of this paper is to propose a methodology that combines both systemic and analytical approaches in order to better understand and improve reproductive performance in a cattle dairy system. The first phase of our methodology consists in a systemic approach to build the terms of the problem. It results in formalising a set of potential risk factors relevant for the particular system under consideration. The second phase is based on an analytical approach that involves both analysing the shapes of the individual lactation curves and carrying out logistic regression procedures to study the links between reproductive performance and the previously identified potential risk factors. It makes it possible to formulate hypotheses about the biotechnical phenomena underpinning reproductive performance. The last phase is another systemic approach that aims at suggesting new practices to improve the situation. It pays particular attention to the consistency of those suggestions with the farmer's general objectives. This methodology was applied to a French system experiment based on an organic low-input grazing system. It finally suggested to slightly modify the dates of the breeding period so as to improve reproductive performance. The formulated hypotheses leading to this suggestion involved both the breed (Holstein or Montbeliarde cows), the parity, the year and the calving date with regard to the turnout date as the identified risk factors of impaired performance. Possible use of such a methodology in any commercial farm encountering a biotechnical problem is discussed. PMID- 22444256 TI - A conceptual model of farmers' informational activity: a tool for improved support of livestock farming management. AB - Farmers have been slow to adopt decision support system (DSS) models and their outputs, mainly owing to (i) the complexity of the data involved, which most potential users are unable to collect and process; and (ii) inability to integrate these models into real representations of their informational environments. This situation raises questions about the way farm management researchers have modelled information and information management, and especially about the quality of the information assessed by the farmers. We consider that to review advisory procedures we need to understand how farmers select and use farm management-related information, rather than focusing on decisions made in particular situations. The aim of this study was to build a conceptual model of the farmer-targeted farm management-related information system. This model was developed using data collected in commercial beef cattle farms. The design structure and operational procedures are based on (i) data categories representing the diversity of the informational activity; and (ii) selected criteria for supporting decisions. The model is composed of two subsystems, each composed of two units. First, an organizational subsystem organizes, finalizes and monitors informational activity. Second, a processing subsystem builds and exploits the informational resources. This conceptual model makes it possible to describe and understand the diverse range of farmers' informational activity by taking into account both the flow of information and the way farmers make sense of that information. This model could serve as a component of biodecisional DSS models for assigning information in the decision-making process. The next task will be to take into account the broad range of farmers' perceptions of the management situations in DSS models. PMID- 22444257 TI - Identification and validation of reference genes for gene expression studies in water buffalo. AB - In gene expression analysis, a key step to obtain informative data from reverse transcription quantitative PCR (RT qPCR) assay is normalization, that is usually achieved by ratio to correct the abundance of the gene of interest against that of an endogenous reference gene. The finding of such reference genes, ideally expressed in a stable way in multiple tissue samples and in different experimental conditions, is a non-trivial problem. In this work, a set of genes potentially useful as reference for gene expression studies in water buffalo has been identified and evaluated. In the first step, a publicly available Bos taurus expressed sequence tags database has been downloaded from the TIGR Gene Index and mined by some simple frequency algorithms to find out which tentative consensuses are present in a remarkable number of different cDNA libraries and, consequently, are more suitable to be included in a starter set of candidate reference genes. To validate the potential of such candidates for their use as normalizers in buffalo gene expression analysis, an RT qPCR analysis has been carried out, in which the expression stability of these genes has been evaluated on a panel of buffalo tissues and organs. Our results indicate that ribosomal proteins L4 and L5 and Gek protein encoding genes can be useful as normalizers to compare gene expression levels across tissues and organs in buffalo. PMID- 22444258 TI - A whole genome scan to detect quantitative trait loci for gestation length and sow maternal ability related traits in a White Duroc * Erhualian F2 resource population. AB - Gestation length and maternal ability are important to improve the sow reproduction efficiency and their offspring survival. To map quantitative trait loci (QTL) for gestation length and maternal ability related traits including piglet survival rate and average body weight of piglets at weaning, more than 200 F2 sows from a White Duroc * Erhualian resource population were phenotyped. A genome-wide scan was performed with 194 microsatellite markers covering the whole pig genome. QTL analysis was carried out using a composite regression interval mapping method via QTL express. The results showed that total number of born piglets was significantly correlated with gestation length (r = -0.13, P < 0.05). Three QTL were detected on pig chromosome (SSC)2, 8 and 12 for gestation length. The QTL on SSC2 achieved the 5% genome-wide significant level and the QTL on SSC8 was consistent with previous reports. Four suggestive QTL were identified for maternal ability related traits including 1 QTL for survival rate of piglets at weaning on SSC8, 3 QTL for average body weight of piglet at weaning on SSC3, 11 and 13. PMID- 22444259 TI - Pedigree estimation of the (sub) population contribution to the total gene diversity: the horse coat colour case. AB - A method to quantify the contribution of subpopulations to genetic diversity in the whole population was assessed using pedigree information. The standardization of between- and within-subpopulation mean coancestries was developed to account for the different coat colour subpopulation sizes in the Spanish Purebred (SPB) horse population. The data included 166264 horses registered in the SPB Studbook. Animals born in the past 11 years (1996 to 2006) were selected as the 'reference population' and were grouped according to coat colour into eight subpopulations: grey (64 836 animals), bay (33 633), black (9414), chestnut (1243), buckskin (433), roan (107), isabella (57) and white (37). Contributions to the total genetic diversity were first assessed in the existing subpopulations and later compared with two scenarios with equal subpopulation size, one with the mean population size (13 710) and another with a low population size (100). Ancestor analysis revealed a very similar origin for the different groups, except for six ancestors that were only present in one of the groups likely to be responsible for the corresponding colour. The coancestry matrix showed a close genetic relationship between the bay and chestnut subpopulations. Before adjustment, Nei's minimum distance showed a lack of differentiation among subpopulations (particularly among the black, chestnut and bay subpopulations) except for isabella and white individuals, whereas after adjustment, white, roan and grey individuals appeared less differentiated. Standardization showed that balancing coat colours would contribute preserving the genetic diversity of the breed. The global genetic diversity increased by 12.5% when the subpopulations were size standardized, showing that a progressive increase in minority coats would be profitable for the genetic diversity of this breed. The methodology developed could be useful for the study of the genetic structure of subpopulations with unbalanced sizes and to predict their genetic importance in terms of their contribution to genetic variability. PMID- 22444260 TI - Heat-treatment, phytase and fermented liquid feeding affect the presence of inositol phosphates in ileal digesta and phosphorus digestibility in pigs fed a wheat and barley diet. AB - The aim was to evaluate the effect of heat-treatment, microbial phytase addition and feeding strategy (dry feeding v. fermented liquid feeding) on degradation of phytate (myo-inositol hexakisphosphate, InsP6) and formation and further degradation of lower inositol phosphates (myo-inositol pentakisphosphate-myo inositol bisphosphate, InsP5-InsP2) at the distal ileum of pigs. Furthermore, the apparent ileal digestibility/degradability (AID) of phosphorus (P), InsP6-P and calcium (Ca) and the apparent total tract digestibility (ATTD) of P and Ca were studied. Pigs were fitted with a T-shaped ileal cannula for total collection of digesta at 2 h intervals during an 8 h sampling period after feeding the morning meal. Each period lasted for 2 weeks: 8 days of adaptation followed by 3 days of total collection of faeces and 3 days of total collection of ileal digesta. The experiment was designed as a 4 * 4 Latin square with four pigs fed four diets. A basal wheat/barley-based diet was fed either as non-heat-treated or heat-treated (steam-pelleted at 90 degrees C). The heat-treatment resulted in an inactivation of plant phytase below detectable level. Diet 1 (non-heat-treated basal diet fed dry); diet 2 (heat-treated basal diet fed dry); diet 3 (as diet 2 but with microbial phytase (750 FTU/kg as fed) fed dry); diet 4 (as diet 3 fed liquid (fermented for 17.5 h nighttime and 6.5 h daytime at 20 degrees C with 50% residue in the tank)). Chromic oxide (Cr2O3) was included as marker and ATTD was determined both by total collection of faeces (ATTDTotal) and Cr2O3 (ATTDCr). InsP6 was completely degraded in diet 4 before feeding resulting in no InsP6-P being present in ileal digesta. InsP6-P concentration in ileal digesta decreased with increasing dietary levels of plant or microbial phytase in pigs fed the dry diets. Consequently, AID and ATTD of P and Ca were greatest for pigs fed diet 4 followed by diets 3, 1 and 2. The ATTD of P depended on the used method as ATTDTotal of P was 72%, 61%, 44% and 34%, whereas ATTDCr of P was 65%, 52%, 38% and 23% for diets 4, 3, 1 and 2, respectively. In all pigs the ileal concentration of InsP5-InsP2-P was extremely small, and thus unimportant for maximisation of ATTD of plant P. In conclusion, fermented liquid feeding with microbial phytase seems to be an efficient approach to improve ATTD of plant P compared with dry feeding. This opens up for further reductions in P excretion. PMID- 22444261 TI - High physiological demands in intensively raised pigs: impact on health and welfare. AB - Genetic selection and better control of the environment of the pigs have resulted in increased production levels concerning both reproduction and growth. Such high performances imply high physiological demands that may deteriorate health and welfare. The aims of this paper are to review the physiological challenges that pigs are facing, to identify possible consequences on health and welfare, to propose ways of detecting and correcting problems whenever possible. At weaning, piglets are submitted to abrupt changes in food supply, housing and social environment. Behavioural changes and efficient adaptations of the digestive tract are critical for their health and welfare. Physiological demands to support these adaptations and risks of failure are inversely related to the age of the pigs. During fattening, modern pigs have high daily weight gain especially of lean tissue as well as elevated feed conversion rate. These high growth performances are suspected to favour stress and disease susceptibility, undesirable behaviours as well as leg weakness, but further experimental data are necessary to validate these effects and find their origin. In reproductive females, high prolificacy generates elevated foetal demands for nutrients and space that are not fully met as shown by an increased number of light piglets having difficulties to adapt successfully to the neonatal life. During lactation, sows with high milk production have high nutrient requirements leading to intense catabolism that may affect their health, welfare and future reproductive abilities. PMID- 22444262 TI - Porcine models for the metabolic syndrome, digestive and bone disorders: a general overview. AB - The aim of this review article is to provide an overview of the role of pigs as a biomedical model for humans. The usefulness and limitations of porcine models have been discussed in terms of metabolic, cardiovascular, digestive and bone diseases in humans. Domestic pigs and minipigs are the main categories of pigs used as biomedical models. One drawback of minipigs is that they are in short supply and expensive compared with domestic pigs, which in contrast cost more to house, feed and medicate. Different porcine breeds show different responses to the induction of specific diseases. For example, ossabaw minipigs provide a better model than Yucatan for the metabolic syndrome as they exhibit obesity, insulin resistance and hypertension, all of which are absent in the Yucatan. Similar metabolic/physiological differences exist between domestic breeds (e.g. Meishan v. Pietrain). The modern commercial (e.g. Large White) domestic pig has been the preferred model for developmental programming due to the 2- to 3-fold variation in body weight among littermates providing a natural form of foetal growth retardation not observed in ancient (e.g. Meishan) domestic breeds. Pigs have been increasingly used to study chronic ischaemia, therapeutic angiogenesis, hypertrophic cardiomyopathy and abdominal aortic aneurysm as their coronary anatomy and physiology are similar to humans. Type 1 and II diabetes can be induced in swine using dietary regimes and/or administration of streptozotocin. Pigs are a good and extensively used model for specific nutritional studies as their protein and lipid metabolism is comparable with humans, although pigs are not as sensitive to protein restriction as rodents. Neonatal and weanling pigs have been used to examine the pathophysiology and prevention/treatment of microbial-associated diseases and immune system disorders. A porcine model mimicking various degrees of prematurity in infants receiving total parenteral nutrition has been established to investigate gut development, amino acid metabolism and non-alcoholic fatty liver disease. Endoscopic therapeutic methods for upper gastrointestinal tract bleeding are being developed. Bone remodelling cycle in pigs is histologically more similar to humans than that of rats or mice, and is used to examine the relationship between menopause and osteoporosis. Work has also been conducted on dental implants in pigs to consider loading; however with caution as porcine bone remodels slightly faster than human bone. We conclude that pigs are a valuable translational model to bridge the gap between classical rodent models and humans in developing new therapies to aid human health. PMID- 22444263 TI - Development of cloned embryos from porcine neural stem cells and amniotic fluid derived stem cells. AB - The aim of this study was to determine the developmental ability of cloned embryos derived from porcine neural stem (NS) cells, amniotic fluid-derived stem (AFS) cells, differentiated cells from NS and AFS cells, fetal fibroblast (FF) cells, adult fibroblast (AF) cells and mammary gland epithelial (MGE) cells. NS, AFS and FF cells were isolated from embryonic day 30 porcine fetus, AF and MGE cells were isolated from adult pig. NS and AFS cells were induced to differentiate into different cell types, respectively. Stem cells and their differentiated cells were harvested for analysis of the markers using reverse transcription PCR. NS and AFS cells, their differentiated cells, FF, AF and MGE cells were used for nuclear transfer, respectively. A total of 100 two-cell stage cloned embryos derived from each cell line were transferred into the oviducts of surrogate mothers. The results showed that the neurospheres were positive for the undifferentiated neural cell marker, Nestin and NS cells widely expressed NogoA, DCX, CyclinD2, CD133, Hes1, Oct4, Desmin, CD-90, Nanog and Sox2. AFS cells widely expressed NogoA, DCX, CyclinD2, CD133, Hes1, Nanog, Sox2, Oct4, Desmin and CD-90. Both NS and AFS cells were differentiated into astrocyte (GFAP+), oligodendrocyte (GalC+), neuron (NF+, NSE+ and MAP2+), adipocyte (LPL+ and PPARgamma-D+), osteoblast (Osteonectin+ and Osteocalcin+), myocyte (myf-6+ and myoD+) and endothelium (CD31+, CD34+, CD144+ and eNOS+). Four cloned fetuses (28 and 32 days) derived from NS and AFS cells were obtained. The developmental potential of the cloned embryos derived from stem cells (NS and AFS cells) were higher (P < 0.05) than that of the cloned embryos derived from somatic cells (the differentiated cells from NS and AFS cells, FF cells, AF cells and MGE cells), which suggests that the undifferentiated state of the donor cells increases cloning efficiency. PMID- 22444264 TI - Accessory sex glands as a tool to measure the efficacy of immunocastration in male pigs. AB - The use of an anti-gonadotropin-releasing hormone vaccine for immunocastration of male pigs has been recently approved in the European Union. This technique is potentially useful for avoiding both castration-associated pain for the animal and boar taint in pork. However, some animals may escape immunocastration and be slaughtered as entire males, potentially exhibiting boar taint. Therefore, it is important to check the efficacy of immunocastration on the slaughter line. To achieve that, the currently proposed method, based on testis weight, is not fully reliable because there is some overlap in the distributions of testis weight between immunocastrates and entire males. On the basis of literature data on the effect of immunocastration on the development of accessory sex glands, this paper provides evidence that the weight of seminal vesicles might be a much better criterion for checking the efficacy of immunocastration, because their size decreases more rapidly, and to a greater extent, than that of the testis. PMID- 22444265 TI - IgG absorption by Santa Ines lambs fed Holstein bovine colostrum or Santa Ines ovine colostrum. AB - The objective of this study was to evaluate the immunoglobulin G (IgG) absorption by Santa Ines lambs under two colostrum management systems usually used by producers. Twenty-seven Santa Ines newborn lambs received two meals of 250 ml of bovine colostrum from Holstein cows (BC group) or ovine colostrum from Santa Ines ewes (OC group) at 0 and 6 h of life. Pools of BC and OC were analyzed by radial immunodiffusion to quantify IgG. Results are expressed as least-square means and standard errors of mean (means +/- s.e.m.). The concentration of IgG in bovine and ovine pools averaged 115.7 +/- 20.5 and 48.1 +/- 5.0 mg/ml, respectively, levels of concentration found in similar regular colostrum managements. The efficiency of IgG absorption was evaluated under two aspects, maximum apparent efficiency of absorption and total apparent efficiency of absorption (AEAmax and AEAtotal, respectively). The AEAmax was calculated taking into account the mass of IgG ingested just in the first meal of colostrum at birth and the serum IgG concentration at 6 h while the AEAtotal took into account the serum IgG concentration at 24 h of life that reflects the first colostrum offered at birth and the second meal at 6 h. The IgG and apparent efficiency of absorption results were transformed into the square root and log base 10, respectively, and were presented as geometric least-square means. In BC, lower (P < 0.05) AEAmax and AEAtotal were verified (14.2% and 15.6%, respectively), in relation to OC (23.6% and 24.4%, respectively). Serum IgG concentrations at 24 h were significantly higher (P < 0.05) in BC (31.4 mg/ml, respectively) compared with OC (22.2 mg/ml, respectively). The results in this study confirm that there is a limitation to the process of IgG absorption by the enterocytes of newborn lambs, which determined a nonlinear behavior of passive immunity acquisition. Similar values of AEAmax and AEAtotal for the two sources of colostrum reveal that the process of IgG absorption from the first and second meals during the first 6 h of life did not change and indicates that the ingestion of a second feeding of quality colostrum can enhance the acquisition of immune protection of newborn lambs. PMID- 22444266 TI - Effect of gut active carbohydrates on plasma IgG concentrations in piglets and calves. AB - Improving immune status in neonates is crucial to health and production. Gut active carbohydrates (GAC) have been associated with increasing immunoglobin levels and immonucompetence development in mammals. The objective of the following studies was to evaluate whether GAC (mannan-oligosaccharides) applied orally to progeny immediately following parturition, improved blood plasma immunoglobulin (Ig) type G concentrations in piglets and calves. Three trials were conducted comparing control groups with those receiving GAC orally. The first two trials used piglets that were monitored for blood IgG at 2 days of age and for changes in body weight (BW), and the third trial monitored calf IgG from birth to 21 days of age. Piglets in the experimental group received 0.75 g GAC in 10 ml saline at birth and 24 h of age. The calf trial compared the control group against calves that received 22.5 g GAC mixed into 4.5 l of colostrum (to give 5 g/l) in the first 24 h after parturition. Blood serum samples were taken at 2 days post partum in piglets, and at several time points from 6 h to 21 days of age in calves, and were analysed for IgG levels by radial immunodiffusion. In the first piglet trial, significantly higher levels (32%) of IgG were observed for piglets fed GAC (P < 0.001), and in the second, IgG concentration was elevated by 23% (P < 0.01) and BW increased by 9% (P = 0.023) with GAC supplementation. Significant improvements for calves were recorded at all time points in those fed GAC (P < 0.05), with an increase in serum IgG observed after the first day, which was maintained throughout the sampling period, resulting in a difference of 39% at the end of the trial (21 d). These findings form a basis for further studies, which are required to investigate possible modes of action involved in enhancing blood immunoglobulin concentrations in young animals, and the longer-term effects this may have on the development of the immune response. PMID- 22444267 TI - Effects of restricted feeding of prepubertal ewe lambs on growth performance and mammary gland development. AB - The aim of this study was to determine the effects of restricted feeding before puberty on growth performance and mammary gland development in replacement ewe lambs. At weaning, 72 Dorset ewe lambs were assigned to one of the three diets: an ad libitum control diet with medium-quality forage (MQF; diet A-MQF); a restricted diet with the same forage as A, but less feed concentrate (diet R MQF); or a high-quality forage (HQF) diet (diet F-HQF). The quantity of concentrate offered to the group R-MQF and F-HQF ewe lambs was adjusted to obtain 70% of the control ewe lambs' growth rate. The diets were offered for 75 days after weaning to cover the allometric phase of mammary gland development. During this period, average daily gain (ADG) was 223 and 229 g/day for groups R-MQF and F-HQF, respectively, compared to 305 g/day for group A-MQF (P < 0.0001). At the end of this period, 28 ewe lambs were slaughtered and their mammary gland was collected. Parenchymal fresh tissue weight tended to be higher for groups R-MQF and F-HQF compared to group A-MQF (P = 0.09). Stroma weight was greater (P < 0.05) for the group A-MQF ewe lambs than for those in the other treatments. Total DNA and total protein in parenchymal tissue tended to be greater for groups R-MQF and F-HQF (P = 0.09 and P = 0.07, respectively). Dry fat-free tissue was greater for groups R-MQF and F-HQF (P < 0.05). The remaining ewe lambs were fed the same haylage and barley diet until their first lambing. During this period, compensatory growth was observed. ADG was greater (P < 0.01) for groups R-MQF and F-HQF than for group A-MQF, and feed conversion was improved (P < 0.01) for groups R-MQF and F-HQF compared with the control, whereas the dry matter intake was similar for all groups. Live body weight, loin eye depth and backfat depth at breeding and around lambing were similar for all groups. The results of this study suggest that restricted feeding before puberty improves mammary gland development without compromising growth performance in ewe lambs. PMID- 22444268 TI - Gnawing bones as enrichment for farmed blue foxes ( Vulpes lagopus). AB - According to present acts and regulations, farmed foxes shall have a gnawing or other enrichment object in their cages. However, research on the welfare effects of gnawing objects has been scarce. We assessed physiology and health, that is weight development, urinary cortisol-creatinine ratio, serum cortisol level after adrenocorticotropic hormone administration, internal organ masses and incidence of gastric ulcerations as well as dental and overall oral health, in pair-housed juvenile blue foxes that were housed either with or without a possibility to interact with bones (cattle femur) during their growing season (July to December). The results show that the physiological effects of the possibility to interact with bones were either non-significant or suggested that competition for bones may jeopardize the welfare of subordinate individuals. However, the results clearly show that gnawing bones are beneficial for the dental health of farmed foxes. PMID- 22444269 TI - Naringin dietary supplementation at 0.15% rates does not provide protection against sub-clinical acidosis and does not affect the responses of fattening lambs to road transportation. AB - Forty Assaf fattening lambs (initial age 13 to 15 weeks) offered a diet of barley straw and a commercial concentrate were used to assess the effect of naringin (a type of citrus flavonoid with proven antioxidant, antimicrobial and anti inflammatory properties in monogastric animals) at a dose of 1.5 g/kg per dry matteron plasma lipid peroxidation thiobarbituric acid reactive substances (TBARS), immune response, ruminal bacterial community and protection provided by the ruminal wall against subclinical acidosis. After 49 days of the experimental diets, lambs were subjected to a 4-h transportation stress period. As expected, TBARS values were significantly increased in all the lambs just after the transportation period, but no effect of naringin was observed. Although naringin lowered red blood cell count, neither the total white blood cells counts nor the production of IFN-gamma were affected by naringin. No anti-inflammation activity preventing rumenitis was detected, but a clear effect on ruminal bacterial community was observed in lambs consuming naringin. Further experiments, using different doses of naringin might show health benefits of naringin supplementation in lambs, but a clear beneficial effect on health was not readily apparent in this study. PMID- 22444270 TI - Immunocastration reduces aggressive and sexual behaviour in male pigs. AB - The aim of this study was to evaluate the effectiveness of a gonadotropin releasing hormone (GnRH) vaccine, ImprovacTM (Pfizer Ltd), in suppressing aggressive and sexual behaviour of male pigs. One hundred and thirty-six pigs were assigned to three treatments: entire male pigs (n = 64), immunocastration against GnRH (n = 48) and surgical castration (n = 24). Surgical castration was performed before the age of 1 week. Vaccination comprised two injections: the first injection was given 8 to 11 weeks before slaughter and the second injection 4 weeks before slaughter. After the second injection, immunocastrated pigs showed less non-violent social and aggressive behaviours than entire male pigs of the same age. Mounting was reduced to the same low level as observed in surgically castrated pigs, and more immunocastrated pigs were without skin lesions compared with entire male pigs. Pigs that received the second injection only 1 week before the observation day did not differ significantly in behaviour from those that received the injection 3 weeks before the observation day. Thus, the behaviour seems to change soon after the second injection and these changes remain until slaughter. PMID- 22444271 TI - A note on heat shock protein 70 expression in goats subjected to road transportation under hot, humid tropical conditions. AB - The influence of two different stocking densities (0.20 m2/animal and 0.40 m2/animal) in transit under the hot, humid tropical conditions on heat shock protein (hsp) 70 induction was investigated in 60 Boer does. The animals were road transported for 3 h and the control group was kept under normal conditions in the farm. Irrespective of stocking density, transportation significantly increased hsp 70 densities (P < 0.05) in the kidneys. The hsp 70 response in the kidneys was more profound compared with those of heart tissues. Higher stocking density was more stressful to the goats based on hsp 70 expression. These results suggest that, irrespective of stocking density, transportation under hot, humid tropical conditions evoked hsp 70 reactions. PMID- 22444272 TI - Correction to "improved coiled-coil design enhances interaction with bcr-abl and induces apoptosis". PMID- 22444273 TI - Erythropoietin enhances cell proliferation and survival of human fetal neuronal progenitors in normoxia. AB - Extensive data reporting the neurogenerative, neuroprotective and neuroregenerative potential of erythropoietin (EPO), mainly on RNA level, can be found in the literature. However, there is still a poor knowledge on the response of neuronal progenitor cells (NPC) upon stimulation with EPO in terms of the protein species involved. Herein, the effect of EPO on the proliferation of human mesencephalic NPC (hmNPC) under normoxia is monitored using cellular assays and proteomic analysis (two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry). The administration of EPO increased the proliferation of hmNPC within 4 days after application. It positively influenced the cell-cycle progression by affecting the G2 phase of the cell cycle. A proteomic analysis of the protein expression in hmNPC cultures 4 days after EPO treatment identified 8 proteins differentially expressed in EPO-treated cultures. It is likely that one or more of the identified proteins are involved in cellular pathways that promote cell proliferation and differentiation of hmNPC under normoxia. Their further characterization could provide cellular targets for the development of new therapeutic agents to treat CNS injury. Moreover, as EPO signaling is hypoxia inducible, our findings may also indicate the beneficial effect of EPO to mimic hypoxia, while bypassing its negative effects, to culture human fetal midbrain derived progenitor cells. PMID- 22444274 TI - Spatiotemporal dynamics of diffusional kurtosis, mean diffusivity and perfusion changes in experimental stroke. AB - Diffusional kurtosis imaging (DKI), which measures the non-Gaussianity of water diffusion, has been demonstrated to be a sensitive biomarker in many neuropathologies. The goal of this study was to longitudinally examine the spatiotemporal dynamics of DKI in cerebral ischemia in an animal model of permanent and transient (45 min) middle cerebral artery occlusion (MCAO) during the hyperacute, acute and chronic phases. Diffusional kurtosis showed different spatiotemporal dynamics. In particular, mean kurtosis (MK) was sensitive to hyperacute and acute stroke changes, and exhibited different contrast than mean diffusivity (MD) and higher contrast than fractional anisotropy (FA) and T2. MK contrast persisted 1 to 7 days post-occlusion, whereas MD showed renormalization at day 1-2 and reversed contrast at day 7. The current study showed that DKI has the potential to complement existing stroke imaging techniques, particularly in the assessment of subacute to early chronic stroke evolution. PMID- 22444275 TI - Perivascular and perineural extension of formed and soluble blood elements in an intracerebral hemorrhage rat model. AB - The perivascular and perineural extension of hematoma has recently been observed in the brain after intracerebral hemorrhage (ICH), which is formed by the leakage of hematoma via the Virchow-Robin spaces (VRS) and the spaces around the nerve fibers (perineurium). The present study investigated the perivascular and perineural extension of a hematoma by studying the distribution of the formed and soluble blood elements labeled with different fluorescein dyes at different times after ICH in a rat model. The ICH rat model was prepared using a modified double injection method. Autologous blood, which contained fluorescein isothiocyanate (FITC)-labeled RBCs or carboxytetramethylrhodamine (TAMRA)-labeled BSA, was injected into the center of the left caudate nucleus. Brain sections were prepared and observed by overlaying fluorescence and hematoxylin and eosin stained images. The formed blood elements extended mainly into the VRS and perineurium in the perihematomal tissue and ipsilateral brain regions near the hematoma. The soluble blood elements extended more extensively to almost all regions of the brain, including some remote brain areas, such as the contralateral cerebral hemisphere and brainstem. Moreover, the fluorescein dyes were observed in lymph sinuses in the bilateral deep cervical lymph nodes as early as 1 hour after ICH. Lymphostasis, which peaked three days after ICH, was observed in the brain tissues around hematoma. The current findings suggest that the perivascular and perineural extension of hematomas widespread distributes in the central nervous system, and is involved in a series of pathologic processes in ICH, such as the remote effects of a hematoma and lymphatic encephalopathy. PMID- 22444276 TI - Hyperbaric oxygen preconditioning protects cortical neurons against oxygen glucose deprivation injury: role of peroxisome proliferator-activated receptor gamma. AB - Ischemic stroke is one of the leading causes of mortality and disability worldwide. Our previous studies have shown that hyperbaric oxygen (HBO) preconditioning can afford significant neuroprotection against cerebral ischemia reperfusion (I/R) injury in rats. However, it is still unknown whether HBO preconditioning can directly protect primary cultured cortical neurons against oxygen-glucose deprivation (OGD). Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a central role in the regulation of apoptosis, oxidative stress and inflammation as well as affords significant neuroprotection against cerebral I/R injury. 15-deoxy-?(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous ligand with a high affinity for PPAR gamma. Recently, some studies demonstrate that activation of PPAR gamma mediates lipopolysaccharide and anesthetic preconditioning. In the present study, we firstly found that OGD exposure caused the significant damage of cultured cortical neurons evaluated by cell viability, lactate dehydrogenase (LDH) release and caspase-3 activity, which were significantly ameliorated by HBO preconditioning. Furthermore, HBO preconditioning significantly increased the levels of PPAR gamma mRNA and protein, PPAR gamma DNA binding activity, 15d-PGJ(2) and antioxidant enzymatic activities in primary cultured cortical neurons with OGD exposure. Moreover, PPAR gamma antagonist GW9662 dose-dependently abolished the protection of HBO preconditioning in OGD-exposed neurons. GW9662 blocked the increase of PPAR gamma DNA binding activity and antioxidant enzymatic activities, but did not influence the 15d-PGJ(2) level in OGD-exposed neurons with HBO preconditioning. However, the cyclooxygenase (COX)-2 inhibitor NS-398 blocked the production of 15d-PGJ(2) in OGD-exposed neurons with HBO preconditioning. In addition, 15d-PGJ(2) preconditioning could also protect cultured neurons against OGD injury. These results demonstrate that HBO preconditioning has directly beneficial effects on ODG-exposed cortical neurons by the activation of PPAR gamma subsequent to the production of 15d-PGJ(2), which in turn increases the downstream antioxidant enzymatic activities. PMID- 22444277 TI - Cognitive control: preparation of task switching components. AB - Task performance often improves when tasks can be prepared in advance. However, the mechanisms that support advance preparation are highly debated. Proceeding under the hypothesis that switch-specific neural activation during advance preparation is the hallmark of controlled processing, this study investigates the behavioral and neural effects of component preparation during task-switching. Toward this end, fMRI was used to observe neural activity during preparation of response rules (RULE task) compared to preparation of stimulus set (PERCEPTUAL task). We predicted that switch-specific activation would be observed for RULE and PERCEPTUAL switching when component preparation was isolated from target related activation. The results indicated that preparation for both tasks was supported by common regions of activation; however preparation for switches of response rule was supported by switch-specific activation of the anterior cingulate (ACC) and left lateral prefrontal cortex (LPFC). Shift-cost was also eradicated in this condition with enough preparation time, and was associated with an increase in ACC activation. Switches of stimulus set were not marked by specific neural activity during the preparation interval. While the amount of preparation time affected overall performance, PERCEPTUAL task switches did not benefit more from preparation time than task repeats. It was concluded that response rules can be reconfigured pre-target due to the support of ACC-LPFC activation, where preparation of stimulus sets is supported by a general type of configuration common to both components. PMID- 22444278 TI - Functional improvement and neuroplastic effects of anodal transcranial direct current stimulation (tDCS) delivered 1 day vs. 1 week after cerebral ischemia in rats. AB - Transcranial direct current stimulation (tDCS) is an emerging tool for improving recovery from stroke. However, there has been no trial to determine whether it has a therapeutic benefit in the early stage of cerebral ischemia, and there is no consensus on the optimal time window of stimulation. Here, we described the effects of anodal tDCS in early cerebral ischemia, assessing functional improvements and changes in neuronal plasticity, and identifying the optimal time window for delivering tDCS to maximize functional gains. Thirty rats were randomly assigned to three groups: sham (n=10); early tDCS (ET), receiving tDCS 1day after ischemia for 5 days (n=10), and late tDCS (LT), receiving tDCS 1 week after ischemia for 5 days (n=10). Both ET and LT groups showed improved Barnes maze performance and motor behavioral index scores. However, only the LT group exhibited improvement in beam balance test. Immunohistochemical stainings showed that the ET group reinforced notable MAP-2 expression and the LT group enhanced mainly the level of GAP-43 in both peri-lesional and contralesional cortex. These immunohistochemical results had significant correlation with behavioral and cognitive functions. However, brain MRI and (1)H MRS showed no significant differences among the three groups in ischemic volume and metabolic alteration. These results suggest that anodal tDCS has the potential to modulate neural plasticity around the ischemic penumbra and even in the contralesional area without aggravating infarction volume and metabolic alteration. The degree of functional improvement was slightly greater when tDCS was applied 1 week rather than 1 day after ischemic injury. PMID- 22444280 TI - De-escalation of surgery for early oral cancer--is it oncologically safe? AB - This study is a review of practice for patients with T1 or T2 squamous cell carcinoma (SCC) of the anterior tongue and floor of the mouth who presented to the regional maxillofacial unit in Liverpool between 1992 and 2007. We examined trends in management and analysed their effects on resection margins, recurrence, and survival. The Liverpool head and neck oncology database was used to identify patients, and to retrieve their clinical, surgical, and pathological data. When data were missing the case notes and pathology records were reviewed. Follow up was taken to January 2011. A total of 382 patients were included. Despite more conservative treatment with closer resection margins (27% in 1992-1995 and 60% in 2004-2007), fewer free flaps (79% in 1992-1995 and 38% in 2004-2007), and less adjuvant radiotherapy (37% in 1992-1995 and 22% in 2004-2007), there has been no significant increase in local recurrence (14% in 1992-1996 and 8% in 2004-2007), and overall survival has not been adversely affected. This is most striking when T1 tumours are considered in isolation with a consistent trend towards fewer clear margins (95% in 1992-1995 and 28% in 2004-2007) and fewer free flaps (53% in 1992-1995 and 11% in 2004-2007). The case mix was similar over the study period. These data support a more conservative approach to the management of early oral cancer. PMID- 22444281 TI - Tardiphaga robiniae gen. nov., sp. nov., a new genus in the family Bradyrhizobiaceae isolated from Robinia pseudoacacia in Flanders (Belgium). AB - Gram-negative, rod-shaped bacteria were isolated from Robinia pseudoacacia root nodules. On the basis of the 16S rRNA gene phylogeny, they are closely related to Bradyrhizobium, Rhodopseudomonas and Nitrobacter species (97% sequence similarity), belonging to the class Alphaproteobacteria and family Bradyrhizobiaceae. The results of physiological and biochemical tests together with sequence analysis of housekeeping genes (atpD, dnaK, gyrB, recA and rpoB) allowed differentiation of this group from other validly published Bradyrhizobiaceae genera. NodA, nodC and nifH genes could not be amplified. On the basis of genotypic and phenotypic data, these organisms represent a novel genus and species for which the name Tardiphaga robiniae gen. nov., sp. nov. (LMG 26467(T)=CCUG 61473(T)), is proposed. PMID- 22444282 TI - The effect of level of feeding, genetic merit, body condition score and age on biological parameters of a mammary gland model. AB - An evolutionary algorithm was applied to a mechanistic model of the mammary gland to find the parameter values that minimised the difference between predicted and actual lactation curves of milk yields in New Zealand Jersey cattle managed at different feeding levels. The effect of feeding level, genetic merit, body condition score at parturition and age on total lactation yields of milk, fat and protein, days in milk, live weight and evolutionary algorithm derived mammary gland parameters was then determined using a multiple regression model. The mechanistic model of the mammary gland was able to fit lactation curves that corresponded to actual lactation curves with a high degree of accuracy. The senescence rate of quiescent (inactive) alveoli was highest at the very low feeding level. The active alveoli population at peak lactation was highest at very low feeding levels, but lower nutritional status at this feeding level prevented high milk yields from being achieved. Genetic merit had a significant linear effect on the active alveoli population at peak and mid to late lactation, with higher values in animals, which had higher breeding values for milk yields. A type of genetic merit * feeding level scaling effect was observed for total yields of milk and fat, and total number of alveoli produced from conception until the end of lactation with the benefits of increases in genetic merit being greater at high feeding levels. A genetic merit * age scaling effect was observed for total lactation protein yields. Initial rates of differentiation of progenitor cells declined with age. Production levels of alveoli from conception to the end of lactation were lowest in 5- to 8-year-old animals; however, in these older animals, quiescent alveoli were reactivated more frequently. The active alveoli population at peak lactation and rates of active alveoli proceeding to quiescence were highest in animals of intermediate body condition scores of 4.0 to 5.0. The results illustrate the potential uses of a mechanistic model of the mammary gland to fit a lactation curve and to quantify the effects of feeding level, genetic merit, body condition score, and age on mammary gland dynamics throughout lactation. PMID- 22444279 TI - Misregulated RNA processing in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) research is undergoing an era of unprecedented discoveries with the identification of new genes as major genetic causes of this disease. These discoveries reinforce the genetic, clinical and pathological overlap between ALS and frontotemporal lobar degeneration (FTLD). Common causes of these diseases include mutations in the RNA/DNA-binding proteins, TDP-43 and FUS/TLS and most recently, hexanucleotide expansions in the C9orf72 gene, discoveries that highlight the overlapping pathogenic mechanisms that trigger ALS and FTLD. TDP-43 and FUS/TLS, both of which participate in several steps of RNA processing, are abnormally aggregated and mislocalized in ALS and FTLD, while the expansion in the C9orf72 pre-mRNA strongly suggests sequestration of one or more RNA binding proteins in pathologic RNA foci. Hence, ALS and FTLD converge in pathogenic pathways disrupting the regulation of RNA processing. This article is part of a Special Issue entitled RNA-Binding Proteins. PMID- 22444283 TI - Genetic and phenotypic parameters for test day milk yield of Sahiwal cattle in the semi-arid tropics. AB - A total of 19 376 test day (TD) milk yield records from the first three lactations of 1618 cows daughters of 162 sires were used to estimate genetic and phenotypic parameters and determine the relationship between daily milk yield and lactation milk yield in the Sahiwal cattle in Kenya. Variance components were estimated using animal models based on a derivative free restricted maximum likelihood procedure. Variance components were estimated using various univariate and multi-trait fixed regression test day models (TDM) that defined contemporary groups either based on the year-season of calving (YSCV) or on the year-season of TD milk sampling (YSTD). Variance components were influenced by CG which resulted in differences in heritability and repeatability estimates between TDM. Models considering YSTD resulted in higher additive genetic variances and lower residual variances compared with models in which YSCV was considered. Heritability estimates for daily yield ranged from 0.28 to 0.46, 0.38 to 0.52 and 0.33 to 0.52 in the first, second and third lactation, respectively. In the first and second lactation, the heritability estimates were highest between TD 2 and TD 4. Genetic correlations among daily milk yields ranged from 0.41 to 0.93, 0.50 to 0.83 and 0.43 to 86 in the first, second and third lactation, respectively. The phenotypic correlations were correspondingly lower. Genetic correlations were different from unit when fitting multi-trait TDM. Therefore, a multiple trait model would be more ideal in determining the genetic merit of dairy sires and bulls based on daily yield records. Genetic and phenotypic correlations between daily yield and lactation yields were high and positive. Genetic correlations ranged from 0.84 to 0.99, 0.94 to 1.00 and 0.94 to 0.97 in the first, second and third lactations, respectively. The corresponding phenotypic correlation estimates ranged from 0.50 to 0.85, 0.50 to 0.83 and 0.53 to 0.87. The high genetic correlation between daily yield and lactation yield imply that both traits are influenced by similar genes. Therefore daily yields records could be used in genetic evaluation in the Sahiwal cattle breeding programme. PMID- 22444284 TI - Economic weights of fertility, prolificacy, milk yield and longevity in dairy sheep. AB - Economic weights have been estimated in two breeds (Latxa and Manchega) using economic and technical data collected in 41 Latxa and 12 Manchega dairy sheep flocks. The traits considered were fertility (lambing per year), prolificacy (number of lambs), milk yield (litres) and longevity (as productive life, in years). A linear function was used, relating these traits to the different costs in the flock. The variable costs involved in the profit function were feed and labour. From this function, economic weights were obtained. Labour is considered in the Latxa breed to be a constraint. Moreover, farm profits are unusually high, which probably means that some costs were not included according to the economic theory. For that reason, a rescaling procedure was applied constraining total labour time at the farm. Genetic gains were estimated with the resulting economic weights to test if they give any practical difference. Milk yield only as selection criterion was also considered. The medians of the estimated economic weights for fertility, prolificacy, milk yield and longevity were 138.60 ? per lambing, 40.00 ? per lamb, 1.18 ? per l, 1.66 ? per year, and 137.66 ? per lambing, 34.17 ? per lamb, 0.73 ? per l, 2.16 ? per year under the linear approach in the Latxa and Manchega breeds respectively. Most differences between breeds can be related to differences in production systems. As for the genetic gains, they were very similar for all economic weights, except when only milk yield was considered, where a correlated decrease in fertility led to a strong decrease in profit. It is concluded that the estimates are robust for practical purposes and that breeding programmes should consider inclusion of fertility. More research is needed to include other traits such as somatic cell score, milk composition and udder traits. PMID- 22444285 TI - Economic weights of somatic cell score in dairy sheep. AB - The economic weights for somatic cell score (SCS) have been calculated using profit functions. Economic data were collected in the Latxa breed. Three aspects have been considered: bulk tank milk payment, veterinary treatments due to high SCS, and culling. All of them are non-linear profit functions. Milk payment is based on the sum of the log-normal distributions of somatic cell count, and veterinary treatments on the probability of subclinical mastitis, which is inferred when individual SCS surpass some threshold. Both functions lead to non standard distributions. The derivatives of the profit function were computed numerically. Culling was computed by assuming that a conceptual trait culled by mastitis (CBM) is genetically correlated to SCS. The economic weight considers the increase in the breeding value of CBM correlated to an increase in the breeding value of SCS, assuming genetic correlations ranging from 0 to 0.9. The relevance of the economic weights for selection purposes was checked by the estimation of genetic gains for milk yield and SCS under several scenarios of genetic parameters and economic weights. The overall economic weights for SCS range from - 2.6 to - 9.5 ? per point of SCS, with an average of - 4 ? per point of SCS, depending on the expected average SCS of the flock. The economic weight is higher around the thresholds for payment policies. Economic weights did not change greatly with other assumptions. The estimated genetic gains with economic weights of 0.83 ? per l of milk yield and - 4 ? per point of SCS, assuming a genetic correlation of - 0.30, were 3.85 l and - 0.031 SCS per year, with an associated increase in profit of 3.32 ?. This represents a very small increase in profit (about 1%) relative to selecting only for milk yield. Other situations (increased economic weights, different genetic correlations) produced similar genetic gains and changes in profit. A desired-gains index reduced the increase in profit by 3%, although it could be greater depending on the genetic parameters. It is concluded that the inclusion of SCS in dairy sheep breeding programs is of low economic relevance and recommended only if recording is inexpensive or for animal welfare concerns. PMID- 22444286 TI - True phosphorus digestibility and the endogenous phosphorus outputs associated with brown rice for weanling pigs measured by the simple linear regression analysis technique. AB - The objectives of this study were to determine true phosphorus (P) digestibility, degradability of phytate-P complex and the endogenous P outputs associated with brown rice feeding in weanling pigs by using the simple linear regression analysis technique. Six barrows with an average initial body weight of 12.5 kg were fitted with a T-cannula and fed six diets according to a 6 * 6 Latin-square design. Six maize starch-based diets, containing six levels of P at 0.80, 1.36, 1.93, 2.49, 3.04, and 3.61 g/kg per kg dry-matter (DM) intake (DMI), were formulated with brown rice. Each experimental period lasted 10 days. After a 7 day adaptation, all faecal samples were collected on days 8 and 9. Ileal digesta samples were collected for a total of 24 h on day 10. The apparent ileal and faecal P digestibility values of brown rice were affected ( P < 0.01) by the P contents in the assay diets. The apparent ileal and faecal P digestibility values increased from - 48.0 to 36.7% and from - 35.6 to 40.0%, respectively, as P content increased from 0.80 to 3.61 g/kg DMI. Linear relationships ( P < 0.05), expressed as g/kg DMI, between the apparent ileal and faecal digestible P and dietary levels of P, suggested that true P digestibility and the endogenous P outputs associated with brown rice feeding could be determined by using the simple regression analysis technique. There were no differences ( P>0.05) in true P digestibility values (57.7 +/- 5.4 v. 58.2 +/- 5.9%), phytate P degradability (76.4 +/- 6.7 v. 79.0 +/- 4.4%) and the endogenous P outputs (0.812 +/- 0..096 v. 0.725 +/- 0.083 g/kg DMI) between the ileal and the faecal levels. The endogenous faecal P output represented 14 and 25% of the National Research Council (1998) recommended daily total and available P requirements in the weanling pig, respectively. About 58% of the total P in brown rice could be digested and absorbed by the weanling pig. Our results suggest that the large intestine of the weanling pigs does not play a significant role in the digestion of P in brown rice. Diet formulation on the basis of total or apparent P digestibility with brown rice may lead to P overfeeding and excessive P excretion in pigs. PMID- 22444287 TI - Effect of complete feed blocks or grazing and supplementation of lambs on performance, nutrient utilisation, rumen fermentation and rumen microbial enzymes. AB - A study to compare two feeding systems, stall feeding (SF) and grazing plus supplementation (GR) was carried out, based on intake, performance and rumen fermentation characteristics of lambs. While SF animals received ad libitum complete feed blocks (CFB), GR animals were allowed grazing for 8 h on a pasture and supplemented with concentrate mixture at 250 g per head per day. Intake in grazing animals was determined using chromium III oxide as internal marker. Intake of dry matter (DM), crude protein (CP) and organic matter (OM) were higher ( P < 0.01) in SF than in GR animals. Similarly, digestibility of OM, CP and energy were higher ( P < 0.01) in SF animals. Average daily gain in SF animals (101 g) was significantly ( P < 0.01) higher than in GR animals (78 g) but total wool yield was similar for the two groups (856 g, SF; 782 g, GR). The pH of the rumen content, concentration of total volatile fatty acids and total activities of carboxymethyl cellulase, xylanase and esterase in the rumen liquor were similar. The concentrations (mg/dl) of total nitrogen (125, SF; 63, GR) and NH3 nitrogen (42, SF; 31, GR) were higher in SF animals than that of GR animals. A significantly higher activity ( P < 0.05) of microcrystalline cellulase (24.5 v. 7.7 units) and lower activity ( P < 0.05) of protease (309 v. 525 units), was observed in the rumen of SF animals than in GR animals. SF animals could therefore harness more energy through degradation of plant cell walls thus reducing breakdown of plant proteins as gluconeogenic source. The SF system of feeding where CFB was offered to sheep appeared superior to GR in terms of intake, nutrient utilisation and animal performance. Therefore the SF feeding system where CFB are offered to animals can be advocated as an alternative to grazing and supplementation feeding strategy for sheep production, especially where the pastures are highly eroded and need resting for regeneration or curing. The CFB feeding can also be adopted under adverse conditions like drought and famine, a common phenomenon in arid and semiarid conditions. PMID- 22444288 TI - A comparative study of the effect of two-stage olive cake added to alfalfa on digestion and nitrogen losses in sheep and goats. AB - This work was conducted to evaluate the effect of tannins, contained in a by product derived from olive oil extraction (two-stage olive cake), on nutrient digestibility, nitrogen (N) losses and liver and kidney functions in goats and wethers. Six Segurena wethers and six Granadina goats were fed three experimental diets: alfalfa hay (AH); alfalfa hay and a concentrate (formulated with two-stage olive cake, barley and a mineral-vitamin mixture) without (AHCO) or with polyethylene glycol (PEG) addition (AHCOP). The inclusion of two-stage olive cake increased condensed tannins content of the diet and led to a decrease ( P < 0.001) in dry matter, organic matter, neutral-detergent fibre, acid-detergent fibre and crude protein (CP) digestibility. PEG supply increased ( P < 0.001) CP digestibility and N losses in urine and faeces only in wethers. Concentrations of creatinine and alkaline phosphatase activity, measured in the serum of animals, were not modified either by olive cake inclusion or by PEG supply. Results from this work indicate a higher sensitivity of sheep to diets containing condensed tannins, compared with goats, and reveal no toxic effect of tannins from two stage olive cake at the concentration used in the experimental diets. PMID- 22444289 TI - Effects of restricted nursing on milk production and collection, kid growth and plasma prolactin and growth hormone concentrations in dairy goats. AB - The milk production of dairy goats under various regimes of mother-young contact from day 4 post partum were studied during the first 2 months of lactation, together with the prolactin (PRL) and growth hormone (GH) responses to udder stimulation. In the control group, 13 goats and their kids were left in permanent contact and did not undergo milking. In two additional groups, goats were machine milked once a day in the morning (at 0800 h) and kids were allowed 10 hours (from 1000 to 2000 h; 10H group, n = 11) or 5 h (from 1000 to 2000 h; 5H group, n = 11) of mother-young interaction per day. In the last group (MO, n = 10), mothers were permanently separated from their kids on day 4 post partum and milked once a day. Milk production during a 24-h period at 37 days post partum performed by controlled nursing and weighing of the kids (groups with kids) or by two machine milking 12 h apart (milking only group) revealed a higher production in the three groups with some mother-young contact than in the MO group. Total milk collected by milking over the 2 months of the study did not differ between the three groups that underwent milking. Kid weights at 2 months were 3.4 to 4.8 kg. lighter in the groups that underwent milking than in the control group. Hormonal profiles were significantly affected by restricted mother-young contact, with highest pre stimulation concentrations of PRL and GH in the 5H group. Restricting mother young contact from the first week postpartum can permit an early collection of milk without major effects on kid growth, when compared with one daily milking in goats totally separated from their young. PMID- 22444290 TI - The effect of rabbit age on in vitro caecal fermentation of starch, pectin, xylan, cellulose, compound feed and its fibre. AB - In vitro gas production kinetics of six different substrates, pectin (PEC), xylan (XYL), starch (STA), cellulose (CEL), commercial compound feed (FEED; 201 g crude protein per kg, 155 g crude fibre per kg, 334 g neutral-detergent fibre (NDF) per kg and 190 g acid-detergent fibre (ADF) per kg) and an NDF prepared from commercial compound feed (NDFFEED) were determined using the caecum contents of weaned rabbits (36 days of age) and of rabbits at slaughter age (78 days of age) as inoculums. The cumulated gas production over 96 h of incubation was modelled with Gompertz model, and the kinetic parameters compared. The total potential gas production (parameter 'B' of the Gompertz model) was not affected (P>0.05) by the inoculum source, except with STA, where rabbits at slaughter weight had significantly higher total potential fermentability (314 ml/g dry matter (DM)) than those at weaning age (189 ml/g DM). Intensities of fermentation (maximum fermentation rate; MFR) of PEC (32.2 ml/h) and XYL (24.4 ml/h) were significantly greater in rabbits at weaning, while that of STA (45 ml/h) was significantly lower than at slaughter age (23.0, 14.3 and 14.0 ml/h for PEC, XYL and STA, respectively). The MFRs of CEL and NDFFEED were very similar between inoculum sources. In the first 10 h of fermentation which correspond to the normal retention time of the substrates in the caecum, the highest amount of gas was produced from PEC, followed by FEED and XYL. These substrates had a time of maximum fermentation rate (TMFR) at both rabbit ages short enough (8.0 and 9.5 h for PEC, 9.5 and 6.6 h for FEED, 13.7 and 14.2 h for XYL at weaning and at slaughter age, respectively) to be almost completely fermented in vivo. PMID- 22444291 TI - The effect of vaccinating infection during pregnancy and dietary protein supply on the peri-parturient immune response of sheep to infection with Teladorsagia circumcincta and Trichostrongylus colubriformis larvae. AB - It is well established that dietary protein supply can influence the peri parturient breakdown of immunity to nematode parasites but there is no information on the importance of exposure to nematode larvae during pregnancy for this response. We investigated this by exposing housed pregnant sheep, scanned as carrying two lambs, to a vaccinating infection with a trickle mixed infection of Teladorsagia circumcincta and Trichostrongylus colubriformis larvae (L3) or to no infection during weeks - 9 to - 4 relative to parturition. At the beginning of week - 3 all sheep were treated with anthelmintic to remove any vaccinating worm burden and from week - 2 to week +6 received a trickle challenge infection with the same nematodes. Within each vaccinating treatment there were two nutritional treatments (no. = 20 per subgroup) designed to provide 1.5 or 1.0 and 1.3 or 0.8 of metabolisable protein (MP) requirement during pregnancy and lactation, respectively. Five ewes were necropsied during weeks +1 and +3 to measure worm burdens and mucosal inflammatory cells and the remainder maintained until week +6. Serum levels of total, IgA and IgE antibodies against L3 antigen of each nematode were measured.Scanning errors and lamb losses resulted in some ewes carrying and/or rearing only one lamb. Numbers of lambs reared was therefore introduced as a treatment effect. Vaccinating infection delayed the peri parturient rise in faecal egg count (FEC) by an average of 2 weeks but its effect on FEC during the first 6 weeks of lactation was smaller and less persistent than that of dietary MP supply and single- v. twin-suckling.Populations of both nematodes were lower in association with high MP supply, vaccination and single suckling. These changes were associated with increases in numbers of mucosal mast cells (MMC) as a result of both increased MP supply and vaccination. Evidence for a more rapid return of host ability to limit populations of the abdominal nematode T. circumcincta than of the intestinal nematode T. colubriformis was associated with fewer eosinophils and more globule leucocytes (GL) in abomasal than in intestinal tissue.None of the serum antibody isotypes was affected by dietary protein supply. Total and IgA antibodies were maintained by a current larval (vaccinating) intake. IgA titres, however, increased progressively during pregnancy, especially in twin-bearing ewes. IgE titres appeared to be sensitive primarily to the reproductive cycle itself, peaking around parturition.This work supports the conclusion that availability of MP supply influences the recruitment and activity of cells of the immune armoury of the gastro-intestinal tract to nematode parasites. The precise outcome may differ with site and/or nematode species. PMID- 22444292 TI - Adipocyte cellularity in different adipose depots in bulls of seven Spanish breeds slaughtered at two body weights. AB - The influence of body weight (BW) at slaughter and genotype on adipocyte size and number in the omental (OM), perirenal (PR), subcutaneous (SC) and intermuscular (IM) adipose tissues was studied in 168 bulls of Spain's local Asturiana, Avilena, Morucha, Parda Alpina, Pirenaica, Retinta, and Rubia Gallega cattle breeds. The young bulls were slaughtered at two BWs, 320 and 540 kg. The results obtained showed the higher amounts of lipids that accumulated between 320 and 540 kg BW (P < 0.001) to be ascribable primarily to adipose cell hypertrophy, i.e. larger adipocyte size, in the OM and PR depots (P < 0.001). In addition to hypertrophy, there was also an increase (P < 0.001) in the number of adipose cells, i.e. hyperplasia, in the SC and IM adipose depots. Significant differences were observed when comparing the different genotypes, with the Morucha, Retinta and Avilena breeds having the highest amount of adipose tissue and the largest adipocytes. The Asturiana and Rubia Gallega breeds had the lowest amount of adipose tissue and the smallest adipocytes. The Pirenaica and Parda Alpina breeds had intermediate values in between the two groups identified above. In short, the results were indicative of different lipid deposition patterns in the different breeds depending on the individual growth and maturation rates in each. Similar findings were made when comparing the different adipose tissue depots, with adipocyte hypertrophy being the main factor responsible for lipid accumulation in the OM and PR depots, as opposed to adipocyte hyperplasia in the SC and IM depots. PMID- 22444293 TI - Determination of nutrient requirements for growth and maintenance of growing pigs under tropical condition. AB - Data from 27 feeding trials conducted on growing pigs from different research institutes across India were subjected to mixed model regression analysis to derive requirements of digestible energy (DE), crude protein (CP) and essential amino acids for maintenance and body weight gains. The ranges of maintenance requirements were determined to be: DE 516 to 702 kJ/kg M0.75, CP 6.98 to 11.62, lysine 0.431 to 0.664, methionine 0.265 to 0.458, methionine + cystine 0.327 to 0.466, cystine 0.055 to 0.184, threonine 0.205 to 0.511, arginine 0.377 to 1.21, isoleucine 0.241 to 0.775, leucine 0.604 to 1.54, phenylalanine + tyrosine 0.496 to 1.33, tryptophan 0.078 to 0.213, and valine 0.330 to 0.892 g/kg M0.75, respectively for different body weight ranges. The corresponding requirements for 1 g gain in body weight were: DE 28.6 to 38.6 kJ, CP 0.27 to 0.44 g, lysine 0.0071 to 0.0126 g, methionine 0.0047 to 0.0133 g, methionine + cystine 0.0151 to 0.0261 g, cystine 0.0043 to 0.0094 g, threonine 0.0052 to 0.0165 g, arginine 0.0045 to 0.0301 g, isoleucine 0.0023 to 0.0198 g, leucine 0.0150 to 0.0447 g, phenylalanine + tyrosine 0.0091 to 0.0382 g, tryptophan 0.0005 to 0.0044 g, and valine 0.0061 to 0.0222 g. Regression equations had high R2 values (ranging from 0.50 to 0.99 for different estimates), low coefficients of variation, low variance of error estimates and the coefficients were highly significant (P < 0.001). Regressed values were used to develop feeding standards. As the new standards derived in the present study are based on a thorough analysis of a larger database than previous Indian standards, the new feeding standard seems to be more appropriate for India and other tropical countries. PMID- 22444294 TI - Effect of volatile compounds in grass silage on voluntary intake by growing cattle. AB - Twenty-four low dry matter (DM) silages differing in fermentation quality were harvested at the same time from a crop that consisted mainly of timothy (Phleum pratense), and meadow fescue (Festuca pratensis). The silage samples were analysed by gas chromatography (GC) - mass spectrometry and gas chromatography - flame ionisation detection in order to determine and quantify volatiles present in silage. The voluntary intake of the 24 silages had been measured in a previous feeding trial with growing steers of Norwegian Red. Thirteen esters, five aldehydes, three alcohols, and one sulphide were identified and quantified. A total of 51 variables describing the chemical composition of the silages were included in a partial least-squares regression, and the relationship of silage fermentation quality to voluntary intake was elucidated. The importance of variables describing silage fermentation quality in relation to intake was judged from a best combination procedure, jack-knifing, and empirical correlations of the variables to intake. The GC-analysed compounds were mainly present in poorly fermented silages. However, compared with other explanatory chemical variables none of these compounds was of importance for the voluntary intake as evaluated by partial least-squares regression. A validated variance of 71% in silage DM intake was explained with the selected variables: total acids (TA), total volatile fatty acids (TVFA), lactic acid/total acid ratio and propionic acid. In this study extent (by the variable TA) and type of silage fermentation (by TVFA) influenced intake. Further, it is suggested that by restricting the fermentation in low DM grass silages the potential intake of silage DM is maximised. PMID- 22444295 TI - Comparison of artificial insemination and natural service cost effectiveness in dairy cattle. AB - Reproductive efficiency in the dairy herd is the most important factor for its economic success and a major concern for dairy farmers when using artificial insemination (AI) or natural service (NS). Our objectives were to estimate, compare and analyse the costs associated with breeding cattle by do-it-yourself (DIY) AI and NS and identify the factors that influence them, under typical dairy farming conditions in Greece. A simulation study was designed based on data from 120 dairy cattle farms that differed in size (range 40 to 285 cows) and milk production level (4000 to 9300 kg per cow per year). Different scenarios were employed to estimate costs associated directly with AI and NS as well as potentially extended calving intervals (ECI) due to AI. Results showed that bull maintenance costs for NS were ?1440 to ?1670 per year ($1,820 to $2,111). Direct AI costs were higher than those for NS for farms with more than 30 cows and ECI constituted a considerable additional burden. In fact, amongst the factors that affected the amount of milk needed to cover total extra AI costs, number of days open was the dominant one. Semen, feed and heifer prices had a very small effect. When, hypothetically, use of NS bulls results in a calving interval of 12 months, AI daughters with a calving interval of 13.5 months have to produce about 705 kg of additional milk in order to cover the extra cost. Their actual milk production, however, exceeds this limit by more than 25%. When real calving intervals are considered (13.0 v. 13.7 months for NS and AI, respectively) AI daughters turn out to produce more than twice the additional amount of milk needed. It was concluded that even under less than average management conditions, AI is more profitable than the best NS scenario. The efficient communication of this message should be a primary concern of the AI industry. PMID- 22444296 TI - Effects of fermented oyster mushroom ( Pleurotus ostreats) by-product supplementation on growth performance, blood parameters and meat quality in finishing Berkshire pigs. AB - The objective of the present study was to investigate the effects of fermented oyster mushroom (Pleurotus ostreats) by-production (FOMP) supplementation on the growth performance, blood parameters, carcass traits and meat quality in finishing Berkshire pigs. FOMP was made by mixing oyster mushroom by-production with rice bran and barley bran and this mixture was fermented for 60 days. The experimental diets were 0, 3, 5 and 7% of FOMP added to C, T1, T2 and T3 in the basis diet for 7 weeks. Average daily gain (kg/day) was higher in C and T1 than in T2 and T3 ( P < 0.05). Average daily feed intake (kg/day) and feed conversion increased by the addition of FOMP ( P < 0.05). Total cholesterol and high-density lipoprotein cholesterol were higher in T3 than other treatments ( P < 0.05). Carcass weight (kg) was higher in C and T1 than in T2 and T3 ( P < 0.05). Dressing (%) was higher in C than in T3 ( P < 0.05). Crude protein was lower in T3 than in other treatments ( P < 0.05). Crude fat was higher in T2 and T3 than in C ( P < 0.05). pH24 was higher in C than in other treatments ( P < 0.05). Cooking loss (%) was higher in T1 than T2 ( P < 0.05). Water-holding capacity (%) was higher in C than in T1 ( P < 0.05). In meat colour, CIE a* was lower by the addition of FOMP ( P < 0.05). CIE b* was higher in C than in other treatments ( P < 0.05). In backfat colour, CIE L* was lower in T3 than other treatments ( P < 0.05). CIE b* was lower by addition of FOMP ( P < 0.05). Palmitoleic and oleic acid were higher in T3 than in other treatments ( P < 0.05). Linoleic and arachidonic acids were higher in T2 than in other treatments ( P < 0.05). The results indicate that 3% of FOMP affected the growth performance, carcass traits, meat quality and fatty acid in contrast to addition of 5% of FOMP for Berkshire pigs during the finishing period. PMID- 22444297 TI - 'Mealthy' food: meat as a healthy and valuable source of micronutrients. AB - Over the last two or three decades meat and especially liver have been looked upon as unhealthy food with high fat content and carcinogenic potential. In addition, its content of highly valuable micronutrients has mostly been ignored. As a result, the mean uptake and serum levels of several micronutrients in the population are below the recommended levels. In the meantime, the contamination of liver with heavy metals and other contaminants has fallen far below the allowed thresholds and sometimes even below the detection limit while its content of micronutrients like iron, folate, selenium or zinc are still high. As a further advantage, the bioavailability of many micronutrients often is better from meat and liver then from plant sources. Considering these advantages and the low content of contaminants in meat and liver leads us to propose that meat - including liver - should be a regular part of a mixed and balanced healthy diet along with vegetables and fruits as the major components to ensure an optimal supply of micronutrients. PMID- 22444298 TI - Reversible and irreversible conformational transitions in myoglobin: role of hydrated amino acid ionic liquid. AB - Hydrated phenylalanine ionic liquid (Phe-IL) has been used to solubilize myoglobin (Mb). Structural stability of Mb in Phe-IL analyzed using fluorescence and circular dichroism spectroscopy shows that for low levels of hydration of Phe IL there is a large red shift in the fluorescence emission wavelength and the protein transforms to complete beta sheet from its native helical conformation. Rehydration or dilution reverses the beta sheet to an alpha helix which on aging organizes to micrometer-sized fibrils. At concentrations higher than 200 MUM, the protein changes from beta to a more random coiled structure. Organization of the protein in Phe-IL in a Langmuir film at the air/water interface has been investigated using the surface pressure-molecular area isotherm and shows nearly the same surface tension for both pure Mb and Mb in Phe-IL. Scanning electron microscopy of the films of Mb in Phe-IL transferred using the Langmuir-Blodgett film technique show layered morphology. This study shows that the conformation of Mb is completely reversible going from beta -> helix -> beta sheet up to 200 MUM of Phe-IL. Similar surface tension values for Mb in water and in Phe-IL suggests that direct ion binding interactions with the protein coupled with the change in local viscosity from the IL seems to not only alter the secondary structure of individual proteins but also drives the self-assembly of the protein molecules leading finally to fibril formation. PMID- 22444301 TI - The interconnection between biofilm formation and horizontal gene transfer. AB - Recent research has revealed that horizontal gene transfer and biofilm formation are connected processes. Although published research investigating this interconnectedness is still limited, we will review this subject in order to highlight the potential of these observations because of their believed importance in the understanding of the adaptation and subsequent evolution of social traits in bacteria. Here, we discuss current evidence for such interconnectedness centred on plasmids. Horizontal transfer rates are typically higher in biofilm communities compared with those in planktonic states. Biofilms, furthermore, promote plasmid stability and may enhance the host range of mobile genetic elements that are transferred horizontally. Plasmids, on the other hand, are very well suited to promote the evolution of social traits such as biofilm formation. This, essentially, transpires because plasmids are independent replicons that enhance their own success by promoting inter-bacterial interactions. They typically also carry genes that heighten their hosts' direct fitness. Furthermore, current research shows that the so-called mafia traits encoded on mobile genetic elements can enforce bacteria to maintain stable social interactions. It also indicates that horizontal gene transfer ultimately enhances the relatedness of bacteria carrying the mobile genetic elements of the same origin. The perspective of this review extends to an overall interconnectedness between horizontal gene transfer, mobile genetic elements and social evolution of bacteria. PMID- 22444300 TI - Clinical significance of the ratio between FOXP3 positive regulatory T cell and interleukin-17 secreting cell in renal allograft biopsies with acute T-cell mediated rejection. AB - The aim of this study is to investigate the clinical significance of the ratio between interleukin-17 (IL-17) secreting cell and FOXP3-positive regulatory T cell (FOXP3(+) Treg) infiltration in renal allograft tissues with acute T-cell mediated rejection (ATCMR). Fifty-six patients with biopsy-proven ATCMR were included. Infiltration of FOXP3(+) Treg and IL-17-secreting cells was evaluated with immunostaining for FOXP3 or IL-17 on the biopsy specimens, and the patients were divided into the FOXP3 high group (Log FOXP3/IL-17 > 0.45) or the IL-17 high group (Log FOXP3/IL-17 < 0.45). We compared the allograft function, severity of tissue injury, and clinical outcome between the two groups. In the IL-17 high group, allograft function was significantly decreased compared with the FOXP3 high group (P < 0.05). The severity of interstitial and tubular injury in the IL 17 high group was higher than the FOXP3 high group (P < 0.05). The proportions of steroid-resistant rejection, incomplete recovery and recurrent ATCMR were higher in the IL-17 high group than in the FOXP3 high group (all indicators, P < 0.05). The IL-17 high group showed lower 1-year (54% versus 90%, P < 0.05) and 5-year (38% versus 85%, P < 0.05) allograft survival rates compared with the FOXP3 high group. Multivariate analysis revealed that the FOXP3/IL-17 ratio was a significant predictor for allograft outcome. The FOXP3/IL-17 ratio is a useful indicator for representing the severity of tissue injury, allograft dysfunction and for predicting the clinical outcome of ATCMR. PMID- 22444302 TI - Genetic parameters for milkability from the first three lactations in Fleckvieh cows. AB - Test-day records for average flow rate (AFR) from the routine dairy recording from Bavarian Fleckvieh cows were analysed. Two data sets with observations on approximately 20 000 cows each were sampled from the total data set. For the estimation of variance parameters, a two-step approach was applied. In a first step multiple-trait restricted maximum likelihood (REML) analyses were carried out. For each of the first three lactations, six time periods with up to 33 days were defined. An algorithm for iterative summing of expanded part matrices was applied in order to combine the estimates. In a second step covariance functions (CF) for additive-genetic variances and non-genetic animal variances were derived using second-order Legendre polynomials plus an exponential term. Estimates of test-day heritability for AFR ranged from 0.21 to 0.40, and were largest in lactation 1. For lactations 1 and 3, heritabilities decreased considerably towards the end of lactation. Genetic correlation estimates within lactation decreased as the distance between days in milk (DIM) increased. Genetic correlations between corresponding DIM in the three lactations were generally large, ranging from 0.80 to 0.99. The largest estimates were found between DIM from lactations 2 and 3. Results from this study suggest that including AFR data from second and third lactations in genetic evaluation systems could the improve accuracy of genetic selection. PMID- 22444303 TI - Associations of PrP genotype with lamb production traits in three commercial breeds of British hill sheep. AB - The National Scrapie Plan (NSP) was launched in Great Britain in 2001, with the aim of eventually eradicating scrapie, a small ruminant transmissible spongiform encephalopathy, from the national sheep flock. Specifically, a selective breeding programme, the Ram Genotyping Scheme, was devised enabling pedigree ram breeders to reduce the number of scrapie-susceptible genotypes from their flocks. The effect of large-scale manipulation of PrP genotypes on commercially important traits within the sheep industry is, however, unknown. We have therefore examined production traits in a total of 43 968 lambs from 32 pedigree breeders across three British hill breeds, comprising 8163 North Country Cheviot (Hill), 21 366 Scottish Blackface and 14 439 Welsh Mountain lambs. Traits examined included: weights at birth, 8 and 20 weeks; ultrasonic fat and muscle depth, and average daily weight gain from 8 to 20 weeks. Linear mixed models were fitted for each trait, including animal (direct) genetic effects and up to three maternal effects. Potential associations with the PrP gene were assessed by fitting either PrP genotype or number of copies of individual alleles as fixed effects. A number of breed-specific significant associations between production traits and the PrP gene were found, but no consistent significant effects were detected across the three breeds. Breed-specific effects were as follows: (i) 0.37 kg higher birth weights (BWTs) in AHQ homozygous North Country Cheviot (Hill) lambs (P < 0.01); (ii) 0.16 kg higher BWTs in ARR homozygous Scottish Blackface lambs (P < 0.05); (iii) 0.5 kg higher 8-week weights in VRQ heterozygous Scottish Blackface lambs (P < 0.01); (iv) a 0.72 kg decrease in scan weight associated with homozygous ARR Welsh Mountain lambs (P < 0.01); (v) 0.51 mm higher ultrasonic muscle depths in AHQ homozygous Welsh Mountain lambs (P < 0.01); (vi) 0.48 mm lower ultrasonic muscle depths in Welsh Mountain lambs carrying one or more copies of the ARR allele (P < 0.05) and (vii) 0.2 mm higher ultrasonic fat depths in heterozygous VRQ Welsh Mountain lambs (P < 0.05). The use of a Bonferroni correction to define appropriate significance thresholds across the three datasets, which account for the large number of independent comparisons made, resulted in breed-specific comparisons, with P < 0.01 becoming significant at P0.05, and the remaining breed specific comparisons no longer being significant. The absence of a common effect across the three breeds suggests that any true association found may be due to breed-specific alleles of neighbouring genes in linkage disequilibrium with the PrP locus. PMID- 22444304 TI - Heritability estimates and genetic correlations for body weight and scrotal circumference adjusted to 12 and 18 months of age for male Nellore cattle. AB - Heritability estimates and genetic correlations were obtained for body weight and scrotal circumference, adjusted, respectively, to 12 (BW12 and SC12) and 18 (BW18 and SC18) months of age, for 10 742 male Nellore cattle. The adjustments to SC12 and SC18 were made using a nonlinear logistic function, while BW12 and BW18 were obtained by linear adjustment. The contemporary groups (CGs) were defined from animals born on the same farm, in the same year and birth season. The mean heritability estimates obtained using the restricted maximum likelihood method in bi-trait analysis were 0.25, 0.25, 0.29 and 0.42 for BW12, BW18, SC12 and SC18, respectively. The genetic correlations were 0.30 +/- 0.11, 0.21 +/- 0.13, 0.21 +/ 0.11, -0.08 +/- 0.15, 0.16 +/- 0.12 and 0.89 +/- 0.04 between the traits BW12 and BW18; BW12 and SC12; BW12 and SC18; BW18 and SC12; BW18 and SC18; and SC12 and SC18. The heritability for SC18 was considerably greater than for SC12, suggesting that this should be included as a selection criterion. The genetic correlation between BW18 and SC12 was close to zero, indicating that these traits did not influence each other. The contrary occurred between SC12 and SC18, indicating that selection using one of these could alter the other. Because of the mean magnitudes of heritabilities in the various measurements of weight and scrotal perimeter, it is suggested that the practice of individual selection for these traits is possible. PMID- 22444305 TI - Influence of dietary fibre level and pelleting on the digestibility of energy and nutrients in growing pigs and adult sows. AB - Two experiments were carried out to investigate the effect of pelleting on the apparent total tract digestibility (ATTD) of energy and nutrients according to the dietary fibre (DF) level in growing pigs (experiment 1) and in adult sows (experiment 2). Four diets based on wheat, barley, maize and soybean meal and supplemented with increased contents of a mixture of wheat bran, maize bran, soybean hulls and sugar beet pulp (116, 192, 268 and 344 g NDF/kg dry matter (DM) in diets 1 to 4) were tested. In experiment 1, 32 growing pigs (62 kg average BW), in two replicates and according to a factorial design, were fed one of the four diets, either as mash or as pellets. The digestibility of energy, organic matter (OM) and all nutrients decreased with DF increasing for both feed forms; the reduction was about 1% for each 1% NDF increase in the diet (P < 0.001). Pelleting improved moderately the digestibility of energy and OM (+1.5% and +1.0%, respectively; P < 0.05) in connection with greater DF (+5%; P < 0.05) and fat digestibility (+25%). Thus, pelleting improved the digestible energy content of diets on average by 0.3 MJ/kg of feed DM (P < 0.01). In experiment 2, four adult dry sows (235 kg average BW) were used in a 4 * 4 Latin square design and fed the four diets used in experiment 1 as pellets. The digestibility of energy, OM and macronutrients also decreased with DF increase (P < 0.001; -0.4% per 1% increase of dietary NDF for energy) while the digestibility of DF (i.e. crude fibre (CF) or ADF) increased (P < 0.001) or remained at a high level. In conclusion, increasing DF in diets decreases the digestibility of nutrients and energy in pigs and in sows. Although positive, the pelleting impact is minor on the energy and nutrients digestibility of fibre-rich diets in growing pigs, even in high-DF diets. PMID- 22444306 TI - Responses in mammary and splanchnic metabolism to altered lysine supply in dairy cows. AB - Lysine is usually taken up in excess by the mammary gland (MG) relative to milk protein output, allowing for mammary synthesis of non-essential (NE) amino acids (AA) from Lys-N. It is unclear whether this NEAA synthesis from Lys is obligate or whether more efficient use of Lys can be made under limiting conditions. Six multi-catheterized dairy cows received a basal diet low in protein plus an abomasal infusion of AA (560 g/day) with or without Lys (50.3 g/day), in a crossover design with 7-day periods. On day 7, all cows received a 7.5-h jugular infusion of [2-15N]lysine. Six blood samples were collected from arterial, portal, hepatic and mammary vessels at 45 min intervals. In addition, cows were milked at 6 and 7 h with the milk casein plus arterial and mammary plasma collected at 7 h analyzed for AA enrichment. Milk protein concentration and casein yield tended (P < 0.10) to decrease with Lys deletion, while Lys secretion in milk protein was lowered (P < 0.05). The addition of Lys in the AA mixture increased the net portal absorption of Lys by the amount infused, suggesting limited oxidation of this extra supply by the gut. Net liver flux of Lys was unaltered by treatment and, therefore, net splanchnic release of Lys reflected closely the amounts absorbed. For both treatments, however, post-liver supply was greater than mammary uptake, which exceeded milk output. Nonetheless, while Lys deletion decreased mammary uptake by 10.1 mmol/h, Lys in milk protein secretion was reduced by only 3.9 mmol/h. On a net basis, there was no evidence of the additional uptake of any other measured AA during the Lys deletion. The mammary uptake to output ratio of Lys decreased from 1.37 to 1.12, but still showed an excess with Lys deletion. The total amount of 15N in milk protein did not change with treatment but the distribution into AA was altered. In conditions that simulated normal feeding (Lys infused), 83% of the 15N was present as Lys, with Glx, Asx, Ser and Ala harvesting, respectively, 6.8%, 2.4%, 2.1% and 1.0%. With Lys depletion, N-transfers from Lys to other AA within the MG were still present, but rates were considerably lower. This would suggest that part, at least, of Lys catabolism in the MG is either needed or cannot be prevented completely, even at low supply of Lys. Such catabolism will provide N to support the synthesis of NEAA. PMID- 22444307 TI - Methodology for concurrent determination of urea kinetics and the capture of recycled urea nitrogen by ruminal microbes in cattle. AB - We measured the incorporation of recycled urea-nitrogen (N) by ruminal microbes, using five ruminally and duodenally fistulated steers (237 kg) fed low-quality grass hay (47 g crude protein/kg dry matter (DM)). Three received 1 kg/day of soybean meal (SBM) and two received no supplemental protein (control). The experiment was 15 days long. Background enrichments of 15N were measured on day 9 and continuous jugular infusion of 0.12 g/day [15N15N]urea began on day 10. Daily samples of urine, feces, ruminal bacteria and duodenal digesta from days 10 through 14 were used to determine plateaus in 15N enrichment. Duodenal and bacterial samples collected on day 15 were used to measure duodenal N flows. Bacterial N flow was calculated as duodenal N flow multiplied by duodenal 15N enrichment divided by bacterial 15N enrichment. Bacterial N from recycled urea-N was calculated as bacterial N flow multiplied by bacterial 15N enrichment divided by urinary urea 15N enrichment. Urinary enrichment of [15N15N]urea plateaued within 24 h, whereas 14N15N urea plateaued within 48 h of [15N15N]urea infusion. Bacteria reached a plateau in 15N enrichment within 24 h and duodenal samples within 48 h. Urea production was 17.6 g of urea-N/day for control and 78.0 g/day for SBM. Gut entry was 0.99 g of urea-N/g of urea-N produced for control and 0.87 g/g for SBM. Incorporation of recycled N into microbial N was 9.0 g of N/day for control and 23.0 g/day for SBM. Recycled urea-N accounted for 0.33 g of N/g of microbial N at the duodenum for control and 0.27 g/g for SBM. Our methods allowed measurement of incorporation of recycled urea-N into ruminal microbial N. PMID- 22444308 TI - Feeding grape seed extract to horses: effects on health, intake and digestion. AB - A feeding trial involving four Thoroughbred race horses was undertaken to establish whether inclusion of grape seed extract (GSE) in the diet of horses undergoing mild exercise had any effects on their general health, intake and digestion. Supplementation with GSE had no effect on either feed or water intake of the horses and the supplement was readily palatable to the horses at all levels of inclusion. Feeding GSE caused no adverse effects in terms of animal health (temperature, pulse and respirations rates), and there were some positive effects related to a presumed alteration in fermentation in the hindgut. Feeding GSE increased faecal pH, changing from acid faeces (pH 6.6) when no GSE was fed to neutral faeces (pH 7.0) when 150 mg GSE/kg body weight (BW) was fed. In addition, blood glucose concentrations were significantly (P < 0.05) decreased when GSE was fed at 100 and 150 mg/kg BW (5.50 +/- 0.26 and 5.32 +/- 0.72 mmol/l, respectively) compared with the control diet (5.77 +/- 0.31 mmol/l). The actual mechanisms causing these alterations are yet to be elucidated, but could have important implications for the prevention of acidosis. PMID- 22444309 TI - Effect of all-trans retinol on in vitro development of preimplantation buffalo embryos. AB - Vitamin A is a well-known antioxidant and is essential for embryonic development, growth and differentiation. Oxidative stress is involved in the etiology of defective embryo development. The present study evaluated whether the presence of all-trans retinol (0, 1, 2, 5 and 10 MUM) in maturation medium or embryo culture medium would enhance the developmental competence of preimplantation buffalo embryos in vitro. In experiment I, cumulus oocytes complex were matured with varying concentrations of all-trans retinol. Treatment with 5 MUM all-trans retinol improved the blastocyst formation (P < 0.001) when compared with control and significant increase (P < 0.01) in total cell number was observed in 5 MUM group when compared with control. Supplementation of all-trans retinol in embryo culture medium for the entire culture period under 5% O2 and 20% O2 was tested in experiments II and III, respectively. Supplementation of 10 MUM all-trans retinol under 5% O2, significantly reduced blastocyst formation and cell numbers. Presence of 5 MUM all-trans retinol under 20% O2 enhanced the frequency of blastocyst formation and total cell number (P < 0.001) when compared with control. DNA damage of individual embryos cultured under 20% oxygen concentration was measured by the comet assay. Supplementation of 5 MUM all-trans retinol significantly reduced the comet tail (P < 0.001) when compared with control. Supplementation of all-trans retinol in embryo culture medium for first 72 h of the 8-day culture period under 5% O2 was tested in experiment IV. Addition of 5 MUM all-trans retinol resulted in significant increase in blastocyst rate and total cell number (P < 0.001) when compared with control. Our results demonstrate that addition of all-trans retinol to maturation or embryo culture medium may enhance the developmental competence of buffalo embryos in vitro by enhancing blastocyst formation rate and total cell number. PMID- 22444310 TI - A pilot study on transcriptome data analysis of folliculogenesis in pigs. AB - Three different stages of pig antral follicles have been studied in a granulosa cell transcriptome analysis on nylon microarrays (1152 clones). The data have been generated from seven RNA follicle pools and several technical replicates were made. The objective of this paper was to state the feasibility of a transcriptomic protocol for the study of folliculogenesis in the pig. A statistical analysis was chosen, relying on the linear mixed model (LMM) paradigm. Low variability within technical replicates was hence checked with a LMM. Relevant genes that might be involved in the studied process were then selected. For the most significant genes, statistical methods such as principal component analysis and unsupervised hierarchical clustering were applied to assess their relevance, and a random forest analysis proved their predictive value. The selection of genes was consistent with previous studies and also allowed the identification of new genes whose role in pig folliculogenesis will be further investigated. PMID- 22444311 TI - Molecular cloning, tissue distribution and ontogenetic expression of sodium proton exchanger isoform 2 ( NHE-2) mRNA in the small intestine of pigs. AB - Molecular cloning, tissue distribution and ontogenetic regulation of sodium/proton exchanger isoform 2 (NHE-2) mRNA expression were evaluated in the pig small intestine during postnatal development. The 2872-bp porcine full cDNA sequence of the NHE-2 (EF672046) cloned in this study showed 80% and 70% homology with known human and mouse gene sequence, respectively. Hydrophobic prediction suggests 13 putative membrane-spanning domains within porcine NHE-2. The porcine NHE-2 mRNA was detected in the brain, liver, kidney, heart, lung, small intestine and muscle. The small intestine had the highest NHE-2 mRNA abundance and the brain, lung and liver had the lowest NHE-2 mRNA abundance (P < 0.05). Along the longitudinal axis, the duodenum had the highest NHE-2 mRNA abundance and the ileum and colon had the lowest NHE-2 mRNA abundance (P < 0.05). The NHE-2 mRNA level was increased from day 1 to day 26 in the duodenum (P < 0.05) and dropped dramatically on day 30 (P < 0.05). There is no difference between day 1 and day 7 (P > 0.05). After day 30, the NHE-2 mRNA level remained the same except on day 90 (P > 0.05). The mRNA expression of NHE-2 was not only differentially regulated by age but also differentially distributed along the small intestine of piglets at early stages and growing stages of life, which may contribute to changes in NHE activity. PMID- 22444312 TI - Six placenta permeability-related genes: molecular characterization and expression analysis in pigs. AB - The nutrient transportation ability of placenta depends on placental size, vascular density and permeability. Regulation of angiogenesis in the placenta is critical for successful gestation. Placenta vascularity exhibits disparity in different gestation stages and different pig breeds. To investigate the expression of genes related to permeability in the porcine placenta of different gestation stages and breeds, molecular cloning and gene expression analysis of six porcine genes, vascular endothelial growth factor (VEGF), VEGF-R1, VEGF-R2, endothelial nitric oxide synthase (eNOS), vascular endothelial cadherin (CDH5) and beta-arrestin2 (Arrb2), were performed in this study. The results demonstrated that from gestation day 33 to day 90, Landrace exhibited significant increase (P < 0.05) in placental VEGF and Arrb2 mRNA expression. Moreover, expression levels of VEGF, VEGF-R1, VEGF-R2 and eNOS mRNA were higher (P < 0.01) in the placenta of Erhualian than those in Landrace on day 90 of gestation. In contrast, CDH5 placental mRNA expression level exhibited significant decrease (P < 0.05) from day 33 to day 90 gestation in Landrace. Erhualian placental CDH5 and Arrb2 expression levels were significantly lower (P < 0.01) than those in Landrace conceptuses on day 90 of gestation. Our study offered new data on the expression of genes in VEGF signal transduction pathway in porcine placenta. PMID- 22444313 TI - An assessment of opportunities to dissect host genetic variation in resistance to infectious diseases in livestock. AB - This paper reviews the evidence for host genetic variation in resistance to infectious diseases for a wide variety of diseases of economic importance in poultry, cattle, pig, sheep and Atlantic salmon. Further, it develops a method of ranking each disease in terms of its overall impact, and combines this ranking with published evidence for host genetic variation and information on the current state of genomic tools in each host species. The outcome is an overall ranking of the amenability of each disease to genomic studies that dissect host genetic variation in resistance. Six disease-based assessment criteria were defined: industry concern, economic impact, public concern, threat to food safety or zoonotic potential, impact on animal welfare and threat to international trade barriers. For each category, a subjective score was assigned to each disease according to the relative strength of evidence, impact, concern or threat posed by that particular disease, and the scores were summed across categories. Evidence for host genetic variation in resistance was determined from available published data, including breed comparison, heritability studies, quantitative trait loci (QTL) studies, evidence of candidate genes with significant effects, data on pathogen sequence and on host gene expression analyses. In total, 16 poultry diseases, 13 cattle diseases, nine pig diseases, 11 sheep diseases and three Atlantic salmon diseases were assessed. The top-ranking diseases or pathogens, i.e. those most amenable to studies dissecting host genetic variation, were Salmonella in poultry, bovine mastitis, Marek's disease and coccidiosis, both in poultry. The top-ranking diseases or pathogens in pigs, sheep and Atlantic salmon were Escherichia coli, mastitis and infectious pancreatic necrosis, respectively. These rankings summarise the current state of knowledge for each disease and broadly, although not entirely, reflect current international research efforts. They will alter as more information becomes available and as genome tools become more sophisticated for each species. It is suggested that this approach could be used to rank diseases from other perspectives as well, e.g. in terms of disease control strategies. PMID- 22444314 TI - Protein supply influences the nutritional penalty associated with the development of immunity in lambs infected with Trichostrongylus colubriformis. AB - The influence of dietary protein supply on the nutritional penalty associated with the acquisition phase of the immune response to gastrointestinal nematodes in lambs was investigated. Groups of lambs were offered either a low-protein diet (L; 62 g metabolizable protein (MP)/kg dry matter (DM)) or high-protein diet (H; 95 g MP/kg DM) while being either infected with the equivalent of 2.000 L3 Trichostrongylus colubriformis/day (IF), similarly infected and concurrently immuno-suppressed with methylprednisolone acetate (ISIF), immuno-suppressed only (IS) or kept as uninfected controls (C). Body composition of all animals was measured on days -8 and 76 of infection using X-ray computed tomography. Temporal changes in serum phosphate and serum albumin concentrations, which provided an indicator of pathological damage, in addition to patterns of total daily nematode egg excretion and comparative worm burdens at slaughter indicated that a protective immune response was developed in H-IF, but not L-IF, H-ISIF or L-ISIF groups. Compared to their respective non-infected controls, the gross efficiency of use of metabolizable energy (ME) for net energy (NE) deposition in the carcass was reduced by 0.23 in H-IF (P < 0.05), 0.13 in H-ISIF (P > 0.05), 0.49 in L-IF (P < 0.01) and 0.23 in L-ISIF (P > 0.05). It is concluded that the reduction in ME utilization and reduced performance, which can be attributed to the immunological response, are lessened in animals offered a high-protein diet. Furthermore, evidence is presented to indicate a possible association between T. colubriformis L3 IgA antibody production and loss of performance in lambs infected with this nematode. PMID- 22444315 TI - Competing risk analyses of longevity in Duroc sows with a special emphasis on leg conformation. AB - A competing risk approach was used to evaluate the influence of several factors on culling risk for 587 Duroc sows. Three different analyses were performed according to whether sow failure was due to death during productive life (DE) or to one of two causes for voluntary culling: low productivity (LP) and low fertility (LF). Sow survival was analyzed by the Cox model. Year at first farrowing (batch effect) significantly affected sow survival in all three analyses (P < 0.05 for DE and P < 0.001 for LP and LF) whereas farm of origin accounted for relevant variation in the LP and LF analyses. LP culling increased with backfat thickness of more than 19 mm at the end of the growth period (P < 0.05), bad teat condition (P < 0.05) and reduced piglets born alive (P < 0.001). For the LF competing risk analysis, culling increased with age at first farrowing (P < 0.1). Special emphasis was placed on the influence of leg and teat conformation on sow survivability, although they did not affect sow failure due to DE (P > 0.1). The overall leg-conformation score significantly influenced sow longevity in LP (P < 0.001) and LF competing risk analyses (P < 0.001), showing a higher hazard ratio (HR) for poorly conformed sows (1.013 and 4.366, respectively) than for well-conformed sows (0.342 and 0.246, respectively). Survival decreased with the presence of abnormal hoof growth in LP and LF analyses (HR = 3.372 and 6.002, respectively; P < 0.001) and bumps or injuries to legs (HR = 4.172 and 5.839, respectively; P < 0.01). Plantigradism reduced sow survival in the LP analysis (P < 0.05), while sickle-hooked leg (P < 0.05) impaired sow survival in the fertility-specific analysis. Estimates of heritability for longevity related to LP culling ranged from 0.008 to 0.024 depending on the estimation procedure, whereas heritability values increased to between 0.017 and 0.083 in LF analysis. These analyses highlighted substantial discrepancies in the sources of variation and genetic background of sow longevity depending on the cause of failure. The estimated heritabilities suggested that direct genetic improvement for sow longevity seemed feasible, although only a small genetic progress was expected. PMID- 22444316 TI - Meat odour and flavour and indoles concentration in ruminal fluid and adipose tissue of lambs fed green herbage or concentrates with or without tannins. AB - A 2 * 2 factorial experiment was carried out to evaluate the effect of herbage or concentrate feeding system and tannin addition to diet on skatole and indole in ruminal fluid and adipose tissue and meat sensory properties. Twenty-eight male lambs aged 45 days were randomly assigned to one of two feeding systems (vetch green herbage or concentrates, n = 14) and within feeding system to one supplement (quebracho tannins added to the diet or none). Animals were kept in singular pens and slaughtered at the age of 105 days. Indole (P < 0.05) and skatole (P < 0.01) concentrations in ruminal fluid were higher in lambs fed herbage compared to those given concentrates. Skatole in ruminal fluid tended to be present at lower concentrations in animals that received the tannin supplementation (P = 0.07). Indole was also higher in the caudal fat of animals fed green vetch compared to those fed concentrate (P = 0.04). Skatole concentration was lower in the fat of lambs fed concentrates compared to those given herbage (P = 0.05) and was lower in the fat of animals supplemented with tannins compared to the animals not supplemented (P = 0.01). Sheep meat odour was lower in meat from animals supplemented with tannins compared to those not supplemented (P < 0.01). It is concluded that tannins are more effective in reducing skatole formation in ruminants when they are associated with concentrate diets than green herbages. PMID- 22444317 TI - Effect of sire breed on carcass characteristics and meat and fat quality of heavy pigs reared outdoor and intended for dry-cured meat production. AB - A trial was conducted to study the effect of sire line (Duroc (DU) and Pietrain (PI)) on carcass, meat and fat quality of pigs reared outdoor and destined to dry cured meat production. No differences between sire genotypes were detected in carcass fat thickness (P > 0.10) but carcasses from DU-sired pigs were longer (P < 0.05) and tended to have a higher yield of trimmed shoulders (P = 0.07) and hams (P = 0.06) than carcasses from PI-sired pigs. Loins from DU-sired genotype showed higher (P < 0.05) L* value and lower (P < 0.01) a* value than loins from PI-sired genotype. Pork from DU-sired offspring tended to have higher (P = 0.09) intramuscular fat (IMF) percentage and lower (P < 0.05) moisture proportion than meat from PI-sired offspring. Also, loins from DU-sired pigs had lower (P < 0.001) thawing losses than loins from PI-sired pigs. The subcutaneous fat from the DU-sired line tended to show lower (P = 0.08) percentage of total polyunsaturated fatty acids (PUFAs) than that from the PI-sire line, mostly due to the higher proportion of C18:2 (P = 0.09) and C20:3 (P < 0.01). However, no effect of crossbreed was detected on the total proportion of saturated, monounsaturated fatty acid (MUFAs) or PUFAs of IMF (P > 0.10). We conclude that both sire lines can be used successfully under outdoor conditions but DU boars are more adequate than PI boars for the production of heavy pigs intended for the dry-cured meat industry. PMID- 22444318 TI - Developmental changes of carcass composition, meat quality and organs in the Jinhua pig and Landrace. AB - The present study was aimed to compare the developmental changes of carcass composition, meat quality characteristics and organ weight in pigs of different breeds. Six pigs (sex balance) of each breed were slaughtered at 35, 80 and 125 days of age, respectively. The carcass was chilled and the left carcass side was dissected into bone, lean meat, fat and skin; additionally, organ weight and meat quality parameters were observed. Carcasses of the Jinhua pig were lighter (P < 0.001), contained less lean meat percentage (P < 0.01) and more carcass fat percentage (P < 0.05) than did carcasses of the Landrace. L*-values were lower in Jinhua pigs than in Landrace at 125 days of age (P < 0.05), but the Jinhua pig had higher a*-values compared with Landrace at the age of 80 days (P < 0.01) and 125 days (P < 0.01), respectively. In addition, Jinhua pigs showed lower colour scores (P < 0.05), higher intramuscular fat (IMF) percentage (P < 0.05), less marbling scores (P < 0.05) and lower drip loss (P < 0.05) than Landrace. For organ weight, Jinhua pigs had higher relative heart weight at the age of 80 days (P < 0.05) and 125 days (P < 0.001), and higher relative liver weight at 125 days of age (P < 0.01) than that of Landrace. In addition, the relative kidney weight was heavier (P < 0.001) in the Jinhua pig than in the Landrace during the whole experiment. These results indicated that developmental changes of carcass composition, meat quality parameters and organ weight displayed breed differences. Jinhua pigs were fatter than Landrace but the former had better quality characteristics in the meat. PMID- 22444319 TI - Hard times or great expectations? PMID- 22444320 TI - Social and health-related correlates of intergenerational and intragenerational social mobility among Swedish men and women. AB - OBJECTIVE: To explore the pattern and determinants of inter- and intragenerational occupational mobility among Swedish men and women. STUDY DESIGN: A Swedish 14-year prospective longitudinal study (response rate 96.5%). METHODS: Detailed information on 546 men and 495 women regarding their occupation, health status, health-related behaviour, psychosocial environment at home and school, material recourses and ethnicity prior to mobility were available at 16, 21 and 30 years of age. Odds ratios and 99% confidence intervals were calculated using logistic regression to determine social mobility. RESULTS: The results indicated that being popular at school predicted upward mobility, and being less popular at school predicted downward mobility. Additionally, material deprivation, economic deprivation, shorter height (women) and poor health behavioural factors predicted downward mobility. Among this cohort, being less popular at school was more common among subjects whose parents had low socio economic status. Occupational mobility was not influenced by ethnic background. CONCLUSIONS: Apart from height (women), health status was not associated with mobility for men or women either inter- or intragenerationally. Unfavourable school environment was a consistent predictor of mobility for both genders. The results indicate that schools should be used as a setting for interventions aimed at reducing socio-economic health inequities. Targeted school interventions that are designed to assist higher educational attainment of socio-economically disadvantaged youth would help to break the social chain of risk experienced during this time, and thereby alter their life course in ways that would reduce subsequent social inequities in health and well-being. PMID- 22444321 TI - Highlights in clinical autonomic neurosciences: vasovagal syncope - insights on diagnosis, pathophysiology and treatment. PMID- 22444322 TI - The influence of glycosaminoglycans on IL-8-mediated functions of neutrophils. AB - Glycosaminoglycans (GAGs) of the extracellular matrix (ECM) contribute to the regulation of physiological processes by binding various immune-competent proteins. Due to their large structural diversity, the analysis of the binding properties and their functional consequences is challenging. The cytokine interleukin-8 (IL-8) is involved in the recruitment of neutrophils to inflammatory sites. Here, we investigated the interaction of heparin hexasaccharides and recombinant human IL-8, consisting of 77 amino acids using fluorescence and NMR spectroscopy. A dissociation constant of 2.0+/-0.4 MUM was determined for the heparin-IL-8 complex, which is slightly higher than what has been found for chondroitin-6-sulfate (K(D)=1.4+/-0.4 MUM) [Pichert, A.; Samsonov, S. A.; Theisgen, S.; Thomas, L.; Baumann, L.; Schiller, J.; Beck-Sickinger, A. G.; Huster, D.; Pisabarro, M. T. Glycobiology2012, 22, 134-145], suggesting an important role of the sulfate group at position 6 of the second ring in the disaccharide unit of the GAGs in this interaction. In addition, the influence of long-chain hyaluronan, chondroitin sulfate, and heparin on IL-8-induced chemotaxis and oxidative activity of neutrophils was examined. Only the incubation of heparin with IL-8 affected the IL-8-mediated chemotaxis of neutrophils. However, all investigated GAGs enhanced the IL-8-induced formation of reactive oxygen species in neutrophils, which is an entirely new finding. This work provides a representative example of how protein functions can be regulated by different GAGs of the ECM. PMID- 22444323 TI - Comparison of the conformational properties of carbasugars and glycosides: the role of the endocyclic oxygen. AB - A series of carbasugars were prepared and their conformational properties studied by means of NMR spectroscopy. The results were compared to those previously found for O-, S-, and C-beta-glycoside analogs. While the rotational populations of the hydroxymethyl group in O-, S-, and C-glycosides are known to depend on the structural nature of their aglycon, in carbasugars it proved to be independent of the pseudo-aglycon. This result confirms that endocyclic oxygen is necessary for the observed relationship between the structure of the aglycon and the rotational populations of the hydroxymethyl group, and indicates that the stereoelectronic exo-anomeric effect is mainly responsible for such conformational dependence. PMID- 22444324 TI - Higher mortality of patients on haemodialysis with pancreatic diabetes compared to type 2-diabetes. AB - In rare cases (1-8%) diabetic patients with end-stage renal disease (ESRD) suffer from diabetic nephropathy (dNP) due to pancreatic diabetes mellitus (PDM). Aim of this study was to investigate differences in the outcome of patients with PDM and those with type 2 diabetes.In a retrospective study we evaluated 96 diabetic patients, who started hemodialysis (HD) in our dialysis centre (1997 2005). In 12 patients PMD was diagnosed, and 84 patients had type 2 diabetes. In both groups we compared vascular risk factors and prevalence of vascular diseases at the start of dialysis. We also evaluated incidence of malnutrition, and 5-year survival in both patient groups.The vascular risk factors were similar in both patient groups, also the prevalence of vascular diseases at the initiation of HD was similar in both groups. In the patients with PDM the mean BMI (kg/m2) was lower (22 + 3 versus 25 + 3), and also their serum albumin was lower (2.7 + 0.3 versus 3.4 + 0.3 g/dl, p < 0.05). Four of these patients (33%) developed malnutrition (BMI < 18.5). In the patients with PDM the age adjusted 5-year survival was significantly lower (8% versus 27%, p < 0.05) than in the type 2 diabetic patients.Conclusions in HD-treated patients with type 2 diabetes or PDM the prevalence of vascular diseases was not significantly different. The lower survival of PDM patients can be related to poor nutrition status. PMID- 22444325 TI - Social burden and lifestyle in adults with congenital heart disease. AB - We aimed to evaluate how the presence and severity of congenital heart disease (CHD) influence social life and lifestyle in adult patients. A random sample (n = 1,496) from the CONgenital CORvitia (n = 11,047), the Dutch national registry of adult patients with CHD, completed a questionnaire on educational attainment, employment and marital statuses, and lifestyle (response 76%). The Utrecht Health Project provided a large reference group (n = 6,810) of unaffected subjects. Logistic regression models were used for subgroup analyses and to adjust for age, gender, and socioeconomic status where appropriate. Of all patients 51.5% were men (median age 39 years, interquartile range 29 to 51) with mild (46%), moderate (44%), and severe (10%) CHD. Young (<40-year-old) patients with CHD were more likely to have achieved a lower education (adjusted odds ratios [ORs] 1.6 for men and 1.9 for women, p <0.05 for the 2 comparisons), significantly more often unemployed (adjusted ORs 5.9 and 2.0 for men and women, respectively), and less likely to be in a relationship compared to the reference group (adjusted ORs 8.5 for men and 4.5 for women). These poorer outcomes were seen in all severity groups. Overall, the CHD population smoked less (adjusted OR 0.5, p <0.05), had more sports participation (adjusted OR 1.2, p <0.05), and had less obesity (adjusted OR 0.7, p <0.05) than the reference group. In conclusion, there was a substantial social disadvantage in adult patients with CHD, which was seen in all severity groups and primarily in young men. In contrast, adults with CHD had healthier lifestyles compared to the reference group. PMID- 22444326 TI - China begins to position for leadership on responsible risk-based global chemicals management. PMID- 22444328 TI - Quantitation of slow release triptorelin in beagle dog plasma by liquid chromatography-tandem mass spectrometry. AB - A sensitive method based on liquid chromatography-tandem mass spectrometry has been developed for the determination of triptorelin levels in beagle dog plasma. Plasma samples were applied to Oasis((r)) HLB solid-phase extraction (SPE) cartridges. Extracted samples were evaporated under a stream of nitrogen and then reconstituted with 100 MUl methanol:water:formic acid (60:40:0.08, v/v/v). The separation was achieved on a Venusil MP-C18 column (2.1 mm * 50 mm, 3 MUm, Agela) with a gradient elution. Detection utilized a Qtrap5500 system operated in the positive ion mode with multiple reaction monitoring of the analyte at m/z 656.5 >249.1 and of the I.S. at m/z 510.8->120.1. The proposed method was validated by assessing the specificity, linearity, precision and accuracy, recovery, matrix effects, and stability. Linear calibration curves were obtained in the concentration range of 0.01-10 ng/ml (the correlation coefficients were above 0.995). The lower limit of quantification (LLOQ) of the method was 0.01 ng/ml. The method was successfully applied to a pharmacokinetic study of a slow release triptorelin formulation in beagle dogs following a single intramuscular injection. PMID- 22444329 TI - Estimation of genetic parameters for growth performance and carcass traits in Mukota pigs. AB - The objective of the study was to determine genetic parameters for growth and carcass traits in Mukota pigs, maintained on a fibrous diet. Records (n = 1961) were obtained from a population housed at the University of Zimbabwe Farm (Harare, Zimbabwe) between January 1998 and August 2003. Backfat thickness was measured at 50 and 75 mm (K5 and K7.5), respectively. Carcass length (CL) was measured from the anterior edge of the first rib to the pubic bone using a measuring tape. Variance components were estimated using a model that accounted for direct, common environmental litter and maternal genetic effects, using average information restricted maximum likelihood. Heritability estimates for average daily gain from birth to weaning (ADGW) and average daily gain from weaning to 12 weeks (ADG1) were 0.15 and 0.27, respectively. Maternal genetic effects accounted for 2.6% of variation for ADG1. Heritability for average daily gain from 12 weeks to slaughter (ADG2) was 0.20. Common environmental litter effects accounted for 18% of phenotypic variance for cold dressed mass (CDM). Heritability estimates for CDM and CL were 0.32 and 0.62, respectively. Maternal genetic effects accounted for 10.5% of variance in CL. Heritability estimates for K5 and K7.5 were 0.64 and 0.40, respectively. The CDM was positively genetically correlated to K5, but negative to K7.5. The K5 and K7.5 had a high genetic correlation (0.88). Genetic correlations between ADGW and K5, K7.5 and CL were 0.30, 0.05 and 0.35, respectively. The existence of sufficient genetic variation makes genetic improvement for many growth and carcass traits in the Mukota breed possible through effective selection methods. PMID- 22444330 TI - Genetic parameters for test day milk yields of first lactation Holstein cows by random regression models. AB - Covariance components for test day milk yield using 263 390 first lactation records of 32 448 Holstein cows were estimated using random regression animal models by restricted maximum likelihood. Three functions were used to adjust the lactation curve: the five-parameter logarithmic Ali and Schaeffer function (AS), the three-parameter exponential Wilmink function in its standard form (W) and in a modified form (W*), by reducing the range of covariate, and the combination of Legendre polynomial and W (LEG+W). Heterogeneous residual variance (RV) for different classes (4 and 29) of days in milk was considered in adjusting the functions. Estimates of RV were quite similar, rating from 4.15 to 5.29 kg2. Heritability estimates for AS (0.29 to 0.42), LEG+W (0.28 to 0.42) and W* (0.33 to 0.40) were similar, but heritability estimates used W (0.25 to 0.65) were highest than those estimated by the other functions, particularly at the end of lactation. Genetic correlations between milk yield on consecutive test days were close to unity, but decreased as the interval between test days increased. The AS function with homogeneous RV model had the best fit among those evaluated. PMID- 22444331 TI - Effect of changes in diet energy density on feed intake, milk yield and metabolic parameters in dairy cows in early lactation. AB - The purpose of this experiment was to investigate how early lactating cows adjust their metabolism and production to acute, but moderate changes in the energy density of the diet. Sixty dairy cows were randomly assigned to one of four treatments: two change-over groups (HNH and NHN) and two control groups (HHH and NNN), where H and N refer to a high and normal energy density in the total mixed ration (TMR), respectively. The experimental period covered the first 9 weeks post calving, which was split up in three 3-week periods. Thus, cows assigned to HNH or NHN shifted TMR in weeks 4 and 7 after calving while cows assigned to HHH or NNN were fed the same TMR for all 9 weeks. Results from cows on treatment HNH were compared with group HHH while cows on treatment NHN were compared with group NNN. When the diet changed from N to H and H to N, cows increased and decreased their dry-matter intake (DMI), respectively compared with control groups. Cows adjusted milk yield accordingly to changes in DMI, although not always significantly. Energy-corrected milk yield was not significantly affected by any of the changes in the energy density of the diet but generally showed same tendencies as milk yield. Non-esterified fatty acids (NEFA), beta-hydroxybutyrate in blood and milk and triacylglycerol and glycogen content in the liver were not significantly affected by changes in the energy density of the diet, except from NEFA at one change. Glucose increased more when the diet changed from N to H and increased less when the diet changed from H to N, compared with control groups, although not always significantly. Collectively, these results suggest that cows adjust their DMI and partly milk yield according to the energy density of the diet and therefore only limited effects were observed in physiological parameters. PMID- 22444332 TI - Glucose tolerance and serum concentrations of hormones and metabolites in goats ( Capra hircus) fed diets supplemented with inorganic and organic chromium salts. AB - Adult goats (no. = 18) were supplemented with chromium (Cr, 0.5 mg/kg concentrate) for 120 days as Cr chloride and Cr yeast complex and their responses in terms of glucose tolerance and serum profiles of metabolites and hormones were measured. The goats were fed 200 g/day of the concentrate and reared under a semi intensive regimen. Cr supplementation significantly reduced serum glucose ( P = 0.049) and cholesterol ( P = 0.0001) levels compared with the same in the control group (calculated as % change between days 0 and 120). Serum cortisol on day 120 was lower in goats fed Cr chloride than in the control group ( P < 0.05). Overall, the mean cortisol level was lower ( P = 0.001) in the goats receiving added dietary Cr. An intravenous glucose tolerance test (IVGTT) was performed on the goats on day 75. The clearance rate (k) of glucose between 5 and 60 min of glucose infusion was significantly higher ( P = 0.004) in the goats supplemented with Cr yeast compared with those on the control or the Cr chloride supplemented diets. The kinetic parameters as well as the k and T1/2 responses for serum insulin during the IVGTT were not affected. The ratio between the insulin k to glucose k increased ( P = 0.011) in the goats fed added dietary Cr as Cr chloride compared with the control and the Cr yeast groups. Post-prandial serum levels of glucose (diet effect P = 0.038) and cholesterol (diet effect P = 0.033) was lower in both the Cr supplemented groups than the control. Serum glucose during an epinephrine challenge test tended to remain elevated ( P = 0.076) 2 h after epinephrine infusion in the Cr yeast group indicating a delayed return of serum glucose to the basal level. However, serum insulin and cortisol remained unaffected. Several changes in selected blood metabolites and hormone measurements were observed when Cr was added as a dietary supplement in the diet of the goats. Contrary to the generally accepted view, supplemental Cr may influence the metabolism of ruminants even in a non-stressed management regime. PMID- 22444333 TI - Effects of the dietary protein content and the feeding level on protein and energy metabolism in Iberian pigs growing from 50 to 100 kg body weight. AB - Nutritional requirements of the Iberian pig, a slow-growing, obese porcine breed, are not well defined and seem to differ from those of conventional or high performing pigs. The effects of the dietary protein content and the feeding level on the utilisation of metabolisable energy (ME) and the rates of gain, protein, and fat deposition were studied with 81 Iberian castrates growing from 50 to 100 kg body weight (BW) by using the comparative slaughter technique. The animals were fed 4 diets providing 145, 120, 95, and 70 g ideal crude protein (CP) per kg dry matter (DM), and containing 13.94, 14.29, 14.56, and 14.83 MJ ME per kg DM, respectively. Three levels of feeding were evaluated: 0.60, 0.80, and 0.95 * ad libitum intake. Growth rate increased (linear and quadratic, P < 0.001) as the dietary ideal CP content decreased. It also increased with the feeding level (linear, P < 0.001; quadratic, P < 0.05). Gain:feed and gain:ME intake improved by decreasing the ideal CP content in the diet (linear, P < 0.001 and P < 0.05, respectively; quadratic P < 0.001 for both variables). Increasing the feeding level improved linearly gain:feed and gain:ME intake ( P < 0.001). Protein deposition (PD):ME intake ranged between 1.23 and 1.44 g/MJ, and it showed a tendency to reach the maximum value when the diet providing 95 g ideal CP per kg DM was fed (quadratic, P = 0.078). When this diet was offered at 0.95 * ad libitum, PD reached a maximum value of 71 g/day. This dietary treatment resulted in average values for average daily gain and retained energy (RE) of 854 g/day and 21.4 MJ/day, respectively. The average rate of gain was 19.93 g/MJ increase in ME intake, equivalent to an energy cost of 50.2 kJ ME per g gain, irrespective of the dietary ideal CP content. Also, the overall marginal efficiency of protein deposition (DeltaPD:DeltaME; g/MJ) was 1.34. Increasing the feeding level led to increases in PD (linear, P < 0.001) and RE (linear, P < 0.001; quadratic, P < 0.01) irrespective of the dietary ideal CP concentrations. Between 50 and 100 kg BW, the chemical composition of 1 kg gain averaged 78, 592, 28.7, and 284 g for CP, fat, ash, and water respectively. The net efficiency of use of ME for growth ( kg) and the maintenance energy requirements were 0.606 and 396 kJ/kg BW 0.75 per day, respectively. The results support earlier findings that the genotype has marked effects on protein and energy metabolism of growing pigs and underline important compositional differences of the Iberian pig compared with conventional or modern porcine genotypes. PMID- 22444334 TI - Effect of lactulose on growth performance and intestinal morphology of pre ruminant calves using a milk replacer containing Enterococcus faecium. AB - The synthetic disaccharide lactulose is known to improve the intestinal microflora by stimulating the growth of selected probiotic bacteria in the gut. In our experiment the effects of lactulose in combination with the probiotic bacteria Enterococcus faecium on growth performance and morphology of the bovine intestine were examined. Calves aged 39 +/- 2 days were randomised to three feeding groups (no. = 14 each group): control (L0), fed milk replacer (MR) containing E. faecium; a lactulose group (L1) containing additional 1% lactulose and a second lactulose group (L3) containing 3% lactulose dry matter. The calves were weighed weekly. After 19 weeks the calves were slaughtered and tissues were collected for histological studies. The average daily live weight gain tended to be higher (P < 0.1) for L3 (1350 g/day) than L0 (1288 g/day). Compared with L0, a reduction (P < 0.001) of ileal villus height due to lactulose treatment of approximately 14% in group L1 and 20% in L3 was determined. A significant decrease in the depth of the crypts about 12% in L1 and 8% in L3 was detected in the caecum. The surface area of lymph follicles from Peyer's patches was decreased by lactulose treatment. Results show that lactulose has an effect on the morphology of intestine. A significant effect on growth performance can not be confirmed. However, results permit the conclusion that lactulose feeding has the tendency to increase growth performance. PMID- 22444335 TI - Net nutrient absorption and liver metabolism in lactating dairy cows fed supplemental dietary biotin. AB - The effect of feeding supplemental biotin on net absorption and metabolism of nutrients by the portal-drained viscera (PDV; the gut, pancreas, spleen and associated fat) and liver of lactating dairy cows was measured. Three cows in early to mid-lactation catheterised for measurements of net nutrient absorption and metabolism by the PDV and liver were fed a total-mixed ration with or without supplemental biotin at 20 mg/day using a switch-back design (ABA v. BAB) with three 2-week periods. There were no effects of feeding biotin on dry matter intake (22.2 kg/day), milk yield (29.5 kg/day) or milk composition. There was also no effect of feeding biotin on net release of glucose by the liver, net liver removal of glucose precursors (propionate, alanine, lactate) or net liver release of beta-hydroxybutyrate. Feeding biotin increased net PDV release of ammonia. Reasons for the response are not certain, but a numerical increase in net PDV release of acetate suggests that rumen or hindgut fermentation was altered. Results of the present study do not support the hypothesis that supplemental biotin increases liver glucose production in lactating dairy cows. PMID- 22444336 TI - Effect of milk deprivation during the lactation period on performance and digestive enzyme activities of the piglets following weaning. AB - Post-weaning performance of piglets from systems where lactation is disrupted (e.g. from multisuckling systems) is superior to conventionally reared piglets. The objective of this study was to establish whether restricted growth prior to weaning caused by disruption of suckling was an important factor in post-weaning performance and also whether there were related changes in gastro-intestinal development. Ten litters of eight piglets were used in a split-plot design. Half of each litter (limited suckling, LS) had suckling disrupted by separation from their dam for 7 h/day from day 14 to 28 after farrowing. The remainder of each litter was allowed to suck normally (normal suckling, NS). The same amount of creep feed was offered to LS piglets as consumed by NS littermates on the previous day. There were no differences in weight between LS and NS piglets at 14 days of age, but restricting access to the sow reduced weaning weight at 28 days of age (7.96 v. 9.00 kg; LS v. NS; P < 0.01; s.e.d. 0.23). Feed intakes were greater for LS than NS piglets over the first 28 days post weaning, particularly in the 1st week after weaning when feed efficiency was also improved (0.91 v. 0.62 kg gain per kg feed; P < 0.01; s.e.d. 0.08). As a result, LS piglets grew more rapidly in the first 28 days post weaning, particularly in the first 7 days after weaning. Subsequent performance to 8 weeks was similar for both groups. Digestive organ weights were not different at 2 and 9 days after weaning; nor were small intestine specific enzyme activities significantly different ( P>0.05). Pancreatic trypsin activity was, however, greater ( P < 0.01) for LS pigs on both days 2 and 9 post weaning. In conclusion the restriction of growth as a result of limited suckling itself is an important factor in determining post weaning performance and may be related to development of pancreatic trypsin activity. PMID- 22444337 TI - Effects of a dietary organic acid mixture and of dietary fibre levels on ileal and faecal nutrient apparent digestibility, bacterial nitrogen flow, microbial metabolite concentrations and rate of passage in the digestive tract of pigs. AB - Six 34-kg barrows were fitted with a post-valve T-caecum cannula and assigned to six dietary treatments according to a 6 * 5 change-over design to study how a mixture of formic acid, sorbate, and benzoate (0 or 8.4 g/kg feed) influences apparent ileal and faecal digestibility coefficients, bacterial nitrogen (N) flow, microbial metabolite concentrations, and passage rate in pigs fed isoenergetic diets with medium, high, or very high fibre content (neutral detergent fibre (NDF): 199, 224, and 248 g/kg dry matter, respectively). These barley and soya-bean meal based diets contained 0, 75, and 150 g/kg barley fibre (NDF: 577 g/kg) and 0, 8, and 16 g/kg rapeseed oil, respectively. The dietary organic acid mixture improved the apparent ileal digestibility of 14 of the 17 amino acids analysed (P < 0.05). Increasing levels of dietary fibre linearly decreased the apparent ileal digestibility of six of the 17 amino acids analysed (P < 0.05). Ileal flows of bacterial N and amino acids as assessed on the basis of purine flow were decreased by the dietary organic acid mixture (P < 0.05) but were not affected by dietary fibre level (P>0.05). As assessed on the basis of diaminopimelic acid flow, bacterial N flow was increased by both the dietary organic acid mixture and increased dietary fibre levels (P < 0.05). The dietary organic acid mixture reduced the concentration of lactic acid and increased that of acetic acid in ileal digesta (P < 0.05), while dietary fibre levels had a quadratic effect on concentrations of acetic, propionic, and butyric acid (P < 0.05). The mean retention time of Co (solute marker) and Yb (particle marker) in the large intestine decreased in a linear manner by increasing dietary fibre levels (P < 0.05) but was not affected by the dietary organic acid mixture (P>0.05). The results show that a dietary organic acid mixture has a positive effect on the apparent ileal digestibility of most amino acids irrespective of dietary fibre levels. This could be at least partly related to changes in bacterial N flow in the ileum. However, different bacterial markers showed opposite effects on bacterial N flow, which makes it questionable to use a constant bacterial marker / bacterial N ratio to estimate bacterial N flow. Increasing levels of dietary fibre had negative effects on the apparent ileal amino acid digestibilities and shortened the mean retention time of digesta in the large intestine. PMID- 22444338 TI - Expression of retinoid receptors during rabbit lung development. AB - Rabbit lung is often used to study the pathophysiology of some congenital anomalies affecting the lung because its development is very comparable with that of human. Retinoids and the molecular transducers of the retinoic signal play a crucial role in mammalian lung development. In the rabbit, the molecular retinoic pathway has so far been poorly studied. As a first step in elucidating this process, we aimed to identify the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We cloned a part of the nuclear receptors (RARs and RXRs), and we used reverse transcription - polymerase chain reaction (RT-PCR) and immunohistochemistry assays to demonstrate the presence of RAR (alpha,beta) and RXR (alpha, beta) at all stages of rabbit lung development. Our results initiate further analysis into the molecular and genetic functions of retinoids during normal and pathological rabbit lung development including the surgical model of congenital diaphragmatic hernia. PMID- 22444339 TI - Comparison among three approaches for evaluation of sexual precocity in Nellore cattle. AB - Restricted breeding seasons used in beef cattle produce censored data for reproduction traits measured in regard to these seasons. To analyze these data, adequate methods must be used. The objective of this paper was to compare three approaches aiming to evaluate sexual precocity in Nellore cattle. The final data set contained 6699 records of age at first conception (AFC14) (in days) and of heifer pregnancy (HP14) (binary) obtained from females exposed to the bulls for the first time at about 14 months of age. Records of females that did not calve in the following year after being exposed to a sire were considered censored (77.5% of total). The models used to obtain genetic parameters and expected progeny differences (EPDs) were a Weibull mixed and a censored linear model for AFC14 and threshold model for HP14. The mean heritabilities obtained were 0.76 and 0.44, respectively, for survival and censored linear models (for AFC14), and 0.58 for HP14. Ranking and Pearson correlations varied (in absolute values) from 0.54 to 0.99 (considering different percentages of sires selected), indicating moderate changes in the classification. Considering survival analysis as the best selection criterion (that would result in the best response to selection), it was observed that selection for HP14 would lead to a more significant decrease in selection response if compared with selection for AFC14 analysed by censored linear model, from which results were very similar to the survival analysis. PMID- 22444340 TI - Seasonality of reproduction and production in farm fishes, birds and mammals. AB - A very large majority of farm animals express seasonal variations in their production traits, thus inducing seasonal availability of fresh derived animal products (meat, milk, cheese and eggs). This pattern is in part the consequence of the farmer's objective to market his products in the most economically favourable period. It may also be imposed by the season-dependent access to feed resources, as in ruminants, or by the specific requirements derived from adaptation to environmental conditions such as water temperature in fish. But seasonal variations in animal products are also the consequence of constraints resulting from the occurrence of a more or less marked seasonal reproductive season in most farm animal species including fish, poultry and mammals. Like their wild counterparts, at mid and high latitudes, most farm animals normally give birth at the end of winter-early spring, the most favourable period for the progeny to survive and thus promote the next generation. As a consequence, most species show seasonal variations in their ovulation frequency (mammals and fish: presence or absence of ovulation; birds: variations or suppression of laying rates), spermatogenic activity (from moderate to complete absence of sperm production), gamete quality (variations in fertilisation rates and embryo survival), and also sexual behaviour. Among species of interest for animal production, fishes and birds are generally considered as more directly sensitive to external factors (mainly temperature in fish, photoperiod in birds). In all species, it is therefore advisable that artificial photoperiodic treatments consisting of extra-light during natural short days (in chickens, turkeys, guinea fowl, sheep and goats) or melatonin during long days (in goats, sheep) be extensively used to either adjust the breeding season to animal producer needs and/or to completely overcome seasonal variations of sperm production in artificial insemination centres (mammals) and breeder flock operations (poultry, fish farming). Pure light treatments (without melatonin), especially when applied in open barns, could be considered as non invasive ones which fully respect animal welfare. PMID- 22444341 TI - Motivation to dust-bathe of laying hens housed in cages and in aviaries. AB - New housing systems for commercial egg production, furnished cages and non-cage systems, should improve the welfare of laying hens. In particular, thanks to the presence of a litter area, these new housing systems are thought to satisfy the dust-bathing motivation of hens more than in conventional cages, in which no litter area is present. However, although apparently obvious, there is no concrete evidence that non-cage systems, particularly aviaries, satisfy hens' motivation to dust-bathe and thus improve hens' welfare in terms of dust-bathing behaviour. The aim of this study was to compare hens' dust-bathing motivation when housed for a long time under similar conditions to commercial conditions in laying aviaries (with litter) and in conventional cages (without litter). Three treatments were compared: hens reared in floor pens then housed in conventional cages, hens reared in furnished floor pens then housed in a laying aviary, and hens reared in rearing aviaries then housed in a laying aviary. All three treatments provided access to litter during the rearing period. After transfer to the laying systems, access to litter was maintained for the aviary hens but stopped for the cage hens. Twelve groups of four hens per treatment were tested 36 to 43 weeks after transfer. The hens were placed in sawdust-filled testing arenas, and latency to dust-bathe, duration and number of dust baths, and number of hens dust-bathing were recorded. Latency to dust-bathe was shorter, dust baths were longer and more numerous and more hens dust-bathed among cage hens than among aviary hens. Our results indicate that hens' motivation to dust-bathe was more satisfied in laying aviaries than in conventional cages. Thus, laying aviaries improve hens' welfare in term of dust-bathing behaviour compared with conventional cages. PMID- 22444342 TI - Effect of time at pasture combined with restricted indoor feeding on production and behaviour in dairy cows. AB - Extremely high nutrient loads have been reported in grazed grassland regimes compared with cutting regimes in some dairy systems that include the use of supplemental feeding. The aim of this study was, therefore, to investigate the effects on productivity and behaviour of high-yielding dairy cows with limited access to indoor feed and restriction in the time at pasture in a continuous stocking system. During a 6-week period from the start of the grazing season 2005, an experiment was conducted with the aim of investigating the effect of restrictive indoor feeding combined with limiting the time at pasture on the productivity and behaviour of high-yielding dairy cows (31.0 +/- 5.4 kg energy corrected milk) in a system based on continuous stocking. The herd was split into three groups allocated to three treatments consisting of 4, 6.5 and 9 h at pasture, respectively. Each group of cows grazed in separate paddocks with three replicates and was separately housed in a cubicle system with slatted floor during the rest of the day. All cows were fed the same amount of supplement, adjusted daily to meet the ad libitum indoor intake of the cows at pasture for nine hours. The herbage allowance was 1650 kg dry matter (DM) per ha, and the intake of supplemental feed was 9.1 kg DM per cow daily. The limitation of the time at pasture to 4 h in combination with restrictive indoor feeding reduced the daily milk, fat and protein yield and live weight compared with 9 h of access to pasture. The proportion of time during which the cows were grazing while at pasture increased from 0.64 to 0.86 and the estimated herbage intake per h at pasture decreased from 2547 g DM to1398 g DM, when time at pasture changed from 4 to 9 h. It can be concluded, that in systems with a high herbage allowance, the cow was able to compensate for 0.8 of the reduction in time at pasture by increasing the proportion of time spent grazing and presumably also both the bite rate and mass, although the latter two have not been directly confirmed in the present study. PMID- 22444343 TI - Diet selection and live-weight changes of two breeds of goats grazing on heathlands. AB - Diet selection, live-weight changes and productivity per hectare of two breeds of goats (Cashmere and local Celtiberic) managed in natural vegetation dominated by heather, and the effect of stocking rate (high or low) in the Cashmere breed, were studied during four grazing seasons. Breed had a significant (P < 0.01) effect on the available biomass and its components over the experimental period as a consequence of the differences in dietary components selected by the animals. Local goats produced a greater reduction in short and tall heather and in the percentage of leaves in the tall heather. Live-weight changes were significantly (P < 0.001) different between breeds. Over all experimental years Cashmere goats maintained weight under both low and high stocking rate (4 and - 1 g/day respectively), while local Celtiberic goats lost 30 g/day.Across all grazing seasons and experimental years stocking rate did not significantly affect individual live-weight changes of Cashmere goats. Productivity per hectare did not differ significantly (P>0.05) between high ( - 0.6 kg/ha) and low stocking rate treatments (4.1 kg/ha). However it was significantly (P < 0.001) worse for the local breed treatment ( - 51 kg/ha).As a consequence, in these vegetation communities with low abundance and poor quality of herbaceous plants it will be impossible to develop sustainable systems from the animal production point of view, and their management would need to be integrated during the grazing season by alternating with vegetation communities with better quality. PMID- 22444344 TI - Feed intake and performance of growing lambs raised on concentrate-based diets under cafeteria feeding systems. AB - Two trials were undertaken to study the effects of cafeteria feeding systems on the feed intake, animal performance and carcass characteristics of growing lambs. Trial 1 was designed to compare conventional and cafeteria feeding systems in terms of the growth of individually reared lambs. For this assay, 26 weaned Merino lambs (15.5 +/- 0.20 kg live weight) were assigned to three dietary treatment groups: (1) a control group fed barley straw and commercial concentrate under a conventional feeding system, (2) group W100S, fed soya-bean meal, whole barley grain and a mineral-vitamin supplement under a cafeteria feeding system, and (3) group W100S-T, fed as in the W100S treatment but allowing the lambs an initial training period so they could learn to identify a number of feeds. The feeding system had no significant effect ( P>0.05) on either average daily live weight gain, carcass weight, or carcass conformation. The food conversion ratio was lower ( P < 0.05) for the cafeteria-reared animals (2.9 +/- 0.16 v. 2.5 +/- 0.08 g dry-matter intake per g average daily gain) than those of the control group. This might be related to the higher crude protein intake seen in the cafeteria groups (150 +/- 5.6 v. 208 +/- 12.5 g per animal per day; P < 0.001).In trial 2, cafeteria and conventional feeding system were compared in terms of the growth of feedlot lambs. Two hundred weaned Merino lambs (13.1 +/- 0.10 kg) were divided into two experimental groups: (1) a control group, offered commercial concentrate and barley straw, and (2) a cafeteria group fed the same diet as W100ST in trial 1. The average daily gain (282 +/- 5.8 and 309 +/- 6.5; P < 0.01) was greater in the cafeteria than in the control group. Whereas neither carcass conformation nor fatness were affected by the feeding system, the dressing percentage was slightly higher ( P>0.001) in the conventional than in the cafeteria system lambs.The use of cafeteria systems for fattening lambs can improve the feed conversion efficiency and body growth rate over those achieved with conventional feeding systems, although the crude protein intake in these systems seems to be in excess of requirements. PMID- 22444345 TI - Butters rich either in trans-10-C18:1 or in trans-11-C18:1 plus cis-9, trans 11 CLA differentially affect plasma lipids and aortic fatty streak in experimental atherosclerosis in rabbits. AB - Dairy fat contains high amounts of saturated fatty acids (FA), which are associated with cardiovascular disease (CVD) risk. Manipulation of dairy cows nutrition allows to decrease the saturated FA content of milk fat, and is associated with increases either in conjugated linoleic acid (CLA) and trans-11 C18:1 contents, or in trans-10-C18:1 content. CLA putatively exhibits beneficial properties on CVD risk, whereas trans FA are suspected to be detrimental. The present study compared the effects of a trans-10-C18:1-rich butter (T10 butter), a trans-11-C18:1+CLA-rich butter (T11-CLA butter) and a standard butter (S butter) on lipid parameters linked to the CVD risk and fatty streaks. Thirty-six White New Zealand rabbits were fed one of the three butters (12% of the diet, plus 0.2% cholesterol) for 6 (experiment 1) or 12 (experiment 2) weeks. Liver lipids, plasma lipids and lipoprotein concentrations (experiments 1 and 2) and aortic lipid deposition (experiment 2) were determined. The T10 butter increased VLDL-cholesterol compared with the two others, and total and LDL-cholesterol compared with the T11-CLA butter ( P < 0.05). The T10 butter also increased non HDL/HDL ratio and aortic lipid deposition compared with the T11-CLA butter ( P < 0.05). The T11-CLA butter non-significantly reduced aortic lipid deposition compared with the S butter, and decreased HDL-cholesterol and increased liver triacyglycerols compared with the two other butters ( P < 0.05). These results suggest that, compared with the S butter, the T10 butter had detrimental effects on plasma lipid and lipoprotein metabolism in rabbits, whereas the T11-CLA butter was neutral or tended to reduce the aortic lipid deposition. PMID- 22444346 TI - Cholesterol and iron availability in yolk of laying hens feed with annatto ( Bixa orellana). AB - Pigmented egg yolks are more attractive. Popular culture treats annatto as a powerful anticholesterolemic agent, besides being widely used in the form of industry pigment. This work evaluated the effects of the addition of annatto (Bixa orellana L.) in the feed of hens, verifying a possible alteration of cholesterol in the yolks, content of carotenes, and iron and available iron, over time. One hundred and twenty-five hens divided in control (0% - T1) and four annatto-added treatments (0.5% - T2; 1.0% - T3; 1.5% - T4, and 2.0% - T5) were used. Eggs were collected at 23, 25, 27, 29 and 30 weeks. The animals were randomly separated into five groups of five animals each. The cholesterol was measured by the colorimetric method, vitamin A (beta and alpha carotene) by spectrophotometry, total iron by atomic absorption spectrophotometry, and dialysable iron by dialysis. Tukey's test was used at the 5% level for comparison of the averages. Regarding cholesterol, treatments T2 and T3 did not differ significantly. However, other treatments differed ( P <= 0.05) from the control, decreasing the cholesterol level as the percentage of annatto in the feed increased. In time, there was a significant increase ( P <= 0.05). For beta and alpha carotene, T5 presented statistically higher values than the others ( P <= 0.05). With regard to total iron, T5 had higher values than the others. Dialysable iron was also higher, probably due to the increase in carotenes. Thus, we can conclude that the use of annatto in the feed of layer hens is useful, as it provokes the reduction of cholesterol and promotes an increase in the content of iron and carotenes in eggs. PMID- 22444347 TI - Perturbation-dependent selection of postural feedback gain and its scaling. AB - In this study we examined whether the selection of postural feedback gain and its scaling is dependent on perturbation type. We compare forward pushes applied to the back of a standing subject to previous work on responses to support translation. As was done in the previous work, we quantified the subject's response in terms of perturbation-dependent feedback gains. Seven healthy young subjects (25+/-3 yr) experienced five different magnitudes of forward push applied by a 1.25 m-long pendulum falling from the height of 1.4m toward the center of mass of the subject's torso. The loads on the pendulum ranged from 2 to 10 kg. Impulsive force, ground reaction forces and joint kinematics were measured, and joint torques were calculated from inverse dynamics. A full-state feedback control model was used to quantify the empirical data, and the feedback gains that minimized the fitting error between the data and model simulation were identified. As in previously published feedback gains for support translation trials, gradual gain scaling with push perturbation magnitude was consistently observed, but a different feedback gain set was obtained. The results imply that the nervous system may be aware of body dynamics being subjected to various perturbation types and may select perturbation-dependent postural feedback gains that satisfy postural stability and feasible joint torque constraints. PMID- 22444348 TI - A force plate based method for the calibration of force/torque sensors. AB - This study describes a novel calibration method for six-degrees-of-freedom force/torque sensors (FTsensors) using a pre-calibrated force plate (FP) as a reference measuring device. In this calibration method, the FTsensor is rigidly connected to a FP and force/torque data are synchronously recorded while a dynamic functional loading procedure is applied by the researcher. Based on these data an accurate calibration matrix for the FTsensor can easily be obtained via least-squares optimization. Using this calibration method, this study further investigated what loading methods are appropriate for the calibration of FTsensors intended for ambulatory measurement of ground reaction forces (GRFs). Seven different loading methods were compared (e.g., walking, pushing while standing on the FTsensor). Calibration matrices were calculated based on the raw data from the seven loading methods individually and all loading methods combined. Performance of these calibration matrices was subsequently compared in an in situ trial. During the in situ trial, five common work tasks (e.g., walking, manual lifting, pushing) were performed by an experimenter, while standing on the FP wearing a "ForceShoe" with two calibrated FTsensors attached to its sole. Root-mean-square differences (RMSDs) between the FTsensor and FP outcomes were calculated over all tasks. Using the calibration matrices based on all loading methods combined resulted in small RMSDs (GRF: <8 N, center of pressure: <2 mm). Using the calibration matrices based on "pushing against manual resistance" resulted in similar RMSDs, proving it to be the best single loading method. PMID- 22444349 TI - Mechanism of fractures of adjacent and augmented vertebrae following simulated vertebroplasty. AB - Percutaneous vertebroplasty (VP) is a minimally invasive procedure that is used to treat osteoporosis-induced vertebral compression fractures (OVCFs). Frequently observed complications are fractures of adjacent and augmented vertebrae. In the present work, mechanisms for these fractures are presented. Fresh 4-level osteoporotic thoracic motion segments were tested. Both ends of the specimen were mounted. The lower level of the free vertebra was compressively fractured and followed by an injection of a 3.5 mL of a PMMA bone cement. Three steps of fatigue loading (5 Hz for 5 h) were incrementally and vertically applied on the specimens from 650 N to 950 N to 1150 N. Specimens of intact, compressively fractured, cement augmented and post-fatigued loading were radiographed for the measurement of deformations of the vertebra, the canal, and the foramen. At the end of fatigue loading, the vertebrae were sliced for micro morphologic analysis. The largest height loss after fatigue loading was at the posterior region of the augmented vertebra. In the augmented vertebra, fissures were found along the bone cement interface. These fissures split the cement and the trabeculae and propagated into the vertebrae and the endplates. The compactness ratio of the trabeculae region of the adjacent cranial vertebra was higher than that for intact and adjacent caudal ones. We attribute the fracture of the augmented vertebra, following simulated VP, to the initiation of fissures along the cement bone interface, which, in turn, may be due to uneven deformation of the vertebra. Fracture of the adjacent cranial vertebra is attributed to collapse of its trabeculae. PMID- 22444351 TI - The reliability of cone-beam computed tomography (CBCT) - generated frontal cephalograms. AB - BACKGROUND: The purpose of this study was to evaluate the reliability of measurements from cone-beam computed tomography (CBCT)-generated frontal cephalogram. MATERIALS AND METHODS: CBCT and conventional posteroanterior (PA) cephalograms were taken from 30 adult patients. CBCT image was set according to the Frankfurt-Horizontal (FH) plane as the horizontal plane and the midsagittal reference (MSR) plane. The CBCT frontal cephalograms were generated using the orthogonal Raycast method (group CT(raycast)), the orthogonal maximum intensity projection (MIP) method (group CT(MIP)) after the head reorientation according to the reference planes, and the generator tool provided by the employed 3 dimensional (3D) imaging software (group CT(generator)), respectively. The differences between the CBCT-generated frontal cephalograms and conventional PA cephalograms (group PA(ceph)) were compared by paired t-test (p<0.05). RESULTS: The significant differences were shown in two measurements for group CT(raycast), in 12 measurements for group CT(MIP), and in eight measurements for group CT(generator). It was confirmed that the CBCT frontal cephalograms, generated by means of the Raycast method (Group CT(raycast)), were more comparable to the conventional PA cephalograms in their measurements than were the others (Groups CT(MIP), CT(generator)). CONCLUSION: This study may well suggest that frontal cephalograms derived by 3D CBCT reorientation can be effectively employed in clinical applications. PMID- 22444352 TI - The platysma myocutaneous flap (PMF) for head and neck reconstruction: a retrospective and multicentric analysis of 91 T1-T2 patients. AB - The platysma myocutaneous flap (PMF) was first applied to intraoral reconstructions in 1978. PMF is not only an alternative to microvascular flaps but it also represents an excellent reconstructive choice especially in cases where free tissue transfer cannot be carried out. Failure and complications rate have been described as varying from 18 to 45% and this is why this flap should not be used in specific cases such as in the presence of cervical metastases and in cases of mandibulectomy and simultaneous reconstruction with alloplastic materials. The purpose of this study is to examine the experience and results obtained in three different and independent institutes where PMF has been adopted in 91 patients for head and neck cancer reconstructions. The authors report their departments' separate but simultaneous experiences with PMF for small and middle size soft tissue defects in a 10-year period. PMID- 22444353 TI - The end of analysis for the analyst (Translated by Ann Kutek). AB - This paper is an account of an analyst's personal exploration to make conceptual sense of the delicate closing stages of an analysis. Jung's theory of complexes provides a model of the functioning of the analytic relationship as an integral whole which itself is the locus of the process that brings an analysis to completion. Clinical vignettes are used to illustrate this. PMID- 22444354 TI - The hero, the anima and the claustrum: anality and idealization. AB - Joe Redfearn's (1979) classic paper 'The captive, the treasure, the hero and the anal stage of development' is recognized as seminal to the development of Jungian thought about anality, particularly its integration with mainstream (Freudian, Kleinian) psychoanalytic perspectives. This paper develops such an approach through drawing on contributions from Meltzer, Green, Bion, Chasseguet-Smirgel and Kernberg. More specifically, it is argued that over-investment in hero and anima archetypal configurations may represent an attempt to replace the resource of the internal parental couple that, at the level of unconscious phantasy, has been destroyed by the aggrieved child's attack on the primal scene. Unless this usually dissociated sadism can be integrated, the creative epistemophilic instinct may remain blunted, giving rise, through projective identification, to the adoption of a pseudo-adult identity based on appropriation or assertion. This in turn may lead to manic attempts to reach authentic ('animating') experience through the (often erotized) excitement of heroic endeavour. Consideration of both Redfearn's and the author's own clinical material demonstrates how close attention to process as well as content is fundamental to revealing and addressing such likely-to-be dissociated scenarios. PMID- 22444355 TI - The shadow of familiarity: a contributor to the intersubjective field. AB - This paper examines the influence of familiarity on the progress of analysis. It is proposed that familiarity is a particular aspect of the intersubjective field which emerges over time and begins to shape and influence the behaviours, perceptions, thoughts, and feelings of the participants. It is also proposed that states of familiarity can have facilitative or defensive functions in an analytic relationship and that it is an influence co-created in the field. The experience of familiarity operates as background to our various foreground concerns in analytic work and therefore exists primarily as an implicit, rather than explicit, experience in analysis. Defensive familiarity often creates a feeling of relatedness that is subtly unrelated, a form of pseudo-intimacy. Parallels between defensive familiarity and related concepts are examined including defences against the unknown, role responsiveness, romantic love, the image of the stranger, and unformulated experience. This paper concludes with two case examples and a discussion of procedural knowledge in the implicit domain as an explanatory framework for the understanding of familiarity states in the analytic setting. PMID- 22444356 TI - When ancestral heritage is a source of discomfort: culture, pre-object relatedness, and self-alienation. AB - The ancestral claims on an individual can evoke mental conflict when they involve separating from an ethnic group whose beliefs and customs are devalued by the dominant culture. However, these claims are engraved on the psyche early in development by caretakers to the level of pre-object relatedness, where contents and affect tones are implicit and may be unavailable for later psychoanalytical interventions. In addition, as the anthropologist Clifford Geertz notes, one's culture of origin precedes the development of psyche and creates its own set of claims that must be renegotiated when one encounters a different domain of cultural symbols, a confrontation that can produce psychological dissonance and self-alienation. In this paper, three cases are examined in which mental conflicts were evoked by attempts at divesting ancestral claims in response to conscious efforts to assimilate into the dominant culture. These patients suffered from separation guilt and unstable self-esteem and reported dream imagery suggesting psychological imbalance. The requirement to carefully delineate the ancestral claims on psyche as well as those contents and affects that may not be accessible to therapeutic intervention is emphasized, and the importance of compromise and acceptance with respect to the psychological demands of the unconscious are considered. PMID- 22444357 TI - Are archetypes transmitted more by culture than biology? Questions arising from conceptualizations of the archetype. AB - The archetype is one of the most important, if not the central concept of analytical psychology. Nevertheless from the beginning the concept was controversial. This paper attempts to review the debate around the term archetype and tries to point out some of the main problems the concept has in the light of contemporary knowledge especially in genetics and neurosciences. It becomes clear that for its use in the practice of Jungian psychotherapy the element of universality in the concept of archetypes is crucial. However, it must be concluded that there is still no firm scientific foundation for the claim that complex symbolic patterns (as for example the myth of the hero) can be transmitted in a way that every human individual has access to them. The paper attempts to show possible ways in which this transmission may be more successfully conceptualized. I would like to have Jung have the last word here. We find a hint in Jung's work where he opens up to ideas much like the ones I have developed here, and this is where Jung says: culture is part of man's nature. PMID- 22444358 TI - Transcendent function or group dysfunction? Comments on 'Transcendence, transmission and transformation: the transcendent function in infant observation' by Virginia Humphrey and Beth Barmack(1). PMID- 22444368 TI - Deciphering structural elements of mucin glycoprotein recognition. AB - Mucin glycoproteins present a complex structural landscape arising from the multiplicity of glycosylation patterns afforded by their numerous serine and threonine glycosylation sites, often in clusters, and with variations in respective glycans. To explore the structural complexities in such glycoconjugates, we used NMR to systematically analyze the conformational effects of glycosylation density within a cluster of sites. This allows correlation with molecular recognition through analysis of interactions between these and other glycopeptides, with antibodies, lectins, and sera, using a glycopeptide microarray. Selective antibody interactions with discrete conformational elements, reflecting aspects of the peptide and disposition of GalNAc residues, are observed. Our results help bridge the gap between conformational properties and molecular recognition of these molecules, with implications for their physiological roles. Features of the native mucin motifs impact their relative immunogenicity and are accurately encoded in the antibody binding site, with the conformational integrity being preserved in isolated glycopeptides, as reflected in the antibody binding profile to array components. PMID- 22444369 TI - Prediction of genetic growth curves in pigs. AB - Genetic growth curves of boars in a test station were predicted on daily weight records collected by automated weighing scales. The data contained 121 865 observations from 1477 Norwegian Landrace boars and 108 589 observations from 1300 Norwegian Duroc boars. Random regression models using Legendre polynomials up to second order for weight at different ages were compared for best predicting ability and Bayesian information criterion (BIC) for both breeds. The model with second-order polynomials had best predictive ability and BIC. The heritability for weight, based on this model, was found to vary along the growth trajectory between 0.32-0.35 for Duroc and 0.17-0.25 for Landrace. By varying test length possibility to use shorter test time and pre-selection was tested. Test length was varied and compared with average termination at 100 kg, termination of the test at 90 kg gives, e.g. 2% reduction in accuracy of estimated breeding values (EBV) for both breeds and termination at 80 kg gives 5% reduction in accuracy of EBVs for Landrace and 3% for Duroc. A shorter test period can decrease test costs per boar, but also gives possibilities to increase selection intensity as there will be room for testing more boars. PMID- 22444370 TI - Evaluation of connectedness between herds for three pig breeds in China. AB - Using data on age at 100 kg of three pig breeds (Large White, Landrace and Duroc) the connectedness between herds in China was evaluated by the connectedness rating (CR) method. The results show that most herds in China have low average CR (0-3.59%) with other herds. In Large White, of the 36 herds analyzed there are 20 herds, which are connected with at least one other herd. In Landrace and Duroc, of the 27 and 18 herds analyzed, only four and five herds, respectively, were found having connectedness with other herds. Generally, the connectedness exists only among two or few herds in the same region. A certain degree of connectedness between herds is a precondition for cross-herd genetic evaluation. A national or regional cross-herd genetic evaluation is not practicable at the present time in China. More intense efforts are needed to establish and enhance the connectedness between herds by means of extensively using artificial insemination (AI) in the swine industry in China. PMID- 22444371 TI - Genetic evaluation of Ethiopian Boran cattle and their crosses with Holstein Friesian in central Ethiopia: milk production traits. AB - Breed additive and non-additive effects, and genetic parameters of lactation milk yield (LYD), 305-day milk yield (305YD), lactation length (LL), milk yield per day of lactation (DM) and lifetime milk yield (LTYD) were estimated in Ethiopian Boran cattle and their crosses with Holstein in central Ethiopia. The data analyzed included 2360 lactation records spread over 15 years. Ethiopian Boran cattle were consistently inferior (P < 0.01) to the Ethiopian Boran-Holstein crosses for the dairy traits studied. When the crosses were compared, LYD, 305YD and DM were higher (P < 0.01) for 75% and 87.5% crosses compared to 50% and 62.5% ones. However, the 50% crosses had higher (P < 0.01) LTYD than the other genetic groups. The individual additive genetic breed differences for milk production traits were all significant (P < 0.01). The estimates, in favor of Holstein, were 2055 +/- 192 kg for LYD, 1776 +/- 142 kg for 305YD, 108 +/- 24 days for LL, 5.9 +/- 0.5 kg for DM and 3353 +/- 1294 kg for LTYD. Crossbreeding of the Holstein with the Ethiopian Boran resulted in desirable and significant (P < 0.01) individual heterosis for all milk production traits. The heterosis estimates were, 529 +/- 98, 427 +/- 72 kg, 44 +/- 12 days 1.47 +/- 0.23 kg and 3337 +/- 681 kg, for LYD, 305YD, LL, DM and LTYD, respectively. The maternal heterotic effects were non-significant (P > 0.05) for all traits. Heritabilities of LYD, 305YD, LL, DM and LTYD for Ethiopian Boran were 0.20 +/- 0.03, 0.18 +/- 0.03, 0.26 +/- 0.03, 0.13 +/- 0.03 and 0.02 +/- 0.04, respectively. The corresponding estimates for crosses were 0.10 +/- 0.002, 0.11 +/- 0.003, 0.63 +/- 0.02, 0.45 +/- 1.05 and 0.24 +/- 0.11, respectively. Selection within each of the genetic groups and crossbreeding should substantially improve the milk production potential of the Ethiopian Boran breed under such production system. PMID- 22444372 TI - An analysis of the genetic relationship between udder health and udder conformation traits in South African Jersey cows. AB - A multi-trait animal model was used to estimate genetic parameters among lactation somatic cell score (SCS) and udder-type traits in South African Jersey cattle, through restricted maximum likelihood (REML) procedures. Data comprised records on 18 321 Jersey cows in 470 herds, collected through the National Milk Recording Scheme from 1996 to 2002. Average SCS in the first three lactations (SCS1, SCS2 and SCS3) were considered as different traits and the udder-type traits were fore udder attachment (FUA), rear udder height (RUH), rear udder width (RUW), udder cleft (UC), udder depth (UD), fore teat placement (FTP), rear teat placement (RTP) and fore teat length (FTL). Heritability estimates for the respective lactation SCS were 0.07 +/- 0.01, 0.11 +/- 0.01 and 0.11 +/- 0.02. Udder-type traits had heritability estimates ranging from 0.14 +/- 0.01 for UD to 0.30 +/- 0.02 for FTL. Genetic correlations between SCS and udder-type traits ranged from -0.003 +/- 0.07 between FUA and SCS3 to -0.50 +/- 0.07 between UD and SCS3. Slow genetic progress is expected when selection is applied independently on SCS and udder-type traits, due to the generally low heritabilities. Tightly attached shallow udders with narrowly placed rear teats are associated with low SCS in the Jersey population. PMID- 22444373 TI - Feed restriction strategy in the growing rabbit. 1. Impact on digestion, rate of passage and microbial activity. AB - The effects of a quantitative feed restriction on the digestive physiology of the young rabbit remain largely unclear. Several digestive functions were thus analysed in the rabbit after weaning, using a monofactorial design that produces a linear reduction of the intake, from ad libitum (AL group) to 80%, 70% and 60% of AL (I80, I70 and I60). The restriction programme was applied by giving a daily meal during 21 days after weaning (34 days), and then a 4-day transition period was managed where the feed intake was fixed at 80% of the AL group, before to be fed ad libitum till 69 days of age. The young rabbit quickly adapted to the restriction programme, since within 4 days after weaning they ate totally their ration within 6-7 h after the feed distribution at 8:00, while AL animals consumed 75% of their feed between 15:00 and 8:00. From 55 to 59 days old, rabbits of I70 and I60 groups reached the intake of the I80 group within 1 day, and then the feed intake of restricted animals increased progressively without over-eating. From 54 to 69 days old, the intake of the four groups did not differ and averaged 143.7 g/day per rabbit. During restriction, the live weight and the weight gain decreased linearly with the restriction level. From 55 to 69 days, the weight gain increased linearly according to the restriction level previously applied, but the final weight of restricted rabbits remained lower than AL ones ( 3%, -5% and -7%, respectively, for I80, I70 and I60). After 7 days of restriction, the digestibility was not significantly affected by the restriction level, except for crude protein that presented a slightly higher (+1.5 unit, P = 0.05) coefficient in I70 and I60 groups. The mean retention time (MRT) of particles increased by 50% for restricted animals (mean: 26.2 h for I80 and I60) compared to the AL ones, while that of the liquid phase (three times longer than the particles) was linearly and moderately increased with restriction (+20% between AL and I60). In restricted groups, the caecal pH was lower (-0.3 unit, P < 0.05) and could be related to their higher volatile fatty acid (VFA) concentration (+16 mmol/l compared to AL, P < 0.05). The fermentation pattern, ammonia concentration and the caecal bacterial fibrolytic activity remained similar among treatments, although the butyrate proportion tended to be higher in restricted animals. Impact of feed restriction on performances and digestive health is reported in the second part of this study. PMID- 22444374 TI - Feed restriction strategy in the growing rabbit. 2. Impact on digestive health, growth and carcass characteristics. AB - A field enquiry mentioned the potential positive impact of a feed restriction on the health of young rabbits, but no objective information relates the intake to digestive health. The effects of a post-weaning feed restriction strategy were thus studied on digestive health and growth and carcass parameters of the growing rabbit, using a monofactorial design that produces a quantitative linear reduction of the intake, from ad libitum (AL group) to 80%, 70% and 60% of AL. The study was performed simultaneously in six experimental sites, on 1984 growing rabbits (496 per treatment) collectively caged from weaning (34 to 38 days of age, depending on the site) to slaughter (68 to 72 days). The feeding programme was applied as followed: restriction during 21 days after weaning, and then ad libitum till slaughter. During the feed restriction period the growth rate was linearly reduced with the restriction level, by 0.5 g/day for each percent of intake reduction. When returning to ad libitum intake (after 54 days old) a compensatory growth and a higher feed efficiency occurred. Therefore, the impact of the feeding programme on the slaughter weight (SW) was significant (-4.5 g/% of restriction), but relatively moderate: the weight loss of the more-restricted rabbits (60%) reached 7.7% (-200 g) compared to the AL group. Over the whole fattening period, the feed restriction reduced linearly and significantly the feed conversion (FC) (-0.0077 unit/% of restriction). Carcass traits were little affected by the feeding programme, except for a slightly lower decrease of the dressing percentage (mean: 1.2 units between AL and the three restricted groups). On the six experimental sites, mortality and morbidity were always caused by acute digestive disorders, namely diarrhoea and/or caecal impaction. Independent of the treatment, the mortality rate strongly varied according to the site (between 7% and 18% from weaning to 54 days and for the AL group). During feed restriction, the mortality was significantly lower from a restriction threshold of 80% (meanly: -9% compared to AL). The morbidity was also significantly reduced (-6%) for the two most restricted groups (70% and 60%). The favourable effect of a lower intake on health did not persist after returning to ad libitum intake (54 days to slaughter), since mortality and morbidity were not significantly different among the treatments. Such a feeding strategy thus represents a double benefit in terms of feed costs and lower losses of young rabbits. PMID- 22444375 TI - Influence of vitamin E supplementation and basal diet on the vitamin E status, performance and tissue fatty acid concentration in lambs. AB - In order to determine the effect of dietary vitamin E level and basal diet on vitamin E status, performance and tissue fatty acid content, five groups of eight Suffolk * Charollais wether lambs with an initial live weight of 28.4 (s.d. 1.6) kg were allocated to one of five concentrate-based diets supplemented with all rac-alpha-tocopheryl acetate to contain 30 mg (C-30), 60 mg (C-60), 120 mg (C 120), 250 mg (C-250) or 500 mg (C-500) alpha-tocopheryl acetate/kg dry matter (DM), for 63 days. Two additional groups of eight lambs entered the study at 31.2 (s.d. 3.3) kg and were fed grass silage and 400 g/day concentrate for 56 days, with the whole diet providing the equivalent of 60 mg (S-60) or 500 mg (S-500) alpha-tocopheryl acetate/kg DM. Lambs were weighed and blood samples obtained by venipuncture weekly. Dietary vitamin E level did not affect performance (P > 0.05), but lambs fed grass silage grew more slowly (P < 0.001) and had a higher (P < 0.001) feed conversion ratio (kg feed/kg gain) than those fed concentrates. At day 0 plasma alpha-tocopherol concentrations were 0.8 MUg/ml and did not differ between treatments (P > 0.05). Plasma alpha-tocopherol concentrations then decreased in all lambs except for those fed S-500, which increased, and at slaughter were (MUg/ml) 0.07, 0.23, 0.39, 0.76 and 1.57 in C-30, C-60, C-120, C 250 and C-500 and 1.18 and 1.93 in S-60 and S-500, respectively. At slaughter, muscle and liver alpha-tocopherol concentrations were in the deficiency range for lambs fed C-30, C-60 or C-120, whereas plasma creatine kinase and tissue polyunsaturated fatty acids were unaffected by dietary vitamin E level, but creatine kinase levels were higher (P < 0.05) and glutathione peroxidise levels lower (P < 0.001) in lambs fed grass silage than concentrates alone. Muscle and liver alpha-tocopherol concentrations were 1.8- and 4.1-fold higher in lambs fed S-60 than C-60, but there was less of a difference between lambs fed S-500 or C 500 with muscle and liver differences of 0.4- and 0.7-fold, respectively. Tissue n-3 polyunsaturated fatty acid concentrations were higher (P < 0.05) and n-6 fatty acids lower in lambs receiving the grass silage compared to concentrate based diets, but were not affected by dietary vitamin E level. It is concluded that lower plasma and tissue levels of alpha-tocopherol are present in lambs supplemented with all-rac-alpha-tocopheryl acetate on a concentrate compared to a mixed diet of silage and concentrates, and that normal growth can be achieved at tissue levels previously considered to represent deficiency. PMID- 22444376 TI - Comparison of microbial fermentation of high- and low-forage diets in Rusitec, single-flow continuous-culture fermenters and sheep rumen. AB - Eight Rusitec and eight single-flow continuous-culture fermenters (SFCCF) were used to compare the ruminal fermentation of two diets composed of alfalfa hay and concentrate in proportions of 80 : 20 (F80) and 20 : 80 (F20). Results were validated with those obtained previously in sheep fed the same diets. Rusitec fermenters were fed once daily and SFCCF twice, but liquid dilution rates were similar in both types of fermenters. Mean values of pH over the 12 h postfeeding were higher (P < 0.001) in Rusitec than in SFCCF, with diet F80 showing higher values (P < 0.001) in both types of fermenters. Concentrations of total volatile fatty acids (VFA) were higher (P < 0.001) in SFCCF than in Rusitec, and in both systems were higher (P = 0.002) for diet F20 than for diet F80. There were significant differences between systems in the proportions of the main VFA, and a fermentation system * diet interaction (P < 0.001) was detected for all VFA with the exception of valerate. No differences (P = 0.145) between the two types of fermenters were detected in dry matter (DM) digestibility, but NDF, microbial N flow and its efficiency were higher (P = 0.001) in SFCCF compared to Rusitec. Whereas pH values and VFA concentrations remained fairly stable through the day in both in vitro systems, pH dropped and VFA increased shortly after feeding in sheep rumen reaching the minimum and maximal values, respectively, about 4 h after feeding. Both in vitro systems detected differences between diets similar to those found in sheep for liquid dilution rate, pH values, DM digestibility, microbial N flow and growth efficiency. In contrast, acetate/propionate ratios were lower for diet F20 than for F80 in sheep rumen (2.73 and 3.97) and SFCCF (3.07 and 4.80), but were higher for diet F20 compared to F80 (4.29 and 3.40) in Rusitec, with values considered to be unphysiological for high-concentrate diets. In vivo NDF digestibility was affected (P = 0.017) by diet, but no differences between diets (P > 0.05) were found in any in vitro system. A more precise control of pH in both types of fermenters and a reduction of concentrate retention time in Rusitec could probably improve the simulation of in vivo fermentation. PMID- 22444377 TI - Dietary fat source affects metabolism of fatty acids in pigs as evaluated by altered expression of lipogenic genes in liver and adipose tissues. AB - Little is known about pig gene expressions related to dietary fatty acids (FAs) and most work have been conducted in rodents. The aim of this study was to investigate how dietary fats regulate fat metabolism of pigs in different tissues. Fifty-six crossbred gilts (62 +/- 5.2 kg BW) were fed one of seven dietary treatments (eight animals per treatment): a semi-synthetic diet containing a very low level of fat (no fat (NF)) and six fat-supplemented diets (ca. 10%) based on barley and soybean meal. The supplemental fat sources were tallow (T), high-oleic sunflower oil (HOSF), sunflower oil (SFO), linseed oil (LO), blend (FB) (55% T, 35% SFO and 10% LO) and fish oil (FO) blend (40% FO and 60% LO). Pigs were slaughtered at 100 kg BW and autopsies from liver, adipose tissue and muscle semimembranousus were collected for qPCR. The messenger ribonucleic acid (mRNA) abundances of genes related to lipogenesis were modified due to dietary treatments in both liver (sterol regulatory element-binding protein-1 (SREBP-1), acetyl CoA carboxylase (ACACA) and stearoyl CoA desaturase (SCD)) and adipose tissue (fatty acid synthase (FASN), ACACA and SCD), but were not affected in semimembranousus muscle. In the liver, the mRNA abundances of genes encoding lipogenic enzymes were highest in pigs fed HOSF and lowest in pigs fed FO. In adipose tissue, the mRNA abundances were highest in pigs fed the NF diet and lowest in pigs fed T. The study demonstrated that dietary FAs stimulate lipogenic enzyme gene expression differently in liver, fat and muscles tissues. PMID- 22444378 TI - The effects of different milking intervals and milking times per day in jennet milk production. AB - In their first 150 days of lactation, nine Ragusana jennets were investigated at the 'Istituto Sperimentale Zootecnico per la Sicilia' (ISZS) in Palermo, to study the effects of different milking typologies on milk production. The jennets were kept in a paddock and were fed hay ad libitum and concentrate (3.5 kg jennet/day). From post-foaling day 21, every 3 weeks individual milk amounts were recorded, and individual milk samples were collected and analyzed for the main qualitative parameters. The compared theses were: two daily milking times with 6- and 3-h intervals; and two, three and eight daily milking times with 3-h interval. The jennets were manually milked. The foals were separated from the jennets at 0800 h, and after the last milking the foals were housed with the jennets. During the day with eight milkings, the milk yield from the jennets was fed to their respective foals, through bottles. The 6-h milking interval produced more milk (+19%) per session than the 3-h interval (P 0.01). The fat content per session, with the eight-time milking frequency (P 0.001), was greater than the others. For each milking typology, the lactation stage had a similar effect on almost all the considered variables. When observing the eight-milking times, the fat content (%) increased from 1100 to 0500 h (P 0.001). The milk yield and the fat percentage produced by two-, three- and eight-milking times were positively correlated. PMID- 22444379 TI - Recovery of intravenously infused chromium EDTA and lithium sulphate in the urine of cattle and their use as markers to measure urine volume. AB - A series of metabolism experiments investigated the recovery of continuous-, intravenously infused chromium complexed with ethylenediamine tetra-acetic acid (CrEDTA) and lithium sulphate in the urine of cattle with a view to using the markers to estimate urine and metabolite output in grazing cattle. The recovery of Cr in urine from these infusions was similar (90%) in metabolism trials when cattle consumed three very contrasting diets: high-grain formulated pellet, lucerne hay (Medicago sativa) or low-quality native grass hay (predominantly Heteropogon contortus). By contrast, Li recovery in urine averaged 46.3 +/- 0.40% and 72.6 +/- 0.43% for native pasture and lucerne hays, respectively, but was not constant across days. There was negligible transfer of Cr from CrEDTA in blood serum to the rumen or faeces, whereas appreciable quantities of infused Li were found in both. The ratio of urine volume estimated by spot samples and marker dilution of Cr, to urine volume measured gravimetrically, was 1.05. In grazing studies using rumen-fistulated (RF) steers grazing seven different tropical and temperate grass and legume pastures, the ratio of concentrations of purine derivatives (PD) to Cr in spot samples of urine was shown to vary diurnally in the range of 49% to 157% of the average 24 h value. This finding indicated the need for regular sampling of urine to achieve an accurate average value for the PD : Cr ratio in urine for use in estimating urinary PD excretion and hence microbial protein production in the rumen. It was concluded that continuous, intravenous infusion of CrEDTA resulted in a constant recovery of Cr in the urine of cattle across diets and, provided an intensive sampling regime was followed to account for diurnal variation, it would be suitable as a marker to estimate urine volume and urinary output of PD in grazing cattle. PMID- 22444380 TI - Effect of feed intake on heat production and protein and fat deposition in milk fed veal calves. AB - Energy requirements for veal calves have not been updated recently despite the increased age at slaughter and the predominance of the Prim'Holstein breed in Europe. The objectives of this study were to determine the effects of four feeding levels (FLs) on protein and fat deposition and heat production in milk fed calves at three stages of fattening and to determine energy requirements of calves. At each stage, 16 Prim'Holstein male calves (mean body weight (BW): 73.4, 151.6 and 237.4 kg) were fed a milk replacer at 79%, 87%, 95% or 103% of a reference FL. Measurements for one stage were conducted over 4 successive weeks in two open-circuit respiration chambers and consisted of a 6-day nitrogen and energy balance followed by a fasting day for estimating fasting heat production (FHP) of the calves. Heat production (HP) measurements were analyzed using a modeling approach to partition it between HP due to physical activity (AHP), feed intake (thermic effect of feeding (TEF)) and FHP. There was no effect of FL and stage on apparent digestibility coefficients, except for a tendency for increased digestibility coefficient of fat as animals got older. The metabolizable energy (ME)/digestible energy (DE) ratio did not depend on FL but decreased (P < 0.01) as animals got older in connection with marked increases in urinary glucose and urea excretion. The AHP and TEF components of HP were not affected by stage or FL and averaged 8.4% and 7.8% of ME intake, respectively. The FHP, expressed per kg BW0.85, increased with increasing FL, suggesting that also ME requirement for maintenance (MEm) may depend on FL. For an average intake of 625 kJ ME/kg BW0.85 per day (95% of the reference FL), FHP was 298 kJ/kg BW0.85 per day. Energy retention as protein and fat increased with increasing FL resulted in higher BW gain. But the rate of increase depended on stage of growth. The slope relating protein deposition to FL was lower in the finishing phase than in the growing phase, while the slope for lipid deposition was greater. Protein and fat contents of BW gain were not affected by FL but increased as animals got older. From these results, the energy requirements of veal calves are proposed according to a new approach, which considers that MEm (expressed per kg BW0.85) depends on ME intake (kJ/kg BW0.85) according to the following relationship: MEm = 197 + 0.25 * ME intake. The corresponding marginal efficiencies of ME utilization for protein and fat deposition are then 82% and 87%, respectively. PMID- 22444381 TI - Gene expression and protein distribution of leptin and its receptor in bovine oocytes and preattachment embryos produced in vitro. AB - Many investigations point out the important role of leptin during the preimplantation development. Transcripts for the leptin gene (LEP) and its receptor (LEPR) have been identified in several tissues related to reproduction (e.g. ovaries, testis and oviduct) in both human and mouse. This work shows for the first time the expression and distribution patterns of LEP and LEPR in bovine oocytes and in vitro-produced embryos. Gene expression was analysed by reverse transcription PCR and real-time PCR, and the proteins were localised by immunostaining. This study included immature and mature oocytes, zygotes, two-, four-, eight- to 16-cell embryos, morulae and blastocysts and the LEP transcript was identified throughout all stages of bovine preimplantation development. However, mRNA for the LEPR gene was detected at all stages, excluding four-cell embryos. Expression of both LEP and LEPR genes was reduced at the eight- to 16 cell stage. This in addition to the absence of LEPR mRNA in four-blastomere embryos may suggest that maternally derived transcripts degenerate towards the eight- to 16-cell stage coinciding with embryonic genome activation at eight- to 16-cell stage and subsequent appearance of embryonic mRNA. Immunofluorescent staining demonstrated that LEP and LEPR proteins form a spherical rim beneath the oolemma. After maturation, however, the proteins became evenly distributed within the cytoplasm. In two- to eight-cell embryos, fluorescence was observed in the apical surface of the blastomeres, and from 10- to 16-cell stage in the apical region of outer blastomeres. This pattern persisted to the blastocyst stage, leading to LEP and LEPR distribution within trophoblast cells, but not in the inner cell mass. These results support previous findings on polar distribution of proteins within mammalian oocytes and embryos, as well as suggests leptin's potential role during early mammalian development and implantation. PMID- 22444382 TI - Intergenerational effects of birth weight on glucose tolerance and reproductive performance. AB - Women who were themselves small-for-gestational age (SGA) are at a greater risk of adulthood diseases such as non-insulin-dependent diabetes mellitus (NIDDM), and twice at risk of having an SGA baby themselves. The aim of this study was to examine the intergenerational pig. Low (L) and normal (N) birth weight female piglets were followed throughout their first pregnancy (generation 1 (G1)). After they had given birth, the growth and development of the lightest (l) and heaviest (n) female piglet from each litter were monitored until approximately 5 months of age (generation 2 (G2)). A glucose tolerance test (GTT) was conducted on G1 pig at 6 months of age and again during late pregnancy; a GTT was also conducted on G2 pigs at 4 months of age. G1 L offspring exhibited impaired glucose metabolism in later life compared to their G1 N sibling but in the next generation a similar scenario was only observed between l and n offspring born to G1 L mothers. Despite G1 L mothers showing greater glucose intolerance in late pregnancy and a decreased litter size, average piglet birth weight was reduced and there was also a large variation in litter weight; this suggests that they were, to some extent, prioritising their nutrient intake towards themselves rather than promoting their reproductive performance. There were numerous relationships between body shape at birth and glucose curve characteristics in later life, which can, to some extent, be used to predict neonatal outcome. In conclusion, intergenerational effects are partly seen in the pig. It is likely that some of the intergenerational influences may be masked due to the pig being a litter-bearing species. PMID- 22444383 TI - Drying and warming immediately after birth may reduce piglet mortality in loose housed sows. AB - The aim of the present experiment was to investigate the effects of placing newborn piglets under the heat lamp or both drying and placing them under the heat lamp on piglet mortality. Sixty-seven healthy (Landrace * Yorkshire) sows were divided equally into three different experimental groups: a control group where the farrowings occurred without supervision from the farmer (C; n = 23 litters), another group where the piglets were placed under the heat lamp in the creep area immediately after birth (HL; n = 22 litters) and a third group where the piglets were dried with straw and paper towels followed by placing them under the heat lamp in the creep area immediately after birth (DHL; n = 22 litters). The sows were individually loose-housed in farrowing pens during farrowing and lactation. The piglets were not closed inside the creep area, but were free to move around in the pen. The routines in the experimental groups required the stock person to attend the farrowings from the onset of birth of the first piglet until the last piglet was born. All the dead piglets were weighed and subjected to a post mortem examination at the farm to ascertain the causes of death. Postnatal mortality (% of live born) was significantly lower in the HL and DHL groups than in the control group (P < 0.0001). This was significant concerning all causes of mortality. Compared to the control group, crushing occurred in significantly fewer litters when the piglets were both dried and placed under the heat lamp (P < 0.05). In the DHL treatment, crushing of one or more piglets by the sow occurred in only 13.6% of the litters, whereas this was increased to 34.8% in the HL and to 47.9% in the control group, respectively. All causes of death, except the proportion of stillborn piglets, increased significantly with increasing litter size. Because of the relatively large potential that these rather simple routines may have to improve piglet survival, different types of management or human interference around the time of farrowing should be compared on a larger scale, both experimentally and on commercial farms. PMID- 22444384 TI - Discrimination of pasture-fed lambs from lambs fed dehydrated alfalfa indoors using different compounds measured in the fat, meat and plasma. AB - The last decade has seen important developments in the use of carotenoid pigments to authenticate pasture-feeding in ruminants. However, dehydrated alfalfa is sometimes incorporated in grain-based concentrates fed to stall-raised lambs, which may affect the reliability of the pasture-feeding authentication methods based on carotenoids in plasma and fat, due to significant residual carotenoid levels post-dehydration. The aim of this study was to examine whether other compounds can give additional information to authenticate diet and discriminate pasture-fed lambs from lambs fed high levels of alfalfa indoors. Two feeding treatments were compared: pasture-feeding (P) v. stall-feeding with dehydrated alfalfa (A). Each treatment group consisted of seven male Romanov * Berrichon lambs. Pasture-fed (P) lambs grazed a permanent graminaceae-rich pasture maintained at a leafy, green stage, offered ad libitum; they received no supplementation at pasture. A-group lambs were individually penned and fed dehydrated alfalfa and straw; their feed level was adjusted to achieve a similar growth pattern as for P-group lambs. Plasma carotenoid concentration was measured at slaughter by spectrophotometry. The reflectance spectrum of perirenal and subcutaneous caudal fat was measured at 24-h post mortem and used to calculate an index (absolute value of the mean integral (AVMI)) quantifying light absorption by carotenoid pigments present in the fat. The nitrogen (N) stable isotopes ratio (delta15N) in both feed and longissimus dorsi muscle was measured by isotopes ratio mass spectrometry (IRMS). Volatile compounds were analyzed in perirenal fat for five randomly chosen lambs per treatment, using dynamic headspace-gas chromatography-mass spectrometry. Plasma carotenoid concentration and AVMI of the fat did not differ significantly between P- and A-group lambs, but there were significant between-treatment differences in meat delta15N values and in the terpene profiles of perirenal fat. A discriminant analysis performed using three compounds in different animal tissues (delta-cadinene in perirenal fat, delta15N value of the meat and plasma carotenoid concentration) clearly separated pasture fed lambs from lambs fed high levels of alfalfa indoors. PMID- 22444385 TI - Influence of pig rearing system on animal performance and manure composition. AB - A total of 200 crossbred pigs (castrated males and females) were used in five replicates to evaluate the influence of rearing conditions for fattening pigs on growth performance, manure production and gaseous emissions. Approximately at 36 kg body weight (BW), littermates were allocated to either a conventional (fully slatted floor, 0.65 m2/pig, considered as control, CON) or an alternative (sawdust bedding, 1.3 m2/pig, with free access to an outdoor area 1.1 m2/pig, OUT) system, until slaughter at approximately 115 kg BW. Pigs had free access to standard growing and finishing diets. Manure was stored as slurry below the slatted floor in the CON system and as litter, for the inside area, or slurry and liquid, for the outside area, in the OUT system. The amount and composition of manure were determined at the end of each replicate. Ammonia emission from the rooms was measured continuously. Dust and odour concentrations were measured in replicates 1 and 2, and CH4, N2O and CO2 emissions were measured in replicate 3. Compared with the CON, the OUT pigs exhibited a faster growth rate (+8%, P < 0.001) due to their greater feed intake (+0.21 kg/day, P < 0.01), resulting in a heavier BW (+7.3 kg, P < 0.001) and a lower lean meat content (-1.6% points, P < 0.001) at slaughter. The total amount of manure produced per pig was similar in both systems (380 kg/pig), but because of the contribution of sawdust, dry matter (DM) content was higher (P < 0.001) and concentrations in N, P, K, Cu and Zn in DM were lower (P < 0.001) in manure from the OUT than from the CON system. In the OUT system, most of the manure DM (70%) was collected indoor, corresponding mostly to the contribution of the sawdust, and most of the manure water (70%) was collected outdoor. Pigs excreted indoor about 60% and 40% of urine and faeces, respectively. Ammonia emission from the room was lower for the OUT system, whereas total NH3 emissions, including the outdoor area, tended to be higher (12.0 and 14.1 g/day N-NH3 per pig for CON and OUT, respectively). Nitrous oxide emission was higher (1.6 and 4.6 g/day N-N2O per pig for CON and OUT, respectively) and methane emission was lower (12.1 and 5.9 g/day per pig for CON and OUT, respectively), for the OUT compared with the CON system. PMID- 22444386 TI - Effect of forage on the content of phyto-oestrogens in bovine milk. AB - Phyto-oestrogens are believed to have a range of beneficial effects on predominant Western diseases. A few studies on phyto-oestrogens in milk exist and show that the composition can be affected by feeding. Therefore, the aim was to study how feeding of lucerne and grass/clover silages (GCSs) affects the concentration of phyto-oestrogens in bovine milk. Sixteen Danish Holstein cows were assigned to a 4 * 4 latin square design with four cows per treatment per period of 3 weeks. The four treatment diets were lucerne silage (LS), 2/3 lucerne silage and 1/3 maize silage (2/3LS), 1/3 lucerne silage and 2/3 maize silage (1/3LS) and GCS. Milk was collected at the end of each period and feed samples on day 6, 13 and 20 in each experimental period. Milk and pooled feed samples were analysed for the concentration of isoflavones, coumestans and lignans. The content of isoflavones was higher and the content of coumestrol lower in the GCS diet than in LS, 2/3LS and 1/3LS diets. For the LS, 2/3LS and 1/3LS diets, the concentration of coumestrol and secoisolariciresinol increased with the proportion of lucerne while the concentration of isoflavones was similar across the diets. The concentrations of the formononetin, daidzein and equol in the milk were significantly higher for the GCS diet than for the LS, 2/3LS and 1/3LS diets. In particular, the concentration of equol was 62-291 times higher for GCS. The concentration of coumestrol was significantly lower for the GCS diet compared to the LS, 2/3LS and 1/3LS diets. No pattern for the concentration of lignans was observed. In conclusion, a high concentration of isoflavones, particularly equol, and a low concentration of coumestrol were measured in the milk from the GCS diet. In contrast, a low concentration of isoflavones and a high concentration of coumestrol were measured in the milk from the LS, 2/3LS and 1/3LS diets. However, the concentration of phyto-oestrogens in bovine milk is low compared to food sources rich in phyto-oestrogens but the high concentration of equol could possibly be of therapeutic importance. PMID- 22444387 TI - Compartment modeling for mammalian protein turnover studies by stable isotope metabolic labeling. AB - Protein turnover studies on a proteome scale based on metabolic isotopic labeling can provide a systematic understanding of mechanisms for regulation of protein abundances and their transient behaviors. At this time, these large-scale studies typically utilize a simple kinetic model to extract protein dynamic information. Although many high-quality, protein isotope incorporation data are available from those experiments, accurate and additionally useful protein dynamic information cannot be extracted from the experimental data by use of the simple kinetic models. In this paper, we describe a formal connection between data obtained from elemental isotope labeling experiments and the well-known compartment modeling, and we demonstrate that an appropriate application of a compartment model to turnover of proteins from mammalian tissues can indeed lead to a better fitting of the experimental data. PMID- 22444388 TI - Social determinants of health and outcomes in New Zealand. PMID- 22444389 TI - Tuberculosis control and elimination in 2012 and beyond. PMID- 22444390 TI - Thyroid disease--more research needed. PMID- 22444391 TI - A sustainable agenda for tuberculosis control and research. PMID- 22444393 TI - Beate Kampmann: research advocate for children with tuberculosis. PMID- 22444395 TI - Diet composition and obesity. PMID- 22444397 TI - Diet composition and obesity. PMID- 22444398 TI - Exclusion of Indigenous youth from important parts of the Australian Health Survey. PMID- 22444399 TI - European mathematics. PMID- 22444400 TI - Rash diagnosis of blood expectoration. PMID- 22444402 TI - Management of asthma in pregnancy. PMID- 22444403 TI - Towards a better National Health and Nutrition Survey in Japan. PMID- 22444404 TI - Understanding human evolutionary history: a meeting report of the Swedish Royal Academy of Sciences symposium of modern human genetic variation. AB - A report on the Swedish Royal Academy of Sciences Symposium on Modern Human Genetic Variation. Stockholm, Sweden. January 19-20, 2012. PMID- 22444405 TI - Genetic relationships of five Indian horse breeds using microsatellite markers. AB - The genetic relationships of five Indian horse breeds, namely Marwari, Spiti, Bhutia, Manipuri and Zanskari were studied using microsatellite markers. The DNA samples of 189 horses of these breeds were amplified by polymerase chain reaction using 25 microsatellite loci. The total number of alleles varied from five to 10 with a mean heterozygosity of 0.58 +/- 0.05. Spiti and Zansakari were the most closely related breeds, whereas, Marwari and Manipuri were most distant apart with Nei's DA genetic distance of 0.071 and 0.186, respectively. In a Nei's DA genetic distances based neighbour joining dendrogram of these breeds and a Thoroughbred horse outgroup, the four pony breeds of Spiti, Bhutia, Manipuri and Zanskari clustered together and then with the Marwari breed. All the Indian breeds clustered independently from Thoroughbreds. The genetic relationships of Indian horse breeds to each other correspond to their geographical/environmental distribution. PMID- 22444406 TI - Using mechanistic animal growth models to estimate genetic parameters of biological traits. AB - Mechanistic animal growth models can incorporate a description of the genotype as represented by underlying biological traits that aim to specify the animal's genetic potential for performance, independent from the environmental factors captured by the models. It can be argued that these traits may therefore be more closely associated to genetic potential, or components of genetic merit that are more robust across environments, than the environmentally dependent phenotypic traits currently used for genetic evaluation. The prediction of merit for underlying biological traits can be valuable for breeding and development of selection strategies across environments.Model inversion has been identified as a valid method for obtaining estimates of phenotypic and genetic components of the biological traits representing the genotype in the mechanistic model. The present study shows how these estimates were obtained for two existing pig breeds based on genetic and phenotypic components of existing performance trait records. Some of the resulting parameter estimates associated with each breed differ substantially, implying that the genetic differences between the breeds are represented in the underlying biological traits. The estimated heritabilities for the genetic potentials for growth, carcass composition and feed efficiency as represented by biological traits exceed the heritability estimates of related phenotypic traits that are currently used in evaluation processes for both breeds. The estimated heritabilities for maintenance energy requirements are however relatively small, suggesting that traits associated with basic survival processes have low heritability, provided that maintenance processes are appropriately represented by the model.The results of this study suggest that mechanistic animal growth models can be useful to animal breeding through the introduction of new biological traits that are less influenced by environmental factors than phenotypic traits currently used. Potential value comes from the estimation of underlying biological trait components and the explicit description of their expression across a range of environments as predicted by the model equations. PMID- 22444407 TI - Post-ruminal or intravenous infusions of carbohydrates or amino acids to dairy cows 1. Early lactation. AB - The objectives of this study were to compare the effects of post-ruminal and intravenous infusions of wheat starch or glucose (CHO) or a mixture of amino acids (AA) on milk protein yield, nitrogen utilisation, plasma metabolites and mammary extraction rate of dairy cows in early lactation. Eight cow, ruminally fistulated, was assigned to two 4 * 4 Latin squares during 14-day periods, where the last 7 days were for infusions. Infusions were: (1) starch in the abomasum (SP), (2) glucose in the blood (GB), (3) AA in the abomasum (AP), and (4) AA in the blood (AB). The experiment started 54 +/- 4 days (mean +/- s.e.) post partum (milk yield 33.4 +/- 1.7 kg). Daily amounts of nutrients infused were 378, 365, 341, and 333 g for SP, GB, AP and AB, respectively. The cows were fed a basal diet consisting of a concentrate mixture and grass silage (55:45 on dry-matter (DM) basis), and DM intake was 17.2 kg/day. Milk production was affected by site of infusion within substrate, whereas infusion substrates within infusion site (CHO or AA) were of minor importance. Compared with SP infusion, GB infusion increased ( P < 0.05) milk protein yield and concentration by 55 g and 1 g/kg. The AB infusion tended to ( P < 0.10) increase milk yield and ECM and increased ( P < 0.05) protein yield and concentration by 1.8 and 2.2 kg, 83 g and 1.1 g/kg compared with AP infusion, respectively. Nitrogen balance data indicated higher losses of metabolic faecal nitrogen (MFN) by abomasal than by intravenous infusions, and an increased ( P < 0.05) catabolism for AP and AB infusions compared with SP and GB infusions. GB infusion did not increase ( P>0.10) plasma glucose or insulin concentrations above that of SP infusion. Compared with the SP infusion, the GB infusion had minor effect on plasma AA. AP infusion increased ( P < 0.05) plasma non-essential AA (NEAA) concentration compared with AB infusion, whereas infusion site of AA had no effect ( P>0.05) on essential AA (EAA) or branched-chain AA (BCAA). Although a higher milk protein synthesis was observed for AB infusion, the mammary extraction rate was not higher ( P>0.05) than for AP infusion. Across infusion site, AP and AB infusions increased plasma concentration of EAA and BCAA, but compared with GB infusion, the mammary extraction rates tended ( P < 0.10) to be lower. It is concluded that abomasal nutrient infusion increases loss of MFN and that the gastrointestinal metabolism influences the nutrients available for milk synthesis. Our conclusion is that when glucose was infused, AA limited a further milk protein synthesis, but when AA was infused, glucose or energy substrate might have been the limiting factor. Our results verify that glucogenic substrates are limiting when cows are in negative energy balance. PMID- 22444408 TI - Post-ruminal or intravenous infusions of carbohydrates or amino acids to dairy cows 2. Late lactation. AB - The objectives of this study were to compare the effects of post-ruminal and intravenous infusions of wheat starch or glucose (CHO) or a mixture of amino acids (AA) on milk protein yield, nitrogen (N) utilisation, plasma metabolites and mammary extraction rate of dairy cows in late lactation. Eight cow, ruminally fistulated, was assigned to two 4 * 4 Latin squares during 14-day periods, where the last 7 days were for infusions. Infusions were: (1) starch in the abomasum (SP), (2) glucose in the blood (GB), (3) AA in the abomasum (AP), and (4) AA in the blood (AB). The experiment started 165 +/- 4 days (mean +/- s.e.) post partum (milk yield 22.5 +/- 1.1 kg) Daily amounts of nutrients infused were 257, 283, 233, and 260 g for SP, GB, AP and AB, respectively. The cows were fed a basal diet consisting of a concentrate mixture and grass silage (55:45 on a dry-matter (DM) basis), where total dry-matter intake (DMI) was 13.3 kg/day. Milk production was affected by site of infusion within substrate, whereas infusion substrates within infusion site (CHO or AA) were of minor importance. Responses to intravenous infusions (GB or AB) were similar to those in early lactation, but more pronounced. Compared with SP infusion, GB infusion increased ( P < 0.05) milk yield, energy-corrected milk (ECM), protein and lactose yield by 1.4 and 0.9 kg, 38 and 59 g, respectively. The AB infusion had 1.4 and 1.3 kg, 51, 52 and 50 g higher ( P < 0.05) milk yield, ECM, protein, fat and lactose yields than the AP infusion, respectively. N balance data indicated higher losses of metabolic faecal nitrogen (MFN) by abomasal than by intravenous infusions, but the catabolism of AA was lower than in early lactation indicated by no difference ( P < 0.05) in urinary N excretion between treatments. Intravenous AA infusion increased plasma glucose and insulin above that of intravenous glucose infusion. The treatment effects on plasma insulin concentrations were higher in late than in early lactation, suggesting a higher sensitivity in late lactation even at similar negative energy balance. Compared with the SP infusion, GB infusion showed lower ( P < 0.05) concentrations of essential AA (EAA) and branched-chain AA (BCAA) resulting in a higher AA utilisation because of a higher milk protein production. AP infusion increased ( P < 0.05) plasma non-essential AA concentration compared with AB infusion, but infusion site of AA had no effect ( P>0.05) on plasma EAA or BCAA. It is concluded that it is the nutrient supply and not the lactation stage per se that is important for the response in milk production. Nevertheless, stage of lactation affects the N metabolism and the response in plasma hormone concentrations even when cows are in negative energy balance in both lactation stages. PMID- 22444409 TI - Effect of a starter diet supplementation with mannan-oligosaccharide or inulin on health status, caecal metabolism, digestibility of nutrients and growth of early weaned rabbits. AB - The effect of a dietary supplementation with mannan-oligosaccharide (MOS, Bio Mos, Alltech Inc.) and inulin (Frutafit(r) IQ) on growth, health, and caecal traits was studied on 348 rabbits (Hyplus(r)), weaned at 25 days of age. Three hundred and thirty rabbits (110 per group) were used for the health status and growth performance trial, while 18 rabbits (six per group) were used for caecal metabolism evaluation at the age of 42 days of age. Three diets were formulated: C (control), M (0.3% MOS) and I diet (4% inulin). Digestibility of the diets was measured in 10 rabbits per group between 36 and 40 days of age. The control diet was fed to rabbits of the C group from weaning to 74 days of age (slaughter). Diets M and I were fed to rabbits of the respective group from weaning to 46 days of age, then were fed with control diet till slaughter. From 25 to 46 days of age, the weight gain was slightly higher in control rabbits ( P = 0.11), while no differences were recorded for the whole period. No differences among groups in the mortality, which was high due to an enteropathy-infected environment, were significant. The lowest morbidity ( P = 0.05) as well as the health risk index were recorded in rabbits fed the diet with inulin ( P = 0.03). After change of diet, the health risk index increased in the rabbits previously fed the diet with additives, thereby no significant differences in the health status were recorded for the whole period. Total caecal volatile fatty acids concentration was higher ( P < 0.01) and the pH ( P < 0.01) and ammonia concentration ( P = 0.01) lower in rabbits fed the inulin diet than in other rabbits. In these animals, acetate molar proportion was higher ( P = 0.01) and that of propionate as well as the propionate/butyrate ratio significantly lower than in other rabbits. Butyrate molar proportion was higher in rabbits fed the diet with MOS ( P < 0.01). In rabbits fed the inulin diet a higher activity of inulinase was recorded ( P < 0.001) than in other rabbits. A significantly lower digestibility of cellulose was observed in rabbits fed the diet with MOS. The results of our study suggest the importance of using inulin-type fructans in the nutrition of young rabbits. The higher health risk index of rabbits after change of diets indicates that prebiotics should be given for a longer time during the fattening period. PMID- 22444410 TI - Effects of dietary sulphur sources on concentrations of hydrogen sulphide in the rumen head-space gas of dairy cows. AB - Three change-over design experiments investigated the origin of hydrogen sulphide in the rumen head-space gas of dairy cows, comparing the effects of single iso-S additions of methionine, cysteine and sodium sulphate, as well as the effects of single meals of fresh ryegrass or white clover. The concentration of hydrogen sulphide in rumen gas declined close to zero within 4 h after withdrawal of the previous feed. Sulphur sources were then given to cows and concentrations of hydrogen sulphide recorded in rumen head-space gas at 30-min intervals. Cysteine addition (8 g) led to a rapid (within 30 min) and a large (490 and 957 p.p.m. respectively in two experiments) increase in hydrogen sulphide concentration. Concentrations were significantly less following methionine addition. Increasing levels of cysteine addition led to significant increases in hydrogen sulphide concentrations ( P < 0.001 for the linear effect), although peak hydrogen sulphide was delayed and concentrations remained higher for longer with the highest (12 g) addition of cysteine ( P < 0.01 for the 'cysteine level' * 'time' interaction). The increase in concentration of hydrogen sulphide from sodium sulphate was smaller (230 p.p.m.) and slower (2 h) than for cysteine. Despite the much higher intake of cystine for white clover in comparison with perennial ryegrass ( P < 0.001), there was almost no increase in hydrogen sulphide concentration in rumen head-space gas from cows fed white clover. It seems likely that this is associated with the use of sulphur to produce thiocyanate to detoxify the hydrogen cyanide from cyanogenic white clover. PMID- 22444411 TI - Effect of grazing pastures with different botanical composition by lambs on rumen fatty acid metabolism and fatty acid pattern of longissimus muscle and subcutaneous fat. AB - In order to study the effect of grazing pastures with a different botanical composition on rumen and intramuscular fatty acid metabolism, 21 male lambs were assigned to three botanically different pastures: botanically diverse (BD) (consisting for 65% of a variety of grass species); Leguminosa rich (L) (consisting for 61% of Leguminosae) and intensive English ryegrass (IR) (with 69% Lolium perenne). Pastures were sampled weekly for 12 weeks for analysis of their fatty acid content and composition and on nine occasions to determine the botanical composition. Ruminal and abomasal contents were sampled at slaughter and muscle and subcutaneous fat 24 h after slaughter. All samples were prepared and analysed for fatty acid composition. The L pasture showed a higher fatty acid content (29.8 mg/g dry matter (DM) v. 18.5 and 25.5 mg/g DM, for BD and IR pastures, respectively), but the sum of the proportions of the major polyunsaturated fatty acids, C18:2 n-6 and C18:3 n-3, were similar for the three pastures (69.9, 69.4 and 71.1% of fatty acids methyl esters (FAME) for BD, L and IR pastures, respectively). The BD pasture was richer in C18:2 n-6 (18.2% of FAME), while IR pasture had a higher C18:3 n-3 content (57.2% of FAME). Rumen data showed that animals grazing the BD pasture presented higher proportions of biohydrogenation intermediates, mainly C18:1 t11, C18:2 t11c15 and CLA c9t11, suggesting an inhibition of biohydrogenation. These changes were associated with shifts in the rumen microbial population as indicated by differences in the rumen pattern of volatile fatty acids, microbial odd- and branched-chain fatty acids. In L pasture animals, the content of C18:2 n-6 and C18:3 n-3 in the abomasum and subcutaneous fat was higher. Finally, higher proportions of C20:4 n-6, C20:5 n-3 and C22:5 n-3 and higher indices for elongation and desaturation activity in the intramuscular fat of BD grazing animals suggest some stimulation of elongation and desaturation of long-chain fatty acids, although this also might have been provoked partially by reduced fat deposition (due to a lower growth rate of the animals). PMID- 22444412 TI - Litter-size-dependent intrauterine growth restriction in sheep. AB - Regulation of foetal development in sheep depends on interactions between the intrinsic capacity of the foetus for growth and the maternal environment. Lambs born in multi-foetus litters have relatively small placentae with fewer cotelydons, and lower birth weights. Litter-size-dependent intrauterine growth restriction (IUGR) is evident at mid gestation when metabolic needs of the conceptus are moderate, and overnutrition of ewes with multiple foetuses does not promote growth of their foetuses to the size of singletons. Those observations suggest that placental and conceptus growth in multi-foetus pregnancies is reprogrammed at mid gestation by an as yet undefined mechanism to attenuate foetal growth. This may protect the foetus from severe nutritional insult during late gestation, when its daily growth rate is at a maximum. In that way, lambs born in large litters with relatively lower birth weights may not experience the long-term physiological insults that can be observed in small lambs born to undernourished ewes. PMID- 22444413 TI - The effect of breed and parity on curves of body condition during lactation estimated using a non-linear function. AB - The objectives of this study were to see if the body condition score curve during lactation could be described using a model amenable to biological interpretation, a non-linear function assuming exponential rates of change in body condition with time, and to quantify the effect of breed and parity on curves of body condition during lactation. Three breeds were represented: Danish Holstein (n = 112), Danish Red (n = 97) and Jerseys (n = 8). Cows entered the experiment at the start of first lactation and were studied during consecutive lactations (average number of lactations 2, minimum 1, maximum 3). They remained on the same dietary treatment throughout. Body condition was scored to the nearest half unit on the Danish scale (see Kristensen (1986); derived from the Lowman et al. (1976) system) from 1 to 5 on days: 2, 14, 28, 42, 56, 84, 112, 168, 224 after calving. Additionally, condition score was recorded on the day of drying off the cow, 35, 21, and 7 days before expected calving and finally on the day of calving. All condition scores were made by the trained personal on the research farm, where the same person made 92% of the scores. The temporal patterns in condition score were modelled as consisting of two underlying processes, one related to days from calving, referred to as lactation only, the other to days from (subsequent) conception, referred to as pregnancy. Both processes were assumed to be exponential functions of time. Each process was modelled separately using exponential functions, i.e. one model for lactation only and one for pregnancy, and then a combined model for both lactation only and pregnancy was fitted. The data set contained 467 lactation periods and 378 pregnancy periods. The temporal patterns in condition score of cows kept under stable and sufficient nutritional conditions were successfully described using a two component non-linear function. First lactation cows had shallower curves, they had greater condition scores at the nadir of the curve. Danish Holstein and Jersey were thinner at the end of the mobilisation period having lost more body condition than the Danish Red breed. Although the dairy breeds ended up being thinner there were no significant differences in the rate at which they lost body condition. PMID- 22444414 TI - Whole wheat versus mixed layer diet as supplementary feed to layers foraging a sequence of different forage crops. AB - In many cases health and welfare problems are observed in organic egg production systems, as are high environmental risks related to nutrient leaching. These disadvantages might be reduced if the layers are allowed to utilise their ability to forage to a higher degree thereby reducing the import of nutrients into the system and stimulating the hens to perform a natural behaviour. However, very little is known about the ability of modern high-producing layers to take advantage of foraging to cover their nutritional needs, and the aim of the present work was to clarify this subject. Six flocks, each of 26 hens and one cock, were moved regularly in a rotation between different forage crops for a period of 130 days. Half of the flocks were fed typical layer feed for organic layers and half were fed whole wheat. The forage crops consisted of grass/clover, pea/vetch/oats, lupin and quinoa. At the beginning of the experiment, wheat-fed hens had a lower intake of supplementary feed (wheat) and a lower laying rate, egg weight and body weight. However, after a period of 6 to 7 weeks, the intake of wheat increased to approximately 100 g per hen per day and the laying rate increased to the same level as for the hens fed layer feed. For both groups of hens egg weight and body weight increased during the remaining part of the experiment. Crop analysis revealed different food preferences for hens fed layer feed and wheat-fed hens. Wheat-fed hens ate less of the cultivated seeds, whereas the amounts of plant material, oyster shells, insoluble grit stone and soil were larger in the crops from wheat-fed hens. Floor eggs were significantly more frequent in the hens fed layer feed, whereas wheat-fed hens only rarely laid floor eggs. Irrespective of treatment, hens were found to have excellent health and welfare. We conclude that nutrient-restricted, high-producing organic layers are capable of finding and utilising considerable amounts of different feed items from a cultivated foraging area without negative effects on their health and welfare. PMID- 22444415 TI - Early lysine deficiency in young broiler chicks. AB - The carry-over effect of a pre-starter diet (0 to 3 days of age) deficient in lysine on subsequent growth and body composition (3 to 10 days) was examined in two experiments on male broiler chicks raised in cages. In experiment 1, lysine deficiency was applied from 3 to 10 days after providing a balanced pre-starter control feed (D+, 1.40% lysine) or a lysine deficient feed (D-) during the first 3 days. Three levels of deficiency (A = 0.63%, B = 0.72%, C = 0.82%) were tested. Growth and feed intake were higher in D+ than in D- chicks ( P < 0.001). However, the feed conversion ratio from 3 to 10 days of age was higher in D+ chicks ( P < 0.001); pre-starter and starter feeds interacted ( P < 0.04) with the feed conversion of treatment D+/A = 2.07 being better than treatment D+/A = 2.61 ( P < 0.05). This suggests that chicks deficient from hatching exhibit a relatively lower sensitivity to lysine deficiency than chicks started on a control diet. In experiment 2, performance, slaughter parameters and body composition were analysed at 3 and 10 days of age, in chicks having received a lysine deficient feed (D0, 0.72% lysine), a control feed (D+, 1.40% lysine) or having been pair fed with control feed adjusted to D0 intake (PF) from 0 to 3 days of age, and then fed D0 ad libitum from 3 to 10 days of age. At 3 days, PF chicks had a higher body weight ( P < 0.05) than D0, and thus a better feed conversion. Body composition in relative values was little or not affected by dietary treatments, but the breast muscle weight at 3 days was higher in D+ and PF chicks compared with D0 ( P < 0.05) and this effect was even accentuated at 10 days of age. The present work confirms that early nutrition can have subsequent consequences on the adjustment of fast growing broiler chicks to their nutritional conditions. It also suggests that breast muscle development is a more reactive parameter than whole body composition in this kind of experiments. PMID- 22444416 TI - Effect of the inclusion of food waste in pig diets on growth performance, carcass and meat quality. AB - Food waste from fish and fruit shops was used as an alternative to the grain in grower-finisher pig diets. Two diets were formulated on an iso-nutrient basis (14 MJ digestible energy per kg, 160 g crude protein per kg on a dry-matter basis) to contain 0 g of food waste per kg in the control diet and 50 g of fish-shop waste per kg and 120 g of fruit-shop waste per kg in the experimental diet. In the study, 28 pigs per diet (seven pigs per pen) were fed ad libitum from 20 kg to 100 kg, then, they were slaughtered and the carcass characteristics determined. The inclusion of food waste in the diet had no significant effect (P>0.05) on average daily feed intake (2.12 v. 2.20 kg/day), average daily gain (0.74 v. 0.78 kg/day), or gain/feed (0.35 v. 0.35 kg per kg). In the case of the experimental diet, backfat thickness was significantly lower (18.0 v. 21.3 mm, P < 0.01). The results of the taste test indicated that the meat from food waste-fed pigs had acceptable organoleptic quality although a very light aroma to fish was observed in the bacon (P < 0.01).It was concluded that food waste from the fish and fruit shops could be included in grower-finisher pig diets without any detrimental effect on growth performance and only minor effects on carcass characteristics and meat quality. PMID- 22444417 TI - Effect of rate of substitution of processed, urea-treated whole-crop wheat for grass silage on the intake, milk production and diet digestibility in dairy cows and ruminal metabolism in vitro. AB - The effect of rate of substitution of processed, urea-treated whole-crop wheat (pWCW) for grass silage on intake, performance and whole-tract digestibility was evaluated using 44 dairy cows. Cows received 10.5 kg of concentrates per day and one of the following forage mixtures (dry matter (DM) basis): grass silage alone (W-0); 0.75 grass silage, 0.25 pWCW (W-25); 0.5 grass silage, 0.5 pWCW (W-50) or 0.25 grass silage, 0.75 pWCW (W-75). Forage DM intake increased linearly with inclusion rate of pWCW from 9.7 kg DM per day in cows fed W-0 to 14.6 kg DM per day in W-75. By contrast, milk and protein yield (kg/day) were higher (P < 0.05) in cows receiving W-25 compared with W-0, but there was no effect (P>0.05) of treatment on fat yield (kg/day). From week 11 of the experiment onwards, body condition score increased with rate of inclusion of pWCW (P < 0.05). Whole-tract apparent digestibility of organic matter (OM) and fibre (kg/kg), decreased linearly with rate of inclusion of pWCW. Assuming a constant digestibility of starch in the other diet components, the apparent digestibility of starch in pWCW was 0.95 kg/kg and was not affected by rate of inclusion (P>0.05). Four continuous culture vessels were used to determine the effect of rate of inclusion of pWCW on ruminal metabolism in four periods, each of 14 d duration with sampling conducted on days 9 to 14. Vessel ammonia concentration increased linearly (P < 0.05) with rate of inclusion of pWCW whilst mean pH tended (P = 0.06) to decrease. The ratio of acetate to propionate increased from 2.5 in vessels receiving W-0 to 3.2 in those receiving W-75 (P < 0.001). There was no effect (P>0.05) of treatment on digestibility (g/g) of OM, fibre or starch or microbial protein flow (g/day). It is concluded that forage DM intake increased linearly with rate of inclusion of pWCW, but there was no further improvement in milk yield from inclusion rates above 0.25 of the forage DM, with body condition score increasing instead. Increasing the inclusion rate of pWCW resulted in a more ketogenic volatile fatty acid profile but did not affect the efficiency of microbial protein synthesis when determined in vitro. PMID- 22444418 TI - Effects of replacing grass silage with either maize or whole-crop wheat silages on the performance and meat quality of beef cattle offered two levels of concentrates. AB - A randomised design involving 66 continental cross beef steers (initial live weight 523 kg) was undertaken to evaluate the effects of the inclusion of maize or whole-crop wheat silages in grass silage-based diets on animal performance, carcass composition, and meat quality of beef cattle. Grass silage was offered either as the sole forage or in addition to either maize or whole-crop wheat silages at a ratio of 40:60, on a dry matter (DM) basis, alternative forage: grass silage. For the grass, maize, and whole-crop wheat silages, DM concentrations were 192, 276, and 319 g/kg, ammonia-nitrogen concentrations were 110, 90, and 150 g/kg nitrogen, starch concentrations were not determined, 225, and 209 g/kg DM and in vivo DM digestibilities were 0.69, 0.69, and 0.58; respectively. The forages were offered ad libitum following mixing in a paddle type complete diet mixer wagon once per day, supplemented with either 3 or 5 kg concentrates per steer per day, in two equal feeds, for 92 days. For the grass, grass plus maize and grass plus whole-crop wheat silage-based diets food intakes were 8.38, 9.08, and 9.14 kg DM per day, estimated carcass gains were 514, 602, and 496 g/day and carcass weights were 326, 334, and 325 kg; respectively. Altering the silage component of the diet did not influence carcass composition or meat eating quality. Increasing concentrate feed level tended ( P = 0.09) to increase estimated carcass fat concentration and increased sarcomere length ( P < 0.05), and lean a* ( P < 0.01), b* ( P < 0.05), and chroma ( P < 0.01). There were no significant silage type by concentrate feed level interactions for food intake, steer performance, carcass characteristics or meat eating quality. It is concluded that replacing grass silage with maize silage increased carcass gain, and weight due to higher intakes, and improved utilisation of metabolisable energy. Whilst replacing grass silage with whole-crop wheat silage increased live weight gain, the reduced dressing proportion resulted in no beneficial effect on carcass gain, probably due to increased food intakes of lower digestible forage increasing gut fill. Meat quality or carcass composition were not altered by the inclusion of maize or whole-crop silages in grass silage based diets. PMID- 22444419 TI - Effect of supplementation of ewes with barley or maize during the last week of pregnancy on colostrum production. AB - The experiment tested the hypothesis that short-term feeding of barley just before lambing would be as effective as maize in stimulating early production of colostrum. Both grains are high in starch, and should provide a substrate for lactose which, in turn, promotes lactogenesis. Thirty-five Corriedale ewes bearing single foetuses and 25 bearing twin-foetuses from a synchronised mating were fed on pasture during most of gestation. Fourteen days before the expected time of lambing the single- and twin-bearing ewes were allocated to three treatments and fed (1) a basal diet of lucerne hay to meet their nutrient requirements, (2) the basal diet plus a supplement of whole barley; or (3) the basal diet plus a supplement of cracked maize. The twin-bearing control ewes accumulated more colostrum than the single-bearing control ewes at birth (292 v. 190 g). However, supplementation with barley or maize increased the colostrum at birth to 360 and 541 g in singles and 648 and 623 g in twins. We conclude that barley is a good alternative to maize to stimulate production of colostrum especially in twin-bearing ewes whose lambs are the most likely to benefit from the supplement. PMID- 22444420 TI - Childhood sexual abuse characteristics, intimate partner violence exposure, and psychological distress among women in methadone treatment. AB - Traumatic experiences and their biopsychosocial sequelae present complex challenges in substance use treatment. For women with substance use problems, childhood sexual abuse (CSA), intimate partner violence exposure (IPV), posttraumatic stress disorder (PTSD), and overall psychological distress are often co-occurring concerns. To address gaps in knowledge and to strengthen practice regarding these critical issues in substance use treatment, we drew upon cross-sectional and longitudinal data from baseline and 12-month interviews with a random sample of 416 women in methadone treatment to examine relationships between CSA characteristics, particularly the presence of force and involvement of family, IPV, and mental health concerns. Although CSA involving force and family was not associated with IPV as hypothesized, it was associated with increased risk of PTSD and overall psychological distress. The multivariate findings underscore the psychological vulnerabilities associated with CSA involving force and family and suggest that drug use and financial circumstances may be important targets to reduce IPV risk. PMID- 22444421 TI - Sexual orientation and substance abuse treatment utilization in the United States: results from a national survey. AB - This study examined substance abuse treatment utilization across three dimensions of sexual orientation (identity, attraction, and behavior) in a large national sample of adults in the United States. Prevalence estimates were based on data collected from the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions. The sample consisted of 34,653 adults 20 years and older, and represented a population that was 52% women, 71% White, 12% Hispanic, 11% African American, 4% Asian, and 2% other race/ethnicities. An estimated 2% of the target population self-identified as lesbian, gay or bisexual; 4% reported same-sex sexual behavior, and 6% reported same-sex sexual attraction. Sexual minorities, especially women, had a greater likelihood of lifetime substance use disorders and earlier age of drinking onset. The majority of respondents with substance use disorders were untreated and lifetime substance abuse treatment utilization differed based on sexual orientation. Sexual minorities were found to have more extensive family histories of substance abuse problems. The findings indicate the underutilization of substance abuse treatment among all adults, and highlight some important factors to consider when working with sexual minorities. PMID- 22444422 TI - Expression and function of interleukin-7 in secondary and tertiary lymphoid organs. AB - Interleukin-7 (IL-7) is known since many years as stromal-cell derived cytokine that plays a key role for the adaptive immune system. It promotes lymphocyte development in the bone marrow and thymus as well as naive and memory T cell homeostasis in the periphery. More recently, IL-7 reporter mice and other approaches have led to the further characterization of the various stromal cell sources of IL-7 in secondary lymphoid organs (SLO) and other tissues. We will review these advances along with a discussion of the regulation of IL-7 and its receptor, and compare the biological effects IL-7 has on adaptive as well as innate immune cells in SLO. Finally, we will review the role of IL-7 in development of SLO and tertiary lymphoid tissues that frequently are associated with sites of chronic inflammation. PMID- 22444423 TI - Community-based strategies for blood pressure control in low-income countries. PMID- 22444424 TI - Body mass index correlates with ischemic heart disease and albuminuria in long standing type 2 diabetes. AB - AIMS: Comprehensive data describing the effect of obesity on type 2 diabetes outcomes is lacking. We sought to address this by analyzing a tertiary hospital clinical database. METHODS: We extracted clinical and biochemical data for patients who attended a tertiary hospital diabetes clinic between 1998 and 2011 and were aged less than 65 years. Body mass index (BMI) was correlated with the prevalence of vascular complications and with cardiovascular risk factors. RESULTS: The means of age and duration of diabetes for the 711 patients (392 men and 319 women) were 53 and 11 years respectively. BMI correlated with the prevalence of ischemic heart disease and, to a lesser degree, albuminuria, but not with the prevalence of cerebrovascular disease, neuropathy, retinopathy or renal function. BMI did not correlate with glycosylated hemoglobin, although obese patients used insulin both more frequently and at higher doses. CONCLUSIONS: In people with long-standing type 2 diabetes who attend a tertiary hospital outpatient clinic, ischemic heart disease, in contrast to other vascular complications, correlates robustly with BMI. These findings indicate that clinical trials of weight loss in type 2 diabetes should use cardiac endpoints as their primary outcomes. PMID- 22444425 TI - Effects of variation in retinol binding protein 4 gene and adipose specific expression of gestational diabetes in Beijing, China. AB - OBJECTIVE: To investigate the clinical features of GDM in China and the effects of RBP4 genetic variants, and also to identify RBP4 expression changes in mRNA and protein levels. RESEARCH DESIGN AND METHODS: 1595 Chinese pregnant women were included in this study. Four known RBP4 single nucleotide polymorphisms (SNPs) were genotyped in 505 cases and 687 controls. Expression levels of adipose specific RBP4 mRNA and protein were detected in 41 samples of subcutaneous adipose tissue. RESULTS: The estimated indices of insulin resistance were gradually increased from NGT, GIGT to GDM. Two single SNPs were associated with GDM (rs3758539 G vs A, OR=1.446, P=0.009; rs3758539 GG vs AG+AA, OR=1.532, P=0.006; rs12265684C vs G, OR=1.296, P=0.038) and a haplotype of 3 common SNPs [G G-T] was increased in subjects with GDM and GIGT (OR=1.322, 95% CI 1.054-1.659, P=0.016). RBP4 mRNA expression in adipose tissue of GDM patients was significantly increased in comparison to control subjects (1.438 +/- 0.187 vs 1.034 +/- 0.062, p=0.025). CONCLUSION: This finding suggests that impaired insulin sensitivity has an early onset in mild gestational intolerance. Two single SNPs were associated with GDM in the case-control study while a haplotype of 3 common SNPs [G-G-T] was increased in glucose intolerance subjects. PMID- 22444426 TI - Kinetic optimisation of the reversed phase liquid chromatographic separation of proanthocyanidins on sub-2 MUm and superficially porous phases. AB - Phenolic compounds, and proanthocyanidins in particular, are important natural molecules which are of significant importance due to their sensory and biological activities. The analysis of proanthocyanidins in natural products is very challenging due to their complex nature. In this study, the kinetic performance of a range of recently developed C18 columns, including sub-2 MUm fully porous and 2.6 MUm superficially porous particle-packed columns, was evaluated for improved proanthocyanidin analysis. The kinetic plot method was employed to compare the ultimate performance limits of each column in terms of efficiency and speed for different maximum pressures and temperatures using representative proanthocyanidins comprising a range of molecular weights and functionalities as test analytes. By combining plate height data with relevant parameters such as column permeability and mobile phase viscosity, plots of practically attainable efficiencies as a function of analysis time for specific experimental configurations were obtained and performance limits for all investigated supports could accurately be compared. Both fully- and superficially porous particles provided significant speed and/or efficiency gains compared to conventional 5 MUm particle packed columns. Analyte properties, particle size and packing quality as well as analysis temperature were all found to have a significant influence on the performance of the presently investigated chromatographic supports. For smaller compounds, higher optimal linear velocities and better performance in the low-efficiency range were observed, while the lower diffusion coefficients of larger procyanidins resulted in lower optimal linear velocities and better performance in the high-efficiency regime. Faster analyses become possible at higher temperatures due to decreased eluent viscosity and faster mass transfer, which was especially beneficial for larger compounds and resulted in dramatic improvement in efficiency. A possible explanation of the abnormal behaviour of oligomeric procyanidins is presented. Our findings indicate that new column formats, when used under optimal conditions, significantly improve the speed and/or efficiency of reversed phase liquid chromatographic analyses of proanthocyanidins. PMID- 22444427 TI - Comparison of the fast gradient performance of new prototype silica monolithic columns and columns packed with fully porous and core-shell particles. AB - The gradient elution performance of narrow-bore 2.3 mm * 50 mm (N733) and wider bore 3.2 mm * 50 mm (N648 and N655) prototype silica monolithic columns was investigated and compared to the performance of commercially available columns packed with sub-2 MUm fully porous particles (2.1 mm * 50 mm, 1.7 MUm BEH-C(18), Waters) and sub-3 MUm superficially porous particles (2.1 mm * 50 mm, 2.7 MUm Halo-ES-Peptide-C(18) (AMT), 1.7 and 2.6 MUm Kinetex-C(18), Phenomenex). Results show that the two wide monolithic columns show peak capacities similar to the one measured for the Kinetex column. In contrast, the narrow-bore monolithic column delivers a lower performance (-30%) than the BEH, the Halo and the Kinetex columns. This work stresses out the importance of reducing the extra-column band broadening contribution of HPLC instruments when short 2.1mm I.D. columns are used. The part of the instrument contribution originating downstream the column is important for all compounds; the one originating upstream the column is significant only for weakly retained compounds. PMID- 22444428 TI - Comparison of indirect and direct quantification of esters of monochloropropanediol in vegetable oil. AB - The presence of fatty acid esters of monochloropropanediol (MEs) in food is a recent concern raised due to the carcinogenicity of their hydrolysable moieties 2 and 3-monochloropropanediol (2- and 3-MCPD). Several indirect methods for the quantification of MEs have been developed and are commonly in use until today, however significant discrepancies among analytical results obtained are challenging their reliability. The aim of the present study was therefore to test the trueness of an indirect method by comparing it to a newly developed direct method using palm oil and palm olein as examples. The indirect method was based on ester cleavage under acidic conditions, derivatization of the liberated 2- and 3-MCPD with heptafluorobutyryl imidazole and GC-MS determination. The direct method was comprised of two extraction procedures targeting 2-and 3-MCPD mono esters (co-extracting as well glycidyl esters) by the use of double solid phase extraction (SPE), and 2- and 3-MCPD di-esters by the use of silica gel column, respectively. Detection was carried out by liquid chromatography coupled to time of flight mass spectrometry (LC-ToF-MS). Accurate quantification of the intact compounds was assured by means of matrix matched standard addition on extracts. Analysis of 22 palm oil and 7 palm olein samples (2- plus 3-MCPD contamination ranged from 0.3 to 8.8 MUg/g) by both methods revealed no significant bias. Both methods were therefore considered as comparable in terms of results; however the indirect method was shown to require less analytical standards, being less tedious and furthermore applicable to all type of different vegetable oils and hence recommended for routine application. PMID- 22444429 TI - Purification of a PEGylated single chain Fv. AB - In this manuscript we describe the two-step purification of a mono-PEGylated anti epidermal growth factor receptor (EGFR) single-chain Fv. A weak cation exchanger was used for capture. Elution using arginine suppressed protein aggregation and allowed a very good resolution with purity and product-recovery was above 90%. Free PEG was removed completely. The use of hydrophobic interaction chromatography (HIC) increased purity to 98%. Increasing the size of PEG from 5 to 30 kDa increased retention on HIC and reduced it on cation exchangers. Bioactivity of PEGylated scFv was confirmed by (125)I based cell tests. Proteins modified with 5 kDa PEG showed higher bioactivity than proteins modified with larger PEGs. The combination of cation exchange and HIC provides a rational and effective basis for PEGylated scFv purification. PMID- 22444430 TI - Rapid determination of hydrogen peroxide in pulp bleaching effluents by headspace gas chromatography. AB - A headspace gas chromatographic (HS-GC) method has been developed for the determination of residual hydrogen peroxide in pulp bleaching effluents. The method is based on the reaction of hydrogen peroxide and permanganate in an acidic medium (0.1 mol/L), in which hydrogen peroxide is quantitatively converted to oxygen within 10 min at 60 degrees C in a sealed headspace sample vial. The released oxygen is then determined by GC equipped with a thermal conductivity detector. The method is robust, sensitive, and accurate, with reproducibility characterized by a relative standard deviation of <0.5%, a sensitivity whose limit of quantification (LOQ) is 0.96 MUmol, and a demonstrated recovery ranging from 98 to 103%. Further, the method is simple, rapid, and automated. PMID- 22444431 TI - Evaluation of a generic multi-analyte method for detection of >100 representative compounds correlated to emergency events in 19 food types by ultrahigh-pressure liquid chromatography-tandem mass spectrometry. AB - A generic extraction procedure combined with triple quadrupole mass spectrometric detection was evaluated for multi-residue analysis in 19 different foods. Measurable peaks could be obtained at relevant concentrations for 108 out of a total of 127 targeted compounds representing a wide range of physicochemical properties and compound classes related to emergency situations. Recoveries were determined for all 19 foods spiked with the 108 compounds. Seventy-five percent of the compounds had extraction recoveries of 70% or higher, with no compound below 46%. Suppression or enhancement effects on the MS response of the compounds dissolved in the extracts were low, as more than 80% of them had matrix effects between -35% and +20% and no compound was below -44% compared to matrix-free standard. In a validation, all compounds could be quantified at 200 MUg/kg and 400 MUg/kg food sample and 81% of the compounds at 40 MUg/kg. It is concluded that the method is useful for the detection of various types of organic chemical toxicants at levels generally well below concentration thresholds for severe acute intoxication. PMID- 22444432 TI - Zeolite Linde Type L as micro-solid phase extraction sorbent for the high performance liquid chromatography determination of ochratoxin A in coffee and cereal. AB - Zeolite Linde Type L (LTL) crystals with different length, diameter and particle size (nanosized LTL, rod LTL, cylinder LTL and needle LTL) were synthesized, characterized and were used as sorbent in the micro-solid phase extraction of ochratoxin A (OTA) before the high performance liquid chromatography detection. Under the optimized conditions, the detection limits of OTA for coffee and cereal were 0.09 ng g(-1) and 0.03 ng g(-1), respectively, while the quantification limits were 0.28 ng g(-1) and 0.08 ng g(-1), respectively. The recoveries of OTA of coffee and cereal spiked at 0.5, 10 and 25 ng g(-1) ranged from 91.7 to 101.0%. The proposed method was applied to forty-five samples of coffee and cereal. The presence of OTA was found in twenty-five samples, ranging from 0.28 to 9.33 ng g(-1). PMID- 22444433 TI - Death of a 6-year-old boy with mental retardation: accident versus child abuse. AB - This case study involved death of a 6-year-old child with a history of mental retardation secondary to meningitis at 11 months, spastic quadriplegia, seizure disorder, and hydrocephaly with a remote ventriculoperitoneal shunt placement and gastric tube feedings. Reportedly, the child was co-sleeping with his mother when she awoke and discovered him lying prone and not breathing on the carpeted floor next to the bed. He was transported to the hospital and died in the emergency room of unknown causes. The medical examiner assumed jurisdiction of the body. The external examination revealed petechial hemorrhages on the neck and face, with patterned linear pressure abrasions on the chest, arms, and face. X-rays revealed leg fractures of different ages. This case emphasizes the importance of coordination of death scene investigation, medical history review, and autopsy results through a forensic team approach to determine the accurate cause and manner of death. PMID- 22444434 TI - StRas2 regulates morphogenesis, conidiation and appressorium development in Setosphaeria turcica. AB - The proteins of Ras family are a large group of monomeric GTPases and act as molecular switches transducing extracellular signals into the cell in higher eukaryotes. However, little is known about roles of Ras family in the foliar pathogens. In this research, we cloned the gene named StRas2 encoding Ras in Setosphaeria turcica and investigated its function by RNA interference technology. We found that the growth rate of RNAi transformants named as R1, R2, R3, R4, R5 and R6, in which the StRas2 silencing efficiency fell in turn. With the highest silencing efficiency, the transformant R1 showed anomalistic hyphae morphology, indicating its growth was significantly affected. The transformants with a middle-silencing efficiency, such as R3, R4, displayed a delay when forming appressoria and invasive hyphae. R1 could not form conidia and appressoria. However, the conidial formation in R5 and R6 was significantly reduced, and these two transformants could form appressoria and penetrate the artificial cellophane, only that its invasive hyphae were fascicular and rarely branched. The HT-toxin biological activity of all transformants showed no difference. All results suggested that StRas2 is involved in the morphogenesis, conidiation, and appressorium development and is not related to the biosynthesis of HT-toxin. PMID- 22444435 TI - Response surface methodology to design a selective co-enrichment broth of Escherichia coli, Salmonella spp. and Staphylococcus aureus for simultaneous detection by multiplex PCR. AB - Escherichia coli, Salmonella spp. and Staphylococcus aureus are frequent co visitors of contaminated foods to cause food-borne diseases. To achieve rapid detection of three organisms by multiplex PCR, a selective co-enrichment broth was considered to design using response surface methodology (RSM) in this work. NaCl, LiCl and KSCN as selective bacterial inhibitors were selected to optimize their concentrations for a matched composition of bacterial biomass with uniform amplification of three targets. Central composite design was employed to collect the data and fit the responses. Three quadratic polynomial models were derived by computer simulation. A statistical analysis was carried out to explore the effects of the variables on the composition of bacterial biomass and PCR amplification yields. In the end, a novel broth (ESS-3 broth) of NaCl 1.60%, LiCl 0.70%, KSCN 0.10% was formulated to allow co-enrichment of the target pathogens and suppress growth of some non-target pathogens. The simultaneous detection of E. coli, Salmonella spp. and S. aureus was developed on a rapid, convenient and sensitive method consisting of selective co-enrichment in ESS-3 broth, DNA extraction with the boiling method and robust test by multiplex PCR. Our work provided broader application of RSM for the simultaneous detection of other combinations of multiple pathogens. PMID- 22444436 TI - In vitro antibacterial potential of Eugenia jambolana seed extracts against multidrug-resistant human bacterial pathogens. AB - The present study was carried out to evaluate the possible in vitro antibacterial potential of extracts of Eugenia jambolana seeds against multidrug-resistant human bacterial pathogens. Agar well diffusion and microbroth dilution assay methods were used for antibacterial susceptibility testing. Kill-kinetics study was done to know the rate and extent of bacterial killing. Phytochemical analysis and TLC-bioautography were performed by colour tests to characterize the putative compounds responsible for this antibacterial activity. Cytotoxic potential was evaluated on human erythrocytes by haemolytic assay method and acute oral toxicity study was done in mice. The plant extracts demonstrated varying degrees of strain specific antibacterial activity against all the test isolates. Further, ethyl acetate fraction obtained from fractionation of most active ethanol extract showed maximum antibacterial effect against all the test isolates. Phytochemical analysis and TLC-bioautography of ethyl acetate fraction revealed that phenolics were the major active phytoconstituents. Ethyl acetate fraction also demonstrated no haemolytic activity on human erythrocytes and no gross behavioural changes as well as toxic symptoms were observed in mice at recommended dosage level. The results provide justification for the use of E. jambolana in folk medicine to treat various infectious diseases and may contribute to the development of novel antimicrobial agents for the treatment of infections caused by these drug resistant bacterial pathogens. PMID- 22444437 TI - The chemistry of the sulfur-gold interface: in search of a unified model. AB - Over the last three decades, self-assembled molecular films on solid surfaces have attracted widespread interest as an intellectual and technological challenge to chemists, physicists, materials scientists, and biologists. A variety of technological applications of nanotechnology rely on the possibility of controlling topological, chemical, and functional features at the molecular level. Self-assembled monolayers (SAMs) composed of chemisorbed species represent fundamental building blocks for creating complex structures by a bottom-up approach. These materials take advantage of the flexibility of organic and supramolecular chemistry to generate synthetic surfaces with well-defined chemical and physical properties. These films already serve as structural or functional parts of sensors, biosensors, drug-delivery systems, molecular electronic devices, protecting capping for nanostructures, and coatings for corrosion protection and tribological applications. Thiol SAMs on gold are the most popular molecular films because the resulting oxide-free, clean, flat surfaces can be easily modified both in the gas phase and in liquid media under ambient conditions. In particular, researchers have extensively studied SAMs on Au(111) because they serve as model systems to understand the basic aspects of the self-assembly of organic molecules on well-defined metal surfaces. Also, great interest has arisen in the surface structure of thiol-capped gold nanoparticles (AuNPs) because of simple synthesis methods that produce highly monodisperse particles with controllable size and a high surface/volume ratio. These features make AuNPs very attractive for technological applications in fields ranging from medicine to heterogeneous catalysis. In many applications, the structure and chemistry of the sulfur-gold interface become crucial since they control the system properties. Therefore, many researchers have focused on understanding of the nature of this interface on both planar and nanoparticle thiol-covered surfaces. However, despite the considerable theoretical and experimental efforts made using various sophisticated techniques, the structure and chemical composition of the sulfur-gold interface at the atomic level remains elusive. In particular, the search for a unified model of the chemistry of the S Au interface illustrates the difficulty of determining the surface chemistry at the nanoscale. This Account provides a state-of-the-art analysis of this problem and raises some questions that deserve further investigation. PMID- 22444438 TI - Development of a fully automated on-line solid phase extraction and high performance liquid chromatography with diode array detection method for the pharmacokinetic evaluation of bavachinin: a study on absolute bioavailability and dose proportionality. AB - A fully automated on-line solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) with diode array detection (DAD) method was developed for determination of bavachinin in mouse plasma. Analytical process was performed on two reversed-phase columns (SPE cartridge and analytical column) connected via a Valco 6-port switching valve. Plasma samples (10 MUL) were injected directly onto a C18 SPE cartridge (MF Ph-1 C18, 10 mm * 4 mm, 5 MUm) and the biological matrix was washed out for 2 min with the loading solvent (5 mM NaH(2)PO(4) buffer, pH 3.5) at a flow rate of 1 mL/min. By rotation of the switching valve, bavachinin was eluted from the SPE cartridge in the back-flush mode and transferred to the analytical column (Venusil MP C18, 4.6 mm * 150 mm, 5 MUm) by the chromatographic mobile phase consisted of acetonitrile-5mM NaH(2)PO(4) buffer 65/35 (v/v, pH 3.5) at a flow rate of 1 mL/min. The complete cycle of the on-line SPE purification and chromatographic separation of the analyte was 13 min with UV detection performed at 236 nm. Calibration curve with good linearity (r=0.9997) was obtained in the range of 20-4000 ng/mL in mouse plasma. The intra-day and inter-day precisions (RSD) of bavachinin were in the range of 0.20-2.32% and the accuracies were between 98.47% and 102.95%. The lower limit of quantification (LLOQ) of the assay was 20 ng/mL. In conclusion, the established automated on-line SPE-HPLC-DAD method demonstrated good performance in terms of linearity, specificity, detection and quantification limits, precision and accuracy, and was successfully utilized to quantify bavachinin in mouse plasma to support the pharmacokinetic (PK) studies. The PK properties of bavachinin were characterized as rapid oral absorption, high clearance, and poor absolute bioavailability. PMID- 22444439 TI - Molecular characterization, polymorphism and association study of lysozyme gene with milk production and somatic cell trait in Bos indicus * Bos taurus cattle. AB - Lysozyme, an anti-bacterial enzyme, is mostly found in the body fluids, various tissues and secretions of animals and humans, and confers immunity against a wide range of bacterial species. The present study was carried out to elucidate the gene sequence of this enzyme in Indian Sahiwal * Holstein Friesian crossbred cattle and to explore the polymorphism of the gene as well as their association with milk production and somatic cell traits. The total length of lysozyme cDNA was found to be of 447 bp. The similarity with Bos taurus, human, pig, monkey, gorilla, mice, rat, chicken, dog and sheep was estimated as 99.1%, 85%, 81.0%, 85.2%, 84.3%, 77.9%, 77.9%, 41.4%, 40.5% and 24.6%, respectively. Polymorphism study of two fragments, extended exon1 including promoter, exon1 and partial intron1 (268 bp), and extended exon2 including partial intron1 and 2, and exon2 region (287 bp) of milk lysozyme gene was carried out by employing single stranded conformation polymorphism (SSCP). In the extended exon1 fragment, three alleles namely A, B and C with frequencies of 0.59, 0.28 and 0.12 were observed while in the exon extended fragment, three different alleles - P, Q and R with respective frequencies of 0.61, 0.38 and 0.01 - were determined in Indian Sahiwal * Holstein Friesian cross. A total of eight haplotypes were found in this population where the most predominant one was h1 (0.52). Genotypes of exon1 extended fragment showed significant association with total milk yield, daily milk yield, peak yield and somatic cell score at P < 0.05 while that of exon2 extended fragment had significant correlation with only total lactational milk yield. Haplotype combinations also revealed significant association with total milk production where h1h1 homozygous showed highest yield during first lactation. PMID- 22444440 TI - A genome scan for loci affecting adipocyte size and number in abdominal fat in a White Duroc * Erhualian F2 resource population. AB - Adipocyte size and number are correlated with fat deposition, which is of major concern to human health and pork producers. To identify quantitative trait loci (QTL) for adipocyte size and number in pigs, a total of 341 F2 animals at 240 days in a White Duroc * Erhualian cross were measured for the area, perimeters, volume and number of adipocyte in abdominal fat. A genome scan was performed on these animals and their parents and grandparents with 183 microsatellite markers spanning the pig genome. Five chromosomal regions showed effects on the traits measured, predominantly on adipocyte size, on pig chromosome (SSC) 1, 4, 7 and 9. Neither of these QTL has been reported before this study. The QTL for adipocyte size detected in this study perfectly correspond to the previously reported QTL for fatness traits on SSC1, 4 and 7. The most significant association was evidenced at 58 cM on SSC7. At the locus, the favorable allele decreasing adipocyte size was unusually originated from the obese Erhualian breed. Only a suggestive QTL was detected for adipocyte number on SSC9. The results shed new lights on the understanding of the genetic basis of fatness traits in pigs. PMID- 22444441 TI - Differences in productive robustness in rabbits selected for reproductive longevity or litter size. AB - The aim of this work was to evaluate the ability of a line selected for reproductive longevity (LP) to confront productive challenges compared to a line selected during 31 generations for litter size at weaning (V). A total of 133 reproductive rabbit does were used (72 and 61 from LP and V lines, respectively). Within each line, three groups with different levels of productive effort were planned: PP9, inseminated at day 4 after the first partum and with nine kits during the second partum, and inseminated after first weaning (30 days) and with nine (PW9) or five kits (PW5) during the second partum. The reproductive performance, body condition (perirrenal fat thickness (PFT)) and lipolytic response were controlled. LP does showed greater mean live weight (LW; +128 g; P < 0.05), PFT (+0.47 mm; P < 0.05) and estimated body energy (EBE; +0.29 MJ/kg; P < 0.01) than V does at second partum. However, LP does that mated at first post partum did not significantly differ in EBE relative to V does at second partum. During the first week of lactation, dry matter (DM) intake was similar for both lines (94 and 95 g DM/kg LW0.75 day for V and LP does, respectively). There was a significant difference in milk yield between both lines during the first week when litter size was nine (60 v. 54 g of milk/kg LW0.75 day for LP and V does, respectively; P < 0.01), but no difference when litter size was five. Consequently, when litter size was nine, LP does showed a lower recovery of PFT (0.6 mm less; P < 0.05) than V does during the first 10 days of lactation. However, when litter size was five, LP does showed a higher LW (+210 g; P < 0.05) than V does at 10 days of lactation and a similar recovery of PFT. During the last 3 weeks of the lactation, LP does showed a higher feed intake (+6 g DM/kg LW0.75 day; P < 0.05) and milk yield (+27 g/day; P < 0.001) than V does when litter size was nine, resulting in no significant differences in LW at 30 days of lactation. However, when litter size was five, both lines showed similar feed intake and milk yield, maintaining their differences in LW at 30 days of lactation (+206 g for LP does; P < 0.05). These results show that the rabbit line selected for reproductive longevity is more robust with respect to coping with productive challenges, than a line selected for reproductive intensity. PMID- 22444442 TI - Genetic parameters for pathogen-specific mastitis resistance in Danish Holstein Cattle. AB - The objective of this study was to estimate heritabilities for and genetic correlations among different pathogen-specific mastitis traits. The traits were unspecific mastitis, which is all mastitis treatments regardless of the causative pathogen as well as mastitis caused by Streptococcus dysgalactiae, Escherichia coli, coagulase-negative staphylococci (CNS), Staphylococcus aureus and Streptococcus uberis. Also groups of pathogens were investigated, Gram-negative v. Gram-positive and contagious v. environmental pathogens. Data from 168 158 Danish Holstein cows calving first time between 1998 and 2006 were used in the analyses. Variances and covariances were estimated using uni- and bivariate threshold models via Gibbs sampling. Posterior means of heritabilities of pathogen-specific mastitis were lower than the heritability of unspecific mastitis, ranging from 0.035 to 0.076 for S. aureus and S. uberis, respectively. The heritabilities of groups of pathogen ranged from 0.053 to 0.087. Genetic correlations among the pathogen-specific mastitis traits ranged from 0.45 to 0.77. These estimates tended to be lowest for bacteria eliciting very different immune responses, which can be considered as the overall pleiotropic effect of genes affecting resistance to a specific pathogen, and highest for bacteria sharing characteristics regarding immune response. The genetic correlations between the groups of pathogens were high, 0.73 and 0.83. Results showed that the pathogen-specific traits used in this study should be considered as different traits. Genetic evaluation for pathogen-specific mastitis resistance may be beneficial despite lower heritabilities than unspecific mastitis because a pathogen-specific mastitis trait is a direct measure of an udder infection, and because the cost of a mastitis case caused by different pathogens has been shown to differ greatly. Sampling bias may be present because there were not pathogen information on all mastitis treatments and because some farms do not record pathogen information. Therefore, improved recording of pathogen information and mastitis treatments in general is critical for a successful genetic evaluation of udder health. Also, economic values have to be specified for each pathogen specific trait separately. PMID- 22444443 TI - Effect of plane of nutrition of 1- and 2-year-old ewes in early and mid-pregnancy on ewe reproduction and offspring performance up to weaning. AB - The objective of the present study was to determine the effect of plane of nutrition in early pregnancy (EP) and mid-pregnancy (MP), on the productive performance of 1- and 2-year-old ewes and their offspring. Over 2 successive years, between days 0 and 39 after synchronized mating (EP), 1- (n = 117) and 2- (n = 52) year-old ewes were allowed 60% (low, L-EP), 100% (medium, M-EP) or 200% (high, H-EP) of requirements for maintenance (M). Between days 40 and 90 (MP), 1 year-old ewes were allowed 140% (M-MP) or 200% (H-MP), while 2-year-old ewes were allowed 80% (M-MP) or 140% (H-MP) of their M requirement. After day 90, all ewes were fed to meet requirements for late pregnancy. Increasing the plane of nutrition between days 0 and 39 resulted in increases in live weight (LW) (P < 0.001) and body condition score (BCS) (P < 0.001) during the EP period (H-EP > M EP > L-EP), differences that in 1-year-old ewes were sustained to lambing (P < 0.05). On day 42 of gestation H-EP ewes had lower plasma progesterone concentrations than L-EP or M-EP ewes in 1- (P < 0.01) and 2- (P < 0.001) year olds. This was concomitant with diet H-EP tending to reduce the number of lambs born per ewe in both age groups (P = 0.06 and 0.07, respectively). Foetuses from 1-year-old L-EP ewes had smaller cranial (P < 0.01) and abdominal (P < 0.05) diameters at day 53 of gestation, with H-EP lambs tending to be heaviest at birth (P = 0.07). Similar findings were recorded for 2-year-old ewes. One-year-old ewes offered diet L-EP presented negative maternal behaviours more frequently (P < 0.05), while the incidence of lamb mortality at 6 weeks tended to be greater for L-EP lambs (P = 0.07). In MP, 1-year-old ewes offered diet M-MP were associated with foetuses with bigger abdominal diameters at day 78 (P < 0.05). However, there were no differences in lamb weight or size at term (P > 0.05). These ewes exhibited more positive maternal behaviours (e.g. increased grooming frequency and duration; P < 0.05) than ewes offered diet H-MP, and their offspring were more successful in suckling (P < 0.05). Results suggest that in young ewes, a temporary nutrient restriction in EP resulted in increased prolificacy. However, ewes and their offspring were lighter at birth and ewe maternal behaviour was poorer, resulting in increased lamb mortality. In MP, a medium plane of nutrition offered to 1-year-old ewes led to improved maternal and offspring behaviour. PMID- 22444444 TI - Effect of fermented liquid diet prepared with Lactobacillus plantarum LQ80 on the immune response in weaning pigs. AB - Probiotics such as lactic acid bacteria directly influence the host's health and have beneficial effects such as decreasing the number of enteric pathogens, regulating intestinal immune responses and preventing diseases. Among domestic animals, probiotics have been expected to be an alternative to antibiotics added in the diet; and fermented liquid diet (FLD) containing probiotics has great potential as a diet for reducing the use of antibiotics. In this study, we evaluated the immunomodulatory effects of FLD, prepared using Lactobacillus plantarum LQ80 (LQ80), on the immune response of weaning pigs. Ten weaning piglets were divided into two groups and were fed the FLD (n = 5) or a non fermented liquid diet (NFLD) (n = 5) for 28 days. At the end of the experiment, the total immunoglobulin M (IgM) and immunoglobulin G (IgG) levels in the sera of the FLD-fed piglets were significantly higher than those of the NFLD-fed piglets (P < 0.05). In contrast, the total immunoglobulin A (IgA) levels in the feces and saliva were not significantly affected by FLD feeding. However, the mean fecal IgA levels of FLD-fed piglets at day 28 were higher than those at 14 and 21 days (P < 0.05). Blood cells from the FLD-fed piglets showed a low level of interferon gamma secretion and mitogen-induced proliferation compared to that of the NFLD fed piglets. Furthermore, the levels of interluekin-8 and tumor necrosis factor alpha, which are proinflammatory cytokines, in the blood cells of the FLD-fed piglets were lower than those of the NFLD-fed piglets (P < 0.05). In conclusion, the FLD used in this study could alter the immune responses of weaning piglets by stimulation of the systemic or mucosal antibody response, without unnecessary inflammatory reactions. This indicates, that the FLD feed prepared with the use of LQ80 may be a candidate feed, with regard to enhancing immune responses and preventing diseases in weaning piglets. PMID- 22444445 TI - Bioavailability of threonine and tryptophan in peanut meal for starter pigs using slope-ratio assay. AB - The objective of the two studies was to determine the bioavailability of threonine (thr) and tryptophan (trp) in peanut meal, relative to l-thr and l-trp, for starter pigs using the slope-ratio bioassay. Basal diets (BDs) contained surfeit amounts of all amino acids for 10 to 20 kg pigs, except for thr (Experiment 1) or trp (Experiment 2). In the first study, four reference diets were formulated by supplementing the BD with 0, 0.4, 0.8 or 1.2 g of l-thr/kg at the expense of cornstarch; two test diets were formulated by replacing cornstarch in the BD with peanut meal at 32 or 64 g/kg of diet to supply 0.4 or 0.8 g thr/kg, respectively. Four reference diets consisting of the BD supplemented with 0, 0.15, 0.3 or 0.45 g of l-trp/kg at the expense of cornstarch and two test diets in which cornstarch in the BD was replaced with peanut meal at 30 or 60 g/kg of diet to supply 0.14 or 0.28 g trp/kg, respectively were used in the second study. Body weight gain responded in a linear way to supplemental l-thr or thr from peanut meal (P < 0.001). There was a linear response (P < 0.001) to thr supplementation from l-thr or peanut meal in gain-to-feed ratio. The addition of trp to the BD linearly increased (P < 0.05) body weight gain, feed intake and gain-to-feed ratio regardless of the trp source. Common-intercept, multiple linear regression in slope-ratio methodology using weight gain or gain-to-feed ratio as dependent variables and supplemental thr intake as independent variable gave relative bioavailability estimates of 71.9% or 75.7%, respectively. Corresponding values for trp were 92% and 75.7%. The fiducial limits for none of the relative bioavailability estimates included 100%. The data from these studies suggest that the bioavailabilities of thr and trp in peanut meal are less than those of l-thr and l-trp, and that the bioavailabilities of thr and trp in peanut meal are 72% to 76% and 76% to 92%, respectively. PMID- 22444446 TI - Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus. Insulin response with and without a long-acting insulin treatment. AB - Streptozotocin-induced diabetes mellitus (STZ-DM) in rats is a model of type 1 diabetes, which is commonly used to study diabetes, but differs from human diabetic pathophysiology in its insulin resistance. An STZ-DM rat can be administered five times the dose of insulin compared to that of a diabetic patient. Thus, attaining normoglycaemia in STZ-DM rats with insulin injections is complicated, and it involves an obvious risk of overdosing before getting a response. This study was designed to investigate whether suboptimal treatment with long-acting insulin restores insulin sensitivity in the STZ-DM rat, and thus an approach to more closely mimic the human condition. Male Sprague-Dawley rats were made diabetic by means of a single intravenous injection of STZ (55 mg/kg body weight (BW)), resulting in an increase in blood glucose (BG) from 6.5 +/- 0.2 to 22.5 +/- 1.0 mmol/l (P 0.05) within 24 h. After treating the STZ-DM rats with vehicle for 14 days, BG was 26.1 +/- 1.1 mmol/l, and the response to a single injection of fast-acting insulin (Humalog, 5 IE/kg BW) was a 23% reduction in BG. Thereafter, the rats were treated daily with a suboptimal dose of long acting insulin for a total of 7 days (Insulatard, 5 IE/kg per day), which resulted in a BG level of 19.4 +/- 2.7. The response to fast-acting insulin after the suboptimal treatment was a 61% reduction in BG. Thereafter, the animals were vehicle-treated for another 7 days, which resulted in a response to fast-acting insulin similar to the initial values (-34%). Furthermore, the group treated with suboptimal doses of long-acting insulin had a longer duration of the reduction in BG (150 min, as opposed to 90 min in the vehicle-treated groups). We conclude that the development of a decreased insulin response occurs rapidly within the first 2 weeks after the onset of diabetes in STZ-DM rats. This leads to a brief and significantly reduced decrease in BG when fast-acting insulin is administered. The insulin response is increased by treatment with suboptimal doses of long-acting insulin, but rapidly decreases again when treatment is withdrawn. Regular administration of suboptimal insulin doses may provide an approach to eliminate the effects of a lowered insulin response. PMID- 22444447 TI - Can audio-visual or visual stimuli from a prospective mate stimulate a reproductive neuroendocrine response in sheep? AB - Stimuli from a prospective mate increase the secretion of luteinising hormone (LH) in sheep. This 'male effect' in ewes and 'female effect' effect in rams is predominantly mediated by olfactory signals, though it is thought that non olfactory signals play synergistic or substitutive roles. In this study, we tested whether exposure to visual or audio-visual stimuli from a prospective mate would stimulate an increase in LH secretion in ewes (Experiment 1) and rams (Experiment 2). In Experiment 1, groups of eight Merino ewes were exposed to one of three stimuli midway through a frequent blood-sampling regimen: full ram contact, still images of rams, a video of ewes and rams mating. Control ewes (n = 8) were completely isolated from rams. Exposure to still images of rams appeared to stimulate an increase in mean LH concentrations (P < 0.05) and tended to increase LH pulse frequency (P < 0.1), but the response was significantly smaller than that observed in ewes exposed to rams (P < 0.01). Audio-visual stimuli had no effect on any parameters of LH secretion (P > 0.1). In Experiment 2, Merino rams were allocated to either an Exposure (n = 7) or a Control (n = 7) group. Exposure rams underwent two exposure periods midway through a frequent blood sampling regimen; exposure to still images of ewes and audio recorded during mating of ewes and rams (audio-visual exposure); exposure to oestrous ewes (ewe exposure). Control rams were sampled at the same frequency but remained isolated from ewe stimuli. Exposure of rams to the audio-visual stimuli did not affect any parameters of LH secretion (P > 0.1). In contrast, exposure to oestrous ewes increased LH pulse frequency (P < 0.05) and advanced the onset of the next LH pulse (P < 0.05). In conclusion, visual signals appear to be involved in eliciting the neuroendocrine response of ewes to rams and are of greater importance to this phenomenon in ewes (male effect) than rams (female effect). However, overall the visual and audio-visual signals used in this study were far less effective than stimulus animals, suggesting that these stimuli are less important than olfactory signals, or a combination of olfactory and audio-visual signals. PMID- 22444448 TI - No effect of the plant growth regulator, chlormequat, on boar fertility. AB - Chlormequat is a commonly used plant growth regulator in agriculture. Defined levels of chlormequat residue are allowed in food and an acceptable daily intake is defined for humans. However, there are results in the literature suggesting that a daily intake below the acceptable level for human is detrimental for mammalian reproduction. In the present experiment we investigated the effect of chlormequat at levels up to that acceptable for humans on reproduction in male pigs. Chlormequat (also known as chlorocholine chloride (CCC)) was mixed into the diet and given to the experimental animals at three levels (three treatment groups), i.e. 0 mg CCC/kg BW per day (Control), 0.025 mg CCC/kg BW per day and 0.05 mg CCC/kg BW per day. Eight mother sows per treatment group were used in the experiment. From the day of insemination, the mother sows received the experimental diets. The piglets were weaned at 4 weeks of age and two boar littermates continued on the same treatment as the dam until maturity and delivery of semen for in vitro fertilization (IVF) and in vivo fertilization. Semen volume, sperm concentration and fraction of live sperms were not (P 0.46) detrimentally affected by chlormequat intake. The fraction of oocytes developing to more than the one-cell stage at day 5 after IVF was not (P = 0.88) detrimentally affected by chlormequat intake. Chlormequat intake did not detrimentally affect the fraction of gilts being pregnant after one insemination (P = 0.65) or the number of embryos in the pregnant gilts (P = 0.36). Serum chlormequat concentration was 0.9 MUg/kg in the 0.025 mg CCC/kg BW per day group and 1.8 MUg/kg in the 0.05 mg CCC/kg BW per day group, but was below the detection limit in control animals. In conclusion, the plant growth regulator chlormequat could not be proven to be detrimental to the selected reproduction traits in male pigs. This is in contrast to existing results from the male mouse. PMID- 22444449 TI - In vitro primary satellite cell growth and differentiation within litters of pigs. AB - Postnatal muscle growth is dependent on satellite cell (SC) proliferation, differentiation and fusion to increase the DNA content of existing muscle fibres and thereby the capacity to synthesize protein. The purpose of the present study was to examine the ability of isolated SCs from low, medium and high weaning weight litter mates of pigs to proliferate and differentiate, and to affect protein synthesis and degradation after fusion into myotubes. At 6 weeks of age, SCs from the lowest weight (LW), medium weight (MW) and highest weight (HW) female pigs within eight litters were isolated. Thereby, eight cultures of SCs were established for each of the three weight groups within litter, representing three groups of SCs from pigs exhibiting differences in postnatal muscle growth performance. Proliferation was estimated as the number of viable cells at different time points after seeding. SC differentiation was evaluated by measuring the activity of the muscle-specific enzyme, creatine phosphokinase, and protein synthesis and degradation were measured by incorporation and release of 3H-tyrosine, respectively. A tendency towards a difference in proliferation between SC cultures was found (P = 0.09). This was evident as the number of viable cells at day 3 was lower in cultures from LW pigs than from HW (P < 0.05) and MW (P < 0.01) pigs. Differentiation was significantly different between cultures (P < 0.05). There was a significant difference between LW and MW cultures at 72 h (P < 0.05), and a tendency towards a difference between LW and HW cultures at 45 h (P = 0.07). Protein synthesis per MUg protein or per MUg DNA did not differ among SC cultures from LW, MW and HW pigs. Neither did protein degradation rate differ significantly among SC cultures from LW, MW and HW pigs. Overall, the results show that SCs from LW pigs seem to proliferate and differentiate at a slower rate than SCs from MW and HW pigs. The results found in this study show no difference in the ability of SCs to affect protein synthesis or degradation between SCs from litter mates exhibiting different growth rates in vivo. PMID- 22444450 TI - Udder quarter milk composition at different levels of somatic cell count in cow composite milk. AB - Automatic milking systems have made possible the separation of high- and low quality milk at the udder quarter level during the milking process. The aim of this study was to investigate the composition and yield of milk from individual udder quarters to determine whether deteriorated milk composition occurs in udders that are assumed to be healthy and whether quarters with high-quality milk are found in udders with high milk somatic cell count (SCC). Milk samples were collected on one occasion from 90 cows at udder quarter level and cow composite level. The milk was analyzed for content of total protein, whey protein, casein, fat, lactose, citric acid and SCC; milk yield was registered. The cows were divided into three groups depending on the SCC of their composite milk. Cows in group 1, cow composite SCC < 100 000 cells/ml, were assumed to have healthy udders. However, instances of increased SCC and decreased milk quality were discovered in one or more udder quarters of approximately 30% of the group. Cows in group 2, cow composite SCC of 100 000 to 300 000 cells/ml, and group 3, cow composite SCC > 300 000 cells/ml, were assumed to have affected udders. However, the majority of these cows had one or more udder quarters in which increased SCC and deteriorated milk quality were not detected. Calculations of bulk-tank milk values, when separation of milk from affected udder quarters was performed, indicate that SCC changes to a much greater degree compared to the other milk components. These results show that milk from affected udder quarters suffers compositional changes, but calculations of simulated separation indicate that the compositional changes in bulk-tank milk are small. The effect of separation of milk from individual udder quarters on bulk-tank milk needs to be further studied. PMID- 22444451 TI - Effect of level of eicosapentaenoic acid on the transcriptional regulation of Delta-9 desaturase using a novel in vitro bovine intramuscular adipocyte cell culture model. AB - Ruminant fat is often perceived as having a negative impact on human health; however, the composition of the fat is under complex biochemical control and can be improved through strategic manipulation of the animal's diet. There were two major objectives of this study, namely (i) to develop and validate a primary bovine intramuscular adipocyte cell line and (ii) to examine the effect of eicosapentaenoic acid (EPA) on the transcriptional regulation of Delta-9 desaturase in vitro using the novel cell line. Intramuscular adipose tissue was obtained from the Musculus longissimus thoracis of a beef heifer. Mature adipocytes were isolated and cultured, and subsequently harvested and evaluated for lipid accumulation and the expression of genes regulating key functional adipocyte protein markers at passages 10, 20 and 30. Isolated cells were shown to accumulate lipid in culture over time. Fatty acid analysis by gas chromatography was carried out at passage 30. Thirteen fatty acids ranging from tetradecanoic acid (C14:0) to the polyunsaturated fatty acid, docosahexaenoic acid (C22:6), were easily detected and measured. High-quality total RNA was isolated from adipocytes and the expression of peroxisome proliferator-activated receptor gamma, fatty acid synthase, fatty acid-binding protein-4, adipocyte lipid-binding protein, CD36, Delta-9 desaturase, sterol regulatory element-binding protein (SREBP), microsomal triglyceride transfer protein and leptin genes were identified by reverse transcriptase-PCR and sequence analysis. Expression of the negative control, liver-specific hepatocyte nuclear factor-1alpha, was not detected. Adipocytes were subsequently incubated in medium containing 0, 50 or 100 MUM EPA for 24 h. Increasing the EPA concentration of the culture media led to a linear increase in adipocyte EPA concentration (P < 0.01). Expression of Delta-9 desaturase mRNA was decreased five- and seven-fold, respectively, following 50 and 100 MUM EPA incubation compared to the control. Gene expression of SREBP-1c was decreased by 6- and 18-fold in cells supplemented with 50 and 100 MUM EPA, respectively, compared to the control. Regression analysis showed a negative linear relationship between EPA concentration and the gene expression of both Delta-9 desaturase (P < 0.001) and SREBP-1c (P < 0.001), while a significant positive relationship was observed between Delta-9 desaturase and SREBP-1c gene expression (P < 0.001). This is the first report demonstrating that EPA treatment of bovine intramuscular adipocyte cells decreased gene expression of both Delta-9 desaturase and SREBP-1c in vitro. The bovine adipocyte cell line developed here is an important resource for future studies facilitating less-expensive, rapid screening of research hypotheses and circumventing the limitations associated with the use of experimental animals including cost, inter-animal variation, pre experimental management and ethics. PMID- 22444452 TI - Origin and assessment of bruises in beef cattle at slaughter. AB - Studies of bruises, as detected on carcasses at the slaughterhouse, may provide useful information about the traumatic situations the animals endure during the pre-slaughter period. In this paper, we review scientific data on the prevalence, risk factors and estimation of the age of bruises in beef cattle. Risk factors such as animal characteristics, transport conditions, stocking density, livestock auction and handling of the animals are discussed. Investigation of the age of bruises could provide information on when in the meat chain bruises occur and, could help to pinpoint where preventive measures should be taken, from the stage of collecting the animals on the farm until slaughter. We review the methods available to assess the age of the bruises; data on human forensic research are also included. The feasibility to identify traumatic episodes during the pre slaughter period, in order to improve animal welfare is discussed. PMID- 22444453 TI - The relationship between the stockperson's personality and attitudes and the productivity of dairy cows. AB - This study investigated the relationships amongst personality traits and attitudes of 311 dairy stockpeople and the milk yield they obtained. A questionnaire pack consisting of a big-five measure of personality (which includes the traits of extraversion, agreeableness, conscientiousness, emotional stability and intellect), a four-factor attitude questionnaire and associated demographic and production questions was posted out to Northern Ireland dairy farmers. Pearson correlations were used to assess the relationship between personality and attitudes and partial correlations were calculated between milk yield and these psychometric measures. The personality traits of agreeableness and conscientiousness were most strongly correlated to positive attitudes towards working with dairy cows. None of the stockpeople's personality traits were significantly correlated with the milk yield they obtained. Three of the attitude scales, however, were significantly correlated with milk yield; milk yield was related to higher levels of empathy and job satisfaction and lower levels of negative beliefs. These findings, along with previous research, suggest stockperson attitudes may be important in relation to dairy cow welfare and production. PMID- 22444454 TI - Microbial pollution of water by livestock: approaches to risk assessment and mitigation. AB - In this study, we investigate the extent to which the incidence of Escherichia coli O157:H7 can be predicted in human faeces, from human intake and infection via water contaminated by livestock and carrying this zoonotic pathogen in North East (NE) and South-West (SW) regions of Scotland. In SW Scotland, there is a risk of coastal recreational waters failing EU standards for faecal indicator organisms, and this is assumed to be the main potential waterborne route of infection. In NE Scotland, the main waterborne route is assumed to be the many private drinking water supplies; these are mainly derived from shallow groundwater and surveys show that there is potential for significant levels of microbial contamination from livestock. The risk to human health from these sources has been assessed using a combination of process models, epidemiological risk-assessment methods and survey data. A key assumption in the calculations is the amount of mixing of pathogenic and non-pathogenic E. coli between animal faecal sources and contaminated water intake by humans. Using the probability distributions of the E. coli O157 content of individual faecal pat material (which would imply no mixing between source and human intake), based on three recent surveys of animal faeces in Scotland, led to predicted annual risks of infection slightly higher than observed human infection incidence. Using the geometric mean to represent partial mixing (which theoretically may over- or underestimate incidence with a concave dose-response curve) gave infection rates similar to those observed for two of the three faecal surveys. Using the arithmetic mean led to over-prediction of risk. This is to be expected if the true dose-response curve is (such as the Beta-Poisson curve used here) concave. Other factors that may lead to over-prediction of incidence are discussed, including under-reporting, loss of infectivity as a result of environmental exposure, immunity and the appropriateness of the Beta-Poisson curve. It is concluded that better epidemiological data for calibration of the dose-response curve, better knowledge of the degree of mixing and understanding of immunity are key requirements for progress in process model-based predictions of infection rate. The paper also explores the potential of improved farm and catchment scale management to deliver cost-effective mitigation of pollution of bathing and drinking water by livestock zoonoses. PMID- 22444455 TI - Is intensification of reproduction rhythm sustainable in an organic sheep production system? A 4-year interdisciplinary study. AB - A 4-year interdisciplinary study was performed to compare two organically managed sheep production systems, using 118 ewes and 24 ha each. The systems differed in the ewes' reproduction rhythm: one lambing per ewe per year (1L/1Y), with the aim of balancing feed self-sufficiency and lamb marketing periods v. three lambings over 2 years (3L/2Y), with the aim of maximising ewes' productivity. The sustainability was evaluated through ewes' reproductive performance, lamb growth rate, carcass characteristics and quality, animal health, forage and feed self sufficiency, soil mineral balance and gross margin. General animal health was assessed by recording ewe and lamb mortality and putative cause of death. Nematode digestive-tract strongyles parasitism was studied using faecal egg counts and necropsies. Carcass quality was assessed by recording carcass weight, conformation and fatness, and colour and firmness of subcutaneous fat. Thirty three percent of 3L/2Y ewes lambed twice a year against 4% of 1L/1Y. Mean ewe productivity was 161.3% and 151.0% in 3L/2Y and 1L/1Y, respectively, and it was more variable between years in 3L/2Y. Average concentrate feed consumption and the corresponding cost per ewe were higher in 3L/2Y than in 1L/1Y (156 v. 121 kg, and ?49.5 v. ?39.3, respectively). Finally, average gross margin was lower in 3L/2Y than in 1L/1Y (?59 v. ?65 per ewe, respectively). Even in year 2002, when ewe productivity was highest in 3L/2Y (193%), gross margin was not different between systems (?90 v. ?86 per ewe in 3L/2Y and 1L/1Y, respectively), because of higher concentrate costs in 3L/2Y. The 3L/2Y animals presented a lower health status, with a higher lamb mortality (P < 0.05) and a higher digestive-tract strongyles and coccidia parasitism level (P < 0.05). Lamb carcass conformation, fatness and fat colour were not different between systems, but carcass weight and subcutaneous dorsal fat firmness were lower in 3L/2Y lambs than in 1L/1Y lambs (P < 0.05 and < 0.001, respectively). Intensification in an organically managed sheep system, through an increased reproduction rhythm, thus did not lead to better economic results and proved riskier, more variable and more difficult to manage, and so less sustainable. The less intensive system (1L/1Y) was both highly efficient from the animal standpoint and highly feed self-sufficient. The technical and economic results of this system were better than those of organic private farms in the same area and matched those of non-organic farms. PMID- 22444456 TI - Does the chicken genotype 'Geline de Touraine' have specific carcass and meat characteristics? AB - The aim of this study was to determine the specific characteristics of carcass and meat from an old French chicken breed, the 'Geline de Touraine' (GT), characterised by a very slow-growing rate and usually slaughtered at 120 days of age. For this purpose, we compared the GT with an experimental crossbreed (EC) exhibiting the same growth rate, and with a 'Label rouge' (LR) genotype usually slaughtered at 84 days of age. A total of 250 males and 250 females per genotype were reared by separating sexes and genotypes. The growth performances were recorded. At 84 days of age, 80 birds per sex and per genotype were slaughtered. The frequency of clawing and pecking injuries on the carcass was noted. We also measured the skin colour and the thickness of wing membrane. The relative percentages of carcass, breast, thigh + drumstick, abdominal fat, testis or ovary to body weight were determined. On breast and thigh muscles the ultimate pH (pHu) and colour were measured. The juice loss after 3 days' storage at +4 degrees C and after cooking at 85 degrees C, and the shear force value of Warner-Bratzler were only measured on breast muscles. At 120 days of age, we repeated the same measurements but only on EC and GT genotypes in order to compare birds at the same age or at the respective slaughter age for each production. Whatever the slaughter age, the body weight of males was always higher than that of the females but the carcass yield was similar for both sexes. The females had higher breast yield and carcass fatness but lower thigh + drumstick yield than the males. The yellowness of skin and meat was higher for the females than for the males while the contrary was observed for the redness of the meat. The breast meat of the females also had higher cooking loss than that of the males. GT and EC birds exhibited a higher occurrence of carcass defects and a higher pHu in meat than LR birds. The GT chickens were characterised by a lower breast yield, a higher fattiness and an earlier sexual maturity than the other genotypes, which could confer typical sensorial attributes to their meat. Finally, the EC chickens exhibited a skin and a meat more coloured than the other genotypes, particularly for yellowness, a character which could be under genetic control. PMID- 22444457 TI - Comparison of biocompatibility and adsorption properties of different plastics for advanced microfluidic cell and tissue culture models. AB - Microfluidic technology is providing new routes toward advanced cell and tissue culture models to better understand human biology and disease. Many advanced devices have been made from poly(dimethylsiloxane) (PDMS) to enable experiments, for example, to study drug metabolism by use of precision-cut liver slices, that are not possible with conventional systems. However, PDMS, a silicone rubber material, is very hydrophobic and tends to exhibit significant adsorption and absorption of hydrophobic drugs and their metabolites. Although glass could be used as an alternative, thermoplastics are better from a cost and fabrication perspective. Thermoplastic polymers (plastics) allow easy surface treatment and are generally transparent and biocompatible. This study focuses on the fabrication of biocompatible microfluidic devices with low adsorption properties from the thermoplastics poly(methyl methacrylate) (PMMA), polystyrene (PS), polycarbonate (PC), and cyclic olefin copolymer (COC) as alternatives for PDMS devices. Thermoplastic surfaces were oxidized using UV-generated ozone or oxygen plasma to reduce adsorption of hydrophobic compounds. Surface hydrophilicity was assessed over 4 weeks by measuring the contact angle of water on the surface. The adsorption of 7-ethoxycoumarin, testosterone, and their metabolites was also determined after UV-ozone treatment. Biocompatibility was assessed by culturing human hepatoma (HepG2) cells on treated surfaces. Comparison of the adsorption properties and biocompatibility of devices in different plastics revealed that only UV-ozone-treated PC and COC devices satisfied both criteria. This paper lays an important foundation that will help researchers make informed decisions with respect to the materials they select for microfluidic cell-based culture experiments. PMID- 22444458 TI - A role for depression in sexual risk reduction for women? A meta-analysis of HIV prevention trials with depression outcomes. AB - Rates of HIV/AIDS and depression in women are significant public health concerns. The current meta-analysis tested the hypothesis that depression levels moderate change in sexual risk behavior in women participating in HIV prevention interventions. Features of the interventions were also explored as possible factors in decreasing levels of depression and sexual risk behavior. Included were HIV primary prevention interventions that measured sexual risk behavior and depression at baseline and follow-up and reported separate results for women. Ten studies (fourteen intervention groups and ten control groups; N = 4,195 women) met the inclusion criteria. The majority of participants were African American; mean age was 28-years old. Both depression and sexual risk behavior decreased significantly in treatment and control groups from baseline to follow-up. Sexual risk decreased more to the extent that interventions sampled (a) participants with higher baseline levels of depression, (b) older women, (c) Hispanics/Latinas, and/or (d) members of risk groups (e.g., drug users, homeless). Interventions that included (e) condom provision, (f) information about condoms, and/or (g) HIV counseling and testing were also more successful in decreasing sexual risk. Finally (h), interventions were more likely to reduce sexual risk behavior when they decreased depression to a large extent relative to baseline levels. Interventions were more likely to decrease depression when they (a) had samples of only women, (b) targeted risk groups, and/or (c) provided self management and coping skills. Reducing depression appears to play a role in decreasing sexual risk behavior, suggesting that interventions should actively address depression. PMID- 22444459 TI - Psychosocial support intervention for HIV-affected families in Haiti: implications for programs and policies for orphans and vulnerable children. AB - Given the increased access of antiretroviral therapy (ART) throughout the developing world, what was once a terminal illness is now a chronic disease for those receiving treatment. This requires a paradigmatic shift in service provision for those affected by HIV/AIDS in low-resource settings. Although there is a need for psychosocial support interventions for HIV-affected youth and their caregivers, to date there has been limited empirical evidence on the effectiveness of curriculum-based psychosocial support groups in HIV-affected families in low-income countries. Therefore, the purpose of this study is to examine the feasibility and assess the preliminary effectiveness of a psychosocial support group intervention for HIV-affected youth and their caregivers in central Haiti. The study was conducted at six Partners In Health affiliated sites between February 2006 and September 2008 and included quantitative as well as qualitative methods. HIV-affected youth (n = 168) and their caregivers (n = 130) completed a baseline structured questionnaire prior to participation in a psychosocial support group intervention. Ninety-five percent of families completed the intervention and a follow-up questionnaire. Psychological symptoms, psychosocial functioning, social support, and HIV-related stigma at baseline were compared with outcomes one year later. Qualitative methods were also used to assess the participants' perspectives of the intervention. Comparing pre- and post-intervention assessment, youth affected by HIV experienced decreased psychological symptoms as well as improved psychosocial functioning and social support. Caregivers (95% HIV-positive) demonstrated a significant reduction in depressive symptoms, improved social support, and decreased HIV-related stigma. Although further study is needed to assess effectiveness in a randomized controlled trial, corroborative findings from qualitative data reflected reduced psychological distress, less social isolation and greater hope for the future for families affected by HIV/AIDS following the intervention. PMID- 22444460 TI - HIV and tuberculosis: the construction and management of double stigma. AB - Mitigation of the tuberculosis (TB) and HIV syndemic is undermined by critical clinical, operational and social challenges of which the social aspects have been least explored. This paper examines the lived experience of TB disease and HIV from the perspective of affected individuals to analyze how they may think about their dual illness; how they understand their illness with TB in relation to HIV, and vice versa; and how they characterize their (stigmatized) experiences in the context of their perceptions and identities. From February-August 2009, qualitative, semi-structured interviews were conducted with 40 adults with HIV and TB disease at three ambulatory clinics in KwaZulu-Natal, South Africa. Subjective meanings of illness experience were analyzed using modified grounded theory. Emergent themes on illness perception and disclosure revealed how patients constructed dichotomous identities associated with TB and HIV through social constructs of moral susceptibility and (im)permanence. Each identity was associated with relatively disparate degrees of stigma as a product of labeling, negative stereotyping and discrimination. HIV bore the least desirable identity and invoked the greatest stigma. However, the confluence of the two epidemics rendered TB symbolic and symptomatic of HIV, and enhanced the visibility of AIDS. Dual illness thus introduced a paradox to patients' identity constructions, and produced a unique, overlapping double stigma. This facilitated new forms of stigma against TB, and aggravated existing stigma against HIV. It also conferred visibility to some forms of extra-pulmonary TB. Patients managed their double stigmas through novel forms of information sharing that relied on segregating their dual illness identities. Patients deflected the dominant stigma of HIV through concurrent processes of HIV 'othering' - their symbolic distancing from persons affected by HIV, and 'covering' - their selective disclosure of illness (and identity associated) with TB over that of HIV. Findings call for greater consideration to the complex role of stigma in the delivery of TB/HIV healthcare. PMID- 22444461 TI - Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Abeta1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH. METHODS: We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Abeta1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Abeta1-42 ratios in the patients in our cohort. RESULTS: We found that high ptau/Abeta1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Abeta1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios. CONCLUSIONS: Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition. PMID- 22444462 TI - A stochastic simulation study on using different models for prediction of breeding values while changing the breeding goal. AB - In a stochastic simulation study the effect of simultaneously changing the model for prediction of breeding values and changing the breeding goal was studied. A population of 100 000 cows with registrations on seven traits was simulated in two steps. In the first step of 15 years the population was selected for production and mastitis occurrence using a univariate model for prediction of breeding values for production and a trivariate model using information on mastitis treatments, udder depth and somatic cell score for prediction of breeding values for mastitis occurrence. In the second step six different scenarios were set up and simulated for 15 years combining two different breeding goals and three different models for prediction of breeding values in 20 replicates. Breeding goal 1 had relative economic value per genetic standard deviation on production (19.4) and mastitis occurrence ( - 50) whereas breeding goal 2 had a economic value on production (19.4), udder depth (4.2), mastitis occurrence ( - 50), non return rate (13.0) and days open ( - 16.75). Model 1 was a model similar to the one used in the first 15 years. Model 2 was an approximate multitrait model where solutions for fixed effects from a model corresponding to model 1 were subtracted from the phenotypes and a multitrait model with an overall mean, a year effect, an additive genetic and a residual effect were applied. Model 3 was a full multitrait model. Average genetic trends for total merit and each individual trait over 20 replicates were compared for each scenario. With the number of replicates the genetic responses using model 2 and 3 were not significant different. With a broad breeding goal using, model 2 or model 3 gave a significantly higher response in total merit than using model 1. Using a narrow breeding goal there was no significant difference between models used for prediction of breeding values. Results showed that with a breeding goal with a lot of emphasis on low heritable traits with a high economic value using a multitrait methodology for prediction of breeding values will redistribute the genetic progress in the total merit index. More gain will come from the low heritable traits in the breeding goal and less from traits with higher heritability. With a broad breeding goal and exploiting the available information in the data the inbreeding coefficient increased though not significantly. PMID- 22444463 TI - Genetic determinism for within-litter birth weight variation and its relationship with litter weight and litter size in the Ripollesa ewe breed. AB - Birth weight plays a central role in lamb survival and growth, and the knowledge of its genetic determinism has become essential in worldwide selection programmes. Within this context, within-litter birth weight variation (BWV) has been suggested as an attractive trait to homogenise litters in prolific species, although it has not been analysed in sheep. The objective of this study was to ascertain whether maternal additive genetic variance exists for BWV in Ripollesa ewes, and to study its genetic, permanent environmental and residual relationships with litter weight (LW) and litter size (LS) at birth. Data were recorded in the Ripollesa experimental flock of the Universitat Autonoma of Barcelona, between 1986 and 2005, and included 1 662 litters from 380 ewes, with 712 records of BWV and 1 530 records of LW. Traits were analysed with a multivariate animal model solved through Bayesian methodologies, and with a threshold characterisation of LS. Additionally, the effect of BWV on lamb survival was studied. Additive genetic variance was observed for BWV (h2 = 0.061), as well as for LW (h2 = 0.200) and LS (h2 = 0.141). Nevertheless, genetic correlations among those traits were not substantial (BWV and LW = 0.151; BWV and LS = - 0.219; LW and LS = - 0.320) and suffered from a high degree of uncertainly, with the null correlation included within the highest posterior interval at 95%. Within-litter birth weight variation and LS showed a negative and large permanent environmental correlation ( - 0.872), and LW and LS were negatively correlated due to residual ( - 0.762) and permanent environmental ( - 0.449) random sources of variation. Within-litter birth weight variation influenced lamb mortality during the first 7 days of life (P < 0.05), increasing and decreasing survivability in heavier and lighter littermates, respectively. Nevertheless, stillbirths and lambs died after the 1st week of life were not affected by BWV (P>0.05). The low heritability found indicates that slow genetic progress may be expected from selecting for BWV. Close to zero genetic correlations suggest that this selection will probably not affect LS and LW, although some significant permanent and residual correlations must be taken into account. Further studies are needed to understand better the genetic architecture among these three reproductive traits. PMID- 22444464 TI - The use of a tannin crude extract from Cistus ladanifer L. to protect soya-bean protein from degradation in the rumen. AB - Cistus ladanifer L. (CL) is a perennial shrub abundant in dry woods and dry land of Mediterranean zone, with high level of tannins. Tannins bind to protein, preventing its degradation in the digestive compartments. This tannin/protein complex may be advantageous when partially protecting good-quality feed protein from excessive rumen protein degradation. The objective of this trial was to use a CL phenol crude extract to prevent excessive rumen degradation of soya-bean meal protein. The phenolic compounds were extracted using an acetone/water solution (70:30, v/v). Soya-bean meal was then treated with this crude CL extract, containing 640 g of total phenols (TP) per kg of dry matter (DM), in order to obtain mixtures with 0, 12.5, 25, 50, 100 and 150 g of TP per kg DM. Three rumen-cannulated rams were used to assess in sacco rumen degradability of DM and nitrogen (N). The three-step in vitro procedure was used to determine intestinal digestibility. Increasing extract concentrations quadratically decreased the N-soluble fraction a (R2 = 0.96, P = 0.0001) and increased the non soluble degradable fraction b (R2 = 0.92, P = 0.005). The rate of degradation c linearly decreased with CL extract doses (R2 = 0.44, P = 0.0065). For the effective rumen degradability of N, a linear reduction (R2 = 0.94, P < 0.0001) was observed. The in vitro intestinal digestibility of protein (ivID) quadratically decreased (R2 = 0.99, P < 0.0001) with TP inclusion and the rumen undegradable protein (RUP) showed a quadratic increase (R2 = 0.94, P = 0.0417). Total intestinal protein availability, computed from the RUP and ivID, linearly decreased with TP inclusion level (R2 = 0.45, P = 0.0033). PMID- 22444465 TI - Effect on digestion and performance of dietary protein content and of increased substitution of lucerne hay with soya-bean protein concentrate in starter diets for young rabbits. AB - The aim of this work was to study the effect of protein source / availability on the intestinal microbiota, digestive traits and nutritional performance of early weaned rabbits. The effects of supplemental antibiotics in the drinking water were also evaluated. Four isoenergetic and isofibrous diets were formulated: a control diet with a high protein (207 g/kg dry matter (DM)) and lucerne hay content (HPHL), a diet with low crude protein (CP) (179 g/kg DM) and high lucerne hay content (LPHL) and low protein diets in which the lucerne hay in diet LPHL was replaced partially (LPML) or totally (LPLL) with soya-bean protein concentrate. Rabbits, weaned at 25 days (52 per diet), were fed the experimental diets for a 2-week period and thereafter received a commercial diet until 56 days of age. The incidence of mortality was investigated using 70 animals per diet without supplemental medication. The profile of the ileal microbiota was studied at 35 days of age in rabbits treated (18 per diet) or not (12 per diet) with antibiotic. As expected, supplementation with antibiotics effectively reduced fattening mortality rate and microbial biodiversity. However, lowering of also the dietary CP content led to a reduction in the mortality rate ( P < 0.05), both in animals treated with (by 80%) or without (by 39%) antibiotics. In addition, there was a reduction ( P < 0.05) in the frequency of Clostridium perfringens in non-medicated animals. Neither jejunal morphology nor growth performance, over the whole fattening period, was affected by dietary CP content of the experimental diets. However, with HPHL, feed efficiency was higher (by 4.8%; P < 0.01) than with LPHL diets. Substitution of lucerne hay with soya-bean meal in low protein diets did not affect apparent faecal or ileal digestibility of DM and CP. However, the ileal digestibility of cystine, alanine, aspartic acid, and proline was lowered ( P < 0.05) with increasing substitution by soya bean. Nevertheless, ileal CP flow, incidence of mortality and presence of C. perfringens were unaffected. Our results suggest that a reduction in dietary CP, resulting in reduced lumenal flows of nitrogen through the ileum, may be beneficial for young rabbits and limit the numbers of potentially harmful bacteria in the lower gut. Modulation of dietary CP should be contemplated as a strategy to increase the intestinal health in rabbits. PMID- 22444466 TI - Production of trans C18:1 and conjugated linoleic acid in continuous culture fermenters fed diets containing fish oil and sunflower oil with decreasing levels of forage. AB - Previously, feeding fish oil (FO) and sunflower seeds to dairy cows resulted in the greatest increases in the concentrations of vaccenic acid (VA, t11 C18:1) and conjugated linoleic acid (CLA) in milk fat. The objective of this study was to evaluate the effects of forage level in diets containing FO and sunflower oil (SFO) on the production of trans C18:1 and CLA by mixed ruminal microbes. A dual flow continuous culture system consisting of three fermenters was used in a 3 * 3 Latin-square design. Treatments consisted of (1) 75:25 forage:concentrate (HF); (2) 50:50 forage:concentrate (MF); and (3) 25:75 forage:concentrate (LF). FO and SFO were added to each diet at 1 and 2 g/100 g dry matter (DM), respectively. The forage source was alfalfa pellets. During 10-day incubations, fermenters were fed treatment diets three times daily (140 g/day, divided equally between three feedings) as TMR diet. Effluents from the last 3 days of incubation were collected and composited for analysis. The concentration of trans C18:1 (17.20, 26.60, and 36.08 mg/g DM overflow for HF, MF, and LF treatments, respectively) increased while CLA (2.53, 2.35, and 0.81 mg/g DM overflow) decreased in a linear manner ( P < 0.05) as dietary forage level decreased. As dietary forage levels decreased, the concentrations of t10 C18:1 (0.0, 10.5, 33.5 mg/g DM) in effluent increased ( P < 0.05) and t10c12 CLA (0.08, 0.12, 0.35 mg/g DM) tended to increases ( P < 0.09) linearly. The concentrations of VA (14.7, 13.9, 0.0 mg/g DM) and c9t11 CLA (1.78, 1.52, 0.03 mg/g DM) in effluent decreased in a linear manner ( P < 0.05) as dietary forage levels decreased. Decreasing dietary forage levels resulted in t10 C18:1 and t10c12 CLA replacing VA and c9t11 CLA, respectively, in fermenters fed FO and SFO. PMID- 22444467 TI - Synchronising the availability of amino acids and glucose increases protein retention in pigs. AB - Effects of synchronising the availability of amino acids and glucose within a day on protein and energy metabolism were studied in growing pigs. Ten pigs of on average 54 (s.e. 1.0) kg live weight were assigned to each of two dietary treatments (synchronous v. asynchronous nutrient supply) in a change-over design. On the synchronous treatment (SYN), pigs received two balanced meals: one at 0800 h and one at 1600 h. On the asynchronous treatment (ASYN), pigs received virtually all protein at 0800 h and all carbohydrates at 1600 h. The dietary supply of ingredients and nutrients to pigs was similar for both treatments. Pigs were housed individually in respiration chambers. Faecal apparent nutrient digestibility was determined and nitrogen and energy balances were measured. Faecal apparent digestibility of energy, organic matter and non-starch polysaccharides was higher ( P < 0.05) for SYN than for ASYN. The efficiency of utilisation of digestible protein with protein gain was higher ( P = 0.001) for SYN (56.7%) than for ASYN (47.1%). The substantial decrease ( P < 0.05) in respiratory quotient and 13C enrichment of the expired CO2 after the morning meal indicated higher amino acid oxidation for ASYN than for SYN. Heat production and energy retention as fat were not affected by nutrient synchrony. In conclusion, an asynchronous availability of glucose and amino acids within a day increases amino acid oxidation, resulting in a substantial reduction in protein utilisation but with virtually no effect on fat retention. PMID- 22444468 TI - Potential of carvacrol to modify in vitro rumen fermentation as compared with monensin. AB - The aim of this study was to assess the effect of carvacrol supplement as a dietary additive to rumen fermentors, fed a barley seed:alfalfa hay (70:30) ration and to compare its effect with monensin supplementation. The material was incubated with goat ruminal fluid and four different treatments were included: no additive (C), 7.5 mg/l monensin (M), 250 mg/l carvacrol (C250) and 500 mg/l carvacrol (C500). The addition of carvacrol reduced in vitro dry matter (DM), crude protein (CP) and neutral-detergent fibre (NDF) digestion. The effects induced by C250 on DM digestion at 72 h of incubation were comparable with those of M, whereas a greater reduction was obtained when carvacrol was supplemented at 500 mg/l concentration (68.9, 68.5 and 53.0 v. 76.1% for M, C250 and C500 v. C, respectively). The reduced CP potential degradability by supplements (51.2, 53.9 and 51.5 v. 72.8% for M, C250 and C500 v. C, respectively) was mainly caused by a reduction of the slowly degradable fraction. Volatile fatty acid (VFA) profiles determined after 48 h of incubation showed C250 increased butyrate and decreased acetate proportions, whereas M mainly stimulated propionate proportions, suggesting that the mechanism of action of carvacrol and M differs. C500 significantly reduced total VFA production. Carvacrol could be of great interest for its usage as a potential modulator of ruminal fermentation. Future research, including in vivo studies, in order to understand the factors that contribute to its antimicrobial activity and the selection of the optimal dose is required. PMID- 22444469 TI - Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype. AB - The molecular basis and control of the biochemical and biophysical properties of skeletal muscle, regarded as muscle phenotype, are examined in terms of fibre number, fibre size and fibre types. A host of external factors or stimuli, such as ligand binding and contractile activity, are transduced in muscle into signalling pathways that lead to protein modifications and changes in gene expression which ultimately result in the establishment of the specified phenotype. In skeletal muscle, the key signalling cascades include the Ras extracellular signal regulated kinase-mitogen activated protein kinase (Erk MAPK), the phosphatidylinositol 3'-kinase (PI3K)-Akt1, p38 MAPK, and calcineurin pathways. The molecular effects of external factors on these pathways revealed complex interactions and functional overlap. A major challenge in the manipulation of muscle of farm animals lies in the identification of regulatory and target genes that could effect defined and desirable changes in muscle quality and quantity. To this end, recent advances in functional genomics that involve the use of micro-array technology and proteomics are increasingly breaking new ground in furthering our understanding of the molecular determinants of muscle phenotype. PMID- 22444470 TI - Urea production and arginine metabolism are reduced in the growth restricted ovine foetus. AB - Urea production may be impaired in intrauterine growth restriction (IUGR), increasing the risk of toxic hyperammonaemia after birth. Arginine supplementation stimulates urea production, but its effects in IUGR are unknown. We aimed to determine the effects of IUGR and arginine supplementation on urea production and arginine metabolism in the ovine foetus. Pregnant ewes and their foetuses were catheterised at 110 days of gestation and randomly assigned to control or IUGR groups. IUGR was induced by placental embolisation. At days 120 and 126 of gestation, foetal urea production was determined from [14C]-urea kinetics and arginine metabolism was determined from the appearance of radioactive metabolites from [3H]-arginine, both at baseline and in response to arginine or an isonitrogenous mixed amino acid supplementation. Urea production decreased with gestational age in the embolised animals (13.9 +/- 3.1 to 11.2 +/ 3.0 MUmol/kg per min, P <= 0.05) but not in the controls (13.3 +/- 3.5 to 14.8 +/- 6.0 MUmol/kg per min). Arginine supplementation increased urea production in both groups, but only at 126 days of gestation (control: 15.0 +/- 8.5 to 17.0 +/ 9.4 MUmol/kg per min; embolised: 11.7 +/- 3.1 to 14.3 +/- 3.1 MUmol/kg per min, P <= 0.05). Embolisation reduced foetal arginine concentrations by 20% ( P <= 0.05) while foetal arginine consumption was reduced by 27% ( P <= 0.05). The proportions of plasma citrulline and hydroxyproline derived from arginine were reduced in the embolised animals. These data suggest that foetal urea production and arginine metabolism are perturbed in late gestation after placental embolisation. PMID- 22444471 TI - Biomechanical gait analysis of pigs walking on solid concrete floor. AB - Inappropriate floors in pig pens and slippery floor conditions may cause leg problems that reduce animal welfare. Therefore the objectives of the present study were to characterise the walk of pigs on dry concrete solid floor, to evaluate whether pigs modify their gait according to floor condition, and to suggest a coefficient of friction (COF) that ensures safe walking on solid concrete floors for pigs. Kinematic (50 Hz video recordings in the sagittal plane) and kinetic (1 KHz force plate measuring three perpendicular ground reaction forces) data were collected from four strides of both the fore- and hindlimbs of 30 healthy pigs walking on dry, greasy and wet concrete floor with 10 pigs on each floor condition. The COF of the floor conditions were tested in a drag-test. The results from the gait analysis showed that the pigs adapted their gait to potentially slippery floors by lowering their walking speed and reducing their peak utilised COF on greasy and wet (contaminated) floors compared with dry floors. Moreover, the pigs shortened their progression length and prolonged their stance phase duration on greasy floor compared with dry and wet floors. Thus the greasy floor appeared the most slippery condition to the pigs, whereas the wet floor was intermediate to the other two conditions. The pigs walked with a four beat gait, and the limbs differed biomechanically, as the forelimbs carried more load, received higher peak vertical forces and had longer lasting stance phases than did the hindlimbs. The utilised COF from the gait analysis indicated that a high floor COF (>0.63) is needed to prevent pigs from slipping and thus to ensure safe walking on dry concrete floors. PMID- 22444472 TI - Modelling farmers' action: decision rules capture methodology and formalisation structure: a case of biomass flow operations in dairy farms of a tropical island. AB - Studies on decision-making processes are generally aimed at identifying farmers' needs and predicting farmers' reactions to technical innovations. In the present paper we study these decision-making processes, with reference to dairy farms, to build a whole-farm computer model (WFM) which simulates farmers' actions. In this study, (i) a multi-tool and multi-step methodology is proposed, which can also be qualified as an iterative and interactive methodology to reveal decision rules and (ii) a generic structure to formalise how action is conducted, termed 'structure for action modelling' (SAM). In the case of forage crop-dairy cattle systems, we have tested the current methodology to capture the decision rules and the SAM to represent action concerning farm management. An 'immersion' approach, inspired by the ethnographic approach has been adapted to access operational technical decisions (taken on a daily basis). This study helped in understanding how detailed and large approaches can be complementary and can facilitate identification of what can be generalised in a conceptual model. To define the generic structure (SAM), a set of descriptive variables concerning technical operations has been selected. The conceptual model generated is composed of decision rules reconstructed by researchers with farmers' committed participation. The validation method is based on participatory approaches and on comparing of actions simulated by the model with practices on the ground. Not contesting the fact that farmers plan their action, this study also revealed the importance of adjustments in action. For example, 20 to 55% of the time the planned food ration is not distributed to the milking cows because of forage unavailability. We also discuss how this structure can facilitate integration of decision mechanisms in biophysical models and how such an integration of adjustment decision rules can produce more realistic simulations of technical actions. Error of biotechnical evaluations done by the WFM is reduced from about 25% to about 10% with the application of the proposed method. PMID- 22444473 TI - Effects of dietary crude protein level on odour from pig manure. AB - The objective of this study was to determine the effects of dietary crude protein (CP) level on odour emission, odour intensity, hedonic tone, and ammonia emission from pig manure and on manure composition (pH, total nitrogen, ammonium, volatile fatty acids, indolic, phenolic and sulphur-containing compounds). An experiment was conducted with growing pigs (n = 18) in a randomised complete-block design with three treatments in six blocks. Treatment groups were 12%, 15% and 18% CP diets. Barley was exchanged for soya-bean meal. Crystalline amino acids (AA) were included in the 12% CP diet up to the level of pigs' requirement; the same amount of AA was added to the 15% and 18% CP diets. Pigs with an initial body weight (BW) of 36.5 +/- 3.4 kg (mean +/- s.d.) were individually penned in partly slatted floor pens and offered a daily feed allowance of 2.8 * maintenance requirement for net energy (NE: 293 kJ/kg BW0.75). Feed was mixed with water, 1/2.5 (w/w). Faeces and urine of each pig were accumulated together in a separate manure pit under the slatted floor. After an adaptation period of 2 weeks, the manure pits were cleaned and manure was collected. In the 5th week of the collection period, air samples for odour and ammonia analyses, and manure samples were collected directly from each manure pit. Air samples were analysed for odour concentration and for hedonic value and intensity above odour detection threshold. Manure samples were analysed for volatile fatty acids, and indolic, phenolic and sulphurous compounds, ammonium and total nitrogen concentrations. Reducing dietary CP from 18% to 12% lowered odour emission ( P < 0.05) and ammonia emission ( P = 0.01) from pig manure by 80% and 53%, respectively. Reduced dietary CP decreased total nitrogen, methyl sulphide, carbon disulphide, ethanethiol, phenol, 4-ethyl phenol, indole and 3-methyl indole concentrations in the manure ( P < 0.05). Volatile fatty acids and cresols concentrations in the manure of pigs fed different dietary CP levels were similar. A reduction of dietary CP and at the same time providing essential AA is an option to reduce odour emission as well as ammonia emission from pig manure. PMID- 22444474 TI - Length of productive life of crossbred sows is affected by farm management, leg conformation, sow's own prolificacy, sow's origin parity and genetics. AB - The purpose of the current study was to determine if the parity of the litter in which a female was born and the number of pigs within that same litter are associated with future length of productive life (LPL). An additional objective of the study was to examine the associations of leg conformation (evaluated at approx. 100 kg of live weight), age at first farrowing, litter size at first farrowing, and age and backfat thickness at 100 kg on LPL in the Finnish crossbred (Landrace * Large White or Large White * Landrace) population. The data analysed contained information on 11 761 sows, and proportional hazard model (Weibull) was fitted on the data using the Survival Kit. Log likelihood tests were utilised to determine if the individual effects have a significant impact on LPL. Farm conditions and management were identified as major factors impacting on LPL ( P < 0.001). Other factors significantly ( P < 0.001) associated with LPL were leg soundness score, age at first farrowing, and litter size at first farrowing. The better the leg score, the younger age at first farrowing, and the larger litter at first farrowing, the longer sows tended to remain in the herd from the present. Although sows born in litters first, second, and sixth parities had slightly greater risk of being culled when compared with sows born in litters from the other parities, the effect was not statistically significant. Sufficient genetic variation exists in the population evaluated in this study for LPL (h2 = 0.25), such that it will be possible to improve LPL through traditional selection methods in an efficient breeding programme. Thus, there are many factors which impact on LPL, and possibilities to improve all of them should be considered in order to improve the economics and animal welfare of modern pork production operations. PMID- 22444475 TI - The effect of cereal type and enzyme addition on pig performance, intestinal microflora, and ammonia and odour emissions. AB - Two 2 * 2 factorial experiments were conducted to investigate the interaction between cereal type (wheat v. barley) and exogenous enzyme supplementation (with or without) on odour and ammonia emissions (experiment 1) and growth performance (experiment 2) in grower-finisher pigs. The enzyme supplement used contained endo 1, 3 (4) - beta- glucanase (EC 3.2.1.6) and endo-1, 4 - beta-xylanase (E.C 3.2.1.8). The diets were formulated to contain similar levels of net energy (9.8 MJ/kg) and lysine (10.0 g/kg). The experimental treatments were as follows: (1) wheat-based diet, (2) wheat-based diet containing a beta-glucanase and beta xylanase mixed enzyme supplement, (3) barley-based diet and (4) barley-based diet containing a beta-glucanase and beta-xylanase mixed enzyme supplement. In experiment 1, the diets were offered to the pigs for 23 days in sealed pens (eight pigs per pen) and this was repeated four times (n = 4). Odour and ammonia emissions were measured on days 9, 11, 14, 16, 21 and 23 of each replicate period. Odour samples were collected in 20-l Nalophan bags and analysed for odour concentration using an ECOMA Yes/No Olfactometer. Ammonia concentrations in the ventilation air were measured using Drager tubes. In experiment 2, 220 pigs were group fed in mixed sex pens using single-space feeders (11 pigs per feeder, six boars and five gilts) (n = 5). There was a cereal * enzyme interaction in odour emission rates, ammonia emissions and selected microbial populations in the caecum and colon (P < 0.05). The addition of an enzyme supplement to the barley based diet increased both odour and ammonia emission, however the addition of an enzyme to the wheat-based diet decreased ammonia emission rates and had no effect on odour emission. Pigs offered the unsupplemented barley-based diet had a significantly (P < 0.05) lower population of Enterobacteriaceae spp. and a higher population of Bifidobacteria spp. compared with enzyme-supplemented barley diets. However, there was no effect of enzyme supplementation in wheat-based diets. In the performance experiment, neither cereal type nor enzyme inclusion had an effect on pig performance or carcass characteristics. In conclusion, the inclusion of an enzyme mix to barley-based diets increased odour and ammonia emissions, while the addition of an enzyme mix to wheat-based diets decreased ammonia emissions. PMID- 22444476 TI - Evaluation of the factors affecting silage intake of dairy cows: a revision of the relative silage dry-matter intake index. AB - An evaluation of the factors affecting silage dry-matter intake (SDMI) of dairy cows was conducted based on dietary treatment means. The data were divided into six subsets based on the silage treatments used in the experiments: concentration of digestible organic matter in dry matter (D-value) influenced by the maturity of grass ensiled (n = 81), fermentation quality influenced by silage additives (n = 240), dry matter (DM) concentration influenced by wilting of grass prior to ensiling (W; n = 85), comparison of silages made from primary growth or regrowth of grass (n = 46), and replacement of grass silage with legume (L; n = 53) or fermented whole-crop cereal (WC; n = 37) silages. The data were subjected to the mixed model regression analysis. Both silage D-value and fermentation quality significantly affected SDMI. The average effects of D-value and total acid (TA) concentration were 17.0 g and - 12.8 per 1 g/kg DM, respectively. At a given D value, silage neutral-detergent fibre (NDF) concentration tended to decrease SDMI. Silage TA concentration was the best fermentation parameter predicting SDMI. Adding other parameters into the multivariate models did not improve the fit and the slopes of the other parameters remained insignificant. Total NDF intake was curvilinearly related to silage D-value the maximum intake being reached at a D-value of 640 g/kg DM. Results imply that physical fill is not limiting SDMI of highly digestible grass silages and that both physical and metabolic factors constrain total DM intake in an interactive manner. Silage DM concentration had an independent curvilinear effect on SDMI. Replacing primary growth silage with regrowth, L or WC silages affected SDMI significantly, the response to regrowth silage being linearly decreasing and to L and WC quadratically increasing. The outcome of factors affecting SDMI was used to update the relative SDMI index as follows: SDMI index = 100+10 * [(D-value - 680) * 0.0170 - (TA - 80) * 0.0128+(0.0198 * (DM - 250) - 0.00002364 * (DM2 - 250 2)) - 0.44 * a+4.13 * b - 2.58 * b2+5.90 * c - 6.14 * c2 - 0.0023 * (550 - NDF)], where a, b and c represent the proportions (0-1) of regrowth, L or WC silages from total silage DM. For the whole data set, one index unit corresponded to the default value of 0.10 kg in SDMI. The SDMI index explained proportionally 0.852 of the variation in SDMI with 0.34 kg DM per day residual. The updated SDMI index provides improved basis for the practical dairy cow ration formulation and economic evaluation. PMID- 22444477 TI - Effect of breed, gender, housing system and dietary crude protein content on performance of finishing beef cattle fed maize-silage-based diets. AB - Maize silage-based diets with three dietary crude protein (CP) supplements were offered to 96 finishing cattle of contrasting breed (Holstein Friesian (HF) v. Simmental * HF (SHF)) and gender (bull v. steer) housed in two types of feeding system (group fed v. individually fed). The three protein supplements differed either in CP or protein degradability (degradable (LUDP) v. rumen undegradable (HUDP)) and provided CP concentrations of 142 (Con), 175 (LUDP) and 179 (HUDP) g/kg dry matter (DM) respectively, with ratios of degradable to undegradable of 3.0, 1.4 and 0.9:1 for diets Con, LUDP and HUDP, respectively. DM intakes were marginally higher (P = 0.102) for LUDP when compared with Con and HUDP. Rates of daily live-weight gain (DLWG) were higher (P = 0.005) in LUDP and HUDP when compared with Con. HF had higher DM intakes than SHF although this did not result in any improvement in HF DLWG. Bulls had significantly better DM intakes, DLWG and feed conversion efficiency than steers. Conformation scores were better in SHF than HF (P < 0.001) and fat scores lower in bulls than steers (P < 0.001). There was a number of first order interactions established between dietary treatment, breed, gender and housing system with respect to rates of gain and carcass fat scores. PMID- 22444478 TI - Effects of carcass maturity on meat quality characteristics of beef semitendinosus muscle for chinese native yellow steers. AB - This work was designed to study the effects of carcass maturity on meat quality characteristics and intramuscular connective tissue of beef semitendinosus muscle from Chinese native Yellow steers. Chemical determinations, histological and mechanical measurements were performed on the raw and cooked meat at 4 days post mortem. In raw meat, intramuscular fat, collagen solubility, mechanical strength and transition temperature of intramuscular connective tissue increased (P < 0.05) with carcass maturity before body maturation, whilst moisture, total collagen, fibre diameter decreased after body maturation. Warner-Bratzlar shear force (WBSF) of cooked meat increased with maturity before body maturation due to the muscle atrophy, and thus the decline of moisture content and the increase of cooking losses. After body maturation, the increase of WBSF was neutralised by the increase of intramuscular fat, the decrease of total collagen and the elongation of sarcomere length. PMID- 22444479 TI - Intensity of parasitic mite infection decreases with hibernation duration of the host snail. AB - Temperature can be a limiting factor on parasite development. Riccardoella limacum, a haematophagous mite, lives in the mantle cavity of helicid land snails. The prevalence of infection by R. limacum in populations of the land snail Arianta arbustorum is highly variable (0-78%) in Switzerland. However, parasitic mites do not occur in host populations at altitudes of 1290 m or higher. It has been hypothesized that the host's hibernation period might be too long at high elevations for mites and their eggs to survive. To test this hypothesis, we experimentally infected snails and allowed them to hibernate at 4 degrees C for periods of 4-7 months. Winter survival of host snails was negatively affected by R. limacum. The intensity of mite infection decreased with increasing hibernation duration. Another experiment with shorter recording intervals revealed that mites do not leave the host when it buries in the soil at the beginning of hibernation. The number of mites decreased after 24 days of hibernation, whereas the number of eggs attached to the lung tissue remained constant throughout hibernation. Thus, R. limacum survives the winter in the egg stage in the host. Low temperature at high altitudes may limit the occurrence of R. limacum. PMID- 22444480 TI - Concentration of selected radionuclides in seawater from Kuwait. AB - No baseline existed for the radionuclides in Kuwait territorial water. With changing trend in the region to embrace nuclear energy, the baseline study is imperative to create a reference and to record the influence-functioning of upcoming power plants. The first one in Bushehr, Iran is ready to start and several more are likely to come-up in UAE, Saudi Arabia and Kuwait. The present baseline concentration of the four considered radionuclide's show low concentration of tritium, polonium, strontium and cesium; their concentration is comparable to most oceanic waters. PMID- 22444481 TI - Patterns of breaks in umbilical cords by different mechanisms. AB - Investigations of perinatal deaths often result in discrepancies between autopsy findings and witness accounts. The mechanism by which the umbilical cord is severed after delivery is a common quandary. Confirming or refuting the mother's stated method frequently has significant investigative importance; however, a surprising paucity of data currently exists to allow an objective opinion about the likely mechanism. Ninety-nine placentas with umbilical cords were examined. By random selection, each cord was severed by one of the following tools or mechanisms: knives, scissors, traction, or crush. Each break was examined and photographed, and a tissue section from the broken end examined microscopically. Differentiation of mechanism was best done grossly based on specific pattern recognition. Umbilical cords severed by blunt force have distinctly different morphology from those severed by sharp force. Even similar-appearing sharp force transections frequently have mechanism-specific distinctive patterns of injury. PMID- 22444482 TI - Size control of giant unilamellar vesicles prepared from inverted emulsion droplets. AB - The production of giant lipid vesicles with controlled size and structure will be an important technology in the design of quantitative biological assays in cell mimetic microcompartments. For establishing size control of giant vesicles, we investigated the vesicle formation process, in which inverted emulsion droplets are transformed into giant unilamellar vesicles (GUVs) when they pass through an oil/water interface. The relationship between the size of the template emulsion and the converted GUVs was studied using inverted emulsion droplets with a narrow size distribution, which were prepared by microfluidics. We successfully found an appropriate centrifugal acceleration condition to obtain GUVs that had a desired size and narrow-enough size distribution with an improved yield so that emulsion droplets can become the template for GUVs. PMID- 22444483 TI - Magnetic Fe3O4@mesoporous silica composites for drug delivery and bioadsorption. AB - Magnetic Fe(3)O(4)@mesoporous silica (MS) composites were synthesized by generating Fe(3)O(4) nanoparticles in the mesoporous silica matrix using the sol gel method in nitrogen atmosphere. The mesoporous silica hosts include SBA-15 particles owning highly ordered p6mm mesostructure, siliceous mesostructured cellular foams (MCFs), and fiber-like mesoporous silica (FMS) with unique pore structures. The X-ray diffraction (XRD), transmission electron microscopy (TEM), and N(2) adsorption/desorption results show that Fe(3)O(4) functionalized MCFs and FMS possess suitable mesoporous structure for the adsorption of both small molecular drug and large biomolecules. The biocompatibility tests on L929 fibroblast cells using MTT assay reveal low cytotoxicity of these systems. These Fe(3)O(4)@mesoporous silica composites show sustained release properties for aspirin in vitro. The release of the aspirin molecules from the pores of the Fe(3)O(4)@mesoporous silica composites is basically a diffusive process. Fe(3)O(4)@MCFs and Fe(3)O(4)@FMS owning larger pore size are good candidates for the adsorption of bovine serum albumin (BSA). These magnetic composites can be potential vectors for drug delivery and bioadsorption. PMID- 22444484 TI - Controlled synthesis of NaYF4 nanoparticles and upconversion properties of NaYF4:Yb, Er (Tm)/FC transparent nanocomposite thin films. AB - Monodisperse oleic acid stabilized pure NaYF(4) nanoparticles with controlled size and shape have been successfully synthesized by changing the initial reaction temperature. Transparent nanocomposite thin films consisting of NaYF(4):Yb, Er (Tm) upconverting nanoparticles (UCNPs) and fluorocarbon resin (FC) are deposited on the slide glass by dip-coating method. The results show that these nanocomposite thin films exhibit intense green and blue upconversion photoluminescence under 980 nm laser excitation and higher transparency than blank substrate. The NaYF(4):Yb,Er (Tm) nanoparticles and NaYF(4):Yb,Er (Tm)/FC nanocomposite thin films have been characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), scanning electron microscopy (SEM), SEM/back-scattered electron (BSE), atomic force microscopy (AFM), UV-Vis spectrophotometer (UVPC), and photoluminescence (PL) spectra. These nanocomposite thin films can be potentially used in solar cells field. PMID- 22444485 TI - Solubilization of two organic dyes by cationic ester-containing gemini surfactants. AB - Solubilization of two different types of organic dyes, Quinizarin with an anthraquinone structure and Sudan I with an azo structure, has been studied in aqueous solutions of a series of cationic gemini surfactants and of a conventional monomeric cationic surfactant, dodecyltrimethylammonium bromide (DTAB). Surfactant concentrations both above and below the critical micelle concentration were used. The concentration of solubilized dye at equilibrium was determined from the absorbance of the solution at lambda(max) with the aid of a calibration curve. The solubilization power of the gemini surfactants was higher than that of DTAB and increased with increasing alkyl chain length. An increase in length of the spacer unit resulted in increased solubilization power while a hydroxyl group in the spacer did not have much effect. Ester bonds in the alkyl chains reduced the solubilization power with respect to both dyes. A comparison between the absorbance spectra of the dyes in micellar solution with spectra in a range of solvents of different polarity indicated that the dye is situated in a relatively polar environment. One may therefore assume that the dye is located just below the head group region of the micelle. Attractive pi-cation interactions may play a role for orienting the dye to the outer region of the micelle. PMID- 22444486 TI - Dietary lipids during early pregnancy differently influence adipose tissue metabolism and fatty acid composition in pregnant rats with repercussions on pup's development. AB - Pregnant rats received soybean (SO), olive (OO), fish (FO) and linseed (LO) oil diets from conception to d12 of gestation (early diets) and standard diet thereafter. At d12 and d20 the lipoprotein lipase (LPL) activity was evaluated in maternal adipose tissues (ATs). Fatty Acid (FA) profile was determined in maternal lumbar AT (LAT), in milk and in pup's plasma and brain. LPL activity was higher in ATs at d12 than d20, all groups presenting hypertriglyceridemia at d20. At d12, the LO diet resulted higher LPL activity and incorporation of 18:3 n-3 into LAT. FA profile in maternal LAT at d20 and colostrum was similar to early diets, reflected also in FA composition of pup's plasma. In FO, brain phospholipids had higher 22:6 n-3 without affecting arachidonic acid. These results suggest that specifics dietary FA in early pregnancy modulates lipid metabolism and the provision of LC-PUFA in milk and pups brain. PMID- 22444487 TI - [Severe hypomagnesemia refractory to oral supplementation associated to omeprazole treatment]. PMID- 22444488 TI - The structural chemistry of metallocorroles: combined X-ray crystallography and quantum chemistry studies afford unique insights. AB - Although they share some superficial structural similarities with porphyrins, corroles, trianionic ligands with contracted cores, give rise to fundamentally different transition metal complexes in comparison with the dianionic porphyrins. Many metallocorroles are formally high-valent, although a good fraction of them are also noninnocent, with significant corrole radical character. These electronic-structural characteristics result in a variety of fascinating spectroscopic behavior, including highly characteristic, paramagnetically shifted NMR spectra and textbook cases of charge-transfer spectra. Although our early research on corroles focused on spectroscopy, we soon learned that the geometric structures of metallocorroles provide a fascinating window into their electronic structural characteristics. Thus, we used X-ray structure determinations and quantum chemical studies, chiefly using DFT, to obtain a comprehensive understanding of metallocorrole geometric and electronic structures. This Account describes our studies of the structural chemistry of metallocorroles. At first blush, the planar or mildly domed structure of metallocorroles might appear somewhat uninteresting particularly when compared to metalloporphyrins. Metalloporphyrins, especially sterically hindered ones, are routinely ruffled or saddled, but the missing meso carbon apparently makes the corrole skeleton much more resistant to nonplanar distortions. Ruffling, where the pyrrole rings are alternately twisted about the M-N bonds, is energetically impossible for metallocorroles. Saddling is also uncommon; thus, a number of sterically hindered, fully substituted metallocorroles exhibit almost perfectly planar macrocycle cores. Against this backdrop, copper corroles stand out as an important exception. As a result of an energetically favorable Cu(d(x2-y2)) corrole(pi) orbital interaction, copper corroles, even sterically unhindered ones, are inherently saddled. Sterically hindered substituents accentuate this effect, sometimes dramatically. Thus, a crystal structure of a copper beta octakis(trifluoromethyl)-meso-triarylcorrole complex exhibits nearly orthogonal, adjacent pyrrole rings. Intriguingly, the formally isoelectronic silver and gold corroles are much less saddled than their copper congeners because the high orbital energy of the valence d(x2-y2) orbital discourages overlap with the corrole pi orbital. A crystal structure of a gold beta-octakis(trifluoromethyl) meso-triarylcorrole complex exhibits a perfectly planar corrole core, which translates to a difference of 85 degrees in the saddling dihedral angles between analogous copper and gold complexes. Gratifyingly, electrochemical, spectroscopic, and quantum chemical studies provide a coherent, theoretical underpinning for these fascinating structural phenomena. With the development of facile one-pot syntheses of corrole macrocycles in the last 10-15 years, corroles are now almost as readily accessible as porphyrins. Like porphyrins, corroles are promising building blocks for supramolecular constructs such as liquid crystals and metal-organic frameworks. However, because of their symmetry properties, corrole-based supramolecular constructs will probably differ substantially from porphyrin-based ones. We are particularly interested in exploiting the inherently saddled, chiral architectures of copper corroles to create novel oriented materials such as chiral liquid crystals. We trust that the fundamental structural principles uncovered in this Account will prove useful as we explore these fascinating avenues. PMID- 22444489 TI - On being better kidney doctors: understanding trajectories, probabilities, predictability, and people. PMID- 22444490 TI - Do children with acute kidney injury require long-term evaluation for CKD? PMID- 22444491 TI - CKD in Central America: a hot issue. PMID- 22444492 TI - Acute kidney injury and CKD: chicken or egg? PMID- 22444494 TI - Secondary capillary leak syndrome related to pemetrexed exposure. PMID- 22444496 TI - Changing terminology in renal research: the impact of consensus. PMID- 22444497 TI - A case of kidney failure and glycosuria. PMID- 22444498 TI - Modulation of immune cell proliferation and chemotaxis towards CC chemokine ligand (CCL)-21 and CXC chemokine ligand (CXCL)-12 in undenatured whey protein treated mice. AB - Whey protein concentrates (WPCs) enhance innate mucosal immunity during early life and have a protective role in some immune disorders. To further elucidate the potential benefits of this protein, the present study investigated the effect of dietary supplementation with WPCs on blood parameters, plasma cytokine profiles, and immune cell proliferation and chemotaxis. A total of 45 male mice were equally distributed into three experimental groups and treated daily for 21 days as follows: group I was a control group that was orally supplemented with distilled water, group II was orally supplemented with undenatured WP (100 mg/kg body weight), and group III was orally supplemented with bovine serum albumin (100 mg/kg body weight). We found that the plasma cytokine levels of interleukin (IL)-1alpha, IL-1beta, IL-10 and tumor necrosis factor-alpha and the levels of reactive oxygen species, cholesterol, triglycerides and the lipid profile were significantly decreased in the WP-treated group compared to the control group. In contrast, the levels of IL-2, IL-4, IL-7, IL-8 and glutathione were significantly elevated, and consequently, the ability of peripheral blood mononuclear cells to proliferate in response to stimulation with different antigens was significantly increased in the WP-treated group. Moreover, the in vitro chemotaxis of B, T and bone-marrow-derived dendritic cells toward CC chemokine ligand-21 and CXC chemokine ligand-12 was significantly increased, by twofold, in WP-treated mice compared to the control group. Taken together, our data reveal the benefits of WP supplementation in enhancing immune cell proliferation and migration to the secondary lymphoid organs. PMID- 22444499 TI - Procyanidins modify insulinemia by affecting insulin production and degradation. AB - Previous studies from our research group have suggested that procyanidins modify glycemia and insulinemia. The aim of this work was to evaluate the effects of procyanidins on beta-cell functionality in a nonpathological system. Four groups of healthy rats were studied. The animals were given daily acute doses of grape seed procyanidin extract (GSPE) for different time periods and at different daily amounts. A beta-cell line (INS-1E) was treated with 25 mg GSPE/L for 24 h to identify possible mechanisms of action for the procyanidins. In vivo experiments showed that different doses of GSPE affected insulinemia in different ways by modifying beta-cell functionality and/or insulin degradation. The islets isolated from rats that were treated with 25 mg GSPE/kg of body weight for 45 days exhibited a limited response to glucose stimulation. In addition, insulin gene expression, insulin synthesis and expression of genes related to insulin secretion were all down-regulated. In vitro studies revealed that GSPE decreased the ability of beta-cells to secrete insulin in response to glucose. GSPE increased glucose uptake in beta-cells under high-glucose conditions but impaired glucose-induced mitochondrial hyperpolarization, decreased adenosine triphosphate (ATP) synthesis and altered cellular membrane potentials. GSPE also modified Glut2, glucokinase and Ucp2 gene expression as well as altered the expression of hepatic insulin-degrading enzyme (Ide), thereby altering insulin degradation. At some doses, procyanidins changed beta-cell functionality by modifying insulin synthesis, secretion and degradation under nonpathological conditions. Membrane potentials and Ide provide putative targets for procyanidins to induce these effects. PMID- 22444500 TI - Docosahexaenoic acid suppresses the expression of FoxO and its target genes. AB - Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has previously been shown to ameliorate obesity-associated metabolic syndrome. To decipher the mechanism responsible for the beneficial effects of DHA on energy/glucose homeostasis and the metabolic syndrome, 30 weaned cross-bred pigs were randomly assigned to three groups and fed ad libitum with a standard diet supplemented with 2% of beef tallow, soybean oil or DHA oil for 30 days, and the gene expression profile of various tissues was evaluated by quantitative real-time polymerase chain reaction. The DHA-supplemented diets reduced the expression of forkhead box O transcription factor (FoxO) 1 and FoxO3 in the liver and adipose tissue. DHA treatments also decreased the expression of FoxO1 and FoxO3 in human hepatoma cells, SK-HEP-1 and human and porcine primary adipocytes. In addition, DHA also down-regulated FoxO target genes, such as microsomal triacylglycerol transfer protein (MTP), glucose-6-phosphatase, apolipoprotein C-III (apoC-III) and insulin-like growth factor binding-protein 1 in the liver, as well as reduced total plasma levels of cholesterol and triacylglycerol in the pig. Transcriptional suppression of FoxO1, FoxO3, apoC-III and MTP by DHA was further confirmed by reporter assays with each promoter construct. Taken together, our study indicates that DHA modulates lipid and glucose homeostasis in part by down regulating FoxO function. The down-regulation of genes associated with triacylglycerol metabolism and very low density lipoprotein assembly is likely to contribute to the beneficial effects of DHA on the metabolic syndrome. PMID- 22444501 TI - Maternal low-protein diet causes epigenetic deregulation of HMGCR and CYP7alpha1 in the liver of weaning piglets. AB - To investigate the effect of maternal dietary protein on hepatic cholesterol metabolism in offspring pigs and to detect underlying epigenetic mechanisms, 14 primiparous purebred Meishan sows were fed standard-protein (SP, n=7) or low protein (LP, 50% of SP, n=7) diets during pregnancy and lactation, respectively. LP piglets showed significantly lower body weight and liver weight at weaning, associated with decreased liver and serum cholesterol content. Hepatic SREBP2, HMGCR and CYP7alpha1 mRNA expressions were all up-regulated in LP piglets, as well as SREBP2 protein content and HMGCR enzyme activity, compared to SP piglets, while the mRNA expression of LDLR, FXR, LXR and CYP27alpha1 was not altered. Hepatic activation of HMGCR gene transcription in LP piglets was associated with promoter hypomethylation, together with decreased histone H3, H3 lysine 9 monomethylation (H3K9me1) and H3 lysine 27 trimethylation (H3K27me3) and increased H3 acetylation. No CpG islands were predicted in the CYP7alpha1 promoter, and the augmented CYP7alpha1 transcription in LP piglets was associated with decreased H3, H3K9me1 and H3K27me3. No alterations were detected for hepatic expression of microRNAs predicted to target 3'-UTR of HMGCR or CYP7alpha1 gene. These results indicate that maternal low-protein diet during gestation and lactation affects hepatic cholesterol metabolism in weaning piglets by modifying the epigenetic regulation of HMGCR and CYP7alpha1 genes, which implicates possible long-term consequences in cholesterol homeostasis later in adult life. PMID- 22444502 TI - Influence of long-term caloric restriction on myocardial and cardiomyocyte contractile function and autophagy in mice. AB - Both clinical and experimental evidence has revealed that calorie restriction (CR) is capable of improving heart function. However, most the reports are focused on the effect of CR on the pathological states such as obesity, while the effect of CR on heart function in otherwise healthy subjects is not well understood. This study examined the long-term CR effect on cardiac contractile function and possible underlying mechanisms involved. C57BL/6 mice were subjected to a 40% CR or ad libitum feeding for 20 weeks. Echocardiographic and cardiomyocyte contractile properties were evaluated. Intracellular signaling pathways were examined using Western blot analysis. Our results showed that CR overtly lessened glucose intolerance, lessened body and heart weights (although not heart size), lowered fat tissue density, decreased left ventricular (LV) wall thickness (septum and posterior wall) in both systole and diastole, and reduced LV mass (not normalized LV mass) without affecting fractional shortening. Cardiomyocyte cell length and cross-sectional area were reduced, while peak shortening amplitude was increased following CR. CR failed to affect maximal velocity of shortening/relengthening and duration of shortening and relengthening. Immunoblotting data depicted decreased and increased phosphorylation of Akt/glycogen synthase kinase-3beta and AMP-dependent protein kinase/acetyl-CoA carboxylase, respectively, following CR. CR also dampened the phosphorylation of mammalian target of rapamycin, extracellular-signal-regulated protein kinase 1/2 and c-Jun, while it increased the phosphorylation of c-Jun NH2 terminal kinase. Last but not least, CR significantly promoted cardiac autophagy as evidenced by increased expression of LC3B-II (and LC3B-II to LC3B-I ratio) and Beclin-1. In summary, our data suggested that long-term CR may preserve cardiac contractile function with improved cardiomyocyte function, lessen cardiac remodeling and promote autophagy. PMID- 22444503 TI - A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay. AB - BACKGROUND: Peanut allergy is relatively common, typically permanent, and often severe. Double-blind, placebo-controlled food challenge is considered the gold standard for the diagnosis of food allergy-related disorders. However, the complexity and potential of double-blind, placebo-controlled food challenge to cause life-threatening allergic reactions affects its clinical application. A laboratory test that could accurately diagnose symptomatic peanut allergy would greatly facilitate clinical practice. OBJECTIVE: We sought to develop an allergy diagnostic method that could correctly predict symptomatic peanut allergy by using peptide microarray immunoassays and bioinformatic methods. METHODS: Microarray immunoassays were performed by using the sera from 62 patients (31 with symptomatic peanut allergy and 31 who had outgrown their peanut allergy or were sensitized but were clinically tolerant to peanut). Specific IgE and IgG(4) binding to 419 overlapping peptides (15 mers, 3 offset) covering the amino acid sequences of Ara h 1, Ara h 2, and Ara h 3 were measured by using a peptide microarray immunoassay. Bioinformatic methods were applied for data analysis. RESULTS: Individuals with peanut allergy showed significantly greater IgE binding and broader epitope diversity than did peanut-tolerant individuals. No significant difference in IgG(4) binding was found between groups. By using machine learning methods, 4 peptide biomarkers were identified and prediction models that can predict the outcome of double-blind, placebo-controlled food challenges with high accuracy were developed by using a combination of the biomarkers. CONCLUSIONS: In this study, we developed a novel diagnostic approach that can predict peanut allergy with high accuracy by combining the results of a peptide microarray immunoassay and bioinformatic methods. Further studies are needed to validate the efficacy of this assay in clinical practice. PMID- 22444504 TI - Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001-2010. AB - All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and September 31, 2010 in which zolpidem was detected, were retrieved. A total of 91 cases were identified. The mean age was 49.4 years, 65.9% were male, and 61.5% were suicides. Zolpidem was a factor contributing to death in 35 (37.3%) cases, of which 31 (34.1%) involved zolpidem toxicity. The median blood zolpidem concentration was 0.20 mg/L (range 0.05-3.50 mg/L), with no significant gender difference. Drug toxicity cases involving zolpidem had significantly higher median blood zolpidem concentrations than other cases (0.50 vs. 0.10 mg/L). In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide. PMID- 22444505 TI - Analysis of results, quality indicators, and postsurgical complications in an outpatient dermatological surgery program. AB - OBJECTIVE: To evaluate the results of an outpatient program for major dermatological surgery in patients with a range of skin conditions. METHODS: We undertook a retrospective, observational study of patients who underwent scheduled dermatological surgery as outpatients in a public hospital between 2004 and 2007. The most common procedures were excision of basal cell or squamous cell carcinoma with or without graft reconstruction. The rates of substitution (of inpatient procedures), cancellation, hospital admission, and readmission were analyzed along with service utilization and systemic complications arising within the first 72 h of surgery. Variables were analyzed as relative frequencies. The occurrence of complications during the study period was analyzed by chi square test. RESULTS: A total of 2789 patients underwent surgery during the study period, and of those, 2757 procedures were performed on an outpatient basis (overall substitution rate, 17.99%). The service utilization was 74.36%. Fourteen patients were admitted to hospital following surgery (2.62%), and of those 12 were admitted immediately (85.71%). Nine patients had serious complications (cardiovascular, neurological, metabolic, or infectious), representing a proportional risk of 1:59. Less serious complications (hypertension, nausea, vomiting, and vasovagal syncope) requiring hospital admission occurred in 25 patients. CONCLUSIONS: Major surgery undertaken on an outpatient basis is an excellent multidisciplinary surgical care model that allows well-selected patients to be treated effectively, safely, and efficiently. A small percentage of postoperative complications of varying severity can still occur despite patients' meeting optimal criteria for success. Fortunately, however, the rate of mortality is practically zero. PMID- 22444506 TI - Atypical calciphylaxis secondary to treatment with acenocoumarol. PMID- 22444507 TI - Intense pulsed light therapy for lupus pernio. PMID- 22444508 TI - Telangiectatic macules in a 90-year-old woman. PMID- 22444509 TI - Rapidly growing ulcer in a patient with neurofibromatosis type I. PMID- 22444510 TI - Determinants of asthma after severe respiratory syncytial virus bronchiolitis. AB - BACKGROUND: The development of asthma after respiratory syncytial virus (RSV) bronchiolitis has been demonstrated in case-control studies, although the determinants of post-RSV asthma remain undefined. OBJECTIVES: We sought to evaluate the potential determinants of physician-diagnosed asthma after severe RSV bronchiolitis during infancy. METHODS: We enrolled 206 children during an initial episode of severe RSV bronchiolitis at 12 months of age or less in a prospective cohort study and followed these children for up to 6 years. In a subset of 81 children, we analyzed CCL5 (RANTES) mRNA expression in upper airway epithelial cells. RESULTS: Forty-eight percent of children had physician diagnosed asthma before the seventh birthday. Independent determinants significantly associated with increased risk for physician-diagnosed asthma by the seventh birthday included maternal asthma (odds ratio [OR], 5.2; 95% CI, 1.7 15.9; P = .004), exposure to high levels of dog allergen (OR, 3.2; 95% CI, 1.3 7.7; P = .012), aeroallergen sensitivity at age 3 years (OR, 10.7; 95% CI, 2.1 55.0; P = .005), recurrent wheezing during the first 3 years of life (OR, 7.3; 95% CI, 1.2-43.3; P = .028), and CCL5 expression in nasal epithelia during acute RSV infection (OR, 3.8; 95% CI, 1.2-2.4; P < .001). White children (OR, 0.19; 95% CI, 0.04-0.93; P = .041) and children attending day care (OR, 0.18; 95% CI, 0.04 0.84; P = .029) had a decreased risk of physician-diagnosed asthma. CONCLUSIONS: Approximately 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis. The presence of increased CCL5 levels in nasal epithelia at the time of bronchiolitis or the development of allergic sensitization by age 3 years are associated with increased likelihood of subsequent asthma. PMID- 22444511 TI - Influence of cytomegalovirus infection on immune cell phenotypes in patients with common variable immunodeficiency. AB - BACKGROUND: A subset of patients with common variable immunodeficiency (CVID) have debilitating inflammatory complications strongly associated with cytomegalovirus (CMV) infection and a hyperproliferative CMV-specific T-cell response. OBJECTIVES: We studied the T-cell response to CMV and the global effect of this virus on immune effector cell populations in patients with CVID. METHODS: Antibody staining, peptide stimulation, and proliferation assays were used to profile CMV-specific T-cell function. RESULTS: CMV infection drives the CD4/CD8 ratio inversion that is characteristic of CVID. The late effector CD8(+) T-cell subset is expanded in CMV-infected patients with CVID. This expansion is largely attributable to CMV-specific cells and correlates with inflammatory disease; within the CMV-specific population, the frequency of late effector cells correlates inversely with the frequency of cells expressing programmed death 1. Supernatants from proliferating CMV-specific CD8(+) cells from patients with inflammatory disease can confer proliferative potential on cells from patients with noninflammatory CVID and healthy subjects. Blocking experiments showed that this proliferation is mediated in part by IFN-gamma and TNF-alpha. CONCLUSIONS: These data strengthen the association of CMV with inflammatory pathology in patients with CVID, explain some of the well-known T-cell abnormalities associated with this condition, and provide a plausible mechanism for the documented therapeutic activity of anti-TNF-alpha and antiviral chemotherapy in managing CVID-associated inflammatory disease. PMID- 22444512 TI - Highly stable electrochemical immunosensor for carcinoembryonic antigen. AB - The long-term stability of sensing interfaces is an important issue in biosensor fabrication. A novel stable gold nanoparticle (AuNP)-modified glassy carbon (GC) electrode interface (GC-Ph-AuNP)-based biosensor for detecting carcinoembryonic antigen (CEA) was developed. GC electrodes were modified with 1,4 phenylenediamine to form a stable layer, and then AuNPs were bound onto the GC electrodes through CAu bonds. Anti-CEA was directly adsorbed on AuNPs fixed on the GC electrode. The linear range of the immunosensor was from 10 fg to 100 ng mL(-1) with a detection limit of 3 fg mL(-1) (S/N=3). The current of the immunosensor was increased by 4% after one month. The GC-Ph-AuNP immunosensor showed high sensitivity, a wide linear range, low detection limit, and good selectivity and stability. The immobilization method of the immunosensor could be widely applied to construct other immunosensors. PMID- 22444513 TI - Functional protease assay using liquid crystals as a signal reporter. AB - We report a functional protease assay in which liquid crystals (LCs) are used as signal reporters to transduce the test results into optical signals. In this assay, an oligopeptide substrate (CLSELDDRADALQAGASQFESSAAKLKRKYWWKNLK) is used as a probe. This oligopeptide can be cleaved by alpha-chymotrypsin at multiple locations and become smaller fragments after the cleavage. When the original oligopeptide is immobilized on a solid surface, its long flexible oligopeptide chain is able to influence the orientation of a thin layer of LC supported on the surface, as is evident as a bright spot on the surface. In contrast, when the shorter oligopeptide fragments are immobilized on the same surface, their shorter, less flexible chains cannot disrupt the orientation of LC, and a dark spot is observed. On the basis of the dark or bright signal from LC, alpha chymotrypsin in buffer solution or complex media such as chicken broth can be detected by using the naked eye. However, when the incubation time is 3h, the limit of detection (LOD) for alpha-chymotrypsin in buffer solution is 50 ng/mL, whereas that in chicken broth is only 500 ng/mL. Unlike traditional antibody based assays which show little difference between active and inactive alpha chymotrypsin, only active protease can be detected in this assay. This study shows the potential utility of LCs for detecting functional proteases with good specificity and sensitivity. PMID- 22444514 TI - Sensitive immobilization-free electrochemical DNA sensor based on isothermal circular strand displacement polymerization reaction. AB - A highly sensitive electrochemical DNA sensor that requires no probe immobilization has been developed based on a target recycling mechanism utilizing a DNA polymerase with a strand displacement activity. The electrochemical detection is realized by taking advantage of the difference in diffusivity between a free ferrocene-labeled peptide nucleic acid (Fc-PNA) and a Fc-PNA hybridized with a complementary DNA, while the DNA polymerase-assisted target recycling leads to signal generation and amplification. The hybridization of the target DNA opens up a stem-loop template DNA with the Fc-PNA hybridized to its extruded 5' end and allows a DNA primer to anneal and be extended by the DNA polymerase, which results in sequential displacement of the target DNA and the Fc PNA from the template DNA. The displaced target DNA will hybridize with another template DNA, triggering another round of primer extension and strand displacement. The released Fc-PNA, due to its neutral backbone, has much higher diffusivity towards a negatively charged electrode, compared to that when it is hybridized with a negatively charged DNA. Therefore, a significantly enhanced signal of Fc can be observed. The outstanding sensitivity and simplicity make this approach a promising candidate for next-generation electrochemical DNA sensing technologies. PMID- 22444515 TI - Preparation of photolithographically patterned inverse opal hydrogel microstructures and its application to protein patterning. AB - Protein pattern has played an important role in biosensors, bioMEMS, tissue engineering, fundamental studies of cell biology, and basic proteomics research. Here, we developed a straightforward and effective protein patterning technique using macroporous poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogel micropatterns as a three-dimensional (3D) template for protein immobilization. Micropatterns of macroporous hydrogels with inverse opal structures were prepared on poly(ethylene glycol) (PEG)-coated silicon substrates by combining a colloidal crystal templating method with photopatterning. The resultant inverse opal hydrogel (IOH) micropatterns were modified with 3-aminopropyltriethoxysilane using the hydroxyl groups in PHEMA for the covalent immobilization of proteins. Proteins were selectively immobilized only on the hydrogel micropatterns, while the PEG regions served as an effective barrier to protein adsorption. Because of their highly ordered and interconnected 3D macroporous structures and large internal surface areas, protein loading in the IOH micropattern was about six times greater than that on a non-porous hydrogel micropattern, which consequently improved the protein activity. The porosity of the hydrogel micropatterns could be controlled using different sizes of colloidal nanoparticles, and using smaller nanoparticles produced hydrogel micropatterns with higher protein loading capacities and activities. To demonstrate the potential use of IOH micropatterns in biosensor systems, biotin was micropatterned on the hydrogels and the specific binding of streptavidin was successfully assayed using IOH micropatterns with better fluorescence signals and sensitivity than that of the corresponding non porous hydrogel micropatterns. PMID- 22444516 TI - [The putative link between the MMR vaccine and autism and refusal to vaccinate]. AB - The paper of Wakefield et al. in The Lancet, triggered a negative reaction to the MMR vaccine, even though it was just a series of cases and the association between vaccination and autism could well be anecdotal. However, it was found that this association was spurious, not only because of hidden biases but also to alterations of the data and other improper behavior of the two authors that they were expelled from medical council. Finally, the article was removed from the magazine. This episode invites to think about the credibility and trust in the authorities and professionals to the population, as well as the suspicions that may arise when there are potential conflicts of interest among professionals, industry magazines and the population. A special area of interest is on the distorted expectations of health interventions, including vaccination, particularly with regard to both individual and collective prevention. PMID- 22444517 TI - Nitrate and trace elements in municipal and bottled water in Spain. AB - OBJECTIVES: To describe levels of nitrate and trace elements in drinking water from the study areas of a multicase-control study of cancer in Spain (MCC-Spain). METHODS: A total of 227 tap water samples were randomly collected from 67 municipalities in 11 provinces and the nine most frequently consumed bottled water brands were sampled to measure levels of nitrate, arsenic, nickel, chromium, cadmium, lead, selenium and zinc. RESULTS: The median nitrate level was 4.2mg/l (range<1-29.0), with similar levels in rural and urban municipalities (p=0.86). Trace elements were unquantifiable in 94% of tap water samples. Differences between areas were significant for nitrate (p<0.001) and arsenic (p=0.03). Only nitrate was quantifiable in bottled water (range 2.3-15.6mg/l). CONCLUSIONS: Nitrate levels in municipal water differed between regions and were below the regulatory limit in all samples, including bottled water. Trace element levels were low and mainly unquantifiable in tap and bottled water. PMID- 22444518 TI - [Predictors of outcome of a smoking cessation treatment by gender]. AB - OBJECTIVE: To identify factors predictive of the outcome of a smoking cessation program by gender. METHODS: A cross-sectional study of smokers starting treatment in a smoking cessation clinic from 2002 to 2007 was conducted. The variables consisted of data on sociodemographic factors, smoking habits, the social context of smoking and psychiatric comorbidity prior to or during the smoking cessation process. All patients received multicomponent treatment consisting of psychological and pharmacological interventions. Success was defined as self reported continuous abstinence confirmed by cooximetry (CO <=10 ppm). Logistic regression was used to analyze the factors predictive of success. RESULTS: A total of 1302 persons (52.1% men and 47.9% women), with a mean age of 43.4 (10.2) years, were included. The mean number of cigarettes smoked per day was 25.3 (10.4) and the mean Fagerstrom test score was 6.2 (2.2) points. The success rate was 41.3% (538) with no differences by gender. Positive predictors were lower nicotine dependence and having a non-smoking partner in men and older age, smoking fewer cigarettes per day, having fewer smoking friends and not experiencing depression or anxiety during the treatment in women. CONCLUSIONS: Men and women have similar tobacco abstinence outcomes although gender factors play a role in determining abstinence. The gender perspective should be incorporated in smoking prevention and cessation programs. PMID- 22444519 TI - [Factors associated with life satisfaction in a cohort of older people in Santiago, Chile]. AB - OBJECTIVE: To evaluate the association between life satisfaction and socioeconomic status and self-reported health in a cohort of older people in Santiago, Chile, in 2005 and 2006. METHODS: We interviewed 2002 individuals aged 65 to 67.9 years registered in 20 primary care centers in the city of Santiago. Participants were living independently with no cognitive impairment, suspected cancer or terminal diseases. We assessed life satisfaction using an abbreviated adaptation of a life satisfaction scale (scored from 0 to 11), and collected self reported information on income, education, social support, and self-reported health and memory. We used a log-binomial model to analyze the association between life satisfaction scores (fourth quartile compared with the first) and socioeconomic and health variables. RESULTS: There was a significant association (bivariate and multivariate analyses) between life satisfaction and income in men and with social support, self-reported health, memory, and diagnosis of joint problems, diabetes and hypertension in both sexes. CONCLUSION: Social support, income and health status were independently associated with life satisfaction in older people aged 65-67.9 years in Santiago. Further studies are required to assess the temporal direction of the effect and the implications of these findings for public health policies in this population. PMID- 22444520 TI - [Seniors' knowledge of and attitudes to advance directive documents]. AB - OBJECTIVES: The aim of this study was to determine seniors' knowledge of and attitudes toward advance directive documents. METHODS: We carried out a cross sectional descriptive study in a primary care setting in the provinces of Albacete and Guadalajara, Spain (n = 464). RESULTS: A total of 86.2% (95% CI: 83.0-89.5) of the participants were unaware of advance directive documents and only 3.4% (95% CI: 1.7-5.3) had formalized one. These documents were positively viewed by 76.7% of the participants (95% CI: 72.8-80.7). The variables associated with positive attitudes toward advance directives in logistic regression were educational level (OR = 4.7; 95% CI: 2.6-8.4) and experience of a situation in which such a document would have helped (OR = 1.7; 95% CI: 1.1-3.4). CONCLUSIONS: Seniors had positive attitudes toward advance directives, but the proportion of persons aware of these documents was low. PMID- 22444521 TI - Spontaneous hemoperitoneum secondary to a ruptured gastric stromal tumour. PMID- 22444522 TI - Massive liver polycystic disease in a kidney transplanted patient. PMID- 22444523 TI - Pancreatic heterotopia at the gastroesophageal junction. PMID- 22444524 TI - Spirulina improves non-alcoholic steatohepatitis, visceral fat macrophage aggregation, and serum leptin in a mouse model of metabolic syndrome. AB - BACKGROUND: Nutritional approaches are sought to overcome the limits of pioglitazone in metabolic syndrome and non-alcoholic fatty liver disease. Spirulina, a filamentous unicellular alga, reduces serum lipids and blood pressure while exerting antioxidant effects. AIM: To determine whether Spirulina may impact macrophages infiltrating the visceral fat in obesity characterizing our metabolic syndrome mouse model induced by the subcutaneous injection treatment of monosodium glutamate. METHODS: Mice were randomized to receive standard food added with 5% Spirulina, 0.02% pioglitazone, or neither. We tested multiple biochemistry and histology (both liver and visceral fat) readouts at 24 weeks of age. RESULTS: Data demonstrate that both the Spirulina and the pioglitazone groups had significantly lower serum cholesterol and triglyceride levels and liver non-esterified fatty acid compared to untreated mice. Spirulina and pioglitazone were associated with significantly lower leptin and higher levels, respectively, compared to the control group. At liver histology, non alcoholic fatty liver disease activity score and lipid peroxide were significantly lower in mice treated with Spirulina. CONCLUSIONS: Spirulina reduces dyslipidaemia in our metabolic syndrome model while ameliorating visceral adipose tissue macrophages. Human studies are needed to determine whether this safe supplement could prove beneficial in patients with metabolic syndrome. PMID- 22444526 TI - [Iron deficiency without anemia]. PMID- 22444525 TI - Tissue engineering 2.0: guiding self-organization during pluripotent stem cell differentiation. AB - Human pluripotent stem cell (hPSC) differentiation aims to mimic development using growth factors or small molecules in a time-dependent and dose-dependent manner. However, the cell types produced using this approach are predominantly fetal-like in phenotype and function, limiting their use in regenerative medicine. This is particularly true in current efforts to produce pancreatic beta cells, wherein robust pancreatic progenitor maturation can only be accomplished upon transplantation into mice. Recent studies have suggested that hPSC-derived cells are capable of self-organizing in vitro, revealing a new paradigm for creating mature cells and tissues. Tissue engineering strategies that provide subtle and dynamic signals to developmentally naive cells may be applied to mimic in vitro the self-organization aspects of pancreatic development. PMID- 22444527 TI - [Thrombosis of abdominal veins]. PMID- 22444528 TI - Flower-like self-assembly of gold nanoparticles for highly sensitive electrochemical detection of chromium(VI). AB - We report here the fabrication of a flower-like self-assembly of gold nanoparticles (AuNPs) on a glassy carbon electrode (GCE) as a highly sensitive platform for ultratrace Cr(VI) detection. Two AuNP layers are used in the current approach, in which the first is electroplated on the GCE surface as anchors for binding to an overcoated thiol sol-gel film derived from 3 mercaptopropyltrimethoxysilane (MPTS). The second AuNP layer is then self assembled on the surface of the sol-gel film, forming flower-like gold nanoelectrodes enlarging the electrode surface. When functionalized by a thiol pyridinium, the fabricated electrode displays a well-defined peak for selective Cr(VI) reduction with an unusually large, linear concentration range of 10-1200 ng L(-1) and a low detection limit of 2.9 ng L(-1). In comparison to previous approaches using MPTS and AuNPs on Au electrodes, the current work expands the use of AuNPs to the GCE. Subsequent functionalization of the secondary AuNPs by a thiol pyridinium and adsorption/preconcentration of Cr(VI) lead to the unusually large detection range and high sensitivity. The stepwise preparation of the electrode has been characterized by electrochemical impedance spectroscopy (EIS), scanning electronic microscopy (SEM), and IR. The newly designed electrode exhibits good stability, and has been successfully employed to measure chromium in a pre-treated blood sample. The method demonstrates acceptable fabrication reproducibility and accuracy. PMID- 22444529 TI - Analytical procedures for the determination of emerging organic contaminants in plant material: a review. AB - In this review, recent developments for the determination of emerging organic contaminants (EOCs) in plant tissues are discussed focusing on the homogenization, extraction and determination steps involved. Eleven classes of EOCs, namely antibiotics, analgesics, antiepileptics, antidepressants, antiseptics, plasticizers, fragrances, surfactants, flame retardants, and phenoxy acid herbicides, have been evaluated. Methods are critically reviewed in terms of all the analytical steps involved in the analysis, sampling and sample preparation, separation, and the detection strategies employed. The extraction from tissue samples was performed in most cases by solid-liquid extraction, whereas the clean-up was performed by solid-phase extraction. The identification and quantification of EOCs in crops from the agricultural field (i.e. parts per billion range) is usually performed by using mass spectrometry techniques such as single quadrupole mass spectrometry or tandem mass spectrometry coupled to high resolution chromatographic techniques. Enzyme-linked immunosorbent assays are more rarely used. New developments such as in vivo solid-phase microextraction (SPME) and the assessment of the bioavailability-bioaccesibility of contaminants in crops are shown. The main scope of this review is to critically evaluate the current state of the art of the analytical techniques used and to identify the research needs in the determination of EOCs in crops. PMID- 22444530 TI - Submicron hard X-ray fluorescence imaging of synthetic elements. AB - Synchrotron-based X-ray fluorescence microscopy (XFM) using hard X-rays focused into sub-micron spots is a powerful technique for elemental quantification and mapping, as well as microspectroscopic measurements such as MU-XANES (X-ray absorption near edge structure). We have used XFM to image and simultaneously quantify the transuranic element plutonium at the L(3) or L(2)-edge as well as Th and lighter biologically essential elements in individual rat pheochromocytoma (PC12) cells after exposure to the long-lived plutonium isotope (242)Pu. Elemental maps demonstrate that plutonium localizes principally in the cytoplasm of the cells and avoids the cell nucleus, which is marked by the highest concentrations of phosphorus and zinc, under the conditions of our experiments. The minimum detection limit under typical acquisition conditions with an incident X-ray energy of 18 keV for an average 202 MUm(2) cell is 1.4 fg Pu or 2.9*10(-20) moles Pu MUm(-2), which is similar to the detection limit of K-edge XFM of transition metals at 10 keV. Copper electron microscopy grids were used to avoid interference from gold X-ray emissions, but traces of strontium present in naturally occurring calcium can still interfere with plutonium detection using its L(alpha) X-ray emission. PMID- 22444531 TI - Determination of copper, iron, nickel and zinc in ethanol fuel by energy dispersive X-ray fluorescence after pre-concentration on chromatography paper. AB - This paper presents an alternative analytical method employing energy dispersive X-ray fluorescence (EDXRF) to determine copper, iron, nickel and zinc ions in ethanol fuel samples after a pre-concentration procedure. Our pre-concentration strategy utilizes analyte retention on cation exchange chromatography paper, a convenient substrate for direct EDXRF measurements. The repeatability, expressed in terms of RSD of standard solutions containing 0.25 MUg mL(-1) of Cu, Fe, Ni and Zn, and calculated from fifteen consecutive measurements, was 2.5, 2.8, 3.0, and 2.7%, respectively. The limits of detection (LOD), defined as the analyte concentration that gives a response equivalent to three times the standard deviation of the blank (n=10), were found to be 13, 15, 15 and 12 MUg L(-1) for Cu, Fe, Ni and Zn, respectively. The proposed method was applied to Cu, Fe, Ni and Zn determination in hydrated ethanol fuel samples collected from different gas stations. PMID- 22444532 TI - Combination of chromatographic and chemometric methods to study the interactions between DNA strands. AB - This work describes the combination of size-exclusion chromatography and chemometric resolution methods to study the formation of complex DNA structures from individual strands. This combined procedure has been applied to two different experimental data. Firstly, the formation of an intermolecular Watson Crick duplex structure formed by the individual unstructured strands. Secondly, the competition between the intermolecular Watson-Crick duplex and intramolecular quadruplex structures formed by two sequences found in the hTERT gene has been studied. The analysis of the recorded chromatograms at just one single wavelength may not always be enough to confirm the existence of a higher order structure. In these cases, recording the entire spectrum at each point of the chromatogram and applying appropriate chemometric resolution methods has shown to be a useful tool to resolve and quantify the contribution of all DNA structures to the analytical signal. In this work, the Multivariate Curve Resolution based on Alternating Least Squares (MCR-ALS) has been used to analyze the three-way data sets acquired along chromatographic runs. PMID- 22444533 TI - Assessment of a geochemical extraction procedure to determine the solid phase fractionation and bioaccessibility of potentially harmful elements in soils: a case study using the NIST 2710 reference soil. AB - Three mineral acid sequential extraction regimes (HNO(3) only, HNO(3) followed by HCl and aqua regia) were applied to the NIST 2710 contaminated reference soil. The major and trace element chemical analysis data from the extractions were subjected to a chemometric self-modelling mixture resolution procedure which identified that 12 distinct physico-chemical components were extracted. The fractionation of As, Cd, Ni and Pb between these components were determined. Tentative assignments of the mineralogical sources of the components were made. The human ingestion bioaccessible fraction of As, Cd and Pb were determined using the in vitro BARGE UBM bioaccessibility test and were found to be 51.6%, 68.0% and 68.4% respectively. The relationship between the lability of the physico chemical components and the bioaccessible fraction of the soils was investigated and the bioaccessible fractions were assigned to specific components. The extraction scheme using aqua regia was found to be the most suitable as it was the only one which extracted the iron sulphide phase in the soil. PMID- 22444534 TI - Electro membrane extraction of sodium diclofenac as an acidic compound from wastewater, urine, bovine milk, and plasma samples and quantification by high performance liquid chromatography. AB - Electro membrane extraction (EME) as a new microextraction method was applied for extraction of sodium diclofenac (SDF) as an acidic compound from wastewater, urine, bovine milk and plasma samples. Under applied potential of 20 V during the extraction, SDF migrated from a 2.1 mL of sample solution (1mM NaOH), through a supported liquid membrane (SLM), into a 30 MUL acceptor solution (10 mM NaOH), exist inside the lumen of the hollow fiber. The negative electrode was placed in the donor solution, and the positive electrode was placed in the acceptor solution. 1-octanol was immobilized in the pores of a porous hollow fiber of polypropylene as SLM. Then the extract was analyzed by means of high-performance liquid chromatography (HPLC) with UV-detection for quantification of SDF. Best results were obtained using a phosphate running electrolyte (10 mM, pH 2.5). The ranges of quantitation for different samples were 8-500 ngmL(-1). Intra- and inter-day RSDs were less than 14.5%. Under the optimized conditions, the preconcentration factors were between 31 and 66 and also the limit of detections (LODs) ranged from 2.7 ng mL(-1) to 5 ng mL(-1) in different samples. This procedure was applied to determine SDF in wastewater, bovine milk, urine and plasma samples (spiked and real samples). Extraction recoveries for different samples were between 44-95% after 5 min of extraction. PMID- 22444535 TI - Method development for proteome stabilization in human saliva. AB - Human saliva is a biological fluid with emerging early detection and diagnostic potentials. However, the salivary proteome suffers from rapid degradation and thus compromises its translational and clinical utilities. Therefore, easy, reliable and practical methods are urgently required for the storage of human saliva samples. In this study, saliva samples from healthy subjects were collected and stored at room temperature (RT) and 4 degrees C for different lengths of time with and without specific protein stabilization treatments. SDS PAGE was run to compare the protein profiling between samples. Reference proteins, beta-actin and interleukin-1 beta (IL1beta), were chosen to evaluate salivary protein stability. Immunoassay was used for the detection of these target proteins. All data was compared with the positive control that had been kept at -80 degrees C. The results show that the salivary proteome that has been stored at 4 degrees C with added protease inhibitors was stable for approximately two weeks without significant degradation. By adding ethanol to the samples, the salivary proteome was stabilized at RT. After optimization, a simple, robust and convenient method is developed for the stabilization of proteins in human saliva that does not affect the downstream translational and clinical applications. The salivary proteome could be stabilized without significant degradation by adding ethanol at RT for about two weeks. This optimized method could greatly accelerate the clinical usage of saliva for future diagnosis. PMID- 22444536 TI - Novel methods for the quantification of (2E)-hexadecenal by liquid chromatography with detection by either ESI QTOF tandem mass spectrometry or fluorescence measurement. AB - Sphingosine-1-phosphate lyase (SPL) is the only known enzyme that irreversibly cleaves sphingosine-1-phosphate (S1P) into phosphoethanolamine and (2E) hexadecenal during the final step of sphingolipid catabolism. Because S1P is involved in a wide range of physiological and diseased processes, determining the activity of the degrading enzyme is of great interest. Therefore, we developed two procedures based on liquid chromatography (LC) for analysing (2E) hexadecenal, which is one of the two S1P degradation products. After separation, two different quantification methods were performed, tandem mass spectrometry (MS) and fluorescence detection. However, (2E)-hexadecenal as a long-chain aldehyde is not ionisable by electrospray ionisation (ESI) for MS quantification and has an insufficient number of corresponding double bonds for fluorescence detection. Therefore, we investigated 2-diphenylacetyl-1,3-indandione-1-hydrazone (DAIH) as a derivatisation reagent. DAIH transforms the aldehyde into an ionisable and fluorescent analogue for quantitative analysis. Our conditions were optimised to obtain the outstanding limit of detection (LOD) of 1 fmol per sample (30 MUL) for LC-MS/MS and 0.75 pmol per sample (200 MUL) for LC determination with fluorescence detection. We developed an extraction procedure to separate and concentrate (2E)-hexadecenal from biological samples for these measurements. To confirm our new methods, we analysed the (2E)-hexadecenal level of different cell lines and human plasma for the first time ever. Furthermore, we treated HT-29 cells with different concentrations of 4-deoxypyridoxine (DOP), which competitively inhibits pyridoxal-5-phosphate (P5P), an essential cofactor for SPL activity, and observed a significant decrease in (2E)-hexadecenal relative to the untreated cells. PMID- 22444537 TI - Determination of triacylglycerol regioisomers using electrospray ionization quadrupole ion trap mass spectrometry with a kinetic method. AB - The kinetic method was applied to differentiate and quantify mixtures of regioisomeric triacylglycerols (TAGs) by generating and mass selecting alkali ion bound metal dimeric clusters with a TAG chosen as reference (ref) and examining their competitive dissociations in a quadrupole ion trap mass spectrometer. This methodology readily distinguished pairs of regioisomers (AAB/ABA) such as LLO/LOL, OOP/OPO and SSP/SPS and consequently distinguished sn-1/sn-3, sn-2 substituents on the glycerol backbone. The dimeric complex ions [ref, Li, TAG((AAB and/or ABA))](+) generated by electrospray ionization mass spectrometry were subjected to collision induced dissociation causing competitive loss of either the neutral TAG reference (ref) leading to [Li(AAB and/or ABA)](+) or the neutral TAG molecule (TAG((AAB and/or ABA))) leading to [ref, Li](+). The ratio of the two competitive dissociation rates, defined by the product ion branching ratio (R(iso)), was related via the kinetic method to the regioisomeric composition of the investigated TAG mixture. In this work, a linear correlation was established between composition of the mixture of each TAG regioisomer and the logarithm of the branching ratio for competitive fragmentation. Depending on the availability of at least one TAG regioisomer as standard, the kinetic method and the standard additions method led to the quantitative analysis of natural TAG mixtures. PMID- 22444538 TI - Nuclear magnetic resonance-based metabolomics for prediction of gastric damage induced by indomethacin in rats. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have side effects including gastric erosions, ulceration and bleeding. In this study, pattern recognition analysis of the (1)H-nuclear magnetic resonance (NMR) spectra of urine was performed to develop surrogate biomarkers related to the gastrointestinal (GI) damage induced by indomethacin in rats. Urine was collected for 5 h after oral administration of indomethacin (25 mg kg(-1)) or co-administration with cimetidine (100 mg kg(-1)), which protects against GI damage. The (1)H-NMR urine spectra were divided into spectral bins (0.04 ppm) for global profiling, and 36 endogenous metabolites were assigned for targeted profiling. The level of gastric damage in each animal was also determined. Indomethacin caused severe gastric damage; however, indomethacin administered with cimetidine did not. Simultaneously, the patterns of changes in their endogenous metabolites were different. Multivariate data analyses were carried out to recognize the spectral pattern of endogenous metabolites related to indomethacin using partial least square-discrimination analysis. In targeted profiling, a few endogenous metabolites, 2-oxoglutarate, acetate, taurine and hippurate, were selected as putative biomarkers for the gastric damage induced by indomethacin. These metabolites changed depending on the degree of GI damage, although the same dose of indomethacin (10 mg kg(-1)) was administered to rats. The results of global and targeted profiling suggest that the gastric damage induced by NSAIDs can be screened in the preclinical stage of drug development using a NMR based metabolomics approach. PMID- 22444539 TI - Application of europium(III) chelates-bonded silica nanoparticle in time-resolved immunofluorometric detection assay for human thyroid stimulating hormone. AB - Eu(III) chelate-bonded silica nanoparticle was used as a fluorescent label to develop a highly sensitive time-resolved immunofluorometric assay (TrIFA) for human thyroid stimulating hormone (hTSH). The limit of detection of the assay calculated according to the 2SD method was 0.0007 mIU L(-1) and became 0.003 mIU L(-1) when serum-based matrix was used for calibrators, indicating that this TrIFA is comparable with the most sensitive assays. The linear range was from 0.005 to 100 mIU L(-1) of hTSH with coefficient of variation between 1.9% and 8.3%. The correlation study using 204 blood spot samples from newborns showed that the results from this new method were coincident with that of the commercial dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) system, with a correlation coefficient of 0.938. The fluorescent nanoparticle label allows directly reading the fluorescent signal, omitting the signal development step required for the DELFIA system, and the whole procedure of this assay is fulfilled within 2 h. Thus, we developed a novel, sensitive, quantitative and simple nanoparticle label-based TrIFA assay, suitable for routine application in hTSH screening of neonatal hypothyroidism. PMID- 22444540 TI - Electrochemical immunoassay of benzo[a]pyrene based on dual amplification strategy of electron-accelerated Fe3O4/polyaniline platform and multi-enzyme functionalized carbon sphere label. AB - An electrochemical immunosensor, basing on a dual amplification strategy by employing a biocompatible Fe(3)O(4)/polyaniline/Nafion (Fe(3)O(4)/PANI/Nafion) layer as sensor platform and multi-enzyme-antibody functionalized highly carbonized spheres (multi-HRP-HCS-Ab(2)) as label, was constructed for sensitive detection of benzo[a]pyrene (BaP). The stable film, Fe(3)O(4)/PANI/Nafion, can not only immobilize biomolecules, but also catalyze the reduction of hydrogen peroxide, indicating an accelerated electron transfer pathway of the platform. The experimental conditions, including the concentration of Nafion, concentration of Fe(3)O(4)/polyaniline (Fe(3)O(4)/PANI), pH of the detection solution and concentrations of biomolecules, were studied in detail. Basing on a competitive immunoassay, the current change was proportional to the logarithm of BaP concentration in the range of 8 pM and 2 nM with the detection limit of 4 pM. The proposed immunosensor exhibited acceptable reproducibility and stability. This new type of dual amplification strategy may provide potential applications for the detection of environmental pollutants. PMID- 22444541 TI - Dipstick based immunochemiluminescence biosensor for the analysis of vitamin B12 in energy drinks: a novel approach. AB - In this article, we describe a dipstick based immunochemiluminescence (immuno-CL) biosensor for the detection of vitamin B(12) in energy drinks. The method is a direct competitive type format involving the immobilization of vitamin B(12) antibody on nitrocellulose membrane (NC) followed by treatment with vitamin B(12) and vitamin B(12)-alkaline phosphatase conjugate to facilitate the competitive binding. The dipstick was further treated with substrate disodium 2-chloro-5-(4 methoxyspiro {1,2-dioxetane-3,2c-(5c-chloro)tricyclo[3.3.1.13,7]decan}-4-yl)-1 phenyl phosphate (CDP-Star) to generate chemiluminescence (CL). The number of photons generated was inversely proportional to the vitamin B(12) concentration. After systematic optimization, the limit of detection was 1 ng mL(-1). The coefficient of variation was below 0.2% for both intra- and inter-assay precision. Vitamin B(12) was extracted from energy drinks with recovery ranged from 90 to 99.4%. Two different energy drinks samples were analyzed, and a good correlation was observed when the data were compared with a reference enzyme linked immuno sorbent assay (ELISA) method. The developed method is suitable for an accurate, sensitive, and high-throughput screening of vitamin B(12) in energy drinks samples. The dipstick technique based on immuno-CL is suitable for the detection of several analyte in food and environmental samples. PMID- 22444542 TI - Chemiluminescence enzyme immunoassay using magnetic nanoparticles for detection of neuron specific enolase in human serum. AB - To detect a biomarker for small cell lung carcinoma, neuron specific enolase (NSE), a sensitive and specific chemiluminescence enzyme immunoassay was developed. Fluorescein isothiocyanate (FITC) labeled NSE capture antibody connected with NSE and alkaline phosphatase (ALP) labeled NSE detection antibody in a sandwich-type detection manner. This immune complex was further reacted with anti-FITC coated magnetic beads. In a magnetic field, the complex was enriched, and the sensitivity was thus enhanced. The limit of detection (LOD) of this method was <0.2 ng mL(-1). The proposed immunoassay was highly selective, and not interfered by hook effect. The recovery was >83.0% and the coefficient of variation was <10.0%. Human sera from 120 patients were tested with the presented and traditional chemiluminescence enzyme immunoassay. An excellent linear relationship was obtained between two techniques. Overall, this immunoassay offers a promising alternative for NSE detection than traditional clinical examinations. PMID- 22444543 TI - Nanosensors lost in space. A random walk study of single molecule detection with single-nanopore sensors. AB - Nanopores by providing single molecule detection and manipulation are lately in the forefront of life science and nanotechnology research. While single nanopore sensors can detect the residence of even one molecule or nanoparticle within the nanopore, the analytical significance of this process is often misunderstood. A fundamental problem of nanosensors is that their sensing zone is generally infinitesimal with respect of the probed sample volume. Consequently, the probability to have in extremely diluted solutions target molecules or nanoparticles encountering the nanosensor is low. Thus, even though the sensor by itself has single molecule detection capability the average time frame in which this occurs is by far not irrelevant for the analysis. In this paper we report on random walk simulations to determine the average time (encounter time) needed by a single molecule to encounter a single nanopore sensor. By assigning the simulation environment with real space and time values a semi-empirical equation for expressing the average encounter time in purely diffusive systems is provided. We also show that random walk simulations can be adapted to evaluate the encounter time in the presence of an external force field acting on the target molecule. As practically relevant application the case of electrophoretically driving DNA strands towards the nanopore sensor is presented and a semi-empirical equation for the encounter time is provided. PMID- 22444544 TI - New development in in-capillary electrophoresis techniques for kinetic and inhibition study of enzymes. AB - Enzymes are often quantified by measuring their biological activity. Capillary electrophoresis is gaining its position in this field due to the ongoing trend to miniaturize biochemical assays. The aim of this work was to compare pre-capillary (off-line) and in-capillary electrophoresis techniques for studying enzymatic activity. The beta-galactosidase (beta-Gal) was chosen as a model enzyme. Each technique was optimized independently in order to decrease analyte consumption (to few tens of nanoliters), incubation time (to few seconds) and analysis time (below 1 min). Several experimental parameters (ionic strength of the background electrolyte (BGE) and of the incubation buffer, incubation time, injected volumes, ...) were optimized by following peak efficiencies, resolution and repeatability. To monitor the performance of each technique, the catalytic constants (V(max) and K(m)) of 4-nitro-phenyl-d-galactopyranoside (PNPG) hydrolysis by beta-Gal as well as the inhibition constants (K(i) and IC(50)) by a competitive inhibitor 2-nitrophenyl-1-thio-beta-d-thiogalactopyranoside (ONPTG) were determined. The results obtained were cross compared and were also evaluated by comparison to a standard spectrophotometric method. EMMA proved to be the best technique in terms of sample consumption and speed. The short-end injection was successfully used which speeded-up electrophoretic analysis (<0.8 min). It is a very powerful tool for studying enzymatic inhibition. Usually, the inhibitor is injected in the capillary mixed to the substrate especially when both have similar mobilities. We show in this work, for the first time, that combining at inlet reaction with EMMA-CE allows enzyme inhibition to be realized without any prior mixing of the substrate and the inhibitor. This approach is very interesting for screening inhibitors, rapidly and without excessive substrate consumption. PMID- 22444545 TI - Increasing opsonizing and killing effect of serum from patients with recurrent K1 Klebsiella pneumoniae liver abscess. AB - BACKGROUND: Klebsiella pneumoniae liver abscess (KLA) is an emerging infectious disease caused by the virulent K pneumoniae strains of capsular serotype K1 and commonly associated with diabetes mellitus. Recurrent KLA is rarely reported and the mechanism of recurrence is uncertain. In this study we evaluated both phagocytosis by neutrophils and serum killing ability of serum from recurrent K1 KLA patients compared to normal healthy subjects (NHS). METHODS: This prospective study included six cases of recurrent K1 KLA consisting of three male and three female patients with a mean age of 67.2 years (range, 56-88 years). The different serotypes of K pneumoniae were reacted with serum from patients with recurrent KLA and NHS. Subsequent phagocytosis by neutrophils was determined using flow cytometry and serum killing assays were performed. RESULTS: The most common underlying disease in patients with recurrent KLA was diabetes mellitus, occurring in about 83.3% (5/6) of patients. The antibiogram of the strains associated with recurrent KLA remained uniquely resistant to ampicillin. The average percentage derived from the serum killing assays showed serotype K1 and K2 resistance to serum from NHS (1281% and 621%, respectively); however, serum susceptibly was observed in the serum of patients with recurrent K1 KLA (0.3% and 1.1%, respectively). A significant increase in neutrophil phagocytosis of serotype K1 was observed following opsonisation with serum from patients with recurrent KLA compared with serum from NHS (p = 0.008). No significant difference in the phagocytic rate of non-K1/K2 or K2 serotypes was observed between NHS and patients with recurrent KLA (p = 0.76 and p = 0.132, respectively). CONCLUSION: These preliminary results showed possible immunologic protection in patients with recurrent KLA due to increasing opsonization and serum killing. PMID- 22444546 TI - Patterns of sensitization to peanut allergen components in Taiwanese Preschool children. AB - BACKGROUND/PURPOSE: Peanut allergy is very common in Western countries, although it is seldom encountered in Eastern countries. Peanuts are comprised of at least 11 components, but the contribution to clinical symptoms by each component in each individual is not known. This study investigated the distributions of sensitivity to peanut allergen components among Taiwanese children who were sensitized to peanuts and followed the evolution of sensitization patterns to these components. METHODS: We enrolled 29 preschool children (age=2.11+/-1.36 years) who were sensitized to peanuts above class 3. Serum was analyzed for specific immunoglobulin E (IgE) antibodies to recombinant Ara h 1, Ara h 2, Ara h 3, Ara h 8, and Ara h 9. Allergen component-specific IgE >=0.35 kU(A)/L was defined as positive. Eighteen children were retested 22.64+/-5.1 months later. Peanut allergy symptoms were recorded from detailed questionnaires. RESULTS: The percentages of children sensitized to Ara h 1, 2, 3, 8, and 9 were, respectively, 51.8%, 65.5%, 62.1%, 13.8%, and 24.1%. Regarding changing patterns of peanut component sensitization at follow-up, children with clinical symptoms to peanuts had persistent elevations of Ara h 2-specific IgE: 12.6+/-1.01 up to 34.15+/-19.4 kU(A)/L; p=0.144. In contrast, Ara h 2 concentrations decreased significantly in children without clinical symptoms. Ara h 8 and 9 were nonspecific for children with or without symptoms. CONCLUSION: Ara h 1, Ara h 2, and Ara h 3 were major components contributing to peanut sensitization in Taiwanese children. Ara h 2 was probably the most important component that contributed to clinical symptoms and remained steady in children who had peanut allergy. PMID- 22444547 TI - Risk factors for scabies in Taiwan. AB - BACKGROUND: Scabies is a global problem. Transmission of scabies is usually due to direct or indirect contact. Delay in diagnosis may result in the spread of the scabies mite. Prompt diagnosis and treatment are important. METHODS: In this study, we collected data from 52 scabies patients and analyzed the risk factors for scabies with the case-control method. RESULTS: Our study has revealed that the patients who were bedridden [odds ratio (OR) 6.72, p < 0.0001], living in a nursing home (OR 9.89, p < 0.0001), had a higher clinical severity status before admission (OR 1.25, p < 0.0001), and a catheter inserted (including nasogastric tube, Foley catheter, Port-A, or Hickman catheter) (OR 9.05, p < 0.0001) were significantly more likely to acquire scabies infection. CONCLUSION: To prevent scabies, proper management of the nursing home setting, including adequate cleaning of the contaminated clothing, bedding and equipment, in combination with treating all suspected scabies patients, and contact isolation are important and necessary. PMID- 22444548 TI - Seminal plasma and seminal plasma proteins added to bulk sorted sperm do not alter the mRNA expression of in vitro produced bovine embryos. AB - Although sex-sorted sperm have been used for AI and IVF for over a decade there is still need to improve the technology as the results are highly variable. The goal of the present study was to assess the effect of seminal plasma and seminal plasma proteins as a supplement to sorted sperm on subsequent embryonic development, as a beneficial effect of these substances has been reported. In vitro matured oocytes were fertilized in vitro with either unsorted sperm (n = 215; Group 1), bulk sorted sperm (n = 226; Group 2), bulk sorted sperm extended in the presence of 1% seminal plasma (n = 185; Group 3) or bulk sorted sperm supplemented with seminal plasma proteins (4 mg mL(-1); n = 254; Group 4). An additional group of oocytes (n = 307; Group 5) was fertilized with the semen of another bull routinely used for IVF and served as a laboratory standard control. Subsequently, the presumptive zygotes were cultured for 8 days under standard conditions (SOFaa, 39 degrees C, 5% CO(2), 5% N(2)). Cleavage rates were assessed on day 3 p.i. (post insemination; group 1: 30.5 +/- 14.7%; group 2: 28.8 +/- 9.8%; group 3: 20.8 +/- 14.9%; group 4: 25.7 +/- 8.2%; group 5: 54.8 +/- 11.5%). Development rates were documented on days 7 p.i. (group 1: 7.3 +/- 6.6%; group 2: 5.6 +/- 3.1%, group 3: 6.2 +/- 7.7%, group 4: 6.7 +/- 5.9%, group 5: 20.2 +/- 6.9%) and 8 p.i. (group 1: 8.9 +/- 7.0%; group 2: 6.0 +/- 2.9%; group 3: 8.6 +/- 11.3%; group 4: 7.8 +/- 6.2%; group 5: 23.3 +/- 7.8%), respectively. Significant differences among cleavage and development rates could only be seen for Group 5 compared to all other groups. However, this difference between Groups 1-4 vs. Group 5 regarding the development rates on Day 8 could not be detected when assessing the development rates on base of the number of cleaved embryos instead of the number of oocytes fertilized (group 1: 31.4 +/- 17.2%; group 2: 26.0 +/- 21.0%; group 3: 33.3 +/- 19.05%; group 4: 26.6 +/- 17.8%; group 5: 42.6 +/- 11.3%). The relative abundance of six different developmentally important gene transcripts (G6PD, HSP1A1, SLC2A3, BAX, BCL2L1, DNMT3A) was determined using single Day 8 expanded blastocysts of all five groups. No significant differences were seen among the embryos of the five groups. Our results show that neither the bulk sorting procedure nor the addition of seminal plasma or seminal plasma proteins, respectively, affected cleavage and development rates when sperm from a specific bull was used. Additionally, sorting and subsequent exposure of sperm to either seminal plasma or seminal plasma proteins did not influence mRNA expression in bovine IVP embryos. PMID- 22444549 TI - Effect of one or three timed artificial inseminations before natural service on reproductive performance of lactating dairy cows not observed for detection of estrus. AB - The objectives were to determine the effects of one or three timed artificial insemination (AI) before natural service (NS) in lactating dairy cows not observed for detection of estrus on hazard of pregnancy, days nonpregnant, and 21 days cycle pregnancy rate. A total of 1050 lactating Holstein cows were subjected to a double Ovsynch program for their first postpartum AI. On the day of first AI (78 +/- 3 days in milk), cows were blocked by parity and randomly assigned to receive either one timed AI (1TAI, n = 533) or three timed AI (3TAI, n = 517) before being exposed to NS. Cows assigned to 1TAI were exposed to bulls 7 days after the first AI. Nonpregnant cows in 3TAI were resynchronized with the Ovsynch protocol supplemented with progesterone twice, with intervals between AI of 42 days, before being exposed to NS 7 days after the third AI. Cows were evaluated for pregnancy 32 days after each timed AI, or every 28 days after being exposed to NS. Pregnant cows were re-examined for pregnancy 28 days later (i.e., 60-day gestation). Exposure to heat stress was categorized based on the first AI being performed during the hot or cool season, according to the temperature-humidity index. Body condition was scored at first AI. All cows were allowed a period of 231 days of breeding, after which nonpregnant cows were censored. Pregnancy to the first AI did not differ between 1TAI and 3TAI on Day 60 after insemination (30.8 vs. 33.5%). Cows receiving 3TAI had a 15% greater hazard of pregnancy and a 17% greater 21-days cycle pregnancy rate than 1TAI and these benefits originated from the first 84 days of breeding. These changes in rate of pregnancy reduced the median and mean days nonpregnant by 9 and 10 d, respectively. Despite the long inter-AI interval in cows subjected to 3TAI, reproductive performance was improved compared with a single timed AI and subsequent exposure to NS. In dairy herds that use a combination of AI and NS, allowing cows additional opportunities to AI before onset of breeding with bulls is expected to improve reproductive performance. PMID- 22444550 TI - Post-thaw addition of seminal plasma reduces tyrosine phosphorylation on the surface of cryopreserved equine sperm, but does not reduce lipid peroxidation. AB - The objective was to verify the relationship between equine semen cryopreservation and changes related to increased lipid peroxidation. Also, addition of autologous or homologous seminal plasma from a stallion with a good freezing response to post-thawed sperm was tested to determine whether it would confer protection. Frozen-thawed sperm were evaluated and allocated into three groups: without plasma addition, and supplemented with either homologous or autologous seminal plasma. All groups were evaluated at 0, 60 and 120 min after incubation at 37 degrees C. Cryopreservation did not increase plasma membrane disorders (mean +/- SEM 9.48 +/- 0.65 and 1.62 +/- 0.23% in raw and frozen-thawed sperm, respectively). However, both membrane peroxidation and protein phosphorylation were increased (P < 0.05) compared to raw semen (1.74 and 5.20 fold, respectively). There was a correlation (r = 0.73; P < 0.05) between the increase in lipid peroxidation and tyrosine phosphorylation. Seminal plasma, regardless of origin, reduced (P > 0.05) tyrosine phosphorylation present on the surface of cryopreserved sperm; however, lipid peroxidation was not significantly reduced. In conclusion, we inferred that emergence of phosphorylated proteins on the surface of cryopreserved sperm was due to increased lipid peroxidation that occurred during the freezing/thawing process; however, reduced tyrosine phosphorylation that occurred after addition of seminal plasma was triggered by other mechanisms, apparently independent from the reduction in membrane peroxidation. PMID- 22444551 TI - Potential applications of sheep oocytes as affected by vitrification and in vitro aging. AB - The present study was carried out to investigate how the interactions between aging, vitrification and post-warming interval affect the credibility of sheep MII-oocytes for in vitro fertilization (IVF), intracytoplasmic injection (ICSI), and parthenogenetic activation (PA). According to our results, aged oocytes had significantly higher rates of chromosome and spindle abnormalities compared to young oocytes. However after vitrification-warming, the total rates of these abnormalities were not significantly different between aged and young oocytes. Unvitrified-aged, and vitrified young and aged oocytes had comparable ultrastructural characteristics, whereas they were completely dissimilar in compared with unvitrified-young oocytes. Although mRNA abundance was reduced during vitrification-warming in both aged and young oocytes, the post-warming interval could improve the relative mRNA abundance. Aged oocytes had lower capacity for IVF and ICSI in compared with young oocytes, but had similar pattern for PA process. The vitrification process decreased developmental competence of both aged and young oocytes in compared with young ones, particularly when warmed oocytes were rested for 2 h before IVF, ICSI and PA. The results of the present study showed that in vitro aged oocytes had higher capacity to be used for parthenogenetic studies rather than IVF and ICSI. Furthermore, it was shown that vitrified oocytes had a time-dependent decline in quality and developmental potential. Notably, the speed of this decline was higher in vitrified-young oocytes, indicating that the vitrified oocytes do not require to be rested post warming. Conclusively, the results of this study can be useful in preserving in vitro aged oocytes to provide a valuable and easy access source of oocytes for research purposed studies. PMID- 22444552 TI - The use of digital infrared thermal imaging to detect estrus in gilts. AB - Yorkshire/Landrace crossbred gilts (N = 32) were evaluated using digital infrared thermal imaging (DITI) to discriminate between estrus and diestrus phases of the porcine estrous cycle. Gilts (N = 32) were part of an ongoing reproductive efficiency study involving the use of raw soybean (RSB; N = 15) versus soybean meal (SBM; N = 17) as a source of dietary protein. Gilts were monitored daily for signs of estrus using a teaser boar. Thermal images of vulva surface temperatures (TEMP) were recorded at standing estrus and diestrus. Measurements for analysis included minimum (MIN), maximum (MAX), mean (AVG), and standard deviation (SD) of temperature gradients. At imaging, ambient (AMB) and rectal temperatures (RT) were recorded, and blood samples taken for serum progesterone (P(4)) concentration analysis (by RIA) to confirm stage of cycle. Mean serum progesterone values at estrus and diestrus were (mean +/- SD) 1.0 +/- 0.1 and 10.9 +/- 0.8 ng/mL, respectively. Vulva MIN, MAX, and AVG thermal images were positively correlated with one another (P < 0.01), and were positively correlated with ambient temperature (P < 0.01). Vulva MAX and AVG thermal temperatures were greater (P < 0.05) at estrus than at diestrus (36.6 +/- 0.2 degrees C and 33.4 +/- 0.3 degrees C vs. 35.6 +/- 0.3 degrees C and 31.8 +/- 0.6 degrees C, respectively), whereas MIN and SD had no differences (P > 0.05) between stages of the cycle. No differences (P > 0.05) in RT were detected between stages and RT was not significantly correlated with vulva thermal images. Diet had no significant effect on RT or vulva temperature. PMID- 22444553 TI - Effects of mineral supplements on ovulation and maturation of dog oocytes. AB - The aim of this study was to assess the effects of trace mineral supplements near the time of ovulation on the number of ovulated oocytes, in vivo oocyte maturation and pregnancy for dog cloning. Sixteen oocyte donor dogs were used in each control and mineral supplement group, and 136 and 166 corpora lutea were counted from each group. No significant difference was observed between oocyte recovery rates in the control (91.2 +/- 2.7%) and mineral (89.9 +/- 2.7) groups. Proportions of mature (86.2 +/- 7.2 and 88.4 +/- 6.8%) and aged (13.8 +/- 7.2 and 11.6 +/- 6.8%) oocytes were not different in the control and mineral groups, respectively. Oocytes with fair (91.5 +/- 3.6 and 93.6 +/- 2.1%) and poor (8.5 +/ 3.6 and 6.4 +/- 2.1%) quality also showed no difference between the control and mineral groups. The concentrations of manganese and ferrous iron were higher and lower on the day of ovulation, respectively, in both groups, but trace element concentrations in peripheral blood were not affected by mineral treatment. Oocytes were used to make cloned embryos; after embryo transfer, four and two pups were delivered from the control and mineral group, respectively, but there was no difference in the delivery rate (4.6 and 2.7%). In conclusion, intravenous mineral supplements administered once close to the LH surge in oocyte donor dogs and recipients had no effect on the number of ovulated oocytes, in vivo oocyte maturation or pregnancy in dog cloning in this study. PMID- 22444554 TI - Cryopreservation of epididymal sperm collected postmortem in the Tasmanian devil (Sarcophilus harrisii). AB - Effective sperm cryopreservation protocols are limited to a small number of marsupial species. In this study, postmortem gamete rescue (PMGR) epididymal sperm samples from Tasmanian devils (N=34) euthanized due to the fatal Devil Facial Tumor Disease were used to develop long-term sperm storage techniques for the species. Cryoprotectant toxicity associated with equilibration of sperm samples in a TEST yolk diluent (TEST; 189 mM N-Tris(hydroxymethyl)methyl-2 aminoethanesulfonic acid, 85 mM Trizma base [Tris], 11 mM glucose, 20% vol/vol egg yolk; pH 7.1, and 315.0+/-5.0 mOsm/kg) with a final concentration of 0.06 M trehalose, or 4%, 10%, and 18% vol/vol of either glycerol or dimethyl sulfoxide (DMSO), was examined over 12 h at 15 degrees C. Trehalose supplementation resulted in an immediate decline (P<0.05) of total motility. After 12 h, total motility was reduced (P<0.05) in treatments containing 18% glycerol, and 10% and 18% dimethyl sulfoxide. The effects of final glycerol concentration (4% and 10%), glycerol equilibration duration (10 min 1 h, or 3 h) prefreeze, freezing rate and the addition of 0.10 M lactose or a combination of 0.10 M lactose and 0.11 M raffinose were assessed during three experiments on the cryopreservation of postmortem gamete rescue samples in TEST. In all experiments, motility and viability were reduced (P<0.01 postthaw). Samples cryopreserved in TEST supplemented with lactose or lactose with raffinose using a fast freezing rate ( 8 degrees C/min from 4 to -40 degrees C, then -65 degrees C/min until -165 degrees C) produced the highest (P<0.05) postthaw motility (18.6+/-5.5% and 16.9+/-8.5%, respectively), which represented 35% to 48% retention of prefreeze motility. These results apparently were the best postthaw results of dasyurid sperm reported to date and will help lay the foundations for developing assisted reproductive technologies for marsupial species. PMID- 22444555 TI - Effect of GSK-3 inhibitor on the proliferation of multipotent male germ line stem cells (mGSCs) derived from goat testis. AB - The glycogen synthase kinase 3 (GSK3) inhibitor, 6-bromoindirubin-3'-oxime (BIO), is a key regulator of many signaling pathways to maintain pluripotency of human and mouse embryonic stem cells (ESCs). However, the effect of BIO on derivation of dairy goat male germline stem cells (mGSCs) remains unclear. The objectives of this study were to investigate whether BIO influences derivation of dairy goat mGSCs. Dairy goat mGSCs were cultured in mTeSR containing BIO medium and its effects on the proliferation ability of goat mGSCs (derived from goats <=2 mo of age) were evaluated by 5-Bromo-2-deoxyuridine (BrdU) incorporation and alkaline phosphatase (AP) staining. Furthermore, its effects on maintenance of the undifferentiated state of mGSCs in late passages of cultures, as well as the capacity of mGSCs to differentiate into embryoid bodies (EBs) were examined. The presence of BIO increased the mitosis index and the number of AP positive colonies, as well as expression of pluripotent markers, Oct4, Nanog, Sox2, C-myc, Klf4, E-cadherin, and the proliferative markers, Pcna and C-myc. In contrast, there was no significant change in expression of apoptosis markers, P53, P21 and cyclin-related genes (Cyclin A, CDK2, Cyclin D1), as determined by RT-PCR analysis. When mGSCs were cultured in mTeSR medium containing BIO, EBs were formed, which were capable of further differentiating into various cell types found in the three embryonic germ layers, as determined by immunofluorescence and/or histologic staining. In conclusion, adding BIO to cultures BIO significantly promoted establishment of goat mGSC colonies and maintained their undifferentiated state. PMID- 22444556 TI - Impact of fine needle aspiration (FNA) and of the number of punctures on the feline testis: clinical, gross anatomy and histological assessment. AB - The safety of testicular fine needle aspiration (FNA) has been proven in dogs but has not been fully established in men, while studies in rats have given contradictory results. Furthermore, the extent of damage inflicted by multiple punctures is unknown. The aim of this study was to determine the impact of FNA and of the number of punctures on the feline testis with clinical, gross anatomy and histological examinations. Twenty-seven sexually mature healthy laboratory Domestic Shorthair cats were randomly assigned to two groups: 5 cats in which no FNA was performed (control group), and 22 cats which had their left and right testis punctured with a 26 ga needle towards 3 and 8 directions, respectively (experimental group). Two cats at a time were orchiectomized 5 or 30 min, 1, 2, 4, 7 or 14 days or 1, 2, 3 or 4 mo post-aspiration. The cats of the control group were also orchiectomized. During the first week post-aspiration clinical examination revealed vaginal cavity hematoma (8/44 testes), while the histological findings were focal hemorrhagic areas (20/24 testes), erythrocytes inside the seminiferous tubules' lumen (9/24 testes), and germinal cell degeneration in <1.94% of the seminiferous tubules (15/24 testes). After the first week the histological findings were germinal cell degeneration in <2.14% of the seminiferous tubules (19/20 testes) and enlargement of the lumen of <5.16% of the seminiferous tubules (7/20 testes). The germinal epithelium and interstitium had an overall normal appearance. No significant differences were observed between the left and right testis. The results of the study indicate that testicular FNA should be considered a safe procedure in the cat when up to 8 punctures are performed. PMID- 22444557 TI - Cyclin B1 turnover and the mechanism causing insensitivity of fully grown mouse oocytes to cycloheximide inhibition of meiotic resumption. AB - Cyclin B1 turnover and the insensitivity of fully-grown mouse oocytes to cycloheximide (CHX) inhibition of germinal vesicle breakdown (GVBD) were examined by assaying GVBD and cyclin B1 levels after treatment of oocytes with various combinations of eCG and CHX. Whereas over 95% of oocytes underwent GVBD after culture for 24 h with CHX alone, only 10% did so after culture with CHX + eCG (P < 0.05). In addition, preculture with eCG alone had no effect, but preculture with eCG + CHX prevented GVBD during a second culture with CHX alone. Therefore, we inferred that eCG delayed GVBD long enough for CHX inhibition of protein synthesis to allow cyclin B1 to decrease below a threshold where GVBD became dependent upon its de novo synthesis. However, western blot revealed no cyclin B1 synthesis, but cyclin B1 degradation, as long as GVs were maintained intact with eCG. Regarding the function of CHX in preculture without protein synthesis to block subsequent GVBD, whereas eCG delayed GVBD for only 3 h, CHX had an ongoing effect that further postponed GVBD, thus allowing cyclin B1 to decrease below the threshold. When oocytes precultured with eCG + CHX were further cultured without eCG and CHX, cyclin B1 first decreased but then, because of the ongoing effects of CHX, increased to a level sufficient to induce GVBD. The content of P34Cdc2 was not altered under any of the culture conditions (P > 0.05). We concluded that insensitivity of mouse germinal vesicle (GV) oocytes to CHX was due to the presence of sufficient cyclin B1, and that cyclin B1 level in such oocytes was maintained by an equilibrium between synthesis and degradation. PMID- 22444558 TI - Separation of bovine spermatozoa proteins using 2D-PAGE revealed the relationship between tektin-4 expression patterns and spermatozoa motility. AB - Poor semen quality has long been associated with bull infertility. However, the molecular basis in spermatozoa cells underlying the mechanisms of bull infertility remain unknown. The purpose of this study was to determine whether there is any protein in bovine spermatozoa related to semen quality. Semen samples from 18 Brahman bulls, 3 to 10 yrs of age, were assessed for semen quality in terms of spermatozoa motility and spermatozoa morphology. Spermatozoa extracts were separated using 2D-PAGE followed by staining with Coomassie blue. At least one duplicate gel was performed for each sample. Each gel was scanned with an ImageScanner System and analyzed for spots by ImageMaster 2D platinum software. The related protein spot(s) with semen quality was cut from the gel and identified by LC MS/MS. The results showed that at least 600 protein spots were detected in the spermatozoa extracts of the Brahman bulls. Of all these spots, there were 3 of 56 kDa at pI 6.4, 6.6 and 6.8 (Z(1), Z(2) and Z(3), respectively) that clearly showed different expression pattern among 18 Brahman bulls. Of 18 bulls (a) five showed the presence of spot Z(1) and Z(2) (pattern A) (b) one of spot Z(3) (pattern B) (c) five of spot Z(2) and Z(3) (pattern C) (d) one of spot Z(1) (pattern D) and (e) six of spot Z(2) (pattern E). Identification of spot Z(1), Z(2) and Z(3) by LC MS/MS had a similar result as matched to the tektin-4 protein of Bos taurus with a respective score of 171, 557 and 591. The statistical analysis of the 56 kDa protein patterns, tektin-4, indicated a significant effect on spermatozoa motility (P < 0.05) albeit non-significant on spermatozoa morphology. The bulls which showed pattern A had a higher percentage of spermatozoa motility than pattern E (P < 0.05) and not different from pattern C (P > 0.05). The statistical analysis also revealed that the presence of spot Z(1) had an effect on the percentage of spermatozoa motility (P < 0.01), whereas the presence of spot Z(2) and Z(3) had no effect (P > 0.05). The correlation coefficient between the relative protein content of spot Z(1) and the percentage of spermatozoa motility was 0.49. Our study demonstrates that the expression patterns of tektin-4 were a proxy for an effect on spermatozoa motility and consequently bull infertility. It may be that these protein patterns can be used as markers for improving bovine reproduction. PMID- 22444559 TI - Regulation of spermatozoa motility in response to cations in Russian sturgeon Acipenser gueldenstaedtii. AB - The aim of this study was to investigate the response of Russian sturgeon (Acipenser gueldenstaedtii) sperm to external cations (Na(+), K(+), Ca(2+), and Mg(2+)) and their susceptibility on the induction of motility and swimming behavior. An in vitro spermatozoa motility assay was used by a computer-aided Motion-Analysis system. Sperm motility was inhibited by 60 mM NaCl (~140 mOsm/kg) and 0.7 mM KCl solutions (~ 21.4 mOsm/kg). The Ca(2+) and Mg(2+) ions were not able to inhibit spermatozoa motility. By contrast, Na(+) within a limited concentration range (between 45 and 55 mm) was able to reverse the inhibitory effect of K(+) at the critical concentration (0.7 mM). Ca(2+) and Mg(2+) were also able to reverse the K(+)-mediated spermatozoa motility restriction at concentrations starting at 0.01 and 0.1 mM, respectively. These results provide evidence for the role of K(+) in suppressing spermatozoa motility, and suggest that Ca(2+), Mg(2+), and possibly Na(+) trigger motility in Russian sturgeon sperm. PMID- 22444560 TI - Fecal 20-oxo-pregnane concentrations in free-ranging African elephants (Loxodonta africana) treated with porcine zona pellucida vaccine. AB - Because of overpopulation of African elephants in South Africa and the consequent threat to biodiversity, the need for a method of population control has become evident. In this regard, the potential use of the porcine zona pellucida (pZP) vaccine as an effective means for population control is explored. While potential effects of pZP treatment on social behavior of African elephants have been investigated, no examination of the influence of pZP vaccination on the endocrine correlates in treated females has been undertaken. In this study, ovarian activity of free-ranging, pZP-treated African elephant females was monitored noninvasively for 1 yr at Thornybush Private Nature Reserve, South Africa, by measuring fecal 5alpha-pregnan-3beta-ol-20-on concentrations via enzyme immunoassay. A total of 719 fecal samples from 19 individuals were collected over the study period, averaging 38 samples collected per individual (minimum, maximum: 16, 52). Simultaneously, behavioral observations were made to record the occurrence of estrous behavior for comparison. Each elephant under study showed 5alpha-pregnan-3beta-ol-20-on concentrations rising above baseline at some period during the study indicating luteal activity. Average 5alpha-pregnan-3beta-ol-20 on concentrations were 1.61 +/- 0.46 MUg/g (mean +/- SD). Within sampled females, 42.9% exhibited estrous cycles within the range reported for captive African elephants, 14.3% had irregular cycles, and 42.9% did not appear to be cycling. Average estrous cycle duration was 14.72 +/- 0.85 wk. Estrous behavior coincided with the onset of the luteal phase and a subsequent rise in 5alpha-pregnan-3beta ol-20-on concentrations. Average 5alpha-pregnan-3beta-ol-20-on levels positively correlated with rainfall. No association between average individual 5alpha pregnan-3beta-ol-20-on concentrations or cyclicity status with age or parity were detected. Earlier determination of efficacy was established via fecal hormone analysis with no pregnancies determined 22 mo post-treatment and onward. Results indicate the presence of ovarian activity amongst pZP-treated female African elephants in 2 yr after initial immunization. Further study should now be aimed toward investigating the long-term effects of pZP vaccination on the reproductive function of female African elephants. PMID- 22444561 TI - Effect of ovarian stimulation on oocyte gene expression in cattle. AB - The objective was to analyze the impact of follicle stimulating hormone (FSH, ovarian stimulation) on the transcriptome of in vivo bovine oocytes three times around the luteinizing hormone (LH) surge. In vivo bovine oocytes were collected 2 h pre-LH surge, 6 h post-LH surge, and 22 h post-LH surge in both naturally ovulating and superovulated animals. To assess potential changes in gene levels, samples were hybridized using a custom bovine microarray. Two series of hybridizations were performed: the first comparing natural vs. stimulated cycles, the second according to time of collection. Among the potential candidates, 13 genes were selected according to their degree of differential expression and their potential link to oocyte competence. Measurements of their relative mRNA levels was made using QPCR. Gene candidates BTG4 (P = 0.0006), PTTG1 (P = 0.0027), PAPOLA (P = 0.0245), and LEO1 (P = 0.0393) had higher mRNA levels in oocytes treated with FSH for all collection times when compared to oocytes produced through the natural cycle. Among our selected candidates, only one gene, GDF9 (P = 0.0261), was present at a higher level in oocytes collected at -2 h and 6 h than 22 h post-LH for all treatments, regardless of the presence of FSH. Although the number of genes influenced by ovarian stimulation seemed low, the observed differences occurred at a time of minimal transcriptional activity and supported the potential impact on the future embryo. These impacts could have been epigenetic in nature, as embryo quality was not reported to be different from stimulated animals. PMID- 22444562 TI - Characterization of male reproductive anatomy of the endangered Arabian oryx (Oryx leucoryx). AB - Reproductive tracts of four male Arabian oryx (Oryx leucoryx) from Shaumari Nature Reserve in Jordan were examined to characterize their reproductive anatomy. Animals were allocated into two groups based on their age: Group 1 (n = 2, males were 12 and 14 mo old) and Group 2 (n = 2, males were 7 and 9 yrs old). Observations regarding the morphology, position and orientation of different reproductive organs were made. The external and internal genital organs of male oryx were similar to other domestic ruminant species with minor differences. PMID- 22444563 TI - The complex process of GETting tail-anchored membrane proteins to the ER. AB - Biosynthesis of membrane proteins requires that hydrophobic transmembrane (TM) regions be shielded from the cytoplasm while being directed to the correct membrane. Tail-anchored (TA) membrane proteins, characterized by a single C terminal TM, pose an additional level of complexity because they must be post translationally targeted. In eukaryotes, the GET pathway shuttles TA-proteins to the endoplasmic reticulum. The key proteins required in yeast (Sgt2 and Get1-5) have been under extensive structural and biochemical investigation during recent years. The central protein Get3 utilizes nucleotide linked conformational changes to facilitate substrate loading and targeting. Here we analyze this complex process from a structural perspective, as understood in yeast, and further postulate on similar pathways in other domains of life. PMID- 22444564 TI - Structure and function in complex macromolecular assemblies: some evolutionary themes. PMID- 22444565 TI - The 2011 Tuscaloosa tornado: integration of pediatric disaster services into regional systems of care. AB - OBJECTIVE: To empirically describe the integration of pediatric disaster services into regional systems of care after the April 27, 2011, tornado in Tuscaloosa, Alabama, a community with no pediatric emergency department or pediatric intensive care unit and few pediatric subspecialists. STUDY DESIGN: Data were obtained in interviews with key informants including professional staff and managers from public health and emergency management agencies, prehospital emergency medical services, fire departments, hospital nurses, physicians, and the trauma program coordinator. RESULTS: A single hospital in Tuscaloosa served 800 patients on the night of the tornado. More than 100 of these patients were children, including more than 20 with critical injuries. Many children were unaccompanied and unidentified on arrival. Resuscitation and stabilization were performed by nonpediatric prehospital and emergency department staff. More than 20 children were secondarily transported to the nearest children's hospital an hour's drive away under the care of nonpediatric local emergency medical services providers. No preventable adverse events were identified in the resuscitation and secondary transport phases of care. Stockpiled supplies and equipment were adequate to serve the needs of the disaster victims, including the children. CONCLUSION: Essential aspects of preparation include pediatric-specific clinical skills, supplies and equipment, operational disaster plans, and interagency practice embedded in everyday work. Opportunities for improvement identified include more timely response to warnings, improved practices for identifying unaccompanied children, and enhanced child safety in shelters. Successful responses depended on integration of pediatric services into regional systems of care. PMID- 22444566 TI - Dual-color upconversion fluorescence and aptamer-functionalized magnetic nanoparticles-based bioassay for the simultaneous detection of Salmonella Typhimurium and Staphylococcus aureus. AB - A sensitive luminescent bioassay for the simultaneous detection of Salmonella Typhimurium and Staphylococcus aureus was developed using aptamer-conjugated magnetic nanoparticles (MNPs) for both recognition and concentration elements and using upconversion nanoparticles (UCNPs) as highly sensitive dual-color labels. The bioassay system was fabricated by immobilizing aptamer 1 and aptamer 2 onto the surface of MNPs, which were employed to capture and concentrate S. Typhimurium and S. aureus. NaY(0.78)F(4):Yb(0.2),Tm(0.02) UCNPs modified aptamer 1 and NaY(0.28)F(4):Yb(0.70),Er(0.02) UCNPs modified aptamer 2 further were bond onto the captured bacteria surface to form sandwich-type complexes. Under optimal conditions, the correlation between the concentration of S. Typhimurium and the luminescent signal was found to be linear within the range of 10(1)-10(5) cfu mL( 1) (R(2)=0.9964), and the signal was in the range of 10(1)-10(5) cfu mL(-1) (R(2)=0.9936) for S. aureus. The limits of detection of the developed method were found to be 5 and 8 cfu mL(-1) for S. Typhimurium and S. aureus, respectively. The ability of the bioassay to detect S. Typhimurium and S. aureus in real water samples was also investigated, and the results were compared to the experimental results from the plate-counting methods. Improved by the magnetic separation and concentration effect of MNPs, the high sensitivity of UCNPs, and the different emission lines of Yb/Er- and Yb/Tm-doped NaYF(4) UCNPs excited by a 980 nm laser, the present method performs with both high sensitivity and selectivity for the two different types of bacteria. PMID- 22444567 TI - Semi-automated alignment and quantification of peaks using parallel factor analysis for comprehensive two-dimensional liquid chromatography-diode array detector data sets. AB - Parallel factor analysis was used to quantify the relative concentrations of peaks within four-way comprehensive two dimensional liquid chromatography-diode array detector data sets. Since parallel factor analysis requires that the retention times of peaks between each injection are reproducible, a semi automated alignment method was developed that utilizes the spectra of the compounds to independently align the peaks without the need for a reference injection. Peak alignment is achieved by shifting the optimized chromatographic component profiles from a three-way parallel factor analysis model applied to each injection. To ensure accurate shifting, components are matched up based on their spectral signature and the position of the peak in both chromatographic dimensions. The degree of shift, for each peak, is determined by calculating the distance between the median data point of the respective dimension (in either the second or first chromatographic dimension) and the maximum data point of the peak furthest from the median. All peaks that were matched to this peak are then aligned to this common retention data point. Target analyte recoveries for four simulated data sets were within 2% of 100% recovery in all cases. Two different experimental data sets were also evaluated. Precision of quantification of two spectrally similar and partially coeluting peaks present in urine was as good as or better than 4%. Good results were also obtained for a challenging analysis of phenytoin in waste water effluent, where the results of the semi-automated alignment method agreed with the reference LC-LC MS/MS method within the precision of the methods. PMID- 22444568 TI - Tucker core consistency for validation of restricted Tucker3 models. AB - In Tucker3 analysis of three-way data array obtained from a chemical or biological system, it is sometimes possible to use a priori knowledge about the system to specify what is called a restricted Tucker3 model. Often, the restricted Tucker3 model is characterized by having some elements of the core forced to zero. As a simple example, an F-component PARAFAC model can be seen as a restricted (F, F, F) Tucker3 model in which only superdiagonal elements of the core are allowed to be nonzero. The core consistency diagnostic was previously introduced by Bro and Kiers for determining the proper number of components in PARAFAC analysis. In the current study, this diagnostic is extended to other restricted Tucker3 models to validate the appropriateness of the applied constraints. The new diagnostic is named Tucker core consistency (TuckCorCon). When the dimensionality and the pattern of the restricted core is valid, the simple core of restricted Tucker3 model and a corresponding unrestricted core will be similar and in this case the TuckCorCon will be close to maximum (100%). A simulated chemical equilibrium data set and two experimental data sets were used to evaluate the applicability of the TuckCorCon to decide about the appropriateness of dimensionality and pattern of the core nonzero elements in the restricted Tucker3 models. PMID- 22444569 TI - Electrochemical detection of a powerful estrogenic endocrine disruptor: ethinylestradiol in water samples through bioseparation procedure. AB - The synthetic estrogen ethinylestradiol (EE2) is an active component of oral contraceptives (OCs), considered as an endocrine disrupting compound (EDC). It is excreted from humans and released via sewage treatment plant effluents into aquatic environments. EDCs are any environmental pollutant chemical that, once incorporated into an organism, affects the hormonal balance of various species including humans. Its presence in the environment is becoming of great importance in water quality. This paper describes the development of an accurate, sensitive and selective method for capture, preconcentration and determination of EE2 present in water samples using: magnetic particles (MPs) as bioaffinity support for the capture and preconcentration of EE2 and a glassy carbon electrode modified with multi-walled carbon nanotubes (MWCNTs/GCE) as detection system. The capture procedure was based on the principle of immunoaffinity, the EE2 being extracted from the sample using the anti-EE2 antibodies (anti-EE2 Ab) which were previously immobilized on MPs. Subsequently the analyte desorption was done employing a sulfuric acid solution and the determination of the EE2 in the pre concentrated solution was carried out by square wave voltammetry (SWV). This method can be used to determine EE2 in the range of 0.035-70 ng L(-1) with a detection limit (LOD) of 0.01 ng L(-1) and R.S.D.<4.20%. The proposed method has been successfully applied to the determination of EE2 in water samples and it has promising analytical applications for the direct determination of EE2 at trace levels. PMID- 22444570 TI - Electrochemical sensor for naphthols based on gold nanoparticles/hollow nitrogen doped carbon microsphere hybrids functionalized with SH-beta-cyclodextrin. AB - Due to awfully harmful to the environment and human health, the qualitative and quantitative determinations of naphthols [1-naphthol (1-NAP) and 2-naphthol (2 NAP)] are of great significance and receive great attention. In this paper, gold nanoparticles (AuNPs)/hollow nitrogen-doped carbon microspheres (HNCMS) hybrids (AuNPs/HNCMS) were prepared and functionalized with thiolated-beta-cyclodextrin (HS-beta-CD) for the first time, and then applied successfully in sensitive and simultaneous electrochemical detection of naphthols. The results show that the oxidation peak currents of naphthols obtained on the HS-beta-CD/AuNPs/HNCMS modified glassy carbon (GC) electrode are much higher than that on the AuNPs/HNCMS/GC, HNCMS/GC and bare GC electrodes. Additionally, compared with other electrochemical sensors developed previously, the proposed electrode results in improved detection limits of about four times for 1-NAP (1.0 nM) and two orders of magnitude for 2-NAP (1.2 nM). The linear response ranges of both 1 NAP and 2-NAP are 2-150 nM. PMID- 22444571 TI - Nonenzymatic glucose sensor based on CuO microfibers composed of CuO nanoparticles. AB - Fluorine tin oxide (FTO) electrode modified by copper oxide microfibers (CuO-MFs) composed of numerous interconnected CuO nanoparticles (CuO-NPs) for nonenzymatic glucose sensor was prepared by electrospinning precursor containing high percentage content of copper nitrate with subsequent calcination. The results of scanning electron microscope (SEM) showed the size of CuO particles composing CuO MFs depended on the percentage content of copper nitrate in precursor solution. With increasing the percentage content of copper nitrate, the interconnected CuO NPs would gradually replace the large-size CuO particles to accumulate the CuO MFs, which have the potential to provide larger surface area and more reaction sites for electrocatalytic activity toward glucose. As a glucose sensor, the CuO MFs modified FTO electrode prepared by 40 wt.% of copper nitrate exhibited a high sensitivity of 2321 MUA mM(-1) cm(-2) with a low detection limit of 2.2 nM (signal/noise ratio (S/N)=3). Additionally, the application of the CuO-MFs modified FTO electrode as a glucose sensor for biological samples was demonstrated with satisfactory results. PMID- 22444572 TI - Bovine serum albumin recognition via thermosensitive molecular imprinted macroporous hydrogels prepared at two different temperatures. AB - A novel temperature-sensitive molecular imprinted hydrogel composed of 2 acrylamido-2-methyl-propanosulfonic acid (AMPS), N-isopropylacrylamide (NIPAm) and acrylamide (AAm) has been prepared by free-radical cross-linking copolymerization in aqueous solution under two different temperatures (25 degrees C and -20 degrees C). Bovine serum albumin (BSA, pI 4.9, MW 66.0 kDa) is used as the template protein. The influence of the external temperature stimuli on the affinity of the hydrogels was investigated, and the optimal binding conditions were tested. The adsorption capacity (Q(max)) and association constant (K) for the specific interaction between the hydrogel and the template protein were determined by Langmuir isotherm plots. Several types of reference protein, which are different in molecular weights and isoelectric points were chosen to investigate the selectivity of the hydrogels. It was shown that the shape memory and the charge effect were the major factors for the recognition. This imprinted hydrogel was used to specifically adsorb the BSA from the protein mixture and real sample, which demonstrated its potential selectivity. PMID- 22444573 TI - Cadmium (II) imprinted 3-mercaptopropyltrimethoxysilane coated stir bar for selective extraction of trace cadmium from environmental water samples followed by inductively coupled plasma mass spectrometry detection. AB - Cd(II) imprinted 3-mercaptopropyltrimethoxysilane (MPTS)-silica coated stir bar was prepared by sol-gel technique combining with a double-imprinting concept for the first time and was employed for stir bar sorptive extraction (SBSE) of trace Cd(II) from water samples followed by inductively coupled plasma mass spectrometry (ICP-MS) detection. A tetramethoxysilane (TMOS) coating was first in situ created on the glass bar surface. Afterward, a sol solution containing MPTS as the functional precursor, ethanol as the solvent and both Cd(II) and surfactant micelles (cetyltrimethylammonium bromide, CTAB) as the template was again coated on the TMOS bar. The structures of the stir bar coating were characterized by FT-IR spectroscopy. Round-bottom vial was used for the extraction of Cd(II) by SBSE to avoid abrasion of stir bar coatings. The factors affecting the extraction of Cd(II) by SBSE such as pH, stirring rate and time, sample/elution volume and interfering ions have been investigated in detail, and the optimized experimental parameters were obtained. Under the optimized conditions, the adsorption capacities of non-imprinted and imprinted coating stir bars were found to be 0.5 MUg and 0.8 MUg bar(-1). The detection limit (3sigma) based on three times standard deviations of the method blanks by 7 replicates was 4.40 ng L(-1) and the relative standard deviation (RSD) was 3.38% (c=1 MUg L(-1), n=7). The proposed method was successfully applied for the analysis of trace Cd(II) in rain water, East Lake and Yangtze River water. To validate the proposed method, certified reference material of GSBZ 50009-88 environmental water was analyzed and the determined value is in a good agreement with the certified value. The developed method is rapid, selective, sensitive and applicable for the analysis of trace Cd(II) in environmental water samples. PMID- 22444574 TI - Proteomic analysis of microvesicles in human saliva by gel electrophoresis with liquid chromatography-mass spectrometry. AB - Microvesicles (MVs) have been shown to affect the physiology of neighboring recipient cells in various ways. They play an important role in tumor progression/metastasis and angiogenesis in cancer and may be useful therapeutic tools, as well as a mechanism of cell-to-cell communication. They have been visioned as an important biomarker or biomarker source for the detection of different diseases. Human saliva is a biological fluid with enormous diagnostic potential, which harbors plenty of salivary MVs. The goal of this study is to investigate the proteomic profiling of MVs in human saliva through a simple preparation procedure by using filtration and centrifugation. Gel electrophoresis was combined with LC-MS/MS (liquid chromatography-mass spectrometry) for the proteomic analysis of MVs. After SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) protein separation, the whole lane was cut into 25 bands, and each band was subjected to in-gel trypsin digestion. The peptides extracted from each band were loaded to LC-MS/MS for protein identification. Through protein database search, 63 proteins were identified for human salivary MVs. Several members of different protein families were identified, including annexin, keratin, actin, immunoglobulin and S100. This study showed that although there was an overlap with the proteins from human saliva and salivary exosomes, salivary MVs contained their own unique proteins. These results will poise human salivary MVs as a non-invasive tool for the early detection of different diseases. PMID- 22444575 TI - Identification of phosphorylated butyrylcholinesterase in human plasma using immunoaffinity purification and mass spectrometry. AB - Paraoxon (diethyl 4-nitrophenyl phosphate) is an active metabolite of the common insecticide parathion and is acutely toxic due to the inhibition of cholinesterase (ChE) activity in the nervous systems. The inhibition of butyrylcholinesterase (BChE) activity by paraoxon is due to the formation of phosphorylated BChE adduct, and the detection of the phosphorylated BChE adduct in human plasma can serve as an exposure biomarker of organophosphate pesticides and nerve agents. In this study, we developed an immunoaffinity purification and liquid chromatography-mass spectrometry (LC-MS) strategy for identifying phosphorylated BChE in human plasma treated by paraoxon. BChE was captured by biotinylated anti-BChE polyclonal antibodies conjugated to streptavidin magnetic beads. Western blot analysis showed that the antibody was effective to recognize both native and modified BChE with high specificity. Using a purified BChE protein, we initially identified the exact phosphorylation site on the serine residue (S198) with a 108 Da modification by both MS/MS and accurately measured parent ion masses and quantified the extent of phosphorylation on S198 following paraoxon treatment to be >99.9%. Then, the phosphorylated BChE peptide in paraoxon-treated human plasma following immunoaffinity purification was successfully identified based on the accurate measured mass and retention time information initially obtained from the purified BChE protein. Thus, immunoaffinity purification combined with LC-MS represents a viable approach for the detection and quantification of phosphorylated BChE as an exposure biomarker of organophosphates and nerve agents. PMID- 22444576 TI - A highly sensitive coupling technique for the determination of trace quercetin based on solid substrate room temperature phosphorimetry and poly (vinyl alcohol) complex imprinting. AB - Al(3+) could react with quercetin (Q) to form [AlQ](3+) complex which could be used as a template for the preparation of poly (vinyl alcohol)-[AlQ](3+) complex imprinting (PVA-C-I). The [AlQ](3+) not only had good matching ability and selectivity with the cavity of PVA-C-I, but also could react with the fluorescein isothiocyanate anion (FITC(-)) on the outside of cavity by electrostatic interaction to form ion-association complex [AlQ](3+).[(FITC)(-)](3). The ion association complex could emit strong and stable room temperature phosphorescence (RTP) on polyamide membrane (PAM) and the DeltaI(p) of the system had linear relationship with the content of Q, showing the highly selective identification of PVA-C-I to Q. Thus, a new coupling technique for the determination of trace Q based on solid substrate room temperature phosphorimetry and poly (vinyl alcohol) complex imprinting (PVA-C-I-SSRTP) was established. The linear range and limit of detection (LOD) of this method were 0.010-2.0 (*10(-12) g mL(-1)) and 2.0*10(-14) g mL(-1), respectively, showing wide linear range and high sensitivity of PVA-C-I SSRTP. This method was used to determine the content of Q in waste water, and the results are consistent with those by spectrofluorimetry. Meanwhile, the mechanism for the determination of Q using PVA-C-I-SSRTP was also discussed. PMID- 22444577 TI - Detection of influenza A virus based on fluorescence resonance energy transfer from quantum dots to carbon nanotubes. AB - In this paper, a simple and sensitive approach for H5N1 DNA detection was described based on the fluorescence resonance energy transfer (FRET) from quantum dots (QDs) to carbon nanotubes (CNTs) in a QDs-ssDNA/oxCNTs system, in which the QDs (CdTe) modified with ssDNA were used as donors. In the initial stage, with the strong interaction between ssDNA and oxCNTs, QDs fluorescence was effectively quenched. Upon the recognition of the target, the effective competitive bindings of it to QDs-ssDNA occurred, which decreased the interactions between the QDs ssDNA and oxCNTs, leading to the recovery of the QDs fluorescence. The recovered fluorescence of QDs was linearly proportional to the concentration of the target in the range of 0.01-20 MUM with a detection limit of 9.39 nM. Moreover, even a single-base mismatched target with the same concentration of target DNA can only recover a limited low fluorescence of QDs, illustrating the good anti interference performance of this QDs-ssDNA/oxCNTs system. This FRET platform in the QDs-ssDNA/oxCNTs system was facilitated to the simple, sensitive and quantitative detection of virus nucleic acids and could have a wide range of applications in molecular diagnosis. PMID- 22444578 TI - A colorimetric and surface-enhanced Raman scattering dual-signal sensor for Hg2+ based on Bismuthiol II-capped gold nanoparticles. AB - The addition of Bismuthiol II to the gold nanoparticles (AuNPs) solution led to the aggregation of AuNPs with a color change from red to blue. As a result, hot spots were formed and strong surface-enhanced Raman scattering (SERS) signal of Bismuthiol II was observed. However, the Bismuthiol II-induced aggregation of AuNPs could be reversed by Hg(2+) in the system, accompanied by a remarkable color change from blue to red. As evidenced by UV-vis and SERS spectroscopy, the variation in absorption band and SERS intensity was strongly dependent on the concentration of Hg(2+), suggesting a colorimetric and SERS dual-signal sensor for Hg(2+). The sensor had a high sensitivity, low detection limits of 2nM and 30nM could be achieved by UV-vis spectroscopy and by SERS spectroscopy, respectively. Other environmentally relevant metal ions did not interfere with the detection of Hg(2+). The method was successfully applied to detect Hg(2+) in water samples. It was simple, rapid and cost-effective without any modifying or labeling procedure. PMID- 22444579 TI - Glucose biosensor based on three dimensional ordered macroporous self-doped polyaniline/Prussian blue bicomponent film. AB - In this paper, a three dimensional ordered macroporous self-doped polyaniline/Prussian blue (3DOM SPAN/PB) bicomponent film was fabricated via the inverted crystal template technique using step-by-step electrodeposition. In this bicomponent film, PB not only acted as a redox mediator, but also presented increased stability in neutral or weak alkaline solution by the protection of SPAN layer on the top. A novel glucose biosensor was fabricated based on the large active surface area and excellent conductivity possessed by the 3DOM SPAN/PB film. The applying experimental conditions of the glucose biosensor have been optimized. Under the optimal conditions, the biosensor showed a wide linear range over three orders of magnitude in glucose concentrations (from 2 to 1600 MUM) and a low detection limit of 0.4 MUM. Moreover, the biosensor exhibited short response time, high selectivity and excellent operation stability, which can be applied to detect the blood sugar in real samples without any pretreatment. PMID- 22444580 TI - A dityrosine-based substrate for a protease assay: application for the selective assessment of papain and chymopapain activity. AB - N,N'-diBoc-dityrosine (DBDY), which was synthesized by the oxidative C-C coupling of 2 N-Boc-L-tyrosine molecules, was conjugated with two isoniazid (INH) molecules. Due to the quenching effect of INH, DBDY-(INH)(2) lacks the fluorescence of DBDY. As such, it was tested for use in the detection of proteases by measuring fluorescence recovery. In this study, serine proteases (chymotrypsin, trypsin, subtilisin, and proteinase K), metalloproteases (thermolysin and carboxypeptidase A, dispase, and collagenase), aspartic proteases (pepsin and aspergillopepsin) and cysteine proteases (papain and chymopapain) were chosen. Reported optimum assay conditions were chosen for each enzyme. Only papain and chymopapain catalyzed the hydrolysis of DBDY-(INH)(2) and led to fluorescence recovery, possibly due to their extensive binding sites and the INH-mediated inhibition of metalloproteases and aspartic proteases. PMID- 22444581 TI - [Early clinical indicators of pervasive development disorders]. AB - INTRODUCTION: Pervasive development disorders (PDD) conditions characterised by deficits in many areas of behaviour, such as delay in social interactions, abnormalities in verbal and non-verbal communication, and the presence of the restrictive and repetitive interests. The relevance of early diagnosis is based on the fact that early intervention could have a beneficial effect on the long term outcome. Due to the increase of the PDD diagnosis in the recent years, we aimed to study easily detectable clinical traits during the first year of life, leading to an improvement in the diagnosis. PATIENTS AND INTERVENTIONS: A prospective and retrospective study was conducted on 37 PDD patients and 69 healthy controls. Somatometric and neurological examinations were performed and a questionnaire with several variables from the Modified Checklist for Autism in Toddlers (M-CHAT) completed by the parents. RESULTS: The male to female ratio (OR: 3.87; 95% CI: 1.23-12.96), delay in the first disyllabic words (PDD=20.1+/ 23 months vs Control=10.8+/-10.3 months; P<.01), absence of visual contact (OR: 0.05; 95% CI: 0.01-0.29), the lack of response to attention call (OR: 0.12; 95% CI: 0.02-0.67), and the increase in tantrums (OR: 6.37; 95% CI: 2.39-17.34), were significantly higher in the PDD group. CONCLUSIONS: The differences detected between groups can not been considered as a diagnostic tool of certainty in this time period, however, we believe that they should be considered in the context of maturational delay, as alarm signs in infants and toddlers, as well as suggesting the existence of an early pervasive development phenotype. PMID- 22444582 TI - Proximal ligand electron donation and reactivity of the cytochrome P450 ferric peroxo anion. AB - CYP125 from Mycobacterium tuberculosis catalyzes sequential oxidation of the cholesterol side-chain terminal methyl group to the alcohol, aldehyde, and finally acid. Here, we demonstrate that CYP125 simultaneously catalyzes the formation of five other products, all of which result from deformylation of the sterol side chain. The aldehyde intermediate is shown to be the precursor of both the conventional acid metabolite and the five deformylation products. The acid arises by protonation of the ferric-peroxo anion species and formation of the ferryl-oxene species, also known as Compound I, followed by hydrogen abstraction and oxygen transfer. The deformylation products arise by addition of the same ferric-peroxo anion to the aldehyde intermediate to give a peroxyhemiacetal that leads to C-C bond cleavage. This bifurcation of the catalytic sequence has allowed us to examine the effect of electron donation by the proximal ligand on the properties of the ferric-peroxo anion. Replacement of the cysteine thiolate iron ligand by a selenocysteine results in UV-vis, EPR, and resonance Raman spectral changes indicative of an increased electron donation from the proximal selenolate ligand to the iron. Analysis of the product distribution in the reaction of the selenocysteine substituted enzyme reveals a gain in the formation of the acid (Compound I pathway) at the expense of deformylation products. These observations are consistent with an increase in the pK(a) of the ferric-peroxo anion, which favors its protonation and, therefore, Compound I formation. PMID- 22444583 TI - Nature cure: bioremediation as a sustainable solution for polluted sites. PMID- 22444584 TI - Cleaning up polyketide synthases. AB - Complex biosynthetic enzymes such as polyketide synthases make mistakes. In this issue of Chemistry & Biology, Jensen et al. report that a discrete family of acyltransferases is responsible for error correction, hydrolyzing key biosynthetic intermediates from a multi-enzyme complex. This activity might find use in understanding polyketide biosynthesis, particularly in uncultivated organisms and in tailoring the synthesis of small molecules. PMID- 22444585 TI - We see the light: chemical-genetic protein regulation. AB - The challenge of studying complex protein networks in whole animals has driven the development of new methods for manipulating protein function with spatial and temporal precision. A novel combination of chemical and genetic protein regulation (Rodriguez and Wolfgang, in this issue of Chemistry & Biology) achieves levels of control that will revolutionize the study of protein function. PMID- 22444586 TI - For MutY, it's all about the OG. AB - MutY and its human ortholog, MUTYH, repair a specific form of DNA damage: adenine mis-paired with the oxidatively modified form of deoxyguanosine, 8-oxo-7,8 dihydro-2'-deoxyguanosine. In a recent issue of Chemistry & Biology, Brinkmeyer et al. utilized mutant forms of MutY to reveal the critical residues in MutY that are required for this selectivity and specificity. PMID- 22444587 TI - Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. AB - The conversion of proteins from their native state to misfolded oligomers is associated with, and thought to be the cause of, a number of human diseases, including Alzheimer's disease, Parkinson's disease, and systemic amyloidoses. The study of the structure, mechanism of formation, and biological activity of protein misfolded oligomers has been challenged by the metastability, transient formation, and structural heterogeneity of such species. In spite of these difficulties, in the past few years, many experimental approaches have emerged that enable the detection and the detailed molecular study of misfolded oligomers. In this review, we describe the basic and generic knowledge achieved on protein oligomers, describing the mechanisms of oligomer formation, the methodologies used thus far for their structural determination, and the structural elements responsible for their toxicity. PMID- 22444588 TI - Polyketide proofreading by an acyltransferase-like enzyme. AB - Trans-acyltransferase polyketide synthases (trans-AT PKSs) are an important group of bacterial enzymes producing bioactive polyketides. One difference from textbook PKSs is the presence of one or more free-standing AT-like enzymes. While one homolog loads the PKS with malonyl units, the function of the second copy (AT2) was unknown. We studied the two ATs PedC and PedD involved in pederin biosynthesis in an uncultivated symbiont. PedD displayed malonyl- but not acetyltransferase activity toward various acyl carrier proteins (ACPs). In contrast, the AT2 PedC efficiently hydrolyzed acyl units bound to N acetylcysteamine or ACP. It accepted substrates with various chain lengths and functionalizations but did not cleave malonyl-ACP. These data are consistent with the role of PedC in PKS proofreading, suggesting a similar function for other AT2 homologs and providing strategies for polyketide titer improvement and biosynthetic investigations. PMID- 22444589 TI - An optimized activity-based probe for the study of caspase-6 activation. AB - Although significant efforts have been made to understand the mechanisms of caspase activation during apoptosis, many questions remain regarding how and when executioner caspases get activated. We describe the design and synthesis of an activity-based probe that labels caspase-3/-6/-7, allowing direct monitoring of all executioner caspases simultaneously. This probe has enhanced in vivo properties and reduced cross-reactivity compared to our previously reported probe, AB50. Using this probe, we find that caspase-6 undergoes a conformational change and can bind substrates even in the absence of cleavage of the proenzyme. We also demonstrate that caspase-6 activation does not require active caspase-3/ 7, suggesting that it may autoactivate or be cleaved by other proteases. Together, our results suggest that caspase-6 activation proceeds through a unique mechanism that may be important for its diverse biological functions. PMID- 22444590 TI - A fluorogenic red fluorescent protein heterodimer. AB - The expanding repertoire of genetically encoded biosensors constructed from variants of Aequorea victoria green fluorescent protein (GFP) enable the imaging of a variety of intracellular biochemical processes. To facilitate the imaging of multiple biosensors in a single cell, we undertook the development of a dimerization-dependent red fluorescent protein (ddRFP) that provides an alternative strategy for biosensor construction. An extensive process of rational engineering and directed protein evolution led to the discovery of a ddRFP with a K(d) of 33 MUM and a 10-fold increase in fluorescence upon heterodimer formation. We demonstrate that the dimerization-dependent fluorescence of ddRFP can be used for detection of a protein-protein interaction in vitro, imaging of the reversible Ca2+-dependent association of calmodulin and M13 in live cells, and imaging of caspase-3 activity during apoptosis. PMID- 22444591 TI - Heterologous expression and genetic engineering of the tubulysin biosynthetic gene cluster using Red/ET recombineering and inactivation mutagenesis. AB - Although the tubulysin (tub) biosynthetic gene cluster has been located in two myxobacterial strains, it appears in both cases to be incomplete as obvious candidates for acyl transfer and oxidation functions are lacking. Here, we report the engineering of a heterologous expression system for the tub biosynthetic pathway from strain Cystobacter sp. SBCb004. The entire tub core cluster was reconstituted from two cosmids using Red/ET recombineering and heterologous expression achieved in strains Pseudomonas putida and Myxococcus xanthus. Availability of the heterologous expression system and the natural producer strain SBCb004 provided a platform for the functional investigation of various biosynthetic genes by targeted inactivation. In addition, BLAST analysis of SBCb004 genome data was used to identify multiple candidate monooxygenases, whose involvement in tubulysin assembly was evaluated using a combination of knockout mutagenesis and heterologous expression. PMID- 22444592 TI - EccA1, a component of the Mycobacterium marinum ESX-1 protein virulence factor secretion pathway, regulates mycolic acid lipid synthesis. AB - Pathogenic mycobacteria, which cause multiple diseases including tuberculosis, secrete factors essential for disease via the ESX-1 protein export system and are partially protected from host defenses by their lipid-rich cell envelopes. These pathogenic features of mycobacterial biology are believed to act independently of each other. Key ESX-1 components include three ATPases, and EccA1 (Mycobacterium marinum MMAR_5443; M. tuberculosis Rv3868) is the least characterized. Here we show that M. marinum EccA1's ATPase activity is required for ESX-1-mediated protein secretion, and surprisingly for the optimal synthesis of mycolic acids, integral cell-envelope lipids. Increased mycolic acid synthesis defects, observed when an EccA1-ATPase mutant is expressed in an eccA1-null strain, correlate with decreased in vivo virulence and intracellular growth. These data suggest that two mycobacterial virulence hallmarks, ESX-1-dependent protein secretion and mycolic acid synthesis, are critically linked via EccA1. PMID- 22444593 TI - Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa. AB - The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K(d,app) of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design. PMID- 22444594 TI - Targeted chemical-genetic regulation of protein stability in vivo. AB - Loss- and gain-of-function transgenic models are powerful tools for understanding gene function in vivo but are limited in their ability to determine relative protein requirements. To determine cell-specific, temporal, or dose requirements of complex pathways, new methodology is needed. This is particularly important for deconstructing metabolic pathways that are highly interdependent and cross regulated. We have combined mouse conditional transgenics and synthetic posttranslational protein stabilization to produce a broadly applicable strategy to regulate protein and pathway function in a cell-autonomous manner in vivo. Here, we show how a targeted chemical-genetic strategy can be used to alter fatty acid metabolism in a reombination and small-molecule-dependent manner in live behaving transgenic mice. This provides a practical, specific, and reversible means of manipulating metabolic pathways in adult mice to provide biological insight. PMID- 22444595 TI - Elucidating the biosynthetic pathway for the polyketide-nonribosomal peptide collismycin A: mechanism for formation of the 2,2'-bipyridyl ring. AB - The gene cluster for the bipyridyl compound collismycin was characterized from Streptomyces sp. CS40. Sequence analysis of a 46.7 kb DNA region revealed 27 open reading frames, 23 of which are involved in collismycin biosynthesis. Eight insertional inactivation mutants were generated in the sequenced region to prove its involvement in collismycin biosynthesis, define the boundaries of the cluster, functionally characterize some genes, and isolate two biosynthetic intermediates. A model for collismycin biosynthesis--which includes the conversion of lysine into picolinic acid, participation of a polyketide synthase non-ribosomal peptide synthetase system, and some further modifications--is proposed. The biosynthetic pathway would include an unusual NRPS-mediated incorporation of a cysteine residue, possibly through a Michael addition and followed by the extension of the peptide chain by leucine incorporation and later removal by amidohydrolase. PMID- 22444596 TI - Structure-based redesign of GST A2-2 for enhanced catalytic efficiency with azathioprine. AB - Glutathione transferase (GST) A2-2 is the most efficient human enzyme in the biotransformation of the prodrug azathioprine (Aza). The activation of Aza has therapeutic potential for possible use of GSTs in targeted enzyme-prodrug treatment of diseases. Based on the assumed catalytic mechanism and computational docking of Aza to the active site of the enzyme, active-site residues were selected for construction of focused mutant libraries, which were thereafter screened for Aza activity. Mutants with elevated Aza activity were identified, DNA sequenced, and the proteins purified. The two most active mutants showed up to 70-fold higher catalytic efficiency than the parental GST A2-2. The structure of the most active triple mutant (L107G/L108D/F222H) enzyme was determined by X ray crystallography demonstrating significant changes in the topography of the active site facilitating productive binding of Aza as a substrate. PMID- 22444597 TI - Unveiling the post-PKS redox tailoring steps in biosynthesis of the type II polyketide antitumor antibiotic xantholipin. AB - Xantholipin from Streptomyces flavogriseus is a curved hexacyclic aromatic polyketide antitumor antibiotic. The entire 52 kb xantholipin (xan) biosynthetic gene cluster was sequenced, and bioinformatic analysis revealed open reading frames encoding type II polyketide synthases, regulators, and polyketide tailoring enzymes. Individual in-frame mutagenesis of five tailoring enzymes lead to the production of nine xantholipin analogs, revealing that the xanthone scaffold formation was catalyzed by the FAD binding monooxygenase XanO4, the delta-lactam formation by the asparagine synthetase homolog XanA, the methylenedioxy bridge generation by the P450 monooxygenase XanO2 and the hydroxylation of the carbon backbone by the FAD binding monooxygenase XanO5. These findings may also apply to other polycyclic xanthone antibiotics, and they form the basis for genetic engineering of the xantholipin and similar biosynthetic gene clusters for the generation of compounds with improved antitumor activities. PMID- 22444598 TI - Relative telomere length: a novel non-invasive biomarker for the risk of non cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection. AB - BACKGROUND AND AIMS: Telomere length has emerged as a promising risk predictor of various cancers including hepatocellular carcinoma (HCC). However, the majority of studies in this area measured telomere length in hepatocytes and one in lymphocytes with conflicting results. Moreover, no studies have been reported on using circulating DNA telomere length as a non-invasive HCC biomarker. METHODS: We conducted a nested case-control study to determine the relative telomere length (RTL) in serum DNA from 140 hepatitis B virus (HBV)-related HCC cases and 280 frequency-matched cancer-free HBV controls. RESULTS: Cases had a significantly longer RTL (median, 0.31; range, 0.02-2.31) than controls (median, 0.20; range, 0.01-1.60) (P = 0.003). Consistently, longer RTLs conferred a significantly increased HCC risk compared to short RTLs in a univariate logistic regression analysis (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.02 2.33, P = 0.038). This association attenuated after multivariate adjustment (OR = 1.40, 95% CI = 0.90-2.19, P = 0.132). In a quartile analysis, a significant dose response relationship was noted in univariate analysis (P(trend) = 0.017) which was again attenuated in multivariate analysis (P(trend) = 0.079). Further analyses revealed that the significant association between serum RTL and HCC risk was evident in non-cirrhotic (OR = 3.54, 95% CI 1.58-7.93 P = 0.002), but not cirrhotic (OR = 0.95, 95% CI 0.55-1.64, P = 0.860) HBV patients. Moreover, the significantly increased HCC risk conferred by cirrhosis was modulated by RTL with a significant interaction effect (P(interaction) = 0.013). CONCLUSIONS: RTL in circulating cell-free serum DNA could potentially be used as a novel non-invasive biomarker for non-cirrhotic HCC. Prospective cohort studies are warranted to validate this finding and assess its clinical significance in HCC prevention. PMID- 22444599 TI - Neurobiological correlates of illness progression in the recurrent affective disorders. AB - Some clinical aspects of affective illness progression, such as episode-, stress , and substance-induced sensitization, have been well documented in the literature, but others have received less attention. These include cognitive deficits, treatment-refractoriness, and neurobiological correlates of illness progression, which are the primary focus of this paper. We review the evidence that cognitive dysfunction, treatment resistance, medical comorbidities, and neurobiological abnormalities increase as a function of the number of prior episodes or duration of illness in the recurrent unipolar and bipolar disorders. Substantial evidence supports the view that cognitive dysfunction and vulnerability to a diagnosis of dementia in old age increases as a function of number of prior mood episodes as does non-response to many therapeutic interventions as well as naturalistic treatment. Neurobiological abnormalities that correlate with the number of mood episodes or duration of illness include: anatomical, functional, and biochemical deficits in the prefrontal cortex and hippocampus, as well as amygdala hyperactivity and cortisol hyper-secretion. Some neurotrophic factors and inflammatory markers may also change with greater illness burden. Causality cannot be inferred from these correlative relationships. Nonetheless, given the potentially grave consequences of episode recurrence and progression for morbidity and treatment non-responsiveness, it is clinically wise to assume episodes are causing some of the progressive cognitive and neurobiological abnormalities. As such, earlier and more sustained long-term prophylaxis to attempt to reduce these adverse outcomes is indicated. PMID- 22444600 TI - Comparison of the course of substance use disorders among individuals with and without generalized anxiety disorder in a nationally representative sample. AB - Generalized anxiety disorder (GAD) and substance use disorders (SUDs) are highly comorbid, and GAD-SUD comorbidity is associated with a host of poor psychosocial outcomes, including higher rates of hospitalization, disability, functional impairment, and inferior GAD and SUD treatment outcomes. Despite the noted severity of this group and clinical implications, current research is limited in a few distinct ways; studies have rarely utilized a longitudinal design and non treatment seeking individuals to examine how GAD comorbidity impacts SUD outcomes over time. The current study utilized a nationally representative sample of individuals in the U.S. assessed in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) at Wave 1 (2001-2002) and Wave 2 (2004 2005), comparing individuals who met criteria for both DSM-IV past year GAD and SUD (n = 286) and those who met criteria for past year SUD only without GAD (n = 5730) at Wave 1. Results indicated that GAD-SUD individuals were significantly more severe than the SUD only group across almost all outcomes assessed (with the exception of alcohol frequency); individuals with GAD-SUD had a more severe psychiatric history, worse health-related quality of life at both waves, greater incidence of new Axis I disorders, higher rates of treatment seeking, and greater self-reported drug use at the follow up. The current study is the first to compare individuals with SUD with and without comorbid GAD over time using a nationally representative sample. Findings further support the clinical severity of this group and suggest the need for GAD-SUD treatment options. PMID- 22444601 TI - A survey of energy drinks consumption practices among student -athletes in Ghana: lessons for developing health education intervention programmes. AB - BACKGROUND: Globally, young adults and college athletes are primary targets of the marketing campaigns of energy drink companies. Consequently, it is reported that young adults and college athletes consume energy drinks frequently. The purpose of this study was to determine the prevalence of energy drink consumption among student-athletes selected from seven public universities in Ghana. The study assessed the energy drink consumption patterns, types usually consumed, frequency of consumption and reasons why athletes consumed energy drinks. METHODS: A total number of 180 student-athletes gave their consent to participate in the study and completed a questionnaire which was administered during an inter university sports competition. RESULTS: Most of the participants (62.2%) reported consuming at least one can of energy drink in a week. A high proportion (53.6%) of the respondents who drink energy drinks indicated that they did so to replenish lost energy after training or a competition. Other reasons given as to why energy drinks were consumed by the study participants included to provide energy and fluids to the body (25.9%), to improve performance (9.8%) and to reduce fatigue (5.4%). CONCLUSION: These results suggest the need to plan health education programmes to particularly correct some wrong perceptions that athletes have regarding the benefits of energy drinks and also create awareness among student-athletes about the side effects of excessive intake of energy drinks. PMID- 22444602 TI - Contemporary management of endometrial cancer. AB - The treatment of endometrial cancer has changed substantially in the past decade with the introduction of a new staging system and surgical approaches accompanied by novel adjuvant therapies. Primary surgical treatment is the mainstay of therapy but the effectiveness and extent of lymphadenectomy has been challenged, and its acceptance as a routine procedure varies by country. The role of radiation has evolved and chemotherapy has been incorporated, either alone or combined with radiation, to treat the many patients in whom cancer recurs because of a tumour outside the originally radiated pelvic and lower abdominal area. Use of traditional adjuvant chemotherapeutics has been challenged in clinical trials of new agents with improved side-effect profiles. Novel agents and targeted therapies are being investigated. Research into genetic susceptibility to endometrial cancer and the potential genetic aberrations that might translate into therapeutic interventions continues to increase. Substantial global variability in the treatment of endometrial cancer has led to examination of long accepted norms, which has resulted in rapidly changing standards. International cooperation in clinical trials will hasten progress in treatment of this ubiquitous cancer. PMID- 22444603 TI - Guest editorial: Ruminant physiology; digestion, metabolism and effects of nutrition on reproduction and welfare. PMID- 22444604 TI - Evolutionary adaptations of ruminants and their potential relevance for modern production systems. AB - Comparative physiology applies methods established in domestic animal science to a wider variety of species. This can lead to improved insight into evolutionary adaptations of domestic animals, by putting domestic species into a broader context. Examples include the variety of responses to seasonally fluctuating environments, different adaptations to heat and drought, and in particular adaptations to herbivory and various herbivore niches. Herbivores generally face the challenge that a high food intake compromises digestive efficiency (by reducing ingesta retention time and time available for selective feeding and for food comminution), and a variety of digestive strategies have evolved in response. Ruminants are very successful herbivores. They benefit from potential advantages of a forestomach without being constrained in their food intake as much as other foregut fermenters, because of their peculiar reticuloruminal sorting mechanism that retains food requiring further digestion but clears the forestomach of already digested material; the same mechanism also optimises food comminution. Wild ruminants vary widely in the degree to which their rumen contents 'stratify', with little stratification in 'moose-type' ruminants (which are mostly restricted to a browse niche) and a high degree of stratification into gas, particle and fluid layers in 'cattle-type' ruminants (which are more flexible as intermediate feeders and grazers). Yet all ruminants uniformly achieve efficient selective particle retention, suggesting that functions other than particle retention played an important role in the evolution of stratification-enhancing adaptations. One interesting emerging hypothesis is that the high fluid turnover observed in 'cattle-type' ruminants - which is a prerequisite for stratification - is an adaptation that not only leads to a shift of the sorting mechanism from the reticulum to the whole reticulo-rumen, but also optimises the harvest of microbial protein from the forestomach. Although potential benefits of this adaptation have not been quantified, the evidence for convergent evolution toward stratification suggests that they must be substantial. In modern production systems, the main way in which humans influence the efficiency of energy uptake is by manipulating diet quality. Selective breeding for conversion efficiency has resulted in notable differences between wild and domestic animals. With increased knowledge on the relevance of individual factors, that is fluid throughput through the reticulo-rumen, more specific selection parameters for breeding could be defined to increase productivity of domestic ruminants by continuing certain evolutionary trajectories. PMID- 22444605 TI - Gene expression in the digestive tissues of ruminants and their relationships with feeding and digestive processes. AB - The gastrointestinal tract (GIT) has multiple functions including digestion, nutrient absorption, secretion of hormones and excretion of wastes. In the ruminant animal, development of this organ system is more complex than that of the monogastric animal due to the necessity to establish a fully functional and differentiated rumen, in which a diverse microbial population of bacteria, fungi and protozoa support fermentation and digestion of dietary fiber. Central to the goal of animal scientists to enhance nutrient uptake and production efficiency of ruminants is the need for a comprehensive understanding of GIT development, as well as conditions that alter the digestion process. The relatively recent availability of genome sequence information has permitted physiological investigations related to the process of digestion for many agriculturally important species at the gene transcript level. For instance, numerous studies have evaluated the expression of ruminant GIT genes to gain insight into mechanisms involved in normal function, physiology and development, such as nutrient uptake and transport across the epithelial cell barrier throughout the alimentary canal, maintenance of rumen pH, and regulation of GIT motility and cell proliferation. Further, multiple studies have examined the effects of dietary modification, including feeding of supplemental fat, starch and protein, or a forage- v. concentrate-based diet on expression of critical gene pathways in the gut. In addition, the expression of genes in the GIT in response to disease, such as infection with gastrointestinal parasites, has been investigated. This review will summarize some of the recent scientific literature related to the gene expression in the GIT of ruminants, primarily cattle, sheep and goats, as it pertains to normal physiology, and dietary, developmental, and disease effects to provide an overview of critical proteins participating in the overall digestive processes, and their physiological functions. Recent findings from our laboratory will be highlighted also related to expression of the glucagon-like peptide two hormone pathway in the GIT of dairy cattle during in various stages of the development and lactation, alterations in gene pathways associated with the rumen development and differentiation in the weaning calf, and genes of the GIT responding to Ostertagia, a common nematode infection of the cattle. Finally, prospective areas of investigation will be highlighted. PMID- 22444606 TI - The role of microbes in rumen lipolysis and biohydrogenation and their manipulation. AB - Despite the fact that the ruminant diet is rich in polyunsaturated fatty acids (PUFA), ruminant products - meat, milk and dairy - contain mainly saturated fatty acids (SFA) because of bacterial lipolysis and subsequent biohydrogenation of ingested PUFA in the rumen. The link between SFA consumption by man and coronary heart disease is well established. In contrast, ruminant products also contain fatty acids that are known to be beneficial to human health, namely conjugated linoleic acids (CLAs). The aims of research in this field have been to understand the microbial ecology of lipolysis and biohydrogenation and to find ways of manipulating ruminal microbes to increase the flow of PUFA and CLA from the rumen into meat and milk. This review describes our present understanding of the microbial ecology of ruminal lipid metabolism, including some apparently anomalous and paradoxical observations, and the status of how the metabolism may be manipulated and the possible consequential effects on other aspects of ruminal digestion. Intuitively, it may appear that inhibiting the ruminal lipase would cause more dietary PUFA to reach the mammary gland. However, lipolysis releases the non-esterified fatty acids that form the substrates for biohydrogenation, but which can, if they accumulate, inhibit the whole process. Thus, increasing lipase activity could be beneficial if the increased release of non-esterified PUFA inhibited the metabolism of CLA. Rumen ciliate protozoa do not carry out biohydrogenation, yet protozoal lipids are much more highly enriched in CLA than bacterial lipids. How could this happen if protozoa do not metabolise PUFA? The answer seems to lie in the ingestion of plant organelles, particularly chloroplasts, and the partial metabolism of the fatty acids by contaminating bacteria. Bacteria related to Butyrivibrio fibrisolvens are by far the most active and numerous biohydrogenating bacteria isolated from the rumen. But do we misunderstand the role of different bacterial species in biohydrogenation because there are uncultivated species that we need to understand and include in the analysis? Manipulation methods include dietary vegetable and fish oils and plant derived chemicals. Their usefulness, efficacy and possible effects on fatty acid metabolism and on ruminal microorganisms and other areas of their metabolism are described, and areas of opportunity identified. PMID- 22444607 TI - Microbial ecosystem and methanogenesis in ruminants. AB - Ruminant production is under increased public scrutiny in terms of the importance of cattle and other ruminants as major producers of the greenhouse gas methane. Methanogenesis is performed by methanogenic archaea, a specialised group of microbes present in several anaerobic environments including the rumen. In the rumen, methanogens utilise predominantly H2 and CO2 as substrates to produce methane, filling an important functional niche in the ecosystem. However, in addition to methanogens, other microbes also have an influence on methane production either because they are involved in hydrogen (H2) metabolism or because they affect the numbers of methanogens or other members of the microbiota. This study explores the relationship between some of these microbes and methanogenesis and highlights some functional groups that could play a role in decreasing methane emissions. Dihydrogen ('H2' from this point on) is the key element that drives methane production in the rumen. Among H2 producers, protozoa have a prominent position, which is strengthened by their close physical association with methanogens, which favours H2 transfer from one to the other. A strong positive interaction was found between protozoal numbers and methane emissions, and because this group is possibly not essential for rumen function, protozoa might be a target for methane mitigation. An important function that is associated with production of H2 is the degradation of fibrous plant material. However, not all members of the rumen fibrolytic community produce H2. Increasing the proportion of non-H2 producing fibrolytic microorganisms might decrease methane production without affecting forage degradability. Alternative pathways that use electron acceptors other than CO2 to oxidise H2 also exist in the rumen. Bacteria with this type of metabolism normally occupy a distinct ecological niche and are not dominant members of the microbiota; however, their numbers can increase if the right potential electron acceptor is present in the diet. Nitrate is an alternative electron sinks that can promote the growth of particular bacteria able to compete with methanogens. Because of the toxicity of the intermediate product, nitrite, the use of nitrate has not been fully explored, but in adapted animals, nitrite does not accumulate and nitrate supplementation may be an alternative under some dietary conditions that deserves to be further studied. In conclusion, methanogens in the rumen co-exist with other microbes, which have contrasting activities. A better understanding of these populations and the pathways that compete with methanogenesis may provide novel targets for emissions abatement in ruminant production. PMID- 22444608 TI - Transport of cations and anions across forestomach epithelia: conclusions from in vitro studies. AB - Secretion of saliva as well as absorptive and secretory processes across forestomach epithelia ensures an optimal environment for microbial digestion in the forestomachs. Daily salivary secretion of sodium (Na+) exceeds the amount found in plasma by a factor of 2 to 3, while the secretion of bicarbonate (HCO3-) is 6 to 8 times higher than the amount of HCO3- in the total extracellular space. This implies a need for efficient absorptive mechanisms across forestomach epithelia to allow for an early recycling. While Na+ is absorbed from all forestomachs via Na+/H+ exchange and a non-selective cation channel that shows increased conductance at low concentrations of Mg2+, Ca2+ or H+ in the luminal microclima and at low intracellular Mg2+, HCO3- is secreted by the rumen for the buffering of ingesta but absorbed by the omasum to prevent liberation of CO2 in the abomasum. Fermentation provides short chain fatty acids and ammonia (NH3) that have to be absorbed both to meet nutrient requirements and maintain ruminal homeostasis of pH and osmolarity. The rumen is an important location for the absorption of essential minerals such as Mg2+ from the diet. Other ions can be absorbed, if delivered in sufficient amounts (Ca2+, Pi, K+, Cl- and NH4+). Although the presence of transport mechanisms for these electrolytes has been described earlier, our knowledge about their nature, regulation and crosstalk has increased greatly in the last years. New transport pathways have recently been added to our picture of epithelial transport across rumen and omasum, including an apical non-selective cation conductance, a basolateral anion conductance, an apical H+-ATPase, differently expressed anion exchangers and monocarboxylate transporters. PMID- 22444609 TI - Carbohydrate quantitative digestion and absorption in ruminants: from feed starch and fibre to nutrients available for tissues. AB - Carbohydrates are the main source of energy in ruminants. Their site, extent and kinetics of digestion highly impact the amount and profile of nutrients delivered to peripheral tissues, and the responses of the animal, i.e. ingestion, efficiency of production, N and methane excretion, quality of products and welfare. Development of multi-objective feed evaluation systems thus requires a more integrated quantitative knowledge on carbohydrate digestion and yield of terminal products, as well as on their metabolism by splanchnic tissues. The objective of this paper is to review (i) quantitative knowledge on fibre, starch and sugar digestion, volatile fatty acids (VFA) and glucose production and splanchnic metabolism and (ii) modelling approaches which aim at representing and/or predicting nutrient fluxes in the digestive tract, portal and hepatic drainage. It shows that the representation of carbohydrate digestion and VFA yield is relatively homogeneous among models. Although published quantitative comparisons of these models are scarce, they stress that prediction of fibre digestion and VFA yield and composition is still not good enough for use in feed formulation, whereas prediction of microbial N yield and ruminal starch digestion seems to be more satisfactory. Uncertainties on VFA stoichiometric coefficients and absorption rates may partly explain the poor predictions of VFA. Hardly any mechanistic models have been developed on portal-drained viscera (PDV) metabolism whereas a few exist for liver metabolism. A qualitative comparison of these models is presented. Most are focused on dairy cows and their level of aggregation in the representation of nutrient fluxes and metabolism highly differs depending on their objectives. Quantitative comparison of these models is still lacking. However, recent advances have been achieved with the empirical prediction of VFA and glucose production and fluxes through PDV and liver based on the current INRA feed evaluation system. These advances are presented. They illustrate that empirical prediction of ruminal VFA and intestinal glucose production can be evaluated by comparison with measured net portal net fluxes. We also illustrate the potential synergy between empirical and mechanistic modelling. It is concluded that concomitant empirical and mechanistic approach may likely help to progress towards development of multi-objective feed evaluation systems based on nutrient fluxes. PMID- 22444610 TI - Nutritional regulation of fetal growth and implications for productive life in ruminants. AB - The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11beta-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring. PMID- 22444611 TI - Efficiency of energy utilisation and voluntary feed intake in ruminants. AB - Energy requirements of animals are most readily expressed in terms of net energy (NE), while the energy yield of feed is, at least initially, expressed in terms of metabolisable energy (ME). Energy evaluation systems 'translate' NE requirements into ME requirements (ME systems) or assign NE values to feeds (NE systems). Efficiency of ME utilisation is higher for maintenance than for production and the NE yield of a feed varies, therefore, with ME intake. In addition, energetic efficiency for maintenance and production is thought to be different for lactating and non-lactating animals and to be affected by diet quality. As a result, there are currently many national energy evaluation systems that are complex, differ in their approach and are, as a result, difficult to compare. As ruminants in most production systems are fed ad libitum, this is also the most appropriate intake level at which to estimate energetic efficiency. Analyses of older as well as more recent data suggest that ad libitum feeding (i) abolishes the effects of diet quality on energetic efficiency (almost) completely, (ii) abolishes the differences between lactating and non-lactating animals (almost) entirely and (iii) results in overall energetic efficiencies that are always close to 0.6. The paper argues that there is now sufficient information to develop an international energy evaluation system for ad libitum fed ruminants. Such a system should (i) unify ME and NE systems, (ii) avoid the systematic bias and large errors that can be associated with current systems (iii) be simpler than current systems and (iv) have as a starting point a constant efficiency of ME utilisation, with a value of around 0.6. The remarkably constant efficiency of ME utilisation in ad libitum fed ruminants could be the result of energetic efficiency as well as feed intake regulation being affected by the same variables or of a direct role of energetic efficiency in feed intake regulation. Models to predict intake on the basis of the latter hypothesis are already available for non-reproducing ruminants but remain to be developed for reproducing animals. PMID- 22444612 TI - Ontogenesis of muscle and adipose tissues and their interactions in ruminants and other species. AB - The lean-to-fat ratio, that is, the relative masses of muscle and adipose tissue, is a criterion for the yield and quality of bovine carcasses and meat. This review describes the interactions between muscle and adipose tissue (AT) that may regulate the dynamic balance between the number and size of muscle v. adipose cells. Muscle and adipose tissue in cattle grow by an increase in the number of cells (hyperplasia), mainly during foetal life. The total number of muscle fibres is set by the end of the second trimester of gestation. By contrast, the number of adipocytes is never set. Number of adipocytes increases mainly before birth until 1 year of age, depending on the anatomical location of the adipose tissue. Hyperplasia concerns brown pre-adipocytes during foetal life and white pre adipocytes from a few weeks after birth. A decrease in the number of secondary myofibres and an increase in adiposity in lambs born from mothers severely underfed during early pregnancy suggest a balance in the commitment of a common progenitor into the myogenic or adipogenic lineages, or a reciprocal regulation of the commitment of two distinct progenitors. The developmental origin of white adipocytes is a subject of debate. Molecular and histological data suggested a possible transdifferentiation of brown into white adipocytes, but this hypothesis has now been challenged by the characterization of distinct precursor cells for brown and white adipocytes in mice. Increased nutrient storage in fully differentiated muscle fibres and adipocytes, resulting in cell enlargement (hypertrophy), is thought to be the main mechanism, whereby muscle and fat masses increase in growing cattle. Competition or prioritization between adipose and muscle cells for the uptake and metabolism of nutrients is suggested, besides the successive waves of growth of muscle v. adipose tissue, by the inhibited or delayed adipose tissue growth in bovine genotypes exhibiting strong muscular development. This competition or prioritization occurs through cellular signalling pathways and the secretion of proteins by adipose tissue (adipokines) and muscle (myokines), putatively regulating their hypertrophy in a reciprocal manner. Further work on the mechanisms underlying cross-talk between brown or white adipocytes and muscle fibres will help to achieve better understanding as a prerequisite to improving the control of body growth and composition in cattle. PMID- 22444613 TI - Genomics of metabolic adaptations in the peripartal cow. AB - The peripartal period is characterized by dramatic alterations in metabolism and function of key tissues such as liver, adipose and mammary. Metabolic regulation relies partly on transcriptional control of gene networks, a collection of DNA segments, which interact with a transcription factor or nuclear receptor, as a mechanism controlling the concentration of key enzymes in cells. These 'global' interactions can govern the rates at which genes in the network are transcribed into mRNA. The study of the entire genome, sub-networks or candidate genes at the mRNA level encompasses the broad field of genomics. Genomics of peripartal metabolic adaptations has traditionally been focused on candidate genes and more recently, using microarrays, on the broader transcriptome landscape. The candidate gene approach has expanded our knowledge on the functional adaptations of ureagenesis, fatty acid oxidation, gluconeogenesis, inflammation and growth hormone signaling in liver. More recent work with peripartal mammary tissue has used a gene network approach to study milk fat synthesis regulation as well as a candidate gene approach to study lipid transport, glucose uptake and inflammatory response. Network and pathway analysis of microarray data from cows fed different levels of dietary energy pre partum has revealed unique clusters encompassing functional categories including signal transduction, endoplasmic reticulum stress, peroxisome proliferator-activated receptors (PPARgamma) signaling, PPARalpha signaling, immune or inflammatory processes and cell death in subcutaneous adipose tissue as well as liver. Of interest from a nutritional perspective is the potential to alter PPARgamma signaling in adipose and PPARalpha signaling in liver as a means to enhance insulin sensitivity as well as fatty acid oxidation post partum. Major advances in understanding the metabolic adaptations of peripartal cows will come from using a systems biology approach to integrate data generated at the mRNA, protein, metabolite and tissue level across different nutritional management approaches and with cows of different genetic merit. This will allow the assembly of the important components needed to improve existing metabolic models of the peripartal cow and provide the tools to manipulate complex processes that could have significant long-term economic impact including lactation persistency, fertility and efficiency. An important goal of the future will be to apply additional experimental tools (e.g. gene silencing) and bioinformatics (e.g. transcription factor binding site identification) to studies focused on peripartal cows. PMID- 22444614 TI - Role of trans fatty acids in the nutritional regulation of mammary lipogenesis in ruminants. AB - Fat is an important constituent contributing to the organoleptic, processing and physical properties of ruminant milk. Understanding the regulation of milk fat synthesis is central to the development of nutritional strategies to enhance the nutritional value of milk, decrease milk energy secretion and improve the energy balance of lactating ruminants. Nutrition is the major environmental factor regulating the concentration and composition of fat in ruminant milk. Feeding low fibre/high-starch diets and/or lipid supplements rich in polyunsaturated fatty acids induce milk fat depression (MFD) in the bovine, typically increase milk fat secretion in the caprine, whereas limited data in sheep suggest that the responses are more similar to the goat than the cow. Following the observation that reductions in milk fat synthesis during diet-induced MFD are associated with increases in the concentration of specific trans fatty acids in milk, the biohydrogenation theory of MFD was proposed, which attributes the causal mechanism to altered ruminal lipid metabolism leading to increased formation of specific biohydrogenation intermediates that exert anti-lipogenic effects. Trans 10, cis-12 conjugated linoleic acid (CLA) is the only biohydrogenation intermediate to have been infused at the abomasum over a range of experimental doses (1.25 to 14.0 g/day) and shown unequivocally to inhibit milk fat synthesis in ruminants. However, increases in ruminal trans-10, cis-12 CLA formation do not explain entirely diet-induced MFD, suggesting that other biohydrogenation intermediates and/or other mechanisms may also be involved. Experiments involving abomasal infusions (g/day) in lactating cows have provided evidence that cis-10, trans-12 CLA (1.2), trans-9, cis-11 CLA (5.0) and trans-10 18:1 (92.1) may also exert anti-lipogenic effects. Use of molecular-based approaches have demonstrated that mammary abundance of transcripts encoding for key lipogenic genes are reduced during MFD in the bovine, changes that are accompanied by decrease in sterol response element binding protein 1 (SREBP1) and alterations in the expression of genes related to the SREBP1 pathway. Recent studies indicate that transcription of one or more adipogenic genes is increased in subcutaneous adipose tissue in cows during acute or chronic MFD. Feeding diets of similar composition do not induce MFD or substantially alter mammary lipogenic gene expression in the goat. The available data suggests that variation in mammary fatty acid secretion and lipogenic responses to changes in diet composition between ruminants reflect inherent interspecies differences in ruminal lipid metabolism and mammary specific regulation of cellular processes and key lipogenic enzymes involved in the synthesis of milk fat triacylglycerides. PMID- 22444615 TI - Metabolic and hormonal acclimation to heat stress in domesticated ruminants. AB - Environmentally induced periods of heat stress decrease productivity with devastating economic consequences to global animal agriculture. Heat stress can be defined as a physiological condition when the core body temperature of a given species exceeds its range specified for normal activity, which results from a total heat load (internal production and environment) exceeding the capacity for heat dissipation and this prompts physiological and behavioral responses to reduce the strain. The ability of ruminants to regulate body temperature is species- and breed-dependent. Dairy breeds are typically more sensitive to heat stress than meat breeds, and higher-producing animals are more susceptible to heat stress because they generate more metabolic heat. During heat stress, ruminants, like other homeothermic animals, increase avenues of heat loss and reduce heat production in an attempt to maintain euthermia. The immediate responses to heat load are increased respiration rates, decreased feed intake and increased water intake. Acclimatization is a process by which animals adapt to environmental conditions and engage behavioral, hormonal and metabolic changes that are characteristics of either acclimatory homeostasis or homeorhetic mechanisms used by the animals to survive in a new 'physiological state'. For example, alterations in the hormonal profile are mainly characterized by a decline and increase in anabolic and catabolic hormones, respectively. The response to heat load and the heat-induced change in homeorhetic modifiers alters post-absorptive energy, lipid and protein metabolism, impairs liver function, causes oxidative stress, jeopardizes the immune response and decreases reproductive performance. These physiological modifications alter nutrient partitioning and may prevent heat-stressed lactating cows from recruiting glucose sparing mechanisms (despite the reduced nutrient intake). This might explain, in large part, why decreased feed intake only accounts for a minor portion of the reduced milk yield from environmentally induced hyperthermic cows. How these metabolic changes are initiated and regulated is not known. It also remains unclear how these changes differ between short-term v. long-term heat acclimation to impact animal productivity and well-being. A better understanding of the adaptations enlisted by ruminants during heat stress is necessary to enhance the likelihood of developing strategies to simultaneously improve heat tolerance and increase productivity. PMID- 22444616 TI - Strategies for optimizing nitrogen use by ruminants. AB - The efficiency of N utilization in ruminants is typically low (around 25%) and highly variable (10% to 40%) compared with the higher efficiency of other production animals. The low efficiency has implications for the production performance and environment. Many efforts have been devoted to improving the efficiency of N utilization in ruminants, and while major improvements in our understanding of N requirements and metabolism have been achieved, the overall efficiency remains low. In general, maximal efficiency of N utilization will only occur at the expense of some losses in production performance. However, optimal production and N utilization may be achieved through the understanding of the key mechanisms involved in the control of N metabolism. Key factors in the rumen include the efficiency of N capture in the rumen (grams of bacterial N per grams of rumen available N) and the modification of protein degradation. Traditionally, protein degradation has been modulated by modifying the feed (physical and chemical treatments). Modifying the rumen microflora involved in peptide degradation and amino acid deamination offers an alternative approach that needs to be addressed. Current evidence indicates that in typical feeding conditions there is limited net recycling of N into the rumen (blood urea-N uptake minus ammonia-N absorption), but understanding the factors controlling urea transport across the rumen wall may reverse the balance to take advantage of the recycling capabilities of ruminants. Finally, there is considerable metabolism of amino acids (AA) in the portal-drained viscera (PDV) and liver. However, most of this process occurs through the uptake of AA from the arterial blood and not during the 'absorptive' process. Therefore, AA are available to the peripheral circulation and to the mammary gland before being used by PDV and the liver. In these conditions, the mammary gland plays a key role in determining the efficiency of N utilization because the PDV and liver will use AA in excess of those required by the mammary gland. Protein synthesis in the mammary gland appears to be tightly regulated by local and systemic signals. The understanding of factors regulating AA supply and absorption in the mammary gland, and the synthesis of milk protein should allow the formulation of diets that increase total AA uptake by the mammary gland and thus reduce AA utilization by PDV and the liver. A better understanding of these key processes should allow the development of strategies to improve the efficiency of N utilization in ruminants. PMID- 22444617 TI - Nutritional sub-fertility in the dairy cow: towards improved reproductive management through a better biological understanding. AB - There has been a significant decline in the reproductive performance of dairy cattle in recent decades. Cows, take longer time to return to the oestrus after calving, have poorer conception rates, and show fewer signs of oestrus. Achieving good reproductive performance is an increasing challenge for the dairy producer. In this study we focus on understanding the overall biological phenomena associated with nutritional sub-fertility rather than the underlying multiplicity of physiological interactions (already described in a number of recent studies). These phenomena are important because they represent the natural adaptations of the animal for dealing with variations in the nutritional environment. They can also be used to monitor and modulate reproductive performance on-farm. There is an underlying trade-off between two aspects of reproduction: investment in the viability of the current calf and investment in future offspring. As the investment in, and viability of, the current calf is related to maternal milk production, we can expect that level of milk production per se has effects on subsequent reproductive performance (investment in future offspring). Lactating cows have a lower proportion of viable embryos, which are of poorer quality, than do non-lactating cows. The same applies to high- compared to medium-genetic merit cows. Another important biological property is the adaptive use of body reserves in support of reproduction. Orchestrated endocrine changes in pregnancy and lactation facilitate the deposition of body lipid during pregnancy and mobilisation in early lactation. When the cow fails to accumulate the reserves she needs to safeguard reproduction she delays committing to further reproductive investment. But how does the cow 'know' that she is failing in energy terms? We argue that the cow does this by 'monitoring' both the body fat mobilisation and body fatness. Excessive body fat mobilisation indicates that current conditions are worse than expected. Body fatness indicates the future ability of the cow to safeguard her reproductive investment is compromised. Both delay further reproductive commitment. The relationship between reproductive performance and; milk production as an index of maternal investment, body fatness as an index of ability to safeguard reproductive investment, and body fat mobilisation as an index of the current nutritional environment - are examined. Nutritional strategies that seek to modulate body mobilisation and the endocrine environment by use of glucogenic and lipogenic diets, and the use of in-line progesterone profiles to monitor reproductive status are then discussed in this biological context. PMID- 22444618 TI - Interactions between nutrition and reproduction in the management of the mature male ruminant. AB - In mature male sheep and goats, changes in feed intake seem to have little effect on gonadal endocrine function but induce profound changes on sperm production. These outcomes are due to changes in size of the seminiferous tubules and in spermatogenic efficiency. Except with severe underfeeding, there are only minor changes in the endocrine function of the testis (testosterone production) unless season-long treatments are imposed. For cattle, nutrition clearly affects testicular development and the production of spermatozoa in young bulls, as it does in other species but, after the period of rapid growth has ended, there appears to be little or no response to nutrition. We are developing a clear picture of the metabolic signals, neuroendocrine processes and hormonal control systems that are involved, particularly for the mature male sheep. The energetic components of the diet, rather than protein, seem to be responsible, so we have envisaged a model of the relationship between energy balance and reproduction that has 4 'dimensions': genotype, structure (organs), communication (chemical and neural signals, nutrient sensing) and time (dynamics, metabolic memory, programming). We have linked these perspectives to 'resource allocation theory' and incorporated them into strategies for 'clean, green and ethical animal production'. In contrast to the clear outcomes with respect to spermatogenesis, the effects of nutrition on sexual behaviour are more difficult to define, perhaps because the behaviour is affected by a complex mix of physiological factors and because of flawed methods for quantifying male behaviour. For example, sexual behaviour is compromised by severe feed restriction, but male sexual behaviour requires intensive motor activity so a decline in libido could be caused by general weakness rather than specific nutritional limitations. The interaction between sexual activity and feeding behaviour also complicates the issue under field conditions. At the other end of the scale, overweight males can show reduced sexual success because they have difficulty courting and mounting. For this reason, exercise can enhance the fertilising capacity of rams. This will be important in extensive mating systems where males need to assemble and guard a harem and then mate many times for several weeks. For artificial insemination centres, there seems to be very few data on the nutritional management of males, but problems with overfed animals appear to be a risk. Future research should concentrate on the intra-testicular systems mediating the effects of nutrition on the production of spermatozoa. PMID- 22444619 TI - Links between ruminants' food preference and their welfare. AB - Nutrition is an important aspect of welfare, and in most recommendations for the welfare of animals adequate nutrition is a primary requirement. However, in intensive livestock production systems the decision for adequate nutrition is made based on traditional paradigms of feeding monotonous rations or plant monocultures, frequently with excesses or imbalances of nutrients relative to the individuals' physiology, which can compromise welfare. Individual ruminants can better meet their needs for nutrients and regulate their intake of secondary compounds when offered a variety of foods than when constrained to a single food, even if the food is nutritionally balanced. The concept of food variety is central because monotonous flavors and feeds and excess nutrients all cause animals to satiate, which in turn causes animals to eat a variety of foods. When offered a variety of foods, satiety for single foods stimulates the selection of a diverse diet and thus food intake, but when restricted to a monotonous diet satiety is aversive and limits food intake. Moreover, if a monotonous diet is aversive to animals then this could be stressful, even if monotony implies consuming a balanced diet. A diverse diet may also increase resistance to disease in ruminants, by allowing consumption of small amounts of compounds with antimicrobial/antiparasitic effects and immunity-enhancing properties. Herbivores also experience the benefits of ingesting compounds with medicinal (i.e. antiparasitic) benefits and they learn to prefer foods containing such compounds as their preferences are associatively conditioned by the food's homeostatic utility to the body. Such learned patterns of behavior begin in utero and feeding experiences early in life cause changes - neurological, morphological and physiological - in animals, which influence on their subsequent behavior and welfare. Such experiences with the environment enable animals to adapt to local diets and stressors and reduce the levels of fear. Finally, feeding behavior in farm animals could be an aid in the early detection and mitigation of pain or sickness, and as such become an important tool in the identification of welfare and health of animals before the appearance of clinical signs. Management strategies in ruminant production systems could benefit by allowing animals to manifest their feeding preferences, thereby acknowledging the animals' role as active players in feeding systems, instead of regarding them as passive entities that just respond to prescriptions and formulations. PMID- 22444620 TI - Stress and microbial endocrinology: prospects for ruminant nutrition. AB - The feed efficiency of ruminant meat and dairy livestock can be significantly influenced by factors within their living environments. In particular, events perceived by the animals as stressful (such as parturition, transport or handling) have been found to affect susceptibility to infection. It has been well documented that even minor stress such as weighing can result in an increase in colonisation and faecal shedding of enteric pathogens such as Salmonella enterica and Escherichia coli O157:H7. Such infections affect both ruminant overall health and therefore performance, and are a particular problem for the meat production industries. Prior explanations for stress enhancing the likelihood of infection is that activation of the sympathetic nervous system under stress leads to the release of neuroendocrine mediators such as the catecholamine stress hormones noradrenaline and adrenaline, which may impair innate and adaptive immunity. More recently, however, another equally compelling explanation, viewed through the lens of the newly recognised microbiological discipline of microbial endocrinology is that the myriad of bacteria within the ruminant digestive tract are as responsive to the hormonal output of stress as the cells of their host. Work from our laboratories has shown that enteric pathogens have evolved systems for directly sensing stress hormones. We have demonstrated that even brief exposure of enteric pathogens to physiological concentrations of stress hormones can result in massive increases in growth and marked changes in expression of virulence factors such as adhesins and toxins. Happy, less stressed ruminants may therefore be better-nourished animals and safer sources of meat. This article reviews evidence that stress, as well as affecting nutrition, in ruminants is correlated with increased risk of enteric bacterial infections, and examines the molecular mechanisms that may be at work in both processes. PMID- 22444621 TI - Sustainability of ruminant agriculture in the new context: feeding strategies and features of animal adaptability into the necessary holistic approach. AB - There are numerous recent studies highlighting sustainability problems for the development of ruminant production systems (RPS) while facing increasing human food necessities and global climate change. Despite the complexity of the context, in our view the main objectives of the ruminants' physiologist should be convergent for both industrialized (IC) and developing countries (DC) in a common and global strategy of advancing knowledge. In DC, this means improving the efficiency of RPS, taking into account the unique possibility of using rangelands. For IC settings, RPS should be revisited in terms of autonomy and environment- friendly feeding and managing practices. Assuming that competition for feed/food use is still a crucial criterion, future ruminant feeding systems (FeSyst) should preferably focus on lignocellulosic sources. According to biome distributions, and the recent increases in volumes of crop residues and their by products, the annually renewed volumes of these biomasses are considerable. Therefore, we need to redesign our strategies for their efficient utilization at the local level. For this purpose, digestion processes and rumen functioning need to be better understood. The renewed vision of ruminal digestion through the reduction of greenhouse gas emissions is also a key aspect as it is an environmental demand that cannot be ignored. With regard to other ruminants' physiological functions, accumulated knowledge could be mobilized into an integrative approach that puts forward the adaptive capacities of animals to face variability in quantity and quality of supplied feeds. Basically, the reduction of inputs that were traditionally used to ensure FeSyst will need more flexible animals. In that sense, the concepts of homeostasis and teleophorhesis need to be updated and adapted to domestic species and breeds that were until now largely excluded from the dominant productive systems. In conclusion, a more holistic approach of research targets is required in which physiological functions and farmers' practices must converge and respond to each particular situation in an integral, dynamic and flexible conceptual perspective. From a scientific point of view, both for ICs and DCs, a broader range of experimental scenarios should be explored in order to arrive at innovative practices and solutions that respect environmental, ethical and economical issues. The clear challenge is to in evaluate the sustainability of RPSs. This includes, in our opinion, a strong interaction with other disciplines (multi- and trans-disciplinary conception), thus structuring new relevant indicators for the evaluation sustainability. PMID- 22444622 TI - Evidence for the likely origin of homochirality in amino acids, sugars, and nucleosides on prebiotic Earth. PMID- 22444623 TI - Anxiety-like behaviour and associated neurochemical and endocrinological alterations in male pups exposed to prenatal stress. AB - Epidemiological studies suggest that emotional liability in infancy could be a predictor of anxiety-related disorders in the adulthood. Rats exposed to prenatal restraint stress ("PRS rats") represent a valuable model for the study of the interplay between environmental triggers and neurodevelopment in the pathogenesis of anxious/depressive like behaviours. Repeated episodes of restraint stress were delivered to female Sprague-Dawley rats during pregnancy and male offspring were studied. Ultrasonic vocalization (USV) was assessed in pups under different behavioural paradigms. After weaning, anxiety was measured by conventional tests. Expression of GABA(A) receptor subunits and metabotropic glutamate (mGlu) receptors was assessed by immunoblotting. Plasma leptin levels were measured using a LINCOplex bead assay kit. The offspring of stressed dams emitted more USVs in response to isolation from their mothers and showed a later suppression of USV production when exposed to an unfamiliar male odour, indicating a pronounced anxiety-like profile. Anxiety like behaviour in PRS pups persisted one day after weaning. PRS pups did not show the plasma peak in leptin levels that is otherwise seen at PND14. In addition, PRS pups showed a reduced expression of the gamma2 subunit of GABA(A) receptors in the amygdala at PND14 and PND22, an increased expression of mGlu5 receptors in the amygdala at PND22, a reduced expression of mGlu5 receptors in the hippocampus at PND14 and PND22, and a reduced expression of mGlu2/3 receptors in the hippocampus at PND22. These data offer a clear-cut demonstration that the early programming triggered by PRS could be already translated into anxiety-like behaviour during early postnatal life. PMID- 22444624 TI - Associations of childhood trauma with hypothalamic-pituitary-adrenal function in borderline personality disorder and major depression. AB - BACKGROUND: Alterations of the hypothalamus-pituitary-adrenal (HPA) axis are hallmarks in major depressive disorder (MDD) and there is some evidence about similar patterns in borderline personality disorder (BPD). This study examines HPA axis abnormalities with respect to clinical characteristics in both BPD (n=24) and MDD patients (n=33) as well as in healthy control participants (n=41). METHOD: A 0.5mg dexamethasone suppression test was administered to evaluate basal cortisol release and HPA feedback sensitivity via salivary cortisol. Traumatic experiences in childhood as well as severity of borderline and depressive symptom severity and dissociation were obtained by self-report questionnaires. RESULTS: Compared to the healthy control group, BPD and MDD patients exhibited both enhanced cortisol concentrations before and after the administration of 0.5mg dexamethasone. Higher cortisol levels were positively correlated to a history of childhood trauma, current dissociative symptoms and severity of borderline and depressive symptoms. Regression analyses revealed that some aspects of early trauma were associated with cortisol release before and after dexamethasone, whereas psychopathology did not contribute to the regression model. CONCLUSIONS: HPA dysfunctions appear to be related rather to childhood trauma than to psychopathology in adulthood. Exposure to childhood trauma may contribute to long lasting alterations in HPA activity and might enhance the risk for the development of later mental disorder. PMID- 22444625 TI - NLRX1 has a tail to tell. AB - In this issue of Immunity, Hong et al. (2012) report the first structural analysis of the C-terminal fragment of an NLR (nucleotide-binding domain [NBD] and leucine-rich repeat [LRR]-containing) protein, NLRX1. This fragment forms a hexamer and binds RNA. PMID- 22444626 TI - Dangerous liaisons: mitochondrial DNA meets the NLRP3 inflammasome. AB - Danger signals released by damaged organelles can promote inflammation. In this issue of Immunity, Shimada et al. (2012) report that oxidized DNA, released by mitochondria, directly binds and activates the NLRP3 inflammasome. PMID- 22444627 TI - B cells, not just for antibody anymore. AB - B cell antibody production is thought to be crucial for protection against virus infection. In this issue of Immunity, Moseman et al. (2012) illustrate an antibody-independent role for B cells in macrophage activation that prevents virus dissemination after subcutaneous infection. PMID- 22444628 TI - Natural "helper" cells in the lung: good or bad help? AB - The natural helper (NH) cell comprises a newly identified Th2 cell-type innate lymphocyte population. In this issue of Immunity, Halim et al. (2012) provide evidence that NH cells reside in the lung and play a critical role in protease allergen-induced airway inflammation. PMID- 22444629 TI - Small molecules and big killers: the challenge of eliminating the latent HIV reservoir. AB - In this issue of Immunity, Shan et al. (2012) explore the elimination of cells latently infected with HIV and the potential implications for strategies to eradicate the virus from infected patients. PMID- 22444630 TI - Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. AB - Numerous regulatory programs have been identified that contribute to the restoration of homeostasis at the conclusion of immune responses and to safeguarding against the detrimental effects of chronic inflammation and autoimmune pathology. Malignant cells may usurp these pathways to create immunosuppressive networks that thwart antitumor responses. Herein we review the role of endogenous lectins (C-type lectins, siglecs, and galectins) and specific N- and O-glycans generated by the coordinated action of glycosyltransferases and glycosidases that together promote regulatory signals that control immune cell homeostasis. We also discuss the mechanisms by which glycan-dependent regulatory programs integrate into canonical circuits that amplify or silence immune responses related to autoimmunity and neoplastic disease. PMID- 22444631 TI - Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1. AB - Through their capacity to sense danger signals and to generate active interleukin 1beta (IL-1beta), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1beta, little is known about how IL-1alpha is regulated. We found that all inflammasome activators also induced the secretion of IL-1alpha, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1alpha was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1alpha secretion. In both cases, IL-1alpha was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1 dependent release of IL-1alpha and IL-1beta was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1alpha antagonists may be beneficial in the treatment of these disorders. PMID- 22444632 TI - Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. AB - Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9 dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes. PMID- 22444633 TI - Additives aided composting of green waste: effects on organic matter degradation, compost maturity, and quality of the finished compost. AB - The effect of various additives such as fly ash, phosphogypsum, jaggery, lime, and polyethylene glycol on green waste composting was investigated through assessing their influence on microbial growth, enzymatic activities, organic matter degradation, bulk density, quality of finished compost including gradation test, heavy metal analysis, etc. A perusal of results showed that addition of jaggery and polyethylene glycol were helpful to facilitate composting process as they significantly influenced the growth of microbes and cellulase activity. The quality of finished compost prepared from jaggery and polyethylene glycol added treatments were superior to other composts, wherein reduction in C/N ratio was more than 8% in jaggery treatment. All other parameters of compost quality including gradation test also favored jaggery and polyethylene glycol as the best additives for green waste composting. PMID- 22444634 TI - Optimization of thermo-alkaline disintegration of sewage sludge for enhanced biogas yield. AB - Optimization of thermo-alkaline disintegration of sewage sludge for enhanced biogas yield was carried out using response surface methodology (RSM) and Box Behnken design of experiment. The individual linear and quadratic effects as well as the interactive effects of temperature, NaOH concentration and time on the degree of disintegration were investigated. The optimum degree of disintegration achieved was 61.45% at 88.50 degrees C, 2.29 M NaOH (24.23%w/w total solids) and 21 min retention time. Linear and quadratic effects of temperature are most significant in affecting the degree of disintegration. The coefficient of determination (R(2)) of 99.5% confirms that the model used in predicting the degree of disintegration process has a very good fitness with the experimental variables. The disintegrated sludge increased the biogas yield by 36%v/v compared to non-disintegrated sludge. The RSM with Box-Behnken design is an effective tool in predicting the optimum degree of disintegration of sewage sludge for increased biogas yield. PMID- 22444635 TI - Characterization of a beta-glucosidase with transgalactosylation capacity from the zygomycete Rhizomucor miehei. AB - An extracellular beta-glucosidase from the zygomycete Rhizomucor miehei NRRL 5282 cultivated in a wheat bran-based solid state fermentation system was characterized. The purified enzyme exhibited an optimum temperature of 68-70 degrees C and pH of 5.0. It efficiently hydrolyzed oligosaccharides having beta (1->4) glycosidic linkages and exhibited some beta- and alpha-galactosidase activity. The V(max) for p-nitrophenyl-beta-d-glucopyranoside and cellobiose was 468.2 and 115.5 U/mg, respectively, while the K(m) was 0.12 mM for both substrates. The enzyme had transglucosylation and transgalactosylation activities resulting in the formation of glycosides from cellobiose, lactose and ethanol. The enzyme increased the amounts of free phenolic antioxidants in sour cherry pomace indicating that its hydrolyzing activity could potentially be applicable to improve the bioavailability of these compounds. PMID- 22444636 TI - Recovery of galactoglucomannan from wood hydrolysate using regenerated cellulose ultrafiltration membranes. AB - Hemicelluloses show promise as a renewable source of raw material for various industrial processes. In this study, galactoglucomannan was recovered from pressurized hot water extract of spruce-sawdust in two steps using hydrophilic regenerated cellulose ultrafiltration membranes having different molecular weight cut-off values. The first step was concentration of galactoglucomannan (GGM) by ultrafiltration using a flat sheet unit and the second step was purification of the retained galactoglucomannan by diafiltration using reverse osmosis filtered water. The highest GGM retention (88%), purity (63%) and recovery (70%) were achieved with the UC005 membrane (cut-off value 5-kDa) at a volume reduction (VR%) of 86%. The UC010 and UC030 membranes (cut-off values 10- and 30-kDa, respectively) partly separated xylan from GGM. Generally, diafiltration did not improve the purity of the GGM due to overlapping of the GGM and lignin molar mass distributions and the fact that most of free low molar mass lignin had already been removed in the concentration filtration step. However, by diafiltration, partial removal of xylan and complete removal of monosaccharides from the GGM rich concentrate was achieved. PMID- 22444637 TI - Biogas production by anaerobic co-digestion of cattle slurry and cheese whey. AB - Biogas yield of mixtures of cattle slurry and cheese whey, rates of production of methane, removal efficiencies of chemical oxygen demand (COD) and biological oxygen demand (BOD) were investigated at 35 degrees C. Stable biogas production of 621 l/kg volatile solids at a hydraulic retention time of 42 days in a mixture containing 50% slurry and whey was obtained. The concentration of methane in the biogas was around 55%. Maximum removal efficiencies for COD and BOD5 were 82% and 90%, respectively. A maximum biogas production increase of 79% with respect to the start-up phase was achieved. The result of this study show that co-digestion of a high volume of whey (up to 65% in volume) is possible without the use of chemicals for pH correction, but also that this kind of mix has a similar energetic potential for anaerobic digestion as energy crops such as maize. PMID- 22444638 TI - Optimizing net energy gain in algal cultivation for biodiesel production. AB - An approach based on energy gain was utilized to optimize algal cultivation in bubble columns. Net energy gain was estimated considering the energy input for mixing and providing carbon dioxide, and the energy that can be generated from the lipids extracted from the algal biomass. Energy input for sparging was minimized based on the gas-to-culture volume ratio and energy output from lipid production was maximized based on nitrate and CO(2) levels. Sparging at a gas-to culture volume ratio of 0.18 min(-1) with CO(2)-enrichment of 0.5% and initial nitrate concentration of 1mM was optimal for improving net energy gain with Nannochloropsis salina. Sparging with CO(2)-enriched air of 0.5% along with nitrogen starvation resulted in 50% more lipid productivity than sparging with ambient air. PMID- 22444639 TI - Application of a moving bed biofilm reactor for tertiary ammonia treatment in high temperature industrial wastewater. AB - This study examines the use of a moving bed biofilm reactor (MBBR) as a tertiary treatment step for ammonia removal in high temperature (35-45 degrees C) effluents, and quantifies different phenotypes of ammonia and nitrite oxidizing bacteria responsible for nitrification at elevated temperatures. Bench scale reactors operating at 35 and 40 degrees C were able to successfully remove greater than 90% of the influent ammonia (up to 19 mg L(-1) NH(3)-N) in both the synthetic and industrial wastewater. No biotreatment was observed at 45 degrees C, although effective nitrification was rapidly recovered when the temperature was lowered to 30 degrees C. Using qPCR, Nitrosomonas oligotropha was found to be the dominant ammonia oxidizing bacterium in the biofilm for the first phases of reactor operation. In the later phases, Nitrosomonas nitrosa was observed and its increased presence may have been responsible for improved ammonia treatment efficiency. Accumulation of nitrite in some instances appeared to correlate with temporary low presence of Nitrospira spp. PMID- 22444640 TI - Fabrication of one-dimensional Ag/multiwalled carbon nanotube nano-composite. AB - Composite made of multiwalled carbon nanotubes coated with silver was fabricated by an electroless deposition process. The thickness of silver layer is about 40 to 60 nm, characterized as nano-crystalline with (111) crystal orientation along the nanotube's axial direction. The characterization of silver/carbon nanotube [Ag/CNT] nanowire has shown the large current carrying capability, and the electric conductivity is similar to the pure silver nanowires that Ag/CNT would be promising as building blocks for integrated circuits.PACS: 81.05.uj, carbon nanotubes, carbon-based materials, diamond/nanocarbon composites. PMID- 22444641 TI - The combined influence of substrate elasticity and ligand density on the viability and biophysical properties of hematopoietic stem and progenitor cells. AB - Hematopoietic stem cells (HSCs) are adult stem cells with the capacity to give rise to all blood and immune cells in the body. HSCs are housed in a specialized microenvironment known as the stem cell niche, which provides intrinsic and extrinsic signals to regulate HSC fate: quiescence, self-renewal, differentiation, mobilization, homing, and apoptosis. These niches provide a complex, three dimensional (3D) microenvironment consisting of cells, the extracellular matrix (ECM), and ECM-bound or soluble biomolecules that provides cellular, structural, and molecular signals that regulate HSC fate decisions. In this study, we examined the decoupled effects of substrate elasticity, construct dimensionality, and ligand concentration on the biophysical properties of primary hematopoietic stem and progenitor cells (HSPCs) using homologous series of two and three dimensional microenvironments. Microenvironments were chosen to span the range of biophysical environments presented physiologically within the bone marrow, ranging from soft marrow and adipose tissue (<1 kPa), to surrounding cell membranes (1-3 kPa), to developing osteoid (>30 kPa). We additionally investigated the influence of collagen ligand density on HSPC biophysical parameters and compared these behaviors to those observed in HSPCs grown in culture on stiff glass substrates. This work suggests the potential for substrate stiffness and ligand density to directly affect the biophysical properties of primary hematopoietic stem and progenitor cells at the single cell level and that these parameters may be critical design criteria for the development of artificial HSC niches. PMID- 22444642 TI - Microcapsules with intrinsic barium radiopacity for immunoprotection and X-ray/CT imaging of pancreatic islet cells. AB - Microencapsulation is a commonly used technique for immunoprotection of engrafted therapeutic cells. We investigated a library of capsule formulations to determine the most optimal formulation for pancreatic beta islet cell transplantation, using barium as the gelating ion and clinical-grade protamine sulfate (PS) as a new cationic capsule cross-linker. Barium-gelated alginate/PS/alginate microcapsules (APSA, diameter = 444 +/- 21 MUm) proved to be mechanically stronger and supported a higher cell viability as compared to conventional alginate/poly-l-lysine/alginate (APLLA) capsules. Human pancreatic islets encapsulated inside APSA capsules, gelated with 20 mm barium as optimal concentration, exhibited a sustained morphological integrity, viability, and functionality for at least 3-4 weeks in vitro, with secreted human C-peptide levels of 0.2-160 pg/ml/islet. Unlike APLLA capsules that are gelled with calcium, barium-APSA capsules are intrinsically radiopaque and, when engrafted into mice, could be readily imaged in vivo with micro-computed tomography (CT). Without the need of adding contrast agents, these capsules offer a clinically applicable alternative for simultaneous immunoprotection and real-time, non invasive X-ray/CT monitoring of engrafted cells during and after in vivo administration. PMID- 22444643 TI - A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. AB - Cell-cell and cell-matrix interactions control cell phenotypes and functions in vivo. Maintaining these interactions in vitro is essential to both produce and retain cultured cell fidelity to normal phenotype and function in the context of drug efficacy and toxicity screening. Two-dimensional (2-D) cultures on culture plastics rarely recapitulate any of these desired conditions. Three dimensional (3-D) culture systems provide a critical junction between traditional, yet often irrelevant, in vitro cell cultures and more accurate, yet costly, in vivo models. This study describes development of an organoid-derived 3-D culture of kidney proximal tubules (PTs) that maintains native cellular interactions in tissue context, regulating phenotypic stability of primary cells in vitro for up to 6 weeks. Furthermore, unlike immortalized cells on plastic, these 3-D organoid kidney cultures provide a more physiologically-relevant response to nephrotoxic agent exposure, with production of toxicity biomarkers found in vivo. This biomimetic primary kidney model has broad applicability to high-throughput drug and biomarker nephrotoxicity screening, as well as more mechanistic drug toxicology, pharmacology, and metabolism studies. PMID- 22444644 TI - Homo-catiomer integration into PEGylated polyplex micelle from block-catiomer for systemic anti-angiogenic gene therapy for fibrotic pancreatic tumors. AB - Homo-poly{N'-[N-(2-aminoethyl)-2-aminoehtyl]aspartamide} [PAsp(DET), H] was attempted to integrate into poly (ethylene glycol) (PEG)-b-PAsp(DET)] (B) formulated polyplex micelle with the aim of enhancing cell transfection efficiency for PEGylated polyplex micelle via H integration. In vitro evaluations verified H integration of potent stimulation in enhancing cell-transfecting activity of PEGylated polyplex micelles via promoted cellular uptake and facilitated endosome escape. In vivo anti-angiogenic tumor suppression evaluations validated the feasibility of H integration in promoting gene transfection to the affected cells via systemic administration, where loaded anti angiogenic gene remarkably expressed in the tumor site, thereby imparting significant inhibitory effect on the growth of vascular endothelial cells, ultimately leading to potent tumor growth suppression. These results demonstrated potency of H integration for enhanced transfection activity and potential usage in systemic applications, which could have important implications on the strategic use of H integration in the non-viral gene carrier design. PMID- 22444645 TI - Core-shell Fe3O4@NaLuF4:Yb,Er/Tm nanostructure for MRI, CT and upconversion luminescence tri-modality imaging. AB - Core-shell Fe(3)O(4)@NaLuF(4):Yb,Er/Tm nanostructure (MUCNP) with multifunctional properties has been developed using a step-wise synthetic method. The successful fabrication of MUCNP has been confirmed by transmission electron microscopy, powder X-ray diffraction, energy-dispersive X-ray analysis and X-ray photoelectron spectroscopy. The MUCNP exhibits superparamagnetic property with saturation magnetization of 15 emu g(-1), and T(2)-enhanced magnetic resonance (MR) effect with an r(2) value of 21.63 s(-1) mM(-1) at 0.5 T, resulting from the Fe(3)O(4) cores. Moreover, the NaLuF(4)-based MUCNP provides excellent X-ray attenuation and upconversion luminescence (UCL) emission under excitation at 980 nm. In vivo MR, computed tomography (CT) and UCL images of tumor-bearing mice show that the MUCNP can be successfully used in multimodal imaging. In vitro tests reveal that the MUCNP is non-cytotoxic. These results suggest that the developed MUCNP could be served as an MR, CT and UCL probe for tri-modality imaging. PMID- 22444646 TI - Direct analysis of bacterial viability in endotracheal tube biofilm from a pig model of methicillin-resistant Staphylococcus aureus pneumonia following antimicrobial therapy. AB - Confocal laser scanning microscopy (CLSM) helps to observe the biofilms formed in the endotracheal tube (ETT) of ventilated subjects and to determine its structure and bacterial viability using specific dyes. We compared the effect of three different treatments (placebo, linezolid, and vancomycin) on the bacterial biofilm viability captured by CLSM. Eight pigs with pneumonia induced by methicillin-resistant Staphylococcus aureus (MRSA) were ventilated up to 96 h and treated with linezolid, vancomycin, or placebo (controls). ETT images were microscopically examined after staining with the live/dead((r)) BacLight(TM) Kit (Invitrogen, Barcelona, Spain) with a confocal laser scanning microscope. We analyzed 127 images obtained by CLSM. The median ratio of live/dead bacteria was 0.51, 0.74, and 1 for the linezolid, vancomycin, and control groups, respectively (P = 0.002 for the three groups); this ratio was significantly lower for the linezolid group, compared with the control group (P = 0.001). Images showed bacterial biofilm attached and non-attached to the ETT surface but growing within secretions accumulated inside ETT. Systemic treatment with linezolid is associated with a higher proportion of dead bacteria in the ETT biofilm of animals with MRSA pneumonia. Biofilm clusters not necessarily attach to the ETT surface. PMID- 22444647 TI - North European short-tailed breeds of sheep: a review. AB - The short-tailed sheep, native of an area stretching from Russia to Iceland, are generally considered a primitive type. These robust northern sheep seem to have been spread by Norse vikings to several countries in this area from the late eighth century to the middle of the eleventh century ad. They have several common characteristics in addition to the fluke-shaped and tapered short tail, such as a wide range of colour patterns, dual-coated wool and the ability to thrive under harsh environmental conditions, often in isolated marginal areas. While 34 short tailed breeds of North European origin can still be identified, it is clear that their population sizes have declined in most cases and several of them are now rare and endangered. Although these breeds have mainly been confined to certain localities, some of them have gained considerable distribution due to their genetic merits, such as prolificacy. Of these, the Finnsheep and the Romanov are best known being exported to several countries in the world where their genetic material has been utilized through crossbreeding with local sheep. This has resulted in the production of some new synthetic breeds. Meat is now generally the main product of the North European short-tailed breeds and their crossbreds, whereas wool, skins and milk are normally regarded as byproducts, yet of considerable economic importance in some cases. Such breeds have clearly a role to play in sustainable grassland-based production systems in the future. PMID- 22444648 TI - Performance and utilization of Northern European short-tailed breeds of sheep and their crosses in North America: a review. AB - The five Northern European short-tailed sheep breeds present in North America are the Finnsheep, Romanov, Icelandic, Shetland and Gotland. The Finnsheep and Romanov were first imported in 1966 and 1986, respectively, for their high reproductive performance. The Shetland, Icelandic and Gotland breeds were first imported in 1980, 1985 and 2005, respectively, for the uniqueness of their physical appearance and their unique fleeces desired by fiber craftspeople. There have been no scientific studies conducted on the performance of the Shetland, Icelandic or Gotland breeds relative to other breeds of sheep in North America. However, the Shetland and Icelandic breeds have become very popular in the United States and ranked 9th and 18th, respectively, among 35 breeds of sheep for number of purebred animals registered in 2008. The performance of the Finnsheep breed in North America relative to domestic breeds has been thoroughly investigated. Compared to several domestic purebreds and crosses, sheep with Finnsheep breeding had a younger age at puberty, greater fertility to autumn mating, greater litter size, greater survival to weaning, similar growth rate, similar subcutaneous fat thickness, smaller loin muscle area and greater percentage of kidney and pelvic fat. Each 1% increase in Finnsheep breeding in ewes was associated with approximately 0.01 more lambs born per ewe lambing. In North American studies, Romanov ewes were superior to Finnsheep ewes for reproductive rate and lamb production per ewe under both autumn and spring mating. Lambs of the two breeds were similar for survival, growth and carcass traits. Romanov and Romanov-cross ewes produced fleeces that were heavily contaminated with medulated and colored fibers and were of very low commercial value. Three composite breeds containing 25% to 49% Finnsheep breeding (Polypay, Rideau Arcott and Outaouais Arcott) were developed in North America and are now more popular than the Finnsheep breed. PMID- 22444649 TI - Gene expression patterns in anterior pituitary associated with quantitative measure of oestrous behaviour in dairy cows. AB - Intensive selection for high milk yield in dairy cows has raised production levels substantially but at the cost of reduced fertility, which manifests in different ways including reduced expression of oestrous behaviour. The genomic regulation of oestrous behaviour in bovines remains largely unknown. Here, we aimed to identify and study those genes that were associated with oestrous behaviour among genes expressed in the bovine anterior pituitary either at the start of oestrous cycle or at the mid-cycle (around day 12 of cycle), or regardless of the phase of cycle. Oestrous behaviour was recorded in each of 28 primiparous cows from 30 days in milk onwards till the day of their sacrifice (between 77 and 139 days in milk) and quantified as heat scores. An average heat score value was calculated for each cow from heat scores observed during consecutive oestrous cycles excluding the cycle on the day of sacrifice. A microarray experiment was designed to measure gene expression in the anterior pituitary of these cows, 14 of which were sacrificed at the start of oestrous cycle (day 0) and 14 around day 12 of cycle (day 12). Gene expression was modelled as a function of the orthogonally transformed average heat score values using a Bayesian hierarchical mixed model on data from day 0 cows alone (analysis 1), day 12 cows alone (analysis 2) and the combined data from day 0 and day 12 cows (analysis 3). Genes whose expression patterns showed significant linear or non-linear relationships with average heat scores were identified in all three analyses (177, 142 and 118 genes, respectively). Gene ontology terms enriched among genes identified in analysis 1 revealed processes associated with expression of oestrous behaviour whereas the terms enriched among genes identified in analysis 2 and 3 were general processes which may facilitate proper expression of oestrous behaviour at the subsequent oestrus. Studying these genes will help to improve our understanding of the genomic regulation of oestrous behaviour, ultimately leading to better management strategies and tools to improve or monitor reproductive performance in bovines. PMID- 22444650 TI - Detecting QTL for feed intake traits and other performance traits in growing pigs in a Pietrain-Large White backcross. AB - Knowing the large difference in daily feed intake (DFI) between Large White (LW) and Pietrain (PI) growing pigs, a backcross (BC) population has been set up to map QTL that could be used in marker assisted selection strategies. LW * PI boars were mated with sows from two LW lines to produce 16 sire families. A total of 717 BC progeny were fed ad libitum from 30 to 108 kg BW using single-place electronic feeders. A genome scan was conducted using genotypes for the halothane gene and 118 microsatellite markers spread on the 18 porcine autosomes. Interval mapping analyses were carried out, assuming different QTL alleles between sire families to account for within breed variability using the QTLMap software. The effects of the halothane genotype and of the dam line on the QTL effect estimates were tested. One QTL for DFI (P < 0.05 at the chromosome-wide (CW) level) and one QTL for feed conversion ratio (P < 0.01 at the CW level) were mapped to chromosomes SSC6 - probably due to the halothane alleles - and SSC7, respectively. Three putative QTL for feed intake traits were detected (P < 0.06 at the CW level) on SSC2, SSC7 and SSC9. QTL on feeding traits had effects in the range of 0.20 phenotypic s.d. The relatively low number of QTL detected for these traits suggests a large QTL allele variability within breeds and/or low effects of individual loci. Significant QTL were detected for traits related to carcass composition on chromosomes SSC6, SSC15 and SSC17, and to meat quality on chromosome SSC6 (P < 0.01 at the genome-wide level). QTL effects for body composition on SSC13 and SSC17 differed according to the LW dam line, which confirmed that QTL alleles were segregating in the LW breed. An epistatic effect involving the halothane locus and a QTL for loin weight on SSC7 was identified, the estimated substitution effects for the QTL differing by 200 g between Nn and NN individuals. The interactions between QTL alleles and genetic background or particular genes suggest further work to validate QTL segregations in the populations where marker assisted selection for the QTL would be applied. PMID- 22444651 TI - Genetic parameters for bone strength, osteochondrosis and meat percentage in Finnish Landrace and Yorkshire pigs. AB - Osteochondrosis (OC) is a major factor causing joint problems that affect animal welfare and pork production profitability. Strong bones are also important in the slaughtering process, especially as broken bones can lead to rejections of parts of the carcass. In this study, 326 Finnish Yorkshire and 464 Finnish Landrace test station pigs were examined post mortem for bone strength and osteochondral lesions. The objective was to estimate genetic parameters for OC and bone strength and their genetic and phenotypic correlations with carcass meat percentage. Two formulas were used for lean meat percentage, the first one (Hennessy meat-%) comprising two fat thickness measurements and one muscle depth measurement, and the second one (test station meat-%) also including the weight of lean meat in ham. Finnish Yorkshire had stronger bones than Finnish Landrace on average, but also more OC in the proximal end of the humerus (36%) and the distal end of the femur (51%) than Finnish Landrace (29% and 31% OC in the humerus and femur, respectively). By using the data on both breeds, the OC heritability estimated was 0.05 in the humerus and 0.26 in the femur. The estimated heritability of bone strength was also moderate (0.26). Test station meat-% showed higher heritability (0.40) than meat-% based on the Hennessy formula (0.29). Genetic correlations between meat percentage and the other studied traits were weak and associated with high standard errors. The results show that a mild form of OC is common in both Finnish pig breeds; bone strength and OC in the distal end of the femur are moderately heritable and can be improved through selection; and selection for high meat percentage does not seem to affect bone strength or OC. PMID- 22444652 TI - Analysis of culling probability in dairy buffalo using survival models. AB - In order to contribute to the genetic breeding programs of buffaloes, this study aimed to determine the influence of environmental effects on the stayability (ST) of dairy female Murrah buffalo in the herd. Data from 1016 buffaloes were used. ST was defined as the ability of the female to remain in the herd for 1, 2, 3, 4, 5 or 6 years after the first calving. Environmental effects were studied by survival analysis, adjusted to the fixed effects of farm, year and season of birth, class of first-lactation milk yield and age at first calving. The data were analyzed using the LIFEREG procedure of the SAS program that fits parametric models to failure time data (culling or ST = 0), and estimates parameters by maximum likelihood estimation. Breeding farm, year of birth and first-lactation milk yield significantly influenced (P < 0.0001) the ST to the specific ages (1 to 6 years after the first calving). Buffaloes that were older at first calving presented higher probabilities of being culled 1 year after the first calving, without any effect on culling at older ages. Buffaloes with a higher milk yield at first calving presented a lower culling probability and remained for a longer period of time in the herd. The effects of breeding farm, year of birth and first lactation milk yield should be included in models used for the analysis of ST in buffaloes. PMID- 22444653 TI - Merino sheep: a further look at quantitative trait loci for wool production. AB - A quantitative trait loci (QTL) analysis of wool traits from experimental half sib data of Merino sheep is presented. A total of 617 animals distributed in 10 families were genotyped for 36 microsatellite markers on four ovine chromosomes OAR1, OAR3, OAR4 and OAR11. The markers covering OAR3 and OAR11 were densely spaced, at an average distance of 2.8 and 1.2 cM, respectively. Body weight and wool traits were measured at first and second shearing. Analyses were conducted under three hypotheses: (i) a single QTL controlling a single trait (for multimarker regression models); (ii) two linked QTLs controlling a single trait (using maximum likelihood techniques) and (iii) a single QTL controlling more than one trait (also using maximum likelihood techniques). One QTL was identified for several wool traits on OAR1 (average curvature of fibre at first and second shearing, and clean wool yield measured at second shearing) and on OAR11 (weight and staple strength at first shearing, and coefficient of variation of fibre diameter at second shearing). In addition, one QTL was detected on OAR4 affecting weight measured at second shearing. The results of the single trait method and the two-QTL hypotheses showed an additional QTL segregating on OAR11 (for greasy fleece weight at first shearing and clean wool yield trait at second shearing). Pleiotropic QTLs (controlling more than one trait) were found on OAR1 (clean wool yield, average curvature of fibre, clean and greasy fleece weightand staple length, all measured at second shearing). PMID- 22444654 TI - Ileal amino acids digestibility of sorghum in weaned piglets and growing pigs. AB - The objective of the study was to determine the coefficients of ileal apparent digestibility (CIAD) of sorghum protein and amino acids (AA) in weaned piglets and growing pigs. Digestibility coefficients were estimated using the regression and difference methods for the weaned piglets; and the direct and difference methods for the growing pigs. To test the hypothesis that CP and AA digestibility of sorghum is lower in weaned piglets than in growing pigs, two experiments were conducted. In experiment one, 20 weaned piglets were fitted with a 'T' cannula at 21 days of age and were fed for 2 weeks one of five dietary treatments: a reference or control diet providing 200 g of CP/kg from casein (C) as the sole protein source, and four casein-sorghum (C-S) diets kept isoproteic to C by the appropriate adjustment of C and maize starch proportions; the amount of sorghum (S) in these diets was 135, 307, 460 and 614 g/kg. In experiment 2, fifteen castrated pigs weighing 57.8 +/- 2.8 kg were used and randomly allotted to one of three dietary treatments: a reference casein-maize starch diet containing C as the sole protein source, a C-S diet, both diets containing 160 g of CP/kg, and a fortified S diet containing 68 g of CP/kg. In piglets the CIAD for CP and AA decreased linearly (P < 0.05) as the amount of S in the diet increased. The average ileal digestibility of AA from C was 0.858 +/- 0.111, and decreased to 0.663 +/- 0.191 at the higher S level. The CIAD estimated using the regression or difference methods were similar for leucine, cysteine, glutamic acid, serine, alanine and tyrosine, and different for the other AA. In growing pigs the CIAD of protein and AA (except alanine and cysteine) were similar (P > 0.05) for the C and the C-S diets, but higher (P < 0.05) than those for the S diet. The CIAD for S obtained by the difference method were higher (P < 0.05) than those obtained using the direct method, except for lysine, isoleucine, valine, methionine, threonine and cysteine. The results indicate that except for lysine and cysteine, growing pigs' ability to digest AA and protein is superior than weaned piglets. PMID- 22444655 TI - A sulfur amino acid deficiency changes the amino acid composition of body protein in piglets. AB - Experiments carried out to determine the amino acid requirement in growing animals are often based on the premise that the amino acid composition of body protein is constant. However, there are indications that this assumption may not be correct. The objective of this study was to test the effect of feeding piglets a diet deficient or not in total sulfur amino acids (TSAA; Met + Cys) on nitrogen retention and amino acid composition of proteins in different body compartments. Six blocks of three pigs each were used in a combined comparative slaughter and nitrogen balance study. One piglet in each block was slaughtered at 42 days of age, whereas the other piglets received a diet deficient or not in TSAA for 19 days and were slaughtered thereafter. Two diets were formulated to provide either 0.20% Met and 0.45% TSAA (on a standardized ileal digestible basis) or 0.46% Met and 0.70% TSAA. Diets were offered approximately 25% below ad libitum intake. At slaughter, the whole animal was divided into carcass, blood, intestines, liver, and the combined head, tail, feet and other organs (HFTO), which were analyzed for nitrogen and amino acid contents. Samples of the longissimus muscle (LM) were analyzed for myosin heavy chain (MyHC) and actin contents. Nitrogen retention was 20% lower in piglets receiving the TSAA-deficient diet (P < 0.01). In these piglets, the nitrogen content in tissue gain was lower in the empty body, carcass, LM and blood (P < 0.05) or tended to be lower in HFTO (P < 0.10), but was not different in the intestines and liver. The Met content in retained protein was lower in the empty body, LM and blood (P < 0.05), and tended to be lower in the carcass (P < 0.10). The Cys content was lower in LM, but higher in blood of piglets receiving the TSAA-deficient diet (P < 0.05). Skeletal muscle appeared to be affected most by the TSAA deficiency. In LM, the Met content in retained protein was reduced by 12% and total Met retention by more than 60%. The MyHC and actin contents in LM were not affected by the TSAA content of the diet. These results show that a deficient TSAA supply affects the amino acid composition of different body proteins. This questions the use of a constant ideal amino acid profile to express dietary amino acid requirements, but also illustrates the plasticity of the animal to cope with nutritional challenges. PMID- 22444656 TI - Does the newly weaned piglet select a zinc oxide supplemented feed, when given the choice? AB - An experiment was conducted to examine whether weaned piglets would display preference for a food containing a pharmacological level of zinc oxide (ZnO). A total of 60 piglets were weaned at 7.8 kg +/- 0.14 (s.e.m.) and 27.8 +/- 0.11 days of age into eight mixed sex groups of seven or eight piglets per pen. Groups were balanced for litter origin, weaning weight and sex. Piglet feeding behaviour was constantly recorded by a multi-spaced feeding behaviour recording system (Leeds University Feeding Behaviour System) in each pen. Each pen of pigs was offered ad libitum access to two different foods (16.2 MJ digestible energy, 16 g lysine/kg), which differed only in the level of ZnO supplementation: unsupplemented (U) or supplemented (Z; ZnO 3100 mg/kg). Both foods contained a basal level of zinc (100 mg/kg). Feeding time was recorded for each individual at each trough. Piglets were weighed at weaning and at 7 and 13 days thereafter. The experiment ran for 13 days. Any piglet observed with post-weaning scour (Y) was recorded and treated appropriately whereas healthy piglets were categorised as N (no scour). Preference for a food was defined as being significantly different from 50% of total feed intake or time spent feeding. There was no difference between piglet numbers selecting each food as their first meal. However, within the first 24 h, piglets preferred (P < 0.001) food U, spending only 36.3% (32.2 to 40.5; 95% confidence interval) of feeding time at food Z. Throughout the experiment, piglets showed aversion (P < 0.001) to food Z, consumption being 8.9% (5.1 to 13.6) and 15.7% (8.9 to 23.9) of total intake in weeks 1 and 2, respectively. Individual piglets showed their preference for food U with only 16.6% (14.6 to 18.5) and 21.8% (19.6 to 24.0) of feeding time spent on food Z in weeks 1 and 2, respectively. Scouring piglets did not show any difference in feeding behaviour from healthy piglets in either week. Average piglet gain (of all piglets) was low, at 0.039 +/- 0.03 and 0.272 +/- 0.04 kg/day in weeks 1 and 2, respectively. Given a choice, weaned piglets showed a clear preference for the food U even when exhibiting post-weaning scour. It can be concluded that the newly weaned, naive, piglet is not able to recognise a food with clear health and performance benefits but selected the food U due to the reduced palatability of the food Z. PMID- 22444657 TI - Feeding behaviour of sheep fed lucerne v. grass hays with controlled post ingestive consequences. AB - Understanding what determines feeding behaviour in herbivores is essential to optimise the use of forages in breeding systems. Herbivores can evaluate foods by associative learning of their pre-ingestive characteristics (taste, odour, etc.) and their post-ingestive consequences. Post-ingestive consequences are acknowledged as influencing intake and food choices, but the role of pre ingestive characteristics is still being debated. Our experiment was designed to test their separate effects on daily dry matter intake (DMI), intake patterns and short-term choices in sheep by crossing the nature of the hay orally consumed (o) ad libitum, lucerne (L) or grass (G), with the nature of the hay introduced into the rumen (r), L or G, at a rate of half the total amount of hay received the day before. We applied four treatments, Go/Gr, Go/Lr, Lo/Gr and Lo/Lr, to test the effects of (i) post-ingestive consequences with similar pre-ingestive characteristics (Go/Gr v. Go/Lr; Lo/Gr v. Lo/Lr) and (ii) pre-ingestive characteristics with similar post-ingestive consequences at the end of the feeding period (Go/Lr v. Lo/Gr). Six rumen-fistulated sheep underwent all the treatments over 11-day periods in a latin square design. Eating time was restricted to 6 h/day, intraruminal introductions were performed just before food offer and choice tests were conducted after food removal. For similar pre ingestive characteristics, DMI increased when L hay was introduced into the rumen rather than G (P < 0.05), possibly owing to a lower fill effect of L due to its lower NDF content and higher rumen degradability. The increased DMI resulted from longer eating time when G was orally consumed (149 v. 192 min, P < 0.05), whereas it resulted from higher intake rate with L (4.8 v. 6.1 g/min, P < 0.05). For similar post-ingestive consequences at the end of the feeding period (Go/Lr and Lo/Gr), DMI were similar (P > 0.05). Pre-ingestive characteristics or palatability per se did not therefore influence daily intake, although they influenced eating patterns. Pre-ingestive characteristics also greatly influenced short-term choices in favour of the hay that was not previously consumed, independently of any post-ingestive influence. This study confirms the effects of post-ingestive consequences on daily intake, but demonstrates that these variations are obtained by different behavioural adjustments under the influence of pre-ingestive characteristics. Preference for novelty, regardless of post ingestive consequences, thus suggests that sheep may seek a diverse diet more for pleasure than for functional purposes, with implications for animal welfare. PMID- 22444658 TI - Factors associated with selling price of cattle at livestock marts. AB - The objective of this study was to determine the factors associated with selling price of animals at livestock marts around Ireland. Data consisted of four distinct maturity categories: calves (2 to 84 days of age, n = 53 838); weanlings (6 to 12 months of age, n = 19 972); post-weanlings (12 to 36 months of age, n = 93 081) and cows (>30 months to 12 years of age, n = 94 839); sold through livestock marts between 2000 and 2008. Factors associated with animal price were determined within each maturity category separately using mixed models; random effects were mart, date of sale nested within mart, and herd of origin nested within year of sale. Mean selling price was ?157, ?580, ?655 and ?592 for calves, weanlings, post-weanlings and cows, respectively. The greatest prices were paid for singleton crossbred male calves, weanlings and post-weanlings from older dams. With the exception of the Aberdeen Angus, beef breeds and their crosses consistently received higher prices than their dairy counterparts across all four maturity categories; increased proportion of Belgian Blue and Charolais was associated with greater prices compared with other beef breeds. When live-weight was included in the multiple regression models the association between price and all factors regressed toward zero but most factors remained associated with price. The highest price was recorded in the spring months for calves, post weanlings and cows, and in the autumn months for weanlings. Results from this study may be used to help farmers make more informed management decisions, as well as provide information for bio-economic models for evaluating alternative production systems or estimating economic values. PMID- 22444659 TI - Effect of dietary crude protein on ammonia-N emission measured by herd nitrogen mass balance in a freestall dairy barn managed under farm-like conditions. AB - The main objective of this experiment was to monitor the impact of barn side and dietary crude protein (CP) on production performance, manure production and composition, and ammonia nitrogen (N) emission from a lactating dairy herd housed in a free-stall barn and managed under farm-like conditions throughout a number of months in each season of the year. The 78-cow lactating herd of the University of Wisconsin-Platteville (USA) was halved and each group was allocated to either the north or south side of the barn and either a recommended (REC) diet with 16.7 +/- 1.3% CP dry matter basis (DM) or an excess (EXC) CP diet containing 1.5 units of CP above the REC diet (18.2 +/- 1.5%). In 7 months between February 2004 and January 2005, total manure collection was conducted by manual scraping of the alleys and ammonia-N emission was calculated as intake N + bedding N - milk N - scraped manure N. Side of the barn (northern v. southern exposure) did not influence measurements and there was no effect of dietary CP on dry matter intake (DMI), milk, milk fat, and milk protein production, but a lower manure N concentration was observed for the group of cows fed the REC diet compared with the EXC diet (3.43% v. 3.66% of DM). Nitrogen intake was 63 g/day lower (643 v. 706 g/day), milk N was unaffected (157 g/day), manure N was 32 g/day lower (391 v. 423 g/day), and ammonia-N emission was 34 g/day lower (93 v. 127 g/day) for the group consuming the REC diet compared with the group consuming the EXC diet. There were larger variations in measured responses among months of the year than between level of dietary CP. Wet and dry manure excretions tended to be higher, but manure pH was reduced when corn silage became unavailable and the diet included additional corn grain and alfalfa silage as the only forage source. Prediction of manure N excretion for a group of cow determined as N intake - N milk was 9% higher than current prediction equations of the American Society of Agricultural Engineers. Ammonia-N loss averaged 110 g/day per lactating cow, but ranged from 64 g/day to 178 g/day with no clear seasonal pattern. There was no clear association between barn temperature, manure temperature or manure pH and ammonia-N emission; however, intake N explained 61% of the variation in ammonia-N emission. PMID- 22444660 TI - Modelling of manure production by pigs and NH3, N2O and CH4 emissions. Part I: animal excretion and enteric CH4, effect of feeding and performance. AB - A mathematical model was developed from literature data to predict the volume and composition of pig's excreta (dry and organic matter, C, N, P, K, Cu and Zn contents), and the emission of greenhouse gases (CH4 and CO2) though respiration and from the intestinal tract, for each physiological stage (post-weaning and fattening pigs and lactating and gestating sows). The main sources of variation considered in the model are related to animal performances (feed efficiency, prolificacy, body weight gain, etc.), to water and nutrient intakes and to housing conditions (ambient temperature). Model predictions were validated by using 19 experimental studies, most of them performed in conditions close to those of commercial farms. Validation results showed that the model is precise and robust when predicting slurry volume (R2 = 0.96), slurry N (R2 = 0.91), P (R2 = 0.95) and to a lesser extent dry matter (R2 = 0.75) contents. Faeces and urine composition (minerals and macronutrients) can also be precisely assessed, provided the composition and the digestibility of the feed are well known. Sensitivity analysis showed strong differences in CH4 emission and excretion amounts and composition according to physiological status, animal performance, temperature and diet composition. The model is an efficient tool to calculate nutrient balances at the animal level in commercial conditions, and to simulate the effect of production alternatives, such as feeding strategy or animal performance, on excreta production and composition. This is illustrated by simulations of three feeding strategies, which demonstrates important opportunities to limit environmental risks through diet manipulations. PMID- 22444661 TI - Modelling of manure production by pigs and NH3, N2O and CH4 emissions. Part II: effect of animal housing, manure storage and treatment practices. AB - A model has been developed to predict pig manure evolution (mass, dry and organic matter, N, P, K, Cu and Zn contents) and related gaseous emissions (methane (CH4), nitrous oxide (N2O) and ammonia (NH3)) from pig excreta up to manure stored before spreading. This model forms part of a more comprehensive model including the prediction of pig excretion. The model simulates contrasted management systems, including different options for housing (slatted floor or deep litter), outside storage of manure and treatment (anaerobic digestion, biological N removal processes, slurry composting (SC) with straw and solid manure composting). Farmer practices and climatic conditions, which have significant effects on gaseous emissions within each option, have also been identified. The quantification of their effects was based on expert judgement from literature and local experiments, relations from mechanistic models or simple emission factors, depending on existing knowledge. The model helps to identify relative advantages and weaknesses for each system. For example, deep litter with standard management practices is associated with high-greenhouse gas (GHG) production (+125% compared to slatted floor) and SC on straw is associated with high NH3 emission (+15% compared to slatted floor). Another important result from model building and first simulations is that farmer practices and the climate induce an intra-system (for a given infrastructure) variability of NH3 and GHG emissions nearly as high as inter-system variability. For example, in deep-litter housing systems, NH3 and N2O emissions from animal housing may vary between 6% and 53%, and between 1% and 19% of total N excreted, respectively. Thus, the model could be useful to identify and quantify improvement margins on farms, more precisely or more easily than current methodologies. PMID- 22444662 TI - Effect of grain type and processing method on rumen fermentation and milk rumenic acid production. AB - It was hypothesized that differences in starch degradability account for observed differences in rumen vaccenic acid (t11-18:1) and milk rumenic acid (RA) concentrations. To test this hypothesis, starch degradability was varied through grain source and by processing. Eight Holstein cows in mid-lactation were assigned to two 4 * 4 Latin squares with four 21-day periods and four diets: dry rolled barley, ground barley, dry rolled corn and ground corn. Diets contained similar starch content and were supplemented with whole sunflower seed to provide similar total polyunsaturated fatty acid (PUFA) (18:2n-6 + 18:3n-3) contents. Forage/concentrate ratios of all diets were 42 : 58. Rumen, plasma and milk samples were collected in the third week of each period. In situ degradation rates (%/h) for rolled corn, ground corn, rolled barley and ground barley were 5.4, 8.9, 17.0 and 19.4, respectively, for dry matter (DM) and 6.3, 10.8, 25.3 and 43.8, respectively, for starch. DM intakes were greater for corn-based diets (CBD) than for barley-based diets (BBD) with no difference between rolled and ground diets. Daily minimum rumen pH was less (5.2 v. 5.5) and pH duration <5.8 (h/d) was greater (7.4 v. 4.3) for BBD than for CBD. Milk fat content and yield were less for BBD than for CBD with greater values observed for rolling compared with grinding. Variability in milk fat yield was strongly related (R2 = 0.55; P < 0.01) to total starch intake (45%) and milk c9t11-CLA (10%) and none of the t 18:1 isomers or CLA isomers that are typically associated with milk fat depression entered the model. The concentrations (%) of t10-18:1 and t11-18:1 were greater for BBD than for CBD in rumen contents (t10-18:1, 3.5 v. 1.3; t11 18:1, 3.2 v. 1.9), plasma (t10-18:1, 1.2 v. 0.2; t11-18:1, 0.97 v. 0.58) and milk (t10-18:1, 3.8 v. 1.0; t11-18:1, 2.6 v. 1.7) despite greater total PUFA intakes for CBD. Milk RA concentration was greater for BBD than for CBD (1.46 v. 0.89) but was not influenced by the method of grain processing. This study clearly demonstrated that the milk content and profile of t-18:1 and CLA isomers were more strongly influenced by the source of grain starch (barley > corn) than by the method of grain processing indicating that factors inherent in the source of starch were responsible for the observed differences and these factors could not be modified by the processing methods used in this study. PMID- 22444663 TI - Genetic polymorphisms and serum levels of mannose-binding lectin in Chinese pediatric patients with common infectious diseases. AB - BACKGROUND: Mannose-binding lectin (MBL) is a collagen-like serum protein that plays an important role in first-line host defense, especially in infants and young children. The objective of this study was to explore the genetic polymorphisms and serum protein levels of MBL in Chinese pediatric patients with common infectious diseases, including recurrent respiratory infection (RRI), acute respiratory infection (ARI), active cytomegalovirus (CMV) infection, localized abscess, and otitis media. METHODS: MBL genetic polymorphisms of 151 pediatric patients with infectious diseases and 105 healthy controls were detected by PCR and sequencing. Serum MBL levels of all the patients and controls were measured using a Human MBL ELISA Kit. Differences in MBL genetic polymorphisms and serum levels between patients and controls were analyzed by statistical methods. RESULTS: The frequencies of allele H/L at position -550 of the promoter and three haplotypes - HYPA, HYPB, and LYPB - were statistically different between patients and controls (p<0.05). The frequencies of genotypes 'YA' and 'XB', relevant to serum protein levels, were also significantly different between patients and controls (p<0.05). Serum MBL levels of patients with active CMV infection were significantly lower than those of controls (p<0.05). Conversely, serum MBL levels of patients with ARI and localized abscess were significantly higher than those of controls (p<0.05). CONCLUSIONS: Genetic polymorphisms attributable to mutations in the promoter and exon 1 of the MBL2 gene appear to be relatively common in pediatric patients with infectious diseases. Low serum MBL levels may play a role in the high sensitivity of pediatric CMV infections. PMID- 22444664 TI - Reducing the fat content in ground beef without sacrificing quality: a review. AB - Americans are becoming more health conscious in their food choices and many are interested in reducing dietary fat intake. Fat replacers can affect meat flavor both by adding flavors of their own, by reducing the original aroma-generating substrate (fat) and by altering release of aroma compounds. When fat is removed from meat, water is generally added to replace it. Water-binding compounds can be added to prevent the added water from cooking out or evaporating and to prevent patty shrinkage. Fat replacers are generally classified by their composition: protein-based replacers including whey, soy and collagen, lipid-based substances such as soy lecithin which function as emulsifiers maintaining the fat that is retained distributed in the product, and carbohydrate-based substances including flours (wheat, soy, oat), starches (potato, modified corn starch, tapioca) and gums (carrageenan, xanthin). Duplication of the characteristics contributed by fat often requires a combination of replacers to address juiciness and texture (firmness) without negatively impacting flavor. PMID- 22444665 TI - Effect of supplementation of two sources and two levels of copper on lipid metabolism in Nellore beef cattle. AB - This study was conducted with 35 Nellore beef cattle to determine the effect of supplementation of two levels and two copper sources (organic and inorganic) on metabolism of lipids and cholesterol of meat. The five treatments used were: CONTROL: without copper supplementation, I10 or I40: 10 or 40 mg/kg DM (as Cu sulfate), O10 or O40: 10 or 40 mg/kg DM (as Cu proteinate). In general, the copper supplementation changed the fatty acid profile of meat (p<0.05), with a higher proportion of unsaturated fatty acids and reduction of saturated fatty acids. There was no effect of supplementation on blood cholesterol and triglycerides, however; in general, there was a reduction in cholesterol concentration in the L. dorsi (p<0.05) compared to the control treatment through the reduction (p<0.05) in the concentrations of GSH and GSH/GSSG ratio. The Cu supplementation did have an influence on metabolism of lipids. The production of healthier meat is beneficial to public health by reducing the risk of cardiovascular disease. PMID- 22444666 TI - Analysis of pork adulteration in commercial meatballs targeting porcine-specific mitochondrial cytochrome b gene by TaqMan probe real-time polymerase chain reaction. AB - A test for assessing pork adulteration in meatballs, using TaqMan probe real-time polymerase chain reaction, was developed. The assay combined porcine-specific primers and TaqMan probe for the detection of a 109 bp fragment of porcine cytochrome b gene. Specificity test with 10 ng DNA of eleven different species yielded a threshold cycle (Ct) of 15.5 +/- 0.20 for the pork and negative results for the others. Analysis of beef meatballs with spiked pork showed the assay can determine 100-0.01% contaminated pork with 102% PCR efficiency, high linear regression (r(2) = 0.994) and <= 6% relative errors. Residuals analysis revealed a high precision in all determinations. Random analysis of commercial meatballs from pork, beef, chicken, mutton and goat, yielded a Ct between 15.89 +/- 0.16 and 16.37 +/- 0.22 from pork meatballs and negative results from the others, showing the suitability of the assay to determine pork in commercial meatballs with a high accuracy and precision. PMID- 22444667 TI - Nonaqueous synthesis of TiO2 nanocrystals using TiF4 to engineer morphology, oxygen vacancy concentration, and photocatalytic activity. AB - Control over faceting in nanocrystals (NCs) is pivotal for many applications, but most notably when investigating catalytic reactions which occur on the surfaces of nanostructures. Anatase titanium dioxide (TiO(2)) is one of the most studied photocatalysts, but the shape dependence of its activity has not yet been satisfactorily investigated and many questions still remain unanswered. We report the nonaqueous surfactant-assisted synthesis of highly uniform anatase TiO(2) NCs with tailorable morphology in the 10-100 nm size regime, prepared through a seeded growth technique. Introduction of titanium(IV) fluoride (TiF(4)) preferentially exposes the {001} facet of anatase through in situ release of hydrofluoric acid (HF), allowing for the formation of uniform anatase NCs based on the truncated tetragonal bipyramidal geometry. A method is described to engineer the percentage of {001} and {101} facets through the choice of cosurfactant and titanium precursor. X-ray diffraction studies are performed in conjunction with simulation to determine an average NC dimension which correlates with results obtained using electron microscopy. In addition to altering the particle shape, the introduction of TiF(4) into the synthesis results in TiO(2) NCs that are blue in color and display a broad visible/NIR absorbance which peaks in the infrared (lambda(max) ~ 3400 nm). The blue color results from oxygen vacancies formed in the presence of fluorine, as indicated by electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS) studies. The surfactants on the surface of the NCs are removed through a simple ligand exchange procedure, allowing the shape dependence of photocatalytic hydrogen evolution to be studied using monodisperse TiO(2) NCs. Preliminary experiments on the photoreforming of methanol, employed as a model sacrificial agent, on platinized samples resulted in high volumes of evolved hydrogen (up to 2.1 mmol h(-1) g(-1)) under simulated solar illumination. Remarkably, the data suggest that, under our experimental conditions, the {101} facets of anatase are more active than the {001}. PMID- 22444668 TI - Maternal inheritance of a promoter variant in the imprinted PHLDA2 gene significantly increases birth weight. AB - Birth weight is an important indicator of both perinatal and adult health, but little is known about the genetic factors contributing to its variability. Intrauterine growth restriction is a leading cause of perinatal morbidity and mortality and is also associated with adult disease. A significant correlation has been reported between lower birth weight and increased expression of the maternal PHLDA2 allele in term placenta (the normal imprinting pattern was maintained). However, a mechanism that explains the transcriptional regulation of PHLDA2 on in utero growth has yet to be described. In this study, we sequenced the PHLDA2 promoter region in 263 fetal DNA samples to identify polymorphic variants. We used a luciferase reporter assay to identify in the PHLDA2 promoter a 15 bp repeat sequence (RS1) variant that significantly reduces PHLDA2-promoter efficiency. RS1 genotyping was then performed in three independent white European normal birth cohorts. Meta-analysis of all three (total n = 9,433) showed that maternal inheritance of RS1 resulted in a significant 93 g increase in birth weight (p = 0.01; 95% confidence interval [CI] = 22-163). Moreover, when the mother was homozygous for RS1, the influence on birth weight was 155 g (p = 0.04; 95% CI = 9-300), which is a similar magnitude to the reduction in birth weight caused by maternal smoking. PMID- 22444669 TI - Linkage-disequilibrium-based binning affects the interpretation of GWASs. AB - Genome-wide association studies (GWASs) are critically dependent on detailed knowledge of the pattern of linkage disequilibrium (LD) in the human genome. GWASs generate lists of variants, usually SNPs, ranked according to the significance of their association to a trait. Downstream analyses generally focus on the gene or genes that are physically closest to these SNPs and ignore their LD profile with other SNPs. We have developed a flexible R package (LDsnpR) that efficiently assigns SNPs to genes on the basis of both their physical position and their pairwise LD with other SNPs. We used the positional-binning and LD based-binning approaches to investigate whether including these "LD-based" SNPs would affect the interpretation of three published GWASs on bipolar affective disorder (BP) and of the imputed versions of two of these GWASs. We show how including LD can be important for interpreting and comparing GWASs. In the published, unimputed GWASs, LD-based binning effectively "recovered" 6.1%-8.3% of Ensembl-defined genes. It altered the ranks of the genes and resulted in nonnegligible differences between the lists of the top 2,000 genes emerging from the two binning approaches. It also improved the overall gene-based concordance between independent BP studies. In the imputed datasets, although the increases in coverage (>0.4%) and rank changes were more modest, even greater concordance between the studies was observed, attesting to the potential of LD-based binning on imputed data as well. Thus, ignoring LD can result in the misinterpretation of the GWAS findings and have an impact on subsequent genetic and functional studies. PMID- 22444670 TI - SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. AB - Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease. PMID- 22444671 TI - Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. AB - CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations. PMID- 22444672 TI - Evaluation of computer-aided detection devices: consensus is developing. PMID- 22444673 TI - Correlations between SUVmax and expression of GLUT1 and growth factors inducing lymphangiogenesis. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to assess the correlations between the maximum standardized uptake value (SUVmax) of colorectal carcinoma and hepatocyte growth factor (HGF), vascular endothelial growth factor C (VEGF-C), and their respective receptors using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). METHODS: Fluorine-18 FDG PET/CT scans were performed on 33 patients with colorectal carcinoma before any treatment. The SUVmax of colorectal carcinoma and the clinicopathologic data associated with lymphatic metastases were analyzed. The expression of glucose transporter 1 (GLUT1), HGF, c-Met, VEGF-C, and vascular endothelial growth factor receptor 3 (VEGFR-3) in tumor tissues was analyzed using immunohistochemical methods. Lymphatic endothelial cells were marked with D2-40, and lymphatic vessel density (LVD) was recorded. The correlations were analyzed among the SUVmax of colorectal carcinoma, LVD, and the expression of GLUT1, HGF, c-Met, VEGF-C, and VEGFR-3 in tumor tissues. RESULTS: SUVmax and LVD in 15 patients with lymphatic metastases were 13.00 +/- 4.51 and 6.25 +/- 1.54, respectively, whereas in 18 patients with nonmetastatic nodes, SUVmax and LVD were 9.66 +/- 4.82 and 4.54 +/- 1.02, respectively. The differences of SUVmax and LVD between metastatic and nonmetastatic patients were statistically significant (F = 4.153, P = .025, and F = 14.501, P = .001, respectively). There were no statistical differences of SUVmax and LVD in variably differentiated colorectal carcinoma (F = 0.708, P = .502, and F = 0.311, P = .735, respectively). The expression rates of GLUT1 in neoplastic and normal tissue were 72.7% (24 of 33) and 21.2% (seven of 33), respectively (P = .001). Moreover, the expression rates of GLUT1 in metastatic and nonmetastatic tissue were 93.33% (14 of 15) and 61.11% (11 of 18), respectively (P = .038). LVD and the integrated optical density of GLUT1 were 5.31 +/- 1.53 and 8.21 * 10(4) +/- 4.30 * 10(4), respectively, in tumor tissue, and there were linear correlations between SUVmax and LVD (r = 0.373, P = .033) and between SUVmax and expression of GLUT1 (r = 0.428, P = .013). The differences of SUVmax in HGF, c-Met, and VEGF-C groups with different expressions were statistically significant (P = .007, P = .009, and P = .030, respectively). No correlation was found between the expression of VEGFR-3 and SUVmax. The expression of GLUT1 and HGF as well as of GLUT1 and VEGF-C was rank correlated (r = 0.521, P = .002, and r = 0.505, P = .003, respectively). No rank correlations were found between the expression of GLUT1 and c-Met, GLUT1, and VEGFR-3. CONCLUSIONS: The SUVmax of colorectal carcinoma was significantly higher in metastatic patients; the uptake of colorectal carcinoma was associated with LVD and the expression of HGF and VEGF-C but not with the expression of VEGFR-3. PMID- 22444674 TI - Radiation safety and medical education: development and integration of a dedicated educational module into a radiology clerkship, outcomes assessment, and survey of medical students' perceptions. AB - RATIONALE AND OBJECTIVES: This study assesses the effect on medical student understanding of a new radiobiology and radiation safety module in a fourth-year radiology clerkship. MATERIALS AND METHODS: A dedicated radiobiology and radiation safety module was incorporated into the fourth-year medical school radiology clerkship at our institution. Student understanding of the material was assessed via pretest and posttest. Statistical analysis was performed to assess significance of changes in student performance. In addition, we surveyed student perceptions of the importance of this material in medical education and practice. RESULTS: Monthly pretest mean scores ranged from 47.8% to 55.6%, with an average monthly pretest score of 50.3%. Monthly posttest mean scores ranged from 77.3% to 91.2%, with an average monthly posttest score of 83.9%. The improvement in exam scores after the educational intervention was statistically significant (all P < .01). CONCLUSION: The introduction of a new educational module can significantly improve medical student understanding of radiobiology and radiation safety. PMID- 22444675 TI - Teaching management of contrast reactions: does it work and how often do we need to refresh? AB - RATIONALE AND OBJECTIVES: Knowledge of the management of acute contrast reactions is lacking among radiologists. Training in the management of acute contrast reactions occurs at the investigators' institution and others, but the durability of that training and the need for refresher training have not been assessed. MATERIALS AND METHODS: A prospective assessment of changes in trainees' knowledge and confidence following a required educational course concerning reactions to contrast material was conducted. Assessments were performed prior to and immediately following the course and at 1, 3, 6, and 9 months after the course. RESULTS: Trainees' knowledge significantly improved following the course and remained improved for 6 months (P < .0001). By 9 months, knowledge was no longer improved over baseline (P = .0644). Trainees' confidence also improved following the course and remained improved throughout follow-up (P = .0356 at 9 months). At 6 months, however, confidence had significantly declined relative to levels immediately after the course (P = .0241). Trainees' knowledge was not dependent on postgraduate year (PGY), but PGY-2 residents were significantly less confident in their ability to manage a contrast reaction than PGY-5 and PGY-6 trainees. Trainees who managed contrast reactions during the follow-up period were more confident in their abilities than trainees who did not (P = .0097). CONCLUSIONS: These data suggest the need for biannual refresher training in the management of acute contrast reactions to maintain trainees' knowledge and confidence. PMID- 22444676 TI - Radiology history lives. PMID- 22444677 TI - Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent. AB - The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively). PMID- 22444678 TI - Fluorescent nucleosides with 'on-off' switching function, pH-responsive fluorescent uridine derivatives. AB - We synthesized various pH-responsive fluorescent deoxyuridine derivatives (1a-g). These fluorescent nucleosides exhibited distinctive fluorescence at 470-600 nm in aqueous solvents containing methanol only at acidic to neutral pH values. In particular, 1f exhibited strong fluorescence only at pH range of 3.1-7.2 with a pK(a) of 6.1. Such pH-sensitive fluorescent nucleosides can be used as 'on-off' fluorescence switch for monitoring pH change in biological systems, particularly for cancer cell detection. PMID- 22444679 TI - Radioiodinated sunitinib as a potential radiotracer for imaging angiogenesis radiosynthesis and first radiopharmacological evaluation of 5-[125I]Iodo sunitinib. AB - Sunitinib(r) (SU11248) is a highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR). Radiolabeled inhibitors of RTKs might be useful tools for monitoring RTKs levels in tumour tissue giving valuable information for anti-angiogenic therapy. We report here the synthesis of a (125)I-labeled derivative of sunitinib(r) and its first radiopharmaceutical characterization. The non-radioactive reference compound 5-iodo-sunitinib 4 was prepared by Knoevenagel condensation of 5-iodo-oxindole with the corresponding substituted 5-formyl-1H-pyrrole. In a competition binding assay against VEGFR-2 a binding constant (K(d)) of 16 nM for 4 was found. The ability of 4 to inhibit tyrosine kinase activity was demonstrated on RTK expressing cells suggesting this radiotracer as a useful tool for monitoring VEGFR expression. 5-[(125)I]lodo sunitinib, [(125)I]-4 was obtained via destannylation of the corresponding tributylstannyl precursor with [(125)I]NaI in the presence of H(2)O(2) in high radiochemical yield (>95%) and radiochemical purity (<98%) after HPLC purification. Determination of human plasma protein binding at time intervals of 0; 1; 2; 4 and 24h suggested a low non-specific binding of 5-10%. Preliminary biodistribution studies of [(125)I]-4 in healthy CD-1 mice showed a relatively high uptake in VEGFR-2 rich tissues like kidney and lung followed by rapid washout (9.6 and 9.7; 4.5 and 3.8% ID/g of kidney and lung at 1 and 4h, respectively). PMID- 22444680 TI - 5-benzylidenerhodanine and 5-benzylidene-2-4-thiazolidinedione based antibacterials. AB - Herein we outline the antibacterial activity of amino acid containing thiazolidinediones and rhodanines against Gram-positive bacteria Staphylococcus aureus ATCC 31890, Staphylococcus epidermidis and Bacillus subtilis ATCC 6633. The rhodanine derivatives were generally more active than the analogous thiazolidinediones. Compounds of series 5 showed some selectivity for Bacillus subtilis ATCC 6633, the extent of which is enhanced by the inclusion of a non polar amino acid at the 5-position of the core thiazolidinediones and rhodanines scaffolds. SAR data of series 8 demonstrated improved activity against the clinically more significant Staphylococci with selectivity over Bacillus subtilis ATCC 6633 induced by introduction of a bulky aryl substituent at the 5-position of the core scaffolds. PMID- 22444681 TI - Thiosemicarbazone fragment embedded within 1,2,4-triazole ring as inhibitors of Entamoeba histolytica. AB - A series of 1,2,4-triazole derivatives containing thiosemicarbazone linkage was synthesized and evaluated for their in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. All the compounds were capable of inhibiting the growth of E. histolytica out of which four compounds (IC(50)=0.28 1.38 MUM) were found to have better efficacy than the standard drug Metronidazole (IC(50)=1.8 MUM). Cytotoxicity of the active compounds was assessed by MTT assay using human breast cancer MCF-7 cell line, which revealed that all the compounds were low cytotoxic in the concentration range of 2.5-250 MUM. PMID- 22444682 TI - Preparation and photophysical properties of a caged kynurenine. AB - We have prepared l-kyurenine 4-hydroxyphenacyl ester, a caged derivative of L kynurenine. N(alpha)-tBOC-L-tryptophan was reacted with 4-hydroxyphenacyl bromide in DMF with K(2)CO(3) as the base to give the N(alpha)-tBOC 4-hydroxyphenacyl ester. The ester was then treated with O(3) in MeOH at -20 degrees C, followed by trifluoroacetic acid in CH(2)Cl(2), then aqueous HCl to obtain the caged kynurenine as the dihydrochloride salt. The caged kynurenine is stable as a dry solid in the dark at -78 degrees C, but in aqueous solutions in phosphate buffer at pH 7-8 hydrolyzes rapidly (t(1/2) ~5 min). Solutions in Tris at pH 7 are more stable (t(1/2) >30 min), and solutions in 1mM HCl are stable for several hours. As expected, the ester is cleaved in microseconds with laser pulses at 355 nm. The caged kynurenine may be useful for preparation of substrate complexes for crystallography or in biological studies on kynurenine. PMID- 22444683 TI - A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation. AB - A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured. PMID- 22444684 TI - Bromophenols as inhibitors of protein tyrosine phosphatase 1B with antidiabetic properties. AB - A series of bromophenol derivatives were synthesized and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors in vitro and in vivo based on bromophenol 4e (IC(50)=2.42 MUmol/L), which was isolated from red algae Rhodomela confervoides. The results showed that all of the synthesized compounds displayed weak to good PTP1B inhibition at tested concentration. Among them, highly brominated compound 4g exhibited promising inhibitory activity against PTP1B with IC(50) 0.68 MUmol/L, which was approximately fourfold more potent than lead compound 4e. Further, compound 4g demonstrated high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). More importantly, in vivo antidiabetic activities investigations of compound 4g also demonstrated inspiring results. PMID- 22444685 TI - A new class of prolylcarboxypeptidase inhibitors, part 2: the aminocyclopentanes. AB - A series of potent inhibitors of prolylcarboxypeptidase (PrCP) was developed by modifying a lead structure that was discovered by high-throughput screening. The tert-butyl pyrrolidine was replaced by an aminocyclopentane to reduce the metabolic liabilities of the original lead. The compounds demonstrated sub nanomolar in vitro IC(50) values, minimal activity shifts in pure plasma and improved pharmacokinetics. Complete ex vivo plasma target engagement was achieved with low brain exposure at the 20 h time point following p.o. dosing in a mouse. The results indicate that the aminocyclopentanes are useful tools for studying the therapeutic potential of peripheral (non-CNS) PrCP inhibition. PMID- 22444686 TI - 3D simulation of morphological effect on reflectance of Si3N4 sub-wavelength structures for silicon solar cells. AB - In this study, we investigate the reflectance property of the cylinder, right circular cone, and square pyramid shapes of silicon nitride (Si3N4) subwavelength structure (SWS) with respect to different designing parameters. In terms of three critical factors, the reflectance for physical characteristics of wavelength dependence, the reflected power density for real power reflection applied on solar cell, and the normalized reflectance (reflected power density/incident power density) for real reflectance applied on solar cell, a full three dimensional finite element simulation is performed and discussed for the aforementioned three morphologies. The result of this study shows that the pyramid shape of SWS possesses the best reflectance property in the optical region from 400 to 1000 nm which is useful for silicon solar cell applications. PMID- 22444687 TI - Biofilm-growing intestinal anaerobic bacteria. AB - Sessile growth of anaerobic bacteria from the human intestinal tract has been poorly investigated, so far. We recently reported data on the close association existing between biliary stent clogging and polymicrobial biofilm development in its lumen. By exploiting the explanted stents as a rich source of anaerobic bacterial strains belonging to the genera Bacteroides, Clostridium, Fusobacterium, Finegoldia, Prevotella, and Veillonella, the present study focused on their ability to adhere, to grow in sessile mode and to form in vitro mono- or dual-species biofilms. Experiments on dual-species biofilm formation were planned on the basis of the anaerobic strains isolated from each clogged biliary stent, by selecting those in which a couple of anaerobic strains belonging to different species contributed to the polymicrobial biofilm development. Then, strains were investigated by field emission scanning electron microscopy and confocal laser scanning microscopy to reveal if they are able to grow as mono- and/or dual species biofilms. As far as we know, this is the first report on the ability to adhere and form mono/dual-species biofilms exhibited by strains belonging to the species Bacteroides oralis, Clostridium difficile, Clostridium baratii, Clostridium fallax, Clostridium bifermentans, Finegoldia magna, and Fusobacterium necrophorum. PMID- 22444688 TI - Bortezomib and panobinostat combination is effective against PTCL. PMID- 22444689 TI - Extramedullary blastic crisis in abdominal lymph nodes in a patient with chronic myelogenous leukemia on imatinib. PMID- 22444690 TI - Elevated HIF-1alpha expression of acute myelogenous leukemia stem cells in the endosteal hypoxic zone may be a cause of minimal residual disease in bone marrow after chemotherapy. PMID- 22444691 TI - Phase transitions of nanoemulsions using ultrasound: experimental observations. AB - The ultrasound-induced transformation of perfluorocarbon liquids to gases is of interest in the area of drug and gene delivery. In this study, three independent parameters (temperature, size, and perfluorocarbon species) were selected to investigate the effects of 476-kHz and 20-kHz ultrasound on nanoemulsion phase transition. Two levels of each factor (low and high) were considered at each frequency. The acoustic intensities at gas bubble formation and at the onset of inertial cavitation were recorded and subsequently correlated with the acoustic parameters. Experimental data showed that low frequencies are more effective in forming and collapsing a bubble. Additionally, as the size of the emulsion droplet increased, the intensity required for bubble formation decreased. As expected, perfluorohexane emulsions require greater intensity to form cavitating bubbles than perfluoropentane emulsions. PMID- 22444692 TI - Relationships between integumental characteristics and thermoregulation in South American camelids. AB - Hair fibre is regarded as a unique mammalian feature with an important role for endothermy. Artificial selection for hair characteristics resulted in marked changes with regard to follicle number, type, distribution, growth and natural shedding. This review focuses on the fine fibre-producing South American camelids (SACs) and the relationship between their hair coat and thermoregulation. SACs have developed several special integumental characteristics. While the hair coat of the wild lamoids vicuna (Vicugna vicugna) and guanaco (Lama guanicoe) is formed by two types of hair (the coarse outer guard hairs and a finer undercoat), the domesticated llamas (Lama glama) and alpaca (Lama pacos) exhibit variably double coat and predominantly single coat, respectively. The distribution of the hair coat across the body is not homogenous. Thermal windows with shorter hair or thinner skin can be identified at the ventral abdomen, axillary space and inside of the thighs (about 20% of the skin), thus allowing to modulate heat dissipation. In contrast to sheep wool, lamoid fibres are mainly medullated. The thermal conductance of summer pelage was higher than that of the winter fleece and highest for the axillar and lower flanks. Lamoids have developed behavioural strategies to modify heat loss by adopting specific postures according to ambient conditions by closing or opening the thermal windows. Energy savings of 67% attributed to posture were calculated. SACs have shown to be able to adapt to a broad range of different climatic conditions. The specific integumental characteristics of SACs indicate that they have developed adaptation mechanisms particularly suited for cooler climates. Accordingly, hyperthermia might become a problem in hot, humid areas outside of their original habitat. Several studies showed the beneficial effect of shearing against heat stress. In particular, fertility in males exposed to heat stress may be improved by shearing. Infrared thermography reveals that in shorn animals the heat is radiated across the entire body surface and is not restricted to the thermal windows. However, shearing also changes the conditions of the protective layer, resulting in a loss of thermal conductance that may result in adverse effects when animals are kept under cold temperatures. The length of residual fibre appears to be crucial in avoiding excessive heat loss in a cold environment, as demonstrated by shearing experiments with different shearing machines. There is, therefore, potential for welfare considerations to conflict with industrial demands for fibre length or homogenous quality. PMID- 22444693 TI - Hair follicle characteristics and fibre production in South American camelids. AB - Hair follicle and fibre characteristics of Peruvian alpaca and llama and Bolivian llama were analysed in three experimental studies. The first experiment was designed to determine the age at which all the secondary follicles reach maturity, as well as to compare the skin follicular structure and activity among these different types of Peruvian camelids. It is concluded that the South American camelids investigated in this study gained a complete and mature skin follicle apparatus at an early age, and hence producers should practise an early first shearing. A second Peruvian experiment investigated comparative fibre cuticular structure on twenty Peruvian domestic camelids comprising huacaya, suri and llama (woolly) 'chacos' genotypes. The results showed that the number of cuticular scales per 100 MUm fibre length proved to be strongly affected by both the fleece type and the fibre diameter. The suri fleece was clearly differentiated from those of both huacaya and llama by possessing the highest percentage of fibres with a number of scales less than eight, the lowest percentage of fibres with more than nine scales, along with the lowest percentage of fibres with a diameter of more than 35 MUm. It is concluded that, with the exception of the scale height, the cuticular parameters investigated in this study can be utilised in textile fibre analyses for distinguishing among these three types of fleece, as well as in selection projects designed to produce homogeneous fibres from Peruvian domestic camelids. A further study was conducted to determine the age at which the hair follicles in Bolivian llamas reach maturity as well as for comparing the skin follicular structure and activity between the two distinct genotypes. Thirty-one llama kids were chosen. They were born between January and April 1998 and were of different sex and of 'Q'aras' (or Carguera) or 'T'amphullis' type. Skin biopsies were taken from the right mid costal region at 2, 4, 6, 8,10,12 and 14 months of age in order to monitor four follicular parameters. In this experiment, secondary to primary (S/P) data show that the Bolivian llama population analysed possessed a complete and mature skin follicle apparatus at birth that remained essentially constant throughout the investigation period. Due to the variation of these traits inside the same genetic population, the present results showed that T and Q types could only be subjective on the basis of S/P ratio. PMID- 22444694 TI - Genetics of fibre production and fleece characteristics in small ruminants, Angora rabbit and South American camelids. AB - This paper reviews genetics of fibre production and fleece characteristics in small ruminants, Angora rabbit and South American camelids with a special distinction between single-coated (SC) and double-coated (DC) species. Considering the biology of fibre production, there are variations in coat composition and structure, fibre growth pattern and fibre structure and quality between these two main kinds of fibre-producing animals. In SC species, all fibres are nearly similar in dimensions and are produced from individual follicles that have a very long period, essentially permanent, of active growth without a synchronous phase of rest between follicles. In contrast, in DC species the fleece comprises a coarse outer coat and a fine inner coat with variations of coat composition and structure, and fibre growth pattern according to the season with a well-defined duration of fibre growth. Genetic basis of hair growth pattern, coat composition and fibre structure are different between species. In small ruminants, these coat characters are additive and because of several genes whereas in rabbit, several autosomal recessive genes determine fibre growth, coat composition and structure. In alpaca, the fleece type (Suri or Huacaya) is determined by a single dominant gene. This paper also reviews genetic parameters of fibre production traits in Angora goat, Angora rabbit and alpaca in which many aspects of the genetic basis of fibre production are analogous. There are many traits controlling both fibre quality and fibre quantity, and most of these traits tend to be moderately to strongly inherited so that a rapid genetic progress in any traits is possible and indeed has been achieved. However, there are differences in breeding programmes. In DC Angora rabbit, selection for one single trait, the easy measurable total fleece weight has general beneficial effects on fleece quality. However, because of antagonistic relations between qualitative and quantitative traits in SC species, achieving this goal requires a multi-trait selection index approach. Gene mapping studies have recently identified several putative quantitative trait loci and major genes affecting fibre and fleece characteristics in sheep, goat and rabbit are reviewed. The whole genome sequence of sheep and rabbit will be available in the near future and the use of high-density single nucleotide polymorphism chip will allow fine mapping and dissection of the genetic basis of many production traits including fibre production and fleece characteristics. The application of these techniques will thus contribute to improving the efficiency, profitability and sustainability of small ruminant and rabbit fibre production. PMID- 22444695 TI - In vitro methodology, hormonal and nutritional effects and fibre production in isolated ovine and caprine anagen hair follicles. AB - Mammalian hair follicles are complex multicellular structures in the skin, which produce hair fibre under the influence of locally produced and systemic signalling systems. Investigation to determine mechanisms of regulation, follicular responses and the importance of nutritional supply have utilised a number of in vivo and in vitro approaches. Included in these are studies on isolated intact anagen secondary follicles singly or in groups with incubation in culture medium. These utilise techniques developed for investigation of follicles from human skin. Results from selected studies reviewed here demonstrate differences in capacity for hair growth and protein synthesis between secondary follicles from Angora and cashmere-bearing goats. Mohair follicles were shown to exhibit faster hair shaft elongation both in vivo and in vitro, to have greater DNA content per follicle and to deposit significantly more protein per follicle and per unit of DNA. Incubation of anagen mohair and cashmere follicles in the presence of melatonin or prolactin showed positive responses in hair shaft growth and protein synthesis to both signalling molecules. This result indicated directly acting effects on the follicle in addition to any indirect effects arising at a whole animal level in response to, for example, variation in photoperiod. Similarly, epidermal growth factor was shown to alter elongation and protein synthesis in mohair follicles and to produce, at higher concentration, club hair structures similar to effects observed in other species. The vitamin biotin was shown to be important in maintaining viability of isolated sheep secondary hair follicles where supplementation increased the proportion continuing to grow. Effects on growth and apparent protein synthesis suggested comparatively lesser effects on follicles, which remained viable. Histology on follicles indicated effects of biotin deficiency in reducing proliferation of basal keratinocytes. The final study, included in this review, demonstrated that supply of the essential sulphur-containing amino acid l-methionine was necessary to maintain the viability and growth of mohair follicles. l-cysteine was not required in the presence of l-methionine, although there was evidence of an optimisation when both amino acids were present in adequate concentrations. Consideration is given to the importance of transport mechanisms and capacity to utilise absorbed nutrients when considering optimising nutritional supply to individual follicles. These may then provide targets for attainment in applied nutrition of animals in vivo. PMID- 22444696 TI - Fundamental hair follicle biology and fine fibre production in animals. AB - Hair 'fine' fibre is an important commercial product of farmed and certain wild animal species. The fibre is produced in follicles embedded in skin. These have properties in common with other tissues of the integument and have importance in determining yield and quality of fibre. Means of understanding and improving these characteristics are informed by knowledge of integumental and follicle biology. This paper reviews contemporary information that identifies the major fibre-producing species and their production characteristic. It surveys knowledge describing fundamental biology of the integument and considers information derived for the hair follicle from studies on a number of species including genetically modified mice. It identifies the composition of the follicle and describes components and interrelationships between epidermal hair-fibre producing epidermis and fibroblast- and connective tissue-containing dermis. The structure of different primary and secondary follicle types, and associated structures, are described. Focus is given to the alterations in anatomy and in behaviour from active to inactive state, which occurs during the hair follicle cycle. Information is provided on the anatomical substructures (hair medulla, cortex, cuticles and supporting sheaths and dermal papilla), cellular and extracellular composition, and adhesion and chemical signalling systems, which regulate development from the early embryo to post-natal state and subsequent cycling. Such signalling involves the dermis and its specialist fibroblasts, which secrete signalling molecules, which along with those from local epidermis and systemic sources, largely determine structure and function of epidermal cells. Such chemical signalling typically includes endocrine-, paracrine-, autocrine- and juxtacrine-acting molecules and interactions with their receptors located on cell membranes or intracellularly with transduction of message mediated by transcription factors at gene level. Important hormones and growth factors and inhibitors regulating morphogenic and/or mitogenic activity are identified. These mediate mechanisms associated with presence or absence in skin and development of patterning for primary or secondary follicles. Reference is made to deposition of individual keratins and keratin-associated proteins in follicle sub-structures and to fibre properties such as length, diameter, medullation, crimp and lustre. Pre- and post-natal regulation of pigmentation by melanocytes is reviewed. Brief attention is given to genomic and non-genomic variation and impact on the phenotypes expressed and the role of regulatory gene products as potential molecular markers for selection of superior animals. The importance of nutrients in providing substrates for follicular structures and enzymes and in molecules facilitating gene expression is also considered. PMID- 22444697 TI - Effects of protected fish oil in the diet of periparturient dairy goats on phenotypic variation in blood and milk leukocytes. AB - The goal of this study was to evaluate the effects of dietary protected fish oil (FO) on phenotypic variation in blood, milk leukocytes, and some productive and metabolic parameters in periparturient dairy goats. About 12 Alpine goats, selected from a larger group of second-parity animals, were fed from 15 days before kidding until the 15th day of lactation with the same basal diet that had been supplemented with either 47 g/head per day of FO or 47 g/head per day hydrogenated palm oil (PO). Dry matter intake, live body weight (LBW), body condition score (BCS), and productive performance were evaluated in 2 weeks after kidding. On days 15, 7, and 2 before kidding and days 2, 7, and 15 after kidding, plasma samples were collected for evaluation of alanine aminotransferase, aspartate aminotransferase, non-esterified fatty acids, glucose, beta hydroxybutyrate, cholesterol, and urea levels. White blood cell and blood leukocyte subsets were counted in whole blood samples on the kidding day, as well as at 1, 4, and 15 days after kidding. In addition, milk somatic cell count, intramammary infection (IMI), and milk leukocyte subsets were evaluated on days 4 and 15 after kidding. No differences were observed in dry matter intake and BCS, while LBW was higher in FO-fed animals. Milk production and composition, plasma metabolites, and liver enzymes were similar in both experimental groups. Blood CD4 positive cells increased constantly (P = 0.05) in FO-fed group, while CD8 and CD14 cell counts significantly increased 4 days after kidding (P < 0.01). Milk leukocyte subsets showed a significant (P < 0.01) decrease in PO-fed group and a non-significant increase (P = 0.34) in FO-fed group, despite the presence of coagulase negative staphylococci IMI. The results of the productive performance evaluation agreed with those of many other studies, which did not find any significant differences between dairy goats fed diets enriched with FO or PO supplements. The administration of FO to dairy goats in transition appeared to affect the variation in blood leukocytes with a constant increase in CD4- and CD8 positive cells in comparison with a PO fat-supplemented diet. PMID- 22444698 TI - Dietary protein, energy and arginine affect LAT1 expression in forebrain white matter differently. AB - L-type amino acid transporter-1 (LAT1) transports large, branched-chain, aromatic and neutral amino acids. About 64 Duroc * Landrace * Yorkshire pigs were used to study the effects of dietary crude protein (CP), energy and arginine on LAT1 expression in forebrain. The results showed that LAT1 expression in forebrain was sensitive to different levels of CP, energy and arginine. On the basis of Western blot analysis, a lower level of LAT1 presented in the brain tissues of pigs fed the low dietary CP diet (P < 0.05), a higher level were found in pigs fed the higher CP diet, with moderate to intense staining seen in pigs fed the diet plus 1% arginine. In contrast, pigs fed the control-energy diet had weak LAT1 expression, and those fed the diet supplemented with 1% arginine showed lowest LAT1 expression (P < 0.05). These results showed that LAT1 was highly expressed in the forebrain, and expression of LAT1 was affected by dietary protein, energy and arginine differently. PMID- 22444699 TI - Effect of mannanoligosaccharides supplementation on caecal microbial activity of rabbits. AB - A total of 200 weaned (35 days) hybrid Hyla rabbits were randomly divided among five groups housed in bicellular cages (20 cages per group). Between 35 and 60 days of age, the groups were submitted to the following treatments: group ANT (positive control) fed a basal diet supplemented with antibiotics (colistin sulphate, 144 mg/kg; tylosin, 100 mg/kg; and oxytetracyclin, 1000 mg/kg); groups MOS_0.5, MOS_1.0 and MOS_1.5 fed the basal diet supplemented with 0.5, 1.0 and 1.5 g/kg mannanoligosaccharides (MOS), respectively; another group fed the basal diet without antibiotics or mannanoligosaccarides supplementation (negative control). Along the trial, an episode of epizootyc rabbit enteropathy occurs so that in the control group mortality rate was very high (78%) and survivor rabbits showed severe symptoms of disease (diarrhoea). Thus, the control group was discarded from the trial. At 60 days of age, samples of caecal content were collected from 10 rabbits per group and used as inocula for an in vitro gas production trial. At the end of fermentation (120 h of incubation), organic matter digestibility (OMd), cumulative gas production, fermentation kinetics, pH, volatile fatty acid (VFA) and NH3 productions were measured. Inoculum from MOS_1.0 rabbits showed the significant higher values of OMd (64.21%, P < 0.05), gas production (262.32 ml/g, P < 0.05), acetate (96.99 mmol/g OM, P < 0.05) and butyrate (26.21 mmol/g OM, P < 0.05) than the other groups. Slight differences were recorded among the groups ANT, MOS_0.5 and MOS_1.5. In addition, branched chain acids, in proportion to total VFAs, were significantly higher in MOS_1.0 inoculum (0.04, P < 0.05). MOS are able to affect fermentation activity of caecal micro-organism, but their activities seem not proportional to their level in the diet. PMID- 22444700 TI - Influence of damaging and wilting red clover on lipid metabolism during ensiling and in vitro rumen incubation. AB - This paper describes the relationship between protein-bound phenols in red clover, induced by different degrees of damaging before wilting and varying wilting duration, and in silo lipid metabolism. The ultimate effect of these changes on rumen biohydrogenation is the second focus of this paper. For this experiment, red clover, damaged to different degrees (not damaged (ND), crushing or frozen/thawing (FT)) before wilting (4 or 24 h) was ensiled. Different degrees of damaging and wilting duration lead to differences in polyphenol oxidase (PPO) activity, measured as increase in protein-bound phenols. Treatment effects on fatty acid (FA) content and composition, lipid fractions (free FAs, membrane lipids (ML) and neutral fraction) and lipolysis were further studied in the silage. In FT, red clover lipolysis was markedly lower in the first days after ensiling, but this largely disappeared after 60 days of ensiling, regardless of wilting duration. This suggests an inhibition of plant lipases in FT silages. After 60 days of ensiling no differences in lipid fractions could be found between any of the treatments and differences in lipolysis were caused by reduced FA proportions in ML of wilted FT red clover. Fresh, wilted (24 h) after damaging (ND or FT) and ensiled (4 or 60 days; wilted 24 h; ND or FT) red clover were also incubated in rumen fluid to study the biohydrogenation of C18:3n-3 and C18:2n-6 in vitro. Silages (both 60 days and to a lower degree 4 days) showed a lower biohydrogenation compared with fresh and wilted forages, regardless of damaging. This suggests that lipids in ensiled red clover were more protected, but this protection was not enhanced by a higher amount of protein-bound phenols in wilted FT compared with ND red clover. The reduction of rumen microbial biohydrogenation with duration of red clover ensiling seems in contrast to what is expected, namely a higher biohydrogenation when a higher amount of FFA is present. This merits further investigation in relation to strategies to activate PPO toward the embedding of lipids in phenol-protein complexes. PMID- 22444701 TI - Temporal expression of TnI fast and slow isoforms in biceps femoris and masseter muscle during pig growth. AB - Biceps femoris (BF) and masseter muscle (MM) are the mixture of slow oxidative and fast-twitch fibres. Compared with MM, BF had the significantly higher expression of myosin heavy chain (MyHC) fast IIx and IIb isoforms (MyHCIIx and MyHCIIb), but lower expression of MyHC slow isoform (MyHCI) and fast IIa isoform (MyHCIIa). The objective of this study was to investigate the expression pattern of troponin I (TnI) slow-twitch isoform (TNNI1) and fast-twitch isoform (TNNI2) in BF and MM of Yorkshire and Meishan pigs which differed significantly in the growth rate. The expression of the TNNI1 and TNNI2 peaked at the postnatal 35 days in Yorkshire pigs and postnatal 60 days in Meishan pigs. The expression of TNNI1 and TNNI2 in Meishan pigs was significantly higher than that in Yorkshire pigs at the foetal 60 days, while the opposite occurred at postnatal 35 days. The expression ratio of TNNI1 relative to TNNI2 favoured TNNI2 expression in BF and MM regardless of Yorkshire and Meishan pigs. TNNI1 expression in MM was significantly higher than that in BF at 60, 120 and 180 days in Meishan pigs and at 120 and 180 days in Yorkshire pigs. On the contrary, no significant difference of TNNI2 expression in BF and MM was found except for Yorkshire pigs of 180 days. This study provided the foundation for future research on TnI isoforms as the model gene to study mechanisms of muscle fibre-specific gene regulation in pigs. PMID- 22444702 TI - Royal jelly: can it reduce physiological strain of growing rabbits under Egyptian summer conditions? AB - Exposure of growing rabbits to heat stress during summer adversely affects their performance leading to major production losses. A total number of 48 rabbits, unsexed V-line weaned rabbits, were randomly divided into four experimental groups, temperature ranged from high at 32 degrees C to low at 23 degrees C. Animals of the 2nd, 3rd and 4th group were individually orally given 200, 400 or 800 mg royal jelly (RJ)/kg BW once a week, respectively, to evaluate RJ ability to reduce physiological strain resulted from heat stress. Weekly BW gain increased by 10.4, 11.8 and 10.8%, and feed conversion ratio was significantly improved by 20, 24 and 18% with RJ treatments. Serum total protein, albumin and globulin increased, whereas serum total lipids, cholesterol and triglycerides decreased with RJ treatments. Creatinine was reduced by 21, 30 and 18% and uric acid by 14, 25 and 18% compared with the heat stressed control with the three doses of RJ. Glucose level increased significantly to reach 116, 125, and 120% of heat stressed control. Calcium, phosphorus and alkaline phosphatase increased significantly with RJ treatments indicating the occurrence of active bone deposition. Thyroid hormone levels increased significantly to reach 108, 111, and 112% of heat stressed control rabbits with the three doses of RJ, counteracting the hypothyroid state resulted from heat stress. It can be concluded that RJ administration to heat stressed growing rabbits can reduce physiological strain resulted from heat stress. PMID- 22444703 TI - Administration of bovine anti-IGF-1 immunoglobulin to dietary protein deficient rats alters dietary intake and plasma IGF-1 binding profiles, but does not affect change in body mass. AB - The potential of antibodies raised against insulin-like growth factor-1 (IGF-1) as a treatment to enhance the anabolic actions of IGF-1 has been demonstrated in both rodent and ruminant models. We investigated whether treatment of genetically normal rats with anti-IGF-1 immunoglobulin (Ig, raised in cattle) would enhance growth and if anti-IGF-1 Ig treatment would ameliorate live-weight loss in genetically normal rats offered a severely protein-restricted diet. Scatchard analysis was used to characterise ammonium sulphate precipitated bovine anti-IGF 1 Ig. Anti-IGF-1 Ig binding to 125I-IGF-1 yielded an almost linear Scatchard plot, with a Hill co-efficient of 0.951 +/- 0.012, indicating a single class of IGF-1 binding sites. The affinity of anti-IGF-1 Ig for IGF-1 was 2.14 +/- 0.66 * 109 l/mol. The non-immune Ig preparation did not bind IGF-1. Rats were offered either a diet with a normal protein level (20%) or protein restricted (4% protein), and each dietary group was further treated with twice-daily i.p. injections of either diluent phosphate buffered saline, non-immune Ig or anti-IGF 1 Ig. Dietary protein level had a significant effect on live-weight gain, but there was no effect of non-immune Ig or anti-IGF-1 Ig on live-weight gain. Treatment with anti-IGF-1 Ig prevented the significant depression of cumulative dietary intake observed in diluent, and non-immune Ig treated groups offered the 4% protein diet. The cumulative dietary intake of the anti-IGF-1 Ig treated, 4% dietary protein group did not differ significantly from those of the groups offered the 20% protein diet. In addition, within the 4% dietary protein group, rats treated with non-immune Ig exhibited a cumulative feed intake that was intermediate between that of the diluent treated and anti-IGF-1 Ig treated groups (P < 0.05). Size exclusion chromatography was used to characterise in vitro 125I IGF-1 binding in end-point plasma from each treatment group. In comparison to control groups, anti-IGF-1 Ig treatment resulted in substantially increased 125I IGF-1 binding in the 30 to 40 kDa region and a concomitant reduction in elution of free 125I-IGF-1. Protein restriction markedly depressed IGF-1 binding at ~150 kDa in the plasma of diluent and non-immune Ig treated groups. Anti-IGF-1 Ig treatment was effective in preventing this decrease in ~150 kDa binding. Thus, anti-IGF-1 Ig appears to have a beneficial effect on dietary intake in protein restricted rats, which is associated with induced changes in IGF-1 binding profiles in plasma. PMID- 22444704 TI - Haptoglobin serum concentration is a suitable biomarker to assess the efficacy of a feed additive in pigs. AB - Levels of haptoglobin and Pig-major acute phase protein (MAP) were analysed in animals from a commercial herd receiving or not a diet enriched with an additive. The group receiving the additive exhibited a decrease in haptoglobin after 3 weeks, suggesting that a better health status has been established, together with an improvement in total body weight and average daily gain. In contrast, Pig-MAP does not significantly change under these conditions. Aujeszky live modified vaccination, which is compulsory in Spain, did cause a significant increment in haptoglobin serum concentration although it did not affect Pig-MAP. The response of acute phase proteins to vaccination was similar in both control and additive treated groups. Interleukins (IL)-1beta and IL-6 was below the detection limits in most of the animals. In conclusion, this study shows that haptoglobin serum concentration, but not Pig-MAP, is a good biomarker to monitorize production parameters and for monitoring Aujeszky modified live vaccine in pigs reared under standard commercial conditions. PMID- 22444705 TI - Effect of breeding system, cycle and cage size during fattening on rabbit doe and growing rabbit performance under heat stress. AB - In order to evaluate heat stress and circadian rhythm 46 nulliparous rabbit does with a BW of 3.67 +/- 0.05 kg (s.e.) were used. They were clipped once or not and rectal temperature, feed and water intake were recorded for 24 h. From this group, 43 rabbit does were mated 7 days after rectal measurements, and randomly assigned to one out of two breeding systems (including in both systems rabbit does that had been clipped or not). In the control one (C) rabbit does were mated 14 days after parturition and litter weaned at 35 days of age, and in the extensive one (E) they were mated 21 after parturition and weaned at 42 days of age. Rabbit doe and litter performance were recorded for 6 months (first three cycles). Two hundred twenty-eight weaned rabbits were divided into two cage sizes: 0.5 and 0.25 m2 with eight and four rabbits per cage, respectively, to study growing performance. Farm and rectal temperatures were minimal and feed and water intake maximal during the night (P < 0.001). Unclipped rabbit does showed higher rectal temperature (P = 0.045) and lower feed intake (P = 0.019) respect to clipped does, which are symptoms of heat stress. Neither breeding system nor cycle number influenced fertility, total number of kits born, born alive or dead per litter (91.6%, 6.98, 5.80 and 1.19 on average, respectively). Kit mortality during lactation tended to increase in E compared with C group (48.5% v. 63.4%; P = 0.070), reducing the number of kits at weaning per litter by 33% (P = 0.038). It also increased in the second and third cycles compared with the first (P ? 0.054). It resulted that feed efficiency (g weaned kits/g feed intake does + litter) tended to decrease in E respect C group (P = 0.093), whereas it was impaired successively from the first to the third cycle by 48% (P = 0.014). Growing rabbits from the E group were heavier at weaning (by 38%; P < 0.001), showed a higher feed intake (+7.4%) and lower feed efficiency (-8.4%) throughout the fattening period (P ? 0.056) respect to C group. However, age at slaughter was not different respect to C group (77.3 days on average). Cage size had minor influence in growing performance. In conclusion, rabbit doe and litter productivity impaired when lactation is extended from 35 to 42 days and along successive reproductive cycles. PMID- 22444706 TI - Does feeding area restriction inhibit social learning of toxic weed ingestion in cattle? AB - Social learning from peers can trigger herd-wide intoxication with white locoweed (Oxytropis sericea), an alkaloid-synthesizing herbaceous legume that grows on rangelands of western North America. We conducted an experiment to test the hypothesis that restriction of the area allocated to animals to feed in would inhibit social facilitation of locoweed ingestion in yearling heifers. Eight heifers that avoided white locoweed (LA) and eight heifers that readily consumed it (LE) were selected from a pool of 40 cross-bred heifers and were randomly assigned to the social facilitation or social interference treatment groups. We conducted 200 10-min feeding trials in three 5-day phases (pre-treatment, treatment, post-treatment) during which animals were presented with a set of bowls arrayed in a test arena, some of which contained ground wheat straw and others contained air-dried ground white locoweed. During the pre-treatment (days 1 to 5) and the post-treatment phases (days 11 to 15) non-social trials were conducted in which the feeding behavior of individual animals was investigated in an 80 m2 arena containing 12 feeding bowls. During the treatment phase (days 6 to 10) social learning trials were conducted in which LA + LE pairs from the social interference group were exposed to 12 bowls of food distributed in an 80 m2 arena intended to induce social interference, and LA + LE pairs from the social facilitation group were exposed to 36 bowls of food distributed in a 240 m2 arena intended to permit social facilitation. During pre-treatment phase, LA heifers consumed detectably less locoweed and wheat straw and exhibited lower preference for locoweed than LE (P ? 0.05) although wheat straw preference of LA and LE was similar. During social learning trials (treatment phase), LA in the social interference group visited similar number of locoweed bowls (mean +/- s.e.m.: 0.2 +/- 0.12) as they had during non-social learning (0.2 +/- 0.20). Conversely, LA heifers in the social facilitation group visited detectably more locoweed bowls during social learning trials (1.6 +/- 0.46) compared with the pre-treatment phase (0.2 +/- 0.16). Correlation between daily number of locoweed bowls visited by LA and LE during social learning trials was detected in the social facilitation (r = 0.70; P < 0.01), but not in the social interference group (r = 0.15; P = 0.52). During testing trials (post-treatment phase), locoweed and wheat straw intake and preference of LA and LE in both treatment groups was similar. Manipulation of the feeding environment delayed, but did not inhibit social learning of toxic weed ingestion in this study. PMID- 22444707 TI - Dairy calf housing systems across Europe and risk for calf infectious diseases. AB - Enteric and respiratory diseases are the most frequent health disorders of calves. They are associated with mortality or lower growth rate and induce treatment costs. Enteric and respiratory pathogens can be transmitted via contacts between calves, which depend on calf housing systems and management. This study aimed at describing the main calf housing systems across Europe and at assessing the consequences of such housing facilities in terms of risk for calf infectious diseases. This was done through the use of a questionnaire distributed to experts in epidemiology and cattle farming systems in each European country. A literature review was performed on the risk factors associated with calf infectious diseases transmission and targeted in the questionnaire. Answers from 14 countries were obtained. A wide range of housing systems were described. However, four main systems could be identified and ranked in ascending order of risk for neonatal diarrhoea and respiratory infectious diseases: individual pen until weaning, individual pen for 4 weeks, individual pen for 2 weeks, and collective pen from the separation of the calf with its dam. Although the housing systems are known to play a role in disease transmission, they are currently not fully described in literature concerning risk factors for calf infectious diseases. In a given farm, the risk assessment for calf infectious diseases should consider classical risk factors such as hygiene, feeding practices and air conditioning, on top of a precise description of the housing system. PMID- 22444708 TI - Energy consumption in mixed crop-sheep farming systems: what factors of variation and how to decrease? AB - Prompted by current concerns about energy resources and greenhouse gas emissions, we sought to assess the impact of certain key factors on energy efficiency in sheep-for-meat production and to evaluate the main directions for improvement. We used a modelling approach to simulate the functioning and performances of sheep for-meat production systems integrating an energy balance calculation module. In the first step of this study, we reconstructed system functions and technical and economic results of four typological groups of farms in plainland areas. This served as a basis for calculating their energy efficiency in order to focus on the main factors of energy efficiency, such as high levels of fodder self sufficiency (low concentrate consumption) and high ewe productivity. The Graze system presented the highest energy efficiency (EE) for sheep unit (EEs = 0.62) with the lowest consumption of equivalent fuel litres requirements (FuReq) per kilogram of lamb carcass produced (1.47), while the 'sheep and cash crop' system had the lowest EEs (0.36) and the highest FuReq per kg carcass (2.54). We then took the 'mixed-farming system' (a 130 ha farm, including 610 ewes and 40 ha of cropland) and studied three adaptations designed to increase the EEs: improvement of feed self-sufficiency (increased proportion of concentrate produced on-farm), introduction of legumes into the rotation (removal of bought-in nitrogen fertilisers), and production of fuel-oil (from rapeseed) with the flock using oil cakes. The most effective adaptation was the removal of the nitrogen fertilisers. The successive adaptations make it possible to cut energy consumption from 2.2 FuReq/kg carcass down to 0.98 after the optimisations, thereby increasing EEs from 0.42 to 0.93. Finally, we went on to study the energy impact of four factors influencing flock functioning and farm structure, i.e. ewe productivity, lamb weight, distances between plots, and flock size. Ewe productivity and lamb weight had a strong positive impact on EEs. When ewe productivity switched from 0.80 to 1.70, EEs increased from 0.29 to 0.48 while FuReq per kilogram carcass dropped from 3.39 to 1.88. When flock size was increased to over 1000 ewes, there were little or no energy-related economies of scale, as farm area also increased and most of the systems required more equipment. PMID- 22444709 TI - Deuterium oxide dilution accurately predicts water intake in sheep and goats. AB - The aim of this study was to test whether the deuterium oxide dilution technique accurately predicts water intake in sheep and goats. Two other issues were also studied: (i) a comparison of water intake in sheep and goats and (ii) an assessment of whether observations of drinking behaviour can accurately measure the water intake. In this study, eight dry Boer goats and eight dry German Black Head Mutton ewes were kept under controlled stable conditions. Animals had access to hay and water ad libitum. Diurnal drinking behaviour was recorded by video. Individual daily water intake was measured and estimated for 2 weeks by re weighing water buckets and from water kinetics using the deuterium oxide dilution technique, respectively. In addition, dry matter intakes were directly measured and were significantly higher in sheep than in goats. The average daily water consumption by drinking differed significantly between the two species, with higher intakes in sheep than in goats. Total body water expressed as a percentage of body mass did not differ between species. Measurement methods of total water intake (TWI) using deuterium oxide dilution and re-weighing water buckets did not differ significantly in both species (P = 0.926). Results obtained for measured and estimated TWI confirm that the isotope dilution technique gives reliable results for estimates of water intake in sheep and goats. The higher amount of water intake in sheep was also reflected by their drinking behaviour. Sheep spent approximately 0.3% per 24-h drinking, while Boer goats spent only 0.1%. However, measured and estimated TWIs were only moderately correlated to the daily time spent drinking. The lower water intake found in Boer goats confirms a superior water management capacity compared with Black Head Mutton sheep even under temperate conditions. PMID- 22444710 TI - Effects of frozen storage temperature on the elasticity of tendons from a small murine model. AB - The basic mechanism of reinforcement in tendons addresses the transfer of stress, generated by the deforming proteoglycan (PG)-rich matrix, to the collagen fibrils. Regulating this mechanism involves the interactions of PGs on the fibril with those in the surrounding matrix and between PGs on adjacent fibrils. This understanding is key to establishing new insights on the biomechanics of tendon in various research domains. However, the experimental designs in many studies often involved long sample preparation time. To minimise biological degradation the tendons are usually stored by freezing. Here, we have investigated the effects of commonly used frozen storage temperatures on the mechanical properties of tendons from the tail of a murine model (C57BL6 mouse). Fresh (unfrozen) and thawed samples, frozen at temperatures of -20 degrees C and -80 degrees C, respectively, were stretched to rupture. Freezing at -20 degrees C revealed no effect on the maximum stress (sigma), stiffness (E), the corresponding strain (epsilon) at sigma and strain energy densities up to epsilon (u) and from epsilon until complete rupture (up). On the other hand, freezing at -80 degrees C led to higher sigma, E and u; epsilon and up were unaffected. The results implicate changes in the long-range order of radially packed collagen molecules in fibrils, resulting in fibril rupture at higher stresses, and changes to the composition of extrafibrillar matrix, resulting in an increase in the interaction energy between fibrils via collagen-bound PGs. PMID- 22444711 TI - The benefits of laparoscopic appendectomies in obese patients. AB - BACKGROUND: Systematic reviews and randomized controlled trials comparing laparoscopic appendectomy (LA) with open appendectomy (OA) show a reduction in wound infections associated with LA but a 3-fold increase in intra-abdominal abscess with LA. Surgical time and operation costs are higher with LA. The advantage of LA over OA is small. Although these patients have not been specifically analyzed in the report, the systematic review recommends the routine use of LA in young women and obese people. The purpose of this study is to determine if obese patients benefit in a shorter length of stay (LOS) by having LA versus OA surgery compared with their nonobese counterparts. METHODS: A retrospective chart review of 315 adult patients who have undergone appendectomies at Royal Columbian and Burnaby Hospitals between April 1, 2010 and March 31, 2011. Appendectomies performed in pregnant women combined with other surgeries and those converted to OA were excluded. Outcomes and the postoperative stay for obese and nonobese patients were assessed. RESULTS: The LOS is shorter with LAs than with OAs (2.06 vs 4.13 days, P < .05). The LOS, in obese patients, is much shorter with LAs than with OAs (1.69 vs 6.82 days, P < .05). The variability in LOS is much higher in obese patients as compared with nonobese patients (standard deviation = 8.57 vs 2.67). The body mass index and the type of surgery contribute to a significant difference in LOS. CONCLUSIONS: Obese patients who undergo LA have a decreased LOS as compared with obese patients who undergo OA for appendicitis. This is the first study showing specifically that LA benefits obese patients and the health care system. PMID- 22444712 TI - Bioprosthetic mesh use for the problematic thoracoabdominal wall: outcomes in relation to contamination and infection. AB - BACKGROUND: Limited controlled data exist regarding the role of bioprosthetic meshes for hernia repair. Often the only option available in contaminated cases, their high cost calls for an evaluation of their utility and indications for use. METHODS: A retrospective review of cases in which human acellular dermal matrix (HADM) was used to reconstruct a thoracoabdominal wall defect at the Foothills Medical Centre of Calgary was conducted. Attention was placed to identify the need for surgical reintervention postoperatively. RESULTS: Over 2 years, 13 patients required the use of HADM for reconstruction of their thoracoabdominal wall; 69.2% of the cases were contaminated or infected. Three patients (23.1%) presented postoperative infectious complications; only 1 required reoperation. No patients required removal of their prosthesis. Two patients presented recurrences (median follow-up = 126 days). CONCLUSIONS: The use of HADM for complex thoracoabdominal wall defects in contaminated or infected settings is a reliable option available for surgeons. PMID- 22444713 TI - Recurrence and virulence of colonic diverticulitis in immunocompromised patients. AB - BACKGROUND: To evaluate the probability of recurrence and the virulence of colonic diverticulitis correlated with immunocompromised status. METHODS: Nine hundred thirty-one patients admitted in a single tertiary referral university hospital over a 14-year period were included. Patients were divided into 2 groups: group 1, 166 immunosuppressed patients, and group 2, 765 nonimmunosuppressed patients. The variables studied were sex, age, American Society of Anesthesiologist status, reasons of immunosuppression (eg, chronic use of corticosteroids, transplant recipients, and diseases affecting the immune system), severity of the diverticulitis episode, recurrence, emergency and elective surgery, and morbidity and mortality rates. RESULTS: Two hundred thirteen patients underwent an emergency operation during the first hospitalization and 26 patients in further episodes. One hundred thirty-six patients developed 1 or more recurrent episodes of diverticulitis. The overall recurrence rate was similar in both groups. Patients in group 1 with a severe first episode presented significantly higher rates of recurrence and severity without needing more emergency surgery. Mortality after emergency surgery was 33.3% in group 1 and 15.9% in group 2 (P = .004). CONCLUSIONS: After successful medical treatment of acute diverticulitis, patients with immunosuppression need not be advised to have an elective sigmoidectomy. PMID- 22444714 TI - The impact of childhood maltreatment history on parenting: a comparison of maltreatment types and assessment methods. AB - OBJECTIVE: Childhood maltreatment is associated with subsequent parenting difficulties; however, most research has relied on self-reported parenting outcomes, and observational measures have revealed mixed findings. Furthermore, research has focused predominantly on histories of sexual and/or physical abuse. This study explored associations between a wide range of childhood maltreatment experiences and both observed and self-reported parenting outcomes. METHODS: Mothers of 4- to 6-year-old children at moderate social risk completed the History of Maltreatment and Trauma Form (HMTF), which assesses a range of maltreatment experiences and delineates specific characteristics such as chronicity and severity. Participants completed questionnaires assessing parenting stress and competence, and their emotional availability (sensitivity, intrusiveness, hostility) toward their children was coded from videorecorded interactions. RESULTS: Construct (factorial, convergent and discriminant) validity of the HMTF was demonstrated through factor analysis and a multi-trait, multi-method matrix comparing it to the Childhood Trauma Questionnaire. HMTF assessed childhood maltreatment, specifically witnessing family violence, neglect and emotional maltreatment, were significantly associated with mothers' observed hostility toward their children, even after controlling for potentially traumatic adult experiences. In contrast, childhood sexual abuse history was associated with self-reported concerns regarding parenting competence, and this association held even after controlling for other forms of childhood maltreatment and potentially traumatic adult experiences. Self-reported parenting outcomes were unrelated to observed parenting behavior. CONCLUSIONS: Findings highlight the complexity of associations between child maltreatment and subsequent parenting outcomes. Although much previous research has focused on sexual and physical abuse, other more contextual forms of maltreatment may be similarly or more strongly associated with certain parenting outcomes. Furthermore, different forms of maltreatment may be associated with perceived versus observed parenting outcomes. PMID- 22444715 TI - Formal synthesis of (+/-)-methyl rocaglate using an unprecedented acetyl bromide mediated Nazarov reaction. AB - To date the prototype Nazarov cyclization of a cross-conjugated pentadienone to the core structure of the rocaglate natural products has not been successful (9 into 12). It has been found that this conversion can be achieved by the use of acetylbromide in excellent yield and results in a strategically very direct route to these antitumor agents. PMID- 22444716 TI - Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial. AB - BACKGROUND: We conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2(+)) metastatic breast cancer (MBC). PATIENTS AND METHODS: The study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m2 orally on days 1 to 14, vinorelbine 25 mg/m2 intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR. RESULTS: Of 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months). CONCLUSIONS: This triplet combination demonstrated promising activity in patients with HER2(+) MBC. PMID- 22444717 TI - Diagnostic performance of magnetic resonance imaging for assessing tumor response in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy is associated with molecular biomarker profile. AB - BACKGROUND: This study aimed to evaluate the influence of hormone receptor (HR) and Ki-67 proliferation markers in predicting the accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in patients with HER2-negative (HER2(-)) breast cancer receiving neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Fifty-four women were studied. Patients received AC (doxorubicin (Adriamycin)/cyclophosphamide) and/or taxane-based regimens. The accuracy of MR determined clinical complete response (CCR) was compared to pathological complete response (pCR). The size of detectable residual tumor on MRI was correlated with pathologically diagnosed tumor size using the Pearson correlation. RESULTS: MRI correctly diagnosed 16 of the 17 cases of pCR. There were 8 false-negative diagnoses: 7 HR(+) and 1 HR(-). The overall sensitivity, specificity, and accuracy of MRI were 78%, 94%, and 83%, respectively. The positive predictive value was 97% and the negative predictive value was 67%. For MRI vs. pathologically determined tumor size correlation, HR(-) cancers showed a higher correlation (R = 0.79) than did HR(+) cancers (R = 0.58). A worse MRI/pathology size discrepancy was found in HR(+) cancer than in HR(-)cancer (1.6 +/- 2.8 cm vs. 0.56 +/- 0.9 cm; P = .05). Tumors with low Ki-67 proliferation (< 40%) showed a larger size discrepancy than did those with high Ki-67 proliferation (>= 40%) (1.2 +/- 2.0 cm vs. 0.4 +/- 0.8 cm; P = .05). CONCLUSIONS: The results showed that the diagnostic performance of MRI for patients with breast cancer undergoing NAC is associated with a molecular biomarker profile. Among HER2(-)tumors, the accuracy of MRI was worse in HR(+)cancers than in HR(-)cancers and was also worse in low-proliferation tumors than in high-proliferation tumors. These findings may help in surgical planning. PMID- 22444718 TI - Quality of life in long-term survivors of metastatic breast cancer. AB - INTRODUCTION: Psychosocial distress is common after a diagnosis of breast cancer. Little is known about the psychosocial adjustment of women living long term with metastatic breast cancer. METHODS: We conducted a cross-sectional survey of women living with metastatic breast cancer for 5 years or longer. The survey included demographic and medical history, the Hospital Anxiety and Depression Scale (HADS), the Revised Impact of Events Scale (IES-R), the Functional Assessment of Cancer Therapy-Breast (FACT-Breast), and the Duke-University of North Carolina (UNC) Functional Social Support (DUFSS) Questionnaire. Demographic and disease characteristics were assessed by using the Wilcoxon rank sum test and the Fisher exact test. The relationships between IES-R, DUFSS, and the HADS were assessed by using the Spearman correlation coefficients. Statistical tests were 2-sided, with significance defined as P <= .05. RESULTS: Eighteen (64%) of 28 eligible women completed the survey. Women who completed the survey were more likely to have had node-positive disease (2P = .0007), to had taken adjuvant therapy (2P = .01), and to have had hormone-receptor positive disease than women who did not (2P = .04). Among those who completed the survey, data from the FACT-Breast and the DUFSS indicated that women are physically functioning well but still face significant emotional challenges. Results from the HADS indicated that 2 (11.1%) of 18 women were depressed and that 2 (11.1%) of 18 women were anxious. Six (33%) of 18 women had scores on the IES-R Scale that indicated a powerful impact of traumatic stress on the ability to function. In the total sample of 18, the IES-R was significantly correlated with the HADS-Anxiety score (Spearman correlation, 0.81; 2P = .0002) but not with the HADS-Depression score (Spearman correlation, 0.40; 2P = .12). CONCLUSIONS: Although overall quality of life is good in this population of women living long term with metastatic breast cancer, there is a subset of women who are dealing with significant anxiety and depression, and a larger group who are experiencing burdensome sadness, hopelessness, and apprehension about their disease. Ongoing work to address the needs of this population is warranted. PMID- 22444719 TI - Experience of young women diagnosed with breast cancer who undergo fertility preservation consultation. AB - BACKGROUND: Fertility preservation (FP) is of increasing concern to young patients with breast cancer. The American Society of Clinical Oncology has recommended referral to a reproductive specialist as early as possible before beginning systemic adjuvant therapy. AIM: To gather information from young patients with breast cancer about their experiences with FP referral, consultation, and decision making. METHODS: An anonymous questionnaire was mailed to consecutive patients with breast cancer who were referred, from January 2005 to January 2010, from our center to the CReATe fertility clinic. Topics included demographics; cancer stage and treatment; previous fertility problems; referral source and timing; options presented and chosen; and satisfaction with the referral, consultation, and decision-making processes. RESULTS: Of the 53 women identified, 27 (51%) participated. The mean age was 31 years (range, 24-41 years). Fifteen (56%) women opted for embryo or oocyte cryopreservation, 2 for ovarian suppression, and 10 for no FP. The choice was not affected by disease stage or by already having a child. Of the 22 women who responded, 14 (64%) were satisfied or very satisfied overall. Eighteen out of 23 (78%) respondents felt that the right amount of information was given. Thirty-nine percent had difficulty with decision making, but only 1 (4%) woman indicated that cost was a deciding factor. A common theme among respondents was inadequate time for decision making. A common complaint was the lack of written material before and/or after their consultation. Sixty-three percent expressed an interest in meeting with a psychosocial counselor. CONCLUSIONS: (1) FP referral should be initiated by the surgeon as soon as a diagnosis of invasive cancer is made, (2) women need written materials before and after FP consultation is needed, and (3) a FP counselor who is able to spend additional time after the consultation could help with decision making. PMID- 22444720 TI - Bioelectrical impedance for detecting and monitoring patients for the development of upper limb lymphedema in the clinic. AB - BACKGROUND: Single-frequency bioelectrical impedance (BI) has been used to measure extracellular fluid in the upper limbs. The purpose of the study was to evaluate BI's ability to detect and monitor upper limb changes in based upon the extent of various treatments and to assess its practicality. METHODS: Patients with newly diagnosed breast cancer were evaluated at baseline and after procedures that could potentially affect fluid accumulation in the arm and signal the possible development of early lymphedema. The magnitude of the change in lymphedema index ratios (LIR) from these procedures was evaluated to determine the sensitivity of BI. RESULTS: A total of 64 patients were evaluated. Although no difference in LIRs was noted by the extent of surgical procedure (lumpectomy 2.1 vs. mastectomy 1.1; P = .49), a trend was noted for increased LIRs with more aggressive axillary staging when sentinel lymph node was compared with axillary lymph node dissection (1.3 vs. 3.4; P = .08). A trend for an increased LIR with more aggressive local therapy also was noted when using a cutoff of less than 4 lymph nodes sampled compared with 4 or more nodes sampled (1.2 vs. 2.6; P = .09). CONCLUSIONS: In this limited analysis, L-Dex readings paralleled the extent of surgical interventions and suggest that they can be used to monitor patients for the early onset of edema. Further studies are needed to help validate the extent, degree, and chronologic time frame of these changes to help define recommendations for closer monitoring of patients and possible early intervention. PMID- 22444721 TI - Low-grade fibromatosis-like spindle cell metaplastic carcinoma of the breast: a case report and literature review. PMID- 22444722 TI - Phase II trial of exemestane in combination with fulvestrant in postmenopausal women with advanced, hormone-responsive breast cancer. AB - INTRODUCTION: Exemestane, the irreversible steroidal aromatase inhibitor, and fulvestrant, the pure estrogen antagonist, are active as single drugs in postmenopausal women with advanced hormone-responsive breast cancer. We designed a phase II study with the purpose of determining whether combining these 2 drugs with different and potentially complementary mechanisms of action will improve the clinical benefit. PATIENTS AND METHODS: Forty postmenopausal women with hormone-responsive advanced breast cancer received intramuscular injection of fulvestrant 250 mg every 28 days in combination with daily exemestane 25 mg until disease progression. We examined the influence of fulvestrant on exemestane pharmacokinetics and the effect of exemestane and fulvestrant on serum IGF-1 (insulin-like growth factor 1) and IGFBP-3 (IGF-binding protein 3) levels. RESULTS: The observed proportion of patients free of progressive disease at 6 months after the initiation of treatment with exemestane and fulvestrant was 50%, a rate similar to that achieved with single-agent exemestane or fulvestrant in the first- or second-line setting. Pharmacokinetics parameters showed that coadministration of fulvestrant did not result in clinically relevant changes in exemestane plasma concentrations. A comparison of IGF-1 and IGFBP-3 levels demonstrated the increase of 35% and 12%, respectively, in mean levels from baseline to day 120. CONCLUSIONS: The combination of exemestane and fulvestrant did not improve clinical benefit. The observed lack of improved efficacy was not related to altered drug exposure. PMID- 22444723 TI - Synthesis and field emission properties of different ZnO nanostructure arrays. AB - In this article, zinc oxide (ZnO) nanostructures of different shapes were fabricated on silicon substrate. Well-aligned and long ZnO nanowire (NW) arrays, as well as leaf-like ZnO nanostructures (which consist of modulated and single phase structures), were fabricated by a chemical vapor deposition (CVD) method without the assistance of a catalyst. On the other hand, needle-like ZnO NW arrays were first fabricated with the CVD process followed by chemical etching of the NW arrays. The use of chemical etching provides a low-cost and convenient method of obtaining the needle-like arrays. In addition, the field emission properties of the different ZnO NW arrays were also investigated where some differences in the turn-on field and the field-enhancement factors were observed for the ZnO nanostructures of different lengths and shapes. It was experimentally observed that the leaf-like ZnO nanostructure is most suitable for field emission due to its lowest turn-on and threshold field as well as its high field enhancement factor among the different synthesized nanostructures. PMID- 22444724 TI - Occurrence and risks of antibiotics in the Laizhou Bay, China: impacts of river discharge. AB - The presence of thirteen antibiotics categorized into four different groups (fluoroquinolones, macrolides, sulfonamides and trimethoprim) was investigated in the rivers discharging to the Laizhou Bay and the seawater of the bay, and the impacts of river discharge on the marine environment were assessed. The results revealed that the same antibiotics predominated in both the river water and the seawater. Additionally, the detected antibiotics in the river water were generally higher than those in the inner bay and in the open bay, reflecting the importance of the riverine inputs as a source of antibiotics. Risk assessment based on the calculated risk quotients (RQ) showed that enoxacin, ciprofloxacin, and sulfamethoxazole in the two aquatic environments both posed high ecological risks (RQ>1) to the most sensitive aquatic organisms Vibrio fischeri, Microcystis aeruginosa and Synechococcus leopoliensis, respectively. PMID- 22444725 TI - Growth inhibition and stimulation of Shewanella oneidensis MR-1 by surfactants and calcium polysulfide. AB - Foam delivery technology (FDT) uses surfactant based foam to immobilize subsurface contaminants in situ. Where traditional approaches are impractical, FDT has the potential to overcome many of the technical challenges facing the remediation of contaminated deep vadose zone environments. However, little is known about the effects these reactive chemicals may have on microorganisms inhabiting the contaminated subsurface. In addition, there are currently no standard assays to assess microbial responses to subsurface remedial treatments while these agents are under development. The objective of this study was to develop a rapid laboratory assay to assess the potential growth inhibition and/or stimulation of microorganisms following exposure to candidate FDT components. Calcium polysulfide (CPS) and several surfactants (i.e. sodium laureth sulfate (SLES), sodium dodecyl sulfate (SDS), cocamidopropyl betaine (CAPB) and NINOL40 CO) have diverse chemistries and are candidate components of FDT. Shewanella oneidensis MR-1 cultures were exposed to a range of concentrations of these chemicals to determine the minimum bactericidal concentration (MBC) and the growth and viability potential of these components. Concentrations of SDS higher than 700 MUM were toxic to S. oneidensis MR-1 growth over the course of four days of exposure. The relative acute toxicity order for these compounds was SDS >> CPS >> NINOL 40-CO>SLES>=CAPB. Dose dependent growth decreases (20-100mM) were observed in the CAPB and SLES treated cultures and both CPS and NINOL 40-CO were toxic at all concentrations tested (1.45-7.25 mM CPS). Both SLES (20-100mM) and SDS at lower concentrations (20-500 MUM) were stimulatory to S. oneidensis MR-1 indicating a capacity to be used as a carbon source. These studies also identified potentially key component characteristics, such as precipitate formation and oxygen availability, which may prove valuable in assessing the response of subsurface microorganisms. This benchtop system provides a capability to assess adverse microbial-remediation responses and contributes to the development of in situ remedial chemistries before they are deployed in the field. PMID- 22444726 TI - Nickel induces hyperglycemia and glycogenolysis and affects the antioxidant system in liver and white muscle of goldfish Carassius auratus L. AB - The toxicity of nickel to mammals is well studied, whereas information on nickel effects on fish is scant. Goldfish exposure to 10-50 mg L(-1) of waterborne Ni(2+) for 96 h showed reduced glycogen levels by 27-33% and 37-40% in liver and white muscle, respectively, accompanied by substantial increases in blood glucose levels (by 15-99%). However, indices of oxidative damage to proteins (carbonyl proteins) and lipids (lipid peroxides) were largely unaffected by nickel exposure. In liver, the activities of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPx), were not affected by Ni(2+) treatment, while catalase activity was elevated by 26%. In white muscle, however, substantial increases in SOD (by 38-147%) and GPx (by 2.5-5.5-fold) activities appeared to compensate for decreased catalase activity (by 59-69%) in order to resist Ni-induced oxidative perturbations. Both hepatic and muscular glutathione reductase activities were suppressed by 10-30% and 12-21%, respectively, after goldfish exposure to all Ni(2+) concentrations used. However, the activity of glucose-6-phosphate dehydrogenase was remarkably enhanced (by 1.6-5.4-fold) in white muscle of Ni-exposed fish, indicating a strong potential increase in NADPH production under Ni exposure. Thus, the exposure of goldfish to 10-50 mg L(-1) of Ni(2+) for 96 h induces glycogenolysis and hyperglycemia, showing some similarities with a hypoxia response, and leads to a substantial activation of defense systems against reactive oxygen species in liver and white muscle in tissue-specific and concentration-dependent manner. PMID- 22444727 TI - Utility of bioassays (lettuce, red clover, red fescue, Microtox, MetSTICK, Hyalella, bait lamina) in ecological risk screening of acid metal (Zn) contaminated soil. AB - The objective of this study was to assess selected bioassays and ecological screening tools for their suitability in a weight of evidence risk screening process of acidic metal contaminated soil. Intact soil cores were used for the tests, which minimizes changes in pH and metal bioavailability that may result from homogenization and drying of the soil. Soil cores were spiked with ZnCl(2) or CaCl(2). Leachate collected from the soil cores was used to account for the exposure pathways through pore water and groundwater. Tests assessed included MetSTICK in soil cores and Microtox in soil leachate, lettuce (Lactuca sativa), red fescue (Festuca rubra) and red clover (Trifolium pratense) in the soil cores and lettuce and red clover in soil leachate, Hyallella azteca in soil leachate, and an ecological soil function test using Bait Lamina in soil cores. Microtox, H. azteca, lettuce and red fescue showed higher sensitivity to low pH than to Zn concentrations and are therefore not recommended as tests on intact acidic soil cores and soil leachate. The Bait Lamina test appeared sensitive to pH levels below 3.7 but should be investigated further as a screening tool in less acidic soils. Among the bioassays, the MetSTICK and the T. pratense bioassays in soil cores were the most sensitive to Zn, with the lowest nominal NOEC of 200 and 400mg Zn/kg d.w., respectively. These bioassays were also tolerant of low pH, which make them suitable for assessing hazards of metal contaminated acid soils. PMID- 22444728 TI - Endocytic trafficking of neurotrophins in neural development. AB - During the formation of neuronal circuits, neurons respond to diffusible cues secreted by target tissues. Often, target-derived signals act on nerve terminals to influence local growth events; in other cases, they are transported long distances back to neuronal cell bodies to effect transcriptional changes necessary for neuronal survival and differentiation. Neurotrophins provide one of the best examples of target-derived cues that elicit an astonishingly diverse array of neuronal responses. Endocytic trafficking of neurotrophins and their receptors is a fundamental feature of neurotrophin signaling, allowing neurotrophins to control neuronal survival by retrograde transport of signaling endosomes containing ligand-receptor complexes. In this review we summarize recent findings that provide new insight into the interplay between neurotrophin signaling and trafficking. PMID- 22444729 TI - Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling. AB - Many cellular processes including apoptosis, autophagy, translation, energy metabolism, and inflammation are controlled by the mammalian target of rapamycin (mTOR) kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR). Although both of these signaling nodes have attracted wide attention in fundamental cell biology and drug discovery, crosstalk between the two pathways has emerged only very recently. mTOR complex 1 (mTORC1) operates both upstream and downstream of ER stress signals, which can either enhance or antagonize the anabolic output of mTORC1. Upon prolonged ER stress, mTORC1 contributes to apoptotic signaling by suppressing the survival kinase Akt through feedback inhibition. Likewise, chronic ER stress obstructs activation of Akt by mTOR complex 2. This review surveys our knowledge of mTOR-ER stress intersections and highlights potential therapeutic implications. PMID- 22444730 TI - Effectiveness of sotalol as first-line therapy for fetal supraventricular tachyarrhythmias. AB - Fetal supraventricular tachycardia (SVT) and atrial flutter (AF) can be associated with significant morbidity and mortality. Digoxin is often used as first-line therapy but can be ineffective and is poorly transferred to the fetus in the presence of fetal hydrops. As an alternative to digoxin monotherapy, we have been using sotalol at presentation in fetuses with SVT or AF with, or at risk of, developing hydrops to attempt to achieve more rapid control of the arrhythmia. The present study was a retrospective review of the clinical, echocardiographic, and electrocardiographic data from all pregnancies with fetal tachycardia diagnosed and managed at a single center from 2004 to 2008. Of 29 affected pregnancies, 21 (16 SVT and 5 AF) were treated with sotalol at presentation, with or without concurrent administration of digoxin. Of the 21, 11 (6 SVT and 5 AF) had resolution of the tachycardia within 5 days (median 1). Six others showed some response (less frequent tachycardia, rate slowing, resolution of hydrops) without complete conversion. In 1 fetus with a slow response, the mother chose pregnancy termination. The 5 survivors with a slow response were all difficult to treat postnatally, including 1 requiring radiofrequency ablation as a neonate. One fetus developed blocked atrial extrasystoles after 1 dose of sotalol and was prematurely delivered for fetal bradycardia. Three grossly hydropic fetuses with SVT showed no response and died within 1 to 3 days of treatment. In conclusion, transplacental sotalol, alone or combined with digoxin, is effective for the treatment of fetal SVT and AF, with an 85% complete or partial response rate in our series. PMID- 22444731 TI - Relation of prolonged tissue Doppler imaging-derived atrial conduction time to atrial arrhythmia in adult patients with congenital heart disease. AB - Atrial arrhythmia (AA) is common in adult patients with congenital heart disease (CHD). To enable the prevention of AA or its complications, timely identification of adult patients with CHD at risk of AA is crucial. Long total atrial activation times have been related to AA. Tissue Doppler imaging (TDI) permits noninvasive evaluation of the total atrial conduction time (PA-TDI duration). The present study evaluated the association between the PA-TDI duration and the development of AA in adult patients with CHD. A total of 223 adult patients with CHD were followed up for the occurrence of AA after PA-TDI duration assessment. The PA-TDI duration was defined as the interval from the onset of the P wave on the electrocardiogram to the peak of the A' wave at the lateral atrial wall on TDI tracings. Among the various clinical and echocardiographic parameters, the association between the PA-TDI duration and AA occurrence was investigated. The median follow-up was 39 months (interquartile range 21 to 57). A PA-TDI duration of >=126 ms was associated with AA during follow-up (log-rank, p <0.001). On multivariate analysis, a PA-TDI duration >126 ms (hazard ratio 2.25, 95% confidence interval 1.21 to 4.19) and history of AA (hazard ratio 4.89, 95% confidence interval 2.75 to 8.71) were independently associated with the occurrence of AA. In conclusion, PA-TDI duration and a history of AA were independently associated with the occurrence of AA in adult patients with CHD. The PA-TDI duration is a useful tool to identify patients with CHD at risk of AA during follow-up. PMID- 22444732 TI - Detection of hydrogen using graphene. AB - Irradiation dynamics of a single graphene sheet bombarded by hydrogen atoms is studied in the incident energy range of 0.1 to 200 eV. Results for reflection, transmission, and adsorption probabilities, as well as effects of a single adsorbed atom to the electronic properties of graphene, are obtained by the quantum-classical Monte Carlo molecular dynamics within a self-consistent-charge density functional tight binding formalism We compare these results with those, distinctly different, obtained by the classical molecular dynamics.PACS: 61.80.Az, 61.48.Gh, 61.80.Jh, 34.50.Dy. PMID- 22444733 TI - Establishing primary cultures of vascular smooth muscle cells from the spiral modiolar artery. AB - OBJECTIVE: This article is reporting a method for establishment primary cultures of vascular smooth muscle cells (VSMCs) from the spiral modiolar artery (SMA). METHODS: VSMCs were isolated from guinea pig SMAs. Arterial tissues were cut and enzymatically digested at 37 degrees C for 20 min using a 0.1% trypsin solution. After digestion, tissue fragments were explanted in a 35-mm culture dish. Contaminated fibroblasts were separated from VSMCs because of their different adhesion abilities. The cells migrated from the explants within 7-10 days and grew to confluence in approximately 4 weeks. RESULTS: We obtained pure and viable VSMCs from the confluent third passage. The morphological and immunofluorescence analyses demonstrated a "hill-and-valley" growth pattern that is characteristics of VSMCs, and the expression of cell type-specific markers (alpha-smooth muscle actin and myosin), respectively. The change of intracellular calcium concentration induced by angiotensin II and CaCl(2) showed that the VSMCs had good cell viability. CONCLUSION: We obtained purified VSMCs using this method. All cell cultures expressed smooth muscle markers (alpha-SM actin, and myosin) and were negative for vWF. This article provides a simple method to obtain VSMCs for in vitro studies of physiology and pathophysiology in the circulation disturbances of the inner ear. In addition, VSMCs are regarded to be an excellent model to evaluate drugs in vitro. PMID- 22444734 TI - Bilateral choanal atresia repair in neonates--a single surgeon experience. AB - OBJECTIVE: To evaluate the success of the transnasal endoscopic repair of bilateral choanal atresia (BCA) repair in neonates based on a single surgeon's experience. METHODS: A retrospective case review was carried out of all neonates with BCA who underwent transnasal endoscopic repair by the senior author (RGB) between September 1993 and September 2009 at the Royal Children's Hospital Melbourne, Australia. RESULTS: Twenty three neonates (18 female and 5 male) aged between 0 and 32 days (mean age, 7.4 days) underwent surgery for BCA between September 1993 and September 2009. Twenty of these patients met the inclusion criteria to calculate success rate of primary surgery. All patients were stented using modified endotracheal tubes for a mean of 75 days (range, 5-158 days). Of the 20 with adequate follow up, 14 patients had successful primary repair (70%). Of the six requiring revision surgery, three had one revision procedure, and three had two revision procedures. All patients were free of recurrence at last follow up. Mean follow up after removal of primary stent was 25.2 months (range, 6.6-77.9 months). CONCLUSION: Endoscopic transnasal repair is a relatively safe and successful technique. Stenting for 3 months was found to reduce the chance of early restenosis. PMID- 22444735 TI - Two novel SLC26A4 mutations in Iranian families with autosomal recessive hearing loss. AB - OBJECTIVE: Due to the fact that SLC26A4 has been suggested as the second cause of hearing loss (HL) in Iran as well as many other countries, obtaining more comprehensive information about SLC26A4 mutations can facilitate more efficient genetic services to the patients with hereditary hearing loss. This investigation aims to detect genetic cause of two Iranian families with hearing loss. METHODS: In the present study, genetic linkage analysis via 4 short tandem repeat markers linked to SLC26A4 was performed for two consanguineous families originating from Hormozgan and Chaharmahal va Bakhtiari provinces of Iran, co-segregating autosomal recessive hearing loss and showed no GJB2 mutations in our preliminary investigation. For identification of mutations, DNA sequencing of SLC26A4 including all the 21 exons, exon-intron boundaries and the promoter was carried out. RESULTS: The results showed linkage to this gene in both families. After sequencing, two novel SLC26A4 mutations (c.65-66insT in exon 2 and c.2106delG in exon 19) were revealed in the two studied families. CONCLUSION: Results of this study stress the necessity of considering the analysis of SLC26A4 in molecular diagnosis of deafness especially when phenotypes such as goiter or enlarged vestibular aqueduct are present. PMID- 22444736 TI - Multisensory processing in children with cochlear implants. AB - OBJECTIVE: The objective of the study was to investigate the functions of the vestibular, tactile, visual, and proprioceptive modalities in children with prelinguistic hearing loss. Specifically, the study sought to examine evidence for the compensation hypothesis (auditory deprivation leads to enhancements in functions of other sensory systems) versus the deficiency hypothesis (functions of the spared senses are compromised as a result of auditory deprivation). METHODS: Twelve children between the ages of 5 years, 1 month and 8 years, 11 months with bilateral severe-profound hearing loss participated in the study. All children used bilateral cochlear implants. Subtests of two norm-referenced instruments, the Sensory Integration and Praxis Test and the Beery-Buktenica Developmental Test of Visual-Motor Integration, were administered to all of the children. Mean subtest scores for children with hearing loss were compared with the mean scores for the normative group. RESULTS: As expected, a majority of children demonstrated vestibular dysfunction. Assessment of other modalities revealed significantly below average performance on two tasks by children with hearing loss when compared to the normative group. Both tasks involved temporal processing of tactile or proprioceptive signals. Conversely, children with hearing loss showed significantly better performance compared to the normative group for a spatial task that involved localization of a tactile stimulus. No group differences were found for any of the visual tasks. CONCLUSIONS: Results supported both the compensation and the deficiency hypotheses. The findings have implications for both assessment and intervention of young children with hearing loss. Further investigations are necessary to replicate these findings with a more comprehensive set of measures on a larger cohort of children with prelinguistic, severe-profound hearing loss. PMID- 22444737 TI - Age-dependent differences of the anterior skull base. AB - OBJECTIVE: Imaging of the anterior skull base and paranasal sinuses is essential before surgery of the nose and paranasal sinuses. It is important to know individual anatomical variations to define a "dangerous ethmoid" to prevent complications such as considerable bleeding or injury to the brain. This study aimed to analyze the relevant parameters with special regard to age-dependent differences. METHODS: This was a retrospective, single center study of 865 patients. Data from cone beam computed tomography (CBCT) of 116 patients less than 18 years of age and 749 adult patients were analyzed. Keros type, the course of the anterior ethmoid artery, the course of the uncinate process and the angle between the lateral lamella and the cribriform of the olfactory fossa were evaluated. RESULTS: Different frequencies of the course of the uncinate process between young and adult persons could be shown: onset at the lamina papyracea 67% vs. 64%; onset at the skull base, 22% vs. 26%; and onset at the middle turbinate, 11% vs. 10%. Differences in the course of the anterior ethmoid artery could be evaluated in the same way: course at the skull base, 49% vs. 44%; free course with a distance to the skull base of less than 3mm, 11% vs. 19%; and free course with a distance to the skull base more than 3mm, 40% vs. 37%. Significant differences could be found in the frequencies of the height of the olfactory fossa: Keros type I, 28% vs. 16%; Keros type II, 51% vs. 60%; and Keros type III, 21% vs. 24%. The angle between the lateral lamella and the cribriform plate showed significant differences dependent on the course of the anterior ethmoid artery (skull base=123 degrees vs. distance<3mm=117 degrees vs. distance>3mm=110 degrees ) and dependent on the height of the olfactory fossa (Keros type I=135 degrees vs. Keros type II=117 degrees vs. Keros type III=104 degrees ). Analysis of the angle as a factor of age and Keros type showed a significant difference in Keros type I (125 degrees vs. 132 degrees ) and Keros type II (105 degrees vs. 110 degrees ). CONCLUSION: Cone beam computed tomography (CBCT) of the anterior skull base allows the assessment of individual anatomical-radiological risk profiles and the identification of a "dangerous ethmoid". Significant age-dependent differences in the frequencies of anatomic landmarks and the angles of the ethmoid roof could be evaluated and led to significantly different risk profiles between children and adults. PMID- 22444738 TI - Effect of cuffed and uncuffed endotracheal tubes on the oropharyngeal oxygen and volatile anesthetic agent concentration in children. AB - BACKGROUND: Over the past 5 years, there has been a change in the clinical practice of pediatric anesthesiology with a transition to the use of cuffed instead of uncuffed endotracheal tubes (ETTs) in infants and children. As the trachea is sealed, one advantage is to eliminate the contamination of the oropharynx with oxygen which should be advantageous during adenotonsillectomy where there is a risk of airway fire. The current study prospectively assesses the oropharyngeal oxygen and volatile anesthetic agent concentration during adenotonsillectomy in infants and children. METHODS: Following the induction of general anesthesia in patients scheduled for adenoidectomy, tonsillectomy or adenotonsillectomy, the trachea was intubated. The use of a cuffed or uncuffed ETT and the use of spontaneous (SV) or positive pressure ventilation (PPV) were at the discretion of the anesthesia team. The oxygen concentration was kept at 100% oxygen until the study was completed. Following placement of the mouth gag, the otolaryngolist placed into the oropharynx a small bore catheter, which was attached to a standard anesthesia gas monitoring device which sampled the gas at 150mL/min. The concentration of the oxygen and the concentration of the anesthetic agent in the oropharynx were measured for 5 breaths. RESULTS: The cohort for the study included 200 patients ranging in age from 1 to 18 years. With the use of a cuffed ETT and either SV or PPV, the oxygen concentration in the oropharynx was 20-21% and the volatile agent concentration was 0% in all 118 patients. With the use of an uncuffed ETT and the administration of 100% oxygen, there was significant contamination of the oropharynx noted during both PPV and SV. The mean oxygen concentration was 71% during PPV with an uncuffed ETT and 65% during SV with an uncuffed ETT. In these patients, the oropharyngeal oxygenation concentration exceeded 30% in 73 of the 82 patients (89%). The oropharyngeal oxygen and agent concentration was greater when the leak around the uncuffed ETT was >=10cmH(2)O versus less than 10cmH(2)O and when the leak around the uncuffed ETT was >=15cmH(2)O versus less than 15cmH(2)O. CONCLUSIONS: With the use of an uncuffed ETT and the administration of 100% oxygen, there was significant contamination of the oropharynx noted during both PPV and SV. The oropharyngeal concentration of oxygen is high enough to support combustion in the majority of patients. The use of a cuffed ETT eliminates oropharyngeal contamination with oxygen during the administration of anesthesia and may be useful in limiting the incidence of an airway fire. PMID- 22444739 TI - Quality of life in children and adolescents with cochlear implants and additional needs. AB - OBJECTIVE: This study aimed to explore the quality of life of deaf children with cochlear implants using a newly developed parent-report measure designed for use in this group. It compared the quality of life of implanted children with additional needs (e.g. physical or learning difficulties), with implanted children without such needs. METHODS: A 22-item questionnaire comprising four sub scales was developed and demonstrated to have good psychometric properties. This questionnaire was mailed to the parents of 199 children and adolescents with at least 2 years cochlear implant use. RESULTS: Responses were received from 89 parents, 42% of whom reported that their child had additional needs. The quality of life of these children was rated as poorer than that of children without additional needs on three of the four subscales as well as on the total quality of life rating. However, despite these significant concerns the great majority of parents reported that their child's quality of life had improved 'moderately' or 'very much', irrespective of whether they had additional needs. CONCLUSIONS: Cochlear implantation has a positive impact on the quality of life of deaf children with additional needs, to a similar extent as for those without such needs. PMID- 22444740 TI - Voice disorders in children and its relationship with auditory, acoustic and vocal behavior parameters. AB - OBJECTIVE: Parameters to distinguish normal from deviant voices in early childhood have not been established. The current study sought to auditorily and acoustically characterize voices of children, and to study the relationship between vocal behavior reported by teachers and the presence of vocal aberrations. METHODS: One hundred children between four and 6 years and 11 months, who attended early childhood educational institutions, were included. The sample comprised 50 children with normal voices (NVG) and 50 with deviant voices (DVG) matched by gender and age. All participants were submitted to auditory and acoustic analysis of vocal quality and had their vocal behaviors assessed by teachers through a specific protocol. RESULTS: DVG had a higher incidence of breathiness (p<0.001) and roughness (p<0.001), but not vocal strain (p=0.546), which was similar in both groups. The average F(0) was lower in the DVG and a higher noise component was observed in this group as well. Regarding the protocol used "Aspects Related to Phonotrauma - Children's Protocol", higher means were observed for children from DVG in all analyzed aspects and also on the overall means (DVG=2.15; NVG=1.12, p<0.001). In NVG, a higher incidence of vocal behavior without alterations or with discrete alterations was observed, whereas a higher incidence of moderate, severe or extreme alterations of vocal behavior was observed in DVG. CONCLUSIONS: Perceptual assessment of voice, vocal acoustic parameters (F(0), noise and GNE), and aspects related to vocal trauma and vocal behavior differentiated the groups of children with normal voice and deviant voice. PMID- 22444741 TI - Genetic parameters for serial, automatically recorded milkability and its relationship to udder health in dairy cattle. AB - Serial measurements of three milkability traits from two commercial dairy farms in Germany were used to estimate heritabilities and breeding values (BVs). Overall, 6352 cows in first, second and third lactations supplied 2 188 810 records based on daily values recorded from 1998 to 2003. Only the records between day 8 and day 305 after calving were considered. The estimated genetic correlations between different parities within the three milkability traits ranged from rg = 0.88 to 0.98, i.e. they were sufficiently high to warrant a repeatability model. The resulting estimated heritability coefficients were h2 = 0.42 for average milk flow, h2 = 0.56 for maximum milk flow and h2 = 0.38 for milking time. We analysed the genetic correlation between milkability and somatic cell score (SCS) and between milkability and the liability to mastitis, respectively, as the optimum milk flow for udder health is not well defined. There were 66 146 records with information on somatic cell count. Furthermore, 23 488 days of medical treatment for udder diseases were available, resulting in 2 600 302 days of observation in total. Heritabilities for the liability to mastitis, estimated with a test-day threshold model, were h2 = 0.19 and h2 = 0.13, depending on the data-recording period (first 50 days of lactation and first 305 days of lactation, respectively). With respect to the relationship between milkability and udder health, the results indicated a slight and linear correlation insofar as one can assume: the higher the milk flow, the worse the udder health. For this reason, bulls and cows with high BVs for milk flow should be excluded from breeding to avoid a deterioration of udder health. The establishment of a special data-recording scheme for functional traits such as milkability and mastitis on commercial dairy farms may be possible according to these results. PMID- 22444742 TI - Effect of starch level and straw intake on animal performance, rumen wall characteristics and liver abscesses in intensively fed Friesian bulls. AB - The objective was to reduce the incidence of liver abscesses (LAs) in young bulls by reducing the starch content of the concentrate and increasing the straw intake by adding molasses without reducing performance. Eighty-five Danish Friesian bulls (146 +/- 2.6 kg live weight (LW)) were allocated to four treatment groups in a 2 * 2 factorial design and were ad libitum fed either a high (H) (43%) or a low (L) (25%) starch concentrate, and either chopped barley straw (S) or a mixture (Sm) of chopped barley straw and sugar-beet molasses (75:25). The bulls were slaughtered at 440 (+/-4.2) kg LW (11.3 months of age) on average. The concentrate dry-matter intake (DMI) was 7.5% higher (P < 0.001), the roughage DMI was 12% higher (P < 0.01), whereas the total net energy intake was 7% lower (P < 0.001) for the L compared with the H concentrate. By adding molasses to the straw, roughage DMI increased from 0.50 to 0.96 kg/day (P < 0.001). Average daily gain (ADG) was not affected by treatment. Feed conversion efficiency (FCE) for dry matter (FCEDM) was decreased (P < 0.001), whereas FCE for net energy (FCENE) was increased with the L concentrate (P < 0.01), suggesting a lower utilisation of the cell wall fraction with the H starch concentrate. There were no major effects of treatment on carcass characteristics. The higher roughage intake with Sm prevented rumen wall damage, but did not reduce the number of animals with LAs. The L concentrate did not affect the rumen wall but reduced the level of LA (2 v. 9 animals, P < 0.02). There was a higher level of respiratory diseases in animals fed the H concentrate (P < 0.05). The experiment showed that it was possible to maintain performance and reduce LA by using a lower starch content of the concentrate. PMID- 22444743 TI - Sparing effect of microbial phytase on zinc supplementation in maize-soya-bean meal diets for chickens. AB - The experiment was conducted to evaluate the sparing effect of microbial phytase on the need for dietary zinc supplementation in chicks. A maize-soya-bean meal basal diet, containing 33 mg of zinc and 16 mg of copper per kg, supplemented with 0, 6, 12, 18, 24, 30 or 60 mg of zinc as sulphate per kg or with 250, 500, 750 or 1000 units (FTU) of microbial phytase (3-phytase from Aspergillus niger, Natuphos(r)) per kg was given to 1-day-old chicks for 20 days. Sixteen chicks placed in individual cages were assigned to each diet except the unsupplemented basal diet which was assigned to 32 cages. Actual range of phytase supplementation was 280 to 850 FTU per kg diet. Growth performance was not affected by microbial phytase. Chicks given the unsupplemented basal diet and the basal diet supplemented with 60 mg of zinc per kg displayed similar performance. Bone weight, bone ash, liver weight and liver dry matter were independent (P > 0.1) of zinc and phytase supplementations. Plasma, bone and liver zinc concentrations increased linearly (P < 0.001) and quadratically (P < 0.001; P < 0.001 and P < 0.05, respectively) with zinc added. Plasma zinc tended to increase linearly (P = 0.07) and bone zinc increased linearly (P < 0.01) with phytase added but no quadratic response was detected (P > 0.1). Liver zinc was unresponsive to phytase added (P > 0.1). Liver copper decreased linearly (P < 0.001) and quadratically (P < 0.01) with zinc supplementation. Mathematical functions were fitted to the responses of plasma and bone zinc to zinc and phytase added and used to calculate zinc equivalency values of phytase. The models included a linear plateau response to zinc added and a linear response to phytase added. In diets without phytase, plasma and bone zinc concentrations were maximised for a dietary zinc concentration of 55 and 51 mg/kg, respectively. Over the range of 280 to 850 FTU, 100 FTU was equivalent to 1 mg of zinc as sulphate. Consequently, in a maize-soya-bean meal chicken diet formulated to contain 60 mg zinc per kg, zinc ingested, and in turn, zinc excreted may be reduced by around 10% if the diet contains 500 FTU as Natuphos(r) per kg. PMID- 22444744 TI - Effects of increasing the intake of dietary beta-glucans by exchanging wheat for barley on nutrient digestibility, nitrogen excretion, intestinal microflora, volatile fatty acid concentration and manure ammonia emissions in finishing pigs. AB - An experiment (complete randomised design) was conducted to investigate the linear and quadratic effects of barley beta-glucan inclusion level on total tract nutrient apparent digestibility, nitrogen excretion, intestinal microflora, volatile fatty acid (VFA) profile and manure ammonia emissions in pigs. Twenty four boars (66 kg) were assigned to one of four treatments: (T1) 0 g/kg barley (control diet) (5.6 g/kg beta-glucan), (T2) 222 g/kg barley (12.1 g/kg beta glucan), (T3) 444 g/kg barley (18.9 g/kg beta-glucan) and (T4) 666 g/kg barley (25 g/kg beta-glucan). Barley was substituted for wheat in the diet. The diets were formulated to contain similar concentrations of digestible energy and digestible lysine. There was a linear decrease (P < 0.001) in the total tract apparent digestibility of dry matter, organic matter, gross energy and neutral detergent fibre with increasing beta-glucan concentration. Faecal nitrogen excretion was affected by dietary beta-glucan concentration (quadratic P < 0.05). There was a linear decrease in Enterobacteria concentrations (P < 0.05) with increasing dietary beta-glucan concentration. Increasing dietary barley levels caused a linear decrease in colonic (P < 0.01) and caecal pH (P < 0.001). Total caecal VFA and propionic acid were affected by dietary beta-glucan concentration (quadratic, P < 0.05). There was a linear decrease in the proportion of acetic acid (P < 0.001), isobutyric acid (P < 0.01) and isovaleric acid (P < 0.05) with increasing levels of dietary barley in both the caecum and colon. There was a linear increase in the proportion of propionic acid (P < 0.001) and butyric acid (P < 0.05) with increasing barley in the colon. In conclusion, high level of dietary beta-glucan (25 g/kg) is required to reduce offensive odour forming branched-chain VFAs; however, diet digestibility is compromised at such levels. PMID- 22444745 TI - In rat hepatocytes, myristic acid occurs through lipogenesis, palmitic acid shortening and lauric acid elongation. AB - The origin of myristic acid in mammalian cells and the regulation of its endogenous cellular low concentration are not known. Another intriguing question is the potential metabolic properties of endogenous myristic acid as compared with exogenous myristic acid. In the present paper, we hypothesised and demonstrated that, in liver cells, in addition to the usual fatty acid synthase (FAS) pathway that produces predominantly palmitic acid and minor amounts of myristic acid, part of endogenous cellular myristic acid also comes from a shortening of palmitic acid, likely by peroxisomal beta-oxidation and from lauric acid by elongation. From a nutritional point of view, C16:0 is universally found in natural fats and its shortening to myristic acid could contribute to a non negligible source of this fatty acid (FA) in the organism. Then, we measured the distribution of endogenously synthesised myristic acid in lipid species and compared it with that of exogenous myristic acid. Our results do not support the hypothesis of different metabolic fates of endogenous and exogenous myristic acid and suggest that whatever the origin of myristic acid, its cellular concentration and lipid distribution are highly regulated. PMID- 22444746 TI - Deposition of copper, iron, manganese and zinc in the empty body of growing lambs of the breed German Merino Landsheep. AB - A growth experiment with 108 lambs (breed: German Merino Landsheep) was carried out to examine the effect of gender, body weight (BW) and feeding intensity on the deposition of Fe, Zn, Cu and Mn in the empty body (whole animal minus contents of the gastrointestinal tract and bladder). The lambs (50% female and 50% male animals) were fed at three feeding levels ('low', 'medium' and 'high' by varying daily amounts of concentrate and hay) and slaughtered at different final BWs (30, 45 or 55 kg). Six male and six female animals were killed at a BW of 18 kg representing the animals' BW at the beginning of the comparative slaughter experiment. There were significant main effects for the treatments growth rate and final weight on the daily rate of accretion of the trace elements examined. Feeding intensity had a marked influence on the accretion rate for Fe (P < 0.001), Zn (P < 0.001), Cu (P < 0.001) and Mn (P = 0.003). With increasing feeding intensity (low, medium, high) the daily deposition of these trace elements increased (4.4, 5.2, 6.6 mg/day for Fe; 4.9, 5.5, 6.9 mg/day for Zn; 0.20, 0.36, 0.44 mg/day for Cu; 0.14, 0.16, 0.21 mg/day for Mn). Heavier final BW led to increased daily retention of Zn (P < 0.001) and Mn (P = 0.002). Gender had a marked influence only on the accretion rate for Zn (P < 0.001). Ram lambs had a higher daily deposition of this element than female lambs. Related to 1000 g empty body gain, the following concentrations were found for the trace elements examined: Fe 26.1 mg, Zn 30.0 mg, Cu 1.41 mg and Mn 1.04 mg. A feeding influence was given for Zn (P < 0.001) and Cu (P = 0.039). Feeding level low had higher Zn and lower Cu concentrations. Male animals showed less Fe (P < 0.001) and Zn (P = 0.034) per kg empty body gain than females. PMID- 22444747 TI - Conjugated linolenic acid (CLnA), conjugated linoleic acid (CLA) and other biohydrogenation intermediates in plasma and milk fat of cows fed raw or extruded linseed. AB - Thirty lactating dairy cows were used in a 3 * 3 Latin-square design to investigate the effects of a raw or extruded blend of linseed and wheat bran (70:30) on plasma and milk fatty-acids (FA). Linseed diets, containing 16.6% linseed blend on a dry-matter basis, decreased milk yield and protein percentage. They decreased the proportions of FA with less than 18 carbons in plasma and milk and resulted in cis-9, cis-12, cis-15 18:3 proportions that were more than three and four times higher in plasma and milk, respectively, whereas cis-9, cis-12 18:2 proportions were decreased by 10-15%. The cis-9, trans-11, cis-15 18:3 isomer of conjugated linolenic acid was not detected in the milk of control cows, but was over 0.15% of total FA in the milk fat of linseed-supplemented cows. Similarly, linseed increased plasma and milk proportions of all biohydrogenation (BH) intermediates in plasma and milk, including the main isomer of conjugated linoleic acid cis-9, trans-11 18:2, except trans-4 18:1 and cis-11, trans-15 18:2 in plasma lipids. In milk fat, compared with raw linseed, extruded linseed further reduced 6:0-16:0 even-chain FA, did not significantly affect the proportions of 18:0, cis-9 18:1 and cis-9, cis-12 18:2, tended to increase cis-9, cis-12, cis-15 18:3, and resulted in an additional increase in the proportions of most BH intermediates. It was concluded that linseed addition can improve the proportion of conjugated linoleic and linolenic acids, and that extrusion further increases the proportions of intermediates of ruminal BH in milk fat. PMID- 22444748 TI - Iron-induced luminescence as a method for assessing lipid peroxidation of frozen thawed goat spermatozoa. AB - Freezing/thawing procedures induce enhanced reactive oxygen species (ROS) formation in mammalian sperm and these ROS may be a cause for the decrease in sperm function following cryopreservation. In the present study, we used a chemiluminescence method to detect ROS-induced damage in goat spermatozoa. Iron induced luminescence of fresh and frozen/thawed sperm cells was assessed using a luminometer. It was shown that the freezing/thawing procedure had a significant effect on some luminescence parameters. Semen freezing significantly increased the values of integral, peak max, T.half (rise) and T.max (peak) parameters. A significant correlation was observed between the percentage of motile spermatozoa and integral, peak max and T.half (rise) parameters. In conclusion, the results of the present study indicate that measurement of induced luminescence can be an alternative, sensitive and relatively simple method for assessing the effect of cryopreservation on oxidative damage to spermatozoa. PMID- 22444749 TI - The response of various muscle types to a restriction -re-alimentation feeding strategy in growing pigs. AB - Muscle lipid concentration is known to influence pork eating quality. This study aimed at evaluating the effect of a restriction-re-alimentation feeding strategy on intramuscular fat deposition in pigs. A total of 70 Duroc * (Large White * Landrace) pigs (castrated males and females) were used. Ten pigs were first slaughtered at 30 kg live weight (LW) to determine initial body and muscle composition. From 30 to 80 kg LW (growing period), pigs were either fed ad libitum (AL) or restricted to 70% of the ad libitum intake of AL pigs (RA). From 80 to 110 kg LW (finishing period), both AL and RA pigs were fed ad libitum. In each group, pigs were slaughtered at 80 kg (n = 10) and at 110 kg (n = 20) LW. During the growing period, the growth rate of RA pigs was reduced by 30% (P < 0.001) compared with AL pigs. During the finishing period, RA pigs had a 7% (P = 0.09) higher growth rate than AL pigs due to compensatory feed intake (+14%). Plasma insulin-like growth factor-1 concentration was lower in RA pigs at 80 kg LW, but markedly increased after re-alimentation up to the level observed in AL pigs (P < 0.001). At 80 kg, the leaner carcasses of RA pigs resulted from a more pronounced reduction in fat than in lean tissue deposition rates. Re-alimentation of RA pigs increased fat tissue deposition (+160% for females, P < 0.01) but not lean deposition in the carcass, leading to limited differences in carcass composition between RA and AL pigs at 110 kg LW. Regarding tissue deposition rates, the response to feeding strategy differs between muscles. In the m. biceps femoris (BF), restriction affected lipid (-50%, P < 0.001) and protein (-25%, P < 0.001) deposition, whereas re-alimentation increased lipid (+62%, P < 0.05) but not protein deposition rates. At market weight, the extent of the difference in BF lipid concentration between RA and AL pigs was strongly reduced, but still significant. By contrast, in the m. longissimus, restriction decreased protein but not lipid deposition, whereas neither of them was modified during re alimentation. Therefore, an increased muscle lipid concentration at 110 kg LW could not be reached in RA pigs. Modifications of onset and/or duration of restriction and re-alimentation periods should be tested to optimise effects on muscle lipid deposition and thereby achieve improved pork quality. PMID- 22444750 TI - Season of birth modifies puberty in female and male goats raised under subtropical conditions. AB - In seasonal goats and sheep breeds, onset of puberty is modified by the season of birth. As adult does and bucks from subtropical Mexico display seasonal variation in their reproductive behaviour, this study was carried out to determine the effect of season of birth on puberty. Three groups of each sex born in January, May and October were used. During the seasons, does and bucks were weaned at an age of 30 days and offered ad libitum alfalfa hay and 100 g of commercial concentrate. In the female kids, the onset of ovulatory activity was determined by progesterone plasma concentrations once in a week from 3 months of age until the onset of puberty. In the male kids, the onset of puberty was individually recorded by observing the ability to mount and intromit an induced oestrous female goat aged 3 months and the presence of spermatozoa in the ejaculate obtained in an artificial vagina 1 week after the first mount. In female kids, there was an effect of the season on the date of first ovulation (P < 0.001). In the May group, ovulatory activity commenced at an earlier age (201 +/- 3 days) compared with January (264 +/- 5 days) and October (344 +/- 5 days) groups (P < 0.001). In the January group also, the ovulatory activity commenced earlier than the October group (P < 0.001). In males, an effect of the season of birth on the first mounting was observed (P < 0.001). The male kids that were born in May (111 +/- 3) and October (112 +/- 5 days) attained puberty earlier than those born in January (131 +/- 4 days; P < 0.001). The time of onset of puberty did not differ between groups of May and October. All males showed the presence of spermatozoa in the first ejaculate obtained 1 week after the first mount. The spermatozoa in all ejaculates were immobile. It was concluded that the season of birth modified the onset of puberty in both genders, but these modifications were more pronounced in the female than in the male kid goats. PMID- 22444751 TI - Behaviour influences cholesterol plasma levels in a pig model. AB - Little is known about the relationship between feed intake behaviour and cholesterol levels in humans. This can be attributed to the fact that feed intake behaviour in humans is difficult to assess. The relationships between feed intake, feed efficiency and feed intake behaviour, and cholesterol and triglyceride levels were investigated at an average age of 187 days, in a pig model consisting of 202 Duroc barrows. Feed intake and feed intake behaviour were recorded individually and daily by means of an electronic identification system. Animals with high levels of total cholesterol also had high levels of high density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol and triglycerides. Animals with high levels of HDL also had high levels of LDL and triglycerides, and animals with high levels of LDL also had high levels of triglycerides. Animals with higher BW, higher backfat thickness, higher BW gain, higher gain of backfat deposition, higher feed intake, higher residual feed intake (RFI) and higher feed intake rate had higher levels of total, HDL and LDL plasma cholesterol. Results indicate that the relationship between feed intake and cholesterol levels is a long-term relationship, while the relationship between RFI and cholesterol levels is more of a short-term nature. The relationship between intake rate and cholesterol plasma levels disappeared after correction for the amount of feed consumed. Results indicate that feed intake independent of metabolic BW, growth and fatness, i.e. 'RFI', was positively correlated with cholesterol plasma levels. This suggests that eating food over and above the maintenance and growth requirements constitutes a health risk independent of the level of fatness. PMID- 22444752 TI - Dietary fibre for gestating sows: effects on parturition progress, behaviour, litter and sow performance. AB - In pig production, parturition progress is a key event for sow's reproductive performance, evaluated by piglet survival and piglets' performance. The aim of this study was to investigate the impact of feeding a high-fibre (HF) diet during gestation on parturition progress and reproductive performance of sows. Forty-two primiparous sows (Large-White * Landrace crossbred) were fed during gestation either a control diet (C diet; 2.40 kg/day, 3.2% crude fibre, in % of dry matter (DM)), or a HF diet (2.80 kg/day, 12.4% crude fibre, in % of DM). All sows received 33 MJ digestible energy per day. Continuous video recordings were done on the parturition day to determine postural changes (standing, sitting, lying) and behavioural activities (nesting behaviour, uterine contractions, restlessness, social behaviour towards piglets) during parturition. Duration of parturition and individual birth intervals were also measured. Piglets' growth was evaluated by weekly weighing from birth until weaning, at 26.5 days of age. Sows were weighed and backfat thickness was measured at mating, on day 105 of gestation, on the 1st day post partum, and at weaning. Durations of parturition and of birth intervals were not affected by the gestation diet and averaged 211 +/- 12 min and 16.5 +/- 0.9 min (mean +/- s.e.), respectively. During the parturition progress, the gestation diet did not affect the frequency and the time devoted to postural and behavioural activities. Dietary treatment during gestation did not influence duration of gestation and weaning-to-oestrus interval, as well as litter size, and number of stillborn and weaned piglets. Piglet weight at birth did not differ between gestation dietary treatments but piglets nursed by HF sows showed a 13.5% greater growth rate during the 1st week of life (P < 0.01) and tended to be heavier at weaning (P = 0.06) compared with C piglets. The HF sows were leaner at the end of gestation (P < 0.05), but variations of sows' weight during gestation and lactation were not affected by the gestation diet. All sows lost the same amount of backfat thickness during lactation. During lactation, the average daily feed intake was not significantly affected by the gestation diet. This study shows that substituting a control diet for a HF diet during gestation has limited effects on farrowing progress and reproductive performance, but improved piglets' growth rate during the 1st week of life and tended to increase their live weight at weaning. PMID- 22444753 TI - Milk intake and carbon dioxide production of piglets determined with the doubly labelled water technique. AB - The present study was undertaken to study different methodological aspects of quantifying CO2 production and milk intake of suckling piglets using the doubly labelled water (DLW) technique. In total, 37 piglets were enriched intraperitoneally with DLW to study equilibration time of 18O (n = 3), to validate the estimation of milk intake and CO2 production (n = 10) of piglets fed milk replacer and to quantify milk intake and CO2 production of piglets nursed ordinarily by sows (n = 24). Enrichment of 18O in expired air was analysed without any sample preparation, whereas enrichment of 18O in serum was analysed after a minimum step of sample preparation, which included pipetting of the sample, blowing gaseous CO2 into the vial for 3 s and equilibrating for 24 h. The 18O enrichment of CO2 in expired air was constant within 30-40 min of intraperitoneal injection, suggesting that DLW was equilibrated within the body water by that time. For piglets fed milk replacer, the estimation of the daily CO2 production by the DLW method (64.0 +/- 2.7 l CO2/day) was in agreement with that obtained by respiration trials (64.7 +/- 1.8 l CO2/day). Furthermore, the intake of milk replacer (891 +/- 63 g/day) determined by deuterium oxide (D2O) dilution was similar in magnitude to that found by weighing the milk disappearance (910 +/- 58 g/day). The milk intake of piglets fed milk replacer was comparable with that of sucking piglets, but sucking piglets had a remarkably higher CO2 production than artificially reared piglets, which likely was caused by a higher intake of milk solids and a higher activity level. For sucking piglets, the daily CO2 production increased curvilinearly with increasing live weight (LW) in kg: piglet CO2 production (l/day) = 25.75 * LW - 1.01 * LW2. In conclusion, 18O equilibrates fast within the body water pool when administered intraperitoneally, and the accuracy of assessing milk intake and rate of CO2 production using the DLW technique is promising. Assessment of excess enrichment of 18O in serum proved to be robust. Finally, the CO2 production of piglets fed milk replacer differs considerably from that of sucking piglets. PMID- 22444754 TI - The effect of fish oil supplementation of pregnant and lactating ewes on milk production and lamb performance. AB - Supplementation of pregnant ewes with long-chain n-3 polyunsaturated fatty acids (PUFA) demonstrably improves indicators of neonatal lamb vigour, potentially improving the number of lambs reared per ewe. The present study investigated the effect of supplementing ewes with fish oil and vitamin E (alpha-tocopherol acetate) throughout both pregnancy and lactation on the performance of lactating ewes and sucking lambs. Forty-eight ewes were supplemented with one of four concentrates containing either Megalac or fish oil plus a basal (50 mg/kg) or supranutritional (500 mg/kg) concentration of vitamin E from 6 weeks pre-partum until 4 weeks post partum in a two-by-two factorial randomised-block design. All concentrates were formulated to contain approximately 60 g/kg supplemental fatty acids. Ewes were housed, penned on sawdust and offered straw ad libitum. Blood samples were taken from ewes and lambs at intervals throughout the experiment and milk samples were obtained at 21 days into lactation. There was no notable effect of dietary vitamin E concentration upon ewe or lamb performance. Ewe dry-matter (DM) intake and yield were unaffected by dietary treatment, although ewes fed fish oil lost less weight during lactation (-1.88 kg compared with -3.97 kg for Megalac-supplemented ewes; P < 0.01). Milk fat concentrations (67.3 g/kg compared with 91.8 g/kg; P < 0.01) and yields (6.65 g/h v. 9.26 g/h; P < 0.01) were reduced in ewes fed fish oil and these decreases were associated with lower litter-growth rates (0.49 g/day compared with 0.54 g/day; P < 0.05). Milk protein yield was increased by fish oil supplementation (3.82 g/h) compared with Megalac supplementation (3.28 g/h; P < 0.05); moreover, there was an interaction between fat source and vitamin E concentration in that both protein concentration and yield were significantly lower in milk from ewes fed treatment with Megalac + basal vitamin E (MB) compared with the other three treatments. Fish oil supplementation increased the concentrations of C18:1 trans-, cis-9, trans-11 conjugated linoleic acid (CLA), C20:5 (n-3) and C22:6 (n-3) within ewe plasma, milk and lamb plasma. The mechanisms by which fish oil supplementation affects milk composition warrants further investigation. PMID- 22444755 TI - Feasibility study on the potential of visible and near infrared reflectance spectroscopy to measure alpaca fibre characteristics. AB - Visible (Vis) and near infrared (NIR) reflectance spectroscopy is a rapid and non destructive technique that has found many applications in assessing the quality of agricultural commodities, including wool. In this study, Vis and NIR spectroscopy combined with multivariate data analysis was investigated regarding its feasibility in predicting a range of fibre characteristics in raw alpaca wool samples. Mid-side samples (n = 149) were taken from alpacas from a range of colours and ages at shearing time over 4 years (2000 to 2004) and subsequently analysed for fibre characteristics such as mean fibre diameter (MFD) and standard deviation (and coefficient of variation), spin fineness, curvature degree (and standard deviation), comfort factor, medullation percentage (by weight and number in white samples only) using traditional reference laboratory testing methods. Samples were scanned in a large cuvette using a FOSS NIRSystems 6500 monochromator instrument in reflectance mode in the Vis and NIR regions (400 to 2500 nm). Partial least squares (PLS) regression was used to develop a number of calibration models between the spectral and reference data. Mathematical pre treatment of the spectra (second derivative) as well as various combinations of wavelength range were used in model development. The best calibration model was found when using the NIR region (1100 to 2500 nm) for the prediction of MFD, which had a coefficient of determination in cross-validation (R2) of 0.88 with a root mean square standard error of cross validation (RMSECV) of 2.62 MUm. The results show the NIR technique to have promise as a semi-quantitative method for screening purposes. The lack of grease in alpaca wool samples suggests that the technique might find ready application as a rapid measurement technique for preliminary classing of shorn fleeces or, if used directly on the animal, the technology might offer an objective tool to assist in the selection of animals in breeding programmes or shows. PMID- 22444756 TI - Adverse effects of conjugated alpha-linolenic acids (CLnA) on lipoprotein profile on experimental atherosclerosis in hamsters. AB - Conjugated linoleic acids (CLAs) such as rumenic acid (RA) have the potential to alter blood lipid profiles in animals and in humans. In contrast, physiological effects of conjugated alpha-linolenic acids (CLnAs), which concomitantly are omega-3 and conjugated fatty acids, are still unknown. The aim of this study was to evaluate the potential of CLnA to interfere in early steps of atherosclerosis by altering lipoprotein profiles and fatty streaks in the aortas. F1B hamsters were fed a control or one of the three hypercholesterolemic (HC) diets: HC control, HC-RA (18:2 cis-9, trans-11) or HC-CLnA (CLnA: equimolar mixture of 18:3 cis-9, trans-11, cis-15 and cis-9, trans-13, cis-15) diet. In low-cholesterol control-fed hamsters, the proportion of high-density lipoprotein cholesterol (HDL C) was around 45% while in HC-fed hamsters, HDL-C was around 10% and cholesterol was mostly (80%) carried by triglyceride-rich lipoproteins (TRL). Low-density lipoprotein (LDL) triglycerides (TGs) increased by approximately 60% in hamsters fed either HC-RA or HC-CLnA compared with HC-controls but not compared with the low-cholesterol control diet. HDL cholesterol decreased by 24% and 16% in hamsters fed HC-RA and HC-CLnA, respectively. Small dense LDL-cholesterol increased by approximately 60% in hamsters fed HC-RA and HC-CLnA compared with the HC-control group and by more than a 100% compared with hamsters on the control diet. The relative percentage of liver cholesteryl ester content increased by 88% in hamsters fed HC diets compared with the control diet. Significant differences in fatty streaks were observed between control and HC diet-fed hamsters. However, no significant difference was observed among the HC diet-fed hamsters. This study shows that animals fed any one of the HC diets developed an adverse lipoprotein profile compared with a normolipidic diet. Also, HC-RA or HC-CLnA diets altered lipoprotein profile compared with animals fed the HC-control diet but had no beneficial effects on atherosclerosis. PMID- 22444757 TI - Effect of botanical composition of silages on rumen fatty acid metabolism and fatty acid composition in longissimus muscle and subcutaneous fat of lambs. AB - To study the effect of feeding silages with different botanical composition, on rumen and lamb fat, 30 male lambs were assigned to five different silage groups for 11 weeks: botanically diverse silage (BDS); white clover silage (WCS); red clover silage (RCS), intensive English ryegrass silage (IRS) and crushed linseed and maize silage (MSL). Besides the silages, animals received organic wheat and barley and the MSL group additionally received bicarbonate (15 g/day). Silages were sampled when the bales were opened and analysed for fatty acid (FA) content and chemical composition. At slaughter, ruminal contents were sampled and 24 h after slaughter, longissimus muscle and subcutaneous (SC) fat were sampled. All samples were analysed for FA composition. The MSL group ingested the highest amount of FA (35.8 g/day v. 13.5, 19.4, 17.2 and 30.4 g/day for MSL v. BDS, WCS, RCS and IRS, respectively) and the sum of the major polyunsaturated FA, C18:2 n-6 and C18:3 n-3, was similar for groups BDS, WCS, RCS and MSL (61.3 g/100 g, 62.3 g/100 g, 62.3 g/100 g, 63.7 g/100 g of FA methylesters (FAME), respectively), while group IRS ingested higher proportions of these FA (74.5 g/100 g of FAME). Rumen data showed that animals fed BDS presented higher proportions of biohydrogenation intermediates, particularly C18:1 t11 and CLA c9t11, suggesting partial inhibition of rumen biohydrogenation. In the MSL group, the content of C18:3 n-3 in the rumen was highest, most probably due to reduced lipolysis and hence biohydrogenation through the combined effect of esterified C18:3 n-3 and seed protection. Additionally, C18:3 n-3 proportions were higher in rumen contents of RCS animals compared with WCS animals, which could be due to the activity of the polyphenol oxidase enzyme in the RC silages. Proportions of C18:3 n-3 were similar between treatments both for SC and intramuscular (IM) fat, whereas CLA c9t11 content was higher in the SC fat of BDS animals and lower in the IM fat of IRS animals compared with the other forage groups. No differences were found for C20:4 n-6, C20:5 n-3, C22:5 n-3 and C22:6 n-3 in the IM fat of the animals. Nevertheless, indices for desaturation and elongation activity in muscle of BDS animals suggest some stimulation of the first three steps of desaturation and elongation (Delta6-desaturase, elongase and Delta5-desaturase) of long-chain FA. PMID- 22444758 TI - Anesthesia and global warming: the real hazards of theoretic science. AB - Recent speculative articles in the medical literature have indicted certain inhalational anesthetics as contributing to global warming. This unfounded speculation may have deleterious patient impact. PMID- 22444759 TI - Re: "Adverse event rates as measures of hospital performance"--conflation and confusion with the use of the complications code. PMID- 22444760 TI - A new approach to the tradeoff between quality and accessibility of health care. AB - INTRODUCTION: Quality of care is associated with patient volume. Regionalization of care is therefore one of the approaches that is suited to improve quality of care. A disadvantage of regionalization is that the accessibility of the facilities can decrease. By investigating the tradeoff between quality and accessibility it is possible to determine the optimal amount of treatment locations in a health care system. In this article we present a new model to quantitatively 'solve' this tradeoff. We use the condition breast cancer in the Netherlands as an example. MATERIALS AND METHODS: We calculated the expected quality gains in Quality Adjusted Lifetime Years (QALY's) due to stepwise regionalization using 'volume-outcome' literature for breast cancer. Decreased accessibility was operationalized as increased (travel) costs due to regionalization by using demographic data, drive-time information, and the national median income. The total sum of the quality and accessibility function determines the optimum range of treatment locations for this particular condition, given the 'volume-quality' relationship and Dutch demographics and geography. RESULTS: Currently, 94 locations offer breast cancer treatment in the Netherlands. Our model estimates that the optimum range of treatment locations for this particular condition in the Netherlands varies from 15 locations to 44 locations. CONCLUSION: Our study shows that the Dutch society would benefit from regionalization of breast cancer care as possible quality gains outweigh heightened travel costs. In addition, this model can be used for other medical conditions and in other countries. PMID- 22444761 TI - Measuring concerns for severity: re-examination of a health scale with purported equal interval properties. AB - Severity of illness is an important official criterion for priority setting in health care in a number of jurisdictions. An 8-point scale of severity and functional status has been used in a number of studies in Norway in order to estimate the strength of concerns for severity in population samples. The scale has attracted international attention and may be of interest to researchers in other countries. For confidence in interpretations of results, the scale should have equal interval properties with respect to individual utility. Close examination suggest that some deviations from equal intervals occur. These deviations do not impact significantly on earlier findings and do not prevent the scale from being a potentially useful tool in future studies of the strength of societal concerns for fairness in health care. However, further research with larger and more representative samples is encouraged. PMID- 22444762 TI - Comparison of three PCR-based methods to detect a Piedmontese cattle point mutation in the Myostatin gene. AB - Despite many recent advances in single nucleotide polymorphism (SNP) genotyping technologies, there is still the need for methodologies with a reasonable throughput. In this study, we compared three PCR-based methods for SNP detection: (1) a conventional PCR-based allele detection system with fluorescent genotyping technology, (2) a SNaPshot methodology by single nucleotide primer extension and, (3) a real-time PCR-based method by allele-specific minor groove-binder probes. These three methodologies were used to analyze 104 meat samples of a particular Italian cattle breed known for producing excellent quality meat and for a characteristic increased development of muscle mass, caused by a point mutation (C313Y) in the Myostatin gene. The analysis revealed 98 samples to be homozygous (mh/mh) and five to be heterozygous (mh/+) for the mutation whereas one sample resulted to be homozygous for the wild type (+/+). The results obtained with the three different assays were consistent. Overall, all three methodologies proved to be efficient for allelic discrimination studies; however, real-time PCR was faster and allowed to genotype up to 96 samples in a single step, minimizing the number of steps required for samples manipulation. PMID- 22444763 TI - Molecular cloning and polymorphism of the porcine H2AFZ gene. AB - H2A histone family, member Z (H2A.Z) is required for early mammalian development. In the present study, the 932 bp of full-length cDNA encoding a 128 amino-acid protein and the sequences of intron 2 to 4 of the porcine H2A histone family, member Z (pH2AFZ) gene were obtained. By comparative sequencing of pH2AFZ gene in Large White and Meishan pigs, a 4 bp deletion/insertion in intron 2 was detected and a PCR-Bsu15I-RFLP was established to detect this variation. In DIV (4th Dam line of Chinese lean-type new lines) pigs, the first-parity females with AA genotype had fewer piglets born alive (-2.64 and -1.83 piglets per litter) than those with AB (P < 0.01) and BB (P < 0.05) genotype. The additive allelic and dominance effect were estimated to be 0.92 (P < 0.05) and -0.87 piglets per litter (P < 0.01) for number of piglets born alive, respectively. This result suggests that the pH2AFZ gene might be a good candidate gene of litter-size trait and provides some marker information for marker-assisted selection. PMID- 22444764 TI - Genetics of crossbred sow longevity. AB - The aim of this study was to estimate genetic parameters for longevity from Swedish crossbred sows to investigate the possibilities of selecting for this trait. Data were collected from 16 commercial piglet-producing herds, on crossbred (Landrace * Yorkshire) sows farrowing in the period 1 January 2001 to 31 December 2004. The data set with records on 10 373 sows was split into two sets according to the breed of the sire, i.e. Landrace sires (LS) or Yorkshire sires (YS). Removal hazard during productive life (PL) was analysed with survival analysis, using a sire model. Stayability from first to second litter (STAY12), stayability from first to third litter (STAY13), length of productive life (LPL) and lifetime production (LTP) were analysed with linear models, using an animal model. Females after the worst sire had 1.7 times higher (progeny of LS) and 2.4 times higher (progeny of YS) risk of removal than females after the best sire. Heritability for PL was estimated at 0.06 (LS) and 0.12 (YS). The heritabilities for the linear longevity traits ranged from 0.03 to 0.08. Genetic correlations between the four linear longevity traits were all high and positive (0.6 to 1.0), as were the phenotypic correlations (0.5 to 0.8). The correlations (Spearman rank) between the sire's estimated breeding values for all the five longevity traits were all significant (P < 0.001) and moderate to strong in both data sets. Estimated breeding value (EBV) correlations between the five longevity traits and traits included in the present Swedish breeding evaluation (Quality Genetics (QG)) were significant in a few cases. Significant and favourable EBV correlations were found between age at first farrowing and both STAY12 and STAY13 (-0.20 and -0.31), as well as between litter weight at 3 weeks and LPL and LTP (0.13 to 0.20). Significant and unfavourable EBV correlations were found between age at 100 kg and STAY12 (0.32), as well as between the exterior conformation score from testing station and PL (-0.20). The level of the estimated heritabilities for longevity indicates that genetic improvement of sow longevity would be possible. However, overall, there was no strong indirect selection for sow longevity with the current Swedish breeding evaluation (QG). PMID- 22444765 TI - Intake, growth and carcass traits in male progeny of sires differing in genetic merit for beef production. AB - Validation of economic indexes under a controlled experimental environment, can aid in their acceptance and use as breeding tools to increase herd profitability. The objective of this study was to compare intake, growth and carcass traits in bull and steer progeny of high and low ranking sires, for genetic merit in an economic index. The Beef Carcass Index (BCI; expressed in euro (?) and based on weaning weight, feed intake, carcass weight, carcass conformation and fat scores) was generated by the Irish Cattle Breeding Federation as a tool to compare animals on genetic merit for the expected profitability of their progeny at slaughter. A total of 107 male suckler herd progeny, from 22 late-maturing 'continental' beef sires of high (n = 11) or low (n = 11) BCI were compared under either a bull or steer production system, and slaughtered at approximately 16 and 24 months of age, respectively. All progeny were purchased after weaning at approximately 6 to 8 months of age. Dry matter (DM) intake and live-weight gain in steer progeny offered grazed grass or grass silage alone, did not differ between the two genetic groups. Similarly, DM intake and feed efficiency did not differ between genetic groups during an ad libitum concentrate-finishing period on either production system. Carcasses of progeny of high BCI sires were 14 kg heavier (P < 0.05) than those of low BCI sires. In a series of regression analyses, increasing sire BCI resulted in increases in carcass weight (P < 0.01) and carcass conformation (P = 0.051) scores, and decreases in carcass fat (P < 0.001) scores, but had no effect on weaning weight or DM intake of the progeny. Each unit increase in sire expected progeny difference led to an increase in progeny weaning weight, DM intake, carcass weight, carcass conformation score and carcass fat score of 1.0 (s.e. = 0.53) kg, 1.1 (s.e. = 0.32) kg, 1.3 (s.e. = 0.31) kg, 0.9 (s.e. = 0.32; scale 1 to 15) and 1.0 (s.e. = 0.25; scale 1 to 15), respectively, none of which differed from the theoretical expectation of unity. The expected difference in profitability at slaughter between progeny of the high and low BCI sires was ?42, whereas the observed phenotypic profit differential of the progeny was ?53 in favour of the high BCI sires. Results from this study indicate that the BCI is a useful tool in the selection of genetically superior sires, and that actual progeny performance under the conditions of this study is within expectations for both bull and steer beef production systems. PMID- 22444766 TI - The stimulatory effect of the organic sulfur supplement, mercaptopropane sulfonic acid on cellulolytic rumen microorganisms and microbial protein synthesis in cattle fed low sulfur roughages. AB - Two metabolism trials (experiments 1 and 2) were conducted to examine the effect of the organic S compound, sodium 3-mercapto-1-propane sulfonic acid (MPS) on feed intake, fiber digestibility, rumen fermentation and abundance of cellulolytic rumen microorganisms in cattle fed low S (<0.11%) roughages. Urea was provided in all treatments to compensate for the N deficiency (<0.6%) in the roughages. In experiment 1, steers (333 +/- 9.5 kg liveweight) were fed Angleton grass (Dicanthium aristatum) supplemented with S in equivalent amounts as either MPS (6.0 g/day) or sodium sulfate (9.56 g/day). Supplementation of Angelton grass with either sulfate or MPS resulted in an apparent increase in flow of rumen microbial protein from the rumen. Sulfur supplementation did not significantly change whole tract dry matter digestibility or intake, even though sulfate and MPS supplementation was associated with an increase in the relative abundance of the fibrolytic bacteria Fibrobacter succinogenes and anaerobic rumen fungi. Ruminal sulfide levels were significantly higher in the sulfate treatment, which indicated that the bioavailability of the two S atoms in the MPS molecule may be low in the rumen. Based on this observation, experiment 2 was conducted in which twice the amount of S was provided in the form of MPS (8.0 g/day) compared with sodium sulfate (6.6 g/day) to heifers (275 +/- 9 kg liveweight) fed rice straw. Supplementation with MPS compared with sulfate in experiment 2 resulted in an increase in concentration of total volatile fatty acids, and ammonia utilization without a change in feed intake or whole tract fiber digestibility even though S and N were above requirement for growing cattle in both these treatment groups. In conclusion, supplementation of an S deficient low-quality roughage diet with either MPS or sodium sulfate, in conjunction with urea N, improved rumen fermentation, which was reflected in an increase in urinary purine excretion. However, MPS appeared to have a greater effect on stimulating short-chain fatty acid production and ammonia utilization when provided at higher concentrations than sulfate. Thus, the metabolism of MPS in the rumen needs to be investigated further in comparison with inorganic forms of S as it may prove to be more effective in stimulating fermentation of roughage diets. PMID- 22444767 TI - Effects of capric acid on rumen methanogenesis and biohydrogenation of linoleic and alpha-linolenic acid. AB - Capric acid (C10:0), a medium chain fatty acid, was evaluated for its anti methanogenic activity and its potential to modify the rumen biohydrogenation of linoleic (C18:2n-6) and alpha-linolenic acids (C18:3n-3). A standard dairy concentrate (0.5 g), supplemented with sunflower oil (10 mg) and linseed oil (10 mg) and increasing doses of capric acid (0, 10, 20 and 30 mg), was incubated with mixed rumen contents and buffer (1 : 4 v/v) for 24 h. The methane inhibitory effect of capric acid was more pronounced at the highest (30 mg) dose compared to the medium (20 mg) (-85% v. -34%), whereas the lower dose (10 mg) did not reduce rumen methanogenesis. A 23% decrease in total short-chain fatty acid (SCFA) production was observed, accompanied by shifts towards increased butyrate at 20 mg and increased propionate at 30 mg of capric acid (P < 0.001). Capric acid linearly decreased the extent of biohydrogenation of C18:2n-6 and C18:3n-3, by up to 60% and 86%, respectively. This reduction was partially due to a lower extent of lipolysis when capric acid was supplemented. Capric acid at 20 and 30 mg completely inhibited the production of C18:0 (P < 0.001), resulting in an accumulation of biohydrogenation intermediates, mainly C18:1t10 + t11 and C18:2t11c15. In contrast to effects on rumen fermentation (methane production and proportions of SCFA), 30 mg of capric acid did not induce major changes in rumen biohydrogenation as compared to the medium (20 mg) dose. This study revealed the dual action of capric acid, being inhibitory to both methane production and biohydrogenation of C18:2n-6 and C18:3n-3. PMID- 22444768 TI - Divergent modulation of swine ileal microbiota by formic acid and methionine hydroxy analogue-free acid. AB - Management of intestinal microbiota of monogastric animals has increased in importance since the ban of growth promoting antibiotics in many countries. Organic acids have been used as alternatives to antibiotics by many feed manufacturers. Regardless of the wide usage, the effect, dose response and mode of action of acids on intestinal microbes is poorly understood. In this study, we investigated the effects of dietary supplementation of three commonly used products, namely formic acid (FA) (90%), dl-methionine (DLM) (99%) and liquid methionine hydroxy analogue-free acid (88%), on ileal microbiota of pigs. Laboratory simulation system, mimicking swine ileum, was used to study the products at various concentrations and combinations. Furthermore, selected combinations were tested in a piglet trial to confirm the findings made in in vitro studies. FA turned out to have a dual effect on ileal microbiota. At concentrations below 0.5%, it significantly stimulated bacteria, but at higher inclusion rates it was highly inhibitory. This finding, which was consistent in in vitro and in vivo studies, implies that reducing the dose of FA does not lead to a diluted inhibitory effect, but in fact, an opposite, stimulatory effect on intestinal microbiota. It is highly important that feed compounders acknowledge this finding. Unlike FA, the inhibitory effect of methionine hydroxy analogue on ileal bacteria was linearly dose dependent and significant at inclusion levels above 0.2%, in vitro. Partial replacement of methionine hydroxy analogue by FA, or FA by methionine hydroxy analogue, led to an unpredictable outcome due to the dual effects of FA; e.g., a minor inclusion of added FA changed the inhibitory effect of methionine hydroxy analogue into microbial stimulation by FA. Inhibition of ileal microbiota by methionine hydroxy analogue was detected only in in vitro studies, suggesting that intact methionine hydroxy analogue may not have reached the ileum, in live animals. Therefore, if the target is to ensure the inhibitory effect of FA, the FA level in feed should be kept above 0.6%, and not reduced, if methionine hydroxy analogue is used as a methionine source instead of DLM. DLM was totally inert with regard to bacterial growth and metabolism, both in vitro and in vivo. The results of these studies reveal the importance of knowing how each acid product works. Inconsistent results in animal trials may have been partly due to quadratic dose-response effects of products, and unpredictable product combination effects. PMID- 22444769 TI - Impairments in pyridoxine-dependent sulphur amino acid metabolism are highly sensitive to the degree of vitamin B6 deficiency and repletion in the pig. AB - The objectives of the current study included the characterization of the temporal changes in indices of sulphur amino acid metabolism in piglets in response to vitamin B6 deficiency and repletion with graded levels of pyridoxine hydrochloride. In Experiment 1, 12 piglets (average initial weight = 5.3 kg; n = 6 per group) were fed a semi-purified diet containing either 0 (deficiency group) or 3 mg (control group) pyridoxine.HCl/kg diet, using a pair-feeding design, for 6 weeks. Piglets consuming vitamin B6-deficient diets exhibited decreased average daily gains on the 4th week and feed conversion efficiency from the 4th week until the end of the trial (P < 0.05). Plasma pyridoxal-5'-phosphate (PLP), in pigs consuming vitamin B6-deficient diets, was significantly lower than controls throughout the experiment (P < 0.01), reaching a nadir of 14% of the control animals' value by the end of the trial. Indices of sulphur amino acid metabolism, including activities of hepatic cystathionine-beta-synthase (CBS), cystathionine gamma-lyase (CGL) and serine hydroxymethyltransferase, as well as hepatic-free cysteine concentrations were markedly decreased after 6 weeks of B6 deficiency (P < 0.05). Total hepatic mRNA expressions for CBS and CGL were not affected. Concurrently, hepatic-free homocysteine concentrations increased by more than eight-fold (P < 0.01) at the end of the trial. An examination of plasma total homocysteine and cysteine concentrations revealed significant (P < 0.05) differences between treatments, with evidence of an abrupt shift in concentrations at 3 weeks post-initiation of dietary treatments (>25-fold increase in homocysteine; halving of cysteine values). At the end of Experiment 1, vitamin B6 deficiency significantly increased plasma methionine and serine levels, but decreased plasma glycine concentrations (P < 0.05). In Experiment 2, 20 pigs of 14 days old (initial BW = 5.0 kg) were subjected to a 4-week vitamin B6 depletion protocol, based on results obtained in Experiment 1. After the depletion period and assessment of baseline status (four pigs), remaining pigs were allocated to one of four dietary vitamin B6 repletion treatments: 0.75, 1.5, 2.25 and 3 mg/kg diet as pyridoxine.HCl (n = 4 per level) for 14 days. Significant dose-dependent increases in plasma PLP and cysteine, and decreases in homocysteine were observed, and these were sensitive to the duration of repletion. In conclusion, data from the current studies support the use of both plasma PLP and homocysteine as sensitive indices of vitamin B6 status in the pig. Additionally, the observed patterns of responses in vitamin B6-sensitive metabolites are supportive of an inclusion level of 2.25 mg/kg diet, as pyridoxine.HCl, in diets for young pigs. PMID- 22444770 TI - Wool fibre crimp is determined by mitotic asymmetry and position of final keratinisation and not ortho- and para-cortical cell segmentation. AB - Crimp, a distinguishing feature of sheep fibres, significantly affects wool value, processing and final fabric attributes. Several explanations for fibre bending have been proposed. Most concentrate on relative differences in the physicochemical properties of the cortical cells, which comprise the bulk of the fibre. However, the associations between cortical properties and fibre crimp are not consistent and may not reflect the underlying causation of fibre curvature (FC). We have formulated a mechanistic model in which fibre shape is dictated primarily by the degree of asymmetry in cell supply from the follicle bulb, and the point at which keratinisation is completed within the follicle. If this hypothesis is correct, one would anticipate that most variations in fibre crimp would be accounted for by quantitative differences in both the degree of mitotic asymmetry in follicle bulbs and the distance from the bulb to the point at which keratinisation is completed. To test this hypothesis, we took skin biopsies from Merino sheep from sites producing wool differing widely in fibre crimp frequency and FC. Mitotic asymmetry in follicle bulbs was measured using a DNA-labelling technique and the site of final keratinisation was defined by picric acid staining of the fibre. The proportion of para- to ortho-cortical cell area was determined in the cross-sections of fibres within biopsy samples. Mitotic asymmetry in the follicle bulb accounted for 0.64 (P < 0.0001) of the total variance in objectively measured FC, while the point of final keratinisation of the fibre accounted for an additional 0.05 (P < 0.05) of the variance. There was no association between ortho- to para-cortical cell ratio and FC. FC was positively associated with a subjective follicle curvature score (P < 0.01). We conclude that fibre crimp is caused predominantly by asymmetric cell division in follicles that are highly curved. Differential pressures exerted by the subsequent asymmetric cell supply and cell hardening in the lower follicle cause fibre bending. The extent of bending is then modulated by the point at which keratinisation is completed; later hardening means the fibre remains pliable for longer, thereby reducing the pressure differential and reducing fibre bending. This means that even highly asymmetric follicles may produce a straight fibre if keratinisation is sufficiently delayed, as is the case in deficiencies of zinc and copper, or when keratinisation is perturbed by transgenesis. The model presented here can account for the many variations in fibre shape found in mammals. PMID- 22444771 TI - Insulin-like growth factor-I feedback regulation of growth hormone and luteinizing hormone secretion in the pig: evidence for a pituitary site of action. AB - Three experiments (EXP) were conducted to determine the role of insulin-like growth factor-I (IGF-I) in the control of growth hormone (GH) and LH secretion. In EXP I, prepuberal gilts, 65 +/- 6 kg body weight and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25 MUg (n = 4) or 75 MUg (n = 4) IGF-I and jugular blood samples were collected. In EXP II, anterior pituitary cells in culture collected from 150-day-old prepuberal gilts (n = 6) were challenged with 0.1, 10 or 1000 nM [Ala15]-h growth hormone-releasing hormone-(1-29)NH2 (GHRH), or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 1000 nM GHRH. Secreted GH was measured at 4 and 24 h after treatment. In EXP III, anterior pituitary cells in culture collected from 150-day old barrows (n = 5) were challenged with 10, 100 or 1000 nM gonadotropin releasing hormone (GnRH) or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 100 nM GnRH. Secreted LH was measured at 4 h after treatment. In EXP I, serum GH and LH concentrations were unaffected by ICV IGF-I treatment. In EXP II, relative to control all doses of GHRH increased (P < 0.01) GH secretion. Only 1, 10, 30 nM IGF-I enhanced (P < 0.02) basal GH secretion at 4 h, whereas by 24 h all doses except for 30 nM IGF-I suppressed (P < 0.02) basal GH secretion compared to control wells. All doses of IGF-I in combination with 1000 nM GHRH increased (P < 0.04) the GH response to GHRH compared to GHRH alone at 4 h, whereas by 24 h all doses of IGF-I suppressed (P < 0.04) the GH response to GHRH. In EXP III, all doses of IGF-I increased (P < 0.01) basal LH levels while the LH response to GnRH was unaffected by IGF-I (P > 0.1). In conclusion, under these experimental conditions the results suggest that the pituitary is the putative site for IGF-I modulation of GH and LH secretion. Further examination of the role of IGF-I on GH and LH secretion is needed to understand the inhibitory and stimulatory action of IGF-I on GH and LH secretion. PMID- 22444772 TI - Autoimmunization of ewes against pregnancy-associated glycoproteins does not interfere with the establishment and maintenance of pregnancy. AB - Pregnancy-associated glycoproteins (PAGs) are a large grouping of placental proteins that belong to the aspartic peptidase gene family. Although useful to detect pregnancy in ruminant species, the function of these molecules is unclear. Several PAGs expressed by trophoblast binucleate cells can enter the maternal circulation, suggesting that they could have a systemic role in altering maternal physiology. The objective of this work was to examine whether these circulating placental antigens were important in pregnancy by actively immunizing ewes against them. PAGs were purified by pepstatin-affinity chromatography and conjugated to the immunogenic protein, keyhole limpet hemocyanin (KLH). Ewes were immunized with PAG-KLH conjugate (n = 22) or with KLH alone (n = 9), and bred to intact rams. Blood samples, collected on Day 0 (day of estrus), Day 10, Days 15 to 25 and weekly throughout pregnancy, were analyzed for PAG by an ELISA. On Day 30, pregnancy was confirmed by ultrasound. Ewes immunized against PAG-KLH produced a range of reactive anti-PAG titers, whereas all immunized ewes had high anti-KLH immunoreactivity. PAGs became detectable in the anti-KLH (control) ewes at Day 21.6 +/- 2.2 of pregnancy. Those ewes immunized against PAGs (n = 7), that had very low immunoreactivity toward PAGs, had measurable PAG by Day 22.9 +/- 1.3, and their PAG serum profiles throughout pregnancy did not differ from the controls. Those exhibiting moderate to high anti-PAG immunoreactivity (n = 15), had significantly lower PAG concentrations than controls, with antigen not becoming detectable until Day 48.1 +/- 15.6. The decrease in circulating PAG in the immunized animals did not correlate with changes in pregnancy rates, lamb number or lamb birth weight. These results suggest that while PAGs may play a role in maintaining pregnancy, their major contribution is likely to be at the fetal-maternal interface. Their actions at extra-placental sites are presumably of more secondary importance. PMID- 22444773 TI - Insulin regulation of amino-acid metabolism in the mammary gland of sheep in early lactation and fed fresh forage. AB - Insulin plays an important role in regulating the partitioning of nutrients to the mammary gland, particularly in lactating ruminants fed concentrate-based diets. There is evidence that the nutritional status of the animals might also affect their response to insulin. This is largely untested in early lactating ruminants fed fresh forage. To investigate nutritional effects on insulin response, 12 lactating sheep, housed indoors, were allocated to one of two treatment groups (hyperinsulinaemic euglycaemic clamp (HEC) or control) in a randomised block design and fed perennial ryegrass (Lolium perenne)/white clover (Trifolium repens) pasture. Mammary amino acid (AA) net uptake from plasma and utilisation for milk protein synthesis was measured during the 4th day of the HEC using arterio-venous concentration differences, and 1-13C-leucine was used to estimate whole body and mammary gland leucine kinetics. There was no change in feed intake, milk protein output and mammary blood flow during the HEC (P > 0.1). The HEC decreased (P < 0.1) the arterial concentrations of all essential AA (EAA) except histidine. The mammary net uptake of some EAA (isoleucine, leucine, methionine and phenylalanine) was reduced by the HEC (P < 0.1). Leucine oxidation in the mammary gland was not altered during the HEC (P > 0.1) but mammary protein synthesis was reduced by the HEC (P < 0.05). These results show that sheep mammary gland can adapt to changing AA precursor supply to maintain milk protein production during early lactation, when fed fresh forage. How this occurs remains unclear, and this area deserves further study. PMID- 22444774 TI - Performance and nursing behaviour of beef cows with different types of calf management. AB - The aim of this experiment was to evaluate the effect of calf management during lactation on dam performance and nursing behaviour. Thirty-six multiparous beef cows (aged 7.5 +/- 0.52 years) of Parda de Montana breed (mean live-weight (LW) at calving 566 +/- 9.3 kg) with a moderate body condition (mean 2.6 +/- 0.02 on a 1 to 5 scale), were assigned to three nursing frequencies from the day after parturition: Once-daily restricted nursing during a 30 min period at 0800 h (RESTR1), twice-daily restricted nursing during two 30 min periods at 0800 and 1530 h (RESTR2) and ad libitum nursing (ADLIB). Cows were fed throughout the experiment 80 MJ/day of metabolizable energy. Cow-calf behaviour recordings were performed on days 30 and 66 of lactation in each treatment. Blood samples were collected fortnightly to analyse non-esterified fatty acids (NEFA) by an enzymatic colorimetric method, and twice weekly to determine progesterone concentrations by radioimmunoassay. Cow LW losses (P < 0.05), fat-corrected milk yield (P < 0.05) and calf average daily gain (P < 0.01) during lactation were higher in ADLIB. Nursing frequency affected the mean serum concentrations of NEFA, being lower in RESTR1 (0.18 mmol/l; P < 0.05) than in RESTR2 and ADLIB cows (0.29 and 0.25 mmol/l, respectively). The highest occurrence of nursing bouts was observed in ADLIB, leading to greater nursing duration per day (not statistically compared) in this treatment (58.8 +/- 5.84 min) than in their restricted nursing counterparts (22.2 +/- 1.42 and 34.3 +/- 1.16 min, in RESTR1 and RESTR2, respectively). The nursing system did not affect the proportion of cows cycling within 3 months post partum (58%, 46% and 55% in RESTR1, RESTR2 and ADLIB, respectively; P > 0.05). The majority of cows in all treatments showed a short oestrus cycle after first ovulation (75%, 100% and 83%; P > 0.05). In conclusion, the post-partum luteal function in cows managed under continuous access to calves was similar to restricted nursing frequencies, despite the greater suckling intensity of the formers. Restricting calf presence does not enhance the resumption of ovarian activity when suckler cows are managed in moderate nutritional conditions. PMID- 22444775 TI - The effects of allowance and frequency of allocation of deferred herbage, and grass silage feed value, when offered to ewes in mid-gestation on ewe and lamb performance and subsequent herbage yield. AB - The effects of (i) herbage allowance, (ii) frequency of allocation and (iii) grass silage feed value on ewe and lamb performance were studied in mid-gestation ewes. Furthermore, the effects of (i) herbage allowance, (ii) frequency of allocation and (iii) grazing date and their interactions on subsequent herbage yield and feed value were also evaluated. Swards, which had a cut of silage removed on 6 September, received fertiliser nitrogen (34 kg/ha) for extended (deferred) grazing between 6 December and 1 February. Two grass silages differing in feed value were ensiled either precision chopped or in big bales from predominantly perennial ryegrass swards, respectively. In experiment 1, a completely randomised study involving 120 crossbred mid-gestation ewes (Belclare * Scottish Blackface) that had been mated in October was undertaken to evaluate the effects of extended grazed herbage allowance (1.0 and 1.8 kg dry matter (DM)/day), frequency of herbage allocation (daily and twice weekly) and grass silage feed value (low and medium) on ewe and subsequent lamb performance. The six diets were offered from days 63 to 120 of gestation. From day 120 of gestation to parturition all ewes were housed and offered the medium feed value silage ad libitum. All ewes received 19 kg concentrate prior to lambing. Increasing herbage allowance increased forage intake (P < 0.05), lamb birth weight (P < 0.01), weaning weight (P < 0.05) and growth rate from birth to weaning (P < 0.05), decreased herbage utilisation (P < 0.05) and tended to increase ewe condition score at lambing (P = 0.06). Frequency of herbage allocation or grass silage feed value did not alter (P > 0.05) ewe or subsequent lamb performance. In experiment 2, the effect of extended grazed herbage allowance (1.0 and 1.8 kg DM/ewe daily), frequency of allocation (daily and twice weekly) and grazing date (6 to 12 December, 27 December to 3 January and 17 to 23 January) on herbage yield at two harvest dates (27 April and 25 May) was examined in a split plot design study consisting of 72 plots. Delaying grazing date decreased herbage yield (P < 0.01) whilst delaying harvest date increased herbage yield (P < 0.05). Frequency of herbage allocation did not alter (P > 0.05) subsequent herbage yield. It is concluded that for ewes in mid-gestation 1.0 kg of low feed value silage DM had the same feed value, as determined by weaned lamb weight, as 1.3 kg herbage DM allowance. Each 1-day delay in grazing date reduced herbage DM yield by 54.2 kg/ha. PMID- 22444776 TI - Effect of different feeding strategies on lactation performance of Holstein and Normande dairy cows. AB - The dairy farming systems of Western Europe are based on a simple feeding system composed of grazed and preserved grass, maize silage and concentrates in variable proportions. There is, nevertheless, a great diversity of feeding strategies between dairy farms. Over 5 years, we studied the direct and delayed effects of four feeding strategies on the lactation and reproduction performances of Holstein and Normande dairy cows. The four feeding strategies (denoted Hh, Hl, Lh and Ll) correspond to two total mixed rations applied in winter from calving to turnout (maize silage with 30% concentrate or grass silage with 15% concentrate), which were subsequently crossed with two levels of concentrate supplementation at grazing to 210 days. Each year, 72 dairy cows managed in grouped winter calving were assigned to the four strategies. Finally, the results of 325 lactations and 295 inseminated cows were analysed. The four strategies resulted in considerable variation in nutrient intake and, in particular, in differences in concentrates consumed, with values of 1407, 1026, 773 and 392 kg dry matter per cow for strategies Hh, Lh, Hl and Ll, respectively. Total milk production (7567, 7015, 6720 and 6238 kg per cow for treatments Hh, Lh, Hl and Ll, respectively), milk fat content (39.0, 37.1, 40.3 and 38.5 g/kg, respectively), milk protein content (33.0, 31.8, 33.1 and 31.6 g/kg, respectively), and the character of the lactation and body condition curves were all highly sensitive to the strategies applied. While no significant interaction was detected on total lactation yield, the Holstein cows reacted more dramatically to each dietary change at each period, compared with the Normande cows. Winter feeding did not affect the production of milk at pasture whereas, at pasture, the milk from the cows of the H groups in winter was higher in milk fat and protein content. Reproduction performance was unaffected by feeding strategy. The Holstein cows, well fed and producing the most milk (Hh and Hb), had the lowest rate of success at first artificial inseminations (21.5%). The dual-purpose Normande cows had a pregnancy rate 10 points higher than Holstein cows. This comparison of strongly contrasting feeding strategies confirms the immediate reactivity of dairy cows (in terms of milk performance and body condition) to variations of nutritive intake throughout lactation, with a weak carryover effect from feeding levels early in lactation. In contrast, reproduction performance was less sensitive to variation in nutrient supply. PMID- 22444777 TI - Influence of carcass suspension on meat quality of Charolais heifers from two sustainable feeding regimes. AB - This study investigated the effects of pelvic suspension on the meat quality of M. longissimus dorsi, M. semimembranosus and M. adductor from 35 heifers with at least 75% Charolais breeding. Two-thirds of the heifers were slaughtered directly from pasture at 18 months of age and one-third was finished indoors and slaughtered at 22 months. After slaughter and electrical stimulation one side of each carcass was re-suspended by either the achilles tendon or the pelvic bone. Longissimus muscles were aged 7 or 14 days and were then evaluated for drip loss, colour, shear force and sensory analysis. As compared to 18-month-old heifers, 22 month-old heifers were heavier, more muscular and fatter (P < 0.05). Intramuscular fat content increased with slaughter age (P < 0.003). Pelvic suspension reduced longissimus peak force values, total energy, pH and thawing losses (P < 0.05) in heifers slaughtered at 18 months. Semimembranosus showed the largest response to pelvic suspension with significantly lower peak force and total energy values. Finishing for 4 months did not affect longissimus shear forces. Achilles-suspended samples had lower shear force values after 14 v. 7 days of ageing. Pelvic-suspended samples aged 7 days were, however, just as tender as those aged 14 days. Sensory analysis of longissimus samples aged 14 days showed that samples from pelvic-suspended sides had higher tenderness, lower bite resistance, more meaty taste and less visible marbling compared with samples from achilles-suspended carcasses. PMID- 22444778 TI - Drinking water is a significant predictor of Blastocystis infection among rural Malaysian primary schoolchildren. AB - Blastocystis infection has a worldwide distribution especially among the disadvantaged population and immunocompromised subjects. This study was carried out to determine the prevalence and the association of Blastocystis infection with the socio-economic characteristics among 300 primary schoolchildren, living in rural communities in Lipis and Raub districts of Pahang state, Malaysia. Stool samples were collected and examined for the presence of Blastocystis using direct smear microscopy after in vitro cultivation in Jones' medium. The overall prevalence of Blastocystis infection was found to be as high as 25.7%. The prevalence was significantly higher among children with gastrointestinal symptoms as compared to asymptomatic children (x2 =4.246; P=0.039). Univariate and multivariate analyses showed that absence of a piped water supply (OR=3.13; 95% CI=1.78, 5.46; P<0.001) and low levels of mothers' education (OR=3.41; 95% CI=1.62, 7.18; P<0.01) were the significant predictors of Blastocystis infection. In conclusion, Blastocystis is prevalent among rural children and the important factors that determine the infection were the sources of drinking water and mothers' educational level. Interventions with provision of clean water supply and health education especially to mothers are required. PMID- 22444779 TI - Influence of obesity indices, metabolic parameters and age on cardiac autonomic function in abdominally obese men. AB - Heart rate variability (HRV) is affected by age, hyperglycemia and accumulation of body fat. This study compares the predictive value of four measurements of adiposity/obesity on HRV and investigates the specific role of age, metabolic contributors and degree/distribution of fat in HRV alterations. The sample consisted of 97 non-diabetic and non-medicated men with features of the metabolic syndrome (50+/-8 years of age, body mass index [BMI] 31+/-3 kg/m(2), waist circumference [WC] 107+/-9 cm, triglycerides 2.3+/-0.7 mmol/L, fasting glucose 6.0+/-0.5 mmol/L, insulin 156+/-71 pmol/L; mean+/-SD). WC, BMI, percent body fat (% fat, from dual energy X-ray absorptiometry) and visceral adipose tissue volume (VAT, from computed tomography) were used as measures of adiposity/obesity. HRV measures were obtained from 24-h, day- and night-time segments of Holter recordings. BMI presented no independent association with HRV. Percentage fat was the strongest obesity index to be associated with HRV: 24-h pNN50, rMSSD, HF and daytime pNN50, rMSSD, HF and LF (-0.27<=std beta<=-0.20, P<.05). VAT was associated with 24-h SDNN, LF (std beta=-0.25 and -0.20, P<.05, respectively) and daytime SDNN (std beta=-0.24, P<.05) while WC was associated with nighttime SDNN and SDANN (std beta=0.22 and 0.32, P<.05). In addition, age, fasting glucose, 2-h oral glucose tolerance test and triglycerides presented independent association with HRV. Adiposity/obesity measurements seem to be differently associated with HRV. An approach considering the combination of age, obesity and glucose metabolism factors could be helpful in the global cardiovascular risk management in abdominally obese men. PMID- 22444780 TI - Race-ethnic differences in adipokine levels: the Study of Women's Health Across the Nation (SWAN). AB - Differences in adipose tissue secretory profile, as measured by adipokine levels, may play a role in race-ethnic disparities in cardiovascular disease (CVD). We examined race-ethnic differences in adipokine levels in a group of mid-life Caucasian, African American (AA), Chinese and Japanese women, after accounting for adiposity. Data on 1876 women from the Study of Women's Health Across the Nation were analyzed. In multivariable adjustment, including total fat mass, differences in total and high molecular weight (HMW) adiponectin, leptin and soluble leptin receptor (sOB-R) levels were examined. Despite intermediate levels of adiposity, Caucasian women had higher levels of both total and HMW adiponectin, when compared to both AA and Chinese and Japanese women. After multivariable adjustment, compared to Caucasian women, AA women had significantly lower total (beta: -3.40; 95% CI: -4.29, -2.52; P<.001) and HMW adiponectin (beta: -0.53; 95% CI: -0.64, -0.43; P<.001) levels, higher leptin levels (beta: 3.26; 95% CI: 1.36, 5.16; P<.001) and lower sOB-R levels (beta: -0.07; 95% CI: 0.11, -0.03; P<.001). Compared to Caucasian women, both Chinese and Japanese women had lower total (Chinese: beta: -5.50; 95% CI: -7.07, -3.93; P<.001; Japanese: beta: -5.48; 95% CI: -6.95, -4.02; P<.001) and HMW adiponectin (Chinese: beta: -0.57; 95% CI: -0.75, -0.38; P<.001; Japanese: beta: -0.61; 95% CI: -0.78, -0.44; P<.001) levels and lower sOB-R levels (Chinese: beta: -0.13; 95% CI: -0.20, -0.06; P<.001; Japanese: beta: -0.09; 95% CI: -0.15, -0.02; P=.008). Significant race-ethnic differences exist in circulating adipokines, even after accounting for adiposity. Further research is needed to explicitly determine if such differences contribute to known racial differences in CVD risk. PMID- 22444781 TI - A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health. AB - Marginal copper deficiency, which may affect cardiovascular disease risk, is proposed to occur in many adults in Western industrialized countries. The present study tested the hypothesis that in a group of USA adults, increased copper intake would alter readings for blood copper enzymes and markers relevant to cardiovascular disease risk. Healthy middle aged adults with moderately high cholesterol, were given either placebo or copper supplementation (2 mg copper/day as copper glycinate) for 8 weeks. Blood samples were taken before and after the 8 weeks. Copper, but not placebo, raised activities for two copper enzymes, erythrocyte superoxide dismutase 1 and plasma ceruloplasmin. In contrast, five cardiovascular health related plasma parameters were not changed significantly by copper: C-reactive protein, homocysteine, and cholesterol (total, LDL and HDL). However, changes in erythrocyte superoxide dismutase 1 correlated positively with changes in plasma HDL and negatively with plasma homocysteine. Also, copper lowered mean oxidized LDL values, a result that was statistically significant, but inconsistent. In this test population, increased copper intake raised copper enzyme activities, but did not consistently improve the cardiovascular health measures studied. PMID- 22444782 TI - Effect of aripiprazole 2 to 15 mg/d on health-related quality of life in the treatment of irritability associated with autistic disorder in children: a post hoc analysis of two controlled trials. AB - BACKGROUND: There are limited published data on the impact of treatment on the health-related quality of life (HRQOL) in individuals with autistic disorder. OBJECTIVE: The aim of this study was to evaluate the impact of aripiprazole on HRQOL in the treatment of irritability in pediatric patients (aged 6-17 years) with autistic disorder. METHODS: This post hoc analysis assessed data from two 8 week, double-blind, randomized, placebo-controlled studies that compared the efficacy of aripiprazole (fixed-dose study, 5, 10, and 15 mg/d; flexible-dose study, 2-15 mg/d) with placebo in the treatment of irritability associated with autistic disorder. HRQOL was assessed at baseline and week 8 using 3 Pediatric Quality of Life Inventory (PedsQLTM) scales. Clinically relevant improvement in HRQOL was determined using an accepted distribution-based criterion-1 standard error of measurement. RESULTS: In total, 316 patients were randomly assigned to receive treatment with aripiprazole (fixed-dose study, 166; flexible-dose study, 47) or placebo (fixed-dose study, 52; flexible-dose study, 51). Aripiprazole was associated with significantly greater improvement than placebo in PedsQL combined scales total score (difference, 7.8; 95% CI, 3.8-11.8; P < 0.001) and in 3 PedsQL scale scores (differences [95% CI]: Emotional Functioning, 7.8 [3.4-12.2]; Social Functioning, 6.2 [0.7-11.8]; Cognitive Functioning, 9.3 [3.8-14.9]; all, P < 0.05). Patients who received aripiprazole were significantly more likely than those who received placebo to have a clinically meaningful improvement on the combined-scales total score (odds ratio [OR] = 1.9; 95% CI, 1.0-3.3; P < 0.05), Emotional Functioning scale (OR = 2.2; 95% CI, 1.2-4.0; P < 0.05) and Social Functioning scale (OR = 2.2; 95% CI, 1.2-4.1; P < 0.05), and were significantly less likely to experience deterioration (OR: 0.3, 95% CI: 0.1-0.8; P < 0.05) when "Stable" was used as the reference group. CONCLUSIONS: The findings from the present post hoc analysis suggest that aripiprazole was associated with improved HRQOL, as assessed using 3 PedsQL scales, in pediatric patients with irritability associated with autistic disorder. PMID- 22444783 TI - Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. AB - BACKGROUND: Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti-tumor necrosis factor therapy. OBJECTIVE: The goal of this study was to summarize the efficacy and safety profile of TCZ. METHODS: A systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration >=6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire-Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZ's pharmacokinetics and pharmacodynamics. RESULTS: Ten published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (P < 0.001), ACR50 (P = 0.002), and ACR70 (P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti-tumor necrosis factor therapy (P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant modified Sharp score (85% had no progression) than the control group (67% had no progression) (P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo. CONCLUSION: The short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk-benefit profile of this agent. PMID- 22444784 TI - Dabigatran etexilate: an oral direct thrombin inhibitor for the management of thromboembolic disorders. AB - BACKGROUND: Until recently, warfarin was the only oral anticoagulant available in the United States. Its narrow therapeutic index, interpatient variability in dose response, and drug and food interactions make it difficult to use. Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor that was approved in the US and in Canada for the prevention of thromboembolic events in patients with atrial fibrillation (AF), as well as in Europe and Canada for the prevention of venous thromboembolism (VTE). OBJECTIVE: To discuss the role of DE for the prevention and treatment of VTE, as well as for the prevention of stroke in patients with AF. METHODS: Peer-reviewed clinical trials, review articles, and treatment guidelines were identified from MEDLINE and the Current Contents database (both 1966-February 15, 2012) using the search terms dabigatran, VTE, Afib, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost effectiveness. Citations from available articles were also reviewed for additional references. RESULTS: For VTE prophylaxis, DE 150 or 220 mg orally daily has demonstrated either superiority or noninferiority to subcutaneous enoxaparin once daily in most studies. However, one study failed to demonstrate noninferiority to subcutaneous enoxaparin dosed BID in the composite end point of VTE, and all-cause mortality. For VTE treatment, DE 150 mg BID orally was shown to be noninferior to warfarin in preventing recurrent events. For AF, DE 150 mg BID orally is superior to warfarin in the prevention of thromboembolism, whereas 110 mg BID is noninferior to warfarin. Pharmacoeconomic analyses performed in the United Kingdom and Ireland found that DE can be cost-saving compared with enoxaparin in the prevention of VTE. Adverse effects of DE reported in clinical studies include dyspepsia (12%-13%) and bleeding (minor bleeding: 6%-22%). CONCLUSIONS: DE exhibited a safety profile and efficacy comparable to enoxaparin for VTE prophylaxis; comparable safety profile and efficacy to warfarin for VTE treatment; and superiority (150 mg BID orally) in the prevention of stroke and systemic embolism compared with warfarin in patients with AF. The relative ease of oral administration, no need for routine monitoring, and lack of significant drug interactions, may favor use of DE over other anticoagulants. However, there is no antidote for DE currently available. PMID- 22444785 TI - Ceftaroline fosamil: a cephalosporin with activity against methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Ceftaroline is a cephalosporin with expanded gram-positive activity recently approved for clinical uses by the US Food and Drug Administration. OBJECTIVE: This article provides an overview of the in vitro and in vivo activities, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of ceftaroline. METHODS: Relevant information was identified through a search of PubMed (1990-April 2011), EMBASE (1990-April 2011), International Pharmaceutical Abstracts (1970-April 2011), and Google Scholar using the key words ceftaroline, PPI-0903, PPI-0903M, T-91825, and TAK 599. A review of the reference lists of identified articles, a search of the US Food and Drug Administration Web site, and posters and abstracts from scientific meetings yielded additional publications. RESULTS: In vitro, ceftaroline exhibits activity against most aerobic gram-positive isolates, common aerobic gram negative respiratory pathogens, and some gram-positive anaerobes. The MIC range for most Staphylococcus aureus isolates, including vancomycin-resistant strains was between <=0.008 and 4 MUg/mL. In Phase III studies (CANVAS 1 and CANVAS 2), ceftaroline was found to be noninferior to vancomycin + aztreonam for the treatment of complicated skin and skin-structure infections, with a clinical cure rate of 91.6% among clinically evaluable patients (ceftaroline versus vancomycin + aztreonam: difference, -1.1; 95% CI, -4.2 to 2.0; P = NS). Ceftaroline's efficacy has also been assessed for the treatment of community-acquired pneumonia in 2 Phase III studies (FOCUS 1 and FOCUS 2) and was equivalent to ceftriaxone, with cure rates of 84.3% and 77.7%, respectively, among clinically evaluable patients in the combined analysis (ceftaroline versus ceftriaxone: difference, 6.7; 95% CI, 1.6 to 11.8). The recommended dosage for patients 18 years and older is 600 mg IV every 12 hours. Dosage adjustment is necessary in patients with renal impairment (creatinine clearance <=50 mL/min). The pharmacokinetic properties of ceftaroline in patients with hepatic impairments are currently unavailable. Ceftaroline appeared to be well tolerated generally. The most frequently (>3%) reported adverse events were nausea, headaches, diarrhea, pruritus, rash, and insomnia; all were usually mild to moderate, self-limiting, and of little clinical significance. CONCLUSIONS: Ceftaroline is a cephalosporin with broad gram-positive activity, including Methicillin-resistant S aureus and vancomycin-resistant S aureus. Its gram-negative activity includes common respiratory pathogens and members of the Enterobacteriaceae. Clinical trials have reported that ceftaroline was noninferior to ceftriaxone, and vancomycin + aztreonam for the treatment of community-acquired pneumonia and complicated skin and skin-structure infections, respectively. PMID- 22444786 TI - Utilization patterns of stimulants in ADHD in the Medicaid population: a retrospective analysis of data from the Texas Medicaid program. AB - BACKGROUND: Some previously published research on treatment utilization patterns in patients with attention deficit/hyperactivity disorder (ADHD) has been focused on data from commercial health plans, whereas research in the Medicaid population is lacking. Thus, little is known about these utilization patterns in Medicaid populations, which typically have demographic and clinical characteristics that differ from those of employer-based groups. OBJECTIVES: The objectives of the present retrospective data analysis were to evaluate the associations of medication groups (categorized by stimulant type [methylphenidate or amphetamine] and duration of action [short-acting (SA) or long-acting (LA)]) with measures of stimulant utilization patterns (adherence, persistence, and switching) in children, adolescents, and adults with ADHD enrolled in the fee-for-service delivery model within the Texas Medicaid Program. METHODS: Texas Medicaid fee-for service claims data were analyzed retrospectively. Data from enrollees with ADHD (6-63 years) were included if patients were newly initiated on medication from January 2006 to September 2007, had >=1 medical claim with a code for ADHD, and had continuous Medicaid eligibility 6 months before and after treatment initiation. Adherence, persistence, and switching were compared by initial stimulant medication group (SA methylphenidate [SA-M], LA-M, SA amphetamine [SA A], and LA-A). Rates were compared overall and by age group (children, adolescents, and adults). Multivariate models were used to control for demographic, clinical, and utilization covariates. RESULTS: Of 15,055 eligible patients, mostly children, 71% were initiated on methylphenidate; 90% received LA formulations (LA-M, 65%; LA-A, 25%). Most children (66%) and adolescents (65%) were initiated on LA-M, followed by LA-A (23% and 29%, respectively). Among adults, 38% each were initiated on LA-M and LA-A. Overall adherence (measured using the days in possession ratio [DPR]) and persistence were significantly greater with the LA versus the SA formulations (mean DPR, 0.497-0.504 vs 0.407 0.418, respectively; mean persistence, 81 vs 66-67 days; both, P < 0.001), and the rates of switching were lower with the LA versus the SA formulations (12.3% 14% vs 27%-28%; P < 0.001). On multivariate analyses, the likelihoods of adherence and persistence were significantly greater with the LA formulations, and the likelihood of being switched was significantly greater with the SA formulations (P < 0.001). These analyses also showed that medication utilization was significantly related to demographic and clinical characteristics. CONCLUSION: Based on the findings from this retrospective analysis, ADHD treatment utilization patterns varied by formulation in this Texas Medicaid population. Persistence at 180 days was poor regardless of the stimulant used. Consideration of stimulant formulations and demographic characteristics in patients in whom long-term ADHD management is being initiated may assist in optimum utilization, perhaps leading to better symptom control and more efficient resource utilization. PMID- 22444787 TI - Network analysis of randomized controlled trials in multiple sclerosis. AB - BACKGROUND: The optimal treatment of multiple sclerosis (MS) is not yet well defined. OBJECTIVE: To estimate the relative effectiveness of treatments in MS, we performed a network of multiple-treatments meta-analysis of randomized controlled trials (RCTs) for relapsing MS using three main efficacy outcomes: relapse-free patients, patients without disease progression, and patients without magnetic resonance imaging progression. METHODS: We systematically searched PubMed and the Cochrane Central Register of Controlled Trials to identify English language articles with RCTs that compared pharmaceutical treatments using the terms multiple sclerosis and randomized controlled trial. All RCTs that involved patients with definite relapsing MS and provided data for calculating the odds ratios for the main outcomes were considered. First, comparative effectiveness relative to placebo was assessed using direct analysis. Then, each therapy was compared with interferon beta-1b (250 MUg)* in direct and indirect analyses. Effect sizes were estimated by applying a random-effects model. RESULTS: We identified 4165 titles; after screening, 109 articles were eligible for inclusion. In total, 26,828 patients were included. The network consisted of 145 treatments involving 59 direct comparisons with placebo and 8 direct comparisons with interferon beta-1b (250 MUg). Two treatments showed better response compared with placebo (direct analysis) for all three efficacy outcomes: natalizumab (300 mg)(?) and fingolimod (0.5 mg). In comparing treatments with interferon beta-1b (250 MUg), the network analysis revealed that no therapy shows better response for all 3 efficacy outcomes and alemtuzumab, 12 and 24 mg, have better response for 2 of the outcomes (relapse-free patients and patients without disease progression). CONCLUSIONS: Although some treatments seem to have better efficacy, the results should be interpreted with caution because the network was dominated by indirect comparisons. Data from the selected studies included in the network cannot be extrapolated beyond them. Large RCTs that make head-to-head comparisons between treatments are needed to draw safe conclusions for the optimal treatment of MS. PMID- 22444788 TI - An assessment of the association between carvedilol exposure and severe hypersensitivity reactions, angioedema, and anaphylactic reactions: a retrospective nested case-control analysis. AB - BACKGROUND: There is limited information in the literature regarding the risk of severe hypersensitivity reactions due to different beta-blocking agents. Most of the available information addresses the potential for increased severity of anaphylaxis or poor response to treatments among patients receiving beta-blocking agents. OBJECTIVE: The objective of this study was to estimate the incidence rates of severe hypersensitivity reactions (angioedema and anaphylactic reactions) for various beta-blockers and to examine the risk of severe hypersensitivity reactions in patients exposed to carvedilol extended-release compared with carvedilol and compared with other beta-blockers. METHODS: A case control analysis nested within a cohort of beta-blocker users in the LabRx Database was conducted. A case was defined as an incident hypersensitivity reaction of either anaphylactic shock (International Classification of Diseases, 9th Revision [ICD-9] code 995.0) or angioneurotic edema (ICD-9 code 995.1). Three controls were matched to each case. Patients were classified according to their beta-blocker exposure in the 30 day-period before the index date. Conditional logistic regression was used to calculate odds ratios and 95% CIs. RESULTS: A total of 1,810,487 beta-blocker users were identified; 7811 hypersensitivity cases and 23,433 controls were included in this analysis. The mean (SD) age of the cohort was 53 (14) years, and 49% were men. The overall incidence rates of severe hypersensitivity reactions among various beta-blockers categories were similar to that in the overall beta-blocker users cohort (2.40 per 1000 person years [95% CI, 2.35-2.45]). The odds ratios of severe hypersensitivity reaction for carvedilol extended-release compared with carvedilol and with other long acting beta-blockers were 0.86 (95% CI, 0.48-1.53) and 1.10 (95% CI, 0.90-1.35), respectively. CONCLUSIONS: This retrospective database analysis of mostly middle aged patients detected no statistically significant differences in the likelihood of severe hypersensitivity reactions among patients who received carvedilol extended-release versus carvedilol or other long-acting beta-blockers. PMID- 22444789 TI - Reduction in size of renal angiomyolipoma after treatment with everolimus in lung transplantation due to lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a rare disease characterized by abnormal proliferation of immature smooth muscle cells and cystic lung destruction, which determines the prognosis of the disease. The kidney angiomyolipomas are usually very common in this disease and are usually asymptomatic unless complications arise. In the absence of a curative treatment, recent publications show promising results in molecular therapy to prevent functional decline and to control the size of the angiomyolipomas. These therapies include mTOR complex inhibitors, especially sirolimus. We report a case of a patient diagnosed with LAM who underwent lung transplantation with reduction of renal angiomyolipoma size after treatment with the mTOR inhibitor everolimus. PMID- 22444790 TI - Cerclage for cervical shortening at fetoscopic laser photocoagulation in twin twin transfusion syndrome. AB - OBJECTIVE: The purpose of this study was to evaluate the benefit of cervical cerclage for cervical length <= 25 mm at the time of fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome. STUDY DESIGN: A multicenter, retrospective cohort study was conducted with 163 patients with a short cervix before FLP for twin-twin transfusion syndrome. Seventy-nine of the patients (48%) had cerclage placement at the surgeon's discretion. The outcome measures that were compared were gestational age at delivery and perinatal mortality rates for patients with cerclage and those who were treated conservatively. Outcomes were evaluated with the use of comparative statistics. RESULTS: There were no differences in the preoperative variables, except cerclage was performed more frequently for a cervical length of <= 15 mm (P < .001). There were no differences in the gestational age at delivery (28.8 +/- 5.4 vs 29.1 +/- 5.6 weeks with and without cerclage, respectively; P = .15); perinatal mortality rates were similar between the 2 groups. CONCLUSION: The benefit of cerclage for patients with short cervix before FLP remains questionable. PMID- 22444791 TI - Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth restricted infants: long-term outcomes of the DIGITAT trial. AB - OBJECTIVE: We sought to study long-term (neuro)developmental and behavioral outcome of pregnancies complicated by intrauterine growth restriction at term in relation to induction of labor or an expectant management. STUDY DESIGN: Parents of 2-year-old children included in the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) answered the Ages and Stages Questionnaire (ASQ) and Child Behavior Checklist (CBCL). RESULTS: We approached 582 (89.5%) of 650 parents. The response rate was 50%. Of these children, 27% had an abnormal score on the ASQ and 13% on the CBCL. Results of the ASQ and the CBCL for the 2 policies were comparable. Low birthweight, positive Morbidity Assessment Index score, and admission to intermediate care increased the risk of an abnormal outcome of the ASQ. This effect was not seen for the CBCL. CONCLUSION: In women with intrauterine growth restriction at term, neither a policy of induction of labor nor expectant management affect developmental and behavioral outcome when compared to expectant management. PMID- 22444792 TI - Virulence of mixed fungal infections in honey bee brood. AB - INTRODUCTION: Honey bees, Apis mellifera, have a diverse community of pathogens. Previous research has mostly focused on bacterial brood diseases of high virulence, but milder diseases caused by fungal pathogens have recently attracted more attention. This interest has been triggered by partial evidence that co infection with multiple pathogens has the potential to accelerate honey bee mortality. In the present study we tested whether co-infection with closely related fungal brood-pathogen species that are either specialists or non specialist results in higher host mortality than infections with a single specialist. We used a specially designed laboratory assay to expose honey bee larvae to controlled infections with spores of three Ascosphaera species: A. apis, the specialist pathogen that causes chalkbrood disease in honey bees, A. proliperda, a specialist pathogen that causes chalkbrood disease in solitary bees, and A. atra, a saprophytic fungus growing typically on pollen brood provision masses of solitary bees. RESULTS: We show for the first time that single infection with a pollen fungus A. atra may induce some mortality and that co-infection with A. atra and A. apis resulted in higher mortality of honey bees compared to single infections with A. apis. However, similar single and mixed infections with A. proliperda did not increase brood mortality. CONCLUSION: Our results show that co-infection with a closely related fungal species can either increase or have no effect on host mortality, depending on the identity of the second species. Together with other studies suggesting that multiple interacting pathogens may be contributing to worldwide honey bee health declines, our results highlight the importance of studying effects of multiple infections, even when all interacting species are not known to be specialist pathogens. PMID- 22444793 TI - Genetic evaluation for semen characteristics in a crossbreeding project involving Saudi and Spanish V-line rabbits. AB - Two parallel schemes of crosses were practised involving the Spanish maternal line called V-line (V) and Saudi Gabali (S) rabbits. The first scheme began by crossing Saudi Gabali bucks with V-line does to get the F1 cross (1/2S1/2V), then does of this F1 were backcrossed with bucks of V-line to get 3/4V1/4S, then the progenies of the backcross were inter se mated to get (3/4V1/4S)2, followed by two more generations of inter se mating of (3/4V1/4S)2 to get a new synthetic maternal line named Saudi 2. The second scheme began by crossing V-line bucks with Saudi does to get the F1 cross (1/2V1/2S), then does of this F1 cross were backcrossed with Saudi bucks to get 1/2S1/2V, then progeny of this backcross were inter se mated to get (3/4S1/4V)2, followed by two generations of inter se mating of (3/4S1/4V)2 to form a new synthetic paternal line named Saudi 3. A generalised least-square procedure was used to estimate differences between lines in direct and maternal additive effects, direct and maternal heterosis, and direct recombination losses. A total number of 2497 ejaculates of 642 bucks were evaluated for ejaculate volume (VE), pH of semen, sperm concentration (SC), percentage of motile spermatozoa (MS), percentage of spermatozoa with abnormal form (AS), percentage of dead spermatozoa (DS) and libido score (LS). The estimates of direct additive effect for DS (14.2%), SC (12.4%) and AS (12.0%) were moderate and favourable to Saudi rabbits. Maternal additive effects for VE (11.7%) were in favour of genes of V-line carried by the dams of bucks, while these estimates were in favour of Saudi genes for DS (18.6%), AS (13.2%), MS (10.8%) and SC (10.0%). Positive estimates of direct heterosis recorded for SC (13.5%), VE (10.6%) and MS (10.5%) and the negative estimates recorded for AS ( 21.5%) and DS (-20.3%) were moderate and well disposed to semen parameters of crossbred bucks. Positive estimates of maternal heterosis for VE (24.0%), MS (21.8%), SC (10.3%) and LS (10.2%) of bucks, and the negative estimates for percentage of DS (-14.7%) and AS (-9.6%) were also significantly favourable. Estimates of direct recombination losses for the majority of semen traits were always not significant. PMID- 22444794 TI - Estimation of genetic trends from 1977 to 1998 for farrowing characteristics in the French Large White breed using frozen semen. AB - The objective of the study was to estimate genetic trends from 1977 to 1998 in the French Large White (LW) breed for stillbirth and associated traits measured at farrowing using frozen semen. Two groups of pigs (G77 and G98) were obtained by inseminating LW sows with semen from LW boars born either in 1977 or in 1998. A second generation was produced by inter se mating in each group. Farrowing was thoroughly supervised through both direct observations and video recording all long farrowing on a total of 137 first- and second-parity litters produced by sows from this second generation (68 G77 and 69 G98 litters, respectively). Measurements included birth time, weight and birth characteristics (including orientation, presence of cyanosis or oedema, membrane obstruction, umbilical cord length/content) of each piglet, as well as sow traits (weight and backfat thickness, farrowing duration, litter size and within-litter variation of weights at birth). The data were analysed using linear or generalised linear mixed models, according to the definition of the trait (continuous or binary data). The importance of several effects to piglet probability of stillbirth was then quantified by computing the reduction of variance associated with the addition of each effect in the model. Litter size did not significantly differ in first parity, but was higher in G98 second-parity sows: the differences for global (including pre partum dead piglets) and total numbers of piglets born per litter were +2.3 +/- 1.1 and +1.3 +/- 0.6, respectively. G98 sows also had a higher number of stillbirths in both parities (+0.7 +/- 0.3 stillborn per litter). Piglets from G98 litters were heavier at birth (+130 +/- 40 g for birth weight adjusted for litter size), without any increase in within-litter heterogeneity of birth weight. No significant difference was detected between G77 and G88 groups for farrowing length and the distribution of time interval between piglet births. G98 stillborn piglets had longer and more often empty umbilical cords at birth. G98 piglets born alive also had more often umbilical nodes than G77 piglets. These characteristics were considered as indicators of increased farrowing difficulties and risk of hypoxia at birth in G98 pigs. Time of birth of each piglet, sow fatness at farrowing and time of first placenta expulsion were the main factors of variation of the piglet's probability of stillbirth. PMID- 22444795 TI - PCR-DGGE analysis reveals a distinct diversity in the bacterial population attached to the rumen epithelium. AB - Bacteria attached to the rumen epithelium (or epimural community) are not well characterised and their role in rumen functioning is not totally understood. There is just one published report of a clone library from one cow that suggests that this epimural community differs from the bacteria associated with the rumen digestive contents. However, this time-consuming approach is not adapted for examining microbial population changes in groups of animals. In in vivo studies, when samples from several animals have to be analysed simultaneously, a simpler technique has to be used. In this study, a genetic fingerprinting technique, polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE), was used to characterise the structure of the bacterial population attached to the rumen epithelium. This community was compared with that present in the solid and liquid phases of rumen content under two contrasting diets. Rumen samples were obtained from four forage-fed and four high-concentrate-fed (80 : 20, wheat grain : hay) 5-month-old lambs. After slaughter, samples from five epithelial sites and the solid and liquid digesta phases were taken for DNA extraction and analysis. Bacterial communities were profiled by PCR-DGGE using bacterial-specific 16S rDNA primers. Analysis of the fingerprint revealed that the epithelial community differed from those of rumen content in both diets. As expected, the nature of the feed influenced the bacterial communities from the solid and liquid rumen phases but no diet effect was observed in the rumen epithelial profiles suggesting a strong host effect on this bacterial population. Additionally, no differences were observed among the five epithelial sampling sites taken from each animal. The profile of the bacterial population attached to the rumen epithelium presented a high inter-animal variation, whether this difference has an influence in the function of this community remains to be determined. PMID- 22444796 TI - Ability of a commercial feed additive to modulate expression of innate immunity in sheep immunosuppressed with dexamethasone. AB - In the first study, we tested the ability of a commercial feed additive (OmniGen AF) to affect markers of innate immunity in immunosuppressed sheep and the ability of a pathogen challenge (mould) to affect the immune response to the additive. Treatments consisted of (1) control, (2) immunosuppressed with dexamethasone (DEX), (3) immunosuppressed plus the feed additive, (4) immunosuppressed plus Aspergillus fumigatus and (5) immunosuppressed, A. fumigatus and the additive. Animal health was monitored and indexes of innate immunity (neutrophil L-selectin and interleukin-1beta (IL-1beta)) were collected. DEX caused immunosuppression (i.e. reduced abundance of neutrophil L-selectin and IL-1beta). This immunosuppressive effect was countered by the provision of the additive in the ration. Provision of mould in the ration increased the ability of the additive to regulate markers of innate immune function. A second study was completed to re-assess the properties of the additive and other feed products. The study consisted of seven treatments: (1) immunosuppressed, (2) immunosuppressed with additive, (3) immunosuppressed with additive in pelleted form (low-temperature pellet) and (4) immunosuppressed with additive in a high temperature pellet. The remaining three treatments assessed abilities of three other additives to regulate markers of innate immune function. In this study, OmniGen-AF increased expression of neutrophil L-selectin abundance in immunosuppressed animals and this was unaffected by the pelleting temperature. None of the other additives affected markers of innate immunity. In these studies we discovered mechanisms by which a feed product may affect the immune function of ruminant livestock. The product countered DEX-dependent down-regulation of markers of innate immune function and its actions were enhanced by the presence of pathogen (mould) in the ration. PMID- 22444797 TI - Lipid composition of lactational diets influences the fatty acid profile of the progeny before and after suckling. AB - The purpose of the present study was to compare the influence of adding no or 8% fat of varying sources (coconut oil, fish oil, rapeseed oil and sunflower oil) to diets for sows 1 week prior to farrowing and during lactation on the composition of fatty acids in plasma and tissues of the progeny while sucking and 3 weeks after weaning from the sow. A control diet without supplemental fat and four diets supplemented with 8% of coconut oil, rapeseed oil, fish oil or sunflower oil were provided to lactating sows (n = 15), and during the post-weaning period the same weaner diet was provided to all piglets (n = 15 litters), which were housed litterwise. The dietary ratio of n-6:n-3 fatty acids of the maternal diets largely influenced the progeny, as the ratio varying from 1.2 (fish oil) to 12.2 (sunflower oil) in the sow milk was reflected in plasma and adipose tissues of the sucking progeny. The liver showed similar variations according to dietary treatments, but a lower n-6:n-3 fatty acids ratio. From day 4 to later on during the suckling period, the concentration of C14:0, C16:0 and C18:1 in the liver of the piglets decreased, irrespective of the dietary treatments of sows. In plasma and liver, the total concentration of saturated fatty acids (SAFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) did not differ markedly in piglets sucking sows fed different dietary fatty acids, whereas the adipose tissue of piglets sucking sows fed sunflower oil and coconut oil showed the highest proportion of PUFA and SAFA, respectively. Weaning lowered the concentration of lipid-soluble extracts in plasma and the concentration of fatty acids in the liver of the piglets. Within the post-weaning period, dietary treatments of sows, rather than age of piglets, influenced the fatty acid composition of plasma and adipose tissue of the piglets, whereas the hepatic fatty acid profile was more affected by the age of the piglets during the post weaning period. This study shows that the fatty acid profile of plasma and tissues of the progeny is highly dependent on the maternal dietary composition, and that the dietary impact persists for up to 3 weeks after the suckling period. PMID- 22444798 TI - Quality and safety of bovine clones and their products. AB - A multidisciplinary research programme was developed to get a scientific expertise for the quality assessment of products obtained from cloned livestock. Thirty-seven bovine Holstein female clones of five different genotypes and their products were analysed in comparison with 38 control animals obtained by conventional artificial insemination and raised under the same conditions at the same experimental farm. Animal evaluation included over 150 criteria and more than 10 000 measurements to check the physiological status and health over a 3 year period. All the parameters studied were in the normal range for age and breed, but some significant differences were detected between clone and control groups in terms of delayed onset of puberty in clones, higher neutrophil counts in haematology or lower biochemical plasma concentrations of gamma glutamyl transferase. Milk and meat analyses were conformable to expected values. We, however, found some differences in fatty acid (FA) composition of milk and muscle suggesting a possible deviation in lipid metabolism as assessed by higher delta-9 desaturase activity indexes in both milk and muscles from clones compared with controls. Repeated muscle biopsies in the semitendinosus muscle of the same animals demonstrated a higher oxidative activity in muscle of young clones (8 months of age) compared with controls, suggesting a delayed muscle maturation in clones. Nutritional evaluation of milk and meat using the rat feeding trials did not show any difference between clone and control products for food intake, growth rate, body composition of the rats, nor for possible allergenicity. Possible reactivation of bovine endogenous retroviruses (BERVs) was analysed and compared between normal and cloned cattle. As expected, these BERV sequences are not transcribed and no RNA was detected in the blood of clones, donor animals or controls; therefore, it may be assumed that the sanitary risk associated with BERV sequences is not higher in cattle derived from somatic nuclear transfer than in cattle born from conventional reproduction. Our results confirm that the quality and safety of products (milk and meat) from adult and clinically healthy cloned cattle is globally similar to normal animals. However, from a strictly biological point of view, the slightly delayed maturation we observed in the muscle of clones together with some marginal differences identified in FA composition of both muscle and milk, point to the need for more refined analysis to totally exclude any risks from the consumption of those products. PMID- 22444799 TI - Stress neuroendocrine profiles in five pig breeding lines and the relationship with carcass composition. AB - Stress neuroendocrine systems (hypothalamic-pituitary-adrenal axis and sympathetic nervous system) were studied in 100 female pigs from each of the five main genetic lines used in Europe for pork production: Pietrain, Large White, Landrace, Duroc and Meishan. Levels of cortisol and catecholamines were measured in urine collected at the farm, after transportation to the slaughterhouse and the next morning before slaughter. With the exception of the Pietrain line that showed intermediate levels of cortisol despite its extreme leanness, a significant positive relationship was found between basal cortisol levels and fatness, both across and within (except in Pietrain and Duroc) lines. Basal cortisol levels were 2.46-fold higher in Meishan (20.46 ng/mg creatinine) than in Large White pigs (8.30 ng/mg creatinine), the two extreme breeds. Post transportation levels were highest but proportional to basal levels, suggesting that the adrenal reactivity to adrenocorticotropic hormone is a major source of variability between lines. Levels of catecholamines were less variable between lines but correlated also with fatness, partlyviapartial correlations with cortisol levels. In serum collected at exsanguination, creatine kinase activity was correlated with muscularity across the five breeds. However, this was due to a much larger activity than expected in Pietrain pigs, although all animals were negative for the allele of the ryanodine receptor gene responsible for stress sensitivity. Serum glucose levels were inversely related to fatness. These data show that the differences between breeds or lines can be utilised by cross breeding and that this can lead to changes in stress hormones and in turn to some degree of changes in carcass traits. PMID- 22444800 TI - Biochemical and biomechanical properties of tendons in two commercial types of chickens. AB - The quality of the attachment of meat to bone is often reported to be insufficient by more and more poultry's consumers. This is particularly true for thigh meat in broilers. The aim of this study was to compare muscle to bone attachment (namely, tendons) from a biomechanical and a biochemical point of view in 50 standard (S) and 50 Label Rouge (LR) chickens. Carcasses weighted around 1.7 kg in the two groups. Two tendons were harvested and proceeded for passive stretch tests, prior to cooking or not, to determine main mechanical characteristics (maximum load, stiffness and longitudinal strain). Biochemical parameters such as dry matter percentage, total collagen content, collagen solubility and sulphated glycosaminoglycans (sGAGs) content were also determined. Results showed that biomechanical values differ largely between the two studied tendons. For a given tendon, the values were also different between the two groups of chickens mainly after cooking. The results clearly showed that, mainly after cooking, the mechanical resistance of tendon to stretch was better in LR than in S chickens. LR chickens were reported to have tendons with higher collagen and sGAGs contents associated with a lower collagen solubility. These differences may explain biomechanical differences observed for the two types of tendons and could be due to increased age and/or higher physical activity of LR chickens. PMID- 22444801 TI - Muscle type-specific responses of myoD and calpain 3 expression to recombinant porcine growth hormone in the pig. AB - Sixteen castrated male Large White * Landrace pigs were employed to investigate the muscle type-specific changes of gene expression in response to recombinant porcine growth hormone (rpGH) administration. Pigs were injected intramuscularly with rpGH (4 mg/day, n = 8) or saline (n = 8) for 28 days. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the mRNA abundance of genes related to muscle growth in longissimus dorsi (LD) and semitendinosus (ST) muscles. Myofibre-type composition was characterised by the ratio of the expression of myosin heavy chain (MyHC) 1, 2a or 2b relative to 2x. The results showed that the relative myofibre-type composition of neither LD nor ST was affected by rpGH administration. rpGH administration did not induce significant changes in the abundances of myostatin and myogenin mRNA in both types of muscle. MyoD and calpain 3 mRNA were significantly increased after rpGH treatment in ST muscle, whereas the difference was not significant in LD muscle. A tendency of down-regulation was observed for PGC-1alpha mRNA expression in ST muscle of rpGH-treated group (P = 0.16). These results suggest that myoD, calpain 3 and probably PGC-1alpha may be involved in the mechanism of exogenous GH action on skeletal muscle growth; rpGH up-regulates mRNA expression of myoD and calpain 3 in a muscle type-specific manner, being more remarkable in ST than in LD, whereas no influences of rpGH on the mRNA expression of myostatin and myogenin were detected. PMID- 22444802 TI - Thyroid hormones in small ruminants: effects of endogenous, environmental and nutritional factors. AB - Appropriate thyroid gland function and thyroid hormone activity are considered crucial to sustain the productive performance in domestic animals (growth, milk or hair fibre production). Changes of blood thyroid hormone concentrations are an indirect measure of the changes in thyroid gland activity and circulating thyroid hormones can be considered as indicators of the metabolic and nutritional status of the animals. Thyroid hormones play a pivotal role in the mechanisms permitting the animals to live and breed in the surrounding environment. Variations in hormone bioactivity allow the animals to adapt their metabolic balance to different environmental conditions, changes in nutrient requirements and availability, and to homeorhetic changes during different physiological stages. This is particularly important in the free-ranging and grazing animals, such as traditionally reared small ruminants, whose main physiological functions (feed intake, reproduction, hair growth) are markedly seasonal. Many investigations dealt with the involvement of thyroid hormones in the expression of endogenous seasonal rhythms, such as reproduction and hair growth cycles in fibre-producing (wool, mohair, cashmere) sheep and goats. Important knowledge about the pattern of thyroid hormone metabolism and their role in ontogenetic development has been obtained from studies in the ovine foetus and in the newborn. Many endogenous (breed, age, gender, physiological state) and environmental factors (climate, season, with a primary role of nutrition) are able to affect thyroid activity and hormone concentrations in blood, acting at the level of hypothalamus, pituitary and/or thyroid gland, as well as on peripheral monodeiodination. Knowledge on such topics mirror physiological changes and possibly allows the monitoring and manipulation of thyroid physiology, in order to improve animal health, welfare and production. PMID- 22444803 TI - Mechanisms of water economy in lactating Ethiopian Somali goats during repeated cycles of intermittent watering. AB - We investigated the physiological and behavioural strategies by which lactating Ethiopian Somali goats endure repeated periods of water deprivation. The experiment lasted for 32 days and was divided into four periods of 8 days each. Measurements were taken during the first 4 days in each period. Seven does (W1) were watered once daily and seven does (W4) were watered once every 4th day. Rectal temperature was taken at 0800 and 1715 h. Blood samples were taken in the evening and milk samples in the morning. The goats were on pasture between 0900 to 1215 h and 1315 to 1630 h with behaviour recorded every 5 min. The does were supplemented with 300 g of concentrates per head per day. Plasma and milk osmolality were determined by freezing point depression. Plasma total protein was measured on a TS refractometer. Plasma vasopressin concentrations were analysed by radio-immunoassay. The mean daily water intake of W1 was 1897 ml compared with the calculated mean of 1075 ml in W4 (P < 0.001). The mean diurnal variation of the rectal temperature was 3.5 degrees C in both groups. Afternoon rectal temperature in W4 during period 1 was higher than that in the W1 on the days of water deprivation (P < 0.05). With repeated periods, plasma osmolality in W4 increased less over the days of water deprivation. It was 336, 321, 311 and 306 mosm/l on the 4th day at periods 1, 2, 3 and 4, respectively. The corresponding vasopressin concentrations were 10.0, 9.2, 4.2 and 4.4 pmol/l. Total plasma protein concentration during period 1 on days 3 and 4 were higher in W4 than in W1 (P < 0.01). During the subsequent periods, it did not increase more in W4 compared with W1, but it was lower in W4 on the days after watering. W4 milk production decreased by 22% compared with W1 in all periods. With increasing days of water deprivation, the W4 goats spent less time in the sun, grazed shorter time and frequently ate cactus (Opuntia ficus-indica) as compared with W1. Results suggested that dehydrated lactating Ethiopian Somali goats economised on water by diurnal variations of rectal temperature, storing water in the extracellular fluid, by changing behaviour at grazing and by decreasing milk production. PMID- 22444804 TI - Developing a HACCP-like system for improving animal health and welfare in organic egg production - based on an expert panel analysis. AB - In the process of developing a generic Hazard Analysis and Critical Control Point (HACCP)-like system for securing animal health and welfare in organic egg production, an expert panel analysis was used to perform the initial hazard analysis. Eighteen advisers and researchers in organic egg production were included in the expert panel. In a series of four questionnaires, the expert panel first scored 34 health and welfare problems seen in Danish organic egg production. Based on scorings of severity and occurrence, 10 problems were selected for further analysis. The experts subsequently suggested and scored risk factors for those problems and finally suggested control points, alarm values indicating the need for corrective actions in order to control the risk factors and monitoring frequencies of these. The 10 selected problems were hunger, thirst, piling, crop impaction, blackhead, pasteurellosis, bone fractures, cannibalism, predators and red mites. A total of 154 different risk factors were suggested for these problems. The 41 risk factors which rated highest in a combined scoring of importance and occurrence were selected for further analysis. There was a high degree of consensus between experts when scoring both problems and risk factors. The level of consensus, as defined by an interquartile range 1, was 79% to 100% when scoring the health and welfare problems (scale 1-5) and 77% to 95% when scoring the risk factors (scale 1-4). On average, 5.8 control points were suggested for every risk factor. Alarm values were often not detailed enough to be of practical significance and further analysis is needed in order to define these. The experts were highly diverse in their suggested monitoring frequencies and establishment of monitoring schemes should be part of developing the farm specific systems. An expert panel analysis based on questionnaires was a useful tool during the first steps of developing a HACCP plan, conducting a hazard analysis and suggesting control points. However, care should be taken regarding the panel's size and fields of expertise in order to assure that the panel fully covers the field of interest throughout the study. A further development of the hazard analysis into a farm-specific HACCP system would include assembling an on farm HACCP team consisting of farmers and advisors for the practical application of control points, alarm values and monitoring schemes. The results from the fourth questionnaire would be useful as input for this work. PMID- 22444805 TI - The reactivity of neonatal rabbits to the mammary pheromone as a probe for viability. AB - Newborn rabbits depend on a daily nursing interaction with the mother to gain milk and to survive. During this interaction, they localise and seize the nipples displaying a typical behaviour triggered by maternal odour cues. The mammary pheromone constitutes such a signal in domestic rabbits: it elicits sucking related movements in more than 90% of the pups. However, some newborns remain unresponsive to the presentation of the pheromone, even pups apparently healthy and highly motivated to suck. The main goal of the present study was therefore to explore the link between the unresponsiveness of rabbit pups to the mammary pheromone and their growth and survival in breeding conditions. To that end, 293 newborns from 30 litters were tested for their head searching-oral grasping responses to the mammary pheromone on days 1 and 3, and their milk intake and mortality were followed up from days 1 to 21. It was hypothesised that unresponsive newborns would have subsequent difficulties in finding nipples, sucking and surviving. Early weight and success in milk intake were further considered as mediating factors in growth and viability. The results showed that pups that were unresponsive to the mammary pheromone on day 1 were less successful in gaining milk and had a higher rate of mortality than the responsive pups. However, this impact was modulated by the weight of pups: it appeared only in the lightest newborns. Moreover, this impact vanished on day 3. On the other hand, the pup weight and sucking success on days 1 to 3 strongly influenced viability and growth during the period extending from days 1 to 21. Taken together, the results show that the day-1 responsiveness of rabbit pups to the mammary pheromone can be considered as an indicator of individual viability in pups having a small weight (<48 g on day 1). The predictive validity of the pups' pheromonal reactivity seems however time-limited as it works only during the first, but crucial, postnatal days. PMID- 22444806 TI - Variability of colostrum yield and colostrum intake in pigs. AB - Colostrum yield and composition of 40 Landrace*Large White sows were determined from the onset of parturition until 24 h post partum. Colostrum yield was calculated by adding individual piglets' colostrum intakes for each litter. Colostrum was assayed for prolactin, progesterone, oestradiol-17beta, immunoglobulin G and its nutritional composition was determined. Piglets' individual colostrum intake averaged 300 +/- 7 g and sows' colostrum yield averaged 3.67 +/- 0.14 kg (minimum 1.91 kg, maximum 5.31 kg). Live weight and characteristics at birth (umbilical cord already ruptured, splayleg, difficulty to breathe) were the major factors influencing individual colostrum intake. Colostrum yield was not affected by litter size, tended to be influenced by parity (P = 0.059) and was lower when farrowing was induced (P = 0.017). On the other hand, no relationships were found between hormone concentrations in colostrum and colostrum yield. Mean piglet birth weight and litter weight variation at birth were related to colostrum yield (r = 0.38; P = 0.015 and r = 0.34; P = 0.030, respectively). These results suggest that determinism of colostrum yield depends, in part, on global vitality of the litter but seems to be, most probably, affected by the capacity of sows to produce enough colostrum for the whole litter. Further studies are needed to understand the endocrine regulation of colostrum secretion in sows. PMID- 22444807 TI - Effect of cattle grazing a species-rich mountain pasture under different stocking rates on the dynamics of diet selection and sward structure. AB - Although stocking rate is a key management variable influencing the structure and composition of pastures, only few studies have simultaneously analysed the seasonal patterns of pasture use by cattle, and the adjustments the animals make to maintain intake of a high-quality diet over the grazing season. Therefore, over a 3-year study, we recorded diet selection, plot use and impact of heifers on sward structure and quality under three different stocking rates (0.6, 1.0 and 1.4 livestock units (LU) per ha) in a species-rich mountain pasture of central France. Measurements were made on three occasions between early June and the end of September each year. Overall, heifers selected for bites dominated by legumes or forbs, and against reproductive grass, whatever the stocking rate or season. Selection for tall mixed (P < 0.05), short mixed (P < 0.05) and short pure grass bites (P < 0.01) was more pronounced in plots grazed at the lowest stocking rate. Although heifers' selection for short patches decreased at the end of the season (P < 0.001), they continued to graze previously grazed areas, thus exhibiting a typical 'patch grazing' pattern, with the animals that grazed at the lowest stocking rate tending to better maintain their selection for short patches in September (treatment * period: P = 0.078). Neither diet quality nor individual animal performance were affected by the different stocking rate treatments despite high variability in the quantity and quality of herbage offered and differences in diet selection. However, at the 1.4 LU per ha stocking rate, the quantity of forage available per animal at the end of the season, 0.79 t dry matter (DM) per ha of green leaves with the median of sward height at 4.6 cm, approached levels limiting cattle's ability to compensate for the effects of increasing stocking rate. In plots grazed at 0.6 LU per ha, the total herbage biomass remained higher than 3 t DM per ha with more than 30% of plot area still covered by reproductive grass patches at the end of the grazing season, which in the medium term should affect the botanical composition of these pastures. Sward heterogeneity was high in plots grazed at 1.0 LU per ha, with sufficient herbage availability (1.1 t DM per ha of green leaves) to maintain animal performance, and more than 15% of plot area was kept at a reproductive stage at the end of the grazing season. Hence, it could represent the optimal balance to satisfy both livestock production and conservation management objectives. PMID- 22444808 TI - Relationship between carcass weight, adipose tissue androstenone level and expression of the hepatic 3beta-hydroxysteroid dehydrogenase in entire commercial pigs. AB - Boar taint is a major meat-quality defect in pigs and is due to excessive accumulation of skatole and androstenone in adipose tissue. The present work investigated the relationship between carcass weight, levels of skatole and androstenone in adipose tissue, and expression of the hepatic androstenone metabolising enzyme 3beta-hydroxysteroid dehydrogenase (3beta-HSD), in 22 entire male and 22 entire female crossbred pigs (Large White (40%) * Landrace (40%) * Duroc (20%)). Animals of each gender were divided into two subgroups (11 pigs in each subgroup): (i) conventional weight (carcass weight 59 to 77 kg) and (ii) heavy weight (carcass weight 84 to 95 kg). No relationship between carcass weight and adipose tissue skatole level was found for entire male pigs (r2 = 0.013, P > 0.05). There was a significant negative relationship between carcass weight and expression of the hepatic 3beta-HSD protein (r2 = 0.502, P < 0.001) and a significant negative relationship between 3beta-HSD protein expression and androstenone level in adipose tissue (r2 = 0.24, P < 0.05) in entire males. No relationship was found between carcass weight and 3beta-HSD protein expression in female pigs (r2 = 0.001, P > 0.05). 3beta-HSD expression was 59% higher in conventional-weight male pigs when compared with heavy-weight animals (P < 0.05) and 36% higher in heavy-weight females when compared with heavy-weight males (P < 0.05). It is concluded that an increase in slaughter weight of entire commercial crossbred Large White pigs is accompanied by inhibition of expression of the hepatic 3beta-HSD protein, which might result in a reduced rate of hepatic androstenone clearance with its subsequent accumulation in adipose tissue. It is suggested that regulation of pig hepatic 3beta-HSD expression is under the control of sex hormones. PMID- 22444809 TI - Effects of dietary incorporation of different antioxidant extracts and free-range rearing on fatty acid composition and lipid oxidation of Iberian pig meat. AB - This investigation was designed to evaluate the effects of feeding either free range or in confinement using concentrated diets with the same ingredients and oil source (5.5% of olive oleins) but with different antioxidant supplementation [control diet with a basal level of alpha-tocopheryl acetate (control); 200 mg/kg synthetic all-rac-alpha-tocopheryl acetate (Eall-rac); 200 mg/kg natural RRR alpha-tocopheryl-acetate (ERRR-); flavonoid extract-enriched diet (AFlav); and phenolic compound-enriched extract (APhen)] on the fatty acid composition and lipid oxidation of Iberian pig muscle longissimus dorsi. The alpha-tocopherol concentration was significantly higher in muscles from free-range and ERRR- pigs than in muscles from Eall-rac pigs, and gamma-tocopherol was only detected in muscles from free-range pigs. Longissimus dorsi muscles from free-range pigs had a significantly lower content of saturated fatty acids and higher content of polyunsaturated fatty acids than muscles from the other five groups of pigs fed in confinement; however, no significant effect on monounsaturated fatty acids was observed. No effect of dietary antioxidant supplementation (synthetic or natural alpha-tocopherol, flavonoid extract, or phenol extract) on the fatty acid composition of muscles was observed. A significant influence of dietary treatment on lipid oxidation was observed after 3 (P < 0.01), and 7 and 10 (P < 0.001) days of refrigerated storage, respectively. The lowest thiobarbituric acid-reactive substances (TBARS) values were found in pork chops from the free-range and ERRR- groups, intermediate values from the Eall-rac group, followed by AFlav and APhen, while the highest TBARS values corresponded to muscles from pigs fed the control concentrate. The source of alpha-tocopherol had a significant effect on lipid oxidation (P < 0.05), whereas the AFlav and APhen groups had similar TBARS values. PMID- 22444810 TI - Young Salers suckled bull production: effect of diet on performance, carcass and muscle characteristics and meat quality. AB - The aim of this work was to improve the knowledge on young suckled Salers bull production and to study the effect of forage type and concentrate level on performance, carcass and muscle characteristics as well as on meat quality. Twenty-four Salers male calves of 150 days of age were assigned to six groups: C0 (fed exclusively with hay and dam's milk and slaughtered at approximately 6 months of age), and HH (hay - high concentrate), HL (hay - low concentrate), GH (cut grass - high concentrate), GL (cut grass - low concentrate) and CP (control pasture: pasture - high concentrate) groups differing in feeds received until slaughter and slaughtered unweaned at approximately 10 months of age. Carcass weights averaged 210 kg at 10 months of age at slaughter. Average daily weight gain (ADWG) in HH and GH groups tended to be higher (P = 0.09) than in HL and GL groups (1354 v. 1248 g/day). ADWG in CP group (1542 g/day) was higher (P < 0.05) than in the other groups. Carcass weight in CP group (230 kg) tended to be higher (P < 0.1) than in HL (198 kg) and GL (200 kg) groups. Carcass muscle weight was higher (P < 0.05) in GH (155 kg) and CP groups (165 kg) than in HL (141 kg) and GL (142 kg) groups. Carcass and offal fatty tissue weights and carcass fatness did not differ between groups. Neither forage type nor concentrate level had significant effect on the area of muscle fibres or on muscle metabolic enzyme activities (namely, lactate dehydrogenase - LDH, phosphofructokinase - PFK, isocitrate dehydrogenase - ICDH, citrate synthase - CS and cytochrome-c oxidase - COX). semitendinosus muscle of CP group presented higher CS enzyme activities (8.10 MUmol/min per g) than HH (5.30 MUmol/min per g) and GL (4.52 MUmol/min per g) groups. Neither total nor insoluble collagen content significantly differed between groups. Lipid content in rectus abdominis muscle was relatively low (average 67.5 mg/g dry matter) and was not affected by diet (P > 0.05). The ratio between n-6 and n-3 polyunsaturated fatty acid content was lower (P = 0.01) in the low-concentrate-fed than in the high-concentrate-fed group (3.95 v. 5.37, respectively). Sensory analysis noted that longissimus thoracis muscle from CP animals was more tender and juicy than that from HH and GH animals (P < 0.05). PMID- 22444811 TI - European pig genetic diversity: a minireview. AB - An evaluation of the European pig diversity has been carried on by several countries, with the support of the European Union over the period of 1994 to 2000. This article presents an overview of the results of this investigation, focussing on two genetic marker techniques, namely microsatellites (MS) and amplification of fragment length polymorphism (AFLP). Nearly 200 loci were characterised on about 50 individuals from each of 59 to 71 breeds, according to the marker considered. The analysis of diversity, based on genetic distances, led to similar conclusions for the two marker types (MS and AFLP), in spite of a markedly lower total diversity of AFLP compared to MS. The analysis of the MS loci showed that the allelic diversity pattern among breeds was quasi-independent from the diversity pattern based on allele frequencies. Genetic distances showed no particular clustering of local with international breeds, confirming the genetic uniqueness of the European local breeds compared to mainstream international breeds. The taxonomy of the local breeds revealed a cluster of the Iberian type breeds, in contrast with a wider dispersal of the breeds from other countries. Phylogeny often disagreed with documented breeds' history, showing the complex migration/admixture patterns which underlie the breeds' relationships. Methodologies developed in this investigation as well as the database and the DNA depository created should provide support for further innovative research in the field of domestic animal diversity management. PMID- 22444812 TI - Binational evaluation of type traits from Germany and France with a single-trait MACE animal model. AB - Binational genetic evaluation between Germany and France were performed for each type trait using a single-trait MACE (multiple across-country evaluation) model. Daughter yield deviations (DYD) of bulls having 30 equivalent daughter contributions or more were the data for parameter estimation. Full pedigree information of bulls was used via sire and dam relationships. In general, across country genetic correlation estimates were in agreement with what is observed by Interbull. The estimated correlations were over 0.93 for stature, rump angle, udder depth, front teat placement, teat length and rear teat placement. These traits have been classified in both countries for a long period of time. However, some other type traits were included later in the French type classification system (most of them since 2000): chest width, body depth, angularity, rump width, rear leg rear view, fore udder and rear udder height. The estimated correlations for these traits were relatively low. In order to check changes in genetic correlations over time, data from bulls born until the end of 1995 were discarded. Higher genetic correlation estimates between both countries were obtained by using more recent data especially for traits having lower genetic correlation, e.g. body depth correlation increased from 0.55 to 0.83. Once genetic correlations were estimated, binational genetic evaluation between Germany and France were performed for each type trait using DYD of bulls. The rankings of bulls obtained from this evaluation had some differences with Interbull rankings but a similar proportion of bulls from each country was found. Finally, more computationally demanding binational evaluations were performed using yield deviations of cows for binational cow comparison. The rankings obtained were influenced by the number of daughters per bull and heritabilities used in each country. PMID- 22444813 TI - Live animal measurements, carcass composition and plasma hormone and metabolite concentrations in male progeny of sires differing in genetic merit for beef production. AB - In genetic improvement programmes for beef cattle, the effect of selecting for a given trait or index on other economically important traits, or their predictors, must be quantified to ensure no deleterious consequential effects go unnoticed. The objective was to compare live animal measurements, carcass composition and plasma hormone and metabolite concentrations of male progeny of sires selected on an economic index in Ireland. This beef carcass index (BCI) is expressed in euros and based on weaning weight, feed intake, carcass weight and carcass conformation and fat scores. The index is used to aid in the genetic comparison of animals for the expected profitability of their progeny at slaughter. A total of 107 progeny from beef sires of high (n = 11) or low (n = 11) genetic merit for the BCI were compared in either a bull (slaughtered at 16 months of age) or steer (slaughtered at 24 months of age) production system, following purchase after weaning (8 months of age) from commercial beef herds. Data were analysed as a 2 * 2 factorial design (two levels of genetic merit by two production systems). Progeny of high BCI sires had heavier carcasses, greater (P < 0.01) muscularity scores after weaning, greater (P < 0.05) skeletal scores and scanned muscle depth pre slaughter, higher (P < 0.05) plasma insulin concentrations and greater (P < 0.01) animal value (obtained by multiplying carcass weight by carcass value, which was based on the weight of meat in each cut by its commercial value) than progeny of low BCI sires. Regression of progeny performance on sire genetic merit was also undertaken across the entire data set. In steers, the effect of BCI on carcass meat proportion, calculated carcass value (c/kg) and animal value was positive (P < 0.01), while a negative association was observed for scanned fat depth pre slaughter and carcass fat proportion (P < 0.01), but there was no effect in bulls. The effect of sire expected progeny difference (EPD) for carcass weight followed the same trends as BCI. Muscularity scores, carcass meat proportion and calculated carcass value increased, whereas scanned fat depth, carcass fat and bone proportions decreased with increasing sire EPD for conformation score. The opposite association was observed for sire EPD for fat score. Results from this study show that selection using the BCI had positive effects on live animal muscularity, carcass meat proportion, proportions of high-value cuts and carcass value in steer progeny, which are desirable traits in beef production. PMID- 22444814 TI - Detection of quantitative trait loci for porcine susceptibility to enterotoxigenic Escherichia coli F41 in a White Duroc * Chinese Erhualian resource population. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhoea in neonatal and postweaning pigs. F41 is one of ETEC fimbriae that adhere to the small intestinal epithelium and lead to development of diarrhoea. The genetic architecture of susceptibility to ETEC F41 remains elusive in pigs. In this study, we determined the in vitro adhesion phenotypes of ETEC F41 in a total of 835 F2 animals from a White Duroc * Erhualian intercross, and performed a genome scan using both F2 and half-sib analyses with 183 microsatellite markers to detect quantitative trait loci (QTL) for porcine susceptibility to ETEC F41. The two analyses consistently revealed a 1% genome-wide significant QTL on pig chromosome 4. Moreover, we determined F41 adhesion phenotypes in 14 purebred Erhualian and 14 White Duroc pigs. The results showed that both the founder breeds are segregating for the F41 adhesion phenotype, while less percentage of Erhualian pigs were adhesive to ETEC F41 compared to White Duroc pigs. PMID- 22444815 TI - Associative effects between forages on feed intake and digestion in ruminants. AB - The feeding value of forage mixtures from permanent and temporary multi-species grasslands cannot always be precisely defined. Indeed, the digestibility and feed intake of a combination of forages can differ from the balanced median values calculated from forages considered separately. In order to present an overview of the associative effects between forages on digestion and intake, a literature study was carried out. The associative effects can be studied in a complementary way in vitro to test digestive interactions of a large number of mixtures and to carry out explanatory experiments, and in vivo to investigate intake and digestion at the whole animal scale. We identified three main situations in which interactions between forages can lead to associative effects on intake and digestion: (i) increased intake that can be observed with grass and legume association can be explained by fast digestion of the soluble fraction of legumes, and a higher rate of particle breakdown and passage through the rumen, (ii) increased digestion when a poor forage is supplemented by a high nitrogen content plant can be explained by stimulation of the microbial activity and (iii) modification of digestive processes in the rumen, including proteolysis and methane production when certain bioactive secondary metabolites such as tannins, saponins or polyphenol oxidase are present. According to the type and concentration of these compounds in the diet, the effects can be favourable or unfavourable on intake and digestive parameters. Reported associative effects between forages show a large variability among studies. This reflects the complexity and multiplicity of nutritional situations affecting intake and the rumen function in a given animal. In order to provide more reliable information, further accumulation of data combining in vitro and in vivo studies is required. A better understanding of the associative effects between forages could help to optimise feed use efficiency, resulting in greater productivity, a reduction of the environmental impact of animal emissions and more sustainable animal production. PMID- 22444816 TI - Role of the protozoan Isotricha prostoma, liquid-, and solid-associated bacteria in rumen biohydrogenation of linoleic acid. AB - From the simultaneous accumulation of hydrogenation intermediates and the disappearance of Isotricha prostoma after algae supplementation, we suggested a role of this ciliate and/or its associated bacteria in rumen biohydrogenation of unsaturated fatty acids. The experiments described here evaluated the role of I. prostoma and/or its associated endogenous and exogenous bacteria in rumen biohydrogenation of C18:2n-6 and its main intermediates CLA c9t11 and C18:1t11. Fractions of I. prostoma and associated bacteria, obtained by sedimentation of rumen fluid sampled from a monofaunated sheep, were used untreated, treated with antibiotics or sonicated to discriminate between the activity of I. prostoma and its associated bacteria, the protozoan or the bacteria, respectively. Incubations were performed in triplicate during 6 h with unesterified C18:2n-6, CLA c9t11 or C18:1t11 (400 MUg/ml) and 0.1 g glucose/cellobiose (1/1, w/w). I. prostoma did not hydrogenate C18:2n-6 or its intermediates whereas bacteria associated with I. prostoma converted a limited amount of C18:2n-6 and CLA c9t11 to trans monoenes. C18:1t11 was not hydrogenated by either I. prostoma or its associated bacteria but was isomerized to C18:1c9. A phylogenetic analysis of clones originating from Butyrivibrio-specific PCR product was performed. This indicated that 71% of the clones from the endogenous and exogenous community clustered in close relationship with Lachnospira pectinoschiza. Additionally, the biohydrogenation activity of solid-associated bacteria (SAB) and liquid-associated bacteria (LAB) was examined and compared with the activity of the non-fractioned I. prostoma monofaunated rumen fluid (LAB + SAB). Both SAB and LAB were involved in rumen biohydrogenation of C18:2n-6. SAB fractions performed the full hydrogenation reaction to C18:0 while C18:1 fatty acids, predominantly C18:1t10 and C18:1t11, accumulated in the LAB fractions. SAB and LAB sequence analyses were mainly related to the genera Butyrivibrio and Pseudobutyrivibrio with 12% of the SAB clones closely related to the C18:0 producing B. proteoclasticus branch. In conclusion, this work suggests that I. prostoma and its associated bacteria play no role in C18:2n-6 biohydrogenation, while LAB convert C18:2n-6 to a wide range of C18:1 fatty acids and SAB produce C18:0, the end product of rumen lipid metabolism. PMID- 22444817 TI - Feeding pregnant ewes a high-salt diet or saltbush suppresses their offspring's postnatal renin activity. AB - If ewes consumed a high-salt diet or saltbush during the last 3 months of pregnancy and for 3 weeks after birth, we expected the renin activity of their lamb to be suppressed at birth and at 3 weeks of age. We also expected an increase in the concentration of cations other than sodium in the ewe's milk and an increase in the plasma Na concentration of the lamb at birth. To test these hypotheses, Merino ewes were fed a high-salt diet (14% NaCl) in an animal house and compared to control ewes eating a control diet (2% NaCl). In addition, we compared ewes grazing saltbush (about 13% salt in diet) to ewes grazing pasture from day 60 of pregnancy to 3 weeks after birth. Lambs born to ewes consuming saltbush had 85% lower (P < 0.001) renin activity than offspring from ewes consuming pasture at 3 weeks of age. Similarly, lambs born to ewes consuming a high-salt diet had 20% lower renin activity at birth and 3 weeks (P = 0.07). Feeding ewes a high-salt diet or saltbush altered the mineral composition of the milk; the largest change was a 10% increase in K levels (P 0.05). Consuming a high-salt diet or saltbush lowered the plasma Na of ewes at 130 days of gestation (by 3-5 mmol/l; P < 0.001), but only lambs from ewes fed the high-salt diet had a lower plasma Na at birth (P < 0.05). Suppression of the renin activity of lambs could lead to permanent physiological changes in salt balance in later life. PMID- 22444818 TI - Proteome dynamics during contractile and metabolic differentiation of bovine foetal muscle. AB - Contractile and metabolic properties of bovine muscles play an important role in meat sensorial quality, particularly tenderness. Earlier studies based on Myosin heavy chain isoforms analyses and measurements of glycolytic and oxidative enzyme activities have demonstrated that the third trimester of foetal life in bovine is characterized by contractile and metabolic differentiation. In order to complete this data and to obtain a precise view of this phase and its regulation, we performed a proteomic analysis of Semitendinosus muscle from Charolais foetuses analysed at three stages of the third trimester of gestation (180, 210 and 260 days). The results complete the knowledge of important changes in the profiles of proteins from metabolic and contractile pathways. They provide new insights about proteins such as Aldehyde dehydrogenase family, Enolase, Dihydrolipoyl dehydrogenase, Troponin T or Myosin light chains isoforms. These data have agronomical applications not only for the management of beef sensorial quality but also in medical context, as bovine myogenesis appears very similar to human one. PMID- 22444819 TI - Developmental programming of skeletal muscle phenotype/metabolism. AB - Skeletal muscle is a highly dynamic and malleable tissue that is able to adapt to different stimuli placed upon it, both during gestation and after birth, ultimately resulting in anatomical changes to muscle fibre composition. Variation in nutrient supply throughout gestation is common, whether in livestock or in the human. The specific effects of maternal nutrition on foetal development are at the forefront of scientific research. However, results describing how different maternal feeding strategies affect skeletal muscle fibre development in the offspring are not fully consistent, even where the same time windows during gestation have been examined. The aim of this study is to determine the effects of increased maternal nutrition (above the recommended levels) on the Musculus semitendinosus phenotype of progeny. In all, 24 pregnant sows were assigned to one of four feeding regimes during gestation; T1 (control group): 30 MJ digestible energy per day (MJ DE/day) throughout gestation, T2: same as that for T1 but increased to 60 MJ DE/day from 25 to 50 days of gestation (dg), T3: same as that for T1 but increased to 60 MJ DE/day from 50 to 80 dg, T4: same as that for T1 but increased nutrition to 60 MJ DE/day from 25 to 80 dg. Light- and heavy weight littermate pairs of the same sex were selected at birth and individually fed to slaughter (c. 158 days). Histochemical and immunohistochemical staining were used to identify the predominantly oxidative (deep) and less oxidative (superficial) regions of the M. semitendinosus, and to determine total fibre number and proportions of fibre types. The results demonstrate that increased maternal nutrition alters skeletal muscle phenotype in the offspring by changing fibre-type proportions, leading to an increased oxidative capacity due to an increase in Type IIA fibres. No change in total muscle area, total muscle fibre number, or fibre cross-sectional area is observed. The precise molecular mechanism(s) by which these findings occur is being investigated. PMID- 22444820 TI - Effect of Holstein-Friesian genetic group on peripartum and early lactation haematological and acute phase proteins profiles, health and fertility. AB - Pasture-based Holstein-Friesian cows from three genetic groups differing in the Irish 'Economic Breeding Index' (EBI) value and genetic background, namely North American (NA) national average EBI genetic merit (LOW-NA, n = 42), North-American high EBI genetic merit (HIGH-NA, n = 42) and New Zealand (NZ) high EBI genetic merit (HIGH-NZ, n = 42), were studied. These genetic groups have been selected in different environments: pasture for NZ and confinement for NA. The objective was to determine the effect of genetic group on haematological and acute phase proteins profiles (white blood cell (WBC) counts, red blood cell (RBC) counts, acute phase proteins: serum amyloid A (SAA) and haptoglobin), health (rectal temperature (RT), clinical mastitis (CM) and somatic cell score), calving performance (stillbirth, calving assistance) and post-partum reproductive parameters (endometritis and ovarian cyclicity). Blood sampling and data recording took place 3 weeks pre-calving up to 7 weeks post-calving. Linear mixed models, logistic regression and generalised estimating equations were used for data analysis. HIGH-NZ animals had the highest (P < 0.05) RBC mean corpuscular volume (50.0 fl), exhibited a different WBC distribution pattern (P < 0.05) and had the lowest (P < 0.05) mean RT (38.4 degrees C) for the first 10 days post calving. These findings suggest enhanced reticulocyte turnover, peripartum response mechanisms and thermoregulation in the HIGH-NZ compared to the other two genetic groups. LOW-NA animals had the highest SAA peak throughout the peripartum period (55.12 mg/l, P < 0.05) and a tendency for higher somatic cell scores (P < 0.10) in early lactation. The HIGH-NA animals had the lowest incidence of udder quarter milk sample bacteria at calving, suggesting better udder health when commencing lactation. No differences were detected between genetic groups in calving performance, post-partum reproductive parameters or CM in the first 42 days post-calving. These results suggest that while inherited peripartum adaptation strategies have been developed by the different genetic groups selected in different environments (pasture = NZ v. confinement = NA), such differences have minimal impact on peripartum clinical health. PMID- 22444821 TI - Shearing at the end of summer affects body temperature of free-living Angora goats ( Capra aegagrus) more than does shearing at the end of winter. AB - Angora goats are known to be vulnerable to cold stress, especially after shearing, but their thermoregulatory responses to shearing have not been measured. We recorded activity, and abdominal and subcutaneous temperatures, for 10 days pre-shearing and post-shearing, in 10 Angora goats inhabiting the succulent thicket of the Eastern Cape, South Africa, in both March (late summer) and September (late winter). Within each season, environmental conditions were similar pre-shearing and post-shearing, but September was an average 5 degrees C colder than March. Shearing resulted in a decreased mean (P < 0.0001), minimum (P < 0.0001) and maximum daily abdominal temperature (P < 0.0001). Paradoxically, the decrease in daily mean (P = 0.03) and maximum (P = 0.01) abdominal temperatures, from pre-shearing to post-shearing, was greater in March than in September. Daily amplitude of body temperature rhythm (P < 0.0001) and the maximum rate of abdominal temperature rise (P < 0.0001) increased from pre shearing to post-shearing, resulting in an earlier diurnal peak in abdominal temperature (P = 0.001) post-shearing. These changes in amplitude, rate of abdominal temperature rise and time of diurnal peak in abdominal temperature suggest that the goats' thermoregulatory system was more labile after shearing. Mean daily subcutaneous temperatures also decreased post-shearing (P < 0.0001), despite our index goat selecting more stable microclimates after shearing in March (P = 0.03). Following shearing, there was an increased difference between abdominal and subcutaneous temperatures (P < 0.0001) at night, suggesting that the goats used peripheral vasoconstriction to limit heat loss. In addition to these temperature changes, mean daily activity increased nearly two-fold after March shearing, but not September shearing. This increased activity after March shearing was likely the result of an increased foraging time, food intake and metabolic rate, as suggested by the increased water influx (P = 0.0008). Thus, Angora goats entered a heat conservation mode after shearing in both March and September. That the transition from the fleeced to the shorn state had greater thermoregulatory consequences in March than in September may provide a mechanistic explanation for Angora goats' vulnerability to cold in summer. PMID- 22444822 TI - The effect of selenium sources and supplementation on neutrophil functions in dairy cows. AB - Selenium (Se), an essential micronutrient, is believed to enhance neutrophil functions. This study aimed to compare the effects of supplemented organic (Sel Plex(r)) and inorganic (sodium selenite) Se on neutrophil functions in high producing dairy cows, during the periparturient period. Twenty-five Holstein cows were randomly allocated to five dietary treatments as follows: control diet (basal diet without Se supplementation), IN 0.3 (basal diet supplemented with inorganic Se at 0.3 mg/kg dry matter (DM)), IN 0.5 (inorganic Se at 0.5 mg/kg DM), OR 0.3 (organic Se at 0.3 mg/kg DM) and OR 0.5 (organic Se at 0.5 mg/kg DM). Some evaluated parameters included neutrophil functions and plasma Se concentrations in cows and plasma Se concentrations in calves. Neutrophil phagocytosis did not significantly differ among the five groups. However, organic Se supplementation significantly increased (P < 0.01) the respiratory burst of neutrophils when compared to cows fed IN 0.3 and the control diet. In comparison to inorganic Se, neutrophil apoptosis was decreased (P < 0.01) when cows were fed organic Se or the control diets. These effects of organic Se on respiratory burst activities and apoptosis of neutrophils were in a dose-dependent manner. Calf plasma Se concentrations were higher (P < 0.05) when cows were fed OR 0.5 and IN 0.5. PMID- 22444823 TI - Lifetime productivity of dairy cows in smallholder farming systems of the Central highlands of Kenya. AB - Evaluation of lifetime productivity is sensible to target interventions for improving productivity of smallholder dairy systems in the highlands of East Africa, because cows are normally not disposed of based on productive reasons. Feeding strategies and involuntary culling may have long-term effects on productive (and therefore economic) performance of dairy systems. Because of the temporal scale needed to evaluate lifetime productivity, experimentation with feedstuffs in single lactations is not enough to assess improvements in productivity. A dynamic modelling approach was used to explore the effect of feeding strategies on the lifetime productivity of dairy cattle. We used LIVSIM (LIVestock SIMulator), an individual-based, dynamic model in which performance depends on genetic potential of the breed and feeding. We tested the model for the highlands of Central Kenya, and simulated individual animals throughout their lifetime using scenarios with different diets based on common feedstuffs used in these systems (Napier grass, maize stover and dairy concentrates), with and without imposing random mortality on different age classes. The simulations showed that it is possible to maximise lifetime productivity by supplementing concentrates to meet the nutrient requirements of cattle during lactation, and during early development to reduce age at first calving and extend productive life. Avoiding undernutrition during the dry period by supplementing the diet with 0.5 kg of concentrates per day helped to increase productivity and productive life, but in practice farmers may not perceive the immediate economic benefits because the results of this practice are manifested through a cumulative, long-term effect. Survival analyses indicated that unsupplemented diets prolong calving intervals and therefore, reduce lifetime productivity. The simulations with imposed random mortality showed a reduction of 43% to 65% in all productivity indicators. Milk production may be increased on average by 1400 kg per lactation by supplementing the diet with 5 kg of concentrates during early lactation and 1 kg during late lactation, although the optimal supplementation may change according to milk and concentrate prices. Reducing involuntary culling must be included as a key goal when designing interventions to improve productivity and sustainability of smallholder dairy systems, because increasing lifetime productivity may have a larger impact on smallholders' income than interventions targeted to only improving daily milk yields through feeding strategies. PMID- 22444824 TI - Growth performance, carcass characteristics and meat quality of group-penned surgically castrated, immunocastrated (Improvac(r)) and entire male pigs and individually penned entire male pigs. AB - The objective of the study was to compare growth performance, carcass characteristics, meat quality and fatty acid composition of the adipose tissue of group-penned barrows, immunocastrated boars and entire males. Furthermore, the effect of housing of entire males on the aforementioned parameters was evaluated. At 55.2 days of age, 52 Swiss Large White pigs were blocked by litter and assigned by BW to four experimental groups: barrows (C), immunocastrated boars (IC), entire males (EMG) reared in group pens and entire males (EMP) reared in individual pens. In experiment 1, the effects of the method of castration were investigated (experimental groups C, IC and EMG). In experiment 2, the effects of housing on entire male pigs were evaluated (experimental groups EMG and EMP). All pigs had ad libitum access to standard diets from weaning to 107 kg BW. The two vaccinations (Improvac(r)) were applied to the IC pigs at an average BW of 22.6 and 73.0 kg. In experiment 1, average daily gain (ADG) did not (P > 0.05) differ among the experimental groups. However, EMG consumed less feed and had a better feed-conversion ratio than C (P < 0.001 for each). For IC, intermediate values were observed, which differed (P < 0.001) from EMG and C. Lean meat percentage decreased (P < 0.05) from EMG to IC, and from IC to C. The androstenone and skatole levels were higher (P < 0.05) in the adipose tissue of EMG than IC and C. Shear force values were higher (P < 0.01) in the longissimus muscle of C and EMG, compared to IC. The concentration of saturated fatty acid in the adipose tissue increased (P < 0.001) from EMG to IC, and from IC to C pigs, and that of polyunsaturated fatty acid decreased (P < 0.001). In experiment 2, ADG did not (P > 0.05) differ between EMP and EMG. However, EMP pigs consumed more feed than EMG pigs and had a poorer feed efficiency (P < 0.01 for each). In conclusion, EMG pigs had a better feed efficiency than IC pigs and their carcasses were leaner, but the risk of boar tainted pork was elevated. Group-housing negatively affected average daily feed intake but not ADG of entire males. At the moment, immunocastration offers a good approach to avoid castration and minimize the risk of boar taint. PMID- 22444825 TI - Effect of replacing calcium salts of palm oil distillate with rapeseed oil, milled or whole rapeseeds on milk fatty-acid composition in cows fed maize silage based diets. AB - Inclusion of rapeseed feeds in dairy cow diets has the potential to reduce milk fat saturated fatty acid (SFA) and increase cis-monounsaturated fatty acid (cis MUFA) content, but effectiveness may depend on the form in which the rapeseed is presented. Four mid-lactation Holstein dairy cows were allocated to four maize silage-based dietary treatments according to a 4 * 4 Latin Square design, with 28 day experimental periods. Treatments consisted of a control diet (C) containing 49 g/kg dry matter (DM) of calcium salts of palm oil distillate (CPO), or 49 g/kg DM of oil supplied as whole rapeseeds (WR), rapeseeds milled with wheat (MR) or rapeseed oil (RO). Replacing CPO with rapeseed feeds had no effect (P > 0.05) on milk fat and protein content, while milk yields were higher (P < 0.05) for RO and MR compared with WR (37.1, 38.1 and 34.3 kg/day, respectively). Substituting CPO with RO or MR reduced (P < 0.05) milk fat total SFA content (69.6, 55.6, 71.7 and 61.5 g/100 g fatty acids for C, RO, WR and MR, respectively) and enhanced (P < 0.05) milk cis-9 18:1 MUFA concentrations (corresponding values 18.6, 24.3, 17.0 and 23.0 g/100 g fatty acids) compared with C and WR. Treatments RO and MR also increased (P < 0.05) milk trans-MUFA content (4.4, 6.8, 10.5 g/100 g fatty acids, C, MR and RO, respectively). A lack of significant changes in milk fat composition when replacing CPO with WR suggests limited bioavailability of fatty acids in intact rapeseeds. In conclusion, replacing a commercial palm oil-based fat supplement in the diet with milled rapeseeds or rapeseed oil represented an effective strategy to alter milk fatty acid composition with the potential to improve human health. Inclusion of processed rapeseeds offered a good compromise for reducing milk SFA and increasing cis-MUFA, whilst minimising milk trans-MUFA and negative effects on animal performance. PMID- 22444826 TI - Air travel and vector-borne disease movement. AB - Recent decades have seen substantial expansions in the global air travel network and rapid increases in traffic volumes. The effects of this are well studied in terms of the spread of directly transmitted infections, but the role of air travel in the movement of vector-borne diseases is less well understood. Increasingly however, wider reaching surveillance for vector-borne diseases and our improving abilities to map the distributions of vectors and the diseases they carry, are providing opportunities to better our understanding of the impact of increasing air travel. Here we examine global trends in the continued expansion of air transport and its impact upon epidemiology. Novel malaria and chikungunya examples are presented, detailing how geospatial data in combination with information on air traffic can be used to predict the risks of vector-borne disease importation and establishment. Finally, we describe the development of an online tool, the Vector-Borne Disease Airline Importation Risk (VBD-Air) tool, which brings together spatial data on air traffic and vector-borne disease distributions to quantify the seasonally changing risks for importation to non endemic regions. Such a framework provides the first steps towards an ultimate goal of adaptive management based on near real time flight data and vector-borne disease surveillance. PMID- 22444827 TI - Fluorescence anisotropy of diphenylhexatriene and its cationic Trimethylamino derivative in liquid dipalmitoylphosphatidylcholine liposomes: opposing responses to isoflurane. AB - BACKGROUND: The mechanism of action of volatile general anesthetics has not yet been resolved. In order to identify the effects of isoflurane on the membrane, we measured the steady-state anisotropy of two fluorescent probes that reside at different depths. Incorporation of anesthetic was confirmed by shifting of the main phase transition temperature. RESULTS: In liquid crystalline dipalmitoylphosphatidylcholine liposomes, isoflurane (7-25 mM in the bath) increases trimethylammonium-diphenylhexatriene fluorescence anisotropy by ~0.02 units and decreases diphenylhexatriene anisotropy by the same amount. CONCLUSIONS: The anisotropy data suggest that isoflurane decreases non-axial dye mobility in the headgroup region, while increasing it in the tail region. We propose that these results reflect changes in the lateral pressure profile of the membrane. PMID- 22444828 TI - When the PilZ don't work: effectors for cyclic di-GMP action in bacteria. AB - The second messenger cyclic di-GMP has emerged as a central regulator of many important bacterial processes including biofilm formation and virulence. Although the pathways of cyclic di-GMP synthesis and degradation have been established, the mechanisms by which this second messenger exerts its action on diverse cellular functions remain relatively poorly understood. Recent studies report considerable advances in identifying different classes of cyclic di-GMP effectors; these include the PilZ protein domain, transcription factors, proteins involved in RNA processing and riboswitches. Here, we review this range of cyclic di-GMP effectors and the biological processes that they govern using examples from several different bacteria. PMID- 22444829 TI - Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. AB - PURPOSE: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial. PARTICIPANTS: Three hundred twenty-one patients randomized to receive either ranibizumab 0.5 mg monotherapy (n = 112), standard fluence (SF) verteporfin PDT combination therapy (n = 104), or reduced fluence (RF) verteporfin PDT combination therapy (n = 105). METHODS: Ranibizumab was administered monthly in the monotherapy group. In both combination therapy groups, ranibizumab was initiated with 3 consecutive monthly injections, followed by retreatment as needed (pro re nata) with monthly monitoring. All patients were evaluated monthly for 12 months. MAIN OUTCOME MEASURES: Mean change in best corrected visual acuity (BCVA) from baseline at month 12 and proportion of patients randomized to either combination therapy with a ranibizumab treatment free interval of 3 months or longer. RESULTS: Two hundred eighty-six patients (89.1%) completed the 12-month study. Mean BCVA change at month 12 was +5.3 and +4.4 letters with verteporfin SF (n = 103) or verteporfin RF (n = 105) plus ranibizumab, respectively, compared with +8.1 letters with ranibizumab monotherapy (n = 110; adjusted 97.5% confidence interval [CI], (-7.90 to infinity); P = 0.0666; and 97.5% CI, (-8.51 to infinity); P = 0.1178; for combination regimens vs. monotherapy, respectively). Noninferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated (primary end point). A ranibizumab treatment-free interval of 3 months or longer was achieved in 92.6% and 83.5% of the patients randomized to verteporfin SF or verteporfin RF groups, respectively, with a mean of 5.1 and 5.7 ranibizumab injections, respectively, and patients in the ranibizumab monotherapy arm received 10.5 injections. At month 12, mean central retinal thickness decreased by 151.7 MUm and 140.9 MUm for the verteporfin SF and RF groups, respectively, and by 172.2 MUm with ranibizumab monotherapy. Safety and tolerability of all 3 regimens were similar to and consistent with previous studies in neovascular AMD. The number of ocular serious adverse events was low and occurred largely as single cases. CONCLUSIONS: Ranibizumab monotherapy or combined with verteporfin PDT improved BCVA at month 12; however, noninferiority (7-letter margin) of combination regimens to ranibizumab monotherapy was not demonstrated. Verteporfin RF did not confer clinical benefits over verteporfin SF. All treatments were well tolerated. PMID- 22444830 TI - Use and outcomes of emergent laparoscopic resection for acute diverticulitis. AB - BACKGROUND: The use and outcomes of laparoscopic sigmoid resection during emergency admissions for diverticulitis are unknown. METHODS: The Nationwide Inpatient Sample was queried for colorectal resections performed for diverticulitis during emergent hospital admissions (2003-2007). Univariate and multivariate analyses including patient, hospital, and outcome variables were performed. RESULTS: A national estimate of 67,645 resections (4% laparoscopic) was evaluated. The rate of conversion to open operation was 55%. Ostomies were created in 66% of patients, 67% open and 41% laparoscopic. Laparoscopy was not a predictor of mortality (odds ratio [OR] =.70; confidence interval [CI], .32 1.53). Laparoscopy predicted routine discharge (OR = 1.31; CI, 1.06-1.63) and a decreased length of stay (absolute days = -.78; CI, -1.19 to -.37). There was no difference in the cost of hospitalization between the 2 groups (P = .45). CONCLUSIONS: In acute diverticulitis, urgent laparoscopic resection decreases the length of stay. However, it is associated with a high conversion rate, no cost savings, and no difference in mortality. PMID- 22444831 TI - Comparison of the prognostic value of tumour and patient related factors in patients undergoing potentially curative resection of gastric cancer. AB - BACKGROUND: There is increasing evidence that the patient-related systemic inflammatory response is a powerful prognostic factor. The aim of the present study was to compare the prognostic value of selected markers of the systemic inflammatory response in patients undergoing resection of gastric cancer. METHODS: One hundred twenty patients undergoing resection of gastric cancer, had measurements of various systemic inflammatory markers in addition to tumor related factors. From these, the modified Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and metastatic lymph node ratio were calculated. RESULTS: On multivariate analysis, only the ratio of positive to total lymph nodes (hazard ratio, 2.29%; 95% confidence interval, 1.57%-3.33%; P < .001) and the mGPS (hazard ratio, 2.23%; 95% confidence interval, 1.40%-3.54%; P = .001) were independently associated with cancer specific survival in patients with gastric cancer. An increase in the mGPS was associated with a higher neutrophil/lymphocyte ratio (P < .05) and poorer survival (P < .001). CONCLUSIONS: The present study indicates that the mGPS, an acute-phase, protein-based prognostic score, is a superior predictor of cancer survival compared with the cellular components of the systemic inflammatory response in patients undergoing resection of gastric cancer. PMID- 22444833 TI - Antagonistic activity of the fungus Pochonia chlamydosporia on mature and immature Toxocara canis eggs. AB - In vitro tests were performed to evaluate the ability of 6 isolates of the nematophagous fungus Pochonia chlamydosporia to infect immature and mature Toxocara canis eggs on cellulose dialysis membrane. There was a direct relationship between the number of eggs colonized and the increase in the days of interaction, as well as between the number of eggs colonized and the increase in the concentration of chlamydospores (P<0.05). Immature eggs were more susceptible to infection than mature eggs. The isolate Pc-04 was the most efficient egg parasite until the 7th day, and showed no difference in capacity to infect mature and immature eggs in comparison to Pc-07 at 14 and 21 days of interaction, respectively. Isolate Pc-04 was the most infective on the two evolutionary phases of the eggs at most concentrations, but its ability to infect immature eggs did not differ from that presented by the isolates Pc-07 and Pc-10 at the inoculum level of 5000 chlamydospores. Colonization of infective larvae inside or outside the egg was observed in treatments with the isolates Pc-03, Pc-04, Pc-07 and Pc 10. The isolate Pc-04 of P. chlamydosporia has great biological capacity to destroy immature and mature T. canis eggs in laboratory conditions. PMID- 22444834 TI - Evaluation of limited blood sampling population input approaches for kinetic quantification of [18F]fluorothymidine PET data. AB - BACKGROUND: Quantification of kinetic parameters of positron emission tomography (PET) imaging agents normally requires collecting arterial blood samples which is inconvenient for patients and difficult to implement in routine clinical practice. The aim of this study was to investigate whether a population-based input function (POP-IF) reliant on only a few individual discrete samples allows accurate estimates of tumour proliferation using [18F]fluorothymidine (FLT). METHODS: Thirty-six historical FLT-PET data with concurrent arterial sampling were available for this study. A population average of baseline scans blood data was constructed using leave-one-out cross-validation for each scan and used in conjunction with individual blood samples. Three limited sampling protocols were investigated including, respectively, only seven (POP-IF7), five (POP-IF5) and three (POP-IF3) discrete samples of the historical dataset. Additionally, using the three-point protocol, we derived a POP-IF3M, the only input function which was not corrected for the fraction of radiolabelled metabolites present in blood. The kinetic parameter for net FLT retention at steady state, Ki, was derived using the modified Patlak plot and compared with the original full arterial set for validation. RESULTS: Small percentage differences in the area under the curve between all the POP-IFs and full arterial sampling IF was found over 60 min (4.2% 5.7%), while there were, as expected, larger differences in the peak position and peak height.A high correlation between Ki values calculated using the original arterial input function and all the population-derived IFs was observed (R2 = 0.85-0.98). The population-based input showed good intra-subject reproducibility of Ki values (R2 = 0.81-0.94) and good correlation (R2 = 0.60-0.85) with Ki-67. CONCLUSIONS: Input functions generated using these simplified protocols over scan duration of 60 min estimate net PET-FLT retention with reasonable accuracy. PMID- 22444832 TI - Trends in the prevalence and distribution of HTLV-1 and HTLV-2 infections in Spain. AB - BACKGROUND: Although most HTLV infections in Spain have been found in native intravenous drug users carrying HTLV-2, the large immigration flows from Latin America and Sub-Saharan Africa in recent years may have changed the prevalence and distribution of HTLV-1 and HTLV-2 infections, and hypothetically open the opportunity for introducing HTLV-3 or HTLV-4 in Spain. To assess the current seroprevalence of HTLV infection in Spain a national multicenter, cross sectional, study was conducted in June 2009. RESULTS: A total of 6,460 consecutive outpatients attending 16 hospitals were examined. Overall, 12% were immigrants, and their main origin was Latin America (4.9%), Africa (3.6%) and other European countries (2.8%). Nine individuals were seroreactive for HTLV antibodies (overall prevalence, 0.14%). Evidence of HTLV-1 infection was confirmed by Western blot in 4 subjects (prevalence 0.06%) while HTLV-2 infection was found in 5 (prevalence 0.08%). Infection with HTLV types 1, 2, 3 and 4 was discarded by Western blot and specific PCR assays in another two specimens initially reactive in the enzyme immunoassay. All but one HTLV-1 cases were Latin Americans while all persons with HTLV-2 infection were native Spaniards. CONCLUSIONS: The overall prevalence of HTLV infections in Spain remains low, with no evidence of HTLV-3 or HTLV-4 infections so far. PMID- 22444835 TI - Undecided membrane proteins insert in random topologies. Up, down and sideways: it does not really matter. AB - It is usually assumed that to ensure proper function, membrane proteins must be inserted in a unique topology. However, a number of dimeric small multidrug transporters can function in the membrane in various topologies. Thus, the dimers can be a random mixture of NiCi (N and C termini facing the cell cytoplasm) and NoCo (N and C termini facing the outside) orientation. In addition, the dimer functions whether the two protomers are parallel (N and C termini of both protomers on the same side of the membrane) or antiparallel (N and C termini of each protomer on opposite sides of the membrane). This unique phenomenon provides strong support for a simple mechanism of transport where the directionality is determined solely by the driving force. PMID- 22444836 TI - Design and comparison of gene-pyramiding schemes in animals. AB - Marker-assisted gene pyramiding provides a promising way to develop new animal breeds or lines, in which genes responsible for certain favorable characters identified in different breeds or lines are incorporated. In consideration of features of animal populations, we proposed five schemes for pyramiding three genes, denoted Scheme A-E, and five schemes for pyramiding four genes, denoted Scheme F-J. These schemes are representative of the possible alternatives. We also provided an algorithm to compute the population sizes needed in each generation. We compared these schemes with respect to the total population size and the number of generations required under different situations. The results show that there is no scheme that is optimal in all cases. Among the schemes for pyramiding three genes from three lines (L1, L2 and L3), Scheme D (a three-way cross between the three lines are first performed, followed by a backcross to L1 and a subsequent intercross to obtain the desired genotype) has a significant advantage over the other schemes when the recombination rate between adjacent genes ranges from 0.1 to 0.4, while Scheme A (a two-way cross between L1 and L2 and a subsequent intercross are performed, followed by a cross with L3 and a subsequent intercross to obtain the desired genotype) is optimal when recombination rate is 0.5. Among schemes for pyramiding four genes from four lines (L1, L2, L3 and L4), Scheme I (seperately, a two-way cross between L1 and L2 (L3 and L4) followed by a backcross to L1 (L3) and a subsequent intercross are performed, then the offspring from the two sides are crossed and followed by a backcross to L1 and a subsequent intercross to obtain the desired genotype) is optimal when the recombination rate ranges from 0.1 to 0.4, while Scheme F (cross and subsequent intercross between the four lines are performed successively) is the optimal when the recombination rate is 0.5. We also disscuss how the animals' reproductive capacity, the probabilities of obtaining the desired genotypes and genetic distance between adjacent genes would affect the design of an optimal scheme. PMID- 22444837 TI - Genetic parameters of a biological lactation model: early lactation and secretion rate traits of dairy heifers. AB - Early lactation parameters are difficult to estimate from commercial dairy records due to the small number of records available before the peak of production. A biological model of lactation was used with weekly milk records from a single Holstein herd to estimate these early lactation parameters and the secretion rate of milk from the average cell throughout lactation. A genetic analysis of the lactation curve parameters, calculated curve characteristics and secretion rate traits was undertaken. Early lactation traits were found to have little genetic variation and effectively zero heritability. Secretion rate traits for milk, protein, lactose and water were all moderately heritable and highly genetically correlated (>0.87) but fat secretion rate had lower genetic correlations with the other secretion rates. A similar pattern of correlations was seen between total lactation yield traits for fat, protein, lactose and water. The genetic correlations between the lactation curve traits and the secretion rate traits were calculated. Total milk yield, peak yield and maximum secretion potential were all highly correlated with milk, lactose and water secretion rates but less so with fat and protein secretion rates. In particular, fat secretion rate had a moderate to low genetic correlation with these lactation curve traits. Persistency of lactation was highly correlated with fat and protein secretion rates, more persistent lactations being associated with lower rates of secretion of these milk components. Similar levels of heritability were found, where trait genetic parameters were directly equivalent to those derived from the same dataset by random regression methods. However, by using a biological model of lactation to analyse lactation traits new insights into the biology of lactation are possible and ways to select cows on a range of lactation traits may be achieved. PMID- 22444838 TI - Genetic correlations between production and semen traits in pig. AB - Genetic correlations between production traits (average daily gain from birth till the end of the field test and ultrasonically predicted lean meat content at the end of the field test) and semen traits (semen volume, sperm concentration, motility, percentage of abnormal spermatozoa, total number of spermatozoa and number of functional spermatozoa) were estimated from a large dataset (44 500 observations for production traits and more than 150 000 ejaculates from 2077 boars). The boars belonged to the breeds Duroc, Pietrain and Large White or were crossbreds between them. All estimated genetic correlations were low (maximal absolute value 0.13). Therefore, selection on production traits is expected to have only low effects on semen traits. PMID- 22444839 TI - Random regression models for genetic evaluation of clinical mastitis in dairy cattle. AB - A genetic analysis of longitudinal binary clinical mastitis (CM) data recorded on about 90 000 first-lactation Swedish Holstein cows was carried out using linear random regression models (RRM). This method for genetic evaluation of CM has theoretical advantages compared to the method of linear cross-sectional models (CSM), which is currently being used. The aim of this study was to investigate the feasibility and suitability of estimating genetic parameters and predicting breeding values for CM with a linear sire RRM. For validation purposes, the estimates and predictions from the RRM were compared to those from linear sire longitudinal multivariate models (LMVM) and CSM. For each cow, the period from 10 days before to 241 days after calving was divided into four 1-week intervals followed by eight 4-week intervals. Within each interval, presence or absence of CM was scored as '1' or '0'. The linear RRM used to explain the trajectory of CM over time included a set of explanatory variables plus a third-order Legendre polynomial function of time for the sire effect. The time-dependent heritabilities and genetic correlations from the chosen RRM corresponded fairly well with estimates obtained from the linear LMVM for the separate intervals. Some discrepancy between the two methods was observed, with the more unstable results being obtained from the linear LMVM. Both methods indicated clearly that CM was not genetically the same trait throughout lactation. The correlations between predicted sire breeding values from the RRM, summarized over different time periods, and from linear CSM were rather high. They were, however, less than unity (0.74 to 0.96), which indicated some re-ranking of sires. Sire curves based on the time-specific breeding values from the RRM illustrated differences in intercept and slope among the best and the worst sires. To conclude, a linear sire RRM seemed to work well for genetic evaluation purposes, but was sensitive for estimation of genetic parameters. PMID- 22444840 TI - Effects of protein and energy supplementation on growth, forage intake, forage digestion and nitrogen balance in meat goat kids. AB - The objective of this study was to further the understanding of the effects of dietary protein and energy supplements on growth, performance, feed intake and grass forage digestibility in growing meat goat wethers. In Experiment 1, an 18% CP complete goat pellet was offered alone (control diet, C) or added (+), or not, as supplement to three grass hays (coastal bermudagrass, CB; Tifton 85 bermudagrass, T; and sorghum-Sudan grass hay, SS), to Boer-cross wethers (n = 72). The resulting seven diets were offered ad libitum. In Experiment 2, four wether goats in metabolism crates were used in a 4 * 4 Latin square design and fed a SS basal diet ad libitum with treatments consisting of no supplement, supplemental urea (200 mg/kg BW daily), supplemental dextrose (0.2% BW daily), or urea + dextrose (200 mg/kg BW daily and 0.2% BW daily, respectively). In Experiment 1, average daily gain (ADG) were -3.8, -5.0 and -6.6 g/day for goats consuming CB, T and SS, respectively, and 69.2, 61.6 and 58.1 g/day for supplemented CB (CB+), T (T+) and SS (SS+), respectively, as compared to 245.8 g/day for ad libitum access to C. Supplementation in Experiment 1 increased (P < 0.01) ADG for all hays when compared to hay-only diets. In Experiment 2, protein and energy supplementation increased (P < 0.01) nitrogen retention but did not impact diet digestibility. The beneficial effects of supplements in Experiment 1 and the increase in nitrogen retention in Experiment 2 cannot be explained by improvements in ruminal fiber utilization, but could be due to post-ruminal nutrient supply and/or increased ruminal microbial protein synthesis. PMID- 22444841 TI - Modelling the variation in performance of a population of growing pig as affected by lysine supply and feeding strategy. AB - Considerable progress has been made in the nutritional modelling of growth. Most models typically predict (or analyse) the response of a single animal. However, the response to nutrients of a single, representative animal is likely to be different from the response of the herd. To address the variation in response between animals, a stochastic approach towards nutritional modelling is required. In the present study, an analysis method is presented to describe growth and feed intake curves of individual pigs within a population of 192 pigs. This method was developed to allow end-users of InraPorc (a nutritional model predicting and analysing growth in pigs) to easily characterise their animals based on observed data and then use the model to test different scenarios. First, growth and intake data were curve-fitted to characterise individual pigs in terms of BW (Gompertz function of age) and feed intake (power function of BW) by a set of five parameters, having a biological or technico-economical meaning. This information was then used to create a population of virtual pigs in InraPorc, having the same feed intake and growth characteristics as those observed in the population. After determination of the mean lysine (Lys) requirement curve of the population, simulations were carried out for each virtual pig using different feeding strategies (i.e. 1, 2, 3 or 10 diets) and Lys supply (ranging from 70% to 130% of the mean requirement of the population). Because of the phenotypic variation between pigs and the common feeding strategies that were applied to the population, the Lys requirement of each individual pig was not always met. The percentage of pigs for which the Lys requirement was met increased concomitantly with increasing Lys supply, but decreased with increasing number of diets used. Simulated daily gain increased and feed conversion ratio decreased with increasing Lys supply (P < 0.001) according to a curvilinear-plateau relationship. Simulated performance was close to maximum when the Lys supply was 110% of the mean population requirement and did not depend on the number of diets used. At this level of Lys supply, the coefficient of variation of simulated daily gain was minimal and close to 10%, which appears to be a phenotypic characteristic of this population. At lower Lys supplies, simulated performance decreased and variability of daily gain increased with an increasing number of diets (P < 0.001). Knowledge of nutrient requirements becomes more critical when a greater number of diets are used. This study shows the limitations of using a deterministic model to estimate the nutrient requirements of a population of pigs. A stochastic approach can be used provided that relationships between the most relevant model parameters are known. PMID- 22444842 TI - Modulation of porcine cytochrome P450 enzyme activities by surgical castration and immunocastration. AB - The present study aimed to evaluate some cytochrome P450 metabolic enzyme activities in hepatic microsomes prepared from entire male pigs (uncastrated pigs), surgically castrated pigs and pigs immunized against gonadotropin releasing hormone (immunocastrated pigs). The activities of the following enzymes were measured: ethoxyresorufin O-deethylase (EROD, CYP1A1/1A2), methoxyresorufin O-deethylase (MROD, CYP1A2), pentoxyresorufin O-depentylase (PROD, CYP2B), coumarin hydroxylase (COH, CYP2A) and p-nitrophenol hydroxylase (PNPH, CYP2A/2E1). The total cytochrome P450 contents were not affected by either surgical or immunocastration. Hepatic microsomal activities for EROD, PROD, COH and PNPH were lower in entire male pigs compared with surgically castrated and immunocastrated pigs (P < 0.05). Surgically and immunocastrated male pigs were similar with respect to EROD, MROD, PROD and COH activities (P > 0.05), whereas surgically castrated pigs exhibited lower PNPH activity compared with immunocastrated pigs (P = 0.029). The effect of different concentrations of testicular steroids - testosterone, 17beta-estradiol, free estrone and androstenone - on enzyme activities was evaluated by in vitro microsomal study. Testosterone at the concentration of 8 pmol/ml inhibited EROD activities and estradiol-17beta at the concentration of 1.8 pmol/ml inhibited PROD activities in hepatic microsomes from surgically castrated pigs. The highest concentration of androstenone (7520 pmol/ml) inhibited COH activities, whereas a 42-fold lower concentration of androstenone (180 pmol/ml) stimulated COH activities in surgically castrated pigs. Both free estrone (3.5 pmol/ml) and androstenone (55 pmol/ml) inhibited EROD activities in microsomes from entire male pigs. Stimulation of COH activities by the highest dose of free estrone (18 pmol/ml) was recorded in microsomes from entire male pigs. However, these effects of steroids were not concentration-dependent and the maximum extent did not exceed +/-15% variation compared with the controls. There was no inhibition of PNPH activities in the hepatic microsomes from either entire or castrated pigs. In conclusion, we showed that EROD, PROD, COH and PNPH activities were lower in entire male pigs compared with those in surgically and immunocastrated pigs. Direct inhibition by the testicular steroids - testosterone, 17beta-estradiol, free estrone and androstenone - was not the primary cause of the reduced enzyme activities. PMID- 22444843 TI - Reproductive organ weights and semen quality of pubertal boars fed dietary fumonisin B1. AB - Fumonisins, a group of toxic metabolites produced by the genus Fusarium, are known to be consumed by farm animals and are the causative agent or a suspected contributing factor in farm animal diseases. Pigs are particularly susceptible to fumonisins. Reproductive inefficiency is recognized as the most costly limiting constraint to efficient animal production. To account for potential reproductive effects of fumonisin in boars, dietary fumonisin B1 (FB1) was fed to 24 male Large White weanling pigs, 8 to 9 weeks of age. The animals were randomly assigned to four diets containing 5.0, 10.0, 15.0 and 0.2 mg FB1/kg constituting diets 1, 2, 3 and control diet, respectively. After 6 months, semen samples were collected from the pubertal boars and analysed. After the semen collection, all the pubertal boars were killed by decapitation, their reproductive systems dissected and the weights of the testes and epididymides as well as the volumes of the testes recorded. Dietary FB1 did not influence both the relative weights of the testes and epididymides as well as the volumes of the testes. Except for the semen volume and spermatozoa morphological abnormalities, all the semen characteristics studied decreased in a dose-dependent manner and the decrease was statistically significant (P < 0.05). The sperm concentration, total sperm and motile sperm per ejaculate of the animals on diet 3 were 83.3%, 79.1% and 59.6% of the controls, respectively. The dietary FB1 levels influenced the mass activities of the semen, which ranged from very turbulent motion for animals on the control diet to absence of wave motion for those on diet 3. The study revealed that male weanling pigs for breeding should not be exposed to dietary FB1 higher than 5 mg/kg for optimum reproductive performance. The results of this present study suggest that the recommendation of 10 mg/kg by the United States Food and Drug Administration as the maximum level of total dietary fumonisins was above the no-observable-effect level of dietary fumonisin for swine. PMID- 22444844 TI - The pig model in brain imaging and neurosurgery. AB - The pig model is increasingly used in the field of neuroscience because of the similarities of its brain with human. This review presents the peculiarities of the anatomy and functions of the pig brain with specific reference to its human counterpart. We propose an approximate mapping of the pig's cortical areas since a comprehensive description of the equivalent of Brodmann's areas is lacking. On the contrary, deep brain structures are received more consideration but a true three-dimensional (3D) atlas is still eagerly required. In the second section, we present an overview of former works describing the use of functional imaging and neuronavigation in the pig model. Recently, the pig has been increasingly used for molecular imaging studies using positron emission tomography (PET). Indeed, the large size of its brain is compatible with the limited spatial resolution of the PET scanner built to accommodate a human being. Similarly, neuronavigation is an absolute requirement to target deep brain areas in human and in pig since the surgeon cannot rely on external skull structures for zeroing the 3D reference frame. Therefore, a large body of methodological refinements has been dedicated to image guided surgery in the pig model. These refinements allow now a millimetre precision: an absolute requirement for basal nuclei targeting. In the third section, several examples of ongoing studies in our laboratory were presented to illustrate the intricacies of using the pig model. For both examples, after a brief description of the scientific context of the experiment, we present, in detail, the methodological steps required to achieve the experimental goals, which are specific to the porcine model. Finally, in the fourth section, the anatomical variations depending on the breed and age are discussed in relation with neuronavigation and brain surgery. The need for a digitized multimodality brain atlas is also highlighted. PMID- 22444845 TI - Perceptions of the importance of different welfare issues in livestock production. AB - The opinions of seven respondent groups about the relative importance of different practices pertaining to the welfare of Australian beef cattle, sheep and goats were surveyed. Respondent groups comprised farmers, livestock transportation representatives, veterinarians, meat processors, animal welfare advocates, animal welfare scientists and government officers. The survey consisted of a web-based adaptive conjoint analysis questionnaire, which was administered to a sample population that was selected randomly for large respondent groups and comprehensively for small groups. The hierarchy of opinion concerning the importance of the different beef cattle practices was: stockmanship > ground (road and rail) transport > spaying > food supply > dehorning > stunning > shelter > identification > pretransport food and water deprivation > castration > sea transport > mustering > confinement. For sheep/goat practices the hierarchy was: parasite control > mulesing > shelter > stockmanship > tail docking > ground transport > feeding > predation > stunning > castration > pretransport food and water deprivation > sea transport > mustering. The method of performing invasive procedures was perceived as less important than the provision of pain relief. Differences in opinion were evident between respondent groups, with animal welfare advocates tending to focus on painful procedures more than those with direct involvement in the industry. PMID- 22444846 TI - Assessing the welfare challenges to out-wintered pregnant suckler cows. AB - Out-wintering beef cows reduces annual housing costs and bedding requirements and there is less exposure to diseases associated with housing. However, to counter these benefits cows may be exposed to conditions that pose a significant challenge to welfare, and ways of assessing this are required. Two feeding treatments were applied to four groups of 10 cows (two groups/treatment), one to maintain condition score (H) and the other to allow a modest loss of condition score (L), which is commonly applied in farm practice. Cow groups were rotated around four paddocks in a Latin Square design of four periods each of 3 weeks, and they were weighed and condition was scored at the end of each period. Their behaviour and location was recorded at 30-min intervals with six 3-h sessions in each period. Ambient temperature, wind speed, rainfall and solar radiation were recorded every 30 min to enable calculation of cow lower critical temperature (LCT). The climatic conditions were wet at the start of the experiment with moderate wind speeds throughout (5 m/s) and relatively mild ambient temperature (5 degrees C). Feeding treatment had no significant effect on any of the variables measured. Cows spent most of the observation sessions standing, particularly at the beginning of the experiment when the soil conditions were wettest. They sought sheltered locations when wind speeds were high and thus their calculated LCT was near or below ambient temperature. Nutritional models predicted periods of cold stress but the cows adapted their behaviour to counteract this, emphasising the need for a combined physical and behavioural approach to assessing welfare challenges. PMID- 22444847 TI - Mortality in Holstein-Friesian calves and replacement heifers, in relation to body weight and IGF-I concentration, on 19 farms in England. AB - The incidence of mortality and culling in Holstein-Friesian heifers from birth through first calving was determined on 19 dairy farms selected from across southern England. The outcome of 1097 calvings was determined. Size (BW, heart girth, crown-rump length and height at withers) and insulin-like growth factor-I concentration of live heifer calves were measured at a mean age of 26 +/- 0.7 days (n = 506). Associations between the heifer-level variables and mortality were determined using clustered binary logistic regression. Perinatal mortality (stillbirths and mortality within the first 24 h of birth) of male and female calves was 7.9%. This figure was significantly higher in cases where calving assistance was required (19.1% v. 5.6%, P < 0.001) and in twin births (18.5% v. 7.0%, P < 0.05), and was lower in pluriparous v. primiparous dams (5.6% v. 12.1%, P < 0.01). On average, 6.8% of heifers died or were culled between 1 day and 6 months of age. Low BW at 1 month was associated with reduced subsequent survival up to 6 months. Between 6 months and first calving, a further 7.7% of heifers either died (42%) or were culled (58%); accidents and infectious disease accounted for the majority of calf deaths between 6 and 15 months, whereas infertility (16/450 animals served, 3.5%) was the main reason for culling following the start of the first breeding period. In total, 11 heifers (2.2%) were culled as freemartins; eight at birth and three around service. Overall, 14.5% of liveborn potential replacement heifers died or were culled before first calving. PMID- 22444848 TI - A pre-partum lift in ewe nutrition from a high-energy lick or maize or by grazing Lotus uliginosus pasture, increases colostrum production and lamb survival. AB - This experiment tested the hypothesis that a lift in the nutrition of ewes, before lambing, to increase colostrum production would enhance lamb survival. In all, 261 mature Corriedale ewes, each with a single fetus from a synchronised mating, grazed native pasture to day 130 after mating; at which point they were weighed, condition scored and allocated to graze either native pasture or a pasture dominant with Lotus uliginosus. Five days later (14 days before the expected start of lambing) the ewes were allocated to one of four treatments and fed: (i) native pasture alone, (ii) native pasture plus a commercial high-energy lick, (iii) L. uliginosus pasture alone or (iv) L. uliginosus pasture plus whole maize. The weight, viscosity and concentration of components and immunoglobulin G in the colostrum that had accumulated at parturition, were measured for 10 ewes in each treatment. The lambs that survived to 20 days of age from the 221 ewes that were not milked, were recorded. The ewes supplemented with the lick or maize grain and those that grazed the L. uliginosus pasture alone accumulated two to three times more colostrum at birth than the ewes that grazed native pasture alone (396, 635 and 662 g v. 206 g; P < 0.01). The colostrum from the ewes that grazed only native pasture was more viscous (lower score) than that from the ewes supplemented with the lick or maize grain or the ewes that grazed the L. uliginosus pasture alone (scores of 4.1 v. 6.2, 6.5 and 6.4, P < 0.001) and, not surprisingly, the concentration of lactose in the colostrum of the ewes fed only native pasture was also much lower (1.1% v. 3.0%, 2.8% and 2.6%; P < 0.001)he survival of lambs from the ewes fed only native pasture was less than that of the lambs from ewes fed native pasture plus the commercial lick (81.8% v. 95.5%; P < 0.05) or the L. uliginosus pasture alone (92.4%, P < 0.05), and also tended to be lower than that for lambs born to ewes fed L. uliginosus pasture plus maize (91.8%, P = 0.08). The concentration of glucose in the blood of the lambs from the ewes that grazed only native pasture was lower than that of the other lambs (42.1 v. 60.2 ng/ml, P = 0.012). We conclude that the marked increase in colostrum production associated with the lift in ewe nutrition, just prior to lambing, enhanced lamb survival. PMID- 22444849 TI - Phyto-oestrogens in herbage and milk from cows grazing white clover, red clover, lucerne or chicory-rich pastures. AB - A grazing experiment was carried out to study the concentration of phyto oestrogens in herbage for cattle and in milk during two periods (May and June). Forty-eight Danish Holstein cows were divided into four groups with four treatment diets; white clover, red clover, lucerne and chicory-rich pastures. Each experimental period lasted 15 days. Herbage samples from the first day and individual milk samples from the last day of the experimental period were analysed for phyto-oestrogens using LC-MS technique. The total concentration of phyto-oestrogens was 21 399 mg/kg dry matter (DM) for red clover and 238 to 466 mg/kg DM for the other three herbages mainly due to a much higher concentration of biochanin A, formononetin and glycitein in red clover. In the milk, the total concentration of phyto-oestrogens was 253 to 397 MUg/l for red clover milk and 56 to 91 MUg/l in the milk from the other three treatments. This was especially due to a higher concentration of equol, daidzein and formononetin in the red clover milk. The concentration of biochanin A was significantly higher in milk from the red clover treatment in May while no differences were observed in June. Enterodiol was similar across treatments while the concentration of enterolactone was significantly lower for red clover milk compared with the other treatments. Of the tested pastures, red clover appears to have the highest concentration and to be the best source of phyto-oestrogens, especially equol, in bovine milk. PMID- 22444850 TI - Effect of supplementation of the maternal diet with fish oil or linseed oil on fatty-acid composition and expression of Delta5- and Delta6-desaturase in tissues of female piglets. AB - The present study investigated whether enrichment of the pig maternal diet with n 3 polyunsaturated fatty acids (PUFA) affects the fatty-acid composition of female piglets via enhancing of expression of the lipogenic enzymes Delta5-desaturase (Delta5d) and Delta6-desaturase (Delta6d). The sows (50% Landrace * 50% Large White) were fed a control diet or one of the experimental diets starting at day 45 in gestation. The experimental diets were supplemented either with linseed oil or fish oil, whereas the control diet contained palm oil. Expression of Delta5d and Delta6d, and fatty-acid composition was determined by Western blotting and gas-liquid chromatography, respectively, in muscle, subcutaneous adipose tissue and liver. The highest Delta5d protein expression was observed in the piglets' muscle, followed by subcutaneous adipose tissue, with the lowest level in the liver. Expression of Delta6d in the piglets' tissues followed an opposite pattern, and was highest in the liver, followed by subcutaneous adipose tissue, with the lowest level in muscle. Supplementation of the maternal diet with fish oil or linseed oil increased the level of n-3 PUFA of the piglets in a tissue specific manner. The response of Delta6d and Delta5d protein expression in female piglets, with average birth weight 2.4 kg, to the dietary manipulation was also tissue-specific. It is suggested that the increase in n-3 PUFA content in the progeny was related, at least partially, to the activation of Delta6d and Delta5d expression. PMID- 22444851 TI - Comparison of accuracy of intramuscular fat prediction in live pigs using five different ultrasound intensity levels. AB - The objective of this study was to evaluate the possibility of prediction of intramuscular fat (IMF) in live pigs using ultrasound method. Moreover, the accuracy of prediction at five different ultrasound intensity levels was investigated. Cross-sectional images of longissimus dorsi muscle (LD) at right last rib area, from hybrid pigs, were taken. Each pig was scanned at the same frequency (3.5 MHz) and at the five different ultrasound intensity levels 70%, 75%, 80%, 85% and 90% of total amplifying of sonograph, using the device ALOKA SSD-500. The video image analysis was used to predict IMF content (ultrasound intramuscular fat (UIMF) 70 to UIMF90). The second day after slaughter, the dissection of right half carcass was done. A sample of LD at the last rib was taken for laboratory analysis of IMF content (LAIMF). Scatter plots with UIMF on the x-axis and LAIMF on the y-axis were constructed to account for individual variability within and between intensity levels. Correlations between LAIMF and UIMF were significantly different from zero (r = 0.40-0.52), except for correlation between LAIMF and UIMF90 (r = 0.14). Statistical model with LAIMF (the dependent variable), UIMF (the same model for each intensity level), live weight (the covariates) and sex (the fixed effect) was developed. Coefficients of determination (R2) were 0.33, 0.38, 0.34, 0.25 and 0.17 with UIMF at the intensity level 70%, 75%, 80%, 85% and 90%. Root mean square errors ranged from 0.516% to 0.639%. Standard errors of individual prediction ranged from 0.523% to 0.649%. Goodness-of-fit of the model was also justified by testing the residuals for normality. Although the results are not quite unequivocal in favour of the one intensity level, it seems that intensity levels 75% and 80% are the most suitable to predict IMF in live pigs. Further research is needed, mainly to increase accuracy of collecting, processing and evaluating the sonograms using video image analysis. PMID- 22444852 TI - Genetic variability in calving success in Aberdeen Angus cows under extensive recording. AB - Data from 2032 Uruguayan Aberdeen Angus cows under extensive management and recording practices were analysed with Bayesian threshold-liability sire models, to assess genetic variability in calving success (CS), defined as a different binary trait for each of the second (CS2), third (CS3) and fourth (CS4) calving opportunities. Sire (herd) variances ranged from 0.08 to 0.11 (0.10 to 0.20) and heritability from 0.27 to 0.35, with large credibility intervals. Correlations between herd effects on CS at different calving opportunities were positive. Genetic correlation between CS2 and CS4 was positive (0.68), whereas those involving adjacent calving opportunities (CS2-CS3 and CS3-CS4) were negative, at 0.39 and -0.54, respectively. The residual correlation CS2-CS3 was negative ( 0.32). The extent of uncertainty associated with the posterior estimates of the parameters was further evaluated through simulation, assuming different true values (-0.4, -0.2, +0.2 and +0.4) for the genetic correlations and changes in the degree of belief parameters of the inverse Wishart priors for the sire covariance matrix. Although inferences were not sharp enough, CS appears to be moderately heritable. The quality of data recording should be improved, in order to effect genetic improvement in female fertility. PMID- 22444853 TI - The Asp298Asn missense mutation in the porcine melanocortin-4 receptor ( MC4R) gene can be used to affect growth and carcass traits without an effect on meat quality. AB - A promising tool to improve daily gain in pigs is the missense mutation (Asp298Asn) in the melanocortin-4 receptor (MC4R) gene, especially in the Belgian pig industry where the slow-growing Pietrain breed is very frequently used as the sire breed. The MC4R is expressed in the appetite-regulating region of the brain where it regulates feed intake and energy balance. The mutation has been associated with differences in fatness, daily gain and feed intake. However, less information on the correlated effects on meat quality is available. In order to evaluate the influence of the MC4R mutation on carcass and meat quality parameters, a total of 1155 pigs of a four-way cross were slaughtered at an average live weight of 109 kg, and data about daily live-weight gain, carcass and meat quality were collected. Allelic frequencies were 0.69 for the G-allele (298Asp variant or well-conserved variant) and 0.31 for the A-allele (298Asn variant or the mutated variant). Barrows and gilts were almost equally distributed in this population with, respectively, 49.9% and 50.1%. Moreover, independent of this mutation, the relationship between average daily gain (ADG) and carcass on the one hand and meat quality traits on the other hand was evaluated in this population. A significant positive influence of the MC4R mutation on ADG (P < 0.001) was found, accompanied by a higher fat thickness (P < 0.05) and a lower carcass lean meat content (P < 0.01), whereas muscle thickness and carcass conformation traits were not affected. The effects on meat quality traits were not significant, except for a lower shear force (P = 0.054) and a higher intramuscular fat content (P = 0.052) in AA animals. In the longissimus, pH and pork quality meter (PQM) values were not influenced, and effects on drip loss and colour were not apparent. Residual correlation coefficients between ADG and carcass lean meat content on the one hand and meat quality traits on the other hand were generally very low (|r|>0.1). Higher ADG, higher carcass fat thickness and lower carcass lean meat content were correlated with slightly lower shear force values (|r|~0.1, P < 0.05). In conclusion, in the studied population, the Asp298Asn mutation in the MC4R gene was associated with improved daily gain, higher carcass fatness and almost no effect on meat quality traits. PMID- 22444854 TI - Identification of the CSN1S1 allele in Indian goats by the PCR-RFLP method. AB - The allelic distributions of the CSN1S1 (alphas1-casein) in the Indian goats are quite different from European goat breeds. Majority of Indian goat breeds and non descript goats carry A, B, E and F alleles at alphas1-casein locus, as found by analysing both DNA and protein levels. However, A and B alleles, known to be associated with better casein yield, were observed in the highest proportion in all the Indian goat breeds. Gene frequency and breed heterozygosity were computed for the CSN1S1 gene. The gene frequency of allele A in Indian goats varies from 0.68 to 1.00 and allele B varies from 0.098 to 0.23. Allele F was observed in Beetal, Marwari, Chegu and non-descript goats of MP (Local MP) in less than 1% of population. The expected heterozygosity (He) varied from 0.141 to 0.506 over the population. The Beetal breed showed the highest gene diversity (0.506) followed by Jamunapari (0.395), Chegu (0.383) and Jakhrana (0.381) breeds. Therefore, the variability at CSN1S1 locus can be utilised for conservation as well as for genetic improvement of Indian goat breeds for increasing both the quality and quantity of milk production. PMID- 22444855 TI - Heritabilities of osteochondral lesions and genetic correlations with production and exterior traits in station-tested pigs. AB - Osteochondrosis might reduce the performance of slaughter pigs, longevity of sows and animal welfare. The aim of the present work was to describe the prevalence in Swiss breeds and to analyse the genetic background of osteochondral lesions. Between January 2002 and December 2005, about 9500 station-tested pigs were examined for several exterior traits before slaughtering at the Swiss pig performance testing station using the Swiss linear description system with a scale from 1 to 7 per trait. The animals belonged to three breeds: Large White dam line, Swiss Landrace and Large White sire line. Additionally, a random sample of these pigs (n = 2622) was examined for osteochondral lesions at seven positions of the carcass after dissection. At first, the surface and shape of the femur, humerus, radius and ulna at the joints were evaluated by a trained person. Afterwards these bones were sawed and the state of the cartilage and the distal epiphyseal cartilage of the ulna was examined at the cutting surface. Osteochondral lesions were scored on a scale from 1 to 6. The prevalence of osteochondral lesions was low at head of humerus, condylus lateralis humeri, radius and ulna proximal and head of femur. Osteochondral lesions at condylus medialis humeri (CMH), distal epiphyseal cartilage of ulna (DEU) and condylus lateralis femoris (CMF) exhibited phenotypic and genetic variance. Their heritabilities ranged from 0.16 to 0.18 using linear mixed animal models. Therefore, it is possible to reduce the prevalence of osteochondral lesions by selection in principle. Exterior traits showed low heritabilities (0.10 to 0.26) but several favourable genetic correlations with osteochondral lesions at CMH, DEU and CMF with low to moderate magnitude. Genetic correlations between osteochondral lesions and production traits were low. PMID- 22444856 TI - The effect of high and low dietary crude protein and inulin supplementation on nutrient digestibility, nitrogen excretion, intestinal microflora and manure ammonia emissions from finisher pigs. AB - A 2 * 2 factorial experiment was performed to investigate the interaction between a high- and low-crude-protein (CP) diet (200 v. 140 g/kg) and inulin supplementation (0 v. 12.5 g/kg) on nutrient digestibility, nitrogen (N) excretion, intestinal microflora, volatile fatty acid (VFA) concentration and manure ammonia emissions from 24 boars (n = 6, 74.0 kg live weight). The diets were formulated to contain similar concentrations of digestible energy and lysine. Pigs offered the high-CP diets had a higher excretion of urinary N (P < 0.001), faecal N (P < 0.01) and total N (P < 0.001) than the pigs offered the low CP diets. Inulin supplementation increased faecal N excretion (P < 0.05) and decreased the urine N : faeces N ratio (P < 0.05) compared with the inulin-free diets. There was no effect (P > 0.05) of dietary treatment on N retention. There was an interaction (P < 0.05) between dietary CP concentration and inulin supplementation on caecal Enterobacteria spp. Pigs offered the diet containing 200 g/kg of CP plus inulin decreased the population of Enterobacteria spp. compared to those with the inulin-supplemented 140 g/kg CP diet. However, CP level had no significant effect on the population of Enterobacteria spp. in the unsupplemented diets. Inulin supplementation increased caecal Bifidobacteria (P < 0.01) compared with the inulin-free diets. There was no effect of inulin supplementation on VFA concentration or intestinal pH (P > 0.05). Pigs offered the 200 g/kg CP diets had higher (P < 0.05) manure ammonia emissions from 0 to 240 h of storage than pigs offered the 140 g/kg CP. In conclusion, inulin supplementation resulted in an increase in Bifidobacteria concentration and a reduction in Enterobacteria spp. at the high CP level indicating that inulin has the ability to beneficially manipulate gut microflora in a proteolytic environment. PMID- 22444857 TI - Genetic variations in the digestibility in sheep of selected whole-crop cereals used as silages. AB - Whole-plant winter cereals could be of great interest if used as silages for ruminant feeding as opposed to summer crops in that they would spare water resources or valorize low-input management. This study aimed to compare the feeding value of rye, barley, wheat (two genotypes) and triticale (six genotypes). The cereals were sown in October and harvested as silage in June. Forages were offered to Texel castrated sheep in order to evaluate the organic matter digestibility (OMd). The OMd of the wheat cultivars was higher (61.6%, P<0.05) than those of barley (57.2%) and rye (54.7%) but no different from that of triticale (60.6%). Within the triticale genotypes, OMd ranged from 54.7 to 62.3%. The presence of rough barbs should explain the relatively low intake of the cereals with the exception of wheat. Winter cereals provide good-quality forage for feeding ruminants. Wheat has a higher nutritional value than barley and rye and a wide variability for digestibility seems to exist within the triticale cultivars. Such variability in a species known for its ability to be cropped under limiting conditions should be explored in much greater depth as it could result in providing farmers with genotypes of good quality with an acceptable yield at a lower cost. PMID- 22444858 TI - The source of fermentable carbohydrates influences the in vitro protein synthesis by colonic bacteria isolated from pigs. AB - Two in vitro experiments were carried out to quantify the incorporation of nitrogen (N) by pig colonic bacteria during the fermentation of dietary fibre, including non-starch polysaccharides and resistant starch. In the first experiment, five purified carbohydrates were used: starch (S), cellulose (C), inulin (I), pectin (P) and xylan (X). In the second experiment, three pepsin pancreatin hydrolysed ingredients were investigated: potato, sugar-beet pulp and wheat bran. The substrates were incubated in an inoculum, prepared from fresh faeces of sows and a buffer solution providing 15N-labelled NH4Cl. Gas production was monitored. Bacterial N incorporation (BNI) was estimated by measuring the incorporation of 15N in the solid residue at half-time to asymptotic gas production (T/2). The remaining substrate was analysed for sugar content. Short chain fatty acids (SCFA) were determined in the liquid phase. In the first experiment, the fermentation kinetics differed between the substrates. P, S and I showed higher rates of degradation (P < 0.001), while X and C showed a longer lag time and T/2. The sugar disappearance reached 0.91, 0.90, 0.81, 0.56 and 0.46, respectively, for P, I, S, C and X. Among them, S and I fixed more N per gram substrate (P < 0.05) than C, X and P (22.9 and 23.2 mg fixed N per gram fermented substrate v. 11.3, 12.3 and 9.8, respectively). Production of SCFA was the highest for the substrates with low N fixation: 562 and 565 mg/g fermented substrate for X and C v. 290 to 451 for P, I and S (P < 0.01). In the second experiment, potato and sugar-beet pulp fermented more rapidly than wheat bran (P < 0.001). Substrate disappearance at T/2 varied from 0.17 to 0.50. BNI were 18.3, 17.0 and 10.2 fixed N per gram fermented substrate, for sugar-beet pulp, potato and wheat bran, respectively, but were not statistically different. SCFA productions were the highest with wheat bran (913 mg/g fermented substrate) followed by sugar-beet pulp (641) and potato (556) (P < 0.05). The differences in N uptake by intestinal bacteria are linked to the partitioning of the substrate energy content between bacterial growth and SCFA production. This partitioning varies according to the rate of fermentation and the chemical composition of the substrate, as shown by the regression equation linking BNI to T/2 and SCFA (r2 = 0.91, P < 0.01) and the correlation between BNI and insoluble dietary fibre (r = 0.77, P < 0.05) when pectin was discarded from the database. PMID- 22444859 TI - Intestinal development and growth performance of early-weaned piglets fed a low threonine diet. AB - High dietary threonine extraction by the digestive tract suggests that threonine contributes to maintain gut integrity. The aims of this study were to investigate the intestine development and the growth performance of early-weaned piglets pair fed either a control well-balanced (C: 9.3 g threonine/kg diet) or a low threonine diet (LT: 6.5 g threonine/kg diet) for 2 weeks. As expected, LT piglets presented lower plasma free threonine compared with C piglets (118 v. 356 +/- 12 MUmol/l, P < 0.001). Dietary threonine supply altered neither growth performance nor growth of the intestine and of the other portal-drained viscera (stomach, spleen and pancreas). Nevertheless, villus height was reduced in the ileum of the LT piglets compared with C piglets (446 v. 714 +/- 74 MUm, P < 0.05). This was also associated with a decrease in crypt width (P < 0.05) and villus height-to crypt depth ratio (P < 0.05). Whereas maltase and lactase activities did not change between the two groups, aminopeptidase nitrogen activity was decreased in the ileum of LT piglets (269 v. 374 +/- 27 IU/mg protein, P < 0.05). The number of mucin-containing goblet cells was not modified in the ileum and in the proximal part of the large intestine of the LT piglets compared with the C piglets. In conclusion, despite no alteration of intestinal growth, villus hypotrophy associated with a reduction of aminopeptidase nitrogen activity suggest an alteration of the structure of the ileum in early-weaned piglets fed a diet supplying inadequate dietary threonine. PMID- 22444860 TI - Dynamic model of the lactating dairy cow metabolism. AB - The whole-animal model described in this paper is intended to be a research model with an intermediary structure between sophisticated and simple cow models. The mechanistic model structure integrates the main metabolic pathways of the lactating dairy cow. Milk yield and related feed intake for varying production potentials were considered to be the driving forces and were empirically defined. The model was designed to explain the main metabolic flows and variations in body reserves associated with the push of nutrients from dry matter intake and their pull by the mammary gland to synthesise milk components throughout lactation. The digestive part of the model uses either known feed unit systems (e.g. PDI system for protein) or published empirical equations for the prediction of digestive flows of organic matter, starch and fatty acids and ruminal volatile fatty acid production. The metabolic sub-system is made up of four tissue compartments (body protein, body lipid, protein in the uterus and triglycerides in the liver) and five circulating metabolites (glucose, amino acids, acetate + butyrate, propionate, and triglycerides and non-esterified fatty acids). A major original aspect of the model is its homeorhetic control system. It was assumed that flows relating to adipose and protein tissue anabolism and catabolism were driven by a couple of linked theoretical hormones controlling mobilisation and anabolism. The evolution in body composition and body weight were outcomes of this control. Another originality of the model is its suitability for milk yields varying from 10 to 50 kg at peak production. This was achieved by homeorhetic control of milk potential acting on several key metabolic flows. Homeostatic regulation was also introduced in order to confine the behaviour of the model within realistic physiological values. For some basic aspects (e.g. Uterine involution, standard kinetics of body protein and fat), it was necessary to build specific databases from the literature and interpret these by meta-analysis. Fairly realistic simulated kinetics were obtained for body composition, liver triglycerides, blood plasma metabolite concentrations, milk protein and fat contents, and also for major groups of milk fatty acids. PMID- 22444861 TI - Tail docking in horses: a review of the issues. AB - Routinely performed painful procedures are of increasing interest and, in 2001 (Royal Order, May 17), Belgium prohibited docking in several vertebrates including horses. In 2004, opponents to this decision submitted a Bill (Doc51 0969/001) to Parliament, intending to obtain derogation for Belgian draught horses, which were traditionally docked. The Animal Welfare Council of Belgium, an official body advising the Minister of Public Health, was asked to evaluate this complex question, including biological, ethical and socio-economic aspects, on the basis of the available peer-reviewed studies. In this context, this study reviews legal aspects (overview of the European legislation), zootechnic aspects (uses of the Belgian draught horse) and biological aspects (pain potentially related to docking; horses' welfare linked to insect harassment and hygiene, communication and reproduction) of tail docking in draught horses. We conclude that (1) there is no benefit for horses in tail docking, including Belgian draught horses, (2) potential advantages of docking are essentially in favour of humans and these advantages could be scrupulously re-evaluated, taking into account practices of other countries. Therefore, there is no need to dock any horse other than for veterinary reasons. PMID- 22444862 TI - Aggregation of measures to produce an overall assessment of animal welfare. Part 1: a review of existing methods. AB - Several systems have been proposed for the overall assessment of animal welfare at the farm level for the purpose of advising farmers or assisting public decision-making. They are generally based on several measures compounded into a single evaluation, using different rules to assemble the information. Here we discuss the different methods used to aggregate welfare measures and their applicability to certification schemes involving welfare. Data obtained on a farm can be (i) analysed by an expert who draws an overall conclusion; (ii) compared with minimal requirements set for each measure; (iii) converted into ranks, which are then summed; or (iv) converted into values or scores compounded in a weighted sum (e.g. TGI35L) or using ad hoc rules. Existing methods used at present (at least when used exclusively) may be insufficiently sensitive or not routinely applicable, or may not reflect the multidimensional nature of welfare and the relative importance of various welfare measures. It is concluded that different methods may be used at different stages of the construction of an overall assessment of animal welfare, depending on the constraints imposed on the aggregation process. PMID- 22444863 TI - Aggregation of measures to produce an overall assessment of animal welfare. Part 2: analysis of constraints. AB - The overall assessment of animal welfare is a multicriterion evaluation problem that needs a constructive strategy to compound information produced by many measures. The construction depends on specific features such as the concept of welfare, the measures used and the way data are collected. Welfare is multidimensional and one dimension probably cannot fully compensate for another one (e.g. good health cannot fully compensate for behavioural deprivation). Welfare measures may vary in precision, relevance and their relative contribution to an overall welfare assessment. The data collected are often expressed on ordinal scales, which limits the use of weighted sums to aggregate them. A sequential aggregation is proposed in the Welfare Quality(r) project, first from measures to welfare criteria (corresponding to dimensions with pre-set objectives) and then to an overall welfare assessment, using rules determined at each level depending on the nature and number of variables to be considered and the level of compensation to be permitted. Scientific evidence and expert opinion are used to refine the model, and stakeholders' approval of general principles is sought. This approach could potentially be extended to other problems in agriculture such as the overall assessment of the sustainability of production systems. PMID- 22444864 TI - Methodological developments in the use of visible reflectance spectroscopy for discriminating pasture-fed from concentrate-fed lamb carcasses. AB - The ability to authenticate the feed given to animals from the animal products has become a major challenge for scientists, monitoring bodies and commercial entities alike. This study compared two methods based on the use of the visible reflectance spectrum of the fat to discriminate pasture-fed (P) from stall concentrate-fed (S) lamb carcasses. A total of 307 (143 P and 164 S) Limousine lambs were used over 2 years. Pasture-fed lambs grazed a permanent pasture that was maintained at a leafy, green vegetative stage, and offered ad libitum; they received no supplementation at pasture. Body weight of P lambs when turning out to pasture and at slaughter averaged 9.2 (standard deviation (s.d.) 2.21) kg and 33.2 (s.d. 2.89) kg, respectively. S lambs were fed indoors on an ad libitum diet of commercial concentrate and hay until slaughter at a mean body weight of 33.7 (s.d. 3.62) kg. The reflectance spectrum of perirenal and subcutaneous caudal fat was measured at slaughter and at 24 h post mortem. Plasma carotenoid concentration was measured at slaughter. In method 1, the fat reflectance spectrum data were used at wavelengths between 450 and 510 nm to calculate an index quantifying light absorption by carotenoid pigments. In method 2, a multivariate analysis was performed over the full set of fat reflectance data at wavelengths between 400 and 700 nm. Method 2 yielded a higher proportion of correctly classified lambs compared with method 1 (P < 0.05 to 0.001), except for measurements made at 24 h post mortem on perirenal fat for S lambs. The proportion of lambs correctly classified using method 2 was 87.4% and 92.9% for measurements made on perirenal and caudal fat at slaughter, and 93.9% and 91.0% for measurements made on perirenal and caudal fat 24 h post mortem. Plasma carotenoid concentrations were higher in P lambs than in S lambs (P < 0.001), which led to correct classification of 90.7% of the lambs. PMID- 22444865 TI - Explaining diversity of livestock-farming management strategies of multiple-job holders: importance of level of production objectives and role of farming in the household. AB - We characterised the livestock-farming management strategies of multiple-job holders and identified which variables contributed most to the differentiation of these strategies. We hypothesised that they would mainly be differentiated by the contribution of the farming income to the total household income and the availability of the household members for farming. The multiple-job holding livestock-farmer's motivations, decisions and actions about both multiple-job holding and livestock farming were obtained in semi-directed interviews of 35 sheep farmers who held multiple jobs, on farm and off farm. They were synthesised into six variables characterising the diversity of the livestock-farming objectives and management guidelines. Thanks to a multiple factorial analysis, we showed that the diversity of the sheep-farming management strategies of multiple job holders was better explained by two factors 'level of motivation of the farmer to get high technical results' and 'more personal fulfilling v. the family business conception of farming', than the factors we hypothesised. Within our sample, the performances ranged from 0.7 to 1.4 weaned lambs per ewe per year. Six sheep-farming management strategies were identified. They illustrated the importance of the level of production objectives and of farming income expectation, which were found to be independent, in explaining diversity. No direct relationship between farm work organisation and sheep-farming management strategy was identified. Explaining the diversity of the livestock-farming management strategies of multiple-job holders appears to require that all the benefits expected from farming and their hierarchy be identified before analysing how they are translated into production objectives and management guidelines. PMID- 22444866 TI - Investigation of growth rate variation between commercial pig herds. AB - The study was designed to provide quantifiable information on both within- and between-herd variation in pig growth rate from birth to slaughter and to examine how this was influenced by moving pigs at a common age to a common environment. Five litters were selected from each of eight pig herds in Northern Ireland with varying growth performance. All eight herds were offered the same nutritional regime. Five pigs (three boars and two gilts) were selected from each litter. In each herd, 22 pigs (12 boars and 10 gilts) were weighed individually, every 4 weeks, from 4 to 20 weeks of age. At 4 weeks of age (weaning) three non-sibling boars were taken from each herd and brought to a common environment where they received medication, were housed individually from 6 weeks of age and offered the same dietary regime. They were weighed and feed intakes were recorded twice weekly. A growth rate difference of 61 g/day (P < 0.001), 112 g/day (P < 0.01) and 170 g/day (P < 0.001) was observed on farm, between the top and bottom quartile of herds during 4 to 8, 8 to 12 and 12 to 20 weeks of age, respectively. This difference in growth rate equated to an average difference in cost of production of c13/kg carcass on a birth to bacon unit. When pigs from the different herds were housed in the common environment, large variation in growth performance (143 g/day (P < 0.01) and 243 g/day (P < 0.001) for 8 to 12 and 12 to 20 weeks, respectively) was also observed between the top and bottom quartile of herds. Although feed efficiency was similar, a significant feed intake difference of 329 g/day (P < 0.01) and 655 g/day (P < 0.001) between 8 to 12 and 12 to 20 weeks of age was observed. The variation in growth rate between pigs whether managed on farm or in the common environment was similar (variation in days to 100 kg on farm and in the common environment was 18 and 19 days, respectively). When housed in the common environment, although the top and bottom quartile of pigs converted feed equally efficiently, pigs in the top quartile had significantly higher feed intakes suggesting greater appetites. It is difficult to assess the extent to which these differences can be attributed to genetic effects or pre-weaning environment, and how much the effects of management, disease or genetics contributed to the variation between and within herds. PMID- 22444867 TI - The effect of grazing on the fatty acid profile of longissimus thoracis muscle in Galician Blond calves. AB - The objective of this work was to examine the effect of different levels of grazing on muscle nutritional fatty acid (FA) profile, including the beneficial n 3 polyunsaturated fatty acids (PUFA) and cis-9, trans-11 (cis-9, trans-11) 18:2 conjugated linoleic acid (CLA). Thirty male Galician Blond (GB) breed calves were randomly assigned to the following three grazing treatments: (1) continuous pasture grazing for 250 days (P); (2) 197-day grazing followed by a 50-day short period of concentrate-based finishing (PC) and (3) 57-day grazing followed by a 165-day long period of concentrate-based finishing (C). Calves kept sucking their mothers up to the time of slaughter. The slaughter weight was similar for all treatments (about 330 kg). Samples of the longissimus thoracis muscle were used for assessment of chemical composition by near infrared reflectance spectroscopy and FA profiles by gas chromatography. Muscle from C calves was fatter and had higher content in total FA, monounsaturated FA (MUFA), cis-9 18:1 than muscle from P calves, whereas PC muscle had generally intermediate values. No significant treatment difference for total saturated FAs (SFA) was found. Content of potentially beneficial n-3 PUFA (18:3n-3, 20:3n-3, 20:5n-3 and 22:6n-3), cis 9, trans-11 CLA and n-6:n-3 ratio were lower and PUFA : SFA ratio were higher in P than in both C and PC calves. Calves fed exclusively on pasture synthesised higher amounts of beneficial FA than calves finished on concentrate. A 50-day period of concentrate-based finishing was sufficient to offset the synthesis of beneficial FA from pasture grazing. PMID- 22444868 TI - Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice. AB - BACKGROUND: Despite decades of intense research efforts, actions of acute opioids are not fully understood. Increasing evidence suggests that in addition to well documented antinociceptive effects opioids also produce paradoxical hyperalgesic and excitatory effects on neurons. However, most studies focus on the pronociceptive actions of chronic opioid exposure. Matrix metalloproteinase 9 (MMP-9) plays an important role in neuroinflammation and neuropathic pain development. We examined MMP-9 expression and localization in dorsal root ganglia (DRGs) after acute morphine treatment and, furthermore, the role of MMP-9 in modulating acute morphine-induced analgesia and hyperalgesia in mice. RESULTS: Subcutaneous morphine induced a marked up-regulation of MMP-9 protein in DRGs but not spinal cords. Morphine also increased MMP-9 activity and mRNA expression in DRGs. MMP-9 up-regulation peaked at 2 h but returned to the baseline after 24 h. In DRG tissue sections, MMP-9 is expressed in small and medium-sized neurons that co-express mu opioid receptors (MOR). In DRG cultures, MOR agonists morphine, DAMGO, and remifentanil each increased MMP-9 expression in neurons, whereas the opioid receptor antagonist naloxone and the MOR-selective antagonist D-Phe-Cys Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) suppressed morphine-induced MMP-9 expression. Notably, subcutaneous morphine-induced analgesia was enhanced and prolonged in Mmp9 knockout mice and also potentiated in wild-type mice receiving intrathecal injection of MMP-9 inhibitors. Consistently, intrathecal injection of specific siRNA targeting MMP-9 reduced MMP-9 expression in DRGs and enhanced and prolonged morphine analgesia. Subcutaneous morphine also produced heat hyperalgesia at 24 h, but this opioid-induced hyperalgesia was not enhanced after MMP-9 deletion or inhibition. CONCLUSIONS: Transient MMP-9 up-regulation in DRG neurons can mask opioid analgesia, without modulating opioid-induced hyperalgesia. Distinct molecular mechanisms (MMP-9 dependent and independent) control acute opioid-induced pronociceptive actions (anti-analgesia in the first several hours and hyperalgesia after 24 h). Targeting MMP-9 may improve acute opioid analgesia. PMID- 22444869 TI - High-fat diet causes iron deficiency via hepcidin-independent reduction of duodenal iron absorption. AB - Obesity is often associated with disorders of iron homeostasis; however, the underlying mechanisms are not fully understood. Hepcidin is a key regulator of iron metabolism and may be responsible for obesity-driven iron deficiency. Herein, we used an animal model of diet-induced obesity to study high-fat-diet induced changes in iron homeostasis. C57BL/6 mice were fed a standard (SD) or high-fat diet (HFD) for 8 weeks, and in addition, half of the mice received high dietary iron (Fe+) for the last 2 weeks. Surprisingly, HFD led to systemic iron deficiency which was traced back to reduced duodenal iron absorption. The mRNA and protein expressions of the duodenal iron transporters Dmt1 and Tfr1 were significantly higher in HFD- than in SD-fed mice, indicating enterocyte iron deficiency, whereas the mRNA levels of the duodenal iron oxidoreductases Dcytb and hephaestin were lower in HFD-fed mice. Neither hepatic and adipose tissue nor serum hepcidin concentrations differed significantly between SD- and HFD-fed mice, whereas dietary iron supplementation resulted in increased hepatic hepcidin mRNA expression and serum hepcidin levels in SD as compared to HFD mice. Our study suggests that HFD results in iron deficiency which is neither due to intake of energy-dense nutrient poor food nor due to increased sequestration in the reticulo-endothelial system but is the consequence of diminished intestinal iron uptake. We found that impaired iron absorption is independent of hepcidin but rather results from reduced metal uptake into the mucosa and discordant oxidoreductases expressions despite enterocyte iron deficiency. PMID- 22444870 TI - Impaired insulin and leptin sensitivity in the offspring of moderate caloric restricted dams during gestation is early programmed. AB - We aimed to assess the mechanisms responsible for hyperphagia and metabolic alterations caused by maternal moderate caloric restriction during gestation. Male and female offspring of control and 20% caloric-restricted rats (CR) were studied. They were fed a normal-fat diet until 4 months of age and then moved to a high-fat diet until 6 months of age. Blood parameters and expression of selected genes in hypothalamus, retroperitoneal white adipose tissue (rWAT) and liver were analyzed at 25 days and 6 months of age. Plasma leptin was measured during suckling. Levels of proteins involved in insulin and leptin signaling were determined at 6 months of age. CR ate more calories than controls, but only males gained more weight. A peak in plasma leptin was found in 9-day-old controls, but was absent in CR. Twenty-five-day-old CR showed lower insulin receptor mRNA levels in hypothalamus, rWAT and liver, and long-form leptin receptor (ObRb) in hypothalamus. At the age of 6 months, homeostatic model assessment for insulin resistance index was higher in CR than controls, and CR males also displayed hyperleptinemia. Adult CR also showed lower ObRb mRNA levels in the hypothalamus (only females, but both showed altered neuropeptide Y/proopiomelanocortin mRNA ratio), rWAT and liver (males), and a decrease of protein kinase C zeta levels in rWAT (females) and liver (males) and of phosphorylated signal transducer and activator of transcription 3 in liver (females). These results suggest that CR animals are programmed for insulin and central leptin resistance, which may explain the dysregulation of appetite and other metabolic alterations, favoring obesity development, although only manifested in males. These early programming effects could be associated with the absence of leptin surge during lactation. PMID- 22444871 TI - Inhibition of NF-kappaB nuclear translocation via HO-1 activation underlies alpha tocopheryl succinate toxicity. AB - alpha-Tocopheryl succinate (alpha-TOS) inhibits oxidative phosphorylation at the level of mitochondrial complex I and II, thus promoting cancer cell death through mitochondrial reactive oxygen species (ROS) generation. Redox imbalance activates NF-E2 p45-related factor 2 (Nrf2), a transcription factor involved in cell protection and detoxification responses. Here we examined the involvement of heme oxygenase-1 (HO-1) in the regulation of nuclear factor kappaB (NF-kappaB) signaling by short exposure to alpha-TOS in prostate cancer cells. A short-term (4 h) exposure to alpha-TOS causes a significant reduction in cell viability (76%+/-9%) and a moderate rise in ROS production (113%+/-8%). alpha-TOS alters glutathione (GSH) homeostasis by inducing a biphasic effect, i.e., an early (1 h) decrease in intracellular GSH content (56%+/-20%) followed by a threefold rise at 4 h. alpha-TOS increases nuclear translocation and electrophile responsive/antioxidant-responsive elements binding activity of Nrf2, resulting in up-regulation of downstream genes cystine-glutamic acid exchange transporter and HO-1, while decreasing NF-kappaB nuclear translocation. This effect is suppressed by the pharmacological inhibition of HO-1 and mimicked by the end-products of HO activity, i.e., bilirubin and carbon monoxide. Results suggest a little understood mechanism for alpha-TOS-induced inhibition of NF-kappaB nuclear translocation due to HO-1 up-regulation. PMID- 22444872 TI - Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90. AB - Sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl) butane)], an isothiocyanate derived from cruciferous vegetables, has been shown to possess potent chemopreventive activity. We analyzed the effect of sulforaphane on the proliferation of pancreatic cancer cells. Sulforaphane inhibited pancreatic cancer cell growth in vitro with IC(50)s of around 10-15 MUM and induced apoptosis. In pancreatic cancer xenograft mouse model, administration of sulforaphane showed remarkable inhibition of tumor growth without apparent toxicity noticed. We found that sulforaphane induced the degradation of heat shock protein 90 (Hsp90) client proteins and blocked the interaction of Hsp90 with its cochaperone p50(Cdc37) in pancreatic cancer cells. Using nuclear magnetic resonance spectroscopy (NMR) with an isoleucine-specific labeling strategy, we overcame the protein size limit of conventional NMR and studied the interaction of sulforaphane with full-length Hsp90 dimer (170 kDa) in solution. NMR revealed multiple chemical shifts in sheet 2 and the adjacent loop in Hsp90 N terminal domain after incubation of Hsp90 with sulforaphane. Liquid chromatography coupled to mass spectrometry further mapped a short peptide in this region that was tagged with sulforaphane. These data suggest a new mechanism of sulforaphane that disrupts protein-protein interaction in Hsp90 complex for its chemopreventive activity. PMID- 22444873 TI - Intrusions in trauma and psychosis: information processing and phenomenology. AB - BACKGROUND: Intrusions are common symptoms of both post-traumatic stress disorder (PTSD) and schizophrenia. It has been suggested that an information processing style characterized by weak trait contextual integration renders psychotic individuals vulnerable to intrusive experiences. This 'contextual integration hypothesis' was tested in individuals reporting anomalous experiences in the absence of a need for care. METHOD: Twenty-six low schizotypes and 23 individuals reporting anomalous experiences were shown a traumatic film with and without a concurrent visuospatial task (VST). Participants rated post-traumatic intrusions for frequency and form, and completed self-report measures of information processing style. It was predicted that, because of their weaker trait contextual integration, the anomalous experiences (AE) group would (1) exhibit more intrusions following exposure to the trauma film, (2) display intrusions characterized by more PTSD qualities and (3) show a greater reduction of intrusions with the concurrent VST. RESULTS: As predicted, the AE group reported a lower level of trait contextual integration and more intrusions than the low schizotypes, both immediately after watching the film and during the following 7 days. Their post-traumatic intrusive memories were more PTSD-like (more intrusive, vivid and associated with emotion). The VST had no effect on the number of intrusions in either group. CONCLUSIONS: These findings provide some support for the proposal that weak trait contextual integration underlies the development of intrusions within both PTSD and psychosis. PMID- 22444874 TI - Methicillin-resistant Staphylococcus aureus carriage at ICU admission: to screen (rapidly) or not to screen? AB - The study by Wassenberg and colleagues shows that rapid diagnostic testing, although not cost-saving, reduces the number of unnecessary isolation days at ICU admission. Here, the strengths and limitations and the usefulness of rapid diagnostic testing are discussed from the collective and individual perspectives. PMID- 22444875 TI - Development of a new class of aromatase inhibitors: design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives. AB - Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4 phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3 (pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC(50) values of 2.4 MUM, 0.26 MUM and 5.8 MUM, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors. PMID- 22444876 TI - Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation. AB - A series of isaindigotone derivatives and analogues were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced beta amyloid (Abeta) aggregation. The synthetic compounds had IC(50) values at micro or nano molar range for cholinesterase inhibition, and some compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE, which were much better than the isaindigotone derivatives previously reported by our group. Most of these compounds showed higher self-induced Abeta aggregation inhibitory activity than a reference compound curcumin. The structure-activity relationship studies revealed that the derivatives with higher inhibition activity on AChE also showed higher selectivity for AChE over BuChE. Compound 6c exhibiting excellent inhibition for both AChE and self-induced Abeta aggregation was further studied using CD, EM, molecular docking and kinetics. PMID- 22444877 TI - In silico discovery and biophysical evaluation of novel 5-(2-hydroxybenzylidene) rhodanine inhibitors of DNA gyrase B. AB - Bacterial DNA gyrase is an established and validated target for the development of novel antibacterials. In our previous work, we identified a novel series of bacterial gyrase inhibitors from the class of 4-(2,4-dihydroxyphenyl) thiazoles. Our ongoing effort was designated to search for synthetically more available compounds with possibility of hit to lead development. By using the virtual screening approach, new potential inhibitors were carefully selected from the focused chemical library and tested for biological activity. Herein we report on a novel class of 5-(2-hydroxybenzylidene) rhodanines as gyrase B inhibitors with activity in low micromolar range and moderate antibacterial activity. The binding of the two most active compounds to the enzyme target was further characterised using surface plasmon resonance (SPR) and differential scanning fluorimetry methods (DSF). PMID- 22444878 TI - Histological characteristics of longissimus dorsi muscle and their correlation with restriction fragment polymorphisms of calpastatin gene in F2 Jinghua * Pietrain crossbred pigs. AB - In order to evaluate the genotype of the calpastatin (CAST) gene and its relationship to muscle histology and other post mortem traits in the Jinhua * Pietrain F2 pig family, 158 barrows and gilts were electrically stunned and exsanguinated. Both blood and muscle samples were collected, and both post mortem traits and meat qualities were recorded. Restriction fragment length polymorphism (RFLP) analysis, the periodic acid Schiff reaction (PAS) and myosin heavy-chain immunohistochemistry were employed to explore the relationship between genotype and muscle histology. Based on PAS reactivity, muscle fibres can be classified into three types: PAS (-), PAS (+) and PAS (++). Myosin heavy-chain immunohistochemistry can differentiate muscle fibres into either slow or fast fibres; the proportion of slow and fast fibres were 6% and 94%, respectively. When the amplification products of the CAST gene were digested with MspI, HinfI and RsaI, two different cleavage patterns could be discriminated from the endonuclease map detected using each enzyme. The results showed that the polymorphisms detected using these three endonucleases are identical. Only three genotypes (AA/CC/EE, AB/CD/EF and BB/DD/FF) were distinguished. Their frequencies were 0.1835, 0.5823 and 0.2342, respectively. Different genotypes had significant association with area and pH45m value of loin muscle, while showing no significant association with the water-holding capacity and conductivity of loin muscle. The results also revealed that the genotypes had a significant correlation with diameter, area, circularity and the aspect ratio of muscle fibres. It was also presented that the genotypes significantly correlated with the percentage of intramuscular connective tissue. PMID- 22444879 TI - Association of the polymorphism in GYS1 and ACOX1 genes with meat quality traits in pigs. AB - Phenotypic information about several pig meat quality traits on 334 Large White * Meishan F2 pigs was collected. Effects of the association of the FokI variants in the seventh intron of the skeletal muscle glycogen synthase (GYS1) gene and the PstI variants in the ninth intron of the palmitoyl acyl-CoA oxidase 1 (ACOX1) gene on the meat quality traits were examined on all pigs. The FokI variants of the GYS1 gene showed significant effects on pH of m. semipinalis capitis (P < 0.05). Linkage analysis indicated that the peak of the quantitative trait loci (QTL) curve was located around this marker for pH, but it did not reach significance (P > 0.05). The results may be due to several reasons such as linkage disequilibrium to the causal mutations, the limited number of animals or balance of another QTL or marker with negative effects. Significant effects of PstI variants of ACOX1 gene were also found on meat colour value and meat marbling score of both m. longissimus dorsi and m. biceps femoris (P < 0.05). Dominant effects for the affected traits at those two loci were significant except for meat marbling score of m. biceps femoris (P < 0.05). The results of this study give us some evidence for the potential of those dominant markers used in the marker-assisted selection of crossbreeding of the Large White pig sire lines and Meishan-derived synthetic dam lines. PMID- 22444880 TI - Association of four new single-nucleotide polymorphisms in follicle-stimulating hormone receptor and zona pellucida glycoprotein with reproductive traits in pigs. AB - Two new single-nucleotide polymorphisms (SNPs) (C1166T and G1190A) were discovered in the follicle-stimulating hormone receptor (FSHR) gene and two (G261A and T302C) in the zona pellucida glycoprotein (ZP3) gene. These SNPs were genotyped in three Chinese domestic purebred sow lines (42 Small Meishan, 46 Qingping and 41 Jinhua sows) and three European purebred sow lines (225 Duroc, 195 Large White and 65 Landrace sows) by using SNP chips. Phenotypic data including the functional teat number (i.e. milk-producing teats, TN) and number of piglets born alive per litter (NBA). These traits were tested for association with the genotypes of four SNPs. The association analysis revealed genotype of G261A in the ZP3 gene was significantly (P < 0.01) associated with overall NBA and NBA at later parities (NBA2+) but not with NBA at first parity (NBA1). There was a significant (P < 0.05) difference between sows with genotype GG (14.83 +/- 0.18) and AA (14.26 +/- 0.09) in TN at position 261 in the ZP3 gene. No significant associations were observed for the SNPs in the FSHR gene with NBA or TN in our populations. The results showed that the new SNPs in the ZP3 gene may be an effective potential marker to be used in conjunction with traditional selection methods. PMID- 22444881 TI - An approach to derive economic weights in breeding objectives using partial profile choice experiments. AB - The aim of this study was to show how choice experiments can be used to derive economic weights in breeding objectives. In a choice experiment, respondents are asked to view various alternative descriptions of a good differentiated by their attributes and levels, and are asked to choose their most preferred alternative. Analysis of the data generated can be used to elicit a quantitative description of respondent preference for contrasting attributes and levels. We simulated a partial profile choice experiment with four different attributes (traits) each at three levels. In a partial profile design, the choices are simplified so that only a subset of traits is used for each comparison, making participation in the experimental process less onerous. Three different choice designs were compared. All three designs included four attributes each at three levels where respondents choose between two alternative genotypes. In the first design, respondents choose between two genotypes differing for all four traits simultaneously. In the second and third designs, respondents made choices based on three or two out of the four traits per choice set respectively. The effectiveness of different designs was evaluated based on comparisons between true and simulated preferences for varying numbers of respondents and choice sets per respondent. Choice design and the simulated respondent choice were analysed using a conditional logit model. Regression coefficients from the conditional logit model based on an average of 200 replicated choices across respondents were used to estimate the relative economic weights of traits. A need to account for discounted gene flow principles when formulating the survey questions was emphasised as a critical component of the method. When the relative importance's of four traits were considered, practical designs involving, e.g., 20 choice sets based on a subset of two traits at each choice, and over 30 respondents provided relatively accurate estimates of relative respondent preferences. The method based on a practical choice experiment design can be used to define economic weights for use in animal breeding selection indexes where traditional approaches such as profit equations and bioeconomic models are not practical. The approach may also be of interest to commercial breeding programs wishing to formulate a quantitative understanding of market preferences for attributes of the genestocks that they sell. PMID- 22444882 TI - Influence of the diet and grazing on adipose tissue lipogenic activities and plasma leptin in steers. AB - The objectives of the two experiments were to determine the respective effects and interactions of diet type (grass v. maize diets) and physical activity (grazing v. zero grazing) on lipogenic enzyme activities and adipose cell size in subcutaneous, perirenal and intermuscular adipose tissues and on plasma metabolites and hormones in Charolais steers. After weaning, the steers were assigned to two (Experiment 1, n = 24) or three (Experiment 2, n = 24) groups, with steers in Experiment 1 grazed grass or indoors maize-silage-fed and steers in Experiment 2 grazed grass, indoors cut grass- or indoors maize-silage-fed. Both experiments lasted for 23 months. All grass-fed animals were fed grass silage during the two winter seasons. During the two summer seasons, steers fed on grass were rotationally grazed on a perennial rye-grass pasture while steers fed on cut grass were fed indoors on freshly cut grass alone. Steers fed on maize silage were fed maize silage indoors during the entire experiment. All animals were reared for similar body weight and growth rates and slaughtered at the same age (31 to 32 months). Activities of lipogenic enzymes were significantly lower in the three adipose tissue sites of steers fed cut grass compared with maize silage, although there were less-marked effects in intermuscular adipose tissue. Plasma insulin and glucose concentrations were also lower in steers fed cut grass whereas plasma leptin concentration was similar. As body fat content was not affected by nutritional treatment, it is suggested that the decrease in potential lipogenic activity was associated with the nature of the diet and not to differences in available net energy. In other respects, grazed grass compared with eating cut grass did not affect lipogenic enzyme activities but decreased plasma leptin concentrations in the older steers and increased plasma non esterified fatty acids and glucose concentrations without affecting adipose tissue weight and adipose cell size. PMID- 22444883 TI - Reduced lipid intake leads to changes in digestive enzymes in the intestine but has minor effects on key enzymes of hepatic intermediary metabolism in rainbow trout ( Oncorhynchus mykiss). AB - For sustainable aquaculture, the removal of marine resource ingredients in fish diets is an important objective. While most studies focus on the replacement of fish oil by vegetable oil, little is known on the nutritional effects of presence (which corresponds to the control diet) or absence of dietary fish oil. We studied fatty acid composition of brush-border membranes and digestive enzyme activities of the intestine and measured the expression and activities of several enzymes involved in the hepatic intermediary metabolism of rainbow trout (Oncorhynchus mykiss) fed for 7 weeks with or without fish oil. The diets were pair-fed to ensure that fish fed either diet had comparable carbohydrate and protein intakes. Absence of fish oil significantly reduced growth rate, protein efficiency and plasma lipid components. Activities of intestinal digestive enzymes were significantly decreased in the anterior intestine in fish fed without fish oil. In liver, dietary fish oil removal did not affect the transcript levels or activities of the main enzymes involved in lipogenesis (fatty acid synthase) and fatty acid beta-oxidation (3-hydroxyacyl-CoA dehydrogenase), glycolysis or amino acid oxidation. It lowered the expression of the genes coding for gluconeogenic enzymes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase), but their enzyme activities were not affected. The activities, but not gene expression of lipogenic enzymes, involved in NADPH and malonyl-CoA formation were also modified after fish oil removal as reflected by higher activities of isocitrate dehydrogenase/glucose-6-phosphate dehydrogenase and acetyl-CoA carboxylase enzymes. Overall, our results indicate that the intestinal digestive capacity was strongly modified by dietary fish oil removal, while hepatic intermediary metabolism was only marginally affected, in fed rainbow trout. PMID- 22444884 TI - Prenatal and pre-weaning growth and nutrition of cattle: long-term consequences for beef production. AB - Severe, chronic growth retardation of cattle early in life reduces growth potential, resulting in smaller animals at any given age. Capacity for long-term compensatory growth diminishes as the age of onset of nutritional restriction resulting in prolonged growth retardation declines. Hence, more extreme intrauterine growth retardation can result in slower growth throughout postnatal life. However, within the limits of beef production systems, neither severely restricted growth in utero nor from birth to weaning influences efficiency of nutrient utilisation later in life. Retail yield from cattle severely restricted in growth during pregnancy or from birth to weaning is reduced compared with cattle well grown early in life, when compared at the same age later in life. However, retail yield and carcass composition of low- and high-birth-weight calves are similar at the same carcass weight. At equivalent carcass weights, cattle grown slowly from birth to weaning have carcasses of similar or leaner composition than those grown rapidly. However, if high energy, concentrate feed is provided following severe growth restriction from birth to weaning, then at equivalent weights post-weaning the slowly-grown, small weaners may be fatter than their well-grown counterparts. Restricted prenatal and pre-weaning nutrition and growth do not adversely affect measures of beef quality. Similarly, bovine myofibre characteristics are little affected in the long term by growth in utero or from birth to weaning. Interactions were not evident between prenatal and pre weaning growth for subsequent growth, efficiency, carcass, yield and beef-quality characteristics, within our pasture-based production systems. Furthermore, interactions between genotype and nutrition early in life, studied using offspring of Piedmontese and Wagyu sired cattle, were not evident for any growth, efficiency, carcass, yield and beef-quality parameters. We propose that within pasture-based production systems for beef cattle, the plasticity of the carcass tissues, particularly of muscle, allows animals that are growth-retarded early in life to attain normal composition at equivalent weights in the long term, albeit at older ages. However, the quality of nutrition during recovery from early life growth retardation may be important in determining the subsequent composition of young, light-weight cattle relative to their heavier counterparts. Finally, it should be emphasised that long-term consequences of more specific and/or acute environmental influences during specific stages of embryonic, foetal and neonatal calf development remain to be determined. This need for further research extends to consequences of nutrition and growth early in life for reproductive capacity. PMID- 22444885 TI - Responses to nutrients in farm animals: implications for production and quality. AB - It is well known that any quantitative (energy and protein levels) and qualitative (nature of the diet, nutrient dynamic) changes in the feeding of animals affect metabolism. Energy expenditure and feed efficiency at the whole body level, nutrient partitioning between and within tissues and organs and, ultimately, tissue and organ characteristics are the major regulated traits with consequences on the quality of the meat and milk produced. Recent progress in biology has brought to light important biological mechanisms which explain these observations: for instance, regulation by the nutrients of gene expression or of key metabolic enzyme activity, interaction and sometimes cross-regulation or competition between nutrients to provide free energy (ATP) to living cells, indirect action of nutrients through a complex hormonal action, and, particularly in herbivores, interactions between trans-fatty acids produced in the rumen and tissue metabolism. One of the main targets of this nutritional regulation is a modification of tissue insulin sensitivity and hence of insulin action. In addition, the nutritional control of mitochondrial activity (and hence of nutrient catabolism) is another major mechanism by which nutrients may affect body composition and tissue characteristics. These regulations are of great importance in the most metabolically active tissues (the digestive tract and the liver) and may have undesirable (i.e. diabetes and obesity in humans) or desirable consequences (such as the production of fatty liver by ducks and geese, and the production of fatty and hence tasty meat or milk with an adapted fatty acid profile). PMID- 22444886 TI - Regulation of gene transcription by fatty acids. AB - Dietary fat is well recognised as an important macronutrient that has major effects on growth, development and health of all animals including humans. The amount and type of fat in the diet impacts on many aspects of metabolism including lipoprotein pathways, lipid synthesis and oxidation, adipocyte differentiation and cholesterol metabolism. It has become increasingly apparent that many of these effects may be due to direct modulation of expression of key genes through the interaction of fatty acids with certain transcription factors. Peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), hepatic nuclear factor 4 (HNF-4) and sterol regulatory binding proteins (SREBPs) represent four such factors. This review focuses on emerging evidence that the activity of these transcription factors are regulated by fatty acids and the interactions between them may be responsible for many of the effects of fatty acids on metabolism and the development of chronic disease. PMID- 22444887 TI - Detection of oestrous-related odour in bovine ( Bos taurus) saliva: bioassay of identified compounds. AB - The present study was designed to identify the volatile constituents across the oestrous cycle of bovine in order to detect oestrous-specific chemical signal. The bovine saliva was extracted with diethyl ether (1 : 1 ratio, v/v) and analysed by gas chromatography-linked mass spectrometry. Numerous compounds were identified during oestrous cycle of bovine saliva. Among these, the compounds, namely, trimethylamine, acetic acid, phenol 4-propyl, pentanoic acid and propionic acid were specific to oestrous stage. The behaviour assay revealed that the compound, trimethylamine, is involved in attracting the male animal. The result concludes that the trimethylamine is considered as a putative oestrous specific salivary chemo-signal in the bovine. PMID- 22444888 TI - Preference of 12-h-old kids for their mother goat is impaired by pre-partum induced anosmia in the mother. AB - We investigated whether kids were able to discriminate their own mother from an alien one in a two-choice test on the day of birth when they had access to acoustic, visual and olfactory cues from their mother, and whether this discrimination depended on the selective maternal behaviour of the mother (i.e. exclusive nursing of own kids). When given the choice between their own mother and an alien equivalent dam, 8-h-old kids did not show a significant preference for their dam, whereas 12- and 24-h-old kids did. When given the choice between their own and an alien mother that were both non-selective because they had been rendered peripherally anosmic by irrigation of the nostrils with zinc sulphate, 12-h-old kids did not show a significant preference for their mother. These results are similar to those reported in sheep and may suggest that the contrast of behaviour between their own and an alien mother existing in normosmic does is important for discrimination of dams by kids at this age. Finally, testing 8-h old kids in a smaller enclosure resulted in some improvement of their performance, although they still failed to display a significant preference for their mother. On the whole, kids are able to discriminate between their own and an alien mother goat as early as previously reported in lambs. The impairment of this ability when mothers are anosmic and not selective suggests that acceptance behaviours displayed by the mother may serve as one of the cues orientating the choice of the kid when given the choice between intact mothers. Finally, the present results do not suggest the existence of fundamental differences in the establishment of a preference for the mother between lambs, which are followers, and kids, which are hiders. PMID- 22444889 TI - Measuring changes in physical size and predicting weight of sows during gestation. AB - Changes in physical body size during gestation were monitored using 529 sets of sow measurements. All sows were from the same herd and production system with a range in parity from 1 to 8. Sows were individually weighed, P2 backfat thickness was determined by ultrasound and morphometric measurements of body size were taken five times during gestation: day 0 (at service), day 25, day 50, day 80 and day 110. The morphometric measurements included sow height (from floor to last rib at the midline, from floor to ventral surface and from floor to hip), heart girth, depth of last rib, length (from snout to tail and from anterior scapula to tail) and width (at ham, at last rib and at shoulder). Regression analyses were used to model the relationship between day of gestation or parity number and morphometric measurements of body size. Regression equations were also developed to estimate sow weight from physical measurements, day of gestation and parity. As expected, sow dimensions, in general, increased as pregnancy progressed and also with increasing parity number. The relationships between day of gestation and body dimensions were described by linear and quadratic regression models, which had a range of adjusted R2 values up to 0.99. Similar relationships to parity number had a range of R2 values between 0.51 and 0.96. Sow depth, which can be used as an estimate of the width of the sow when lying, equalled the maximum width of the gestation stall (650 mm) at day 103 of gestation. However, by day 40 of gestation, predicted mean sow depth (570 mm) equalled the width at the rear of the crate. The implication of this is that after day 40 of gestation, the average sow was too wide for the rear of the crate when lying in a recumbent position. On day 110 of gestation, 95% of the mean sow body depths would be accommodated in stalls that were 674 mm wide; however, the range in body sizes with increasing parity number suggests the use of more than one stall width would be appropriate. Sow weight could be estimated with an adjusted R2 value of 0.81 and with a residual standard deviation (r.s.d.) of 16.5 kg using heart girth alone, or more accurately using a model with parity, day of gestation, P2 backfat depth and heart girth as the parameters (R2 = 0.89, r.s.d. 12.4 kg). PMID- 22444890 TI - Carryover of aflatoxin from feed to milk in dairy cows with low or high somatic cell counts. AB - Aflatoxin M1 (AFM1) residues in milk are regulated in many parts of the world and can cost dairy farmers significantly due to lost milk sales. Additionally, due to the carcinogenicity of this compound contaminated milk can be a major public health concern. Thirty-four lactating dairy cows were utilised to investigate the relationship between somatic cell counts (SCC), milk yield and conversion of dietary aflatoxin B1 (AFB1) into milk AFM1 (carryover (CO)). The AFM1 in milk increased as soon as the first milking after animal ingestion with a pattern of increment up to the observed plateau (between 7th and 12th days of AFB1 ingestion). There was a significant (P < 0.01) effect of the milk yield whereas no effect could be attributed to the SCC levels or to the milk yield * SCC interaction. Similarly, the main effect of milk yield was also observed (P < 0.01) on the total amount of AFM1 excreted during the ingestion period. Although the plasma concentration of gamma-glutamyl transferase was significantly affected by aflatoxin administration, levels of this liver enzyme were within the normal range for lactating dairy cows. The current data suggest that milk yield is the major factor affecting the total excretion of AFM1 and that SCC as an indicator of mammary gland permeability was not related to an increase in AFM1 CO. PMID- 22444891 TI - Body condition score and live-weight effects on milk production in Irish Holstein Friesian dairy cows. AB - The objective of the present study was to quantify the relationships among body condition score (BCS; scale 1 to 5), live weight (WT) and milk production in Irish Holstein-Friesian spring calving dairy cows. Data were from 66 commercial dairy herds during the years 1999 and 2000. The data consisted of up to 9886 lactations with records for BCS or WT at least once pre-calving, or at calving, nadir or 60 days post-calving. Change in BCS and WT was also calculated between time periods. Mixed models with cow included as a random effect were used to quantify the effect of BCS and WT, as well as change in each trait, on milk yield, milk fat concentration and milk protein concentration. Significant and sometimes curvilinear associations were observed among BCS at calving or nadir and milk production. Total 305-day milk yield was greatest in cows calving at a BCS of 4.25 units. However, cows calving at a BCS of 3.50 units produced only 68 kg less milk than cows calving at a BCS of 4.25 units while cows calving at 3.25 or 3.00 BCS units produced a further 50 and 114 kg less, respectively. Cows that lost more condition in early lactation produced more milk of greater fat and protein concentration, although the trend reversed in cows that lost large amounts of condition post-calving. Milk yield increased with WT although the marginal effect decreased as cows got heavier. Milk fat and protein concentration in early lactation also increased with WT pre-calving, calving and nadir, although WT did not significantly affect average lactation milk fat concentration. PMID- 22444892 TI - Self-medication and homeostatic behaviour in herbivores: learning about the benefits of nature's pharmacy. AB - Traditional production systems have viewed animals as homogeneous 'machines' whose nutritional and medicinal needs must be provided in a prescribed manner. This view arose from the lack of belief in the wisdom of the body to meet its physiological needs. Is it possible for herbivores to select diets that meet their needs for nutrients and to write their own prescriptions? Our research suggests it is. Herbivores adapt to the variability of the external environment and to their changing internal needs not only by generating homeostatic physiological responses, but also by operating in the external environment. Under this view, food selection is interpreted as the quest for substances in the external environment that provide homeostatic utility to the internal environment. Most natural landscapes are diverse mixes of plant species that are literally nutrition centres and pharmacies with vast arrays of primary (nutrient) and secondary (pharmaceutical) compounds vital in the nutrition and health of plants and herbivores. Plant-derived alkaloids, terpenes, sesquiterpene lactones and phenolics can benefit herbivores by, for instance, combating internal parasites, controlling populations of fungi and bacteria, and enhancing nutrition. Regrettably, the simplification of agricultural systems to accommodate inexpensive, rapid livestock production, coupled with a view of secondary compounds as toxins, has resulted in selecting for a biochemical balance in forages favouring primary (mainly energy) and nearly eliminating secondary compounds. There is a global need to create a more sustainable agriculture, with less dependence on external finite resources, such as fossil fuels and their environmentally detrimental derivatives. Self-medication has the potential to facilitate the design of sustainable grazing systems to improve the quality of land as well as the health and welfare of animals. Understanding foraging as the dynamic quest to achieve homeostasis will lead to implementing management programs where herbivores have access not only to diverse and nutritious foods but also to arrays of medicinal plants. PMID- 22444893 TI - Bioactivity of phytochemicals in some lesser-known plants and their effects and potential applications in livestock and aquaculture production systems. AB - Livestock and aquaculture production is under political and social pressure, especially in the European Union (EU), to decrease pollution and environmental damage arising due to animal agriculture. The EU has banned the use of antibiotics and other chemicals, which have been shown to be effective in promoting growth and reducing environment pollutants because of the risk caused to humans by chemical residues in food and by antibiotic resistance being passed on to human pathogens. As a result of this, scientists have intensified efforts in exploiting plants, plant extracts or natural plant compounds as potential natural alternatives for enhancing the livestock productivity. This paper discusses work on the effects of various phytochemicals and plant secondary metabolites in ruminant and fish species. The focus is on (i) plants such as Ananas comosus (pine apple), Momordica charantia (bitter gourd) and Azadirachta indica (neem) containing anthelmintic compounds and for their use for controlling internal parasites; (ii) plants containing polyphenols and their applications for protecting proteins from degradation in the rumen, increasing efficiency of microbial protein synthesis in rumen and decreasing methane emission; for using as antioxidants, antibacterial and antihelmintic agents; and for changing meat colour and for increasing n-3 fatty acids and conjugated linoleic acid in meat; (iii) saponin-rich plants such as quillaja, yucca and Sapindus saponaria for increasing the efficiency of rumen fermentation, decreasing methane emission and enhancing growth; for producing desired nutritional attributes such as lowering of cholesterol in monogastric animals; for increasing growth of fish (common carp and Nile tilapia) and for changing male to female ratio in tilapia; and for use as molluscicidal agents; (iv) Moringa oleifera leaves as a source of plant growth factor(s), antioxidants, beta-carotene, vitamin C, and various glucosinolates and their degraded products for possible use as antibacterial, antioxidant, anticarcinogenic and antipest agents; (v) Jatropha curcas toxic variety with high levels of various phytochemicals such as trypsin inhibitor, lectin, phytate and phorbol esters in seeds limiting the use of seed meal in fish and livestock diets; and the use of phorbol esters as bio-pesticidal agent; and (vi) lesser known legumes such as Entada phaseoloides seeds containing high levels of trypsin inhibitor and saponins, Sesbania aculeate seeds rich in non-starch polysaccharides and Mucuna pruriens var. utilis seeds rich in l-3,4 dihydroxyphenylalanine and their potential as fish feed; Cassia fistula seeds as a source of antioxidants; and the use of Canavalia ensiformis, C. gladiata and C. virosa seeds containing high levels of trypsin inhinitor, lectins and canavanine. The paper also presents some challenges and future areas of work in this field. PMID- 22444894 TI - Medicinal plants for helminth parasite control: facts and fiction. AB - The use of medicinal plants for the prevention and treatment of gastro-intestinal parasitism has its origin in ethnoveterinary medicine. Although until recently the majority of the evidence on the antiparasitic activity of medicinal plants was anecdotal and lacked scientific validity, there is currently an increasing number of controlled experimental studies that aim to verify and quantify such plant activity. There are indeed a large number of plants whose anthelmintic activity has been demonstrated under controlled experimentation, either through feeding the whole plant or administering plant extracts to parasitised hosts. However, contrary to traditional expectation, there are also a great number of plants with purported antiparasitic properties, which have not been reproduced under experimental conditions. In this paper, we discuss the source of such inconsistencies between ethnoveterinary wisdom and scientific experimentation. We focus on the strengths and weaknesses of the existing methodologies used in the controlled studies to determine the activity of antiparasitic plants. We discuss issues like the seasonal and environmental variability of the plant composition, and how this can affect their antiparasitic properties and highlight the importance of identifying the mechanisms of action of such plants and the target parasite species. In addition to their antiparasitic properties, medicinal plants may also have anti-nutritional properties, which can affect animal performance and behaviour. For this reason, we emphasise the need for considering additional dimensions when evaluating medicinal plants. We also question whether using similar criteria as those used for the evaluation of anthelmintics is the way forward. We propose that a holistic approach is required to evaluate the potential of medicinal plants in parasite control and maximise their benefits on parasitised hosts. PMID- 22444895 TI - Hazardous medical waste generation rates of different categories of health-care facilities. AB - Goal of this work was to calculate the hazardous medical waste unit generation rates (HMWUGR), in kg bed(-1)d(-1), using data from 132 health-care facilities in Greece. The calculations were based on the weights of the hazardous medical wastes that were regularly transferred to the sole medical waste incinerator in Athens over a 22-month period during years 2009 and 2010. The 132 health-care facilities were grouped into public and private ones, and, also, into seven sub categories, namely: birth, cancer treatment, general, military, pediatric, psychiatric and university hospitals. Results showed that there is a large variability in the HMWUGR, even among hospitals of the same category. Average total HMWUGR varied from 0.012 kg bed(-1)d(-1), for the public psychiatric hospitals, to up to 0.72 kg bed(-1)d(-1), for the public university hospitals. Within the private hospitals, average HMWUGR ranged from 0.0012 kg bed(-1)d(-1), for the psychiatric clinics, to up to 0.49 kg bed(-1)d(-1), for the birth clinics. Based on non-parametric statistics, HMWUGR were statistically similar for the birth and general hospitals, in both the public and private sector. The private birth and general hospitals generated statistically more wastes compared to the corresponding public hospitals. The infectious/toxic and toxic medical wastes appear to be 10% and 50% of the total hazardous medical wastes generated by the public cancer treatment and university hospitals, respectively. PMID- 22444896 TI - Strong heterozygote deficit in Tibetan Mastiff of China based on microsatellite loci. AB - Tibetan Mastiff is one of the most archaic, ferocious and the largest dogs in the world. A total of 140 individuals from four geographically separated populations in China (Tibet, Gansu, Qinghai and Beijing) were sampled and genetic diversity was assessed using 10 microsatellite loci on eight different chromosomes. The mean number of alleles per locus ranged from 6 to 13. The mean observed and expected heterozygosities, polymorphism information content and allelic richness were 0.69, 0.79, 0.76 and 7.59, respectively, indicating relatively high genetic diversity in Tibetan Mastiff. However, a highly significant deficiency in heterozygote was observed within populations (mean FIS = 0.11, bootstrap 95% confidence interval (0.06, 0.17)) and total inbreeding (mean FIT = 0.12, bootstrap 95% confidence interval (0.06, 0.18)), along with strong inbreeding coefficients within populations (Fis > 0.09), all of which suggested that intense inbreeding practices occurred in Tibetan Mastiff. Therefore, effective and appropriate breeding management projects in present Tibetan Mastiff will be desirable and urgent. Low genetic differentiation was obtained with a mean FST of 0.01 (bootstrap 95% confidence interval (0.007, 0.019)). Additionally, the four Tibetan Mastiff populations showed close relationships in the neighbor-joining polygenetic tree based on the coancestral genetic distances. Tibetan Mastiff was investigated by using microsatellite loci at the first time, which could facilitate the better understanding of present situation at the molecular level, breed conservation and utilization in Tibetan Mastiff. PMID- 22444897 TI - Identification of mitochondrial markers for genetic traceability of European wild boars and Iberian and Duroc pigs. AB - Iberian pigs and wild boars are the source of highly priced meat and dry-cured products. Iberian maternal origin is mandatory for labeled Iberian products, making necessary the authentication of their maternal breed origin. Discrimination between wild and domestic pig maternal origin may be useful to distinguish labeled wild boar meat obtained from hunting or farming. In order to detect useful polymorphisms to trace Iberian, Duroc and wild boar maternal lineages, we herein investigated the complete porcine mitochondrial DNA (mtDNA) using three complementary approaches. Near-complete mtDNA sequences (16989 bp), excluding the minisatellite present in the displacement loop region (D-loop), were successfully determined in six Iberian pigs, two Duroc and six European wild boars. To complete the mtDNA analysis, the D-loop minisatellite region was also analyzed in the same set of samples by amplification and capillary electrophoresis detection. Finally, the frequencies of Asian and European Cytochrome B (Cyt B) haplotypes were estimated in Iberian (n = 96) and Duroc (n = 125) breeds. Comparison of near-complete mtDNA sequences revealed a total of 57 substitutions and two Indels. Out of them, 32 polymorphisms were potential Iberian markers, 10 potential Duroc markers and 16 potential wild boar markers. Fourteen potential markers (five Iberian and nine Duroc), were selected to be genotyped in 96 Iberian and 91 Duroc samples. Five wild boar potential markers were selected and tested in samples of wild boars (73) and domestic pigs including: 96 Iberian, 16 Duroc, 16 Large White and 16 Landrace. Genotyping results showed three linked markers (m.7998C>T, m.9111T>C, m.14719A>G) absent in Duroc and present in Iberian pigs with a frequency 0.72. Six markers (m.8158C>T, m.8297T>C, m.9230G>A, m.11859A>G, m.13955T>C, m.16933T>C), three of them linked, were absent in Iberian pigs and present in Duroc with a joint frequency of almost 0.50. Finally three linked markers (m.7188G>A, m.9224T>C, m.15823A>G) were solely detected in wild boars with a frequency 0.22. The D-loop minisatellite results showed overlapping ranges of fragment sizes and suggested heteroplasmy, a result that nullify the use of this region for the development of breed diagnostic markers. The Cyt B haplotype results showed the presence of European haplotypes in Iberian while one of the Asian haplotypes was detected in Duroc with a frequency 0.22, linked to the Duroc marker m.9230G>A. Our results are valuable to resolve the problems of Iberian and wild boar maternal origin determination but additional markers are required to achieve totally useful genetic tests. PMID- 22444898 TI - Refinement of a quantitative gene locus on equine chromosome 16 responsible for osteochondrosis in Hanoverian warmblood horses. AB - Osteochondrosis (OC) is an inherited developmental disease in young horses most frequently observed in thoroughbreds, trotters, warmblood and coldblood horses. Quantitative trait loci (QTL) for equine OC have been identified in Hanoverian warmblood horses employing a whole genome scan with microsatellites. A QTL on ECA16 reached the genome-wide significance level for hock osteochondrosis dissecans (OCD). The aim of this study was to refine this QTL on ECA16 using an extended marker set of 34 newly developed microsatellites and 15 single nucleotide polymorphisms (SNPs). We used the same 14 paternal half-sib groups as in the above-mentioned whole genome scan. The QTL for OCD in hock joints on ECA16 could be delimited at an interval between 17.60 and 45.18 Mb using multipoint non parametric linkage analyses. In addition, six microsatellites and one SNP were significantly associated with hock OCD in the QTL region between 24.26 and 42.41 Mb. Furthermore, our analysis revealed a second QTL for fetlock OC between 6.55 and 24.26 Mb on ECA16. This report is a further step towards unravelling the genes underlying QTL for equine OC and towards the development of a marker test for OC in Hanoverian warmblood horses. PMID- 22444899 TI - Effects of genotype and plane of nutrition on growth and carcass characteristics of lambs from hill sheep systems. AB - The objective of this study was to determine the effect of lamb genotype and plane of nutrition on post-weaning lamb growth, and carcass characteristics in hill sheep systems. The lamb genotypes compared were as follows: purebred Scottish Blackface, Swaledale * Scottish Blackface, Cheviot * Scottish Blackface, Lleyn * Scottish Blackface and Texel * Scottish Blackface lambs. During the finishing period, lambs were allocated to a (i) low plane of nutrition (LP), based on a fixed allowance of dried grass pellets representing a grass-based system; (ii) high plane of nutrition (HP-cereal), with a diet consisting proportionately of 0.20 dried grass pellets : 0.80 cereal-based concentrate offered ad libitum; (iii) high plane of nutrition (HP-cereal/oil), with a diet consisting proportionately of 0.20 dried grass pellets : 0.80 cereal-based concentrate containing oilseed rape offered ad libitum. There were significant genotype * diet interactions for dry matter (DM) intake (P < 0.001), live weight gain (P < 0.05) and carcass gain (P < 0.05). On the LP diet, carcass gains were higher for Texel cross compared to Blackface and Swaledale cross lambs (P < 0.05). On both HP diets, carcass gains were lower in Blackface and Swaledale crosses compared with the Cheviot, Lleyn and Texel cross lambs (P < 0.01). Feed conversion efficiency, expressed in terms of carcass gain per unit of DM, was highest for Texel cross and Cheviot cross, lowest in Swaledale cross and Blackface and intermediate for Lleyn cross lambs (P < 0.001). Conformation classification was lowest for Swaledale cross (P < 0.05) and highest for Texel cross lambs (P < 0.001), whilst those of Blackface, Cheviot and Lleyn cross lambs were similar. Carcasses from Blackface and Lleyn cross lambs had higher fat classifications than Texel and Cheviot cross lambs (P < 0.01). Feed conversion efficiency was lowest with the LP diet compared with the HP diets, resulting in a 5-week longer finishing period and lower carcass weights, fat scores, dressing proportions and subcutaneous fat depth measurements. These results indicate that crossbreeding can have a major effect on lamb performance in the hill sheep sector. Feeding a HP increased lamb growth rates, particularly for high growth potential genotypes, improved feed efficiency, shortened the finishing period but increased carcass fatness. Including oilseed rape in concentrate-based diets did not affect performance. PMID- 22444900 TI - Effects of feeding state on glycaemic and insulinaemic responses to a starchy meal in horses: a methodological approach. AB - A standardised methodology is required for classification of starchy diets. One important question is what feeding status is optimal to describe glycaemic and insulinaemic responses to the respective starchy diet. Four horses were fed, in a randomised order, four different feeding protocols relative to offering hay before or after cracked corn (CC): (i) ad libitum hay for 12 h before feeding CC and ad libitum hay after CC intake for 9 h (+CC+), (ii) ad libitum hay for 12 h before feeding CC and no hay after CC intake for 9 h (+CC-), (iii) feed restriction for 12 h before feeding CC and ad libitum hay after CC intake for 9 h (-CC+) and (iv) 1.2 kg hay/100 kg body weight (BW) per day, divided into two equal portions and offered at 0900 h and 1900 h, feed restriction for 12 h before feeding CC and no hay after CC intake for 9 h (-CC-). CC intake was adjusted to a starch intake of 2 g/kg BW. The different hay offerings did not affect basal plasma glucose and insulin levels. A significant rise in plasma glucose and insulin was found after CC intake for all diets. The highest peak glucose levels were analysed for -CC+, and the lowest glucose peaks were found for +CC- (diet P < 0.05). The highest insulin peaks were monitored for -CC+ (31.27 +/- 18.19 MUU/ml) and lower peaks for +CC- (13.36 +/- 2.93 MUU/ml) (diet P < 0.05). Insulin for -CC- and +CC- returned to resting values about 300 min after CC feeding. For +CC+ and -CC+, insulin levels were still above resting levels 510 min after CC intake (diet P < 0.05). The present data suggest that feed restriction for 12 h before feeding the starchy diet and no further roughage intake during blood sampling period provide the best-defined conditions. PMID- 22444901 TI - Eremophila glabra is an Australian plant that reduces lactic acid accumulation in an in vitro glucose challenge designed to simulate lactic acidosis in ruminants. AB - Lactic acidosis is a major welfare issue affecting animal health and production systems such as dairy and feedlot beef. We used two bioassays to identify bioactive plants of Australia with the potential to prevent acidosis in ruminants. In the first bioassay, a potentially acidotic environment was induced by adding glucose to rumen fluid and pH and gas production were used to estimate the effect on acid production and microbial fermentation after 5-h incubation. Australian plants (n = 104) were screened for their ability to prevent a decline in the pH without inhibiting normal gas production, and five plants namely Eremophila glabra, Kennedia eximia, Acacia saligna, Acacia decurrens and Kennedia prorepens with such properties were identified. We investigated further the two top ranking plants, E. glabra and K. prorepens, in the second bioassay to determine the extent of their effect in vitro, by extending the incubation to 24 h and measuring d-lactate, and volatile fatty acids (VFA) in addition to pH and gas production. These were measured at 0, 5, 10, 16 and 24 h after inoculation. Eremophila glabra maintained pH values that were higher and d-lactate concentrations that were lower than the control (P < 0.001), and comparable to the antibiotic-protected environment (AB; 12 MUg of virginiamycin/ml). Eremophila glabra and AB treatments did not restrict fermentation, as judged by gas production and VFA. Kennedia prorepens slowed the decline in pH and reduced the accumulation of lactate but inhibited gas production. We concluded that, in vitro, E. glabra was effective at controlling events that can lead to acidosis and the effect was comparable to that of virginiamycin, while K. prorepens was less effective than E. glabra and also inhibited fermentation. PMID- 22444902 TI - High dietary vitamin A interferes with tissue alpha-tocopherol concentrations in fattening pigs: a study that examines administration and withdrawal times. AB - This study aimed to assess the interaction between different dietary vitamin A (dVitA) levels and the same concentration of vitamin E (100 IU all-rac-alpha tocopheryl acetate/kg feed) in growing-finishing pigs. In the first experiment, two fat sources * two dVitA levels (0 v. 100 000 IU) were used. The supplementation of 100 000 IU dVitA induced a range of 5.13 to 30.03 MUg retinol/g liver, 62.78 to 426.88 MUg retinol palmitate/g liver, and 0.60 to 1.96 MUg retinol/g fat. Dietary fat did not affect retinol or retinyl palmitate deposition in pigs. The high concentration of dVitA produced lower fat and liver alpha-tocopherol concentrations, and increased susceptibility of muscle tissue to oxidation. A second experiment was carried out to study the retinol and alpha tocopherol retention at different withdrawal times prior to slaughter (two dVitA levels; 0 v. 100 000 IU). A high dose of 100 000 IU vitamin A during a short 2 week period was enough to induce alpha-tocopherol depletion in liver and fat to a similar extent as when 100 000 IU were administered during the whole fattening. Muscle, fat and liver alpha-tocopherol concentrations were not affected by dVitA in the 1300-13 000 IU/kg range, but liver alpha-tocopherol concentration was higher when vitamin A was removed from the vitamin mix 5 weeks prior to slaughter (experiment 3). PMID- 22444903 TI - The effect of a progesterone (P4) intravaginal device (CIDR) on resynchronisation of oestrus and embryonic loss in previously timed inseminated dairy heifers. AB - A study was done to evaluate the effect of using progesterone (P4) intravaginal device (CIDR: controlled internal drug-releasing dispenser) to synchronise the return to oestrus of previously timed inseminated (TAI) dairy heifers, and to evaluate embryo survival and pregnancy rate (PR) in the return to oestrus heifers. At the onset of the artificial insemination (AI) breeding period (day 9), heifers were randomly assigned into two groups (treated group CGPG, n = 79) and (control group GPG, n = 83). Every heifer in both groups was injected with gonadotropin-releasing hormone (GnRH) agonist and prostaglandin F2-alpha (PGF2alpha) as follows: GnRH on day -9; PGF2alpha on day -2; GnRH and TAI on day 0. Heifers in both groups received TAI within 30 min after the second GnRH injection. Artificial insemination at first breeding was conducted for all heifers during 55 days from day 0. On day 14 after timed insemination, every heifer in the CGPG group received CIDR device for 6 days. Within 3 days after CIDR removal, more heifers in CGPG group showed oestrus within 1.9 days compared to heifers that showed oestrus within 2.9 days in the control. Within 10 days after CIDR removal, more heifers in the CGPG group showed oestrus within 2.4 days compared to heifers that showed oestrus within 6.7 days in the control. PRs on days 30 and 55 were not different between both groups, while PR on day 55 during September were higher (P = 0.032) in CGPG group (58.0%) than GPG group (37.0%). In addition, PR from first to second AI was higher (P = 0.037) for CGPG group (79.8%) than for GPG group (65.1%) but it was similar after that. Pregnancy losses between days 30 and 55 tended to be lower (P = 0.089) for the CGPG group (12.7%) compared to 25.1% for the GPG group. Interval between first and second AI was lower (P = 0.052) for the CGPG group (27.5 +/- 1.6 days) compared to 31.6 +/- 1.3 days for heifers in the GPG group but no differences were detected for intervals from second to third AI and from third to fourth AI between the two groups. Number of services per pregnancy was not different between CGPG and GPG groups. Results indicate that the CIDR device improved synchronisation to return to oestrus and increased PR to first AI during high temperature months by reducing embryonic losses. PMID- 22444904 TI - Return of testicular function after vaccination of boars against GnRH: consequences on testes histology. AB - Traditionally, male pigs are surgically castrated without anaesthesia to avoid later occurrence of the sex odour of androstenone in the carcass. Active immunization against gonadotropin-releasing hormone (GnRH) is a painless alternative which inhibits LH and thus steroidogenesis in the Leydig cells. In a preceding study we clarified the return of Leydig cell function after the last dose of antigen by measuring hormones, and found a considerable variation (10 to 24 weeks) till return of their function (testosterone 0.5 ng/ml blood plasma). The present paper analyses histological data on testes characteristics of the same six boars at an age of 52 weeks (26 weeks after last immunization). Data were compared to another four boars which were not immunized but slaughtered at the same age. Testis weight was related to the concentration of testosterone in blood. In boars, that first returned to testicular function, testis weight even exceeded those in controls probably due to rebound phenomena. Differences in testis weight were mainly due to differences of Leydig cell content of cytoplasm, and less to the size of nuclei. Additionally, the height of seminiferous epithelium was slightly dependent on testosterone concentrations and contributed moderately to differences in testis weight. Altogether, normalization of testicular function, even after return to steroidogenesis, requires another 13 weeks. PMID- 22444905 TI - Ovariohysterectomy alters body composition and adipose and skeletal muscle gene expression in cats fed a high-protein or moderate-protein diet. AB - The objective of this study was to measure changes in body composition, physical activity and adipose and skeletal muscle gene expression of cats fed a high protein (HP) diet or moderate-protein (MP) diet, following ovariohysterectomy. Eight cats were randomized onto HP or MP diets and were fed those diets for several months prior to baseline. All cats underwent an ovariohysterectomy at baseline (week 0) and were allowed ad libitum access to dietary treatments for 24 weeks. Food intake was measured daily, and BW and body condition score were measured weekly. Blood, adipose and skeletal muscle tissue samples were collected, physical activity was measured, and body composition was determined using DEXA (dual-energy X-ray absorptiometry) at weeks 0, 12 and 24. Caloric intake increased soon after ovariohysterectomy, resulting in increased (P < 0.05) BW at weeks 12 and 24 compared to week 0. Body condition score and body fat percentage increased (P < 0.05) over time. Blood glucose increased (P < 0.05) linearly over time. Non-esterified fatty acids were decreased (P < 0.05) at weeks 12 and 24 compared to week 0. Blood leptin increased (P < 0.05) over time. Total physical activity decreased (P < 0.05) from week 0 to weeks 12 and 24 in all cats. Adipose tissue mRNA abundance of adiponectin, hormone sensitive lipase, toll-like receptor-4, uncoupling protein-2 (UCP2) and vascular endothelial growth factor decreased (P < 0.05) linearly over time, regardless of diet. Skeletal muscle mRNA abundance for glucose transporter-1, hormone sensitive lipase and UCP2 were decreased (P < 0.05), regardless of dietary treatment. Our research noted metabolic changes following ovariohysterectomy that are in agreement with gene expression changes pertaining to lipid metabolism. Feeding cats ad libitum after ovariohysterectomy is inadvisable. PMID- 22444906 TI - Growth heterogeneity in rearing sea bass ( Dicentrarchus labrax): test of hypothesis with an iterative energetic model. AB - This study aimed at modeling the relative importance of food intake on growth heterogeneity among cultured sea bass (Dicentrarchus labrax). First, we designed an individual growth model comprising five compartments (Energy intake, Losses, Net Energy, Recovered Energy and Maintenance). This model was calibrated with a first experiment carried out in eight tanks; A total of 130 juveniles (11 g) per tank were fed by a self-feeder (84 days, 20 degrees C, 16L : 8D, 30 g NaCl/l). A second experiment was performed to better understand the relation between individual food intake, individual growth and growth heterogeneity, using the model as a tool for a hypothetico-deductive approach on growth heterogeneity (135 passive integrated transponder-tagged fish, same rearing conditions as above and individual food intake measured by X-ray every 14 days). The tested hypotheses were that food intake was (a) homogeneous, (b) proportional to the fish weight (i.e. to W1.00) X-ray (c) proportional to W0.66 and (d) reflected by the X-ray measurements of food intake. For each hypothesis, a simple linear regression between experimental and simulated results was produced. The Fitness indicators of these analyses, together with their confidence intervals (calculated by bootstrapping), allowed testing the relevance of these hypotheses. The analysis indicated that growth heterogeneity was largely accounted for by individual variations of food intake, as revealed by the X-ray analysis, and that food intake was proportional to W1.00, which suggests a dominance hierarchy where small fish are incapable of feeding maximally. PMID- 22444907 TI - Foraging opportunity: a crucial criterion for horse welfare? AB - This study aimed at determining the effect of the increase of foraging opportunities on the behaviour and welfare of breeding mares housed in individual boxes but allowed outside 6 h a day in a bare paddock. One hundred Arab breeding mares were divided into two groups of 50 according to the treatment and allowed outside in two bare paddocks at the same density (115 mare/ha) where water and shelter were provided. The treatment consisted in providing the opportunity to forage on hay. Twenty-minute animal focal samplings and scan samplings were used to determine the time budget of the mares during the period from 0900 to 1500 h and study their social behaviour. A total of 300 focal sampling (6000 min), 3300 individual scan sampling (6000 min) and 62 group observations (1240 min) corresponding to the 100 mares were recorded. Non-parametric tests were used to analyse data. Results showed that experimental mares spent more time feeding (65.12% +/- 2.40% v. 29.75% +/- 2.45%, P < 0.01) and less time in locomotion (11.70% +/- 1.31% v. 23.56% +/- 1.34%, P < 0.01), stand resting (11.76% +/- 2.57% v. 27.52% +/- 2.62%, P < 0.01) and alert standing (5.23% +/- 1.2% v. 14.71% +/- 1.23%, P < 0.01). There was more bonding among experimental mares than control ones (26 v. 14, P < 0.05). Experimental mares showed more positive social interactions (P < 0.01) and less aggression (P < 0.01). These results suggest that giving densely housed mares foraging opportunities improves their welfare. PMID- 22444908 TI - Physiological variables of horses after road transport. AB - In order to investigate the effects of short road transport stress on total and free iodothyronines, body weight (BW), rectal temperature and heart rate (HR) changes, 126 healthy stallions were studied in basal conditions, before and after transport. A total of 60 Thoroughbred and 66 crossbred stallions aged 4 to 15 years with previous travelling experience were transported by road in a commercial trailer for a period of about 3 to 4 h (distance under 300 km). Blood samples and functional variables were collected in each horse box, one week before loading and transport in basal conditions (control samples), one week later immediately before loading (pre-samples) and again after transport and unloading (about 3 to 4 h) in each new horse box, within 30 min of their arrival at the breeding stations (post-samples). Compared to the before-transport values, increases in circulating T3, T4 and fT4 levels (P < 0.01) were observed after transport, irrespective of breed, but not for fT3 levels. Lower T4 and fT4 levels were observed in basal II (at 1100 h) (P < 0.01) than in basal I (at 0800 h) conditions and before transport. Thoroughbreds showed higher fT3 (P < 0.05) and fT4 (P < 0.01) levels after transport than crossbred stallions. No significant differences were observed for T3 and T4. Compared to the before-transport values, significant increases in rectal temperature (P < 0.01) and HR (P < 0.05) were observed after transport. No differences were observed between basal I, II and before values for functional variables. Significant correlations between T3 and rectal temperature, BW and HR were found. The results indicate that short road transport induces a preferential release of T3, T4 and fT4 hormones from the thyroid gland in relation to different breed, and an increase in rectal temperature and HR. No significant changes in BW were observed. No differences were observed in relation to different ages. The data obtained suggest that the stallion's thyroid hormones and functional variables may play an important role in assessing the effects of transport stress and a horse's coping strategy. PMID- 22444909 TI - Individual and social determinants of spontaneous group movements in cattle and sheep. AB - Group-living animals travel together to collectively exploit the resources of their environment. This study investigates how social relationships and individual temperament traits affect movement orders in domestic cattle and sheep. We analysed spontaneous group movements occurring at pasture after a resting period in a group of 15 18-month-old Charolais heifers and a group of 19 1-year-old Romane ewe-lambs. For each species, animals had similar social experience and no kinship ties. Before that, animals were observed within the group to establish their social status (e.g. dominance and preferential relationships, and sociability), then in individual tests in order to assess their emotional traits. In both species, most individuals could initiate a group movement but some individuals were more successful than others in recruiting the rest of the group. Ewe-lambs, and to a lesser extent heifers, held preferential positions during travel. We did not find any significant correlations in either species between animal order and their position in the dominance hierarchy (heifers: P = 0.438; ewe-lambs: P = 0.574) while individuals linked by preferential bonds frequently followed each other during group movements (heifers: P < 0.001; ewe-lambs: P < 0.001). With regard to social traits, heifers with a low cohesion index, and with a lower number of partners with whom they develop frequent affinitive interactions, acted more frequently as 'first movers' (P = 0.040 and 0.023, respectively), as well as did ewe-lambs with a high spatial independency index (P = 0.002). Ewe-lambs with the highest cohesion indices were more frequently observed in front of the group while moving halfway between departure and arrival (P = 0.028). We did not find significant correlations between individual positions during group movements and emotional traits such as reactivity, boldness and fearfulness. We conclude that preferential bonds and individual traits related to social dependence were more influential in spontaneous group movements at pasture than were emotional traits and dominance status. PMID- 22444910 TI - Winter feeding systems and dairy cow breed have an impact on milk composition and flavour of two Protected Designation of Origin French cheeses. AB - This study investigates the effects of two feeding systems and two dairy cow breeds on milk yield and composition, physical and sensorial properties of Camembert and Pont-l'Eveque cheeses. The experiment consisted of a 2 * 2 factorial arrangement of treatments. A low energy grass diet with only 15% of concentrate (LowGS) was compared with a high-energy maize silage diet with 30% concentrate (HighMS). Thirty-four Holstein (Ho) and 34 Normande (No) cows in early lactation were assigned to one of two feeding systems for a 6-week period. Cows on the LowGS feeding system had lower milk yield, fat and protein content. In both feeding systems, No cows had lower milk yields but higher milk protein contents than Ho cows. The LowGS feeding system altered milk fatty acid (FA) composition by reducing saturated FA. Breed had only a small impact on milk FA. Concerning milk coagulating properties, only the firmness was reduced by the LowGS feeding and the Ho breed. The effects of breed and feeding system on the protein content of cheeses were more marked in Camembert cheese than in Pont l'Eveque cheese. However, the Camembert cheese from Ho-LowGS was, in fact, characterized especially by lower protein content. LowGS feeding system and No breed produced more yellow cheeses. Feeding systems had limited effects on the firmness of Camembert and Pont-l'Eveque cheeses measured by penetrometry. In sensory analysis, Ho breed and LowGS feeding produced a Camembert cheese with a more melting texture in the mouth due to the increase of spreadability index and of proteolysis. The type of cheese also had an influence: the effects were more important on Camembert cheese than on Pont-l'Eveque cheese. Only the Ho-LowGS treatment produced a very specific Camembert cheese different from the others. The feeding systems and breed of dairy cow have no determinant effect on PDO (protected designation of origin) Camembert and Pont-l'Eveque cheeses, especially regarding taste. In this kind of trial, despite the effects of feeding systems and breed on milk composition, the role of cheese ripening and microbiology appears to be of considerable importance. PMID- 22444911 TI - Carriage of methicillin-resistant Staphylococcus pseudintermedius in dogs--a longitudinal study. AB - BACKGROUND: Methicillin-resistant S. pseudintermedius strains (MRSP) are reported with increasing frequency in bacterial cultures from dogs. The objectives of this study were to determine whether MRSP could be found in dogs several months after a clinically apparent infection and whether the length of carriage varied depending on systemic antimicrobial treatment, diagnosis at time of the first positive MRSP culture and the presence of skin disease or wounds. Thirty-one dogs previously diagnosed with a clinical infection were sampled repeatedly for a minimum of eight months or, with the exception of two dogs, until two consecutive negative results were obtained. Five specified locations were sampled, and the results were evaluated to determine future recommendations concerning sample strategies when screening for MRSP carriage. Information was collected from medical records and questionnaires to evaluate factors that may influence length of carriage. RESULTS: The overall median length of MRSP carriage was 11 months (48 weeks). The presence of wounds and signs of dermatitis did not influence length of carriage. Systemic treatment for three weeks or longer with antimicrobial agents to which the bacterium was resistant was associated with prolonged carriage compared to dogs treated for a shorter period of time. Three of five dogs treated with an antimicrobial to which their MRSP-isolates were susceptible (tetracycline) were found to still be MRSP-positive when sampled after the end of treatment. Wound samples had the highest positive MRSP yield (81%) for the positive sample sites, compared to less than 70% for each of the other four sample sites. Cultures from the nostrils were less likely to detect MRSP carriage relative to the pharynx, perineum, wounds and the corner of the mouth. CONCLUSIONS: Dogs can carry MRSP for more than a year after a clinically apparent infection. Systemic antimicrobial treatment of infections with antimicrobial agents to which the MRSP-bacteria are resistant should be avoided when possible in dogs with possible or confirmed MRSP carriage or infection, since it may prolong time of MRSP carriage. Simultaneous sampling of pharynx, perineum, and the corner of the mouth as well as wounds when present is recommended when screening for MRSP. Cultures from nostrils were shown to be less likely to detect MRSP carriage. PMID- 22444912 TI - Prevalence of GB virus type C viraemia in MSM with or without HIV-1 infection in Beijing, China. AB - GB virus C (GBV-C) is frequently identified in patients co-infected with human immunodeficiency virus type 1 (HIV-1) due to the similar transmission routes. However, it remains unclear how these two viruses interact with each other and how one virus affects the replication of the other in the human body. In this study, we performed a case-control study to determine whether GBV-C viraemia could prevent the acquisition of HIV-1 infection, and a cohort study to determine the prevalence, genotypic characteristics and incidence of GBV-C infection in men who have sex with men (MSM) populations in Beijing, China. The prevalence of GBV C infection in HIV-1-negative subjects was similar to that in HIV-1-positive subjects. Before HIV-1 acquisition, the prevalence of GBV-C was 17.7%, which increased to 27.2% at the acute stage and to 34% at the chronic stage. Genotype 3 was the major genotype of GBV-C in both groups. A significantly positive correlation was observed between the CD4+ T-cell counts and GBV-C viral loads at the acute stage of HIV infection. At the chronic stage (12 months later), this correlation was no longer significant, although it was still positive. Overall, this study demonstrated that pre-existing GBV-C viraemia could not prevent the acquisition of HIV-1 infection and transmission of HIV-1 significantly increased the prevalence of GBV-C viraemia. PMID- 22444913 TI - Myostatin gene targeting in cultured China Han ovine myoblast cells. AB - Myostatin (MSTN), a member of the transforming growth factor-beta superfamily, has been shown to be a negative regulator of myogenesis. Natural mutation in beef cattle causes double-muscling phenotypes. We report an investigation designed to knockout the MSTN gene by gene targeting in ovine myoblast cells. Two promoter trap targeting vectors MSTN-green fluorescent protein (GFP) and MSTN-neo were constructed and used to transfect foetal and neonatal ovine primary myoblast cells. Both GFP-expressing cells and drug-resistant cells were obtained. Targeted cells expressing GFP were confirmed by polymerase chain reaction (PCR) assay and drug-resistant cells were characterised by PCR and Southern blot after growing into cell clones. PMID- 22444914 TI - Estimation of genetic trends from 1977 to 1998 of body composition and physiological state of Large White pigs at birth. AB - Genetic trends for body composition and blood plasma parameters of newborn piglets were estimated through the comparison of two groups of pigs (G77 and G98, respectively) produced by inseminating Large White (LW) sows with semen from LW boars born either in 1977 or in 1998. Random samples of 18 G77 and 19 G98 newborn piglets were used for whole carcass and tissue sampling. Plasma concentrations of glucose, albumin and IGF-1 were determined on 75 G77 and 90 G98 piglets from 18 litters. The G98 piglets had less carcass dry matter, protein and energy (P < 0.01) than their G77 counterparts. When expressed in g/kg birth weight, livers were lighter (P < 0.001) and contained less glycogen (P < 0.01) in G98 piglets, with no difference in the activity of the hepatic glucose-6-phosphatase between G98 and G77 piglets. Concentrations of protein, DNA, RNA in longissimus dorsi muscle were unaffected by selection. Plasma concentrations of glucose (P < 0.05) and IGF-1 (P < 0.01) were lower in G98 than in G77 piglets. On the whole, the results suggest that the improvement in lean growth rate and in sow prolificacy from 1977 to 1998 has resulted in a lower maturity of piglets at birth. PMID- 22444915 TI - Industry benefits from recent genetic progress in sheep and beef populations. AB - An analytical model that evaluates the benefits from 10 years of genetic improvement over a 20-year time frame was specified. Estimates of recent genetic trends in recorded traits, industry statistics and published estimates of the economic values of trait changes were used to parameterise the model for the UK sheep and beef industries. Despite rates of genetic change in the relevant performance-recorded breeding populations being substantially less than theoretical predictions, the financial benefits of genetic change were substantial. Over 20 years, the benefits from 10 years of genetic progress at recently achieved rates in recorded hill sheep, sheep crossing sire and sheep terminal sire breeding programmes was estimated to be L5.3, L1.0 and L11.5 million, respectively. If dissemination of genetic material is such that these rates of change are also realised across the entire ram breeding industry, the combined benefits would be L110.8 million. For beef cattle, genetic evaluation systems have been operating within all the major breeds for some years with quite widespread use of performance recording, and so genetic trends within the beef breeds were used as predictors of industry genetic change. Benefits from 10 years of genetic progress at recent rates of change, considering a 20-year time frame, in terminal sire beef breeds are expected to be L4.9 million. Benefits from genetic progress for growth and carcass characters in dual-purpose beef breeds were L18.2 million after subtraction of costs associated with a deterioration in calving traits. These benefits may be further offset by unfavourable associated changes in maternal traits. Additional benefits from identification and use of the best animals available from the breeding sector for commercial matings through performance recording and genetic evaluation could not be quantified. When benefits of genetic improvement were expressed on an annual present value basis and compared with lagged annual investment costs to achieve it, the internal rate of return (IRR) on the combined investment in sheep and beef cattle was 32%. Despite a much higher rate of participation in performance recording, the present value of benefits and the IRR were lower for beef cattle than for sheep. The implications of these results for future national and industry investment in genetic improvement infrastructure were discussed. PMID- 22444916 TI - Genetic selection, sex and feeding treatment affect the whole-body chemical composition of sheep. AB - Hypotheses on total body chemical composition were tested using data from 350 Suffolk sheep grown to a wide range of live weights, and fed in a non-limiting way, or with reduced amounts of feed, or ad libitum on feeds of reduced protein content. The sheep were from an experiment where selection used an index designed to increase the lean deposition rate while restricting the fat deposition rate. Ultrasound muscle and fat depths were the only composition measurements in the index. The animals were males and females from a selection (S) line and its unselected control (C). The protein content of the lipid-free dry matter was unaffected by live weight, sex or feeding treatment with only a very small effect of genetic line (0.762 kg/kg in S and 0.753 kg/kg in C; P < 0.05). The form of the relationship between water and protein was not affected by any of the factors; in the different kinds of sheep it was consistent with no effect other than through differences in mature protein weight. The water : protein ratio at maturity was estimated as 3.45. Over the whole dataset, lipid weight (L) increased with protein weight (P) according to L = 0.3135 * P1.850. Allowing for this scaling, fatness increased on low-protein feeds, was greater in females than in males and in C than in S (P < 0.001). Lipid content (g/kg fleece-free empty body weight) was reduced by restricted feeding only in males at the highest slaughter weight (114 kg). The lines differed in lipid content (P < 0.001) with means of 265.1 g/kg for C and 237.3 g/kg for S. Importantly, there was no interaction between line and feeding treatments. A higher proportion of total body protein was in the carcass in S than in C (0.627 v. 0.610; P < 0.001). For lipid, the difference was reversed (0.736 v. 0.744; P < 0.05). The total energy content increased quadratically with slaughter weight. At a particular weight, the energy content of gain was higher in females than in males and in C than in S. Genetic selection affected body composition at a weight favouring the distribution of protein to the carcass and lipid to the non-carcass. Once allowing for effects of genetic selection, sex and feeding treatment on fatness, simple rules can be used to generate the chemical composition of sheep. PMID- 22444917 TI - Effects of xylanase and antibiotic supplementations on the nutritional utilisation of a wheat diet in growing chicks from genetic D+ and D- lines selected for divergent digestion efficiency. AB - The experiment consisted of a 2 * 2 * 2 factorial design testing the two D+ and D chicken lines selected for divergent digestion efficiency (fifth selection generation), xylanase (with or without) and ampicillin and collistin (with or without) supplementations. From 8 to 22 days, 144 chickens (18 birds per treatment) were fed a diet containing 55% wheat from a high-viscosity cultivar (Rialto). Effects of treatments were evaluated on individual growth performance (8 to 19 days), digestibilities of lipids and dry matter, dietary energy value (apparent metabolisable energy corrected to zero-nitrogen retention (AMEn)), digestive organ and breast sizes, and intestinal bile acids at 3 weeks of age. Individual variabilities were much lower in D+ than in D- birds for feed : gain ratios, digestibilities and AMEn values. In all cases, feed : gain ratios were lower in the D+ than in the D- line (P < 0.001), and D+ birds showed 22% to 86% higher values than in D- birds (P < 0.001) for digestibilities and AMEn. In D- birds, antibiotics but not xylanase supplementation had significant effects on lipid digestibility (P < 0.01) and AMEn (P < 0.05), whereas both supplements improved these parameters in D+ birds (P < 0.001 for both additives on lipids digestibility, P < 0.05 for xylanase and P < 0.01 for antibiotics on AMEn). Relative weights of gizzard and proventriculus, and gizzard : intestine weight ratio were higher in D+ than in D- birds, while relative weight of intestine was increased in D- birds compared with D+ birds. Antibiotics reduced intestine relative weight in D+ (P < 0.001) and D- (P < 0.01) lines. AMEn variations were efficiently predicted by the gizzard : intestine weight ratio. In conclusion, antibiotics were very efficient for improving growth performance, AMEn and digestibility values in both chicken lines. Xylanase was less efficient than antibiotics. Because of their low individual variabilities, D+ birds were much more efficient than D- ones for the detection of significant effects induced by xylanase supplementation. Differences between lines in feed : gain ratio, digestibilities and AMEn were reduced when xylanase and antibiotics were added together. Effects of xylanase supplementation and animal genetics on lipid digestibility could not be entirely explained in terms of intestinal bile acids. Other factors should be involved, especially for the lipid digestibility difference induced by animal genetics. The gizzard : intestine weight ratio was an efficient parameter for predicting AMEn variations due to animal genetics and additives. PMID- 22444918 TI - Use of 'natural' products as alternatives to antibiotic feed additives in ruminant production. AB - The banning in 2006 of the use of antibiotics as animal growth promoters in the European Union has increased demand from producers for alternative feed additives that can be used to improve animal production. This review gives an overview of the most common non-antibiotic feed additives already being used or that could potentially be used in ruminant nutrition. Probiotics, dicarboxylic acids, enzymes and plant-derived products including saponins, tannins and essential oils are presented. The known modes of action and effects of these additives on feed digestion and more especially on rumen fermentations are described. Their utility and limitations in field conditions for modern ruminant production systems and their compliance with the current legislation are also discussed. PMID- 22444919 TI - Expression pattern of HIF1alpha mRNA in brain, heart and liver tissues of Tibet chicken embryos in hypoxia revealed with quantitative real-time PCR. AB - The problem of hypoxia adaptation in high altitudes is an unsolved brainteaser in the field of the life sciences. As one of the best chicken breeds with adaptability to highland environment, the Tibet chicken, is genetically different from lowland chicken breeds. It is well known that hypoxia has significant impact on growth by inducing the expression of the alpha subunit of the heterodimeric transcription factor, hypoxia-inducible factor 1 (HIF1alpha). In the present study, HIF1alpha expression in brain, heart and liver tissues of the Tibet and Dwarf Recessive White chicken embryos were investigated at the different development stages of days 10, 17 and 20 by real-time PCR, and the expression pattern of HIF1alpha in chicken embryos of the two chicken breeds incubated under conditions of hypoxia (13% O2) and normoxia (21% O2) was studied. The incubation mortality of the Tibet chicken was lower than the Dwarf Recessive White chicken during the whole incubation in hypoxia, and the mRNA expression of HIF1alpha had presented the differences in three tissues. The results implied that the hypoxia adaptability of the Tibet chicken embryo was higher than the Dwarf Recessive White chicken, especially in the early stage (day 10) and at a later time (day 20) during the incubation period, but the mechanism of the oxygen transfer of embryos of mountain species is not completely understood, and hypoxia adaptability of the Tibetan chicken remains to be studied further. PMID- 22444920 TI - Specific features of in vivo and in vitro sperm storage in birds. AB - This review focuses on some of the main features of sperm selection and storage in birds mainly on the basis of studies performed in poultry species, with emphasis on the initial selection of sperm at the female vagina level prior to migration towards the sperm storage tubules. Sperm originating from low-quality males or subjected to inappropriate in vitro storage conditions are rapidly discarded, resulting in impaired fertility in corresponding flocks. In the absence of accessible and appropriate technology for matching the 'storing' potential of sperm in the oviduct, conditions for prolonged sperm storage under a liquid (through the use of semen extenders) or a solid state (cryopreservation) have received only limited attention, despite their potential interest to facilitate male and female management in poultry flocks. Despite this, technology for short-term liquid storage is currently used in turkeys, guinea fowl and muscovy ducks and also in progress in chickens. In addition, technology for cryopreservation of avian semen has become available for some species (chicken, goose) to facilitate the management of genetic resources, including the preservation of rare and economically important breeds. PMID- 22444921 TI - Growth and development of offspring following supplementation of sow diets with oil during early to mid gestation. AB - The role of dietary fat during early pregnancy in sows has not yet been fully established. The aim of the study was to determine the consequences of altering the fatty acid profile of sow diets during the first half of gestation; oils of different fatty acid composition were chosen as energy supplements to provide diets with different fatty acid profiles. A group of 48 multiparous sows were used to evaluate the effects of supplemental feeding during the first 60 days of gestation (term ~ 115 days). Sows were allocated (eight per treatment) to either 3 kg/day of commercial sow pellets (control; C) or an experimental diet consisting of 3 kg/day of commercial sow pellets supplemented with 10% extra energy in the form of excess pellets (E), palm oil (P), olive oil (O), sunflower oil (S) or fish oil (F). Differential effects were observed with respect to the fatty acid profile of the diet during the first half of gestation. P sows gave birth to the largest litters. Both P and O supplementation of the maternal diet resulted in heavier piglets at birth, after correction for differences in litter size. P piglets possessed the most fat at birth and remained fatter throughout the pre-weaning period; in contrast, the offspring of O sows contained the least fat throughout life (0 to 140 days of age). The offspring of F sows exhibited improved growth performance during the neonatal period. In conclusion, altering the fatty acid profile of sow diets during the first half of gestation has long term consequences for the growth and development of their offspring. PMID- 22444922 TI - Growth and development of offspring following supplementation of sow diets with oil during mid to late gestation. AB - This study aimed to determine the consequences of altering the fatty acid profile of sow diets during mid-to-late gestation; oils of different fatty acid composition were chosen as energy supplements to provide diets with different fatty acid profiles. Forty-eight multiparous sows were used to evaluate the effects of fat supplementation from day 60 of gestation until parturition. Sows were allocated to either 3 kg/day of commercial sow pellets (control; C) or an experimental diet consisting of 3 kg/day of commercial sow pellets supplemented with 10% extra energy in the form of excess pellets (E), palm oil (P), olive oil (O), sunflower oil (S) or fish oil (F). From days 0 to 60 of gestation, all sows were given 3 kg/day of sow pellets as for the C group. The E diet resulted in the heaviest piglets at birth whereas the offspring of O and S sows were the lightest at birth. The offspring of S sows remained lighter throughout the pre-weaning period, and were also the leanest by 14 days of age. In contrast, pigs born to S sows possessed more fat by the time they reached commercial end point (~140 days of age). In conclusion, altering the fatty acid profile of the sow diet during the second half of gestation has long-term consequences for the development of their offspring. PMID- 22444923 TI - Once-a-day milking of Holstein and Montbeliarde cows for 7 weeks in mid lactation. AB - This study aimed at comparing the effects of once-a-day (OAD) milking during the descending phase of lactation between cows from the two most common breeds in France (Holstein and Montbeliarde). This study was carried on during two successive summers on a total of 50 Holstein and 38 Montbeliarde cows. During 7 weeks, half of the cows from each breed was milked OAD while the other half was milked twice a day (TAD). The animals were also followed for the next 3 or 5 weeks when they were all milked TAD, to check for any residual effect of OAD milking. The behaviour of OAD cows was observed around milking time. The incidence of diseases, the main performance variables (milk production, milk flow rate, live weight and body condition score), the detailed composition of milk (fat, protein, lactose, somatic cells, minerals, pH, free fatty acid (FFA), nitrogen fractions and enzymes) and some technological variables (clotting time and curd firmness) were measured on all cows.Some signs of disturbance were observed in the OAD cows at the time when milking was omitted: some cows mooed, some went close to the exit of the paddock, some leaked milk prior to milking. However, these signs disappeared after 2 days. After the experimental period, the live weight and the body condition score of TAD and OAD cows did not differ significantly. OAD cows produced 4.5 kg/day less than TAD (P < 0.001), this being more marked in Holstein (5.7 kg/day, P < 0.001) than Montbeliarde (3.3 kg/day, P < 0.001) cows. The milk contents of fat, whey protein, casein, total protein and phosphorus, and its plasminogen activity, were higher with OAD cows while lactose and FFA contents, and lipoprotein lipase activity were lower, with no interaction observed with breed. During the subsequent 3 weeks, when all cows were again milked TAD, OAD cows still produced 1.7 kg/day less milk (P < 0.01) with slightly higher fat and protein content.OAD milking for 7 weeks during the descending phase of lactation decreased milk production but increased milk content of most components, with a low residual effect. Montbeliarde cows were less affected by OAD milking than Holstein cows. PMID- 22444924 TI - Beef production potential of Norwegian Red and Holstein-Friesian bulls slaughtered at two ages. AB - There is a paucity of data on the beef production potential of Norwegian Red (NOR) compared with 'modern' Holstein-Friesian (HF) cattle. The present study used a total of 64 bulls in a 2 * 2 factorial design study encompassing two breeds (HF and NOR) and two slaughter ages (485; E, and 610; L, days). The mean initial age and live weight of the HF bulls were 179 (s.d. 47.1) days and 203 (s.d. 64.0) kg, while the corresponding data for the NOR bulls were 176 (s.d. 39.7) days and 185 (s.d. 63.6) kg, respectively. Bulls were offered a 50 : 50 mixture (dry matter (DM) basis) of grass silage and concentrates. No breed * slaughter group interactions were recorded for any parameters evaluated (P > 0.05). HF bulls had higher (P < 0.001) DM intake and poorer (P < 0.01) efficiency of conversion of food to carcass gain than NOR bulls. HF bulls tended (P = 0.07) to have a higher rate of live-weight gain and were heavier (P < 0.001) at slaughter than NOR bulls, though both carcass weight and rate of carcass gain did not differ between the breeds (P > 0.05). NOR bulls had higher (P < 0.001) dressing proportion and carcass conformation score than HF bulls, while breed of bull had no influence (P > 0.05) on carcass fat classification, depth of subcutaneous fat, marbling score or on the weight of fat in the internal depots. Daily food intakes did not differ (P > 0.05) across the two slaughter age groups, though efficiency of conversion of food to carcass gain was poorer (P < 0.05) in the L compared with E bulls. Rate of live-weight gain was lower (P < 0.01) for L bulls, although rate of carcass gain did not differ (P > 0.05) between the E and L bulls. Increasing age at slaughter increased (P < 0.01 or greater) dressing proportion, carcass fat class, depth of subcutaneous fat, marbling score and internal fat depots, but had no effect (P > 0.05) on the carcass conformation score. Instrumental measures of meat quality indicated that meat from NOR bulls was tougher (P < 0.01) than meat from HF bulls, while delaying slaughter increased (P < 0.001) a* and C*ab, and decreased (P < 0.01) h0, indicating improved redness. It is concluded that NOR bulls have higher food efficiency and produce more highly conformed carcasses than HF bulls, but HF bulls produce more tender meat. PMID- 22444925 TI - Gaseous emissions during the fattening of pigs kept either on fully slatted floors or on straw flow. AB - The aim of this study was to compare the environmental impact of the straw-flow system for fattening pigs with the slatted-floor system by measuring pollutant gas emissions such as ammonia (NH3), nitrous oxide (N2O), methane (CH4) and carbon dioxide (CO2), manure nitrogen (N) content and emissions of water vapour (H2O). Three successive batches of 32 pigs were fattened. For each batch, pigs were allotted to two groups raised in separated rooms fitted either with a concrete totally slatted-floor system (0.75 m2 per pig) or with a straw-flow system (0.79 m2 per pig). With this last system, pigs were kept on a sloped floor, straw being provided daily at the top of the pen. Throughout the fattening period, about 34.4 kg of straw were supplied per pig. The straw, mixed with dung, travelled down the slope by pig motion and went out of the pen to a scraped passage. The solid fraction was scraped every day, stored in a heap in the room and removed every month, 1 week before each period of gaseous emission measurement. The liquid fraction was automatically pumped from the scraped passage into a hermetic tank, which was emptied at the end of each fattening period. Rooms were ventilated mechanically in order to maintain a constant ambient temperature. Once a month, the emissions of NH3, N2O, CH4, CO2 and H2O were measured hourly for 6 consecutive days via infrared photoacoustic detection. Mean daily emissions per pig fattened on the slatted floor or on the sloped floor were, respectively, 4.98 and 13.31 g NH3, 0.67 and 0.68 g N2O, 15.2 and 8.88 g CH4, 548 g and 406 g CO2 equivalents, 1.61 and 1.77 kg CO2 and 2.33 and 2.95 kg H2O. Except for N2O emissions, all the differences were statistically significant (P < 0.001). From the slatted-floor system, the amount of slurry removed per fattening period was on average 256 kg per pig. From the straw-flow system, solid manure amounted on average to 209 kg per pig and liquid manure to 53 kg per pig. The total N-content of the manure was 2.23 kg N per pig with the straw-flow system (solid and liquid manure) v. 3.26 kg N per pig for slurry from the slatted floor system. This reduction of 30% observed with the sloped floor was mainly explained by the higher level of NH3-N emissions. PMID- 22444926 TI - Genetic analyses of sensory characteristics and relationships with fatty acid composition in the meat from Scottish Blackface lambs. AB - Genetic parameters for eating quality assessed by trained taste panellists were estimated on longissimus thoracis et lumborum (LTL) muscle in Scottish Blackface lambs, comprising lines previously divergently selected for carcass lean content (FAT and LEAN lines) as well as crosses between these lines. Also, relationships between eating quality assessments and fatty acid composition were investigated. Eating quality and fatty acid phenotypic measurements were made on 350 male lambs, at ca. 8 months of age. Eating quality measurements included 18 descriptive terms and fatty acid composition measurements included in total 17 fatty acids of three types: saturated, monounsaturated and polyunsaturated. The FAT line had juicier meat and more vegetable flavour than the LEAN line. Most of the eating quality traits were moderately to highly heritable, with heritabilities ranging from 0.21 (lamb flavour) to 0.92 (sweet flavour). Lamb flavour, juiciness and overall liking were strongly negatively correlated with individual polyunsaturated fatty acids, with the correlations being significantly different from zero. Overall liking was strongly positively correlated with the proportion of total monounsaturated fatty acids. This study provides new information on genetic parameters for eating quality traits in sheep, which may lead to novel opportunities for genetically improving these traits. PMID- 22444927 TI - Mating animals by minimising the covariance between ancestral contributions generates less inbreeding without compromising genetic gain in breeding schemes with truncation selection. AB - We reasoned that mating animals by minimising the covariance between ancestral contributions (MCAC mating) will generate less inbreeding and at least as much genetic gain as minimum-coancestry mating in breeding schemes where the animals are truncation-selected. We tested this hypothesis by stochastic simulation and compared the mating criteria in hierarchical and factorial breeding schemes, where the animals were selected based on breeding values predicted by animal model BLUP. Random mating was included as a reference-mating criterion. We found that MCAC mating generated 4% to 8% less inbreeding than minimum-coancestry mating in the hierarchical and factorial breeding schemes without any loss in genetic gain. Moreover, it generated upto 28% less inbreeding and about 3% more genetic gain than random mating. The benefits of MCAC mating over minimum coancestry mating are worthwhile because they can be achieved without extra costs or practical constraints. MCAC mating merely uses pedigree information to pair the animals more appropriately and is clearly a worthy alternative to minimum coancestry mating and probably any other mating criterion. We believe, therefore, that MCAC mating should be used in breeding schemes where pedigree information is available. PMID- 22444928 TI - Evaluation of crude annual parturition rate estimates in a small-holder African ruminant farming system. AB - Many parameters have been proposed for evaluating livestock reproduction performances in tropical farming systems. In tropical free-ranged and small holder systems, where reproduction cycles cannot be individually observed without expensive field surveys, one of these parameters is the average number of parturitions (h) expected by reproductive female, if the female spends the whole year in the herd. A frequent approach for estimating h is to use the ratio hc = m/T, so-called 'crude annual parturition rate', where m is the observed number of parturitions and T is the total time of presence of the reproductive females in the herd during the year. The bias encountered when h is estimated by hc was evaluated in this paper. Six methods of estimation were used, where T was the exact observed time of presence (hc1) or approximated by monthly, quarterly, half yearly and yearly averages or final size of the reproductive herd size (hc2 to hc6). Data came from long-term follow-up of cattle and small-ruminant herds (with data recorded at animal level) in extensive agro-pastoral systems in Senegal. In general, h was correctly estimated by hc1. Nevertheless hc1 was sensitive to competing risks (e.g. deaths, sales and slaughtering of reproductive females) and was seriously biased when intensive withdrawals of females occurred before or during the parturition peak. Reliability of crude rates progressively decreased from hc2 to hc6, corresponding to the degradation of information used for approximating T. This decrease was much lower for cattle (for which all methods had acceptable reliability) than for small ruminants. Among the compared methods, the lower reliability was observed for hc6 that we do not recommend for small ruminants. Methods hc5 and hc6 are currently used in rapid cross-sectional retrospective surveys based on the recall of the farmers on the demographic events which occurred in the herd over the last past 12 months. The study has showed that such surveys and estimates hc5 and hc6 can generate seriously biased results. More globally, annual parturition rates can be highly variable depending on the 12-month periods considered. Annual parturition rates estimated on short term data, even with precise herd follow-up surveys, must be considered cautiously. PMID- 22444929 TI - Estimation of genetic associations between reproduction and production traits based on a sire and dam line with common ancestry. AB - Genetic parameters for survival, reproduction and production traits were estimated for a sire and dam line, originating from one Large White breed separated more than 25 years ago. The change in parameters due to different selection pressure on reproduction and production traits in both lines was also examined. Data collected between 1990 and 2007 were available for the analysis of reproduction traits in 4713 litters (sire line) and 14836 litters (dam line) and for the production traits in 58329 pigs (sire line) and 108912 pigs (dam line). Genetic parameters were estimated using a Bayesian approach. Average phenotypic differences between lines were substantial with 1.5 more piglets born in the dam line and 1.7 mm less backfat thickness (BF) in the sire line. Based on a multiple trait analysis which included both reproduction and production traits, heritabilities for survival and litter size traits in the sire (or dam) line were estimated at 0.03 +/- 0.01 (0.06 +/- 0.01) for percentage of stillborn piglets (SB), 0.10 +/- 0.03 (0.11 +/- 0.01) for total number of piglets born (NBT) and 0.09 +/- 0.03 (0.09 +/- 0.01) for number of piglets born alive. Heritabilities for production traits were estimated at 0.29 +/- 0.01 (0.29 +/- 0.01) for average daily gain, 0.50 +/- 0.01 (0.42 +/- 0.01) for BF and 0.41 +/- 0.01 for muscle depth. Selection pressure on litter size in the dam line resulted in a slightly unfavourable correlation for SB-NBT (0.21 +/- 0.11), which was only marginally unfavourable in the sire line (0.06 +/- 0.24). Selection pressure on BF in the sire line may have resulted in the moderately undesirable correlation with SB ( 0.46 +/- 0.15), which was not significant in the dam line (-0.08 +/- 0.06). Changing the base population in the dam line to animals born since the year 2000 indicated that selection pressure on different traits has altered the heritabilities and correlations of the traits within the line. The undesirable correlations between survival at birth and reproduction traits or production traits were low so that simultaneous improvement of all traits can be achieved. Heritabilities for survival at birth and reproduction traits were low, but genetic variation was substantial and extensive pedigree information can be used to improve the accuracy of breeding values, so that genetic improvement is expected to be efficient. PMID- 22444930 TI - Association analysis between pseudorabies antibody and five single-nucleotide polymorphisms in pigs. AB - Pseudorabies has become endemic and represents a widespread problem for pig production in the world, causing great economic losses associated with reproductive failure and neonatal mortality in the pig industry. Most diseases are the results of mutations of functional genes. Single-nucleotide polymorphisms (SNPs) from the coding regions of the mediators of pro-inflammatory responses or other candidate genes in pigs could indicate their potential involvement in susceptibility or resistance to PrV (pseudorabies virus) infection. There have been no previous association studies with candidate host genes that may influence PrV phenotypic traits. In order to perform association studies to identify genes contributing to PrV phenotypes, the genotypes of five SNPs from four genes (IL10, CXCL12, BAT2 and EHMT2) were determined for 178 sow samples using a high throughput microarray-based methodology. PrV antibodies were tested by enzyme linked immunosorbent assay (ELISA) to determine whether there was an association between antibody levels and particular genotypes. The association between SNP genotypes and the PrV antibody levels were analysed using the Duncan method of one-way ANOVA procedure using the SAS (Statistical Analysis Systems) software package. The results showed that the glycoprotein E-ELISA antibody level of pigs with genotypes 11(AA) and 12(AG) was significantly higher than in pigs with genotype 22(GG) (P < 0.05) of SNP in the gene EHMT2-SNP2. The SNP of EHMT2 may be an effective potential tool to identify susceptible and resistant animals when used in conjunction with traditional selection methods. PMID- 22444931 TI - Effects of feeding dry propylene glycol to early postpartum Holstein dairy cows on production and blood parameters. AB - In all, 18 multiparous and 19 primiparous Holstein dairy cows were used in a completely randomized design with restrictions to evaluate the effects of feeding propylene glycol (PG) as a dry product, via two delivery methods, on production and blood parameters. PG treatments were administered from parturition through 21 days postpartum. Treatments were: (i) control, no PG; (ii) top dress, 162.5 g PG/day by top dressing onto the total mixed ration (TMR) and; (iii) mixing, 162.5 g PG/day as a part of the TMR by incorporating it into the TMR. PG used was a dry product which contained 65% pure PG and 35% silicon dioxide as the dry carrier. Coccygeal blood was sampled on 4, 7, 14 and 21 days in milk (+/-1.50 pooled s.d.). Supplementation of dry PG by top dressing onto, or incorporating into, the TMR had no effects on average dry matter intake, milk yield and composition, serum insulin, serum and plasma metabolites and milk ketones. Concentrations of urine ketones tended (P = 0.10) to be reduced by PG supplementation from 41.5 to 15.2 mg/dl. Supplementation of PG tended (P = 0.07) to decrease the incidence for subclinical ketosis from 39% to 24% and 13% for cows fed a TMR supplemented with no dry PG, with dry PG as a top dress and dry PG as a part of the TMR, respectively. It is concluded that supplementing PG as a dry product via incorporating into the TMR is as effective as when used as a top dress, based on the efficacies of both delivery methods to numerically reduce urine ketones concentrations and, therefore, the incidence for subclinical ketosis during the first 21 days of lactation. However, it should be noted that the number of cows used in the current study was minimal, and more cows are needed to confirm the efficacy of supplementing PG as a dry product on reducing the prevalence of subclinical ketosis in dairy cows during the first month of lactation. PMID- 22444932 TI - Apparent absorption of methionine and 2-hydroxy-4-methylthiobutanoic acid from gastrointestinal tract of conventional and gnotobiotic pigs. AB - The effect of commensal microbiota and feeding corn or wheat/barley-based diets on the apparent gastrointestinal absorption of dl-methionine (MET) and 2-hydroxy 4-methylthiobutanoic acid (MHA-FA) was studied in conventional (n = 32) and gnotobiotic pigs (n = 24). Conventional pigs (CON) were vaginally delivered and sow-reared until weaning at 14 days of age. Gnotobiotic pigs were derived by caesarian section and reared in HEPA (high efficiency particulate air)-filtered isolator units with ad libitum access to a milk-based formula. Corn or wheat/barley-based diets were fed to all pigs from 14 to 24 days of age. At 24 days of age, after an overnight fast, pigs were fed 20 g/kg BW of experimental diet supplemented with 107 Bq of either 3H-l-MET or 3H-l-MHA-FA per kg of feed and chromic oxide (0.5% wt/wt). Pigs were killed for sample collection 3 h after consuming the meal. Residual 3H-MET and 3H-MHA-FA were estimated in gastrointestinal contents as the ratio of 3H : chromic oxide in digesta samples to the ratio of 3H : chromic oxide in feed. In CON pigs, feeding a wheat/barley based diet increased (P < 0.05) total aerobes, whereas supplementation with MHA FA increased (P < 0.05) total aerobes and lactobacilli populations in proximal small intestine (SI). Among the gnotobiotic pigs, bacterial contamination occurred such that eight pigs (two isolators) were monoassociated with a Gram negative bacteria closely related to Providencia spp. and 16 pigs (four isolators) were monoassociated with Gram positive Enterococcus faecium. Species of monoassociated bacterial contaminant and diet composition did not affect residual methionine or MHA-FA in digesta. In both CON and monoassociated (MA) pigs, methionine and MHA-FA were retained in stomach (92%) but disappeared rapidly from proximal SI. Residual methionine and MHA-FA in digesta was not different in MA pigs; however, in CON pigs, less (P < 0.01) apparent residual methionine was found in digesta recovered at 25% (from cranial to caudal) and 75% of SI length compared with MHA-FA. Apparent residual methionine was 16% and 8% compared with 34% and 15% for MHA-FA, at the 25% and 75% locations, respectively. In proximal SI tissue, significantly (P < 0.05) higher radioactivity (cpm/mg wet tissue) was associated with MET pigs (8.56 +/- 0.47) as compared to MHA-FA ones (5.45 +/- 0.50). This study suggests that microbial metabolism of MHA-FA increases retention in small intestinal digesta relative to methionine and contributes, in part, to the lower bioefficacy of MHA-FA compared to methionine. PMID- 22444933 TI - Responses of hepatic blood flows to changes in intake in sheep: a meta-analysis. AB - This work set out to establish the response equations for hepatic blood flows in sheep and the contribution of hepatic arterial flow to hepatic venous blood flow due to changes in intake levels at constant diet composition. The FLORA (FLuxes across Organs and tissues in Ruminant Animals) database was used, and meta analysis performed. The meta-analysis involved selection of published papers, identification of studies, description and coding of the selected dataset and statistical analysis using a covariance model. Meta-analyses were carried out using a within-study approach. To ensure absence of bias, the analysis incorporated interfering variables and factors studied in between-study comparisons. Variables concerned diet composition; qualitative factors concerned the physiological state of the animals and the methods used to measure blood flow. The results obtained showed that hepatic blood flows were positively related to intake in sheep. The magnitude of the response (as indicated by the slope) varied with the level of intake and the blood vessel (portal, hepatic venous or arterial). Nine linear relationships were established for the portal, hepatic venous and arterial blood flows as a function of dry matter intake (DMI) with below- and above-maintenance levels considered separately. Data obtained at below- and above-maintenance levels were considered together and four quadratic relationships were established for hepatic blood flows as a function of DMI. These relationships expressed a strong effect of intake on hepatic blood flows. The contribution of hepatic arterial to hepatic venous blood flow averaged 18.2%, with a wide variability. It did not vary significantly with level of intake. Although in between-study comparisons the arterial/venous blood flow was positively influenced by the organic matter digestibility of the diet, the relationships we obtained were robust. They can be used in models of net hepatic nutrient fluxes to predict variations and absolute values of hepatic blood flows from variations and absolute values of DMI. PMID- 22444934 TI - Reproductive and productive performance of rabbit does submitted to an oral glucose supplementation. AB - In order to investigate the effect of different levels of oral glucose supplementation and/or reproductive method on productive and reproductive performance of New Zealand White (NZW) doe rabbits in the tropic, 36 bucks and 120 doe NZW rabbits were equally divided among four treatment groups (n = 9 bucks + 30 does). The treatments consisted of supplementing drinking water with 0 (control), 2.5, 5 and 10 g glucose/l, respectively. To study the effect of reproduction method (natural v. artificial), each group was divided into two sub groups (naturally mated and artificially inseminated) with the same bucks of the same treatment group. Glucose supplementation at 5 or 10 g/l of water increased (P < 0.01) litter weight at birth and at weaning, and litter weight gain during the 4 weeks. However, glucose supplementation at 2.5 or 5.0 g/l water decreased (P < 0.01) feed consumption from 7 to 14 days after delivery. Glucose supplementation at 2.5 g/l water did not affect productive and reproductive performance of rabbits. Artificially inseminated does had higher daily litter weight gain between 21 and 28 days post partum. Artificially inseminated group had better milk conversion during the 1st and 4th week as compared to naturally mated groups. Compared with the control group, the economic efficiency and performance index of NZW rabbits was significantly improved by 5 g glucose supplementation under tropic condition. PMID- 22444935 TI - Dietary n-6- or n-3-rich vegetable fats and alpha-tocopheryl acetate: effects on fatty acid composition and stability of rabbit plasma, liver and meat. AB - We supplemented diets with alpha-tocopheryl acetate (100 mg/kg) and replaced beef tallow (BT) in feeds with increasing doses of n-6- or n-3-rich vegetable fat sources (linseed and sunflower oil), and studied the effects on the fatty acid (FA) composition, the alpha-tocopherol (alphaT) content and the oxidative stability of rabbit plasma and liver. These effects were compared with those observed in a previous study in rabbit meat. As in meat, the content of saturated, monounsaturated and trans FA in plasma and liver mainly reflected feed FA profile, except stearic acid in liver, which increased as feeds contained higher doses of vegetable fat, which could be related to an inhibition of the activity of the stearoyl-CoA-desaturase. As linseed oil increased in feeds, the n 6/n-3 FA ratio was decreased in plasma and liver as a result of the incorporation of FA from diets and also, due to the different performance and selectivity of desaturase enzymes. However, an increase in the dose of vegetable fat in feeds led to a significant reduction in the alphaT content of plasma and liver, which was greater when the fat source was linseed oil. Increasing the dose of vegetable fat in feeds also led to an increase in the susceptibility to oxidation (lipid hydroperoxide (LHP) value) of rabbit plasma, liver and meat and on the thiobarbituric acid (TBA) values of meat. Although the dietary supplementation with alpha-tocopheryl acetate increased the alphaT content in plasma and liver, it did not modify significantly their TBA or LHP values. In meat however, both TBA and LHP values were reduced by the dietary supplementation with alpha tocopheryl acetate. The plasma alphaT content reflected the alphaT content in tissues, and correlated negatively with tissue oxidability. From the studied diets, those containing 1.5% linseed oil plus 1.5% BT and 100 mg of alpha tocopheryl acetate/kg most improved the FA composition and the oxidative stability of rabbit tissues. PMID- 22444936 TI - Effects of feeding propylene glycol on dry matter intake, lactation performance, energy balance and blood metabolites in early lactation dairy cows. AB - The objectives of this study were to evaluate effects of feeding propylene glycol (PG) on feed intake, milk yield and milk composition, blood metabolites and energy balance in Holstein dairy cows from 1 to 63 days in milk. Thirty-two multiparous cows, blocked by lactation number, previous 305-day milk production and expected calving date, were arranged into four groups in a randomized block design. Treatments were: control, low PG, medium PG and high PG with 0, 150, 300 and 450 ml PG per cow per day, respectively. The supplement of food grade PG (0.998 g/g PG) was hand-mixed into the top one-third of the daily ration. Cows were fed ad libitum a total mixed ration consisting of forage and concentrate (50 : 50, dry matter basis). Feed intake, milk yield and milk components were not affected (P > 0.05) by PG supplementation. Overall, body weight (BW) loss tended (P < 0.08) to be linearly reduced, and energy status was linearly improved with increasing PG supplementation. Concentrations of glucose in plasma were higher for cows fed PG relative to control (55.6 v. 58.9 mg/dl) and linearly increased (P < 0.01) with increasing PG supplementation. Plasma concentrations of non esterified fatty acids and beta-hydroxybutyrate were linearly increased, but urine acetoacetate concentration was quadratically changed with the highest for control diet and the lowest for 450 ml/day of PG. These results indicated that supplementation of PG in the early lactating cow diets had minimal effects on feed intake and milk production, but may potentially reduce contents of milk fat and milk protein. Supplementation of early lactating dairy cow diets with PG is beneficial in terms of improving energy status and reducing BW loss. PMID- 22444937 TI - Concentration of the mammalian lignans enterolactone and enterodiol in milk of cows fed diets containing different concentrations of whole flaxseed. AB - A total of 32 lactating Holstein cows with mean body weight of 622 kg (s.e. = 24) were allotted, at week 25 of lactation, to eight groups of four cows blocked for similar days in milk. The objective of the experiment was to determine the effect of feeding four dietary concentrations (0, 50, 100 or 150 g/kg of dry matter) of whole flaxseed, which contains the plant lignan precursor secoisolariciresinol diglucoside (SDG), on concentrations of two mammalian lignans (enterodiol and enterolactone) in milk. The effects of the four diets on feed intake, milk production, milk composition and digestion were also studied. Cows within each block were assigned to one of the four isonitrogenous and isoenergetic total mixed diets and the experiment was carried out from week 25 to 29 of lactation. Diets were fed for ad libitum intake. Enterolactone was the mammalian lignan, of the two metabolites studied, detected in the milk of cows and its concentration in milk tended (P = 0.08) to increase linearly with higher intake of SDG in the diet. Feed intake, milk yield and milk composition were similar among diets. Milk fatty acid profile was slightly improved by feeding flaxseed, as shown by higher concentrations of fatty acids (e.g. n-3) recognized as being beneficial for human health. Those results suggest that feeding of whole flaxseed may result in changes in milk fatty acid composition and enterolactone content, which offer benefits for consumers. PMID- 22444938 TI - Expression of HMGR and corresponding cholesterol content in tissues of two pig breeds. AB - The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) is an essential enzyme in cholesterol biosynthesis. To study the expression of HMGR and corresponding cholesterol content in liver, adipose and muscle, six Chinese local breed (Huai pig) and Landrace pigs were selected. The results indicated that significant differences of cholesterol content in adipose (P < 0.01), liver (P < 0.05) and muscle (P < 0.01) tissues were detected between pigs of differing genetic backgrounds. HMGR mRNA expression were noted for adipose, liver and muscle of the two vastly differing genetics. Moreover cholesterol content differed (P < 0.01) among tissues across breed. Likewise, HMGR mRNA expression was different between adipose and liver tissues, muscle and liver tissues in both breeds; however, no difference was noted between adipose and muscle tissues. Results from this study indicate that cholesterol content and HMGR mRNA expression are higher in Huai pig tissues suggesting this gene is expressed in a breed- and tissue-dependent manner in pigs. Understanding the causes of variation in HMGR gene expression may provide crucial information about cholesterol biosynthesis. PMID- 22444939 TI - Dietary vitamin A can improve immune function in heat-stressed broilers. AB - This experiment was undertaken to evaluate the effect of dietary vitamin A on the performance and immune competence of broilers under heat stress (HS). A total of 180 birds, at 22 days of age, were randomly assigned to be reared either at 24 degrees C (thermoneutral, TN, 24 degrees C, constant) or 24 degrees C to 38 degrees C (heat stress, HS, cycling) until the age of 42 days. Birds were then supplemented with vitamin A at 750, 1500, 15 000 IU/kg. Each of the 2 * 3 factorially arranged treatments were replicated in six cages, each containing five birds. Humoral immunity was assessed by intravenous injection of 7% sheep red blood cells (SRBC) followed by evaluation of serum for antibody titers in primary and secondary responses. Cell-mediated immunity was assessed by using a Sephadax stimulation method to recruit abdominal exudate cells (AEC) to evaluate macrophage phagocytic ability. Body weight (BW) and feed conversion were significantly affected by dietary vitamin A (P < 0.05). HS significantly reduced BW, feed intake and feed conversion (P < 0.05). Numbers of AEC, percentage of macrophages in AEC, phagocytic macrophages, internalized opsonized and unopsonized SRBC were increased by dietary vitamin A (P < 0.05). Both primary and secondary antibody responses were characterized by increasing titers of antibody to SRBC by dietary vitamin A when birds were exposed to HS (P < 0.05). Lymphoid organ weights, antibody responses, incidence of macrophages in AEC and phagocytic ability of macrophages were all significantly reduced under HS. These results indicated that HS severely reduced performance and immunocompetence of broilers, whereas the immune response of broilers improved by dietary vitamin A supplementation under HS. PMID- 22444940 TI - Effect of infrared temperature on thermoregulatory behaviour in suckling piglets. AB - The objective of this study was to investigate the effect of infrared (IR) temperature on thermoregulatory behaviour in suckling piglets in the first 3 weeks after farrowing. A total of 10 piglets from each of the 16 litters were exposed to recommended IR temperature conditions at 1, 2 and 3 weeks of age, with a mild offset (4 degrees C) in IR temperature during the first experiment and a more challenging offset (8 degrees C) during the second experiment. Digital photos were taken when all piglets had settled in the creep area, and the lying posture and huddling behaviour were analysed. A lying posture score and a huddling score was calculated by multiplying the number of piglets in each category with a given value for each category, based on different lying postures and different degrees of huddling behaviour. With a 4 degrees C change in IR temperature, the piglets tended to alter their lying posture, while an 8 degrees C change had a significant effect on lying posture (P < 0.01). A change in IR temperature of 4 degrees C had no effect on the degree of huddling. The huddling score decreased significantly with 8 degrees C change in IR temperature (P < 0.05). Postural changes, rather than changes in degree of huddling were the preferred thermoregulatory strategy for suckling piglets. PMID- 22444941 TI - Prediction of methane emission from beef cattle using data measured in indirect open-circuit respiration calorimeters. AB - The objectives of the present study were to examine relationships between methane (CH4) output and animal and dietary factors, and to use these relationships to develop prediction equations for CH4 emission from beef cattle. The dataset was obtained from 108 growing-to-finishing beef steers in five studies and CH4 production and energy metabolism data were measured in indirect respiration calorimeter chambers. Dietary forage proportion ranged from 29.5% to 100% (dry matter (DM) basis) and forages included grass silage, fresh grass, dried grass and fodder beet. Linear and multiple regression techniques were used to examine relationships between CH4 emission and animal and dietary variables, with the effects of experiment or forage type removed. Total CH4 emission was positively related to live weight (LW), feeding level and intake of feed (DM and organic matter) and energy (gross energy (GE), digestible energy (DE) and metabolisable energy (ME)) (P < 0.001), while CH4/DM intake (DMI) was negatively related to energy digestibility and ME/GE (P < 0.05 or less). Using LW alone to predict CH4 emission produced a poor relationship when compared to DMI and GE intake (GEI) (R2 = 0.26 v. 0.68 and 0.70 respectively). Adding feeding level, dietary NDF concentration and CP/ME or feeding level, energy digestibility and ME/GE to support LW resulted in a R2 of 0.66 or 0.84. The high R2 (0.84) was similar to that obtained using DMI or GEI together with energy digestibility and ME/GE as predictors. Further inclusion of dietary forage proportion and ADF and NDF concentration to the multiple relationships using GEI as the primary predictor resulted in a R2 of 0.87. These equations were evaluated through internal validation, by developing a range of similar new equations from two-thirds of the present data and then validating these new equations with the remaining one-third of data. The validation indicated that addition of energy digestibility and ME/GE to support LW with feeding level, DMI and GEI considerably increased the prediction accuracy. It is concluded that CH4 emission of beef steers can be accurately predicted from LW plus feeding level, DMI or GEI together with energy digestibility and ME/GE. The dataset was also used to validate a range of prediction equations for CH4 production of cattle published elsewhere. PMID- 22444942 TI - Performance of dairy cows milked twice daily at contrasting intervals. AB - The time constraints of the classic twice-daily milking routine are less easily endured by individual dairy farmers, because of their impact on quality of life. Our aim was to evaluate milk production responses by dairy cows milked twice daily at contrasting intervals. In experiments 1 (20 cows) and 2 (28 cows), four milking regimes were compared during a 3-week period beginning after the peak of lactation. Three groups of five cows were milked twice daily (TDM) with milking intervals of 11 : 13, 7 : 17 and 3 : 21 h in experiment 1, and three groups of seven cows at 11 : 13, 5 : 19 and 2.5 : 21.5 h in experiment 2. One group (five and seven cows respectively) was milked once daily (ODM) in each experiment. In experiment 3 (three groups, 12 cows per group), one group was milked at 10 : 14 h and one at 5 : 19 h, and the third group once daily. Milking treatments began during the second week of lactation and continued for an average of 23 weeks. In experiments 1 and 2, daily milk yields were reduced by 4.1%, 11.5% and 28%, for the 5 : 19, 3 : 21 and ODM milking treatments compared with the 11 : 13 h interval. In experiment 3, the decrease in daily milk yields for 5 : 19 h and ODM was 10% and 40% compared with the 10 : 14 h time interval. In the average daily milk, fat and protein contents and somatic cell counts were not different between the TDM groups, and the ODM group had (or tended to have) a higher fat and protein content. For a given milking, milk fat content decreased from about 60 to 32 g/kg as the preceding milking interval increased from 2.5 to 3 h up to 12 h. It then levelled out and even increased, mainly after 18 to 20 h. Somatic cell count showed a similar trend, and protein content did not change steadily. Dry matter intake, body weight and body condition score were not affected by contrasting milking intervals. After resumption of TDM with conventional intervals, productions of milk, fat and protein no longer differed between the TDM groups. Milk yield of previously ODM cows remained lower by 2 kg/day (P = 0.15) in experiments 1 and 2, and by 7 kg/day (P < 0.05) in experiment 3. These results suggest that TDM at contrasting intervals up to 5 : 19 h is feasible as it decreases milk yield only moderately, especially if implemented from peak of lactation. PMID- 22444943 TI - The epidemiology of published norovirus outbreaks: a review of risk factors associated with attack rate and genogroup. AB - The purpose of this study was to examine global epidemiological trends in human norovirus (NoV) outbreaks by transmission route and setting, and describe relationships between these characteristics, viral attack rates, and the occurrence of genogroup I (GI) or genogroup II (GII) strains in outbreaks. We analysed data from 902 reverse transcriptase-polymerase chain reaction-confirmed, human NoV outbreaks abstracted from a systematic review of articles published from 1993 to 2011 and indexed under the terms 'norovirus' and 'outbreak'. Multivariate regression analyses demonstrated that foodservice and winter outbreaks were significantly associated with higher attack rates. Foodborne and waterborne outbreaks were associated with multiple strains (GI+GII). Waterborne outbreaks were significantly associated with GI strains, while healthcare-related and winter outbreaks were associated with GII strains. These results identify important trends for epidemic NoV detection, prevention, and control. PMID- 22444944 TI - Prognostic utility of tumor thickness at the tumor-normal interface in chemotherapy-treated hepatic colorectal metastasis. AB - In a recent report, tumor thickness at the tumor-normal interface (TNI) was confirmed as a prognosticator for patients with hepatic metastases from colorectal carcinoma after adjuvant chemotherapy. We retrospectively reviewed the hepatectomy specimens with metastasis from colonic adenocarcinoma in a single tertiary hospital. Only 23 patients could be included in this study. Following the recommendations by Maru et al., two independent pathologists, blinded to the outcome of the patients, measured the tumor thickness at the TNI in hematoxylin eosin stained representative slides of the hepatectomy specimens. The outcome was estimated as the time elapsed between hepatectomy and death due to disease (disease-specific survival; DSS). Two patients showed a complete pathological response, 16 cases a major response, and 5 cases a minor pathological response. The mean thickness at the TNI was 0.73mm (0.01-2.5). The ROC analysis defined a cut-off point of 1.34mm best discriminated between patients with a good and a poor prognosis. The mean thickness at the TNI for patients dying of disease was 1.99 (1.06 for survivors). A comparison of the survival curves confirmed that thickness at the TNI was a significant predictor of disease-free survival (p=0.025). This study demonstrates the value of tumor thickness and TNI in predicting disease-free survival. These results are consistent with previous studies demonstrating that thickness of TNI is an important prognostic variable following hepatic resection of colon metastases. Prospective studies are necessary to confirm these retrospective results. Pathology reporting of this parameter, together with the pathological response and margin, may help clinicians to make decisions regarding further therapy. PMID- 22444945 TI - A cluster randomised stepped wedge trial to evaluate the effectiveness of a multifaceted information technology-based intervention in reducing high-risk prescribing of non-steroidal anti-inflammatory drugs and antiplatelets in primary medical care: the DQIP study protocol. AB - BACKGROUND: High-risk prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelet agents accounts for a significant proportion of hospital admissions due to preventable adverse drug events. The recently completed PINCER trial has demonstrated that a one-off pharmacist-led information technology (IT)-based intervention can significantly reduce high-risk prescribing in primary care, but there is evidence that effects decrease over time and employing additional pharmacists to facilitate change may not be sustainable. METHODS/DESIGN: We will conduct a cluster randomised controlled with a stepped wedge design in 40 volunteer general practices in two Scottish health boards. Eligible practices are those that are using the INPS Vision clinical IT system, and have agreed to have relevant medication-related data to be automatically extracted from their electronic medical records. All practices (clusters) that agree to take part will receive the data-driven quality improvement in primary care (DQIP) intervention, but will be randomised to one of 10 start dates. The DQIP intervention has three components: a web-based informatics tool that provides weekly updated feedback of targeted prescribing at practice level, prompts the review of individual patients affected, and summarises each patient's relevant risk factors and prescribing; an outreach visit providing education on targeted prescribing and training in the use of the informatics tool; and a fixed payment of 350 GBP (560 USD; 403 EUR) up front and a small payment of 15 GBP (24 USD; 17 EUR) for each patient reviewed in the 12 months of the intervention. We hypothesise that the DQIP intervention will reduce a composite of nine previously validated measures of high-risk prescribing. Due to the nature of the intervention, it is not possible to blind practices, the core research team, or the data analyst. However, outcome assessment is entirely objective and automated. There will additionally be a process and economic evaluation alongside the main trial. DISCUSSION: The DQIP intervention is an example of a potentially sustainable safety improvement intervention that builds on the existing National Health Service IT-infrastructure to facilitate systematic management of high-risk prescribing by existing practice staff. Although the focus in this trial is on Non-steroidal anti-inflammatory drugs and antiplatelets, we anticipate that the tested intervention would be generalisable to other types of prescribing if shown to be effective. TRIAL REGISTRATION: ClinicalTrials.gov, dossier number: NCT01425502. PMID- 22444946 TI - Is it necessary to resect bone for low-grade mucoepidermoid carcinoma of the palate? AB - Minor intraoral tumours of the salivary glands are relatively uncommon. Most are histologically low grade and display no aggressive clinical features such as bony invasion or regional metastases. The aim of this study was to investigate retrospectively a bone-sparing approach to resection of low grade mucoepidermoid carcinoma of the hard palate in 18 patients. Only one had radiographic evidence of bony invasion and was treated by composite resection of the hard palate. Sixteen patients were treated by wide local excision with 1cm margins of soft tissue using the periosteum of the hard palate as the deep margin. The mean (SD) follow-up time was 44 months, (range 2-140). Among patients who had only soft tissue resection the histological margins were clear in 11 patients, and 5 had close or invaded margins that were all localised to the deep margin. There were no local recurrences during the follow-up period. We suggest that a bone-sparing approach to such tumours gives adequate local control, and composite resections should be reserved for tumours that have obviously invaded the hard palate. PMID- 22444947 TI - Head and neck cancer in the south west of England, Hampshire, and the Isle of Wight: trends in survival 1996-2008. AB - There are reasons why survival may have improved in people with head and neck cancer, but few studies have reported on trends in the UK, and results are not consistent. We examined recent trends in survival for people diagnosed with head and neck cancer in the south west of England. Patients were identified over four one-year audits in a population (roughly 6.5 million) served by five cancer networks, and the work was collated by the South West Public Health Observatory (SWPHO) tumour panel. The SWPHO cancer registry provided data on death. Prognostic data, including stage, time to treatment, and deprivation index were extracted or derived from clinical records. A total of 2164 cases of oral, laryngeal, and pharyngeal squamous cell carcinomas (SCC) were diagnosed. Crude total 5-year mortality decreased from 55% (95% CI 50.3-59.4) in people diagnosed in 1996 to 44% (95% CI 37.9-46.4) in those diagnosed in 2003 (p<0.001). Adjusted hazard ratios (HRs) for death within five years of diagnosis for surveys 2, 3, and 4 (compared with survey 1), respectively, were reduced in subsequent groups: HR 0.79 (95% CI 0.64-0.98), HR 0.70 (95% CI 0.56-0.87), and HR 0.72 (95% CI 0.58 0.90) (chi square for trend, p<0.001). Improvements over time were most pronounced among those with late-stage disease and with pharyngeal tumours. We have shown that survival has improved for people with head and neck cancer. Further large prospective studies are required to understand how quality of care, treatment, aetiology of tumour, individual risk, and behaviour contribute to survival. PMID- 22444948 TI - Next-generation polymer solar cell materials: designed control of interfacial variables. AB - Organic bulk heterojunction solar cells (BHJSCs) are the focus of a burgeoning research effort. While extensive characterization is performed in the course of many reported experimental studies, correlation of performance and physical parameters among studies done in different laboratories is low, pointing out the need to address some aspects of BHJSC active materials that have received relatively little attention. This Perspective describes how a new polymer additive series described by Lobez et al. in this issue of ACS Nano, along with some emerging morphological tools and scanning electronic nanoprobes, can help fill in some of this needed insight. A brief statistical discussion of interstudy correlations and a summary of past work on additives and interfacial studies are presented. PMID- 22444949 TI - Energy biotechnology. PMID- 22444950 TI - Preoccupation and distress are relevant dimensions in delusional beliefs. AB - BACKGROUND AND PURPOSE: A large number of subjective experiences and beliefs with some degree of affinity with psychotic symptoms can be found in the general population. However, the appraisal of these psychotic-like experiences in terms of associated distress, raised preoccupation, and the conviction with which the experience is held can be more discriminative in distinguishing people in need for care from those who simply hold unusual or uncommon beliefs because of cultural reasons. METHOD: In this study, 81 patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or an affective disorder with psychotic features were compared on the Peters et al Delusions Inventory (PDI) to 210 people from the same local area, who had never received a formal diagnosis of a mental disorder. RESULTS: Patients scored higher than controls on the PDI total score and on its distress, preoccupation, and conviction subscales. A stepwise logistic regression model showed PDI-preoccupation (odds ratio, 2.46; 95% confidence interval, 1.52-3.98) and, marginally, PDI-distress (odds ratio = 1.58; 95% confidence interval, 0.93 2.58) adding discriminative power to PDI total score in distinguishing patients from controls. CONCLUSIONS: The evaluation of the severity of delusion-like experiences and beliefs is important in discriminating patients diagnosed with psychosis from people who are not in need of care. PMID- 22444951 TI - Neurocognition, psychopathology, and subjective disturbances in schizophrenia: a comparison between short-term and remitted patients. AB - Patients with schizophrenia present deficits in multiple domains of cognition. The study of the relationship between cognitive performance and symptoms of schizophrenia has yielded heterogeneous results. The purposes of this study were to examine the extent of the relationship between psychopathologic symptoms, cognitive function, and subjective disturbances in a group of patients affected by schizophrenia spectrum disorders and to compare short-term with remitted patients. Seventy-nine patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for schizophrenia, schizophreniform disorder, and schizoaffective disorder were assessed through the Positive and Negative Syndrome Scale, the Frankfurt Complaint Questionnaire, and a neuropsychologic battery exploring the 7 Measurement and Treatment Research to improve Cognition in Schizophrenia cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) plus executive control. Neuropsychologic and psychopathologic variables were compared and correlated. Treatment groups did not differ in neuropsychologic and psychopathologic measures. The cognitive factor of the Positive and Negative Syndrome Scale correlated with worse performance on cognitive tasks and with higher scores on the Frankfurt Complaint Questionnaire 24 in the short-term, remitted, and combined groups. Subjective disturbances correlated with impaired executive control, reasoning and problem solving, and social cognition but not during the short-term phase. Both "objective" and subjective psychopathology are intertwined with cognitive function, suggesting some common underlying neural bases. The condition of being in a short-term or a remitted phase of the illness influences this interrelationship, regardless of the type of antipsychotic medication taken. PMID- 22444952 TI - Chronic tolerance to the locomotor stimulating effect of ethanol in preweanling rats as a function of social stress. AB - During early stages of development rats are highly sensitive to the locomotor stimulating effect of relatively high ethanol doses, an effect strongly modulated by social stress. This ethanol effect can be modulated by pharmacological treatments that also can attenuate the development of ethanol-induced locomotor sensitization in mice. By the end of the preweanling period the mechanisms underlying sensitization induced by psychostimulants are functional. The aim of the present study was to analyze the locomotor response to ethanol in preweanling rats as a function of repeated exposure to the drug under two different social conditions. Subjects were treated with ethanol between postnatal days 15 and 18 after being isolated for four hours (Experiment 1a) or simply residing in their home-cage (Experiment 1b). After two days of withdrawal locomotor response to ethanol was assessed in both social conditions. In Experiment 2 naive rats were tested in terms of ethanol-induced activation of the locomotor response in both social conditions. Results from the present study showed no evidence of locomotor sensitization in preweanling rats in any of the social conditions. Instead we observed behavioral tolerance to the stimulating effect of ethanol in animals trained in the home-cage condition, in which subjects trained with ethanol showed sedation in response to ethanol at testing. Overall these results contribute to the understanding of the sensitivity of rats to the acute and chronic locomotor response to ethanol in an ontogenetic period characterized by high sensitivity to ethanol. PMID- 22444953 TI - Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp): implications for alcohol-induced behavioral plasticity. AB - Neuronal activity dependent pentraxin (Narp) interacts with alpha-amino-3 hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors to facilitate excitatory synapse formation by aggregating them at established synapses. Alcohol is well-characterized to influence central glutamatergic transmission, including AMPA receptor function. Herein, we examined the influence of injected and ingested alcohol upon Narp protein expression, as well as basal Narp expression in mouse lines selectively bred for high blood alcohol concentrations under limited access conditions. Alcohol up-regulated accumbens Narp levels, concomitant with increases in levels of the GluR1 AMPA receptor subunit. However, accumbens Narp or GluR1 levels did not vary as a function of selectively bred genotype. We next employed a Narp knock-out (KO) strategy to begin to understand the behavioral relevance of alcohol-induced changes in protein expression in several assays of alcohol reward. Compared to wild-type mice, Narp KO animals: fail to escalate daily intake of high alcohol concentrations under free-access conditions; shift their preference away from high alcohol concentrations with repeated alcohol experience; exhibit a conditioned place-aversion in response to the repeated pairing of 3 g/kg alcohol with a distinct environment and fail to exhibit alcohol-induced locomotor hyperactivity following repeated alcohol treatment. Narp deletion did not influence the daily intake of either food or water, nor did it alter any aspect of spontaneous or alcohol-induced motor activity, including the development of tolerance to its motor-impairing effects with repeated treatment. Taken together, these data indicate that Narp induction, and presumably subsequent aggregation of AMPA receptors, may be important for neuroplasticity within limbic subcircuits mediating or maintaining the rewarding properties of alcohol. PMID- 22444955 TI - Changes in cytokine levels during admission and mortality in acute alcoholic hepatitis. AB - Cytokine levels are raised in acute alcoholic hepatitis. However, there are disparate results regarding the duration of altered plasma levels, and there are also discrepancies about the relation of changes during the first 15 days after admission with short-term (in-hospital) or long-term mortality. In 56 patients with acute alcoholic hepatitis we found that IL-8, IL-4, Interferon-gamma (IFN gamma), malondialdehyde and C-reactive protein remained higher in patients than in 18 age- and sex-matched controls at admission, at the 7th day and at the 15th day after admission. Moreover, IL-4 levels (and to a lesser extent, IL-10 and IFN gamma ones) increased along the three determinations. However, comparing patients who died during the admission with those who did not, there were no statistically significant differences, but there was a nearly significant trend for MDA (Z=1.89; p=0.059), with higher levels among those who died. When changes between the first and the second determinations were compared with long-term survival, only IL-8 and IFN-gamma showed a relation with mortality. IFN-gamma values increased among those who survived and decreased among those who died (p=0.048). IFN-gamma values at the first determination also showed a relation with long-term mortality, especially when patients with IFN-gamma values in the first quartile were compared with those of the 4th one (log rank=5.64; p=0.018; Breslow=4.64; p=0.031). Besides Interferon-gamma, only C-reactive protein showed differences between the first and the 4th quartile regarding mortality (Log rank=4.50; p=0.034; Breslow 4.33; p=0.038). In contrast with other studies, no relation was found between TNF-alpha or IL-6 and mortality. PMID- 22444954 TI - Urocortins: CRF's siblings and their potential role in anxiety, depression and alcohol drinking behavior. AB - It is widely accepted that stress, anxiety, depression and alcohol abuse-related disorders are in large part controlled by corticotropin-releasing factor (CRF) receptors. However, evidence is accumulating that some of the actions on these receptors are mediated not by CRF, but by a family of related Urocortin (Ucn) peptides Ucn1, Ucn2 and Ucn3. The initial narrow focus on CRF as the potential main player acting on CRF receptors appears outdated. Instead it is suggested that CRF and the individual Ucns act in a complementary and brain region-specific fashion to regulate anxiety-related behaviors and alcohol consumption. This review, based on a symposium held in 2011 at the research meeting on "Alcoholism and Stress" in Volterra, Italy, highlights recent evidence for regulation of these behaviors by Ucns. In studies on stress and anxiety, the roles of Ucns, and in particular Ucn1, appear more visible in experiments analyzing adaptation to stressors rather than testing basal anxiety states. Based on these studies, we propose that the contribution of Ucn1 to regulating mood follows a U-like pattern with both high and low activity of Ucn1 contributing to high anxiety states. In studies on alcohol use disorders, the CRF system appears to regulate not only dependence-induced drinking, but also binge drinking and even basal consumption of alcohol. While dependence-induced and binge drinking rely on the actions of CRF on CRFR1 receptors, alcohol consumption in models of these behaviors is inhibited by actions of Ucns on CRFR2. In contrast, alcohol preference is positively influenced by actions of Ucn1, which is capable of acting on both CRFR1 and CRFR2. Because of complex distribution of Ucns in the nervous system, advances in this field will critically depend on development of new tools allowing site-specific analyses of the roles of Ucns and CRF. PMID- 22444956 TI - Effects of binge drinking on infant growth and development in an Inuit sample. AB - Prenatal exposure to an average of 0.5 oz absolute alcohol per day (the equivalent of 7 standard drinks per week) during pregnancy has been found to be associated with numerous adverse effects on pre- and postnatal development. In the animal model, concentrated alcohol exposure has been found to lead to more adverse effects than exposure to the same total quantity of alcohol ingested in smaller doses over a longer period of time. The primary aim of this study is to determine whether, in a population where binge drinking is common but total alcohol consumption across pregnancy is low, prenatal exposure to alcohol is associated with effects on prenatal growth, visual acuity and cognitive development during infancy. The second aim is to determine which of several indicators of alcohol consumption best predicts pre- and postnatal outcomes. Data were collected from 216 Inuit women and their infants living in Nunavik, the northern region of Quebec. Maternal interviews were conducted during mid pregnancy and at 1 and 6 months postpartum. Birth weight, length, and head circumference were assessed at delivery. Visual acuity and cognitive development were assessed at 6 months of age. In this population in which infrequent heavy episodic drinking is common, even occasional binge exposure was associated with reduced prenatal growth and poorer visual acuity at 6 months of age. A simple dichotomous measure of binge drinking during pregnancy provided the best predictor of fetal growth and 6-month acuity. The population studied here is unusual in terms of its pattern of binge alcohol consumption. To our knowledge, this is the first study to observe effects of binge drinking during pregnancy on infant growth and development in a sample where the average daily alcohol intake is low (<0.5 ounces). PMID- 22444957 TI - A protocol for the cryoconservation of breeds by low-cost emergency cell banks - a pilot study. AB - A protocol was developed for collection and storage of somatic cell samples under adverse conditions with little infrastructure, for somatic-cell banks as a backup for endangered livestock breeds. The procedure, which is uniform across species, includes sample collection with ear taggers with an integrated tag/vial system, and recording of global positioning system (GPS) coordinates, digital images and breed information. In a pilot study, the procedures were tested on six local Vietnamese populations of pigs, sheep and goats. Initial investment was around ?3000, while the total variable cost for sampling one breed with 25 females and 25 males was less than ?1000. With support from local organisations, the sampling of six breeds with 300 animals was carried out in 2 months. The protocol and the complete workflow for setting up a somatic-cell bank, together with data collection, are described. The procedure has proved practicable and exceedingly cheap relative to the cryopreservation of semen or embryos. PMID- 22444958 TI - Bayesian prediction of breeding values for multivariate binary and continuous traits in simulated horse populations using threshold-linear models with Gibbs sampling. AB - Simulated data were used to determine the properties of multivariate prediction of breeding values for categorical and continuous traits using phenotypic, molecular genetic and pedigree information by mixed linear-threshold animal models via Gibbs sampling. Simulation parameters were chosen such that the data resembled situations encountered in Warmblood horse populations. Genetic evaluation was performed in the context of the radiographic findings in the equine limbs. The simulated pedigree comprised seven generations and 40 000 animals per generation. The simulated data included additive genetic values, residuals and fixed effects for one continuous trait and liabilities of four binary traits. For one of the binary traits, quantitative trait locus (QTL) effects and genetic markers were simulated, with three different scenarios with respect to recombination rate (r) between genetic markers and QTL and polymorphism information content (PIC) of genetic markers being studied: r = 0.00 and PIC = 0.90 (r0p9), r = 0.01 and PIC = 0.90 (r1p9), and r = 0.00 and PIC = 0.70 (r0p7). For each scenario, 10 replicates were sampled from the simulated horse population, and six different data sets were generated per replicate. Data sets differed in number and distribution of animals with trait records and the availability of genetic marker information. Breeding values were predicted via Gibbs sampling using a Bayesian mixed linear-threshold animal model with residual covariances fixed to zero and a proper prior for the genetic covariance matrix. Relative breeding values were used to investigate expected response to multi- and single-trait selection. In the sires with 10 or more offspring with trait information, correlations between true and predicted breeding values ranged between 0.89 and 0.94 for the continuous traits and between 0.39 and 0.77 for the binary traits. Proportions of successful identification of sires of average, favourable and unfavourable genetic value were 81% to 86% for the continuous trait and 57% to 74% for the binary traits in these sires. Expected decrease of prevalence of the QTL trait was 3% to 12% after multi-trait selection for all binary traits and 9% to 17% after single-trait selection for the QTL trait. The combined use of phenotype and genotype data was superior to the use of phenotype data alone. It was concluded that information on phenotypes and highly informative genetic markers should be used for prediction of breeding values in mixed linear-threshold animal models via Gibbs sampling to achieve maximum reduction in prevalences of binary traits. PMID- 22444959 TI - A study of heterogeneity of environmental variance for slaughter weight in pigs. AB - This work presents an analysis of heterogeneity of environmental variance for slaughter weight (175 days) in pigs. This heterogeneity is associated with systematic and additive genetic effects. The model also postulates the presence of additive genetic effects affecting the mean and environmental variance. The study reveals the presence of genetic variation at the level of the mean and the variance, but an absence of correlation, or a small negative correlation, between both types of additive genetic effects. In addition, we show that both, the additive genetic effects on the mean and those on environmental variance have an important influence upon the future economic performance of selected individuals. PMID- 22444960 TI - The effects of selection indices for sustainable hill sheep production on carcass composition and muscularity of lambs, measured using X-ray computed tomography. AB - A multi-trait selection index designed to improve the overall economic performance of hill sheep, including both maternal and lamb traits, has been developed and tested in a selection experiment over 7 years. Two versions of the index were tested, with different economic weights applied to the traits, on two different hill farms: one version including maternal and growth traits; the other version with additional breeding goals of carcass weight, fatness and conformation scores. Responses to selection, using both versions of the index, suggest that improvements are being made in overall index score and lamb growth. This study investigated the indirect effects of these selection indices on lamb carcass composition and muscularity traits, as measured using X-ray computed tomography (CT) scanning. A total of 499 lambs from the two hill farms were CT scanned at weaning (approximately 120 days of age). Approximately half of the lambs from each farm were from the selection line (S, animals with highest index scores selected for breeding), while the other half were from a control line (C, animals with average index scores selected). Composition and muscularity traits were estimated on each lamb from CT data and differences between genetic lines investigated, within farm, using restricted maximum likelihood analyses, adjusting for either live weight or age. Results showed that the selection index without carcass traits produced lambs with carcass composition that was not significantly different to control lambs at a given live weight or age. Including carcass traits in the index resulted in lambs with no compositional differences (except for a slight increase in bone) at a set age compared with controls. At a given live weight however, selection lambs had less fat and lower carcass weights and killing-out percentage. Muscularity (3-D muscle shape) and muscle area shape (2-D) were not improved as a result of selection on either version of the index (including carcass weight and grades in the breeding goals or not) and, at a fixed live weight, muscularity in hind leg and lumbar regions tended to be higher in the C line. To accelerate changes in carcass composition and muscularity within the context of a multi-trait selection index for hill sheep, consideration should therefore be given to including objective CT-derived carcass traits in the index in addition to the Meat and Livestock Commission (MLC) carcass grades or ultrasound measurements. PMID- 22444961 TI - Relationships between lamb carcass quality traits measured by X-ray computed tomography and current UK hill sheep breeding goals. AB - Genetic parameters were estimated between current UK hill sheep breeding goals and lamb carcass composition and muscularity traits derived using X-ray computed tomography (CT). To produce these estimates, a total of 648 lambs from two hill farms were CT scanned at weaning (ca 120 days of age), over 3 years, and total weights of carcass muscle (MUSC), fat (CFAT) and bone (BONE) and internal fat (IFAT) were predicted. Previously derived muscularity indices were also calculated for the hind leg (HLMI) and lumbar (LRMI) regions, to assess muscle shape. Data for current breeding goals (lamb performance and maternal traits) were also included from a total of 10 297 lamb records and 12 704 ewe records. Heritabilities were estimated for each trait and genetic and phenotypic correlations were calculated between each CT trait and other lamb or ewe traits. Moderate to high positive genetic correlations were found between CT-predicted tissue weights and breeding goals, which were also weights (lamb weaning weight, carcass weight, mature ewe weight, average weight of lambs reared by the ewe). CFAT was positively genetically correlated with ultrasound backfat depth at weaning (UFD) and subjective fatness grade at slaughter (MLCF), suggesting that carcass fat could be decreased using selection on any of these predictors. Ultrasound muscle depth at weaning (UMD) and subjective conformation score at slaughter (MLCC) had high genetic correlations with the muscularity indices (HLMI and LRMI), but correlations with MUSC were not significantly different from zero. This implies that selection to improve MLCC is likely to be increasing the 'roundness' of muscle shape in the high-priced carcass region, but having little impact on total lean meat yield. Correlations of CT traits with the other ewe traits (number of lambs weaned, number of lambs lost, longevity, fleece weight) were generally small or not significantly different from zero. The genetic parameters generated in this study can now be used in selection index calculations to assess the benefits of including lamb CT traits in future selection programmes for hill sheep. PMID- 22444962 TI - Modelling purine derivative excretion in dairy goats: endogenous excretion and the relationship between duodenal input and urinary output. AB - To determine the endogenous contribution of purine derivatives (PD) to renal excretion and the urinary recovery of duodenal purine bases (PB), five dairy Granadina goats (initial weight +/- s.e.: 38.6 +/- 2.78 kg) were each fitted with a duodenal infusion catheter. Animals were offered ad libitum a mixed diet (75 : 25; alfalfa hay : concentrate), which was supplied in equal portions every 3 h. To label microbial PB, (15NH4)2SO4 was added to the concentrate. The lower enrichment of urinary PD (15N-allantoin) compared with duodenal PB enrichment confirmed the presence of an endogenous PD fraction (268.5 +/- 21.98 MUmol/kg weight0.75 or 0.386 of the total PD excretion). The recovery of PD in urine and milk increased linearly in response to increasing amounts of duodenally infused RNA (starting on day 21 after parturition). On average, 0.74 of infused PB from RNA was recovered in urine. Milk PD constituted a minor (<0.01) fraction of the total PD excretion and this fraction decreased as the amount of infused PB increased. Our findings indicate that lactation in goats did not affect the urinary recovery of duodenal PB but increased the endogenous contribution to urinary excretion of PD. PMID- 22444963 TI - Nutritional status of adult ewes during early and mid-pregnancy. 1. Effects of plane of nutrition on ewe reproduction and offspring performance to weaning. AB - The objective of this study was to determine the effects of plane of nutrition during early and mid-pregnancy on the performance of mature ewes and their offspring. From day 0 to day 39 post mating (early pregnancy, EP), 82 multiparous ewes were fed to provide either 60% (low, L), 100% (medium, M) or 200% (high, H) of predicted metabolisable energy (ME) requirements for maintenance, following a synchronised mating. From day 40 to day 90 (mid-pregnancy, MP), ewes were provided with either 80% (M) or 140% (H) of ME requirements. After 90 days of gestation, all ewes were fed to meet requirements for late pregnancy. During EP, mean live weight (LW) and body condition score (BCS) change of ewes were -6.3, 0.8 and +6.0 kg and -0.02, +0.10 and +0.22 units in the L-, M- and H-EP treatments, respectively. During MP, mean LW and BCS change were -0.8 and +4.9 kg and -0.09 and +0.09 units in the M- and H-MP treatments, respectively (P < 0.001). Treatments had no effect (P > 0.05) on conception rate, although there tended to be an inverse relationship (P = 0.085) between plane of nutrition in EP and plasma progesterone concentrations at day 42 of gestation. EP nutrition influenced foetal development with lambs from ewes offered diet L-EP being smaller (P < 0.01) at day 56 than M- or H-EP lambs. However, at parturition L-EP lambs were heavier (P < 0.05) and tended to have higher (P = 0.056) immunoglobulin status 24 h after birth. Mortality rates at weaning were reduced (P < 0.05) for lambs born from ewes offered diet L-EP compared with M- or H-EP lambs. Diet M during mid-pregnancy resulted in larger (P < 0.05) foetuses at day 80 of gestation. At parturition, these lambs had longer head and crown-rump lengths than H-MP lambs (P < 0.05). Lambs born to ewes offered diet M-MP tended to progress faster to attempting to suckle than H-MP lambs (P = 0.089). There was an interaction between plane of nutrition in early and mid-pregnancy, whereby the highest number of lambs weaned was a result of diet L-EP followed by diet M-MP. These results indicate that in adult ewes, temporary nutrient restriction during early pregnancy results in better lamb survival; and mild nutrient restriction in mid-pregnancy tends to improve neonatal behaviour and results in lambs with longer skeletal size. PMID- 22444964 TI - Nutritional status of adult ewes during early and mid-pregnancy. 2. Effects of supplementation with selenised yeast on ewe reproduction and offspring performance to weaning. AB - The objective of this study was to determine the effects of selenium (Se) supplementation of mature ewes in the period from day -14 to day 90 post mating on Se status, productivity and viability of ewes and their offspring. Multiparous crossbred ewes (n = 82) were randomly assigned to receive a standard dried grass based diet (control) or dried grass diet supplemented with 1 g of selenised yeast (Selplex(r)), providing 0.5 mg Se per ewe per day. After day 90 post mating, all ewes were offered grass-based diets supplemented with a standard multivitamin and mineral mix, up to lambing. Ewes that were fed additional Se had increased (P < 0.001) activity of glutathione peroxidase enzyme (GPx) and increased plasma Se concentrations throughout the treatment period. At lambing, GPx activity of supplemented ewes was higher (P < 0.001) than that of controls. Twenty-four hours after birth, lambs of ewes given Se had higher (P < 0.001) concentration of Se in plasma, greater (P < 0.001) activity of GPx and better (P < 0.01) immune status. Lambs of ewes that received supplementation showed a faster progression to stand than control lambs (P < 0.05), independent of maternal behaviour which was not affected. Supplementation reduced perinatal lamb mortality (0.04 v. 0.17; P < 0.05). However, overall mortality from birth to weaning was unaffected (P > 0.05). Supplemented ewes weaned lambs on average 2 kg heavier than control ewes, due to the higher (P < 0.05) growth rates achieved by their offspring. In conclusion, for ewes with a marginal Se status, an organic source of Se supplemented throughout pregnancy, compared with supplementation only in the last trimester, positively affected measures of lamb viability and survival. PMID- 22444965 TI - Growth and development of adipose tissue and gut and related endocrine status during early growth in the pig: impact of low birth weight. AB - With genetic selection, the increase in litter size has led to higher variation in within-litter birth weights in pigs. This has been associated with a reduction in mean birth weights and a rise in the proportion of piglets weighing less than 1 kg at birth. Low birth weight pigs exhibit lower postnatal growth rates and feed efficiency, which may be explained by an inadequate digestion and/or nutrient use as a consequence of prenatal undernutrition. It is now documented that there is a relationship between birth weight and subsequent pattern of growth and development of tissues and organs. During the neonatal period, the rapid somatic growth is accompanied by tremendous anatomical, physiological and chemical composition changes. The present review focuses primarily on the influence of low birth weight on adipose tissue and the gastrointestinal tract growth and development during the suckling period. The importance of the somatotropic axis, insulin, thyroid hormones, glucocorticoids, epidermal growth factor and leptin in the regulation of these developmental processes is also considered. PMID- 22444966 TI - Ovarian follicular development, lipid peroxidation, antioxidative status and immune response in laying hens fed fish oil-supplemented diets to produce n-3 enriched eggs. AB - The objective of the present study was to research the effect of feeding laying hens fish oil-supplemented diets to produce n-3-enriched eggs on their ovarian follicular development, serum lipid peroxidation, antioxidative status and immune response. A total of 105 white Bovens hens at 24 weeks of age were housed in cages in an open-sided building under a 16 h light : 8 h dark lighting schedule. Birds were randomly divided into five treatments and were fed, ad libitum, diets containing 0% (control), 1.25%, 2.5%, 3.5% or 5.0% fish oil from 24 to 36 weeks of age. Egg production and weight were recorded. By weeks 35 and 36 of age 15 eggs were taken at random from each treatment to determine the yolk lipid profile and cholesterol content. At the end of the experimental period, 10 females from each treatment were randomly chosen, anaesthetised and killed by decapitation. Ovary and oviduct samples were immediately weighted and ovarian follicles were classified. Serum thiobarbituric acid-reactive substance (TBARS), hepatic TBARS and hepatic glutathione peroxidase (GSH-Px) activity were measured. No clear trend was observed concerning egg production and egg yolk cholesterol. As dietary fish oil levels increased, n-3-polyunsaturated fatty acids (n-3 PUFA) increased, whereas n-6 PUFA tended to decrease in yolk lipids. No negative effects were detected in ovary and oviduct weights, expressed in both absolute terms and relative to body weight. The numbers and total weights of large yellow follicles (LYF) in the ovary were not significantly affected by fish oil supplementation. Low levels (1.25% to 2.5%) of fish oil reduced both plasma and hepatic TBARS and enhanced GSH-Px activity. It is also interesting to note that inclusion of 2.5% fish oil in laying hen diets enhanced the antibody titre in laying hens. Therefore, it could be concluded that inclusion of fish oil in laying hen diets at moderate levels increased the n-3 fatty acids content in eggs, improved antioxidative status, enhanced the antibody response and did not have a negative influence on the different reproductive morphology parameters in laying hens. PMID- 22444967 TI - Regulation of lipid accumulation in 3T3-L1 cells: insulin-independent and combined effects of fatty acids and insulin. AB - The insulin-independent and combined effects of fatty acids (FA; linoleic and oleic acids) and insulin in modulating lipid accumulation and adipogenesis in 3T3 L1 cells was investigated using a novel protocol avoiding the effects of a complex hormone 'induction' mixture. 3T3-L1 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) plus serum (control) or in DMEM plus either 0.3 mmol/l linoleic or oleic acids with 0.3 mmol/l FA-free bovine serum albumin in the presence or absence of insulin. Cells were cultured for 4 to 8 days and cell number, lipid accumulation, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and glucose transporter 4 (GLUT-4) protein expression were determined. Cell number appeared to be decreased in comparison with control cultures. In both oleic acid and linoleic acid-treated cells, notably in the absence (and presence) of insulin, oil-red O stain-positive cells showed abundant lipid. The percentage of cells showing lipid accumulation was greater in FA treated cultures compared with control cells grown in DMEM plus serum (P < 0.001). Treatment with both linoleic and oleic acid-containing media evoked higher levels of PPAR-gamma than observed in control cultures (P < 0.05). GLUT-4 protein also increased in response to treatment with both linoleic and oleic acid containing media (P < 0.001). Lipid accumulation in 3T3-L1 cells occurs in response to either oleic or linoleic acids independently of the presence of insulin. Both PPAR-gamma and GLUT-4 protein expression were stimulated. Both proteins are considered markers of adipogenesis, and these observations suggest that these cells had entered the physiological state broadly accepted as differentiated. Furthermore, 3T3-L1 cells can be induced to accumulate lipid in a serum-free medium supplemented with FA, without the use of induction protocols using complex hormone mixtures. We have demonstrated a novel model for the study of lipid accumulation that will improve the understanding of adipogenesis in adipocyte lineage cells. PMID- 22444968 TI - Effect of ferrous sulphate and ascorbic acid on motility, viability and lipid peroxidation of crossbred cattle bull spermatozoa. AB - Numerous factors influence male fertility, one of these being the oxidative stress, which has elicited enormous interest recently. In sperm, induction of oxidation decreases motility and viability but increases lipid peroxidation (LPO). The optimum dose of ferrous ascorbate (FeAA: FeSO4 + ascorbic acid) for inducing oxidative stress by affecting motility, viability and LPO has been ascertained in local crossbred cattle bull spermatozoa. The fractions of spermatozoa suspended in 2.9% sodium citrate were subjected to three doses of FeAA (100 : 500, 150 : 750, 200 : 1000; MUmol/l FeSO4 : MUmol/l ascorbic acid). These fractions were assessed for various parameters. Increase in the incubation period and promoter concentration induced a decrease in motility and viability, but an increase in LPO. Among three doses of FeAA, 150 : 750 MUmol/l ascorbic acid is suggested to be the optimum/best dose as it induces the oxidative stress/LPO to a significant extent and also maintains better motility and viability as compared with the other two doses, and such conditions may enhance the fertilising potential of bull spermatozoa. PMID- 22444969 TI - Modelling batch farrowing management within a farrow-to-finish pig herd: influence of management on contact structure and pig delivery to the slaughterhouse. AB - Pathogen spread within pig host populations can vary depending on within-herd interactions among pigs also called the contact structure. The recommended batch farrowing management, allowing for a fixed-interval mating for groups of sows of equal size, called batches, leads to an all-in/all-out management of pigs in which animals in different batches have no contact. To maintain a profitable pig delivery, producers have to deliver groups of pigs at a given weight, what needs sometimes herd management adaptations. However, producers' adaptations that avoid delivering pigs below slaughtering weight (out-of-range pigs), result in increasing the contact between animals from different batches. To study the influence of herd management on contact structure and on pig delivery, a stochastic mathematical model representing population dynamics within a farrow-to finish herd was elaborated. Sixteen management systems were represented combining or not the all-in/all-out management system with producers' decisions: batch mixing, use of an extra room, suppression of the drying period and sale of post weaning batches. Two types of contact were considered: via the animals themselves, when batch mixing occurred; and via the room, when decontamination was not complete. The impact of producers' decisions on contact structure and on pig delivery, differed radically when pig growth was normal and when it was slow (i.e. mean age at slaughtering weight increased by 20%). When pig growth was normal, the all-in/all-out management prevented both contact via the animals and via the room but resulted in 9% of pigs delivered out of range. The use of an extra room or batch mixing decreased this percentage, the latter resulting in very frequent contact between batches via the animals. When pig growth was slow, the all-in/all-out management led to a very high percentage of pigs delivered out of range (almost 80%). The suppression of the drying period at the end of the finishing period and the sale of post-weaning batches induced a significant decrease in this percentage (down to 2% to 20%), the latter allowing to reduce the percentage of batches that made contact via the room (40% instead of 80%). This pig herd model helped to understand the compromise for producers between implementing internal biosecurity or maintaining a profitable pig delivery. Our results show that there was no unique optimal system and that efficient producers' decisions (for biosecurity and delivery) may differ, depending on pig growth. PMID- 22444970 TI - The effect of organic diets on the performance of pullets maintained under semi organic conditions. AB - The effects of organic diets, with or without supplements of betaine, saponin, fructo-oligosaccharide and methionine, on the health, performance and gut flora of pullets were investigated. A comparison was also made between birds fed organic diets and those fed a non-organic diet. Day-old Lohmann Tradition pullets were reared in 24 groups of 64 chicks indoors until 11 weeks, and then in 48 groups of 24 to 27 chicks with access to range until 17 weeks of age. Groups of birds were fed one of eight diets, a conventional rearing diet with supplementary amino acids, an organic basal diet, organic basal plus methionine and organic basal supplemented with one of the test ingredients. At most stages of growth the birds fed the conventional diet and those fed the basal diet with methionine performed better than those that had no supplemental methionine. Other dietary treatments had no consistently significant effect on growth, the microbial populations within the gastro-intestinal tract of the birds or the number of parasite eggs excreted. After 5 weeks with access to range, the birds that were fed three out of five diets regarded as deficient in sulphur amino acids achieved similar weights (P > 0.05) to birds that received diets adequate in sulphur amino acids. Health and welfare of birds fed organic diets was not adversely affected; however, an investigation of birds housed in larger flocks and taken into the laying phase, when physical demands on birds are greatest, is required. PMID- 22444971 TI - Faecal alkane recoveries from multi-component diets and effects on estimates of diet composition in sheep. AB - In a feeding trial with sheep, four animals each were fed one of the three roughages (perennial ryegrass (PR), meadow fescue (MF) and red clover (RC)) or one of the four different mixtures (g/day 250 : 250 : 250, 375 : 75 : 300, 525 : 187.5 : 37.5 and 75 : 525 : 150, respectively) of those three roughages, both with and without the inclusion of 100 g of beeswax-labelled barley. Further, four sheep received a pure lucerne diet to enlarge available data on single species faecal recoveries. All sheep except those fed single-component diets and the 250 : 250 : 250 roughage mix were administered intra-ruminal alkane controlled release devices (CRD). The aim of the study was to investigate the effect of diet composition on faecal alkane recoveries, and to assess the accuracy of the alkane based estimate of diet composition and intake based either upon a general set of faecal recoveries across diets or upon dietary recoveries and dietary samples more specifically attributable to individual dietary treatments. For each roughage component independently, the accuracy of diet composition estimates was assessed using linear regression across all diets. The estimates of the proportion of barley were analysed further using mean differences and mean prediction errors. Faecal alkane recovery increased with increasing chain length and was affected by diet composition. RC had a significantly higher faecal recovery for alkanes C25, C27, C29 and C31 than at least one of the other single roughage diets. When considering mixed diets consisting of PR, MF, RC and barley, the composition of the roughage component significantly affected faecal recovery of all alkanes except C30 and C33. The inclusion of beeswax-labelled barley caused a decrease in faecal recovery of alkanes up to C29. This effect was attributable to the beeswax rather than the barley itself. By contrast, the decrease of faecal recovery of synthetic dosed alkanes from the CRD in diets containing barley, compared with the corresponding diets without barley, was attributable to the supplement itself. It was concluded that synthetic dosed alkanes behaved differently during gut transit from natural alkanes. The proportions of individual dietary components were estimated well over a wide range of proportions. Generally, the more information available, the more accurate the estimates achieved. However, a general set of faecal alkane recoveries and bulked samples of dietary components yielded estimates of diet composition sufficiently accurate for a large number of studies, especially in situations where groups of animals are of concern and not the individual animal. PMID- 22444972 TI - Effect of dam factors on milk intake and performance of Belgian Blue suckling calves. AB - Milk intake data were collected at 4-week intervals from Belgian Blue double muscled (BBDM) suckling calves up to 16 weeks after birth. Dams were fed at 100%, 90%, 80% or 70% of their energy requirements during a 140-day indoor period from the beginning of December to the end of April (restriction period). Afterwards, cows were turned out on pasture (re-alimentation period). Mean calving date was 3 June, but parturitions were spread over the year. A total of 521 individual milk intake (IMI) and 120 average daily milk intake (AMI, mean of IMI) records were collected. IMI amounted to 7.0 +/- 2.2 kg/day and was not affected by energy level during the indoor period. It was highest in May and June. Calves born out of multiparous cows consumed more milk than those born out of primiparous cows (7.4 v. 6.2 kg per day; P = 0.001), while intake tended to be higher in female than in male calves (7.2 v. 6.8 kg per day; P = 0.044). Dam age at calving, parity, post partum weight and body condition were only weakly correlated with AMI (r 0.4). AMI was correlated with pre-weaning live-weight gain (r = 0.807) and weaning weight (r = 0.783), with a slightly higher correlation for male than for female calves. Daily live-weight gain during the suckling period was increased by 79 g per extra kg daily milk intake on average, and by 86 and 74 g, respectively, for male and female calves. Calf solid feed intake was low, even when milk intake was low. In terms of net energy intake, milk was only substituted for solid feed by 29%. It can be concluded from the calf intake that milk production in BBDM cows is comparable with that of cows from other beef breeds, but its variation is considerable, complicating an accurate estimation. PMID- 22444973 TI - Measurement of methane emission from sheep by the sulphur hexafluoride tracer technique and by the calorimetric chamber: failure and success. AB - The aim of this study was to evaluate the sulphur hexafluoride (SF6) tracer technique for methane (CH4) emission measurement in sheep. Ten cryptorchid Romney sheep were involved in two indoor trials (T1 and T2), where daily CH4 emissions were individually measured both by the SF6 tracer ('tracer CH4') and by the indirect calorimetry chamber ('chamber CH4') techniques while fed on lucerne hay at 1.2 times maintenance requirements. Separate sets of permeation tubes with pre calibrated permeation rates ('pre-calibrated PRs') were used in the two trials (for tracer CH4) and at the time of T1 and T2 these tubes had been deployed in the rumen for 250 and 30 days, respectively. The tracer CH4 measurements were carried out for 2 (T1) and 5 (T2) days in digestibility crates housed within a building (T1) or a well-ventilated covered yard (T2). Sheep were transferred to calorimetry chambers for 3 days acclimatisation, followed by measurement of CH4 emission for 7 (T1) and 3 (T2) days. In T1 samples from the chamber, outflow and inflow (collected over ~22 h) were analysed for CH4 and SF6 concentrations using the tracer protocol. Thus, PRs of SF6 at the time of the trials ('calculated PRs') could be inferred and the corresponding CH4 emissions are then calculated using either the pre-calibrated PR or calculated PR. Permeation tubes were recovered at the end of the animal trials and their 'post-recovery PR' determined. In trial T1, the tracer CH4 estimates (based on the pre-calibrated PR) were much higher and more variable than the chamber CH4 values. In this trial, the calculated PR and the post-recovery PR were similar from each other but smaller than the pre-calibrated PR, and when the calculated PR was used in place of the pre-calibrated PR the CH4 emission estimates agreed well with the chamber CH4 values. This suggested that the discrepancy was due to a declining PR during the long deployment time of the tubes in T1, an observation reported elsewhere. When the long intra-ruminal deployment was avoided in T2, good agreement between the techniques for CH4 emission measurement was observed. PMID- 22444974 TI - The effects of grain treatment, grain feed level and grass silage feed value on the performance of and meat quality from, finishing beef cattle. AB - A completely randomised design study involving 132 continental crossbred beef steers was undertaken to evaluate the effects of method of grain treatment and feed level, and grass silage feed value on animal performance, carcass characteristics and meat quality of beef cattle. Winter wheat was harvested and the grain was stored either ensiled crimped and treated with 4.5 l/t of a proprietary acid-based additive (crimped), ensiled whole and treated with 20 kg feed-grade urea per t (urea) or stored conventionally in an open bin treated with 3 l propionic acid per t. Two grass silages, of contrasting feed value (L and H) were ensiled. For the conventional, crimped and urea treatments, grain dry matter (DM) concentrations were 802, 658 and 640 g/kg, respectively. For the L- and H feed value silages, DM concentrations were 192 and 240 g/kg and D values were 671 and 730 g/kg DM, respectively. The silages were offered as the sole forage supplemented with either conventional, crimped or urea-treated grain-based concentrate at either 3.5 or 6.0 kg DM per steer per day. The grain supplement consisted of 850 and 150 g/kg DM of grain and citrus pulp, respectively. For the conventional, urea and crimped treatments, DM intakes were 8.85, 9.43 and 9.04 kg/day (standard error (s.e.) = 0.129); estimated carcass gains were 0.60, 0.55 and 0.61 kg/day (s.e. = 0.020), respectively. For the low- and high- feed value grass silages, estimated carcass gains were 0.56 and 0.61 kg/day (s.e. = 0.014), respectively. For the low and high grain feed levels, estimated carcass gains were 0.56 and 0.61 kg/day, respectively. Grain treatment, grain feed level or silage feed value did not alter (P > 0.05) meat quality, lean colour or fat colour. There were significant silage feed value * grain feed level interactions (P < 0.05) for final live weight (LW) and daily live-weight gain (DLWG). Increasing grain feed level increased final LW and DLWG when offered with the low feed value silage, however, grain feed level had no effect on final LW or DLWG when offered with the high-feed value silage. It is concluded that urea treatment of grain increased silage intake and feed conversion ratio (kg DM intake per kg carcass) and tended to decrease carcass gain. Crimping provides a biologically equally effective method to store grain as conventional methods. Improving grass silage feed value had a greater impact on animal performance than increasing grain feed level by 2.4 kg DM per day. PMID- 22444975 TI - Simplified milk-recording protocols adapted to low-input environments with very small herd size. AB - Milk production data from Holstein * Zebu cows in small farms (2.4 cows per farm on average) in Maharashtra, India, followed by Bharatiya Agro Industries Foundation (BAIF), an Indian non-governmental organisation, were analysed to evaluate the impact of simplified milk-recording systems. The aim was to investigate, in developing tropical areas, less-costly protocols compared with the one currently implemented at BAIF, used as a reference. The latter can be considered an 'AT2' protocol with the recording made by specialised technicians at 2-week intervals. The simplified protocols were simulated from an initial data file by sampling test days according to each protocol. Bias and accuracy on the 305-day cow milk production and on the resulting reliability of the estimated breeding value of bulls were the criteria used in the comparison with the reference protocol. One type of simplified protocol considered an increase in the interval between two tests to at least 4 and up to 8 weeks. Another alternative studied corresponded to the situation where milk yield information measured by the farmer is collected by the artificial insemination technicians themselves when visiting a farm. This could be an option in the case of very small herd sizes (two or three cows). The results suggest that simplifying the current milk recording protocol leads to a clear decrease in accuracy of estimating 305-day cow production but it has a limited effect on the reliability of bull proofs. No economic comparison was carried out, but the results strongly suggest that properly managed simplified milk-recording schemes could permit a substantial decrease of costs of milk recording per cow without damaging the efficiency of progeny testing in tropical areas with small herd size. Moreover, with the proposed simplified milk-recording protocols, up to three to four times more bulls could be tested with the same number of records. PMID- 22444977 TI - Editorial announcement: letters to the editor. PMID- 22444976 TI - Chronic psychosocial stress results in sensitization of the HPA axis to acute heterotypic stressors despite a reduction of adrenal in vitro ACTH responsiveness. AB - Although chronic psychosocial stress is often accompanied by changes in basal hypothalamo-pituitary-adrenal (HPA) axis activity, it is vital for a chronically stressed organism to mount adequate glucocorticoid (GC) responses when exposed to acute challenges. The main aim of the present study was to test whether this is true or not for the chronic subordinate colony housing (CSC, 19 days) paradigm, an established and clinically relevant mouse model of chronic psychosocial stress. As shown previously, CSC mice are characterized by unaffected morning and decreased evening plasma corticosterone (CORT) levels despite enlarged adrenals, suggesting a maladaptive breakdown of adrenal functioning. Plasma CORT levels, determined by repeated blood sampling via jugular vein catheters, as well as relative right adrenal CORT content were increased in CSC compared with single housed control (SHC) mice in response to acute elevated platform (EPF, 5min) exposure. However, in vitro stimulation of adrenal explants with physiological and pharmacological doses of ACTH revealed an attenuated responsiveness of both the left and right adrenal glands following CSC, despite mRNA and/or protein expression of melanocortin 2 receptor (Mc2r), Mc2r accessory protein (MRAP), and key enzymes of steroidogenesis were not down-regulated. Taken together, we show that chronic psychosocial stressor exposure impairs in vitro ACTH responsiveness of both the left and right adrenal glands, whereas it increases adrenal responsiveness to an acute heterotypic stressor in vivo. This suggests that an additional factor present during acute stressor exposure in vivo rescues left and right adrenal ACTH sensitivity, or itself acts as CORT secretagogue in chronically stressed CSC mice. PMID- 22444978 TI - Letter to the Editor on the surgical castration of piglets. PMID- 22444979 TI - Response to the Letter to the Editor on the surgical castration of piglets. PMID- 22444980 TI - Guest editorial: Scientific and practical issues associated with piglet castration. PMID- 22444981 TI - Practice on castration of piglets in Europe. AB - PIGCAS (Attitudes, practices and state of the art regarding piglet castration in Europe) is to our knowledge the first project that has focused on castration practice across European countries (European Union minus Bulgaria, Malta and Romania, plus Norway and Switzerland). About 250 million pigs are slaughtered in Europe each year. Of the 125 million male pigs, approximately 20% are left entire, less than 3% are castrated with anaesthesia and the rest is castrated without anaesthesia. The study identified large variations in castration procedures, both within and between countries. In females, castration is very rare, but is practiced without anaesthesia in special breeds/production systems in some of the southern countries. PMID- 22444982 TI - Animal welfare implications of surgical castration and its alternatives in pigs. AB - This paper constitutes a review on the welfare aspects of piglet castration that considers the scientific literature published after 2004. Castrating during the neonatal period (1 to 3 days of age) is clearly painful. In addition, inflammatory processes may take place at the sites of incision, thus adding further pain to the procedure. Surgical castration with general and local anaesthesia, in combination with long-term analgesia, has been shown to reduce pain but the additional handling and injection of the anaesthetic, the effectiveness and limited safety margins have to be thoroughly evaluated. Raising entire males during the whole fattening period or immunocastration of males towards the end of the fattening period are other alternatives with welfare benefits in young pigs compared to current surgical castration, but with some potential welfare drawbacks regarding handling stress and behaviour during fattening. Based on the current knowledge, it can be concluded that sperm sexing and raising entire males after genetic control of boar taint are potentially preferable alternatives to current practices, but need further research, as these methods are not yet available. PMID- 22444983 TI - Pig meat quality from entire males. AB - This paper constitutes an updated review of the production and meat quality aspects of rearing entire male pigs. Since a major obstacle in rearing entire males is the incidence of boar taint, possible methods for detection are also summarised. Safe and fast methods for detection of boar taint would be valuable in avoiding complaints from consumers. Pig meat quality is determined by many aspects, among which odour and taste are the most important attributes. Odour may be negatively affected by the presence of a pheromonal steroid, androstenone, and a fermentation product of l-tryptophan, skatole. Male pigs are surgically castrated in many countries to minimise the risk of accumulation of high levels of androstenone and skatole. Raising entire male pigs is more profitable because they have superior production characteristics and improved meat quality due to leaner carcasses and higher protein content, as compared to castrated pigs. Furthermore, surgical castration is negative from an animal welfare point of view. In most studies, no differences in sensory quality have been found between lean meat from entire male pigs with low levels of androstenone and skatole and pork from castrates and females. The question that remains is: which substances are responsible for boar taint besides androstenone and skatole and whether they need to be considered? The threshold values used for androstenone and skatole might also be too high for highly sensitive persons. Recent research shows that a human odorant receptor, ORD7D4, is involved in sensitivity to androstenone. If the ORD7D4 genotypes of consumer and expert panels are known, this might facilitate consumer studies in the future. There is still a great need for rapid on/at-line detection methods in abattoirs for identifying carcasses with unacceptable levels of boar taint compounds. Several emerging rapid technologies with a potential for boar taint detection have been investigated. They represent various measurement principles such as chemical sensor arrays (electronic noses), mass-spectrometry fingerprinting, ultra-fast gas chromatography, gas-phase spectrometry and biosensors. An industrial detection method should allow 100% correct classification of both acceptable and not-acceptable samples with regard to boar taint sorting criteria. There are, however, still too high a percentage of false negatives ranging from 5% to 20%. In addition, these methods do not yet seem to fulfil the industrial specifications with regard to cost efficiency, simplicity and analysis time. There is still no dedicated measurement technology available for on/at-line detection of boar-tainted carcasses that measures both androstenone and skatole. PMID- 22444984 TI - Biochemical, nutritional and genetic effects on boar taint in entire male pigs. AB - Pork odour is to a great extent affected by the presence of malodorous compounds, mainly androstenone and skatole. The present review outlines the current state of knowledge about factors involved in the regulation of androstenone and skatole in entire male pigs. Androstenone is a pheromonal steroid synthesised in the testes and metabolised in the liver. Part of androstenone accumulates in adipose tissue causing a urine-like odour. Skatole is produced in the large intestine by bacterial degradation of tryptophan and metabolised by hepatic cytochrome P450 enzymes and sulphotransferase. The un-metabolised part accumulates in adipose tissue, causing faecal-like odour. Androstenone levels are mostly determined by genetic factors and stage of puberty, whereas skatole levels in addition to genetic background and hormonal status of the pigs are also controlled by nutritional and environmental factors. To reduce the risk of tainted carcasses entering the market, male pigs are surgically castrated in many countries. However, entire males compared to castrates have superior production characteristics: higher growth rate, better feed efficiency and leaner carcasses. Additionally, animal welfare aspects are currently of particular importance in light of increasing consumers' concerns. Nutrition, hormonal status, genetic influence on boar taint compounds and the methods to develop genetic markers are discussed. Boar taint due to high levels of skatole and androstenone is moderately heritable and not all market weight entire males have boar taint; it should thus be possible to select for pigs that do not have boar taint. In these studies, it is critical to assess the steroidogenic potential of the pigs in order to separate late-maturing pigs from those with a low genetic potential for boar taint. A number of candidate genes for boar taint have been identified and work is continuing to develop genetic markers for low boar taint. More research is needed to clarify the factors involved in the development of boar taint and to develop additional methods to prevent the accumulation of high concentrations of skatole and androstenone in fat. This review proposes those areas requiring further research. PMID- 22444985 TI - Resource efficiency and economic implications of alternatives to surgical castration without anaesthesia. AB - This paper presents an analysis of the economic implications of alternative methods to surgical castration without anaesthesia. Detailed research results on the economic implications of four different alternatives are reported: castration with local anaesthesia, castration with general anaesthesia, immunocastration and raising entire males. The first three alternatives have been assessed for their impact on pig production costs in the most important pig-producing Member States of the EU. The findings on castration with anaesthesia show that cost differences among farms increase if the anaesthesia cannot be administered by farmers and when the veterinarian has to be called to perform it. The cost of veterinarian service largely affects the total average costs, making this solution economically less feasible in small-scale pig farms. In all other farms, the impact on production costs of local anaesthesia is however limited and does not exceed 1 ?ct per kg. General anaesthesia administered by inhalation or injection of Ketamin in combination with a sedative (Azaperone, Midazolan) is more expensive. These costs depend heavily on farm size, as the inhalation equipment has to be depreciated on the largest number of pigs possible. The overall costs of immunocastration - including the cost of the work load for the farmer - has to be evaluated against the potential benefits derived from higher daily weight gain and feed efficiency in comparison with surgical castrates. The economic feasibility of this practice will finally depend on the price of the vaccine and on consumer acceptance of immunocastration. The improvement in feed efficiency may compensate almost entirely for the cost of vaccination. The main advantages linked to raising entire males are due to the higher efficiency of feed conversion, to the better growth rate and to the higher leanness of carcass. A higher risk of boar taint on the slaughter line has to be accounted for. Raising entire males should not generate more than 2.5% of boar taint among slaughter pigs, in order to maintain the considerable economic benefits of better feed efficiency of entire males with respect to castrates. PMID- 22444986 TI - Effects of a quantitative trait locus for increased muscularity on carcass traits measured by subjective conformation and fat class scores and video image analysis in crossbred lambs. AB - A quantitative trait locus (QTL) for increased loin muscularity (TM-QTL) has previously been identified in purebred Texel sheep. Crossbred lambs born out of Mule ewes mated to heterozygous Texel sires for the TM-QTL were evaluated for a range of carcass traits. Lambs were genotyped and classified as carriers (n = 62) of a single copy of the TM-QTL and non-carriers (n = 49). In this study, the effects of the TM-QTL on carcass attributes were investigated using subjective classification scores for conformation and fatness, and measurements from a video image analysis (VIA) system. In addition, refined prediction equations to estimate weights of primal joints (leg, chump, loin, breast and shoulder) were obtained by calibrating the VIA system against computer tomography (CT) measurements in the loin region. The new refined prediction models increased the accuracy of prediction of all primal cuts on an average of 16% compared to previously derived standard VIA prediction equations. The coefficient of determination (R2) of the VIA system to predict in vivo CT measurements ranged from 0.39 to 0.72 for measurements of Musculus longissimus lumborum (MLL) area, width and depth, lumbar spine length, loin muscle volume and loin muscularity index. Using VIA estimates of CT-measured loin muscle traits, a significant increase in depth (+2.7%) of the MLL was found to be associated with the TM-QTL. Conformation and fatness scores and the shape of the carcass measured as individual lengths, widths and areas by VIA were not significantly influenced by the TM-QTL. Primal meat yields estimated using both standard and refined VIA prediction equations were not significantly affected by the TM-QTL. However, carcass 'compactness' was found to have significantly increased in carrier lambs. The weight of the dissected MLL estimated using VIA information was greater (+2.6%) for carriers compared to non-carriers. To conclude, neither the current industry carcass evaluation system for conformation and fatness nor the standard VIA system is able to identify the effect of the TM-QTL in the loin region in the moment. However, the calibration of the VIA system against CT measurements resulted in improved VIA prediction equations for primal meat yields and also showed moderate potential to estimate loin muscle traits measured by CT and to detect, partially, the effect of the TM-QTL on these traits. PMID- 22444987 TI - Genetics of animal temperament: aggressive behaviour at mixing is genetically associated with the response to handling in pigs. AB - Aggression when pigs are mixed into new social groups has negative impacts on welfare and production. Aggressive behaviour is moderately heritable and could be reduced by genetic selection. The possible wider impacts of selection for reduced aggressiveness on handling traits and activity in the home pen were investigated using 1663 male and female pedigree pigs (898 purebred Yorkshire and 765 Yorkshire * Landrace). Aggressive behaviour was observed over 24 h after pigs were mixed at 10 weeks of age into groups balanced for unfamiliarity and weight. Aggression was highly heritable (duration of involvement in reciprocal fighting h2 = 0.47 +/- 0.03, and duration of delivering one-sided aggression h2 = 0.34 +/- 0.03). Three weeks after mixing, home pen inactivity (indicated by the frequency of lying) was observed over 24 h. Inactivity was weakly heritable (h2 = 0.05 +/- 0.01) but showed no significant genetic association with aggression. Pigs' behaviour during handling by humans was assessed on entry to, whilst inside and on exit from a weigh crate at both mixing and end of test at 22 weeks. Pigs were generally easy to handle, moving easily into and out of the crate. Scores indicating 'very difficult to move' were rare. Handling scores at weighing were weakly heritable (h2 = 0.03 to 0.17), and moderately correlated across the two weighings (rg = 0.28 to 0.76). Aggressive behaviour at mixing was genetically associated with handling at the end of test weighing: pigs that fought and delivered one-sided aggression had handling scores indicating more active behaviour at weighing (e.g. moving quickly into the crate v. fighting rg = 0.41 +/- 0.05 and v. bullying rg = 0.60 +/- 0.04). Also, there was a genetic association between receiving one-side aggression at mixing and producing high pitched vocalisations in the weigh crate (rg = 0.78 +/- 0.08). Correlated behavioural responses occurring across different challenging situations (e.g. social mixing and human handling) have been described by the concept of animal temperament (also known as coping styles, personality or behavioural syndromes), but this has rarely been demonstrated at the genetic level in farm animals. These findings may have practical implications for the development of breeding programmes aimed at altering animal temperament. Breeding to reduce aggression could result in some reduction in activity at weighing. This would have consequences for animal production, because pigs which are inactive at weighing take longer to move into and out of the weigh crate, and perhaps also for animal welfare. PMID- 22444988 TI - The effect of late pregnancy supplementation of ewes with vitamin E on lamb vigour. AB - The experiment measured lamb responses to supplementation of the pregnant ewe diet with vitamin E above requirement. Crossbred ewes were mated with either Suffolk or Texel rams. Twin-bearing ewes were randomly allocated (approximately 21 months of age at allocation) to one of four treatment groups (20 ewes per group, 10 mated with Suffolk and 10 with Texel rams). Treatments imposed were 50, 100, 150 or 250 IU supplementary vitamin E per ewe per day to give a four treatment by two sire-type factorial experimental design. Ewes were fed concentrates to meet energy requirements for stage of pregnancy and hay ad libitum. Diets were introduced approximately 6 weeks before lambing. Blood samples were obtained prior to introduction of diets, 17 days after introduction of diets and within 24 h of lambing from a subset of eight ewes per treatment (32 total). Colostrum samples were obtained from 10 ewes per treatment, 12 h after birth of the first lamb. All births were observed and a lamb vigour score was assigned to each lamb 5 min after birth. At 1 and 12 h after birth, rectal temperature, and at 12 h after birth, sex, crown-rump length and BW of each lamb were recorded. Mean ewe plasma alpha-tocopherol concentration prior to introduction of the diets was 1.5 MUg/ml (s.e.m. 0.09) and did not differ between groups. There were positive linear (P < 0.001) effects of dietary vitamin E on plasma (17 days after introduction of diets) and colostrum (12 h after birth) alpha-tocopherol concentrations. Lamb vigour scores were superior (P < 0.001) for lambs sired by Texel rather than Suffolk rams but there were no differences as a result of vitamin E supplementation. Lamb mortality was low and unrelated to either sire or supplementary vitamin E. Lamb birth and weaning weights were also unaffected by vitamin E supplementation. Supplementing the ewe with vitamin E therefore had no effect on any lamb measurements. PMID- 22444989 TI - Soybean oil and linseed oil supplementation affect profiles of ruminal microorganisms in dairy cows. AB - The objective of this study was to evaluate changes in ruminal microorganisms and fermentation parameters due to dietary supplementation of soybean and linseed oil alone or in combination. Four dietary treatments were tested in a Latin square designed experiment using four primiparous rumen-cannulated dairy cows. Treatments were control (C, 60 : 40 forage to concentrate) or C with 4% soybean oil (S), 4% linseed oil (L) or 2% soybean oil plus 2% linseed oil (SL) in a 4 * 4 Latin square with four periods of 21 days. Forage and concentrate mixtures were fed at 0800 and 2000 h daily. Ruminal fluid was collected every 2 h over a 12-h period on day 19 of each experimental period and pH was measured immediately. Samples were prepared for analyses of concentrations of volatile fatty acids (VFA) by GLC and ammonia. Counts of total and individual bacterial groups (cellulolytic, proteolytic, amylolytic bacteria and total viable bacteria) were performed using the roll-tube technique, and protozoa counts were measured via microscopy in ruminal fluid collected at 0, 4 and 8 h after the morning feeding. Content of ruminal digesta was obtained via the rumen cannula before the morning feeding and used immediately for DNA extraction and quantity of specific bacterial species was obtained using real- time PCR. Ruminal pH did not differ but total VFA (110 v. 105 mmol/l) were lower (P < 0.05) with oil supplementation compared with C. Concentration of ruminal NH3-N (4.4 v. 5.6 mmol/l) was greater (P < 0.05) due to oil compared with C. Compared with C, oil supplementation resulted in lower (P < 0.05) cellulolytic bacteria (3.25 * 108 v. 4.66 * 108 colony-forming units (CFU)/ml) and protozoa (9.04 * 104 v. 12.92 * 104 cell/ml) colony counts. Proteolytic bacteria (7.01 * 108 v. 6.08 * 108 CFU/ml) counts, however, were greater in response to oil compared with C (P < 0.05). Among oil treatments, the amount of Butyrivibrio fibrisolvens, Fibrobacter succinogenes and Ruminococcus flavefaciens in ruminal fluid was substantially lower (P < 0.05) when L was included. Compared to C, the amount of Ruminococcus albus decreased by an average of 40% regardless of oil level or type. Overall, the results indicate that some ruminal microorganisms, except proteolytic bacteria, are highly susceptible to dietary unsaturated fatty acids supplementation, particularly when linolenic acid rich oils were fed. Dietary oil effects on ruminal fermentation parameters seemed associated with the profile of ruminal microorganisms. PMID- 22444990 TI - Effects of feeding level and protein content of milk replacer on the performance of dairy herd replacements. AB - It has been suggested that United Kingdom recommendations for feeding the neonatal calf (500 g milk replacer (MR)/day; 200-230 g CP/kg milk powder) are inadequate to sustain optimal growth rates in early life. The current study was undertaken with 153 high genetic merit, male and female Holstein-Friesian calves (PIN2000 = L48) born between September and March, with heifers reared and bred to calve at 24 months of age. Calves were allocated to one of four pre-weaning dietary treatments arranged in a 2 MR feeding level (5 v. 10 l/day) * 2 MR protein content (210 v. 270 g CP/kg dry matter (DM)) factorial design. MR was reconstituted at a rate of 120 g/l of water, throughout, and was offered via computerised automated milk feeders. Calves were introduced to pre-weaning diets at 5 days of age and weaned at day 56. During the first 56 days of life, calves offered 10 l MR/day had significantly higher liveweight gains (P < 0.001) than calves fed 5 l MR/day. No significant differences in liveweight gain were found between calves fed 210 g CP/kg DM MR and those fed 270 g CP/kg DM MR from birth to day 56. Differences in live weight and body size due to feeding level disappeared by day 90. Neither MR feeding level nor MR CP content affected age at first service or age at successful service, and with no milk production effects, the results indicate no post-weaning benefits of increased nutrition during the milk-feeding period in dairy heifers. PMID- 22444991 TI - Fat metabolism is regulated by altered gene expression of lipogenic enzymes and regulatory factors in liver and adipose tissue but not in semimembranosus muscle of pigs during the fattening period. AB - It has been shown previously that lipid metabolism is regulated by fatty acids (FA) and that thyroid hormones are important regulators of energy metabolism. The effects of weight, dietary fat level and dietary FA profile on thyroid hormone levels and expression of lipogenic genes and tissue FA composition were studied. Sixty-one crossbred gilts weighing 62 +/- 5.2 kg BW average were either slaughtered at the beginning of the trial (n = 5) or fed one of seven diets (n = 8 pigs per diet): a semi-synthetic diet formulated to contain a very low level of fat (NF) and six diets based on barley-soybean meal supplemented with approximately 10% fat of different origin and slaughtered at 100 kg BW. The supplemental fats were tallow, high-oleic sunflower oil, sunflower oil (SFO), linseed oil, fat blend (55% tallow, 35% sunflower oil, 10% linseed oil) and fish oil blend (40% fish oil, 60% linseed oil). In general, the dietary FA profiles altered the FA composition of liver, semimembranosus muscle and adipose tissues. Pigs fed the NF diet had the highest free and total triiodothyronine (T3) values followed by pigs fed SFO. Total T3 levels were higher in pigs at 60 kg than in pigs at 100 kg. Correlations between thyroid hormones and genes encoding enzymes of fat synthesis in adipose tissue (acetyl CoA carboxylase (ACACA), fatty acid synthase and stearoyl CoA desaturase (SCD)) and the large differences in expression of lipogenic genes at different weights (60 and 100 kg BW), suggest a role for thyroid hormones and for T3, in particular, in regulating whole animal fat metabolism, with effects brought about by altered expression of lipogenic genes. Liver sterol receptor element binding protein-1 (SREBP1) mRNA content was affected by dietary treatment (P < 0.001) and was correlated with ACACA and SCD, whereas adipose tissue SREBP1 was not correlated with the mRNA abundance of any lipogenic enzyme. Weight and tissue factors showed greater influence on mRNA abundance of genes related with lipid metabolism than diet and tissue FA composition. In the pig, FA synthesis appear to be of greater magnitude in adipose tissue than in the liver as suggested by the higher expression of lipogenic genes in adipose tissue. PMID- 22444992 TI - Ethical policies on animal experiments are not compromised by whether a journal is freely accessible or charges for publication. AB - The advent of the open access (OA) movement in publishing has been instrumental in causing a shift in the accessibility of research findings published in academic journals. The adoption of OA and other online publication models means that the results of scientific research published in journals using a free access (FA) framework are now available, free of charge, to anyone with access to the Internet. FA journals typically require a payment from the authors of a manuscript, which has raised concerns about the quality of work published in them; accepting payment from an author may compromise a journal's acceptance criteria. This study addresses whether journal policy on the treatment of animals is influenced by whether a journal follows a FA publishing model, and whether a requirement to pay for publication has an influence. A random sample of 332 biomedical journals listed in the ISI Web of Knowledge and Directory of Open Access Journals databases were assessed for whether they had an ethical policy on publishing animal studies, and what form of publication framework they used (103 of the journals followed a FA framework; 101 charged in some way for publication). Only 135 (40.7%) of the journals surveyed demanded that submissions comply with a pre-defined ethical stance. FA journals are just as likely to have an ethical policy on the treatment and presentation of animal studies as 'traditional', non-FA journals (significance of there being a difference: P = 0.98), and there is no relationship between policy and whether an author is required to pay for publication (significance of there being a difference: P = 0.57). Older journals are more likely to have an ethical policy (P = 0.03). There is, therefore, no obvious compromise shown by FA journals in the explicit policies on reporting studies involving animals. However, since anyone can read published FA studies online, FA journals that do not have an explicit policy about publishing animal research are urged to consider adopting one. PMID- 22444993 TI - Management factors affecting udder health and effects of a one year extension program in organic dairy herds. AB - The first part of this study was a cross-sectional analysis of the impact of 29 management factors on udder health in organic dairy farms in Switzerland. All 77 farms joined the extension program 'pro-Q'. As a measure of udder health the theoretical bulk milk somatic cell count (TBMSCC) calculated by the monthly cow composite somatic cell count over a time period of 1 year was chosen. The basic udder health of the farms was determined by TBMSCC during the year prior to the start of the project (mean for all farms = 176 460 cells/ml). In the multivariable analysis, the five factors 'swiss brown breed', 'alpine summer pasturing', 'calf feeding with milk from mastitis diseased cows', 'hard bedding' and 'no post-milking' remained as significant risk factors on udder health. In the second part of the study, the development of management factors and the udder health situation affected by an extension program after 1 year was investigated. A partial improvement of the management factors on the farms but no overall improvement on udder health and no association between management changes and udder health changes were found. Improvement of udder health was more likely in farms with higher basic TBMSCC than in those farms with less udder health problems at the beginning of the project. PMID- 22444994 TI - The potential use of long-chain alcohols and fatty acids as diet composition markers: factors influencing faecal recovery rates and diet composition estimates in sheep. AB - The limitations of the alkane technique in estimating the diet components of herbivores call for the introduction of new diet composition markers. Recently, long-chain alcohols (alcohols) and long-chain fatty acids (acids) have received the most attention and show great potential, when combined with alkanes, to estimate composition of complex diets. In the current study, faecal recoveries of alcohols and acids were determined in sheep in four different live weight groups fed three herbage species, either Leymus chinensis, L. dasystachys or Elymus sibiricum. Analysis of variance (ANOVA) was used to examine the effects of herbage species and live weight of sheep on faecal recoveries of individual alcohols and acids. Further, an indoor experiment with six sheep fed a diet of equal proportions, on dry matter (DM) basis, of three herbages was performed, allowing to assess the accuracy of alcohols and/or acids in combination with alkanes, to estimate diet composition. A one-sample t-test was carried out to test the accuracy of these estimates. Results of the first experiment indicated that the faecal recoveries of alcohols and acids were significantly affected by herbage species (P < 0.05). While the effects were significant or near significant for the faecal recoveries of some alcohols (C24-ol, C30-ol and C26 ol) (P 0.05), no effect of live weight on faecal recoveries of acids was observed (P > 0.05). Therefore, adjustments based on diet-specific faecal recoveries might improve diet composition estimates. This was illustrated by the results of the second experiment. The diet composition estimated from alcohols or all combinations of alcohols with other marker types, after diet-specific correction of faecal recoveries, did not significantly differ from the actual composition (P > 0.05). However, using acids as additional markers resulted in poorer diet composition estimates. This study confirmed the utility of alcohols, combined with alkanes, as markers to estimate composition of complex diets. Although corrections based on mean faecal recoveries, average over animals and diets, resulted in some accuracy loss, results were still satisfactory and better than without recovery correction. PMID- 22444995 TI - The relationship of live animal muscular and skeletal scores, ultrasound measurements and carcass classification scores with carcass composition and value in steers. AB - This study examined the relationship of muscular and skeletal scores and ultrasound measurements in the live animal, and carcass conformation and fat scores with carcass composition and value using 336 steers, slaughtered at 2 years of age. Live animal scores and measurements were recorded at 8 to 12 months of age and pre-slaughter. Following slaughter, each carcass was classified for conformation and fatness and the right side dissected into meat, fat and bone. Carcass conformation scores and fat scores were both measured on a continuous 15 point scale and ranged from 2.0 to 12.0 and from 2.8 to 13.3, respectively. Pre slaughter muscular scores showed positive correlations (P < 0.001) ranging from 0.31 to 0.86 with carcass meat proportion, proportion of high-value cuts in the carcass, conformation score and carcass value, significant negative correlations with carcass fat (r = -0.13) and bone (r = -0.81) proportions, and generally low non-significant relationships with the proportion of high-value cuts in meat and carcass fat score. Pre-slaughter ultrasound muscle depth and carcass conformation score showed similar correlations with carcass traits to those using the pre slaughter muscular scoring procedure. Pre-slaughter ultrasound fat depth showed positive correlations (P < 0.001) with carcass fat proportion (r = 0.59) and fat score (r = 0.63), and significant negative correlations (-0.23 to -0.50) with carcass meat and bone proportions, high-value cuts in the carcass and in meat, and carcass value. Pre-slaughter skeletal scores generally showed poor correlations ranging from -0.38 to 0.52 with the various carcass traits. Corresponding correlations (-0.26 to 0.44) involving records collected at 8 to 12 months of age were lower than those using pre-slaughter records. A one-unit increase in carcass conformation score increased carcass meat proportion and value by 11.2 g/kg and 5.6 cents/kg, respectively. Corresponding values for fat score were -8.2 g/kg and -5.1 cents/kg. In conclusion, both pre-slaughter live animal scores/measurements and carcass classification scores, explained an appreciable amount of the total variation in carcass meat, fat and bone proportions and carcass value, and a moderate amount of the variation in proportion of high-value meat cuts in the carcass. PMID- 22444996 TI - [SIDIAP database: electronic clinical records in primary care as a source of information for epidemiologic research]. PMID- 22444998 TI - Brachial plexus-associated neuropathy after high-dose radiation therapy for head and-neck cancer. AB - PURPOSE: To identify clinical and treatment-related predictors of brachial plexus associated neuropathies after radiation therapy for head-and-neck cancer. METHODS AND MATERIALS: Three hundred thirty patients who had previously completed radiation therapy for head-and-neck cancer were prospectively screened using a standardized instrument for symptoms of neuropathy thought to be related to brachial plexus injury. All patients were disease-free at the time of screening. The median time from completion of radiation therapy was 56 months (range, 6-135 months). One-hundred fifty-five patients (47%) were treated by definitive radiation therapy, and 175 (53%) were treated postoperatively. Radiation doses ranged from 50 to 74 Gy (median, 66 Gy). Intensity-modulated radiation therapy was used in 62% of cases, and 133 patients (40%) received concurrent chemotherapy. RESULTS: Forty patients (12%) reported neuropathic symptoms, with the most common being ipsilateral pain (50%), numbness/tingling (40%), motor weakness, and/or muscle atrophy (25%). When patients with <5 years of follow-up were excluded, the rate of positive symptoms increased to 22%. On univariate analysis, the following factors were significantly associated with brachial plexus symptoms: prior neck dissection (p = 0.01), concurrent chemotherapy (p = 0.01), and radiation maximum dose (p < 0.001). Cox regression analysis confirmed that both neck dissection (p < 0.001) and radiation maximum dose (p < 0.001) were independently predictive of symptoms. CONCLUSION: The incidence of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer may be underreported. In view of the dose-response relationship identified, limiting radiation dose to the brachial plexus should be considered when possible. PMID- 22444999 TI - Postoperative radiotherapy for prostate cancer: a comparison of four consensus guidelines and dosimetric evaluation of 3D-CRT versus tomotherapy IMRT. AB - PURPOSE: Despite the benefits of adjuvant radiotherapy after radical prostatectomy, approximately one-half of patients relapse. Four consensus guidelines have been published (European Organization for Research and Treatment of Cancer, Faculty of Radiation Oncology Genito-Urinary Group, Princess Margaret Hospital, Radiation Therapy Oncology Group) with the aim of standardizing the clinical target volume (CTV) delineation and improve outcomes. To date, no attempt has been made to compare these guidelines in terms of treatment volumes or organ at risk (OAR) irradiation. The extent to which the guideline-derived plans meet the dosimetric constraints of present trials or of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) trial is also unknown. Our study also explored the dosimetric benefits of intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 20 patients treated with postoperative RT were included. The three-dimensional conformal radiotherapy (3D CRT) plans were applied to cover the guideline-generated planning target volumes (66 Gy in 33 fractions). Dose-volume histograms (DVHs) were analyzed for CTV/planning target volume coverage and to evaluate OAR irradiation. The OAR DVHs were compared with the constraints proposed in the QUANTEC and Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trials. 3D-CRT plans were compared with the tomotherapy plans for the Radiation Therapy Oncology Group planning target volume to evaluate the advantages of IMRT. RESULTS: The CTV differed significantly between guidelines (p < 0.001). The European Organization for Research and Treatment of Cancer-CTVs were significantly smaller than the other CTVs (p < 0.001). Differences in prostate bed coverage superiorly accounted for the major volumetric differences between the guidelines. Using 3D-CRT, the DVHs rarely met the QUANTEC or RADICALS rectal constraints, independent of the guideline used. The RADICALS bladder constraints were met most often by the European Organization for Research and Treatment of Cancer consensus guideline (14 of 20). The tomotherapy IMRT plans resulted in significant OAR sparing compared with the 3D-CRT plans; however, the RADICALS and QUANTEC criteria were still missed in a large percentage of cases. CONCLUSION: Treatment volumes using the current consensus guidelines differ significantly. For the four CTV guidelines, the rectal and bladder DVH constraints proposed in the QUANTEC and RADICALS trials are rarely met with 3D-CRT. IMRT results in significant OAR sparing; however, the RADICALS dose constraints are still missed for a large percentage of cases. The rectal and bladder constraints of RADICALS should be modified to avoid a reduction in the CTVs. PMID- 22445000 TI - Generalizable class solutions for treatment planning of spinal stereotactic body radiation therapy. AB - PURPOSE: Spinal stereotactic body radiation therapy (SBRT) continues to emerge as an effective therapeutic approach to spinal metastases; however, treatment planning and delivery remain resource intensive at many centers, which may hamper efficient implementation in clinical practice. We sought to develop a generalizable class solution approach for spinal SBRT treatment planning that would allow confidence that a given plan provides optimal target coverage, reduce integral dose, and maximize planning efficiency. METHODS AND MATERIALS: We examined 91 patients treated with spinal SBRT at our institution. Treatment plans were categorized by lesion location, clinical target volume (CTV) configuration, and dose fractionation scheme, and then analyzed to determine the technically achievable dose gradient. A radial cord expansion was subtracted from the CTV to yield a planning CTV (pCTV) construct for plan evaluation. We reviewed the treatment plans with respect to target coverage, dose gradient, integral dose, conformality, and maximum cord dose to select the best plans and develop a set of class solutions. RESULTS: The class solution technique generated plans that maintained target coverage and improved conformality (1.2-fold increase in the 95% van't Riet Conformation Number describing the conformality of a reference dose to the target) while reducing normal tissue integral dose (1.3-fold decrease in the volume receiving 4 Gy (V(4Gy)) and machine output (19% monitor unit (MU) reduction). In trials of planning efficiency, the class solution technique reduced treatment planning time by 30% to 60% and MUs required by ~20%: an effect independent of prior planning experience. CONCLUSIONS: We have developed a set of class solutions for spinal SBRT that incorporate a pCTV metric for plan evaluation while yielding dosimetrically superior treatment plans with increased planning efficiency. Our technique thus allows for efficient, reproducible, and high-quality spinal SBRT treatment planning. PMID- 22445001 TI - Quality assessment in oncology. AB - The movement to improve healthcare quality has led to a need for carefully designed quality indicators that accurately reflect the quality of care. Many different measures have been proposed and continue to be developed by governmental agencies and accrediting bodies. However, given the inherent differences in the delivery of care among medical specialties, the same indicators will not be valid across all of them. Specifically, oncology is a field in which it can be difficult to develop quality indicators, because the effectiveness of an oncologic intervention is often not immediately apparent, and the multidisciplinary nature of the field necessarily involves many different specialties. Existing and emerging comparative effectiveness data are helping to guide evidence-based practice, and the increasing availability of these data provides the opportunity to identify key structure and process measures that predict for quality outcomes. The increasing emphasis on quality and efficiency will continue to compel the medical profession to identify appropriate quality measures to facilitate quality improvement efforts and to guide accreditation, credentialing, and reimbursement. Given the wide-reaching implications of quality metrics, it is essential that they be developed and implemented with scientific rigor. The aims of the present report were to review the current state of quality assessment in oncology, identify existing indicators with the best evidence to support their implementation, and propose a framework for identifying and refining measures most indicative of true quality in oncologic care. PMID- 22445002 TI - Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. AB - PURPOSE: To analyze retrospectively the results of intraoperative radiotherapy (IORT) with or without external beam radiotherapy (+/- EBRT) for localized pancreatic cancer in the past three decades and to analyze prognostic factors by multivariate analysis. METHODS AND MATERIALS: Records for 322 patients with pancreatic cancer treated by IORT +/- EBRT in Tohoku University Hospital between 1980 and 2009 were reviewed. One hundred ninety-two patients who had no distant organ metastases or dissemination at the time of laparotomy were enrolled in the present study. RESULTS: Eighty-three patients underwent gross total resection (R0: 48 patients, R1: 35 patients), and 109 patients underwent only biopsy or palliative resection. Fifty-five patients underwent adjuvant EBRT, and 124 underwent adjuvant chemotherapy. The median doses of IORT and EBRT were 25 and 40 Gy, respectively. The median follow-up period was 37.5 months. At the time of the analysis, 166 patients had disease recurrence, and 35 patients had local failure. The 2-year local control (LC) and overall survival (OS) rates were 71.0% and 16.9%, respectively. Comparison of the results for each decade showed that OS was significantly improved decade by decade (2-year: 25.0% vs. 18.8% vs. 4.2%, p < 0.001). Multivariate analysis showed that degree of resection (R0-1 vs. R2, hazard ratio = 1.97, p = 0.001) and adjuvant chemotherapy (yes vs. no, hazard ratio = 1.54, p = 0.028) had significant impacts on OS. Late gastrointestinal morbidity of Common Terminology Criteria for Adverse Events version 3.0 grade 4 or 5 was observed in four patients. CONCLUSION: Excellent local control for pancreatic cancer with few cases of severe late toxicity was achieved by using IORT. OS of patients with pancreatic cancer treated by IORT +/- EBRT improved significantly decade by decade. Multivariate analysis showed that degree of resection and adjuvant chemotherapy had significant impacts on OS. PMID- 22445003 TI - Modern outcomes of inflammatory breast cancer. AB - PURPOSE: To report contemporary outcomes for inflammatory breast cancer (IBC) patients treated in the modern era of trastuzumab and taxane-based chemotherapy. METHODS AND MATERIALS: We retrospectively reviewed the charts of 104 patients with nonmetastatic IBC treated between January 2000 and December 2009. Patients who received chemotherapy, surgery, and radiation therapy were considered to have completed the intended therapy. Kaplan-Meier curves estimated locoregional control (LRC), distant metastases-free survival (DMFS), and overall survival. RESULTS: The median follow-up time was 34 months; 57 (55%) patients were estrogen receptor progesterone receptor (ER/PR) negative, 34 (33%) patients were human epidermal growth factor receptor 2 (her2)/neu amplified, and 78 (75%) received definitive postoperative radiation. Seventy-five (72%) patients completed all of the intended therapy, of whom 67 (89%) received a taxane and 18/28 (64%) of her2/neu-amplified patients received trastuzumab. For the entire cohort, the 5 year rates of overall survival, LRC, and DMFS were 46%, 83%, and 44%, respectively. The ER/PR-negative patients had a 5-year DMFS of 39% vs. 52% for ER/PR-positive patients (p = 0.03). The 5-year DMFS for patients who achieved a pathologic complete response compared with those who did not was 83% vs. 44% (p < 0.01). Those patients who received >60.4 Gy (n = 15) to the chest wall had a 5 year LRC rate of 100% vs. 83% for those who received 45 to 60.4 Gy (n = 49; p = 0.048). On univariate analysis, significant predictors of DMFS included achieving a complete response to neoadjuvant chemotherapy (hazard ratio [HR] = 5.8; 95% confidence interval [CI] = 1.4-24.4; p = 0.02) and pathologically negative lymph nodes (HR = 4.1; 95% CI = 1.4-11.9; p < 0.01), but no factor was significant on multivariate analysis. CONCLUSIONS: For IBC patients, the rate of distant metastases is still high despite excellent local control, particularly for patients who received >60.4 Gy to the chest wall. Despite the use of taxanes and trastuzumab, outcomes remain modest, particularly for those with ER/PR-negative disease and those without a pathologic complete response. PMID- 22445004 TI - Chloroquine improves survival and hematopoietic recovery after lethal low-dose rate radiation. AB - PURPOSE: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. METHODS AND MATERIALS: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 MUg per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. RESULTS: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). CONCLUSION: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection against the harmful effects of LDR radiation. PMID- 22445005 TI - Phase II trial of radiosurgery to magnetic resonance spectroscopy-defined high risk tumor volumes in patients with glioblastoma multiforme. AB - PURPOSE: To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). METHODS AND MATERIALS: Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. RESULTS: The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. CONCLUSIONS: This represents the first prospective trial using selective MRS-targeted functional SRS combined with radiotherapy for patients with GBM. This treatment is feasible, with acceptable toxicity and patient survivals higher than in historical controls. This study can form the basis for a multicenter, randomized trial. PMID- 22445006 TI - Quality assurance peer review chart rounds in 2011: a survey of academic institutions in the United States. AB - PURPOSE: In light of concerns regarding the quality of radiation treatment delivery, we surveyed the practice of quality assurance peer review chart rounds at American academic institutions. METHODS AND MATERIALS: An anonymous web-based survey was sent to the chief resident of each institution across the United States. RESULTS: The response rate was 80% (57/71). The median amount of time spent per patient was 2.7 minutes (range, 0.6-14.4). The mean attendance by senior physicians and residents was 73% and 93%, respectively. A physicist was consistently present at peer review rounds in 66% of departments. There was a close association between attendance by senior physicians and departmental organization: in departments with protected time policies, good attendance was 81% vs. 31% without protected time (p = 0.001), and in departments that documented attendance, attending presence was 69% vs. 29% in departments without documentation (p < 0.05). More than 80% of institutions peer review all external beam therapy courses; however, rates were much lower for other modalities (radiosurgery 58%, brachytherapy 40%-47%). Patient history, chart documentation, and dose prescription were always peer reviewed in >75% of institutions, whereas dosimetric details (beams, wedges), isodose coverage, intensity-modulated radiation therapy constraints, and dose-volume histograms were always peer reviewed in 63%, 59%, 42%, and 50% of cases, respectively. Chart rounds led to both minor (defined as a small multileaf collimator change/repeated port film) and major (change to dose prescription or replan with dosimetry) treatment changes. Whereas at the majority of institutions changes were rare (<10% of cases), 39% and 11% of institutions reported that minor and major changes, respectively, were made to more than 10% of cases. CONCLUSION: The implementation of peer review chart rounds seems inconsistent across American academic institutions. Brachytherapy and radiosurgical procedures are rarely reviewed. Attendance by senior physicians is variable, but it improves when scheduling clashes are avoided. The potential effect of a more thorough quality assurance peer review on patient outcomes is not known. PMID- 22445007 TI - What is the optimal treatment of large brain metastases? An argument for a multidisciplinary approach. AB - PURPOSE: Single-modality treatment of large brain metastases (>2 cm) with whole brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity. PATIENTS AND METHODS: We retrospectively evaluated 97 patients with brain metastases >2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by the Kaplain-Meier product-limit method. RESULTS: The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status (>=80 vs. <80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity. CONCLUSION: Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC. PMID- 22445008 TI - Identification of differentially expressed genes and quantitative expression of complement genes in the liver of marine medaka Oryzias melastigma challenged with Vibrio parahaemolyticus. AB - The innate immune system of fish is the primary defense against acute diseases. The marine medaka Oryzias melastigma has been shown to be a potential marine fish model for ecotoxicology, but little is known about the innate immune system of this small fish. In this study, suppression subtractive hybridization (SSH) was used to identify differentially expressed immune genes in the liver of O. melastigma infected with Vibrio parahaemolyticus. Among the 396 genes identified, based on NCBI BLAST search of the 1279 sequenced clones in the SSH libraries, 38 (9.6%) were involved in the immune process. Besides, genes involved in biological regulations (5.6%); cellular metabolism (24.7%); general response to stimuli (4.8%); cellular component organization (2.3%); signal transduction (2.5%) and transport process (2.8%) were also obtained. Ten complement component genes involved in four activation pathways were quantified (using q-PCR) and exhibited different patterns of transcription between the control and challenged individuals. The results reported upon here support the feasibility of developing O. melastigma as a marine model fish to understand the basic biological processes related to immune function and for immunotoxicological research. Findings of this study established a genetic platform for studying immune function using O. melastigma. PMID- 22445009 TI - The Norwegian sheep breeding scheme: description, genetic and phenotypic change. AB - The developments in Norwegian sheep breeding since the early 1990s are reviewed. For the largest breeding population, the Norwegian White Sheep, results are presented for both genetic and phenotypic changes. Of the nine traits that make up the aggregate genotype, the largest gain per year, in per cent of the corresponding phenotypic average, was found for carcass grade (1.66%) and carcass weight (0.99%), number of lambs born at 1, 2 and 3 years of age (0.32% to 0.60%) and the maternal effect on weaning weight (0.26%). For fat grade, a genetic deterioration was estimated. This may be due to the too small weighting of this trait in the aggregate genotype and the true genetic parameters being somewhat different from the estimates in the prediction of breeding values. For lamb as well as ewe fleece weight, genetic change was close to zero - interpreted as mainly a correlated response to other traits in the aggregate genotype. Data for the two traits of fleece weight were, respectively, selected and few. Thus, phenotypic change was calculated for all traits except for fleece weight, and in addition for number of lambs at weaning, being indirectly selected for through number of lambs born. For all traits, with the exception of fat grade, advantageous phenotypic change was estimated. For weaning and carcass weight, the phenotypic change was less than the genetic change, while the opposite was observed for carcass and fat grade and number of lambs born. The latter traits can be more easily controlled by environmental actions, and the results thus exemplify the interdependency between environmental and genetic change. PMID- 22445010 TI - Empirical Bayes factor analyses of quantitative trait loci for gestation length in Iberian * Meishan F2 sows. AB - The aim of this study was to investigate chromosomal regions affecting gestation length in sows. An experimental F2 cross between Iberian and Meishan pig breeds was used for this purpose and we genotyped 119 markers covering the 18 porcine autosomal chromosomes. Within this context, we have developed a new empirical Bayes factor (BF) approach to compare between nested models, with and without the quantitative trait loci (QTL) effect, and after including the location of the QTL as an unknown parameter in the model. This empirical BF can be easily calculated from the output of a Markov chain Monte Carlo sampling by averaging conditional densities at the null QTL effects. Linkage analyses were performed in each chromosome using an animal model to account for infinitesimal genetic effects. Initially, three QTL were detected at chromosomes 6, 8 and 11 although, after correcting for multiple testing, only the additive QTL located in cM 110 of chromosome 8 remained. For this QTL, the allelic effect of substitution of the Iberian allele increased gestation length in 0.521 days, with a highest posterior density region at 95% ranged between 0.121 and 0.972 days. Although future studies are necessary to confirm if detected QTL is relevant and segregating in commercial pig populations, a hot-spot on the genetic regulation of gestation length in pigs seems to be located in chromosome 8. PMID- 22445011 TI - Variance and covariance components for liability of piglet survival during different periods. AB - Variance and covariance components for piglet survival in different periods were estimated from individual records of 133 004 Danish Landrace piglets and 89 928 Danish Yorkshire piglets, using a liability threshold model including both direct and maternal additive genetic effects. At the individual piglet level, the estimates of direct heritability in Landrace were 0.035, 0.057 and 0.027, and in Yorkshire the estimates were 0.012, 0.030 and 0.025 for liability of survival at farrowing (SVB), from birth to day 5 (SV5) and from day 6 to weaning (SVW), respectively. The estimates of maternal heritability for SVB, SV5 and SVW were, respectively, 0.057, 0.040 and 0.030 in Landrace, and 0.050, 0.038 and 0.019 in Yorkshire. Both direct and maternal genetic correlations between the three survival traits were low and not significantly different from zero, except for a moderate direct genetic correlation between SVB and SV5 and between SV5 and SVW in Landrace. Direct and maternal genetic correlations between piglet birth weight (BW) and SV5 were moderately high, but the correlations between BW and SVB and between BW and SVW were low and most of them were not significantly different from zero. These results suggest that effective genetic improvement in piglet survival before weaning by selection should be based on both direct and maternal additive genetic effects and treat survival in different periods as different traits. PMID- 22445012 TI - Effect of polymorphism in the porcine cytochrome b5 ( CYB5A) gene on androstenone and skatole concentrations and sexual development in Swedish pig populations. AB - The present study investigated the presence of a single-nucleotide polymorphism (G > T) at base -8 upstream of ATG in 5' untranslated region of cytochrome b5 (CYB5A) gene in Swedish pig populations and evaluated the significance of this polymorphism for androstenone and skatole levels, sexual development and performance parameters in pigs. Frequencies of the T allele were 6.7% for Swedish Yorkshire * Landrace crossbred pigs (n = 245), 6.5% for Swedish Yorkshire (n = 99) and 12.8% for Landrace breed (n = 74). No deviations from Hardy-Weinberg equilibrium were observed in the investigated populations. In Swedish Yorkshire * Landrace crossbred entire male pigs (n = 193), plasma samples were analysed for skatole, androstenone, testosterone and oestrone sulphate, and fat samples were analysed for androstenone, skatole and free oestrone. Additionally, testis weight and bulbourethral gland length for crossbred pigs were recorded. Plasma androstenone levels were significantly lower in the G/T genotype at 90 kg live weight compared with the wild G/G genotype at the same live weight (P = 0.006). In heavier pigs, plasma androstenone levels did not differ between genotypes (P = 0.382). Fat androstenone levels were not affected by CYB5A genotype (P = 0.252). Skatole levels in the G/T genotype at 115 kg live weight were lower compared with those in the G/G genotype in plasma (P = 0.048) and fat (P = 0.028), although no differences were observed in lighter pigs. Testis weight, bulbourethral gland length, testosterone and oestrone sulphate levels in plasma, and oestrone levels in fat were not affected by genotype. We concluded that the presence of the T allele in the CYB5A gene resulted in lower androstenone levels in plasma, and lower skatole levels in fat and plasma; this reduction, however, was dependent on the live weight of the animals. Reproductive hormones and growth rate did not differ between the pigs of different genotypes, whereas a higher lean meat content was found in the G/T genotype in comparison with the G/G genotype. The practical application of those results in Sweden is doubtful because of lack of the effect on androstenone in fat and the low frequency of the T allele in the studied Swedish pig populations. PMID- 22445013 TI - The effects of cobalt and iodine supplementation of the pregnant ewe diet on immunoglobulin G, vitamin E, T3 and T4 levels in the progeny. AB - Sixty twin-bearing ewes were allocated to one of four dietary treatments investigating the effects of supplementary iodine or cobalt during late pregnancy on lamb serum immunoglobulin G (IgG), triiodothyronine (T3), thyroxine (T4) and vitamin E concentrations, and lamb IgG absorption efficiency. Ewes were offered grass silage ad libitum supplemented with 800 g per ewe per day of a 190 g/kg crude protein (CP) concentrate from day 126 of gestation until parturition plus one of the following supplements (n = 15 per treatment); no supplement (C); 26.6 mg iodine per day for final 3 weeks pre partum (I-3); 26.6 mg iodine/day for final week pre partum (I-1); 20 mg cobalt/day for final 3 weeks pre partum (Co 3). Lambs were blood sampled at 24 and 72 h post partum for serum IgG and vitamin E concentrations. Ten lambs from C and I-3 were blood sampled at 1 h post partum for serum IgG, vitamin E, T3 and T4 concentrations. There were no differences in serum IgG, vitamin E or T4 values (P > 0.05) at 1 h post partum between lambs born to the C and I-3 ewes. T3 levels were lower in I-3 compared with C progeny (P < 0.05). Supplemental iodine reduced colostral IgG absorption efficiency (P < 0.001) and lamb serum IgG concentrations at 24 and 72 h post partum (P < 0.001). Serum vitamin E concentration in I-3 and I-1 lambs was lower than in Co-3 lambs at 24 h post partum, while at 72 h post partum I-3, I-1 and Co-3 lambs had significantly lower concentrations than C lambs (P < 0.001). Supplementing the ewe's diet with 26.6 mg/day of iodine for the final week of pregnancy reduced lamb serum IgG concentration at 24 and 72 h post partum. The lower total and free T3 values in the progeny of I-3-treated ewes suggest interference in the synthesis and metabolism of thyroid hormones when ewes receive excessive dietary iodine for 3 weeks immediately pre partum. Based on these findings, the indications are that the toxicity level for iodine in the diet of the pregnant ewe should be lowered to 20 mg per ewe per day, equivalent to 40% of its current level. The finding that high-level cobalt supplementation during the final 3 weeks of pregnancy will have a negative effect on serum vitamin E concentration at 72 h post partum is a new and significant finding and previously has not been reported in the literature. PMID- 22445014 TI - Caecal fermentation characteristics, blood composition and growth of rabbits on substitution of soya-bean meal by unconventional high-glucosinolate mustard ( Brassica juncea) meal as protein supplement. AB - Effect of graded levels of high-glucosinolate mustard (Brassica juncea) meal as substitute of soya-bean meal (SBM) in broiler rabbit diets was studied. Forty weaning rabbits of Soviet Chinchilla and White Giant breed were randomly allocated to one of four experimental diets containing mustard meal (MM) 0, 80, 160 and 245 g/kg. The experiment lasted for 8 weeks. MM had 54.8 mg total glucosinolates (TGLSs) per g dry matter (DM). Diets had TGLS 3.8, 8.4 and 11.98 mg/g DM in 80, 160 and 245 g MM diets, respectively. MM-incorporated diets had higher digestible and linearly (P < 0.01) higher metabolisable energy (ME) content. However, the effect on total tract apparent digestibility of DM, and crude protein was quadratic. Average daily gain (ADG) reduced (P < 0.05) linearly with increasing MM levels in diet, still 80 and 160 g MM diets had similar ADG compared to that of SBM diet. Caecum weight reduced linearly (P < 0.05) with increasing MM levels in diet. The pH of caecal content ranged between 5.85 and 6.19, total N between 1.19 and 1.48 (g per 100 g) and total volatile fatty acids between 4.7 and 5.8 mmol per 100 g, and they were not statistically different. NH3-N ranged between 31.2 and 39.0 mg per 100 ml, and reduced linearly (P < 0.05) while trichloroacetic acid-precipitable nitrogen increased linearly (P < 0.01, ranged between 114 and 247 mg per 100 ml) with increasing MM levels in diet. Blood haemoglobin, packed cell volume and lymphocytes were higher (quadratic effects, P < 0.05) on 245 MM diet, whereas white blood cell count reduced linearly (P < 0.01). Serum aspartate aminotransferase increased linearly (P < 0.01) while alanine aminotransferase and alkaline phosphatase activity, protein, erythrocytes sedimentation rate and red blood cell counts were not affected by MM. Serum Cu, Na and K content increased linearly (P < 0.05) with increasing MM levels. Liver Cu concentration showed quadratic (P < 0.05) increase. Rabbits tolerated 8.4 mg TGLS per g diet (160 g MM per kg) during active growth without any apparent effect on health and growth. It is concluded that MM can replace up to 66% SBM protein in rabbit feeding, whereas complete replacement of SBM with MM reduced feed intake and ADG by 23% and 13%, respectively. Further studies are required to confirm these inclusion levels and glucosinolate tolerance of rabbits. PMID- 22445015 TI - Growth performance and immune responses in chickens after challenge with lipopolysaccharide and modulation by dietary different oils. AB - The study was conducted to investigate the effects of different oils on growth performance and immune responses of chickens after challenge with lipopolysaccharide (LPS). A total of 288 chickens were assigned in a 2 * 2 factorial design. Factors were dietary fat type (4.5% maize oil or 4.5% fish oil) and immunological challenge (LPS or saline). At 20 days and 27 days of age, chickens were injected intraperitoneally with either 1 mg/kg body weight of LPS or sterile saline. LPS decreased feed intake from 21 days to 28 days of age and body-weight gain from 21 days to 42 days of age. Fish oil improved feed conversion efficiency of chickens after LPS challenge for the first time. Fish oil supplementation decreased lymphocyte proliferation (21 days: P < 0.0001; 28 days: P < 0.0001) and the ratio of CD3+CD4+/CD3+CD8+ (21 days: P = 0.0479; 28 days: P = 0.0009) after LPS challenge. LPS challenge increased the levels of interleukin-1 (IL-1) (21 days: P < 0.0001; 28 days: P = 0.0030), IL-6 (21 days: P < 0.0001; 28 days: P = 0.0001) and tumor necrosis factor-alpha (TNF-alpha) (21 days: P = 0.0008; 28 days: P = 0.0018). And fish oil alleviated the elevations in the production of IL-6 (21 days: P = 0.0359; 28 days: P = 0.0302) and TNF-alpha (21 days: P = 0.0055; 28 days: P = 0.0391) induced by the LPS challenge. Fish oil alleviated the mRNA abundance elevation of nuclear factor kappa B (NFkappaB) (21 days: P = 0.0079; 28 days: P = 0.0017) after LPS challenge. These results showed that fish oil acts as an anti-inflammatory agent, which may be associated with down-regulation of the activated immune system. The results of pro-inflammatory cytokines and mRNA abundance results suggested that fish oil might alleviate the elevation of IL-6 and TNF-alpha induced by LPS through down-regulating NFkappaB expression. PMID- 22445016 TI - Towards non-invasive methods to determine the effect of treatment of soya-bean meal on lysine availability in dairy cows. AB - Lysine (Lys) availability in three different soya-bean meal (SBM) products was determined using the following techniques: whole body (WB) net flux of Lys, digestible Lys (duodenal flow * intestinal digestibility) and the plasma Lys response curve method of Rulquin and Kowalczyk (2003). Four multiparous Holstein cows (173 days in milk) were equipped with ruminal and duodenal cannulas and used in a 4 * 4 Latin square experiment with 14-day periods. The animals were fed either solvent-extracted SBM (SE), expeller-processed SBM (EP) or lignosulphonate treated SBM (LS) at 23% of the diet dry matter (DM). The fourth treatment (SE70) consisted of a continuous infusion of Lys (70 g/day) into the omasum of cows fed the SE diet. Chromium(III) oxide was included as a digesta marker in order to determine the duodenal flow of amino acids (AA). On day 12 of each experimental period, six blood samples were collected to determine plasma Lys concentrations. Immediately after that, a pulse dose of L-[2-15N] Lys was administered in the jugular vein. Jugular blood samples were then collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 16, 19, 25 and 31 min after the injection to determine 15N Lys enrichment. On each of days 13 and 14, eight digesta samples were collected and pooled by period. Amongst the diets of SBM (SE, EP, LS), no differences were observed for duodenal Lys flow or digestible Lys. Duodenal flow of microbial N with SE was numerically higher, compared with EP and LS, indicating enhanced duodenal supply of microbial Lys for this diet, and this may have compensated for the additional Lys derived from undegradable protein in rumen-protected SBM products (EP and LS). The use of the plasma response curve method as well as the measurement of WB Lys flux also revealed no differences in Lys availability among the SBM products. The WB flux method resulted in 100% post-ruminal recovery of the Lys infused with diet SE70 compared with the control diet SE, which indicates that the method is reliable for determining Lys availability. The Lys flux approach not only allows for the estimation of intestinally available essential AA but also it avoids the use of cannulated animals. PMID- 22445017 TI - Simple representation of physiological regulations in a model of lactating female: application to the dairy goat. AB - A dynamic model of the lactating dairy goat, combining a minimum of mechanistic representations of homeorhetic regulations and a long-term approach, was developed. It describes (i) the main changes in body weight, dry-matter intake, milk production and composition of a dairy goat; (ii) the succession of pregnancy and lactation throughout the productive life; and (iii) the major changes in dynamics induced by the female profile (production potential and body weight at maturity). The model adopts a 'pull' approach including a systematic expression of the production potential and not representing any feed limitation. It involves three sub-systems. The reproductive events sub-system drives the dynamics through time with three major events: service, kidding and drying off. It also accounts for the effect of production potential (kg of milk at the peak of lactation) and lactation number (potential reached at the fourth lactation). The regulating sub system represents the homeorhetic mechanisms during pregnancy and lactation with two sets of theoretical hormones, one representing gestation and the other lactation. The operating sub-system describes the main physiological flows and the energetic requirements linked to these functions through a compartmental structure. Simulations were run in order to test (i) the behaviour of the model at the scale of the productive life for an average profile of female (60 kg at maturity and 4 kg of milk at peak); (ii) the sensitivity of the simulated dynamics (mainly milk production and body reserves) to the production potential and body weight at maturity; (iii) external validation with comparison of model outputs to data from the experimental flock of Grignon and data from the French milk record organization (French organism in charge of animal recording for dairy farmers). The results at the scale of one productive life show the model simulates a relevant set of dynamics. The sensitivity analysis suggests that the model fairly well simulates the link between a female's ability to produce and mobilise reserves. Finally, external validation confirms the model's ability to simulate a relevant set of physiological dynamics while pointing out some limits of the model (simulation of milk fat and protein content dynamics, for example). The results illustrate the relevance of the model in simulating biological dynamics and confirm the possibility of including minimum representations of homeorhetic regulations with a simple structure. This simplicity gives an opportunity to integrate this basic element in a herd simulator and test interactions between females' regulations and management rules. PMID- 22445018 TI - Risk factors for new intramammary infections during the dry period in untreated dairy cows from herds using selective dry cow therapy. AB - This study aimed at investigating risk factors for new intramammary infections (IMI) during the dry period in untreated cows from herds using selective dry cow antibiotic therapy (DCT). A total of 980 uninfected quarters in 347 untreated cows from 28 herds using selective DCT were included in a prospective survey. A herd-level questionnaire and an individual cow-level recording sheet were implemented to collect data on putative risk factors. Quarter milk samples were taken at drying-off and on day 3 after calving to assess the occurrence of new IMI during the dry period. A multivariate model including a herd effect as random and a cow effect as repeated was run at the quarter level. Interactions between risk factors and the cow infection status at drying-off (cow infected in at least one quarter v. uninfected) were checked. Three risk factors were found significantly associated with the risk for new IMI without interaction (P < 0.05): cows infected in at least one quarter at drying-off (v. uninfected cows) (relative risks (RR) = 1.58); long preceding lactation (>355 days v. shorter length) (RR = 1.62); long dry period (>65 days v. shorter length) (RR = 1.46). One risk factor acted only in interaction with the cow infection status at drying off: in cows uninfected at drying-off, the risk for new IMI was significantly higher in cows with short teats (RR = 1.21) when compared with cows with long or normal teats, while the reverse relationship was observed in cows infected at drying-off. Risk factors can be translated in recommendations, for instance to have dry periods not longer than 2 months. Moreover, as suggested by our results, the efficacy of selective DCT towards the prevention of new IMI would be improved if all infected cows were detected and treated. Criteria to accurately identify these infected cows should be therefore further investigated. PMID- 22445019 TI - Social models fail to induce diet and feeding site avoidance in naive yearling steers. AB - Social learning can be of critical importance to cattle grazing rangeland environments with high variability of food resources across space and time. Experienced individuals can greatly facilitate foraging decisions (what to eat and where to eat) of naive peers in such settings. We conducted an experiment with cattle to investigate strength and persistence of socially induced food and feeding site avoidance behaviours. Sixteen naive yearling steers were paired with 16 social models that had either not been trained (control) or been trained with an emetic (LiCl), electrical shock or both to avoid: (a) an unsafe high-quality food (LiCl); (b) an unsafe high-quality feeding site (shock); or (c) both the unsafe high-quality food and the unsafe high-quality feeding site (LiCl + shock). Ten-minute trials were conducted in an experimental arena containing three artificial feeding sites each consisting of groups of bowls with either high- (HQ) or moderate-quality (MQ) foods (HQ = barley and oat grain; MQ = Bermuda grass hay). Unsafe high-quality (UHQ, surrounded by traffic cones) and safe moderate-quality (SMQ) feeding sites consisted of nine rubber bowls containing either HQ or MQ foods. The safe high-quality (SHQ) feeding site consisted of two groups of eight bowls containing HQ food, which surrounded the UHQ and SMQ feeding sites. Social models did not induce diet and feeding site avoidance behaviours in naive steers; they exerted small and transient changes in the feeding behaviour of their naive counterparts. Consequences to the individual outweighed social influences; when naive animals experienced the same punishment contingencies as their social models, their behavioural patterns closely resembled those of their social model. Conditioned food and location aversions via LiCl were apparently influenced by prior exposure to target foods and the experimental arena. Conversely, conditioned feeding site avoidance via shock was apparently not influenced by prior exposure to target foods or the experimental arena. PMID- 22445020 TI - Effect of mild heat stress and mild infection pressure on immune responses to an E. coli infection in chickens. AB - Outdoor or organic farming demands robust chickens that are able to combat common infections before they spread to the flock. Priming the immune system of the chickens early in life with micro-organisms that they will encounter later in life prepares chickens to a life in environments where they are subjected to a more natural level of infection pressure. Also, exposure to non-infectious stressful situations may prepare the immune system to combat infectious challenges. The present study investigated whether the immune system could be primed by applying small doses of infective material to the chicken flock or by exposure to short-term non-infectious stimulation, and whether the effect of those stimuli would depend on the genetic material chosen. The effect of the stimulations was examined on selected immunological variables in two chicken strains, using small amounts of manure and litter from other chickens or short term heat stress, respectively. After 6 weeks of treatment, all chickens were subjected to an Escherichia coli infection and followed for another 3 weeks. Measures of body weight gain, chicken mannan-binding lectin (cMBL), percentage of CD4+ and MHCII+ lymphocytes, mean fluorescence intensity (m.f.i.) of CD4 on CD4+ cells and MHCII on MHCII+ cells and antibody titres to E. coli were taken. In conclusion, the chickens redistribute lymphocyte populations in peripheral blood in response to potentially infectious agents as well as to stressful non infectious treatments. Responses to stress situations were dependent on the frequencies of stress exposures and on the chicken breed. This may reflect the superiority of one breed over another in adapting to treatments or in discriminating whether a treatment is harmless or dangerous. However, the differences did not influence the disease resistance to infection with a mixture of E. coli O2, O11 and O78 in the present study. PMID- 22445021 TI - The effect of temporary deprivation of lying and feeding on the behaviour and production of lactating dairy cows. AB - Two experiments were conducted to examine the effects of depriving dairy cows of the ability to feed and lie down for short periods, on behaviour and production. In experiment 1, cows were deprived by confining them in pairs in a pen for 2 or 4 h, and they more frequently exhibited behaviour likely to suggest discomfort - leg stamping, repositioning themselves, shifting their weight between legs and butting. After deprivation, the cows deprived for 2 h made up their lost feeding time within 24 h, but cows deprived for 4 h did not restore their feeding time within the 41-h period of observation. Lying time was not restored in either treatment within the 41-h period. Milk yield was not affected by the treatment. However, in experiment 2, when cows were deprived of feeding and lying for 4 h, during which time their hooves were trimmed (which is likely to be a painful and stressful procedure and result in some discomfort for a period post-trimming) the evidence suggested that milk yield was reduced by approximately 2 l/day for 3 days, with corresponding increases during the subsequent 2 days. Walking speed on returning to the herd was the same as before the treatment. In summary, temporary deprivation of feeding and lying for 2 and 4 h/day induced behaviours that were indicative of discomfort and frustration but had no negative effect on milk production, except when 4 h of deprivation was accompanied by foot trimming. PMID- 22445022 TI - Developmental orthopaedic disease in limbs of foals: between-breed variations in the prevalence, location and severity at weaning. AB - Developmental orthopaedic disease (DOD) affects all breeds and is a common cause of pain and lameness for horses in sports. A thorough knowledge of between-breed variations for the prevalence of DOD, for its distribution among the various joints and for its severity at earlier stages in the disease process is needed in order to improve the relevance and the cost-effectiveness of DOD screening protocols. However, no prevalence study for DOD simultaneously performed on several breeds with similar farming systems and based on radiographic findings (RF) on quite a large number of joints and views, has been reported earlier. The objective of this study was to describe variations in the prevalence, location and severity of DOD in foals at weaning among Warmbloods (Wb), Standardbreds (St) and Thoroughbreds (Tb) with similar farming systems. DOD assessment was based on RF on the limb joints. A total of 392 foals from 21 volunteer stud farmers were included. To determine the statuses of foals regarding DOD, they were X-rayed on the front- and hind-limb digit, carpus, hock and stifle joints. X-ray data were analysed by three experienced equine veterinarians who gave a common assessment about the entity and the severity of RF. Between-breed variations were analysed in two steps: the first implemented for each anatomical site; the second considered only foals affected by DOD to explore RF association patterns on the affected sites, at foal level. The three breeds were represented by 25.0% of Wb, 41.1% of St and 33.9% of Tb. DOD was present in 66.3% of the foals (95% confidence interval (CI) = 61.6% to 71.0%). Prevalence of foals affected by DOD and distribution of the RF severity score on the anatomical sites differed depending on the breed: Wb foals seemed to be the most affected by DOD. Cluster analyses showed no clear association among sites. However, Wb and Tb foals were preferentially classified together because they were affected on the same sites, whereas St foals were distributed in other classes. The most severely affected sites were the proximal part of the hock and the femoro-patellar joint for Wb and St foals, and the fore fetlock and the distal part of the hock for Tb foals. This is the first epidemiological study reporting between-breed variations in DOD distribution and severity, for the limb joints of foals. These results contribute to broaden the knowledge on DOD and are of great interest to improve detection of DOD within a particular breed. PMID- 22445023 TI - Tail docking in pigs: acute physiological and behavioural responses. AB - Tail docking of piglets is a routine procedure on farms to control tail-biting behaviour; however, docking can cause an acute stress response. The objectives of this research were to determine the stress responses to tail docking in piglets and to compare two methods of tail docking; cautery iron (CAUT) and the more commonly used blunt trauma cutters (BT). At approximately 6 days of age, piglets were tail docked using CAUT (n = 20), BT (n = 20) or sham tail docked with their tails remaining intact (CON; n = 40). Blood samples were taken prior to tail docking and at 30, 60 and 90 min after tail docking to evaluate the effect of tail docking on white blood cell (WBC) measures and cortisol concentrations. The above experiment was repeated to observe behaviour without the periodic blood sampling, so as not to confound the effects of blood sampling on piglet behaviour. Piglet behaviour was recorded in the farrowing crate using 1 min scan samples via live observations for 60 min prior to and 90 min after tail docking. Total WBC counts were reduced (P > 0.05) among BT and CAUT compared with CON piglets 30 min after tail docking. Cortisol concentrations were higher (P < 0.01) among BT compared with CON and CAUT piglets 60 min after tail docking. Cautery and BT-docked piglets spent more (P < 0.05) time posterior scooting compared with CON piglets between 0 and 15 min, and 31 and 45 min after tail docking. Piglets tail docked using CAUT and BT tended to spend more (P < 0.07) time sitting than CON piglets between 0 and 15 min post tail docking. Elevated blood cortisol can be reduced by the use of the CAUT rather than the BT method of tail docking. Although the tail docking-induced rise in cortisol was prevented by using CAUT, the behavioural response to BT and CAUT docking methods was similar. PMID- 22445024 TI - Tick susceptibility and its effects on growth performance and carcass characteristics of Nguni, Bonsmara and Angus steers raised on natural pasture. AB - The objective of the current study was to compare tick loads, growth and carcass characteristics of dipped and non-dipped Nguni, Bonsmara and Angus steers raised on natural pasture. One hundred 7-month-old castrated weaners were kept at the University of Fort Hare Farm for 12 months. There were 30 weaners each of Angus and Bonsmara, and 40 weaners of the Nguni breed. Half the Bonsmara, Angus and 14 Nguni weaners were dipped every fortnight. The rest were not dipped. Monthly weights and tick counts under the tail, on scrotum, belly, sternum and ears of the steers were recorded. The dipped Nguni steers had lowest (P < 0.05) tick counts, and the non-dipped Angus steers had the highest (P < 0.05) tick counts. There were more ticks (P < 0.05) during the warm wet season than during the cool dry season. Ears had the highest (P < 0.05) tick infestation. Average daily gain (ADG) was similar (P > 0.05) among the three breeds. The non-dipped Bonsmara steers had the heaviest (P < 0.05) carcasses (142 +/- 5.4) while the non-dipped Nguni steers had the lightest (P < 0.05) carcasses (111 +/- 4.5 kg). The non dipped Bonsmara had the highest (P < 0.05) eye muscle area (3996 +/- 120.8 mm2) while the non-dipped Angus had the smallest (P < 0.05) eye muscle area (3291 +/- 210.6 mm2). The non-dipped Bonsmara also had the highest (P < 0.05) dressing percentage (53.8 +/- 1.01) while the non-dipped Nguni had the lowest (P < 0.05) dressing percentage (50.3 +/- 0.84). The current study has shown that while the non-dipped steers had higher (P < 0.05) tick loads than the dipped steers, their growth and carcass characteristics were similar (P > 0.05). The study has also shown that, despite being a small-framed breed, the Nguni steers had similar (P > 0.05) ADG to the large-framed Bonsmara and Angus steers. Therefore, the Nguni cattle have the potential to produce organic beef. However, a reasonable assessment of organic beef production potential of the Nguni requires an evaluation of its meat quality traits under natural pasture. PMID- 22445025 TI - Effect of caponisation on growth and on carcass and meat characteristics in Castellana Negra native Spanish chickens. AB - This paper analyses the effect of caponisation at 8 weeks on growth and on carcass and meat characteristics of Castellana Negra chickens slaughtered at 29 weeks. Caponisation did not result in weight improvements as compared with uncastrated birds. No changes were observed in the growth rate or in the parameters determining the point of inflection in the growth curve (sexual maturity). Regarding carcass characteristics, castration resulted in a wider breast angle and heavier pectoral muscles in caponised birds than in uncastrated birds, but with no differences in thigh and drumstick weight and length. Capon meat showed a higher fat content than that of cocks, making it juicier and less fibrous. No differences were found in fatty acid content (C 14:0, C 18:0, C 18:1 and C 18:2). Nor were there any differences in colour measurements, pH or water loss from the meat. While cocks' thighs + drumsticks were found to be tougher than their breasts, there were no such differences in capons because after castration, thigh + drumstick meat became more tender. PMID- 22445026 TI - Dairy ruminant exposure to persistent organic pollutants and excretion to milk. AB - Human activities produce polluting compounds such as persistent organic pollutants (POPs), which may interact with agriculture. These molecules have raised concern about the risk of transfer through the food chain via the animal product. POPs are characterised by a strong persistence in the environment, a high volatility and a lipophilicity, which lead to their accumulation in fat tissues. These compounds are listed in international conventions to organise the information about their potential toxicity for humans and the environment. The aim of this paper is to synthesise current information on dairy ruminant exposure to POPs and the risk of their transfer to milk. Three major groups of POPs have been considered: the polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), the polychlorobiphenyls (PCBs) and the polycyclic aromatic hydrocarbons (PAHs). The results show that contamination of fodder and soil by these compounds is observed when they are exposed to emission sources (steelworks, cementworks, waste incinerators or motorways) compared with remote areas. In general, soil contamination is considered higher than plant contamination. Highest concentrations of POPs in soil may be close to 1000 ng/kg dry matter (DM) for PCDD/Fs, to 10 000 mg/kg DM for PAHs and 100 MUg/kg DM for PCBs. The contamination of milk by POPs depends on environmental factors, factors related to the rearing system (fodder and potentially contaminated soil, stage of lactation, medical state of the herd) and of the characteristics of the contaminants. Transfer rates to milk have been established: for PCBs the rate of transfer varies from 5% to 90%, for PCDD/Fs from 1% to 40% and for PAHs from 0.5% to 8%. The differential transfer of the compounds towards milk is related to the hydrophobicity of the pollutants as well as to the metabolic susceptibility of the compounds. PMID- 22445027 TI - Polymorphisms of POR, SULT2A1 and HSD11B1 in children with premature adrenarche. AB - Premature adrenarche (PA) refers to an earlier than normal increase in adrenocortical androgen production. The pathogenesis of PA remains largely unknown. We hypothesized that common polymorphisms at P450 oxidoreductase (POR), steroid sulfotransferase (SULT2A1), or 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) genes could contribute to the polygenic pathogenesis of PA. We performed a case-control study on the polymorphisms rs1057868 at POR, rs182420 at SULT2A1, and rs12086634 at HSD11B1. The study cohort comprised 73 prepubertal children with PA (defined by clinical signs) and 97 age- and gender-matched healthy controls from a Finnish Caucasian population. Genotype distributions and clinical and metabolic phenotypes were determined. The genotype distributions of the polymorphisms were similar between the study groups. No variant was associated with alterations in serum adrenal steroid concentrations. The minor C variant at SULT2A1 was associated with higher serum sex hormone binding globulin (SHBG) concentrations (T/T, n=64 vs T/C&C/C, n=33; mean 94 vs 116 nmol/L; P=.001) and a trend for lower dehydroepiandrosterone sulfate/dehydroepiandrosterone ratios in the controls (P=.06), and with higher plasma total cholesterol concentrations in the PA subjects (T/T, n=42 vs T/C&C/C, n=31; 4.0 vs 4.6 mmol/L; P<.001). The minor G variant at HSD11B1 was associated with lower plasma triglyceride concentration in the controls (T/T, n=65 vs T/G&G/G, n=32; 0.61 vs 0.49 mmol/L; P=.013). Common polymorphisms at POR, SULT2A1 or HSD11B1 were not associated with PA in a Finnish Caucasian population. PMID- 22445028 TI - Neighborhood deprivation and clinical outcomes among head and neck cancer patients. AB - The unique effects of neighborhood-level economic deprivation on survival, recurrence, and second primary malignancy development were examined using adjusted Cox proportional hazards regression models among 1151 incident squamous cell carcinomas of the head and neck patients. Cancer site was examined as a potential moderator. Main analyses yielded null results; however, interaction analyses indicated poorer overall survival [HR=1.59 (1.00-2.53)] and greater second primary malignancy development [HR=2.99 (1.46-6.11)] among oropharyngeal cancer patients from highly deprived neighborhoods relative to less deprived neighborhoods. Results suggest a dual focus on individual and neighborhood risk factors could help improve clinical outcomes among oropharyngeal cancer patients. PMID- 22445029 TI - Tornado hazard communication disparities among Spanish-speaking individuals in an English-speaking community. AB - BACKGROUND: The state of Oklahoma, known for destructive tornados, has a native Spanish-speaking (NSS) population of approximately 180,241, of which 50% report being able to speak English "very well" (US Census Bureau). With almost 50% of these native Spanish-speaking persons being limited English proficient (LEP), their reception of tornado hazard communications may be restricted. This study conducted in northeast Oklahoma (USA) evaluates the association between native language and receiving tornado hazard communications. METHODS: This study was a cross-sectional survey conducted among a convenience sample of NSS and native English-speaking (NES) adults at Xavier Clinic and St. Francis Trauma Emergency Center in Tulsa, OK, USA from September 2009 through December 2009. Of the 82 surveys administered, 80 were returned, with 40 NES and 40 NSS participants. A scoring system (Severe Weather Information Reception (SWIR)) was developed to quantify reception of hazard information among the study participants (1-3 points=poor reception, 4-5=adequate reception, 6-8=excellent reception). Pearson's chi-squared test was used to calculate differences between groups with Yates' continuity correction applied where appropriate, and SWIR scores were analyzed using ANOVA. P-values<.05 were considered significant. RESULTS: NSS fluency in English was 25.6%. No significant association was found between native language and those who watch television, listen to radio, have a National Oceanic and Atmospheric Administration (NOAA) All Hazards radio or telephone, or are in audible range of a tornado siren. NSS were less likely to have Internet access (P<.004), and less likely to know of local telephone warning programs (P<.03). The mean NSS SWIR score was 3.2 (95% CI, 2.8-3.7) while LEP NSS averaged 2.8 (95% CI, 2.4-3.2). The mean NES SWIR score was 4.5 (95% CI, 4.1-5.0). CONCLUSION: Results demonstrate a disparity in tornado warning reception between NSS and NES. Poor English proficiency was noted to be 75% among NSS, which is approximately 25% more than estimated by the US Census Bureau. This study demonstrates a need for emergency managers to recognize when appropriate and overcome communication disparities among limited English proficient populations. PMID- 22445030 TI - Ultrasound-guided insertion of intramuscular electrodes into suboccipital muscles in the non-human primate. AB - The head-neck system is highly complex from a biomechanical and musculoskeletal perspective. Currently, the options for recording the recruitment of deep neck muscles in experimental animals are limited to chronic approaches requiring permanent implantation of electromyographic electrodes. Here, we describe a method for targeting deep muscles of the dorsal neck in non-human primates with intramuscular electrodes that are inserted acutely. Electrode insertion is guided by ultrasonography, which is necessary to ensure placement of the electrode in the target muscle. To confirm electrode placement, we delivered threshold electrical stimulation through the intramuscular electrode and visualized the muscle twitch. In one animal, we also compared recordings obtained from acutely- and chronically-implanted electrodes. This method increases the options for accessing deep neck muscles, and hence could be used in experiments for which the invasive surgery inherent to a chronic implant is not appropriate. This method could also be extended to the injection of pharmacological agents or anatomical tracers into specific neck muscles. PMID- 22445031 TI - Performance contracting and quality improvement in outpatient treatment: effects on waiting time and length of stay. AB - We evaluate the effects of a performance contract (PC) implemented in Delaware in 2001 and participation in quality improvement (QI) programs on waiting time for treatment and length of stay (LOS) using client treatment episode level data from Delaware (n = 12,368) and Maryland (n = 147,151) for 1998-2006. Results of difference-in-difference analyses indicate that waiting time declined 13 days following the PC, after controlling for client characteristics and historical trends. Participation in the PC and a formal QI program was associated with a decrease of 20 days. LOS increased 22 days under the PC and 24 days under the PC and QI programs, after controlling for client characteristics. The PC and QI programs were associated with improvements in LOS and waiting time, although we cannot determine which aspects of the programs (incentives, training, and monitoring) resulted in these changes. PMID- 22445032 TI - Should we treat all haemangiomas with beta-blockers? PMID- 22445033 TI - Genetic and phenotypic parameters of lactations longer than 305 days (extended lactations). AB - Test-day milk yield and somatic cell count data over extended lactation (lactation to 540-600 days) were analysed considering part lactations as different traits and fitting random regression (RR) models. Data on Australian Jersey and Holstein Friesian (HF) were used to demonstrate the shape of the lactation curve and data on HF were used for genetic study. Test-day data from about 100 000 cows that calved between 1998 and 2005 were used for this study. In all analyses, a sire model was used.When part lactations were considered as different traits, protein yield early in the lactation (e.g. first 2 months) had a genetic correlation of about 0.8 with protein yield produced after 300 days of lactation. Genetic correlations between lactation stages that are adjacent to each other were high (0.9 or more) within parity. Across parities, genetic correlations were high for both protein and milk yield if they are within the same stage of lactation. Phenotypic correlations were lower than genetic correlations. Heritability of milk-yield traits estimated from the RR model varied from 0.15 at the beginning of the lactation to as high as 0.37 by the 4th month of lactation. All genetic correlations between different days in milk were positive, with the highest correlations between adjacent days in milk and decreasing correlations with increasing time-span. The pattern of genetic correlations between milk yield in the second 300 days (301 to 600 days of lactation) do not markedly differ from the pattern in the first 300 days of lactation. The lowest estimated genetic correlation was 0.15 between milk yield on days 45 and 525 of lactation. The result from this study shows that progeny of bulls with high estimated breeding values for yield traits and those that produce at a relatively high level in the first few months are the most likely candidates for use in herds favouring extended lactations. PMID- 22445034 TI - Rabbit milk protein genes: from mRNA identification to chromatin structure. AB - Milk protein genes are among the most intensively expressed and they are active only in epithelial mammary cells of lactating animals. They code for proteins which represent 30% of the proteins consumed by humans in developed countries. Mammary gland development occurs essentially during each pregnancy. This offers experimenters attractive models to study the expression mechanisms of genes controlled by known hormones and factors (prolactin, glucocorticoids, progesterone, insulin-like growth factor-1 and others) as well as extracellular matrix. In the mid-1970s, it became possible to identify and quantify mRNAs from higher living organisms using translation in reticulocyte lysate. A few years later, the use of radioactive cDNAs as probes made it possible for the quantification of mRNA in various physiological situations using hybridisation in the liquid phase. Gene cloning offered additional tools to measure milk protein mRNAs and also to identify transcription factors. Gene transfer in cultured mammary cells and in animals contributed greatly to these studies. It is now well established that most if not all genes of higher eukaryotes are under the control of multiple distal regulatory elements and that local modifications of the chromatin structure play an essential role in the mechanisms of differentiation from embryos to adults. The technique, known as ChIP (chromatin immunoprecipitation), is being implemented to identify the factors that modify chromatin structure at the milk protein gene level during embryo development, mammogenesis and lactogenesis, including the action of hormones and extracellular matrix. Transgenesis is not just a tool to study gene regulation and function, it is also currently used for various biotechnological applications including the preparation of pharmaceutical proteins in milk. This implies the design of efficient vectors capable of directing the secretion of recombinant proteins in milk at a high concentration. Milk protein gene promoters and long genomic-DNA fragments containing essentially all the regulatory elements of milk protein genes are used to optimise recombinant protein production in milk. PMID- 22445035 TI - Environmental effects on lactation curves included in a test-day model genetic evaluation. AB - A large number of environmental factors affect the daily milk production of a cow. Lactation curves included in the French test-day model are modelled as a function of days in milk with semi-parametric curves (splines). The proper modelling of environmental effects in the test-day analysis was investigated using test-day records collected from the first three lactations of French Montbeliarde cows from 1988 to 2005. Four lactation-curve effects describing calving month, length of dry period, age at calving and gestation defined within parity-class were fitted. The shape of lactation curves did not depend on year of calving, which can be modelled as a constant over the whole lactation. To reduce computational requirements and time, data were pre-adjusted in a first step for fixed effects with no year interaction, and then used for genetic evaluation. Correlations for each lactation between 305-day estimates of genetic and permanent environment effects computed using pre-adjustment factors obtained at a 4-year interval were virtually one. The use of a two-step procedure had a very limited impact on the estimates of genetic and permanent environment effects. The minimum correlations with values estimated with a one-step procedure were 0.9984 and 0.9974, respectively. The knowledge of systematic environmental effects affecting the cow daily yield through lactation curves offers interesting perspectives to predict future daily milk production. PMID- 22445036 TI - Estimates of (co)variance components due to direct and maternal effects for body weights in Jamunapari goats. AB - Estimates of (co)variance components were obtained for weights at birth, weaning and at 6, 9 and 12 months of age in Jamunapari goats maintained at the Central Institute for Research on Goats, Makhdoom, Mathura, India, over a period of 23 years (1982 to 2004). Records of 4301 kids descended from 204 sires and 1233 does were used in the study. Analyses were carried out by restricted maximum likelihood (REML), fitting an animal model and ignoring or including maternal genetic or permanent environmental effects. Six different animal models were fitted for all traits. The best model was chosen after testing the improvement of the log-likelihood values. Direct heritability estimates were inflated substantially for all traits when maternal effects were ignored. Heritability estimates for weights at birth, weaning and at 6, 9 and 12 months of age were 0.12, 0.18, 0.13, 0.17 and 0.21, respectively. Maternal heritability of body weight declined from 0.19 at birth to 0.08 at weaning and was near zero and not significant thereafter. Estimates of the fraction of variance due to maternal permanent environmental effects were 0.09, 0.13 and 0.10 for body weights at weaning, 6 months and 9 months of age, respectively. Results suggest that maternal additive effects were important only in the early stages of growth, whereas a permanent environmental maternal effect existed from weaning to 9 months of age. These results indicate that modest rates of genetic progress appear possible for all weights. PMID- 22445037 TI - Genetic analysis of insect bite hypersensitivity (summer eczema) in Icelandic horses. AB - There is a lack of knowledge about the genetic background of eczema due to insect bite hypersensitivity, also called summer eczema, in horses. The condition is known in several horse breeds and countries and it causes reduced welfare of the horse and economic losses to the owner. The aim of this study was to estimate genetic parameters for summer eczema in Swedish-born Icelandic horses. A questionnaire was sent to owners of horses sired by stallions with more than 50 offspring born in Sweden between 1991 and 2001. Variance components of summer eczema classified as healthy, mild, moderate or severe were estimated using the threshold methodology with sire models. In addition, summer eczema was analysed as a binary trait (healthy v. affected). The analyses included 1250 horses sired by 33 stallions. The prevalence of summer eczema was 8%, with a range of 0% to 30% in different paternal half-sib groups. Offspring of dams suffering from eczema had a higher risk of developing eczema. The heritability for severity of summer eczema was estimated at 0.3 (s.d. < 0.2) with a threshold sire model. In contrast to the age of the horse, different geographic areas and gender were significantly associated with severity of the eczema. We conclude that genetic selection could decrease the prevalence of summer eczema among Swedish-born Icelandic horses. The amount and quality of data are, however, crucial for the possibility to introduce a genetic evaluation of summer eczema. The symptoms should be classified in several classes according to severity, and this classification could be made by the horse owner. PMID- 22445038 TI - Effects of a charcoal powder-wood vinegar compound solution in piglets for raw pigeon pea seed meal. AB - Histological intestinal villus alterations were studied in piglets fed a raw pigeon pea meal (PM) diet including a powder mixture of amorphous charcoal carbon and wood vinegar compound solution (CWVC). Twenty-eight male castrated piglets were divided into seven dietary groups of four piglets each. The control group was fed raw PM supplemented to the basal diet (178 g/kg crude protein, 4.23 kcal/g gross energy) at 0 g/kg (CONT), 200 g/kg (PM200) and 400 g/kg (PM400). The treatment groups were fed CWVC in both PM200 and PM400 diet groups at levels of 10 g/kg and 30 g/kg (PM200 + CWVC10, PM200 + CWVC30, PM400 + CWVC10 and PM400 + CWVC30). With increasing dietary PM levels, daily feed intake tended to increase. In contrast, daily body-weight gain tended to decrease, significantly in the PM400 group (P < 0.05), resulting in a significant decrease of feed efficiency in PM groups (P < 0.05). Body-weight gain and feed efficiency were higher in the CWVC groups compared with the PM groups. The duodenum and ileum were longer (P < 0.05) in the PM400 group than in CONT, but were similar to CONT in CWVC groups. The liver was heavier (P < 0.05), whereas the weights of the heart, kidney and stomach were decreased in the CWVC groups than in other groups. Most values for the intestinal villus height, cell area and cell mitosis number were lower in PM groups than those in CONT (P < 0.05) for each intestinal segment; however, these values were higher in CWVC groups than in PM groups (P < 0.05). The epithelial cells on the duodenal villus surface of the PM200 group showed cell morphology almost similar to CONT. However, the PM400 group had a smooth villus surface due to the presence of flat cells. The epithelial cells of the CWVC groups were protuberated, resulting in a much rougher surface than CONT. The current growth performance and histological intestinal alterations in piglets fed PM and PM + CWVC diets demonstrate that the intestinal features might be atrophied by feeding PM, resulting in decreased growth performance. CWVC might prevent the harmful effects of PM dietary toxins on intestinal function, resulting in a normal growth performance. PMID- 22445039 TI - Selenium persistency and speciation in the tissues of lambs following the withdrawal of dietary high-dose selenium-enriched yeast. AB - The objective was to determine the concentration of total selenium (Se) and the proportion of total Se comprised as selenomethionine (SeMet) and selenocysteine (SeCys) in post mortem tissues of lambs in the 6 weeks period following the withdrawal of a diet containing high-dose selenised yeast (HSY), derived from a specific strain of Saccharomyces cerevisae CNCM (Collection Nationale de Culture de Micro-organism) I-3060. Thirty Texel * Suffolk lambs used in this study had previously received diets (91 days) containing either HSY (6.30 mg Se per kg dry matter (DM)) or an unsupplemented control (C; 0.13 mg Se per kg DM). Following the period of supplementation, all lambs were then offered a complete pelleted diet, without additional Se (0.15 mg Se per kg DM), for 42 days. At enrolment and 21 and 42 days later, five lambs from each treatment were blood sampled, euthanased and samples of heart, liver, kidney and skeletal muscle (longissimus dorsi and psoas major) tissue were retained. Total Se concentration in whole blood and tissues was significantly (P < 0.001) higher in HSY lambs at all time points that had previously received long-term exposure to high dietary concentrations of SY. The distribution of total Se and the proportions of total Se comprised as SeMet and SeCys differed between tissues, treatment and time points. Total Se was greatest in HSY liver and kidney (22.64 and 18.96 mg Se per kg DM, respectively) and SeCys comprised the greatest proportion of total Se. Conversely, cardiac and skeletal muscle (longissimus dorsi and psoas major) tissues had lower total Se concentration (10.80, 7.02 and 7.82 mg Se per kg DM, respectively) and SeMet was the predominant selenised amino acid. Rates of Se clearance in HSY liver (307 MUg Se per day) and kidney (238 MUg Se per day) were higher compared with HSY cardiac tissue (120 MUg Se per day) and skeletal muscle (20 MUg Se per day). In conclusion, differences in Se clearance rates were different between tissue types, reflecting the relative metabolic activity of each tissue, and appear to be dependent on the proportions of total Se comprised as either SeMet or SeCys. PMID- 22445040 TI - Influence of tannic acid application on alfalfa hay: in vitro rumen fermentation, serum metabolites and nitrogen balance in sheep. AB - Alfalfa protein is poorly utilised by ruminants due to its rapid degradation in rumen. The objective of the study was to assess the influence of spraying tannic acid (TA) on chopped alfalfa hay on in vitro rumen fermentation and nitrogen (N) retention by sheep. Alfalfa hay with and without TA was fed to sheep to determine nutrient digestibility and N balance. TA was sprayed on chopped alfalfa at three concentrations to determine its effect on in vitro fermentation of dry matter (DM) and N balance in sheep. Final TA concentrations were 0, 30, 60 and 90 g TA per kg DM. The control was sprayed with the same amount of water but without TA. In vitro DM degradation and the production of gas, ammonium-N (NH4-N) and short chain fatty acid (SCFA) were measured. TA-sprayed alfalfa and the control were fed to sheep to determine nutrient digestibility and N retention. Addition of TA had no influence on the extent and rate of gas production but significantly decreased NH4-N concentration at 30 (P < 0.05), 60 and 90 (P < 0.0001) g/kg DM. Addition of polyethylene glycol (PEG) to TA-sprayed alfalfa increased NH4-N to a level comparable to non-TA-sprayed alfalfa. Spraying of alfalfa with TA significantly decreased (P < 0.05) isovalerate but did not affect the total and individual SCFA acid production. Tannic acid significantly (P < 0.05) reduced in vitro true degradability of DM (IVTD) after 24 h incubation at levels of 60 and 90 g TA per kg DM. Neutral-detergent fibre digestibility (dNDF) after 24 h (P < 0.01), 60 and 90 (P < 0.0001) g TA per kg DM. The effect of TA on either IVTD or dNDF was not significant (P > 0.05) after 48 h of incubation. There was a strong linear relationship between percentage increase in gas production due to PEG and protein precipitation capacity (R2 = 0.94). N digestibility was significantly reduced with all three levels of TA additions. However, the proportion of urine-N to total N output was reduced by adding 60 g (P < 0.05) and 90 g (P < 0.01) TA per kg DM. Serum metabolites and liver enzymes were not affected by TA (P > 0.05). Higher faecal N as the TA level increased indicates incomplete dissociation of tannin-protein complexes post ruminally. Factors affecting dissociation of tannin-protein complexes need further study. PMID- 22445041 TI - DGGE and 16S rDNA analysis reveals a highly diverse and rapidly colonising bacterial community on different substrates in the rumen of goats. AB - In the rumen, plant particles are colonised and degraded by the rumen micro organisms. Although numerous important findings about fibre-associated bacterial community were obtained using traditional or molecular techniques, little information is available on the dynamics of bacteria associated with feed particles during incubation in the rumen. In the present study, ryegrass leaf, ryegrass stem and rice straw, representing different carbohydrate compositions, were used as substrates and placed in the rumen of goats by using nylon bags, and PCR/DGGE (denaturing gradient gel electrophoresis) with subsequent sequence analysis were used to monitor the dynamics of and identify bacteria associated with the substrates during 24 h of incubation. DGGE results showed that substrate samples collected from 10 min to 6 h had similar DGGE patterns, with up to 24 predominant bands to each sample, including 14 common bands to all samples, suggesting a rapid and stable colonisation by a highly diverse bacterial community. Substrate samples collected at 12 and 24 h showed similar DGGE patterns but had great difference in DGGE patterns from those collected at 10 min to 6 h, suggesting an apparent shift in bacterial community. Sequence analysis indicated that most substrate-associated bacteria were closely related to fibrolytic bacteria. In conclusion, a highly diverse and similar rumen bacterial community could immediately colonise to different substrates and remained stable during the initial 6 h of incubation, but experienced a marked change after 12 h of incubation. Italian ryegrass leaf, Italian ryegrass stem and rice straw were colonised with a similar bacterial community. PMID- 22445042 TI - Effect of exogenous melatonin on the ovary, the embryo and the establishment of pregnancy in sheep. AB - Administration of melatonin to advance the breeding season in sheep has been widely used, since this hormone conveys the photoperiodic signal to the reproductive neuroendocrine axis. An increased lambing percentage has been reported following such treatment during anoestrus, which could be mediated through a higher rate of embryonic survival, either by an improvement in luteal function or by a reduction in the antiluteolytic mechanisms. The aim of this article is to review the body of knowledge on the effect of melatonin on the ovine ovary, the embryo and the establishment of pregnancy. Some studies using synchronized ewes have found that melatonin treatments during anoestrus do not improve ovulation rate by modifying the timing of follicle emergence, but increasing the number of ovulatory follicles by decreasing the atresia of medium and large follicles. On the other hand, the addition of melatonin to the in vitro maturation medium does not improve oocyte maturation rate in oocytes from sheep ovaries recovered either in anoestrus or in the breeding season. However, a luteotrophic effect of melatonin at either short or medium term has been reported. We have recently observed that melatonin implants tend to improve the survival of embryos collected from ewes after superovulation in anoestrus. More specifically, melatonin induced a significant reduction of the number and rate of non-viable (degenerate and retarded) embryos. Preliminary data from our laboratory suggest that the uterine sensitivity to progesterone - in terms of progesterone receptor expression - of superovulated ewes could be reduced by melatonin treatment. It can be concluded that the success of exogenous melatonin as a means to improve lamb production of sheep is due, at least in part, to an improvement of luteal support and embryonic survival. PMID- 22445043 TI - Effects of weight, temperature and behaviour on the circadian rhythm of salivary cortisol in growing pigs. AB - In farm animals, salivary cortisol has become a widely used parameter for measuring stress responses. However, only few studies have dealt with basal levels of concentration of cortisol in pigs and its circadian rhythm. The aim of this study was to examine the effects of ambient temperature and thermoregulatory behaviour on the circadian rhythm of salivary cortisol levels in fattening pigs. Subjects were 30 fattening pigs of different weight (60 to 100 kg), kept in six groups in an uninsulated building in pens with partly slatted floors. Saliva samples were taken every 2 h over periods of 24 h at different ambient temperatures at two times in winter and four times in summer. Thermoregulatory behaviour was recorded in the same 24-h time periods. The effect of time of day, body weight, ambient temperature and behaviour on the cortisol level was analysed using a mixed-effects model. Two peaks of cortisol levels per day were found. This circadian pattern became more pronounced with increasing weight and on days where thermoregulatory behaviour was shown. Mean cortisol levels per day were affected by weight but not by thermoregulatory behaviour. From our data, we conclude that long-term variations in cortisol concentration may be influenced by increasing age and weight more than by the respective experimental situation. In assessing animal welfare, it seems more reliable to consider the circadian pattern of cortisol concentration instead of only one value per day. PMID- 22445044 TI - Exploitation of a natural pasture by wild horses: comparison between nutritive characteristics of the land and the nutrient requirements of the herds over a 2 year period. AB - In the Molise region (Italy), some autochthonous populations are still bred and, between them, some wild horses named 'Pentro horses.' The breeding area is a natural pasture. It is 2200 ha extended including a broad plane surrounded by wooden hills. The aim of this research was to determine the nutritional characteristics of this area over a 2-year period to improve the management of the herd and to define the stocking rate in relation to the forage production in terms of production and quality. The forage samples were collected over two successive years during the grazing period (May to October) from five experimental areas and analysed for dry matter (DM), organic matter (OM), crude protein (CP), crude fibre (CF), neutral-detergent fibre (NDF), acid-detergent fibre (ADF), acid-detergent lignin (ADL) and gross energy (GE). Horse feed units (HFU) and horse-digestible crude protein (HDCP) were also predicted. Data were analysed with a one-way ANOVA test using month and area as factors. The DM, HFU and HDCP total production was determined to be compared with the total nutrient requirements of the herds from May to October. The results show that seasonal and yearly climatic variations significantly affect chemical composition and nutritive value of the pasture. The parameters most influenced were DM, CP, ADF and to a less extent NDF, while OM, ADL and GE show smaller differences during the observed period. The results show a low production per ha; nevertheless, because of the low stocking rate (0.3 to 0.6 head per ha), nutrient production meets the nutrient requirements of the horses regarding DM and energy. The differences among the areas have to be ascribed to the different botanical compositions and to the different draining capacity of the soil, and also in this case the greatest variations are for DM, CP and ADF. PMID- 22445045 TI - Canonical discriminant analysis applied to broiler chicken performance. AB - The mechanisms involved in the control of growth in chickens are too complex to be explained only under univariate analysis because all related traits are biologically correlated. Therefore, we evaluated broiler chicken performance under a multivariate approach, using the canonical discriminant analysis. A total of 1920 chicks from eight treatments, defined as the combination of four broiler chicken strains (Arbor Acres, AgRoss 308, Cobb 500 and RX) from both sexes, were housed in 48 pens. Average feed intake, average live weight, feed conversion and carcass, breast and leg weights were obtained for days 1 to 42. Canonical discriminant analysis was implemented by SAS(r) CANDISC procedure and differences between treatments were obtained by the F-test (P < 0.05) over the squared Mahalanobis' distances. Multivariate performance from all treatments could be easily visualised because one graph was obtained from two first canonical variables, which explained 96.49% of total variation, using a SAS(r) CONELIP macro. A clear distinction between sexes was found, where males were better than females. Also between strains, Arbor Acres, AgRoss 308 and Cobb 500 (commercial) were better than RX (experimental). Evaluation of broiler chicken performance was facilitated by the fact that the six original traits were reduced to only two canonical variables. Average live weight and carcass weight (first canonical variable) were the most important traits to discriminate treatments. The contrast between average feed intake and average live weight plus feed conversion (second canonical variable) were used to classify them. We suggest analysing performance data sets using canonical discriminant analysis. PMID- 22445046 TI - Effect of crude protein concentration and sugar-beet pulp on nutrient digestibility, nitrogen excretion, intestinal fermentation and manure ammonia and odour emissions from finisher pigs. AB - A 2 * 2 factorial experiment was conducted to investigate the interaction between high and low dietary crude protein (CP) (200 v. 150 g/kg) and sugar-beet pulp (SBP) (200 v. 0 g/kg) on nutrient digestibility, nitrogen (N) excretion, intestinal fermentation and manure ammonia and odour emissions from 24 boars (n = 6, 74.0 kg live weight). The diets were formulated to contain similar concentrations of digestible energy (13.6 MJ/kg) and lysine (10.0 g/kg). Pigs offered SBP-containing diets had a reduced (P < 0.05) digestibility of dry matter, ash, N, gross energy and an increased (P < 0.001) digestibility of neutral-detergent fibre compared with pigs offered diets containing no SBP. There was an interaction between CP and SBP on urinary N excretion and the urine : faeces N ratio. Pigs offered the 200 g/kg CP SBP-based diet had reduced urine : faeces N ratio (P < 0.05) and urinary N excretion (P < 0.05) compared with those offered the 200 g/kg CP diet without SBP. However, there was no effect of SBP in pigs offered 150 g/kg CP diets. Manure ammonia emissions were reduced by 33% from 0 to 240 h (P < 0.01); however, odour emissions were increased by 41% (P < 0.05) when pigs were offered SBP diets. Decreasing dietary CP to 150 g/kg reduced total N excretion (P < 0.001) and ammonia emissions from 0 to 240 h (P < 0.05). There was an interaction between dietary CP and SBP on branched-chain fatty acids (P < 0.001) in caecal digesta. Pigs offered the 200 g/kg CP SBP-containing diet reduced branched-chain fatty acids in the caecum compared with pigs offered the 200 g/kg CP diet containing no SBP. However, there was no effect of SBP in the 150 g/kg CP diet. In conclusion, pigs offered SBP-containing diets had a reduced manure ammonia emissions and increased odour emissions compared with diets containing no SBP. Pigs offered the 200 g/kg CP SBP-containing diet had a reduced urine : faeces N ratio and urinary N excretion compared with those offered the 200 g/kg CP diet containing no SBP. PMID- 22445047 TI - Qualification and assessment of work organisation in livestock farms. AB - Farmers have to cope with both society and market pressures in their working practices, as well as with the enlargement of farms, off-farm opportunities and profound changes in the workforce. Expectations in terms of working duration and rhythms are increasingly expressed by farmers, meaning that working conditions and the efficiency of work organisation are critical issues nowadays. The bibliography shows that work organisation is mainly discussed by social scientists, but that livestock scientists make a significant contribution to the debate. Indeed, technical changes modify working calendars, priorities between tasks and interchangeability among workers; technical adaptations are levers to solving problems of work with equipment, buildings and the workforce. We present here French approaches to work organisation that take into account livestock management and its implications in work organisation. The 'Work Assessment' method represents the work organisation and evaluates work durations and time flexibility for farmers. The ATELAGE model describes and qualifies work organisation with its various regulations and time scales, integrating the other activities - economic or private - that farmers can carry on. Three principles underpin them: not all workers are interchangeable; tasks have different temporal characteristics (rhythms, postponement, etc.); and the year is a succession of work periods that differ in their daily form of organisation. We illustrate with concrete examples how these approaches contribute to helping and guiding farmers in their thoughts about change. PMID- 22445048 TI - Multivariate study of different beef quality traits from local Spanish cattle breeds. AB - Different raw beef quality traits from four local Spanish cattle breeds were studied using correlation, factorial, discriminant and multiple regression analysis. The following variables were studied after 0, 5, 10 and 15 days of storage under 60% O2, 30% CO2 and 10% N2 modified atmosphere packaging (MAP): colour physical variables, meat pigments, sensory degradation of odour and colour, microbial counts, thiobarbituric acid (TBA), pH, drip loss, lipid composition and volatile compounds. The degradation of raw beef quality was related to the increase in 2,3,3-trimethylpentane, 2,2,5-trimethylhexane, 3 methyl-2-heptene, 2-octene, 3-octene, 2-propanone, Enterobacteriaceae and aerobial plate counts (APC), metmyoglobin (MMb), lightness (L*), yellowness (b*), drip loss and TBA. Among these variables, TBA, b* and MMb may be useful in evaluating raw beef quality. No variables related to fat, except for TBA, including pH were limiting factors of the colour and odour shelf-life of raw beef under MAP. Each breed had some characteristics that were unique and these differences may influence the stability of meat to oxidation depending on myoglobin concentration and the polyunsaturated fatty acid (PUFA)/saturated fatty acid (SFA) ratio. PMID- 22445049 TI - Effects of deep-bedded finishing system on market pig performance, composition and pork quality. AB - The purpose of this study was to compare effects of finishing environment on growth performance, pork quality and lipid composition of pork. Environments compared were standard confinement (CON) and deep-bedded semi-outdoor systems. The deep-bedded method employed in the current study was the use of hoop structures. Hoops are large, tent-like shelters with cornstalks or straw for bedding. Gilts ranging in weight from 59 to 71 kg were randomly assigned to treatments of Hoop (n = 50) and CON (n = 18) environments. Gilts were fed a two phase dietary sequence, ad libitum for 45 days. Six gilts per treatment were selected for carcass composition and quality evaluation. The experiment was replicated a total of five times. Pigs raised in the Hoop environment gained significantly less and required significantly more feed for growth than pigs raised in the CON environment. Carcasses from CON-finished pigs were significantly fatter at the 10th rib, which lowered carcass percentage fat-free lean(FFL) and they also had greater loin marbling scores compared with carcasses from Hoop-finished pigs (P < 0.05). Significant replication effects were noted on beginning weight, live weight, carcass weight, percentage FFL, backfat, lipid content and adipose firmness. Carcasses from Hoop pigs had lower proportions of palmitic acid (P < 0.05), and higher proportions of oleic and linoleic acid (P < 0.05) in the inner layer of adipose tissue. The proportion of saturated fatty acid was lower, and that of mono- and poly-unsaturated fatty acid was higher in the inner layer of the adipose tissue of Hoop pigs. Variations in fatty acid composition and lipid deposition may have been caused by environmental temperature, since decreases in environmental temperature accompanied compositional variation of the adipose, leading to higher proportions of monounsaturated fatty acid and lower proportions of saturated and polyunsaturated fatty acid in adipose tissue, regardless of treatment. Volatile profile analysis revealed that adipose tissue of Hoop pigs had significantly higher amounts of 3 butanal and heptanal compared with CON pigs, which may be related to the amount of oleic and linoleic acids composing the adipose tissue. These data indicate finishing pigs in hoop structures allows for exposure to fluctuating temperatures, which may influence the growth of pigs, as well as fatty acid composition and firmness of pork products. PMID- 22445050 TI - Effects of space allocation within a deep-bedded finishing system on pig growth performance, fatty acid composition and pork quality. AB - The objectives of the current study were to determine the degree to which space allocation in a deep-bedded system influences swine performance and pork quality. The deep-bedded method employed was hoop structures, which are large, tent-like shelters with cornstalks or straw for bedding. One hundred gilts ranging in weight from 59 to 71 kg were randomly assigned to treatments of low (0.70 m2 per pig, n = 50) or high (1.13 m2 per pig, n = 50) space allocation. During the 45 day experimental period, gilts were ad libitum fed a two-phase diet. Six gilts per treatment were used for carcass composition and pork quality evaluation for each replication. Five replications were conducted over a period of 4 months. Pigs finished with greater space allocation had smaller longissimus muscle area and produced pork that appeared to be darker. Variations in fatty acid composition and lipid percentage of subcutaneous adipose and longissimus dorsi muscle were observed when space allocation was changed within hoop structures. Less space resulted in greater proportion of lipid present as polyunsaturated fatty acids. Greater space allocation resulted in lower total lipid in subcutaneous pork adipose tissue. Space allocation did not affect fat firmness. Replications spanned the months of August to November, with temperatures ranging from 32 degrees C to -2 degrees C within the hoop structure. As environmental temperature declined, the proportion of monounsaturated fatty acids increased. Providing more space during finishing in these systems had only a small affect on pig growth and pork quality. Variations observed from replication to replication at fluctuating temperatures provide insight to seasonal differences in growth and adipose tissue composition and firmness. Therefore, finishing pigs in these systems may lead to seasonal variation in lipid composition. PMID- 22445051 TI - The effect of ingesting a saltbush and barley ration on the carcass and eating quality of sheepmeat. AB - Forage halophytes such as saltbush (Atriplex spp.) are widely used to revegetate Australian saline land and can provide a medium-quality fodder source. An animal house experiment was conducted to investigate differences in the carcass and eating quality of sheep ingesting saltbush from saline land in combination with a barley supplement. Twenty-six merino hoggets (two groups of 13) were fed either a 60 : 40 dried saltbush (Atriplex nummularia): barley (S + B) ration or a 33 : 25 : 42 lupins : barley : oaten hay ration (C) for 10 weeks prior to commercial slaughter. After 10 weeks, all sheep were commercially slaughtered and a single loin (from 12th rib to chump) collected from each animal for taste-panel analysis. Carcass weight, total tissue depth over the 12th rib 110 mm from the midline (GR fat depth), ultimate pH and colour were determined and X-ray bone densitometry used to estimate the fat content of the carcass. Blood samples were taken to assess the hormonal response to ingesting these diets and fatty acid profiles of the subcutaneous and intramuscular fat were determined. Both groups grew at the same rate (62 g/day) and had similar hot carcass weights (P > 0.01) (17.2 +/- 0.3 kg for S + B and 17.9 +/- 0.3 kg for C). However, these live weights may not be high enough to be commercially viable such that saltbush and barley may only be suitable as a maintenance feed. The S + B-fed sheep had a significantly (P = 0.055) lower fat and higher lean content (P < 0.05) than the C group. This is a positive finding as fat denudation is a significant cost to processors and farmers can produce sheep that are depositing less fat or more lean per unit of live-weight gain. The decreased fat and increased lean content were attributed to the higher protein : energy ratio available for production and lower circulating insulin and higher growth hormone of the S + B-fed sheep. The lower body-fat content and lower metabolisable energy and digestible organic matter intake did correlate with the sheep fed the S + B diet, having a significantly lower percentage of unsaturated fat and equal levels of saturated fat than the C treatment. Diet had no effect on the ultimate pH or colour of the meat. Treatment had no significant effect on any of the eating-quality attributes (P > 0.1). The drying of the saltbush, the shorter length of the experimental period and the low carcass fat content were believed to have contributed to this result. Further field experiments are needed to clarify the benefits to carcass and eating quality of ingesting saltbush. PMID- 22445052 TI - Can a within/between-session change in pain during reassessment predict outcome using a manual therapy intervention in patients with mechanical low back pain? AB - The purposes of the study were to determine whether the combined occurrence of within/between-session changes were significantly associated with functional outcomes, pain, and self-report of recovery in patients at discharge who were treated with manual therapy for low back pain. A secondary purpose was to determine the extent of change needed for the within/between-session change with association to function. The study involved 100 subjects who were part of a randomized controlled trial that examined manual therapy techniques who demonstrated a positive response to manual therapy during the initial assessment. Within- and between-session findings (within/between session) were defined as a change in pain report from baseline to after the second physiotherapy visit. Within/between-session changes were analyzed for associations between pain change scores at discharge, rate of recovery, and a 50% reduction of the Oswestry disability index (ODI) by discharge. The results suggest there is a significant association between a within/between-session change after the second physiotherapy visit and discharge outcomes for pain and ODI in this sample of patients who received a manual therapy intervention. A 2-point change or greater on an 11-point scale is associated with functional recovery at discharge and accurately described the outcome in 67% of the cases. This is the first study that has shown an association of within/between-session changes with disability scores at discharge and is the first to define the extent of change necessary for prognosis of an outcome. A within/between-session change should be considered as a complimentary artifact along with other examination findings during clinical decision making. PMID- 22445053 TI - Metabolic disorders following kidney transplantation. AB - Kidney transplantation in patients suffering from end-stage renal disease, although beneficial, may result in potential complications increasing cardiovascular risk of mortality. Common metabolic problems after surgery are weight gain, hypertension, hyperlipidemia, and insulin resistance. Immunosuppressant therapy can enhance comorbidity progression. Early identification and treatment of these abnormalities can promote transplant function. Lifestyle modifications have shown to be promising in the reduction of the metabolic syndrome symptoms, but there remain limited trials focusing on this area. This article reflects a comprehensive review of the available research of each of the potential metabolic complications within the renal transplant population. Immunosuppressant medication effects, biochemical values, and medical nutrition therapy intervention are also included with regard to their influence with these metabolic disorders. Methods for review completion included a MEDLINE search for peer-reviewed research, using the following keywords: transplant, chronic kidney disease, nutrition, metabolic syndrome, and diet after transplantation. PMID- 22445054 TI - Vitamin B6 and the immunity in kidney transplant recipients. AB - OBJECTIVE: The study aimed to determine vitamin B6 status in elderly (age >= 60 years) and younger (age <60 years) recipients of allogeneic kidney graft and to investigate associations between vitamin B6 status and immunity markers. DESIGN: A retrospective observational study. SETTING: The study was conducted at the Medical University of Gdansk, Poland. SUBJECTS: We recruited 34 kidney allograft recipients (17 males and 17 females) and allocated them into 2 groups: patients aged >= 60 years (18 patients) and those aged <60 years (16 patients). Exclusion criteria included patients receiving vitamin B6 supplementation or drugs known to influence vitamin B6 metabolism. MAIN OUTCOME MEASURE: Plasma levels of pyridoxal 5'-phosphate (PLP), pyridoxal, pyridoxine, pyridoxamine, pyridoxamine 5' phosphate, and 4 pyridoxic acid were determined by high-performance liquid chromatography. Measured immunity markers were serum cytokines (interleukin-6, interleukin-10, and transforming growth factor-beta), levels of T-lymphocyte subsets, and the proliferative ability of peripheral blood mononuclear cells. RESULTS: Concentrations of all vitamin B6 vitamers in plasma (PLP, pyridoxal, pyridoxamine 5'-phosphate, pyridoxamine, pyridoxine, 4 pyridoxic acid) were comparable in the 2 studied groups. There were no cases of PLP deficiency in the study population, but 29% of patients had PLP concentrations more than the upper reference limit. Vitamin B6 vitamer concentrations were not influenced by gender, estimated glomerular filtration rate, and circulating phosphate concentration. There was no difference in immunity markers according to age. However, the plasma concentrations of vitamin B6 vitamers were inversely associated with levels of CD28(+) lymphocyte subsets, as well as with the proliferative response of peripheral blood mononuclear cells in both groups. CONCLUSIONS: No cases of vitamin B6 deficiency were found among kidney allograft recipients, and we report inverse links between vitamin B6 vitamer concentrations and markers of cellular immunity, suggesting that bioactive vitamin B6 concentration in kidney allograft recipients merits further investigation. PMID- 22445055 TI - Protection against cold in prehospital care: evaporative heat loss reduction by wet clothing removal or the addition of a vapor barrier--a thermal manikin study. AB - INTRODUCTION: In the prehospital care of a cold and wet person, early application of adequate insulation is of utmost importance to reduce cold stress, limit body core cooling, and prevent deterioration of the patient's condition. Most prehospital guidelines on protection against cold recommend the removal of wet clothing prior to insulation, and some also recommend the use of a waterproof vapor barrier to reduce evaporative heat loss. However, there is little scientific evidence of the effectiveness of these measures. OBJECTIVE: Using a thermal manikin with wet clothing, this study was conducted to determine the effect of wet clothing removal or the addition of a vapor barrier on thermal insulation and evaporative heat loss using different amounts of insulation in both warm and cold ambient conditions. METHODS: A thermal manikin dressed in wet clothing was set up in accordance with the European Standard for assessing requirements of sleeping bags, modified for wet heat loss determination, and the climatic chamber was set to -15 degrees Celsius ( degrees C) for cold conditions and +10 degrees C for warm conditions. Three different insulation ensembles, one, two or seven woollen blankets, were chosen to provide different levels of insulation. Five different test conditions were evaluated for all three levels of insulation ensembles: (1) dry underwear; (2) dry underwear with a vapor barrier; (3) wet underwear; (4) wet underwear with a vapor barrier; and (5) no underwear. Dry and wet heat loss and thermal resistance were determined from continuous monitoring of ambient air temperature, manikin surface temperature, heat flux and evaporative mass loss rate. RESULTS: Independent of insulation thickness or ambient temperature, the removal of wet clothing or the addition of a vapor barrier resulted in a reduction in total heat loss of 19-42%. The absolute heat loss reduction was greater, however, and thus clinically more important in cold environments when little insulation is available. A similar reduction in total heat loss was also achieved by increasing the insulation from one to two blankets or from two to seven blankets. CONCLUSION: Wet clothing removal or the addition of a vapor barrier effectively reduced evaporative heat loss and might thus be of great importance in prehospital rescue scenarios in cold environments with limited insulation available, such as in mass-casualty situations or during protracted evacuations in harsh conditions. PMID- 22445056 TI - [Incidence of rotavirus gastroenteritis among children under 5 years consulting a paediatrician or a general practitioner in France]. AB - BACKGROUND: Rotavirus (RV) is the main infectious agent of severe acute gastroenteritis (AGE) in infants and children under 5 years. Given the recent availability of new vaccines, it is important to accurately assess the incidence of rotavirus gastroenteritis (GERV) and their medical and epidemiological consequences. METHODS: This work is the French part of study program called SPRIK, a multicenter, prospective, observational study conducted from October 2005 to May 2007 to estimate the annual incidence of GERV within children under 5 years visiting a general practitioner or pediatrician. It presents data collected by 41 general practitioners and 36 paediatricians located throughout the French metropolitan territory. A stool sample was taken for every child. Rotavirus presence was sought by the physician using a rapid immunochromatographic test. French results are presented in this article. RESULTS: A total of 1648 GEA episodes corresponding to 1463 eligible patients were included in the study mainly from December to May (peak in February-March). The incidence rate of GERV leading to consultations in general practice was 1357 cases per 100,000 patient years (PY) (1.36%), with a 95% confidence interval of [1345-1368]. The peak incidence occurs before 2 years. GERV accounted for 21% of all GEA cases seen by paediatricians and general practitioners. Patients with GERV were younger (14.1 +/- 10.8 versus 18.4 +/- 13.9 months for other GEA, P<0.0001) and had more severe clinical symptoms: presence of fever (32.6% versus 20.0%, P<0.0001), behavioural symptoms (45.6% versus 20.8%, P<0.0001) and dehydration (48.7% versus 21.2%, P<0.0001). GERV episodes were considered severe in 79.7% of cases, using the Vesikari scale. More than 86% patients received oral rehydration during the episode and 13 patients (5.8%) were hospitalized. Nearly 80% GERV episodes were considered severe using the Vesikari scale. Main genotypes were G1P[8] rotavirus (44%) and G9P[8] rotavirus (35%) types. CONCLUSION: The incidence rate reported in this study is close to results of previous studies done in Europe. The frequency and severity relative to GERV support vaccination in very young children to reduce the burden associated with this pathology. PMID- 22445057 TI - Ramadan fasting and diabetes: an observational study among Turkish migrants in Belgium. AB - AIMS: To investigate (i) Ramadan participation, (ii) provision of Ramadan-related advice by healthcare providers, (iii) medication use during Ramadan fasting among Turkish migrants with diabetes in Belgium. METHODS: This pilot observational study was conducted among a convenience sample of 52 Turkish migrants with diabetes in Belgium. Two questionnaires collected information on socio demographic characteristics, diabetes-related characteristics, current hypoglycaemic medication with dosing regimen, participation in the past Ramadan, reasons for (non-)participation, use of hypoglycaemic medication during the past Ramadan, advice from their healthcare providers about fasting during Ramadan and follow-up of this advice. RESULTS: Sixteen patients (31%) had fasted during the past Ramadan. Main reason for Ramadan participation was reinforcement of faith (12/15), while the main reason for non-participation was having diabetes (34/36). About 56% of the study population had received recommendations from their healthcare provider(s) about fasting and diabetes during Ramadan. The most commonly provided advice was not to participate in Ramadan, followed by modification of drug therapy. Only 3 patients ignored the advice of their health professionals. In addition, only 60% of those who actually fasted received recommendations about intake of diabetes medication during the Ramadan. Most fasters continued their medication dose unchanged (87% of OHA users and 80% of the insulin users). CONCLUSIONS: This pilot study found a low prevalence of Ramadan fasting among Turkish migrants with diabetes in Belgium. We also found that provision of advice by healthcare providers could be improved. Larger scale studies are warranted to confirm these findings. PMID- 22445058 TI - Amputation rate and risk factors in type 2 patients with diabetic foot syndrome under real-life conditions in Germany. AB - AIMS: To determine the risk of amputation and the influencing factors for amputation for patients with type 2 diabetes with diabetic foot syndrome. METHODS: Longitudinal data from general practices in Germany (Disease Analyzer database, IMS Health) were analyzed. 3892 type 2 diabetes patients (mean age: 66.0 (SD: 10.9 years), 39.1% female) with a first-time diagnosis of diabetic foot syndrome between 01/200 and 12/2004 and at least 5 year follow-up documentation in the practices were included. The analyses of amputation-free survival were carried out using Kaplan-Meier curves and log-rank tests. A multivariate Cox regression model was fitted with the incident of diabetes-associated amputations as the dependent variable and adjusted for clinical and demographic characteristics. RESULT: The cumulative incidence of diabetes-associated lower limb amputations was 18.2%. Amputations are independently associated with higher age, male gender, higher HbA1c value and longer diabetes duration but also some other diabetes complications. DISCUSSION: The diabetic foot syndrome can but must not lead to a lower limb amputation. Due to the great medical and economic burden on the health system caused by diabetic complications, early therapeutic intervention is essential for patients with diabetic foot syndrome. PMID- 22445059 TI - Why pigs are important in Papua? Wealth, height and reproductive success among the Yali tribe of West Papua. AB - Many studies have investigated how different variables influence the reproductive success (RS) in the populations of natural birth control. Here, we tested hypotheses about positive relationship between wealth, height and several measures of RS in an indigenous, traditional society from West Papua. The study was conducted among the Yali tribe in a few small, isolated mountain villages. In this tribe, a man's wealth is measured by the number of pigs he possesses. We found that wealth was related to fertility and number of living children, but not to child mortality in both men and women. Additionally, child mortality increased with the number of children in a family. Finally, we did not observe any relationship between height and reproductive success measures or wealth. We provide several possible explanations of our results and also put forward hypothetical background for further studies of indigenous populations. PMID- 22445060 TI - Rethinking heredity, again. AB - The refutation of 'soft' inheritance and establishment of Mendelian genetics as the exclusive model of heredity is widely portrayed as an iconic success story of scientific progress. Yet, we are witnessing a re-emergence of debate on the role of soft inheritance in heredity and evolution. I argue that this reversal reflects not only the weight of new evidence but also an important conceptual change. I show that the concept of soft inheritance rejected by 20th-century genetics differs fundamentally from the current concept of 'nongenetic inheritance'. Moreover, whereas it has long been assumed that heredity is mediated by a single, universal mechanism, a pluralistic model of heredity is now emerging, based on a recognition of multiple, parallel mechanisms of inheritance. PMID- 22445061 TI - Metastatic lymph node ratio versus number of metastatic lymph nodes as a prognostic factor in gastric cancer. AB - OBJECTIVE: Knowledge of prognostic factors in gastric cancer is essential to decide on single patient management. We aim to establish the value of lymph node ratio compared to lymph node involvement in the prediction of gastric cancer survival and treatment approach. METHODS: Charts of ninety-six consecutive patients undergoing gastrectomy for resectable gastric cancer were reviewed between January 1996 and December 2005. Receiver operating characteristic (ROC) curves were plotted to verify the accuracy of metastatic lymph node ratio (MLNR) and number of metastatic lymph node (NMLN) cut-off values for survival prediction. Patients were divided into two groups according to ROC curve cut-offs and accuracy in prognosis was reviewed. RESULTS: ROC curves showed that 5 metastatic nodes and a node ratio value of 20% had the best survival prognostic correlation. The median survival of patients with MLNR and NMLN were similar according to cut-off determinations (<= 5/> 5 metastatic nodes and <=20/>20% lymph node ratio). Five-year survival rates were 70.9% vs 17.1% and 72.4% vs 15.6%, respectively (p < 0.001). Positive correlation coefficient was found between the number of excised nodes and the number of metastatic nodes. CONCLUSION: Number of metastatic lymph nodes showed greater accuracy than lymph node ratio for survival prediction in gastric cancer. PMID- 22445062 TI - Induction of inducible nitric oxide synthase by isoflurane post-conditioning via hypoxia inducible factor-1alpha during tolerance against ischemic neuronal injury. AB - Recent studies have shown that isoflurane protects against ischemic injury via inducible nitric oxide synthase (iNOS). Hypoxia inducible factor (HIF)-1alpha is a transcriptional factor that activates after cerebral ischemia. However, whether iNOS gene containing the sequence of the hypoxia response element (HRE) is a HIF 1alpha target during tolerance against ischemic neuronal injury induced by isoflurane post-conditioning remains unknown. In this study, we report that HIF 1alpha and iNOS gene expression were augmented after cerebral ischemia in rats. Furthermore, isoflurane post-conditioning resulted in greater accumulation of HIF 1alpha and iNOS gene expression, following by HIF-1alpha transcriptional activity enhancement and co-localization of HIF-1alpha and iNOS. Accordingly, in the primary cortical neuron cultures, silencing of HIF-1alpha attenuated the accumulation of iNOS and the protective effects of isoflurane post-conditioning. Our results suggest the involvement of HIF-1alpha in the regulation of iNOS during tolerance against cerebral ischemia induced by isoflurane post conditioning, which provide a mechanistic basis of novel therapeutic strategies for ischemic stroke. PMID- 22445063 TI - Coadministration of bicuculline and NMDA induces paraplegia in the rat. AB - Motor neurons (MNs) of an adult rat are normally insensitive to the neurotoxic action of NMDA. Meanwhile, the experiments in non-motor neurons showed that sensitivity to NMDA can be increased by bicuculline, an antagonist at GABA(A) receptors. The aim of the present work was to examine whether bicuculline would produce such an effect in the adult MNs. In adult Wistar rats, intrathecal injection of bicuculline and NMDA individually failed to affect motor activity of the extremities. In contrast, bicuculline-NMDA combination dose-dependently impaired hindlimb functions. At the 9th day after injections of the combination, a paraplegia with persistent bilateral spastic extension developed in all animals. Light microscopic assessment showed that the development of the motor deficit is associated with pathological changes in spinal motor neurons (swelling, accumulation of the Nissl substance near nucleus, hyperchromatosis, shrinkage, and chromatolysis), mainly in the lumbar ventral horns. Additionally, distinct abnormalities were observed in the white matter of the lumbar cords. The bicuculline-NMDA combination induced a loss of spinal cord MNs while sparing the dorsal horn neurons. The effects of the combination were reversed by muscimol, a GABA(A) agonist. Thus, an inhibition of GABA(A)ergic processes can induce NMDA sensitivity in adult MNs. The present data may provide new insights into the mechanism of motor disorders in amyotrophic lateral sclerosis and other states wherein the combination of glutamatergic overstimulation and GABA(A)ergic understimulation takes place. PMID- 22445066 TI - Towards understanding plant bioacoustics. AB - Little is known about plant bioacoustics. Here, we present a rationale as to why the perception of sound and vibrations is likely to have also evolved in plants. We then explain how current evidence contributes to the view that plants may indeed benefit from mechanosensory mechanisms thus far unsuspected. PMID- 22445064 TI - The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. AB - Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable 'prion domain' enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), Alzheimer's disease and Huntington's disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion like transfer mechanisms involving the prion domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system. This article is part of a Special Issue entitled RNA-Binding Proteins. PMID- 22445067 TI - NAC proteins: regulation and role in stress tolerance. AB - The plant-specific NAC (NAM, ATAF1,2 and CUC2) proteins constitute a major transcription factor family renowned for their roles in several developmental programs. Despite their highly conserved DNA-binding domains, their remarkable diversification across plants reflects their numerous functions. Lately, they have received much attention as regulators in various stress signaling pathways which may include interplay of phytohormones. This review summarizes the recent progress in research on NACs highlighting the proteins' potential for engineering stress tolerance against various abiotic and biotic challenges. We discuss regulatory components and targets of NAC proteins in the context of their prospective role for crop improvement strategies via biotechnological intervention. PMID- 22445069 TI - Gait and motor imagery of gait in early schizophrenia. AB - Although gait disorders were described in schizophrenia, motor imagery of gait has not yet been studied in this pathology. We compared gait, motor imagery of gait and the difference between these two conditions in patients with schizophrenia and healthy age-matched controls. The mean +/- standard deviation (S.D.) of Timed Up and Go (TUG), imagined TUG (iTUG) and delta time (i.e.; difference between TUG and iTUG), was used as outcomes. Covariables include Mini Mental State Examination, the Frontal Assessment Battery (FAB), FAB's subitems, the Positive and Negative Syndrome Scale and the Unified Parkinson's Disease Rating Scale (UPDRS). Seventeen patients with early schizophrenia and 15 healthy age-matched controls were assessed. Schizophrenia patients performed the TUG and the iTUG slower than the controls. Multivariate linear regressions showed that iTUG and delta time were associated with the conflicting instruction of the FAB. The present study provides the first evidence that patients with schizophrenia performed gait and motor imagery of gait slower than healthy controls. These deficits could be in part explained by impaired executive function and specifically by a disturbance in the sensitivity to interference. PMID- 22445068 TI - Omics and therapy - a basis for precision medicine. AB - A founding premise of the human genome project was that knowledge of the spectrum of abnormalities that comprise cancers and other human diseases would lead to improved disease management by identifying molecular abnormalities that could guide disease detection and diagnosis, suggest new therapeutic strategies and be developed as markers to predict response to therapy. This project led to elucidation of a reference normal human genome sequence and normal polymorphisms therein against which sequences from diseased tissues can be compared to enable identification of causal abnormalities. It also stimulated development of an array of computational tools for genomic analysis and catalyzed public and private sector development of revolutionary tools for genome analysis that transformed analysis of whole genomes from an enterprise that required international teams and hundreds of millions of dollars to a process that can be carried out in core facilities for only a few thousand dollars per sample. Indeed, the $1000 genome is nearly upon us. Applications of these technologies to human cancers in international cancer genome projects are now revealing the spectra of abnormalities that comprise thousands of individual cancers. Analyses of these data are leading to the promised improvements in disease management. We review several aspects of cancer genomics with emphasis on aspects that are relevant to improving cancer therapy. PMID- 22445070 TI - Sensitivity to detect change and the correlation of clinical factors with the Hamilton Depression Rating Scale and the Beck Depression Inventory in depressed inpatients. AB - Discrepancies between scores on the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI), as well as differences regarding their sensitivity to detect change, have been reported. This study investigates discrepancies and their potential prediction on the basis of demographic, personality, and clinical factors in depressed inpatients and analyzes the sensitivity to change. The HAMD and the BDI were administered to 105 inpatients with major depressive disorder randomized to 5 weeks of either interpersonal psychotherapy or clinical management. Personality was assessed with the NEO Five Factor Inventory. Low extraversion and high neuroticism were associated with relatively higher endorsement of depressive symptoms on the BDI compared with the HAMD. The HAMD presented a greater reduction of symptom scores than the BDI. Patients with high BDI scores, high HAMD scores or both revealed the greatest change, possibly due to a statistical effect of regression to the mean. Restricted by sample size, analyses were not differentiated by treatment condition. Regression to the mean cannot be tested directly, but it might be considered as a possible explanation. The HAMD and the BDI should be regarded as two complementary rather than redundant or competing instruments as the discrepancy is associated with personality characteristics. Attributing large effect sizes solely to effective treatment and a sensitive measure may be misleading. PMID- 22445071 TI - A step toward an objective quantification of subtle neurological signs in schizophrenia. AB - Numerous reports have emphasized the value of neurological soft signs (NSS) as endophenotypic markers in schizophrenia. NSS also appear as useful prognostic predictors for functional outcome, response and tolerance to antipsychotics. Although several standardized scales have been proposed and offer fair inter rater reliability, they still rely on the experience and accuracy of the investigators. This study was designed to assess NSS objectively. We evaluated 27 patients who met the Diagnostic and Statistical Manual, fourth edition (DSM-IV) criteria for schizophrenia and 15 healthy controls using a standardized examination encompassing a 23-item NSS scale as well as an assessment of parkinsonism and dyskinesia. Movements were then recorded using inertia sensors while the patients were performing a selection of motor items from the aforementioned scale (balance tasks, rapid alternative movements, rigidity). To our knowledge, this study is the first to provide an objective assessment of specific NSS in schizophrenia using inertial sensors. The results objectively demonstrate impairments in patients with schizophrenia when balance relies on proprioceptive information, with specific differences in groups of patients based on their NSS scores. Inertia sensors are promising, inexpensive and 'easy-to-use' tools that could improve the assessment of motor and sensory impairments in patients with schizophrenia in daily clinical practice, especially when the dysfunction is subtle. PMID- 22445072 TI - Verticillosides A-M: Polyoxygenated pregnane glycosides from Asclepias verticillata L. AB - As part of our ongoing effort to explore the chemical diversity of plants of the United States Midwest region, the isolation and identification of 13 pregnane glycosides named verticillosides A-M from Asclepias verticillata L. are reported. The structures of these compounds were elucidated by various spectroscopic techniques, including 1D and 2D NMR, IR, UV, and HRMS. The cytotoxicity of the isolates was evaluated against paired breast cell lines Hs578T (cancer) and Hs578Bst (normal), however, no significant growth inhibition was observed. PMID- 22445073 TI - Immunolocalisation of spermidine synthase in Solanum tuberosum. AB - Spermidine synthase (SPDS) catalyses the formation of spermidine, which is an essential polyamine and widespread in living organisms. Spermidine is formed from putrescine by transfer of an aminopropyl group from decarboxylated S adenosylmethionine. Spermidine is also a precursor to further polyamines, such as spermine and thermospermine, most of which contribute to tolerance against drought and salinity in plants. Thermospermine is indispensible for vascular tissue growth. Plant spermidine synthases have been cloned from several angiosperms; organ-specific gene expression levels are known for Arabidopsis only. In this study, immunolocalisation of SPDS in potato (Solanum tuberosum) organs is presented. Polyclonal antibodies for SPDS from potato produced in rabbits were purified by affinity chromatography. Cross-reaction with potato putrescine N-methyltransferase was eliminated. Accumulation of SPDS protein in the phloem region of vascular tissues throughout the potato plant is demonstrated. PMID- 22445074 TI - Labdane diterpenoids from Leonotis leonurus. AB - Three known (leoleorins A-C) and eight hitherto unknown (leoleorins D-J and 16 epi-leoleorin F) labdane diterpenoids, were isolated from leaves of Leonotis leonurus. The absolute configurations of leoleorins A and D were established by X ray crystallographic analyses. In a competitive binding assay, all isolated compounds showed inhibition in excess of 50% at various CNS receptors. Leoleorin C showed moderate binding affinity (Ki=2.9 MUM) for the Sigma 1 receptor. PMID- 22445075 TI - [Trends in the characteristics of ESRD patients at the initiation of dialysis]. AB - Changing trends concerning the incidence, sociodemographic features, and comorbidities observed among patients, starting their first renal replacement therapy by dialysis were studied in nine geographic regions in France participating in the REIN registry from 2004 to 2009. The standardized incidence of patients on dialysis remained stable while patient age tended to increase. After adjustment for age, the overall number of comorbid conditions remained unchanged, with a decrease in the number of patients with cardiovascular disease. These results, together with trends in laboratory results, suggest that the general health status of the patient population remains unchanged despite increasing age and that care for chronic renal failure has improved, generating an environment of prudent optimism for the future. PMID- 22445076 TI - The mouse dendritic cell marker CD11c is down-regulated upon cell activation through Toll-like receptor triggering. AB - Dendritic cells (DC) play a key role in regulating immune responses and are the best professional antigen-presenting cells. Two major DC populations are defined in part according to cell surface CD11c expression levels. Unexpectedly, we observed that mouse DC strongly down-regulate the typical DC marker CD11c upon activation. To better characterize DC responses, we have analyzed CD11c expression on mouse and human myeloid DC after Toll-like receptor (TLR) triggering. Here we show that mouse bone marrow-derived DC (BMDC) as well as spleen DC down-regulate cell surface CD11c upon activation by TLR3/4/9 agonists. In all cases, full DC activation was reached, as determined by cytokine secretion, cell stimulation in mixed leukocyte reactions (MLR), and CD40/CD86/major histocompatibility complex (MHC) up-regulation. Interestingly, membrane CD11c down-regulation correlated with increased cytoplasmic pools of CD11c. In contrast to the up-regulation of CD40 and MHC class II molecules, lipopolysaccharide (LPS)-induced CD11c down-regulation was MyD88-dependent. Polyinosinic-polycytidylic acid (poly I:C), which does not signal through MyD88, also induced cell surface CD11c down-regulation. Notably, CD11c down-regulation was not observed upon activation of human DC, either through TLR-dependent or independent cell activation. Thus, activated mouse DC may be transiently CD11c negative in vivo, hampering the identification of those cells. On the other hand, cell surface CD11c down-regulation may serve as a new activation marker for mouse DC. PMID- 22445078 TI - Treatment with fixed thyroxine doses in pregnant women with subclinical hypothyroidism. AB - BACKGROUND: Hypothyroidism is usually treated with thyroxine doses on patient weight. In some cases, however, fixed doses have proved to useful to normalize TSH levels, which is especially important during pregnancy. PATIENTS AND METHODS: Sixty-eight women diagnosed with subclinical hypothyroidism, autoimmune or not, during pregnancy were given a fixed dose of thyroxine 50 mcg/day. TSH measurements were performed to assess the need to change the dose, which was increased or decreased by 25 mcg/day when necessary. RESULTS: With a dose of 50 mcg/day of thyroxine, 42% of patients reached a TSH level less than 3 MUU/mL, 79.4% reached a TSH level less than 4.5 MUU/mL, and 20.6% had TSH levels higher than 4.5 MUU/mL. DISCUSSION: Our data suggest that a fixed dose of thyroxine 50 mcg/day is inadequate in a significant proportion of pregnancy-diagnosed hypothyroidism regardless of whether the reference of TSH level used is 4.5 or 3 MUU/mL. S starting dose of 75 mcg/day is probably more adequate, but studies are needed to evaluate the possibility of overtreatment with such dose. PMID- 22445079 TI - Reversible Henoch-Schonlein purpura complicating adalimumab therapy. AB - The tumour necrosis factor antagonists have demonstrated efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. These agents are generally well tolerated but with the increasing number of patients receiving anti-tumour necrosis factor-alpha (anti-TNFalpha) therapy, more adverse reactions are expected to occur. Cutaneous eruptions complicating treatment with anti-TNFalpha agents are common, occurring in around 20% of patients. Most reactions are mild-to-moderate and rarely warrant treatment withdrawal. We herein present a case of Henoch-Shonlein purpura (HSP) vasculitis following treatment with the monoclonal anti-TNFalpha antibody adalimumab for ileo-colic Crohn's disease. The reaction occurred after 18 months of adalimumab therapy and discontinuation of the anti-TNFalpha resulted in rapid improvement of the condition. The causal relationship has become even more likely when the purpura reappeared after restarting adalimumab. The patient started infliximab, with disease control and no cutaneous side effects. To the best of our knowledge, this is the second case report of HSP complicating adalimumab therapy. Although adalimumab is theoretically less related to immune-mediated reactions, clinicians must be aware that adverse side effects may still occur. This is the first case that shows that infliximab can be safely used in patients with adalimumab related HSP. We discuss the literature and potential causal mechanisms and propose possible approaches to its management. PMID- 22445080 TI - Comment on: predictors of immune recovery and the association with late mortality while on antiretroviral treatment in Cambodia. PMID- 22445081 TI - Comment on: preventive chemotherapy in human helminthiasis: theoretical and operational aspects. PMID- 22445082 TI - Assessment of performance of selected serological tests for diagnosing brucellosis in pigs. AB - Swine brucellosis due to Brucella suis is considered an emerging zoonotic disease whose control is based on serological testing and the subsequent culling of seropositive animals or the full depopulation of affected flocks. Here we assessed the performance of several serological tests (Rose Bengal Test [RBT], indirect ELISA [i-ELISA], blocking ELISA [b-ELISA], and two competitive ELISAs [c ELISA]) for diagnosing swine brucellosis caused by B. suis biovar 2. Both frequentistic and Bayesian statistical inference were used. A frequentistic analysis, using sera from known gold standard (GS) populations (i.e., from truly infected or brucellosis free animals), resulted in maximum (100%) diagnostic sensitivity (Se) and specificity (Sp) in the RBT, i-ELISA and b-ELISA tests. However, c-ELISAs resulted in lower diagnostic Se (ranging from 68.5% to 92.6%, according to the different cut-offs selected). A Bayesian analysis of tests yielding the best diagnostic performance with GS sera (RBT, i-ELISA and b-ELISA), but using a large collection of field sera, resulted in similar Se among tests but markedly lower (~ 80%) than that resulting from the frequentistic analysis using the GS serum populations. By contrast, the estimated Sp in the Bayesian analysis was only slightly lower than 100%, thus similar to that obtained frequentistically. Our results show that adequate diagnostic tests for brucellosis in swine are available, but also emphasize the need for more extensive validation studies before applying these tests under field conditions. PMID- 22445083 TI - Is an odds ratio of 3 too high a threshold for true associations in clinical epidemiology? PMID- 22445084 TI - No difference demonstrated between faxed or mailed prenotification in promoting questionnaire response among family physicians: a randomized controlled trial. AB - OBJECTIVE: Achieving high survey participation rates among physicians is challenging. We aimed to assess the effectiveness of response-aiding strategies in a postal survey of 1,000 randomly selected Australian family physicians (FPs). STUDY DESIGN AND SETTING: A two * two randomized controlled trial was undertaken to assess the effectiveness of a mailed vs. faxed prenotification letter and a mailed questionnaire sealed with a label marked attention to doctor vs. a control label. At the time of our final reminder, we randomized remaining nonresponders to receive a more or less personalized mail-out. RESULTS: Response did not significantly differ among eligible FPs receiving a prenotification letter via mail or fax. However, 25.6% of eligible FPs whose questionnaires were sealed with a label marked attention to the doctor responded before reminders were administered and compared with 18.6% of FPs whose questionnaires were sealed with a control label (P=0.008). Differences were not statistically significant thereafter. There was no significant difference in response between FPs who received a more vs. less personalized approach at the time of the final reminder (P=0.16). CONCLUSION: Mail marked attention to doctor may usefully increase early response. Prenotification letters delivered via fax are equally effective to those administered by mail and may be cheaper. PMID- 22445085 TI - Among nonagenarians, congruence between self-rated and proxy-rated health was low but both predicted mortality. AB - OBJECTIVE: The congruence between self-rated global health (SRH) and proxy-rated global health (PRH), the factors associated with congruence between SRH and PRH, and their associations with mortality are examined using data from the Vitality 90+ study. STUDY DESIGN AND SETTING: The data consist of 213 pairs of subjects- aged 90 years and older--and proxies. The relationship between SRH and PRH was analyzed by chi-square test and Cohen's kappa. Logistic regression analysis was used to find out the factors that are associated with the congruence between health ratings. The association between SRH and PRH with mortality was studied using Cox proportional hazard models. RESULTS: The subjects rated their health more negatively than the proxies. Kappa value indicated only slight congruence between SRH and PRH, and they also predicted mortality differently. Good self reported functional ability was associated with congruence between SRH and PRH. CONCLUSIONS: The results imply that the evaluation processes of SRH and PRH differ, and the measures are not directly interchangeable. Both measures are useful health indicators in very old age but SRH cannot be replaced by PRH in analyses. PMID- 22445086 TI - Case-crossover design: an alternative strategy for detecting drug-induced liver injury. AB - OBJECTIVE: Our observational study was conducted to assess if the case--crossover design could be applied to detect the risk of hepatoxic drugs on liver injury in the automated databases. STUDY DESIGN AND SETTING: The study was conducted on approximately 22 million people enrolled in Taiwan's National Health Insurance database from 1997 to 2004. We applied case--crossover and case--control designs to assess the estimated risks of liver injury related to well-known hepatoxic drugs, including isoniazid, rifampicin, erythromycin, and diclofenac. Using case- crossover and case--control designs, we analyzed to explore the association between hospitalization and our target drugs through a conditional logistic regression model. RESULTS: The adjusted odds ratios (ORs) of isoniazid, rifampicin, erythromycin, and diclofenac showed 24.4 (confidence interval [CI] =10.7-55.5), 30.8 (CI=14.1-67.1), 2.1 (CI=1.4-3.1), and 2.9 (CI=2.4-3.5) among 4,413 hospitalized liver injury patients during the 30-day exposure window by the case--crossover designs. Most adjusted ORs by case--crossover design were more conservative than ORs by case--control design. CONCLUSIONS: In addition to a case -control design, the case--crossover design is a suitable method, for detecting the potential hepatotoxicity of drugs. PMID- 22445087 TI - Which questionnaire to use when measuring continuity of care. PMID- 22445088 TI - Available tools to comprehensively assess continuity of care from the patients' perspective. PMID- 22445089 TI - Dermal and pulmonary absorption of ethanol from alcohol-based hand rub. AB - BACKGROUND: Ethanol intoxication of healthcare workers (HCWs) using alcohol-based hand rubs (ABHRs) in the workplace is a potentially serious issue. This study quantified the level of ethanol absorption among HCWs after hygienic hand disinfection. METHODS: Eighty-six HCWs from Nancy University Hospital were tested before and after a 4-h shift. Participants used ABHR containing 70% ethanol. Levels of ethanol, acetaldehyde and acetate in blood and urine were determined using gas chromatography. A breathalyzer was used to measure the level of ethanol in expired air. RESULTS: Ethanol [mean concentration 0.076 (standard deviation 0.05) mg/L] was detected in the expired air of 28 HCWs 1-2 min post exposure. Ethanol, acetaldehyde and acetate were undetectable in blood after a 4-h shift, and urine tests were negative in all participants. CONCLUSION: Ethanol exposure from ABHR, particularly inhalation of vapours, resulted in positive breathalyzer readings 1-2 min after exposure. Dermal absorption of ethanol was not detected. Pulmonary absorption was detected but was below toxic levels. PMID- 22445090 TI - Lessons from a large norovirus outbreak: impact of viral load, patient age and ward design on duration of symptoms and shedding and likelihood of transmission. AB - BACKGROUND: Hospital norovirus outbreaks cause significant financial and operational disruption which should be minimised by optimal handling of affected areas and use of isolation facilities. AIM: To identify factors associated with increased duration of symptoms and viral excretion and increased probability of transmission. METHODS: Retrospective observational study of a large norovirus outbreak at a UK teaching hospital in the winter of 2009-2010 where patients were diagnosed using a real-time polymerase chain reaction (PCR) assay. FINDINGS: Symptom duration was significantly associated with patient age (Spearman rank correlation coefficient: 0.197; P = 0.002) but not with PCR cycle threshold (C(T)) value. Duration of viral excretion was found to be longer in patients with higher viral loads. Transmission within a ward bay was not significantly associated either with age or with C(T) value but was more likely to occur in some ward blocks than others, which may relate to differences in ward design. Transfer of patients into isolation rooms or cohorted area within two days of symptom onset did not significantly influence probability of onward transmission (52% vs 47%; P = 0.67). CONCLUSIONS: The presented data suggest that C(T) value may guide timing of repeat sample collection if ongoing gastrointestinal symptoms may relate to other pathologies, and that patients developing symptoms of norovirus may remain in their current bay rather than being moved into isolation facilities. The bay or ward should be closed to new admissions but it should be anticipated that duration of symptoms and therefore closure will be longer when the outbreak involves elderly patients. PMID- 22445091 TI - A patient with an implanted cardiac defibrillator not deactivated during acute and maintenance electroconvulsive therapy. PMID- 22445092 TI - [Sedation and analgesia in emergency structure. Which prerequisites and formations are mandatory to perform sedation and/or analgesia in the emergency structure?]. PMID- 22445093 TI - Anogenital granulomatosis. PMID- 22445094 TI - Toward a complete Drosophila deficiency kit. AB - Targeted chromosome engineering has facilitated the development of new deletions that now cover virtually the entire genome of Drosophila, providing greater precision and resolution. PMID- 22445095 TI - The PI3K/AKT/mTOR signalling pathway is active in salivary gland cancer and implies different functions and prognoses depending on cell localisation. AB - OBJECTIVES: The PI3K/AKT/mTOR signalling axis controls cell proliferation and survival and has achieved major importance as a target for cancer therapy. This investigation evaluated the expression of the major components P-AKT, P-mTOR, PI3K and P-S6rp in salivary gland cancer. MATERIALS AND METHODS: Immunohistochemical expression of P-AKT, P-mTOR, PI3K and P-S6rp was evaluated and correlated to clinicopathological parameters and survival of 272 patients with salivary gland carcinomas. RESULTS AND CONCLUSION: Analysis of all tumours together revealed an increased expression of all components of the pathway in comparison to normal salivary gland control tissue. Nuclear expression of P-AKT was associated with young age, localised tumour stage, absence of lymph node metastases and favourable prognosis. On the contrary, cytoplasmic P-AKT displayed unfavourable tumour characteristics like high-grade malignancy, and worse overall survival. In comparison to cytoplasmic/membrane mTOR expression, nuclear P-mTOR was associated with absence of lymph node metastases and higher survival rates. PI3K and P-S6rp were exclusively found in the cytoplasm. Expression of P-S6rp was correlated to increased age, advanced tumour size and lymph node metastases. In all tumours together, nuclear P-AKT positively correlated with nuclear P-mTOR, whereas P-S6rp was associated with expression of PI3K and cytoplasmic P-AKT. In acinic cell carcinoma, cytoplasmic expression of P-AKT, P-mTOR, PI3K and P-S6rp was positively associated with each other. In conclusion, PI3K/AKT/mTOR signalling is active in salivary gland cancer and might function as a target for personalised therapy. P-AKT and P-mTOR possess distinct molecular functions with impact on prognosis depending on their cellular localisation. PMID- 22445096 TI - Ultrastructure of the human retina in aging and various pathological states. AB - Vision is hampered in aging and diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and glaucoma. This review collates the fine structural alterations of the human retina in aging and various pathological situations and their links to the disease pathogenesis. It transpires that most changes occur at the level of the retinal pigment epithelium -Bruch's membrane and the photoreceptor layer, causing visual problems to the sufferers. These changes include loss of normal, essential features of these cells and their gradual disappearance. It is important to understand in depth the selective vulnerability of this retinal region to alterations in aging and diseases. Evidence indicates that some of these changes may be mediated by the effects of oxidative stress, inflammation, and chronic light exposure. There are changes also in the inner retinal layers, wherein hypertension, auto-immunity, hypoxia and ischemia could play significant roles in disease pathogenesis. Results of extensive research utilizing animal models have broadened our idea about photoreceptor pathology. However, equivalent knowledge on various changes in aging human retina and in dystrophies that affect the macula is not complete. Since cone photoreceptor and ganglion cell death are a potential problem, it is imperative to know about the basic facts on how they are affected and the mechanisms involved in their death. Thus, prevention of cone and ganglion cell loss should be the target of choice. This review also highlights the significant role played by electron microscopy in understanding such ultrastructural changes and future strategies utilizing it and other techniques to fill some of the existing lacunae and advance our knowledge. PMID- 22445097 TI - Flow patterns and deposition fraction of particles in the range of 0.1-10MUm at trachea and the first third generations under different breathing conditions. AB - The velocity field and deposition fraction of the particles in the trachea and the first third generations of tracheobronchial tree are investigated with CFD simulation. The air flow rate of trachea is considered to be in the range of 15 60l/min in accordance to four different activity levels of male adults. A physiologically realistic dichotomic airway bifurcation geometry with structured hexahedral meshes are constructed. The simulations with different hexahedral mesh densities have shown that the grid independent results will be reached with the average dimensionless distance of the first cell to the walls of y(+)~0.5. The deposition fraction graph for particles in the range of 0.1-10MUm diameter has a minimum in the range of 0.1-1MUm particle diameter and after that it increases for larger particles. The results of the simulations under different breathing pattern have shown that deposition fraction significantly increases at higher Reynolds and Stokes numbers. PMID- 22445098 TI - Molecular mechanisms of hypertension--reactive oxygen species and antioxidants: a basic science update for the clinician. AB - Many factors have been implicated in the pathophysiology of hypertension such as upregulation of the renin-angiotensin-aldosterone system, activation of the sympathetic nervous system, perturbed G protein-coupled receptor signalling, inflammation, and altered T-cell function. Common to these processes is increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress) due to excess ROS generation, decreased nitric oxide (NO) levels, and reduced antioxidant capacity in the cardiovascular, renal, and nervous systems. Although oxidative stress may not be the sole etiology of hypertension, it amplifies blood pressure elevation in the presence of other prohypertensive factors. In the cardiovascular system ROS play a physiological role in controlling endothelial function, vascular tone, and cardiac function, and a pathophysiological role in inflammation, hypertrophy, proliferation, apoptosis, migration, fibrosis, angiogenesis, and rarefaction, all of which are important processes contributing to endothelial dysfunction and cardiovascular remodelling in hypertension. A major source for cardiovascular ROS is a family of nonphagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox1, Nox2, Nox4, and Nox5). Other sources include mitochondrial enzymes, xanthine oxidase, and uncoupled NO synthase (NOS). Although convincing data from animal studies support a causative role for oxidative stress in the pathogenesis of hypertension, there is still no solid evidence that oxidative stress causes hypertension in humans. However, biomarkers of excess ROS are increased in patients with hypertension and oxidative damage is important in the molecular mechanisms associated with cardiovascular and renal injury in hypertension. Although clinical trials failed to show beneficial antihypertensive effects of antioxidants, strategies that combat oxidative stress by targeting Noxs in an isoform-specific manner may have therapeutic potential. PMID- 22445099 TI - Endothelial progenitor cell function inversely correlates with long-term glucose control in diabetic patients: association with the attenuation of the heme oxygenase-adiponectin axis. AB - BACKGROUND: Endothelial progenitor cells (EPCs) are attenuated, both in number and functionality, in animal models of chronic cardiovascular and metabolic disorders. This effect has subsequently been linked to the aggravation of long term morbidity and mortality associated with such disorders. The objective was to examine EPC number and survival in chronic diabetic vs nondiabetic patients in conjunction with the examination of their redox, inflammatory, and antioxidant defense system (Nrf2 genes) status in serum and visceral fat. METHODS: Visceral adipose tissue from diabetic and nondiabetic patients undergoing coronary artery bypass graft surgery was analyzed for Nrf2-dependent genes. Oxidative stress was evaluated using thiobarbituric acid-reactive substance assay (TBARS). Peripheral blood, collected 1 day prior to surgery, was evaluated for inflammatory cytokines and EPCs. RESULTS: When compared with controls (P < 0.05), results of the thiobarbituric acid-reactive substance assay were higher in diabetic patients. Although Nrf2-dependent antioxidant proteins (thioredoxin-1 [Trx-1], nicotinamide adenine dinucleotide phosphate [NAD(P)H] quinone oxidoreductase [NQO1], glutathione S-transferase [GST]) were upregulated, heme oxygenase (HO-1) and adiponectin protein expression were lower in the diabetic group (P < 0.05). Serum levels of bilirubin were lower (P < 0.005) while the levels of inflammatory cytokines were higher in diabetic patients (P < 0.05). EPC levels and their colony forming units were significantly lower (P < 0.05) with reduced viability in diabetic patients as compared with nondiabetic patients. CONCLUSIONS: These results demonstrate for the first time that in diabetic patients, there is an inadequate heme oxygenase-adiponectin axis response, which could compromise the compensatory antioxidant and anti-inflammatory effects consequently contributing toward EPC dysfunction in these patients. PMID- 22445100 TI - The prognostic significance of fragmented QRS in patients with left ventricular noncompaction cardiomyopathy. AB - BACKGROUND: Fragmented QRS complexes (fQRS) were proven to be associated with the prognosis of several heart diseases. However, no data is available regarding fQRS in left ventricular noncompaction cardiomyopathy (LVNC), in which the outcome varies greatly and a simple yet practicable prognostic predictor is needed. The purpose of this study was to determine the prognostic value of fQRS in LVNC patients. METHODS: Sixty-four LVNC patients were evaluated. Fragmented narrow QRS (f-nQRS) included single or multiple notches in the R or S wave in at least 2 contiguous electrocardiogram (ECG) leads and QRS duration < 120 ms, fragmented wide QRS (f-wQRS) included more than 2 notches and QRS duration > 120 ms. RESULTS: f-nQRS and f-wQRS was present in 24 (38%) and 7 (11%) patients respectively. During follow-up, 13 patients died and 7 patients underwent heart transplantation. Kaplan-Meier analysis revealed that compared with the non-f-nQRS group, the f-nQRS group associated with a significantly lower survival (P = 0.005). The f-wQRS group also demonstrated a substantially lower survival as compared with the non-f-wQRS group (P = 0.02). Multivariate analysis indicated f nQRS was an independent predictor of all-cause mortality (HR: 5.33; P = 0.045). CONCLUSIONS: In LVNC patients, the presence of f-nQRS has significant prognostic value and may provide a valid method of risk stratification. PMID- 22445101 TI - Defining frequent use: the numbers no longer count. PMID- 22445102 TI - Towards multivalent CD1d ligands: synthesis and biological activity of homodimeric alpha-galactosyl ceramide analogues. AB - A library of dimeric CD1d ligands, containing two alpha-galactosyl ceramide (alpha-GalCer) units linked by spacers of varying lengths has been synthesised. The key dimerisation reactions were carried out via copper-catalysed click reactions between a 6"-azido-6"-deoxy-alpha-galactosyl ceramide derivative and various diynes. Each alpha-GalCer dimer was tested for its ability to stimulate iNKT cells. PMID- 22445103 TI - Fully acetylated 1,5-anhydro-2-deoxypent-1-enitols and 1,5-anhydro-2,6-dideoxyhex 1-enitols in DFT level theory conformational studies. AB - Geometry optimizations at the B3LYP level of density functional theory (DFT) are reported for the (4)H(5) and (5)H(4) conformations of four glycals: 3,4-di-O acetyl-1,5-anhydro-2-deoxy-D-erythro-pent-1-enitol (3,4-di-O-acetyl-D-arabinal), its D-threo isomer (3,4-di-O-acetyl-D-xylal), 3,4-di-O-acetyl-1,5-anhydro-2,6 dideoxy-D-arabino-hex-1-enitol (3,4-di-O-acetyl-D-rhamnal), and its D-lyxo isomer (3,4-di-O-acetyl-D-fucal). The Gibbs free energies, relative Gibbs free energies and geometry parameters are presented for all the optimized structures. Conformational analysis of both the acetoxy groups and 1,2-unsaturated pyranoid ring is performed. It is demonstrated that the acetoxy group is planar and adopts two conformations with regard to the Ac-O bond rotations, one of which is strongly preferred. One of the hydrogen atoms of the methyl group is always oriented synperiplanarly whereas the remaining two anticlinally with respect to the carbonyl oxygen. With regard to the AcO-R bond rotations some of the orientations are forbidden. The calculations indicate that 3,4-di-O-acetyl-D arabinal adopts mainly the (4)H(5) conformation, whereas 3,4-di-O-acetyl-D-xylal prefers the (5)H(4) form, owing to the vinylogous anomeric effect (VAE). Competition between the VAE and quasi 1,3-diaxial interactions means that both 3,4-di-O-acetyl-D-rhamnal and 3,4-di-O-acetyl-D-fucal remain in the (4)H(5)?(5)H(4) conformational equilibrium, shifted in the (4)H(5) direction. It seems that the orientation of the 4-OAc group influences the quasi 1,3-diaxial interactions between 3-OAc and 5-CH(3) groups. Theoretical results are compared with assignments based on (1)H NMR studies. PMID- 22445104 TI - The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome. AB - BACKGROUND: Chromosomal deletions are used extensively in Drosophila melanogaster genetics research. Deletion mapping is the primary method used for fine-scale gene localization. Effective and efficient deletion mapping requires both extensive genomic coverage and a high density of molecularly defined breakpoints across the genome. RESULTS: A large-scale resource development project at the Bloomington Drosophila Stock Center has improved the choice of deletions beyond that provided by previous projects. FLP-mediated recombination between FRT bearing transposon insertions was used to generate deletions, because it is efficient and provides single-nucleotide resolution in planning deletion screens. The 793 deletions generated pushed coverage of the euchromatic genome to 98.4%. Gaps in coverage contain haplolethal and haplosterile genes, but the sizes of these gaps were minimized by flanking these genes as closely as possible with deletions. In improving coverage, a complete inventory of haplolethal and haplosterile genes was generated and extensive information on other haploinsufficient genes was compiled. To aid mapping experiments, a subset of deletions was organized into a Deficiency Kit to provide maximal coverage efficiently. To improve the resolution of deletion mapping, screens were planned to distribute deletion breakpoints evenly across the genome. The median chromosomal interval between breakpoints now contains only nine genes and 377 intervals contain only single genes. CONCLUSIONS: Drosophila melanogaster now has the most extensive genomic deletion coverage and breakpoint subdivision as well as the most comprehensive inventory of haploinsufficient genes of any multicellular organism. The improved selection of chromosomal deletion strains will be useful to nearly all Drosophila researchers. PMID- 22445105 TI - Intercomparison of methods for coincidence summing corrections in gamma-ray spectrometry--part II (volume sources). AB - The second part of an intercomparison of the coincidence summing correction methods is presented. This exercise concerned three volume sources, filled with liquid radioactive solution. The same experimental spectra, decay scheme and photon emission intensities were used by all the participants. The results were expressed as coincidence summing corrective factors for several energies of (152)Eu and (134)Cs, and different source-to-detector distances. They are presented and discussed. PMID- 22445106 TI - Radioactivity measurement of 18F in 16 ml vials for calibration of radionuclide calibrators. AB - Fluorine-18 is obtained through the reaction (18)O(p, n)(18)F using a cyclotron that is situated in a hospital in Jakarta. Standardization of the (18)F solution is performed by gamma spectrometry using calibration sources of (152)Eu, (60)Co and (137)Cs that have traceability to the International System of units (SI). The activities in the 16 ml vials that were used for calibrating the radionuclide calibrators were between 1 and 2 GBq, with expanded uncertainties of 3.8%. The expanded uncertainty, at a coverage factor of k=2, on the derived calibration factor for the radionuclide calibrator was 6.6%. PMID- 22445107 TI - Zoster sine herpete causing facial palsy. AB - OBJECTIVES: The aims of this study were to verify the characteristics of zoster sine herpete (ZSH) causing facial palsy and the effects of different treatments and to confirm the difference from other etiologies. METHODS: From March 2010 to March 2011, a prospective study was performed on patients with ZSH with facial palsy. Patients were divided into a steroid-treated group and a steroid-antiviral combination group, and then the effects according to regimen of treatment were prospectively analyzed. Last, the difference between the ZSH group and patients diagnosed with Bell palsy and Ramsay Hunt syndrome in the same study period was confirmed retrospectively. RESULTS: Forty-five patients were diagnosed as having ZSH. Significant improvement was not observed in the ZSH group regardless of the treatment regimen during a 3-week period (P < .05). In patients with ZSH with accompanying typical pain, significant continuous improvement after 6 weeks was observed in patients with combination therapy (P < .05). Compared with patients with Bell palsy and Ramsay Hunt syndrome, there was a significant difference in recovery rate between patients with ZSH (accompanying pain) and those with Bell palsy (89.9%) (P < .05). CONCLUSION: The initiation of recovery in ZSH started later than that in other peripheral palsies, and slower recovery was shown in patients with ZSH with pain compared with those with Bell palsy. Steroid antiviral combination therapy was a more effective regimen for treatment compared with steroid-only treatment. To improve the accuracy of ZSH diagnosis, confirming the presence of accompanying typical pain is necessary. PMID- 22445108 TI - Laparoscopic myomectomy in peri- and post-menopausal women is safe, efficacious and associated with long-term patient satisfaction. AB - OBJECTIVE: Women in the peri- and post-menopause may ask for uterus-preserving therapy options when presenting with benign uterine disorders such as symptomatic fibroids. Laparoscopic myomectomy (LM) for patients in the peri- and post menopause as a surgical alternative to hysterectomy is widely considered to be non-standard treatment. The aim of this study was to analyze safety and outcome of LM beyond the reproductive period. STUDY DESIGN: We evaluated the surgical outcome and patient satisfaction for a total of 451 patients: 85 peri- or post menopausal women as group A and, for reference, 366 premenopausal women in group B, who received LM from 1998 to 2008 in our department. We analyzed data from our medical records and applied a patient questionnaire in September 2009. RESULTS: The average number of fibroids removed and size of the leading fibroid were similar in both groups. Time of surgery was different in group A, at 102.8 min, compared to group B, 128.6 min (p<0.01). Rates of intra- (2.21% overall) and post operative complications (6.22% overall) were comparable for both groups. Post surgical hospitalization was shorter in group B (4.4 days) compared to group A (5.0 days) (p<0.01). Evaluation of the questionnaire showed high satisfaction with the results of LM in both subgroups with a significantly lower number of relapses in group A (3.5%) compared to group B (11.2%). CONCLUSION: Laparoscopic myomectomy as a surgical treatment option in the peri- and post-menopause was characterized by a low rate of complications and relapses as well as a high degree of patient satisfaction in our analysis. PMID- 22445109 TI - Patients with complicated Pott's disease: management in a rehabilitation department and functional prognosis. AB - OBJECTIVE: The objective is to study the rehabilitation management and to assess autonomy in daily life activities as well as walking recovery in patients with complicated Pott's disease. PATIENTS AND METHODS: Retrospective study in nine patients over a period of 8 years extending from 2000 to 2008, collated in the Department of Physical Medicine and Functional Rehabilitation, CHU Sahloul, Sousse, Tunisia. RESULTS: The mean age of our patients was 43.8 years; sex ratio was 5/4. The spine involvement of tuberculosis was dorsal in seven cases, dorso lumbar in one patient, and multiple (cervical, dorsal and lumbar) in one case. All patients were paraplegic with a neurological involvement of the bladder. They had prior antituberculosis chemotherapy for at least 8 months. Decompression surgery was performed in six cases. Two female patients presented disorders of spinal posture during treatment requiring surgical revision with osteosynthesis. All patients received additional rehabilitation care. Following a mean duration of hospitalisation in the Rehabilitation department of 47 days with twice-daily sessions of tailored physiotherapy, three patients remained in complete paraplegia, autonomous in wheel-chair and with vesical and sphincter incontinence. The measure of functional independence (MFI) was at admission/discharge 71/92. CONCLUSION: Rehabilitation takes an important place in the medico-surgical management in Pott's disease, to limite or compensate the disabilities and handicap related to this pathology. PMID- 22445110 TI - Global relative and absolute quantitation in microbial proteomics. AB - Proteomic studies are designed to yield either qualitative information on proteins (identification, distribution, posttranslational modifications, interactions, structure and function) or quantitative information (abundance, distribution within different localizations, temporal changes in abundance due to synthesis and degradation or both). To this end these studies can draw upon a wide range of qualitative and quantitative gel-based and gel-free techniques. This review summarizes current proteomic workflows for global relative or absolute protein quantitation and their application in microbial physiology. PMID- 22445111 TI - [Distal femoral bypass under local anaesthesia]. AB - INTRODUCTION: The aim of this article is to present our experience in performing distal femoral bypass under local anaesthesia for high risk patients. MATERIAL AND METHODS: Lower limb revascularisation surgery under local anaesthesia was performed on 8 patients in our centre between January and May 2010. The common characteristics of the patients were, advanced age, chronic ischaemic heart disease on antiplatelet treatment, and chronic obstructive pulmonary disease (COPD). RESULTS: All 8 patients (100%) tolerated the procedure well without having to resort to sedation or invasive anaesthetic procedures. The receiving artery was the posterior tibial in 6 cases (75%) and the popliteal and peroneal in 1 (12%). Early patency of the graft was achieved 7 patients and 1 had early thrombosis with a supracondylar amputation. The technique used was femoral popliteal in 1 case, femoral-posterior tibial in 6 cases, and popliteal-peroneal in 1 case. The saphenous vein was the graft used, inverted in 1 patient (12%), and in situ in 7 (88%) with a 3mm BARDTM valvotomy. There were no post-operative complications as regards haemorrhage, infections or death. A minor amputation was performed on 3 patients (37%), and after a mean of 3 months (1-4 months) follow up, 7 cases were free of major amputation. CONCLUSIONS: Revascularisation of the distal zone of the lower limbs can be safely and effectively performed using local anaesthesia, avoiding the risks of general anaesthesia and without the need to stop antiplatelet treatment. Anatomical problems (obesity) may limit the procedure. PMID- 22445112 TI - [Increased bone mineral density in patients with tertiary hyperparathyroidism after total parathyroidectomy and autotransplantation of the parathyroid gland]. AB - INTRODUCTION: Changes in bone metabolism and bone mineral density are observed in renal transplant patients with tertiary hyperparathyroidism. The objective of this work was to analyse the increase in bone mineral density, as well the laboratory results, after total parathyroidectomy and autotransplantation in renal transplant patients with tertiary hyperparathyroidism. MATERIAL AND METHODS: A retrospective study was conducted in which the bone mineral density values at femoral and lumbar level were analysed, together with the serum levels of calcium, phosphorous, parathyroid hormone (PTH), and alkaline phosphatase in 13 renal transplant patients with tertiary hyperparathyroidism before and after total parathyroidectomy and autotransplantation of the parathyroid glands. RESULTS: Parathyroidectomy is associated with an increase in bone mineral density at femoral and lumbar level, with an increase of 8.6 +/- 6.7% at lumbar level, and 4 +/- 16.1% at femoral level. The decrease in calcium after the parathyroidectomy was 2.8 mg/dL (95% CI; 1.9-4). The decrease in PTH was 172 pg/mL (95% CI; 98-354) and the decrease in alkaline phosphatase was 229 U/L (95% CI; 70-371). CONCLUSIONS: Total parathyroidectomy and autotransplantation of the parathyroid glands in renal transplant patients with tertiary hyperparathyroidism increases the bone mineral density. Furthermore, the calcium, PTH and alkaline phosphatase returned to normal in the long-term. PMID- 22445113 TI - The Hepatocyte nuclear factor-1 alpha ( HNF1A) gene is associated with fatness and loin muscle area in the pig. AB - The significance of hepatocyte nuclear factors (HNFs) in beta-cell development and function has been generally recognized in humans, as evidenced by their associations with cases of maturity onset diabetes of the young (MODY). Common Hepatocyte nuclear factor-1 alpha (HNF1A), Hepatocyte nuclear factor-1 beta (HNF1B) and Hepatocyte nuclear factor-4 alpha (HNF4A) mutations could lead to monogenic forms 3, 5 and 1 of diabetes mellitus, respectively, and were characterized by MODY in humans. In this study, multiple variants were discovered in the porcine HNF1A and HNF4A genes, and one single-nucleotide polymorphism (SNP) was detected in the HNF1B gene. Using the Iowa State University Berkshire * Yorkshire pig resource population, the HNF1A, HNF1B and HNF4A genes were mapped on chromosomes 14, 12 and 17, respectively. The linkage disequilibrium (LD) analyses indicated that most of the HNF1A variants were not in strong LD with each other; however, nearly all of them were highly significantly (P < 0.01) associated with loin muscle area (LMA). The SNPs c.327-19G>T and c.1768+40_23del were significantly (P < 0.05) associated with backfat and total lipid percentage, and the latter was also associated with muscle glycogen metabolism measures. Four major haplotypes were observed and the association analyses suggested that haplotype 3 (-CGCGD-, I indicates Insertion and D indicates Deletion) was favorable for reduced backfat, while haplotype 1 (-CACGI-) was unfavorably associated with backfat and LMA. There was no significant interaction effect on backfat among the SNPs c.327-19G>T, c.1768+40_23del of the HNF1A gene and c.646C>T of the transcription factor-7-like 2 (TCF7L2) gene. These findings suggest that the HNF1A gene has significant effects on both fatness- and meat production-related traits. No significant associations with production traits with the SNPs from the HNF1B and HNF4A genes were observed in the study. PMID- 22445114 TI - Profitability of a dairy sheep genetic improvement program using artificial insemination. AB - This simulation study investigated the farm-level economic benefits of a genetic improvement scheme using artificial insemination (AI) with fresh ram semen in dairy sheep of the Chios breed in Greece. Data were collected from 67 farms associated with the Chios Sheep Breeders' Cooperative 'Macedonia', describing the percentage of ewes that would be artificially inseminated in the flock, pregnancy rate, annual ram costs that could be saved using AI rather than natural mating, expected improvement in milk production, annual costs of semen and feed, milk price and number of years of AI usage. The study considered 77 760 possible scenarios in a 3 * 4 * 4 * 3 * 3 * 3 * 4 * 15 factorial arrangement. Analysis of variance was used to investigate the effect of each factor on farm profitability. All factors considered were statistically significant (P < 0.001), but their effect varied. The number of years using AI had the greatest effect on profitability and farmers should become aware that using AI is a long-term investment. Semen price, pregnancy rate and improvement in milk production also had substantial effects. The price of milk and feed had a considerably lower effect on profitability, as did the annual cost of maintaining rams that would be replaced by AI. A positive annual and cumulative return was achieved in the model within the first 6 years. The cost of semen was estimated at 8? to 10? per dose for the first 5 years. Where the annual improvement in milk production was 1% of annual phenotypic mean (e.g. 3.0 kg) profitability of the scheme was improved greatly. PMID- 22445115 TI - Effects of phytase and 25-hydroxyvitamin D3 inclusions on the performance, mineral balance and bone parameters of grower-finisher pigs fed low-phosphorus diets. AB - Two experiments, a performance experiment and a mineral balance study, were conducted on grower-finisher pigs (42 to 101 kg live weight) to investigate the effects of Peniophora lycii phytase enzyme and 25-hydroxyvitamin D3 (25-OHD3) on growth performance, carcass characteristics, nutrient retention and excretion, and bone and blood parameters. The two experiments were designed as a 2 * 2 factorial (two levels of phytase and two levels of 25-OHD3). The four diets were T1, low-phosphorous diet; T2, T1 + phytase; T3, T1 + 25-OHD3 and T4, T1 + phytase + 25-OHD3 diet. In all, 25 MUg of 25-OHD3 was used to replace 1000 IU of vitamin D3 in diets T3 and T4. Diets were pelleted (70 degrees C) and formulated to contain similar concentrations of energy (13.8 MJ DE/kg), lysine (9.5 g/kg) and digestible phosphorus (P; 1.8 g/kg). Neither the inclusion of phytase nor 25-OHD3 in the diet had any effect on pig performance. There was an interaction between phytase and 25-OHD3 on calcium (Ca) and P retention (P < 0.01) and on the apparent digestibility of ash (P < 0.01), P (P < 0.001) and Ca (P < 0.001). Pigs offered phytase diets only, had a higher retention of Ca and P and digestibility of ash (P < 0.01), P (P < 0.001) and Ca (P < 0.01) compared with pigs offered unsupplemented diets. However, when the combination of phytase and 25-OHD3 were offered, no effects were detected compared with 25-OHD3 diets only. Pigs fed phytase diets had higher bone ash (P < 0.01), bone P (P < 0.01) and bone Ca (P < 0.05) concentrations compared with pigs offered non-phytase diets. In conclusion, pigs offered phytase diets had a significantly increased bone ash, Ca and P than pigs offered unsupplemented phytase diets. However, there was no advantage to offering a combination of phytase and 25-OHD3 on either bone strength or mineral status compared to offering these feed additives separately. PMID- 22445116 TI - Effects of varying proportions of concentrates on ruminal-reducing power and bacterial community structure in dry dairy cows fed hay-based diets. AB - The objectives of this study were to evaluate the influence of diet composition on ruminal parameters, more particularly redox potential (Eh). Four Holstein dry dairy cows, fitted with ruminal cannulas, were allocated in a 4 * 4 Latin square design. They were given four experimental hay-based diets D0, D25, D42 and D56 consisting of 0%, 25%, 42% and 56% of ground wheat and barley concentrate mixture, respectively. They were fed at a daily feeding rate of 8.0 kg DM per cow during a 24-day experimental period (a 21-day diet adaptation, three consecutive days of measurement and sampling). The physicochemical parameters, such as pH and Eh, were measured and Clark's exponent (rH) was calculated from 1 h before feeding to 8 h after feeding at 1-h interval. Samples of ruminal fluid were taken at 0, 1, 2, 4, 6 and 8 h after feeding for the determination of volatile fatty acid (VFA) and ammonia N (NH3-N) concentrations. Ruminal bacterial populations were also studied by means of capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) technique to focus on the structure of the ruminal microbiota and the diversity index was calculated. Mean ruminal Eh and rH were not modified by the concentrate-to-forage ratio and averaged - 210 mV and 6.30, respectively, across diets. The pH decreased slightly by 0.10 pH unit between treatments D0 and D56 with an average of 6.58. Nevertheless, the time during which physicochemical parameters remained at nadir value after feeding varied with diets: 2 and 7 h for D0 and 6 and 5 h for D56, respectively for pH and Eh. Moreover, fermentative parameters were altered by treatments: total VFA and NH3-N were greater in D56 (72.2 mM and 17.5 mg/100 ml) compared with D0 (65.2 mM and 14.2 mg/100 ml). However, neither the structure of bacterial populations of the rumen nor the diversity index (Shannon) was altered by treatments. PMID- 22445117 TI - Whole inedible date in the grower-finisher broiler diets and the impact on productive performance, nutrient digestibility and meat quality. AB - The growth performance, carcass characteristics and meat quality measurements were evaluated on broiler chicks fed different dietary levels of whole inedible dates (WID). WID used in this study were consisted of date fruits (~850 g/kg) and date pits (~150 g/kg). Three hundred unsexed Lohman broiler chicks were randomly and equally distributed into six groups. Each was formed of 50 chicks (five replicates, 10 chicks per replicate), and was assigned to a dietary treatment. Six dietary treatments of WID (0, 30, 60, 90, 120 and 150 g/kg feed) were included in the formation of isocaloric (metabolizable energy of ~3060 kcal/kg feed) and isonitrogenous (CP of ~192 g/kg feed) broiler rations. The treated rations were fed to the group chicks between 15 and 42 days of age (the experimental period). A straight-run design was considered. At 42 days of age, five males from each treatment were randomly chosen and slaughtered to determine carcass characteristics, internal organs and meat quality measurements. Digestibility of nutrients was measured at the end of the experimental period using five caged-individual males per treatment. The inclusion of broiler rations on WID for up to 150 g/kg feed, over the experimental period, did not significantly influence body weight gain (1452 to 1521 g/chick), feed intake (3268 to 3621 g/chick), feed conversion ratio (2.26 to 2.36 kg/kg) and dressed carcass (63.4% to 67.3%). In addition, levels of WID for up to 150 g/kg feed did not significantly influence the digestibility of nutrients and meat quality measurements. Such results suggest the possible inclusion of broiler rations on WID for up to 150 g/kg feed, during the period of 15 to 42 days of age without adverse effects on growth performance and meat quality. PMID- 22445118 TI - Increasing weaning age of piglets from 4 to 7 weeks reduces stress, increases post-weaning feed intake but does not improve intestinal functionality. AB - This study tested the hypothesis that late weaning and the availability of creep feed during the suckling period compared with early weaning, improves feed intake, decreases stress and improves the integrity of the intestinal tract. In this study with 160 piglets of 16 litters, late weaning at 7 weeks of age was compared with early weaning at 4 weeks, with or without creep feeding during the suckling period, on post-weaning feed intake, plasma cortisol (as an indicator of stress) and plasma intestinal fatty acid binding protein (I-FABP; a marker for mild intestinal injury) concentrations, intestinal morphology, intestinal (macro)molecular permeability and intestinal fluid absorption as indicators of small intestinal integrity. Post-weaning feed intake was similar in piglets weaned at 4 weeks and offered creep feed or not, but higher (P < 0.001) in piglets weaned at 7 weeks with a higher (P < 0.05) intake for piglets offered creep feed compared with piglets from whom creep feed was witheld. Plasma cortisol response at the day of weaning was lower in piglets weaned at 7 weeks compared with piglets weaned at 4 weeks, and creep feed did not affect cortisol concentration. Plasma I-FABP concentration was not affected by the age of weaning and creep feeding. Intestinal (macro)molecular permeability was not affected by the age of weaning and creep feeding. Both in uninfected and enterotoxigenic Escherichia coli-infected small intestinal segments net fluid absorption was not affected by the age of weaning or creep feeding. Creep feeding, but not the age of weaning, resulted in higher villi and increased crypt depth. In conclusion, weaning at 7 weeks of age in combination with creep feeding improves post-weaning feed intake and reduces weaning stress but does not improve functional characteristics of the small intestinal mucosa. PMID- 22445119 TI - Fate of transgenic DNA and evaluation of metabolic effects in goats fed genetically modified soybean and in their offsprings. AB - The presence of DNA fragments in blood and milk from goats fed conventional (control) or Roundup Ready(r) soybean meal solvent extracted (s.e.; treated) was investigated by using a polymerase chain reaction approach. The same investigation was carried out on blood, skeletal muscle and organs from kids of both groups fed only dams' milk until weaning. Moreover, the possible effects on cell metabolism were evaluated by determination of several specific enzymes in serum, heart, skeletal muscle, liver and kidney. Fragments of the multicopy chloroplast (trnL) gene were found in blood and milk samples from goats of both groups. In kids, the chloroplast fragments were found in samples of both groups. In samples, which proved positive for the presence of chloroplast DNA, fragments of the specific soybean single copy gene (lectin) were detected in several blood and milk samples. The same fragment was also found in control and treated groups of kids. Transgenic fragments were not found in those samples, which were found positive for chloroplast fragments of control groups of either goats or kids. On the contrary, in blood and milk of treated goats, fragments both of the 35S promoter and the CP4 epsps gene were detected. These fragments were also found in treated kids with a significant detection of the 35S promoter in liver, kidney and blood, and of the CP4 epsps gene fragment in liver, kidney, heart and muscle. A significant increase in lactic dehydrogenase, mainly concerning the lactic dehydrogenase-1 isoenzyme was found in heart, skeletal muscle and kidney of treated kids, thus suggesting a change in the local production of the enzyme. Finally, no significant differences were detected concerning kid body and organ weight. PMID- 22445120 TI - Enzyme activity and acute phase proteins in milk utilized as indicators of acute clinical E. coli LPS-induced mastitis. AB - The importance of non-visual and on-line monitoring of udder health increases as the contact between humans and animals decreases, for example, in robotic milking systems. Several indicator systems have been introduced commercially, and a number of techniques are currently in use. This study describes the kinetics of seven indigenous milk parameters for monitoring udder inflammation in an Escherichia coli lipopolysaccharide (LPS, endotoxin)-induced mastitis model. Proportional milk from LPS-infused quarters was compared with milk from parallel quarters, which were placebo-treated with sterile 0.9% NaCl solution. Somatic cell counts (SCCs), the acute phase proteins (APP), that is, milk amyloid A (MAA) and haptoglobin (Hp), and the enzymes N-acetyl-beta-D-glucosaminidase (NAGase), lactate dehydrogenase (LDH), alkaline phosphatase (AP) and acid phosphatase (AcP) were measured at fixed intervals during the period from -2 to +5 days after LPS and NaCl infusions. All parameters responded significantly faster and were more pronounced to the LPS infusions compared with the NaCl infusions. All parameters were elevated in the proportional milk collected at the first milking 7 h after infusion and developed a monophasic response, except Hp and MAA that developed biphasic response. SCC, LDH, NAGase and Hp peaked at 21 h followed by AP, AcP and MAA peaking at 31 h with the highest fold changes seen for MAA (23 780*), LDH (126*), NAGase (50*) and Hp (16*). In the recovery phase, AP, AcP and Hp reached base levels first, at 117 h, whereas LDH, NAGase and MAA remained elevated following the pattern of SCC. Minor increases of the milk parameters were also seen in the neighboring (healthy) quarters. Distinction between inflamed and healthy quarters was possible for all the parameters, but only for a limited time frame for AP and AcP. Hence, when tested in an LPS mastitis model, the enzymes LDH, NAGase and AP in several aspects performed equally with SCC and APP as inflammatory milk indicators of mastitis. Furthermore, these enzymes appear potent in the assessment of a valuable time sequence of inflammation, a necessary ingredient in modeling of programs in in-line surveillance systems. PMID- 22445121 TI - Effects of dietary l-arginine supplementation to gilts during early gestation on foetal survival, growth and myofiber formation. AB - The effects of l-arginine on porcine foetal development and myogenesis were determined. Twenty Swiss Large White gilts were randomly allocated to either the control (C) or l-arginine treatment (A). In addition to the standard gestation diet, A-sows received 26 g l-arginine daily from days 14 to 28 of gestation. At day 75 of pregnancy, sows were sacrificed and the number and weight of foetuses were recorded. From each litter, the lightest, heaviest and the ones with an average foetal weight (FtW) were selected. Primary (P), secondary (S) and total myofiber number as well as S/P ratio were determined in the semitendinosus (ST) and rhomboideus (RH) muscles. In A-sows, the number of viable foetuses (13.0 v. 9.3) and total FtW (4925 v. 3729 g) was greater (P ? 0.04) than in C-sows. Compared to C-sow foetuses, the ST of A-sow foetuses had 7% more (17 699 v. 16 477; P = 0.04) P myofibers and the S/P ratio in both muscles was lower (ST = 20.3 v. 21.5; RH = 24.1 v. 27.1; P ? 0.07). Regardless of the maternal diet, the S myofiber number and the S/P ratio in both muscles were greater (P ? 0.01) in foetuses with a high FtW compared to low FtW. These data suggest that l-arginine supplemented to gilts during early gestation enhanced foetal survival and in the ST positively affected the primary phase of myofiber formation. PMID- 22445122 TI - Early life experiences affect the adaptive capacity of rearing hens during infectious challenges. AB - This study aimed to investigate whether pre- and early postnatal experiences of rearing hens contribute to the ability to cope with infectious challenges at an older age. In a 2 * 2 factorial arrangement, 352 Lohmann Brown chicks were exposed to either suboptimal or optimized incubation plus hatch conditions, and to cage or enriched rearing from week 0 to 7 of age. After week 7 all rearing conditions were similar until the end of the experiment. The development of adaptive capacity to infectious challenges was investigated by introducing an Eimeria and Infectious Bronchitis (IB) infection on day 53 and day 92, respectively. BW gain and feed intake during the infections, duodenal lesions and amount of positive stained CD4+ T cells, CD8+ T cells and macrophages at day 4 and day 7 after Eimeria infection, as well as the IB antibody titer throughout the experimental period were determined. The results showed a significant interaction between incubation plus hatch and rearing environment. Optimized incubation plus hatch conditions followed by an enriched rearing environment resulted in the least weight loss (P < 0.05) and the highest feed intake (P < 0.01) from day 3 to day 7 after the Eimeria infection (day 56 to 60 of age), compared with all other treatments. In addition, the optimized * enriched chicks had the highest BW gain from day 7 to day 14 after IB infection (day 99 to 106 of age), compared with chicks housed in a cage environment (P < 0.01). Besides the interaction, optimized incubation plus hatch alone resulted in reduced macrophage numbers in the duodenal tissue at day 4 after Eimeria infection, compared with suboptimal incubation plus hatch, whereas the enriched rearing environment stimulated the recovery of intestinal damage caused by Eimeria (P < 0.05) and reduced the production of specific antibodies after IB infection (P < 0.05), compared with the cage environment. In conclusion, this study shows that early life experiences can indeed affect the capacity of rearing hens to cope with an Eimeria and IB infection at an older age, in which performance of chicks is best maintained after optimized incubation plus hatch followed by enriched rearing. This suggests that the development of adaptive capacity to infectious challenges can be influenced with management during a short period in pre- or early postnatal life, but that effects last for a considerable time after cessation of the specific management. PMID- 22445123 TI - A comparison of the occurrence of common dental abnormalities in stabled and free grazing horses. AB - The purpose of this study was to gain evidence on the prevalence of dental abnormalities in stable-kept horses in comparison with free-living horses. It is expected that free-living horses that graze for as much as 16 h/day will have fewer dental abnormalities than stable-kept horses. In this study, the latter group was fed a diet that was based on a relatively high-energy, cereal-based feed. This was thought to be a representative of common practice in domesticated, stable-kept horses. Compound diets such as this have previously been shown to increase the frequency of chewing cycles and decrease mediolateral excursion. The occurrence of 10 named dental abnormalities present in the dentition of 60 Thoroughbred-type horses was recorded. Half of the population was at grass all year round in New South Wales, Australia. The remainder were stabled for 24 h/day in Gloucestershire, UK. All horses were between 5 and 15 years of age. The same, experienced, equine dental technician examined all horses using a full-mouth speculum and produced a routine dental chart. Stable-kept horses had a significantly higher total occurrence of abnormalities (P < 0.001) than free living horses. The stable-kept group had a significantly higher prevalence of exaggerated transverse ridging across the occlusal surface of the cheek teeth, focal or ramped overgrowths of the cheek teeth and periodontal disease (P < 0.01 in all cases). All horses in both groups had some occurrence of sharp edges of the buccal and lingual edges of the cheek teeth. The results are in agreement with anecdotal evidence that a fibre-based, grazed diet results in fewer dental abnormalities. However, sharp edges may occur even with what is perceived as a 'natural' diet. PMID- 22445124 TI - Immunomodulatory effects of ovine serum immunoglobulin in the growing rat. AB - This study aimed to determine whether orally administered ovine serum immunoglobulin (Ig) modulates aspects of immunity such as phagocytosis, lymphocyte proliferation, cytokine production, intestinal and plasma Ig concentrations in growing rats. Forty-five male Sprague-Dawley rats (n = 15/group) were used in the 21-day study, and fed a basal control diet (BD; no Ig) or two test diets: freeze-dried ovine Ig (FDOI) and inactivated ovine Ig (IOI). Phagocytic activity of peripheral blood leukocytes and lymphocyte proliferation in the presence of the mitogen concanavalin A (ConA) was greater (P < 0.05) for the FDOI-fed rats than for the BD- and IOI-fed groups. ConA-stimulated and unstimulated spleen cell culture produced higher (P < 0.05) interferon-gamma and interleukin-4, respectively, from rats fed the FDOI than rats fed the BD diet. In the jejunum, ileum and plasma, rats fed FDOI produced higher (P < 0.05) concentrations of secretory IgA (sIgA) than rats fed IOI or BD. Rats fed the FDOI diet had greater jejunal (P = 0.037) and lower plasma (P = 0.025) rat IgG concentrations than rats fed either BD or IOI. In conclusion, an ovine Ig fraction selectively modulated various indices of immune function. PMID- 22445125 TI - Effects of housing conditions during the rearing and laying period on adrenal reactivity, immune response and heterophil to lymphocyte (H/L) ratios in laying hens. AB - This study was conducted to evaluate the effect of early rearing conditions on physiological, haematological and immunological responses relevant to adaptation and long-term stress in white Leghorn hens with intact beaks housed in furnished cages (FC) or conventional cages (CC) during the laying period. Pullets were cage reared (CR) or litter floor reared (FR). From 16 to 76 weeks of age, hens were housed in FC (eight hens per cage) or in CC (three hens per cage). As measures of long-term stress at the end of the laying period, adrenal reactivity was quantified by assessing corticosterone responses to adrenocorticotropin challenge, and immune response was assessed by measuring antibody responses after immunization with sheep red blood cells (SRBC) and keyhole limpet haemocyanin (KLH). Heterophil to lymphocyte (H/L) ratio was employed as an indicator of stress. Rearing conditions significantly affected anti-SRBC titres (P < 0.0001) and tended to affect H/L ratios (P = 0.07), with the highest values found in FR hens. Layer housing affected H/L ratio (P < 0.01); the highest ratio was found in FR birds housed in FC during the laying period. This study shows that early rearing environment affects immunological indicators that are widely used to assess stress in laying hens. However, while results on H/L ratio indicated that FR birds experienced more stress particularly when they were housed in FC during the laying period, the immune responses to SRBC in FR hens was improved, indicating the opposite. This contradiction suggests that the effects on immune response may have been associated with pathogenic load due to environmental complexity in FR and FC hens rather than stress due to rearing system or housing system per se. PMID- 22445126 TI - Effects of available surface on gaseous emissions from group-housed gestating sows kept on deep litter. AB - In the European Union, the group-housed pregnant sows have to have a minimal legal available area of 2.25 m2/sow. However, it has been observed that an increased space allowance reduces agonistic behaviour and consecutive wounds and thus induces better welfare conditions. But, what about the environmental impacts of this greater available area? Therefore, the aim of this study was to quantify pollutant gases emissions (nitrous oxide, N2O, methane, CH4, carbon dioxide, CO2 and ammonia, NH3), according to the space allowance in the raising of gestating sows group-housed on a straw-based deep litter. Four successive batches of 10 gestating sows were each divided into two homogeneous groups and randomly allocated to a treatment: 2.5 v. 3.0 m2/sow. The groups were separately kept in two identical rooms. A restricted conventional cereals based diet was provided once a day in individual feeding stalls available only during the feeding time. Rooms were automatically ventilated. The gas emissions were measured by infra red photoacoustic detection during six consecutive days at the 6th, 9th and 12th weeks of gestation. Sows performance (body weight gain, backfat thickness, number and weight of piglets) was not significantly different according to the space allowance. In the room with 3.0 m2/sow and compared with the room with 2.5 m2/sow, gaseous emissions were significantly greater for NH3 (6.29 v. 5.37 g NH3 N/day per sow; P < 0.01) and significantly lower for N2O (1.78 v. 2.48 g N2O N/day per sow; P < 0.01), CH4 (10.15 v. 15.21 g/day per sow; P < 0.001), CO2 equivalents (1.11 v. 1.55 kg/day per sow; P < 0.001), CO2 (2.12 v. 2.41 kg/day per sow; P < 0.001) and H2O (3.10 v. 3.68 kg/day per sow; P < 0.001). In conclusion, an increase of the available area for group-housed gestating sow kept on straw-based deep litter seems to be ambiguous on an environmental impacts point of view. Compared with a conventional and legal available area, it favoured NH3 emissions, probably due to an increased emitting surface. However, about greenhouse gases, it decreased N2O, CH4 and CO2 emissions, probably due to reduced anaerobic conditions required for their synthesis, and led to a reduction of CO2 equivalents emissions. PMID- 22445127 TI - Resource use efficiency in urban and peri-urban sheep, goat and cattle enterprises. AB - Urban livestock husbandry receives growing attention given the increasing urban demand for livestock products. At the same time, little is known about the resource use efficiency in urban livestock enterprises and eventual negative externalities. In livestock production, feeds are an important resource whose nutrients are transformed into products (meat and milk) to generate financial return to the producer. The lack of knowledge on nutrient supply through feed might lead to oversupply with severe environmental impacts. In Niamey, a typical West African city and capital of the Republic of Niger, urban livestock production is constrained by feed scarcity, especially during the dry season. Here, the issue of resource use efficiency was studied in 13 representative and differently managed sheep/goat and cattle enterprises characterized by high and low feed inputs, respectively, during a period of 28 months. Nitrogen (N), phosphorus (P) and potassium (K) inflows into each farm through livestock feeds and outflows through manure were determined using a semi-structured questionnaire; interviews were accompanied by regular weighing of feed supplied and dung produced. Live weight gain (LWG) and efficiency of conversion of total feed dry matter offered (kg TDMO/kg LWG) were computed along with nutrient balances (NBs) per metabolic body mass (kg0.75). NBs (per kg0.75/day) in the high input (HI) sheep/goat enterprises were +1762.4 mg N, +127.2 mg P and +1363.5 mg K and were significantly greater (P < 0.05) than those in low-input (LI) units (+69.1 mg N, -98.3 mg P and +16.5 mg K). In HI cattle enterprises, daily balances averaged +454.1 mg N, +40.1 mg P and +341.8 mg K compared to +34.4 mg N, -9.0 mg P and +68.3 mg K (P > 0.05) in LI cattle systems. All systems were characterized by poor conversion efficiencies of offered feed, which ranged from 13.5 to 46.1 kg TDMO/kg LWG in cattle and from 15.7 to 43.4 kg TDMO/kg LWG in sheep/goats. LWG in HI sheep/goats was 53 g/day in the rainy season, 86 g/day in the hot dry season and 104 g/day in the cool dry season, while HI cattle lost 79 g/day in the hot dry season and gained 121 g/day and 92 g/day in the cool dry and rainy seasons, respectively. The data indicate that there is nutrient wasting and scope for improvement of feeding strategies in Niamey's livestock enterprises, which might also decrease nutrient losses to the urban environment. PMID- 22445128 TI - Investigation of uniformity in pig carcass and meat quality traits. AB - The study was carried out to provide information on uniformity of commercial pigs on some of the most important traits determining pork quality: carcass, loin, ham and shoulder weights, fatness, drip loss, pH and colour. Three batches of pigs raised at the same farm and slaughtered at four different dates in the same commercial abattoir were considered. Batches included halothane-free females and castrated males, Duroc and Pietrain sire lines and two slaughter weights, but a common maternal line. The first batch was obtained using commercial Duroc sire boars, and included a total of 112 animals (56 castrated males and 56 females). The second batch used Duroc and Pietrain sire boars with the target to achieve two different final weights (105 and 115 kg live weight); 128 animals were controlled (64 castrated males and 64 females), 16 for each combination of sire boar, sex and final weight. The last batch used only Pietrain sire boars with 96 controlled pigs (48 castrated males and 48 females). The uniformity was measured by the coefficient of variation (CV) and the coefficient of dispersion (CD) for all data available, and for groups of common sex, sire breed and slaughter weight. Differences in uniformity were tested among traits and groups by using confidence intervals (CIs) at 95% confidence level (CI95%) for the CV and CD. Results showed a significantly lower uniformity for drip loss (CV = 40.4%, CI95% 36.9% to 44.7%; CD = 32.1%, CI95% 28.7% to 35.4%) and backfat (CV = 22.8%, CI95% 21.1% to 24.8%; CD = 18.3%, CI95% 17.1% to 20.2%) the pH being the most uniform trait (CV = 3.2%, CI95% 3.0% to 3.5%; CD = 2.6%, CI95% 2.4% to 2.9%). When comparing different 'sire breed-sex-slaughter weight' groups, no consistent sex and slaughter weight differences in uniformity were found, but animals from Pietrain sire breed showed a tendency to be less uniform for carcass traits than animals from Duroc sire breed. Nevertheless, variability within those groups was very high and often similar to that observed when considering all the animals from all the groups. Small differences were found comparing uniformity when using the CV or the CD. CIs of these coefficients have proved to be a simple and useful tool for testing differences in uniformity. PMID- 22445129 TI - Rangeland utilization in Mediterranean farming systems. AB - In the countries surrounding the Mediterranean basin, most of the semi-natural grazing lands are covered by rangelands. Rangelands can be defined as highly heterogeneous natural vegetation communities with high conservation value, growing in harsh environments (poor soils, unfavourable climatic conditions). In the recent socio-economic context, traditional livestock grazing practices that enabled one to reconcile rangeland preservation and animal production no longer apply, especially because they require labour that has become scarce and costly. The consequence is rangeland degradation, due to underutilization in Southern Europe, and overutilization in Northern Africa. We analysed issues raised by rangeland utilization in livestock farming systems of the Mediterranean basin. Based on a review of the scientific literature about rangeland utilization in this area, we argue that the best way to reconcile animal production and rangeland preservation would be to promote management practices allowing animals to express their adaptative capacities in feeding behaviour and productive response. In order to propose management practices adapted to extensive and simplified systems, we conclude that research efforts should focus on: (i) proposing a functional characterization of vegetation heterogeneity at the scale of the vegetation community, (ii) validating the criteria determining animals' foraging behaviour on Mediterranean rangelands, (iii) developing and using simulation models to test management strategies against seasonal and long-term variability in climatic conditions and (iv) evaluating the potential of modern technologies for improving rangeland utilization. PMID- 22445130 TI - Economic consequences of mastitis and withdrawal of milk with high somatic cell count in Swedish dairy herds. AB - The main aim was to assess the impact of mastitis on technical and economic results of a dairy herd under current Swedish farming conditions. The second aim was to investigate the effects obtained by withdrawing milk with high somatic cell count (SCC). A dynamic and stochastic simulation model, SimHerd, was used to study the effects of mastitis in a herd with 150 cows. Results given the initial incidence of mastitis (32 and 33 clinical and subclinical cases per 100 cow years, respectively) were studied, together with the consequences of reducing or increasing the incidence of mastitis by 50%, modelling no clinical mastitis (CM) while keeping the incidence of subclinical mastitis (SCM) constant and vice versa. Six different strategies to withdraw milk with high SCC were compared. The decision to withdraw milk was based on herd-level information in three scenarios: withdrawal was initiated when the predicted bulk tank SCC exceeded 220 000, 200 000 or 180 000 cells/ml, and on cow-level information in three scenarios: withdrawal was initiated when the predicted SCC in an individual cow's milk exceeded 1 000 000, 750 000 or 500 000 cells/ml. The accuracy with which SCC was measured and predicted was assumed to affect the profitability of withdrawing milk with high SCC and this was investigated by applying high, low or no uncertainty to true SCC. The yearly avoidable cost of mastitis was estimated at ?8235, assuming that the initial incidence of mastitis could be reduced by 50%. This cost corresponded to 5% of the herd net return given the initial incidence of mastitis. Expressed per cow-year, the avoidable cost of mastitis was ?55. The costs per case of CM and SCM were estimated at ?278 and ?60, respectively. Withdrawing milk with high SCC was never profitable because this generated a substantial amount of milk withdrawal that was not offset by a sufficient increase in the average price per delivered kg milk. It had the most negative impact on net return when high incidence of mastitis was simulated. Withdrawing milk with high SCC based on low-uncertainty information reduced the amount of withdrawn milk and thus resulted in less negative effect on net return. It was concluded that the current milk-pricing system makes it more profitable for farmers to sell a larger amount of milk with higher SCC than to withdraw milk with high SCC to obtain payment premiums, at least in herds with mastitis incidences within the simulated ranges. PMID- 22445131 TI - Effect of weight at slaughter and breed on beef intramuscular lipid classes and fatty acid profile. AB - The effect of slaughter weight and breed on the composition of intramuscular fat (IMF) of seven Spanish cattle breeds was studied. Lipid classes and fatty acids were evaluated in young bulls of seven local Spanish cattle breeds, Asturiana, Avilena, Morucha, Parda Alpina, Pirenaica, Retinta and Rubia Gallega, slaughtered at a live weight of 320 kg (veal type) and 550 kg (yearling bull type). Higher slaughter weight and early maturating breeds produced higher IMF content in the longissimus muscle (P < 0.001), which was linked to a reduction in phospholipids, monoglycerides, diglycerides, cholesterol and free-fatty acids content, but an increase in triacylglycerols. Besides, heavier animals displayed a higher percentage of saturated and monounsaturated fatty acids (MUFA), but a lower polyunsaturated fatty acids (PUFA) percentage (P < 0.001). The increase in triglycerides (TG), saturated fatty acids (SFA) and MUFA illustrates the increasing importance of lipid storage as fattening proceeds and the acquisition of ruminal functionality. The feeding system based on cereals had a strong influence on the fatty acid profile, giving the studied beef a relatively high PUFA/SFA and n-6/n-3 ratios. PMID- 22445132 TI - Solid-state NMR in materials for energy storage and conversion. PMID- 22445133 TI - Pulmonary function in children with idiopathic scoliosis. AB - Idiopathic scoliosis, a common disorder of lateral displacement and rotation of vertebral bodies during periods of rapid somatic growth, has many effects on respiratory function. Scoliosis results in a restrictive lung disease with a multifactorial decrease in lung volumes, displaces the intrathoracic organs, impedes on the movement of ribs and affects the mechanics of the respiratory muscles. Scoliosis decreases the chest wall as well as the lung compliance and results in increased work of breathing at rest, during exercise and sleep. Pulmonary hypertension and respiratory failure may develop in severe disease. In this review the epidemiological and anatomical aspects of idiopathic scoliosis are noted, the pathophysiology and effects of idiopathic scoliosis on respiratory function are described, the pulmonary function testing including lung volumes, respiratory flow rates and airway resistance, chest wall movements, regional ventilation and perfusion, blood gases, response to exercise and sleep studies are presented. Preoperative pulmonary function testing required, as well as the effects of various surgical approaches on respiratory function are also discussed. PMID- 22445134 TI - Comparison of cardiac positron emission tomography perfusion defects during stress induced by hemodialysis versus adenosine. AB - The cardiac stress imposed by hemodialysis may differ from that induced by pharmacologic agents used for myocardial perfusion imaging-based stress testing. With repetitive intradialytic [(13)N]ammonia positron emission tomography, we showed that standard hemodialysis had an acute adverse effect on cardiac perfusion and left ventricular function that was not detected by standard diagnostic adenosine stress testing. PMID- 22445135 TI - Close to threshold transcranial electrical stimulation preferentially activates inhibitory networks before switching to excitation with higher intensities. AB - BACKGROUND: Recently we have shown that transcranial random noise (tRNS) and 140 Hz transcranial alternating current stimulations (tACS), applied over the primary motor cortex (M1) and using 10 min stimulation duration and 1 mA intensity, significantly increases cortical excitability as measured by motor evoked potentials at rest before and after stimulation. OBJECTIVE/HYPOTHESIS: Here, by decreasing the stimulation intensity in 0.2 mA steps from 1.0 mA, we investigate to what extent intensity depends on the induced after-effects. METHODS: All twenty-five subjects participated in two different experimental sessions each. They received tACS using 140 Hz frequency and full spectrum tRNS at five different intensities on separate days. Sham stimulation was used as a control. RESULTS: Instead of receiving a simple threshold, unexpectedly, in these two independent data sets at threshold intensities of 0.4 mA we found a switch of the already known excitation achieved with an intensity of 1 mA to inhibition. The intermediate intensity ranges of 0.6 and 0.8 mA had no effect at all. Interestingly, the inhibition produced by 140 Hz tACS was stronger than that induced by tRNS. CONCLUSIONS: In summary, we have shown here the possibility of selectively controlling the enhancement or reduction of M1 excitability by applying different intensities of high frequency transcranial electrical stimulation. PMID- 22445136 TI - Placebo forte: ways to maximize unspecific treatment effects. AB - Placebo effects spark more and more interest in both medicine and psychotherapy. Neurobiological findings have helped to understand underlying biochemical and neurological mechanisms although many questions remain to be answered. One common denominator of empirical findings regarding placebo effects across a wide range of clinical conditions (e.g., depression, Parkinson's disease, pain, neurological disorders) is the involvement of higher cognitive brain functions associated with the prefrontal cortex. It is meanwhile commonly accepted that placebo effects involve self-regulatory mechanisms whose role in mediating those effects have not been thoroughly investigated yet. We propose a theoretical framework which helps to identify relevant functional mechanisms. Drawing on psychological findings, we propose a mechanism by which placebo effects can be maximized in any type of medical and psychotherapeutic setting. PMID- 22445137 TI - IMRT for locally advanced anal cancer: clinical experience of the Montpellier Cancer Center. AB - PURPOSE: To assess outcomes of patients with carcinoma of the anal canal (CAC) treated with intensity-modulated radiation therapy (IMRT). METHOD AND MATERIALS: From August 2007 to January 2011, seventy-two patients suffering from CAC were treated with IMRT. Concurrent chemotherapy was added in case of locally advanced tumors. Radiation course consisted in delivering an initial plan to the PTV1 defined as the primary tumor and the risk area including pelvic and inguinal nodes. Forty-five Gy in daily 1.8 Gy-daily fractions were delivered five days a week. A second plan of 14.4-20 Gy to the primary tumor (PTV2) was administered in 1.8-2 Gy-daily fractions, 5 days a week. We present here the results of dosimetry, toxicities, and clinical outcome of the first 39 patients with a median follow-up of 24 months. RESULTS: Thirty-one women and eight men were included in the present analysis. Tumors were classified as stages I, II, III and IV in 2, 7, 27 and 2 patients, respectively. Median age was 59 years (range, 38 85). Radiotherapy alone (RT) or combined with chemotherapy (RCT) were delivered in 6 (15%) and 33 (85%) patients, respectively.Six patients (15%) required a treatment break >= 3 days, and median time for treatment break was 8 days (range, 3-14 days). Acute grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were seen in 10 and 5% of patients, respectively. Grade 4 toxicity was only hematologic and occurred in 12% patients receiving RCT. With a median follow-up of 24 months, no patient experienced any late grade 4 toxicity. The 2-year overall survival rate was 89%, the 2-year local relapse free survival was 77% and the 2-year colostomy-free survival rate was 85%. CONCLUSION: IMRT is well tolerated with acceptable treatment interruption allowing dose escalation. PMID- 22445138 TI - Pathologic prostate cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of contemporary protocols. AB - BACKGROUND: Although the rationale for active surveillance (AS) in patients with low-risk prostate cancer is well established, eligibility criteria vary significantly across different programs. OBJECTIVE: To compare the ability of contemporary AS criteria to identify patients with certain pathologic tumor features based on the results of an extended transrectal prostate biopsy. DESIGN, SETTINGS, AND PARTICIPANTS: The study cohort included 391 radical prostatectomy patients who had prostate cancer with Gleason scores <= 6 on transrectal biopsy with >= 10 cores. INTERVENTION: Radical prostatectomy without neoadjuvant treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We identified patients who fulfilled the inclusion criteria of five AS protocols including those of Epstein, Memorial Sloan-Kettering Cancer Center, Prostate Cancer Research International: Active Surveillance (PRIAS), University of California, San Francisco, and University of Miami (UM). We evaluated the ability of these criteria to predict three pathologic end points: insignificant disease defined using a classical and updated formulation, and organ-confined Gleason <= 6 prostate cancer. Measures of diagnostic accuracy and areas under the receiver operating curve were calculated for each protocol and compared. RESULTS AND LIMITATIONS: A total of 75% of the patients met the inclusion criteria of at least one protocol; 23% were eligible for AS by all studied criteria. The PRIAS and UM criteria had the best balance between sensitivity and specificity for both definitions of insignificant prostate cancer and a higher discriminative ability for the end points than any criteria including patients with two or more positive cores. The Epstein criteria demonstrated high specificity but low sensitivity for all pathologic end points, and therefore the discriminative ability was not superior to those of other protocols. CONCLUSIONS: Significant variations exist in the ability of contemporary AS criteria to predict pathologically insignificant prostate cancer at radical prostatectomy. These differences should be taken into account when making treatment choices in patients with low-risk prostate cancer. PMID- 22445139 TI - Selected hormonal and neurotransmitter mechanisms regulating feed intake in sheep. AB - Appetite control is a major issue in normal growth and in suboptimal growth performance settings. A number of hormones, in particular leptin, activate or inhibit orexigenic or anorexigenic neurotransmitters within the arcuate nucleus of the hypothalamus, where feed intake regulation is integrated. Examples of appetite regulatory neurotransmitters are the stimulatory neurotransmitters neuropeptide Y (NPY), agouti-related protein (AgRP), orexin and melanin concentrating hormone and the inhibitory neurotransmitter, melanocyte-stimulating hormone (MSH). Examination of messenger RNA (using in situ hybridization and real time PCR) and proteins (using immunohistochemistry) for these neurotransmitters in ruminants has indicated that physiological regulation occurs in response to fasting for several of these critical genes and proteins, especially AgRP and NPY. Moreover, intracerebroventricular injection of each of the four stimulatory neurotransmitters can increase feed intake in sheep and may also regulate either growth hormone, luteinizing hormone, cortisol or other hormones. In contrast, both leptin and MSH are inhibitory to feed intake in ruminants. Interestingly, the natural melanocortin-4 receptor (MC4R) antagonist, AgRP, as well as NPY can prevent the inhibition of feed intake after injection of endotoxin (to model disease suppression of appetite). Thus, knowledge of the mechanisms regulating feed intake in the hypothalamus may lead to mechanisms to increase feed intake in normal growing animals and prevent the wasting effects of severe disease in animals. PMID- 22445140 TI - Endocrine and metabolic regulation of muscle growth and body composition in cattle. AB - Muscle metabolism (in interaction with other organs and tissues, including adipose tissue) plays an important role in the control of growth and body composition. Muscle ontogenesis has been described in different genotypes of cattle for myofibres, connective tissue and intramuscular depots. The ontogenesis or the action of putatively important factors controlling muscle development (IGF II expression, IGF receptors, growth hormone (GH) receptor, myostatin, basic fibroblast growth factor, transforming growth factor-beta1, insulin and thyroid hormones) has also been studied on bovine foetal muscle samples and satellite cells. The glucose/insulin axis has been specifically studied in both the bovine adipose tissue and heart. Clearly, cattle, like sheep, are mature species at birth based on their muscle characteristics compared to other mammalian or farm animal species. The different myoblast generations have been well characterised in cattle, including the second generation which is liable to be affected by foetal undernutrition at least in sheep. Interesting genotypes, for example, double-muscled genotype, have been characterised by an altered metabolic and endocrine status associated with a reduced fat mass, specific muscle traits and different foetal characteristics. Finally, the recent development of genomics in cattle has allowed the identification of novel genes controlling muscle development during foetal and postnatal life. Generally, a high muscle growth potential is associated with a reduced fat mass and a switch of muscle fibres towards the glycolytic type. The possibility and the practical consequences of manipulating muscle growth and, hence, body composition by nutritional and hormonal factors are discussed for bovines based on our current biological knowledge. PMID- 22445141 TI - Predicting beef carcass composition using tissue weights of a primal cut assessed by computed tomography. AB - The potential of the composition of the forerib measured by X-ray computed tomography (CT) as a predictor of carcass composition was evaluated using data recorded on 30 Aberdeen Angus and 43 Limousin crossbred heifers and steers. The left sides of the carcasses were split into 20 cuts, which were CT scanned and fully dissected into fat, muscle and bone. Carcass and forerib tissue weights were assessed by dissection and CT. Carcass composition was assessed very accurately by CT scanning of the primal cuts (adj-R2 = 0.97 for the three tissues). CT scanning predicted weights of fat, muscle and bone of the forerib with adj-R2 of 0.95, 0.91 and 0.75, respectively. Single regression models with the weights of fat, muscle or bone in the forerib measured by CT as the only predictors to estimate fat, muscle or bone of the left carcass obtained by CT showed adjusted coefficients of determination (adj-R2) of 0.79, 0.60 and 0.52, respectively. By additionally fitting breed and sex, accuracy increased to 0.85, 0.73 and 0.67. Using carcass and forerib weights in addition to the previous predictors improved significantly the prediction accuracy of carcass fat and muscle weights to adj-R2 values of 0.92 and 0.96, respectively, while the highest value for carcass bone weight was 0.77. In general, equations derived using CT data had lower adj-R2 values for bone, but better accuracies for fat and muscle compared to those obtained using dissection. CT scanning could be considered as an alternative very accurate and fast method to assess beef carcass composition that could be very useful for breeding programmes and research studies involving a large number of animals, including the calibration of other indirect methods (e.g. in vivo and carcass video image analysis). PMID- 22445142 TI - Bovine mtDNA D-loop haplotypes exceed mutations in number despite reduced recombination: an effective alternative for identity control. AB - Mitochondrial (mt) DNA D-loop heterogeneity, haplotype distribution and possible sub-population structures within the relevant populations are important for DNA based traceability. To gain insight into this distribution, we compared 1515 Bos taurus mtDNA D-loop sequences available from GenBank to 219 sequences that we sequenced de novo. A pronounced ambiguous trace typical of C-track length heteroplasmy was encountered in 5% of the samples, which were excluded from the analysis. Previously undescribed mutations and haplotypes were observed in 6% and 63% of the sequences, respectively. B. taurus haplotypes divided into the taurus, indicus and grunniens types and 302 variable sites formed the 858 taurus haplotypes detected. Fifty-five sites displayed a complex level of variation. As each level represents an independent mutation event, a total of 399 mutations were traced, which could potentially explain independent formation of less than half (47%) of the haplotypes encountered: most haplotypes were derived from different combinations of these mutations. We suggest that a mutational hotspot may explain these results and discuss the usefulness of mtDNA for identity and maternity assurance. PMID- 22445143 TI - Effects of long-time series of data on genetic evaluations for performance of Swedish Warmblood riding horses. AB - For Swedish Warmblood sport horses, breeding values (BVs) are predicted using a multiple-trait animal model with results from competitions and young horse performance tests. Data go back to the beginning of the 1970s, and earlier studies have indicated that some of the recorded traits have changed through the years. The objective of this study was to investigate the effects of including all performance data or excluding the older ones compared to a bivariate model (BM) considering performance traits in early and late periods as separate traits. The bivariate approach was assumed to give the most correct BVs for the actual breeding population. Competition results in dressage and show jumping for almost 40 000 horses until 2006 were available. For riding horse quality test (RHQT), data of 14 000 horses judged between 1973 and 2007 were used. Genetic correlations of 0.69 to 1.00 were estimated between traits recorded at different time periods (RHQT data) or different birth year groups (competition data). A cross-validation study and comparison of BVs using different sets of data showed that most accurate and similar results were obtained when BVs were predicted from either the BM or the univariate model including all data from the beginning of the recording. We recommend using all data and applying the univariate model to minimise the computational efforts for genetic evaluations and for provision of reliable BVs for as many horses as possible. PMID- 22445144 TI - Genetic parameters of meat quality traits in two pig breeds measured by rapid methods. AB - To study genetic variation in meat quality traits measured by rapid methods, data were recorded between 2005 and 2008 on samples of M. longissimus dorsi (LD) in Landrace (n = 3838) and Duroc (n = 2250) pigs included in the Norwegian pig breeding scheme. In addition, ultimate pH levels in the glycolytic LD (loin muscle) and M. gluteus medius (GM, ham muscle), and in the oxidative m. gluteus profundus (GP, ham muscle) were recorded as an extended data set (n = 16 732 and n = 7456 for Landrace and Duroc, respectively) from 1998 to 2008. Data were analysed with a multi-trait animal model using AI-REML methodology. Meat from Duroc had considerably more intramuscular fat (IMF), less moisture and protein, appeared darker with higher colour intensity and had lower drip loss than meat from Landrace. The heritability estimates (s.e. 0.01 to 0.07) for pH in LD (0.19 and 0.27 for Landrace and Duroc, respectively), GM (0.12 and 0.22) and GP (0.19 and 0.38), drip loss (0.23 and 0.33), colour values: L* (lightness) (0.41 and 0.28), a* (redness) (0.46 and 0.43), b* (yellowness) (0.31 and 0.33), IMF (0.50 and 0.62), muscle moisture (0.31 and 0.50) and muscle protein content (0.40 and 0.54) in LD all demonstrated moderate-to-high genetic variation for these traits in both breeds. Near infrared spectroscopy and EZ-DripLoss are modern technologies used in this study for the determination of chemical components and drip loss in meat. These methods gave higher heritabilities than more traditional methods used to measure these traits. The estimated genetic correlations between moisture and IMF in Duroc, and pH and drip loss in Duroc were both -0.89. Interesting differences between the two breeds in numerical value of some genetic correlations were observed, probably reflecting the differences in physiology and selection history between Landrace and Duroc. The estimated genetic correlation between drip loss and pH was much stronger in Duroc than in Landrace (-0.89 and 0.63, respectively). This might be due to the high pH in Duroc, whereas Landrace had a lower pH closer to the iso-electric point for muscle proteins. The positive genetic correlation between the L* value in meat and IMF in Duroc (0.50) was an effect of differences in visible marbling, rather than meat colour. For Landrace, this correlation was negative (-0.20). IMF content showed favourable genetic correlations to drip loss (-0.36 and -0.35 for Landrace and Duroc, respectively). PMID- 22445145 TI - Meta-analysis of phosphorus utilisation by broilers receiving corn-soyabean meal diets: influence of dietary calcium and microbial phytase. AB - Pollution relative to phosphorus excretion in poultry manure as well as the soaring prices of phosphate, a non-renewable resource, remain of major importance. Thus, a good understanding of bird response regarding dietary phosphorus (P) is a prerequisite to optimise the utilisation of this essential element in broiler diets. A database built from 15 experiments with 203 treatments was used to predict the response of 21-day-old broilers to dietary non phytate P (NPP), taking into account the main factors of variation, calcium (Ca) and microbial phytase derived from Aspergillus niger, in terms of average daily feed intake (ADFI), average daily gain (ADG), gain to feed (G:F) and tibia ash concentration. All criteria evolve linearly (P < 0.001) and quadratically (P < 0.001) with dietary NPP concentration. Dietary Ca affected the intercept and linear component for ADG (P < 0.01), G:F (P < 0.05) and tibia ash concentration (P < 0.001), whereas for ADFI, it affected only the intercept (P < 0.01). Microbial phytase addition impacted on the intercept, the linear and the quadratic coefficient for ADFI (P < 0.01), ADG (P < 0.001) and G:F (P < 0.05), and on the intercept and the linear component (P < 0.001) for tibia ash concentration. An evaluation of these models was then performed on a database built from 28 experiments and 255 treatments that were not used to perform the models. Results showed that ADFI, ADG and Tibia ash concentration were predicted fairly well (slope and intercept did not deviate from 0 to 1, respectively), whereas this was not the case for G:F. The increase in dietary Ca concentration aggravated P deficiency for all criteria while phytase addition had a positive effect. The more P deficiency was marked, the more the bird response to ADFI, ADG, G:F and tibia ash concentration was exacerbated. It must also be considered that even if the decrease in dietary Ca may improve P utilisation, it could in turn become limiting for bone mineralisation. In conclusion, this meta-analysis provides ways to reduce dietary P in broiler diets without impairing performance, taking into account dietary Ca and microbial phytase. PMID- 22445146 TI - Effects of increasing amounts of hempseed cake in the diet of dairy cows on the production and composition of milk. AB - This study explored the potential for using seed cake from hemp (Cannabis sativa L.) as a protein feed for dairy cows. The aim was to evaluate the effects of increasing the proportion of hempseed cake (HC) in the diet on milk production and milk composition. Forty Swedish Red dairy cows were involved in a 5-week dose response feeding trial. The cows were allocated randomly to one of four experimental diets containing on average 494 g/kg of grass silage and 506 g/kg of concentrate on a dry matter (DM) basis. Diets containing 0 g (HC0), 143 g (HC14), 233 g (HC23) or 318 g (HC32) HC/kg DM were achieved by replacing an increasing proportion of compound pellets with cold-pressed HC. Increasing the proportion of HC resulted in dietary crude protein (CP) concentrations ranging from 126 for HC0 to 195 g CP/kg DM for HC32. Further effects on the composition of the diet with increasing proportions of HC were higher fat and NDF and lower starch concentrations. There were no linear or quadratic effects on DM intake, but increasing the proportion of HC in the diet resulted in linear increases in fat and NDF intake, as well as CP intake (P < 0.001), and a linear decrease in starch intake (P < 0.001). The proportion of HC had significant quadratic effects on the yields of milk, energy-corrected milk (ECM) and milk protein, fat and lactose. The curvilinear response of all yield parameters indicated maximum production from cows fed diet HC14. Increasing the proportion of HC resulted in linear decreases in both milk protein and milk fat concentration (P = 0.005 and P = 0.017, respectively), a linear increase in milk urea (P < 0.001), and a linear decrease in CP efficiency (milk protein/CP intake; P < 0.001). In conclusion, the HC14 diet, corresponding to a dietary CP concentration of 157 g/kg DM, resulted in the maximum yields of milk and ECM by dairy cows in this study. PMID- 22445147 TI - Comparison of gastrointestinal transit times between chickens from D+ and D- genetic lines selected for divergent digestion efficiency. AB - D+ (high digestion efficiency) and D- (low digestion efficiency) genetic chicken lines selected for divergent digestion efficiency were compared in this experiment. Gizzard functions were tested in terms of digesta mean retention time and reactions to high dilution of a corn diet with 15% coarse sunflower hulls. The corn standard (S) and high fibre (F) experimental diets were given from 9 days of age to chickens from both lines. Besides the measurements of growth efficiencies (9 to 20 days), digestibilities (20 to 23 days) and gut anatomy (0, 9, 29, 42 and 63 days), two digestive transit studies were performed at 9 and 29 days of age. For the transit studies, the S and F diets were labelled with 0.5% TiO2 and 1% Cr-mordanted sunflower hulls. These diets were fed ad libitum during 3 days, and then the birds were euthanized. The digestive contents were analysed for the determination of marker concentrations and mean retention times (MRTs) in digestive compartments (crop + oesophagus, proventriculus + gizzard, duodenum + jejunum, ileum, rectum + cloaca and caeca) were determined. D+ birds were confirmed as better digesters than D- birds during the growth period, in association with larger gizzard and pancreas, and lighter small intestine in D+ than in D-birds. The MRT in the proventriculus-gizzard system, higher in D+ than in D- birds, was a major factor associated with differences between D+ and D- birds regarding digestion efficiencies and gut anatomy. Diet dilution with fibres reduced differences in digestion efficiencies and proventriculus-gizzard MRT between lines. Differences in gut anatomy between lines tended to disappear after 8 weeks of age. In conclusion, this study showed that MRT in the proventriculus gizzard system was a major factor associated with genotype differences between the D+ and D- genetic chicken lines selected for divergent digestion efficiency, with longer MRT found in D+ than in D- birds. PMID- 22445148 TI - Feed restriction and genetic selection on the expression and activity of metabolism regulatory enzymes in rabbits. AB - This work aims at the identification of relevant intermediate metabolism enzymes contributing to improved meat production due to genetic selection. A wild rabbit (WR) breed and a highly meat selected breed (New Zealand (NZ) rabbit) were used. Food restriction was used as an experimental condition so as to enhance differences within the metabolic pathways under study. During a period of 30 days, NZ and WR experimental breeds were subjected to, respectively, 40% and 60% ad libitum food restriction leading to 17.7% and 21.1% initial weight. Hepatic glycolytic, lipidic and protein regulatory enzyme activity, transcriptional and metabolite levels were determined. Insulin-like growth factor (IGF-1), triiodothyronine, and cortisol were also evaluated. In the glycolytic pathways, the NZ control rabbits presented a higher phosphofructokinase and pyruvate kinase activity level when compared to the WR, while the latter group showed a higher expression of glycogen synthase, although with less glycogen content. In the nitrogen metabolism, our results showed a lower activity level of glutamate dehydrogenase in WR when subjected to food restriction. Within the lipid metabolism, results showed that although WR had a significantly higher mRNA hepatic lipase, non-esterified fatty acid levels were similar between the experimental groups. NZ rabbits presented a better glycemia control and greater energy substrate availability leading to enhanced productivities in which triiodothyronine and IGF-1 played a relevant role. PMID- 22445149 TI - Effect of vitamin A supplementation at different gaseous environments on in vitro development of pre-implantation sheep embryos to the blastocyst stage. AB - Vitamin A (all-trans retinol) is an important antioxidant whose role in embryo development in vitro and in vivo is well established. Oxidative stress is a major cause of defective embryo development. This study evaluated the effects of all trans retinol supplementation to maturation and embryo culture media under different gaseous environments on the development of ovine oocytes and embryos in vitro. The percentages of cleavage, morula and blastocyst, total cell count and comet assay were taken as indicators of developmental competence of embryos. In experiments I and II, all-trans retinol at concentrations of 0, 2, 4, 6, 8 and 10 MUM were supplemented to the oocyte maturation medium and cultured in an environment of 5% or 20% O2 respectively. All-trans retinol supplementation (6 MUM) to the maturation medium at 5% O2 levels significantly increased blastocyst yield and total cell number (P < 0.05). Maturation of oocytes in a 20% O2 environment bettered cleavage rates in the 6 MUM supplemented group compared with the control group (P < 0.05). In experiments III and IV, all-trans retinol, at the aforesaid concentrations was supplemented to embryo culture media under a 5% or 20% O2 environment, respectively. All-trans retinol supplementation to the embryo culture medium at 5% O2 levels did not yield any significant result whereas the culture at 20% O2 levels gave significantly higher blastocyst yield in the 6 MUM supplemented group compared with the control group (P < 0.01). PMID- 22445150 TI - A moderate inflammation caused by the deterioration of housing conditions modifies Trp metabolism but not Trp requirement for growth of post-weaned piglets. AB - Deterioration of the environment in which piglets are housed after weaning induces a moderate inflammatory response and modifies tryptophan (Trp) metabolism that can, in turn, decrease Trp availability for growth. We hypothesised that a Trp supply above the current recommendations may be required to preserve Trp availability and to maximise the growth of pigs suffering from moderate inflammation. The aim of this experiment was to compare growth performance and plasma concentrations of Trp and some of its metabolites in piglets, suffering or not from moderate inflammation, when they were fed diets containing graded levels of standardised ileal digestible (SID) Trp, obtained with the addition of crystalline l-Trp to the same basal diet (15%, 18%, 21% or 24%, relative to SID lysine). Differences in inflammatory status were obtained by housing the pigs under different sanitary conditions. Forty blocks of four littermate piglets each were selected and weaned at 4 weeks of age. The experimental design consisted of a split plot where the housing conditions (moderate inflammation v. control) were used as the main plot and dietary Trp content as the subplot. Body weight gain and feed intake were recorded 3, 5 and 7 weeks after weaning. Blood was sampled 13, 36 and 43 days after weaning to measure plasma concentrations of Trp, kynurenine and nicotinamide (i.e. two metabolites of Trp catabolism) and haptoglobin, a major acute phase protein in pigs. There was no interaction between dietary Trp and inflammatory status, irrespective of the response criterion. Compared with control pigs, pigs housed in poor housing conditions consumed less feed (P < 0.0001), had a lower growth rate (P < 0.001), higher plasma concentrations of haptoglobin (P < 0.05) and lower concentrations of plasma Trp irrespective of the Trp content in the diet. Increasing the Trp content in the diet improved feed intake (P < 0.05), growth rate and feed/gain (P < 0.05), but did not prevent the deterioration of performance induced by moderate inflammation because of poor housing conditions. The results of this study suggest that an inflammatory response caused by poor housing sanitary conditions altered Trp metabolism and growth performance, but this was not prevented by additional dietary crystalline l-Trp. PMID- 22445151 TI - The impact of chronic environmental stressors on growing pigs, Sus scrofa (Part 1): stress physiology, production and play behaviour. AB - Commercially farmed animals are frequently housed in conditions that impose a number of concurrent environmental stressors. For pigs housed indoors, elevated levels of mechanical noise, atmospheric ammonia and low light intensities are commonplace. This experiment examined the effects on growing pigs of chronic exposure to combinations of commercially relevant levels of these potential stressors. Four-week-old hybrid female pigs (n = 224) were housed under experimentally manipulated conditions of nominally either <5 or 20 ppm atmospheric concentration of ammonia (24 h), a light intensity of 40 lux or 200 lux (12 h) and mechanical noise at either ?60 or 80 dB(A) (24 h) for 15 weeks in a fully factorial arrangement (23) of treatments. The response of pigs to these environmental factors was assessed using a suite of physiological, production and behavioural measures. These included indicators of hypothalamic-pituitary-adrenal (HPA) axis activation such as salivary cortisol and adrenal morphometry, as well as body weight, food conversion efficiency and general health scores. Play behaviour was recorded as it is thought to be inversely related to stress. Chronic exposure to ammonia produced the strongest effect, shown by lower concentrations of salivary cortisol and larger adrenal cortices in the pigs reared under 20 ppm ammonia, which may have been indicative of a period of HPA activation leading to a downregulation of cortisol production. The pigs in the ammoniated rooms also performed less play behaviour than pigs in non-ammoniated rooms. There was evidence for an interaction between high noise and ammonia on the health scores of pigs and for brighter light to ameliorate the effect of ammonia on salivary cortisol. However, there was no measurable impact of these potential stressors on the productivity of the pigs or any of the other physiological parameters measured. We conclude that there should be little concern in terms of performance about the physical stressors tested here, within current European Union legal limits. However, 20 ppm ammonia may have had an adverse influence on the well-being of growing pigs. In this study, all other aspects of the pigs' husbandry were optimal; therefore, it is possible that under less favourable conditions, more pronounced effects of ammonia, noise and dim light would be observed. PMID- 22445152 TI - The impact of chronic environmental stressors on growing pigs, Sus scrofa (Part 2): social behaviour. AB - The effects of common and concurrent environmental stressors on the social behaviour of farm animals are poorly understood. Here, we report the results of a multifactorial experiment designed specifically to examine the individual, additive or interactive effects of elevated ammonia, noise and low light (LL) levels on the social behaviour of growing pigs. Social behaviour was measured in terms of the nature, frequency and duration of both initiated and response behaviours for 4 weeks following mixing of the groups. General activity patterns, group cohesion and social discrimination were also examined as a function of the environmental treatments. Elevated concentrations of atmospheric ammonia (~20 v. <5 ppm) and LL intensity (~40 v. 200 lux) had the most pronounced effects, particularly on the nature of social interactions, with pigs under these conditions showing more aggression in the early stages of the experiment. In addition, pigs exposed to a high level of mechanical noise representative of artificial ventilation (~80 v. 40 dB [A]) were less submissive to aggressive acts, while pigs in ~20 ppm ammonia showed more reciprocated aggression when in coincident LL (<40 lux). The results indicate that atmospheric ammonia at commonly experienced concentrations may undermine social stability, particularly in the presence of low lighting, though the mechanisms are currently unknown. These findings have implications for the welfare of growing pigs and hence policy makers and farmers alike, with respect to the improvement of welfare in intensive pig farming. PMID- 22445153 TI - The interrelationships between clinical signs and their effect on involuntary culling among pregnant sows in group-housing systems. AB - Sows suffering from clinical signs of disease (e.g. lameness, wounds and shoulder ulcers) are often involuntarily culled, affecting the farmer's economy and the welfare of the animals. In order to investigate the interrelationships between clinical signs of individual pregnant group-housed sows, we performed an explanatory factor analysis to identify factors describing the patterns of variation of clinical signs. Moreover, we investigated how these emerging factors affected the probability of a sow to be either (i) euthanized, (ii) suddenly dead, (iii) sent to slaughter due to clinical signs of disease such as claw lesions or wounds or (iv) involuntarily culled (representing a pool of sows that were either euthanized, dead or sent to slaughter due to disease). Data from 2.989 pregnant sows in group-housing systems from 33 sow herds were included in the study. A thorough clinical examination was performed for each sow by using a protocol including 16 different clinical signs. Farmers recorded all cullings and deaths and the reasons for these actions in a 3-month period after the clinical examination. Among the observed sows, 4.2% were involuntarily culled during the 3 month period. From the explanatory factor analysis, we identified three factors describing the underlying structure of the 16 clinical variables. We interpreted the factors as 'pressure marks', 'wounds' and 'lameness' Logistic analyses were performed to investigate the effect of the three factors and the parity number of each sow on the four outcomes: (i) euthanized, (ii) suddenly dead, (iii) sent to slaughter due to clinical signs of disease and (iv) involuntarily culled. The analyses showed that 'lameness' significantly increased the risk of sows to be involuntarily culled (P = 0.016) or sent to slaughter due to clinical signs of disease (P = 0.026). Lameness is generally considered to be an important welfare problem in sows, which could explain the increased risk seen in this study. By contrast, 'pressure marks' and 'wounds' did not have any significant effect on the four outcomes (P > 0.05). PMID- 22445154 TI - Oxidized oils and dietary zinc and alpha-tocopheryl acetate supplementation: effects on rabbit plasma, liver and meat fatty acid composition and meat Zn, Cu, Fe and Se content. AB - The effects of the addition of heated oils to feeds (3%, w/w) and the dietary supplementation with alpha-tocopheryl acetate (TA; 100 mg/kg) and Zn (200 mg/kg) on rabbit tissue fatty acid (FA) composition and on the Zn, Cu, Fe and Se content in meat were assessed. Heating unrefined sunflower oil (SO) at 55 degrees C for 245 h increased its content in primary oxidation products and reduced its alpha tocopherol content. However, this did not significantly affect tissue FA composition. Heating SO at 140 degrees C for 31 h increased its content in secondary oxidation products and in some FA isomers as c9,t11-CLA and di-trans CLA. This led to increases in di-trans CLA in liver and in t9,c12-18:2 in meat. The c9,t11-CLA was the most incorporated CLA isomer in tissues. The dietary supplementation with alpha-TA did not affect the FA composition of plasma, liver or meat. The cooking of vacuum-packed rabbit meat at 78 degrees C for 5 min reduced significantly but slightly its polyunsaturated FA content. The dietary supplementation with Zn did not modify the content of Zn, Fe or Se in meat, but it reduced its Cu content. On the other hand, it increased the content of some FAs in meat when SO heated at 140 degrees C for 31 h was added to feeds. PMID- 22445155 TI - Detecting incipient cavitation by assessing low frequency acceleration and analysis of CMC. AB - Cavitation is a common phenomenon in a fluid circuit especially wherever local pressure is lower than fluid saturated pressure. The cavitation negatively affects a fluid system and structure in different ways: i.e. erosion, flow rate reduction, noise and vibration. In order to diminish cavitation, adding some nanomaterials seem to be applicable in different ways. This research aims at assessing the effects of CMC (Carboxy methyl cellulose) additives on incipient cavitation by analyzing the resultant change in low frequency acceleration. Furthermore, this study attempts to examine the accuracy of low frequency acceleration for detecting incipient cavitation. PMID- 22445156 TI - 'A real man smells of tobacco smoke'--Chinese youth's interpretation of smoking imagery in film. AB - Previous studies have associated youth's exposure to filmic images of smoking with real-life smoking acquisition; initial research in low- and middle-income countries confirms this relationship. The present study in Yunnan, southwest China sought answers to the following questions: How do young people in China make sense of smoking imagery they have seen in film? How are these perceptions shaped by the cultural and social context of images? How do these understandings relate to real-life tobacco use? A study with focus groups and grounded theory was conducted in 2010 and 2011 (Sept-Jan) with middle-school students ages 12 and 13 (n=68, focus groups=12, schools=6). Films and media literacy were important means through which knowledge about smoking was constructed and communicated. Film representations of smoking concurred with Chinese social behaviour (Confucian social networks, face-making, and the notion of society as a harmonious social unit), and were interpreted as congruent with real-life smoking. This pattern, in turn, was intertwined with perceived gender identities of smokers, gender-specific social behaviour, and willingness of girls to explore issues of gender equity. These findings lend new insights into interaction between smoking imagery in film and Chinese youth's smoking beliefs. Tobacco control programs in China should consider young people's interpretations of smoking and the ways they are nested in cultural and social milieu. PMID- 22445157 TI - Attitudes and beliefs related to HIV/AIDS in urban religious congregations: barriers and opportunities for HIV-related interventions. AB - HIV-related stigmas have been seen as a barrier to greater religious congregation involvement in HIV prevention and care in the United States and elsewhere. We explored congregational and community norms and attitudes regarding HIV, sexuality, and drug use through a qualitative case study of 14 diverse religious congregations in Los Angeles County, California between December 2006 and May 2008. Data collected included semi-structured interviews with 57 clergy and lay leaders across the congregations, structured observations of congregational activities, review of archival documents, and a questionnaire on congregational characteristics. Across and within congregations, we found a wide range of views towards HIV, people with HIV, and populations at risk for HIV, from highly judgmental and exclusionary, to "loving the sinner, not the sin," to accepting and affirming. Attitudes and norms about HIV, homosexuality, and substance abuse appeared to be related to the type and intensity of congregational HIV-related activities. However, even among the higher activity congregations, we found a range of perceptions, including ones that were stigmatizing. Results suggest that affirming norms and attitudes are not a prerequisite for a congregation to initiate HIV activities, a finding relevant for HIV service providers and researchers seeking to engage congregations on this issue. HIV stigma reduction is not a prerequisite for congregational HIV involvement: both may occur simultaneously, or one before the other, and they dynamically affect each other. Strategies that are congruent with congregations' current levels of comfort and openness around HIV can themselves facilitate a process of attitudinal and normative change. PMID- 22445158 TI - Results of anatomic nonconstrained prosthesis in primary osteoarthritis with biconcave glenoid. AB - BACKGROUND: Biconcave glenoids in primary osteoarthritis represent a challenge because of the associated static posterior instability of the humeral head and secondary posterior glenoid erosion. This study evaluated the influence of different preoperative radiographic measurements on the outcome of total shoulder arthroplasty (TSA), particularly regarding the development of complications. MATERIALS AND METHODS: We retrospectively evaluated 92 anatomic TSAs performed in 75 patients with primary osteoarthritis and a biconcave glenoid. All patients underwent preoperative imaging with an axial computed tomography arthrogram. Measurements were taken for posterior bone erosion depth and ratio as well as humeral head subluxation. Clinical outcomes were evaluated with the Constant score. RESULTS: At an average follow up of 77 months (range, 14-180 months), 15 revisions (16.3%) were performed for glenoid loosening (6.5%), posterior instability (5.5%), or soft tissue problems (4.3%). At the final follow-up, the mean Constant score improved significantly from 32.4 to 68.8 points (P = .0001). Subjectively, 66.3% of patients were very satisfied or satisfied. Glenoid loosening was observed in 20.6% and was significantly associated with posterior bone erosion in depth (P = .005) and wear ratio (P = .02), humeral head subluxation (P = .01), and neoglenoid (P = .002) and intermediate glenoid retroversion (P = .001). Dislocation was correlated only with neoglenoid retroversion (P = .01). CONCLUSIONS: Performing TSA in patients with osteoarthritis and biconcave glenoids resulted in acceptable clinical outcomes but a very high rate of complications. We found that the preoperative measurement of the neoglenoid retroversion was best for predicting postoperative complications in terms of glenoid loosening and dislocation. PMID- 22445159 TI - Comparison of ultrasound-guided versus blind glenohumeral injections: a cadaveric study. AB - BACKGROUND: Intra-articular glenohumeral (GH) injections are important for diagnostic and therapeutic purposes. It has been suggested that ultrasound guided injections are more accurate than blind or freehand injections. This study assessed the accuracy of ultrasound-guided GH injections compared with freehand injections in fresh cadavers. METHODS: The study used 80 shoulder specimens from fresh cadavers. Ultrasound guidance was used to inject radiopaque contrast in 40 shoulders, and freehand technique was used in the remaining 40. All injections were performed by 2 surgeons (A and B) through a posterior approach. After the injections, radiographs were obtained of the specimens to assess the accuracy of the injections. RESULTS: Sixty-six of 80 (82.5%) injections were accurately administered into the GH joint. Ultrasound-guided injections were accurate in 37 of 40 specimens (92.5%) compared with freehand injections, which were accurate in only 29 of 40 specimens (72.5%; P = .02). Both surgeons independently had higher accuracy using ultrasound-guidance compared with the freehand technique (surgeon A: 90% vs 65%, P = 0.058; surgeon B: 95% vs 80%, P = 0.15). The average time for injections was 52 seconds by the freehand technique and 166 seconds using ultrasound guidance (P < 0.001). CONCLUSIONS: The data from this cadaveric study suggest that ultrasound-guided injections are more accurate at reaching the GH joint than freehand injections. The ultrasound-guided injections took substantially longer to administer. Once familiar with the technique, surgeons can expect improved accuracy and efficacy of GH joint injections using ultrasound guidance in the clinical setting. PMID- 22445160 TI - Effect of stem length on prosthetic radial head micromotion. AB - BACKGROUND: Osteointegration of press-fit radial head implants is achieved by limiting micromotion between the stem and bone. Aspects of stem design that contribute to the enhancement of initial stability (ie, stem diameter and surface coating) have been investigated. The importance of total prosthesis length and level of the neck cut has not been examined. METHODS: Cadaveric radii were implanted with cementless, porous-coated radial head stems. We resected 10, 12, 15, 20, and 25 mm of radial neck in each specimen. Stem-bone micromotion was measured after each cut. Values were expressed in terms of quotients (cantilever quotient). RESULTS: A threshold effect was observed at 15 mm of neck resection (cantilever quotient, 0.4), with a significant increase in micromotion observed between 12 mm (40 +/- 10 MUm) and 15 mm (80 +/- 25 MUm). A cantilever quotient of 0.35 or less predicted implant stability, whereas implants with a cantilever quotient of 0.6 or more were unstable. In between, the stems were "at risk" of instability. CONCLUSION: Initial stem stability of a porous-coated, cementless radial head implant is dependent on length of the implant stem within bone and the level of the cut (amount of bone resected). Stability may be compromised by an implant with a combined head and neck length that is too long compared with the stem length within the canal. We found a critical ratio of exposed prosthesis to total implant length (cantilever quotient of 0.4), which puts the prosthesis at risk of inadequate initial stability. These data carry important implications for implant design and use. PMID- 22445161 TI - Surgeon perceptions and patient outcomes regarding proximal ulna fixation: a multicenter experience. AB - BACKGROUND: Our objective was to determine surgeon- and patient-based perceptions concerning proximal ulna fixation, including rates of implant removal and overall satisfaction. METHODS: Orthopedic surgeons were surveyed about surgical experience managing proximal ulna fractures and their perception regarding implant removal/revision. A retrospective chart review identified all patients who underwent fixation for proximal ulna fractures and osteotomies between January 2004 and December 2008. RESULTS: In total, 583 surgeons responded to the survey (80%). Of these, 67% believed that their implant removal rate was the same as other surgeons whereas 31% believed that their rate was lower. Seventy-one percent believed that patients required hardware removal less than 30% of the time. Ninety-eight percent believed that they were the same surgeons to remove the implant. In total, 138 consecutive patients were surveyed about their proximal ulna implant. Plating was performed in 80 (58%), and tension banding was performed in 55 (40%). The overall rate of implant removal was 64.5% (89 of 138) at 18.8 months. A second surgeon performed the removal in 68 patients (76%). Of the 49 patients without implant removal, 11 (22%) reported satisfaction with the implant and 19 (39%) reported a functional impairment because of the implant. If guaranteed a safe surgery, 36 (73%) would have the implant removed. CONCLUSION: Surgeons underestimate the rates of proximal ulna implant removal and patient dissatisfaction. Because 76% of the implant removals were performed by a second surgeon, in sharp contrast to the surgeon-perceived rate of 2%, we challenge surgeons to become more aware of this problem in their practices. PMID- 22445162 TI - Do the rotator cuff tendons of young athletic subjects hypertrophy in response to increased loading demands? AB - BACKGROUND: The rotator cuff is composed of muscle and tendon units. Although muscle has been shown to adapt to mechanical loads, the response of human tendon is not well defined. We hypothesized that increased loading demands on the rotator cuff of young trainees would cause an adaptive muscle response but not an adaptive hypertrophic tendon response. METHODS: The hypertrophic response of the rotator cuff tendon, shoulder strength, aerobic fitness, and the lean body weight of 70 young male recruits were studied before and after a 1-year course of elite infantry training. Shoulder strength was assessed by the maximum number of pull ups done and the rotator cuff thickness by ultrasound measurement of the supraspinatus thickness. Aerobic physical fitness was assessed by maximum oxygen consumption (Vo(2) max). Lean body weight was measured by skin-fold thickness. RESULTS: The mean number of pull-ups done increased from 17.5 to 21.7 (P = .01), but the supraspinatus thickness at the beginning of training (6.1 mm) was unchanged at the end of the training. Vo(2) max increased from 57 to 64 mL/kg/min (P = .0001). Lean body weight increased from 58.3 to 64.7 kg (P = .0001). CONCLUSIONS: As a result of increased loading, the strength of the rotator cuff muscles of young trainees increased, but by the parameter of hypertrophy, no evidence was found of a parallel adaptive response of the rotator cuff tendon. PMID- 22445163 TI - Suprascapular neuropathy: what does the literature show? AB - Suprascapular neuropathy remains a rare, albeit increasingly recognized, diagnosis. Despite its relatively low prevalence, it must be kept in the shoulder surgeon's mind as a potential cause of shoulder pain, particularly in patients where the history, physical examination, and imaging studies do not adequately explain a patient's symptoms or disability. Although challenging to identify, suprascapular neuropathy can be successfully treated. The current literature shows that the location and mechanism of nerve injury are the most important factors guiding management. Different treatment strategies are required, depending on the specific location and type of nerve injury. Controversy regarding if and when to perform an isolated suprascapular nerve release continues. Furthermore, no recommendations regarding suprascapular nerve release in conjunction with rotator cuff repair can be made at this time, and further research is necessary to better delineate the indications in the future. PMID- 22445164 TI - Revision total shoulder arthroplasty for painful glenoid arthrosis after humeral head replacement: the nontraumatic shoulder. AB - BACKGROUND: Patients treated with humeral head replacement (HHR) may require revision to total shoulder arthroplasty (TSA) due to glenoid arthrosis. This study characterizes the outcomes of revision TSA in patients who initially underwent HHR for nontraumatic glenohumeral arthritis. METHODS: From 1982 to 2005, 68 shoulders underwent revision TSA for glenoid arthrosis. The initial HHR was performed for non-fracture-related arthritis. Revisions were grouped according to complexity for analysis. Stem revision and soft tissue reconstruction were assessed in relation to outcome. RESULTS: Pain scores decreased from 4.4 to 2.8, abduction increased from 85 degrees to 116 degrees , external rotation increased from 36 degrees to 48 degrees , and internal rotation remained unchanged. Survivorship free of repeat revision was 95.6%, 84.1%, and 72.9% at 1, 5, and 10 years. The Neer rating yielded 20 excellent, 10 satisfactory, and 38 unsatisfactory outcomes. No differences in motion, survivorship, or the Neer rating occurred between groups by procedure complexity. There was, however, less reduction in pain for the group requiring a humeral stem revision. Of the 9 shoulders with postoperative instability, 7 had compromised soft tissues preoperatively. CONCLUSIONS: Revision TSA after HHR results in decreased pain and increased motion. Result ratings, however, are quite variable and, in many cases, unsatisfactory. Stratification of the procedures according to complexity does not demonstrate differences in motion, satisfaction, or survivorship. Stem revision, however, results in reduced pain score improvement. Coexisting instability associated with subscapularis and anterior shoulder capsule damage may not be correctable using an unconstrained shoulder arthroplasty. PMID- 22445165 TI - Stabilizing effect of saccharides on bovine plasma protein: a calorimetric study. AB - Bovine plasma proteins provide the needed amino acids for the growth and development of an organism. With the purpose of preserving the native structure, related with the protein functional properties, the oligosaccharide inulin was used as protective agent and was compared with glucose and sucrose, during freeze drying. In the present study, the thermal stability of protein was investigated as a function of type of saccharide in a concentration range of 5-15% (w/v), and at different pHs. The effect of these variables on phase transition, thermal stability and miscibility was assessed by differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The results of thermal protein properties (denaturation temperature and enthalpy), demonstrated that endothermic transition shifted to higher temperatures, being the stabilizing effect: inulin>glucose>sucrose. The thermal behavior suggests compatibility or interactions between the components of blends. In this way, the micrographs showed a homogeneous distribution of the different phases, corroborating the miscibility in the matrix. The unfolding process was irreversible and could be adequately described by a two-state model. PMID- 22445166 TI - [Is it necessary to find and resect polyps?]. PMID- 22445167 TI - [Is it always necessary to section the septate uterus?]. PMID- 22445168 TI - [What to do with sub-mucosal type 2 myomas in the infertile woman?]. PMID- 22445169 TI - [Post-curettage and aspiration synechiae: is there value in an anti-adhesion agent?]. PMID- 22445170 TI - Acute pancreatitis due to pancreatic hydatid cyst: a case report and review of the literature. AB - Hydatid disease is a major health problem worldwide. Primary hydatid disease of the pancreas is very rare and acute pancreatitis secondary to hydatid cyst has rarely been reported. We report the case of a 38-year-old man who presented acute pancreatitis. A diagnosis of hydatid cyst of the pancreas, measuring 10 cm, was established by abdominal computed tomography before surgery. The treatment consisted of a distal pancreatectomy. The postoperative period was uneventful. Additionally, a review of the literature regarding case reports of acute pancreatitis due to pancreatic hydatid cyst is presented. PMID- 22445171 TI - [Study of skin retraction applied to the treatment of skin tumors. Mapping of the human body]. AB - SUBJECT: Skin, the main organ of the human body, is equipped with own biomechanical characteristics, highly variable depending on intra-individual factors (location, weight status, dermatological diseases...) and interindividual (age, sex...). Despite some recent cutometric studies, our review of the literature shows that there is no currently reliable analytical model representing the biomechanical behavior of the skin. Yet, this is a central issue in dermatology surgery, especially in the treatment of skin tumors, for the proper observance of surgical margins. PATIENTS AND METHODS: We studied prospectively on 75 resection specimens (about 71 patient(s)), for the treatment of skin lesions tumor suspicious or known malignant or benign. Room dimensions were measured before and 5 minutes after excision, leading us to calculate a ratio of retraction of the skin surface. This retraction was correlated with age, gender, tumor type, and anatomic location of the site of excision. RESULTS: The power of retraction of the skin varies significantly by region of the body. It is maximum in the upper limb (hand excluded) and in the cervical region. At the cephalic region, skin of the ear and periorbital skin have capacities of important early retraction. Unlike the lower limb (foot excluded), the back skin of the nose and face appear to be a minimum of shrinkage. Age also seems to change on that capacity shrinkage, sex would have no influence. CONCLUSION: Our study confirms the variations in the ability of skin retraction based on a number of factors. In dermato-oncology, that power retraction could cause significant differences between clinical surgical margins and final pathologist margins. We believe it must be taken into account by the couple surgeon-pathologist, especially in the context of invasive and/or recurrent tumors. PMID- 22445173 TI - A role for small RNAs in DNA double-strand break repair. AB - Eukaryotes have evolved complex mechanisms to repair DNA double-strand breaks (DSBs) through coordinated actions of protein sensors, transducers, and effectors. Here we show that ~21-nucleotide small RNAs are produced from the sequences in the vicinity of DSB sites in Arabidopsis and in human cells. We refer to these as diRNAs for DSB-induced small RNAs. In Arabidopsis, the biogenesis of diRNAs requires the PI3 kinase ATR, RNA polymerase IV (Pol IV), and Dicer-like proteins. Mutations in these proteins as well as in Pol V cause significant reduction in DSB repair efficiency. In Arabidopsis, diRNAs are recruited by Argonaute 2 (AGO2) to mediate DSB repair. Knock down of Dicer or Ago2 in human cells reduces DSB repair. Our findings reveal a conserved function for small RNAs in the DSB repair pathway. We propose that diRNAs may function as guide molecules directing chromatin modifications or the recruitment of protein complexes to DSB sites to facilitate repair. PMID- 22445172 TI - ATP-triggered conformational changes delineate substrate-binding and -folding mechanics of the GroEL chaperonin. AB - The chaperonin GroEL assists the folding of nascent or stress-denatured polypeptides by actions of binding and encapsulation. ATP binding initiates a series of conformational changes triggering the association of the cochaperonin GroES, followed by further large movements that eject the substrate polypeptide from hydrophobic binding sites into a GroES-capped, hydrophilic folding chamber. We used cryo-electron microscopy, statistical analysis, and flexible fitting to resolve a set of distinct GroEL-ATP conformations that can be ordered into a trajectory of domain rotation and elevation. The initial conformations are likely to be the ones that capture polypeptide substrate. Then the binding domains extend radially to separate from each other but maintain their binding surfaces facing the cavity, potentially exerting mechanical force upon kinetically trapped, misfolded substrates. The extended conformation also provides a potential docking site for GroES, to trigger the final, 100 degrees domain rotation constituting the "power stroke" that ejects substrate into the folding chamber. PMID- 22445174 TI - Critical care rehabilitation and early mobilisation: an emerging standard of care. PMID- 22445175 TI - Bacterial diterpene synthases: new opportunities for mechanistic enzymology and engineered biosynthesis. AB - Diterpenoid biosynthesis has been extensively studied in plants and fungi, yet cloning and engineering diterpenoid pathways in these organisms remain challenging. Bacteria are emerging as prolific producers of diterpenoid natural products, and bacterial diterpene synthases are poised to make significant contributions to our understanding of terpenoid biosynthesis. Here we will first survey diterpenoid natural products of bacterial origin and briefly review their biosynthesis with emphasis on diterpene synthases (DTSs) that channel geranylgeranyl diphosphate to various diterpenoid scaffolds. We will then highlight differences of DTSs of bacterial and higher organism origins and discuss the challenges in discovering novel bacterial DTSs. We will conclude by discussing new opportunities for DTS mechanistic enzymology and applications of bacterial DTS in biocatalysis and metabolic pathway engineering. PMID- 22445176 TI - Cognitive outcome after stereotactic amygdalohippocampectomy. AB - PURPOSE: We sought to determine the neuropsychological outcome after stereotactic radiofrequency amygdalohippocampectomy performed for intractable mesial temporal lobe epilepsy. METHODS: The article describes the cases of 31 patients who were evaluated using the Wechsler Adult Intelligence Scale-Revised and the Wechsler Memory Scale-Revised prior to, and one year after, surgery. KEY FINDINGS: Patients showed increases in their mean Full Scale, Verbal and Performance IQ scores of 4, 3 and 4 IQ points respectively (p<.05). 5 (17.2%), 4 (13.8%) and 4 (13.3%) patients improved in their Full-scale, Verbal and Performance IQ respectively. No significant changes were found in memory performance - with a mean increase of 1, 3 and 0 MQ points in Global, Verbal and Visual memory respectively (p<.05). Global memory improved in 3 (10.3%) patients, verbal memory in 1 (3.4%) and 1 patient (3.3%) showed deterioration in visual memory. SIGNIFICANCE: Our results provide evidence for unchanged memory in patients with MTLE after the procedure. No verbal memory deterioration was detected in any of our patients, while improvements were found in intellectual performance. The results suggest that stereotactic radiofrequency amygdalahippocampectomy could be superior to open surgery in terms of its neurocognitive outcomes. A larger randomised trial of these approaches is justified. PMID- 22445177 TI - [The resident as a teacher, Quo vadis?]. AB - Residents play an important role in the clinical teaching of medical students. Although this role is usually considered beneficial for both students and residents, it has rarely been evaluated and lacks academic recognition. Despite the fact that students value the teaching provided by residents positively, residents feel unprepared to teach. Some programs to improve resident teaching skills have been successfully developed. Association between hospitals and universities is essential to develop and provide with academic recognition these programs, whose funding should be shared. Internal Medicine should participate actively in clinical teaching and promote the figure of the resident as teacher by means of training activities adapted to the new times of our speciality. PMID- 22445178 TI - Predictors of invasive breast cancer in mammographically detected microcalcification in patients with a core biopsy diagnosis of flat epithelial atypia, atypical ductal hyperplasia or ductal carcinoma in situ and recommendations for a selective approach to sentinel lymph node biopsy. AB - 15+/-30% of malignancies detected through screening programs are ductal carcinoma in situ (DCIS), and the majority of DCIS cases present in the form of mammographic microcalcification. This study was performed in order to determine the value of features in predicting invasive disease in patients with mammographic calcification and to help determine which patients (with, Core Needle Biopsy-diagnosed DCIS) are the most appropriate candidates for Sentinel Lymph Node (SLN) biopsy. The original aspect of this study was to select patients with mammographic microcalcification but without an associated mass. The factor that we identified to be associated with invasive disease at final surgical excision was the presence of necrosis at core histology. SLN biopsy or complete axillary lymph node dissection was performed in 22 (40%) patients of whom only one (4.5%) had a micrometastasis. Further larger studies are needed to see if it would be interesting to propose a SLN biopsy in case of necrosis on CNB-diagnosed DCIS with microcalcifications but not associated with a mass. PMID- 22445179 TI - Timing is everything. PMID- 22445180 TI - Effect of pretreatment with simvastatin on spinal cord ischemia-reperfusion injury in rats. AB - OBJECTIVE: The aim of this study was to evaluate the pretreatment effect of simvastatin on spinal cord ischemia-reperfusion injury. DESIGN: Prospective, interventional study. SETTING: University research laboratory. PARTICIPANTS: Forty-five male Sprague-Dawley rats. INTERVENTIONS: Rats were treated with oral simvastatin, 10 mg/kg (simvastatin group; n = 15) or saline (control group; n = 15) for 5 days before ischemia. Spinal cord ischemia was induced using a balloon tipped catheter placed in the proximal descending aorta in the control and simvastatin groups, but not in the sham group (n = 15). MEASUREMENTS AND MAIN RESULTS: Neurologic function was assessed daily using the motor deficit index until 7 days after reperfusion. After the last neurologic evaluation, a histologic examination of the spinal cord was performed. At day 1 after reperfusion, the simvastatin group showed a significantly lower motor deficit index compared with the control group (2.0, 2.0-2.0, v 4.0, 3.5-5.0; p < 0.001). This trend was sustained at day 7 (2.0, 1.5-2.0, v 4.0, 3.0-4.0; p < 0.001). The simvastatin group displayed a significantly larger number of normal motor neurons compared with the control group (mean +/- SD, 31.7 +/- 6.1 v 20.4 +/- 4.4; p < 0.001). However, compared with the sham group, the simvastatin group displayed fewer intact motor neurons (sham group, 38.5 +/- 5.1; p = 0.005). CONCLUSIONS: Pretreatment with simvastatin, 10 mg/kg, given orally for 5 days before the ischemia-reperfusion insult, improved the neurologic outcome and preserved more normal motor neurons compared with the control group in a rat model of spinal cord ischemia-reperfusion. PMID- 22445181 TI - Severe intra-aortic balloon pump complications: a single-center 12-year experience. AB - OBJECTIVE: An intra-aortic balloon pump (IABP) is used routinely in high-risk patients undergoing cardiac surgery to prevent or treat low-cardiac-output syndrome and to reduce perioperative mortality. The insertion and management of IABP carry the risk of major vascular complications. The authors reviewed their database to ascertain the incidence of IABP-related severe complications. DESIGN: A retrospective study. SETTING: A teaching hospital. PARTICIPANTS: Ten thousand three hundred sixty-five patients scheduled for elective or emergency cardiac surgery over a 12-year period at a single center. INTERVENTIONS: Four hundred twenty-three patients received an IABP perioperatively. Careful preoperative screening for peripheral arterial disease, strict postoperative control, and the sheathless insertion technique to spare the arterial flow to the lower limb were performed routinely. MEASUREMENTS AND MAIN RESULTS: The use of a perioperative IABP was 0.7% at the beginning of the observation period in 1999 and 7.3% in 2010, showing a fluctuating trend. Two patients (0.47%) died of direct complications, arterial wall damage and bleeding. Immediate surgical exploration and control of bleeding were followed by multiple-organ failure and death. Vascular complications, leading to lower-limb ischemia, occurred in 4 of 423 patients (0.94%). All of them underwent urgent vascular surgery and survived. Local sepsis occurred in 2 other patients (0.47%). CONCLUSIONS: These data indicate that an IABP is a valuable option in high-risk patients undergoing cardiac surgery even if not devoid of intrinsic risks for vascular complications (0.94%), septic complications (0.47%) and mortality (0.47%). PMID- 22445182 TI - Constriction of an endotracheal tube by a nasogastric tube during general anesthesia resulting in pulmonary edema. PMID- 22445183 TI - Flexibility of centromere and kinetochore structures. AB - Centromeres, and the kinetochores that assemble on them, are essential for accurate chromosome segregation. Diverse centromere organization patterns and kinetochore structures have evolved in eukaryotes ranging from yeast to humans. In addition, centromere DNA and kinetochore position can vary even within individual cells. This flexibility is manifested in several ways: centromere DNA sequences evolve rapidly, kinetochore positions shift in response to altered chromosome structure, and kinetochore complex numbers change in response to fluctuations in kinetochore protein levels. Despite their differences, all of these diverse structures promote efficient chromosome segregation. This robustness is inherent to chromosome segregation mechanisms and balances genome stability with adaptability. In this review, we explore the mechanisms and consequences of centromere and kinetochore flexibility as well as the benefits and limitations of different experimental model systems for their study. PMID- 22445184 TI - Predictors of excellent early outcome after total hip arthroplasty. AB - BACKGROUND: Not all patients gain the same degree of improvement from total hip replacement and the reasons for this are not clear. Many investigators have assessed predictors of general outcome after hip surgery. This study is unique in its quest for the predictors of the best possible early outcome. METHODS: We prospectively collected data on 1318 total hip replacements. Prior to surgery patient characteristics, demographics and co-morbidities were documented. Hip function and general health was assessed using the Harris Hip score (HHS) and the Short-Form 36 respectively. The HHS was repeated at three years. We took a maximal HHS of 100 to represent an excellent outcome (102 patients). Multiple logistic regression analysis was used to identify independent predictors of excellent outcome. RESULTS: The two strongest predictive factors in achieving an excellent result were young age and a high pre-operative HHS (p = 0.001). CONCLUSIONS: It was the young and those less disabled from their arthritis that excelled at three years. When making a decision about the timing of hip arthroplasty surgery it is important to take into account the age and pre operative function of the patient. Whether these patients continue to excel however will be the basis of future research. PMID- 22445185 TI - The Keck and Kelly wedge calcaneal osteotomy for Haglund's deformity: a technique for reproducible results. AB - Surgical treatment of Haglund's deformity typically involves either bump removal or a closing wedge calcaneal osteotomy. Although bump removal may initially seem easier to perform and quicker to heal, there are advantages to avoiding bone resection adjacent to the Achilles tendon. Healing of the wedge osteotomy can be faster and more predicable than tendon healing at the Achilles insertion, which is beneficial to the young and active population that tends to have this condition. This article describes a reproducible Keck and Kelly closing wedge osteotomy technique that effectively decompresses the posterior/superior aspect of the calcaneus without need for dissection around the Achilles insertion. Our technique allows for consistent correction of Haglund's deformity, reliable symptom relief, and minimal opportunity for intraoperative or postoperative complications. Technique pearls include patient selection criteria for bump removal versus wedge osteotomy and a preoperative template protocol. PMID- 22445186 TI - Airborne contact dermatitis to drugs. AB - Contact dermatitis is defined as "airborne" when the causative factor is present in the environment and may determine irritative or allergic skin reactions. It is often work-related. In this review of the literature, we focus our attention on airborne contact dermatitis due to pharmaceutical compounds. Contact reactions to medications, often occupation-related, occur mainly in two exposed groups: employees of pharmaceutical industries involved in the production of the drugs and healthcare workers who use the drugs for therapeutic aims. PMID- 22445187 TI - Is it a safe practice to administer oxygen during uncomplicated delivery: a randomized controlled trial? AB - BACKGROUND: Newborns exposed to oxygen suffer from an oxidative stress with significant alterations in the concentrations of superoxide dismutase (SOD) and glutathione (GSSG). OBJECTIVE: To investigate the biological and clinical effects of oxygen administration to delivering mothers. METHODS: We conducted a randomized, double-blinded, controlled trial on a cohort of delivering women (n=56) with an uncomplicated term pregnancy. Women were randomly assigned to one of two groups: Oxygen group or Room Air group. The Oxygen group received 100% oxygen (2l/min) via nasal cannula for at least 30 min before delivery. Subjects in the Room Air group were connected to a nasal cannula while on room air. Concentrations of SOD (MUg/g of Hb) and GSSG (MUM/ml) were measured in maternal and umbilical cord blood. Bivariate and multivariate analyses were used to compare the two groups using the SAS system. RESULTS: Maternal SOD and GSSG did not differ between the two groups at baseline or after delivery. Concentrations of SOD and GSSG in umbilical cord blood did not differ between groups. More infants in Oxygen Group required delivery room resuscitation (20% vs. 0%, P=0.03). This difference could not be explained by mode of delivery, infant sex, or other confounders. CONCLUSIONS: Maternal exposure to oxygen during delivery is not associated with changes in umbilical cord SOD or GSSG. Further studies are needed to explore mechanisms responsible for the need of resuscitation in the oxygen group. PMID- 22445188 TI - Fullerene nanoparticles exhibit greater retention in freshwater sediment than in model porous media. AB - Increasing production and use of fullerene-based nanomaterials underscore the need to determine their mobility in environmental transport pathways and potential ecological exposures. This study investigated the transport of two fullerenes (i.e., aqu/C(60) and water-soluble C(60) pyrrolidine tris-acid [C(60) PTA]) in columns packed with model porous media (Iota quartz and Ottawa sand) and a sediment from Call's creek under saturated and unsaturated steady-state flows. The fullerenes had the least retention in Iota quartz, and the greatest retention in the sediment at near neutral pH, correlating with the degree of grain surface chemical heterogeneity (e.g., amorphous Al hydroxides concentration increasing in the order of Iota quartz=1.97), PLR (>=9.14), albumin (<=4.15 g/dl) and serum CA 125 (>=32.50 U/ml) for pre-operative diagnosis of LN metastasis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of serum CA-125 were 63.3%, 87.6%, 37.3%, 95.4% and 85.1%, respectively. No pre-operative SIR markers were superior to serum CA-125 in terms of sensitivity, specificity, PPV, NPV or accuracy, with the exception of the slightly higher sensitivity of PLR (64.5%). CONCLUSIONS: Pre-operative SIR markers do not appear to be more effective in predicting LN metastasis than serum CA-125 in endometrioid endometrial adenocarcinoma. PMID- 22445207 TI - Uterine fibroid pseudocapsule studied by transmission electron microscopy. AB - OBJECTIVE: The fibroid pseudocapsule is a structure which surrounds the uterine fibroid, separates it from the uterine tissue and contains a vascular network rich in neurotransmitters like a neurovascular bundle. The authors examined the composition of the fibroid pseudocapsule using electron microscopy. STUDY DESIGN: Twenty non-pregnant patients were submitted to laparoscopic myomectomy by the intracapsular method and samples of the removed pseudocapsules were analyzed using transmission electron microscopy. RESULTS: At the ultrastructural level the pseudocapsule cells have the features of smooth muscle cells similar to the myometrium. So, the pseudocapsules are part of the myometrium which compresses the leiomyoma. CONCLUSION: This ultrastructural feature suggests that when removing fibroids their pseudocapsules should be preserved. This study confirms preliminary evidence that pseudocapsules contain neuropeptides together with their related fibers, as a neurovascular bundle. The surgeon's behavior should be directed to carefully control and spare this muscular surrounding tissue during fibroid excision, in order to preserve the myometrium as much as possible. PMID- 22445209 TI - Hyperthermia and children left in cars. PMID- 22445210 TI - Best practice guidelines: fetal cardiology. PMID- 22445211 TI - Prenatal isolated mild ventriculomegaly is associated with persistent ventricle enlargement at ages 1 and 2. AB - BACKGROUND: Enlargement of the lateral ventricles is thought to originate from abnormal prenatal brain development and is associated with neurodevelopmental disorders. Fetal isolated mild ventriculomegaly (MVM) is associated with the enlargement of lateral ventricle volumes in the neonatal period and developmental delays in early childhood. However, little is known about postnatal brain development in these children. METHODS: Twenty-eight children with fetal isolated MVM and 56 matched controls were followed at ages 1 and 2 years with structural imaging on a 3T Siemens scanner and assessment of cognitive development with the Mullen Scales of Early Learning. Lateral ventricle, total gray and white matter volumes, and Mullen cognitive composite scores and subscale scores were compared between groups. RESULTS: Compared to controls, children with prenatal isolated MVM had significantly larger lateral ventricle volumes at ages 1 and 2 years. Lateral ventricle volume at 1 and 2 years of age was significantly correlated with prenatal ventricle size. Enlargement of the lateral ventricles was associated with increased intracranial volumes and increased gray and white matter volumes. Children with MVM had Mullen composite scores similar to controls, although there was evidence of delay in fine motor and expressive language skills. CONCLUSIONS: Children with prenatal MVM have persistent enlargement of the lateral ventricles through the age of 2 years; this enlargement is associated with increased gray and white matter volumes and some evidence of delay in fine motor and expressive language development. Further study is needed to determine if enlarged lateral ventricles are associated with increased risk for neurodevelopmental disorders. PMID- 22445212 TI - Does prior antidepressant treatment of major depression impact brain function during current treatment? AB - The relationship between prior antidepressant treatment and prefrontal brain functional response to subsequent treatment with antidepressant medication or placebo is unknown. Eighty-nine adults with Major Depressive Disorder (MDD), characterized as antidepressant-experienced or antidepressant-naive, received one week of single-blind placebo treatment prior to eight weeks of randomized treatment with medication (fluoxetine or venlafaxine; n = 47) or placebo (n = 42) in one of three similar placebo-controlled trials. Brain function was assessed at baseline, end of placebo lead-in, and during randomized treatment using quantitative electroencephalography (qEEG). The authors assessed change in prefrontal theta-band cordance (PFC) in antidepressant-experienced vs. antidepressant-naive subjects. Treatment history groups differed significantly on PFC change during the placebo lead-in even when controlling for clinical and demographic variables (F(1,62) = 4.27, p = .04). As assessed in linear mixed models that examined treatment history (antidepressant-experienced or antidepressant-naive), treatment assignment (medication or placebo), and their interaction as predictors, treatment history also predicted PFC change during the randomized phase of treatment even when controlling for pretreatment clinical and demographic and symptom improvement during treatment (F(1,5o) = 5.20, p = .03). The interaction was not significant. Post hoc analyses showed that antidepressant experienced subjects treated with placebo showed PFC changes that did not differ from PFC changes seen in the medication group. Results suggest that prefrontal brain functional changes during treatment for MDD may differ depending upon prior treatment with antidepressant medication. PMID- 22445213 TI - Mechanism of inactivation of ocriplasmin in porcine vitreous. AB - Ocriplasmin, a 249-amino acid recombinant C-terminal fragment of human plasmin, has the potential to degrade, within the eye, the protein scaffold that links the vitreous to the retina. This may be beneficial to the treatment of a number of important ophthalmic indications, such as symptomatic vitreomacular adhesion. We demonstrate here that ocriplasmin used at therapeutically-relevant concentrations is inactivated in porcine vitreous through autolytic degradation. Autolytic cleavage occurs at a limited number of sites, primarily K156-E157, K166-V167 and R177-V178, which, as predicted, contain a positively-charged arginine or lysine residue at the P1 position. Our data also suggest that autolytic degradation requires at least local or partial unfolding of the protein. PMID- 22445214 TI - Quantitative analyses of the behavior of exogenously added bacteria during an acidulocomposting process. AB - The behavior of adventitious bacteria during an acidulocomposting process was quantitatively analyzed in garbage-free trials. The numbers of the added Bacillus subtilis and Pseudomonas putida cells diminished in a first-order manner with t(1/2) values of 0.45d and 0.79d, respectively, consistent with the observed stability of the acidulocomposting function. PMID- 22445215 TI - Necrotizing Sweet syndrome: a new variant of neutrophilic dermatosis mimicking necrotizing fasciitis. AB - BACKGROUND: We report a series of patients initially given the diagnosis of necrotizing fasciitis whose course progressed despite surgical debridement, antibiotic therapy, or both, but who responded rapidly to systemic corticosteroids. OBJECTIVE: We sought to evaluate the clinical data, histopathologic and microbiology information, and treatment course of this unusual entity. METHODS: This was a descriptive study/case series. RESULTS: Three immunocompromised patients who presented with signs and symptoms of necrotizing fasciitis were included. They appeared septic, failed multiple courses of antibiotics, demonstrated pathergy, and two of them underwent extensive surgical debridement. None of the cases yielded a microbial source. Dermatologic consultation and histopathology confirmed deep Sweet syndrome in all cases, with marked necrosis of the soft tissue--including myonecrosis--in the two patients with debridement. All patients responded rapidly to high-dose systemic corticosteroids. LIMITATIONS: To our knowledge, this is the first report of this unusual presentation; there are a limited number of cases. CONCLUSION: We propose that these cases represent a new variant of neutrophilic dermatosis: "necrotizing Sweet syndrome," an acute necrotizing neutrophilic dermatosis. This subtype is also characterized by the rapid onset of progressive erythematous, warm, edematous cutaneous lesions with deep-tissue neutrophilic infiltration and soft tissue necrosis, in the absence of infectious cause. Awareness of this entity and early dermatologic consultation is critical as debridement results in expansion of the process, resulting in additional and aggressive resection--a vicious cycle with significant possible morbidity. PMID- 22445216 TI - Decreased cortical complexity in methamphetamine abusers. AB - This study aimed to investigate if methamphetamine (MA) abusers exhibit alterations in complexity of the electroencephalogram (EEG) and to determine if these possible alterations are associated with their abuse patterns. EEGs were recorded from 48 former MA-dependent males and 20 age- and sex-matched healthy subjects. Approximate Entropy (ApEn), an information-theoretical measure of irregularity, of the EEGs was estimated to quantify the degree of cortical complexity. The ApEn values in MA abusers were significantly lower than those of healthy subjects in most of the cortical regions, indicating decreased cortical complexity of MA abusers, which may be associated with impairment in specialization and integration of cortical activities owing to MA abuse. Moreover, ApEn values exhibited significant correlations with the clinical factors including abuse patterns, symptoms of psychoses, and their concurrent drinking and smoking habits. These findings provide insights into abnormal information processing in MA abusers and suggest that ApEn of EEG recordings may be used as a potential supplementary tool for quantitative diagnosis of MA abuse. This is the first investigation to assess the "severity-dependent dynamical complexity" of EEG patterns in former MA abusers and their associations with the subjects' abuse patterns and other clinical measures. PMID- 22445217 TI - Parental psychological control and dysfunctional separation-individuation: a tale of two different dynamics. AB - This study examined associations between psychologically controlling parenting and two possible manifestations of problematic separation-individuation (i.e., dysfunctional dependence and dysfunctional independence). To explain these associations, it has been argued that psychological control is an inherently independence-stifling parenting dimension that gives rise to a dysfunctional dependent orientation. In this study, it was argued that psychological control may relate to dysfunctional dependence and dysfunctional independence, depending on whether parents' use of psychological control is driven by issues of interpersonal closeness (i.e., dependency-oriented psychological control) or by issues of achievement (i.e., achievement-oriented psychological control). A Belgian sample of 232 emerging adults, involved in the process of home leaving, and their parents completed self-report questionnaires. Regression analyses indicated that domain-specific expressions of psychological control were related differentially to dysfunctional dependent and dysfunctional independent manifestations of problematic separation-individuation. Emerging adults' residential status did not moderate these associations. Implications and directions for future research are discussed. PMID- 22445218 TI - Inherited bleeding disorders in older women. AB - Inherited bleeding disorders (IBDs) are by definition life-long. The commonest IBD is von Willebrand disease (VWD), a deficiency of von Willebrand factor (VWF), with a prevalence 1% in the general population and 13% in women with menorrhagia. Other IBDs include carriers of haemophilia A (factor VIII deficiency) and haemophilia B, (factor IX deficiency) and rare bleeding disorders (RBDs), deficiencies of factors XI, X, V, VII, II, I and inherited platelet disorders. Diagnosis is the synthesis of a bleeding history, family history and specialised laboratory tests. Women with IBDs are more likely to suffer HMB, to be symptomatic, and to present with bleeding in association with gynaecological problems. Heavy and/or abnormal menstrual bleeding increases with age due increased anovulatory cycles and gynaecological pathologies in older women. Thus, older women with IBDs are more likely to present with gynaecological bleeding symptoms, have impaired QOL and require surgical interventions. Treatment with specific clotting factor concentrates may be required and this requires an expert in haematology. Awareness of IBDs among health care providers, early diagnosis and appropriate management in a multidisciplinary approach is required to minimise the bleeding complications for women with IBDs. PMID- 22445219 TI - Menopause with cardiovascular disease and its risk factors among rural Chinese women in Beijing: a population-based study. AB - OBJECTIVES: This study was to explore the independent influence of menopause on cardiovascular disease (CVD) and its risk factors in rural Chinese females. STUDY DESIGN: This cross-sectional population-based study enrolled 2245 premenopausal and 2498 postmenopausal women aged 40-59 years in Fangshan district, Beijing, China. Data was collected by face-to-face interview, physical examination and biochemical examination during 2009 and 2010. General liner models were employed to calculate age-adjusted means of cardiovascular risk factors (CRFs). The comparisons of CVD and it risk factors according to menopausal status, and calculation of adjusted odds ratios/coefficients and their 95% confidence intervals for the associations of quartiles of elapsed time since menopause and age at menopause with CVD and its risk factors was performed by multivariate logistic/liner regression models separately. RESULTS: After adjustment for age and other confounders, no statistically significant association of menopause with CVD was observed in our participants; however, dyslipidemia prevalence and levels of waist-to-hip ratio, triglycerides, total cholesterol and low-density lipoprotein cholesterol were presented higher in postmenopausal group, compared to the premenopausal one (P<0.05). Compared to women who had been menopausal for less than1 year, those with the elapsed time since menopause of 2-3 years had higher CHD prevalence, higher triglycerides level and lower high-density lipoprotein cholesterol level (P<0.05). CONCLUSIONS: Postmenopausal women in rural China had worse CRFs profile than the premenopausal ones, which implied menopause might aggravate the CRFs epidemic beyond effects of aging, and would increase the CVD burden during and after their middle ages. PMID- 22445221 TI - Re: Bas W.G. van Rhijn, Theo H. van der Kwast, Sultan S. Alkhateeb, et al. A New and highly prognostic system to discern T1 bladder cancer substage. Eur Urol 2012;61:378-84. PMID- 22445222 TI - Long-term results of artificial urinary sphincter for women with type III stress urinary incontinence. AB - BACKGROUND: The use of the artificial urinary sphincter (AUS) in women is limited. OBJECTIVE: To analyse long-term results and mechanical survival of the AUS (AMS 800; American Medical Systems, Minnetonka, MN, USA) in women with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD). DESIGN, SETTING, AND PARTICIPANTS: Women with SUI who were treated between January 1987 and March 2007 were included in this prospective study. Only women with low closure pressure at urethral profile and negative continence tests, indicators of severe ISD, were included. INTERVENTIONS: An AUS was implanted. The surgical technique was modified in 1999, involving opening the endopelvic fascia on both sides and dissection in contact with the vaginal wall. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Assessment of complications was made pre- and postoperatively and continence status was based on pad usage. Kaplan-Meier survival curves were used to calculate mechanical survival of the device. Student t test and the chi-square test were used to compare continence and complication rates. RESULTS AND LIMITATIONS: A total of 376 AUS were implanted in 344 patients, whose mean age was 57 yr. The mean follow-up, plus or minus standard deviation, was 9.6+/-4.0 yr. At last follow-up, postoperative continence rates, assessed as fully continent (no leakage), socially incontinent (some drops but no pad), or incontinent (one pad or more), were 85.6%, 8.8%, and 5.6%, respectively. The 3-, 5-, and 10-yr device survival rates were 92.0%, 88.6%, and 69.2%, respectively. The mean mechanical survival was 176 mo (14.7 yr). Three risk factors for AUS survival were the number of previous incontinence surgeries, the presence of neurogenic bladder, and simultaneous augmentation enterocystoplasty. Principal limitation of the study is the absence of validated incontinence questionnaire. CONCLUSIONS: The AUS provides excellent outcome in women with ISD, with low explantation rate and very good device survival. PMID- 22445223 TI - Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. AB - BACKGROUND: Evolution of cryotherapy for prostate cancer is likely to result in parenchyma-sparing modifications adjacent to the urethra and neurovascular bundle. Results of initial series of focal therapy to minimize cryosurgery related morbidity without compromising oncologic control have been encouraging, but limited in short-term outcomes. OBJECTIVE: To retrospectively report (1) median 3.7-yr follow-up experience of primary focal cryotherapy for clinically unilateral prostate cancer with oncologic and functional outcomes, and (2) matched-pair analysis with contemporaneous patients undergoing radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Over 8.5 yr (September 2002 to March 2011), focal cryoablation (defined as ablation of one lobe) was performed in 73 carefully selected patients with biopsy-proven, clinically unilateral, low-intermediate risk prostate cancer. All patients underwent transrectal ultrasound (TRUS) and Doppler-guided sextant and targeted biopsies at entry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-therapy follow-up included measuring prostate-specific antigen (PSA) level every 3-6 mo; TRUS biopsies at 6-12 mo and yearly, as indicated; and validated symptom questionnaires. Matched-pair analysis compared oncologic outcomes of focal cryotherapy and RP (matched for age, PSA, clinical stage, and biopsy Gleason score). RESULTS AND LIMITATIONS: Complete follow-up was available in 70 patients (median follow-up: 3.7 yr; range: 1-8.5 yr). No patient died or developed metastases. Precryotherapy mean PSA was 5.9 ng/ml and Gleason score was 6 (n=30) or 7 (n=43). Postcryotherapy mean PSA was 1.6 ng/ml (70% reduction compared to precryotherapy; p<0.001). Of 48 patients undergoing postcryotherapy biopsy, 36 (75%) had negative biopsies; positive biopsy for cancer (n=12) occurred in the untreated contralateral (n=11) or treated ipsilateral lobe (n=1). Complete continence (no pads) and potency sufficient for intercourse were documented in 100% and 86% of patients, respectively. Matched-pair comparison of focal cryotherapy and RP revealed similar oncologic outcome, defined as needing salvage treatment. CONCLUSIONS: Primary focal cryoablation for low-intermediate risk unilateral cancer affords encouraging oncologic and functional outcomes over a median 3.7-yr follow-up. Close surveillance with follow-up whole-gland biopsies is mandatory. PMID- 22445224 TI - [Sedation and analgesia in emergency structure. Paediatry: Which sedation and analgesia for pediatric patients? Pharmacology]. PMID- 22445225 TI - [Sedation and analgesia in emergency structure. Which sedation and/or analgesia during pregnancy?]. PMID- 22445226 TI - Swi2/Snf2 remodelers: hybrid views on hybrid molecular machines. AB - Swi2/Snf2 (switch/sucrose non-fermentable) enzymes form a large and diverse class of proteins and multiprotein assemblies that remodel nucleic acid:protein complexes, using the energy of ATP hydrolysis. The core Swi2/Snf2 type ATPase domain belongs to the 'helicase and NTP driven nucleic acid translocase' superfamily 2 (SF2). It serves as a motor that functionally and structurally interacts with different targeting domains and functional modules to drive a plethora of remodeling activities in chromatin structure and dynamics, transcription regulation and DNA repair. Recent progress on the interaction of Swi2/Snf2 enzymes and multiprotein assemblies with their substrate nucleic acids and proteins, using hybrid structural biology methods, illuminates mechanisms for complex chemo-mechanical remodeling reactions. For Mot1, a hybrid mechanism of remodeler and chaperone emerged. PMID- 22445227 TI - Mapping membrane protein structure with fluorescence. AB - Membrane proteins regulate many cellular processes including signaling cascades, ion transport, membrane fusion, and cell-to-cell communications. Understanding the architecture and conformational fluctuations of these proteins is critical to understanding their regulation and functions. Fluorescence methods including intensity mapping, fluorescence resonance energy transfer (FRET), and photo induced electron transfer, allow for targeted measurements of domains within membrane proteins. These methods can reveal how a protein is structured and how it transitions between different conformational states. Here, I will review recent work done using fluorescence to map the structures of membrane proteins, focusing on how each of these methods can be applied to understanding the dynamic nature of individual membrane proteins and protein complexes. PMID- 22445228 TI - New currency for old rope: from coiled-coil assemblies to alpha-helical barrels. AB - alpha-Helical coiled coils are ubiquitous protein-protein-interaction domains. They share a relatively straightforward sequence repeat, which directs the folding and assembly of amphipathic alpha-helices. The helices can combine in a number of oligomerisation states and topologies to direct a wide variety of protein assemblies. Although in nature parallel dimers, trimers and tetramers dominate, the potential to form larger oligomers and more-complex assemblies has long been recognised. In particular, complexes above pentamer are interesting because they are barrel-like, having central channels or pores with well-defined dimensions and chemistry. Recent empirical and rational design experiments are beginning to chart this potential new territory in coiled-coil space, leading to intriguing new structures, and possibilities for functionalisation and applications. PMID- 22445229 TI - The relationship between subjective sleep duration and psychological wellbeing is modified by perception of sleep. PMID- 22445230 TI - The longitudinal course and impact of non-restorative sleep: a five-year community-based follow-up study. AB - BACKGROUND: There is a dearth of data on the longitudinal course and outcome of non-restorative sleep (NRS). METHODS: A total of 2291 middle-aged adults (mean [SD]=46.3 [5.1] years old, 50.0% males at follow-up) were recruited into a 5-year follow-up study. NRS was defined as morning unfreshness after getting up >= 3 times/week over the past 12 months. Socio-demographics, other concurrent sleep complaints, and daytime symptoms were measured at baseline. Chronic medical problems in the past one year were additionally assessed at follow up. RESULTS: Several sleep problems (including other insomnia subtypes, snoring, and nightmares) and daytime symptoms were strongly associated with NRS at baseline. NRS had considerable persistence (31.9%), partial remission (22.7%), and incidence rate (5.2%). New incidence of NRS was predicted by female gender (AOR=1.67), preferring not to get up in the morning (AOR=1.96), fatigue (AOR=2.18), and short sleep duration (AOR=1.87), whereas persistence of NRS was predicted by difficulty initiating sleep (AOR=2.36). In the fully adjusted models, baseline NRS was significantly associated with multiple medical disorders at follow-up, including frequent allergic rhinitis (AOR=1.62) and laryngopharyngitis (AOR=2.47), diabetes mellitus (AOR=2.63), gastroesophageal reflux disease (AOR=2.03), eye problems (AOR=2.45), eczema (AOR=2.18), and poor mental health (AOR=1.68). CONCLUSIONS: The persistent course and independent association of NRS with adverse medical and mental outcomes argue for a distinct nosological status and the need for rigorous medical attention. PMID- 22445231 TI - Economic difficulties and subsequent sleep problems: evidence from British and Finnish occupational cohorts. AB - BACKGROUND: Social determinants of sleep may prove to be as important as health status. In this study we examined the extent to which persistent and changing economic difficulties are associated with sleep problems in two prospective occupational cohorts. METHODS: We used data from Finnish (baseline 2000-2002; follow-up 2007; n=6328) and British (baseline 1997-1999; follow-up 2003-2004; n=5002) public sector employees. Economic difficulties, sleep problems, and a variety of covariates were assessed at baseline and follow-up. RESULTS: Prevalence of frequent sleep problems at follow-up was 27% and 20% among women and men in the Finnish cohort, and 34% and 27% in the British cohort, respectively. Odds for sleep problems were higher among those with persistent economic difficulties (frequent economic difficulties at baseline and follow-up) compared to those with no difficulties. This association remained after multiple adjustments, including parental and current socioeconomic position, in the Finnish (OR 1.72, 95% CI 1.35-2.18) cohort. Increases in economic difficulties were similarly associated with sleep problems in the Finnish and the British cohort. CONCLUSION: Evidence from two occupational cohorts suggests strong associations between economic difficulty and poor sleep. Awareness of this association will help health care professionals identify and prevent sleep problems. PMID- 22445232 TI - Assessment of glycemic control among diabetic residents in nursing homes. AB - We assessed hemoglobin A1c (HbA1c) among 88 diabetic residents in three Italian nursing homes, and compared figures with current guidelines and reports in the literature. Mean HbA1c was 6.5%; this paper from Southern Europe confirms recent findings in nursing homes on HbA1c values well below recommended targets. PMID- 22445233 TI - Downregulation of chemerin and alleviation of endoplasmic reticulum stress by metformin in adipose tissue of rats. AB - AIMS: To investigate whether metformin regulates chemerin expression in vivo by alleviating ER stress. METHODS: Male Sprague-Dawley rats were fed a high-fat or normal diet for 10 weeks to induce insulin resistance. During the following 6 weeks, the rats were divided into four groups: normal diet without treatment (NC), normal diet with metformin treatment (NM), high-fat diet without metformin (HF), and high-fat diet with metformin (HM). Body weight, fasting glucose, basal insulin level, insulin sensitivity, chemerin expression in serum and adipose tissue, ER stress marker and its pathway were measured. RESULTS: After 6 weeks treatment, metformin reduced the body weight gain and enhanced insulin sensitivity of high-fat fed rats. The basal insulin level in the HM group was lower than in the HF group. Metformin reduced chemerin expression in the HM group compared with HF. Metformin reduced the GRP78 mRNA expression in HM rats. Activation of IRE1 alpha was lower in the HM group than the HF group. CONCLUSIONS: Metformin treatment decreased the chemerin expression and alleviated the ER stress in the visceral adipose tissue of high-fat diet-induced insulin resistant rats. These data may also provide a further rationale for exploring the use of metformin in the treatment of insulin resistance. PMID- 22445234 TI - Interfacial and foaming interactions between casein glycomacropeptide (CMP) and propylene glycol alginate. AB - Proteins and polysaccharides are widely used in food formulation. While most of the proteins are surface active, only few polysaccharides can adsorb at the air water interface; this is the case of propylene glycol alginates (PGA). It is known that casein glycomacropeptide (CMP), a bioactive polypeptide derived from kappa-casein by the action of chymosin, presents a great foaming capacity but provides unstable foams. So, the objective of this work was to analyze the impact of mixing CMP and a commercial variety of PGA, Kelcoloid O (KO), on the interfacial and foaming properties at pH 7.0. It was determined the surface pressure isotherm, the dynamics of adsorption and the foaming properties for CMP, KO and the mixed system CMP-KO. CMP dominated the surface pressure of CMP-KO mixed system. The presence of KO synergistically improved the viscoelastic properties of surface film. The foaming capacity of CMP was altered by KO. KO foam presented a higher stability than CMP foam and it controlled the stability against drainage and the initial collapse in the mixed foam. PMID- 22445235 TI - Production and characterization of biosurfactant produced by a novel Pseudomonas sp. 2B. AB - Biosurfactant-producing bacteria were isolated from terrestrial samples collected in areas contaminated with petroleum compounds. Isolates were screened for biosurfactant production using Cetyl Tri Ammonium Bromide (CTAB)-Methylene blue agar selection medium and the qualitative drop-collapse test. An efficient bacterial strain was selected based on rapid drop collapse activity and highest biosurfactant production. The biochemical characteristics and partial sequenced 16S rRNA gene of isolate, 2B, identified the bacterium as Pseudomonas sp. Five different low cost carbon substrates were evaluated for their effect on biosurfactant production. The maximum biosurfactant synthesis (4.97 g/L) occurred at 96 h when the cells were grown on modified PPGAS medium containing 1% (v/v) molasses at 30 degrees C and 150 rpm. The cell free broth containing the biosurfactant could reduce the surface tension to 30.14 mN/m. The surface active compound showed emulsifying activity against a variety of hydrocarbons and achieved a maximum emulsion index of 84% for sunflower oil. Compositional analysis of the biosurfactant reveals that the extracted biosurfactant was a glycolipid type, which was composed of high percentages of lipid (~65%, w/w) and carbohydrate (~32%, w/w). Fourier transform infrared (FT-IR) spectrum of extracted biosurfactant indicates the presence of carboxyl, hydroxyl and methoxyl functional groups. The mass spectra (MS) shows that dirhamnolipid (l rhamnopyranosyl-l-rhamnopyranosyl-3-hydroxydecanoyl-3-hydroxydecanoate, Rha-Rha C(10)-C(10)) was detected in abundance with the predominant congener monorhamnolipid (l-rhamnopyranosyl-beta-hydroxydecanoyl-beta-hydroxydecanoate, Rha-C(10)-C(10)). The crude oil recovery studies using the biosurfactant produced by Pseudomonas sp. 2B suggested its potential application in microbial enhanced oil recovery and bioremediation. PMID- 22445236 TI - Fabrication of magnetic chitosan nanoparticles grafted with beta-cyclodextrin as effective adsorbents toward hydroquinol. AB - The adsorption characteristics of hydroquinol from aqueous solutions onto the beta-cyclodextrin modified magnetic chitosan nanoparticles (CMCN) had been investigated. The characteristics results of FTIR, SEM and XRD showed that CMCN was successfully prepared. The influences of the pH of the solution and the contact time on the adsorption amounts had been discussed, and the appropriate process conditions for the adsorption of hydroquinol had been obtained. Equilibrium experiments fitted well with the Freundlich isotherm model, and the maximum adsorption capacity of the CMCN at 303 K was determined to be 1.75 mmol/g for hydroquinol at the concentration of 9.0 mmol/L, much higher than some conventional adsorbents. The CMCN was stable and easily recovered. Moreover, the adsorption capacity was about 90% of the initial saturation adsorption capacity after being used four times. PMID- 22445237 TI - Targeted next-generation sequencing expands the spectrum of mitochondrial disorders. AB - Next-generation sequencing has become a powerful tool for testing genetically and clinically heterogeneous conditions such as mitochondrial disorders. A recent study published in Science Translational Medicine underscores the considerable clinical benefits of targeted next-generation sequencing for the diagnosis of mitochondrial disorders. The findings also suggest that the genetic heterogeneity that can result in mitochondrial disease appears much broader than previously thought. PMID- 22445238 TI - Leukocoria and retinoblastoma--pitfalls of the digital age? PMID- 22445239 TI - Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. AB - BACKGROUND: The relative safety of drug-eluting stents and bare-metal stents, especially with respect to stent thrombosis, continues to be debated. In view of the overall low frequency of stent thrombosis, large sample sizes are needed to accurately estimate treatment differences between stents. We compared the risk of thrombosis between bare-metal and drug-eluting stents. METHODS: For this network meta-analysis, randomised controlled trials comparing different drug-eluting stents or drug-eluting with bare-metal stents currently approved in the USA were identified through Medline, Embase, Cochrane databases, and proceedings of international meetings. Information about study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. FINDINGS: 49 trials including 50,844 patients randomly assigned to treatment groups were analysed. 1-year definite stent thrombosis was significantly lower with cobalt chromium everolimus eluting stents (CoCr-EES) than with bare-metal stents (odds ratio [OR] 0.23, 95% CI 0.13-0.41). The significant difference in stent thrombosis between CoCr-EES and bare-metal stents was evident as early as 30 days (OR 0.21, 95% CI 0.11-0.42) and was also significant between 31 days and 1 year (OR 0.27, 95% CI 0.08-0.74). CoCr-EES were also associated with significantly lower rates of 1-year definite stent thrombosis compared with paclitaxel-eluting stents (OR 0.28, 95% CI 0.16-0.48), permanent polymer-based sirolimus-eluting stents (OR 0.41, 95% CI 0.24-0.70), phosphorylcholine-based zotarolimus-eluting stents (OR 0.21, 95% CI 0.10-0.44), and Resolute zotarolimus-eluting stents (OR 0.14, 95% CI 0.03-0.47). At 2-year follow-up, CoCr-EES were still associated with significantly lower rates of definite stent thrombosis than were bare-metal (OR 0.35, 95% CI 0.17-0.69) and paclitaxel-eluting stents (OR 0.34, 95% CI 0.19 0.62). No other drug-eluting stent had lower definite thrombosis rates compared with bare-metal stents at 2-year follow-up. INTERPRETATION: In randomised studies completed to date, CoCr-EES has the lowest rate of stent thrombosis within 2 years of implantation. The finding that CoCr-EES also reduced stent thrombosis compared with bare-metal stents, if confirmed in future randomised trials, represents a paradigm shift. FUNDING: The Cardiovascular Research Foundation. PMID- 22445240 TI - Stent thrombosis: has the firestorm been extinguished? PMID- 22445241 TI - [Orthostatic hypotension: epidemiology and mechanisms]. AB - Orthostatic hypotension (OH) is defined as a decrease in systolic blood pressure more than or equal to 20 mm Hg or diastolic more than or equal to 10 mm Hg within three minutes of standing up. Discharge records for 0.4% of all hospitalizations include OH as a diagnosis. The prevalence of OH is related to aging, reaching 5 to 30% in unselected elders aged more than or equal to 65 years, especially those treated for hypertension and/or living in nursing homes or health care facilities. OH is associated with an increased risk of syncope and subsequent cardiovascular mortality. Standing results in pooling of 25-30% of blood in the lower extremities and splanchnic-mesenteric circulation, thereby reducing venous return, ventricular filling, cardiac output and, in turn, blood pressure. Compensatory mechanisms to maintain BP involve the baroreflex and the sympathetic nervous system (SNS). Failure of SNS results in neurogenic OH, which is severe in multiple system atrophy with dysautonomia (Shy-Drager syndrome), also commonly seen in patients with Lewy body dementia and in patients with Parkinson's disease, in whom OH is less severe and occurs later. Conversely, SNS function is preserved in secondary OH associated with hypovolemia, anemia, antihypertensive or psychotropic drugs. Clinical manifestations and tolerance of OH depends on its severity and on cerebral blood flow autoregulation, which both impact on the risk of syncope, trauma and subsequent prognosis. PMID- 22445242 TI - Characterization of dissolved extracellular organic matter (dEOM) and bound extracellular organic matter (bEOM) of Microcystis aeruginosa and their impacts on UF membrane fouling. AB - Extracellular organic matter (EOM) of cyanobacteria was classified into the dissolved EOM (dEOM) which was released into culture solution and the bound EOM (bEOM) which surrounded the cells. The dEOM and bEOM extracted from Microcystis aeruginosa in stationary phase were used to study their characteristic differences and then their impacts on ultrafiltration (UF) membrane fouling. Component analyses showed that dEOM was comprised of proteins, polysaccharides and humic-like substances, while that bEOM contained only proteins and polysaccharides. Additionally, polysaccharides dominated in dEOM with a polysaccharide/DOC ratio of 1.11 mg mg(-1), while proteins were the primary components of bEOM with a protein/DOC ratio of 1.08 mg mg(-1). Results of size fractionation and XAD resin fractionation revealed that bEOM was mainly distributed in the high-MW and hydrophobic fractions, while that dEOM was more hydrophilic. Result of UF experiments indicated that dEOM which had a higher organic content and stronger hydrophilicity caused more severe flux decline and reversible fouling, and that bEOM led to slower flux decline but more irreversible fouling due to less electrostatic repulsive and more hydrophobic adhesion. The impacts of these two kinds of EOM on the UF fouling caused by cyanobacterial cells were also investigated. It was found that both flux decline and irreversible membrane fouling caused by the cells were aggravated when cells were together with EOM, especially for bEOM which might increase the surface hydrophobicity of the cells. PMID- 22445243 TI - Hybrid stent-graft repair of an iatrogenic complex proximal right common carotid artery injury. AB - BACKGROUND: Iatrogenic carotid trauma requires early diagnosis and adequate treatment. Classic open repair may be technically challenging if trauma is in base of the neck. We present a case of an iatrogenic carotid pseudoaneurysm treated with endovascular repair. METHODS: An 87-year-old woman presented with a pulsatile neck mass 10 days after coronary artery bypass graft surgery. A computed tomographic angiogram showed a 1.6 * 1.0 * 2.0-cm pseudoaneurysm arising from the posterior wall of the proximal right common carotid artery. Endovascular management was considered, and a percutaneous angiogram demonstrated an arteriovenous fistula in addition to the pseudoaneurysm. Through a cervical cut down, retrograde percutaneous access was obtained through the common carotid artery, which allowed easier access to the area of trauma owing to vessel tortuosity. Subsequently, a 5 mm * 2-cm Viabahn was deployed. The postdilation angiogram showed a significant endoleak that kept filling the pseudoaneurysm. A second 6 mm * 5-cm Viabahn was placed and successfully postdilated with a 6 mm * 4-cm balloon. No endoleaks or fistulas were noted on the completion angiogram. RESULTS: The patient remains asymptomatic after 15 months. Follow-up images showed thrombosis of pseudoaneurysm. CONCLUSION: Endovascular treatment with self expanding stent-grafts and open cut-down access are excellent options to treat major vessel injuries at the base of the neck, where anatomy and cumbersome access make open surgery a more difficult option. PMID- 22445244 TI - Assessment of protective effects of methylprednisolone and pheniramine maleate on reperfusion injury in kidney after distant organ ischemia: a rat model. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury of tissues is a common problem that cardiovascular surgeons are faced with. Suppression of inflammation, which plays an important role in the pathogenesis of I/R injury, may reduce this damage. The aim of this study is to investigate the protective effects of methylprednisolone (MP)--a potent anti-inflammatory agent--and pheniramine maleate (FM)--an antihistamine that also has some anti-inflammatory effects--on reperfusion injury of kidneys developing after ischemia of the left lower extremity of rats. METHODS: Twenty-eight randomly selected male Sprague-Dawley rats weighing 320 to 370 g were divided into four groups, each consisting of seven rats. Group 1 was the control group. Group 2 was the sham group. Rats in group 3 were subjected to I/R and given FM, and rats in group 4 were subjected to I/R and given MP. A tourniquet was applied at the level of the left groin to subjects in group 2 after induction of anesthesia. One hour of ischemia was performed, and no drug was administered. In group 3, half of a total dose of 10 mg/kg FM was administered before ischemia, and the remaining half was given intraperitoneally before reperfusion. In group 4, subjects received a single dose of 50 mg/kg MP intraperitoneally in the 30th minute of ischemia. Kidneys of all subjects were removed after 24 hours. Extracted tissues were investigated regarding histological and biochemical parameters. RESULTS: Malondialdehyde--the end product of lipid peroxidation as an important indicator of I/R injury--levels were significantly lower in group 3 than in group 2 (P < 0.05). Malondialdehyde levels were also lower in group 4 than in group 2, but this difference was insignificant (P > 0.05). Superoxide dismutase and glutathione peroxidase enzyme activities were found to be significantly higher in group 3 than in group 2 (P < 0.05). However, there was no difference between group 4 and group 2 in terms of these activities. Histological examination demonstrated that both MP and FM had protective effects against I/R injury, but this effect was more potent for FM than for MP. CONCLUSIONS: FM has a protective effect against reperfusion injury in rat kidney after distant organ ischemia. PMID- 22445246 TI - Aortic aneurysm surgery: long-term patency of the reimplanted intercostal arteries. AB - BACKGROUND: During aortic surgery, the long-term patency of reimplanted intercostal arteries is unknown, limiting the relevance to preserve spinal cord vascularization. METHODS: Between January 2001 and January 2007, 40 patients were operated for either thoracic aortic aneurysm (TAA) or thoracoabdominal aortic aneurysm (TAAA). Twenty cases of aneurysms limited to the proximal descending thoracic aorta were treated using endovascular repair, without preoperative spinal cord artery identification. Twenty patients--seven with extensive TAA, seven with type I TAAA, two with type II TAAA, and four with type III TAAA- underwent open surgery. Before open surgery, preoperative angiography was performed to identify spinal cord vascularization; in one case, the angiography failed to identify it. The segmental artery destined to the spinal cord artery was identified as originating from outside the aneurysm in 7 patients and inside the aneurysm in 12 patients: T6 R (1), T8 L (2), T9 L (3), T10 L (3), T11 L (3), L1 L (1). During the surgery, normothermic and femorofemoral bypass was used for visceral protection. All segmental arteries identified as critical before surgery were reattached in the graft. Twenty-four months later, computed tomography scans were performed to assess the patency of the reattached segmental arteries. RESULTS: Three patients died, including one with paraplegia (T9 L). No other cases of paraplegia were reported. Computed tomography scans were performed in 10 patients. Segmental artery reattachment was patent in nine patients. CONCLUSION: Our experience indicates the long-term patency of reimplanted segmental artery, without any convincing evidence of its utility in preventing neurologic events during TAA and TAAA direct repair. PMID- 22445245 TI - Role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia: therapeutic potential for prevention of vein graft failure? AB - The saphenous vein remains the most widely used conduit for peripheral and coronary revascularization despite a high rate of vein graft failure. The most common cause of vein graft failure is intimal hyperplasia. No agents have been proven to be successful for the prevention of intimal hyperplasia in human subjects. The renin-angiotensin system is essential in the regulation of vascular tone and blood pressure in physiologic conditions. However, this system mediates cardiovascular remodeling in pathophysiologic states. Angiotensin II is becoming increasingly recognized as a potential mediator of intimal hyperplasia. Drugs modulating the renin-angiotensin system include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs are powerful inhibitors of atherosclerosis and cardiovascular remodeling, and they are first-line agents for management of several medical conditions based on class I evidence that they delay progression of cardiovascular disease and improve survival. Several experimental models have demonstrated that these agents are capable of inhibiting intimal hyperplasia. However, there are no data supporting their role in prevention of intimal hyperplasia in patients with vein grafts. This review summarizes the physiology of the renin-angiotensin system, the role of angiotensin II in the pathogenesis of cardiovascular remodeling, the medical indications for these agents, and the experimental data supporting an important role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia. PMID- 22445247 TI - A phase II study of RO4929097 in metastatic colorectal cancer. AB - BACKGROUND: The Notch signalling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by gamma-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of gamma-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer. PATIENTS AND METHODS: Patients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3 days on and 4 days off continuously. Cycle length was 28 days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN and the downstream target HES1. RESULTS: Thirty-seven patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only six patients had stable disease as their best response. Median PFS was 1.8 months and median overall survival (OS) was 6.0 months. CONCLUSION: In this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy. PMID- 22445248 TI - A comparison of clinical and objective measures of freezing of gait in Parkinson's disease. AB - Freezing of gait, a paroxysmal motor block, is common in the latter stages of Parkinson's disease. The current 'gold standard' of assessing the severity of freezing is based on clinical identification (by up to 3 raters) of the number of episodes from video. The aims of this study were to systematically assess this 'gold standard' across multiple Parkinson's disease centers, and to compare these clinical ratings with objective measures derived from lower limb acceleration data. Video recordings were acquired during a timed up-and-go task from 10 Parkinson's disease patients (with a clinical history of freezing) in the 'off' state. Patients were instrumented with accelerometers on the lateral aspect of each shank. Ten experienced clinicians were recruited from four Parkinson's disease centers to independently assess the videos for number and duration of freezing events. The reliability of clinical video assessment for number of freezing events was moderate (intraclass correlation coefficient 0.63). Percent time frozen (cumulative duration of freezing episodes/total duration of the walking task) demonstrated stronger agreement between raters (0.73). Agreement of accelerometry-derived measures of freezing severity with mean clinician ratings was strong for number of episodes (0.78) and very strong for percent time frozen (0.93). The results demonstrate the viability of objective measures of freezing, and that percent time frozen is a more reliable metric of severity than number of freezing events for both clinical and objective measures. The large variability between clinicians suggests that caution should be used when comparing subjective ratings across centers. PMID- 22445249 TI - Differentiating symptomatic Parkin mutations carriers from patients with idiopathic Parkinson's disease: contribution of automated segmentation neuroimaging method. AB - BACKGROUND: Parkin (PARK2) gene mutations are the predominant cause of autosomal recessive parkinsonism. Characteristic features include: early onset symptoms with slow clinical course, good response to low doses of levodopa, and frequently treatment-induced dyskinesia. Studies using a voxel-based morphometry approach showed a decrease in the gray matter volume of the basal ganglia in mutation carriers during the symptomatic stages. A bilateral, presumably compensatory increase of basal ganglia gray matter value was recently demonstrated in asymptomatic Parkin mutation carriers. Behavioral disorders including: anxiety, psychosis, panic attacks, depression, disturbed sexual, behavioral and obsessive compulsive disorders have been reported in these patients. METHOD: A total of 28 Parkinson's Disease (PD) patients consisting of 10 Young-Onset without Parkin mutations (YOPD), 9 Young-Onset with Parkin mutations (YOPD-p), 9 Late-Onset without Parkin mutations (LOPD) and 32 healthy control subjects were studied with an automated volumetric assessment method to quantify subcortical atrophy. Patients but not controls also underwent a neuropsychological and neuropsychiatric assessment. RESULTS: Results revealed a reduction of bilateral caudate nuclei volumes in YOPD-p patients compared to the YOPD patients while there were no statistically significant differences between other groups. YOPD-p patients showed similar results to other patient groups on neuropsychiatric and neuropsychological evaluation measures. CONCLUSION: YOPD-p and YOPD patients showed a different pattern of volume changes in basal ganglia. Despite its relatively benign clinical course, carrying the Parkin mutation seems to be associated with greater atrophy in subcortical structures. Failure of compensatory mechanisms, different mutation types and pathophysiologic processes may underlie this diverse pattern of subcortical brain changes. PMID- 22445250 TI - Analysis of LRRK2, SNCA, Parkin, PINK1, and DJ-1 in Zambian patients with Parkinson's disease. AB - Recent studies delineate substantial genetic components in Parkinson's disease (PD). However, very few studies were performed in Sub-Saharan African populations. Here, we explore the contribution of known PD-causing genes in patients of indigenous Zambian ancestry. We studied thirty-nine Zambian patients, thirty-eight with PD and one with parkinsonian-pyramidal syndrome (18% familial; average onset age 54.9 +/- 12.2 years). In the whole group, all SNCA exons and LRRK2 exons 29 to 48 (encoding for important functional domains) were sequenced. In the familial patients and those with onset <55 years (n = 22) the whole LRRK2 coding region was sequenced (51 exons). In the patients with onset <50 years (n = 12), all parkin, PINK1, and DJ-1 exons were sequenced, and dosage analysis of parkin, PINK1, DJ-1, LRRK2, and SNCA was performed. Dosage analysis was also performed in the majority of the late-onset patients. The LRRK2 p.Gly2019Ser mutation was not detected. A novel LRRK2 missense variant (p.Ala1464Gly) of possible pathogenic role was found in one case. Two heterozygous, likely disease causing deletions of parkin (exon 2 and exon 4) were detected in an early-onset case. Pathogenic mutations were not detected in SNCA, PINK1, or DJ-1. We also report variability at several single nucleotide polymorphisms in the above mentioned genes. This is the first molecular genetic study in Zambian PD patients, and the first comprehensive analysis of the LRRK2 and SNCA genes in a Sub-Saharan population. Common disease-causing mutations were not detected, suggesting that further investigations in PD patients from these populations might unravel the role of additional, still unknown genes. PMID- 22445251 TI - Hydrophobic poly (amino acid) modified PEI mediated delivery of rev-casp-3 for cancer therapy. AB - Recent studies in amphiphilic cationic polymers have demonstrated their potential as gene carriers with high transfection efficiency and low cytotoxicity in the in vitro settings to deliver drug, siRNA and plasmid DNA. Yet their safety and efficacy in vivo remain to be a challenge, and require further investigation. In our previous work, PP80 was synthesized as a novel amphiphilic cationic polymer by grafting hydrophobic polyphenylalanine segment on PEI, which displayed higher transfection efficiency than PEI in a number of cell lines in vitro. Here, we reported the favorable biocompatibility displayed by PP80/pDNA complex both in vitro and in vivo. Furthermore, when therapeutic gene rev-casp-3 was conjugated to PP80 and administered intratumorally to a HeLa xenograft model, significant tumor apoptosis was induced with concurrent tumor growth inhibition, indicating that PP80 mediated expression of rev-casp-3 gene in solid tumors with not detectable side effects on the tumor-bearing mice. These data demonstrated that PP80 warrants further investigation as a promising cancer gene delivery vehicle. PMID- 22445252 TI - Hyperbranched cationic amylopectin derivatives for gene delivery. AB - A series of hyperbranched cationic amylopectin derivatives conjugated with 1,2 ethylenediamine, diethylenetriamine and 3-(dimethylamino)-1-propylamine residues, named as EDA-Amp, DETA-Amp and DMAPA-Amp, were synthesized by the N,N' carbonyldiimidazole activation method at room temperature. Their structures were characterized by FTIR and (1)H NMR analyses, and their buffering capability was assessed by acid-base titration. The amylopectin derivatives exhibited better blood compatibility and lower cytotoxicity when compared to branched polyethyleneimine (bPEI) in the hemolysis and MTT assays. Atomic force microscopy and optical microscopy confirmed that the amylopectin derivatives exhibited lower damage for erythrocytes than bPEI. The amylopectin derivatives could bind and condense plasmid DNA (pDNA) to form the complexes with the size ranging from 100 to 300 nm. The resultant complexes showed higher transfection efficiency in 293T cells than in A549 cells. The DMAPA-Amp derivative-mediated gene transfection for Forkhead box O1 exhibited higher protein expression than that of the EDA-Amp and DETA-Amp derivatives in 293T cells, which was analyzed by western blot, flow cytometry and Hoechst staining assay. On the basis of these data, amylopectin derivatives exhibit potential as nonviral gene vectors. PMID- 22445253 TI - The promotion of hepatic maturation of human pluripotent stem cells in 3D co culture using type I collagen and Swiss 3T3 cell sheets. AB - Hepatocyte-like cells differentiated from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) are known to be a useful cell source for drug screening. We recently developed an efficient hepatic differentiation method from hESCs and hiPSCs by sequential transduction of FOXA2 and HNF1alpha. It is known that the combination of three-dimensional (3D) culture and co-culture, namely 3D co-culture, can maintain the functions of primary hepatocytes. However, hepatic maturation of hESC- or hiPSC-derived hepatocyte like cells (hEHs or hiPHs, respectively) by 3D co-culture systems has not been examined. Therefore, we utilized a cell sheet engineering technology to promote hepatic maturation. The gene expression levels of hepatocyte-related markers (such as cytochrome P450 enzymes and conjugating enzymes) and the amount of albumin secretion in the hEHs or hiPHs, which were 3D co-cultured with the Swiss 3T3 cell sheet, were significantly up-regulated in comparison with those in the hEHs or hiPHs cultured in a monolayer. Furthermore, we found that type I collagen synthesized in Swiss 3T3 cells plays an important role in hepatic maturation. The hEHs or hiPHs that were 3D co-cultured with the Swiss 3T3 cell sheet would be powerful tools for medical applications, such as drug screening. PMID- 22445254 TI - Poly(caprolactone)-modified Pluronic P105 micelles for reversal of paclitaxcel resistance in SKOV-3 tumors. AB - Three poly(caprolactone)-modified Pluronic P105 polymers (P105/PCLs) were synthesized using commercially available epsilon-caprolactone monomers and Pluronic P105 copolymers. The chemical structures, compositions and molecular weights of the P105/PCLs were confirmed by FT-IR, (1)H NMR and GPC measurements. Three paclitaxel (PTX)-loaded P105/PCL polymeric micelles were then prepared, and they showed average diameters in the range of 30-150 nm, drug-loading coefficients of 0.15%-5.43%, and encapsulation ratios of 2.1%-76.53%. The in vitro cytotoxicity assay demonstrated that three PTX-loaded P105/PCL micelles were able to sensitize the resistant SKOV-3/PTX tumor cells. The PTX-loaded P105/PCL(50) micelle was then selected for an in vivo antitumor efficacy study. The tumor volumes in nude mice bearing s.c. resistant SKOV-3/PTX carcinoma treated with this micellar PTX were significantly less than the control group treated with Taxol. It was demonstrated that three PCL-modified P105 monomers and micelles inhibited P-gP efflux activity in the resistant SKOV-3/PTX cells via at least three intracellular events: 1) inhibition of ATPase of P-gP, 2) decrease of membrane microviscosity and 3) a loss of mitochondrial membrane potential and subsequent decrease of ATP levels at the concentration of monomers (0.001%) and/or micelles (0.01-1.0%). Considering other favorable characteristics, such as sustained PTX release in vitro, long-circulating time in vivo and increased PTX concentration in the tissues of ovaries and uterus in mice, the PCL-modified Pluronic P105 polymeric micelle system could have important clinical implications for delivery of paclitaxel and treatment of the resistant ovarian tumors. PMID- 22445255 TI - The accumulation of dual pH and temperature responsive micelles in tumors. AB - An optimized, biodegradable, dual temperature- and pH-responsive micelle system conjugated with functional group Cy5.5 was prepared in order to enhance tumor accumulation. The Dynamic light scattering (DLS) measurements showed that these diblock copolymers form micelle in PBS buffer with a size of around 50 nm by heating of an aqueous polymer solution from below to above the cloud point (CP). Anticancer drug, doxorubicin was incorporated into the inner core of micelle by hot shock protocol. The size and stability of the micelle were controlled by the copolymer composition and is fine tuned to extracellular pH of tumor. The mechanism then caused pH change and at body temperature which induce doxorubicin release from micelles and have strong effects on the viability of HeLa, ZR-75-1, MCF-7 and H661 cancer cells. Our in vivo results revealed a clear distribution of Doxorubicin-loaded mixed micelle (Dox-micelle) and efficiency targeting tumor site with particles increasing size in the tumor interstitial space, and the particles could not diffuse throughout the tumor matrix. In vivo tumor growth inhibition showed that Dox-micelle exhibited excellent antitumor activity and a high rate of anticancer drug in cancer cells by this strategy. PMID- 22445256 TI - [Pulmonary paracoccidioidomycosis: a case report with high-resolution computed tomography findings]. AB - Paracoccidioidomycosis is a systemic mycosis which is endemic in rural areas of Latin America, an important European source of immigrants and a growing European touristic destination as well, with most cases occurring in Brazil, Argentina, Venezuela and Colombia. The authors report a case of a 43 year old man who previously worked in Venezuela and is living in Portugal for 8 years, presenting with a single cutaneous lesion. Despite the absence of valuable respiratory complaints, severe lung damage was found with high-resolution computed tomography (HRCT). Biopsy of the cutaneous lesion and mycologic sputum examination were performed revealing Paracoccidioides brasiliensis infection. PMID- 22445257 TI - Application of titanium dioxide in arsenic removal from water: A review. AB - Natural arsenic pollution is a global phenomenon and various technologies have been developed to remove arsenic from drinking water. The application of TiO(2) and TiO(2)-based materials in removing inorganic and organic arsenic was summarized. TiO(2)-based arsenic removal methods developed to date have been focused on the photocatalytic oxidation (PCO) of arsenite/organic arsenic to arsenate and adsorption of inorganic and organic arsenic. Many efforts have been taken to improve the performance of TiO(2) by either combing TiO(2) with adsorbents with good adsorption property in one system or developing bifunctional adsorbents with both great photocatalytic ability and high adsorption capacity. Attempts have also been made to immobilize fine TiO(2) particles on supporting materials like chitosan beads or granulate it to facilitate its separation from water. Among the anions commonly exist in groundwater, humic acid and bicarbonate have significant influence on TiO(2) photocatalyzed oxidation of As(III)/organic arsenic while phosphate, silicate, fluoride, and humic acid affect arsenic adsorption by TiO(2)-based materials. There has been a controversy over the TiO(2) PCO mechanisms of arsenite for the past 10 years but the adsorption mechanisms of inorganic and organic arsenic onto TiO(2)-based materials are relatively well established. Future needs in TiO(2)-based arsenic removal technology are proposed. PMID- 22445258 TI - Screening for anal cancer: endpoints needed. PMID- 22445259 TI - Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. AB - BACKGROUND: Men who have sex with men (MSM) are at greatly increased risk of human papillomavirus (HPV)-associated anal cancer. Screening for the presumed cancer precursor, high-grade anal intraepithelial neoplasia (AIN), followed by treatment in a manner analogous to cervical screening, has been proposed. We aimed to assess available data for anal HPV disease that can inform pre-cancer screening programmes. METHODS: We searched PubMed, OVID Medline, and Embase for all studies published before Nov 1, 2011, that reported prevalence and incidence of anal HPV detection, AIN, and anal cancer in MSM. We calculated summary estimates using random-effects meta-analysis. FINDINGS: 53 studies met the inclusion criteria, including 31 estimates of HPV prevalence, 19 estimates of cytological abnormalities, eight estimates of histological abnormalities, and nine estimates of anal cancer incidence. Data for incident HPV and high-grade AIN were scarce. In HIV-positive men, the pooled prevalence of anal HPV-16 was 35.4% (95% CI 32.9-37.9). In the only published estimate, incidence of anal HPV-16 was 13.0% (9.6-17.6), and clearance occurred in 14.6% (10.2-21.2) of men per year. The pooled prevalence of histological high-grade AIN was 29.1% (22.8-35.4) with incidences of 8.5% (6.9-10.4) and 15.4% (11.8-19.8) per year in two estimates. The pooled anal cancer incidence was 45.9 per 100,000 men (31.2-60.3). In HIV negative men, the pooled prevalence of anal HPV-16 was 12.5% (9.8-15.4). Incidence of HPV-16 was 11.8% (9.2-14.9) and 5.8% (1.9-13.5) of men per year in two estimates. The pooled prevalence of histological high-grade AIN was 21.5% (13.7-29.3), with incidence of 3.3% (2.2-4.7) and 6.0% (4.2-8.1) per year in two estimates. Anal cancer incidence was 5.1 per 100,000 men (0-11.5; based on two estimates). There were no published estimates of high-grade AIN regression. INTERPRETATION: Anal HPV and anal cancer precursors were very common in MSM. However, on the basis of restricted data, rates of progression to cancer seem to be substantially lower than they are for cervical pre-cancerous lesions. Large, good-quality prospective studies are needed to inform the development of anal cancer screening guidelines for MSM. FUNDING: Australian Government Department of Health and Ageing. PMID- 22445260 TI - Vestibular impairment after bacterial meningitis delays infant posturomotor development. AB - OBJECTIVE: To examine the findings and impact of postmeningitis vestibular dysfunction on early posturomotor development. Meningitis in children is frequently associated with postural instability, which is often attributed to an undefined neurologic disorder but it could actually be due to vestibular impairment. STUDY DESIGN: In a retrospective cohort study, we compared groups with vestibular loss before versus after independent walking: 37 children (18 girls, 19 boys; median age: 2.3 years) hospitalized for bacterial meningitis and referred for postural instability. A complete vestibular evaluation included 3 tests for function of the 6 semicircular canals (caloric, earth vertical axis rotation, head impulse tests), 2 tests for otolith function assessment (vestibular evoked myogenic potentials, off vertical axis rotation), audiologic evaluation, neurologic examination, and brain and temporal bone imaging. RESULTS: Twenty-nine children (10.5% of the 276 children hospitalized with bacterial meningitis) had vestibular impairment. Vestibular loss was complete bilaterally in 16 of 37 children and partial in 13 of 37, and 8 cases had normal vestibular responses. Neurologically normal children who had meningitis before they walked independently and had complete bilateral vestibular loss walked significantly later and their postural instability lasted longer than children in the other groups. The degree of vestibular impairment correlated with the postural instability duration and with the degree of hearing loss. CONCLUSIONS: Bacterial meningitis in young children can impair vestibular function completely, leading to delayed posturomotor development if meningitis occurs before independent walking, even in absence of neurologic impairment. Vestibular evaluations are encouraged for postmeningitis evaluation, particularly in cases with postural instability exceeding 8 days, hearing impairment, and programmed cochlear implant. PMID- 22445261 TI - Importance of the cytomegalovirus seropositive recipient as a contributor to disease burden after solid organ transplantation. AB - BACKGROUND: The incidence of cytomegalovirus (CMV) syndrome/disease after adult solid organ transplantation in the era effective antiviral therapy has not been fully assessed. OBJECTIVE: To determines the incidence of CMV syndrome/disease after solid organ transplantation in the UK. STUDY DESIGN: A retrospective analysis of 1807 solid organ transplants from 12 UK solid organ transplant centres representing 32.7% of all transplant activity occurring in the UK between 1/04/2004 and 31/03/2006. Patients were categorised into those experiencing an episode of symptomatic CMV infection after transplant or those who remained free of symptoms. All patients were followed up for 2 years for the occurrence of CMV syndrome/disease. RESULTS: The majority of the transplant centres used valganciclovir prophylaxis in the high risk D+R- patients (91.6%) whereas management of the lower risk D+R+ and D-R+ patients was more variable with deployment of both prophylactic and pre-emptive strategies in ~50% of centres. CMV syndrome/disease occurred in 20.5% of the D+R- patients representing 55 cases whereas the incidence was only 8.1% and 9% in the D+R+ and D-R+ group, respectively (p<0.001 compared to the D+R- group), but representing a further 58 cases of CMV syndrome/disease. CMV viraemia in the D+R- group was associated with a high probability (65%) of CMV syndrome/disease in renal transplant recipients whereas this was less apparent in the intermediate risk groups. CONCLUSIONS: CMV syndrome/disease remains an important healthcare burden after solid organ transplantation with the intermediate risk groups contributing similar numbers of cases as the high risk group. PMID- 22445262 TI - New natural variants of hepatitis B virus among Amerindians from Argentina with mainly occult infections. AB - BACKGROUND: Hepatitis B virus infection is frequent among Amerindians. In Argentina HBV genotypes A, B, C, D, E, F and H were described in different populations, while some cases of occult hepatitis B infection (OBI) were reported in human immunodeficiency virus (HIV) coinfected patients. OBJECTIVE: To determine the prevalence, genetic diversity of HBV and to analyze the deduced amino acid sequence of both S and viral polymerase (P) genes among Amerindians of Argentina. STUDY DESIGN: A cross-sectional study including 561 individuals belonging to distinct ethnic groups, the Mbya-guarani (MG), the Kolla (K), the Sagua-Huarpe (SH) and the Wichi (W) was performed. RESULTS: The prevalence of HBsAg was 1.7% and 1.4% for the MG and SH, respectively, while anti-HBc was detected in all communities. HBV DNA of S/P and preCore-Core genomic regions were amplified by nested polymerase chain reaction in 59 reactive samples for anti-HBc total Ig and/or HBsAg. Of them, thirteen exhibited detectable HBV DNA, eleven of which were identified as OBI. Genotype F was predominant in the MG community with co-circulation of subgenotypes F4, F1b, A2 and D3, while subgenotype C2 prevailed within the SH community. All cases exhibited the polymorphism rtL217R within the RT domain associated to resistance to adefovir. Mutations rtD206E and rtV207I associated with lamivudine resistance were found in two MG and three SH respectively. Other new substitutions were described within the P sequence. CONCLUSIONS: This study shows for the first time the predominance of OBI, HBV subgenotypes and natural variants in Amerindians from Argentina. PMID- 22445263 TI - Evaluation of a 4th generation rapid HIV test for earlier and reliable detection of HIV infection in pregnancy. AB - BACKGROUND: Currently used 3rd generation rapid HIV-tests in resource-limited settings do not detect acute HIV-infections (AHI). They are known to detect HIV infections after or late in the "window period". Detecting incident-HIV infections early in pregnancy increases opportunities for initiating antiretroviral prophylaxis to prevent mother-to-child transmission of HIV. OBJECTIVES: We evaluated the Determine((r)) HIV1/2 Ag/Ab Combo Rapid Test (Combo RT), a 4th generation test against two 3rd generation tests (SENSA-HIV1/2/0 Tri line, SD-Bioline) for early detection of HIV-infection in pregnancy. STUDY DESIGN: In a cohort study, plasma samples from 32 pregnant women who seroconverted at a subsequent antenatal visit (incident-infection), samples from 189 women who tested HIV positive at baseline (established-infections) and samples from 32 women remaining HIV-seronegative at a subsequent antenatal visit were tested with 3rd generation (antibody detection only) and 4th generation (antibody/antigen detection) rapid HIV tests. The HIV-1 NucliSENSEasyQ((r)) v2.0 PCR test was used to quantify HIV-viral copies in women with incident HIV infections. RESULTS: Eighteen of 32 (56.3%) women (incident-infections) had detectable viral copies (baseline); 16 (88.9%) were antibody reactive with the Combo RT. None of the 32 specimens were reactive on the antigen component of the Combo RT. The sensitivity and specificity of the Combo RT in detecting HIV infections prior to seroconversion is 59.4% (95%CI 40.6-76.3) and 96.9% (95%CI 83.8-99.9) respectively. The Combo RT detected 94.0% of all HIV-infections if used as a screening test (baseline) compared to 85.5% detected by 3rd generation tests. CONCLUSIONS: The Combo RT does not identify AHI but is superior to 3rd generation tests in detecting HIV antibody responses. PMID- 22445264 TI - Removal and recovery of phosphorus as struvite from swine wastewater using microbial fuel cell. AB - Air-cathode single chamber microbial fuel cells (MFCs) were operated with swine wastewater. The maximum power density, the maximum current density, the average value of COD-removal efficiency, and the coulombic efficiency were 1-2.3 W/m(2), 6.0-7.0 A/m(2), 76-91%, and 37-47%, respectively. During operation, 70-82% of the phosphorus was removed from the influent, and some precipitations were observed on the surface of the liquid side of the cathodes. The amount of phosphorus contained in these precipitates was estimated to be equivalent 4.6-27% of the influent. The main component of these precipitates was revealed by X-ray diffraction analysis to be struvite. Furthermore, our results indicate that phosphorus in suspended solid form was first dissolved, and then precipitated on the cathode. By scanning electron microscope observation, the morphology of the precipitates was irregularly shaped, including crystals with hexagonal cross section surfaces, and was different from the familiar needle-like ones. These results indicate that simultaneous recovery of electrical power and phosphorus from wastewater by microbial fuel cell is possible. PMID- 22445265 TI - Comparison between MBR and SBR on Anammox start-up process from the conventional activated sludge. AB - Anammox start-up performances from the conventional activated sludge were compared between a MBR and SBR. Both the reactors successfully started up Anammox process. The start-up period in the MBR (59 days) was notably shorter than that in the SBR (101 days), and the max nitrogen (NH(4)(+)+NO(2)(-)) removal capacity of 345.2 mg N L(-1) d(-1) in the MBR was also higher than that of 292.0 mg N L( 1) d(-1) in the SBR. FISH analysis showed that Anammox bacteria predominated in both reactors. Phylogenetic analysis further disclosed that the MBR had the better biodiversity of Anammox bacteria and gained a higher ecological stability. Generally, the results showed that MBR exhibited a more excellent performance for Anammox start-up. PMID- 22445266 TI - Biosorption of aquatic cadmium(II) by unmodified rice straw. AB - Cadmium is the most common toxic metal threatening safe rice supply. Rice straw has the potential to remove Cd from large-scale effluent contaminated by heavy metals since it exhibited a short biosorption equilibrium time of 5 min, high biosorption capacity (13.9 mg g(-1)) and high removal efficiency at a pH range of 2.0-6.0. The main Cd biosorption mechanism was Cd(2+) ion exchange with K(+), Na(+), Mg(2+) and Ca(2+), together with chelation with functional groups such as C=C, CO, OH and carboxylic acids. When 0.5% (w/v) rice straw was exposed to 50 mg mL(-1) CdSO(4) solution with shaking at 150 r min(-1) for 3h, about 80% of the aquatic Cd was absorbed and the Cd content in rice straw reached 8-10 mg g(-1), suggesting that the metal-enriched rice straw could become high quality bio-ore by virtue of the industrial mining grade of its metal content and easy metal recovery. PMID- 22445267 TI - Effect of carbonate on anaerobic acidogenesis and fermentative hydrogen production from glucose using leachate as supplementary culture under alkaline conditions. AB - Carbonate was added into a co-culture of glucose and fresh leachate under alkaline condition to enhance batched acidogenesis and fermentative hydrogen production simultaneously. Results indicated carbonate has positive effect on both H(2) production and acetic acid generation. The highest hydrogen yield (about 1.40 mol/mol glucose) was obtained at [CO(3)(2-)] = 280 mg/L with pH 8.0 and [CO(3)(2-)] = 560 mg/L with pH 9. The dominant liquid metabolites were ethanol, acetic and butyric acid. The highest total volatile fatty acid yield (0.38 g/g glucose) was achieved at [CO(3)(2-)] = 560 mg/L with pH 9. In this case, the acetic acid yield reached 0.13 g/g glucose. Verification tests using simulated wastewater as substrate were also carried out at pH 9. Results demonstrated calcium ions inhibit hydrogenogens activity while carbonate addition can alleviate the suppression effect caused by Ca(2+). PMID- 22445268 TI - Identification of Escherichia coli biomarkers responsive to various lignin hydrolysate compounds. AB - Aberrations in the growth and transcriptome of Escherichia coli str. BL21(DE3) were determined when exposed to varying concentrations of ferulic acid (0.25-1 g/L), an aromatic carboxylic acid identified within lignin-cellulose hydrolysate samples. The expression of several individual genes (aaeA, aaeB, inaA and marA) was significantly induced, i.e., more than 4-fold, and thus these genes and the heat shock response gene htpG were selected as biomarkers to monitor E. coli's responses to five additional hydrolysate-related compounds, including vanillic acid, coumaric acid, 4-hydroxybenzoic acid, ferulaldehyde and furfural. While all of the biomarkers showed dose-dependent responses to most of the compounds, expression of aaeA and aaeB showed the greatest induction (5-30-fold) for all compounds tested except furfural. Lastly, the marA, inaA and htpG genes all showed higher expression levels when the culture was exposed to spruce hydrolysate samples, demonstrating the potential use of these genes as biomarkers. PMID- 22445269 TI - Trial investigation of post-mortem non-invasive transnasal endoscopy. AB - We performed a trial investigation of transnasal endoscopy for post-mortem examinations to assess its efficacy in superficial post-mortem examinations. Transnasal endoscopy proved capable of permitting detailed visual inspections of the respiratory and the upper gastrointestinal tract, equal to direct viewing, on an LCD digital display. In 18 (40.9%) of 44 cases, findings obtained by post mortem transnasal endoscopy (PMTNE) provided valuable clues regarding cause of death. The cases examined included seven deaths by fire, four by hypothermia, four by asphyxia (three involving death by mechanical asphyxia, the other by choking), two by drowning and one case of lung cancer. In two cases, PMTNE also led to informative findings not directly related to the cause of death. Under Japan's current systems, we are required to diagnose the cause of death for over 80% of all the unnatural death cases based solely on superficial post-mortem examinations, in the absence of an autopsy. Introducing PMTNE to superficial post mortem examinations will undoubtedly provide much more information on the cause of death than relying solely on superficial post-mortem examinations. PMID- 22445270 TI - DWI of the brain: postmortal DWI of the brain in comparison with in vivo data. AB - PURPOSE: Changes in water diffusion can be quantified by diffusion-weighted MR imaging. However, there are only few reports about changes in post mortem brain. The aim of this study was to investigate the temporal pattern of the apparent diffusion coefficient (ADC) in the brain after death, to compare the values to in vivo brain and to assess the value of ex vivo DWI as a forensic tool. MATERIAL AND METHODS: The study was approved by the local Ethics Committee, and informed consent was obtained from all relatives and the control subjects. Twenty-one corpses, died of natural cause, were examined (13 males, 8 females; age: 70.5+/ 8.7 y, weight 74+/-18 kg). Diffusion-Weighted Imaging (DWI) was performed with b values of 0 and 1000 s/mm(2) at 1.5 T. Scans were repeated in intervals of 1 h. ADC-maps were calculated in thalamus, cerebrum and cerebellum. The obtained values were statistically compared to healthy volunteers (n=3) and to literature data. RESULTS: The ADC in the three regions decreased characteristically during the examination time. In the cerebrum there was a significant difference between ex vivo and in vivo ADC (p<0.001) as well as in the other regions (thalamus: p<0.001, cerebellum: p=0.045). CONCLUSION: DWI of the postmortal brain can be added to the MRI methods for a post mortem imaging. PMID- 22445271 TI - [Anthropometric measurements and cardiovascular status in a Cuban population of centenarians]. PMID- 22445272 TI - Omics and chemical biology--a powerful synergism. PMID- 22445273 TI - Informed consent in opioid therapy: a potential obligation and opportunity. AB - Most patients receiving opioids for the spectrum of pain disorders tolerate opioids well without major complications. However, a subset of this population encounters significant difficulties with opioid therapy (OT). These problems include protracted adverse effects, as well as misuse, abuse, and addiction, which can result in significant morbidity and mortality and make informed consent an important consideration. Opioid treatment agreements (OTAs), which may include documentation of informed consent, have been used to promote the safe use of opioids for pain. There is a debate regarding the effectiveness of OTAs in reducing the risk of opioid misuse; however, most practitioners recognize that OTAs provide an opportunity to discuss the potential risks and benefits of OT and establish mutually agreed-on treatment goals, a clear plan of treatment, and circumstances for continuation and discontinuation of opioids. Informed consent is an important component of an OTA but not often the focus of consideration in discussions of OTAs. This article examines the principles, process, and content of informed consent for OT of pain in the context of OTAs. PMID- 22445274 TI - Refining a checklist for reporting patient populations and service characteristics in hospice and palliative care research. AB - CONTEXT: In specialist hospice and palliative care services, variations occur in diagnoses and prognoses of subpopulations referred, service configuration, and the health systems delivering care. These three levels of variation limit the ability to generalize study findings. OBJECTIVES: This article reports on coding one year of palliative care research using a previously developed checklist. The aims were to 1) quantify current reporting of factors related to generalizability in specialist palliative care research; 2) review and potentially refine the checklist in light of the first aim; 3) demonstrate the feasibility of collecting these data; and 4) set out simple processes to aid researchers in reporting, and clinicians in applying, new research evidence in hospice and palliative care. METHODS: A previously published checklist (five domains, 14 core subdomains, and 24 noncore subdomains) was used to code all research articles (n=189) published in 2007 in the three leading palliative care research journals. RESULTS: The most frequently reported subdomains were patient age, gender, and diagnosis; model of service delivery; and patient performance status. Data in subdomains, including time from referral to death, socioeconomic indices, and ethnicity, were rarely reported; none reported whole-of-service or whole-of-population data. In total, 2646 (189*14) core subdomains could have been reported. Data were provided in 28% (746/2646). CONCLUSION: Checklists such as the Consolidated Standards of Reporting Trials evaluate study design, focusing mainly on internal validity. The proposed checklist deals with specific content of hospice and palliative care, focusing on external validity. PMID- 22445275 TI - Are we prescribing too much or too little immunotherapy for children with allergic rhinitis? PMID- 22445276 TI - Advancing the management of primary immunodeficiency diseases in Latin America: Latin American Society for Immunodeficiencies (LASID) Initiatives. AB - Primary immunodeficiency diseases (PIDD) are associated with significant morbidity and mortality and result in a significant public health burden. This is in part due to the lack of appropriate diagnosis and treatment of these patients. It is critical that governments become aware of this problem and provide necessary resources to reduce this impact on health care systems. Leading physicians in their respective countries must be supported by their own governments in order to implement tools and provide education and thus improve the diagnosis and treatment of PIDD. The Latin American Society of Primary Immunodeficiencies (LASID) has initiated a large number of activities aimed at achieving these goals, including the establishment of a PIDD registry, development of educational programmes and guidelines, and the introduction of a PIDD fellowship programme. These initiatives are positively impacting the identification and appropriate treatment of patients with PIDD in Latin America. Nevertheless, much remains to be done to ensure that every person with PIDD receives proper therapy. PMID- 22445277 TI - Contrast-response functions of the multifocal steady-state VEP (MSV). AB - OBJECTIVES: To measure contrast-response functions (CRFs) for 9 visual field (VF) regions and nonlinear interactions between regions using a multifocal steady state VEP (MSV). METHODS: Ten normal adults were tested (51.7 +/- 16.9 yr, 5 females). Stimuli resembling those of the Frequency Doubling Technology (FDT) perimeter were presented in 9 VF regions simultaneously, which were modulated at incommensurate temporal frequencies (mean 19.7 Hz). Responses were recorded to 11 contrasts from 3% to 89%, using 8 scalp electrodes. Two repeats of a 20s duration stimulus were averaged for each contrast. RESULTS: The CRFs were log-linear except for a depression near 7% contrast (p=0.0008), which was prominent in the central VF. The effects of VF region, stimulus frequency and recording electrode were significant (all p<0.016). Significant responses at frequencies corresponding to interactions between VF regions also appeared. Electrodes that were best for the interactions and second harmonic responses differed, suggesting different cortical sources. CONCLUSIONS: Despite short recording durations the saturating CRFs meant that significant responses could be measured to low contrasts, and be distinguished from nonlinear interactions. SIGNIFICANCE: Recording MSVs to low contrast FDT-like stimuli might be useful for quantifying damage by glaucoma and other visual disorders. PMID- 22445278 TI - Nerve conduction studies of the sural nerve: normative data from a single-center experience. PMID- 22445279 TI - The dopamine b-hydroxylase 19 bp insertion/deletion polymorphism was associated with first-episode but not medicated chronic schizophrenia. AB - BACKGROUND: Numerous studies report dysfunctional dopaminergic and noradrenergic neurotransmission in the pathogenesis of schizophrenia. Dopamine beta-hydroxylase (DBH) is an intracellular enzyme catalyzing the conversion of dopamine to noradrenaline. Functional polymorphisms have been reported in the promoter region of DBH gene, including a 19 bp insertion/deletion polymorphism. The purpose of this study was to investigate whether there was an association between the functional polymorphism (DBH5'-Ins/Del) and schizophrenia in a Han Chinese population. METHODS: This polymorphism was genotyped in 221 first-episode schizophrenics, 360 chronic schizophrenics and 318 healthy controls using a case control design. We assessed their psychopathology using the Positive and Negative Syndrome Scale (PANSS). RESULTS: We showed that the DBH5'-Ins/Del deletion (Del) allelic and genotypic frequencies were significantly lower in controls than first episode of schizophrenics (FES) (both p < 0.001), but controls were not different from chronic schizophrenics. Furthermore, the PANSS positive symptom and total scores were significantly higher in FES with the Del/Del genotype than those with Ins/Del and Ins/Ins genotypes (all p < 0.05). CONCLUSIONS: The DBH5'-Ins/Del polymorphism may play a role in susceptibility to the positive symptoms of FES and to these FES not progressing on to chronic schizophrenia. PMID- 22445280 TI - Financial inequality and gender in older people. AB - Gender inequalities in the financial resources in later life result from the combined effect of women's atypical life courses, which include interrupted employment records and periods of care provision, and the fact that pension systems have generally been slow in mitigating 'diversions' from continuous and full-time working lives. Gender differentials in financial resources can often result in a greater likelihood of facing poverty for older women compared to older men, and such risk can be experienced for longer periods for women, as a result of their higher life expectancy on average. For example, across the EU-27, 16% of men compared to 23% of women aged 65 and over faced a poverty risk, and at age 65, men can expect to live another 17 years on average, while women another 21 years. Although modern pension systems are increasingly recognising the diversity of women's patterns of paid and unpaid work, for example by accounting for periods of childcare in the calculation of the state pension, research continues to show a 'penalty' for women who have spent significant periods of their life providing care to children or dependent adults in and outside the household. Reducing such penalty is particularly important as population ageing and an increasing demand for formal and informal care are likely to present challenges with critical policy implications for societies and individuals alike. PMID- 22445281 TI - Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells. AB - BACKGROUND: Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. METHODS: Naive CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. RESULTS: CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-gamma production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to that from splenocytes of untreated recipients. Flow cytometry studies showed an increased CD4+CD25+ Forkhead box P3 (Foxp3)+ cell population in splenocytes from those mice. CONCLUSION: Our findings indicate that exposure to opera music, such as La traviata, could affect such aspects of the peripheral immune response as generation of regulatory CD4+CD25+ cells and up-regulation of anti-inflammatory cytokines, resulting in prolonged allograft survival. PMID- 22445282 TI - Strategies for improving the efficacy and therapeutic ratio of glucocorticoids. AB - Although glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for example asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future. PMID- 22445283 TI - Oxidized phospholipid signaling in immune cells. AB - Oxidized phospholipids (oxPLs) that can be generated either enzymatically or non enzymatically are fast becoming recognized as important signaling mediators of the immune system. Hundreds of structures exist, but only a small fraction have been studied in detail. Their known activities include regulation of adhesion molecule expression, pro-coagulant activity and inhibition of Toll-like receptor signaling, and several have been detected in models of human and animal disease. In this review, the most studied structures of oxPLs will be summarized, along with descriptions of their known biological actions. Subsequently, the focus will be on the more recently described forms generated acutely by lipoxygenases (LOX) in human and murine immune cells. PMID- 22445284 TI - Genetic variation in human muscle strength--opportunities for therapeutic interventions? AB - Inter-individual variation in muscle mass and muscular fitness is broad; being at the upper tail of the distribution not only contributes to improve elite sport performance, but is also associated with longer independent living and higher quality-of-life in the aging population. Heritability estimates of muscle phenotypes are substantial and warrant the search for genetic components underlying this individual variability. The 'kinesiogenomics' field is young, but genetic associations with muscle strength-related phenotypes have been reported already for more than 40 candidate genes, and genome-wide scans revealed several additional regions of interest in the genome. Although genetic findings may reveal attractive targets for novel muscle atrophy therapy, the benefit of exercise as a major stimulus for natural muscle mass enhancement or maintenance cannot be underestimated. PMID- 22445285 TI - Design and synthesis of novel opioid ligands with an azabicyclo[2.2.2]octane skeleton and their pharmacologies. AB - A novel opioid ligand possessing a stable and cyclic imine 16 and its derivatives with an azabicyclo[2.2.2]octane skeleton were synthesized. The imine 16 showed higher affinity for the MU receptor than compound 21 with an oxabicyclo[2.2.2]octane skeleton. Azabicyclo[2.2.2]octane derivative 18d with a cyclopropylmethyl group on the 8-nitrogen showed the highest affinity for the MU receptor among the synthesized derivatives. PMID- 22445286 TI - Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor. AB - A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K(i)'s <= 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K(i) value by 25-fold over a 24-h time-period. PMID- 22445287 TI - Assessment and treatment of adolescent sexual offenders: implications of recent research on generalist versus specialist explanations. AB - OBJECTIVE: Adolescent sex offenders (ASOs) are commonly considered a special kind of juvenile offender, with distinct risk and etiological factors from other adolescent offenders. However, a growing body of research suggests that ASOs are more similar to other adolescent non-sex offenders than they are different (e.g., Awad, Saunders, & Levine, 1984; Elliott, 1994; France & Hudson, 1993). The purpose of the present article is to review recent literature pertaining to the distinction between generalist and specialist adolescent sex offenders (ASOs). METHOD: This article summarizes the findings from Seto and Lalumiere's (2010) meta-analysis on theoretically derived risk and etiological factors for adolescent sexual offending. Based on these findings, recommendations for the assessment and treatment of this population are made. RESULTS: The results of Seto and Lalumiere's (2010) meta-analysis suggests the majority of ASOs are generalist offenders who are similar to other adolescent non-sex offenders, while a minority of ASOs are specialist offenders, who have unique risk and etiological factors including childhood sexual abuse/maltreatment and atypical sexual interests. CONCLUSIONS: A clear distinction has been shown between generalist ASOs and specialist ASOs. Assessment measures and treatment targets geared toward one of these groups may be less effective with the other group, which means that this distinction is clinically important. It is expected that if treatment is matched to ASO type, sexual and nonsexual recidivism will be reduced and positive changes in other clinically important areas will be evident. PMID- 22445288 TI - The three main stumbling blocks for anticancer T cells. AB - Memory and effector T cells have the potential to counteract cancer progression, but often fail to control the disease, essentially because of three main stumbling blocks. First, clonal deletion leads to relatively low numbers or low to-intermediate T cell receptor (TCR) affinity of self/tumor-specific T cells. Second, the poor innate immune stimulation by solid tumors is responsible for inefficient priming and boosting. Third, T cells are suppressed in the tumor microenvironment by inhibitory signals from other immune cells, stroma and tumor cells, which induces T cell exhaustion, as demonstrated in metastases of melanoma patients. State-of-the-art adoptive cell transfer and active immunotherapy can partially overcome the three stumbling blocks. The reversibility of T cell exhaustion and novel molecular insights provide the basis for further improvements of clinical immunotherapy. PMID- 22445289 TI - Nonconvulsive status epilepticus due to drug induced neurotoxicity in chronically ill children. AB - Nonconvulsive status epilepticus (NCSE) is a specific form of status epilepticus and is defined as epileptic activity on an EEG without seizures and as an alteration in mental status lasting more than 30 min. NCSE may be caused by drugs, cerebrovascular events, metabolic disorders or toxins. Herein, we present four cases of patients with drug-induced NCSE who were chronically ill due to renal failure or childhood leukemia. NCSE should be suspected in patients with an altered mental status without clinical seizures who are being treated with multiple drugs. PMID- 22445290 TI - [Comprehensive care program for sexual violence victims in Escuintla, Guatemala]. AB - We implemented a comprehensive care program for sexual violence victims in six municipalities of Escuintla. Sexual violence victims received both medical and psychological care. Clinical and epidemiological information relevant to the sexual violence event was collected. Samples were taken for sexually transmitted infections (STIs), HIV, and pregnancy testing. In two years, 164 sexual violence victims were attended: 111 (67.6%) were under 18 years old, 91 (64.5%) were females and 20 (86.9%) were males, and the mean age was 12 and 8.3 years, respectively. The most frequently reported type of sexual violence was vaginal and/or anal penetration in 69.9% of cases. In 30.5% of cases the assailant was a stranger. We identified 11 cases of STIs. The project was able to influence national policy through active participation in the development of a national protocol for the care of sexual violence victims. Activities to promote gender equity and child protection should be intensified. PMID- 22445291 TI - Persistent postsurgical pain in a general population: prevalence and predictors in the Tromso study. AB - Population-based data on the prevalence of persistent postsurgical pain are scarce. This study aimed to assess the prevalence of persistent postsurgical pain in a general population and to describe associated physical, social, and psychological factors, including symptoms of nerve injury and sensitization. A cross-sectional survey was performed in northern Norway with questionnaire items covering surgery, pain, and sensory abnormalities in the area of surgery. Of the 12,982 participants, 24.0% (3111) had undergone one or more surgical procedures during the 3 years preceding the survey. Of these, 2043 had the surgery performed more than 3 months before the investigation. Persistent pain in the area of surgery was reported by 40.4% of the patients (826 of 2043), moderate or severe pain by 18.3% (373 of 2043). Hypoesthesia, hyperesthesia, or both was reported by 24.5% (501 of 2043). There were strong associations between sensory abnormalities and persistent pain, increasingly with higher pain intensities; odds ratios were 2.68 for hypoesthesia and 6.27 for hyperesthesia. Of the 826 individuals reporting persistent pain in the anatomical area of surgery, 51.0% reported chronic pain when questioned without specific reference to the surgery. The present study supports evidence from clinical studies of persistent postsurgical pain, indicating a high prevalence, but reveals large discrepancies in report of pain, depending on the questions asked and the context in which the questions are presented. Strong associations between sensory abnormalities and pain indicate neuropathic mechanisms in a major proportion of cases. PMID- 22445292 TI - Who receives opioids for acute pain in emergency departments? Considering evidence, patient and provider preferences. PMID- 22445293 TI - Endoscopic ultrasound-fine needle aspiration diagnosis and treatment of a gastric intramural pseudocyst. PMID- 22445295 TI - MicroRNA regulation in experimental autoimmune encephalomyelitis in mice and marmosets resembles regulation in human multiple sclerosis lesions. AB - Here we demonstrate that miRNA regulation in marmoset (Callithrix jacchus) and C57/BL6 mouse EAE lesions largely resembles miRNA regulation in active human MS lesions. Detailed quantitative PCR analyses of the most up- and downregulated miRNAs of active human MS lesions in dissected lesions from marmoset EAE brains and inflamed spinal cords of EAE mice revealed that the conserved and highly regulated miRNAs, miRNA-155, miRNA-142-3p, miRNA-146a, miRNA-146b and miRNA-21, turned out to be similarly upregulated in marmoset and mouse EAE lesions. PMID- 22445294 TI - Chemokine receptor CXCR2: physiology regulator and neuroinflammation controller? AB - The innate immune system is a crucial component of inflammatory reactions, while the central nervous system (CNS) is the most vulnerable site of the body to inflammatory tissue injury. Neuroinflammatory brain pathologies are disorders in which the CNS is threatened by its own immune system. Chemokine receptor CXCR2 and its ligands have been implicated in several neuroinflammatory brain pathologies, as well as in neutrophil recruitment and in the developmental positioning of neural cells. This review focuses on the basics of CXCR2, its regulating role in bone marrow neutrophil recruitment, oligodendrocyte progenitor cell positioning and neural repair mechanisms, as well as its diverse roles in neuroinflammatory brain pathologies. PMID- 22445296 TI - Clinical outcome for nasopharyngeal carcinoma with predominantly WHO II histology treated with intensity-modulated radiation therapy in non-endemic region of China. AB - OBJECTIVES: To evaluate the clinical outcomes of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC) in Northwest China, including assessments of failure patterns, toxicities and potential prognostic factors. METHODS AND MATERIALS: Between January 2006 and June 2010, 193 newly diagnosed non-metastatic NPCs were treated by IMRT with simultaneous-integrated boost (SIB) technique in Xijing Hospital of Northwest China. Cisplatin-based chemotherapy was offered to 85.5% patients. Acute and late toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) scoring criteria. Prognostic factors were assessed by univariate or multivariate analysis. Statistical analyses were performed on survival and failure patterns. RESULTS: Median follow-up was 34 months. WHO type II was the predominant histology for NPCs (69.9%) in our study group. Twelve patients experienced local regional failure and total distant metastasis occurred in 34 patients, representing the major mode of failure. The 3-year local recurrence-free (LRFS), regional recurrence-free (RRFS), distant metastasis-free (DMFS) and overall survival (OS) rates were 86.6%, 86.7%, 86.4%, and 85.7%, respectively. Multivariate analyses showed N-classification, age (<= 50 vs. >50) and WHO type (WHO II vs. WHO III) were independent predictors for DMFS, LRFS and OS. Tumor volume (<= 50 cm(3) vs. >50 cm(3)) and presence of anemia were independent significant prognostic factors for profession-free survival (PFS). No significant difference was observed between different T categories. Acute and late toxicities were mild or moderate. No grade IV toxicities were observed. CONCLUSIONS: WHO II was the predominant histology and a significant poor prognostic factor in our study group, indicating different carcinogenetic pathways of NPC between endemic and non-endemic regions. Our experience of using IMRT in the treatment of NPC in non-endemic region showed excellent locoregional control and favorable toxicity profiles. PMID- 22445297 TI - Mutual repression by bantam miRNA and Capicua links the EGFR/MAPK and Hippo pathways in growth control. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) and Hippo signaling pathways control cell proliferation and apoptosis to promote tissue growth during development. Misregulation of these pathways is implicated in cancer. Our understanding of the mechanisms that integrate the activity of these pathways remains fragmentary. This study identifies bantam microRNA as a common target of these pathways and suggests a mechanistic link between them. RESULTS: The EGFR pathway acts through bantam to control tissue growth. bantam expression is regulated by the EGFR pathway, acting via repression of the transcriptional repressor Capicua. Thus EGFR signaling induces bantam expression by alleviating the effects of a repressor. bantam in turn acts in a negative feedback loop to limit Capicua expression. CONCLUSIONS: bantam appears to be a transcriptional target of both the EGFR and Hippo growth control pathways. Feedback regulation by bantam on Capicua provides a means to link signal propagation by the EGFR pathway to activity of the Hippo pathway and may play an important role in integration of these two pathways in growth control. PMID- 22445298 TI - Mid-Mesozoic flea-like ectoparasites of feathered or haired vertebrates. AB - Parasite-host associations among insects and mammals or birds are well attended by neontological studies [1]. An Eocene bird louse compression fossil [2, 3] and several flea specimens from Eocene and Oligocene ambers [4-8], reported to date, are exceptionally similar to living louse and flea taxa. But the origin, morphology, and early evolution of parasites and their associations with hosts are poorly known [9, 10] due to sparse records of putative ectoparasites with uncertain classification in the Mesozoic, most lacking mouthpart information and other critical details of the head morphology [11-15]. Here we present two primitive flea-like species assigned to the Pseudopulicidae Gao, Shih et Ren familia nova (fam. nov.), Pseudopulex jurassicus Gao, Shih et Ren genus novum et species nova (gen. et sp. nov) from the Middle Jurassic [16] and P. magnus Gao, Shih et Ren sp. nov. from the Early Cretaceous in China [17]. They exhibit many features of ectoparasitic insects. Large body size and long serrated stylets for piercing tough and thick skin or hides of hosts suggest that these primitive ectoparasites might have lived on and sucked the blood of relatively large hosts, such as contemporaneous feathered dinosaurs and/or pterosaurs or medium-sized mammals (found in the Early Cretaceous, but not the Middle Jurassic). PMID- 22445299 TI - Free extracellular diffusion creates the Dpp morphogen gradient of the Drosophila wing disc. AB - BACKGROUND: How morphogen gradients form has long been a subject of controversy. The strongest support for the view that morphogens do not simply spread by free diffusion has come from a variety of studies of the Decapentaplegic (Dpp) gradient of the Drosophila larval wing disc. RESULTS: In the present study, we initially show how the failure, in such studies, to consider the coupling of transport to receptor-mediated uptake and degradation has led to estimates of transport rates that are orders of magnitude too low, lending unwarranted support to a variety of hypothetical mechanisms, such as "planar transcytosis" and "restricted extracellular diffusion." Using several independent dynamic methods, we obtain data that are inconsistent with such models and show directly that Dpp transport occurs by simple, rapid diffusion in the extracellular space. We discuss the implications of these findings for other morphogen systems in which complex transport mechanisms have been proposed. CONCLUSIONS: We believe that these findings resolve a major, longstanding question about morphogen gradient formation and provide a solid framework for interpreting experimental observations of morphogen gradient dynamics. PMID- 22445300 TI - Dynein tethers and stabilizes dynamic microtubule plus ends. AB - Microtubules undergo alternating periods of growth and shortening, known as dynamic instability. These dynamics allow microtubule plus ends to explore cellular space. The "search and capture" model posits that selective anchoring of microtubule plus ends at the cell cortex may contribute to cell polarization, spindle orientation, or targeted trafficking to specific cellular domains. Whereas cytoplasmic dynein is primarily known as a minus-end-directed microtubule motor for organelle transport, cortically localized dynein has been shown to capture and tether microtubules at the cell periphery in both dividing and interphase cells. To explore the mechanism involved, we developed a minimal in vitro system, with dynein-bound beads positioned near microtubule plus ends using an optical trap. Dynein induced a significant reduction in the lateral diffusion of microtubule ends, distinct from the effects of other microtubule-associated proteins such as kinesin-1 and EB1. In assays with dynamic microtubules, dynein delayed barrier-induced catastrophe of microtubules. This effect was ATP dependent, indicating that dynein motor activity was required. Computational modeling suggests that dynein delays catastrophe by exerting tension on individual protofilaments, leading to microtubule stabilization. Thus, dynein mediated capture and tethering of microtubules at the cortex can lead to enhanced stability of dynamic plus ends. PMID- 22445301 TI - Parallel selection mapping using artificially selected mice reveals body weight control loci. AB - Understanding how polygenic traits evolve under selection is an unsolved problem, because challenges exist for identifying genes underlying a complex trait and understanding how multilocus selection operates in the genome. Here we study polygenic response to selection using artificial selection experiments. Inbred strains from seven independent long-term selection experiments for extreme mouse body weight ("high" lines weigh 42-77 g versus 16-40 g in "control" lines) were genotyped at 527,572 SNPs to identify loci controlling body weight. We identified 67 parallel selected regions (PSRs) where high lines share variants rarely found among the controls. By comparing allele frequencies in one selection experiment against its unselected control, we found classical selective sweeps centered on the PSRs. We present evidence supporting two G protein-coupled receptors GPR133 and Prlhr as positional candidates controlling body weight. Artificial selection may mimic natural selection in the wild: compared to control loci, we detected reduced heterozygosity in PSRs in unusually large wild mice on islands. Many PSRs overlap loci associated with human height variation, possibly through evolutionary conserved functional pathways. Our data suggest that parallel selection on complex traits may evoke parallel responses at many genes involved in diverse but relevant pathways. PMID- 22445302 TI - Defining target volumes for stereotactic ablative radiotherapy of early-stage lung tumours: a comparison of three-dimensional 18F-fluorodeoxyglucose positron emission tomography and four-dimensional computed tomography. AB - AIMS: High local control rates are achieved in stage I lung cancer using stereotactic ablative radiotherapy. Target delineation is commonly based on four dimensional computed tomography (CT) scans. Target volumes defined by positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional') (18)F fluorodeoxyglucose ((18)F-FDG) PET/CT. MATERIALS AND METHODS: For 16 stage I non small cell lung cancer tumours, six approaches for deriving PET target volumes were evaluated: manual contouring, standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV (35%SUV(MAX)), 41% of SUV(MAX) (41%SUV(MAX)) and two different source to background ratio techniques (SBR-1 and SBR-2). PET derived target volumes were compared with the internal target volume (ITV) from the modified maximum intensity projection (MIP(MOD) ITV). Volumetric and positional correlation was assessed using the Dice similarity coefficient (DSC). RESULTS: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP(MOD) ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV(MAX) = 0.63, 41%SUV(MAX) = 0.57. SBR-1 = 0.52, SBR-2 = 0.49. PET-based target volumes were smaller than corresponding MIP ITVs. CONCLUSIONS: Conventional three-dimensional (18)F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use (MIP(MOD) ITV). Caution is required in using three-dimensional PET for motion encompassing target volume delineation. PMID- 22445303 TI - Pregnancy outcomes in women with severe needle phobia. AB - OBJECTIVES: Needle phobia in pregnancy poses a problem as women may refuse medical care because of their fear. The present study investigates the impact of needle phobia on the antenatal and intrapartum care of needle phobic women and reports on the pregnancy and neonatal outcomes. STUDY DESIGN: A retrospective cohort of 112 cases, divided into severe and mild cases of needle phobia, was collected from the anaesthetic referral database. The data were collected manually as well as by using the computerised hospital database, and were analysed using SPSS version 19. Chi-square analysis and unpaired t-test were used to analyse categorical and continuous variables, respectively. The overall departmental statistics for 2009 and 2010 were used as a comparator. RESULTS: Women with severe needle phobia, compared to those with mild needle phobia, registered late with the antenatal services (17 weeks vs 14 weeks, p<0.05), had a significant delay in obtaining their first antenatal blood tests (25 weeks vs 15 weeks, p<0.0001), consented less often to the booking blood tests (62.8% vs 98.6%, p<0.0001) and antenatal tests (30.2% vs 76.8%, p<0.0001), had low use of pethidine (4.7% vs 24.6%, p<0.01) and a higher demand for general anaesthesia (11.6% vs 0%, p<0.01) and had an increased number of physiological deliveries of the placenta (37.2% vs 8.7%, p<0.0001). The incidence of maternal and neonatal adverse outcomes in both groups was low. CONCLUSION: Despite the differences in choice of analgesia and acceptance of routine blood tests, pregnancy outcomes in women with severe needle phobia were good. The study highlighted the importance of adequate risk assessment of all women disclosing their needle phobic status, and of provision of high-standard multidisciplinary care involving primary and secondary healthcare professionals. PMID- 22445304 TI - The effect of edaravone on ischemia-reperfusion injury in rat ovary. AB - OBJECTIVE: The aim of this study was to investigate the effect of edaravone on experimentally induced ovarian torsion/detorsion ischemia/reperfusion (I/R) injury. STUDY DESIGN: Forty-six female adult Wistar-Albino rats were utilized to create five groups: In group 1, only 5 mg/kg edaravone was given and ovary torsion was not performed. In group 2, torsion was not performed and no drug was given. In group 3, vehicle was given and torsion/detorsion was performed. In group 4, 1 mg/kg edaravone was given and torsion/detorsion was performed. In group 5, edaravone; 5 mg/kg drug was administered and torsion/detorsion was performed. Right ovarian torsion was simulated for a 3-h period of ischemia and a 1-h reperfusion period. Right ovaries were then surgically extirpated in all groups. In ovarian tissue samples malondialdehyde (MDA) levels and activity of superoxide dismutase were studied. Microscopic ovarian tissue damage was scored by histologic and electron microscopic findings. RESULTS: The MDA level in the group 5 was significantly lower than group 3 (p<0.001). Superoxide dismutase activity in the group 5 was significantly higher than group 3 (p<0.001). Histopathological ovarian tissue damage in the group 5 were significantly lower than group 3 (p<0.001). CONCLUSION: These results indicate that edaravone could be an effective agent in the short-term treatment and prevention of ovarian ischemia and reperfusion damage. PMID- 22445305 TI - Sensitive determination of isoprostanes in exhaled breath condensate samples with use of liquid chromatography-tandem mass spectrometry. AB - Oxidative stress is the hallmark of various inflammatory lung diseases. Increased concentrations of reactive oxygen species in the lungs are reflected by elevated concentrations of oxidative stress markers in the breath, airways, lung tissue and blood. The aim of this work was to develop a method for the fast measurement of F2-isoprostanes in exhaled breath condensate (EBC) samples using equipment which is nowadays available and routinely exploited in analytical laboratories, liquid chromatography coupled with tandem mass spectrometry. Because of the limited volume of an EBC sample and the very low concentrations of biomarkers, we chose lyophilization as the preconcentration technique. The diastereoisomers determined show similar fragmentation patterns, which is why complete chromatographic separation with excellent peak shapes was essential for accurate quantitation. Isoprostanes were separated using a narrow-bore Agilent Extend C-18 column in isocratic elution mode using acetonitrile/methanol and water with the addition of 0.01%(v/v) formic acid. The limits of determination and quantitation for the determination of four isoprostanes in samples of EBC ranged from 1 to 3 pg/ml. The recoveries of all isoprostanes ranged from 96.7 to 101.7, with a relative standard deviation of <7%. The stability of the isoprostanes at different temperatures was measured as well. PMID- 22445306 TI - Evaluation of human interferon adsorption performance of Cibacron Blue F3GA attached cryogels and interferon purification by using FPLC system. AB - In this study, we have focused our attention on preparing supermacroporous cryogels as a potential dye-affinity adsorbent for interferon purification. For this purpose, 2-hydroxyethyl methacrylate (HEMA) and Cibacron Blue F3GA (CB) were selected as main monomer and dye-ligand. Cibacron Blue F3GA attached supermacroporous poly(2-hydroxyethyl methacrylate) [poly(HEMA)/CB] cryogels were prepared and characterized by swelling test, scanning electron microscopy, elemental analysis, and FTIR. After that, the effecting factors such as pH, concentration, interaction time, and ionic strength on the interferon separation were evaluated. The maximum adsorption capacity of poly(HEMA)/CB cryogels was obtained as 38.2mg/g at pH 6.0. Fast protein liquid chromatography (FPLC) system was used for interferon purification from human gingival fibroblast extract. The chromatography parameters, capacity and selectivity factors, resolution and theoretical plate number were found as 7.79, 9.62, 4.23 and 554, respectively. Although some decreases in total protein content, from 320 MUg to 18 MUg, and interferon activity, from 2.6 * 10(3)IU to 2.2 * 10(3)IU, were determined, specific antiviral activity increased from 7.19 IU/MUg to 122.2 IU/MUg. The purified interferon samples have 97.6% purity determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After repeated ten adsorption desorption cycles, no significant decrease was determined in adsorption capacity of cryogel. In result, poly(HEMA)/CB cryogels have an application potential for rapid, cheap and specific purification of interferon. PMID- 22445307 TI - Simultaneous quantitative determination of paracetamol and its glucuronide conjugate in human plasma and urine by liquid chromatography coupled to electrospray tandem mass spectrometry: application to a clinical pharmacokinetic study. AB - A specific, sensitive and rapid method based on high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed for the simultaneous determination of paracetamol (APAP) and its glucuronide conjugate (PG) in human plasma and urine. Plasma samples were precipitated with the mixture of acetonitrile and propylene glycol (90:10, v/v) solution and urine samples were diluted with the mobile phase, which were used to isolate the analytes from biological matrices followed by injection of the extracts onto a C(18) column with isocratic elution. Detection was carried out on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode using positive electrospray ionization (ESI(+)). The method was validated over the concentration range of 10-30,000 ng/mL and 100-6000 ng/mL for APAP in human plasma and urine as well as 10-15,000 ng/mL and 200-60,000 ng/mL for PG in human plasma and urine, respectively. Inter- and intra-run precisions of APAP and PG were less than 15% and the accuracy was within 85-115% for both plasma and urine. The average extraction recoveries were 93.1% and 89.1% for APAP, and 93.7% and 92.3% for PG in human plasma and urine, respectively. The linearity, recovery and stability were validated for APAP and PG in human plasma and urine. The method proved to be simple, robust and time efficient. PMID- 22445308 TI - PEGylation, detection and chromatographic purification of site-specific PEGylated CD133-Biotin antibody in route to stem cell separation. AB - Recovery and purification of stem cells are determining steps in order to obtain the purity and viability required for transplantation. In this context, immunochemical techniques have been widely preferred due to their high selectivity. CD133, a glycoprotein expressed by stem cells, is a well-used marker for isolation of neural stem cells. Transplantation of neural stem cells into patients can promote neural growth and improve neuronal functions. In this study, a new method for site-specific PEGylation of CD133-Biotin antibody is performed through streptavidin-biotin conjugation. Purification was carried out by ion exchange chromatography. The characterization of the single PEGylated CD133 Biotin antibody was confirmed using electrophoresis with silver staining and I(2) BaCl(2) for PEG detection. Moreover, online PEG quantification directly after the chromatographic step was conducted (in each fraction) to detect exact elution times of PEG. In conclusion, the novel CD133-Biotin antibody PEGylation strategy conducted in this study could be used as a process step in route to neural stem cell recovery and purification via the modification of existing techniques such as aqueous two phase systems, PEGylated affinity columns or fluidized chromatography. PMID- 22445309 TI - Analysis of 8-hydroxy-2'-deoxyguanosine in human urine using hydrophilic interaction chromatography with tandem mass spectrometry. AB - Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a widely used noninvasive biomarker of oxidative stress. A selective, sensitive and rapid method for determining 8-OHdG in human urine was developed using hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) with electrospray ionization. 8-OHdG and isotopically labeled 8-OHdG (internal standard) were separated on a HILIC column with a mobile phase of 10 mM ammonium acetate: acetonitrile (1:9, v/v) within 10 min and detected by using a positive electrospray ionization interface under the selected reaction monitoring mode. The detection limits of 8-OHdG (corresponding to a signal-to-noise ratio of 3) for the HILIC-MS/MS system and the conventional method using a reversed-phase column with MS/MS were 1.0 and 26.0 fmol/injection, respectively. The proposed method makes it possible to monitor the basal level of urinary 8-OHdG from non exposed healthy subjects and can be used for large-scale human studies. PMID- 22445310 TI - Antimicrobial susceptibility and molecular subtyping of 55 Turkish Bacillus anthracis strains using 25-loci multiple-locus VNTR analysis. AB - Anthrax, which is caused by the bacterium Bacillus anthracis, is one of the oldest documented infectious diseases in both livestock and humans. The differentiation of B. anthracis strains is difficult because of their highly homogeneous genomes. We used multiple-locus variable-number tandem repeat analysis (MLVA) with 25 markers to genotype 55 B. anthracis isolates from 16 distinct regions of Turkey. The antimicrobial susceptibility of the isolates was investigated using the agar dilution method. An eight-loci MLVA assay revealed six unique genotypes (G(K)13, G(K)27, G(K)35, G(K)43, G(K)44, and G(K)61). However, the 25-loci MLVA was more discriminatory, revealing the presence of ten genotypes instead of six. The additional genotypes resulted from the split of four subtypes: G(K)35 (b and c), G(K)43 (a and f), G(K)44 (d and e), and G(K)61 (i and j). All of the Turkish B. anthracis isolates were susceptible to ciprofloxacin, levofloxacin, tigecycline, linezolid, and vancomycin. One isolate was resistant to penicillin and to doxycycline. A total of 34 isolates were susceptible, 20 isolates were partially susceptible, and one isolate was resistant to erythromycin. None of the isolates exhibited susceptibility to cefotaxime. A total of 53 isolates were susceptible to gentamicin, and two were resistant. The genotypes G(K)35 (n=24), G(K)44 (n=13), and G(K)43 (n=10) were the most prevalent in 10, 6, and 5 regions, respectively, of the total 16 provinces. The B. anthracis isolates collected from these regions implied that the movement of B. anthracis is a result of the increased transportation of livestock and the resultant cross contamination. PMID- 22445311 TI - Laboratory validation of an in-home method for assessing circadian phase using dim light melatonin onset (DLMO). AB - OBJECTIVE: To determine whether an accurate circadian phase assessment could be obtained from saliva samples collected by patients in their home. METHODS: Twenty four individuals with a complaint of sleep initiation or sleep maintenance difficulty were studied for two evenings. Each participant received instructions for collecting eight hourly saliva samples in dim light at home. On the following evening they spent 9h in a laboratory room with controlled dim (<20 lux) light where hourly saliva samples were collected. Circadian phase of dim light melatonin onset (DLMO) was determined using both an absolute threshold (3 pg ml( 1)) and a relative threshold (two standard deviations above the mean of three baseline values). RESULTS: Neither threshold method worked well for one participant who was a "low-secretor". In four cases the participants' in-lab melatonin levels rose much earlier or were much higher than their at-home levels, and one participant appeared to take the at home samples out of order. Overall, the at-home and in-lab DLMO values were significantly correlated using both methods, and differed on average by 37 (+/- 19)min using the absolute threshold and by 54 (+/- 36)min using the relative threshold. CONCLUSIONS: The at-home assessment procedure was able to determine an accurate DLMO using an absolute threshold in 62.5% of the participants. Thus, an at-home procedure for assessing circadian phase could be practical for evaluating patients for circadian rhythm sleep disorders. PMID- 22445312 TI - Acute shift of a case of moderate obstructive sleep apnea syndrome towards one of severe central sleep apnea syndrome after an ischemic stroke. PMID- 22445313 TI - Detection of Actinobacillus pleuropneumoniae in pigs by real-time quantitative PCR for the apxIVA gene. AB - A real-time quantitative PCR (qPCR) for detection of the apxIVA gene of Actinobacillus pleuropneumoniae was validated using pure cultures of A. pleuropneumoniae and tonsillar and nasal swabs from experimentally inoculated Caesarean-derived/colostrum-deprived piglets and naturally infected conventional pigs. The analytical sensitivity was 5colony forming units/reaction. In comparison with selective bacterial examination using tonsillar samples from inoculated animals, the diagnostic sensitivity of the qPCR was 0.98 and the diagnostic specificity was 1.0. The qPCR showed consistent results in repeatedly sampled conventional pigs. Tonsillar brush samples and apxIVA qPCR analysis may be useful for further epidemiological studies and monitoring for A. pleuropneumoniae. PMID- 22445314 TI - Palatal eversion: a new technique in treatment of nasopharyngeal stenosis. AB - OBJECTIVE: The treatment of nasopharyngeal stenosis is challenging because of a high incidence of recurrence after surgical correction. Therefore, many treatment modalities are being tried to cure this problem. The aim of this study is to assess the efficacy of palatal eversion as a new technique for treatment of nasopharyngeal stenosis after adenotonsillectomy. STUDY DESIGN: Case series. METHODS: This study was conducted on 12 patients with nasopharyngeal stenosis after adenotonsillectomy were subjected to treatment by palatal eversion by dividing the soft palate in the midline and removal of the fibrous tissue causing stenosis followed by evertion and fixation of the two palatal division on either side for six weeks to allow complete epithelialization of the stenotic area followed by another operation to reunion the soft palate in the midline. Post operative follow up was done for one year by flexible nasopharyngoscopy, perceptual speech analysis and polysomnography. RESULTS: Flexible nasopharyngosopic examination of the 12 patients at the end of post-operative period revealed a freely mobile soft palate with no nasopharyngeal stenosis or palatal fistula. Velopharyngeal function and speech assessment by perceptual speech analysis was normal in all 12 cases. No obstructive episodes were recorded in polysomnograms. CONCLUSIONS: Palatal eversion is a promising technique in treatment of post-adenotonsillectomy nasopharyngeal stenosis and it is recommended to be used in a wider scale of patients and other indications as nasopharyngeal stenosis following uvulopalatoplasty and post nasopharyngeal radiotherapy. LEVEL OF EVIDENCE: 4 (case series). PMID- 22445316 TI - Assessment of quality of life in advanced non-small-cell lung cancer: an overview of recent randomized trials. AB - BACKGROUND: Health-related quality of life (HRQOL) parameters are often used as secondary endpoints in advanced non-small-cell lung cancer (NSCLC). We assessed the frequency and correlates of both usage and gain in HRQOL endpoints in NSCLC phase III trials. METHODS: We searched PubMed for phase III trials on systemic anticancer therapies for NSCLC published between 1/98 and 12/09 in 13 leading journals. RESULTS: The search yielded 122 trials that enrolled a total of 56,031 patients in 273 trial arms. HRQOL was reportedly used as an endpoint in 72 trials (59%). HRQOL parameters were used as primary or co-primary endpoints in nine trials, whereas overall survival (OS) was the primary endpoint or one of the co primary endpoints in 90 trials. There was no temporal trend for usage of HRQOL parameters as endpoints. Formal statistical comparisons involving HRQOL were reported in 68/72 cases, and a significant difference was found in 37/68 trials (54.4%), 24 of which favored the experimental arm. In many cases, such differences were restricted to specific symptoms or even favored more than one regimen according to symptoms analyzed. We found no significant association between gain in HRQOL and gain in OS or any other trial feature. CONCLUSIONS: HRQOL has been assessed formally in nearly 60% of contemporary phase III trials in advanced NSCLC, and a significant gain in HRQOL has been found in almost one half of cases. It is questionable, however, whether HRQOL results may help select between treatments with no differential impact on OS. PMID- 22445317 TI - Minority inclusion in randomized clinical trials of panic disorder. AB - In 1993, the National Institutes of Health issued a mandate that funded research must include participation by racial and ethnic minority groups, and researchers were required to include in their proposals strategies by which they would achieve diversity in their samples. A methodological search for randomized clinical trials of panic disorder was conducted to evaluate ethnoracial differences in panic disorder symptoms, rates of minority inclusion in North American studies, and effective methods of minority recruitment. Less than half of the studies identified reported ethnic and racial data for their sample. Of the 21 studies that did report this information (n=2687), 82.7% were European American/non-Hispanic White, 4.9% were African American/Black, 3.4% were Hispanic, 1.1% were Asian American, and 1.4% were another ethnicity. The remaining 6.5% was simply classified as other/non-White. The primary recruitment techniques utilized were clinical referral and advertising, but neither of these methods were correlated with improved minority participation, nor was the number of recruitment sites. As minorities are greatly underrepresented in panic disorder studies, reported treatment outcomes may not generalize to all ethnic and cultural groups. Researchers have not followed NIH guidelines regarding inclusion of special populations. Inclusion of minorities in future studies is needed to fully understand issues related to the treatment of panic disorder in non-White populations. Suggestions for improved recruitment of ethnoracial minorities are discussed. PMID- 22445318 TI - Characterizing the association between parenting and adolescent social phobia. AB - OBJECTIVES: For characterizing the association between parenting and offspring social phobia (SP), contrasting maternal vs. paternal contributions, putative predictors of unfavorable parenting behaviors and its specificity for SP are warranted to delineate targeted prevention and intervention strategies. METHODS: A population-based sample of 1053 adolescents was followed-up using the M-CIDI. Parenting was assessed via questionnaire in offspring passing the high risk period for SP-onset. Natal complications and childhood serious health problems as assessed by maternal reports were hypothesized to relate to unfavorable parenting. RESULTS: The pattern of maternal overprotection, paternal rejection and lower emotional warmth was associated with SP, but not with other offspring anxiety disorders. Natal complications were related to overprotection and lower emotional warmth; trend-level associations emerged for serious health problems and unfavorable parenting. CONCLUSIONS: Paternal behavior appears particularly relevant for SP. The pattern of maternal overprotection, paternal rejection and lower emotional warmth was observed in SP only, suggesting that its detailed assessment provides a promising opportunity for targeted prevention and intervention in SP. PMID- 22445320 TI - Acupuncture for IVF: do not let needles stand in the way of empathy. PMID- 22445321 TI - Inadequate description of an acupuncture treatment study for polycystic ovaries. PMID- 22445322 TI - Low copy expression vectors for use in Yersinia sp. and related organisms. AB - In Yersinia, the most commonly used expression vectors for genetic studies such as gene complementation do not effectively allow for both induction and repression of gene expression. Additionally, there is no expression system available that can be induced in bacteria growing in vitro as well as in vivo, e.g. in eukaryotic cell lines or in living animal models. Here, we present a series of novel inducible low copy expression vectors that are well suited for use in the Yersinia species. Their tet operator/promoter/repressor system makes them distinct from other vectors, and gene transcription in bacteria can easily be induced by addition of anhydrotetracyline (ATc) either to the growth medium, to tissue culture medium during bacterial infections of cell lines or by injection into animals infected with bacteria. Researchers can choose between two different antibiotic resistances (kanamycin or spectinomycin), between two copy numbers (5 or 12-22) as well as between two different versions for expression from either the native RBS and ATG or RBS and ATG encoded in the plasmid. The whole vector series contains the same multi-cloning site from pBluescript II KS+ that allows for easy subcloning. Moreover, these vectors are built in a modular fashion that makes it simple to adapt them for other purposes. Finally, in addition to their use in Yersinia they are suitable for use in many other Enterobacteriaceae. PMID- 22445323 TI - Can we teach an old drug new tricks? AB - Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions. PMID- 22445324 TI - Reduced aging defects in estrogen receptive brainstem nuclei in the female hamster. AB - The nucleus pararetroambiguus (NPRA) and the commissural nucleus of the solitary tract (NTScom) show estrogen nuclear receptor-alpha immunoreactivity (nuclear ER alpha-IR). Both cell groups are involved in estrous cycle related adaptations. We examined in normally cycling aged hamsters the occurrence/amount/frequency of age related degenerative changes in NPRA and NTScom during estrus and diestrus. In 2640 electron microscopy photomicrographs plasticity reflected in the ratio of axon terminal surface/dendrite surface (t/d) was morphometrically analyzed. Medial tegmental field (mtf, nuclear ER-alpha-IR poor), served as control. In aged animals, irrespective of nuclear ER-alpha-IR+ or nuclear ER-alpha-IR- related cell groups, extensive diffuse degenerative structural aberrations were observed. The hormonal state had a strong influence on t/d ratios in NPRA and NTScom, but not in mtf. In NPRA and NTScom, diestrous hamsters had significantly smaller t/d ratios (NPRA, 0.750 +/- 0.050; NTScom, 0.900 +/- 0.039) than the estrous hamsters (NPRA, 1.083 +/- 0.075; NTScom, 1.204 +/- 0.076). Aging affected axodendritic ratios only in mtf (p < 0.001). IN CONCLUSION: in the female hamster brain, estrous cycle-induced structural plasticity is preserved in NPRA and NTScom during aging despite the presence of diffuse age-related neurodegenerative changes. PMID- 22445325 TI - Extracellular signal-regulated kinase is involved in alpha-synuclein-induced mitochondrial dynamic disorders by regulating dynamin-like protein 1. AB - Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinson's disease (PD) by inducing neurotoxicity. Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remains unclear. This study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also significantly increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). To further investigate the mechanism of SNCA's effect on mitochondrial dynamics, the proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The extracellular signal-regulated kinase (ERK) was confirmed to be involved in the regulation of DLP1 and SNCA-mediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in the future. PMID- 22445326 TI - High frequency of the expanded C9ORF72 hexanucleotide repeat in familial and sporadic Greek ALS patients. AB - An intronic expansion of a hexanucleotide GGGGCC repeat in the C9ORF72 gene has recently been shown to be an important cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in familial and sporadic cases. The frequency has only been defined in a small number of populations where the highest sporadic rate was identified in Finland (21.1%) and the lowest in mainland Italy (4.1%). We examined the C9ORF72 expansion in a series of 146 Greek ALS cases, 10.95% (n = 16) of cases carried the pathological expansion defined as greater than 30 repeats. In the 10 familial ALS probands, 50% (n = 5) of them carried a pathologically large expansion. In the remaining 136 sporadic ALS cases, 11 were carriers (8.2%). None of the 228 Greek controls carried an expanded repeat. The phenotype of our cases was spinal (13/16) or bulbar (3/16) ALS, the familial cases were all spinal ALS and none of our cases had behavioral frontotemporal dementia. Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. The frequency is higher than other populations with the exception of Finland and this may be due to Greece being a relatively isolated population. PMID- 22445327 TI - Effect of aging on 5-hydroxymethylcytosine in brain mitochondria. AB - Nuclear epigenetics of the mammalian brain is modified during aging. Little is known about epigenetic modifications of mitochondrial DNA (mtDNA). We analyzed brain samples of 4- and 24-month-old mice and found that aging decreased mtDNA 5 hydroxymethylcytosine (5hmC) but not 5-methylcytosine (5mC) levels in the frontal cortex but not the cerebellum. Transcript levels of selected mtDNA-encoded genes increased during aging in the frontal cortex only. Aging affected the expression of enzymes involved in 5-methylcytosine and 5-hydroxymethylcytosine synthesis (mitochondrial DNA methyltransferase 1 [mtDNMT1] and ten-eleven-translocation [TET]1-TET3, respectively). In the frontal cortex, aging decreased mtDNMT1 messenger RNA (mRNA) levels without affecting TET1-TET3 mRNAs. In the cerebellum, TET2 and TET3 mRNA content was increased but mtDNMT1 mRNA was unaffected. Using Western immunoblotting of samples from primary neuronal cultures, we found TET immunoreactivity in the mitochondrial fraction. At the single cell level, TET immunoreactivity was detected in the nucleus and in the perinuclear/intraneurite areas where it frequently colocalized with a mitochondrial marker. Our results demonstrated the presence and susceptibility to aging of mitochondrial epigenetic mechanisms in the mammalian brain. PMID- 22445328 TI - Discovery of flavonoid derivatives as anti-HCV agents via pharmacophore search combining molecular docking strategy. AB - Common feature based pharmacophore and structure-based docking approaches have been employed in the identification of novel anti-HCV candidates from our in house database. A total of 31 hits identified in silico were screened in vitro assay. 20 Compounds demonstrated anti-HCV activities (EC(50)<50 MUM), including two naturally occurring flavones apigenin (21) and luteolin (22) with low micromole EC(50) values and three compounds (23, 24 and 25) of novel scaffolds with moderate potencies. In addition, pharmacophore refinement was also conducted based on the current knowledge of flavone-derived anti-HCV candidates and the results of combined in silico and in vitro assays. PMID- 22445329 TI - Fetal and infant origins of diabetes and ill health: evidence from Puerto Rico's 1928 and 1932 hurricanes. AB - A natural experiment is employed to analyze the relationship between living standards, diabetes, and cardiovascular disease. Results show that shocks generated by two powerful tropical storms striking Puerto Rico during the late 1920s and early 1930s had long-term consequences consistent with the fetal origins hypothesis. Individuals in the womb or early infancy in the aftermath of the storms are more likely to report a diagnosis of hypertension, high cholesterol, diabetes, and are considerably more likely to have no formal schooling. PMID- 22445330 TI - Glycopyrrolate for chronic drooling in children. AB - BACKGROUND: Sialorrhea, or drooling, is seen in the pediatric population, especially in patients with cerebral palsy and other neurodevelopmental disabilities. If medication use is warranted, anticholinergic agents are the drug of choice; however, adverse effects limit their use. Glycopyrrolate, a synthetic anticholinergic that acts at peripheral muscarinic receptors, has been used off label for excessive drooling in children with neurodevelopmental disabilities for years. Product formulations restricted the use of glycopyrrolate. However, an oral solution was approved by the US Food and Drug Administration for children ages 3 to 16 years with neurologic disorders for chronic severe drooling in 2010; it became available for use in 2011. OBJECTIVE: This article provides an overview of the pharmacology, clinical efficacy, and tolerability of glycopyrrolate when used for sialorrhea in children. METHODS: To evaluate the efficacy and safety profile of glycopyrrolate for the treatment of sialorrhea in children, a comprehensive search was performed of the MEDLINE database (1966-February 25, 2012) and International Pharmaceutical Abstracts as well as references from additional review articles identified. Searches were conducted using the terms glycopyrrolate, sialorrhea, drooling, secretion, and pediatrics. The terms drug induced and Parkinson disease-associated sialorrhea were excluded from the search. The pharmaceutical manufacturer of the oral solution was contacted for medical and study information. RESULTS: Oral bioavailability of glycopyrrolate varies widely, with a median of 3.3%. Mean C(max) in children was determined to be 0.37 MUg/mL, and mean T(max) was 3.1 hours. The clearance in children ranges from 0.6 to 1.43 L/kg/h. The t(1/2) ranges from 22 to 130 minutes and 19 to 99 minutes in infants and children, respectively. Six studies describing the use of glycopyrrolate for drooling in children were identified. A double-blind, crossover trial of 27 patients (age range, 4-19 years) demonstrated a reduced mean drooling score (modified Teacher's Drooling Scale [1 = never drools to 9 = clothing, hands, and objects frequently become wet]) for glycopyrrolate (mean highest tolerated dose, 0.11 mg/kg) compared with placebo of 1.85 versus 6.33 (P < 0.001). In a parallel study of 36 patients (age range, 3-16 years), 14 of 20 patients randomized to receive glycopyrrolate solution showed improvement in the mean modified Teacher's Drooling Scale score compared with only 3 patients receiving placebo (-3.5 vs -0.1, respectively). Glycopyrrolate was initiated at 0.02 mg/kg per dose orally TID (Max dose: 3 mg) and titrated over a 4-week period. Adverse effects identified in studies include dry mouth (9%-41%), constipation (9%-39%), and behavioral changes (18%-36%). CONCLUSIONS: Glycopyrrolate is effective in decreasing sialorrhea in children with cerebral palsy or other neurodevelopmental disabilities. Adverse effects did occur, more frequently at higher doses, and should be monitored. PMID- 22445331 TI - Transcriptional profiling of layers of the primate cerebral cortex. AB - In this issue of Neuron, Bernard et al. (2012) report microarray-based transcriptional profiling of individually isolated layers from several cortical areas in adult Rhesus monkeys (Macaca mulatta). The resulting molecular signatures of neocortical organization are compared with human and mouse. PMID- 22445332 TI - Sonic hedgehog, BOC, and synaptic development: new players for an old game. AB - In this issue of Neuron, Harwell et al. (2012) identify a new role for the secreted molecule Shh and its receptor Boc in synapse formation. These results add an unexpected new player to the expanding list of extracellular cues regulating the spatial specificity of synapse formation. PMID- 22445333 TI - Human structural plasticity at record speed. AB - How rapidly does learning shape our brains? A new study in this issue of Neuron by Sagi et al. (2012) that uses diffusion magnetic resonance imaging in both humans and rats suggests that just 2 hr of spatial learning is sufficient to change brain structure. PMID- 22445334 TI - Disintegrating brain networks: from syndromes to molecular nexopathies. AB - In this issue of Neuron, Raj et al. (2012) and Zhou et al. (2012) use graph theory to suggest that neurodegenerative diseases spread diffusively via intrinsic brain networks. These studies provide a powerful model for understanding and predicting disease-specific profiles of neurodegeneration. PMID- 22445335 TI - Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders. AB - We describe a project aimed at studying a large number of individuals (>200) with specific recurrent genetic variations (deletion or duplication of segment 16p11.2) that increase the risk of developing autism spectrum (ASD) and other developmental disorders. The genetics-first approach augmented by web-based recruitment, multisite collaboration and calibration, and robust data-sharing policies could be adopted by other groups studying neuropsychiatric disorders to accelerate the pace of research. PMID- 22445336 TI - Growth cone travel in space and time: the cellular ensemble of cytoskeleton, adhesion, and membrane. AB - Growth cones, found at the tip of axonal projections, are the sensory and motile organelles of developing neurons that enable axon pathfinding and target recognition for precise wiring of the neural circuitry. To date, many families of conserved guidance molecules and their corresponding receptors have been identified that work in space and time to ensure billions of axons to reach their targets. Research in the past two decades has also gained significant insight into the ways in which growth cones translate extracellular signals into directional migration. This review aims to examine new progress toward understanding the cellular mechanisms underlying directional motility of the growth cone and to discuss questions that remain to be addressed. Specifically, we will focus on the cellular ensemble of cytoskeleton, adhesion, and membrane and examine how the intricate interplay between these processes orchestrates the directed movement of growth cones. PMID- 22445337 TI - Transcriptional architecture of the primate neocortex. AB - Genome-wide transcriptional profiling was used to characterize the molecular underpinnings of neocortical organization in rhesus macaque, including cortical areal specialization and laminar cell-type diversity. Microarray analysis of individual cortical layers across sensorimotor and association cortices identified robust and specific molecular signatures for individual cortical layers and areas, prominently involving genes associated with specialized neuronal function. Overall, transcriptome-based relationships were related to spatial proximity, being strongest between neighboring cortical areas and between proximal layers. Primary visual cortex (V1) displayed the most distinctive gene expression compared to other cortical regions in rhesus and human, both in the specialized layer 4 as well as other layers. Laminar patterns were more similar between macaque and human compared to mouse, as was the unique V1 profile that was not observed in mouse. These data provide a unique resource detailing neocortical transcription patterns in a nonhuman primate with great similarity in gene expression to human. PMID- 22445338 TI - Neuroprotection from stroke in the absence of MHCI or PirB. AB - Recovery from stroke engages mechanisms of neural plasticity. Here we examine a role for MHC class I (MHCI) H2-Kb and H2-Db, as well as PirB receptor. These molecules restrict synaptic plasticity and motor learning in the healthy brain. Stroke elevates neuronal expression not only of H2-Kb and H2-Db, but also of PirB and downstream signaling. KbDb knockout (KO) or PirB KO mice have smaller infarcts and enhanced motor recovery. KO hippocampal organotypic slices, which lack an intact peripheral immune response, have less cell death after in vitro ischemia. In PirB KO mice, corticospinal projections from the motor cortex are enhanced, and the reactive astrocytic response is dampened after MCAO. Thus, molecules that function in the immune system act not only to limit synaptic plasticity in healthy neurons, but also to exacerbate brain injury after ischemia. These results suggest therapies for stroke by targeting MHCI and PirB. PMID- 22445339 TI - Differential motion dynamics of synaptic vesicles undergoing spontaneous and activity-evoked endocytosis. AB - Synaptic vesicle exo- and endocytosis are usually driven by neuronal activity but can also occur spontaneously. The identity and differences between vesicles supporting evoked and spontaneous neurotransmission remain highly debated. Here we combined nanometer-resolution imaging with a transient motion analysis approach to examine the dynamics of individual synaptic vesicles in hippocampal terminals under physiological conditions. We found that vesicles undergoing spontaneous and stimulated endocytosis differ in their dynamic behavior, particularly in the ability to engage in directed motion. Our data indicate that such motional differences depend on the myosin family of motor proteins, particularly myosin II. Analysis of synaptic transmission in the presence of myosin II inhibitor confirmed a specific role for myosin II in evoked, but not spontaneous, neurotransmission and also suggested a functional role of myosin II mediated vesicle motion in supporting vesicle mobilization during neural activity. PMID- 22445340 TI - Sonic hedgehog expression in corticofugal projection neurons directs cortical microcircuit formation. AB - VIDEO ABSTRACT: The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. PMID- 22445341 TI - Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 Uncovers their roles in dendrite arborization and spine development. AB - Dendrite arborization and synapse formation are essential for wiring the neural circuitry. The evolutionarily conserved NDR1/2 kinase pathway, important for polarized growth from yeast to mammals, controls dendrite growth and morphology in the worm and fly. The function of NDR1/2 in mammalian neurons and their downstream effectors were not known. Here we show that the expression of dominant negative (kinase-dead) NDR1/2 mutants or siRNA increase dendrite length and proximal branching of mammalian pyramidal neurons in cultures and in vivo, whereas the expression of constitutively active NDR1/2 has the opposite effect. Moreover, NDR1/2 contributes to dendritic spine development and excitatory synaptic function. We further employed chemical genetics and identified NDR1/2 substrates in the brain, including two proteins involved in intracellular vesicle trafficking: AAK1 (AP-2 associated kinase) and Rabin8, a GDP/GTP exchange factor (GEF) of Rab8 GTPase. We finally show that AAK1 contributes to dendrite growth regulation, and Rabin8 regulates spine development. PMID- 22445342 TI - The X-linked intellectual disability protein TSPAN7 regulates excitatory synapse development and AMPAR trafficking. AB - Mutations in TSPAN7--a member of the tetraspanin protein superfamily--are implicated in some forms of X-linked intellectual disability. Here we show that TSPAN7 overexpression promotes the formation of filopodia and dendritic spines in cultured hippocampal neurons from embryonic rats, whereas TSPAN7 silencing reduces head size and stability of spines and AMPA receptor currents. Via its C terminus, TSPAN7 interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), to regulate PICK1 and GluR2/3 association and AMPA receptor trafficking. These findings indicate that, in hippocampal neurons, TSPAN7 regulates AMPA receptor trafficking by limiting PICK1 accessibility to AMPA receptors and suggest an additional mechanism for the functional maturation of glutamatergic synapses, whose impairment is implicated in intellectual disability. PMID- 22445343 TI - Thin dendrites of cerebellar interneurons confer sublinear synaptic integration and a gradient of short-term plasticity. AB - Interneurons are critical for neuronal circuit function, but how their dendritic morphologies and membrane properties influence information flow within neuronal circuits is largely unknown. We studied the spatiotemporal profile of synaptic integration and short-term plasticity in dendrites of mature cerebellar stellate cells by combining two-photon guided electrical stimulation, glutamate uncaging, electron microscopy, and modeling. Synaptic activation within thin (0.4 MUm) dendrites produced somatic responses that became smaller and slower with increasing distance from the soma, sublinear subthreshold input-output relationships, and a somatodendritic gradient of short-term plasticity. Unlike most studies showing that neurons employ active dendritic mechanisms, we found that passive cable properties of thin dendrites determine the sublinear integration and plasticity gradient, which both result from large dendritic depolarizations that reduce synaptic driving force. These integrative properties allow stellate cells to act as spatiotemporal filters of synaptic input patterns, thereby biasing their output in favor of sparse presynaptic activity. PMID- 22445344 TI - GABA neurons of the VTA drive conditioned place aversion. AB - Salient but aversive stimuli inhibit the majority of dopamine (DA) neurons in the ventral tegmental area (VTA) and cause conditioned place aversion (CPA). The cellular mechanism underlying DA neuron inhibition has not been investigated and the causal link to behavior remains elusive. Here, we show that GABA neurons of the VTA inhibit DA neurons through neurotransmission at GABA(A) receptors. We also observe that GABA neurons increase their firing in response to a footshock and provide evidence that driving GABA neurons with optogenetic effectors is sufficient to affect behavior. Taken together, our data demonstrate that synaptic inhibition of DA neurons drives place aversion. PMID- 22445345 TI - Activation of VTA GABA neurons disrupts reward consumption. AB - The activity of ventral tegmental area (VTA) dopamine (DA) neurons promotes behavioral responses to rewards and environmental stimuli that predict them. VTA GABA inputs synapse directly onto DA neurons and may regulate DA neuronal activity to alter reward-related behaviors; however, the functional consequences of selective activation of VTA GABA neurons remains unknown. Here, we show that in vivo optogenetic activation of VTA GABA neurons disrupts reward consummatory behavior but not conditioned anticipatory behavior in response to reward predictive cues. In addition, direct activation of VTA GABA projections to the nucleus accumbens (NAc) resulted in detectable GABA release but did not alter reward consumption. Furthermore, optogenetic stimulation of VTA GABA neurons directly suppressed the activity and excitability of neighboring DA neurons as well as the release of DA in the NAc, suggesting that the dynamic interplay between VTA DA and GABA neurons can control the initiation and termination of reward-related behaviors. PMID- 22445346 TI - Learning in the fast lane: new insights into neuroplasticity. AB - The timescale of structural remodeling that accompanies functional neuroplasticity is largely unknown. Although structural remodeling of human brain tissue is known to occur following long-term (weeks) acquisition of a new skill, little is known as to what happens structurally when the brain needs to adopt new sequences of procedural rules or memorize a cascade of events within minutes or hours. Using diffusion tensor imaging (DTI), an MRI-based framework, we examined subjects before and after a spatial learning and memory task. Microstructural changes (as reflected by DTI measures) of limbic system structures (hippocampus and parahippocampus) were significant after only 2 hr of training. This observation was also found in a supporting rat study. We conclude that cellular rearrangement of neural tissue can be detected by DTI, and that this modality may allow neuroplasticity to be localized over short timescales. PMID- 22445347 TI - A network diffusion model of disease progression in dementia. AB - Patterns of dementia are known to fall into dissociated but dispersed brain networks, suggesting that the disease is transmitted along neuronal pathways rather than by proximity. This view is supported by neuropathological evidence for "prion-like" transsynaptic transmission of disease agents like misfolded tau and beta amyloid. We mathematically model this transmission by a diffusive mechanism mediated by the brain's connectivity network obtained from tractography of 14 healthy-brain MRIs. Subsequent graph theoretic analysis provides a fully quantitative, testable, predictive model of dementia. Specifically, we predict spatially distinct "persistent modes," which, we found, recapitulate known patterns of dementia and match recent reports of selectively vulnerable dissociated brain networks. Model predictions also closely match T1-weighted MRI volumetrics of 18 Alzheimer's and 18 frontotemporal dementia subjects. Prevalence rates predicted by the model strongly agree with published data. This work has many important implications, including dimensionality reduction, differential diagnosis, and especially prediction of future atrophy using baseline MRI morphometrics. PMID- 22445348 TI - Predicting regional neurodegeneration from the healthy brain functional connectome. AB - Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network "epicenters" whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures. PMID- 22445349 TI - Human areas V3A and V6 compensate for self-induced planar visual motion. AB - Little is known about mechanisms mediating a stable perception of the world during pursuit eye movements. Here, we used fMRI to determine to what extent human motion-responsive areas integrate planar retinal motion with nonretinal eye movement signals in order to discard self-induced planar retinal motion and to respond to objective ("real") motion. In contrast to other areas, V3A lacked responses to self-induced planar retinal motion but responded strongly to head centered motion, even when retinally canceled by pursuit. This indicates a near complete multimodal integration of visual with nonvisual planar motion signals in V3A. V3A could be mapped selectively and robustly in every single subject on this basis. V6 also reported head-centered planar motion, even when 3D flow was added to it, but was suppressed by retinal planar motion. These findings suggest a dominant contribution of human areas V3A and V6 to head-centered motion perception and to perceptual stability during eye movements. PMID- 22445350 TI - The role of autophagy in the midgut epithelium of Eubranchipus grubii (Crustacea, Branchiopoda, Anostraca). AB - Eubranchipus grubii (Crustacea, Branchiopoda, Anostraca) is an omnivorous filter feeder whose life span lasts no more than 12 weeks. Adult males and females of E. grubii were used for ultrastructural studies of the midgut epithelium and an analysis of autophagy. The midgut epithelium is formed by columnar digestive cells and no regenerative cells were observed. A distinct regionalization in the distribution of organelles appears - basal, perinuclear and apical regions were distinguished. No differences in the ultrastructure of digestive cells were observed between males and females. Autophagic disintegration of organelles occurs throughout the midgut epithelium. Degenerated organelles accumulate in the neighborhood of Golgi complexes, and these complexes presumably take part in phagophore and autophagosome formation. In some cases, the phagophore also surrounds small autophagosomes, which had appeared earlier. Fusion of autophagosomes and lysosomes was not observed, but lysosomes are enclosed during autophagosome formation. Autophagosomes and autolysosomes are discharged into the midgut lumen due to apocrine secretion. Autophagy plays a role in cell survival by protecting the cell from cell death. PMID- 22445351 TI - A transportable magnetic resonance imaging system for in situ measurements of living trees: the Tree Hugger. AB - This paper presents the design of the 'Tree Hugger', an open access, transportable, 1.1 MHz (1)H nuclear magnetic resonance imaging system for the in situ analysis of living trees in the forest. A unique construction employing NdFeB blocks embedded in a reinforced carbon fibre frame is used to achieve access up to 210 mm and to allow the magnet to be transported. The magnet weighs 55 kg. The feasibility of imaging living trees in situ using the 'Tree Hugger' is demonstrated. Correlations are drawn between NMR/MRI measurements and other indicators such as relative humidity, soil moisture and net solar radiation. PMID- 22445352 TI - Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. AB - BACKGROUND: Haemoglobinopathies can reduce the risk of malaria syndromes. We aimed to quantify the relation between different haemoglobin mutations and malaria protection to strengthen the foundation for translational studies of malaria pathogenesis and immunity. METHODS: We systematically searched the Medline and Embase databases for studies that estimated the risk of malaria in patients with and without haemoglobinopathies up to Sept 9, 2011, and identified additional studies from reference lists. We included studies that enrolled mainly children or pregnant women and had the following outcomes: Plasmodium falciparum severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy associated malaria, and Plasmodium vivax malaria. Two reviewers identified studies independently, assessed quality of the studies, and extracted data. We produced odds ratios (ORs; 95% CIs) for case-control studies and incidence rate ratios (IRRs; 95% CIs) for prospective studies. We did the meta-analysis with a random-effects model when equivalent outcomes were reported in more than one study. FINDINGS: Of 62 identified studies, 44 reported data for haemoglobin AS, 19 for haemoglobin AC and CC, and 18 for alpha-thalassaemia. Meta-analysis of case-control studies showed a decreased risk of severe P. falciparum malaria in individuals with haemoglobin AS (OR 0.09, 95% CI 0.06-0.12), haemoglobin CC (0.27, 0.11-0.63), haemoglobin AC (0.83, 0.67-0.96), homozygous alpha thalassaemia (0.63, 0.48-0.83), and heterozygous alpha-thalassaemia (0.83, 0.74 0.92). In meta-analysis of prospective trials only haemoglobin AS was consistently associated with protection from uncomplicated malaria (IRR 0.69, 95% CI 0.61-0.79); no haemoglobinopathies led to consistent protection from asymptomatic parasitaemia. Few clinical studies have investigated beta thalassaemia, haemoglobin E, P. vivax malaria, or pregnancy-associated malaria. INTERPRETATION: Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous alpha-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia. Through attenuation of severity of malaria, haemoglobinopathies could serve as a model for investigation of the mechanisms of malaria pathogenesis and immunity. FUNDING: US National Institute of Allergy and Infectious Diseases. PMID- 22445353 TI - Balancing act: haemoglobinopathies and malaria. PMID- 22445354 TI - Population-wide vaccination against human papillomavirus in adolescent boys: Australia as a case study. AB - Female-only vaccination programmes for human papillomavirus (HPV) have been introduced in many countries aimed at the prevention of cervical cancer in women. One HPV vaccine is registered for male vaccination, but boys, men, or both, are not yet included in nationally funded HPV vaccination programmes. In this Review we discuss the different considerations relevant to the introduction of population-wide HPV vaccination of boys in Australia, which was the first country to publicly fund HPV vaccination of girls. Several factors need to be taken into account during decision making around the introduction of population-based vaccination programmes, such as local disease burden, vaccine efficacy, vaccine safety, and cost-effectiveness. Social and ethical factors are also important. Although evidence for men is increasing in these areas, uncertainties need to be kept in mind. The features discussed in this Review are likely to be applicable, with caveats, to policy making in other developed countries. PMID- 22445355 TI - Tumorigenic adenovirus 12 cells evade NK cell lysis by reducing the expression of NKG2D ligands. AB - Activation of natural killer (NK) cells depends on a balance between signals received from activation and inhibitory ligands expressed on the surface of target cells. Tumorigenic human adenovirus 12 (Ad12) transformed cells express low levels of the NK cell inhibitory ligand MHC I, but do not exhibit increased sensitivity to NK cell lysis compared to their non-tumorigenic counterparts. Analysis of the expression of activation ligands that bind to the NKG2D receptor revealed that RAE1beta and H60 were reduced on the surface of Ad12 mouse cells as well as at the level of transcription. In accord with these results, RAE1 localization to the synapse and sensitivity to NK cell cytotoxicity were also diminished. The reduced transcription of the rat NKG2D ligands, RAEt1L and RRTL, in tumorigenic rat cells compared to non-tumorigenic counterparts implies that both mouse and rat cell lines share a common mechanism of NKG2D ligand activation subverted by Ad12. PMID- 22445356 TI - Neutrophil phagocytosis is down-regulated by nucleotides until encounter with pathogens. AB - Extracellular nucleotides such as ATP, ADP, UTP, UDP and UDPG can trigger intracellular signal transduction via purinergic (P2Y) receptors, and their interaction induces a wide range of biological effects in various cells. In this study, we investigated P2Y expression and the effects of nucleotides on chemotaxis and phagocytosis in human neutrophils. RT-PCR detected broad expression of P2Y subfamilies in neutrophils, as well as monocytes. Moreover, intracellular Ca(2+) increased in response to ATP, ADP, UTP and UDP in these cells, suggesting that P2Y receptors were functionally expressed. In neutrophils, chemotactic activity was increased significantly in response to ATP and ADP, and moderately in response to UTP and UDP; actin polymerization by ATP, ADP, UTP and UDP was also evident in the cells. Interestingly, we found that ATP and ADP, which enhanced chemotaxis activity significantly, had inhibitory effects on phagocytosis by neutrophils. These findings provide new evidence for the regulation of neutrophil phagocytosis by nucleotides. Furthermore, this inhibitory effect was completely lost upon co-culture with fMLP or LPS, known constituents of bacteria, resulting in recovery of normal phagocytic activity. Taken together, these findings suggest that ATP and ADP constantly stimulate the chemotactic activity of neutrophils in peripheral blood, but may inhibit their phagocytic activity until they encounter pathogens, in order to prevent them acting against self-tissues or cells, as fMLP and LPS commonly present in pathogens would again trigger normal phagocytic activity. PMID- 22445357 TI - CD40 stimulation induces vincristine resistance via AKT activation and MRP1 expression in a human multiple myeloma cell line. AB - Various co-stimulatory receptors are expressed in multiple myeloma (MM) both in immune microenvironment and in the tumor microenvironment in vivo. In relapsed human MM, these receptors are known to increase cell proliferation and induce conventional drug resistance. However, the mechanism of drug resistance induced via co-stimulatory receptors is poorly understood. In this study, we examined the role of CD40 expressed on MM cell lines. Out of all of the KMS MM cell lines, the KMS28BM cells expressed high levels of the CD40 receptor. When stimulated with anti-CD40 antibody or recombinant human CD40L, the proliferation of KMS28BM cells was increased 1.7 fold. In CD40-stimulated KMS28BM cells, signaling via the AKT pathway caused an increase in the expression of multidrug resistance-associated gene 1 (MRP1) and IL-6 by 2.2 fold and 30 fold, respectively, but not the MDR1 gene. Furthermore, CD40-stimulated KMS28BM cells were observed to be substantially resistant to the anticancer drug vincristine, and when cells were treated with the MRP1 specific inhibitor, MK-571, drug resistance was decreased. We also found that CD40-stimulated, MRP1-expressing KMS28BM cells significantly increased calcein efflux, and calcein efflux was inhibited through treatment with MK-571. Therefore, blocking CD40 and inhibiting MRP1 are potential targets to treat CD40-induced drug resistance in multiple myeloma. PMID- 22445358 TI - Surgical smoke - a health hazard in the operating theatre: a study to quantify exposure and a survey of the use of smoke extractor systems in UK plastic surgery units. AB - Surgeons and operating theatre personnel are routinely exposed to the surgical smoke plume generated through thermal tissue destruction. This represents a significant chemical and biological hazard and has been shown to be as mutagenic as cigarette smoke. It has previously been reported that ablation of 1 g of tissue produces a smoke plume with an equivalent mutagenicity to six unfiltered cigarettes. We studied six human and 78 porcine tissue samples to find the mass of tissue ablated during 5 min of monopolar diathermy. The total daily duration of diathermy use in a plastic surgery theatre was electronically recorded over a two-month period. On average the smoke produced daily was equivalent to 27-30 cigarettes. Our survey of smoke extractor use in UK plastic surgery units revealed that only 66% of units had these devices available. The Health and Safety Executive recommend specialist smoke extractor use, however they are not universally utilised. Surgical smoke inhalation is an occupational hazard in the operating department. Our study provides data to quantify this exposure. We hope this evidence can be used together with current legislation to make the use of surgical smoke extractors mandatory to protect all personnel in the operating theatre. PMID- 22445359 TI - Form and function in the trypanosomal secretory pathway. AB - Recent advances in secretory biology of African trypanosomes reveal both similarities and striking differences with other model eukaryotic organisms. Secretion is streamlined for rapid and selective transport of the major cargo, VSG. Selectivity in the early and post-Golgi compartments is dependent on glycosylphosphatidyl inositol anchors. Streamlining includes reduced organellar abundance, and close association of ER exit sites with Golgi and with unique flagellar cytoskeletal elements that govern organellar replication and segregation. These elements include a novel centrin containing bilobe structure. Innate signals for post-Golgi sorting of biosynthetic lysosomal cargo trafficking have been defined, as have pathways for both biosynthetic and endocytic trafficking to the lysosome. Less well-defined secretory organelles such as the multivesicular body and acidocalcisomes are receiving closer scrutiny. PMID- 22445360 TI - The moving junction, a key portal to host cell invasion by apicomplexan parasites. AB - One defining feature of apicomplexan parasites is their special ability to actively invade host cells. Although rapid, invasion is a complicated process that requires coordinated activities of host cell attachment, protein secretion, and motility by the parasite. Central to this process is the establishment of a structure called moving junction (MJ), which forms a tight connection between invading parasite and host cell membranes through which the parasite passes to enter into the host. Although recognized microscopically for decades, molecular characterization of the MJ was only enabled by the recent discovery of components that make up this multi-protein complex. Exciting progress made during the past few years on both the structure and function of the components of the MJ is reviewed here. PMID- 22445361 TI - Artificial activation of toxin-antitoxin systems as an antibacterial strategy. AB - Toxin-antitoxin (TA) systems are unique modules that effect plasmid stabilization via post-segregational killing of the bacterial host. The genes encoding TA systems also exist on bacterial chromosomes, and it has been speculated that these are involved in a variety of cellular processes. Interest in TA systems has increased dramatically over the past 5 years as the ubiquitous nature of TA genes on bacterial genomes has been revealed. The exploitation of TA systems as an antibacterial strategy via artificial activation of the toxin has been proposed and has considerable potential; however, efforts in this area remain in the early stages and several major questions remain. This review investigates the tractability of targeting TA systems to kill bacteria, including fundamental requirements for success, recent advances, and challenges associated with artificial toxin activation. PMID- 22445362 TI - Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma. AB - Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG may help further distinguish this unique neoplasm from diffuse glioma. PMID- 22445363 TI - Clinical significance of myosin in colorectal cancer. AB - Myosin has raised an interest in cancer research because of its role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of myosin in colorectal cancer (CC). Myosin was detected in CC tumors with recurrence using matrix-assisted laser desorption/ionization time-of-flight analysis. An immunohistochemical study was performed using tissue arrays and specific antibodies against myosin heavy chain. Determinations on cancer specimens from 91 patients with resectable CCs were performed. The minimum follow up period was of 12.5 years for these patients without tumor recurrence. Western blot and real-time polymerase chain reaction analysis were also performed. Samples of carcinomas with recurrence showed an increased expression of myosin. Tumors with high myosin expression by tumor cell were significantly associated with higher probability of metastasis. Our results suggest that myosin expression in CCs is associated with tumor progression and metastasis development. Therefore, myosin tumor expression may contribute to an improved prognostic evaluation in patients with CC. PMID- 22445364 TI - Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1. AB - An exaggerated inflammatory process is considered an important pathophysiological feature of complex regional pain syndrome type 1 (CRPS-1). The hypothalamic pituitary-adrenal (HPA) axis serves as a negative feedback mechanism for inflammatory processes. The present study examined the HPA axis function in patients with CRPS-1 by a determination of cortisol concentrations in saliva. Three sets of saliva samples were sequentially collected from 24 patients with CRPS-1 during medication (on-Med), 72 h after stopping medication (off-Med) and 8h after the oral administration of 1mg dexamethasone. One set of saliva samples was collected from healthy controls. The cortisol awakening response (CAR) and diurnal cortisol decline (DCD) were used as indices for HPA axis function. Cortisol levels during the post-awakening period in patients were increased following withdrawal of medications. The CAR during the off-Med condition was disappeared after administration of dexamethasone. Among the examined CRPS related numerical variables, the frequency of spontaneous pain attacks showed relationships with the indices of HPA axis function. After classifying the patients into two subgroups, we observed that the CAR and DCD in patient who had a relatively high frequency of spontaneous pain attacks (subgroup 5 <=) were lower and less steep than those in patient who had a relatively low frequency of spontaneous pain attacks (subgroup 0-4) for the on- and off-Med conditions. The CAR and DCD in subgroup 5 <= during their off-Med condition were comparable to those in controls. These results suggest that the increase in frequency of spontaneous pain attacks is associated with a reduced CAR and flattened DCD in patients CRPS-1. PMID- 22445365 TI - Genetic and epigenetic determinants of neurogenesis and myogenesis. AB - The regulatory networks of differentiation programs have been partly characterized; however, the molecular mechanisms of lineage-specific gene regulation by highly similar transcription factors remain largely unknown. Here we compare the genome-wide binding and transcription profiles of NEUROD2-mediated neurogenesis with MYOD-mediated myogenesis. We demonstrate that NEUROD2 and MYOD bind a shared CAGCTG E box motif and E box motifs specific for each factor: CAGGTG for MYOD and CAGATG for NEUROD2. Binding at factor-specific motifs is associated with gene transcription, whereas binding at shared sites is associated with regional epigenetic modifications but is not as strongly associated with gene transcription. Binding is largely constrained to E boxes preset in an accessible chromatin context that determines the set of target genes activated in each cell type. These findings demonstrate that the differentiation program is genetically determined by E box sequence, whereas cell lineage epigenetically determines the availability of E boxes for each differentiation program. PMID- 22445367 TI - Milk and meat in our diet: good or bad for health? AB - Foods derived from animals are an important source of nutrients in the diet but there is considerable uncertainty about whether or not these foods contribute to increased risk of various chronic diseases. For milk in particular there appears to be an enormous mismatch between both the advice given on milk/dairy foods items by various authorities and public perceptions of harm from the consumption of milk and dairy products, and the evidence from long-term prospective cohort studies. Such studies provide convincing evidence that increased consumption of milk can lead to reductions in the risk of vascular disease and possibly some cancers and of an overall survival advantage from the consumption of milk, although the relative effect of milk products is unclear. Accordingly, simply reducing milk consumption in order to reduce saturated fatty acid (SFA) intake is not likely to produce benefits overall though the production of dairy products with reduced SFA contents is likely to be helpful. For red meat there is no evidence of increased risk of vascular diseases though processed meat appears to increase the risk substantially. There is still conflicting and inconsistent evidence on the relationship between consumption of red meat and the development of colorectal cancer, but this topic should not be ignored. Likewise, the role of poultry meat and its products as sources of dietary fat and fatty acids is not fully clear. There is concern about the likely increase in the prevalence of dementia but there are few data on the possible benefits or risks from milk and meat consumption. The future role of animal nutrition in creating foods closer to the optimum composition for long-term human health will be increasingly important. Overall, the case for increased milk consumption seems convincing, although the case for high-fat dairy products and red meat is not. Processed meat products do seem to have negative effects on long-term health and although more research is required, these effects do need to be put into the context of other risk factors to long-term health such as obesity, smoking and alcohol consumption. PMID- 22445366 TI - Botch promotes neurogenesis by antagonizing Notch. AB - Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development. PMID- 22445368 TI - Polymorphism of the caprine malic enzyme 1 ( ME1) gene and its association with milk quality traits in Murciano-Granadina goats. AB - Malic enzyme 1 plays a fundamental role in lipid metabolism because it yields a significant amount of the NADPH necessary for fatty acid biosynthesis. In ruminants, however, its contribution to this biochemical process seems to be less relevant than in other livestock species. In this study, we have partially sequenced the goat ME1 gene with the aim of identifying polymorphic sites. Structural analysis of the goat ME1 amino acid partial sequence evidenced the existence of two dinucleotide-binding motifs, located at positions 158 to 163 (GLGDLG) and 301 to 306 (GAGEAA), and three amino acid residues (E245, D246 and D269) involved in the binding of Mn2+ and strongly conserved among mammalian species. Moreover, multiple sequence alignment allowed us to identify four single nucleotide polymorphisms at exons 5 (c.483C > T), 6 (c.667G > A), 9 (c.927C > T) and 11 (c.1200G > A). The effects of ME1 genotype on milk production and composition traits were investigated in a Murciano-Granadina goat population. None of the associations found reached statistical significance after applying Benjamini-Hochberg correction. At most, associations with uncorrected P-values below 0.01 were observed for C16:0, C18:1n-9t and total conjugated linoleic acids. These negative results reinforce the notion that ME1 plays an ancillary role in ruminant lipogenesis. PMID- 22445369 TI - A catalogue of validated single nucleotide polymorphisms in bovine orthologs of mammalian imprinted genes and associations with beef production traits. AB - Genetic (or 'genomic') imprinting, a feature of approximately 100 mammalian genes, results in monoallelic expression from one of the two parentally inherited chromosomes. To date, most studies have been directed on imprinted genes in murine or human models; however, there is burgeoning interest in the effects of imprinted genes in domestic livestock species. In particular, attention has focused on imprinted genes that influence foetal growth and development and that are associated with several economically important production traits in cattle, sheep and pigs. We have re-sequenced regions in 20 candidate bovine imprinted genes in order to validate single nucleotide polymorphisms (SNPs) that may influence important production traits in cattle. Putative SNPs detected via re sequencing were subsequently re-formatted for high-throughput SNP genotyping in 185 cattle samples comprising 138 performance-tested European Bos taurus (all Limousin bulls), 29 African B. taurus and 18 Indian B. indicus samples. Analysis of the resulting genotypic data identified 117 validated SNPs. Preliminary genotype-phenotype association analyses using 83 SNPs that were polymorphic in the Limousin samples with minor allele frequencies ?0.05 revealed significant associations between two candidate bovine imprinted genes and a range of important beef production traits: average daily gain, average feed intake, live weight, feed conversion ratio, residual feed intake and residual gain. These genes were the Ras protein-specific guanine nucleotide releasing factor gene (RASGRF1) and the zinc finger, imprinted 2 gene (ZIM2). Despite the relatively small sample size used in these analyses, the observed associations with production traits are supported by the purported biological function of the RASGRF1 and ZIM2 gene products. These results support the hypothesis that imprinted genes contribute significantly to important complex production traits in cattle. Furthermore, these SNPs may be usefully incorporated into future marker-assisted and genomic selection breeding schemes. PMID- 22445370 TI - Genotype by feeding system interaction in the genetic evaluation of Jersey cattle for milk yield. AB - Results of studies in dairy cattle about the magnitude of the genotype environment interaction (GEI) are variable, depending on the definitions of genotype and environment. Therefore, the objective of this study was to determine the magnitude of the interaction of genotype and feeding system (confinement and grazing) in the Mexican genetic evaluation of Jersey cattle for milk yield. The number of lactations and animals in the pedigree used were 5122 and 18 432. An animal model and the MTDFREML program were used to estimate genetic parameters and predict genetic values of the animals. Bivariate analysis was carried out considering the performance of confined and grazing cows as two different traits. Three indicator variables were used to assess GEI: (i) magnitude of the genetic correlation coefficients, (ii) correlation between predicted breeding values and (iii) frequency of coincidence in the ranking of top sires. The magnitude of GEI depended on the choice of the indicator variable. The estimate of genetic correlation coefficient less than unity (0.76; P < 0.05) suggested the presence of biologically important GEI. The differences in phenotypic averages and variances between confinement and grazing systems seem to be the main causes for the genotype by environment interaction detected. However, the correlation coefficient between breeding values from confined and grazing animals (0.96) and the frequency of coincidence between breeding values of common sires within the top 100 in confinement and grazing (0.86) indicated low-to-moderate re-ranking of animals or top sires. In addition, the high correlations between predicted breeding values of Mexican genetic evaluation and the two environments (0.99 and 0.93 for confinement and grazing) indicated that for the two feeding systems, breeding values from national analyses could be safely used. PMID- 22445371 TI - Consequences of the inscription of local breeds in protected designation of origin cow cheese specifications for the genetic management of the herds. AB - In the mountainous areas of Europe with a humid climate, dairy cattle production is a major agricultural activity, and the milk is often processed into cheese according to protected designation of origin (PDO) specifications. We analyzed the extent to which PDO specifications and/or a mountain environment influence the spatial distribution of estimated breeding values (EBVs) of cows and the herd year effects (HYEs) for milk yield (kg/lactation) and protein and fat contents (g/kg), as well as lactation ranks and calving months. The study focused on the northern French Alps. A total of 37 023 lactations, recorded in 2006, in 1153 herds were analyzed. The cows belonged to the Montbeliarde (21 516 lactations), Abondance (10 346 lactations) and Tarentaise (5161 lactations) breeds. The two factors of variation considered were the status of the commune where the farm was located in relation to PDO (three categories: area with no PDO, area with a PDO with no milk yield limit, area with a PDO with a milk yield limit) and 'mountain' environment (four categories based on the European regulation: plain, piedmont, mountain and high mountain). In the Abondance breed, the average lactation rank increased with an increase in production constraints due to the PDO or to a mountain environment. In the Abondance and Tarentaise breeds, grouping of calving in winter was most marked in the 'PDO with a milk yield limit' and 'high mountain' categories. In the Tarentaise breed, no significant effect on any trait and any variable was found in the 'PDO' or 'mountain' categories. In the other two breeds, the average EBV for milk yield decreased with an increase in the constraints due to PDO, with differences of 226 and 93 kg between extreme values in the Abondance and Montbeliarde breeds, respectively. The average HYE for milk yield was higher in the Abondance breed in the 'PDO with no milk yield limit' category than in the other categories (+740 and +1110 kg, respectively); HYE was not affected by the 'PDO' factor in the Montbeliarde breed or by the 'mountain' factor in either breed. Concerning the protein and fat contents, the effect of the 'PDO' and 'mountain' factors depended on the trait, the variable and the breed. The proportion of individual decisions (the farmer makes the decision) v. collective decisions (breed management) concerning herd dynamics in the face of existing constraints is discussed. PMID- 22445372 TI - In vitro prediction of standardised ileal crude protein and amino acid digestibilities in grain legumes for growing pigs. AB - The study was conducted to validate in vitro prediction of standardised ileal digestibilities (SID) of crude protein (CP) and amino acids (AA) in grain legumes for growing pigs using six different cultivars of faba beans (Vicia faba), six different cultivars of field peas (Pisum sativum), and five different cultivars of lupins (Lupinus spp.). The SID for CP and AA were predicted from in vitro analysis by means of a two-step enzymatic method using pepsin and pancreatin incubations. In vitro predicted SID values of CP and AA were generally higher than the corresponding SID values measured in vivo. There were strong linear relationships (r2 = 0.73 for Lys to r2 = 0.91 for Cys and Trp) between in vivo and in vitro predicted SID values in the assay feed ingredients if grain legume species (i.e. faba beans, field peas and lupins) was included as a covariate in multiple linear regression analysis. However, to rapidly and accurately predict SID of CP and AA in individual batches of various feed ingredients, further studies are warranted. PMID- 22445373 TI - Effects of restricted feeding of prepubertal ewe lambs on reproduction and lactation performances over two breeding seasons. AB - The aim of this study was to determine the effects of restricted feeding before puberty on reproduction, lactation and offspring growth performance in replacement ewe lambs over two breeding seasons. At weaning, 41 Dorset ewe lambs were assigned to one of three diets: an ad libitum control diet with medium quality forage (MQF; 13.3% crude protein (CP), 1.81 Mcal metabolizable energy per kg, 42.8% ADF; diet A-MQF); a restricted diet with the same forage as A but less feed concentrate (diet R-MQF); or a high-quality forage (HQF) diet (14.8% CP, 2.15 Mcal ME/kg, 34.7% ADF; diet F-HQF). The quantity of concentrate offered to the group R-MQF and F-HQF ewe lambs was adjusted to obtain 70% of the control ewe lambs' growth rate. The diets were offered for 75 days following weaning to cover the allometric phase of mammary gland development. Prepubertal restriction did not affect (P > 0.10) the gestation rate, number of lambs born or the body weight and body condition score of ewes at lambing or at the end of lactation. Ewes from groups R-MQF and F-HQF tended to produce more milk during their first lactation compared to those from group A-MQF (P = 0.07). During the second lactation, groups R-MQF and F-HQF had better standardized milk production than group A-MQF (P < 0.05), and group R-MQF produced more milk than group F-HQF (P < 0.05). Milk fat and protein content were not affected by treatments (P > 0.10) Fat and protein yield were affected by treatments only at the second lactation (P < 0.10 and P < 0.05, respectively). Lamb birth and weaning weights were not affected by prepubertal restriction of feeding in their mother (P > 0.10). However, the average daily gain of second breeding season lambs was higher for the R-MQF group than the F-HQF group (P < 0.05), and a similar trend was observed for total gain (P < 0.10). Restricted feeding before puberty does not impair future reproductive performance; however, it has a positive impact on lactation and on lambs' growth performance. PMID- 22445374 TI - Effect of N,N-dimethylglycine supplementation in parturition feed for sows on metabolism, nutrient digestibility and reproductive performance. AB - The current pilot study assessed the influence of N,N-dimethylglycine (DMG) on insulin sensitivity, glucose and fat metabolism, nutrient digestibility and reproductive performance of sows in the peripartal period. At day 105 of gestation, 25 sows were randomly assigned to the control (n = 13) or the DMG group (n = 12). Sows from the DMG group were supplemented with 1 g DMG/kg feed until day 3 of lactation. After an overnight fast 1 day after farrowing, a blood sample of each sow was drawn. The plasma was analyzed for insulin, glucose, fructosamine, leptin, thiobarbituric acid reactive substances (TBARS), ferric reducing ability of plasma (FRAP), non-esterified fatty acids (NEFA) and triglycerides (TG) and an oral glucose tolerance test was performed. A rectal feces sample was collected and the apparent fecal digestibility (AFD) of crude fat (CFAT), crude protein (CP) and nitrogen-free extract (NFE) was calculated after proximate analyses. Finally, a colostrum sample was collected from each sow and analyzed for the presence of DMG. Reproductive performance parameters were recorded. The results showed an improvement in the AFD of CFAT, CP and NFE when DMG was supplemented. This beneficial effect confirms the hypothesis that DMG acts as an emulsifying agent. The improvement in digestibility in the DMG group was accompanied by a numerical increase in plasma TG (P = 0.067). Plasma NEFA concentrations were not different between treatment groups. DMG supplementation neither affected glucose clearance nor influenced plasma insulin, glucose, fructosamine or leptin levels. TBARS and FRAP also remained unaffected, despite previously reported anti-oxidative properties of DMG. Furthermore, no significant impact on reproductive performance could be recorded. In conclusion, DMG supplementation significantly improved nutrient digestibility. Possible beneficial effects on energy metabolism and reproductive performance of sows should be tested when DMG is supplemented for a longer period of time or at a higher dose. PMID- 22445375 TI - Stimulation of reproductive activity in anovulatory Alpine goats exposed to bucks treated only with artificially long days. AB - Two experiments were conducted in a subtropical latitude to determine the response of Alpine male goats to a treatment with artificially long days (experiment 1), and the response of anovulatory lactating Alpine does exposed to males treated only with artificially long days (experiment 2). In experiment 1, one group of males was kept under natural photoperiod (n = 4) while another was exposed to 2.5 months of artificially long days (16 h of light/day) from 1 December (n = 4). Plasma testosterone concentrations were determined weekly. Intensity of odor of males was determined every 2 weeks. Sexual behavior of bucks was observed during 3 days about 90 days after the end of the long day treatment. A treatment-by-time interaction was detected for testosterone secretion (P < 0.001). In control males, low plasma concentrations of testosterone were observed from March to June. In contrast, in long-day treated males, high levels of testosterone were observed from March to June (P < 0.05). A treatment-by-time interaction was detected for the intensity of male odor (P < 0.01). The male odor was stronger in long-day treated bucks than in untreated ones from March to June (P < 0.05). The number of ano-genital sniffing, nudging and flehmen was greater in long-day treated males than in untreated ones when exposed to anestrous does (P < 0.05). In experiment 2, one group of males was left under natural photoperiod variations (n = 5) and the other (n = 5) was submitted to the same photoperiodic treatment described in experiment 1. On 3 May, three untreated and three long-day treated males were put in contact with anestrous Alpine does left under natural photoperiod. Fertility was higher in does exposed to light-treated males (36/45, 80%) than those in contact with untreated ones (3/45, 7%; P < 0.05). Prolificacy was similar (P > 0.05) in does exposed to treated (1.8 +/- 0.1) and untreated males (1.7 +/- 0.3). These results indicate that the sexual activity of Alpine male goats raised in subtropical latitudes can be induced using only artificially long days and that such males are effective in stimulating reproductive activity in anovulatory females in late spring. PMID- 22445376 TI - Effects of dietary n-3 fatty acids on characteristics and lipid composition of ovine sperm. AB - The fatty acid composition of sperm affects the fertilization rate. The objective was to investigate the effects of dietary fish oil (as a source of n-3 fatty acids) on semen quality and sperm fatty acid composition in sheep. Eight Zandi fat-tailed rams were randomly allocated into two groups and fed either a control diet or a diet supplemented with fish oil. Both diets were isocaloric and isonitrogenous and were fed for 13 weeks, starting in the middle of the breeding season. Semen samples were collected weekly and their characteristics evaluated by standard methods, whereas samples collected at the start and end of the study were assessed (gas chromatography) for sperm lipid composition. Mean (+/-s.e.m.) sperm concentrations (4.3 * 109 +/- 1.3 * 108 v. 3.9 * 109 +/- 1.3 * 108 sperm/ml and percentages of motile (77.25 +/- 3.34 v. 60.8 +/- 3.34) and progressively motile sperm (74.13 +/- 1.69 v. 62.69 +/- 1.69) were significantly higher in the fish oil group than control. Dietary fish oil increased the proportion of docosahexaenoic acid (DHA, C22:6 n-3) in sperm fatty acid composition. We concluded that feeding fish oil as a source of n-3 fatty acids attenuated seasonal declines in semen quality in rams, perhaps through increased DHA in sperm. PMID- 22445377 TI - High expression of the mRNA of cytochrome P450 and phase II enzymes in the lung and kidney tissues of cattle. AB - The objective of this study was to investigate the tissue-specific mRNA expression of different cytochrome P450 (CYP) isoforms, UDP glucuronsyl transferase 1A1 (UGT1A1) and glutathione-S-transferase (GSTA1) in the different tissues (liver, mammary gland, lungs, spleen, kidney cortex, heart, masseter muscle and tongue) of cattle, using quantitative real-time polymerase chain reaction (qPCR). CYP1A1-like mRNA was expressed in all of the tissues examined, including the liver, with the highest expression level in the kidney. CYP1A2-, 2E1- and 3A4-like mRNAs were only expressed hepatically. Interestingly, significant expression of CYP2B6-like mRNA was recorded in the lung tissue, while CYP2C9-like mRNA was expressed in the liver and kidney tissues of the cattle examined. UGT1A1- and GSTA1-like mRNAs were expressed in all of the examined tissues, except the mammary glands, and the highest expression levels were recorded in the kidney. The high expression of UGT1A1 in the lung tissue and GSTA1 in the liver tissue was unique to cattle; this has not been reported for rats or mice. The findings of this study strongly suggest that the liver, kidneys and lungs of cattle are the major organs contributing to xenobiotics metabolism. PMID- 22445378 TI - A teleonomic model describing performance (body, milk and intake) during growth and over repeated reproductive cycles throughout the lifespan of dairy cattle. 1. Trajectories of life function priorities and genetic scaling. AB - The prediction of the control of nutrient partitioning, particularly energy, is a major issue in modelling dairy cattle performance. The proportions of energy channelled to physiological functions (growth, maintenance, gestation and lactation) change as the animal ages and reproduces, and according to its genotype and nutritional environment. This is the first of two papers describing a teleonomic model of individual performance during growth and over repeated reproductive cycles throughout the lifespan of dairy cattle. The conceptual framework is based on the coupling of a regulating sub-model providing teleonomic drives to govern the work of an operating sub-model scaled with genetic parameters. The regulating sub-model describes the dynamic partitioning of a mammal female's priority between life functions targeted to growth (G), ageing (A), balance of body reserves (R) and nutrient supply of the unborn (U), newborn (N) and suckling (S) calf. The so-called GARUNS dynamic pattern defines a trajectory of relative priorities, goal directed towards the survival of the individual for the continuation of the specie. The operating sub-model describes changes in body weight (BW) and composition, foetal growth, milk yield and composition and food intake in dairy cows throughout their lifespan, that is, during growth, over successive reproductive cycles and through ageing. This dynamic pattern of performance defines a reference trajectory of a cow under normal husbandry conditions and feed regimen. Genetic parameters are incorporated in the model to scale individual performance and simulate differences within and between breeds. The model was calibrated for dairy cows with literature data. The model was evaluated by comparison with simulations of previously published empirical equations of BW, body condition score, milk yield and composition and feed intake. This evaluation showed that the model adequately simulates these production variables throughout the lifespan, and across a range of dairy cattle genotypes. PMID- 22445379 TI - A teleonomic model describing performance (body, milk and intake) during growth and over repeated reproductive cycles throughout the lifespan of dairy cattle. 2. Voluntary intake and energy partitioning. AB - This is the second of two papers describing a teleonomic model of individual performance during growth and over repeated reproductive cycles throughout the lifespan of dairy cattle. The model described in the first paper is based on the coupling of a regulating sub-model of the dynamic partitioning of a female mammal's priority over a lifetime with an operating sub-model of whole-animal performance. The model provides a reference pattern of performance under normal husbandry and feed regimen, which is expressed in this paper in a reference dynamic pattern of energy partitioning adapted to changes in nutrient supply. This paper deals with the representation of deviations from the reference pattern of performance. First, a model of intake regulation, accounting for feed allowance, physical limitation of the digestive tract and energy demand, is used to determine the actual intake, which may generate a deviation from the energy input under the reference pattern of partitioning. Second, a theoretical model is proposed to apportion the energy deviation between flows involved in performance and thus simulate lifetime performance when actual intake is above or below requirements. The model explicitly involves a homeorhetic drive by way of the tendency to home on to the teleonomic trajectory and a homeostatic control by way of the tendency to maintain an energy equilibrium in response to nutritional constraints. The model was evaluated through simulations reproducing typical feeding trials in dairy cows. Model simulations shown in graphs concern the effect of dietary energy content on intake, body weight and condition score, and milk yield. Results highlight the ability of the model to simulate the combination of physical and energetic regulation of intake, the accelerated, retarded and compensatory patterns of growth and the short- and long-term residual effects of pre-partum feeding on lactation. PMID- 22445380 TI - Amniotic fluid is important for the maintenance of maternal responsiveness and the establishment of maternal selectivity in sheep. AB - Amniotic fluid (AF) is important for the establishment of maternal behaviour in inexperienced ewes, but its role in experienced mothers remains to be studied. Here, the maintenance of post-partum maternal responsiveness and the establishment of exclusive bonding was investigated in multiparous ewes when AF was removed from the neonate or/and physical contact with the young was precluded for the first 4 h post partum. Maintenance of maternal responsiveness and establishment of exclusive bonding were measured by the proportion of mothers accepting their own lamb and alien lambs that had been either washed or not washed, and by comparing an acceptance score for each type of lamb. The acceptance score was computed by summing standardised variables of acceptance (low bleats, acceptance at udder, nursing and licking time) and subtracting standardised variables of rejection (high-pitched bleats, rejection at the udder and aggressive behaviour). Washing the neonate reduced its acceptance score, but the proportion of mothers rejecting their own lamb was reduced only when washing the neonate and prevention of physical contact for 4 h were combined (7/15 v. 0/10 in controls, P = 0.02). In addition, washing the neonate increased the acceptance score of the washed alien lamb, but not of the unwashed alien. However, washing and privation of physical contact did not increase significantly the proportion of mothers accepting an alien lamb at 4 h post partum. We conclude that AF is important in experienced ewes for the establishment of maternal responsiveness, as already found in primiparous mothers. In addition, our results indicate that AF also carries some chemosensory information facilitating exclusive bonding. PMID- 22445381 TI - The effect of different types of stressors during mid- and late pregnancy on lamb weight and body size at birth. AB - Mid-pregnancy shearing has consistently been shown to increase lamb birth weight, which can lead to an increase in lamb survival rates. However, shearing ewes during the winter months and under outdoor pastoral farming conditions can expose the recently shorn ewe to a greater risk of hypothermia. The aim of this study was to determine if exposure of ewes to repeated stressors, in mid- and late pregnancy, would result in an increase in lamb birth weight. This information may assist in the elucidation of the mechanism for the birth weight response to mid pregnancy shearing, which in turn could assist in the design of management options to increase lamb birth weight without placing the ewe at risk. One hundred and forty-four twin-bearing Romney ewes were allocated to one of six mid pregnancy treatments: control, isolation on 2 or 10 occasions, sham-shearing on 10 occasions, intramuscular cortisol injection on 10 occasions or shearing. Isolation, sham-shearing and cortisol treatments were conducted twice a week beginning, on average, day 74 of pregnancy and shearing occurred on day 76. During pregnancy, ewe treatment had no effect on ewe live weight. However, average ewe body condition scores were higher in the shorn group than in the sham shorn or cortisol groups (P < 0.05). Intramuscular injections of cortisol had a greater effect on ewe plasma cortisol concentrations than all other treatments (P < 0.05). Shearing produced a greater plasma cortisol response than isolation * 10 and sham-shearing (P < 0.05). Ewe plasma cortisol responses decreased during the 5 weeks of isolation and sham-shearing but cortisol injections produced a greater response during the fifth treatment than the first or ninth treatments (P < 0.05). Lambs born to shorn ewes were heavier and had a longer crown rump, forelimb and hind limb lengths than all other lambs (P < 0.05). In addition, lambs born to ewes in the cortisol treatment were lighter than lambs born to control, isolation * 2, isolation * 10 and shorn ewes (P < 0.05). The plasma cortisol concentrations observed for ewes injected with cortisol were far greater than those observed in all other groups, which is likely to explain the low birth weights of lambs born to ewes in that group. These results indicate that the mechanism by which mid-pregnancy shearing increases lamb birth weight is unlikely to be repeated stressors. PMID- 22445382 TI - Physiology and behavior of pigs before and after castration: effects of two topical anesthetics. AB - Surgical castration of male piglets is a common management practice conducted on commercial swine farms to prevent the occurrence of boar taint and aggressive behavior. However, the procedure of surgical castration causes acute pain-induced distress, which is an animal welfare concern. The objective of this study was to evaluate the use of two topical anesthetics to alleviate the pain caused by castration in piglets as measured by physiological and behavior indices of stress. At 3 days of age, 40 weight-matched piglets were allocated to one of four treatment groups. Treatments included: (i) sham castration (CON), (ii) surgical castration (CAS), (iii) castration and short-acting local anesthetic applied topically to the castration wound (SHORT) and (iv) castration and long-acting local anesthetic applied topically to the castration wound (LONG). Blood samples were collected from piglets before and 30, 60, 120 and 180 min after castration to measure leukocyte and differential counts and cortisol concentrations. The above experiment was repeated without blood collection and behavior was recorded for 30 min before and 180 min after castration or handling. Stress vocalizations were recorded during castration and handling. All piglets were weighed before and 24 h after castration and wound healing was recorded daily for the first 14 days after castration. Leukocyte counts and differentials did not differ (P > 0.05) among any of the treatments. Cortisol concentrations were elevated (P < 0.06) in CAS, SHORT and LONG piglets compared with controls 30 and 60 min after castration. The percentage of stress vocalizations was greater (P < 0.05) among castrated piglets compared with CON piglets, regardless of anesthetic treatment. Piglets that were castrated and not given a topical anesthetic spent more time (P < 0.05) lying without contact compared with piglets castrated and given a topical anesthetic, regardless of the topical anesthetic administered. Body weight change did not differ (P > 0.05) among treatments 24 h after castration or control handling and wound healing scores were greater (P < 0.05) in SHORT compared with CAS and LONG piglets 9 to 14 days after castration. In this study, the use of a short- or long-acting topical anesthetic was not effective in reducing the pain induced distress caused by castration in piglets. Further research is needed to evaluate alternative practical methods to reduce the pain caused by the on-farm castration of piglets. PMID- 22445383 TI - Lower serum IgA levels in horses kept under intensive sanitary management and physical training. AB - Quantity and variety of environmental antigens, age, diet, vaccine protocols, exercising practice and mucosal cytokine microenvironment are factors that influence serum immunoglobulin (Ig) levels. IgA, IgG, IgG(T) and IgM were quantified in 60 horses, which were classified into two groups, 'intensive' or 'relaxed', according to sanitary standards of the facilities and physical exercise to which animals were subjected to. The 'intensive' group presented lower means for all isotypes, but only IgA presented a significant (P < 0.0064) difference when compared to the 'relaxed' group. This suggests that mucosal immunity found in the 'intensive' group is lower when compared to the 'relaxed' group. Our data suggest that athlete horses may be less poised to mount an effective mucosal immunity response to environmental challenges and should not be considered by the same perspectives as a free-ranging horse. PMID- 22445384 TI - An individual-based model simulating goat response variability and long-term herd performance. AB - Finding ways of increasing the efficiency of production systems is a key issue of sustainability. System efficiency is based on long-term individual efficiency, which is highly variable and management driven. To study the effects of management on herd and individual efficiency, we developed the model simulation of goat herd management (SIGHMA). This dynamic model is individual-based and represents the interactions between technical operations (relative to replacement, reproduction and feeding) and individual biological processes (performance dynamics based on energy partitioning and production potential). It simulates outputs at both herd and goat levels over 20 years. A farmer's production project (i.e. a targeted milk production pattern) is represented by configuring the herd into female groups reflecting the organisation of kidding periods. Each group is managed by discrete events applying decision rules to simulate the carrying out of technical operations. The animal level is represented by a set of individual goat models. Each model simulates a goat's biological dynamics through its productive life. It integrates the variability of biological responses driven by genetic scaling parameters (milk production potential and mature body weight), by the regulations of energy partitioning among physiological functions and by responses to diet energy defined by the feeding strategy. A sensitivity analysis shows that herd efficiency was mainly affected by feeding management and to a lesser extent by the herd production potential. The same effects were observed on herd milk feed costs with an even lower difference between production potential and feeding management. SIGHMA was used in a virtual experiment to observe the effects of feeding strategies on herd and individual performances. We found that overfeeding led to a herd production increase and a feed cost decrease. However, this apparent increase in efficiency at the herd level (as feed cost decreased) was related to goats that had directed energy towards body reserves. Such a process is not efficient as far as feed conversion is concerned. The underfeeding strategy led to production decrease and to a slight feed cost decrease. This apparent increase in efficiency was related to goats that had mobilised their reserves to sustain production. Our results highlight the interest of using SIGHMA to study the underlying processes affecting herd performance and analyse the role of individual variability regarding herd response to management. It opens perspectives to further quantify the link between individual variability, herd performance and management and thus further our understanding of livestock farming systems. PMID- 22445385 TI - Production systems of Creole goat and their implications for a breeding programme. AB - The Creole goat is a local meat breed well adapted to the tropical environment of Guadeloupe, a French island in the Caribbean. A survey of 47 goat farmers was conducted in May 2008 to describe the Guadeloupean goat farming systems. It was the preliminary step for the implementation of a breeding programme for Creole goats. Farmers had 31 does on average. A small number (4%) kept only Creole goats. Most of them (62%) had a mixed herd of Creole and crossbreds. One-third of them (34%) reared only crossbred goats. Farmers appreciate the rusticity and resistance of the Creole goat but consider its growth as too slow. The most desired traits for goat selection were conformation and growth for males (77% of the answers). These traits were also important for females (30% of the answers). Maternal qualities were also frequently cited (maternal behaviour 23%, reproduction 20% and milk production 17%). Disease resistance was not seen as an important trait (10% and 7% of the answers for bucks and does, respectively). A typology constituted of five groups of farmers was also created. Farmers of three groups were retained to participate at a selection programme. They kept Creole goats and have expressed a strong willingness to join a selection programme. The results of the survey suggest that a breeding programme should mostly focus on the Creole goat as a maternal breed. Real consideration should be given to disease resistance. The Creole goat has indeed a key role to play in the sustainability of local farming systems. PMID- 22445386 TI - Synthesis and comparative assessment of a labeled RGD peptide bearing two different 99mTc-tricarbonyl chelators for potential use as targeted radiopharmaceutical. AB - During the past decade radiolabeled RGD-peptides have been extensively studied to develop site-directed targeting vectors for integrins. Integrins are heterodimeric cell-surface adhesion receptors, which are upregulated in cancer cells and neovasculature during tumor angiogenesis and recognize the RGD aminoacid sequence. In the present study, we report the synthesis and development of two derivatives of the Nepsilon-Lys derivatized cyclic Arg-Gly-Asp-D-Phe-Lys peptide, namely of cRGDfKHis and cRGDfK-CPA (CPA: 3-L-Cysteine Propionic Acid), radiolabeled via the [(99m)Tc(H(2)O)(3)(CO)(3)](+) metal aquaion at a high yield even at low concentrations of 10-5M (>87%) for cRGDfK-10-5M (>93%) for cRGDfK CPA. Radiolabeled peptides were characterized with regard to their stability in saline, in His/Cys solutions, as well as in plasma, serum and tissue homogenates and were found to be practically stable. Internalization and efflux assays using alphavbeta3-receptor-positive MDA-MB 435 breast cancer cells showed a good percentage of quick internalization (29.1 +/- 9.8% for (99m)Tc-HiscRGDfK and 37.0 +/- 0.7% for (99m)Tc-CPA-cRGDfK at 15 min) and no retention of radioactivity for both derivatives. Their in vivo behavior was assessed in normal mice and pathological SCID mice bearing MDA-MB 435 alphanubeta3 positive breast tumors. Both presented fast blood clearance and elimination via both the urinary and hepatobiliary systems, with (99m)Tc-His-cRGDfK remaining for a longer time than (99m)Tc-CPA-cRGDfK in all organs examined. Tumor uptake 30 min pi was higher for (99m)Tc-CPAcRGDfK (4.2 +/- 1.5% ID/g) than for (99m)Tc-His-cRGDfK (2.8 +/- 1.5% ID/g). Dynamic scintigraphic studies showed that the tumor could be visualized better between 15 and 45 min pi for both radiolabeled compounds but low delineation occurred due to high abdominal background. It was finally noticed that the accumulated activity on the tumor site was depended on the size of the experimental tumor; the smaller the size, the higher was the radioactivity concentration. PMID- 22445387 TI - The global role of kidney transplantation. PMID- 22445388 TI - Comparison of real-time reverse transcription loop-mediated isothermal amplification and real-time reverse transcription polymerase chain reaction for duck Tembusu virus. AB - Duck Tembusu virus (DTMUV) has caused huge losses to the poultry industry in China since the spring of 2010. The development of a rapid, convenient, and reliable method to diagnose this emerging duck infectious disease is critical. In the present study, a real-time reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was compared with the real-time reverse transcription polymerase chain reaction (RT-PCR) for detection of DTMUV. The sensitivity of real-time RT-LAMP was equal to that of the real-time RT-PCR, with a detection limit of 0.01 ELD(50) (50% egg lethal dose). The specificity of the real-time RT-LAMP and real-time RT-PCR was confirmed using RNAs and DNAs extracted from related viruses which cause duck infections. The reproducibility of the real-time RT-PCR assay was better than that of the real-time RT-LAMP. Only three results from 96 tissue samples differed between the real-time RT-LAMP and this real-time RT-PCR, confirming the reliability of these methods. This study indicated that the real-time RT-LAMP is simpler, less time-consuming, and more convenient than the real-time RT-PCR. With its high sensitivity, specificity, and convenience, the real-time RT-LAMP is a practical molecular diagnostic method for rapid and quantitative detection of DTMUV infection in a resource-limited setting. PMID- 22445389 TI - Ecotoxicological assessment of metal-polluted urban soils using bioassays with three soil invertebrates. AB - This study aimed at assessing the quality of urban soils by integrating chemical and ecotoxicological approaches. Soils from five sites in downtown Naples, Italy, were sampled and characterized for physical-chemical properties and total and water-extractable metal concentrations. Bioassays with Eisenia andrei, Enchytraeus crypticus and Folsomia candida were performed to assess toxicity of the soils, using survival, reproduction and growth as the endpoints. Metal bioaccumulation in the animals was also measured. The properties and metal concentrations of the soils strongly differed. Metal bioaccumulation was related with total metal concentrations in soil and was highest in E. crypticus, which was more sensitive than E. andrei and F. candida. Responses of the three species to the investigated soils seemed due to both metal contamination and soil properties. PMID- 22445390 TI - Decreased anti-Mullerian hormone concentration in follicular fluid of female smokers undergoing artificial reproductive techniques. AB - BACKGROUND: Several reports indicate that women who smoke have an increased risk of failure to conceive compared with their non-smoker counterparts. Here, we assessed the effect of smoking during the Assisted Reproduction Therapy (ART) on a potential marker of ovarian reserve, anti-mullerian hormone (AMH) in the follicular fluid (FF). MATERIALS AND METHODS: This was a cohort prospective study to assess the association between cigarette smoking and AMH concentrations in FF in fifty-six women undergoing their first ART cycle. Self-reported smoking status over time was also collected through personal interview. The main outcome measured was the association between current smoking and AMH concentrations in FF. Smoking status was assessed by FF cotinine concentrations. Analysis of covariance was performed to test statistical interaction between the main outcome and confounders. RESULTS: The mean concentration of AMH in follicular fluid was significantly decreased among smokers (1.02+/-0.14 vs. 1.74+/-0.15, P<0.05). No statistical interaction was found between this difference in AMH concentrations and confounders like age and BMI. Thus, our data support the idea that AMH is decreased in active smokers across the fertile age. CONCLUSIONS: The hypothesis of decreased AMH concentration in follicular fluid in female smokers was confirmed. The mechanisms through which cigarette smoking induces this fall in AMH are unknown and additional research is needed to improve our comprehension of the negative impact of smoking on ART outcomes. PMID- 22445391 TI - Field and laboratory studies of the fate and enantiomeric enrichment of venlafaxine and O-desmethylvenlafaxine under aerobic and anaerobic conditions. AB - The stereoselectivity of R,S-venlafaxine and its metabolites R,S-O desmethylvenlafaxine, N-desmethylvenlafaxine, O,N-didesmethylvenlafaxine, N,N didesmethylvenlafaxine and tridesmethylvenlafaxine was studied in three processes: (i) anaerobic and aerobic laboratory scale tests; (ii) six wastewater treatment plants (WWTPs) operating under different conditions; and (iii) a variety of wastewater treatments including conventional activated sludge, natural attenuation along a receiving river stream and storage in operational and seasonal reservoirs. In the laboratory and field studies, the degradation of the venlafaxine yielded O-desmethylvenalfaxine as the dominant metabolite under aerobic and anaerobic conditions. Venlafaxine was almost exclusively converted to O-desmethylvenlafaxine under anaerobic conditions, but only a fraction of the drug was transformed to O-desmethylvenlafaxine under aerobic conditions. Degradation of venlafaxine involved only small stereoisomeric selectivity. In contrast, the degradation of O-desmethylvenlafaxine yielded remarkable S to R enrichment under aerobic conditions but none under anaerobic conditions. Determination of venlafaxine and its metabolites in the WWTPs agreed well with the stereoselectivity observed in the laboratory studies. Our results suggest that the levels of the drug and its metabolites and the stereoisomeric enrichment of the metabolite and its parent drug can be used for source tracking and for discrimination between domestic and nondomestic wastewater pollution. This was indeed demonstrated in the investigations carried out at the Jerusalem WWTP. PMID- 22445392 TI - Incidence of cervical intraepithelial neoplasia in a cohort of HIV-infected women. AB - OBJECTIVE: To assess cervical intraepithelial neoplasia (CIN) incidence in HIV positive women and the risk factors for these lesions. METHODS: A retrospective and longitudinal cohort study was conducted from June 13, 1997, to December 18, 2009. At the first visit, the 348 participants had a normal cytologic finding but a negative Schiller test result, or an abnormal cytologic finding but no histologic diagnosis of CIN. Infection with HPV was detected by polymerase chain reaction. The main outcome measure was CIN incidence. RESULTS: During a mean follow-up of 40 months, 47 women (13.5%) developed CIN, for an incidence of 4.1 cases per 100 person-years of follow-up. The HPV prevalence was 68.1%, 42 women (89.4%) developed CIN 1, and no invasive cervical cancers were identified. On multivariate analysis, women younger than 19 years at first sexual intercourse (RR, 2.6; 95% CI, 1.24-5.35) and women who had never used antiretrovirals or used them only during pregnancy (RR, 2.3; 95% CI, 1.31-4.19) were at higher risk for CIN. CONCLUSION: The CIN incidence was low despite the high HPV prevalence. Being younger than 19 years at first sexual intercourse and not using antiretroviral medications were found to be the main risk factors for CIN. PMID- 22445393 TI - Pregnancy during a sporotrichosis epidemic in Rio de Janeiro, Brazil. PMID- 22445394 TI - The weakest t-norm based intuitionistic fuzzy fault-tree analysis to evaluate system reliability. AB - In this paper, a new approach of intuitionistic fuzzy fault-tree analysis is proposed to evaluate system reliability and to find the most critical system component that affects the system reliability. Here weakest t-norm based intuitionistic fuzzy fault tree analysis is presented to calculate fault interval of system components from integrating expert's knowledge and experience in terms of providing the possibility of failure of bottom events. It applies fault-tree analysis, alpha-cut of intuitionistic fuzzy set and T(omega) (the weakest t-norm) based arithmetic operations on triangular intuitionistic fuzzy sets to obtain fault interval and reliability interval of the system. This paper also modifies Tanaka et al.'s fuzzy fault-tree definition. In numerical verification, a malfunction of weapon system "automatic gun" is presented as a numerical example. The result of the proposed method is compared with the listing approaches of reliability analysis methods. PMID- 22445395 TI - Decentralized PI/PID controllers based on gain and phase margin specifications for TITO processes. AB - In this paper, a decentralized PI/PID controller design method based on gain and phase margin specifications for two-input-two-output (TITO) interactive processes is proposed. The decouplers are designed for systems to minimize the interaction between the loops, and the first order plus dead time (FOPDT) model is achieved for each decoupled subsystem based on the frequency response fitting. An independent PI/PID controller is designed for each reduced order decoupled subsystem to obtain the desired gain and phase margins, and the performance is verified on the original interactive system to show the effectiveness of the proposed design method for the general class of TITO systems. Simulation examples are incorporated to validate the usefulness of the presented algorithm. An experimentation is performed on the Level-Temperature reactor process to show the practical applicability of the proposed method for the interactive system. PMID- 22445396 TI - Results of an international comparison for the activity measurement of 177Lu. AB - An international Key Comparison of (177)Lu has recently been carried out. Twelve laboratories performed assays for radioactivity content on aliquots of a common master solution of (177)Lu, leading to eleven results submitted for entry into the Key Comparison Database of the Mutual Recognition Arrangement. A proposed Comparison Reference Value (CRV) was calculated to be 3.288(4)MBq/g using all eleven results. Degrees of equivalence and their uncertainties were calculated for each laboratory based on the CRV. Most of the values reported by the participating laboratories were within 0.6% of the CRV. PMID- 22445397 TI - Measurement of the 226Th and 222Ra half-lives. AB - The half-lives of (226)Th and (222)Ra were measured by counting alpha-particle emissions from sources as a function of time. The (226)Th sources were prepared from an open (230)U source, capturing recoil atoms after alpha-particle decay on glass disks or even directly onto a detector. Similarly, the (222)Ra sources were obtained by self-transfer of recoil atoms from (226)Th sources. The activity measurements were performed in (nearly-)2pi geometry with an ion-implanted silicon detector. The decay curves were analysed in different ways, incl. moment analysis, trying to avoid the pitfalls of bias of least-squares fits to Poisson distributed data. The observed half-life values are T(1/2)((226)Th)=30.70 (3) min and T(1/2)((222)Ra)=33.6 (4) s. Literature values show some inconsistency. PMID- 22445398 TI - Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy: risk factors and dose-volume relationship. AB - PURPOSE: The purpose of this study was to clarify the incidence, the clinical risk factors, and the dose-volume relationship of radiation-induced rib fracture (RIRF) after hypofractionated stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: One hundred sixteen patients treated with SBRT for primary or metastatic lung cancer at our institution, with at least 6 months of follow-up and no previous overlapping radiation exposure, were included in this study. To determine the clinical risk factors associated with RIRF, correlations between the incidence of RIRF and the variables, including age, sex, diagnosis, gross tumor volume diameter, rib-tumor distance, and use of steroid administration, were analyzed. Dose-volume histogram analysis was also conducted. Regarding the maximum dose, V10, V20, V30, and V40 of the rib, and the incidences of RIRF were compared between the two groups divided by the cutoff value determined by the receiver operating characteristic curves. RESULTS: One hundred sixteen patients and 374 ribs met the inclusion criteria. Among the 116 patients, 28 patients (46 ribs) experienced RIRF. The estimated incidence of rib fracture was 37.7% at 3 years. Limited distance from the rib to the tumor (<2.0 cm) was the only significant risk factor for RIRF (p = 0.0001). Among the dosimetric parameters used for receiver operating characteristic analysis, the maximum dose showed the highest area under the curve. The 3-year estimated risk of RIRF and the determined cutoff value were 45.8% vs. 1.4% (maximum dose, >=42.4 Gy or less), 51.6% vs. 2.0% (V40, >=0.29 cm(3) or less), 45.8% vs. 2.2% (V30, >=1.35 cm(3) or less), 42.0% vs. 8.5% (V20, >=3.62 cm(3) or less), or 25.9% vs. 10.5% (V10, >=5.03 cm(3) or less). CONCLUSIONS: The incidence of RIRF after hypofractionated SBRT is relatively high. The maximum dose and high-dose volume are strongly correlated with RIRF. PMID- 22445399 TI - Expression of seasonality in Merinos d'Arles ewes of different genotypes at the MT1 melatonin receptor gene. AB - Spontaneous ovulatory activity (SOA) in spring has been used to study the out-of season breeding ability of Merinos d'Arles (MA) ewes. Within this breed, an association was found between more intense seasonality and genotype -/- at a MnlI restriction site (allele - for its absence v. + for its presence) in Exon II of the MT1 receptor gene. This study was designed to ascertain whether this association results in a direct effect of the MT1 genotype on the expression of seasonality in MA ewes. In the first year of the study, genotyping of 314 MA ewes at locus MnlI was carried out and resulted in frequencies of 43.0%, 44.9% and 12.1% for genotypes +/+, +/- and -/-, respectively. The SOA of these ewes was determined in early April of two consecutive years by assaying plasma progesterone concentrations in two blood samples taken 9 days apart. Groups of 30 ewes of each homozygous genotype (+/+ and -/-) were identified from this population and their SOA was followed by taking blood samples at regular intervals between January and mid-April of the second and third year of the study. In the second year, groups of ewes were managed together on rangelands, whereas in the third year each group was split into two subgroups given differential feed levels. The results clearly showed that genotype had no significant effect on SOA during the 2- to 3-month period preceding the introduction of rams for spring mating. In the second year of the study, in which the experimental procedure allowed a fair comparison of the fertility of ewes in spring mating, fertility was similar for both genotypes. The reciprocity of the association was not demonstrated and the MnlI polymorphic site could not be used as a genetic marker of selection for out-of-season breeding ability, at least not in the MA breed. The percentage of cycling ewes significantly decreased between January and April, and older ewes (5 or 6 years old depending on the year of the study) were more cyclic than younger ones (2 and 3 years old, respectively). The differential feeding level of ewes from early February did not significantly affect their SOA during the time period studied in the third year of the study. PMID- 22445400 TI - A definition of unknown parent groups based on bull usage patterns across herds. AB - In genetic evaluations, the definition of unknown parent groups (UPG) is usually based on time periods, selection path and flows of foreign founders. The definition of UPG may be more complex for populations presenting genetic heterogeneity due to both, large national expansion and coexistence of artificial insemination (AI) and natural service (NS). A UPG definition method accounting for beef bull flows was proposed and applied to the French Charolais cattle population. It assumed that, at a given time period, unknown parents belonged to the same UPG when their progeny were bred in herds that used bulls with similar origins (birth region and reproduction way). Thus, the birth period, region and AI rate of a herd were pointed out to be the three criteria reflecting genetic disparities at the national level in a beef cattle population. To deal with regional genetic disparities, 14 regions were identified using a factorial approach combining principal component analysis and Ward clustering. The selection nucleus of the French cattle population was dispersed over three main breeding areas. Flows of NS bulls were mainly carried out within each breeding area. On the contrary, the use and the selection of AI bulls were based on a national pool of candidates. Within a time period, herds of different regions were clustered together when they used bulls coming from the same origin and with an estimated difference of genetic level lower than 20% of genetic standard deviation (sigmag) for calf muscle and skeleton scores (SS) at weaning. This led to the definition of 16 UPG of sires, which were validated as robust and relevant in a sire model, meaning numerically stable and corresponding to distinct genetic subpopulations. The UPG genetic levels were estimated for muscle and SS under sire and animal models. Whatever the trait, differences between bull UPG estimates within a time period could reach 0.5 sigmag across regions. For a given time period, bull UPG estimates for muscle and SS were generally larger by 0.30 to 0.75 sigmag than those of cows. Including genetic groups in the evaluation model increased the estimated genetic trends by 20% to 30%. It also provoked re ranking in favor of bulls and cows without pedigree. PMID- 22445401 TI - Comparison of the longevity and lifetime performance of Scottish Blackface ewes and their crosses within hill sheep flocks. AB - A study was undertaken to compare the longevity and lifetime lamb output of purebred Scottish Blackface (BF) ewes with a range of crossbred genotypes from Scottish BF dams. For up to five successive breeding seasons, 1143 Scottish BF, Swaledale * BF (SW * BF), North Country Cheviot * BF (CH * BF), Lleyn * BF (LL * BF) and Texel * BF (T * BF) ewes were mated to a range of sire breeds on six hill farms across Northern Ireland. Dentition and lamb output were recorded annually until completion of the study or until the ewe was removed due to death or culling. Timing of mortality and the main reason for culling were also recorded. When survival analysis was undertaken, SW * BF and CH * BF ewes had better longevity (P < 0.05) than BF ewes due to their lower culling rate (P < 0.01) and lower mortality rate (P = 0.06), respectively. The relative proportion of LL * BF and T * BF culled due to infertility was lower (P < 0.05) than SW * BF and CH * BF, while a higher (P < 0.05) proportion of LL * BF and T * BF ewes were culled for prolapses compared with the other breed crosses. SW * BF ewes had consistently higher bite scores (P < 0.001) compared with BF, LL * BF and T * BF, indicating a greater prevalence and degree of overshoot. In ewes aged 5.5 years old, SW * BF also had a higher incidence of tooth loss (P < 0.01) compared with the other breeds. However, the proportion of SW * BF culled due to poor teeth condition was lower (P < 0.05) than BF. Across all breeds, the chances of surviving to their next mating were influenced by ewe breed (P < 0.05), age at mating (P < 0.001), body condition score at weaning (P < 0.001), number of missing teeth (P < 0.001) and average daily live weight gain per litter (P < 0.05). The cumulative number and weight of lambs weaned per ewe over five successive matings was higher (P < 0.05) for crossbred compared with pure BF ewes; however there were no differences in lifetime output between the different crossbred ewes studied. This study demonstrates that the higher lamb output of crossbred hill ewes does not compromise their longevity compared with pure Blackface, resulting in greater total lifetime production. When the crossbred ewes are sired by a second hill breed, longevity may be improved. PMID- 22445402 TI - Effects of breed and age on the performance of crossbred hill ewes sourced from Scottish Blackface dams. AB - The aim of this study was to evaluate the effects of age and breed on the reproductive performance and lamb output of crossbred hill ewes relative to purebred Scottish Blackface (BF). BF ewes were compared alongside Swaledale (SW) * BF, North Country Cheviot (CH) * BF, Lleyn (LL) * BF and Texel (T) * BF ewes on six commercial hill farms across Northern Ireland, on which all the ewes were born and reared. Ewes were mated to a range of sire breeds, balanced across breeds, for up to five successive breeding seasons. Mature live weight of adult BF, SW * BF, CH * BF, LL * BF and T * BF ewes was 52.8, 54.9, 60.3, 55.6 and 58.6 kg (P < 0.001), respectively. Compared with the pure BF, the number of lambs born per ewe lambed was higher with LL * BF and SW * BF (P < 0.05), whereas the number of lambs weaned per ewe lambed was greater for LL * BF and T * BF (P < 0.01). Total litter weight at birth of all the crossbred ewes was heavier (P < 0.01) than the pure BF, except in primiparous 2-year-old ewes. Lambs born to CH * BF and T * BF dams were 0.24 to 0.35 kg heavier at birth (P < 0.01) than the other ewe breeds, whereas lambs born to CH * BF, LL * BF and T * BF dams were, on average, 1.7, 1.3 and 1.5 kg, respectively, heavier (P < 0.01) at weaning than those from BF dams due to their higher (P < 0.05) average daily gain. Compared with the pure BF, total weaned lamb output per ewe lambed was 3.7, 4.8, 6.7 and 5.4 kg heavier (P < 0.05) for SW * BF, CH * BF, LL * BF and T * BF, respectively. However, as a result of the heavier live weight of the crossbred ewes, production efficiency (lamb output per kilogram live weight (W) and lamb output per kilogram metabolic live weight (W0.75)) was higher (P < 0.001) for LL * BF ewes only. For all ewe breeds, litter size at birth per ewe lambed, total lamb birth weight per ewe lambed and litter size at weaning increased (P < 0.001) with age up to 5 years, but decreased in 6-year-old ewes. Average lamb weaning weight and total weaned lamb output per ewe lambed increased (P < 0.001) with age up to 4 years . Production efficiency of the 6-year-old ewes was lower (P < 0.01) than the younger ewes. This study shows that adopting a flock replacement policy based on crossing BF ewes with LL, SW, T and CH sires can lead to significant improvements in the productivity of hill flocks. PMID- 22445403 TI - Sheep breeding schemes utilising artificial insemination; large-scale simulation with a complex breeding goal. AB - Alternative Norwegian sheep breeding schemes were evaluated by stochastic simulation of a breeding population with about 120 000 ewes, considering the gain for an aggregate genotype including nine traits and also the rate of inbreeding. The schemes were: a scheme where both young unproven rams (test rams) and proven rams (elite rams) are used in artificial insemination (AI scheme), a scheme with test rams in natural mating in ram circles and elite rams (from one and a half years of age) in AI across all flocks in the country (NMAI2 scheme), a scheme where, in addition to testing rams, the youngest elite rams (one and a half years of age) are also used in natural mating in ram circles, while older elite rams are used in AI (NMAI1 scheme), and a scheme, acting as a control, where both test and elite rams are used in natural mating (NM scheme). Within the NMAI- and AI schemes, experimentation was performed for percent ewes inseminated to elite rams v. test rams (EM%), numbers of ewes inseminated per elite ram (EAIn), and numbers of ewes mated per test ram by natural service (TNMn) or by AI (TAIn), respectively. With a restriction on the rate of inbreeding (?0.8% per generation), the AI scheme gave similar gain to the NMAI2 scheme (and about 40% more than did the NM scheme). Less gain was generated by the NMAI1 scheme, but it was still considerably more than for the NM scheme (about 25%). In the AI scheme, relatively few ewes (200/300) should be inseminated to each test/elite ram, and a low EM% should be chosen (10%). In the NMAI schemes, TNMn should be relatively high (40 to 50), combined with average and somewhat larger than average EAIn (NMAI2: 700 ewes, NMAI1: 900 ewes), and EM% medium (30%). PMID- 22445404 TI - The effect of cereal type and enzyme supplementation on carcass characteristics, volatile fatty acids and intestinal microflora and boar taint in entire male pigs. AB - A 2 * 2 factorial experiment was conducted to investigate the effects of cereal type (barley v. oat) and exogenous enzyme supplementation (with or without) on intestinal fermentation, and on indole and skatole levels in the intestinal content and the adipose tissue in finisher boars. The experimental treatments were as follows: (i) barley-based diet, (ii) barley-based diet with enzyme supplement, (iii) oat-based diet and (iv) oat-based diet with enzyme supplement. The enzyme supplement contained endo-1,3(4)-beta-glucanase (EC 3.2.1.6) and endo 1,4-beta-xylanase (EC 3.2.1.8). The animals were fed ad libitum for 45 days from 76.0 to 113.6 kg live weight. Feeding barley-based diets led to higher (P < 0.05) total volatile fatty acids concentrations in the large intestine. Proportions of propionic- and butyric-acids were higher and that of acetic acid lower in digesta from barley-based in comparison to oat-based diets (P < 0.001). Consequently, pH in the large intestine was higher after feeding oat-based in comparison to barley based diets. Animals fed unsupplemented oat-based diet had higher (P < 0.01) indole concentrations in the digesta from the proximal colon than those fed barley-based diets. Feeding oat-based diets led to lower (P < 0.01) skatole and higher (P < 0.001) indole concentrations in the digesta from the terminal colon than barley-based diets. skatole concentrations in the adipose tissue did not differ (P > 0.05) between the experimental treatments. Pigs offered the barley based diets had lower (P < 0.001) indole concentrations in the adipose tissue compared with those fed the oat-based diet. In conclusion, barley-based diets were more efficient than oat-based diets in limiting concentrations of indole in the adipose tissue. PMID- 22445405 TI - Production and egg quality in layers fed organic diets with mussel meal. AB - The first limiting nutrients in typical laying hen diets are the sulphur containing amino acids and, in particular, methionine. To fulfil the birds' recommended requirement, conventional diets are supplemented with synthetic methionine. As this is not allowed in organic production it becomes very important to have access to alternative high-quality protein feed ingredients. An experiment was performed to evaluate the possibility to compose a diet with 100% organically approved feed ingredients using mussel meal as a major source of methionine. The experiment included 678 Lohman Selected Leghorn (LSL) and 678 Hyline White, W-98, layers during 20 to 72 weeks of age. There were 12 aviary pens with 113 birds in each. The birds were fed one of the two experimental diets containing either 3.5% or 7% dried mussel meat meal or a commercial organic diet from a Swedish feed manufacturer for comparison. Production and mortality were recorded daily per group, and egg weight was recorded once weekly. At 33, 55 and 70 weeks, 10 eggs from each treatment group were collected and analysed for internal egg quality. Diets had no significant effect on laying percentage, egg mass, feed intake, feed conversion ratio, mortality, bird live weight or proportion misplaced, cracked or dirty eggs. Egg quality, that is, shell deformation, shell breaking strength, albumen height, shell percentage and proportion of blood and meat spots were also unaffected. There was a significant difference in egg yolk pigmentation, that is, the egg yolk was more coloured when feeding 7% mussel meal compared with the other diets. Hyline hens had lower feed intake and laying percentage, and higher egg weight, but lower egg mass production than LSL birds. The age of the birds influenced all egg quality traits except for meat and blood spots. The dry matter of the excreta was significantly lower for both genotypes fed the 7% mussel meal diet. These results indicate that mussels may be a high-quality protein source and may replace fishmeal in organic diets for layers. PMID- 22445406 TI - Changes in digestive enzyme activity, intestine morphology, mucin characteristics and tocopherol status in mink kits (Mustela neovision) during the weaning period. AB - Weaning of livestock mammals is often associated with digestive problems related to profound changes in the physiology of the gastrointestinal tract. This study was undertaken to study the developmental changes in the gastrointestinal tract of mink kits during the period of 34 to 59 days of age. Twenty-four mink kits from eight litters were included in the experiment. The dams and their litters were kept under standard farm conditions. The dams and the kits were fed a diet consisting of 48.1% protein, 40.7% fat and 11.1% carbohydrate of metabolizable energy. The mink kits were weaned at 42 days of age. At 34, 47 and 59 days of age, one male mink kit from each litter was euthanized. The activity of amylase, trypsin, chymotrypsin and lipase in the pancreatic tissue increased during the experimental period, whereas the activity of carboxyl ester hydrolase remained constant. The vitamin E concentration in plasma was stable from 34 to 59 days of age, whereas the concentration decreased in the liver. The stereochemical composition of alpha-tocopherol showed a steep decrease in the concentration of the biologically most active natural isomer in both plasma and liver through the whole weaning period, whereas the biologically less active 2S isomers showed a clear increase. The concentration of bile salts did not change during the experimental period. The villous height increased in the proximal part of the small intestine and decreased in the distal part, whereas the crypt depth was doubled in both the proximal and distal part of the small intestine. The mucin staining area on the villi was markedly reduced during the experimental period but no change in the mucin-staining area in the crypts was observed. PMID- 22445407 TI - In vivo production and molar percentages of volatile fatty acids in the rumen: a quantitative review by an empirical approach. AB - Despite their major contribution to the energy supply of ruminants, the production of volatile fatty acids (VFA) in the rumen is still poorly predicted by rumen models. We have developed an empirical approach, based on the interpretation of large bibliographic databases gathering published in vivo measurements of ruminal VFA production rate (PR), rates of duodenal and faecal digestion and molar percentages of VFA in the rumen. These databases, covering a wide range of intake levels and dietary composition, were studied by meta analysis using within-experiment models. We established models to quantify response laws of total VFA-PR and individual VFA molar percentages in the rumen to variations in intake level and dietary composition. The rumen fermentable organic matter (RfOM) intake, estimated from detailed knowledge of the chemical composition of diets according to INRA Feed Tables, appears as an accurate explanatory variable of measured total VFA-PR, with an average increment of 8.03 +/- 0.64 mol total VFA/kg RfOM intake. Similar results were obtained when total VFA-PR was estimated from measured apparent RfOM (total VFA-PR/RfOM averaging 8.3 +/- 1.2 mol/kg). The VFA molar percentages were related to dry matter intake and measured digestible organic matter (OM), digestible NDF and rumen starch digestibility, with root mean square error of 1.23, 1.45, 0.88 and 0.41 mol/100 mol total VFA for acetate, propionate, butyrate and minor VFA, respectively, with no effect of pH on the residuals. Stoichiometry coefficients were calculated from the slopes of the relationships between individual VFA production (estimated from measured apparent RfOM and individual VFA molar percentages) and measured fermented fractions. Coefficients averaged, respectively, 66, 17, 14 and 3 mol/100 mol for NDF; 41, 44, 12 and 4 mol/100 mol for starch; and 46, 35, 13 and 6 mol/100 mol for crude protein. Their use to predict VFA molar percentages appear relevant for most dietary conditions, that is, when the digested NDF/digested OM ratio exceeded 0.12. This study provides a quantitative review on VFA yield in the rumen. It contributes to the development of feed evaluation systems based on nutrient fluxes. PMID- 22445408 TI - Road transport of farm animals: effects of journey duration on animal welfare. AB - Transport of farm animals gives rise to concern about their welfare. Specific attention has been given to the duration of animal transport, and maximum journey durations are used in legislation that seek to minimise any negative impact of transport on animal welfare. This paper reviews the relatively few scientific investigations into effects of transport duration on animal welfare in cattle, sheep, horses, pigs and poultry. From the available literature, we attempt to distinguish between aspects, which will impair welfare on journeys of any duration, such as those associated with loading, and those aspects that may be exacerbated by journey time. We identify four aspects of animal transport, which have increasing impact on welfare as transport duration increases. These relate to (i) the physiological and clinical state of the animal before transport; and - during transport - to (ii) feeding and watering; (iii) rest and (iv) thermal environment. It is thus not journey duration per se but these associated negative aspects that are the cause of compromised welfare. We suggest that with a few exceptions, transport of long duration is possible in terms of animal welfare provided that these four issues can be dealt with for the species and the age group of the animals that are transported. PMID- 22445409 TI - A note on overdispersion as an index of behavioural synchrony: a pilot study in dairy cows. AB - We developed a method for studying the synchrony of behaviour based on calculations of overdispersion of a binomial process. The lying behaviour of cows was investigated under two different housing units inside the same barn. The first unit housed 30 cows undergoing conventional milking and the second unit housed 27 cows undergoing automatic milking. The lying behaviour of the cows was observed over 3 weeks in 12 periods of 6 h each. Every 5 min, we counted the number of cows lying down in the cubicles. As external cues, like feeding and conventional milking, can promote synchrony in dairy cows, we expected that cows conventionally milked would show more behavioural synchrony than automatically milked cows. Cows lied down synchronously in both units (overdispersion 1.67, P < 0.01). Lying synchrony tended to be slightly bigger in automatically than in conventionally milked cows (overdispersion 1.76 v. 1.58, P = 0.09), although the proportion of cows lying down was on average greater in conventionally than in automatically milked cows (60.7% v. 45.6%). This suggests that synchronized lying behaviour in cows is a constant phenomenon that depends on social facilitation rather than on external cues. The overdispersion index appears to be a useful tool for studying the synchrony of animal behaviour when observations are made at the group level. PMID- 22445410 TI - No apparent effect of an experimental narrow confinement on heart activity and cortisol in domestic pigs. AB - The effects of continuing spatial restraint were examined in domestic pigs. For this purpose, the animals (German Landrace barrows) were housed individually in metabolic cages (12 animals) and, as controls, in single pens (six animals). In six replications with two experimental animals and one control animal, we collected saliva each morning (0730 h) for the cortisol analysis, recorded the behaviour and the heart beat for 3 h/day (0800 to 0900 h, 1100 to 1200 h, 1400 to 1500 h). Each replication consisted of 5 days of habituation to single housing and 8 experimental days during which the experimental animals lived continuously in the metabolic cages. Weight gain, cortisol, heart rate and heart rate variability were not significantly affected by experimental narrow confinement that only had a significant influence on the behaviours, locomotion and sitting. In conclusion, the experimental animals adapted very fast and did not show physiological indications of chronic stress. However, the absence of apparent stress does not exclude other, subtler, welfare impairments. PMID- 22445411 TI - A family of protein growth curves with extension to other chemical body components together with application to animal nutrition and improvement. AB - Theory that successfully explains the magnitude and range of estimates of protein retention (PR) efficiency from the cost of turnover of existing protein indicates that conventional curves for growth description are inappropriate for protein growth. A solution to this problem is found in the consideration that the rate limiting steps for protein synthesis (PS) and breakdown are likely to be associated with the diffusion of metabolites in and between cells. The algebraic scaling of nuclear and cellular diffusion capacity with tissue or total body protein leads to a parameterization of the primal differential equation for PR (kg/day) based on two terms representing PS and breakdown, viz.where c is an arbitrary constant, Q is the proportion of nuclei active in cell growth or division in a tissue or the whole body, alpha is the limit mass for protein (P, kg) in a tissue or the whole body, the power X + Z represents the rate-limiting steps in protein breakdown and Y is the power of the relationship between cell volume and the amount of tissue protein. For the whole body, the contribution of the different tissues should be weighted in proportion to their PS rates with, on average, Y = 1/2. The constant 4/9 arises from the scaling of the specific diffusion rate of DNA activator precursors from nuclear dimensions and from the relationship between nuclear and cell volume. Experimental evidence on protein breakdown rate as well as protein and body mass points of inflection indicates that the range of theoretically possible numerical values of the rate-limiting powers X + Z = (i + 3)/9 for i = 1, 2, ... ,12 seems adequate for the description of the range of observed whole body protein and body mass growth patterns for mammals. Q = 1 represents maximal protein retention, and for 0 < Q < 1, experimental evidence exists in support of a theoretical relationship between Q and food ingestion. The conclusion follows that some knowledge of the protein limit mass (alpha) and of the point of inflection (related to X + Z) is the main requirement for the application of the theory for description and prediction in animal nutrition and breeding. PMID- 22445412 TI - Enteric and manure-derived methane and nitrogen emissions as well as metabolic energy losses in cows fed balanced diets based on maize, barley or grass hay. AB - Ruminant husbandry constitutes the most important source of anthropogenic methane (CH4). In addition to enteric (animal-derived) CH4, excreta are another source of CH4, especially when stored anaerobically. Increasing the proportion of dietary concentrate is often considered as the primary CH4 mitigation option. However, it is unclear whether this is still valid when diets to be compared are energy balanced. In addition, non-structural carbohydrates and side effects on nitrogen (N) emissions may be important. In this experiment, diet types representing either forage-only or mixed diets were examined for their effects on CH4 and N emissions from animals and their slurries in 18 lactating cows. Apart from a hay only diet, treatments included two mixed diets consisting of maize stover, pelleted whole maize plants and gluten or barley straw and grain and soy bean meal. The diets were balanced in crude protein and net energy for lactation. After adaptation, data and samples were collected for 8 days including a 2-day CH4 measurement in respiratory chambers. Faeces and urine, combined proportionately according to excretion, were used to determine slurry-derived CH4 and N emissions. Slurry was stored for 15 weeks at either 14 degrees C or 27 degrees C, and temperatures were classified as 'cool' and 'warm', respectively. The low-starch hay-only diet had high organic matter and fibre digestibility and proved to be equally effective on the cows' performance as mixed diets. The enteric CH4 formation remained unaffected by the diet except when related to digested fibre. In this case emission was lowest with the hay-only diet (61 v. 88 to 101 g CH4/kg digested NDF). Feeding the hay diet resulted in the highest slurry-CH4 production after 7 weeks of storage at 14 degrees C and 27 degrees C, and after 15 weeks at 14 degrees C. CH4 emissions were, in general, about 10-fold higher at 27 degrees C compared with 14 degrees C but only after 15 weeks of storage. Urinary N losses were highest with the barley diet and lowest with the maize diet. There was a trend towards similar differences in N losses from the slurry of these cows (significant at 14 degrees C). However, contrary to CH4, slurry-N emissions seemed to be temperature-independent. In conclusion, energetically balanced diets proved to be widely equivalent in their emission potential when combining animal and their slurry, this even at a clearly differing forage : concentrate ratio. The variation in CH4 emission from slurry stored shortly or at cold temperature for 15 weeks was of low importance as such conditions did not support methanogenesis in slurry anyway. PMID- 22445413 TI - Probiotics - do they have a role in the pig industry? AB - The delivery of certain living microorganisms in food has long been suggested as having positive health effects in humans. This practice has extended into food animal production, with a variety of microorganisms being used; lactic acid bacteria, various Bacillus species and the yeast Saccharomyces cerevisiae have been particularly used in the pig industry. The increased interest in probiotics is essentially due to the problem of microbial resistance to antibiotics and following the ban of the use of antibiotics in animal production, probiotics being considered an alternative means to reduce pathogen infection and improve animal health especially around the time of weaning. However, there is still a need to clarify the probiotic effectiveness in pigs, and the underlying mechanisms. When assessing the efficacy of probiotics one must consider the particular strain of organism being used and the production stage of the pigs being treated. The reproducible delivery of probiotics in industrial pig production is problematic as maintenance of viability is key to their beneficial activity, but difficult to achieve with commonly used feed processing technologies. One specific context where probiotics organisms may be reliably delivered is in systems utilising fermented liquid feeds. Liquid feed may be fermented by the activity of wild lactic acid bacteria or may be stimulated using specific isolates as 'starters'; the latter system has advantages in terms of reproducibility and speed of fermentation. The farm context in which the organism is used is likely to be critical; the use of probiotics is more likely to result in measurable economic gains in animals living in sub-optimal conditions rather than in those reared in the highest welfare and husbandry conditions. The establishment of a beneficial lactic acid bacteria population at birth may lead to healthier animals, this may be most effectively achieved by treating sows, which provide an amplification step and flood the neonatal pigs' environment with desirable bacterial strains. In contrast, it may be sufficient to provide a supportive, protective microbiota around the time of weaning as this is a time of major crisis with instability and loss of certain bacterial populations. PMID- 22445414 TI - Adjusting homestead feeding to requirements and nutrient intake of grazing goats on semi-arid, subtropical highland pastures. AB - Intensive livestock grazing can largely deplete the natural fodder resources in semi-arid, subtropical highlands and together with the low nutritional quality of the pasture vegetation limit the growth and production of grazing animals. To evaluate the contribution of homestead feeding of grazing goats to rangeland conservation and animal nutrition, two researcher-managed on-farm trials were conducted in a mountain oasis of Northern Oman. Goats' feed intake on pasture in response to four rations containing different levels of locally available green fodder and concentrate feeds was determined in six male goats each (35 +/- 10.2 kg body weight (BW)). Total feed intake was estimated using titanium dioxide as external fecal marker as well as the diet organic matter (OM) digestibility derived from fecal crude protein concentration. The nutritional quality of selected fodder plants on pasture was analyzed to determine the animals' nutrient and energy intake during grazing. The pasture vegetation accounted for 0.46 to 0.65 of the goats' total OM intake (87 to 107 g/kg0.75 BW), underlining the importance of this fodder resource for the husbandry system. However, metabolizable energy (7.2 MJ/kg OM) and phosphorus concentrations (1.4 g/kg OM) in the consumed pasture plants were low. Homestead feeding of nutrient and energy rich by-products of the national fishery and date palm cultivation to grazing goats increased their daily OM intake (R2 = 0.36; P = 0.005) and covered their requirements for growth and production. While the OM intake on pasture was highest in animals fed a concentrate-based diet (P = 0.003), the daily intake of 21 g OM/kg0.75 BW of cultivated green fodder reduced the animals' feed intake on pasture (R2 = 0.44; P = 0.001). Adjusting homestead supplementation with locally available feedstuffs to the requirements of individual goats and to the nutritional quality of the pasture vegetation improves animal performance and eases the grazing pressure exerted on the natural vegetation. This management strategy therefore appears to be a valuable alternative to intensive livestock feeding in zero-grazing systems and may contribute to sustainable livestock production in ecologically fragile, semi-arid mountain regions. PMID- 22445415 TI - Variation in meat quality characteristics between Sanga (Bos taurus africanus) and Sanga-derived cattle breeds and between Sanga and Brahman (Bos indicus). AB - Cattle breeds indigenous to Africa (Sanga) compare favourably to Bos indicus breeds with regard to adaptation to harsh environments. This study compared the meat quality of three Sanga breeds (Nguni, Tuli and Drakensberger), a Sanga related breed (Bonsmara) and a B. indicus breed (Brahman) and supported these results with biochemical and histological measurements on the M. longissimus lumborum. Twelve young grain-fed steers of each breed were slaughtered and carcasses were electrically stimulated. All Sanga (and related) breeds, with the exception of the Tuli, had lower Warner-Bratzler shear force (SF) values at 2 and 21 days post mortem compared with the BR (P < 0.05). Measurements related to the calcium-dependent protease system and myofibrillar fragmentation explained the bulk of the variation among breeds, whereas variation in fibre type, sarcomere length and connective tissue properties gave less convincing support. With the exception of the Tuli, Sanga and Sanga-related breeds produced more tender (according to SF) meat than BR, mainly due to favourable calpain-to-calpastatin ratios. Small differences in colour, drip loss and cooking properties were found among breeds (P < 0.05). PMID- 22445416 TI - A systematic review of the recurrence rate for keratocystic odontogenic tumour in relation to treatment modalities. AB - This systematic review was undertaken to determine the overall and detailed recurrence rate of keratocystic odontogenic tumour in relation to specific treatment methods. Online electronic databases were searched to identify articles published in English language from 1956 to 2010. Articles were independently appraised by two reviewers in three separate rounds. Any disagreement was settled by discussion with a third judge. Of 1568 potentially relevant articles, 168 articles related to the treatment of keratocystic odontogenic tumour/parakeratinised type of odontogenic keratocyst and its recurrence rate entered the second round for evaluation. Fourteen papers entered the third round for critical appraisal. Two retrospective reviews entered the final analysis. One hundred eight lesions were found in the material analysed. Six treatment modalities were identified. The recurrence rates were 0% for resection, 0% for enucleation with peripheral ostectomy and Carnoy's solution, 18.18% for enucleation with peripheral ostectomy, 26.09% for enucleation alone, 40% for marsupialisation, and 50% for enucleation with Carnoy's solution. The overall recurrence rate was 23.15%. The present review discusses the methodological weaknesses of many of the studies analysed. No high quality evidence was obtained to evaluate recurrence rates related to treatment modalities of keratocystic odontogenic tumour. PMID- 22445417 TI - Mechanisms of IFN-gamma-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. AB - BACKGROUND: Enhanced apoptosis of keratinocytes is the main cause of eczema and spongiosis in patients with the common inflammatory skin disease atopic dermatitis (AD). OBJECTIVE: The aim of the study was to investigate molecular mechanisms of AD-related apoptosis of keratinocytes. METHODS: Primary keratinocytes isolated from patients with AD and healthy donors were used to study apoptosis by using annexin V/7-aminoactinomycin D staining. Illumina mRNA Expression BeadChips, quantitative RT-PCR, and immunofluorescence were used to study gene expression. In silico analysis of candidate genes was performed on genome-wide single nucleotide polymorphism data. RESULTS: We demonstrate that keratinocytes of patients with AD exhibit increased IFN-gamma-induced apoptosis compared with keratinocytes from healthy subjects. Further mRNA expression analyses revealed differential expression of apoptosis-related genes in AD keratinocytes and skin and the upregulation of immune system-related genes in skin biopsy specimens of chronic AD lesions. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-gamma in primary keratinocytes. The protein expression of IFITM1, CCL5, and CCL8 was verified in AD skin. In line with the functional studies and AD-related mRNA expression changes, in silico analysis of genome-wide single nucleotide polymorphism data revealed evidence of an association between AD and genetic markers close to or within the IFITM cluster or RAB31, DUSP1, and ADM genes. CONCLUSION: Our results demonstrate increased IFN-gamma responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD. PMID- 22445418 TI - Review of risk and protective factors of substance use and problem use in emerging adulthood. AB - This review examines the evidence for longitudinal predictors of substance use and abuse in emerging adulthood. Nationally representative data from the 2007 National Survey on Drug use and Health suggest that many substance use problems reach their peak prevalence during emerging adulthood (usually defined as the period from age 18 to age 26). This stage of development is characterized by rapid transitions into new social contexts that involve greater freedom and less social control than experienced during adolescence. Concurrent with this newfound independence is an increase in rates of substance use and abuse. Understanding the risk and protective factors associated with emerging adult substance use problems is an important step in developing interventions targeting those problems. While multiple reviews have examined risk and protective factors for substance use during adolescence, and many of these earlier predictors may predict emerging adult substance use, few studies have focused primarily on the emerging adult outcomes examining predictors from both adolescence and emerging adulthood. This review used the databases PubMed and PsycInfo to identify articles pertaining to longitudinal predictors of substance use problems in emerging adulthood, building from the conceptual framework presented in a review on risk and protective factors for adolescent substance abuse by Hawkins and colleagues (Hawkins, Catalano, & Miller, 1992). Predictors identified as predictors of substance use in adolescence, sometimes decreased in strength and in one case reversed direction. Unique predictors in emerging adulthood were also identified. Implications for prevention science during adolescence and emerging adulthood are discussed as well as suggestions for future research. PMID- 22445419 TI - Dimensions of impulsivity among heavy drinkers, smokers, and heavy drinking smokers: singular and combined effects. AB - Alcohol use and cigarette smoking commonly co-occur. The role impulsivity may play as a common underlying mechanism in alcohol use and cigarette smoking is of particular interest due to emerging evidence of it being a critical component across multiple forms of addiction. Impulsivity can be examined through several constructs including, risky decision-making, response inhibition, and delay reward discounting. Impulsivity and each of these specific constructs play significant roles in the initiation of drug use, continued use despite negative consequences, and potential to relapse. This study used three behavioral tasks to measure risky decision-making (balloon analog risk test; BART), response inhibition (stop signal task; SST), and delay reward discounting (delay discounting task; DDT). This study advances research on impulsivity and substance use by parsing out the various components of impulsivity and examining them across three groups, heavy drinkers only (HD) (N=107), smokers only (S) (N=67), and heavy drinking smokers (HDS) (N=213). Participants completed questionnaires, interviews, and neurocognitive tasks including the SST, BART, and DDT. Analyses supported an additive effect of alcohol and nicotine use in delay reward discounting. Heavy drinking smokers displayed steeper delay discounting of small rewards than did smokers only (p<.05) and heavy drinkers only (p<.05). This additive effect of smoking and drinking was not observed for risky decision making and response inhibition, suggesting specificity of the effects for delay reward discounting. These findings indicate that those who both drink heavily and smoke cigarettes daily have increased delay reward discounting, than those in the S and HD groups. Future studies should examine these constructs longitudinally, as well as incorporate genetic and/or a neuroimaging component to these group comparisons in order to ascertain the biological bases of these behavioral findings. PMID- 22445421 TI - Expanding data and resources for forensic use of SNPs in individual identification. AB - The potential value of SNPs for individual identification has been recognized by many researchers and different panels have been proposed. Here we present a new interface in the ALFRED database to access compendia of allele frequencies for several published panels of markers for forensic uses. One of those is our panel of individual identification SNPs (IISNPs) based on samples of 44 populations originating from many parts of the world. Here we also present additional data and additional statistical analyses that continue to support the value of our panel of IISNPs as a universal panel. We also describe initial developments of multiplex methods and various robustness analyses for our 45 marker IISNP panel. PMID- 22445420 TI - Signaling the mitochondrial unfolded protein response. AB - Mitochondria are compartmentalized organelles essential for numerous cellular functions including ATP generation, iron-sulfur cluster biogenesis, nucleotide and amino acid metabolism as well as apoptosis. To promote biogenesis and proper function, mitochondria have a dedicated repertoire of molecular chaperones to facilitate protein folding and quality control proteases to degrade those proteins that fail to fold correctly. Mitochondrial protein folding is challenged by the complex organelle architecture, the deleterious effects of electron transport chain-generated reactive oxygen species and the mitochondrial genome's susceptibility to acquiring mutations. In response to the accumulation of unfolded or misfolded proteins beyond the organelle's chaperone capacity, cells mount a mitochondrial unfolded protein response (UPR(mt)). The UPR(mt) is a mitochondria-to-nuclear signal transduction pathway resulting in the induction of mitochondrial protective genes including mitochondrial molecular chaperones and proteases to re-establish protein homeostasis within the mitochondrial protein folding environment. Here, we review the current understanding of UPR(mt) signal transduction and the impact of the UPR(mt) on diseased cells. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 22445422 TI - Awareness of and attitudes toward congenital cytomegalovirus infection among pregnant women in Singapore. AB - OBJECTIVE: To assess the level of awareness of congenital cytomegalovirus (CMV) infection and attitudes toward prenatal CMV serologic testing among pregnant women. METHODS: A questionnaire was distributed to pregnant women who attended a specialist outpatient clinic at Singapore General Hospital, Singapore, between September and December 2010. RESULTS: Among 200 respondents, 40 (20.0%) were aware of CMV. Healthcare workers were more likely to be aware of CMV (odds ratio 6.91, confidence interval 2.14-22.30; P=0.001). Most respondents found it "very" or "somewhat" easy to adhere to standard guidelines for primary prevention of CMV. Among the respondents, 62.0% (124/200) would like to be given the option of prenatal CMV screening and 72.0% (144/200) were keen to be screened. On multivariate analysis, respondents who were keen to undergo serologic screening for CMV were not more likely to consider invasive testing or termination of pregnancy should the test results demonstrate primary maternal CMV infection. CONCLUSION: Pregnant women who were keen to undergo CMV testing demonstrated attitudes toward invasive testing and termination of pregnancy that were not significantly different from those of women who would refuse testing. Patient choice and expectations should be considered in the implementation of preventive measures against congenital CMV. PMID- 22445423 TI - Influence of early self-diagnosis and treatment of bacterial vaginosis on preterm birth rate. AB - OBJECTIVE: To assess whether early self-diagnosis and treatment of bacterial vaginosis (BV) could lower the preterm birth rate among a group of Indonesian women. METHODS: A randomized controlled trial of 331 pregnant women (14-18 weeks) was conducted. Participants were randomly assigned to either the active model group (n=176) or the control group (n=155). Women in the active model group were equipped with a kit to self-evaluate vaginal pH; those with a positive test result were treated with a twice daily dose of 500 mg of metronidazole for 7 days. The primary end point was preterm birth rate. RESULTS: There were 6 (3.8%) and 8 (5.4%) preterm births in the active model and control groups, respectively (P=0.468). No spontaneous abortions were recorded in either group. When compared with the gold standard (Gram staining), the vaginal acidity test had low ability to detect BV, with 88.7% specificity and 36.9% sensitivity. The positive predictive value of the test was 35.0% PPV, while the negative predictive value was 89.4%. CONCLUSION: Early self-diagnosis and treatment of BV did not reduce the preterm birth rate of the study group. ClinicalTrial.govnumber:NCT01232192. PMID- 22445424 TI - Effects of transvaginal repair of symptomatic rectocele on symptom-specific distress and impact on quality of life. AB - OBJECTIVE: To determine symptom-specific distress and quality-of-life impact outcomes among women who had undergone transvaginal repair of symptomatic rectocele. METHODS: Women who underwent transvaginal repair of symptomatic rectocele at the University of Alabama at Birmingham, USA, between April 2006 and June 2009 were included in a retrospective case series. Minimum follow-up was 1 year post-surgery. Women who underwent concomitant surgery, other than perineoplasty and/or midurethral sling, were excluded. End points were assessed using the Pelvic Floor Distress Inventory (PFDI-20) and the Pelvic Floor Impact Questionnaire (PFIQ-7). RESULTS: Overall, 113 women underwent repair of symptomatic rectocele, of whom 69 (61.1%) completed preoperative questionnaires and 66 (58.4%) responded to follow-up questionnaires. Mean time from surgery was 31.2+/-11.2 months. PFDI-20 and PFIQ-7 scores were significantly improved following surgery, with a median pre- and post-surgery difference of 35.4 (P<0.001) and 31.0 (P=0.002), respectively. CONCLUSION: Patients who underwent transvaginal repair of symptomatic rectocele reported improvements in symptom specific distress and impact on quality of life. PMID- 22445425 TI - Neonatal outcome following long-distance air travel for fetoscopic laser coagulation treatment of twin-to-twin transfusion syndrome. AB - OBJECTIVE: To investigate the impact of undertaking long-distance air travel to a specialized medical center while pregnant in order to undergo fetoscopic laser coagulation (FLC) for twin-to-twin transfusion syndrome (TTTS). METHODS: A retrospective cohort study was conducted of women with TTTS who travelled by air (n=16) or land (n=61) to the Centre of Perinatal Diagnosis and Microinvasive Fetal Surgery, Mainz, Germany, between January 1, 2006, and December 31, 2010. All women underwent FLC on arrival at the study center. Neonatal outcome, postoperative neonatal survival rates, and rates of adverse effects were recorded. RESULTS: The postoperative survival rate for a single twin was 100.0% (n=16) in the flight group and 98.3% in the land transportation group (n=60). The postoperative survival rate for both twins was 81.3% in the flight group (n=13) and 75.4% (n=46) in the land transportation group. No differences in neonatal outcome or the rate of adverse effects were observed between the 2 groups. No flight-related pregnancy complications were recorded. CONCLUSION: Long-distance air travel to a specialized tertiary care medical center is sufficiently safe to warrant recommendation to pregnant women with TTTS who require FLC. PMID- 22445426 TI - A new type of absorbable barbed suture for use in laparoscopic myomectomy. AB - OBJECTIVE: To compare effectiveness, feasibility, and suturing time required between an absorbable barbed wire (V-Loc) uterine suture and a classic continuous suture with intracorporeal knots among women undergoing laparoscopic myomectomy. METHODS: From January 2010 to February 2011, women with single symptomatic intramural myoma were prospectively enrolled in a single-center study at a university hospital in Rome, Italy. A control group with characteristics meeting the criteria for study inclusion was retrospectively identified from the hospital databases. In the prospective group uterine wall defects were closed with V-Loc suture, whereas in the control group they were closed by classical continuous suture with intracorporeal knots. Data were analyzed via Student t test, Mann Whitney U test, and Fisher exact test. RESULTS: The mean operative time was shorter in the V-Loc (51+/-18.1 min) than in the control (58+/-17.8 min) group. Suturing time was significantly lower in the V-Loc than in the control (9.9+/-4.3 versus 15.8+/-4.7 min; P=0.0004) group. Both intraoperative bleeding and drop in hemoglobin were significantly lower in the V-Loc group (P=0.0076 and P=0.0176, respectively). CONCLUSION: Use of a barbed suture may aid surgeons during laparoscopic suturing by reducing operative time, suturing time, and blood loss. PMID- 22445427 TI - Treatment of twin reversed arterial perfusion sequence with alcohol ablation or bipolar cord coagulation. AB - OBJECTIVE: To evaluate perinatal outcome in pregnancies complicated by TRAP sequence. METHODS: The perinatal outcomes of 15 TRAP sequence pregnancies referred to Kanuni Sultan Suleyman Research and Teaching Hospital, Turkey, were evaluated. Six cases were treated conservatively. Alcohol ablation and bipolar coagulation were performed in 5 and 4 cases, respectively. RESULTS: In 12 cases, there were signs of fetal compromise and acardiac/pump twin abdominal circumference ratio of more than 50%. In 3 cases without intervention, the ratio was less than 50%. Three of the 6 pregnancies treated conservatively resulted in intrauterine death of the pump twin. Alcohol ablation was successful in 3 cases, with delivery of live fetuses at 36-38 weeks, whereas intrauterine death occurred in 1 case and abortion occurred in 1 case. In 2 of the cases involving bipolar cord coagulation, live birth occurred at 39 weeks; preterm premature rupture of membranes and abortion occurred at 18 weeks in 1 case, and pregnancy was terminated in 1 case because of ventriculomegaly. CONCLUSION: Conservative therapy is suitable for mild cases of TRAP sequence in which the pump twin dominates. If there are signs of pump twin compromise, alcohol ablation and bipolar cord coagulation can be performed successfully. PMID- 22445428 TI - Cisplatin induces platelet apoptosis through the ERK signaling pathway. AB - Cisplatin (cis-diamminedichloroplatinum II) is one of the most widely used anti tumor agents. However, cisplatin-based chemotherapy is usually accompanied by adverse side effects such as thrombocytopenia, and the mechanism remains unclear. Here we show that cisplatin induced several platelet apoptotic events including up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-X(L), mitochondrial translocation of Bax, mitochondrial inner transmembrane potential depolarization, caspase-3 activation and phosphatidylserine (PS) exposure. Cisplatin dose-dependently induced activation of extracellular signal-regulated protein kinase (ERK) in platelets. Caspase-3 inhibitor z-DEVD-fmk dramatically inhibited cisplatin-induced caspase-3 activation and PS exposure without affecting ERK activation. Blockade of the ERK pathway significantly prevented platelet apoptosis. Furthermore, levels of reactive oxygen species (ROS) and Ca(2+) were significantly elevated by cisplatin, and scavenging of ROS and Ca(2+) obviously inhibited platelet apoptosis induced by cisplatin. In addition, cisplatin did not induce platelet activation, whereas it obviously impaired platelet functions. These data indicate that cisplatin induces platelet apoptosis through the ERK signaling pathway, which might contribute to cisplatin-related haematological toxicity. PMID- 22445429 TI - Outcomes of management of acute coronary syndrome in patients with congenital bleeding disorders: a single center experience and review of the literature. AB - INTRODUCTION: Evidence-based guidelines for the management of acute coronary syndrome (ACS) in patients with congenital bleeding disorders are lacking and largely confined to case reports. METHODS: Outcomes of acute and long-term management of ACS in patients with mild hemophilia and von Willebrand disease managed at our institution from 2000-2011 were reviewed. RESULTS: Between 2000 2011, 8 patients (median age 74 years) experienced 10 ACS events. In the emergency room, 3 of 4 patients received aspirin 325 mg and intravenous unfractionated heparin therapy, with no acute bleeding complications. The 8 patients underwent 10 coronary angiography procedures. Prophylactic factor concentrates were not administered for 6/10 (60%) of the procedures; bleeding complications (groin hematoma) occurred in 1/6 (17%). Two patients receiving bare metal stents and glycoprotein IIb/IIIa inhibitor infusion with factor concentrates experienced no acute hemorrhagic complications. On discharge, aspirin was initiated/continued in 6/10 events; the 2 patients receiving dual anti-platelet therapy for 1 month did not receive factor concentrates and experienced no bleeding complications. During a median follow-up of 8.5 years (1 11.5 years), 2 of 5 patients developed minor bleeding complications while on aspirin. CONCLUSION: Our data demonstrate that in patients with mild congenital bleeding disorders, despite not receiving factor concentrates prior to coronary angiography, the acute management of ACS did not result in severe hemorrhagic complications. Short-term dual anti-platelet therapy seemed to be well tolerated. In patients receiving long-term aspirin for secondary prevention for ACS, bleeding complications were mild, however such patients warrant close follow-up. PMID- 22445430 TI - A novel anti-platelet peptide (Z4A5) potential for glycoprotein IIb/IIIa inhibits platelet aggregation. AB - INTRODUCTION: Z4A5 is a novel peptide that inhibits platelet aggregation and formation of platelet thrombi, but the mechanism of its anti-platelet effects remains unknown. This study explores the anti-platelet effect and mechanism of Z4A5. METHODS: We investigated the anti-platelet activity of Z4A5 on platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA) and thrombin (TH) in human platelet-rich plasma (PRP). Fibrinogen and PAC-1 binding to glycoproteinIIb/IIIa (GPIIb/IIIa) were measured by flow cytometry. In addition, we investigated the integrin specificity of Z4A5 in attachment and detachment assays using human umbilical vein endothelial cells (HUVEC) and assessed the relative cell number using the MTT assay. RESULTS: In vitro, Z4A5 inhibited ADP-, AA- and TH-induced human platelet aggregation with IC(50) values of 0.46 +/- 0.05 MUM (n = 10), 0.23 +/- 0.0 5 MUM (n = 10) and 0.21 +/- 0.02 MUM (n = 10), respectively. Z4A5 inhibited fibrinogen, and PAC-1 bound to platelet GPIIb/IIIa with IC(50) values of 0.48 +/- 0.07 MUM (n = 8) and 0.63 +/- 0.12 MUM (n = 6), respectively. Z4A5 failed to inhibit alpha(V)beta(3) integrin-mediated HUVEC attachment to vitronectin and did not cause any significant detachment of HUVEC monolayer when compared with the controls. CONCLUSIONS: Z4A5 is a potential anti-platelet drug that inhibits fibrinogen binding to GPIIb/IIIa, but does not affect the structurally similar integrin alpha(V)beta(3). PMID- 22445431 TI - Body weight and composition in users of levonorgestrel-releasing intrauterine system. AB - BACKGROUND: There is little information about body weight and body composition (BC) among users of the levonorgestrel-releasing intrauterine system (LNG-IUS). The aim of this study was to evaluate body weight and BC in LNG-IUS users compared to users of the TCu380A intrauterine device (IUD). STUDY DESIGN: A prospective study was done with 76 new users of both contraceptive methods. Women were paired by age (+/-2 years) and body mass index (BMI, kg/m2, +/-2). Body weight and BC (% lean mass and % fat mass) were evaluated by a trained professional at baseline and at 1 year of contraceptive use. The BC measurements were obtained using Lunar DXA equipment. Weight and BC were evaluated in each woman at baseline and at 12 months and analyzed as the mean change within each woman. Then, the changes in weight and BC for each woman were calculated and then compared between LNG-IUS and TCu380A IUD users (paired data for each woman). The central-to-peripheral fat ratio was calculated by dividing trunk fat by the upper and lower limb fat. RESULTS: There were no significant differences at time of IUD insertion between LNG-IUS and TCu380A IUD users regarding age (mean+/-SD) (34.4+/ 7.5 vs. 33.9+/-8.0 years), BMI (25.3+/-4.1 vs. 25.9+/-4.1) and number of pregnancies (1.9+/-0.2 vs. 1.7+/-0.2), respectively. Mean body weight gain of 2.9 kg was observed among LNG-IUS users at 12 months (p=.0012), whereas the body weight of TCu380A IUD users only increased by 1.4 kg (p=.067). There was no significant difference in body weight change between the two groups of users at 12 months. The variation in the central-to-peripheral fat ratio was the same between the two groups (-1.6% vs. -0.2%; p=.364). LNG-IUS users showed a 2.5% gain in fat mass (p=.0009) and a 1.4% loss of lean mass, whereas TCu380A IUD users showed a loss of 1.3% of fat mass (p=.159) and gain of 1.0% of lean mass (p=.120). TCu380A IUD users gained more lean mass than LNG-IUS users (p=.0270), although there was no significant difference between the two groups after 12 months of use. CONCLUSIONS: Although an increase in mean fat mass among LNG-IUS users at 12 months of use was observed, it should be noted that an increase of body weight was also observed in both groups after 1 year of insertion of the device. However, a study with a larger number of women and long-term evaluation is necessary to evaluate these body changes. PMID- 22445432 TI - Condom type may influence sexual behavior and ejaculation and complicate the assessment of condom functionality. AB - BACKGROUND: Studies that evaluate condom effectiveness are affected by factors related to how the condom was used, and these factors may not be consistent between different types of condoms. Also, subjective assessments of the sexual act may be unreliable. STUDY DESIGN: We performed a secondary data analysis of a randomized crossover trial of male and female condoms among 108 couples. RESULTS: Self-reported duration and activeness of coital acts were significantly different for uses of the male condom compared to uses of the female condom. Fewer individuals reported ejaculation occurring with the female condom. Reliability of self-reports of ejaculation compared to a biological marker of semen detected inside the used male and female condoms was not strong. CONCLUSIONS: We found that sexual behaviors appear to differ by the type of condom used for the coital act. Studies should consider sexual behavior when evaluating condom effectiveness. Furthermore, studies would be strengthened by the use of a biological marker of semen to determine whether ejaculation, and therefore a true risk of exposure, occurred. PMID- 22445433 TI - Comment on research article: "Co-prescription of antiepileptic drugs and contraceptives". PMID- 22445435 TI - The antifertility effectiveness of a novel copper-containing composite used in intrauterine contraceptive devices and the releasing behavior of cupric ions contained in the composite in rats. AB - BACKGROUND: This study was conducted to investigate the antifertility effectiveness of a novel copper-containing composite used in intrauterine contraceptive devices (IUDs) that contain cupric chloride/silicon dioxide/poly(vinyl alcohol) (CuCl2/SiO2/PVA) and the releasing behavior of cupric ions in the composite into the serum and uterine fluid in rats. STUDY DESIGN: Two hundred and forty sexually mature female Sprague-Dawley rats were randomly divided into six groups: sham-operated control group (n=20), bulk copper group (Cu group, n=40), SiO2/PVA group (n=40), CuCl2/SiO2/PVA groups I (n=40, copper ion was released from IUD at a rate of 5-10 mcg/220 mm2 per day) and II (n=40, copper ion was released from IUD at a rate of 10-20 mcg/220 mm2 per day), and normal control group (n=20). IUD was inserted into the uterus of rats after acclimatization of 1 week. At different time points after implantation of the IUDs, cupric ion concentrations were measured in the serum and local uterine fluid in each group by flame atomic absorption, respectively. After 30 days of insertion, half of the rats in each group were mated with fertile male rats, and the antifertility rates were observed at 14 days of pregnancy. After the IUDs were removed, the remaining rats in each group were mated again to determine their fertility. RESULTS: Antifertility rates in the Cu group and CuCl2/SiO2/PVA groups I and II were 100%, and each of these rates was significantly higher than that in the other groups (p<.05). There were no differences in fertility restoration rates after the IUD was removed among the Cu group and the CuCl2/SiO2/PVA group (p>.05). No significant change in time dependence was found for the serum cupric ion concentrations in each group (p>.05), while the local uterine fluid cupric ion concentrations in the other groups were significantly lower than those in the Cu group (p<.05) and without a burst release of cupric ions in the initial days of application. CONCLUSIONS: The novel copper-containing composite used in intrauterine contraceptive devices (CuCl2/SiO2/PVA composite IUD) had a low pregnancy rate and high contraceptive efficacy without a burst release of cupric ions in the initial days of application. PMID- 22445436 TI - Evaluation of efficacy, safety and effects on symptoms of androgenization of a generic oral contraceptive containing chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg. AB - BACKGROUND: This prospective noninterventional study assessed the contraceptive efficacy, safety and the effects on signs of androgenization of the generic oral contraceptive containing 2 mg chlormadinone acetate/0.03 mg ethinylestradiol (CMA/EE) in a real-world setting. STUDY DESIGN: A total of 1440 women were investigated during a six-cycle period by 229 gynecological practices throughout Germany. RESULTS: The adjusted Pearl index was 0.136 (unadjusted: 0.271). Of 463 patients with cycle irregularities at baseline, 83.4% had regular cycles after six cycles. Likewise, 74.1% of 162 patients with spotting or breakthrough bleeding at baseline were free from these symptoms at the end of study. The percentage of patients with dysmenorrhea decreased significantly from baseline (36.5%) to visit 3 after six cycles (12.3%; p=.0001), with a significant reduction in the use of pain medication (p<.0001). Additionally, the number of patients with skin and hair problems was significantly reduced (skin: 56.3% at baseline, 19.6% after six cycles; hair: 45.7% at baseline, 13.4% after six cycles; p=.001). CMA/EE was well tolerated by the patients, and 89.44% of the gynecologists were satisfied with the treatment. CONCLUSION: Generic CMA/EE exhibits very good contraceptive efficacy, cycle control and dysmenorrhea reduction. Furthermore, treatment with generic CMA/EE led to a favorable reduction of skin and hair problems in our study. PMID- 22445437 TI - Discriminant analysis of the metabolic effects of a new combined contraceptive vaginal ring containing Nestorone/EE vs. a second-generation oral contraceptive containing levonorgestrel/EE. AB - BACKGROUND: Discriminant analysis (DA) was performed on data of two combined hormonal contraceptives (CHC) differing in estrogen ratio to explore whether a combination of variables rather than a single variable distinguishes CHCs better. STUDY DESIGN: Data were used of a parallel study in premenopausal women treated for three cycles (21 days on, 7 days off) with a contraceptive vaginal ring delivering Nestorone and ethinyl estradiol (EE) or an oral contraceptive containing levonorgestrel and EE. DA was performed on the change from baseline (CFB) and the end-of-treatment values at 3 months for lipids, sex-hormone binding globulin (SHBG), C-reactive protein, angiotensinogen, blood pressure and hemostasis variables, and on the hemostasis variables only. RESULTS: For the complete set, the CFB for factor VII (FVII), SHBG and plasminogen (PLG), or end of-treatment SHBG- and FVII level discriminated the treatments best. Maximal discrimination for the hemostasis data was by CFB for FVII and PLG or end-of treatment FVII level. CONCLUSIONS: DA identifies differences between CHCs and may provide information on the factors associated with thrombotic risk. PMID- 22445438 TI - Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women. AB - BACKGROUND: We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E2V) and dienogest (DNG). STUDY DESIGN: CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E2V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC(0-24 h)] and maximum serum concentration (C(max)) of E2 and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E2V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC(0 24 h) and C(max) of E2 and DNG on days 7 and 14 are presented. RESULTS: Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E2C(max) and AUC(0-24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E2 of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C(max) and AUC(0-24 h) of both E2 and DNG. Geometric mean ratios of C(max) and AUC(0-24 h) for E2 were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively. CONCLUSIONS: Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E2V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable. PMID- 22445439 TI - Tailored health messaging improves contraceptive continuation and adherence: results from a randomized controlled trial. AB - BACKGROUND: Discontinuation and incorrect use of contraceptive methods may contribute to as many as 1 million unintended pregnancies annually in the United States. Interventions to improve contraceptive method continuation and adherence are needed. STUDY DESIGN: A three-arm randomized controlled trial was conducted at two family planning sites testing the efficacy of a computer-based contraceptive assessment module in increasing the proportion of patients who continued use of their chosen contraceptive method 4 months after the family planning visit (n=224). RESULTS: In analyses adjusting for clinical site of recruitment, family planning patients who used the module and received individually tailored health materials (n=78), compared to those in the control group (n=70), were significantly more likely to continue use of their chosen contraceptive method [95% compared to 77%; odds ratio (OR)=5.48; 95% confidence interval (CI): 1.72-17.42] and to adhere to their method (86% compared to 69%; OR=2.74; 95% CI: 1.21-6.21). No significant differences in these outcomes were found for participants who used the module but did not receive tailored materials (n=76), compared to the control group. CONCLUSIONS: Tailored health materials significantly improved contraceptive method continuation and adherence. Additional research on the impact of the intervention on continuation and adherence in a larger sample and over a longer follow-up period is merited. PMID- 22445440 TI - Complications of surgical termination of second-trimester pregnancy in obese versus nonobese women. AB - BACKGROUND: Obesity is becoming increasingly common in obstetric and gynecologic populations, which may affect the safety of surgical termination of pregnancy. STUDY DESIGN: We performed a retrospective review of all patients undergoing second-trimester surgical termination of pregnancy by under ultrasound guidance termination between 13 0/7 and 24 0/7 weeks of gestational age (GA) to compare perioperative risks in obese and nonobese women. Complication rates, operative times and anesthesia times were compared between obese [body mass index (BMI) >=30 kg/m2] and nonobese women (BMI <30). RESULTS: Of 1044 women, 29.0% were obese. The mean complication rate was 6.1% and similar between groups (5.5% nonobese, 7.6% obese, p=.20). Operative times were 4.4 min longer and mean anesthesia times were 5 min longer in obese patients (p<.001 for each). There was a nonsignificant trend toward more complications with gestational ages above 18 weeks (5.5% vs. 7.7%, p=.20). A history of one or more cesarean sections had an independent association with major complications after adjustment for confounders (adjusted odds ratio 4.2, p=.001). CONCLUSIONS: Both anesthesia and operative times were modestly increased in obese women versus nonobese women undergoing second-trimester surgical termination, without significant differences in complication rates. For patients at advanced GA with prior cesarean delivery, clinicians should be aware of the potential increase in complications as well as increased operative time in obese women, and counsel appropriately. PMID- 22445441 TI - A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. AB - BACKGROUND AND PURPOSE: It remains undetermined whether the addition of ezetimibe to ongoing statin therapy is more effective than increasing the dose of statin for reducing remnant lipoprotein levels in patients with remnant lipoproteinemia on previous statin treatment. This study examined whether combined ezetimibe and statin therapy resulted in a greater improvement in remnant lipoprotein levels and endothelial function than with the dose of statin in patients with remnant lipoproteinemia on previous statin treatment. METHODS AND RESULTS: A total of 63 patients with stable coronary artery disease and high levels of remnant-like lipoprotein particle cholesterol (RLP-C) (>=5.0 mg/dL) on statin treatment were assigned randomly to two groups and treated with either addition of ezetimibe (10mg/day, n=32) or doubling of statin dose (n=31). The lipid profiles and flow mediated dilation (FMD) of the brachial artery were measured at enrollment and after 6 months of treatment. Statin and ezetimibe combined therapy reduced RLP-C and improved FMD to a greater extent than doubling the statin dose (% reduction in RLP-C, 48 +/- 18% vs. 33 +/- 24%, respectively, p=0.01; % improvement in FMD, 47 +/- 48% vs. 24 +/- 23%, respectively, p=0.02). CONCLUSIONS: The addition of ezetimibe to ongoing statin treatment reduced RLP-C levels and improved endothelial dysfunction to a greater extent than doubling the statin dose in patients with high RLP-C levels on previous statin treatment. The present results are preliminary and should be confirmed by further studies on a larger number of study patients. PMID- 22445442 TI - Confocal Raman microscopic analysis of the zirconia/feldspathic ceramic interface. AB - OBJECTIVES: Esthetic demands and biocompatibility have prompted the development of all-ceramic dental crowns. Yttria tetragonal zirconia polycrystalline (Y-TZP) framework material has the best mechanical properties compared to other all ceramic systems, but the interface is the weakest component of core veneered restorations. Confocal Raman microscopy possibilities are used to ensure the understanding of the zirconia-feldspathic ceramic relationship, which is not well known. METHODS: Bilayered zirconia (Vita In-Ceram((r)) YZ) veneer (Vita VM((r))9) blocks were manufactured. Raman analyses were performed using two protocols: (1) single spectra, line scans and images on a sectioned and polished specimen and (2) in depth line scans on unprepared specimen. Single spectra, images and line scans provide information about the crystalline phases, their distribution and the existence of a possible diffusion at the Y-TZP/VM((r))9 interface, respectively. The elemental distribution of zirconium (Zr) and silicon (Si) around this interface were investigated using energy dispersive X-ray spectroscopy (EDS). RESULTS: Raman single spectra embodied a unique spectrum (crystalline) on Y-TZP and two spectra (crystalline and amorphous) on VM((r))9; these spectra were clearly distinguished. Raman line scans showed a series of transition spectra across the interface from VM((r))9 to Y-TZP. It emphasized an interdiffusion zone, which was estimated at a maximum of 2 microns, found on 2d Raman images and confirmed by EDS. The elemental distribution with EDS showed a mutual diffusion of Zr and Si and was mainly dominated by Si diffusion in Y-TZP. SIGNIFICANCE: Confocal Raman microscopy highlights an interdiffusion zone at the zirconia-feldspathic ceramic interface. The elemental transition layer is estimated and is supported by EDS analysis as a coupling technique. PMID- 22445443 TI - Increased titers of anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients with reduced H-ficolin levels but normal MASP-2 activity. AB - BACKGROUND AND AIMS: Mannan-binding lectin (MBL) and ficolins are microbial pattern recognition molecules that activate the lectin pathway of complement. We previously reported the association of MBL deficiency with anti-Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn's disease (CD). However, ASCA are also frequently found in MBL-proficient CD patients. Here we addressed expression/function of ficolins and MBL-associated serine protease-2 (MASP-2) regarding potential association with ASCA. METHODS: ASCA titers and MBL, ficolin and MASP-2 concentrations were determined by ELISA in the serum of patients with CD, ulcerative colitis (UC), and in healthy controls. MASP-2 activity was determined by measuring complement C4b-fixation. Anti-MBL autoantibodies were detected by ELISA. RESULTS: In CD and UC patients, L-ficolin concentrations were significantly higher compared to healthy controls (p<0.001 and p=0.029). In contrast, H-ficolin concentrations were slightly reduced in CD and UC compared to healthy controls (p=0.037 for UC vs. hc). CD patients with high ASCA titers had significantly lower H-ficolin concentrations compared to ASCA-low/negative CD patients (p=0.009). However, MASP-2 activity was not different in ASCA-negative and ASCA-positive CD patients upon both, ficolin- or MBL-mediated MASP-2 activation. Finally, anti-MBL autoantibodies were not over-represented in MBL proficient ASCA-positive CD patients. CONCLUSIONS: Our results suggest that low expression of H-ficolin may promote elevated ASCA titers in the ASCA-positive subgroup of CD patients. However, unlike MBL deficiency, we found no evidence for low expression of serum ficolins or reduced MASP-2 activity that may predispose to ASCA development. PMID- 22445444 TI - A systematic survey instrument translation process for multi-country, comparative health workforce studies. AB - BACKGROUND: As health services research (HSR) expands across the globe, researchers will adopt health services and health worker evaluation instruments developed in one country for use in another. This paper explores the cross cultural methodological challenges involved in translating HSR in the language and context of different health systems. OBJECTIVES: To describe the pre-data collection systematic translation process used in a twelve country, eleven language nursing workforce survey. DESIGN AND SETTINGS: We illustrate the potential advantages of Content Validity Indexing (CVI) techniques to validate a nursing workforce survey developed for RN4CAST, a twelve country (Belgium, England, Finland, Germany, Greece, Ireland, Netherlands, Norway, Poland, Spain, Sweden, and Switzerland), eleven language (with modifications for regional dialects, including Dutch, English, Finnish, French, German, Greek, Italian, Norwegian, Polish, Spanish, and Swedish), comparative nursing workforce study in Europe. PARTICIPANTS: Expert review panels comprised of practicing nurses from twelve European countries who evaluated cross-cultural relevance, including translation, of a nursing workforce survey instrument developed by experts in the field. METHODS: The method described in this paper used Content Validity Indexing (CVI) techniques with chance correction and provides researchers with a systematic approach for standardizing language translation processes while simultaneously evaluating the cross-cultural applicability of a survey instrument in the new context. RESULTS: The cross-cultural evaluation process produced CVI scores for the instrument ranging from .61 to .95. The process successfully identified potentially problematic survey items and errors with translation. CONCLUSIONS: The translation approach described here may help researchers reduce threats to data validity and improve instrument reliability in multinational health services research studies involving comparisons across health systems and language translation. PMID- 22445445 TI - A longitudinal study of semantic memory impairment in patients with Alzheimer's disease. AB - INTRODUCTION: The present study explored the nature of the semantic deterioration normally displayed in the course of Alzheimer's disease (AD). The aim was to disentangle the extent to which semantic memory problems in patients with AD are best characterized as loss of semantic knowledge rather than difficulties in accessing semantic knowledge. METHOD: A longitudinal approach was applied. The same semantic tests as well as same items were used across three test occasions a year apart. Twelve Alzheimer patients and 20 matched control subjects, out of a total of 25 cases in each group, remained at the final test occasion. RESULTS AND CONCLUSIONS: Alzheimer patients were impaired in all the semantic tasks as compared to the matched comparison group. A progressing deterioration was evident during the study period. Our findings suggest that semantic impairment is mainly due to loss of information rather than problems in accessing semantic information. PMID- 22445446 TI - A sensational illusion: vision-touch synaesthesia and the rubber hand paradigm. AB - For individuals with vision-touch synaesthesia, the sight of touch on another person elicits synaesthetic tactile sensation on the observer's own body. Here we used the traditional rubber hand paradigm (Botvinick and Cohen, 1998) and a no touch rubber hand paradigm to investigate and to authenticate synaesthetic tactile sensation. In the traditional rubber hand paradigm, the participant views a prosthetic hand being touched by the Examiner while the participant's hand - hidden from view - is also touched by the Examiner. Synchronous stimulation of the prosthetic hand and the participant's hidden hand elicits the rubber hand illusion. It may seem to the participant that she is feeling touch at the location of the viewed prosthetic hand - visual capture of touch, and that the prosthetic hand is the participant's own hand - illusion of ownership. Thus, for participants who experience the traditional rubber hand illusion, tactile sensation on the participant's hidden hand is referred to the prosthetic hand. In our no-touch rubber hand paradigm, the participant views a prosthetic hand being touched by the Examiner but the participant's hand - hidden from view - is not touched by the Examiner. Questionnaire ratings indicated that only individuals with vision-touch synaesthesia experienced the no-touch rubber hand illusion. Thus, synaesthetic tactile sensation on the (untouched) hidden hand was referred to the prosthetic hand. These individuals also demonstrated proprioceptive drift (a change, from baseline, in proprioceptively perceived position) of the hidden hand towards the location of the prosthetic hand, and a pattern of increased proprioceptive drift with increased trial duration (60 sec, 180 sec, 300 sec). The no-touch rubber hand paradigm was an excellent method to authenticate vision touch synaesthesia because participants were naive about the rubber hand illusion, and they could not have known how they were expected to perform on either the traditional or the no-touch rubber hand paradigm. PMID- 22445447 TI - Gene trees, species trees, and morphology converge on a similar phylogeny of living gars (Actinopterygii: Holostei: Lepisosteidae), an ancient clade of ray finned fishes. AB - Extant gars represent the remaining members of a formerly diverse assemblage of ancient ray-finned fishes and have been the subject of multiple phylogenetic analyses using morphological data. Here, we present the first hypothesis of phylogenetic relationships among living gar species based on molecular data, through the examination of gene tree heterogeneity and coalescent species tree analyses of a portion of one mitochondrial (COI) and seven nuclear (ENC1, myh6, plagl2, S7 ribosomal protein intron 1, sreb2, tbr1, and zic1) genes. Individual gene trees displayed varying degrees of resolution with regards to species-level relationships, and the gene trees inferred from COI and the S7 intron were the only two that were completely resolved. Coalescent species tree analyses of nuclear genes resulted in a well-resolved and strongly supported phylogenetic tree of living gar species, for which Bayesian posterior node support was further improved by the inclusion of the mitochondrial gene. Species-level relationships among gars inferred from our molecular data set were highly congruent with previously published morphological phylogenies, with the exception of the placement of two species, Lepisosteus osseus and L. platostomus. Re-examination of the character coding used by previous authors provided partial resolution of this topological discordance, resulting in broad concordance in the phylogenies inferred from individual genes, the coalescent species tree analysis, and morphology. The completely resolved phylogeny inferred from the molecular data set with strong Bayesian posterior support at all nodes provided insights into the potential for introgressive hybridization and patterns of allopatric speciation in the evolutionary history of living gars, as well as a solid foundation for future examinations of functional diversification and evolutionary stasis in a "living fossil" lineage. PMID- 22445448 TI - Random roots and lineage sorting. AB - Lineage sorting has been suggested as a major force in generating incongruent phylogenetic signal when multiple gene partitions are examined. The degree of lineage sorting can be estimated using the coalescent process and simulation studies have also pointed to a major role for incomplete lineage sorting as a factor in phylogenetic inference. Some recent empirical studies point to an extreme role for this phenomenon with up to 50-60% of all informative genes showing incongruence as a result of lineage sorting. Here, we examine seven large multi-partition genome level data sets over a large range of taxonomic representation. We took the approach of examining outgroup choice and its impact on tree topology, by swapping outgroups into analyses with successively larger genetics distances to the ingroup. Our results indicate a linear relationship of outgroup distance with incongruence in the data sets we examined suggesting a strong random rooting effect. In addition, we attempted to estimate the degree of lineage sorting in several large genome level data sets by examining triads of very closely related taxa. This exercise resulted in much lower estimates of incongruent genes that could be the result of lineage sorting, with an overall estimate of around 10% of the total number of genes in a genome showing incongruence as a result of true lineage sorting. Finally we examined the behavior of likelihood and parsimony approaches on the random rooting phenomenon. Likelihood tends to stabilize incongruence as outgroups get further and further away from the ingroup. In one extreme case, likelihood overcompensates for sequence divergence but increases random rooting causing long branch repulsion. PMID- 22445449 TI - Genetic diversity of mountain plants: two migration episodes of Mediterranean Erodium (Geraniaceae). AB - This paper examines the phylogeny of Erodium subsect. Petraea, a group of six morphologically and genetically very similar species from the mountains of the western Mediterranean. Combined trnL-F-ITS analysis was unable to determine the phylogenetic relationships of these species owing to sequence similarity. AFLP fragment analysis showed different populations to cluster in six closely related phylogroups that partially coincided with morphological species. In the Iberian Peninsula, high temperatures during interstadial periods probably impeded the survival of these species at low altitudes, and their populations may have been forced to migrate northward within Iberia or remain isolated on high mountains. AFLP variation suggests that this might have led to their differentiation into groups and speciation during interglacials, but it probably also provided the basis for recurrent recolonisations and the mixing of neighbouring populations at the last glacial maxima. The genetic diversity of the two Erodium lineages suggests two migration episodes took place from southern Iberia towards the north, with one lineage migrating via western Iberia and the other via eastern Iberia. The patterns of genetic diversity observed in populations of 56 European species (27 genera) leads to the hypothesis that disparate proportions of unique polymorphic fragments are the result of the evolutionary histories of their mountain populations irrespective of the currently recognised species. PMID- 22445450 TI - Induction of oxidative stress in brain of glutaryl-CoA dehydrogenase deficient mice by acute lysine administration. AB - In the present work we evaluated a variety of indicators of oxidative stress in distinct brain regions (striatum, cerebral cortex and hippocampus), the liver, and heart of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice. The parameters evaluated included thiobarbituric acid-reactive substances (TBA RS), 2-7-dihydrodichlorofluorescein (DCFH) oxidation, sulfhydryl content, and reduced glutathione (GSH) concentrations. We also measured the activities of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD) and glucose-6-phosphate dehydrogenase (G6PD). Under basal conditions glutaric (GA) and 3-OH-glutaric (3OHGA) acids were elevated in all tissues of the Gcdh(-/-) mice, but were essentially absent in WT animals. In contrast there were no differences between WT and Gcdh(-/-) mice in any of the indicators or oxidative stress under basal conditions. Following a single intra-peritoneal (IP) injection of lysine (Lys) there was a moderate increase of brain GA concentration in Gcdh(-/-) mice, but no change in WT. Lys injection had no effect on brain 3OHGA in either WT or Gcdh(-/-) mice. The levels of GA and 3OHGA were approximately 40% higher in striatum compared to cerebral cortex in Lys-treated mice. In the striatum, Lys administration provoked a marked increase of lipid peroxidation, DCFH oxidation, SOD and GR activities, as well as significant reductions of GSH levels and GPx activity, with no alteration of sulfhydryl content, CAT and G6PD activities. There was also evidence of increased lipid peroxidation and SOD activity in the cerebral cortex, along with a decrease of GSH levels, but to a lesser extent than in the striatum. In the hippocampus only mild increases of SOD activity and DCFH oxidation were observed. In contrast, Lys injection had no effect on any of the parameters of oxidative stress in the liver or heart of Gcdh(-/-) or WT animals. These results indicate that in Gcdh(-/-) mice cerebral tissue, particularly the striatum, is at greater risk for oxidative stress than peripheral tissues following Lys administration. PMID- 22445451 TI - The potential benefits of hydrogen-rich saline in ischemia and reperfusion injury. PMID- 22445452 TI - The necessity of indwelling gastrointestinal decompression after gastrectomy: a meta-analysis. AB - BACKGROUND: This meta-analysis was designed to evaluate the necessity of indwelling gastrointestinal decompression after gastrectomy. METHODS: Medline, Embase, and the Cochrane Library were searched. We identified randomized controlled trials that compared individuals with or without gastrointestinal decompression after gastrectomy, and a meta-analysis was performed on data regarding the recovery time of gastrointestinal function, length of hospital stay, complications, and mortality using fixed effect and random effect models. RESULTS: Eight randomized controlled trials that had enrolled 975 patients were included in the present study. The difference in the interval to oral intake (weighted mean difference 0.56, 95% confidence interval [CI] 0.16-0.96, P = 0.006) between the decompression group and nondecompression group was significant, but no significant differences were found in the interval to flatus (weighted mean difference 0.24, 95% CI -0.13 to 0.61, P = 0.20) or length of hospital stay (weighted mean difference 1.04, 95% CI -0.05 to 2.14, P = 0.06). Additionally, no significant differences were found in complications, including nausea or vomiting (odds ratio [OR] 1.23, 95% CI 0.57-2.65, P = 0.59), fever (OR 1.55, 95% CI 0.96-2.51, P = 0.07), pulmonary complications (OR 1.41, 95% CI 0.82 2.43, P = 0.22), anastomotic leakage (OR 1.15, 95% CI 0.55-2.40, P = 0.70), paralytic ileus or small bowel obstruction (OR 1.80, 95% CI 0.57-5.70, P = 0.32), intra-abdominal abscess (OR 1.08, 95% CI 0.50-2.34, P = 0.84), wound infection (OR 1.29, 95% CI 0.56-2.96, P = 0.55), or wound dehiscence (OR 1.47, 95% CI 0.43 4.95, P = 0.54) between the two groups. A sensitivity analysis of the pooled data from high-quality studies and studies with >20 cases per group showed that the length of hospital stay was prolonged significantly in the decompression group compared with the nondecompression group. CONCLUSIONS: Routine gastrointestinal decompression after gastrectomy does not promote the recovery of gastrointestinal function or reduce the incidence of postoperative complications. In our series, decompression was correlated with a prolonged interval to oral intake, a longer duration of hospitalization, and increased patient discomfort. PMID- 22445453 TI - Fibrin-thrombin coated sealant increases strength of esophagogastric anastomoses in a rat model. AB - BACKGROUND: Anastomotic leakage is a feared complication after esophagectomy. The purpose of this study was to investigate whether the use of a fibrin-thrombin coated collagen patch (TachoSil; Nycomed, Zurich, Switzerland), applied as a sealant, would strengthen the esophagogastric anastomosis and stimulate anastomotic healing in a rat model. METHODS: Hand sewn, end-to-side esophagogastric anastomoses were performed in 54 rats. Animals were randomized for an unsealed or sealed anastomosis. Rats were sacrificed on postoperative d 0, 3, 5, and 7. Primary parameter was bursting pressure. Secondary outcomes were complications, weight, and immunohistochemical staining for collagen formation and fibroblast activity. RESULTS: Bursting pressure at d 0 and 3 was significantly increased when a sealant was used (55.1 +/- 4.6 mmHg versus 102.4 +/- 7.3 mmHg, P < 0.010; and 19.7 +/- 3.3 mmHg versus 34.6 +/- 4.9 mmHg, P < 0.050 respectively). There was no difference in bursting pressure at d 5 and 7 between unsealed and sealed anastomoses (60.9 +/- 18.2 mmHg versus 53.4 +/- 6.6 mmHg, P = 0.690; and 118.8 +/- 20.2 mmHg versus 97.2 +/- 8.3 mmHg, P = 0.374 respectively). Application of sealant independently influenced bursting pressure (P < 0.010). Increased fibroblastic activity was noticed at d 7 in sealed anastomoses (P < 0.050). There were no differences in weight gain between groups. CONCLUSIONS: Additional sealing of the anastomosis increased anastomotic strength during early postoperative recovery when anastomotic strength is at its weakest. The findings indicate that sealing of the anastomosis has the potential to prevent leakage after esophagectomy in humans. PMID- 22445454 TI - The resident as surgeon: an analysis of ACS-NSQIP. AB - BACKGROUND: Data on the characteristics and outcomes of patients operated on by surgical residents are limited. METHODS: Using ACS-NSQIP (2005-2008), characteristics and outcomes of patients who underwent cholecystectomy, appendectomy, or inguinal hernia repair by a resident (R) without an attending scrubbed in the operating room, a scrubbed attending with resident (AR), or an attending without resident (A) were pooled and compared. Data analyses involved chi(2), ANOVA, and multivariate regression. RESULTS: The R group performed <1% of ACS-NSQIP cases; the 10 most common procedures represented 69.1% of cases. There were 912 cases of cholecystectomy, appendectomy, or inguinal hernia repair performed by R. Compared with A/AR patients, R patients were more likely to have inpatient (42.6%, 48.9% versus 64.8%), emergent (28.6%, 30.8% versus 35.5%) , and open procedures (27.0%, 29.4% versus 28.9%) (all P < 0.001). In unadjusted analyses, R patients had higher complication rates (4.8% versus 4.4%, 3.4%, P < 0.001) and longer operating time (64.4 min versus 62.2 min, 44.7 min, P < 0.001) than AR/A patients respectively. After risk adjustment, a resident operating without an attending scrubbed in the operating room was not independently associated with increased complications risk (odds ratio 1.2, 95% CI: 0.8-1.8, P = 0.2). Compared with A/AR patients, there was a 1-min difference in adjusted operating time for patients who underwent surgery by R (P < 0.001). CONCLUSIONS: In ACS-NSQIP, a resident rarely performs surgery without an attending scrubbed in the operating room; surgical attendings appear to exercise good judgment in determining the appropriate extent of resident supervision in the operating room without compromising patient outcomes. PMID- 22445455 TI - Single-stage laparoscopic sleeve gastrectomy: safety and efficacy in the super obese. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is increasingly used as a single-stage bariatric procedure. However, its safety and efficacy in super-obese patients (body mass index [BMI] > 50 kg/m(2)) is less well defined. This series reports on 400 consecutive patients who underwent LSG at our institution, to evaluate safety and efficacy in the super-obese. MATERIALS AND METHODS: We performed a retrospective review of prospectively collected data on 400 consecutive patients who underwent LSG at our institution. We analyzed baseline demographic data, median length of hospital stay, complications, length of follow up, weight loss, and comorbidity resolution. We graded complications according to the Clavien-Dindo classification system. We classified patients as super-obese and non-super-obese and compared outcomes between groups. We used the two-tailed t-test and Fisher's exact test as necessary. RESULTS: There were 400 patients, 291 of whom were female (73%). The mean age was 44 y (standard deviation [SD] +/- 9 y). The mean preoperative weight and BMI were 140 kg (SD +/- 31 kg) and 49 kg/m(2) (SD +/- 9 kg/m(2)), respectively. There were 67 complications (16%) in total. The major complication rate was 7.2%, with one recorded death. The median length of hospital stay was 3 d, and the mean follow-up period was 1 y. A total of 170 patients (43%) were super-obese, with a mean preoperative BMI of 56 kg/m(2) (SD +/- 5 kg/m(2)). The mean absolute weight loss (59 versus 36.7 kg; P < 0.01) and percentage excess weight loss (58.9% versus 45.9%; P < 0.01) was significantly higher in the super-obese. The mean postoperative BMI for super obese patients was 38.9 kg/m(2). There was no difference between groups in the incidence of major complications (8.2% versus 6.5%; P = 0.56). CONCLUSION: Laparoscopic sleeve gastrectomy is safe and effective in the super-obese, with acceptable weight loss and no increase in the major complication rate. PMID- 22445456 TI - Protective effect of dexmedetomidine in a rat model of alpha-naphthylthiourea induced acute lung injury. AB - BACKGROUND: We assessed the effects of dexmedetomidine in a rat model of alpha naphthylthiourea (ANTU)-induced acute lung injury. METHODS: Forty Wistar Albino male rats weighing 200-240 g were divided into 5 groups (n = 8 each), including a control group. Thus, there were one ANTU group and three dexmedetomidine groups (10-, 50-, and 100-MUg/kg treatment groups), plus a control group. The control group provided the normal base values. The rats in the ANTU group were given 10 mg/kg of ANTU intraperitoneally and the three treatment groups received 10, 50, or 100 MUg/kg of dexmedetomidine intraperitoneally 30 min before ANTU application. The rat body weight (BW), pleural effusion (PE), and lung weight (LW) of each group were measured 4 h after ANTU administration. The histopathologic changes were evaluated using hematoxylin-eosin staining. RESULTS: The mean PE, LW, LW/BW, and PE/BW measurements in the ANTU group were significantly greater than in the control groups and all dexmedetomidine treatment groups (P < 0.05). There were also significant decreases in the mean PE, LW, LW/BW and PE/BW values in the dexmedetomidine 50-MUg/kg group compared with those in the ANTU group (P < 0.01). The inflammation, hemorrhage, and edema scores in the ANTU group were significantly greater than those in the control or dexmedetomidine 50-MUg/kg group (P < 0.01). CONCLUSION: Dexmedetomidine treatment has demonstrated a potential benefit by preventing ANTU-induced acute lung injury in an experimental rat model. Dexmedetomidine could have a potential protective effect on acute lung injury in intensive care patients. PMID- 22445457 TI - A 9-Year retrospective review of antibiotic cycling in a surgical intensive care unit. AB - BACKGROUND: Six years after initiating a monthly antibiotic cycling protocol in the surgical intensive care unit (SICU), we retrospectively reviewed antibiogram derived sensitivities of predominant gram-negative pathogens before and after antibiotic cycling. We also examined susceptibility patterns in the medical intensive care unit (MICU) where antibiotic cycling is not practiced. MATERIALS AND METHODS: Antibiotic cycling protocol was implemented in the SICU starting in 2003, with monthly rotation of piperacillin/tazobactam, imipenem/cilastin, and ceftazidime. SICU antibiogram data from positive clinical cultures for years 2000 and 2002 were included in the pre-cycling period, and those from 2004 to 2009 in the cycling period. RESULTS: Profiles of SICU pseudomonal isolates before (n = 116) and after (n = 205) implementing antibiotic cycling showed statistically significant improvements in susceptibility to ceftazidime (66% versus 81%; P = 0.003) and piperacillin/tazobactam (75% versus 85%; P = 0.021), while susceptibility to imipenem remained unaltered (70% in each case; P = 0.989). Susceptibility of E. coli isolates to piperacillin/tazobactam improved significantly (46% versus 83%; P < 0.0005), trend analysis showing this improvement to persist over the study period (P = 0.025). Similar findings were not observed in the MICU. Review of 2004-2009 antibiotic prescription practices showed monthly heterogeneity in the SICU, and a 2-fold higher prescribing of piperacillin/tazobactam in the MICU (P < 0.0001). CONCLUSIONS: Six years into antibiotic cycling, we found either steady or improved susceptibilities of clinically relevant gram-negative organisms in the SICU. How much of this effect is from cycling is unknown, but the antibiotic heterogeneity provided by this practice justifies its ongoing use. PMID- 22445458 TI - Mitomycin-C-treated peripheral blood mononuclear cells (PBMCs) prolong allograft survival in composite tissue allotransplantation. AB - BACKGROUND: Composite tissue allotransplantation (CTA) was introduced as a potential treatment for complex reconstructive procedures and has become a clinical reality. Hand and face transplantation, the most widely recognized forms of CTA, have intensified immunological research in this emerging field of transplantation. Mitomycin C (MMC) is an alkylating agent that suppresses allogeneic T-cell responses. MMC-treated dendritic cells/PBMCs have been shown to induce donor-specific tolerance in solid organ allograft transplantations. METHODS: Fully mismatched rats were used as hind limb donors [Lewis (RT1(1))] and recipients [Brown-Norway (RT1(n))]. Fifty-five allogeneic hind limb transplantations were accomplished in six groups. Group A (n = 10) received donor derived MMC-treated PBMCs on transplantation day. Group B (n = 10) rats received no immunosuppression, group C (n = 10) received FK506 and prednisolon, group D consisted in isograft transplantation without immunosuppression, group E (n = 10) received non-treated PBMCs, and group F (n = 5) received PBS without any donor derived cells. Rejection was assessed clinically and histologically. RESULTS: In group A, the survival times of the allografts were prolonged to an average of 8.0 d. Rejection was significantly delayed compared with the averages of the corresponding control groups B, E, and F (5.5, 5.9, and 5.8 d). No rejection was seen in control groups C and D. CONCLUSION: These results demonstrate that MMC treated donor PBMCs significantly prolong allograft survival when administered systemically on the day of transplantation. However, the immunomodulatory effect is relatively modest with further research being required to clarify dose-effect relations, cell characteristics, and an optimized mechanism and timing for cell application. PMID- 22445459 TI - Energetic recovery in porcine grafts by minimally invasive liver oxygenation. AB - BACKGROUND: Gaseous insufflation of oxygen via the venous vascular system has proven to be an effective tool for preventing anoxic tissue injury after extended time periods of ischemic liver preservation. Most experimental studies so far have been undertaken in rat models and include a series of pinpricks into postsinusoidal venules as an outlet for the insufflated gas. Here, we describe a simplified technique for minimally invasive liver oxygenation in porcine grafts, representing a hassle-free access to organ oxygenation without vascular lesions. METHODS: We retrieved livers from Landrace pigs and cold-stored them in histidine tryptophan-ketoglutarate solution. Subsequent to 18 h preservation, we treated some livers for an additional 2 h with gaseous oxygen, insufflated via silicone tubing inserted into the suprahepatic caval vein. Gas pressure was limited to 18 mm Hg. We occluded the infrahepatic caval vein with a bulldog clamp. Gas bubbles left the graft via the portal vein. We assessed liver integrity by energetic tissue status and by controlled in vitro reperfusion with autologous blood. RESULTS: Magnetic resonance imaging demonstrated homogeneous gas distribution in the persufflated tissue without major shunting. Biochemical analyses revealed effective and homogeneous restoration of energetic homeostasis in the ischemic graft before reperfusion. Sinusoidal endothelial clearance of hyaluronic acid was significantly improved upon reperfusion, as was hepatic arterial flow. Parenchymal enzyme loss was concordantly mitigated after minimally invasive liver oxygenation. CONCLUSIONS: Our results indicate that gaseous oxygen persufflation of the porcine liver is possible without tissue trauma, and significantly enhances post-preservation recovery of the graft. PMID- 22445460 TI - Biological underpinnings of the commonalities in depression, somatization, and Chronic Fatigue Syndrome. AB - BACKGROUND: Somatization is a multisomatoform disorder characterized by medically unexplained, functional or psychosomatic symptoms. Similar somatic symptoms are key components of depression and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). METHODS: This paper reviews the evidence that such symptoms are organically based. We use the term "physio-somatic" to describe these symptoms. RESULTS: Inflammation, cell-mediated immune (CMI) activation and alterations in the tryptophan catabolite (TRYCAT) pathway are associated with the physio-somatic symptoms of depression, ME/CFS and/or somatization. Proinflammatory cytokines, decreased tryptophan and aberrations in TRYCATs may cause physio-somatic symptoms, such as fatigue, autonomic symptoms, hyperalgesia and somatic presentations. CONCLUSIONS: The data suggest co-ordinated and interacting biological pathways driving the occurrence of physio-somatic symptoms across these three disorders, giving a biologically validated "pathway phenotype". These data have far-reaching implications for DSM-IV diagnostic conceptualizations of somatization (and ME/CFS) suggesting the presence of an emerging organic explanation. Future research should focus on the role of immune regulation, and co-ordination, of neuronal activity and, through larger data sets, ultimately creating new, biologically validated classification rules. These data have implications for the development of novel therapies utilizing these insights, buttressing the role of psychotherapy in psychosomatic presentations. PMID- 22445461 TI - Niacin subsensitivity is associated with functional impairment in schizophrenia. AB - OBJECTIVE: Sensitivity to the skin flush effect of niacin is reduced in a portion of patients with schizophrenia. Though this peripheral physiological abnormality has been widely replicated, its relevance to neuropsychiatric manifestations of the illness has been unclear. The goal of this study was to determine if the niacin response abnormality in schizophrenia is associated with functional impairment. METHODS: Following psychiatric assessment, a Global Assessment of Functioning (GAF) score was assigned to each of 40 volunteers with schizophrenia. For each subject, the blood flow responses to several concentrations of topical methylnicotinate were recorded. Blood flow was measured objectively, using laser Doppler flowmetry. From the dose-response data, EC(50) values were derived. GAF scores were assigned without knowledge of the participants' niacin response data. RESULTS: There was a significant negative correlation between GAF scores and EC(50) values for methylnicotinate (Pearson r=-0.42; p=0.007). CONCLUSIONS: Reduced niacin sensitivity is associated with greater functional impairment among patients with schizophrenia. These findings raise the possibility that a subset of schizophrenia patients possesses a biochemical abnormality that reduces niacin sensitivity in the skin and contributes to functional impairment from the disease. PMID- 22445462 TI - Cognitive impairment is related to oxidative stress and chemokine levels in first psychotic episodes. AB - INTRODUCTION: This study measures the levels of various markers of oxidative stress and inflammation in blood samples from first-episode psychosis (FEP) patients, and examines the association between these peripheral biomarkers and cognitive performance at 6 months after treatment. METHODS: Twenty-eight FEP patients and 28 healthy controls (matched by age, sex and educational level) had blood samples taken at admission for assessment of total antioxidant status, superoxide dismutase (SOD), total glutathione (GSH), catalase (CAT), glutathione peroxidase, lipid peroxidation, nitrites and the chemokine monocyte chemoattractant protein-1 (MCP-1). A battery of cognitive tests was also applied to the healthy controls and those FEP patients who were in remission at 6 months after the acute episode. RESULTS: FEP patients had significantly lower levels of total antioxidant status, catalase and glutathione peroxidase, compared with the healthy controls. Regression analyses found that MCP-1 levels were negatively associated with learning and memory (verbal and working), nitrite levels were negatively associated with executive function, and glutathione levels were positively associated with executive function. CONCLUSION: Our results suggest an association between certain peripheral markers of oxidative stress and inflammation and specific aspects of cognitive functioning in FEP patients. Further studies on the association between MCP-1 and cognition are warranted. PMID- 22445463 TI - Self-determination and first-episode psychosis: associations with symptomatology, social and vocational functioning, and quality of life. AB - Self-determination theory (SDT) postulates that satisfaction of three basic psychological needs (i.e., autonomy, competence, and well-being) promotes motivation, well-being, and growth across domains of functioning. Thus, per SDT, we examined satisfaction of basic psychological needs among individuals with first-episode psychosis. First, we quantified the level of need satisfaction among a sample of individuals with first-episode psychosis and compared their level of need satisfaction to that of individuals without psychosis. Second, we examined the association between need satisfaction and several domains of well being among individuals with first-episode psychosis (i.e., symptomatology, social/vocational functioning, and quality of life). Our results indicated that individuals with first-episode psychosis experience less satisfaction of basic psychological needs as compared to their same-aged counterparts. There was a modest association between need satisfaction and well-being among individuals with first-episode, with the need of relatedness being the need most frequently associated with indices of well-being. Although modest in scope, the results of the current study raise the possibility that further investigation of SDT among individuals with first-episode psychosis may reveal important strategies through which early intervention services can better promote well-being and recovery. PMID- 22445464 TI - Apelin, a promising target for type 2 diabetes treatment? AB - Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM. PMID- 22445465 TI - Aseptic arthritis after ACL reconstruction by Tape Locking Screw (TLS(r)): report of two cases. AB - In Tape Locking Screw (TLS((r))) ligamentoplasty, transplant bone fixation uses polyethylene terephthalate (PET). We report two cases of aseptic arthritis following anterior cruciate ligament (ACL) reconstruction using this material. Diagnosis was founded on negative sampling and complete cure following arthroscopic lavage and synovectomy without curative antibiotherapy. This complication was also described with other synthetic materials used in this indication (Dacron, PFTE, carbon), and with PET as transplant material but never as bone fixation material. The physiopathological hypothesis is in terms of PET particle release in the suprapatellar bursa; sinking the strips into the bone as fully as possible on implantation could avoid impingement. Longer TLS((r)) ligamentoplasty series with adequate follow-up will be needed in order to estimate the true incidence of this complication. PMID- 22445466 TI - Impact of miR-7 over-expression on the proteome of Chinese hamster ovary cells. AB - MicroRNAs play critical roles in the regulation of biological processes such as growth, apoptosis, productivity and secretion thus representing a potential route toward enhancing desirable characteristics of mammalian cells for biopharmaceutical production. We have previously found that miR-7 over-expression significantly inhibits the growth of CHO-SEAP cells without impacting cellular viability, with an associated increase in normalised productivity. Understanding the biological basis of this effect might open the way to new strategies for bioprocess-relevant growth regulation. In this study we have carried out a quantitative label-free LC-MS profiling study of proteins exhibiting altered levels following over-expression of miR-7 to gain insights into potential mechanisms involved in the observed phenotype. From the analysis we found 93 proteins showing decreased levels and 74 proteins with increased levels following over-expression of miR-7. Pathway analysis suggests that proteins involved in protein translation (e.g. ribosomal proteins), RNA and DNA processing (including histones) are enriched in the list of proteins showing decreased expression. Proteins involved in protein folding and secretion were found to be up-regulated following miR-7 over-expression. In silico bioinformatic analysis using miRWalk, which combined the output from 6 selected miRNA target prediction algorithms, was used to evaluate if any of the down-regulated proteins were potential direct targets of miR-7. Two genes, stathmin and catalase, which both have known roles in the regulation of cellular growth, were found to overlap a number of the predictive target database searches in both mouse and rat, and are likely to be possible direct targets of miR-7 in CHO cells. This is the first report investigating the impact of a miRNA on the proteome of CHO cells. PMID- 22445467 TI - Myostatin gene silencing by RNA interference in chicken embryo fibroblast cells. AB - Myostatin (MSTN), a member of transforming growth factor-beta (TGF-beta) superfamily, is a negative regulator of the skeletal muscle growth, and suppresses the proliferation and differentiation of myoblast cells. Dysfunction of MSTN gene either by natural mutation or genetic manipulation (knockout or knockdown) has been reported to interrupt its proper function and to increase the muscle mass in many mammalian species. RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) has become a powerful tool for gene knockdown studies. In the present study transient silencing of MSTN gene in chicken embryo fibroblast cells was evaluated using five different shRNA expression constructs. We report here up to 68% silencing of myostatin mRNA using these shRNA constructs in transiently transfected fibroblasts (p<0.05). This was, however, associated with induction of interferon responsive genes (OAS1, IFN beta) (3.7-64 folds; p<0.05). Further work on stable expression of antimyostatin shRNA with minimum interferon induction will be of immense value to increase the muscle mass in the transgenic animals. PMID- 22445468 TI - GSTT1 gene abnormality in minimal change nephrotic syndrome with elevated serum immunoglobulin E. AB - INTRODUCTION: Imbalance between T-helper 1 (Th1) and 2 (Th2) lymphocytes and effects of reactive oxygen species (ROS) upon glomerular capillary walls have been implicated in minimal change nephrotic syndrome (MCNS). METHODS: By polymerase chain reaction and comparative genomic hybridization, we evaluated mutations of the GSTT1 gene (GSTT1), a member of the glutathione S-transferase (GST) supergene family associated with both protection of cells from ROS and control of allergic reactions and serum immunoglobulin (Ig) E. RESULTS: Among 15 children with MCNS, IgE elevation (over 2,000 IU/l) and GSTT1 deletion was found in 2 who showed severe allergic symptoms. Serum ROS concentrations in these 2 patients were significantly higher than in healthy controls or other MCNS patients. In addition, a Th2 shift caused by increased serum interleukin (IL)- 4 was observed. CONCLUSION: These results suggest presence of a GSTT1 abnormality in some children with MCNS having marked serum IgE elevations and various allergic complications. Defective ROS degradation and Th1/Th2 imbalance caused by GSTT1 abnormality could initiate proteinuria leading to MCNS. PMID- 22445469 TI - Gastrointestinal symptoms predict peritonitis rates in CAPD patients. AB - OBJECTIVE: Peritonitis is still one of the major causes of peritoneal dialysis (PD) patients' dropout. In the present study, we analyzed the relationship between gastrointestinal (GI) problems and peritonitis in our CAPD patients. METHODS: It is a prospective observational study. In December, 2008, 158 patients on continuous ambulatory peritoneal dialysis (CAPD) for more than 3 months from our PD unit were included in this study. A questionnaire was used to evaluate their GI symptoms score (GISS). All patients were followed up for 24 months or until they dropped out from our PD program. All peritonitis events were recorded. RESULTS: The patients' PD duration was 22 (4 - 132) months before the study. During the 24 months follow-up, 37 patients dropped out. And 37 patients had 46 episodes of peritonitis (peritonitis group) whereas the other 121 patients did not have peritonitis (peritonitisfree group). The overall peritonitis rate was one episode per 75.87 patient months. The peritonitis free group had lower GISS (1.35 +/- 1.94 vs. 2.95 +/- 3.19, p = 0.006), higher albumin level and longer dialysis duration at baseline as compared to the peritonitis group. Multivariate Cox-regression analysis showed that only GISS (OR 1.206, 95% CI 1.093 - 1.330) and dialysis duration (OR 1.018, 95% CI 1.006 - 1.031) were the risk factors for the time to first peritonitis episodes during the follow-up. Further analysis identified 2 GISS components, belching and constipation, as the strongest predictors of peritonitis during the follow-up period (p < 0.005). CONCLUSION: Our study showed that GI symptoms could predict peritonitis in CAPD patients. Prevention and treatment for GI problems may thus be helpful to decrease peritonitis rate. PMID- 22445470 TI - Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. AB - BACKGROUND: Endothelial dysfunction (ED) is a key event in the development of atherosclerotic cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Association of hyperuricemia with CVD has been previously reported in the nonuremic population. In this prospective study, we aimed to evaluate the effects of treatment of hyperuricemia with allopurinol on ED and changes in the serum reactive oxygen species in patients with CKD. METHODS: In this study, 19 (13 male) hyperuricemic (UA > 7 mg/dl) nondiabetic CKD patients without any comorbidity, aged < 60 years with creatinine clearance (CrCl) between 20 and 60 ml/min were evaluated. Endothelial functions were assessed by ischemia-induced forearm vasodilatation method (EDD). Oxidative stress was evaluated by measuring the serum oxidized LDL (ox-LDL), advanced oxidation protein products (AOPP) and nitrotyrosine (NT) levels. After measuring all these tests at baseline, allopurinol therapy was commenced for 8 weeks. After 8 weeks of allopurinol treatment, all measurements were repeated. Then, allopurinol treatment was ceased and same measurements were also repeated 8 weeks after ceasing of the treatment. RESULTS: Serum creatinine, total cholesterol, albumin, hs-CRP, CrCl and proteinuria levels of the patients were similar among three study periods. After allopurinol therapy, the mean serum UA and NT levels significantly reduced as compared to baseline. At the 8th week after cessation of allopurinol treatment, serum UA levels were significantly increased. After allopurinol therapy, EDD value increased from 5.42 +/- 8.3% at baseline to 11.37 +/- 9% (p < 0.001). At the 8th week after ceasing allopurinol treatment, EDD returned to baseline values (5.96 +/- 8%, p < 0.001). CONCLUSION: Treatment of hyperuricemia with allopurinol improve ED in patients with CKD. However, mechanism responsible for this beneficial effect seems to be apart from antioxidant effects of allopurinol. PMID- 22445471 TI - Renal histology in patients with elevated serum creatinine and concurrent normal urinalysis. AB - INTRODUCTION: Diagnosis of kidney disease is currently and primarily based on the measurement of serum creatinine, blood urea nitrogen, and urine output, and most kidney diseases with elevated serum creatinine accompany abnormal findings of urinalysis with microscopy, such as proteinuria or hematuria. The purpose of the current study was to determine the histologic diagnosis of patients with elevated serum creatinine and a concurrent normal urinalysis without underlying disease. METHODS: The medical records of patients who had undergone kidney biopsies between January 1, 2003 and March 1, 2008 in three medical centers were retrospectively reviewed. The patients with an elevated serum creatinine level and a normal urinalysis were enrolled. The exclusion criteria were as follows: diabetes mellitus; hypertension; chronic liver disease; malignancies; autoimmune diseases; dependence on medications; hypokalemic nephropathy; age < 18 years. Age, duration of follow-up, post-biopsy management, and the change in levels of BUN and serum creatinine from pre-biopsy to the last visit were analyzed. RESULTS: All 15 patients were included. The most frequent single diagnosis was acute interstitial interstitial nephritis, followed by hypertensive nephrosclerosis. Chronic interstitial nephritis, mesangial proliferative glomerulonephritis, acute tubular necrosis, secondary amyoloidosis, focal segmental glomerulosclerosis, and minor glomerular change were listed. The young group (< 40 years of age) included more patients with acute interstitial nephritis, and the old group (>= 40 years of age) included more patients with hypertensive nephrosclerosis. CONCLUSION: Based on a correct histological diagnosis, all of the patients, except one, were properly managed and had preserved kidney function until the last visit. PMID- 22445472 TI - Rituximab therapy for Type I membranoproliferative glomerulonephritis. AB - AIMS: Type I membranoproliferative glomerulonephritis (MPGN) is an immune-complex disease with a relatively poor prognosis. It has no established treatment in adults. Our hypothesis was that this disease would respond to B cell depletion with rituximab, an anti-CD20 monoclonal antibody. METHODS: We conducted an openlabel trial, in Canada and the United States, of rituximab in 6 adult patients with Type I MPGN (4 idiopathic, 2 with cryoglobulinemia). The rituximab dose was 1,000 mg intravenously on Day 1 and on Day 15. The patients were followed for 1 year. The primary outcome was the change in proteinuria. RESULTS: Peripheral blood B cells were suppressed, after rituximab, in all patients. The mean urinary protein excretion was 3.9 +/- 2.0 g/d before treatment. Proteinuria fell in all patients, at all-time points, after rituximab administration. The difference was statistically significant (p < 0.05) at 6, 9 and 12 months, but not at 3 months. The minimum mean urinary protein excretion was 1.4 +/- 1.4 g/d at 9 months. There were 2 complete and 3 partial remissions among the 6 patients. The creatinine clearance did not change significantly over the course of the study. There were no adverse effects. CONCLUSIONS: Rituximab reduced proteinuria among patients with Type I MPGN. This trial suggests that B cells may play a role in this disease and that additional study of B-cell suppression is warranted. PMID- 22445473 TI - Evaluation of T-Cell receptor diversity in pediatric patients with minimal change nephrotic syndrome. AB - AIMS: To further elucidate the clinical relevance of T-cell abnormalities in minimal change nephrotic syndrome (MCNS), and to predict the consequences of MCNS, we studied T-cell receptor (TCR) diversity by analyzing CDR3 size distribution and the frequency of Vbeta repertoire usage. METHODS: Participants comprised 36 pediatric patients with MCNS. 18 were frequent relapsers (FRs) and/or steroid-dependent (SD) and 18 were non-frequent relapsers (NFRs). Serial changes in TCR Vbeta repertoires were analyzed for these two groups of patients. Frequencies of Vbeta repertoire usage were determined by flow cytometry, and TCR CDR3 length distribution was analyzed by GeneScan. RESULTS: In NFRs, abnormalities in the distribution of Vbeta repertoires were few in both CD4+ and CD8+ T cells. In FRs/ SD patients, patterns were normal in CD4+ T cells, while selected Vbeta repertoires were significantly increased in CD8+ T cells in some patients. Furthermore, TCR diversity was significantly reduced in CD8+ T cells in FRs/SD patients, as shown by marked skewing of CDR3 size distributions. Of note was the finding that some FRs/SD patients showed improvements in the initially abnormal TCR diversity with improvement in clinical symptoms, eventually becoming NFRs. CONCLUSION: Analysis of TCR diversity may delineate the subgroup of FRs/SD patients and provide a rationale for early intervention with immunosuppressive therapy for these patients. PMID- 22445474 TI - Relation of homocysteine to early nephropathy in patients with Type 2 diabetes. AB - AIM: To explore the relationship between plasma total homocysteine concentration and diabetic nephropathy in patients with Type 2 diabetes. METHODS: Chinese patients with Type 2 diabetes (n = 183) were enrolled in a cross-sectional hospital based study. Early diabetic nephropathy status was documented by presence of microalbuminuria. Plasma total homocysteine concentration was measured using fluorescence polarization immunoassay. Traditional risk factors for diabetic nephropathy were obtained from fasting blood samples and interviewer questionnaire. RESULTS: Plasma total homocysteine levels were higher in subjects with early diabetic nephropathy than without (13.3 +/- 2.9) MUmol/l vs. (8.5 +/- 1.4) MUmol/l, p < 0.01). The association of homocysteine with the diabetic nephropathy was independent of major traditional risk factors for diabetic nephropathy (duration of diabetes, HbA1c, and blood pressure) and determinants of higher homocysteine concentration (age, gender, serum folate and vitamin B12, serum cystatin and creatinine levels, and Biguanide use) (OR: 1.37 (0.89 - 2.24), p < 0.05). Furthermore, per increase of 4.0 MUmol/l plasma homocysteine was related to nephropathy, after controlling for per unit increase of other factors (OR: 1.15 (0.94 - 1.29), p < 0.05). CONCLUSION: Plasma total homocysteine concentration was independently associated with occurrence of early diabetic nephropathy in Chinese patients. Future prospective studies are warranted to clarify the relationship. PMID- 22445475 TI - A comparison of measured and estimated glomerular filtration rate in successfully treated HIV-patients with preserved renal function. AB - BACKGROUND: Monitoring of renal function becomes increasingly important in the aging population of HIV-1 infected patients. We compared Cockroft & Gault (C&G), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Cystatin C- and 24 h urine-based estimated GFR (eGFR) with the gold standard, measured GFR (mGFR) using [125I]-iothalamate. METHODS: Substudy within a randomized, multinational trial comparing continuing zidovudine/ lamivudine with switching to tenofovir/ emtricitabine in patients with suppressed HIV-1 infection. Accuracy (defined as the mean difference between eGFR and mGFR) and precision (defined as standard deviation (SD) of the mean difference between eGFR and mGFR) of the eGFRs were calculated using linear regression and Bland & Altman analysis. RESULTS: We included 19 patients, 18 men, 15 Caucasian, mean (SD) age 46.0 y (+/- 8.9) and BMI 23.9 kg/m2 (+/- 3.0). Mean (SD) mGFR was 102 ml/min/1.73 m2 (+/- 19), 4 patients had mild renal dysfunction. All eGFRs tended to underestimate true GFR, with best accuracy for C&G (-1 ml/min/1.73 m2), CKD-EPI (-1 ml/min/1.73 m2), 24 hcreatinine clearance (-2 ml/min/1.73 m2) and MDRD-6 (0 ml/min/1.73 m2), and worst for cystatin C-based (-9 ml/min/1.73 m2) and MDRD-4 estimations (-10 ml/min/1.73 m2). Accuracy worsened at higher mGFR, but was not significantly influenced by age. C&G tended to overestimate at higher BMI. Precision was comparable for all GFR estimations. CONCLUSIONS: In this limited number of patients with preserved renal function and suppressed HIV-infection C&G and CKD-EPI appeared to be the best reflection of real GFR and most practical tool for monitoring GFR. PMID- 22445476 TI - Membranous nephropathy: a rare renal manifestation of IgG4-related systemic disease. AB - This is a case of IgG4-related systemic disease (ISD) and its rare renal manifestation as membranous nephropathy (MGN). The patient presented with peripheral edema, hematuria and proteinuria. 24-h urine revealed proteinuria of up to 15 g/d. Renal biopsy revealed MGN and many IgG4-positive plasma cells. Serum IgG4 levels were elevated at 750 mg/dl (9 - 89 mg/d). Biopsies of multiple tissues revealed many IgG4-positive plasma cells. Prednisone was initiated after making the diagnosis of ISD. However, the patient progressed into renal failure and eventually needed dialysis despite rituximab therapy. The renal manifestation of ISD typically shows tubulointerstitial nephritis, but, rarely, it may include glomerular abnormalities such as MGN or membranoproliferative glomerulonephritis. Castleman disease (CD) and ISD share similarities in pathology, particularly in the lymph nodes. Rituximab has shown promising results in some patients with ISD, CD, and MGN, and its use should be considered in steroid-resistant cases. Clinicians need to be made aware of ISD and its varied presentations. Timely initiation of steroid therapy can induce remission, and delay in therapy can cause permanent organ damage. Therefore, clinicians must have a high index of suspicion to make an early diagnosis of ISD in order to initiate appropriate treatment. PMID- 22445477 TI - Vancomycin levels are frequently subtherapeutic during continuous venovenous hemodialysis (CVVHD). AB - Continuous renal replacement therapy (CRRT) is frequently used in the intensive care setting for the treatment of acute kidney injury. Dosing guidelines for many commonly used antibiotics were established during intermittent dialysis or in studies examining CRRT at lower blood and dialysis flow rates than are used in common practice. Herein we present data demonstrating frequent subtherapeutic levels of vancomycin in a population of patients on CRRT. Nephrology trainees should be educated as to the risks of under-dosing antibiotics in this population. PMID- 22445479 TI - Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome revisited. PMID- 22445478 TI - Diabetic nephropathy among Mexican Americans. AB - The incidence of diabetic nephropathy (DN) is growing rapidly worldwide as a consequence of the rising prevalence of Type 2 diabetes mellitus (T2DM). Among U.S. ethnic groups, Mexican Americans have a disproportionately high incidence and prevalence of DN and associated end-stage renal disease (ESRD). In communities bordering Mexico, as many as 90% of Mexican American patients with ESRD also suffer from T2DM compared to only 50% of non-Hispanic Whites (NHW). Both socio-economic factors and genetic predisposition appear to have a strong influence on this association. In addition, certain pathogenetic and clinical features of T2DM and DN are different in Mexican Americans compared to NHW, raising questions as to whether the diagnostic and treatment strategies that are standard practice in the NHW patient population may not be applicable in Mexican Americans. This article reviews the epidemiology of DN in Mexican Americans, describes the pathophysiology and associated risk factors, and identifies gaps in our knowledge and understanding that needs to be addressed by future investigations. PMID- 22445480 TI - Gray-matter volume in methamphetamine dependence: cigarette smoking and changes with abstinence from methamphetamine. AB - BACKGROUND: Group differences in brain structure between methamphetamine dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants. METHODS: Gray matter was measured using voxel-based morphometry in three groups: 18 control nonsmokers, 25 control smokers, and 39 methamphetamine dependent smokers (methamphetamine-abstinent 4-7 days). Subgroups of methamphetamine-dependent and control participants (n=12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence. RESULTS: Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent Smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than control nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease. CONCLUSIONS: Gray-matter volume deficits in the orbitofrontal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse. PMID- 22445481 TI - Subjective effects for alcohol, tobacco, and marijuana association with cross drug outcomes. AB - METHODS: The cross-drug relationship of subjective experiences between alcohol, tobacco, and marijuana and problem drug use behaviors were examined. Data were drawn from 3853 individuals between the ages of 11 and 30 years of age participating in the Colorado Center on Antisocial Drug Dependence [CADD]. Subjective experiences were assessed using a 13-item questionnaire that included positive and negative responses for alcohol, tobacco, and marijuana. Lifetime abuse and dependence on these three drugs was assessed using the Composite International Diagnostic Interview, Substance Abuse Module [CIDI-SAM]. RESULTS: Positive and negative subjective experience scales were similar for alcohol, tobacco, and marijuana, although the hierarchical ordering of items differed by drug. Subjective experience scales for each of the three drugs examined correlated significantly, with the strongest relationship being for alcohol and marijuana experiences. Significant associations were identified between how a person experienced a drug and abuse and dependence status for the same or different drug. CONCLUSION: Cross-drug relationships provide evidence for a common liability or sensitivity towards responding in a similar manner to drugs of abuse within and across different pharmacological classes. PMID- 22445482 TI - Highly efficient magnetic stem cell labeling with citrate-coated superparamagnetic iron oxide nanoparticles for MRI tracking. AB - Tracking of transplanted stem cells is essential to monitor safety and efficiency of cell-based therapies. Magnetic resonance imaging (MRI) offers a very sensitive, repetitive and non-invasive in vivo detection of magnetically labeled cells but labeling with commercial superparamagnetic iron oxide nanoparticles (SPIONs) is still problematic because of low labeling efficiencies and the need of potentially toxic transfection agents. In this study, new experimental citrate coated SPIONs and commercial Endorem and Resovist SPIONs were investigated comparatively in terms of in vitro labeling efficiency, effects on stem cell functionality and in vivo MRI visualization. Efficient labeling of human mesenchymal stem cells (MSCs) without transfection agents was only achieved with Citrate SPIONs. Magnetic labeling of human MSCs did not affect cell proliferation, presentation of typical cell surface marker antigens and differentiation into the adipogenic and osteogenic lineages. However, chondrogenic differentiation and chemotaxis were significantly impaired with increasing SPION incorporation. Transplanted SPION-labeled MSCs were visualized in vivo after intramuscular injection in rats by 7T-MRI and were retrieved ex vivo by Prussian Blue and immunohistochemical stainings. Though a careful titration of SPION incorporation, cellular function and MRI visualization is essential, Citrate SPIONs are very efficient intracellular magnetic labels for in vivo stem cell tracking by MRI. PMID- 22445483 TI - Pure upbeat nystagmus in association with bilateral internuclear ophthalmoplegia. AB - A 66-year-old man developed primary position upbeat nystagmus and bilateral internuclear ophthalmoplegia (INO). Video-oculography showed primary position upbeat nystagmus with exponentially decreasing slow phases, which disappeared in darkness. Brain MRI disclosed enhancing lesions involving bilateral dorsomedial pons extending from the middle to upper portion. Upbeat nystagmus in association with bilateral INO may be attributed by the damage of the cell groups of the paramedian tracts (PMT), the projections from the interstitial nucleus of Cajal (INC) to PMT, or the connections between INC and the nucleus of Roller. PMID- 22445484 TI - BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. AB - Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1 deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku. PMID- 22445485 TI - Embryonic stem cells induce pluripotency in somatic cell fusion through biphasic reprogramming. AB - It is a long-held paradigm that cell fusion reprograms gene expression but the extent of reprogramming and whether it is affected by the cell types employed remain unknown. We recently showed that the silencing of somatic genes is attributable to either trans-acting cellular environment or cis-acting chromatin context. Here, we examine how trans- versus cis-silenced genes in a somatic cell type behave in fusions to another somatic cell type or to embryonic stem cells (ESCs). We demonstrate that while reprogramming of trans-silenced somatic genes occurs in both cases, reprogramming of cis-silenced somatic genes occurs only in somatic-ESC fusions. Importantly, ESCs reprogram the somatic genome in two distinct phases: trans-reprogramming occurs rapidly, independent of DNA replication, whereas cis-reprogramming occurs with slow kinetics requiring DNA replication. We also show that pluripotency genes Oct4 and Nanog are cis-silenced in somatic cells. We conclude that cis-reprogramming capacity is a fundamental feature distinguishing ESCs from somatic cells. PMID- 22445486 TI - Genome-wide functional annotation of dual-specificity protein- and lipid-binding modules that regulate protein interactions. AB - Emerging evidence indicates that membrane lipids regulate protein networking by directly interacting with protein-interaction domains (PIDs). As a pilot study to identify and functionally annodate lipid-binding PIDs on a genomic scale, we performed experimental and computational studies of PDZ domains. Characterization of 70 PDZ domains showed that ~40% had submicromolar membrane affinity. Using a computational model built from these data, we predicted the membrane-binding properties of 2,000 PDZ domains from 20 species. The accuracy of the prediction was experimentally validated for 26 PDZ domains. We also subdivided lipid-binding PDZ domains into three classes based on the interplay between membrane- and protein-binding sites. For different classes of PDZ domains, lipid binding regulates their protein interactions by different mechanisms. Functional studies of a PDZ domain protein, rhophilin 2, suggest that all classes of lipid-binding PDZ domains serve as genuine dual-specificity modules regulating protein interactions at the membrane under physiological conditions. PMID- 22445488 TI - Effect of varying salt and fat levels on the sensory quality of beef patties. AB - The interactive effects of varying levels of salt and fat on the sensory and physiochemical properties of beef patties were investigated. Twenty beef patties with varying levels of fat (30% 40% 50% 60% w/w) and salt (0.5%, 0.75% 1.0% 1.25% 1.5% w/w) were manufactured. All samples were assessed instrumentally for colour, moisture, fat, cooking loss and texture profile analysis. Sensory consumer evaluation was conducted using 25 consumers. The consumers rated each coded product, in duplicate, in terms of colour, texture, tenderness, juiciness, salt, taste, meat flavour, off flavour and overall acceptability. The data indicate that the most consumer acceptable beef patty was that containing 40% fat with a salt level of 1%. This is a 20% decrease in fat and a 50% decrease in salt levels when compared to commercial patties available in Ireland and the UK. PMID- 22445487 TI - The TOR complex 1 is a direct target of Rho1 GTPase. AB - The TOR complex 1 (TORC1) in yeast is regulated by various stress conditions. However, the underlying mechanism is poorly understood. In this study, we show that stresses affect TORC1 function through Rho1, a member of Rho family GTPases. Upon activation by stresses, Rho1 binds directly to Kog1, a unique component of TORC1, resulting in downregulation of TORC1 activity and disruption of its membrane association. The binding also triggers the release and activation of the Tap42-2A phosphatase, a major effector of TORC1 that resides on the complex. Rapamycin and caffeine also induce Rho1 activation. While the two agents inhibit TOR directly, their effects on TORC1 signaling are largely dependent on Rho1 activation. Our findings demonstrate that TORC1 acts both upstream and downstream of Rho1 GTPase, unveiling a mechanism that integrates stress and nutrient signals to coordinate Rho1-mediated spatial expansion and TORC1-dependent mass increase. PMID- 22445489 TI - Beyond celery and starter culture: advances in natural/organic curing processes in the United States. AB - Over the past 10years there has been ongoing development of curing processes with natural ingredients designed to meet consumer demand and regulatory requirements for natural and organic processed meats. Initially, these processes utilized celery concentrates with a high nitrate content combined with a nitrate-reducing starter culture. Subsequent advances included celery concentrates with the nitrate converted to nitrite by suppliers. Further, as questions developed concerning reduced concentration of preservatives and the microbiological safety of these processed meats, additional advances have resulted in a wide variety of ingredients and processes designed to provide supplementary antimicrobial effects for improved product safety. PMID- 22445490 TI - Different scalding techniques do not affect boar taint. AB - The prevention of unpleasant boar taint is the main reason for castration of male piglets. For animal welfare reasons, castration is announced to be banned in the European Community. This study aimed to investigate whether androstenone, skatole and indole in backfat of boars may be reduced by different scalding technologies. To discriminate ante and post mortem effects, carcasses were sampled before and after scalding in two abattoirs using either horizontal (TANK) or vertical (TUNNEL) scalding. Backfat samples were analysed using gas chromatography (androstenone) and liquid chromatography (skatole, indole). Neither TANK nor TUNNEL scalding did significantly reduce malodorous compounds. Skatole and androstenone in backfat obtained after scalding averaged 112 +/- 123 ng/g and 1196 +/- 885 ng/g melted fat, respectively; significant differences between abattoirs were observed for skatole. Increased skatole levels were tentatively assigned to longer transport duration. Concluding from recent consumer research and subsequent application of suggested sensory rejection thresholds for androstenone (2000 ng/g) and skatole (150 ng/g), nearly 30% of the carcasses may be unacceptably tainted. PMID- 22445491 TI - Signal enhancement in polysaccharide based sensors for infections by incorporation of chemically modified laccase. AB - Bioresponsive polymers (BRPs) allow the detection of potentially pathogenic microorganisms. Here, peptidoglycan and cellulose based hydrogels were constructed with potential for diagnosis of wound infection or, for example, Aspergillosis, respectively. These systems respond to extracellular enzymes from microbes or enzymes secreted from the human immune system in case of infection. Laccases as 'enhanzymes' were incorporated into these devices for signal and stability enhancement when compared to simple dye release based systems. To retain the enhanzymes within the BRPs, they were either PEGylated laccase (Laccase_PEG) to increase size or methacrylated laccase (Laccase_MA) to allow covalent attachment to the polysaccharide matrices. PEGylation of Trametes hirsuta laccase led to a fivefold increase in size to 270kDa according to size exclusion chromatography (SEC). Likewise, successful methacrylation of the laccase was demonstrated by using reversed phase chromatography while SEC analysis proved covalent attachment of the enzyme to the methacrylated polysaccharide matrix. Upon incubation of peptidoglycan based BRPs with fluid from infected wounds, the difference to controls was four times higher for Laccase_PEG based signalling when compared to simple dye release. Similarly, the control signals (i.e. leaching) were considerably reduced in case of Laccase_MA incorporated in crosslinked peptidoglycan (PG) and carboxymethylcellulose (CMC) hydrogels for signalling. In addition, Laccase_MA catalysed colour formation enhanced the signal dramatically with factors between 100- and 600-fold. Laccase_MA was demonstrated to oxidise silica gel immobilised ferulic acid incorporated into the BRP with clearly visible colour changes of 4.5 DeltaE units according the CIELab concept upon incubation by trigger enzymes as well as infected wound fluids. PMID- 22445492 TI - Gemcitabine is active against clinical multiresistant Staphylococcus aureus strains and is synergistic with gentamicin. AB - This study provides insight into the antibacterial activity of the cytotoxic nucleoside analogue gemcitabine against clinical multiresistant Staphylococcus aureus strains. Classical methods were used for determination of the minimum inhibitory concentration (MIC) and synergy in vitro, and polymerase chain reaction (PCR) products were sequenced to search for mutations in nucleoside kinase genes in resistant strains. Gemcitabine and its derivative CP-4126 were effective against meticillin-susceptible S. aureus (MSSA), meticillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) isolates, with MICs ranging between 0.06 mg/L and 4.22 mg/L. Bactericidal activity was shown in time-kill studies as well as synergy with gentamicin. Mutations in the nucleoside kinase gene SadAK were observed in resistant strains, indicating a role for this enzyme in gemcitabine activity. Nucleoside analogues have antimicrobial activity and these results could be used for further identification and development of new antibiotics. PMID- 22445493 TI - Outpatient parenteral antimicrobial therapy (OPAT) in a teaching hospital-based practice: a retrospective cohort study describing experience and evolution over 10 years. AB - Use of outpatient parenteral antimicrobial therapy (OPAT) is increasing in settings with advanced healthcare systems internationally. This study describes a large OPAT service cohort developed in the west of Scotland and includes trends over a 10-year period of this service. Data were retrieved from a prospectively maintained electronic case database. Patient and logistic variables were collated for all OPAT episodes (n=2638, resulting in 39035 days of patient care over 10 years). Skin and soft-tissue infections and bone and joint infections accounted for 77% of OPAT cases, but a wide range of other conditions have been treated in this cohort. Outcome variables were evaluated for all first OPAT attendances (n=2233), amongst which a successful outcome (cure or improvement) was found for 2063 (92.4%). Unplanned admission was observed in 9.1% of patients (6.3 events per 1000 OPAT patient days). Healthcare-associated infection rates were low: amongst first OPAT attendances, 14 intravenous line infections were observed (0.4 per 1000 OPAT patient days). Statistically significant trends over time included: a decrease in OPAT treatment time; increased referrals from non-local and secondary care sources; increased rate of co-morbidity of OPAT referrals; and increased self/carer administration of antimicrobials. Outcome proportions (success and adverse events) did not vary over time. This cohort study adds to the increasing observational data suggesting that OPAT is safe, effective and acceptable for treating a wide variety of infections. Observed trends over a 10 year period suggest that this model of infection management is adaptable and sustainable. PMID- 22445494 TI - Prevalence and analysis of microbiological factors associated with phenotypic heterogeneous resistance to carbapenems in Acinetobacter baumannii. AB - The objectives of this study were to determine the prevalence of Acinetobacter baumannii with phenotypic heterogeneous resistance (PHR) to carbapenems (colonies inside the halo of inhibition) and to analyse its association with several microbiological variables. Acinetobacter baumannii isolates collected in Spain were used to analyse: (i) minimum inhibitory concentrations (MICs) of carbapenems; (ii) heteroresistance to carbapenems; (iii) genes encoding beta lactamases (bla genes); (iv) insertion sequences; and (v) inactivation of genes encoding porins (CarO, OprD and Omp33-36) and genes associated with the AdeABC efflux system (adeB, adeR and adeS). Polymerase chain reaction (PCR) amplification was used for gene detection. The rate of PHR was 20% to imipenem and 24% to meropenem. Susceptibility to imipenem was observed in 39% of PHR isolates. MICs of carbapenems for colonies were similar (+/- 1 log(2) dilution) to those of their parental isolates. These colonies growing inside the inhibition halo also reproduced the PHR to carbapenems. Differences observed between PHR isolates and non-PHR isolates were: bla(OXA-58-like), 57% vs. 0%; oprD-like, 96% vs. 56%; adeB, 89% vs. 94%; adeR, 82% vs. 94%; adeS, 82% vs. 94%; ISAba2, 61% vs. 31%; and ISAba3, 57% vs. 0%. No interruption of genes encoding porins or the efflux-related genes (adeB, adeR and adeS) was observed. In conclusion, A. baumannii strains with PHR to carbapenems are widespread in Spain. This phenotype is present in carbapenem-susceptible isolates as well as those that are not susceptible to carbapenems. Heteroresistance cannot explain the PHR to carbapenems, which appears to relate more to persistence or tolerance to carbapenems. bla(OXA-58-like), bla(OXA-51-like), ISAba2 and ISAba3 are associated with PHR to carbapenems. Inactivation of genes encoding porins or genes related to AdeABC is infrequent. PMID- 22445495 TI - Database screening and in vivo efficacy of antimicrobial peptides against methicillin-resistant Staphylococcus aureus USA300. AB - Natural antimicrobial peptides (AMPs) are promising candidates for developing a generation of new antimicrobials to meet the challenge of antibiotic-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). To facilitate the search for new candidates, we have utilised the Antimicrobial Peptide Database (APD), which contains natural AMPs from bacteria, fungi, plants and animals. This study demonstrates the identification of novel templates against MRSA by screening 30 peptides selected from the APD. These peptides are short (<25 residues), cysteine-free, cationic and represent candidates from different biological sources such as bacteria, insects, arachnids, tunicates, amphibians, fish and mammals. Six peptides, including ascaphin-8, database screened antimicrobial peptide 1 (DASamP1), DASamP2, lycotoxin I, maculatin 1.3 and piscidin 1, were found to exert potent antimicrobial activity against an MRSA USA300 isolate. Although five of the six peptides showed broad-spectrum antibacterial activity, DASamP1 displayed killing of MRSA in vitro but not of Escherichia coli, Bacillus subtilis or Pseudomonas aeruginosa. In addition, DASamP1 suppressed early biofilm formation in a mouse model of catheter associated MRSA infection. DASamP1 is a novel, short and potent peptide that will be a useful starting template for further developing novel anti-MRSA peptides. PMID- 22445496 TI - A case of spontaneous intracranial hypotension: from Meniere-like syndrome to cerebral involvement. AB - INTRODUCTION: Spontaneous intracranial hypotension (SIH) is a rare pathology caused by unexplained and variably localized leakage of cerebrospinal fluid (CSF). The prime symptom is orthostatic headache, although other less specific clinical signs may predominate, and mislead diagnosis. CASE REPORT: A 47-year-old man presented with Meniere-like symptoms of sudden onset. Secondary orthostatic headache led to the performance of cerebral MRI, which found signs suggestive of intracranial hypotension. A blood-patch was immediately carried out, and was followed by consciousness disorder associated with onset of bilateral subdural hematoma, which required iterative neurosurgical drainage. Myelo-CT confirmed CSF leakage facing the right 12th dorsal nerve root sheath. Radio-guided sealing with biologic glue provided complete regression of all symptoms. DISCUSSION/CONCLUSION: Auditory signs may predominate in the clinical presentation of SIH. Their orthostatic character is suggestive. The present case is of a rare severe form. The role of neurosurgery in such cases remains to be defined. PMID- 22445497 TI - An unusual cause of tracheal stenosis: diagnosis and management? Tracheopathia osteochondroplastica. PMID- 22445498 TI - Clinical features and outcome of sphenoid sinus aspergillosis: A retrospective series of 15 cases. AB - INTRODUCTION: Sphenoid sinusitis is uncommon, and aspergillus infections represent a minority of these cases. This study was designed to describe the characteristics of this disease and present a review of the literature. PATIENTS AND METHOD: Retrospective study from 2004 to 2010 based on 15 patients managed at Nantes University Hospital. Risk factors and history, symptoms, intranasal examination, imaging, histological and mycological results as well as analysis of the response to treatment and outcome were analysed. RESULTS AND DISCUSSIONS: Patients were aged between 14 to 78 years, almost 75% of patients were older than 50 and 73% of patients were women. The most common symptoms were headache [80%], nasal blockage or discharge [33%], and recurrent mild epistaxis [20%]. Predisposing factors were immunodepression in three patients, with no cases of diabetes. Two patients had a history of intranasal surgery and one had a history of facial trauma. Nasal endoscopy was normal in 40% of cases. CT was suggestive of sphenoid sinus aspergillosis in more than one half of cases [8/15] and demonstrated osteolysis in four patients. An incorrect preoperative diagnosis of mucocele was proposed in three patients. Histological examination demonstrated spore-forming structures in every case, but culture was positive in only four cases. Only two patients required antifungal therapy, including one patient with invasive aspergillosis. CONCLUSION: Chronic noninvasive sphenoid sinus aspergillosis appears to be a benign disease, essentially affecting women and patients over the age of 50 years. Symptoms are fairly non-specific. Imaging and histological examination are essential for management. The invasive form is a serious disease requiring rapid, multidisciplinary management. PMID- 22445499 TI - Exposure techniques in endoscopic skull base surgery: posterior septectomy, medial maxillectomy, transmaxillary and transpterygoid approach. PMID- 22445500 TI - Effects of interleukin-33 on cardiac fibroblast gene expression and activity. AB - Interleukin-33 (IL-33) is a recently described member of the interleukin-1 (IL-1) family. It is produced by diverse cell types in response to a variety of stresses including hemorrhage and increased mechanical load. Though only relatively recently discovered, IL-33 has been shown to participate in several pathological processes including promoting type 2 T helper cell-associated autoimmune diseases. In contrast, IL-33 has been also found to have protective effects in cardiovascular diseases. Recent studies have illustrated that IL-33 attenuates cardiac fibrosis induced by increased cardiovascular load in mice (transaortic constriction). Since cardiac fibrosis is largely dependent on increased production of extracellular matrix by cardiac fibroblasts, we hypothesized that IL-33 directly inhibits pro-fibrotic activities of these cells. Experiments have been carried out with isolated rat cardiac fibroblasts to evaluate the effects of IL-33 on the modulation of cardiac fibroblast gene expression and function to test this hypothesis. The expression of the IL-33 receptor, interleukin-1 receptor-like 1 (ST2), was detected at the mRNA and protein levels in isolated adult rat cardiac fibroblasts. Subsequently, the effects of IL-33 treatment (0 100 ng/ml) on the expression of extracellular matrix proteins and pro inflammatory cytokines/chemokines were examined as well as the effects on rat cardiac fibroblast activities including proliferation, collagen gel contraction and migration. While IL-33 did not directly inhibit collagen I and collagen III production, it yielded a dose-dependent increase in the expression of interleukin 6 and monocyte chemotactic protein-1. Treatment of rat cardiac fibroblasts with IL-33 also impaired the migratory activity of these cells. Further experiments illustrated that IL-33 rapidly activated multiple signaling pathways including extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, c Jun N-terminal kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in a dose-dependent manner. Experiments were carried out with pharmacological inhibitors to determine the role of specific signaling pathways in the response of fibroblasts to IL-33. These experiments illustrated that the activation of p38 mitogen-activated protein kinase and extracellular signal regulated kinases are critical to the increased production of interleukin-6 and monocyte chemotactic protein-1 in response to IL-33. These studies suggest that IL-33 has an important role in the modulation of fibroblast function and gene expression. Surprisingly, IL-33 had no effect on the expression of genes encoding extracellular matrix components or on proliferation, markers typical of fibrosis. The major effects of IL-33 detected in these studies included inhibition of cell migration and activation of cytokine/chemokine expression. The previously reported inhibition of cardiac fibrosis may include more complicated mechanisms that involve other cardiac cell types. Future studies aimed at determining the effects of IL-33 on other cardiac cell types are warranted. PMID- 22445501 TI - Interleukin-1 receptor antagonist reverses stroke-associated peripheral immune suppression. AB - INTRODUCTION: Infections are common following stroke and adversely affect outcome. Cellular immune suppression associated with acute stroke may increase susceptibility to infection. Cytokines are important contributors to both stroke pathology and the response to infection. Since interleukin (IL)-1 blockade is a candidate treatment for cerebral ischemia, we examined whether administration of interleukin-1 receptor antagonist (IL-1Ra) to patients with acute stroke affected innate cellular immune responses in a phase II placebo-controlled trial. METHODS: Venous blood samples were taken prior to treatment initiation, at 24h and 5 to 7d. Blood was also drawn from stroke-free controls. Lipopolysaccharide (LPS) stimulation of whole-blood cultures assessed the potential of leukocytes to produce cytokines. RESULTS: Induction of tumor necrosis factor (TNF)-alpha, IL 1beta, IL-6, IL-8 and IL-10 by LPS was significantly reduced in patients at admission, compared to controls. At 24h, cytokine induction remained suppressed in the placebo group. In contrast, for patients treated with IL-1Ra, induction of TNF-alpha, IL-6 and IL-10 was similar to controls and IL-1beta induction was significantly greater than in the placebo group. At 5 to 7d, TNF-alpha and IL 1beta induction remained suppressed only in the placebo group (p<0.05). Plasma cortisol concentrations, elevated at admission in patients compared to controls, were substantially reduced at 24h in the patients receiving IL-1Ra (p<0.05) and inversely correlated (p<0.001) with either TNF-alpha (r=-0.71) or IL-1beta induction (r=-0.67) at admission. CONCLUSION: Treatment with IL-1Ra reverses peripheral innate immune suppression in the acute phase of stroke, which is associated with attenuated cortisol production. The mechanisms underlying these observations, including the potential impact of IL-1Ra on stroke severity and the clinical significance of immune suppression, require further evaluation in larger studies. PMID- 22445502 TI - Blood plasma clinical-chemical parameters as biomarker endpoints for organohalogen contaminant exposure in Norwegian raptor nestlings. AB - Raptors are exposed to biomagnifying and toxic organohalogenated compounds (OHCs) such as organochlorines, brominated flame retardants and perfluorinated compounds. To investigate how OHC exposure may affect biochemical pathways we collected blood plasma from Norwegian northern goshawk (n=56), golden eagle (n=12) and white-tailed eagle (n=36) nestlings during three consecutive breeding seasons. We found that blood plasma concentrations of calcium, sodium, creatinine, cholesterol, albumin, total protein, urea, inorganic phosphate, protein:creatinine, urea:creatinine and uric acid:creatinine ratios and liver enzymes ALKP and ALAT were positively correlated to PCBs, chlordanes, p,p'-DDE, HCB, PFCs and/or PBDEs. Total bilirubin and glucose were negatively correlated to PCBs while magnesium and potassium were negatively correlated to HCB and p,p' DDE. In addition, protein:creatinine and ALAT were also negatively correlated to PCBs and PFCs, respectively. The most significant relationships were found for the highly contaminated northern goshawks and white-tailed eagles. The statistical relationships between OHCs and BCCPs indicate that biochemical pathways could be influenced while it is uncertain if such changes have any health effects. The OHC concentrations were below concentrations causing reproductive toxicity in adults of other raptor species but similar to those of concern for endocrine disruption of thyroid hormones in e.g., bald eagles. PMID- 22445503 TI - [Methods for analyzing uncertainty]. AB - Current budgetary restrictions in health systems have increased the influence of economic evaluation studies on decision making. Nevertheless, uncertainty about the parameters used in pharmacoeconomic models is inevitable and may affect the conclusions drawn. The present article aims to review the main methods proposed to quantify the uncertainty inherent in pharmacoeconomic evaluations applied to health technologies. The most accurate pharmacoeconomic estimations are obtained by probabilistic methods of uncertainty analysis such as Monte Carlo simulation, repetitive sampling and the Fieller method. Alternatives to these methods are calculation of the cost-effectiveness acceptability curve or net health benefit. Equally, the economic impact of uncertainty in the pharmacoeconomic models used in the decision-making process can be estimated by obtaining what is known as the value of perfect information. PMID- 22445504 TI - [Structural sensitivity analysis]. AB - The aim of this study was to perform a structural sensitivity analysis of a decision model and to identify its advantages and limitations. A previously published model of dinoprostone was modified, taking two scenarios into account: eliminating postpartum hemorrhages and including both hemorrhages and uterine hyperstimulation among the adverse effects. The result of the structural sensitivity analysis shows the robustness of the underlying model and confirmed the initial results: the intrauterine device is more cost-effective than intracervical dinoprostone gel. Structural sensitivity analyses should be congruent with the situation studied and clinically validated. Although uncertainty may be only slightly reduced, these analyses provide information and add greater validity and reliability to the model. PMID- 22445505 TI - [Application of pharmacoeconomics in clinical management]. AB - The present article discusses the importance of clinical management in the transformation of organizations and its role in the daily activities of health professionals and, in particular, of hospital pharmacists. Because of social changes, healthcare models must make the shift from more rigid management models toward new organizational models based on clinical management. From this perspective, pharmacoeconomics is viewed as a useful tool to introduce the criteria of efficiency in all decisions subject to clinical management, including those on pharmacotherapeutics. Subsequently, the application of this discipline is discussed in real decision-making scenarios and settings for its use within the context of the work of hospital pharmacy are proposed. PMID- 22445506 TI - [Pharmacoeconomic aspects of oral cytostatic agents]. AB - When validating oral chemotherapy, pharmacists should confirm the suitability and correctness of the prescription, applying the same safety standards as those used for parenteral cytostatic drugs. There are an increasing number of cancers for which orally administered drugs are available, which increases patient satisfaction as these drugs can be taken at home without the need to visit a hospital. As oral cytostatic treatments increase, so does the importance of ensuring optimal treatment compliance. The new oral cytostatic agents are less toxic, reduce indirect costs and imply less loss of time for patients and their families. However, the cost of these agents should be below a threshold acceptable for society. As an aid to decision making, pharmacoeconomic tools should be used. PMID- 22445507 TI - [Are drugs worth their cost?]. AB - Drugs constantly jeopardize the balance among Bioethical Principles governing Healthcare. Their correct use implies more than a correct clinical diagnosis and an academic prescription and demands thorough coordination among all healthcare levels (Regulatory Agencies, the State, the Pharmaceutical Industry and professionals) and the necessary incentive for the research and development process to provide true therapeutic innovations. The interannual growth of Pharmaceutical Expenditure in the public sector in the last few years has greatly exceeded growth in the consumer price index and the gross domestic product. The economic problem of drugs utilization therefore centers on their opportunity cost and on their impact on the sustainability of the system overall. Cost-utility, as an accepted principle for the incorporation and use of new technologies is not always taken into account in prioritization, decision-making and interventions. PMID- 22445508 TI - Orai1 mediates store-operated Ca2+ entry during fertilization in mammalian oocytes. AB - The presence of the store-operated Ca(2+) entry channel Orai1 and its function in signal transduction during fertilization have been investigated in mammalian oocytes using the pig as a model. RT-PCR cloning and sequence analysis revealed that Orai1 is expressed in the oocytes with a coding sequence of 921bp. After indirect immunocytochemistry or the overexpression of EGFP-tagged Orai1, the fluorescent signal was present primarily in the cell cortex consistent with plasma membrane localization of the protein. Western blot and real-time PCR results showed that Orai1 expression decreases during oocyte maturation; this is associated with the oocytes gaining the ability to generate a large Ca(2+) influx after store depletion. Downregulation of Orai1 expression by siRNA microinjection blocked Ca(2+) influx after store depletion and subsequent Ca(2+) add-back; the Ca(2+) oscillations induced by the fertilizing sperm were also inhibited in oocytes with downregulated Orai1 levels. At the same time, overexpression of Orai1 in the oocytes also modified store-operated Ca(2+) entry and had an inhibitory effect on the fertilization Ca(2+) signal. The abnormal Ca(2+) signaling due to Orai1 downregulation had a strong negative impact on subsequent embryo development. Co-overexpression of Orai1 and STIM1 on the other hand, led to a dramatic increase in Ca(2+) entry after store depletion. The findings indicate that Orai1 is a plasma membrane-resident Ca(2+) channel that is responsible for mediating Ca(2+) entry after the mobilization of intracellular Ca(2+) in oocytes. Orai1 and a functional store-operated Ca(2+) entry pathway are required to maintain the Ca(2+) oscillations at fertilization and to support proper embryo development. PMID- 22445510 TI - Laser ablation of the sonic hedgehog-a-expressing cells during fin regeneration affects ray branching morphogenesis. AB - The zebrafish fin is an excellent system to study the mechanisms of dermal bone patterning. Fin rays are segmented structures that form successive bifurcations both during ontogenesis and regeneration. Previous studies showed that sonic hedgehog (shha) may regulate regenerative bone patterning based on its expression pattern and functional analysis. The present study investigates the role of the shha-expressing cells in the patterning of fin ray branches. The shha expression domain in the basal epidermis of each fin ray splits into two prior to ray bifurcation. In addition, the osteoblast proliferation profile follows the dynamic expression pattern of shha. A zebrafish transgenic line, 2.4shh:gfpABC#15, in which GFP expression recapitulates the endogenous expression of shha, was used to specifically ablate shha-expressing cells with a laser beam. Such ablations lead to a delay in the sequence of events leading to ray bifurcation without affecting the overall growth of the fin ray. These results suggest that shha-expressing cells direct localized osteoblast proliferation and thus regulate branching morphogenesis. This study reveals the fin ray as a new accessible system to investigate epithelial-mesenchymal interactions leading to organ branching. PMID- 22445509 TI - Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle. AB - The basic helix-loop-helix (bHLH) transcription factor Math5 (Atoh7) is transiently expressed during early retinal histogenesis and is necessary for retinal ganglion cell (RGC) development. Using nucleoside pulse-chase experiments and clonal analysis, we determined that progenitor cells activate Math5 during or after the terminal division, with progressively later onset as histogenesis proceeds. We have traced the lineage of Math5+ cells using mouse BAC transgenes that express Cre recombinase under strict regulatory control. Quantitative analysis showed that Math5+ progenitors express equivalent levels of Math5 and contribute to every major cell type in the adult retina, but are heavily skewed toward early fates. The Math5>Cre transgene labels 3% of cells in adult retina, including 55% of RGCs. Only 11% of Math5+ progenitors develop into RGCs; the majority become photoreceptors. The fate bias of the Math5 cohort, inferred from the ratio of cone and rod births, changes over time, in parallel with the remaining neurogenic population. Comparable results were obtained using Math5 mutant mice, except that ganglion cells were essentially absent, and late fates were overrepresented within the lineage. We identified Math5-independent RGC precursors in the earliest born (embryonic day 11) retinal cohort, but these precursors require Math5-expressing cells for differentiation. Math5 thus acts permissively to establish RGC competence within a subset of progenitors, but is not sufficient for fate specification. It does not autonomously promote or suppress the determination of non-RGC fates. These data are consistent with progressive and temporal restriction models for retinal neurogenesis, in which environmental factors influence the final histotypic choice. PMID- 22445511 TI - Drosophila Argonaute 1 and its miRNA biogenesis partners are required for oocyte formation and germline cell division. AB - Argonaute 1 (Ago1) is a member of the Argonaute/PIWI protein family involved in small RNA-mediated gene regulation. In Drosophila, Ago1 plays a specific role in microRNA (miRNA) biogenesis and function. Previous studies have demonstrated that Ago1 regulates the fate of germline stem cells. However, the function of Ago1 in other aspects of oogenesis is still elusive. Here we report the function of Ago1 in developing egg chambers. We find that Ago1 protein is enriched in the oocytes and is also highly expressed in the cytoplasm of follicle cells. Clonal analysis of multiple ago1 mutant alleles shows that many mutant egg chambers contain only 8 nurse cells without an oocyte which is phenocopied in dicer-1, pasha and drosha mutants. Our results suggest that Ago1 and its miRNA biogenesis partners play a role in oocyte determination and germline cell division in Drosophila. PMID- 22445512 TI - Fatty acid flux and oxidation are increased by rimonabant in obese women. AB - This study aimed to determine in obese women if endocannabinoid receptor antagonism has effects on fatty acid and triglyceride metabolism and insulin sensitivity which are independent from the metabolic effects of weight loss. Fourteen obese (BMI=33.0+/-0.5 kg/m(2)) (mean+/-SEM) Caucasian post-menopausal women, aged 57.8+/-4.7 years were studied. The women were randomised to 2 groups, one group received the endocannabinoid receptor antagonist rimonabant (20 mg/d) for 12 weeks. A control group achieved the same weight loss by a hypocaloric dietary intervention over 12 weeks. Palmitate production rate (Ra), a measure of lipolysis, and palmitate oxidation rate, and VLDL(1) and VLDL(2) triglyceride (TG) kinetics, were measured using isotopic tracers before and after the intervention. Weight loss was not different in the 2 groups; 2.6+/-0.5 kg with rimonabant and 3.1+/-1.0 kg in the control group. Palmitate Ra increased with rimonabant with no change in the control group (p=0.03 between groups). Palmitate oxidation rate increased with rimonabant but decreased in the control group (p=0.005 between groups). VLDL(1) TG secretion rate decreased in the control group and increased in the rimonabant group (p=0.008 between groups). There was no significant effect on insulin sensitivity. This study suggests that endocannabinoid receptor antagonism for 12 weeks in obese women increased lipolysis and fatty acid oxidation. The increase in VLDL(1) TG secretion rate may be due to the increase in lipolysis which exceeded the increase in fatty acid oxidation. PMID- 22445513 TI - Intestinal fatty acid infusion modulates food preference as well as calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways in rats. AB - The intestine plays important roles in the regulation of feeding behavior by sensing macronutrients. Intestinal fatty acids strongly suppress food intake, but little is known about whether intestinal fatty acids affect food preference. We investigated the effects of jejunal fatty acids infusion on food preference by conducting two-diet choice experiments in rats fed a high-fat diet (HFD) and a high-carbohydrate diet (HCD). Jejunal linoleic acid (18:2) infusion reduced HFD intake dose-dependently, while HCD intake increased with the middle dose of the infusion we examined (100 MUL/h) and reduced to the control level with the higher doses (150 and 200 MUL/h). alpha-Linolenic acid (18:3), but not caprylic acid (8:0), altered the food preference and total calorie intake in the same manner as linoleic acid. Linoleic acid infusion dose-dependently increased plasma glucagon like peptide-1, peptide YY and cholecystokinin levels, but not ghrelin levels. Subdiaphragmatic vagotomy or midbrain transection prevented the change in food preference and total calorie intake by linoleic acid infusion. Jejunal linoleic acid infusion increased norepinephrine turnover in the paraventricular hypothalamic nucleus, while intracerebroventricular injection of idazoxan, an alpha2-adrenergic receptor (AR) antagonist, suppressed the increased HCD intake, but did not affect the decreased HFD intake. These findings indicated that intestinal long-chain fatty acids modulated food preference as well as total calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways. The effects of the alpha2-AR antagonist in the brain suggested that the brain distinctly controlled HCD and HFD intake in response to jejunal linoleic acid infusion. PMID- 22445514 TI - Estimating insulin secretion in youth using simple indices derived from the oral glucose tolerance test. AB - AIM: Simple estimates of insulin secretion feasible for large epidemiological studies have been proposed in adults, but have been little evaluated in young people. For this reason, this study examined the correlation between OGTT-derived and fasting-based indices of insulin secretion against the acute insulin response to glucose (AIRg) in children. METHODS: Twenty subjects (nine boys and 11 girls; mean [SD] age: 9 [2] years) were studied. Their mean (SD) BMI Z score was 1.5 (0.8). All participants had normal fasting and 2-h post-load glucose. Each subject underwent an insulin-modified minimal model frequently sampled intravenous glucose tolerance test (FSIVGTT) as the reference method, and a 3-h OGTT. AIRg was computed from the FSIVGTT. A total of ten indices were calculated using OGTT data, while HOMA%beta (original formula) and HOMA2%beta (computer based) were computed from fasting samples. Correlations were established using Spearman's rank correlations. RESULTS: Of the ten indices derived from the OGTT, those most closely correlated with the AIRg (using FSIVGTT) included the insulinogenic index(t30)(min) (r = 0.80), insulin/glucose ratio(t30)(min) (r = 0.71) and ratio of the area under the curve for insulin to glucose(t0-30)(min) (r = 0.74). Both the HOMA%beta and HOMA2%beta correlated modestly with AIRg (r = 0.62 and r=0.65, respectively). CONCLUSION: Our results suggest that OGTT-derived measures of insulin secretion provide adequate estimates of first-phase insulin secretion in youth. HOMA2%beta and HOMA%beta represent acceptable compromises, although HOMA2%beta may be preferable in younger individuals, as it allows for a wider spectrum of insulin and glucose values that are physiological in this age group. PMID- 22445515 TI - Pulse-transient adapted C-symmetry pulse sequences. AB - In solid-state NMR, pulse sequences make often use of pulses which are short compared to the recovery time of the probe head. Especially, rotorsynchronized dipolar recoupling experiments under magic-angle-spinning conditions can profit from the use of very high pulse amplitudes which in turn will reduce the length of the individual pulses. In this contribution we show that C-symmetry based pulse sequences used for double-quantum filtering experiments can strongly be influenced by pulse transients. We analyze the origin of pulse transients and show that the quadrature component can be minimized by cable-length variation which causes a mutual cancellation of probe-external and internal contributions. We implement and test a model to investigate the influence of pulse-transients by numerically exact calculations of the spin-density matrix allowing for composite pulses consisting of slices which are short compared to the circuit recovery time constant. Moreover we introduce a phase-tuned C-element, which can be applied to gamma-encoded experiments from the C-symmetry class, to reconstitute an almost ideal performance of the sequence. We have validated the modified transient adapted pulse sequences theoretically on the basis of numerically exact calculations of the spin-dynamics. While comparably easy to apply the scheme proved also robust in practical application to (15)N, (13)C and (31)P double quantum filtered experiments and leads to a significantly increased conversion efficiency. PMID- 22445516 TI - TKTL-1 expression in lung cancer. AB - Study of the physiological changes associated with the development of malignancy demonstrates a metabolic signature for the different stages of tumorigenesis. Increased glucose uptake and lactate production have been detected during malignant transformation. Based on energy production, malignancies can be divided into two subclasses: (a) tumor cells which use the mitochondrial machinery for ATP synthesis, and (b) tumor cells which generate ATP by glucose fermentation and lactate production even in the presence of oxygen (aerobic glycolysis). Recently, transketolase-like protein 1 (TKTL1) gene expression has been shown to contribute to carcinogenesis through increased aerobic glycolysis and hypoxia-inducible factor alpha stabilization. In the present study, 197 patients suffering from lung cancer were investigated by immunohistochemistry for the presence of TKTL1 protein expression. We detected: (1) moderate to strong TKTL1 expression (immune reactive score>100) in 39.1% of the investigated lung cancer patients; (2) a complete lack of TKTL1 by immunohistochemistry in 12.7% of lung cancer cases, with small cell lung cancer (SCLC) being most frequent in this subgroup; (3) no correlation of TKTL1 with overall survival, disease-free survival, any of the established variables of the TNM system, grading, stage, smoking status, or gender. Based on this data, we conclude that TKTL1 could be a target protein for improved therapeutic strategies in some cases of lung cancer. PMID- 22445517 TI - Direct reprogramming of fibroblasts into neural stem cells by defined factors. AB - Recent studies have shown that defined sets of transcription factors can directly reprogram differentiated somatic cells to a different differentiated cell type without passing through a pluripotent state, but the restricted proliferative and lineage potential of the resulting cells limits the scope of their potential applications. Here we show that a combination of transcription factors (Brn4/Pou3f4, Sox2, Klf4, c-Myc, plus E47/Tcf3) induces mouse fibroblasts to directly acquire a neural stem cell identity-which we term as induced neural stem cells (iNSCs). Direct reprogramming of fibroblasts into iNSCs is a gradual process in which the donor transcriptional program is silenced over time. iNSCs exhibit cell morphology, gene expression, epigenetic features, differentiation potential, and self-renewing capacity, as well as in vitro and in vivo functionality similar to those of wild-type NSCs. We conclude that differentiated cells can be reprogrammed directly into specific somatic stem cell types by defined sets of specific transcription factors. PMID- 22445518 TI - Direct conversion of fibroblasts into stably expandable neural stem cells. AB - Recent advances have suggested that direct induction of neural stem cells (NSCs) could provide an alternative to derivation from somatic tissues or pluripotent cells. Here we show direct derivation of stably expandable NSCs from mouse fibroblasts through a curtailed version of reprogramming to pluripotency. By constitutively inducing Sox2, Klf4, and c-Myc while strictly limiting Oct4 activity to the initial phase of reprogramming, we generated neurosphere-like colonies that could be expanded for more than 50 passages and do not depend on sustained expression of the reprogramming factors. These induced neural stem cells (iNSCs) uniformly display morphological and molecular features of NSCs, such as the expression of Nestin, Pax6, and Olig2, and have a genome-wide transcriptional profile similar to that of brain-derived NSCs. Moreover, iNSCs can differentiate into neurons, astrocytes, and oligodendrocytes. Our results demonstrate that functional NSCs can be generated from somatic cells by factor driven induction. PMID- 22445519 TI - Bodybuilding, energy, and weight-loss supplements are associated with deployment and physical activity in U.S. military personnel. AB - PURPOSE: The characteristics of U.S. military personnel who use dietary supplements have not been well described. This study aimed to determine whether deployment experience and physical activity were associated with the use of bodybuilding, energy, or weight-loss supplement among U.S. military personnel. METHODS: Self-reported data from active-duty, Reserve, and National Guard participants of the Millennium Cohort Study collected from 2007-2008 (n = 106,698) on supplement use, physical activity, and other behavioral data were linked with deployment and demographic data. We used multivariable logistic regression sex-stratified models to compare the adjusted odds of each type of supplement use among those with deployment experience in support of operations in Iraq or Afghanistan and those engaged in aerobic or strength-training activities. RESULTS: Overall, 46.7% of participants reported using at least one type of supplement, and 22.0% reported using multiple supplements. Male deployers were more likely to use bodybuilding supplements, whereas female deployers were more likely to use weight-loss supplements. Physically active and younger subjects reported all types of supplement use. Men and women reporting 5 or less hours of sleep per night were more likely to use energy supplements. CONCLUSIONS: The high prevalence of supplement use and important characteristics found to be associated with their use, including deployment, physical activity, and suboptimal sleep, suggest focus areas for future research and adverse event monitoring. PMID- 22445520 TI - [Treatment of vaginal prolapse and urinary stress incontinence]. PMID- 22445521 TI - [Active surveillance for the secondary prevention of prostate cancer]. PMID- 22445522 TI - [Treatment of small kidney tumors]. PMID- 22445523 TI - [Diagnosis and therapy of upper and lower urinary tract urothelial carcinoma]. PMID- 22445524 TI - Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells. AB - A compromised protein degradation machinery has been implicated in methamphetamine (MA)-induced neurodegeneration. However, the signaling mechanisms that induce autophagy and ubiquitin-proteasome system (UPS) dysfunction are not well understood. The present study investigates the contributions of protein kinase C delta (PKCdelta)-mediated signaling events in MA-induced autophagy, UPS dysfunction, and cell death. Using an in vitro mesencephalic dopaminergic cell culture model, we demonstrate that MA-induced early induction of autophagy is associated with reduction in proteasomal function and concomitant dissipation of mitochondrial membrane potential (MMP), followed by significantly increased PKCdelta activation, caspase-3 activation, accumulation of ubiquitin-positive aggregates and microtubule-associated light chain-3 (LC3-II) levels. Interestingly, siRNA-mediated knockdown of PKCdelta or overexpression of cleavage resistant mutant of PKCdelta dramatically reduced MA-induced autophagy, proteasomal function, and associated accumulation of ubiquitinated protein aggregates, which closely paralleled cell survival. Importantly, when autophagy was inhibited either pharmacologically (3-MA) or genetically (siRNA-mediated silencing of LC3), the dopaminergic cells became sensitized to MA-induced apoptosis through caspase-3 activation. Conversely, overexpression of LC3 partially protected against MA-induced apoptotic cell death, suggesting a neuroprotective role for autophagy in MA-induced neurotoxicity. Notably, rat striatal tissue isolated from MA-treated rats also exhibited elevated LC3-II, ubiquitinated protein levels, and PKCdelta cleavage. Taken together, our data demonstrate that MA-induced autophagy serves as an adaptive strategy for inhibiting mitochondria-mediated apoptotic cell death and degradation of aggregated proteins. Our results also suggest that the sustained activation of PKCdelta leads to UPS dysfunction, resulting in the activation of caspase-3 mediated apoptotic cell death in the nigrostriatal dopaminergic system. PMID- 22445525 TI - Pharmacological evidence that spinal alpha(2C)- and, to a lesser extent, alpha(2A)-adrenoceptors inhibit capsaicin-induced vasodilatation in the canine external carotid circulation. AB - During a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), producing cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the role of spinal alpha2 adrenoceptors and their subtypes (i.e. alpha(2A), alpha(2B) and/or alpha(2C) adrenoceptors) in the inhibition of the canine external carotid vasodilator responses to capsaicin. Anaesthetized vagosympathectomized dogs were prepared to measure arterial blood pressure, heart rate and external carotid conductance. The thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, alpha-CGRP and acetylcholine. A cannula was inserted intrathecally for spinal (C1 C3) administration of 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d] azepin-dihydrochloride (B-HT 933; a selective alpha2-adrenoceptor agonist) and/or the alpha2-adrenoceptor antagonists rauwolscine (alpha(2A/2B/2C)), 2-[(4,5 dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408; alpha(2A)), imiloxan (alpha(2B)) or acridin-9-yl-[4-(4-methylpiperazin 1-yl)-phenyl]amine (JP-1302; alpha(2C)). Infusions of capsaicin, alpha-CGRP and acetylcholine dose-dependently increased the external carotid conductance. Intrathecal B-HT 933 (1000 and 3100 MUg) inhibited the vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine. This inhibition, abolished by rauwolscine (310 MUg), was: (i) unaffected by 3,100 MUg imiloxan; (ii) partially blocked by 310 MUg of BRL44408 or 100 MUg of JP-1302; and (iii) abolished by 1,000 MUg of BRL44408 or 310 MUg of JP-1302. Thus, intrathecal B-HT 933 inhibited the external carotid vasodilator responses to capsaicin. This response, mediated by spinal alpha2-adrenoceptors unrelated to the alpha(2B) adrenoceptor subtype, resembles the pharmacological profile of alpha(2C) adrenoceptors and, to a lesser extent, alpha(2A)-adrenoceptors. PMID- 22445526 TI - [The chin fat pad]. AB - The chin fat pad is poorly described in anatomic publications. To improve its knowledge, we performed 10 dissections, we studied 10 CT Scanners and ten RMN from patients without mental scar, and we performed a CT scanner of this area in a man at rest and during the lips protraction. A histological study has been performed comparing the chin fat pad with the subcutaneous fat and the buccal fat pad. The chin fat pad was cylindric, measuring 20 mm long, 7,5 mm wide and 4 mm high. It became thinner during the lips protraction. The histological study revealed a lot of fibrous septa. It was more similar to the subcutaneous fat than to the buccal fat pad. PMID- 22445527 TI - [The size of the bile duct by echograph. A study]. AB - The purpose of this work was to determine the size of the bile duct by echograph. The frequent injuries of the bile duct in various pathologies in particular infection, made of it a very investigated organ especially by echograph. Its size can be modified by various pathologies. So it is of interest to know about its normal size. PATIENTS AND METHOD: Sixty normal subjects, among which 29 women, were examined by echograph in the university hospital of the Point G. They were voluntary subjects with an empty stomach for 12 hours. Three different sonographers successively performed this examination according to the same protocol with an Aloka SSD 1700 device type and a Kontron Medical/Imagic Maestro. These devices were provided with a convex probe of 3.5-megahertz multifrequency and with a linear probe of 7.5-megahertz. The subjects were in dorsal position. Reference points for the display of the bile duct were the liver, the gallbladder and the pancreas. The limits of the bile duct were marked by the cursor of the echograph. The transverse diameter (in mm) of the bile duct was measured in its origin and in its ending. No subject of the sample was obese enough to hamper the visibility of the gall-bladder and the bile duct and no subject had histories of cholecystectomy. Data analysis was made using the software Ear information version 6. The difference between variables was considered as significant when P<0,05. RESULTS: Forty subjects out of 60 were between 20 and 39 years old. The transverse diameter of the bile duct was measured 38 times (63.3%) in its origin and 50 times (83.3%) in its ending. The failure of visibility of the proximal segment was 37.7% and the failure of visibility of the distal segment of the bile duct was 17.7%. The average transverse diameter of the bile duct in its origin was 2.61.4 mm; extremes were 2 and 5 mm. The average transverse diameter of the bile duct in its ending was 3.10.7 mm; extremes were 2 and 5 mm. The transverse diameter of the bile duct in its origin of the subjects was contained between 3 and 4 mm in 80% of the cases. The transverse diameter of the bile duct in its ending of the subjects was contained between 3 and 4 mm in 40% of the cases. The difference was very significant between the diameter of the bile duct in its origin and in its ending (P<10(-6)). CONCLUSION: The distal segment of the bile duct was seen more accurately than the proximal segment by echograph. The diameter of the bile duct in its ending was significantly superior to that of the bile duct in its origin. PMID- 22445528 TI - [A rare cause of acute small bowel obstruction: incarcerated Spieghelian hernia. Case-report and literature review]. AB - A 73-year-old man, who previously underwent laparotomy for pancreatic adenocarcinoma, was admitted in the emergency room for acute small bowel obstruction related to a strangulated Spieghelian hernia. On CT-scan, the hernia was located at the lateral border of the right rectus abdominis muscle below the external oblique muscle, among the transverse abdominis and internal oblique muscles layers. Spieghelian hernias (or hernia of the linea semilunaris) often occur at the level of a weak spot where the linea accurata crosses the linea semilunaris, when the posterior layer of the rectus gain changes its conformation. This weak spot is limited underneath by the inferior epigastric artery. When examining a patient with a previous history of laparotomy presenting with acute small bowel obstruction, it is mandatory to exclude a possible strangulated Spieghelian hernia before concluding to postoperative intra abdominal adhesions. Spieghelian hernias are asymptomatic in approximately 90% of cases but entail a high risk of strangulation. Consequently, herniorrhaphy through a local approach route or open/laparoscopic mesh repair is always required. PMID- 22445529 TI - Morphological study of lingula of the mandibles in South Indian population. AB - PURPOSE OF THE STUDY: The objectives were to study the morphology of the lingulae in adult human dried mandibles of South Indian population. MATERIALS AND METHODS: The study was carried out on 67 (37 males and 30 females) dry mandibles and the morphological variants of the shapes of the lingulae were macroscopically noted and classified. Totally, 134 lingula were studied from both sides of mandibles. RESULTS: From our observations, 29.9% (40) of the lingula had triangular shape, 27.6% (37) were truncated, 29.9% (40) were found nodular and 12.6% (17) were assimilated. In 61.2% (41) of the mandibles, the shape of the lingula was symmetrical on both the sides. The triangular lingulae were found bilaterally in 14, truncated in 11, nodular in 10 and assimilated in six mandibles. CONCLUSION: In our specimens, the majority of the mandibles were having triangular shaped lingula and the shape of the lingula was symmetrical on both sides. There was sexual dimorphism observed, as in males the triangular shape was more common and in females it was nodular. The incidence of different forms of lingulae can be used as an anthropological marker to assess the different group of population and races, with other non-metric variants of the skull. The morphology of this subject is important to the maxillofacial and orodental surgeons as the inferior alveolar nerve is close to the lingula and may assist in the inferior alveolar block. PMID- 22445530 TI - Uncertainty about the true source. A note on the likelihood ratio at the activity level. AB - This paper focuses on likelihood ratio based evaluations of fibre evidence in cases in which there is uncertainty about whether or not the reference item available for analysis - that is, an item typically taken from the suspect or seized at his home - is the item actually worn at the time of the offence. A likelihood ratio approach is proposed that, for situations in which certain categorical assumptions can be made about additionally introduced parameters, converges to formula described in existing literature. The properties of the proposed likelihood ratio approach are analysed through sensitivity analyses and discussed with respect to possible argumentative implications that arise in practice. PMID- 22445531 TI - Single- and multivoxel proton spectroscopy in pediatric patients with diffuse intrinsic pontine glioma. AB - PURPOSE: To determine the feasibility of two magnetic resonance spectroscopy (MRS) techniques for treating pediatric patients with diffuse intrinsic pontine gliomas (DIPGs) and to evaluate the relationship of metabolic profiles determined by each technique. Utility of each technique for improving patient management is also discussed. METHODS AND MATERIALS: Children with DIPG (n = 36) were evaluated using single-voxel spectroscopy (SVS) and magnetic resonance spectroscopic imaging (MRSI) during the same imaging session. Patients were followed longitudinally (n = 150 total studies). Technical feasibility was defined by sufficient water and lipid suppression for detection of metabolites. Correlation of metabolic data obtained by SVS and MRSI was determined using the Spearman rank method. Metabolite ratios, including choline:N-acetyl-aspartate (Cho:NAA) and Cho:creatine (Cho:Cr), were obtained from SVS and MRSI. RESULTS: SVS and MRSI acquisitions were feasible in >90% of studies. Maximum Cho:NAA and Cho:Cr from MRSI analysis were strongly associated with Cho:NAA and Cho:Cr obtained by SVS (r = 0.67 and 0.76, respectively). MRSI Cho:NAA values were more heterogeneous than Cho:Cr values within the same lesion, and a strong linear relationship between the range and maximum Cho:NAA values was observed. CONCLUSIONS: SVS and MRSI acquisitions were feasible, with a strong correlation in metabolic data. Both techniques may improve diagnostic evaluation and management of DIPG. SVS is recommended for global assessment of tumor metabolism before and after therapy. MRSI showed heterogeneous patterns of metabolic activity within these tumors and is recommended for planning and monitoring targeted therapies and evaluating nearby tissue for tumor invasion. PMID- 22445532 TI - The clinical teaching preference questionnaire (CTPQ): an exploratory factor analysis. AB - BACKGROUND: Peer assisted learning is growing internationally as a beneficial pedagogical strategy in health care and tertiary education. Therefore having instruments such as the Clinical Teaching Preference Questionnaire (CTPQ) with strong measurement properties to use in educational research is vital. OBJECTIVES: To investigate the factor structure of the CTPQ when completed by a group of respondents from a large Australian university. METHODS: Data from the CTPQ completed by first year undergraduate nurses were analysed with a factor analysis using a Principal Axis Factoring (PAF) with Oblique Oblimin rotation. FINDINGS: A total of (n=265) first year undergraduate nursing students participated in the study. The vast majority of the participants were female 89% (n=236) and aged between 17 and 21 years of age 74% (n=197). Factor analysis of the 10 items revealed two factors with eigenvalues above 1, accounting for 68.3% of the total variance. Items with loadings greater than +/- .30, with the factor in question, were used to characterise the factor solutions. CONCLUSIONS: Findings from the exploratory factor analysis provide preliminary results that the CTPQ has adequate construct validity and reliability. This offers those involved in peer-assisted teaching and learning with a practical and usable instrument. PMID- 22445533 TI - Supporting rural/remote primary health care placement experiences increases undergraduate nurse confidence. AB - This paper reports on the analysis of data from undergraduate nursing students who participated in the Primary Health Care Intensive Programme (PHCIP) in far west New South Wales between 2006 and 2008. This analysis looks specifically at pre/post confidence levels of participants in relation to their grasp of underlying principles associated with primary health care practice and Indigenous health care delivery. Bachelor of nursing curricula remains heavily weighted towards acute care in large metropolitan facilities however; universities actively seek clinical fieldwork experiences in rural/remote and Indigenous communities for their students. The PHCIP was developed and delivered through the Broken Hill University Department of Rural Health, University of Sydney, and sought to address the disparity in student preparedness for practice in these settings through the provision of a structured and educational rural and remote clinical placement experience. Pre/post questionnaires, focus groups and three month post-placement phone interviews provided data on levels of participant confidence in the areas of primary health care delivery and culturally knowledgeable practice. This study indicates that structured preparation for practice, underpinned by authentic learning experiences and aligned with comprehensive education programmes can have a positive impact in the areas of skills, knowledge and attitudes and enhance the confidence of undergraduate nurses undertaking clinical placements in these settings. These findings are relevant to contemporary nursing education and evolving models of health care delivery for rural and remote communities. PMID- 22445534 TI - Phosphene thresholds correlate with paired-pulse suppression of visually evoked potentials. AB - BACKGROUND: Phosphene thresholds (PT) induced by transcranial magnetic stimulation (TMS) as well as paired-pulse suppression (PPS) of visually evoked potentials (VEP) are used to characterize visual cortex excitability, however, their relation remains unknown. METHODS: We measured PT after single TMS over the occipital lobe, and recorded VEPs after paired-pulse stimulation at short stimulus-onset-asynchronies in the same subject. PPS was expressed by the ratio second to first response. RESULTS: We found a negative correlation between PT and PPS (r = -0.36, P = 0.039) indicating that higher PT were associated with smaller ratios indicative of low excitability, and vice versa. There was no difference in PPS between subjects who perceived phosphenes and those who did not. CONCLUSIONS: Although both approaches target different mechanisms, PT and PPS seem to reflect common characteristics of visual cortex excitability. The lack of differences in PPS in subjects not perceiving phosphenes suggests that they might not have higher excitability levels. PMID- 22445535 TI - How far can TMS coils be optimized? A partial resolution. PMID- 22445536 TI - Plasticity of motor threshold and motor-evoked potential amplitude--a model of intrinsic and synaptic plasticity in human motor cortex? AB - BACKGROUND: Neuronal plasticity is the physiological correlate of learning and memory. In animal experiments, synaptic (i.e. long-term potentiation (LTP) and depression (LTD)) and intrinsic plasticity are distinguished. In human motor cortex, cortical plasticity can be demonstrated using transcranial magnetic stimulation (TMS). Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity. OBJECTIVE/HYPOTHESIS: We investigated the role of changes of motor threshold and their relation to changes of MEP amplitudes. METHODS: We induced plasticity by paired associative stimulation (PAS) with 25 ms or 10 ms inter stimulus interval or by motor practice (MP) in 64 healthy subjects aged 18-31 years (median 24.0). RESULTS: We observed changes of MEP amplitudes and motor threshold after PAS[25], PAS[10] and MP. In all three protocols, long-term individual changes in MEP amplitude were inversely correlated to changes in motor threshold (PAS[25]: P = .003, n = 36; PAS[10]: P = .038, n = 19; MP: P = .041, n = 19). CONCLUSION: We conclude that changes of MEP amplitudes and MT represent two indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent LTP-like or LTD-like synaptic plasticity of motor cortex output neurons, changes of MT may be considered as a correlate of intrinsic plasticity. PMID- 22445537 TI - The association between teat end hyperkeratosis and teat canal microbial load in lactating dairy cattle. AB - Most pathogens that cause bovine mastitis invade the udder lumen through the teat canal. Amino acids and intercellular lipids may support microbial colonisation of the teat canal epithelium by pathogenic microorganisms. The aim of this study was to investigate the association between teat end hyperkeratosis, which is induced by machine milking, and teat canal microbial load. Contralateral teats, which differed in teat end hyperkeratosis scores, were identified in a split-udder experiment. The teat canal's microbial load was evaluated using the wet and dry swab technique. Staphylococcus (S.) aureus, Streptococcus (Sc.) uberis, Escherichia (E.) coli and other coliforms were detected by agar plate cultures. The positive detection of E. coli and the log(10)-transformed E. coli load of a teat canal were significantly associated with the teat end hyperkeratosis score (P<0.05). There were significant differences with respect to positive findings for E. coli, as well as the microbial load of E. coli and Sc. uberis, between the less-calloused and the more-calloused teat of a pair. For S. aureus, no significant associations between hyperkeratosis score and teat canal microbial load were detected. In general, a teat with a highly calloused teat end had an increased teat canal microbial load compared with the contralateral teat, characterised by a lower callosity. The results of the present study indicate that the environmental pathogen load is associated with teat end hyperkeratosis. Further research is needed to identify factors that may affect teat canal microbial load in lactating dairy cattle. PMID- 22445538 TI - Circulation of bovine ephemeral fever in the Middle East--strong evidence for transmission by winds and animal transport. AB - Bovine ephemeral fever virus (BEFV) is an economically important arbovirus of cattle. The main routes of its transmission between countries and continents are not completely elucidated. This study aimed to explore BEFV transmission in the Middle-East. A phylogenetic analysis was performed on the gene encoding the G protein of BEFV isolates from Israel from 2000 and 2008 with isolates from Turkey (2008), Egypt (2005), Australia (1968-1998) and East Asia (1966-2004). Calf sera collected during the years 2006-2007 were tested by serum neutralization in order to explore for recent exposure to BEFV before 2008. These were followed by a meteorological analysis, aimed to reveal movement of air parcels into Israel in the two weeks preceding the first case of BEF in Israel in 2008. The 2008 Israeli and Turkish isolates showed 99% identity and formed a new cluster with the 2000 Israeli isolate. The serological survey showed no new exposure to BEFV during 2006 and 2007. These results coincided with the meteorological analysis, which revealed that air parcels originating in Southern Turkey had reached the location of outbreak onset in Israel nine days before the discovery of the index case. The Egyptian isolate clustered phylogenetically with the Taiwanese isolates, coinciding with data on importation of cattle from China to the Middle East in the year preceding the isolation of the Egyptian isolates. These results suggest that both winds and animal transport may have an important role in trans-boundary transmission of BEFV. PMID- 22445539 TI - Pharmacodynamic responses to combined treatment regimens with the calcium sensing receptor antagonist JTT-305/MK-5442 and alendronate in osteopenic ovariectomized rats. AB - Parathyroid hormone (PTH) is the anabolic standard of care for patients with severe osteoporosis. The CaSR allosteric antagonist JTT-305/MK-5442, a PTH secretagogue, could offer an oral osteoanabolic treatment alternative for postmenopausal women with osteoporosis. Here we disclose the pharmacokinetic profile of JTT-305/MK-5442 and its activity on bone remodeling in ovariectomized (OVX) osteopenic rats. Daily treatments (0.3 to 2.4 mg/kg/d) for 12 weeks resulted in plateaued BMD increases (3.8 to 5.3%) at axial and appendicular skeletal sites. However, treatment effects were not statistically significant, in agreement with effects seen in animals treated with low dose PTH (1-84) (5 MUg/kg/d). In a consecutive study we tested JTT-305/MK-5442 effects on bone formation in OVX-rats challenged with combined alendronate (ALN) treatment paradigms. At 7 month, JTT-305/MK-5442 treatment significantly increased BMD in lumbar vertebrae (LV), while no change in BMD was observed in femora or tibiae. ALN add-on co-treatment produced incremental increases in LV, distal femur (DF) and proximal tibia (PT) BMD over the respective ALN control. Histological analyses confirmed modest increases in mineralized surface (MS/BS) and bone formation rate (30.5+/-1.9%) on trabecular surfaces by JTT-305/MK-5442. As expected, ALN administration profoundly reduced bone formation, however, JTT 305/MK-5442 significantly stimulated MS/BS and BFR in ALN treated groups. In summary, JTT-305/MK-5442 acts as a PTH secretagogue in the osteopenic OVX-rat, eliciting consistent, though modest effects on remediation of BMD due to estrogen depletion. Induction of bone formation by JTT-305/MK-5442 at trabecular bone surfaces appears to be resilient to ALN-mediated suppression of bone formation. This study provides for the first time, a mechanistic evaluation of combination treatment of a PTH secretagogue with ALN. PMID- 22445540 TI - Quality control for bone quality parameters affected by subject motion in high resolution peripheral quantitative computed tomography. AB - Subject motion during high-resolution peripheral quantitative computed tomography (HR-pQCT) causes image artifacts that affect morphological analysis of bone quality. The aim of our study was to determine effectiveness of techniques for quality control in the presence of motion in vivo including automated and manual approaches. First, repeatability of manual grading was determined within and between laboratories. Given proper training using a standardized scale and training images (provided by the manufacturer), we found that manual grading is suitable for repeatable image quality grading within and across sites (ICC>0.7). Both a new automated technique providing motion measures based on projection moments, and traditional manual grading (1=best, 5=worst) were subsequently used to assess subject data for motion in N=137 image pairs (scan/re-scan) from the Canadian Multicentre Osteoporosis Study (CaMos) Calgary cohort. High quality image pairs were selected and measurement precision was estimated by calculating the coefficient of variation (CV). Consistent with previous data, density parameters (e.g. total bone mineral density) are more robust than structural (e.g. trabecular number) or finite element parameters (e.g. failure load). To obtain acceptable measurement precision, images should not exceed a manual grading of 3 (on a scale from 1 to 5) or an automatic (epsilon(T)) grading of 1.2. Automatic and manual grading provide comparable quality control, but the advantage of the automated technique is its ability to provide a motion value at scan time (providing a basis for real time decision regarding re-scan requirements), and the assessment is objective. Notably, automatic motion measurement can be performed retrospectively based on original scan data, and is therefore well suited for multi-center studies as well as any research where objective quality control is paramount. PMID- 22445541 TI - Lipoteichoic acid of Staphylococcus aureus enhances IL-6 expression in activated human basophils. AB - At allergic inflammation, cross-linking of FcERI with multivalent antigen-bound IgE triggers the signaling pathways via activation of protein kinase C (PKC) and mobilization of intracellular Ca(2+) leading to the production of various mediators such as interleukin-6 (IL-6). Accumulating reports demonstrated that interaction of Toll-like receptor 2 (TLR2) expressed on basophils with a TLR2 ligand, lipoteichoic acid (LTA) of Staphylococcus aureus, exacerbated allergic inflammation. Here, we showed that staphylococcal LTA (Sa.LTA) substantially enhanced IL-6 expression at both the protein and the mRNA levels in the human basophil line, KU812, in the presence of a PKC activator (phorbol 12-myristrate 13-acetate; PMA), and a calcium ionophore (A23187), whereas Sa.LTA alone could not induce IL-6 expression. PMA/A23187 augmented the expression of CD14 and TLR2 on the surface of KU812 cells and concomitantly increased the binding of fluorochrome-labeled Sa.LTA to the cells. Sa.LTA enhanced the phosphorylation of mitogen-activated protein (MAP) kinases in PMA/A23187-stimulated KU812 cells. Notably, Sa.LTA could not enhance PMA/A23187-induced IL-6 expression in the presence of inhibitors of MAP kinases, reactive oxygen species, or protein kinase C. Furthermore, Sa.LTA enhanced the PMA/A23187-increased DNA-binding activities of the transcription factors NF-kappaB and AP-1. Experiments using human peripheral blood mononuclear cells demonstrated that not only PMA/A23187 but also Sa.LTA increased the intracellular IL-6 expression in the basophil population and Sa.LTA plus PMA/A23187 further enhanced the IL-6 expression. Collectively, these results suggest that Sa.LTA exacerbates allergic inflammation by potentiating IL 6 production from activated basophils. PMID- 22445542 TI - "Cleansing" anatomical collections: The politics of removing specimens from German anatomical and medical collections 1988-92. AB - In 1989-90 an intense debate erupted in the Federal Republic of Germany over the status of anatomical specimens from the period of National Socialism. Pressure was brought on the German universities and research institutes to remove body parts. The solution was deemed rapid burial of all specimens whose provenance was in doubt. A range of options was considered, and the eventual decision to bury cremated remains was deemed the best way to draw a line under an uncomfortable past of Nazi medical atrocities. The aim was to achieve closure on this issue by a rapid "cleansing" of collections. However, identification of victims was left unresolved amidst the heated debates at the time. PMID- 22445543 TI - [Poorly differentiated neuroendocrine carcinoma of the colon with liver metastases]. AB - Neuroendocrine tumors of the gastrointestinal tract are highly infrequent. We report the case of a 57-year-old woman who presented with toxic syndrome, vomiting and a 3-month history diarrhea, with a final diagnosis of poorly differentiated neuroendocrine tumor. Based on this case, we review the clinical characteristics, diagnostic procedures, prognostic factors and therapeutic possibilities in this type of tumor. Neuroendocrine tumors should be considered in the diagnosis of colonic tumors with hyperechoic liver metastases. PMID- 22445544 TI - New bronchodilators. AB - Bronchodilators are central in the treatment of airway diseases including chronic obstructive pulmonary disease (COPD). Bronchodilators in COPD aim to improve lung function, reduce symptoms, prevent exacerbation, and enhance quality of life. The majority of programs in development for novel bronchodilators are focused on enhancing existing targets to once daily dosing and improving their safety profiles. However, just as important are other programs that aim to discover novel pharmacologic targets such as EP4 receptor agonists, bitter taste receptors, and selective PDE inhibitors. Furthermore, existing and novel bronchodilators have become vital components of multiple combination therapies targeting COPD. This review will discuss emerging bronchodilators highlighting preclinical data and available clinical trials. PMID- 22445545 TI - Lost in translation: regulation of skeletal muscle protein synthesis. AB - Skeletal muscle accounts for about 50% of the body's mass in higher vertebrates. Besides its obvious role in motor activity, it also can serve as a reservoir for amino acids during times of starvation, or even as a metabolic water supply for migratory birds' during long flights. An imbalance between anabolic and catabolic processes can lead to the loss of muscle mass and life-threatening cachexia or sarcopenia. This review summarizes the current state of knowledge about the regulation of protein translation in skeletal muscle; it also discusses the role of the mTOR pathway, as well as new findings about the influence of specific miRNAs on protein expression in skeletal muscle. PMID- 22445546 TI - Renal dysfunction and CABG. AB - Renal dysfunction after coronary artery bypass grafting is common and is associated with increased morbidity and mortality. A number of strategies with potential renoprotective effects have been investigated, but no single one has been found to warrant routine use in CABG except fenoldopam in which the data to date appear promising. Other measures such as avoidance of nephrotoxic agents, including recent radiocontrast for coronary angiography, may reduce the incidence of renal dysfunction after cardiac surgery and should be implemented in routine care, whenever possible. The best renal protection strategy remains the same as for other organ protection and consists of optimizing haemodynamics, oxygenation, metabolic states and hydration. PMID- 22445547 TI - Is losartan the drug for all seasons? PMID- 22445548 TI - Logic models: a useful way to study theories of evaluation practice? AB - This paper comments on the papers in the special volume on logic modeling and evaluation theory. Logic modeling offers a potentially useful approach to learning about the assumptions, activities, and consequences described in an evaluation theory and may facilitate comparative analysis of evaluation theories. However, logic models are imperfect vehicles for depicting the contingent and dynamic nature of evaluation theories. Alternative approaches to studying theories are necessary to capture the essence of theories as they may work in actual practice. PMID- 22445549 TI - Inverse production of IL-6 and IL-10 by abdominal aortic aneurysm explant tissues in culture. AB - BACKGROUND: Abdominal aortic aneurysm is considered an atherosclerosis-related disease, but the mechanisms underlying abdominal aortic aneurysm remain poorly defined. Despite the large number of cytokines identified in an aneurysm sample, the relative importance of particular cytokines in aneurysm formation is unknown. We have studied the production of interleukin-6 and interleukin-10 cytokines in plasma and cultures of abdominal aortic aneurysm explant samples obtained from patients subjected to elective surgery and their correlation with cellular composition. MATERIALS AND METHODS: Inflammatory cells from the abdominal aortic aneurysm samples were phenotypically characterized using specific monoclonal antibodies (anti-CD3, -CD4, -CD8, -CD19, -CD38, -CD68, -HLA-DR) by means of immunocytochemistry staining. Production of interleukin-6 and interleukin-10 in culture supernatants of abdominal aortic aneurysm explant samples expanded in vitro for 24 h was measured by enzyme-linked immunosorbent assay. RESULTS: We showed that the levels of interleukin-6 and interleukin-10 in supernatants of abdominal aortic aneurysm sample cultures were higher by 73 and 86 times compared to their levels in plasma, respectively. In individual abdominal aortic aneurysm explant cultures, a negative correlation between interleukin-6 and interleukin-10 production was observed. Such inverse correlation was not detected in plasma. Based on these results, we divided abdominal aortic aneurysm into two cytokine producing groups and showed that the interleukin-6(hi)/interleukin-10(lo) group contained higher percentages of granulocytes, HLA-DR(+), and CD68(+) cells but lower percentages of lymphocytes and plasma cells compared to the interleukin 6(lo)/interleukin-10(hi) group. Exogenously added interleukin-10 suppresses the production of interleukin-6 by abdominal aortic aneurysm explants. CONCLUSION: These results suggest that interleukin-6 and interleukin-10 may have a different role in the pathogenesis of abdominal aortic aneurysm. PMID- 22445550 TI - Androgen deprivation therapy for localized and nonmetastatic prostate cancer: too much of a good thing? PMID- 22445551 TI - The effect of curcin from Jatropha curcas on apoptosis of mouse sarcoma-180 cells. AB - Curcin is a ribosome-inactivating protein expressed in the endosperm of Jatropha curcas. Curcin can inhibit growth of mouse sarcoma-180 cells. At a curcin concentration of 100 MUg/ml, mouse sarcoma-180 cell growth was inhibited by over 40% after seven days of incubation. Acridine orange staining and flow cytometry analysis also showed that the curcin could induce apoptosis of mouse sarcoma-180 cells. These observations provide a possible explanation for the anti-tumor properties of curcin. PMID- 22445552 TI - Cytotoxic dimeric indole alkaloids from Catharanthus roseus. AB - Three new dimeric indole alkaloids (1-3), together with five known ones (4-8), were isolated from the whole plants of Catharanthus roseus. The structures and absolute configurations of new compounds were elucidated by means of NMR and CD analyses. All these compounds were evaluated for their in vitro cytotoxic activities against human breast cancer cell line MDA-MB-231. PMID- 22445553 TI - An unusual taxodione derivative from hairy roots of Salvia austriaca. AB - From a root culture of Salvia austriaca, transformed with Agrobacterium rhizogenes, a new diterpenoid was isolated and its chemical structure was determined as 7-(2-oxohexyl)-11-hydroxy-6, 12-dioxo-7,9(11),13- abietatriene [= 7 (2-oxohexyl)-taxodione] on the basis of spectroscopic methods, especially 1D and 2D NMR, and by comparison with structurally related compounds. This compound represents a hitherto unknown 2-oxohexyl diterpenoid derivative. Cytotoxic studies revealed that the new compound exhibited high cytotoxic activity against three cancer cell lines with IC(50) values ranging from 0.63 to 0.72MUM. Its cytotoxic effectiveness against the cancer cells was ten fold higher than that of taxodione. PMID- 22445554 TI - Reproducibility of radiographic hip measurements in adults. AB - INTRODUCTION: Hip dysplasia may cause pain and premature hip osteoarthritis. Here, our objective was to assess the inter- and intraobserver reproducibility of radiographic hip parameter measurement in adults. METHODS: We used anteroposterior pelvic radiographs and false-profile lateral hip radiographs from 30 individuals (60 hips) enrolled in a prevalence study of hip osteoarthritis. For each hip, two independent observers recorded five parameters twice, at an interval of 1 month. The five parameters were the vertical-center-edge angle (VCE), the anterior center-edge angle (vertical-center-anterior angle, VCA), the acetabular roof angle (HTE), the neck-shaft angle (CC'D), and acetabulum depth (AD). Reproducibility was assessed using Bland-Altman plots, intraclass correlation coefficients (ICCs), and kappa coefficients for the radiographic diagnosis of hip dysplasia using widely accepted cutoffs. RESULTS: Of the 60 hips, 51 were assessable. Intraobserver ICC values ranged from 0.72 to 0.94 and interobserver ICC values from 0.68 to 0.84. Kappa coefficients were between 0.60 and 1.00, except for the VCA angle (kappa=0.41). CONCLUSION: In this study, reproducibility of the main radiographic hip parameters was good according to all evaluation methods used. However, CC'D and, to an even greater extent, the VCA angle seemed challenging to measure. PMID- 22445555 TI - Mechanism of action of hydrogen sulfide on cyclic AMP formation in rat retinal pigment epithelial cells. AB - Hydrogen sulfide (H(2)S), a colorless gas with the pungent odor of rotten eggs has been reported to produce pharmacological actions in ocular and non-ocular tissues. We have evidence that H(2)S, using sodium hydrosulfide (NaHS) and sodium sulfide (Na(2)S) as donors can increase cyclic AMP (cAMP) production in neural retina. In the present study, we investigated the mechanism of action of H(2)S on cyclic nucleotide production in rat retinal pigment epithelial cells (RPE-J). Cultured RPE-J cells were incubated for 30 min in culture medium containing the cyclic nucleotide phosphodiesterase (PDE) inhibitor, IBMX (2 mM). Cells were exposed to varying concentrations of NaHS, the H(2)S substrate (L-cysteine), cyclooxygenase (COX) inhibitors or the diterpene activator of adenylate cyclase, forskolin in the presence or absence of H(2)S biosynthetic enzymes or the ATP sensitive potassium (K(ATP)) channel antagonist, glibenclamide. Following drug treatment at different time intervals, cell homogenates were prepared for cAMP assay using a well established methodology. In RPE-J cells, NaHS (10 nM-1 MUM) produced a time-dependent increase in cAMP concentrations over basal levels which reached a maximum at 20 min. At this time point, both NaHS (1 nM-100 MUM) and L cysteine (1 nM-10 MUM) produced a concentration-dependent significant (p<0.05) increase in cAMP concentrations over basal level. The effects of NaHS on cAMP levels in RPE-J cells was enhanced significantly (p<0.01) in the presence of the COX inhibitors, indomethacin and flurbiprofen. In RPE-J cells, the effects caused by forskolin (10 MUM) on cAMP production were potentiated by addition of low concentrations of NaHS. Both the inhibitor of cystathionine beta-synthase (CBS), aminooxyacetic acid (AOA, 1 mM) and the inhibitor of cystathionine gamma-lyase (CSE), proparglyglycine (PAG, 1mM) significantly attenuated the increased effect of L-cysteine on cAMP production. The K(ATP) channel antagonist, glibenclamide (100 MUM) caused inhibition of NaHS induced-increase of cAMP formation in RPE-J cells. We conclude that, H(2)S (using H(2)S donor and substrate) can increase cAMP production in RPE-J cells, and removal of the apparent inhibitory effect of prostaglandins unmasks an excitatory activity of H(2)S on cAMP. Effects elicited by the H(2)S substrate on cAMP formation are dependent on biosynthesis of H(2)S catalyzed by the biosynthetic enzymes, CBS and CSE. In addition to the adenylyl cylcase pathway, K(ATP) channels are involved in mediating the observed effects of the H(2)S on cAMP production. PMID- 22445556 TI - [Critical ischemia in patients over 80: waiting or evidence-based surgical treatment?]. AB - Critical ischemia is defined by continuous pain, impending sleep, with ankle pressure less than 50mm Hg, and/or first toe pressure less than 30 mm Hg (Dormandy et Rutherford, 2000; Norgren et al., 2007). Treatment of patients aged over 80 requires specific knowledge of arteriopathy at this age and an evaluation of co-morbidity factors (diabetes mellitus, renal failure, ischemic cardiopathy). Assessment should include: the degree of ischemia, the extension of arterial disease, the co-morbidity factors, and the diffusion of the atherosclerotic disease. A transatlantic consensus conference has enabled a classification of arterial lesions determining therapeutic indications. Aorto-iliac lesions may be treated by surgery or angioplasty. Femoro-popliteal or crural lesions may be treated by surgery or angioplasty. Type C or D lesions should be treated by femoro-popliteal or crural bypass. Bypass to the ankle or foot are done on high peripheral resistances. These bypasses require a venous graft. Several authors have shown the utility of short grafts: popliteo-tibial, tibiotibial, tibiopedal artery bypass, tibioplantar artery bypass. In patients over 80, the presence of arteriopathy is an important mortality factor, which is four or five times more important than in the normal population. Twenty-five percent of patients will require amputation. PMID- 22445557 TI - Brush-based self-sampling in combination with GP5+/6+-PCR-based hrHPV testing: high concordance with physician-taken cervical scrapes for HPV genotyping and detection of high-grade CIN. AB - BACKGROUND: Studies have shown that self-sampling for hrHPV testing (HPV self sampling) is highly acceptable to women, increases screening participation rate, and may therefore further reduce cervical cancer incidence. However, it is important to clinically validate HPV self-sampling procedures for screening purposes. OBJECTIVES: Clinical validation of combined brush-based self-sampling with GP5+/6+-PCR EIA for primary cervical screening. In addition, HPV type specific agreement between sample types and acceptability of brush-based self sampling were evaluated. STUDY DESIGN: 135 women referred for colposcopy took a self-sample at home prior to vaginal- and cervical sampling by a gynaecologist. All women were biopsied for histology. HPV testing was done by GP5+/6+-PCR EIA, with genotyping by reverse line blotting (RLB). Acceptability of sampling methods was measured with a questionnaire. RESULTS: In this outpatient population, hrHPV test results showed good concordance between self-samples and physician-taken cervical scrapes (86%, k=0.70), with sensitivities and specificities for CIN2+ that did not differ significantly (93% and 51%, 91% and 51%, respectively (P=1.0)). The clinical sensitivity of brush-based self-sampling combined with GP5+/6+-PCR EIA hrHPV testing for detection of CIN2+ was non-inferior to that of hrHPV testing on physician-taken cervical samples (P=0.018). In addition, hrHPV genotyping results were highly concordant between sample types, with almost perfect agreement for HPV16 (k=0.81) and HPV18 (k=0.92). Finally, 91% of participants described brush-based self-sampling as easy-to-use. CONCLUSIONS: Brush-based self-sampling in combination with GP5+/6+-PCR EIA hrHPV testing is acceptable to women and valid for assessing the risk of CIN2+ in comparison to hrHPV testing on physician-taken scrapes. In addition, there was high concordance of HPV genotyping results. Therefore, this HPV self-sampling procedure may be considered for use in routine cervical screening. PMID- 22445558 TI - Effect of curcumin and quercetin on lysosomal enzyme activities in streptozotocin induced diabetic rats. AB - BACKGROUND & AIMS: Diabetes causes impairment of various enzyme activities in the physiological system, including lysosomal enzymes. The effect of feeding curcumin, quercetin and aminoguanidine on lysosomal enzyme activities viz., N acetyl-beta-d-glucosaminidase, beta-d-glucuronidase, beta-d-galactosidase and acid phosphatase were studied in different tissues of streptozotocin-induced diabetic rats. METHOD: Rats were divided into four control groups and four diabetic groups. Experimental groups were fed with diet supplemented with curcumin (0.5%) or quercetin (0.1%) or aminoguanidine (0.05%). Lysosomal enzyme activities were determined in various tissues. RESULTS: The specific activity of N-acetyl-beta-d-glucosaminidase in liver of diabetic rats was decreased when compared to control rats and was ameliorated with curcumin and quercetin treatment by 67% and 78%, respectively. On the other hand, beta-d-glucuronidase activity was higher in the brain of diabetic rats (0.90 +/- 0.04 nmol/mg protein/min), when compared to control rats (0.45 +/- 0.02 nmol/mg protein/min) and was decreased in curcumin (0.75 +/- 0.05 nmol/mg protein/min) and quercetin (0.74 +/- 0.11 nmol/mg protein/min) treated rats. beta-d-galactosidase activity in spleen of curcumin and quercetin fed diabetic group rats was ameliorated by 68% and 58%, respectively, in comparison to diabetic rats. Acid phosphatase activity in diabetic rats decreased in testis when compared to control. CONCLUSION: Curcumin and quercetin feeding modulated lysosomal enzyme activities in different tissues during diabetes and the effect was comparable to well-known anti-glycative agent - aminoguanidine. PMID- 22445559 TI - Fuzzy linguistic model for bioelectrical impedance vector analysis. AB - BACKGROUNDS & AIMS: The boundaries between the categories of body composition provided by vectorial analysis of bioimpedance are not well defined. In this paper, fuzzy sets theory was used for modeling such uncertainty. METHODS: An Italian database with 179 cases 18-70 years was divided randomly into developing (n = 20) and testing samples (n = 159). From the 159 registries of the testing sample, 99 contributed with unequivocal diagnosis. Resistance/height and reactance/height were the input variables in the model. Output variables were the seven categories of body composition of vectorial analysis. For each case the linguistic model estimated the membership degree of each impedance category. To compare such results to the previously established diagnoses Kappa statistics was used. This demanded singling out one among the output set of seven categories of membership degrees. This procedure (defuzzification rule) established that the category with the highest membership degree should be the most likely category for the case. RESULTS: The fuzzy model showed a good fit to the development sample. Excellent agreement was achieved between the defuzzified impedance diagnoses and the clinical diagnoses in the testing sample (Kappa = 0.85, p < 0.001). CONCLUSIONS: fuzzy linguistic model was found in good agreement with clinical diagnoses. If the whole model output is considered, information on to which extent each BIVA category is present does better advise clinical practice with an enlarged nosological framework and diverse therapeutic strategies. PMID- 22445560 TI - Environmental toxicants: lead and mercury. PMID- 22445561 TI - [Preterm newborn with suspected infection by vertical transmission]. PMID- 22445562 TI - Fournier gangrene: description of 37 cases and analysis of associated health care costs. AB - BACKGROUND AND OBJECTIVES: Fournier gangrene is a urological emergency associated with a high mortality. It is a necrotizing fasciitis caused by polymicrobial infection originating in the anorectal or genitourinary area. The aim of this study was to analyze the epidemiological and clinical characteristics of Fournier gangrene along with the variables that influence disease course and mortality in patients treated in our department. MATERIAL AND METHODS: We carried out a retrospective study of 37 patients diagnosed with Fournier gangrene between January 2001 and October 2010. RESULTS: All the patients were men, 43.2% had diabetes, and the mean age of the patients was 57.68 years. Statistically significant differences were observed between the age of surviving patients and that of patients who died (55.8 and 69.6 years, respectively). The mean hospital stay was 27.54 days and 32.4% of patients required admission to the intensive care unit. Etiology was unknown in 39.8% of cases. Polymicrobial infection was observed in 59.5% of cases. The mean health care cost associated with a patient diagnosed with Fournier gangrene admitted to intensive care and requiring at least 1 procedure in the operating room was ?25,108.67. Mortality was 13.5%. Based on analysis of individual comorbid conditions, only ischemic heart disease displayed a statistically significant association with mortality due to Fournier gangrene; ischemic heart disease was also associated with longer hospital stay. CONCLUSIONS: Fournier gangrene is associated with high mortality despite appropriate early treatment. Although the condition is infrequent, the high associated health care costs suggest that primary and secondary prevention measures should be implemented. PMID- 22445563 TI - Lichen sclerosus and squamous cell carcinoma. AB - Lichen sclerosus is a chronic inflammatory disease that can progress to malignancy. The literature indicates an association with anogenital squamous cell carcinoma and verrucous carcinoma. Two pathogenic pathways, differentiated vulvar and penile intraepithelial neoplasias, which have recently been described in relation to squamous cell carcinoma, are both highly associated with genital lichen sclerosus independently of human papilloma virus (HPV) infection. Furthermore, tumor-promoting molecular changes unrelated to HPV infection have been demonstrated and may explain the malignant potential of lichen sclerosus. The possible relationship between HPV and genital lichen sclerosus currently remains open to discussion, and the prognostic importance of the overlapping of these 2 diseases is still unclear. This review considers the relationship between lichen sclerosus and squamous cell and verrucous carcinomas, the possible oncogenic mechanisms involved, and their possible association with HPV infection. PMID- 22445564 TI - Halo nevi associated with interferon beta-1a therapy. PMID- 22445565 TI - Sarcoid-type allergic contact granuloma caused by earrings in a boy. PMID- 22445566 TI - Superficial acral fibromyxoma: a CD34+ periungual tumor. PMID- 22445567 TI - Brain ultrasound findings in neonates treated with intrauterine transfusion for fetal anaemia. AB - BACKGROUND: The main causes of severe fetal anaemia are red-cell allo immunization, parvo B19 virus infection and feto-maternal haemorrhage. Treatment consists of intrauterine transfusion (IUT). Neuro-imaging studies in surviving neonates treated with IUT are scarce. AIMS: To assess if neonates treated with IUT for fetal anaemia are at risk for cerebral injury, report the incidence and severity of brain ultrasound (US) abnormalities and explore the relation between brain US findings and perinatal parameters and neurological outcome. PATIENTS AND METHODS: Brain US scans of neonates born alive between 2001 and 2008 with at least one IUT were retrospectively reviewed and classified as normal, mildly or moderately/severely abnormal. Incidences of abnormalities were calculated for full-term and preterm neonates. Presence and severity of abnormalities were related to clinical and IUT related parameters and to neurological outcome around 2 years of age (adverse: moderate or severe disability; favourable: normal or mild disability). RESULTS: A total of 127 neonates (82 born preterm) were included. Median number of IUTs was 3 (range 1-6) and of brain US 2 (1-6). Median gestational age and weight at birth were 36.6 (26.0-41.1) weeks and 2870 (1040 3950)g. In 72/127 (57%) neonates >=1 abnormality was seen on brain US, classified as moderate/severe in 30/127 (24%). Neurological outcome was adverse in 5 infants. Presence of brain US abnormalities was not significantly related to any of the perinatal parameters or to neurological outcome. CONCLUSIONS: Neonates undergoing IUT for fetal anaemia are at high risk of brain injury. PMID- 22445568 TI - Myocardial hypertrophy and dysfunction in maternal diabetes. AB - Diabetes in pregnancy, both pre-gestational and gestational, is a frequent cause of fetal myocardial hypertrophy, partly due to fetal hyperinsulinism. In fetal life, cardiac function may be impaired, especially during diastole, as a result of decreased left ventricular distensibility and altered left atrial dynamics secondary to myocardial hypertrophy. In neonates, the hypertrophy is a transient disorder, with spontaneous regression of the increased myocardial thickness during the first months of life. Nevertheless, cardiac hypertrophy may be associated with neonatal cardiomegaly and respiratory distress secondary to poor left ventricular compliance. The development of a number of new echocardiographic parameters discussed in this article, and primarily based on the pathophysiological consequences of myocardial hypertrophy, highlight an area of research priority: the assessment of diastolic function in fetuses of diabetic mothers with (and without) myocardial hypertrophy. A score for grading the severity of fetal diastolic dysfunction in these fetuses is proposed. PMID- 22445569 TI - Genetic variants associated with adult blood pressure and kidney function do not affect fetal kidney volume. The Generation R Study. AB - BACKGROUND: Smaller kidneys with reduced number of nephrons in early life lead to impaired kidney function and risk for hypertension and chronic kidney disease. These associations might be partly explained by common genetic variation. AIMS: To assess the associations between common genetic variants, which have recently shown to be associated with blood pressure or kidney function, with fetal kidney volume. STUDY DESIGN: A prospective population based cohort study in Rotterdam, The Netherlands. SUBJECTS: 855 children, followed from early fetal life onwards (born 2003-2005). PREDICTOR: Common genetic variants previously associated with blood pressure or kidney function. OUTCOME MEASURES: Combined third trimester fetal kidney volume. RESULTS: After taking into account multiple testing, only rs12940887 (near ZNF652) was significantly associated with fetal kidney volume (beta: 0.88 (95% CI: 0.40; 1.37) cm(3) per minor allele, P-value<0.001), but the effect showed the opposite direction as expected. The remaining common genetic variants were not associated with fetal kidney volume. We also did not find associations of genetic variants previously shown to affect newborn kidney volume, with third trimester fetal kidney volume. CONCLUSIONS: Our results suggest that common genetic variants, associated with kidney function or disease and blood pressure, do not affect the third trimester fetal kidney volume. Further studies are needed to elucidate the mechanisms underlying the associations between small kidney size and increased risks of hypertension and impaired kidney function in adulthood. PMID- 22445570 TI - Genetic susceptibility to experimental autoimmune glomerulonephritis in the Wistar Kyoto rat. AB - In experimental autoimmune glomerulonephritis (EAG), a model of Goodpasture's disease, Wistar Kyoto (WKY) rats immunized with collagenase-solubilized glomerular basement membrane (GBM) or the recombinant NC1 domain of the alpha3 chain of type IV collagen [alpha3(IV)NC1] develop anti-GBM antibodies and focal necrotizing glomerulonephritis with crescent formation. However, Lewis (LEW) rats, which share the same major histocompatibility complex (MHC) haplotype, are resistant to EAG development. A genome-wide linkage analysis of backcrossed animals with EAG revealed a major quantitative trait locus (QTL) on rat chromosome 13 (LOD = 3.9) linked to the percentage of glomerular crescents. To investigate the role of this QTL in EAG induction, reciprocal congenic rats were generated (LEW.WCrgn1 congenic and WKY.LCrgn1 congenic), immunized with recombinant rat alpha3(IV)NC1, and assessed for EAG development. WKY.LCrgn1 rats showed a marked reduction in albuminuria, severity of crescentic nephritis, and number of glomerular macrophages compared with WKY controls. No reduction in antibody levels was observed. However, LEW.WCrgn1 rats were resistant to EAG development, as were LEW controls. Macrophage activation in vitro was assessed in parental and congenic rat bone marrow-derived macrophages (BMDMs). WKY.LCrgn1 BMDMs showed a significant reduction in Fc receptor-mediated oxidative burst, phagocytosis of opsonised polystyrene beads, and LPS-induced levels of MCP-1 secretion and iNOS mRNA expression compared with WKY rats. These results confirm the importance of Crgn1 on chromosome 13 in EAG susceptibility, mediated partly through differences in Fc receptor-mediated macrophage activation. PMID- 22445572 TI - Anatomy and evolution of the mandibular, hyopalatine, and opercular muscles in characiform fishes (Teleostei: Ostariophysi). AB - The Characiformes are distributed throughout large portions of the freshwaters of Africa and America. About 90% of the almost 2000 characiform species inhabit the American rivers, with their greatest diversity occurring in the Neotropical region. As in most other groups of fishes, the current knowledge about characiform myology is extremely poor. This study presents the results of a survey of the mandibular, hyopalatine, and opercular musculature of 65 species representing all the 18 traditionally recognized characiform families, including the 14 subfamilies and several genera incertae sedis of the Characidae, the most speciose family of the order. The morphological variation of these muscles across the order is documented in detail and the homologies of the characiform adductor mandibulae divisions are clarified. Accordingly, the mistaken nomenclature previously applied to these divisions in some characiform taxa is herein corrected. Contradicting some previous studies, we found that none of the examined characiforms lacks an A3 section of the adductor mandibulae, but instead some taxa have an A3 continuous with A2. Derived myological features are identified as new putative synapomorphies for: the Characoidei; the clade composed of the Alestidae, Characidae, Gasteropelecidae, Cynodontoidea, and Erythrinoidea; the clade Cynodontoidea plus Erythrinoidea; the clade formed by Ctenoluciidae and Erythrinidae; the Serrasalminae; and the Triportheinae. Additionally, new myological data seems to indicate that the Agoniatinae might be more closely related to cynodontoids and erythrinoids than to other characids. PMID- 22445571 TI - Skeletal muscle-specific genetic determinants contribute to the differential strain-dependent effects of hindlimb ischemia in mice. AB - Genetics plays an important role in determining peripheral arterial disease (PAD) pathology, which causes a spectrum of clinical disorders that range from clinically silent reductions in blood flow to limb-threatening ischemia. The cell type specificity of PAD pathology, however, has received little attention. To determine whether strain-dependent differences in skeletal muscle cells might account for the differential responses to ischemia observed in C57BL/6 and BALB/c mice, endothelial and skeletal muscle cells were subjected to hypoxia and nutrient deprivation (HND) in vitro, to mimic ischemia. Muscle cells were more susceptible to HND than were endothelial cells. In vivo, C57BL/6 and BALB/c mice displayed strain-specific differences in myofiber responses after hindlimb ischemia, with significantly greater myofiber atrophy, greater apoptosis, and attenuated myogenic regulatory gene expression and stress-responsive signaling in BALB/c mice. Strain-specific deficits were recapitulated in vitro in primary muscle cells from both strains after HND. Muscle cells from BALB/c mice congenic for the C57BL/6 Lsq-1 quantitative trait locus were protected from HND-induced atrophy, and gene expression of vascular growth factors and their receptors was significantly greater in C57BL/6 primary muscle cells. Our results indicate that the previously identified specific genetic locus regulating strain-dependent collateral vessel density has a nonvascular or muscle cell-autonomous role involving both the myogenic program and traditional vascular growth factor receptor expression. PMID- 22445573 TI - Functional morphology and adhesive performance of the stick-capture apparatus of the rove beetles Stenus spp. (Coleoptera, Staphylinidae). AB - The adhesive prey-capture apparatus of the representatives of the rove beetle genus Stenus (Coleoptera, Staphylinidae) is an outstanding example of biological adhesive systems. This unique prey-capture device is used for catching elusive prey by combining (i) hierarchically structured adhesive outgrowths, (ii) an adhesive secretion, and (iii) a network of cuticular fibres within the pad. The outgrowths arise from a pad-like cuticle and are completely immersed within the secretion. To date, the forces generated during the predatory strike of these beetles have only been estimated theoretically. In the present study, we used force transducers to measure both the compressive and adhesive forces during the predatory strike of two Stenus species. The experiments revealed that the compressive forces are low, ranging from 0.10 mN (Stenus bimaculatus) to 0.18 mN (Stenus juno), whereas the corresponding adhesive forces attain up to 1.0 mN in S. juno and 1.08 mN in S. bimaculatus. The tenacity or adhesive strength (adhesive force per apparent unit area) amounts to 51.9 kPa (S. bimaculatus) and 69.7 kPa (S. juno). S. juno beetles possess significantly smaller pad surface areas than S. bimaculatus but seem to compensate for this disadvantage by generating higher compressive forces. Consequently, S. juno beetles reach almost identical adhesive properties and an equal prey-capture success in attacks on larger prey. The possible functions of the various parts of the adhesive system during the adhesive prey-capture process are discussed in detail. PMID- 22445574 TI - Serotonin-immunoreactive neurons in scorpion pectine neuropils: similarities to insect and crustacean primary olfactory centres? AB - The pectines of scorpions are a single pair of mechano- and chemosensory appendages located ventrally behind the most posterior pair of walking legs. They are used for probing the substrate in behaviours such as prey tracking and courtship. The sensory afferents on the pectines supply large segmental neuropils with a conspicuous glomerular structure. The pectine neuropils thus bear similarities to insect and crustacean deutocerebral chemosensory centres associated with the antennae, but they also possess idiosyncratic features. One characteristic property of many insect and decapod crustacean olfactory neuropils is their innervation by single, or very few, large serotonergic (inter-) neurons. This feature, among others, has been proposed to support homology of the olfactory lobes in the two arthropod groups. A possible serotonergic innervation of the scorpion pectine neuropils has not yet been studied, despite its apparent diagnostic and functional importance. We thus examined serotonin-immunoreactivity in the pectine neuropils of Androctonus australis and Pandinus imperator. Both scorpion species yielded similar results. The periphery of the neuropil and the matrix between the glomeruli are supplied by a dense network of serotonin immunoreactive (5-HT-ir) arborisations and varicosities, while the glomeruli themselves are mostly free of 5-HT-ir fibres. The 5-HT-ir supply of the pectine neuropils has two origins. The first is a pair of neurons on each body side, up to 30 MUm in diameter and thus slightly larger than the surrounding somata. These cell bodies are and associated with the neuromeres of the genital and pectine segments. The situation is reminiscent of the 5-HT supply of insect and crustacean olfactory and antennal neuropils. The second 5-HT innervation of the pectine neuropils is from a group of some 10-20 ipsilateral neuronal somata of slightly smaller size (15-20 MUm). These are part of a much larger 5-HT-ir group comprising 70-90 somata. The whole group is located more anteriorly than the single soma mentioned above, and associated with the neuromere of the last (4th) walking leg. When compared to data from other arthropods, our findings may suggest that glomerular organisation is an ancestral feature of primary chemosensory centres innervated by arthropod appendages. This idea needs further scrutiny, although supporting evidence may have been overlooked previously, due to the small size of chemosensory neuropils in walking legs and in reduced segmental appendages. PMID- 22445575 TI - Comparing evaluation activities across multiple theories of practice. AB - This article compares and contrasts the evaluation activities described in Practical Participatory Evaluation (Cousins & Whitmore, 1998), Values-engaged Evaluation (Greene, 2005), and Emergent Realist Evaluation (Mark, Henry, & Julnes, 1998). Using the logic models developed to depict each of the three evaluation theories (Hansen, Alkin, & Wallace, 2013) as a starting point, both quantitative and qualitative analysis techniques are employed to discuss the similarities and differences across the practice prescriptions. The approaches are then described according to Miller's (2010) standards for empirical examinations of evaluation theory. Specifically, I offer speculation about their operational specificity and feasibility in practice. I argue that none of the models is completely specific, or wholly unique, and they all present challenges of adaptation into the field. However, the models each offer varying degrees of guidance and unique elements through their prescriptions. PMID- 22445576 TI - Estimating the subjective value of future rewards: comparison of adjusting-amount and adjusting-delay procedures. AB - The present study examined whether equivalent discounting of delayed rewards is observed with different experimental procedures. If the underlying decision making process is the same, then similar patterns of results should be observed regardless of procedure, and similar estimates of the subjective value of future rewards (i.e., indifference points) should be obtained. Two experiments compared discounting on three types of procedure: adjusting-delay (AD), adjusting immediate-amount (AIA), and adjusting-delayed-amount (ADA). For the two procedures for which discounting functions can be established (i.e., AD and AIA), a hyperboloid provided good fits to the data at both the group and individual levels, and individuals' discounting on one procedure tended to be correlated with their discounting on the other. Notably, the AIA procedure produced the more consistent estimates of the degree of discounting, and in particular, discounting on the AIA procedure was unaffected by the order in which choices were presented. Regardless of which of the three procedures was used, however, similar patterns of results were obtained: Participants systematically discounted the value of delayed rewards, and robust magnitude effects were observed. Although each procedure may have its own advantages and disadvantages, use of all three types of procedure in the present study provided converging evidence for common decision-making processes underlying the discounting of delayed rewards. PMID- 22445577 TI - Prison structure, inmate mortality and suicide risk in Europe. AB - Suicide presents a major complication during imprisonment and greatly contributes to the high mortality rate of prisoners. All international studies have found increased suicide rates among prisoners compared to the general population. This study examines risk factors for suicide and mortality in prisoners using supranational data from the Council of Europe Annual Penal Statistics (Statistiques Penales Annuelles du Conseil du L'Europe or SPACE) from 1997 to 2008. Macrostructural risk factors for prison suicide are analyzed from this supranational data set and the identified indicators are further evaluated on the single country level. Sexual offenders, offenders charged with violent crimes and prisoners sentenced for short- and long-term imprisonment are considered to be at an elevated risk for suicide. In addition, prison mortality is associated with overcrowding. PMID- 22445578 TI - Effectiveness of percutaneous coronary intervention in patients with silent myocardial ischemia (post hoc analysis of the COURAGE trial). AB - Previous studies have suggested that percutaneous coronary intervention (PCI) decreases long-term mortality in patients with silent myocardial ischemia (SMI), but whether PCI specifically decreases mortality when added to intensive medical therapy is unknown. We performed a post hoc analysis of clinical outcomes in patients in the COURAGE trial based on the presence or absence of anginal symptoms at baseline. Asymptomatic patients were classified as having SMI by electrocardiographic ischemia at rest or reversible stress perfusion imaging (exercise-induced or pharmacologic). Study end points included the composite primary end point (death or myocardial infarction [MI]); individual end points of death, MI, and hospitalization for acute coronary syndrome; and need for revascularization. Of 2,280 patients 12% (n = 283) had SMI and 88% were symptomatic (n = 1,997). There were no between-group differences in age, gender, cardiac risk factors, previous MI or revascularization, extent of angiographic disease, or ischemia by electrocardiogram or imaging. Compared to symptomatic patients, those with SMI had fewer subsequent revascularizations (16% vs 27%, p <0.001) regardless of treatment assignment and fewer hospitalizations for acute coronary syndrome (7% vs 12%, p <0.04). No significant differences in outcomes were observed between the 2 treatment groups, although there was a trend toward fewer deaths in the PCI group (n = 7, 5%) compared to the optimal medical therapy (OMT) group (n = 16, 11%, p = 0.12). In conclusion, addition of PCI to OMT did not decrease nonfatal cardiac events in patients with SMI but showed a trend toward fewer deaths. Although underpowered, given similar outcomes in other small studies, these findings suggest the need for an adequately powered trial of revascularization versus OMT in SMI patients. PMID- 22445579 TI - Nausea and vomiting in acute myocardial infarction. PMID- 22445580 TI - ST-segment elevation in electrocardiogram lead aVR. PMID- 22445581 TI - Analysis of very late in-stent thrombosis in the EVASTENT patients. PMID- 22445583 TI - Noncompaction in neuromuscular disorders is not at variance from noncompaction in chromosomal disorders, congenital, or non-hereditary disease. PMID- 22445585 TI - The stress state of the fraenal notch region in complete upper dentures. AB - The present study determines the stress field in the region of the labial flange of the complete upper denture (CUD). Using commercial edentulous molds and standardized procedures eight identical CUDs were fabricated with an initial fraenal notch of 5 mm. Three addition notch conditions were produced by deepening the notch two times giving a total depth of the notch of 7 and 9 mm respectively. Finally an incisal diastema of 7 mm was created in every CUD. Three elements rosette strain gauge was cemented onto the midline of each denture specimen near the fraenal notch, for calculating the two principal stresses and the maximum shear stress. It is less possible that a failure crack in a CUD will be initiated from the region of the fraenal notch, due to the compressive nature of the principal stresses (they are varied significantly among the four notch conditions with P=0.035 for sigma(1) and P=0.007 for sigma(2)) and the low value of the maximum shear stress. The creation of an incisal diastema significantly decreased the values of the principal stresses sigma(1) (P=0.012) and sigma(2) (P=0.025). Further investigation is needed to detect the region of the CUD where a failure crack may be initiated. PMID- 22445586 TI - The role of physical activity in changes in walking mechanics with age. AB - While age-related declines in walking mechanics have been documented, it remains unclear if changes in walking mechanics with age occur as a natural consequence of aging and to what extent these changes are related to a reduction in fitness and physical activity with aging. The study aim was to determine if the walking mechanics of an older (>50) yet highly active population are different from a younger population (<40). Gait mechanics data for 79 middle-aged (50-64 yrs) and 54 older (65-80 yrs) individuals with >= 7500 steps/day, based on a 7 day activity monitoring history, and 33 younger adults (ages 18-40) were collected. The older subjects did not reduce self-selected walking speed relative to the younger subjects. However, the walking speed was maintained by increasing cadence while reducing stride-length for middle-aged and older subjects. Middle-aged and older adults had less ankle dorsi-flexion landing at heel-strike and older adults also had less plantar flexion at toe-off. Small decreases in the ankle dorsi flexion moments (p=0.019, p=0.008) and increases in the hip extension moments (p=0.004, p=0.005) were found for two normalized walking speeds for the middle aged and older adults compared to the young adults. These results provide quantitative evidence that increased activity with aging can mitigate declines in walking performance and mechanics with age. The high volume of walking activity in the older subjects did not fully prevent changes in gait mechanics, but may have minimized the magnitude of age-related changes on ambulatory function relative to other reports of older inactive subjects. PMID- 22445587 TI - Toxoplasma gondii: the vaccine potential of three trivalent antigen-cocktails composed of recombinant ROP2, ROP4, GRA4 and SAG1 proteins against chronic toxoplasmosis in BALB/c mice. AB - Toxoplasmosis is one of the world's most widespread zoonoses caused by protozoan parasite Toxoplasma gondii. The development of an effective vaccine for controlling toxoplasmosis is an extremely important issue due to the serious clinical and veterinary outcomes of this parasitosis. The objective of this study was evaluation of vaccine potential of three trivalent subunit recombinant vaccines composed of rROP2+rGRA4+rSAG1, rROP2+rROP4+rGRA4 and rROP2+rROP4+rSAG1 against chronic toxoplasmosis in BALB/c (H-2(d)) mice. All tested vaccines provided a partial protection against challenge with tissue cysts of the low virulence DX T. gondii strain, but the strongest level of protection was induced by the mixtures of both rhoptry proteins (rROP2 and rROP4) administered with the dense granule rGRA4 antigen or the main surface rSAG1 protein. The average parasite burden in these groups of vaccinated BALB/c mice was reduced by 84% and 77%, respectively, compared to the control PBS-injected animals. The vaccine induced protection was correlated with the development of cellular and humoral immune responses demonstrated by the antigen-specific in vitro proliferation of spleen cells, the specific antigen-induced in vitro synthesis of Th1-type cytokines, IFN-gamma and IL-2, and the generation of the high titers of systemic antigen-specific IgG1 and IgG2a antibodies. This study completed and confirmed our earlier investigations in C3H/HeJ (H-2(k)) and C57BL/6 (H-2(b)) mouse strains on the utility of the tested trivalent recombinant antigen-cocktails as potential vaccines against chronic toxoplasmosis and showed that particularly rROP2+rROP4+rGRA4 and rROP2+rROP4+rSAG1 protein-combinations are very effective in the development of a high level of protection irrespective of the genetic backgrounds and innate resistance to toxoplasmosis of the laboratory mice. It makes these two mixtures of recombinant antigens very promising for further experiments. PMID- 22445588 TI - Host-pathogen interactions revealed by human genome-wide surveys. AB - Genome-wide association studies (GWAS) have now convincingly shown that the diverse outcomes (such as the resolution of infection, clinical deterioration to severe disease, or progression from acute infection to persistent infection) that occur following microbial infection can be at least partly explained by human genetic variation. Unbiased whole-genome approaches have revealed unprecedentedly robust associations between genetic markers and susceptibility to disease, providing clear insights into our understanding of infectious disease biology by revealing the crucial host-pathogen interaction sites. Further work characterizing both the host causative variations and pathogenic microbial strains with distinct host interactions and disease outcomes is now required to provide potential new intervention strategies. PMID- 22445589 TI - Respiratory polygraphy for follow-up of obstructive sleep apnea in children. AB - OBJECTIVES: (1) To evaluate the effectiveness of adenotonsillectomy for the treatment of Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) in children. (2) To evaluate the usefulness of respiratory polygraphy (RP) for controlling post adenotonsillectomy effects. METHODS: The children studied were referred to the Burgos Sleep Unit (SU) with clinical suspicion of OSAHS before undergoing adenotonsillectomy. For all patients, a clinical history was taken and a general physical examination, as well as a specific ear, nose, and throat examination was done. RP before adenotonsillectomy, and seven months afterwards, was also done. OSAHS was diagnosed if the Apnea Hypopnea Index (AHI) was >= 4.6. RESULTS: Of the 100 children studied, 68 were male and 32 female, with an age of 4.17 +/- 2.05 years. Using RP, 86 of them were diagnosed with OSAHS before undergoing adenotonsillectomy. There was a significant improvement in all clinical and polygraphic variables after adenotonsillectomy. The pre and post surgery AHI index was 11.9 +/- 11.0 and 2.6 +/- 1.5, respectively, with a significant mean difference (9.4 +/- 10.9, p<0.01). The residual OSAHS was 11.6% (CI 95%: 4.3 19%). CONCLUSIONS: Respiratory polygraphy is a useful tool for monitoring the effectiveness of surgical treatment and the detection of residual OSAHS in children with adenotonsillar hypertrophy. PMID- 22445590 TI - Volume assured pressure support ventilation--induced arousals. PMID- 22445591 TI - Sodium oxybate in the treatment of childhood narcolepsy-cataplexy: a retrospective study. AB - OBJECTIVE: To evaluate the efficacy and side effect profile of sodium oxybate in the treatment for narcolepsy-cataplexy in the pediatric age group. METHODS: A retrospective study was conducted on 15 children and adolescents with narcolepsy cataplexy who had been treated with sodium oxybate. The mean age at diagnosis of narcolepsy was 11 years (range 3-17 years). Subjects were followed for 3-90 months (mean 33) after starting sodium oxybate. During this period of time they were also maintained on other medications for sleepiness (n=14) and cataplexy (n=6). The charts were reviewed for documentation of improvement in sleepiness or cataplexy, side effects, and functioning in daily life. RESULTS: Subsequent to the addition of sodium oxybate, sleepiness improved in 13/15 patients. In patients who had Epworth Sleepiness Scale (ESS) assessments, the score fell from a baseline median of 18 to 12 (n=10, p=0.01). The number of cataplexy episodes estimated by parents decreased from a median of 38/week pre-treatment to <1/week post treatment (n=14, p<0.001). Cataplexy severity, measured on an arbitrary scale, fell from a median of 3 (severe) to 1 (mild) in all 15 subjects (p<0.001). Two of the 15 patients (13%) discontinued sodium oxybate, one for insurance reasons and the other due to constipation and dissociative feelings. A third patient stopped the medication temporarily due to body aches and dizziness, but then resumed treatment without recurrence of symptoms. Side effects in four others included tremor, blurring of vision, nocturnal awakenings, and increased nightmares. Overall, side effects occurred in 6/15 (40%) individuals. Improvement in social/academic spheres was noted in 11/15 (73%) subjects after starting sodium oxybate. The median BMI before and after treatment remained unchanged at 23 (n=14, p=0.99). Median values of height and weight before and after treatment also did not change significantly. The mean dose of sodium oxybate was 5 +/- 2 g. Dose escalation owing to development of tolerance was not encountered. CONCLUSIONS: Sodium oxybate is effective in alleviating sleepiness and cataplexy in childhood onset narcolepsy-cataplexy. The therapeutic response was sustained over time, and without development of tolerance. Forty percent of the subjects experienced adverse effects. PMID- 22445592 TI - MR imaging findings of the corpus callosum region in the differentiation between multiple sclerosis and neuromyelitis optica. AB - PURPOSE: To evaluate MR imaging findings in corpus callosum region for the discrimination between opticospinal multiple sclerosis (OSMS) and neuromyelitis optica (NMO). MATERIALS AND METHODS: Forty-two definite OSMS with seronegative NMO-IgG and 23 NMO with seropositive NMO-IgG, and 27 age-matched normal controls (NC) were recruited. Sagittal T2-FLAIR images with 2-mm slice thickness were obtained. Subcallosal dot-dash (SCDD) sign and subcallosal striations (SCS) sign were reviewed. RESULTS: SCDD was more commonly detected in OSMS (28 of 42 patients) than in NMO (5 of 23 patients) (P<0.05). SCS showed no difference between OSMS (31 of 42 patients) and NMO (12 of 23 patients) (P>0.05). For comparing ROC analysis among SCDD, SCS, and SCDD+SCS for predicted probability through binary logistic regression analysis, SCDD+SCS had the largest area under ROC curve (0.777) than SCDD (0.725) and SCS (0.608). CONCLUSION: SCDD may be helpful in distinguishing OSMS from NMO. The regression equation may also be a simple and effective method of choice for the differentiation between OSMS and NMO. PMID- 22445593 TI - Breast elasticity: principles, technique, results: an update and overview of commercially available software. AB - Breast ultrasound elasticity evaluation has become a routine tool in addition to diagnostic ultrasound during the last five years. Two elasticity evaluation modes are currently available: free-hand elastography and shear-wave elastography (SWE). Most of the commercially available elastography scanners have specific procedures which must be understood by the users. Free-hand elastography usually displays qualitative imaging such as an elastogram, but most of the companies now use it to quantify the relative stiffness between a lesion and the surrounding breast tissue. SWE is a new mode theoretically independent of the sonographer which displays more quantitative information, and can be useful for characterizing breast lesions. Recent studies on elastography suggest that elasticity imaging can increase B-mode accuracy and specificity in differentiating benign and malignant breast lesions. This functional imaging mode could help reduce the number of biopsies performed for benign breast lesions. This review gives a detailed description of the main commercially available systems and the results of current applications in the evaluation of breast elasticity. PMID- 22445594 TI - Relationship between 24-h Holter recordings and clinical outcomes in patients with permanent atrial fibrillation. AB - OBJECTIVES: This study aimed to test the hypothesis that the range of 24-h total heart beats (24 h-tHB) correlates with cardiac outcomes (cardiac death and incidence of hospitalization with heart failure) in patients with permanent atrial fibrillation (AF). METHODS AND RESULTS: We divided 252 consecutive outpatients with permanent AF into 4 groups according to their 24 h-tHB and examined clinical outcomes. Initial 24 h-tHB at enrollment was significantly associated with patient characteristics including age, sex, presence of structural heart diseases, and left ventricular ejection fraction (EF). The cumulative incidence of heart failure was high in the lowest 24 h-tHB group compared with other groups and significantly different from the highest one (23.9% vs. 7.2% at 5 years, p=0.0074). Multivariate analysis showed that 24 h tHB<100,000 was associated with cardiac events [hazard ratio, 2.45; 95% confidence interval (CI), 1.09-5.49; p=0.03), along with structural heart disease (hazard ratio, 9.81; 95% CI, 3.34-28.83; p=0.0001) and EF (hazard ratio, 0.97; 95% CI, 0.94-0.99; p=0.002). CONCLUSIONS: Surprisingly, low but not high heart rate was significantly associated with higher incidence of heart failure in Japanese patients. This finding should be further evaluated in future prospective studies. PMID- 22445595 TI - Association between clinical outcome and antiarrhythmic treatment in heart failure patients who have atrial fibrillation upon admission to the hospital. AB - BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) are associated with significant mortality and morbidity. We sometimes encounter patients who have AF upon admission to the hospital, but it spontaneously converts to sinus rhythm within several days (i.e. converter). PURPOSE: We examined the association between the outcome and types of strategy for AF treatment in converters. METHODS: From January 2000 to December 2005, we identified 95 converters (age 69 +/- 12 years) presenting with worsening HF and AF upon admission, in which sinus rhythm was restored within 7 days without either electrical or pharmacological cardioversion. The patients were classified into three groups according to the antiarrhythmic drug (AAD) therapy used: class I AAD, class III AAD, and rate control drug. The patients were followed for 36 +/- 23 months. RESULTS: The left ventricular ejection fraction (LVEF) significantly improved with conversion to sinus rhythm (38 +/- 14% vs. 47 +/- 13%, p<0.05). Those receiving class I AAD had a trend toward a well-preserved LVEF (50 +/- 13%, n=35) as compared to those receiving class III AAD (43 +/- 12%, n=24) or rate-control drug (47 +/- 14%, n=36). In the patients receiving class I AAD, the rate of all-cause death increased 1.9-fold (p=0.009) compared to those receiving class III AAD, and 1.7 fold (p=0.010) compared to those taking rate-control drug. A hospitalization for HF was observed in 49 (52%) patients, however there was no significant difference in the rate of hospitalization among the three groups (p=0.890). Those receiving rate-control drugs had a 50% lower rate of the development of persistent AF than those taking class III AAD (p=0.019). CONCLUSIONS: A rate-control strategy should be the primary approach for converters to reduce mortality and development of persistent AF. PMID- 22445596 TI - Relationship between left ventricular ejection fraction and mitral annular displacement derived by speckle tracking echocardiography in patients with different heart diseases. AB - BACKGROUND: Speckle tracking echocardiography (STE)-derived mitral annular displacement (MAD) utilizes the speckle tracking technique to measure strain vectors, which provides accurate estimates of left ventricular ejection fraction (LVEF). Here, we investigated a link between STE-derived MAD and LVEF in patients with different heart diseases and evaluated its clinical usefulness. METHODS: This study included 266 outpatients and 84 controls. Of the study patients, 52 patients had ischemic heart disease (IHD), 37 patients had dilated cardiomyopathy (DCM), 34 patients had hypertrophic cardiomyopathy (HCM), 74 patients had valvular heart disease (VHD), and 69 patients had hypertensive heart disease (HHD). STE continuously tracked annular motion throughout the cardiac cycle in the apical 4- and 2-chamber views. RESULTS: In all participants, the curvilinear relationship was found between STE-derived MAD and LVEF (R(2)=0.642). The strong correlation between STE-derived MAD and LVEF was also found in the patients with IHD (R(2)=0.733, p=0.001) and in those with DCM (R(2)=0.614, p=0.008). However, such a correlation was not found in the patients with HCM, VHD, or HHD. CONCLUSION: The specificity in the correlation between STE-derived MAD and LVEF was found in patients with each heart disease, which should be taken into account when assessing these parameters. PMID- 22445597 TI - Comparison of early outcomes after primary stenting in Japanese patients with acute myocardial infarction between clopidogrel and ticlopidine in concomitant use with proton-pump inhibitor. AB - BACKGROUND: Recent studies have reported that concomitant use of clopidogrel with proton-pump inhibitors (PPIs) might decrease antiplatelet effects and increase the risk of adverse outcomes after coronary stenting. However, little is known about the difference between clopidogrel and ticlopidine in concomitant use with PPIs, especially within the Asian population. METHODS: We retrospectively analyzed 302 consecutive patients (248 males, mean age 66 +/- 12 years) undergoing primary stenting for acute myocardial infarction from July 2006 to June 2010. PPIs were administered to 92% (278/302) of the patients. The patients were divided into two groups on the basis of clopidogrel (clopidogrel group, n=187) or ticlopidine (ticlopidine group, n=91) with PPI. Their characteristics, medications, and 30-day clinical outcomes were examined. RESULTS: There were no significant differences in 30-day major adverse cardiac events (cardiac death, non-fatal myocardial infarction, and definite stent thrombosis), bleeding events, and stroke between the two groups. The discontinuation of clopidogrel due to side effects was significantly less frequent than that of ticlopidine (1.1% vs 7.7%, p=0.003, respectively). CONCLUSION: Our findings suggest that concomitant use of clopidogrel with PPIs might be safer than ticlopidine with PPIs in patients undergoing primary stenting for acute myocardial infarction. PMID- 22445598 TI - Depressive symptoms are common and associated with adverse clinical outcomes in heart failure with reduced and preserved ejection fraction. AB - BACKGROUND: Little is known about depressive symptoms in heart failure with preserved ejection fraction (HFpEF, EF >=50%). We aimed to assess the prevalence of depression, to clarify the impact of depressive symptoms upon clinical outcomes, and to identify factors associated with these symptoms in HF with reduced EF (HFrEF, EF <50%) and HFpEF. METHODS AND RESULTS: A total of 106 HF outpatients were enrolled. Of them, 61 (58%) had HFpEF. Most patients were male (HFrEF 80%, HFpEF 70%) and the mean of plasma B-type natriuretic peptide (BNP) level in the HFrEF group was similar to that in the HFpEF group (164.8 +/- 232.8 vs. 98.7 +/- 94.8 pg/mL). HFrEF patients were treated more frequently with beta blockers compared with HFpEF patients (71% vs. 43%, p=0.004). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES D). The prevalence of depression (CES-D score >=16), and CES-D score did not significantly differ between HFrEF and HFpEF (24% vs. 25%, 14.1 +/- 8.3 vs. 12.1 +/- 8.3, respectively). During the 2-year follow-up, depressed patients had more cardiac death or HF hospitalization in HFrEF (55% vs. 12%, p=0.002) and HFpEF (35% vs. 11%, p=0.031). Cox proportional hazard analysis revealed that a higher CES-D score, indicating increased depressive symptoms, predicted cardiac events independent of BNP in HFrEF [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.01-1.13] and HFpEF (HR 1.09, 95% CI 1.04-1.15). Multiple regression analyses adjusted for BNP showed that independent predictors of depressive symptoms were non-usage of beta-blockers and being widowed or divorced in HFrEF. On the other hand, usage of warfarin was the only independent risk factor for depressive symptoms in HFpEF (all, p<0.05). CONCLUSIONS: Depressive symptoms are common and independently predict adverse events in HFrEF/HFpEF patients. This study suggests that beta-blockers reduce depressive symptoms in HFrEF. In contrast, treatment for depression remains to be elucidated in HFpEF. PMID- 22445599 TI - Effects of isoproterenol and propranolol on the inducibility and frequency of ventricular fibrillation in patients with Brugada syndrome. AB - BACKGROUND: Isoproterenol (ISP), a beta-adrenergic agonist, suppresses arrhythmic storm in patients with sporadic Brugada syndrome (BS). However, the influence of ISP and the beta-adrenergic antagonist propranolol (PRO) on the inducibility and frequency of ventricular fibrillation (VF) in BS patients remains unclear. METHODS AND RESULTS: Twenty-seven BS patients with induced VF>10s in a control state were enrolled. Electrophysiological stimulation (EPS) testing was performed during ISP and after PRO in selected patients. The inducibility and frequency of VF were compared. Dominant frequency (DF) was obtained by Fast Fourier transform from 4-s data (phase) and sequentially every 2s up to phase 5. ISP prevented induction of VF in 20 of 25 patients (80%). During ISP, 5 patients experienced induction of VF. ISP significantly influenced DF transition compared with the control state. DF gradually increased but was unchanged after the middle phase. PRO had no effect on incidence of induced VF in 5 patients; increased PRO induced VF in 5 (83.3%) of 6 patients who tested negative during ISP. After PRO, 10 patients experienced induction of VF. Thus, PRO significantly influenced DF transition. DF after PRO was higher than that in the corresponding phase in the control state. CONCLUSION: ISP suppressed induction of VF and the increase of DF with time. PRO aggravated VF and accelerated DF. PMID- 22445600 TI - Macrophage autophagy plays a protective role in advanced atherosclerosis. AB - In advanced atherosclerosis, macrophage apoptosis coupled with defective phagocytic clearance of the apoptotic cells (efferocytosis) promotes plaque necrosis, which precipitates acute atherothrombotic cardiovascular events. Oxidative and endoplasmic reticulum (ER) stress in macrophages are important causes of advanced lesional macrophage apoptosis. We now show that proapoptotic oxidative/ER stress inducers trigger another stress reaction in macrophages, autophagy. Inhibition of autophagy by silencing ATG5 or other autophagy mediators enhances apoptosis and NADPH oxidase-mediated oxidative stress while at the same time rendering the apoptotic cells less well recognized by efferocytes. Most importantly, macrophage ATG5 deficiency in fat-fed Ldlr(-/-) mice increases apoptosis and oxidative stress in advanced lesional macrophages, promotes plaque necrosis, and worsens lesional efferocytosis. These findings reveal a protective process in oxidatively stressed macrophages relevant to plaque necrosis, suggesting a mechanism-based strategy to therapeutically suppress atherosclerosis progression and its clinical sequelae. PMID- 22445601 TI - Differentiating the roles of mGlu2 and mGlu3 receptors using LY541850, an mGlu2 agonist/mGlu3 antagonist. AB - Despite the potential therapeutic relevance of group II metabotropic glutamate (mGlu) receptors, there has been a lack of pharmacological tools for separating the roles of mGlu2 and mGlu3 receptor subtypes. LY541850 was claimed from human mGlu receptors expressed in non-neuronal cells to be a selective orthosteric mGlu2 agonist and mGlu3 antagonist. We have verified this pharmacological profile of LY541850 in hippocampal slices. Field excitatory post-synaptic potentials (fEPSPs) evoked by stimulation of the temporo-ammonic path (TAP) input to CA1 stratum lacunosum moleculare (SLM) were inhibited by LY541850 in mGlu3-/- mice (EC(50) 38 nM) and wild-type littermates (EC(50) 42 nM) to a similar extent but were not significantly affected in mGlu2-/- mice. The group II agonist, DCG-IV, inhibited the fEPSP in all three genotypes. Co-application of DCG-IV and LY541850 in mGlu3-/- and wild-type littermates resulted in an additive effect, whereas in mGlu2-/- mice, LY541850 reversed the inhibitory action of DCG-IV. These results confirm the selective mGlu2 agonist and mGlu3 antagonist actions of LY541850. A similar profile of activity was seen in medial perforant path synapse to the dentate gyrus. Systemic administration of LY541850 to wild-type mice, reduced the increase in locomotor activity following both phencyclidine and amphetamine administration. These data support the hypothesis that mGlu2 receptors mediate the antipsychotic effects of mixed group II agonists. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22445603 TI - Patent foramen ovale: a potential cause of refractory hypoxemia in off-pump coronary artery bypass surgery. PMID- 22445602 TI - The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. AB - The National Center for Complementary and Alternative Medicine (NCCAM) estimates that nearly 40% of adults in the United States use alternative medicines, often in the form of an herbal supplement. Extracts from the tree bark of magnolia species have been used for centuries in traditional Chinese and Japanese medicines to treat a variety of neurological diseases, including anxiety, depression, and seizures. The active ingredients in the extracts have been identified as the bi-phenolic isomers magnolol and honokiol. These compounds were shown to enhance the activity of GABA(A) receptors, consistent with their biological effects. The GABA(A) receptors exhibit substantial subunit heterogeneity, which influences both their functional and pharmacological properties. We examined the activity of magnolol and honokiol at different populations of both neuronal and recombinant GABA(A) receptors to characterize their mechanism of action and to determine whether sensitivity to modulation was dependent upon the receptor's subunit composition. We found that magnolol and honokiol enhanced both phasic and tonic GABAergic neurotransmission in hippocampal dentate granule neurons. In addition, all recombinant receptors examined were sensitive to modulation, regardless of the identity of the alpha, beta, or gamma subunit subtype, although the compounds showed particularly high efficacy at delta-containing receptors. This direct positive modulation of both synaptic and extra-synaptic populations of GABA(A) receptors suggests that supplements containing magnolol and/or honokiol would be effective anxiolytics, sedatives, and anti-convulsants. However, significant side-effects and risk of drug interactions would also be expected. PMID- 22445604 TI - A woman with a history of stroke and a mass in the aorta. PMID- 22445605 TI - Case 4--2012. Intrathoracic fire during coronary artery bypass graft surgery. PMID- 22445606 TI - Cd14 SNPs regulate the innate immune response. AB - CD14 is a monocytic differentiation antigen that regulates innate immune responses to pathogens. Here, we show that murine Cd14 SNPs regulate the length of Cd14 mRNA and CD14 protein translation efficiency, and consequently the basal level of soluble CD14 (sCD14) and type I IFN production by murine macrophages. This has substantial downstream consequences for the innate immune response; the level of expression of at least 40 IFN-responsive murine genes was altered by this mechanism. We also observed that there was substantial variation in the length of human CD14 mRNAs and in their translation efficiency. sCD14 increased cytokine production by human dendritic cells (DCs), and sCD14-primed DCs augmented human CD4T cell proliferation. These findings may provide a mechanism for exploring the complex relationship between CD14 SNPs, serum sCD14 levels, and susceptibility to human infectious and allergic diseases. PMID- 22445607 TI - [Use of intravenous artemisinin derivatives in severe malaria]. PMID- 22445608 TI - Duplication of exons 3-10 of the HSD17B3 gene: a novel type of genetic defect underlying 17beta-HSD-3 deficiency. AB - The clinical, biochemical and genetic features of a Cypriot origin male of non consanguineous parents due to 17beta-hydroxysteroid dehydrogenase type 3 (17beta HSD-3) deficiency are presented. The patient, currently a 10 old male, was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Mullerian structures identified on pelvic ultrasound. Chromosomal analysis showed an apparently normal male 46,XY karyotype. Diagnosis of 17beta-HSD-3 deficiency in the newborn was suspected based on biochemical findings, following human chorionic gonadotrophin (hCG) stimulation test. Sequence analysis and real time PCR along with MLPA identified the patient with a novel 11.96 kb duplication that spans exons 3-10 of the HSD17B3 gene and extends from intron 2 to intron 10 in compound heterozygosity with the known p.R80Q missense mutation leading to 17beta-HSD-3. In conclusion, 17beta-HSD-3 deficiency was diagnosed in this patient based on endocrinologic evaluation and confirmed with genetic analysis of the HSD17B3 gene. The novel large duplication spanning exons 3-10 of the HSD17B3 gene that we report here in compound heterozygosity with the known p.R80Q leads to 17beta-HSD-3 deficiency presenting as 46,XY Disorder of Sex Development. Following diagnosis and appropriate genetic counselling, the patient was raised a boy and successfully underwent surgical correction of crytptorchidism and hypospadias. PMID- 22445609 TI - Microsatellite markers based genetic diversity and bottleneck studies in Zanskari pony. AB - Genetic diversity in Zanskari pony breed was evaluated at 48 microsatellite loci using fifty adult, healthy and unrelated animals. Allele frequency data was used to detect genetic diversity and bottleneck. The estimated average number of alleles (+/-s.e.) was 8.5208+/-2.5010 with a total of 409 alleles. A high level of genetic diversity within this breed was observed in terms of number of alleles, observed heterozygosity (0.6763+/-0.1704), expected Leven's heterozygosity (0.7724+/-0.795), expected Nei's heterozygosity (0.7644+/-0.0787) and polymorphism information content (>0.5). In-breeding coefficient (F(is)) was 0.115+/-0.0209, suggesting moderately high in-breeding in Zanskari breed. Although analysis of bottleneck revealed no bottleneck in recent past but population of Zanskari ponies has decreased drastically and only a few thousand pure-bred animals are left. The information is useful for proposing effective population management strategies for future. PMID- 22445610 TI - Site specific inelasticity of arterial tissue. AB - Understanding the mechanical behaviour of arterial tissue is vital to the development and analysis of medical devices targeting diseased vessels. During angioplasty and stenting, stress softening and permanent deformation of the vessel wall occur during implantation of the device, however little data exists on the inelastic behaviour of cardiovascular tissue and how this varies through the arterial tree. The aim of this study was to characterise the magnitude of stress softening and inelastic deformations due to loading throughout the arterial tree and to investigate the anisotropic inelastic behaviour of the tissue. Cyclic compression tests were used to investigate the differences in inelastic behaviour for carotid, aorta, femoral and coronary arteries harvested from 3-4 month old female pigs, while the anisotropic behaviour of aortic and carotid tissue was determined using cyclic tensile tests in the longitudinal and circumferential directions. The differences in inelastic behaviour were correlated to the ratio of collagen to elastin content of the arteries. It was found that larger inelastic deformations occurred in muscular arteries (coronary), which had a higher collagen to elastin ratio than elastic arteries (aorta), where the smallest inelastic deformations were observed. Lower magnitude inelastic deformations were observed in the circumferential tensile direction than in the longitudinal tensile direction or due to radial compression. This may be as a result of non-collagenous components in the artery becoming more easily damaged than the collagen fibres during loading. Stress softening was also found to be dependent on artery type. In the future, computational models should consider such site dependant, anisotropic inelastic behaviour in order to better predict the outcomes of interventional procedures such as angioplasty and stenting. PMID- 22445611 TI - Metabolic and reproductive status are not improved from 11 to 25 day post-partum in non-weaned primiparous rabbit does. AB - The aim of present work was to analyze the body reserves and ovarian features of lactating primiparous rabbit does under extensive reproductive management (artificial insemination (AI) at 25 days post-partum (dpp)) compared with the common insemination rhythm at 11 dpp. A total of 48 primiparous Californian*New Zealand White rabbit does suckling 8 kits were used to assess liveweight, estimated body composition, serum metabolic and endocrine parameters (oestradiol and progesterone concentrations) and ovarian features like follicle population and atresia rate, and oocyte maturation. Rabbit does were randomly allocated in two experimental groups: (a) lactating does euthanized at early post-partum period (11 dpp) according to a semi-intensive rhythm (n=24), and (b) lactating does euthanized at later post-partum period (25 dpp) according to a more extensive rhythm (n=24). Liveweight, body energy content, lipid depots and serum non-esterified fatty acids (NEFA) concentrations decreased from parturition to post-partum period (P<0.05). In addition, serum protein and glucose concentrations increased in the post-partum period (P<0.05). Similar oestradiol and progesterone levels were found in rhythms as well as similar follicle population and nuclear and cytoplasmic maturation rates measured as metaphase II and cortical granule migration, respectively in both post-partum times. However, the number of preovulatory follicles on the ovarian surface was lower (P<0.05) and the atresia rate tended to be higher with a lower percentage of healthy follicles (P<0.1) in ovaries from females of extensive group. In conclusion, the body reserves, serum metabolic parameters and oocyte quality of primiparous non weaned rabbits does at the late post-partum time (25 days) were not improved. Thus this reproductive management did not present any advantages compared to earlier post-partum (11 days) reproductive rhythm. PMID- 22445612 TI - Effect of Spermine-NONOate on acrosome reaction and associated protein tyrosine phosphorylation in Murrah buffalo (Bubalus bubalis) spermatozoa. AB - The present study was conducted to know the role of Nitric Oxide (NO) on the acrosome reaction (AR) in Murrah buffalo (Bubalus bubalis) spermatozoa. Ejaculated buffalo spermatozoa were washed, suspended in sp-TALP media containing 6 mg BSA/mL and cell concentration was adjusted to 50*10(6) cells/mL. The cells were incubated for 6h in the absence or presence of heparin (10 MUg/mL) to induce capacitation. Fully capacitated spermatozoa were incubated in presence of 100 MUg/mL Lysophosphatidyl choline (LPC, T1) or 100 MUM Spermine-NONOate (T2) or 100 mM L-NAME (T3) or 100 MUM Spermine-NONOate+100 mM L-NAME (T4) or 1 mM db-cAMP + 0.1 mM IBMX (T5) or 100MUM H-89 (T6) or 100 MUM Spermine-NONOate+100 MUM H-89 (T7) in combination to induce acrosome reaction. The extent of AR was assessed by dual-staining of spermatozoa with trypan blue/Giemsa stain. AR-associated tyrosine-phosphorylated proteins were detected by SDS-PAGE followed by immunoblotting using monoclonal anti-phosphotyrosine antibody. Significant (P<0.05) number of spermatozoa were acrosome reacted in Spermine-NONOate (T2) treated cells but it was significantly (P<0.05) lower than LPC (T1) induced AR. Addition of Spermine-NONOate + L-NAME (T4) resulted in non significant (P>0.05) decrease in acrosome reaction. On addition of H-89 + Spermine-NONOate (T7) to sperm culture medium, resulted in significant (P<0.05) decrease in the percent acrosome reaction. Conversely, addition of db-cAMP+IBMX (T5, cAMP analogue) resulted in the significantly (P<0.05) higher number of acrosome reacted spermatozoa. Pattern of sperm protein tyrosine phosphorylation was also different in NO induced acrosome reaction compared to that of LPC. The present study concluded that nitric oxide is involved in acrosome reaction of buffalo spermatozoa by causing the tyrosine phosphorylation of proteins mainly p17 and p20 and through activation of cAMP/PKA pathway. PMID- 22445613 TI - The association between radiographic severity and pre-operative function in patients undergoing primary knee replacement for osteoarthritis. AB - OBJECTIVE: To determine the association between radiographic osteoarthritis (OA) and pre-operative function in patients undergoing primary knee replacement. METHODS: Single centre study examining pre-operative outcomes in a consecutive series of 525 patients who underwent primary knee replacement for OA between January 2006 and December 2007. Pre-operative data included: demographics, American Society of Anaesthesiologists (ASA) status and OA in the contralateral knee. The International Knee Society (IKS) rating and Short Form-12 (SF-12) were recorded for each patient. Pre-operative radiographs were read by a single observer for Kellgren and Lawrence (K&L) grading and Osteoarthritis Research Society International (OARSI) atlas features. Multiple linear regression was used to assess the strength of associations between radiographic OA severity and function, adjusting for clinically relevant variables. RESULTS: Lateral tibiofemoral osteophyte grade was an independent predictor of pre-operative function as determined by the functional sub-scale of the IKS in patients undergoing primary knee replacement (coefficient=2.58, p=0.033). No associations were evident between pre-operative function and modified K&L, joint space narrowing, Ahlback attrition and coronal plane deformity. Other statistically significant predictors of poorer pre-operative function included: advancing age, female gender, knee pain and poorer SF-12 mental component summary scores which including osteophyte grade accounted for 24.6% of the variation in functional scores, (r=0.496). CONCLUSION: Osteophytes in the lateral compartment of the knee were associated with pre-operative function in patients with advanced knee OA. Further studies are required which examine individual radiographic features specifically in patients with advanced knee OA to determine their relationship to pre-operative pain and function. PMID- 22445614 TI - Stimulus-induced rhythmic, periodic, or ictal discharges--a case report. PMID- 22445615 TI - MR imaging in the early stage of 5-fluorouracil-induced leukoencephalopathy: DWI, MR perfusion, and MR spectroscopy. PMID- 22445616 TI - Associations of cigarette smoking with intracranial atherosclerosis in the patients with acute ischemic stroke. AB - BACKGROUND: Although cigarette smoking has been established as an important risk factor for stroke, the effect on the atherosclerotic stenosis, which are based on observational studies, have been controversial. We set out to examine the differences in the risk factors between smokers and nonsmokers and to investigate the association of cigarette smoking with cerebral arterial stenosis. METHODS: A total of 989 consecutive patients with acute noncardioembolic ischemic stroke were prospectively enrolled from June 2004 to January 2010. The risk factor profiles were compared between smokers and nonsmokers. We analyzed the degree of stenosis in all MRA, and evaluated influencing factors in the patients with intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS) who were randomly matched by age and sex. RESULTS: There were differences in the distribution of risk factors between the 467 (70.0%) nonsmokers and the 215 (30.0%) smokers. Nonsmokers were older (71.7+/-11.0 versus 61.7+/-12.0, p<0.001) and had a higher frequency of hypertension than smokers had (75.4% versus 64.0%, p=0.002). When smokers and nonsmokers were age- and sex-matched, smoking was more prevalent in patients with ICAS than with ECAS (32.9% versus 28.2%). Conditional regression analysis revealed that smoking and hypertension increased the odds of ICAS [smoking, odds ratio (OR): 1.83, p=0.026; hypertension, OR: 1.84, p=0.01], whereas hyperlipidemia increased the odds of ECAS (OR: 1.87, p=0.034). CONCLUSION: The distributions of the major risk factors for ischemic stroke were different between smokers and nonsmokers. Cigarette smoking may be more associated with ICAS than with ECAS after adjusting for potential risk factors. PMID- 22445617 TI - Experience of (123)I-iomazenil SPECT study for crossed cerebellocerebral diaschisis: report of two cases. PMID- 22445618 TI - Long-term follow-up of vanishing tumors in the brain: how should a lesion mimicking primary CNS lymphoma be managed? AB - OBJECTIVES: The spontaneous disappearance of a tumor is referred to as a vanishing tumor. Most vanishing tumors in the brain are eventually diagnosed as malignant tumors or multiple sclerosis. However, their long-term clinical course remains unclear. This study aims to elucidate the management of vanishing tumors in the brain. PATIENTS AND METHODS: We defined a vanishing tumor as a case in which the tumor spontaneously disappeared or decreased to less than 70% of the initial tumor volume before definitive diagnosis and treatment (other than steroid treatment). Ten cases of vanishing tumors are reviewed. RESULTS: Nine patients underwent biopsy at least once. Five patients, all of whom had malignant tumors (primary central nervous system lymphoma: 4, germinoma: 1) that recurred in 4-45 months (median: 7 months), underwent a second biopsy after the reappearance of the tumors. Five patients (tumefactive demyelinating lesion: 1, undiagnosed: 4) who had no relapse are alive, and their median follow-up time is 44 months. No cases have yet been reported of malignant brain tumors that recurred more than 5 years after spontaneous regression. CONCLUSIONS: Patients with vanishing tumors should be followed up carefully by magnetic resonance imaging for at least 5 years, even after the disappearance of an enhancing lesion. PMID- 22445619 TI - Restorative neurology: past, present, and future. PMID- 22445620 TI - Non-Hodgkin lymphoma presenting with foot drop. PMID- 22445621 TI - Bilateral intracranial vertebral artery dissection presenting as sudden bilateral hearing loss. PMID- 22445622 TI - Dose-response relationship between tobacco or alcohol consumption and the development of diabetes mellitus in Japanese male workers. AB - BACKGROUND: The aim of this study was to examine the dose-response relationships between tobacco or alcohol consumption and the development of diabetes mellitus. METHODS: An 8-year prospective cohort study was conducted in 8423 male workers who received annual health check-ups between 2002 and 2010 at a Japanese steel company. The endpoints were defined as an HbA(lc)>=6.1% or taking any anti diabetic medication. The dose-response relationships of tobacco or alcohol consumption were investigated using a proportional hazards regression with time dependent covariates selected from baseline age, body mass index, mean arterial pressure, total serum cholesterol, aspartate aminotransferase, creatinine and uric acid, shift work or day work, and habitual exercise by stepwise selection method. RESULTS: A positive dose-response relationship between tobacco consumption and the development of diabetes mellitus was observed, with a significantly higher hazard ratio (HR) seen with higher tobacco consumption (11 20 cigarettes/day, HR 1.26 [95% confidence interval (CI), 1.00-1.59], >=21 cigarettes/day, HR 1.54 [95%CI, 1.20-1.97]). In contrast, we observed a negative dose-response relationship between alcohol consumption and the development of diabetes mellitus, with a significantly lower HR with higher weekly alcohol consumption (7.0-13.9 gou/week [154-307 g/week], HR 0.73 [95% CI, 0.55-0.97], >=14.0 gou/week [308 g/week], HR 0.75 [95% CI, 0.57-0.98]). CONCLUSIONS: The results indicated that decreasing tobacco consumption will achieve significant prevention of diabetes mellitus. On the other hand, we observed a significant, negative dose-response relationship between alcohol consumption and the development of diabetes mellitus, in contrast to previous studies that reported a positive relationship in the Japanese population. PMID- 22445623 TI - Development and validation of the cannabis refusal self-efficacy questionnaire (CRSEQ) in adult cannabis users in treatment. AB - BACKGROUND: There are few valid clinical assessment instruments for cannabis. Self-efficacy, or the ability of users to resist temptation, is a central feature of social cognitive theory. This study outlines the development and validation of the cannabis refusal self-efficacy questionnaire (CRSEQ), which measures the situational confidence to refuse cannabis. METHOD: One thousand two hundred and forty-six patients referred for cannabis assessment completed the CRSEQ including measures of cannabis consumption and dependence severity (severity of dependence scale-cannabis, SDS-C). The CRSEQ was subject to independent exploratory (n=621, mean age 26.88, 78.6% male) and confirmatory (n=625, mean age 27.51, 76.8% male) factor analysis. RESULTS: Three factors: Emotional Relief, Opportunistic and Social Facilitation were identified. They provided a good statistical and conceptual fit for the data. Emotional relief cannabis refusal self-efficacy was identified as most predictive of cannabis dependence, after controlling for cannabis consumption. CONCLUSIONS: The CRSEQ is recommended as a psychometrically sound and clinically useful measure for cannabis misuse treatment planning and assessment. PMID- 22445624 TI - Silymarin regulates the cytochrome P450 3A2 and glutathione peroxides in the liver of streptozotocin-induced diabetic rats. AB - This study aimed to investigate the protective and regulatory effects of silymarin (SMN) and melatonin (MEL) on streptozotocin (STZ)-induced diabetic changes in cytochrome P450 3A2 (CYP 3A2) and glutathione peroxidase (GPX) expression and antioxidant status in the liver. Male Wistar rats were divided into five groups, including: control (C), untreated diabetic animals (D), SMN treated diabetics (S, 50 mg/kg, orally), MEL-treated diabetics (M, 10 mg/kg, i.p.), and SMN plus MEL-treated diabetics (S+M). Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). The blood glucose level, daily urinary volume and body weight changes were measured. After the 28 days treatment period, antioxidant status was analyzed by means of the determination of malondialdehyde (MDA) content, nitric oxide (NO) and total thiol molecules (TTM) levels in the liver. The glycogen depletion in the liver was examined by histochemical staining. The CYP 3A2 and GPX expression at mRNA level was determined using RT-PCT technique. SMN and MEL both individually or in combination prevented from diabetes-induced weight loss and lowered daily urinary volume significantly (p<0.05). None of the test compounds could lower the blood glucose level significantly (p>0.05). Both SMN and MEL could convert the diabetes induced elevated levels of MDA and NO and the diabetes-reduced TTM content to the control level. Moreover, the diabetes-up regulated CYP 3A2 and down regulated GPX, returned to normal values after SMN treatment. Histochemical and histopathological examinations revealed that the diabetes-induced glycogen depletion and single cell necrosis markedly improved with the SMN and SMN plus MEL treatment. Our data suggest that the STZ-induced diabetes in addition of disturbing the antioxidant status, alters the expression levels of CYP 3A2 and GPX. Moreover, the SMN and SMN plus MEL treatment was able to normalize both the antioxidant status and the expression of CYP 3A2 and GPX in the liver of diabetic rats. PMID- 22445625 TI - Case report: Post-traumatic memories triggered by donepezil in a dose-dependent pattern. AB - BACKGROUND: This case report describes a new adverse drug event due to use of donepezil in a patient with probable Alzheimer's Disease. CASE SUMMARY: While receiving a 10-mg dose of donepezil nightly, an 87-year old veteran of World War II experienced irrepressible memories of a kamikaze strike. This symptom did not occur at a 5-mg dose of donepezil and resolved with downward titration of this agent. CONCLUSIONS: This sequence of dosage and symptoms suggests acetylcholinesterase inhibition was the trigger for release of these memories, which are otherwise mostly chronically repressed in this individual. PMID- 22445626 TI - Does scapular dyskinesis affect top rugby players during a game season? AB - BACKGROUND: Scapular dyskinesis represents a considerable risk of shoulder injury to overhead athletes; however, there is a shortage of detailed epidemiologic information about scapular dyskinesis among the participants in collision sports. PURPOSE: To describe the incidence and relationship of scapular dyskinesis to shoulder discomfort and variables related to the shoulder in top rugby players. METHODS: One hundred twenty top rugby football players in Japan were evaluated by means of questionnaires, physical examinations, and a video analysis during their preseason. Data were assessed by a logistic regression analysis calculating odds ratios. The primary outcome was processed to assess the relationship between scapular dyskinesis and other variables at the preseason. The secondary outcome was processed to assess an influence of scapular dyskinesis to shoulder discomfort during their regular season that were reassigned by second questionnaires. RESULTS: Scapular dyskinesis was identified in 33 (32%) shoulders, and type III was prominent. Scapular dyskinesis was significantly associated with shoulder discomfort (OR [odds ratio] = 4.4), and was also associated with variables of the affected shoulder. In addition, the players with asymptomatic scapular dyskinesis at the preseason would have high incident with shoulder discomfort during their regular season (OR = 3.6). CONCLUSIONS: Scapular dyskinesis was associated significantly with both subjective and objective symptoms of the affected shoulder. These appearances may be of particular relevance in the early screening of chronic shoulder disorders in the rugby population. Further study to investigate and evaluate its reliability is needed to characterize its impact on the participants in collision sports. PMID- 22445627 TI - Western Ontario Osteoarthritis Shoulder (WOOS) index: a cross-cultural adaptation into Swedish, including evaluation of reliability, validity, and responsiveness in patients with subacromial pain. AB - BACKGROUND: The aim of the present study was to translate the Western Ontario Osteoarthritis Shoulder (WOOS) index into Swedish and to test its validity, reliability, and responsiveness in patients with subacromial pain. METHODS: The validity of the WOOS translation was tested in 54 patients who completed the WOOS and the Shoulder Rating Questionnaire, Swedish version (SRQs). Of these patients, 46 were retested to assess reliability. Responsiveness was evaluated in 29 subjects who completed the WOOS and SRQs before surgery and again at 3 months after surgery, when they also rated perceived change in shoulder function. The relationship between the questionnaires and patient-perceived improvement was assessed. RESULTS: A high correlation was found between the Swedish version of WOOS and the SRQs. The correlations were similar in a group of working patients (r = -0.832) and in all patients (r = -0.843; P < .001). A high degree of agreement between WOOS at test and retest was also observed. A Bland-Altman plot showed a small mean difference and no trend across the range of WOOS values. A strong significant agreement was also shown by a kappa value of 0.649 (P < .001) and an intraclass correlation coefficient of 0.95 (95% confidence interval, 0.92 0.97, P < .001) as well as by a low difference between the test and retest means. Responsiveness, calculated by standardized response mean, was excellent (1.02). CONCLUSION: The results of the present study provide evidence that the Swedish version of WOOS is valid, reliable, and responsive in patients with subacromial pain and performs similarly to the original Canadian version. PMID- 22445628 TI - Glare's causes, consequences, and clinical challenges after a century of ophthalmic study. AB - PURPOSE: To provide a multidisciplinary synthesis of scientific information on disability, discomfort, dazzling, and scotomatic (photostress) glare. DESIGN: Perspective. METHODS: Analysis and integration of relevant historical and contemporary publications on glare in ophthalmology, illumination engineering, neurology, and other relevant disciplines. RESULTS: Disability glare is caused by scattered intraocular light (straylight) not useful for vision. Straylight casts a veiling luminance on the retina, reducing image contrast and impairing vision. In common environments, glare and target illumination sources have the same or similar spectra. Colored spectacle or intraocular lens filters reduce both proportionately, so they do not increase retinal image contrast or decrease disability glare. Discomfort glare is caused by situational illumination too intense or variable. Dazzling glare occurs when high illuminances are spread across the retina. Neurophysiological research is clarifying how discomfort and dazzling glare depend on different retinal photoreceptors and nociceptive brain pathways involving the trigeminal ganglion and thalamus. Photostress is caused by excessive local retinal photopigment bleaching uncommon in ordinary situations. Optical glare countermeasures are available for daytime driving but not oncoming automobile headlights at night. Filters that decrease daytime discomfort or dazzling glare also reduce nighttime mesopic and scotopic sensitivity. CONCLUSIONS: Glare is problematic for patients and clinicians despite a century of scientific research. Advances in understanding glare have been hampered by its complex, multidisciplinary nature and limited interdisciplinary communication. We provide one pathway through the forest of glare nomenclature and mechanisms. Improved diagnostic and therapeutic methodologies await continuing progress in understanding glare. PMID- 22445630 TI - Evaluation of the nerve fiber layer and macula in the eyes of healthy children using spectral-domain optical coherence tomography. PMID- 22445631 TI - A randomized comparison of pupil-centered versus vertex-centered ablation in LASIK correction of hyperopia. PMID- 22445633 TI - Prognostic indicators for no light perception after open-globe injury: eye injury vitrectomy study. PMID- 22445634 TI - Prognostic indicators for no light perception after open-globe injury. PMID- 22445637 TI - Panretinal photocoagulation for proliferative diabetic retinopathy. PMID- 22445638 TI - Choice of analytic approach for eye-specific outcomes: one eye or two? PMID- 22445641 TI - Clinical outcomes of penetrating keratoplasty after autologous cultivated limbal epithelial transplantation for ocular surface burns. PMID- 22445643 TI - Curcumin prevents chronic alcohol-induced liver disease involving decreasing ROS generation and enhancing antioxidative capacity. AB - Our previous study found that curcumin, a major active component of turmeric, could ameliorate ethanol-induced hepatocytes oxidative stress in vitro. The objective of this work was to investigate the effect of curcumin on chronic alcoholic liver disease (ALD) in vivo. Ethanol-exposed (2.4g/kg/day ethanol for the initial 4 weeks and 4g/kg/day for another 2 weeks) Balb/c mice were simultaneously treated with curcumin for 6 weeks. The results showed that curcumin attenuated ethanol-induced histopathological changes of the liver and ameliorated the evident release of cellular alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Ethanol exposure resulted in reactive oxygen species (ROS) generation, malondialdehyde (MDA) elevation, glutathione (GSH) depletion and antioxidant defense system impairment, which were significantly reversed by curcumin treatment. In conclusion, curcumin provided protection against chronic ALD and the mechanism might be related to the alleviation of oxidative damage. PMID- 22445644 TI - Intrahospitalary dissemination of Klebsiella pneumoniae carrying bla(DHA-1) and qnrB4 genes within a novel complex class 1 integron. PMID- 22445645 TI - Actinomyces cardiffensis septicemia: a case report. AB - Actinomyces cardiffensis is an anaerobic, Gram-positive, non-spore-forming rod that was first identified by Hall et al. (Hall V. et al. (2002) J Clin Microbiol 40:3427-31). Here we report a case of bacteremia with liver and lung abscesses associated with A. cardiffensis. A 67-year-old man was hospitalized with fever and headache for 20 days. Blood culture revealed an Actinomyces species, which was ultimately identified as A. cardiffensis by 16S rRNA gene sequencing. A computed tomography scan of his chest showed small abscesses in his lung and liver. After a 3-week course of intravenous ceftriaxone, the patient showed rapid improvement. The patient was transitioned to oral amoxicillin for the remainder of his antibiotic treatment. PMID- 22445646 TI - Cephalometric outcome of two types of palatoplasty in complete unilateral cleft lip and palate. AB - In complete unilateral cleft lip and palate (CLP), a vomerplasty is assumed to improve midfacial growth because of the reduction in scarring in the growth sensitive areas of the palate. Our aim, therefore, was to evaluate maxillofacial morphology after a modified Langenbeck technique or a vomerplasty in children with complete unilateral CLP who were operated on by a single surgeon. As part of a one-stage closure of complete unilateral CLP done during the first year of life, the technique for repair of the hard palate repair differed between the two groups. In the modified group (n=37, mean age 11 years) a modified von Langenbeck technique was used that resulted in denudation of the bony surface on the non cleft side only. In the vomerplasty group (n=37, mean age 11 years) a vomerplasty was used to cover the palatal bone. Lateral cephalograms from both groups were compared using the Eurocleft protocol. Fourteen angular variables were measured and 2 ratios calculated. Skeletal morphology in the groups was comparable. Maxillary incisor inclination (ILs/NL angle) and interincisal angle (ILs/ILi) were better after vomerplasty (p=0.001 and 0.04, respectively) but soft tissue facial convexity (gs-prn-pgs) was less good after vomerplasty (p=0.009). However, there was no difference between the groups in the other variable that reflected facial convexity (gs-sn-pgs) (p=0.22). Modification of the palatoplasty had a limited effect on skeletal morphology in preadolescent children, but it resulted in better inclination of the maxillary incisors. PMID- 22445647 TI - Simultaneous actinomycosis with aspergillosis in maxillary sinus. AB - We report a case with review of literature of actinomycosis accompanied with aspergillosis arising in unilateral maxillary sinus, in which it was completely cured after endoscopic sinus surgery and short term antibiotic therapy. To the best of our knowledge, this is the first case report in literature reporting actinomycosis in combination with aspergillosis in the paranasal sinus. Also, we suggest short term antibiotic therapy within one month may be sufficient if the surgical opening of paranasal sinus involved by actinomycosis could be well preserved. PMID- 22445648 TI - Comment on: Superior weight loss and lower HbA1c three years after duodenal switch compared to Roux-en-Y gastric bypass--a randomized controlled trial. PMID- 22445649 TI - Roux-en-Y gastric bypass achieves substantial resolution of migraine headache in the severely obese: 9-year experience in 81 patients. AB - BACKGROUND: Although migraine headache (MH) is more severe in the obese, the risk of developing MH in the obese population is controversial. The effect of surgical weight loss on morbidly obese patients with MH provides a unique opportunity to evaluate this potential association. METHODS: We analyzed the data from 702 morbidly obese patients who underwent Roux-en-Y gastric bypass (RYGB) from 2000 to 2009. We identified patients with physician-diagnosed MH taking antimigraine medication. RESULTS: The data are presented as the mean +/- SEM, with the range in parentheses. Of the 102 patients with preoperative MH, 21 were excluded because they had <12-month follow-up data and 81 were followed up for 38.6 +/- 3 months (range 12-123). Of the 81 patients, 90% were women. Their body mass index was 48 +/- 1 kg/m(2) (range 37-85), and their age was 40 +/- 1 years (range 18 62). After surgical weight loss, clinical improvement in MH was seen in 89% of patients within 5.6 +/- .9 months (range 1-36; P < .01, chi-square test), with 57 reporting total resolution and 15 reporting partial resolution (9 experienced no change). Using logistic regression analysis, we showed that the improvement in MH after RYGB was independent of the improvement in migraine-associated co morbidities, such as sleep apnea, menstrual dysfunction, depression, and anxiety. We also compared patients who developed MH after obesity onset with those who had MH before obesity. The MH after obesity onset group included 51 patients, of whom 48 showed clinical improvement (41 complete, 7 partial, and 3 no improvement). The MH before obesity group included 24 patients, of whom 18 showed clinical improvement (11 complete, 7 partial, and 6 no improvement). The MH after obesity group showed a greater rate of complete resolution of MH after RYGB than did the MH before obesity group (P < .01; chi-square test). CONCLUSIONS: Weight loss after RYGB substantially resolves MH, especially when obesity onset precedes MH onset. It remains to be determined whether RYGB-induced endocrine alterations or a reduction in adipokine burden contribute to migraine improvement. PMID- 22445650 TI - Optimizing screening of severe obstructive sleep apnea in patients undergoing bariatric surgery. AB - BACKGROUND: Obstructive sleep apnea is common in patients waiting for bariatric surgery (BS). International consensuses have recommended assessment of obstructive sleep apnea in the preoperative evaluation to avoid perioperative complications. Polysomnography is the standard diagnostic method but is expensive and time-consuming. The aim of our study was to detect those patients who merit treatment before BS using a simple predictor model. The study was conducted at 3 university hospitals (Hospital de Bellvitge, Hospital de la Santa Creu i Sant Pau, Hospital Clinic de Barcelona). METHODS: A prospective cross-sectional study was conducted of 136 consecutive bariatric subjects. The outcome variable was severe obstructive sleep apnea, defined as an apnea-hypoapnea index of >=30 events/hr by polysomnography. The predictors evaluated were anthropometric and clinical in the first model, with an oxygen desaturation index of >=3% added to the second model. Predictive models were constructed using multivariate logistic regression analysis. The best model was selected according to the area under the receiver operating characteristic curve. RESULTS: The first model identified 4 independent factors: age, waist circumference, systolic blood pressure, and witnessed apnea episodes, with a sensitivity of 78%, specificity of 68%, and area under the receiver operating characteristic curve of .83 (95% confidence interval .76-.90, P < .001). The second model identified 2 independent factors (witness apnea episodes, oxygen desaturation index of >=3%), with a sensitivity of 91%, specificity of 85%, and area under the receiver operating characteristic curve of .94 (95% confidence interval .89-.98, P < .001). The 2-step model predictive values were sensitivity of 90%, specificity of 91%, and accuracy of 90% (95% confidence interval 84-94%). After applying the first model and then the second, 45% of subjects would have been ruled out (15% and 30%, respectively) and 55% would require additional sleep management before BS. CONCLUSION: The proposed model could be useful for improving the management of complex patients before BS and optimizing limited polysomnography resources. PMID- 22445651 TI - Bioguided fractionation and isolation of natural inhibitors of advanced glycation end-products (AGEs) from Calophyllum flavoramulum. AB - Advanced glycation end-products (AGEs) are associated with many pathogenic disorders such as Alzheimer's disease, pathogenesis of diabetes, atherosclerosis or endothelial dysfunction leading to cardiovascular events. Clusiaceae and Calophyllaceae families are rich in compounds like polyphenols which are able to inhibit their formation and are therefore of great interest. Calophyllum flavoramulum Hend. & Wyatt-Sm., a native Malaysian plant, was selected after an anti-AGEs screening conducted on DCM and MeOH extracts from plants belonging to these aforementioned families. In a first study, bioguided fractionation of the MeOH leaf extract of C. flavoramulum afforded amentoflavone, 3-methoxy-2 hydroxyxanthone, 3,4-dihydroxy-tetrahydrofuran-3-carboxylic acid, quercitrin, 3,4 dihydroxybenzoic acid, canophyllol and apetalactone. Amentoflavone and 3-methoxy 2-hydroxyxanthone were found to be very potent (IC(50)=0.05 and 0.06 mM respectively), while anti-AGEs activities of quercitrin and 3,4-dihydroxybenzoic acid appeared as moderately strong (IC(50)=0.5 mM). In a second study, a systematic phytochemical study of the cyclohexane, DCM and EtOAc extracts obtained from the same plant was conducted to isolate the following products: flavoramulone, 6-deoxyjacareubin, rheediachromenoxanthone, 2,3 dihydroamentoflavone and benzoic acid. 3,4-Dihydroxy-tetrahydrofuran-3-carboxylic acid and flavoramulone were isolated for the first time and their structures were identified by means of IR, MS and NMR spectrometries. PMID- 22445652 TI - Regioisomer separation and identification of triacylglycerols containing vaccenic and oleic acids, and alpha- and gamma-linolenic acids, in thermophilic cyanobacteria Mastigocladus laminosus and Tolypothrix sp. AB - Reversed phase liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (RP-HPLC/APCI-MS) was used for direct analysis of triacylglycerols (TAGs) from different strains of the cyanobacteria Mastigocladus laminosus, Tolypothrix cf. tenuis and Tolypothrix distorta. This technique enabled us to identify and quantify the specific molecular species of TAGs directly from lipid extracts of the cyanobacteria. The regioisomeric series of TAGs having alpha-linolenic and gamma-linolenic and also oleic and cis-vaccenic acids were separated by RP-HPLC and identified by APCI-MS. M. laminosus produced only a few molecular species of TAGs, including both isomers of octadecenoic (oleic and vaccenic) acid, while T. distorta contained tens of molecular species of TAGs having FAs with up to four double bonds (stearidonic acid and including also its positional isomer, i.e. 3,6,9,12-octadecatetraenoic acid) and both positional isomers (alpha and gamma) of linolenic acids. Individual strains of both cyanobacteria exhibited different contents of polyunsaturated fatty acids (Tolypothrix sp.) and different distribution of positional isomers of monoenoic fatty acids in TAGs (M. laminosus). PMID- 22445653 TI - Task-sensitivity of unconscious word processing in spatial neglect. AB - Neuropsychological studies of spatial neglect have shown that ignored visual stimuli can produce measurable behavioral changes without eliciting subjective perceptual experience. However, such non-conscious, implicit cognitive processing may not be fully automatic but rather could be influenced by the patients' voluntary behavioral control. Using a hemifield priming paradigm with two different task instructions, we studied spatial neglect patients to assess whether non-conscious processing of ignored words is modulated by behavioral task requirements. In each trial, participants named or categorized a centrally presented target following a masked prime flashed to the left or right hemifield. By delivering equally invisible stimuli to both hemifields, this design allowed rigorous testing of the impact of task instructions on non-conscious processing in neglect patients and control participants. We observed that neglect patients showed slightly different patterns of masked priming from those obtained in healthy and right-hemisphere control patients. Importantly, however, all these three groups showed strong sensitivity to task contexts during the unconscious processing of masked words. The present results provide neuropsychological evidence that robust task-sensitive neural pathways are covertly operating on weak and normally imperceptible visual stimuli even when visuospatial attention is severely compromised. PMID- 22445654 TI - The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy. AB - The regulation of the immune system is controlled by many cell surface receptors. A prominent representative is the 'molecular switch' HVEM (herpes virus entry mediator) that can activate either proinflammatory or inhibitory signaling pathways. HVEM ligands belong to two distinct families: the TNF-related cytokines LIGHT and lymphotoxin-alpha, and the Ig-related membrane proteins BTLA and CD160. HVEM and its ligands have been involved in the pathogenesis of various autoimmune and inflammatory diseases, but recent reports indicate that this network may also be involved in tumor progression and resistance to immune response. Here we summarize the recent advances made regarding the knowledge on HVEM and its ligands in cancer cells, and their potential roles in tumor progression and escape to immune responses. Blockade or enhancement of these pathways may help improving cancer therapy. PMID- 22445655 TI - Perivascular administration of drugs and genes as a means of reducing vein graft failure. AB - Coronary artery bypass surgery is a highly effective and durable therapy of coronary artery disease. Together with internal mammary arteries the saphenous vein grafts are the most important conduits for coronary surgery. We reviewed the topic of local pharmacologic and gene therapeutic treatment approaches to prevent neointimal hyperplasia in vein grafts. Perivascular therapy of veins before arterialization would be a simple approach that avoids systemic side effects of medications. The current data available show that there are promising experimental approaches (in vitro models, animal in vivo models) for pharmacological and gene therapeutic treatment of vein graft failure. PMID- 22445656 TI - Re-irradiation plus regional hyperthermia for recurrent non-small cell lung cancer: a potential modality for inducing long-term survival in selected patients. AB - PURPOSE: The purpose of this study was to assess the toxicity and efficacy of re irradiation plus regional hyperthermia for recurrent NSCLC and to identify the predictors of long-term survival. METHODS AND MATERIALS: A total of 33 patients with recurrent NSCLC treated with re-irradiation plus regional hyperthermia were retrospectively analyzed. The median total dose of initial radiotherapy and re irradiation were 70 Gy and 50 Gy, respectively. A median of 5 hyperthermia treatments using an 8-MHz radiofrequency-capacitive device were applied during re irradiation in all patients. RESULTS: Toxicity of Grade 3 was seen in 3 (9%) patients, and no Grade 4 or 5 toxicity was observed. The median overall survival, local control, and disease progression-free survival times after re-irradiation were 18.1, 12.1, and 6.7 months, respectively. Eight patients achieved a long term survival (more than 3 years after re-irradiation), and 4 of them underwent a third round of irradiation for re-recurrent tumors. Univariate analyses showed that a smaller tumor size (<4 cm) and the absence of distant metastases were significant predictors for a better overall survival. The absence of distant metastases was also found to be a significant predictor for better disease progression-free survival in the univariate analyses. In the subset analyses of 23 patients treated with hyperthermia using electrodes of 30 cm in diameter, the use of a higher radiofrequency-output power tended to be associated with a better prognosis in terms of the local control rate. CONCLUSIONS: Re-irradiation plus regional hyperthermia for recurrent NSCLC appears feasible, with acceptable toxicity, and may be a promising treatment that can result in the long-term survival of patients without distant metastasis and larger recurrent tumors. PMID- 22445657 TI - IkappaBalpha is not required for axon initial segment assembly. AB - The inhibitor of NF-kappaB alpha (IkappaBalpha) protein is an important regulator of the transcription factor NF-kappaB. In neurons, IkappaBalpha has been shown to play a role in neurite outgrowth and cell survival. Recently, a phosphorylated form of IkappaBalpha (pIkappaBalpha Ser32/36) was reported to be highly enriched at the axon initial segment (AIS) and was proposed to function upstream of ankyrinG in AIS assembly, including ion channel recruitment. However, we report here that the AIS clustering of ankyrinG and Na(+) channels in the brains of IkappaBalpha knockout (Nfkbia(-/-)) mice is comparable to that in wild-type littermates. Furthermore, we found that multiple phospho-specific antibodies against pIkappaBalpha Ser32/36 non-specifically label AIS in Nfkbia(-/-) cortex and AIS in dissociated Nfkbia(-/-) hippocampal neurons. With the exception of ankyrinG, shRNA-mediated knockdown of known AIS proteins in cultured hippocampal neurons did not eliminate the AIS labeling with pIkappaBalpha antibodies. Instead, the pIkappaBalpha antibodies cross-react with a phosphorylated epitope of a protein associated with the microtubule-based AIS cytoskeleton that is not integrated into the AIS membrane complex organized by ankyrinG. Our results indicate that pIkappaBalpha is neither enriched at the AIS nor required for AIS assembly. PMID- 22445658 TI - Fragrance material review on 2-hydroxy-3,4-dimethyl-2-cyclopenten-1-one. AB - A toxicologic and dermatologic review of 2-hydroxy-3,4-dimethyl-2-cyclopenten-1 one when used as a fragrance ingredient is presented. 2-Hydroxy-3,4-dimethyl-2 cyclopenten-1-one is a member of the fragrance structural group Ketones Cyclopentanones and Cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-hydroxy-3,4-dimethyl-2-cyclopenten-1-one were evaluated, then summarized and includes physical properties data. A safety assessment of the entire Ketones Cyclopentanones and Cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Ketones Cyclopentanones and Cyclopentenones in fragrances. PMID- 22445659 TI - Fragrance material review on 3-methyl-2-pentylcyclopentan-1-one. AB - A toxicologic and dermatologic review of 3-methyl-2-pentylcyclopentan-1-one when used as a fragrance ingredient is presented. 3-methyl-2-pentylcyclopentan-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-methyl-2-pentylcyclopentan-1-one were evaluated then summarized and includes physical properties data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445660 TI - Fragrance material review on 2-hexylcyclopentanone. AB - A toxicologic and dermatologic review of 2-hexylcyclopentanone when used as a fragrance ingredient is presented. 2-Hexylcyclopentanone is a member of the fragrance structural group Ketones Cyclopentanones and Cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2 hexylcyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, and photoallergy data. A safety assessment of the entire Cyclopentanones and Cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all cyclopentanones and cyclopentenones in fragrances. PMID- 22445661 TI - Fragrance material review on 2-cyclopentylcyclopentanone. AB - A toxicologic and dermatologic review of 2-cyclopentylcyclopentanone when used as a fragrance ingredient is presented. 2-cyclopentylcyclopentanone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2 cyclopentylcyclopentanone were evaluated then summarized and includes physical properties data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445662 TI - Fragrance material review on 2-pentylcyclopentan-1-one. AB - A toxicologic and dermatologic review of 2-pentylcyclopentan-1-one when used as a fragrance ingredient is presented. 2-Pentylcyclopentan-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2 pentylcyclopentan-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitisation, elicitation, phototoxicity, photoallergy, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445663 TI - Fragrance material review on 2-heptylcyclopentanone. AB - A toxicologic and dermatologic review of 2-heptylcyclopentanone when used as a fragrance ingredient is presented. 2-Heptylcyclopentanone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2 heptylcyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, photoallergy, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445664 TI - Fragrance material review on cyclopentanone. AB - A toxicologic and dermatologic review of cyclopentanone when used as a fragrance ingredient is presented. Cyclopentanone is a member of the fragrance structural group ketones cyclopentanones and cyclopentanones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentanone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for cyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, repeated dose, reproductive toxicity, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445665 TI - Fragrance material review on cis-jasmone. AB - A toxicologic and dermatologic review of cis-jasmone when used as a fragrance ingredient is presented. cis-Jasmone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for cis-jasmone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, photoallergy, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445666 TI - Fragrance material review on 3-methyl-2-(2-pentenyl)-2-cyclopenten-1-one. AB - A toxicologic and dermatologic review of 3-methyl-2-(2-pentenyl)-2-cyclopenten-1 one when used as a fragrance ingredient is presented. 3-methyl-2-(2-pentenyl)-2 cyclopenten-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-methyl-2-(2-pentenyl)-2-cyclopenten-1-one were evaluated then summarized and includes physical properties data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445667 TI - Fragrance material review on 3-ethyl-2-hydroxy-2-cyclopenten-1-one. AB - A toxicologic and dermatologic review of 3-ethyl-2-hydroxy-2-cyclopenten-1-one when used as a fragrance ingredient is presented. 3-Ethyl-2-hydroxy-2-cyclopenten 1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-ethyl-2-hydroxy-2-cyclopenten-1-one were evaluated then summarized and includes physical properties, skin irritation, skin sensitization, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445669 TI - The association between childhood rickets and nonaffective psychosis: a Danish record-linkage study. PMID- 22445668 TI - Gray matter volume in schizophrenia and bipolar disorder with psychotic features. AB - There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD. PMID- 22445670 TI - Cytokine production by co-cultures exposed to monodisperse amorphous silica nanoparticles: the role of size and surface area. AB - The aim of this study was to test the influence of nanoparticle size and surface area (SA) on cytokine secretion by co-cultures of pulmonary epithelial cells (A549), macrophages (differentiated THP-1 cells) and endothelium cells (EA.hy926) in a two-compartment system. We used monodisperse amorphous silica nanoparticles (2, 16, 60 and 104 nm) at concentrations of 5 MUg/cm2 cell culture SA or 10 cm2 particle SA/cm2. A549 and THP-1 cells were exposed to nanoparticles for 24h, in the presence of EA.hy926 cells cultured in an insert introduced above the bi culture after 12h. Supernatants from both compartments were recovered and TNF alpha, IL-6, IL-8 and MIP-1alpha were measured. Significant secretion of all cytokines was observed for the 2 nm particles at both concentrations and in both compartments. Larger particles of 60 nm induced significant cytokine secretion at the dose of 10 cm2 particle SA/cm2. The use of multiple cellular types showed that cytokine secretion in single cell cultures is amplified or mitigated in co cultures. The release of pro-inflammatory mediators by endothelial cells not directly exposed to nanoparticles indicates a possible endothelium activation after inhalation of silica particles. This work shows the role of size and SA in cellular response to amorphous nanosilica. PMID- 22445671 TI - The use of FISH-comet to detect c-Myc and TP 53 damage in extended-term lymphocyte cultures treated with terbuthylazine and carbofuran. AB - Terbuthylazine and carbofuran are suspected to cause non-Hodgkin's lymphoma and lung cancer. We evaluated the effects of prolonged exposure to low concentrations on primary DNA damage by comet assay, and on the structural integrity of c-Myc and TP 53 genes by FISH-comet. Another novelty in studying these pesticides' genotoxicity is the use of 14-day extended-term human lymphocyte cultures. Concentrations corresponded to values of ADI and OEL: for terbuthylazine 0.58 ng/ml and 8 ng/ml; for carbofuran 8 ng/ml and 21.6 ng/ml, respectively. A possible effect of metabolic activation (S9) was also considered. Carbofuran treatment induced a significant migration of DNA into the tail in a concentration dependent manner, while for terbuthylazine the effect was significant only at the higher concentration. Terbuthylazine caused migration of both c-Myc signals into the comet tail. A significant occurrence of TP 53 signals in the tail was observed at 8 ng/ml. Prolonged carbofuran treatment significantly elevated the migration of a single c-Myc signal into the tail in a concentration-dependent manner. With S9, distribution of signals shifted toward increased presence of both signals in tail. Our results showed impaired structural integrity of c-Myc and TP 53 due to prolonged exposure to terbuthylazine and carbofuran. PMID- 22445672 TI - Statin therapy and new-onset diabetes: a cause for concern? PMID- 22445673 TI - Neuropsychological performance in a sample of 13-25 year olds with a history of non-psychotic major depressive disorder. AB - BACKGROUND: There is evidence for neuropsychological dysfunction in depression among adult and elderly participants but little research has been conducted on the neuropsychological functioning of youth with depression. The aim of the present study was to investigate the neuropsychological functioning of outpatient young participants with depression. METHODS: Computerised neuropsychological tests requiring executive functioning, working memory, attention, verbal memory and learning, planning, and visuospatial skills were carried out in a sample of 13-25year-olds with a lifetime history of non-psychotic major depression (n=32) and in healthy age balanced controls (n=65). Psychiatric diagnoses were ascertained using the MINI International Neuropsychiatric Interview. RESULTS: Participants with current or previous major depressive disorder demonstrated impairments in executive function tasks requiring conceptual skills and set shifting, attention and working memory. However, planning skills were found to be largely intact. Positive affect was associated to better attention, working memory and verbal learning in depressed participants, independently from gender and education. LIMITATIONS: The results may be affected by the small sample size and heterogeneity of the sample. CONCLUSION: The findings from this study indicate, and are one of the first to identify, that young subjects aged between 13 and 25, with a lifetime history of depression, have impaired executive and working memory functioning. PMID- 22445674 TI - Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits. AB - Alzheimer's disease is rapidly becoming one of the most prevalent human diseases. Inhibition of human acetylcholinestrase (hAChE) and butyrylcholinestrase (BChE) has been linked to amelioration of Alzheimer's symptoms and research into inhibitors is of critical importance. Purification of the methanol extract of Paulownia tomentosa fruits yielded potent hAChE and BChE inhibitory flavonoids (1 9). A comparative activity screen indicated that a geranyl group at C6 is crucial for both hAChE and BChE. For example, diplacone (8) showed 250-fold higher efficacy than its parent eriodictyol (12). IC(50)s of diplacone (8) were 7.2 MUM for hAChE and 1.4 MUM for BChE. Similar trends were also observed for 4'-O methyldiplacone (4) (vs its parent, hesperetin 10) and mimulone (7) (vs its parent, naringenin 11). Representative inhibitors (1-8) showed mixed inhibition kinetics as well as time-dependent, reversible inhibition toward hAChE. The binding affinities of these compounds to hAChE were investigated by monitoring quenching of inherent enzyme fluorescence. The affinity constants (K(SA)) increased in proportion to inhibitory potencies. PMID- 22445675 TI - Antibody-cytokine fusion proteins. AB - Cytokines are key players in stimulating and regulating immune responses in physiological and pathophysiological processes. Various cytokines have been approved for therapy of cancer and other diseases and many more are under development. However, therapeutic efficacy is often hampered by severe side effects and poor pharmacokinetic properties. Fusion of cytokines to antibodies or antibody fragments allows for a targeted delivery and should, therefore, improve efficacy and pharmacokinetics. This review provides a comprehensive summary of the developments in the field of targeted cytokine delivery by genetic engineering of antibody-cytokine fusion proteins. PMID- 22445676 TI - The specific effect of metronome guidance on the quality of one-person cardiopulmonary resuscitation and rescuer fatigue. AB - BACKGROUND: Metronome guidance is a simple and economic feedback method of guiding cardiopulmonary resuscitation (CPR). It has been proven for its usefulness in regulating the rate of chest compression and ventilation, but it is not yet clear how metronome use may affect compression depth or rescuer fatigue. STUDY OBJECTIVE: The aim of this study was to assess the specific effect that metronome guidance has on the quality of CPR and rescuer fatigue. METHODS: One person CPRs were performed by senior medical students on Resusci Anne(r) manikins (Laerdal, Stavanger, Norway) with personal-computer skill-reporting systems. Half of the students performed CPR with metronome guidance and the other half without. CPR performance data, duration, and before-after trial differences in mean arterial pressure (MAP) and heart rate (HR) were compared between groups. RESULTS: Average compression depth (ACD) of the first five cycles, compression rate, no-flow fraction, and ventilation count were significantly lower in the metronome group (p=0.028, < 0.001, 0.001, and 0.041, respectively). Total CPR duration, total work (ACD * total compression count), and the before-after trial differences of the MAP and HR did not differ between the two groups. CONCLUSIONS: Metronome guidance is associated with lower chest compression depth of the first five cycles, while shortening the no-flow fraction and the ventilation count in a simulated one-person CPR model. Metronome guidance does not have an obvious effect of intensifying rescuer fatigue. PMID- 22445677 TI - Impact of physician screening in the emergency department on patient flow. AB - BACKGROUND: Physician triage is one of many front-end interventions being implemented to improve emergency department (ED) efficiency. STUDY OBJECTIVE: We aim to determine the impact of this intervention on some key components of ED patient flow, including time to physician evaluation, treatment order entry, diagnostic order entry, and disposition time for admitted patients. METHODS: We conducted a 2-year before-after analysis of a physician triage system at an urban tertiary academic center with 90,000 annual visits. The goal of the physician in triage was to arrange safe disposition of straightforward patients as well as to initiate work-ups. All medium-acuity patients arriving during the hours of the intervention were impacted and thus included in the analysis. Our primary outcome was the time to disposition decision. In addition to before-after analysis, comparison was made with high-acuity patients, a group not impacted by this intervention. Patient flow data were extracted from the ED information system. Outcomes were summarized with medians and interquartiles. Multivariable regression analysis was performed to investigate the intervention effect controlling for potential confounding variables. RESULTS: The median time to disposition decision decreased by 6min, and the time to physician evaluation, analgesia, antiemetic, antibiotic, and radiology order decreased by 16, 70, 66, 36, and 16min, respectively. These findings were all statistically significant. Similar results were observed from the multivariable regression models after controlling for potential confounding factors. CONCLUSIONS: Physician triage led to earlier evaluation, physician orders, and a decrease in the time to disposition decision. PMID- 22445678 TI - Thrombotic thrombocytopenic purpura: a hematological emergency. AB - BACKGROUND: Thrombotic thrombocytopenic purpura is a hematological emergency and diagnostic challenge. The critical determinant of outcome is timely diagnosis and treatment. OBJECTIVES: Describe the pathophysiology, presentation, diagnosis, and treatment of thrombotic thrombocytopenic purpura. DISCUSSION: Thrombotic thrombocytopenic purpura has a varied presentation and a tendency to mimic several disorders. However, it may be at least provisionally diagnosed in the patient with thrombocytopenia and microangiopathic hemolytic anemia without alternate cause. The mainstay of treatment is immediate plasma exchange to be repeated until platelet count is stabilized. Adjuvant therapies include corticosteroids, rituximab, and cyclosporine. CONCLUSION: It is essential for the emergency physician to be aware of thrombotic thrombocytopenic purpura's range of presentations, diagnostic criteria, and treatment. PMID- 22445680 TI - A 9-year-old boy with exertional syncope. AB - BACKGROUND: Syncope in the pediatric population is a common and mostly benign event. There is a subset of patients, however, in whom exertional syncope is the manifestation of a life-threatening cardiac abnormality. OBJECTIVE: We present a rare but serious cause of syncope in children that often presents as sudden cardiac death. CASE REPORT: A 9-year-old boy presented to the Emergency Department (ED) after an episode of exertional syncope while in physical education class. This was the patient's second episode of exercise-induced syncope within a 2-year period. There was no family history of sudden death or cardiac disease. The child had not undergone any prior diagnostic work-up for the syncope. He was admitted to the hospital for further evaluation, and was found to have an anomalous left coronary artery on transthoracic echocardiogram. CONCLUSION: As a potential precursor of sudden death, exertional syncope in pediatric patients should prompt a thorough evaluation for a cardiac etiology. PMID- 22445679 TI - Transfusion of packed red blood cells is not associated with improved central venous oxygen saturation or organ function in patients with septic shock. AB - BACKGROUND: The exact role of packed red blood cell (PRBC) transfusion in the setting of early resuscitation in septic shock is unknown. STUDY OBJECTIVE: To evaluate whether PRBC transfusion is associated with improved central venous oxygen saturation (ScvO(2)) or organ function in patients with severe sepsis and septic shock receiving early goal-directed therapy (EGDT). METHODS: Retrospective cohort study (n=93) of patients presenting with severe sepsis or septic shock treated with EGDT. RESULTS: Thirty-four of 93 patients received at least one PRBC transfusion. The ScvO(2) goal>70% was achieved in 71.9% of the PRBC group and 66.1% of the no-PRBC group (p=0.30). There was no difference in the change in Sequential Organ Failure Assessment (SOFA) score within the first 24 h in the PRBC group vs. the no-PRBC group (8.6-8.3 vs. 5.8-5.6, p=0.85), time to achievement of central venous pressure>8 mm Hg (732 min vs. 465 min, p=0.14), or the use of norepinephrine to maintain mean arterial pressure>65 mm Hg (81.3% vs. 83.8%, p=0.77). CONCLUSIONS: In this study, the transfusion of PRBC was not associated with improved cellular oxygenation, as demonstrated by a lack of improved achievement of ScvO(2)>70%. Also, the transfusion of PRBC was not associated with improved organ function or improved achievement of the other goals of EGDT. Further studies are needed to determine the impact of transfusion of PRBC within the context of early resuscitation of patients with septic shock. PMID- 22445681 TI - Inhibition of heat shock protein (Hsp) 27 potentiates the suppressive effect of Hsp90 inhibitors in targeting breast cancer stem-like cells. AB - Heat shock protein (Hsp) 90 is an ATP-dependent chaperone and its expression has been reported to be associated with poor prognosis of breast cancer. Cancer stem cells (CSCs) are particular subtypes of cells in cancer which have been demonstrated to be important to tumor initiation, drug resistance and metastasis. In breast cancer, breast CSCs (BCSCs) are identified as CD24-CD44 + cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Although the clinical trials of Hsp90 inhibitors in breast cancer therapy are ongoing, the BCSC targeting effect of them remains unclear. In the present study, we discovered that the expression of Hsp90alpha was increased in ALDH + human breast cancer cells. Geldanamycin (GA), a Hsp90 inhibitor, could suppress ALDH + breast cancer cells in a dose dependent manner. We are interesting in the insufficiently inhibitory effect of low dose GA treatment. It was correlated with the upregulation of Hsp27 and Hsp70. By co-treatment with HSP inhibitors, quercetin or KNK437 potentiated BCSCs, which determined with ALDH+ population or mammosphere cells, toward GA inhibition, as well as anti-proliferation and anti migration effects of GA. With siRNA mediated gene silencing, we found that knockdown of Hsp27 could mimic the effect of HSP inhibitors to potentiate the BCSC targeting effect of GA. In conclusion, combination of HSP inhibitors with Hsp90 inhibitors could serve as a potential solution to prevent the drug resistance and avoid the toxicity of high dose of Hsp90 inhibitors in clinical application. Furthermore, Hsp27 may play a role in chemoresistant character of BCSCs. PMID- 22445682 TI - P-bodies and mitochondria: which place in RNA interference? AB - Micro-RNAs (miRNAs) are major actors of RNA interference (RNAi), a regulation pathway which leads to translational repression and/or degradation of specific mRNAs. They provide target specificity by incorporating into the RISC complex and guiding its binding to mRNA. Since the discovery of RNAi, many progresses have been made on the mechanism of action of the RISC complex and on the identification of target mRNAs. However, the regulation of RNAi has been poorly investigated so far. Recently, various studies have revealed physical and functional relationships between RNAi, P-bodies and mitochondria. This review intends to recapitulate these data and discuss their potential importance in cell metabolism. PMID- 22445683 TI - Gender, brain-derived neurotrophic factor Val66Met, and frequency of methamphetamine use. AB - BACKGROUND: Frequency of pretreatment methamphetamine (MA) use is an important predictor of outcomes of treatment for MA dependence. Preclinical studies suggest females self-administer more MA than males, but few clinical studies have examined potential sex differences in the frequency of MA use. Estrogen increases expression of brain-derived neurotrophic factor (BDNF), which has effects on MA induced striatal dopamine release and protects against MA-induced neurotoxicity. OBJECTIVE: We examined potential effects of sex, the Val66Met polymorphism in BDNF, and their interaction on frequency of MA use among 60 Caucasian MA dependent volunteers screening for a clinical trial. METHODS: Data was taken from 60 Caucasian MA-dependent volunteers screening for a clinical trial. RESULTS: Females reported significantly more pretreatment days with MA use in the past 30 days than males. There was a significant interaction between sex and BDNF Val66Met, with the highest frequency of MA use among females with Val/Val genotype. CONCLUSIONS: These results, although preliminary, add to the literature documenting sexual dimorphism in response to stimulants, including MA, and suggest a potential biological mechanism involving BDNF that might contribute to these differences. Additional research characterizing the biological basis of altered response to MA among females is warranted. PMID- 22445684 TI - Age- and ethnic-specific sex differences in stroke risk. AB - BACKGROUND: In white populations, age seems to modify the effect of sex on stroke risk, and compared with men, women are protected from stroke until approximately age 75 to 85 years, after which the protection is lost or reversed. Compared with non-Hispanic whites (NHWs), Mexican Americans (MAs) are at higher risk of stroke; however, age- and sex-specific stroke incidence data are currently not available for this population. OBJECTIVE: This study was performed to compare the age specific sex differences in stroke risk in MAs and NHWs. METHODS: Data were derived from the BASIC (Brain Attack Surveillance in Corpus Christi) Project, a population-based stroke surveillance study conducted in Nueces County Texas. Incident strokes (n = 2421, including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) that occurred between January 1, 2000 and May 25, 2007 in individuals aged 45 years or older were included in the analysis. Poisson regression using the generalized additive models framework was used to analyze the relationship between sex, age (5-year intervals), and race/ethnicity (NHW or MA) and incident stroke risk. RESULTS: Among both NHWs and MAs aged 45 to 79 years, men were at higher risk of stroke than women were. The magnitude of increased stroke risk in men compared with women diminished with age, and after age 79 years, no sex difference in stroke risk was observed. CONCLUSIONS: Reasons for the loss of protection from stroke in aging women of all races/ethnicities are not fully understood, and further study is warranted. PMID- 22445685 TI - Synthesis and biological evaluation of novel steroidal[17,16 d][1,2,4]triazolo[1,5-a]pyrimidines. AB - The preparation of steroidal[17,16-d][1,2,4]triazolo[1,5-a]pyrimidines and their biological evaluation as potential anticancer agents are herein reported. These novel heterosteroids (2, 4) were prepared through the condensation reaction of 3 amino-1,2,4-triazole with 16-arylidene-17-ketosteroids (1, 3). All the synthesized compounds were evaluated for their anticancer activity in vitro against PC-3 (human prostatic carcinoma), MCF-7 (human breast carcinoma) and EC9706 (human esophageal carcinoma) cell lines. Among the screened compounds, 2i, 2n and 4f showed significant inhibitory activity against all the three human cell lines. PMID- 22445686 TI - Highly oxygenated stigmastane-type steroids from the aerial parts of Vernonia anthelmintica Willd. AB - Nine new highly oxygenated stigmastane-type steroids, vernoanthelcin A-I (1-9), and two new stigmastane-type steroidal glycosides, vernoantheloside A and B (10 and 11) were isolated from the aerial parts of Vernonia anthelmintica Willd. The structures of compounds 1-11 were determined on the basis of IR, MS, 1D-NMR, and 2D-NMR, and their absolute configurations were deduced using single-crystal X-ray diffraction and the CD exciton chirality method. Compounds 1, 5, 7, 9 and 10 were tested for their effects on estrogen biosynthesis in human ovarian granulosa-like cells (KGN cells). PMID- 22445687 TI - Phylogenetic evidence for pollinator-driven diversification of angiosperms. AB - Since Darwin, the diversity of flowers has been attributed to selection by pollinators. Although pollinators commonly act as selective agents on floral traits, determining the extent to which they have influenced angiosperm diversification requires a historical perspective. Here we review recent studies that combine species-level phylogenies with pollinator data and show that pollinator shifts are common, being associated with at least a quarter of documented divergence events. However, shift frequency and directionality vary extensively, owing to variation in intrinsic factors such as floral features and phylogenetic history, as well as extrinsic factors such as interactions with local pollinator assemblages. Despite technical advances, phylogenies remain limited in their power to distinguish among various pollinator-driven evolutionary processes. PMID- 22445688 TI - Design and characterization of polytope construct with multiple B and TH epitopes of Japanese encephalitis virus. AB - Japanese encephalitis (JE) remains a major public health threat with vaccination as the only measure for its prevention. Epitope-based vaccination is a promising approach for achieving protective immunity and avoid immunopathology in Japanese encephalitis virus (JEV) infection due to flavivirus cross-reactivity. We have mapped B-cell epitopes from JEV envelope protein, responsible for elicitation of neutralizing antibodies. Incorporation of T helper (T(H)) epitopes, along with these, imparted protective immunity to the host. In the present study, based on in silico epitope selection we optimized and proposed a polytope DNA construct (P JEV) consisting B-cell and T(H) epitopes from the JEV envelope (E) protein as well as non-structural protein-1 (NS1). The immunogenicity and protective efficacy of P-JEV was assessed by in vitro and in vivo experiments. The expressed P-JEV showed reactivity in in vitro assays with JEV monoclonal antibodies. Protective efficacy of P-JEV was assessed in BALB/c mice. Our findings indicate that P-JEV may be a candidate vaccine for the prevention of JEV infection. PMID- 22445689 TI - A single amino acid substitution controls DAF-dependent phenotype of echovirus 11 in rhabdomyosarcoma cells. AB - Decay accelerating factor (DAF, CD55) is used by DAF-dependent (Daf+) variants of echovirus 11 (EV11) as a primary cellular receptor. The interaction of EV11 with DAF is completely reversible, therefore DAF-dependent variants require an unidentified coreceptor to initiate uncoating. Daf- variants of EV11, which do not interact with DAF, use an alternative primary cellular receptor. The aim of this study was to test the hypothesis whether the coreceptor, which is necessary for the uncoating of DAF-dependent variants, may act as an alternative primary receptor for the Daf- variants of EV11. By using the model of the two closely related daf+ and daf- clones of EV11 in rhabdomyosarcoma (RD) cell line, it was shown that a single amino acid substitution in the capsid protein VP2 could control the expression of the DAF-dependent phenotype. Anti-DAF monoclonal antibody has blocked the infection of RD cells by the DAF-dependent daf+ clone, but not by the daf- clone of EV11. Since the structural proteins of the two clones differed only in the receptor binding site for DAF, the unidentified non DAF primary receptor for the daf- clone might have the same conformation as the uncoating coreceptor required for the daf+ clone. Despite the difference in primary receptors, both daf+ and daf- clones were equally inhibited by a monoclonal antibody to beta2-microglobulin. The monoclonal antibody B9.12.1 to class I human leukocyte antigen molecules showed no inhibitory effect in regards to either clone. The hypothesis of convergent intracellular traffic of Daf+ and Daf- variants of EV11 is discussed. PMID- 22445690 TI - In vitro and in vivo activity of AS101 against West Nile virus (WNV). AB - There are currently no effective drugs to treat serious complications caused by WNV infection. The inhibition of WNV by the pluripotent immunomodulator AS101 [ammonium trichloro(dioxyethylene-0-0')tellurate] was evaluated in vitro and in vivo, and its mechanism was explored. Adding AS101 to Vero cells 1h or 5 min before infection increased cell survival from 21% to 84% and decreased plaque formation by 87% and virus yield by 2 logs. Following infection, high titer of WNV remained in the culture supernatants indicating interference with virus cell attachment. The binding of alpha(V)beta(3) integrin to WNV and of Vero cells to anti-alpha(V)beta(3) antibody were inhibited by AS101, suggesting that AS101 may block this cellular WNV receptor. Daily treatment of mice with AS101 starting 1 day before lethal infection with WNV resulted in 48% survival. However, treatment beginning 3 days post infection resulted only in 16% survival. Similarly, a single dose of anti-WNV IVIG three days post infection resulted in 16% survival compared to 100% if IVIG was given on the same day of infection or 1 day later. However, when mice received combined treatment with AS101 and IVIG starting 3 days post infection, an additive effect of 33% survival was observed. Our study suggests that AS101 has a potential preventive and therapeutic effect against WNV infection. PMID- 22445691 TI - Lore's fascia and the platysma-auricular ligament are distinct structures. AB - BACKGROUND: Lore's fascia and the platysma-auricular ligament are discreet fascial structures anterior and inferior to the auricle respectively. The nomenclature and descriptions of these structures have been presented inconsistently in the literature. There is also concern that placement of platysma suspension sutures into these structures may risk damage to the underlying facial nerve trunk. The aim of this study was to clarify the anatomy of Lore's fascia and the platysma-auricular ligament, and their relationship to the facial nerve trunk. MATERIALS & METHODS: A cadaveric study utilising twelve fresh cadaveric hemi-faces was undertaken, investigating the anatomy of Lore's fascia and the platysma-auricular ligament. This comprised dissection of the periauricular fascial layers and identification of the relationship of these two structures to the facial nerve trunk. A histological study of Lore's fascia was performed. RESULTS: Lore's fascia and the platysma-auricular ligament were identified in all 12 hemi-faces. The structures were anatomically distinct in all cases. The relationship of the facial nerve was documented in each case, with the facial nerve trunk found to lie at least 2 cm deep to the most superficial parts of both structures. Lore's fascia was demonstrable with histology. CONCLUSIONS: Lore's fascia and the platysma-auricular ligament are separate and consistently demonstrable structures. Both are suitable for platysma suspension sutures in terms of facial nerve trunk safety, and Lore's ligament can be used as a guide to facial nerve preservation in parotidectomy. PMID- 22445692 TI - Subungual melanoma: an important tip. AB - Acral lentiginous melanoma is rare, representing approximately 1% of malignant melanomas. Overall 5 year survival is disproportionately poor (25-51%) compared to other histological subtypes. This has been attributed to diagnostic delay resulting in more advanced presentation. Subungual presentation in the fingers is uncommon, reported in 1-13% of all acral lentiginous melanomas. We report a unique and diagnostically challenging case. Contrary to previously reported examples in the literature, the actual neoplastic pathology was detected in the less pigmented finger tip skin rather than the deeply pigmented nail bed germinal and sterile matrix that showed no evidence of malignancy. We therefore advocate that in cases where skin surrounding the nail is involved, this surrounding skin should also be biopsied, even if it is less pigmented than the primary lesion. PMID- 22445693 TI - The medial head of triceps brachii: a muscular flap. PMID- 22445694 TI - Refinements in smile reanimation: 10-year experience with the lengthening Temporalis Myoplasty. AB - The lengthening Temporalis Myoplasty (LTM) is an innovative dynamic facial reanimation procedure that has been used to great effect following its conception during the early 1990s by the senior author. Since its first description in the literature the technique has been refined and it has become clear from correspondence that certain technical aspects of the procedure require particular attention to detail. We discuss from experience of more than a hundred cases and highlight not only the important technical aspects of the procedure but also the importance of pre-operative assessment and the avoidance of complications. PMID- 22445695 TI - The vasodilatory effect of testosterone on renal afferent arterioles. AB - BACKGROUND: Sex differences exist in a variety of cardiovascular and renal diseases, and testosterone may contribute to the discrepancy. Afferent arterioles (Af-Arts) are the major resistance vessels in the kidney, and they play an important role in the development of renal injury and hypertension. OBJECTIVE: We sought to determine the acute effect and underlying mechanism(s) of action of testosterone on Af-Arts. METHODS: The mRNA expression of androgen receptors (ARs) in microdissected Af-Arts was measured by reverse transcription-polymerase chain reaction (RT-PCR). An in vitro microperfusion model was used to measure the diameter of Af-Arts in mice. Nitric oxide (NO) was evaluated by an NO-sensitive fluorescent dye, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate. RESULTS: Testosterone had no effect on microperfused Af-Arts when added to the bath. Therefore, we preconstricted the Af-Arts to approximately 30% with norepinephrine (10(-6) M); administration of testosterone (10(-9)-10(-7) M) subsequently dilated the Af-Arts in a dose-dependent manner (P < 0.001; n = 7). The AR mRNA was expressed in microdissected Af-Arts measured by RT-PCR. An AR antagonist, flutamide (10(-5) M), totally blocked the testosterone (10(-8) M) induced vasodilator effect. Mean (SEM) NO production of the Af-Art wall was increased when testosterone was added to the bath solution after norepinephrine treatment, from 278.4 (12.1) U/min to 351.2 (33.1) U/min (P < 0.05; n = 3). In the presence of NO inhibition with N(G)-nitro-L-arginine methyl ester (3 * 10(-4) M), the testosterone-induced dilatation was blunted compared with norepinephrine (P < 0.05). CONCLUSIONS: Testosterone dilated preconstricted mouse Af-Arts in a dose-dependent manner by activation of ARs and partially mediated by NO. PMID- 22445696 TI - Serologic allergic bronchopulmonary aspergillosis (ABPA-S): long-term outcomes. AB - BACKGROUND AND AIM: ABPA is radiologically classified on the presence or absence of central bronchiectasis (CB) as ABPA-CB and serologic ABPA (ABPA-S) respectively. Few studies have described the follow-up of patients with ABPA-S. The aim of this retrospective study was to describe the outcomes of ABPA-S. METHODS: Patients were diagnosed as ABPA-S if they met all the following criteria: asthma, immediate cutaneous hyperreactivity to Aspergillus fumigatus antigen, total IgE levels >1000 IU/mL, A. fumigatus specific IgE levels >0.35 kUA/L and normal HRCT of the chest. They were treated with glucocorticoids and followed up with history, physical examination, chest radiograph and total IgE levels every 6 weeks to 3 months. In addition, an annual spirometry and a biennial HRCT chest were performed in all patients. RESULTS: Of the 55 patients with ABPA-S, 41 (17 men, 24 women; mean age, 38.3 years) consented for performance of repeat HRCT scans. The median duration of asthma prior to diagnosis of ABPA was six years. The duration of follow-up ranged from 24 to 77 months with the mean (SD) follow-up duration being 43.7 (10.1) months. There was improvement in FEV(1) but not the FVC values during the follow-up period (p values = 0.001 and 0.5 for FEV(1) and FVC respectively). There was no development of CB in any patient. Sixteen patients had a relapse during the follow-up period, and six patients were classified as glucocorticoid-dependent ABPA. CONCLUSIONS: Although relapses are frequently seen, the long-term outcome of ABPA-S is good with no patient developing CB. PMID- 22445697 TI - Neural correlates of tinnitus related distress: an fMRI-study. AB - Chronic tinnitus affects approximately 5% of the population. Severe distress due to the phantom noise is experienced by 20% of the tinnitus patients. This distress cannot be predicted by psychoacoustic features of the tinnitus. It is commonly assumed that negative cognitive emotional evaluation of the tinnitus and its expected consequences is a major factor that determines the impact of tinnitus-related distress. Models of tinnitus distress and recently conducted research propose differences in limbic, frontal and parietal processing between highly and low distressed tinnitus patients. An experimental paradigm using verbal material to stimulate cognitive emotional processing of tinnitus-related information was conducted. Age and sex matched highly (n = 16) and low (n = 16) distressed tinnitus patients and healthy controls (n = 16) underwent functional magnetic resonance imaging (fMRI) while sentences with neutral, negative or tinnitus-related content were presented. A random effects group analysis was performed on the basis of the general linear model. Tinnitus patients showed stronger activations to tinnitus-related sentences in comparison to neutral sentences than healthy controls in various limbic/emotion processing areas, such as the anterior cingulate cortex, midcingulate cortex, posterior cingulate cortex, retrosplenial cortex and insula and also in frontal areas. Highly and low distressed tinnitus patients differed in terms of activation of the left middle frontal gyrus. A connectivity analysis and correlational analysis between the predictors of the general linear model of relevant contrasts and tinnitus-related distress further supported the idea of a fronto-parietal-cingulate network, which seems to be more active in highly distressed tinnitus patients. This network may present an aspecific distress network. Based on the findings the left middle frontal gyrus and the right medial frontal gyrus are suggested as target regions for neuromodulatory approaches in the treatment of tinnitus. For future studies we recommend the use of idiosyncratic stimulus material. PMID- 22445698 TI - Ameliorating effect of low frequency repetitive transcranial magnetic stimulation over the premotor cortex in a case of possible painless legs and moving toes syndrome. PMID- 22445699 TI - Female genital schistosomiasis - icebergs of morbidity ahead? PMID- 22445700 TI - The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use. AB - OBJECTIVE: To determine the impact of maternal and fetal single nucleotide polymorphisms in key betamethasone pathways on neonatal outcomes. STUDY DESIGN: DNA was obtained from women given betamethasone and their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway single nucleotide polymorphisms. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis using relevant clinical variables and genotypes to model for associations with neonatal respiratory distress syndrome was performed. RESULTS: One hundred nine women delivering 117 infants were analyzed. Sixty-four infants (49%) developed respiratory distress syndrome. Multivariable analysis revealed that respiratory distress syndrome was associated with maternal single nucleotide polymorphisms in CYP3A5 (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.16-2.30) and the glucocorticoid resistance (OR, 0.28; 95% CI, 0.08-0.95) and fetal single nucleotide polymorphisms in ADCY9 (OR, 0.17; 95% CI, 0.03-0.80) and CYP3A7*1E (rs28451617; OR, 23.68; 95% CI, 1.33-420.6). CONCLUSION: Maternal and fetal genotypes are independently associated with neonatal respiratory distress syndrome after treatment with betamethasone for preterm labor. PMID- 22445702 TI - Do burnout and work engagement predict depressive symptoms and life satisfaction? A three-wave seven-year prospective study. AB - BACKGROUND: Burnout and work engagement have been viewed as opposite, yet distinct states of employee well-being. We investigated whether work-related indicators of well-being (i.e. burnout and work engagement) spill-over and generalize to context-free well-being (i.e. depressive symptoms and life satisfaction). More specifically, we examined the causal direction: does burnout/work engagement lead to depressive symptoms/life satisfaction, or the other way around? METHODS: Three surveys were conducted. In 2003, 71% of all Finnish dentists were surveyed (n=3255), and the response rate of the 3-year follow-up was 84% (n=2555). The second follow-up was conducted four years later with a response rate of 86% (n=1964). Structural equation modeling was used to investigate the cross-lagged associations between the study variables across time. RESULTS: Burnout predicted depressive symptoms and life dissatisfaction from T1 to T2 and from T2 to T3. Conversely, work engagement had a negative effect on depressive symptoms and a positive effect on life satisfaction, both from T1 to T2 and from T2 to T3, even after adjusting for the impact of burnout at every occasion. LIMITATIONS: The study was conducted among one occupational group, which limits its generalizability. CONCLUSIONS: Work-related well-being predicts general wellbeing in the long-term. For example, burnout predicts depressive symptoms and not vice versa. In addition, burnout and work engagement are not direct opposites. Instead, both have unique, incremental impacts on life satisfaction and depressive symptoms. PMID- 22445703 TI - Effortful information processing in patients with major depression - a 10-year follow-up study. AB - The aim of the present study was to longitudinally investigate effortful cognitive functioning in a group of patients diagnosed with major depressive disorder (MDD) in a 10-year follow-up period. Results at inclusion in the acute phase of MDD showed impaired effortful processing and that this impairment prevailed at a 6-month follow-up, despite significant symptom reduction. Non effortful processing was normal as compared to healthy controls. Sixteen patients along with 16 healthy controls were included in the 10-year follow-up. They all participated in the original study and were matched for age and educational length. The mean symptom load at the time of testing at the 10-year follow-up indicated that the patients as a group were in remission. All participants were examined with a visual search paradigm, with demands for effortful and non effortful processing. Results showed that the patient group had normalized their performance for effortful information processing and no longer differed significantly from the healthy controls at the 10-year follow-up, and the lack of difference between the groups for non-effortful processing remained the same. These results indicate that short-term effortful cognitive impairments normalize over the course of long-term recovery that goes together with clinical improvement and remission. PMID- 22445704 TI - Negative symptoms in individuals at clinical high risk of psychosis. AB - Negative symptoms are present in the psychosis prodrome. However, the extent to which these symptoms are present prior to the onset of the first episode of psychosis remains under-researched. The goal of this study is to examine negative symptoms in a sample of individuals at clinical high risk (CHR) for psychosis and to determine if they are predictive of conversion to psychosis. Participants (n=138) were all participants in the North American Prodrome Longitudinal Study (NAPLS 1) project. Negative symptoms were assessed longitudinally using the Scale of Prodromal Symptoms. The mean total negative symptom score at baseline was 11.0, with 82.0% of the sample scoring at moderate severity or above on at least one negative symptom. Over the course of 12 months, the symptoms remained in the above moderate severity range for 54.0% of participants. Associations between individual symptoms were moderate, and a factor analysis confirmed that all negative symptoms loaded heavily on one factor. Negative symptoms were more severe and persistent overtime in those who converted to psychosis, significantly predicting the likelihood of conversion. Thus, early and persistent negative symptoms may represent a vulnerability for risk of developing psychosis. PMID- 22445705 TI - Psychopathology and offense types in detained male juveniles. AB - A substantial proportion of violent crime is committed by juveniles. In detained juveniles, high rates of psychopathology have been found. The objective of this study was to determine psychopathology associated with offense characteristics in detained male adolescents. The Mini International Neuropsychiatric Interview was used to assess juvenile detainees. The final sample included 275 males (mean age=16.45, S.D.=1.27 years). Multivariate logistic regressions yielded significant associations between psychopathology and specific offense types: The presence of substance use disorders (without alcohol) (SUD) was found to predict drug-related crimes, and the presence of alcohol use disorders (AUD) without further SUD were a predictor of violent crime, especially in older juveniles. The absence of anxiety disorder, especially in younger juveniles, was found to be relevant for the prediction of robbery. The results of the study suggest that the use and abuse of legal and illegal substances might be a trigger for serious violent and drug-related crimes in juveniles. In particular, the presence of AUD is presumed to have a pivotal role in the development of impulsive aggression. These findings are important when considering the serious social impact of violent behaviors in adolescents. PMID- 22445706 TI - Multiplexing analysis of the polyspecific intrathecal immune response in multiple sclerosis. AB - Intrathecal synthesis of the antibodies specific to neurotrofic viruses: measles (M), rubella (R), Varicella-Zoster (Z), and/or H. simplex (H), known as "MRZH reaction" plays important diagnostic role in multiple sclerosis (MS). Whereas the analysis of the oligoclonal IgG bands provides high sensitivity, the MRZH reaction shows high specificity, and hence these methods complement each other. For the first time we applied multiplexing bead-based technology to simultaneously analyze cerebrospinal fluid (CSF) and serum concentrations of antibodies against these viruses, and to calculate the antibody specific indices (ASI's). The method shows reasonable precision: intra-assay, 2.9-6.7%, and inter assay, 2.0-3.2%. The results are comparable with these obtained with other methods (ELISAs), including two runs of the certified external quality control schemes. Eighty-one percent of the MS cases (n=27) and none of the sex- and age matched controls (n=14), except one subject with "borderline" anti-measles ASI of 1.5, showed intrathecal synthesis of IgG against at least one of the viruses discussed. The ratios of the MRZH-positive cases in the MS group were: 12/22 for M, 12/19 for R, 13/26 for Z, and 7/26 for H. We conclude that the multiplexing technology can be applied as a tool to study the intrathecal immune response in the diagnosis of MS. PMID- 22445707 TI - Automated flow cytometry for monitoring CHO cell cultures. AB - Flow cytometry has been used to accurately monitor cell events that indicate the spatio-temporal state of a bioreactor culture. The introduction of process analytical technology (PAT) has led to process improvements using real-time or semi real-time monitoring systems. Integration of flow cytometry into an automated scheme for improved process monitoring can benefit PAT in bioreactor based biopharmaceutical productions by establishing optimum process conditions and better quality protocols. Herein, we provide detailed protocols for establishing an automated flow cytometry system that can be used to investigate and monitor cell growth, viability, cell size, and cell cycle data. A method is described for the use of such a system primarily focused on CHO cell culture, although it is foreseen the information gathered from automated flow cytometry can be applied to a variety of cell lines to address both PAT requirements and gain further understanding of complex biological systems. PMID- 22445708 TI - GFR and cardiovascular outcomes after acute myocardial infarction: results from the Korea Acute Myocardial Infarction Registry. AB - BACKGROUND: Despite strong evidence linking decreased glomerular filtration rate (GFR) to worse outcomes, the impact of GFR on mortality and morbidity in patients with acute myocardial infarction (AMI) is not well defined. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 12,636 patients with AMI in the Korea AMI Registry database from November 2005 to July 2008. 93% of patients in this registry had coronary angiography, and 91% of patients with coronary angiography had percutaneous coronary intervention (PCI). PREDICTOR: GFR was estimated (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation, and patients were grouped into 5 eGFR categories: >90, 60-89, 30 59, 15-29, and <15 mL/min/1.73 m(2). OUTCOMES: Primary end points were death and in-hospital complications. Secondary end points were major adverse cardiac events (MACEs) during a 1-month (short-term) and 1-year (long-term) follow-up after AMI. RESULTS: Mean eGFR was 72.8 +/- 24.6 mL/min/1.73 m(2), mean age was 64 +/- 13 years, and 70.4% were men. A graded association was observed between eGFR and clinical outcomes. In adjusted analyses, compared with eGFR >90 mL/min/1.73 m(2), patients with eGFR of 30-59, 15-29, and <15 mL/min/1.73 m(2) experienced increased risks of short- (respective HRs of 2.30 [95% CI, 1.70-3.11], 3.10 [95% CI, 2.14-4.14], and 3.64 [95% CI, 2.44-5.43]; P < 0.001) and long-term MACEs (HRs of 1.58 [95% CI, 1.32-1.90], 2.12 [95% CI, 1.63-2.75], and 2.50 [95% CI, 1.89 3.29]; P < 0.001). Older age, Killip class higher than I, PCI, and high sensitivity C-reactive protein level also were associated with higher short- and long-term MACEs. Use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and statins was associated with decreased risk of MACEs. LIMITATIONS: Single assessment of serum creatinine. CONCLUSION: eGFR was associated independently with mortality and complications after AMI. PCI, beta-blocker, ACE inhibitor or ARB, and statin use were associated with decreased risks of short- and long-term MACEs. PMID- 22445709 TI - Cost-effectiveness of cinacalcet hydrochloride for hemodialysis patients with severe secondary hyperparathyroidism in Japan. AB - BACKGROUND: Cinacalcet effectively reduces elevated levels of parathyroid hormone (PTH) in patients with secondary hyperparathyroidism (SHPT), even those with severe disease for whom parathyroidectomy can be the treatment of choice. The objective of this study was to estimate the cost-effectiveness of cinacalcet treatment in hemodialysis patients with severe SHPT in Japan. STUDY DESIGN: Cost effectiveness analysis. SETTING & POPULATION: Patients with severe SHPT (intact PTH >500 pg/mL) who were receiving hemodialysis in Japan. MODEL, PERSPECTIVE, & TIMEFRAME: A Markov model was constructed from the health care system perspective in Japan. Patients were followed up over their lifetime. Dialysis costs were not included in the base case. INTERVENTION: Cinacalcet as an addition to conventional treatment compared to conventional treatment alone. In both arms, patients underwent parathyroidectomy if intact PTH level was >500 pg/mL for 6 months and they were eligible for surgery. OUTCOMES: Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: ICERs for cinacalcet for those who were eligible for surgery and those who were not were $352,631/QALY gained and $21,613/QALY gained, respectively. Sensitivity and scenario analyses showed that results were fairly robust to variations in model parameters and assumptions. In the probabilistic sensitivity analysis, cinacalcet was cost-effective in only 0.9% of simulations for those eligible for surgery, but in more than 99.9% of simulations for those ineligible for surgery, if society would be willing to pay $50,000 per additional QALY. LIMITATIONS: Data for the long-term effect of cinacalcet on patient-level outcomes are limited. The model predicted rates for clinical events using data for the surrogate biochemical end points. CONCLUSIONS: The use of cinacalcet to treat severe SHPT is likely to be cost-effective for only those who cannot undergo parathyroid surgery for medical or personal reasons. PMID- 22445710 TI - Where is the truth when it comes to cancer risk in Barrett's esophagus? PMID- 22445711 TI - Photon emission probabilities of 176Lu. AB - An aqueous solution containing dissolved lutetium nitrate with a natural isotopic composition was measured by means of gamma-ray spectrometry to determine emission probabilities of photons which are emitted as a consequence of the decay of the primordial isotope (176)Lu. The geometry and matrix of the sample were taken into account in terms of efficiency transfer factors computed with the aid of the upgraded Monte Carlo simulation software GESPECOR. A combination of these results, with the activity determination via liquid scintillation counting using the CIEMAT/NIST efficiency tracing method, yields absolute values of P(X)(54.61 keV)=0.095(4), P(X)(55.79 keV)=0.168(5), P(gamma)(88.36 keV)=0.149(5), P(gamma)(201.83 keV)=0.777(9) and P(gamma)(306.84 keV)=0.929(9). In addition, the upper limit of the probability for a potential electron-capture decay of (176)Lu was improved using additional high resolution gamma-ray spectra taken with a planar HPGe detector. PMID- 22445712 TI - Results of an international comparison for the determination of radionuclide activity in bilberry material. AB - Radioactivity found in wild food products has assumed greater importance when assessing the total exposure of the population. For this reason, IRMM has been developing a reference material for the activity concentration of three radionuclides in bilberry samples. In order to characterise this new material, a CCRI(II) supplementary comparison was organised. The difficulties encountered in this comparison are discussed, in particular the efficiency calibration for volume sources of gamma-ray emitters, and comparison reference values for (137)Cs and (40)K are calculated. PMID- 22445713 TI - Attitudes and beliefs to the uptake and maintenance of physical activity among community-dwelling South Asians aged 60-70 years: a qualitative study. AB - OBJECTIVES: To identify the attitudes and beliefs associated with the uptake and adherence of physical activity among community-dwelling South Asians aged 60-70 years. STUDY DESIGN: A qualitative research study using an ethnographic approach. METHODS: Focus groups and in-depth interviews were conducted to explore motivational factors associated with initiating and maintaining physical activity. Data analysis followed the framework approach. RESULTS: Health, maintaining independence and social support were important in terms of initiating physical activity. Social support, psychosocial elements of activity, health and integrating physical activity within everyday activities were important for adherence to physical activity. The need for gendered physical activity sessions was important to initiating exercise among Muslim South Asians aged 60-70 years. CONCLUSION: Promoting active lifestyles and building physical activity in and around day-to-day activities are important strategies in increasing activity levels. However, the needs for culturally appropriate facilities, peer mentors who could assist those with language barriers, specific tailored advice, advice on integrating physical activity in everyday life and general social support could promote uptake and subsequent adherence among this population group. PMID- 22445714 TI - Pertussis resurgence among vaccinated children in Khairpur, Sindh, Pakistan. AB - OBJECTIVES: To investigate the aetiology of persistent cough among vaccinated children as suspected cases of pertussis in Khairpur District, Sindh, Pakistan. Pertussis or whooping cough, caused by Bordetella pertussis, is re-appearing in many countries despite vaccination coverage. In Khairpur, persistent cough and symptoms similar to pertussis among vaccinated children are common but the aetiology has not been investigated previously. STUDY DESIGN: B. pertussis was isolated from cough samples of suspected pertussis patients (n = 700) using the cough plate method with charcoal agar. METHODS: Isolation and confirmation of the clinical isolates of B. pertussis was performed by culture on Bordet-Gengou medium, biochemical tests and polymerase chain reaction. RESULTS: In total, 22 strains of B. pertussis were isolated from clinical cough samples. CONCLUSION: To the authors' knowledge, this is the first report of the presence of pertussis in vaccinated children in Khairpur. There is a need for continuous monitoring of pertussis after immunization programmes in order to assess the efficacy of pertussis vaccination. PMID- 22445715 TI - Physical activity, abdominal obesity and the risk of coronary heart disease: a Korean national sample study. AB - OBJECTIVES: To examine the interaction between physical activity and abdominal obesity in relation to the Framingham Risk Score (FRS) for predicting the 10-year risk of coronary heart disease (CHD) using a representative sample of Korean adults. STUDY DESIGN: Cross-sectional study. METHODS: Drawing from the 2007 Korean National Health and Nutrition Examination Survey (NHANES IV-1), data from 2112 adults aged 30-74 years were analysed. The risk of CHD was calculated according to the FRS, and odds ratios (ORs) were analysed for the at-risk group (probability > 10%) with multivariate logistic regression. RESULTS: Compared with physically active men with a normal waist circumference (WC), inactive men with a large WC had an OR for CHD risk of 2.91 [95% confidence interval (CI) 1.63-5.22]. Compared with active women with a normal WC, inactive women with a large WC had an OR of 6.37 (95% CI 3.44-11.80). Among women with a normal WC, inactive women were at increased risk of CHD compared with active women (OR 2.16, 95% CI 1.19 3.93). Among active individuals, both men and women with large WCs were at increased risk of CHD compared with those with normal WCs. CONCLUSIONS: Abdominal obesity was associated with risk of CHD regardless of the level of physical activity. The 10-year risk of CHD associated with physical inactivity and abdominal obesity was much stronger in Korean women than in Korean men. While the importance of obesity control and physical activity is clear, future interventions should incorporate more targeted abdominal obesity prevention and control efforts, especially for women. PMID- 22445716 TI - Short- and long-term impact of health education in improving water supply, sanitation and knowledge about intestinal helminths in rural Bangladesh. AB - OBJECTIVE: To investigate the long-term impact of health education in intestinal helminth infection control in rural Bangladesh. STUDY DESIGN: Longitudinal study to compare knowledge, awareness and practice for intestinal helminths between four communities: two receiving health education and two not receiving health education. METHODS: Parents of 1497 children aged between 2 and 8 years [781 (52.2%) received health education] were investigated by interview at baseline, endline (18 months) and follow-up (5 years). RESULTS: Health education had a significant effect on the installment of tubewells and latrines, but only had a temporary effect on health knowledge. CONCLUSION: This long-term follow-up study showed the lack of sustainability of knowledge and awareness in the long-term after health education interventions. PMID- 22445717 TI - Hydrated lime for metals immobilization and explosives transformation: Treatability study. AB - Fragmentation grenades contain Composition B (RDX and TNT) within a steel shell casing. There is the potential for off-site migration of high explosives and metals from hand grenade training ranges by transport in surface water and subsurface transport in leachate. This treatability study used bench-scale columns and mesocosm-scale laboratory lysimeters to investigate the potential of hydrated lime as a soil amendment for in situ remediation of explosives and metals stabilization in hand grenade range soils. Compared to the unamended soil there was a 26-92% reduction of RDX in the leachate and runoff water from the lime treated soils and a 66-83% reduction of zinc in the leachate and runoff water samples; where the hand grenade range metals of concern were zinc, iron, and manganese. The amended soil was maintained at the target pH of greater than 10.5 for optimum explosives decomposition. The treatability study indicated a high potential of success for scale-up to an in situ field study. PMID- 22445718 TI - Intestinal commensals: influence on immune system and tolerance to pathogens. AB - The interactions of commensal microorganisms with the host's immune system are in the spotlight. The intestinal microbiota provides both stimulatory and inhibitory signals to the host ensuring its own survival and contributing to resistance to pathogens. Some microbial lineages do this better than others and are attracting a lot of attention. The microbial influences go beyond the gut and have profound effects on infections and autoimmunity in distant locations. Commensals are also involved in regulation of 'tolerance to pathogens', a fundamental type of response to infections that does not reduce pathogen burden but keeps the host healthy. PMID- 22445719 TI - Study of ion translocation by respiratory complex I. A new insight using (23)Na NMR spectroscopy. AB - The research on complex I has gained recently a new enthusiasm, especially after the resolution of the crystallographic structures of bacterial and mitochondrial complexes. Most attention is now dedicated to the investigation of the energy coupling mechanism(s). The proton has been identified as the coupling ion, although in the case of some bacterial complexes I Na(+) has been proposed to have that role. We have addressed the relation of some complexes I with Na(+) and developed an innovative methodology using (23)Na NMR spectroscopy. This allowed the investigation of Na(+) transport taking the advantage of directly monitoring changes in Na(+) concentration. Methodological aspects concerning the use of (23)Na NMR spectroscopy to measure accurately sodium transport in bacterial membrane vesicles are discussed here. External-vesicle Na(+) concentrations were determined by two different methods: 1) by integration of the resonance frequency peak and 2) using calibration curves of resonance frequency shift dependence on Na(+) concentration. Although the calibration curves are a suitable way to determine Na(+) concentration changes under conditions of fast exchange, it was shown not to be applicable to the bacterial membrane vesicle systems. In this case, the integration of the resonance frequency peak is the most appropriate analysis for the quantification of external-vesicle Na(+) concentration. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22445720 TI - Genetic decrease in fatty acid unsaturation of phosphatidylglycerol increased photoinhibition of photosystem I at low temperature in tobacco leaves. AB - Leaves of transgenic tobacco plants with decreased levels of fatty acid unsaturation in phosphatidylglycerol (PG) exhibited a slightly lower level of the steady state oxidation of the photosystem I (PSI) reaction center P700 (P700(+)) than wild-type plants. The PSI photochemistry of wild-type plants was only marginally affected by high light treatments. Surprisingly, all plants of transgenic lines exhibited much higher susceptibility to photoinhibition of PSI than wild-type plants. This was accompanied by a 2.5-fold faster re-reduction rate of P700(+) in the dark, indicating a higher capacity for cyclic electron flow around PSI in high light treated transgenic leaves. This was associated with a much higher intersystem electron pool size suggesting over-reduction of the PQ pool in tobacco transgenic lines with altered PG unsaturation compared to wild type plants. The physiological role of PG unsaturation in PSI down-regulation and modulation of the capacity of PSI-dependent cyclic electron flows and distribution of excitation light energy in tobacco plants under photoinhibitory conditions at low temperatures is discussed. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22445721 TI - RNAi screen in apoptotic cancer cell-stimulated human macrophages reveals co regulation of IL-6/IL-10 expression. AB - Tumor-associated macrophages (TAM) are a major supportive component within neoplasms and are characterized by a plethora of functions that facilitate tumor outgrowth. Mechanisms of macrophage attraction and differentiation to a tumor promoting phenotype, defined among others by distinct cytokine patterns such as pronounced interleukin (IL-10) production, are ill-defined. We aimed to identify signaling pathways that contribute to the generation of TAM-like macrophages using an adenoviral RNAi-based approach. Primary human monocyte-derived macrophages were stimulated with apoptotic tumor cell supernatants (ACM) to induce a TAM-like phenotype, characterized by secretion of IL-10, IL-6, IL-8 but repression of IL-12. For the high-throughput screen, macrophages were transduced with 8495 constructs of the adenoviral shRNA SilenceSelect((r)) library of Galapagos BV, which aims at identifying druggable targets. We identified 96 genes involved in IL-10 production in response to ACM and observed a pronounced cluster of targets regulating both IL-10 and IL-6. Validation of five targets within the IL-10/IL-6 cluster was performed using siRNA or pharmacological inhibitors in human primary macrophages. Among those, interleukin 4 receptor-alpha and cannabinoid receptor 2 were confirmed as regulators of IL-10 and IL-6 secretion by ACM-stimulated macrophages. Our approach characterizes cellular functions of transfection-resistant, highly plastic and versatile cells and identifies novel targets involved in the generation of a TAM-like phenotype in human macrophages. PMID- 22445722 TI - Down-regulation of interleukin-2 production by CD4(+) T cells expressing TIM-3 through suppression of NFAT dephosphorylation and AP-1 transcription. AB - TIM-3 is expressed by TH1 cells and negatively regulates cytokine production by these cells. The aim of the present study was to explore the mechanisms by which IL-2 production is suppressed in TIM-3-expressing T cells. First, the activity of two transcription factors that bind to the IL-2 promoter was examined in Jurkat T cells expressing TIM-3. Both AP-1 and NFAT activity were reduced in TIM-3 expressing cells stimulated with a phorbol ester and a calcium ionophore. At the same time, expression of the AP-1 components, c-Fos and c-Jun, was induced to a lesser extent in stimulated human primary CD4(+) T cells expressing high levels of TIM-3 than in those expressing low levels of TIM-3. Furthermore, TIM-3 expression inhibited the stimulation-induced dephosphorylation and nuclear translocation of NFAT in Jurkat T cells and primary CD4(+) T cells. Finally, the cytoplasmic tail of TIM-3 was required for the suppression of IL-2 production and for AP-1 and NFAT activation. Taken together, these results suggest that IL-2 production by T cells may be downregulated by TIM-3-mediated signals, leading to suppression of NFAT dephosphorylation and AP-1 transcription. PMID- 22445723 TI - Genetic mapping of the region containing the bla(OXA-40) gene in isolates of Acinetobacter baumannii. PMID- 22445724 TI - An apolipoprotein E4 fragment affects matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1 and cytokine levels in brain cell lines. AB - Apolipoprotein (apo) E4 isoform, a major risk factor for Alzheimer disease (AD), is more susceptible to proteolysis than apoE2 and apoE3 isoforms. ApoE4 fragments have been found in AD patients' brain. In the present study, we examined the effect of full-length apoE4 and apoE4 fragments apoE4[Delta(186-299)] and apoE4[Delta(166-299)] on inflammation in human neuroblastoma SK-N-SH and human astrocytoma SW-1783 cells. Western blot and zymography analysis showed that treatment of SK-N-SH cells with apoE4[Delta(186-299)], but not full-length apoE4 or the shorter apoE4[Delta(166-299)] fragment, leads to increased extracellular levels of matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase 1 (TIMP1). Real-time PCR showed that interleukin (IL)-1beta gene expression is also increased in SK-N-SH cells treated with apoE4[Delta(186 299)]. Treatment of SK-N-SH cells with IL-1beta leads to increased MMP9 and TIMP1 extracellular levels, suggesting that the induction of IL-1beta may be the mechanism by which apoE4[Delta(186-299)] regulates MMP9 and TIMP1 levels in these cells. In contrast to SK-N-SH cells, treatment of SW-1783 cells with apoE4[Delta(186-299)], and to a lesser extent with apoE4, leads to increased TIMP1 extracellular levels without affecting MMP9 levels. Additionally, apoE4[Delta(186-299)] leads to decreased IL-10 gene expression in SK-N-SH cells, whereas both apoE4 and apoE4[Delta(186-299)] lead to decreased TNFalpha gene expression without affecting IL-1beta and IL-10 gene expression in SW-1783 cells. Overall, our findings indicate that a specific apoE4 fragment (apoE4[Delta(186 299)]), with molecular mass similar that of apoE4 fragments detected in AD patients' brain, can influence the level of inflammatory molecules in brain cell lines. It is possible that these phenomena contribute to AD pathogenesis. PMID- 22445725 TI - Effects of acute restraint-induced stress on glucocorticoid receptors and brain derived neurotrophic factor after mild traumatic brain injury. AB - We have previously reported that experimental mild traumatic brain injury results in increased sensitivity to stressful events during the first post-injury weeks, as determined by analyzing the hypothalamic-pituitary-adrenal (HPA) axis regulation following restraint-induced stress. This is the same time period when rehabilitative exercise has proven to be ineffective after a mild fluid percussion injury (FPI). Here we evaluated effects of stress on neuroplasticity. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. Rats were exposed to 30 min of restraint stress, followed by tail vein blood collection at post-injury days (PID) 1, 7, and 14. The response to dexamethasone (DEX) was also evaluated. Hippocampal tissue was collected 120 min after stress onset. Brain-derived neurotrophic factor (BDNF) along with glucocorticoid (GR) and mineralocorticoid (MR) receptors was determined by Western blot analysis. Results indicated injury-dependent changes in glucocorticoid and mineralocorticoid receptors that were influenced by the presence of dexamethasone. Control and FPI rats responded differentially to DEX in that GR increases after receiving the lower dose of DEX were longer lasting in the FPI group. A suppression of MR was found at PID 1 in vehicle-treated FPI and Sham groups. Decreases in the precursor form of BDNF were observed in different FPI groups at PIDs 7 and 14. These findings suggest that the increased sensitivity to stressful events during the first post-injury weeks, after a mild FPI, has an impact on hippocampal neuroplasticity. PMID- 22445726 TI - Sexuality among Spanish adults with diabetes: a population-based case control study. AB - OBJECTIVES: To describe and compare sexuality between subjects with diabetes with matched non-diabetic controls. METHODS: Population based case control study using individual data from the Spanish National Sexual Health Survey. Diabetes status was self reported, we selected type 2 patients. We identified 461 diabetes sufferers. Two controls were matched by age, sex and sexual partner for each diabetic case. Sexuality measures included: sexual activity, importance of sex, satisfaction with partner, bothersome with one's sexual life and self-rated sexual health. Independent variables included: socio-demographics, physical health, chronic diseases and medications use. RESULTS: No differences were found in "Sexually activity", "Importance of sex" or "Bothersome" between those with and without diabetes. Dissatisfaction with partner was 25% in women with diabetes and 12.9% in non-diabetic controls (Adjusted-OR 1.82 95%CI 1.02-4.85). Diabetes sufferers reported sexual health as "fair/poor/very poor" more than their non diabetic control, 58.1% vs. 45.1% for women (Adjusted-OR 1.74 95%CI 1.15-2.63) and 54.3% vs. 38% for men (Adjusted-OR 1.88 95%CI 1.29-2.75). Among diabetes sufferers "fair/poor/very poor" sexual health was associated with poorer physical health, not having a sexual partner and among men taking heart medications. CONCLUSIONS: Women and men with diabetes have significantly worse sexuality measures than non diabetic controls. PMID- 22445727 TI - Nanoparticle-based clodronate delivery mitigates murine experimental colitis. AB - In inflammatory bowel disease (IBD) the disruption of the intestinal barrier function and the strong presence of immune-related cells like macrophages in inflamed tissue allow the selective accumulation of particulate carrier systems at the site of action. We developed clodronate loaded nanoparticles (ClNP) based on a cationic polymethacrylate (Eudragit RL) using a modified solvent displacement method. Particle diameter of ClNP was around 120nm and dissolution experiments showed that ionic interactions with either the dissolution medium or mucin have to take place to enable complete drug release. In murine experimental colitis in-vivo, myeloperoxidase activity decreased significantly in 2,4,6 trinitrobenzenesulfonic acid (TNBS)-colitis and oxazolone (OXA)-colitis models after treatment with ClNP while free clodronate did not show a mitigating effect. Similarly, alkaline phosphatase could be lowered significantly from 12.5+/-1.9 to 6.8+/-2.2ng/mg tissue in TNBS-colitis and from 16.6+/-6.2 to 11.8+/-2.7ng/mg tissue in OXA-colitis. In cultured RAW 264.7 cells, only ClNP but not clodronate alone led to a decrease in tumor necrosis factor-alpha and interleukin-6 secretion of the activated macrophages. The therapeutic benefit of ClNP was confirmed in-vivo although it is limited compared to data with other drugs. Cell culture experiments indicated that intracellular delivery of clodronate was necessary to obtain an anti-inflammatory effect. PMID- 22445728 TI - Detection of aminoglycoside resistance genes in Riemerella anatipestifer isolated from ducks. PMID- 22445729 TI - Molecular characterization of African swine fever virus isolates originating from outbreaks in the Russian Federation between 2007 and 2011. AB - African swine fever is one of the most important viral diseases of pigs and which caused significant economic damage on the pig production worldwide. Nowadays, it is still present on the African continent, in Transcaucasus countries (TCC), on Island of Sardinia and in Russia. Outbreaks of the disease have been reported in Russia for the last four years, affected especially the Southern Federal District of the country. Since 2010, a new outbreak area has been observed in the Northwestern Federal District. In order to study the evolution of African swine fever virus (ASFV) isolates, strains were collected in the Russian Federation from 2007 to 2011 and investigated by means of partial sequencing and fragment length polymorphism. In detail, 7 variable regions, namely B646L, E183L, I196L, B602L, I73R/I329R, I78R/I215L and KP86R were investigated. Phylogenetic analyses revealed 100% nucleotide identity of B646L and E183L gene sequences of all examined isolates. All isolates formed one genetic cluster within genotype II. Moreover, no amplified fragment length polymorphism (AFLP) was observed for B602L, I196L, I73R/I329R, and I78R/I215L genes. The flanking primers used to amplify the KP86R gene failed to amplify a product in all the isolates. The obtained data strongly suggests that only one ASFV virus variant caused the outbreaks from 2007 to 2011 in the territory of the Russian Federation. PMID- 22445730 TI - Doctor's attire influences perceived empathy in the patient-doctor relationship. AB - OBJECTIVE: This study investigated whether doctors' attire influences the perception of empathy in the patient-doctor relationship during a therapeutic encounter. METHODS: A total number of 143 patients were divided into four groups when they were consulting a Traditional Korean Medicine doctor. Depending on the group, the same doctor was wearing four different attires--Casual, Suit, Traditional dress, White coat--when having a clinical consultation with the patients. RESULTS: The patients preferred white coat and traditional dress more than other attires, giving highest scores to white coat in competency, trustworthiness and preference of attire and to traditional dress in comfortableness and contentment with the consultation. The "Consultation and Relational Empathy (CARE)" score was significantly higher in the "White coat" and "Traditional" groups, compared to the "Casual" and "Suit" groups. CONCLUSION: The strong association between the patients' preference of doctors' attire and the CARE score indicates that the doctor's attire plays not only an important role for establishing confidence and trustworthiness but also for the perception of empathy in the patient-doctor relationship. PRACTICE IMPLICATIONS: The doctor's attire can function as an effective tool of non-verbal communication in order to signal confidence, trust and empathy and establish a good patient-doctor relationship. PMID- 22445731 TI - Communication about self-care in traditional acupuncture consultations: the co construction of individualised support and advice. AB - OBJECTIVE: To analyse the co-construction of self-care advice in traditional acupuncture consultations. METHOD: Analysis of 27 audio-recorded and transcribed consultations, involving 7 practitioners, augmented by integrating the data from 15 patient interviews and regular practitioner discussions. RESULTS: Self-care talk was initiated equally by practitioner and patient, and was threaded through and between acupuncture consultations. It involved interactive discussions that were interwoven with other types of talk, especially life-world and acupuncture talk. Practitioner engagement in self-care talk appeared to increase with experience. The self-care talk was co-constructed within the context of a relationship that was characterised by continuity, mutuality and trust. CONCLUSION: Self-care support and advice was integral to the practice of traditional acupuncture and individualised in terms of the patient's life-world and/or the Chinese medicine diagnosis. The co-construction of self-care talk did not replicate the asymmetry of conventional medical consultations. PRACTICE IMPLICATIONS: The active participation of both patients and acupuncture practitioners in self-care talk may be related to professional practice that is underpinned by a holistic theory base such as Chinese medicine and is delivered in the context of therapeutic relationships based on continuity, mutuality and trust. These findings may inform professional education and the design of multi disciplinary care pathways. PMID- 22445732 TI - Risk factors for clinical failure in patients hospitalized with cellulitis and cutaneous abscess. AB - OBJECTIVE: The objective of this study was to evaluate clinical outcomes and risk factors associated with clinical failure in patients hospitalized with cellulitis with or without abscess. METHODS: We performed a retrospective cohort study among adults admitted for cellulitis/cutaneous abscess from July 1, 2009 through June 30, 2010. Binary univariate and multivariate logistic regression analyses were performed to identify risk factors for clinical failure among evaluable patients. RESULTS: A total of 210 cases met inclusion criteria. Among 106 evaluable cases, clinical failure occurred in 34 (32.1%) patients. Weight over 100 kg (Odds ratio [OR] = 5.20, P = 0.01), body mass index (BMI) >=40 (OR 4.10, P = 0.02), inadequate empiric antibiotic therapy (OR = 9.25, P < 0.01), recent antimicrobial therapy (OR = 2.98, P = 0.03), and lower end of antibiotic dosing per treatment guidelines upon discharge (OR = 3.64, P < 0.01) were independent risk factors for clinical failure. Further subgroup analysis demonstrated that morbidly obese patients were at higher risk for clinical failure if they were discharged on a low oral dose of clindamycin or trimethoprim/sulfamethoxazole (P = 0.002). CONCLUSION: Inappropriate antimicrobial selection and dosing may adversely affect clinical outcomes among patients with cellulitis/cutaneous abscess. Obese individuals may be at particular risk for clinical failure secondary to inadequate dosing of antimicrobial therapy. PMID- 22445733 TI - Absence of replicative senescence in cultured cells from the short-lived killifish Nothobranchius furzeri. AB - A major challenge in age research is the absence of short-lived vertebrate model organisms. The turquoise killifish Nothobranchius furzeri has the shortest known lifespan of a vertebrate that can be bred in captivity. The short lived GRZ strain only reaches a maximum age of 3-4 months, whereas other strains (MZM) reach 6-10 months. Most importantly, the short lifespan is associated with typical signs of ageing. To find out more about possible cellular factors that might contribute to the short lifespan and to the difference in lifespan between strains, we analyzed the expression of markers for cellular senescence. Expression of Tp53, Cdkn1a and Cdkn2a/b in skin revealed no change in the short lived GRZ but increased expression of the cell cycle inhibitors Cdkn1a and Cdkn2a/b in the long-lived MZM strain with age. This suggests that expression of distinct cell cycle inhibitors reflects rather chronological than biological age in N. furzeri. To study the relationship of organismal life span and in vitro life span of cells, we established a primary cell culture model. For both strains we demonstrate here the absence of replicative senescence as analysed by morphology, expression of Cdkn1a and Cdkn2a/b, population doubling times and gammaH2AFX in long-term and short-term cultured cells. We reason this to be on account of sustained telomerase activity and maintained telomeric length. Hence, we propose that differences in maximum life span of different N. furzeri strains is not reflected by differences in proliferation speed or replicative potential of the respective cultured cells. PMID- 22445734 TI - Serum free estradiol and estrogen receptor-alpha mediated activity are related to decreased incident hip fractures in older women. AB - There is paucity of data from Asian women on the association between serum estrogens and osteoporotic hip fracture risk. We conducted a case-control study nested within a population-based prospective cohort, The Singapore Chinese Health Study, to evaluate serum estrogens levels, ERalpha-mediated estrogenic activity and hip fracture risk in postmenopausal Asian women. Among 35,298 women who were recruited between 1993 and 1998, 15,410 women donated blood for research between 1999 and 2004. From this subcohort, we identified 140 cases who subsequently suffered hip fracture after blood donation, and 278 age-matched controls. Serum levels of total estrone, estradiol and sex hormone binding globulin levels were measured in a blinded fashion among cases and controls. ERalpha-mediated estrogenic activity of serum samples was quantified using a sensitive ERalpha driven cell bioassay. Women with hip fracture had lower serum estrogens than control women. Compared to the lowest quintile, women in the highest quintile of free estradiol exhibited a statistically significant 57% reduction in risk of hip fracture (95% confidence interval (CI), 6-80%), with a dose-dependent relationship (p for trend=0.021). High levels of ERalpha-mediated estrogenic activity were also associated with decreased risk of hip fracture (p for trend=0.048). Overall, women with relatively high levels of both free estradiol and ERalpha-mediated estrogenic activity had a 55% reduction in hip fracture risk (95% CI, 17-76%) compared to women with low levels of both. High levels of free estradiol and ERalpha-mediated estrogen activity in sera were associated with reduced hip fracture risk in Chinese postmenopausal women. PMID- 22445735 TI - Developmental cell behavior. PMID- 22445736 TI - Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming? AB - At fertilization, fusion of two differentiated gametes forms the zygote that is capable of forming all of the varied cell lineages of an organism. It is widely thought that the acquisition of totipotency involves extensive epigenetic reprogramming of the germline state into an embryonic state. However, recent data argue that this reprogramming is incomplete and that substantial epigenetic information passes from one generation to the next. In this review we summarize the changes in chromatin states that take place during mammalian gametogenesis and examine the evidence that early mammalian embryogenesis may be affected by inheritance of epigenetic information from the parental generation. PMID- 22445737 TI - Systematic comparison of nutraceuticals and antioxidant potential of cultivated, in vitro cultured and commercial Melissa officinalis samples. AB - Melissa officinalis (lemon balm) infusions are used worldwide for digestive, analgesic and other pharmaceutical applications. Herein, the nutraceuticals production and antioxidant potential in garden cultivated, in vitro cultured and two commercial samples (bags and granulated) of lemon balm was compared. The profile of in vitro cultured lemon balm is closer of garden cultivated sample than of both commercial samples (bag or granulate). It presented the highest levels of proteins and ash, and the lowest energetic value. The most favorable n6/n3 ration, as also the highest PUFA (mostly alpha-linolenic acid), tocopherols (including alpha-, gamma- and delta-isoforms) and ascorbic acid contents were also observed in this sample. Nevertheless, it was the commercial bag lemon balm that gave the highest antioxidant activity and the highest levels of phenolics and flavonoids. As far as we kwon, this is the first comparison of nutraceuticals and antioxidant potential of cultivated, in vitro cultured and commercial lemon balm samples. Moreover, it proved that in vitro culture might be used to stimulate vitamins production. PMID- 22445738 TI - An active extract of Ulmus pumila inhibits adipogenesis through regulation of cell cycle progression in 3T3-L1 cells. AB - Obesity and its associated metabolic disorders has become a major obstacle in improving the average life span. In this regard therapeutic approach using natural compounds are currently receiving much attention. Herbal compounds rich in triterpenes are well known to regulate glucose and lipid metabolism. Here, we have found that Ulmus pumila (UP) contained at least four different triterpenoids and inhibited adipogenesis of 3T3-L1 cells. The cell viability was dose dependently decreased by UP showing the increase of cell accumulation in G1 phase while reducing in S and G2/M phase of cell cycle. UP treatment also significantly decreased the GPDH activity and intracellular lipid accumulation. In addition, UP inhibited the mRNA levels of adipogenic transcription factors and lipogenic genes such as PPARgamma, C/EBPalpha, SREBP1c and FAS while showing no effects on C/EBP beta and C/EBP-delta. Importantly enough, treatment of cells with UP suppressed the TNF-alpha induced activation of NF-kappaB signaling. Collectively, our results indicate that UP extract effectively attenuated adipogenesis by controlling cell cycle progression and down regulating adipogenic gene expression. PMID- 22445739 TI - IFN-gamma deficiency exacerbates experimental autoimmune neuritis in mice despite a mitigated systemic Th1 immune response. AB - Previous studies have shown that interferon-gamma (IFN-gamma) is a proinflammatory cytokine that contributes to the pathogenesis of Guillain-Barre syndrome and its animal model, experimental autoimmune neuritis (EAN). Treatments with anti-IFN-gamma antibodies improve clinical outcome in GBS patients and EAN animals and administration of IFN-gamma markedly worsens EAN. Paradoxically, the mice deficient in IFN-gamma remain susceptible to experimental autoimmune encephalomyelitis, an analogous disease in the central nervous system. These observations raise a question whether IFN-gamma might be protective in autoimmune demyelinating diseases. To clarify the role of IFN-gamma in the pathogenesis of autoimmune demyelinating diseases, we used P0 protein peptide 180-199 to induce EAN in IFN-gamma knockout (KO) mice. After the acute phase of EAN, the clinical signs of IFN-gamma KO mice were significantly more severe than those of wild type (WT) controls. After antigenic stimulation, the proliferation of splenic mononuclear cells was significantly higher in IFN-gamma KO than in WT mice with EAN. At the peak of EAN, the proportion of interleukin (IL)-17A expressing cells in cauda equina (CE) infiltrating cells, and the levels of IL-17A in sera were elevated in IFN-gamma KO mice when compared with their WT counterparts. The proportions of major histocompatibility complex (MHC) II, macrosialin, and IL 12/IL-23p40 expressing cells, relative to total CE infiltrating cells were correspondingly higher in IFN-gamma KO than in WT mice with EAN. However, IFN gamma deficiency reduced the production of NO by cultured macrophages in response to proinflammatory stimuli and induced a systemic Th2-oriented immune response. In conclusion, IFN-gamma deficiency exacerbates EAN via upregulating Th17 cells despite a mitigated systemic Th1 immune response. PMID- 22445740 TI - Sex hormone-dependent attenuation of EAE in a transgenic mouse with astrocytic expression of the RNA regulator HuR. AB - In experimental autoimmune encephalomyelitis (EAE) and other neurodegenerative diseases, astrocytes play an important role in promoting or attenuating the inflammatory response through induction of different cytokines and growth factors. HuR plays a major role in regulating many of these factors by modulating RNA stability and translational efficiency. Here, we engineered transgenic mice to express HuR in astrocytes using the human glial fibrillary acidic protein promoter and found that female transgenic mice had significantly less clinical disability and histopathological changes in the spinal cord. Ovariectomy prior to EAE induction abrogated the protective effect. Our findings support a role for the astrocyte and posttranscriptional regulation in hormonally-mediated attenuation of EAE. PMID- 22445741 TI - Expression and purification recombinant human dentin sialoprotein in Escherichia coli and its effects on human dental pulp cells. AB - Dentin sialoprotein (DSP) is cleaved from dentin sialophosphoprotein (DSPP) and most abundant dentinal non-collagenous proteins in dentin. DSP is believed to participate in differentiation and mineralization of cells. In this study, we first constructed recombinant human DSP (rhDSP) in Escherichia coli (E. coli) and investigated its odontoblastic differentiation effects on human dental pulp cells (hDPCs). Cell adhesion activity was measured by crystal violet assay and cell proliferation activity was measured by MTT assay. To assess mineralization activity of rhDSP, Alizarin Red S staining was performed. In addition, the mRNA levels of collagen type I (Col I), alkaline phosphatase (ALP), and osteocalcin (OCN) were measured due to their use as mineralization markers for odontoblast /osteoblast-like differentiation of hDPCs. The obtained rhDSP in E. coli was approximately identified by SDS-PAGE and Western blot. Initially, rhDSP significantly enhanced hDPCs adhesion activity and proliferation (p<0.05). In Alizarin Red S staining, stained hDPCs increased in a time-dependent manner. This odontoblastic differentiation activity was also verified through mRNA levels of odontoblast-related markers. Here, we first demonstrated that rhDSP may be an important regulatory ECM in determining the hDPCs fate including cell adhesion, proliferation, and odontoblastic differentiation activity. These findings indicate that rhDSP can induce growth and differentiation on hDPCs, leading to improve tooth repair and regeneration. PMID- 22445742 TI - In vivo evaluation of [18F]FEAnGA-Me: a PET tracer for imaging beta-glucuronidase (beta-GUS) activity in a tumor/inflammation rodent model. AB - INTRODUCTION: The PET tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2 nitrophenyl)-O-beta-d-glucopyronuronate ([(18)F]FEAnGA), was recently developed for PET imaging of extracellular beta-glucuronidase (beta-GUS). However, [(18)F]FEAnGA exhibited rapid renal clearance, which resulted in a relatively low tracer uptake in the tumor. To improve the pharmacokinetics of [(18)F]FEAnGA, we developed its more lipophilic methyl ester analog, [(18)F]FEAnGA-Me. METHODS: [(18)F]FEAnGA-Me was obtained by alkylation of the O-protected glucuronide methyl ester precursor with [(18)F]-fluoroethylamine ([(18)F]FEA), followed by removal of the acetate protecting groups with NaOMe/MeOH. The PET tracer was evaluated by in vitro and in vivo studies. RESULTS: [(18)F]FEAnGA-Me was obtained in 5%-10% overall radiochemical yield. It is 10-fold less hydrophilic than [(18)F]FEAnGA and it is stable in PBS and in the presence of beta-GUS for 1 h. However, in the presence of esterase or plasma [(18)F]FEAnGA-Me is converted to [(18)F]FEAnGA, and subsequently converted to [(18)F]FEA by beta-GUS. MicroPET studies in Wistar rats bearing a C6 glioma and a sterile inflammation showed similar uptake in tumors after injection of either [(18)F]FEAnGA-Me or [(18)F]FEAnGA. Both tracers had a rapid two-phase clearance of total plasma radioactivity with a half-life of 1 and 8 min. The [(18)F]FEAnGA fraction generated from [(18)F]FEAnGA-Me by in vivo hydrolysis had a circulation half-life of 1 and 11 min in plasma. Similar distribution volume in the viable part of the tumor was found after injection of either [(18)F]FEAnGA-Me or [(18)F]FEAnGA. CONCLUSION: The imaging properties of [(18)F]FEAnGA-Me were not significantly better than those of [(18)F]FEAnGA. Therefore, other strategies should be applied in order to improve the kinetics of these tracers. PMID- 22445743 TI - Nephrotoxicity profiles and threshold dose values for [177Lu]-DOTATATE in nude mice. AB - INTRODUCTION: In peptide receptor radionuclide therapy for neuroendocrine tumors the main dose-limiting tissue is found in the kidneys because of tubular reabsorption and retention of radioactivity. The aim of this study was to quantify late effects in renal cortex of nude mice exposed to high amounts of [(177)Lu]-DOTA-Tyr(3)-octreotate ([(177)Lu]-DOTATATE), and to determine whether a threshold dose value exists for these findings. METHODS: Nude mice were exposed to 90, 120 or 150 MBq of [(177)Lu]-DOTATATE. Renal toxicity was evaluated up to 6 months after injection. Blood samples were collected to examine renal functional markers, and after sacrifice at 6 months changes in renal morphology were explored. Tissue damage was estimated by quantifying the relative area of the different subunits in the renal cortex using point counting. Additional morphological signs of radiation damage were also noted. The absorbed doses to the kidneys were estimated by previously determined kidney pharmacokinetics and Monte Carlo simulations for different assumptions regarding the activity distribution. RESULTS: Increased serum creatinine and urea values indicated long term renal toxicity. The tissue area occupied by proximal tubules decreased with increasing doses of [(177)Lu]-DOTATATE, whereas the other subunits in cortex slightly increased. The mean absorbed dose in the renal cortex for [(177)Lu] DOTATATE was estimated to be 35-58 Gy for the different groups of animals. A dose response relationship was observed for proximal tubular damage, and a threshold dose value of 24 Gy (BED 37 Gy) was determined. CONCLUSIONS: Selective morphological changes in kidney cortex of nude mice were quantified and appeared in a dose dependent manner after injection of high amounts of [(177)Lu]-DOTATATE. PMID- 22445744 TI - Novel synthesis and preclinical evaluation of folic acid derivatives labeled with (18)F-[FDG] for PET imaging of folate receptor-positive tumors. AB - There is a need to develop more potent radiofluorinated folic acid conjugates for a better visualization of folate receptors that overexpress on many human cancers. Due to the clinical importance of [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) and its availability in almost every positron-emission tomography center, new radiofluorinated [(18)F]-FDG-folate and methotrexate conjugates ([(18)F]-5 and [(18)F]-8) were synthesized using [(18)F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [(18)F]-5 and [(18)F] 8 conjugates were prepared in high radiochemical yields (>80%) with total synthesis time of almost 20 min, and radiochemical purities were found to be greater than 98% without high-performance liquid chromatography purification, which make these approaches amenable for automation. In vitro tests on KB cell line showed that a significant amount of the radioconjugates were associated with the cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and hepatobiliary systems for [(18)F]-5 and [(18)F]-8 conjugates, respectively. Biodistribution studies in nude mice-bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable kinetics profile for [(18)F]-5 over the other conjugate. The uptake in the tumors was blocked by the excess coinjection of cold folic acid, suggesting the receptor-mediated process. These results demonstrate that [(18)F]-5 may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to the treatment. PMID- 22445745 TI - Impact of American College of Surgeons Oncology Group Z0011 and National Surgical Adjuvant Breast and Bowel Project B-32 trial results on surgeon practice in the Pacific Northwest. AB - BACKGROUND: Recent clinical trials have suggested no survival benefit for completion axillary node dissection (CALND) after sentinel lymph node biopsy (American College of Surgeons Oncology Group Z0011) and no clinically meaningful benefit for the routine use of immunohistochemistry (National Surgical Adjuvant Breast and Bowel Project B-32) in clinically node-negative breast cancer. METHODS: A 12-question electronic survey was distributed to members of 3 Pacific Northwest surgical societies. Surgeons were queried regarding the impact of the trial results on their surgical management of breast cancer. RESULTS: The 181 respondents reported performing fewer CALNDs (63%), fewer intraoperative frozen sections (21%), and no immunohistochemistry (12%) because of trial data. However, 28% of surgeons continued to perform CALND in patients with 1 to 2 positive sentinel lymph nodes undergoing lumpectomy and postoperative radiation. CONCLUSIONS: Recent trial data have impacted the performance of CALNDs and the pathological evaluation of sentinel lymph nodes among Pacific Northwest surgeons. Our results suggest a need for regional surgical societies to disseminate practice-changing trial data to members. PMID- 22445746 TI - The anticancer activity of chloroquine-gold nanoparticles against MCF-7 breast cancer cells. AB - In the present study, 11-mercaptoundecanoic acid-modified gold nanoparticles (~7 nm) were conjugated with chloroquine to explore their potential application in cancer therapeutics. The anticancer activity of chloroquine-gold nanoparticle conjugates (GNP-Chl) was demonstrated in MCF-7 breast cancer cells. The MCF-7 cells were treated with different concentrations of GNP-Chl conjugates, and the cell viability was assayed using trypan blue, resulting in an IC(50) value of 30 +/- 5 MUg/mL. Flow cytometry analysis revealed that the major pathway of cell death was necrosis, which was mediated by autophagy. The drug release kinetics of GNP-Chl conjugates revealed the release of chloroquine at an acidic pH, which was quantitatively estimated using optical absorbance spectroscopy. The nature of stimuli-responsive drug release and the inhibition of cancer cell growth by GNP Chl conjugates could pave the way for the design of combinatorial therapeutic agents, particularly nanomedicine, for the treatment of cancer. PMID- 22445747 TI - Investigating wettability alteration during MEOR process, a micro/macro scale analysis. AB - Wettability alteration is considered to be one of the important mechanisms that lead to increased oil recovery during microbial enhanced oil recovery (MEOR) processes. Changes in wettability will greatly influence the petrophysical properties of the reservoir rocks and determine the location, flow and distribution of different fluids inside the porous media. Understanding the active mechanisms of surface wettability changes by the bacteria would help to optimize the condition for more oil recovery. As the mechanisms behind wettability alteration are still poorly understood, the objective of this study is to investigate the wettability alteration at pore scale and find the most effective mechanism of wettability changes in different cases. The experiments were performed on different substrates at fresh condition or aged in crude oil to mimic various wetting conditions. Using an Enterobacter cloacae strain, the influence of bacterial metabolites, bacterial adhesion and bacterial solution with two different carbon sources on wettability were determined for different aging periods. Contact angle measurements were used to quantify the wettability alteration of the solid surfaces. Atomic force microscopy (AFM) experiments were also utilized to combine the macroscopic measurements of wettability with the microscopic study of the surface changes. It was found that the surface wettability could vary from neutral- or oil-wet to water-wet state. Bacterial adhesion and biofilm formation seems to be the dominant mechanism of wettability alteration. The aged glass surfaces regained their initial water wetness where the bacteria could remove the polar and asphaltene compounds from them. PMID- 22445748 TI - An alternative channel for the Mitrofanoff principle based on transverse skin flaps: an extraperitoneal minimal invasive approach (the RPM technique). AB - OBJECTIVE: The Mitrofanoff principle is a well established strategy in pediatric urology, with the appendix and Yang-Monti tube being the most used channels. The search for an alternative tube with less morbidity is justified. Hence, we present a patient treated via an alternative approach in which the channel was constructed from two lower abdominal transverse skin flaps (the RPM technique). METHODS: A 17-year-old patient with posterior urethral valves, hypocontractile bladder and experiencing pain on urethral clean intermittent catheterization was selected. The procedure consisted of defining two rectangular transverse skin flaps of 5 * 1 cm opposite to each other. The flaps were rotated 90 degrees and anastomosed to create a tube. A small extraperitoneal bladder wall incision was performed and the tube was connected to the bladder. Two rectal abdomen muscle strips were crossed in the midline as a neosphincter. RESULTS: The patient had an uneventful postoperative course and remains continent for intervals of 4 h. The stoma and incision have a good cosmetic aspect at 16 months follow-up. CONCLUSION: The RPM technique is an alternative approach for a minimal invasive strategy according to the Mitrofanoff principle. Long-term follow-up is necessary to confirm the excellent initial results. PMID- 22445749 TI - Differential investment into testes and sperm production in alternative male reproductive tactics of the African striped mouse (Rhabdomys pumilio). AB - Males that follow alternative reproductive tactics might differ in their investment into testis development and sperm production. The resource-allocation hypothesis predicts that males following a sneaker tactic should invest more into sperm production than dominant territorial males which should invest more into mate guarding. This hypothesis is supported by studies in species where individual males cannot switch between tactics (fixed tactics). Here we present the first data for a species where males can switch between tactics (plastic tactics). We studied African striped mice (Rhabdomys pumilio) in captivity, mimicking three tactics observed in the field: philopatric group-living males, singly-housed males representing roaming males, and group-living breeding males. We measured quantitative and qualitative reproductive traits, as well as serum and testis hormone concentrations. We found no support for the resource allocation hypothesis, since breeding and singly-housed males invested similarly in testes and sperm. However, philopatric males had significantly smaller testes and epididymides, lower sperm counts, lower testosterone and higher corticosterone levels than males of the two other tactics. Philopatric males did not reach a larger body mass than singly-housed males with well developed reproductive traits, indicating that they did not trade investment in sperm production against growth. Interestingly, testis testosterone concentrations of philopatric males did not differ from those of other males. Our data suggest that philopatric males are reproductively suppressed by the breeding male, but might be ready to increase their serum testosterone levels when social and environmental conditions allow for this physiological switch accompanying the behavioral switch between tactics. PMID- 22445750 TI - [Gender differences according to cardiovascular diseases]. PMID- 22445751 TI - Differential degradation of photosystem I subunits under iron deficiency in rice. AB - Rice (Oryza sativa) is one of the staple foods of the world. Iron (Fe) deficiency is a major abiotic stress factor that contributes world-wide to losses in crop yield and decline in nutritional quality. As cofactor for many enzymes and proteins, iron is an essential element. It plays a pivotal role in chlorophyll (Chl) biosynthesis, and iron deficiency may result in decreased Chl production and, thus, reduced photosynthetic capacity. Photosystem I (PSI) is a prime target of iron deficiency because of its high iron content (12 Fe per PS). To understand the protein level changes in the light-harvesting complex (LHC) of PSI (LHCI) under iron deficiency, rice seedlings were grown in Hoagland's nutrient medium with and without Fe. Chlorophyll content and photosynthetic efficiency decreased under iron deficiency. Protein gel blots probed with antibodies against the PSI core and Lhca 1-4 proteins revealed that the core subunits PsaA and PsaB remained stable under iron deficiency, whereas PsaC and PsaD decreased by about 50%, and PsaE was completely degraded. Among the LHCI subunits, Lhca1 and Lhca2 decreased by 40 and 50%, respectively, whereas Lhca3 and Lhca4 were completely degraded. We propose that the dissociation of LHCI subunits may be due to increased levels of reactive oxygen species, which is suggested by the increased activity of superoxide dismutase. PMID- 22445752 TI - Octaphlorethol A, a novel phenolic compound isolated from a brown alga, Ishige foliacea, increases glucose transporter 4-mediated glucose uptake in skeletal muscle cells. AB - Skeletal muscle is the major site of glucose disposal. Promoting glucose uptake into this tissue may attenuate the insulin resistance that precedes type 2 diabetes. However, the anti-diabetic effect of marine algae on glucose uptake and metabolism in skeletal muscle remains poorly understood. Here, we report the glucose uptake effects of octaphlorethol A (OPA), a novel phenolic compound isolated from Ishige foliacea, on skeletal muscle cells. OPA increased glucose uptake in differentiated L6 rat myoblast cells in a dose-dependent manner relative to the control. In addition, we found that OPA increased glucose transporter 4 (Glut4) translocation to the plasma membrane. Furthermore, we also demonstrated these OPA effects essentially depended on the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) activation. In summary, PI3-K/Akt and AMPK activation were involved in mediating the effects of OPA on glucose transport activation and insulin sensitivity. OPA can be further developed as a potential anti-diabetic therapy. PMID- 22445753 TI - Characterization of the single transmembrane domain of human receptor activity modifying protein 3 in adrenomedullin receptor internalization. AB - Two receptor activity-modifying proteins (RAMP2 and RAMP3) enable calcitonin receptor-like receptor (CLR) to function as two heterodimeric receptors (CLR/RAMP2 and CLR/RAMP3) for adrenomedullin (AM), a potent cardiovascular protective peptide. Following AM stimulation, both receptors undergo rapid internalization through a clathrin-dependent pathway, after which CLR/RAMP3, but not CLR/RAMP2, can be recycled to the cell surface for resensitization. However, human (h)RAMP3 mediates CLR internalization much less efficiently than does hRAMP2. Therefore, the molecular basis of the single transmembrane domain (TMD) and the intracellular domain of hRAMP3 during AM receptor internalization was investigated by transiently transfecting various RAMP chimeras and mutants into HEK-293 cells stably expressing hCLR. Flow cytometric analysis revealed that substituting the RAMP3 TMD with that of RAMP2 markedly enhanced AM-induced internalization of CLR. However, this replacement did not enhance the cell surface expression of CLR, [(125)I]AM binding affinity or AM-induced cAMP response. More detailed analyses showed that substituting the Thr(130)-Val(131) sequence in the RAMP3 TMD with the corresponding sequence (Ile(157)-Pro(158)) from RAMP2 significantly enhanced AM-mediated CLR internalization. In contrast, substituting the RAMP3 target sequence with Ala(130)-Ala(131) did not significantly affect CLR internalization. Thus, the RAMP3 TMD participates in the negative regulation of CLR/RAMP3 internalization, and the aforementioned introduction of the Ile-Pro sequence into the RAMP3 TMD may be a strategy for promoting receptor internalization/resensitization. PMID- 22445754 TI - Long chain acyl CoA synthetase 1 and gelsolin are oppositely regulated in adipogenesis and lipogenesis. AB - Our previous proteomics study revealed that long chain acyl CoA synthetase 1 (ACSL1) and gelsolin (GSN) are oppositely regulated in white adipose tissue of diet-induced obese rats. To firmly establish these proteins as mediators of adipogenic and/or lipogenic events, we efficiently knocked down the Acsl1 and Gsn genes using siRNA in 3T3-L1 adipocyte cells. Expectedly, Acsl1 knockdown stimulated expression of lipogenic genes. Interestingly, Gsn knockdown suppressed expression of lipogenic genes but strikingly increased that of Tnfalpha and Il6, which may have connections with lipolytic capacity of these genes. Conclusively, we provide clear evidence that ACSL1 and GSN are potential target proteins in the context of obesity. PMID- 22445755 TI - Systematic screen for genes involved in the regulation of oxidative stress in the nematode Caenorhabditis elegans. AB - Oxygen is essential for animals, but high concentrations of oxygen are toxic to them probably because of an increase in reactive oxygen species (ROS). Many genes are involved in the regulation of ROS, but they largely remain to be identified. To identify these genes, we employed the nematode Caenorhabditis elegans as a model organism, and systematically screened for genes that, when down-regulated by RNAi, lead to an increased sensitivity to ROS. We examined approximately 2400 genes on linkage group I and found that knock-down of 9 genes which participate in various cellular functions led to an increased sensitivity to ROS. This finding suggests an implication of a variety of cellular processes in the regulation of oxidative stress. PMID- 22445756 TI - Low-affinity copper transporter CTR2 is regulated by copper-sensing transcription factor Mac1p in Saccharomyces cerevisiae. AB - Copper is an indispensable metal for life. For convenience of genetic manipulation and sharing similar metabolic pathway of metals with mammalian cells, the yeast Saccharomyces cerevisiae is widely used for metal homeostasis studies. Storage and mobilization of copper ions in yeast vacuoles or mammalian lysosomes are important for cells to avoid their toxicity and elevate their utility. Though regulation of other genes involved in copper homeostasis is well understood, the regulation of gene encoding low-affinity copper transporter Ctr2p, which mediates mobilization of vacuolar or lysosomal stored copper ions, is still unclear. In this study, we found that copper depletion can upregulate yeast CTR2 gene transcription while copper overload downregulate it. The copper depletion induced CTR2 transcription can be abrogated by genetic deletion of copper-sensing transcription factor Mac1p. Though absent of consensus Mac1p binding sequences, CTR2 promoter region is demonstrated to be occupied by Mac1p, according to our results of chromatin immunoprecipitation (ChIP) assay. Overexpression of Mac1p can upregulate CTR2 transcription and partially complement the growth defect of copper-deficient yeast strain. Taken together, our results suggest that Mac1p can activate the expression of vacuolar copper transporter Ctr2p in response to copper deficiency, resulting in yeast resistance to copper starvation. PMID- 22445757 TI - The p53 inhibitor, pifithrin-alpha, suppresses self-renewal of embryonic stem cells. AB - Recent studies have reported the role of p53 in suppressing the pluripotency of embryonic stem (ES) cells after DNA damage and blocking the reprogramming of somatic cells into induced pluripotent stem (iPS) cells. However, to date no evidence has been presented to support the function of p53 in unstressed ES cells. In this study, we investigated the effect of pifithrin (PFT)-alpha, an inhibitor of p53-dependent transcriptional activation, on self-renewal of ES cells. Our results revealed that treatment of ES cells with PFT-alpha resulted in the inhibition of ES cell propagation in a dose-dependent manner, as indicated by a marked reduction in the cell number and colony size. Also, PFT-alpha caused a cell cycle arrest and significant reduction in DNA synthesis. In addition, inhibition of p53 activity reduced the expression levels of cyclin D1 and Nanog. These findings indicate that p53 pathway in ES cells rather than acting as an inactive gene, is required for ES cell proliferation and self-renewal under unstressful conditions. PMID- 22445758 TI - A miRNA machinery component DDX20 controls NF-kappaB via microRNA-140 function. AB - Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide, but the molecular mechanisms in tumorigenesis remain largely unknown. Previously, a DEAD-box protein DDX20, a component of microRNA-containing ribonucleoprotein complexes, was identified as a liver tumor suppressor candidate in an oncogenomics-based in vivo RNAi screen. However, the molecular mechanisms were unknown. Here, we show that deficiency of DDX20 results in the enhancement of NF-kappaB activity, a crucial intracellular signaling pathway closely linked with hepatocarcinogenesis. While DDX20 normally suppresses NF-kappaB activity by regulating NF-kappaB-suppressing miRNA-140 function, this suppressive effect was lost in DDX20-deficient cells. The impairment of miRNA function due to DDX20 deficiency appears to be miRNA species-specific at the point of loading miRNAs into the RNA-induced silencing complex. These results indicate that DDX20 deficiency enhances NF-kappaB activity by impairing the NF-kappaB-suppressive action of microRNAs, and suggest that dysregulation of the microRNA machinery components may also be involved in pathogenesis in various human diseases. PMID- 22445759 TI - nNOS downregulation attenuates neuronal apoptosis by inhibiting nNOS-GluR6 interaction and GluR6 nitrosylation in cerebral ischemic reperfusion. AB - Glutamate receptor 6 (GluR6) is well documented to play a pivotal role in ischemic brain injury, which is mediated by the GluR6.PSD95.MLK3 signaling module and subsequent c-Jun N-terminal kinase (JNK) activation. Our recent studies show that GluR6 is S-nitrosylated in the early stages of ischemia-reperfusion. NO (Nitric Oxide) is mainly generated from neuronal nitric oxide synthase (nNOS) in cerebral neurons during the early stages of reperfusion. Here, the effect of nNOS downregulation on GluR6 S-nitrosylation and GluR6-mediated signaling was investigated in cerebral ischemia and reperfusion. Administration of nNOS oligonucleotides confirmed that GluR6 nitrosylation is induced by nNOS-derived endogenous NO and further activates the GluR6.PSD95.MLK3 signaling module and JNK signaling pathway. Moreover, this study revealed for the first time that nNOS can bind with GluR6 during ischemic reperfusion, and PSD95 is involved in this interaction. In summary, our results suggest that nNOS binds with GluR6 via PSD95 and then produces endogenous NO to S-nitrosylate GluR6 in cerebral ischemia reperfusion, which provides a new approach for stroke therapy. PMID- 22445760 TI - AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is caused by mutations that expand a polyglutamine region in the amino-terminal domain of Huntingtin (Htt), leading to the accumulation of intracellular inclusions and progressive neurodegeneration. Recent reports indicate the engagement of endoplasmic reticulum (ER) stress responses in human HD post mortem samples and animal models of the disease. Adaptation to ER stress is mediated by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates protein folding stress by controlling the expression of distinct transcription factors including X-Box binding protein 1 (XBP1). Here we targeted the expression of XBP1 on a novel viral-based model of HD. We delivered an active form of XBP1 locally into the striatum of adult mice using adeno-associated vectors (AAVs) and co expressed this factor with a large fragment of mutant Htt as a fusion protein with RFP (Htt588(Q95)-mRFP) to directly visualize the accumulation of Htt inclusions in the brain. Using this approach, we observed a significant reduction in the accumulation of Htt588(Q95)-mRFP intracellular inclusion when XBP1 was co expressed in the striatum. These results contrast with recent findings indicating a protective effect of XBP1 deficiency in neurodegeneration using knockout mice, and suggest a potential use of gene therapy strategies to manipulate the UPR in the context of HD. PMID- 22445761 TI - Genome-wide association study of SSRI/SNRI-induced sexual dysfunction in a Japanese cohort with major depression. AB - Sexual dysfunction is a major side effect of selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). We conducted a genome-wide association study to identify the genetic factors contributing to the risk of SSRI/SNRI-induced sexual dysfunction by testing 186 320 single nucleotide polymorphism (SNP) markers in a cohort of 201 Japanese major depression patients including 36 with sexual dysfunction induced by SSRI (paroxetine or fluvoxamine) or SNRI (milnacipran). The Cochran-Armitage trend test showed that 11 SNPs, tightly clustered in a distinct region on chromosome 14q21.3, were associated with SSRI/SNRI-induced sexual dysfunction at a genome wide significance level after false discovery rate (FDR) correction, and the strongest SNP association was with rs1160351 (P=3.04 * 10(-7), risk ratio=2.92, 95% confidence interval (CI)=1.79-4.76). These SNPs mapped to the intronic region of the MDGA2 gene. A Manhattan plot showed that the strong association peak remained in MDGA2 after adjustment for sex and age in a multivariable logistic regression analysis although P values increased slightly and became non significant. Replication studies with larger sample sizes are required to validate this exploratory study, but our findings may provide insights into the genetic basis of sexual dysfunction induced by SSRI/SNRI. PMID- 22445762 TI - Picturing obesity: analyzing the social epidemiology of obesity conveyed through US news media images. AB - News media coverage can affect how Americans view health policy issues. While previous research has investigated the text content of news media coverage of obesity, these studies have tended to ignore the photographs and other images that accompany obesity-related news coverage. Images can convey important messages about which groups in society are more or less affected by a health problem, and, in turn, shape public understanding about the social epidemiology of that condition. In this study, we analyzed the images of overweight and obese individuals in Time and Newsweek coverage over a 25-year period (1984-2009), and compared these depictions, which we characterize as representing the "news media epidemiology" of obesity, to data describing the true national prevalence of obesity within key populations of interest over this period. Data collected included descriptive features of news stories and accompanying images, and demographic characteristics of individuals portrayed in images. Over the 25-year period, we found that news magazines increasingly depicted non-whites as overweight and obese, and showed overweight and obese individuals less often performing stereotypical behaviors. Even with increasing representation of non whites over time, news magazines still underrepresented African Americans and Latinos. In addition, the elderly were starkly underrepresented in images of the overweight and obese compared to actual prevalence rates. Research in other policy arenas has linked media depictions of the populations affected by social problems with public support for policies to combat them. Further research is needed to understand how news media depictions can affect public stigma toward overweight and obese individuals and public support for obesity prevention efforts. PMID- 22445763 TI - Limits to evidence-based health policymaking: policy hurdles to structural HIV prevention in Tanzania. AB - Despite the well-documented role of highly co-endemic biological cofactors in facilitating HIV transmission and the availability of comparatively inexpensive tools to control them, cofactor-related interventions are only hesitantly included into African HIV prevention strategies. Against this background, this study analyzes political obstacles to policy-uptake of evidence concerning structural HIV prevention. The data used stem from fieldwork conducted in Tanzania between 2007 and 2009. They include 92 in-depth interviews with key AIDS policymakers and observations of 8 national-level policy meetings. Adopting a political economy perspective, the study shows that 1) assuming cost-aversion as a spontaneous reflex of policymakers is empirically wrong and analytically misleading, 2) that political constituencies induce a path dependence of allocative decisions inconducive to structural prevention, 3) that interventions' political attractiveness depends on the nature of their outputs and the expected temporality of political returns, 4) that policy fragmentation entailed by vertical disease control disfavours the consideration of broader causalities, and 5) that cofactor-based measures are hampered by policymakers' perception of structural prevention as being excessively complex and ultimately tantamount to poverty eradication. Confronting the policy players' reading of the Tanzanian situation with recent and classical literature on evidence-based decision-making and the politics of public health, this paper shows that, far from being strictly evidence-driven, HIV prevention policies result from a politically negotiated aggregation of competing, frequently non-optimizing rationalities. A realistic appraisal of policy processes suggests that the failure to consider the invariably political nature of HIV-related policymaking hampers the formulation of effective, politically informed strategies for positive change. Consequently, developing policy practitioners' understanding of how to effectively engage in evidence-influenced political struggles over priorities might be more instrumental in improving HIV prevention strategies than attempts to sidestep these ineradicably antagonistic controversies though technical decision tools meant to optimize health outcomes via the formulation of 'rational consensus'. PMID- 22445764 TI - Residents' perceptions of effective community representation in local health decision-making. AB - Community participation in local health decision-making has been envisioned as a key strategy to improve the design and delivery of health services in the USA. While much literature has sought to understand this participatory approach, considerably fewer studies have engaged the essential first-order question: How would we know who the appropriate community representatives are? An important first analytic step is to learn from community members themselves what characteristics they feel a 'good' representative should possess. Two primary research questions are addressed: 1) To what degree can low-income adults identify and articulate what they believe constitutes an effective community health representative and 2) What do low-income adults believe are the specific characteristics an effective community health representative should possess? In depth, open-ended interviews were conducted with 14 African-American and Latino residents of four low-income communities on the Southside of Chicago, USA. A theoretical sampling strategy was used with residents varying by age, education, employment, and years of residence on the Southside. We found that respondents had difficulty articulating what a community health representative might do or generating the names of potential representatives, but were able to express clear preferences for what would constitute good representation when given meaningful choices. Three primary characteristics were identified: 1) outcomes 2) expertise, and 3) active communication. These characteristics did not operate in isolation but together communicated the trust and commitment that respondents found fundamental to representation. In exploring this essential yet often neglected question, we sought to build an empirical foundation to more fully examine the precursors to effective community health representation. These data provide important clues as to how to build an inclusive process that expands rather than constrains the pool of community-based representatives. PMID- 22445765 TI - The decision-making process of genetically at-risk couples considering preimplantation genetic diagnosis: initial findings from a grounded theory study. AB - Exponential growth in genomics has led to public and private initiatives worldwide that have dramatically increased the number of procreative couples who are aware of their ability to transmit genetic disorders to their future children. Understanding how couples process the meaning of being genetically at risk for their procreative life lags far behind the advances in genomic and reproductive sciences. Moreover, society, policy makers, and clinicians are not aware of the experiences and nuances involved when modern couples are faced with using Preimplantation Genetic Diagnosis (PGD). The purpose of this study was to discover the decision-making process of genetically at-risk couples as they decide whether to use PGD to prevent the transmission of known single-gene or sex linked genetic disorders to their children. A qualitative, grounded theory design guided the study in which 22 couples (44 individual partners) from the USA, who were actively considering PGD, participated. Couples were recruited from June 2009 to May 2010 from the Internet and from a large PGD center and a patient newsletter. In-depth semi-structured interviews were completed with each individual partner within the couple dyad, separate from their respective partner. We discovered that couples move through four phases (Identify, Contemplate, Resolve, Engage) of a complex, dynamic, and iterative decision making process where multiple, sequential decisions are made. In the Identify phase, couples acknowledge the meaning of their at-risk status. Parenthood and reproductive options are explored in the Contemplate phase, where 41% of couples remained for up to 36 months before moving into the Resolve phase. In Resolve, one of three decisions about PGD use is reached, including: Accepting, Declining, or Oscillating. Actualizing decisions occur in the Engage phase. Awareness of the decision-making process among genetically at-risk couples provides foundational work for understanding critical processes and aids in identifying important gaps for intervention and future research. PMID- 22445766 TI - Canine welfare: we know everything, don't we? PMID- 22445767 TI - Development of heavy mineral and heavy element database of soil sediments in Japan using synchrotron radiation X-ray powder diffraction and high-energy (116 keV) X-ray fluorescence analysis: 1. Case study of Kofu and Chiba region. AB - We have started the construction of a nationwide forensic soil sediment database for Japan based on the heavy mineral and trace heavy element compositions of stream sediments collected at 3024 points all over Japan obtained by high resolution synchrotron X-ray powder diffraction (SR-XRD) and high-energy synchrotron X-ray fluorescence analysis (HE-SR-XRF). In this study, the performance of both techniques was demonstrated by analyzing soil sediments from two different geological regions, the Kofu and Chiba regions in Kanto province, to construct database that can be applied in the future to provenance analysis of soil evidence from a crime scene. The sediments from the quaternary volcanic lithology of the Chiba region were found to be dominated by heavy minerals of volcanic origin - orthopyroxene, clinopyroxene, and amphibole, and the REEs (rare earth elements) within the region showed similar geochemical behavior. On the other hand, four distinct heavy mineral groups were identified in the sediments of the Kofu region, where there is a great variety of underlying bedrock, and the geochemical behavior of the REEs in the sediments also varied accordingly to their geological origins. As such, our study shows that high-resolution SR-XRD data can provide information on the spatial distribution patterns of heavy minerals in stream sediments, playing an important role in determining their likely geographical origin. Meanwhile, the highly sensitive HE-SR-XRF data allow us to study the geochemical behavior of trace heavy elements, especially the REEs in the sediments, providing additional support to further constrain the likely geographical origin of the sediments determined by heavy minerals. PMID- 22445768 TI - Conversion of solar energy into electricity by using duckweed in Direct Photosynthetic Plant Fuel Cell. AB - In the present study we demonstrate for the first time the possibility for conversion of solar energy into electricity on the principles of Direct Photosynthetic Plant Fuel Cell (DPPFC) technology by using aquatic higher plants. Lemna minuta duckweed was grown autotrophically in specially constructed fuel cells under sunlight irradiation and laboratory lighting. Current and power density up to 1.62+/-0.10 A.m(-2) and 380+/-19 mW.m(-2), respectively, were achieved under sunlight conditions. The influence of the temperature, light intensity and day/night sequencing on the current generation was investigated. The importance of the light intensity was demonstrated by the higher values of generated current (at permanently connected resistance) during daytime than those through the nights, indicating the participation of light-dependent photosynthetic processes. The obtained DPPFC outputs in the night show the contribution of light-independent reactions (respiration). The electron transfer in the examined DPPFCs is associated with a production of endogenous mediator, secreted by the duckweed. The plants' adaptive response to the applied polarization is also connected with an enhanced metabolism resulting in an increase of the protein and carbohydrate intracellular content. Further investigations aiming at improvement of the DPPFC outputs and elucidation of the electron transfer mechanism are required for practical application. PMID- 22445769 TI - Reinstatement of fear in humans: autonomic and experiential responses in a differential conditioning paradigm. AB - The present study investigated reinstatement of fear in humans using an aversive differential conditioning paradigm. Two neutral human face pictures were presented during habituation, acquisition, extinction, and postreinstatement phases. One picture served as a conditioned stimulus (CS) reinforced by an unconditioned stimulus (US) in the form of electrical stimulation (CS+) and the second picture as a control stimulus that was never reinforced (CS-). The prediction that in a reinstatement manipulation a previously extinguished fear response in humans can be reinstated in a reinstatement group by the mere presentation of three unpredicted electrical stimulations (USs) was tested. Participants in the control group were not exposed to unpredicted USs and no reinstatement effect was expected. Outcome measures included subjective US expectancy ratings and skin conductance responses. Results showed non-selective return of the fear response due to fear recovery associated with both CSs (CS+/CS ) in the reinstatement group. Unexpected fear recovery was observed for both CSs (CS+/CS-) in control participants. Results are discussed with respect to context conditioning, fear generalisation, and anxiety-related cognitive mechanisms underlying fear recovery after extinction. PMID- 22445770 TI - Nonsymbolic numerical magnitude comparison: reliability and validity of different task variants and outcome measures, and their relationship to arithmetic achievement in adults. AB - The numerical ratio effect (NRE) and the Weber fraction (w) are common metrics of the precision of the approximate numbers sense (ANS), a cognitive mechanism suggested to play a role in the development of numerical and arithmetic skills. The task most commonly used to measure the precision of the ANS is the numerical comparison task. Multiple variants of this task have been employed yet it is currently unclear how these affect metrics of ANS acuity, and how these relate to arithmetic achievement. The present study investigates the reliability, validity and relationship to standardized measures of arithmetic fluency of the NRE and w elicited by three variants of the nonsymbolic number comparison task. Results reveal that the strengths of the NRE and w differ between task variants. Moreover, the reliability and validity of the reaction time NRE and the w were generally significant across task variants, although reliability was stronger for w. None of the task variants revealed a correlation between ANS metrics and arithmetic fluency in adults. These results reveal important consistencies across nonsymbolic number comparison tasks, indicating a shared cognitive foundation. However, the relationship between ANS acuity and arithmetic performance remains unclear. PMID- 22445771 TI - Association of adult-onset asthma with specific cardiovascular conditions. AB - BACKGROUND: While asthma is known to be associated with cardiovascular disease (CVD), the relation to specific manifestations of CVD has not been previously described. Our objective was to explore the relation of child and adult-onset asthma with specific CVD conditions. METHODS: We examined data from 16,943 (projected 178 million) U.S. adults aged 18-90 years old with relevant information on asthma and CVD. The study was a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999-2006. We determined the prevalence of CVD risk factors and likelihood of CVD conditions according to gender and asthma status using multiple logistic regression adjusted for age, gender and other CVD risk factors. RESULTS: The proportions of subjects with child and adult-onset asthma were 4.8% (n=702) and 3.3% (n=534), respectively. Adult-onset asthma was significantly associated with total CVD (OR=2.07, CI=1.2 3.7), but child-onset asthma was not associated with any CVD conditions. Of the four specific CVD endpoints, adult-onset asthma overall was only associated with coronary heart disease (CHD) (OR=2.26, CI=1.2-4.2) in the total population. CONCLUSIONS: Our data suggests that CHD is the major cardiovascular condition associated with asthma; a prospective study must be done to confirm a causal relationship. PMID- 22445772 TI - Air trapping is a major determinant of persistent airway obstruction in asthmatics. AB - Chronic persistent airway obstruction has been observed in moderate-to-severe asthmatics despite treatment with inhaled corticosteroids. We investigated which airway changes were associated with this obstruction. High-resolution computed tomography (HRCT) was performed at study entry and reexamined at the time of follow-up when the FEV1 reached a maximally constant level after treatment for 1 year or more with inhaled corticosteroids. Bronchial wall area and air trapping extent were compared in the recovered group (n = 18) and the persistent airway obstruction group (n = 14). Bronchial wall area and air trapping of the initial HRCT were similar between the two groups. On follow-up HRCT, air trapping was markedly decreased in the recovered group compared with that on initial HRCT (P = 0.017), whereas bronchial wall area did not change. In the persistent-airway obstruction group, these two parameters did not change during follow-up. When follow-up HRCT was compared, air trapping was significantly greater in the persistent-airway-obstruction group than in the recovered group (P = 0.003). Difference post-bronchodilator FEV1 value between at initial and 2nd HRCT exam was correlated with difference air trapping value between at initial and 2nd HRCT exam(%) on the follow-up HRCT (P = 0.017). The presence of persistent airflow obstruction were significantly associated with the air trapping % difference between initial and 2nd time (RR = 1.70, P = 0.018). Persistence of AT could be a main contributing factor to chronic persistent airflow obstruction in asthma. PMID- 22445773 TI - Are "bath salts" the next generation of stimulant abuse? AB - "Bath salts" are stimulants with high abuse potential that are known to contain agents such as 3,4-methylenedioxypyrovalerone and 4-methylmethcathinone (mephedrone). They are marketed locally and through online retailers as legitimate products in order to evade legal control and facilitate widespread distribution. They have been present in Europe since 2007 but are now becoming a burgeoning presence in American hospitals. Though preliminary efforts are underway in the United States to restrict their usage and distribution, there remains a general unawareness on the part of physicians regarding the drugs' physiological effects. While they mimic the effects of other known stimulants, they are not detected on standard urine screens. We present a clinical case that illustrates a typical pattern of usage along with a description of their basic chemistry, appearance, methods of delivery, withdrawal and intoxication characteristics, treatment recommendations, and areas for further research. PMID- 22445774 TI - Nordic adolescents' school lunch patterns and their suggestions for making healthy choices at school easier. AB - This article examines Nordic adolescents' school lunch patterns and their perceptions of how making healthy choices at school could be easier. Analysis is based on a quantitative data-set collected between 2006 and 2007 as part of a Nordic research project. The sample of 1539 respondents consisted of 14-17 year old adolescents from Finland, Sweden, Denmark, and Norway. The number of adolescents regularly eating either a packed lunch or a hot school lunch differed between countries and statistically significant differences were found between girls' and boys' school lunch patterns in the Swedish and Finnish data. Results suggest that adolescents have an understanding of what is healthy, but that school resources do not always support their ability to make healthy choices. Adolescents' own suggestions for improvement imply that more attention should be paid to building a healthy school food environment. An important future challenge is trying to involve school health care personnel and aligning classroom activities more coherently with adolescents' eating patterns during the school day. PMID- 22445775 TI - Taste of a 24-h diet and its effect on subsequent food preferences and satiety. AB - The objective of this study was to investigate the effect of taste of a 24-h diet on subsequent food preferences (food choice and intake of specific food categories) and satiety. We used a crossover design, consisting of a 24-h fully controlled dietary intervention, during which 39 healthy subjects consumed diets that were predominantly sweet tasting, savory tasting, or a mixture. The diets were similar in energy content, macronutrient composition, and number of different products used. Following the intervention an ad libitum lunch buffet was offered the next day, consisting of food items differing in taste (sweet/savory) and protein content (low/high) and intake was measured. The results showed that the taste of the diet significantly altered preference for food according to their taste properties (p<0.0001); after the savory diet, intake of sweet foods was higher than of savory foods. After the sweet diet, savory foods tended to be preferred (p=0.07). No interaction was seen between the taste of the diet and food preference according to their protein content (p=0.67). No differences in total energy intake (kJ) at the ad libitum lunch buffet were observed (p=0.58). It appears that in healthy subjects, taste of a 24 h diet largely affects subsequent food preferences in terms of sensory appetite, whereby savory taste exerts the strongest modulating effect. Taste of a 24-h diet has no effect on macronutrient appetite. PMID- 22445776 TI - Effect of the dopamine D3 receptor antagonist GSK598809 on brain responses to rewarding food images in overweight and obese binge eaters. AB - The dopamine D(3) receptor is thought to be a potential target for treating compulsive disorders such as drug addiction and obesity. Here, we used functional Magnetic Resonance Imaging (fMRI) to investigate the effects the selective dopamine D(3) receptor antagonist GSK598809 on brain activation to food images in a sample of overweight and obese binge-eating subjects. Consistent with previous studies, processing of food images was associated with activation of a network of reward areas including the amygdala, striatum and insula. However, brain activation to food images was not modulated by GSK598809. The results demonstrate that D(3) receptor manipulation does not modulate brain responses to food images in overweight and obese subjects. PMID- 22445777 TI - Identification of a permease gene involved in lactose utilisation in Aspergillus nidulans. AB - Lactose is intracellularly hydrolysed by Aspergillus nidulans. Classical mutation mapping data and the physical characteristics of the previously purified glycosyl hydrolase facilitated identification of the clustered, divergently transcribed intracellular beta-galactosidase (bgaD) and lactose permease (lacpA) genes. At the transcript level, bgaD and lacpA were coordinately expressed in response to d galactose, lactose or l-arabinose, while no transcription was detectable in the additional presence of glucose. In contrast, creA loss-of-function mutants derepressed for both genes to a considerable extent (even) under non-inducing or repressing growth conditions. Lactose- and d-galactose induction nevertheless occurred only in the absence of glucose, indicating a regulatory role for CreA independent repression. Remarkably, bgaD deletion mutants grew normal on lactose. In contrast, lacpA deletants grew at a much slower rate in lactose liquid medium than wild-type while strains that carried more than one copy of lacpA grew faster, showing that transport is the limiting step in lactose catabolism. The effect of lacpA gene deletion on lactose uptake was exacerbated at lower substrate concentrations, evidence for the existence of a second transport system with a lower affinity for this disaccharide in A. nidulans. PMID- 22445778 TI - An insight into the Phlebotomus perniciosus saliva by a proteomic approach. AB - Sand fly saliva is known to play an important role in the establishment of Leishmania spp. infection. As a consequence, identifying antigenic salivary proteins of different leishmaniasis vectors has currently become a major task in the field of anti-Leishmania vaccine development. The purpose of this work was to improve the knowledge of Phlebotomus perniciosus salivary proteins by combining two-dimensional gel electrophoresis (2DE) methodology, mass spectrometry and Western blotting (WB). Salivary protein profiles of three P. perniciosus colonies from different geographic origins in Spain were compared through SDS-PAGE, leading to a similar pattern with no qualitatively noticeable differences. A gradual increase of the protein content was significantly detected with the age of sand flies, reaching the complete salivary protein profiles at day four. The 2DE revealed a reproducible protein profile that matched the classic monodimensional SDS-PAGE pattern (1DE). More spots rather than protein bands (19 versus 11) were visualized by 2DE and 1DE, respectively, suggesting the presence of either protein isoforms or posttranslational modifications. Sera of mice and hamsters immunized through exposure to sand fly bites following different immunization schedules showed elevated anti-saliva IgG levels. These sera allowed the detection of 5 bands and 16 immunogenic spots in 1DE and 2DE, respectively, followed by WB. These antigens were identified by MALDITOF/TOF as SP03, SP03B, SP08, SP01, SP01B, SP04, SP04B, SP02, Phlebotomus ariasi SP16, and Phlebotomus argentipes SP13. This work is assumed to be the first attempt to establish 2DE proteomic maps of P. perniciosus saliva. All spots were identified as salivary proteins, confirming this technology as an interesting tool to improve sand fly salivary knowledge. PMID- 22445779 TI - Effects of chewing efforts on the sensory and pain thresholds in human facial skin: a pilot study. AB - The aim of this study was to examine the effect of chewing efforts on sensory and pain thresholds of the orofacial skin of symptom-free subjects. Fourteen healthy volunteers were recruited. Using a stair-case method, the tactile detection threshold (TDT) and the filament-prick pain detection threshold (FPT) on the cheek skin (CS) and the skin overlying the palm side of the thenar skin (TS) were measured before and after chewing gum for 5 min (Time 1: T1) and keeping the jaw relaxed for 5 min (Time 2: T2) as a control. Both for the test and control situation, the TDT was higher in all measurement sites after 5 min. As for the FPT, the reactions between T1 and T2 were quite opposite: the FPT increased and/or remained stable in T1, while, it decreased at all sites in T2. There were significant session effects (T1-T2) on the FPT at the left CS (P<0.01), right CS (P<0.05) and TS (P<0.05). The increase of TDT after chewing/no chewing could be due to habituation, while the decrease of FPT observed in the control situation might be due to sensitization, respectively. This potential sensitization, however, was not observed after chewing efforts. Further studies are needed to clarify the modulating effect of masticatory function on the trigeminal sensory system. PMID- 22445780 TI - Inter-individual differences in the habitual use of cognitive reappraisal and expressive suppression are associated with variations in prefrontal cognitive control for emotional information: an event related fMRI study. AB - Two different emotion regulation strategies, cognitive reappraisal and expressive suppression, are strongly associated with increased neural activity in the prefrontal cognitive control network. In this event-related fMRI study, we investigated whether individual differences in habitual reappraisal and suppression tendencies are related to differences in prefrontal cognitive control processes for emotional information. In order to measure cognitive control over inhibiting a dominant response to happy or sad stimuli (in favor of the opposite valence), thirty-one healthy female participants performed the Cued Emotional Conflict Task (CECT). The Emotion Regulation Questionnaire was used to measure individual differences in everyday use of emotion regulation. Results demonstrate that high reappraisers are behaviorally faster and exert more fronto-cingulate activity when inhibiting a response to sad faces (compared to happy faces, FDR corrected). On the other hand, suppression scores are not correlated with performance to CECT trials. Interestingly, suppression scores are associated with higher amygdala activation during the inhibition of a response to sad faces (compared to happy faces). These data suggest that habitual reappraisal is associated with underlying functional cognitive control processes to inhibit a dominant response to negative material. In contrast, the effort to control negative material has negative consequences in individuals who have a tendency to suppress emotions. PMID- 22445781 TI - Elderly adults through compensatory responses can be just as capable as young adults in inhibiting the flanker influence. AB - The goals of this study were to determine whether there is an age-related flanker effect, whether elderly adults produce compensatory responses to overcome their deficiencies, and the extent to which any compensatory responses vary depending on the degree of task demands. To achieve these goals, we manipulated different degrees of demands in cognitive control in a flanker-task paradigm, such as by arranging different proportions of trials in which either a compatible or an incompatible response with respect to the target's pointing direction was required. Throughout the three experiments, we did not observe an increased flanker effect on behavioral measures exhibited by elderly adults compared with young adults. However, several compensatory responses by elderly adults were observed, as evident by the results of event-related potential components. Furthermore, these age-related compensatory responses did not vary as a function of different degrees of task demands. The results suggest that, through the use of compensatory responses, elderly adults are just as capable as young adults in inhibiting flanker influence. PMID- 22445782 TI - Testosterone and relationship quality across the transition to fatherhood. AB - Recent research points to decreasing testosterone (T) levels as well as decreasing relationship quality during the transition to fatherhood, and it has been suggested that T reflects and affects motivation and behavior with respect to mating or paternal effort. Accordingly, we hypothesized that decreases in T are associated with decreasing relationship quality in new fathers. Thirty-seven fathers and 38 men in committed romantic relationships without children (controls) were recruited. All subjects participated actively by collecting saliva samples for T assessment three times a day on two assessment days, four weeks prior to birth (day 1) and eight weeks after birth (day 2) for fathers, and three months after the first assessment for controls and by filling out questionnaires on relationship quality. Results revealed significantly lower T levels (AUCg-T) in fathers than in controls at day 2 and significant decreases in relationship quality from day 1 to day 2 in fathers, but not in controls. In particular, the new fathers reported tenderness in their relationship to have significantly decreased from pre to post birth in comparison to the controls. These results were partially moderated by T levels at day 1. We interpret our results as being in line with the "challenge hypothesis" in humans, according to which T levels are positively associated with mating effort and negatively related to paternal activities. PMID- 22445783 TI - Poor sleep quality and exaggerated salivary cortisol reactivity to the cold pressor task predict greater acute pain severity in a non-clinical sample. AB - Poor sleep is often independently associated with greater pain sensitivity and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (e.g., greater basal cortisol and exaggerated stress-induced cortisol reactivity). However, the interactions among sleep, pain, and the HPA axis have not been adequately evaluated. In this study, 40 healthy adults provided self-report regarding perceived sleep quality over the past month prior to completion of an acute noxious physical stressor (i.e., cold pressor task; CPT). Following the CPT, they reported on the severity of pain experienced. Salivary cortisol was sampled before, immediately following, and during recovery from CPT. Using bootstrapped confidence intervals with a bias correction, results showed that poor sleep quality was significantly associated with greater reports of CPT-induced pain severity and greater cortisol reactivity (i.e., increase from baseline). Furthermore, greater cortisol reactivity to the CPT was found to significantly mediate the relationship between poor sleep and pain severity. PMID- 22445784 TI - Neural correlates coding stimulus level and perception of capsaicin-evoked urge to-cough in humans. AB - The perception of airways irritation is represented in a distributed brain network. However, the functional roles of sub-regions of this network are yet to be determined. The aim of this study was to measure brain activation in healthy participants as they inhaled two doses of capsaicin to identify dose-dependent and dose-independent responses. Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measures of brain responses during inhalation of saline, and a low and high dose of capsaicin were made from 16 healthy participants. Subjective ratings of the urge-to-cough were also made during capsaicin challenges. The majority of brain regions that were activated during capsaicin inhalation, including insula and mid cingulate cortex, showed graduated responses to the two doses of capsaicin. Prefrontal and parietal regions had dose independent activation, whereas premotor regions and the cerebellum activated exclusively at the high dose of capsaicin. Activation in the somatosensory and mid-cingulate cortices correlated with ratings of urge-to-cough. In the brainstem, capsaicin produced dose-dependent activations in respiratory-related regions of the dorsal pons and lateral medulla. These data show dissociable response patterns to capsaicin inhalation that may represent different regional processes involved in monitoring and assessing stimulus intensity, determining the spatial localization of the stimulus and suppressing motor responses. PMID- 22445785 TI - Heightened activity in a key region of the ventral attention network is linked to reduced activity in a key region of the dorsal attention network during unexpected shifts of covert visual spatial attention. AB - To enable unexpected shifts of covert visual spatial attention, a ventral attention network is thought to dampen activity in a dorsal attention network that maintains the current focus of attention. However, direct evidence to support this view is scarce. In the present study, we investigated this hypothesis by asking healthy young adults to perform a covert visual spatial attention task while their brain activity was recorded with functional magnetic resonance imaging (fMRI). In each trial, participants discriminated the orientation of a target-colored letter in the cued visual field (valid trials) or, occasionally, in the uncued visual field (invalid trials). Consistent with prior work, the ventral attention network was more active in invalid trials than in valid trials. Most importantly, functional connectivity analyses revealed that an increase of activity in the right inferior frontal gyrus (a key region of the ventral attention network) was linked to smaller increases of activity in (a) the right inferior parietal lobe (a key region of the dorsal attention network) and (b) the left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex (other regions enabling the control of attention) in invalid trials, relative to valid trials. These findings provide novel support for the view that key regions of the ventral attention network help to enable unexpected shifts of covert visual spatial attention by dampening activity in brain regions that participate in maintaining the current focus of attention. PMID- 22445786 TI - Scientific Apps are here (and more will be coming). AB - The world of Apps is now well upon us although the application of this tool was a bit slow in coming to the scientific community. In this column I will briefly take a look at some of the Apps now available that are applicable to biomedical research. I will restrict my coverage to the Apple format, not because I am totally an Apple user (my PC is a Dell) but only because I do not have an Android device. PMID- 22445787 TI - Production of shikimic acid. AB - Shikimic acid is a key intermediate for the synthesis of the antiviral drug oseltamivir (Tamiflu(r)). Shikimic acid can be produced via chemical synthesis, microbial fermentation and extraction from certain plants. An alternative production route is via biotransformation of the more readily available quinic acid. Much of the current supply of shikimic acid is sourced from the seeds of Chinese star anise (Illicium verum). Supply from star anise seeds has experienced difficulties and is susceptible to vagaries of weather. Star anise tree takes around six-years from planting to bear fruit, but remains productive for long. Extraction and purification from seeds are expensive. Production via fermentation is increasing. Other production methods are too expensive, or insufficiently developed. In the future, production in recombinant microorganisms via fermentation may become established as the preferred route. Methods for producing shikimic acid are reviewed. PMID- 22445788 TI - A review of lignocellulose bioconversion using enzymatic hydrolysis and synergistic cooperation between enzymes--factors affecting enzymes, conversion and synergy. AB - Lignocellulose is a complex substrate which requires a variety of enzymes, acting in synergy, for its complete hydrolysis. These synergistic interactions between different enzymes have been investigated in order to design optimal combinations and ratios of enzymes for different lignocellulosic substrates that have been subjected to different pretreatments. This review examines the enzymes required to degrade various components of lignocellulose and the impact of pretreatments on the lignocellulose components and the enzymes required for degradation. Many factors affect the enzymes and the optimisation of the hydrolysis process, such as enzyme ratios, substrate loadings, enzyme loadings, inhibitors, adsorption and surfactants. Consideration is also given to the calculation of degrees of synergy and yield. A model is further proposed for the optimisation of enzyme combinations based on a selection of individual or commercial enzyme mixtures. The main area for further study is the effect of and interaction between different hemicellulases on complex substrates. PMID- 22445789 TI - Hydroxyapatite effect on photopolymerization of self-etching adhesives with different aggressiveness. AB - OBJECTIVE: To understand the correlation of the acidic monomer/hydroxyapatite (HAp) reaction with the photopolymerization behaviour of self-etching adhesives with different aggressiveness. METHODS: Two commercial self-etching adhesives the strong Adper Prompt L-Pop (APLP, pH ~ 0.8) and the mild Adper Easy Bond (AEB, pH ~ 2.5) were used. HAp powders were incorporated into both adhesives to acquire solutions with concentrations of 0, 1, 3, 5, 7 wt%. The attenuated total reflectance Fourier transform infrared (ATR/FT-IR) technique was employed to collect the in situ spectra during light-curing, from which the degree of conversion (DC) and polymerization rate (PR) were calculated. The pH of each tested solution was also measured. RESULTS: Without HAp incorporation, the DC and PR of the strong APLP (7.8% and 0.12%/s, respectively) were much lower than those of the mild AEB (85.5% and 5.7%/s, respectively). The DC and PR of APLP displayed an apparent increasing trend with the HAp content. For example, the DC increased from 7.8% to 58.4% and the PR increased from 0.12 to 3.8%/s when the HAp content increased from 0 to 7 wt%. In contrast, the DC and PR of AEB were much less affected by the HAp content. The observations were correlated well with the spectral and pH changes, which indicated that APLP underwent a higher extent of chemical reaction with HAp than AEB. CONCLUSIONS: The results disclosed the important role of the acidic monomer/HAp chemical reaction in improving the photopolymerization of the strong (low-pH) self-etching adhesives such as APLP. The phenomenon of polymerization improvement strongly depended on the adhesive aggressiveness. PMID- 22445790 TI - Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat. AB - This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were compared with those of a previously developed PBK model for methyleugenol (ME) in male rat. The results obtained reveal that formation of 1'-hydroxymethyleugenol glucuronide (1'HMEG), a major metabolic pathway in male rat liver, appears to represent a minor metabolic pathway in human liver whereas in human liver a significantly higher formation of 1'-oxomethyleugenol (1'OME) compared with male rat liver is observed. Furthermore, formation of 1'-sulfooxymethyleugenol (1'HMES), which readily undergoes desulfonation to a reactive carbonium ion (CA) that can form DNA or protein adducts (DA), is predicted to be the same in the liver of both human and male rat at oral doses of 0.0034 and 300 mg/kg bw. Altogether despite a significant difference in especially the metabolic pathways of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol (1'HME) between human and male rat, the influence of species differences on the ultimate overall bioactivation of methyleugenol (ME) to 1'-sulfooxymethyleugenol (1'HMES) appears to be negligible. Moreover, the PBK model predicted the formation of 1' sulfooxymethyleugenol (1'HMES) in the liver of human and rat to be linear from doses as high as the benchmark dose (BMD10) down to as low as the virtual safe dose (VSD). This study shows that kinetic data do not provide a reason to argue against linear extrapolation from the rat tumor data to the human situation. PMID- 22445791 TI - Extending across continents: Travel medicine and Latin America. PMID- 22445792 TI - HLA antigen expression in melanocytic lesions: is acquisition of HLA antigen expression a biomarker of atypical (dysplastic) melanocytes? AB - BACKGROUND: Although criteria are established for the histologic diagnosis of atypical nevi (AN), consensus about the criteria in the diagnosis of and in the definition of AN is limited. Moreover, intraobserver and interobserver differences in the application of these criteria for the diagnosis of AN have been observed. OBJECTIVE: We sought to determine the usefulness of HLA antigen expression as a biomarker of AN. METHODS: The immunoperoxidase reaction was used to mark common nevi and AN with HLA class I heavy chain-, beta2microglobulin (beta2m)-, and HLA class II beta chain-specific monoclonal antibodies. RESULTS: HLA class I heavy chain, beta2m, and HLA class II beta chain were expressed in 5 (8.6%) of the 58 common nevi and in 46 (~72%) of the 64 atypical melanocytic lesions. Among common lesions, only halo nevi expressed HLA class I heavy chain, beta2m, and HLA class II beta chain. The level of HLA class I heavy chain beta2m and of HLA class II beta chain expression correlated with the degree of cytologic atypia and architectural disorder. LIMITATIONS: The number of lesions tested and the subjective nature of the analysis of immunohistochemical staining of tissue sections are both limitations. CONCLUSIONS: The data presented suggest that HLA antigen expression is an objective biomarker that correlates well with the degree of cytologic atypia in AN and may: (1) be useful to distinguish common nevi from AN, and (2) represent a more objective measure to determine which AN should be excised. PMID- 22445793 TI - Katz et al., efficacy and safety of tanezumab in the treatment of chronic low back pain [Pain 2011;152:2248-2258] and Hill, blocking the effects of NGF as a route to safe and effective pain relief - fact or fancy? [Pain 2011;152:2200 2201]. PMID- 22445794 TI - Structure-based development of bacterial nitroreductase against nitrobenzodiazepine-induced hypnosis. AB - Nitrobenzodiazepine (NBDZ) is an addictive drug of the abused substances that causes severe neurological effects and even death. Bacterial type I nitroreductase NfsB (EC 1.5.1.34) has been reported to catalyze NBDZ into inactive metabolite 7-amino-benzodiazepine (7ABDZ) with promising activity, so as to become an attractive candidate for treatment of NBDZ overdose and addiction. Here, we investigate the nitroreduction of an NBDZ, flunitrazepam (FZ), by various mutants of NfsB designed from the solved crystal structure and characterize their in vitro and in vivo potency. Conformational changes occurred in the active site of N71S/F124W in contrast to the wild-type, including the flipping on the aromatic rings of W124 and F70 as well as the extension on the hydrogen bond network between flavin mononucleotide (FMN) and S71, which allow the significant enlargement in the active site pocket. In the complex structure of N71S/F124W and nicotinamide (NIA), stacking sandwich attractions of W124-FMN NIA were also found, implying the importance of W124 in substrate accessibility. Consequently, N71S/F124W exhibited increased 7AFZ production in vitro with nearly no toxicity and reduced 50% sleeping time (hypnosis) in vivo. Taken together, we demonstrate for the first time that N71S/F124W can serve as an effective antidote for NBDZ-induced hypnosis and provide the molecular basis for designing NfsB and the like in the future. PMID- 22445795 TI - MR enterography correlates highly with colonoscopy and histology for both distal ileal and colonic Crohn's disease in 310 patients. AB - BACKGROUND AND AIMS: To evaluate the efficacy of MR enterography (MRE) in patients with known or suspected Crohn's disease without the use of anti peristaltic pharmacologic agents compared to colonoscopy and histology. METHODS: A retrospective review of 850 consecutive patients who underwent routine MRE to evaluate known or suspected Crohn's disease was performed. Of these, 310 patients also underwent colonoscopy with biopsy(s) within 90 days. The results of the MRE were compared to the colonoscopy and pathology reports to determine the presence or absence of disease in evaluable bowel segments. Individual imaging parameters (including wall thickening, enhancement, T2 signal, mesenteric vascular prominence and adenopathy) were also separately analyzed to determine their independent predictive value. RESULTS: In 310 patients, the overall sensitivity and specificity of MRE (using endoscopy as a gold standard) were 85% and 80% respectively (kappa=0.65). The sensitivity of MRE for detection of pathologically severe disease was 87% in the terminal ileum (TI) and 88% in the colon. In the subset of 162 patients who underwent colonoscopy within 30 days of MRE, the overall sensitivity remained 85% but the specificity increased to 85% (kappa=0.69). Wall thickening and abnormal enhancement were sensitive indicators of Crohn's disease (75% and 78%), while abnormal T2 signal, mesenteric vascular prominence and adenopathy were specific (86%, 91% and 93%). CONCLUSION: MRE compares favorably to colonoscopy for evaluation of known or suspected Crohn's disease noninvasively and without the exposure to ionizing radiation associated with CT enterography (CTE). PMID- 22445796 TI - Protistan parasites as mortality drivers in cold water crab fisheries. AB - From a historical perspective, several protistan taxa, including the recently re aligned Microsporidia, have been associated with or identified as causes of mortalities in crustacean populations. Depending upon the host species, associated protistan prevalences could be as low as 5% or approach 100%. It has generally been assumed that reported prevalences translated directly into significant mortalities that could impact the distribution and abundance of affected populations. However, this assumption may be incorrect especially when the dynamics of host-pathogen-environment interactions are not entirely understood. We will discuss the presumed impact of several protistan pathogens on temperate and cold water commercial crab species. By using selected examples such as a ciliate in the Dungeness crab (Cancer magister) and Hematodinium sp. infections in North Pacific crabs, we will attempt to contrast differences between prevalence and mortality, acute and chronic infections/mortalities, age or size selectivity of affected population, and geographically restricted and widespread epizootics. We will also briefly discuss the potential impact of environmental changes such as climate change and ocean acidification on both host and protistan pathogen. PMID- 22445797 TI - The influence of peak airway pressure and oxygen requirement on infant tracheostomy. AB - OBJECTIVE: To determine if and how the preoperative peak airway pressure and oxygen requirement of an infant (less than 6 months of age) who requires mechanical ventilation influences the physician's decision to perform a tracheostomy on that infant. STUDY DESIGN: Nationwide survey. SUBJECTS: Pediatric Otolaryngologists. METHODS: A web-based survey was developed and sent to all members of the American Society of Pediatric Otolaryngology. RESULTS: 150 of the 348 surveys were returned (43%). The majority of respondents do not consider the patient's requirement for elevated peak airway pressure (PAP) or the patient's requirement for a high percentage of oxygen as a contraindication to performing a tracheostomy in that patient (54.7 and 72.1% respectively). The presence of preoperative high PAP influenced 68.2% of respondents to consider using a cuffed tracheostomy tube. In the immediate postoperative period, the most common complication resulting in significant morbidity or mortality was mucous plugging, and the majority of respondents attributed postoperative morbidity and mortality to preoperative pulmonary comorbidity. CONCLUSIONS: Preoperative PAP and the patient's oxygen requirement do not influence the surveyed otolaryngologists' decision whether or not to perform a tracheostomy in the infant population. However, PAP do influence whether or not a cuffed tracheostomy tube is used. PMID- 22445798 TI - The role of auditory brainstem response in diagnosing auditory impairments of Dejerine-Sottas. AB - Dejerine-Sottas disease is classified as hereditary motor sensory neuropathy (HMSN) type III and shows evidence of Friedreich's ataxia, significant reduction in nerve conduction velocity (NCV), hypomyelination and demyelination of the nerve fibers. In this study, a 10-years-old girl with Dejerine-Sottas disease is presented in which routine clinical signs (ataxia and reduced NCV) seem with significant impairments of auditory brainstem pathway. It is indicated that pure tone audiometry, standard tympanometry (tympanometry and acoustic reflex), and otoacoustic emissions (OAEs) showed normal results in both ears (normal peripheral auditory system). In contrast, auditory brainstem responses (ABRs) indicated abnormal findings in absolute latencies of I, III, and V and inter-peak latencies of I-III and I-V. These findings suggested auditory brainstem involvement especially in low and mid regions. PMID- 22445799 TI - Pediatric high speed digital imaging of vocal fold vibration: a normative pilot study of glottal closure and phase closure characteristics. AB - OBJECTIVE: The aim of the study is to characterize normal vibratory patterns of both glottal closure and phase closure in the pediatric population with the use of high speed digital imaging. METHODS: For this prospective study a total of 56 pre-pubertal children, 5-11 years (boys=28, girls=28) and 56 adults, 21-45 years (males=28, females=28) without known voice problems were examined with the use of a new technology of high speed digital imaging. Recordings were captured at 4000 frames per second for duration of 4.094 s at participants' typical phonation. With semi-automated software, montage analysis of glottal cycles was performed. Three trained experienced raters, rated features of glottal configuration and phase closure from glottal cycle montages. RESULTS: Posterior glottal gap was the predominant glottal closure configuration in children (girls=85%, boys=68%) with normal voice. Other glottal configurations observed were: anterior gap (girls=3.6%, boys=0%), complete closure (girls=7%, boys=10%) and hour glass (girls=0%, boys=11%). Adults with normal voice also demonstrated predominantly higher percentage of posterior glottal gap configuration (females=75% male=54%) compared to the configurations of anterior gap (females=0% male=7%), complete closure (females=2% male=39%), hour glass (females=3.6% male=3.6%). A predominantly open phase (51-70% of the glottal cycle) was observed in 86% girls and 71% boys. Compared to children, adult females showed a predominantly balance phased closure 46%, followed by open phase (39%) and predominantly closed phase (14%). Adult males showed a predominantly closed phase (43%), followed by predominantly open phase (39%), followed by a balanced phase (18%). CONCLUSIONS: This is a first study investigating characteristics of normal vibratory motion in children with high speed digital imaging. Glottal configuration and phase closure for children with normal voices are distinctly different compared to adults. The results suggest that posterior glottal gap and a predominantly open phase of the glottal cycle should be considered as normal glottal configuration in children during modal pitch and loudness. This study provides preliminary information on the vibratory characteristics of children with normal voice. The data presented here may provide the bases for differentiating normal vibratory characteristics from the disordered in the pediatric population. PMID- 22445800 TI - Reliability of pediatric reach test in children with hearing impairment. AB - OBJECTIVE: The objective of this study was to evaluate the reliability of pediatric reach test in children with hearing impairment. METHODS: A total of 65 hearing impaired children completed the standing section of PRT. Two raters evaluated all the included children in standing section of PRT on two separate occasions. RESULTS: ICC was used to generate reliability coefficients for intra rater and inter-rater PRT measurements using a two-way mixed effects model, single measure reliability with absolute agreement. The ICC values reported good to excellent reliability as the lower values of the 95% CI was above 0.4. The SEMs reported in this study was below 0.5cm. CONCLUSION: This study indicates that PRT can reliably measure the limits of stability in children with hearing impairment. Using the PRT, balance deficits can be identified, and a reliable baseline measures may be established for hearing impaired children before initiating interventions. PMID- 22445801 TI - Herpes zoster oticus (Ramsay Hunt syndrome) in children: case report and literature review. AB - INTRODUCTION: Approximately 10% of patients with peripheral facial nerve palsy are children. Facial nerve palsy is usually idiopathic. An uncommon cause is herpes zoster oticus (Ramsay Hunt syndrome). This syndrome usually affects adults and is rare in children. METHODS: We reviewed the literature and describe the cause, clinical manifestations, and treatment of Ramsay Hunt syndrome. We also report a case of the syndrome in a 12-year-old boy. CONCLUSION: Ramsay Hunt syndrome is characterized by peripheral facial paralysis associated with herpetic eruption on the auricula and external ear, and by vestibulocochlear dysfunction. It occurs by reactivation of latent varicella-zoster virus (VZV) in the geniculate ganglion, affecting the seventh and eighth cranial nerves. The diagnosis is based on history and physical findings. Treatment of Ramsay Hunt syndrome uses a combination of high-dose corticosteroids and acyclovir. Although the prognosis is better in children than in adults, it is not good enough. PMID- 22445802 TI - A rare cause of facial nerve palsy in children: hyperostosis corticalis generalisata (Van Buchem disease). Three new pediatric cases and a literature review. AB - Differential diagnosis of facial nerve palsy in children is extensive. We report on three pediatric cases presenting with facial nerve palsy caused by hyperostosis corticalis generalisata (Van Buchem disease). This autosomal recessive disease is characterized by progressive bone overgrowth, with narrowing of the neuroforamina in the skull causing cranial neuropathies. These three new cases of Van Buchem disease are of interest because of exceptionally early presentation of symptoms. Furthermore, this is the first report describing bilateral papilledema in a child with Van Buchem disease. Head computerized tomography (CT) scan revealed thickened calvarium, skull base and mandible in all three children, with narrowed facial nerve canals. Bone mineral density (BMD) was markedly increased at all measured points and biochemical markers of bone formation were significantly elevated. Diagnosis of Van Buchem disease was genetically confirmed. The cases are unique in that these are the first well documented pediatric cases of Van Buchem disease. PMID- 22445803 TI - Dairy fat blends high in alpha-linolenic acid are superior to n-3 fatty-acid enriched palm oil blends for increasing DHA levels in the brains of young rats. AB - Achieving an appropriate docosahexaenoic acid (DHA) status in the neonatal brain is an important goal of neonatal nutrition. We evaluated how different dietary fat matrices improved DHA content in the brains of both male and female rats. Forty rats of each gender were born from dams fed over gestation and lactation with a low alpha-linolenic acid (ALA) diet (0.4% of fatty acids) and subjected for 6 weeks after weaning to a palm oil blend-based diet (10% by weight) that provided either 1.5% ALA or 1.5% ALA and 0.12% DHA with 0.4% arachidonic acid or to an anhydrous dairy fat blend that provided 1.5% or 2.3% ALA. Fatty acids in the plasma, red blood cells (RBCs) and whole brain were determined by gas chromatography. The 1.5% ALA dairy fat was superior to both the 1.5% ALA palm oil blends for increasing brain DHA (14.4% increase, P<.05), and the 2.3% ALA dairy blend exhibited a further increase that could be ascribed to both an ALA increase and n-6/n-3 ratio decrease. Females had significantly higher brain DHA due to a gender-to-diet interaction, with dairy fats attenuating the gender effect. Brain DHA was predicted with a better accuracy by some plasma and RBC fatty acids when used in combination (R(2) of 0.6) than when used individually (R(2)=0.47 for RBC n-3 docosapentaenoic acid at best). In conclusion, dairy fat blends enriched with ALA appear to be an interesting strategy for achieving optimal DHA levels in the brain of postweaning rats. Human applications are worth considering. PMID- 22445804 TI - Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels. AB - Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5 HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5 HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse. PMID- 22445805 TI - Timing-dependent reduction in ethanol sedation and drinking preference by NMDA receptor co-agonist d-serine. AB - NMDA receptors become a major contributor to acute ethanol intoxication effects at high concentrations as ethanol binds to a unique site on the receptor and inhibits glutamatergic activity in multiple brain areas. Although a convincing body of literature exists on the ability of NMDA receptor antagonists to mimic and worsen cellular and behavioral ethanol effects, receptor agonists have been less well-studied. In addition to a primary agonist site for glutamate, the NMDA receptor contains a separate co-agonist site that responds to endogenous amino acids glycine and d-serine. d-serine is both selective for this co-agonist site and potent in boosting NMDA dependent activity even after systemic administration. In this study, we hypothesized that exogenous d-serine might ameliorate some acute ethanol behaviors by opposing NMDA receptor inhibition. We injected adult male C57 mice with a high concentration of d-serine at various time windows relative to ethanol administration and monitored sedation, motor coordination and voluntary ethanol drinking. d-serine (2.7 g/kg, ip) prolonged latency to a loss of righting reflex (LoRR) and shortened LoRR duration when given 15 min before ethanol (3 g/kg) but not when it was injected with or shortly after ethanol. Blood samples taken at sedative recovery and at fixed time intervals revealed no effect of d-serine on ethanol concentration but an ethanol induced decrease in l-serine and glycine content was prevented by acute d-serine pre-administration. d-serine had no effect on ethanol-induced (2 g/kg) rotarod deficits in young adult animals but independently and interactively degraded motor performance in a subset of older mice. Finally, a week-long series of daily ip injections resulted in a 50% decrease in free choice ethanol preference for d serine treated animals compared to saline-injected controls in a two-bottle choice experiment. PMID- 22445806 TI - Protective effect of Opuntia ficus indica f. inermis prickly pear juice upon ethanol-induced damages in rat erythrocytes. AB - Juice from the fruit of the cactus Opuntia ficus indica is claimed to possess several health-beneficial properties. The present study was carried out to determine whether O. ficus indica f. inermis fruit extract might have a protective effect upon physiological and morphological damages inflicted to erythrocytes membrane by chronic ethanol poisoning, per os, in rat. Chemical analysis of the extract revealed the presence of polyphenols, flavonoids, ascorbic acid, carotenoids, and betalains. Ethanol administration (3 g/kg b.w, per day for 90 days) induced an increase of malondialdehyde (MDA) and carbonylated proteins levels and a decrease of glutathione (GSH) level in erythrocyte. Ethanol administration also reduced the scavenging activity in plasma and enhanced erythrocytes hemolysis, as compared to control rats. In addition, ethanol intake increased the erythrocyte shape index by +895.5% and decreased the erythrocyte diameter by -61.53% as compared to controls. In animals also given prickly pear juice during the same experimental period, the studied parameters were much less shifted. This protective effect was found to be dose dependent. It is likely that the beneficial effect of the extract is due to the high content of antioxidant compounds. PMID- 22445808 TI - Measuring people's knowledge about vaccination: developing a one-dimensional scale. AB - We propose a new scale to measure people's general knowledge about vaccinations. The scale's psychometric properties and its relationship with people's willingness to vaccinate were examined in two studies. In Study 1, a representative sample of the German- and French-speaking populations in Switzerland (N=1123) responded to a mail survey. In Study 2, members of an online panel answered the same questions (N=233). The results of both studies suggest that people differ considerably in their ability to correctly answer questions related to vaccinations. Mokken scale analyses and a test-retest analysis showed that nine items form a one-dimensional scale with good psychometric properties. In both studies, a substantial correlation between knowledge and willingness to vaccinate was observed. The scale proposed in this study is well suited for research examining group differences. In a time when new media such as the Internet is highly accessible to most people, misconceptions can easily be spread. A good knowledge scale is important for measuring possible knowledge changes. PMID- 22445807 TI - Effects of alcohol on the membrane excitability and synaptic transmission of medium spiny neurons in the nucleus accumbens. AB - Chronic and excessive alcohol drinking lead to alcohol dependence and loss of control over alcohol consumption, with serious detrimental health consequences. Chronic alcohol exposure followed by protracted withdrawal causes profound alterations in the brain reward system that leads to marked changes in reinforcement mechanisms and motivational state. These long-lasting neuroadaptations are thought to contribute to the development of cravings and relapse. The nucleus accumbens (NAcc), a central component of the brain reward system, plays a critical role in alcohol-induced neuroadaptive changes underlying alcohol-seeking behaviors. Here we review the findings that chronic alcohol exposure produces long-lasting neuroadaptive changes in various ion channels that govern intrinsic membrane properties and neuronal excitability, as well as excitatory and inhibitory synaptic transmission in the NAcc that underlie alcohol seeking behavior during protracted withdrawal. PMID- 22445809 TI - A comparison of parent and provider reported influenza vaccination status of adolescents. AB - OBJECTIVE: To compare parent and provider reported influenza vaccination status among adolescents. METHODS: Data from the 2009 National Immunization Survey-Teen (NIS-Teen) were analyzed. The NIS-Teen is a nationally representative random digit-dialed telephone survey of households with adolescents 13-17 years at the time of interview, followed by a mail survey to the adolescent's vaccination providers to obtain provider-reported vaccination histories. During the interview a parent or guardian was asked if the adolescent had received an influenza vaccination and whether their response was based upon recall only or from consulting a parent-held vaccination record (i.e., shot card) with recall of additional vaccinations not recorded on the shot card. Parent-reported influenza vaccination status was compared with provider-reported vaccination status by calculating various validity measures (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], and kappa), overall and stratified by several demographic characteristics. In the main analysis, provider reported vaccinations were considered the gold standard. To evaluate the completeness of provider-reporting, we conducted additional analysis that also considered vaccinations reported by parents from the shot card or reported received in a non-medical setting as "true" vaccinations. RESULTS: During the 2008-2009 season, influenza vaccination coverage among adolescents based on provider report was 11.3%. Based on parent report, influenza vaccination coverage was 21.7%. Twenty-two percent of parents retrieved and referred to a shot card during the interview. In the shot card group, provider versus parent reported coverage was 12.5% versus 18.2% while among the recall only group coverage was 10.9% versus 22.7%, respectively. Overall, compared to provider report as the gold standard, parental report of influenza vaccination had a sensitivity of 86.7%, a specificity of 86.2%, a positive predictive value (PPV) of 43.1%, and a negative predictive value (NPV) of 98.0%. Among the shot card group, of vaccinations reported either by provider or by parent reading vaccination off shot card, only 66% were reported by providers. In the shot card group, the "true" vaccination level (16-17%) was closer to the parent reported coverage when it was assumed that vaccinations read by the parent from a shot card but not reported by a provider were considered true vaccinations. Overall, assuming that providers reported 64% of "true" vaccinations, sensitivity increased to 91%, specificity to 93%, and PPV to 71%. CONCLUSIONS: Overall estimated influenza vaccination coverage was more than ten percentage points higher based on parental report than on provider report, with the difference between provider and parent report greater among the recall only group. The two estimates are closer for those with shot cards, but few parents utilized shot cards in our study and most national surveys do not ask parents to consult shot cards when responding about their adolescent's vaccination. The actual vaccination coverage of adolescents studied is likely between coverage estimates obtained from parent report and provider report. PMID- 22445810 TI - Wnt family genes and their modulation in the ovary-independent and persistent vaginal epithelial cell proliferation and keratinization induced by neonatal diethylstilbestrol exposure in mice. AB - Proliferation and differentiation of cells in female reproductive organs, the oviduct, uterus and vagina, are regulated by endogenous estrogen. In utero exposure to a synthetic estrogen, diethylstilbestrol (DES), induces vaginal clear cell adenocarcinoma in humans. In mice, perinatal exposure to DES results in abnormalities such as polyovular follicles, uterine circular muscle disorganization and persistent vaginal epithelial cell proliferation. We reported the persistent gene expression change such as interleukin-1 (IL-1) related genes, insulin-like growth factor-I (IGF-I) and its downstream signaling in the mouse vagina exposed neonatally to DES. In this study, we found persistent up regulation of Wnt4 and persistent down-regulation of Wnt11 in the vagina of mice exposed neonatally to DES and estrogen receptor alpha specific ligand. Also Wnt4 expression in vagina is correlated to the stratification of epithelial cells with the superficial keratinization of vagina, but not epithelial cell stratification only. PMID- 22445812 TI - Few associations between income and fruit and vegetable consumption. AB - OBJECTIVE: To examine the association between income and the consumption of fruits and vegetables using the poverty income ratio (PIR). DESIGN: Association between PIR and intake of fruits and vegetables combined. The PIR was divided into 5 groups ranging from < poverty threshold (PT) to >= 400% PT. PARTICIPANTS: Adults aged 18 years and older (N = 16,232) who participated in the 1999-2006 National Health and Nutrition Examination Survey and fit the qualifiers. MAIN OUTCOME MEASURES: The amount of combined fruit and vegetable intake based on income level. ANALYSES: Using ANCOVA, a base model with increasing number of covariates was analyzed. RESULTS: Mean daily intake ranged from 253-324 g for those who consumed both fruits and vegetables (N = 16,213). In the base model, significant differences in intake occurred between those who were at >= 400% PT and PIR groups < 400. When age, sex, race/ethnicity, and calorie intake were added to the base model, these differences remained. Adding educational level to the model removed these differences. CONCLUSIONS AND IMPLICATIONS: Dietary intake of fruits and vegetables is directly related to income when income reaches levels of >= 400% PT. These differences are mediated by education. Providing nutrition education may help individuals to reach the recommended level of consumption of fruits and vegetables. PMID- 22445811 TI - Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS). AB - Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 * 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome wide significant signals from real SNP associations. PMID- 22445813 TI - Exploring the feasibility of an academic course that provides nutrition education to collegiate student-athletes. AB - The purpose of this article is to explore the delivery of nutrition education to collegiate student-athletes through an academic course. Existing literature has established the need for nutrition education among collegiate athletes. This article considers the collaboration of the university and the athletic department to better serve this population. Academic wellness courses for student-athletes can be used as models. Finally, benefits, barriers, and proposed course objectives are considered. This report proposes a potential solution to provide consistent, sustainable nutrition education to collegiate student-athletes. PMID- 22445814 TI - In-hospital chest compressions--the patient on a bed. PMID- 22445815 TI - From clinical judgment to odds: a history of prognostication in anoxic-ischemic coma. AB - Persistent coma from a major anoxic-ischemic injury to the brain may indicate there is less chance for full recovery. The tools of prognostication to assess comatose survivors of cardiopulmonary resuscitation have developed over several decades. Physicians would initially base their judgment on experience and data on outcome in these patients in the early years were merely on awakening not on disability. In the late 1970s, a large multicenter prospective study was performed on outcome in nontraumatic coma. The impetus for this study was the result of Plum and Jennet's collaboration. In 1981--for the first time--complex statistics were used to improve the accuracy of prognosis and became known as the "Levy algorithms." These early seminal studies shaped the prediction models and implied that clinical information alone could assist physicians in making a prediction. Later, probabilistic methods became more commonplace. PMID- 22445816 TI - Dissociable stages of problem solving (II): first evidence for process-contingent temporal order of activation in dorsolateral prefrontal cortex. AB - In a companion study, eye-movement analyses in the Tower of London task (TOL) revealed independent indicators of functionally separable cognitive processes during problem solving, with processes of building up an internal representation of the problem preceding actual planning processes. These results imply that processes of internalization and planning should also be distinguishable in time and space with respect to concomitant brain activation patterns. To investigate this possibility, here we conducted analyses of fMRI data for left and right dorsolateral prefrontal cortex (dlPFC) during problem solving in the TOL task by accounting for the trial-by-trial variability of onsets and durations of the different cognitive processing stages. Comparisons between stimulus-locked and response-locked modeling approaches affirmed that activation in left dlPFC was elicited particularly during early processes of internalization, comprising the extraction of goal information and the generation of an internal problem representation, whereas activation in right dlPFC was predominantly attributable to later processes of mental transformations on this representation, that is planning proper. Thus, present data corroborate the proposal that often observed bilateral dlPFC activation patterns during complex cognitive tasks such as problem solving may reflect functionally and, to some extent, even temporally separable processes with opposing lateralizations. PMID- 22445817 TI - Enhancement of the anti-Salmonella immune response in CD154-deficient mice by an attenuated, IFN-gamma-expressing, strain of Salmonella enterica serovar Typhimurium. AB - Previously, we demonstrated that cell-cell communications via the CD40-CD154 pathway play a critical role in the induction of type 1 cytokine responses, including IL-12 and IFN-gamma, which in turn greatly influence the response to Salmonella infections. Mice genetically deficient in the expression of CD154 exhibited markedly increased susceptibility to infection by an attenuated, double auxotrophic (aroA-aroD-) strain, designated BRD509, of Salmonella enterica Serovar Typhimurium. In the present study, we used a strain of Salmonella engineered to express murine IFN-gamma, designated GIDIFN, in order to assess its potential to enhance the host's immune response in CD154-deficient animals. We demonstrate that infection of animals with GIDIFN results in markedly enhanced anti-bacterial response, as evidenced by the significant reduction in bacterial loads in target organs and decreased animal mortality. This was associated with a more robust proinflammatory cytokine response, including IL-6, IL-12, TNF-alpha and IFN-gamma. In protection studies, GIDIFN strain was demonstrably superior than the BRD509 strain in affording protection against virulent Salmonella challenge in naive CD154-/- mice. Interestingly, however, infection with GIDIFN failed to correct the isotype switching defect in CD154-/- mice, suggesting that the enhanced immunity triggered by GIDIFN strain occurs independently of humoral immune responses. These findings demonstrate that GIDIFN has immunopotentiating effects on the host's immune response and provide direct evidence for the utility of IFN-gamma-expressing attenuated Salmonella in enhancement of immune responsiveness in immunodeficient hosts. PMID- 22445818 TI - The role of WlaRG, WlaTB and WlaTC in lipooligosaccharide synthesis by Campylobacter jejuni strain 81116. AB - Campylobacter jejuni is a major bacterial cause of gastroenteritis world-wide. C. jejuni produces a range of glycans including lipooligosaccharide (LOS), an important virulence factor. The genetic content of the LOS synthesis locus varies between C. jejuni strains and 19 classes have been described. Three LOS synthesis genes of C. jejuni strain 81116 (NCTC 11828), wlaRG, wlaTB and wlaTC were the focus of this study. WlaRG and the remaining two proteins of interest share sequence similarity to aminotransferases and glycosyltransferases, respectively. These genes were insertionally inactivated and phenotypically characterised. Each mutant produced truncated LOS. Mutants lacking WlaRG, WlaTB and WlaTC produced LOS with reduced immunogenicity. Both the wlaRG and wlaTC mutants were non-motile and aflagellate. In vitro invasion and adhesion assays revealed that the wlaRG, wlaTB and wlaTC mutants displayed reduced adherence to chicken embryo fibroblasts. All mutants were less invasive of human cells than 81116 confirming the role of intact LOS during invasion of human cells in vitro. Here we propose the general composition for the 81116 LOS core backbone based on capillary electrophoresis-mass spectrometry. PMID- 22445819 TI - Interaction between mammalian cells and Pasteurella multocida B:2. Adherence, invasion and intracellular survival. AB - A Pasteurella multocida B:2 strain from a case of bovine haemorrhagic septicaemia (HS) and a derivative, JRMT12, that was attenuated by a deletion in the aroA gene, were shown to adhere to, invade and survive within cultured embryonic bovine lung (EBL) cells. By comparison, bovine strains of Mannheimia haemolytica serotype A1 and P. multocida serotype A:3, although able to adhere to EBL cells, were not found intracellularly. The B:2 strains were viable intracellularly over a 7 h period, although a steady decline in viability was noted with time. Entry into the mammalian cells was inhibited by cytochalasin D, indicating that cell uptake was by an actin-dependent process. Viability assessment of EBL cells by trypan blue staining indicated that none of the bacterial strains was toxic for the EBL cells. Transmission electron microscopy (TEM) showed that, after entry into the mammalian cells, the B:2 strain resided in a vacuolar compartment. However, only a low percentage of mammalian cells appeared to contain one or more P. multocida B:2, suggesting that only certain EBL cells in the population were capable of being invaded by, or of taking up, the bacteria. TEM showed that P. multocida A:3 and M. haemolytica A:1 were found loosely adhering to the cell surface of EBL cells and were not detected intracellularly. The cell-invasive capacity of P. multocida B:2 may be a virulence property related to its ability to translocate from the respiratory tract into the blood stream. PMID- 22445820 TI - Differences in biofilm formation and virulence factors between clinical and fecal enterococcal isolates of human and animal origin. AB - The present study investigated the possible correlation between carriage of the virulence genes esp and fsrb, production of hemolysin and gelatinase and biofilm formation in human vs. animal enterococcal isolates. A collection of 219 enterococcal isolates recovered from clinical and fecal surveillance samples of hospitalized patients and 132 isolates from animal feces were studied. Isolates were tested for hemolysin and gelatinase phenotypically and for quantitative biofilm production by a microtitre method. Genes esp and fsrb were detected by PCR. Human Enterococcus faecium and Enterococcus faecalis isolates from both surveillance and clinical samples produced biofilm significantly more often than animal isolates (P < 0.0001 for both species). The quantity of biofilm did not differ significantly between human and animal isolates, while was significantly higher in esp-positive compared with esp-negative human E. faecium isolates (P < 0.0001). The frequency of esp gene carriage was significantly higher in human compared with animal E. faecium and E. faecalis isolates (P < 0.0001). The gene fsrb was detected significantly more often in animal than human E. faecium isolates (P 0.004). Hemolysin production was significantly more common in human clinical compared with animal E. faecalis isolates (P < 0.0001). Similar proportions of animal and human E. faecalis produced gelatinase, which was significantly correlated with the presence of fsrb gene (P < 0.0001) in both human clinical and animal E. faecalis isolates. The hemolysin trait did not exhibit any correlation with the presence of esp and fsrb genes, but appeared to be linked with enhanced quantity of biofilm production in both human clinical and animal E. faecalis isolates. Production of gelatinase was associated with the proportion and the degree of biofilm production mainly in animal E. faecalis isolates. PMID- 22445821 TI - Systematics of the grey mullets (Teleostei: Mugiliformes: Mugilidae): molecular phylogenetic evidence challenges two centuries of morphology-based taxonomy. AB - The family Mugilidae comprises mainly coastal marine species that are widely distributed in all tropical, subtropical and temperate seas. Mugilid species are generally considered to be ecologically important and they are a major food resource for human populations in certain parts of the world. The taxonomy and systematics of the Mugilidae are still much debated and based primarily on morphological characters. In this study, we provide the first comprehensive molecular systematic account of the Mugilidae using phylogenetic analyses of nucleotide sequence variation at three mitochondrial loci (16S rRNA, cytochrome oxidase I, and cytochrome b) for 257 individuals from 55 currently recognized species. The study covers all 20 mugilid genera currently recognized as being valid. The family comprises seven major lineages that radiated early on from the ancestor to all current forms. All genera that were represented by two species or more, except Cestraeus, turned out to be paraphyletic or polyphyletic. Thus, the present phylogenetic results generally disagree with the current taxonomy at the genus level and imply that the anatomical characters used for the systematics of the Mugilidae may be poorly informative phylogenetically. The present results should provide a sound basis for a taxonomic revision of the mugilid genera. A proportion of the species with large distribution ranges (including Moolgarda seheli, Mugil cephalus and M. curema) appear to consist of cryptic species, thus warranting further taxonomic and genetic work at the infra-generic level. PMID- 22445822 TI - Anticoagulation factor I, a snaclec (snake C-type lectin) from Agkistrodon acutus venom binds to FIX as well as FX: Ca2+ induced binding data. AB - Anticoagulation factor I (ACF I), a snake C-type lectin (snaclec) from the venom of Agkistrodon acutus binds specifically with activated factor X (FXa) in a Ca2+ dependent manner and prolongs the blood-clotting time in vitro. In this study, the inhibition of the coagulation pathway by ACF I was measured in vivo by activated partial thromboplastin time and prothrombin time assays and the binding of ACF I to factor IX (FIX) was investigated by native PAGE and surface plasmon resonance. The results indicate that ACF I inhibits both intrinsic and extrinsic coagulation pathways, but does not inhibit thrombin activity. ACF I also binds FIX in a Ca2+-dependent manner and their maximal binding occurs at 0.25 mM Ca2+. ACF I has a higher binding-affinity to FIX than to FX. Ca2+ is required to maintain in vivo function of FIX Gla domain for its recognition of ACF I. However, Ca2+ at high concentrations (>0.25 mM) inhibits the binding of ACF I to FIX. Ca2+ functions as a switch for the binding between ACF I and FIX. The results suggest that the binding of ACF I with FIX may play a dominant role in the anticoagulation activity of ACF I in vivo. PMID- 22445823 TI - Cytotoxic effect and apoptosis induction by Bothrops leucurus venom lectin on tumor cell lines. AB - Neoplastic transformation is the abnormal proliferation of cells. These transformations are often related to changes in cell surface glycoconjugates which can be detected by lectins. We evaluated the anti-tumor potential of BlL, a galactoside-binding lectin isolated from Bothrops leucurus venom as well as its cytotoxicity and hemolysis activity. The phosphatidylserine externalization and mitochondrial membrane potential were also determined. BlL exhibited cytotoxic activity against all tumor cell lines tested by induced phosphatidylserine externalization and mitochondrial depolarization, indicating cell death by apoptosis. PMID- 22445824 TI - The standard mouse assay of anti-venom quality does not measure antibodies neutralising the haemorrhagic activity of Vipera ammodytes venom. AB - The venom of Vipera ammodytes ammodytes (Vaa), like the venoms of other Viperinae snakes, is largely haemorrhagic and necrotising, and only to a lesser extent neurotoxic to humans. The components most extensively studied so far, and most probably involved in generating the observed pathologies, are haemorrhagins (H), members of the metalloproteinase group of enzymes, and neurotoxic ammodytoxins (Atxs), that belong to the secretory phospholipases A2. Rabbit antisera were prepared containing functional antibodies specific for each class of pathology inducing venom constituents and for both classes together. The involvement of these antibodies in neutralising the toxicity of whole Vaa venom was assessed using the ED50 assay in mice. This assay is the only regulatorily approved assay for estimating anti-venom potency and as such has the task to quantify the active compound neutralising venom-induced pathology of the anti-venom. Fully functional anti-Atx antibodies were shown to be responsible for neutralising the portion of venom toxicity, while anti-H antibodies were not protective in this assay. Thus, the mouse ED50 assay, intended to measure the active principle of the anti-venom, does not measure antibodies specific for Vaa venom haemorrhagins, and consequently does not fulfil its primary task from the regulatory point of view. PMID- 22445825 TI - Usefulness of reversed-phase HPLC enriched with room temperature imidazolium based ionic liquids for lipophilicity determination of the newly synthesized analgesic active urea derivatives. AB - Lipophilicity of several novel analgesic active 1-(1-arylimidazolidyn-2-ylidyn)-3 arylalkyl urea derivatives has been estimated by the use of chromatographic method. The investigated compounds were analyzed by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol or acetonitrile and water with addition of imidazolium based room temperature ionic liquids varying in an anion chaotropicity as the mobile phases. The relationships between log k values vs. concentration of organic solvent was used for determination of the log k(w) values by extrapolation technique. The partition coefficients (log P) values were calculated by means of the Pallas 3.1.1.2. and Spartan 10.0 softwares and further correlated with log k(w) measured experimentally in classical organic-aqueous eluent system and systems modified with ionic liquids addition. It was found that log k(w) values measured in eluent system modified with butyl-methyl imidazoilum chloride correlate the best with the logarithm of partition coefficient calculated by Pallas software (log P(calc.)). Furthermore, it was found that the examined compounds form H-bonding with imidazoilum cation of modifiers improving the chromatographic peak parameters (the symmetry factor, the theoretical plates number) especially when ionic liquid's anion was more chaotropic. Amphiphilic ionic liquid possessing longer alkyl chain substituent (OMIM BF(4)) can be considered as a new cationic surfactant. Micellar conditions improved separation selectivity of chloro- and methoxy substituted derivatives. PMID- 22445826 TI - Sample preparation method to minimize chemical shift variability for NMR-based urinary metabonomics of genetically hypertensive rats. AB - Urinary metabonomics based on proton nuclear magnetic resonance ((1)H NMR) has been widely employed to study metabolic differences associated with gene function and pathophysiological and toxicological stimuli. However, the chemical shift variability of (1)H NMR signals, which is due to differences in pH and ionic strength among urine samples, remains an outstanding problem for efficient data mining. Thus, we have proposed an improved sample preparation method where urine samples are lyophilized and reconstituted in a buffer solution (pH 7.40) so that the extent of urine concentration becomes constant based on creatinine concentration. In order to examine the usefulness of the proposed method, urine samples taken from spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) were treated not only by the proposed method but also by the usual method where urine with various concentrations is mixed with an equivalent volume of buffer solution (pH 7.40). Consequently, the pH of the urine samples prepared by the proposed method was precisely controlled to 6.89-7.01, whereas the pH of samples by the usual method was in the range of 6.81-7.18. The chemical shift variations of various metabolites having ionizable groups such as succinate, alpha-ketoglutarate, cis-aconitate, taurine, and glycine were significantly reduced with decreases in pH variability. A preliminary multivariate statistical analysis was carried out for the (1)H NMR spectral data obtained by the proposed method, where the metabolic profiles were distinguished between the SHR and SHRSP. The proposed sample preparation method will be particularly useful to closely inspect NMR-based urinary metabonomic data for the exploration of metabolic changes. PMID- 22445827 TI - Evidence for the genotoxic effect of daunomycin in multipotent hematopoietic cells of mouse bone marrow: chromatin proteins analysis. AB - Severe bone marrow suppression and anemia are the main side effects of using chemotherapeutic agents like daunomycin. In this study the effect of daunomycin on viability and chromosomal proteins of multipotent hematopoietic cells (MHCs) of mouse bone marrow was investigated. The cells were separated from mature cells according to their adherence, incubated in the absence and presence of various concentrations of daunomycin and viability was determined by trypan blue exclusion and MTT assay. The histones and high mobility group (HMG) proteins were extracted by acid and salt, respectively and analyzed on SDS-PAGE and immunoblot. The results revealed that daunomycin exhibited time and dose dependent cytotoxicity on the cells and upon increasing the concentrations of drug, the extractability of histone and HMG proteins decreased. Agarose gel electrophoresis showed aggregation of DNA in the presence of drug. Flow cytometry analysis suggested that there are differences in type and amount of histones H2A and H2B of these cells in comparison with thymus histones. Moreover histone H3 was not subjected to trimethylation at lysine 9 and daunomycin decreased H3K9 dimethylation and H3K9 acetylation in these cells in a dose-dependent manner. From these results it is concluded that the binding of daunomycin to chromatin precedes chromatin of multipotent hematopoietic cells of bone marrow into compaction/aggregation and beside DNA, histones and HMG proteins also play an important role in this process. PMID- 22445828 TI - Gene transcripts in spermatozoa: markers of male infertility. AB - The presence of a complex population of gene transcripts in mature human sperm is well established, and numerous mRNAs and non-coding mRNAs have been identified in sperm of men and other mammalian species using microarray and RT-PCR. The traditional concept that RNAs in mature sperm are only remnants from spermatogenesis and have no biological functions is in doubt. The findings that reverse transcriptases in sperm are active and that sperm can independently activate translation of stored mRNAs suggest that sperm RNAs may have significant effects on male fertility. The differences in expression profiles among RNAs in mature sperm from fertile and infertile men, and the regulation of sperm RNAs in embryonic development make them appealing markers for therapeutic and diagnostic tools in male infertility. In this review, methods for the detection and description of the diversity of gene transcript in sperm are discussed along with their putative roles in functional aspects of sperm and in embryogenesis. PMID- 22445829 TI - High-resolution melting (HRM) analysis for the detection of single nucleotide polymorphisms in microRNA target sites. AB - BACKGROUND: The function of microRNAs (miRNAs) depends on the binding of miRNAs to their target sequences in the 3'UTR of messenger RNAs (mRNAs), which enhances the degradation of mRNAs and consequently, represses their expression. Single nucleotide polymorphisms (SNPs) in the miRNA target sequences may affect or impair the binding of miRNAs. Studies have shown that SNPs in miRNA target sites (miR-TS-SNPs) have a great influence on diverse biological functions, including pharmacogenomics and disease susceptibilities in human. METHODS: High-resolution melting (HRM) analysis was applied for investigating the allele frequencies of 3 miR-TS-SNPs (PLA2G2A, IL-16, and NOD2) in acute leukemia. We also compared the genotypes of acute lymphoblastic leukemia patients at initial diagnosis and complete remission. RESULTS: HRM analysis revealed 3 genotypes (both homozygous and heterozygous) in the 3 miR-TS-SNPs. The allele frequencies of all 3 miR-TS SNPs were similar in normal individuals and patients with acute myelogenous leukemia. Most patients with acute lymphoblastic leukemia had the same genotypes at initial diagnosis and complete remission. CONCLUSIONS: Large scale scanning of case-control studies for miR-TS-SNPs may contribute to the investigation of their roles and pathogenesis mechanisms in human diseases. Our study showed that HRM analysis can be an efficient tool for studies of miR-TS-SNPs. PMID- 22445830 TI - Reference interval computation: which method (not) to choose? AB - BACKGROUND: When different methods are applied to reference interval (RI) calculation the results can sometimes be substantially different, especially for small reference groups. If there are no reliable RI data available, there is no way to confirm which method generates results closest to the true RI. METHODS: We randomly drawn samples obtained from a public database for 33 markers. For each sample, RIs were calculated by bootstrapping, parametric, and Box-Cox transformed parametric methods. Results were compared to the values of the population RI. RESULTS: For approximately half of the 33 markers, results of all 3 methods were within 3% of the true reference value. For other markers, parametric results were either unavailable or deviated considerably from the true values. The transformed parametric method was more accurate than bootstrapping for sample size of 60, very close to bootstrapping for sample size 120, but in some cases unavailable. CONCLUSIONS: We recommend against using parametric calculations to determine RIs. The transformed parametric method utilizing Box-Cox transformation would be preferable way of RI calculation, if it satisfies normality test. If not, the bootstrapping is always available, and is almost as accurate and precise as the transformed parametric method. PMID- 22445831 TI - Dual-band selective double cross polarization for heteronuclear polarization transfer between dilute spins in solid-state MAS NMR. AB - A sinusoidal modulation scheme is described for selective heteronuclear polarization transfer between two dilute spins in double cross polarization magic angle-spinning nuclear magnetic resonance spectroscopy. During the second N->C cross polarization, the (13)C RF amplitude is modulated sinusoidally while the (15)N RF amplitude is tangent. This modulation induces an effective spin-lock field in two selective frequency bands in either side of the (13)C RF carrier frequency, allowing for simultaneous polarization transfers from (15)N to (13)C in those two selective frequency bands. It is shown by experiments and simulations that this sinusoidal modulation allows one to selectively polarize from (15)N to its covalently bonded (13)Calpha and (13)C' carbons in neighboring peptide planes simultaneously, which is useful for establishing the backbone connectivity between two sequential residues in protein structural elucidation. The selectivity and efficiency were experimentally demonstrated on a uniformly (13)C,(15)N-labeled beta1 immunoglobulin binding domain of protein G (GB1). PMID- 22445832 TI - Gravity-driven fingers in fractures: experimental study and dispersion analysis by moment method for a point-source injection. AB - In this study, we investigate the behavior of a dense contaminant injected from a point-source in a fracture. Our experimental model is a transparent Hele-Shaw cell, 0.5 mm of aperture. A saline solution is injected locally representing the point-source pollution. A Laser Induced Fluorescence (LIF) method provides concentration measurement of the pollution plume. Two propagation patterns have been observed: one and two-finger plumes. If the upper part of the plume is stable over time regardless of the second configuration, the moment when the plume separates into two fingers is highly dependent on both injection flow-rate and contaminant concentration. To further investigate the dispersion process inside the fracture, experimental results are interpreted by the spatial and time moment methods. Resulting dispersivities and plume propagation mean velocity are compared to theoretical values derived from a modified Taylor-Aris dispersion tensor. The longitudinal macro-dispersion obtained suggests an asymptotical behavior of the plume spread regardless of the studied configurations. Experimental local dispersivities derived from time and space moments proved to be close at large times to theoretical values predicted by the density-dependent dispersion tensor (Oltean et al., 2004). Based on those observations the mechanism behind the separation of the plume into two fingers is believed to be significantly impacted by the pre-asymptotic behavior of the dispersion tensor. PMID- 22445833 TI - Experimental and modeling analysis of coupled non-Fickian transport and sorption in natural soils. AB - We present experimental breakthrough curve (BTC) data and a modeling investigation of conservative and sorbing tracer transport in natural soils. By analyzing the data using the continuous time random walk (CTRW) model, we probe the traditional approach of using conservative tracer model parameters as a basis for quantifying the transport of sorbing solutes in the same domain when non Fickian transport is present. Many known contaminants in groundwater are sorbed to the host solid porous medium, to varying extents, while being transported; this enhances the long tailing of BTCs which often already occurs because of the inherent non-Fickian nature of the transport. The CTRW framework has been shown to account very well for non-Fickian conservative (nonsorbing) transport. Here, we examine two BTC data sets in laboratory columns packed with natural soils; the first (previously analyzed by Mao and Ren (2004)) comprises transport of (conservative) bromide and (sorbing) atrazine tracers, while the second presents new data with bromide and tribromoneopentyl alcohol (TBNPA), a key flame retardant, as a sorbing solute. TBNPA has received little attention in the past, and is shown to be sorbed onto Bet Dagan soil in a nonlinear manner. We find that the transport behavior of bromide is non-Fickian in all cases, which is caused by the heterogeneity of the soil. Comparative model analysis of the non-Fickian BTCs of the conservative, and sorbing tracers and examination of the fitting parameters, exemplify the coupling between transport and adsorption/desorption processes. The difference in transport parameters used to match the conservative and sorbing data sets shows that conservative tracer parameters (average velocity and dispersion coefficient) are not valid for the transport of reactive tracers. PMID- 22445834 TI - Physico-chemical assessment of a fixated flue-gas desulfurization sludge cap emplaced along with other coal-combustion residues to abate acid mine drainage. AB - Long term monitoring of the physical and chemical effects of using coal combustion residues (CCRs), in particular fixated flue gas desulfurization (FGD) sludge, as a major component in the reclamation of a pyritic refuse deposit was undertaken to determine the beneficial and detrimental consequences of placing these controversial materials in an unrestricted environment. Monitoring wells, neutron probe access tubes, and weirs were installed before and after reclamation to observe hydrologic conditions and determine how the use of FGD sludge as a recharge barrier was affecting hydrochemical response to ambient weather conditions. Data were collected for six months prior to reclamation and then for an additional 13 years (more intensively during the first 5 years). Statistical analyses of water levels in the pyritic refuse deposit indicate a shift from precipitation- to barometric-controlled fluctuations. These findings, along with minimal variability in soil moisture within the CCR cap and transient perching of groundwater above the cap, are evidence that recharge of the refuse aquifer has been minimized. Statistically significant improvements in the quality of groundwater on-site and surface water leaving the site include long-term declines in acidity, As, and Fe concentrations within the refuse aquifer, attributed to a decrease in recharge of oxygenated water as supported by an analysis of calculated mineral saturation indices. Long-term declines in acidity and associated trace metals discharging from the site are attributed to the post reclamation loss of sulfate salts brought to the surface by capillary forces. The results of this study indicate that strategic usage of CCRs in reclamation programs can produce beneficial effects, including acid drainage reductions, that are beyond those achieved using traditional reclamation approaches such as the utilization of mine spoil as capping and fill material. PMID- 22445835 TI - Indirect estimation of the Convective Lognormal Transfer function model parameters for describing solute transport in unsaturated and undisturbed soil. AB - Solute transport in partially saturated soils is largely affected by fluid velocity distribution and pore size distribution within the solute transport domain. Hence, it is possible to describe the solute transport process in terms of the pore size distribution of the soil, and indirectly in terms of the soil hydraulic properties. In this paper, we present a conceptual approach that allows predicting the parameters of the Convective Lognormal Transfer model from knowledge of soil moisture and the Soil Moisture Characteristic (SMC), parameterized by means of the closed-form model of Kosugi (1996). It is assumed that in partially saturated conditions, the air filled pore volume act as an inert solid phase, allowing the use of the Arya et al. (1999) pragmatic approach to estimate solute travel time statistics from the saturation degree and SMC parameters. The approach is evaluated using a set of partially saturated transport experiments as presented by Mohammadi and Vanclooster (2011). Experimental results showed that the mean solute travel time, MU(t), increases proportionally with the depth (travel distance) and decreases with flow rate. The variance of solute travel time sigma2(t) first decreases with flow rate up to 0.4 0.6 Ks and subsequently increases. For all tested BTCs predicted solute transport with MU(t) estimated from the conceptual model performed much better as compared to predictions with MU(t) and sigma2(t) estimated from calibration of solute transport at shallow soil depths. The use of MU(t) estimated from the conceptual model therefore increases the robustness of the CLT model in predicting solute transport in heterogeneous soils at larger depths. In view of the fact that reasonable indirect estimates of the SMC can be made from basic soil properties using pedotransfer functions, the presented approach may be useful for predicting solute transport at field or watershed scales. PMID- 22445836 TI - Extracorporeal shock waves improve angiogenesis after full thickness burn. AB - OBJECTIVE: Extensive wounds of burn patients remain a challenge due to wound infection and subsequent septicemia. We wondered whether extracorporeal shock wave application (ESWA) accelerates the healing process. The aim of the study was to analyze microcirculation, angiogenesis and leukocyte endothelium interaction after burns by using ESWA with two types of low intensity. METHODS: Full thickness burns were inflicted to the ears of hairless mice (n=51; area: 1.3 mm(2)). The mice were randomized into five groups: (A) low-energy shock waves after burn injury (0.04 mJ/mm(2)); (B) very low-energy shock waves after burn injury (0.015 mJ/mm(2)); (C) mice received burns but no ESWA (control group); (D) mice without burn were exposed to low-energy shock waves; (E) mice without burns and with no shock wave application. Intravital fluorescent microscopy was used to assess microcirculatory parameters, angiogenesis and leukocyte behavior. ESWA was performed on day 1, 3 and 7 (500 shoots, 1 Hz). Values were obtained straight after and on days 1, 3, 7 and 12 post burn. RESULTS: Group A showed accelerated angiogenesis (non-perfused area at day 12: 5.3% vs. 9.1% (group B) and 12.6% (group C), p=0.005). Both shock wave groups showed improved blood flow after burn compared to group C. Shock waves significantly increased the number of rolling leukocytes compared to the non-ESWA-treated animals (group D: 210.8% vs. group E: 83.3%, p=0.017 on day 7 and 172.3 vs. 90.9%, p=0.01 on day 12). CONCLUSION: Shock waves have a positive effect on several parameters of wound healing after burns, especially with regard to angiogenesis and leukocyte behaviour. In both ESWA groups, angiogenesis and blood flow outmatched the control group. Within the ESWA groups the higher intensity (0.04 mJ/mm(2)) showed better results than the lower intensity group. Moreover, shock waves increased the number of rolling and sticking leukocytes as a part of an improved metabolism. PMID- 22445837 TI - TRAF3IP2 gene is associated with cutaneous extraintestinal manifestations in inflammatory bowel disease. AB - BACKGROUND AND AIMS: Genome-wide association (GWA) studies recently identified a novel gene, TRAF3IP2, involved in the susceptibility to psoriasis. Common immune mediated mechanisms involving the skin or the gut have been suggested. We therefore aimed to assess the role of TRAF3IP2 gene in IBD, with particular regard to the development of cutaneous extraintestinal manifestations (pyoderma gangrenosum, erythema nodosum). The association with psoriasis was also assessed in a secondary analysis. METHODS: The analysis included 267 Crohn's disease (CD), 200 ulcerative colitis (UC) patients and 278 healthy controls. Three TRAF3IP2 SNPs were genotyped by allelic discrimination assays. A case/control association study and a genotype/phenotype correlation analysis have been performed. RESULTS: All three SNPs conferred a high risk to develop cutaneous manifestations in IBD. A higher risk of pyoderma gangrenosum and erythema nodosum was observed in CD patients carrying the Rs33980500 variant (OR 3.03; P=0.026). In UC, a significantly increased risk was observed for both the Rs13190932 and the Rs13196377 SNPs (OR 5.05; P=0.02 and OR 4.1; P=0.049). Moreover, association of TRAF3IP2 variants with ileal (OR=1.92), fibrostricturing (OR=1.91) and perianal CD (OR=2.03) was observed. CONCLUSIONS: This is the first preliminary report indicating that TRAF3IP2 variants increase the risk of cutaneous extraintestinal manifestations in IBD suggesting that the analysis of the TRAF3IP2 variants may be useful for identifying IBD patients at risk to develop these manifestations. PMID- 22445838 TI - The risk of contracting pediatric inflammatory bowel disease in children with celiac disease, epilepsy, juvenile arthritis and type 1 diabetes--a nationwide study. AB - BACKGROUND AND AIMS: The association of celiac disease with inflammatory bowel disease (IBD) in children is unclear. This study assesses the risk of IBD in children diagnosed with celiac disease and three other chronic diseases, namely epilepsy, juvenile idiopathic arthritis (JIA) and type 1 diabetes using nationwide, comprehensive registers. METHODS: We identified Finnish children born between 1994 and 2008 and diagnosed with IBD (n=596) by October 2010 (aged up to 16 years) in a national register of medical reimbursements, which all these patients are entitled to. The presence of other chronic diseases, such as celiac disease, epilepsy, JIA and type 1 diabetes, diagnosed before the diagnosis of IBD was accordingly identified in patients and their population-based, individually matched controls (n=2380). The data on chronic diseases are based on certificates including the diagnostic criteria. The risk of contracting IBD in children with a diagnosis of a chronic disease was analyzed using conditional logistic regression analysis. RESULTS: Chronic diseases were more common in children contracting IBD than in their matched controls (frequency of chronic diseases 5.9% and 1.0%, respectively, p<0.001). Celiac disease associated with later development of ulcerative colitis (p<0.01) but the association with Crohn's disease was less clear (p<0.05). For the other chronic diseases, association was seen only between epilepsy and ulcerative colitis (p<0.01). CONCLUSION: Pediatric patients with celiac disease or epilepsy have an increased risk of developing IBD during their childhood but the risk is not high. This finding warrants a thorough investigation of intestinal symptoms in these children. PMID- 22445839 TI - [Screening, referring and counseling of adolescents for substance abuse. A randomized controlled study on 2120 students]. AB - OBJECTIVES: The DEP-ADO assessment questionnaire defines three alcohol- and drug related risk levels: low (green light), intermediate (yellow light) and high risk (red light). Our study sought to evaluate whether a DEP-ADO systematic screening by school nurses and physicians improves referring to specialized addiction consultations. METHOD: Randomized controlled study with allocation of subjects by matched pairs of school classes: 1045 adolescents received a group information; 1075 adolescents were met individually and filled in the questionnaire; then either they received a risk reduction oriented intervention (yellow light) or were referred to an addiction outpatient clinic (red light). RESULTS: In the DEP ADO group, 27 yellow lights (2.8%) and 15 red lights (1.6%) were identified. One adolescent of the DEP-ADO group actually went to the addiction consultation during the 3 months following the intervention (NS). Twenty youths consulted at least a second time the school nurse or physician, among whom 18 belonging to the intervention group and two to the control group (p=0.0003). CONCLUSION: A systematic screening with the DEP-ADO questionnaire did not increase the reference rate to the addiction consultation. The links between age, smoking and risk level suggest screening strategies restraining, for the younger, proposal of the DEP-ADO to the pupils smoking tobacco. ROC-ADO study demonstrates the need to empower the relations between school health providers and addiction consultations. PMID- 22445840 TI - Fragrance material review on piperonyl acetate. AB - A toxicologic and dermatologic review of piperonyl acetate when used as a fragrance ingredient is presented. Piperonyl acetate is a member of the fragrance structural group aryl alkyl alcohol simple acid esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand alone document. Available data for piperonyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, toxicokinetics, and genotoxicity data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances. PMID- 22445841 TI - Fragrance material review on 3-methyl-2-(n-pentanyl)-2-cyclopenten-1-one. AB - A toxicologic and dermatologic review of 3-methyl-2-(n-pentanyl)-2-cyclopenten-1 one when used as a fragrance ingredient is presented. 3-methyl-2-(n-pentanyl)-2 cyclopenten-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-methyl-2-(n-pentanyl)-2-cyclopenten-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22445842 TI - Fragrance material review on 2-(3,7-dimethyl-2,6-octadienyl)cyclopentanone. AB - A toxicologic and dermatologic review of 2-(3,7-dimethyl-2,6 octadienyl)cyclopentanone when used as a fragrance ingredient is presented. 2 (3,7-Dimethyl-2,6-octadienyl)cyclopentanone is a member of the fragrance structural group Ketones Cyclopentanones and Cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-(3,7-dimethyl 2,6-octadienyl)cyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, and skin sensitization data. A safety assessment of the entire Ketones Cyclopentanones and Cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Ketones Cyclopentanones and Cyclopentenones in fragrances. PMID- 22445843 TI - Fragrance material review on 1,1-dimethyl-2-phenylethyl acetate. AB - A toxicologic and dermatologic review of 1,1-dimethyl-2-phenylethyl acetate when used as a fragrance ingredient is presented. 1,1-Dimethyl-2-phenylethyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an Aryl Alkyl Alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to 1,1-dimethyl-2-phenylethyl acetate and is not intended as a stand-alone document. Available data were evaluated, then summarized, and includes: physical properties; acute toxicity; skin irritation; mucous membrane (eye) irritation; skin sensitization; elicitation; and toxicokinetics data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances. PMID- 22445844 TI - Inhibitory Killer Immunoglobulin-like Receptors to self HLA-B and HLA-C ligands contribute differentially to Natural Killer cell functional potential in HIV infected slow progressors. AB - Inhibitory Killer Immunoglobulin-like Receptors (iKIR) interact with their ligands, HLA molecules, to license Natural Killer (NK) cells for functional competence. Previous studies stimulating peripheral blood mononuclear cells (PBMCs) with the HLA-devoid K562 cell line revealed that NK cells from individuals with an iKIR encoded by the KIR3DL1 locus with self HLA-Bw4 as their ligands, had higher frequencies of tri-functional NK cells that expressed the degranulation marker CD107a and secreted Interferon-gamma and Tumor Necrosis Factor-alpha than those from individuals who were homozygous for HLA-Bw6 alleles, which are not ligands for these iKIR. To assess the effect of other iKIR to self HLA (S-iKIR) on the NK cell response, we compared HIV-infected slow progressors (SP) carrying S-iKIR to HLA-C alleles with or without S-iKIR to HLA-Bw4. We show that S-iKIR to HLA-B and C alleles differ in their contribution to NK cell functional potential in HIV-infected SP upon stimulation with K562 targets. PMID- 22445845 TI - Imaging central neurochemical alterations in chronic pain with proton magnetic resonance spectroscopy. AB - Proton magnetic resonance spectroscopy has been used extensively in the study of various neurobiological disorders: depression, schizophrenia, autism, etc. But its application to chronic pain is relatively new. Not many studies in chronic pain have used (1)H-MRS. The unique ability of (1)H-MRS to assess both static and dynamic levels of glutamate and gamma-aminobutyric acid (GABA) gives this method a unique position in neuroscience. Emerging evidence in chronic pain suggests an elevated excitatory/inhibitory neurotransmitter ratio is present within brain regions involved in pain processing. The combination of (1)H-MRS imaging with pharmacologic interventions holds significant promise as a direct one-to-one matching of disease pathology with drug mechanism of action can be made. As such (1)H-MRS may be useful in discovery of novel compounds for chronic pain. Research in these areas may lead to improved diagnosis and treatment of these complex patients. PMID- 22445846 TI - Adjunctive azithromycin in the treatment of aggressive periodontitis: microbiological findings of a 12-month randomized clinical trial. AB - OBJECTIVES: To compare the subgingival microbiological outcomes of azithromycin or placebo as adjuncts to scaling and root planing (SRP) in the treatment of aggressive periodontitis (AgP), and to secondarily evaluate the microbiological effect of supragingival scaling in AgP patients. METHODS: Twenty-four AgP subjects 13-26 years of age received a 15-day programme of supragingival scaling (SC) and were then randomly assigned to SRP with systemic azithromycin or placebo. Subgingival samples were taken with sterile paper points at baseline, 15 days after SC, and at 3, 6 and 12 months following SRP. Microbiological analysis was performed by the checkerboard DNA-DNA hybridization. RESULTS: Changes in bacterial levels from baseline to 15 days after SC were similar in the 2 groups. When subjects were analysed as a single group, significant reductions after SC were observed for Actinomyces gerencseriae, Capnocytophaga ochracea, and Treponema denticola. During the 12-month follow-up, levels of most of the bacteria decreased in both groups in a similar pattern. For instance, Actinomyces israelli, Veillonella parvula, Streptococcus gordonii, C. ochracea, Eikenella corrodens, Eubacterium nodatum, Fusobacterium periodonticum and Fusobacterium nucleatum ssp. polymorphum decreased significantly within the groups. CONCLUSIONS: Azithromycin was ineffective in lowering the subgingival levels of important putative periodontal pathogens in young AgP subjects compared to placebo. CLINICAL SIGNIFICANCE: Scaling and root planing with adjunctive systemic azithromycin provides little additional benefit compared to placebo in reductions of major subgingival periodontal pathogens. PMID- 22445847 TI - Nanographene-based tyrosinase biosensor for rapid detection of bisphenol A. AB - Hydrophilic nanographene (NGP) prepared by ball milling of graphite was used as the support to construct a novel tyrosinase biosensor for determination of bisphenol A (BPA). The performances of the nanographene-based tyrosinase biosensor were systematically compared with those of multiwall carbon nanotubes (MWNTs) modified tyrosinase biosensors. The results indicated that the nanographene-based tyrosinase biosensor provided significant advantages over MWNTs-based tyrosinase biosensor in term of response, repeatability, background current and limit of detection (LOD), which could be attributed to its larger specific surface area and unique hierarchical tyrosinase-NGP nanostructures. The nanographene-based tyrosinase biosensor displayed superior analytical performance over a linear range from 100 nmol L(-1) to 2000 nmol L(-1), with LOD of 33 nmol L(-1) and sensitivity of 3108.4 mA cm(-2)M(-1). The biosensor was further used for detecting BPA (leaching from different vessels) in tap water, and the accuracy of the results was validated by high performance liquid chromatography (HPLC). The nanographene-based tyrosinase biosensor proved to be a promising and reliable tool for rapid detection of BPA leached from polycarbonate plastic products and for on-site rapid analysis of emergency pollution affairs of BPA. PMID- 22445848 TI - Translational research--improving everyday pediatric nursing practice through research and evidence-based practice. PMID- 22445849 TI - Multiple antibiotic-resistant Pseudomonas aeruginosa and lung function decline in patients with cystic fibrosis. AB - BACKGROUND: The goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF). METHODS: Using data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to >=1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after >=2 years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1 second (FEV(1)) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies. RESULTS: In total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV(1) and received more oral (p<0.013) and inhaled (p<0.001) antibiotic therapy. Mean FEV(1) decline did not change significantly after MARPA detection (-2.22% predicted/year before detection and 2.43 after, p=0.45). There was no relationship between persistent infection or FEV(1) quartile and FEV(1) decline. CONCLUSIONS: Newly detected MARPA was not associated with a significant change in the rate of FEV(1) decline. These results suggest that MARPA is more likely to be a marker of more severe disease and more intensive therapy, and less likely to be contributing independently to more rapid lung function decline. PMID- 22445850 TI - Bioactive oxidatively truncated phospholipids in inflammation and apoptosis: formation, targets, and inactivation. AB - This report reviews structurally related phospholipid oxidation products that are biologically active where molecular mechanisms have been defined. Phospholipids containing polyunsaturated fatty acyl residues are chemically or enzymatically oxidized to phospholipid hydroperoxides, which may fragment on either side of the newly introduced peroxy function to form phospholipids with a truncated sn-2 residue. These truncated phospholipids not subject to biologic control of their production and, depending on the sn-2 residue length and structure, can stimulate the plasma membrane receptor for PAF. Alternatively, these chemically formed products can be internalized by a transport system to either stimulate the lipid activated nuclear transcription factor PPARgamma or at higher levels interact with mitochondria to initiate the intrinsic apoptotic cascade. Intracellular PAF acetylhydrolases specifically hydrolyze truncated phospholipids, and not undamaged, biosynthetic phospholipids, to protect cells from oxidative death. Truncated phospholipids are also formed within cells where they couple cytokine stimulation to mitochondrial damage and apoptosis. The relevance of intracellular truncated phospholipids is shown by the complete protection from cytokine induced apoptosis by PAF acetylhydrolase expression. This protection shows truncated phospholipids are the actual effectors of cytokine mediated toxicity. This article is part of a Special Issue entitled: Oxidized phospholipids-their properties and interactions with proteins. PMID- 22445851 TI - Age-related impairments in memory and in CREB and pCREB expression in hippocampus and amygdala following inhibitory avoidance training. AB - This experiment examined whether age-related changes in CREB and pCREB contribute to the rapid forgetting seen in aged animals. Young (3-month-old) and aged (24 month-old) Fischer-344 rats received inhibitory avoidance training with a low (0.2 mA, 0.4 s) or moderate (0.5 mA, 0.5 s) foot shock; memory was measured 7 days later. Other rats were euthanized 30 min after training, and CREB and pCREB expression levels were examined in the hippocampus, amygdala, and piriform cortex using immunohistochemistry. CREB levels decreased with age in the hippocampus and amygdala. After training with either shock level, young rats exhibited good memory and increases in pCREB levels in the hippocampus and amygdala. Aged rats exhibited good memory for the moderate but not the low shock but did not show increases in pCREB levels after either shock intensity. These results suggest that decreases in total CREB and in pCREB activation in the hippocampus and amygdala may contribute to rapid forgetting in aged rats. After moderate foot shock, the stable memory in old rats together with absence of CREB activation suggests either that CREB was phosphorylated in a spatiotemporal pattern other than analyzed here or that the stronger training conditions engaged alternate mechanisms that promote long-lasting memory. PMID- 22445852 TI - Manipulation of in vivo iron levels can alter resistance to oxidative stress without affecting ageing in the nematode C. elegans. AB - Iron-catalyzed generation of free radicals leads to molecular damage in vivo, and has been proposed to contribute to organismal ageing. Here we investigate the role of free iron in ageing in the nematode Caenorhabditis elegans. Media supplementation with Fe(III) increased free iron levels in vivo, as detected by continuous-wave electron paramagnetic resonance spectroscopy and elevated expression of the iron-sensitive reporter transgene pftn-1::gfp. Increased free iron levels caused elevated levels of protein oxidation and hypersensitivity to tert-butyl hydroperoxide (t-BOOH) given 9 mM Fe(III) or greater, but 15 mM Fe(III) or greater was required to reduce lifespan. Treatment with either an iron chelator (deferoxamine) or over-expression of ftn-1, encoding the iron sequestering protein ferritin, increased resistance to t-BOOH and, in the latter case, reduced protein oxidation, but did not increase lifespan. Expression of ftn 1 is greatly increased in long-lived daf-2 insulin/IGF-1 receptor mutants. In this context, deletion of ftn-1 decreased t-BOOH resistance, but enhanced both daf-2 mutant longevity and constitutive dauer larva formation, suggesting an effect of ferritin on signaling. These results show that high levels of iron can increase molecular damage and reduce lifespan, but overall suggest that iron levels within the normal physiological range do not promote ageing in C. elegans. PMID- 22445853 TI - Activation of the Hog1p kinase in Isc1p-deficient yeast cells is associated with mitochondrial dysfunction, oxidative stress sensitivity and premature aging. AB - The Saccharomyces cerevisiae Isc1p, an orthologue of mammalian neutral sphingomyelinase 2, plays a key role in mitochondrial function, oxidative stress resistance and chronological lifespan. Isc1p functions upstream of the ceramide activated protein phosphatase Sit4p through the modulation of ceramide levels. Here, we show that both ceramide and loss of Isc1p lead to the activation of Hog1p, the MAPK of the high osmolarity glycerol (HOG) pathway that is functionally related to mammalian p38 and JNK. The hydrogen peroxide sensitivity and premature aging of isc1Delta cells was partially suppressed by HOG1 deletion. Notably, Hog1p activation mediated the mitochondrial dysfunction and catalase A deficiency associated with oxidative stress sensitivity and premature aging of isc1Delta cells. Downstream of Hog1p, Isc1p deficiency activated the cell wall integrity (CWI) pathway. Deletion of the SLT2 gene, which encodes for the MAPK of the CWI pathway, was lethal in isc1Delta cells and this mutant strain was hypersensitive to cell wall stress. However, the phenotypes of isc1Delta cells were not associated with cell wall defects. Our findings support a role for Hog1p in the regulation of mitochondrial function and suggest that constitutive activation of Hog1p is deleterious for isc1Delta cells under oxidative stress conditions and during chronological aging. PMID- 22445855 TI - Direct effects of arsenic trioxide on action potentials in isolated cardiac tissues: importance of the choice of species, type of cardiac tissue and perfusion time. AB - INTRODUCTION: The aim of the present study was to evaluate direct/acute effects of arsenic trioxide on action potentials (APs) in isolated cardiac tissues, and to investigate if the choice of species and tissue and the duration of the perfusion play a role in arsenic-induced acute/direct prolongation of AP/QT. METHODS AND RESULTS: Direct electrophysiological effects of arsenic trioxide were measured in cardiac tissues isolated from four different species using micro electrode recording. Arsenic (after 30 to 95 min perfusion at 10 MUM) significantly prolonged APD(90), increased triangulation of the AP and elicited early afterdepolarizations (EADs) only in isolated guinea-pig and dog Purkinje fibers but not in rabbit and porcine (minipig) Purkinje fibers. Arsenic induced a prolongation of the APD(90) and increases in triangulation and the occurrence of EADs was not observed in papillary muscles of guinea-pigs and rabbits. Arsenic at 4 increasing concentrations from 0.1 MUM to 10 MUM at the standard perfusion-time of 15 min per concentration, and after a continuous 90-min perfusion at 1 MUM and 1 Hz did not induce these direct effects on APD(90), triangulation and EADs in isolated guinea-pig Purkinje fibers, but it at 1 uM elicited EADs in 2 out of 7 preparations after 90 min at 0.2 Hz. DISCUSSION: The present study demonstrates that the choice of species and cardiac tissue as well as perfusion-time play important roles in arsenic-induced direct/acute effects on APD(90) and induction of EADs in vitro. PMID- 22445856 TI - Developing an action plan for patient radiation safety in adult cardiovascular medicine: proceedings from the Duke University Clinical Research Institute/American College of Cardiology Foundation/American Heart Association Think Tank held on February 28, 2011. AB - Technological advances and increased utilization of medical testing and procedures have prompted greater attention to ensuring the patient safety of radiation use in the practice of adult cardiovascular medicine. In response, representatives from cardiovascular imaging societies, private payers, government and nongovernmental agencies, industry, medical physicists, and patient representatives met to develop goals and strategies toward this end; this report provides an overview of the discussions. This expert "think tank" reached consensus on several broad directions including: the need for broad collaboration across a large number of diverse stakeholders; clarification of the relationship between medical radiation and stochastic events; required education of ordering and providing physicians, and creation of a culture of safety; development of infrastructure to support robust dose assessment and longitudinal tracking; continued close attention to patient selection by balancing the benefit of cardiovascular testing and procedures against carefully minimized radiation exposures; collation, dissemination, and implementation of best practices; and robust education, not only across the healthcare community, but also to patients, the public, and media. Finally, because patient radiation safety in cardiovascular imaging is complex, any proposed actions need to be carefully vetted (and monitored) for possible unintended consequences. PMID- 22445857 TI - Identification of rheumatoid arthritis patients with vertebral fractures using bone mineral density and trabecular bone score. AB - The aim of this study was to test bone mineral density (BMD), trabecular bone score (TBS), and their combination, for detection of rheumatoid arthritis (RA) patients with vertebral fractures (VFs). One hundred eighty-five women aged 56.0 +/- 13.5 yr, with RA since 15.5 +/- 9.9 yr were studied. Lumbar spine, total hip, and femoral neck BMD were assessed by dual-energy X-ray absorptiometry (DXA). TBS was calculated from anteroposterior image of lumbar spine BMD. VFs from T4 to L4 were evaluated using Vertebral Fracture Assessment software on DXA device. The proportions of patients with VF and T-scores <=-2.5 were only 24.2%, 21.2%, and 33.3% at lumbar spine, total hip, and femoral neck, respectively. T-scores were significantly lower in patients with VF than in patients without VF, the largest difference being observed at femoral neck (p=0.0001). TBS was significantly lower in patients with VF vs without VF (p=0.0001). The areas under the curves were 0.621, 0.704, 0.703, 0.719, and 0.727 for lumbar spine BMD, TBS, lumbar spine BMD+TBS, total hip BMD, and femoral neck BMD, respectively. The threshold of 1.173 for TBS had the best sensitivity (63%) and specificity (74%). TBS measured at the lumbar spine has a better discrimination value than lumbar spine BMD, and similar to femoral neck BMD, for prediction of presence of VF in patients with RA. In RA subjects with osteopenia, the proportion of patients with VF was higher in the lowest tertile of TBS when compared with the highest tertile. In this population, at low risk according to BMD, TBS could help to detect patients with VF. PMID- 22445858 TI - Validation of FRC, a fracture risk assessment tool, in a cohort of older men: the Osteoporotic Fractures in Men (MrOS) Study. AB - We evaluated the performance of the Fracture Risk Calculator (FRC) in 5893 men who participated in the baseline visit (March 2000-April 2002) of the Osteoporotic Fractures in Men Study. FRC estimates for 10-yr hip and major osteoporotic (hip, clinical spine, forearm, and shoulder) fractures were calculated and compared with observed 10-yr fracture probabilities. Possible enhancement of the tool's performance when bone mineral density (BMD) was included was evaluated by comparing areas under receiver operating characteristic curves and by Net Reclassification Improvement (NRI). A total of 5893 men were followed-up for an average of 8.4 yr. For most quintiles of predicted fracture risk, the ratios of observed to predicted probabilities were close to unity. Area under the curves improved when BMD was included (p<0.001; 0.79 vs 0.71 for hip fracture and 0.70 vs 0.66 for major osteoporotic fracture, respectively). Using National Osteoporosis Foundation clinical treatment thresholds, BMD inclusion increased NRI significantly, 8.5% (p<0.01) for hip and 4.0% (p=0.01) for major osteoporotic fracture. We conclude that the FRC calibrates well with hip and major osteoporotic fractures observed among older men. Further, addition of BMD to the fracture risk calculation improves the tool's performance. PMID- 22445859 TI - Aflatoxins B(1), B(2) and G(1) modulate cytokine secretion and cell surface marker expression in J774A.1 murine macrophages. AB - Aflatoxins are fungal products which occur in food and feed. They are potent hepatocarcinogens, and are known to cause immunosuppression. We investigated the effect of aflatoxin B(1) (AFB(1)), aflatoxin B(2) (AFB(2)) and aflatoxin G(1) (AFG(1)) exposure, alone and in combination, on the secretion of key pro- and anti-inflammatory cytokines from the murine macrophage cell line, J774A.1. Exposure of macrophages to low doses of aflatoxin (0.01 or 0.1ng/mL) resulted in a statistically significant change in the secretion of a number of cytokines following stimulation with lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls. Specifically, treatment with AFB(1) or AFB(2) alone significantly decreased (P<0.01) the secretion of the anti-inflammatory cytokine interleukin (IL) 10 (IL-10), while the secretion of the pro-inflammatory cytokine IL-6 was significantly increased (P<0.01). In addition, aflatoxin exposure affected expression levels of key cell surface markers involved in the inflammatory response. Toll-like receptor 2 (TLR2) and Cluster of Differentiation 14 (CD14) expression levels decreased significantly (P<0.01), but Toll-like receptor 4 (TLR4) expression was unaffected. This data provides further insight into the mechanisms by which aflatoxins modulate the host immune response to exert their immunosuppressive activity. PMID- 22445860 TI - The interaction between desferrioxamine and hemin: a potential toxicological implication. AB - Our previous research demonstrated that iron chelating agent desferrioxamine (DFO) could promote iron donor hemin-induced protein oxidation due to the combination of DFO and hemin, but the binding constant and thermodynamic parameters of DFO-hemin interaction have not been examined before. In this study, affinity capillary electrophoresis (ACE) was applied to investigate the interaction between DFO and hemin for the first time. The binding constants of DFO-hemin were calculated to be 10(4)-10(5)M(-1) at various temperatures. The negative value of various thermodynamic parameters (DeltaG, DeltaS, and DeltaH) suggested that the binding was spontaneous and the interaction was exothermic and entropically driven. In addition, the high binding affinity between DFO with hemin seemed to be the key factor on promoting hemin- catalyzed formation of cytotoxic radicals, such as superoxide (O(2)(-)), which was related to the potential toxicity of this drug in clinical use. PMID- 22445861 TI - Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells. AB - Aristolochic acid (AA), derived from the Aristolochia species, has been associated with aristolochic acid nephropathy (AAN), which has emerged as a worldwide disease. Aristolochic acid I (AAI) is the main ingredient of AA, and the underlying mechanisms for AAI-induced nephrotoxicity are still unclear. In this study, we investigated whether endoplasmic reticulum (ER) stress was involved in AAI-induced nephrotoxicity. The results showed that treatment of HK-2 cells (a human proximal tubular epithelial cell line) with AAI caused an increase in eukaryotic initiation factor-2alpha (eIF2alpha) phosphorylation, X-box binding protein 1 (XBP1) mRNA splicing and the expression of glucose-regulated protein (GRP) 78 and CAAT/enhancer-binding protein-homologous protein (CHOP). These events represent typical markers of the ER stress-related signaling pathway. Pretreatment with 4-phenylbutyrate (4-PBA) or salubrinal (Sal) significantly inhibited AAI-induced apoptosis, indicating the role of ER stress in AAI-induced apoptosis. In addition, AAI-induced cell death followed an increase of reactive oxygen species (ROS) formation in HK-2 cells. Pretreatment with N-acetyl cysteine (NAC) or glutathione (GSH) significantly inhibited AAI-induced ER stress proteins and cell death, suggesting that ROS mediate AAI-induced ER stress. Taken together, these results suggest that the ER stress response is involved in apoptosis induced by AAI in HK-2 cells, thus offering a new insight into the nephrotoxicity of AAI. PMID- 22445862 TI - Docetaxel and 5-fluorouracil induce human p53 tumor suppressor gene transcription via a short sequence at core promoter element. AB - The p53 tumor suppressor protein is involved in cellular defense against agents that can cause genetic damage. Induction of p53 gene expression at transcriptional and post-transcriptional levels by such agents results in p53 regulated gene activation or suppression. Docetaxel (DOC), a member of the taxanes family that is widely used in cancer chemotherapy, activates p53 at the transcriptional level. We demonstrated that p53 is induced by low dose DOC treatment, resulting in MDR-1 gene suppression in human lung cancer cells. To identify the cis-element of p53 promoter that responds to DOC, p53 promoter region was cloned and promoter activity was analyzed on luciferase gene reporter assay. Promoter region (-78 to +129) contained the highest basal p53 promoter activity and deletion of +86 to +129 severely reduced basal promoter activity. Basal promoter region included the 21-bp element (PE21) that determines UV inducible expression of p53 and mediates DOC-inducible p53 expression. On site specific mutagenesis of PE21 (-78 to -58), with mutation of ATTG (-62 to -59) to CGGT, completely diminished the response to DOC. The same mutations also inhibited 5-fluorouracil (5-FU)-inducible p53 expression. Our data revealed that a sequence located at PE21 of p53 core promoter regulates p53 induction by chemotherapeutic agents. PMID- 22445863 TI - The physiological stress response in elasmobranch fishes: selected papers from a symposium at the 26th annual meeting of the American Elasmobranch Society. PMID- 22445864 TI - TORC1 is required to balance cell proliferation and cell death in planarians. AB - Multicellular organisms are equipped with cellular mechanisms that enable them to replace differentiated cells lost to normal physiological turnover, injury, and for some such as planarians, even amputation. This process of tissue homeostasis is generally mediated by adult stem cells (ASCs), tissue-specific stem cells responsible for maintaining anatomical form and function. To do so, ASCs must modulate the balance between cell proliferation, i.e. in response to nutrients, and that of cell death, i.e. in response to starvation or injury. But how these two antagonistic processes are coordinated remains unclear. Here, we explore the role of the core components of the TOR pathway during planarian tissue homeostasis and regeneration and identified an essential function for TORC1 in these two processes. RNAi-mediated silencing of TOR in intact animals resulted in a significant increase in cell death, whereas stem cell proliferation and stem cell maintenance were unaffected. Amputated animals failed to increase stem cell proliferation after wounding and displayed defects in tissue remodeling. Together, our findings suggest two distinct roles for TORC1 in planarians. TORC1 is required to modulate the balance between cell proliferation and cell death during normal cell turnover and in response to nutrients. In addition, it is required to initiate appropriate stem cell proliferation during regeneration and for proper tissue remodeling to occur to maintain scale and proportion. PMID- 22445865 TI - Potential negative effects of epinephrine on carotid blood flow and ETCO2 during active compression-decompression CPR utilizing an impedance threshold device. AB - OBJECTIVES: This study examines the effects of IV epinephrine administration on carotid blood flow (CBF) and end tidal CO(2) (ETCO(2)) production in a swine model of active compression-decompression CPR with an impedance threshold device (ACD-CPR+ITD). METHODS: Six female swine (32 +/- 1 kg) were anesthetized, intubated and ventilated. Intracranial, thoracic aorta and right atrial pressures were measured via indwelling catheters. CBF was recorded. ETCO(2), SpO(2) and EKG were monitored. V-fib was induced and went untreated for 6 min. Three minutes each of standard CPR (STD), STD-CPR+impedance threshold device (ITD) and active compression-decompression (ACD)-CPR+ITD were performed. At minute 9 of the resuscitation, 40 MUg/kg of IV Epinephrine was administered and ACD-CPR+ITD was continued for 1 min. Statistical analysis was performed with a paired t-test. p values of <0.05 were considered statistically significant and all values are reported in mmHg unless otherwise noted. RESULTS: Aortic pressure, cerebral and coronary perfusion pressures increased from STD=80 mm Hg for >=1 min. Short-term survival was defined 20 or 60 min, depending on protocol. Categorical variables were compared with chi-square test and Fisher's exact test. Continuous variables were compared with two-sample t-test and one-way ANOVA. Multiple logistic regression determined predictors of ROSC and SURV, utilizing cluster analysis by experimental protocol. Candidate variables were sex, weight, anesthesia duration, VF duration, and CPR ratio. RESULTS: Of 263 swine analyzed (53.2% male), 58.6% of males and 68.3% of females had ROSC (p=0.10), whereas 50.0% of males and 61.0% of females experienced SURV (p=0.07). RESULTS: Of 263 swine analyzed (53.2% male), 58.6% of males and 68.3% of females had ROSC (p=0.10), whereas 50.0% of males and 61.0% of females experienced SURV (p=0.07). Neither sex nor any identified candidate variable predicted ROSC or SURV. Both models had acceptable fit with Hosmer-Lemeshow values of 0.35 and 0.31, respectively. CONCLUSIONS: Sex predicts neither ROSC nor SURV in a swine model of prolonged VF. PMID- 22445867 TI - Early adrenaline administration does not improve circulatory recovery during resuscitation from severe asphyxia in newborn piglets. AB - AIM OF THE STUDY: To investigate the effects of early intravenous adrenaline administration on circulatory recovery, cerebral reoxygenation, and plasma catecholamine concentrations, after severe asphyxia-induced bradycardia and hypotension. METHODS: One-day-old piglets were left in apnoea until heart rate and mean arterial pressure were less than 50 min(-1) and 25 mmHg, respectively. They randomly received adrenaline, 10 MUgkg(-1) (n=16) or placebo (n=15) and were resuscitated with air ventilation and, when needed, closed-chest cardiac massage (CCCM). Eight not asphyxiated animals served as time controls. RESULTS: CCCM was required in 13 piglets given adrenaline and in 13 given placebo. Time to return of spontaneous circulation was: 72 (66-85)s vs. 77 (64-178)s [median (quartile range)] (p=0.35). Time until cerebral regional oxygen saturation (CrSO(2)) had increased to 30% was 86 (79-152)s vs. 126 (88-309)s (p=0.30). The two groups did not differ significantly in CrSO(2), heart rate, arterial pressure, right common carotid artery blood flow, or number of survivors: 13 vs. 11 animals. Plasma concentration of adrenaline, 2.5 min after resuming ventilation, was 498 (268 868)nmoll(-1) vs. 114 (80-306)nmoll(-1) (p=0.01). Corresponding noradrenaline concentrations were 1799 (1058-4182)nmoll(-1)vs. 1385 (696-3118)nmoll(-1) (ns). In the time controls, the concentrations were 0.4 (0.2-0.6)nmoll(-1) of adrenaline and 1.8 (1.3-2.4)nmoll(-1) of noradrenaline. CONCLUSION: The high endogenous catecholamine levels, especially those of noradrenaline, may explain why early administered adrenaline did not significantly improve resuscitation outcome. PMID- 22445868 TI - Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy? AB - Intravascular delivery of cells has been increasingly used in stroke models and clinical trials. We compared the biodistribution and therapeutic effects of bone marrow mononuclear cells (BMMCs) delivered by intra-arterial (IA) or intravenous (IV) injection after cortical ischemia. For the biodistribution analyses, BMMCs were labeled with (99m)Technetium ((99m)Tc). At 2 h, gamma-well counting of the brain and of the other organs evaluated did not show differences between the non ischemic and ischemic groups or between injection routes, and the organs with the highest uptake were the liver and lungs, with low uptake in the brain. At 24 h, the liver maintained the highest activity, and a marked decrease was seen in pulmonary uptake in all groups. At this time point, although the activity in the brain remained low, the lesioned hemisphere showed greater homing than the contralateral hemisphere, for both the IV and IA ischemic groups. Histological analysis by CellTrace labeling indicated similar homing between both routes in the peri-infarct region 24 h after transplantation and functional recovery was observed in both groups up to 11 weeks after the lesion. In conclusion, transplantation of BMMCs by IA or IV routes may lead to similar brain homing and therapeutic efficacy after experimental stroke. PMID- 22445869 TI - The toxicity potential of pharmaceuticals found in the Douro River estuary (Portugal): evaluation of impacts on fish liver, by histopathology, stereology, vitellogenin and CYP1A immunohistochemistry, after sub-acute exposures of the zebrafish model. AB - Qualitative and quantitative approaches were tested to assess zebrafish liver effects after sub-acute exposures of certain pharmaceuticals. Carbamazepine, fenofibric acid, propranolol, sulfamethoxazole and trimethoprim were tested individually and in mixtures, including low environmental levels. Overall, data showed sex specific reactions in liver, with the major alterations being observed in males. Males treated with propranolol, fenofibric acid and with mixtures, showed an increase of vitellogenin immunostaining, compared with the control. Males also evidenced a tendency for an increased hepatic mass, after individual and mixture exposures. The volume-weighted nuclear volume of hepatocytes was high in males after exposures to either mixture, which together with the greater cytoplasmic eosinophilia and changes in cytochrome P450 1A immunoreactivity, point to an increase in metabolic/detoxification activity. These investigations revealed distinct impacts depending on the exposure type, and strengthened the importance of studying non-steroidal compounds in mixtures, including environmental levels and both sexes. PMID- 22445870 TI - Chemical exposure in occupational settings and related health risks: a neglected area of research in Pakistan. AB - In Pakistan a huge number of workers is routinely exposed to various types of chemical contaminants but there is a dearth of information as to the impact of these agents, due to a lack of a routine surveillance system and proper reporting. Prolonged and sometimes acute occupational exposures to varied organic chemicals may result in numerous health related problems. Studies from all over the world have shown adverse health outcomes of chemicals that are commonly used in various occupations. Such chemical exposures are not just confined to the workplace, but the residents surrounding industrial sites also face significant health risks due to indirect chemical exposure. Occupational exposure is a multidimensional risk factor that varies from one occupation to another, and is associated with health decline in workers. Common determinants of workplace hazards include improper, or lack of use of self-protective equipment, active and passive exposure to cigarette smoke as well as the socio-demographic and economic background of workers. There may be more than one cause of occupational stress and psychophysical disturbance among workers such as workload, lower salaries, and lack of social and medical facilities; indeed, their general health is poor. Therefore, in Pakistan, it is particularly important to focus on these issues and set rules and regulations to create occupational hazard awareness among workers, which will promote health safety at work places. If priorities are given to the correct use of self-protective equipment, adopting proper hygiene at the workplace and to avoid smoking, occupational exposures and consequent health risks may be minimized significantly. PMID- 22445871 TI - Using molecular docking between organic chemicals and lipid membrane to revise the well known octanol-water partition coefficient of the mixture. AB - The octanol-water partition coefficient of a mixture has been widely used to predict the baseline toxicity of non-polar narcotic chemical mixtures, since toxic effects are usually generated by multiple mixtures. However, it remains unclear whether the validity of log Kowmix can be demonstrated, because experimental methods cannot be used to determine this parameter. The invalidity and the further revision of log Kowmix were therefore studied by using molecular docking between non-polar narcotic chemicals and lipid membrane (E(binding)). The results show E(binding) is a feasible substitute parameter for log Kow because their relationship is linear. Based on a molecular docking and QSAR model, a new calculated method of log Kowmix was proposed as follows: log(Kowmix)=?x(i)log Kowi. Comparison of this new method with the established methods demonstrates the invalidity of the latter, and therefore the former is suggested to be used to calculate the log Kowmix of organic chemical mixtures. PMID- 22445872 TI - The social and economic impacts of epilepsy on women in Nigeria. AB - BACKGROUND: Persons with epilepsy in sub-Saharan Africa experience stigma and social marginalization. There is paucity of data on the social and economic impacts of epilepsy in these patients and in particular, groups like women. We sought to determine the social and economic impacts of epilepsy on Nigerian women and especially how it affects their treatment and outcomes. METHODS: We carried out a cross-sectional survey of 63 women with epilepsy (WWE) and 69 controls matched for age, social status and site of care. A structured questionnaire was used to document information on demographic characteristics, education, employment status, economic status, health care use, personal safety and perceived stigma. The data were collated and analyzed with SPSS version 15. RESULTS: Unemployment, fewer years of formal education, lower marriage rates and higher stigma scores were more frequent among WWE than controls. Physical and sexual abuse with transactional sex was also reported among WWE. We also noted poorer environmental and housing conditions and lower mean personal and household incomes among WWE compared to the control group. CONCLUSION: WWE in this sample from Nigeria have worse social and economic status when compared with women with other non-stigmatized chronic medical conditions. PMID- 22445873 TI - Establishment of human ovarian serous carcinomas cell lines in serum free media. AB - Ovarian cancers are the fifth leading cause of cancer death among US woman. The majority of ovarian cancers belong to a category of serous adenocarcinomas. This type of cancer is often diagnosed at a late stage of the disease. Surgical debulking, followed by chemotherapy is the current treatment. Half of all patients will die within 5 years of diagnosis of the disease. Poor survival may be due to disease progression as a consequence of development of drug resistance, cancer cell heterogeneity within the tumor, or the persistence of cancer stem cells. Cancer stem cells (CSC) are defined as a minority cell type in the tumor, which retains the capacity, through asymmetric division, for self-renewal as well as differentiation into multiple cell types. Through this process, CSC can regenerate the entire tumor phenotype and subsequent metastases. Initial in vitro work in the area of solid tumor CSC biology has focused on the isolation and propagation of cells with CSC-like properties from breast and colon tumors. Breast and colon cell lines with CSC-like properties have been isolated and maintained in vitro for extended periods of time. The in vitro maintenance of these CSC requires growth in hormone-supplemented serum-free media and the use of matrix or growth as tumor spheres (Roberts, Ricci-Vitiani et al., Cammareri et al.). Based on the pioneering work generating breast and colon CSC, our lab has begun to develop methods for the establishment cell lines with CSC-like properties from additional solid tumors. In this article, we describe methods, using defined medium, which allow for the successful establishment of continuous cell cultures from a minority cell type within serous ovarian cancers. The cell lines established using these methods grow in serum-free hormone-supplemented medium either as a monolayer on a matrix, or as tumor spheres in suspension. These cells express markers previously reported for tumor stem cells, including CD44 and CD133, and form tumors that recreate the morphology of the original patient tumor when implanted in immune deficient mice. The introduction of this method will facilitate the expansion of ovarian cancer cells for investigating cancer stem cell biology as well as providing tools to aid in the development of new treatments for this deadly disease. PMID- 22445874 TI - Adult congenital heart disease: new challenges. AB - Improved surgical care from the last five decades, together with the advances in medical management, led to a remarkable increase of survival of patients with congenital heart disease (CHD). However, aging of the CHD population brings new challenges. Given that many patients with CHD are prone to residua and sequelae, life-long surveillance is essential. Therefore, the first of many challenges is to optimize the transition of patients with CHD from pediatric to adult cardiology to prevent lost to follow-up, and to ensure that there are enough specialized adult cardiologists to take care of this expanding patient population. Another important challenge is the expansion of knowledge on long term complications and comorbidity in these patients. Increased efforts are needed to gain further understanding on how to prevent and treat these. Furthermore, as patients reach the reproductive age, family planning becomes more important and research on the risks and management of pregnancy should be further extended. Finally, to improve the well-being and social life of adults with CHD efforts should be made to improve employability and insurability. PMID- 22445875 TI - Persistence of systolic and diastolic regional dysfunction after brief episodes of myocardial ischemia evaluated with velocity vector imaging. AB - BACKGROUND: The time course and characteristics of persistent regional dysfunction after ischemia remain unclear. Velocity vector imaging (VVI) allows accurate quantification of regional myocardial function. The aim of this study was to characterize the time course of regional diastolic and systolic abnormality after recovery from different durations of ischemia by VVI. METHODS: 72 rats underwent brief left coronary occlusion (3, 5, 10 and 15 min, respectively) followed by reperfusion for 4-8h. Hemodynamic measurements and VVI were performed at various time points. Regional systolic and diastolic functions were estimated from peak diastolic and systolic circumferential strain rate (SR-d and SR-s) of the left ventricle, respectively. RESULTS: Both SR-d and SR-s were significantly decreased in the ischemic segment during occlusion compared to non ischemic segment. With the increase in occlusive time, the duration of reduced SR d and SR-s after reperfusion was prolonged. Both SR-d and SR-s returned to pre occlusion values in less than 30 min after reperfusion in the 3 min and 5 min ischemia groups. However, in the 10- and 15-min ischemia groups, SR-d did not fully recovered even at 240 min after reperfusion despite complete recovery of SR s. The left ventricular hemodynamics during occlusion were significantly changed in all groups and returned to baseline immediately after reperfusion. CONCLUSION: The persistence of diastolic regional dysfunction is longer than systolic regional dysfunction after a relative longer ischemic event, suggesting that recent myocardial ischemic insult mimicking variant angina may be recognized with the evaluation of regional diastolic function. PMID- 22445876 TI - Radiation doses among residents living 37 km northwest of the Fukushima Dai-ichi Nuclear Power Plant. AB - External and internal radiation doses were estimated for 15 residents who lived approximately 37 km northwest of the Fukushima Dai-ichi Nuclear Power Plant, which released radioactive plumes on March 11, 2011 as the result of the Tohoku earthquake and subsequent tsunami damage. Residents were interviewed on where they stayed and what they ate after the incident. To estimate external dose, the air dose rate around each person's home was measured, and cumulative effective doses up to 54 d after the deposition were calculated. To estimate committed effective dose, urinary bioassays were performed using a low-background Ge spectrometer on 54 d and 78-85 d after the deposition. The average cumulative effective dose was 8.4 mSv for adults and 5.1 mSv for children. The average committed effective dose from (134)Cs and (137)Cs was 0.055 mSv for adults and 0.029 mSv for children. Iodine-131 was observed from urinary samples of five residents, the equivalent doses for thyroid gland were 27-66 mSv at maximum. We discuss the necessity of reducing the risk of further exposure. PMID- 22445877 TI - Pu-239+240 and Cs-137 in Montenegro soil: their correlation and origin. AB - The (239+240)Pu activity concentrations in soil from Montenegro (six samples from three localities) have been measured for the first time. The alpha and gamma spectrometric measurements are used to determine the (239+240)Pu/(137)Cs activity ratio, and it was found to be with an average of 0.02 and standard deviation of 0.007. This average activity ratio was applied to estimate (239+240)Pu in soil samples from the other 21 localities at which (137)Cs activity concentrations were measured. In this research obtained (either experimentally or estimated) (239+240)Pu activity concentrations (0.036-8.265 Bq kg(-1)) are comparable with those measured in some other European countries. On the basis of the results obtained in the present study and a survey of relevant literature, it is possible to conclude that Chernobyl contribution to (137)Cs contamination of Montenegro soils is dominant, whilst Pu contamination comes from the global fallout of nuclear weapon tests. PMID- 22445878 TI - Radon ((222)Rn) concentration in indoor air near the coal mining area of Nui Beo, North of Vietnam. AB - Concentrations of radioactive radon gas ((222)Rn) were measured using passive monitors based on LR115 solid state track detectors during June-July 2010 in indoor air of dwellings in the Nui Beo coal mining area, mostly in Cam Pha and Ha Long coastal towns, Quang Ninh province, in the North of Vietnam. Global results of (222)Rn concentrations indoors varied from <=6 to 145 Bq m(-3) averaging 46 +/ 26 Bq m(-3) (n = 37), with a median value of 47 Bq m(-3). This was similar to outdoor (222)Rn concentrations in the region, averaging 43 +/- 19 Bq m(-3) (n = 10), with a median value of 44 Bq m(-3). Indoor (222)Rn concentrations in the coastal town dwellings only were in average lower although not significantly different from indoor (222)Rn concentrations measured at the coal storage field near the harbor, 67 +/- 4 Bq m(-3) (n = 3). Furthermore, there was no significant difference in the average (222)Rn concentration in indoor air measured in the coastal towns region and those at the touristic Tuan Chau Island located about 45 km south of the coal mine, in the Ha Long Bay. The indoor (222)Rn concentration in a floating house at the Bai Tu Long Bay, and assumed as the best estimate of the baseline (222)Rn in surface air, was 27 +/- 3 Bq m(-3) (n = 3). Indoor average concentration of (222)Rn in dwellings at the Ha Noi city, inland and outside the coal mining area, was determined at 30 Bq m(-3). These results suggest that (222)Rn exhalation from the ground at the Nui Beo coal mining area may have contributed to generally increase (222)Rn concentration in the surface air of that region up to 1.7 times above the baseline value measured at the Bai Tu Long Bay and Ha Noi. The average indoor concentration of (222)Rn in Cam Pha-Ha Long area is about one-third of the value of the so-called Action Level set up by the US EPA of 148 Bq m(-3). Results suggest that there is no significant public health risk from (222)Rn exposure in the study region. PMID- 22445879 TI - Oxidative stress induced by crude venom from the jellyfish Pelagia noctiluca in neuronal-like differentiated SH-SY5Y cells. AB - Marine toxins are a suitable research model and their mechanism of action is intriguing and still under debate. Either a pore formation mechanism or oxidative stress phenomena may explain the damage induced by toxins. The effect of crude venom from isolated nematocysts of the jellyfish Pelagia noctiluca on neuronal like cells derived from human neuroblastoma SH-SY5Y has been here studied. To prove the possible oxidative stress events, cell viability, assessed by MTT quantitative colorimetric assay, intracellular reactive oxygen species (ROS) quantified by the non-fluorescent probe H2DCF-DA and changes in mitochondrial transmembrane potential (DeltaPsim) measured by the incorporation of a cationic fluorescent dye rhodamine-123 were verified on venom-treated cells (0.05 0.5MUg/ml doses). A dose- and time-dependent reduction of all parameters was observed after venom treatment. NAC (N-acetyl-cysteine), antioxidant applied before crude venom application, significantly counteracted the decrease in cell viability and ROS production, while DeltaPsim was only partially restored. The disruption of mitochondrial membrane by P. noctiluca crude venom may thus induce oxidative stress by inhibiting mitochondrial respiration and uncoupling oxidative phosphorylation, sensitizing mitochondria in SH-SY5H cells and facilitating membrane permeability. In sum, our findings suggest that P. noctiluca crude venom directly induces DeltaPsim collapse with further generation of ROS and add novel information to the understanding of such toxins, still not completely clarified. PMID- 22445880 TI - Inhibitory effects of oenanthotoxin analogues on GABAergic currents in cultured rat hippocampal neurons depend on the polyacetylenes' polarity. AB - Oenanthotoxin (OETX) and dihydro-OETX are polyacetylenic diols occurring in Oenanthe crocata and are known to exert proconvulsant effects. We have recently demonstrated that these compounds downregulated GABAergic currents (Appendino et al., 2009) and that OETX induced open channel block and allosterically modulated GABA(A) receptors (Wyrembek et al., 2010). O. crocata also contains several minor OETX analogues and in the present study we tested whether their effect on GABA(A) receptors depends on the compounds' polarity. We investigated a series of five polyacetylenes characterized by a higher lipophylicity than OETX, (1-acetyl-2,3 dihydrooenanthotoxin - X1, 14-acetyloenanthotoxin-X2, 1-deoxyoenanthotoxin - X3, 14-deoxyoenanthotoxin - X4, 14-dehydro-1-deoxyOETX - X5, polarity sequence: X1>X2>X3>X4>X5). Their effects were tested first on miniature inhibitory postsynaptic currents (mIPSCs). All but X3, significantly decreased the mIPSC amplitudes while X1, X2, X4 decreased, and X3 and X5 increased the mIPSC frequency. The lack of a clear correlation between the compounds' polarity and their effect on mIPSCs might result from their presynaptic effects. We thus considered their impact on current responses to exogenous GABA applications. Amplitude reduction of current responses was most prominent for X1 and virtually absent for X5 indicating a dependence on the compound's polarity. Only X1 and X2 showed open channel block, while the kinetics of currents were affected only by X1 which further supports a dependence of the drug's effects on their polarity. In conclusion, GABA(A) receptors are inhibited and allosterically modulated by naturally occurring OETX analogues (except X5) and these effects are positively correlated with the compounds' polarity. PMID- 22445881 TI - Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro. AB - An orphan G-protein-coupled receptor, T cell death-associated gene 8 (TDAG8) which has been reported to be a proton sensor, inhibits the production of pro inflammatory cytokines induced by extracellular acidification. Recently, we have found that TDAG8 knockout mice showed significant exacerbation in various immune mediated inflammation disease models. To elucidate the role of TDAG8, we screened an in-house library to find compounds which have a profile as a TDAG8 agonist using a cyclic adenosine 5'-monophosphate assay. Among the screening hits, we focused on (3-[(2,4-dichlorobenzyl)thio]-1,6-dimethyl-5,6-dihydro-1H pyridazino[4,5-e][1,3,4]thiadiazin-5-one) (named BTB09089). BTB09089 did not act on other proton sensing G-protein-coupled receptors such as G-protein-coupled receptor 4 (GPR4) nor ovarian cancer G-protein-coupled receptor 1 (OGR1). Moreover, BTB09089 increased cAMP level in the splenocytes from wild-type littermates but not from TDAG8-deficient mice. Thus, BTB09089 was found to be a TDAG8 specific agonist. We then investigated the effects of BTB09089 on T cells and macrophages in vitro. In splenocytes, BTB09089 suppressed the production of IL-2 stimulated with anti-CD3 and anti-CD28 antibodies. In peritoneal exuded macrophages induced by thioglycollate, BTB09089 suppressed the production of TNF alpha and IL-6 while it increased that of IL-10 when stimulated with lipopolysaccharide. These effects were observed in cells from wild type mice, but not those from TDAG8 knockout mice. These results indicate that activation of TDAG8 attenuates immune-mediated inflammation by regulating the cytokine production of T cells and macrophages. PMID- 22445882 TI - Effects of the histamine H1 receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward. AB - Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H1 receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction. PMID- 22445883 TI - Involvement of matrix metalloproteinase-9 in the development of morphine tolerance. AB - Matrix metalloproteinase-9 (MMP-9) is involved in tissue remodeling or neural plasticity in various clinical states (e.g. inflammation, neuropathic pain). We focused on the effect of MMP-9 on development of morphine tolerance after repeated morphine treatment. To develop morphine tolerance, mice were given morphine (10mg/kg; s.c.) once daily for 5 days. The antinociceptive effect of morphine was measured by the tail flick method. Development of morphine tolerance was significantly inhibited by daily treatment of the non-specific MMP inhibitor GM6001 (5 MUg/mouse, i.c.v.). A MMP-9 inhibitor (5 MUg/mouse, i.c.v.) partially, yet significantly, inhibited the development of morphine tolerance. Intrathecal treatment of a MMP-9 inhibitor did not affect morphine tolerance. In MMP-9((-/-)) mice, the development of morphine tolerance was partially, yet significantly, inhibited compared with wild-type mice. MMP-9 protein expression levels in the midbrain gradually increased 12h to 24h after morphine treatment on day 1, but were unchanged on days 3-5. In the spinal cord, MMP-9 protein expression levels were unchanged. In gelatin zymography analyses, MMP-9 activity in the midbrain gradually increased 12 to 24h after morphine treatment. Increment in MMP-9 activity in the midbrain was also observed on days 3-5. Our findings suggest that persistent MMP-9 activation observed after the transient increment in MMP-9 expression from the early phase of morphine treatment may contribute to the development of morphine tolerance. PMID- 22445884 TI - Structural and neurochemical plasticity in both supraoptic and paraventricular nuclei of hypothalamus of a desert rodent Meriones shawi after a severe dehydration versus opposite treatment by rehydration: GFAP and vasopressin immunohistochemical study. AB - Various lines of evidence indicate that astrocytes can undergo morphological changes that modify their relationship to adjacent neurons in response to physiological stimulation such as dehydration. Supraoptic (SON) and paraventricular (PVN) nuclei of hypothalamus represent obvious examples of activity-dependent neuro-astrocytic plasticity. In the present study, Meriones shawi is used as an animal model. Moreover, GFAP and vasopressin expressions are used as indicators successively of astrocytes and neuronal activations. In order to evaluate the reversibility of the neuro-astrocytic plasticity in SON and PVN, prolonged episode of water deprivation followed by episode of rehydration were examined. Hence, we studied the immunoreactivity in various hydration states: water ad libitum, dehydration, and rehydration of animals. Our results showed that dehydration of Meriones induced a significant decrease of GFAP immunoreactivity accompanied by a significant increase of AVP immunoreactivity, the latter concerns both cell bodies and fibers in the same hypothalamic nuclei SON and PVN. Conversely, rehydration of animals shows a reversible phenomenon leading a return of vasopressin and GFAP immunoreactivities to the control level. These results show that both astrocytes and vasopressin neurons display a remarkable structural and physiological plasticity, allowing to M. shawi, a great ability to support the hostile conditions in dry environment. PMID- 22445885 TI - Evaluation of the effects of treatment with sAPPalpha on functional and histological outcome following controlled cortical impact injury in mice. AB - Treatment with sAPPalpha, the product of non-amyloidogenic processing of the amyloid precursor protein (APP) has been shown to be protective following diffuse traumatic brain injury (TBI), by improving motor outcome and reducing axonal injury. However the effects of treatment with sAPPalpha following a focal TBI have yet to be determined. To investigate this, mice were subjected to a controlled cortical impact injury and treated with either sAPPalpha or its vehicle at 30 min post-injury. Following treatment with sAPPalpha the mice showed a significant improvement in motor and cognitive function early following injury, as determined on the ledged beam and Barnes Maze, respectively, relating to a more rapid rate of recovery. However the effect of treatment with sAPPalpha was not as dramatic as that seen previously following a diffuse injury. Nonetheless, these improvements in functional outcome were acompanied by a small but significant improvement in the amount of cortical and hippocampal at 7 days post injury, and provide further support for the efficacy of sAPPalpha as a potential neuroprotective agent following TBI. PMID- 22445886 TI - VEGF upregulates Homer 1a gene expression via the mitogen-activated protein kinase cascade in cultured cortex neurons. AB - In alternative splice variants of Homer 1 transcripts, Homer 1a messenger RNA (mRNA) has been shown to be upregulated selectively and rapidly by neural stimulation and represents a member of the immediate early gene (IEG) family. In our study, Homer 1 variants were expressed in cultured neurons as investigated by RT-PCR and Western blot analysis. After stimulation of VEGF, neurons selectively upregulated Homer 1a mRNA via Flk-1. The induction of Homer 1a mRNA peaked at 2h and sustained to 8h, while no significant change was observed of Homer 1b/c mRNA levels. Inhibitor analysis as well as Western blot analysis has indicated that the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade plays an important role in VEGF-stimulated induction of Homer 1a mRNA. These results demonstrate that MAPK is a key mediator that links distinct extracellular VEGF stimuli to the transcriptional activation of Homer 1a mRNA. PMID- 22445887 TI - Rodent functional and anatomical imaging of pain. AB - Human brain imaging has provided much information about pain processing and pain modulation, but brain imaging in rodents can provide information not attainable in human studies. First, the short lifespan of rats and mice, as well as the ability to have homogenous genetics and environments, allows for longitudinal studies of the effects of chronic pain on the brain. Second, brain imaging in animals allows for the testing of central actions of novel pharmacological and nonpharmacological analgesics before they can be tested in humans. The two most commonly used brain imaging methods in rodents are magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI provides better spatial and temporal resolution than PET, but PET allows for the imaging of neurotransmitters and non-neuronal cells, such as astrocytes, in addition to functional imaging. One problem with rodent brain imaging involves methods for keeping the subject still in the scanner. Both anesthetic agents and restraint techniques have potential confounds. Some PET methods allow for tracer uptake before the animal is anesthetized, but imaging a moving animal also has potential confounds. Despite the challenges associated with the various techniques, the 31 studies using either functional MRI or PET to image pain processing in rodents have yielded surprisingly consistent results, with brain regions commonly activated in human pain imaging studies (somatosensory cortex, cingulate cortex, thalamus) also being activated in the majority of these studies. Pharmacological imaging in rodents shows overlapping activation patterns with pain and opiate analgesics, similar to what is found in humans. Despite the many structural imaging studies in human chronic pain patients, only one study has been performed in rodents, but that study confirmed human findings of decreased cortical thickness associated with chronic pain. Future directions in rodent pain imaging include miniaturized PET for the freely moving animal, as well as new MRI techniques that enable ongoing chronic pain imaging. PMID- 22445889 TI - Knockdown of the sphingosine-1-phosphate receptor S1PR1 reduces pain behaviors induced by local inflammation of the rat sensory ganglion. AB - Sphingosine 1-phosphate (S1P) is a key immune mediator regulating migration of immune cells to sites of inflammation. S1P actions are mediated by a family of five G protein-coupled receptors. Sensory neurons express many of these receptors, and in vitro S1P has excitatory effects on small-diameter sensory neurons, many mediated by the S1P receptor 1 (S1PR1). This study investigated the role of S1P in regulating the sensitivity of DRG neurons. We found that in vivo perfusion of the normal L5 DRG with S1P increased mechanical sensitivity. Microelectrode recordings in isolated whole ganglia showed that large- and medium diameter cells, as well as small-diameter cells, increased firing in the presence of S1P. To further determine the role of S1PRs, we examined the effects of in vivo S1PR1 knockdown in the L4 and L5 sensory ganglia. Small interfering RNA directed against S1PR1 did not affect baseline mechanical sensitivity in normal animals, in which S1P levels are expected to be low. However, when the L5 ganglion was locally inflamed, a procedure that leads to rapid and sustained mechanical hypersensitivity, S1PR1 siRNA injected animals showed significantly less hypersensitivity than animals injected with scrambled siRNA. Reduced expression of S1PR1, but not S1PR2 or S1PR3, was confirmed with qPCR methods. The results indicate that the S1PR1 receptors in sensory ganglia cells may play an important role in regulating behavioral sensitivity during inflammation. PMID- 22445888 TI - The use of functional neuroimaging to evaluate psychological and other non pharmacological treatments for clinical pain. AB - A large number of studies have provided evidence for the efficacy of psychological and other non-pharmacological interventions in the treatment of chronic pain. While these methods are increasingly used to treat pain, remarkably few studies focused on the exploration of their neural correlates. The aim of this article was to review the findings from neuroimaging studies that evaluated the neural response to distraction-based techniques, cognitive behavioral therapy (CBT), clinical hypnosis, mental imagery, physical therapy/exercise, biofeedback, and mirror therapy. To date, the results from studies that used neuroimaging to evaluate these methods have not been conclusive and the experimental methods have been suboptimal for assessing clinical pain. Still, several different psychological and non-pharmacological treatment modalities were associated with increased pain-related activations of executive cognitive brain regions, such as the ventral- and dorsolateral prefrontal cortex. There was also evidence for decreased pain-related activations in afferent pain regions and limbic structures. If future studies will address the technical and methodological challenges of today's experiments, neuroimaging might have the potential of segregating the neural mechanisms of different treatment interventions and elucidate predictive and mediating factors for successful treatment outcomes. Evaluations of treatment-related brain changes (functional and structural) might also allow for sub-grouping of patients and help to develop individualized treatments. PMID- 22445890 TI - A novel vaccine combined with an alum adjuvant for porcine encephalomyocarditis virus (EMCV)-induced reproductive failure in pregnant sows. AB - To evaluate a novel vaccine for porcine encephalomyocarditis virus (EMCV), which causes reproductive failure in pregnant sows, virus like particles (VLPs) were generated and immunized twice in 2 week intervals before sow mating. Sows were divided into 4 groups (n=4, per group). Group 1 was immunized with the alum adjuvant alone, Group 2 with VLPs alone, Group 3 with VLPs mixed alum adjuvant, and Group 4 with a commercial killed vaccine. In Group 2, seroconversion was observed at very low levels, while in Group 3, neutralizing antibodies were maintained at a high level until 30 days after farrowing. Similar levels neutralizing antibodies were observed in Group 4. The gestation period of the pregnant sows was on average 115 days, and no injection site reaction or side effects were observed. The mean temperature of the sows after immunization increased temporarily to 38.7-39.1 degrees C for 1 day. The numbers and weights of surviving piglets were similar among the groups. These data describe a novel EMCV vaccine composed of VLPs mixed with an alum adjuvant that is safe to use during sow gestation and induces and maintains high levels of seroconversion. This vaccine could thus be a candidate for protecting against EMCV induced reproductive failure in pig farms. PMID- 22445891 TI - Expression of OsSPY and 14-3-3 genes involved in plant height variations of ion beam-induced KDML 105 rice mutants. AB - The culm length of two semidwarf rice mutants (PKOS1, HyKOS1) obtained from low energy N-ion beam bombardments of dehusked Thai jasmine rice (Oryza sativa L. cv. KDML 105) seeds showed 25.7% and 21.5% height reductions and one spindly rice mutant (TKOS4) showed 21.4% increase in comparison with that of the KDML 105 control. A cDNA-RAPD analysis identified differential gene expression in internode tissues of the rice mutants. Two genes identified from the cDNA-RAPD were OsSPY and 14-3-3, possibly associated with stem height variations of the semidwarf and spindly mutants, respectively. The OsSPY gene encoded the SPY protein which is considered to be a negative regulator of gibberellin (GA). On the other hand, the 14-3-3 encoded a signaling protein which can bind and prevent the RSG (repression of shoot growth) protein function as a transcriptional repressor of the kaurene oxidase (KO) gene in the GA biosynthetic pathway. Expression analysis of OsSPY, 14-3-3, RSG, KO, and SLR1 was confirmed in rice internode tissues during the reproductive stage of the plants by semi quantitative RT-PCR technique. The expression analysis showed a clear increase of the levels of OsSPY transcripts in PKOS1 and HyKOS1 tissue samples compared to that of the KDML 105 and TKOS4 samples at the age of 50-60 days which were at the ages of internode elongation. The 14-3-3 expression had the highest increase in the TKOS4 samples compared to those in KDML 105, PKOS1 and HyKOS1 samples. The expression analysis of RSG and KO showed an increase in TKOS4 samples compared to that of the KDML 105 and that of the two semidwarf mutants. These results indicate that changes of OsSPY and 14-3-3 expression could affect internode elongation and cause the phenotypic changes of semidwarf and spindly rice mutants, respectively. PMID- 22445892 TI - Can expectation enhance response to suggestion? De-automatization illuminates a conundrum. AB - Disparate theoretical viewpoints construe hypnotic suggestibility either as a stable trait, largely determined by underlying cognitive aptitude, or as a flexible skill amenable to attitudinal factors including beliefs and expectations. Circumscribed findings support both views. The present study attempted to consolidate these orthogonal perspectives through the lens of expectancy modification. We surreptitiously controlled light and sound stimuli to convince participants that they were responding strongly to hypnotic suggestions for visual and auditory hallucinations. Extending our previous findings, we indexed hypnotic suggestibility by de-automatizing an involuntary audiovisual phenomenon-the McGurk effect. Here we show that, regardless of expectancy modification, the experimental procedure led to heightened expectations concerning future hypnotic response. We found little effect of expectation, however, on actual response to suggestion. Our findings intimate that, at least in the present experimental context, expectation hardly correlates with--and is unlikely to be a primary determinant of--high hypnotic suggestibility. PMID- 22445893 TI - Thyroglobulin (Tg) activates MAPK pathway to induce thyroid cell growth in the absence of TSH, insulin and serum. AB - The growth of thyroid cells is tightly regulated by thyroid stimulating hormone (TSH) through the cyclic adenosine 3', 5'-monophosphate (cAMP) signaling pathway by potentiating the mitogenic activity of insulin and insulin-like growth factors (IGFs). However, we recently reported that thyroglobulin (Tg), a major product of the thyroid, also induces the growth of thyroid cells cultured in 0.2% serum in the absence of TSH and insulin. In this report, we demonstrate that Tg induced phosphorylation of molecules of the c-Raf/MEK/ERK pathway of the mitogen activated protein kinase (MAPK). The MEK-1/2 inhibitor PD98059 suppressed Tg induced phosphorylation of ERK1/2 and reduced bromodeoxyuridine (BrdU) incorporation. Tg also induced expression of the essential transcriptional factors c-Myc, c-Fos and c-Jun and phosphorylation of the retinoblastoma (Rb) protein. The present results, together with the previous report, suggest that Tg utilizes multiple signaling cascades to induce thyroid cell growth independent of TSH/cAMP stimulation. PMID- 22445894 TI - Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5. AB - Glucocorticoids may play a significant role in the etiology of neuropsychiatric illnesses. Abnormalities in plasma cortisol levels, glucocorticoid sensitivity, and HPA-axis function often accompany clinical symptoms of stress-related illnesses such as PTSD and depression. Of particular interest are genetic association studies that link single nucleotide polymorphisms of HPA-axis genes with illnesses only in the context of an early-life trauma exposure such as child abuse. These studies suggest that dysregulation of HPA-axis function can have lasting repercussions in shaping mood and anxiety, long after termination of the traumatic experience. As persistent glucocorticoid-induced loss of DNA methylation in FK506 binding protein 5 (Fkbp5) was previously observed in the hippocampus and blood and in the neuronal cell line HT-22, we asked whether these epigenetic alterations occur in non-neuronal, HPA-axis relevant cells. We used the pituitary adenoma cell line AtT-20 to demonstrate that the intronic enhancer region of Fkbp5 undergoes loss of DNA methylation in response to dexamethasone treatment in a dose-dependent manner. We also focused on the mouse hippocampal dentate gyrus to test whether these changes would be enriched in a region implicated in the HPA-axis stress response, neurogenesis, and synaptic plasticity. We observed an increase in enrichment of DNA methylation loss in the dentate gyrus, as compared to whole hippocampal tissues that were similarly treated with glucocorticoids. We then asked whether DNA methyltransferase 1 (Dnmt1), a methyltransferase enzyme involved in maintaining DNA methylation following cell division, is involved in the observed epigenetic alterations. We found a dose-dependent decrease of Dnmt1 expression in the AtT-20 cells following dexamethasone treatment, and a similar decrease in corticosterone-treated mouse hippocampus. Taken together, we provide evidence that these glucocorticoid induced epigenetic alterations have a broader validity in non-neuronal cells and that they may involve the DNA methylation machinery. PMID- 22445895 TI - Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF-like domain independent manner. AB - Amphiregulin (AREG), an EGF family protein, is synthesized as a type I transmembrane precursor (proAREG) and expressed on the cell surface with an extracellular EGF-like domain and an intracellular short cytoplasmic tail. The ectodomain shedding yields a soluble EGF receptor ligand (soluble AREG) which binds to EGF receptor (EGFR) and concomitantly induces migration of unshed proAREG from the plasma membrane to the nuclear envelope (NE). AREG is known to play a potential role in breast cancer and has been intensively investigated as an EGF receptor ligand, while the function of the NE-localized proAREG remains unknown. In this study we used a truncated mutant that mimics NE-localized proAREG without shedding stimuli to discriminate between the functions of NE localized and plasma membrane-localized proAREG and demonstrate that NE-localized proAREG activates breast cancer cell migration, but suppresses cell growth. Moreover, the present study shows that induction of cell migration by NE localized proAREG does not require the extracellular growth factor domain or EGF receptor function. Collectively these data demonstrate a novel function mediated by the intracellular domain of proAREG and suggest a significant role for NE localized proAREG in driving human breast cancer progression. PMID- 22445896 TI - "Stayin' alive": a novel mental metronome to maintain compression rates in simulated cardiac arrests. AB - BACKGROUND: A novel and yet untested memory aid has anecdotally been proposed for aiding practitioners in complying with American Heart Association (AHA) cardiopulmonary resuscitation (CPR) compression rate guidelines (at least 100 compressions per minute). OBJECTIVES: This study investigates how subjects using this memory aid adhered to current CPR guidelines in the short and long term. METHODS: A prospective observational study was conducted with medical providers certified in 2005 AHA guideline CPR. Subjects were randomly paired and alternated administering CPR compressions on a mannequin during a standardized cardiac arrest scenario. While performing compressions, subjects listened to a digital recording of the Bee Gees song "Stayin' Alive," and were asked to time compressions to the musical beat. After at least 5 weeks, the participants were retested without directly listening to the recorded music. Attitudinal views were gathered using a post-session questionnaire. RESULTS: Fifteen subjects (mean age 29.3 years, 66.7% resident physicians and 80% male) were enrolled. The mean compression rate during the primary assessment (with music) was 109.1, and during the secondary assessment (without music) the rate was 113.2. Mean CPR compression rates did not vary by training level, CPR experience, or time to secondary assessment. Subjects felt that utilizing the music improved their ability to provide CPR and they felt more confident in performing CPR. CONCLUSIONS: Medical providers trained to use a novel musical memory aid effectively maintained AHA guideline CPR compression rates initially and in long-term follow-up. Subjects felt that the aid improved their technical abilities and confidence in providing CPR. PMID- 22445897 TI - Cannabinoid receptors activation and glucocorticoid receptors deactivation in the amygdala prevent the stress-induced enhancement of a negative learning experience. AB - The enhancement of emotional memory is clearly important as emotional stimuli are generally more significant than neutral stimuli for surviving and reproduction purposes. Yet, the enhancement of a negative emotional memory following exposure to stress may result in dysfunctional or intrusive memory that underlies several psychiatric disorders. Here we examined the effects of stress exposure on a negative emotional learning experience as measured by a decrease in the magnitude of the expected quantity of reinforcements in an alley maze. In contrast to other fear-related negative experiences, reward reduction is more associated with frustration and is assessed by measuring the latency to run the length of the alley to consume the reduced quantity of reward. We also examined whether the cannabinoid receptors agonist WIN55,212-2 (5 MUg/side) and the glucocorticoid receptors (GRs) antagonist RU-486 (10 ng/side) administered into the rat basolateral amygdala (BLA) could prevent the stress-induced enhancement. We found that intra-BLA RU-486 or WIN55,212 before stress exposure prevented the stress induced enhancement of memory consolidation for reduction in reward magnitude. These findings suggest that cannabinoid receptors and GRs in the BLA are important modulators of stress-induced enhancement of emotional memory. PMID- 22445898 TI - c-Fos expression reveals aberrant neural network activity during cued fear conditioning in APPswe transgenic mice. AB - The neural circuitry underlying emotional learning and memory is known to involve both the amygdala and hippocampus. Both of these structures undergo anatomical and functional changes during the course of Alzheimer's disease. The present study used expression of the immediate early gene c-Fos to examine the effect of amyloid-induced synaptic pathology on neural activity in the hippocampus and amygdala immediately following Pavlovian fear conditioning. Tg2576 mice underwent cued fear conditioning and the regional interdependencies of c-Fos expression in the hippocampus and the amygdala were assessed using structural equation modelling. Tg2576 mice displayed normal acquisition of conditioned freezing to a punctate auditory cue paired with shock. However, the analysis of c-Fos expression indicated abnormal regional activity in the hippocampal dentate gyrus of Tg2576 mice. Structural equation modelling also supported the view that activity within the amygdala was independent of hippocampal activity in Tg2576 mice (unlike control mice) and regional interaction between the dentate gyrus and CA3 region was disrupted. The results provide novel insight into the effects of excess amyloid production on brain region interdependencies underpinning emotional learning. PMID- 22445899 TI - Leptin, adiponectin and pulmonary diseases. AB - Adipose tissue produces leptin and adiponectin - energy-regulating adipokines that may also play a role in inflammatory pulmonary conditions, as suggested by some murine studies. Leptin and adiponectin and their respective receptors are expressed in the human lung. The association between systemic or airway leptin and asthma in humans is currently controversial, particularly among adults. The majority of the evidence among children however suggests that systemic leptin may be associated with greater asthma prevalence and severity, particularly among prepubertal boys and peripubertal/postpubertal girls. Systemic and airway leptin concentrations may also be disproportionately higher in chronic obstructive pulmonary disease (COPD) patients, particularly among women, and reflect greater airway inflammation and disease severity. Quite like leptin, the association between systemic and airway adiponectin and asthma in humans is also controversial. Some but not all studies, demonstrate that serum adiponectin concentrations are protective against asthma among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are inversely associated with asthma severity among boys but positively associated among men. Further, systemic and airway adiponectin concentrations are higher in COPD patients than controls, as demonstrated by case-control studies of men. Systemic adiponectin is also positively associated with lung function in healthy adults but inversely associated with lung function in subjects with COPD. It is therefore possible that pro-inflammatory effects of adiponectin dominate under certain physiologic conditions and anti-inflammatory effects under others. The adipokine-lung disease literature has critical gaps that include a lack of adequately powered longitudinal or weight-intervention studies; inadequate adjustment for confounding effect of obesity; and unclear understanding of potential sex interactions. It is also uncertain whether adipokine derangements precede pulmonary disease or are a consequence of it. Future research will determine whether modulation of adipokines, independent of BMI, may allow novel ways to prevent or treat inflammatory pulmonary conditions. PMID- 22445900 TI - Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies. AB - Cornea transplantation is one of the most performed graft procedures worldwide with an impressive success rate of 90%. However, for "high-risk" patients with particular ocular diseases in addition to the required surgery, the success rate is drastically reduced to 50%. In these cases, cyclosporin A (CsA) is frequently used to prevent the cornea rejection by a systemic treatment with possible systemic side effects for the patients. To overcome these problems, it is a challenge to prepare well-tolerated topical CsA formulations. Normally high amounts of oils or surfactants are needed for the solubilization of the very hydrophobic CsA. Furthermore, it is in general difficult to obtain ocular therapeutic drug levels with topical instillations due to the corneal barriers that efficiently protect the intraocular structures from foreign substances thus also from drugs. The aim of this study was to investigate in vivo the effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. An established rat model for the prevention of cornea graft rejection after a keratoplasty procedure was used. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared to a physiological saline solution and to a systemic administration of CsA. In our studies, the topical CsA treatment was carried out for 14 days, and the three parameters (a) cornea transparency, (b) edema, and (c) neovascularization were evaluated by clinical observation and scoring. Compared to the control group, the treated group showed a significant higher cornea transparency and significant lower edema after 7 and 13 days of the surgery. At the end point of the study, the neovascularization was reduced by 50% in the CsA-micelle treated animals. The success rate of cornea graft transplantation was 73% in treated animals against 25% for the control group. This result was as good as observed for a systemic CsA treatment in the same animal model. This new formulation has the same efficacy like a systemic treatment but without the serious CsA systemic side effects. Ocular drug levels of transplanted and healthy rat eyes were dosed by UPLC/MS and showed a high CsA value in the cornea (11710 +/- 7530 ng(CsA)/g(tissue) and 6470 +/- 1730 ng(CsA)/g(tissue), respectively). In conclusion, the applied formulation has the capacity to overcome the ocular surface barriers, the micelles formed a drug reservoir in the cornea from, where a sustained release of CsA can take place. This novel formulation for topical application of CsA is clearly an effective and well-tolerated alternative to the systemic treatment for the prevention of corneal graft rejection. PMID- 22445901 TI - Risk factors for perinatal arterial ischaemic stroke in full-term infants: a case control study. AB - OBJECTIVE: The incidence of perinatal arterial ischaemic stroke (PAIS) is about 1 in 2300 live births. Evidence about the aetiology is still lacking. The aim of this study was to identify maternal, perinatal and neonatal risk factors for symptomatic PAIS in full-term infants. METHODS: Each full-term infant with PAIS was matched to three healthy controls for gestational age, date of birth and hospital of birth. Antenatal and perinatal risk factors were studied using univariate and multivariate conditional logistic regression analysis. RESULTS: Fifty-two infants were diagnosed with PAIS. Significant risk factors in the univariate analysis (p<0.05) were nulliparity (64% vs 47%), maternal fever (>38 degrees C) during delivery (10% vs 1%), fetal heart rate decelerations (63% vs 16%), meconium-stained amniotic fluid (44% vs 17%), emergency caesarean section (35 vs 2%), Apgar score (1 min) <=3 (29% vs 1%), Apgar score (5 min) <7 (25% vs 1%), umbilical artery pH <7.10 (56% vs 10%), hypoglycaemia <2.0 mmol/l (29% vs 3%) and early-onset sepsis/meningitis (14% vs 2%). In the multivariate analysis, maternal fever (OR 10.2; 95% CI 1.3 to 78.5), Apgar score (5 min) <7 (OR 18.1; 95% CI 3.4 to 96.8), hypoglycaemia <2.0 mmol/l (OR 13.0; 95% CI 3.2 to 52.6) and early-onset sepsis/meningitis (OR 5.8; 95% CI 1.1 to 31.9) were significantly associated with PAIS. CONCLUSIONS: Maternal fever during delivery and early-onset sepsis/meningitis were found to be involved with PAIS as was previously noted. Apgar score (5 min) <7 and hypoglycaemia were found to be important risk factors in term PAIS. PMID- 22445902 TI - Using Tablet for visual exploration of second-generation sequencing data. AB - The advent of second-generation sequencing (2GS) has provided a range of significant new challenges for the visualization of sequence assemblies. These include the large volume of data being generated, short-read lengths and different data types and data formats associated with the diversity of new sequencing technologies. This article illustrates how Tablet-a high-performance graphical viewer for visualization of 2GS assemblies and read mappings-plays an important role in the analysis of these data. We present Tablet, and through a selection of use cases, demonstrate its value in quality assurance and scientific discovery, through features such as whole-reference coverage overviews, variant highlighting, paired-end read mark-up, GFF3-based feature tracks and protein translations. We discuss the computing and visualization techniques utilized to provide a rich and responsive graphical environment that enables users to view a range of file formats with ease. Tablet installers can be freely downloaded from http://bioinf.hutton.ac.uk/tablet in 32 or 64-bit versions for Windows, OS X, Linux or Solaris. For further details on the Tablet, contact tablet@hutton.ac.uk. PMID- 22445903 TI - Data mining the human gut microbiota for therapeutic targets. AB - It is well known that microbes have an intricate role in human health and disease. However, targeted strategies for modulating human health through the modification of either human-associated microbial communities or associated human host targets have yet to be realized. New knowledge about the role of microbial communities in the microbiota of the gastrointestinal tract (GIT) and their collective genomes, the GIT microbiome, in chronic diseases opens new opportunities for therapeutic interventions. GIT microbiota participation in drug metabolism is a further pharmaceutical consideration. In this review, we discuss how computational methods could lead to a systems-level understanding of the global physiology of the host-microbiota superorganism in health and disease. Such knowledge will provide a platform for the identification and development of new therapeutic strategies for chronic diseases possibly involving microbial as well as human-host targets that improve upon existing probiotics, prebiotics or antibiotics. In addition, integrative bioinformatics analysis will further our understanding of the microbial biotransformation of exogenous compounds or xenobiotics, which could lead to safer and more efficacious drugs. PMID- 22445904 TI - [Summary of the consensus document: "Clinical practice guide for the management of low cardiac output syndrome in the postoperative period of heart surgery"]. AB - Low cardiac output syndrome is a potential complication in cardiac surgery patients and is associated with increased morbidity and mortality. This guide provides recommendations for the management of these patients, immediately after surgery and following admission to the ICU. The recommendations are grouped into different sections, addressing from the most basic concepts such as definition of the disorder to the different sections of basic and advanced monitoring, and culminating with the complex management of this syndrome. We propose an algorithm for initial management, as well as two others for ventricular failure (predominantly left or right). Most of the recommendations are based on expert consensus, due to the lack of randomized trials of adequate design and sample size in patients of this kind. The quality of evidence and strength of the recommendations were based on the GRADE methodology. The guide is presented as a list of recommendations (with the level of evidence for each recommendation) for each question on the selected topic. For each question, justification of the recommendations is then provided. PMID- 22445905 TI - [Clinical practice guide for the management of low cardiac output syndrome in the postoperative period of heart surgery]. AB - The low cardiac output syndrome is a potential complication in cardiac surgery patients and associated with increased morbidity and mortality. This guide is to provide recommendations for the management of these patients, immediately after surgery, admitted to the ICU. The recommendations are grouped into different sections, trying to answer from the most basic concepts such as the definition to the different sections of basic and advanced monitoring and ending with the complex management of this syndrome. We propose an algorithm for initial management, as well as two other for ventricular failure (predominantly left or right). Most of the recommendations are based on expert consensus because of the lack of randomized trials of adequate design and sample size in this group of patients. The quality of evidence and strength of the recommendations were made following the GRADE methodology. The guide is presented as a list of recommendations (and level of evidence for each recommendation) for each question on the selected topic. Then for each question, we proceed to the justification of the recommendations. PMID- 22445906 TI - Naturally acquired antibodies to Plasmodium vivax blood-stage vaccine candidates (PvMSP-119 and PvMSP-3alpha359-798 and their relationship with hematological features in malaria patients from the Brazilian Amazon. AB - An important step when designing a vaccine is identifying the antigens that function as targets of naturally acquired antibodies. We investigated specific antibody responses against two Plasmodium vivax vaccine candidates, PvMSP-119 and PvMSP-3alpha359-798. Moreover, we assessed the relationship between these antibodies and morbidity parameters. PvMSP-119 was the most immunogenic antigen and the frequency of responders to this protein tended to increase in P. vivax patients with higher parasitemia. For both antigens, IgG antibody responses tended to be lower in patients who had experienced their first bout of malaria. Furthermore, anemic patients presented higher IgG antibody responses to PvMSP 3alpha359-798. Since the humoral response involves a number of antibodies acting simultaneously on different targets, we performed a Principal Component Analysis (PCA). Anemic patients had, on average, higher first principal component scores (IgG1/IgG2/IgG3/IgG4 anti-MSP3alpha), which were negatively correlated with hemoglobin levels. Since antibodies against PfMSP-3 have been strongly associated with clinical protection, we cannot exclude the possibility of a dual role of PvMSP-3 specific antibodies in both immunity and pathogenesis of vivax malaria. Our results confirm the high immunogenicity of the conserved C terminus of PvMSP 1 and points to the considerable immunogenicity of polymorphic PvMSP-3alpha359 798 during natural infection. PMID- 22445907 TI - Featuring the special issue editor: associate professor Alexandros G. Georgakilas. AB - In this 'Featuring the editor' article, we introduce Assoc. Professor Alexandros G. Georgakilas as the guest editor for this Special Issue of Cancer Letters. His main research, educational and editorial achievements in his academic career are presented with emphasis on the various milestones of his involvement in science for more than twenty years. His primary interests in research focus on various radiation and cancer biology aspects especially the involvement of clustered DNA lesions in carcinogenesis. PMID- 22445908 TI - Pancreatic cancer stem cells: emerging target for designing novel therapy. AB - In the past few years, there have been significant advances in the research on cancer stem cells (CSCs). The emerging evidences have demonstrated that CSCs and epithelial-mesenchymal transition (EMT)-type cells, which share molecular characteristics with CSCs, play critical roles in drug resistance, invasion, and metastasis. Pancreatic cancer (PC) has a high mortality due to both intrinsic (de novo) and extrinsic (acquired) drug resistance, leading to increased invasive and metastatic potential of PC cells. Therefore, targeting pancreatic CSCs and EMT type cells could be a novel therapeutic strategy for the treatment of PC. In this article, we will review the current state of our knowledge on the role of pancreatic CSCs and EMT-type cells, and summarize the novel therapeutic strategies that could target pancreatic CSCs and EMT-type cells, leading to the reversal of EMT phenotype, the induction of drug sensitivity, and the inhibition of invasion and metastasis of PC, which is expected to yield better treatment outcome. PMID- 22445909 TI - Human breast and melanoma cancer stem cells biomarkers. AB - Cancer progression in humans is difficult to infer because we do not routinely sample patients at multiple stages of their disease. The identification cancer stem cell (CSC) subpopulations inside tumor opens a new view of cancer development, since it implies that tumors can only be eradicated by targeting CSCs. Several markers have been proposed in the literature to identify CSCs both in breast and melanoma but no consensus has been reached, leading to the hypothesis that the CSC phenotype might be dynamically switched. Herein we provide a critical discussion of the biological markers described in the literature for breast cancer and melanoma. Due to its complexity the field would benefit from an interdisciplinary approach to investigate tumor heterogeneity and its progression. Similar considerations could also be relevant for normal tissue stem cells. PMID- 22445910 TI - Fibrinoid reaction after lens extraction in rabbit eyes. AB - PURPOSE: To measure the inflammatory reaction in the anterior chamber after lens extraction in a rabbit model and to evaluate the effect of nonsteroidal antiinflammatory drugs (NSAIDs) or steroids on the amount of inflammation as measured by fibrinogen levels in the aqueous humor. SETTING: Animal laboratory, Goldschleger Research Institute, Tel Aviv University, Sheba Medical Center, Ramat Gan, Israel. DESIGN: Experimental study. MATERIALS: Twenty-six eyes of New Zealand white rabbits had lens extraction surgery. One day later, aqueous humor (~0.1 mL) was withdrawn from the anterior chamber and examined for fibrinogen concentration. Control rabbits received no treatment (9 eyes) or artificial tear eyedrops (5 eyes). One study group received NSAID drops (diclofenac) (6 eyes), and another study group received steroid drops (dexamethasone-neomycin) (6 eyes). All rabbits were treated hourly for 9 applications. Aqueous humor (~0.1 mL) was withdrawn from the anterior chamber and examined for fibrinogen concentration 1 day later. Fibrinogen levels were also measured in the aqueous in 8 unoperated eyes. RESULTS: Steroid-treated eyes achieved the lowest inflammatory score, followed by NSAID eyes, artificial tears eyes, and untreated eyes. The mean fibrinogen concentrations in the aqueous humor were 69.1 mg% untreated, 52.0 mg% artificial tears, 18.5 mg% NSAIDs, and 2.8 mg% steroids (P=.002). CONCLUSIONS: Measurement of aqueous fibrinogen after lens extraction surgery in a rabbit animal model was simple and provided a useful parameter for precise evaluation of postoperative intraocular reaction. Steroids and NSAIDs were effective in reducing postoperative inflammation. Steroids reduced inflammation to almost undetectable values. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22445911 TI - Bioengineering and management for efficient phosphorus utilization in crops and pastures. AB - Phosphorus (P) is one of the three macronutrients for plants. Because of its low mobility and high fixation in soils, low P availability is a worldwide constraint for crop productivity. Molecular biology provides great opportunities to improve P efficiency in plants. However, transgenic plants cannot be commercialized before integrating all the knowledge on bottlenecks for improving P efficiency of crops/pastures. This review intends to summarize the main strategies of bioengineering to improve P efficiency of crops/pastures, including conventional and molecular assisted breeding, identification and application of key genes for biotech plants. It highlights recent advances in the understanding of improving P efficiency through the integration of bioengineering with P fertilization and cultivation management. PMID- 22445912 TI - Longitudinal stent deformation: quantitative coronary angiographic analysis from the PERSEUS and PLATINUM randomised controlled clinical trials. AB - AIMS: Recent reports have suggested susceptibility of novel thin-strut coronary stents to incur longitudinal stent deformation during or following deployment. This analysis assesses the incidence of longitudinal stent deformation in three stent platforms. METHODS AND RESULTS: Quantitative angiographic analysis (QCA) of 2,403 stents from the PERSEUS Workhorse (WH) and PLATINUM-WH trials was performed by an independent core laboratory. The distribution of QCA measured: nominal stent length ratios was compared between platforms to evaluate longitudinal stent deformation. Stent length ratio averaged 0.95 +/- 0.07 in the TAXUS Express arm and 0.94 +/- 0.06 in the ION (TAXUS Element) arm of the PERSEUS-WH trial (p=0.16). In the PLATINUM-WH trial, the mean ratio in the PROMUS cohort was slightly smaller (0.92 +/- 0.09) than PROMUS Element (0.94 +/- 0.08; p=0.004). Manual, blinded re-examination by the core laboratory of the angiograms corresponding to the 20 lowest and highest ratios in each trial did not identify any cases of stent deformation. CONCLUSIONS: Systematic analysis by an independent angiographic core laboratory of 2,403 stents implanted in patients enrolled in two large multicentre randomised trials demonstrated no stent deformation or meaningful differences in stent length ratios between ION and TAXUS Express or between PROMUS Element and PROMUS in the patient populations studied using the methodology employed. PMID- 22445913 TI - Detection of Escherichia coli O157:H7 and Salmonella in ground beef by a bead free quantum dot-facilitated isolation method. AB - The aims of this study were to introduce a new immunological bead-free cell detection method using quantum dots (QDs) as reporter markers for foodborne pathogen detection. QDs are nanosized particles with long-term photostability, high quantum yield, broad absorption spectra, and narrow, symmetric emission and high signal-to-noise ratio. The chemical compound [(1-ethyl-3-3 dimethylaminopropyl) carbodiimide hydrochloride] (EDC) and protein A were used as crosslinkers for manufacturing QD-antibody conjugates. To minimize the inhibition of QD fluorescence by the magnetic beads, the beads were removed after the primary pathogen isolation and before fluorescence measurement. Detection signals were increased four-fold after employing the bead-free isolation method. With a 24-h enrichment, the bead-free QD-facilitated detection method was able to detect 10 CFU/g Escherichia coli O157:H7 and Salmonella from artificially contaminated ground beef. To our knowledge, this detection method is the first research that combined a new EDC-protein A QD-labeling technique and bead-free fluorescence measurement to detect E. coli O157:H7 and Salmonella in ground beef. PMID- 22445914 TI - Characterization and evaluation of the spoilage potential of Lactococcus piscium isolates from modified atmosphere packaged meat. AB - A total of 222 psychrotrophic lactococci isolated from use-by day, modified atmosphere packaged (MAP) meat were identified to the species level by numerical analyses of EcoRI and ClaI ribopatterns and phylogenetic sequence analyses of 16S, rpoA and pheS genes. In addition, their meat spoilage potential was studied. The majority of the isolates (n=215) were identified as Lactococcus piscium, while seven isolates belonged to Lactococcus raffinolactis. L. piscium was shown to be adapted to growing in a variety of MAP meat products including broiler, turkey, pork, and minced meat from beef and pork, where they belonged to the predominating microbiota at the end of the storage. Numerical analyses of EcoRI and ClaI ribopatterns, and phylogenetic sequence analyses of rpoA and pheS genes were shown to be reliable tools in species level identification of meat lactococci. The spoilage potential of L. piscium was evaluated by inoculating representative isolates to MAP pork stored at 6 degrees C for 22 days. Development of spoilage population was monitored using a culture-independent T RFLP approach. The sensory shelf life of pork inoculated with L. piscium was shortened compared to the uninoculated control. Alongside with the inoculated L. piscium isolates, Leuconostoc spp. present as initial contaminants in the samples thrived. This shows that even though lactococci were inoculated at higher levels compared to the natural microbiota, they did not occupy the niche and prevent the growth of other lactic acid bacteria. PMID- 22445915 TI - Speech-in-noise perception deficit in adults with dyslexia: effects of background type and listening configuration. AB - Developmental dyslexia is associated with impaired speech-in-noise perception. The goal of the present research was to further characterize this deficit in dyslexic adults. In order to specify the mechanisms and processing strategies used by adults with dyslexia during speech-in-noise perception, we explored the influence of background type, presenting single target-words against backgrounds made of cocktail party sounds, modulated speech-derived noise or stationary noise. We also evaluated the effect of three listening configurations differing in terms of the amount of spatial processing required. In a monaural condition, signal and noise were presented to the same ear while in a dichotic situation, target and concurrent sound were presented to two different ears, finally in a spatialised configuration, target and competing signals were presented as if they originated from slightly differing positions in the auditory scene. Our results confirm the presence of a speech-in-noise perception deficit in dyslexic adults, in particular when the competing signal is also speech, and when both signals are presented to the same ear, an observation potentially relating to phonological accounts of dyslexia. However, adult dyslexics demonstrated better levels of spatial release of masking than normal reading controls when the background was speech, suggesting that they are well able to rely on denoising strategies based on spatial auditory scene analysis strategies. PMID- 22445916 TI - Assessment of articular cartilage repair tissue after matrix-associated autologous chondrocyte transplantation or the microfracture technique in the ankle joint using diffusion-weighted imaging at 3 Tesla. AB - OBJECTIVE: The objective was to compare patients after matrix-associated autologous chondrocyte transplantation (MACT) and microfracture therapy (MFX) of the talus using diffusion-weighted imaging (DWI), with morphological and clinical scoring. MATERIALS AND METHODS: Twenty patients treated with MACT or MFX (10 per group) were examined using 3 T magnetic resonance imaging (MRI) at 48 +/- 21.5 and 59.6 +/- 23 months after surgery, respectively. For comparability, patients from each group were matched by age, body mass index, and follow-up. American Orthopaedic Foot and Ankle Society (AOFAS) score served as clinical assessment tool pre- and postoperatively. DWI was obtained using a partially balanced, steady-state gradient echo pulse sequence, as well as the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, based on a 2D proton density-weighted turbo spin-echo sequence and a 3D isotropic true fast imaging with steady-state precession sequence. Semi-quantitative diffusion quotients were calculated after region of interest analysis of repair tissue (RT) and healthy control cartilage, and compared among both groups. RESULTS: The mean AOFAS score improved significantly (P = 0.001) for both groups (MACT: 48.8 +/- 20.4-83.6 +/- 9.7; MFX: 44.3 +/- 16.5-77.6 +/- 13.2). No differences in the AOFAS (P = 0.327) and MOCART (P = 0.720) score were observed between MACT and MFX postoperatively. DWI distinguished between healthy cartilage and cartilage RT in the MFX group (P = 0.016), but not after MACT treatment (P = 0.105). Significant correlations were found between MOCART score and DWI index after MFX (Pearson: -0.648; P = 0.043), and between the diffusivity and longer follow-up interval in MACT group (Pearson: -0.647, P = 0.043). CONCLUSION: Whereas conventional scores reveal a similar outcome after MACT or MFX treatment in the ankle joint, DWI was able to distinguish between different RT qualities, as reported histologically for these diverse surgical procedures. PMID- 22445917 TI - CT arthrography of the human knee to measure cartilage quality with low radiation dose. AB - OBJECTIVE: Recently, CT arthrography (CTa) was introduced as a non-destructive technique to quantitatively measure cartilage quality in human knees. This study investigated whether this is also possible using lower radiation dose CT protocols. Furthermore, we studied the ability of (lower radiation) CTa to distinguish between local sulphated glycosaminoglycan (sGAG) content differences. DESIGN: Of ten human cadaveric knee joints, six CT scans using different radiation doses (81.33-8.13 mGy) were acquired after intra-articular ioxaglate injection. The capability of CTa to measure overall cartilage quality was determined in seven anatomical regions of interest (ROIs), using equilibrium partitioning of an ionic contrast agent using (EPIC)-microCT (MUCT) as reference standard for sGAG content. To test the capability of CTa to spatially distinguish between local differences in sGAG content, we calculated the percentage of pixels incorrectly predicted as having high or low sGAG content by the different CTa protocols. RESULTS: Low radiation dose CTa correlated well with EPIC-MUCT in large ROIs (R = 0.78; R(2) = 0.61; P < 0.0001). CTa can also distinguish between high and low sGAG content within a single slice. However, the percentage of incorrectly predicted quality pixels increases (from 35% to 41%) when less radiation is used. This makes is hard or even impossible to differentiate between spatial differences in sGAG content in the lowest radiation scans. CONCLUSIONS: CTa acquired using low radiation exposure, comparable to a regular knee CT, is able to measure overall cartilage quality. Spatial sGAG distribution can also be determined using CTa, however for this purpose a higher radiation dose is necessary. Nevertheless, radiation dose reduction makes CTa suitable for quantitative analysis of cartilage in clinical research. PMID- 22445918 TI - The effects of radial oxygen loss on arsenic tolerance and uptake in rice and on its rhizosphere. AB - Understanding the complex biotic and abiotic interactions invoked by the rice root system in oxygen-depleted soil is an important step in screening genotypes for low toxic metal or metalloid accumulation. A hydroponic and a rhizobox experiment have been conducted to explore the effects of varying root oxygen release on chemical changes, As fractionation in rhizosphere soil and Fe plaque formation, As uptake and tolerance by different rice genotypes. The results showed that rice genotypes with higher rates of radial oxygen loss (ROL) and at the bolting stage, tended to have greater effects on rhizosphere Eh, pH, Fe(3+)/Fe(2+) quotients, As fractionation and mobility and also on Fe plaque formation compared to those with lower ROL and at the tillering stage. Genotypes with higher ROL have a strong ability to reduce As accumulation in shoots and increase As tolerance by reducing As mobilization in the rhizosphere and by limiting As translocation. PMID- 22445919 TI - Predicting the risk of arsenic contaminated groundwater in Shanxi Province, Northern China. AB - Shanxi Province is one of the regions in northern China where endemic arsenicosis occurs. In this study, stepwise logistic regression was applied to analyze the statistical relationships of a dataset of arsenic (As) concentrations in groundwaters with some environmental explanatory parameters. Finally, a 2D spatial model showing the potential As-affected areas in this province was created. We identified topography, gravity, hydrologic parameters and remote sensing information as explanatory variables with high potential to predict high As risk areas. The model identifies correctly the already known endemic areas of arsenism. We estimate that the area at risk exceeding 10 MUg L(-1) As occupies approximately 8,100 km(2) in 30 counties in the province. PMID- 22445920 TI - How healthy is urban horticulture in high traffic areas? Trace metal concentrations in vegetable crops from plantings within inner city neighbourhoods in Berlin, Germany. AB - Food production by urban dwellers is of growing importance in developing and developed countries. Urban horticulture is associated with health risks as crops in urban settings are generally exposed to higher levels of pollutants than those in rural areas. We determined the concentration of trace metals in the biomass of different horticultural crops grown in the inner city of Berlin, Germany, and analysed how the local setting shaped the concentration patterns. We revealed significant differences in trace metal concentrations depending on local traffic, crop species, planting style and building structures, but not on vegetable type. Higher overall traffic burden increased trace metal content in the biomass. The presence of buildings and large masses of vegetation as barriers between crops and roads reduced trace metal content in the biomass. Based on this we discuss consequences for urban horticulture, risk assessment, and planting and monitoring guidelines for cultivation and consumption of crops. PMID- 22445921 TI - Bioaccumulation of cadmium bound to ferric hydroxide and particulate organic matter by the bivalve M. meretrix. AB - Ferric hydroxide and particulate organic matter are important pools of trace metals in sediments and control their accumulation by benthic animals. We investigated bioaccumulation of cadmium in bivalve Meretrix meretrix by using a simplified system of laboratory synthesized iron oxides and commercially obtained humic acids to represent the inorganic and organic matrix found in nature. The results showed that bioaccumulation characteristics were distinctly different for these two substrates. Bioaccumulation from ferric hydroxide was not observed at 70 and 140 mg/kg, while the clams started to absorb Cd at 140 mg/kg from organic matter and the bioaccumulation rate was faster than that from ferric hydroxide. Within 28 d, accumulation of Cd from organic matter appeared to reach a steady state after rising to a certain level, while absorption from ferric hydroxide appeared to follow a linear profile. The findings have implications about the assimilation of trace metals from sediments by benthic animals. PMID- 22445922 TI - Levels, isomer profiles and chiral signatures of particle-bound hexabromocyclododecanes in ambient air around Shanghai, China. AB - Hexabromocyclododecanes (HBCDs) have been considered candidate persistent organic pollutants, however, environmental data on their presence in China, a major world market, are limited. In this study, airborne particle-bound HBCDs in Shanghai, China were quantified with liquid chromatography-tandem mass spectrometry, and their total concentrations varied from 3.21 to 123 pg/m(3). The industrial area showed about three times higher HBCD levels than the urban areas. Gamma-HBCD dominated in particle-associated HBCDs in the industrial area, while alpha-HBCD was the major diastereomer of the urban areas, which is quite different from the pattern of technical products. Besides alpha-, beta- and gamma-HBCDs, delta-HBCD was also detected in all samples (0.09-6.31 pg/m(3)), while no E-HBCD was found. Airborne beta- and gamma-HBCDs were racemic in most studied areas due to their chiral signatures showing no significant difference from commercial mixture. Fractions of (+)-alpha-HBCD (0.417-0.467), however, suggested the enrichment of ( )-alpha-HBCD and the involvement of enantioselective bioprocesses. PMID- 22445923 TI - Updated stomatal flux and flux-effect models for wheat for quantifying effects of ozone on grain yield, grain mass and protein yield. AB - Field measurements and open-top chamber experiments using nine current European winter wheat cultivars provided a data set that was used to revise and improve the parameterisation of a stomatal conductance model for wheat, including a revised value for maximum stomatal conductance and new functions for phenology and soil moisture. For the calculation of stomatal conductance for ozone a diffusivity ratio between O(3) and H(2)O in air of 0.663 was applied, based on a critical review of the literature. By applying the improved parameterisation for stomatal conductance, new flux-effect relationships for grain yield, grain mass and protein yield were developed for use in ozone risk assessments including effects on food security. An example of application of the flux model at the local scale in Germany shows that negative effects of ozone on wheat grain yield were likely each year and on protein yield in most years since the mid 1980s. PMID- 22445924 TI - A novel model of intimal hyperplasia with graded hypoosmotic damage. AB - BACKGROUND: The purpose was to develop a rabbit model of intimal hyperplasia with controllable lesion. METHODS: Following 1 week of a 2% cholesterol diet, 32 New Zealand White male rabbits underwent right femoral arteries surgical perfusion with distilled water for 1, 3, 5, or 7 min (n=8/group). After a further 4 weeks of the same diet, serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein were measured in all rabbits. Intimal hyperplasia in histological sections of arteries were assessed by intimal proliferation ratio. Macrophage numbers and levels of proteins matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 2, and alpha smooth muscle actin in lesions were analyzed by immunohistochemistry. RESULTS: Serum lipids levels showed no statistical difference between experimental groups. Intimal proliferation ratio increased gradually with perfusion time, and a positive linear correlation was calculated between intimal proliferation ratio and duration of distilled water perfusion. Similarly, number of macrophages and levels of matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 2, and alpha smooth muscle actin in lesions increased with perfusion time. CONCLUSIONS: A novel model of intimal hyperplasia was established by intravascular distilled water perfusion in high-cholesterol-fed rabbits. Importantly, this model exhibits time-dependent neointimal proliferation lesions that can be readily controlled in terms of extent, thus providing an avenue for further studies. PMID- 22445925 TI - Proteasome inhibitor treatment reduced fatty acid, triacylglycerol and cholesterol synthesis. AB - In the present study, the beneficial effects of proteasome inhibitor treatment in reducing ethanol-induced steatosis were investigated. A microarray analysis was performed on the liver of rats injected with PS-341 (Bortezomib, Velcade), and the results showed that proteasome inhibitor treatment significantly reduced the mRNA expression of SREBP-1c, and the downstream lipogenic enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ELOVL6, which is responsible for fatty acids long chain elongation, was also significantly downregulated by proteasome inhibitor treatment. Moreover, PS-341 administration significantly reduced the expression of acyl-glycerol-3 phosphate acyltransferase (AGPAT), and diacylglycerol acyltransferase (DGAT), enzyme involved in triacylglycerol (TAG) synthesis. Finally, PS-341 was found to downregulate the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA synthase (HMG-CoA synthase) that is responsible for cholesterol synthesis. Proteasome inhibitor was also found to play a role in intestinal lipid adsorption because apolipoproteins A (apoA-I, apoAII, apoA-IV and ApoCIII) were downregulated by proteasome inhibitor treatment, especially ApoA-II that is known to be a marker of alcohol consumption. Proteasome inhibitor treatment also decreased apobec-1 complementation factor (ACF) leading to lower level of editing and production of ApoB protein. Moreover apolipoprotein C-III, a major component of chylomicrons was significantly downregulated. However, lipoprotein lipase (Lpl) and High density lipoprotein binding protein (Hdlbp) mRNA levels were increased by proteasome inhibitor treatment. These results suggested that proteasome inhibitor treatment could be used to reduce the alcohol-enhanced lipogenesis and alcohol induced liver steatosis. A morphologic analysis, performed on the liver of rats fed ethanol for one month and treated with PS-341, showed that proteasome inhibitor treatment significantly decreased ethanol-induced liver steatosis. SREBP-1c, FAS and ACC were increased by ethanol feeding alone, but were significantly decreased when proteasome inhibitor was administered to rats fed ethanol. Our results also show that both mRNA and protein levels of these lipogenic enzymes, up regulated by ethanol, were then downregulated when proteasome inhibitor was administered to rats fed ethanol. It was also confirmed that alcohol feeding caused an increase in AGPAT and DGAT, which was prevented by proteasome inhibitor treatment of the animal fed ethanol. Chronic alcohol feeding did not affect the gene expression of HMG-CoA synthase. However, PS341 administration significantly reduced the HMG-CoA synthase mRNA levels, confirming the results obtained with the microarray analysis. C/EBP transcription factors alpha (CCAAT/enhancer-binding protein alpha) has been shown to positively regulate SREBP-1c mRNA expression, thus regulating lipogenesis. Proteasome inhibition caused a decrease in C/EBP alpha mRNA expression, indicating that C/EBP downregulation may be the mechanism by which proteasome inhibitor treatment reduced lipogenesis. In conclusion, our results indicate that proteasome activity is not only involved in downregulating fatty acid synthesis and triacylglycerol synthesis, but also cholesterol synthesis and intestinal lipid adsorption. Proteasome inhibitor, administrated at a non-toxic low dose, played a beneficial role in reducing lipogenesis caused by chronic ethanol feeding and these beneficial effects are obtained because of the specificity and reversibility of the proteasome inhibitor used. PMID- 22445926 TI - Mature breast adipocytes promote breast cancer cell motility. AB - Adipocytes express substances involved in both normal physiology and pathological processes. One such adipocyte protein is the Serpin (serine protease inhibitor) plasminogen activator inhibitor-1 (PAI-1). PAI-1 functions to inhibit urokinase type plasminogen activator (uPA) though PAI-1 itself is also implicated in breast cancer progression. While the role of adipocytes in breast cancer development is not fully understood, obesity is a known risk factor associated with breast cancer. Thus, we characterized adipocytes from breast and omental tissues for PAI 1 and uPA, and the influence of adipocytes on breast cancer cell motility. Using preadipocyte cells from breast and omental adipose tissue, we differentiated each site into mature adipocytes. PAI-1 protein was found in breast adipocytes>omental preadipocytes>omental adipocytes>breast preadipocytes. Interestingly, uPA protein was not detected in any of these cell types. We then incubated breast adipocyte conditioned media (Adip-CM) and preadipocyte conditioned media (PreAdip-CM) on both normal (MCF-10A) and malignant (MCF-10CA1) breast epithelial cell lines. Adip-CM, but not PreAdip-CM, (a) increased cell motility in both MCF-10A and MCF 10CA1 cells; (b) increased cell-associated uPA activity in both cell lines; (c) increased phosphorylated-Akt levels in MCF-10CA1 cells; and (d) gene array profiles show altered expression of several genes associated with cancer adhesion, metastasis and signaling. Our results suggest that mature breast adipocytes are capable of altering the epithelial cell phenotype, producing a more motile cell type and further provide a potential link between obesity and risk of breast cancer. PMID- 22445927 TI - Emerging technologies for endoscopic hemostasis. PMID- 22445928 TI - Identification of TROSPA homologue in Ixodes persulcatus Schulze, the specific vector for human Lyme borreliosis in Japan. AB - The tick receptor for outer surface protein A (TROSPA) is an Ixodes scapularis (I. scapularis) receptor for Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme disease in North America. The blockade of TROSPA has been shown to reduce B. burgdorferi adherence to the I. scapularis gut in vivo. Thus, TROSPA is one of the potential targets for the development of vector-antigen-based vaccines to prevent the transmission of B. burgdorferi. The aim of this study is to identify the TROSPA gene in I. persulcatus Schulze, the specific vector for human Lyme borreliosis in Japan. The cDNA clone encoding the TROSPA-like sequence with 483 nucleotides was obtained from whole-body homogenates of fed nymphs of I. persulcatus. The putative amino acid sequence of I. persulcatus TROSPA was 88.2% and 87.8% identical to that of I. scapularis and I. ricinus, respectively. This finding will facilitate investigations on the role of I. persulcatus TROSPA and its interaction with Borrelia spp. and will have important implications on endeavors to develop a tick vaccine. PMID- 22445929 TI - Seasonal activity and tick-borne pathogen infection rates of Ixodes ricinus ticks in Hungary. AB - Ixodes ricinus is the most important tick species in Europe as it is most widely distributed and transmits the majority of tick-borne zoonotic pathogens. As limited data are available for Hungary, the aim of the present study was to investigate the seasonal timing of questing by I. ricinus and the infection rate of this tick species with all major tick-borne zoonotic pathogens. Monthly collections of I. ricinus were carried out over 3 consecutive years by dragging a blanket in 6 biotopes representing different areas of Hungary. Altogether, 1800 nymphs (300 per collection point) were screened as pooled samples (each of 5 specimens) by PCR-based methods for tick-borne pathogens. I. ricinus larvae, nymphs, and adults had bimodal activity patterns with a major peak in the spring. As newly moulted ticks of all stages are thought to emerge in the autumn of each year, it appears that most newly emerged ticks delayed their questing until the following spring. The minimum prevalence of Borrelia burgdorferi sensu lato was 2.5%. Borr. afzelii, Borr. burgdorferi sensu stricto, Borr. garinii, Borr. lusitaniae, and Borr. valaisiana were identified by hybridization. The minimum infection rate with spotted fever group rickettsiae was 1.9%. Rickettsia helvetica was identified in all biotopes. The minimum prevalence of Anaplasma phagocytophilum, Babesia divergens and Bab. microti was low (0.3-0.5%). Bartonella spp.-, Francisella tularensis-, and TBE virus-specific amplification products were not detected. Relative to the results of comparable studies carried out in the Carpathian Basin, the prevalence of tick-borne pathogens was low in Hungary. This might be attributed to the climatic difference between the lowland areas of Hungary and submountain areas of the surrounding countries involved in the studies. PMID- 22445930 TI - Translation of drug effects from experimental models of neuropathic pain and analgesia to humans. AB - Neuropathic pain research remains a challenging undertaking owing to: (i) the lack of understanding about the underlying disease processes; and (ii) poor predictive validity of the current models of evoked pain used for the screening of novel compounds. Common consensus is that experimental models replicate symptoms (i.e. have face validity but no construct validity). Another issue that requires attention is the sensitivity of endpoints to discriminate drug effects that are relevant to the disease in humans. In this paper we provide an overview of the pre-clinical models that can be used in conjunction with a model-based approach to facilitate the prediction of drug effects in humans. Our review strongly suggests that evidence of the concentration-effect relationship is necessary for translational purposes. PMID- 22445931 TI - The AKT/NF-kappaB inhibitor xanthohumol is a potent anti-lymphocytic leukemia drug overcoming chemoresistance and cell infiltration. AB - Although the vast majority of patients with acute lymphocytic leukemia (ALL) attain remission with modern therapies, relapsed leukemia will continue to be a common malignancy both in childhood and in adults, until new treatments are available. Therapeutic options for advanced B-cell acute lymphocytic leukemia are still limited and acquired drug resistance and extramedullary tissue infiltration are two major obstacles during treatment. The prenylflavonoid xanthohumol (XN) has shown in vitro and in vivo therapeutic potential against a range of tumors. In the present study we investigated the effects of XN on B-ALL cells in vitro and in an ALL-like xenograft mouse model. Treatment of ALL cell lines with XN resulted in growth arrest and apoptosis induction. XN retained its cytotoxicity when adriamycin resistant cells were examined while ALL cell clones adapted to long-term exposure to XN resulted highly responsive to cytotoxic drugs. Administration of 50MUg XN/mouse (5 days/week) significantly increased animal life span by delaying the insurgence of neurological disorders due to leukemic cells dissemination. In agreement with a less invasive phenotype, cell migration and invasion were impaired by XN and basal levels of FAK, AKT and NF-kappaB signaling pathways were down-regulated in ALL cells upon XN exposure. Our data indicate that XN has significant antileukemic activity both in vitro and in vivo, which associates with impaired cell migration and invasion. Interestingly, this activity overcomes mechanisms leading to drug-resistance. XN represents a promising agent perspective for ALL therapy and recurrence prevention and would deserve clinical testing in the near future. PMID- 22445932 TI - The gamma-secretase blocker DAPT impairs recovery from lipopolysaccharide-induced inflammation in rat brain. AB - gamma-Secretase is an important contributing enzyme in Alzheimer's disease and is therefore an important therapeutic target. However, the impact of gamma-secretase inhibition is not well studied in acute neuroinflammation induced by systemic infection. In this study the influence of gamma-secretase on the expression of some proinflammatory markers was assessed in the acute phase as well as the subsiding phase of neuroinflammation. Cerebral gamma-secretase cleavage activity was measured by a fluorometric assay after lipopolysaccharide (LPS) intraperitoneal administration. Time profiles of TNF-alpha and COX-II expression were then determined to detect the time points relevant to the maximal inflammatory responses and the subsequent recovery phase. gamma-Secretase activity coincident with TNF-alpha protein expression returned to its basal level till 8-12 h after systemic challenge with low dose LPS while COX-II over expression lasted for 48-72 h later. Pharmacological inhibition of gamma secretase with local or systemic administration of DAPT (N-[N-(3,5 difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) was performed to indicate the results on the developmental and sinking phases of inflammatory responses in 6 and 72 h post LPS respectively. Our results demonstrate that both local and systemic modulation of gamma-secretase hyper-activity with DAPT increase the duration of TNF-alpha, COX-II, and NFkappaB induction. We consistently found mild augmented apoptosis in animals treated with DAPT as determined by measuring cleaved caspase-3 expression and by TUNEL assay 72 h following LPS injection. These results suggest that gamma-secretase modulation interferes with certain immune regulatory pathways which may restrict some inflammatory transcription factors such as NFkappaB. PMID- 22445933 TI - Role of pulmonary stretch receptors and sympathetic system in the inhibition of reflex bradycardia produced by chemical stimulation of the periaqueductal gray matter of the rat. AB - The present study examined the role of the sympathetic system and pulmonary afferent feedback in the baroreflex inhibition by chemical stimulation of the dorsal periaqueductal gray matter (DPAG) of the anesthetized rat. The baroreflex bradycardia was induced by phenylephrine infusions (PHE, 50 MUg/ml/min, i.v.) given either alone or combined with glutamate microinjections (GLU, 10 nmol/100 nl) into the DPAG. GLU microinjections alone produced marked increases in respiratory amplitude (67+/-19%), but barely changed the respiratory frequency (15+/-3 cpm) and blood pressure (14+/-2 mm Hg), and did not affect the heart rate. In contrast, the same injections produced a 92% inhibition of PHE-induced bradycardia (from -62 to -5 bpm). Because GLU microinjections per se had little effects on blood pressure, the baroreflex inhibition should be credited to the deactivation of both the vagal and sympathetic reflex pathways at the medulla. Indeed, the baroreflex was inhibited in only 47% following the DPAG stimulation of atenolol-treated rats. The GLU-evoked inhibition of baroreflex was also correlated with concomitant increases in respiratory amplitude. The role of pulmonary feedback in baroreflex inhibition was thus examined before and after the neuromuscular blockade of atenolol-treated rats. In spontaneously breathing rats, GLU microinjections reversed PHE-induced bradycardia to tachycardia, thereby producing a 153% inhibition of reflex bradycardia (from -38 bpm to +20 bpm). In contrast, the baroreflex inhibition was attenuated in only 53% after neuromuscular blockade (from -34 to -16 bpm). Data are the first evidence of the contribution of pulmonary stretch receptor feedback in DPAG-evoked inhibition of reflex bradycardia. PMID- 22445935 TI - Risky decision making in adults with ADHD. AB - BACKGROUND AND OBJECTIVES: Risky decision making and disadvantageous choices constitute core characteristics of patients with attention-deficit/hyperactivity disorder (ADHD). Consequences include negative psychosocial and health-related outcomes. However, risky decision making and its interrelations with emotional states in ADHD are poorly understood. Therefore, the authors investigated risky decision making without and after boredom induction in adults with and without ADHD. METHODS: In study 1, ADHD patients (n = 15) and age/education matched controls (CG; n = 16) were compared on the Game of Dice Task (GDT), an established task measuring decision making in unambiguous situations. In study 2, ADHD patients (n = 14) and CG (n = 13) underwent boredom induction prior to the GDT. RESULTS: In study 1, ADHD patients selected the disadvantageous alternatives significantly more often than CG. In study 2, no significant group differences were found due to an increase in risky decision making in CG following the boredom induction. LIMITATIONS: Even if severity of depression did not affect our results, it may be necessary to compare GDT responses in ADHD patients with and without current depression. CONCLUSIONS: Risk as a motor of disadvantageous decision making needs to be taken into account in therapeutic contexts as a maintenance factor of dysfunctional behaviour. The findings of study 2 are in line with postulated alterations of emotional state adjustment in ADHD. The link between decisions making and emotional regulation in ADHD needs further attention in research. PMID- 22445934 TI - Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery. AB - We have recently documented that treatment with the alternative biofuel, acetyl-L carnitine (ALC, 300 mg/kg), as late as 1 h after T10 contusion spinal cord injury (SCI), significantly maintained mitochondrial function 24 h after injury. Here we report that after more severe contusion SCI centered on the L1/L2 segments that are postulated to contain lamina X neurons critical for locomotion (the "central pattern generator"), ALC treatment resulted in significant improvements in acute mitochondrial bioenergetics and long-term hind limb function. Although control injured rats were only able to achieve slight movements of hind limb joints, ALC treated animals produced consistent weight-supported plantar steps 1 month after injury. Such landmark behavioral improvements were significantly correlated with increased tissue sparing of both gray and white matter proximal to the injury, as well as preservation of choline acetyltransferase (ChAT)-positive neurons in lamina X rostral to the injury site. These findings signify that functional improvements with ALC treatment are mediated, in part, by preserved locomotor circuitry rostral to upper lumbar contusion SCI. Based on beneficial effects of ALC on mitochondrial bioenergetics after injury, our collective evidence demonstrate that preventing mitochondrial dysfunction acutely "promotes" neuroprotection that may be associated with the milestone recovery of plantar, weight-supported stepping. PMID- 22445936 TI - The contribution of threat probability estimates to reexperiencing symptoms: a prospective analog study. AB - BACKGROUND AND OBJECTIVES: Individuals with posttraumatic stress disorder (PTSD) are hypothesized to have a "sense of current threat." Perceived threat from the environment (i.e., external threat), can lead to overestimating the probability of the traumatic event reoccurring (Ehlers & Clark, 2000). However, it is unclear if external threat judgments are a pre-existing vulnerability for PTSD or a consequence of trauma exposure. We used trauma analog methodology to prospectively measure probability estimates of a traumatic event, and investigate how these estimates were related to cognitive processes implicated in PTSD development. METHODS: 151 participants estimated the probability of being in car accident related situations, watched a movie of a car accident victim, and then completed a measure of data-driven processing during the movie. One week later, participants re-estimated the probabilities, and completed measures of reexperiencing symptoms and symptom appraisals/reactions. RESULTS: Path analysis revealed that higher pre-existing probability estimates predicted greater data driven processing which was associated with negative appraisals and responses to intrusions. Furthermore, lower pre-existing probability estimates and negative responses to intrusions were both associated with a greater change in probability estimates. Reexperiencing symptoms were predicted by negative responses to intrusions and, to a lesser degree, by greater changes in probability estimates. LIMITATIONS: The undergraduate student sample may not be representative of the general public. The reexperiencing symptoms are less severe than what would be found in a trauma sample. CONCLUSIONS: Threat estimates present both a vulnerability and a consequence of exposure to a distressing event. Furthermore, changes in these estimates are associated with cognitive processes implicated in PTSD. PMID- 22445937 TI - [Severe gastrointestinal bleeding secondary to colon metastases from a cutaneous melanoma]. PMID- 22445938 TI - [Timing of polyethylene glycol administration is a key factor in the tolerability and efficacy of colon preparation in colorectal cancer screening]. AB - INTRODUCTION: The quality and tolerability of antegrade gut lavage bowel preparation are key elements in the success of population-based colorectal cancer screening. OBJECTIVES: To evaluate cleansing quality and tolerability according to the timing of polyethylene glycol administration in persons undergoing colorectal cancer screening. METHOD: Participants in colorectal cancer screening were randomized to two groups: a) control group (colonoscopy scheduled at 9-12 h); preparation with polyethylene glycol on the previous afternoon; b) study group (colonoscopy scheduled at 12-15 h): preparation with polyethylene glycol on the morning of the colonoscopy, with the option of a split dose. The quality of cleansing was evaluated with the Boston scale and tolerability through a questionnaire. RESULTS: A total of 282 participants were included: preparation was carried out the day before the procedure in 134 and on the same day in 148, of which 26 received a split dose. Cleansing was adequate in 95% (n=268) of the participants. The quality of cleansing was higher in the study group (P=.045). The interval between the end of administration and the beginning of the procedure was inversely correlated with the Boston scale score (P=.036; r=-0.125). Tolerability was unrelated to the time of administration (P>.2). Acceptance of the timing of administration was lower in the study group than in the control group (26% vs 10%, respectively; P=.001). CONCLUSIONS: Preparation as close as possible to the colonoscopy improves the quality of cleansing with no detrimental effects on tolerability, although this option is less comfortable. PMID- 22445939 TI - [Dieulafoy's lesion of the esophagus resolved through endoscopic band ligation]. PMID- 22445940 TI - [Metastatic Crohn's disease. Response to adalimumab dose intensification]. AB - Inflammatory bowel disease is accompanied by extraintestinal manifestations in a high percentage of patients. Cutaneous lesions are the second most prevalent of these manifestations, and within these, metastatic Crohn's disease is one of the least common, being the least frequent specific cutaneous manifestation of Crohn's disease. This entity includes cutaneous and subcutaneous lesions with a non-caseating granulomatous appearance on histological analysis identical to that of Crohn's disease. These lesions are not found adjacent to the digestive tract. Due to the low prevalence of these manifestations, conclusive trials on the treatment of choice have not been performed and there is no well-defined therapeutic strategy. Distinct therapies with varying results have been reported. We report the case of a female patient with longstanding and complex Crohn's disease who developed metastatic cutaneous manifestations while receiving adalimumab. The cutaneous manifestations responded well to dose intensification of this drug. A review of the literature is provided. PMID- 22445941 TI - [Non-obstructive enterolithiasis: report of two cases]. AB - Enterolithiasis, or coprolithiasis, stones formed mainly in the intestine, is uncommon in humans and is generally associated with intestinal stasis. This entity is highly common in some animals, such as horses. Enterolithiasis is usually asymptomatic but may lead to intestinal occlusion and should be considered as a possible cause of this event. We report two cases of enterolithiasis, in which the diagnosis was established by simple abdominal radiography and computed tomography. Although both patients had factors favoring the development of enterolithiasis, a genetic substrate predisposing them to this uncommon clinical entity cannot be excluded. PMID- 22445942 TI - Focus on molecules: neural retina leucine zipper (NRL). PMID- 22445943 TI - Special issue on electron tomography. PMID- 22445944 TI - Flavor preferences conditioned by intragastric glucose but not fructose or galactose in C57BL/6J mice. AB - The present study determined if mice, like rats, differ in their flavor conditioning responses to intragastric (IG) infusions of three common monosaccharide sugars. In Experiment 1, C57BL/6J mice were trained to drink a flavored saccharin solution (the CS+) paired with intragastric (IG) self infusions of 16% glucose, fructose or galactose and a different flavored solution (the CS-) paired with IG water infusions during 22 h/day training sessions. The glucose infusions increased CS+ intakes during training and produced a strong CS+ preference (~87%) in two-bottle choice tests. In contrast, the fructose and galactose infusions reduced CS training intakes and did not condition a CS+ preference. Experiment 2 determined if reducing fructose and galactose concentration would enhance conditioning. However, IG infusions of 8% sugar also failed to condition CS+ preferences. The robust conditioning response to IG glucose confirms results obtained with rats, but the indifference of mice to IG fructose and galactose contrasts with preference and avoidance responses observed in rats. The effectiveness of glucose to condition preferences suggests an important role for glucose-specific sensors rather than gut "sweet" taste receptors in the postoral modulation of carbohydrate appetite. PMID- 22445945 TI - A molecular transporter engineering approach to improving xylose catabolism in Saccharomyces cerevisiae. AB - Traditional metabolic pathway engineering rarely considers the influence of molecular transport. Here, we describe the directed evolution of two heterologous transporters, Candida intermedia GXS1 and Scheffersomyces stipitis XUT3. Growth rate on xylose was improved up to 70% by mutant transporter expression. Most mutants were found to exhibit vastly improved V(max) values and display an increase in high cell density sugar consumption rates. Mixed glucose and xylose fermentations reveal that mutant transporters can alter the diauxic shift dynamics and the simultaneous sugar utilization capacity of the host strain. Analysis of mutations highlights several important residues influencing transporter function including point mutations at F40 of C. intermedia GXS1 and at E538 of S. stipitis XUT3. This work is the first to demonstrate that molecular transporter proteins can be improved for biotechnological applications through directed evolution in yeast. PMID- 22445946 TI - Cognitive reactivity, dysfunctional attitudes, and depressive relapse and recurrence in cognitive therapy responders. AB - Dysfunctional attitudes can foreshadow depressive relapse/recurrence. Priming mood, through induction paradigms, is hypothesized to activate dysfunctional attitudes. Cognitive reactivity (CR) refers to mood-linked increases in dysfunctional attitudes after priming. Here we explored the extent to which CR as well as residual, unprimed, dysfunctional attitudes predicted depressive relapse/recurrence among depressed patients who responded to acute phase cognitive therapy (CT). Consenting adults, aged 18-70, with recurrent major depressive disorder (n = 523) participated in a two-site randomized controlled trial examining the durability of continuation phase treatments. Patients received 16-20 sessions of CT. Among the 245 incompletely remitted responders, 213 agreed to undergo a mood induction paradigm. After 8 months of continuation phase treatments, participants were followed an additional 24 months. Although the mood induction significantly lowered mood in 80% of responders, the expected CR was not evident. By contrast, higher unprimed dysfunctional attitudes following CT did predict relapse/recurrence over 20 and 32 months post randomization. The findings of this large longitudinal study of incompletely remitted CT responders challenge the notion that it is necessary to prime mood in order to maximize dysfunctional attitudes' prediction of relapse and/or recurrence. While findings cannot be generalized beyond CT responders, they emphasize the clinical importance of reducing dysfunctional attitudes in preventing depression. PMID- 22445947 TI - The role of maladaptive beliefs in cognitive-behavioral therapy: Evidence from social anxiety disorder. AB - Beliefs that are negatively biased, inaccurate, and rigid are thought to play a key role in the mood and anxiety disorders. Our goal in this study was to examine whether a change in maladaptive beliefs mediated the outcome of individual cognitive-behavioral therapy (CBT) for social anxiety disorder (SAD). In a sample of 47 individuals with SAD receiving CBT, we measured maladaptive interpersonal beliefs as well as emotional and behavioral components of social anxiety, both at baseline and after treatment completion. We found that (a) maladaptive interpersonal beliefs were associated with social anxiety at baseline and treatment completion; (b) maladaptive interpersonal beliefs were significantly reduced from baseline to treatment completion; and (c) treatment-related reductions in maladaptive interpersonal beliefs fully accounted for reductions in social anxiety after CBT. These results extend the literature by providing support for cognitive models of mental disorders, broadly, and SAD, specifically. PMID- 22445948 TI - Toxicogenomics: the challenges and opportunities to identify biomarkers, signatures and thresholds to support mode-of-action. AB - Toxicogenomics (TGx) can be defined as the application of "omics" techniques to toxicology and risk assessment. By identifying molecular changes associated with toxicity, TGx data might assist hazard identification and investigate causes. Early technical challenges were evaluated and addressed by consortia (e.g. ISLI/HESI and the Microarray Quality Control consortium), which demonstrated that TGx gave reliable and reproducible information. The MAQC also produced "best practice on signature generation" after conducting an extensive evaluation of different methods on common datasets. Two findings of note were the need for methods that control batch variability, and that the predictive ability of a signature changes in concert with the variability of the endpoint. The key challenge remaining is data interpretation, because TGx can identify molecular changes that are causal, associated with or incidental to toxicity. Application of Bradford Hill's tests for causation, which are used to build mode of action (MOA) arguments, can produce reasonable hypotheses linking altered pathways to phenotypic changes. However, challenges in interpretation still remain: are all pathway changes equal, which are most important and plausibly linked to toxicity? Therefore the expert judgement of the toxicologist is still needed. There are theoretical reasons why consistent alterations across a metabolic pathway are important, but similar changes in signalling pathways may not alter information flow. At the molecular level thresholds may be due to the inherent properties of the regulatory network, for example switch-like behaviours from some network motifs (e.g. positive feedback) in the perturbed pathway leading to the toxicity. The application of systems biology methods to TGx data can generate hypotheses that explain why a threshold response exists. However, are we adequately trained to make these judgments? There is a need for collaborative efforts between regulators, industry and academia to properly define how these technologies can be applied using appropriate case-studies. PMID- 22445949 TI - Development and validation of an in vitro micronucleus assay platform in TK6 cells. AB - The Organization for Economic Co-operation and Development (OECD) has recently adopted Test Guideline 487 (TG487) for conducting the in vitro micronucleus (MNvit) assay. The purpose of this study is to evaluate and validate treatment conditions for the use of p53 competent TK6 human lymphoblastoid cells in a TG487 compliant MNvit assay. The ten reference compounds suggested in TG487 (mitomycin C, cytosine arabinoside, cyclophosphamide, benzo-a-pyrene, vinblastine sulphate, colchicine, sodium chloride, nalidixic acid and di(2-ethylhexyl)phthalate and pyrene) and noscapine hydrochloride were chosen for this study. In order to optimize the micronucleus response after treatment with some positive substances, we extended the recovery time after pulse treatment from 2 cell cycles recommended in TG487 to 3 cell cycles for untreated cells (40h). Each compound was tested in at least one of four exposure conditions: a 4h exposure followed by a 40h recovery, a 4h exposure followed by a 24h recovery, a 4h exposure in the presence of an exogenous metabolic activation system followed by a 40h recovery period, and a 27h continuous direct treatment. Results show that the direct acting clastogens, clastogens requiring metabolic activation and aneugens caused a robust increase in micronuclei in at least one test condition whereas the negative compounds did not induce micronuclei. The negative control cultures exhibited reproducibly low and consistent micronucleus frequencies ranging from 0.4 to 1.8% (0.8+/-0.3% average and standard deviation). Furthermore, extending the recovery period from 24h to 40h produced a 2-fold higher micronucleus frequency after a 4h pulse treatment with mitomycin C. In summary, the protocol described in this study in TK6 cells produced the expected result with model compounds and should be suitable for performing the MNvit assay in accordance with guideline TG487. PMID- 22445950 TI - Feasibility of training Zambian nurse-midwives to perform postplacental and postpartum insertions of intrauterine devices. AB - OBJECTIVE: To explore the feasibility of competency-based training of Zambian nurse-midwives in postplacental and postpartum intrauterine device (PPIUD) insertion and to estimate learning curves for this procedure. METHODS: A pilot service-delivery project was conducted, involving 9 nurse-midwives who participated in a 10-day PPIUD insertion training course at the University Teaching Hospital, Lusaka, Zambia. US and Zambian clinicians taught the didactic and practical curriculum. Checklists were used for standardization and a pelvic model was developed to achieve PPIUD insertion competency in the classroom before moving to clinical practice. Patients were recruited during prenatal visits, in early labor, and postpartum. Informed, voluntary consent was obtained. All clinical PPIUD insertions were supervised or performed by experienced trainers. RESULTS: All 9 nurse-midwives achieved competency on the pelvic model after 3 attempts. During the training period, 38 PPIUDs were inserted in postpartum women; no complications occurred. By the end of training, 4 of the nurse-midwives were deemed competent to independently insert PPIUDs. On average, 4 PPIUD insertions were needed to achieve clinical competency. CONCLUSIONS: Concentrated, competency-based training in PPIUD insertion is feasible in an African setting. Replication of such training could increase the popularity and prevalence of PPIUD use among African women. PMID- 22445951 TI - The impact of emergency obstetric care training in Somaliland, Somalia. AB - OBJECTIVE: To provide and evaluate in-service training in "Life Saving Skills - Emergency Obstetric and Newborn Care" in order to improve the availability of emergency obstetric care (EmOC) in Somaliland. METHODS: In total, 222 healthcare providers (HCPs) were trained between January 2007 and December 2009. A before after study was conducted using quantitative and qualitative methods to evaluate trainee reaction and change in knowledge, skills, and behavior, in addition to functionality of healthcare facilities, during and immediately after training, and at 3 and 6 months post-training. RESULTS: The HCPs reacted positively to the training, with a significant improvement in 50% of knowledge and 100% of skills modules assessed. The HCPs reported improved confidence in providing EmOC. Basic and comprehensive EmOC healthcare facilities provided 100% of expected signal functions-compared with 43% and 56%, respectively, at baseline-with trained midwives performing skills usually performed by medical doctors. Lack of drugs, supplies, medical equipment, and supportive policy were identified as barriers that could contribute to nonuse of new skills and knowledge acquired. CONCLUSION: The training impacted positively on the availability and quality of EmOC and resulted in "up-skilling" of midwives. PMID- 22445952 TI - High fidelity tonotopic mapping using swept source functional magnetic resonance imaging. AB - Tonotopy, the topographic encoding of sound frequency, is the fundamental property of the auditory system. Invasive techniques lack the spatial coverage or frequency resolution to rigorously investigate tonotopy. Conventional auditory fMRI is corrupted by significant image distortion, sporadic acoustic noise and inadequate frequency resolution. We developed an efficient and high fidelity auditory fMRI method that integrates continuous frequency sweeping stimulus, distortion free MRI sequence with stable scanner noise and Fourier analysis. We demonstrated this swept source imaging (SSI) in the rat inferior colliculus and obtained tonotopic maps with ~2 kHz resolution and 40 kHz bandwidth. The results were vastly superior to those obtained by conventional fMRI mapping approach and in excellent agreement with invasive findings. We applied SSI to examine tonotopic injury following developmental noise exposure and observed that the tonotopic organization was significantly disrupted. With SSI, we also observed the subtle effects of sound pressure level on tonotopic maps, reflecting the complex neuronal responses associated with asymmetric tuning curves. This in vivo and noninvasive technique will greatly facilitate future investigation of tonotopic plasticity and disorders and auditory information processing. SSI can also be adapted to study topographic organization in other sensory systems such as retinotopy and somatotopy. PMID- 22445953 TI - Polymer coating of copper oxide nanoparticles increases nanoparticles uptake and toxicity in the green alga Chlamydomonas reinhardtii. AB - Copper oxide nanoparticles (CuO NPs) are frequently used in a polymer-coated form, to be included in paints or fabrics for antimicrobial properties. Their application in antifouling paints may lead to the contamination of aquatic ecosystems. However, the toxicological risk of NPs in the environment is hard to evaluate due to a lack of knowledge on the mechanisms of NP interaction with biological systems. In this study, we investigated the effect of polymer coating on CuO NP toxicity in the green alga Chlamydomonas reinhardtii by comparing bare and polymer-coated CuO NPs prepared from the same CuO nanopowder. Both CuO NP suspensions were toxic to C. reinhardtii after 6 h treatment to concentrations of 0.005-0.04 g L(-1). Bare and polymer-coated CuO NPs induced a decrease of Photosystem II activity and the formation of reactive oxygen species. Polymer coated CuO NP was found to be more toxic than the uncoated CuO NP. The higher toxicity of CS-CuO NP was mainly associated with the increased capacity of polymer-coated CuO NP to penetrate the cell compared to bare CuO NPs. These results indicates that the high toxicity of polymer-coated CuO NPs in algal cells results of intracellular interactions between NPs and the cellular system. PMID- 22445954 TI - Comparison of batch, stirred flow chamber, and column experiments to study adsorption, desorption and transport of carbofuran within two acidic soils. AB - Different methods (batch, column and stirred flow chamber experiments) used for adsorption and desorption of carbofuran studies were compared. All tested methods showed that the carbofuran adsorption was higher in the soil with the higher organic matter content, whereas the opposite behaviour was observed for the percentage of carbofuran desorbed. However, different methods have revealed some discrepancies in carbofuran adsorption/desorption kinetics. Although batch method showed interesting data on equilibrium experiments, such as a low heterogeneity for the carbofuran adsorption sites independent of soil organic matter content, it had some disadvantages for carbofuran adsorption/desorption kinetic studies. The disadvantages were related with the excessive limitations of this method on kinetics, i.e., no difference could be detected between different soils. However, with column and stirred flow chamber methods the carbofuran adsorption/desorption kinetics of different soils could be compared. Moreover, the absolute values of carbofuran adsorption/desorption and its rate were higher in the stirred flow chamber than in the batch and column experiments. Using stirred flow chamber experiments the carbofuran desorption was significantly faster than its adsorption, whereas carbofuran using column experiments they were similar. These discrepancies should be considered when the results obtained only with one method is discussed. PMID- 22445955 TI - Responses of CH(4), CO(2) and N(2)O fluxes to increasing nitrogen deposition in alpine grassland of the Tianshan Mountains. AB - To assess the effects of nitrogen (N) deposition on greenhouse gas (GHG) fluxes in alpine grassland of the Tianshan Mountains in central Asia, CH(4), CO(2) and N(2)O fluxes were measured from June 2010 to May 2011. Nitrogen deposition tended to significantly increase CH(4) uptake, CO(2) and N(2)O emissions at sites receiving N addition compared with those at site without N addition during the growing season, but no significant differences were found for all sites outside the growing season. Air temperature, soil temperature and water content were the important factors that influence CO(2) and N(2)O emissions at year-round scale, indicating that increased temperature and precipitation in the future will exert greater impacts on CO(2) and N(2)O emissions in the alpine grassland. In addition, plant coverage in July was also positively correlated with CO(2) and N(2)O emissions under elevated N deposition rates. The present study will deepen our understanding of N deposition impacts on GHG balance in the alpine grassland ecosystem, and help us assess the global N effects, parameterize Earth System models and inform decision makers. PMID- 22445956 TI - Chronic exposure to contaminated drinking water stimulates PPAR expression in mice livers. AB - Mice were fed with source water (SW) and tap water (TW) for 90 d to evaluate hepatotoxicity induced by the drinking water. Histopathologic observation showed no obvious damage to hepatic tissue in the SW and TW groups. However, microarray analysis indicated that the SW and TW exposures affected many metabolic pathways, among which PPAR (peroxisome proliferator-activated receptors) signaling was most susceptible. Immunohistochemical staining demonstrated that both PPAR-alpha and PPAR-gamma were significantly increased in the exposure groups compared to control. Enzyme-linked immunosorbent assay revealed that PPAR-alpha expression level was increased from 23.37+/-0.53 ng g(-1) liver weight in control group to 26.60+/-1.43 ng g(-1) liver weight in SW group and 27.68+/-1.10 ng g(-1) liver weight in TW group (p<0.05). For PPAR-gamma, the expression level was also significantly enhanced from 0.83+/-0.07 ng g(-1) liver weight in control group to 1.11+/-0.20 ng g(-1) liver weight in SW group and 1.16+/-0.07 ng g(-1) liver weight in TW group (p<0.05). The SW and DW posed no obvious hepatotoxicity on mice and PPAR-alpha/-gamma could be used as a novel biomarker to assess public health risk induced by slightly contaminated drinking water. PMID- 22445957 TI - The OH-induced degradation mechanism of 4-chloro-2-methylphenoxyacetic acid (MCPA) with two forms in the water: a DFT comparison. AB - The initial degradation mechanisms of iOH and 4-chloro-2-methylphenoxyacetic acid (MCPA) including molecular form and anionic form are studied at the MPWB1K/6 311+G(3df, 2p)//MPWB1K/6-31+G(d, p) level. Possible reaction pathways of H-atom abstraction and iOH addition are considered in detail. By result comparison analysis, it is found that the reaction mechanisms for iOH and two forms of MCPA are different, and most reactions for anionic MCPA are easier than those for molecular MCPA. For H-atom abstraction reactions, the calculated energies show that iOH abstracting H-atom from -CH(3) group of molecular MCPA is the most kinetically favorable process; the potential energy surface for anionic MCPA indicates that H-atom in -CH(2) group is slightly easier to be abstracted than that in -CH(3) group. For iOH addition reactions, the addition of iOH to the C1 site is the initial step for molecular MCPA and the predominant product is 4 chloro-2-methylphenol (denoted P3), while the C4 site is the most reactive site for anionic MCPA and the primary product results from the hydroxylation of the aromatic ring, which is in good agreement with the experimental observation. In additional, results from PCM calculations show that most reactions in water phase are more kinetically favorable than those in gas phase, though the mechanisms discussed above will not be changed. PMID- 22445958 TI - Laboratory experiments on simultaneous removal of K and P from synthetic and real urine for nutrient recycle by crystallization of magnesium-potassium-phosphate hexahydrate in a draft tube and baffle reactor. AB - The simultaneous removal of K and P from urine for nutrient recycling by crystallization of magnesium potassium phosphate hexahydrate (MPP) in a laboratory-scale draft tube and baffle reactor (DTBR) is investigated. Results show that mixing speed and hydraulic retention time are important operating factors that influence crystallization and crystal settlement. Slurry should be discharged at a crystal retention time of 11 h to maintain fluidity in the reactor. Further applications of the DTBR using real urine (pretreated by ammonia stripping and diluted five times) showed that 76% K and 68% P were recycled to multi-nutrient products. The crystals collected were characterized and confirmed mainly as a mixture of magnesium ammonium phosphate hexahydrate, MPP, and magnesium sodium phosphate heptahydrate. Results indicate that the DTBR effectively achieved the simultaneous recycling of K and P from urine to multi nutrient products through MPP crystallization. PMID- 22445959 TI - A gene for carotene cleavage required for pheromone biosynthesis and carotene regulation in the fungus Phycomyces blakesleeanus. AB - Mating and sexual development in fungi are controlled by molecular mechanisms that are specific for each fungal group. Mating in Phycomyces blakesleeanus and other Mucorales requires pheromones derived from beta-carotene. Phycomyces mutants in gene carS accumulate large amounts of beta-carotene but do not enter the sexual process. We show that carS encodes a beta-carotene-cleaving oxygenase that catalyzes the first step in the biosynthesis of a variety of apocarotenoids, including those that act as pheromones. Therefore carS mutants cannot stimulate their sexual partners, although they respond to them. CarS catalyzes the biosynthesis of a beta-ring-containing apocarotenoid that inhibits the activity of the carotenogenic enzyme complex in vegetative cells and provides a feedback regulation for the beta-carotene pathway. The carS gene product is a keystone in carotenogenesis and in sexual reproduction. PMID- 22445960 TI - Analysis of the role of transcription factor VAD-5 in conidiation of Neurospora crassa. AB - Conidiation is the major mode of reproduction in many filamentous fungi. The Neurospora crassa gene vad-5, which encodes a GAL4-like Zn2Cys6 transcription factor, was suggested to contribute to conidiation in a previous study using a knockout mutant. In this study, we confirmed the positive contribution of vad-5 to conidiation by gene complementation. To understand the role of vad-5 in conidiation, transcriptomic profiles generated by digital gene expression profiling from the vad-5 deletion mutant and the wild-type strain were compared. Among 7559 detected genes, 176 genes were found to be transcriptionally down regulated and 277 genes transcriptionally upregulated in the vad-5 deletion mutant, using >=1-fold change as a cutoff threshold. Among the down-regulated genes, four which were already known to be involved in conidiation -fluffy, ada 6, rca-1, and eas - were examined further in a time course experiment. Transcription of each of the four genes in the vad-5 deletion mutant was lower than in the wild-type strain during conidial development. Phenotypic observation of deletion mutants for 132 genes down-regulated by vad-5 deletion revealed that deletion mutants for 17 genes, including fluffy, ada-6, and eas, produced fewer conidia than the wild type. By phenotypic observation of deletion mutants for 211 genes upregulated in the vad-5 deletion mutant, two types of deletion mutants were found. One type, which produced more conidia than the wild-type strain, includes deletion mutants for previously characterized genes cat-2, cat-3, and sah-1 and for a non-characterized gene NCU07221. Deletion mutants of NCU06302 and NCU11090, representing the second type, produced conidia earlier than the wild type strain. Based on these conidiation phenotypes, we designated NCU07221 as high conidial production-1 (hcp-1) and named NCU06302 and NCU11090 as early conidial development-1 (ecd-1) and ecd-2, respectively. Given the collective results from this study, we propose that vad-5 exerts an effect on conidiation by activating genes that positively contribute to conidiation as well as by repressing genes that negatively influence conidial development. PMID- 22445961 TI - Rutin inhibits beta-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines. AB - Alzheimer's disease (AD) is a complex, multi-factorial neurodegenerative disease. The aggregation of soluble beta-amyloid (Abeta) into fibrillar deposits is a pathological hallmark of AD. The Abeta aggregate-induced neurotoxicity, inflammatory reactions, oxidative stress, and nitric oxide (NO) generation are strongly linked to the etiology of AD. Here, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Abeta42 fibrillization and attenuate Abeta42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. Moreover, rutin decreases the formation of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), and malondialdehyde (MDA), reduces inducible nitric oxide synthase (iNOS) activity, attenuates mitochondrial damage, increases the glutathione (GSH)/GSSG ratio, enhances the activities of super oxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and modulates the production of proinflammatory cytokines by decreasing TNF-alpha and IL-1beta generation in microglia. Taken together, the actions of rutin on multiple pathogenic factors deserves further investigation for the prevention and treatment of AD. PMID- 22445962 TI - Cabazitaxel rechallenge at prostate-specific antigen relapse after previous cabazitaxel and docetaxel chemotherapy: case report. PMID- 22445963 TI - The role of receptor binding specificity in interspecies transmission of influenza viruses. AB - Influenza A virus infection begins with the binding of the hemagglutinin (HA) glycoprotein to sialic acid-containing receptors on the surface of the target cell. Avian influenza viruses, including avian H5N1, H7, and H9N2 viruses, can occasionally cross the species barrier and infect humans; however, these viruses do not spread efficiently from person to person, perhaps, partly, owing to differences in the receptor-binding specificities of human and avian influenza viruses. The HAs of avian influenza viruses must adapt to receptors in humans to acquire efficient human-to-human transmissibility. In this review, we discuss the receptor binding specificity of influenza A viruses and its role in interspecies transmission. PMID- 22445964 TI - Degrees of maturity: the complex structure and biology of flaviviruses. AB - Flaviviruses are small enveloped virions that enter target cells in a pH dependent fashion. Virus attachment, entry, and membrane fusion are orchestrated by the envelope (E) and pre-membrane (prM) proteins, the two structural proteins displayed on the surface of virions. Flaviviruses assemble as an immature non infectious form onto which prM and E form trimeric spikes. During egress from infected cells, flaviviruses undergo dramatic structural changes characterized by the formation of a herringbone arrangement of E proteins that lie flat against the surface of the virion and cleavage of the prM protein by the cellular protease furin. The result is a relatively smooth, infectious mature virion. This dynamic process is now understood in structural detail at the atomic level. However, recent studies indicate that many of the virions released from cells share structural features of both immature and mature virus particles. These mosaic partially mature virions are infectious and interact uniquely with target cells and the host immune response. Here, we will discuss recent advances in our understanding of the biology and significance of partially mature flaviviruses. PMID- 22445965 TI - Filovirus entry into cells - new insights. AB - Filoviruses are hemorrhagic fever-causing agents that produce enveloped virions with a filamentous morphology. The viral surface glycoprotein, GP, orchestrates the surprisingly complex process by which filoviruses gain access to the cytoplasm of their host cells. GP mediates viral attachment to cells through multiple, redundant interactions with cell-surface factors. GP then induces virion internalization by a process that resembles cellular macropinocytosis. Within the endo/lysosomal pathway, GP undergoes a series of structural rearrangements, controlled by interactions with host factors, that prime and activate it to bring about fusion between the viral and cellular lipid bilayers. Membrane fusion delivers the viral nucleocapsid core into the cytoplasm, which is the site of filovirus replication. This review summarizes our understanding of the filovirus entry mechanism, with emphasis on recent findings. PMID- 22445966 TI - Comment on Gallistel: behavior theory and information theory: some parallels. AB - In this article, Gallistel proposes information theory as an approach to some enduring problems in the study of operant and classical conditioning. PMID- 22445967 TI - DHEA and DHEA-S response to acute psychosocial stress in healthy men and women. AB - This study investigates the effect of acute psychosocial stress on serum concentrations of DHEA and DHEA-S in healthy men and women. Twenty men and 19 women (age 30-50 years) underwent Trier Social Stress Test (TSST). Physiological measurements were performed before, directly after the stress test and after 30 mins of recovery. In both men and women, significantly elevated DHEA and DHEA-S levels were observed in response to the stressor. There was a large inter individual variation in the magnitude of the response, especially for DHEA but no statistical difference between men and women. Magnitude of the change in the levels of DHEA was found to be positively associated with the magnitude of the changes in ACTH, cortisol and heart rate. Furthermore, the results of this study suggest that the capacity to secrete DHEA and DHEA-S during acute psychosocial stress declines with age. PMID- 22445968 TI - Therapeutic effect of intravenous bone marrow-derived mesenchymal stem cell transplantation on early-stage LPS-induced acute lung injury in mice. AB - OBJECTIVE: To investigate the effect of intravenous bone marrow-derived mesenchymal stem cell (MSC) transplantation for early intervention of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: Thirty six mice were randomized into control group, PBS-treated ALI group, and MSC treated ALI group. In the latter two groups, mouse models of ALI were established by intranasal instillation of LPS, and 1 h later, the 4th passage of MSCs isolated from the bone marrow of mice or PBS were administered via the tail vein. The histological findings, lung wet/dry (W/D) weight ratio, neutrophil count and protein and cytokine contents in the bronchoalveolar lavage fluid (BALF), and myeloperoxidase (MPO) level in the lung tissue were analyzed at 24 h after MSC administration. Engraftment of MSCs in the recipient lung was determined by fluorescent PKH26 staining and flow cytometry. RESULTS: Compared with the control group, PBS-treated ALI group showed significantly higher protein levels, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and neutrophil count in the BALF and MPO content in the lung tissue, with also severe damage of lung histology. MSCs administration significantly reduced the lung W/D weight ratio, the levels of protein, TNF-alpha, IL-6 and neutrophil count in the BALF and MPO content in the lung tissue, and obviously lessened the lung injury 24 h after the transplantation. MSC administration also significantly increased the level of IL 10 in the BALF. CONCLUSION: Intravenous MSC transplantation can effectively improve the lung histology, attenuate the inflammatory response, reduce pulmonary edema in the early stage of LPS-induced ALI in mice, and such effects are independent of MSC engraftment in the lungs. PMID- 22445969 TI - [Hsa-miR-654-5p regulates osteogenic differentiation of human bone marrow mesenchymal stem cells by repressing bone morphogenetic protein 2]. AB - OBJECTIVE: To study the effect of hsa-miR-654-5p in repressing bone morphogenetic protein 2 (BMP2) mRNA and protein in human bone marrow mesenchymal stem cells (hBMSCs), and explore its regulatory role in osteogenic differentiation of hBMSCs. METHODS: hBMSCs in the 4th passage were cultured for 16 h and transfected with hsa-miR-654-5p followed by further culture for 48 h. qRT-PCR and Western blotting were performed to detect the expressions of BMP2 mRNA and protein. Dual luciferase?reporter gene assay was employed to examine the repression of the BMP2 gene. RESULTS: BMP2 mRNA and protein expressions were significantly down regulated in hBMSCs with hsa-miR-654-5p overexpression. Dualluci-ferase reporter gene assay indicated that the predicted target site of BMP2 was repressed directly by hsa-miR-654-5p, but this repression did not occur at the mutant predicted target site of BMP2. CONCLUSION: hsa-miR-654-5p can directly repress the mRNA and protein expressions of BMP2 by binding to a specific target site. The changes in hsa-miR-654-5p can play an important role in osteogenic differentiation regulation of hBMSCs. PMID- 22445970 TI - [Responses of pancreatic cancer cells to stimulations by nerve growth factor and the role of Trk-A expression]. AB - OBJECTIVE: To study the responses of different pancreatic cancer cells to stimulations by nerve growth factor (NGF) and explore the role of Trk-A in such responses. METHODS: Five pancreatic cancer cell lines (MIA-PaCa-2, PANC-1, SW 1990, AsPC-1, and BxPC-3) were exposed to different concentrations of NGF (0, 4, 20, 100, and 500 ng/ml). MTT and Matrigel invasion method were used to observe the changes in the cell proliferation and invasion ability. Trk-A expression in these cells was detected by PCR and Western blotting, and the relations of Trk-A expression to the cell proliferative and invasive abilities following NGF treatment were analyzed. RESULTS: NGF at 100 ng/ml most obviously stimulated the cell proliferation, and PANC-1 cells showed the highest while AsPC-1 cells showed the least sensitivity to 100 ng/ml NGF stimulation. Matrigel invasion test showed that NGF enhanced the invasiveness of PANC-1 and MIA-PaCa-2 cells but produced only limited effect on AsPC-1 cells; the effect of NGF was completely inhibited by the Trk-A inhibitor CEP701. The expression levels of Trk-A mRNA and protein were the highest in PANC-1 cells and the lowest in AsPC-1 cells. CONCLUSION: NGF can enhance the proliferation and invasiveness of pancreatic cancer cells, and this effect is possibly mediated by Trk-A protein. PMID- 22445971 TI - [Feasibility of cartilage link protein of hyaluronic acid for defining radiotherapeutic target volume in a mouse model of lung tumor]. AB - OBJECTIVE: To investigate the feasibility of using cartilage link protein of hyaluronic acid (HA-CLP) for defining the tumor boundary in a mouse model of lung carcinoma. METHODS: Lung carcinoma was induced in KM mice by chemical carcinogenesis. HA-CLP separated from bovine cartilage and purified by affinity chromatography was labeled with (125)I for autoradiography. Immunohistochemical analysis and Western blotting were used to examine the efficiency of HA-CLP in defining the boundaries of the lung tumors. RESULTS: With autoradiography, the clearest image of lung cancer was obtained at 2 h. With immunohistochemical method, the tumor boundary was the most clearly displayed at 2 h when the strongest signals of HA-CLP was detected; Western blotting also showed the clearest bands of HA-CLP at 2 h. CONCLUSION: HA-CLP has the immunogenicity of HABP, and can efficiently indicate lung tumor boundary in autoradiography and immunohistochemistry. PMID- 22445972 TI - [Construction of has-miR-335 lentiviral vector and verification of the target gene of miR-335]. AB - OBJECTIVE: To construct a lentiviral vector of miR-335 gene and verify the target gene of miR-335. METHODS: The precursor sequence of miR-335 gene was amplified from the genomic DNA by PCR and cloned into the lentiviral vector PLVTHM labeled with GFP. Real-time quantitative RT-PCR was used to detect miR-335 and RASA1 expression in different colorectal cancer cell lines. A recombinant vector psiCHECK-2-RASA1 containing RASA1 3'UTR was constructed followed by site-directed mutagenesis of RASA1 3'UTR to establish the vector psiCHECK-2-RASA1-Mut. Co transfection of hsa-mir-335 or a NC with these recombined vectors in HEK293A and SW480 cells was performed, and dual-luciferase reporter assay was utilized to examine the changes in luciferase activities. The recombinant PLVTHM-miR335 plasmid was packaged into mature lentivirus by 293FT cells and used to infect SW620 cells. Flow cytometry was employed for sorting the GFP+ cells. The expression of miR-335 and RASA1 were determined by qRT-PCR, and Western blotting was used to detect the expression of RASA1 protein in SW620 cell lines. RESULTS: The recombinant lentiviral vector PLVTHM-miR335, psiCHECK-2-RASA1 and the mutation expression vector psiCHECK-2-RASA1-Mut were successfully constructed. Dual-luciferase reporter assay showed that miR-335 decreased luciferase activity in cells co-transfected with psiCHECK-2-RASA1. The expression of miR-335 in SW620 cells infected with the lentivirus PLVTHM-miR335 was significantly increased, but the expression of RASA1 showed only slight changes. Overexpression of miR-335 suppressed the expression of RASA1 protein in SW620 cells. CONCLUSION: We have successfully constructed the lentiviral vector containing mir-335 gene and a SW620 cell line with miR-335 overexpression. MiR-335 can suppress RASA1 gene expression by targeting the specific sequence of RASA1 3'UTR. PMID- 22445973 TI - [Establishment of BGC-823/pBaBb-puro-MACC1 gastric cancer cell line stably expressing MACC1 and its tumor-related gene expression profiles]. AB - OBJECTIVE: To establish a gastric cancer cell line with stable expression of metastasis-associated in colon cancer 1 (MACC1) and detect the changes in tumor related gene expression profiles for investigating the possible regulation mechanisms between MACC1 and the differentially expressed genes. METHODS: The full-length MACC1 cDNA was amplified from human embryonic kidney 293FT cells and cloned into the pBaBb-puro vector. The recombinant pBaBb-puro-MACC1 expression vector, after identification with restriction enzyme digestion, was transfected into 293FT cells, and the expression of fluorescent reporter gene was observed. pBaBb-puro-MACC1 vector was transfected into human gastric cancer BGC-823 cell line to establish BGC-823/pBaBb-puro-MACC1 cell line stably expressing MACC1. Quantitative RT-PCR and Western blotting were used to detect MACC1 expression in both BGC-823/pBaBb-puro-MACC1 and control BGC-823 cells. High-throughout cDNA microarray was used to screen the effects of MACC1 on the gene expression profiles of gastric cancer cells. RESULTS: The recombinant pBaBb-puro-MACC1 plasmid was successfully constructed and verified by PCR and sequencing. BGC 823/pBaBb-puro-MACC1 cells showed significantly increased MACC1 mRNA expression as compared with the control cells. The results of cDNA microarray identified 33 up-regulated and 24 down-regulated genes in the cells after MACC1 transfection involved were in various cellular functions. CONCLUSION: The established BGC 823/pBaBb-puro-MACC1 gastric cancer cell line show some important molecular changes caused by MACC1. PMID- 22445974 TI - [Construction of a recombinant lentiviral vector of p38 MAPK and establishment of a human prostatic carcinoma cell line stably expressing p38 MAPK]. AB - OBJECTIVE: To construct a recombinant lentiviral vector for p38 MAPK and establish a human prostatic carcinoma cell line that stably expresses p38 MAPK. METHODS: EGFP/p38 fusion gene was subcloned into the lentiviral vector pTYF- EF1alpha-IRES-EGFP. The recombinant lentiviral vector pTYF-EF1alpha-EGFP/p38 was indentified by restriction enzyme digestion, and packaged in HEK 293T cells using lipofectamintm2000 with the packaging plasmid psPAX2 and envelope plasmid pMD2.G. The viral titer was tested according to the expression level of GFP. The resulting recombinant lentiviral vector was transduced into human prostatic carcinoma DU145 cells, and stably transduced cells were selected by limiting dilution analysis. The intracellular expression level of total p38 was detected by Western blotting and the cell growth curve was drawn. RESULTS: DNA restriction enzyme digestion demonstrated that the recombinant lentiviral vector of the fusion gene EGFP/p38 (pTYF-EF1alpha-EGFP/p38) was constructed successfully. The recombinant lentiviral vector was packaged in 293T with a viral titer of 4.7*10(6) TU/ml. A stable cell line, EGFP/p38-DU145, was established, which stably expressed exogenous EGFP/p38 MAPK fusion protein as detected by Western blotting and showed a lowered growth rate compared to the control cells. CONCLUSION: We have successfully constructed a recombinant lentiviral vector of the fusion gene EGFP/p38 and established a stable cell line EGFP/p38-DU145. Overexpression of p38 has a significant inhibitory effect on the proliferation of DU145 cells in vitro. PMID- 22445975 TI - [Protective effect of atrovastatin against myocardial ischemia-reperfusion injury and on liver and kidney functions in aged rats]. AB - OBJECTIVE: To observe the effect of atorvastatin against myocardial ischemia reperfusion injury and its protective effect on liver and kidney functions. METHODS: Ten-month-old Wistar rats were fed to the age of 20 months, and atorvastatin statins gavage was administered till 24 months. The rats were divided into high-dose statin group, small-dose statin group, aged control group and young control group. The myocardial ischemia-reperfusion model was established by ligating the coronary artery. The mortality, hemodynamic changes, infarct size and liver and kidney functions of the rats were recorded or measured. RESULTS: Compared with the aged control group, the young control group and high-dose statin group showed significantly lower mortality rate, reduced hemodynamic abnormalities, and smaller myocardial infarct size following myocardial ischemia-reperfusion (P<0.05). The liver and kidney functions of the young control group and high-dose statin group underwent no significant deterioration after myocardial ischemia and reperfusion, but those in the small dose statin group and aged control group showed significant deteriorations (P<0.05). CONCLUSION: Atorvastatin offers protective effects on the heart, liver, and kidney in the event of myocardial ischemia-reperfusion in aged rats. PMID- 22445976 TI - [Influence of Cx26/Cx32 gap junction channel on antineoplastic effect of etoposide in Hela cells]. AB - OBJECTIVE: To observe the influence of Cx26/Cx32 gap junction channel on the antineoplastic effect of etoposide in Hela cervical cancer cells. METHODS: Fluorescence trace was used to assay the gap junction intercellular communication mediated by Cx26/Cx32 in Hela cells and its functional modulation by the pharmacological agents (oleamide, retinoid acid). A standard colony-forming assay was applied to determine the cell growth-inhibiting effect of etoposide in Hela cells with functional modulation of the gap junction. Hoechst 33258 staining was used to assess the changes in etoposide-induced apoptosis of Hela cells with altered gap junction functions. RESULTS: Oleamide markedly decreased while retinoid acid obviously increased the gap junction function in Hela cells. Standard colony-forming assay showed that etoposide produced a lowered antiproliferative effect in Hela cells with reduced gap junction and an increased antiproliferative effect in cells with enhanced gap junction function. In cells with a reduced gap junction function, etoposide induced a lowered apoptosis rate, which increased obviously in cells with an enhanced gap junction function. CONCLUSION: The antineoplastic effect of etoposide is reduced in Hela cells with a decreased gap junction intercellular communication mediated by Cx26/Cx32 and is enhanced in cells with an increased gap junction intercellular communication. PMID- 22445977 TI - [Relationship between spinal function and the severity of spinal cord injury by needle puncture]. AB - OBJECTIVE: To observe the changes in spinal cord pathophysiology, motor function and electrophysiology after spinal cord injuries induced by punctures with different needles, and explore a new means for studying spinal neurotoxicity of local anesthetics. METHODS: A total of 144 SD rats were randomly allocated into the sham-operated group (n=36) and 3 spinal cord injury groups (n=36) with the L4 5 segment of the dura mater of the spinal cord punctured using 29G, 25G, and 21G needles. The BBB scores before surgery were recorded, and at 8 h, 24 h, 72 h, 1 week, and 2 weeks after the surgery, the motor evoked potential (MEP), spinal cord pathology and the BBB scores were examined. RESULTS: In the control group, the rats showed normal BBB score, spinal function and microstructure. Spinal cord puncture with 29G needle did not cause obvious pathologies of the spinal cord, whereas puncture with 21G needle resulted in marked changes in the motor function, electrophysiology and histology of the spinal cord, which showed significant improvements at 2 weeks postoperatively. CONCLUSION: Puncture with a 29G needle causes less injuries and minimal functional changes of the spinal cord, which can serve as a new means for studying spinal neurotoxicity of local anesthetics. PMID- 22445978 TI - [Mechanisms of Chansu Injection in reversing multidrug resistance of HL60/ADM cells]. AB - OBJECTIVE: To investigate the mechanisms underlying the effect of Chansu Injection (CHS) in reversing multi-drug resistance (MDR) of HL60/ADM cells. METHODS: MTT assay was used to investigate the effect of CHS on adramycin (ADM) sensitivity of HL-60/ADM cells. Flow cytometry was used to observe the effect of CHS on the cell cycle of HL60/ADM cell. The expressions of NF-kappaB, MRP, GST pi, and iNOS were detected by immunocytochemistry. RESULTS: Treatment with CHS lowered the IC(50) of ADM in HL60/ADM cells from 34.1971 umol/L to 17.4393 umol/L, and caused an increase in G(0)/G1 and G(2)/M phase cells with decreased S phase cells. CHS decreased the expressions of MRP mRNA and GST-pi and MRP proteins but increased the expressions of iNOS and NF-kappaB proteins in the cells. CONCLUSION: CHS can partly reverse MDR in HL60/ADM cells possibly by down regulating MRP and GST-pi, up-regulating NF-kappaB and iNOS, and promoting cell apoptosis, thereby increase ADM sensitivity of HL-60/ADM cells. PMID- 22445979 TI - [Construction of recombinant lentiviral vectors containing Rheb gene and its mutant Rheb'D60K gene and their expression in human liver cancer cells]. AB - OBJECTIVE: To construct recombinant lentiviral vectors carrying Rheb gene and its mutant Rheb'D60K gene, and examine their expression in human liver cancer cells. METHODS: Rheb gene was amplified by PCR to construct the recombinant plasmid LV31 Rheb-WT and LV31-Rheb-D60K. HEK-293 FT cells were contransfected with the recombinant lentiviral vector together with a lentiviral package plasmid to produce the lentiviral particles. The expression of PS6 protein was detected in the lentivirus-infected MCF-7 cells. The apoptosis of SK-HEP-1 cells transfected with LV31-Rheb-WT or LV31-Rheb-D60K was observed. RESULTS: The recombinant LV31 Rheb-WT and LV31-Rheb-D60K vectors were confirmed by PCR and DNA sequencing. Western blotting showed that PS6 protein expression was increased in LV31-Rheb-WT transfected cells while decreased in LV31-Rheb-D60K-transfected cells. LV31-Rheb D60K-transfected SK-HEP-1 cells showed more obvious apoptosis after starvation than LV31-Rheb-WT-transfected cells. CONCLUSION: Lentiviral vectors carrying Rheb gene and its mutant has been successfully constructed, which can be useful in further investigation of the role of Rheb gene in cancer cells. PMID- 22445980 TI - [Anti-apoptotic role of mitochondrial aldehyde dehydrogenase 2 in myocardial ischemia/reperfusion injury in diabetic rats]. AB - OBJECTIVE: To evaluate the anti-apoptotic effect of aldehyde dehydrogenase 2 (ALDH2) on myocardial ischemia/reperfusion (I/R) injury in diabetic rats. METHODS: Normal male SD rats were divided into normal, diabetes and ethanol (the agonist of ALDH2) + diabetes groups. In the latter two groups, diabetes was induced by an intraperitoneal injection of 55 mg/kg STZ. Four weeks after the modeling, myocardial I/R was mimicked ex vivo, and lactate dehydrogenase (LDH) content in the coronary flow was determined. The activities of caspase-3 and ALDH2 were evaluated, and the expressions of Bcl-2 and Bax mRNA in the left anterior myocardium were detected using RT-PCR. RESULTS: In diabetic group, LDH release and caspase-3 activity were increased, while ALDH2 activity and Bcl-2/Bax mRNA expression were decreased as compared to those in normal control group. Compared with the diabetic group, ALDH2 agonist ethanol significantly reduced LDH release and caspase-3 activity, increased ALDH2 activity and Bcl-2/Bax mRNA expression. CONCLUSION: In diabetic rats, enhanced ALDH2 expression can offer mycardial protection possibly in relation to suppress cell apoptosis. PMID- 22445981 TI - [Long-term culture and identification of CD133+ hematopoietic progenitor cells from human umbilical cord blood]. AB - OBJECTIVE: To isolate CD133(+) hematopoietic progenitor cells from human umbilical cord blood and optimize the culture condition for maintaining their stem cell characteristics. METHODS: CD133(+) hematopoietic progenitor cells were isolated from human umbilical cord blood using magnetic cell sorting system, and the cells were detected by flow cytometry. Four methods were used for culturing cells. After 8 weeks' culture, cytomorphology, flow cytometry, immunocytochemistry and immunofluorescence assay were used to identify the characteristics of the stem cells. RESULTS: Over 80% of CD133(+) hematopoietic progenitor cells were isolated from human umbilical cord blood using magnetic cell sorting system. The cells were effectively expanded using optimized serum free medium after 8 weeks of cell culture, whereas the cells in other media differentiated into adherent cells in a poor state. CONCLUSION: The optimized serum-free medium allows effective expansion of CD133(+) hematopoietic progenitor cells that maintain stem cell characteristics after a long-term culture. PMID- 22445982 TI - [Short-term spontaneous fluctuation of viral load in patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate the short-term spontaneous fluctuation of viral load in patients with chronic hepatitis B (CHB) and explore the related factors in treatment naive CHB patients during immune clearance phase. METHODS: A total of 123 treatment naive HBeAg-positive CHB patients with ALT>2 * ULN were enrolled in this study. Paired serum samples were obtained at the first and second visits with an interval of less than 4 weeks. The levels of quantitative HBV DNA (Roche COBAS), quantitative HBsAg, ALT and AST were analyzed. Liver biopsy specimen were collected within 4 weeks and evaluated using Knodell and Ishak histological scoring system. RESULTS: Of the 123 patients, 93 (75.6%) and 30 (24.4%) had HBV DNA fluctuation <= 0.5 Log IU/ml and >0.5 Log IU/ml, respectively. Binary logistic multivariate regression analysis identified Knodell necroinflammation score and HBV DNA level as the factors related to HBV DNA fluctuation. Patients with Knodell necorinflammation score >= 10 or HBV DNA<7 Log IU/ml had significantly higher rates of HBV DNA fluctuation>0.5 Log IU/ml (50.0% vs 18.3%, P=0.042; 42.9% vs 20.6%, P=0.030). CONCLUSION: Treatment naive CHB patients in immune clearance phase show short-term spontaneous fluctuation of HBV DNA, and nearly 25% of the patients have HBV DNA fluctuation >0.5 Log IU/ml. Such fluctuation is related to liver inflammation and quantity of HBV DNA. PMID- 22445983 TI - [Virtual colonoscopy navigation based on colon division]. AB - OBJECTIVE: To develop a virtual navigation mode to enlarge the field of view and decrease the deformation of the visual area. METHOD: The method was implemented in 3 steps. The entire colon was first divided into consecutive sections, and each section was split into two halves by a plane. The virtual camera was finally assigned onto each half of the sections for navigation. RESULTS: Adequate subsections were achieved with this method, which also offer an enlarged field of view for the benefit of focal inspection. CONCLUSION: The division navigation mode is suitable for the development of a virtual colonoscopy navigation and diagnosis system. PMID- 22445984 TI - [Concurrent chemoradiotherapy followed by consolidation chemotherapy and sequential chemoradiotherapy for stage III non-small cell lung cancer: comparison in 93 patients]. AB - OBJECTIVE: To compare the efficacy and toxicity of concurrent chemoradiotherapy followed by consolidation chemotherapy (CCRT-CT) and sequential chemoradiotherapy (SCRT) in the treatment of stage III non-small cell lung cancer. METHODS: From February, 2007 to June, 2010, 93 patients with unresectable stage III non-small cell lung cancer were treated with SCRT or CCRT-CT. SCRT group (50 cases) received radiotherapy after 2-6 cycles of chemotherapy (median 2 cycles) followed by 0-4 cycles (median 2 cycles) of chemotherapy. CCRT-CT group (43 cases) received 2 cycles of chemotherapy every 3 weeks with concurrent radiotherapy followed by 2-4 cycles (median 2 cycles) of chemotherapy with the same drugs. The chemotherapy consisted of cisplatin plus gemcitabine, docetaxel or vinorelbine. Radiotherapy was administered using two-dimensional conformal irradiation (36-40 Gy/18-20f) followed by three-dimensional conformal boost to 56-70 Gy/28-35f (median DT64Gy) or using three-dimensional conformal irradiation 50-74 Gy/25-37f (median DT62Gy). RESULTS: The response rates were 76.7% and 54.0% in CCRT-CT and SCRT group, respectively (P<0.05). The median progression-free time in the two groups was 16.0 and 10.0 months, with the overall survival time of 18.0 and 12.5 months, respectively. The 1-, 2- and 3-year overall survival rates were 83.7%, 48.8% and 20.9% in CCRT-CT group and 52.0%, 20.0%, and 2.0% in SCRT group, respectively (P<0.05). CCRT-CT group showed a significantly lower rate of distant metastasis than SCRT group (P<0.05), but the local recurrence rate was similar between the two groups. The main side effects included radiation pneumonitis, radiation esophagitis, nausea/vomiting and anemia/leucopenia/thrombocytopenia. CCRT-CT group had a significantly higher rate of III-IV grade nausea/vomiting and anemia/leucopenia/thrombocytopenia than SCRT group. CONCLUSION: Compared to SCRT, CCRT-CT can improve the response rate, progression free survival and overall survival and decrease the rate of distant metastasis, but is associated with a higher toxicity. PMID- 22445985 TI - [Contrast-enhanced ultrasound imaging features of diabetic foot ulcers]. AB - OBJECTIVE: To investigate contrast-enhanced ultrasound imaging features of diabetic foot ulcers. METHODS: Sixteen patients with diabetic foot ulcers underwent conventional and contrast-enhanced ultrasound examinations, and the features of contrast-enhanced ultrasound imaging were analyzed. Pathological examination was also carried out in some cases. RESULTS: Contrast-enhanced ultrasound showed slow enhancement in the artery phase in the 16 ulcers after administration of SonoVue. The mean time of initial enhancement was 30.02 +/- 2.35 s, and the mean time for the occurrence of peak enhancement was 37.54 +/- 4.13 s. In 5 cases a homogeneous enhancement pattern was clearly displayed, and in the other 11 cases, a pattern of homogenous peripheral enhancement with non enhanced patches within the ulcers was found. Contrast-enhanced ultrasound showed a greater ulcerous area than conventional ultrasound. CONCLUSION: Contrast enhanced ultrasound is a valuable means for evaluating the ulcerous area and the treatment efficacy for diabetic foot ulcers. PMID- 22445986 TI - [Comparison of different methods for PAS staining of renal biopsy tissue sections]. AB - OBJECTIVE: To compare the performance of a modified PAS staining, traditional PAS staining, Lyon's PAS staining, and Tsunahico Watanabe staining for staining sections of renal biopsy tissue. METHODS: The sections of the renal biopsy tissue were stained with the 4 methods and their staining performance was compared. RESULTS: The modified PAS staining method produced a better contrast and a higher resolution and showed a greater stability after repeated use than the other 3 methods for staining the renal tissue sections (P<0.05). CONCLUSION: The modified PAS staining method shows a better applicability than the other 3 PAS methods for staining sections of renal biopsy tissue. PMID- 22445987 TI - [Proton magnetic resonance spectroscopy and diffusion tensor imaging study of first-episode patients with positive symptoms of schizophrenia]. AB - OBJECTIVE: To study the changes in the frontal white matter, the head of the hippocampus, and the anterior cingulate fasciculus metabolites in first-episode patients with positive symptoms of schizophrenia. METHODS: Twenty first-episode patients with positive symptoms of schizophrenia underwent diffusion tensor imaging (DTI) and proton multi-voxel spectroscopy (1H-MRS) examination. 1H-MRS images were obtained from two sides of the frontal white matter, the head of the hippocampus and the anterior cingulate fasciculus regions. The metabolites detected included N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine and phosphocreatine (Cr), and the ratios of NAA/Cr, Cho/Cr and NAA/Cho were determined. The fractional anisotropy (FA) values were measured in the frontal white matter, the head of the hippocampus, and the anterior cingulate fasciculus. RESULTS: The Cho/Cr ratio was significantly reduced in the left frontal white matter (1.18 +/- 0.21) of the patients as compared to the right side (1.44 +/- 0.34, P<0.05). In the left head of the hippocampus, NAA/Cr (1.34 +/- 0.45) and Cho/Cr (1.41 +/- 0.39) were significantly reduced compared to those of the right side (1.75 +/- 0.15 and 1.76 +/- 0.36, respectively, P<0.05). No significant differences in the metabolite levels were found between the left and right anterior cingulate fasciculus (P>0.05). DTI showed similar FA values between the left and right sides of the frontal white matter, the head of the hippocampus, and the anterior cingulate fasciculus (P>0.05). CONCLUSIONS: Patients with positive symptoms of schizophrenia have diminished neuronal integrity and/or function in the left frontal white matter and head of the hippocampus, but not in the anterior cingulate fasciculus. PMID- 22445988 TI - [Effect of arctiin on mouse podocyte epithelial-mesenchymal transition induced by advanced oxidation protein products]. AB - OBJECTIVE: To study the effect of arctiin on mouse podocyte epithelial mesenchymal transition (EMT) induced by advanced oxidation protein products (AOPP). METHODS: Mouse podocytes were stimulated by 200 ug/ml AOPP for 24 h in the presence of 50, 100, 200, and 400 umol/L arctiin. The expressions of alpha smooth muscle actin, Grp78 and CHOP were detected using Western blotting. RESULT: The expressions of alpha-SMA, Grp78 and CHOP were inhibited by arctiin, showing a dose-dependent effect within a given range of arctiin concentration. CONCLUSION: AOPP causes endoplasmic reticulum stress to induce EMT of mouse podocytes, and arctiin can decrease EMT by alleviating the stress. This finding sheds light on a new scope of research of renal fibrosis. PMID- 22445989 TI - [Effect of sphingosine-1-phosphate on chemotherapy-induced ovarian damage and on the efficacy of chemotherapy in mice bearing S180 tumor]. AB - OBJECTIVE: To investigate the effects of sphingosine-1-phosphate (S1P) on cyclophosphamid (CTX) and cisplatin (DDP)-induced ovarian damage and on the efficacy of chemotherapy in mice bearing S180 murine sarcoma. METHODS: Fifty-two female C57BL/6 mice were randomized into normal control group (n=10), tumor bearing model group (n=14), CTX+DDP group (n=14), and S1P+CTX+DDP group (n=14). Before medication and on day 11 of medication during diestrus stage, the mice were sacrificed to measure the ovarian weight, numbers of primordial follicles and growing follicles, tumor weight, and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol ( E2). RESULTS: At day 11 of medication, the levels of serum FSH and E2, but not LH, showed significant differences in CTX+DDP group from those in the other groups (P<0.01). FSH, E2, and LH levels were comparable between S1P+CTX+DDP group and the control group (P>0.05). The number of primodial follicles and weight of ovaries in CTX+DDP group decreased significantly compared to those in the other groups (P<0.01). The number of growing follicles in CTX+DDP group was significantly lower than that in the control and model groups(P<0.01), but similar to that in S1P group (P>0.05). The number of primodial follicles and growing follicles and ovarian weight in S1P+CTX+DDP group were close to those in the control and model groups (P>0.05). In CTX+DDP and S1P+CTX+DDP groups, the tumor weight were significantly lower than that in the other two groups (P<0.01), and the tumor inhibition rates were both higher than 60%. CONCLUSION: S1P can ameliorate chemotherapy-induced ovarian damage in mice without affecting the efficacy of chemotherapy. PMID- 22445990 TI - [Effects of somatostatin in a rabbit model of abdominal compartment syndrome induced by prolonged intra-abdominal hypertension]. AB - OBJECTIVE: To establish a rabbit model of abdominal compartment syndrome (ACS) induced by prolonged intra-abdominal hypertension (IAH) and evaluate the therapeutic effect of somatostatin on ACS. METHODS: Twelve New Zealand rabbits were randomized equally into normal saline (NS) group and somatostatin group. ACS model was established by intra-abdominal bleeding (IAB) and intra-abdominal infusion with nitrogen gas to achieve an intra-abdominal pressure of 15 mmHg. The hemodynamics (SP, HR, CVP), hepatic function (ALT), renal function (BUN), antioxidation level (SOD, MDA) and blood electrolyte level (pH, [Na(+)], [Cl(-)], [CaNa(2+)], [KNa(+)]) of the rabbits were recorded 1-6 h after establishment of IAH. RESULTS: Prolonged IAH caused decreased hemodynamic functions and antioxidation level as well as hyperkalemia and hypocalcemia (P<0.05), but these changes showed no significant differences between NS group and somatostatin group. CONCLUSION: Prolonged IAH causes cardiovascular function damages in rabbits possibly related to acidosis, electrolyte disturbances, and oxidative damage due to tissue ischemia and hypoxia. Somatostatin produces no obvious protective effects against the occurrence and progression of ACS. PMID- 22445991 TI - [Slow-release recombinant human bone morphogenetic protein-2 suppresses chromium wear particle-induced osteolysis in rats]. AB - OBJECTIVE: To observe the effect of a slow-release recombinant human bone morphogenetic protein-2 (rhBMP-2) formulation on the expressions of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in a murine air pouch model of bone implantation. METHODS: A cranial bone allograft was implanted in the air pouch induced on the back of the recipients. The rat models were then randomized into 5 groups, including a blank control group, chromium particle group, and 3 rhBMP-2 groups receiving 50, 100 or 200 ug/L slow release rhBMP-2 in addition to chromium particles. Three weeks later, the expressions of RANKL and OPG in the air pouch was detected using Western blotting and RT-PCR, and the positively stained area for osteoclasts in the bone graft was determined with TRAP staining for drug effect assessment. RESULTS: RANKL and OPG expressions were found in the air pouches in all the 5 groups. RANKL and OPG protein and mRNA expressions, RANKL/OPG ratio and osteoclast staining area in the bone graft were the highest in chromium particle group (P<0.05), but were significantly decreased by treatment with the slow-release rhBMP-2 formulation (P<0.05); the measurements showed no significant differences between the blank control group and 200 ug/L rhBMP-2 group (P>0.05). CONCLUSION: Chromium particles can cause osteolysis by increasing the RANKL/OPG ratio in rats, and intervention with slow-release rhBMP-2 can significantly promote bone formation and suppress bone resorption by decreasing RANKL/OPG ratio. PMID- 22445992 TI - [Echo-tracking technology for evaluating the impact of blood pressure on vascular endothelial function]. AB - OBJECTIVE: To evaluate the effect of blood pressure on vascular endothelial function using echo-tracking (ET) technology. METHODS: Thirty hypertensive (HP) patients, 30 subjects with high normal blood pressure (HN), and 30 normotensive control (NC) subjects were enrolled in this study. For each subject, conventional two-dimensional ultrasound was performed to measure the intima-media thickness (IMT), and an ET system was utilized to assess the carotid elasticity (Ep, beta, AC, AI, and PWVbeta). RESULTS: As the blood pressure increased, IMT, Ep, beta, AI, and PWVbeta values all increased and AC value decreased. Before excluding the confounding factors, the difference in IMT, Ep, beta, AC, AI, and PWVbeta values were significant between the 3 groups. After excluding the confounding factors, only PWVbeta value was significantly different between HN group and NC group; but between HP and NC group and between HP and HN group, the other parameters still showed significant differences. Systolic blood pressure had significant influences on IMT, Ep, AC, AI, and PWVbeta values, diastolic blood pressure significantly affected AI value, and pulse pressure significantly affected Ep and beta values. CONCLUSION: High normal blood pressure has no obvious effects on vascular function, and blood pressure is an independent risk factor of vascular endothelial dysfunction only in the stage of early hypertention. In early atherosclerosis, systolic blood pressure is the most significant factors affecting vascular endothelial function, followed by pulse pressure and diastolic blood pressure. PMID- 22445993 TI - [Application of genome-wide microarray for screening genes related to peritoneal metastasis of colorectal cancer]. AB - OBJECTIVE: To screen genes related to peritoneal metastasis of colorectal cancer. METHODS: Specimens of primary cancer and normal mucosa tissues were collected from 3 patients with peritoneal metastasis of colorectal cancer. The total RNA were extracted and inversely transcribed into cDNA to synthesize aRNA using in vitro RNA synthesis. The synthesized aRNA, after labeling with Cy3, were hybridized with the whole human genome oligo microarray. The Empirical Bayes method was used to screen the differentially expressed genes, followed by confirmation of the selected genes by semi-quantitative RT-PCR. RESULTS: With a threshold of P<=0.05, a total of 105 differentially expressed genes were identified in primary cancer lesions, including 42 up-regulated and 63 down regulated genes. Three of the up-regulated genes (S100P, PRDX1 and SLPI) were selected and confirmed by RT-PCR, which yielded results consistent with those from gene microarray. CONCLUSION: Gene microarray technique can provide valuable clues for locating the tumor markers of peritoneal metastasis in colorectal cancer patients. PMID- 22445994 TI - [Establishment of a rabbit model of lumbar intervertebral disc degeneration via the paraspinal approach]. AB - OBJECTIVE: To establish a rabbit model of intervertebral disc degeneration by puncturing the anulus fibrosus through an approach between the longissimus dorsi muscle and obliquus externus abdominis. METHODS: The L(4/5) and L(5/6) intervetebral discs of 6 New Zealand white rabbits were punctured by an 18-gauge pin in the anterolateral annular fibrosus through an approach between the longissimus dorsi muscle and the obliquus externus abdominis with the right transverse processes of L(5) and L(6) resected; the L(2/3) discs were used as the control without exposure or needle stab, and the L(3/4) discs were subjected to sham operation with the discs exposed but not punctured after resecting the right transverse process of L(4). X-ray and magnetic resonance imaging (MRI) were performed preoperatively and at the 4th week after puncture. At 4 weeks after the operation, histological and immunohistochemical analyses of the discs were carried out. RESULTS: X-ray of the punctured discs at 4 weeks after the operation presented a significant decrease of disc height, osteophytosis formation, and end plate stiffness; an obvious decrease of signal intensity on T(2)-weighted images was found in the puncture group but not in the control or sham-operated groups. Gross morphological inspection showed atrophy of the nucleus pulposus, which became loose, soft, and fragile with a light yellow color. Histological and immunohistochemical analyses showed a significant decrease of notochordal cells and type II collagen in the nucleus pulposus in the puncture group as compared to the control and sham-operated groups. CONCLUSION: Puncture through the approach between the longissimus dorsi muscle and the obliquus externus abdominis allows the establishment of a reliable animal model for studying intervertebral disc degeneration. PMID- 22445995 TI - [Application of fenestration and suction drainage for treatment of large odontogenic mandibular cystic lesions]. AB - OBJECTIVE: To evaluate the effect of fenestration and suction drainage in the treatment of large odontogenic mandibular cystic lesions. METHODS: From 2005 to 2009, 24 cases of large odontogenic mandibular cystic lesions were treated with fenestration and suction drainage. The clinical symptoms and radiographical findings were evaluated before the operation and at 1 month and 6 months after suction drainage. RESULTS: Follow-up for 1-3 years showed that all the cystic lesions disappeared without recurrence, and the clinical symptoms were resolved. CONCLUSION: Fenestration and suction drainage can reduce the cystic size and rapidly correct the deformity to serve as a useful modality for primary management of large odontogenic mandibular cystic lesions. PMID- 22445996 TI - [Value of MN/CAIX in the diagnosis of renal cell carcinoma]. AB - OBJECTIVE: To investigate the expression of MN/CAIX in patients with renal cell carcinoma (RCC) and assess the value of MN/CAIX in the diagnosis of RCC. METHODS: RT-PCR was employed to detect MN/CAIX mRNA in the carcinoma tissue and peripheral blood of 62 patients with RCC, using normal renal tissue and peripheral blood sample from 32 patients without RCC as control. Immunohistochemistry was used to detect MN/CAIX protein in the tissue specimens of clear cell RCC (n=36), non clear cell renal neoplasm (n=17) and normal kidney (n=16). RESULTS: The positivity rate of MN/CAIX mRNA was 82.3% (51/62) in renal carcinoma tissues and 54.8% (34/62) in the peripheral blood from patients with RCC, significantly higher than the rates in the control cases (P<0.05). In cases of clear cell renal cell carcinoma, the positivity rate of MN/CAIX mRNA was 98% (49/50) in the carcinoma tissues and 66% (33/50) in the peripheral blood, significantly higher than the rates in cases of non-clear cell type of RCC (P<0.05). Immunohistochemistry showed a significantly higher positivity rate of MN/CAIX protein in clear cell RCC tissues [97.2% (35/36)] than in non-clear cell renal neoplasm and normal renal tissues (P<0.05). CONCLUSION: MN/CAIX is specifically overexpressed in RCC, especially in clear cell RCC, suggesting its potential in the diagnosis and prognostic and therapeutic evaluation of RCC. PMID- 22445997 TI - [Application of 1H-NMR-based pattern recognition in serum metabolomics of patients with chronic heart failure]. AB - OBJECTIVE: To investigate the feasibility of applying (1)H-NMR-based pattern recognition in the studies of serum metabonomics in chronic heart failure (HF). METHODS: (1)H-NMR technique was applied for examination of the serum samples from 9 patients with chronic heart failure and 6 healthy individuals. The data were analyzed for pattern recognition through principal component analysis (PCA) and Orthogonal Partial Least Square (OPLS) to determine the differences in serum metabolites between the two groups. The recognition ability of the two analysis methods were compared. RESULTS: The serum (1)H-NMR spectra of heart failure patients and healthy individuals were significantly different. The PCA method failed to distinguish the patterns between the two groups, but OPLS clearly differentiated the two groups. CONCLUSIONS: (1)H-NMR technique is effective in the study of serum metabolomics in chronic heart failure. The serum metabonomics of patients with chronic heart failure and the healthy individuals are significantly different. OPLS pattern recognition method is superior to PCA method in that the former can remove the influence of non-experimental factors and provide an improved characterization. PMID- 22445998 TI - [Expression of NOB1 and its significance in colorectal cancer]. AB - OBJECTIVE: To investigate the expression of NOB1 in colorectal cancer and its relationship with the clinicopathological characteristics. METHODS: The expression of NOB1 was detected immunohistochemically in 60 primary colorectal cancer tissues and the corresponding normal epithelia (3.0 cm away from the cancer margin) and graded according to the staining intensity and the percentage of positively stained tumor cells. RESULTS: NOB1 overexpression was found in 32 of the 60 cases (53.3%). NOB1 overexpression in the adjacent non-neoplastic tissues was found in 10 of the cases (16.7%), a rate significantly lower than that in the cancer tissues (P<0.05). NOB1 expression was not correlated to such tumor characteristics as gender, age, histological differentiation grade, depth of invasion and lymph node metastasis (P>0.05). CONCLUSIONS: NOB1 expression is higher in colorectal cancer than in normal colorectal tissues, suggesting its involvement in the tumorigenesis and progression of colorectal cancer. PMID- 22445999 TI - [Color Doppler ultrasonic measurements of normal mesenteric lymph nodes in healthy children]. AB - OBJECTIVE: To assess the value of color Doppler ultrasound in evaluating the mesenteric lymph nodes in healthy children. METHODS: The mesenteric lymph nodes were examined with color Doppler ultrasonography for 730 randomly selected healthy children under 14 years of age, including 410 boys and 298 girls who did not report any recent medical conditions. RESULTS: Abdominal lymph node detection rate was higher in boys than in girls. Abdominal lymph nodes were detected most often in children between the ages of 1 and 4 years, and the lymph node size decreased gradually with age. CONCLUSION: Color Doppler ultrasonography is valuable for evaluating abdominal lymph nodes in children. PMID- 22446000 TI - [Effect of propofol at uptake equilibrium on gamma-aminobutyric acid in different cerebral regions in dogs]. AB - OBJECTIVE: To investigate the effect of propofol at doses for different anesthesia depths on gamma-aminobutyric acid (GABA) in different cerebral regions at propofol uptake equilibrium in dogs. METHODS: Twelve 12-18-month-old healthy hybrid dogs weighing 10-12 kg were randomly divided into light anesthesia group (n=6) and deep anesthesia group (n=6) with a single bolus dose of propofol (5.5 and 7.0 mg/kg, respectively) completed in 15 s followed by intravenous propofol infusion at a constant rate (55 and 70 mg.kg(-1).h(-1), respectively). Blood samples (2 ml) were taken from the internal carotid artery and jugular vein to measure plasma propofol concentrations 50 min after the start of the infusion. The dogs were then sacrificed and tissues were taken from different brain regions and the cervical cord to measure GABA concentrations using high-pressure liquid chromatography (HPLC). RESULTS: The plasma propofol concentrations in internal carotid artery and jugular vein were similar in both light anesthesia group (3.00 +/- 0.31 and 3.10 +/- 0.51 ug/ml, respectively, P>0.05) and deep anesthesia group (6.41 +/- 0.05 and 6.40 +/- 0.11 ug/ml, respectively, P>0.05). GABA concentrations in the brain regions were significantly higher in deep anesthesia group than in light anesthesia group (P<0.05). The dorsal thalamus and hypothalamus showed greater GABA variations [(83.83 +/- 2.230%) and (85.83 +/- 1.72)%] compared to other brain regions at different anesthesia depths (P<0.05). CONCLUSIONS: In both groups, plasma propofol concentrations in the internal carotid artery and internal jugular vein reach equilibrium at 50 min of propofol infusion. The variation of GABA is associated with the anesthesia depth of propofol, and GABA variation in the dorsal thalamus and hypothalamus plays an important role in propofol anesthesia. PMID- 22446001 TI - [Clinical analysis of 17 cases of Gitelman syndrome]. AB - OBJECTIVE: To analyze the clinical and laboratory characteristics of Gitelman syndrome. METHODS: Seventeen patients with Gitelman syndrome (male/female: 11/6) were analyzed for their clinical symptoms, laboratory test results, imaging findings, treatments and outcomes. RESULTS: Fifteen of the 17 patients presented with varying degrees of lower limb weakness, and 8 experienced flaccid paralysis. The laboratory tests showed hypokalemia (17/17), hypomagnesemia (17/17) and hypocalcemia (17/17). Blood renin activity (17/17), angiotensin II (14/17) and aldosterone levels (7/17) were significantly higher in the patients than in normal subjects. The symptoms were relieved by potassium alone or in combination with indomethacin, spironolactone and other potassium magnesium asparaginate, but the serum potassium and magnesium failed to recover the normal levels after the treatments. CONCLUSION: The primary clinical manifestations of Gitelman syndrome are lower extremity weakness with hypokalemia and hypomagnesemia. Combined drug therapies including potassium, magnesium, aldosterone antagonists and other drugs are recommended. The prognosis of the patients is favorable. PMID- 22446002 TI - [Adipose tissue sample preparation for scanning electron microscopy]. AB - Conventional sample preparation technique for adipose tissue is difficult to achieve satisfactory results for scanning electron microscopy (SEM). We adopted a strategy of postfix with osmium tetroxide to stabilize the fatty acids, phospholipids protein, and hence the membrane structure. Also by extending the dehydration time to fully replace the organic solvents, we achieved satisfactory results for SEM of adipose samples. PMID- 22446003 TI - [Suppurative arthritis caused by Gemella morbillorum in a patient with rheumatoid arthritis of the knee]. AB - Rheumatoid arthritis of the knee is a common disease, but suppurative arthritis caused by Gemella morbillorum in the same joint is rare. We report a case of suppurative arthritis caused by Gemella morbillorum in a patient with rheumatoid arthritis. Because the infection symptoms was not typical, the diagnosis was delayed, and the delayed diagnosis and therapy led to a poor outcome of the patient. PMID- 22446004 TI - A molecular view on signal transduction by the apoptosome. AB - Apoptosomes are signaling platforms that initiate the dismantling of a cell during apoptosis. In mammals, assembly of the apoptosome is the pivotal point in the mitochondrial pathway of apoptosis, and is prompted by binding of cytochrome c to the apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP. The resulting wheel-like heptamer of seven molecules Apaf-1 and seven molecules cytochrome c binds and activates the initiator caspase-9, which in turn ignites the downstream caspase cascade. In this review we discuss the molecular determinants for the formation of the mammalian apoptosome and caspase activation and describe the related signaling platforms in flies and nematodes. PMID- 22446005 TI - A specific increase in inositol 1,4,5-trisphosphate 3-kinase B expression upon differentiation of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are of great hope for regenerative medicine due to their dual pluripotency and self-renewal properties. We report a comparison of inositol phosphate (InsP(s)) production in undifferentiated, differentiated hESCs and in two cancer cell lines, Ntera2 cells, a human embryonal carcinoma cell (hECC) line and HeLa cells. To evaluate the potential impact of InsP(s) in differentiation, hESCs were spontaneously differentiated in culture for two weeks. The distribution of the different InsP(s) was affected upon differentiation: the level of highly phosphorylated InsP(s) was decreased. In contrast, the total level of phosphoinositides (PI) was increased. Using real time quantitative PCR (qPCR), the mRNA expression of several enzymes of the metabolism of InsP(s) was determined: a specific increase in inositol 1,4,5 trisphosphate 3-kinase A and B (ITPKA and ITPKB) was observed upon hESCs spontaneous differentiation. Ins(1,4,5)P(3) 3-kinase activity, undetectable in undifferentiated hESCs, increased upon differentiation. The same observation was made by Western blotting using an antibody directed against human ITPKB. This is the first report showing the potential implication of soluble InsP(s) in hESCs and possible function of isoenzymes of the inositol trisphosphate 3-kinase family in differentiation. PMID- 22446006 TI - Interactions between bone marrow stromal microenvironment and B-chronic lymphocytic leukemia cells: any role for Notch, Wnt and Hh signaling pathways? AB - B-cell chronic lymphocytic leukemia (CLL), which is the most common lymphoproliferative disorder, displays characteristics consistent with a defect in programmed cell death and exhibit prolonged survival of affected cells in vivo. When recovered from peripheral blood or lymphoid tissues of patients and cultured in vitro, CLL malignant cells rapidly undergo spontaneous apoptosis. CLL B-cells co-culture with different adherent cell types, collectively referred to as stromal cells, induces leukemia cell survival, migration, and drug resistance. In addition, such survival-promoting microenvironments can rescue leukemia cells from cytotoxic therapy, giving way to disease relapse. Quite surprisingly considering that many anti-cancer drugs, including gamma-secretase inhibitors, Cyclopamine and Quercetin, were reported to block Notch, Wnt, and Hedgehog anti apoptotic signaling pathways respectively, the link between the latter anti apoptotic pathways and bone marrow stromal cells in CLL has been pointed out only recently. Data concerning the pathogenesis of CLL have been critically reviewed in regards to the growing body of evidence indicating deregulations of Notch, Wnt and Hedgehog anti-apoptotic signaling pathways in the stromal microenvironment of affected cells. PMID- 22446007 TI - Incidence of catheter-related bloodstream infection in a general hospital using two different detection methods. AB - INTRODUCTION: The aim of this study was to determine the incidence of central venous catheter-related bloodstream infection (CRBSI) in a general hospital, using two different assessment methods. METHODS: Method A: One observer prospectively followed up all patients with central venous catheters (CVCs) placed in our hospital over a period of 1 year, recording all CRBSI episodes. Incidence was calculated in two ways, in relation to the total number of catheter days, and in relation to the total number of hospital days of all patients hospitalized during this period. Method B: Another observer recorded all CRBSI episodes diagnosed during the same time period using microbiology data in which blood culture and catheter culture were positive for the same microorganism. Incidence was calculated in relation to the total number of hospital days of all hospitalized patients. The patient's demographic characteristics and the catheter related variables were recorded and analysed. Based on clinical and microbiological criteria, catheters were classified as uninfected, colonized, or CRBSI. RESULTS: Over the study period, 878 central venous catheters were placed in 704 patients. The total number of catheter days was 7357, and the mean duration of catheter use was 8.15 days (1-86). The total number of hospital stays in this period was 92,167. Method A: 15 episodes of CRBSI were detected, yielding an overall incidence of 2.03 episodes/1000 catheter days or 0.16 episodes/1000 hospital days. Method B: 11 episodes of CRBSI, with an incidence of 0.12 episodes/1000 hospital days. CONCLUSION: The two methods studied yielded different CRBSI rates, with a higher incidence reported by prospective follow-up (Method A). In addition, this method enabled a better assessment to be made of CRBSI risk as the calculation could be performed in relation to the days patients were catheterized. PMID- 22446008 TI - [ARCHITECT Chagas((r)): a new diagnostic tool in Chagas disease]. AB - OBJECTIVE: To evaluate a new chemiluminescent microparticle immunoassay (ARCHITECT Chagas((r)), Abbott). METHODS: In this study, 165 samples were tested by two different serological tests. The ARCHITECT Chagas((r)) assay was performed using ARCHITECT i2000(SR) system (Abbott). RESULTS: The sensitivity and specificity of ARCHITECT assay was 100% and 96.6%, respectively. The concordance rate was 0.96 (95%CI: 0.92-1) for ELISA and 0.91 (95%CI: 0.85-0.97) for immunofluorescence assay (IFA). CONCLUSIONS: The ARCHITECT Chagas((r)) assay demonstrates a sensitivity and specificity similar to ELISA and IFA assays; it allows a large volume of samples to be processed with a good standardization and reproducibility, as well as an objective interpretation. PMID- 22446009 TI - Physiological and circuit mechanisms of postural control. AB - The postural system maintains a specific body orientation and equilibrium during standing and during locomotion in the presence of many destabilizing factors (external and internal). Numerous studies in humans have revealed essential features of the functional organization of this system. Recent studies on different animal models have significantly supplemented human studies. They have greatly expanded our knowledge of how the control system operates, how the postural functions are distributed within different parts of CNS, and how these parts interact with each other to produce postural corrections and adjustments. This review outlines recent advances in the studies of postural control in quadrupeds, with special attention given the neuronal postural mechanisms. PMID- 22446010 TI - Dynamical changes in neurological diseases and anesthesia. AB - Dynamics of neuronal networks can be altered in at least two ways: by changes in connectivity, that is, the physical architecture of the network, or changes in the amplitudes and kinetics of the intrinsic and synaptic currents within and between the elements making up a network. We argue that the latter changes are often overlooked as sources of alterations in network behavior when there are also structural (connectivity) abnormalities present; indeed, they may even give rise to the structural changes observed in these states. Here we look at two clinically relevant states (Parkinson's disease and schizophrenia) and argue that non-structural changes are important in the development of abnormal dynamics within the networks known to be relevant to each disorder. We also discuss anesthesia, since it is entirely acute, thus illustrating the potent effects of changes in synaptic and intrinsic membrane currents in the absence of structural alteration. In each of these, we focus on the role of changes in GABAergic function within microcircuits, stressing literature within the last few years. PMID- 22446011 TI - Molecular similarities and differences between Trichinella spp., isolated from canine skeletal muscle in Zacatecas, Mexico. AB - Four different isolates of Trichinella spp. (Z1, Z2, Z3, and Z4) obtained from the skeletal muscle of street dogs in the state of Zacatecas, Mexico were serial passaged in Wistar rats; infective larvae from the skeletal muscle of the rats were collected and frozen in liquid nitrogen. After centrifugation, DNA was extracted and the 5SRNAr and IsRNAr genes were amplified. The isolates were identified by the size of the amplified products from the 5SRNAr and IsRNAr genes (750 and 290 bp, respectively). The amplicons obtained by PCR were sequenced, aligned, and compared to the reference strain Trichinella spiralis MSUS/MEX/91//EM isolated from pigs. Based on our results, we determined that the Trichinella isolates from canine (Z1-Z4) belonged to the T. spiralis species and had 83% identity with the reference strain. The phylogenetic tree constructed from the sequences showed differences between the isolates from pig and dog. These genetic differences may be related to the immune response of the host or the pathogenicity of the isolates. Therefore, these findings have important epidemiological and public health implications. PMID- 22446012 TI - Molecular and morphological identification of larval opecoelids (Digenea: Opecoelidae) parasitising prosobranch snails in a Western Mediterranean lagoon. AB - In a study of the digeneans parasitising molluscs in the Els Alfacs lagoon (Ebro Delta, Western Mediterranean) we found heavy infections with sporocysts emitting two types of cotylocercous cercariae in the prosobranch trochid gastropod Gibbula adansonii and with metacercariae in the prosobranch nassariid gastropod Cyclope neritea. A comparative analysis using ITS ribosomal DNA sequences from these larval stages and published sequences of 17 larval and adult opecoelid stages allowed us to elucidate the life-cycle of Macvicaria obovata and to confirm the identification of Cainocreadium labracis based on cercarial morphology. We provide molecular evidence for the identification and the first detailed morphological descriptions of the intramolluscan larval stages of the two opecoelid species as well as partial 28S rDNA sequences to aid future studies on systematic relationships within the Opecoelidae. PMID- 22446013 TI - Unconditioned freezing is enhanced in an appetitive context: implications for the contextual dependency of unconditioned fear. AB - It has been well established that expression of conditioned fear is context independent, but the context dependency of unconditioned fear expression has rarely been explored. A recent study reported that unconditioned freezing in rats is enhanced in a familiar context, which suggests that unconditioned fear expression can be modulated by contextual processing. In order to further explore this possibility we examined unconditioned freezing in novel, familiar, and appetitive contexts; and attempted to identify brain regions critical for context related changes in unconditioned freezing by measuring c-Fos mRNA levels in emotional circuits. Unconditioned freezing was enhanced in the appetitive context, and this enhancement was accompanied by increased c-Fos mRNA expression in the medial amygdala and hippocampus, but attenuated expression in the medial prefrontal cortex. In the appetitive context, expectation of a reward coupled with detection of threat may have enhanced unconditioned fear expression, which suggests that unconditioned fear expression can be modulated by contextual factors. Context-related expectancy mismatch may explain the enhancement of unconditioned fear expression seen in this study and warrants further examination. PMID- 22446014 TI - Mobilized peripheral blood stem cells compared with bone marrow as the stem cell source for unrelated donor allogeneic transplantation with reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission: an analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient's age was higher in the PBSC versus BM groups 57 (range, 17-77 years) and 51 (range, 17-76 years), respectively (P < .0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (aGVHD) grade >II was significantly higher in the PBSC group: 27% versus 12% in the BM group (P < .002). Similarly, chronic graft-versus-host disease (cGVHD; at 2 years) was somewhat higher in the PBSC group with 43% +/- 3% versus 35% +/- 6% in the BM group, respectively (P = .04). The 2-year probabilities of leukemia-free survival (LFS) were 46% +/- 3% for the PBSC group in comparison to 43% +/- 6% for the BM transplant group (P = NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% +/- 6% versus 32% +/- 3%, respectively (P = .014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% +/- 2% versus 13% +/- 4%, respectively (P = .004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of aGVHD (grade II IV; hazard ratio [HR] = 2.33; P = .06), higher NRM (HR = 2.3; P = .015), and a decreased relapse incidence (HR, 0.61; P = .02) with no statistical difference of LFS between the 2 groups (P = .88). In conclusion, our results indicate significantly higher incidence of aGVHD and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT. PMID- 22446015 TI - Bone marrow B cell precursor number after allogeneic stem cell transplantation and GVHD development. AB - Patients without chronic graft-versus-host disease (cGVHD) have robust B cell reconstitution and are able to maintain B cell homeostasis after allogeneic hematopoietic stem cell transplantation (HSCT). To determine whether B lymphopoiesis differs before cGVHD develops, we examined bone marrow (BM) biopsies for terminal deoxynucleotidyl transferase (TdT) and PAX5 immunostaining early post-HSCT at day 30 when all patients have been shown to have high B cell activating factor (BAFF) levels. We found significantly greater numbers of BM B cell precursors in patients who did not develop cGVHD compared with those who developed cGVHD (median = 44 vs 2 cells/high powered field [hpf]; respectively; P < .001). Importantly, a significant increase in precursor B cells was maintained when patients receiving high-dose steroid therapy were excluded (median = 49 vs 20 cells/hpf; P = .017). Thus, we demonstrate the association of BM B cell production capacity in human GVHD development. Increased BM precursor B cell number may serve to predict good clinical outcome after HSCT. PMID- 22446016 TI - Total activity of glutathione-S-transferase (GST) and polymorphisms of GSTM1 and GSTT1 genes conferring risk for the development of age related cataracts. AB - The pathogenesis of cataract is influenced by a number of factors including oxidative stress. Glutathione-S-transferase (GST) catalyses the nucleophilic addition of the thiol of GSH to electrophilic acceptors. It is important for detoxification of xenobiotics in order to protect tissues from oxidative damage. In humans, GSTT1 and GSTM1 deletion genotypes are associated with a variety of pathological conditions including certain ophthalmic diseases. In the present study, it is aimed to determine the risk of genetic polymorphisms of GSTM1 and GSTT1 isoforms of GST for developing of age related cataracts (ARCs). We compared the prevalence of GSTT1 and GSTM1 deletion genotypes, which were determined by multiplex polymerase chain reaction, in 455 patients with ARCs (108 with nuclear (NC), 105 with cortical (CC), 96 with posterior subcapsular, (PSC) and 146 with mixed type (MT)) and 205 age and sex matched controls. The GST activity in erythrocytes (RBC) and cataractous lenses was measured spectrophotometrically using 1-chloro-2,4-dinitrobenzene (CDNB) as substrate. The frequency of GSTM1 positive individuals was significantly higher in MT cataracts followed by NC, CC and PSC types with corresponding decrease in the GSTM1 null genotypes as compared to controls. Considering the GSTT1 locus, GSTT1 null genotypes showed high frequency in patients in general as compared to controls with corresponding reduction in the GSTT1 positive genotype. The activity of GST in RBC was higher in all the types of cataracts as compared to that in controls and in cataractous lenses the mean values were slightly higher in cases of NC cataracts as compared to CC, PSC and MT. The data suggests that GSTM1 positive, GSTT1 null and double null (GSTM1 null and GSTT1 null) genotypes may confer risk for the development of ARC. The increased activity of GST found in the present study could be due to a compensatory mechanism operating in response to increased oxidative stress. PMID- 22446017 TI - Influence of cadmium concentration and length of exposure on metabolic rate and gill Na+/K+ ATPase activity of golden shiners (Notemigonus crysoleucas). AB - Although metabolic rate is considered to be useful as a general indicator of the biological effects of exposure to metals, it is seldom measured in conjunction with specific physiological, biochemical or cellular parameters. The purpose of this investigation was to examine the influence of cadmium (Cd) exposure on metabolic rate and gill Na(+)/K(+) ATPase activity in golden shiners (Notemigonus crysoleucas). Shiners were exposed to six levels of Cd (ranging from control to the maximum sublethal concentration) for 24- and 96-h periods. After 24-h, metabolic rate and Na(+)/K(+) ATPase activity of individual fish were strongly correlated. Shiners exposed to the four highest Cd concentrations (500, 800, 1100, and 1400 MUg L(-1)) for 24-h exhibited a shock response that was characterized by mean values for metabolic rate and Na(+)/K(+) ATPase activity that were significantly lower compared to the control. Although results for 96-h exposures reflect a repair/recovery phase, there was no significant correlation between metabolic rate and Na(+)/K(+) ATPase activity. Metabolic rate of shiners was significantly elevated (65-100%) at all concentrations compared to the control after 96-h, whereas Na(+)/K(+) ATPase activity did not differ from the control. Elevated metabolic rate after 96-h likely reflects the influence of a variety of energetically demanding processes associated with repair and recovery. PMID- 22446018 TI - Prognostic significance of peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 in cholangiocarcinoma. AB - We performed a comparative proteomic analysis of protein expression profiles in 4 cholangiocarcinoma cell lines: K100, M156, M213, and M139. The H69 biliary cell line was used as a control. Peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 were selected for further validation by immunohistochemistry using a cholangiocarcinoma tissue microarray (n = 301) to assess their prognostic value in this cancer. Both peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 were overexpressed in cholangiocarcinoma tissues compared with normal liver tissues. Of the 301 cholangiocarcinoma cases, overexpression of peroxiredoxin 1 in 103 (34.3%) was associated with an age-related effect in young patients (P = .011) and the absence of cholangiocarcinoma in lymphatic vessels and perineural tissues (P = .004 and P = .037, respectively). Expression of radixin-moesin-binding phosphoprotein 50 correlated with histopathologic type, with 180 (59.8%) of moderately or poorly differentiated tumors (P = .039) being higher, and was associated with the presence of cholangiocarcinoma in lymphatic and vascular vessels (P < .001 and P < .001, respectively). The high expression of radixin-moesin-binding phosphoprotein 50 and the low expression of peroxiredoxin 1 correlated with reduced survival by univariate analysis (P = .017 and P = .048, respectively). Moreover, the impact of peroxiredoxin 1 and radixin moesin-binding phosphoprotein 50 expression on patient survival was an independent predictor in multivariate analyses (P = .004 and P = .025, respectively). Therefore, altered expression of peroxiredoxin 1 and radixin moesin-binding phosphoprotein 50 may be used as prognostic markers in cholangiocarcinoma. PMID- 22446019 TI - A classification tree approach for pituitary adenomas. AB - It is difficult to evaluate the recurrence and progression potential of pituitary adenomas at presentation. The World Health Organization classification of endocrine tumors suggests that invasion of the surrounding structures, size at presentation, an elevated mitotic index, a Ki-67 labeling index higher than 3%, and extensive p53 expression are indicators of aggressive behavior. Nevertheless, Ki-67 and p53 labeling index evaluation is subject to interobserver variability, and their cutoff values are controversial. In the present study, the prognostic value of Ki-67 and p53 protein labeling indices and their correlation with clinical and radiologic parameters were evaluated using digital image analysis in a series of 166 pituitary adenomas in patients having undergone a follow-up of at least 6 years to evaluate the impact on the recurrence and progression potential of pituitary adenomas. The data were analyzed using the receiver operating characteristic curve and classification and regression tree analysis. The results showed that, in the unstratified data set, the commonly used threshold of the Ki 67 index of 3% has a high specificity (89.5%) but a low sensitivity (53.8%). Unsatisfactory performance results were obtained by performing receiver operating characteristic curve analysis on the p53 labeling index. On the contrary, the classification and regression tree analysis-derived tree demonstrated that each pituitary adenoma subtype has specific prognostic factors. Specifically, the Ki 67 labeling index is a useful prognostic factor in nonfunctioning, adrenocorticotropin, and prolactin adenomas, but with different thresholds. In conclusion, our study emphasizes that the term pituitary adenomas includes different types of tumors, each one having specific prognostic factors. PMID- 22446020 TI - Concordance in KRAS and BRAF mutations in endoscopic biopsy samples and resection specimens of colorectal adenocarcinoma. AB - BACKGROUND: KRAS testing is mandatory if anti-EGFR therapy is considered in patients with metastatic colorectal cancer (CRC). In addition, BRAF mutations seem to be an important negative prognostic factor. The aim of this study is to establish the concordance of KRAS and BRAF mutational status in paired biopsy and resection specimens of primary CRC using several analytic methods. METHODS: DNA was extracted from paraffin blocks of 126 CRC patients. KRAS codon 12/13 and BRAF V600E mutational status was assessed using high resolution melting (HRM), direct sequencing (DS) of the HRM polymerase chain reaction (PCR) product. In addition, the Therascreen Amplification Refractory Mutation System (ARMS)-Scorpion KRAS assay and BRAF pyrosequencing were employed; both assays claim to require less tumour cells in comparison with DS. RESULTS: KRAS and BRAF were found to be mutually exclusive. Mutation frequencies were 33.9% for KRAS, and for BRAF 19.0%, respectively. Concordance of KRAS mutational status between biopsy and resection specimens was 97.4% (ARMS), 98.4% (DS) and 99.2% (HRM), respectively. For BRAF concordance was 98.4% (Pyro, DS) and 99.2% (HRM). CONCLUSIONS: KRAS and BRAF mutational status of endoscopic biopsies and resection specimens of CRC showed a >95% concordance. Endoscopic biopsies can be confidently used for molecular analysis. PMID- 22446021 TI - Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer. AB - INTRODUCTION: Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval. METHOD: Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10 years event-free survival. RESULTS: In total, 7751 early stage breast cancer patients were included with a median follow up of 10.9 years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p<0.001). In the subgroup of patients developing a LRR after at least 5 or 10 years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p <= 0.001) and distant DFS (HR 4.42, HR 7.57 p<0.001). CONCLUSION: This is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease. PMID- 22446022 TI - Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. AB - BACKGROUND: The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies. METHODS: Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests. RESULTS: In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p<0.001) and ORR (odds ratio 2.16; p<0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours. CONCLUSION: Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis. PMID- 22446023 TI - Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. AB - AIMS: To provide a quantitative assessment of the association between excess body weight (EBW) and the risk of primary liver cancer (PLC), we performed an updated meta-analysis of prospective observational studies. METHODS: We searched PUBMED and EMBASE for studies of body mass index and the risk of PLC published through 15 th September 2011. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. The meta regression and stratified methods were used to examine heterogeneity across studies. RESULTS: A total of 26 prospective studies, including 25,337 PLC cases, were included in this analysis. Overall, excess body weight (EBW: body mass index (BMI) >= 25 kg/m2) and obesity (BMI >= 30 kg/m2) were associated with an increased risk of PLC, with significant heterogeneity (EBW: SRRs 1.48, 95% CIs 1.31-1.67, P(h)<0.001, I2=83.6%; Obesity: SRRs 1.83, 95% CIs 1.59-2.11, P(h)<0.001, I2=75.0%). Subgroup analyses revealed that the positive associations were independent of geographic locations, alcohol consumption, history of diabetes or infections with hepatitis B (HBV) and/or hepatitis C virus (HCV). Obese males had a higher risk of PLC than obese females did (P=0.027). A stronger risk of PLC with EBW was observed for patients with HCV (but not HBV) infection or cirrhosis compared with the general population. CONCLUSIONS: Findings from this meta-analysis strongly support that EBW or obesity is associated with an increased risk of PLC in both males and females. PMID- 22446024 TI - Photoluminescence lineshape features of carbon delta-doped GaAs heterostructures. AB - Photoluminescence lineshape properties of quasi-two-dimensional electron systems in setback delta-doped GaAs heterostructures are studied at liquid helium temperature. Contributions from the ground and the first excited two-dimensional subband are clearly observed. A simple fit to the lineshape including broadening demonstrates that there is an exponential low-energy tail associated with the ground subband. No such tail is observed for the first excited subband. The fit precisely reveals the subband bottom energies, the Fermi energy, the electron temperature and the recombination intensities. A self-consistent calculation of subband properties including the potential contribution of the setback delta doping reproduces well the subband properties and the recombination intensities. PMID- 22446025 TI - Two-start design within a Sephadex inflammatory model--a means to generate reliable ED50 data whilst significantly reducing the number of animals used. AB - Pulmonary inflammation disorders represent a major healthcare burden, and novel anti-inflammatory agents are critically needed for the treatment of patients unresponsive to current therapies. In vivo animal models play a key role in the preclinical assessment of novel anti-inflammatory compounds. The implementation of streamlined in vivo experimental designs that are time-and cost-efficient, while keeping animal usage low, is a key consideration for drug optimization programs. The Sephadex rat model of pulmonary inflammation captures many pathophysiologic characteristics of clinical asthma and allergy, such as eosinophilic infiltration andinterstitial edema. Using the in vivo Sephadex model, we compared two different study designs that were implemented to screen and select two novel candidate drugs for a drug discovery project. The traditional one-start design, which utilizes few dose-testing groups with many animals per group, was used to select the first candidate drug. Due to tight timelines, the selection process for the second candidate drug had to be optimized, leading to the development of the novel two-start design, an approach whereby dose ranges are optimized in two experimental phases. Here we show that both study designs were comparable in their generation of robust median effective dose values for selected candidate drugs, as represented by similar confidence interval ratios. However, implementation of the two-start design resulted in approximately 50% fewer animals and 50% less time taken to assess the efficacy of an equal number of compounds compared with the one-start design. These results demonstrate that the two-start design is a more efficient experimental approach, and its widespread implementation in drug optimization programs will impact upon the selection process for candidate drugs with regards to time, cost, and animal usage. PMID- 22446026 TI - Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning. AB - Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS-/- mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS-/- mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS-/- mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS-/- mice. Conversely, CEES induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS-/- mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. PMID- 22446027 TI - Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice. AB - OBJECTIVE: Proliferation signal inhibitors/mTOR-inhibitors have been shown to reduce de novo development of hypercholesterolemic atherosclerosis in animal models. However, their effect on pre-existing atherosclerosis has not yet been studied. METHODS AND RESULTS: Feeding LDL-R-KO mice a high cholesterol diet for 12 weeks resulted in formation of moderate fibroatheroma (induction phase). Sixty mice received either everolimus (1 or 5 mg/kg) or no everolimus for further 12 weeks (treatment phase). Everolimus significantly enhanced hypercholesterolemia (plasma cholesterol +45%, p<0.001). Atherosclerosis progressed obstructively in treated and non-treated mice. Everolimus (5 mg/kg) tended to reduced progression in aortic root lesions (0.28+/-0.02 vs. 0.33+/-0.03 mm(2), p=ns) and brachiocephalic lesions (0.044+/-0.006 vs. 0.066+/-0.012 mm(2), p=ns) but without significance. Everolimus (5mg/kg) resulted in an arrest of CD68 positive plaque area (p=0.03) and nearly halved CD68 fraction (p=0.05) in aortic root lesions but not in brachiocephalic lesions. Taken together, despite a trend to reduced progression and inflammatory cell content there was less conclusive net effect of everolimus treatment than expected. CONCLUSION: A higher potential of everolimus in the treatment of atherosclerosis might be obscured by its concomitant hypercholesterolemia. Considering stronger effects in previous studies we suggest that everolimus might exert more potent anti-atherogenic properties in earlier stages of atherogenesis than in advanced atherosclerosis. PMID- 22446028 TI - Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. PMID- 22446029 TI - Effect of substrate stiffness on pulmonary fibroblast activation by TGF-beta. AB - Peptide crosslinkers containing the sequence C-X-CG (X represents various adhesive peptides) were incorporated into poly(ethylene glycol) (PEG) hydrogel networks with different mechanical properties. Pulmonary fibroblasts (PFs) exhibit increased adhesion to rigid hydrogels modified with X=RGDS, DGEA and IKVAV (0.5 and/or 5 mM) compared with a scrambled control (X=HRPNS). PFs exhibit increased adhesion to softer hydrogels when X=DGEA at low (0.5 mM) peptide concentration. PFs seeded onto hydrogels modified with X=RGDS produce alpha smooth muscle actin (alpha-SMA), a myofibroblast marker, and form an extensive cytoskeleton with focal adhesions. Decreasing substrate stiffness (achieved through hydrolytic degradation) results in down-regulation of alpha-SMA expression by PFs. Substrate stiffness increases the sensitivity of PFs to exogenously applied transforming growth factor beta (TGF-beta1); PFs on the most rigid gels (E=900 kPa) express alpha-SMA when treated with low concentrations of TGF-beta1 (1 ng ml(-1)), while those on less rigid gels (E=20-60 kPa) do not. These results demonstrate the importance of both mechanical and chemical cues in studying pulmonary fibroblast activation, and establish PEG hydrogels as a viable material for further study of IPF etiology. PMID- 22446030 TI - Strut size and surface area effects on long-term in vivo degradation in computer designed poly(L-lactic acid) three-dimensional porous scaffolds. AB - Current developments in computer-aided design (CAD) and solid free-form fabrication (SFF) techniques enable fabrication of scaffolds with precisely designed architectures and mechanical properties. The present study demonstrates the effect of precisely designed three-dimensional scaffold architectures on in vivo degradation. Specifically, three types of porous poly(L-lactic acid) (PLLA) scaffolds with variable pore sizes, strut sizes, porosities, and surface areas fabricated by indirect SFF. In addition, one experimental group of PLLA solid cylinders was fabricated. The scaffolds and cylinders were subcutaneously implanted into mice for 6, 12 and 21 weeks. The solid cylinders exhibited a faster percentage mass loss than all porous scaffolds. Among the porous scaffolds the group with the largest strut size lost percentage mass faster than the other two groups. Strong correlations between surface area and percentage mass loss were found at 12 (R(2)=0.681) and 21 (R(2)=0.671) weeks. Scaffold porosity, however, was not significantly correlated with degradation rate. Changes in molecular weight and crystallinity also resulted in changes in the chemical structures due to degradation, and the solid cylinders had faster crystallization due to more advanced degradation than the porous scaffolds. Scaffold compressive moduli decreased with degradation, but the resulting modulus was still within the lower range of human trabecular bone even after 21 weeks. The loss in compressive moduli, however, was a complex function of both degradation and the initial scaffold architecture. This study suggests that CAD and fabrication, within a given material, can significantly influence scaffold degradation profiles. PMID- 22446031 TI - Mouse models for peroxisome biogenesis defects and beta-oxidation enzyme deficiencies. AB - Peroxisome biogenesis and peroxisomal beta-oxidation defects are rare inherited metabolic disorders in which several organs can be affected. A panel of mouse models has been created in which genes crucial to these processes were inactivated and the ensuing pathologies studied. In mice with enzyme defects of peroxisomal beta-oxidation, the disease state strongly depends on the kind of substrates that are metabolized by the enzyme and the dietary composition. Because mice with generalized biogenesis defects seldom reach adulthood, conditional knockout models were generated to study the consequences of peroxisome deficiency in hepatocytes, different brain cell types and Sertoli cells. Although the precise relationship between the biochemical anomalies and pathologies was often not resolved, the mouse models allowed to document in detail histological abnormalities, metabolic and gene expression deregulations some of which are mediated by PPARalpha, and to uncover the essential role of peroxisomes in some unsuspected cell types. PMID- 22446032 TI - Primary hyperoxalurias: disorders of glyoxylate detoxification. AB - Glyoxylate detoxification is an important function of human peroxisomes. Glyoxylate is a highly reactive molecule, generated in the intermediary metabolism of glycine, hydroxyproline and glycolate mainly. Glyoxylate accumulation in the cytosol is readily transformed by lactate dehydrogenase into oxalate, a dicarboxylic acid that cannot be metabolized by mammals and forms tissue-damaging calcium oxalate crystals. Alanine-glyoxylate aminotransferase, a peroxisomal enzyme in humans, converts glyoxylate into glycine, playing a central role in glyoxylate detoxification. Cytosolic and mitochondrial glyoxylate reductase also contributes to limit oxalate production from glyoxylate. Mitochondrial hydroxyoxoglutarate aldolase is an important enzyme of hydroxyproline metabolism. Genetic defect of any of these enzymes of glyoxylate metabolism results in primary hyperoxalurias, severe human diseases in which toxic levels of oxalate are produced by the liver, resulting in progressive renal damage. Significant advances in the pathophysiology of primary hyperoxalurias have led to better diagnosis and treatment of these patients, but current treatment relies mainly on organ transplantation. It is reasonable to expect that recent advances in the understanding of the molecular mechanisms of disease will result into better targeted therapeutic options in the future. PMID- 22446033 TI - Prevalence and risk factors for diabetic microvascular complications in newly diagnosed type II diabetes mellitus. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS, report 27). AB - PURPOSE: The aims of this study were to report the prevalence of various microvascular complications and to identify the various clinical and biochemical characteristics related to these complications in subjects with newly diagnosed type II diabetes. METHODS: Of the 5999 subjects enumerated, 1414 subjects with diabetes (both known and newly diagnosed) were analyzed for the study. Among the diabetic subjects, 248 (17.5%) were newly diagnosed with diabetes and the remaining had history of diabetes. All subjects underwent a detailed standard evaluation to detect diabetic retinopathy (fundus photography), neuropathy (vibration pressure threshold), and nephropathy (microalbuminuria). RESULTS: The prevalence of any form of microvascular complication was 30.2% (95% confidence interval [CI]=24.5-35.9). The prevalence of diabetic retinopathy was 4.8%, and that of diabetic nephropathy and neuropathy was 10.5%. The risk factors for developing any form of microvascular complication were increasing age (odds ratio [OR]=1.07, 95% CI=1.04-1.11, P<.0001), increasing systolic blood pressure (OR=1.03, 95% CI=1.01-1.06, P=.001), and increasing hemoglobin (OR=1.39, 95% CI=1.09-1.79, P=.011). The risk factors for diabetic retinopathy and diabetic nephropathy were increasing systolic blood pressure (OR=1.06 [P=.001] for retinopathy and OR=1.04 [P=.012] for nephropathy) and increasing hemoglobin (OR=2.20 [P=.007] for retinopathy and OR=1.57 [P=.023] for nephropathy). The risk factor for diabetic neuropathy was increasing age (OR=1.12, P<.0001). CONCLUSIONS: Nearly one third of the newly diagnosed type II diabetes subjects had some form of microvascular complication; nephropathy, and neuropathy being commoner than retinopathy. PMID- 22446034 TI - Is silent myocardial infarction more common in women with type 2 diabetes than in men? AB - OBJECTIVE: Our aim was to determine if silent myocardial infarction (MI) is more common in women with type 2 diabetes than in men. Our secondary aim was to examine the relationships between silent MI and risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) database was used to determine if women had more silent MI on baseline electrocardiograms (ECGs) than did men with a similar unremarkable cardiovascular history. MI was diagnosed using ECG analysis according to the Minnesota code. Multivariable logistic regression analysis was used to compare demographic and clinical associations. Interactive effects of risk factors by gender were tested using a forward selection algorithm. RESULTS: Men were found to have a higher prevalence of silent MI on baseline ECGs than women (6% vs 4%, P = .001). Women had lower odds of silent MI than men after adjusting for other risk factors (OR = 0.80, P = .04). Race and ethnicity were significantly associated with silent MI (P = .02), with Asians having the highest and African Americans and Hispanics having lower odds relative to whites. CONCLUSIONS: Our main findings provide no evidence that silent MI, as detected by the Minnesota code, was more common in women than in men in the ACCORD cohort. If, as in the general population, the women in ACCORD are found to have a higher heart disease mortality rate than the men, it seems unlikely that failure to recognize clinically silent heart disease in the years before study enrollment could be a major cause. PMID- 22446035 TI - Patient and physician factors associated with adherence to diabetes medications. AB - PURPOSE: The purpose of this study was to examine the influence of patient and physician psychosocial, sociodemographic, and disease-related factors on diabetes medication adherence. These factors were also examined as effect modifiers of the association between quality of the patient-physician relationship and medication adherence. METHODS: Data were collected from 41 Geisinger Clinic primary care physicians and 608 of their patients with type 2 diabetes. Adherence to oral hypoglycemic medications was calculated using a medication possession ratio based on physician orders in electronic health records (MPR(EHR)). MPR(EHR) was defined as the proportion of total time in the 2 years prior to study enrollment that the patient was in possession of oral hypoglycemic medications. Linear regression was used to examine the influence of patient- and physician-level factors on adherence. Effect modification of the patient-physician relationship-adherence association was evaluated by adding the main effects of the individual-level factors and their cross-products to the models. RESULTS: In adjusted analyses, satisfaction with the physician's patient education skills, patient beliefs about the need for their medications, and lower diabetes-related knowledge were associated with better adherence to oral hypoglycemic medications. Shorter duration of time with diabetes and taking only oral hypoglycemic medications were also associated with better adherence. Finally, the association between shared decision making and medication adherence was significantly modified by patients' level of social support. CONCLUSIONS: This study identified several patient-, physician-, and disease-related factors that should be targeted to maximize the potential for developing tailored adherence-enhancing interventions within the context of a collaborative patient-physician relationship. PMID- 22446036 TI - Facilitating pediatric patient-provider communications using wireless technology in children and adolescents with sickle cell disease. AB - INTRODUCTION: Use of wireless devices has the potential to transform delivery of primary care services for persons with sickle cell disease (SCD). The study examined text message communications between patients and an advanced practice registered nurse (APRN) and the different primary care activities that emerged with use of wireless technology. METHODS: Patients (N = 37; mean age 13.9 +/- 1.8 years; 45.9% male and 54.1% female) engaged in intermittent text conversations with the APRN as part of the Wireless Pain Intervention Program. Content analyses were used to analyze the content of text message exchanges between patients and the APRN. RESULTS: The primary care needs that emerged were related to pain and symptom management and sickle cell crisis prevention. Two primary care categories (collaborating and coaching), four primary care subcategories (screening, referring, informing, and supporting), and 16 primary care activities were evident in text conversations. DISCUSSION: The use of wireless technology may facilitate screening, prompt management of pain and symptoms, prevention or reduction of SCD-related complications, more efficient referral for treatments, timely patient education, and psychosocial support in children and adolescents with SCD. PMID- 22446037 TI - Reply to letter to the editor. PMID- 22446038 TI - Statins and postoperative atrial fibrillation: a long way ahead. PMID- 22446039 TI - Systematic identification of common functional modules related to heart failure with different etiologies. AB - The development of heart failure (HF) is a complex process that can be initiated by multiple etiologies. Identifying common functional modules associated with HF is a challenging task. Here, we developed a systems method to identify these common functional modules by integrating multiple expression profiles, protein interactions from four species, gene function annotations, and text information. We identified 1439 consistently differentially expressed genes (CDEGs) across HF with different etiologies by applying three meta-analysis methods to multiple HF related expression profiles. Using a weighted human interaction network constructed by combining interaction data from multiple species, we extracted 60 candidate CDEG modules. We further evaluated the functional relevance of each module by using expression, interaction network, functional annotations, and text information together. Finally, five functional modules with significant biological relevance were identified. We found that almost half of the genes in these modules are hubs in the weighted network, and that these modules can accurately classify HF patients from healthy subjects. We also identified many significantly enriched biological processes that contribute to the pathophysiology of HF, including two new ones, RNA splicing and vesicle-mediated protein transport. In summary, we proposed a novel framework to analyze common functional modules related to HF with different etiologies. Our findings provide important insights into the complex mechanism of HF. Further biological experimentations should be required to validate these novel biological processes. PMID- 22446040 TI - A novel locus for body mass index on 5p15.2: a meta-analysis of two genome-wide association studies. AB - OBJECTIVE: Genetic factors play an important role in modulating the vulnerability to body mass index (BMI). The purpose of this study is to identify novel genetic variants for BMI using genome-wide association (GWA) meta-analysis. METHODS: PLINK software was used to perform meta-analysis of two GWA studies (the FUSION and Marshfield samples) of 5218 Caucasian individuals with BMI. A replication study was conducted using the SAGE sample with 762 individuals. RESULTS: Through meta-analysis we identified 33 SNPs associated with BMI with p<10(-4). The most significant association was observed with rs2967951 (p=1.19*10(-6)) at 5p15.2 within ROPN1L gene. Two additional SNPs within ROPN1L and 5 SNPs within MARCH6 (the top SNP was rs2607292 with 4.27*10(-6)) further supported the association with BMI on 5p15.2 (p<1.8*10(-5)). Conditional analysis on 5p15.2 could not distinguish the effects of ROPN1L and MARCH6. Several SNPs within MARCH6 and ROPN1L were replicated in the SAGE sample (p<0.05). CONCLUSION: We identified a novel locus for BMI. These findings offer the potential for new insights into the pathogenesis of BMI and obesity and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in BMI and obesity. PMID- 22446041 TI - A screen for non-coding RNA in Mycobacterium tuberculosis reveals a cAMP responsive RNA that is expressed during infection. AB - A key to the success of Mycobacterium tuberculosis (Mtb) is the bacteria's ability to survive and thrive in the presence of numerous stresses mounted by the host. Small, non-coding RNAs (sRNAs) have been shown to modulate numerous stress responses in bacteria, yet to date only two studies have screened the Mtb transcriptome to identify sRNA. Their association with oxidative and acid stress has been demonstrated but the cellular function and role of these sRNAs in the pathogenesis of tuberculosis (TB) remain unknown. Here, we have identified an sRNA, ncrMT1302, in a locus involved in cAMP metabolism and demonstrate that expression of ncrMT1302 responds to changes in pH and cAMP concentration. The differential expression of ncrMT1302 observed in wild-type Mtb during growth is abolished in a strain lacking MT1302, an adenylyl cyclase encoding gene. We report that ncrMT1302 is expressed in Mtb residing in the lungs of mice during an active infection. PMID- 22446042 TI - Two novel N-terminal coding exons of Prkar1b gene of mouse: identified using a novel approach of in silico and molecular biology techniques. AB - The Prkar1b gene encodes regulatory type 1 beta subunit of protein kinase A. Here we report that mouse R1beta gene produces three alternative splice variants (designated as mR1beta1, mR1beta2 and mR1beta3) that have different N-terminal protein structures. New splice variants were identified using combinatorial approach of bioinformatics pipeline involving online available tools and databases, and molecular biology techniques involving RT-PCR, semi-nested PCR and sequencing. Except mR1beta3, which was not detected by RT-PCR in brain and muscle tissues of 3day old mice, all three spliced isoforms were found to be ubiquitously expressed in tissues and postnatal developmental stages examined. The presence of different N-termini in isoforms may be important for unique docking interactions with A kinase anchoring proteins. PMID- 22446043 TI - Identification and characterization of canine growth differentiation factor-9 and its splicing variant. AB - Growth differentiation factor-9 (GDF-9), a member of the transforming growth factor-beta (TGF-beta) superfamily, is expressed exclusively in the oocyte within the ovary and plays essential roles in the ovarian function in mammals. However, a possible involvement of GDF-9 in canine ovarian physiology that has a unique ovulation process among mammals has not been studied. Interestingly, we have isolated two types of cDNA clones generated by an alternative splicing from a canine ovarian total RNA. The predominant long form cDNA shares a common precursor structure with GDF-9s in other species whereas the minor short form cDNA has a 172 amino acid truncation in the proregion. Using a transient expression system, we found that the long form cDNA has a defect in mature protein production whereas the short form cDNA readily produces mature protein. However, mutations at one or two N-glycosylation sites in the mature domain of the short form GDF-9 caused a loss in mature protein production. These results suggest that the prodomain and N-linked glycosylation of the mature domain regulate proper processing and secretion of canine GDF-9. Based on the biological functions of GDF-9, these characteristics of canine GDF-9 could be causatively linked to the unique ovulation process in the Canidae. PMID- 22446044 TI - Characterization of miR-10a mediated gene regulation in avian splenocytes. AB - It is well established that microRNAs (miRNAs) are an important class of post transcriptional regulators of gene expression. Although numerous miRNA expression profiles have been generated for many eukaryotic organisms, little is known about the specific functions of individual miRNAs in regulating gene expression. We previously reported that the miRNA, miR-10a, is highly expressed during spleen development in embryonic chicks. In this current study we have identified genes and potential pathways that are both directly and indirectly influenced by miR 10a expression. To achieve this goal, miRNA Real-Time (RT) PCR analysis was first utilized to examine miR-10a expression across tissues during both embryonic and post-hatch chick development. Next, microarray analysis was employed to determine alterations in global gene expression associated with miR-10a in embryonic chick splenocytes subjected to an in vitro miR-10a inhibitor treatment. Finally the miRNA target prediction algorithm miRanda was used to predict potential chicken genes directly targeted by miR-10a. A select group of potential miR-10a target genes was validated using an RCAS-miRNA expression based luciferase assay. Our results indicate that miR-10a is highly expressed in the avian spleen, lung, kidneys, and fat tissues. Functional analysis suggests that miR-10a is involved in regulating gene expression in pathways associated with Ras signaling, intracellular trafficking, and development of immune functions. Additionally, we confirmed that chicken HOXA1 is a miR-10a target gene, suggesting a conserved role for miR-10a in the regulation of hematopoiesis across vertebrates. PMID- 22446045 TI - MLPA: a prenatal diagnostic tool for the study of congenital heart defects? AB - Congenital heart defects (CHD) represent the most common birth defects, so they are not a rare finding when performing routine ultrasound examinations during pregnancy. Once chromosome abnormalities have been excluded in a fetus with a CHD, chromosome 22q11.2 deletion is usually investigated by FISH, as it is the most frequent microdeletion syndrome and is generally associated with cardiac malformations. If 22q11.2 microdeletion is ruled out, the etiology of the CHD remains generally unexplained, making familial genetic counseling difficult. To evaluate the usefulness of Multiplex Ligation-dependent Probe Amplification (MLPA) kits designed for the study of 22q11.2 and other genomic regions previously associated with syndromic CHD, we performed MLPA in 55 pregnancies with fetuses presenting CHD, normal karyotype and negative FISH results for 22q11.2 microdeletion, which constitutes the largest prenatal series reported. Definitive MLPA results were obtained in 50 pregnancies, and in this setting such MLPA kits did not detect any imbalance. On the other hand, to compare FISH and MLPA techniques for the study of 22q11.2 microdeletions, we performed MLPA in 4 pregnancies known to have 22q11.2 deletions (by FISH). All four 22q11.2 microdeletions were also detected by MLPA, which corroborates that it is a reliable technique for the diagnosis and characterization of 22q11.2 deletions. Finally, we evaluated the possibility of replacing conventional FISH by MLPA for the prenatal diagnosis of CHD, comparing the diagnostic potential, results delivery times, repetition and failure rates and cost of both techniques, and concluded that FISH should still be the technique of choice for the prenatal diagnosis of fetuses with CHD. PMID- 22446046 TI - Novel in-frame deletion mutation in FLCN gene in a Korean family with recurrent primary spontaneous pneumothorax. AB - Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant disease presenting with skin fibrofolliculomas, pulmonary cysts, primary spontaneous pneumothorax (PSP), and renal cancer. It is caused by germline mutations in the FLCN gene, which encodes folliculin. Here we report a novel in-frame deletion mutation p.F143del (c.427_429delTTC) in exon 6 of FLCN gene in the proband and her two sisters. The proband was a 40-year-old Korean woman who presented with right-sided pneumothorax and papular lesions on the face and neck area but without renal cancer. Her father also had a history of PSP and died of renal cancer at the age of 75. Her older sisters have been treated for recurrent PSP but did not have skin lesions suspicious of fibrofolliculoma. The relative expression of FLCN was significantly reduced in the proband and one of the sibling who was confirmed to have FLCN mutation. In-frame deletions in the FLCN gene have rarely been reported but have been shown to impose significant effect on protein stability of FLCN. Identification of a novel genotype in BHDS will provide clues to the phenotype genotype relations and may aid in explaining the molecular pathogenesis of diseases related to FLCN mutation. PMID- 22446047 TI - Ethanol fermentation kinetics in a continuous and closed-circulating fermentation system with a pervaporation membrane bioreactor. AB - The kinetics of ethanol fermentation by Saccharomyces cerevisiae was studied in a continuous and closed-circulating fermentation (CCCF) system with a polydimethylsiloxane (PDMS) pervaporation membrane bioreactor. Three sequential 500-h cycles of CCCF experiments were carried out. A glucose volumetric consumption of 3.8 g L(-1) h(-1) and ethanol volumetric productivity of 1.39 g L( 1) h(-1) were obtained in the third cycle, with a specific glucose utilization rate of 0.32 h(-1) and ethanol yield rate of 0.13 h(-1). The prolonged fermentation time and good fermentation performance indicate that the CCCF would be a feasible and promising fermentation process technology. PMID- 22446048 TI - Surface properties of SAC and its adsorption mechanisms for phenol and nitrobenzene. AB - The physicochemical properties of an activated carbon produced from sewage sludge (SAC) were determined and compared with those of a market activated carbon (MAC). Phenol and nitrobenzene were selected as the target compounds and their adsorption behaviors in water and cyclohexane were studied and compared. The experimental results showed that the surface area of SAC was only 1/4 of that of the MAC. Functional groups on the SAC are all acid groups while basic groups are the dominant on the MAC. Based on the properties of the activated carbons and the adsorption behaviors of the two organic pollutants, it could be inferred preliminarily that phenol adsorption was mainly affected by surface area but nitrobenzene adsorption was affected by both surface area and surface functional groups. In water, when the initial concentration is between 0.1 and 10 mmol/L, the maximum phenol and nitrobenzene adsorption capacity of SAC is 0.48 and 1.26 mmol/g respectively, which is 1/4 and 1/3 of that of MAC. In cyclohexane, SAC's phenol adsorption capacity is higher and nitrobenzene adsorption capacity is lower than that in water; but MAC's phenol adsorption capacity does not change much and nitrobenzene adsorption capacity decreases a lot compared that in water. The results further indicate that the hydrophobicity and the polarity of the organic pollutants can greatly affect their adsorption in water. For SAC, polar interaction and hydrophobic interaction may be the main mechanisms affecting the sorption of nitrobenzene in water. For MAC, hydrophobic interaction and pi-pi interaction may be the main mechanisms affecting the sorption of nitrobenzene in water. For both phenol and nitrobenzene, the adsorption capacities of MAC are higher than that of SAC. PMID- 22446049 TI - Electricity generation from a floating microbial fuel cell. AB - A floating microbial fuel cell (FMFC) has been designed and its performance has been evaluated for 153 days. The power output gradually increased to a maximum value of 390 mW/m(3) at 125 days. The polarization resistance of the anode (R(p)(a)) changed with operating time reaching a minimum value at 125 days, while the polarization resistance of the cathode (R(p)(c)) was relatively constant and much smaller than R(p)(a). It has been demonstrated that the observed changes of the internal resistance (R(int)) and the maximum power (P(max)) with exposure time were mainly due to the changes of R(p)(a). Compared with sediment MFCs for which the anode is embedded in marine or river sediments, the application of the FMFC, which could be installed in a buoy, is not limited by the depth of the ocean. The FMFC has the potential to supply electricity to low-power consuming electronic devices at remote locations. PMID- 22446050 TI - Pretreatment of rice hulls by ionic liquid dissolution. AB - As a highly available waste product, rice hulls could be a starting block in replacing liquid fossil fuels. However, their silica covering can make further use difficult. This preliminary study investigates effects of dissolving rice hulls in the ionic liquids 1-ethyl-3-methylimidazolium acetate (EMIM Ac), 1-hexyl 3-methylimidazolium chloride, (HMIM Cl), and 1-allyl-3-methylimidazolium chloride (AMIM Cl), and what lignocellulosic components can be precipitated from the used ionic liquid with water and ethanol. EMIM Ac dissolution at 110 degrees C for 8 h was found to completely remove lignin from rice hulls, while ethanol was capable of precipitating lignin out of the used EMIM Ac. With 8h dissolution at 110 degrees C using HMIM Cl, approximately 20% of the cellulose in the rice hull sample can be precipitated out using water as co-solvent, while more than 60% of the hemicellulose can be precipitated with ethanol. PMID- 22446051 TI - Performance and model of a novel membrane bioreactor to treat the low-strengthen complex wastewater. AB - A MLMBR and a conventional IMBR with DO control system were investigated for simultaneously removing organic carbon and nitrogen in the low-strengthen complex wastewater. Four stages of the laboratory scale system with SRT of 30 day and HRTs of 20, 16, 12, and 8 h, respectively, were conducted. During the 4 months experimental period, COD removal efficiencies averaged at 92.2% and 85.3%, SS removal efficiencies averaged at 93.8% and 85.2%, and NH(4)(+)-N removal efficiencies averaged at 84.1% and 65.3%, respectively, for MLMBR and IMBR. What's more, the sludge characteristics were explored explicitly, results demonstrate that MLMBR not only perform better in substrates removal, also can alleviate the membrane fouling due to better sludge characteristics. In addition, mathematical statistical models, built on the linear regression techniques were developed for explore the inner relationship between HRTs and the performance of the MLMBR. PMID- 22446052 TI - Fractionation of wheat straw by prehydrolysis, organosolv delignification and enzymatic hydrolysis for production of sugars and lignin. AB - Wheat straw was fractionated using a three-step biorefining approach: (1) aqueous pretreatment for hemicellulose prehydrolysis into sugars, (2) organosolv delignification, and (3) enzymatic cellulose hydrolysis into glucose. Prehydrolysis was applied to avoid degradation of hemicellulose sugars during organosolv delignification. Maximum xylose yield obtained was 67% or 0.17 kg/kg straw (prehydrolysis: 175 degrees C, 30 min, 20mM H(2)SO(4)) compared to 4% in case of organosolv without prehydrolysis (organosolv: 200 degrees C, 60 min, 60% w/w aqueous ethanol). Prehydrolysis was found to reduce the lignin yield by organosolv delignification due to the formation of 'pseudo-lignin' and lignin recondensation during prehydrolysis. This reduction could partly be compensated by increasing the temperature of the organosolv delignification step. Prehydrolysis substantially improved the enzymatic cellulose digestibility from 49% after organosolv without prehydrolysis to 80% (20 FPU/g substrate). Increasing the organosolv delignification temperature to 220 degrees C resulted in a maximum enzymatic glucose yield of 93% or 0.36 kg/kg straw. PMID- 22446053 TI - Continuous hydrogen production from co-digestion of municipal food waste and kitchen wastewater in mesophilic anaerobic baffled reactor. AB - This study was carried out to assess the impact of organic loading rate (OLR) on the performance of mesophilic anaerobic baffled reactor (ABR) for H(2) production from a co-digestion of municipal food waste and kitchen wastewater. The reactor was operated at different organic loading rates (OLRs) of 29, 36 and 47 g COD(total)/Ld. The hydraulic retention time (HRT) was kept constant at 1.6d. The results showed that increasing the OLR from 29 to 36 g COD(total)/Ld, leads to a significant (p ? 0.01) drop in the H(2) production from 6.0+/-0.5 to 5.4+/-1.04 L H(2)/d, respectively. However, the H(2) production remained at the same level of 5.3+/-1.04 L H(2)/d at increasing the OLR from 36 to 47 g COD(total)/Ld. The H(2) generation was mainly due to conversion of COD (57%) and carbohydrate (81%). Protein and lipids conversion represents only 23.3% and 4.1% respectively for H(2) production. PMID- 22446054 TI - The contrast study of anammox-denitrifying system in two non-woven fixed-bed bioreactors (NFBR) treating different low C/N ratio sewage. AB - Two non-woven fixed-bed bioreactors (NFBR) based on different substrates (nitrite and nitrate) were constructed to study the environmental adaptability for temperature and organic matter of anammox-denitrifying system and nitrogen removal performance. The two reactors were successfully operated for 200 days. The average removal rates of nitrogen and COD of R2 were 81% and 93%, respectively. Besides, the nitrogen removal rate of R1 was 95% under not more than 105 mg/l of COD. The experimental results indicated that the R2 based on nitrate had a good nitrogen removal performance at room temperature (25 degrees C). Additionally, the analysis results of fluorescence in situ hybridization (FISH) showed that the percentage compositions of anammox in R1 and R2 were 84% and 65% on day 189. Finally, the possible nitrogen removal model of anammox denitrifying system was constructed. According to nitrogen balance and C/N ratios of denitrification, the nitrogen removal approaches of R1 and R2 were obtained. PMID- 22446055 TI - Use of an Automatic Methane Potential Test System for evaluating the biomethane potential of sugarcane bagasse after different treatments. AB - A multi-channel analyzer was used to evaluate biogas potential of sugarcane bagasse (SCB). The Automatic Methane Potential Test System contained fifteen parallel reactors and the same number of gas flow meters attached to the acquisition system. The set of reactors - gas flow meters gave reproducible results during anaerobic digestion of chemically defined carbon source and the units were used to evaluate the biomethane potential of SCB after different pretreatments, such as treatment with water, acid, acid followed by enzymatic treatment and acid followed by treatment with inactive enzymes. Combined pretreatment with 2% sulphuric acid and enzymatic hydrolysis (3.5% enzymes) resulted in conversion of 79% to monomeric sugars present in SCB. SCB treated with acid followed by enzymatic hydrolysis achieved the methane yield of 200 NL per kg VS(added). Enzymatic saccharification of acid pretreated SCB resulted in increase of methane yield by 16+/-5% compared to that from acid treated SCB. PMID- 22446056 TI - Our new president--Loren A. Laine, MD. PMID- 22446057 TI - Diffuse hepatic metastasis--or not? PMID- 22446058 TI - Infusion of BDNF into the nucleus accumbens of aged rats improves cognition and structural synaptic plasticity through PI3K-ILK-Akt signaling. AB - To investigate the involvement of the nucleus accumbens (NAc) in cognitive impairment and the therapeutic effects of brain-derived neurotrophic factor (BDNF) in an animal model of cognitive deficit, we infused BDNF into the NAc of cognitively impaired aged rats. Cognition was evaluated by Morris water maze test. Structural synaptic plasticity was measured by Golgi staining. Brain tissue homogenization was used to measure the changes in signal molecules. Cultured PC 12 cells expressing tyrosine kinase receptor (Trk) B/p75 neurotrophin receptor (p75(NTR)), p75(NTR) or TrkA/p75(NTR) receptors were used for BDNF stimulation assays. Significant decreases in the levels of BDNF, phosphatidylinositol-3 kinase (PI3K) and integrin-linked kinase (ILK) activity, protein kinase B (Akt) Ser473 phosphorylation, dendritic branching, and density of dendritic spines on medium spiny neurons were observed in the NAc. Importantly, infusion of BDNF restored cognition, synaptic plasticity, and cell signaling. In cultured PC-12 cells, BDNF activated PI3K/Akt signaling through the TrkB receptor, whereas stimulation of ILK/Akt occurred through TrkA/p75(NTR) heteroreceptor. Our study suggested that the decreased BDNF level and its downstream signaling as well as loss of synaptic plasticity in the NAc are associated with cognitive impairments in aged rats. The BDNF-activated PI3K-Akt and ILK-Akt signaling play a key role in structural synaptic plasticity. Our study also suggested that BDNF could be a mechanism-based treatment for dementia. PMID- 22446059 TI - Repeated treatment with a low dose of reserpine as a progressive model of Parkinson's disease. AB - Animal models are widely used to study alterations caused by Parkinson's disease (PD). However, in general, pharmacological models do not express the progressive nature of the disease, being characterized by immediate severe motor impairment after a single dose of the drug. Reserpine administration in rodents has been suggested as a pharmacological model of PD based on the effects of this monoamine depleting agent on motor activity. Here, we describe that repeated administration with a low dose (0.1 mg/kg) of reserpine in rats induces a gradual appearance of motor signs, evaluated by catalepsy behavior. Furthermore, these motor signs are accompanied by increased levels of striatal lipid peroxidation. However, treatment with reserpine failed to induce memory impairments (evaluated by novel object recognition and discriminative avoidance tasks) and alterations in hippocampal lipid peroxidation. Thus, repeated treatment with low doses of reserpine progressively induces alterations in motor function and an increase in striatal oxidative stress, indicating a possible application of this model in the study of the neuroprogressive nature of the motor signs in PD. PMID- 22446060 TI - Impacts of gas drilling on human and animal health. AB - Environmental concerns surrounding drilling for gas are intense due to expansion of shale gas drilling operations. Controversy surrounding the impact of drilling on air and water quality has pitted industry and lease-holders against individuals and groups concerned with environmental protection and public health. Because animals often are exposed continually to air, soil, and groundwater and have more frequent reproductive cycles, animals can be used as sentinels to monitor impacts to human health. This study involved interviews with animal owners who live near gas drilling operations. The findings illustrate which aspects of the drilling process may lead to health problems and suggest modifications that would lessen but not eliminate impacts. Complete evidence regarding health impacts of gas drilling cannot be obtained due to incomplete testing and disclosure of chemicals, and nondisclosure agreements. Without rigorous scientific studies, the gas drilling boom sweeping the world will remain an uncontrolled health experiment on an enormous scale. PMID- 22446061 TI - The structural and functional diversification of the Toxicofera reptile venom system. AB - The evolutionary origin and diversification of the reptilian venom system is described. The resolution of higher-order molecular phylogenetics has clearly established that a venom system is ancestral to snakes. The diversification of the venom system within lizards is discussed, as is the role of venom delivery in the behavioural ecology of these taxa (particularly Varanus komodoensis). The more extensive diversification of the venom system in snakes is summarised, including its loss in some clades. Finally, we discuss the contentious issue of a definition for "venom", supporting an evolutionary definition that recognises the homology of both the venom delivery systems and the toxins themselves. PMID- 22446062 TI - Dominant ferromagnetism in the spin-1/2 half-twist ladder 334 compounds, Ba3Cu3In4O12 and Ba3Cu3Sc4O12. AB - The magnetic properties of polycrystalline samples of Ba(3)Cu(3)In(4)O(12) (In 334) and Ba(3)Cu(3)Sc(4)O(12) (Sc-334) are reported. Both 334 phases have a structure derived from perovskite, with CuO(4) squares interconnected to form half-twist ladders along the c-axis. The Cu-O-Cu angles, ~90 degrees , and the positive Weiss temperatures indicate the presence of significant ferromagnetic (FM) interactions along the Cu ladders. At low temperatures, T < 20 K, sharp transitions in the magnetic susceptibility and heat capacity measurements indicate three-dimensional (3D) antiferromagnetic (AFM) ordering at T(N). T(N) is suppressed on application of a field and a complex magnetic phase diagram with three distinct magnetic regimes below the upper critical field can be inferred from our measurements. The magnetic interactions are discussed in relation to a modified spin-1/2 FM-AFM model and the 334 half-twist ladder is compared to other two-rung ladder spin-1/2 systems. PMID- 22446063 TI - A quality by design study applied to an industrial pharmaceutical fluid bed granulation. AB - The pharmaceutical industry is encouraged within Quality by Design (QbD) to apply science-based manufacturing principles to assure quality not only of new but also of existing processes. This paper presents how QbD principles can be applied to an existing industrial pharmaceutical fluid bed granulation (FBG) process. A three-step approach is presented as follows: (1) implementation of Process Analytical Technology (PAT) monitoring tools at the industrial scale process, combined with multivariate data analysis (MVDA) of process and PAT data to increase the process knowledge; (2) execution of scaled-down designed experiments at a pilot scale, with adequate PAT monitoring tools, to investigate the process response to intended changes in Critical Process Parameters (CPPs); and finally (3) the definition of a process Design Space (DS) linking CPPs to Critical to Quality Attributes (CQAs), within which product quality is ensured by design, and after scale-up enabling its use at the industrial process scale. The proposed approach was developed for an existing industrial process. Through enhanced process knowledge established a significant reduction in product CQAs, variability already within quality specifications ranges was achieved by a better choice of CPPs values. The results of such step-wise development and implementation are described. PMID- 22446064 TI - Oxidative stress-mediated cytotoxicity and apoptosis induction by TiO2 nanofibers in HeLa cells. AB - Titanium dioxide nanoparticles are increasingly being used in pharmaceutical and cosmetic products. The high aspect ratio of fibrous nanomaterials, such as carbon nanotubes and TiO(2) nanofibers (TiO(2)NFs), similar to the one used in this study makes them an attractive structural material and has attracted a lot of attention due to their possible negative health effects as suggested by their morphological similarities with asbestos. In the present study, therefore, toxicity of TiO(2)NFs was evaluated in human cervical adenocarcinoma HeLa cells. The TEM and XRD analyses showed that TiO(2)NFs used in this study are pure with uniform diameter of around 200 nm, and their length to width aspect ratio ranged between 5 and 15. Exposure of HeLa cells to TiO(2)NFs induced significant cytotoxicity even at doses as low as 2 MUg/ml. The intracellular uptake of TiO(2)NFs in cells was shown by Alizarin Red S (ARS) labeled nanofibers. The mechanism of toxicity is mainly due to the induction of cellular oxidative stress, as revealed by elevated ROS levels, reduced antioxidant levels, and increased lipid peroxidation leading to apoptosis. The cell cycle analysis indicated G(2)/M cell cycle arrest in the cells exposed to TiO(2)NF. TiO(2)NFs treatment to HeLa cells resulted in increased expression of proapoptotic proteins Bax with an increase in cytosolic Cytochrome-C and inhibition of anti-apoptotic protein Bcl-2. Our results revealed the potential mechanism of cellular effects of TiO(2)NFs. PMID- 22446065 TI - Hand pressure distribution during Oldowan stone tool production. AB - Modern humans possess a highly derived thumb that is robust and long relative to the other digits, with enhanced pollical musculature compared with extant apes. Researchers have hypothesized that this anatomy was initially selected for in early Homo in part to withstand high forces acting on the thumb during hard hammer percussion when producing stone tools. However, data are lacking on loads experienced during stone tool production and the distribution of these loads across the hand. Here we report the first quantitative data on manual normal forces (N) and pressures (kPa) acting on the hand during Oldowan stone tool production, captured at 200 Hz. Data were collected from six experienced subjects replicating Oldowan bifacial choppers. Our data do not support hypotheses asserting that the thumb experiences relatively high loads when making Oldowan stone tools. Peak normal force, pressure, impulse, and the pressure/time integral are significantly lower on the thumb than on digits 2 and/or digit 3 in every subject. Our findings call into question hypotheses linking modern human thumb robusticity specifically to load resistance during stone tool production. PMID- 22446066 TI - Reassessment of Dolichopithecus (Kanagawapithecus) leptopostorbitalis, a colobine monkey from the Late Pliocene of Japan. AB - In the original description of Dolichopithecus (Kanagawapithecus) leptopostorbitalis, Iwamoto, Hasegawa and Koizumi, 2005, a moderately large-sized colobine monkey from the Late Pliocene of central Japan, affinities to the European Dolichopithecus rather than to the Transbaikalian Parapresbytis were noted based on the similarities in cranial morphology. Computed tomography scans confirm the presence of the maxillary sinus in the holotype, whereas it is probably absent in specimens of the European Dolichopithecus ruscinensis, the type species of this genus. This feature is either present or absent homogeneously in any given genus of living anthropoids. Its presence or absence is unknown in Parapresbytis, but the distinct morphology of the maxillary incisors in this taxon suggests that this form had different feeding habits from the Japanese colobines. These findings suggest that the Japanese colobine should be referred to henceforth as Kanagawapithecus leptopostorbitalis. Kanagawapithecus shares many important facial and dental features with Dolichopithecus rather than with Parapresbytis, but this association depends largely on the limited availability of comparable materials for the latter. Among colobines, the presence of the maxillary sinus is recorded only in Libypithecus and Cercopithecoides. The maxillary sinus is absent in all modern Asian colobines, implying that Kanagawapithecus is an isolated form without any relationship to living forms. Nevertheless, such phylogenetic interpretations are largely dependent on the restricted fossil evidence from the Pliocene and Pleistocene of eastern Eurasia and will be reexamined when new findings are made. PMID- 22446067 TI - Paint4Net: COBRA Toolbox extension for visualization of stoichiometric models of metabolism. AB - A visual analysis of reconstructions and large stoichiometric models with elastic change of the visualization scope and representation methods becomes increasingly important due to the rapidly growing size and number of available reconstructions. The Paint4Net is a novel COBRA Toolbox extension for automatic generation of a hypergraph layout of defined scope with the steady state rates of reaction fluxes of stoichiometric models. Directionalities and fluxes of reactions are constantly represented in the visualization while detailed information about reaction (ID, name and synonyms, and formula) and metabolite (ID, name and synonyms, and charged formula) appears placing the cursor on the item of interest. Additionally Paint4Net functionality can be used to: (1) get lists of involved metabolites and dead end metabolites of the visualized part of the network, (2) exclude (filter) particular metabolites from representation, (3) find isolated parts of a network and (4) find running cycles when all the substrates are cut down. Layout pictures can be saved in various formats and easily distributed. The Paint4Net is open source software under the GPL v3 license. Relevant documentation and sample data is available at http://www.biosystems.lv/paint4net. The Paint4Net works on MATLAB starting from version of 2009. PMID- 22446068 TI - Risk of surgical glove perforation in oral and maxillofacial surgery. AB - Oral and maxillofacial surgery, which involves several sharp instruments and fixation materials, is consistently at a high risk for cross-contamination due to perforated gloves, but it is unclear how often such perforations occur. This study aimed to address this issue. The frequency of the perforation of surgical gloves (n=1436) in 150 oral and maxillofacial surgeries including orthognathic surgery (n=45) was assessed by the hydroinsufflation technique. Orthognathic surgery had the highest perforation rate in at least 1 glove in 1 operation (91.1%), followed by cleft lip and palate surgery (55.0%), excision of oral soft tumour (54.5%) and dental implantation (50.0%). The perforation rate in scrub nurses was 63.4%, followed by 44.4% in surgeons and first assistants, and 16.3% in second assistants. The odds ratio for the perforation rate in orthognathic surgery versus other surgeries was 16.0 (95% confidence interval: 5.3-48.0). The protection rate offered by double gloving in orthognathic surgery was 95.2%. These results suggest that, regardless of the surgical duration and blood loss in all fields of surgery, orthognathic surgery must be categorized in the highest risk group for glove perforation, following gynaecological and open lung surgery, due to the involvement of sharp objects. PMID- 22446069 TI - Can a single pain rating replace a multiple pain rating in third molar surgery studies? Analysis of 220 patients. AB - This study describes the comparison of multiple and single pain ratings in patients after surgical removal of the third molar. Correlation and agreement analysis were performed between the average pain intensity measured three times a day over a period of 7 days and one single pain rating (designated the 'recalled average' pain, as assessed by the patient) after surgical removal of the lower third molar. The study population consisted of patients participating in three randomized trials. The results show that both measurement correlated good to excellent, but there was a large variation in agreement between the ratings. In conclusion, in patients with surgical third molar removal a single pain rating is not an accurate predictor of the average pain measured by a multiple pain-rating test. A single pain rating cannot replace a multiple pain assessment. PMID- 22446070 TI - Mandibular metastases as first clinical sign of an occult male breast cancer. AB - A 73-year-old man presented with a painful swelling of the left temporomandibular joint with no other symptoms. Panoramic radiography showed an osteolytic lesion in the left mandibular body, while magnetic resonance imaging provided the most accurate view of an osteolytic lesion in the left condyle. Skeletal scintigraphy showed increased uptake in the mandibular anatomical area. A diagnosis of metastatic breast adenocarcinoma was made from mandibular biopsies which proved to be ductal carcinoma, with no evidence of any other metastases. Clinicopathologic features of this case are reviewed. PMID- 22446071 TI - Odontogenic tumours in children and adolescents: a collaborative study of 431 cases. AB - This study describes the oral and maxillofacial pathological characteristics of a series of odontogenic tumours in children and adolescents from three Brazilian reference centres. The records were reviewed for all odontogenic tumours in patients up to 18 years old based on criteria proposed by the World Health Organization (WHO) in 2005. Data concerning sex, age, skin colour and tumour location were collected and plotted. Four hundred and thirty one odontogenic tumours in children and adolescents were found, accounting for 37.5% of the total number of odontogenic tumours diagnosed. Benign tumours were predominant (99.8% of the cases), and odontoma was the most frequent type (41.4%), followed by keratocystic odontogenic tumours (25.5%) and ameloblastoma (14.6%). Odontogenic tumours were rarely detected in early childhood, and their prevalence increased with age. An almost equal distribution was observed with respect to sex and the site of the lesions. This study is the largest reported retrospective analysis describing odontogenic tumours in children and adolescents to date. The authors detected some variation in the relative frequency of odontogenic tumours compared with similar reports. Additional studies should be conducted based on the new WHO classification and predetermined age parameters to enable comparative analysis among different worldwide populations. PMID- 22446072 TI - Worldwide regulatory guidance values for surface soil exposure to noncarcinogenic polycyclic aromatic hydrocarbons. AB - Regulatory guidance values are used worldwide to control residential exposures to surface soil contamination. A total of 1791 values used in 39 nations to control exposures to eight polycyclic aromatic hydrocarbons (PAH) not normally considered to be carcinogenic (acenaphthene, acenaphthylene, anthracene, benzo(g,h,i)perylene, fluroanthene, fluorene, phenanthrene and pyrene) are examined. The guidance values vary over 5.8 to 8.3 orders of magnitude and have distributions that strongly resemble distributions of lognormal random variables. Where the U.S. Environmental Protection Agency (USEPA) has provided values, they fall near the upper end of the distributions and appear to exert influence on values from other U.S. jurisdictions. Approximately 84% of all U.S. values fall above a median PAH value. Uncertainty bounds approximated from the USEPA risk model encompass 28% of the regulatory values and these are predominantly from U.S. jurisdictions. An unusually high degree of toxicology data uncertainty for these PAH appears to be a significant factor influencing variability. The USEPA assigns its highest toxicology uncertainty factor value of 3000 to these components. PMID- 22446073 TI - Evaluation of the air quality benefits of the subway system in Sao Paulo, Brazil. AB - Air pollution is a severe problem in major urban areas due to increasing numbers of vehicles, reduced road capacity and few investments in public transportation, especially in developing countries. Public transportation has a special role in avoiding congestion and consequent environmental and health impacts but is considered expensive. The objective of this paper was to analyze the benefits of the Sao Paulo subway in terms of the air pollution in the city through strikes events, analyzing both the health outcomes and the related economic burden. For the strike events, increases in air pollutant concentrations during the strike day was observed when compared to a similar day in terms of day of the week and meteorological conditions. Increases in mortality were also observed and the associated economic burden calculated. Despite the elevated construction and operation costs of the subway, when environment and social values are considered, cost-benefit analysis results would indicate a worthwhile investment. The consideration of these aspects is essential to sustainable transportation analyses, and in the case of the Sao Paulo subway, our analysis clearly demonstrated the important role of this system in the city's environmental, social and economic attributes. PMID- 22446074 TI - Concerns on liquid mercury and mercury-containing wastes: a review of the treatment technologies for the safe storage. AB - Due to the adverse effects of mercury on human health and the environment, restrictive legislations and world-wide common efforts are now under way to reduce both the supply and demand of mercury. As a result, all excess Hg must be stored in safe conditions in secure places. This paper is an attempt to review the various treatment technologies types of liquid mercury (Hg(0)) and mercury containing wastes, which can be used to store these residues in a safe way. The different treatments were classified as a function of the waste treated. The main treatments described are amalgamation, formation of sulfides, thermal treatments, vitrification, soil washing, sulfur polymer stabilization solidification, chemically bonded phosphate ceramics and other encapsulation processes, being highlighted the stabilization/solidification processes that are the treatments that provide better results, according to the consulted bibliography. PMID- 22446075 TI - The anticommons and the environment. AB - Augustin Cournot's original concept of "complementary oligopoly" has recently had a rebirth of interest after being relabeled "the tragedy of the anticommons" and finding fresh applications in the legal and economics literatures. The tragedy of the anticommons (the mirror image of the more well-known tragedy of the commons) occurs when too many rights holders to a good lead to sub-optimal usage. Inefficient outcomes are only overcome when rights holders are reduced or consolidated. Despite its renewed interest in other spheres, the theory of the anticommons has yet to garner noticeable attention in environmental resource applications. This paper attempts to show how the theory of the anticommons appears relevant to the environmental sphere, in particular, with an application to river-basin water regulation in the U.S. PMID- 22446076 TI - Investigation of chronic alcohol consumption in rodents via ultra-high performance liquid chromatography-mass spectrometry based metabolite profiling. AB - Alcohol consumption in man, when seen in its extreme form of alcoholism, is a complex and socially disruptive disorder that can result in significant levels of liver injury. Here the rodent "intragastric feeding model" was used together with UHPLC-TOFMS analysis to determine changes in global metabolite profiles for plasma and urine from alcohol treated rats and mice compared to control animals. Multivariate statistical analysis (using principal components analysis, PCA) revealed robust differences between profiles from control and alcohol-treated animals from both species. A large number of metabolites were seen to differ between control and alcohol-treated animals, for both biofluids. PMID- 22446077 TI - A hydrophilic immobilized trypsin reactor with N-vinyl-2-pyrrolidinone modified polymer microparticles as matrix for highly efficient protein digestion with low peptide residue. AB - In this work, a novel kind of N-vinyl-2-pyrrolidinone (NVP) modified poly acrylic ester microspheres was prepared, followed by trypsin immobilization to prepare a hydrophilic immobilized enzyme reactor (IMER), to achieve highly efficient protein digestion with low peptide residue. The nonspecific adsorption of peptides on such an IMER was evaluated by the in sequence digestion of bovine serum albumin (BSA) and myoglobin. Without NVP modification, both proteins could be identified after digestion by a 5 cm-length IMER, but 18 peptides of BSA were found in the digests of myoglobin caused by the nonspecific adsorption of the matrix. With NVP modification, the hydrophilicity of IMER was greatly improved, resulting in not only the sequence coverage of myoglobin increased from 63% to 73%, but also no residual peptides from BSA observed in myoglobin digests. Although the sequence coverages of proteins obtained by the IMER were comparable to those obtained by in-solution digestion, the digestion time was shortened from 24h to 1 min. By such an IMER, a protein mixture, containing BSA, myoglobin, and cytochrome c (100, 1 and 0.01 MUg/mL, respectively), was digested, and all proteins were unambiguously identified with improved sequence coverages than that achieved by in-solution digestion. Furthermore, the hydrophilic IMER was also off line coupled to nano-RPLC-ESI-MS/MS for the analysis of proteins extracted from yeast. After 1.5 min digestion, 271 protein groups with at least 2 distinct peptides were identified, much more than those obtained by 24h in-solution digestion (192 protein groups), indicating the great potential of such an IMER for proteome analysis. PMID- 22446078 TI - Study of chemical selectivity of molecular binary mixed micelles of sodium 10 undecenyl sulfate and sodium N-undecenyl leucinate using linear solvation energy relationships model. AB - Poly(sodium 10-undecenyl sulfate) (poly-SUS), poly(sodium N-undecenyl leucinate) (poly-SUL) and their five molecular binary mixed micelles with varied SUS:SUL composition were prepared and used as pseudostationary phases in micellar electrokinetic chromatography (MEKC). Linear solvation energy relationships (LSERs) model and free energy of transfer studies were used to characterize the retention behavior and the selectivity differences among the seven surfactant systems. System constant differences and regression models for varied benzene derivative compounds are used to establish the selectivity differences of the seven pseudostationary phases. The cavity formation and dispersion interaction (the v system constant) and the hydrogen-bonding acidity (the b system constant) of the surfactant systems were found to have the most significant influence on selectivity and MEKC retention. The molecular micelle with sulfate head group, poly-SUS, was found to be more hydrogen-bond acidic than the molecular micelle with leucinate head group, poly-SUL. The other system constants (a, s and e) have modest effect on the retention and selectivity of the benzene derivatives. The model intercept coefficients (c system constants), which are negative for all surfactant systems have unusually large values. The free energy changes of transfer for the functional groups studied have all negative values except phenol and benzyl alcohol. Selectivity differences between pseudostationary phases were also compared by plotting the log k values against each other and were found to agree well with LSER results. PMID- 22446079 TI - Preparation and characterization of bonded silica hydride intermediate from triethoxysilane and dimethylmethoxysilane using supercritical carbon dioxide and dioxane as reaction medium. AB - This research examines bonding methodology, surface coverage and silanol conversion efficiencies on the preparation of silica hydride (SiH) intermediate from triethoxysilane (TES) and dimethylmethoxysilane (DMMS) using sc-CO(2) and dioxane as reaction solvent. Under sc-CO(2) reaction conditions (at temperature and pressure of 100 degrees C, 414 bar, respectively and 3h reaction time), the surface coverages of SiH (evaluated from %C obtained from elemental analysis) prepared with DMMS (3.39 MUmol/m(2)) and TES (4.46 MUmol/m(2)) increased by 2- and 4-folds respectively, when compared to reaction performed in dioxane (2.66 MUmol/m(2), SiH, DMMS and 0.69 MUmol/m(2), SiH, TES). The relatively higher surface coverage of SiH from TES over DMMS generated in sc-CO(2) is due to the inherent trialkoxy moiety of the TES that favours siloxane crosslinkage, forming polymeric surface attachments to yield a higher ligand density than the monomeric DMMS ligand. A conversion efficiency of ~84.4% of SiH prepared from TES in sc CO(2) estimated from (29)Si CP/MAS NMR analysis is comparable to TES silanization in dioxane or toluene. Moreover, silica hydride (SiH) conversion efficiency of ca. 42.4% achieved for the hydride intermediate prepared from DMMS in sc-CO(2) is more superior to 33.3% efficiency obtained in dioxane. The differences in conversion efficiencies is attributed to the ability of sc-CO(2) being able to access silica pores that are inaccessible in organic solvents. Bonded silica hydride from TES, DMMS prepared in sc-CO(2) were characterized using elemental analysis, thermogravimetric analysis (TGA), BET surface area, Fourier transform infrared (FI-IR) and solid state NMR spectroscopy. Silica hydride technology/chemical functionalization of silica in sc-CO(2) avoid extended purification steps (i.e. filtration and washing), generation of waste organic solvent and the need of costly or energy consuming drying processing with improved modification efficiency. PMID- 22446080 TI - FISHing: new methods to improve the diagnostic sensitivity of fine needle aspiration cytology. PMID- 22446082 TI - Surgery of the mind, mood, and conscious state: an idea in evolution. AB - Since the beginning of recorded history, humans have sought a physical means of altering disordered behavior and consciousness. This quest has spawned numerous innovations in neurosurgery and the neurosciences, from the earliest prehistoric attempts at trepanation to the electrocortical and anatomic localization of cerebral function that emerged in the 19th century. At the start of the 20th century, the overwhelming social impact of psychiatric illness intersected with the novel but imperfect understanding of frontal lobe function, establishing a decades-long venture into the modern origin of psychosurgery, the prefrontal lobotomy. The subsequent social and ethical ramifications of the widespread overuse of transorbital lobotomies drove psychosurgery to near extinction. However, as the pharmacologic treatment of psychiatric illness was established, numerous concomitant technical and neuroscientific innovations permitted the incremental development of a new paradigm of treating the disordered mind. In this article, we retrospectively examine these early origins of psychosurgery and then look to the recent past, present, and future for emerging trends in surgery of the psyche. Recent decades have seen a revolution in minimalism, noninvasive imaging, and functional manipulation of the human cerebrum that have created new opportunities and treatment modalities for disorders of the human mind and mood. Early contemporary efforts were directed at focal lesioning of abnormal pathways, but deep-brain stimulation now aims to reversibly alter and modulate those neurologic activities responsible for not only psychiatric disorders, but also to modulate and even to augment consciousness, memory, and other elements of cerebral function. As new tools become available, the social and medical impact of psychosurgery promises to revolutionize not only neurosurgery, but also humans' capability for positively impacting life and society. PMID- 22446083 TI - Bile-based detection of extrahepatic cholangiocarcinoma with quantitative DNA methylation markers and its high sensitivity. AB - Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses. PMID- 22446084 TI - Microarray gene expression analysis of fixed archival tissue permits molecular classification and identification of potential therapeutic targets in diffuse large B-cell lymphoma. AB - Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has a poor prognosis. Novel drugs targeting the constitutively activated NF-kappaB pathway characteristic of ABC-DLBCL are promising, but evaluation depends on accurate activated B cell-like (ABC)/germinal center B cell-like (GCB) molecular classification. This is traditionally performed on gene microarray expression profiles of fresh biopsies, which are not routinely collected, or by immunohistochemistry on formalin-fixed, paraffin-embedded (FFPE) tissue, which lacks reproducibility and classification accuracy. We explored the possibility of using routine archival FFPE tissue for gene microarray applications. We examined Affymetrix HG U133 Plus 2.0 gene expression profiles from paired archival FFPE and fresh-frozen tissues of 40 ABC/GCB-classified DLBCL cases to compare classification accuracy and test the potential for this approach to aid the discovery of therapeutic targets and disease classifiers in DLBCL. Unsupervised hierarchical clustering of unselected present probe sets distinguished ABC/GCB in FFPE with remarkable accuracy, and a Bayesian classifier correctly assigned 32 of 36 cases with >90% probability. Enrichment for NF-kappaB genes was appropriately seen in ABC-DLBCL FFPE tissues. The top discriminatory genes expressed in FFPE separated cases with high statistical significance and contained novel biology with potential therapeutic insights, warranting further investigation. These results support a growing understanding that archival FFPE tissues can be used in microarray experiments aimed at molecular classification, prognostic biomarker discovery, and molecular exploration of rare diseases. PMID- 22446085 TI - Yellow coloration phenomena of incorporated indomethacin into folded sheet mesoporous materials. AB - Solid-state (13)C nuclear magnetic resonance (NMR) spectroscopy that included relaxation time measurement was utilized to evaluate the yellow coloration of evaporated samples (EVPs) of indomethacin (IMC) with commercially available folded sheet mesoporous materials (TMPS). Colorimetric analysis by visible light reflection spectroscopy clarified the color differences in each sample: deep yellow-colored melt-quenched amorphous IMC, a slightly yellow-colored EVP of TMPS 1.5 (pore size: 1.8nm), and a yellow-colored EVP of TMPS-7 (pore size: 7.3nm). The color of EVPs changed from yellow to white after washing with ethanol, indicating the reversible coloration without a chemical reaction. Powder X-ray diffractometry and differential scanning calorimetry demonstrated that the EVPs of TMPS-7 entrapped greater amounts of amorphous IMC into the mesopore than TMPS 1.5. The amount of amorphous IMC in the mesopores could affect the strength of yellow coloration. Solid-state (13)C NMR spectroscopy that included spin-lattice relaxation time (T(1)) measurement revealed that the mobility of the aromatic rings of amorphous IMC in TMPS mesopores was higher than that in melt-quenched amorphous IMC. The difference in color between amorphous IMC in TMPS mesopores and melt-quenched amorphous IMC can be explained by their distinct intramolecular pi-conjugation systems. PMID- 22446086 TI - Does ligation of the thoracic duct during oesophagectomy reduce the incidence of post-operative chylothorax? AB - A best evidence topic in surgery was written according to a structured protocol. The question addressed was whether prophylactic thoracic duct ligation during oesophagectomy results in a lower incidence of post-operative chylothorax. 29 relevant papers were found using the reported search, of which 5 papers represented the best evidence to answer the clinical question. The authors, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. Of these studies, only one was a prospective randomised controlled study with sizeable patient numbers. This was also the most recent study and demonstrated a significant decrease in post operative chylothorax incidence following intra-operative thoracic duct ligation. Of the four remaining retrospective studies, one showed an increase in chylothorax rate following ligation whilst three showed a reduction in the incidence of chylothorax (although in only one of these three studies was this decrease statistically significantly). We conclude that for patients undergoing oesophagectomy, although there are conflicting results from retrospective studies, prospective randomised controlled trial evidence points to prophylactic ligation of the thoracic duct as an effective measure to reduce the incidence of post-operative chylothorax. PMID- 22446087 TI - The development of an Oncoplastic Training Center - OTC. AB - INTRODUCTION: Breast cancer now occurs worldwide and each country has its own approach to breast surgery, which is constantly evolving. A training program was established in Brazil to familiarize breast surgeons with basic oncoplastic techniques and recent developments. MATERIALS AND METHODS: The first 12 breast surgeons participating in the oncoplastic training program were surveyed regarding their experience of Urban's classification of oncoplastic procedures, and whether the training course met their expectations. RESULTS: The most part (11) of the breast surgeons surveyed had been breast specialists for more than five years. Just under one third (27.3%) wished to perform oncoplastic procedures in conjunction with a plastic surgeon. After the course the experience of the first group showed that just over half (seven) of the twelve specialists developed their skills sufficiently to perform Urban procedures at level III, and eleven others could perform until level II procedures. CONCLUSION: Organized oncoplastic training centers can enable breast surgeons to undertake reconstructive breast procedures without the assistance of a plastic surgeon. PMID- 22446088 TI - In patients with radiologically-staged resectable oesophago-gastric junctional tumours, is diagnostic laparoscopy useful as an additional staging procedure? AB - A best evidence topic in surgery was written according to a structured protocol. The question addressed was in patients with oesophago-gastric junctional tumours which have been radiologically-staged as potentially resectable, is diagnostic laparoscopy useful as an additional staging procedure. 292 papers were found using the reported search, of which 5 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers are tabulated. We conclude that as an additional tool following radiological staging of oesophago-gastric junctional tumours, diagnostic laparoscopy does appear to detect previously occult peritoneal metastases as well as liver metastases and lymph nodes and these findings do in turn lead to changes in management in over ten percent of patients. The procedure is however associated with some morbidity and its efficacy in changing management in the era of routine PET scanning remains to be evaluated. PMID- 22446089 TI - Specific expression of Kcna10, Pxn and Odf2 in the organ of Corti. AB - The development of the organ of Corti and the highly specialized cells required for hearing involves a multitude of genes, many of which remain unknown. Here we describe the expression pattern of three genes not previously studied in the inner ear in mice at a range of ages both embryonic and early postnatal. Kcna10, a tetrameric Shaker-like potassium channel, is expressed strongly in the hair cells themselves. Odf2, as its centriolar isoform Cenexin, marks the dendrites extending to and contacting hair cells, and Pxn, a focal adhesion scaffold protein, is most strongly expressed in pillar cells during the ages studied. The roles of these genes are yet to be elucidated, but their specific expression patterns imply potential functional significance in the inner ear. PMID- 22446090 TI - 3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2). AB - Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)-N-(4 bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors. PMID- 22446091 TI - Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9 dideazaadenosine C-nucleosides. AB - A series of 1'-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R=CN was attributed to inhibition of HCV NS5B polymerase and intracellular concentration of the corresponding nucleoside triphosphate. PMID- 22446092 TI - Antitumor activity of annonaceous acetogenins in HepS and S180 xenografts bearing mice. AB - Annonaceous acetogenins (ACGs), as one of the most powerful groups of mitochondrial complex I inhibitors, exhibit potent cytotoxic activity against a variety of human tumor cell lines. In this study, the antitumor activities of three main types of ACGs were investigated using S180 and HepS xenografts bearing mice simultaneously. The results revealed that select ACGs suppressed tumor growth in a dose-dependent fashion. Tested ACGs showed more selective antitumor activity against HepS. Furthermore, adjacent bis-THF ACGs were more active than mono-THF and nonadjacent bis-THF ACGs against HepS and S180; nonadjacent bis-THF ACGs were more active than mono-THF ACGs against S180, but mono-THF ACGs were more potent than nonadjacent bis-THF ACGs against HepS. PMID- 22446093 TI - Lanthanide(III) complexes of pyridine-tetraacetic acid-glycoconjugates: synthesis and luminescence studies of mono and divalent derivatives. AB - A potent lanthanide chelate, fulfilling the requirements for the development of MRI contrast agents or luminescent probes, was armed with alkyne groups. We then implemented a click methodology to graft the bifunctional ligand to azide containing glucoside and maltoside scaffolds. The resulting hydrophilic glycoconjugates retained the ligand binding capacity for Eu(3+) or Tb(3+) ion as evidenced by the number of bound water molecules to the lanthanide ion. Divalent Eu(3+) and Tb(3+) complexes were shown to double the brightness of the emitted fluorescent signal compared to its monovalent derivatives. Designing multivalent lanthanide luminescent probes would enable the fluorescent signal of labeled biomolecules to be enhanced. PMID- 22446094 TI - Sinularioside, a triacetylated glycolipid from the Indonesian soft coral Sinularia sp., is an inhibitor of NO release. AB - Chemical analysis of the Indonesian soft coral Sinularia sp. (order Alcyonacea, family Alcyoniidae) afforded a known glucosylcerebroside of the sarcoehrenoside type and sinularioside (2), a new naturally triacetylated glycolipid containing two alpha-D-arabinopyranosyl residues and a myristyl alcohol unit. Their complete stereostructures were solved by interpretation of MS and NMR data along with CD analysis of degradation products. Sinularioside proved to moderately inhibit LPS induced NO release, providing interesting clues into the poorly understood structure-activity relationships for anti-inflammatory glycolipids. PMID- 22446095 TI - Changes in visfatin levels after oral glucose tolerance test in women with gestational diabetes mellitus. AB - Visfatin levels increased following an oral glucose tolerance test (OGTT) in normal pregnancy, and this increase correlated with metabolic indexes such as blood glucose, blood fat, and insulin resistance. Conversely, visfatin levels in women with gestational diabetes mellitus (GDM) increased to lesser extent than in normal pregnancy, which suggests a disorder in the relationship between visfatin, blood glucose and insulin. PMID- 22446096 TI - Circulating soluble tumor necrosis factor related apoptosis inducing-ligand (TRAIL) is decreased in type-2 newly diagnosed, non-drug using diabetic patients. AB - We examined the association between serum sTRAIL measured by ELISA and HbA1C levels, pre/post-prandial blood glucose levels and body mass index in 22 newly diagnosed type-2 diabetic patients. A significant difference in sTRAIL levels was found between study group and controls. PMID- 22446097 TI - Effect of the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes. AB - AIMS: Liraglutide reduces bodyweight in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanisms underlying this effect. METHODS: The comparative effects of liraglutide, glimepiride and placebo on energy intake, appetite, nausea, gastric emptying, antral distension, bodyweight, gastrointestinal hormones, fasting plasma glucose and resting energy expenditure (REE), were assessed in subjects with T2DM randomised to treatment A (liraglutide placebo), B (placebo-glimepiride) or C (glimepiride-liraglutide). Assessments were performed at the end of each 4-week treatment period. RESULTS: Energy intake was less (NS) with liraglutide vs placebo and glimepiride, and 24-h REE was higher (NS) with liraglutide vs placebo and glimepiride. Fasting hunger was less (p=0.01) with liraglutide vs placebo and glimepiride, and meal duration was shorter with liraglutide (p=0.002) vs placebo. Paracetamol AUC(0-60 min) and C(max) were less (p<0.01) and fasting peptide YY was lower (p <= 0.001) after liraglutide vs placebo and glimepiride. Bodyweight reductions of 1.3 and 2.0 kg were observed with liraglutide vs placebo and glimepiride (p<0.001). There were no differences on antral distension, nausea, or other gastro-intestinal hormones. CONCLUSION: Liraglutide caused decreased gastric emptying and increased reduction in bodyweight. The mechanisms of the liraglutide-induced weight-loss may involve a combined effect on energy intake and energy expenditure. PMID- 22446098 TI - A comparison of TO-PRO-1 iodide and 5-CFDA-AM staining methods for assessing viability of planktonic algae with epifluorescence microscopy. AB - Two fluorescent dyes, TO-PRO-1 iodide and 5-CFDA-AM, were evaluated for LIVE/DEAD assessment of unicellular marine algae Brachiomonas submarina and Tetraselmis suecica. Epifluorescence microscopy was used to estimate cell viability in predetermined mixtures of viable and non-viable algal cells and validated using microplate growth assay as reference measurements. On average, 5-CFDA-AM underestimated live cell abundance by ~25% compared with viability estimated by the growth assay, whereas TO-PRO-1 iodide provided accurate viability estimates. Furthermore, viability estimates based on staining with TO-PRO-1 iodide were not affected by a storage period of up to one month in -80 degrees C, making the assay a good candidate for routine assessment of phytoplankton populations in field and laboratory studies. PMID- 22446099 TI - A simple and cost-effective cover-glass test for the differentiation between staphylococci and micrococci in clinical laboratory. AB - A cover-glass placed on a heavily inoculated culture plate clearly differentiates facultatively anaerobic staphylococci growing underneath the cover-glass after overnight incubation from nongrowing aerobic micrococci. Even if there are some exceptions, all medically significant staphylococci can grow in the test. Thus, the test provides a cost-effective and highly specific tool for separation of both genera which fundamentally differ in their pathogenicity. PMID- 22446100 TI - Effect of granulocyte colony-stimulating factor administration on tissue regeneration due to carbon tetrachloride-induced liver damage in experimental model. AB - The mechanism by which granulocyte colony-stimulating factor (G-CSF) could lead to the protection from liver injury is not well known. Therefore, the resolution of this role needs further basic and clinical experimental investigation. Acute liver injury was induced in rats by single intraperitoneal injection of a 0.50 mL/kg dose of carbon tetrachloride (CCl4 ). Granulocyte colony-stimulating factor or vehicle of 150 ug/kg was given immediately after intoxicating the liver by CCl4 . The animals were divided into four groups of twelve each. Administration of G-CSF caused a decrease in the activity of liver enzymes, aminotransferases, compared with the untreated group. PMID- 22446101 TI - GnRH regulation of Jun and Atf3 requires calcium, calcineurin, and NFAT. AB - GnRH binds to its receptor on gonadotropes and activates multiple members of the MAPK signaling family that in turn regulates the expression of several immediate early genes (IEGs) including Jun, Fos, Atf3, and Egr1. These IEGs confer hormonal responsiveness to gonadotrope-specific genes including Gnrhr, Cga, Fshb, and Lhb. In this study we tested the hypothesis that GnRH specifically regulates the accumulation of Jun and Atf3 mRNA through a pathway that includes intracellular Ca2+, calcineurin, and nuclear factor of activated T cells (NFAT). Our results indicate that pretreatment of murine LbetaT2 cells with 1, 2-bis-(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)-ester, a Ca2+ chelator, reduced the expression of all the IEGs to varying degrees, whereas treatment with thapsigargin, an intracellular Ca2+ protein pump inhibitor, increased the expression of the IEG. Furthermore, cyclosporin A, a calcineurin-specific inhibitor, reduced the ability of GnRH to regulate accumulation of Jun and Atf3 mRNA and to a lesser extent Fos. In contrast, Egr1 mRNA was unaffected. NFATs are transcription factors regulated by calcineurin and were detected in LbetaT2 cells. GnRH increased luciferase activity of an NFAT-dependent promoter reporter that was dependent on intracellular Ca2+ and calcineurin activity. Additionally, although small interfering RNA specific for Nfat4 only marginally reduced GnRH regulation of Jun, Fos, and Atf3 mRNA accumulation, activity of an activator protein-1-responsive reporter construct was reduced by 48%. Together these data suggest that calcineurin and NFAT are new members of the gonadotrope transcriptional network that confer hormonal responsiveness to several key genes required for gonadotropin synthesis and secretion. PMID- 22446102 TI - Research resource: whole-genome estrogen receptor alpha binding in mouse uterine tissue revealed by ChIP-seq. AB - To advance understanding of mechanisms leading to biological and transcriptional endpoints related to estrogen action in the mouse uterus, we have mapped ERalpha and RNA polymerase II (PolII) binding sites using chromatin immunoprecipitation followed by sequencing of enriched chromatin fragments. In the absence of hormone, 5184 ERalpha-binding sites were apparent in the vehicle-treated ovariectomized uterine chromatin, whereas 17,240 were seen 1 h after estradiol (E2) treatment, indicating that some sites are occupied by unliganded ERalpha, and that ERalpha binding is increased by E2. Approximately 15% of the uterine ERalpha-binding sites were adjacent to (<10 kb) annotated transcription start sites, and many sites are found within genes or are found more than 100 kb distal from mapped genes; however, the density (sites per base pair) of ERalpha-binding sites is significantly greater adjacent to promoters. An increase in quantity of sites but no significant positional differences were seen between vehicle and E2 treated samples in the overall locations of ERalpha-binding sites either distal from, adjacent to, or within genes. Analysis of the PolII data revealed the presence of poised promoter-proximal PolII on some highly up-regulated genes. Additionally, corecruitment of PolII and ERalpha to some distal enhancer regions was observed. A de novo motif analysis of sequences in the ERalpha-bound chromatin confirmed that estrogen response elements were significantly enriched. Interestingly, in areas of ERalpha binding without predicted estrogen response element motifs, homeodomain transcription factor-binding motifs were significantly enriched. The integration of the ERalpha- and PolII-binding sites from our uterine sequencing of enriched chromatin fragments data with transcriptional responses revealed in our uterine microarrays has the potential to greatly enhance our understanding of mechanisms governing estrogen response in uterine and other estrogen target tissues. PMID- 22446103 TI - Estrogen regulates JNK1 genomic localization to control gene expression and cell growth in breast cancer cells. AB - Steroid hormone and MAPK signaling pathways functionally intersect, but the molecular mechanisms of this cross talk are unclear. Here, we demonstrate a functional convergence of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways at the genomic level in breast cancer cells. We find that JNK1 binds to many promoters across the genome. Although most of the JNK1-binding sites are constitutive, a subset is estrogen regulated (either induced on inhibited). At the estrogen-induced sites, estrogen receptor (ER)alpha is required for the binding of JNK1 by promoting its recruitment to estrogen response elements or other classes of DNA elements through a tethering mechanism, which in some cases involves activating protein-1. At estrogen-regulated promoters, JNK1 functions as a transcriptional coregulator of ERalpha in a manner that is dependent on its kinase activity. The convergence of ERalpha and JNK1 at target gene promoters regulates estrogen-dependent gene expression outcomes, as well as downstream estrogen-dependent cell growth responses. Analysis of existing gene expression profiles from breast cancer biopsies suggests a role for functional interplay between ERalpha and JNK1 in the progression and clinical outcome of breast cancers. PMID- 22446104 TI - Palmitoylation regulates 17beta-estradiol-induced estrogen receptor-alpha degradation and transcriptional activity. AB - The estrogen receptor-alpha (ERalpha) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17beta-estradiol (E2). ERalpha transcriptional activity is regulated by E2-evoked 26S proteasome mediated ERalpha degradation and ERalpha serine (S) residue 118 phosphorylation. Furthermore, ERalpha mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. These E2 rapid effects require a population of the ERalpha located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl transferases. However, whether membrane-initiated and transcriptional ERalpha activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ERalpha palmitoylation on E2-induced ERalpha degradation and S118 phosphorylation. The lack of palmitoylation renders ERalpha more susceptible to E2-dependent degradation, blocks ERalpha S118 phosphorylation and prevents E2-induced ERalpha estrogen-responsive element-containing promoter occupancy. Consequently, ERalpha transcriptional activity is prevented and the receptor addressed to the nuclear matrix subnuclear compartment. These data uncover a circuitry in which receptor palmitoylation links E2-dependent ERalpha degradation, S118 phosphorylation, and transcriptional activity in a unique molecular mechanism. We propose that rapid E2-dependent signaling could be considered as a prerequisite for ERalpha transcriptional activity and suggest an integrated model of ERalpha intracellular signaling where E2-dependent early extranuclear effects control late receptor dependent nuclear actions. PMID- 22446105 TI - Squelching of ETS2 transactivation by POU5F1 silences the human chorionic gonadotropin CGA subunit gene in human choriocarcinoma and embryonic stem cells. AB - The subunit genes encoding human chorionic gonadotropin, CGA, and CGB, are up regulated in human trophoblast. However, they are effectively silenced in choriocarcinoma cells by ectopically expressed POU domain class 5 transcription factor 1 (POU5F1). Here we show that POU5F1 represses activity of the CGA promoter through its interactions with ETS2, a transcription factor required for both placental development and human chorionic gonadotropin subunit gene expression, by forming a complex that precludes ETS2 from interacting with the CGA promoter. Mutation of a POU5F1 binding site proximal to the ETS2 binding site does not alter the ability of POU5F1 to act as a repressor but causes a drop in basal promoter activity due to overlap with the binding site for DLX3. DLX3 has only a modest ability to raise basal CGA promoter activity, but its coexpression with ETS2 can up-regulate it 100-fold or more. The two factors form a complex, and both must bind to the promoter for the combination to be transcriptionally effective, a synergy compromised by POU5F1. Similarly, in human embryonic stem cells, which express ETS2 but not CGA, ETS2 does not occupy its binding site on the CGA promoter but is found instead as a soluble complex with POU5F1. When human embryonic stem cells differentiate in response to bone morphogenetic protein-4 and concentrations of POU5F1 fall and hCG and DLX3 rise, ETS2 then occupies its binding site on the CGA promoter. Hence, a squelching mechanism underpins the transcriptional silencing of CGA by POU5F1 and could have general relevance to how pluripotency is maintained and how the trophoblast lineage emerges from pluripotent precursor cells. PMID- 22446106 TI - The interplay between toxin-releasing beta-glucosidase and plant iridoid glycosides impairs larval development in a generalist caterpillar, Grammia incorrupta (Arctiidae). AB - Herbivores with polyphagous feeding habits must cope with a diet that varies in quality. One of the most important sources of this variation in host plant suitability is plant secondary chemistry. We examined how feeding on plants containing one such group of compounds, the iridoid glycosides, might affect the growth and enzymatic activity in a polyphagous caterpillar that feeds on over 80 plant species in 50 different families. Larvae of the polyphagous arctiid, Grammia incorrupta, were reared exclusively on one of two plant species, one of which contains iridoid glycosides (Plantago lanceolata, Plantaginaceae) while the other does not (Taraxacum officinale, Asteraceae). Larval weight was measured on the two host plants, and midgut homogenates of last instar larvae were then assayed for activity and kinetic properties of beta-glucosidases, using both a standard substrate, 4-nitrophenyl-beta-D-glucose (NPbetaGlc), and the iridoid glycoside aucubin, one of the two main iridoid glycosides in P. lanceolata. Larvae feeding on P. lanceolata weighed significantly less and developed more slowly compared to larvae on T. officinale. While the larval midgut beta glucosidase activity determined with NPbetaGlc was significantly decreased when fed on P. lanceolata, aucubin was substantially hydrolyzed and the larval beta glucosidase activity towards both substrates correlated negatively with larval weight. Our results demonstrate that host plants containing high concentrations of iridoid glycosides have a negative impact on larval development of this generalist insect herbivore. This is most likely due to the hydrolysis of plant glycosides in the larval midgut which results in the release of toxic aglycones. Linking the reduced larval weight to the toxin-releasing action of an iridoid glycoside cleaving beta-glucosidase, our results thus support the detoxification limitation hypothesis, suggesting fitness costs for the larvae feeding solely on P. lanceolata. Thus, in addition to the adaptive regulation of midgut beta glucosidase activity, host plant switching as a behavioral adaptation might be a prerequisite for generalist herbivores that allows them to circumvent the negative effects of plant secondary compounds. PMID- 22446107 TI - Luminance contrast in the background makes flashes harder to detect during saccades. AB - To explore a visual scene we make many fast eye movements (saccades) every second. During those saccades the image of the world shifts rapidly across our retina. These shifts are normally not detected, because perception is suppressed during saccades. In this paper we study the origin of this saccadic suppression by examining the influence of luminance borders in the background on the perception of flashes presented near the time of saccades in a normally illuminated room. We used different types of backgrounds: either with isoluminant red and green areas or with black and white areas. We found that the ability to perceive flashes that were presented during saccades was suppressed when there were luminance borders in the background, but not when there were isoluminant color borders in the background. Thus, masking by moving luminance borders plays an important role in saccadic suppression. The perceived positions of detected flashes were only influenced by the borders between the areas in the background when the flashes were presented before or after the saccades. Moreover, the influence did not depend on the kind of contrast forming the border. Thus, the masking effect of moving luminance borders does not appear to play an important role in the mislocalization of flashes that are presented near the time of saccades. PMID- 22446108 TI - Nitrogen and phosphorus economy of a legume tree-cereal intercropping system under controlled conditions. AB - Considerable amounts of nitrogen (N) and phosphorus (P) fertilizers have been mis used in agroecosystems, with profound alteration to the biogeochemical cycles of these two major nutrients. To reduce excess fertilizer use, plant-mediated nutrient supply through N(2)-fixation, transfer of fixed N and mobilization of soil P may be important processes for the nutrient economy of low-input tree based intercropping systems. In this study, we quantified plant performance, P acquisition and belowground N transfer from the N(2)-fixing tree to the cereal crop under varying root contact intensity and P supplies. We cultivated Acacia senegal var senegal in pot-culture containing 90% sand and 10% vermiculite under 3 levels of exponentially supplied P. Acacia plants were then intercropped with durum wheat (Triticum turgidum durum) in the same pots with variable levels of adsorbed P or transplanted and intercropped with durum wheat in rhizoboxes excluding direct root contact on P-poor red Mediterranean soils. In pot-culture, wheat biomass and P content increased in relation to the P gradient. Strong isotopic evidence of belowground N transfer, based on the isotopic signature (delta(15)N) of tree foliage and wheat shoots, was systematically found under high P in pot-culture, with an average N transfer value of 14.0% of wheat total N after 21 days of contact between the two species. In the rhizoboxes, we observed limitations on growth and P uptake of intercropped wheat due to competitive effects on soil resources and minimal evidence of belowground N transfer of N from acacia to wheat. In this intercrop, specifically in pot-culture, facilitation for N transfer from the legume tree to the crop showed to be effective especially when crop N uptake was increased (or stimulated) as occurred under high P conditions and when competition was low. Understanding these processes is important to the nutrient economy and appropriate management of legume-based agroforestry systems. PMID- 22446109 TI - Environmental changes and macroinvertebrate responses in Patagonian streams (Argentina) to ashfall from the Chaiten Volcano (May 2008). AB - On May 2nd of 2008 the Chaiten Volcano (Chile, 42 degrees 50'S and 72 degrees 39'W) erupted explosively producing a strong emission of volcanic ash. As a result of this eruption wide areas on the Argentinean side became covered by ashes. In order to investigate the effects of ashfall on environmental features, water quality and macroinvertebrate communities we conducted a study on 10 rivers affected by ash deposition in their hydrographic basins. Sites were visited seasonally (June 2008-March 2010) and results were compared with data obtained from previous research projects. Measures of pH, conductivity, oxygen content, main nutrients, and total suspended solids (TSS) were taken. Macroinvertebrate samples were obtained from riffles and pools. Community attributes were measured and metrics were calculated. A strong and significant increase in TSS values at most sites was recorded and although the peak diminished rapidly during the following months, resuspension and remobilization of ash continue even 20 months after. No significant changes in pH, conductivity and nutrients, comparing with data previous to the ashfall, were detected. Most rivers showed a strong diminution on macroinvertebrate density and richness, being small rivers more severely affected than the big ones. Correspondence analysis based on abundance data allows distinguishing preeruption from posteruption dates at five rivers. Density data and species richness showed low values in March of 2010, indicating that the community was not completely recovered at some sites. At least 25 taxa resulted significantly and negatively affected. Increased mortality could be related to several factors such as habitat deterioration, food quality diminution, interference with breathing mechanisms and with other physiological and morphological characteristics. Specific-taxa responses on the recolonization process were related to dispersal mechanisms and specific strategies. PMID- 22446110 TI - Coupling geochemical and biological approaches to assess the availability of cadmium in freshwater sediment. AB - Sediments are considered as a sink for metals, and the assessment of metal bioavailability for benthic organisms represents a great challenge. Diffusive Gradient in Thin films (DGT), developed to measure labile metals in aquatic media, have more recently been applied to sediment. Nevertheless, few studies have determined the relation between measurements from DGT and bioaccumulation in different benthic organisms. The aim of our work was to determine if labile metal measured by DGT in sediment is representative of bioavailable metal for benthic organisms. We focused our work on Cd and chose to use the diversity of ecological traits from different organisms to better understand the measurement given by DGT. We exposed simultaneously DGT and 3 macroinvertebrates species (the chironomid, Chironomus riparius; the amphipod, Gammarus fossarum; the mudsnail, Potamopyrgus antipodarum) to a natural sediment Cd-spiked at environmental relevant concentrations. The nature of sediment-bound Cd was also determined by means of sequential extractions in order to better interpret DGT measurements. Cadmium concentrations were determined in DGT and in the 3 organisms after one week of exposure. Results provided by DGT indicated that Cd was poorly released from particulate phase to pore water, suggesting that Cd measured by DGT was representative of the pore water labile fraction. Sequential extractions showed that the percentage of Cd bound to carbonate fraction increased simultaneously with Cd-spiking level; hence, this Cd fraction was poorly reactive to supply DGT demand. Cadmium accumulation rates were similar between DGT measurements and P. antipodarum, suggesting that labile Cd in pore waters was representative of bioavailable Cd for this species. Cadmium accumulation rates in C. riparius were higher than in DGT, demonstrating that C. riparius can mobilize Cd bound to carbonate phase. G. fossarum showed the lowest Cd accumulation rates, suggesting that they were mainly exposed to Cd from overlaying waters. PMID- 22446111 TI - Drugs of abuse in urban groundwater. A case study: Barcelona. AB - This study is concerned with drugs of abuse (DAs) and their metabolites in urban groundwater at field scale in relation to (1) the spatial distribution of DAs in Barcelona's groundwater, (2) the depth of the groundwater samples, (3) the presence of DAs in recharge sources, and (4) the assessment of the fate of DAs in Barcelona aquifers. To this end, 37 urban groundwater samples were collected in the city of Barcelona and a total of 21 drugs were analyzed including cocainics, amphetamine-like compounds, opioids, lysergics and cannabinoids and the prescribed drugs benzodiazepines. Overall, the highest groundwater concentrations (around 200 ng/L in SAP-4) and the largest number of detected DAs were found in zones basically recharged by a river that receives large amounts of effluents from waste water treatment plants (WWTPs). In contrast, the urbanized areas yielded not only lower concentrations but also a much smaller number of drugs, which suggests a local origin. In fact, cocaine and its metabolite were dominant in more prosperous neighborhoods, whereas the cheaper MDMA was the dominant DA in poorer districts. Measured concentrations were consistently smaller than those estimated from the waste water fraction in groundwater samples, suggesting that DAs undergo removal processes in both reducing and oxidizing conditions. PMID- 22446112 TI - Multi-trace element levels and arsenic speciation in urine of e-waste recycling workers from Agbogbloshie, Accra in Ghana. AB - To understand human contamination by multi-trace elements (TEs) in electrical and electronic waste (e-waste) recycling site at Agbogbloshie, Accra in Ghana, this study analyzed TEs and As speciation in urine of e-waste recycling workers. Concentrations of Fe, Sb, and Pb in urine of e-waste recycling workers were significantly higher than those of reference sites after consideration of interaction by age, indicating that the recycling workers are exposed to these TEs through the recycling activity. Urinary As concentration was relatively high, although the level in drinking water was quite low. Speciation analysis of As in human urine revealed that arsenobetaine and dimethylarsinic acid were the predominant As species and concentrations of both species were positively correlated with total As concentration as well as between each other. These results suggest that such compounds may be derived from the same source, probably fish and shellfish and greatly influence As exposure levels. To our knowledge, this is the first study on human contamination resulting from the primitive recycling of e-waste in Ghana. This study will contribute to the knowledge about human exposure to trace elements from an e-waste site in a less industrialized region so far scantly covered in the literature. PMID- 22446113 TI - Increased serum level of epidermal growth factor receptor in liver cancer patients and its association with exposure to arsenic. AB - Arsenic is a human carcinogen and can activate epidermal growth factor receptor (EGFR) in human cell lines. As EGFR is associated with the occurrence of cancers, we conducted a study to evaluate whether serum EGFR may increase in liver cancer patients, particularly in those with exposure to arsenic. We recruited 100 patients of liver cancer and 100 age- and sex-matched controls in Taiwan and determined EGFR levels in sera by enzyme-linked immunosorbent assay. The patients had higher EGFR levels (668.1 vs. 243.1 fmol/mL, p<0.01), and after adjusting for hepatitis B and C, they still had an average EGFR level 406.1 fmol/mL higher than that of the controls (p<0.01). When we compared 22 patients residing in an endemic area of arsenic intoxication to 22 age- and sex-matched patients residing outside the area, we found that patients from the endemic area had higher EGFR levels (882.8 vs. 511.6 fmol/mL, p = 0.04). We concluded that EGFR is over expressed in patients of liver cancer, particularly in those with exposure to arsenic, and therefore, serum EGFR level is not only a potential biomarker of liver cancer, but also a potential biomarker of cancers associated with arsenic exposure. PMID- 22446114 TI - Adverse events following immunization (AEFI) with the novel influenza a (H1N1) 2009 vaccine: findings from the national registry of all vaccine recipients and AEFI and the passive surveillance system in South Korea. AB - This study characterized the adverse events following immunization (AEFI) with the novel influenza A (H1N1) 2009 vaccine in Korea. Data on immunization and AEFI were collected between October 27, 2009 and March 15, 2010 through the national immunization registry and passive surveillance systems. The frequency of AEFI and serious adverse events (SAEs) were calculated according to age, sex, priority group, and vaccine type. In 13,758,527 vaccine recipients aged 6 months or older, 2,530 AEFI were reported (18.4 per 100,000 immunizations). The AEFI reporting rate was highest among people aged 10-19 years (29.6 per 100,000 immunizations) and was higher in female recipients than in male recipients (20.0 versus 16.7 per 100,000 immunizations). Most AEFIs were nonspecific systematic reactions that occurred within 24 h (77.4%) after vaccine administration. A total of 178 vaccine-related SAEs were identified, and vaccine-related mortalities were not reported. This study showed that the AEFI reporting rate after influenza A (H1N1) 2009 vaccinations was relatively high, especially in the younger population. Mild systemic reactions accounted for the majority of reported AEFI, and fatal SAEs were rare. This study also implied that passive surveillance might be an efficient safety monitoring system that can detect relatively rare AEFI. PMID- 22446115 TI - Viral shedding of 2009 pandemic H1N1 and evaluation of quarantine recommendations. AB - Public health authorities recommend that isolation precautions for influenza should be continued for 7 days after illness onset or until 24 h after the resolution of symptoms, whichever event lasts longer. However, little data are available regarding the duration of isolation for patients with 2009 pandemic H1N1 (pH1N1). We recruited patients with confirmed pH1N1 virus infection at a 2,000-bed tertiary care center. Influenza viral loads from oropharyngeal swab specimens were serially determined by reverse transcriptase quantitative polymerase chain reaction every other day, and the risk factors for prolonged viral shedding were investigated. To evaluate the current recommendations for isolation precautions, we measured the intervals between symptom onset and the last viral RNA detection, and that between the last viral RNA detection and the point at which the patient was symptom-free for 24 h. From November 2009 to January 2010, 26 patients were enrolled, and viral RNA was detected in more than half of the eligible patients (10 of 19, 52.6%) for >=7 days after symptom onset. While evaluating the policy for lifting quarantine, we found that viral RNA was detected in 4 of 15 patients (26.7%) beyond the recommended duration of isolation. In conclusion, viral RNA was detected in a substantial proportion of hospitalized patients even when they fulfilled the recommended conditions for lifting quarantine, and we believe that more prudence is required in this aspect. PMID- 22446116 TI - An enrichment medium for increasing a very small number of vibrio parahaemolyticus cells to the detection limit of the loop-mediated isothermal amplification (LAMP) assay. AB - We developed an enrichment medium for use with the loop-mediated isothermal amplification (LAMP) assay (enrichment media + LAMP assay) to quickly increase a very small number of Vibrio parahaemolyticus cells to the detection limit of the assay. Thirty-nine different enrichment media were prepared based on evaluating 12 potential ingredients. From our assessment of the 39 media, enrichment medium #36, which contained 2% sodium chloride, 1% proteose peptone no. 2, 0.1% trehalose, 0.5% alpha-ketoglutaric acid, 0.25% pyruvic acid, and 0.5% yeast extract (pH 8.6), was found to be most effective at enhancing the proliferation of V. parahaemolyticus during incubation for 3 h at 40oC. We compared the detection limits of the LAMP assay, the enrichment medium #36 + LAMP assay, and the cultivation method using bacterial cell and spiked shrimp sample tests. The detection limits of the LAMP assay, the medium #36 + LAMP assay, and the cultivation method were 10(3), 10(0)-10(-1), and 10(-1) CFU ml(-1), respectively. Enrichment medium #36 promoted a 10(3)- to 10(4)-fold increase in the bacterial population, and the detection limit of the enrichment media + LAMP assay was the same as that of the cultivation method. PMID- 22446117 TI - Antimicrobial resistance in Shiga toxin-producing Escherichia coli O157 and O26 isolates from beef cattle. AB - This study was conducted to determine the prevalence of antimicrobial resistance in Shiga toxin-producing Escherichia coli (STEC) O157 (n = 241) and O26 (n = 11) isolated from beef cattle and to characterize their antimicrobial resistance profiles. Resistance to dihydrostreptomycin was detected most frequently (STEC O157, 9.5%; STEC O26, 54.5%), followed by resistance to oxytetracycline (7.9%; 45.5%) and ampicillin (5.4%; 36.4%). Resistance to one or more antimicrobial agents was detected in 13.3% (32/241) of the STEC O157 isolates and 54.5% (6/11) of the STEC O26 isolates. The antimicrobial resistance rate in the STEC O26 isolates was significantly higher than that in the STEC O157 isolates (P = 0.002, Fisher's exact test). The antimicrobial resistance rate in the STEC O157 isolates possessing both stx(1) and stx(2) genes was 26.3% (15/57), while that in the isolates possessing stx(2c) gene alone was 3.9% (3/77). These findings suggest that the antimicrobial resistance in STEC O157 is associated with serogroups and the Shiga toxin genotype. PMID- 22446118 TI - Prevalence of beta-lactamase-negative ampicillin-resistant haemophilus influenzae isolated from patients of a teaching hospital in Thailand. AB - The aim of this study was to investigate the prevalence of beta-lactamase negative ampicillin-resistant (BLNAR) Haemophilus influenzae isolated from patients of a teaching hospital in Thailand. Eighty-eight isolates of H. influenzae were collected between September 2005 and March 2008. All isolates were identified and characterized for biotypes and capsular types. The beta lactamase production of these isolates was examined, and their susceptibility to the following 12 antimicrobial agents was determined: ampicillin (AMP), amoxicillin-clavulanate (AMC), cefotaxime (CTX), cefuroxime (CXM), meropenem (MEM), clarithromycin (CLR), telithromycin (TEL), tetracycline (TET), ciprofloxacin (CIP), levofloxacin (LEV), trimethoprim-sulfamethoxazole (SXT), and chloramphenicol (CHL). Of the 88 H. influenzae isolates, 69 (78.4%), 13 (14.8%), 4 (4.5%), and 2 (2.3%) were from the respiratory tract, pus, the genital tract, and blood, respectively. Half of the isolates were biotype II (44 isolates, 50%). The other half comprised biotypes I (23 isolates, 26.1%), III (15 isolates, 17.1%), and IV (6 isolates, 6.8%). All isolates were capsular non typeable, except for 2 isolates that were type f. Antimicrobial susceptibility showed that all isolates were susceptible to AMC, CTX, MEM, TEL, CIP, and LEV (100%), whereas 96.6%, 94.3%, 80.7%, 68.2%, 50.0%, and 44.3% were susceptible to CXM, CLR, CHL, TET, AMP, and SXT, respectively. The beta-lactamase-production rate of H. influenzae isolates was 40.9%, and the prevalence of BLNAR was 18.2%. PMID- 22446119 TI - 12-Methyltetradecanoic acid, a branched-chain fatty acid, represses the extracellular production of surfactants required for swarming motility in Pseudomonas aeruginosa PAO1. AB - Pseudomonas aeruginosa is known to produce surfactants that are involved in its swarming motility behavior, such as rhamnolipids and their precursors-3-(3 hydroxyalkanoyloxy)-alkanoic acids (HAAs). In P. aeruginosa PAO1, swarming motility is inhibited by some fatty acids, including branched-chain fatty acids and unsaturated fatty acids. In the present study, addition of 12 methyltetradecanoic acid (12-MTA, anteiso-C15:0) to an agar medium markedly repressed surfactant activity in the extracellular fraction of a P. aeruginosa culture in a drop collapse assay. Further, an extracellular fraction of a culture of rhlA mutant P. aeruginosa, which did not produce both rhamnolipids and HAAs, showed a complete loss of surfactant activity and markedly reduced swarming activity. In contrast, an extracellular fraction of a culture of rhlB mutant P. aeruginosa, which produced HAAs but not rhamnolipids, showed moderate swarming activity and weak extracellular surfactant activity that was lost on the addition of 12-MTA to the agar medium. Expression of the rhlAB operon from the plasmid pMR2 restored normal swarming motility on 12-MTA-containing agar medium. Taken together, these findings indicate that 12-MTA reduced extracellular surfactant activity, thus resulting in a swarming defect in P. aeruginosa PAO1. PMID- 22446120 TI - Case-Based Surveillance of Pandemic (H1N1) 2009 in Maebashi City, Japan. AB - After national case-based surveillance for pandemic influenza A (H1N1) ceased on July 23, 2009, a daily case-based surveillance system was implemented in Maebashi City, Japan. All medical facilities in the city reported all patients who had positive rapid antigen tests for influenza A. When the epidemic exploded in late October, case-based surveillance for influenza-like illness (ILI) was implemented from November 3, 2009 until the end of the epidemic. A total of 7,781 influenza cases were reported between July 25 and November 2, 2009, with a cumulative incidence rate of 22.5 per 1,000 population. Nearly 70% of the patients were under 15 years old. Between November 3, 2009 and the end of March 2010, a total of 16,394 ILI cases were reported, with a cumulative incidence rate of 47.4 per 1,000 population. Of the ILI cases reported, 63% were in patients younger than 15 years old. Only one death with laboratory confirmation of the H1N1 2009 virus was reported during the epidemic. The age-specific reproduction number among children under 15 years of age was almost 1.40, whereas between children and adults (15 years of age and above) it was considerably less than 1.0. The reproduction number derived from the next generation matrix using data from September 30 to October 14 was estimated to be 1.48 (95% confidence interval, 1.41-1.56). Among individuals under 15 years of age, the infection rate calculated using the final size equation under the assumption of no mitigation measures was nearly twice the rate reported during the epidemic. These findings indicate that the majority of the transmission of influenza A (H1N1) 2009 in the city occurred among children. PMID- 22446121 TI - Characterization of the monoclonal antibody response to botulinum neurotoxin type A in the complexed and uncomplexed forms. AB - Clostridium botulinum produces large complex toxins, which include botulinum neurotoxin (BoNT) and auxiliary non-toxic proteins. We prepared monoclonal antibodies (mAbs) from mice that were immunized several times with BoNT/A after basal immunization with toxoid. We then examined the reactivities of these mAbs to BoNT and toxoid and showed that some mAbs reacted to only BoNT. This result indicates that the antigenicity of BoNT/A partially disappeared with formalin treatment. Some mAbs that specifically recognized either BoNT/A1 or BoNT/A2 were considered useful as detection antibodies specific for the BoNT/A subtype. Results of a neutralizing test with mAbs against either BoNT/A1 or BoNT/A2 showed that neutralizing antibody recognition sites were present in the light chain, heavy chain (N-terminal half), and heavy chain (C-terminal half) domains. Investigation of the different binding capabilities of the mAbs to BoNT and the complex toxin by immunoprecipitation suggested that the light chain of BoNT is exposed at the molecular surface of the complex toxin since there was no difference in the binding of light chain-specific mAb to BoNT and the complex toxin. The heavy chain is related to BoNT binding to non-toxic components, because the reactivity of the heavy chain to some mAbs was influenced by non toxic components. PMID- 22446122 TI - Alterations in bacterial spectrum and increasing resistance rates in isolated microorganisms from device-associated infections in an intensive care unit of a teaching hospital in Istanbul (2004-2010). AB - The aim of the present study was to determine the rate of device-associated infection (DAI) and the change in profiles and antimicrobial resistance patterns of the causative microorganisms in a medical-surgical intensive care unit (ICU), as well as to evaluate the effect of a new nationwide hospital infection control program (NHICP), which has been implemented in Turkey. In this study, 5,772 patients that were hospitalized for a total of 43,658 days acquired 1,321 DAIs, with an overall rate of 30.2% per 1,000 ICU days. Between 2004 (before the NHICP) and 2010, the incidence densities of catheter-associated urinary tract infection (CAUTI) decreased from 10.2 to 5.7 per 1,000 device-days (P < 0.0001), and central venous catheter-associated bloodstream infection (CVC-BSI) decreased from 5.3 to 2.1 per 1,000 device-days (P < 0.0001). However, ventilator associated pneumonia increased from 27.0 to 31.5 per 1,000 device-days. Multidrug-resistant species rates increased from 5.8% to 76.6% (P < 0.0001) for Acinetobacter spp. and from 6.8% to 53.1% (P < 0.0001) for Pseudomonas aeruginosa. The extended-spectrum beta-lactamase-producing Enterobacteriaceae rate increased from 23.1% to 54.2% (P = 0.01); the vancomycin-resistance rate among Enterococcus spp. increased from 0% in 2004 to 12.5% in 2010 (P = 0.0003). In conclusion, while a significant decrease was achieved in the incidences of CAUTI and CVC-BSI, the NHICP was not completely effective in our ICU. The high incidence of DAI and the increasing prevalence of multidrug-resistant microorganisms indicate that further interventions are urgently needed. PMID- 22446123 TI - Natural infection of Plasmodium falciparum induces inhibitory antibodies against gametocyte development in human hosts. AB - We identified naturally induced antibodies from malaria patients in Thailand and clarified the effect of the antibodies on gametocyte development. Fifty-nine percent of the Plasmodium falciparum-infected blood samples (17 of 29) fed to female Anopheles mosquitoes showed no oocyst infection. Seventeen percent of the samples (5 of 29) distorted the morphology and hampered the maturity of the gametocytes. A possible mechanism for the gametocyte inhibitory activity was shown by the binding of the plasma antibodies to live, immature, intraerythrocytic gametocytes during the incubation period. One hundred fifty seven proteins specific to different gametocyte stages were explored to find the targets of the antisera that bound to the live gametocytes. However, no additional gametocyte transmission-blocking vaccine candidate was detected. Therefore, the development of alternative transmission-blocking vaccines in high transmission areas should focus on the identification of more gametocyte antigens inducing inhibitory antibodies that reduce gametocytemia. PMID- 22446124 TI - Analysis of hospital-based sentinel surveillance data on leptospirosis in Sri Lanka, 2005-2008. AB - In Sri Lanka, leptospirosis is a notifiable disease. In addition to having a routine disease reporting system, Sri Lanka has implemented a hospital-based sentinel surveillance system since 2004. This report discusses the findings of a descriptive analysis of the sentinel surveillance data collected from 2005 to 2008. Of the 4,000 suspected leptospirosis cases, 46.9% and 26.8% were recorded from the Western and Sabaragamuwa provinces, respectively. Most of the individuals were male (83.5%), and approximately 45.6% were aged 30-49 years. Farmers accounted for 16.5%, and laborers for 16.1%; however, the occupation of nearly half (44.8%) of the study population was unknown. More than half (53.9%) of the individuals worked in paddy fields. Almost all had acute fever (98.8%), myalgia (92.9%), and headache (92.7%), but fewer had other related symptoms. Out of the 4,000 individuals, 2,496 (62.4%) underwent a laboratory test; however, the laboratory test results of only 1,445 (57.9%) and the microscopic agglutination results of 41 (2.8%) were available at the sentinel sites. Less than 2% of the reported individuals underwent prophylactic treatment. These findings will help enhance the ongoing efforts for controlling and preventing leptospirosis in Sri Lanka. Sentinel surveillance is a useful tool, but the data quality needs to be improved by supplementing the findings with adequate laboratory diagnosis data. PMID- 22446125 TI - Molecular epidemiology of an outbreak of imipenem-resistant Acinetobacter baumannii carrying the ISAba1-bla(OXA-51-like) genes in a Korean hospital. AB - Between January 2004 and December 2004, an outbreak of imipenem-resistant Acinetobacter baumannii (IRAB) in 2 intensive care units (ICU) of Chosun University Hospital, Korea affected 77 patients. A case-control study revealed that the time spent in the hospital and mechanical ventilation practices were risk factors. IRAB was isolated from the hands of 4% (5/124) of healthcare workers; 27.3% (21/77) of the samples obtained from the ICU environment. A pulsed field gel electrophoresis analysis showed that 82.1% (23/28) of clinical IRAB isolates and 85.7% (6/7) of environmental IRAB isolates were type A. The ISAba1F/OXA-51-likeR PCR showed that 93.7% (30/32) of IRAB strains had the ISAba1 gene upstream of the bla(OXA-51-like) gene. Two ISAba1F/OXA-51-likeR PCR negative IRAB strains were bla(IMP-1) positive. All of the IRAB strains tested by PCR were negative for bla(VIM), bla(SIM), bla(GIM-1), bla(SPM-1), bla(GES), bla(OXA-23-like), bla(OXA-24-like), and bla(OXA-58-like) carbapenemase genes. After implementing an infection control strategy, a steady reduction in the attack rate of IRAB infection was observed. PMID- 22446126 TI - Isolation and characterization of Toxoplasma gondii genotypes from goats at an abattoir in Okinawa. AB - Toxoplasma gondii genotypes were isolated and characterized from cephalic muscle samples collected from 24 goats slaughtered at an abattoir in Okinawa between 2008 and 2009. Of the 24 samples assayed using latex agglutination, 18 were seropositive, 2 were pseudo-positive, and 4 were seronegative against T. gondii antibodies. The samples were then inoculated into laboratory mice to isolate the parasite. Among the isolated samples, 13 (72.2% of the 18 seropositive strains in the latex agglutination assay) were seropositive, 1 (50%) was pseudo-positive, and none were seronegative. However, after being frozen and stored at -20oC, all samples were found to be T. gondii-free. Of the 14 isolates of the GRA6 genotype, 6 were of type I, 7 were of type II, and 1 was of type III; the genotype distribution ratio was similar to that of T. gondii strains isolated from locally raised pigs. Moreover, no sulfonamide-tolerant dhps gene mutant of T. gondii was detected. PMID- 22446127 TI - Phenotypic and PCR-based identification of bacterial strains isolated from patients with suspected streptococcus suis infection in northern Thailand. AB - Twenty bacterial strains isolated from the blood of patients with suspected Streptococcus suis infection based on clinical symptoms in northern Thailand between 2009 and 2010 were subjected to phenotypic and genotypic identification. Commercial identification kits and a PCR-based assay targeting the S. suis specific 16S rDNA sequence correctly identified S. suis isolated from patients in northern Thailand; however, there was a risk of misidentifying S. gallolyticus as S. suis using a PCR assay targeting the S. suis-specific house keeping gene encoding glutamate dehydrogenase. This is the first paper to report S. gallolyticus infection in humans in Thailand. PMID- 22446128 TI - Epidemiological and microbiological analysis of community-associated methicillin resistant Staphylococcus aureus strains isolated from a Japanese hospital. AB - Reports of community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) infections have recently increased in Japan; however, these studies contain limited information on their epidemiology. We performed a single-center study in the Tokyo Medical University Hospital located in Shinjuku, a central area of Tokyo, Japan. From 2,099 MRSA isolates obtained during July 2007 to March 2009, we selected 44 MRSA isolates with a MIC of <2 MUg/mL for imipenem. Among 44 isolates, 28 strains had type IV or type V SCCmec, and we classified them as CA-MRSA. We identified only 1 Panton-Valentine leukocidin (PVL)-positive MRSA strain, which belonged to SCCmec type V. The PVL-positive CA-MRSA strain was isolated from a patient with multiple subcutaneous abscesses. The patient had returned to Japan from India; thus, the strain may have been contracted from outside of Japan. Thirteen (46.4%) and 15 strains (53.6%) were isolated from outpatients and inpatients, respectively. The major sites of infection included the respiratory tract (8 strains, 28.6%), skin/soft tissue (4 strains, 14.3%), and nasal cavity (4 strains, 14.3%). It is important to note that the most common site of CA-MRSA infection in inpatients was the respiratory tract; respiratory infections with CA-MRSA frequently cause severe infectious diseases. PMID- 22446129 TI - Genetic structure of Ascaris roundworm in Japan and patterns of its geographical variation. AB - Ascaris roundworm isolates from Japan and central Europe were examined by sequencing analyses to better understand geographically induced nucleotide variation and genotype distribution according to host. Three well-supported clusters (denoted as A, B, C) were identified by generating cox1 sequences of mtDNA from these regions. Among 5 pig isolates collected in eastern Honshu, Japan, in 2010, 3 carried DNA characteristics for cluster A and 2 corresponded with the characteristics of cluster B. The sequence of the human isolate JH1 from north-central Honshu, fixed in formalin since 1972, conformed to the characteristics of cluster A. Differential analysis of ribosomal ITS1 region revealed the JH1 isolate sequence profile of Ascaris lumbricoides. Cluster C, which was the most distinguish cluster, was formed by reference Slovak isolates and has been so far found almost exclusively in European pigs. A fluctuating prevailing distribution of A and B lineages in human and pig hosts in different territories of the world and the global distribution of several haplotypes indicate their establishment before secondary differentiation in a given region due to host affiliation. The protocol established for DNA isolation from formalin-fixed specimens using the modified procedure with the Qiagen extraction set can be used as a tool for retrospective studies in ascarid helminths when only archival specimens are available. PMID- 22446130 TI - Fatal pneumonia in HIV-infected patients from a novel ST239 methicillin-resistant Staphylococcus aureus carrying the toxic shock syndrome toxin-1 gene in Krasnoyarsk, Siberian Russia. PMID- 22446131 TI - Parameters that characterize different food-poisoning outbreaks. PMID- 22446132 TI - Use of concomitant glucose-lowering therapies and associated treatment results observed in clinical trials of twice-daily exenatide. AB - OBJECTIVE: To explore, by post hoc analyses of pooled data, the efficacy and safety of the use of exenatide twice daily (BID) in patients stratified by baseline glucose-lowering therapies. METHODS: Patients with type 2 diabetes from long-term randomized controlled trials who were treated with exenatide BID were classified into concomitant medication groups on the basis of background treatment (diet and exercise only, metformin only, sulfonylurea only, thiazolidinedione only, metformin + sulfonylurea, metformin + thiazolidinedione, or insulin with or without other oral antihyperglycemic medications). Seventeen studies were included in the analyses (N = 2,096). RESULTS: In these analyses of patients treated with exenatide BID for 12 to 30 weeks, there were significant decreases from baseline in hemoglobin A(1c) (A1C) and fasting glucose levels in all groups and significant decreases from baseline in body weight in all groups except the thiazolidinedione-only group. The decrease in A1C appeared to be greater in the insulin group than in the other groups, likely because the insulin dose was titrated whereas doses of concomitant antihyperglycemic medications were generally not titrated. Overall, changes in blood pressure and lipids were small. Across all groups, the most common adverse effects were gastrointestinal events. Hypoglycemia was more common in the sulfonylurea-only, metformin + sulfonylurea, and insulin groups than it was in the other concomitant medication groups. CONCLUSION: The use of exenatide BID across a wide range of background therapies was associated with reductions in A1C, fasting glucose, and body weight. Gastrointestinal adverse events were common. PMID- 22446133 TI - Dyshormonia Iatrogenica: crossroads of medicine, malpractice law, and professional ethics in clinical endocrinology. AB - OBJECTIVE: To present 2 challenging cases of patients who request endocrine therapies that their physician considers to be outside of the standard of care. METHODS: With these complex cases as a backdrop, we explore the constructs of medicine, malpractice law, and professional ethics that guide physicians' medical decision-making processes. RESULTS: These cases illustrate a common conundrum for clinical endocrinologists, who often find themselves struggling to balance patient satisfaction and well-being with generally accepted standards of medical care. From the perspective of a malpractice lawyer, we review the keys to limiting medicolegal liability, with emphasis on thorough documentation, informed consent, and effective doctor-patient communication. We then review the constructs of professional ethics that guide patient care, with emphasis on virtues of the "good physician," patients' right to self-determination, and paternalism. Finally, we explore some justifications for a compassionate physician to refuse a patient's desired treatment plan. CONCLUSION: In the end, we hope that this manuscript helps to facilitate best medical, legal, professional, and ethical practices of clinical endocrinology. PMID- 22446134 TI - Rehabilitation options for inland waterways impacted by sulfidic sediments--field trials in a south-eastern Australian wetland. AB - The accumulation of significant pools of sulfidic sediments in inland wetlands and creeks is an emerging risk for the management of inland waterways. We used replicated plot trials to appraise the viability of various strategies for neutralizing oxidized, acidified sulfidic sediments in a highly degraded wetland. Of the twenty different treatments trialed only addition of calcium hydroxide or calcium carbonate, burning of wood, and planting of Phragmites australis, Typha domingensis and Atriplex nummularia into beds prepared with CaCO3 or P. australis and T. domingensis into beds of sediment and mulch, decreased total actual acidity (TAA) in the top 5 cm of sediment in the first two weeks following treatment. Only the calcium hydroxide treatments and planting of P. australis, T. domingensis and A. nummularia into beds prepared with CaCO3 decreased TAA for a longer period of time (6 months). None of the treatments, except the planting of P. australis into beds prepared with lime, decreased TAA in the 5-30 cm layer of sediments. Therefore, the only effective treatment appears to be the application of highly alkaline ameliorants which need to be transported to the site. A survey of the wetland was undertaken to estimate the total amount of actual and potential acidity stored in the wetland's sediment and overlying water and showed that up to 1200 tonnes of calcium carbonate would be required to neutralise all of the actual and potential acidity in the 10 ha wetland. However, neutralisation of the remaining water in the wetland (about 12.5 ML) would produce approximately 2750 m3 of metal rich sludge (approximately 100 tonnes dry weight) that would require separate disposal. PMID- 22446135 TI - Application of activated carbon derived from 'waste' bamboo culms for the adsorption of azo disperse dye: kinetic, equilibrium and thermodynamic studies. AB - The utilization of activated carbon derived from 'waste' bamboo culms (BAC) for the removal of Disperse Red 167 (DR167), an azo disperse dye, was investigated. Studies of the properties of the adsorbent, the effect of contact time, the initial pH of the solution, the initial concentration of the dye solution and temperature indicated that a low initial pH or concentration of dye solution favors the adsorption process; temperature exerts a greater effect on the removal of azo disperse red 167 dye from aqueous solution. Kinetic and isotherm data were fitted to five non-linear kinetic and nine non-linear isotherm equations. In addition, the fits were evaluated in terms of the non-linear coefficient, Chi square test, Marquardt's percent standard deviation error function and small sample-corrected Akaike Information Criterion (AICc) methodology. The results showed that the AICc analysis was the best statistical tool for analyzing the data, the intra-particle diffusion and the pseudo-first-order models played important roles in the controlling rate step, and the Temkin equation best described the BAC isotherm data. Furthermore, the thermodynamic analysis indicated that the adsorption was a spontaneous, endothermic, entropy-increasing and physical process. Two types of commercial activated carbon, Filtrasorb 400 and Filtrasorb (F400 and F300), were used as contrast adsorbents. The contrast experiments revealed that BAC exhibits similar properties to F400 and F300. The utilization of bamboo wastes as carbon precursors is feasible. PMID- 22446136 TI - Immobilizer-assisted management of metal-contaminated agricultural soils for safer food production. AB - Production of food crops on metal contaminated agricultural soils is of concern because consumers are potentially exposed to hazardous metals via dietary intake of such crops or crop derived products. Therefore, the current study was conducted to develop management protocols for crop cultivation to allow safer food production. Metal uptake, as influenced by pH change-induced immobilizing agents (dolomite, steel slag, and agricultural lime) and sorption agents (zeolite and compost), was monitored in three common plants representative of leafy (Chinese cabbage), root (spring onion) and fruit (red pepper) vegetables, in a field experiment. The efficiency of the immobilizing agents was assessed by their ability to decrease the phytoavailability of metals (Cd, Pb, and Zn). The fruit vegetable (red pepper) showed the least accumulation of Cd (0.16-0.29 mgkg(-1) DW) and Pb (0.2-0.9 mgkg(-1) DW) in edible parts regardless of treatment, indicating selection of low metal accumulating crops was a reasonable strategy for safer food production. However, safer food production was more likely to be achievable by combining crop selection with immobilizing agent amendment of soils. Among the immobilizing agents, pH change-induced immobilizers were more effective than sorption agents, showing decreases in Cd and Pb concentrations in each plant well below standard limits. The efficiency of pH change-induced immobilizers was also comparable to reductions obtained by 'clean soil cover' where the total metal concentrations of the plow layer was reduced via capping the surface with uncontaminated soil, implying that pH change-induced immobilizers can be practically applied to metal contaminated agricultural soils for safer food production. PMID- 22446137 TI - Natural weathering in dry disposed ash dump: Insight from chemical, mineralogical and geochemical analysis of fresh and unsaturated drilled cores. AB - Some existing alternative applications of coal fly ash such as cement manufacturing; road construction; landfill; and concrete and waste stabilisation use fresh ash directly collected from coal-fired power generating stations. Thus, if the rate of usage continues, the demand for fresh ash for various applications will exceed supply and use of weathered dry disposed ash will become necessary alternative. As a result it's imperative to understand the chemistry and pH behaviour of some metals inherent in dry disposed fly ash. The bulk chemical composition as determined by XRF analysis showed that SiO2, Al2O3 and Fe2O3 were the major oxides in fresh ash and unsaturated weathered ashes. The unsaturated weathered ashes are relatively depleted in CaO, Fe2O3, TiO2, SiO2, Na2O and P2O5 due to dissolution and hydrolysis caused by chemical interaction with ingressing CO2 from the atmosphere and infiltrating rain water. Observed accumulations of Fe2O3, TiO2, CaO, K2O, Na2O and SO3 and Zn, Zr, Sr, Pb, Ni, Cr and Co in the lower layers indicate progressive downward movement through the ash dump though at a slow rate. The bulk mineralogy of unsaturated weathered dry disposed ash, as determined by XRD analysis, revealed quartz and mullite as the major crystalline phases; while anorthite, hematite, enstatite, lime, calcite, and mica were present as minor mineral phases. Pore water chemistry revealed a low concentration of readily soluble metals in unsaturated weathered ashes in comparison with fresh ash, which shows high leachability. This suggests that over time the precipitation of transient minor secondary mineral phases; such as calcite and mica might retard residual metal release from unsaturated weathered ash. Chloride and sulphate species of the water soluble extracts of weathered ash are at equilibrium with Na+ and K+; these demonstrate progressive leaching over time and become supersaturated at the base of unsaturated weathered ash. This suggests that the ash dump does not encapsulate the salt or act as a sustainable salt sink due to over time reduction in pore water pH. The leaching behaviours of Ca, Mg, Na+, K+, Se, Cr and Sr are controlled by the pH of the leachant in both fresh and unsaturated weathered ash. Other trace metals like As, Mo and Pb showed amphoteric behaviour with respect to the pH of the leachant. The precipitation of minor quantities of secondary mineral phases in the unsaturated weathered ash has significant effects on the acid susceptibility and leaching patterns of chemical species in comparison with fresh ash. The unsaturated weathered ash had lower buffering capacity at neutral pH (7.94-8.00) compared to fresh (unweathered) ash. This may be due to the initial high leaching/flushing of soluble basic buffering constituents from fly ash after disposal. The overall results of the acid susceptibility tests suggest that both fresh ash and unsaturated weathered ash would release a large percentage of their chemical species when in contact with slightly acidified rain. Proper management of ash dumps is therefore essential to safeguard the environmental risks of water percolation in different fly ashes behaviour. PMID- 22446138 TI - Short-term effects of irrigation with treated domestic wastewater on microbiological activity of a Vertic xerofluvent soil under Mediterranean conditions. AB - Approximately 70% of the world water use, including all the water diverted from rivers and pumped from underground, is used for agricultural irrigation, so the reuse of treated domestic wastewater (TWW) for purposes such as agricultural and landscape irrigation reduces the amount of water that needs to be extracted from natural water sources as well as reducing discharge of wastewater to the environment. Thus, TWW is a valuable water source for recycling and reusing in arid and semi-arid regions which are frequently confronting water shortages. In this regard, this study was planned to reveal the short-term effects of advanced TWW irrigation on microbial parameters of Vertic xerofluvent soil. For this purpose, certain parameters were measured in the study, including soil total organic carbon (C(org)), N-mineralization (N(min)), microbial biomass carbon (C(mic)), soil microbial quotient (C(mic)/C(org)) and the activities of the enzymes dehydrogenase (DHG), urease (UA), alkaline phosphatase (ALKPA), beta glucosidase (GLU) and aryl sulphatase (ArSA) in soils irrigated with TWW and fresh water (FW). All of the microbial parameters were negatively affected by TWW irrigation. Microbial parameters decreased by 10.1%-54.1% in comparison with the FW plots. This decrease especially in enzymatic activities of soil irrigated with TWW, presumably due to some heavy metals inhibited their activity associated with the soil types and the concentrations of heavy metals in wastewater. In contrast, C(mic)/C(org) was found higher in the plots irrigated with TWW at the end of the experiment. The addition of organic matter to soil by irrigation with TWW is cause for the increase in this ratio. The dose of irrigation should be modified to reduce the quantity and to increase the frequency of application to avoid the loss of aggregation and salt accumulation. TWW irrigation is a strategy with many benefits to agricultural land management; however, long-term studies should be implemented to investigate the microbiological characteristics of soil and to assess the feasibility of wastewater reuse for irrigation. PMID- 22446139 TI - Low temperature regeneration of activated carbons using microwaves: revising conventional wisdom. AB - The purpose of this work was to explore the application of microwaves for the low temperature regeneration of activated carbons saturated with a pharmaceutical compound (promethazine). Contrary to expectations, microwave-assisted regeneration did not lead to better results than those obtained under conventional electric heating. At low temperatures the regeneration was incomplete either under microwave and conventional heating, being this attributed to the insufficient input energy. At mild temperatures, a fall in the adsorption capacity upon cycling was obtained in both devices, although this was much more pronounced for the microwave. These results contrast with previous studies on the benefits of microwaves for the regeneration of carbon materials. The fall in the adsorption capacity after regeneration was due to the thermal cracking of the adsorbed molecules inside the carbon porous network, although this effect applies to both devices. When microwaves are used, along with the thermal heating of the carbon bed, a fraction of the microwave energy seemed to be directly used in the decomposition of promethazine through the excitation of the molecular bonds by microwaves (microwave-lysis). These results point out that the nature of the adsorbate and its ability to interact with microwave are key factors that control the application of microwaves for regeneration of exhausted activated carbons. PMID- 22446140 TI - Sustaining the environment through recycling: an empirical study. AB - This paper examines the determinants of recycling behaviour among 200 university students from the perspective of the theory of planned behaviour (TPB). Data was analysed using Structural Equation Modelling technique. Findings indicate that environmental awareness was significantly related to attitude towards recycling, whilst attitude and social norms had significant impact on recycling behaviour. However, convenience and cost of recycling were not significant reasons for recycling. The study has enhanced the understanding of the determinants of recycling behaviour and has implications for schools and governmental agencies in educating and encouraging positive recycling behaviour. It also confirms the appropriateness of the TPB in examining studies of this nature. Further suggestions for future research are offered. PMID- 22446141 TI - The Beck Cognitive Insight Scale: psychometric properties in a Canadian community sample. PMID- 22446142 TI - Gastrointestinal inflammation and associated immune activation in schizophrenia. AB - Immune factors are implicated in normal brain development and in brain disorder pathogenesis. Pathogen infection and food antigen penetration across gastrointestinal barriers are means by which environmental factors might affect immune-related neurodevelopment. Here, we test if gastrointestinal inflammation is associated with schizophrenia and therefore, might contribute to bloodstream entry of potentially neurotropic milk and gluten exorphins and/or immune activation by food antigens. IgG antibodies to Saccharomyces cerevisiae (ASCA, a marker of intestinal inflammation), bovine milk casein, wheat-derived gluten, and 6 infectious agents were assayed. Cohort 1 included 193 with non-recent onset schizophrenia, 67 with recent onset schizophrenia and 207 non-psychiatric controls. Cohort 2 included 103 with first episode schizophrenia, 40 of whom were antipsychotic-naive. ASCA markers were significantly elevated and correlated with food antigen antibodies in recent onset and non-recent onset schizophrenia compared to controls (p<=0.00001-0.004) and in unmedicated individuals with first episode schizophrenia compared to those receiving antipsychotics (p<=0.05-0.01). Elevated ASCA levels were especially evident in non-recent onset females (p<=0.009), recent onset males (p<=0.01) and in antipsychotic-naive males (p<=0.03). Anti-food antigen antibodies were correlated to antibodies against Toxoplasma gondii, an intestinally-infectious pathogen, particularly in males with recent onset schizophrenia (p<=0.002). In conclusion, gastrointestinal inflammation is a relevant pathology in schizophrenia, appears to occur in the absence of but may be modified by antipsychotics, and may link food antigen sensitivity and microbial infection as sources of immune activation in mental illness. PMID- 22446143 TI - Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia. AB - While placebo-controlled studies continue to be required by regulatory authorities for the licensing of new drugs for schizophrenia to demonstrate maintenance of effect, the long-term risks to participants are largely unknown. We compared the response to treatment with paliperidone palmitate before and after relapse in such a study. This was a post-hoc analysis of 97 patients with schizophrenia who relapsed while receiving placebo in a multinational relapse prevention clinical trial. Patients underwent an initial open-label treatment phase of 33 weeks (comprising a 9-week transition phase to switch patients to paliperidone palmitate, a 12-week flexible-dose phase and a 12-week fixed-dose phase); a double-blind phase of variable duration during which stabilized patients were randomized 1:1 to either continue paliperidone palmitate or receive placebo; and an optional 52-week open-label flexible-dose extension phase. There was a small but significant increase in PANSS total scores after eight months of treatment following relapse (56.7[12.68]) compared with prerelapse endpoint (54.5[11.74]) (p=0.026). Fourteen of 97 (14.4%) patients who had initially responded favorably to treatment met predefined nonresponse criteria in the postrelapse treatment phase, suggesting that treatment refractoriness may evolve in a subset of patients after relapse. However, relapses occurred in 18% of patients randomized to ongoing treatment in the double-blind phase, raising the possibility that treatment failure may also evolve in patients receiving continuous treatment. These findings may help inform decisions regarding the future of placebo-controlled trials in schizophrenia. PMID- 22446144 TI - Survey of systematic reviews and meta-analyses published in ophthalmology. AB - PURPOSE: To analyse the types of systematic reviews and meta-analyses published in the field of ophthalmology. METHODS: The systematic reviews and meta-analysis in ophthalmology published in peer-reviewed journals were retrieved. The distribution of systematic reviews and meta-analyses in various ophthalmic subspecialties, type of study and country of origin were determined. RESULTS: A total of 533 records were identified as systematic reviews and meta-analysis in ophthalmology. Overall, retina and glaucoma were the two major subspecialties accounting for 35% and 21% of the published systematic reviews and meta-analyses, respectively. The major topics published in retina were age-related macular degeneration (37%), tumours (14%), and diabetic retinopathy (12%). More than half (56%) the systematic reviews and meta-analyses were interventional. The author affiliations of these studies were largely from the USA (30%) and the UK (22%). About 60% of the systematic reviews and meta-analyses were published in ophthalmology journals, followed by the Cochrane Library (15.75%) and other non ophthalmic journals (25.14%), respectively. The number of publications increased from 3 per year in 1994 to almost 100 per year in 2010. CONCLUSIONS: The number of published systematic reviews and meta-analyses has been increasing progressively over the past few years. Retina and glaucoma are the two most commonly published topics. Non-ophthalmology journals form a sizeable proportion of avenues for ophthalmic publications. PMID- 22446145 TI - Endophthalmitis following intravitreal injection versus endophthalmitis following cataract surgery: clinical features, causative organisms and post-treatment outcomes. AB - AIMS: To describe and compare the causative organisms, clinical features and visual outcomes of endophthalmitis following intravitreal injection (IVI) to endophthalmitis following cataract surgery. METHODS: Patient population and setting: A retrospective case series of patients with acute endophthalmitis following either cataract surgery or IVI presenting to a tertiary referral centre -Sydney Eye Hospital--between 2007 and 2010. MAIN OUTCOME MEASURES: (1) identification of the causative organism; (2) time to presentation; (3) odds of improvement in visual acuity (VA) following treatment; (4) odds of final VA of counting fingers (CF) or less and (5) odds of enucleation. RESULTS: Of the 101 patients in our study, 48 had preceding cataract surgery and 53 had preceding IVI. There was an increased incidence of Streptococcus spp. endophthalmitis in post-IVI cases (24.53% vs 6.25%; OR 5.85; p=0.022). Endophthalmitis following IVI had increased likelihood of a final VA of CF or less (OR=6.0; p<0.01), decreased likelihood of any improvement in acuity following treatment (OR=0.13; p<0.01) and an increased likelihood of presenting within a week of the procedure (OR=3.93; p<0.01). Endophthalmitis caused by Streptococcus spp. was associated with increased likelihood of a final VA of CF or less (OR=10.2; p<0.01), decreased likelihood of any improvement in acuity following treatment (OR=0.06; p<0.01) and increased likelihood of enucleation (OR=17.11; p<0.01). CONCLUSIONS: Endophthalmitis following IVI is associated with an increased incidence of Streptococcus spp. infection, earlier presentation and poorer visual outcomes when compared with endophthalmitis following cataract surgery. PMID- 22446146 TI - Study of colloidal particle Brownian aggregation by low-coherence fiber optic dynamic light scattering. AB - The aggregation kinetics of particles in dense polystyrene latex suspensions is studied by low-coherence fiber optic dynamic light scattering. Low-coherence fiber optic dynamic light scattering is used to measure the hydrodynamic radius of the aggregates. The aggregation kinetics data obtained can be fitted into a single exponential function, which is the characteristic of slow aggregation. It is found that the aggregation rate of particles increased with higher electrolyte levels and with larger particle concentrations. The experimental results can be explained by use of the Derjaruin-Landau-Verwey-Overbeer (DLVO) theory. PMID- 22446147 TI - Ionic transport across tailored nanoporous anodic alumina membranes. AB - Highly ordered Nanoporous Alumina Membranes (NPAMs) with a precise control of the pore size and different porosity but thickness around 63 MUm were fabricated by the two-step anodization process using different acidic aqueous solutions, oxalic (Al-Ox), sulfuric (Al-Sf), and phosphoric (Al-Ph) acids, respectively. The pore size was controlled by properly changing the anodization voltage and the electrochemical bath conditions, obtaining the following average pores diameter values, d(p), as determined by scanning electron micrographic analysis: Al-Ox (d(p)=46+/-2 nm), Al-Sf (d(p)=27+/-2 nm), and Al-Ph (d(p)=240+/-20 nm). A pore increasing of around 5% for samples Al-Ox and Al-Sf was obtained after membranes immersion in 5 wt.% phosphoric acid for a certain etching time. Electrochemical characterization of NPAMs was performed with the samples in contact with NaCl solutions at different electrolyte concentrations. Ionic transport numbers and effective membrane fixed charge were determined from membrane potential measurements, which clearly show the significant influence of the pore diameter on ions transport. Moreover, frictional and electrical effects on mass transfer parameters (salt and ions diffusion coefficients) into the pores of alumina membranes were also evaluated from these results. PMID- 22446148 TI - Synthesis of temperature-responsive anion exchanger via click reaction. AB - The temperature-responsive anion exchanger was synthesized by immobilizing the poly(N-isopropylacrylamide) (PNIPAM), a kind of the temperature-responsive polymer, on the external surface of mesoporous silica via click reaction. The structure of this synthesized composite was characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), elemental analysis, and nitrogen adsorption experiment. The amount of PNIPAM immobilized on the external surface of mesoporous silica, which was calculated from the weight loss measured by thermogravimetry, increased from 5.3 wt.% to 12.9 wt.% (dry) depending on the amount of PNIPAM added in the click reaction. The adsorption-desorption behavior of methyl orange (MO) ions in this synthesized anion exchanger was affected by the temperature of aqueous solution: the MO ions were adsorbed and desorbed reversibly and repeatedly with changing the pH of the solution at 25 degrees C, while the amount of adsorbed MO ions remained nearly constant at about 0.05 mmol/g independent of the pH of the solution at 40 degrees C. Also, the amount of PNIPAM immobilized on the mesoporous silica influenced the adsorption rate of MO ions, suggesting that the adsorption rate in this composite is controlled by the diffusion of MO ions through the PNIPAM layer. PMID- 22446149 TI - Water-AOT-alkylbenzene microemulsions: influence of alkyl chain length on structure and percolation behavior. AB - We study the percolation behavior of the water-in-oil (w/o) droplet phase of AOT (sodium bis[2-ethylhexyl] sulfosuccinate)-based microemulsions with different alkylbenzenes (toluene, ethylbenzene, butylbenzene or octylbenzene) as oil phase. We use microemulsions of varying composition with molar water to surfactant ratios 0<=W<= 50 and droplet (water plus surfactant) volume fractions 10%<=phi<=50%. Using dielectric spectroscopy, a percolation transition is observed in w/o microemulsions with butylbenzene or octylbenzene. With increasing molecular weight of the alkylbenzene, the percolation temperature T(P) decreases. The structure of the microemulsions is determined by small angle X-ray scattering (SAXS). With increasing molar weight of the alkylbenzene, the stability range of the L(2) droplet phase extends to higher W. The larger amount of solubilizable water can be related to variable oil penetration of the AOT monolayer, which affects the spontaneous curvature of the surfactant shell. PMID- 22446150 TI - Tuning properties of silver particle monolayers via controlled adsorption desorption processes. AB - Using the well-defined silver particle suspension, systematic studies of adsorption kinetics on mica modified by poly(allylamine hydrochloride) (PAH) were carried out. The coverage of adsorbed particles was directly determined by AFM and SEM imaging. The dependence of the coverage on adsorption time, bulk suspension concentration, and ionic strength was systematically studied. It was confirmed that adsorption was diffusion controlled, with the initial rate proportional to the bulk concentration of particles. On the other hand, for long adsorption times, the saturation coverage was attained, which increased systematically with the ionic strength of the particle suspension. The adsorption kinetic runs were adequately reflected for the entire range of times and bulk concentration by the random sequential adsorption (RSA) model. Additionally, particle desorption kinetics from previously formed monolayers were studied. The decrease in the surface coverage of particles as a function of time was measured, which allowed one to determine the equilibrium adsorption constant K(a). The binding energy of silver particles (energy minimum depth) derived form these measurements varied between -16.9 kT and -17.8 kT, which suggests that it is mainly controlled by electrostatic interactions. Knowing the equilibrium adsorption constant, a particle adsorption isotherm was theoretically derived using the RSA model. Experimental data obtained for various bulk concentration of particles were in agreement with these theoretical predictions. These measurements suggest that it is feasible to produce uniform silver particle monolayers of desired coverage in the self-assembly process of particles. PMID- 22446151 TI - Current prospects in vascular biology and medicine. PMID- 22446152 TI - Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation. AB - Tumor microenvironment is a complex and highly dynamic milieu that provides very important clues on tumor development and progression mechanisms. Tumor-associated endothelial cells play a key role in stroma organization. They achieve tumor angiogenesis, a formation of tumor-associated (angiogenic) vessels mainly through sprouting from locally preexisting vessels and/or recruitment of bone marrow derived endothelial progenitor cells. This process participates to supply nutritional support and oxygen to the growing tumor. Endothelial cells constitute the interface between circulating blood cells, tumor cells and the extracellular matrix, thereby controlling leukocyte recruitment, tumor cell behavior and metastasis formation. Hypoxia, a critical parameter of the tumor microenvironment, controls endothelial/tumor cell interactions and is the key to tumor angiogenesis development. Under hypoxic stress, tumor cells produce factors that promote angiogenesis, vasculogenesis, tumor cell motility, metastasis and cancer stem cell selection. Targeting tumor vessels is a therapeutic strategy that has lately been fast evolving from antiangiogenesis to vessel normalization as discussed in this review. We shall focus on the pivotal role of endothelial cells within the tumor microenvironment, the specific features and the part played by circulating endothelial precursors cells. Attention is stressed on their recruitment to the tumor site and their role in tumor angiogenesis where they are submitted to miRNAs-mediated de/regulation. Here the compensation of the tumor deregulated angiogenic miRNAs - angiomiRs - is emphasized as a potential therapeutic approach. The strategy is to over express anti-angiomiRs in the tumor angiogenesis site upon selective delivery by precursor endothelial cells as miRs carriers. PMID- 22446153 TI - Unexpected recovery after robotic locomotor training at physiologic stepping speed: a single-case design. AB - OBJECTIVES: To investigate the effect of walking speed on the emergence of locomotor electromyogram (EMG) patterns in an individual with chronic incomplete spinal cord injury (SCI), and to determine whether central pattern generator activity during robotic locomotor training (RLT) transfers to volitional EMG activity during overground walking. DESIGN: Single-case (B-A-B; experimental treatment-withdrawal-experimental treatment) design. SETTING: Freestanding rehabilitation research center. PARTICIPANT: A 50-year-old man who was nonambulatory for 16 months after incomplete SCI (sub-T11). INTERVENTIONS: The participant completed two 6-week blocks of RLT, training 4 times per week for 30 minutes per session at walking speeds up to 5km/h (1.4m/s) over continuous bouts lasting up to 17 minutes. MAIN OUTCOME MEASURES: Surface EMG was recorded weekly during RLT and overground walking. The Walking Index for Spinal Cord Injury (WISCI-II) was assessed daily during training blocks. RESULTS: During week 4, reciprocal, patterned EMG emerged during RLT. EMG amplitude modulation revealed a curvilinear relationship over the range of walking speeds from 1.5 to 5km/h (1.4m/s). Functionally, the participant improved from being nonambulatory (WISCI II 1/20), to walking overground with reciprocal stepping using knee-ankle-foot orthoses and a walker (WISCI-II 9/20). EMG was also observed during overground walking. These functional gains were maintained greater than 4 years after locomotor training (LT). CONCLUSIONS: Here we report an unexpected course of locomotor recovery in an individual with chronic incomplete SCI. Through RLT at physiologic walking speeds, it was possible to activate the central pattern generator even 16 months postinjury. Further, to a certain degree, improvements from RLT transferred to overground walking. Our results suggest that LT-induced changes affect the central pattern generator and allow supraspinal inputs to engage residual spinal pathways. PMID- 22446154 TI - Exercise adherence to pelvic floor muscle strengthening is not a significant predictor of symptom reduction for women with urinary incontinence. AB - OBJECTIVE: To explore the predictors of treatment effectiveness for women with urinary incontinence (UI) receiving pelvic floor muscle (PFM) strengthening. DESIGN: Four-month cohort study. SETTING: Laboratory. PARTICIPANTS: Volunteers (N=68; mean age +/- SD, 50.5+/-6.0y) with UI. INTERVENTION: Four-month daily PFM strengthening exercise program at home. MAIN OUTCOME MEASURES: Outcome measures included self-reported improvement, Severity Index score, 3-days diary, strength of PFM, and quality of life. The participants' recall of the amount of exercise after the 4-month exercise period was used to assess the exercise adherence. RESULTS: Fifty-one (75%) of 68 women reported that their condition improved after 4 months of exercise. There were significant reductions in Severity Index score, number of voidings per day, number of leakages per day, and impact on quality of life (P<.05). In addition, the score of PFM strength was significantly improved (P=.001). There were no significant correlations between the change score of the Severity Index and age, body mass index, parity, type of UI, duration of UI, menopausal status, and amount of exercise (all P>.10). Multiple regression analysis revealed that initial severity of symptoms and improvement of PFM strength predicted 51.3% of variance in 4-month exercise effectiveness (change score of the Severity Index). CONCLUSIONS: The effectiveness of the 4-month PFM strengthening program was influenced by the severity of symptoms and the improvement score of PFM strength instead of exercise adherence. Women who had more significant symptoms of leakage (higher score on the Severity Index at baseline) and who had more improvement of PFM strength showed more improvement of symptoms after PFM strengthening. PMID- 22446155 TI - Affect recognition, empathy, and dysosmia after traumatic brain injury. AB - OBJECTIVE: To investigate if olfaction is associated with affect recognition and empathy deficits after traumatic brain injury (TBI). Prior research has shown that TBI often leads to loss of smell. We hypothesized a relationship with emotion perception, because the neural substrates of the olfactory system overlap with the ventral circuitry of the orbital frontal cortex, which play a critical role in affective responses, such as empathy. DESIGN: Comparative study investigating differences between participants with TBI who had impaired olfaction (dysosmia) with those with normal olfaction (normosmia). SETTING: Postacute rehabilitation facilities in the United States, Canada, and New Zealand. PARTICIPANTS: Participants (N=106) in the current study were a convenience sample of adults with moderate to severe TBI who were tested for olfactory function as part of a larger, related study on affect recognition. On average, participants were 11.5 years postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Olfaction (Brief Smell Identification Test), facial affect recognition (Diagnostic Assessment of Nonverbal Affect 2-Adult Faces [DANVA2 AF]), vocal affect recognition (Diagnostic Assessment of Nonverbal Affect 2-Adult Paralanguage [DANVA2-AP]), emotional inference (Emotional Inference from Stories Test [EIST]), and empathy (Interpersonal Reactivity Index [IRI]). RESULTS: Fifty six percent of participants were dysosmic and only 36% of these participants were aware of their deficit. Participants with dysosmia performed significantly poorer on the DANVA2-AF (P=.003), DANVA2-AP (P=.007), EIST (P=.016), and IRI (P=.013). Medium effect sizes were found for all measures. Dysosmia had a sensitivity value of 86.4% for detecting facial affect recognition impairments and 67.8% for vocal affect recognition impairments. CONCLUSIONS: This study shows that olfactory deficits may be indicative of affect recognition impairments and reduced empathy. Early knowledge of affect recognition and empathy deficits would be valuable so that treatment could be implemented predischarge. PMID- 22446156 TI - Optimization and diagnostic performance of a single multiparameter lineblot in the serological workup of systemic sclerosis. AB - INTRODUCTION: Detection of systemic sclerosis-associated antibodies (SSc-Ab) in routine clinical practice is mostly restricted to anti-centromere and anti topoisomerase-I antibodies. However, also other SSc-Ab (e.g. anti-RNA-polymerase III, anti-PM/Scl, anti-fibrillarin and anti-Th/To) have been shown to be valuable diagnostic and prognostic markers for the disease, but testing methodologies for their detection are laborious and time-consuming. This study aimed to optimize interpretational criteria of a multiparameter lineblot (LB) for the parallel detection of SSc-Ab. We also assessed its global diagnostic value as an alternative for combined conventional techniques (CCT) in the serological workup of systemic sclerosis (SSc) patients. METHODS: The presence of SSc-Ab (anti centromere, anti-topoisomerase-I, anti-RNA-polymerase-III, anti-PM/Scl, anti fibrillarin and anti-Th/To) was identified by LB on 145 consecutive SSc patients and on 277 disease controls. Diagnostic sensitivity and specificity were calculated for both individual reactivities and the global LB. Cohen's kappa coefficient was used to examine agreement between LB and CCT and guided the definition of final interpretational criteria for LB. RESULTS: Applying the optimal cut-off values and interpretational criteria, LB identified SSc-Ab in 110 SSc patients (sensitivity=76%) and in 19 disease controls (specificity=93%). Globally, there was a substantial agreement between CCT and LB (kappa=0.787, concordance 92.4%). LB and CCT showed a very good correlation (kappa>0.800) for most SSc-Ab (anti-centromere, anti-topoisomerase-I, anti-RNA-polymerase-III and anti-PM/Scl). The best agreement for anti-RNA-polymerase-III and anti-PM/Scl was achieved when positivity for both components was taken as a criterion. CONCLUSIONS: LB is a reliable alternative for the laborious and time-consuming conventional techniques in the diagnostic workup of SSc, especially for the detection of anti-centromere, anti-topoisomerase-I, anti-RNA-polymerase-III and anti-PM/Scl. PMID- 22446157 TI - The influence of active site loop mutations on the thermal stability of azurin from Pseudomonas aeruginosa. AB - The copper site and overall structures of azurin (AZ) variants in which the amicyanin (AMI) and plastocyanin (PC) metal binding loops have been introduced, AZAMI and AZPC, respectively, are similar to that of AZ, whereas the loop conformations resemble those in the native proteins. To assess the influence of these loop mutations on stability, the thermal unfolding of AZAMI and AZPC has been investigated by differential scanning calorimetry, absorption and fluorescence spectroscopy. The calorimetric profiles of both variants exhibit a complex shape consisting of two endothermic peaks and an exothermic peak. The temperature of the maximum heat of absorption for the single endothermic peak is 82.7 degrees C for AZ, whereas for AZAMI and AZPC the most intense endothermic peaks are at 74.9 and 68.1 degrees C comparable to values for AMI and PC, respectively. Denaturation investigated using the temperature dependence of the absorbance at ~600nm and Trp emission, also demonstrates decreased stability for both loop mutants. The thermal transition between the native and the denaturated states is irreversible, scan rate dependent and consistent with the two-state irreversible model. The structure of the active-site loop has a dramatic effect on the kinetic stability and the unfolding pathway of cupredoxins. PMID- 22446158 TI - Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. AB - Like the vitamin D receptor (VDR), the CYP27B1-hydroxylase is expressed widely in human tissues. This expression profile establishes the potential for interaction of the VDR with the product of the CYP27B1, 1,25-dihydroxyvitamin D (1,25 (OH)(2)D), in either an intracrine or paracrine mode. This expansive expression profile also suggests that the local production and action of 1,25-(OH)(2)D to regulate VDR-directed gene expression may be similarly wide-ranging and distinct from what occurs in the kidney; the proximal renal tubular epithelial cell is the richest source of the CYP27B1 and the site for production of 1,25-(OH)(2)D destined to function as a hormone. Existence of the CYP27B1 at extrarenal sites has been widely documented, although the functional impact of the enzyme in these tissues has yet to be fully demonstrated. Two notable exceptions are the disease activated macrophage (e.g., in sarcoidosis or tuberculosis) and the placenta. These two tissues are capable of generating enough 1,25-(OH)(2)D so as to be detectable in the general circulation. As such, this review will focus on CYP27B1 expression only at these two sites, theorizing that 1,25-(OH)(2)D production at these sites is for the purpose of local immunoregulatory function, not for controlling calcium balance in the host or the fetus. PMID- 22446159 TI - Sterol C24-methyltransferase: Physio- and stereo-chemical features of the sterol C3 group required for catalytic competence. AB - Sterol C24-methyltransferases (24-SMTs) catalyze the electrophilic alkylation of Delta(24)-sterols to a variety of sterol side chain constructions, and the C3- moiety is the primary determinant for substrate binding by these enzymes. To determine what specific structural features of the C3-polar group ensure sterol catalysis, a series of structurally related C3-analogs of lanosterol that differed in stereochemistry, bulk and electronic properties were examined against the fungal 24-SMT from Paracoccidioides brasiliensis (Pb) which recognize lanosterol as the natural substrate. Analysis of the magnitude of sterol C24 methylation activity (based on the kinetic constants of V(max)/K(m) and product distributions determined by GC-MS) resulting from changes at the C3-position in which the 3beta-OH was replaced by 3alpha-OH, 3beta-acetyl, 3-oxo, 3-OMe, 3beta F, 3beta-NH(2) (protonated species) or 3H group revealed that lanosterol and five substrate analogs were catalyzed and yielded identical side chain products whereas neither the 3H- or 3alpha-OH lanosterol derivatives were productively bound. Taken together, our results demonstrate a chemical complementarity involving hydrogen bonding formation of specific active site contacts to the nucleophilic C3-group of sterol is required for proper orientation of the substrate C-methyl intermediate in the activated complex. PMID- 22446160 TI - Uterine cells are recruited to the infarcted heart and improve cardiac outcomes in female rats. AB - We evaluated the hypothesis that uterine cells home to the heart after injury and improve cardiac outcomes. Premenopausal women have fewer cardiovascular complications than age-matched men, but the mechanisms responsible for this protection have not been conclusively identified. Hysterectomy was performed in young female rats (leaving the ovaries intact), and 7 days later the left coronary artery was ligated to produce a myocardial infarction (MI). Cardiac function at 28 days post-MI was measured using echocardiography. Fractional shortening was best in non-hysterectomized (non-Hx) females and lower in both Hx females and males. Uteri were then removed from GFP rats and heterotopically transplanted into non-GFP recipients to investigate homing of uterine cells to the infarcted myocardium. Seven days later, the uterine transplant recipients underwent coronary ligation. GFP(+) cells were found in the recipient hearts 7 days after MI and persisted for 6 months. Confocal analysis showed that homed uterine cells were located around blood vessels, suggesting their involvement in neovascularization. We then evaluated uterine cell transplantation by intravenously injecting GFP(+) uterine cells into Hx females immediately after MI. These GFP(+) cells were found to home to the injured myocardium, stimulate angiogenesis, improve cardiac function, and increase survival. This study demonstrates that uterine cells can home to the injured myocardium, enhance tissue repair, and prevent cardiac dysfunction. Uterine cells may play a role in the prevention of cardiovascular complications in females. PMID- 22446161 TI - Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B. AB - Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure. PMID- 22446162 TI - Cyclophilin A affects inflammation, virus elimination and myocardial fibrosis in coxsackievirus B3-induced myocarditis. AB - Extracellular cyclophilin A (CyPA) and its receptor Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) modulate inflammatory processes beyond metalloproteinase (MMP) activity. Recently, we have shown that CyPA and CD147 are upregulated in patients with inflammatory cardiomyopathy. Here we investigate the role of CyPA and CD147 in murine coxsackievirus B3 (CVB3)-induced myocarditis. CVB3-infected CyPA(-/-) mice (129S6/SvEv) revealed a significantly reduced T-cell and macrophage recruitment at 8 days p.i. compared to wild-type mice. In A.BY/SnJ mice, treatment with the cyclophilin-inhibitor NIM811 was associated with a reduction of inflammatory lesions and MMP-9 expression but with enhanced virus replication 8 days p.i. At 28 days p.i. the extent of lesion areas was not affected bei NIM811, whereas the collagen content was reduced. Initiation of NIM811-treatment on day 12 (after an effective virus defense) resulted in an even more pronounced reduction of myocardial fibrosis. In conclusion, in CVB3-induced myocarditis CyPA is important for macrophage and T cell recruitment and effective virus defense and may represent a pharmacological target to modulate myocardial remodeling in myocarditis. PMID- 22446163 TI - Thermal stability of glucokinase (GK) as influenced by the substrate glucose, an allosteric glucokinase activator drug (GKA) and the osmolytes glycerol and urea. AB - We investigated how glycerol, urea, glucose and a GKA influence kinetics and stability of wild-type and mutant GK. Glycerol and glucose stabilized GK additively. Glycerol barely affected the TF spectra of all GKs but decreased k(cat), glucose S(0.5) and K(D) values and ATP K(M) while leaving cooperativity unchanged. Glycerol sensitized all GKs to GKA as shown by TF. Glucose increased TF of GKs without influence of glycerol on the effect. Glycerol and GKA affected kinetics and binding additively. The activation energies for thermal denaturation of GK were a function of glucose with K(D)s of 3 and 1mM without and with glycerol, respectively. High urea denatured wild type GK reversibly at 20 and 60 degrees C and urea treatment of irreversibly heat denatured GK allowed refolding as demonstrated by TF including glucose response. We concluded: Glycerol stabilizes GK indirectly without changing the folding structure of the apoenzyme, by restructuring the surface water of the protein, whereas glucose stabilizes GK directly by binding to its substrate site and inducing a compact conformation. Glucose or glycerol (alone or combined) is unable to prevent irreversible heat denaturation above 40 degrees C. However, urea denatures GK reversibly even at 60 degrees C by binding to the protein backbone and directly interacting with hydrophobic side chains. It prevents irreversible aggregation allowing complete refolding when urea is removed. This study establishes the foundation for exploring numerous instability mutants among the more than 600 variant GKs causing diabetes in animals and humans. PMID- 22446164 TI - Substitution for Asn460 cripples beta-galactosidase (Escherichia coli) by increasing substrate affinity and decreasing transition state stability. AB - Substrate initially binds to beta-galactosidase (Escherichia coli) at a 'shallow' site. It then moves ~3A to a 'deep' site and the transition state forms. Asn460 interacts in both sites, forming a water bridge interaction with the O3 hydroxyl of the galactosyl moiety in the shallow site and a direct H-bond with the O2 hydroxyl of the transition state in the deep site. Structural and kinetic studies were done with beta-galactosidases with substitutions for Asn460. The substituted enzymes have enhanced substrate affinity in the shallow site indicating lower E.substrate complex energy levels. They have poor transition state stabilization in the deep site that is manifested by increased energy levels of the E.transition state complexes. These changes in stability result in increased activation energies and lower k(cat) values. Substrate affinity to N460D-beta galactosidase was enhanced through greater binding enthalpy (stronger H-bonds through the bridging water) while better affinity to N460T-beta-galactosidase occurred because of greater binding entropy. The transition states are less stable with N460S- and N460T-beta-galactosidase because of the weakening or loss of the important bond to the O2 hydroxyl of the transition state. For N460D-beta galactosidase, the transition state is less stable due to an increased entropy penalty. PMID- 22446165 TI - The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. AB - Diabetic neuropathy is a neurological complication of diabetes that causes significant morbidity and, because of the obesity-driven rise in incidence of type 2 diabetes, is becoming a major international health problem. Mitochondrial phenotype is abnormal in sensory neurons in diabetes and may contribute to the etiology of diabetic neuropathy where a distal dying-back neurodegenerative process is a key component contributing to fiber loss. This review summarizes the major features of mitochondrial dysfunction in neurons and Schwann cells in human diabetic patients and in experimental animal models (primarily exhibiting type 1 diabetes). This article attempts to relate these findings to the development of critical neuropathological hallmarks of the disease. Recent work reveals that hyperglycemia in diabetes triggers nutrient excess in neurons that, in turn, mediates a phenotypic change in mitochondrial biology through alteration of the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) signaling axis. This vital energy sensing metabolic pathway modulates mitochondrial function, biogenesis and regeneration. The bioenergetic phenotype of mitochondria in diabetic neurons is aberrant due to deleterious alterations in expression and activity of respiratory chain components as a direct consequence of abnormal AMPK/PGC-1alpha signaling. Utilization of innovative respirometry equipment to analyze mitochondrial function of cultured adult sensory neurons from diabetic rodents shows that the outcome for cellular bioenergetics is a reduced adaptability to fluctuations in ATP demand. The diabetes-induced maladaptive process is hypothesized to result in exhaustion of the ATP supply in the distal nerve compartment and induction of nerve fiber dissolution. The role of mitochondrial dysfunction in the etiology of diabetic neuropathy is compared with other types of neuropathy with a distal dying-back pathology such as Friedreich ataxia, Charcot-Marie-Tooth disease type 2 and human immunodeficiency virus-associated distal-symmetric neuropathy. PMID- 22446166 TI - Usefulness of 4D-CT for radiation treatment planning of gastric MZBCL/MALT. AB - It is well known that significant variations in stomach size, shape, and respiratory motion lead to uncertainties in target localization during treatment for gastric lymphoma. In this study, the usefulness of 4D-CT for radiation planning of gastric MZBCL/MALT was evaluated. Treatment planning using 4DCT (plan A) and conventional planning with a uniform margin (plan B) were compared using dose volume histograms (DVH) of the planning target volume (PTV) and the organ at risk, as well as the dose coverage of the clinical target volume (CTV) assessed by weekly online cone beam CT (CBCT) during the treatment course. In addition, regarding the image quality of CBCT , the interobserver agreement for the delineated volume of the CTV on CBCT was analyzed. The mean PTV of plan A was significantly smaller than that of plan B (p = 0.008). The mean doses to the liver and heart in plan A were significantly lower than those in plan B (p = 0.02 and 0.03, respectively). The reductions of V(20) of each kidney in plan A compared with those in plan B were 4.8 +/- 2.4% in the right kidney and 16.3 +/- 10.4% in the left. There was no significant difference in the dose coverage of the CTV between the plans during the treatment course. The interobserver agreement for the volume of the CTV was moderate correlation. Treatment planning using 4DCT for gastric MZBCL/MALT was useful for effective and safe irradiation with minimizing exposure of the organ at risk. PMID- 22446167 TI - Limb salvage: revision of failed intramedullary nail in hindfoot and ankle surgery in the diabetic neuropathic patient. AB - Herein, we illustrate an operative technique to attain limb salvage after a failed intramedullary nail in the diabetic Charcot neuropathic patient. The use of the blade plate, or T-plate, in combination with external fixation, fastened into the body of the calcaneus allows for greater bone capture. Our experience has shown that this provides for a stable, long-lasting construct. PMID- 22446168 TI - Hemostatic properties of the FVIIa analog NN1731. AB - Recombinant activated coagulation factor VII (rFVIIa) has proven to be a useful prohemostatic agent in patients with hemophilia and antibody inhibitors. It has also been used off-label in other settings. A major mechanism of its hemostatic efficacy is its ability to activate factor X on the surface of activated platelets in a tissue factor (TF)-independent manner. Novel analogs of FVIIa have been designed to have greater platelet-surface activity in the hope that these will be more active and reliable hemostatic agents. The analog NN1731 (vatreptacog alfa) was designed to have greater activity in the absence of TF, with the same substrate specificity as FVIIa. Surprisingly, it also binds to a greater number of sites on activated platelets by an, as yet, unknown mechanism. This molecule exhibits greater potency than FVIIa in biochemical assays, in vitro and animal models, and in early phase clinical trials. PMID- 22446169 TI - Resistance training volume, energy balance and weight management: rationale and design of a 9 month trial. AB - The increased prevalence of obesity and the lack of treatment success both argue for the design and evaluation of strategies to prevent the development of overweight and obesity. To date, the role of resistance training (RT) in this regard is largely unexplored. RT may be effective for weight management as a result of increased fat-free mass (FFM), which may result in increased resting metabolic rate and increased physical activity energy expenditure. However, the literature relative to the efficacy of RT protocols recommended for healthy adults to alter the aforementioned parameters is inconsistent or inadequately evaluated. We will conduct a 9 month randomized controlled efficacy trial to compare changes in body composition (fat mass, FFM, % body fat) and energy balance in response to 2 volumes of RT (1 vs. 3 sets vs. non-exercise control) both at the completion of training (9 months) and 1 year later (body composition). This investigation will be conducted in a sample of healthy, normal and overweight, sedentary, young adult men and women; a group at high risk for development of overweight and obesity. Our results will provide information relative to the minimum volume of RT that may be associated with body weight/fat gain which may inform the development of guidelines for RT to prevent weight gain or to alter body composition. PMID- 22446170 TI - Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. AB - OBJECTIVE: To examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone. RESEARCH DESIGN AND METHODS: Treatment naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. They were then randomized, along with patients previously receiving pioglitazone >=30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10 mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA(1c) change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis. RESULTS: At week 24, the mean reduction from baseline in HbA(1c) was -0.42% for placebo versus -0.82 and -0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7-1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6-9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0-8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1-4.3%) compared with placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare. CONCLUSIONS: In patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA(1c) levels and mitigated the pioglitazone related weight gain without increasing hypoglycemia risk. PMID- 22446171 TI - Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and beta-cell function. AB - OBJECTIVE: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control. RESEARCH DESIGN AND METHODS: We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 +/- 1.9 years, BMI 29.4 +/- 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, beta-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT. RESULTS: Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 +/- 0.1 to 5.7 +/- 0.1 mmol/L, P < 0.05, and from 5.86 +/- 0.06 to 5.76 +/- 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 +/- 28.5 to 198.8 +/- 23.6 mmol/L . min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L . min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2 295.2] pmol/L . min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL . min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change. CONCLUSIONS: Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, beta-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK. PMID- 22446172 TI - The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial. AB - OBJECTIVE: To study the effects of long-term oral benfotiamine supplementation on peripheral nerve function and soluble inflammatory markers in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study randomly assigned 67 patients with type 1 diabetes to receive 24-month benfotiamine (300 mg/day) or placebo supplementation. Peripheral nerve function and levels of soluble inflammatory variables were assessed at baseline and at 24 months. RESULTS: Fifty-nine patients completed the study. Marked increases in whole-blood concentrations of thiamine and thiamine diphosphate were found in the benfotiamine group (both P < 0.001 vs. placebo). However, no significant differences in changes in peripheral nerve function or soluble inflammatory biomarkers were observed between the groups. CONCLUSIONS: Our findings suggest that high-dose benfotiamine (300 mg/day) supplementation over 24 months has no significant effects upon peripheral nerve function or soluble markers of inflammation in patients with type 1 diabetes. PMID- 22446174 TI - Prepregnancy consumption of fruits and fruit juices and the risk of gestational diabetes mellitus: a prospective cohort study. AB - OBJECTIVE: Examine the association of prepregnancy habitual consumption of fruits and fruit juices and gestational diabetes mellitus (GDM) risk. RESEARCH DESIGN AND METHODS: A prospective study among women with at least one singleton pregnancy in the Nurses' Health Study II from 1991 to 2001. RESULTS: Among 13,475 women, 860 reported a first diagnosis of GDM. The adjusted relative risks (RRs) for GDM from the lowest to highest quintile of whole fruit consumption were 1.00 (referent), 0.80 (95% CI 0.65-0.98), 0.90 (0.73-1.10), 0.80 (0.64-1.00), and 0.93 (0.76-1.16), respectively. The corresponding RRs for fruit juice were 1.00, 0.82 (0.66-1.01), 0.78 (0.63-0.96), 0.84 (0.68-1.04), and 1.00 (0.81-1.23). CONCLUSIONS: These data suggest that prepregnancy higher consumption of whole fruits is not associated with an increased GDM risk. The association between fruit juices and GDM risk appears to be nonlinear. PMID- 22446175 TI - Effect of diabetes on severity and hospital mortality in patients with acute pancreatitis: a national population-based study. AB - OBJECTIVE: Diabetes may increase the risk of acute pancreatitis (AP). We aimed to further investigate whether diabetes may also adversely affect outcomes of patients with AP. RESEARCH DESIGN AND METHODS: In this retrospective cohort study, we compared 18,990 first-attack AP with diabetes to 37,980 matched control subjects from Taiwan's National Health Insurance Research Database between 2000 and 2009. Primary outcomes were development of severe AP, defined by a modified Atlanta classification scheme, and hospital mortality. Analyses were performed using univariable and multivariable logistic regression model with generalized estimating equations accounting for hospital clustering effect. RESULTS: After baseline characteristics were adjusted, AP patients with diabetes had a higher risk of a severe attack than their nondiabetic counterparts (adjusted odds ratio [OR] 1.21, 95% CI 1.16-1.26). When severity criteria were analyzed individually, diabetic AP patients had a 58% higher risk of intensive care unit admission and a 30% higher risk of local complications, but a 16% lower risk of gastrointestinal bleeding, than AP patients without diabetes. The risk of organ failure at least one system) was similar between the two groups. Conversely, AP patients with diabetes were associated with a lower risk of hospital mortality (adjusted OR 0.77, 95% CI 0.65-0.91). CONCLUSIONS: Although diabetes may adversely affect the disease process of AP, it seems to protect patients from AP-related mortality. PMID- 22446176 TI - Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease. AB - OBJECTIVE: Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status. RESEARCH DESIGN AND METHODS: Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). RESULTS: Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30-39 vs. 20-29, P < 0.001; FGF23: eGFR 50-59 vs. 40-49, P < 0.001). CONCLUSIONS: Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD. PMID- 22446173 TI - Zinc transporter-8 autoantibodies improve prediction of type 1 diabetes in relatives positive for the standard biochemical autoantibodies. AB - OBJECTIVE: We assessed diabetes risk associated with zinc transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma associated protein 2 antigen (IA-2A). RESEARCH DESIGN AND METHODS: For this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody negative relatives. RESULTS: ZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA(+) vs. 8 of 911 [0.8%] BAA(-), P < 0.001) and BAA number (177 of 1,683 [10.5%] single-, 221 of 384 [57.6%] double-, and 150 of 189 [79.4%] triple-BAA positivity, P < 0.001). The 4-year diabetes risk was higher in single BAA(+) relatives with ZnT8A than ZnT8A(-) relatives (31 vs. 7%, P < 0.001). In multivariable analysis, age <= 20 years (hazard ratio 2.13, P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not (P = 0.81 and 0.86, respectively). CONCLUSIONS: In relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies. PMID- 22446177 TI - Risk of cardiovascular and all-cause mortality: impact of impaired health-related functioning and diabetes: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. AB - OBJECTIVE: There is an established link between health-related functioning (HRF) and cardiovascular disease (CVD) mortality, and it is known that those with diabetes predominantly die of CVD. However, few studies have determined the combined impact of diabetes and impaired HRF on CVD mortality. We investigated whether this combination carries a higher CVD risk than either component alone. RESEARCH DESIGN AND METHODS: The Australian Diabetes, Obesity and Lifestyle (AusDiab) study included 11,247 adults aged >= 25 years from 42 randomly selected areas of Australia. At baseline (1999-2000), diabetes status was defined using the World Health Organization criteria and HRF was assessed using the SF-36 questionnaire. RESULTS: Overall, after 7.4 years of follow-up, 57 persons with diabetes and 105 without diabetes had died from CVD. In individuals with and without diabetes, HRF measures were significant predictors of increased CVD mortality. The CVD mortality risks among those with diabetes or impaired physical health component summary (PCS) alone were similar (diabetes only: hazard ratio 1.4 [95% CI 0.7-2.7]; impaired PCS alone: 1.5 [1.0-2.4]), while those with both diabetes and impaired PCS had a much higher CVD mortality (2.8 [1.6-4.7]) compared with those without diabetes and normal PCS (after adjustment for multiple covariates). Similar results were found for the mental health component summary. CONCLUSIONS: This study demonstrates that the combination of diabetes and impaired HRF is associated with substantially higher CVD mortality. This suggests that, among those with diabetes, impaired HRF is likely to be important in the identification of individuals at increased risk of CVD mortality. PMID- 22446178 TI - Questionable reliability of the speech-evoked auditory brainstem response (sABR) in typically-developing children. PMID- 22446179 TI - Gray matter in the brain: differences associated with tinnitus and hearing loss. AB - Tinnitus, usually associated with hearing loss, is characterized by the perception of sound without an external sound source. The pathophysiology of tinnitus is poorly understood. In the present study, voxel-based morphometry (VBM) was employed to identify gray matter differences related to hearing loss and tinnitus. VBM was applied to magnetic resonance images of normal-hearing control subjects (n = 24), hearing-impaired subjects without tinnitus (n = 16, HI group) and hearing-impaired subjects with tinnitus (n = 31, HI + T group). This design allowed us to disentangle the gray matter (GM) differences related to hearing loss and tinnitus, respectively. Voxel-based VBM analyses revealed that both HI and HI + T groups, relative to the controls, had GM increases in the superior and middle temporal gyri, and decreases in the superior frontal gyrus, occipital lobe and hypothalamus. We did not find significant GM differences between both patient groups. Subsequent region-of-interest (ROI) analyses of all Brodmann Areas, the cerebellum and the subcortical auditory nuclei showed a GM increase in the left primary auditory cortex of the tinnitus patients compared to the HI and control groups. Moreover, GM decreases were observed in frontal areas and mainly GM increases in limbic areas, both of which occurred for hearing loss irrespective of tinnitus, relative to the controls. These results suggest a specific role of the left primary auditory cortex and the additional involvement of various non-auditory brain structures in tinnitus. Understanding the causal relation between these GM changes and tinnitus will be an important next step in understanding tinnitus mechanisms. PMID- 22446180 TI - Properties of echo delay-tuning receptive fields in the inferior colliculus of the mustached bat. AB - One role of the inferior colliculus (IC) in bats is to create neuronal delay tuning, which is used for the estimation of target distance in the echolocating bat's auditory system. In this study, we describe response properties of IC delay tuned neurons of the mustached bat (Pteronotus parnellii) and compare it with those of delay-tuned neurons of the auditory cortex (AC). We also address the question if frequency content of the stimulus (pure-tone (PT) or frequency modulated (FM) pairs stimulation) affects combination-sensitive interaction in the same neuron. Sharpness and sensitivity of delay-tuned neurons in the IC are similar to those described in the AC. However, in contrast to cortical responses, in collicular neurons the delay at which the neurons show the maximum response does not change with changes in echo level. This tolerance to changes in the echo level seems to be a property of collicular delay-tuned neurons, which is modified along the ascending auditory pathway. In the IC we found neurons that showed a facilitated delay-tuned response when stimulated with FM components and did not show any delay-tuning with PT stimulation. This result suggests that not only is echo delay-tuning generated in the IC but also its FM-specificity observed in the cortex could be created to some extent in the IC and then topographically organized at higher levels. PMID- 22446181 TI - Parkinson's disease: don't mess with calcium. AB - The hallmark of the movement disorder Parkinson's disease (PD) is progressive degeneration of dopaminergic neurons. Mitochondrial dysfunction, impaired ubiquitin-mediated proteolysis of alpha-synuclein, and ER stress are each implicated in the complex and poorly understood sequence of events leading to dopaminergic neuron demise. In this issue of the JCI, Selvaraj et al. report that in a mouse neurotoxin-based model of PD, reduced Ca2+ influx through transient receptor potential C1 (TRPC1) channels in the plasma membrane of dopaminergic neurons triggers a cell death-inducing ER stress response. These new findings suggest that TRPC1 channels normally function in Ca2+-mediated signaling pathways that couple adaptive/neurotrophic responses to metabolic and oxidative stress and suggest that disruption of these pathways may contribute to PD. PMID- 22446182 TI - A "so cilia" network: cilia proteins start "social" networking. AB - Cilia are unique cellular organelles found in nearly all cell types. In recent years, the importance of these organelles has been highlighted by the discovery that mutations in genes encoding proteins related to cilia biogenesis and function cause a class of complex syndromes termed ciliopathies. Emerging evidence suggests interactions among the various ciliopathy-associated proteins, but the precise mechanisms by which these interactions generate functional networks have remained elusive. In this issue of the JCI, Rachel and colleagues have now clearly linked two ciliopathy-associated proteins (CEP290 and MKKS). Surprisingly, the effects of a hypomorphic disease-causing Cep290 allele were rescued by loss of MKKS function, suggesting that it might be possible to treat some ciliopathies by fine-tuning interactions within the expanding ciliary network. PMID- 22446183 TI - Chk'ing p53-deficient breast cancers. AB - Loss or functional impairment of p53 occurs in many human cancers, and its absence is often associated with a poor response to conventional chemotherapy. Hence, much effort is currently devoted to developing novel treatments for p53 deficient malignancies. One approach is to target pathways that are selectively required for the survival of p53-deficient cancer cells, thus exploiting a synthetic lethal interaction. Previous studies have demonstrated that inhibition of the ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (Chk1) pathway in p53-deficient cells can induce such a synthetic lethal outcome. In this issue of the JCI, Ma et al. take these findings a step closer to the clinic by demonstrating that highly specific inhibitors of Chk1 synergize with chemotherapy to stem progression of p53-deficient triple-negative breast cancers in a xenotransplant model of this disease. Together with other recent studies, this report highlights the promise of ATR and Chk1 inhibitors in targeted cancer treatment. PMID- 22446184 TI - Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. AB - Blood transfusion represents the first and most prescribed cell-based therapy; however, clinical safety and efficacy trials are lacking. Clinical cohort studies have suggested that massive transfusion and/or transfusion of aged stored blood may contribute to multiorgan dysfunction in susceptible patients. In this issue of the JCI, Baek and colleagues report that aged stored blood hemolyzes after massive transfusion in a guinea pig model. Hemolysis led to vascular and kidney injury that was mediated by cell-free plasma hemoglobin and prevented by coinfusion of the specific hemoglobin scavenger protein, haptoglobin. These studies support an expanding body of research indicating that intravascular hemolysis is a pathological mechanism in several human diseases, including multiorgan dysfunction after either massive red blood cell transfusion or hemoglobin-based blood substitute therapy, the hemoglobinopathies, malaria, and other acquired and genetic hemolytic conditions. PMID- 22446185 TI - Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy. AB - Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients. PMID- 22446186 TI - Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. AB - Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters Ca2+ homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca2+ entry (SOCE), which is critical for maintaining ER Ca2+ levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and Ca2+ entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca2+ levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca2+ entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1-/- mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating Ca2+ homeostasis and inhibiting the UPR and thus contributes to neuronal survival. PMID- 22446187 TI - Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis. AB - Cilia are highly specialized microtubule-based organelles that have pivotal roles in numerous biological processes, including transducing sensory signals. Defects in cilia biogenesis and transport cause pleiotropic human ciliopathies. Mutations in over 30 different genes can lead to cilia defects, and complex interactions exist among ciliopathy-associated proteins. Mutations of the centrosomal protein 290 kDa (CEP290) lead to distinct clinical manifestations, including Leber congenital amaurosis (LCA), a hereditary cause of blindness due to photoreceptor degeneration. Mice homozygous for a mutant Cep290 allele (Cep290rd16 mice) exhibit LCA-like early-onset retinal degeneration that is caused by an in-frame deletion in the CEP290 protein. Here, we show that the domain deleted in the protein encoded by the Cep290rd16 allele directly interacts with another ciliopathy protein, MKKS. MKKS mutations identified in patients with the ciliopathy Bardet-Biedl syndrome disrupted this interaction. In zebrafish embryos, combined subminimal knockdown of mkks and cep290 produced sensory defects in the eye and inner ear. Intriguingly, combinations of Cep290rd16 and Mkksko alleles in mice led to improved ciliogenesis and sensory functions compared with those of either mutant alone. We propose that altered association of CEP290 and MKKS affects the integrity of multiprotein complexes at the cilia transition zone and basal body. Amelioration of the sensory phenotypes caused by specific mutations in one protein by removal of an interacting domain/protein suggests a possible novel approach for treating human ciliopathies. PMID- 22446189 TI - Repolarization gradients in the intact heart: transmural or apico-basal? AB - Controversies regarding the genesis of the T wave in the electrocardiogram and the role of midmural M cells in the intact heart include: In normal, intact canine and human hearts there is no significant transmural gradient in repolarization times. The T wave results primarily from apico-basal differences in repolarization times. Also, in the intact heart there is no midmural region of prolonged action potential duration. This contrasts with isolated preparations, such as the wedge preparation or myocardial slices or disaggregated myocytes in which M cells, with action potentials longer than those of endocardial and epicardial myocardium, can be found. This disparity in action potential duration probably results from partial uncoupling of myocardial cells in the regions where measurements are made, e.g., the cut surface of a wedge preparation. In regions of a wedge where cellular coupling is normal, or in isolated myocardial bundles or sheets, no evidence for M cells is detected. In some wedge preparations, a drug-induced large transmural repolarization gradient, involving M cells, can lead to Torsade de Pointes, possibly caused by so-called phase two reentry. In contrast, when a gradient of repolarization times of more than 100 ms was created in intact hearts, no evidence for reentry was found and no spontaneous arrhythmias occurred. In conclusion, in the intact heart, M cells appear not to contribute to repolarization gradients and arrhythmias. Furthermore, no significant repolarization gradients between endocardium and epicardium exist. The T wave in the body surface electrocardiogram is caused by apico-basal and anterior-posterior differences in repolarization times. PMID- 22446188 TI - Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models. AB - Patients with triple-negative breast cancer (TNBC) - defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification - have a poor prognosis. There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage. Previous studies have shown that inhibition of Chk1 in a p53-deficient background results in apoptosis [corrected] in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models. Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5). These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors. Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy. These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition. PMID- 22446190 TI - Similar structures but different mechanisms: Prediction of FABPs-membrane interaction by electrostatic calculation. AB - The role of fatty acid binding proteins as intracellular fatty acid transporters may require their direct interaction with membranes. In this way different mechanisms have been previously characterized through experimental studies suggesting different models for FABPs-membrane association, although the process in which the molecule adsorbs to the membrane remains to be elucidated. To estimate the importance of the electrostatic energy in the FABP-membrane interaction, we computationally modeled the interaction of different FABPs with both anionic and neutral membranes. Free Electrostatic Energy of Binding (dE), was computed using Finite Difference Poisson Boltzmann Equation (FDPB) method as implemented in APBS (Adaptive Poisson Boltzmann Solver). Based on the computational analysis, it is found that recruitment to membranes is facilitated by non-specific electrostatic interactions. Also energetic analysis can quantitatively differentiate among the mechanisms of membrane association proposed and determinate the most energetically favorable configuration for the membrane-associated states of different FABPs. This type of calculations could provide a starting point for further computational or experimental analysis. PMID- 22446191 TI - The neuroprotective role of TERT via an antiapoptotic mechanism in neonatal rats after hypoxia-ischemia brain injury. AB - Telomerase reverse transcriptase (TERT) can regulate cell apoptosis and proliferation. It has been shown that TERT expression can be induced in models of adult brain ischemia. In the present study, we investigated the role of TERT in ischemic neuronal death in neonatal hypoxic-ischemic rats model. Postnatal day 10 Sprague-Dawley rats were used to establish hypoxia-ischemia (HI) model and hypoxia alone (H) model. Pups were killed at 4, 8, 12, 24, or 48 h after the insult. Plasmid containing mock, TERT antisense or sense fragment mixed with Fugene HD was injected to the right lateral ventricle immediately after the insult respectively. Additional injection was performed after 24 h. Pups were sacrificed 24h after the administration. TERT and cleaved caspase-3 (CC3) expression were measured by Western blot. Apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. We found that H/HI treatment induced neuronal apoptosis and expression of TERT and CC3. However, TERT was higher in H than in HI pups whereas CC3 and apoptosis were opposite, TERT antisense plasmid markedly attenuated TERT expression induced by HI, upregualted CC3 expression, and increased apoptosis. Our results indicate that TERT might function as an anti-apoptotic protein by inhibiting activation of caspase-3, while further studies are needed to evaluate underlying mechanisms. PMID- 22446192 TI - Expression of activating transcription factor 3 (ATF 3) and caspase 3 in Schwann cells and axonal outgrowth after sciatic nerve repair in diabetic BB rats. AB - The aim of this study was to evaluate nerve regeneration in relation to the transcription factor, Activating Transcription Factor 3 (ATF 3), and an apoptotic marker, caspase 3, in the Schwann cells of diabetic BB rats (i.e. display type 1 diabetes phenotype). Sciatic nerves in healthy Wistar rats and in diabetic BB rats were transected and immediately repaired. Axonal outgrowth (neurofilament staining) and expression of ATF 3 and caspase 3 were quantified by immunohistochemistry after six days. There was no difference in axonal outgrowth between healthy and diabetic rats. However, the sciatic nerve in the diabetic rats exhibited a larger number of ATF 3 expressing Schwann cells at the site of the lesion and also a higher number of caspase 3 expressing Schwann cells. Similar differences were observed in the distal nerve segment between the healthy and diabetic rats. There were no correlations between the number of Schwann cells expressing ATF 3 and caspase 3. Thus, diabetic BB rats display an increased activation of ATF 3 and also a rise in apoptotic caspase 3 expressing Schwann cells, but with no discrepancy in length of axonal outgrowth after nerve injury and repair at six days. Knowledge about signal transduction mechanisms in diabetes after stress may provide new insights into the development of diabetic neuropathy and neuropathic pain. PMID- 22446193 TI - Mapping novel labels to actions: how the rhythm of words guides infants' learning. AB - We investigated the effect of lexical stress on 16-month-olds' ability to form associations between labels and paths of motion. Disyllabic English nouns tend to have a strong-weak (trochaic) stress pattern, and verbs tend to have a weak strong (iambic) pattern. We explored whether infants would use word stress information to guide word-action associations during learning. Infants heard two novel words with either verb-like iambic stress or noun-like trochaic stress. Each word was paired with a single novel object performing one of two path actions and was tested using path-switch trials. Only infants in the iambic stress condition learned the association between the novel words and the path actions. To further investigate infants' difficulty in mapping the trochaic labels to the actions, we conducted an additional study in which infants were given an object switch task using the trochaic labels. In this case, infants were able to associate the trochaic labels with the objects, providing further support that infants use lexical stress to guide label-referent associations. This study demonstrates that by 16months, English-learning infants have developed a bias to expect disyllabic action labels to have iambic stress patterns, consistent with native language stress patterns. PMID- 22446194 TI - Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with inflammatory bowel disease. AB - BACKGROUND & AIMS: Cell adhesion is one function regulated by cellular prion protein (PrP(c)), a ubiquitous, glycosylphosphatidylinositol-anchored glycoprotein. PrP(c) is located in cell-cell junctions and interacts with desmosome proteins in the intestinal epithelium. We investigated its role in intestinal barrier function. METHODS: We analyzed permeability and structure of cell-cell junctions in intestine tissues from PrP(c) knockout (PrP(c-/-)) and wild-type mice. PrP(c) expression was knocked down in cultured human Caco-2/TC7 enterocytes using small hairpin RNAs. We analyzed colon samples from 24 patients with inflammatory bowel disease (IBD). RESULTS: Intestine tissues from PrP(c-/-) mice had greater paracellular permeability than from wild-type mice (105.9 +/- 13.4 vs 59.6 +/- 10.1 mg/mL fluorescein isothiocyanate-dextran flux; P < .05) and impaired intercellular junctions. PrP(c-/-) mice did not develop spontaneous disease but were more sensitive than wild-type mice to induction of colitis with dextran sulfate (32% mortality vs 4%, respectively; P = .0033). Such barrier defects were observed also in Caco-2/TC7 enterocytes following PrP(c) knockdown; the cells had increased paracellular permeability (1.5-fold over 48 hours; P < .001) and reduced transepithelial electrical resistance (281.1 +/- 4.9 vs 370.6 +/- 5.7 Omega.cm(2); P < .001). Monolayer shape and cell-cell junctions were altered in cultures of PrP(c) knockdown cells; levels of E-cadherin, desmoplakin, plakoglobin, claudin-4, occludin, zonula occludens 1, and tricellulin were decreased at cell contacts. Cell shape and junctions were restored on PrP(c) re expression. Levels of PrP(c) were decreased at cell-cell junctions in colonic epithelia from patients with Crohn's disease or ulcerative colitis. CONCLUSIONS: PrP(c) regulates intestinal epithelial cell-cell junctions and barrier function. Its localization is altered in colonic epithelia from patients with IBD, supporting the concept that disrupted barrier function contributes to this disorder. PMID- 22446197 TI - Proteasome inhibition of pathologic shedding of enterocytes to defend barrier function requires X-linked inhibitor of apoptosis protein and nuclear factor kappaB. AB - BACKGROUND & AIMS: Although we are beginning to understand where, when, and how intestinal epithelial cells are shed, physiologically, less is understood about alterations in cell fate during minimally invasive epithelial infections. We used a piglet model of Cryptosporidium parvum infection to determine how elimination of infected enterocytes is balanced with the need to maintain barrier function. METHODS: We studied the effects of enterocyte shedding by C parvum-infected ileum on barrier function ex vivo with Ussing chambers. The locations and activities of caspase-3, nuclear factor kappaB (NF-kappaB), and inhibitor of apoptosis proteins (IAP) were assayed by enzyme-linked immunosorbent assay, immunoblot, and tissue immunoreactivity analyses and using specific pharmacologic inhibitors. The location, specificity, and magnitude of enterocyte shedding were quantified using special stains and light microscopy. RESULTS: Infection with C parvum activated apoptotic signaling pathways in enterocytes that resulted in cleavage of caspase 3. Despite caspase-3 cleavage, enterocyte shedding was confined to villus tips, coincident with apoptosis, and observed more frequently in infected cells. Epithelial expression of X-linked inhibitor of apoptosis protein (XIAP), activation of NF-kappaB, and proteasome activity were required for control of cell shedding and barrier function. The proteasome blocked activity of caspase-3; this process was mediated by expression of XIAP, which bound to cleaved caspase 3. CONCLUSIONS: We have identified a pathway by which villus epithelial cells are maintained during C parvum infection. Loss of barrier function is reduced by active retention of infected enterocytes until they reach the villus tip. These findings might be used to promote clearance of minimally invasive enteropathogens, such as by increasing the rate of migration of epithelial cells from the crypt to the villus tip. PMID- 22446198 TI - Measurement of shear strength for HOPG with scanning tunneling microscopy by thermal excitation method. AB - An experimental observation of force interactions in scanning tunneling microscopy (STM) is presented. A technique for measuring force interactions between a conventional STM probe and a sample by spectra analysis of its thermal fluctuations from tunneling current in STM is developed theoretically and experimentally. Thermally excited fluctuation of the STM probe is exactly discerned in air and then force gradient is determined from its corresponding eigen-frequency with a formula similar to that for a small-amplitude atomic force microscopy (AFM). The observed force interactions are consistent with forces in dynamic AFM. Shear strength of 7 GPa for highly oriented pyrolytic graphite (HOPG) under compressive stress is obtained from the experiment and using the elastic theory. We believe that this technique is of scientific significance as it enables accurate measurement of short-range force interactions at atomic scale under true STM conditions. PMID- 22446199 TI - Effect of the tip-sample contact force on the nanostructure size fabricated by local oxidation nanolithography. AB - Nanofabrication technique based on atomic force microscope (AFM)/scanning tunneling microscope (STM) can be applied to the fabrication of semiconductor micro/nano devices. Here, many oxide wires on Si surface were fabricated using conductive contact mode and tapping mode AFM in ambient atmosphere. The experiments show that tip-sample contact force plays an important role in electric-field-induced anodization with AFM. It is proved that the height and aspect ratio of oxide structures fabricated by contact mode AFM nano-oxidation technique will decrease gradually with increasing contact force between the tip and the sample. Compared with oxide structures fabricated by contact mode AFM, nanofabrication based on tapping mode AFM gives higher aspect ratio and height of oxide structures and narrower oxide width because of decreased contact force. In addition, field-induced oxidation by tapping mode AFM gives higher flexibility on the control of oxide size and aspect ratio by varying the oscillation amplitude, the range of the damping ratio with about 10%~38% can optimize the height and aspect ratio of oxide structures. PMID- 22446200 TI - Coupled high Q-factor surface nanoscale axial photonics (SNAP) microresonators. AB - We experimentally demonstrate series of identical two, three, and five coupled high Q-factor surface nanoscale axial photonics (SNAP) microresonators formed by periodic nanoscale variation of the optical fiber radius. These microresonators are fabricated with a 100 MUm period along an 18 MUm radius optical fiber. The axial FWHM of these microresonators is 80 MUm and their Q-factor exceeds 10(7). In addition, we demonstrate a SNAP microresonator with the axial FWHM as small as 30 MUm and the axial FWHM of the fundamental mode as small as 10 MUm. These results may potentially enable the dense integration of record low loss coupled photonic microdevices on the optical fiber platform. PMID- 22446201 TI - Ultrafast laser-written dual-wavelength waveguide laser. AB - We report the performance of a dual-wavelength waveguide laser based on a phase modulated sampled-grating architecture fabricated using the femtosecond laser direct-write technique. The waveguide laser was written in Yb-doped phosphate glass and had a narrow linewidth (<10 pm), high signal-to-noise ratio (>60 dB), 5 mW output power per channel, and wavelength separation of 10 nm. PMID- 22446202 TI - 2.1 MUm waveguide laser fabricated by femtosecond laser direct-writing in Ho3+, Tm3+:ZBLAN glass. AB - We report the first Ho3+ doped waveguide laser, which was realized by femtosecond direct-writing of a depressed cladding structure into ZBLAN glass. Tm3+ sensitizing allows the 9 mm long Ho3+ gain medium to be conveniently pumped at 790 nm, achieving an optical-to-optical slope efficiency of 20% and a threshold of 20 mW. The potentially widely tunable laser produces up to 76 mW at 2052 nm and also operates at shorter wavelengths near 1880 nm and 1978 nm for certain cavity configurations. PMID- 22446203 TI - Generation of sub wavelength super-long dark channel using high NA lens axicon. AB - We investigate the focusing properties of a double-ring-shaped azimuthally polarized beam by a high numerical aperture (NA) lens axicon based on vector diffraction theory. We observe that our proposed system generates a sub wavelength focal hole of 0.5lambda having large uniform focal depth of 48lambda without any annular aperture. We also observed that the distribution of the total intensity near the focus has little variation with the degree of truncation beta of the incident beam by the pupil. The authors expect such a super-long dark channel may find applications in optical, biological, and atmospheric sciences. PMID- 22446204 TI - Perfect blazing with echelle gratings in TE and TM polarization. AB - Perfect blazing with echelle gratings in a high-order Littrow mount exists not only with TM polarization, as can perhaps be assumed, but also with TE and TM polarizations simultaneously. This finding contradicts with a heuristic explanation as to why perfect blazing is not possible simultaneously in TE and TM polarizations given by Loewen and Popov [Diffraction Gratings and Applications (Marcel Dekker, 1997)]. As a matter of fact, in the ideal case of infinite conductivity, light is diffracted in the Littrow order with 100% efficiency for both polarization states. For metal gratings, a small loss occurs. Three conditions are necessary for perfect blazing: (A) the apex angle must be very close to 90 degrees , (B) a specific Littrow order has to be used, and (C) the blaze angle has to be 4 degrees to 6 degrees larger than the Littrow angle. The last property is particularly intriguing because typically the difference between the two angles is smaller than 1.0 degrees . PMID- 22446205 TI - Robust laser frequency stabilization by serrodyne modulation. AB - We report the relative frequency stabilization of a distributed feedback erbium doped fiber laser on an optical cavity by serrodyne frequency shifting. A correction bandwidth of 2.3 MHz and a dynamic range of 220 MHz are achieved, which leads to a strong robustness against large disturbances up to high frequencies. We demonstrate that serrodyne frequency shifting reaches a higher correction bandwidth and lower relative frequency noise level compared to a standard acousto-optical modulator based scheme. Our results allow us to consider promising applications in the absolute frequency stabilization of lasers on optical cavities. PMID- 22446206 TI - 2 GHz clock quantum key distribution over 260 km of standard telecom fiber. AB - We report a demonstration of quantum key distribution (QKD) over a standard telecom fiber exceeding 50 dB in loss and 250 km in length. The differential phase shift QKD protocol was chosen and implemented with a 2 GHz system clock rate. By careful optimization of the 1 bit delayed Faraday-Michelson interferometer and the use of the superconducting single photon detector (SSPD), we achieved a quantum bit error rate below 2% when the fiber length was no more than 205 km, and of 3.45% for a 260 km fiber with 52.9 dB loss. We also improved the quantum efficiency of SSPD to obtain a high key rate for 50 km length. PMID- 22446207 TI - Direct link of a mid-infrared QCL to a frequency comb by optical injection. AB - A narrow-linewidth comb-linked nonlinear source is used as master radiation to injection lock a room-temperature mid-infrared quantum cascade laser (QCL). This process leads to a direct lock of the QCL to the optical frequency comb, providing the unique features of narrow linewidth, absolute frequency, higher output power, and wide mode-hop-free tunability. The QCL reproduces the injected radiation within more than 94%, with a reduction of the frequency-noise spectral density by 3 to 4 orders of magnitude up to about 100 kHz, and a linewidth narrowing from a few MHz to 20 kHz. PMID- 22446208 TI - Monotonically chirped pulse evolution in an ultrashort pulse thulium-doped fiber laser. AB - We report on monotonically positively chirped pulse operation of a hybridly mode locked thulium fiber laser. Dispersion management was realized with a small-core, high-NA fiber providing normal dispersion in the 2 MUm wavelength region. The laser delivered pulses with 0.7 nJ energy at the 1927 nm center wavelength and sub-500-fs pulse duration after compression. PMID- 22446209 TI - Control of single emitter radiation by polarization- and position-dependent activation of dark antenna modes. AB - We study the modification of the decay rates of a single dipolar emitter positioned in the vicinity of metallic linear nanoantennas when higher-order plasmonic excitations are induced. We show that it is possible to effectively tune the enhancement or suppression of both the radiative and nonradiative decay processes by controlling the position and orientation of the dipole with respect to the antenna. Transverse polarization of a single emitter, with respect to the antenna axis, located at the center of the antenna activates dark antenna modes that modify dramatically both the intensity and the spectral features of the decay rates. PMID- 22446210 TI - Stamp printing of silicon-nanomembrane-based photonic devices onto flexible substrates with a suspended configuration. AB - In this Letter, we demonstrate for the first time (to our best knowledge) stamp printing of silicon nanomembrane (SiNM)-based in-plane photonic devices onto a flexible substrate using a modified transfer printing method that utilizes a suspended configuration, which can adjust the adhesion between the released SiNM and the "handle" silicon wafer. With this method, 230 nm thick, 30 MUm wide, and up to 5.7 cm long SiNM-based waveguides are transferred to flexible Kapton films with >90% transfer yield. The propagation loss of the transferred waveguides is measured to be ~1.1 dB/cm. Scalability of this approach to transfer intricate structures, such as photonic crystal waveguides and multimode interference couplers with a minimum feature size of 200 nm and 2 MUm, respectively, is also demonstrated. PMID- 22446211 TI - In situ quantification of noise as a function of signal in digital images. AB - An efficient and accurate algorithm for determining the magnitude of noise as a function of signal in an arbitrary digital image is presented and demonstrated. The algorithm is robust and largely independent of the form of the image, returning the noise function with subcount error across the full dynamic range of a synthetic test image where noise of a known form has been added. The noise performance of a CCD under different image recording and processing conditions is examined using the algorithm. The effect of different noise functions on pattern matching measurements of electronic structure by quantitative convergent beam electron diffraction is investigated. PMID- 22446212 TI - Low-coherence enhanced backscattering from highly forward scattering media. AB - We present a theoretical basis for calculation of the angular profile of the coherent backscattering intensity under low spatial coherence illumination. We take into account two contributions to the intensity, namely, the diffusion contribution and the contribution from the waves that experience the small-angle multiple scattering before and after single deflection in the backward direction. The latter contribution describes transport of light at subdiffusion length scales and is responsible for the wings of the backscattering angular profile. Our results are in good agreement with data of Monte-Carlo simulations and experiment. PMID- 22446213 TI - Three-dimensional direct femtosecond laser writing of second-order nonlinearities in glass. AB - We demonstrate that direct femtosecond laser writing in silver-containing zinc and gallium phosphate glass enables generation of three-dimensional (3D) optical second-order nonlinear microstructures having an chi(2) value about 2.5 times that of quartz. The proposed physical model involves photo-reduction, photo dissociation, and migration of silver species within the glass matrix. 3D laser written second-order nonlinear structures could become a new class of nonlinear optical components. PMID- 22446214 TI - Influence of ferroelectric domain walls on the Raman scattering process in lithium tantalate and niobate. AB - We report changes in the Raman spectra at ferroelectric domain walls in near stoichiometric LiNbO3 and stoichiometric LiTaO3. We find a decrease of intensity for the regular bulk Raman peaks along with increases of intensity in spectral regions that correspond to phonons, which propagate at an angle with respect to the incident light. In the backscattering geometry, such modes are not supported in the bulk crystal due to momentum conservation. We confirm that these changes are due to the domain wall itself and are independent of intrinsic defects or charging effects. PMID- 22446215 TI - Stable two-dimensional solitons supported by radially inhomogeneous self-focusing nonlinearity. AB - We demonstrate that modulation of the local strength of the cubic self-focusing (SF) nonlinearity in the two-dimensional geometry, in the form of a circle with contrast Deltag of the SF coefficient relative to the ambient medium with a weaker nonlinearity, stabilizes a family of fundamental solitons against the critical collapse. The result is obtained in an analytical form, using the variational approximation and Vakhitov-Kolokolov stability criterion, and corroborated by numerical computations. For the small contrast, the stability interval of the soliton's norm scales as DeltaN~Deltag (the replacement of the circle by an annulus leads to a reduction of the stability region by perturbations breaking the axial symmetry). To further illustrate this mechanism, we demonstrate, in an exact form, the stabilization of one-dimensional solitons against the critical collapse under the action of a locally enhanced quintic SF nonlinearity. PMID- 22446216 TI - Wideband omnidirectional infrared absorber with a patchwork of plasmonic nanoantennas. AB - In this Letter, we demonstrate experimentally that a patchwork of four metal insulator-metal patches leads to an unpolarized wideband omnidirectional infrared absorption. Our structure absorbs 70% of the incident light on a 2.5 MUm bandwidth at 8.5 MUm. It paves the way to the design of wideband efficient plasmonic absorbers in the infrared spectrum. PMID- 22446217 TI - Redistributing energy flow and polarization of a focused azimuthally polarized beam with rotationally symmetric sector-shaped obstacles. AB - The redistribution of transversal energy flow and polarization in the focal field are represented by obstructing an azimuthally polarized beam with rotationally symmetric sector-shaped obstacles. Several energy flow rings that can finally transport the absorptive particles into fixed locations are formed in the focal plane. Furthermore, the local polarization state of the focal field is also modified by use of the rotationally symmetric obstacles. This kind of energy flow may have wide applications in optical trapping and manipulation. PMID- 22446218 TI - Radial mode dependence of optical beam shifts. AB - It is known that orbital angular momentum (OAM) couples the Goos-Hanchen and Imbert-Fedorov shifts. Here, we present the first study of these shifts when the OAM-endowed LG(l,p) beams have higher-order radial mode index (p>0). We show theoretically and experimentally that the angular shifts are enhanced by p while the positional shifts are not. PMID- 22446219 TI - Dynamically phase-matched terahertz generation. AB - We present the generation of intense terahertz pulses by optical rectification of 780 nm pulses in a large area gallium phosphide crystal. The velocity mismatch between optical and terahertz pulses thereby limits the bandwidth of the terahertz pulses. We show that this limitation can be overcome by a dynamic modification of the refractive index of the gallium phosphide crystal through generation of hot phonons. This is confirmed by excellent agreement between experimental results and model calculations. PMID- 22446220 TI - Theoretical analysis of the characteristic impedance in metal-insulator-metal plasmonic transmission lines. AB - We propose a closed form formulation for the impedance of the metal-insulator metal (MIM) plasmonic transmission lines by solving the Maxwell's equations. We provide approximations for thin and thick insulator layers sandwiched between metallic layers. In the case of very thin dielectric layer, the surface waves on both interfaces are strongly coupled resulting in an almost linear dependence of the impedance of the plasmonic transmission line on the thickness of the insulator layer. On the other hand, for very thick insulator layer, the impedance does not vary with the insulator layer thickness due to the weak coupling/decoupling of the surface waves on each metal-insulator interface. We demonstrate the effectiveness of our proposed formulation using two test scenarios, namely, almost zero reflection in T-junction and reflection from line discontinuity in the design of Bragg reflectors, where we compare our formulation against previously published results. PMID- 22446221 TI - Aerosol-based coherent random laser. AB - We demonstrate coherent random lasing from an aerosol of dye-doped microdroplets in air. The aerosol is in the form of a linear array of polydisperse, arbitrarily shaped, and randomly spaced microdroplets with average dimensions of about 30 MUm. Upon optical excitation, ultranarrow lasing modes were observed in the emission along the axis of the linear array, while the transverse emission exhibited intrascatterer resonance peaks. Direct spatiospectral imaging and lasing threshold studies confirmed the origin of the lasing peaks to be from spatial modes that extended over the array of the polydisperse microdroplets. PMID- 22446222 TI - Role of spatial coherence in Goos-Hanchen and Imbert-Fedorov shifts: comment. AB - It is shown that the spatial Goos-Hanchen shift is greatly affected by spatial coherence. A typical example is given. PMID- 22446224 TI - Tunable ultrafast nonlinear optofluidic coupler. AB - We present an optofluidic nonlinear coupler fabricated by selective filling of two strands of a photonic crystal fiber with the liquid CCl4 which exhibits a large ultrafast Kerr nonlinearity. We demonstrate power dependent switching in this novel optofluidic device. The large thermo-optical effect of liquids enables us to tune the behavior of the nonlinear coupler by changing the coupling strength with temperature. This opens the road towards flexible designs and realization of a new class of tunable ultrafast nonlinear couplers with switching times below 1 ps. PMID- 22446225 TI - Mueller matrix polarimetry for improved liver fibrosis diagnosis. AB - An experimental Mueller matrix polarimeter is used to quantify human liver fibrosis by measuring retardance and depolarization of thin biopsies. The former parameter is sensitive to fibrillar collagen, the latter is specifically sensitive to fibrillar collagen around blood vessels, which is not significant for liver fibrosis diagnosis. By using depolarization like a filter, retardance distribution enables distinguishing between disease stages and limits the high degree of observer discrepancy. PMID- 22446226 TI - Distributed high-temperature pressure sensing using air-hole microstructural fibers. AB - We present spatially resolved Rayleigh scattering measurements in different polarization-maintaining (PM) fibers for high-temperature pressure sensing. The pressure-induced birefringence in the fiber cores is interrogated using polarization-resolved frequency-swept interferometry. The pressure responses of a PM photonic crystal fiber and a twin-air-hole PM fiber are investigated for a pressure range of 0 to 13.8 MPa (0-2000 psi) at room temperature and at temperatures as high as 800 degrees C. The proposed sensing system provides, for the first time to our knowledge, a truly distributed pressure-sensing solution for high-temperature applications. PMID- 22446227 TI - The influence of sparsity property of images on ghost imaging with thermal light. AB - The influence of sparsity property of images on ghost imaging via sparsity constraints (GISC) is investigated. We find experimentally that the reconstruction quality is in proportion to the sparse ratio of images. Employing the method of representation transform to obtain different sparsity properties for the same object, the effect of three sparse representation bases on the quality of GISC is also discussed. PMID- 22446228 TI - Nonimaging speckle interferometry for high-speed nanometer-scale position detection. AB - We experimentally demonstrate a nonimaging approach to displacement measurement for complex scattering materials. By spatially controlling the wavefront of the light that incidents on the material, we concentrate the scattered light in a focus on a designated position. This wavefront acts as a unique optical fingerprint that enables precise position detection of the illuminated material by simply measuring the intensity in the focus. By combining two fingerprints we demonstrate position detection along one in-plane dimension with a displacement resolution of 2.1 nm. As our approach does not require an image of the scattered field, it is possible to employ fast nonimaging detectors to enable high-speed position detection of scattering materials. PMID- 22446229 TI - 26 mJ, 130 W Q-switched fiber-laser system with near-diffraction-limited beam quality. AB - We demonstrate a Q-switched fiber laser system emitting sub-60 ns pulses with 26 mJ pulse energy and near-diffraction-limited beam quality (M2<1.3). In combination with a repetition rate of 5 kHz, a corresponding average output power of 130 W is achieved. This record performance is enabled by a large-pitch fiber with a core diameter of 135 um. This fiber allows for effective single-mode operation with mode field diameters larger than 90 um even at average output powers exceeding 100 W. PMID- 22446230 TI - Highly efficient 2 MUm Tm:YAG ceramic laser. AB - We have experimentally demonstrated a highly efficient diode-pumped Tm:YAG ceramic laser operating at 2 MUm wavelength. The maximum output power of 6.05 W was realized with a slope efficiency as high as 65%. As far as we know, it is the highest slope efficiency reported for Tm:YAG ceramic laser. The wavelength tuning experiment of Tm:YAG ceramic laser was carried out and the results suggest that Tm:YAG ceramic laser could operate simultaneously at multiple wavelengths in a wide range of 1884-2017 nm. PMID- 22446231 TI - Disorder mapping in VCSELs using frequency-selective feedback. AB - We report on a simple method with a high spectral and spatial resolution for mapping variations in the cavity resonance of a plano-planar broad-area laser based on frequency-selective feedback. The demonstration experiment uses a vertical-cavity surface-emitting-laser (VCSEL), in which growth induced inhomogeneities are of particular importance. It relies only on a standalone laser with a narrow-bandwidth passive filter avoiding the need for an expensive tunable laser or high-resolution spectrometer. PMID- 22446232 TI - Dispersive shock waves in phase-mismatched second-harmonic generation. AB - We investigate wave-breaking and dispersive shock wave formation driven by a pulse undergoing second-harmonic generation in a quadratic medium. We show that the process is accessible in the regime of high phase-mismatch (cascading limit) and weak dispersion. Insight into the phenomenon is obtained by means of a suitable hydrodynamic reduction of the equations that govern the mixing. PMID- 22446233 TI - Laser based accelerator for ultracold atoms. AB - We present our first results on our implementation of a laser based accelerator for ultracold atoms. Atoms cooled to a temperature of 420 nK are confined and accelerated by means of laser tweezer beams, and the atomic scattering is directly observed in laser absorption imaging. The optical collider has been characterized using 87Rb atoms in the |F=2, m(F)=2] state, but the scheme is not restricted to atoms in any particular magnetic substates and can readily be extended to other atomic species as well. PMID- 22446234 TI - Fabrication and characterization of a biomimetic polarization selective lens. AB - Incorporating optical structures on curved lens surfaces can improve performance, consolidate functions, and create novel, miniaturized devices. Although commonly found in biological systems, patterning of micro- and nano-optical structures on curved surfaces is challenging for conventional methods. Previous works have demonstrated the ability to pattern curved surfaces but have done little to create functioning devices. In this Letter, we describe a novel spray-coating technique coupled with interferometric exposure and dry etching to create near-IR wire-grid polarizers on convex lens surfaces. Experimental measurements show extinction ratios of >40:1 and transmission values of >80%, which are comparable to modeled results of similar polarizers on flat surfaces. PMID- 22446235 TI - Synchronized retroreflection-pumped femtosecond optical parametric oscillator. AB - We report a flexible technique for threshold reduction and output power enhancement in synchronously pumped optical parametric oscillators (SPOPOs) based on synchronized retroreflection of the undepleted pump using a collimating system and a delay line, which allows easy and independent adjustment of the spatial and temporal overlap of the retroreflected beam in the nonlinear crystal. The method permits initial synchronization of the forward and retroreflected pump by interferometry, providing threshold reduction before oscillation is initiated. We demonstrate the technique in a femtosecond SPOPO based on BiB3O6, where a threshold reduction of 22% and an output power enhancement of 70% are achieved compared with single-pass pumping, with no detrimental effect on the spectral and temporal characteristics of the output pulses. PMID- 22446236 TI - Diffraction phase microscopy with white light. AB - We present white light diffraction phase microscopy (wDPM) as a quantitative phase imaging method that combines the single shot measurement benefit associated with off-axis methods, high temporal phase stability associated with common path geometries, and high spatial phase sensitivity due to the white light illumination. We propose a spatiotemporal filtering method that pushes the limit of the pathlength sensitivity to the subangstrom level at practical spatial and temporal bandwidths. We illustrate the utility of wDPM with measurements on red blood cell morphology and HeLa cell growth over 18 hours. PMID- 22446237 TI - Role of the null space of the DRM in the performance of modulated polarimeters. AB - Imaging polarimeters infer the spatial distribution of the polarization state of the optical field as a function of time and/or wavelength. A polarimeter indirectly determines the polarization state by first modulating the intensity of the light field and then demodulating the measured data to infer the polarization parameters. This Letter considers passive Stokes parameter polarimeters and their inversion methods. The most widely used method is the data reduction matrix (DRM), which builds up a matrix equation that can be inverted to find the polarization state from a set of intensity measurements. An alternate strategy uses linear system formulations that allow band limited reconstruction through a filtering perspective. Here we compare these two strategies for overdetermined polarimeters and find that design of the null space of the inversion operator provides degrees of freedom to optimize the trade off between accuracy and signal to-noise ratio. We further describe adaptive filtering techniques that could optimize the reconstruction for a particular experimental configuration. This Letter considers time-varying Stokes parameters, but the methods apply equally to polarimeters that are modulated in space or in wavelength. PMID- 22446238 TI - Aberration characterization for the optimal design of high-resolution endoscopic optical coherence tomography catheters. AB - We study the major factors causing degradation in the lateral resolution of gradient-index-lens-based catheters used for high-resolution optical coherence tomography. Chromatic aberration and astigmatism were taken into account in the propagation of broadband single-mode Gaussian beams through the catheter geometry. It was found that, while chromatic aberration did not preclude achieving high resolution, astigmatism posed a major technical difficulty, because its correction requires a very sensitive adjustment of parameters, especially for catheters with long working distances. PMID- 22446239 TI - Ultrawide-bandwidth, superluminescent light-emitting diodes using InAs quantum dots of tuned height. AB - An ultrawide-bandwidth, superluminescent light-emitting diode (SLED) utilizing multiple layers of dots of tuned height is reported. Due to thermal effect, the superluminescent phenomenon is observed only under pulse-mode operation. The device exhibits a 3 dB bandwidth of 190 nm with central wavelength of 1020 nm under continuous-wave (cw) conditions. The maximum corresponding output power achieved in this device under cw and pulsed operation conditions are 0.54 mW and 17 mW, respectively. PMID- 22446240 TI - Colorizing silicon surface with regular nanohole arrays induced by femtosecond laser pulses. AB - We report on the formation of one- and two-dimensional (1D and 2D) nanohole arrays on the surface of a silicon wafer by scanning with a femtosecond laser with appropriate power and speed. The underlying physical mechanism is revealed by numerical simulation based on the finite-difference time-domain technique. It is found that the length and depth of the initially formed gratings (or ripples) plays a crucial role in the generation of 1D or 2D nanohole arrays. The silicon surface decorated with such nanohole arrays can exhibit vivid structural colors through efficiently diffracting white light. PMID- 22446241 TI - Hybrid light-emitting devices based on phosphorescent platinum(II) complex sensitized CdSe/ZnS quantum dots. AB - We report on hybrid light-emitting devices based on the emission of phosphorescent sensitized colloidal CdSe/ZnS quantum dots (QDs). Emission lifetime measurements demonstrated that the energy transfer (ET) from square planar platinum(II) complex [4-CF3-(NC^N^)PtC=CC6H-4'-F] (NC^HN^=1, 5-bis(2' pyridyl)benzene) (Pt-2) to QDs is more efficient than that from octahedral iridium(III) complex bis[(4,6-difluorophenyl)pyridinato-N, C2] (picolinato)iridium (FIrpic). This different ET efficiency might be attributed to the different spatial structures between Pt-2 and FIrpic. Pure red emission with CIE coordinates of (0.66, 0.33) and maximum external quantum efficiency of 2.08% and white emission with power efficiency of 3.15 lm/W were realized at different concentrations of Pt-2 and QDs, respectively. PMID- 22446242 TI - n-ZnO/LaAlO3/p-Si heterojunction for visible-blind UV detection. AB - A visible-blind UV photodetector (PD) using a double heterojunction of n ZnO/LaAlO3 (LAO)/p-Si was demonstrated. Inserted LAO layers exhibit electrical insulating properties and serve as blocking layers for photoexcited electrons from p-Si to n-ZnO, leading to an enhanced rectification ratio and a visible blind UV detectivity of the n-ZnO/LAO/p-Si PDs due to the high potential barrier between LAO and p-Si layers (~2.0 eV). These results support the use of n ZnO/LAO/p-Si PDs in the visible-blind UV PDs in a visible-light environment. PMID- 22446243 TI - Fabrication of twisted nematic structure and vector grating cells by one-step exposure on photocrosslinkable polymer liquid crystals. AB - We present a simple yet efficient method to automatically fabricate the twisted nematic structure by one-step exposure on an empty glass cell coated with photocrosslinkable polymer liquid crystal (PCLC) films. The resultant photoalignment directions of two substrates can be orthogonal to each other by controlling the difference between the exposure energy for upper and lower PCLC films and the twisted nematic (TN) structure can be automatically fabricated. The vector grating liquid crystalline cell with TN structure was also fabricated by means of a developed method, and the diffraction properties were well explained by the theoretical calculation on the basis of Jones calculus. PMID- 22446244 TI - Single-shot time-frequency imaging spectroscopy using an echelon mirror. AB - We demonstrate single-shot time-frequency imaging spectroscopy with an echelon mirror for measuring ultrashort laser pulses as well as ultrafast responses of materials using the same optical setup. The echelon mirror produces a spatially encoded time delay for the probe pulse whereby both the probe and pump pulses are focused on samples with small spot size. Using the optical Kerr gate apparatus, we successfully mapped the time-frequency images of ultrashort laser pulses and subsequently evaluated the chirp characteristics with the phase-retrieval procedure on a single-shot basis. By simply replacing the Kerr medium with samples, we could also visualize the phonon-polariton oscillations in ferroelectric LiNbO3. PMID- 22446245 TI - Analytic design of multiple-axis, multifocal diffractive lenses. AB - In this Letter, we introduce an analytic procedure for designing diffractive lenses using the combination of wavefronts aberrated by Zernike polynomials. We show how to design amplitude-only, phase-only, continuous, and binary lenses providing equivalent results. As an example we apply it to the design of a multiple-axis, multifocal lens. The number of foci and their positions can be easily controlled. Theoretical predictions have been experimentally confirmed. The main advantage of this procedure is that, because it is simple and intuitive, it can be used successfully for the design of complex lenses. PMID- 22446246 TI - Compact dipole nanoantenna coupler to plasmonic slot waveguide. AB - Optical nanoantennas can be used for coupling radiation to or from waveguides in analogy to micro- and radio-wave systems. In this letter we provide a systematic description of the design approaches for a coupler to a plasmonic slot waveguide in the telecom range around 1.55 um with realistic excitation from a lensed optical fiber. We show that the best coupling efficiency of 26% can be achieved by utilizing a dipole antenna with side and bottom reflectors, and such coupling efficiency is 185 times larger than for the bare waveguide. The nanoantenna coupler provides a compact interface between an optical fiber and a plasmonic slot waveguide for future optical integrated circuits. PMID- 22446247 TI - Theoretical application of z-dependent gain coefficient to describe amplified spontaneous emission. AB - Based on the geometrical modeling of the unified gain coefficient and the reported amplified spontaneous emission (ASE) output energy measurement epsilon(ASE) versus amplifying excitation length, l(AMP) in a KrF laser oscillator, we managed, as an example, to explain the ASE output energy behavior both numerically and analytically. In this approach, introducing the ASE gain coefficient profile for the KrF laser, g(0,KrF)(ASE), was not avoidable. It was found that while the g(0,KrF)(ASE) profile follows the introduced gain-modeling formulation, it is, however, slightly lower than the KrF laser gain profile, g(0,KrF)(exp), deduced from the measurements reported by different researchers. The present approach, up to the present time, is able to explain all of the existing ambiguities on understanding the ASE behavior. PMID- 22446248 TI - Quenching electron runaway in positive high-voltage-impulse discharges in air by laser filaments. AB - Strong hard (epsilon>100 keV) x rays being observed from impulse atmospheric discharges with maximal voltages from U=0.5 to 0.9 MV just before the breakdown were completely stopped with the use of femtosecond-laser-filament plasma. Runaway electrons generating such x rays and being estimated to achieve their maximal energy, epsilon~U, near the positive electrode disappear if a laser filament plasma is ignited perpendicularly to the runaway near the positive electrode. A preheating mechanism for formation of the electron runaway in air is proposed. PMID- 22446249 TI - Highly efficient 1 GHz repetition-frequency femtosecond Yb3+:KY(WO4)2 laser. AB - We present a highly efficient, diode-pumped, femtosecond Yb3+:KY(WO4)2 (Yb:KYW) laser operating at a 1.024 GHz repetition rate. The output was centered at a wavelength of 1042 nm and had a bandwidth of 3.8 nm, leading to transform-limited pulses with durations of 278 fs determined by fringe-resolved autocorrelation measurements. The optical-to-optical conversion efficiency and slope efficiency were 61% and 69%, respectively, and the relative intensity noise was <0.1%. PMID- 22446250 TI - The BDA - into the future. PMID- 22446251 TI - Sterility testing of devices. PMID- 22446252 TI - A preposterous claim? PMID- 22446253 TI - An entrepreneur first and foremost. PMID- 22446254 TI - Still deserves a place. PMID- 22446255 TI - Ridiculous logistics. PMID- 22446256 TI - Standing strong on prescribing. PMID- 22446266 TI - Prosthodontic complications associated with implant retained crowns and bridgework: a review of the literature. AB - This article reviews the incidence, aetiology, prevention and management of prosthodontic complications, which may occur following the delivery of implant retained crowns and bridgework. Problems associated with the calculation of complication rates are discussed. Examples of common complications and their management are presented. PMID- 22446272 TI - An evaluation of remote communication versus face-to-face in clinical dental education. AB - Distance learning and internet-based delivery of educational content are becoming very popular as an alternative to real face-to-face delivery. Clinical-based discussions still remain greatly face-to-face despite the advancement of remote communication and internet sharing technology. In this study we have compared three communication modalities between a learner and educator: audio and video using voice over internet protocol (VoIP) alone [AV]; audio and video VoIP with the addition of a three dimensional virtual artefact [AV3D] and physical face-to face [FTF]. Clinical case discussions based on fictitious patients were held between a 'learner' and an 'expert' using the three communication modalities. The learner presented a clinical scenario to the experts, with the aid of a prop (partially dentate cast, digitised for AV3D), to obtain advice on the management of the clinical case. Each communication modality was tested in timed exercises in a random order among one of three experts (senior clinical restorative staff) and a learner (from a cohort of 15 senior clinical undergraduate students) all from the School of Clinical Dentistry, University of Sheffield. All learners and experts used each communication modality in turn with no prior training. Video recording and structured analysis were used to ascertain learner behaviour and levels of interactivity. Evaluation questionnaires were completed by experts and learners immediately after the experiment to ascertain effectiveness of information exchange and barriers/facilitators to communication. The video recordings showed that students were more relaxed with AV and AV3D than FTF (p = 0.01). The evaluation questionnaires showed that students felt they could provide (p = 0.03) and obtain (p = 0.003) more information using the FTF modality, followed by AV and then AV3D. Experts also ranked FTF better than AV and AV3D for providing (p = 0.012) and obtaining (p = 0) information to/from the expert. Physical face-to-face learning is a more effective communication modality for clinical case-based discussions between a learner and an expert. Remote, internet based discussions enable a more relaxed discussion environment. The effectiveness of 3D supported internet-based communication is dependent upon a robust and simple to use interface, along with some prior training. PMID- 22446286 TI - Occlusal pitfalls and how to avoid them. AB - Occlusion conjures up various emotions in dentists. Some say they were taught nothing about it at dental school so it must be unimportant. Others, through their own experience and postgraduate study, realise that misdirected or excessive occlusal forces can be damaging to restorations, teeth/implants and periodontium. However, they shy away from actively managing patients' occlusions because they fear retribution from their patients or colleagues. A third group actively embraces all things occlusion, but sadly uncritical enthusiasm may lead to inappropriate or excessive treatment. In my lecture I aim to raise awareness of occlusal pitfalls and suggest ways towards a more predictable treatment outcome. PMID- 22446290 TI - Discharge destination as a surrogate for Modified Rankin Scale defined outcomes at 3- and 12-months poststroke among stroke survivors. AB - OBJECTIVE: To determine the predictive value of discharge destination as a surrogate for defining unfavorable outcome at 3- and 12-months poststroke. DESIGN: Analysis of the prospectively collected data from a randomized, placebo controlled trial in patients with ischemic stroke presenting within 3 hours of symptom onset. SETTING: Post hoc analysis of patients recruited in a clinical trial. PARTICIPANTS: Patients (N=530) discharged alive from the hospital after ischemic stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Positive and negative predictive value and likelihood ratios of discharge destination for unfavorable outcome at 3- and 12-months poststroke defined by a Modified Rankin Scale (MRS) score of 2 to 6, 3 to 6, or 4 to 6. A likelihood ratio indicates how many times more (or less) likely a particular discharge destination is seen in patients with an unfavorable outcome compared with those without unfavorable outcome. RESULTS: The positive predictive value of nursing home and rehabilitation facility discharges was highest for unfavorable outcome defined by an MRS score of 2 to 6 (95%) and rehabilitation facility (89%) at 3-months poststroke, respectively. The positive predictive value of rehabilitation facility/nursing home (90%) was also highest for unfavorable outcomes defined by an MRS score of 2 to 6 compared with those defined by MRS scores of 3 to 6 (79%) and 4 to 6 (57%). The positive likelihood ratio was highest for nursing home discharges (13; 95% confidence interval [CI], 4.1-41) followed by rehabilitation facility discharges for unfavorable outcome defined by an MRS score of 2 to 6 at 3-months poststroke (5.3; 95% CI, 3.5-7.9). The negative likelihood ratio was the highest for home discharge for unfavorable outcome defined by an MRS score of 2 to 6 (4.5; 95% CI, 3.4-6.1). A similar pattern was observed with unfavorable outcome defined using various thresholds at 12 months. CONCLUSIONS: Discharge destination can provide high predictive values and likelihood ratios for death and disability at 3-months poststroke, as defined by an MRS of score of 2 to 6. PMID- 22446291 TI - Cardiac rehabilitation in chronic heart failure: effect of an 8-week, high intensity interval training versus continuous training. AB - OBJECTIVE: To compare the effects of an 8-week, high-intensity interval training protocol versus continuous training. DESIGN: Randomized controlled trial. SETTING: Cardiac rehabilitation center. PARTICIPANTS: Patients (N=26; mean age +/ SD, 54+/-12y) with chronic heart failure were enrolled in a cardiac rehabilitation program for 8 weeks. INTERVENTIONS: Patients were randomly assigned into 2 groups that performed either interval training (IT) or continuous training (CT). IT consisted of 3 sessions of 12 repetitions of 30 seconds of exercise at very high intensity, followed by 60 seconds of complete rest. The CT group performed CT exercises, which consisted of 45 minutes of aerobic exercise. MAIN OUTCOME MEASURES: Parameters of gas exchanges: peak oxygen consumption (Vo(2)peak), first ventilator threshold (VT1), distance at six-minute walk test (6MWT), and level of anxiety and depression were measured. RESULTS: The IT group increased significantly their Vo(2)peak, the duration of the exercise test, the oxygen pulse, oxygen consumption at the VT1, and the distance walked during the 6MWT. The CT group only increased the time at the VT1 and the distance performed at the 6MWT. The improvement in the time at the VT1 was significantly higher for the IT group than for the CT group. CONCLUSIONS: This study shows that IT at very high intensity for patients with heart failure appears to be more effective than CT in improving indices of submaximal exercise capacity. PMID- 22446292 TI - Optimizing terminology for stroke motor rehabilitation: recommendations from the American Congress of Rehabilitation Medicine Stroke Movement Interventions Subcommittee. AB - As knowledge and interest in stroke motor rehabilitation continue to increase, consistent terminologies that are specific to this discipline must be established. Such language is critical to effective rehabilitative team communication, and is important to facilitating communication among the diverse groups interested in the science and practice of stroke motor rehabilitation. The purpose of this article is to provide operational definitions for 3 concepts that are common-and commonly mislabeled-attributes of stroke motor rehabilitation interventions: intensity, duration, and frequency. In developing these guidelines, conceptual frameworks used in the pharmaceutical, exercise, and rehabilitative therapy realms were used. Implications of these definitions for research and clinical practice are also discussed. PMID- 22446293 TI - The symptom inventory disability-specific short forms for multiple sclerosis: reliability and factor structure. AB - OBJECTIVE: To further the development of the 99-item Symptom Inventory (SI) for multiple sclerosis (MS) using modern test theory methods to create 3 disability specific short forms for MS patient subgroups identified using Performance Scale (PS) items. DESIGN: A web-based cross-sectional study. SETTING: National MS Registry. PARTICIPANTS: People with MS (N=1532) who participate in the North American Research Committee on Multiple Sclerosis Registry. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The SI; the disease-specific PS and the Patient-Determined Disease Steps; and the generic Short-Form 12. RESULTS: When the original SI subscales did not demonstrate unidimensionality, exploratory factor analysis was conducted yielding 14 factors that could be classified using the structure of the PS. Confirmatory factor analysis confirmed the unidimensionality of the hand function, vision, fatigue, cognitive, bowel/bladder, spasticity, and pain scales. The mobility scale was split into mobility and use of assistive devices; the sensory scale was split into sensory and vasomotor. Item response theory analyses revealed good model fit. CONCLUSIONS: This study provides empirical support for a 10-scale symptom measure for use in MS clinical research, with short forms in 5 scales tailored to have good specificity for people with mild, moderate, and severe disability and single forms for the remaining 5 scales. The PS items can serve as a screener for these disability-specific short forms, which provide choice and flexibility that are similar to a computerized adaptive test but without the reliance on real-time computer infrastructure. PMID- 22446294 TI - Variation in adherence to new quality-of-care indicators for the acute rehabilitation of children with traumatic brain injury. AB - OBJECTIVE: To determine variations in care provided by 9 inpatient rehabilitation units for children with traumatic brain injury (TBI) using newly developed quality indicators. DESIGN: Retrospective cohort study. SETTING: Nine inpatient rehabilitation units. PARTICIPANTS: Children (N=174; age range, 0-17y) admitted for the inpatient rehabilitation of moderate to severe TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Adherence to 119 newly developed quality-of care indicators in 7 different domains: general care, family-centered care, cognitive-communication, motor, neuropsychological, school, and community integration. RESULTS: There was substantial variation both within and between institutions in the percentage of patients receiving recommended care in the 7 domains. The lowest scores were found for the school domain. Only 5 institutions scored above 50% for all quality indicators, and only 1 institution scored above 70% overall. Greater adherence to quality indicators was found for facilities with a higher proportion of therapists with pediatric training and for facilities that only admitted children. Patient volume was not associated with adherence to quality indicators. CONCLUSIONS: The results indicate a tremendous variability and opportunity for improvement in the care of children with TBI. PMID- 22446295 TI - Inpatient rehabilitation utilization for Medicare beneficiaries with multiple sclerosis. AB - OBJECTIVE: To explore the use of inpatient rehabilitation facility services and levels of impairment for Medicare beneficiaries with multiple sclerosis (MS) by comparing differences in service utilization and clinical characteristics between Medicare beneficiaries with MS to the overall Medicare population. DESIGN: Medicare beneficiaries with MS were identified using Medicare claims data. Claims and assessment data were analyzed to compare outcomes for beneficiaries with MS who used inpatient rehabilitation compared with a random sample of Medicare beneficiaries without MS. SETTING: Inpatient rehabilitation facilities. PARTICIPANTS: Medicare beneficiaries with a diagnosis of MS who received inpatient rehabilitation during the 2007 calendar year (n=4669) and a random sample of Medicare beneficiaries without MS (n=14,397). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in functional impairment levels between admission and discharge to inpatient rehabilitation and length of stay. RESULTS: There were several differences in beneficiary characteristics between the 2 groups. Beneficiaries with MS had lower change in functional levels (-3.3 points on the FIM) and longer length of stay (0.4d). CONCLUSIONS: While beneficiaries with MS account for a small proportion of the Medicare population, the benefit is important to those who qualify for Medicare coverage. This study illustrates the differences between the subpopulation of beneficiaries with MS and other Medicare beneficiaries. The findings show that populations with MS had less functional improvement than other Medicare populations using the inpatient rehabilitation setting. Higher rates of depression within the MS Medicare population was a secondary finding that presents another important consideration for rehabilitation service needs for this group. PMID- 22446296 TI - Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients. AB - APG101 is a glycosylated fusion protein consisting of the extracellular domain of human CD95 (APO-1/Fas) and the Fc domain of human IgG1. Administration of APG101 blocks the interaction between CD95 and its cognate ligand CD95L, thereby inhibiting various pathways involved in e.g. proliferation, migration, differentiation and apoptosis induction. The safety and tolerability of ascending single doses of intravenously applied APG101 was examined in a randomized, double blind, placebo-controlled, mono-centre "first in man" dose escalation study in 34 healthy male volunteers. Pharmacokinetics and pharmacodynamics were also assessed. The maximum serum concentration of 460 MUg/ml was achieved following 1h infusion of the highest dose of 20 mg/kg. The systemic clearance was low (0.4 to 0.5 ml/hkg). Mean terminal elimination half-life was 12 to 15 days. Two patients suffering from malignant glioma received APG101 intravenously under compassionate use conditions. They received doses ranging from 5mg to 600 mg APG101. No adverse events and no clinical significant changes in laboratory parameters related to APG101 were reported. The presence of anti-drug-antibodies (ADA) was investigated and revealed no detectable levels of ADA. Overall, single ascending doses of APG101 up to 20 mg/kgbody weight (bw) administered as infusion over 1h were considered as safe and well tolerated in healthy volunteers. After the application of multiple doses of 400 mg in two glioma patients, steady state for APG101 seemed to be reached. These results support further clinical evaluation of APG101 at a dose of 400 mg per week in glioblastoma patients. PMID- 22446297 TI - T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro. AB - Matrix metalloproteinases (MMPs) have a pivotal role in the destruction of cartilage in rheumatoid arthritis (RA) joint, which is mainly produced by fibroblast-like synoviocytes (FLS). T-614 is effective for patients with active RA, however the mechanism has not been clarified. We first focus on the MMPs level in RA patients after T-614 treatment, in vivo. Eighty-six RA patients were assigned into 3 treatment groups randomly: T-614 group 1 (T-614 for the first 4 weeks with an oral dosage of 25mg once daily, and 50mg/day for the subsequent 20 weeks with an oral dosage of 25mg twice daily), T-614 group 2 (T-614 with an oral dosage of 25mg twice daily), or the MTX group (MTX 10 mg/week orally for the first 4 weeks and 15 mg/week for the subsequent 20 weeks). Serum samples were obtained at 0 and 24 weeks. Levels of MMP-1 and MMP-3 were decreased significantly after 24 week treatment of T-614 group 2 or MTX group. In vitro, RA FLS were pretreated with different doses of T-614 and then stimulated with TNF alpha, IL-1beta or IL-17A, respectively. Protein and mRNA levels of MMP-1 and MMP 3 were further determined. MMP-1 production was significantly inhibited at 50 MUg/ml T-614 and MMP-3 production was significantly inhibited at 5 MUg/ml or more T-614. The mRNA expression profile was in accordance with the protein production. Inhibition of invasiveness was also seen after T-614 treatment. These results suggest that T-614 inhibits the invasiveness through decreasing the MMP-1 and MMP 3 production. PMID- 22446298 TI - Impact of meditation training on the default mode network during a restful state. AB - Mindfulness meditation has been shown to promote emotional stability. Moreover, during the processing of aversive and self-referential stimuli, mindful awareness is associated with reduced medial prefrontal cortex (MPFC) activity, a central default mode network (DMN) component. However, it remains unclear whether mindfulness practice influences functional connectivity between DMN regions and, if so, whether such impact persists beyond a state of meditation. Consequently, this study examined the effect of extensive mindfulness training on functional connectivity within the DMN during a restful state. Resting-state data were collected from 13 experienced meditators (with over 1000 h of training) and 11 beginner meditators (with no prior experience, trained for 1 week before the study) using functional magnetic resonance imaging (fMRI). Pairwise correlations and partial correlations were computed between DMN seed regions' time courses and were compared between groups utilizing a Bayesian sampling scheme. Relative to beginners, experienced meditators had weaker functional connectivity between DMN regions involved in self-referential processing and emotional appraisal. In addition, experienced meditators had increased connectivity between certain DMN regions (e.g. dorso-medial PFC and right inferior parietal lobule), compared to beginner meditators. These findings suggest that meditation training leads to functional connectivity changes between core DMN regions possibly reflecting strengthened present-moment awareness. PMID- 22446299 TI - Common representation of pain and negative emotion in the midbrain periaqueductal gray. AB - Human neuroimaging offers a powerful way to connect animal and human research on emotion, with profound implications for psychological science. However, the gulf between animal and human studies remains a formidable obstacle: human studies typically focus on the cortex and a few subcortical regions such as the amygdala, whereas deeper structures such as the brainstem periaqueductal gray (PAG) play a key role in animal models. Here, we directly assessed the role of PAG in human affect by interleaving in a single fMRI session two conditions known to elicit strong emotional responses--physical pain and negative image viewing. Negative affect and PAG activity increased in both conditions. We next examined eight independent data sets, half featuring pain stimulation and half negative image viewing. In sum, these data sets comprised 198 additional participants. We found increased activity in PAG in all eight studies. Taken together, these findings suggest PAG is a key component of human affective responses. PMID- 22446300 TI - Family socioeconomic status modulates the coping-related neural response of offspring. AB - Substantial research links economic adversity to poor coping in stressful or threatening environments. Neuroimaging studies suggest that activation of the right ventrolateral prefrontal cortex (rVLPFC) plays a key role in self-control, and it seems that individual differences in neurocognitive systems underlying self-control are determined in part by subjective childhood socioeconomic status (SES). The present study used near-infrared spectroscopy (NIRS) to investigate whether subjective childhood SES moderates rVLPFC activity during one form of threatening environment: social exclusion. Twenty-five undergraduates participated in a NIRS session in which they were socially included and then excluded during an online ball-tossing game. Lower subjective childhood SES was associated with higher levels of social distress and lower levels of rVLPFC activity during social exclusion. The present findings suggest that early family environments are reliably associated with deficits in offspring coping resources and processes, as well as with difficulties in regulating interpersonal circumstances. PMID- 22446301 TI - Oxytocin facilitates accurate perception of competition in men and kinship in women. AB - Despite the dominant role of the hormone oxytocin (OT) in social behavior, little is known about the role of OT in the perception of social relationships. Furthermore, it is unclear whether there are sex differences in the way that OT affects social perception. Here, we employed a double-blind, placebo-controlled crossover design to investigate the effect of OT on accurate social perception. Following treatment, 62 participants completed the Interpersonal Perception Task, a method of assessing the accuracy of social judgments that requires identification of the relationship between people interacting in real life video clips divided into three categories: kinship, intimacy and competition. The findings suggest that OT had a general effect on improving accurate perception of social interactions. Furthermore, we show that OT also involves sex-specific characteristics. An interaction between treatment, task category and sex indicated that OT had a selective effect on improving kinship recognition in women, but not in men, whereas men's performance was improved following OT only for competition recognition. It is concluded that the gender-specific findings reported here may point to some biosocial differences in the effect of OT which may be expressed in women's tendency for communal and familial social behavior as opposed to men's tendency for competitive social behavior. PMID- 22446302 TI - Human umbilical cord is a unique and safe source of various types of stem cells suitable for treatment of hematological diseases and for regenerative medicine. AB - Cord blood (CB) is a rich source of hematopoietic stem cells (HSCs) and for this reason CB transplantation has been used successfully for the treatment of some malignant and nonmalignant diseases. However, this technique is limited by the relatively low number of HSCs present in each CB unit and by the delayed engraftment of platelets and neutrophils. To bypass these obstacles efforts have been made to develop strategies to expand CB HSCs in vitro for transplantation. CB is also an important source of other stem cells, including endothelial progenitors, mesenchymal stem cells (MSCs), very small embryonic/epiblast-like (VSEL) stem cells, and unrestricted somatic stem cells (USSC), potentially suitable for use in regenerative medicine. For some of these stem cell populations, such as MSCs, clinical studies have been started and for other stem cell populations potential clinical applications have been identified and clinical studies will follow. In addition to CB, other parts of umbilical cord, such as the Wharton's jelly, or tissues strictly linked such as the placenta are also rich sources of stem cells. PMID- 22446303 TI - Community structure and in situ activity of nitrifying bacteria in Phragmites root-associated biofilms. AB - The amount of oxygen released by Phragmites roots and the community structure and in situ activity of nitrifying bacteria in the root biofilms were analyzed by the combined use of 16S rRNA gene-cloning analysis, quantitative PCR (qPCR) assay and microelectrodes. Axial and radial O2 microprofiles were obtained for individual roots of Phragmites in a horizontal flow reactor fed with artificial medium continuously. Axial O2 profiles revealed that O2 was released at a rate of 0.21 MUmol O2 cm-2 (root surface area) h-1 only in the apical region (up to ca. 40 mm from the root apex), where there was a high abundance (107 to 108 copies g-1 biomass) of Nitrosomonas-like AOB and Nitrospira-like NOB. This abundance, however, sharply declined to the detection limit at positions more basal than 80 mm. Phylogenetic analysis based on 16S rRNA gene identified strains related to Nitrosomonas oligotropha and Nitrosomonas cryotolerans as the predominant AOB and strains related to Nitrospira marina and Nitrospira moscoviensis as the predominant NOB in the root biofilms. Based on radial O2 microprofiles, the oxic region only extended about 0.5 mm into the surrounding sediment due to a high rate of O2 consumption in the rhizosphere. The net NH4+ and O2 consumption rates in the apical region were higher than those determined at the oxic sediment surface in which the abundance of AOB and NOB was one order of magnitude lower than in the rhizosphere. These results clearly indicated that Phragmites root biofilms played an important role in nitrification in the waterlogged anoxic sediment. PMID- 22446304 TI - Rapid enumeration of active Legionella pneumophila in freshwater environments by the microcolony method combined with direct fluorescent antibody staining. AB - In this study, a microcolony technique was combined with direct fluorescent antibody staining for the specific detection and enumeration of Legionella pneumophila in freshwater samples with growth activity. This method allowed the detection of active L. pneumophila (within 48 h) in 91 bath water samples collected from 30 bathing facilities, with similar sensitivity of a conventional plate-counting method. These results suggest that the microcolony method combined with fluorescent antibody staining could be useful as a monitoring technique for the prevention of Legionnaires' disease through the early detection of L. pneumophila in freshwater. PMID- 22446305 TI - Diversity of purple phototrophic bacteria, inferred from pufM gene, within epilithic biofilm in Tama River, Japan. AB - The diversity of purple phototrophic bacteria in algae-dominated biofilm of a streambed in Tama River, Japan was investigated. Clone library analysis of the pufM gene encoding a subunit of the photochemical reaction center of purple bacteria detected 18 operational taxonomic units (OTUs) in several classes of Proteobacteria. Most of the OTUs showed less than 85% identity to the PufM amino acid sequences of known phototrophic bacteria. These results suggest that phylogenetically divergent and unknown purple phototrophic bacteria are present in the epilithic biofilm of the river. PMID- 22446306 TI - Inoculation of Bacillus sphaericus UPMB-10 to young oil palm and measurement of its uptake of fixed nitrogen using the 15N isotope dilution technique. AB - There are increasing applications of diazotrophic rhizobacteria in the sustainable agriculture system. A field experiment on young immature oil palm was conducted to quantify the uptake of N derived from N2 fixation by the diazotroph Bacillus sphaericus strain UPMB-10, using the 15N isotope dilution method. Eight months after 15N application, young immature oil palms that received 67% of standard N fertilizer application together with B. sphaericus inoculation had significantly lower 15N enrichment than uninoculated palms that received similar N fertilizers. The dilution of labeled N served as a marker for the occurrence of biological N2 fixation. The proportion of N uptake that was derived from the atmosphere was estimated as 63% on the whole plant basis. The inoculation process increased the N and dry matter yields of the palm leaflets and rachis significantly. Field planting of young, immature oil palm in soil inoculated with B. sphaericus UPMB-10 might mitigate inorganic fertilizer-N application through supplementation by biological nitrogen fixation. This could be a new and important source of nitrogen biofertilizer in the early phase of oil palm cultivation in the field. PMID- 22446307 TI - Occurrence of hand-foot-and-mouth disease pathogens in domestic sewage and secondary effluent in Xi'an, China. AB - Hand, foot and mouth disease (HFMD), caused by a group of enteric viruses such as Enterovirus 71 (EV71), Coxsackievirus A16 (CVA16) and Coxsackievirus A10 (CVA10), is heavily epidemic in East Asia. This research focused on investigating the occurrence of HFMD pathogens in domestic sewage and secondary effluent before disinfection in a wastewater treatment plant (WWTP) in Xi'an, the largest megacity in northwest China. In order to simultaneously detect all three HFMD pathogens, a semi-nested RT-PCR assay was constructed with a newly designed primer set targeting conservative gene regions from the 5' untranslated region (UTR) to VP2. As a result, 86% of raw sewage samples and 29% of the secondary effluent samples were positive for the HFMD viral gene, indicating that HFMD pathogens were highly prevalent in domestic wastewater and that they could also persist, even with lower probability, in the secondary effluent before disinfection. Of the three HFMD pathogens, CVA10 was positive in 48% of the total samples, while the occurrences of CVA16 and EV71 were 12% and 2%, respectively. It could thus be stated that CVA10 is the main HFMD pathogen prevailing in the study area, at least during the investigation period. High genetic diversity in the conservative gene region among the same serotype of the HFMD pathogen was identified by phylogenetic analysis, implying that this HFMD pathogen replicates frequently among the population excreting the domestic sewage. PMID- 22446308 TI - Isolation and characterization of novel sulfate-reducing bacterium capable of anaerobic degradation of p-xylene. AB - A novel strain of p-xylene-degrading sulfate reducer was isolated in pure culture. Strain PP31 was obtained from a p-xylene-degrading enrichment culture established from polluted marine sediment. Analyses of the 16S rRNA gene and two functional genes involved in sulfate respiration and anaerobic degradation of aromatic compounds revealed that the isolate was closely related to members of the genus Desulfosarcina. Strain PP31 was capable of growing on p-xylene under sulfate-reducing conditions, and the ratio of generated sulfide and consumed p xylene suggested complete oxidation by the novel isolate. The strain could not grow on benzene, toluene, ethylbenzene, m-xylene o-xylene, or n-hexane as an electron donor. Strain PP31 is the first isolated bacterium that degrades p xylene anaerobically, and will be useful to understanding the mechanism of anaerobic degradation of p-xylene. PMID- 22446309 TI - Diversity of cultivable methane-oxidizing bacteria in microsites of a rice paddy field: investigation by cultivation method and fluorescence in situ hybridization (FISH). AB - The diversity of cultivable methane-oxidizing bacteria (MOB) in the rice paddy field ecosystem was investigated by combined culture-dependent and fluorescence in situ hybridization (FISH) techniques. Seven microsites of a Japanese rice paddy field were the focus of the study: floodwater, surface soil, bulk soil, rhizosphere soil, root, basal stem of rice plant, and rice stumps of previous harvest. Based on pmoA gene analysis and transmission electron microscopy (TEM), four type I, and nine type II MOB isolates were obtained from the highest dilution series of enrichment cultures. The type I MOB isolates included a novel species in the genus Methylomonas from floodwater and this is the first type I MOB strain isolated from floodwater of a rice paddy field. In the type I MOB, two isolates from stumps were closely related to Methylomonas spp.; one isolate obtained from rhizosphere soil was most related to Methyloccocus-Methylocaldum Methylogaea clade. Almost all the type II MOB isolates were related to Methylocystis methanotrophs. FISH confirmed the presence of both types I and II MOB in all the microsites and in the related enrichment cultures. The study reported, for the first time, the diversity of cultivable methanotrophs including a novel species of type I MOB in rice paddy field compartments. Refining growth media and culture conditions, in combination with molecular approaches, will allow us to broaden our knowledge on the MOB community in the rice paddy field ecosystem and consequently to implement strategies for mitigating CH4 emission from this ecosystem. PMID- 22446310 TI - Novel conjugative transferable multiple drug resistance plasmid pAQU1 from Photobacterium damselae subsp. damselae isolated from marine aquaculture environment. AB - The emergence of drug-resistant bacteria is a severe problem in aquaculture. The ability of drug resistance genes to transfer from a bacterial cell to another is thought to be responsible for the wide dissemination of these genes in the aquaculture environment; however, little is known about the gene transfer mechanisms in marine bacteria. In this study, we show that a tetracycline resistant strain of Photobacterium damselae subsp. damselae, isolated from seawater at a coastal aquaculture site in Japan, harbors a novel multiple drug resistance plasmid. This plasmid named pAQU1 can be transferred to Escherichia coli by conjugation. Nucleotide sequencing showed that the plasmid was 204,052 base pairs and contained 235 predicted coding sequences. Annotation showed that pAQU1 did not have known repA, suggesting a new replicon, and contained seven drug resistance genes: bla(CARB-9)-like, floR, mph(A)-like, mef(A)-like, sul2, tet(M) and tet(B). The plasmid has a complete set of genes encoding the apparatus for the type IV secretion system with a unique duplication of traA. Phylogenetic analysis of the deduced amino acid sequence of relaxase encoded by traI in pAQU1 demonstrated that the conjugative transfer system of the plasmid belongs to MOB(H12), a sub-group of the MOB(H) plasmid family, closely related to the IncA/C type of plasmids and SXT/R391 widely distributed among species of Enterobacteriaceae and Vibrionaceae. Our data suggest that conjugative transfer is involved in horizontal gene transfer among marine bacteria and provide useful insights into the molecular basis for the dissemination of drug resistance genes among bacteria in the aquaculture environment. PMID- 22446311 TI - Diversity and distribution of N-acylhomoserine lactone (AHL)-degrading activity and AHL-lactonase (AiiM) in genus microbacterium. AB - N-Acylhomoserine lactone (AHL)-degrading enzyme, AiiM, was identified from the potato leaf-associated Microbacterium testaceum StLB037. In this study, we cloned eight aiiM gene homologues from other AHL-degrading Microbacterium strains. The similarity of the chromosomal locus of the aiiM gene is associated with the phylogenetic classification based on 16S rRNA. Degenerate PCR revealed that the aiiM gene was only conserved in AHL-degrading Microbacterium strains, but not in fifteen Microbacterium type strains or two Microbacterium isolates from other plants. These results suggested that the high level of AHL-degrading activity in Microbacterium strains was caused by the aiiM gene encoded on their chromosome. PMID- 22446312 TI - Microbial communities associated with holothurians: presence of unique bacteria in the coelomic fluid. AB - Marine invertebrates interact with various microorganisms ranging from pathogens to symbionts. One-to-one symbiosis between a single microbial species and a single host animal has served as a model for the study of host-microbe interactions. In addition, increasing attention has recently been focused on the complex symbiotic associations, e.g., associations between sponges and their symbionts, due to their biotechnological potential; however, relatively little is known about the microbial diversity associated with members of the phylum Echinodermata. Here, for the first time, we investigated microbial communities associated with a commercially important holothurian species, Apostichopus japonicus, using culture-dependent and -independent methods. Diverse and abundant heterotrophs, mostly Gammaproteobacteria members, were cultured semi quantitatively. Using the cloning and sequencing technique, different microbial communities were found in different holothurian tissues. In the holothurian coelomic fluid, potentially metabolically active and phylogenetically unique members of Epsilonproteobacteria and Rickettsiales were discovered. This study suggests that coelomic fluids of marine invertebrates, at least those inhabiting intertidal areas where physical and chemical conditions fluctuate, provide microbes with unique and stable habitats. PMID- 22446313 TI - Production and consumption of hydrogen in hot spring microbial mats dominated by a filamentous anoxygenic photosynthetic bacterium. AB - Microbial mats containing the filamentous anoxygenic photosynthetic bacterium Chloroflexus aggregans develop at Nakabusa hot spring in Japan. Under anaerobic conditions in these mats, interspecies interaction between sulfate-reducing bacteria as sulfide producers and C. aggregans as a sulfide consumer has been proposed to constitute a sulfur cycle; however, the electron donor utilized for microbial sulfide production at Nakabusa remains to be identified. In order to determine this electron donor and its source, ex situ experimental incubation of mats was explored. In the presence of molybdate, which inhibits biological sulfate reduction, hydrogen gas was released from mat samples, indicating that this hydrogen is normally consumed as an electron donor by sulfate-reducing bacteria. Hydrogen production decreased under illumination, indicating that C. aggregans also functions as a hydrogen consumer. Small amounts of hydrogen may have also been consumed for sulfur reduction. Clone library analysis of 16S rRNA genes amplified from the mats indicated the existence of several species of hydrogen-producing fermentative bacteria. Among them, the most dominant fermenter, Fervidobacterium sp., was successfully isolated. This isolate produced hydrogen through the fermentation of organic carbon. Dispersion of microbial cells in the mats resulted in hydrogen production without the addition of molybdate, suggesting that simultaneous production and consumption of hydrogen in the mats requires dense packing of cells. We propose a cyclic electron flow within the microbial mats, i.e., electron flow occurs through three elements: S (elemental sulfur, sulfide, sulfate), C (carbon dioxide, organic carbon) and H (di-hydrogen, protons). PMID- 22446314 TI - Carbonate-dissolving bacteria from 'miliolite', a bioclastic limestone, from Gopnath, Gujarat, Western India. AB - In the present investigation, the abundance and molecular phylogeny of part of the culturable bacterial population involved in the dissolution of "miliolite", a bioclastic limestone, from Gopnath, India, was studied. Carbonate-dissolving bacteria were isolated, enumerated and screened for their ability to dissolve miliolite. Amplified ribosomal DNA restriction analysis (ARDRA) indicated 14 operational taxonomic units (OTUs) to be distributed in 5 different clades at a similarity coefficient of 0.85. Then, 16S rRNA sequence analysis helped to decipher that the majority of carbonate-dissolving bacteria were affiliated to phyla Firmicutes (Families Bacillaceae and Staphylococcaceae) and Actinobacteria (Family Promicromonosporaceae) indicating their role in miliolite weathering. PMID- 22446315 TI - Applying unconventional secretion of the endochitinase Cts1 to export heterologous proteins in Ustilago maydis. AB - The demand on the biotechnological production of proteins for pharmaceutical, medical and industrial applications is steadily growing. For the production of challenging proteins, we aim to establish a novel expression platform in the well characterized eukaryotic microorganism Ustilago maydis. In filaments of this fungus, secretion of the endochitinase Cts1 depends on mRNA transport along microtubules, which is mediated by the key RNA-binding protein Rrm4. Here, we report two important findings: (i) Cts1 secretion occurs via a novel unconventional route and (ii) this secretory mechanism can be exploited for the export of active heterologous proteins. Initially, we used beta-glucuronidase (Gus) as a reporter for unconventional secretion. This bacterial enzyme is inactivated by N-glycosylation during its passage through the conventional eukaryotic secretory pathway. By contrast, in our system Gus was exported in its active form by fusion to Cts1 confirming its secretion by an unconventional route. As a proof-of-principle for economically important biopharmaceuticals we expressed an active single-chain antibody. Importantly, the novel protein export pathway circumvents N-glycosylation which is advantageous in many applications, e.g., to avoid undesired immune reactions in humans. Thus, the unconventional Cts1 secretion machinery has a high potential for the production of biotechnologically relevant proteins. PMID- 22446316 TI - Incompatibility between X chromosome factor and pericentric heterochromatic region causes lethality in hybrids between Drosophila melanogaster and its sibling species. AB - The Dobzhansky-Muller model posits that postzygotic reproductive isolation results from the evolution of incompatible epistatic interactions between species: alleles that function in the genetic background of one species can cause sterility or lethality in the genetic background of another species. Progress in identifying and characterizing factors involved in postzygotic isolation in Drosophila has remained slow, mainly because Drosophila melanogaster, with all of its genetic tools, forms dead or sterile hybrids when crossed to its sister species, D. simulans, D. sechellia, and D. mauritiana. To circumvent this problem, we used chromosome deletions and duplications from D. melanogaster to map two hybrid incompatibility loci in F(1) hybrids with its sister species. We mapped a recessive factor to the pericentromeric heterochromatin of the X chromosome in D. simulans and D. mauritiana, which we call heterochromatin hybrid lethal (hhl), which causes lethality in F(1) hybrid females with D. melanogaster. As F(1) hybrid males hemizygous for a D. mauritiana (or D. simulans) X chromosome are viable, the lethality of deficiency hybrid females implies that a dominant incompatible partner locus exists on the D. melanogaster X. Using small segments of the D. melanogaster X chromosome duplicated onto the Y chromosome, we mapped a dominant factor that causes hybrid lethality to a small 24-gene region of the D. melanogaster X. We provide evidence suggesting that it interacts with hhl(mau). The location of hhl is consistent with the emerging theme that hybrid incompatibilities in Drosophila involve heterochromatic regions and factors that interact with the heterochromatin. PMID- 22446317 TI - Developmental genetics of secretory vesicle acidification during Caenorhabditis elegans spermatogenesis. AB - Secretory vesicles are used during spermatogenesis to deliver proteins to the cell surface. In Caenorhabditis elegans, secretory membranous organelles (MO) fuse with the plasma membrane to transform spermatids into fertilization competent spermatozoa. We show that, like the acrosomal vesicle of mammalian sperm, MOs undergo acidification during development. Treatment of spermatids with the V-ATPase inhibitor bafilomycin blocks both MO acidification and formation of functional spermatozoa. There are several spermatogenesis-defective mutants that cause defects in MO morphogenesis, including spe-5. We determined that spe-5, which is on chromosome I, encodes one of two V-ATPase B paralogous subunits. The spe-5 null mutant is viable but sterile because it forms arrested, multi-nucleate spermatocytes. Immunofluorescence with a SPE-5-specific monoclonal antibody shows that SPE-5 expression begins in spermatocytes and is found in all subsequent stages of spermatogenesis. Most SPE-5 is discarded into the residual body during spermatid budding, but a small amount remains in budded spermatids where it localizes to MOs as a discrete dot. The other V-ATPase B subunit is encoded by vha-12, which is located on the X chromosome. Usually, spe-5 mutants are self sterile in a wild-type vha-12 background. However, an extrachromosomal transgene containing wild-type vha-12 driven by its own promoter allows spe-5 mutant hermaphrodites to produce progeny, indicating that VHA-12 can at least partially substitute for SPE-5. Others have shown that the X chromosome is transcriptionally silent in the male germline, so expression of the autosomally located spe-5 gene ensures that a V-ATPase B subunit is present during spermatogenesis. PMID- 22446318 TI - Multiple pathways suppress telomere addition to DNA breaks in the Drosophila germline. AB - Telomeres protect chromosome ends from being repaired as double-strand breaks (DSBs). Just as DSB repair is suppressed at telomeres, de novo telomere addition is suppressed at the site of DSBs. To identify factors responsible for this suppression, we developed an assay to monitor de novo telomere formation in Drosophila, an organism in which telomeres can be established on chromosome ends with essentially any sequence. Germline expression of the I-SceI endonuclease resulted in precise telomere formation at its cut site with high efficiency. Using this assay, we quantified the frequency of telomere formation in different genetic backgrounds with known or possible defects in DNA damage repair. We showed that disruption of DSB repair factors (Rad51 or DNA ligase IV) or DSB sensing factors (ATRIP or MDC1) resulted in more efficient telomere formation. Interestingly, partial disruption of factors that normally regulate telomere protection (ATM or NBS) also led to higher frequencies of telomere formation, suggesting that these proteins have opposing roles in telomere maintenance vs. establishment. In the ku70 mutant background, telomere establishment was preceded by excessive degradation of DSB ends, which were stabilized upon telomere formation. Most strikingly, the removal of ATRIP caused a dramatic increase in telomeric retrotransposon attachment to broken ends. Our study identifies several pathways that suppress telomere addition at DSBs, paving the way for future mechanistic studies. PMID- 22446320 TI - Synaptic polarity depends on phosphatidylinositol signaling regulated by myo inositol monophosphatase in Caenorhabditis elegans. AB - Although neurons are highly polarized, how neuronal polarity is generated remains poorly understood. An evolutionarily conserved inositol-producing enzyme myo inositol monophosphatase (IMPase) is essential for polarized localization of synaptic molecules in Caenorhabditis elegans and can be inhibited by lithium, a drug for bipolar disorder. The synaptic defect of IMPase mutants causes defects in sensory behaviors including thermotaxis. Here we show that the abnormalities of IMPase mutants can be suppressed by mutations in two enzymes, phospholipase Cbeta or synaptojanin, which presumably reduce the level of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)). We also found that mutations in phospholipase Cbeta conferred resistance to lithium treatment. Our results suggest that reduction of PIP(2) on plasma membrane is a major cause of abnormal synaptic polarity in IMPase mutants and provide the first in vivo evidence that lithium impairs neuronal PIP(2) synthesis through inhibition of IMPase. We propose that the PIP(2) signaling regulated by IMPase plays a novel and fundamental role in the synaptic polarity. PMID- 22446321 TI - In vitro anti inflammatory activity of Aloe vera by down regulation of MMP-9 in peripheral blood mononuclear cells. AB - AIM OF THE STUDY: The anti-inflammatory activity of Aloe vera was investigated through MMP inhibition studies. The effect of Aloe vera on MMP-9 inhibition was tested on peripheral blood mononuclear cells (PBMC). MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from the heparinised venous blood by Ficoll Diatrizoate gradient centrifugation. The cell count and viability was determined using dye exclusion technique. Cytotoxicity was evaluated by MTT assay. Activation of MMP-9 was visualized by gelatin zymography. Inhibition of MMP-9 in the presence of aqueous extract of Aloe vera was detected by gelatin zymography and confirmed by RT-PCR. RESULTS: Peripheral blood mononuclear cells (PBMC) showed significant inhibition in the activity of MMP-9, indicating the in vitro inhibitory effect of Aloe vera on MMP-9. Zymographic analysis and RT-PCR showed that it caused a significant reduction in the production of MMP-9 in a concentration dependent manner. CONCLUSION: The inhibition of MMP-9 production in the cells was detected by gelatin zymography and was confirmed by RT-PCR. PMID- 22446322 TI - X-chromosome inactivation pattern analysis for the assessment of cell clonality in cats. AB - X-chromosome inactivation pattern (XCIP) analysis has been widely used to assess cell clonality in various types of neoplasms in humans. In the present study, a polymerase chain reaction-based feline XCIP analysis using the feline androgen receptor gene was developed. To construct the system of the analysis, polymorphism in CAG tandem repeats within the feline androgen receptor gene was explored using somatic DNAs from 50 male and 103 female cats. CAG tandem repeats in exon 1 of the feline androgen receptor gene were found to be polymorphic, containing 15 to 22 CAG repeats. Of the 103 female cats, 70 (68%) were heterozygous for the number of CAG repeats, indicating the possible usefulness of XCIP analysis in cats. Application of the feline XCIP analysis to 3 feline mammary gland adenocarcinoma cell lines revealed distinctly skewed XCIPs in these cell lines, indicating their clonal origins. Twelve (80%) of the 15 primary tissue/cell samples obtained from cats with various neoplastic diseases showed skewed XCIPs. Moreover, bone marrow samples from 3 cats with myelodysplastic syndrome were also found to have skewed XCIPs. The polymerase chain reaction based XCIP analysis developed in this study can provide information on cell clonality in female cats, potentially facilitating the differential diagnosis of various disorders in cats. PMID- 22446319 TI - Telomere-targeted retrotransposons in the rice blast fungus Magnaporthe oryzae: agents of telomere instability. AB - The fungus Magnaporthe oryzae is a serious pathogen of rice and other grasses. Telomeric restriction fragments in Magnaporthe isolates that infect perennial ryegrass (prg) are hotspots for genomic rearrangement and undergo frequent, spontaneous alterations during fungal culture. The telomeres of rice-infecting isolates are very stable by comparison. Sequencing of chromosome ends from a number of prg-infecting isolates revealed two related non-LTR retrotransposons (M. oryzae Telomeric Retrotransposons or MoTeRs) inserted in the telomere repeats. This contrasts with rice pathogen telomeres that are uninterrupted by other sequences. Genetic evidence indicates that the MoTeR elements are responsible for the observed instability. MoTeRs represent a new family of telomere-targeted transposons whose members are found exclusively in fungi. PMID- 22446323 TI - CD25 is expressed by canine cutaneous mast cell tumors but not by cutaneous connective tissue mast cells. AB - Canine cutaneous mast cell tumors (MCT) of different histological grades have distinct biological behaviors. However, little is known about underlying molecular mechanisms that lead to tumor development and increasing malignancy with higher tumor grade. Recent studies have identified the interleukin-2 receptor (IL-2R) subunits CD25 and CD2 as markers that distinguish nonneoplastic from neoplastic mast cells in human systemic mastocytosis. In this study, their potential as a marker for canine MCT and their possible impact on MCT carcinogenesis were evaluated. mRNA expression levels of both genes were compared between grade 1 (n = 12) and grade 3 (n = 8) MCT, and protein expression levels of CD25 were compared in 90 MCT of different tumor grades. mRNA expression levels of both CD25 and CD2 were upregulated in grade 3 MCT. In contrast, CD25 protein was expressed by fewer tumor cells and at decreased levels in grade 3 tumors, while most grade 1 MCT had strong CD25 protein expression. Moreover, CD25 was not expressed by nonneoplastic, resting cutaneous mast cells, while few presumably activated mast cells in tissue samples from dogs with allergic dermatitis had weak CD25 expression. Taken together, these findings suggest that CD25 may play a critical role in early MCT development and may be a stimulatory factor in grade 1 MCT, while grade 3 MCT seem to be less dependent on CD25. Because of the low number of CD25-positive tumor cells in high-grade tumors, the usefulness of CD25 as a tumor marker is, however, questionable. PMID- 22446324 TI - Novel genital alphapapillomaviruses in baboons (Papio hamadryas anubis) with cervical dysplasia. AB - Genital Alphapapillomavirus (alphaPV) infections are one of the most common sexually transmitted human infections worldwide. Women infected with the highly oncogenic genital human papillomavirus (HPV) types 16 and 18 are at high risk for development of cervical cancer. Related oncogenic alphaPVs exist in rhesus and cynomolgus macaques. Here the authors identified 3 novel genital alphaPV types (PhPV1, PhPV2, PhPV3) by PCR in cervical samples from 6 of 15 (40%) wild-caught female Kenyan olive baboons (Papio hamadryas anubis). Eleven baboons had koilocytes in the cervix and vagina. Three baboons had dysplastic proliferative changes consistent with cervical squamous intraepithelial neoplasia (CIN). In 2 baboons with PCR-confirmed PhPV1, 1 had moderate (CIN2, n = 1) and 1 had low grade (CIN1, n = 1) dysplasia. In 2 baboons with PCR-confirmed PhPV2, 1 had low grade (CIN1, n = 1) dysplasia and the other had only koilocytes. Two baboons with PCR-confirmed PhPV3 had koilocytes only. PhPV1 and PhPV2 were closely related to oncogenic macaque and human alphaPVs. These findings suggest that alphaPV infected baboons may be useful animal models for the pathogenesis, treatment, and prophylaxis of genital alphaPV neoplasia. Additionally, this discovery suggests that genital alphaPVs with oncogenic potential may infect a wider spectrum of non human primate species than previously thought. PMID- 22446325 TI - Monocyte-endothelial adhesion is modulated by Cx43-stimulated ATP release from monocytes. AB - Adhesion of circulating monocytes to vascular endothelial cells is a crucial event in development of vascular inflammatory conditions, including atherosclerosis. We investigated the roles of connexin43 (Cx43) and ATP release on monocyte-endothelial adhesion. Cx43 function and expression were manipulated by connexin channel inhibitors, overexpression and siRNA. Connexin channel inhibitors rapidly decreased ATP release from U937 monocytes and increased adhesion to human umbilical vein endothelial cells (HUVEC). Monocyte ATP release correlated with Cx43 expression, not with Cx37 expression. Exogenous adenosine (ADO) or ATP decreased adhesion, and inhibition of ATP conversion to ADO increased adhesion. We infer that monocyte Cx43 channel activity causes ATP release, likely via Cx43-containing hemichannels, and that ATP decreases adhesion via conversion to ADO. Inhibition of HUVEC connexin channel activity did not affect ATP release or adhesion. In contrast, expression of Cx43 protein in U937 cells enhanced adhesion. Thus, Cx43 channel function and expression have opposite effects: Cx43 channel function in monocytes, but not in HUVEC, rapidly decreases adhesion via ATP release and conversion to ADO, whereas Cx43 expression itself enhances adhesion. These studies suggest that local regulation of monocyte Cx43 activity within the vasculature can dynamically modulate the monocyte-endothelial adhesion that is an initiating event in vascular inflammatory pathologies, with the baseline adhesion set by Cx43 expression levels. This balance of rapid and tonic influences may be crucial in development of vascular pathologies. PMID- 22446326 TI - Binding of human BiP to the ER stress transducers IRE1 and PERK requires ATP. AB - ER stress is activated in a number of important diseases such as diabetes, cancer, and neurodegeneration, but the molecular interactions governing the response are still being elucidated. In the absence of stress, protein complexes exist between the ER-resident chaperone BiP and three transmembrane signalling molecules which are responsible for signal transmission. Previous results suggested that cofactors might participate in these interactions, but the molecular details are not well understood. We coexpressed BiP and the lumenal domains of each of the three ER stress transducers and copurified the complexes in the presence of ATP and ADP in order to better understand how the complex is formed. ATP, but not ADP, was required to isolate the BiP-IRE1 and the BiP-PERK complexes, but the BiP-ATF6 complex was purified in all conditions tested. Based on the results, we hypothesize that in contrast to its mode of binding ATF6 and unfolded proteins, BiP binds to IRE1 and PERK in a different manner. PMID- 22446327 TI - UAP56 is a novel interacting partner of Bcr in regulating vascular smooth muscle cell DNA synthesis. AB - Bcr is a serine/threonine kinase that is a critical regulator of vascular smooth muscle cell inflammation and proliferation. We have previously demonstrated that Bcr acts in part via phosphorylation and inhibition of PPARgamma. We have identified the RNA helicase UAP56 as another substrate of Bcr. In this report we demonstrate that knockdown of UAP56 blocks Bcr induced DNA synthesis in vascular smooth muscle cells (VSMC). We also found that over expression of Bcr increased the expression of cyclin E and decreased the expression of p27. Knockdown of UAP56 reversed the effect of Bcr on cyclin E and p27 expression. Furthermore, we found that Bcr binds to UAP56 and demonstrate that binding of UAP56 to Bcr is critical for Bcr induced DNA synthesis in VSMC. Our data identify UAP56 as an important binding partner of Bcr and a novel target for inhibiting vascular smooth muscle cell proliferation. PMID- 22446328 TI - Destabilization of a bovine B12 trafficking chaperone protein by oxidized form of glutathione. AB - The protein, bCblCpro, is a bovine B(12) trafficking chaperone involved in intracellular B(12) metabolism. bCblCpro is highly thermolabile (T(m)=~42 degrees C) and the reduced form of glutathione, GSH, has been found to stabilize bCblCpro as a positive regulator. In this study, we discovered that the oxidized form of glutathione, GSSG, destabilizes bCblCpro, which is derived from changes in the conformation of the protein upon GSSG binding. The binding affinity for GSSG was determined to be similar with the affinity for GSH. The AC(50)=2.8 +/- 0.4 mM of GSSG for destabilization of bCblCpro was consistently similar with the AC(50)=2.1 +/- 0.5 mM of GSH for stabilization of the protein. These results suggest that GSSG is a negative regulator of bCblCpro and that the molar ratio of [GSH]/[GSSG] in cells may determine the stability of the B(12) trafficking chaperone. PMID- 22446329 TI - In vitro binding properties of tumor suppressor p53 with PUMA and NOXA. AB - The p53-upregulated modulator of apoptosis (Puma) and Noxa, are direct targets in p53-mediated apoptosis localized to the mitochondria. Tumor suppressor p53 induces apoptosis by transcriptional induction of Puma and Noxa, which encode proapoptotic BH3-only member Bcl-1 family proteins. However, at a molecular level, the mechanism of action of Puma and Noxa proteins remain poorly defined. In addition, there have been no reports on whether or not p53 directly interacts with Puma and Noxa, in vitro. Here, we provide evidence indicating that the DNA binding domain (DBD) of p53 directly interacted with the BH3 domains of human PUMA and NOXA. Our studies revealed that PUMA has a weak affinity for p53, but NOXA has significant affinity for p53. In this study, we developed a molecular docking model using homology modeling based on the structures of truncated p53, PUMA and NOXA. In addition, we investigated whether or not six mutants of p53 (K101A, T102A, L111A, D186A, G199A and S227A) were able to bind to PUMA and NOXA. Four structure-based mutations (T102A, L111A, D186A and G199A) disrupted the p53 PUMA/NOXA interaction. Our study suggested that these four mutations lowered the stability of the p53 DBD domain and induced aggregation of structurally destabilized p53, and thus disrupted the p53-PUMA/NOXA interaction. PMID- 22446330 TI - Synthetic retinoid CD437 induces apoptosis and acts synergistically with TRAIL receptor-2 agonist in malignant melanoma. AB - The novel synthetic retinoid, CD437, shows potent anti-tumor activity in a range of different cancer cell lines and now serves as a prototype for development of new retinoid related molecules (RRMs). The purpose of this study was to examine the effect and cellular targets of CD437 in the human metastatic melanoma cell lines FEMX-1 and WM239. We showed that treatment with CD437 led to cell cycle arrest and induced apoptosis through both the extrinsic- and intrinsic pathways (caspase 8, -9 and PARP cleavage) in both cell lines. Interestingly, apoptosis was induced independently of DNA-fragmentation in FEMX-1 cells, and appeared partially caspase-independent in the WM239 cells. Additionally, up-regulation of CHOP mRNA and cathepsin D protein expression, following retinoid treatment, suggests involvement of the endoplasmatic reticulum (ER) and lysosomes, respectively. Combination of suboptimal concentrations of CD437 and lexatumumab, a TRAIL death receptor-2 agonist, resulted in synergistic reduction of viable cells, along with increased PARP cleavage. These results indicate that CD437 has a strong anti-neoplastic effect alone and in combination with lexatumumab in melanoma cell lines. PMID- 22446331 TI - Chronic hypoxia in cultured human podocytes inhibits BKCa channels by upregulating its beta4-subunit. AB - Accumulating evidence suggests that podocyte hypoxia is an alternative mechanism for the pathogenesis of renal diseases. Functional, large-conductance, calcium activated potassium channels (BK(Ca) channels) are expressed in podocytes as mechanosensitive channels; however, whether BK(Ca) channels are involved in the podocyte response to chronic hypoxia and the possible underlying mechanisms remain unclear. Here, we use the patch clamp technique to show that the exposure of human podocytes to 2% O(2) for 24 h causes a significant reduction in BK(Ca) channel currents. Molecular biology experiments showed that chronic hypoxia increased BK(Ca) channel beta4-subunit mRNA and protein expression, but not the expression of the BK(Ca) pore-forming alpha- or beta3-subunits. Furthermore, chronic hypoxia shifted the channel activation range toward more depolarized voltages and slowed its activation kinetics, which are similar to the properties conferred by the beta4-subunit. We conclude that BK(Ca) channels are involved in the response of podocytes to chronic hypoxia via the upregulation of the beta4 subunit. These findings provide new insight into the mechanism underlying the cellular responses of podocytes to hypoxia. PMID- 22446332 TI - miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients. AB - MicroRNAs, as a kind of negative gene regulators, were demonstrated to be involved in many types of diseases. In this study, we found that transforming growth factor-beta 1 could induce the expression of miR-181a and miR-181b, and miR-181b increased in the much higher folds than miR-181a. Because of the important role of transforming growth factor-beta 1 in HSC activation and liver cirrhosis, we investigate the effect of miR-181a and miR-181b on HSC proliferation. The results showed that miR-181b could promote HSC-T6 cell proliferation by regulating cell cycle. Further study showed p27, the cell cycle regulator, was the direct target of miR-181b in HSC-T6 cell. But miR-181a had no effects on HSC-T6 cell proliferation and cell cycle, and did not target p27. Interestingly, miR-181b is elevated significantly in serum of liver cirrhosis cases comparing to that of normal persons, whereas miR-181a expression was in the similar level with that of normal persons. These results suggested that miR-181b could be induced by TGF-beta1 and promote the growth of HSCs by directly targeting p27. The elevation of miR-181b in serum suggested that it may be potential diagnostic biomarkers for cirrhosis. As for miR-181a, it may work in TGF-beta1 pathway by a currently unknown mechanism. PMID- 22446333 TI - Modelling heterogeneous host immune response in a multi-strain system. AB - We explore the dynamics that occur when multiple variants of a virus are released in a population, where hosts can make an immune response to only one epitope of the virus. A heterogeneous immune response was implemented by varying the probability for making a response at a locus of the virus variants. A framework based on an SIR model is presented which allows for the explicit representation of the virus variants and the immune histories of the population. From this we are able to calculate the proportion of the population infected by each variant and the number of times a host has been infected when there have been multiple epidemics. When there are discrete epidemics, we use the framework to calculate the proportion of the population infected analytically, demonstrating a method which reduces the calculations required in comparison with solving the full system of differential equations. However, when there are multiple strains present in the population at any time, we show that the full set of ODEs must be solved to fully describe the infection dynamics. PMID- 22446334 TI - Differences in lateral ankle laxity measured via stress ultrasonography in individuals with chronic ankle instability, ankle sprain copers, and healthy individuals. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To use stress ultrasonography to measure the change in anterior talofibular ligament length during the simulated anterior drawer and ankle inversion stress tests. BACKGROUND: In approximately 30% of individuals, ankle sprains may eventually develop into chronic ankle instability (CAI) with recurrent symptoms. Individuals with CAI and those who have a history of ankle sprain (greater than 1 year prior) without chronic instability (copers) may or may not have mechanical laxity. METHODS: Sixty subjects (n=60 ankles) were divided into 3 groups: 1) Control subjects without ankle injury history (n=20; mean +/- SD age; 24.8 +/- 4.8 years; height, 173.7 +/ 9.4 cm; weight, 77.2 +/- 19.5 kg), ankle sprain copers (n=20; 22.3 +/- 2.9 years; 172.8 +/- 11.3 cm; 72.4 +/- 14.3 kg), and subjects with CAI (n=20; 23.5 +/ 4.2 years; 174.6 +/- 9.6 cm; 74.8 +/- 17.3 kg). Ligament length change with the anterior drawer and end range ankle inversion was calculated from ultrasound images. The Foot and Ankle Ability Measure (FAAM) was used to quantify self reported function on activities-of-daily living (ADL) and sports. RESULTS: The anterior drawer test resulted in length changes that were greater (F2,57=6.2, P=.004) in the CAI (mean +/- SD length change, 15.6 +/- 15.1%, P=.006) and the coper groups (14.0 +/- 15.9%, P=.016) compared to the control group (1.3 +/- 10.7%); however the length change for the CAI and coper groups were not different (P=.93). Ankle inversion similarly resulted in greater ligament length change (F2,57=6.5, P=.003) in the CAI (25.3 +/- 15.5%, P=.003) and coper groups (20.2 +/ 19.6%, P=.039) compared to the control group (7.4 +/- 12.9%); with no difference in length change between the copers and CAI groups (P=.59). The CAI group had a lower score on the FAAM-ADL (87.4 +/- 13.4%) and FAAM-Sports (74.2 +/- 17.8%) when compared to the control (98.8 +/- 2.9% and 98.9 +/- 3.1%, P<.0001) and coper groups (99.4 +/- 1.8% and 94.6 +/- 8.8%, P<.0001). CONCLUSION: Stress ultrasonography identified greater length changes of the anterior talofibular ligament in both the coper and CAI groups compared to the control group. Only subjects with CAI had reductions in self-reported function. PMID- 22446335 TI - Editorial comment. PMID- 22446336 TI - Tumorigenic and prognostic significance of RASSF1A expression in low-grade (WHO grade 1 and grade 2) nonmuscle-invasive bladder cancer. AB - OBJECTIVE: To investigate RASSF1A expression in an attempt to understand the effect of RASSF1A in low-grade, nonmuscle-invasive bladder cancer (NMIBC). METHODS: A total of 101 tumor tissues and normal donor-matched adjacent tissues from patients with primary low-grade NMIBC were selected. RASSF1A expression was measured by quantitative real-time polymerase chain reaction and is expressed as the ratio between the normal tissue level and the tumor tissue level (N/T ratio). RASSF1A promoter methylation was assessed using methylation-specific polymerase chain reaction. RESULTS: RASSF1A mRNA expression was significantly lower in patients with RASSF1A methylation than in those with no methylation (P = .046), and RASSF1A mRNA expression was lower in the tumor tissues than in the matched normal bladder mucosa (P < .001). The RASSF1A N/T ratio was greater in grade 2 and large tumors than in grade 1 and small tumors (P < .05 for each). Kaplan Meier estimates revealed that the differences in the RASSF1A N/T ratio were associated with significant differences in the interval to tumor recurrence (P = .018) in low-grade NMIBC. Multivariate Cox regression analysis showed that the RASSF1A N/T ratio (hazards ratio 2.354, P = .015) was an independent predictor of recurrence. CONCLUSION: Decreased RASSF1A expression correlates with the transition from normal mucosa to bladder cancer and has prognostic value in low grade NMIBC. PMID- 22446338 TI - Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy. AB - OBJECTIVE: Preoperative prognostic factors in bladder cancer patients have not been fully established. This study was undertaken to investigate preoperative prognostic factors, including neutrophil-to-lymphocyte ratio (NLR), and to develop a novel prognostic factors-based risk stratification model for disease specific survival (DSS) in bladder cancer patients treated with radical cystectomy (RC). METHODS: We performed a retrospective analysis of 189 consecutive bladder cancer patients treated with RC at our institution. Prognostic value of the preoperative clinical and laboratory parameters were evaluated by univariate and multivariate Cox proportional hazard model analyses, and patients were stratified according to relative risks (RRs) for DSS. RESULTS: One-, 3-, and 5-year DSS rates were 86.8%, 70.8%, and 61.7%, respectively. In univariate analysis, tumor size, clinical T stage, hydronephrosis, concomitance of carcinoma in situ, and some laboratory findings (hemoglobin [Hb] level, platelet count, C-reactive protein, neutrophil count, lymphocyte count, and NLR) were significantly associated with poor prognosis. In multivariate analysis, tumor size, hydronephrosis, Hb level, and NLR were independent factors for predicting poor prognosis. Patients were stratified into 3 risk groups: low (RR = 1.000-3.717), intermediate (RR = 4.149-9.315), and high (RR = 10.397-38.646). The differences among the groups were significant. CONCLUSIONS: NLR was an independent prognostic factor, as were tumor size, hydronephrosis, and Hb levels, and the combination of these factors can stratify DSS risks in bladder cancer patients treated with RC. This information may be useful for identifying patients who might be candidates for clinical trials of multimodal treatment strategies, including innovative neoadjuvant treatments. PMID- 22446339 TI - Identification of a hyperpolarization-activated cyclic nucleotide-gated channel and its subtypes in the urinary bladder of the rat. AB - OBJECTIVE: To investigate the distribution and effects of hyperpolarization activated cyclic nucleotide-gated (HCN) channel and its isoforms in bladder, especially in bladder interstitial cells of Cajal (ICC). METHODS: Four HCN isoforms were detected in bladder tissue from rats using reverse transcription polymerase chain reaction and Western blotting. The HCN1 subtype was observed in bladder ICCs by double-labeled fluorescence. The effect of the HCN blocker, ZD7288, was investigated using the bladder smooth muscle strip test. RESULTS: HCN1-4 isoforms were all identified in bladder ICCs using reverse transcription polymerase chain reaction and Western blotting. Based on our semiquantitative analysis, HCN1 was found to be the most prominent isoform. The expression of HCN1 was confirmed in bladder ICCs by double-labeled fluorescence through colabeling of HCN1 and kit (CD117). ZD7288 significantly decreased the bladder excitation. CONCLUSION: All 4 HCN channel isoforms exist in the bladder, and they affect the bladder excitation, presumably via bladder ICCs. PMID- 22446340 TI - Half Fourier single-shot turbo spin-echo magnetic resonance urography for the evaluation of suspected renal colic in pregnancy. AB - OBJECTIVE: To report our experience with magnetic resonance urography (MRU) in pregnant women suspected of having obstructing upper tract calculi. The diagnosis of an upper tract calculus in the pregnant woman can be challenging. Recent evidence suggests that MRU can be used to effectively evaluate renal colic. METHODS: From 2008-2011, 9 pregnant women were referred for evaluation of suspected renal colic caused by an obstructing upper tract stone. All patients underwent MRU with a half Fourier single-shot turbo spin-echo (HASTE) protocol. Medical records and imaging studies were reviewed for demographic and clinical data as well as outcome measures. RESULTS: The mean age of the subjects was 25 years (range 20-34); average gestational age of the fetus was 23 weeks (range 9 36). In all cases, a renal ultrasound was the initial imaging study obtained, with nondiagnostic findings. HASTE MRU detected 4 ureteral stones and 4 cases of physiological hydronephrosis of pregnancy. In one case, interpretation of the MRU was limited as a result of patient motion. Of the patients with obstructing stones, 1 required endourologic management during her pregnancy and 3 were followed conservatively. No adverse events related to MRU occurred. CONCLUSION: HASTE MRU is an informative imaging study for pregnant women with suspected upper tract stone disease. Information gathered from this study augments that gained from alternative modalities, and aids in medical decision-making. The lack of ionizing radiation exposure, coupled with the capture of detailed anatomic imaging, makes HASTE MRU a particularly useful study in this setting. PMID- 22446341 TI - Outcomes in patients with clinical stage III NSGCT who achieve complete clinical response to chemotherapy at extraretroperitoneal disease site. AB - OBJECTIVE: To compare the survival outcomes of patients with advanced nonseminoma and extraretroperitoneal (ERP) disease observed for a clinical complete response (CCR) with those demonstrating a pathologic complete response (PCR). METHODS: From 1989 to 2003, 237 patients with clinical Stage III nonseminoma underwent induction chemotherapy followed by retroperitoneal lymph node dissection. After chemotherapy, 107 demonstrated a CCR to treatment at the ERP disease site. Of the remaining 130 patients with radiographic evidence of residual ERP disease, 86 (66%) had fibrosis only on pathologic review (ie, PCR). The probability of progression-free and disease-specific survival was estimated using the Kaplan Meier method. Cox proportional hazards regression analysis was used to determine the prognostic significance of risk factors for progression and survival. RESULTS: The median follow-up was similar for both CCR and PCR patients (44.5 and 50.7 months, respectively). Overall, the 5-year probability of freedom from progression (93% vs 72%, respectively; P = .0005) and disease-specific survival (96% vs 87%, respectively; P = .08) rates were far better for men with a PCR. The predictors of disease progression included residual retroperitoneal nodal size after chemotherapy (P = .05), and resection of the residual disease at the ERP site was protective (P = .02). CONCLUSION: A CCR at the ERP disease site is associated with a greater likelihood of relapse compared with a PCR, underscoring the limitations of radiographic imaging after chemotherapy in detecting microscopic residual disease and need for rigorous monitoring of patients observed after a CCR. Furthermore, until more accurate clinical predictors of ERP histologic features are identified, we advocate for complete surgical resection of all sites of residual disease, when feasible. PMID- 22446342 TI - Role of 5alpha-reductase inhibitors in prostate cancer prevention and treatment. AB - Although testosterone is the most abundant serum androgen, dihydrotestosterone is the main prostatic androgen. Testosterone is converted to dihydrotestosterone by the enzyme 5alpha-reductase (5alpha-R). Dihydrotestosterone plays an important role in several human diseases, including benign prostate enlargement and prostate cancer. The observation that males born with 5alpha-R 2 deficiency have never been reported to develop prostate cancer stimulated interest in development of 5alpha-R inhibitors. Thus far, 2 5alpha-R inhibitors are approved for clinical use. Several trials evaluated the use of 5alpha-R inhibitors in prostate cancer prevention and treatment and will be reviewed in this article. PMID- 22446343 TI - Cystographic images of Youssef syndrome: flower on top of the bladder. AB - Vesicouterine fistula after obstructed labor is very rare. Hysterosalpingography is the investigation of choice. Cystography primarily does not demonstrate the fistula because the intrauterine pressures are higher than the vesical pressure. A 38-year-old woman presented to us with vecisovaginal fistula and vesicouterine fistula that had developed 13 years earlier after obstructed labor and vaginal delivery of a stillborn neonate. She was found to have normal renal function, but she had developed small capacity bladder and the cystogram performed with Foley catheter showed contrast spilling into the uterus. She was managed by continent urinary diversion. PMID- 22446344 TI - Retroperitoneal mixed germ cell tumor mimicking a renal neoplasm: a case report. AB - Retroperitoneal malignant germ cell tumors (GCTs) are rare and of uncertain origin. Almost all retroperitoneal GCTs with seminomatous histology have been reported in male patients. Pediatric hypertension in a girl secondary to a retroperitoneal mixed GCT (dysgerminoma plus mature monodermal teratoma) has not been reported previously in the literature. We present the first case of an 11 year-old girl with a retroperitoneal mixed GCT presenting with hypertension. PMID- 22446345 TI - Does salvage radiation therapy change the biology of recurrent prostate cancer based on PSA doubling times? Results from the SEARCH database. AB - OBJECTIVE: To investigate whether salvage radiation therapy (SRT) may promote prostate cancer (PCa) transformation to more aggressive phenotypes. To accomplish that, we identified men who underwent SRT after radical prostatectomy for PCa and failed SRT. PSA doubling time (PSADT) was used as a surrogate endpoint for cancer aggressiveness. We compared PSADT calculated before start of SRT and after SRT failure. METHODS: Of 287 men in the SEARCH database since 1988 who underwent SRT, we detected 78 with SRT failure defined as PSA >= 0.2 ng/mL above the post-SRT nadir. Of these, 39 had PSADT available before and after SRT, which was compared using Wilcoxon's paired test with men serving as their own controls. We tested predictors of PSADT change using multivariable logistic regression. RESULTS: There were no differences in PSADT before and after SRT (10.2 vs 12.6 months; P = .46). However, in some individual cases, large changes were observed. Only seminal vesicle invasion showed a trend towards an association with a shorter post-SRT PSADT relative to the pre-SRT PSADT (P = .13). CONCLUSION: Overall, the PSADT after and before SRT were statistically identical, suggesting that after SRT failure, PCa does not emerge with more aggressive biological features. Further studies are needed to identify predictors and the clinical relevance of individual PSADT changes noted in our study. PMID- 22446346 TI - Robotic single-site kidney surgery: evaluation of second-generation instruments in a cadaver model. AB - OBJECTIVE: To evaluate the second generation of single-site instruments for robotic laparoendoscopic single-site surgery (R-LESS) for kidney procedures in a cadaver model. METHODS: Three procedures, including 1 pyeloplasty, 1 partial nephrectomy, and 1 nephrectomy, were conducted in a female cadaver model. A da Vinci Si system (Intuitive Surgical, Sunnyvale, CA) and the second generation of single-site instruments, specifically designed for R-LESS, were used. RESULTS: All the procedures were completed successfully without the addition of extra ports. Time to set up the port and instruments was 40 minutes. In the pyeloplasty, time to complete the anastomosis was 39 minutes. In the partial nephrectomy, simulated ischemia time was 21 minutes. In the nephrectomy, time to complete the resection was 13 minutes. No significant gas leak was noticed during the procedures. There were no injuries to intraabdominal organs or vessels. CONCLUSION: Robotic single-site renal surgery using a second generation of specifically designed instruments was feasible in a cadaver model, obviating many limitations of LESS. Lack of articulation at the tip of the instruments represents the main disadvantage of this novel instrumentation, especially in case of reconstructive procedures. PMID- 22446347 TI - Laparoscopically assisted vaginal pull-through for high urogenital sinus: a new surgical technique. AB - OBJECTIVE: To evaluate feasibility and outcome of a laparoscopically assisted vaginal pull through procedure for suprasphincteric high urogenital sinus malformation with hydrometrocolpos and normal external genitalia. METHODS: A tension-free anastomosis of the vagina to the perineum was realized after laparoscopic mobilization of the vagina, separation from the bladder neck at the confluence and pull-through via an externally introduced expandable trocar, thereby avoiding perineal or perirectal dissection. RESULTS: The approach resulted in good cosmetic and unimpaired functional outcome. Voiding cystourethrography showed normal lower urinary tract anatomy. No disturbances of bladder function could be detected 2 years after surgery. CONCLUSION: Laparoscopic assisted vaginal pull-through is a new approach for high UGS that significantly improved exposure of the uretro-vaginal junction, allowed extensive mobilization of the vagina and showed excellent cosmetic and functional result. PMID- 22446348 TI - Bacillus Calmette-Guerin induces cellular reactive oxygen species and lipid peroxidation in cancer cells. AB - OBJECTIVE: To determine whether Bacillus Calmette-Guerin (BCG) and/or BCG-soluble factors could modulate cellular reactive oxygen species (ROS) in human bladder cancer cells and the impact this could have on response to therapy. METHODS: The expression of alpha5beta1 integrins on human bladder cancer cell lines and their ability to internalize BCG were determined. The effect of live and lyophilized BCG on cellular ROS, lipid peroxidation, and DNA damage was determined using H(2)DCF-DA, TBARS, and comet assays. The cytotoxic effects of live and lyophilized BCG on cancer cells were determined after 24 hours. ROS modulation by Antigen 85B and mycobacterial protein tyrosine phosphatases was monitored. RESULTS: Live and lyophilized BCG were internalized to a similar extent, but live BCG increased cellular ROS, whereas lyophilized BCG reduced ROS. High ROS levels correlated with increased lipid peroxidation. The cytotoxic effect of BCG was independent of cellular ROS but dependent on internalization. Lyophilized BCG was more cytotoxic to bladder cancer cells than live BCG. BCG soluble factors such as Antigen85B could increase cellular ROS. Internalization of lyophilized BCG abrogated the ROS, and lipid peroxidation increase induced by BCG soluble factors. Both live and lyophilized BCG induced DNA damage but to different extents. CONCLUSION: The end products of ROS, such as lipid peroxides and superoxide, could induce DNA damage, which could lead to mutations in cancer cells that select for their survival. Reducing BCG instillations may reduce the risk of mutational changes occurring in remnant cancer cells. PMID- 22446349 TI - The clinical spectrum of the presenting signs and symptoms of anterior urethral stricture: detailed analysis of a single institutional cohort. AB - OBJECTIVE: To accurately delineate the presentation of anterior urethral stricture in an economically developed patient cohort. It is widely assumed that patients with urethral stricture typically present with lower urinary tract symptoms (LUTS). There is a paucity of data examining this assumption. With no uniformly accepted clinical definition or measure of treatment success, a clear clinical description of urethral stricture is important. METHODS: Retrospective detailed analysis was performed on 611 patients presenting with anterior urethral stricture from July 2004 to June 2010. Both the presenting complaint and associated signs and symptoms were classified according to one of 10 clinical categories. RESULTS: The most common presenting complaint was LUTS typical of those found on the American Urological Association-Symptom Score (54.3%) and another 23.4% of patients presented initially with acute urinary retention (AUR). Symptoms other than LUTS or urinary retention accounted for 22.3% of presenting complaints. In addition, 22.9% of patients had genitourinary pain, 50.7% of patients required emergent urologic treatment, and 7.4% of patients presented with renal insufficiency or urethral abscess/necrotizing fasciitis directly related to urethral stricture. CONCLUSION: Although many patients with urethral stricture present initially with LUTS or AUR, almost one quarter of patients have a different presenting complaint. Defining successful treatment of anterior urethral stricture should include more than improvement in LUTS or absence of urinary retention. Urethral stricture is not just a "quality of life" condition because >50% of patients require emergent treatment and 7.4% have a life threatening condition directly related to the stricture. PMID- 22446350 TI - Interobserver variability limits exact preoperative staging by computed tomography in bladder cancer. AB - OBJECTIVE: To evaluate the agreement between radiologic staging of bladder cancer using multidetector row computed tomography (CT) and histopathologic staging and estimate the influence of interobserver variability of the CT findings as a potential limitation of this imaging modality. The available data on the value of multidetector row CT in clinical staging before cystectomy are controversial. METHODS: The multidetector row CT reports of all patients undergoing radical cystectomy at our institution from 2004 to 2008 were retrospectively reviewed and compared in a blinded expert review by an experienced abdominal/genitourinary radiologist. The results of both radiologic reviews were subsequently correlated with the pathologic findings of the surgical specimens. The interobserver variability of radiology reports was estimated using kappa statistics. RESULTS: Preoperative CT scans were available for 276 patients who underwent radical cystectomy. The accuracy of the primary and reference radiologists in predicting the correct local tumor stage was 49% (kappa 0.23, P < .001) and 51% (kappa 0.24, P < .001), respectively. The accuracy in predicting the presence of lymph node metastases was 54% (kappa 0.04, P = .297) and 58% (kappa 0.15, P = .011). The agreement between both radiologists was fair with regard to the local tumor stage (kappa 0.23, P < .001) and the presence of lymph node metastases (kappa 0.35, P < .001). CONCLUSION: The overall agreement between the local bladder cancer stage between CT and pathologic staging was poor to fair. Significant interobserver variability was found in the CT findings that might contribute to the limited accuracy of CT in the detection of extravesical tumor spread, infiltration of extravesical organs, and lymph node involvement. PMID- 22446351 TI - Analysis on the reactivity of five subunits of antigen B family in serodiagnosis of echinococcosis. AB - In this study, the reactivity and differences of five subunits of echinococcus antigen B (AgB) family, recognizing specific antibodies in echinococcosis patient serum, were analyzed. Eight recombinant subunit antigens from Echinococcus granulosus (EgAgB1-EgAgB4) and Echinococcus multilocularis (EmAgB1-EmAgB3 and EmAgB5) were tested by ELISA using a panel of 243 serum samples collected from cystic echinococcosis (CE), alveolar echinococcosis (AE), cysticercosis (CC) patients and clinically normal individuals (NH). The results showed that the diagnostic sensitivity of the subunits for CE sera were 83.06%, 62.90%, 29.03%, 75.81% and 41.13%, and the specificities were 73.95%, 72.27%, 76.47%, 73.11% and 85.71%, respectively. The reactivity of three paralogous subunits, EgAgB1, EgAgB2 and EgAgB3 from E. granulosus and EmAgB1, EmAgB2 and EmAgB3 from E. multilocularis were compared by serological assay. All of the orthologous subunits showed no statistical difference (P>0.05) in detecting CE and AE sera; it revealed that the reactive epitopes may be similar between the orthologous subunits. In a total of 124 CE sera, the positive recognition rate by EgAgB1 was the highest (103/124), yet cocktail subunit antigens may detect even more positives from 100/124 to 112/124 using different subunit combinations. IgG4 subclass was the predominant antibody in reacting with subunit antigens. To conclude, the epitopes of orthologous AgB subunits from E. granulosus and E. multilocularis that recognize specific antibodies may be similar. The paralogous subunits EgAgB1, EgAgB2 and EgAgB4 were the main reactive subunit in sera detection and may have utility as echinococcosis diagnostics, with EgAgB1 possessing the greatest potential. Cocktail subunits may improve the positive detection rate. PMID- 22446352 TI - Do we really need to thank the Beatles for the financing of the development of the computed tomography scanner? AB - It is commonly believed that the revenues from the selling of the Beatles' records by Electric and Musical Industries (EMI) allowed the company to develop the computed tomography (CT) scanner. Some went to define this as the Beatles' gift to medicine. However, significant controversies and discrepancies arise from analysis of this statement, making its correctness doubtful. The details of financing required for the CT development and the part of EMI in financial input have never been publicly announced. This work analyzes the financial contributions to the CT development and investigates if the revenues received from the sales of the Beatles' records were used for the creation of the CT scanner. Timeline of the development of the EMI CT scanner and the financial inputs of EMI and British Department of Health and Social Security (DHSS) were assessed. Without salary expenses to Godfrey Hounsfield and his team, the development of the CT scanner cost EMI approximately L100,000. The British DHSS's expenses were L606,000. Hence, the financial contribution of DHSS into the development of the CT scanner was significantly bigger than that of EMI. Accordingly, British tax payers and officials of British DHSS are to be thanked for the CT scanner. The Beatles' input into the world's culture is valuable and does not require decoration by nonexistent connection to the development of CT. A positive aspect to this misconception is that it keeps in public memory the name of the company that developed the CT scanner. PMID- 22446353 TI - Effect of in utero exposure of iodinated intravenous contrast on neonatal thyroid function. AB - PURPOSE: Administration of radioactive iodine to a pregnant woman for thyroid ablation has been shown to affect neonatal thyroid levels. Thus, there is a theoretical risk in affecting a neonate's thyroid level upon birth with prior administration of intravenous contrast containing iodine to a pregnant woman during a computed tomographic scan. However, there is no literature to support this theoretical risk. This study attempted to determine if there is any effect on a newborn's thyroid levels after exposure to this type of contrast material in utero. MATERIALS AND METHODS: The medical charts of 96 pregnant women during the years 2004 through 2009 on whom computed tomographic scans were performed were reviewed. A total of 29 charts were excluded secondary to missing neonatal records, missed abortions, and intrauterine fetal demise. The rest were subdivided into those who received intravenous (IV) +/- oral contrast material and those who did not. The medical records of the newborns of these patients were also reviewed. The subject group consisted of 61 pregnant women who received IV +/- oral contrast and their 64 neonates. The control group consisted of 6 pregnant patients who did not receive IV contrast and their 6 neonates. RESULTS: Of the 64 neonates in the subject group, only one neonate was found to have a low thyroxine level with a normal thyroid stimulating hormone level. This infant was severely premature, being born at the 25th week of gestation, and developed respiratory distress syndrome and sepsis, which were potential confounding factors. All of the 6 neonates in the control group had normal thyroid levels. CONCLUSION: This study concludes that there is no significant adverse clinical risk of thyroid function abnormalities to the fetus after IV iodinated contrast material to their mothers. PMID- 22446354 TI - Idiopathic nonspecific interstitial pneumonia: changes in high-resolution computed tomography on long-term follow-up. AB - OBJECTIVE: This study aimed to assess the change in findings of nonspecific interstitial pneumonia (NSIP) from high-resolution computed tomography (HRCT) on long-term follow-up (median, 38 months). MATERIALS AND METHODS: A retrospective review of changes in HRCT in 68 patients with NSIP (fibrotic progression, 61) with follow-up HRCT of at least 1-year interval was conducted. RESULTS: Follow-up HRCT findings showed a decreased extent of ground-glass opacity and consolidation, with increased honeycombing, traction bronchiectasis, and architectural distortion (all P < 0.05). Radiological improvement was seen in 36%, stability was seen in 23%, and fibrotic progression was seen with recurrence in 13% and without recurrence in 28%. In 3 patients (4.9%), HRCT converted to a definite usual interstitial pneumonia pattern. Honeycombing and reticulation were independent predictors for mortality in fibrotic NSIP (P < 0.01). CONCLUSIONS: Although most of the follow-up HRCT scans showed improvement in the extent of ground-glass opacity and consolidation, approximately one third showed fibrotic progression or recurrence, with transition from NSIP to definite usual interstitial pneumonia pattern. PMID- 22446355 TI - Multidetector computed tomography for detection and characterization of pulmonary hypertension in consideration of WHO classification. AB - OBJECTIVE: We evaluated the reliability of various multidetector computed tomography (MDCT) parameters for diagnosis and severity assessment of pulmonary hypertension (PH) with consideration of World Health Organization (WHO) classification. METHODS: A total of 172 patients were included in this retrospective study. One hundred fourteen patients had a diagnosis of PH (mean pulmonary artery pressure >=25 mm Hg), and 58 patients without PH (mean pulmonary artery pressure <20 mm Hg) served as control subjects. The patients with PH were grouped according to the WHO classification based on PH etiology. RESULTS: The patients with PH had significantly greater main, left, and right pulmonary artery diameters than the control subjects (P < 0.001). No significant differences within the PH subgroups were found. Receiver operating characteristic analysis showed reasonable sensitivity and specificity for selected MDCT parameters. The severity of PH did not correlate with MDCT parameters. CONCLUSIONS: Easy-to determine MDCT parameters allow detection of PH independent of the WHO group. In patients with dilated aorta, the vertebra can be an alternative internal standard. Severity of PH cannot be estimated by MDCT parameters. PMID- 22446356 TI - Serial 3-dimensional volumetric computed tomography evaluation of lung cancer growth rate in patients with chronic obstructive pulmonary disease findings. AB - PURPOSE: The objectives of this study were to compare volume doubling time (VDT) of lung cancer with chronic obstructive pulmonary disease (COPD) findings with that without COPD findings using serial 3-dimensional (3D) volumetric computed tomography (CT) and to investigate the association between VDT and COPD findings. METHODS: This study included 45 patients with surgically diagnosed non-small cell lung cancer with serial preoperative follow-up CT. Volume doubling time of the nodule was calculated by using 3D volumetric computer software. RESULTS: Volume doubling time of lung cancer with COPD findings (n = 26) tended to be shorter than that without COPD findings (n = 19) (998 +/- 2178 vs 2226 +/- 6748 days; P = 0.066). Among COPD findings, severity and pattern of emphysema were significantly correlated with VDT (P < 0.001). CONCLUSIONS: Volume doubling time of lung cancer with COPD findings on 3D volumetric CT tended to be shorter than that of lung cancer without COPD findings. Severe or paraseptal emphysema may be associated with short VDT of lung cancer with COPD findings. PMID- 22446357 TI - Prospective evaluation of unsuspected pulmonary embolism on coronary computed tomographic angiography. AB - OBJECTIVE: This study aimed to analyze patients with unsuspected pulmonary embolism (PE) in coronary computed tomographic angiography (CCTA) and to draw some conclusions regarding their characteristics. METHODS: All patients suspected of coronary heart disease undergoing CCTA between May 2006 and December 2010 were prospectively analyzed. Patients with previous or suspected current PE were excluded. The CCTA images were reviewed, and the degree of contrast enhancement and the presence or absence of PE were recorded. Where PE was found, the level of the most proximal thrombus was identified. Patients' demographics were recorded. RESULTS: Of 7287 patients, 65 had unsuspected PE--an overall incidence of 0.9% (1.3% among inpatients and 0.3% among outpatients). Unsuspected PE was more common with increasing age, occurring in 0.4% of all patients younger than 60 years and 1.2% (52/4203) of those older than 60 years (P < 0.05). Of the 65 scans positive for disease, 43 (66.2%) were at the segmental or the subsegmental level. Patients with paroxysmal atrial fibrillation (AF) or AF history and cardiac insufficiency (3.2% and 4.1%) were more likely to have an unsuspected PE compared with those without (0.7%), and this was supported by the statistics. Deep vein thrombosis of the lower extremity was found in 8 (13.1%) of 61 patients with PE and in 12 (19.4%) of 62 patients with a D-dimer level of 500 ng/mL or higher. CONCLUSIONS: Unsuspected PE was found in 0.9% of all patients undergoing CCTA, and this kind of PE has its own characteristics compared with the typical PE from the literature. Radiologists should routinely analyze the pulmonary arteries in all patients undergoing CCTA, especially for older patients and the patients with AF or AF history and cardiac insufficiency. PMID- 22446358 TI - Lower iodine load in routine contrast-enhanced CT: an alternative imaging strategy. AB - OBJECTIVE: To demonstrate an alternative imaging strategy for routine thoracic computed tomography using low intravenous contrast volume. METHODS: Based on radiologists' clinical judgment, 61 thoracic computed tomographic examinations were performed using 15 mL of iohexol intravenous contrast. Indications included patients with relative con traindications to contrast, American College of Radiology appropriateness rating of 1 to 6 for contrast, rating of 7 or greater for contrast with a modifying condition, and cases without specific rating in which contrast may have been useful although not mandatory. Images were retrospectively reviewed to determine adequacy as part of an American Board of Radiology Practice Quality Improvement project. Ascending aorta and right and left pulmonary artery enhancement was measured and compared to most recent routine contrast protocol examination if available. RESULTS: All studies were adequate for evaluation of the given indication. Degree of vascular opacification was sufficient for discriminating between mediastinal structures. Computed tomography number (Hounsfield units) +/- standard deviation using 15 mL of contrast compared to routine protocol was 134 +/- 47.8 and 240.8 +/- 86.6 in ascending aorta, 109.6 +/- 47.6 and 185 +/- 59.3 in right pulmonary artery, and 112 +/- 50 and 186 +/- 56.3 in left pulmonary artery, respectively. Mean difference in computed tomography number was significant. Low contrast dose studies demonstrated relatively decreased soft tissue enhancement. CONCLUSIONS: The 15-mL protocol results in reduced vascular and soft tissue enhancement; however, reasonable-quality images are obtained that are diagnostic for a wide range of indications, namely, those involving thoracic inlet, mediastinal, and hilar structures. PMID- 22446359 TI - Magnetic resonance imaging of the breast in evaluating residual diseases at lumpectomy site soon after excisional biopsy. AB - OBJECTIVE: To evaluate the role of magnetic resonance imaging (MRI) in the detection of residual disease for patients after excisional biopsy of breast carcinoma, before re-excision. MATERIALS AND METHODS: We performed a retrospective review of 97 patients who underwent MRI soon after excisional biopsy of breast carcinoma with undeterminable margin status before further surgical intervention to determine the value of MRI in detecting residual disease. RESULTS: The positive predictive value was 50.0%. The negative predictive value was 78.9%. The MRI detected 54.5% of the residual disease for invasive ductal carcinoma and 100% for ductal carcinoma in situ. Positive predictive value and sensitivity for MRI conducted within 14 days of the original surgery were lower than those for MRI conducted after 14 days of the original surgery, being 31.6% and 46.2% versus 66.7% and 73.4%, respectively. The difference between the positive predictive value within 14 days versus after 14 days was statistically significant. CONCLUSION: Magnetic resonance imaging in detecting residual disease soon after excisional biopsy for breast carcinoma had a low positive predictive value and moderately high negative predictive value. Magnetic resonance imaging was more sensitive in detecting residual ductal carcinoma in situ than invasive ductal carcinoma. Magnetic resonance imaging conducted more than 14 days after the original biopsy had a significantly higher positive predictive value than MRI done within 14 days. PMID- 22446360 TI - Magnetic resonance imaging patterns of tumor regression after neoadjuvant chemotherapy in breast cancer patients: correlation with pathological response grading system based on tumor cellularity. AB - PURPOSE: The objectives of the study were to analyze the tumor shrinkage pattern on magnetic resonance imaging (MRI) after neoadjuvant chemotherapy and to evaluate whether there is any difference in shrinkage pattern between pathological responder and nonresponder groups. In addition, we wanted to compare tumor diameter obtained from MRI with histological diameter according to the tumor shrinkage pattern. METHODS: Between July 2008 and December 2010, 55 consecutive patients (56 lesions) with pathologically proven breast cancer who underwent neoadjuvant chemotherapy followed by surgery were retrospectively enrolled. The shrinkage pattern was classified into 4 categories: I (concentric shrinkage without surrounding lesion), II (concentric shrinkage with surrounding lesions), III (shrinkage with residual multinodular lesions, and IV (diffuse contrast enhancement in whole quadrants). Histological regression was scored on a 5-point scale regarding tumor cellularity reduction (Miller-Payne grading system). Patients with Miller-Payne grade 1 or 2 were classified into the nonresponder group, and patients with grade 3, 4, or 5 were in the responder group. RESULTS: Of 56 lesions, pattern I was seen in 29 lesions, pattern II in 13 lesions, pattern III in 5 lesions, and pattern IV in 4 lesions. Three lesions were not visualized on MRI after neoadjuvant chemotherapy, and 2 lesions were increased in size. There was a statistically significant difference in the tumor shrinkage pattern between responder and nonresponder groups (P = 0.017). All 5 lesions with type III shrinkage pattern were found in the responder group, and all 4 lesions with pattern IV were in the nonresponder group. Magnetic resonance imaging diameter of lesions with types I, II, and IV patterns showed significant correlation with the histological diameter. Among them, the correlation factor was highest in pattern IV (rho = 0.94, P < 0.001) followed by pattern I (rho = 0.67, P < 0.01) and pattern II (rho = 0.502, P = 0.08). However, in type III shrinkage pattern, tumor size measured on MRI was not significantly correlated with histological size (P = 0.87). CONCLUSIONS: Types III and I shrinkage patterns were more frequently observed in the pathological responder group, and type IV was more frequently noted in the nonresponder group. Tumor diameter measured on MRI showed strong correlation with histological diameter in lesions with types I and IV shrinkage patterns, whereas lesions with type III did not show significant correlation. Type II pattern showed similar frequencies between the 2 groups and moderate correlation between sizes obtained from MRI and histology. PMID- 22446361 TI - Abdominal manifestations of extraosseous myeloma: cross-sectional imaging spectrum. AB - Extraosseous myeloma, defined as the myelomatous involvement outside the skeleton system, is rare and often associated with advanced multiple myeloma. There has been a recent increase in the clinicoradiological incidence of this entity, possibly secondary to increased survival of patients and frequent use of imaging. This has led to the development of new clinical staging guidelines for multiple myeloma, which include the use of imaging modalities positron emission tomography/computed tomography and magnetic resonance imaging for accurate detection and optimal management. The aims of this review were to discuss the significance of identification of extraosseous disease, to describe the spectrum and common sites of extraosseous involvement in the abdomen, and to review the imaging findings of extraosseous myeloma in the abdomen. PMID- 22446362 TI - Multidetector computed tomography triphasic evaluation of the liver before transplantation: importance of equilibrium phase washout and morphology for characterizing hypervascular lesions. AB - OBJECTIVE: We aim to identify the sensitivity and positive predictive value (PPV) of arterial phase imaging in detecting hepatocellular carcinoma (HCC) and determine the added value of portal venous and equilibrium phase imaging and lesion morphology characterization. METHODS: We reviewed all patients who underwent liver transplantation at our institution that had a triphasic multidetector computed tomography examination within 6 months of transplantation. Forty-seven hypervascular lesions were identified in 24 patients. Imaging findings were correlated with explant pathologic correlation. RESULTS: Hypervascularity in the arterial phase resulted in sensitivity of 87.5% and PPV of 29.8%. The presence of washout in the equilibrium phase increased the PPV to 92.9% with a slight decrease in sensitivity (81.3%). The negative predictive value of hypervascular lesions without washout in the equilibrium phase was 97.1%. There was significant correlation between larger lesions and HCC and between round lesions and HCC. CONCLUSIONS: The presence of washout in the equilibrium phase is a better indicator of malignancy. PMID- 22446363 TI - Variation in hepatic segmental volume distribution according to different causes of liver cirrhosis: CT volumetric evaluation. AB - OBJECTIVE: To investigate if there is difference in hepatic segmental volume distribution according to causes of liver cirrhosis (LC) using computed tomography volumetric analysis. METHODS: On computed tomographic scans, hepatic segmental volumes were measured in 90 patients with LC of 4 different causes (alcohol, hepatitis B virus (HBV), hepatitis C virus (HCV), and cryptogenic cirrhosis). The volumetric indices were compared. RESULTS: The volume proportion of the lateral segment in the liver in patients with HBV was significantly higher than in the patients with HCV (P = 0.038). Hepatic volume distribution in alcoholic LC showed differences: larger caudate lobe volume than HBV- and HCV induced LC (P = 0.029 and P = 0.031), larger right lobe volume (P = 0.043) and smaller proportion of the lateral segment in the liver (P = 0.003) than in HBV induced LC. CONCLUSIONS: Computed tomography volumetric analysis showed differences in hepatic segmental volume distribution in cirrhotic patients according to causes of LC. PMID- 22446364 TI - Computed tomographic perfusion imaging for the therapeutic response of chemoembolization for hepatocellular carcinoma. AB - BACKGROUND: Computed tomographic (CT) perfusion imaging has been applied in many clinical areas, but few studies have addressed the values of CT perfusion imaging in evaluating the therapeutic response of chemoembolization for hepatocellular carcinoma (HCC). OBJECTIVE: To assess the perfusion changes of HCC after transarterial chemoembolization, and to investigate the values of CT perfusion imaging in chemoembolization procedure. METHODS: Multidetector computed tomographic perfusion imaging was performed in 24 patients with HCC 1 week before and 4 weeks after chemoembolization. The CT perfusion parameters, including hepatic arterial perfusion (HAP), hepatic portal perfusion (HPP), total liver perfusion (TLP), and hepatic arterial perfusion index (HAPI), were calculated by using the slope method. The t statistic was used to analysis the difference of CT perfusion parameter values before and after chemoembolization therapy. RESULTS: The values of HAP, TLP, and HAPI in tumors 4 weeks after chemoembolization were significantly decreased than those before chemoembolization (P < 0.05), but the value of HPP in tumors was not (P > 0.05). CONCLUSION: Computed tomographic perfusion imaging has the ability to evaluate the perfusion changes in HCC after chemoembolization, which can be used to evaluate the therapeutic response of chemoembolization for hepatocellular carcinoma. PMID- 22446365 TI - Differentiation of pancreatic serous cystadenoma from endocrine tumor and intraductal papillary mucinous neoplasm based on washout pattern on multiphase CT. AB - OBJECTIVE: To evaluate the washout (WO) pattern of serous cystadenomas (SCAs) compared with endocrine tumors (ETs) and intraductal papillary mucinous neoplasm (IPMN). METHODS: Patients with serous cystadenoma (n = 12), ET (n = 29), and IPMN (n = 35) underwent 4-phase computed tomography CT. Tumors were categorized as hyperdense or hypodense. Computed tomographic values measured were unenhanced attenuation (AU), pancreatic attenuation (A12, 12 seconds), portal attenuation (A35), and equilibrium (A158). Computed tomographic parameters calculated were wash-in (WI) = A12 - AU; WO = A12 - A35; and washout ratio (WOR) = WO/WI * 100/22. RESULTS: Hyperdense SCAs had significantly higher WOR than did hyperdense ETs (P = 0.001). Among the 3 hypodense tumors, SCAs had the significantly highest WOR (P < 0.05/3). Relative to the pancreas, the WOR of SCAs were equivalent, whereas the WOR of ETs and IPMNs were significantly lower. CONCLUSIONS: Hyperdense SCAs had significantly higher WOR than did hyperdense ETs, and hypodense SCAs had the significantly highest WOR among the three. PMID- 22446366 TI - Computed tomography perfusion analysis of pancreatic carcinoma. AB - OBJECTIVE: The purpose of this study was to evaluate CT perfusion of pancreatic carcinomas using the Patlak model for assessing perfusion, permeability, and blood volume. METHODS: A total of 25 patients with pancreatic carcinoma were examined prospectively with a 64-slice computed tomography (CT) using a dynamic sequence after intravenous injection of 80-mL contrast material (370 mg/mL; flow rate, 5 mL/s). Eighty-kilovolt (peak) perfusion acquisitions were evaluated for estimating perfusion parameters for carcinoma and healthy tissue using a 2 compartment model (Patlak model). RESULTS: Twenty patients had hypodense tumors; in 5 patients, the tumor could not be delineated in contrast-enhanced CT. All carcinomas could be identified clearly in the color-coded perfusion maps. Perfusion, permeability, and blood volume values were significant lower in pancreatic carcinomas compared to healthy pancreatic tissue (0.27 +/- 0.20 vs 0.89 +/- 0.19 min, P < 0.0001; 0.43 +/- 0.20 vs 0.75 +/- 0.16 * 0.5 min, P < 0.0001; and 38.9 +/- 20.7 vs 117.8 +/- 46.9 mL/100 mL, P < 0.0001). CONCLUSION: Computed tomographic perfusion of the pancreas using a 2-compartment perfusion model is feasible. Color-coded perfusion maps could be a helpful tool to delineate pancreatic carcinomas even if they are not visible in contrast-enhanced CT. PMID- 22446367 TI - Clinical significance of bladder urothelial thickening and enhancement revealed on MDCT urography after transurethral resection of tumor. AB - OBJECTIVE: To assess multidetector-row computed tomographic (MDCT) urography for detection of recurrence of bladder tumor after transurethral resection (TUR), and to assess significance of the MDCT findings like urothelial enhancement or thickening as a recurrence. METHODS: A total of 216 MDCT urography examinations were performed for 100 patients undergoing follow-up after TURs were reviewed by 2 radiologists, according to MDCT findings (urothelial enhancement or thickening) and location (TUR site or distant sites of transitional cell carcinoma). Multidetector-row CT urography was confirmed by cystoscopy and urine cytologic examination. Analyses of per-MDCT urography and per-lesion basis were performed, assessing receiver operating characteristic analysis for combining excretory phases to noncontrast and portal venous phases. RESULTS: Fifty-two MDCT findings were positive, and 164 MDCT findings were negative. Of the 52 positive MDCT urography, 19 were true positive 33 were false positive. Of the 60 separate lesions, 25 lesions were true positive. Both urothelial enhancement and thickening were revealed in 19 lesions, urothelial enhancement in 4 lesions, and urothelial thickenings in 2 lesions. Nineteen lesions were revealed in TUR site, and 6 lesions were revealed in distant site of transitional cell carcinoma. For MDCT urography combining excretory phases to noncontrast and portal venous phases, a substantial agreement between radiologists was revealed (area under the curve; 0.910 +/- 0.035, 0.749 +/- 0.055; 8.3%; kappa score of 0.65). CONCLUSIONS: Multidetector-row CT urography has efficacy in detecting recurrence of bladder tumor in patients undergoing follow-up after TUR. PMID- 22446368 TI - Magnetic resonance imaging of cervical ectopic pregnancy in the second trimester. AB - OBJECTIVE: To describe the magnetic resonance imaging findings of cervical ectopic pregnancy in the second trimester. CONCLUSIONS: Magnetic resonance imaging findings of cervical ectopic pregnancy in the second trimester include intracervical location of the fetus, endometrial hyperplasia within an otherwise empty endometrial cavity, and irregular placentation in the cervix. Correct recognition of the condition is critical because of the potential for catastrophic and life-threatening maternal bleeding. PMID- 22446369 TI - Intravaginal gel for staging of female pelvic cancers--preliminary report of safety, distention, and gel-mucosal contrast during magnetic resonance examination. AB - To more fully outline cervical and vaginal contours and distend the vagina, we have filled the vagina with sterile water-based gel before the magnetic resonance (MR) examination. The technique is similar to that used for defecating MR proctography and other MR examinations, but has not been well described for MR imaging of female pelvic cancer. We present our preliminary clinical experience, including a review of safety imaging characteristics and maintenance of the distention during the examination. PMID- 22446370 TI - Hematoma after femoral arterial blood sampling: incidence, imaging features, and course of hematoma. AB - OBJECTIVE: This study evaluated the incidence and course of a hematoma occurring after femoral arterial sampling. MATERIALS AND METHODS: We studied 270 patients who underwent computed tomography (CT) including the pelvis and blood gas sampling from femoral artery using a 22-gauge needle during 2010. This population comprised 176 men and 94 women with a mean (SD) age of 54.9 (24.3) years (range, 0-97 years). We evaluated whether hematoma was present at the femoral artery. Size and location of the hematoma, the short-axial luminal diameter of artery contact with the hematoma was also assessed. RESULTS: The CT images showed hematoma around the femoral artery in 128 patients (47.4%); this group comprised 84 men and 44 women with a mean (SD) age of 51.1 (24.1) years (range, 0-92 years). Hematoma was not observed in 142 patients (52.6%; 92 men and 50 women; mean [SD] age, 58.3 [24.2] years; range, 0-97 years). There was no significant difference in age, sex, altered hemostasis, or time between arterial puncture and CT between the 2 groups with or without hematoma. Arterial stenosis of 50% or greater was observed in 7 patients (mean [SD] age, 17.1 [8.97] years; range, 6-31 years; 4 males and 3 females). CONCLUSIONS: Our data revealed a high frequency of small hematoma around the femoral artery is following arterial blood sampling that was independent of bleeding diathesis. No patient progressed to a severe condition, although temporary arterial stenosis did occur. PMID- 22446371 TI - Ureteral intussusception: a case report and literature review. AB - We present the case of a 64-year-old man with intussusception of the right ureter as a complication of an underlying transitional cell carcinoma. To our knowledge, this is the first case report that illustrates ureteral intussusception by both multidetector computerized tomography and magnetic resonance imaging. Although ureteral intussusceptions are thought to be associated with benign masses, our comprehensive review of the literature demonstrates that almost half of the cases are associated with underlying malignancy. PMID- 22446372 TI - Computed inverse resonance imaging for magnetic susceptibility map reconstruction. AB - OBJECTIVE: This article reports a computed inverse magnetic resonance imaging (CIMRI) model for reconstructing the magnetic susceptibility source from MRI data using a 2-step computational approach. METHODS: The forward T2*-weighted MRI (T2*MRI) process is broken down into 2 steps: (1) from magnetic susceptibility source to field map establishment via magnetization in the main field and (2) from field map to MR image formation by intravoxel dephasing average. The proposed CIMRI model includes 2 inverse steps to reverse the T2*MRI procedure: field map calculation from MR-phase image and susceptibility source calculation from the field map. The inverse step from field map to susceptibility map is a 3 dimensional ill-posed deconvolution problem, which can be solved with 3 kinds of approaches: the Tikhonov-regularized matrix inverse, inverse filtering with a truncated filter, and total variation (TV) iteration. By numerical simulation, we validate the CIMRI model by comparing the reconstructed susceptibility maps for a predefined susceptibility source. RESULTS: Numerical simulations of CIMRI show that the split Bregman TV iteration solver can reconstruct the susceptibility map from an MR-phase image with high fidelity (spatial correlation ~ 0.99). The split Bregman TV iteration solver includes noise reduction, edge preservation, and image energy conservation. For applications to brain susceptibility reconstruction, it is important to calibrate the TV iteration program by selecting suitable values of the regularization parameter. CONCLUSIONS: The proposed CIMRI model can reconstruct the magnetic susceptibility source of T2*MRI by 2 computational steps: calculating the field map from the phase image and reconstructing the susceptibility map from the field map. The crux of CIMRI lies in an ill-posed 3-dimensional deconvolution problem, which can be effectively solved by the split Bregman TV iteration algorithm. PMID- 22446373 TI - The five-vessel arch: independent origin of both vertebral arteries from the aortic arch. AB - An independent origin of the left vertebral artery from the aortic arch is the second most common aortic arch anomaly and occurs in 7% of otherwise healthy persons. Bilateral and independent origins of vertebral arteries are distinctly unusual. We present and illustrate such a case. PMID- 22446374 TI - Imaging of glaucoma drainage devices. AB - Previously reserved for patients with refractory glaucoma, glaucoma drainage devices (GDDs) are being used more frequently as a primary treatment option. Several types of GDDs are currently manufactured, only one of which is radiopaque. Knowledge of their typical imaging appearance in addition to pertinent background information is therefore vital for radiologists. We present a case of bilateral glaucoma drainage devices and briefly review the surgical aspect of implantation. PMID- 22446375 TI - Deformable anatomic templates embed knowledge into brain images: part 2. Validation using functional magnetic resonance imaging of the motor hand. AB - OBJECTIVE: This study evaluated the concordance between the Deformable Anatomic Template (DAT)-identified origin of motor hand fibers and localization of the motor cortex of the hand by functional magnetic resonance imaging (fMRI). METHODS: Preoperative fMRI during hand motor tasks was performed on 36 hemispheres in 26 patients with gliomas in or near eloquent areas. Reformatted volume-rendered surface images were labeled with the DAT's hand motor fibers and fMRI data. Five reviewers assessed the data for concordance. RESULTS: Available fMRI data were diagnostically usable in 92% (33/36 analyzed hemispheres), with DAT anatomic accuracy in the remaining cases. The DAT prediction and fMRI findings were concordant in all 9 normal hemispheres and in 20 (83%) of 24 glioma bearing hemispheres. The 4 discordant cases resulted from substantial mass effect by large frontal tumors. CONCLUSIONS: This study validated DAT's anatomic atlas and alignment process for the expected position of the motor cortex of the hand. PMID- 22446376 TI - Different endocytic functions of AGEF-1 in C. elegans coelomocytes. AB - BACKGROUND: ADP-ribosylation factors (ARFs) are a family of small GTP-binding proteins that play roles in membrane dynamics and vesicle trafficking. AGEF-1, which is thought to act as a guanine nucleotide exchange factor of class I ARFs, is required for caveolin-1 body formation and receptor-mediated endocytosis in oocytes of Caenorhabditis elegans. This study explores additional roles of AGEF-1 in endocytic transport. METHODS: agef-1 expression was knocked down by using RNAi in C. elegans. Markers that allow analysis of endocytic transport in scavenger cells were investigated for studying the effect of AGEF-1 on different steps of membrane transport. RESULTS: Knockdown of AGEF-1 levels results in two apparent trafficking defects in coelomocytes of C. elegans. First, there is a delay in the uptake of solutes from the extracellular medium. Second, there is a dramatic enlargement of the sizes of lysosomes, even though lysosomal acidification is normal and degradation still occurs. CONCLUSION: Our results suggest that AGEF-1 regulates endosome/lysosome fusion or fission events, in addition to earlier steps in endocytic transport. GENERAL SIGNIFICANCE: AGEF-1 is the first identified GTPase regulator that functions at the lysosome fusion or fission stage of the endocytic pathway. Our study provides insight into lysosome dynamics in C. elegans. PMID- 22446377 TI - Sequence determination and anticoagulant and antithrombotic activities of a novel sulfated fucan isolated from the sea cucumber Isostichopus badionotus. AB - BACKGROUND: The aim is to analyze the structure, anticoagulant and antithrombotic activities of a sulfated fucan isolated from sea cucumber Isostichopus badionotus (fucan-Ib). METHODS: Fucan-Ib was hydrolyzed under mild acid conditions. The oligosaccharide fragments were fractionated by gel-filtration chromatography and the structures were determined by negative-ion electrospray tandem mass spectrometry with collision-induced dissociation and two-dimensional NMR. Anticoagulant activities were measured by activated partial thromboplastin, thrombin and prothrombin times, and by in vitro inhibition experiments with factors IIa and Xa. Antithrombotic activities were determined in vitro by measuring the length and weight of the thrombus generated. RESULT: The linear polysaccharide sequence of fucan-Ib was deduced from the structures of its oligosaccharide fragments produced by acid hydrolysis. Under mild conditions, the glycosidic bonds between the non-sulfated and 2,4-O-disulfated fucose residues were selectively cleaved and highly ordered oligosaccharide fragments with a tetrasaccharide repeating unit [->3Fuc(2S,4S)alpha1->3Fuc(2S)alpha1 >3Fuc(2S)alpha1->3Fucalpha1->]n were obtained. In in vitro assays fucan-Ib showed good anticoagulant and antithrombotic activities compared with heparin and the fucosylated chondroitin sulfate isolated from the same source (fCS-Ib). The two polysaccharides, fucan-Ib and fCS-Ib, differ in the mechanism of action; the former exhibited activity mainly by potentiation of antithrombin acted on thrombin and factor Xa whereas the latter mainly through heparin cofactor II. CONCLUSION: Fucan-Ib has a well defined structure with tetrasaccharide tandem repeats and good anticoagulant and antithrombotic activities. GENERAL IMPORTANCE: Fucan-Ib has a well defined structure and can be readily quality-controlled, and therefore has potential therapeutic value as an affective antithrombotic drug with low risk of bleeding. PMID- 22446378 TI - Induction of 6-sulfated glycans with cell adhesion activity via T-bet and GATA-3 in human helper T cells. AB - BACKGROUND: Cell surface 6-sulfated glycans play important roles in various immunological events through cell-to-cell interactions. The 6-sulfation process is mediated by 6-sulfotransferase family isoenzymes. We previously demonstrated that GlcNAc6ST-1, one of the isoenzyme genes, is induced by GATA-3 and NF-kappaB in human helper T (Th) cells. However, transcriptional regulation of HEC GlcNAc6ST, another isoenzyme important in Th cells, remains unclear. METHODS: 5' RACE analysis, chromatin immunoprecipitation, and reporter assays were performed to reveal transcriptional regulation of HEC-GlcNAc6ST. RNA-knockdown and forced expression experiments were performed to demonstrate the contribution of HEC GlcNAc6ST to the 6-sulfated glycan expression. RESULTS: We identified potential binding sites of Sp1, T-bet, and GATA-3 in the HEC-GlcNAc6ST promoter. Reporter assays indicated that transfection of Sp1 enhanced the activity, whereas mithramycin A, an Sp1-specific inhibitor, repressed it. Transfection of T-bet increased the activity, which was inhibited by introducing a mutation into the potential T-bet binding site. GATA-3 alone could not elevate the activity, although co-transfection of protein kinase A, which is known to enhance IL-5 transcription in Th2 cells through phosphorylation of GATA-3, caused elevation. RNA-knockdown and forced expression of HEC-GlcNAc6ST in Jurkat cells down- and up regulated alpha2,6-sialylated 6-sulfo N-acetyllactosamine, a preferential ligand for B-cell-specific CD22 antigen, respectively. From these results, we concluded that T-bet and GATA-3 as well as Sp1 control the expression of glycan with cell adhesion activity by regulating HEC-GlcNAc6ST transcription in Th cells. GENERAL SIGNIFICANCE: These results may provide a clue to biological regulation of Th cell interaction with selectins and other carbohydrate-recognition molecules by T bet and GATA-3. PMID- 22446379 TI - Comparison of Pause Predictions of Two Sequence-Dependent Transcription Models. AB - Two recent theoretical models, Bai et al. (2004, 2007) and Tadigotla et al. (2006), formulated thermodynamic explanations of sequence-dependent transcription pausing by RNA polymerase (RNAP). The two models differ in some basic assumptions and therefore make different yet overlapping predictions for pause locations, and different predictions on pause kinetics and mechanisms. Here we present a comprehensive comparison of the two models. We show that while they have comparable predictive power of pause locations at low NTP concentrations, the Bai et al. model is more accurate than Tadigotla et al. at higher NTP concentrations. Pausing kinetics predicted by Bai et al. is also consistent with time-course transcription reactions, while Tadigotla et al. is unsuited for this type of kinetic prediction. More importantly, the two models in general predict different pausing mechanisms even for the same pausing sites, and the Bai et al. model provides an explanation more consistent with recent single molecule observations. PMID- 22446380 TI - APOBEC3B and AID have similar nuclear import mechanisms. AB - Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage. PMID- 22446381 TI - Fragmentation-tree density representation for crystallographic modelling of bound ligands. AB - The identification and modelling of ligands into macromolecular models is important for understanding molecule's function and for designing inhibitors to modulate its activities. We describe new algorithms for the automated building of ligands into electron density maps in crystal structure determination. Location of the ligand-binding site is achieved by matching numerical shape features describing the ligand to those of density clusters using a "fragmentation-tree" density representation. The ligand molecule is built using two distinct algorithms exploiting free atoms with inter-atomic connectivity and Metropolis based optimisation of the conformational state of the ligand, producing an ensemble of structures from which the final model is derived. The method was validated on several thousand entries from the Protein Data Bank. In the majority of cases, the ligand-binding site could be correctly located and the ligand model built with a coordinate accuracy of better than 1 A. We anticipate that the method will be of routine use to anyone modelling ligands, lead compounds or even compound fragments as part of protein functional analyses or drug design efforts. PMID- 22446382 TI - Substrate-dependent millisecond domain motions in DNA polymerase beta. AB - DNA polymerase beta (Pol beta) is a 39-kDa enzyme that performs the vital cellular function of repairing damaged DNA. Mutations in Pol beta have been linked to various cancers, and these mutations are further correlated with altered Pol beta enzymatic activity. The fidelity of correct nucleotide incorporation into damaged DNA is essential for Pol beta repair function, and several studies have implicated conformational changes in Pol beta as a determinant of this repair fidelity. In this work, the rate constants for domain motions in Pol beta have been determined by solution NMR relaxation dispersion for the apo and substrate-bound, binary forms of Pol beta. In apo Pol beta, molecular motions, primarily isolated to the DNA lyase domain, are observed to occur at 1400 s(-1). Additional analysis suggests that these motions allow apo Pol beta to sample a conformation similar to the gapped DNA-substrate-bound form. Upon binding DNA, these lyase domain motions are significantly quenched, whereas evidence for conformational motions in the polymerase domain becomes apparent. These NMR studies suggest an alteration in the dynamic landscape of Pol beta due to substrate binding. Moreover, a number of the flexible residues identified in this work are also the location of residues, which upon mutation lead to cancer phenotypes in vivo, which may be due to the intimate role of protein motions in Pol beta fidelity. PMID- 22446383 TI - The role of CUGBP1 in age-dependent changes of liver functions. AB - Aging liver is characterized by alterations of liver biology and by a reduction of many functions which are important for the maintenance of body homeostasis. The main dysfunctions include appearance of enlarged hepatocytes, impaired liver regeneration after partial hepatectomy (PH), development of hepatic steatosis, reduction of secretion of proteins and alterations in the hepatic sinusoid. RNA binding proteins are involved in the regulation of gene expression in all tissues including regulation of biological processes in the liver. This review is focused on the role of a conserved, multi-functional RNA-binding protein, CUGBP1, in the development of aging phenotype in the liver. CUGBP1 has been identified as a protein which binds to RNA CUG repeats expanded in Myotonic Dystrophy type 1 (DM1). CUGBP1 is highly expressed in the liver and regulates translation of proteins which are critical for maintenance of liver functions. In livers of young mice, CUGBP1 forms complexes with eukaryotic translation initiation factor eIF2 and supports translation of C/EBPbeta and HDAC1 proteins, which are involved in liver growth, differentiation and liver cancer. Aging changes several signaling pathways which lead to the elevation of the CUGBP1-eIF2alpha complex and to an increase of translation of C/EBPbeta and HDAC1. These proteins form multi-protein complexes with additional transcription factors and with chromatin remodeling proteins causing epigenetic alterations of gene expression in livers of old mice. It appears that CUGBP1-mediated translational elevation of HDAC1 is one of the key events in the epigenetic changes in livers of old mice, leading to the development of age-associated dysfunctions of the liver. This review will also discuss a possible role of CUGBP1 in liver dysfunction in patients affected with DM1. PMID- 22446384 TI - Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models. AB - Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinical testing is a challenge that has not yet been met although tremendous advances have been made. A combined approach of cell culture and mouse models of human cancer is most likely to predict the efficacy of novel anti-cancer treatments in human clinical trials. PMID- 22446385 TI - A versatile strategy for tuning the color of electrochemiluminescence using silica nanoparticles. AB - Colour emission of core-shell silica-PEG nanoparticles in water is tuned with an electrochemically induced energy transfer approach. The lack of solubility problems, side electrochemical reactions involving donors and acceptors within the nanoparticle, and the possibility of using many classes of dyes in ECL applications confirm the validity of this strategy. PMID- 22446386 TI - A prospective study of stress and alcohol craving in heavy drinkers. AB - Recent work has examined the relationship between stress and relapse to alcohol use in clinical populations. Few prospective studies, however, have examined stress as a precipitant of alcohol problems. The present study is a longitudinal examination of the role of stress reactivity and alcohol craving in the etiology of alcohol problems in a sample of 41 (mean age=20.8), heavy-drinking, young adults. Participants completed a guided imagery exposure to stressful life events, followed by exposure to a neutral imagery control. Following the exposure, participants completed an alcohol cue exposure paradigm. Measures of negative mood (Profile of Mood States (POMS) depression/dejection scale), tension (POMS tension/anxiety scale) and alcohol craving (measured by the Alcohol Urge Questionnaire (AUQ)) were used as indicators of reactivity to stress and to alcohol cues. Polymorphisms of the corticotropin-releasing hormone binding protein (CRH-BP) gene and of the MU-opioid receptor (OPRM1) gene were examined as moderators of this relationship. Results revealed that stress-induced negative mood predicted negative consequences of drinking (scores on the Drinker's Inventory of Consequences (DrInC-2R)), whereas stress and cue-induced alcohol craving did not predict alcohol use or problems. Additionally, the CRH-BP genotype was found to moderate the relationship between stress-induced negative affect and the negative consequences of drinking. The current study supports and extends laboratory research describing phenotypes of stress-induced alcohol craving. PMID- 22446388 TI - Crystal structure of the human spastin AAA domain. AB - Hereditary spastic paraplegia (HSP) is a motor neuron disease caused by a progressive degeneration of the motor axons of the corticospinal tract. Point mutations or exon deletions in the microtubule-severing ATPase, spastin, are responsible for approximately 40% of cases of autosomal dominant HSP. Here, we report the 3.3 A X-ray crystal structure of a hydrolysis-deficient mutant (E442Q) of the human spastin protein AAA domain. This structure is analyzed in the context of the existing Drosophila melanogaster spastin AAA domain structure and crystal structures of other closely related proteins in order to build a more unifying framework for understanding the structural features of this group of microtubule-severing ATPases. PMID- 22446389 TI - Munc18-1 mutations that strongly impair SNARE-complex binding support normal synaptic transmission. AB - Synaptic transmission depends critically on the Sec1p/Munc18 protein Munc18-1, but it is unclear whether Munc18-1 primarily operates as a integral part of the fusion machinery or has a more upstream role in fusion complex assembly. Here, we show that point mutations in Munc18-1 that interfere with binding to the free Syntaxin1a N-terminus and strongly impair binding to assembled SNARE complexes all support normal docking, priming and fusion of synaptic vesicles, and normal synaptic plasticity in munc18-1 null mutant neurons. These data support a prevailing role of Munc18-1 before/during SNARE-complex assembly, while its continued association to assembled SNARE complexes is dispensable for synaptic transmission. PMID- 22446390 TI - Shaping the role of mitochondria in the pathogenesis of Huntington's disease. AB - Intense research on the pathogenesis of Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, revealed multiple potential mechanisms, among which mitochondrial alterations had emerged as key determinants of the natural history of the disease. Pharmacological and genetic animal models of mitochondrial dysfunction in the striatum, which is mostly affected in HD corroborated a key role for these organelles in the pathogenesis of the disease. Here, we will give an account of the recent evidence indicating that the mitochondria-shaping machinery is altered in HD models and patients. Since its correction can counteract HD mitochondrial dysfunction and cellular damage, drugs impacting on mitochondrial shape are emerging as a new possibility of treatment for this devastating condition. PMID- 22446392 TI - Topological pattern selection in recurrent networks. AB - The impact of adding correlation to a population of neurons on the information and the activity of the population is one of the fundamental questions in recent system neuroscience. In this paper, we would like to introduce topology-based correlation at the level of storing patterns in a recurrent network. We then study the effects of topological patterns on the activity and memory capacity of the network. The general aim of the present work is to show how the repertoire of possible stored patterns is determined by the underlying network topology. Two topological probability rules for pattern selection in recurrent network are introduced. The first one selects patterns according to a Gibbs-type distribution. We start with a Hopfield-type dynamics on a ring model and then a Langevin model on a general random graph is treated. The phenomenon of phase transition in pattern selection motivated us to introduce an alternative topological rule for pattern selection. In a network of N neurons on a random d regular graph, two asymptotic cases, d/N->0 and d/N->1, have been discussed for the new rule, and it is shown that capacity of the network grows considerably as d/N->1. By introducing the notions of asymptotic eigenvector, we will be able to study the behaviour of the discrete model in the limit d/N->0. It will be proved that for degree d less than a critical value there is a positive role for noise, in which case increasing the number of patterns will improve the storage capacity. PMID- 22446391 TI - HIF1alpha induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. AB - The function of metabolic state in stemness is poorly understood. Mouse embryonic stem cells (ESC) and epiblast stem cells (EpiSC) are at distinct pluripotent states representing the inner cell mass (ICM) and epiblast embryos. Human embryonic stem cells (hESC) are similar to EpiSC stage. We now show a dramatic metabolic difference between these two stages. EpiSC/hESC are highly glycolytic, while ESC are bivalent in their energy production, dynamically switching from glycolysis to mitochondrial respiration on demand. Despite having a more developed and expanding mitochondrial content, EpiSC/hESC have low mitochondrial respiratory capacity due to low cytochrome c oxidase (COX) expression. Similarly, in vivo epiblasts suppress COX levels. These data reveal EpiSC/hESC functional similarity to the glycolytic phenotype in cancer (Warburg effect). We further show that hypoxia-inducible factor 1alpha (HIF1alpha) is sufficient to drive ESC to a glycolytic Activin/Nodal-dependent EpiSC-like stage. This metabolic switch during early stem-cell development may be deterministic. PMID- 22446393 TI - Ocular and olfactory forebrain abnormalities within a neonatal alpaca (Vicugna pacos). AB - A 5-day-old Huacaya alpaca cria (Vicugna pacos) was euthanized due to deteriorating health. At birth, the cria had ophthalmologic abnormalities, but had appropriate mentation. At 2 days of age, the cria gradually stopped suckling and began to circle. At 5 days old, the owner elected euthanasia due to declining clinical condition. Grossly, the right iris had a scalloped pupillary margin, and the right olfactory bulb was malformed. Histopathology revealed persistent hyperplastic primary vitreous bilaterally and iridal abnormalities, as well as aplasia of the olfactory ventricle, olfactory tract, and olfactory foramen on the right side. PMID- 22446394 TI - Hematocrit and plasma chemistry values in adult collared scops owls (Otus lettia) and crested serpent eagles (Spilornis cheela hoya). AB - In this study, we report hematocrit and plasma chemistry values for adult captive collared scops owls (Otus lettia) and crested serpent eagles (Spilornis cheela hoya). In particular, we address the gender-specific differences within these values. We measured hematocrit (HCT) and plasma chemistry values for uric acid (UA), plasma urea nitrogen (BUN), total protein (TP), albumin (ALB), glucose (GLU), cholesterol (CHO), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total bilirubin (TBIL), creatine (CRE), creatine phosphokinase (CPK), amylase (AMY), calcium (CA), ionic phosphorous (IP) and sodium (NA), potassium (K) and chloride ions (CL) in 37 adult captive collared scops owls and 39 adult captive crested serpent eagles. Significant differences between the sexes were found for UA, GLU and CPK in the collared scope owls. UA and GLU concentrations were significantly higher (P<0.01 and P<0.05) among males than females, while the CPK concentration was significantly lower (P<0.05) in males. There were no significant differences in of all of the measured parameters between male and female eagles. These finding suggested that HCT and plasma chemistry values of raptors vary individually according to species and sex. Our results provide the 1st available reference data for ranges of plasma values in adult captive collared scops owls and crested serpent eagles, making them a potentially useful complementary diagnostic tool for veterinary care of individuals for both species in captivity. PMID- 22446395 TI - Molecular analysis of aspermic Fasciola flukes from Korea on the basis of the nuclear ITS1 region and mitochondrial DNA markers and comparison with Japanese aspermic Fasciola flukes. AB - It has been speculated that populations of aspermic Fasciola flukes in Korea and Japan have a close phylogenetic relationship. To evaluate this, we analyzed 33 Korean aspermic Fasciola flukes on the basis of nuclear ribosomal internal transcribed spacer 1 (ITS1) and mitochondrial NADH dehydrogenase subunit 1 (nad1) and cytochrome c oxidase 1 (cox1) sequences. Fh, Fg, and Fh/Fg types were detected in the ITS1 region and displayed the fragment patterns of F. hepatica, F. gigantica, and both species, respectively by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Additionally, three concatenated haplotypes of nad1 and cox1(nad1/cox1) were detected, and 2 of these, Kor1/Kor1 (Fsp1/Fsp1) haplotype and Kor2a/Kor2 (Fsp2/Fsp2) haplotype, were shared by Korean and Japanese aspermic flukes. The Fst value (0.019), calculated using the concatenated sequences, indicated that Korean and Japanese aspermic Fasciola populations were genetically undifferentiated. Interestingly, a combination of the Fh/Fg type and Kor1/Kor1 haplotype was found at the highest frequency in Korean aspermic flukes, whereas the Fg type and Fsp2/Fsp2 haplotype combination was found at a conspicuously high frequency in Japanese aspermic flukes. This indicates that a founder effect caused by the introduction of infected hosts may have played a key role in the introduction of aspermic Fasciola flukes from Korea into Japan. PMID- 22446396 TI - Characterization of Erysipelothrix rhusiopathiae strains isolated from recent swine erysipelas outbreaks in Japan. AB - The objective of the present study was to characterize Erysipelothrix sp. strains from recent erysipelas outbreaks in Japan. Eighty-three (100%) strains were identified as E. rhusiopathiae, based on serotyping and spaA PCR. Fifty (60.3%), 5 (6.0%), and 28 (33.7%) strains were isolated from animals with acute, subacute and chronic outbreaks, respectively, of which 79 (95.2%), 1 (1.2%), and 3 (3.6%) belonged to serotypes 1a, 2a, and untypeable, respectively. Fifteen strains (including 3, 2, and 10 from acute, subacute, and chronic cases, respectively) were sensitive to acriflavine, and showed high levels of virulence in mice; of which strains from acute cases, and from subacute and chronic cases killed 100%, and 80 to 100% mice, respectively at challenge doses of 10(2) CFU per mouse. Based on sequence analysis of a 432-bp hypervariable region in spaA gene, 83 strains could be divided into 3 groups: (i) group 1 (3 strains of serotype 1a) had Ala-195 and Ile-203; (ii) group 2 (76 strains of serotype 1a and 3 of untypeable) had Asp-195 and Met-203; and (iii) group 3 (one strain of serotype 2a) had Asn-195 and Ile-203. The results of the present study suggest that the serotype 1a strains belonging to the group 2 might be widespread in pig populations in Japan. PMID- 22446397 TI - Recovery of leptospires from miniature pigs experimentally infected with Leptospira interrogans serovar Manilae strain UP-MMC under immunosuppressive conditions by dexamethasone. AB - Leptospira interrogans serovar Manilae strain UP-MMC was inoculated into miniature pigs to assess its pathogenicity. Leptospires were recovered from the whole blood, kidneys, and livers in the acute phase without showing any clinical signs. Under immunosuppressive conditions by dexamethasone, leptospires were recovered from the kidneys and their genes were detected from the urine in the chronic phase. These results indicate that leptospires persisted in the kidneys until the chronic phase, and excretion of leptospires in the urine was enhanced under immunosuppressive conditions, resulting in horizontal transmission among pigs on farms. PMID- 22446398 TI - Perivertebral B-cell lymphoma in a Queensland koala (Phascolarctos cinereus adustus) with paralytic symptoms in the hind limbs. AB - A male Queensland koala (Phascolarctos cinereus adustus) at Kanazawa Zoological Gardens (Kanagawa, Japan) exhibited paralytic symptoms in the hind limbs. Computed tomography and magnetic resonance imaging revealed a mass on the left ventral side of the 11th to 13th thoracic vertebrae, and the presence of myelitis or edema in the spinal cord. The koala was under anesthesia during the examination and suddenly developed ventricular fibrillation and died. Necropsy revealed a firm flat ovoid hemorrhagic mass on the vertebrae. Following a microscopic examination including immunohistochemistry, the perivertebral mass was diagnosed as B cell lymphoma. Therefore, neoplastic cell infiltration into the spinal cord may cause paralytic symptoms in the hind limbs. PMID- 22446399 TI - Specific labeling of neurogenic, endothelial, and myogenic differentiated cells derived from human amniotic fluid stem cells with silica-coated magnetic nanoparticles. AB - Stem cell based cell therapies offer significant potential for the field of regenerative medicine. Human amniotic fluid stem cells (hAFSCs) are an attractive source for lineage-specific differentiated stem cell therapy since they have properties that are able to differentiate into cells representing all three germ layers. To better understand the fate and location of implanted hAFSCs, a means to monitor cells in living subjects is essential. Here, we showed that differentiated cells, such as neurogenic, endothelial, and myogenic cells, derived from hAFSCs can be effectively labeled by the FITC-incorporated silica coated nanoparticles, MNPs@SiO2 (FITC), although the labeling efficacy and cytotoxicity were distinct depending on the differentiated cell type. In addition, we observed that MNPs@SiO2-labeled cells provided sufficient signals for detection by optical and confocal microscope imaging when transplanted into the mice. These results suggest that the fluorescent dye incorporated MNPs@SiO2 are a useful tool for the cell labeling and in vivo tracking of differentiated cells derived from hAFSCs. PMID- 22446400 TI - Production of GM-CSF mediated by cysteine protease of Der f in canine keratinocytes. AB - House dust mite (HDM) allergens are the most common allergens for induction of IgE-mediated hypersensitivity. Recently, epicutaneous sensitization with HDM allergens has been emphasized in the development of atopic dermatitis (AD) by producing various soluble factors in keratinocytes. Among the soluble factors, GM CSF is a key molecule that activates Langerhans cells, antigen-presenting cells in the epidermis. In the present study, we investigated the effects of Dermatophagoides farinae (Der f) on GM-CSF production in a canine keratinocyte cell line, CPEK. CPEKs were found to produce GM-CSF upon stimulation by Der f. The GM-CSF production was suppressed by addition of a cysteine protease inhibitor. The present results suggest that cysteine protease-derived Der f may be an initiator of allergic inflammation by inducing the production of GM-CSF in keratinocytes. PMID- 22446401 TI - Effect of bacteriophage in enterotoxigenic Escherichia coli (ETEC) infected pigs. AB - We evaluated effect of enterotoxigenic Escherichia coli (ETEC) specific lytic phage CJ12 in ETEC infected pigs. Phage was mixed with feed at a ratio of 1:1,000 (0.1%). One week after initially providing phage mixed feed, pigs were challenged orally with 10(11) CFU of ETEC and body weight, diarrhea score, bacterial CFU and phage PFU in the feces were measured. Pigs of phage treated groups C (10(6) PFU/g) and D (10(8) PFU/g) showed more resistance to diarrhea due to ETEC infection compared to positive control group B on the third day after the initial challenge. Moreover, during the quantitation of ETEC in feces, both groups C and D showed approximately 63.92 and 60.73% reduced ETEC compared to positive control group B. Phages were successfully isolated from feces in both groups C and D during the experiment without any adverse effects, suggesting the possibility of using CJ12 as a feed additive. PMID- 22446402 TI - Changes in cyclooxygenase-2 immunoreactivity in the hippocampus in a model of streptozotocin-induced type 1 diabetic rats. AB - In this study, we investigated diabetic stage dependent cyclooxygenase-2 (COX-2) immunoreactivity in the dentate gyrus in streptozotocin (STZ)-induced type 1 diabetic rats. The animals were sacrificed at 2, 3 and 4 weeks after STZ treatment. Blood glucose levels were increased after STZ treatment. COX-2 immunoreactivity in dentate gyrus was significantly increased in these regions 3 weeks after STZ treatment and restored to its basal level to 4 weeks after STZ treatment. In contrast, COX-2 immunoreactivity was not changed in CA3 region in all groups. These results suggest that STZ-induced type 1 diabetes transiently, but not permanently, decreased synaptic transmission and plasticity 3 weeks after STZ treatment in the dentate gyrus. PMID- 22446403 TI - Effect of compound of gelatin hydrogel microsphere incorporated with platelet rich-plasma and alginate on sole defect in cattle. AB - Platelet-rich plasma (PRP) was administered to cattle with hoof defects (10-mm drill hole) to promote sole defect healing. Two types of gels were prepared. One was a mixed gel [compound of gelatin microspheres (GM) incorporated with PRP and alginate] and was used for the test group, while the other was an alginate gel used for the control group. Each hole was filled with one of these gels. The drill hole depth, pressure pain, and hardness of the regenerated tissue were measured for 3 weeks after treatment. These measurements improved significantly in the test group than in the control group. The results suggest that a compound of GM incorporated with PRP and alginate had a hoof-regenerating effect in cattle. PMID- 22446404 TI - Extraskeletal myxoid chondrosarcoma with systemic metastasis in a five-month-old Irish setter dog. AB - Extraskeletal myxoid chondrosarcoma was found in a five-month-old male Irish setter dog. At necropsy, the largest mass, measuring 15 * 13 * 13 cm, was found in the right caudal lobe of the lung, and metastatic small masses were observed in multiple organs. Microscopically, the tumor comprised mainly atypical mesenchymal cells and myxoid stroma, which stained positively with Alcian blue. Immunohistochemically, the tumor cells stained positively for vimentin, S-100 protein, neuron-specific enolase, calretinin, and chromogranin A. Ultrastructurally, the cytoplasm of the tumor cells was comprised abundant rough endoplasmic reticulum, mitochondria, Golgi complex, free ribosomes and short irregular microvillous processes extending from the cytoplasm. Based on these pathological findings, this tumor was diagnosed as extraskeletal myxoid chondrosarcoma. PMID- 22446405 TI - Immunological identification and characterization of extracellular serine protease-like protein encoded in a putative espP2 gene of Haemophilus parasuis. AB - Haemophilus parasuis is known to produce a group of virulence-associated autotransporter (AT) proteins, VtaAs; however, no other ATs have been characterized yet. On the basis of the reported sequence of a putative espP2 gene for extracellular serine protease (ESP)-like protein of H. parasuis, this putative AT gene was successfully amplified from H. parasuis serotype 5 field strain HPS0819, cloned and sequenced. The confirmed ORF sequence showed 100% identity with the reported putative espP2 gene. The recombinant ESP-like protein purified from Escherichia coli with a pET expression system was used for immunological characterization. An approximately 85 kDa antigen was detected in cultured H. parasuis by using antiserum to the purified ESP-like protein, and antibodies against the recombinant ESP-like protein were detected in a selected serum from pigs with experimental H. parasuis infection. The results indicated that H. parasuis could produce ESP-like protein in vitro and in vivo. In an immune protection study using guinea pigs, 6 out of 10 animals immunized with the recombinant ESP-like protein survived after challenge with 5 * 10(9) bacteria of strain HPS0819, whereas 7 out of 10 animals immunized with formalin-inactivated H0819 bacterin survived after challenge. The results suggest that ESP-like protein could be one of the vaccine antigen candidates for H. parasuis infection. PMID- 22446406 TI - Detection of Nesopora caninum-specific DNA from cerebrospinal fluid by polymerase chain reaction in a dog with confirmed neosporosis. AB - A one-month male Greyhound dog presented with a swinging gait of the hindlimbs, and later developed muscular atrophy of the femoral region and hyperextension of hindlimbs. The dog had positive serum IFAT titers to Neospora caninum, but a negative titer in the cerebrospinal fluid (CSF). N. caninum-specific DNA was amplified from the CSF using a semi-nested polymerase chain reaction assay. Clusters of protozoa in biopsied muscle fibers were subsequently confirmed as N. caninum tachyzoites by immunohistochemical examination. Early recognition and treatment are necessary for effective recovery of clinical canine neosporosis, but antemortem diagnosis is difficult. We suggest that the detection of parasite deoxyribonucleic acid in the CSF is a useful antemortem diagnostic method in facilitating treatment of this disease. PMID- 22446407 TI - Identification of a new locoweed (Oxytropis serioopetala) and its clinical and pathological features in poisoned rabbits. AB - By a series of experiments, we identified a new member of the locoweed family, Oxytropis serioopetala, that produces swainsonine, a phytotoxin harmful to livestock. In order to evaluate the toxicity of Oxytropis serioopetala, its extract was administered to ten rabbits by gavage at a dose of 1.5 mg/kg body weight as swainsonine once daily. After the 20th day, the rabbits appeared depressive and anorexic. In addition, intention tremors were apparent upon movement. Their eyes were dull. The rear limbs were severely weak and even progressed to partial paresis. The activities of serum aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (AKP) and urea nitrogen (BUN) levels in the poisoned rabbits increased significantly. Serum alpha-mannosidase (AMA) activity decreased markedly. Pathomorphological lesions in the locoweed-poisoned rabbits developed severe microvacuolation of visceral and neurological tissue. Extensive vacuolation was observed in the liver, kidney and brain. These clinical and pathological features are similar to the symptoms of locoism. PMID- 22446408 TI - Economic impact of paclitaxel shortage in patients with newly diagnosed ovarian cancer. AB - OBJECTIVE: To determine the potential economic impact of a paclitaxel drug shortage in patients with newly diagnosed, untreated ovarian cancer. METHODS: A modified Markov state transition model with a 6 cycle time horizon compared two scenarios: (1) Standard treatment (STD): paclitaxel 175 mg/m2/carboplatin AUC 5 * 6 cycles; (2) Paclitaxel drug shortage (DS): docetaxel 75 mg/m2/carboplatin AUC 5 * 6 cycles. Adverse events, quality of life, and costs of chemotherapy, neuropathy, febrile neutropenia, and anemia were incorporated. Key assumptions: (1) Costs and consequences were assigned only to grade 2+ neuropathy, febrile neutropenia, and grade 3-4 anemia; (2) Grade 2+ neuropathy prompted a switch from paclitaxel/carboplatin to docetaxel/carboplatin or from docetaxel/carboplatin to carboplatin alone; (3) Febrile neutropenia resulted in inpatient hospitalization followed by G-CSF prophylaxis. RESULTS: The mean cost of 6 cycles of chemotherapy was $4939 in the STD and $16,107 in the DS scenario, for a cost difference of $11,168 per patient over 6 cycles of treatment. STD was the dominant strategy (less expensive and more effective than the drug shortage scenario). In sensitivity analysis, DS was more costly over a wide range of clinical estimates in each arm. A drug shortage that affects approximately 50% of women initiating chemotherapy is expected to impact 779 women and cost third party payers an additional $8,699,872 monthly. CONCLUSIONS: Our model indicates that chemotherapy drug shortages can have a significant negative impact on the average cost of primary treatment for ovarian cancer and have the potential to negatively impact health system costs. PMID- 22446409 TI - Vulvar reconstruction by a "supra-fascial" lotus petal flap after surgery for malignancies. AB - OBJECTIVE: The aim of this study is to report on our experience with the supra fascial lotus petal flap following the resection of vulvar cancer. METHODS: The original lotus petal flap or gluteal-fold flap technique was initially described with fascial elevation. However, flap harvesting in a supra-fascial plane is feasible. Between 2008 and 2011, we performed and evaluated this modified flap technique for labia majora reconstruction on five elderly females (mean age: 72 years). RESULTS: Resection and reconstruction were performed in the same operative time with a median time procedure of 118 min. We observed neither flap failure nor partial necrosis. Functional evaluation beyond six months showed low donor site morbidity and good aesthetic results. CONCLUSION: Immediate vulvar reconstruction with supra-fascial lotus petal flap is a fast, easy and reliable procedure. It enables wide resection and safety margin following tumor removal with free tension suture, good aesthetic results and a favourable functional outcome. PMID- 22446410 TI - Reversible heat inactivation of copper sites precedes thermal unfolding of molluscan (Rapana thomasiana) hemocyanin. AB - Hemocyanin (Hc) is a type-3 copper protein, containing dioxygen-binding active sites consisting of paired copper atoms. In the present study the thermal unfolding of the Hc from the marine mollusc Rapana thomasiana (RtH) has been investigated by combining differential scanning calorimetry, Fourier transform infrared (FTIR) and UV-vis absorption spectroscopy. Two important stages in the unfolding pathway of the Hc molecule were discerned. A first event, with nonmeasurable heat absorption, occurring around 60 degrees C, lowers the binding of dioxygen to the type-3 copper groups. This pretransition is reversible and is ascribed to a slight change in the tertiary structure. In a second stage, with midpoint around 80 degrees C, the protein irreversibly unfolds with a loss of secondary structure and formation of amorphous aggregates. Experiments with the monomeric structural subunits, RtH1 and RtH2, indicated that the heterogeneity in the process of thermal denaturation can be attributed to the presence of multiple 50kDa functional units with different stability. In accordance, the irreversible unfolding of a purified functional unit (RtH2-e) occurred at a single transition temperature. At slightly alkaline pH (Tris buffer) the C-terminal beta-sheet rich domain of the functional unit starts to unfold before the alpha-helix-rich N terminal (copper containing) domain, triggering the collapse of the global protein structure. Even around 90 degrees C some secondary structure is preserved as shown by the FTIR spectra of all investigated samples, confirming the high thermostability of molluscan Hc. PMID- 22446411 TI - Proteome analysis of a CTR9 deficient yeast strain suggests that Ctr9 has function(s) independent of the Paf1 complex. AB - The Ctr9 protein is a member of the Paf1 complex implicated in multiple functions: transcription initiation and elongation by RNA pol II, RNA processing and histone modifications. It has also been described as a triple-helical DNA binding protein. Loss of Ctr9 results in severe phenotypes similar to the loss of Paf1p, a Paf1 complex subunit. However, the exact role of Ctr9 is not entirely established. To study the biological role of the protein Ctr9 in yeast, we used 2 D gel electrophoresis and characterized proteome alterations in a ctr9Delta mutant strain. Here we present results suggesting that Ctr9 has function distinct from its established role in the Paf1 complex. This role could be linked to its ability to bind to DNA complex structures as triplexes that may have function in regulation of gene expression. PMID- 22446413 TI - Characterization of the uterine leiomyoma microRNAome by deep sequencing. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are negative regulators of gene expression. Many genes in human uterine leiomyoma (ULM) are aberrantly expressed and in some cases this can be due to dysregulation of miRNAs. Here we present the first study to determine genome-wide miRNA expression patterns in uterine leiomyoma and myometrium using Solexa high-throughput sequencing. We found more than 50 miRNAs, which were differentially expressed, and furthermore we extend the list of putative new miRNA genes. The top five significantly de-regulated miRNAs in ULMs that we found in our libraries were miR 363, miR-490, miR-137, miR-217 and miR-4792. We also observed "isomiRs" with higher copy number than referenced mature miRNA specific for the leiomyoma libraries, which have a potential role in tumorigenesis. The microRNA transcriptomes obtained in this study deliver insights and further expand our understanding the role of small RNAs in uterine leiomyoma development. PMID- 22446414 TI - Professionalism in the real sense of the practice of medicine and surgery. PMID- 22446415 TI - Avoiding becoming the disruptive plastic surgeon. PMID- 22446416 TI - Professionalism: teaching professional responsibility in medical education. PMID- 22446417 TI - Professionalism in plastic surgery. PMID- 22446418 TI - Force-induced craniosynostosis via paracrine signaling in the murine sagittal suture. AB - INTRODUCTION: The role of genetic phenomena has been given central importance in the development of craniosynostosis. Proponents have dismissed the role of force as a key etiologic factor. Nonetheless, compressive forces on the developing calvarium have been shown to result in premature suture fusion. The purpose of this study was to determine whether cyclical loading of the murine calvarium could induce suture fusion in cocultured calvarial specimens. MATERIALS AND METHODS: Calvarial coupons from postnatal day 21, B6CBA wild-type mice (n = 24) were harvested and cultured. A custom appliance capable of delivering compressive loads was applied perpendicular to the sagittal suture in vitro. Six coupons were subjected to 0.3 g of force for 30 minutes each day for a total of 14 days. Six additional coupons were cocultured within the same medium. Control groups were devised. Histologic analysis of suture phenotype was performed. RESULTS: Sagittal sutures cocultured with unloaded specimens remained patent. In contradistinction, 4 of 6 specimens cocultured with loaded coupons demonstrated craniosynostosis (P = 0.03). Increased osteoid, alkaline phosphatase staining, and bone sialoprotein expression were observed when compared with matched controls. DISCUSSION: An in vitro model of force-induced craniosynostosis via paracrine effects has been devised. Premature fusion of the murine sagittal suture was induced in unloaded specimens cocultured with cyclically loaded calvarial coupons. These results implicate that abnormal forces may act through soluble factors to cause premature suture fusion in vitro. The findings support our global hypothesis that epigenetic phenomena play a crucial role in the pathogenesis of nonsyndromic craniosynostosis. PMID- 22446419 TI - Degradation of LactoSorb fixation devices in the craniofacial skeleton. AB - Numerous reports about bioabsorbable internal fixation in the craniofacial skeleton substantiate successful clinical outcomes, especially in pediatric patients. Despite this, little physicochemical data exist to document the rate of device degradation in the human body. In vitro and in vivo animal studies are often used to study the degradation characteristics during product development; however, there has been little effort to correlate preclinical device degradation studies with clinical studies. This study analyzed a fragment of a LactoSorb copolymer plate that was removed from a 17-month-old patient with sagittal synostosis after 3 months' residence. The retrieval was performed during the second part of a planned 2-stage intervention. The fragment was white, opaque, and very brittle, with some signs of mass loss. The inherent viscosity, a measure of mean molecular weight, was determined to be 0.32 +/- 0.02 dL/g. LactoSorb implants, as manufactured, have an inherent viscosity of about 1.30 to 1.55 dL/g. Thus, the inherent viscosity was reduced by approximately 75% to 80% over this 3 month interval in the patient. Assuming an exponential decline in inherent viscosity over time, this corresponds to a half-life of about 40 to 44 days. This may be compared with a half-life of about 36 to 45 days derived from prior in vitro studies. The mass loss observed in the LactoSorb implants also corresponds, qualitatively, to that which has been shown to occur in animal models. Thus, the limited data at hand suggest that the degradation profile of LactoSorb copolymer in this human patient is consistent with that reported in prior in vitro and in vivo animal studies. PMID- 22446420 TI - New sterilization technology and the effects on bone pencil. AB - BACKGROUND: The changing technology today with sterilizing surgical tools has called into question the ability to adequately sterilize the bone pencil. Concern has arisen as to the sterilization of bone pencil and whether the new technology used in sterilizing the operating equipment meets the standards set by the Centers for Disease Control and Prevention. This study was performed to compare the older gas sterilizing technology (ETO) with the newer hydrogen peroxide-based Sterrad sterilizer. METHODS: An equal number of standard number 2 pencils were used for both methods of sterilization. Three separate batches were used for a total of 13 pencils in each group. All pencils were cultured at 24 and 48 hours after sterilization. RESULTS: All culture plates showed no growth during the incubation process. CONCLUSIONS: Bone pencil can be sterilized using the new gas sterilization equipment as well as the older equipment. PMID- 22446421 TI - Areal measures of healthy adults' hippocampal formation on brain magnetic resonance imaging. AB - This study measured the area of the hippocampal structure using brain magnetic resonance imaging. We rebuilt a three-dimensional reconstruction of the brain and selected specific sections on the coronal plane, the cross section, and the sagittal plane and then measured the areas of the hippocampus using a software on the computer. In different sections, the left and right hippocampal areas were significantly different (P < 0.05), but the hippocampal areas of males and females are not concordant. There is no significant difference in the area in those aged 20 to 60 years. The hippocampal area is not correlated with the brain area in the same section. In conclusion, the standardization of the hippocampus is not suitable to judge the difference between males and females. The hippocampal area of healthy adults provides the criteria for atrophy of the hippocampus and a brief approach instead of the volumetric measures to apply in clinical diagnosis. PMID- 22446422 TI - Differentiation of osteoprogenitor cells is induced by high-frequency pulsed electromagnetic fields. AB - Craniofacial defect repair is often limited by a finite supply of available autologous tissue (ie, bone) and less than ideal alternatives. Therefore, other methods to produce bony healing must be explored. Several studies have demonstrated that low-frequency pulsed electromagnetic field (PEMF) stimulation (ie, 5-30 Hz) of osteoblasts enhances bone formation. The current study was designed to investigate whether a Food and Drug Administration-approved, high frequency PEMF-emitting device is capable of inducing osteogenic differentiation of osteoprogenitor cells. Osteoprogenitor cells (commercially available C3H10T1/2 and mouse calvarial) in complete Dulbecco modified Eagle medium were continuously exposed to PEMF stimulation delivered by the ActiPatch at a frequency of 27.1 MHz. Markers of cellular proliferation and early, intermediate, and terminal osteogenic differentiation were measured and compared with unstimulated controls. All experiments were performed in triplicate. High-frequency PEMF stimulation increases alkaline phosphatase activity in both cell lines. In addition, high frequency PEMF stimulation augments osteopontin and osteocalcin expression as well as mineral nodule formation in C3H10T1/2 cells, indicating late and terminal osteogenic differentiation, respectively. Cellular proliferation, however, was unaffected by high-frequency PEMF stimulation. Mechanistically, high-frequency PEMF-stimulated osteogenic differentiation is associated with elevated mRNA expression levels of osteogenic bone morphogenetic proteins in C3H10T1/2 cells. Our findings suggest that high-frequency PEMF stimulation of osteoprogenitor cells may be explored as an effective tissue engineering strategy to treat critical-size osseous defects of the craniofacial and axial skeleton. ABBREVIATIONS: ALP, alkaline phosphatase; BMP, bone morphogenetic protein; ERK-1, extracellular signal-regulated kinase 1; iCALs, immortalized calvarial cells; IHC, immunohistochemical; MAP, mitogen-activated protein; MSC, mesenchymal stem cell; OCN, osteocalcin; OPN, osteopontin; p38alpha, p38-reactivating kinase; PBS, phosphate-buffered saline; PEMF, pulsed electromagnetic field. PMID- 22446423 TI - Osteoinduction in the palatal submucosa by injecting BMP-2 on 2 different carriers. AB - In this work, we investigated the ability of injected recombinant human bone morphogenetic protein 2 (rhBMP-2) on brushite cement (a beta-tricalcium phosphate based biomaterial) and collagen gel as carriers to induce osteogenic differentiation in the palatal submucosa of 10-day-old rats. This was part of a broader study aiming to create bone in the palatal submucosa at cleft palate edges in the search for a minimally invasive treatment. Thirteen treated animals, 7 with rhBMP-2/brushite cement and 6 with rhBMP-2/collagen gel, were injected with 5 to 10 MUL of each biomaterial in the right palatal submucosa at the level between the second and third rugae. The contralateral site was uninjected and served as the control. Six weeks after injection, both brushite cement and collagen gel were histologically unrecognizable in all treated animals. New bone structures such as ossicles of woven bone were not detected. However, an augmentation in the thickness of the palatal fibromucosa was observed at the injection site of all palates. In addition, immunolabeling for osteopontin, proliferating cell nuclear antigen, and TUNEL revealed intense osteogenic induction at the injection site with both constructs, which was negative in the control site from the same specimens; no differences regarding cell proliferation and death were observed. The present study confirms the feasibility of generating osteogenic cells in the palatal submucosa by injecting low doses of rhBMP-2 in these 2 biomaterials, together with their inability to form bone. PMID- 22446424 TI - Giant malignant meningioma invading the calvarial bone and scalp. AB - Meningiomas are common and mostly benign intracranial tumors, but malignant meningioma is a rare subtype with high recurrence rate and poor prognosis. Also, most meningiomas grow intracranially, and extracranial growth of meningiomas has rarely been reported. We present here a rare case of a giant malignant meningioma with multiple recurrences. The patient was a 73-year-old woman who was evaluated to have a malignant meningioma of the frontal part of the skull 3 years before being admitted to our hospital and received surgical treatment. The tumor recurred 3 years after the first surgery and was classified as a giant meningioma on admission to our hospital. We performed total resection of the giant meningioma and reconstructed the defect with artificial dura, skull, and a local rotating flap. The patient recovered and lived well for 1 year. However, 15 months after surgery, the patient died of the recurrent tumor after refusing any treatment. Meningiomas are usually common and benign intracranial tumors; however, the anaplastic subtype of meningiomas is rare and malignant. Despite the high rates of recurrence and metastasis, surgery is still an option. For giant invasive tumors, the cooperation of neurosurgeons and plastic surgeons is essential. PMID- 22446425 TI - Giant congenital epiglottic cyst presenting with airway obstruction at birth. AB - Congenital laryngeal cysts (CLCs) are rare and may be fatal. Although CLCs have the potential to cause severe airway obstruction and death, these are not common presentations at birth. The most common CLCs are the aryepiglottic cysts, with the epiglottic cysts being the least common. In this report, a newborn with severe airway obstruction at birth, caused by a giant congenital epiglottic cyst, is presented. PMID- 22446426 TI - Superficial temporal arteriovenous fistula as a complication of rhytidectomy. AB - A 67-year-old woman who had undergone rhytidectomy 5 years before her presentation experienced increasing pulsatile tinnitus on the left side that had begun 2 years earlier. Angiography revealed a direct arteriovenous fistula between the superficial temporal artery and superficial temporal vein in front of her left ear. There was a scar from the earlier cosmetic surgery at the site. The fistula was embolized with N-butyl cyanoacrylate, and her tinnitus disappeared. We posit that the fistula was a complication of rhytidectomy and that a small arteriovenous fistula formed at the time of surgery and enlarged over time. This case indicates that arteriovenous fistulae can occur as a delayed complication of cosmetic surgery. PMID- 22446427 TI - Optimizing pediatric interdental fixation by use of a paramedian palatal fixation site. AB - Condylar fractures are the most common injury seen in pediatric mandibular trauma. These injuries often cannot be adequately stabilized by conservative techniques such as splinting. The pediatric condyle fracture often requires a period of intermaxillary fixation. Because of the characteristics of the developing dentition, circumdental wiring is often not possible. Surgeons commonly achieve interdental stabilization by the connection of a circum mandibular wire and a second wire placed through a drill hole in the piriform aperture. This method can be problematic in the young patient whose palatal suture is still patent. In this brief technical note, the use of a paramedian drill hole through the palate posterior to the maxillary incisors is described. It is believed that this method is superior to other techniques because it avoids injury to the deciduous tooth buds and allows for the maxillary wire to be seated in more structurally sound tissues. PMID- 22446428 TI - Cavernous hemangioma--uncommon presentation in zygomatic bone. AB - Hemangiomas are benign vascular neoplasms characterized by an abnormal proliferation of blood vessels. They may occur in any vascularized tissue including skin, subcutaneous tissue, muscle, and bone. Intraosseous hemangiomas are uncommon, constituting less than 1% of all osseous tumors. The most frequent sites are the calvaria and the vertebral column. Involvement of the facial bones is rare and occurs most commonly in the maxilla, mandible, and nasal bones. In literature, only 20 cases of zygomatic involvement have been reported. We report a case of an intraosseous hemangioma of the zygoma with the history and physical findings of slowly growing, bony, hard tumor causing facial and ocular deformity. The typical clinicopathologic and radiologic findings helped to set up the correct diagnosis. Early recognition and excision are recommended to preserve facial contour. Operative blood loss is minimal, and there is no need for preoperative angiography. PMID- 22446429 TI - Guided surgery in unusual palatal torus. AB - Palatine torus is a benign congenital outgrowth of bone that affects the hard palate and palatine processes, resulting from the "overworking" of osteoblasts and bone deposition along the line of the palatine fusion. Surgical excision is the only treatment for torus, and such patients are susceptible to intraoperative and postoperative complications of a traumatic, functional, or infectious nature. This article describes an atypical case of torus palatinus measuring 20.31 * 27.25 * 59.20 mm, which is the largest size ever described in the literature. This case required the use of a surgical guide in the intraoperative phase, with viable use in the postoperative phase as well. This guide proved versatile in reducing the risk of undercorrection and complications, offering greater patient comfort. PMID- 22446430 TI - Cervical branchial cartilaginous remnant. AB - Failure of proper migration, fusion, or maturation of the branchial apparatus components results in a variety of congenital defects. Most branchial cysts and fistulae are considered to be derived from the first and second branchial clefts. Of these, cervical cartilaginous rests are infrequent, whereas branchial cysts and sinuses are relatively more common. Our patient, a 4-year-old girl, had been operated on with simple skin excision and excision of the combined platysma. Finding from histopathology revealed a hyaline cartilage. Cervical branchial remnants do not have fistulous tracts or connections with important deeper organs; hence, they can be safely transected at the level of the superficial musculature. Therefore, we believe that the most important points are optimal incision for branchial cartilaginous remnants and surgical excision with preservation of the normal anatomy. PMID- 22446431 TI - Surgical management of a projectile within the temporomandibular joint. AB - Facial gunshot wounds pose a challenge for head and neck surgeons as it is usually accompanied by significant soft and bone tissue loss and impairment of the stomatognathic system. This article reports the case of a patient who had sustained facial gunshot wound and had the projectile lodged at the upper disk space of the right-side temporomandibular joint, which caused mandible function impairment and pain. The projectile was surgically removed via endaural access, and the patient was later submitted to physiotherapy. After treatment, the function of the joint was reestablished, the pain disappeared, and the aesthetics results were considered excellent, with no sequels. The surgical removal of the projectile of the temporomandibular joint combined with the postsurgical physiotherapy showed to be an efficient treatment to the present case. PMID- 22446432 TI - Signs and symptoms of temporomandibular dysfunction in fibromyalgic patients. AB - OBJECTIVE: The objective of this study was to determine the frequency of signs and symptoms of temporomandibular disorder (TMD) in fibromyalgic patients. METHODS: Sixty subjects of both sexes (mean age, 49.2 +/- 13.8 years) with fibromyalgia (FM) diagnosis were included in this study. All patients were examined by a calibrated investigator to identify the presence of TMD using the Research Diagnostic Criteria for TMD. RESULTS: The most common signs (A) and symptoms (B) reported by FM patients were (A) pain in the masticatory muscles (masseter, 80%; posterior digastric, 76.7%), pain in the temporomandibular joint (83.3%), and 33.3% and 28.3%, respectively, presented joint sounds when opening and closing the mouth; (B) headache (97%) and facial pain (81.7%). In regard to the classic triad for the diagnosis of the TMD, it was found that 35% of the FM patients presented, at the same time, pain, joint sounds, and alteration of the mandibular movements. It was verified that myofascial pain without limitation of mouth opening was the most prevalent diagnosis (47%) for the RDC subgroup I. For the subgroup II, the disk displacement with reduction was the most prevalent diagnosis (21.6%). For the subgroup III, 36.7% of the subjects presented osteoarthritis. CONCLUSIONS: Thus, there is a high prevalence of signs and symptoms of TMD in FM patients, indicating the need for an integrated diagnosis and treatment of these patients, which suggest that the FM could be a medium- or long-term risk factor for the development of TMD. PMID- 22446433 TI - Suspected IMALAS publication. PMID- 22446434 TI - Heterotopic bone formation (osseous metaplasia) in nasal polyps. PMID- 22446435 TI - Resonance and speech articulation after midface advancement in craniofacial dysostosis. AB - OBJECTIVE: This study aimed to analyze changes in resonance and speech articulation after midface advancement in syndromic craniofacial patients and to assess the influence of craniofacial diagnosis and the presence or absence of a cleft palate. METHODS: This study is a retrospective analysis of resonance and speech articulation in patients after midface advancement. This project was carried out in a multidisciplinary pediatric craniofacial service. Eighteen patients underwent midface advancement between 2002 and 2009. Three were excluded because of inadequate records or presence of tracheostomy. Midface advancement was done by Le Fort III, facial bipartition, or monobloc, either conventional surgery or distraction osteogenesis. Outcomes include perceptual assessment of articulation and resonance using GOS.SP.ASS.98 revised and recommendation for speech surgery. RESULTS: Hypernasality scores decreased in 7 patients (46.7%), and 5 patients were recommended for speech surgery. Hyponasality scores improved in 10 patients (66.7%), were unchanged in 3 patients (20%), and decreased in 2 patients (13%). Articulation changed (improved) in 1 patient (6.7%) only. Hypernasality scores decreased in 33.3% of Crouzon and 71.4% of Apert patients. Five patients had a cleft palate, 4 had Apert syndrome, and hypernasality scores decreased in 3 patients. Of 3 patients with Apert syndrome but no cleft palate, 2 (66.7%) also had a decrease in hypernasality scores. CONCLUSIONS: Our findings suggest a high incidence of deterioration in velopharyngeal function after midface advancement, particularly in Apert syndrome, regardless of the presence of a cleft, and an improvement in hyponasality, but minimal change in articulation. Larger prospective multicenter studies are required to investigate these findings further. PMID- 22446436 TI - Treatment of "en coup de sabre" deformity with adipose-derived regenerative cell enriched fat graft. AB - Linear scleroderma "en coup de sabre" is characterized by atrophy and furrowing of the skin of the front parietal region above the level of the eyebrow. In most cases, it occurs as a single paramedian line that may be associated with hypoplasia of underlying structures and hemiatrophy of the face. The affected region is a depression that may be associated with hypoplasia of the underlying soft tissues and bone that results in facial hemiatrophy. If the lesion is narrow, it can be resected and directly sutured; in the case of a wide lesion, many different reconstructive techniques, directed at augmentation of deficient soft tissue volume, have been proposed such as autologous tissue grafts, biomaterials, pedicled flaps, and free flaps. Adipose-derived regenerative cells (ADRCs) can be easily processed from lipoaspirated fat and can provide a significant quantity of multipotent cells for a variety of therapeutic regenerative medicine therapies. There is an increasing interest in a possible therapeutic role of ADRCs from processed lipoaspirate for many applications, including their use as soft-tissue fillers. We introduce the application of a successful ADRC therapy for a linear scleroderma en coup de sabre deformity. PMID- 22446437 TI - Technical tips for a cosmetic approach to parotid surgery. AB - PURPOSE: Recently, skin incisions have tended to be smaller if surgical exposure is not greatly compromised, especially for benign lesions of the head and neck. An incision in a visible area of the neck needs to be moved to hidden or less prominent sites or away from the head and neck. For aesthetic considerations, the preauricular broken/postauricular trichophytic skin incision was developed for parotid surgery. PATIENTS AND METHODS: This retrospective clinical study enrolled 36 patients (20 women and 16 men) with benign preneural parotid tumors. Six months after surgery, patients were specifically asked to rate their satisfaction with their postoperative appearance on a scale of 1 to 10, with higher scores meaning better patient satisfaction, and whether they would consent to the operation again. RESULTS: All patients were satisfied with the cosmetic outcome: 24, 9, and 3 patients rated the procedure 8, 9, and 10, respectively. CONCLUSIONS: The preauricular broken/postauricular trichophytic skin incision provides generous access to the parotid gland, which is at least as good as the access provided by a Blair incision. It is an aesthetically superior incision that allows good surgical access and improved contour reconstruction. PMID- 22446438 TI - Effect of partially selective cyclooxygenase-2 inhibitor in the removal of third molars. AB - A randomized, double-blind clinical trial was carried out involving 25 patients scheduled for the removal of symmetrically positioned lower third molars in separate procedures. Either 100 mg of nimesulide or 7.5 mg of meloxicam was administered 1 hour before surgery and every 12 hours after surgery for 2 days. Evaluations were carried out in the preoperative period as well as on the second and seventh days after surgery. Objective and subjective parameters were recorded for comparison purposes. The patients having received nimesulide had less of a need for additional pain medication in the first 48 hours and had lower pain scale values (P < 0.05). There was less trismus in the meloxicam group (P > 0.05). Postoperative swelling was lower in the nimesulide group (P < 0.05). All measurements on the second day were lower in the nimesulide group (P < 0.001), and only one of these parameters was lower on the seventh day in the nimesulide group, distance from the lower edge of the tragus to the lip commissure on the operated side (P = 0.009, P < 0.001) compared with another group. Nimesulide proved effective in controlling pain and swelling after surgical removal of the lower third molars, with few adverse effects. Meloxicam proved effective in diminishing trismus. PMID- 22446439 TI - Flabby ridge correction using an auxiliary technique with connective tissue graft. AB - A common finding in patients with edentulous maxilla and partially dentate mandible is mainly the presence of flabbiness in the anterior edentulous alveolar ridge that can compromise the retention and stability of a denture. Thus, this case report presents the correction of a flabby ridge, using an auxiliary technique combining surgical excision and autogenous connective tissue grafting. The technique improved the quality of the osteomucosal support of the alveolar ridge and increased the vestibule deepness, whose result increased the success rate of the new conventional total prosthesis. PMID- 22446440 TI - Muenke syndrome associated with multiple osteochondromas. AB - Muenke syndrome caused by the FGFR3 Pro250Arg mutation is associated with craniosynostosis, hearing loss, and various bony anomalies. Although this mutation is involved in bone growth and development, bony tumors are rare in this condition. We describe a patient with a molecular diagnosis of Muenke syndrome who also presented with multiple osteochondromas of the upper and lower extremities. This association has only been described once before in a patient with an isolated osteochondroma of the proximal tibia. Altered expression of FGFR3, an important mediator of chondrocyte proliferation and differentiation during in the growth plates of long bones, may help to explain the development of osteochondromatous lesions in this patient. PMID- 22446441 TI - Central granular cell odontogenic tumor of the maxilla. AB - The central granular cell odontogenic tumor (CGCOT) is a rare benign odontogenic neoplasm composed of varying amounts of large eosinophilic granular cells and apparently inactive odontogenic epithelium. It tends to occur as a small asymptomatic swelling in the posterior region of the mandible with nonaggressive appearance. We report an unusual case of CGCOT in the maxillary region with clinical features of malignancy. The patient underwent surgical treatment, and the 2-year follow-up revealed no signs of recurrence. Central granular cell odontogenic tumor is a very rare condition with few cases reported, especially in the maxillary region. This case highlights the possibility of aggressive behavior by these lesions. PMID- 22446442 TI - Foreign body ingestion during dental implant procedures. AB - Two cases of swallowing of foreign material related to dental implants during dental practice are described. A conservative approach by clinical-radiographic follow-up was performed in both cases; however, one of the patients required colonoscopy under general anesthesia for the removal of the impacted foreign body from the intestinal region. These complications not only have associated economic cost but also carry the risk of malpractice litigation against the professional; thus, the surgeon was responsible for all the costs of hospital and surgery management of this case. Details of the clinical signs, radiographic examinations, type of treatment, and follow-up are presented. PMID- 22446443 TI - Giant maxillary mucocele occurring after reduction malarplasty. AB - Reduction malarplasty for patients with a prominent malar complex is a popular procedure in Asia. However, a range of complications have been reported after reduction malarplasty, such as hematoma, orbital complications, asymmetric face, and nonunion. A medially displaced fracture or bony fragment can induce sinusitis and subsequent trauma to bones in combination with chronic inflammatory processes, which can lead to chronic obstruction of mucus-secreting glands. In our case, 46-year-old man presented with a large mucocele in the maxillary sinus after malar reduction approximately 20 years ago. PMID- 22446444 TI - Maxillary sinus squamous cell carcinoma with concurrent prolonged foreign body impaction. AB - Several elements in the maxillary sinus are reported to be carcinogenic. Also, foreign body reaction can cause cancer in any part of the body. We report a case of squamous cell carcinoma at the site in the maxillary sinus where a bullet splinter, analyzed as iron afterward, was inserted during the Korean War, approximately 60 years earlier. PMID- 22446445 TI - Efficacy of deep subfascial approach to the temporomandibular joint. AB - INTRODUCTION: The aim of this study was to report the efficacy of the deep subfascial approach for the treatment of temporomandibular joint pathologies. The procedure set out below satisfies a wide-access approach for the prevention of facial nerve injury. MATERIALS AND METHODS: The preauricular approach with the additional deep subfascial approach was applied to 18 patients who had various problems from ankylosis to internal derangement. All patients were assessed at the following postoperative times. Facial nerve functions were evaluated after surgery and 24 hours after surgery by the House-Brackmann facial nerve grading system. RESULTS: Temporary facial nerve palsy was seen in a patient who had a residual keratocyst in the condylar neck region. Other patients tolerated the procedure well, and there were no other complications. DISCUSSION: This procedure significantly decreased the risk of facial nerve injury. However, soft tissue traction at the condylar neck region or zygomatic arch where the facial nerve passes close by may increase the risk of nerve damage. PMID- 22446446 TI - Mandibular rehabilitation using immediate implant loading after computer-guided surgery. AB - Computed tomographic scan is a precise complementary examination of diagnostic imaging and a noninvasive surveying technique that enables the professional to improve precision of implant placement by building a prototype that allows the confection of surgical guides. The authors present a clinical case of mandible rehabilitation based on computed tomography of a patient; the cross sections were reformatted and used to construct a virtual planning of the implants and a guide template in Dental Slice. Immediate loading of 5 titanium implants were placed in the mandible using a Slice Guide System. This technique allows a better surgical planning, makes the procedures more accurate, and reduces surgery time. PMID- 22446447 TI - Distinctive genital folliculosebaceous cystic hamartomas in a patient with fibrous dysplasia. AB - Folliculosebaceous cystic hamartoma is a benign tumor composed of follicular, sebaceous, and mesenchymal components. Usually, it appears in adulthood as a dome or a pedunculated nodule on the face, especially the nose. Extracephalic lesions are sporadically reported, such as on the upper back, forearm, ear, labia majora, and the nipple. Herein, we report a patient with left maxillary fibrous dysplasia who experienced bilateral labia majora disfigurement after her puberty. She experienced physical distress because of tenderness due to the tangled, stretched hamartomas and psychological distress because of failure to have sexual contacts. The exophytic dark skin-colored fusing polypoid labia majora deformities were excised, and the folliculosebaceous cystic hamartoma was impressed by the pathology. We used an advancing flap for labiaplasty, and the outcome was aesthetically satisfactory. There is no recurrence in the 6-month follow-up period. To our knowledge, this is the first report of a folliculosebaceous cystic hamartoma on the bilateral labia majora in a patient with fibrous dysplasia. This extraordinary presentation is much different from others owing to its unusual appearance and a larger size. PMID- 22446448 TI - Early diagnosis of regional odontodysplasia in an infant. AB - Regional odontodysplasia is a rare and significant dental malformation. It is a dental alteration of unknown etiology, involving both mesodermal and ectodermal dental components, which present clinical, radiographic, and histologic features. This article reports a clinical case of a 10-month-old child who was diagnosed with regional odontodysplasia in the maxilla, confirmed by radiographic examination, with a follow-up of 5 years. The clinical, radiographic, and histologic features were reviewed. PMID- 22446449 TI - Metastatic renal cell carcinoma to the orbit and the ethmoid sinus. AB - The orbit is an unusual site for metastatic renal cell carcinoma (RCC), and concurrent metastases of RCC to the ethmoid sinus and the orbit occur very rarely. The treatment goal of orbital and paranasal metastatic RCC is total exenteration. We report a rare case of metastatic RCC to the orbit and the ethmoid sinus. The patient underwent total exenteration, craniotomy, and total maxillectomy. Six years after surgery, the patient showed no sign of metastasis and had successful cosmetic result by using orbital prosthesis. PMID- 22446450 TI - Stylohyoid syndrome: surgical approach. AB - The best-known cervicopharyngeal pain is Eagle syndrome, in which symptomatic elongation of the stylomandibular process occurs and may be accompanied by stylohyoid ligament calcification. Among the causes of elongation of the styloid process, the following may be mentioned: history of trauma, styloid ligament calcification, and formation of bony tissue in the insertion of the styloid ligament. When there is no history of trauma or surgery, it is called the stylohyoid syndrome. In the current study, the clinical case of 34-year-old woman is reported, complaining of pain in the region of the neck, without any history of neck surgery or trauma. A panoramic radiograph and computed tomographic scan showed bilateral elongation of the styloid process. Extraoral surgical intervention was the treatment of choice. It is important to point out that dentists should be aware of this condition to contribute to a better diagnosis and therapeutic procedure. PMID- 22446451 TI - Management of an unusual craniofacial impalement injury by a metallic foreign body. AB - Craniofacial penetrating injuries caused by foreign bodies other than bullets or glass from traffic crashes are quite rare. Hence, there is a lack of knowledge regarding systematic management strategies or analysis of complications for craniomaxillofacial surgeons. Between 2002 and 2010, 82 patients underwent surgery for penetrating craniofacial injuries in 2 craniomaxillofacial trauma centers. Among these patients, we included patients who had retained foreign metallic bodies. Data regarding age, sex, injury materials, entrance, injured structures, operative records, and complications were reviewed retrospectively for 8 patients. All of the patients were evaluated precisely in the emergency department without removal of retained materials, and a multidisciplinary team approach was performed for the removal of the foreign body under general anesthesia.In this study, 6 men and 2 women presented with penetrating injuries that retained metal objects. The mean age of the patients was 44.3 years. All of the patients were hemodynamically stable, and no active bleeding was found. However, all of the patients had postoperative complications. Three patients had damaged vascular structures, and 3 patients had injuries to facial nerve branches. Seven patients had posttraumatic stress disorder. Two patients underwent subsequent emergent procedures because of massive bleeding and cerebrospinal fluid leakage.Penetrating injuries in the head and neck regions are complicated. Although a multidisciplinary team approach was performed from initial management to outpatient management in patients with unusual impalement injuries, numerous postoperative complications still remained. Preoperative patient informed consent was important. PMID- 22446452 TI - One-stage replacement surgery of orbital implants with noninfectious complications. AB - Orbital implant-associated complications always affect patients, resulting in multiple operations. One-stage replacement of complicated implants has been attractive for reducing operation times and preventing long-time appearance without artificial eye. We retrospectively analyzed the outcomes of 1-stage replacement surgery of orbital implant. A total of 21 eyes in 21 cases with noninfectious complications, who failed conservative therapies and surgical repairs, were treated with 1-stage orbital implant replacement. After a detailed ophthalmic history was obtained and examinations performed, patients with apparent purulent secretion in conjunctival sac were excluded. The preexisting orbital implant was carefully removed, and a new hydroxyapatite sphere was implanted simultaneously. Wound healing status, prosthesis movement, and cosmetic features were evaluated and recorded after at least 6 months' follow-up. Orbital implant exposure(16 cases) was the main indication of the replacement surgery; other causes included superior orbital area depression (2 cases), conjunctival fistula (1 case), orbital implant malposition (1 case), and the metal material of implant obstructing magnetic resonance imaging scan in 1 case. Eye-socket hollow was redressed in all cases immediately, and 95.23% cases (20/21) could wear an artificial eye and had a good cosmetic appearance, whereas conjunctival sac fistula reoccurred in 1 patient, and the implant was removed ultimately. Conjunctival sac constrictions occurred in 4 cases after operation and were treated by secondary conjunctival sac reconstruction 6 months later. In conclusion, 1-stage replacement of orbital implants offers an effective and efficient strategy for dealing with severe postimplantation noninfectious complications in achieving a symmetrically cosmetic appearance without delay. PMID- 22446453 TI - Revision of "A 223-kb de novo deletion of PAX9 in a patient with oligodontia". AB - The PAX (paired box) genes are a family of transcription factors critical for fetal growth and organogenesis. Abnormalities of PAX2, PAX3, PAX6, and PAX9 are associated with various congenital craniofacial anomalies, including tooth abnormalities. We present here a boy with oligodontia. Dental radiographs showed that he lacked primary molars and was missing most of his permanent teeth. A genome-wide single-nucleotide polymorphism-based microarray revealed a de novo 223-kb heterozygous deletion on 14q13.3 that included the PAX9 gene. The findings in this patient illustrate the role of the PAX9 gene in tooth development and provide the first example of a de novo deletion of 14q13.3 manifesting primarily with oligodontia. This report also supports the utility of genome-wide microarrays in determining the genetic cause of craniofacial abnormalities. PMID- 22446454 TI - Biomechanical effects of cranioplasty for defects using autogenous calvarial bone. AB - INTRODUCTION: Harvesting autogenous calvarial bone grafts can potentially weaken the donor site and make it more susceptible to trauma. Conversely, restoring the integrity of the cranial vault structure can result in better dissipation of traumatic energy. This study proposes to mathematically model traumatic situations to evaluate the effect of cranioplasty on biomechanical properties of the craniofacial skeleton. METHODS: Preoperative and 6-month postoperative computed tomography-generated DICOM data were used to extract a tetrahedral volumetric representation of the craniofacial skeleton. These data were then used in finite element solver-simulating traumatic events. RESULTS: Deformational stresses accumulate around defect edges and can serve as seed points for calvarial fractures at much lower energy levels in the preoperative models when compared to the postoperative models. Accumulation of stresses in the orbital roof/medial orbital wall areas was observed, similar to fracture patterns observed in the younger pediatric population CONCLUSIONS: Restoring architectural integrity of the craniofacial skeleton results in significant increased resistance to deformational stresses despite structural weakening caused by harvesting cranial bone. PMID- 22446455 TI - Digital versus conventional panoramic radiography in predicting inferior alveolar nerve injury after mandibular third molar removal. AB - The aim of the study was to compare the accuracy of conventional and digital panoramic radiography (OPG) in relation to 4 specific high-risk signs (interruption of the superior cortical line, diversion, narrowing of the canal, and dark band of the root), which would indicate a close anatomic relationship between third molar roots and the inferior alveolar canal.Four hundred mandibular third molar surgical removals after conventional and 272 after digital radiographs were evaluated in the study. The association between postoperative inferior alveolar nerve (IAN) paresthesia and the presence of any preoperative high-risk signs in the OPG was investigated. Bivariate and multivariate logistic regression analyses were completed to compare the accuracy of conventional and digital radiographic techniques detecting high-risk signs predicting possible IAN paresthesia.Digital OPG results showed significantly higher sensitivity in diversion (P = 0.014) and narrowing (P < 0.002) of the canal, whereas the specificity of these signs was significantly lower (P < 0.001 and P = 0.035). The likelihood ratio analysis and multivariate logistic regression analysis did not prove the significant difference between digital and conventional imaging according to the examined high-risk signs. Positive predictive values of the signs were found in conventional radiography between 3.6% and 10.9%, whereas in the digital images, it ranged from 2.9% to 7.9%.The results of this study failed to prove significant difference between the accuracy of digital and conventional OPG for predicting IAN paresthesia, whereas low positive predictive values indicate both imaging techniques as inadequate screening methods for predicting IAN paresthesia after mandibular third molar removal. PMID- 22446456 TI - Pott puffy tumor appearing with a frontocutaneous fistula. AB - Pott puffy tumor is defined as a forehead-localized swelling with overlying subperiosteal abscess and osteomyelitis of the frontal bone. It is an uncommon disease entity and more rarely reported with its frontocutaneous fistula. We report the unusual case of Pott puffy tumor appearing with a frontocutaneous fistula. We performed a frontal sinus surgery using a combined endonasal and percutaneous approach and frontal bone reconstruction with a resorbable mesh plate and bone cement. During a follow-up 1 year after the surgery, there was no recurrence, and we achieved excellent result from the aesthetic point of view. PMID- 22446457 TI - Fracture of the anterior nasal spine. AB - A 24-year-old man was assaulted and complained of vague discomfort with tenderness on the nose. Physical examination manifested pain over the nasolabial angle region aggravated by upper lip closure. Computed tomography with three dimensional reconstruction of the facial bone revealed a fracture of the anterior nasal spine accompanying the overt displacement. The patient underwent open reduction and internal fixation. Clinical symptoms were completely resolved after the surgery. Regular diet was recommenced in 2 weeks without any complications. The purpose of this study was to emphasize the awareness of the clinical feature and the modality of treatment in case of anterior nasal spine fracture with displacement. PMID- 22446458 TI - Value of the ViziLite Plus System as a diagnostic aid in the early detection of oral cancer/premalignant epithelial lesions. AB - The aim of the study was to assess the value of the chemiluminescent light and 1% tolonium chloride as a diagnostic aid in the early detection of oral cancer/premalignant epithelial lesions. Thirty consecutive patients with 41 visually identified oral lesions suggestive of being premalignant underwent chemiluminescence and tolonium chloride examination followed by incisional biopsy with histopathologic evaluation. The biopsies of 34 lesions (82.92%) revealed no dysplasia, 3 lesions (7.32%) revealed mild dysplasia, 3 lesions (7.32%) demonstrated severe dysplasia, and 1 lesion (2.44%) was malignant (squamous cell carcinoma). The chemiluminescent examination improved the brightness (58.54% of the cases), sharpness (56.1% of the cases), texture (60.98% of the cases), and size of the lesion (53.66% of the cases). With references to serious pathologies, 7 cases (100.0%) were brighter, and size was more visualized in 6 cases (85.71%) when using chemiluminescence examination than under incandescent light. Twenty five (73.53%) of nonserious pathology and 7 (100.0%) of serious pathology (6 dysplasias, 1 squamous cell carcinoma) were positively stained by toluidine blue. Three (8.82%) of nonserious pathology and 0 (0.0%) of serious pathology lesions were identified as true negatives when toluidine blue staining was used. The overall toluidine blue sensitivity and specificity were 81.8% and 37.5%, respectively. Chemiluminescent light demonstrates better visualization (brightness, size) of serious pathology lesions in comparison with conventional clinical oral examination under incandescent light. Toluidine blue demonstrates 100% sensitivity in staining serious pathology. The ViziLite Plus system may help the practitioner to visualize oral pathologies that are not readily detectable with conventional incandescent lighting. PMID- 22446459 TI - Numerous recurrent trichilemmal cysts of the scalp: differential diagnosis and surgical management. AB - Trichilemmal cysts are common benign soft tissue tumors that occur in hairy areas, especially the scalp, where they present themselves as solitary masses that could be easily treated by surgical excision followed by pathologic identification. It is unusual to find these benign masses in very large numbers in 1 scalp. In the current article, we describe a 43-year-old woman who presented with 51 scalp masses, some of which recurred after repetitive excisions somewhere else by different surgeons under local anesthesia. These masses involved only the scalp and spared all the face. The patient presented to our clinic for a radical solution to clear her scalp from the unaesthetic look and appearance that forbid her from exposing her head and for hygienic reasons relating to the foul smell of repeated previous recurrences and infections. Her clinical presentation is described, and the suggested differential diagnosis and management for such a patient is discussed. PMID- 22446460 TI - Pigmented villonodular synovitis of the temporomandibular joint. AB - Pigmented villonodular synovitis is a benign lesion of unclear etiology involving the synovial membranes of joints, bursae, and tendon sheaths. Its occurrence in the temporomandibular joint is particularly rare. Despite its benign nature, pigmented villonodular synovitis is described as being locally destructive to the surrounding structures. Imaging evaluation and histopathologic examination are crucial for correct diagnosis.The purposes of the surgical treatment are for relief of pain and swelling, improvement of joint function, and prevention of further joint damage.The authors report a case involving an adult male patient; complete excision of the temporomandibular joint lesion through an open arthroplasty approach was performed. To date, after 18 months of follow-up, the patient is disease free with an adequate preservation of function. PMID- 22446461 TI - TMJ herniation associated with lymphangioma of the parotid region. AB - OBJECTIVE: The objective of this study was to present clinical, audiological, and radiologic findings of a rare case of the temporomandibular joint herniation associated with lymphangioma of the parotid region. CLINICAL REPORT: A 21-year old man with the complaints of a mass on the right side of the face, otalgia, and hearing loss in the right ear was referred to our department. The examination revealed a herniating temporomandibular joint into the right external auditory meatus when the patient closed his mouth. He had also hearing loss when he closed his mouth. Upon opening the mouth, the temporomandibular joint returned into its normal position within the glenoid fossa, and the hearing became normal. The patient had also lymphangioma involving mainly the parotid region. CONCLUSIONS: Temporomandibular joint herniation into the external auditory meatus may be rarely due to parotid lymphangioma, which leads to pseudo-conductive hearing loss. PMID- 22446462 TI - Oral myiasis. AB - Human myiasis results from parasitic tissue infestation by maggots. It often develops in open or necrotic wounds and has its highest prevalence among poor populations in tropical regions. This study reports 2 cases of human myiasis in the oral cavity and describes its clinical aspect and treatment. PMID- 22446463 TI - Alveolar cleft closure by osseodistraction: pitfalls and troubleshooting. AB - Segmental maxillary osseodistraction is a proper method to close alveolar gaps in patients with clefts of lip, palate, and alveolus. The technique is mainly used in very wide clefts after failure of conventional bone grafting procedures. The aim of the study was to analyze problems that may occur during the distraction process. Patients with uncommon wide alveolar clefts or recurrent oronasal fistulas and patients with bilateral clefts of lip, plate, and alveolus and an additional vertical deficit of the posterior cleft segment underwent distraction procedures. The patients were subdivided according to the vector of distraction: linear (following the dental arch) and vertical. The devices for horizontal distraction were tooth-borne and manufactured to the specific clinical situation. For vertical distraction, standard devices were used. Of this sample, patients with complications occurring during or after surgery and during the distraction period were selected as the study participants. On the basis of the data collected on these complications, the need for additional bone grafting procedures was evaluated. Results suggest that modifications in preoperative planning and the construction of the distraction devices may be necessary to prevent unexpected problems in segmental maxillary distraction procedures. Considerations concerning the placement of distraction devices are discussed. PMID- 22446464 TI - Assessment of facial and cranial development and comparison of anthropometric ratios. AB - BACKGROUND: Anthropometry is the biologic science of human body measurement. Craniofacial anthropometry discusses the characteristics on the measures of different soft and hard tissues of the head and face, and it is considered an important paraclinical record for the growth and development of the index and also for the diagnosis and curing orthodontic matters. Studying the craniofacial anthropometrics ratios is very useful in sciences such as dentistry, medicine, maxillofacial surgery, growth and development studies, plastic surgery, bioengineering, and nonmedical branches such as respiratory equipment and eye glasses industries. OBJECTIVES: The aims of this study were to determine Iranian cranial and facial anthropometric ratios and compare anthropometric ratios between Iranian and Canadian populations. METHODS: This cross-sectional analytical study was done randomly on 564 four-to-eleven-year-old boys from Shirvan (North Khorasan, Iran) with normal face patterns. Facial and cranial ratios were estimated and compared. Data were analyzed by SPSS software. The mean values of these parameters were calculated .Finally, the regression line and the growth coefficient were determined for each parameter. Furthermore, the mean anthropometric measurement of Iranians was compared with Canadians. Student t test was used for comparing the measured values. RESULTS: Iranian population when born has hypereuryprosopic face and hypercephalic cranium form. While getting older, the midface height increases, face becomes more prominent, chin becomes shorter, and the face and cranium change to eurycephalic and hyperleptoprosopic form, respectively. Comparison of results related to the face and cranium size between Iranian and Canadian boys (4-11 years old) showed that many craniofacial ratios have significant differences (P < 0.05). CONCLUSIONS: Approximately, all of the anthropometric measurements in Iranian population and Canadians were significantly different. Considering the significant difference in the facial and cranial anthropologic ratios and size among Iranians and Canadians, the results obtained from Canadians should not be applied as criteria for treatment plans. Because of the wide population affinity combinations in Iran, more studies, with wider variations, should be conducted among different Iranian population affinity. PMID- 22446465 TI - Peripheral osteoma bilateral of the mandible without association with Gardner syndrome. AB - Periosteal osteoma is a rare benign pathologic lesion in the jaws and the mandible is the anatomic region most frequently involved. Elective treatment consists of surgical excision. The aim of this report was to report a rare case of bilateral periosteal osteoma involving the mandible--a painless, firm, and well-circumscribed lesion, with more bony prominence on the left than on the right side. The patient had no history of facial trauma or systemic changes that could intervene with the progression of the lesion. It was diagnosed as a periosteal osteoma, and surgical excision was performed. No recurrence after 4 years of follow-up was demonstrated. Surgical excision of the periosteal osteoma was demonstrated to be a useful technical strategy that simplifies and accelerates the surgical procedures and probably contributes to establish harmony of the jaws. Periodical clinical and radiographic follow-ups after surgery are advised. PMID- 22446466 TI - Giant arteriovenous malformation of the floor of the mouth presenting with dysarthria and difficulty in swallowing. AB - Arteriovenous malformation (AVM) is a vascular abnormality resulting in the development of abnormal connection between an artery and vein without capillary connections. An AVM develops mainly intracranially. Extracranial AVMs are rarely seen. Cheek, ear, nose, auricle, and forehead are the more common sites in the extracranial involvement. They cause cosmetic problems when located in the head and neck region. We report a case of a giant AVM in the floor of the mouth, which has not been specified and has not been reported until now. The lesion, in an elderly man, was supplied by multiple vessels and caused difficulty in speaking and swallowing. The lesion was totally excised after embolization of feeding vessels. PMID- 22446467 TI - Reconstruction of complex aplasia cutis congenita. AB - Aplasia cutis congenita is a rare scalp defect with occasional absence of underlying bone and dura. Patients with small defects respond well to conservative management. However, larger defects often can pose management and technical challenge. Successful management of a large, composite aplasia cutis congenita defect using Integra dermal regeneration matrix is presented. At 16 months, the patient showed a stable and supple scalp with evidence of calvarial regeneration. PMID- 22446468 TI - Sequential second free fibula flap for the reconstruction of metachronous osteoradionecrosis of the mandible. AB - Osteoradionecrosis (ORN) of the mandible is a potentially catastrophic complication of external beam radiation therapy for head and neck malignancies. A 55-year-old man treated with chemoradiation for base-of-tongue cancer presented with a necrotic left mandibular body and underwent left mandibulectomy with right free fibula osteocutaneous flap reconstruction. Two and a half years later, he presented with right mandibular body ORN and underwent a second mandibular resection and subsequent reconstruction with a left fibula osteocutaneous free flap fixed in the midline to the previously placed contralateral fibula. He recovered well from all procedures. To the best of our knowledge, we report the first case of a patient with metachronous ORN of the mandible requiring resection and subsequent reconstruction with sequential free fibula flaps. Even in the presence of prior microvascular reconstructions, patients can successfully undergo additional reconstructive procedures to restore their function, appearance, and quality of life. PMID- 22446469 TI - Mandibular symphyseal fracture simulated by a foreign body in the chin. AB - INTRODUCTION: Penetrating foreign bodies occurring after maxillofacial injuries are a diagnostic challenge for the trauma surgeon. Different materials and various sites of penetration in the maxillofacial region are described in the literature. We present the peculiar course of a patient with an endoral retained foreign body after a penetrating facial injury. The diagnostic pitfall in this type of trauma is highlighted owing to the hyperdensity of the foreign body that, at the computed tomographic (CT) axial scan, simulated a vestibular cortical fracture of the mandibular body and deceived both the radiologist and the surgeon. CLINICAL REPORT: We introduce the case of a boy who fell from his bicycle. Computed tomography was performed to detect any bone injuries. The radiologic report stated that a left condylar fracture was presented, associated to a vestibular cortical fracture of the mandibular body. Anamnestic questions revealed that the boy fell from his bicycle in a dug-up street. Clinical examination revealed 2 extraoral open wounds in the subnasal and periorbital areas and an endoral linear wound in the inferior fornix at the mandibular symphyseal region. Consequently, the left condylar fracture was surgically treated, and the mandibular body was explored by the endoral wound revealing an intact cortex: the road metal was removed from the soft tissue of the chin. The initial diagnostic pitfall was clarified: the radiodense foreign bodies penetrated the endoral wound in the soft tissue of the chin during the fall. They simulated a vestibular cortical fracture of the mandibular body at the CT scan deceiving both the radiologist and the surgeon. DISCUSSION: According to the literature, soft tissue foreign bodies can be detected by ultrasonography, plain radiography, CT, and magnetic resonance imaging. Superficially retained foreign bodies are easily detected with ultrasonography if they are not covered by overlying bone or gas. If this easily available technique had been applied initially in this case, the correct diagnosis might have been established at the initial admittance. Deeply located foreign bodies are best visualized by CT. The foreign body in the case introduced was made by radiopaque substance it presented the same radiodensity as the bone. PMID- 22446470 TI - Intraorbital epidermoid cyst: a 5-year-old with exophthalmos and strabismus. AB - A 5-year-old girl with right exophthalmos and esotropia presented to ophthalmology outpatient clinics. Orbital computed tomography revealed a 20- to 30-mm oval soft tissue mass lying superolateral to the right lateral rectus muscle in the orbit. The patient was operated on by a neurosurgical team, the csyt was removed totally, and examination of the pathologic specimen, which reveals the epidermoid cyst, was performed. After the operation, exophthalmos and esotropia were improved, and visual acuity was increased. Although itis seen as a rare entity in the orbit, epidermoid cyst must be considered during the investigation of exophthalmos. PMID- 22446471 TI - Aesthetic and anatomic subunit reconstruction of composite mandibular gunshot wound. AB - BACKGROUND: Gunshot facial traumas involving the mandible and surrounding soft tissues are represented by the potential for loss of relationships between the functional and the aesthetic subunits of the head. METHODS: A patient presented with an 8-cm composite mandibular defect, resulting from a self-inflicted gunshot injury. Taking into account the anatomic/aesthetic subunits involved, a fibular osseoseptocutaneous flap was transferred to reconstruct the left lateral mandibular segment and the floor of the mouth, whereas a preexpanded temporal scalp flap was transferred to restore the hair-bearing skin of the left buccomandibular subunit. A review of the literature is also presented. RESULTS: A satisfactory functional and aesthetic outcome was achieved. Although current literature supports the value of aesthetic subunit face reconstruction and the use of double flaps for the reconstruction of through-and-through oromandibular defects, there is no previous report of the combined use of temporal scalp flap and fibular osseocutaneous flap. CONCLUSIONS: The combined use of hair-bearing skin and osseocutaneous flap may achieve optimal results in through-and-through oromandibular defects. PMID- 22446472 TI - Preliminary experience with a dynamic resorbable fixation device for craniosynostosis surgery. AB - The advent of resorbable osteosynthesis material has revolutionized craniomaxillofacial surgery. The need to provide rigid bony fixation in the surgical treatment of craniofacial deformities has inspired an ongoing evolution of surgical innovations and implants. Stability of the plates has been improved, but the duration of their stability remains an ongoing problem. In infant craniofacial fixation, it is important to provide initial stability, but after 4 to 6 weeks, this is no longer required as the brain is rapidly expanding. Surgery was performed on 10 patients with sagittal suture synostosis with conventional suture resection, remodeling, and fixation with resorbable miniplate (PolyMax RAPID) struts held in position with modeled resorbable pockets affixed to the neurocranium with resorbable screws placed across the resected suture between June 2004 and September 2008. All the patients presented a satisfactory aesthetic result without complications after at least 1-year follow-up. We present a further innovative method of craniofacial fixation in infants using resorbable plates as floating struts providing stability and at the same time controlled dynamic expansion of the cranial vault guided by brain growth. PMID- 22446473 TI - Public-private collaborations and partnerships in stratified medicine: making sense of new interactions. AB - The field of personalised or stratified medicine is evolving alongside the formation of a plethora of public/private partnerships and collaborations. These new institutional forms, or 'social technologies', are varied and emerge in response to several drivers, including the need to draw on a broader base of data inputs relating to genomics, patient behaviour and healthcare system differentiation. This paper discusses some of these drivers of partnerships and collaborations. Although the number of such partnerships is growing, their rationale and basis for collaboration remains unclear. Public-private collaborations are at the core of the set of new life sciences policies in the UK but there is little indication in the policy documents of clear boundaries for these partnerships. In part, this is due to the lack of empirical evidence at the system level for conceptualising what is still a relatively new approach. The collection of evidence in the form of broad evaluations, rather than tightly focused theoretical studies, is more likely to be related back to systems and be of more use for formulating policy rationales. PMID- 22446474 TI - Selecting a fellowship in gastroenterology. PMID- 22446475 TI - A specific PCR assay for the identification and differentiation of Schistosoma japonicum geographical isolates in mainland China based on analysis of mitochondrial genome sequences. AB - In the present study, near-complete mt genome sequences for eight representative Schistosoma japonicum samples from seven endemic provinces in mainland China were analyzed. Sequence differences among the eight mt genomes of S. japonicum samples were 0.20-2.51%. Variation in protein-coding genes was greater than that in rRNA genes. The mt DNA sequences of S. japonicum samples from south-western (SW) China were 2 bp [position 11727-11728 within tRNA-Cys, microsatellite (AG) indel] longer than those of the parasites from the lower Yangtze/Zhejiang areas. Representative DNA sequencing confirmed that such (AG) indel could be exploited for identification and differentiation of S. japonicum populations in SW China's Yunnan and Sichuan province which have two (AG) repeats from those in all remaining endemic provinces along the Yangtze River below the Three Gorges regions or close to the east coast of China (e.g., Zhejiang) which have only one (AG) repeat. Phylogenetic analyses based on the concatenated amino acids of 12 protein-coding genes also showed that samples from SW China (Sichuan and Yunnan provinces), above the Three Gorges Dam, formed a distinct cluster. Based on this indel polymorphism, a pair of specific primers was designed and used to develop a specific-PCR polyacrylamide gel detection assay. There was an obvious length difference in the amplified PCR products between S. japonicum samples from the two endemic types. The specific-PCR assay allowed the specific identification of S. japonicum, with no amplicons being amplified from other closely related trematodes, and the minimum amount of DNA detectable was 0.05 ng. This approach is inexpensive, easy to perform and the whole detection process can be completed within 4h. Examination of 81 S. japonicum samples from SW China's Yunnan and Sichuan provinces, and 264 samples from the lower Yangtze provinces (Hubei, Jiangsu, Jiangxi, Anhui and Hunan) and from Zhejiang validated the value of the specific PCR assay and proved its reliability. These findings indicate that the specific PCR assay would provide a useful tool for the epidemiological surveillance and for tracing the source of S. japonicum infection in humans and animals in China. PMID- 22446476 TI - Low back and hip pain in a postpartum runner: applying ultrasound imaging and running analysis. AB - STUDY DESIGN: Case report. BACKGROUND: Postpartum low back and hip dysfunction may be caused by an incomplete recovery of abdominal musculature and impaired neuromuscular control. The purpose of this report is to describe the management of a postpartum runner with hip and low back pain through exercise training via ultrasound imaging (USI) biofeedback combined with running-form modification. CASE DESCRIPTION: A postpartum runner with hip and low back pain underwent dynamic lumbar stabilization training with USI biofeedback and running-form modification to reduce mechanical loading. Muscle thickness of transversus abdominis and internal oblique was measured with USI preintervention and 7 weeks after completion of the intervention. Additionally, 3-dimensional lower extremity joint motions, moments, and powers were calculated during treadmill running. OUTCOMES: The patient's pain with running decreased from a constant 9/10 (0, no pain; 10, worst pain) to an occasional 3/10 posttreatment. Transversus abdominis muscle thickness increased 6.3% during the abdominal drawing-in maneuver and 27.0% during the abdominal drawing-in maneuver with straight leg raise. Changes were also noted in the internal oblique. These findings corresponded to improved lumbopelvic control: pelvic list and axial rotation during running decreased 38% and 36%, respectively. The patient's running volume returned to preinjury levels (8.1-9.7 km, 3 days per week) with no hip pain and minimal low back pain, and she successfully completed her goal of running a half-marathon. DISCUSSION: The successful outcomes of this case support the consideration of dynamic lumbar stabilization exercises, USI biofeedback, and running-form modification in postpartum runners with lumbopelvic dysfunction. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 22446477 TI - Collagen adsorption on quercetin loaded polycaprolactone microspheres: approach for "stealth" implant. AB - We recently experimented with collagen coating on the surface of quercetin loaded polycaprolactone microspheres by simple adsorption technique to mimic extra cellular matrix and reduce immune or inflammatory responses at the site of implants. The collagen immobilization on polymeric scaffold surfaces through various surface modification techniques was the current scenario to improve bio integration of the polymers with the in vivo system. Nevertheless, it requires other chemicals or processing methods to modify the surface of polymers to immobilize the collagen covalently. Here protein adsorption principle is used for the coating of collagen onto the surface of solid microspheres and characterized. Optical, ATR-FTIR, SEM analysis confirm collagen coating. The reduction in burst release of the quercetin from the PCL microspheres further confirms its presence and role in the controlled release. The results indicate that the adsorption technique can be the simple strategy to coat collagen on the surface of polyester implants to develop stealth implant in shorter time with low cost technology. PMID- 22446478 TI - HCN and KV7 (M-) channels as targets for epilepsy treatment. AB - Voltage-gated ion channels are important determinants of cellular excitability. The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) and KV7 (M-) channels are voltage-gated ion channels. Both channels are activated at sub threshold potentials and have biophysical properties that mirror each other. KV7 channels inhibit neuronal excitability. Thus, mutations in KV7 channels that are associated with Benign Familial Neonatal Convulsions (BFNC) are likely to be epileptogenic. Mutations in HCN channels have also been associated with idiopathic epilepsies such as GEFS+. In addition, HCN channel expression and function are modulated during symptomatic epilepsies such as temporal lobe epilepsy. It is, though, unclear as to whether the changes in HCN channel expression and function associated with the various forms of epilepsy promote epileptogenesis or are adaptive. In this review, we discuss this as well as the potential for KV7 and HCN channels as drug targets for the treatment of epilepsy. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. PMID- 22446484 TI - Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. AB - Membrane-anchored ephrinB2 and its receptor EphB4 are involved in the formation of blood and lymphatic vessels in normal and pathologic conditions. Eph/ephrin activation requires cell-cell interactions and leads to bidirectional signaling pathways in both ligand- and receptor-expressing cells. To investigate the functional consequences of blocking ephrinB2 activity, 2 highly specific human single-chain Fv (scFv) Ab fragments against ephrinB2 were generated and characterized. Both Ab fragments suppressed endothelial cell migration and tube formation in vitro in response to VEGF and provoked abnormal cell motility and actin cytoskeleton alterations in isolated endothelial cells. As only one of them (B11) competed for binding of ephrinB2 to EphB4, these data suggest an EphB receptor-independent blocking mechanism. Anti-ephrinB2 therapy reduced VEGF induced neovascularization in a mouse Matrigel plug assay. Moreover, systemic administration of ephrinB2-blocking Abs caused a drastic reduction in the number of blood and lymphatic vessels in xenografted mice and a concomitant reduction in tumor growth. Our results show for the first time that specific Ab-based ephrinB2 targeting may represent an effective therapeutic strategy to be used as an alternative or in combination with existing antiangiogenic drugs for treating patients with cancer and other angiogenesis-related diseases. PMID- 22446485 TI - Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim dependent process. AB - Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34(+) cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 processing and LC3-green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML. PMID- 22446486 TI - Maturation-related histone modifications in the PU.1 promoter regulate Th9-cell development. AB - Epigenetic histone modifications are thought to underlie the rapid memory immune response to recall antigen that develops after vaccination. However, histone modification patterns in genes encoding transcription factors regulating cytokine production have not been investigated in either memory and naive T cells or as the immune system matures to understand the differences in cytokine response patterns. In the present study, we analyzed histone modifications in promoter regions of T-bet, GATA-3, PU.1, IRF4, and RORC in neonatal naive T cells and in adult naive and memory CD4 T cells, and found a unique and dynamic histone modification pattern in the PU.1 promoter that was related to age and the naive/memory status of a T cell. Naive T cells required more intense stimulation to switch the chromatin pattern in the PU.1 promoter from a repressive to permissive state, and therefore to produce IL-9 than did memory T cells. Inhibition of repressive histone methylation by the specific inhibitor 3 deazaneplanocin induced Th9-specific PU.1 expression, even in conditions that would normally yield only Th0 cytokines. Conversely, prevention of histone acetylation by the histone acetyltransferase inhibitor curcumin diminished PU.1 expression after IL-9-inducing stimulation. Our findings identify age- and differentiation-status-related epigenetic modifications of PU.1 as a unique regulator of Th9 memory acquisition and Th9 immunity. PMID- 22446487 TI - Adapting an HIV/STDs Prevention Curriculum to Fit the Needs of Women With Alcohol Problems. AB - Alcohol and drug dependent women are at increased risk for HIV/STDs. This paper discusses how a prevention curriculum, "Safer Sex Skill Building" (SSB), designed to reduce the contraction of HIV/STDs among drug-abusing women, could be modified to fit the needs of alcohol-abusing women in a residential treatment program. Authors modified the SSB by incorporating feedback from expert consultants as well as by engaging study participants in revising the therapy manual in order to create a curriculum that speaks to participants' experiences. Specific steps to assist those who would want to adapt an empirically-based manual-driven treatment intervention are provided. PMID- 22446489 TI - A dual-subsystem model of the brain's default network: self-referential processing, memory retrieval processes, and autobiographical memory retrieval. AB - Most internally oriented mental activities are known to strongly activate the default network, which includes remembering the past, future thinking and social cognition, and are heavily self-referential, and demanding of memory retrieval processes. Based on these observations and building on related findings from the literature, the present article proposed a simple, dual-subsystem model of the default network. The ability of the model to estimate brain activity during autobiographical memory (AM) retrieval and related reference conditions was then tested by performing a quantitative meta-analysis of relevant literature. The model divided the default network into two subsystems. The first, called the 'cortical midline subsystem (CMS)', was comprised of the anteromedial prefrontal cortex and posterior cingulate cortex, and primarily mediates self-referential processing. The other, termed the 'parieto-temporal subsystem (PTS)', included the inferior parietal lobule, medial temporal lobe and lateral temporal cortex, and mainly supports memory retrieval processes. The meta-analysis of AM retrieval contrasts yielded a double dissociation that was consistent with this model. First, CMS regions associated more with an AM>laboratory-based memory (LM) contrast than with an AM>rest contrast, confirming that these regions play more critical roles in self-referential processing than memory retrieval processes. Second, all three PTS regions showed a greater association with an AM>rest contrast than with an AM>LM contrast, confirming that their role in memory retrieval processes is greater than in self-referential processing. Although the present model is limited in scope, both in terms of anatomical and functional specifications, it integrates diverse processes such as self-referential processing, episodic and semantic memory and subsystem interface, and provides useful heuristics that can guide further research on fractionation of the default network. PMID- 22446488 TI - Individual differences in brain structure underpin empathizing-systemizing cognitive styles in male adults. AB - Individual differences in cognitive style can be characterized along two dimensions: 'systemizing' (S, the drive to analyze or build 'rule-based' systems) and 'empathizing' (E, the drive to identify another's mental state and respond to this with an appropriate emotion). Discrepancies between these two dimensions in one direction (S>E) or the other (E>S) are associated with sex differences in cognition: on average more males show an S>E cognitive style, while on average more females show an E>S profile. The neurobiological basis of these different profiles remains unknown. Since individuals may be typical or atypical for their sex, it is important to move away from the study of sex differences and towards the study of differences in cognitive style. Using structural magnetic resonance imaging we examined how neuroanatomy varies as a function of the discrepancy between E and S in 88 adult males from the general population. Selecting just males allows us to study discrepant E-S profiles in a pure way, unconfounded by other factors related to sex and gender. An increasing S>E profile was associated with increased gray matter volume in cingulate and dorsal medial prefrontal areas which have been implicated in processes related to cognitive control, monitoring, error detection, and probabilistic inference. An increasing E>S profile was associated with larger hypothalamic and ventral basal ganglia regions which have been implicated in neuroendocrine control, motivation and reward. These results suggest an underlying neuroanatomical basis linked to the discrepancy between these two important dimensions of individual differences in cognitive style. PMID- 22446490 TI - Effect of paroxetine and bupropion on human resting brain perfusion: an arterial spin labeling study. AB - Due to the physiological coupling with metabolism, brain perfusion is a potential aid in understanding the effects of medication on neural activity in vivo. In this study, arterial spin labeling (ASL) was used to quantify the effect of seven days of administration of paroxetine (20 mg), bupropion (150 mg) on cerebral blood flow levels at rest in a double-blind, placebo-controlled crossover design in N=21 healthy participants. Paroxetine administration was associated with diffuse cortical perfusion decrements, more marked in the prefrontal region, and with decrements in the striatum, caudate and the basal forebrain. The effect of bupropion on the cortex was similar but less conspicuous. In the brainstem, there was suggestive evidence of perfusion decrements in the main serotonergic and noradrenergic nuclei. These results demonstrate the existence of effects on rest perfusion of antidepressant medication of potential use in monitoring its action. The observed perfusion reductions may be related to compensatory decrements of monoaminergic neural activity in the initial phases of treatment that are observed under both drugs following the increase in extracellular concentration of transmitters. PMID- 22446491 TI - One-year test-retest reliability of intrinsic connectivity network fMRI in older adults. AB - "Resting-state" or task-free fMRI can assess intrinsic connectivity network (ICN) integrity in health and disease, suggesting a potential for use of these methods as disease-monitoring biomarkers. Numerous analytical options are available, including model-driven ROI-based correlation analysis and model-free, independent component analysis (ICA). High test-retest reliability will be a necessary feature of a successful ICN biomarker, yet available reliability data remains limited. Here, we examined ICN fMRI test-retest reliability in 24 healthy older subjects scanned roughly one year apart. We focused on the salience network, a disease-relevant ICN not previously subjected to reliability analysis, as well as the default mode network. Most ICN analytical methods proved reliable (intraclass coefficients>0.4) and were further improved by wavelet analysis. Seed-based ROI correlation analysis showed high scan-wise reliability, whereas graph theoretical analysis and temporal concatenation group ICA proved most reliable at the individual unit-wise level (voxels, ROIs). Including global signal regression in ROI-based correlation analyses reduced reliability. Our study provides a direct comparison between the most commonly used ICN fMRI methods and potential guidelines for measuring intrinsic connectivity in aging control and patient populations over time. PMID- 22446493 TI - Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog. AB - Hereditary muscle-type phosphofructokinase (PFK) deficiency causing intermittent hemolytic anemia and exertional myopathy due to a single nonsense mutation in PFKM has been previously described in English Springer and American Cocker Spaniels, Whippets, and mixed breed dogs. We report here on a new missense mutation associated with PFK deficiency in Wachtelhunds. Coding regions of the PFKM gene were amplified from genomic DNA and/or cDNA reverse-transcribed from RNA of EDTA blood of PFK-deficient and clinically healthy Wachtelhunds and control dogs. The amplicons were sequenced and compared to the published canine PFKM sequence. A point mutation (c.550C>T, in the coding sequence of PFKM expressed in blood) was found in all 4 affected Wachtelhunds. This missense mutation results in an amino acid substitution of arginine (Arg) to tryptophan (Trp) at position 184 of the protein expressed in blood (p.Arg184Trp). The mutation is located within an alpha-helix, and based on the SIFT analysis, this amino acid substitution is not tolerated. Amplifying the region around this mutation and digesting the PCR fragment with the restriction enzyme MspI, produces fragments that readily differentiate between PFK-deficient, carrier, and normal animals. Furthermore, we document 2 additional upstream PFKM exons expressed in canine testis but not in blood. Despite their similar phenotypic appearance and use for hunting, Wachtelhunds and English Springer Spaniels are not thought to have common ancestors. Thus, it is not surprising that different mutations are responsible for PFK deficiency in these breeds. Knowledge of the molecular basis of PFK deficiency in Wachtelhunds provides an opportunity to screen and control the spread of this deleterious trait. PMID- 22446492 TI - Measuring and comparing brain cortical surface area and other areal quantities. AB - Structural analysis of MRI data on the cortical surface usually focuses on cortical thickness. Cortical surface area, when considered, has been measured only over gross regions or approached indirectly via comparisons with a standard brain. Here we demonstrate that direct measurement and comparison of the surface area of the cerebral cortex at a fine scale is possible using mass conservative interpolation methods. We present a framework for analyses of the cortical surface area, as well as for any other measurement distributed across the cortex that is areal by nature. The method consists of the construction of a mesh representation of the cortex, registration to a common coordinate system and, crucially, interpolation using a pycnophylactic method. Statistical analysis of surface area is done with power-transformed data to address lognormality, and inference is done with permutation methods. We introduce the concept of facewise analysis, discuss its interpretation and potential applications. PMID- 22446494 TI - Potential exposure of medical students to blood borne viruses on medical elective and the use of HIV post exposure prophylaxis. PMID- 22446495 TI - Computed tomography angiography in patients with tuberculous meningitis. AB - BACKGROUND: Strokes in tuberculous meningitis are important determinant of prognosis. Strokes are caused by tuberculosis-related vasculopathy. In this study, we aimed to demonstrate the value of computed tomography angiography. We also assessed value of angiographic findings in determining the prognosis. METHODS: We included consecutive patients of tuberculous meningitis and prospectively followed them for 6 months. Computed tomography angiography was performed at inclusion. Follow-up angiography, after 6 months, was done in the patients, who had given consent. Angiographic findings were evaluated by experienced neuroradiologists. RESULTS: Initial computed tomography angiography revealed arterial narrowing or occlusion in 33 patients. In 30 patients the anterior cerebral circulation and in 9 patients posterior cerebral circulation was involved. Six (18.2%) patients had lesions in both the territories. The most frequently involved arteries were supraclinoid portion of the internal carotid artery, and proximal portions of the anterior cerebral and middle cerebral arteries. On univariate analysis, predictors of angiographic abnormalities were impaired vision (p = 0.019), hemiparesis (p = 0.002), hydrocephalous (p < 0.001), basal exudates (p < 0.001), meningeal enhancement (p = 0.026) and infarcts (p < 0.001). On multivariate analysis basal exudates was a significant predictor. Angiographic abnormalities were associated with insignificantly poorer prognosis. On follow-up angiograms, 3 patients showed resolution in vascular abnormalities. Two patients had developed new angiographic abnormalities. CONCLUSION: Arterial narrowing and occlusion is seen in majority of patients with tuberculous meningitis. Angiographic abnormalities may be associated with poor prognosis. PMID- 22446497 TI - Proteomic identification of serum biomarkers for gastric cancer using multi dimensional liquid chromatography and 2D differential gel electrophoresis. AB - BACKGROUND: Early diagnosis and treatment of gastric cancer patients is essential for improving prognosis. However, no available serum-based test provides sufficient sensitivity or specificity for widespread use. Therefore, in this study we aimed to identify cancer biomarkers in human sera using 2-dimensional difference gel electrophoresis (2D-DIGE), and to characterize protein biomarkers with tandem mass spectrometry. METHODS: We compared the serum proteomic profiles of 20 gastric cancer patients and 10 healthy volunteers. Serum samples were first chromatographed using an immunoaffinity high-performance liquid chromatography (HPLC) column to selectively remove albumin, immunoglobulins, transferrin, haptoglobin, and antitrypsin. Differential protein analysis was then performed using DIGE. Significantly increased and decreased protein spot features were excised, trypsin digested, and analyzed by tandem matrix-assisted laser desorption/ionization (MALDI) time of flight (TOF)/TOF and a linear trap quadrupole (LTQ) mass spectrometer. RESULTS: Seventeen protein spot features were significantly increased and 7 were significantly decreased in cancer serum samples compared to healthy controls. We identified 7 unique proteins that were upregulated, including plasminogen, apolipoprotein A-IV, Kininogen-1, complex forming glycoprotein HC, complement component C4A, apolipoprotein J, and clusterin, and 5 that were decreased. CONCLUSIONS: These results suggest that the combination of multi-dimensional HPLC and 2D-DIGE provides a valuable tool for serum proteomics in gastric cancer. PMID- 22446498 TI - A liquid chromatography-tandem mass spectrometry assay for detection and quantitation of the dipeptide Gly-Gln in rat brain. AB - The enzymatic cleavage products of beta-endorphin (beta-endorphin1-27 and Gly Gln) reduce voluntary alcohol consumption in alcohol-preferring (P) rats. Gly-Gln also inhibits the reward-benefiting effects of morphine and nicotine. It would be useful for the investigation of these effects to have an analytical method suitable for Gly-Gln detection and quantitation. Given the now widespread availability of liquid chromatography-tandem mass spectrometry (LC-MS/MS) instruments, the development of an LC-MS/MS-based approach seemed a viable option. An LC-MS/MS method for Gly-Gln quantitation was developed based on derivatization with Marfey's reagent. The Marfey's adduct of Gly-Gln (Mar-Gly Gln) was chromatographically resolved and readily detected and quantitated by LC MS/MS. Precursor/product positive ions of 456.2/366.2, 456.2/237.2, and 456.2/147.0 were used for detection and quantitation. This method shows good linearity from 1 to 500 pmol of Mar-Gly-Gln (R2 > 0.99). The assay also demonstrated good accuracy and precision, with an average percentage standard deviation for Gly-Gln over the range of the assay of less than 5%. A combination of multiple reaction monitoring (MRM) fragment ratio normalization and chromatographic peak shifting was used to ensure that the LC-MS/MS peak for Mar Gly-Gln was free from possible isobar interferences. This assay was then demonstrated for the determination of in vivo Gly-Gln levels in P and Sprague Dawley rat cortex and nucleus accumbens samples. PMID- 22446499 TI - Separation and detection of individual Abeta aggregates by capillary electrophoresis with laser-induced fluorescence detection. AB - The separation and detection of individual amyloid beta (Abeta) aggregates by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was demonstrated. Samples were prepared with either Abeta (1-40) or Abeta (1-42) peptides and were characterized by CE with ultraviolet (UV) absorbance detection and transmission electron microscopy (TEM). Using thioflavin T (ThT) in the electrophoresis buffer, electrophoresis of aggregate-containing samples (5.0-s injection) produced up to several hundred narrow (< 20 ms FWHM [full width at half maximum]) fluorescence peaks. Injection of Abeta (1-40) monomer samples resulted in no additional peaks compared with controls. The CE-LIF results were validated by bulk ThT fluorescence measurements for the same samples. The potential of laser-induced fluorescence anisotropy (LIFA) with CE to characterize individual Abeta aggregates also was investigated. PMID- 22446500 TI - Intramuscular temperature changes during and after 2 different cryotherapy interventions in healthy individuals. AB - STUDY DESIGN: Crossover. OBJECTIVES: To compare the time required to decrease intramuscular temperature 8 degrees C below baseline temperature, and to compare intramuscular temperature 90 minutes posttreatment, between 2 cryotherapy modalities. BACKGROUND: Cryotherapy is used to treat pain from muscle injuries. Cooler intramuscular temperatures may reduce cellular metabolism and secondary hypoxic injury to attenuate acute injury response, specifically the rate of chemical mediator activity. Modalities that decrease intramuscular temperature quickly may be beneficial in the treatment of muscle injuries. METHODS: Eighteen healthy subjects received 2 cryotherapy conditions, crushed-ice bag (CIB) and cold-water immersion (CWI), in a randomly allocated order, separated by 72 hours. Each condition was applied until intramuscular temperature decreased 8 degrees C below baseline. Intramuscular temperature was monitored in the gastrocnemius, 1 cm below subcutaneous adipose tissue. The primary outcome was time to decrease intramuscular temperature 8 degrees C below baseline. A secondary outcome was intramuscular temperature at the end of a 90-minute rewarming period. Paired t tests were used to examine outcomes. RESULTS: Time to reach an 8 degrees C reduction in intramuscular temperature was not significantly different between CIB and CWI (mean difference, 2.6 minutes; 95% confidence interval: -3.10, 8.30). Intramuscular temperature remained significantly colder 90 minutes post-CWI compared to CIB (mean difference, 2.8 degrees C; 95% confidence interval: 2.07 degrees C, 3.52 degrees C). CONCLUSION: There was no difference in time required to reduce intramuscular temperature 8 degrees C 1 cm below adipose tissue using CIB and CWI. However, intramuscular temperature remained significantly colder 90 minutes following CWI. These results provide clinicians with information that may guide treatment-modality decisions. PMID- 22446501 TI - Natural killer cell immune escape in acute myeloid leukemia. AB - As central players of the innate immune system, natural killer (NK) cells can exert direct and indirect anti-tumor effects via their cytotoxic and immune regulatory capacities, pivotal in the induction of an effective adaptive anti tumor immune response. Hence, NK cells are considered to be important in the immune surveillance of cancer. In acute myeloid leukemia (AML) patients, however, significantly impaired NK cell functions can facilitate escape from immune surveillance and affect patient outcome. Here, we review various NK cell defects and AML evasion mechanisms to escape from NK cell-mediated immune surveillance and we discuss NK cell-related parameters as prediction factors of AML patient outcome. On the basis of these observations, novel immunotherapeutic strategies capitalizing on the potentiation of NK cell functions have emerged in AML immunotherapy, as discussed in this review. Increased knowledge on AML escape routes from NK cell immune surveillance will further aid in the design of novel NK cell-based immunotherapy approaches for the treatment of AML. PMID- 22446502 TI - Early molecular and cytogenetic response is predictive for long-term progression free and overall survival in chronic myeloid leukemia (CML). AB - In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with <=1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with <=35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with <=1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks. PMID- 22446503 TI - Ephedrine hydrochloride protects mice from LPS challenge by promoting IL-10 secretion and inhibiting proinflammatory cytokines. AB - Sepsis and its derivative endotoxic shock are still serious conditions with high mortality in the intensive care unit. The mechanisms that ensure the balance of proinflammatory cytokines and anti-inflammatory cytokine production are of particular importance. As an active alpha- and beta-adrenergic agonist, ephedrine hydrochloride (EH) is a widely used agent for cardiovascular diseases, especially boosting blood pressure. Here we demonstrate that EH increased Toll-like receptor 4 (TLR4)-mediated production of interleukin 10 (IL-10) through p38 MAPK activation. Simultaneously, EH negatively regulated the production of proinflammatory cytokines. Consistently, EH increased lipopolysaccharide (LPS) induced serum IL-10 and inhibited tumor necrotic factor-alpha (TNFalpha) production in vivo. As a result, EH treatment protected mice from endotoxic shock by lethal LPS challenge. In brief, our data demonstrated that EH could contribute to immune homeostasis by balancing the production of proinflammatory cytokines and anti-inflammatory cytokine in TLR4 signaling. This study provides a potential usage of EH in autoimmunologic diseases or other severe inflammations. PMID- 22446504 TI - Reducing specimen identification errors. AB - In 2006, the University of Wisconsin Hospital and Clinics identified that the number of specimen identification errors each month was much greater than desired and represented a significant patient safety issue. A collaborative performance improvement approach between nursing and the laboratory was undertaken for the inpatient, ambulatory, and surgical services areas, with the focus on creation of a just culture. Between 2007 and 2011, interventions were successful in significantly reducing the number of errors by 85%. PMID- 22446505 TI - Aged-related increase of high sensitive Troponin T and its implication in acute myocardial infarction diagnosis of elderly patients. AB - High sensitive cardiac Troponin T (hs-cTnT) represents an important tool in acute myocardial infarction (AMI) diagnosis. Even though the hs-cTnT evaluation is relevant for AMI diagnosis in elderly patients characterized by clinical and instrumental atypical presentation, the overall reliability in elderly patients is unknown. We aimed at: (1) defining the hs-cTnT 99th percentile value in an aged healthy reference population and (2) testing hs-cTnT diagnostic accuracy in elderly patients with a suspected AMI. 294 healthy subjects (50-105 years old) and 299 elderly patients (75-96 years old) with suspected AMI at presentation, were enrolled. Conventional cTnT, hs-cTnT, NT-proBNP and creatinine levels were determined in all participants. Our main results are: (1) a significant hs-cTnT age-related increase was observed in an healthy reference population ranging 50 105 years old; (2) hs-cTnT levels showed an age-related multimodal distribution in the healthy reference population: 16 ng/L corresponds to the 99th percentile in subjects ranging 50-75 years old, whereas 70.6 ng/L corresponds to the 99th percentile in subjects >=75 years old; (3) 86.8 ng/L resulted the hs-cTnT cut-off value with the highest efficiency in AMI diagnosis of geriatric patients. Our data suggest that the hs-cTnT cut-off value must be age-tailored to improve the AMI diagnostic accuracy. PMID- 22446506 TI - The electronic structure of the neutral isoalloxazine semiquinone within Anabaena flavodoxin: new insights from HYSCORE experiments. AB - A complete study of Anabaena flavodoxin in the neutral semiquinone state by means of the EPR pulse technique HYSCORE is here presented. The results provide new information about the hyperfine interactions of the unpaired electronic spin and the nuclei in the isoalloxazine ring. This allows a better knowledge of the electronic structure of the neutral flavin radical within the protein. Combination of these results with other previously obtained by using other EPR related techniques allowed producing a very precise mapping of the flavin spin distribution in the neutral semiquinone state. This information can be very useful for determining the relationship between the electronic structure and mechanisms in flavoproteins. An experimental protocol for measuring the electronic structure details available to date is suggested. PMID- 22446507 TI - Toward single-shot pure-shift solution 1H NMR by trains of BIRD-based homonuclear decoupling. AB - Achieving homonuclear 1H decoupling remains one of the key challenges in liquid state NMR. Such spectra would endow a variety of organic and analytical applications with an increased resolution, and would ideally do so even in a one dimensional format. A number of parallel efforts aimed at achieving this goal using two-dimensional acquisitions have been proposed; approaches demonstrated over recent years include, among others, new modes for achieving purely absorptive J spectroscopy, the use of spatially-selective manipulations, and exploiting the natural spin dilution afforded by heteronuclei. The present study relies on the latter approach, and explores the use of BIRD pulses distinguishing between protons bonded to (13)C from those bonded to (12)C, to achieve homonuclear decoupling in a continuous 1D scan. Studies on several representative compounds demonstrate that this goal can be implemented in a robust format, provided that suitable care is also taken to suppress unwanted coherences, of making all manipulations sufficiently broad-banded, and to provide adequate heteronuclear decoupling of the targeted protons. Dependable homonuclear decoupling performance can then be achieved, with minimal line width, fine tuning, and sensitivity penalties. PMID- 22446508 TI - Scavenger deterrent factor (SDF) from symbiotic bacteria of entomopathogenic nematodes. AB - Entomopathogenic nematodes (EPNs) in the genera Steinernema and Heterorhabditis are symbiotically associated with bacteria in the genera Xenorhabdus and Photorhabdus, respectively. The symbiotic bacteria produce a chemical compound(s) that deterred ants from feeding on nematode-killed insects (i.e., cadavers) and has been previously referred to as an Ant Deterrent Factor (ADF). We studied the response of different arthropod scavenger species which included the ant Lepisiota frauenfeldi, cricket Gryllus bimaculatus, wasps Vespa orientalis and Paravespula sp., and calliphorid fly Chrysomya albiceps, to ADF. These scavengers (ants, crickets, and wasps) were exposed to cadavers with and without the nematode/bacterium complex or to Photorhabdus luminescens cultures of different ages on different substrates. The ant, cricket, and wasp species did not feed on nematode-killed insects containing the nematode/bacterium complex that were 2 days old and older but fed on 1-day-old nematode-killed and freeze -killed insects. Crickets consumed 2- to 7-day-old axenic nematode-killed insects, 1-, 4 , and 5-day-old insects killed by the bacterium, Serratia marcescens, and freeze killed, putrid insects that were up to 10 days old. The crickets only partially consumed 2- and 3-day-old insects killed by S. marcescens which differed significantly from the 1-, 4-, and 5-day-old killed insects by this bacterium. Ants fed only on 5% sucrose solution (control) and 1- to 3- day old cultures of P. luminescens containing 5% sucrose but not on older cultures of P. luminescens. Wasps did not feed on meat treated with P. luminescens supernatant, whereas they fed on meat treated with Escherichia coli supernatant and control meat. Calliphorid flies did not oviposit on meat treated with P. luminescens supernatant but did oviposit on untreated meat. Based on the response of these scavengers, the chemical compound(s) responsible for this deterrent activity should be called "scavenger deterrent factor" (SDF). PMID- 22446509 TI - Migration of lymphocytes into hepatic sinusoids. PMID- 22446510 TI - Maternal hypertension induces tissue-specific modulations of the apelinergic system in the fetoplacental unit in rat. AB - Apelin and its receptor APJ are expressed in fetal tissues but their function and regulation remain largely unknown. In rat, maternal treatment with a nitric oxide synthase inhibitor inducing hypertension was used to investigate apelin plasma levels in mother/fetus pairs and on the gene expression level of the apelin/APJ system in fetal tissues and placenta. At term, plasma levels of apelin were not modulated but APJ expression was increased in placenta and lung but reduced in heart. Apelin expression was increased only in the heart. We postulate that the apelinergic system may control fetal growth and cardiovascular functions in utero. PMID- 22446511 TI - Selective arene functionalization through sequential oxidative and non-oxidative Heck reactions. AB - A sequence of acetamide directed oxidative Heck reaction and deacetylation diazotation-Heck coupling allows the traceless removal of the acetamide group and its dual exploitation as a catalyst directing group and a leaving group. PMID- 22446512 TI - Multi-centre calibration of an adaptive thresholding method for PET-based delineation of tumour volumes in radiotherapy planning of lung cancer. AB - PURPOSE: To evaluate the calibration of an adaptive thresholding algorithm (contrast-oriented algorithm) for FDG PET-based delineation of tumour volumes in eleven centres with respect to scanner types and image data processing by phantom measurements. METHODS: A cylindrical phantom with spheres of different diameters was filled with FDG realizing different signal-to-background ratios and scanned using 5 Siemens Biograph PET/CT scanners, 5 Philips Gemini PET/CT scanners, and one Siemens ECAT-ART PET scanner. All scans were analysed by the contrast oriented algorithm implemented in two different software packages. For each site, the threshold SUVs of all spheres best matching the known sphere volumes were determined. Calibration parameters a and b were calculated for each combination of scanner and image-analysis software package. In addition, "scanner-type specific" calibration curves were determined from all values obtained for each combination of scanner type and software package. Both kinds of calibration curves were used for volume delineation of the spheres. RESULTS: Only minor differences in calibration parameters were observed for scanners of the same type (Deltaa <=4%, Deltab <=14%) provided that identical imaging protocols were used whereas significant differences were found comparing calibration parameters of the ART scanner with those of scanners of different type (Deltaa <=60%, Deltab <=54%). After calibration, for all scanners investigated the calculated SUV thresholds for auto-contouring did not differ significantly (all p>0.58). The resulting sphere volumes deviated by less than -7% to +8% from the true values. CONCLUSION: After multi-centre calibration the use of the contrast-oriented algorithm for FDG PET-based delineation of tumour volumes in the different centres using different scanner types and specific imaging protocols is feasible. PMID- 22446514 TI - Impact of wastewater treatment plant discharge of lidocaine, tramadol, venlafaxine and their metabolites on the quality of surface waters and groundwater. AB - The presence of the anesthetic lidocaine (LDC), the analgesic tramadol (TRA), the antidepressant venlafaxine (VEN) and the metabolites O-desmethyltramadol (ODT) and O-desmethylvenlafaxine (ODV) was investigated in wastewater treatment plant (WWTP) effluents, in surface waters and in groundwater. The analytes were detected in all effluent samples and in only 64% of the surface water samples. The mean concentrations of the analytes in effluent samples from WWTPs with wastewater from only households and hospitals were 107 (LDC), 757 (TRA), 122 (ODT), 160 (VEN) and 637 ng L(-1) (ODV), while the mean concentrations in effluents from WWTPs treating additionally wastewater from pharmaceutical industries as indirect dischargers were for some pharmaceuticals clearly higher. WWTP effluents were identified as important sources of the analyzed pharmaceuticals and their metabolites in surface waters. The concentrations of the compounds found in surface waters ranged from =0.4-0.8m/s; >0.8m/s) ambulation at the time of discharge. Validity of the results was evaluated on a second sample of participants. MAIN OUTCOME MEASURE: Discharge 10-m walk speed. RESULTS: Admission Berg Balance Scale and FIM walk item scores explained most of the variance in discharge walk speed. The odds ratio of achieving only household ambulation at discharge was 20 (95% confidence interval [CI], 6-63) for sample 1 and 32 (95% CI, 10-96) for sample 2 when the combination of having a Berg Balance Scale score of <=20 and a FIM walk item score of 1 or 2 was present. CONCLUSIONS: A Berg Balance Scale score of <=20 and a FIM walk item score of 1 or 2 at admission indicates that a person with stroke is highly likely to only achieve household ambulation speeds at discharge from an IRF. PMID- 22446517 TI - Additional Saturday allied health services increase habitual physical activity among patients receiving inpatient rehabilitation for lower limb orthopedic conditions: a randomized controlled trial. AB - OBJECTIVE: To determine whether adults with lower limb orthopedic conditions who received additional weekend physical therapy (PT) and occupational therapy (OT) demonstrated increased habitual physical activity. DESIGN: Randomized controlled trial. SETTING: Inpatient rehabilitation center. PARTICIPANTS: Adults (N=105, 72 women; mean age +/- SD, 74+/-12y) admitted with a lower limb orthopedic condition, cognitively alert and able to walk. INTERVENTION: The control group received PT and OT Monday to Friday; in addition, the experimental group also received a full Saturday PT and OT service. Participants wore an activity monitor for 7 days. MAIN OUTCOME MEASURES: Daily steps and daily upright time (hours). RESULTS: Overall, participants took a mean of 589+/-640 steps per day and spent a mean of 1.2+/-0.9 hours upright per day. Experimental group participants took more than twice as many steps (mean difference, 428 steps; 95% confidence interval [CI], 184-673) and spent 50%+/-20% more time upright (mean difference, 0.5h; 95% CI, 0.1-0.9) than control group participants on Saturdays. In the days after additional therapy, experimental group participants took 63%+/-28% more steps (mean difference, 283 steps; 95% CI, 34-532) and spent 40%+/-17% more time upright (mean difference, 0.4h; 95% CI, 0.1-0.8) per day than participants in the control group. CONCLUSIONS: Providing additional rehabilitation services on the weekend increased habitual activity, but patients with lower limb orthopedic conditions admitted to rehabilitation remained relatively inactive even with additional therapy. PMID- 22446518 TI - Effects of aging on mRNA profiles for drug-metabolizing enzymes and transporters in livers of male and female mice. AB - Aging is a physiological process characterized by progressive functional decline in various organs over time. To reveal possible molecular mechanisms of altered xenobiotic disposition and toxicity in elderly individuals, age-dependent mRNA profiles for 101 xenobiotic-processing genes (XPGs), including seven uptake transporters, 41 phase I enzymes, 36 phase II enzymes, 10 efflux transporters, and seven transcription factors, were characterized in livers of male and female mice from 3 to 27 months of age. Gender differences across the lifespan (significant at five ages or more) were observed for 52 XPGs, including 15 male predominant genes (e.g., Oatp1a1, Cyp3a11, Ugt1a6a, Comt, and Bcrp) and 37 female predominant genes (e.g., Oatp1a4, Cyp2b10, Sult1a1, Ugt1a1, and Mrp3). During aging, the mRNA levels for 44% of the 101 XPGs changed in male mice and 63% changed in female mice. In male mice, mRNA levels for 40 XPGs (e.g., Oatp1a1, Ces2c, Gstm4, Gstp1, and Ces1e) were lower in aged mice (more than 21 months of age), whereas mRNA levels for four XPGs (e.g., Oat2 and Gstm2) were higher in aged mice. In female mice, mRNA levels for 43 XPGs (e.g., Oatp1a1, Cyp1a2, Ces1f, Sult3a1, Gstt2, Comt, Ent1, Fmo3, and Mrp6) were lower in aged mice, whereas mRNA levels for 21 XPGs (e.g., Oatp1a4, Nqo1, Adh7, Sult2a1/2, Gsta1, and Mrp4) were higher in aged mice. In conclusion, 51% of the 101 XPGs exhibited gender differences in liver mRNA levels across the lifespan of mice; the mRNA levels for 40% of the XPGs were lower in aged male mice and 43% were lower in aged female mice. PMID- 22446519 TI - Ontogeny of novel cytochrome P450 gene isoforms during postnatal liver maturation in mice. AB - The ontogeny of the first four families of cytochromes P450 (P450s) (i.e., Cyp1 Cyp4) can affect the biotransformation of drugs and dietary chemicals in liver, resulting in unique pharmacological reactions in children. Because genome-scale investigations have identified many novel P450 isoforms, it is critical to perform a systematic characterization of these P450s during liver development. In this study, livers were collected from C57BL/6 mice 2 days before birth and at various postnatal ages (0-45 days of age). The mRNA levels for 75 P450 isoforms (Cyp1-Cyp4) were quantified with branched DNA assays and reverse transcription polymerase chain reaction assays. More than half of the mouse P450s are conserved in humans, but there are more isoforms in mice. The P450 mRNA levels increased after birth in mouse liver, forming four distinct ontogenic patterns. The majority of P450s form a total of eight genomic clusters, namely, Cyp1a1 and Cyp1a2 genes on chromosome 9 (cluster 1), Cyp2a, Cyp2b, Cyp2f, Cyp2g, and Cyp2t genes on chromosome 7 (cluster 2), Cyp2c genes on chromosome 19 (cluster 3), Cyp2d genes on chromosome 15 (cluster 4), Cyp2j genes on chromosome 4 (cluster 5), Cyp3a genes on chromosome 5 (cluster 6), Cyp4a, Cyp4b, and Cyp4x genes on chromosome 4 (cluster 7), and Cyp4f genes on chromosome 17 (cluster 8). Some P450 isoforms within the same genomic cluster showed similar ontogenic patterns. In conclusion, the present study revealed four patterns of ontogeny for P450s in liver and showed that many P450s within a genomic cluster exhibited similar ontogenic patterns, which suggests that some P450s within a cluster are likely regulated by a common pathway during liver development. PMID- 22446520 TI - Contributions of arylacetamide deacetylase and carboxylesterase 2 to flutamide hydrolysis in human liver. AB - Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The major metabolic pathways of flutamide are hydroxylation and hydrolysis. The hydrolyzed metabolite, 5-amino-2-nitrobenzotrifluoride (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. Our previous study demonstrated that arylacetamide deacetylase (AADAC), one of the major serine esterases expressed in the human liver and gastrointestinal tract, catalyzes the flutamide hydrolysis. However, the enzyme kinetics in human tissue microsomes were not consistent with the kinetics by recombinant human AADAC. Thus, it seemed that AADAC is not the sole enzyme responsible for flutamide hydrolysis in human. In the present study, we found that recombinant carboxylesterase (CES) 2 could hydrolyze flutamide at low concentrations of flutamide. In the inhibition assay, the flutamide hydrolase activities at a flutamide concentration of 5 MUM in human liver and jejunum microsomes were strongly inhibited by a selective CES2 inhibitor, 10 MUM loperamide, with the residual activities of 22.9 +/- 3.5 and 18.6 +/- 0.7%, respectively. These results suggest that CES2 is also involved in the flutamide hydrolysis in human tissues. Using six individual human livers, the contributions of AADAC and CES2 to flutamide hydrolysis were estimated by using the relative activity factor. The relative contribution of CES2 was approximately 75 to 99% at the concentration of 5 MUM flutamide. In contrast, the relative contribution of AADAC increased in parallel with the concentration of flutamide. Thus, CES2, rather than AADAC, largely contributed to the flutamide hydrolysis in clinical therapeutics. PMID- 22446521 TI - Flower constancy in insect pollinators: Adaptive foraging behaviour or cognitive limitation? AB - As first noted by Aristotle in honeybee workers, many insect pollinators show a preference to visit flowers of just one species during a foraging trip. This "flower constancy" probably benefits plants, because pollen is more likely to be deposited on conspecific stigmas. But it is less clear why insects should ignore rewarding alternative flowers. Many researchers have argued that flower constancy is caused by constraints imposed by insect nervous systems rather than because flower constancy is itself an efficient foraging method. We argue that this view is unsatisfactory because it both fails to explain why foragers flexibly adjust the degree of flower constancy and does not explain why foragers of closely related species show different degrees of constancy. While limitations of the nervous system exist and are likely to influence flower constancy to some degree, the observed behavioural flexibility suggests that flower constancy is a successful foraging strategy given the insect's own information about different foraging options. PMID- 22446522 TI - An archaeal origin for the actin cytoskeleton: Implications for eukaryogenesis. AB - A hallmark of the eukaryotic cell is the actin cytoskeleton, involved in a wide array of processes ranging from shape determination and phagocytosis to intracellular transport and cytokinesis. Recently, we reported the discovery of an actin-based cytoskeleton also in Archaea. The archaeal actin ortholog, Crenactin, was shown to belong to a conserved operon, Arcade (actin-related cytoskeleton in Archaea involved in shape determination), encoding an additional set of cytoskeleton-associated proteins. Here, we elaborate on the implications of these findings for the evolutionary relation between archaea and eukaryotes, with particular focus on the possibility that eukaryotic actin and actin-related proteins have evolved from an ancestral archaeal actin gene. Archaeal actin could thus have played an important role in cellular processes essential for the origin and early evolution of the eukaryotic lineage. Further exploration of uncharacterized archaeal lineages is necessary to find additional missing pieces in the evolutionary trajectory that ultimately gave rise to present-day organisms. PMID- 22446523 TI - The next phase of life-sciences spaceflight research: Harnessing the power of functional genomics. AB - Recently we demonstrated that the effectiveness of RNAi interference (RNAi) for inhibiting gene expression is maintained during spaceflight in the worm Caenorhabditis elegans and argued for the biomedical importance of this finding. We also successfully utilized green fluorescent protein (GFP)-tagged proteins to monitor changes in GPF localization during flight. Here we discuss potential applications of RNAi and GFP in spaceflight studies and the ramifications of these experiments for the future of space life-sciences research. PMID- 22446524 TI - Cla4, but not Rac1, regulates the filamentous response of Ustilago maydis to low ammonium conditions. AB - Ustilago maydis, the fungal pathogen of maize, undergoes a dimorphic transition from budding yeast-like growth to filamentous growth, both as part of its program for pathogenesis and distinctly, in response to environmental cues, such as acid pH or low nitrogen availability. Smu1 is a p21-activated protein kinase (PAK) with roles in both the mating response required for the former function, as well as for the nutrient response. Hsl7 may be a negative regulator of Smu1 and appears to play a role in cell length and cell cycle. Additional proteins that participate in cell polarity and filamentation pathways include the small G protein, Rac1, and its effector PAK kinase, Cla4. Here we describe further experiments that explore the roles of Cla4 and Rac1 in the response to nitrogen availability. While deletion of rac1severely delays filamentous growth on solid media low in ammonium (SLAD), we found that deletion of cla4 does not abolish filamentous cell morphology on solid SLAD. Unexpectedly, however, the Dcla4 mutants also filament in liquid SLAD. The filamentous cell morphology of the cla4 mutant in liquid SLAD has only been seen previously for one other mutant, a strain deleted for hsl7 that simultaneously over-expresses smu1. PMID- 22446525 TI - A blueprint for functional engineering: Single point mutations reconstitute phosphatidylinositol presentation in a pseudo-Sec14 protein. AB - Phosphoinositides, phosphorylated species of phosphatidylinositol (PtdIns), are critical regulatory lipids in all eukaryotic cells. The molecular mechanisms that lead to the phosphorylation of an individual PtdIns- or phosphoinositide molecule remain largely unkown even though lipid kinases and phosphatases involved in these processes have been studied in detail. The observation by us and others that liposomal PtdIns (and phosphoinositide) molecules are poor in vitro substrates for kinases and phosphatases raises the question of how these enzymes execute their function in living cells. Recent work indicates that Sec14, the founding member of a large superfamily of eukaryotic proteins, is crucial for the process of PtdIns phosphorylation. The collective data suggest that Sec14 mediates a heterotypic phospholipid exchange reaction of PtdIns with phosphatidylcholine (PtdCho) during which PtdIns becomes vulnerable for kinase attack and thereby promotes the generation of phosphoinositides.1,2 In a recent paper we address the molecular mechanism of this phospholipid (PL) exchange reaction in a pseudo-Sec14 protein (Sfh1) that we rendered functional by a directed evolution approach. We find that enhanced PL-cycling into and out of the hydrophobic pocket of these activated Sfh1 mutants depends on the reconfiguration of interactions between a C-terminal string motif and the floor of the hydrophobic pocket that results in increased oscillations in a helical gate that controls pocket access. Here we further discuss our findings and propose molecular dynamics simulations as a tool to approach energetically unfavorable transition states and to identify novel protein-ligand interactions invisible to X-ray crystallography. PMID- 22446526 TI - Evolution of sodium channels and the new view of early nervous system evolution. AB - Advances in genomics have revealed that many genes implicated in the nervous systems of bilaterians were already present in the last common ancestor (LCA) of animals, and some even before that.(1) (-) (5) This new information coincides with a growing reinterpretation of cnidarian nervous systems which holds that they are 'fundamentally conventional' with regards to bilaterian nervous systems,(6) and do not represent ancient forms. Since in general adult forms are expected to be the most derived features of organisms, the study of non bilaterian larval forms may be a better way to investigate potential plesiomorphies. We recently showed that voltage-gated sodium channel (Na(v)) genes, which make action potentials in nerves and muscles, were present in the LCA of animals and choanoflagellates, the closest unicellular relatives to animals.(2) This addendum will attempt to put this finding within the context of the new views of nervous system evolution. PMID- 22446527 TI - Complex structures - smart solutions: Formation of siliceous spicules. AB - The siliceous skeletal elements of the sponges, the spicules, represent one of the very few examples from where the molecule toolkit required for the formation of an extracellular mineral-based skeleton, has been elucidated. The distinguished feature of the inorganic matrix, the bio-silica, is its enzymatic synthesis mediated by silicatein. Ortho-silicate undergoes in the presence of silicatein a polycondensation reaction and forms bio-silica under release of reaction water. The protein silicatein aggregates non-covalently to larger filaments, a process that is stabilized by the silicatein-associated protein, silintaphin-1. These structured clusters form the axial filament that is located in the center of the spicules, the axial canal. Surprisingly it has now been found that the initial axial orientation, in which the spicules grow, is guided by cell processes through evagination. The approximately two um wide cell extensions release silicatein that forms the first organic axial filament, which then synthesizes the inner core of the siliceous spicule rods. In parallel, the radial growth of the spicules is controlled by a telescopic arrangement of organic layers, into which bio-silica and ortho-silicate are deposited. Hence, the formation of a mature siliceous spicule is completed by a centrifugal accretion of bio-silica mediated by the silicatein in the axial filament, and a centripetal bio-silica deposition catalyzed by the extra-spicular silicatein. Finally this contribution highlights that for the ultimate determination of the spicule shapes, their species-specific morphologies, bio-silica hardens during a process which removes reaction water. The data presented can also provide new blueprints for the fabrication of novel biomaterials for biomedical applications. PMID- 22446528 TI - Population dynamics during swarming of Pseudomonas aeruginosa. AB - Swarming is a group motility behavior exhibited by bacteria that coordinate to spread over surfaces. Swarms of the bacterium Pseudomonas aeruginosa often develop tendril patterns and tendril development requires production of the surfactant rhamnolipid. We recently showed that harder surfaces limit induction of quorum sensing genes including those responsible for rhamnolipid synthesis, but it is not yet clear why similar populations of cells should behave differently on hard surfaces compared with soft (agar) surfaces. Here we explore the population dynamics during P. aeruginosa swarming. We find that the population of P. aeruginosa does not immediately increase as the swarm expands. We also detail three stages of population development during swarming. PMID- 22446529 TI - Merits of the double-stranded form of the actin filament revealed by structures of the filament ends. AB - Actin forms a double-stranded filament, and the majority of actin filaments in the cell undergo the dynamic process of polymerization and depolymerization at both ends. Actin dynamics plays numerous important roles in eukaryotic cells. In order to understand actin dynamics, structural elucidation of the actin filament ends is particularly important because polymerization and depolymerization occurs only at the ends. We have developed original image analysis procedures to determine the structures of the actin filament ends from cryo-electron micrographs, and two structures have been determined. The structures revealed that the actin filament takes advantage of its double-stranded form to regulate its dynamics at both ends by a surprisingly simple mechanism. PMID- 22446530 TI - C. elegans model of neuronal aging. AB - Aging of the nervous system underlies the behavioral and cognitive decline associated with senescence. Understanding the molecular and cellular basis of neuronal aging will therefore contribute to the development of effective treatments for aging and age-associated neurodegenerative disorders. Despite this pressing need, there are surprisingly few animal models that aim at recapitulating neuronal aging in a physiological context. We recently developed a C. elegans model of neuronal aging, and showed that age-dependent neuronal defects are regulated by insulin signaling. We identified electrical activity and epithelial attachment as two critical factors in the maintenance of structural integrity of C. elegans touch receptor neurons. These findings open a new avenue for elucidating the molecular mechanisms that maintain neuronal structures during the course of aging. PMID- 22446531 TI - Dynamic processes at stress promoters regulate the bimodal expression of HOG response genes. AB - Osmotic stress triggers the activation of the HOG (high osmolarity glycerol) pathway in Saccharomyces cerevisiae. This signaling cascade culminates in the activation of the MAPK (mitogen-activated protein kinase) Hog1. Quantitative single cell measurements revealed a discrepancy between kinase- and transcriptional activities of Hog1. While kinase activity increases proportionally to stress stimulus, gene expression is inhibited under low stress conditions. Interestingly, a slow stochastic gene activation process is responsible for setting a tunable threshold for gene expression under basal or low stress conditions, which generates a bimodal expression pattern at intermediate stress levels. PMID- 22446532 TI - Membrane traffic as a coordinator of cell migration and junction remodeling. AB - The change in the overall shape of developing organs is a consequence of the cumulative movement, reshaping, and proliferation of the individual mural cells that make up the walls of these organs. Recent observations suggest that the shape and the position of endothelial cells (ECs) in growing blood vessels are highly dynamic, implying that these cells remodel their junctions extensively and do not preserve their initial relative positions. In order to determine the mechanisms that confer the dynamic behavior of mural ECs, we tracked the trafficking of a cell junction protein complex that consists of the RhoA-specific guanine exchange factor (GEF) Syx, the scaffold protein Mupp1, and the phospholipid binding protein Amot.1 We found that RhoA co-trafficked with this complex on the same endocytic vesicles, and that its cellular activity pattern was determined by Rab13-dependent trafficking. The vesicles were targeted by a Rab13-associated protein complex to Tyr(1175)-phosphorylated VEGFR2 at the leading edge of ECs migrating under a VEGF gradient. These results indicate that the dynamic behavior of ECs in sprouting vessels is conferred by using the same protein complex for the regulation of both cell junctions and cell motility. Together with previous studies that demonstrated regulation of Rac signaling by Rab5-dependent trafficking,(2) it appears now that membrane traffic is tightly coupled to the regulation of Rho GTPases, and, consequently, to the regulation of the actin cytoskeleton, cell junctions, and cell migration. PMID- 22446533 TI - Interplay between ionotropic receptors modulates inhibitory synaptic strength. AB - The essence of neuronal function is to generate outputs in response to synaptic potentials. Synaptic integration at a synapse determines neuronal outputs in the CNS. In a recent study, we describe that excitatory and inhibitory transmitter gated channels physically crosstalk each other at the cellular and molecular level. Increased membrane expression of ATP P2X4 receptors by using an interference peptide competing with the intracellular endocytosis motif enhances neuronal excitability, which is further enhanced by reciprocal interaction between post-synaptic ATP- and GABA-gated channels. Molecular interaction is supported by experiments of co-immunoprecipitation and mutagenesis of P2X4 subunit. Two amino acids in the intracellular carboxyl tail of P2X4 subunit appears to be responsible for this crosstalk. Our recent study provides molecular and electrophysiological evidence for physical interaction between excitatory and inhibitory receptors that appears to be crucial in determining synaptic strength at central synapses. PMID- 22446534 TI - Comparing geometric models for orientation: Medial vs. principal axes. AB - Research examining the encoding of geometry for orientation has received considerable attention in the last 25 years with the proposition of a geometric module.1 Supporting the importance of geometry in the formation of a spatial representation, to date the majority of species studied show an encoding of geometry, even when presumably more salient and reliable features could be used. Although studies have shown that animals encode geometric information such as distance, direction or angular amplitude from the environment, few have tested the assumption that geometry is encoded using global properties such as the major principal axis, a strongly supported proposition. Here we present an alternative model to principal axis, specifically medial axis. In addition we describe the straight skeleton model, which may also offer insights into the understanding of geometric encoding by orienting animals. PMID- 22446535 TI - Avian ultraviolet/violet cones as magnetoreceptors: The problem of separating visual and magnetic information. AB - In a recent paper, we described the localization of cryptochrome 1a in the retina of domestic chickens, Gallus gallus, and European robins, Erithacus rubecula: Cryptochrome 1a was found exclusively along the membranes of the disks in the outer segments of the ultraviolet/violet single cones. Cryptochrome has been suggested to act as receptor molecule for the avian magnetic compass, which would mean that the UV/V cones have a double function: they mediate vision in the short wavelength range and, at the same time, magnetic directional information. This has important implications and raises a number of questions, in particular, how the two types of input are separated. Here, we point out several possibilities how this could be achieved. PMID- 22446536 TI - Interaction between environmental stressors mediated via the same sensory pathway. AB - The great pond snail, Lymnaea stagnalis, is a calciphile, requiring approximately 20 mg/l dissolved calcium for natural populations to live long and prosper. However, despite population survival we have previously demonstrated that acute exposure for 1 week to low environmental calcium (20 mg/l) acts as a stressor on the snail, blocking long-term memory (LTM) formation. This response to calcium availability is mediated by the snail directly sensing the calcium concentration in its environment using a sensory structure called the osphradium. In addition to sensing the calcium environment, the osphradium also mediates the response to predator kairomones which has an opposite effect on memory i.e. kairomone exposure during training enhances LTM formation. Here we demonstrate how these two stressors (low calcium availability and predator kairomones), that alter memory formation in opposing directions via the same sensory system, interact when experienced simultaneously. PMID- 22446537 TI - Neural innovations and the diversification of African weakly electric fishes. AB - In African mormyrid fishes, evolutionary change in a sensory region of the brain established an ability to detect subtle variation in electric communication signals. In one lineage, this newfound perceptual ability triggered a dramatic increase in the rates of signal evolution and species diversification. This particular neural innovation is just one in a series of nested evolutionary novelties that characterize the sensory and motor systems of mormyrids, the most speciose group of extant osteoglossomorph fishes. Here we discuss the behavioral significance of these neural innovations, relate them to differences in extant species diversity, and outline possible scenarios by which some of these traits may have fueled diversification. We propose that sensory and motor capabilities limit the extent to which signals evolve and, by extension, the role of communication behavior in the process of speciation. By expanding these capabilities, neural innovations increase the potential for signal evolution and species diversification. PMID- 22446538 TI - Mechanisms underlying contextual fear learning. AB - The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. In a recent study,we found that the inhibitory avoidance (IA) task, a hippocampus-dependent contextual fear learning paradigm, drives GluR1 containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus.We expressed mutated membrane-proxymal region (14 amino acids) of the GluR1-cytoplasmic tail (serines mutated to phospho-mimicking aspartates:MPR-DD) in the dorsal hippocampus to block the synaptic delivery of endogenous AMPARs. Learning-driven synaptic AMPARs delivery in CA1 neurons was prevented by the expression of MPR DD. Bilateral expression of MPR-DD in CA1 region of the dorsal hippocampusattenuated IA learning, indicating that synaptic GluR1 trafficking in the hippocampus is required for encoding contextual fear memories. Furthermore, fraction of CA1 neurons with synaptic strengthening positively correlated with the performance in the IA fear memory task. Thus, the robustness of a contextual fear memory may depend on thenumber of hipppocampal neurons that are involved in the encoding of a memory trace. PMID- 22446539 TI - New findings in insect fungiculture: Have ants developed non-food, agricultural products? AB - The interaction between Allomerus plant-ants and an ascomycete fungus growing on and strengthening their galleries is not opportunistic. We previously demonstrated that this association is highly specific as only one fungal species represented by a few haplotypes was found associated with the ants. We also discovered that the ants' behavior revealed a major investment in manipulating and enhancing the growth of their associated fungus. We have growing evidence that this specificity is consistent with selection by the ants. Here, we discuss this selection within the framework of insect agriculture, as we believe these ants fulfill all of the prerequisites to be considered as farmers. Allomerus ants promote their symbiont's growth, protect it from potential pathogens and select specific cultivars. Taken together, we think that the interaction between Allomerus ants and their cultivar might represent the first case of insect fungiculture used as a means of obtaining building material. PMID- 22446540 TI - Does the cycad genotoxin MAM implicated in Guam ALS-PDC induce disease-relevant changes in mouse brain that includes olfaction? AB - Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), a prototypical neurodegenerative disease (tauopathy) affecting distinct genetic groups with common exposure to neurotoxic chemicals in cycad seed, has many features of Parkinson's and Alzheimer's diseases (AD), including early olfactory dysfunction. Guam ALS-PDC incidence correlates with cycad flour content of cycasin and its aglycone methylazoxymethanol (MAM), which produces persistent DNA damage (O(6)-methylguanine) in the brains of mice lacking O(6) methylguanine methyltransferase (Mgmt(-/-)). We described in Mgmt(-/-)mice up to 7 days post-MAM treatment that brain DNA damage was linked to brain gene expression changes found in human neurological disease, cancer, and skin and hair development. This addendum reports 6 months post-MAM treatment- related brain transcriptional changes as well as elevated mitogen activated protein kinases and increased caspase-3 activity, both of which are involved in tau aggregation and neurofibrillary tangle formation typical of ALS-PDC and AD, plus transcriptional changes in olfactory receptors. Does cycasin act as a "slow (geno)toxin" in ALS PDC? PMID- 22446541 TI - Quantifying collective effervescence: Heart-rate dynamics at a fire-walking ritual. AB - Collective rituals are ubiquitous and resilient features of all known human cultures. They are also functionally opaque, costly, and sometimes dangerous. Social scientists have speculated that collective rituals generate benefits in excess of their costs by reinforcing social bonding and group solidarity, yet quantitative evidence for these conjectures is scarce. Our recent study measured the physiological effects of a highly arousing Spanish fire-walking ritual, revealing shared patterns in heart-rate dynamics between participants and related spectators. We briefly describe our results, and consider their implications. PMID- 22446542 TI - Secretion of alphaB-Crystallin via exosomes: New clues to the function of human retinal pigment epithelium. AB - alphaB-crystallin (alphaB) is an archetypical small heat shock protein whose physiological function is not clearly defined. The interest in this protein arises from its well-established but poorly understood association with a myriad of neurodegenerative diseases, cancer and cardiomyopathies. The discovery of the secretion of alphaB from human adult retinal pigment epithelial cells (ARPE19) via exosomes not only points to the involvement of this protein in lateral transfer of information between cells in the visual system but also to the status of this protein as a potential ligand that may activate or modulate immune and stress responses, normal growth and oncogenic pathways. Retinal pigment epithelium (RPE) is a single layer of polarized cells that supports photoreceptor physiology and function. We have initiated investigations on understanding the origin of the elevated levels of alphaB in extracellular sub-retinal proteolipid deposits (known as "drusen") associated with the death of photoreceptor neurons in age-related macular degeneration (AMD). Here we discuss the potential implications of the presence and transport of alphaB in exosomes across cell membranes in RPE. PMID- 22446543 TI - Receptor sorting and actin dynamics at early endosomes. AB - The sorting machinery in early endosomes is crucial for intracellular homeostasis and signal transduction and its disruption leads to the development of various diseases. In spite of its significance, the molecular mechanism underlying this machinery remains largely unknown. Actin filaments are implicated in intracellular trafficking, including membrane fission at endocytosis, membrane stretching at the Golgi complex, and maturation of endosomes. We have recently found that actin is required for receptor sorting in early endosomes and identified cortactin as a candidate for actin regulation in early endosomes. Inhibition of actin dynamics leads to enlargement of early endosomes and impairment of the sorting; the latter is also observed in cortactin-depleted cells. The endosomal localization of cortactin was enhanced by dynasore, a dynamin inhibitor that effectively inhibits endosomal sorting, indicating that cortactin is involved in the sorting machinery in early endosomes. Here we discuss the role of actin filaments in early endosomes and other molecules implicated in endosomal trafficking. PMID- 22446544 TI - Micropatterning chiral morphogenesis. AB - A recently developed technique enables quantitative study of the initiation of left-right asymmetry using cells grown on micropatterns with close appositional boundaries. It was found that mammalian cells exhibit either a left or right bias in their migratory behavior, which was determined by cell phenotype, different for certain cancer and normal cells, and dependent on functionality of the actin cytoskeleton. We discuss here the relevance of this simple technique to study of development and birth defects in laterality. PMID- 22446545 TI - A novel role for retromer in the control of epithelial cell polarity. AB - The establishment and maintenance of epithelial cell polarity is essential throughout the development and adult life of all multicellular organisms. A key player in maintaining epithelial polarity is Crumbs (Crb), an evolutionarily conserved type-I transmembrane protein initially identified in Drosophila. Correct Crb levels and apical localization are imperative for its function. However, as is the case for many polarized proteins, the mechanisms of its trafficking and strict apical localization are poorly understood. To address these questions, we developed a liposome-based assay to identify trafficking coats and interaction partners of Crb in a native-like environment. Thereby, we demonstrated that Crb is a cargo for Retromer, a trafficking complex required for transport from endosomes to the trans-Golgi-network. The functional importance of this interaction was revealed by studies in Drosophila epithelia, which established Retromer as a novel regulator of epithelial cell polarity and verified the vast potential of this technique. PMID- 22446546 TI - Fuse or die: Shaping mitochondrial fate during starvation. AB - Mitochondria continuously change their shape and thereby influence different cellular processes like cell death or development. Recently, we showed that during starvation mitochondria fuse into a highly connected network. The change in mitochondrial shape was dependent on inactivation of the fission protein Drp1, through targeting of two different phosphorylation sites. This rapid inhibition of mitochondrial fission led to unopposed fusion, protecting mitochondria from starvation-induced degradation and enabling the cell to survive nutrient scarce conditions. PMID- 22446547 TI - Actions speak louder than words in socially foraging human groups. AB - SOCIAL FORAGING IN HUMANS HAS A DEEP EVOLUTIONARY HISTORY: early hominids searched for dispersed food sources in a patchy, uncertain environment. A fundamental assumption is that social foragers benefit by exchanging information about food sources, in order to make collective decisions based on pooled information. We conducted the first experimental test of this assumption, and showed that, as predicted, communication significantly enhanced group performance. A further, unexpected result was that physical communication through gesturing, rather than verbal communication, appeared to play a crucial role in the early stages of group interaction, facilitating consensus decision making by groups. The importance of gestures in human interactions may therefore be underestimated, and this has important implications for modern human societies, where communications are becoming increasingly dominated by virtual modes of communication that preclude the use of gestures. PMID- 22446548 TI - Visual input and path stabilization in walking ants. AB - Most animals use vision to navigate the outside world. Eyes are the sensory organs for visual perception and can vary in their form, structure and function to suit the visual requirement of the individual species. In insects, mainly the two compound eyes but also the less-conspicuous ocelli are in charge for visual input. Much knowledge has been obtained about compound eyes but little is known about the role of ocelli in walking insects. Recently it has been shown that ant ocelli contribute to encoding celestial compass information for homing. However, ocelli could not compute terrestrial cues for navigating back to the nest. Here we focus on further investigations on the ants' paths stabilization under different visual input conditions. The pitch and roll stabilization of walking paths seems to be independent of visual input and controlled by idiothetic cues. The yaw (meander) stabilisation in walking paths is adjusted for navigational rather than for stabilizing purposes and depends on at least three factors: the odometric component of the path integrator (via idiothetic cues), the perception of the celestial compass information (via ocelli and compound eyes), and the visual matching of the familiar route scenery (via the compound eyes). PMID- 22446549 TI - Defining host-symbiont collaboration in termite lignocellulose digestion: "The view from the tip of the iceberg". AB - Termites have the unique ability to exploit lignocellulose as a primary nutrition source. Traditionally, termite lignocellulose digestion has been considered as a gut-symbiont-mediated process; however, in recent years the importance of host digestive capabilities have become apparent. Despite this growing understanding, how digestive enzymes from different origins specifically collaborate (i.e., additively or synergistically) has remained largely unknown. In a recent study, we undertook translational-genomic studies to address these questions in the lower termite Reticulitermes flavipes (Isoptera: Rhinotermitidae) and its symbiotic gut fauna. We used a combination of native gut tissue preparations and recombinant enzymes derived from the host gut transcriptome to identify synergistic collaborations between host and symbiont, and also among enzymes produced exclusively by the host termite. These findings provided important new evidence of synergistic collaboration among enzymes in the release of fermentable monosaccharides from wood lignocellulose, and laid a foundation for future integrative studies into termite digestion, symbiosis and eusociality. PMID- 22446550 TI - Why do we see what's not there? AB - Conscious perception is not the result of passively processing sensory input, but to large extent of active inference based on previous knowledge. This process of inference does go astray from time to time, and may lead to illusory perception: sometimes people see things that are not there. In a recent study we have shown that this inference may also be influenced by mood. Here we present some additional data, suggesting that illusory percepts are the result of increased top-down processing, which is normally helpful in detecting real stimuli. Finally, we speculate on a possible function of mood-dependent modulation of this top-down processing in social perception in particular. PMID- 22446551 TI - Is there intracellular cellulose in the appendicularian tail epidermis? A tale of the adult tail of an invertebrate chordate. AB - All tunicates produce a cellulosic extracellular matrix external to the epidermis; this is the most remarkable character of the subphylum (Tunicata = Urochordata). In Ascidiacea and Thaliacea, two of the three classes of Tunicata, cellulose is the main component of the tunic matrix that covers the whole body. In Appendicularia, however, the animals do not possess a tunic, and instead secrete a feeding apparatus called a "house" that is composed of cellulose. In the appendicularian Oikopleura dioica, we found a unique intracellular matrix in the apical cytoplasm of the adult tail epidermis that appears to form a tough shell supporting the tail. Although some experimental data suggest that this matrix may contain cellulose, the composition is still unknown. The significance of the tunicate capacity for cellulose synthesis is briefly discussed. PMID- 22446552 TI - Cell motility: The necessity of Rac1 GDP/GTP flux. AB - The Ras proto-oncogenic proteins, prototypes of the small GTPases, work as molecular switches: they are active when bound to GTP and inactive when bound to GDP. A variety of evidence suggested that the Ras paradigm is not fully valid for the Rho-family of small GTPases. Indeed, permanent activation is not sufficient but it is rather the continuous oscillation between the GDP-bound and GTP-bound conformations (namely the GDP/GTP cycling or GTPase flux), that is required for Rho-GTPases to perform their biological functions and properly coordinate actin cytoskeleton reorganization. In our recent study, we show that Rac1 needs to cycle between the GDP and GTP states in order to efficiently control cell motility. Similarly, it was previously reported that GDP/GTP cycling is required by RhoA for cytokinesis and by Cdc42 for cell polarization. The future challenge is to understand why the GTPase flux is so important for the biological actions of Rho GTPases. PMID- 22446553 TI - Sonic hedgehog distribution within mature hippocampal neurons. AB - Sonic hedgehog (Shh) regulates neural progenitor cells in the adult brain but its role in postmitotic mature neurons is not well understood. Using immunoelectron microscopy, we have recently demonstrated the postsynaptic distribution of Patched (Ptch) and Smoothened (Smo), the receptors for Shh, in hippocampal neurons of the adult rat brain. In this study, we describe the distribution of Shh protein in these adult hippocampal neurons. We find that Shh is present in both presynaptic and postsynaptic terminals. In presynaptic terminals, Shh is located either at the center or on the side of the synaptic junction. In postsynaptic terminals, Shh is mostly located on the side of the synaptic junction. We also find Shh in dendrites. Synaptic and dendritic Shh often reside in or are associated with vesicular structures that include dense-cored vesicles, synaptic vesicles, and endosomes. Thus, our subcellular map of Shh and its receptors provides a foundation for elucidating the functional significance of Shh signaling in mature neurons. PMID- 22446554 TI - Arthropod invasion disrupts Cycas micronesica seedling recruitment. AB - We recently described characteristics of reproductive effort for the cycad Cycas micronesica on the island of Guam. The data were serendipitously recorded just prior to the devastating invasion of the armored scale Aulacaspis yasumatsui. This invasion decimated the cycad population and after six years of infestation no recruitment is occurring among the survivors. We describe various underlying mechanisms that may explain how this homopteran insect has eliminated host recruitment among categories including plant-pollinator mutualism disruptions, direct damage to reproductive structures, population level responses to declining plant health, and failures of seedlings to establish. Our pre-invasion data on reproductive effort will serve as the benchmark for quantifying how this alien pest is endangering the endemic cycad. PMID- 22446555 TI - The topology of the triacylglycerol synthesizing enzyme Lro1 indicates that neutral lipids can be produced within the luminal compartment of the endoplasmatic reticulum: Implications for the biogenesis of lipid droplets. AB - Eukaryotes store metabolic energy in form of neutral lipids, which are deposited within a dedicated organelle, termed lipid droplet (LD). While neutral lipids are synthesized by ER localized integral membrane proteins, the fate of these lipids after their synthesis and the mechanism resulting in their accumulation in LDs are not well understood. We have recently shown that LDs are functionally connected to the ER membrane allowing for a bidirectional and energy-independent transport of integral membrane proteins and possibly lipids between the two compartments during lipogenesis or lipolysis. To further characterize the nature of this connection, we investigated the topology of triacylglycerol (TAG) formation. Here we show that the active site residues of the TAG biosynthetic enzyme in yeast, Lro1, a homolog of the lecithin cholesterol acyltransferase (LCAT)-related proteins, are located within the ER luminal domain of the enzyme, suggesting that TAG formed by Lro1 is initially present in the ER luminal leaflets of the ER membrane. The topology of TAG formed by Lro1 thus contrasts that of the second TAG biosynthetic enzyme, Dga1, which has a cytosolic acyl-CoA binding domain and thus is likely to catalyze TAG formation in the cytosolic leaflet of the ER membrane. Since TAG formed by either Dga1 or Lro1 can be efficiently packed into LDs we conclude that neutral lipids from both the cytosolic as well as the luminal leaflets of the ER membrane can be concentrated and packed into LDs. PMID- 22446556 TI - Tracking vesicle fusion from hair cell ribbon synapses using a high frequency, dual sine wave stimulus paradigm. AB - Recent experiments describe a technique for tracking membrane capacitance during depolarizations where membrane conductance is varying. This is a major advance over traditional technologies that can only monitor capacitance when conductance is constant because it gives direct information regarding release kinetics from single stimulations. Presented here is additional data supporting the use of this technology with multiple conductances being active including BK-Ca-activated potassium channels, SK Ca-activated potassium conductances and also the rapidly activating sodium conductance. It goes further to illustrate the ability to monitor rapid capacitative changes. And finally, it points out the need to evaluate single step responses because of the use-dependent movement of vesicles. PMID- 22446557 TI - The aeta - pinatubo loop. AB - The impact of Mount Pinatubo's 1991 eruption on the traditional use of natural resources by the indigenous Aeta was devastating. The damage resulted in the immediate and sustained disconnection of traditional knowledge from the biological resources integral to practice that knowledge. The relatively slow ecosystem recovery a full 20 years after the event hinders the transfer of traditional knowledge to younger generations of Aeta. Their traditional knowledge is at risk of disappearing from the cultural fabric of the Philippines. In seeking to adapt, decisions by the Aeta to accept the development of foreign designed ecotourism enterprises may negatively affect natural ecosystem recovery. Alternatives to the existing ecotourism practices may be warranted to safeguard Aeta traditional knowledge. PMID- 22446558 TI - Refilin holds the cap. AB - The Refilins (RefilinA and RefilinB) are a novel family of short-lived actin regulatory proteins that are expressed during changes in cellular phenotype such as epithelial to mesenchymal transition (EMT). The Refilins promote to the formation of actin- and myosin-rich perinuclear bundles that are characteristic of cellular phenotypic switches. In epithelial cells, RefilinB is up-regulated in response to TGF-beta stimulation and function in organization of apical perinuclear actin fibers during early stage of the EMT process1. In fibroblasts, RefilinB stabilizes perinuclear parallel actin bundles which resemble actin cap 2. Refilins bind and modulate the function of Filamin A (FLNA). Upon binding to Refilins, FLNA is capable of assembling actin filaments into parallel bundles, possibly by undergoing conformational changes at the C-terminal. Perinuclear actin structures determine nuclear shape, cell morphology, cell adhesion and possibly cell proliferation and gene regulation. Identifying the role of Refilins in organizing perinuclear actin networks provides additional insight in the process of intracellular mechanotransduction that regulate changes in cellular phenotype such as those observed during EMT. PMID- 22446559 TI - Vesicular calcium channels as regulators of the exocytotic post-fusion phase. AB - Regulated secretion is a fundamental cellular process in many different types of eukaryotic cells with Ca2(+-)triggered exocytosis taking centre stage. Elevations of the cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) regulate multiple steps from vesicle fusion with the plasma membrane to fusion pore dilation and subsequent retrieval of spent vesicles. The general view is that the rise in [Ca(2+)](c) initiates during the pre-fusion stage and either results from Ca(2+) influx via Ca(2+) channels in the plasma membrane or from release from intracellular Ca(2+)-stores. However, there is increasing evidence that exocytosis of secretory vesicles triggers additional, localised Ca(2+) signals via insertion of vesicle-associated Ca(2+) channels into the cell surface. These restricted Ca(2+) signals following fusion are ideally suited for regulating the post-fusion fate of individual secretory vesicles. In invertebrates they have been shown to trigger compensatory endocytosis. Recently we have reported that exocytosis of lamellar bodies in alveolar type II epithelial cells results in a localized Ca(2+)-influx via vesicular P2X(4) receptors which regulates fusion pore expansion and vesicle content release. This finding expands the emerging picture that post-fusion Ca(2+) entry via vesicle-associated Ca(2+) channels plays a central role for regulated exocytosis. PMID- 22446560 TI - Apropos "Seroprevalence of dengue infection: a cross-sectional study in mainland Tanzania and on Pemba Island, Zanzibar". PMID- 22446561 TI - Can an 86-year-old woman with advanced lung disease be a world class athlete? AB - We describe the case of an 86-year-old woman with advanced obstructive lung disease (forced expiratory volume in 1 s/forced vital capacity ratio (FEV(1)/FVC)=34%) who remains capable of superior athletic performance. Detailed pulmonary function testing was performed to characterize this patient's baseline respiratory impairment. An incremental symptom limited cycle exercise test was performed to characterize her sensory, ventilatory, cardiovascular and respiratory mechanical responses to exercise. Despite significant respiratory mechanical constraints, her peak cycle work rate and oxygen uptake were 177 and 175% predicted, respectively, and she achieved this while experiencing only moderate exertional dyspnea. She holds numerous world and national masters swim records despite her substantial objective respiratory impairment and continues to compete and set records to this day. We propose that lifelong participation in rigorous endurance training resulted in desensitization to dyspnea and has led to important cardiorespiratory adaptations that may have counterbalanced the known negative effects of obstructive lung disease on exercise performance and dyspnea. PMID- 22446562 TI - Cigarette smoke dissociates inflammation and lung remodeling in OVA-sensitized and challenged mice. AB - We evaluated the effects of cigarette smoke (CS) on lung inflammation and remodeling in a model of ovalbumin (OVA)-sensitized and OVA-challenged mice. Male BALB/c mice were divided into 4 groups: non-sensitized and air-exposed (control); non-sensitized and exposed to cigarette smoke (CS), sensitized and air-exposed (OVA) (50 MUg+OVA 1% 3 times/week for 3 weeks) and sensitized and cigarette smoke exposed mice (OVA+CS). IgE levels were not affected by CS exposure. The increases in total bronchoalveolar fluid cells in the OVA group were attenuated by co exposure to CS, as were the changes in IL-4, IL-5, and eotaxin levels as well as tissue elastance (p<0.05). In contrast, only the OVA+CS group showed a significant increase in the protein expression of IFN-gamma, VEGF, GM-CSF and collagen fiber content (p<0.05). In our study, exposure to cigarette smoke in OVA challenged mice resulted in an attenuation of pulmonary inflammation but led to an increase in pulmonary remodeling and resulted in the dissociation of airway inflammation from lung remodeling. PMID- 22446563 TI - Regulation of respiratory-related hypoglossal motor output by alpha1 adrenergic and serotonin 5-HT3 receptor activation in isolated adult turtle brainstems. AB - The effects of brainstem alpha(1) adrenergic receptor activation on respiratory control in reptiles are poorly understood. Isolated adult turtle brainstems were exposed to phenylephrine (alpha(1) adrenergic agonist) and respiratory motor bursts were recorded on hypoglossal nerves. Phenylephrine acutely increased burst frequency, amplitude (low concentrations only), and regularity of the time interval between the start of respiratory events (single or clustered bursts), and decreased bursts/respiratory event. Burst frequency and timing changes persisted during a 2.0 h washout. Acute increases in burst frequency and amplitude were blocked by prazosin (alpha(1) adrenergic antagonist). Pretreatment with prazosin and tropisetron (5-HT(3) antagonist) blocked the increase in respiratory event regularity, but did not alter the decrease in bursts/respiratory event. Intermittent phenylephrine application (4 * 5.0 min separated by 20 min) did not produce long-lasting changes in burst frequency and amplitude, bursts/respiratory event, or respiratory event regularity. Thus, sustained alpha(1) adrenergic receptor activation in turtle brainstems produces acute and long-lasting changes in respiratory burst frequency and pattern. PMID- 22446564 TI - Regionalisation of out-of-hospital cardiac arrest care for patients without prehospital return of spontaneous circulation. AB - STUDY OBJECTIVES: The aim of this study was to evaluate the risk of prolonged transportation against the benefit of treatment in high-volume centres for out-of hospital cardiac arrest (OHCA) patients without prehospital return of spontaneous circulation (ROSC). METHODS: This study used a nationwide EMS-assessed OHCA database (2006-2008). Patients with cardiac aetiology were selected from the registry. A high-volume centre was defined as a hospital that received an average of more than 33 cases per year. OHCA patients without prehospital ROSC were divided into subgroups according to their destination (high-volume centre vs. low volume centre) and transport interval. The rates of survival to discharge were compared among these groups using multivariate logistic regression analysis. RESULTS: During the study period, 54,499 OHCA patients were assessed by EMS in Korea. Of these patients, prehospital resuscitation was attempted for 29,345 patients with presumed cardiac origin. After excluding cases with inappropriate time data, 27,662 cases were selected for further analysis. 15,885 (57.4%) patients were transported to low-volume centres while the rest were transported to high-volume centres. The rate of survival to discharge was 1.43% and 4.78%, respectively. A multivariate analysis indicated that even with a longer transport interval (TI)(TI 5-9 min vs. TI 0-4 min), the high-volume centres presented a better overall outcome. CONCLUSION: A higher rate of survival to discharge was demonstrated when OHCA patients without prehospital ROSC were transported to high volume rather than low-volume centres. The rate was still significantly higher when the transportation time was longer compared with that of low-volume centres. PMID- 22446565 TI - Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of concept randomized double-blind placebo-controlled trial. AB - OBJECTIVE: To test our hypothesis that valacyclovir, an antiherpes virus-specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1). METHODS: Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response. RESULTS: Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen's d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve. CONCLUSIONS: Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test. PMID- 22446566 TI - Toxoplasma gondii and other risk factors for schizophrenia: an update. AB - The failure to find genes of major effect in schizophrenia has refocused attention on nongenetic, including infectious factors. In a previous study, antibodies to Toxoplasma gondii were found to be elevated in 23 studies of schizophrenia (OR 2.73; 95% CI 2.10-3.60). The current study replicates this finding with 15 additional studies (OR 2.71; 95% CI 1.93-3.80) and compares this with other identified schizophrenia risk factors. The highest risk factors are having an affected mother (relative risks [RR] 9.31; 95% CI 7.24-11.96), father (RR 7.20; 95% CI 5.10-10.16), or sibling (RR 6.99; 95% CI 5.38-9.08) or being the offspring of immigrants from selected countries (RR 4.5; 95% CI 1.5-13.1). Intermediate risk factors, in addition to infection with T. gondii, include being an immigrant from and to selected countries (RR 2.7; 95% CI 2.3-3.2), being born in (RR 2.24; 95% CI 1.92-2.61) or raised in (RR 2.75; 95% CI 2.31-3.28) an urban area, cannabis use (OR 2.10-2.93; 95% CI 1.08-6.13), having minor physical anomalies (OR 2.23; 95% CI 1.42-3.58), or having a father 55 or older (OR 2.21 5.92; 95% CI 1.46-17.02). Low-risk factors include a history of traumatic brain injury (OR 1.65; 95% CI 1.17-2.32), sex abuse in childhood (OR 1.46; 95% CI 0.84 2.52), obstetrical complications (OR 1.29-1.38; 95% CI 1.00-1.84), having a father 45 or older (OR 1.21-1.66; 95% CI 1.09-2.01), specific genetic polymorphisms (OR 1.09-1.24; 95% CI 1.06-1.45), birth seasonality (OR 1.07-1.95; 95% CI 1.05-2.91), maternal exposure to influenza (RR 1.05; 95% CI 0.98-1.12), or prenatal stress (RR 0.98-1.00; 95% CI 0.85-1.16). PMID- 22446567 TI - Fragile early visual percepts mark genetic liability specific to schizophrenia. AB - Disruption of visual percepts by a subsequent stimulus (ie, backward masking) has been consistently noted in schizophrenia, with some evidence that this fragility in early perception is present in people with genetic liability for the disorder. Given the potential of backward masking paradigms to mark neural processes that confer risk for schizophrenia, it is important to test the diagnostic specificity of abnormalities in visual perception. To more fully assess whether masking visual stimuli reveals a marker of genetic liability (ie, endophenotype) specific to schizophrenia, we tested 44 people with the disorder, 29 people with bipolar disorder, 56 first-degree biological relatives of people with schizophrenia, 26 first-degree biological relatives of people with bipolar disorder, and 43 nonpsychiatric control participants using a magnocellular-biased visual backward masking procedure that included target-to-mask onset asynchronies ranging from 0 to 80 ms. Relatives of people with schizophrenia who were without schizophrenia spectrum disorders exhibited impaired performance compared with nonpsychiatric control participants and relatives of people with bipolar disorder when a visual mask interrupted early perception (eg, 27 ms). A similar vulnerability of early processes was noted in people with schizophrenia, yet they also had impaired performance when masks occurred at later time points (ie, 80 ms). Performance deficits were not attributable to intellectual function, measures of attention and memory, symptomatology, or medication dosage. Bipolar patients and their relatives failed to exhibit deficits on the backward masking task. Fragility of early visual percepts appears to mark genetic liability specific to schizophrenia and may serve as an endophenotype for the disorder. PMID- 22446568 TI - Auditory hallucinations in schizophrenia and nonschizophrenia populations: a review and integrated model of cognitive mechanisms. AB - While the majority of cognitive studies on auditory hallucinations (AHs) have been conducted in schizophrenia (SZ), an increasing number of researchers are turning their attention to different clinical and nonclinical populations, often using SZ findings as a model for research. Recent advances derived from SZ studies can therefore be utilized to make substantial progress on AH research in other groups. The objectives of this article were to (1) present an up-to-date review regarding the cognitive mechanisms of AHs in SZ, (2) review findings from cognitive research conducted in other clinical and nonclinical groups, and (3) integrate these recent findings into a cohesive framework. First, SZ studies show that the cognitive underpinnings of AHs include self-source-monitoring deficits and executive and inhibitory control dysfunctions as well as distortions in top down mechanisms, perceptual and linguistic processes, and emotional factors. Second, consistent with SZ studies, findings in other population groups point to the role of top-down processing, abnormalities in executive inhibition, and negative emotions. Finally, we put forward an integrated model of AHs that incorporates the above findings. We suggest that AHs arise from an interaction between abnormal neural activation patterns that produce salient auditory signals and top-down mechanisms that include signal detection errors, executive and inhibition deficits, a tapestry of expectations and memories, and state characteristics that influence how these experiences are interpreted. Emotional factors play a particular prominent role at all levels of this hierarchy. Our model is distinctively powerful in explaining a range of phenomenological characteristics of AH across a spectrum of disorders. PMID- 22446570 TI - Minimum unit price for alcohol is planned for England and Wales. PMID- 22446569 TI - Clinical and cost effectiveness of mobile phone supported self monitoring of asthma: multicentre randomised controlled trial. AB - OBJECTIVE: To determine whether mobile phone based monitoring improves asthma control compared with standard paper based monitoring strategies. DESIGN: Multicentre randomised controlled trial with cost effectiveness analysis. SETTING: UK primary care. PARTICIPANTS: 288 adolescents and adults with poorly controlled asthma (asthma control questionnaire (ACQ) score >= 1.5) from 32 practices. INTERVENTION: Participants were centrally randomised to twice daily recording and mobile phone based transmission of symptoms, drug use, and peak flow with immediate feedback prompting action according to an agreed plan or paper based monitoring. MAIN OUTCOME MEASURES: Changes in scores on asthma control questionnaire and self efficacy (knowledge, attitude, and self efficacy asthma questionnaire (KASE-AQ)) at six months after randomisation. Assessment of outcomes was blinded. Analysis was on an intention to treat basis. RESULTS: There was no significant difference in the change in asthma control or self efficacy between the two groups (ACQ: mean change 0.75 in mobile group v 0.73 in paper group, mean difference in change -0.02 (95% confidence interval -0.23 to 0.19); KASE-AQ score: mean change -4.4 v -2.4, mean difference 2.0 (-0.3 to 4.2)). The numbers of patients who had acute exacerbations, steroid courses, and unscheduled consultations were similar in both groups, with similar healthcare costs. Overall, the mobile phone service was more expensive because of the expenses of telemonitoring. CONCLUSIONS: Mobile technology does not improve asthma control or increase self efficacy compared with paper based monitoring when both groups received clinical care to guidelines standards. The mobile technology was not cost effective. TRIAL REGISTRATION: Clinical Trials NCT00512837. PMID- 22446571 TI - A review of the knowledge base on healthy worksite culture. AB - OBJECTIVE: To identify the need for worksite cultures of health, the organizational factors that support worksite cultures of health, the tools that have been used to measure worksite cultures of health, and the research needs related to healthy worksite culture. METHODS: A cross-sectional survey involving a sample of 500 companies representing a broad spectrum of industries and business sectors. A literature review was conducted. RESULTS: Similar to a culture of safety that encourages safer behaviors and enables a safer workplace, a culture of health provides a supportive work leadership with a favorable work environment and health-related policies that promote employee health and result in substantial decrease in employee health risks and medical costs. CONCLUSION: Worksite policies and environments supporting a culture of health are important to helping employees adopt and maintain healthy behaviors. PMID- 22446572 TI - Lung function and respiratory symptoms in hard metal workers exposed to cobalt. AB - OBJECTIVE: To follow-up lung function and airway symptoms in workers exposed to cobalt dust at a hard metal plant. METHODS: A total of 582 employees underwent spirometry and completed a questionnaire. A historical exposure matrix was created, assigning figures for historical and recent work-related exposure. RESULTS: At the time of employment, 5% reported symptoms from respiratory tract. At follow-up, 5% suffered from persistent coughing and 7% reported asthma; 20% were daily smokers. Among nonsmokers without asthma, an evident, statistically nonsignificant, dose-response effect was seen between increasing cobalt exposure and decline in FEV1 (forced expiratory volume in the first second). In all exposure categories, the FEV1 in smokers declined 10 mL more per year than for nonsmokers. CONCLUSIONS: Even low levels of cobalt exposure seem to hamper lung function both in smokers and nonsmokers. This impact is considered low in relation to the effect of aging. PMID- 22446573 TI - Workers' compensation benefits and shifting costs for occupational injury and illness. AB - BACKGROUND: Whereas national prevalence estimates for workers' compensation benefits are available, incidence estimates are not. Moreover, few studies address which groups in the economy pay for occupational injury and illness when workers' compensation does not. METHODS: Data on numbers of cases and costs per case were drawn from the Bureau of Labor Statistics and National Council on Compensation Insurance data sets. Costs not covered by workers' compensation were estimated for private and public entities. RESULTS: Total benefits in 2007 were estimated to be $51.7 billion, with $29.8 billion for medical benefits and $21.9 billion for indemnity benefits. For medical costs not covered by workers' compensation, other (non-workers' compensation) insurance covered $14.22 billion, Medicare covered $7.16 billion, and Medicaid covered $5.47 billion. CONCLUSION: Incidence estimates of national benefits for workers' compensation were generated by combining existing published data. Costs were shifted to workers and their families, non-workers' compensation insurance carriers, and governments. PMID- 22446574 TI - Self-reported skin rash or irritation symptoms among World Trade Center Health Registry participants. AB - OBJECTIVES: We described self-reported skin rash 2 to 3 and 5 to 6 years after 9/11 and examined its association with exposures to 9/11 dust/debris. METHODS: We analyzed a longitudinal study of New York City World Trade Center Health Registry participants who resided or worked in Lower Manhattan or worked in rescue/recovery in two surveys (W1 and W2). RESULTS: Among 42,025 participants, 12% reported post-9/11 skin rash at W1, 6% both times, 16% at W2. Among participants without posttraumatic stress disorder or psychological distress, W1 self-reported post-9/11 skin rash was associated with intense dust cloud exposure (adjusted odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.3 to 1.9), home/workplace damage (adjusted OR = 1.8; 95% CI, 1.4 to 2.3), and working more than 90 days (adjusted OR = 1.7; 95% CI, 1.3 to 2.2) or 31 to 90 days (adjusted OR = 1.6; 95% CI, 1.3 to 2.1) at the World Trade Center site. CONCLUSIONS: Post 9/11 skin rash may be related to acute and long-term exposure to dust, though subjectivity of skin symptoms may bias findings. PMID- 22446575 TI - Health status and risk indicator trends of the aging US health care workforce. AB - OBJECTIVES: To describe the health status and risk indicator trends in a representative sample of US health care workers aged 45 years and older. METHODS: Using pooled data from the 1997 to 2009 National Health Interview Survey, logistic regression analyses were performed to determine whether age-group specific morbidity risks differed within occupational subgroups of the health care workforce (N = 6509). Health and morbidity trends were examined via complex survey adjusted and weighted chi-squared tests. RESULTS: Rates of functional limitation and hypertension increased among diagnosing/assessing health care workers. The prevalence of hearing impairment, cancer, and hypertension was two to three times greater in health-diagnosing/assessing workers aged 60 years and older than in younger workers. Health care service workers were up to 19 times more likely to be obese than workers who diagnose/assess health. CONCLUSIONS: Healthier workplaces and targeted interventions are needed to optimize the ability to meet health care demands of this aging workforce. PMID- 22446576 TI - Common features between chromaffin and neural progenitor cells. PMID- 22446583 TI - Spinal astrocytes contribute to the circadian oscillation of glutamine synthase, cyclooxygenase-1 and clock genes in the lumbar spinal cord of mice. AB - Spinal astrocytes have key roles in the regulation of pain transmission. However, the relationship between astrocytes and the circadian system in the spinal cord remains poorly defined. In the current study, the circadian variations in the expression of several clock genes in the lumbar spinal cord of mice were examined by using real-time PCR. The expression of Period1, Period2 and Cryptochrome1 showed significant circadian oscillations, each gene peaking in the early evening. The expression of Bmal1 mRNA also exhibited a circadian pattern, peaking from around midnight to early morning. The mRNA levels of Cryptochrome2 were slightly, but not significantly altered. Molecules related to pain transmission were also investigated. The mRNA expression of glutamine synthase (GS), and cyclooxygenases (COXs), known to be involved in various spinal sensory functions, showed rhythmicity with a peak in the early evening, although the expression of the neurokinin-1 receptor, subunits of the N-methyl-d-aspartate receptor, and glutamate transporters did not change. In addition, we found that protein levels of GS and COX-1 were also high at midnight compared with midday. Furthermore, we examined the effect of intrathecal fluorocitrate (100pmol), an inhibitor of astrocytic metabolism, on the expression of oscillating genes in lumbar spinal cord. Fluorocitrate significantly suppressed astrocyte function. Furthermore, the circadian oscillation of clock gene expression and GS and COX-1 expression were suppressed. Together, these results suggest that a significant circadian rhythmicity of the expression of clock genes is present in the spinal cord and that the components of the circadian clock timed by astrocytes might contribute to spinal functions, including nociceptive processes. PMID- 22446584 TI - Characterization and differential expression analysis of complete coding sequences of Vitis vinifera L. sirtuin genes. AB - The sirtuin/Sir2 (Silent information regulator 2) family of NAD+-dependent deacetylases and mono-ADP-ribosyltransferases plays an important role in several cellular processes including gene silencing, cell cycle regulation and life span extension in yeast and animals. Compared to other eukaryotes, plants have relatively fewer SIR2 related genes encoding only two putative SIR2 family proteins. Recently, two putative sirtuin genes were identified also in the grapevine genome. Starting from the predicted coding sequences present in the database, we have been able to obtain two truly expressed coding sequences from the start to the stop codon for both sirtuin genes that were named VvSRT1 and VvSRT2. The search for the expressed coding sequences was performed by comparing the predicted sequences with the recently available grape RNA seq database with the aim to develop the primers to be used in reverse transcriptase PCR reactions to amplify the genes of interest. Finally, in order to better understand the physiological role of both sirtuins, we investigated the expression of these genes in young leaves, mature leaves, and berries sampled at different growing stages. In leaves, usually it has been observed that VvSRT1 is less expresses than VvSRT2, moreover in young leaves VvSRT2 showed the higher expression during setting while in mature leaves during the flowering time. No particular variations have been observed concerning VvSRT1. In berries the two genes showed more similar expression level, and they showed the highest expression during the flowering time. Finally, the expression of VvSRT2 in berries is smaller than in leaves. PMID- 22446585 TI - In situ phytoremediation of a soil historically contaminated by metals, hydrocarbons and polychlorobiphenyls. AB - In the past several years, industrial and agricultural activities have led to serious environmental pollution, resulting in a large number of contaminated sites. As a result, much recent research activity has focused on the application of bioremediation technologies as an environmentally friendly and economically feasible means for decontamination of polluted soil. In this study horse manure and Populus nigra (var. italica) (HM + P treatment) have been used, at real scale level, as an approach for bioremediation of a soil historically contaminated by metals (Pb, Cr, Cd, Zn, Cu and Ni) and organic contaminants, such as polychlorobiphenyls and petroleum hydrocarbon. After one year, the HM + P phytotreatment was effective in the reclamation of the polluted soil from both organic and inorganic contaminants. A reduction of about 80% in total petroleum hydrocarbon (TPH), and 60% in polychlorobiphenyls (PCBs) and total metals was observed in the HM + P treatment. In contrast, in the horse manure (HM) treatment, used as control, a reduction of only about 30% of TPH was obtained. In order to assess both effectiveness and evolution of the remediation system to a biologically active soil ecosystem, together with the pollution parameters, the parameters describing the evolution of the soil functionality (enzymatic activities and protein SDS-PAGE pattern) were investigated. A stimulation of the metabolic soil processes (increase in dehydrogenase activity) was observed in the HM + P compared to the HM treatment. Finally, preliminary protein SDS-PAGE results have permitted the identification of proteins that have been recovered in the HM + P soil with respect to the HM; this may become a basic tool for improving the biogeochemical status of soil during the decontamination through the identification of microbial populations that are active in soil decontamination. PMID- 22446587 TI - Functional versatility of a single protein surface in two protein:protein interactions. AB - The ability of the Escherichia coli protein BirA to function as both a metabolic enzyme and a transcription repressor relies on the use of a single surface for two distinct protein:protein interactions. BirA forms a heterodimer with the biotin acceptor protein of acetyl-coenzyme A carboxylase and catalyzes posttranslational biotinylation. Alternatively, it forms a homodimer that binds sequence-specifically to DNA to repress transcription initiation at the biotin biosynthetic operon. Several surface loops on BirA, two of which exhibit sequence conservation in all biotin protein ligases and the remainder of which are highly variable, are located at the two interfaces. The function of these loops in both homodimerization and biotin transfer was investigated by characterizing alanine substituted variants at 18 positions of one constant and three variable loops. Sedimentation equilibrium measurements reveal that 11 of the substitutions, which are distributed throughout conserved and variable loops, significantly alter homodimerization energetics. By contrast, steady-state and single-turnover kinetic measurements indicate that biotin transfer to biotin carboxyl carrier protein is impacted by seven substitutions, the majority of which are in the constant loop. Furthermore, constant loop residues that function in biotin transfer also support homodimerization. The results reveal clues about the evolution of a single protein surface for use in two distinct functions. PMID- 22446588 TI - A conserved TGFbeta1/HuR feedback circuit regulates the fibrogenic response in fibroblasts. AB - Persistent fibroblast activation in wound repair is believed to be the key reason for fibrosis and transforming growth factor (TGF)beta is considered as one of the key mediators for the fibrogenic response, with the detailed mechanism largely unknown. Here we found that TGFbeta1 treatment could induce a significant increase of endogenous TGFbeta1 expression by enhancing the mRNA stability in cardiac fibroblasts. Further study revealed that TGFbeta1 treatment translocated the nuclear HuR into cytoplasm, which in turn bound the ARE in the 3'UTR of TGFbeta1 and increased the mRNA stability as seen from the RNA-IP and reporter assay. Knockdown of HuR decreased the endogenous expression of TGFbeta1 under exogenous TGFbeta1 treatment, simultaneously with the decrease of Col1a, Col3a and fibronectin expression. Our study here established a TGFbeta1/HuR feedback circuit regulating the fibrogenic response in fibroblasts, and targeting this feedback loop is of great potential to control fibrosis. PMID- 22446589 TI - MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis. AB - Core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin 3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis. PMID- 22446590 TI - The first performance report for the Bio-Rad Dx CT/NG/MG assay for simultaneous detection of Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium in urogenital samples. AB - We evaluated the clinical performance of the Bio-Rad Dx CT/NG/MG assay for the detection of Chlamydia trachomatis, Mycoplasma genitalium and Neisseria gonorrhoeae in urogenital samples in comparison with the Roche COBAS(r) TaqMan(r) CT assay for C. trachomatis and an in-house TaqMan PCR assay for M. genitalium. Swab specimens were cultured for N. gonorrhoeae. In this prospective study, urogenital samples were obtained from symptomatic and asymptomatic patients attending the sexually transmitted disease clinic of Bordeaux, France, from January to April 2010. A total of 658 clinical specimens (259 male and 180 female urines, 191 vaginal, 21 endocervical and 7 urethral swabs) from 453 patients were analyzed. The prevalence of C. trachomatis and M. genitalium infections was 8.1% (21/260) and 1.9% (5/260) in men and 10.4% (20/193) and 2.1% (4/193) in women, respectively. The Bio-Rad Dx CT/NG/MG clinical sensitivity was 100% for C. trachomatis and M. genitalium in men and women. In male urine, the clinical specificity was 99.6% for C. trachomatis and 100% for M. genitalium. In women, the specificity was 99.5% for swabs and 100% for urines for detecting C. trachomatis and M. genitalium. All seven N. gonorrhoeae PCR-positive samples were also positive by culture. Patients were co-infected in 5/57 cases (8.8%), with C. trachomatis and M. genitalium in three cases, and C. trachomatis and N. gonorrhoeae in two cases. In conclusion, the Bio-Rad Dx CT/NG/MG assay can be recommended for the simultaneous detection of C. trachomatis, M. genitalium and N. gonorrhoeae in urogenital specimens of symptomatic and asymptomatic individuals. PMID- 22446591 TI - Role of systemic chemotherapy in the management of resected or resectable colorectal liver metastases: a systematic review and meta-analysis of randomized controlled trials. AB - Liver metastases are a common event in patients with colorectal cancer. Surgical resection, if feasible, produces a survival benefit. We performed a systematic review of randomized clinical trials (RCT) and meta-analysis to address the question if current available studies support the use of systemic chemotherapy as an adjunct to surgery in resected/resectable patients. The search was based on major databases (Pubmed, CancerLit, Embase, Medscape and Cochrane) of published literature and selecting abstracts from major cancer meetings. We performed a literature for the January 1982-May 2010 time frame. The hazard ratios (HRs), with confidence intervals, as presented in retrieved studies, referred to the disease- and/or progression-free (DFS and/or PFS) and overall survival (OS) were extracted. The meta-analysis was carried out by the fixed-effect and the random effects model. Three studies randomizing combined treatment vs. surgery alone for a total of 666 patients (642 evaluable for survival analysis) were selected and included in the final analysis. Evidence for chemotherapy-induced benefit in terms of both DFS (pooled HR, 0.71; CI, 0.582-0.878; p=0.001) and PFS (pooled HR, 0.75; CI, 0.620-0.910; p=0.003) was demonstrated. However, our meta-analysis failed to demonstrate a significant advantage of combined treatment in terms of OS (pooled HR, 0.743; CI, 0.527-1.045; p=0.088). Chemotherapy combined with surgical resection of colorectal liver metastases improves DFS and PFS whereas the benefit in OS is not demonstrated on the basis of the available results of RCTs. New prospective trials in the era of targeted therapy are eagerly awaited on this specific topic. PMID- 22446592 TI - Shapes of supramolecular cages by ion mobility mass spectrometry. AB - Mass spectrometry and drift tube ion mobility mass spectrometry have been used to analyse several isobaric, multicomponent cages yielding information on three dimensional structure, interactions and dynamics of assembly in the gas phase. PMID- 22446593 TI - Slow axoplasmic transport under scrutiny. AB - The origin of axoplasmic proteins is central for the biology of axons. For over fifty years axons have been considered unable to synthesize proteins and that cell bodies supply them with proteins by a slow transport mechanism. To allow for prolonged transport times, proteins were assumed to be stable, i.e., not degraded in axons. These are now textbook notions that configure the slow transport model (STM). The aim of this article is to cast doubts on the validity of STM, as a step toward gaining more understanding about the supply of axoplasmic proteins. First, the stability of axonal proteins claimed by STM has been disproved by experimental evidence. Moreover, the evidence for protein synthesis in axons indicates that the repertoire is extensive and the amount sizeable, which disproves the notion that axons are unable to synthesize proteins and that cell bodies supply most axonal proteins. In turn, axoplasmic protein synthesis gives rise to the metabolic model (MM). We point out a few inconsistencies in STM that MM redresses. Although both models address the supply of proteins to axons, so far they have had no crosstalk. Since proteins underlie every conceivable cellular function, it is necessary to re-evaluate in-depth the origin of axonal proteins. We hope this will shape a novel understanding of the biology of axons, with impact on development and maintenance of axons, nerve repair, axonopathies and plasticity, to mention a few fields. PMID- 22446594 TI - Regulation of Pax7 protein levels by caspase-3 and proteasome activity in differentiating myoblasts. AB - The transcription factor Pax7 negatively regulates the activity of the muscle regulatory transcription factor MyoD, preventing muscle precursor cells from undergoing terminal differentiation. In this context, the ratio between Pax7 and MyoD protein levels is thought to be critical in allowing myogenesis to proceed or to maintain the undifferentiated muscle precursor state. We have previously shown that Pax7 is subject to rapid down regulation in differentiating myoblasts, via a proteasome-dependent pathway. Here we present evidence indicating that Pax7 is also subject to caspase-3-dependent regulation. Furthermore, simultaneous inhibition of caspase-3 and proteasome activity induced further accumulation of Pax7 protein in differentiating myoblasts. These results suggest that at early stages of muscle differentiation, Pax7 levels are regulated by at least two independent mechanisms involving caspase-3 and proteasome activity. PMID- 22446595 TI - Porcine oviduct sperm binding glycoprotein and its deleterious effect on sperm: a mechanism for negative selection of sperm? AB - In their journey through the oviduct some subpopulations of sperm are preserved in a reservoir, while others are negatively selected. Sperm binding glycoprotein (SBG) is a pig oviductal epithelial cell glycoprotein that produces, under capacitating conditions, acrosome alteration, p97 tyrosine-phosphorylation and reduction of the motility of sperm. In this paper, we show that SBG is accessible at the extracellular surface of the oviductal epithelial cells, supporting a sperm interaction biological role in situ. We analyze the possible dependence of the tyrosine-phosphorylation of p97 on the PKA mechanism, finding that apparently it is not PKA dependent. Also, after SBG treatment the phosphorylated proteins locate mainly at the detached periacrosomal region and at the tail of sperm; the latter may be related to SBG's motility reduction effect. The study of the time course effect of SBG on sperm as detected by chlortetracycline (CTC) staining and of its binding to sperm by immunodetection in conjunction with CTC, shows results in agreement with the hypothesis that this glycoprotein is involved in the alteration of acrosomes in a specific sperm subpopulation. The results suggest that SBG may be part of a mechanism for negative selection of sperm. PMID- 22446596 TI - Accumulation of antioxidants in apricot fruit through ripening: characterization of a genotype with enhanced functional properties. AB - Two apricot genotypes, 'Gonci magyarkajszi' and 'Preventa' were assayed at three ripening stages for flesh color indices (L*, a*, b*, C* and Ho), contents of total phenolics and vitamin C, and both water- and lipid-soluble antioxidant capacities (ferric reducing antioxidant power; 2,2'-diphenyl-1-picrylhydrazyl scavenging activity; total radical scavenging activity; and Photochem lipid soluble antioxidant capacity) to compare their dynamics in the accumulation of antioxidant compounds and capacities through ripening. The increase in a*, b* and C* and decrease in Ho during ripening represented a color shift from green to yellow and orange due to carotenoid accumulation. Parallel to carotenoid accumulation, contents of total phenolics and vitamin C and antioxidant capacity increased significantly (p < 0.05) from unripe to fully ripe fruits. More phenolics and vitamin C accumulated in fully ripe fruits of 'Preventa' than 'Gonci magyarkajszi'. The accumulation patterns of these compounds were different: while the vitamin C contents in unripe fruit of 'Preventa' and 'Gonci magyarkajszi' were identical (approx. 6 mg/100 g fresh weight), unripe 'Preventa' contained even more phenolics (approx. 12 mmolGA/l) than fully ripe 'Gonci magyarkajszi' (8 mmolGA/l). Our results confirm that fully ripe 'Preventa' fruits are characterized by outstanding functional properties due to the increased accumulation of vitamin C and phenolics throughout the ripening process. PMID- 22446597 TI - Genetic characterization of pomegranate (Punica granatum L.) genotypes by AFLP markers. AB - The Coruh Valley, located in Northeastern Turkey, is one of the most important centers of diversity in pomegranate in Turkey. In this study, we attempted to characterize 19 promising pomegranate genotypes originating from the Coruh Valley in using fluorescent dye AFLP markers and capillary electrophoresis. Four AFLP primer combinations were used, generating a total of 297 fragments, 213 of which were polymorphic (73.0%). Resolving powers of the AFLP primers ranged from 0.700 to 1.018, with a total of 3.440, while polymorphism information contents ranged from 0.707 to 0.837 with an average of 0.764. UPGMA clustering of the genotypes showed two major groups. Most of the fruit characteristics of the genotypes within the same group were variable. Therefore, the results showed that molecular characterization is necessary to get reliable relationships among pomegranate genotypes and AFLP markers can be used effectively in pomegranate. PMID- 22446598 TI - The PcACE1 transcription factor from Phanerochaete chrysosporium contains a Cys- and Ser-rich transactivation domain. AB - Transcription factor Ace1 from Saccharomyces cerevisiae regulates the expression of target genes when the copper concentration reaches 200 iI levels. We are studying the ortholog of Ace1 from fungus Phanerochaete chrysosporium PcACE1, isolated by complementation in yeast. In this report we show the localization of the transactivation region of PcACE1. Different PcACE1 fragments were ligated in frame to the GAL4 DNA-binding domain by site-directed mutagenesis in a suitable yeast expression vector. Transformation of an appropriate Saccharomyces cerevisiae strain was used as host. This strain contains the fusion GAL1:lacZ in its genome under the control of promoter sequences recognized by GAL4. Finally, we measured a-galactosidase activity in each yeast clone. The activation of the reporter gene is proportional to the transactivation capacity of the transcription factor PcACE1. The results obtained indicate that PcACE1 transactivation domain is located in the carboxy terminal half and contains an array of cysteines in the form of Cys-X-Cys and Cys-X2-Cys and a 60% of Ser. Therefore, these results show that this type of Cys motif can function as transcription activating domain not only in transcription factors that respond to minimal copper concentrations but also in those that respond to high copper concentrations. This is the first transactivation domain reported in a basidiomycete fungus. PMID- 22446599 TI - Trait anxiety affects the orofacial nociceptive response in rats. AB - The aims of the present study were to assess the influence of: a) trait anxiety on orofacial pain; and b) orofacial pain on state anxiety. Forty-four rats were initially exposed to the free-exploratory paradigm for the evaluation of their anxiety profiles. In accordance to the parameter "Percentage of time in the novel side", the animals were considered as presenting high or low levels of trait anxiety when presenting values below the 1st quartile, or above the 3rd quartile, respectively. A week later, formalin-1.5% was injected into the upper lip of each animal. The behavioural nociceptive response, characterized by increased orofacial rubbing (OR), was quantified for 30 minutes, as follows: Total time OR (0-30 minutes: total pain), 1st phase OR (0-6 minutes: neurogenic pain), and 2nd phase OR (12-30 minutes: inflammatory pain). Immediately after this test, but still under the effect of formalin, the rats were submitted to the Elevated Plus maze test (EPM). The results showed that the high trait anxiety individuals presented higher frequency of OR than the low trait anxiety ones, except during the neurogenic pain period. However, no correlation was found between OR frequency and levels of state anxiety presented on the EPM. In conclusion, the animals presenting higher anxiety profiles were the most susceptible to orofacial pain, nevertheless, orofacial pain did not influence state anxiety. PMID- 22446600 TI - Anti-inflammatory and redox-protective activities of citronellal. AB - The anti-inflammatory and redox protective effects of the citronellal (CT) were evaluated using in vivo and in vitro tests. Intraperitoneal (i.p.) administration of CT (50, 100, and 200 mg/kg) inhibited (p < 0.05) the carrageenan-induced leukocyte migration to the peritoneal cavity. Additionally, the carrageenan- and arachidonic acid-induced rat hind paw edema was significantly inhibited (p < 0.05) by i.p. administration of 100 and 200 mg/kg of the compound. When the redox activity was evaluated, CT (200 mg/kg) significantly reduced hepatic lipoperoxidation (p < 0.001), as well as oxidation of plasmatic (p < 0.05) and hepatic (p < 0.01) proteins. The results of the present study support the hypothesis that CT possesses anti-inflammatory and redox protective activities. It is suggested that its effects are associated with the inhibition of the enzymes in the arachidonic acid pathway, which prevent cell migration by inhibiting leukotriene production, edema formation and the increase of reactive oxygen species in tissues. Therefore, CT is of potential benefit to manage inflammatory disorders and correlated damages caused by oxidant agents. PMID- 22446601 TI - High-level expression of modified gene encoding human adiponectin in transgenic rice. AB - Adiponectin is a polypeptide specifically secreted from human adipocytes, and its deficiency is closely linked to increased obesity and type II diabetes. There is an urgent demand for large-scale production of human adiponectin for pharmaceutical applications. Here, we report that we have successfully obtained a high-level of expression of modified genes encoding human adiponectin in transgenic rice. The 735 bp cDNA of the native human sequence was adopted to rice codon usage, fused to the translation initiation sequence in the N terminus and to the KDEL signal sequence in the C terminus. An amplification promoting sequence acting as an enhancer of transcription was also introduced to enhance gene expression. The presence of the transgene and mRNA transcripts was confirmed by PCR, Southern blot and RT-PCR. Western blot analysis revealed that a protein of approximately 30 kDa was produced in rice leaves. ELISA analysis was used to determine the amount of recombinant adiponectin in transformants with the modified gene in up to 0.32% of total soluble leaf protein. Our results establish the feasibility of high-level expression of recombinant human adiponectin in transgenic rice. PMID- 22446602 TI - Elevated yield of monacolin K in Monascus purpureus by fungal elicitor and mutagenesis of UV and LiCl. AB - In China, Monascus spp., a traditional fungus used in fermentation, is used as a natural food additive. Monascus spp. can produce a secondary metabolite, monacolin K namely, which is proven to be a cholesterol-lowering and hypotensive agent. Hence, recently, many researchers have begun focusing on how to increase the production of monacolin K by Monascus purpureus. In the present study, we investigated the effect of the fungal elicitor and the mutagenesis of UV & LiCl on the amount of monacolin K produced by Monascus purpureus. The fugal elicitor, Sporobolomyces huaxiensis, was isolated from tea leaves and its filtrate was added into the culture filtrate of Monascus purpureus during growth to induct the production of monacolin K. The results showed that the highest amount of monacolin K produced by the liquid fermentation was 446.92 mg/mL, which was produced after the fungal elicitor was added to the culture filtrate of Monascus purpureus on the day 4; this amount was approximately 6 times greater than that of the control culture filtrate, whereas the highest amount of monacolin K produced by the mutated strain was 3 times greater than the control culture after the irradiation of UV light in the presence of 1.0 % LiCl in the medium. PMID- 22446603 TI - Mycoplasma hyorhinis and Mycoplasma fermentans induce cell apoptosis and changes in gene expression profiles of 32D cells. AB - Infection of mycoplasmas has been linked to various human diseases including arthritis, pneumonia, infertility and cancer. While Mycoplasma hyorhinis and Mycoplasma fermentans have been detected in gastric adenocarcinomas, the mechanisms underlyine the pathogenesis are unknown. In this study, cell growth kinetics, Hoechst 33258 staining, DNA ladder assays, Western blotting analysis and cDNA microarray assays were performed to investigate the roles of M. hyorhinis and M. fermentans during infection of mammalian cells. Our data demonstrated that these mycoplasmas inhibid the growth of immortalised cell lines (32D and COS-7) ane tumor cell lines (HeLa and AGS). In addition, the infection of the 32D cell line with M. hyorhinis and M. fermentans induced compression of the nucleus, degradation of the cell genome and dysregulation of the expression of genes related to proliferation, apoptosis, tumorigenesis, signaling pathway and metabolism. Apoptosis related proteins Bcl-2, Bid and p53 were down regulated, Fas was up-regulated and Bax was dysregulated in mycoplasma-infected 32D cells. Together, our data demonstrated that infection of mycoplasmas inhibitd cele growts through modification of gene expression profiles and post-translation modification of proliferation and apoptosis related proteins. PMID- 22446604 TI - Human sociogenetics. AB - In three cities of Chile (Santiago, Valparaiso, Valdivia) the A allele and phenotype (ABO blood group) are more frequent in the higher socioeconomic strata (SES) and the O allele and phenotype are in the lower ones. This constitutes a structured sociogenetic cline (SGC). The B allele and phenotypes (B+AB) present a rather erratic or contradictory distribution among SES. This SGC was also found in England. The standard interpretation of the origin and maintenance of this SGC in Chile is founded on socio-ethno-historic-cultural and drift factors followed by socioeconomic assortative mating that has occurred since the origin of Chileans by the admixture of Europeans and Amerindians. This interpretation is insufficient to explain the coincidence of the cline in England and Chile, and for some findings in Chile. 1) The A and Rh(-) frequencies of the highest SES in Chile are significantly higher than those found in Europeans. 2) The B gene and phenotypes (with AB) behave differently and in contradiction to the socio-ethno cultural-historical process. 3) There is a significant interaction of the SGC with gender in Chile and England. There is not at present a putative relationship between ABO and psycho-social factors that could account for this sociogenetic interaction. This SGC seems to be present in societies with a hierarchical organization in relation to power, prestige, ownership, income and life style, and when sampling includes the most extreme SES. It has not been found in two samples from Ireland and in a sample from Chile taken from a public hospital, probably because those variables and conditions were not ascertained. PMID- 22446605 TI - Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma. AB - Myeloma relapse is the main cause of death after allogeneic stem cell transplantation. The aim of our observational study was to evaluate the anti myeloma effect of lenalidomide followed by donor-lymphocyte infusion (DLI) as post-transplantation adoptive immunotherapy. Twelve patients with refractory myeloma were analyzed. The median age at transplantation was 56 years (range, 46 64 years). All patients received reduced-intensity conditioning. Patients were included if progressive or residual disease was observed at day +100 and if no signs of graft-vs-host disease were evident. DLIs were administered after two cycles of lenalidomide. Median dose of lenalidomide was 15 mg (range, 10-25 mg). Patients received a median of six cycles (range, 1-10 cycles). Nine patients (60%) received an escalating dose of DLI. The 1 and 2-year probability of progression-free survival was 75% and 50%, and overall survival was 83% and 69%, respectively. Median overall survival was not reached and median progression-free survival was 23 months. Lenalidomide is well tolerated after allogeneic stem cell transplantation; the combination with DLI did not cause a higher risk of graft-vs host disease; an immunological synergistic effect was probably present with this strategy. This combination should be evaluated further in a larger cohort of patients. PMID- 22446606 TI - Efficacy of a nationwide screening colonoscopy program for colorectal cancer. AB - BACKGROUND & AIMS: Screening colonoscopy examinations for colorectal cancer are offered in the United States and some European countries. Data on results and adverse effects of screening colonoscopy are limited. In autumn 2002, colonoscopy was introduced as part of a nationwide cancer screening program in Germany; it was offered to the general population for individuals 55 years of age or older. We collected and analyzed data from this program. METHODS: We performed a prospective cross-sectional study, collecting results from 2,821,392 screening colonoscopies performed at more than 2100 practices by highly qualified endoscopists in Germany from January 2003 to December 2008. Data on participation, colorectal adenoma and cancer detection, and complications were collected using standardized documentation forms. The data generated were centrally processed and evaluated. RESULTS: The cumulative participation rate was 17.2% of eligible women and 15.5% of eligible men 55-74 years old. The adenoma detection rate (ADR) was 19.4%, with a higher rate in men (25.8% vs 16.7% in women). Advanced adenomas were found in 6.4% of patients. Carcinomas were detected in 25,893 subjects (0.9%); most were of an early UICC stage (I, 47.3%; II, 22.3%; III, 20.7%; IV, 9.6%). The ADRs for gastroenterologists and nongastroenterologists were 25.1% and 22.3%, respectively (adjusted odds ratio, 1.18; 95% confidence interval, 1.16-1.21). The overall complication rate was 2.8/1000 colonoscopies, and the rate of serious complications was 0.58/1000 colonoscopies. CONCLUSIONS: A nationwide colonoscopy screening program that uses highly qualified endoscopists can detect a significant number of adenomas and early-stage carcinomas. The ADR for gastroenterologists was higher than for nongastroenterologists. PMID- 22446607 TI - Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. AB - Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (eg, umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, peri-, and posttransplant exposures and risk factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplantation experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT. PMID- 22446608 TI - Endometrial stromal sarcoma: prognostic factors and impact of adjuvant therapy in early stages. AB - BACKGROUND AND OBJECTIVES: Endometrial stromal sarcomas (ESS) are rare uterine neoplasms. surgery remains the cornerstone of treatment for early stages and consists of an abdominal hysterectomy with bilateral salpingo-oopherectomy. Despite appropriate surgical treatment, relapse rates are high (18% to 45%) and the value of adjuvant therapies is not clear. We evaluated prognostic factors and the impact of adjuvant treatment on localized ESS (stages I and II). DESIGN AND SETTING: Retrospective, case-control study conducted at the National Institute Of Oncology in Rabat, Morocco over 10 years from 2000 to 2009. PATIENTS AND METHODS: twenty-one cases of localized ESS were included in the analysis. RESULTS: standard surgery was performed in 71.4% of our patients. Myometrial invasion was noted in 57.1% of cases. Mitotic activity was considered high in five patients. Adjuvant treatment was given to 52.3% of patients: endocrine therapy in five patients and radiotherapy in six. Survival was significantly longer in the group of patients who underwent standard surgical treatment (P=.0007), in the absence of deep myometrial invasion (P=.0248) in cases with a low mitotic index (P<.0001) and in patients who received adjuvant therapy (hormone or radiotherapy) (P=.0048). In a multivariate analysis independent risk factors for monitoring were inadequate surgical treatment and absence of adjuvant treatment. CONCLUSIONS: Myometrial invasion and mitotic index appear to be important prognostic factors. the reference surgery is hysterectomy with bilateral salpingo oopherectomy. Lymph node dissection does not appear to provide a benefit. finally adjuvant treatment may carry a significant survival benefit. PMID- 22446609 TI - A randomized trial of brief treatment of early- stage Hodgkin lymphoma: Is it effective? AB - BACKGROUND AND OBJECTIVES: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin lymphoma with a favorable prognosis remains unclear. Therefore, we conducted this randomized trial, comparing two treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. DESIGN AND SETTING: Prospective, randomized, in patients referred to the Department Of Clinical Oncology And Nuclear Medicine. PATIENTS AND METHODS: Ninety-eight patients with histologically proven early-stage Hodgkin lymphoma with a favorable prognosis were enrolled in this study between January 2008 and June 2010. They were randomly assigned in one of two treatment arms: arm I received four cycles of ABVD (adriamycin, belomycin, vinblastine, dacarbazine) followed by 30 Gy of involved-field radiation therapy; arm II received two cycles of ABVD followed by 20 Gy of involved-field radiation therapy. RESULTS: During the follow-up period, the 2-year relapse-free survival rates were 96% and 95% in arm I and arm II, respectively (P=.8), while the 2-year overall survival rates were 98% and 95% in arm I and arm II, respectively (P=.16). acute toxicity affected 54% of patients treated with four cycles of ABVD, who had grade III or IV toxicity, as compared with 30% of those receiving two cycles (P<.02). The rates of acute toxicity (grade III or IV) were also higher among patients treated with 30 Gy of involved-field radiation therapy than among those receiving 20 Gy (16% vs. 2.5%, P<.03) . CONCLUSION: In patients with early-stage Hodgkin lymphoma and a favorable prognosis, treatment with two cycles of aBVD followed by 20 Gy of involved-field radiation therapy was as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. PMID- 22446610 TI - A simplified method for autologous stem cell transplantation in multiple myeloma. AB - BACKGROUND AND OBJECTIVES: We evaluated the efficacy and safety of non cryopreserved storage of autologous hematopoietic stem cells with no post transplant granulocyte colony-stimulating factor (G-CSF) support in adult patients undergoing autologous stem cell transplantation (ASCT) for multiple myeloma (MM). DESIGN AND SETTING: Retrospective review of patients undergoing ASCT from May 2009 to July 2011. PATIENTS AND METHODS: Autologous stem cell were mobilized using G-CSF. Leukapheresis to harvest stem cells was performed on day 2 and -1. The grafts were kept in a conventional blood bank refrigerator at 4 degrees C until reinfusion on day 0. The conditioning regimen consisted of melphalan 200 mg/m2 in all patients. The post-chemotherapy myeloablative phase was managed without growth factors. RESULTS: Between May 2009 to July 2011, 54 adults with MM were treated in our center in Oran. The median age at ASCT was 55 years (range, 35-65). There were 37 males and 17 females. The median harvested CD34+ cell count was 3.60X106/kg (range, 1.90 to 10.52). All patients had neutrophil engraftment on the median of day 10 (range, 6-17) and platelet transfusion independence on the median of day 13 (range 9-24). In the 47 evaluable patients the median post-transplant overall survival had not been reached; the estimated overall survival at 30 months was 93.8% (0.05%) , and the estimated disease-free survival at 27 months was 93.6% (0.05%). CONCLUSION: High dose chemotherapy and ASCT using non-cryopreserved stem cells and no G-CSF support is safe and feasible in the treatment of MM under our work conditions in developing countries. PMID- 22446611 TI - Prevalence of HBV and HCV infection among multi-transfused Egyptian thalassemic patients. AB - BACKGROUND AND OBJECTIVES: Though regular blood transfusion improves the overall survival of patients with beta-thalassemia, it carries a definite risk of infection with blood-borne viruses. The present study was carried out to estimate the real frequency of hepatitis B virus (HBV) and hepatitis C virus (HCV) among Egyptian beta-thalassemic patients, and determine the infection-associated risk factors in these patients. DESIGN AND SETTING: A prospective study conducted in a university hospital from January 2009 to January 2010. PATIENTS AND METHODS: Two hundred patients with beta-thalassemia major were enrolled in this study. Using enzyme-linked immunoabsorbent assay (ELISA), their sera were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis C core antigen (anti-HBc), and HCV antibody (HCV Ab). The positive HCV Ab results were confirmed by second generation recombinant immunoblot assay (RIBA). RESULTS: The study sample consisted of 111 males and 89 females, with a median age of 13 years. Eighty-one (40.5%) patients were HCV Ab positive by ELISA and 39 (19.5) were anti-HCV positive by RIBA; 58 (29.0%) were HBsAg positive and 13 (6.5%) were anti-HBC positive. Older age, an increased number of transfusion units, and HBsAg seropositivity were significantly associated with a higher prevalence of HCV and HBV. CONCLUSION: The prevalence of HCV and HBV infections are very high among Egyptian beta-thalassemic patients, which calls for a critical look into the prevailing transfusion practices and adoption of stricter donor selection criteria to decrease the incidence rate of both HCV and HBV infections effectively. Furthermore, there is a compressing need for the use of more specific and sensitive methods for HCV testing in Mansoura university hospitals. PMID- 22446612 TI - Choroidal metastasis as the sole initial presentation of metastatic lung cancer. AB - Choroidal metastasis as an initial presenting feature of metastatic lung cancer is exceedingly rare. External beam radiotherapy (EBRT) is an effective and widely accepted therapeutic modality. However, data addressing the effectiveness of other treatment strategies is limited. We present a patient with choroidal metastases secondary to lung cancer and review the relevant literature. A 25-year old male presented with deterioration of vision. His evaluation revealed bilateral choroidal metastasis secondary to adeno- carcinoma of the lung. Unfortunately, his vision continued to deteriorate despite treatment with EBRT and chemotherapy. Choroidal metastasis as an initial presentation of metastatic lung cancer is exceedingly rare, as only 30 cases have been reported. EBRT and systemic chemotherapy are effective therapeutic modalities. This case report could prove helpful to clinicians faced with a similar exceedingly rare scenario. PMID- 22446613 TI - Incidence of gynecological malignancy among the Saudi population. PMID- 22446614 TI - A phase 2 study of the combination of gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines with/without taxanes. AB - BACKGROUND AND OBJECTIVES: Many patients with relapsed metastatic breast cancer are pre-treated with taxanes and anthracyclines, which are usually given in the neoadjuvant/adjuvant setting or as first-line treatment for metastatic disease. The primary objective of this study was to determine the overall response rate for combination treatment with gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer who had relapsed after receiving one adjuvant/neoadjuvant or first-line metastatic chemotherapy regimen containing an anthracycline with/without a taxane. Secondary endpoints included duration of response, time to progression, one-year survival probability, and toxicity. DESIGN AND SETTING: A single-arm, open-label, phase 2 study conducted at 17 investigative sites in Egypt. PATIENTS AND METHODS: treatment consisted of gemcitabine (1250 mg/m2) on Days 1 and 8 and cisplatin (70 mg/m2) on Day 1 of each 21-day cycle. Treatment continued until disease progression or a maximum of 6 cycles. RESULTS: Of 144 patients all were evaluable for safety and 132 patients were evaluable for efficacy. The overall response rate was 33.3% and 45.5% of the patients with stable disease as their best response. The median time-to progression was 5.1 months and the one-year survival probability was 73%. The most common grade 3/4 adverse events were nausea/vomiting (20.1%), neutropenia (19.4%), anemia (13.9%), asthenia (11.1%), diarrhea (9.7%), stomatitis (7.6%), leucopenia (7.6%), and thrombocytopenia (6.2%). twelve (8.3%) patients had serious adverse events. CONCLUSIONS: The results of this study indicate that gemcitabine and cisplatin were active and generally well tolerated in pretreated patients with locally advanced or metastatic breast cancer. PMID- 22446615 TI - JAK2 mutation-negative essential thrombocythemia in a child presenting with cerebral venous thrombosis. AB - Essential thrombocythemia (ET) is a rare myeloproliferative disorder occurring predominantly in the elderly population. Its occurence in the pediatric age group is even more rare. We report a 13-year-old girl who presented with isolated cerebral venous thrombosis and was diagnosed with essential thrombocythemia. family screening for any thrombocytosis was 20 negative. With no secondary cause apparent for persistent thrombocytosis, we looked for the JAK2 mutation, but the result was negative. in contrast to linkage of JAK2 mutation positivity with increased thrombotic risk, our case showed that thrombosis can occur in the absence of JAK2 mutation in a case of essential thrombocythemia. the indications for treatment and the best treatment of children with ET are currently not known, and guidelines for the management of children with ET are needed. Adult patients have near-normal life expectancy because of the low rate of leukemic conversion, but no child has been monitored long enough to assess prognosis. PMID- 22446616 TI - Bone mineral density in ex-thalassemic pediatric patients. PMID- 22446617 TI - Ecological risk assessment of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in marine environment using Isochrysis galbana, Paracentrotus lividus, Siriella armata and Psetta maxima. AB - Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are anthropogenic substances classified as persistent bioaccumulative compounds and are found in various environmental compartments throughout the world, from industrialized regions to remote zones far from areas of production. In this study, we assessed the effects of PFOA and PFOS on early life stages of marine test species belonging to three different trophic levels: one microalga (Isochrysis galbana), a primary consumer (Paracentrotus lividus) and two secondary consumers (Siriella armata and Psetta maxima). Acute EC(50) values for PFOS were 0.11 mg L(-1) in P. maxima, 6.9 mg L(-1) in S. armata, 20 mg L(-1) in P. lividus and 37.5 mg L(-1) in I. galbana. In the case of PFOA, the toxicity was lower but the ranking was the same; 11.9 mg L(-1) in P. maxima, 15.5 mg L(-1) in S. armata, 110 mg L(-1) in P. lividus and 163.6 mg L(-1) in I. galbana. The Predicted No Effect Concentration (PNEC) for PFOS and PFOA in marine water derived from these acute toxicity values are 1.1 MUg L(-1) for PFOS and 119 MUg L(-1) for PFOA. This study established a baseline dataset of toxicity of PFOS and PFOA on saltwater organisms. The data obtained suggest that PFOA pose a minor risk to these organisms through direct exposure. In the perspective of risk assessment, early life stage (ELS) endpoints provide rapid, cost-effective and ecologically relevant information, and links should be sought between these short term tests and effects of long-term exposures in more realistic scenarios. PMID- 22446618 TI - A remarkable anion effect on palladium nanoparticle formation and stabilization in hydroxyl-functionalized ionic liquids. AB - Pd nanoparticles (NPs) with a small size and narrow size distribution were prepared from the decomposition of Pd(OAc)(2) in a series of hydroxyl functionalized ionic liquids (ILs) comprising the 1-(2'-hydroxylethyl)-3 methylimidazolium cation and various anions, viz. [C(2)OHmim][OTf] (2.4 +/- 0.5 nm), [C(2)OHmim][TFA] (2.3 +/- 0.4 nm), [C(2)OHmim][BF(4)] (3.3 +/- 0.6 nm), [C(2)OHmim][PF(6)] (3.1 +/- 0.7 nm) and [C(2)OHmim][Tf(2)N] (4.0 +/- 0.6 nm). Compared with Pd NPs isolated from the non-functionalized IL, [C(4)mim][Tf(2)N] (6.2 +/- 1.1 nm), it would appear that the hydroxyl group accelerates the formation of the NPs, and also helps to protect the NPs from oxidation once formed. Based on the amount of Pd(OAc)(2) that remains after NP synthesis (under the given conditions) the ease of formation of the Pd NPs in the [C(2)OHmim](+) based ILs follows the trend [Tf(2)N](-), [PF(6)](-) > [BF(4)](-) > [OTf](-) > [TFA](-). Also, the ability of the [C(2)OHmim](+)-based ILs to prevent the Pd NPs from undergoing oxidation follows the trend [Tf(2)N](-) > [PF(6)](-) > [TFA](-) > [OTf](-) > [BF(4)](-). DFT calculations were employed to rationalize the interactions between Pd NPs and the [C(2)OHmim](+) cation and the various anions. PMID- 22446619 TI - A novel genome-based approach correlates TMPRSS3 overexpression in ovarian cancer with DNA hypomethylation. AB - OBJECTIVE: In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-l-methionine (SAM). METHODS: Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP). RESULTS: Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors, compared to low-malignant potential ovarian tumors and normal ovarian tissue. CONCLUSIONS: Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethylation of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models. PMID- 22446621 TI - Ovarian Sertoli-Leydig cell tumors. a retrospective MITO study. AB - OBJECTIVE: To evaluate clinicopathologic features and to investigate the outcome of patients with ovarian Sertoli-Leydig cell tumors (SLCTs). METHODS: Data concerning 21 patients treated in 11 MITO centers were retrospectively reviewed. RESULTS: Median age was 37 (range 16-76). FIGO stage was: 17 (81%) IA, 1 (4.8%) IC, 1 (4.8%) IIB and 2 (9.5%) IIIC. Five patients (23.8%) had G1 tumor, ten (47.6%) had G2, and six (28.6%) had G3. Fertility-sparing operation was performed in 11 patients, while hysterectomy with bilateral salpingo-oophorectomy was executed in 10 patients; five patients received adjuvant chemotherapy (G2-3). Seven patients (33.3%) relapsed with a median time to recurrence of 14 months. Six recurrent patients had G2-3 disease, while one had G1. Four patients had stage IA disease, one IC and 2 stage IIIC. Patients with stage IA disease did not receive adjuvant chemotherapy. Two patients had pelvic recurrence, 4 abdominal (one with lymph nodal involvement), one on the contralateral ovary and the trocar access. Five patients underwent salvage surgery plus chemotherapy, while one received only salvage chemotherapy and one palliation. Five patients died of disease, four had received first treatment not in a MITO center. 5 year overall survival was 100% for patients with G1 disease and 77.8% for G2-3. 5 year overall survival was 92.3% for stage I and 33.3% for stage>I. CONCLUSIONS: The prognosis of patients with grade 1 SLCT is excellent without adjuvant chemotherapy. Patients with advanced stage or grade 2-3 tumors appear to benefit from postoperative chemotherapy. PMID- 22446622 TI - Progression-free and overall survival of a modified outpatient regimen of primary intravenous/intraperitoneal paclitaxel and intraperitoneal cisplatin in ovarian, fallopian tube, and primary peritoneal cancer. AB - OBJECTIVE: GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen. METHODS: Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135 mg/m(2)) over 3h on day 1, IP cisplatin (75 mg/m(2)) on day 2, and IP paclitaxel (60 mg/m(2)) on day 8, given every 21 days for 6 cycles. RESULTS: We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43 months. The median age at diagnosis was 57 years (range, 23-76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); <= 1 cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6 cycles. The median PFS and OS were 29 and 67 months, respectively. CONCLUSIONS: By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study. PMID- 22446623 TI - A self-administered family history questionnaire improves identification of women who warrant referral to genetic counseling for hereditary cancer risk. AB - OBJECTIVES: This study was undertaken to assess a self-administered family history questionnaire in order to better identify women within a gynecologic oncology practice for referral to genetic counseling services. METHODS: Returning patients at an outpatient gynecologic oncology clinic completed a self administered family health history questionnaire and a detailed telephone interview. A genetic counselor separately assessed blinded information garnered from the questionnaire, structured genetic interview, and electronic medical records to determine whether these data warranted referral to genetic counseling based on established criteria. The structured genetic interview was considered the gold standard to which the questionnaire and medical record information were compared. RESULTS: Of the 45 total participants in the study, 26 (58%) were identified from the structured genetic interview as meeting criteria for referral to genetic counseling. The questionnaire identified 21 (81%) of these 26 referrals, while the medical record identified 13 (50%) of these 26 referrals. This led to a 62% increase in referral capture by the questionnaire. The median time to complete the questionnaire was 17 min (range 5-57 min). Thirty-four participants (75.6%) had more family members with cancer identified on the questionnaire compared to the electronic medical record. The questionnaire identified fewer family members with cancer in the five cases that were missed for appropriate referral. CONCLUSIONS: Current standard clinical practices are insufficient at identifying patients in need of referral to genetic counseling. A self-administered questionnaire improves recognition of candidates for genetic counseling in a gynecologic oncology practice. PMID- 22446624 TI - A phase II study of a urokinase-derived peptide (A6) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study. AB - PURPOSE: This multi-institutional phase II trial assessed the activity and tolerability of the anti-metastatic A6 peptide that binds CD44 in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (EOC/FTC/PPC). PATIENTS AND METHODS: Women with persistent or recurrent EOC/FTC/PPC were eligible for participation if they had measurable disease defined by RECIST criteria, good performance status, and good overall organ function. Patients must have received one prior platinum-based chemotherapeutic regimen and were allowed to have received one additional cytotoxic regimen for the management of recurrent or persistent disease. Women received a 150 mg twice daily subcutaneous dose of A6 and continued on treatment until disease progression or unacceptable toxicity. Primary measures of clinical efficacy were objective tumor response and progression-free survival (PFS) at 6 months. The association of CD44 in archival tissue specimens with clinical outcome was investigated. RESULTS: Thirty-one eligible patients were evaluated. No responses were observed. Two patients (6.5%) were progression free for at least 6 months. The median PFS was 2.0 months, and median overall survival has not yet been reached. One patient died of hemorrhage which was possibly study related. There were no grade 4 toxicities. The most common grade 3 toxicities were constitutional (2/31; 6.5%). Archival specimens were available for 27 patients, and 5 (18.5%) were CD44 positive by immunohistochemistry. CD44 expression was not associated with the 6-month PFS (p=0.342). CONCLUSION: A6 was well tolerated but had minimal activity in patients with persistent or recurrent EOC/FTC/PPC. PMID- 22446625 TI - Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes. AB - In most eukaryotes, the progressive loss of chromosome-terminal DNA sequences is counteracted by the enzyme telomerase, a reverse transcriptase that uses part of an RNA subunit as template to synthesize telomeric repeats. Many cancer cells express high telomerase activity, and mutations in telomerase subunits are associated with degenerative syndromes including dyskeratosis congenita and aplastic anaemia. The therapeutic value of altering telomerase activity thus provides ample impetus to study the biogenesis and regulation of this enzyme in human cells and model systems. We have previously identified a precursor of the fission yeast telomerase RNA subunit (TER1) and demonstrated that the mature 3' end is generated by the spliceosome in a single cleavage reaction akin to the first step of splicing. Directly upstream and partly overlapping with the spliceosomal cleavage site is a putative binding site for Sm proteins. Sm and like-Sm (LSm) proteins belong to an ancient family of RNA-binding proteins represented in all three domains of life. Members of this family form ring complexes on specific sets of target RNAs and have critical roles in their biogenesis, function and turnover. Here we demonstrate that the canonical Sm ring and the Lsm2-8 complex sequentially associate with fission yeast TER1. The Sm ring binds to the TER1 precursor, stimulates spliceosomal cleavage and promotes the hypermethylation of the 5'-cap by Tgs1. Sm proteins are then replaced by the Lsm2-8 complex, which promotes the association with the catalytic subunit and protects the mature 3'-end of TER1 from exonucleolytic degradation. Our findings define the sequence of events that occur during telomerase biogenesis and characterize roles for Sm and Lsm complexes as well as for the methylase Tgs1. PMID- 22446626 TI - DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation. AB - Alternative messenger RNA splicing is the main reason that vast mammalian proteomic complexity can be achieved with a limited number of genes. Splicing is physically and functionally coupled to transcription, and is greatly affected by the rate of transcript elongation. As the nascent pre-mRNA emerges from transcribing RNA polymerase II (RNAPII), it is assembled into a messenger ribonucleoprotein (mRNP) particle; this is the functional form of the nascent pre mRNA and determines the fate of the mature transcript. However, factors that connect the transcribing polymerase with the mRNP particle and help to integrate transcript elongation with mRNA splicing remain unclear. Here we characterize the human interactome of chromatin-associated mRNP particles. This led us to identify deleted in breast cancer 1 (DBC1) and ZNF326 (which we call ZNF-protein interacting with nuclear mRNPs and DBC1 (ZIRD)) as subunits of a novel protein complex--named DBIRD--that binds directly to RNAPII. DBIRD regulates alternative splicing of a large set of exons embedded in (A + T)-rich DNA, and is present at the affected exons. RNA-interference-mediated DBIRD depletion results in region specific decreases in transcript elongation, particularly across areas encompassing affected exons. Together, these data indicate that the DBIRD complex acts at the interface between mRNP particles and RNAPII, integrating transcript elongation with the regulation of alternative splicing. PMID- 22446627 TI - Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. AB - The immunostimulatory cytokine interleukin-2 (IL-2) is a growth factor for a wide range of leukocytes, including T cells and natural killer (NK) cells. Considerable effort has been invested in using IL-2 as a therapeutic agent for a variety of immune disorders ranging from AIDS to cancer. However, adverse effects have limited its use in the clinic. On activated T cells, IL-2 signals through a quaternary 'high affinity' receptor complex consisting of IL-2, IL-2Ralpha (termed CD25), IL-2Rbeta and IL-2Rgamma. Naive T cells express only a low density of IL-2Rbeta and IL-2Rgamma, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rbeta and IL-2Rgamma. Here, using in vitro evolution, we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 'superkine' (also called super-2) with increased binding affinity for IL 2Rbeta. Crystal structures of the IL-2 superkine in free and receptor-bound forms showed that the evolved mutations are principally in the core of the cytokine, and molecular dynamics simulations indicated that the evolved mutations stabilized IL-2, reducing the flexibility of a helix in the IL-2Rbeta binding site, into an optimized receptor-binding conformation resembling that when bound to CD25. The evolved mutations in the IL-2 superkine recapitulated the functional role of CD25 by eliciting potent phosphorylation of STAT5 and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, the IL-2 superkine induced superior expansion of cytotoxic T cells, leading to improved antitumour responses in vivo, and elicited proportionally less expansion of T regulatory cells and reduced pulmonary oedema. Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy. PMID- 22446629 TI - An apolar extract of Critonia morifolia inhibits c-Myc, cyclin D1, Cdc25A, Cdc25B, Cdc25C and Akt and induces apoptosis. AB - Investigating the bioactivity of traditional medical remedies under the controlled conditions of a laboratory is an option to find additional applications, novel formulations or lead structures for the development of new drugs. The present work analysed the anti-neoplastic activity of increasing polar extracts of the rainforest plant Critonia morifolia (Asteraceae) that has been successfully used as traditional remedy to treat various inflammatory conditions in the long-lasting medical tradition of the Central American Maya, which was here also confirmed in vitro. The apolar petroleum ether extract exhibited the most potent anti-proliferative and pro-apoptotic effects in HL-60 cells and triggered down-regulation of Cdc25C and cyclin D1 within 30 min followed by the inhibition of c-Myc expression and the onset of caspase-3 activation within 2 h. Subsequent to these very rapid molecular responses Chk2 and H2AX became phosphorylated (gamma-H2AX) after 4 h. Analysis of the cell cycle distribution showed an accumulation of cells in the G2-M phase within 8 h and after 24 h in S phase. This was temporally paralleled by the down-regulation of Cdc25A, Cdc25B, Wee1 and Akt. Therefore, the attenuation of cell cycle progression in the G2-M phase was consistent with the known role of Chk2 for G2-M arrest and with the role of Cdc25B in S-phase progression. These findings suggest the presence of two distinct active principles in the petroleum ether extract of C. moriflia. These facilitated the strong apoptotic response evidenced by the rapid activation of caspase-3 that was later enforced by the inhibition of the survival kinase Akt. Importantly, the efficient down-regulation of Akt, which is successfully tested in current clinical trials, is a unique property of C. morifolia. PMID- 22446628 TI - IFITM3 restricts the morbidity and mortality associated with influenza. AB - The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins' in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans. PMID- 22446630 TI - Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core: in vitro and in vivo evaluation. AB - A functional drug carrier comprised of folic acid modified lipid-shell and polymer-core nanoparticles (FLPNPs) including poly(D,L-lactide-co-glycolide) (PLGA) core, PEGylated octadecyl-quaternized lysine modified chitosan (PEG-OQLCS) as lipid-shell, folic acid as targeting ligand and cholesterol was prepared and evaluated for targeted delivery of paclitaxel (PTX). Confocal microscopy analysis confirmed the coating of the lipid-shell on the polymer-core. Physicochemical characterizations of FLPNPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. The internalization efficiency and targeting ability of FLPNPs were demonstrated by flow cytometry and confocal microscopy. PTX loaded FLPNPs showed a significantly higher cytotoxicity than the commercial PTX formulation (Taxol(r)). The intravenous administration of PTX encapsulated FLPNPs led to tumor regression and improvement of animal survival in a murine model, compared with that observed with Taxol(r) and biodistribution study showed that PTX concentration in tumor for PTX encapsulated FLPNPs was higher than other PTX formulations. Our data indicate that PTX loaded FLPNPs are a promising nano-sized drug formulation for cancer therapy. PMID- 22446631 TI - Effects of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in EGFR-mutated non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) is one of the most promising targets for non-small cell lung cancer (NSCLC). Our study demonstrated the antitumor effects of icotinib hydrochloride, a highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in two EGFR-mutated lung cancer cell lines compared to A549, a cell line without EGFR mutations. We incubated PC-9 and HCC827 human lung cancer cell lines both with (E746-A750) mutations with various concentrations of icotinib and gefitinib for 48 h. Cell proliferation and migration were determined using a real-time cell invasion and migration assay and cytotoxicity assay. Apoptosis was assessed by measuring Annexin V staining using flow cytometry. The antitumor effects of icotinib compared to gefitinib were similar and were most effective in reducing the proliferation of EGFR-mutated cells compared to non-mutated controls. Our results suggest the possibility of icotinib as a new therapeutic agent of EGFR-mutated cancer cells, which has the potential to be used in the first-line treatment of EGFR-mutated NSCLC. PMID- 22446632 TI - Effect of needle length for response to hepatitis B vaccine in macrosomic neonates: a prospective randomized study. AB - OBJECTIVES: The objective of this study was to determine whether use of a longer (1 in.) rather than a standard (5/8 in.) needle used for macrosomic neonates (birthweight over 4000 g) may affect antibody titers after immunization against hepatitis B virus (HBV). METHODS: Fifty nine healthy infants were vaccinated at birth, 1, and 6 months of age with hepatitis B vaccine, with follow up to 7 months of age. Infants were randomized into two groups according to needle length of first vaccine at birth. First group vaccinated with standart needle length and other group received vaccine by longer needle length. RESULTS: Macrosomic infants who were immunized with a longer needle achieved significantly higher antibody titers to hepatitis B surface antigen than standart needle length (median, 3890.2 vs 1311.7 mIU/mL, respectively; p=0.001). CONCLUSIONS: Macrosomic neonates benefit from longer needle length with higher levels of antibody titers after HBV vaccination. PMID- 22446633 TI - Efficacy of Rhipicephalus (Boophilus) microplus Bm86 against Hyalomma dromedarii and Amblyomma cajennense tick infestations in camels and cattle. AB - The recombinant Bm86-based tick vaccines have shown their efficacy for the control of cattle ticks, Rhipicephalus (Boophilus) microplus and R. annulatus infestations. However, cattle ticks often co-exist with multi-host ticks such as Hyalomma and Amblyomma species, thus requiring the control of multiple tick infestations for cattle and other hosts. Vaccination trials using a R. microplus recombinant Bm86-based vaccine were conducted in cattle and camels against Hyalomma dromedarii and in cattle against Amblyomma cajennense immature and adult ticks. The results showed an 89% reduction in the number of H. dromedarii nymphs engorging on vaccinated cattle, and a further 32% reduction in the weight of the surviving adult ticks. In vaccinated camels, a reduction of 27% and 31% of tick engorgement and egg mass weight, respectively was shown, while egg hatching was reduced by 39%. However, cattle vaccination with Bm86 did not have an effect on A. cajennense tick infestations. These results showed that Bm86 vaccines are effective against R. microplus and other tick species but improved vaccines containing new antigens are required to control multiple tick infestations. PMID- 22446634 TI - Immunization with high epitope density of M2e derived from 2009 pandemic H1N1 elicits protective immunity in mice. AB - As highly conserved amongst human influenza A strains, the extracellular domain of influenza M2 protein (M2e) is considered and proved as a promising candidate for a universal influenza vaccine. However, there are four amino acid variations in the M2e sequence of the 2009 pandemic H1N1 (referred to as "swine flu M2e, SFM2e") compared with the conventional M2e consensus sequence. Whether the sequence variation alters the immunogenicity and protection of SFM2e epitope remains unclear. In our present study, we synthesized SFM2e peptide and constructed a series of GST fusion proteins containing various copies of the SFM2e epitope and immunized mice to evaluate their immunogenicity and protective activity. We found that although the amino acid variations have weakened the immunogenicity of the SFM2e peptide, the SFM2e fusion proteins with high epitope densities induced intense and diverse antibody response as well as T cell response. Moreover, mice immunized with high epitope density of SFM2e were nearly fully protected against a lethal challenge by the mouse-adapted influenza virus A/Porto Rico/8/34. Our study could provide new available data to improve the epitope vaccine strategy against influenza pandemic. PMID- 22446635 TI - Assessing the immunological response to hepatitis B vaccination in HIV-infected patients in clinical practice. AB - Hepatitis B vaccination is recommended in HIV-infected patients. Achieving seroprotection rates (anti-HBs >= 10I U/L) comparable to the general population remains a challenge. The aim of this study was to analyze the proportion of responders among patients infected with HIV receiving primary HBV vaccination and identify factors associated with seroprotection rates. We analyzed the response to vaccination (antiHBs titers) in 474 HIV-infected patients receiving >= 1 doses of vaccine between 1994 and 2009. Factors associated with response to vaccination were analyzed using a logistic regression model. Considering the first vaccine courses administered, a response rate of 60.3% (286/474) was obtained. Eighty seven patients began a second course, responding in 58.6% of cases. Regardless of the number of doses, schedules, and whether or not they completed the course, the response rates were 71.1% (337/474). After adjustment for year of reception of the first dose, responders were less likely to have a higher baseline HIV 1-RNA viral load (OR: 0.78 95% CI: 0.68-0.91) and more likely to have a CD4 count >= 350 cells/MUL (OR: 1.64, 95% CI: 1.03-3.62). Patients receiving less than three doses of vaccine (OR: 0.31 95% CI 0.15-0.61) or three doses of the rapidly accelerated schedule (OR: 0.35 95% CI 0.15-0.81) had a lower probability of response in comparison with those receiving three doses of an accelerated schedule. In patients diagnosed with HIV, HBV vaccination before evolution to greater immunosuppression (CD4 < 350 cells/MUL) or delaying vaccination until the CD4 count is higher could provide better seroprotection rates. The rapidly accelerated vaccination schedule should be used with caution, due to its lower effectiveness. If seroprotection is not achieved after the first course, revaccination seems to be effective in increasing the proportion of responders. PMID- 22446636 TI - Health and economic impact of the seasonal influenza vaccination programme in England. AB - BACKGROUND: The seasonal influenza vaccination programme in England targets individuals over 65 years old and in clinical risk groups. METHODS: A model of influenza transmission and disease was fitted to weekly primary care consultations due to influenza in a typical pre-pandemic season (2006/2007). Different scenarios were constructed about influenza severity and how well vaccines match circulating strains to assess the impact and cost-effectiveness of the current vaccination programme. RESULTS: A well-matched vaccine may reduce the incidence of laboratory-confirmed influenza illness from 8.2% (95% range 4.3-13%) to 5.9% (95% range 2.9-9.7%), with 56-73% of this due to indirect protection. The programme is likely to be cost-effective unless both low severity and poor matching is assumed. CONCLUSION: The current seasonal influenza vaccination programme appears to substantially reduce disease burden and provides good value for money. PMID- 22446637 TI - What lies behind the low rates of vaccinations among nurses who treat infants? AB - BACKGROUND: In most countries rates of immunizations of health care workers with recommended vaccines are not satisfactory. OBJECTIVES: To identify reasons behind the low rates of compliance of Israeli nurses in Mother and Child Healthcare Centers (MCHC) with an official request for pertussis vaccination. METHODS: Three focus groups were conducted. Qualitative analysis identified themes that could explain the nurses' non-compliance. RESULTS: Trust in health authorities was low, mainly following the A/H1N1 purported influenza pandemic. In addition, nurses did not see the importance of being role models for the public and demanded the autonomy to decide whether to receive vaccinations. The nurses differentiated between their role as nurses and their personal life, expressed fear of new vaccines and exhibited low levels of risk perception. Misconceptions regarding vaccinations were expressed by the nurses. CONCLUSIONS: Antivaccinationist ideas were expressed by MCHC nurses and these attitudes may have led to non-compliance with vaccination guidelines. PMID- 22446638 TI - A randomized clinical trial to identify the optimal antigen and MF59((r)) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects. AB - BACKGROUND: Vaccines against pandemic A/H1N1 influenza are required to protect the entire population. This dose range study aimed to identify priming antigen and adjuvant doses resulting in optimal levels of antibody-mediated protection after primary and one-year booster immunizations. METHODS: This randomised trial enrolled 410 healthy adult (18-60 years) and 251 healthy elderly (>60 years) participants. Subjects received vaccine containing either 3.75 MUg or 7.5 MUg antigen, adjuvanted with half the standard dose, or a standard dose of MF59((r)) (Novartis Vaccines) adjuvant, respectively. An additional adult cohort received non-adjuvanted vaccine containing 15 MUg antigen. Two doses of investigational vaccine were administered three weeks apart, followed by a single booster dose of adjuvanted seasonal influenza vaccine one year after priming. Immunogenicity was assessed by haemagglutination inhibition and microneutralization assays pre- and post-immunization, the safety profile of each vaccine was also evaluated. RESULTS: All of the vaccine formulations investigated were highly immunogenic and well tolerated in both adult and elderly subjects. The 7.5 MUg formulation induced the highest antibody titres after primary and booster immunizations, and resulted in better long-term antibody persistence, in both age groups. Assessment according to European licensure criteria for influenza vaccines concluded that single adjuvanted priming doses containing 3.75 MUg and 7.5 MUg antigen were optimal for the adult and elderly populations, respectively. CONCLUSIONS: These data demonstrate that one priming dose of MF59-adjuvanted A/H1N1 vaccine provided healthy adult (3.75 MUg or 7.5 MUg formulations) and healthy elderly (7.5 MUg formulation) individuals with adequate levels of seroprotection. Booster administration after two priming doses of either vaccine formulation resulted in the rapid development of seroprotective antibody titres. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00971906). PMID- 22446639 TI - Enhancing the reproducibility of serological methods used to evaluate immunogenicity of pandemic H1N1 influenza vaccines-an effective EU regulatory approach. AB - Haemagglutination-inhibition (HI) and virus neutralisation (VN) assays are routinely applied to evaluate influenza vaccine immunogenicity for regulatory approval. Despite their frequent use both assays are currently only poorly standardised causing considerable inter-laboratory variation of serological results that is particularly evident for pandemic influenza vaccines. The present study was conducted in association with the European Medicines Agency (EMA) to directly compare assay variability between vaccine manufacturer's and European regulatory agency's laboratories in an influenza pandemic scenario. To this end, a defined subset of H1N1 pdm clinical trial sera from all manufacturers that had applied at EMA for approval of pandemic H1N1 vaccines were re-tested by the National Institute for Biological Standards and Control (for HI) and the Paul Ehrlich Institute (for VN). Comparative analysis of test results determined for almost 2000 serum samples revealed a marked inter-laboratory variation for HI titres (up to 5.8-fold) and even more for neutralisation titres (up to 7.0-fold). When the absolute titres were adjusted relative to the calibrated International Antibody Standard 09/194 variation was drastically reduced and acceptable agreement of results from different laboratories could be achieved. Hence, inclusion of an appropriate calibrated antibody standard for adjustment of original titres is a powerful tool to substantially increase reproducibility of serological results from different laboratories and to significantly improve regulatory evaluation of influenza vaccine efficacy. PMID- 22446640 TI - Killed Bacillus subtilis spores as a mucosal adjuvant for an H5N1 vaccine. AB - Heat killed spores of the Gram-positive bacterium Bacillus subtilis have been evaluated as a vaccine delivery system with mucosal adjuvant properties for influenza. Killed spores were able to bind H5N1 virions (NIBRG-14; clade 1) and, when intra-nasally administered to mice, resulting immune responses, both humoral and cell mediated, were enhanced compared to immunization with the virion alone. Levels of both systemic IgG and mucosal sIgA specific to the virion were elevated. Levels of IgG2a (a Th(1) antibody type) were strongly enhanced when the virion was co-administered with killed spores. Cytokine induction in stimulated splenocytes was also apparent indicating balanced T(h)1 and T(h)2 responses. Evidence of cross-neutralization of clade 2.2 viruses was shown. In a challenge experiment mice dosed two times with spores adsorbed with just 20 ng HA (hemagglutinin) of inactivated NIBRG-14 were fully protected against challenge with 20 LD(50) of H5N2 virus. Interestingly, partial protection (60%) was observed in animals dosed only with killed spores. Mice dosed only with killed spores were shown to be fully protected against H5N2 (5 LD(50)) infection indicating that innate immunity and its stimulation by spores may play an important role in protection. Supporting this killed spores were (i) shown to stimulate TLR-mediated expression of NF-kappaB, and (ii) able to recruit NK cells into lungs and induce maturation of DCs. This work demonstrates the potential and underlying mechanism for the use of bacterial spores as an adjuvant for H5N1 vaccination. PMID- 22446641 TI - Cyanobacterial biofuel production. AB - The development of new technologies for production of alternative fuel became necessary to circumvent finite petroleum resources, associate rising costs, and environmental concerns due to rising fossil fuel CO2 emissions. Several alternatives have been proposed to develop a sustainable industrial society and reduce greenhouse emissions. The idea of biological conversion of CO2 to fuel and chemicals is receiving increased attention. In particular, the direct conversion of CO2 with solar energy to biofuel by photosynthetic microorganisms such as microalgae and cyanobacteria has several advantages compared to traditional biofuel production from plant biomass. Photosynthetic microorganisms have higher growth rates compared with plants, and the production systems can be based on non arable land. The advancement of synthetic biology and genetic manipulation has permitted engineering of cyanobacteria to produce non-natural chemicals typically not produced by these organisms in nature. This review addresses recent publications that utilize different approaches involving engineering cyanobacteria for production of high value chemicals including biofuels. PMID- 22446642 TI - [Acute myocardial infarction mortality in Chile: thrombolysis or angioplasty]. AB - During recent decades, acute myocardial infarction short-term mortality has decreased to one digit levels, in the United States. Data from Chilean registries give figures around 11% for patients receiving thrombolysis, and 5 to 6 % for patients treated with angioplasty. The decrease in mortality in Chile is related to the implementation of the AUGE program at a national level, initiative than gives patients the opportunity to receive at least thrombolytic therapy as well as a standardized and rapid diagnosis and treatment for this condition. There is a lack of Outcome Research studies in Chile, that would guide public health decisions such as the use of fibrin-specific agents for early presentation and high risk cases, and a rational system providing better access to primary angioplasty. PMID- 22446643 TI - [Angioplasty compared to thrombolysis as the initial reperfusion therapy in acute myocardial infarction]. AB - BACKGROUND: Primary angioplasty is superior to intravenous thrombolysis as reperfusion therapy for acute myocardial infarction. AIM: To compare the results of available reperfusion strategies for initial management of acute myocardial infarction during hospitalization and 5 years follow up. PATIENTS AND METHODS: Historical cohort study from a prospective registry of patients admitted with acute myocardial infarction to our center. Patients treated with primary angioplasty were identified and were then matched by age, sex and date of event with patients treated with throm-bolysis. The clinical outcomes were compared including hospitalization and 5-years follow-up. RESULTS: From March 1993 to August 2001, 98 patients were treated with primary angioplasty and matched with 98 thrombolyzed patients. The groups were comparable. Compared to thrombolysis, angioplasty had a higher success rate (68 and 91% respectively), resulted in less complications and reduced mortality (11 and 2% respectively), required less revascularization procedures and shorter hospital stay (17 and 13 days, respectively). During the follow-up of survivors, no differences in events or additional mortality were detected at 1 or 5 years. CONCLUSIONS: Primary angioplasty is superior as treatment in terms of achieving success and reducing mortality during hospitalization. Evolution after hospitalization is independent of initial therapy. PMID- 22446644 TI - [The adaptation methodology of a guideline for the management of adults with community-acquired pneumonia]. AB - BACKGROUND: Clinical practice guidelines (CPG) are widely used as tools for improving quality of health care. Guidelines developed elsewhere, can be adapted using a valid and systematic process. AIM: To describe the methodology used in the process of adaptation of a guideline for the management of adults with community-acquired pneumonia (CAP) in a private health care organization. MATERIAL AND METHODS: We used the ADAPTE framework involving three main phases. At the set-up phase a guideline adaptation group integrated by medical specialists from different disciplines, a methodologist and a nurse coordinator was formed. At the adaptation phase, the specific clinical questions to be addressed by the guidelines were identified. RESULTS: Twenty five guidelines were initially retrieved. After their assessment, the number was reduced to only three. Recommendations from these guidelines were 'mapped' and focused searches were carried out where 'evidence gaps' were identified. An initial draft was written and revised by the adaptation group. At the finalization phase, the external review of the guideline was carried out and a process for the regular review and update of the adapted guideline was defined. CONCLUSIONS: We developed a guideline for the management of adults with CAP, adapted to the local context of our health care system, using guidelines developed elsewhere. This guideline creation method can be an efficient means of saving professional resources. PMID- 22446645 TI - [Results of gastric bypass for morbid obesity after a follow up of seven to 10 years]. AB - BACKGROUND: There is a paucity of information about the long term effects of gastric bypass for morbid obesity. AIM: To study the evolution of weight and complications of obesity, seven to 10 years after gastric bypass surgery. MATERIAL AND METHODS: One hundred eighteen subjects with morbid obesity, aged 15 to 66 years (103 women), were followed for a mean of 94 months after surgery. Body weight, fasting blood glucose, total cholesterol, triglycerides and hemoglobin were measured before surgery and during follow up. RESULTS: At 24 months of follow up, all patients lost weight and there was a mild weight increase at 94 months, that paralleled the preoperative body mass index. Diabetes, hypercholesterolemia and hypertriglyceridemia subsided in 95, 87 and 94% of cases, respectively. Twenty percent of patients had mild anemia and 11% moderate or severe anemia. No patient recovered the preoperative weight. CONCLUSIONS: Weight reducing effects of gastric bypass are maintained after 94 months of follow up with the expected health benefits. PMID- 22446646 TI - [Pregnancy and inflammatory bowel disease: experience in 17 patients]. AB - BACKGROUND: Inflammatory bowel disease (IBD) has a peak incidence between 15 and 25 years of age, thereby affecting women of reproductive age. Fertility rates with inactive IBD are similar to the general population, and drugs currently used, with the exception of methotrexate and thalidomide, have a good safety and efficacy profile during pregnancy. Starting a pregnancy with inactive IBD significantly reduces the potential maternal and fetal complications. AIM: To assess the evolution of pregnancy and the underlying disease in women with IBD. PATIENTS AND METHODS: Retrospective and prospective study of female patients with IBD controlled in our hospital who became pregnant from January 1994 to February, 2011. RESULTS: We followed 17 patients with a total of 19 pregnancies. In two patients the onset of IBD occurred during pregnancy and from the remaining, 11 patients became pregnant during remission of IBD. Most of the patients continued the same treatment during pregnancy and the few flares that occurred were treated satisfactorily. Major complications occurred in three patients, all associated with IBD activity. Fifteen patients had full-term deliveries and the majority of the newborns had normal weight and Apgar score. None had malformations. CONCLUSIONS: Pregnancies among patients with an inactive IBD, have a good evolution. A multidisciplinary approach and patient education are invaluable to achieve these good results. PMID- 22446647 TI - [Factorial structure and reliability of Fisher, King & Tague's self-directed learning readiness scale in Chilean medical students]. AB - BACKGROUND: Continuous education is crucial among physicians. Therefore, medical schools must teach self-directed learning skills to their students. AIM: To evaluate the factorial structure and reliability of the Spanish version of the Self-Directed Learning Readiness Scale of Fisher, King & Tague, applied to medical students. MATERIAL AND METHODS: The survey was answered by 330 students aged between 17 and 26years (58% men, with 10 missing cases). Factorial structure, internal reliability and temporary stability of scale was evaluated. RESULTS: The Exploratory Factorial Analysis, conducted using a principal factor method, identified five factors in the structure of the survey. Internal consistency was adequate with a Cronbach's alpha between 0.66 and 0.88. Test retest reliability, comparing the results of the survey applied six months after the first application, showed Pearson correlation coefficients that fluctuated between 0.399 and 0.68. CONCLUSIONS: These results show a defined factorial structure with adequate reliability of the survey. PMID- 22446648 TI - [Normal plasma insulin and HOMA values among Chilean children and adolescents]. AB - BACKGROUND: Plasma insulin and HOMA (homeostasis model assessment) index, used to determine insulin resistance, do not have local standard values for children and adolescents in Chile. AIM: To establish the normal reference intervals for insulin and HOMA in children and adolescents aged 10-15 years, according to sex and puberal maturation. MATERIAL AND METHODS: A cross-sectional study of 2,153 children and adolescents from Puente Alto County was performed, during 2009 and 2010. Anthropometry and self-report of puberal maturation were assessed. Fasting glucose (hexoquinase) and insulin blood levels (chemiluminiscence), were determined and HOMA index was calculated. Percentile distributions of these variables were calculated. RESULTS: The reference group included only subjects with normal body mass index and fasting blood glucose (n = 1,192). Girls had higher insulin and HOMA values than boys (12.5 +/- 6.0 and 9.1 +/- 4.9 MUupsilon/mL (p < 0.01) and 2.7 +/- 1.4 and 2.1 +/- 1,1 (p < 0.01), respectively). Subjects with Tanner I and II pubertal stages had lower insulin and HOMA mean values than subjects with Tanner III and IV (9.0 +/- 4.3 and 12.5 +/- 6.2MUupsilon/ml (p < 0.01) and2.0 +/- 1 and2.8 +/- 1.4 (p < 0.01), respectively). CONCLUSIONS: The 90th percentile of insulin and HOMA distributions according to sex and maturation, was selected as the upper cut-off point to identify individuals with insulin resistance. HOMA cutoff point for Tanner I and II boys was 3.2, for Tanner I and II girls was 4.1, for Tanner III and IV boys was 4.2 and for Tanner III and IV girls was 5.0. PMID- 22446649 TI - [Plasma fructosamine to evaluate metabolic control among women with gestational diabetes]. AB - BACKGROUND: Metabolic control of diabetic pregnant women is assessed using glycated hemoglobin (HbAlc) levels and fasting blood sugar. Another glycated protein, namely fructosamine, can be an indicator of average glucose levels during the last three weeks. AIM: To evaluate plasma fructosamine as an indicator of glycemic control in women with gestational diabetes. PATIENTS AND METHODS: Prospective cohort study of 41 pregnant women aged 30 to 37 years, with gestational and pre-gestational diabetes. Blood glucose, HbAlc, fructosamine were measured. Newborn weight, and other prenatal and postnatal variables, were used to evaluate the correlation between metabolic control and the presence or absence of macrosomia. RESULTS: The correlation observed between fructosamine and fasting blood glucose (r = 0.627, p < 0.001) was superior to that of HbA1c and blood glucose (r = 0.516, p < 0.001). No association was observed between macrosomia and levels of fructosamine, nor between the other studied variables. CONCLUSIONS: Fructosamine levels were not associated with macrosomia, but it could be better for the evaluation of glycemic control in patients with gestational diabetes since it allows short-term monitoring. PMID- 22446650 TI - [Intensity modulated radiotherapy treatment for prostate cancer, first experience in Chile]. AB - BACKGROUND: Intensity modulated radiotherapy (IMRT) is an important step forward in cancer treatment. AIM: To report the first experience in Chile with IMRT for prostate cancer and compare the results obtained with different doses. PATIENTS AND METHODS: From January 1997 through June 2008, 156 patients with a mean age of 70 years, were treated with radiotherapy and 121 with IMRT. Patients were staged according to American Commission on Cancer Staging. Their biochemical relapse risk was classified according to the MD Anderson classification. Patients were routinely checked during and after therapy to evaluate side effects and relapse. RESULTS: Median follow up was 46 months (4-120). Overall five years survival was 85%. Biochemical relapse free five years survival for low, intermediate and high risk patients was 100, 82 and 70%, respectively. Biochemical relapse free survival for patients receiving radiotherapy doses over 76 Gy was 83%, compared to 30% for those receiving lower doses (p < 0.05). Urinary and gastrointestinal acute toxicity was low in 80% and 90% of patients respectively. Late toxicity developed in less than 3% of patients. CONCLUSIONS: IMRT for prostate cancer is readily available and safe in Chile. Biochemical disease free survival improved with higher doses with low toxicity rates. PMID- 22446651 TI - [Prospective assessment of medication errors in critically ill patients in a university hospital]. AB - BACKGROUND: Critically ill patients are especially vulnerable to medication errors (ME) due to their severe clinical situation and the complexities of their management. AIM: To determine the frequency and characteristics of ME and identify shortcomings in the processes of medication management in an Intensive Care Unit. PATIENTS AND METHODS: During a 3 months period, an observational prospective and randomized study was carried out in the ICU of a university hospital. Every step of patient's medication management (prescription, transcription, dispensation, preparation and administration) was evaluated by an external trained professional. Steps with higher frequency of ME and their therapeutic groups involved were identified. Medications errors were classified according to the National Coordinating Council for Medication Error Reporting and Prevention. RESULTS: In 52 of 124 patients evaluated, 66 ME were found in 194 drugs prescribed. In 34% of prescribed drugs, there was at least 1 ME during its use. Half of ME occurred during medication administration, mainly due to problems in infusion rates and schedule times. Antibacterial drugs had the highest rate of ME. CONCLUSIONS: We found a 34% rate of ME per drug prescribed, which is in concordance with international reports. The identification of those steps more prone to ME in the ICU, will allow the implementation of an intervention program to improve the quality and security of medication management. PMID- 22446652 TI - [Analysis of the explicit guarantees of health inclusion criteria for elderly burned patients]. AB - BACKGROUND: The guidelines for the treatment of severely burned patients, included in the explicit guarantees in health care (GES), accept having a Garces' index over 70, among others, as an inclusion criterion. This criterion allows elderly patients with small total burn surface area (TBSA) to have access to GES. AIM: To analyze if a universal access to GES for this group of patients is justified. MATERIAL AND METHODS: Revision of medical records of adult patients admitted to a burn service. Causative agent, TBSA, associated illnesses and outcome were compared between 218 subjects aged 65 years or more and 720 subjects aged less than 65 years. RESULTS: Older subjects had smaller TBSA, a lower prevalence of inhalation injury and more associated diseases. Their lethality was three times greater than that of younger subjects and their risk of dying. When adjusting for TBSA, presence of inhalation injury and associated diseases was 11 times greater. CONCLUSIONS: The inclusion of older people with lower TBSA in the explicit guarantees in health is fully justified, considering the lethality of burns in this age group. PMID- 22446653 TI - [Primary amyloidosis associated with multiple myeloma and renal failure: case report]. AB - We report a 53-year-old female on chronic dialysis, presenting with weight loss, the development of big soft masses in the shoulders ("shoulder pads"), forearms and buttocks, macroglossia and rigidity of hands and lower limbs. Laboratory confirmed the presence of amyloidosis and myeloma with lambda chain restricted plasma cell infiltration of bone marrow. The diagnosis of multiple myeloma associated with primary amyloidosis in a patient with terminal renal failure, was reached. PMID- 22446654 TI - [Multiple paragangliomas associated to a SDHB gene mutation: report of one case]. AB - Paragangliomas are tumors arising from sympathetic and parasympathetic tissues. The classic associated syndromes are neurofibromatosis type 1, multiple endocrine neoplasia type 2 and von Hippel-Lindau. Germline mutations of succinate dehydrogenase subunits genes, are associated with familial paraganglioma syndromes 1,2,3 and 4. We report a 29-year-old woman with a family background of pheochromocytoma and history of paroxysmal headache, nausea, sweating, palpitations, associated with severe hypertension. The patient had elevated plasma noradrenalin and urinary normetanephrines. Imaging studies revealed three retroperitoneal extra-adrenal masses. The clinical and laboratory study of classic syndromes associated with paraganglioma was negative. The patient was operated and the pathological study of the surgical specimen was consistent with paragangliomas. The genetic study showed a mutation in the SDHB succinate dehydrogenase gen, Exon 2 of CCTCA c.300_304 (p.P56delYfsX5). PMID- 22446655 TI - Late diagnosis of nodular melanoma of the foot in a 74-year-old Brazilian man. AB - The incidence and mortality of malignant melanoma is increasing. Its early diagnosis can contribute to a favorable prognosis. We report a 74-year-old black man with a dark brown mole in the right plantar area, that grew slowly in the last decade. A biopsy of the lesion revealed a nodular malignant melanoma. A wide excision of the tumor was performed 18 months ago, followed by chemotherapy for nine months. At admission, the patient was debilitated, and presented with numerous nodules in the lower limb and suprapubic area. Imaging studies disclosed chest and abdominal nodules. The patient died 13 days after admission. PMID- 22446656 TI - Successful rituximab therapy in refractory autoimmune hepatitis and Evans syndrome. AB - A 44-year-old woman was found to have elevated aminotransferases, twice the upper limit of normal. Liver biopsy demonstrated a mixed inflammatory process suggestive of both primary biliary cirrhosis and autoimmune hepatitis (AIH). Prednisone and azathioprine were started, with normalization of aminotransferases. Six months later, she returned with worsening pruritus and re evaluation demonstrated probable reactivation of AIH with acute elevation of liver injury tests. Repeat liver biopsy was suggestive of a flare of AIH which did not respond to prednisone, azathioprine, or mycophenolate mofetil. One month later the patient was hospitalized for sudden onset of anemia and thrombocytopenia, suggestive of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura consistent with Evans syndrome. Rituximab was initiated and mycophenolate mofetil discontinued. After one infusion of rituximab, liver injury tests significantly improved. Within four weeks of rituximab infusion (4 doses) the patient's Evans syndrome completely resolved with normal hemoglobin and platelet levels; aminotransferases also significantly improved to less than twice the upper limit of normal. PMID- 22446657 TI - [Spinal lumbar stenosis: an update]. AB - Spinal lumbar stenosis is a disease that occurs mainly between the 5th and 7th decade of life and can be congenital or acquired. The latter has many etiologies, but a degenerative cause is the most common. Stenosis is a narrowing of the spinal canal diameter caused by many factors such as bulging discs, hypertrophy of flavum ligament, facet capsule thickening and osteophyte formation. The classical symptom of the disease is sciatic pain, that improves with lumbar flexion and worsens with ambulation. Neurological examination is often normal and the most useful imaging test is magnetic resonance imaging (MRI). Conservative management consists in non-steroidal anti-inflammatory drugs, muscle relaxants, physical therapy and epidural - radicular infiltrations. Spinal infiltrations have a proven efficacy for pain management. A good result of this therapy predicts a favorable outcome after surgery. Surgical treatment consists in decompression with or without lumbar fusion. The addition of an arthrodesis is recommended for degenerative spondylolisthesis, correction of deformities, recurrent spinal stenosis with instability, sagittal or coronal imbalance and adjacent segment disease. PMID- 22446658 TI - [Detection of Salmonella and Mycobacterium species in seagulls captured in Talcahuano, Chile]. AB - BACKGROUND: Salmonella can be isolated from the feces of seagulls. Therefore these birds can be a vector for dissemination of this pathogen. AIM: To evaluate the possible role of gulls as vectors of two important human and animal pathogens (My-cobacteria and Salmonella). MATERIAL AND METHODS: One hundred twenty three Kelp gull (Larus dominicanus) and 60 Franklin gulls (Leucophaeus pipixcan) captured off the coast of the seaport of Talcahuano, were analyzed. Using traditional microbiological methods, the presence of Mycobacteria in cloacal swabs and feet lavages, was analyzed in both types of gulls. To detect the presence of Salmonella, feces, fecal and tracheal swabs, and feet lavage were analyzed from Franklin gulls. Feces, feet lavage, intestine, spleen, liver, kidney and lung, were examined in Kelp gulls. RESULTS: All Mycobacteria cultures were negative. Salmonella enterica cultures were positive in 25 % of Kelp gulls and 6.7 % of Franklin gulls. Four serovars were identified by serotyping. Enteritidis and Senfteberg serovars were found in both types of gulls. Anatum and Infantis serovars were found only in Kelp gulls. Feces of gulls captured during the winter had the highest yield of positive cultures (36.1%). CONCLUSIONS: Seagulls are an important Salmonella vector in Chile. PMID- 22446659 TI - [A proposal to improve sick leaves granted by physicians]. AB - From time to time, sick leaves granted by physicians, cause concern among professionals, patients and institutions that administer the funds required to finance the days of work. This document analyzes different aspects of the form that must be filled by the physician to grant the sick leave, reflects on some important difficulties that are faced by health care professionals to complete the document and proposes changes to the form to correct such difficulties. Also, a proposal for a fairest solution for professionals and patients is presented. PMID- 22446660 TI - [Impact of a diploma on medical education in a medical school in Chile]. AB - BACKGROUND: The medical school of the Pontificia Universidad Catolica de Chile offers a Diploma on Medical Education (DME) for its faculty since 2000. However its impact had never been evaluated. AIM: To determine the perception of the graduates of the impact of DME, using the Kirkpatrick model for evaluation of educational outcomes. MATERIAL AND METHODS: A questionnaire containing closed and pre-post retrospective questions that represented Kirkpatrick's four levels of evaluation, was sent to all the graduates in 2009. RESULTS: Eighty two of 91 graduates returned the questionnaire. Ninety one percent had a high level of satisfaction at Kirkpatrick Level 1 (Reaction), and perceived an average of 81.8% completed objectives. Most respondents reported modification of attitudes and perceptions about teaching, at Kirkpatrick Level 2 (Learning). All the differences between the pre and posttest retrospective questionnaire were statistically significant. More than 98% of responded stated that they improved their role as teacher using the skills learned during DME, according to Kirkpatrick Level 3 (Behavior). According to Kirkpatrick Level 4 (Outcomes), 66% stated that the DME contributed to appreciate the value of teaching at an institutional level. CONCLUSIONS: According to the perception of the respondents, the DME has had a positive impact at all the levels described in the Kirkpatrick model. PMID- 22446661 TI - [Evaluation of post graduate teaching programs in chile]. PMID- 22446662 TI - [Potentiation of Aripiprazole extrapiramidal adverse effects with the concomitant use of serotonin selective reuptake inhibitors]. PMID- 22446663 TI - Synthesis of monolithic meso-macroporous silica and carbon with tunable pore size. AB - Monolithic porous silica and carbon structures have been obtained by the synthesis of silica inside the aqueous phase of a sponge-like Swollen Liquid Crystal, and the parallel preparation of carbon replica. PMID- 22446664 TI - Effect of load positioning on the kinematics and kinetics of weighted vertical jumps. AB - One of the most popular exercises for developing lower-body muscular power is the weighted vertical jump. The present study sought to examine the effect of altering the position of the external load on the kinematics and kinetics of the movement. Twenty-nine resistance-trained rugby union athletes performed maximal effort jumps with 0, 20, 40, and 60% of their squat 1 repetition maximum (1RM) with the load positioned (a) on the posterior aspect of the shoulder using a straight barbell and (b) at arms' length using a hexagonal barbell. Kinematic and kinetic variables were calculated through integration of the vertical ground reaction force data using a forward dynamics approach. Performance of the hexagonal barbell jump resulted in significantly (p < 0.05) greater values for jump height, peak force, peak power, and peak rate of force development compared with the straight barbell jump. Significantly (p < 0.05) greater peak power was produced during the unloaded jump compared with all trials where the external load was positioned on the shoulder. In contrast, significantly (p < 0.05) greater peak power was produced when using the hexagonal barbell combined with a load of 20% 1RM compared with all other conditions investigated. The results suggest that weighted vertical jumps should be performed with the external load positioned at arms' length rather than on the shoulder when attempting to improve lower-body muscular performance. PMID- 22446665 TI - Effects of whole-body vibration training on explosive strength and postural control in young female athletes. AB - This study aimed to evaluate the effectiveness of a whole-body vibration training program to improve neuromuscular performance in young elite female athletes. Twenty-three women basketball players (14-18 years old) were randomly assigned to a control group (CG, n = 11) or to a whole-body vibration group (WBVG, n = 12). During the study period, both groups continued their usual training program, but the WBVG also underwent a 15-week vibration training program. We analyzed the countermovement jump test (CMJ), the 1-leg hop test for the right leg and for the left leg, and the single-limb standing balance for both legs and with eyes open and closed at 3 time points: before training (T1), after an 8-week training period (T2), and after a further 7-week training period (T3). Compared with the CG, CMJ increased significantly in the WBVG from T1 to T2 (6.47%, p < 0.001), T1 to T3 (10.07%, p = 0.005), and T2 to T3 (3.38%, p < 0.001). One-leg hop test for the right and left legs also showed significantly higher values in WBVG from T1 to T2 (10.12%, p < 0.001 and 9.63%, p = 0.002, respectively) and T1 to T3 (14.17%, p = 0.001 and 15.17%, p = 0.004, respectively). Lateral deviation of the center of pressure in the closed eyes test decreased significantly in WBVG for both right and left leg, from T1 to T2 (-22.20%, p = 0.043 and -34.77%, p < 0.001, respectively) and from T1 to T3 (-33.14%, p = 0.027 and -33.58%, p = 0.043, respectively) compared with the CG. In conclusion, our results show that a 15-week whole-body vibration training program improves explosive strength and postural stability in adolescent female basketball players. PMID- 22446666 TI - A comparison of maximal squat strength and 5-, 10-, and 20-meter sprint times, in athletes and recreationally trained men. AB - The purpose of this study was to identify whether there was a relationship between relative strength during a 1 repetition maximum (1RM) back squat and 5-, 10-, and 20-m sprint performances in both trained athletes and recreationally trained individuals. Professional rugby league players (n = 24) and recreationally trained individuals (n = 20) participated in this investigation. Twenty-meter sprint time and 1RM back squat strength, using free weights, were assessed on different days. There were no significant (p >= 0.05) differences between the well-trained and recreationally trained groups for 5-m sprint times. In contrast, the well-trained group's 10- and 20-m sprint times were significantly quicker (p = 0.004; p = 0.002) (1.78 + 0.06 seconds; 3.03 + 0.09 seconds) compared with the recreationally trained group (1.84 + 0.07 seconds; 3.13 + 0.11 seconds). The athletes were significantly stronger (170.63 + 21.43 kg) than the recreationally trained individuals (135.45 + 30.07 kg) (p = 0.01); however, there were no significant differences (p > 0.05) in relative strength between groups (1.78 + 0.27 kg/kg; 1.78 + 0.33 kg/kg, respectively). Significant negative correlations were found between 5-m sprint time and relative squat strength (r = -0.613, power = 0.96, p = 0.004) and between relative squat strength and 10- and 20-m sprint times in the recreationally trained group (r = 0.621, power = 0.51, p = 0.003; r = -0.604, power = 0.53, p = 0.005, respectively). These results, indicating that relative strength, are important for initial sprint acceleration in all athletes but more strongly related to sprint performance over greater distances in recreationally trained individuals. PMID- 22446667 TI - Maximal strength on different resistance training rowing exercises predicts start phase performance in elite kayakers. AB - This study aimed to examine the relationship existing between maximum strength values in 2 common resistance training row exercises (bilateral bench pull [BBP] and one-arm cable row [OACR]) and short sprint performance in elite kayakers. Ten junior kayakers (5 women and 5 men) were tested on different days for 1 repetition maximum (1RM) and maximal voluntary isometric contraction in both exercises. Moreover, a 12-m sprint kayak was performed in a dew pond to record split times (2, 5, and 10 m), peak velocity, distance completed considering the first 8 strokes, and mean acceleration induced by right blade and left blade strokes. No differences (p > 0.05) were observed when right and left arms were compared in sprint testing or strength testing variables. Maximal strength values in BBP and OACR were significantly correlated with short sprint performance variables, showing the bilateral exercise with slightly stronger correlation coefficients than the unilateral seated row. Moreover, the relationship between strength testing and sprint testing variables is stronger when maximal force is measured through a dynamic approach (1RM) in comparison with an isometric approach. In conclusion, maximal strength in BBP and OACR is a good predictor of the start phase performance in elite sprint kayakers, mainly the 1RM value in BBP. PMID- 22446668 TI - International field hockey players perform more high-speed running than national level counterparts. AB - This study compared the activity profile of national and international male field hockey athletes. Sixteen players (mean (+/-SD) age, stature, and body mass: 22 +/ 4 y, 178 +/- 8 cm, and 78 +/- 9 kg, respectively) competing in the national level Australian Hockey League (AHL) and 16 players [mean (+/-SD) age, stature, and body mass: 27 +/- 4 y, 179 +/- 5 cm, and 77 +/- 5 kg, respectively] competing in the international Champions Trophy (CT) tournament participated in this study. Global positioning systems assessed total distance (TD), meters per minute (m.min(-1)), and high-speed running distance (HSR; >4.17 m.s(-1)). Differences in multistage fitness test performance, movement between competition, positions, and halves were assessed using effect size and percent difference +/-90% confidence intervals. The CT players had a 10.1% greater multistage fitness test, 13.9% and 42.0% more TD and HSR, respectively, than AHL. During CT, strikers performed 10.1 +/- 7.4% less HSR than midfielders and 26.6 +/- 8.2% more HSR than defenders. The AHL defenders covered less TD and HSR distance compared with strikers and midfielders (8.1 +/- 3.6% and 8.4 +/- 2.6%; 36.1 +/- 11.1% and 51.5 +/- 12.1%, respectively). The AHL strikers, midfielders, and defenders (19.9 +/- 8.8%, 32.1 +/- 7.9%, and 30.3 +/- 10.7%, respectively), all performed less HSR distance than their CT counterparts. Finally, TD decreased from the first to second halves across all positions (6.1-7.5%) in both competitions. International competition increases the running profile of hockey players, with greater HSR at the elite level and positional differences including decreased running during the second half in both competitions. PMID- 22446669 TI - Oral contraceptive cycle phase does not affect 200-m swim time trial performance. AB - The purpose of this study was to examine whether swimming performance was affected by acute hormonal fluctuation within a monophasic oral contraceptive (OC) cycle. Six competitive swimmers and water polo players completed a 200-m time trial at 3 time points of a single OC cycle: during the consumption phase (CONS), early (WITH1), and late in the withdrawal phase (WITH2). Split times and stroke rate were recorded during the time trial, and heart rate, blood lactate, glucose, and pH were measured after each performance test. Resting endogenous serum estradiol and progesterone concentrations were also assessed. No significant differences were observed between phases for body composition, 200-m swim time, mean stroke rate, peak heart rate, or blood glucose (p > 0.05). The mean peak blood lactate was significantly lower during WITH2 (9.9 +/- 3.0 mmol.L( 1)) compared with that of CONS (12.5 +/- 3.0 mmol.L(-1)) and mean pH higher during WITH2 (7.183 +/- 0.111) compared with that of CONS (7.144 +/- 0.092). Serum estradiol levels were significantly greater during WITH2 compared with that during WITH1 and CONS, but there was no difference in serum progesterone levels. These results demonstrate that for monophasic OC users, cycle phase does not impact the 200-m swimming performance. There was a reduction in blood lactate and an increase in pH during the withdrawal phase, possibly because of an increase in fluid retention, plasma volume, and cellular alkalosis. Therefore, female 200-m swimmers taking a monophasic OC need not be concerned by the phase of their cycle with regard to competition and optimizing performance. However, coaches and scientists should exercise caution when interpreting blood lactate results obtained from swimming tests and consider controlling for cycle phase for athletes taking an OC. PMID- 22446670 TI - Effects of the number of players and game type constraints on heart rate, rating of perceived exertion, and technical actions of small-sided soccer games. AB - The purpose of this study was to identify the variation of heart rate (HR), rating of perceived exertion (RPE), and technical actions between 2 soccer small sided games (SSGs; 3 * 3 and 4 * 4) in 3 game type constraints (when playing only offense [OFF], playing only defense [DEF], and both situations [GAME]). Sixteen high-level young male players were analyzed (age 15.75 +/- 0.45 years; height 172.4 +/- 4.83 cm; body mass 64.5 +/- 6.44 kg; HRmax199.1 +/- 9.08 b.min(-1); and 8.06 +/- 1.98 years of soccer practice). All tasks were performed in 4 periods of 4 minutes interspersed with 2 minutes of active recovery. The HR was measured continuously and then analyzed by the time spent into 4 training zones according to individual %HRmax (zone 1 <75%; zone 2 75-84.9%; zone 3 85-89.9%; and zone 4 >=90%). Results identified that players were most frequently in zones 2 and 3. The 3 * 3 SSGs elicited higher HR and RPE and the most intense situation was GAME. Despite the known higher frequencies from technical actions in SSGs with fewer players, player effectiveness in 3 * 3 and 4 * 4 was identical. The use of GAME, OFF, and DEF game type constraints should be carefully planned. Using the 3 * 3 format seems more adequate when aiming for aerobic performance optimal effects; however, DEF situations should only be used to promote aerobic recovery effects. The inclusion of an additional player in SSGs had different interactions in game type constraints, and only GAME presented adequate intensity. PMID- 22446671 TI - The reliability of jump kinematics and kinetics in children of different maturity status. AB - The purpose of this study was to determine the reliability of eccentric (ECC) and concentric (CON) kinematic and kinetic variables thought to be critical to jump performance during bilateral vertical countermovement jump (VCMJ) and horizontal countermovement jump (HCMJ) across children of different maturity status. Forty two athletic male and female participants between 9 and 16 years of age were divided into 3 maturity groups according to peak height velocity (PHV) offset (Post-PHV, At-PHV, and Pre-PHV) and percent of predicted adult stature. All the participants performed 3 VCMJ and HCMJ trials and the kinematics, and kinetics of these jumps were measured via a force plate over 3 testing sessions. In both jumps, vertical CON mean and peak power and jump height or distance were the most reliable measures across all groups (change in the mean [CM] = -5.4 to 6.2%; coefficient of variation [CV] = 2.1-9.4%; Intraclass correlation coefficient [ICC] = 0.82-0.98), whereas vertical ECC mean power was the only ECC variable with acceptable reliability for both jumps (CM = -0.7 to 10.1%; CV = 5.2-15.6%; ICC = 0.74-0.97). A less mature state was "likely" to "very likely" to reduce the reliability of the HCMJ ECC kinetics and kinematics. These findings suggested that movement variability is associated with the ECC phase of CMJs, especially in Pre-PHV during the HCMJ. Vertical CON mean and peak power and ECC mean power were deemed reliable and appropriate to be used in children as indicators of jump and stretch-shortening cycle performance. PMID- 22446672 TI - Effect of short burst activities on sprint and agility performance in 11- to 12 year-old boys. AB - There are limited data on how coordinative sprint drills and maximal short burst activities affects children's sprint and agility performance. The purpose of the present study was to investigate the effect of short burst activities on sprint and agility performance in 11- to 12-year-old boys. A training group (TG) of 14 boys followed a 6-week, 1-hour.week(-1), training program consisting of different short burst competitive sprinting activities. Eleven boys of similar age served as controls (control group [CG]). Pre- and posttests assessed 10-m sprint, 20-m sprint, and agility performance. Results revealed significant performance improvement in all tests within TG (p < 0.05), but not between TG and CG in the 10-m sprint test. Furthermore, the relationships between the performances in straight-line sprint and agility showed a significant transfer effect (r = 0.68 0.75, p < 0.001). Findings from the present study indicate that competitive short burst activities executed with maximal effort may produce improvement in sprint and agility performance in 11- to 12-year-old boys. PMID- 22446673 TI - Energy expenditure comparison between walking and running in average fitness individuals. AB - Increased energy expenditure (EE) is a key component in maintaining a healthy body mass. Walking and running are 2 common aerobic activities that increase EE above resting values. The purpose of this study was to compare the EE of individuals with average fitness during a walk and run for 1600 meters at 86 m.min(-1) and 160 m.min(-1), respectively. In addition, EE after the walk and run was compared. Fifteen females and 15 males (21.90 +/- 2.52 y; 168.89 +/- 11.20 cm; 71.01 +/- 17.30 kg; 41.51 +/- 6.31 ml(-1).kg(-1).min(-1)) volunteered to participate. Each participant completed a VO2max test. In addition, oxygen consumption was measured at rest for 10 minutes before exercise, during the walk and run, and after the walk and run for 30 minutes of recovery. EE during exercise was 372.54 +/- 78.16 kilojoules for the walk and 471.03 +/- 100.67 kilojoules for the run. Total EE including excess postexercise EE was 463.34 +/- 80.38 kilojoules and 664.00 +/- 149.66 kilojoules for the walk and run, respectively. Postexercise EE returned to resting values 10 minutes after the walk and 15 minutes after the run. Walking and running are both acceptable activities that increase EE above rest and can be performed without the expense of a health club membership and meet adequate kilojoule expenditure according to American College of Sports Medicine guidelines. PMID- 22446674 TI - Comparison between Nintendo Wii Fit aerobics and traditional aerobic exercise in sedentary young adults. AB - Exergaming is becoming a popular recreational activity for young adults. The purpose was to compare the physiologic and psychological responses of college students playing Nintendo Wii Fit, an active video game console, vs. an equal duration of moderate-intensity brisk walking. Twenty-one healthy sedentary college-age students (mean age 23.2 +/- 1.8 years) participated in a randomized, double cross-over study, which compared physiologic and psychological responses to 30 minutes of brisk walking exercise on a treadmill vs. 30 minutes playing Nintendo Wii Fit "Free Run" program. Physiologic parameters measured included heart rate, rate pressure product, respiratory rate, and rating of perceived exertion. Participants' positive well-being, psychological distress, and level of fatigue associated with each exercise modality were quantified using the Subjective Exercise Experience Scale. The mean maximum heart rate (HRmax) achieved when exercising with Wii Fit (142.4 +/- 20.5 b.min(-1)) was significantly greater (p = 0.001) compared with exercising on the treadmill (123.2 +/- 13.7 b.min(-1)). Rate pressure product was also significantly greater (p = 0.001) during exercise on the Wii Fit. Participants' rating of perceived exertion when playing Wii Fit (12.7 +/- 3.0) was significantly greater (p = 0.014) when compared with brisk walking on the treadmill (10.1 +/- 3.3). However, psychologically when playing Wii Fit, participants' positive well-being decreased significantly (p = 0.018) from preexercise to postexercise when compared with exercising on the treadmill. College students have the potential to surpass exercise intensities achieved when performing a conventional standard for moderate-intensity exercise when playing Nintendo Wii Fit "Free Run" with a self selected intensity. We concluded that Nintendo Wii Fit "Free Run" may act as an alternative to traditional moderate-intensity aerobic exercise in fulfilling the American College of Sports Medicine requirements for physical activity. PMID- 22446675 TI - Comparison of muscle activation levels during arm abduction in the plane of the scapula vs. proprioceptive neuromuscular facilitation upper extremity patterns. AB - This study quantified activation of 8 muscles of the shoulder, trunk, and back during standing performance of (a) arm abduction in the plane of the scapula (scaption), (b) proprioceptive neuromuscular facilitation (PNF) diagonal 1 flexion (D1F), and (c) PNF diagonal 2 flexion (D2F) while lifting a dumbbell with the dominant hand. Twelve men (26.1 +/- 4.4 years) and 13 women (24.5 +/- 1.9 years) volunteered to participate. Electromyographic signals were collected with DE-3.1 double-differential surface electrodes at a sampling frequency of 1,000 Hz. Electromyographic signals were normalized to peak activity in the maximum voluntary isometric contraction (MVIC) trial and expressed as a percentage. One way repeated-measures analysis of variance with Bonferroni corrections (alpha = 0.05) examined muscle activation patterns across the 3 conditions. For the middle trapezius, average activation was greater (p < 0.001) for D2F (70.5 +/- 23.4% MVIC) than D1F (46.4 +/- 19.6% MVIC). Lower trapezius average activation was greater (p < 0.001) for D2F (55.3 +/- 23.8% MVIC) than D1F (40.1 +/- 16% MVIC). The anterior deltoid showed greater activation (p = 0.009) for scaption (92.4 +/- 26% MVIC) than D1F (74.4 +/- 21.4% MVIC). The erector spinae showed greater activation for D2F (34.2 +/- 12% MVIC; p < 0.001) and D1F (41.7 +/- 21.4% MVIC; p < 0.001) than scaption (14.5 +/- 12.3% MVIC). During D2F and scaption, all 6 muscles of the shoulder complex demonstrated very high activation levels (>60% MVIC) with the exception of the lower trapezius (55% MVIC). In contrast, erector spinae and external oblique muscles exhibited moderate activation (21-40% MVIC) during arm elevation. The 6 muscles of the shoulder complex displayed high to very high muscle activation at a level appropriate for strength training during all 3 exercise conditions. PMID- 22446676 TI - Modifying spike jump landing biomechanics in female adolescent volleyball athletes using video and verbal feedback. AB - Landing awkwardly from a jump is a common mechanism of injury for the anterior cruciate ligament (ACL) of the knee. Augmented feedback, such as verbal or visual instruction, has been shown to cause an immediate, positive change in landing biomechanics in a laboratory setting. No data exist on the longer term effects of feedback on jump landing biomechanics in a sports-specific setting. The purpose of this study was to explore whether providing video and verbal feedback to adolescent (12-14 years old) female volleyball athletes would improve their landing technique. Trunk and lower extremity kinematic variables were measured in 19 participants before a feedback session was provided to the intervention group (IG). Follow-up kinematic measurements of the IG were taken immediately postintervention, and again after 2 and 4 weeks. Two-way repeated measures analysis of variance (ANOVA) was used to compare the IG with a control group (CG), who received no feedback. The IG (n = 10) demonstrated increased maximal hip and trunk flexion compared with the CG (n = 9) at week 4 (p <= 0.05). One-way repeated measures ANOVA was used to determine if changes were evident within the IG over time. Ankle dorsiflexion, right knee and hip flexion, and trunk flexion changed significantly (p <= 0.05) over the 4-week period. Augmented feedback appeared to produce a positive change in landing biomechanics in adolescent female volleyball athletes performing a sports-specific skill. Courtside video and verbal feedback may present a relatively simple, cost-effective method of introducing one component of a comprehensive ACL injury prevention program at a young age. PMID- 22446677 TI - The effect of fatigue and training status on firefighter performance. AB - Firefighting is a strenuous occupation that requires optimal levels of physical fitness. The National Fire Protection Association suggests that firefighters should be allowed to exercise on duty to maintain adequate fitness levels. However, no research has addressed the effect of exercise-induced fatigue on subsequent fire ground performance. Therefore, the primary purpose of this study was to determine the effect that a single exercise session had on the performance of a simulated fire ground test (SFGT). Secondarily, this study sought to compare the effect of physical training status (i.e., trained vs. untrained firefighters) on the performance of an SFGT. Twelve trained (age: 31.8 +/- 6.9 years; body mass index [BMI]: 27.7 +/- 3.3 kg.m(-2); VO2peak: 45.6 +/- 3.3 ml.kg(-1).min(-1)) and 37 untrained (age: 31.0 +/- 9.0 years; BMI: 31.3 +/- 5.2 kg.m(-2); VO2peak: 40.2 +/- 5.2 ml.kg(-1).min(-1)) male career firefighters performed a baseline SFGT. The trained firefighters performed a second SFGT after an exercise session. Time to complete the SFGT, heart rate, and blood lactate were compared between baseline and exercise SFGT (EX-SFGT) conditions. In the trained firefighters, time to complete the SFGT (9.6% increase; p = 0.002) and heart rate (4.1% increase; p = 0.032) were greater during the EX-SFGT compared with baseline, with no difference in post-SFGT blood lactate (p = 0.841). The EX-SFGT time of the trained firefighters was faster than approximately 70% of the untrained firefighters' baseline SFGT time. In addition, the baseline SFGT time of the trained firefighters was faster than 81% of the untrained firefighters. This study demonstrated that on-duty exercise training reduced the work efficiency in firefighters. However, adaptations obtained through regular on-duty exercise training may limit decrements in work efficiency because of acute exercise fatigue and allow for superior work efficiency compared with not participating in a training program. PMID- 22446678 TI - A dynamic warm-up model increases quadriceps strength and hamstring flexibility. AB - Research suggests that static stretching can negatively influence muscle strength and power and may result in decreased functional performance. The dynamic warm-up (DWU) is a common alternative to static stretching before physical activity, but there is limited research investigating the effects of a DWU. The purpose of this study was to compare the acute effects of a DWU and static stretching warm-up (SWU) on muscle flexibility, strength, and vertical jump using a randomized controlled trial design. Forty-five volunteers were randomly assigned into a control (CON), SWU, or DWU group. All participants rode a stationary bicycle for 5 minutes and completed a 10-minute warm-up protocol. During this protocol, the DWU group performed dynamic stretching and running, the SWU group performed static stretching, and the CON group rested. Dependent variables were measured immediately before and after the warm-up protocol. A digital inclinometer measured flexibility (degrees) for the hamstrings, quadriceps, and hip flexor muscles. An isokinetic dynamometer measured concentric and eccentric peak torque (N.m/kg) for the hamstrings and quadriceps. A force plate was used to measure vertical jump height (meters) and power (watts). In the DWU group, there was a significant increase in hamstring flexibility (pretest: 26.4 +/- 13.5 degrees , posttest: 16.9 +/- 9.4 degrees ; p < .0001) and eccentric quadriceps peak torque (pretest: 2.49 +/- 0.83 N.m/kg, posttest: 2.78 +/- 0.69 N.m/kg; p = 0.04). The CON and SWU did not significantly affect any flexibility, strength, or vertical jump measures (p > 0.05). The DWU significantly improved eccentric quadriceps strength and hamstrings flexibility, whereas the SWU did not facilitate any positive or negative changes in muscle flexibility, strength, power, or vertical jump. Therefore, the DWU may be a better preactivity warm-up choice than an SWU. PMID- 22446679 TI - The effect of resistance exercise on p53, caspase-9, and caspase-3 in trained and untrained men. AB - Apoptosis is a programmed cell death that has been demonstrated in human and animal studies and plays an essential role to remove injured cells after acute strenuous exercise. Protein p53 plays important roles in regulating apoptosis via mitochondrial pathway. Therefore, the aims of this study were to determine the effects of acute resistance exercise (RE) on serum p53, caspase-9, and caspase-3, markers of apoptosis, and whether resistance training status influences the magnitude of the RE-induced apoptosis. Nine resistance-trained (RT) (age, 22.37 +/- 1.99 years; height, 174 +/- 5.04 cm; body weight, 71.32 +/- 5.57 kg; and body mass index [BMI] 23.58 +/- 2.05 kg.m(-2)) and 9 untrained (UT) college-age men (age, 22.25 +/- 2.13 years; height, 171 +/- 3.4 cm; body weight, 68.45 +/- 3.23 kg; and BMI, 23.41 +/- 1.08 kg.m(-2)) volunteered to participate in this study. Resistance-trained and UT men completed an RE bout consisting of 4 sets of 6 exercise at 80% of 1 repetition maximum until failure. Serum levels of p53, caspase-9, and caspase-3 were examined at preexercise (pre), immediately post (IP), 3 hours post (3 hours post), and 24 hours post RE (24 hours post). In UT, serum levels of p53, caspase-9, and caspase-3 were significantly increased at IP compared with RT. However, plasma insulin-like growth factor 1 level was higher for RT compared with UT at IP. Collectively, our data suggest the role of p53 in regulating apoptosis through mitochondrial pathway as measured by caspase-9 and caspase-3 after acute RE in UT. Our results also revealed that regular RT alters apoptosis biomarkers, especially the intrinsic pathway of apoptosis. PMID- 22446680 TI - Perceived social support from strength and conditioning coaches among injured student athletes. AB - Injuries suffered by student athletes not only affect their physical ability to perform in sport but also have psychological effects as well. The purpose of this study was to examine student athletes' perceptions, expectations, and satisfaction of the social support provided by their strength and conditioning coach (SC) during the later reconditioning stage of their rehabilitation and their views on the overall level of importance of each type of social support. One hundred and sixty-five participants aged 20.21 +/- 1.32 years from 6 Division I Universities in the Midwest region of the USA completed the modified Social Support Survey. The results of a chi-square test assessing the responses for 6 types of social support provided by SCs based on athletes' age, gender, and sport revealed a significant difference (chi2[13,105] = 26.46, p = 0.015) for listening support differing by sport. A significant difference (chi2[13,105] = 267.74, p = 0.010) was also revealed for reported emotional challenge by sport. Results showed that the SC had a significant psychosocial impact on student-athletes' overall psychological well-being during reconditioning. This study provides evidence of the vital psychosocial role that SCs can play during an injured student-athlete's reconditioning program. PMID- 22446681 TI - Effects of localized and general fatigue on static and dynamic postural control in male team handball athletes. AB - In team sports, sensorimotor impairments resulting from previous injuries or muscular fatigue have been suggested to be factors contributing to an increased injury risk. Although it has been widely shown that physical fatigue affects static postural sway, it is still questionable as to what extent these adaptations are relevant for dynamic, sports-related situations. The objective of this study was to determine the effects of whole-body and localized fatigue on postural control in stable and unstable conditions. Nineteen male team handball players were assessed in 2 sessions separated by 1 week. Treadmill running and single-leg step-up exercises were used to induce physical fatigue. The main outcome measures were center of pressure (COP) sway velocity during a single-leg stance on a force plate and maximum reach distances of the star excursion balance test (SEBT). The COP sway velocity increased significantly (p < 0.05) after general (+47%) and localized fatigue (+10%). No fatigue effects were found for the SEBT. There were no significant correlations between COP sway velocity and SEBT mean reach in any condition. The results showed that although fatigue affects static postural control, sensorimotor mechanisms responsible for regaining dynamic balance in healthy athletes seem to remain predominantly intact. Thus, our data indicate that the exclusive use of static postural sway measures might not be sufficient to allow conclusive statements regarding sensorimotor control in the noninjured athlete population. PMID- 22446682 TI - Actin filaments play a primary role for structural integrity and viscoelastic response in cells. AB - This atomic force microscopy (AFM) study is devoted to the analysis of the mouse ovarian cancer cell's cytoskeleton components and the impact of both actin and microtubulin filaments on a cell's deformation behavior. Early stage, non tumorigenic cancer cells show abundant well-organized cytoskeletal structures consisting of both actin and microtubule filaments. In sharp contrast, cells representing late and more aggressive stages of cancer display highly disorganized actin and microtubule structures. With the use of actin microfilament targeting drugs, together with the suberoylanilide hydroxamic acid (SAHA) and tubastatin A anti-cancer drugs, we modified the cell architectural framework and performed nano-indentation tests to evaluate cell elasticity and viscosity as a function of each biopolymer's weighted presence. Results demonstrate that both mechanical properties are heavily influenced by the levels and organization state of actin microfilaments; decreasing the actin organization of cells results in 85% and 79% decrease in cell elasticity and viscosity, respectively. In contrast, microtubule organization was shown to exert only marginal effects on either property. Furthermore, the anti-cancer drug, SAHA, was shown to exert little impact on the viscoelastic response of cancer cells. Finally, we report for the first time that tubastatin A, a specific HDAC6 inhibitor, increased cell elasticity as revealed by AFM tests without exerting drastic changes to the actin microfilament or microtubule networks. Our findings raise interest in a potential HDAC6 target that affects cellular mechanics just as effectively as the conventionally known cytoskeleton components. PMID- 22446683 TI - Linker histone subtypes differ in their effect on nucleosomal spacing in vivo. AB - Linker histone H1 is located on the surface of the nucleosome where it interacts with the linker DNA region and stabilizes the 30-nm chromatin fiber. Vertebrates have several different, relatively conserved subtypes of H1; however, the functional reason for this is unclear. We have previously shown that H1 can be reconstituted in Xenopus oocytes, cells that lack somatic H1, by cytosolic mRNA injection and incorporated into in vivo assembled chromatin. Using this assay, we have expressed individual H1 subtypes in the oocytes to study their effect on chromatin structure using nucleosomal repeat length (NRL) as readout. We have compared chicken differentiation-specific histone H5, Xenopus differentiation specific xH1(0) and the somatic variant xH1A as well as the ubiquitously expressed human somatic subtypes hH1.2, hH1.3, hH1.4 and hH1.5. This shows that all subtypes, except for human H1.5, result in a saturable increase in NRL. hH1.4 results in an increase of approximately 13-20 bp as does xH1(0) and xH1A. chH5 gives rise to the same or slightly longer increase compared to hH1.4. Interestingly, both hH1.2 and hH1.3 show a less extensive increase of only 4.5-7 bp in the NRL, thus yielding the shortest increase of the studied subtypes. We show for the first time in an in vivo system lacking H1 background that ubiquitously expressed and redundant H1 subtypes that coexist in most types of cells of higher eukaryotes differ in their effects on the nucleosomal spacing in vivo. This suggests that H1 subtypes have different roles in the organization and functioning of the chromatin fiber. PMID- 22446684 TI - Structure-based inhibition of Norovirus RNA-dependent RNA polymerases. AB - Caliciviridae are RNA viruses with a single-stranded, positively oriented polyadenylated genome, responsible for a broad spectrum of diseases such as acute gastroenteritis in humans. Recently, analyses on the structures and functionalities of the RNA-dependent RNA polymerase (RdRp) from several Caliciviruses have been reported. The RdRp is predicted to play a key role in genome replication, as well as in synthesis and amplification of additional subgenomic RNA. Starting from the crystal structures of human Norovirus (hNV) RdRp, we performed an in silico docking search to identify synthetic compounds with predicted high affinity for the enzyme active site. The best-ranked candidates were tested in vitro on murine Norovirus (MNV) and hNV RdRps to assay their inhibition of RNA polymerization. The results of such combined computational and experimental screening approach led to the identification of two high-potency inhibitors: Suramin and NF023, both symmetric divalent molecules hosting two naphthalene-trisulfonic acid heads. We report here the crystal structure of MNV RdRp alone and in the presence of the two identified inhibitors. Both inhibitory molecules occupy the same RdRp site, between the fingers and thumb domains, with one inhibitor head close to residue 42 and to the protein active site. To further validate the structural results, we mutated Trp42 to Ala in MNV RdRp and the corresponding residue (i.e., Tyr41 to Ala) in hNV RdRp. Both NF023 and Suramin displayed reduced inhibitory potency versus the mutated hNV RdRp, thus hinting at a conserved inhibitor binding mode in the two polymerases. PMID- 22446685 TI - Genomic organization of evolutionarily correlated genes in bacteria: limits and strategies. AB - The need for efficient molecular interplay in time and space within a cell imposes strong constraints that could be partially relaxed if relative gene positions along chromosomes were appropriate. Comparative genomics studies have demonstrated the short-scale conservation of gene proximity along bacterial chromosomes. Additionally, the long-range periodic positioning of evolutionarily correlated genes within Escherichia coli has recently been highlighted. To gain further insight into these different genetic organizations, we examined the compromise between chromosomal proximity and periodicity for all available eubacterial genomes by evaluating groups of evolutionarily correlated genes from a benchmark data set. In enterobacteria, strict chromosomal proximity is found to be limited to groups under 20 genes, whereas periodicity is significant in all groups over 50. The E. coli K12 genome bears 511 periodic genes (12% of the genome), whose orthologs are found to be periodic in all eubacterial phyla. These periodic genes predominantly function in macromolecular synthesis and spatial organization of cellular components. They are enriched in essential and housekeeping genes and tend to often be constitutively expressed. On this basis, it is argued that chromosomal proximity and periodicity are ubiquitous complementary genomic strategies that favor the build-up of local concentrations of co-functional molecules. In particular, the periodic layout may facilitate chromosome folding to spatially organize the construction of major cell components. The transition at 20 genes is reminiscent of the size of the longest operons and of topological microdomains. The range for which DNA neighborhood optimizes biochemical interactions might therefore be defined by DNA topology. PMID- 22446686 TI - LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis. AB - Long non-coding RNAs (lncRNAs) have recently emerged as a major class of regulatory molecules involved in a broad range of biological processes and complex diseases. Our aim was to identify important lncRNAs that might play an important role in contributing to glioblastoma (GBM) pathogenesis by conducting lncRNA and mRNA profile comparison between GBM and normal brain tissue. The differentially expressed lncRNA and mRNA profiles of the tissue between GBM patient and age-matched donor without GBM diseases were analyzed using microarrays. We propose a novel model for the identification of lncRNA-mRNA targeting relationships that combine the potential targets of the differentially expressed lncRNAs with the differentially expressed mRNA abundance data. Bioinformatic analysis of the predicted target genes (gene ontology, pathway and network analysis) was performed for further research. The lncRNA microarray reveals differentially expressed lncRNAs between GBM and normal brain tissues. In the GBM group, 654 lncRNAs were upregulated and 654 were downregulated (fold change >=4.0 or <=0.25, P<0.01). We found 104 matched lncRNA-mRNA pairs for 91 differentially expressed lncRNAs and 84 differentially expressed genes. Target gene-related pathway analysis showed significant changes in PPAR pathways in the GBM group compared with the normal brain group (P<0.05). By further conducting lncRNA gene network analysis, we found that ASLNC22381 and ASLNC2081 were likely to play roles in the regulation of glioma signaling pathways. In conclusion, our results indicated that the lncRNA expression profile in GBM tissue was significantly altered. These results may provide important insights into the mechanisms responsible for GBM progression and pathogenesis. This study also suggests that ASLNC22381 and ASLNC20819 may play important roles via their target IGF-1 in the recurrence and malignant progression of GBM. PMID- 22446687 TI - Comparative proteomics reveals a significant bias toward alternative protein isoforms with conserved structure and function. AB - Advances in high-throughput mass spectrometry are making proteomics an increasingly important tool in genome annotation projects. Peptides detected in mass spectrometry experiments can be used to validate gene models and verify the translation of putative coding sequences (CDSs). Here, we have identified peptides that cover 35% of the genes annotated by the GENCODE consortium for the human genome as part of a comprehensive analysis of experimental spectra from two large publicly available mass spectrometry databases. We detected the translation to protein of "novel" and "putative" protein-coding transcripts as well as transcripts annotated as pseudogenes and nonsense-mediated decay targets. We provide a detailed overview of the population of alternatively spliced protein isoforms that are detectable by peptide identification methods. We found that 150 genes expressed multiple alternative protein isoforms. This constitutes the largest set of reliably confirmed alternatively spliced proteins yet discovered. Three groups of genes were highly overrepresented. We detected alternative isoforms for 10 of the 25 possible heterogeneous nuclear ribonucleoproteins, proteins with a key role in the splicing process. Alternative isoforms generated from interchangeable homologous exons and from short indels were also significantly enriched, both in human experiments and in parallel analyses of mouse and Drosophila proteomics experiments. Our results show that a surprisingly high proportion (almost 25%) of the detected alternative isoforms are only subtly different from their constitutive counterparts. Many of the alternative splicing events that give rise to these alternative isoforms are conserved in mouse. It was striking that very few of these conserved splicing events broke Pfam functional domains or would damage globular protein structures. This evidence of a strong bias toward subtle differences in CDS and likely conserved cellular function and structure is remarkable and strongly suggests that the translation of alternative transcripts may be subject to selective constraints. PMID- 22446688 TI - Human aldosterone synthase: recombinant expression in E. coli and purification enables a detailed biochemical analysis of the protein on the molecular level. AB - Aldosterone, the most important human mineralocorticoid, is involved in the regulation of the blood pressure and has been reported to play a key role in the formation of arterial hypertension, heart failure and myocardial fibrosis. Aldosterone synthase (CYP11B2) catalyzes the biosynthesis of aldosterone by successive 11beta- and 18-hydroxylation followed by an 18-oxidation of 11 deoxycorticosterone and thus comprises an important drug target. For more than 20 years, all attempts to purify recombinant human CYP11B2 in significant amounts for detailed analysis failed due to its hydrophobic nature as a membrane protein. Here, we present the successful expression of the protein in E. coli yielding approx. 90 nmol/l culture, its purification and detailed enzymatic characterization. Biochemical analyses have been performed using in vitro conversion assays which revelead a V(max) of 238+/-8 nmol products/nmol hCYP11B2/min and a K(m) of 103+/-8 MUM 11-deoxycorticosterone. Furthermore, binding analyses indicated a very loose binding of the first intermediate of the reaction, corticosterone with a K(d) value of 115+/-6 MUM whereas for 11 deoxycorticosterone a K(d) of 1.34+/-0.13 MUM was estimated. Upon substrate conversion of 11-deoxycorticosterone, new intermediates have been identified as 19- and 18-hydroxylated products not described before for the human enzyme. To understand the differences in substrate conversion, we constructed a new homology model based on the 3D structure of CYP11A1, performed docking studies and calculated the activation energy for hydrogen abstraction of the different ligands. The data demonstrated that the 11beta-hydroxylation requires much less abstraction energy than hydroxylation at C18 and C19. However, the C18 and C19 hydroxylated products might be of clinical importance. Finally, purified CYP11B2 represents a suitable tool for the investigation of potential inhibitors of this protein for the development of novel drugs against hypertension and heart failure as was shown using ketoconazole. PMID- 22446689 TI - Transcriptional regulators in hepatocarcinogenesis--key integrators of malignant transformation. AB - Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies with poor prognosis and increasing incidence in the Western world. Only for a minority of HCC patients, surgical treatment options offer potential cure and therapeutic success of pharmacological approaches is limited. Highly specific approaches (e.g., kinase inhibitors) did not significantly improve the situation so far, possibly due to functional compensation, genetic heterogeneity of HCC, and development of resistance under selective pressure. In contrast, transcriptional regulators (especially transcription factors and co-factors) may integrate and process input signals of different (oncogenic) pathways and therefore represent cellular bottlenecks that regulate tumor cell biology. In this review, we want to summarize the current knowledge about central transcriptional regulators in human hepatocarcinogenesis and their potential as therapeutic target structures. Genomic and transcriptomic data of primary human HCC revealed that many of these factors showed up in subgroups of HCCs with a more aggressive phenotype, suggesting that aberrant activity of transcriptional regulators collect input information to promote tumor initiation and progression. Therefore, expression and dysfunction of transcription factors and co-factors may gain relevance for diagnostics and therapy of HCC. PMID- 22446690 TI - Portal vein thrombosis, cirrhosis, and liver transplantation. AB - Portal vein thrombosis is not uncommon in candidates for transplantation. Partial thrombosis is more common than complete thrombosis. Despite careful screening at evaluation, a number of patients are still found with previously unrecognized thrombosis per-operatively. The objective is to recanalize the portal vein or, if recanalization is not achievable, to prevent the extension of the thrombus so that a splanchnic vein can be used as the inflow vessel to restore physiological blood flow to the allograft. Anticoagulation during waiting time and transjugular intrahepatic portosystemic shunt (TIPS) are two options to achieve these goals. TIPS may achieve recanalization in patients with complete portal vein thrombosis. However, a marked impairment in liver function, which is a characteristic feature of most candidates for transplantation, may be a contraindication for TIPS. Importantly, the MELD score is artificially increased by the administration of vitamin K antagonists due to prolonged INR. When patency of the portal vein and/or superior mesenteric vein is not achieved, only non-anatomical techniques (renoportal anastomosis or cavoportal hemitransposition) can be performed. These techniques, which do not fully reverse portal hypertension, are associated with higher morbidity and mortality risks. Multivisceral transplantation including the liver and small bowel needs to be evaluated. In the absence of prothrombotic states that may persist after transplantation, there is no evidence that pre transplant portal vein thrombosis justifies long term anticoagulation post transplantation, provided portal flow has been restored through conventional end to-end portal anastomosis. PMID- 22446691 TI - Establishment of a bioluminescent MDA-MB-231 cell line for human triple-negative breast cancer research. AB - The aim of this study was to establish a bioluminescent MDA-MB-231 cell line stably expressing luciferase and green fluorescent protein for the generation of a xenografted model of human triple-negative breast cancer (TNBC) in nude mice. Lentivirus vectors carrying eGFP, firefly luc2 and neo fusion genes were used to transduce the MDA-MB-231 human TNBC cells in vitro. After 8 weeks of G418 selection, eGFP and luc2 expression was determined using a fluorescence microscope and a Xenogen IVIS200 bioluminescent imaging system, respectively. The MTT, transwell invasion and wound healing assays were performed to confirm whether cellular proliferation, invasion and migration were altered by lentiviral infection. Cells were orthotopically implanted into female BALB/c nude mice to test the sensitivity and stability of reporter gene expression. Growth of the tumors was monitored with the in vivo imaging system once a week until they were large enough for experiments. The tumor tissues were resected for histology, and cancer cells were harvested for culture. The lentivirus-transduced MDA-MB-231 cells could stably express luc2 and eGFP, and the luciferase activity reached 9689 photons/sec/cell. Meanwhile, no significant difference in biological activities was observed between the lentivirus-transduced MDA-MB-231 cells and parental cells. An orthotopically implanted tumor model of human TNBCs was successfully established in BALB/c nude mice. Lentiviruses may be ideal carriers for luciferase genes due to their highly efficient infectivity and stable transgene expression. The modified MDA-MB-231 cell line stably expressing luciferase could be detected, allowing for immediate and sensitive detection of metastasis sites in nude mice. As the eGFP and luc2 combination are superior to single reporter genes in their ability to mark cells in vivo and in vitro, these cells may provide a visualizable, convenient and sensitive platform for research on the mechanisms of metastasis and the development of new antitumor drugs for human TNBC. PMID- 22446692 TI - A proteomics approach for the identification and cloning of monoclonal antibodies from serum. AB - We describe a proteomics approach that identifies antigen-specific antibody sequences directly from circulating polyclonal antibodies in the serum of an immunized animal. The approach involves affinity purification of antibodies with high specific activity and then analyzing digested antibody fractions by nano flow liquid chromatography coupled to tandem mass spectrometry. High-confidence peptide spectral matches of antibody variable regions are obtained by searching a reference database created by next-generation DNA sequencing of the B-cell immunoglobulin repertoire of the immunized animal. Finally, heavy and light chain sequences are paired and expressed as recombinant monoclonal antibodies. Using this technology, we isolated monoclonal antibodies for five antigens from the sera of immunized rabbits and mice. The antigen-specific activities of the monoclonal antibodies recapitulate or surpass those of the original affinity purified polyclonal antibodies. This technology may aid the discovery and development of vaccines and antibody therapeutics, and help us gain a deeper understanding of the humoral response. PMID- 22446693 TI - Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. AB - The ability to specifically upregulate genes in vivo holds great therapeutic promise. Here we show that inhibition or degradation of natural antisense transcripts (NATs) by single-stranded oligonucleotides or siRNAs can transiently and reversibly upregulate locus-specific gene expression. Brain-derived neurotrophic factor (BDNF) is normally repressed by a conserved noncoding antisense RNA transcript, BDNF-AS. Inhibition of this transcript upregulates BDNF mRNA by two- to sevenfold, alters chromatin marks at the BDNF locus, leads to increased protein levels and induces neuronal outgrowth and differentiation both in vitro and in vivo. We also show that inhibition of NATs leads to increases in glial-derived neurotrophic factor (GDNF) and ephrin receptor B2 (EPHB2) mRNA. Our data suggest that pharmacological approaches targeting NATs can confer locus specific gene upregulation effects. PMID- 22446694 TI - Reading DNA at single-nucleotide resolution with a mutant MspA nanopore and phi29 DNA polymerase. AB - Nanopore technologies are being developed for fast and direct sequencing of single DNA molecules through detection of ionic current modulations as DNA passes through a pore's constriction. Here we demonstrate the ability to resolve changes in current that correspond to a known DNA sequence by combining the high sensitivity of a mutated form of the protein pore Mycobacterium smegmatis porin A (MspA) with phi29 DNA polymerase (DNAP), which controls the rate of DNA translocation through the pore. As phi29 DNAP synthesizes DNA and functions like a motor to pull a single-stranded template through MspA, we observe well-resolved and reproducible ionic current levels with median durations of ~28 ms and ionic current differences of up to 40 pA. Using six different DNA sequences with readable regions 42-53 nucleotides long, we record current traces that map to the known DNA sequences. With single-nucleotide resolution and DNA translocation control, this system integrates solutions to two long-standing hurdles to nanopore sequencing. PMID- 22446696 TI - A meta-analysis of total hip arthroplasty and hemiarthroplasty outcomes for displaced femoral neck fractures. AB - BACKGROUND: Total hip arthroplasty or hemiarthroplasty are used to treat displaced femoral neck fractures. However, the optimal treatment of these fractures remained controversial. OBJECTIVE: To assess the effects that compare total hip arthroplasty with hemiarthroplasty for the treatment of femoral neck fractures in the elderly. METHODS: We searched MEDLINE (January 1980 to 2010), EMBASE (January 1980 to 2010), and the Cochrane Library 2010; issue 1. Only prospective randomized controlled trials (RCTs) that compare total hip arthroplasty with hemiarthroplasty for the treatment of femoral neck fracture in the elderly were included. The analysis was performed with software RevMan5.0 from the Cochrane Collaboration. RESULTS: We identified seven relevant randomized controlled trials with a total of 828 participants. The meta-analysis showed relative risk of re-operation was 0.40 (95% CI = 0.24-0.67, P = 0.0004), the dislocation was 2.02 (95% CI = 1.26-3.25, P = 0.002), the mobility as functional outcome was 1.70 (95% CI = 1.21-2.38, P = 0.002). It was reported that the average operating room times and blood loss volumes in total hip arthroplasty were more than in hemiarthroplasty (P < 0.001). Other results were not significantly different. CONCLUSIONS: Total hip arthroplasty is associated with better functional outcome and lower reoperation rate than hemiarthroplasty in treatment of displaced femoral neck fractures in the elderly patients. PMID- 22446695 TI - Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids. AB - Microbial production of chemicals is now an attractive alternative to chemical synthesis. Current efforts focus mainly on constructing pathways to produce different types of molecules. However, there are few strategies for engineering regulatory components to improve product titers and conversion yields of heterologous pathways. Here we developed a dynamic sensor-regulator system (DSRS) to produce fatty acid-based products in Escherichia coli, and demonstrated its use for biodiesel production. The DSRS uses a transcription factor that senses a key intermediate and dynamically regulates the expression of genes involved in biodiesel production. This DSRS substantially improved the stability of biodiesel producing strains and increased the titer to 1.5 g/l and the yield threefold to 28% of the theoretical maximum. Given the large number of natural sensors available, this DSRS strategy can be extended to many other biosynthetic pathways to balance metabolism, thereby increasing product titers and conversion yields and stabilizing production hosts. PMID- 22446697 TI - The Humerusblock NG: a new concept for stabilization of proximal humeral fractures and its biomechanical evaluation. AB - BACKGROUND: The Humerusblock NG represents a new semi-rigid angular stable fixation device for minimally invasive stabilization of proximal humeral fractures. This study evaluates the function and stability of the Humerusblock NG and its biomechanical properties on the basis of two different fracture models under cyclic loading. METHODS: Six fresh frozen human humeri were tested in a dynamic shoulder joint abduction motion test bench, simulating abduction between 15 degrees and 45 degrees . A stable wedge fracture with intact medial hinge and an unstable fracture with 5-mm gap were loaded for 500 cycles. Radiological measurement of implant migration was performed. RESULTS: The stable fracture model showed a slow constant fracture settling. The unstable fracture model showed initial fracture settling with closure of the medial fracture gap during the first 20 cycles. Thereafter, a slow constant settling of the fracture was measured comparable to the stable fracture model. Maximum varus tilt was 3.17 degrees for the stable and 3.68 degrees for the unstable fracture pattern. Radiological analysis showed no change in the tip apex distance and a significant settling of the implants fixation pins in the unstable fracture model. None of the specimen failed during the testing. CONCLUSION: The Humerusblock NG allows for angular stable dynamic fixation of two-part proximal humeral fractures. It enables closure of the fracture gap and maintains fracture compression during loading, a concept already established in the stabilization of femoral neck fractures (dynamic hip screw). Clinical trials will be necessary to evaluate the value of this device in daily practice. LEVEL OF EVIDENCE: Basic science study. PMID- 22446698 TI - [Relation between suicidal ideation and parenting styles among a group of Chilean adolescents]. AB - BACKGROUND: In Chile, there has been an increase in suicide rates from 1.1 to 2.6 per 100,000 among adolescents aged 10 to 14 years and from 4.4 to 8.9 per 100,000 among those aged 15 to 19 years AIM: To identify protective factors for suicidal ideation according to parenting styles, as described by Barber et al. MATERIAL AND METHODS: The relation between suicidal ideation and parenting styles was assessed in a random sample of 2,346 Chilean school attending adolescents aged 13 to 20 years old (59% women) from three cities: Antofagasta (Northern Chile, II Region), Santiago (Central, Metropolitan Region) and Concepcion (Southern, VIII Region). Participants were tested with the Chilean adaptation of the Cross National Adolescents Program (CNAP) Plus questionnaire developed by Barber et al. The relation between suicidal ideation and parenting styles was assessed using regression analyses. RESULTS: Correlations between suicidal ideation and parenting styles were mostly significant, yet weak. High odds ratios were observed among parents who had a strong psychological control, inconsistent control, lack of expression of affection and covered marital hostility. CONCLUSIONS: High adolescent self-esteem, a good relationship with parents, psychological parental autonomy, expression of physical affection, social support and paternal monitoring were protective factors against suicidal ideation. PMID- 22446699 TI - [Formulation of an equation to predict fat mass using bioelectrical impedance in adults in a wide range of ages and body mass index]. AB - BACKGROUND: Bioelectrical impedance (BIA) has a good correlation and agreement with reference techniques, such as dual energy X-ray absorptiometry (DEXA), to assess body composition. AIM: To develop and assess the concordance of an equation to predict body fat mass derived from anthropometric data, gender, age and resistance obtained from bioelectrical impedance in adults, using DEXA as the reference method. PATIENTS AND METHODS: Cross-sectional study of 62 women and 59 men aged 18 to 64 years with a body mass index ranging from 18.5 to 34.8 kg/ m2. The equation was constructed using a predictive statistical model, considering sex, age, weight, resistance index (height2(cm)/ resistance (ohms)), as independent variables, and fat mass as the dependent variable. RESULTS: The R2 of the regression model was 0.96, and the standard error of estimation was 2.58 kg (p < 0.001). When comparing with DEXA, no significant differences were observed for the estimation of FM, between the equation developed in this work and that proposed by the manufacturer of the BIA equipment. However, the latter equation, underestimated FM by -2.5 +/- 9.5% (p > 0.05) and - 4.5 +/- 8,9% (p < 0.05) in both genders and in women, respectively. CONCLUSIONS: The concordance between estimation of fat mass by the formula developed in this work and by DEXA was better than the estimation obtained using the formula proposed by the manufacturer of the BIA equipment. PMID- 22446700 TI - [Long-term results of mitral valve repair for ischemic mitral insufficiency]. AB - BACKGROUND: The preferred treatment for ischemic mitral insufficiency is mitral valve repair with a prosthetic ring, because it does not deteriorate left ventricular function, allowing better immediate and long-term results. AIM: To assess long-term results of mitral annuloplasty with a prosthetic ring for ischemic mitral insufficiency. PATIENTS AND METHODS: One hundred patients (68 men), with a mean age of 65.7 +/- 8.6 years were included. They underwent a mitral annuloplasty with a prosthetic ring to treat ischemic mitral insufficiency, between February 1992 and May 2009. Forty four had a history of prior myocardial infarction and 46 had an evolving acute coronary syndrome. The inferior left ventricular wall was involved, exclusively or associated with an adjacent wall, in 72 cases. Coronary artery bypass grafts were performed in 92 patients and 32 required intra-aortic balloon pumping at some time during the peri-operative period. RESULTS: Operative mortality was 10% (10 patients). During follow-up 30 patients died, at an average of 39 months after surgery (range: 3 142 months). Actuarial long-term survival rates at 1, 3 and 5 years were 79%, 72% and 64.5%, respectively. Trans esophageal echocardiogram performed in the operating room showed none or minimal residual mitral insufficiency in 96% of the cases. Echocardiographic follow-up was completed in 80% of the survivors; 79% of them had no or minimal mitral insufficiency. Only one patient was re-operated on due to severe mitral insufficiency and 4 required a permanent pacemaker. CONCLUSIONS: Considering the critical illness of these patients, good long-term results were observed after treatment of ischemic mitral regurgitation performing a mitral annuloplasty with a prosthetic ring. PMID- 22446701 TI - [Neuropsychological dysfunction after cardiac surgery: Cerebral saturation and bispectral index: A longitudinal study]. AB - BACKGROUND: Neuropsychological dysfunction is a major cause of morbidity and mortality after cardiac surgery. AIM: To evaluate if intraoperative cerebral desaturation and depth of anesthesia measured by bispectral index are related to postoperative cognitive dysfunction in cardiac surgery. MATERIAL AND METHODS: Prospective study in patients undergoing elective cardiac surgery with cardiopulmonary bypass. A comprehensive neuropsychological assessment was applied preoperatively and 3 months after surgery. Postoperative dysfunction was defined as a decrease of at least one standard deviation in two or more neuropsychological tests. Cerebral oxygenation and bispectral index were continuously recorded and corrected throughout surgery. Cerebral oxygenation data were analyzed by the mean value and at three thresholds: 50%, 40% and < 25% of the basal value. Bispectral index was analyzed at threshold of 45. RESULTS: Fifty six patients were initially enrolled and 48 completed the study. Nine of these (18.8 %) presented postoperative cognitive dysfunction. Mean cerebral saturation and bispectral index data were not different among the patients with or without cognitive dysfunction. There was no association between cerebral desaturation and bispectral index with changes in neurocognitive tests or with length of stay in the intensive care unit. A significant but weak correlation was found between baseline Ray-neurocognitive score and intensive care unit stay (rho = -0.46; P = 0.001). CONCLUSIONS: We did not find a significant association between cerebral desaturation and depth of anesthesia with postoperative cognitive decline in this population of patients. PMID- 22446702 TI - [Reduction of physical activity in patients with chronic obstructive pulmonary disease]. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) decrease their physical activity. However, it is unknown at which stage of the disease the reduction occurs and whether dyspnea is a limiting factor. AIM: To compare physical activity between patients with COPD and controls of similar age and to assess its association with disease severity. MATERIAL AND METHODS: We studied 112 patients with mild to very severe COPD and 55 controls. Lung function, six minutes walking test (SMWT), and physical activity through the International Physical Activity Questionnaire (IPAQ) were measured. RESULTS: Compared to controls, physical activity was significantly reduced in COPD patients (1823 +/- 2598 vs. 2920 +/- 3040 METs min/week; p = 0.001). Patients were more frequently sedentary (38 vs. 11%), while controls were more often very active (31 vs. 19%) or moderately active (58 vs. 43%). Physical activity was reduced from Global Initiative for Obstructive Chronic Lung Disease (GOLD) stage 2 and from Modified Medical Research Council (MMRC) dyspnea grade 1. Weak relationships were observed between lung function, SMWT and physical activity. CONCLUSIONS: Physical activity decreases early in the course of the disease and when dyspnea is still mild, among patients with COPD. PMID- 22446703 TI - [Prevalence of tabacco, alcohol and marijuana consumption among university students]. AB - BACKGROUND: University students are especially vulnerable towards substance abuse AIM: To describe and compare drug consumption in students of a Chilean university who attended first and fourth year of studies, according to gender and faculty. MATERIAL AND METHODS: A representative, stratified and proportional sample of 305 students was randomly chosen by faculty, career, grade and gender during 2009. The consumption of alcohol, tobacco and illicit drugs was evaluated using an anonymous survey. RESULTS: Students from health care faculties had the lower prevalence of consumption of tobacco, alcohol, tobacco-alcohol and marijuana, during the first and fourth year. Education area and social sciences faculties had the highest prevalence of consumption. Fourth year students had higher rates of consumption than their first year counterparts. Females had significantly lower rates of alcohol and marijuana consumption. CONCLUSIONS: Alcohol, tobacco and marijuana consumption was higher among students from education and social sciences faculties and those attending the fourth year of studies. PMID- 22446704 TI - [Total prostatic specific antigen levels among subjects exposed and not exposed to arsenic in drinking water]. AB - BACKGROUND: There is an association between arsenic exposure and prostatic cancer mortality. AIM: To analyze and to compare the serum levels of total prostatic specific antigEn (TPSA) in asymptomatic men of a rural zone, exposed and not exposed to high concentrations of arsenic (As) in drinking water. MATERIAL AND METHODS: The study included 161 men that were subjected to a clinical evaluation, serum TPSA determination and a trans rectal ultrasonography. Exposed and non exposed subjects were divided in groups GA, GB and GC according to TPSA levels (<4 ng/ml, 4.1-10 ng/ml and >10.1 ng/ml respectively). RESULTS: Exposed and non exposed subjects had similar TPSA levels. Among exposed subjects, 88.2, 8,8 and 3% were ascribed to groups GA, GB and GC respectively. The figures for non exposed subjects were 90. 6, 6,3 and 3,1%. The area under the receiver operating characteristic (ROC) curve for TPSA in exposed and non-exposed subjects was 0.64 (95% confidence intervals (CI) 0.40-0.9) and 0.71 (95% CI 0.6-0.8) respectively. CONCLUSIONS: No differences in TPSA levels between subjects exposed and non exposed to arsenic were observed in this study. PMID- 22446705 TI - [Meningomyelitis associated with infection by human herpes virus 7: report of two cases]. AB - Human herpesvirus 7 (HHV-7) may cause encephalomyelitis in immune competent adults. We report two patients infected by the virus. A 34-year-old male presenting with paraparesis and a sensitive deficiency located in D6 dermatome. Cerebrospinal fluid had 35 white blood cells per mm3 and 75 mg protein per dl. A PCR-microarray examination was positive for HHV-7. The patient was treated with prednisolone and ganciclovir with full recovery. A 27-year-old male presenting with headache, fever and diarrhea. Cerebrospinal fluid analysis showed 160 cells per mm3 and 75 mg protein per dl. Viral RNA detection was positive for HHV-7. The patient was managed with analgesia and rest and was discharged with the diagnosis of viral meningitis. Our communication supports the notion that HHV-7 may be considered as pathogen factor in humans, even in immune competent ones. PMID- 22446706 TI - [Sweet's syndrome associated with acute myeloid leukemia. Report of one case]. AB - Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized by fever, neutrophilia, erythematous and tender skin lesions that typically show a diffuse infiltrate of neutrophils in the upper dermis. This disorder has been associated with myeloproliferative syndromes. We report the case of a 53-year-old woman with an acute myeloid leukemia, presenting a Sweet's syndrome. A worsening of cutaneous lesions injuries was observed when granulocyte colony stimulating factor was added to treatment. PMID- 22446707 TI - [Ergotism secondary to ergotamine-ritonavir association. Report of three cases]. AB - Ergotism is a complication of the acute intoxication or chronic abuse of ergot derivatives. It may be manifested by a vasomotor syndrome with peripheral vascular disease frequently involving extremities. We report three patients infected with human immunodeficiency virus (HIV), in antiretroviral treatment (ART) that included a protease inhibitor as ritonavir, and had received self medicated ergotamine. They developed symptoms of peripheral vascular disease and the physical examination showed no arterial pulses in the affected vessels. Arterial Doppler confirmed signs of diffuse arterial spasm in all of them. An arteriography was performed to the second patient and it showed obliteration of the distal sector of the ulnar and radial arteries. Ergotism secondary to ergotamine-ritonavir association was diagnosed. Patients were treated discontinuing the administration of involved drugs, arterial vasodilators and prophylactic anticoagulation, with marked improvement of symptoms. PMID- 22446708 TI - [Mutation in the ED1, Ala349Thr in a patient with X-linked hypohidrotic ectodermal dysplasia]. AB - Hypohidrotic ectodermal dysplasia (HED) is a very rare disease characterized by the absence of eccrine glands, dry skin, scanty hair, and dental abnormalities. It is caused by mutations within the ED1 gene, which encodes a protein, ectodysplasin-A (EDA). Clinical characteristic are frontal bossing, saddle nose, pointed chin, a prominent supraorbital ridge with periorbital hyperpigmenta-tion, and anodontia. Those affected show great intolerance to heat. We report the first Mexican 2-year-old boy with an Ala349Thr missense mutation from Tamaulipas, Mexico. PMID- 22446709 TI - [Virulence factors of Mycobacterium tuberculosis]. AB - Mycobacterium tuberculosis, the etiological agent of human tuberculosis, causes annually three million deaths and latently infects about two billion people. Immunodeficiency caused by malnutrition, senescence or co-infection with HIV enhances the risk of developing active tuberculosis, either from a primary infection or by reactivation of a latent infection. The increasing appearance of multidrug-resistant strains to existing drugs is worrisome, since it leaves patients practically without treatment options. The understanding of the mechanisms of transmission, pathogenesis and virulence of M. tuberculosis is important. The analysis of its genome shows the presence of alternative sigma factors, transcriptional repressors and activators, two component signaling systems, metabolic enzymes and cellular secretory systems, that are associated with virulence in a series of pathogenic micro-organisms. Environmental stimuli such as pH, temperature, osmolality, oxygen availability are processed, activating or repressing virulence genes. The molecular mechanisms of action of these genes have been elucidated in in vitro and in vivo models. PMID- 22446710 TI - [Biomedical informatics]. AB - Biomedical Informatics is a new discipline that arose from the need to incorporate information technologies to the generation, storage, distribution and analysis of information in the domain of biomedical sciences. This discipline comprises basic biomedical informatics, and public health informatics. The development of the discipline in Chile has been modest and most projects have originated from the interest of individual people or institutions, without a systematic and coordinated national development. Considering the unique features of health care system of our country, research in the area of biomedical informatics is becoming an imperative. PMID- 22446711 TI - [Knowledge about health care rights among a group of Chilean patients with knee osteoarthritis]. AB - BACKGROUND: Mild to moderate osteoarthritis of the knee in people over 55 years of age is one of the diseases whose management is covered by the explicit guaranties in health system (GES) in Chile. All beneficiaries with the disease should be informed about their rights to receive free treatment. AIM: To assess the degree of awareness about their rights among patients with knee osteoarthritis, admitted to GES. MATERIAL AND METHODS: Two hundred forty one patients aged 55 to 93 years (180 women) with knee osteoarthritis admitted to GES, answered at their homes a survey about their rights to receive health care, included in the GES system and about their disease. RESULTS: Fifty percent of patients did not know what GES system was, 26% admitted to have a limited knowledge and 24%, a full knowledge. Sixty two percent were not informed about the nature of their disease and 42% perceived their health as less than optimal. There was a significant association between the level of knowledge about GES and osteoarthritis and their self-perception of health. CONCLUSIONS: Half of the patients with knee osteoarthritis surveyed, were not aware of their health care rights included in GES and received scanty information about their disease. PMID- 22446712 TI - [National Agency for Medicaments (ANAMED, Chile): an opportunity not to be missed]. PMID- 22446713 TI - Short-term effects of air pollution on respiratory morbidity at Rio de Janeiro- Part II: health assessment. AB - The effects of air pollution on health have been studied worldwide. Given that air pollution triggers oxidative stress and inflammation, it is plausible that high levels of air pollutants cause higher number of hospitalisations. This study aimed to assess the impact of air pollution on the emergency hospitalisation for respiratory disease in Rio de Janeiro, Brazil. The study was divided in two parts: Part I specifically addressing the air pollution assessment and Part II addressing the health assessment. Accordingly, this Part II aimed to estimate the association between the concentrations of PM10, SO2 and CO observed in Rio de Janeiro and the number of emergency hospitalisations at a central hospital due to respiratory diseases. The pollutant concentrations were measured at two different sites in Rio de Janeiro, but the excess relative risks were calculated based on the concentrations observed at one of the sites, where limits were generally exceeded more frequently, between September 2000 and December 2005. A time series analysis was performed using the number of hospitalisations, divided in three categories (children until 1 year old, children aged between 1 and 5 years old and elderly with 65 years old or more) as independent variable, the concentrations of pollutants as dependent variables and temperature, relative humidity, long term trend, and seasonality as confounders. Data were analysed using generalised additive models with smoothing for some of the dependent variables. Results showed an excess risk of hospitalisation for respiratory disease higher than 2% per 10 MUg m-3 increase in PM10 concentrations for children under 5 years old, of 2% per 10 MUg m-3 increase in SO2 for elderly above 65 years old and around 0.1% per 10 MUg m-3 increase in CO for children under 1 year and elderly. Other studies have found associations that are in agreement with the results achieved in this study. The study suggests that the ambient levels of air pollutants experienced in Rio de Janeiro between 2000 and 2005 were linked to the number of hospitalisations for respiratory diseases among children and elderly. PMID- 22446716 TI - Buried disc drusen have hypo-reflective appearance on SD-OCT. AB - PURPOSE: Buried disc drusen are an important differential diagnosis for papilledema. Spectral domain optical coherence tomography (SD-OCT) affords clinicians with new non-invasive opportunities to probe below the surface of the optic nerve. Clinicians may use the knowledge of this appearance to rule out buried disc drusen in patients with irregular optic nerve borders or a bulging, hyperemic appearance. METHODS: SD-OCTs were obtained in a patient with one surfacing disc druse, identifying the nature of the appearance of this disc druse and others in this and the contralateral eye when imaged with this technology. B scan ultrasonography was used to confirm the presence of disc drusen. Additional scans in multiple patients with confirmed buried drusen were obtained for comparison. RESULTS: Drusen appear as rounded hyporeflectant areas on SD-OCT, similar in appearance to blood vessels. They share the appearance of cysts but show a fine hyperreflective border anteriorly. These same discrete hyporeflective areas were found at various depths within optic nerve heads with confirmed buried disc drusen. CONCLUSIONS: The hyporeflective appearance may not be anticipated by clinicians, as B-scans show calcified drusen as hyperreflective on echo. It is hypothesized that the hyporeflectant appearance of drusen is due to a constancy in refractive index through the druse, as OCT detects changes in optical reflectivity. Thus, drusen are likely dense and homogenous. SD-OCT may be more useful in those patients with buried disc drusen which are not calcified as B scan often contributes little in such cases. PMID- 22446714 TI - The pathobiological impact of cigarette smoke on pancreatic cancer development (review). AB - Despite extensive efforts, pancreatic cancer remains incurable. Most risk factors, such as genetic disposition, metabolic diseases or chronic pancreatitis cannot be influenced. By contrast, cigarette smoking, an important risk factor for pancreatic cancer, can be controlled. Despite the epidemiological evidence of the detrimental effects of cigarette smoking with regard to pancreatic cancer development and its unique property of being influenceable, our understanding of cigarette smoke-induced pancreatic carcinogenesis is limited. Current data on cigarette smoke-induced pancreatic carcinogenesis indicate multifactorial events that are triggered by nicotine, which is the major pharmacologically active constituent of tobacco smoke. In addition to nicotine, a vast number of carcinogens have the potential to reach the pancreatic gland, where they are metabolized, in some instances to even more toxic compounds. These metabolic events are not restricted to pancreatic ductal cells. Several studies show that acinar cells are also greatly affected. Furthermore, pancreatic cancer progenitor cells do not only derive from the ductal epithelial lineage, but also from acinar cells. This sheds new light on cigarette smoke-induced acinar cell damage. On this background, our objective is to outline a multifactorial model of tobacco smoke-induced pancreatic carcinogenesis. PMID- 22446717 TI - New directions in ophthalmic optical coherence tomography. AB - The rapid development of optical coherence tomography (OCT) and its ophthalmic applications has resulted in the emergence of new laboratory and commercial systems that vary in performance and functionality. The introduction of high speed imaging capabilities has abrogated the primary limitation of early OCT technology by providing in vivo three-dimensional volumetric reconstructions of both anterior and posterior segments of the human eye within reasonable time constraints. Currently, high-speed swept source OCT technology has made it possible to achieve OCT acquisition speeds of several million A-scans/s. Another direction of OCT development includes the introduction of adaptive optics to imaging of the posterior segment of the eye that allows correction of the eye's static and dynamic aberrations, resulting in the achievement of volumetric cellular resolution retinal imaging. In this review, we introduce readers to various aspects of the development of OCT technology within the context of its ophthalmic applications. We point out directions for future development and indicate different perspectives on this dynamically expanding method. We give a few examples of how OCT has been used over the past few years and describe how high-speed OCT imaging may be used in the future in clinical practice. PMID- 22446718 TI - Diurnal variation of retinal thickness with spectral domain OCT. AB - PURPOSE: To investigate whether diurnal variation occurs in retinal thickness measures derived from spectral domain optical coherence tomography (SD-OCT). METHODS: Twelve healthy adult subjects had retinal thickness measured with SD-OCT every 2 h over a 10 h period. At each measurement session, three average B-scan images were derived from a series of multiple B-scans (each from a 5 mm horizontal raster scan along the fovea, containing 1500 A-scans/B-scan) and analyzed to determine the thickness of the total retina, as well as the thickness of the outer retinal layers. Average thickness values were calculated at the foveal center, at the 0.5 mm diameter foveal region, and for the temporal parafovea (1.5 mm from foveal center) and nasal parafovea (1.5 mm from foveal center). RESULTS: Total retinal thickness did not exhibit significant diurnal variation in any of the considered retinal regions (p > 0.05). Evidence of significant diurnal variation was found in the thickness of the outer retinal layers (p < 0.05), with the most prominent changes observed in the photoreceptor layers at the foveal center. The photoreceptor inner and outer segment layer thickness exhibited mean amplitude (peak to trough) of daily change of 7 +/- 3 MUm at the foveal center. The peak in thickness was typically observed at the third measurement session (mean measurement time, 13:06). CONCLUSIONS: The total retinal thickness measured with SD-OCT does not exhibit evidence of significant variation over the course of the day. However, small but significant diurnal variation occurs in the thickness of the foveal outer retinal layers. PMID- 22446719 TI - Panoramic autofluorescence: highlighting retinal pathology. AB - PURPOSE: Recent technological advances in fundus autofluorescence (FAF) are providing new opportunities for insight into retinal physiology and pathophysiology. FAF provides distinctly different imaging information than standard photography or color separation. A review of the basis for this imaging technology is included to help the clinician understand how to interpret FAF images. Cases are presented to illustrate image interpretation. METHODS: Optos, which manufactures equipment for simultaneous panoramic imaging, has recently outfitted several units with AF capabilities. Six cases are presented in which panoramic autofluorescent (PAF) images highlight retinal pathology, using Optos' Ultra-Widefield technology. Supportive imaging technologies, such as Optomap(r) images and spectral domain optical coherence tomography (SD-OCT), are used to assist in the clinical interpretation of retinal pathology detected on PAF. RESULTS: Hypofluorescent regions on FAF are identified to occur along with a disruption in the photoreceptors and/or retinal pigment epithelium, as borne out on SD-OCT. Hyperfluorescent regions on FAF occur at the advancing zones of retinal degeneration, indicating impending damage. PAF enables such inferences to be made in retinal areas which lie beyond the reach of SD-OCT imaging. PAF also enhances clinical pattern recognition over a large area and in comparison with the fellow eye. Symmetric retinal degenerations often occur with genetic conditions, such as retinitis pigmentosa, and may impel the clinician to recommend genetic testing. CONCLUSIONS: Autofluorescent ophthalmoscopy is a non invasive procedure that can detect changes in metabolic activity at the retinal pigment epithelium before clinical ophthalmoscopy. Already, AF is being used as an adjunct technology to fluorescein angiography in cases of age-related macular degeneration. Both hyper- and hypoautofluorescent changes are indicative of pathology. Peripheral retinal abnormalities may precede central retinal impacts, potentially providing early signs for intervention before impacting visual acuity. The panoramic image enhances clinical pattern recognition over a large area and in comparison between eyes. Optos' Ultra-Widefield technology is capable of capturing high-resolution images of the peripheral retina without requiring dilation. PMID- 22446720 TI - Adaptive optics scanning laser ophthalmoscope-based microperimetry. AB - PURPOSE: To develop and test the application of an adaptive optics scanning laser ophthalmoscope (AOSLO) with eye tracking for high-resolution microperimetric testing. METHODS: An AOSLO was used to conduct simultaneous high-resolution retinal imaging and visual function testing in six normal subjects. Visual sensitivity was measured at test locations between the fovea and 5.0 degrees eccentricity via an increment threshold approach using a 40-trial, yes-no adaptive Bayesian staircase procedure (QUEST). A high-speed eye tracking algorithm enabled real-time video stabilization and the delivery of diffraction limited Goldmann I-sized stimuli (diameter = 6.5 arc min = ~32 MUm; lambda = 680 nm) to targeted retinal loci for 200 ms. Test locations were selected either manually by the examiner or automatically using Fourier-based image registration. Cone spacing was assessed at each test location and sensitivity was plotted against retinal eccentricity. Finally, a 4.2 arc min stimulus was used to probe the angioscotoma associated with a blood vessel located at 2.5 degrees eccentricity. RESULTS: Visual sensitivity decreases with eccentricity at a rate of -1.32 dB/deg (R = 0.60). The vertical and horizontal errors of the targeted stimulus delivery algorithm averaged 0.81 and 0.89 arc min (~4 MUm), respectively. Based on a predetermined exclusion criterion, the stimulus was successfully delivered to its targeted location in 90.1% of all trials. Automated recovery of test locations afforded the repeat testing of the same set of cones over a period of 3 months. Thresholds measured over a parafoveal blood vessel were 1.96 times higher (p < 0.05; one-tailed t-test) than those measured in directly adjacent retina. CONCLUSIONS: AOSLO-based microperimetry has the potential to test visual sensitivity with fine retinotopic precision. Automated recovery of previously tested locations allows these measures to be tracked longitudinally. This approach can be implemented by researchers interested in establishing the functional correlates of photoreceptor mosaic structure in patients with retinal disease. PMID- 22446721 TI - The dynamics of melittin-induced membrane permeability. AB - The transport of co-encapsulated solutes through the melittin-induced pores in the membrane of giant phospholipid vesicles was studied, and the characteristics of the pore formation process were modeled. Molecules of two different sizes (dextran and the smaller, fluorescent marker Alexa Fluor) were encapsulated inside the vesicles. The chosen individual vesicles were then transferred by micromanipulation from the stock suspension to the environment with the melittin (MLT). The vesicles were observed optically with a phase-contrast microscope and by monitoring the fluorescence signal. Such an experimental setup enabled an analysis of a single vesicle's response to the MLT on the basis of simultaneous, separate measurements of the outflow of both types of encapsulated molecules through the MLT-induced pores in the membrane. The mechanisms of the MLT's action were suggested in a model for MLT pore formation, with oligomeric pores continuously assembling and dissociating in the membrane. Based on the model, the results of the experiments were explained as a consequence of the membrane's permeability dynamics, with a continuously changing distribution of pores in the membrane with regard to their size and number. The relatively stable "average MLT pore" characteristics can be deduced from the proposed model. PMID- 22446722 TI - Effect of the A30P mutation on the structural dynamics of micelle-bound alphaSynuclein released in water: a molecular dynamics study. AB - Atomistic molecular dynamics simulation has been used to probe the effect of the A30P mutation on the structural dynamics of micelle-bound, helical alphaSynuclein when released in an aqueous environment. On the timescales simulated, the effect of the mutation on the secondary structure is restricted to local changes close to the mutation site in the N-terminal helical domain. The changes are transient, and all residues except Lys23 recover their initial structure. The local behavior due to the mutation gives rise to a global difference in the A30P mutant in the form of a permanent kink in the N-terminal helical domain. PMID- 22446723 TI - Optimising women's diets. An examination of factors that promote healthy eating and reduce the likelihood of unhealthy eating. AB - The majority of nutrition promotion research that has examined the determinants of unhealthy or healthy dietary behaviours has focused on factors that promote consumption of these foods, rather than factors that may both promote healthy eating and buffer or protect consumption of unhealthy foods. The purpose of this paper is to identify factors that both promote healthy eating and also reduce the likelihood of eating unhealthily amongst women. A community sample of 1013 Australian women participated in a cross-sectional self-report survey that assessed factors associated with diet and obesity. Multiple logistic regressions were used to examine the associations between a range of individual, social and environmental factors and aspects of both healthy and unhealthy eating, whilst controlling for key covariates. Results indicated that women with high self efficacy for healthy eating, taste preferences for fruit and vegetables, family support for healthy eating and the absence of perceived barriers to healthy eating (time and cost) were more likely to consume components of a healthy diet and less likely to consume components of a unhealthy diet. Optimal benefits in overall diet quality amongst women may be achieved by targeting factors associated with both healthy and unhealthy eating in nutrition promotion efforts. PMID- 22446724 TI - Body fat fluctuations among female adolescents with restrained eating behaviours. AB - Body fat fluctuation during varying competing academic demand was examined among female adolescents with high (n=24) or low (n=24) restrained eating behaviours. Body fat, perceived stress, energy intake, and exercise behaviour were measured three times with 10 weeks between consecutive sessions. High restrained eaters' body fat increased during a period when academic demands were high. Significant results were found for exercise behaviours but not for food consumption. Post hoc analyses did not reveal significant results for low restrained eaters. The results lend support to Muraven and Baumeister's limited strength model of self regulation. PMID- 22446725 TI - Irregular breakfast consumption in adolescence and the family environment: underlying causes by family structure. AB - Data from the 2002, 2006 and 2010 Scottish Health Behaviour in School-aged Children (HBSC) surveys were analysed using logistic multilevel regression for outcome variable irregular breakfast consumption (IBC). IBC prevalence in Scotland was higher among young people from reconstituted and single parent families, and particularly single father families. Family characteristics, found previously to be associated with breakfast consumption, such as number of siblings, perceived parenting, parental involvement and family affluence, differed by family structure. Family structure inequalities in IBC existed, also after adjustment for year and child's sex, age, grade and ethnicity. Across all family structures, IBC was more prevalent at the older age groups, among those who had difficult communication with their parents, and where household routines were infrequent. Greater number of siblings and lower family affluence were associated with higher odds of IBC in single mother and both parent families, while having a second home was associated with higher odds in reconstituted households. Fair parenting and being close to at least one parent was associated with reduced odds of IBC in single mother households, while being close to all parents was in single father households. In single mother homes, having a working mother was also positively associated with IBC. Family structure differences should be considered when addressing irregular breakfast consumption in adolescence. PMID- 22446726 TI - Usefulness of C-reactive protein as a marker of early post-infarct left ventricular systolic dysfunction. AB - OBJECTIVE: To assess the usefulness of in-hospital measurement of C-reactive protein (CRP) concentration in comparison to well-established risk factors as a marker of post-infarct left ventricular systolic dysfunction (LVSD) at discharge. MATERIALS AND METHODS: Two hundred and four consecutive patients with ST-segment elevation myocardial infarction (STEMI) were prospectively enrolled into the study. CRP plasma concentrations were measured before reperfusion, 24 h after admission and at discharge with an ultra-sensitive latex immunoassay. RESULTS: CRP concentration increased significantly during the first 24 h of hospitalization (2.4 +/- 1.9 vs. 15.7 +/- 17.0 mg/L; p < 0.001) and persisted elevated at discharge (14.7 +/- 14.7 mg/L), mainly in 57 patients with LVSD (2.4 +/- 1.8 vs. 25.0 +/- 23.4 mg/L; p < 0.001; CRP at discharge 21.9 +/- 18.6 mg/L). The prevalence of LVSD was significantly increased across increasing tertiles of CRP concentration both at 24 h after admission (13.2 vs. 19.1 vs. 51.5 %; p < 0.0001) and at discharge (14.7 vs. 23.5 vs. 45.6 %; p < 0.0001). Multivariate analysis demonstrated CRP concentration at discharge to be an independent marker of early LVSD (odds ratio of 1.38 for a 10 mg/L increase, 95 % confidence interval 1.01-1.87; p < 0.04). CONCLUSION: Measurement of CRP plasma concentration at discharge may be useful as a marker of early LVSD in patients after a first STEMI. PMID- 22446727 TI - Predicting renal graft failure by sCD30 levels and de novo HLA antibodies at 1year post-transplantation. AB - HLA antibodies and sCD30 levels were detected in the serum sampled from 620 renal graft recipients at 1 year post-transplantation, which were followed up for 5 years. Six-year graft and patient survivals were 81.6% and 91.0%. HLA antibodies were detected in 45 recipients (7.3%), of whom there were 14 cases with class I antibodies, 26 cases with class II, and 5 cases with both class I and II. Much more graft loss was record in recipients with HLA antibodies than those without antibodies (60% vs. 15.1%, p<0.001). Significantly higher sCD30 levels were recorded in recipients suffering graft loss than the others (73.9+/-48.8 U/mL vs. 37.3+/-14.6 U/mL, p<0.001). Compared with those with high sCD30 levels, recipients with low sCD30 levels (<50 U/mL) had much better 6-year graft survival (92.4% vs. 46.6%, p<0.001). Further statistical analysis showed that detrimental effect of de novo HLA antibodies and high sCD30 on graft survival was not only independent but also additive. Therefore, post-transplantation monitoring of HLA antibodies and sCD30 levels is necessary and recipients with elevated sCD30 level and/or de novo HLA antibody should be paid more attention in order to achieve better graft survival. PMID- 22446728 TI - A question of quality? A single questionnaire for measuring asthma control, structuring asthma reviews, and monitoring health service standards. PMID- 22446729 TI - Methods of assessing tubal patency. PMID- 22446730 TI - Acetylcholinesterase inhibition dose-response modeling for chlorpyrifos and chlorpyrifos-oxon. AB - This paper evaluates new data for cholinesterase inhibition with chlorpyrifos (CPF). Marty et al. (2012) recently conducted a CPF cholinesterase inhibition study in rats that included testing of males and females, dosing by gavage or diet, administration in corn oil or milk, and with pups and adults. Additionally, the study included cholinesterase inhibition testing for CPF-oxon, the active moiety that inhibits cholinesterase. The study included 5-6 dose groups with eight animals/sex/group for most of the tests. This paper provides a benchmark dose (BMD) analysis of the data from Marty et al. (2012), including a BMD meta analysis that includes CPF cholinesterase inhibition data from different assays within the Marty et al. (2012) study and, in one case, from another study. From the meta-analysis, the recommended BMD(10)s, based on brain acetylcholinesterase inhibition, are 1.7 mg/kg/day (BMDL10 = 1.3mg/kg/day) for acute doses to children and adults, and 0.67 mg/kg/day (BMDL10 = 0.53 mg/kg/day) for repeat doses to children and adults. At the dose levels considered in this analysis, there was no evidence of a difference in responses between males and females, corn oil versus milk administration, or pups versus adults. The data on pups versus adults show that an extra safety factor to protect the young is not needed for CPF. CPF data from the literature suggest that brain cholinesterase inhibition is the most appropriate metric for cholinesterase inhibition risk assessment. PMID- 22446731 TI - Detailed insight into the hydrogen bonding interactions in acetone-methanol mixtures. A molecular dynamics simulation and Voronoi polyhedra analysis study. AB - Voronoi polyhedra (VP) analysis of mixtures of acetone and methanol is reported on the basis of molecular dynamics computer simulations, performed at 300 K and 1 bar. The composition of the systems investigated covers the entire range from neat acetone to neat methanol. Distribution of the volume, reciprocal volume and asphericity parameter of the VP as well as that of the area of the individual VP faces and of the radius of the empty voids located between the molecules are calculated. To investigate the tendency of the like molecules to self-associate the analyses are repeated by disregarding one of the two components. The self aggregates of the disregarded component thus turn into large empty voids, which are easily detectable in VP analysis. The obtained results reveal that both molecules show self-association, but this behavior is considerably stronger among the acetone than among the methanol molecules. The strongest self-association of the acetone and methanol molecules is found in their mole fraction ranges of 02 0.5 and 0.5-0.6, respectively. The caging effect around the methanol molecules is found to be stronger than around acetones. Finally, the local environment of the acetone molecules turns out to be more spherical than that of the methanols, not only in the respective neat liquids, but also in their mixtures. PMID- 22446732 TI - MHC class I target recognition, immunophenotypes and proteomic profiles of natural killer cells within the spleens of day-14 chick embryos. AB - Chicken natural killer (NK) cells are not well defined, so little is known about the molecular interactions controlling their activity. At day 14 of embryonic development, chick spleens are a rich source of T-cell-free CD8alphaalpha(+), CD3(-) cells with natural killing activity. Cell-mediated cytotoxicity assays revealed complex NK cell discrimination of MHC class I, suggesting the presence of multiple NK cell receptors. Immunophenotyping of freshly isolated and recombinant chicken interleukin-2-stimulated d14E CD8alphaalpha(+) CD3(-) splenocytes provided further evidence for population heterogeneity. Complex patterns of expression were found for CD8alpha, chB6 (Bu-1), CD1-1, CD56 (NCAM), KUL01, CD5, and CD44. Mass spectrometry-based proteomics revealed an array of NK cell proteins, including the NKR2B4 receptor. DAVID and KEGG analyses and additional immunophenotyping revealed NK cell activation pathways and evidence for monocytes within the splenocyte cultures. This study provides an underpinning for further investigation into the specificity and function of NK cells in birds. PMID- 22446733 TI - Time course proteomic profiling of cellular responses to immunological challenge in the sea urchin, Heliocidaris erythrogramma. AB - Genome sequences and high diversity cDNA arrays have provided a detailed molecular understanding of immune responses in a number of invertebrates, including sea urchins. However, complementary analyses have not been undertaken at the level of proteins. Here, we use shotgun proteomics to describe changes in the abundance of proteins from coelomocytes of sea urchins after immunological challenge and wounding. The relative abundance of 345 reproducibly identified proteins were measured 6, 24 and 48 h after injection. Significant changes in the relative abundance of 188 proteins were detected. These included pathogen-binding proteins, such as the complement component C3 and scavenger receptor cysteine rich proteins, as well as proteins responsible for cytoskeletal remodeling, endocytosis and intracellular signaling. An initial systemic reaction to wounding was followed by a more specific response to immunological challenge involving proteins such as apolipophorin, dual oxidase, fibrocystin L, aminopeptidase N and alpha-2-macroglobulin. PMID- 22446734 TI - Retrospective cohort study: a comparison of two different management strategies in patients with preterm premature rupture of membranes. AB - PURPOSE: Perinatal outcomes were compared before and after changes in the treatment policy to improve the management for preterm PROM (pPROM). METHODS: This is a retrospective analysis of 99 cases of pPROM diagnosed between 27 and 34 weeks of gestation, which were managed according to the following two different protocols. Group A (47 cases): tocolytic therapy was continued to prevent preterm delivery until clinical chorioamnionitis (CAM) was diagnosed between January 2000 and June 2004. Group B (52 cases): labor was induced or cesarean section performed when oligohydramnios was diagnosed and/or elevation elastase (EL) of amnion was detected by amniocentesis between July 2004 and July 2009. The outcomes of the cases in each group were compared with regard to the extension of pregnancy period, reasons for delivery, perinatal complications, stage of pathological CAM and funisitis (FUN), neonatal serum IgM concentration, mortality, and morbidity. RESULTS: The incidences of pathological CAM and FUN were significantly lower in Group B than in Group A. The concentration of neonatal serum IgM was also significantly lower in Group B than in Group A. CONCLUSIONS: The addition of oligohydramnios and elevation EL of amnion as indicative factors of intrauterine infection might lead to a reduction in the severity of fetal infection in cases of pPROM. PMID- 22446736 TI - Src42A-dependent polarized cell shape changes mediate epithelial tube elongation in Drosophila. AB - Although many organ functions rely on epithelial tubes with correct dimensions, mechanisms underlying tube size control are poorly understood. We analyse the cellular mechanism of tracheal tube elongation in Drosophila, and describe an essential role of the conserved tyrosine kinase Src42A in this process. We show that Src42A is required for polarized cell shape changes and cell rearrangements that mediate tube elongation. In contrast, diametric expansion is controlled by apical secretion independently of Src42A. Constitutive activation of Src42A induces axial cell stretching and tracheal overelongation, indicating that Src42A acts instructively in this process. We propose that Src42A-dependent recycling of E-Cadherin at adherens junctions is limiting for cell shape changes and rearrangements in the axial dimension of the tube. Thus, we define distinct cellular processes that independently control axial and diametric expansion of a cylindrical epithelium in a developing organ. Whereas exocytosis-dependent membrane growth drives circumferential tube expansion, Src42A is required to orient membrane growth in the axial dimension of the tube. PMID- 22446737 TI - Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size. AB - Networks of epithelial and endothelial tubes are essential for the function of organs such as the lung, kidney and vascular system. The sizes and shapes of these tubes are highly regulated to match their individual functions. Defects in tube size can cause debilitating diseases such as polycystic kidney disease and ischaemia. It is therefore critical to understand how tube dimensions are regulated. Here we identify the tyrosine kinase Src as an instructive regulator of epithelial-tube length in the Drosophila tracheal system. Loss-of-function Src42 mutations shorten tracheal tubes, whereas Src42 overexpression elongates them. Surprisingly, Src42 acts distinctly from known tube-size pathways and regulates both the amount of apical surface growth and, with the conserved formin dDaam, the direction of growth. Quantitative three-dimensional image analysis reveals that Src42- and dDaam-mutant tracheal cells expand more in the circumferential than the axial dimension, resulting in tubes that are shorter in length-but larger in diameter-than wild-type tubes. Thus, Src42 and dDaam control tube dimensions by regulating the direction of anisotropic growth, a mechanism that has not previously been described. PMID- 22446738 TI - The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. AB - BID, a BH3-only BCL2 family member, functions in apoptosis as well as the DNA damage response. Our previous data demonstrated that BID is an ATM effector acting to induce cell-cycle arrest and inhibition of apoptosis following DNA damage. Here we show that ATM-mediated BID phosphorylation plays an unexpected role in maintaining the quiescence of haematopoietic stem cells (HSCs). Loss of BID phosphorylation leads to escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. We also demonstrate that BID phosphorylation plays a role in protecting HSCs from irradiation, and that regulating both quiescence and survival of HSCs depends on BID's ability to regulate oxidative stress. Moreover, loss of BID phosphorylation, ATM knockout or exposing mice to irradiation leads to an increase in mitochondrial BID, which correlates with an increase in mitochondrial oxidative stress. These results show that the ATM-BID pathway serves as a critical checkpoint for coupling HSC homeostasis and the DNA-damage stress response to enable long-term regenerative capacity. PMID- 22446739 TI - Effect of offering different levels of support and free nicotine replacement therapy via an English national telephone quitline: randomised controlled trial. AB - OBJECTIVE: To compare the effects of free nicotine replacement therapy or proactive telephone counselling in addition to standard smoking cessation support offered through a telephone quitline. DESIGN: Parallel group, 2 * 2 factorial, randomised controlled trial. SETTING: National quitline, England. PARTICIPANTS: 2591 non-pregnant smokers aged 16 or more residing in England who called the quitline between February 2009 and February 2010 and agreed to set a quit date: 648 were each randomised to standard support, proactive support, or proactive support with nicotine replacement therapy, and 647 were randomised to standard support with nicotine replacement therapy. INTERVENTIONS: Two interventions were offered in addition to standard support: six weeks' nicotine replacement therapy, provided free, and proactive counselling sessions (repeat telephone calls from, and interaction with, cessation advisors). MAIN OUTCOME MEASURES: The primary outcome was self reported smoking cessation for six or more months after the quit date. The secondary outcome was cessation validated by exhaled carbon monoxide measured at six or more months. RESULTS: At six months, 17.7% (n = 229) of those offered nicotine replacement therapy reported smoking cessation compared with 20.1% (n = 261) not offered such therapy (odds ratio 0.85, 95% confidence interval 0.70 to 1.04), and 18.2% (n = 236) offered proactive counselling reported smoking cessation compared with 19.6% (n = 254) offered standard support (0.91, 0.75 to 1.11). Data validated by carbon monoxide readings changed the findings for nicotine replacement therapy only, with smoking cessation validated in 6.6% (85/1295) of those offered nicotine replacement therapy compared with 9.4% (122/1296) not offered such therapy (0.67, 0.50 to 0.90). CONCLUSIONS: Offering free nicotine replacement therapy or additional (proactive) counselling to standard helpline support had no additional effect on smoking cessation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00775944. PMID- 22446740 TI - Smoking cessation strategies. PMID- 22446741 TI - Test based on natural processes cannot be patented, rules US court. PMID- 22446742 TI - Netherlands drops plans to deliver acute obstetric care in 15 minutes. PMID- 22446743 TI - NICE advises screening for TB in hostels and prisons to reduce UK cases. PMID- 22446744 TI - Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads. AB - The parasite Plasmodium falciparum is the main agent responsible for malaria. In this study, we exploited a recently published chemical library from GlaxoSmithKline (GSK) that had previously been confirmed to inhibit parasite growth of the wild type (3D7) and the multi-drug resistance (D2d) strains, in order to uncover the weak links in the proteome of the parasite. We predicted 293 proteins of P. falciparum, including the six out of the seven verified targets for P. falciparum malaria treatment, as targets of 4645 GSK active compounds. Furthermore, we prioritized druggable targets, based on a number of factors, such as essentiality for growth, lack of homology with human proteins, and availability of experimental data on ligand activity with a non-human homologue of a parasite protein. We have additionally prioritized predicted ligands based on their polypharmacology profile, with focus on validated essential proteins and the effect of their perturbations on the metabolic network of P. falciparum, as well as indication of drug resistance emergence. Finally, we predict potential off-target effects on the human host with associations to cancer, neurological and dermatological disorders, based on integration of available chemical-protein and protein-protein interaction data. Our work suggests that a large number of the P. falciparum proteome is potentially druggable and could therefore serve as novel drug targets in the fight against malaria. At the same time, prioritized compounds from the GSK library could serve as lead compounds to medicinal chemists for further optimization. PMID- 22446745 TI - Large variations in bacterial ribosomal RNA genes. AB - Ribosomal RNA (rRNA) genes, essential to all forms of life, have been viewed as highly conserved and evolutionarily stable, partly because very little is known about their natural variations. Here, we explored large-scale variations of rRNA genes through bioinformatic analyses of available complete bacterial genomic sequences with an emphasis on formation mechanisms and biological significance. Interestingly, we found bacterial genomes in which no 16S rRNA genes harbor the conserved core of the anti-Shine-Dalgarno sequence (5'-CCTCC-3'). This loss was accompanied by elimination of Shine-Dalgarno-like sequences upstream of their protein-coding genes. Those genomes belong to 1 or 2 of the following categories: primary symbionts, hemotropic Mycoplasma, and Flavobacteria. We also found many rearranged rRNA genes and reconstructed their history. Conjecturing the underlying mechanisms, such as inversion, partial duplication, transposon insertion, deletion, and substitution, we were able to infer their biological significance, such as co-orientation of rRNA transcription and chromosomal replication, lateral transfer of rRNA gene segments, and spread of rRNA genes with an apparent structural defect through gene conversion. These results open the way to understanding dynamic evolutionary changes of rRNA genes and the translational machinery. PMID- 22446746 TI - MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice. AB - Heat shock proteins (HSPs), molecular chaperones that assist in protein folding, have become a research focus in Parkinson's disease (PD) since the pathogenesis of PD is characterized by intracellular protein misfolding and inclusion body formation. This study investigated the effect of the knockout (KO) of the Hsp70.1 (approved gene symbol Hspa1b) gene on the sensitivity of murine nigrostriatal dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced toxicity. We confirmed changes in motor coordination and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra following MPTP treatment of C57BL/6 normal mice and Hspa1b KO mice. MPTP treatment led to motor control impairment and induced TH-positive dopaminergic neurodegeneration in normal mice. Compared to untreated normal mice, rotarod duration and the density of TH-positive neurons in the substantia nigra were also significantly lower in untreated KO mice (p<0.01). MPTP-treated KO mice had markedly decreased rotarod duration and reduced density of TH-positive neurons, compared to MPTP-treated normal mice. These results indicate that Hspa1b KO mice are more vulnerable to the neurotoxic effects of MPTP and are consistent with the hypothesis that HSPs represent an important molecular target for neuroprotective strategies in the treatment of PD. PMID- 22446747 TI - Today's and tomorrow's imaging and circulating biomarkers for pulmonary arterial hypertension. AB - The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients' long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed. PMID- 22446748 TI - Tetraspanin15 regulates cellular trafficking and activity of the ectodomain sheddase ADAM10. AB - A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10. PMID- 22446750 TI - Complications of endoscopic microdiscectomy using the EASYGO! system: is there any difference with conventional discectomy during the learning-curve period? AB - BACKGROUND: Microendoscopic discectomy (MED) is emerging as a minimally invasive alternative to conventional microsurgical discectomy (MSD). EASYGO! is a new system for spinal endoscopy that claims smooth transition from MSD to MED, with a reduced learning curve period. The aims of this study were to describe the complications that appeared during the learning curve period of MED and to compare their incidence with the rate and type of complications that occurred during a simultaneous non-randomised series of standard MSDs. METHODS: Between July 2009 and December 2010, 138 patients underwent scheduled first-time discectomy in our institution, 37 using an MED approach and 101 by a conventional MSD. A MED learning curve was obtained by plotting every case with its respective operative time. Complications, length of hospital stay, need of further surgery and outcome were prospectively recorded in both groups. RESULTS: The mean operative time was 66 min for the MSD group and 100 min for the MED group, although for the last 14 cases of the latter group the time was reduced. Curve fitting techniques showed that the inverse equation, f(x) = 122.12/x + 73.05, had the best correlation between case number and operative time. The learning curve was overcome after the 30th case. Complications occurred in 9.8 % of the MSD group and 8.1 % of the MED group (P = 0.49). Average length of hospital stay was 2.36 days for the MED group and 3.36 days for the MSD group (P = 0.01). The procedure successfully relieved patient symptoms in 68.63 % of the MSD group and 89.92 % of the MED group. No revision surgery was required in the MED group, but it was necessary in ten patients of the MSD group. CONCLUSIONS: Between 25 and 30 cases are needed to reach the learning curve's asymptote of MED. Even during this initial learning period MED is a safe procedure, with comparable results to those obtained with conventional MSD and with a similar complication rate. The key points for reducing intraoperative complications are an adequate expertise in MSD, a precise selection of initial cases, a proper surgical planning and a careful technique, which are mandatory to avoid unnecessary neurological injury in an otherwise secure surgical approach. PMID- 22446749 TI - Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases. AB - Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase 1-mediated maturation of the precursors of IL-1beta and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-kappaB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases. PMID- 22446751 TI - Study of pressure induced phase transformation in CTAB capped CdS nanoparticles. AB - Effect of high pressure on as prepared 20mM CTAB capped CdS nanoparticles (size ~4nm) has been analyzed in this paper. Raman scattering has been used to observe the phase transition pressure. X-ray diffraction pattern is used for structural characterization. Raman scattering predicts the phase transition occur from mixed cubical phase to rock salt phase above 6.6 GPa. One of the representative XRD pattern at 9.7 GPa confirms the existence of rock salt phase above 6.6 GPa. PMID- 22446752 TI - The spectroscopic (FTIR, FT-Raman, NMR and UV), first-order hyperpolarizability and HOMO-LUMO analysis of methylboronic acid. AB - The solid phase FTIR and FT-Raman spectra of methylboronic acid (MBA) have been recorded in the regions 400-4000 and 50-4000 cm(-1), respectively. The spectra were interpreted interms of fundamentals modes, combination and overtone bands. The structure of the molecule was optimized and the structural characteristics were determined by density functional theory (B3LYP) and HF method with 6 311++G(d,p) as basis set. The vibrational frequencies were calculated for most stable conformer and were compared with the experimental frequencies, which yield good agreement between observed and calculated frequencies. The infrared and Raman spectra were also predicted from the calculated intensities. (1)H and (13)C NMR spectra were recorded and (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. UV-visible spectrum of the compound was recorded in the region 200 400 nm and the electronic properties HOMO and LUMO energies were calculated by time-dependent TD-DFT approach. Mulliken charges of the MBA molecule was also calculated and interpreted. The geometric parameters, energies, harmonic vibrational frequencies, IR intensities, Raman intensities and absorption wavelengths were compared with the available experimental data of the molecule. PMID- 22446753 TI - Spectral study of the interaction between 2-pyridinecarbaldehyde-p phenyldihydrazone and ferric iron and its analytical application. AB - The synthesis and spectral characterization of a schiff base, 2 pyridinecarbaldehyde-p-phenylenedihydrazone (short for 2PC-PPH), were described. It was found that ferric ion (Fe(3+)) could selectively quench the fluorescence of 2PC-PPH, whereas many other metal ions, such as Mn(2+), Zn(2+), Cu(2+), K(+), Al(3+), Ca(2+), Ni(2+), Co(2+), Cr(3+) and Fe(2+), could not quench its fluorescence. Based on this, a sensitive method for ferric ion selective detection was established. Under the optimum conditions, the decreasing fluorescence intensity of 2PC-PPH is proportional to the concentration of Fe(3+) within the range of 6.0*10(-7)-1.0*10(-5) mol L(-1). The detection limit (3sigma) for Fe(3+) determination is 3.6*10(-7) mol L(-1). The proposed method was successfully applied to determine iron in tea and milk powder. PMID- 22446754 TI - FT-IR, FT-Raman and computational study of (E)-N-carbamimidoyl-4-((4 methoxybenzylidene)amino)benzenesulfonamide. AB - The FT-IR and FT-Raman spectra of (E)-N-carbamimidoyl-4-((4 methoxybenzylidene)amino)benzenesulfonamide were recorded and analyzed. Geometry and harmonic vibrational wavenumbers were calculated theoretically using Gaussian 03 set of quantum chemistry codes. Calculations were performed at the Hartree Fock (HF) and density functional theory (DFT) levels of theory. The calculated wavenumbers (B3LYP) agree well with the observed wavenumbers. Potential energy distribution is done using GAR2PED program. The red shift of the N-H stretching bands in the infrared spectrum from the computed wavenumber indicates the weakening of the N-H bond. The calculated first hyperpolarizability is comparable with the reported value of similar derivative and may be an attractive object for further studies of nonlinear optics. The variations in the CN bond lengths of the title molecule suggest an extended pi-electron delocalization over the sulfaguanidine moiety which is responsible for the nonlinearity of the molecule. The geometrical parameters of the title compound are in agreement with that of reported similar derivatives. PMID- 22446755 TI - Photocatalytic degradation of monoethanolamine in wastewater using nanosized TiO2 loaded on clinoptilolite. AB - The use of titanium dioxide (TiO(2)) as photocatalyst to degrade the organic compounds is an effective method of oxidation process and has been widely studied in environmental engineering. In this investigation photocatalytic degradation of monoethanolamine (MEA) using TiO(2) (in form of anatase) loaded on surface of clinoptilolite (CP) (TiO(2)-CP) in wastewater was studied. The surface interaction between TiO(2) and CP was investigated by means of transmission electron microscope (TEM), atom force microscope (AFM), IR and X-ray diffraction (XRD). Then the effects of some parameters such as pH, amount of photocatalyst, and initial concentration of MEA on degradation percentage of MEA were examined. The obtained results show that the TiO(2)-CP is an active photocatalyst as compared with TiO(2) nanopowders. All these results indicated that this proposed method can be useful for the development of wastewater treatment applications. PMID- 22446756 TI - Dielectric characterization and catalytic activity studies of nickel chloride doped carboxymethyl cellulose films. AB - Cast technique was used to prepare films of sodium carboxymethyl cellulose (CMC) doped with different ratios of NiCl(2).6H(2)O in the range of 0-40Ni(2+) wt.%. Thermal analysis (DTA) in the range of 25-600 degrees C and dielectric properties in the temperature range of 30-150 degrees C and frequency range of 0.1-100 kHz were measured for the prepared samples. DTA analysis showed new exothermic peaks which were attributed to structural phase transitions. Different molecular motions are separated via dielectric relaxation spectroscopy. In the high temperature range (higher than 100 degrees C), the sigma-relaxation, which is associated with the hopping motion of ions through polymer material, was detected. The detailed analysis of the results showed that the dielectric dispersion consists of both dipolar and interfacial polarization. Measurements of ac conductivity as a function of frequency at different temperatures indicated that the correlated barrier hopping model (CBH) is the most suitable mechanism for the ac conduction behavior. The catalytic activity of CMC doped with Ni(2+) was tested in the reduction of the hazardous pollutant 4-nitrophenol to the functional 4-aminophenol with an excess amount of NaBH(4). Ni-free CMC did not exhibit any catalytic activity for the studied reaction. However, Ni(2+)-doped CMC showed a significant catalytic activity that is proportional to the ratio of Ni(2+) included in CMC. The activation energy (E(a)) was estimated in the temperature range of 25-40 degrees C. The estimated value of E(a) decreased with increasing the ratio of Ni(2+). Finally, the optimum catalyst mass was found to be ~0.6 g/l. PMID- 22446757 TI - Photophysical studies of fused phenanthrimidazole derivatives as versatile pi conjugated systems for potential NLO applications. AB - Two new heterocyclic imidazole derivatives consists of pi-conjugated system attached to a phenanthrimidazole moiety have been synthesized in moderate yield by the condensation of 1,10-phenanthroline-5,6-dione with substituted aromatic aldehydes and 4-methoxyaniline in the presence of ammonium acetate in ethanol medium. The photophysical properties of these imidazole derivatives were studied in several solvents. These derivatives were evaluated concerning their solvatochromic properties and molecular optical nonlinearities. Their electric dipole moment (MU) and hyperpolarizability (beta) have been calculated theoretically and the results indicate that the extension of the pi-framework of the ligands has an effect on the NLO properties of these imidazole derivatives. The non-zero tensor components of these imidazole derivatives reveal that they possess potent non-linear optical (NLO) behavior. The energies of the HOMO and LUMO levels and the molecular electrostatic potential (MEP) energy surface studies have exploited the existence of intramolecular charge transfer (ICT) within the molecule. PMID- 22446758 TI - Differential contribution of Igepal and CnTAB micelles on the photophysics of nonsteroidal drug Naproxen. AB - Spectroscopic studies of Naproxen (NP), a nonsteroidal drug have been carried out in well characterized, micellar media of cationic surfactants of a homologous series having general formula C(n)TAB (alkyl trimethyl ammonium bromide) and of nonionic surfactants of Igepal (Ig) series (poly(oxyethylene) nonyl phenol). The fluorescence behavior of the drug molecule in C(n)TAB micelles has been found to be opposite to that in Igepal micelles. The binding constants during probe micelle binding have been evaluated from relevant fluorescence data. Location and nature of the surrounding medium of the probe in micellar media have been ascertained from fluorescence quenching study. Fluorescence anisotropy parameter has been monitored for exploring the imposed motional restriction of the microenvironment around the probe. Contrasting behavior of the drug molecule has been observed in two different types of micelles. Based on the experimental and theoretical studies, an attempt has been made to explain the different behavior of the probe in different media. PMID- 22446759 TI - Spectroscopic, colorimetric and theoretical investigation of salicylidene hydrazine based reduced Schiff base and its application towards biologically important anions. AB - A reduced Schiff base anionic receptor 1 [N,N'-bis-(2-hydroxy-5-nitro benzyl)hydrazine] has been synthesized, characterized and reported as a selective chromogenic receptor for fluoride, acetate and phosphate anions over the other tested anions such as chloride, bromide, iodide and hydrogensulphite. Colorimetric naked-eye detection and UV-vis absorption spectroscopic techniques were used to distinguish the recognition behaviours towards various anions. The receptor-anion complexation mainly occurs via hydrogen bonding interactions which facile to generate the charge transfer band in the UV-vis spectra and cause large bathochromic shift as well as naked-eye colour change. Complexation stoichiometry, binding constant and free energy change due to complex formation were determined from Benesi-Hildebrand plot. The binding constant and the free energy change values are well interactive for spontaneous complexation. The experimental results have been correlated with the theoretical calculations using B3LYP hybrid functional and 6-311++G(d,p) basis set for both the receptor and complex by Density Functional Theory (DFT) method. PMID- 22446760 TI - Vibrational spectroscopic studies, molecular orbital calculations and chemical reactivity of 6-nitro-m-toluic acid. AB - The potential energy surface scan for the selected dihedral angle of 6-nitro-m toluic acid (NTA) has been performed to identify stable conformer. The optimized structure parameters and vibrational wavenumbers of stable conformer have been predicted by density functional B3LYP method with 6-311++G(d,p) basis set. The formation of dimer species through carboxylic acid group of the title molecule has also been discussed. The theoretical dimer geometries have been compared with that of monomer and the variations of bond lengths and bond angles upon dimerization were also discussed. Natural bond orbital (NBO) analysis has been performed on both monomer and dimer geometries. The significant changes in occupancies and the energies of bonding and anti-bonding orbitals upon dimerization have been explained in detail. The predicted frontier molecular orbital energies at B3LYP/6-311++G(d,p) method set show that charge transfer occurs within the molecule. The nucleophilic and electrophilic sites obtained from the molecular electrostatic potential (MEP) surface were compared with their derived fitting point charges. The vibrational wavenumbers of NTA affected profusely by the nitro group substitution in comparison to the toluic acid have been interpreted in this work. PMID- 22446761 TI - Spectrophotometric studies of visible light induced photocatalytic degradation of methyl orange using phthalocyanine-modified Fe-doped TiO2 nanocrystals. AB - In this paper, preparation and visible light induced photocatalytic activity of phthalocyanine-modified Fe-doped TiO(2) nanocrystals (Pc/Fe-TiO(2)) with different Fe doping content (0, 0.05, 0.5 and 3.0 mol% Fe) as photocatalysts for the degradation of methyl orange have been reported. The study carried out using XRD, FT-IR, EDX, BET, DRS, UV-Vis, SEM and TEM techniques. Results revealed that modified TiO(2) nanocrystals possessed only the anatase phase with crystal sizes of about 10-23 nm and high surface areas of 2.8-37.3 m(2)/g. It can be seen phthalocyanine and Fe(3+) ion exist in photocatalysts based on analysis of FT-IR and EDX. The doping amount of Fe remarkably affects the activity of modified TiO(2) nanocrystals as catalysts. The 0.5 mol% Fe doping exhibited enhanced photocatalytic activity in this work. It was found that phthalocyanine and Fe induced a shift in the energy band gap to lower energies, which changes from 3.26 to 2.26 eV for pure TiO(2) and Pc/3% Fe-TiO(2) nanocrystals, respectively. Results of the degradation of methyl orange revealed that modified TiO(2) nanocrystals showed much more photocatalytic activity than pure TiO(2) under visible light which makes the applicability of TiO(2) photocatalysts even more versatile. PMID- 22446762 TI - Quantum mechanical study and spectroscopic (FT-IR, FT-Raman, 13C, 1H, UV) study, first order hyperpolarizability, NBO analysis, HOMO and LUMO analysis of 4-[(4 aminobenzene) sulfonyl] aniline by ab initio HF and density functional method. AB - The Fourier transform infrared (FT-IR) and FT-Raman of 4-[(4-aminobenzene) sulfonyl] aniline have been recorded and analyzed. The equilibrium geometry, harmonic vibrational frequencies have been investigated with the help of HF and DFT methods with 6-31G(d,p) as basis set. A detailed interpretation of the vibrational spectra of this compound has been made on the basis of the calculated potential energy distribution (PED). The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by GIAO method. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The linear polarizability (alpha) and the first order hyperpolarizability (beta) values of the investigated molecule have been computed using DFT quantum mechanical calculations. UV-vis spectrum of the compound was recorded and electronic properties, such as HOMO and LUMO energies were also performed. Finally the calculations results were applied to simulated infrared and Raman spectra of the title compound which show good agreement with observed spectra. PMID- 22446763 TI - Nickel(II)-Schiff base complex recognizing domain II of bovine and human serum albumin: spectroscopic and docking studies. AB - It has been spectroscopically monitored that a mononuclear nickel(II)-Schiff base complex {[NiL].CH(3)OH=NSC} exhibits greater binding affinity for bovine serum albumin (BSA) than that of its human counterpart (HSA). Moreover the modes of binding of NSC with the two serum albumins also differ significantly. Docking studies predict a relatively rare type of 'superficial binding' of NSC at domain IIB of HSA with certain mobility whereas for BSA such phenomena has not been detected. The mobile nature of NSC at domain IIB of HSA has been well correlated with the spectroscopic results. It is to be noted that thermodynamic parameters for the NSC interaction also differ for the two serum albumins. Occurrence of energy transfer between the donor (Trp of BSA and HSA) and acceptor (NSC) has been obtained by means of Forster resonance energy transfer (FRET). The protein stability on NSC binding has also been experimented by the GuHCl-induced protein unfolding studies. Interestingly it has been found that NSC-HSA interaction enhances the protein stability whereas NSC-BSA binding has no such impact. Such observations are indicative of the fact that the conformation of NSC is responsible in recognizing the two serum albumins and selectively enhancing protein stability. PMID- 22446764 TI - Studies on DNA binding behaviour of biologically active transition metal complexes of new tetradentate N2O2 donor Schiff bases: inhibitory activity against bacteria. AB - A series of Cu(II), Ni(II) and Zn(II) complexes of the type ML have been synthesized with Schiff bases derived from o-acetoacetotoluidide, 2 hydroxybenzaldehyde and o-phenylenediamine/1,4-diaminobutane. The complexes are insoluble in common organic solvents but soluble in DMF and DMSO. The measured molar conductance values in DMSO indicate that the complexes are non-electrolytic in nature. All the six metal complexes have been fully characterized with the help of elemental analyses, molecular weights, molar conductance values, magnetic moments and spectroscopic data. The analytical data helped to elucidate the structure of the metal complexes. The Schiff bases are found to act as tetradentate ligands using N(2)O(2) donor set of atoms leading to a square-planar geometry for the complexes around all the metal ions. The binding properties of metal complexes with DNA were investigated by absorption spectra, viscosity measurements and cyclic voltammetry. Detailed analysis reveals that the metal complexes intercalate into the DNA base stack as intercalators. All the metal complexes cleave the pUC19 DNA in presence of H(2)O(2.) The Schiff bases and their complexes have been screened for their antibacterial activity against five bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae) by disk diffusion method. All the metal complexes have potent biocidal activity than the free ligands. PMID- 22446765 TI - Study on the interaction of silver(I) complex with bovine serum albumin by spectroscopic techniques. AB - The interaction of silver(I) complex, [Ag (2,9-dimethyl-1,10 phenanthroline)(2)](NO(3)).H(2)O, and bovine serum albumin (BSA) was investigated by spectrophotometry, spectrofluorimetry and circular dichroism (CD) techniques. The experimental results indicated that the quenching mechanism of BSA by the complex was a static procedure. Various binding parameters were evaluated. The negative value of DeltaH, negative value of DeltaS and the negative value of DeltaG indicated that van der Waals force and hydrogen bonding play major roles in the binding of the complex and BSA. Based on Forster's theory of non-radiation energy transfer, the binding distance, r, between the donor (BSA) and acceptor (Ag(I) complex) was evaluated. The results of CD and UV-vis spectroscopy showed that the binding of this complex could bind to BSA and be effectively transported and eliminated in the body. PMID- 22446766 TI - Ultrasound-assisted cloud point extraction for speciation and indirect spectrophotometric determination of chromium(III) and (VI) in water samples. AB - Ultrasound-assisted cloud point extraction (UACPE) procedure was developed for speciation and indirect spectrophotometric determination of chromium(III) and (VI) in environmental water samples. The method is based on the reduction of Cr(VI) by iodide in acidic media and subsequently formation of I(3)(-) anion. The I(3)(-) formed can further react with cetyltrimethylammonium bromide (CTAB) and induce its clouding due to formation of an ion-association complex. The formed complex was separated from solution and dissolved in ethanol for spectrophotometric measurement. Cerium(IV) ammonium sulphate was chosen as an oxidizing reagent for pre-oxidation step of Cr(III) to Cr(VI) species before the addition of iodide to the system, up to chromium in trivalent can be determined by the procedure. Experimental parameters for both spectrophotometric reaction and extraction procedure have been optimized. Under optimized conditions Cr(VI) can be determined in the range 20-400 ng mL(-1) (R(2)=0.999). Detection limit, preconcentration factor and relative standard deviation were 12 ng mL(-1), 20.0 and 2.2% (n=5), respectively with 10 mL sample volumes. The proposed method has been successfully applied for determination of chromium(V) in spiked water, synthetic seawater and electroplating wastewater samples with average recoveries of 100.1, 99.4 and 99.1%, respectively. PMID- 22446767 TI - Spectroscopic investigation on formation and growth of mineralized nanohydroxyapatite for bone tissue engineering applications. AB - Synthetic calcium hydroxyapatite (HAP,Ca(10)(PO(4))(6)(OH)(2)) is a well-known bioceramic material used in orthopaedic and dental applications because of its excellent biocompatibility and bone-bonding ability. Substitution of trace elements, such as Sr, Mg and Zn ions into the structure of calcium phosphates is the subject of widespread investigation. In this paper, we have reported the synthesis of Sr, Mg and Zn co-substituted nanohydroxyapatite by soft solution freezing method. The effect of pH on the morphology of bioceramic nanomaterial was also discussed. The in vitro bioactivity of the as-synthesized bioceramic nanomaterial was determined by soaking it in SBF for various days. The as synthesized bioceramic nanomaterial was characterized by Fourier transform infrared spectroscopy, X- ray diffraction analysis, Scanning electron microscopy and Energy dispersive X-ray analysis and Transmission electron microscopic techniques respectively. The results obtained in our study have revealed that pH 10 was identified to induce the formation of mineralized nanohydroxyapatite. It is observed that the synthesis of bioceramic nanomaterial not only support the growth of apatite layer on its surface but also accelerate the growth which is evident from the in vitro studies. Therefore, mineralized nanohydroxyapatite is a potential candidate in bone tissue engineering. PMID- 22446768 TI - Phenol-photodegradation on ZrO2. Enhancement by semiconductors. AB - On illumination with light of wavelength 365 nm phenol undergoes degradation on the surface of ZrO(2). The rate of degradation enhances linearly with the concentration of phenol and also the light intensity but decreases with increase of pH. The photonic efficiency of degradation is higher with illumination at 254 nm than with 365 nm. The diffuse reflectance spectral study suggests phenol sensitized activation of ZrO(2) with 365 nm light. TiO(2), Fe(2)O(3), CuO, ZnO, ZnS, Nb(2)O(5) and CdO particles enhance the photodegradation on ZrO(2), indicating inter-particle charge-transfer. Determination of size of the particles under suspension, by light scattering technique, shows agglomeration of particles supporting the proposition of charge-transfer between particles. PMID- 22446769 TI - Growth, crystalline perfection and characterization of benzophenone oxime crystal. AB - Single crystals of benzophenone oxime (BPO) have been grown by slow evaporation solution growth technique from ethanol at room temperature. The single crystal X ray diffraction study reveals that the crystal belongs to monoclinic system and cell parameters are, a=9.459 A, b=8.383 A, c=26.690 A, v=2115 A(3) and beta=92.807 degrees . The structure and the crystallinity of the materials were further confirmed by powder X-ray diffraction analysis. The various functional groups present in the molecule are confirmed by FT-IR analysis. The TG/DSC studies reveal the purity of the material and the crystals are transparent in the entire visible region having a lower optical cut-off at ~300 nm. The crystalline perfection was evaluated by high-resolution X-ray diffraction (HRXRD). The crystal is further characterized by Kurtz powder technique, dielectric studies and microhardness analysis. PMID- 22446770 TI - Spectrophotometric, Fourier transform infrared spectroscopic and theoretical studies of the charge-transfer complexes between methyldopa [(S)-2 amino-3-(3,4 dihydroxyphenyl)-2-methyl propanoic acid] and the acceptors (chloranilic acid, o chloranil and dichlorodicyanobenzoquinone) in acetonitrile and their thermodynamic properties. AB - Methyldopa is a much used antihypertensive drug. It is the subject matter of study mostly for the determination and estimation of methyldopa in pharmaceutical properties. These considerations led us to study the charge-transfer interactions between methyldopa, a centrally acting antihypertensive agent of limited use with the known acceptors like o-chloranil (o-ClN), chloranilic acid (ClA) and dichlorodicyanobenzoquinone (DDQ). Methyldopa (MDP) formed beautifully colored complexes (having absorption maxima at 581 nm and 368 nm; 519 nm; 583.5 nm, 547 nm and 346 nm, respectively) with the acceptors mentioned before. The physico chemical properties of the complexes were studied using UV-visible spectrophotometry and FTIR measurements. The composition, the accurate association constants and thermodynamics of the complexes were determined spectrophotometrically. Attempts were made to interpret the thermodynamics of complexes in terms of I(D)(V), E(A)(V) and hnu(CT). Solid CT complexes between MDP+o-ClN, MDP+ClA and MDP+DDQ were prepared and FTIR spectra of the complexes were studied. The energies hnu(CT) of the charge-transfer complexes and vertical ionization potential I(D)(V) of methyldopa were compared with the theoretical values of hnu(CT) obtained from HOMO and LUMO of the donors and acceptors calculated using Density Function Theory utilizing different basis sets. The agreement between the results can be regarded to be reasonable. Oscillator strengths and dipole strengths of the complexes were determined theoretically and experimentally and the limitations of the calculations were outlined. PMID- 22446771 TI - Relationship of carbohydrate molecular spectroscopic features in combined feeds to carbohydrate utilization and availability in ruminants. AB - To date, there is no study on the relationship between carbohydrate (CHO) molecular structures and nutrient availability of combined feeds in ruminants. The objective of this study was to use molecular spectroscopy to reveal the relationship between CHO molecular spectral profiles (in terms of functional groups (biomolecular, biopolymer) spectral peak area and height intensity) and CHO chemical profiles, CHO subfractions, energy values, and CHO rumen degradation kinetics of combined feeds of hulless barley with pure wheat dried distillers grains with solubles (DDGS) at five different combination ratios (hulless barley to pure wheat DDGS: 100:0, 75:25, 50:50, 25:75, 0:100). The molecular spectroscopic parameters assessed included: lignin biopolymer molecular spectra profile (peak area and height, region and baseline: ca. 1539-1504 cm(-1)); structural carbohydrate (STCHO, peaks area region and baseline: ca. 1485-1186 cm( 1)) mainly associated with hemi- and cellulosic compounds; cellulosic materials peak area (centered at ca. 1240 cm(-1) with region and baseline: ca. 1272-1186 cm(-1)); total carbohydrate (CHO, peaks area region and baseline: ca. 1186-946 cm(-1)). The results showed that the functional groups (biomolecular, biopolymer) in the combined feeds are sensitive to the changes of carbohydrate chemical and nutrient profiles. The changes of the CHO molecular spectroscopic features in the combined feeds were highly correlated with CHO chemical profiles, CHO subfractions, in situ CHO rumen degradation kinetics and fermentable organic matter supply. Further study is needed to investigate possibility of using CHO molecular spectral features as a predictor to estimate nutrient availability in combined feeds for animals and quantify their relationship. PMID- 22446772 TI - SERS spectroscopy of kaempferol and galangin under the interaction of human serum albumin with adsorbed silver nanoparticles. AB - Raman and surface-enhanced Raman scattering (SERS) spectroscopy were employed to probe the interaction of the flavonol drugs, kaempferol and galangin, with human serum albumin (HSA). SERS spectra of both flavonol derivatives were obtained from a colloidal silver surface in physiological condition, based on the high performance of the enhanced substrate, the most enhanced modes of kaempferol and galangin were those with certain motions perpendicular to the metal surface. The SERS spectra were allowed to predict similar orientation geometry for both of the drugs on the colloidal surface with minor difference. In addition, both flavonols HSA complexes were prepared in different concentration ratios and the orientated differences between kaempferol and galangin were investigated by SERS. PMID- 22446773 TI - Spectroscopic and kinetic studies on the degradation of methylene blue using the supramolecular coordination polymer [(Ph3Sn)4FeCN(6)] as catalyst. AB - The structure of the supramolecular coordination polymer (SCP), [(Ph(3)Sn)(4)Fe(CN)(6)], 1, consists of octahedral [Fe(CN)(6)](4-) building blocks which are connected by the TBPY-5 configured Ph(3)Sn(CN...)(2) fragments creating 3D-network structure that contains terminal cyanide groups. The catalytic behavior of the SCP 1 was utilized for Fenton and photo-Fenton degradation of methylene blue dye (MB). The plot of kinetic degradation indicates pseudo first-order rate with respect to the MB dye concentration, K(obs.)=0.071 min(-1). On the other hand, the observed rate constant of the photo catalytic degradation of MB equals to 1.45 min(-1) indicating that irradiation enhances, significantly, the rate of degradation of MB dye. Discoloration of the dye was obtained in less than 3h. Meanwhile, the conjugated structure and the phenyl rings of the MB molecule were destroyed or even broken down into small organic acids and inorganic ions, as indicated by FT-IR spectra. Disodium salt of terephthalic acid photoluminescence probing technology and radical scavenging measurements were carried out to identify the reactive oxygen species. The different parameters that affect MB degradation rate were evaluated. Moreover, the efficiency of recycled the SCP 1 and the mechanism of degradation of MB dye was investigated. PMID- 22446774 TI - Study of neutron irradiation on CoS nanoparticles grown on AlMCM-41 matrix. AB - In this research, cobalt sulfide nanoparticles (NPs) were grown on AlMCM-41 matrix by using ion exchange method. The prepared sample was irradiated by thermalized neutron that emitted from Am-Be source. After that, X-ray diffraction (XRD), UV-vis spectroscopy, Fourier transform infrared (FTIR), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used for irradiated and non-irradiated samples characterization. The results show the increase of nanoparticles size and aggregation under neutron irradiation. The TEM images show average size of CoS NPs before and after neutron radiation about 20 and 50 nm, respectively. The XRD patterns show that nanoparticles size is increased after neutron radiation. The DRS results show that Co(2+) ions produced after neutron radiation, located in tetrahedral sites in AlMCM-41. The results indicate host materials have important role in decrease of radiation defects (RDs). PMID- 22446775 TI - Micro-Raman, FTIR, SEM-EDX and structural analysis of the Canakkale meteorite. AB - This study demonstrates for the first time, the spectroscopic characterization of Canakkale Meteorite that fell at Canakkale, Republic of Turkey (40 degrees 8'44"N; 26 degrees 24'23"E). The olivine group [(Mg, Fe)(2)SiO(4)], enstatite [Mg(2)Si(2)O(6)] (one of the orthopyroxene minerals) and plagioclase were identified by the micro-Raman and FTIR spectroscopies and EDX-SEM analyses. This meteorite has not yet been classified in the World's Database of Meteorites. The aim of this study is to investigate this meteorite by vibrational spectroscopic techniques and open the possibility to classify it and list in the World's Database of Meteorites. PMID- 22446776 TI - Chemical speciation and equilibria of some nucleic acid compounds and their iron(III) complexes. AB - The pH effect on electronic absorption spectra of some biologically active nucleic acid constituents have been studied at room temperature and the mechanism of ionization was explained. These compounds are of two categories (pyrimidines: [barbital; 5,5'-diethyl-barbituric acid], [SBA; 4,6-dihydroxy-2-mercapto pyrimidin], [NBA; 5-nitro-2,4,6(1H,3H,5H)-pyrimidine trione] and [TU; 2,3-dihydro 2-thioxo-pyrimidin-4(1H)-one]) and (purines: [adenine; 6-amino purine], its [Schiff bases derived from adenine-acetylacetone; (Z)-4-(7H-purin-6 ylimino)pentan-2-one) and adenine-salicylaldehyde; 2-((7H-purin-6-ylimino) methyl) phenol] and its [Azo derived from adenine-resorcinol; 4-((7H-purin-6-yl) diazenyl) benzene-1,3-diol]. The phenomena of tautomerization assigned different tautomers. Different spectrophotometric methods are applied to evaluate the pK's values that explained with their molecular structures. The interaction of Fe(3+) with some selected pyrimidines (barbital, NBA and SBA) was explained using familiar six spectrophotometric methods. The data typified the existence of different absorbing species with the different stoichiometries 1:1, 1:2, 1:3 and 2:3. The stability constant of the complexes was computed. More approach was deduced to assign the existence of different species applying the distribution diagrams. PMID- 22446777 TI - Biophysical influence of isocarbophos on bovine serum albumin: spectroscopic probing. AB - Isocarbophos (ICP) is a phosphorous pesticide with high toxicity. It has been detected in several kinds of food and therefore can enter human body. In this paper, spectroscopic approaches including three-dimensional fluorescence (3D-FL) spectroscopy, UV-visible absorption spectroscopy and circular dichroism (CD) spectroscopy were employed to explore the binding of ICP to bovine serum albumin (BSA) at simulated physiological conditions. It was found that the fluorescence quenching of BSA was caused by the formation of ICP-BSA complex at ground state and belonged to static quenching mechanism. The binding constants, the number of binding sites, enthalpy change (DeltaH(theta)), Gibbs free energy change (DeltaG(theta)) and entropy change (DeltaS(theta)) were calculated at four different temperatures according to Scatchard model and thermodynamic equations. To identify the binding location, fluorescence probe techniques were used. The results showed that warfarin, an acknowledged site marker for BSA, could be partially replaced by ICP when ICP was added to warfarin-BSA systems, which demonstrated that ICP primarily bound on Sudlow's site I in domain IIA of BSA molecule. The distance r (3.06 nm) between donor (Trp-212) and acceptor (ICP) was obtained based on Forster's non-radiation fluorescence resonance energy transfer (FRET) theory. Furthermore, the CD spectral results indicated that the secondary structure of BSA was changed in presence of ICP. The study is helpful to evaluating the toxicology of ICP and understanding its effects on the function of protein during the blood transportation process. PMID- 22446778 TI - Growth, crystalline perfection and characterization of hexaaquanickel(II) dipotassium tetrahydrogen tetra-o-phthalate tetrahydrate crystals. AB - Pale-green single crystals of hexaaquanickel(II) dipotassium tetrahydrogen tetra o-phthalate tetrahydrate K(2)[Ni(H(2)O)(6)] (C(8)H(5)O(4))(4).4H(2)O (PNHP), of dimension ~33 mm * 18 mm * 4 mm have been grown by slow evaporation solution growth technique (SEST) and modified Sankaranarayanan-Ramasamy (SR) method. The powder XRD profiles and FT-IR are used for identifying the material. The lattice parameters of the as-grown crystals obtained by single crystal X-ray diffraction analysis confirm the formulae. Lower optical cut-off at ~300 nm and optical transparency in the visible region were observed. The structural perfection of the grown crystal has been analyzed for SEST and SR method grown crystals by high resolution X-ray diffraction (HRXRD) rocking curves (DC). The DCs of both the specimens are asymmetric with respect to Bragg position and more of scattered intensity in the negative direction is indicative of predominantly vacancy defects. Interestingly, SR method grown crystal has a better crystalline perfection than the conventionally grown crystal. The dielectric, thermal and mechanical behaviors of the specimen were also studied. PMID- 22446779 TI - Molecular structure, heteronuclear resonance assisted hydrogen bond analysis, chemical reactivity and first hyperpolarizability of a novel ethyl-4-{[(2,4 dinitrophenyl)-hydrazono]-ethyl}-3,5-dimethyl-1H-pyrrole-2-carboxylate: a combined DFT and AIM approach. AB - A new ethyl-4-{[(2,4-dinitrophenyl)-hydrazono]-ethyl}-3,5-dimethyl-1H-pyrrole-2 carboxylate (EDPHEDPC) has been synthesized and characterized by FT-IR, (1)H NMR, UV-vis, DART-Mass spectroscopy and elemental analysis. Quantum chemical calculations have been performed by DFT level of theory using B3LYP functional and 6-31G(d,p) as basis set. The (1)H NMR chemical shifts are calculated using gauge including atomic orbitals (GIAO) approach in DMSO as solvent. The time dependent density functional theory (TD-DFT) is used to find the various electronic transitions and their nature within molecule. A combined theoretical and experimental wavenumber analysis confirms the existence of dimer. Topological parameters such as electron density (rho(BCP)), Laplacian of electron density (nabla(2)rho(BCP)), kinetic electron energy density (G(BCP)), potential electron density (V(BCP)) and the total electron energy density (H(BCP)) at bond critical points (BCP) have been analyzed by Bader's 'Atoms in molecules' AIM theory in detail. The intermolecular hydrogen bond energy of dimer is calculated as -12.51 kcal/mol using AIM calculations. AIM ellipticity analysis is carried out to confirm the presence of resonance assisted intra and intermolecular hydrogen bonds in dimer. The calculated thermodynamic parameters show that reaction is exothermic and non-spontaneous at room temperature. The local reactivity descriptors such as Fukui functions (f(k)(+), f(k)(-)), local softnesses (s(k)( ), s(k)(+)) and electrophilicity indices (omega(k)(+), omega(k)(-)) analyses are performed to determine the reactive sites within molecule. Nonlinear optical (NLO) behavior of title compound is investigated by the computed value of first hyperpolarizability (beta(0)). PMID- 22446780 TI - A comparative study on vibrational, conformational and electronic structure of 2 chloro-4-methyl-3-nitropyridine and 2-chloro-6-methylpyridine. AB - Experimental FTIR and FT-Raman spectroscopic analysis of 2-chloro-4-methyl-3 nitropyridine (2C4M3NP) and 2-chloro-6-methylpyridine (2C6MP) have been performed. A detailed quantum chemical calculations have been carried out using B3LYP and B3PW91 methods with 6-311++G** and cc-pVTZ basis sets. Conformation analysis was carried for 2C4M3NP and 2C6MP. The temperature dependence of thermodynamic properties has been analysed. The atomic charges, electronic exchange interaction and charge delocalisation of the molecule have been performed by natural bond orbital (NBO) analysis. Molecular electrostatic surface potential (MESP), total electron density distribution and frontier molecular orbitals (FMOs) are constructed at B3LYP/6-311++G** level to understand the electronic properties. The charge density distribution and site of chemical reactivity of the molecules have been obtained by mapping electron density isosurface with electrostatic potential surfaces (ESP). The electronic properties, HOMO and LUMO energies were measured by time-dependent TD-DFT approach. PMID- 22446781 TI - Quantification of creatinine in biological samples based on the pseudoenzyme activity of copper-creatinine complex. AB - Glomerular filtration rate (GFR), the marker of chronic kidney disease can be analyzed by the concentration of cystatin C or creatinine and its clearance in human urine and serum samples. The determination of cystatin C alone as an indicator of GFR does not provide high accuracy, and is more expensive, thus measurement of creatinine has an important role in estimating GFR. We have made an attempt to quantify creatinine based on its pseudoenzyme activity of creatinine in the presence of copper. Creatinine in the presence of copper oxidizes paraphenylenediamine dihydrochloride (PPDD) which couples with dimethylamino benzoicacid (DMAB) giving green colored chromogenic product with maximum absorbance at 710 nm. Kinetic parameters relating this reaction were evaluated. Analytical curves of creatinine by fixed time and rate methods were linear at 8.8-530 MUmol L(-1) and 0.221-2.65 mmol L(-1), respectively. Recovery of creatinine varied from 97.8 to 107.8%. Limit of detection and limit of quantification were 2.55 and 8.52 MUmol L(-1) respectively whereas Sandell's sensitivity and molar absorption coefficient values were 0.0407 MUg cm(-2) and 0.1427*10(4) L mol(-1) cm(-1) respectively. Precision studies showed that within day imprecision was 0.745-1.26% and day-to-day imprecision was 1.55-3.65%. The proposed method was applied to human urine and serum samples and results were validated in accordance with modified Jaffe's procedure. Wide linearity ranges with good recovery, less tolerance from excipients and application of the method to serum and urine samples are the claims which ascertain much advantage to this method. PMID- 22446782 TI - Quantum mechanical study of the structure and spectroscopic (FT-IR, FT-Raman, 13C, 1H and UV), NBO and HOMO-LUMO analysis of 2-quinoxaline carboxylic acid. AB - The FTIR and FT-Raman spectra of 2-quinoxaline carboxylic acid (2-QCA) has been recorded in the region 4000-450 and 4000-100 cm(-1), respectively. The conformational analysis, optimized geometry, frequency and intensity of the vibrational bands of 2-QCA were obtained by the density functional theory (DFT) with complete relaxation in the potential energy surface using 6-31G(d) basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. The (1)H and(13)C NMR spectra have been recorded and (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method and their respective linear correlations were obtained. The theoretical UV-visible spectrum of the compound using CIS method and the electronic properties, such as HOMO and LUMO energies, were performed by time-dependent DFT (TD-DFT) approach. The calculated HOMO and LUMO energies show that charge transfer occurs within molecule. The Mulliken charges, the values of electric dipole moment (MU) of the molecule were computed using DFT calculations. The change in electron density (ED) in the sigma* antibonding orbitals and stabilization energies E(2) have been calculated by natural bond (NBO) analysis to give clear evidence of stabilization originating in the hyper conjugation of hydrogen-bonded interactions. PMID- 22446783 TI - Spectral, thermal and biological studies of Mn(II) and Cu(II) complexes with two thiosemicarbazide derivatives. AB - Two derivatives of thiosemicarbazide were prepared. Their complexes were prepared using Mn(II) and Cu(II) salts. All the isolated complexes are characterized using the following spectra: IR, UV-Vis, Mass, (1)H NMR and X-ray diffraction. Magnetic measurements and thermal analysis are the other additive tools for complete investigation. Mononuclear and binuclear complexes are proposed based on elemental analysis mainly. The IR spectra offer the mode of coordination of each ligand with each metal ion. The electronic spectra and magnetic measurements are proposing the structural geometry of the investigated complexes. The octahedral geometry proposed for Mn(II) complexes but the square-planar for Cu(II) complexes. The (1)H NMR spectra were done for all organic compounds used in this study and displaying the most suitable tautomer of them. X-ray diffraction of H(2)L(1) and its complexes show their amorphous nature but H(2)L(2) ligand and its complexes show their nanocrystalline nature. The TG analysis was used to prove the presence of solvent molecules attached with the complexes as covalently or physically. Finally, the biological investigation was carried out for H(2)L(2) ligand and its complexes and displaying the inhibition activity of Cu(II) complex than the Mn(II) one. PMID- 22446784 TI - Synthesis, characterization and thermal studies of binary and/or mixed ligand complexes of Cd(II), Cu(II), Ni(II) and Co(III) based on 2-(Hydroxybenzylidene) thiosemicarbazone: DNA binding affinity of binary Cu(II) complex. AB - A new series of metal complexes of Cd(II), Cu(II), Ni(II) and Co(III) with Schiff base ligand, H(2)L, 2-(Hydroxybenzylidene) thiosemicarbazone were synthesized. The mixed ligand complexes were prepared by using glycine (Gly), 2-aminopyridine (2-Ampy) and 1,10-phenanthroline (Phen) as secondary ligands. The structure of these complexes was identified and confirmed by elemental analysis, molar conductivity, UV-Vis, FT-IR and (1)H NMR spectroscopy and magnetic moment measurements as well as TG-DSC technique. The discussions of the prepared complexes indicate that the ligand behaves as a monoanionic tridentate ligand through ONS donor sites. Thermal studies suggested a mechanism for the degradation of the metal complexes as a function of temperature supporting the chelation modes and showed the possibility of obtaining new complexes pyrolytically in the solid state which cannot be synthesized from the solution. The absorption studies support that the binary Cu(II) complex exhibits a significant binding affinity to HS-DNA through intercalative mode. PMID- 22446785 TI - Synthesis, spectroscopic characterizations and quantum chemical computational studies of (Z)-4-[(E)-p-tolyldiazenyl]-6-[(2-hydroxyphenylamino)methylene]-2 methoxycyclohexa-2,4-dienone. AB - In this study, the molecular structure and spectroscopic properties of title compound were characterized by X-ray diffraction, FT-IR and UV-vis spectroscopies. These properties of title compound were also investigated from calculative point of view. The X-ray diffraction and FT-IR analyses reveal the existence of keto form in the solid state. UV-vis spectra were recorded in different organic solvents. The results show that title compound exists in both keto and enol forms in DMSO, EtOH but it exists in enol form in benzene. In addition, the title compound in DMSO showed new absorption band at 436 nm due to the high ionizing effect of this solvent. The geometry optimization of title compound in gas phase was performed using DFT method with B3LYP applying 6 311G(d,p) basis set. TD-DFT calculations starting from optimized geometry were carried out in gas phase to calculate excitation energies of title compound. The non-linear optical properties were computed with the same level of theory and title compound showed a good second order nonlinear optical property. In addition, thermodynamic properties were obtained in the range of 100-500 K. PMID- 22446786 TI - The spectroscopic (FT-IR, FT-Raman, UV) and first order hyperpolarizability, HOMO and LUMO analysis of 3-aminobenzophenone by density functional method. AB - In this work, experimental and theoretical study on the molecular structure and the vibrational spectra of 3-aminobenzophenone (3-ABP) is presented. The vibrational frequencies of the title compound were obtained theoretically by DFT/B3LYP calculations employing the standard 6-311++G(d,p) basis set for optimized geometry and were compared with Fourier transform infrared spectrum (FTIR) in the region of 400-4000 cm(-1) and with Fourier Transform Raman spectrum in the region of 50-4000 cm(-1). Complete vibrational assignments, analysis and correlation of the fundamental modes for the title compound were carried out. The vibrational harmonic frequencies were scaled using scale factor, yielding a good agreement between the experimentally recorded and the theoretically calculated values. PMID- 22446787 TI - Is the mineral borickyite (Ca,Mg)(Fe3+,Al)4(PO4,SO4,CO3)(OH)(8).3-7.5H2O the same as delvauxite CaFe4(3+)(PO4,SO4)2(OH)(8).4-6H2O? AB - The two minerals borickyite and delvauxite CaFe(4)(3+)(PO(4),SO(4))(2)(OH)(8).4 6H(2)O have the same formula. Are the minerals identical or different? The minerals borickyite and delvauxite have been characterised by Raman spectroscopy. The minerals are related to the minerals diadochite and destinezite. Both minerals are amorphous. Delvauxite appears to vary in crystallinity from amorphous to semi-crystalline. The minerals are often X-ray non-diffracting. The minerals are found in soils and may be described as 'colloidal' minerals. Vibrational spectroscopy enables an assessment of the molecular structure of borickyite and delvauxite. Bands are assigned to phosphate and sulphate stretching and bending modes. Multiple water bending and stretching modes imply that non-equivalent water molecules in the structure exist with different hydrogen bond strengths. The two minerals show differing spectra and must be considered as different minerals. PMID- 22446788 TI - Forster resonance energy transfer between pyrene and bovine serum albumin: effect of the hydrophobic pockets of cyclodextrins. AB - The phenomenon of Forster resonance energy transfer (FRET) between pyrene and bovine serum albumin (BSA) protein in presence of cyclodextrins (CDs) is explored in the present work. CDs provide hydrophobic environment and thus the aromatic molecules get encapsulated in them depending on the relative size and space. In this work we revealed that along with pyrene monomer, the side chains of amino acids in BSA can get trapped partly in the hydrophobic cavities of CDs if space permits. While being encapsulated by beta-CD as pyrene monomer, it can interact with the BSA tryptophan moiety exposed toward the aqueous environment to form a dimer through pi-pi interaction. This, in turn, affects the energy transfer process by reducing the efficiency. On the other hand, pyrene excimer gets encapsulated in a gamma-CD molecule due to availability of enough space. The excimer shows a new band at a higher wavelength. This further reduces FRET efficiency due to scarcity of acceptor for the tryptophan moieties in BSA. PMID- 22446789 TI - Structural, vibrational and thermal studies of a new nonlinear optical material: L-asparagine-L-tartaric acid. AB - Crystals of a new nonlinear optical (NLO) material, viz., L-asparagine-L-tartaric acid (LALT) (1) were grown by slow evaporation of an aqueous solution containing equimolar concentrations of L-asparagine and L-tartaric acid. The structure of the title compound which crystallizes in the non-centrosymmetric monoclinic space group P2(1) consists of a molecule of L-asparagine and a molecule of free l tartaric acid both of which are interlinked by three varieties of H-bonding interactions namely O-H...O, N-H...O and C-H...O. The UV-Vis-NIR spectrum of 1 reveals its transparent nature while the vibrational spectra confirm the presence of the functional groups in 1. The thermal stability and second harmonic generation (SHG) conversion efficiency of 1 were investigated. PMID- 22446790 TI - Synthesis of Al nanoparticles: transmission electron microscopy, thermal and spectral studies. AB - Nanoparticles of Al(0) were synthesized by solution reduction process successfully. The influence of parameters on the size of Al(0) nanoparticles were studied and the referential process parameters were obtained. The morphology and structure of the synthesized Al(0) nanoparticles were characterized by Transmission Electron Microscopy (TEM), Powder X-ray Diffraction (XRD), Thermal Gravimetric Analysis (TGA), QELS Data and Infrared Spectroscopy (IR). The results show that nanoparticles of Al(0) are of high purity. XRD analysis revealed all relevant Bragg's reflection for crystal structure of Al metal. XRD spectrum also indicates there is no oxidation of Al(0) nanoparticles to aluminum oxide. TEM showed nearly uniform distribution of the particles in methanol and it was confirmed by QELS. Al(0) nanoparticles can be synthesized easily by reducing agent and are quite stable too. PMID- 22446791 TI - Multivariate statistical analysis of mid-infrared spectra for a G1 allyl terminated carbosilane dendrimer. AB - The FTIR spectra were measured for G1 allyl terminated carbosilane dendrimer over a temperature range of 25-200 degrees C to explore the temperature-dependent changes. The dendrimer spectra exhibited complicated patterns and thus were analyzed by both the exploratory principal component analysis (PCA) and two dimensional (2D) correlation spectroscopy. Boltzmann fitting and score plots of PCA evidenced the phase transition temperature to be about 172 degrees C. Frequency variables, which strongly contributed to each principal component highlighted in their loadings plot, were linked to the frequencies assigned to vibrations of the CH(2) and CH(3) groups, as well as to vibrations of the SiCH groups. 2D correlation spectroscopy discerned all the sequences of group motion of dendrimer, indicating that during the heating process a reorganization of core structure takes place, followed by a conformational rearrangement of the terminal units. PMID- 22446792 TI - Impact of aeration and agitation on metabolic heat and protease secretion of Aspergillus tamarii in a real-time biological reaction calorimeter. AB - The effects of aeration and agitation on metabolic heat, alkaline protease production and morphology for Aspergillus tamarii MTCC5152 are reported in this manuscript. Measurement of metabolic heat has been attempted by the continuous and dynamic heat balance method in a biological real-time reaction calorimeter. At lower agitation intensities, growth-related processes were dominating. As a result the protease activity and the product heat yields were lower than those for 350 and 450 rpm. Although biomass growth was necessary to obtain maximum protease yield, agitation seemed to play a vital role in the protease production process. Energy dissipation per circulation function of the process is also deduced from power input. At optimal conditions, 350 rpm and 1 vvm, the gassed power required was 0.133 W. Pellet morphology and protease production were studied under different aeration and agitation intensities of A. tamarii. Pellet structure was considerably influenced by DO, a higher DO level resulted in denser pellets (1,018.4 kg/m(3)) leading to higher protease activity. Coupling of hydrodynamics and bio-reaction highlighted the complex relationship between energy dissipation, substrate uptake rate and fungal physiology. This study emphasised the potential of biocalorimetry as a reliable monitoring and robust control tool for aerobic fermentation of A. tamarii, using agricultural by products. PMID- 22446793 TI - Carboxylesterase 2 production and characterization in human cells: new insights into enzyme oligomerization and activity. AB - Carboxylesterase 2 (CES2), the main carboxylesterase expressed in human intestine, is an increasingly important enzyme in anti-cancer combined therapies for the treatment of different pathologies like colon adenocarcinoma and malignant glioma. The production of human recombinant CES2, in human embryonic kidney cells (HEK-293T cells) using serum-free media, is herein described. CES2 secretion to the media was achieved by the simple addition of an in-frame C terminal 10* histidine tag (CES2-10xHis) without the need of addition of extra N terminal signalling sequences or the mutation or deletion of the C-terminal HTEL motif responsible for retaining the protein in the lumen of endoplasmic reticulum. This secretion allowed a fourfold increase in CES2 production. The characterization of human recombinant CES2 showed that this protein exists in other active and inactive forms than the described 60 kDa monomer. PMID- 22446794 TI - Expression of the soybean allergenic protein P34 in Escherichia coli and its indirect ELISA detection method. AB - To detect the soybean allergen P34 (Gly m Bd 30K) from soybean products, the full length cDNA sequence of P34 was synthesized and inserted into the prokaryotic expression vector pET-28a. The P34 protein was expressed in Escherichia coli BL21 (DE3) as an inclusion body under the induction of 0.8 mmol/L isopropyl beta-D-1 thiogalactopyranoside. After purification with His-Bind affinity chromatography, the purity quotient of the recombinant protein was over 92 %, and its molecular weight (approximately 33 kDa) was very close to that of the native soybean P34. The polyclonal antibody (pAB) against P34 was prepared with the purified recombinant P34. The generated pAB, named as pAB-P34, exhibited high specificity to the P34 protein of the soybean meal. The indirect enzyme-linked immunosorbent assay (iELISA) based on pAB-P34 was established to determine the P34 content of soybean products. The CVs of the recovery tests of P34 were less than 7.77 %, which indicated that iELISA had high reproducibility and accuracy. Therefore, the recombinant P34 produced in the E. coli expression system, the prepared pAB-P34, and the developed iELISA could provide a valuable tool for sensitive detection of P34 in various soybean products and for future studies on allergies related to soybean P34. PMID- 22446796 TI - The future of osteoarthritis management and care. PMID- 22446797 TI - The state of the science in the prevention and management of osteoarthritis: experts recommend ways to increase nurses' awareness and knowledge of osteoarthritis. AB - OVERVIEW: In July 2011 a symposium on osteoarthritis convened experts in many areas-nursing, epidemiology, rheumatology, public policy, geriatrics, pharmacotherapy, physical therapy, and complementary modalities-to discuss the importance of nurses in reducing the disability caused by osteoarthritis. The planning committee included representatives from AJN, the National Association of Orthopaedic Nurses, and the Hospital for Special Surgery. Symposium attendees recommended ways in which nurses could take on greater leadership roles in research, policy, education, and clinical practice for the early diagnosis and management of this prevalent condition. PMID- 22446799 TI - Osteoarthritis: the patient's experience: Kathy Geller describes her life with this chronic illness. PMID- 22446800 TI - The impact of osteoarthritis in the United States: a population-health perspective: A population-based review of the fourth most common cause of hospitalization in U.S. adults. AB - OVERVIEW: Arthritis, of which osteoarthritis (OA) is the most common type, is the most frequent cause of disability among adults in the United States. The authors reviewed the epidemiologic literature to identify studies that describe the population-based burden of OA-that is, the burden in all adults in the community. They found that 27 million adults-more than 10% of the U.S. adult population-had clinical OA in 2005, and in 2009 OA was the fourth most common cause of hospitalization. OA is the leading indication for joint replacement surgery; 905,000 knee and hip replacements were performed in 2009 at a cost of $42.3 billion. Obesity is a strong risk factor for OA of the knee and hip. Nurses can improve the quality of life of people with OA by raising awareness among their patients and peers of the substantial OA burden and the strategies, such as physical activity, that can reduce it. PMID- 22446801 TI - Making osteoarthritis a public health priority: several initiatives are placing this chronic illness on the national agenda. AB - OVERVIEW: National, state, and local policymakers and society at large are paying growing attention to osteoarthritis. This movement is fueled by organizations and coalitions that are championing important initiatives. This article spotlights several initiatives sponsored by the Arthritis Foundation and other organizations. PMID- 22446802 TI - Assessing for risk and progression of osteoarthritis: the nurse's role: understanding pathophysiology, epidemiology, and risk will aid nurses who are seeking to expand their role in management. AB - OVERVIEW: The authors review the primary and secondary risk factors for osteoarthritis (OA), its pathophysiology and epidemiology, the evidence-based approaches to slowing progression, and the role of nurses encountering OA in primary care and other settings. PMID- 22446803 TI - Rehabilitation interventions for pain and disability in osteoarthritis: a review of interventions including exercise, manual techniques, and assistive devices. AB - OVERVIEW: Osteoarthritis (OA) results in progressive destruction of articular cartilage and bone at the joint margins, leading to impairments extending far beyond the synovial joint. Rehabilitation interventions that target specific impairments and activity restrictions can help restore independence and promote healthy living. Such interventions include exercise, physical modalities (ice, heat, ultrasonography), manual techniques (mobilization and manipulation), and assistive devices. The predominance of evidence on the effects of rehabilitation interventions for knee and hip OA suggest that they afford modest pain relief, reduced disability, and improved function. Research is needed to identify the modes of exercise and the effective doses for relief of symptoms and functional limitations. PMID- 22446804 TI - Pharmacologic management of osteoarthritis-related pain in older adults: a review shows that many drug therapies provide small-to-modest pain relief. AB - OVERVIEW: Because pain is a common and debilitating symptom of osteoarthritis in older adults, the authors reviewed data on the efficacy and safety of commonly used oral, topical, and intraarticular drug therapies in this population. A search of several databases found that most studies have focused on knee osteoarthritis and reported only short-term outcomes. Also, treatment efficacy was found to vary by drug class; the smallest effect was observed with acetaminophen and the largest with opioids and viscosupplements.Acetaminophen and topical agents had the best safety profiles, whereas oral nonsteroidal antiinflammatory drugs and opioids had the worst. Little data were available on patients ages 75 years old and older and on patients from diverse racial and ethnic groups. Most drug therapies gave mild-to-moderate pain relief; their long term safety and efficacy and their effects in diverse populations (particularly older adults) remain undetermined. PMID- 22446805 TI - Complementary and alternative modalities to relieve osteoarthritis symptoms: a review of the evidence on several therapies often used for osteoarthritis management. AB - OVERVIEW: Conventional medical treatment of osteoarthritis often successfully relieves pain but can also produce adverse gastrointestinal and cardiovascular effects, especially with long-term use. Hence, many patients use complementary and alternative medicine (CAM) to prevent, control, and manage the pain of osteoarthritis. The author reviews the evidence on the efficacy and safety of several CAM therapies often used for osteoarthritis management, including mind body therapies, supplements, and body-based treatments. PMID- 22446806 TI - Panel discussion: Issues and strategies for nurses caring for adults with osteoarthritis: at the July 2011 symposium, three nurses discussed best practices and challenges. PMID- 22446807 TI - Strategies to support self-management in osteoarthritis: five categories of interventions, including education. AB - OVERVIEW: This overview of successful strategies for supporting self-management in patients with osteoarthritis (OA) defines the concepts of self-management, self-management support (SMS), and self-management education (SME); describes five categories of SMS interventions; identifies common elements across SMS categories; and provides evidence for and examples of self-management tools that are useful in OA. SMS categories include SME, other skill-building and behavior change interventions, supportive provider interactions, ongoing supportive follow up, and environmental changes. Where available, relevant OA-specific SMS strategies are used to illustrate these categories. PMID- 22446809 TI - Jeju ground water containing vanadium induced immune activation on splenocytes of low dose gamma-rays-irradiated mice. AB - Vanadium, an essential micronutrient, has been implicated in controlling diabetes and carcinogenesis and in impeding reactive oxygen species (ROS) generation. gamma-ray irradiation triggers DNA damage by inducing ROS production and causes diminution in radiosensitive immunocytes. In this study, we elucidate the immune activation capacities of Jeju water containing vanadium on immunosuppression caused by gamma-ray irradiation, and identify its mechanism using various low doses of NaVO(3). We examined the intracellular ROS generation, DNA damage, cell proliferation, population of splenocytes, and cytokine/antibody profiles in irradiated mice drinking Jeju water for 180 days and in non-irradiated and in irradiated splenocytes both of which were treated with NaVO(3). Both Jeju water and 0.245 MUM NaVO(3) attenuated the intracellular ROS generation and DNA damage in splenocytes against gamma-ray irradiation. Splenocytes were significantly proliferated by the long-term intake of Jeju water and by 0.245 MUM NaVO(3) treatment, and the expansion of B cells accounted for the increased number of splenocytes. Also, 0.245 MUM NaVO(3) treatment showed the potency to amplify the production of IFN-gamma and total IgG in irradiated splenocytes, which correlated with the expansion of B cells. Collectively, Jeju water containing vanadium possesses the immune activation property against damages caused by gamma irradiation. PMID- 22446810 TI - CTB glycoprotein (75kDa) inhibits IgE releasing, TNF-alpha and IL-6 expressed by bisphenol A in vivo and in vitro. AB - Cudrania tricuspidata Bureau (CTB) has been used to treat allergies and inflammatory disease as folk medicine in Korea. The objective of this study is to determine whether a glycoprotein isolated from CTB (75 kDa) has a preventive potential of allergic inflammation caused by bisphenol A (BPA) in BALB/c mice and RBL-2H3 cells. Production of immunoglobulin (Ig) E and releasing of beta hexosaminidase and histamine at treatment of CTB glycoprotein (5-10mg/kg, BW) were evaluated in mice serum. Activation of extracellular signal-regulated kinases (ERK) and p38 mitogen-activated protein kinase (MAPK), activator protein (AP)-1, expressions of pro-inflammatory cytokines, nitric oxide (NO) production and cyclooxygenase (COX)-2 were assessed in RBL-2H3 cells. In the results, CTB glycoprotein (10mg/kg, BW) inhibited the production of IgE and releasing of beta hexosaminidase and histamine. Also, the CTB glycoprotein (100 MUg/ml) blocked phosphorylation of ERK1/2 and p38 MAPK, and the activation of AP-1, while it inhibited the NO production, activities of COX-2, tumor necrosis factor (TNF) alpha, and interleukin (IL)-6, but not IL-1beta. Taken together, the results of this study indicated that the CTB glycoprotein modulates the expression of allergic inflammation-related factors via the suppression of MAPK/AP-1 activation. PMID- 22446811 TI - Fragrance material review on 3-methyl-2-(pentyloxy)-2-cyclopenten-1-one. AB - A toxicologic and dermatologic review of 3-methyl-2-(pentyloxy)-2-cyclopenten-1 one when used as a fragrance ingredient is presented. 3-Methyl-2-(pentyloxy)-2 cyclopenten-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-methyl-2-(pentyloxy)-2-cyclopenten-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, and photoallergy data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22446812 TI - Fragrance material review on dihydroisojasmone. AB - A toxicologic and dermatologic review of dihydroisojasmone when used as a fragrance ingredient is presented. Dihydroisojasmone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for dihydroisojasmone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, skin sensitization, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22446813 TI - Protective effect of isoorientin-2"-O-alpha-L-arabinopyranosyl isolated from Gypsophila elegans on alcohol induced hepatic fibrosis in rats. AB - Alcohol abuse is one of the major causes of liver fibrosis, which shows a sharply increasing trend worldwide, yet effective therapeutic options for advanced alcohol fibrosis are limited. Recently we investigated the effect of anti fibrosis by isoorientin-2"-O-alpha-L-arabinopyranosyl (IOA) isolated from Gypsophila elegans. During the experiment, the model group received alcohol only, and treatment groups received the corresponding drugs plus alcohol respectively, while the normal control group received an equal volume of saline. Analysis at the end of 24-week experiments showed that IOA could significantly improve the liver function, as indicated by decreasing levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyltransferase, interleukin-6 and tumor necrosis factor-alpha. Moreover, IOA could effectively inhibit collagen deposition and reduce the pathological tissue damage. Research on mechanism showed that IOA was able to markedly reduce lipid peroxidation, recruit the anti-oxidative defense system, and induce HSC apoptosis by down regulating bcl-2 mRNA, as well as inhibit the expression of alpha-smooth muscle actin and transforming growth factor beta1 proteins. In short, our results showed that IOA is effective in attenuating hepatic injury and fibrosis in the alcohol induced rat model, which should be developed as a new drug to treat liver fibrosis and even cirrhosis. PMID- 22446814 TI - Genetic toxicology evaluation of essential oil of Alpinia zerumbet and its chemoprotective effects against H(2)O(2)-induced DNA damage in cultured human leukocytes. AB - Essential oil (EO) of Alpinia zerumbet leaves, at non-toxic concentrations (50 300 MUg/mL), did not induce genotoxicity in human leukocytes. However, at the highest concentration (500 MUg/mL) tested caused a reduction in cell proliferation and viability, and an increase in DNA damage. Moreover, in vivo experiments showed that EO (400 mg/kg) did not exert mutagenicity on peripheral blood cells and bone marrow in mice. In DPPH test, EO showed scavenging effects against DPPH radicals, and other free radicals (determination of intracellular GSH and lipid peroxidation assays). Furthermore, EO was able to reduce the intracellular levels of ROS, and prevented leukocytes DNA against oxidative damage. The ability of EO to reduce H(2)O(2) toxicity was observed only when cells were treated with EO during and after exposure to H(2)O(2). With the co- and post-treatment procedures, EO decreased the frequency of apoptotic and micronucleated leukocytes as well DNA strand breaks. However, a synergistic effect was observed in cultures exposed to 500 MUg/mL EO. In conclusion, EO at concentrations up to 300 MUg/mL or doses up to 400mg/kg are not mutagenic in leukocytes and in mice, but do have antioxidative and protective effects against the cytotoxicity and clastogenesis induced by H(2)O(2). PMID- 22446815 TI - New aspects of induction chemotherapy for head and neck cancer: POSTASCO 2011. AB - Treatment options of patients with advanced head and neck cancer developed in the last years. Surgical approaches with or without radiotherapy used to be the standard therapy for a long time. Calls for organ preservation, poor overall survival and unsatisfactory quality of life made changes in this therapy regime necessary. Systemical approaches were evaluated, first concepts of platinum-based chemotherapy paired with 5-fluorouracil (PF) made up the basis of induction chemotherapy (ICT). Hypothesized advantage of this regime was improvement in local and distant tumor responsiveness with an acceptable toxicity profile. Further investigations proved the addition of docetaxel (TPF) superior to PF, which presents the gold standard of current induction chemotherapy regimes. Long term results underlining well-known aspects of this regime as well as new approaches of induction chemotherapy were published at ASCO 2011, including the addition of bioimmunotherapy to radiotherapy, adding nanoparticle-bound albumin to chemotherapy and investigations in toxicity reduction. Further investigations are still made not only to increase survival outcomes and local control but also to improve quality of life by reducing acute and late toxicities. PMID- 22446816 TI - Strategies for the optimisation of in vivo experiments in accordance with the 3Rs philosophy. AB - There are a large number of chemicals in current use for which adequate toxicity data are not available. Whilst there are clear ethical and legal obligations to obtain data from sources other than in vivo experiments wherever possible, in certain cases in vivo assays may be deemed necessary. In such circumstances, it is essential to ensure that the maximum amount of high quality data is obtained from the minimum number of animals, using the most humane procedures, in accordance with the philosophy of reduction, refinement and replacement (3Rs). The aim of this report is to provide a strategy for anyone involved in animal experimentation, for either toxicological or pharmacological purposes, as to how in vivo experiments may be optimised. The impact of generic and endpoint specific sources of variability has been highlighted in a proof-of-principle analysis considering the variation in protocols for assays for four human health endpoints (skin sensitisation, reproductive/developmental toxicity, mutagenicity and carcinogenicity). Other factors such as operator training, experimental/statistical design, use of lower species and use of combined assays are also discussed. Recommendations for optimisation of in vivo assays, in terms of the 3Rs philosophy, applied to performing tests, harvesting data and appropriate reporting are summarised as a checklist of issues to be addressed prior to undertaking such assays. PMID- 22446817 TI - The neutral analogue of Roussin's red salt anion: a density functional study. AB - Density functional calculations on the experimentally unknown neutral analogue of Roussin's red salt anion, namely Fe(2)(NO)(4)S(2), predict ground state structures with diradical character. The presence of a reactive diradical ground state with unpaired electrons for the neutral Fe(2)(NO)(4)S(2) system could explain why it has not yet been synthesized. PMID- 22446818 TI - Management of scabies. AB - Scabies is a common contagious parasitic dermatosis. Transmission of the mite Sarcoptes scabiei var hominis generally occurs by skin-to-skin contact, but with crusted scabies it may also occur through fomites, such as infected clothing or bedding. Diagnosis is usually clinical. A 2010 updated Cochrane review concluded that management of scabies is based on topical scabicides, mainly 5% permethrin. However, oral ivermectin, although not licensed in many countries, may be useful, particularly for patients who cannot tolerate or comply with topical therapy and in institutional scabies epidemics. Patients should also receive detailed information about the infestation to limit further spreading. Cases resulting from close physical or sexual contact, even without symptoms, should be systematically treated. Hygienic measures should be taken after treatment is completed. Patients should be followed to confirm cure, including resolution of itching, which may take up to 4 weeks or longer. PMID- 22446819 TI - Silk fabrics in the management of atopic dermatitis. AB - Many factors may worsen atopic dermatitis (AD) including sweating, skin infections, food, inhalant allergens, climatic conditions, stress, and chemical or physical irritants. Especially in children, clothing can be an effective barrier against flare-inducing factors and persistent scratching, allowing more rapid improvement of the eczematous lesions. On the contrary, some fabrics used for clothing may exacerbate skin conditions due to their rough fibers, such as wool and nylon. Conventional silk has smooth fibers that are generally woven for textiles in the manufacturing of clothes, but this material is not particularly useful in the management of children with AD since it reduces transpiration and may cause discomfort. Herein, we evaluate the data concerning a special silk fabric (MICROAIR DermaSilk(r)) shown to be suitable for patients with AD. The unique properties of this knitted silk allow the skin to breathe and lack irritative potential. Moreover, this fabric is treated with a water-resistant antimicrobial finish known as AEGIS AEM 5772/5. This novel knitted silk fabric appears to be useful in managing children with AD due to its non-irritating and antibacterial features. Additionally, a synthetic silk-like fabric (DermaTherapy(r)) has received US FDA clearance as a Class I medical device and is commercially available as bedding; their use by AD patients has shown interesting results. PMID- 22446820 TI - Facelift complications and the risk of venous thromboembolism: a single center's experience. AB - BACKGROUND: The number of facelifts performed in the United States has steadily increased over the past decade. Moreover, the risk of venous thromboembolism in plastic surgery has been established in recent studies. OBJECTIVES: The authors investigate the overall complication rate in a single-center series to identify risk factors and determine the risk of venous thromboembolism. METHODS: A retrospective chart review was performed for patients who underwent a facelift procedure at a private clinic in Atlanta, Georgia, between January 2004 and December 2010. A total of 630 patients were included. The data collected included patient demographics, comorbidities, body mass index, smoking history, operative time, and concurrent procedures. All postoperative complications were recorded. RESULTS: The mean age of the patients in this series was 58.4+/-7.3 years. A small percentage of the patients were men (8.1%); 23.2% had hypertension; 4.9% were smokers; and 3.5% had a history of taking prophylactic aspirin. The mean operative time was 255.6+/-81.6 minutes. Almost a quarter (23.6%) of the patients underwent concurrent procedures. There were 38 complications, including 29 hematomas, two deep vein thromboses (DVTs), two eye infections, two instances of partial skin loss, and one ectropion. Risk of complications was significantly higher in men, patients over 55, and those with a body mass index>30 kg/m2. The risk of hematoma was higher (P<.05) in men, patients over 55, those with a history of hypertension, and those taking aspirin. The risk of DVT increased when the procedure time was longer than five hours. Both patients who developed DVT had undergone a facelift in combination with another procedure. There was also an increase in the risk of complications when the facelift was combined with two or more procedures. CONCLUSIONS: Identifying various risk factors for complications, especially DVT, can help to minimize those factors in the postoperative period and treat complications effectively when they occur. The data indicate that the number of concurrent procedures is a specific risk factor for development of DVT, so care should be taken when planning for multiple treatment sites. Combining facelift with other procedures also increases the risk of complications, especially DVT. LEVEL OF EVIDENCE: 4. PMID- 22446821 TI - Construction of large signaling pathways using an adaptive perturbation approach with phosphoproteomic data. AB - Construction of large and cell-specific signaling pathways is essential to understand information processing under normal and pathological conditions. On this front, gene-based approaches offer the advantage of large pathway exploration whereas phosphoproteomic approaches offer a more reliable view of pathway activities but are applicable to small pathway sizes. In this paper, we demonstrate an experimentally adaptive approach to construct large signaling pathways from phosphoproteomic data within a 3-day time frame. Our approach- taking advantage of the fast turnaround time of the xMAP technology--is carried out in four steps: (i) screen optimal pathway inducers, (ii) select the responsive ones, (iii) combine them in a combinatorial fashion to construct a phosphoproteomic dataset, and (iv) optimize a reduced generic pathway via an Integer Linear Programming formulation. As a case study, we uncover novel players and their corresponding pathways in primary human hepatocytes by interrogating the signal transduction downstream of 81 receptors of interest and constructing a detailed model for the responsive part of the network comprising 177 species (of which 14 are measured) and 365 interactions. PMID- 22446822 TI - P-glycoprotein (P-gp) in the monogonont rotifer, Brachionus koreanus: molecular characterization and expression in response to pharmaceuticals. AB - P-glycoprotein is involved in the efflux of diverse chemicals, including hydrophobic compounds and pharmaceuticals as a first line of defense. Here, we firstly identified and characterized the P-gp (Bk-P-gp) gene in the rotifer, Brachionus koreanus. Bk-P-gp was highly conserved in genomic organization compared to the human P-gp gene. Messenger RNA expression of Bk-P-gp revealed that it would be regulated by temperature change via 14 heat shock response elements in its promoter region. Bk-P-gp showed a high similarity of motifs/domains compared to those of vertebrates in its amino acid sequences. To check whether Bk-P-gp would be inducible, we exposed B. koreanus to six pharmaceuticals including antibiotics for use in aquaculture and observed dose- and time-dependency on transcripts of Bk-P-gp for 24h over a wide range of concentration. Efflux assay and membrane topology supported its conserved function for transportation of a number of chemicals upon cellular damage. To reveal the effect of pharmaceuticals on the rotifer, we measured survival rate and population growth rate after exposure to six pharmaceuticals. In an acute toxicity test, both NOEC and LC50 values for all the pharmaceuticals were high for 24 h. ATP, CBZ, SMX, and TMP markedly inhibited the population growth of B. koreanus after exposure up to 100 mg/L for 10 days. In this paper, we demonstrated that various pharmaceuticals can retard growth rate with up regulation of the P-gp gene as a cellular defense system. This finding provides a better understanding of molecular mechanisms involved in pharmaceutical-mediated cellular damage in B. koreanus. PMID- 22446823 TI - Low-level pyrene exposure causes cardiac toxicity in zebrafish (Danio rerio) embryos. AB - It is widely accepted that the most abundant polycyclic aromatic hydrocarbons (PAHs) in weathered crude oils is cardiotoxic. Although PAHs toxic endpoints show strong correlation with the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, and is thought to be a potent inducer of cytochrome P4501A, the action mechanism of PAHs on vertebrate cardiovascular development and disease is unclear. Herein, we address the cardiac developmental effects of exposure to the weak AhR agonist pyrene on the early life-stages of zebrafish. Embryos were exposed to 0, 0.05, 0.5, 5, and 50 nmol/L pyrene up to 72h post-fertilization (hpf). Pyrene-treated embryos showed dose-dependent heart abnormalities, such as pericardial edema and cardiac looping defects. Changes in AhR1a, AhR1b, AhR2, and Cyp1A expression were assessed by real-time RT-PCR. The results showed that low level pyrene failed to alter these genes expression. However, the homeodomain transcription factor Nkx2.5, which plays an essential role in the development of the cardiovascular system, was down-regulated in a dose-dependent manner by pyrene exposure. The bone morphogenetic protein 2b (Bmp2b), which has been identified as the upstream gene of Nkx2.5, also was inhibited in a dose-dependent manner after treatment with pyrene. Taken together, these data indicated that embryonic exposure of zebrafish to low-level environmental pyrene disrupt normal cardiac development and alter expression of defective cardiac differentiation related genes. PMID- 22446824 TI - Tissue specificity of aryl hydrocarbon receptor (AhR) mediated responses and relative sensitivity of white sturgeon (Acipenser transmontanus) to an AhR agonist. AB - Sturgeons are endangered in some parts of the world. Due to their benthic nature and longevity sturgeon are at greater risk of exposure to bioaccumulative contaminants such as dioxin-like compounds that are associated with sediments. Despite their endangered status, little research has been conducted to characterize the relative responsiveness of sturgeon to dioxin-like compounds. In an attempt to study the biological effects and possible associated risks of exposure to dioxin-like compounds in sturgeon, the molecular and biochemical responses of white sturgeon (Acipenser transmontanus) to a model aryl hydrocarbon receptor (AhR) agonist, beta-naphthoflavone (betaNF) were investigated. White sturgeon were injected intraperitoneally with one of three doses of betaNF (0, 50, or 500mg/kg, bw). Rainbow trout (Oncorhynchus mykiss) were used as a reference species since their responses have been well characterized in the past. Three days following injection with betaNF, fish were euthanized and livers, gills, and intestines collected for biochemical and molecular analyses. White sturgeon exposed to betaNF had significantly greater ethoxyresorufin O-deethylase (EROD) activity in liver (up to 37-fold), gill (up to 41-fold), and intestine (up to 36-fold) than did unexposed controls. Rainbow trout injected with betaNF exhibited EROD activity that was significantly greater in liver (88-fold), than that of controls, but was undetectable in gills or intestine. Abundance of CYP1A transcript displayed a comparable pattern of tissue-specific induction with intestine (up to 189-fold), gills (up to 53-fold), and liver (up to 21-fold). Methoxyresorufin O-deethylase (MROD) and pentoxyresorufin O-deethylase (PROD) activities were undetectable in unexposed white sturgeon tissues while exposed tissues displayed MROD activity that was only moderately greater than the activity that could be detected. Differential inducibility among liver, gill, and intestine following exposure to an AhR agonist is likely associated with tissue specific regulation of the AhR signalling pathway. Liver and gill of white sturgeon had significantly greater AhR transcript abundance than did the intestine, however following exposure to betaNF, significantly greater induction in AhR transcript abundance was detected in intestine (up to 35-fold) compared to liver (up to 5-fold) or gills (up to 11-fold). It was shown that white sturgeon are responsive to AhR agonists in the liver, gill, and intestine and could be among the more sensitive fish species with regard to inducibility of CYP1A. PMID- 22446825 TI - Characterization of phospholipid hydroperoxide glutathione metabolizing peroxidase (gpx4) isoforms in Coho salmon olfactory and liver tissues and their modulation by cadmium. AB - Exposure to environmental contaminants, including various pesticides and trace metals, can disrupt critical olfactory-driven behaviors of fish such as homing to natal streams, mate selection, and an ability to detect predators and prey. These neurobehavioral injuries have been linked to reduced survival and population declines. Despite the importance of maintaining proper olfactory signaling processes in the presence of chemical exposures, little is known regarding chemical detoxification in the salmon olfactory system, and in particular, the antioxidant defenses that maintain olfactory function. An understudied, yet critical component of cellular antioxidant defense is phospholipid hydroperoxide glutathione peroxidase (PHGPx/GPx4), an isoform within the family of selenium dependent glutathione peroxidase (GPx) enzymes that can directly reduce lipid peroxides and other membrane-bound complex hydroperoxides. In this study, we cloned two gpx4 isoforms (gpx4a and gpx4b) from Coho salmon olfactory tissues and compared their modulation in olfactory and liver tissues by cadmium, an environmental pollutant and olfactory toxicant that cause oxidative damage as a mechanism of toxicity. Amino acid sequence comparisons of the two gpx4 isoforms shared 71% identity, and also relatively high sequence identities when compared with other fish GPx4 isoforms. Sequence comparisons with human GPx4 indicated conservation of three important active sites at selenocysteine (U46), glutamine (Q81), and tryptophan (W136), suggesting similar catalytic activity between fish and mammalian GPx4 isoforms. Tissue profiling confirmed the expression of gpx4a and gpx4b in all ten Coho tissues examined. The expression of gpx4 mRNAs in the Coho olfactory system was accompanied by comparably high initial rates of GPx4 enzymatic activity in mitochondrial and cytosolic fractions. Exposure to low (3.7 ppb) and high (347 ppb) environmental Cd concentrations for 24-48 h significantly decreased gpx4a expression in Coho olfactory rosettes, whereas olfactory gpx4b mRNA expression was not modulated by exposures at these concentrations. In summary, Coho salmon express two paralogs of gpx4, a key enzyme in the maintenance of signal transduction processes that protect against cellular oxidative damage. The Cd-associated downregulation of salmon olfactory gpx4a expression in particular, may be associated with the loss of olfactory signal transduction that accompanies metal-associated loss of olfaction in salmonids. PMID- 22446826 TI - Malachite green toxicity assessed on Asian catfish primary cultures of peripheral blood mononuclear cells by a proteomic analysis. AB - The potential genotoxic and carcinogenic properties reported for malachite green (MG) and the frequent detection of MG residues in fish and fish products, despite the ban of MG, have recently generated great concern. Additional toxicological data are required for a better understanding of the mechanism of action and a more comprehensive risk assessment for the exposure of fish to this fungicide. To date, the use of fish peripheral blood mononuclear cells (PBMCs) has not been exploited as a tool in the assessment of the toxicity of chemicals. However, PBMCs are exposed to toxicants and can be easily collected by blood sampling. The present study aims at better understanding the effects of MG by a proteomic analysis of primary cultured PBMC from the Asian catfish, Pangasianodon hypophthalmus, exposed to MG. The two lowest concentrations of 1 and 10 ppb were selected based on the MTS (water soluble tetrazolium salts) cytotoxicity test. Using a proteomic analysis (2D-DIGE), we showed that 109 proteins displayed significant changes in abundance in PBMC exposed during 48 h to MG. Most of these proteins were successfully identified by nano LC-MS/MS and validated through the Peptide and Protein Prophet of ScaffoldTM software, but only 19 different proteins were considered corresponding to a single identification per spot. Our data suggest that low concentrations of MG could affect the mitochondrial metabolic functions, impair some signal transduction cascades and normal cell division, stimulate DNA repair and disorganize the cytoskeleton. Altogether, these results confirm that the mitochondrion is a target of MG toxicity. Further studies on the identified proteins are needed to better understand the mechanisms of MG toxicity in fish produced for human consumption. PMID- 22446827 TI - Combined effects of high environmental ammonia, starvation and exercise on hormonal and ion-regulatory response in goldfish (Carassius auratus L.). AB - Due to eutrophication, high environmental ammonia (HEA) has become a frequent problem in aquatic environments, especially in agricultural or densely populated areas. During certain periods, e.g. winter, feed deprivation may occur simultaneously in natural waters. Additionally, under such stressful circumstances, fish may be enforced to swim at a high speed in order to catch prey, avoid predators and so on. Consequently, fish need to cope with all these stressors by altering physiological processes which in turn are controlled by genes expression. Therefore, in the present study, ammonia toxicity was tested in function of nutrient status (fed versus starved) and swimming performance activity (routine versus exhaustive). Goldfish, a relatively tolerant cyprinid, were exposed to HEA (1 mg/L; Flemish water quality guideline for surface water) for a period of 3 h, 12 h, 1 day, 4 days, 10 days, 21 days and 28 days and were either fed (2% body weight) or starved (kept unfed for 7 days prior to sampling). Results showed that the activity of Na+/K+-ATPase in the gills was stimulated by HEA and disturbance in ion balance was obvious with increases in plasma [Na+], [Cl-] and [Ca2+] after prolonged exposure. Additionally, osmoregulation and metabolism controlling hormones like cortisol and thyroid hormones (T3 and T4) were investigated to understand adaptive responses. The expression kinetics of growth, stress and osmo-regulatory representative genes such as Insulin-like growth factor 1 (IGF-I), growth hormone receptor (GHR), thyroid hormone receptor beta (THRbeta), prolactin receptor (PRLR), cortisol receptor (CR) and Na+/K+ ATPase alpha(3) were examined. Overall effect of HEA was evident since Na+/K+ ATPase activity, plasma cortisol, Na+ and Ca2+ concentration, expression level of CR and Na+/K+-ATPase alpha3 mRNA in fed and starved fish were increased. On the contrary, transcript level of PRLR was reduced after 4 days of HEA; additionally T3 level and expression of GHR, IGF-I and THRbeta genes were decreased following 10-21 days of HEA. Starvation, the additional challenge in the present study, significantly increased plasma cortisol level and CR transcript level under HEA compared to the fed exposed and control fish. Furthermore, a remarkable reduction in T3 and mRNA levels of THRbeta, IGF-I and GHR genes was observed under starvation. The toxic effects in both feeding treatments were exacerbated when imposed to exhaustive swimming with more pronounced effects in starved fish. This confirms that starvation makes fish more vulnerable to external ammonia, especially during exercise. PMID- 22446828 TI - Induction of cytochrome P450 family 1 mRNAs and activities in a cell line from the frog Xenopus laevis. AB - Cytochrome P450 family 1 (CYP1) includes four subfamilies of enzymes: CYP1A, CYP1B, CYP1C, and CYP1D. In many vertebrates, CYP1A, 1B, and 1C expression is induced by agonists of the aryl hydrocarbon receptor, including toxic contaminants such as chlorinated dioxins, coplanar chlorinated biphenyls, and polynuclear aromatic hydrocarbons. Assessed at the level of mRNA, protein, or enzyme activity, CYP1s (especially CYP1As) represent potent and popular biomarkers of contaminant exposure in aquatic vertebrates. Alkylated resorufins are synthetic substrates used to detect, quantify, and describe catalytic activities of cytochrome P450s. The ability to oxidize specific resorufin-based substrates can distinguish the catalytic activities of individual CYP1s. Xenopus laevis, the African clawed frog, is the most widely employed amphibian model in aquatic toxicology, yet the number, inducibility, and activities of CYP1s have not been systematically characterized in this species. Here we report the cloning of cDNAs encoding two new CYP1 family members, X. laevis CYP1B and CYP1C, along with an integrated assessment of the induction of alkyloxyuresorufin-O-dealkylase (AROD) activities and mRNA expression of four known X. laevis CYP1s: CYP1A6, CYP1A7, CYP1B, and CYP1C. Using XLK-WG, an X. laevis kidney epithelial cell line, we determined that EROD (ethoxyresorufin substrate) and MROD (methoxyresorufin) were both induced 3000- to 5000-fold following 2,3,7,8 tetrachlorodibenzo-p dioxin (TCDD) exposure up to 250 nM, while BROD (benzyloxyresorufin) and PROD (pentyloxyresorufin) activity was not detectable regardless of TCDD treatment. TCDD induced CYP1A6 and CYP1A7 mRNAs by 2-3 orders of magnitude, while CYP1B and CYP1C were unchanged. The more potent AHR agonist, FICZ (6-formylindolo[3,2 b]carbazole), induced CYP1B up to 10-fold at concentrations between 0.1 and 250 nM, while CYP1C induction was less than 3-fold. CYP1B mRNA showed the highest constitutive mRNA expression, 5- to 75-fold greater than the other CYP1 transcripts. Taken together, these results suggest that CYP1A6 and CYP1A7 perform the bulk of EROD and MROD activities we observed in these cells. The ability of each X. laevis CYP1 to catalyze oxidation of individual resorufin substrates remains to be determined. Correlating CYP1 mRNA and induced AROD activity is a significant step toward clarifying the biochemical meaning of these biomarkers and the roles of CYP1 enzymes in X. laevis. The cell culture approach represents an important complement to the long standing use of frog embryos and tadpoles in toxicological studies, providing a well suited model system for determining the molecular mechanisms underlying the regulation of these important biomarkers of contaminant exposure. PMID- 22446829 TI - Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish. AB - Organophosphate flame retardants (OPFRs) are frequently detected in environment and biota. However, knowledge on their potential toxicological effects is limited. Endocrine disrupting potentials of six OPFRs, i.e., tris-(2-chloroethyl) phosphate (TCEP), tris-(2-chloroisopropyl) phosphate (TCPP), tris-(1,3-dichloro-2 propyl) phosphate (TDCPP), tris-(2-butoxyethyl) phosphate (TBEP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP), were investigated using human cell lines as well as zebrafish (Danio rerio). Sex hormone synthesis and steroidogenic gene transcriptions were measured using H295R cells. With MVLN cells, estrogen receptor binding activities of OPFRs were evaluated. In zebrafish, sex hormones and related gene transcriptions were determined for each sex after 14d exposure to OPFRs. All six OPFRs increased both 17beta-estradiol (E2) and testosterone (T) concentrations in H295R cells. In addition, transcription of four major steroidogenic genes was up-regulated and that of two sulfotransferase genes was down-regulated. In MVLN cells, no OPFRs acted as estrogen receptor agonists, while TDCPP, TPP, and TCP acted as antagonists inhibiting binding of E2 to estrogen receptor. After 14d of zebrafish exposure, TCP, TDCPP, or TPP significantly increased plasma T and E2 concentrations, but did not change 11-ketotestosterone (11-KT) among female fish. Among males, both T and 11-KT decreased and E2 increased. In general, transcription of CYP17 and CYP19a genes was significantly up-regulated in both sexes, while vitellogenin (VTG) 1 gene was down- and up-regulated in female and male fish, respectively. The results of this study showed that OPFRs could alter sex hormone balance through several mechanisms including alterations of steroidogenesis or estrogen metabolism. PMID- 22446830 TI - Multi-species comparison of the mechanism of biotransformation of MeO-BDEs to OH BDEs in fish. AB - Polybrominated diphenyl ethers (PBDEs) and their methoxylated- (MeO-) and hydroxylated- (OH-) analogs are ubiquitously distributed in the environment worldwide. The OH-BDEs have greater potency than PBDEs and can be produced from the transformation of MeO-BDEs. The objectives of the current study were to (1) identify the enzyme(s) that catalyze biotransformation of 6-MeO-BDE-47 to 6-OH BDE-47 in livers from rainbow trout, and (2) compare biotransformation of 6-MeO BDE-47 to 6-OH-BDE-47 among rainbow trout, white sturgeon and goldfish. Cytochrome P450 1A (CYP1A) enzymes did not catalyze the biotransformation reaction. However, biotransformation was significantly inhibited by the CYP inhibitors clotrimazole and 1-benzylimidazole but not gestodene. Therefore, the reaction is likely catalyzed by CYP2 enzymes. When biotransformation was compared among species, concentrations of 6-OH-BDE-47 were significantly 3.4- and 9.1-fold greater in microsomes from rainbow trout compared to goldfish or white sturgeon, respectively. Concentrations of 6-OH-BDE-47 in microsomes from goldfish were non significantly 2.7-fold greater than in sturgeon. The initial rate of biotransformation in microsomes from livers of rainbow trout was significantly 2.0- and 6.2-fold greater than the initial rate of biotransformation in microsomes from livers of goldfish or sturgeon, respectively, while the initial rate in goldfish was significantly 3.1-fold greater than in sturgeon. It is hypothesized that differences in CYP-mediated biotransformation of MeO-BDEs to OH BDEs could influence concentrations of OH-BDEs in different species of fish. PMID- 22446831 TI - Alteration of the kidney membrane proteome of Mizuhopecten yessoensis induced by low-level methyl parathion exposure. AB - Methyl parathion (MP) is a widely used organophosphorus pesticide that causes severe health and environmental effects. We investigated the alteration of the proteomic profile in the membrane enriched fraction of the kidneys of the scallop Mizuhopecten yessoensis exposed to low-level MP. Gas chromatography analysis showed that MP residues were significantly accumulated in the kidneys and the digestive glands of the scallops. According to two-dimensional electrophoresis, 17 proteins were differentially modulated under MP exposure. The mRNA expressions of 12 differential proteins were analyzed using quantitative PCR, and 10 showed consistent alteration of mRNA level with that of protein expression level. Altered expressions of two proteins (mitochondrial processing peptidase and alpha tubulin) were also examined using Western blotting, showing that the mitochondrial processing peptidase was down-regulated but alpha-tubulin remained unchanged in response to MP exposure. Subcellular locations of all the identified proteins that were predicted using bioinformatics tools indicate that few of them are permanently located in the membrane. The differentially expressed proteins are involved in several critical biological processes, and their relevance to human health has been illuminated. These data taken together have provided some novel insights into the chronic toxicity mechanism of MP and have suggested mitochondrial processing peptidase as a potential biomarker for human health and environmental monitoring. PMID- 22446832 TI - Influence of survivin and Bcl-2 expression on the biological behavior of non small cell lung cancer. AB - Survivin and Bcl-2 are generally considered to be inhibitors of apoptosis and are frequently overexpressed in several types of human cancers. However, their role in regulating the biological behavior of non-small cell lung carcinoma (NSCLC) remains controversial. We aimed to determine the expression of survivin and Bcl-2 and explore their correlation with clinicopathological features and prognosis. The expression of survivin and Bcl-2 proteins in 62 specimens of NSCLC tissues and 30 specimens of tumor adjacent tissues was detected using immunohistochemistry. The correlation between protein expression and clinicopathological features and prognosis was analyzed. The percentage of survivin-positive samples obtained from NSCLC tissues was 58.06% (36/62), which was significantly higher compared to that in normal lung tissues (10%, 3/30; P<0.05). Similarly, the percentage of Bcl-2-positive samples obtained from NSCLC tissues was statistically higher compared to that from normal lung tissues (51.61%, 32/62 vs. 6.67%, 2/30; P<0.05). Survivin expression was closely correlated with tumor differentiation, lymph node metastasis and TNM stage (P<0.05), while Bcl-2 expression was only associated with TNM stage (P<0.05). The expression of survivin was positively correlated with that of Bcl-2 (P<0.05). A five-year follow-up study revealed that the expression of survivin and Bcl-2 was negatively correlated with post-operative survival duration. Our findings suggest that survivin and Bcl-2 may act synergistically in the occurrence, development, invasion and metastasis of NSCLC, both of which are up-regulated in NSCLC tissues. The co-expression of survivin and Bcl-2, which is closely related to malignancy, may serve as a biomarker for predicting prognosis. PMID- 22446833 TI - Stress relaxation of swine growth plate in semi-confined compression: depth dependent tissue deformational behavior versus extracellular matrix composition and collagen fiber organization. AB - Mechanical environment is one of the regulating factors involved in the process of longitudinal bone growth. Non-physiological compressive loading can lead to infantile and juvenile musculoskeletal deformities particularly during growth spurt. We hypothesized that tissue mechanical behavior in sub-regions (reserve, proliferative and hypertrophic zones) of the growth plate is related to its collagen and proteoglycan content as well as its collagen fiber orientation. To characterize the strain distribution through growth plate thickness and to evaluate biochemical content and collagen fiber organization of the three histological zones of growth plate tissue. Distal ulnar growth plate samples (N = 29) from 4-week old pigs were analyzed histologically for collagen fiber organization (N = 7) or average zonal thickness (N = 8), or trimmed into the three average zones, based on the estimated thickness of each histological zone, for biochemical analysis of water, collagen and glycosaminoglycan content (N = 7). Other samples (N = 7) were tested in semi-confined compression under 10% compressive strain. Digital images of the fluorescently labeled nuclei were concomitantly acquired by confocal microscopy before loading and after tissue relaxation. Strain fields were subsequently calculated using a custom-designed 2D digital image correlation algorithm. Depth-dependent compressive strain patterns and collagen content were observed. The proliferative and hypertrophic zone developed the highest axial and transverse strains, respectively, under compression compared to the reserve zone, in which the lowest axial and transverse strains arose. The collagen content per wet mass was significantly lower in the proliferative and hypertrophic zones compared to the reserve zone, and all three zones had similar glycosaminoglycan and water content.Polarized light microscopy showed that collagen fibers were mainly organized horizontally in the reserve zone and vertically aligned with the growth direction in the proliferative and hypertrophic zones. Higher strains were developed in growth plate areas (proliferative and hypertrophic) composed of lower collagen content and of vertical collagen fiber organization. The stiffer reserve zone, with its higher collagen content and collagen fibers oriented to restrain lateral expansion under compression, could play a greater role of mechanical support compared to the proliferative and hypertrophic zones, which could be more susceptible to be involved in an abnormal growth process. PMID- 22446834 TI - A three-constituent damage model for arterial clamping in computer-assisted surgery. AB - Robotic surgery is an attractive, minimally invasive and high precision alternative to conventional surgical procedures. However, it lacks the natural touch and force feedback that allows the surgeon to control safe tissue manipulation. This is an important problem in standard surgical procedures such as clamping, which might induce severe tissue damage. In complex, heterogeneous, large deformation scenarios, the limits of the safe loading regime beyond which tissue damage occurs are unknown. Here, we show that a continuum damage model for arteries, implemented in a finite element setting, can help to predict arterial stiffness degradation and to identify critical loading regimes. The model consists of the main mechanical constituents of arterial tissue: extracellular matrix, collagen fibres and smooth muscle cells. All constituents are allowed to degrade independently in response to mechanical overload. To demonstrate the modularity and portability of the proposed model, we implement it in a commercial finite element programme, which allows to keep track of damage progression via internal variables. The loading history during arterial clamping is simulated through four successive steps, incorporating residual strains. The results of our first prototype simulation demonstrate significant regional variations in smooth muscle cell damage. In three additional steps, this damage is evaluated by simulating an isometric contraction experiment. The entire finite element simulation is finally compared with actual in vivo experiments. In the short term, our computational simulation tool can be useful to optimise surgical tools with the goal to minimise tissue damage. In the long term, it can potentially be used to inform computer-assisted surgery and identify safe loading regimes, in real time, to minimise tissue damage during robotic tissue manipulation. PMID- 22446835 TI - Rationally designed families of orthogonal RNA regulators of translation. AB - Our ability to routinely engineer genetic networks for applications is limited by the scarcity of highly specific and non-cross-reacting (orthogonal) gene regulators with predictable behavior. Though antisense RNAs are attractive contenders for this purpose, quantitative understanding of their specificity and sequence-function relationship sufficient for their design has been limited. Here, we use rationally designed variants of the RNA-IN-RNA-OUT antisense RNA mediated translation system from the insertion sequence IS10 to quantify >500 RNA RNA interactions in Escherichia coli and integrate the data set with sequence activity modeling to identify the thermodynamic stability of the duplex and the seed region as the key determinants of specificity. Applying this model, we predict the performance of an additional ~2,600 antisense-regulator pairs, forecast the possibility of large families of orthogonal mutants, and forward engineer and experimentally validate two RNA pairs orthogonal to an existing group of five from the training data set. We discuss the potential use of these regulators in next-generation synthetic biology applications. PMID- 22446836 TI - Rapid and orthogonal logic gating with a gibberellin-induced dimerization system. AB - Using a newly synthesized gibberellin analog containing an acetoxymethyl group (GA(3)-AM) and its binding proteins, we developed an efficient chemically inducible dimerization (CID) system that is completely orthogonal to existing rapamycin-mediated protein dimerization. Combining the two systems should allow applications that have been difficult or impossible with only one CID system. By using both chemical inputs (rapamycin and GA(3)-AM), we designed and synthesized Boolean logic gates in living mammalian cells. These gates produced output signals such as fluorescence and membrane ruffling on a timescale of seconds, substantially faster than earlier intracellular logic gates. The use of two orthogonal dimerization systems in the same cell also allows for finer modulation of protein perturbations than is possible with a single dimerizer. PMID- 22446837 TI - An engineered eukaryotic protein glycosylation pathway in Escherichia coli. AB - We performed bottom-up engineering of a synthetic pathway in Escherichia coli for the production of eukaryotic trimannosyl chitobiose glycans and the transfer of these glycans to specific asparagine residues in target proteins. The glycan biosynthesis was enabled by four eukaryotic glycosyltransferases, including the yeast uridine diphosphate-N-acetylglucosamine transferases Alg13 and Alg14 and the mannosyltransferases Alg1 and Alg2. By including the bacterial oligosaccharyltransferase PglB from Campylobacter jejuni, we successfully transferred glycans to eukaryotic proteins. PMID- 22446838 TI - Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands. AB - Benzodiazepines exert their anxiolytic, anticonvulsant, muscle-relaxant and sedative-hypnotic properties by allosterically enhancing the action of GABA at GABA(A) receptors via their benzodiazepine-binding site. Although these drugs have been used clinically since 1960, the molecular basis of this interaction is still not known. By using multiple homology models and an unbiased docking protocol, we identified a binding hypothesis for the diazepam-bound structure of the benzodiazepine site, which was confirmed by experimental evidence. Moreover, two independent virtual screening approaches based on this structure identified known benzodiazepine-site ligands from different structural classes and predicted potential new ligands for this site. Receptor-binding assays and electrophysiological studies on recombinant receptors confirmed these predictions and thus identified new chemotypes for the benzodiazepine-binding site. Our results support the validity of the diazepam-bound structure of the benzodiazepine-binding pocket, demonstrate its suitability for drug discovery and pave the way for structure-based drug design. PMID- 22446839 TI - Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism. AB - Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases. PMID- 22446840 TI - A fluorene-modified porphyrin for efficient dye-sensitized solar cells. AB - Porphyrins bearing a polyaromatic or a heterocyclic group are prepared to study their fundamental and photovoltaic properties. Solar cells sensitized with a fluorene-modified porphyrin outperform other dyes in the series, reaching ~90% efficiency of N719 dye. PMID- 22446841 TI - Multimodality correlations of patellar height measurement on X-ray, CT, and MRI. AB - PURPOSE: To investigate whether the universally accepted range of normal patellar height ratios derived from radiography for the Insall-Salvati (IS) and Blackburne Peel (BP) methods could be similarly applied to both CT and MRI. MATERIALS AND METHODS: Institutional review board approval was obtained with waiver of informed consent for this HIPPA-compliant study. A total of 45 knees in 42 patients (15 men, 27 women; age range 11 to 75 years, mean age 39 +/- 20 years) who underwent tri-modality (radiograph, CT, and MRI) examinations were selected. All patients had knee imaging obtained for a variety of reasons and measurements were performed by two independent readers who were blinded to each other's measurements or the respective measurements derived from each of the methods. Paired t test was used to compare the mean values among the modalities. Inter observer and inter-method agreements were assessed using intra-class correlation coefficients. RESULTS: Statistically significant, but small quantitative differences are noted between tri-modality patellar height ratios. For comparable results, the small addition of 0.13 and 0.10 are needed for the Insall-Salvati measurements on MRI and CT respectively, compared with radiographs. For the Blackburne-Peel ratio, an additional adjustment of 0.09 is needed between radiographs and MRI, but not between radiographs and CT. These adjustments are independent of gender. The interobserver reproducibility was excellent (ICC >= 0.94) for both the Insall-Salvati and Blackburne-Peel methods for all modalities. CONCLUSION: The results indicate that cut-off values for patella alta and baja derived from radiographs should not be directly transposed to CT and MRI; however, the adjustments are relatively minor. These measurements show excellent reproducibility for all modalities currently used for patellar height measurements. PMID- 22446842 TI - [Shortening osteotomy for alloarthoplastic joint replacement for hip dislocation in adults]. AB - OBJECTIVE: Total hip arthroplasty to create an articulating hip joint. Acetabular cup implantation in the original rotational center of the pelvis. Simultaneous femoral shortening osteotomy to prevent neurovascular damage and equalize leg length in patients with unilateral occurrence. INDICATIONS: Developmental dysplasia of the hip (DDH) in adults; type 3 and 4 dislocation according to Crowe. CONTRAINDICATIONS: Cerebrospinal dysfunction with permanent restriction of coordination ability, muscular dystrophies, and multiple malformations of the musculoskeletal system. Apparent disturbance of the bone metabolism. SURGICAL TECHNIQUE: The Watson-Jones interval approach to the hip joint is used to avoid functional disorders of the hip abductors. After preparation of the proximal femur and femoral neck resection, adjustment of the non-regularly developed acetabular cavity with reduced anterior coverage takes place. The cup component is implanted and the interval between the vastus intermedius and the vastus lateralis below the lesser trochanter examined. Loss of periosteum of the femoral cortex due to blunt spreading is to be avoided. Following the femoral shortening osteotomy initially the preparation of the distal bone segment takes place to adjust the endofemoral canal for shaft implantation in the following preparation of the metaphyseal segment. Afterwards osteotomy-bridging implantation of a cementless, distal anchoring stem design is performed. POSTOPERATIVE MANAGEMENT: Partial weight bearing of the leg with 20 kp is necessary for 6 weeks combined with therapy of existing contractures and active pelvic rotation training. Within 10 postoperative weeks full weight bearing is usually reached. After this period mobilization without crutches is possible. Inpatient rehabilitation is possible after bony recovery of the femoral osteotomy. RESULTS: From 1993 to 1999, the first 15 total hip arthroplasties were performed in adult patients with DDH; they were treated with simultaneous femoral shortening osteotomy and without additive osteosynthesis. During the midterm follow-up (4.3 years), no failure of the femoral component was observed with complication-free osseous healing of the osteotomy. One cup revision was necessary in this period. The Merle d'Aubigne score increased from 8.2 preoperatively to 15.5 points. PMID- 22446843 TI - [Free latissimus dorsi flap transfer for reconstruction of soft tissue defects of the lower extremity]. AB - OBJECTIVE: Sustainable and durable soft tissue coverage at the lower extremity following trauma, tumor resections, sequelae of radiation therapy or osteomyelitis using free latissimus dorsi muscle transfer is provided by a free latissimus dorsi muscle flap. INDICATIONS: Soft tissue defects at the lower extremity following trauma, tumor resections, and sequelae of radiation therapy or osteomyelitis. CONTRAINDICATIONS: Thoracotomy with incision of the latissimus dorsi muscle; a relative contraindication in wheelchair drivers as well as in overhead athletes due to potential diminished strength and shoulder proprioception following latissimus dorsi muscle transplantation. SURGICAL TECHNIQUE: Under general anesthesia the patient is positioned laterally, and a substantial and meticulous debridement of the defect is performed, as is the identification and preparation of the target vessel, which is preferentially the posterior tibial artery at the calf, or more proximally the popliteal or femoral artery from the medial side as well as concomitant veins/the great saphenous vein. A tailored latissimus dorsi musculocutaneous flap is harvested with subsequent microsurgical anastomosis to the target vessel with preferential end to-side anastomosis of the artery and end-to-end anastomosis of one or two veins. POSTOPERATIVE MANAGEMENT: A 24-h intermediate care unit, clinical flap monitoring for at least 5-7 days, dangling of the flap using an elastic bandage for an initial 3 times 5 min starting on POD 7, compression stockings for at least 6 months subsequently. RESULTS: From 2001-2007 75 free latissimus dorsi flaps were performed (53 +/- 17 years) for soft tissue coverage at the lower extremity. In 58% the target vessel was the posterior tibial artery, in 11% the femoral artery, in 8% the anterior tibial artery and in 8% the popliteal artery. In 15% an arteriovenous (AV) loop was applied. Overall free flap survival was 95%. We encountered four total flap losses, exclusively in complex reconstructions with AV-loop situations. PMID- 22446844 TI - [Osteotomies for endoprothesis]. PMID- 22446845 TI - Efficient down-regulation of glia maturation factor expression in mouse brain and spinal cord. AB - Long-lasting siRNA-based down-regulation of gene of interest can be achieved by lentiviral-based expression vectors driving the production of short hairpin RNA (shRNA). We investigated an attractive therapeutic approach to target the expression of proinflammatory GMF by using lentiviral vector encoding GMF specific shRNA to reduce GMF levels in the spinal cord and brain of mice. To determine the effect of GMF-shRNA on GMF protein levels, we performed quantitative ELISA analysis in brain and in thoracic, cervical and lumbar regions of spinal cord from mice followed by GMF-shRNA (G-shRNA) or control shRNA (C shRNA) treatments. Our results show a marked reduction of GMF protein levels in brain and spinal cord of mice treated with GMF-shRNA compared to control shRNA treatment. Consistent with the GMF protein analysis, the immunohistochemical examination of the spinal cord sections of EAE mice treated with GMF-shRNA showed significantly reduced GMF-immunoreactivity. Thus, the down-regulation of GMF by GMF-shRNA was efficient and wide spread in CNS as evident by the significantly reduced levels of GMF protein in the brain and spinal cord of mice. PMID- 22446846 TI - Statistical methodological issues in handling of fatty acid data: percentage or concentration, imputation and indices. AB - Basic aspects in the handling of fatty acid-data have remained largely underexposed. Of these, we aimed to address three statistical methodological issues, by quantitatively exemplifying their imminent confounding impact on analytical outcomes: (1) presenting results as relative percentages or absolute concentrations, (2) handling of missing/non-detectable values, and (3) using structural indices for data-reduction. Therefore, we reanalyzed an example dataset containing erythrocyte fatty acid-concentrations of 137 recurrently depressed patients and 73 controls. First, correlations between data presented as percentages and concentrations varied for different fatty acids, depending on their correlation with the total fatty acid-concentration. Second, multiple imputation of non-detects resulted in differences in significance compared to zero-substitution or omission of non-detects. Third, patients' chain length-, unsaturation-, and peroxidation-indices were significantly lower compared to controls, which corresponded with patterns interpreted from individual fatty acid tests. In conclusion, results from our example dataset show that statistical methodological choices can have a significant influence on outcomes of fatty acid analysis, which emphasizes the relevance of: (1) hypothesis-based fatty acid presentation (percentages or concentrations), (2) multiple imputation, preventing bias introduced by non-detects; and (3) the possibility of using (structural) indices, to delineate fatty acid-patterns thereby preventing multiple testing. PMID- 22446847 TI - Proteomic analysis of oxidative modification in endothelial colony-forming cells treated by hydrogen peroxide. AB - Endothelial progenitor cells (EPCs) which circulate in the peripheral blood and reside in blood vessels are proven to promote the repair of damaged endothelium and improve the function of endothelial cells after vascular injury. Recently, EPCs have been extensively studied as risk biomarkers and a potential therapeutic tool for cardiovascular disease. It is known that oxidative stress is one of the most important pathogenetic factors impairing endothelial function. During the repair process after endothelial injury, EPCs are exposed to oxidative stress. In this study, we treated endothelial colony-forming cells (ECFCs) with hydrogen peroxide (H2O2) as an oxidative stress model and observed the changes in cytology and morphology of ECFCs. In addition, we investigated the alterations in oxidative levels of proteins associated with H2O2-induced morphological and cytological changes in ECFCs by proteomic analysis of oxidative modification. The results showed that H2O2 treatment led to a decreased proliferation, increased apoptosis and impaired tube-forming ability of ECFCs in a dose-dependent manner. Five proteins with upregulated oxidative levels were identified successfully. The upregulated oxidative levels of these five proteins may be responsible for the dysfunction of ECFCs under oxidative stress. Our results may provide some novel insights into the molecular mechanisms of oxidative stress action on ECFCs. PMID- 22446848 TI - (1)H, (13)C, and (15)N resonance assignments of the second immunoglobulin domain of neurolin from Carassius auratus. AB - Neurolin is a member of the superfamily of immunoglobulin-like cell surface receptors. It is essential during neuronal development in the model organism Carassius auratus (goldfish) and involved in the guidance of the growing axon. Among the five extracellular immunoglobulin (Ig) domains, the second Ig domain is crucial for axon pathfinding. In the present study, we report the NMR assignment and secondary structure prediction of the second Ig domain of neurolin. PMID- 22446849 TI - (1)H, (13)C, and (15)N resonance assignments of the dsRBDs of mouse RNA helicase A. AB - RNA helicase A (RHA) is a multifunctional protein that regulates gene expression. RHA has two double-stranded RNA-binding domains (dsRBDs) that serve as modules for highly structured RNA binding and protein-protein interactions. Using the dsRBDs, RHA binds to cellular and viral mRNAs, exports them from the nucleus, and regulates splicing as well as translational initiation. The RHA dsRBDs also reportedly mediate interactions with small RNAs and other dsRBD-containing proteins, and altogether form a processing complex involved in RNA silencing pathways. In addition, the RHA dsRBDs bridge RNA polymerase II with several transcription factors. Here we report the (1)H, (13)C, and (15)N chemical shift assignments of the dsRBDs of RHA. The resonance assignments obtained in this work will contribute to the elucidation of the interactions between RHA and transcriptional or post-transcriptional gene regulators. PMID- 22446850 TI - Resonance assignments of cohesin and dockerin domains from Clostridium acetobutylicum ATCC824. AB - Cohesin and dockerin domains are critical assembling components of cellulosome, a large extracellular multienzyme complex which is used by anaerobic cellulolytic bacteria to efficiently degrade lignocellulose. According to sequence homology, cohesins can be divided into three major groups, whereas cohesins from Clostridium acetobutylicum are beyond these groups and emanate from a branching point between the type I and type III cohesins. Cohesins and dockerins from C. acetobutylicum show low sequence homology to those from other cellulolytic bacteria, and their interactions are specific in corresponding species. Therefore the interactions between cohesins and dockerins from C. acetobutylicum are meaningful to the studies of both cellulosome assembling mechanism and the construction of designer cellulosome. Here we report the NMR resonance assignments of one cohesin from cellulosome scaffoldin cipA and one dockerin from a cellulosomal glycoside hydrolase (family 9) of C. acetobutylicum for further structural determination and functional studies. PMID- 22446851 TI - Photo-controlled release of zinc metal ions by spiropyran receptors anchored to single-walled carbon nanotubes. AB - Light controllable release of antinflammatory zinc ions by a smart multifunctional material composed of spiropyrans and single walled carbon nanotubes (SWNTs) is demonstrated. The exploitation of a number of complementary characterization techniques allows the investigation of both composition and performance of the multifunctional SP/SWNT nanomaterial developed. Moreover, its suitability for potential applications in bio-systems is suggested by the effective removal of the metal catalyst and the introduction of biocompatible linkers into the SP/SWNT material. The realization of potential photo controllable SP/SWNTs based drug delivery systems (DDSs) is envisaged, where nanotubes act as intracellular carriers of light modulated receptors for bioactive agents. PMID- 22446852 TI - On the prognostic & predictive impact of immune cells system in colorectal cancer. PMID- 22446853 TI - The future of bioprosthetic heart valves. PMID- 22446854 TI - Newborn hearing screening in developing countries: needs & new directions. PMID- 22446855 TI - Prodromal symptoms of recurrences of mood episodes in bipolar disorder. PMID- 22446856 TI - Do we care asthma? PMID- 22446857 TI - Typhoid fever & vaccine development: a partially answered question. AB - Typhoid fever is a systemic disease caused by the human specific Gram-negative pathogen Salmonella enterica serovar Typhi (S. Typhi). The extra-intestinal infections caused by Salmonella are very fatal. The incidence of typhoid fever remains very high in impoverished areas and the emergence of multidrug resistance has made the situation worse. To combat and to reduce the morbidity and mortality caused by typhoid fever, many preventive measures and strategies have been employed, the most important being vaccination. In recent years, many Salmonella vaccines have been developed including live attenuated as well as DNA vaccines and their clinical trials have shown encouraging results. But with the increasing antibiotic resistance, the development of potent vaccine candidate for typhoid fever is a need of the hour. This review discusses the latest trends in the typhoid vaccine development and the clinical trials which are underway. PMID- 22446858 TI - Low cost calibrated mechanical noisemaker for hearing screening of neonates in resource constrained settings. AB - BACKGROUND & OBJECTIVES: There is a need to develop an affordable and reliable tool for hearing screening of neonates in resource constrained, medically underserved areas of developing nations. This study valuates a strategy of health worker based screening of neonates using a low cost mechanical calibrated noisemaker followed up with parental monitoring of age appropriate auditory milestones for detecting severe-profound hearing impairment in infants by 6 months of age. METHODS: A trained health worker under the supervision of a qualified audiologist screened 425 neonates of whom 20 had confirmed severe profound hearing impairment. Mechanical calibrated noisemakers of 50, 60, 70 and 80 dB (A) were used to elicit the behavioural responses. The parents of screened neonates were instructed to monitor the normal language and auditory milestones till 6 months of age. This strategy was validated against the reference standard consisting of a battery of tests - namely, auditory brain stem response (ABR), otoacoustic emissions (OAE) and behavioural assessment at 2 years of age. Bayesian prevalence weighted measures of screening were calculated. RESULTS: The sensitivity and specificity was high with least false positive referrals for 70 and 80 dB (A) noisemakers. All the noisemakers had 100 per cent negative predictive value. 70 and 80 dB (A) noisemakers had high positive likelihood ratios of 19 and 34, respectively. The probability differences for pre- and post- test positive was 43 and 58 for 70 and 80 dB (A) noisemakers, respectively. INTERPRETATION & CONCLUSIONS: In a controlled setting, health workers with primary education can be trained to use a mechanical calibrated noisemaker made of locally available material to reliably screen for severe-profound hearing loss in neonates. The monitoring of auditory responses could be done by informed parents. Multi-centre field trials of this strategy need to be carried out to examine the feasibility of community health care workers using it in resource constrained settings of developing nations to implement an effective national neonatal hearing screening programme. PMID- 22446859 TI - Detection of prodromal symptoms of relapse in mania and unipolar depression by relatives and patients. AB - BACKGROUND & OBJECTIVES: Detection of prodromal symptoms among patients with mania by their immediate relatives has been seldom examined. We carried out this study to examine the ability to detect and report prodromol symptoms of manic relapses by patients themselves and their relatives. METHODS: The ability of patients and their relatives to detect prodromal symptoms was examined among 60 remitted patients, 30 each with DSM-IV diagnoses of bipolar disorder and recurrent depressive disorder, with recent manic/depressive relapses, and their 60 immediate relatives, using an instrument composed of items from common symptom scales, as well as by unstructured interview. RESULTS: Seventy per cent of patients with mania reported prodromes prior to relapse. This was significantly (P<0.01) less than the proportion of their relatives (97%), as well as the proportion of patients with unipolar depression (93%), reporting prodromal symptoms (P<0.05) among patients. Mean duration of the prodromal period reported by patients with mania was about 20 days (median-10 days); relatives reported durations which were longer by about 5 days. Prodromes of unipolar depression (mean 42.7 days; median- 21 days), were significantly longer than of mania, when reported by patients, but not by their relatives. Differences in reporting of prodromes, between relatives and patients seen in mania, were not observed in unipolar depression. The number and type of prodromal symptoms of mania reported was similar among patients and relatives. INTERPRETATION & CONCLUSIONS: Our findings showed that relatives of patients with mania were better at detecting prodromes of relapse; thus, input from relatives can improve the early detection of prodromal symptoms to prevent relapses of bipolar disorder. PMID- 22446860 TI - Quality of asthma management in an urban community in Delhi, India. AB - BACKGROUND & OBJECTIVES: High prevalence and poor control of asthma make its management a major public health issue worldwide, especially in developing countries. Optimum review of asthma management in the community is essential to improve asthma control. This study was conducted to investigate the quality of asthma management, knowledge about asthma and quality of life of asthma patients referred to a public tertiary care chest hospital in Delhi. METHODS: Diagnosis of asthma was confirmed by symptoms and reversible spirometry in 50 referred patients on their first visit. Patients were interviewed using three questionnaires on quality of asthma management before visiting referral hospital, asthma knowledge and asthma quality of life (AQLQ). Correlation amongst quality of treatment, asthma quality of life, and asthma knowledge was also determined. RESULTS: Findings revealed that only 60 per cent of patients were informed about their disease, and 10 per cent had undergone lung function tests previously. Only 44 per cent of patients were prescribed inhalers. None were provided with any educational material. Patients had poor knowledge of aetiology, pathophysiology, medication and how to assess the severity of their asthma. The mean scores in AQLQ indicated a moderate degree of impairment in quality of life. INTERPRETATIONS & CONCLUSIONS: This study provides evidence of unsatisfactory asthma management and patient-doctor interaction as patients had limited knowledge of asthma disease, its management and had poor quality of life as measured by a standardized questionnaire. Thus, there is need to implement suitable interventions to improve asthma management according to standard treatment guidelines in the community. PMID- 22446861 TI - Retrospective analysis of lung function abnormalities of Bhopal gas tragedy affected population. AB - BACKGROUND & OBJECTIVES: A large numbers of subjects were exposed to the aerosol of methyl isocyanate (MIC) during Bhopal gas disaster and lung was one of the most commonly affected organs. The aim of the present study was to analyze retrospectively the lung function abnormalities among the surviving MIC exposed population (gas victims) and to compare it with the non-MIC exposed (non gas exposed) population. METHODS: The spirometry data of both gas victims and non gas exposed population who attended the Bhopal Memorial Hospital & Research Centre for evaluation of their respiratory complaints from August 2001 to December 2009, were retrospectively evaluated and compared. RESULTS: A total 4782 gas victims and 1190 non gas exposed individuals performed spirometry during the study period. Among the gas victims, obstructive pattern was the commonest (50.8%) spirometric abnormality followed by restrictive pattern (13.3%). The increased relative risk of developing restrictive abnormality among gas victims was observed in 20-29 yr age group only (adjusted relative risk: 2.94, P<0.001). Male gas victims were more affected by severe airflow obstruction than females and the overall increased relative risk (1.33 to 1.45, P<0.001) of developing obstructive pattern among gas victims was observed. INTERPRETATION & CONCLUSIONS: The present study showed that the relative risk for pulmonary function abnormalities in gas victims was significantly more among those who were young at the time of disaster. Increased smoking habit among gas victims might have played an additive effect on predominance of obstructive pattern in spirometry. PMID- 22446862 TI - Knowledge, experience & attitudes concerning electroconvulsive therapy among patients & their relatives. AB - BACKGROUND & OBJECTIVES: Electroconvulsive therapy (ECT) is used frequently in developing countries, but investigations of patients' awareness and perception of ECT are rare. The present study thus attempted a comprehensive examination of knowledge, experience and attitudes concerning ECT among patients treated with brief-pulse, bilateral, modified ECT, and their relatives. METHODS: Of the 153 recipients of ECT, 77 patients and relatives were eventually assessed using questionnaires designed to evaluate their awareness and views about ECT. RESULTS: Patients were middle-aged, poorly-educated, often unemployed, with chronic, severe, and predominantly psychotic illnesses. Relatives were mainly parents, older, better-educated and usually employed. Apart from the very rudimentary aspects, patients were largely unaware of the procedure. Though most did not find the experience of ECT upsetting, sizeable proportions expressed dissatisfaction with aspects such as informed consent, fear of treatment and memory impairment. Although patients were mostly positive about ECT, ambivalent attitudes were also common, but clearly negative views were rare. Relatives were significantly likely to be more aware, more satisfied with the experience and have more favourable attitudes towards ECT, than patients. INTERPRETATION & CONCLUSIONS: The results endorse the notion that recipients of ECT are generally well-disposed towards the treatment, but also indicate areas where practice of ECT needs to be improved to enhance satisfaction among patients and relatives. PMID- 22446863 TI - Effect of intermittent hypobaric hypoxia on efficacy & clearance of drugs. AB - BACKGROUND & OBJECTIVES: People travelling to high altitude for occupational, recreational or religious purposes are mostly healthy and fit but sometimes they use drugs for common ailments like influenza, acute mountain sickness or chronic disease like diabetes. Limitation of oxygen at high altitude may compromise metabolism of drugs. Hence, we undertook this study to assess the effect of hypobaric hypoxia on some commonly used drugs in rats and rabbits. METHODS: Effect of intermittent hypobaric hypoxia on phenotypic expression of anesthetic drugs pentabarbitone, thiopentone and zoxazolamine (sleeping time) was assessed in rats exposed to 282.4 mm Hg equivalent to 25000 feet in a decompression chamber. Plasma clearance of some commonly used drugs was investigated in rabbits exposed to 429 mm Hg equivalent to 15000 feet. Pharmacokinetic parameters were computed by plotting drug concentration versus time curve on semi log scale. RESULTS: A significant delay in regaining rightening reflex was observed in rats exposed to intermittent hypobaric hypoxia in response to zoxazolamine, pentobarbitone and thiopentone sodium. Pharmacokinetics of acetyl salicylic acid, gentamicin, phenobarbitone and acetazolamide showed increase in plasma half life (t 1/2), decrease in elimination rate constant (k el) and hence prolonged residence of these drugs in hypoxic animals. INTERPRETATION & CONCLUSIONS: This experimental study showed that hypoxia altered therapeutic effectiveness and clearance of several drugs, in rats and rabbits exposed to intermittent hypobaric hypoxia. s0 uch studies need to be done in human volunteers to see the effect of hypoxia on pharmacokinetics of some common drugs. PMID- 22446864 TI - A study on inorganic elements in psammomas from ovarian & thyroid cancer. AB - BACKGROUND & OBJECTIVES: Concentric lamellar calcifications known as psammoma bodies (PB) are found in benign and malignant tumours. Whether or not the inorganic element concentrations in psammomas are similar to serous adenocarcinoma of the ovary and thyroid papillary cancer tissues has not yet been ascertained. We undertook this retrospective study to establish if there is any difference in the concentrations of inorganic ions found in psammomas in serous adenocarcinoma of the ovary, and those found in thyroid papillary cancer tissue. METHODS: PB samples from patients with adenocarcinoma of the ovary (n = 10) and with thyroid papillary cancer (n = 10) were analyzed through inductively-coupled plasma spectroscopy (ICP). RESULTS: There were no significant differences in the concentrations of inorganic elements in PB from thyroid papillary cancer than in those PB from ovarian cancer. INTERPRETATION & CONCLUSIONS: Differences in the concentrations of inorganic elements may be due to the variation in environmental pollution. Our study had limitation of small sample size. Our results suggest that some inorganic elements can participate in the origin of psammoma bodies. PMID- 22446865 TI - Efficacy of glucosamine alendronate alone & in combination with dihydroquercetin for treatment of osteoporosis in animal model. AB - BACKGROUND & OBJECTIVES: Considerable efforts are being made to develop new, more effective drugs for osteoporosis, including novel forms of bisphosphonates. The present study was carried out to compare the effect of a novel agent glucosamine alendronate (GA) alone and is combination with dihydroquercetin (DHQ) against the effect of a known drug alendronate (ALN) in the senescence-accelerated OXYS rats as model of osteoporosis. METHODS: Male OXYS and Wistar (control) rats were randomized across four experimental groups (n=15), which received 1.26 mg GA, 0.84 mg ALN, or 1.26 mg GA + 5.06 mg DHQ per kg of body weight. Untreated rats were used as control groups. At the end of treatment, the bone mineral density (BMD), bone biomechanical properties, and the levels of serum osteocalcin, alphaC terminal crosslinked telopeptides of type I collagen (alpha-CTx) and calcium were measured. RESULTS: All treatments increased BMD in rats of both strains, but the improvement was more pronounced in OXYS rats: GA+DHQ increased both the strength of the femur by 20 per cent (P<0.01) and BMD by 7.6 per cent (P<0.023). GA+DHQ and ALN reduced serum alpha-CTx in OXYS rats. Only GA increased the level of osteocalcin in OXYS rats (P<0.05). ALN increased the cross-sectional area of the femur by 9 per cent (P<0.04) in OXYS and by 12 per cent (P<0.05) in Wistar rats. INTERPRETATION & CONCLUSIONS: The combined treatment with GA+DHQ appears to be more effective at maintaining strength of the femur and BMD in OXYS rats, when compared to the individual drugs GA and ALN. PMID- 22446866 TI - Chronic infections & coronary artery disease with special reference to Chalmydia pneumoniae. AB - BACKGROUND & OBJECTIVES: Studies on cardiovascular diseases (CVD) in India have shown about 10-20 per cent of cases with no obvious risk factors, raising a suspicion of infections as a cause. There is a paucity of data on this possible role of infections. This study was, therefore, undertaken to find out the association between infection due to Chlamydia pneumoniae and other organisms and coronary artery disease (CAD). METHODS: Patients with CAD were selected in group I (acute myocardial infarction, AMI) and group III (patients undergoing coronary artery bypass graft (CABG) surgery), and normal controls in group II. Routine biochemical, haematological and inflammatory tests [C-reactive protein (CRP), total leucocyte count (TLC), fibrinogen, ESR], serodiagnostic tests for IgA and IgG antibodies to C. pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), Mycoplasma pneumoniae and Parvovirus B-19 by ELISA kits, C. pneumoniae antigen by microimmunofluorescence and PCR from endothelial tissue obtained at CABG were carried out. Aortic punch biopsies were done in patients who underwent CABG. RESULTS: Acute MI patients had a significantly higher association with accepted cardiac risk factors, lipid profile, inflammatory and thrombogenic tests. IgG and IgA antibodies levels against C. pneumoniae were not significantly different in the controls as against the AMI group. However, C. pneumoniae antigen seropositive group had significant association with HDL cholesterol, lipid tetrad index (P<0.001) and with triglycerides. Parvovirus B antigen was detected in 8.3 per cent of tissue specimens by PCR and of 44 patients with AMI (6.8%) were also positive for parvovirus B-19 IgG antibodies. INTERPRETATION & CONCLUSIONS: There was no direct evidence of the involvement of C. pneumoniae and other infective agents and viruses in CAD. It is possible that such infections produce an indirect adverse effect on the lipid profile. PMID- 22446867 TI - Effects of heat stress on endocrine functions & behaviour in the pre-pubertal rat. AB - BACKGROUND & OBJECTIVES: Heat stress related hyperthermia may cause damage to various organ systems. There are very few studies on the effects of hyperthermia on the endocrine system. We therefore, investigated effects of exogenously induced hyperthermia on adrenal, testicular and thyroid functions and behavioural alterations in pre-pubertal male Sprague-Dawley rats. METHODS: Three groups of 30 day old rats (n=7 per group) were used. Body temperature was increased to 39 degrees C (Group I) and 41 degrees C (Group II) in a hyperthermia induction chamber for 30 min. The rats in the Group III served as control (36 degrees C). All animals received saline and were decapitated 48 h after the experiments. Serum free triiodothyronin (fT3), free thyroxine (fT4), total testosterone and dehydroepiandrosterone sulphate (DHEA-S) levels were determined by chemiluminescence assay, and corticosterone by enzyme immunoassay. Testes, pituitary and adrenal glands were dissected out and processed for histopathological examination. To assess activity and anxiety of the animals, the open field test and elevated-0-maze test, respectively, were used in all groups 24 h before (day 29) and after (day 31) hyperthermia induction. RESULTS: Serum corticosterone levels (3.22 +/- 1.3) were significantly reduced in the 39 degrees C (1.3 +/- 0.9) and 41 degrees C (1.09 +/- 0.7) hyperthermia groups (P<0.01) compared to controls. Serum levels of thyroid hormones did not significantly differ among the groups. DHEA-S and testosterone values were below the limit of detection in all groups. Histopathological examination revealed that there was mild hydropic degeneration in the pituitary and adrenal glands. Apoptotic germ cells were seen in the seminiferous tubules of pre-pubertal male rats exposed to hyperthermia (41 degrees C). Progression time in the open field test was significantly decreased and anxiety test scores increased in animals exposed to 39 degrees C compared to the control group (P<0.01). These parameters were more pronounced in the 41 degrees C hyperthermia group. INTERPRETATION & CONCLUSIONS: Our results show that heat exposure-induced stress may cause delayed reduction in serum corticosterone levels which may be associated with behavioural deficits in pre-pubertal male rats. PMID- 22446868 TI - Evaluation of disease modifying activity of Coriandrum sativum in experimental models. AB - BACKGROUND & OBJECTIVES: Coriandrum sativum (CS), has been widely used in traditional systems of medicine for treatment of rheumatoid arthritis. However, the mechanism of action for its antiarthritic effects is not clearly known. Therefore, the present study was carried out to evaluate the antiarthritic activity of CS in rats in two experimental models. METHODS: The antiarthritic activity of CS seed hydroalcoholic extract (CSHE) was evaluated in adult Wistar rats by using two experimental models, viz. formaldehyde and Complete Freund's adjuvant (CFA) induced arthritis. The expression of pro-inflammatory cytokines (predominantly contributed by macrophages) was also evaluated. TNF- alpha level was estimated in serum by ELISA method. TNF-R1, IL-1 beta and IL-6 expression in the synovium was analysed by immunohistochemistry. RESULTS: CSHE produced a dose dependent inhibition of joint swelling as compared to control animals in both, formaldehyde and CFA induced arthritis. Although there was a dose dependent increase in serum TNF-alpha levels in the CSHE treated groups as compared to control, the synovial expression of macrophage derived pro-inflammatory cytokines/cytokine receptor was found to be lower in the CSHE treated groups as compared to control. INTERPRETATION & CONCLUSIONS: Our results demonstrate that the antiarthritic activity of CSHE may be attributed to the modulation of pro inflammatory cytokines in the synovium. In further studies CSHE could be explored to be developed as a disease modifying agent in the treatment of RA. PMID- 22446869 TI - How endemic is cholera in India? PMID- 22446870 TI - Diagnosis of TB from smear & culture negative sputum specimens by IS 6110 based PCR. PMID- 22446871 TI - Evaluation of antibiotic & antibiotic modifying activity of pilocarpine & rutin. PMID- 22446872 TI - Medical PG seats being sold! The conundrum of privatized medical education. PMID- 22446873 TI - Lacunae of disability certification in mental health. PMID- 22446874 TI - Downregulation of human farnesoid X receptor by miR-421 promotes proliferation and migration of hepatocellular carcinoma cells. AB - The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenal gland, and intestine. It plays an important role in regulating the progression of several cancers including hepatocellular carcinoma (HCC). So it is necessary to study the regulation of FXR. In this study, we found that the expression of miR-421 was inversely correlated with FXR protein level in HCC cell lines. Treatment with miR-421 mimic repressed FXR translation. The reporter assay revealed that miR-421 targeted 3' untranslated region of human FXR mRNA. Furthermore, downregulation of FXR by miR 421 promoted the proliferation, migration, and invasion of HCC cells. These results suggest that miR-421 may serve as a novel molecular target for manipulating FXR expression in hepatocyte and for the treatment of HCC. PMID- 22446875 TI - Dynamic eicosanoid responses upon different inhibitor and combination treatments on the arachidonic acid metabolic network. AB - The arachidonic acid (AA) metabolic network produces key inflammatory mediators which have been considered as hallmark contributors in various inflammatory related diseases. Enzymes in this network, such as 5-lipoxygenase (5-LOX), cyclooxygenase (COX), leukotriene A(4) hydrolase (LTA4H) and prostaglandin E synthase (PGES), have been used as targets for anti-inflammatory drug discovery. Multi-target drugs and drug combinations have also been developed for this network. However, how the inhibitors alter the dynamics of metabolite production and which combinatorial target intervention solutions are better needs further exploration. We did a system based intervention analysis on the AA metabolic network. Using an LC-MS/MS method, we quantitatively studied the eicosanoid metabolites responses of AA metabolic network during stimulation of Sprague Dawley rat blood samples with the calcium ionophore. Our results indicate that inhibiting the upstream rather than the downstream target of 5-LOX pathway will simultaneously alter the AA metabolism to the COX pathway (and vice versa). Therefore, single-target inhibitors cannot control all the inflammatory mediators at the same time. We also suggest that in the case of multiple-target anti inflammatory solutions, the combination of inhibitors of the downstream enzymes may have stronger inhibition efficiency and cause less side-effects compared to the other solutions. One therapeutic strategy, LTA4H/COX inhibition solution, was found promising for the intervention of inflammatory mediator biosynthesis and at the same time stimulating the production of anti-inflammatory agents. PMID- 22446876 TI - Improvement of myocardial lipid accumulation and prevention of PGC-1alpha induction by fenofibrate. AB - We recently demonstrated that fenofibrate induces the activities of citrate synthase and NADH oxidase in cardiac mitochondria. To further determine the molecular mechanisms underlying fenofibrate action, 8-week-old mice were administered fenofibrate (100 mg/kg/day) for 7 and 14 days, and the expression of genes involved in cardiac mitochondrial function, such as nuclear respiratory factor 1 transcript variant 2 (NRF-1-L) and 6 (NRF-1-S), mitochondrial outer membrane protein 40 (Tom40), lipoic acid synthetase (Lias), cytochrome b, medium chain acyl-coenzyme A dehydrogenase (MCAD) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) was determined. Expression of PGC 1alpha, a key regulator of the entire fatty acid oxidation system, was significantly downregulated after 14 days of fenofibrate administration. Moreover, ventricular triglycerides were also accumulated following 14 days of fenofibrate administration. Thus, fenofibrate functions to improve myocardial lipid accumulation and to prevent PGC-1alpha induction, which is crucial for understanding the molecular mechanisms underlying fenofibrate action on the heart. PMID- 22446877 TI - Correlating brain blood oxygenation level dependent (BOLD) fractal dimension mapping with magnetic resonance spectroscopy (MRS) in Alzheimer's disease. AB - OBJECTIVES: To correlate temporal fractal structure of resting state blood oxygen level dependent (rsBOLD) functional magnetic resonance imaging (fMRI) with in vivo proton magnetic resonance spectroscopy ((1)H-MRS), in Alzheimer's disease (AD) and healthy age-matched normal controls (NC). MATERIALS AND METHODS: High temporal resolution (4 Hz) rsBOLD signal and single voxel (left putamen) magnetic resonance spectroscopy data was acquired in 33 AD patients and 13 NC. The rsBOLD data was analyzed using two types of fractal dimension (FD) analysis based on relative dispersion and frequency power spectrum. Comparisons in FD were performed between AD and NC, and FD measures were correlated with (1)H-MRS findings. RESULTS: Temporal fractal analysis of rsBOLD, was able to differentiate AD from NC subjects (P = 0.03). Low FD correlated with markers of AD severity including decreased concentrations of N-acetyl aspartate (R = 0.44, P = 0.015) and increased myoinositol (mI) (R = -0.45, P = 0.012). CONCLUSION: Based on these results we suggest fractal analysis of rsBOLD could provide an early marker of AD. PMID- 22446878 TI - Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition. AB - A consortium of inhibitory neurons control the firing patterns of pyramidal cells, but their specific roles in the behaving animal are largely unknown. We performed simultaneous physiological recordings and optogenetic silencing of either perisomatic (parvalbumin (PV) expressing) or dendrite-targeting (somatostatin (SOM) expressing) interneurons in hippocampal area CA1 of head fixed mice actively moving a treadmill belt rich with visual-tactile stimuli. Silencing of either PV or SOM interneurons increased the firing rates of pyramidal cells selectively in their place fields, with PV and SOM interneurons having their largest effect during the rising and decaying parts of the place field, respectively. SOM interneuron silencing powerfully increased burst firing without altering the theta phase of spikes. In contrast, PV interneuron silencing had no effect on burst firing, but instead shifted the spikes' theta phase toward the trough of theta. These findings indicate that perisomatic and dendritic inhibition have distinct roles in controlling the rate, burst and timing of hippocampal pyramidal cells. PMID- 22446879 TI - Mitochondrial Ca(2+) mobilization is a key element in olfactory signaling. AB - In olfactory sensory neurons (OSNs), cytosolic Ca(2+) controls the gain and sensitivity of olfactory signaling. Important components of the molecular machinery that orchestrates OSN Ca(2+) dynamics have been described, but key details are still missing. Here, we demonstrate a critical physiological role of mitochondrial Ca(2+) mobilization in mouse OSNs. Combining a new mitochondrial Ca(2+) imaging approach with patch-clamp recordings, organelle mobility assays and ultrastructural analyses, our study identifies mitochondria as key determinants of olfactory signaling. We show that mitochondrial Ca(2+) mobilization during sensory stimulation shapes the cytosolic Ca(2+) response profile in OSNs, ensures a broad dynamic response range and maintains sensitivity of the spike generation machinery. When mitochondrial function is impaired, olfactory neurons function as simple stimulus detectors rather than as intensity encoders. Moreover, we describe activity-dependent recruitment of mitochondria to olfactory knobs, a mechanism that provides a context-dependent tool for OSNs to maintain cellular homeostasis and signaling integrity. PMID- 22446880 TI - A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. AB - Cell type-specific expression of optogenetic molecules allows temporally precise manipulation of targeted neuronal activity. Here we present a toolbox of four knock-in mouse lines engineered for strong, Cre-dependent expression of channelrhodopsins ChR2-tdTomato and ChR2-EYFP, halorhodopsin eNpHR3.0 and archaerhodopsin Arch-ER2. All four transgenes mediated Cre-dependent, robust activation or silencing of cortical pyramidal neurons in vitro and in vivo upon light stimulation, with ChR2-EYFP and Arch-ER2 demonstrating light sensitivity approaching that of in utero or virally transduced neurons. We further show specific photoactivation of parvalbumin-positive interneurons in behaving ChR2 EYFP reporter mice. The robust, consistent and inducible nature of our ChR2 mice represents a significant advance over previous lines, and the Arch-ER2 and eNpHR3.0 mice are to our knowledge the first demonstration of successful conditional transgenic optogenetic silencing. When combined with the hundreds of available Cre driver lines, this optimized toolbox of reporter mice will enable widespread investigations of neural circuit function with unprecedented reliability and accuracy. PMID- 22446881 TI - Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. AB - Endocannabinoid mediated spike timing-dependent depression (t-LTD) is crucially involved in the development of the sensory neocortex. t-LTD at excitatory synapses in the developing rat barrel cortex requires cannabinoid CB(1) receptor (CB(1)R) activation, as well as activation of NMDA receptors located on the presynaptic terminal, but the exact signaling cascade leading to t-LTD remains unclear. We found that astrocytes are critically involved in t-LTD. Astrocytes gradually increased their Ca(2+) signaling specifically during the induction of t LTD in a CB(1)R-dependent manner. In this way, astrocytes might act as a memory buffer for previous coincident neuronal activity. Following activation, astrocytes released glutamate, which activated presynaptic NMDA receptors to induce t-LTD. Astrocyte stimulation coincident with afferent activity resulted in long-term depression, indicating that astrocyte activation is sufficient for the induction of synaptic depression. Taken together, our findings describe the retrograde signaling cascade underlying neocortical t-LTD. The critical involvement of astrocytes in this process highlights their importance for experience-dependent sensory remodeling. PMID- 22446882 TI - Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. AB - Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism. PMID- 22446883 TI - Bombyx mori nucleopolyhedrovirus ORF54, a viral desmoplakin gene, is associated with the infectivity of budded virions. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) ORF54 (Bm54), a member of the viral desmoplakin N-terminus superfamily, is homologous to Autographa californica nucleopolyhedrovirus (AcMNPV) ORF66, which is required for the efficient egress of nucleocapsids from the nucleus and occlusion body formation. In this paper, we generated a bacmid with the Bm54 gene deleted via homologous recombination in Escherichia coli and characterized the mutant virus using a transfection infection assay and transmission electron microscopy analysis. Our results demonstrated that the cells transfected with viral DNA lacking Bm54 produced non infectious budded viruses (BVs). Electron microscopy showed that although the deletion of Bm54 did not affect assembly and release of nucleocapsids, it severely affected polyhedron formation. In conclusion, deletion of Bm54 resulted in non-infectious BV and defective polyhedra. Although the sequences of Bm54 and Ac66 are very similar, the two genes function quite differently in the regulation of viral life cycle. PMID- 22446884 TI - Virus-induced gene silencing of Mlo genes induces powdery mildew resistance in Triticum aestivum. AB - Powdery mildew is one of the most important cereal diseases worldwide. Genetic analysis has revealed that mutant alleles of the Mlo gene cause broad-spectrum resistance against this pathogen in barley. In this study, the possibility of inducing broad-spectrum powdery mildew resistance against this pathogen by RNAi of the barley Mlo ortholog in wheat was examined using virus-induced gene silencing (VIGS). A clear correlation was found between resistance and accumulation of Mlo-specific siRNAs, raising the possibility of designing powdery mildew resistance in wheat by RNA silencing using both transgenic and non transgenic approaches. PMID- 22446885 TI - Framing the issues: moral distress in health care. AB - Moral distress in health care has been identified as a growing concern and a focus of research in nursing and health care for almost three decades. Researchers and theorists have argued that moral distress has both short and long term consequences. Moral distress has implications for satisfaction, recruitment and retention of health care providers and implications for the delivery of safe and competent quality patient care. In over a decade of research on ethical practice, registered nurses and other health care practitioners have repeatedly identified moral distress as a concern and called for action. However, research and action on moral distress has been constrained by lack of conceptual clarity and theoretical confusion as to the meaning and underpinnings of moral distress. To further examine these issues and foster action on moral distress, three members of the University of Victoria/University of British Columbia (UVIC/UVIC) nursing ethics research team initiated the development and delivery of a multi faceted and interdisciplinary symposium on Moral Distress with international experts, researchers, and practitioners. The goal of the symposium was to develop an agenda for action on moral distress in health care. We sought to develop a plan of action that would encompass recommendations for education, practice, research and policy. The papers in this special issue of HEC Forum arose from that symposium. In this first paper, we provide an introduction to moral distress; make explicit some of the challenges associated with theoretical and conceptual constructions of moral distress; and discuss the barriers to the development of research, education, and policy that could, if addressed, foster action on moral distress in health care practice. The following three papers were written by key international experts on moral distress, who explore in-depth the issues in three arenas: education, practice, research. In the fifth and last paper in the series, we highlight key insights from the symposium and the papers in the series, propose to redefine moral distress, and outline directions for an agenda for action on moral distress in health care. PMID- 22446886 TI - Intravitreal ranibizumab for exudative age-related macular degeneration with good baseline visual acuity. AB - PURPOSE: To clarify the efficacy of ranibizumab for treating age-related macular degeneration in patients with baseline visual acuity exceeding 20/40. METHODS: We retrospectively reviewed 40 eyes of Japanese patients with age-related macular degeneration (32 men, 8 women) treated with intravitreal injections of ranibizumab (0.5 mg/0.05 mL) (ranibizumab group). We compared the results with observation of 52 eyes (control group). All patients were followed-up for at least 12 months. RESULTS: In the ranibizumab group, the mean logarithm of the minimum angle of resolution best-corrected visual acuity (Snellen equivalent) with typical age-related macular degeneration (22 eyes) and polypoidal choroidal vasculopathy (18 eyes) statistically significantly (P < 0.0001, P = 0.015, respectively) improved from 0.17 (20/29) and 0.14 (20/28) at baseline to 0.07 (20/24) and 0.07 (20/24) at Month 12, respectively (mean numbers of treatments, 4.6 and 4.9). The central retinal thickness decreased from 262 +/- 105 MUm at baseline to 187 +/- 62 MUm at Month 12 in the ranibizumab group. In the control group, the mean logarithm of the minimum angle of resolution best-corrected visual acuity in eyes with typical age-related macular degeneration (19 eyes) and polypoidal choroidal vasculopathy (33 eyes) statistically significant (P = 0.017, P = 0.023, respectively) declined from 0.08 (20/24) and 0.10 (20/25) at baseline to 0.18 (20/30) and 0.23 (20/34) at Month 12, respectively. CONCLUSION: Intravitreal ranibizumab maintained or improved visual acuity and anatomic changes in patients with age-related macular degeneration with better than 20/40 visual acuity. PMID- 22446887 TI - Dicer 1, ribonuclease type III modulates a reprogramming effect in colorectal cancer cells. AB - Complete cell reprogramming can be achieved by the introduction of specific transcription factors, Oct4 [also known as POU class 5 homeobox 1 (Pou5f1)]; sex determining region Y (SRY)-box 2 (Sox2); Kruppel-like factor 4 (Klf4); and myelocytomatosis viral oncogene homolog (c-Myc), into terminally differentiated mouse somatic fibroblasts. This reprogramming process may be accelerated or suppressed by various factors, including microRNAs (miRNAs). Introduction of these transcription factors or miRNAs considerably modifies the malignant phenotype of cancer cells. We studied the effect of introducing these transcription factors into two distinct colorectal cancer (CRC) cell lines, HCT116 and DLD-1, in the presence and absence of Dicer 1, ribonuclease type III (Dicer1), a critical miRNA processing enzyme. We assessed cell reprogramming based on the number of cells exhibiting alkaline phosphatase staining and an increase in embryonic stem cell-like gene expression, indicating the return of cells to an immature state. Dicer1-deficient CRC cells showed a reduced number of alkaline phosphatase-positive reprogrammed cells than wild-type (WT) cells. Before reprogramming, endogenous expression of an immature carbohydrate epitope, TRA-1-60, was high in Dicer1-deficient CRC cells, whereas after reprogramming, the expression of this epitope was increased in Dicer1-sufficient more than in Dicer1-deficient CRC cells. Our data demonstrate the critical role of miRNAs in the reprogramming process and determination of a differentiated phenotype of CRC cells. PMID- 22446888 TI - Abstracts of LEAP: Lead, Excel, Achieve, Perform, the UHC Annual Conference 2011. September 21-23, 2011. Chicago, Illinois, USA. PMID- 22446889 TI - Photo-sensitive self-motion of a BQ disk. AB - The photo-sensitive self-motion of a benzoquinone (BQ) disk was investigated on a hydroquinone (HQ) aqueous solution. The mode-switching of self-motion, i.e., continuous -> intermittent -> no motion, was observed with an increase in the concentration of HQ. Upon irradiation with UV light (~254 nm), the critical concentrations of HQ that were associated with the three modes of motion shifted to lower values, and the average speed of motion decreased. We discuss the mechanism of the photo-sensitive self-motion in relation to the photochemical reaction from BQ to HQ and the driving force of the disk. PMID- 22446890 TI - A comparative proteomic approach to better define Deinococcus nucleoid specificities. AB - Compared to radiation-sensitive bacteria, the nucleoids of radiation-resistant Deinococcus species show a higher degree of compaction. Such a condensed nucleoid may contribute to the extreme radiation resistance of Deinococcus by limiting dispersion of radiation-induced DNA fragments. Architectural proteins may play a role in this high degree of nucleoid compaction, but comparative genomics revealed only a limited number of Deinococcus homologs of known nucleoid associated proteins (NAPs) from other species such as Escherichia coli. A comparative proteomic approach was used to identify potentially novel proteins from isolated nucleoids of Deinococcus radiodurans and Deinococcus deserti. Proteins in nucleoid enriched fractions were identified and semi-quantified by shotgun proteomics. Based on normalized spectral counts, the histone-like DNA binding protein HU appeared to be the most abundant among candidate NAPs from both micro-organisms. By immunofluorescence microscopy, D. radiodurans HU and both DNA gyrase subunits were shown to be distributed throughout the nucleoid structure and absent from the cytoplasm. Taken together, our results suggest that D. radiodurans and D. deserti bacteria contain a very low diversity of NAPs, with HU and DNA gyrase being the main proteins involved in the organization of the Deinococcus nucleoids. PMID- 22446891 TI - Venom variability and envenoming severity outcomes of the Crotalus scutulatus scutulatus (Mojave rattlesnake) from Southern Arizona. AB - Twenty-one Mojave rattlesnakes, Crotalus scutulatus scutulatus (C. s. scutulatus), were collected from Arizona and New Mexico U.S.A. Venom proteome of each specimen was analyzed using reverse-phase HPLC and SDS-PAGE. The toxicity of venoms was analyzed using lethal dose 50 (LD(50)). Health severity outcomes between two Arizona counties U.S.A., Pima and Cochise, were determined by retrospective chart review of the Arizona Poison and Drug Information Center (APDIC) database between the years of 2002 and 2009. Six phenotypes (A-F) were identified based on three venom protein families; Mojave toxin, snake venom metalloproteinases PI and PIII (SVMP), and myotoxin-A. Venom changed geographically from SVMP-rich to Mojave toxin-rich phenotypes as you move from south central to southeastern Arizona. Phenotypes containing myotoxin-A were only found in the transitional zone between the SVMP and Mojave toxin phenotypes. Venom samples containing the largest amounts of SVMP or Mojave toxin had the highest and lowest LD(50s), respectively. There was a significant difference when comparing the presence of neurotoxic effects between Pima and Cochise counties (p=0.001). No significant difference was found when comparing severity (p=0.32), number of antivenom vials administered (p=0.17), days spent in a health care facility (p=0.23) or envenomation per 100,000 population (p=0.06). Although not part of the original data to be collected, death and intubations, were also noted. There is a 10* increased risk of death and a 50* increased risk of intubations if envenomated in Cochise County. PMID- 22446892 TI - Characterization of photosynthesis in Arabidopsis ER-to-plastid lipid trafficking mutants. AB - Vascular plants use two pathways to synthesize galactolipids, the predominant lipid species in chloroplasts-a prokaryotic pathway that resides entirely in the chloroplast, and a eukaryotic pathway that involves assembly in the endoplasmic reticulum. Mutants deficient in the endoplasmic reticulum pathway, trigalactosyldiacylglycerol (tgd1-1 and tgd2-1) mutants, had been previously identified with reduced contents of monogalactosyldiacylglycerol and digalactosyldiacylglycerol, and altered lipid molecular species composition. Here, we report that the altered lipid composition affected photosynthesis in lipid trafficking mutants. It was found that proton motive force as measured by electrochromic shift was reduced by ~40% in both tgd mutants. This effect was accompanied by an increase in thylakoid conductance attributable to ATPase activity and so the rate of ATP synthesis was nearly unchanged. Thylakoid conductance to ions also increased in tgd mutants. However, gross carbon assimilation in tgd mutants as measured by gas exchange was only marginally affected. Rubisco activity, electron transport rate, and photosystem I and II oxidation status were not altered. Despite the large differences in proton motive force, responses to heat and high light stress were similar between tgd mutants and the wild type. PMID- 22446893 TI - Can we overcome the 'clinico-radiological paradox' in multiple sclerosis? AB - The association between common neuroradiological markers of multiple sclerosis (MS) and clinical disability is weak, a phenomenon known as the clinico radiological paradox. Here, we investigated to which degree it is possible to predict individual disease profiles from conventional magnetic resonance imaging (MRI) using multivariate analysis algorithms. Specifically, we conducted cross validated canonical correlation analyses to investigate the predictive information contained in conventional MRI data of 40 MS patients for the following clinical parameters: disease duration, motor disability (9-Hole Peg Test, Timed 25-Foot Walk Test), cognitive dysfunction (Paced Auditory Serial Addition Test), and the expanded disability status scale (EDSS). It turned out that the information in the spatial patterning of MRI data predicted the clinical scores with correlations of up to 0.80 (p < 10(-9)). Maximal predictive information for disease duration was identified in the precuneus and somatosensory cortex. Areas in the precuneus and precentral gyrus were maximally informative for motor disability. Cognitive dysfunction could best be predicted using data from the angular gyrus and superior parietal lobe. For EDSS, the inferior frontal gyrus was maximally informative. In conclusion, conventional MRI is highly predictive of clinical disability in MS when pattern-based algorithms are used for prediction. Thus, the so-called clinico-radiological paradox is not apparent when using suitable analysis techniques. PMID- 22446894 TI - Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model. AB - Previous in vitro studies suggest that the endothelin A receptor (ETAR) could be a potential therapeutic target for osteosarcoma (OS) metastasis. In the present study, we assessed for the first time the role of ETAR in OS proliferation and pulmonary metastasis in vivo. MG-63 human OS cells were stably transduced with ETAR shRNA or scramble control shRNA and injected into the tibia of nude mice to generate an orthotopic xenograft OS model. The mice were divided into three groups (n=10 each group): i) the untransduced control group, where the mice were injected with untransduced MG-63 cells; ii) the scramble control group, where the mice were injected with cells stably transduced with the scramble control shRNA; iii) the ETAR-shRNA group, where the mice were injected with cells stably transduced with ETAR shRNA. The ETAR shRNA knocked down more than 75% of endogenous ETAR expression and significantly inhibited invasion, but not proliferation/viability of MG-63 cells in vitro. In the orthotopic xenograft OS mouse model, no significant difference in the tumor volume was observed over time among the untransduced control, the scramble control and the ETAR-shRNA groups. However, a combination of clinical signs, organ examinations and quantitative clonogenic lung metastasis assays showed that lung metastasis in the ETAR-shRNA group was significantly lower than that in the control groups. Immunohistochemical analyses revealed that the matrix metalloproteinase-2 (MMP-2) expression was significantly reduced in the ETAR-shRNA group compared with the control groups. The results were confirmed with western blot analyses using primary tumor tissues or the stably transduced MG-63 cells. In conclusion, we demonstrated in an orthotopic xenograft OS model that ETAR is critical for OS pulmonary metastasis, but not for tumor growth. This study provides the first in vivo evidence suggesting an important role for ETAR in OS pulmonary metastasis. PMID- 22446895 TI - Laparoscopic adjustable gastric banding. AB - Laparoscopic adjustable gastric banding is one of several weight loss procedures in the bariatric surgeon's armamentarium to treat morbid obesity. Laparoscopic gastric banding has the lowest perioperative risk compared to laparoscopic gastric bypass, sleeve gastrectomy, and duodenal switch (Buchwald et al., JAMA 292:1724-1737, 2004). The adjustable gastric band results in approximately 50% excess weight loss at 5 years (O'Brien and Dixon,J Laparoendosc Adv Surg Tech A 13:265-270, 2003). In the long-term, reoperation rates can be high with the percentage of reoperations varying enormously in reported studies from 2% to 80% (Schouten et al., Surg Obes Relat Dis 7:99-109, 2011), although with changes in technique, reoperation rates after gastric banding have decreased (O'Brien et al., Obes Surg 15:820-826, 2005). Aftercare is critical to the success of the banded patient, in terms of adjusting the band as well as monitoring the patient's symptoms (Weichman et al., Surg Endosc 25:397-403, 2011). Several studies have shown that patients who are seen more than six to seven times in the first postoperative year have better weight loss. PMID- 22446896 TI - Comparison between dynamic cystocolpoproctography and dynamic pelvic floor MRI: pros and cons: which is the "functional" examination for anorectal and pelvic floor dysfunction? AB - "Functional" imaging of anorectal and pelvic floor dysfunction has assumed an important role in the diagnosis and management of these disorders. Although defecography has been widely practiced for decades to evaluate the dynamics of rectal emptying, debate concerning its clinical relevance, how it should be done and interpreted continues. Due to the recognition of the association of defecatory disorders with pelvic organ prolapse in women, the need to evaluate the pelvic floor as a unit has arisen. To meet this need, defecography has been extended to include not only evaluation of defecation disorders but also the rest of the pelvic floor by opacifying the small bowel, vagina, and the urinary bladder. The term "dynamic cystocolpoproctography" (DCP) has been appropriately applied to this examination. Rectal emptying performed with DCP provides the maximum stress to the pelvic floor resulting in complete levator ani relaxation. In addition to diagnosing defecatory disorders, this method of examination demonstrates maximum pelvic organ descent and provides organ-specific quantification of organ prolapse, information that is only inferred by means of physical examination. It has been found to be of clinical value in patients with defecation disorders and the diagnosis of associated prolapse in other compartments that are frequently unrecognized by history taking and the limitations of physical examination. Pelvic floor anatomy is complex and DCP does not show the anatomical details pelvic magnetic resonance imaging (MRI) provides. Technical advances allowing acquisition of dynamic rapid MRI sequences has been applied to pelvic floor imaging. Early reports have shown that pelvic MRI may be a useful tool in pre-operative planning of these disorders and may lead to a change in surgical therapy. Predictions of hypothetical increase cancer incidence and deaths in patients exposed to radiation, the emergence of pelvic floor MRI in addition to questions relating to the clinical significance of DCP findings have added to these controversies. This review analyses the pros and cons between DCP and dynamic pelvic floor MRI, addresses imaging and interpretive controversies, and their relevance to clinical management. PMID- 22446897 TI - Limited value and utility of breast MRI in patients undergoing breast-conserving cancer surgery. AB - BACKGROUND: Our aim was to compare the accuracy of magnetic resonance imaging (MRI) and ultrasonography (US) in measuring the size of invasive breast cancer (IBC) and carcinoma in situ (CIS). We also examined the utility of routinely performing MRI in addition to US before breast-conserving surgery (BCS). PATIENTS AND METHODS: Data from 1558 consecutive patients diagnosed with IBC and/or CIS between 2003 and 2005 were reviewed. For comparing the accuracy of US and MRI, paired t test was done comparing pathologic and imaging (US and MRI) tumor size in 821 patients who received both breast US and MRI. In instance of attempted BCS (n = 794), operative approach, resection margins, and clinical outcomes of non MRI and MRI groups were compared. RESULTS: For CIS, IBC without CIS, and IBC with CIS, MRI was more accurate in estimating tumor size than US. When BCS was attempted (n = 794), the rate of tumor involvement in initial resection margins did not differ between non-MRI and MRI groups (23.0% and 23.4%, P = .926). Similarly, rates of re-excision (13.1% vs 17.5%, P = .130) and conversion to mastectomy (2.3% vs 2.1%, P = .893) were comparable, as were ipsilateral breast tumor recurrence, locoregional recurrence, and disease-free survival (log rank P = .284, .950, and .955, respectively). CONCLUSIONS: Breast MRI provided more accurate estimates of tumor size, correlating better with pathologic tumor size than US for both IBC and CIS. However, no clear benefit in terms of lower re excision rate, higher breast conservation success, or reduced recurrence emerged for routine use of breast MRI before BCS. PMID- 22446898 TI - The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. AB - BACKGROUND: Studies show that women with low vitamin D levels have an increased risk of breast cancer (BC) incidence and mortality, but there is a lack of research examining vitamin D levels and prognostic variables in BC patients. The aim of this study is to examine 25-OH vitamin D levels between BC cases and controls and by prognostic indicators among BC cases. METHODS: 25-OH vitamin D levels were collected from 194 women who underwent BC surgery and 194 cancer-free (CF) controls at the University of Rochester between January 2009 and October 2010. Mean 25-OH vitamin D levels and odds ratios (OR) were calculated by case/control status for the overall cohort and by prognostic indicators (invasiveness, ER status, triple-negative status, Oncotype DX score, molecular phenotype) for BC cases. RESULTS: BC cases had significantly lower 25-OH vitamin D levels than CF controls (BC: 32.7 ng/mL vs. CF: 37.4 ng/mL; P = .02). In case series analyses, women with suboptimal 25-OH vitamin D concentrations (<32 ng/mL) had significantly higher odds of having ER- (OR = 2.59, 95% confidence interval [95% CI] = 1.08-6.23) and triple-negative cancer (OR = 3.15, 95% CI = 1.05-9.49) than those with optimal 25-OH D concentrations. Women with basal-like phenotype had lower 25-OH vitamin D levels than women luminal A phenotype (basal-like: 24.2 ng/mL vs. luminal A: 32.8 ng/mL; P = 0.04). CONCLUSIONS: BC patients with a more aggressive molecular phenotype (basal-like) and worse prognostic indicators (ER- and triple-negative) had lower mean 25-OH vitamin D levels. Further research is needed to elucidate the biological relationship between vitamin D and BC progression. PMID- 22446899 TI - Novel multiple apoptotic mechanism of shikonin in human glioma cells. AB - BACKGROUND: Shikonin is the main naphthoquinone compound of the root of Lithospermum erythrorhizon. Our previous study demonstrated that shikonin possesses anticancer activity in human hepatoma cells. However, the anticancer mechanism of shikonin in human glioma cells is unclear at present. In the present study, we demonstrated that shikonin induces apoptosis in three human glioma cell lines: U87MG, Hs683, and M059K cells. METHODS: Cell cycle, generation of reactive oxygen species (ROS), depletion of glutathione (GSH), and disruption of mitochondrial transmembrane potential in shikonin-treated cells were determined by flow cytometry. Apoptosis-related proteins, catalase, and superoxide dismutase 1 (SOD-1) were determined by Western blot testing. N-acetylcysteine (NAC), pifithrin-alpha (PFT-alpha), or cyclosporin A were applied to evaluate the molecular mechanism of shikonin in apoptosis. RESULTS: Shikonin induces the generation of ROS, depletion of GSH, disruption of mitochondrial transmembrane potential, upregulation of p53, and cleavage of PARP [poly(ADP-ribose) polymerase] in U87MG glioma cells. Moreover, shikonin causes catalase downregulation and SOD-1 upregulation as well as decreased Bcl-2 and increased Bax expression. Pretreatment with NAC, PFT-alpha, or cyclosporin A causes the recovery of shikonin-induced apoptosis. The ROS generation and GSH depletion induced by shikonin trigger mitochondrial transmembrane potential disruption. ROS production was partially dependent on the upregulation of p53 upon shikonin treatment. CONCLUSIONS: These studies are the first to show that shikonin-induced apoptosis occurs through multiple pathways in human glioma cells. We conclude that shikonin may be used as a potential chemotherapeutic agent against human glioma. PMID- 22446900 TI - Greetings from the editors desk! PMID- 22446901 TI - Thyroid associated orbitopathy. AB - Thyroid associated orbitopathy, also known as Graves' orbitopathy, is typically a self-limiting autoimmune process associated with dysthyroid states. The clinical presentation may vary from very mild disease to severe irreversible sight threatening complications. Despite ongoing basic science and clinical research, the pathogenesis and highly effective therapeutic strategies remain elusive. The present article reviews the pathophysiology, clinical presentation, and management of this common, yet poorly understood disease, which remains a challenge to the ophthalmologist. PMID- 22446902 TI - Retinal arterial occlusions in the young: systemic associations in Indian population. AB - PURPOSE: To determine the systemic associations in retinal arterial occlusions (RAO) in young Indian individuals less than 40 years of age. MATERIALS AND METHODS: Case records of 32 patients (35 eyes) of less than 40 years, with non traumatic RAO were analysed. All patients underwent detailed ophthalmic and systemic evaluation including hemogram, lipid profile, coagulation profile, vasculitis screening, carotid Doppler, echocardiogram. RESULTS: In the study 21 were males and 11 were females. The age ranged from 11-39 years (Mean 27.6 +/- 8.43). Nine (28%) patients were below 20 years of age. Among 35 eyes, 28 (80%) had central retinal artery occlusion (CRAO), three (8.6%) had branch retinal artery occlusion (BRAO), two (5.7%) each had cilio-retinal (CLAO) and hemi retinal artery occlusion (HRAO). Vision ranged from no perception of light to 20/20. On systemic evaluation, in 21 (65.6%) patients a hypercoagulable state was responsible for the RAO. Conditions leading to a hypercoagulable state included hyperhomocysteinemia (21.9%), hyperlipidemia (15.6%), anticardiolipin antibody (6.2%), antiphospholipid antibody (6.2%), polycythemia, thrombocytosis, protein S deficiency, use of oral contraceptives and renal disorder (3.1% each). Six (18.7%) patients had cardiac valvular defects. Vasculitis screening was positive in three (9.4%) patients. Two (6.2%) had isolated systemic hypertension. In two (6.2%) patients no abnormality could be detected. CONCLUSION: The systemic associations of RAOs in the Indian population were distinctly different from those reported in the Western population. Hyperhomocysteinemia was the commonest association found. Whereas associations reported in the Western population such as cardiac abnormalities, coagulation disorders, hemoglobinopathies and oral contraceptive use were uncommon. PMID- 22446903 TI - Comparison of visual acuity estimates using three different letter charts under two ambient room illuminations. AB - BACKGROUND: Visual acuity is an essential estimate to assess ability of the visual system and is used as an indicator of ocular health status. AIM: The aim of this study is to investigate the consistency of acuity estimates from three different clinical visual acuity charts under two levels of ambient room illumination. MATERIALS AND METHODS: This study involved thirty Malay university students aged between 19 and 23 years old (7 males, 23 females), with their spherical refractive error ranging between plano and -7.75D, astigmatism ranging from plano to -1.75D, anisometropia less than 1.00D and with no history of ocular injury or pathology. Right eye visual acuity (recorded in logMAR unit) was measured with Snellen letter chart (Snellen), wall mounted letter chart (WM) and projected letter chart (PC) under two ambient room illuminations, room light on and room light off. RESULTS: Visual acuity estimates showed no statistically significant difference when measured with the room light on and with the room light off (F1,372 = 0.26, P = 0.61). Post-hoc analysis with Tukey showed that visual acuity estimates were significantly different between the Snellen and PC (P = 0.009) and between Snellen and WM (P = 0.002). CONCLUSIONS: Different levels of ambient room illumination had no significant effect on visual acuity estimates. However, the discrepancies in estimates of visual acuity noted in this study were purely due to the type of letter chart used. PMID- 22446904 TI - Effect of dacryocystorhinostomy on systemic adverse effects of topical timolol maleate. AB - PURPOSE: To evaluate whether transformation of the naso-lacrimal passage as happens after dacryocystorhinostomy (DCR) operation has any effect on the systemic adverse effects of topically administered timolol maleate. MATERIALS AND METHODS: Fifty otherwise healthy adult patients without any prior history of cardiac or pulmonary problems scheduled for elective DCR surgery received a drop of timolol maleate 0.5% on the healthy eye. This eye served as a control. Six weeks after successful DCR surgery, the operated eye received the same medication. Parameters compared included intraocular pressure (IOP), pulse rate, blood pressure and forced expiratory volume in the first second (FEV1) findings. OBSERVATIONS: Post DCR patients showed an increased incidence of reduced pulse rate and FEV1. CONCLUSION: Timolol maleate ophthalmic preparation should be used with caution in post-DCR patients. PMID- 22446905 TI - Dynamic distance direct ophthalmoscopy, a novel technique to assess accommodation in children. AB - AIM: To describe and compare dynamic distance direct ophthalmoscopy (DDDO) with dynamic retinoscopy (DR) in assessment of accommodation in children. MATERIALS AND METHODS: This prospective observational study had four components. Component 1: to understand the characteristic digital images of DDDO. Component 2: to compare DDDO with DR for detection of accommodative defects in children (1-16 years). Component 3: to compare DDDO with DR for the detection of completeness of pharmacologically induced cycloplegia in children (5-16 years) and Component 4: to assess which one of the two techniques was more sensitive to detect onset of cycloplegia after instillation of 1% cyclopentolate eye drops. RESULTS: Component 1: image analysis of DDDO on two subjects (7 years and 35 years) demonstrated superior pupillary crescent that progressively disappeared with increasing accommodation. Concurrently an inferior crescent appeared that became bigger in size with increasing accommodation. Component 2: the prevalence of defects in accommodation was 3.3% (33/1000 children). Three had unilateral accommodation failure. Sensitivity of DDDO was 94%, specificity 100%, positive predictive value 100%, negative predictive value 99%, and clinical agreement (kappa) 0.97. Component 3: in the detection of completeness of pharmacologically induced cycloplegia (n=30), the sensitivity of DDDO was 94%, specificity 96%, positive predictive value 97%, negative predictive value 93% and kappa 0.9. DR had two false positives. DDDO had one false negative. Component 4: DDDO detected onset of pharmacologically induced cycloplegia 5 min earlier than DR (n=5). CONCLUSION: DDDO is a novel, simple, clinical and reliable method to assess accommodation in young children. This test can assess the accommodative response of both eyes simultaneously. PMID- 22446906 TI - Sphingosine-1 phosphate prevents ethanol-induced corneal epithelial apoptosis. AB - BACKGROUND: Apoptosis is a programmed cell death in multicellular organisms, found in a wide variety of conditions, including inflammatory process, everywhere in the body, including the cornea and conjunctiva. AIM: To evaluate the effect of a new topical formulation of sphingosine-1 phosphate on preventing apoptosis of the corneal epithelium. SETTING: Medical University. MATERIALS AND METHODS: We tested several formulations suitable for topical application. Twenty-five rabbits were distributed among five groups. Group 1 comprised the controls. In Group 2, 20% ethanol was applied topically for 20 seconds; in Group 3, 50 MUM topical sphingosine-1 phosphate was applied 2 hours prior to 20% ethanol application. In Group 4, 200 MUM topical sphingosine-1 phosphate was applied 2 hours before the 20% ethanol application. In Group 5, only 200 MUM topical sphingosine-1 phosphate was applied. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (TUNEL) assay. Pairwise comparisons were performed using t-tests with Scheffe's correction. Data were analyzed using STATA 9.0 statistical software. RESULTS: A suspension of sphingosine-1 phosphate in the presence of Montanox 80 was stable and could be formulated without sonication. Epithelial apoptosis was detected only in Groups 2 and 3. CONCLUSION: Sphingosine-1 phosphate can prevent ethanol-induced apoptosis in the corneal epithelium of rabbits. PMID- 22446907 TI - Principles and practice of external digital photography in ophthalmology. AB - It is mandatory to incorporate clinical photography in an ophthalmic practice. Patient photographs are routinely used in teaching, presentations, documenting surgical outcomes and marketing. Standardized clinical photographs are part of an armamentarium for any ophthalmologist interested in enhancing his or her practice. Unfortunately, many clinicians still avoid taking patient photographs for want of basic knowledge or inclination. The ubiquitous presence of the digital camera and digital technology has made it extremely easy and affordable to take high-quality images. It is not compulsory to employ a professional photographer or invest in expensive equipment any longer for this purpose. Any ophthalmologist should be able to take clinical photographs in his/her office settings with minimal technical skill. The purpose of this article is to provide an ophthalmic surgeon with guidelines to achieve standardized photographic views for specific procedures, to achieve consistency, to help in pre-operative planning and to produce accurate pre-operative and post-operative comparisons, which will aid in self-improvement, patient education, medicolegal documentation and publications. This review also discusses editing, storage, patient consent, medicolegal issues and importance of maintenance of patient confidentiality. PMID- 22446908 TI - Smartphones in ophthalmology. AB - The potential usefulness of smartphones in the medical field is evolving everyday. This article describes various tools available on smartphones, largely focusing on the iPhone, for the examination of an ophthalmic patient, for patient and physician education, as well as reference tools for both ophthalmologists and vision researchers. Furthermore, the present article discusses how smartphones can be used for ophthalmic photography and image management, and foremost, the usefulness of the applications such as the Eye Handbook for the ophthalmologist and interested students, patients, physicians, and researchers, currently available in the iPhone. PMID- 22446909 TI - Bilateral spontaneous dislocation of posterior chamber intraocular lens in a patient with gyrate atrophy. AB - We report a patient with gyrate atrophy, a rare metabolic disease, who had bilateral late spontaneous posterior dislocation of in-the-bag posterior chamber intraocular lens (PCIOL). He underwent pars plana vitrectomy, PCIOL retrieval and anterior chamber intraocular lens implantation in both eyes. This report may imply that patients with gyrate atrophy are at risk for spontaneous dislocation of intraocular lenses. PMID- 22446910 TI - Unilateral conjunctival ulcer due to Stenotrophomonas maltophilia infection. AB - We report a case of unilateral conjunctival ulcer due to Stenotrophomonas maltophilia infection in an immunocompetent individual. A 44-year-old male presented with complaints of pain and yellowish discharge in the right eye for one week. Patient underwent complete ophthalmic evaluation and relevant laboratory investigations. Anterior segment examination revealed localized conjunctival and episcleral congestion with conjunctival ulceration on the bulbar conjunctiva in the right eye. Gram's stain revealed gram-negative bacilli. Culture and sensitivity revealed S. maltophilia and responded well to topical moxifloxacin with systemic co-trimoxazole therapy. PMID- 22446911 TI - Floppy iris syndrome with oral imipramine: a case series. AB - Intraoperative floppy iris syndrome (IFIS) has commonly been seen with long-term use of alpha1-adrenoceptor blocking agents. We observed IFIS in three patients during phacoemulsification due to oral imipramine therapy. The three patients took imipramine for 25 years, 10 months and 1 year, respectively. However, only the first patient was on oral therapy at the time of surgery, while the other two patients had stopped 4 months and 2 months prior to undergoing phacoemulsification. The first and third patients developed complete IFIS features, while the second had only partial IFIS characteristics. Phacoemulsification could be completed in all three patients without any complication. None of these patients had history of taking any of the alpha1 adrenoceptor blocking agents. This is the first anecdotal report of IFIS with the oral use of imipramine and hence further evidences are required to ascertain the association of oral imipramine therapy and IFIS. However, ophthalmologists undertaking phacoemulsification on patients on imipramine therapy should be alert for the occurrence of IFIS. PMID- 22446912 TI - Deep anterior lamellar keratoplasty for the management of iatrogenic keratectasia occurring after hexagonal keratotomy. AB - Iatrogenic keratectasia has been reported subsequent to refractive surgery or trauma. Hexagonal keratotomy (HK) is a surgical incisional technique to correct hyperopia. A number of complications have been reported following this procedure, including irregular astigmatism, wound healing abnormalities and corneal ectasia. When visual acuity is poor because of ectasia or irregular astigmatism and contact lens fitting is not possible, penetrating or lamellar keratoplasty can be performed. Since incisions in refractive keratotomy are set at 90-95% depth of cornea, intraoperative microperforations are known to occur and lamellar keratoplasty may become difficult. We describe deep anterior lamellar keratoplasty (DALK) used to successfully manage keratectasia after HK. Pre DALK vision was 20/400 and post DALK vision was 20/30 two months after surgery. This report aims to show improved visual outcome in corneal ectasia secondary to HK. DALK can be a procedure of choice with proper case selection. PMID- 22446913 TI - Fulminant toxoplasmic retinochoroiditis following intravitreal triamcinolone administration. AB - We report two cases of fulminant toxoplasmic retinochoroiditis following intravitreal triamcinolone acetonide (IVTA) administration. Case 1: A 42-year-old female received IVTA for presumed non-infectious panuveitis. Within 2 months, she developed diffuse macular retinochoroiditis with optic disc edema. Upon starting anti-toxoplasmic therapy (ATT), her intraocular inflammation resolved with catastrophic damage to the disc and macula. Case 2: A 30-year-old male received IVTA for presumed reactivation of previously scarred toxoplasmic retinochoroiditis. Despite simultaneous ATT, within 6 weeks, he developed extensive, multifocal macular retinochoroiditis. He continued to require ATT for 18 months and later underwent vitrectomy with silicone oil placement for severe epiretinal proliferation. Aqueous tap polymerase chain reactions were found positive for Toxoplasma gondii in both cases. In conclusion, IVTA administration can lead to fulminant toxoplasmic retinochoroiditis even when used with appropriate ATT. Extreme caution should be exercised while administering depot corticosteroids in eyes with panuveitis of unknown origin. PMID- 22446914 TI - Completion rates of anterior and posterior continuous curvilinear capsulorrhexis in pediatric cataract surgery for surgery performed by trainee surgeons with the use of a low-cost viscoelastic. AB - CONTEXT: Pediatric cataract surgery is traditionally done with the aid of high molecular-weight viscoelastics which are expensive. It needs to be determined if low-cost substitutes are just as successful. AIMS: The study aims to determine the success rates for anterior and posterior capsulorrhexis and intraocular lens (IOL) implantation in the bag for pediatric cataract surgery performed with the aid of a low-molecular-weight viscoelastic. SETTINGS AND DESIGN: Nonrandomized observational study. MATERIALS AND METHODS: Children less than 6 years of age who underwent cataract surgery with IOL implantation in the period May 2008-May 2009 were included. The surgeries were done by pediatric ophthalmology fellows. A standard procedure of anterior capsulorrhexis, lens aspiration with primary posterior capsulorrhexis, anterior vitrectomy, and IOL implantation was followed. Three parameters were studied: successful completion of anterior and posterior capsulorrhexis and IOL implantation in the bag. RESULTS: 33 eyes of 28 children were studied. The success rate for completion was 66.7% and 88.2 % for anterior and posterior capsulorrhexis, respectively. IOL implantation in the bag was successful in 87.9%. CONCLUSIONS: 2% hydroxypropylmethylcellulose is a viable low cost alternative to more expensive options similar to high-molecular-weight viscoelastics. This is of great relevance to hospitals in developing countries. PMID- 22446915 TI - A truly knotless technique for scleral fixation of intraocular lenses: two-year results. AB - Scleral fixated intraocular lens (SFIOL) is a safe and effective option for managing optical aphakia. Suture related complications like suture erosion, suture breakage, endophthalmitis, etc. are unique to SFIOL. The knots can be covered by partial thickness flaps or they can be rotated into scleral tissues without flaps to reduce the complications. We performed a recently described novel technique which obviates the need for knot and scleral flaps in securing the SFIOL. This novel 2-point Ab externo knotless technique may reduce the knot related problems. Twenty-three eyes undergoing this knotless SFIOL procedure were analyzed for intraoperative and postoperative complications. Twenty-two eyes either maintained or improved on their preoperative vision. All patients had a minimum follow-up of 24 months. PMID- 22446916 TI - Delayed-onset bilateral abducens paresis after head trauma. AB - Bilateral sixth nerve paresis following closed head injury, though rare, is a known entity. However, delayed-onset post-traumatic bilateral abducens paresis is extremely rare. We present two cases. The first patient had onset of bilateral abducens paresis 2 weeks after closed head injury and the second patient after 3 days. The cause in the former was detected to be chronic subdural hematoma and in the latter is speculated to be edema/ischemia due to injury to soft tissue structures housing these nerves. The delayed onset of bilateral abducens paresis following head injury may vary according to the cause. There may be another mechanism of injury apart from direct trauma. Though rare, it needs to be evaluated and may have a treatable cause like elevated intracranial pressure. PMID- 22446917 TI - Short-term outcome of Boston Type 1 keratoprosthesis for bilateral limbal stem cell deficiency. AB - This study reports the short-term functional and anatomical outcome of Boston Type 1 keratoprosthesis (Boston Kpro) implantation for bilateral limbal stem cell deficiency (LCSD). Retrospective analysis was done on eight eyes of eight patients who underwent Boston Kpro implantation between July 2009 and October 2009. The best corrected visual acuity (BCVA) and slit-lamp biomicroscopy findings were assessed at 1, 3 and 6 months postoperatively. All eight eyes retained the prosthesis. BCVA of 20/40 or better was achieved in 8, 6, and 5 eyes at 1, 3, and 6 months, respectively, postoperatively. One patient each developed epithelial defect, sterile stromal melt and fungal keratitis in the late postoperative period associated with antecedent loss of the soft contact lens from the eye. Boston Kpro has good short-term visual and anatomical outcome in patients with bilateral LSCD, provided compliance with postoperative care can be ensured. PMID- 22446918 TI - Impact of a month-long training program on the clinical skills of ophthalmology residents and practitioners. PMID- 22446919 TI - Community-acquired methicillin-resistant Staphylococcus aureus bilateral acute dacryocystitis in a neonate. PMID- 22446920 TI - Pain-free cataract surgery in patients with cardiac risk. PMID- 22446921 TI - Is it really a study of community-acquired bacterial infections? PMID- 22446922 TI - Toxic optic neuropathy. PMID- 22446923 TI - Feed back of the parents and/or relatives witnessing a squint surgery of their ward in the operation theatre. PMID- 22446924 TI - Comment on: Feedback of the patients and/or relatives witnessing a squint surgery of their ward in operation theatre. PMID- 22446925 TI - Aggravation of polypoidal choroidal vasculopathy after cataract surgery. PMID- 22446926 TI - DNA chip-assisted diagnosis for ocular toxoplasmosis: a comment. PMID- 22446927 TI - Features, diagnosis, and treatment of nonalcoholic fatty liver disease. AB - As the global incidence of obesity has increased, nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern. NAFLD occurs in children and adults of all ethnicities and includes isolated fatty liver and nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma and have increased all-cause mortality. NAFLD is associated with a variety of clinical conditions and is an independent risk factor for hepatocellular carcinoma. The pathogenesis of NAFLD and the specific steps that lead to NASH and advanced fibrosis are not fully understood, although researchers have found that a combination of environmental, genetic, and metabolic factors lead to advanced disease. There have been improvements in noninvasive radiographic methods to diagnose NAFLD, especially for advanced disease. However, liver biopsy is still the standard method of diagnosis for NASH. There are many challenges to treating patients with NASH, and no therapies have been approved by the U.S. Food and Drug Administration; multimodal approaches are being developed and becoming the standard of care. We review pathogenesis and treatment approaches for the West's largest liver-related public health concern. PMID- 22446928 TI - Tropical calcific pancreatitis. PMID- 22446929 TI - A mutagenesis-derived broad-spectrum disease resistance locus in wheat. AB - Wheat leaf rust, stem rust, stripe rust, and powdery mildew caused by the fungal pathogens Puccinia triticina, P. graminis f. sp. tritici, P. striiformis f. sp. tritici, and Blumeria graminis f. sp. tritici, respectively, are destructive diseases of wheat worldwide. Breeding durable disease resistance cultivars rely largely on continually introgressing new resistance genes, especially the genes with different defense mechanisms, into adapted varieties. Here, we describe a new resistance gene obtained by mutagenesis. The mutant, MNR220 (mutagenesis derived new resistance), enhances resistance to three rusts and powdery mildew, with the characteristics of delayed disease development at the seedling stage and completed resistance at the adult plant stage. Genetic analysis demonstrated that the resistance in MNR220 is conferred by a single semidominant gene mapped on the short arm of chromosome 2B. Gene expression profiling of several pathogenesis related genes indicated that MNR220 has an elevated and rapid pathogen-induced response. In addition to its potential use in breeding for resistance to multiple diseases, high-resolution mapping and cloning of the disease resistance locus in MNR220 may lead to a better understanding of the regulation of defense responses in wheat. PMID- 22446930 TI - A multiple gene complex on rice chromosome 4 is involved in durable resistance to rice blast. AB - Quantitative trait loci (QTLs) for resistance to rice blast offer a potential source of durable disease resistance in rice. However, few QTLs have been validated in progeny testing, on account of their small phenotypic effects. To understand the genetic basis for QTL-mediated resistance to blast, we dissected a resistance QTL, qBR4-2, using advanced backcross progeny derived from a chromosome segment substitution line in which a 30- to 34-Mb region of chromosome 4 from the resistant cultivar Owarihatamochi was substituted into the genetic background of the highly susceptible Aichiasahi. The analysis resolved qBR4-2 into three loci, designated qBR4-2a, qBR4-2b, and qBR4-2c. The sequences of qBR4 2a and qBR4-2b, which lie 181 kb apart from each other and measure, 113 and 32 kb, respectively, appear to encode proteins with a putative nucleotide-binding site (NBS) and leucine-rich repeats (LRRs). Sequence analysis of the donor allele of qBR4-2a, the region with the largest effect among the three, revealed sequence variations in the NBS-LRR region. The effect of qBR4-2c was smallest among the three, but its combination with the donor alleles of qBR4-2a and qBR4-2b significantly enhanced blast resistance. qBR4-2 comprises three tightly linked QTLs that control blast resistance in a complex manner, and thus gene pyramiding or haplotype selection is the recommended strategy for improving QTL-mediated resistance to blast disease through the use of this chromosomal region. PMID- 22446931 TI - Hypergolic ionic liquids to mill, suspend, and ignite boron nanoparticles. AB - Boron nanoparticles prepared by milling in the presence of a hypergolic energetic ionic liquid (EIL) are suspendable in the EIL and the EIL retains hypergolicity leading to the ignition of the boron. This approach allows for incorporation of a variety of nanoscale additives to improve EIL properties, such as energetic density and heat of combustion, while providing stability and safe handling of the nanomaterials. PMID- 22446932 TI - A genome-wide RNAi screen identifies novel targets of neratinib resistance leading to identification of potential drug resistant genetic markers. AB - Neratinib (HKI-272) is a small molecule tyrosine kinase inhibitor of the ErbB receptor family currently in Phase III clinical trials. Despite its efficacy, the mechanism of potential cellular resistance to neratinib and genes involved with it remains unknown. We have used a pool-based lentiviral genome-wide functional RNAi screen combined with a lethal dose of neratinib to discover chemoresistant interactions with neratinib. Our screen has identified a collection of genes whose inhibition by RNAi led to neratinib resistance including genes involved in oncogenesis (e.g. RAB33A, RAB6A and BCL2L14), transcription factors (e.g. FOXP4, TFEC, ZNF), cellular ion transport (e.g. CLIC3, TRAPPC2P1, P2RX2), protein ubiquitination (e.g. UBL5), cell cycle (e.g. CCNF), and genes known to interact with breast cancer-associated genes (e.g. CCNF, FOXP4, TFEC, several ZNF factors, GNA13, IGFBP1, PMEPA1, SOX5, RAB33A, RAB6A, FXR1, DDO, TFEC, OLFM2). The identification of novel mediators of cellular resistance to neratinib could lead to the identification of new or neoadjuvant drug targets. Their use as patient or treatment selection biomarkers could make the application of anti-ErbB therapeutics more clinically effective. PMID- 22446933 TI - Rates of stroke and kidney failure in diabetes patients are at record high. PMID- 22446934 TI - Geriatricians, surgeons, and oncologists must work together to improve care for older cancer patients. PMID- 22446935 TI - Apoptosis induced by pneumolysin in human endothelial cells involves mitogen activated protein kinase phosphorylation. AB - Pneumolysin (Ply) is an essential virulence factor of S. pneumoniae, which can induce apoptosis in a variety of host cells to facilitate infection of pathogenic bacteria by as yet unclear mechanisms. To confirm the apoptosis-inducing properties of pneumolysin in endothelial cells, human umbilical vein endothelial cells (HUVECs) were exposed to pneumolysin. The proliferation of HUVECs was inhibited by pneumolysin in a dose- and time-dependent manner. Flow cytometry analysis and ultrastructural changes of the cells indicated the apoptotic response. Exposure to pneumolysin significantly increased the number of apoptotic cells and the activities of caspases-3 and -8. This change was associated with activation of p38 mitogen-activated protein kinase (MAPK) and suppression of extracellular signaling regulation kinase (ERK)1/2. Pre-exposure to the p38 MAPK inhibitor SB-203850 prevented human endothelial cells from apoptosis induced by pneumolysin. In conclusion, these findings demonstrate that pneumolysin induces apoptosis in endothelial cells and the involvement of p38 MAPK activation and ERK1/2 deactivation. PMID- 22446936 TI - Prevention of high-mobility group box 1-mediated early loss of transplanted mouse islets in the liver by antithrombin III. AB - BACKGROUND: The low efficiency of pancreatic islet transplantation mainly because of the early loss of transplanted islets hampers its clinical application. Previously, we have shown in mice that the early loss of transplanted islets in the liver is caused by innate immune rejection in concert with dendritic cells, natural killer T cells, and neutrophils to produce interferon (IFN)-gamma, which is triggered by high-mobility group box 1 (HMGB1) released from transplanted islets. We herein determined whether the HMGB1-mediated early loss of transplanted mouse islets is prevented by antithrombin (ATIII). METHODS: The effect of ATIII on in vitro and in vivo HMGB1-stimulated IFN-gamma production of hepatic mononuclear cells was examined. Then, the effect of ATIII on amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving 200 syngeneic islets from a single donor was determined. RESULTS: In vitro and in vivo IFN gamma production of mononuclear cells in the liver of mice in response to HMGB1 was suppressed by ATIII. Hyperglycemia of streptozotocin-induced diabetic mice receiving 200 syngeneic islets into the liver from a single donor was ameliorated with down-regulation of IFN-gamma production of natural killer T cells and neutrophils in the liver when ATIII but not vehicle was administered once at the time of islet transplantation. The favorable effect of ATIII was similarly achieved in mice receiving islet allografts when rejection was prevented with anti-CD4 antibody treatment. CONCLUSIONS: These findings demonstrate that ATIII prevents HMGB1-mediated early loss of transplanted islets caused by innate immune rejection, suggesting a potential application of ATIII to improve efficiency of clinical islet transplantation. PMID- 22446937 TI - The role of nuclear medicine in modern therapy of cancer. AB - Nuclear medicine is a multidisciplinary field that develops and uses instrumentation and tracers (radiopharmaceuticals) to study physiological processes and noninvasively diagnose, stage, and treat diseases. Particularly, it offers a unique means to study cancer biology in vivo and to optimize cancer therapy for individual patients. A tracer is either a radionuclide alone, such as iodine-131 or a radiolabel in a carrier molecule such as (18)F in fluorodeoxyglucose ((18)F-FDG), or other feasible radionuclide attached to a drug, a protein, or a peptide, which when introduced into the body, would accumulate in the tissue of interest. Nuclear medicine imaging, including single photon emission computer tomography and positron emission tomography, can provide important quantitative and functional information about normal tissues or disease conditions, in contrast to conventional, anatomical imaging techniques such as ultrasound, computed tomography, or magnetic resonance imaging. For treatment, tumor-targeting agents, conjugated with therapeutic radionuclides, may be used to deposit lethal radiation at tumor sites. This review outlines the role of nuclear medicine in modern cancer therapy. PMID- 22446938 TI - An in vivo role of Mrp2 in the rat hepatocytes by immunocytochemistry for amoxicillin using the transporter-deficient EHBR. AB - An in vivo role of the multidrug resistant-associated protein (Mrp2) in rat hepatocytes was examined by immunocytochemistry (ICC) for amoxicillin (AMPC) by the use of the transporter-deficient Eisai hyperbilirubinemic rats (EHBR). The ICC revealed that in the liver of EHBR at 3-h post-administration, amoxicillin accumulated in the cytoplasmic pools and nuclei of the hepatocytes in a characteristic granular morphology on the bile capillaries. However, no amoxicillin was observed on the surface of the lumina ranging from the bile capillaries to the interlobular bile ducts. The drug persisted at least for 6-h after administration. In contrast, in the control rat liver at 3-h post administration, AMPC-adsorption occurred on such luminal surface, while AMPC accumulated to a less level in both the cytoplasm and nuclei of the hepatocytes. The drug completely disappeared in the hepatocytes at 6-h post-administration. These results strongly suggest that AMPC taken up into the cytoplasm of the hepatocytes excretes via Mrp2 into the bile flow. Furthermore, electron microscopy demonstrated that the lower electron density areas in large sizes, corresponding to the cytoplasmic pools in ICC for AMPC, occurred in the cytoplasm peripheral to the nuclei of the hepatocytes in EHBR at 3-h post-administration, and then disappeared 24 h after administration. PMID- 22446939 TI - Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients. AB - We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses. PMID- 22446940 TI - PTEN hamartoma of soft tissue: a distinctive lesion in PTEN syndromes. AB - PTEN hamartoma tumor syndrome (PHTS) presents in a spectrum that encompasses the eponymous disorders Cowden and Bannayan-Riley-Ruvalcaba. Herein, we delineate the distinctive histopathology of a predominantly intramuscular lesion in PHTS, often called "arteriovenous malformation," because of certain imaging and histopathologic features. Cases were identified by review of lesions resected from patients with PHTS registered at our Vascular Anomalies Center and of unusual intramuscular vascular anomalies in our pathology database from 1985 to 2008. Thirty-four patients with this lesion were identified: 20 had a clinical diagnosis of, or were suspected to have, PHTS (genetically confirmed in 16). In 4 patients without clinical manifestations of PHTS, 2 had PTEN mutations, 1 did not, and in 1 the mutation was intronic. In the remaining 10, there was insufficient clinical information to fully assess whether they had manifestations of PHTS. Lesions manifested by 15 years of age, normally with pain and swelling, and were most often located in the lower extremity. The major mass was usually intramuscular, but often there were fascial and subcutaneous components and not infrequently a cutaneous vascular stain. Magnetic resonance imaging generally showed an infiltrative soft tissue lesion involving the muscle, fascia, and subcutis with frequently enlarged, serpiginous vessels, small arteriovenous fistulae with disproportionately dilated draining veins, and a prominent adipocytic component. Some lesions involved contiguous muscles, and 20% were multifocal. Resected specimens ranged in size from 1.2 to 25 cm; in 1 patient, amputation was necessary. Histopathologically, these unencapsulated masses, often with a nodular appearance at scanning magnification, consisted of: (1) a variable admixture of mature adipocytic and dense and/or myxoid fibrous tissues (50% to 90% of surface area); (2) a vascular component (10% to 50% of surface area) with: (a) clusters of venous channels, some with excessively and irregularly muscularized complex walls and lumens, and others with thin walls resembling pulmonary alveoli, (b) tortuous, thick-walled arteries with concentric muscular hyperplasia and relatively small lumens, (c) numerous small vessels (arteries, veins, and indeterminate channels), and (d) occasional arteriovenous communications; (3) lymphoid follicles (50%); (4) foci of bone (20%); and (5) hypertrophic nerves with "onion bulb" proliferation of periaxonal spindled cells (9%). We designate this disorganized overgrowth of essentially mesenchymal elements as PTEN hamartoma of soft tissue. It differs from other vascular and connective tissue lesions that occur in patients with PHTS. PTEN hamartoma of soft tissue is histopathologically distinctive, and its identification should prompt a thorough investigation for PHTS. PMID- 22446941 TI - Immunohistochemical staining characteristics of low-grade adenosquamous carcinoma of the breast. AB - BACKGROUND: Low-grade adenosquamous carcinoma (LGASC) is an uncommon variant of metaplastic carcinomas of the breast. The immunohistochemical profile of this entity has not been well characterized and is likely because of its seemingly inconsistent staining patterns when commonly used immunohistochemical stains are employed. We set out to further elucidate the immunohistochemical profile of this uncommon entity in a sizable cohort of patients. MATERIALS AND METHODS: Thirty cases of LGASC were identified in our files. Commonly used immunohistochemical stains such as myoepithelial and cytokeratin markers used to evaluate a small glandular proliferation in the breast (the differential diagnosis of which includes LGASC) were utilized. The pattern and location of immunoreactivity were recorded in each case. Results were compared for staining trends. RESULTS: All cases of LGASC demonstrated variable staining in both lesional glands and stromal cells for myoepithelial (p63, smooth muscle myosin, smooth muscle actin, CD10, calponin) and cytokeratin (CK AE1/3, CK5/6, CK7, CK 34betaE12, Cam 5.2) markers. Within a single case, circumferential staining using myoepithelial markers was complete, discontinuous, and absent in over a third of the studied cases. A minority of cases showed either complete circumferential staining (or complete absence) by any single immunohistochemical stain. Lamellar staining of stromal cells surrounding glands was best highlighted using smooth muscle myosin heavy chain or calponin. Using cytokeratin stains, core staining (luminal glandular cells demonstrating distinctly stronger staining intensity than the basally located cells in the same gland) was observed in approximately half of the studied cases. These lesional stromal cells were negative for all cytokeratins, with the exception of 1, which was focally positive for 1 cytokeratin immunostain (CK7) while being negative for 3 others. CONCLUSIONS: LGASC consistently stains in an inconsistent manner using commonly used immunohistochemical stains. In addition, we found lamellar staining and core staining using myoepithelial and cytokeratin stains, respectively, to be distinctive and therefore diagnostically valuable. PMID- 22446942 TI - Role of Foxp3-positive tumor-infiltrating lymphocytes in the histologic features and clinical outcomes of hepatocellular carcinoma. AB - The role of Foxp3-positive regulatory T cells (Foxp3 Tregs) in suppression of antitumoral immune response is well documented in patients with cancer. However, it is not known whether Foxp3 Tregs are associated with specific clinicopathologic characteristics of hepatocellular carcinoma (HCC). The aims of the present study were: (1) to investigate the relationship between Foxp3 Tregs and histologic differentiation, Edmondson-Steiner (ES) nuclear grade, vascular invasion, and pathologic stage of HCC in patients undergoing surgery for their disease; and (2) to evaluate any Foxp3 Treg-defined difference in the risk for tumor recurrence or death. The study sample included 131 histologic sections of HCC. The number of tumor-infiltrating CD3, CD8, and Foxp3 lymphocytes was assessed by immunohistochemistry. An increased Foxp3:CD3 ratio was associated with more poorly differentiated HCC (P=0.0016) and higher ES nuclear grade (P=0.0407). An increased Foxp3:CD8 ratio was also associated with poorer differentiation (P=0.0044), higher ES nuclear grade (P=0.0179), recurrence (P=0.0183), decreased overall survival (hazard ratio=1.153; 95% confidence interval, 1.019-1.304; P=0.0235), and decreased disease-free survival (hazard ratio=1.138; 95% confidence interval, 1.016-1.273; P=0.0249). Tumor size and type of surgery (surgical resection) were associated with decreased disease-free survival on univariate analysis but not on multivariate analysis. In conclusion, a higher concentration of tumor-infiltrating Foxp3 Tregs in HCC is associated with higher grade and poorly differentiated tumors and signifies an unfavorable prognosis. PMID- 22446943 TI - NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma. AB - Ewing sarcoma is a high-grade round cell sarcoma that affects bones and soft tissues in children and young adults. Its diagnosis can be challenging, and the differential diagnoses include a wide variety of small round cell tumors. CD99 and FLI-1 are the currently accepted immunohistochemical markers for Ewing sarcoma, but their accuracy has been controversial. NKX2.2 is a homeodomain containing transcription factor that plays a critical role in neuroendocrine/glial differentiation. The NKX2.2 gene was recently identified as a target of EWS-FLI-1, the fusion protein specific to Ewing sarcoma, and was shown to be differentially upregulated in Ewing sarcoma on the basis of array based gene expression analysis. However, the immunohistochemical diagnostic potential of this marker has not been tested. We immunostained representative sections of 30 genetically confirmed Ewing sarcomas and 130 non-Ewing small round cell tumors by using an antibody to NKX2.2. Nuclear staining in at least 5% of the cells was deemed positive. Twenty-eight (93%) of the 30 Ewing sarcomas were positive for NKX2.2. The staining was diffuse (>50%) in all the positive cases and was moderate or strong in intensity for most cases (25 of 28). NKX2.2 was also positive in 14 non-Ewing tumors, including all the olfactory neuroblastomas and a minor subset of small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and malignant melanomas. All the other non-Ewing tumors tested were negative for this marker. NKX2.2 is a valuable marker for Ewing sarcoma, with a sensitivity of 93% and a specificity of 89%, and aids in the differential diagnosis of small round cell tumors. PMID- 22446944 TI - Translocation renal cell carcinomas in adults: a single-institution experience. AB - Translocation renal cell carcinoma is a newly recognized subtype of renal cell carcinoma (RCC) with chromosomal translocations involving TFE3 (Xp11.2) or, less frequently, TFEB (6p21). Xp11 translocation RCC was originally described as a pediatric neoplasm representing 20% to 40% of pediatric RCCs, with a much lower frequency in the adult population. TFEB translocation RCC is very rare, with approximately 10 cases reported in the literature. Here, we describe the clinicopathologic features of adult translocation RCC from a single institution. Using tissue microarray, immunohistochemistry, cytogenetic examination, and fluorescence in situ hybridization, we identified 6 (~5%) cases of TFE3 translocation RCC and 1 (<1%) case of TFEB translocation RCC in 121 consecutive adult RCC cases between 2001 and 2009. Our results suggest that weak TFE3 staining of a significant proportion of RCC cases may be because of expression of the full-length TFE3 protein rather than the chimeric fusion protein resulting from chromosomal translocation. PMID- 22446945 TI - Lymphocyte composition and distribution in inflammatory, well-differentiated retroperitoneal liposarcoma: clues to a potential adaptive immune response and therapeutic implications. PMID- 22446946 TI - Expression of brachyury in hemangioblastoma: potential use in differential diagnosis. AB - Hemangioblastoma (HBL) accounts for up to 2.5% of all intracranial tumors. It may occur as a sporadic entity or as a part of Von Hippel-Lindau syndrome. Patients with Von Hippel-Lindau syndrome are also at an increased risk of developing clear cell renal cell carcinoma (CCRCC). The distinction of HBL from CCRCC metastatic to the central nervous system (CNS) or from other histologic mimics can be challenging at times when based solely on hematoxylin and eosin-stained sections. In the present study we evaluated the potential use of the immunohistochemical evaluation of brachyury protein in the differential diagnosis of these lesions. Archival tissues from 22 HBLs, 16 primary CCRCCs, 8 CCRCCs metastatic to the CNS, and 4 angiomatous and 4 clear cell meningiomas were retrieved from our surgical pathology files and submitted to the immunohistochemical procedures against brachyury. Cases showing nuclear and/or cytoplasmic staining were considered to be positive for brachyury. Positive cytoplasmic staining was evidenced in the stromal cells of 20 of the 22 HBLs. In most cases, >50% of the neoplastic cells were labeled, with strong or moderate intensity of staining. No nuclear or cytoplasmic staining for brachyury was observed in any of the primary renal or metastatic CCRCCs, nor in either of the meningioma types. Thus, brachyury cytoplasmic staining was demonstrated to be highly specific for HBL (specificity, 100%) and represented a sensible (sensitivity, 91%) method, with high positive (100%) and negative (89%) predictive values and high diagnostic accuracy (95%) in the differential diagnosis between HBL and CCRCC metastatic to the CNS or meningioma. On the basis of our findings we propose the use of brachyury as an additional helpful immunohistochemical marker to resolve the differential diagnosis of HBL toward histologic mimics. PMID- 22446947 TI - Reclaiming the person: intersectionality and dynamic social categories through a psychological lens. AB - Psychology's conventionally treatment of individuals' engagement with and resistance to the societal processes in which they are embedded has come under scrutiny amid the rise of postmodernist and critical feminist perspectives (among many others) in the social sciences. A sample of social psychology's responses to these critiques is presented in the recently published book, Social Categories in Everyday Experience edited by Shaun Wiley et al. (2011). In this essay, the challenges of seriously addressing the critiques of psychology's conventional treatment of social categories, which implicate fundamental assumptions of the discipline, are discussed. Further, it is argued that in order to effectively construct psychological accounts of political activism and social change amid theories that are increasingly cognizant of the complexities and contingencies of social embeddiness, the person must be reclaimed and revisioned. Notions of agency that complement an intersectional and systemic vision of the social world are discussed. PMID- 22446948 TI - Effects of personality disorder and impulsivity on emotional adaptations in prison among women offenders. AB - The present study sought to better understand the influence of personality disorders and impulsivity on women's ability to adapt to incarceration. We analyzed the influence of personality disorders as screened with the structured clinical interview for personality disorders, and impulsivity as assessed with the Barratt impulsivity scale on depression and anxiety, sleeping problems, and feeling afraid of being attacked in prison among a large sample of women incarcerated in a Virginia prison. Results from regression models indicated that schizotypal, borderline, avoidant and dependent personality disorders and cognitive impulsivity were significant predictors of symptoms of anxiety and depression net of demographic covariates. Women possessing a diagnosis of paranoid personality disorder were at increased odds of having difficulty sleeping in prison and borderline, dependent, and paranoid personality disorder were at increased odds of experiencing fear in prison. Women who had been in prison before were significantly less likely to experience these problems. Implications of study findings for policies and practices involving women offenders are discussed. PMID- 22446949 TI - Pulmonary aspergilloma treated by limited thoracoplasty with simultaneous cavernostomy and muscle transposition flap. AB - We describe the successful treatment of pulmonary aspergilloma by limited thoracoplasty used simultaneously with single-stage cavernostomy and a muscle transposition flap. An 80-year-old man with dyspnea on effort and hemoptysis consulted our hospital. Chest computed tomography revealed a thick wall cavity containing a fungus ball surrounded by a crescent of air and diseased lung parenchyma, indicating complex pulmonary aspergilloma (CPA). As curative pulmonary resection was considered too invasive for this patient, limited thoracoplasty with simultaneous single-stage cavernostomy and myoplasty was performed as an alternative treatment. During the operation, transposition flap of the latissimus dorsi muscle was created by preserving the feeding artery. Fungus, in the ball that was removed, proved to be aspergilloma by culture and histopathological examination. On postoperative day 15, the patient was discharged uneventfully, and 4 months after surgery, no relapse of the aspergilloma has been observed.We consider that limited thoracoplasty with simultaneous single-stage cavernostomy and a muscle transposition flap is effective for treatment of high-risk CPA. PMID- 22446950 TI - Successful surgical repair of pulmonary artery aneurysm and regurgitation. AB - Pulmonary artery aneurysm (PAA) is generally a rare lesion, and there is no definitive approach for it. We report the case of a 45-year-old man who was admitted for the evaluation of dyspnea. In childhood, he had been diagnosed with PAA with congenital pulmonary valve stenosis and regurgitation, and he had a percutaneous transvenous pulmonary valve commissurotomy. Transthoracic echocardiogram showed dilatation of the right atrium and right ventricle, with right ventricular hypertrophy. There was severe pulmonary valve regurgitation, and the main pulmonary artery was dilated to 68 mm in diameter. From the surgical findings, the left leaflet of pulmonary valve was torn from commissure with failure to coapt with the other leaflet. After direct sutures of edges of the left leaflet, a nearly normal valvular competence was restored. The PAA was repaired with a Y-shaped 24 * 12 mm Dacron graft replacement. The postoperative course was uneventful, and the patient was discharged. PMID- 22446951 TI - Acute aortic regurgitation due to local avulsion of the aortic valve commissure. AB - A 69-year-old man was transferred to our hospital because of sudden onset precordial pain and dyspnea. Transesophageal echocardiography revealed massive aortic regurgitation, diastolic separation of the closure line of the aortic cusps and prolapsing motion of the cusps during diastolic toward the left ventricular outflow tract. Aortic valve replacement was successfully performed. During the operation, we found a commissure between the left coronary cusp and the non-coronary cusp that had avulsed from the aortic wall and prolapsed into the left ventricular outflow tract. Valvular cusps were excised and replaced with a mechanical prosthesis. The postoperative course was uneventful and the patient was discharged from the hospital, 25 days after his operation. The histopathological examination showed fibrosis, hyalinosis of the avulsed commissure, and mucoid degeneration of the valve. There was no evidence of pathologic changes, such as aortitis, infective endocarditis, or specific connective tissue disorders. PMID- 22446952 TI - Acute subdural hematoma following thoracoabdominal aortic repair in a patient with Marfan syndrome: a rare complication of cerebrospinal fluid drainage. AB - Cerebrospinal fluid (CSF) drainage is a routinely used adjunct in operation of thoracoabdominal aortic aneurysm (TAAA), which may reduce the incidence of perioperative paraplegia by improving spinal cord perfusion. Neurological complications of CSF drainage have been reported, possibly due to excessive CSF drainage, and acute subdural hematoma (SDH) in particular may lead to catastrophic complications. We present a rare case of acute SDH due to CSF drainage that was not excessive, after TAAA repair in a patient with Marfan syndrome, who recovered without invasive treatment. PMID- 22446953 TI - Late-stage non-anastomotic rupture of axillo-bifemoral bypass graft. AB - An 82-year-old woman, who underwent axillo-bifemoral bypass for infrarenal aortic occlusion and peripheral arterial occlusive disease 9 years before, was admitted to our hospital for swelling in the left subclavicular region. Ultrasound examination revealed a leak in the wall of the bypass graft with the formation of a false aneurysm. No signs of infection, either locally or systemically, were observed. Resection of the aneurismal segment with interposition using a Dacron graft was performed. Macroscopic findings during surgery confirmed an intact anastomotic region of the left axillary artery and Dacron graft. Two possible mechanisms for the formation of this false aneurysm, either cumulative stress on the graft over the years or Dacron graft biodegradation, were hypothesized. PMID- 22446954 TI - Tricuspid valve endocarditis with septic pulmonary emboli in a drug addict. AB - Presented is a case of a young, polytoxicomaniac male with a history of intravenous drug abuse. He arrived at our department in a septic state with fever and showed signs of right-sided decompensated cardiac insufficiency. The patient tested positive for hepatitis C, and blood cultures were positive for Staphylococcus aureus. A thoracic computed tomographic scan revealed bilateral, multiple septic pulmonary emboli. Transesophageal echocardiography disclosed large mobile vegetations on the tricuspid valve associated with severe regurgitation. The infected tricuspid valve was replaced with a mechanical heart valve, and the patient recovered uneventfully from surgery. PMID- 22446955 TI - Incidence of acute exacerbation of interstitial pneumonia in operated lung cancer: institutional report and review. AB - PURPOSE: Several small studies have reported that acute exacerbation (AE) of idiopathic interstitial pneumonia (IIP) can occur after lung resection for patients with non-small cell lung cancer, though the incidence rate is unclear. METHODS: We examined our institutional data and performed a search of the MEDLINE database for publications regarding AE of IIP following surgery for lung cancer. Studies reporting the incidence rates of IIP and AE were included. RESULTS: Eleven studies including our institutional data were determined to be eligible. Seven studies designated the incidence of IIP. Of 4749 patients (from 7 studies) who underwent lung resection for NSCLC, 277 had IIP, for an incidence rate of 5.8% (range 1.1%-11.7%). Eleven studies designated the incidence of AE from IIP patient, 67 (15.8%) of 424 IIP patients (from 11 studies) developed AE after surgery, of whom 38 (56.7%) died during the postoperative course. CONCLUSION: Coexistent IIP in patients with lung cancer increases the risk of lung cancer surgery. Furthermore, AE of IIP may be a major cause of operation-related death. PMID- 22446956 TI - Biomechanical, cardiorespiratory, metabolic and perceived responses to electrically assisted cycling. AB - The aims of the present study were to characterize the effects of cycling in varying terrain with the assistance of an electric motor with respect to (1) power output, velocity, and electromyography (EMG) signals; (2) cardiorespiratory parameters; (3) energy expenditure (EE); (4) rate of perceived exertion (RPE) and enjoyment and to compare these effects with those of non-assisted cycling. Eight sedentary women (age: 38 +/- 15 years, BMI: 25.3 +/- 2.1 kg m(-2)) cycled 9.5 km on varying terrain (change in elevation: 102 m, maximum incline: 5.8 %) at their own pace, once with and once without motorized assistance, in randomized order. With electrical assistance, the mean power output (-29 %); EMG patterns of the m. biceps femoris (-49 %), m. vastus lateralis (-33 %), m. vastus medialis (-37 %), and m. gastrocnemius medialis (-29 %); heart rate (-29.1 %); oxygen uptake (-33.0 %); respiratory exchange ratio (-9.0 %); and EE (-36.5 %) were all lower, whereas the mean cycling speed was higher (P < 0.05) than that without such assistance. In addition, following assisted exercise the mean blood lactate concentration and RPE were lower (P < 0.05) and ratings of enjoyment higher (P < 0.05). Moreover, motorized cycling was associated with (1) lower EMG with higher power output and speed; (2) less cardiorespiratory and metabolic effort; (3) lower respiratory exchange ratio; (4) lower RPE with more enjoyment; and (5) sufficient EE, according to present standards, to provide health benefits. Thus, electrically assisted cycling may represent an innovative approach to persuading reluctant sedentary women to exercise. PMID- 22446957 TI - The low intracellular oxygen tension during exercise is a function of limited oxygen supply and high mitochondrial oxygen affinity. PMID- 22446958 TI - Junction studies on electrochemically fabricated p-n Cu(2)O homojunction solar cells for efficiency enhancement. AB - p-n Cu(2)O homojunction solar cells were electrochemically fabricated by consecutively depositing an n-Cu(2)O layer on a p-Cu(2)O layer. In order to better understand the Fermi levels of the electrochemically grown polycrystalline p- and n-Cu(2)O layers and maximize the overall cell performance, the back and front contacts of the Cu(2)O homojunction cells were systematically changed and the I-V characteristics of the resulting cells were examined. The result shows that the intrinsic doping levels of the electrochemically prepared p-Cu(2)O and n Cu(2)O layers are very low and they made almost Ohmic junctions with Cu metal with which previously studied p-Cu(2)O layers prepared by thermal oxidation of Cu foils are known to form Schottky junctions. The best cell performance (an eta of 1.06%, a V(OC) of 0.621 V, an I(SC) of 4.07 mA cm(-2), and a fill factor (ff) of 42%) was obtained when the p-Cu(2)O layer was deposited on a commercially available ITO substrate as the back contact and a sputter deposited ITO layer was used as the front contact on the n-Cu(2)O layer. The unique features of the p-n Cu(2)O homojunction solar cell are discussed in comparison with other Cu(2)O based heterojunction solar cells. PMID- 22446959 TI - What's next? Alternative materials for articulation in total joint replacement. AB - The use of an artificial joint is always related to a certain amount of wear. Its biological effects, e.g., the osteolysis potential, are a function of the bulk material as well as its debris. Following comprehensive experiences with polyethylene (PE) wear, material science is tracking two ways to minimize the risk of a particle-induced aseptic implant loosening: (i) reduction of the PE debris by a low-wearing articulation partner; and (ii) replacement of the PE by other materials. Therefore, new ceramics (e.g., ZTA, Si(3)N(4)), as well as coatings (e.g., TiN, "diamond-like" carbon) and modifications of a bulk metal (e.g., oxidizes zirconium) or cushion bearings (polyurethane, hydrogels), are currently available for total joint replacements or have been used for pre clinical testing. This review gives a brief overview and evaluates the potential of those that have recently been published in literature. PMID- 22446961 TI - Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. AB - To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 * 10(-8)). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis. PMID- 22446960 TI - Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. AB - The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases. PMID- 22446962 TI - A genome-wide association study identifies three new risk loci for Kawasaki disease. AB - We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22 23 (rs2254546, P = 8.2 * 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 * 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 * 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 * 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease. PMID- 22446963 TI - Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. AB - Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation. We report a meta-analysis of genome-wide association studies (GWAS) in a Japanese population including 4,074 individuals with rheumatoid arthritis (cases) and 16,891 controls, followed by a replication in 5,277 rheumatoid arthritis cases and 21,684 controls. Our study identified nine loci newly associated with rheumatoid arthritis at a threshold of P < 5.0 * 10(-8), including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. ANXA3 was also associated with susceptibility to systemic lupus erythematosus (P = 0.0040), and B3GNT2 and ARID5B were associated with Graves' disease (P = 3.5 * 10(-4) and 2.9 * 10(-4), respectively). We conducted a multi-ancestry comparative analysis with a previous meta-analysis in individuals of European descent (5,539 rheumatoid arthritis cases and 20,169 controls). This provided evidence of shared genetic risks of rheumatoid arthritis between the populations. PMID- 22446964 TI - Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. AB - Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 * 10(-15)), PRIC285 (P = 3.0 * 10(-10)) and an upstream region of CDKN1A (P = 2 * 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor gamma (PPARgamma) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility. PMID- 22446965 TI - Evaluation of circulating CD4+CD25+ and liver-infiltrating Foxp3+ cells in HCV associated liver disease. AB - In hepatitis C virus (HCV)-associated liver disease, the immune system is unable to clear the viral infection. Previous studies have raised the possibility of an involvement of regulatory T cells (Tregs). In this study, we analysed the peripheral blood from 30 patients with HCV-associated chronic liver disease and 20 healthy controls by flow cytometry for the evaluation of the Treg population [CD4+CD25hi forkhead box protein 3 (Foxp3)+], as well as the activated/effector CD4+ T cells (CD4+CD25low) and IFN-gamma-secreting cells. We also analysed liver biopsies of the patients by immunohistochemical evaluation of Foxp3+ cells. Our results showed higher proportions of CD4+CD25low and IFN-gamma+ cells in the patients than in the controls. By contrast, the proportions of peripheral CD4+CD25hi cells did not significantly differ. The 11 patients displaying Foxp3+ cells in the liver infiltrates showed significantly higher proportions of peripheral CD4+CD25low cells. Moreover, we found lower serum transaminase levels in the patients than in the controls, as shown by Foxp3+ immunohistochemistry, although these results were only statistically significant as regards alanine transaminase (ALT). In conclusion, these data suggest that the presence of Tregs infiltrating the liver is associated with high levels of activated/effector T cells in the peripheral blood and lower activity of hepatitis. Therefore, liver infiltrating Tregs may play a role in limiting tissue damage and may thus support an effective immune response against HCV. PMID- 22446966 TI - Identifying high-functioning dyslexics: is self-report of early reading problems enough? AB - We used a questionnaire to identify university students with self-reported difficulties in reading acquisition during elementary school (self-report; n=31). The performance of the self-report group on standardized measures of word and non word reading and fluency, passage comprehension and reading rate, and phonological awareness was compared to that of two other groups of university students: one with a recent diagnosis (diagnosed; n=20) and one with no self reported reading acquisition problems (comparison group; n=33). The comparison group outperformed both groups with a history of reading difficulties (self report and diagnosed) on almost all measures. The self-report and diagnosed groups performed similarly on most tasks, with the exception of untimed reading comprehension (better performance for diagnosed) and reading rate (better performance for self-report). The two recruitment methods likely sample from the same underlying population but identify individuals with different adaptive strategies. PMID- 22446967 TI - Photo-induced toxicity of four polycyclic aromatic hydrocarbons (PAHs) to embryos and larvae of the carpet shell clam Ruditapes decussatus. AB - In this work, we assessed the photo-toxicity of four polycyclic aromatic hydrocarbons (PAHs) to embryos and larvae of the European clam Ruditapes decussatus. The exposure of R. decussatus embryos (24 h) and larvae (96 h) to anthracene, fluoranthene, pyrene and benzo[a]pyrene resulted in reduction of normal D-veliger percentages and high larval mortality, both in darkness and under sunlight conditions. Based on the calculated EC(50) and LC(50) values, the toxicity of the forementioned PAHs was respectively enhanced 72, 35, 60 and 23 times in the embryotoxicity test and 32, 31, 12 and 61 times in the larval mortality test when exposures were performed under sunlight conditions. Simultaneous exposure to sunlight and these PAHs enhanced their toxicity in comparison to dark conditions. The clam embryos and larvae appear to be environmentally relevant life-stages in assessing the toxic and photo-toxic risk of PAHs that enter the marine environment. PMID- 22446968 TI - Effect of aquifer heterogeneity on non-pumped, reactive well networks for removing pollutants in groundwater. AB - This purpose of this study was to evaluate the impact of heterogeneity in aquifer hydraulic conductivity on configurations of non-pumped wells filled with reactive media for removing contaminant plumes in groundwater. Among one homogeneous and three heterogeneous simulated aquifers, 2-16 wells were necessary to contain a plume, with no clear relationship between degree of heterogeneity and number of wells. Generally, heterogeneous aquifers with initial plumes having broad rather than narrow downgradient margins required more wells and showed greater tendency for plumes to move around wells. Cleanup time increased up to 181 % with degree of heterogeneity in hydraulic conductivity. PMID- 22446969 TI - Diet and effects of diet management on quality of life and symptoms in patients with irritable bowel syndrome. AB - The present study investigated the diet and quality of life of irritable bowel syndrome (IBS) patients in comparison to the background population. Furthermore, it studied the effects of guidance on diet management on changes in food intake, quality of life and symptoms. A total of 35 healthy controls, 36 IBS patients and 43 IBS patients who had received guidance on diet management 2 years earlier were included. The controls and patients were asked to complete an FFQ questionnaire, an SF-NDI questionnaire, an IBS-QoL questionnaire and a Birmingham IBS symptom score questionnaire. There were no statistical differences in the intake of calories, carbohydrates, proteins and fat between the controls and IBS patients, with or without guidance on diet management. IBS patients made a conscious choice to avoid certain food items, some of which belong to fermentable oligosaccharides, disaccharides, monosacharides and polyols (FODMAPs). They had a higher consumption, however, of other food items that are rich in FODMAPs. They also avoided other food sources which are crucial for their health. Two years after receiving guidance on diet management, IBS patients had a different diet profile. They avoided all FODMAP-rich food, consumed more food with probiotic supplements and did not avoid food sources that were crucial to their health. In addition, they had improved quality of life and reduced symptoms. Although at first sight the diet of IBS patients did not differ from that of the background population, detailed examination showed avoidance of certain food items. Guidance on the management of diet improved their choice of a healthier diet, improved quality of life and reduced IBS symptoms. PMID- 22446970 TI - Technology-neutral green procurement in practice - an example from Swedish waste management. AB - Green public procurement has been criticized for its excessive reliance on detailed technology specifications, which can distort incentives in the short term and discourage innovation in the longer term. Economists therefore tend to prefer technology-neutral procurement, which rewards outcomes rather than technologies. However, technology-neutral procurement can also be problematic in practice. The present study investigated green public procurement of waste management, a rapidly growing field. In one of the most sophisticated models for technology-neutral procurement applied in Sweden in recent years, different environmental impacts were assigned weights, but no weight was given to the particular technology employed. Even here, however, potential inefficiencies were found where the scoring rule could have led to arbitrary, and presumably unwanted, outcomes. Explicitly assigning monetary surcharges to desirable and undesirable environmental effects may be a better way to reach environmental targets. PMID- 22446971 TI - Quality standards and requirements for solid recovered fuels: a review. AB - The utilization of solid recovered fuels (SRF) for energy recovery has been increasing steadily in recent years, and this development is set to continue. In order to use SRF efficiently, it is necessary to define quality standards and introduce targeted quality assurance measures. SRF can be used both in mono incineration and in co-incineration systems, for instance in power generation and cement plants; but as quality requirements differ, it is necessary to unambiguously define the term 'solid recovered fuel'. The purpose of this article is to provide an overview of the origin, development and the current status of quality assurance for SRF. The basic principles of quality assurance for SRF are explained with reference to the development of the German RAL Quality Assurance System and in addition specifications that have emerged from European standardization work of CEN/TC 343 are analysed. PMID- 22446972 TI - Pathogen reduction efficiency of on-site treatment processes in eco-sanitation system. AB - An experimental study was conducted to assess the pathogen removal efficiency of primary treatment of ecological sanitation (eco-san) system. Ash, lime and soil were used as covering and treatment materials of faeces in the system. A significant rise in pH was observed when the faeces were treated with lime and ash, with a pH value of 11.3 and 9, respectively. Lime treatment was effective in complete destruction of faecal coliforms within 24 h while ash treatment took 30 days of storage to give the same result. On the other hand, no immediate destruction of Ascaris ova was observed during primary treatment of eco-san faeces. Dehydration and storage were other parameters which were considered in the experiment. Faecal coliforms tolerated a moisture content of 3% in untreated faeces while a large number of Ascaris lumbricoides eggs were inactivated by the same level of desiccation, even in the absence of alkaline treatment. The study showed a strong direct relationship between moisture content and viability of Ascaris egg (r = 0.806, p = 0.01) and a negative correlation between viability of eggs and storage time (r = -0.895, p = 0.01). Generally, the treatment methods used in this experiment showed a substantial potential of faeces sanitization, with removals ranging from 54 to 100% after a minimum of 40 days storage. PMID- 22446973 TI - Sequencing treatment of landfill leachate using ammonia stripping, Fenton oxidation and biological treatment. AB - Landfill leachates contain a wide variety of pollutants such as organic matter, refractory compounds, ammonia, particulate and dissolved solids and hazardous metals requiring application of advanced and well designed treatment processes before release to the environment. The main purpose of this research was to evaluate the efficiency of combined air stripping, Fenton oxidation and biological treatment in treating landfill leachate, especially the elimination of ammonia and refractory organics. The laboratory scale set-up consisted of three sequential but separate steps. The optimum conditions for air stripping and the Fenton oxidation were determined for landfill leachate from Karaj city, Iran. The final step was a moving bed bioreactor with HRTs of 18, 12 and 6 h. The highest NH(3)-N removal was 79% in the air stripping process at pH 10.5. At the optimum conditions for the Fenton reaction at a reaction time of 90 min, pH 3 and a H(2)O(2)/Fe(2+) mass ratio of 20, the COD removal was 61% and improved the BOD/COD ratio from 0.42 to 0.78. The overall COD removal including the final biological reactor with a HRT of 6 h resulted in an effluent COD concentration of less than 100 mg L(-1). PMID- 22446974 TI - One pot glucose detection by [Fe(III)(biuret-amide)] immobilized on mesoporous silica nanoparticles: an efficient HRP mimic. AB - An [Fe(III)(biuret-amide)] complex has been immobilized onto mesoporous silica nanoparticles via Cu(I) catalyzed azide-alkyne click chemistry. This hybrid material functions as an efficient peroxidase mimic and was successfully used for the quantitative determination of hydrogen peroxide and glucose via a one-pot colorimetric assay. PMID- 22446975 TI - Establishing and evaluating the key functions of an interactive systems framework using an assets-getting to outcomes intervention. AB - Community practitioners can face difficulty in achieving outcomes demonstrated by prevention science. Building a community practitioner's prevention capacity-the knowledge and skills needed to conduct critical prevention practices-could improve the quality of prevention and its outcomes. The purpose of this article is to: (1) describe how an intervention called Assets-Getting To Outcomes (AGTO) was used to establish the key functions of the ISF and present early lessons learned from that intervention's first 6 months and (2) examine whether there is an empirical relationship between practitioner capacity at the individual level and the performance of prevention at the program level-a relationship predicted by the ISF but untested. The article describes an operationalization of the ISF in the context of a five-year randomized controlled efficacy trial that combines two complementary models designed to build capacity: Getting To Outcomes (GTO) and Developmental Assets. The trial compares programs and individual practitioners from six community-based coalitions using AGTO with programs and practitioners from six similar coalitions that are not. In this article, we primarily focus on what the ISF calls innovation specific capacity and discuss how the combined AGTO innovation structures and uses feedback about its capacity building activities, which can serve as a model for implementing the ISF. Focus group discussions used to gather lessons learned from the first 6 months of the AGTO intervention suggest that while the ISF may have been conceptualized as three distinct systems, in practice they are less distinct. Findings from the baseline wave of data collection of individual capacity and program performance suggest that practitioner capacity predicts, in part, performance of prevention programs. Empirically linking practitioner capacity and performance of prevention provides empirical support for both the ISF and AGTO. PMID- 22446976 TI - Community-based prevention support: using the interactive systems framework to facilitate grassroots evidenced-based substance abuse prevention. AB - The community plays an important role in the success of substance abuse prevention efforts. However, current funding structures and a focus on limited approaches to prevention delivery have created a large gap between what substance abuse prevention professionals practice and what the community at large knows about prevention. The concept of "community" has not always been well-defined in the field of prevention, and there are few mechanisms to engage grassroots community members in evidence-based substance abuse prevention. This article explains how Wandersman et al.'s (Am J Community Psychol 41:171-181, 2008) Interactive Systems Framework can be applied to grassroots prevention efforts. The authors describe a Community Prevention Support System that collaborates with the Professional Prevention Support System to promote the adoption of evidence based substance abuse prevention practices at the grassroots, community level. PMID- 22446977 TI - Hypothesis: butyrate is not an HDAC inhibitor, but a product inhibitor of deacetylation. AB - The short-chain fatty acid butyrate is classically referred to as an inhibitor of histone deacetylases (HDACi), however evidence from direct assays is both sparse and contradictory. This paper assesses the strength of the historical evidence, potential gaps, inadequacies and simplifications in the butyrate-as-HDACi hypothesis. An alternate model to explain the action of butyrate is proposed wherein butyrate acts as a product inhibitor of deacetylation. The model makes testable predictions which may enable future determination of the mode of action of this and other SCFAs. PMID- 22446978 TI - Planning estimates for the mental health community support sector. AB - OBJECTIVE: To describe the approach undertaken to derive planning estimates for the mental health community support sector in Queensland, Australia. METHODS: We quantified the needs for services by calculating the prevalence of mental illness in Queensland and by stratifying mental illness by severity. A taxonomy of services in the mental health community support sector was developed and target groups for services identified. Resource targets were set based on a review of the academic and grey literature, expert opinion and consultation with the funding body. RESULTS: To provide adequate supported accommodation, 88 beds per 100,000 population are required, with 33.6 full-time equivalents (FTEs) per 100,000 population of attached personalised support. An additional 12.7 FTEs per 100,000 population of personalised support is required for individuals living independently in the community. We estimated that 6.9 FTEs per 100,000 population would be required for the provision of group support services. We estimated that a target of 1.6% of total mental health community support sector budget should be allocated to mutual support and self-help and 5% to community development. CONCLUSIONS: The mental health community support sector is now a major provider of services for people with mental illness, and is likely to continue to grow. When compared to public sector clinical mental health services, the mental health community support sector has lacked clarity surrounding what services are provided, and the quantity of resources required to provide these services. In the absence of other planning information for the community mental health support sector, the estimates described here provide a first step to guide governments and policymakers. Further research and testing in the real world by mental health community support sector practitioners is required to increase the evidence base and refine resource targets. PMID- 22446979 TI - Mindfulness of the psyche, mindfulness of the self. PMID- 22446980 TI - Feasibility, reliability and validity of the Thai version of the Pediatric Quality of Life Inventory 3.0 cerebral palsy module. AB - BACKGROUND: Quality of Life (QOL) and Health-related Quality of Life (HRQOL) are now considered as necessary outcome measures for children with cerebral palsy (CP). Various reliable and valid condition-specific HRQOL tools are available for these children. One of these is Pediatric Quality of Life Inventory (PedsQL) 3.0 CP module which has been widely used and was translated to many languages. As no Thai version is available, the authors have completed this translation. PURPOSE: This study then aimed to investigate psychometric properties of the newly translated Thai PedsQL 3.0 CP module and to establish parent confidence in their ratings in the translated tool. METHODS: Translation of the PedsQL 3.0 CP module was performed based on linguistic translation guidelines. Then, the psychometric properties of the Thai version were established. PedsQL 3.0 CP module was completed by children with CP and their parents or caregivers twice with 2-4 weeks. RESULTS: Respondents were 97 parents or caregivers and 54 children. Minimal missing data were found. Acceptable internal consistency was supported except for Movement and Balance Scale (self-report). Intraclass correlation coefficients for parent proxy and self-report were good to excellent (0.684 0.950). CONCLUSIONS: The feasibility, reliability and validity of the translated tool were supported. PMID- 22446981 TI - Population pharmacokinetics of cyclosporine A based on NONMEM in Chinese allogeneic hematopoietic stem cell transplantation recipients. AB - To set up a population pharmacokinetic (PPK) model of cyclosporine A (CsA) in Chinese allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients to provide reference for individualized medication in clinical practice. 281 trough plasma concentrations of CsA and covariates such as demographics, clinical laboratory values and coadministration were retrospectively collected from 73 allo-HSCT patients. Population modeling was performed using general model of NONMEM expressed by differential equation. Hematocrit (HCT), plasma albumin (ALB) level, and coadministration of itraconazole (ITR) were found to significantly affect the clearance of CsA (CL, L/h). The final model formula was: CL = 28.2 * [1 - 0.0263 * (HCT - 26.62)] * [1 - 0.0289 * (ALB - 37.63)] * [1 - 0.146 * ITR] (L/h); V = 1,080 (L); K (a) = 1.28 (h-1); F = 0.711. The interindividual variabilities for CL, V and F were 21.4, 41.5 and 6.07 %, respectively. The residual error was 0.00422 mg/L. The PPK model was validated to be effective and stable by bootstrap method. Clinical applications showed there was a good linear correlation between the predicted concentrations and the observed (y = 1.0095x + 0.0082, r = 0.9309, p < 0.0001). The PPK final model of CsA in Chinese allo-HSCT patients can be established using the NONMEM program which can be applied in clinical allo-HSCT practice when characteristics of patients fit in with those of subpopulation in the study. PMID- 22446982 TI - Objective assessment of the immediate postoperative analgesia using pupillary reflex measurement: a prospective and observational study. AB - BACKGROUND: The evaluation of pain intensity during the immediate postoperative period is a key factor for pain management. However, this evaluation may be difficult in some circumstances. The pupillary dilatation reflex (PDR) has been successfully used to assess the analgesic component of a balanced anesthetic regimen. We hypothesized that PDR could be a reliable index of pain intensity and could guide morphine administration in the immediate postoperative period. METHODS: One hundred patients scheduled to undergo general surgery were included in this prospective observational study. Pain intensity was assessed by using a simple five-item verbal rating scale (VRS). After patients awoke from general anesthesia, those experiencing mild or more severe pain (VRS more than 1) received intravenous morphine titration. Before and after intravenous morphine titration, the PDR induced by a standardized noxious stimulus was measured with a portable pupillometer. A receiver-operating curve was built to estimate the accuracy of PDR in objectively detecting patients requiring morphine titration. Results are given as median (95% CI). RESULTS: On the initial evaluation, a correlation was found between VRS and PDR (rho = 0.88 [0.83-0.92], P < 0.0001). In the 39 patients that had a VRS more than 1, PDR before and after morphine titration was respectively 35% (31-43) versus 12% (10-14); P < 0.0001. The PDR threshold value corresponding to the highest accuracy to have VRS more than 1 was 23%, with 91% and 94% sensitivity and specificity, respectively. CONCLUSION: In the immediate postoperative period, the PDR is significantly correlated with the VRS. The pupillometer could be a valuable tool to guide morphine administration in the immediate postoperative period. PMID- 22446983 TI - Active emergence from propofol general anesthesia is induced by methylphenidate. AB - BACKGROUND: A recent study showed that methylphenidate induces emergence from isoflurane general anesthesia. Isoflurane and propofol are general anesthetics that may have distinct molecular mechanisms of action. The objective of this study was to test the hypothesis that methylphenidate actively induces emergence from propofol general anesthesia. METHODS: Using adult rats, the effect of methylphenidate on time to emergence after a single bolus of propofol was determined. The ability of methylphenidate to restore righting during a continuous target-controlled infusion (TCI) of propofol was also tested. In a separate group of rats, a TCI of propofol was established and spectral analysis was performed on electroencephalogram recordings taken before and after methylphenidate administration. RESULTS: Methylphenidate decreased median time to emergence after a single dose of propofol from 735 s (95% CI: 598-897 s, n = 6) to 448 s (95% CI: 371-495 s, n = 6). The difference was statistically significant (P = 0.0051). During continuous propofol anesthesia with a median final target plasma concentration of 4.0 MUg/ml (95% CI: 3.2-4.6, n = 6), none of the rats exhibited purposeful movements after injection of normal saline. After methylphenidate, however, all six rats promptly exhibited arousal and had restoration of righting with a median time of 82 s (95% CI: 30-166 s). Spectral analysis of electroencephalogram data demonstrated a shift in peak power from delta (less than 4 Hz) to theta (4-8 Hz) and beta (12-30 Hz) after administration of methylphenidate, indicating arousal in 4/4 rats. CONCLUSIONS: Methylphenidate decreases time to emergence after a single dose of propofol, and induces emergence during continuous propofol anesthesia in rats. Further study is warranted to test the hypothesis that methylphenidate induces emergence from propofol general anesthesia in humans. PMID- 22446985 TI - MR, CT, and PET imaging in pericardial disease. AB - Although echocardiography remains the standard diagnostic tool for identifying pericardial diseases, procedures with better delineation of morphology and heart function are often required. The pericardium consists of an inner visceral (epicardium) and outer parietal layer (pericardium), which constitute for the pericardial cavity. Pericardial effusion can occur as transudate, exudate, pyopneumopericardium, or hemopericardium. Potential causes are inflammatory processes, that is, pericarditis due to autoimmune or infective reasons, neoplasms, irradiation, or systemic disorders, chronic renal failure, endocrine, or metabolic diseases. Pericardial fat can mimic pericardial effusion. Using various image-acquisition sequences, MRI allows identifying and separating fluid and solid structures. Fast spin-echo T1-weighted sequences with black-blood preparation are favourably used for morphological evaluation. Fast spin-echo T2 weighted sequences, particularly with fat saturation, and short-tau inversion recovery sequences are useful to visualize oedema and inflammation. For further tissue characterization, delayed inversion-recovery imaging is used. Therefore, image acquisition is performed at 5-20 min subsequent to contrast agent administration, the so-called technique of late gadolinium enhancement. Ventricular volumes and myocardial mass can be assessed accurately by steady state free-precession sequences, which is required to measure cardiac function and ventricular wall stress. Constrictive pericarditis usually results from chronic inflammatory processes leading to increased stiffness, which impedes the slippage of both pericardial layers and thereby the normal cardiac filling. CT imaging can favourably assess pericardial calcification. Thus, MR and CT imaging allow a comprehensive delineation of the pericardium. Superior to echocardiography, both methods provide a larger field of view and depiction of the complete chest including abnormalities of the surrounding mediastinum and lungs. PET provides unique information on the in vivo metabolism of 18 fluorodeoxyglucose that can be superimposed on CT findings and is useful for identifying inflammatory processes or masses, for example neoplasms. These imaging techniques provide advanced information of anatomy and cardiac function to optimize the pericardial access, for example by the AttachLifter system, for diagnosis and treatment. PMID- 22446986 TI - Tandem three-component reactions of aldehyde, alkyl acrylate, and dialkylmalonate catalyzed by ethyl diphenylphosphine. AB - A new highly efficient three-component reaction of alkyl acrylate, aldehyde and dialkyl malonate using ethyl diphenylphosphine as organocatalyst has been described. Various highly functional compounds bearing hydroxyl groups and the ester functions can be easily prepared in moderate to good yields according to our one-step procedure. The reactions are believed to proceed via Morita-Baylis Hillman reactions of alkyl acrylate and aldehydes, followed by the Michael addition reactions of dialkyl malonates. Our reactions indicated that the intermediate species formed in the phosphine-catalyzed MBH reaction are an effective organic base to catalyze the Michael addition reactions of dialkyl malonates to the preformed MBH adducts. PMID- 22446984 TI - Rodent models of heart failure: an updated review. AB - Heart failure (HF) is one of the major health and economic burdens worldwide, and its prevalence is continuously increasing. The study of HF requires reliable animal models to study the chronic changes and pharmacologic interventions in myocardial structure and function and to follow its progression toward HF. Indeed, during the past 40 years, basic and translational scientists have used small animal models to understand the pathophysiology of HF and find more efficient ways of preventing and managing patients suffering from congestive HF (CHF). Each species and each animal model has advantages and disadvantages, and the choice of one model over another should take them into account for a good experimental design. The aim of this review is to describe and highlight the advantages and drawbacks of some commonly used HF rodents models, including both non-genetically and genetically engineered models, with a specific subchapter concerning diastolic HF models. PMID- 22446987 TI - Laterality, hand control and scholastic performance: a British birth cohort study. AB - OBJECTIVES: To use simple measures of laterality and hand control that can identify a greater risk of poorer scholastic ability, potentially signalling suboptimal hemispheric lateralisation. DESIGN: Analysis of material from a birth cohort study. SETTING: Members of the National Child Development Study, a British birth cohort study following people born in 1958. PARTICIPANTS: 10 612 children who undertook tests at age 11 years. PRIMARY OUTCOME MEASURES: Teacher administered tests of non-verbal general ability, verbal general ability, reading comprehension and mathematics. RESULTS: Linear regression produced associations (and 95% CIs) with tests of verbal general ability, non-verbal general ability, reading comprehension and mathematics scores for the lowest third (compared with highest) of a left-hand control test involving picking up matches of -1.21 (-1.73 to -0.68; p<0.001), -0.72 (-1.14 to -0.29; p=0.001), -0.70 (-1.06 to -0.35; p<0.001) and -1.32 (-1.90 to -0.73; p<0.001). Among those in the lowest third of the right-hand control test score, mixed-handedness compared with right handedness was associated with poorer scholastic performance, with regression coefficients (and 95% CIs; p values) of 1.90 (-3.01 to -0.80; p=0.001), -1.25 ( 2.15 to -0.35; p=0.007), -1.28 (2.04 to -0.53; p=0.001) and -1.33 (-2.53 to 0.13; p=0.030). The estimates are for a point change in the scholastic test scores, after adjustment for sex, left-hand motor function and social class. Statistically significant associations with mixed-handedness were only observed for the lowest third of right-hand motor function. CONCLUSIONS: Measures involving poorer left-hand motor function may represent useful markers of reduced cognitive function possibly reflecting suboptimal hemispheric lateralisation. Crude measures of laterality such as reported non-right-handedness may be more useful for research when combined with measures of motor function. PMID- 22446988 TI - Trends in sudden cardiac death and its risk factors in Japan from 1981 to 2005: the Circulatory Risk in Communities Study (CIRCS). AB - OBJECTIVE: There is little evidence whether sudden cardiac death (SCD) is increasing in Asia, although the incidence of coronary heart disease among urban middle-aged Japanese men has increased recently. We examined trends in the incidence of SCD and its risk factors in the Circulatory Risk in Communities Study. DESIGN AND SETTING: This was a population-based longitudinal study. Surveillance of men and women for SCD incidence and risk factors was conducted from 1981 to 2005. SUBJECTS: The surveyed population was all men and women aged 30-84 years who lived in three rural communities and one urban community in Japan. MAIN OUTCOME MEASURES: Trends in SCD incidence and its risk factors. RESULTS: Age-adjusted and sex-adjusted incidence of SCD decreased from 1981-1985 to 1991-1995, and plateaued thereafter. The annual incidence per 100 000 person years was 76.0 in 1981-1985, 57.9 in 1986-1990, 39.3 in 1991-1995, 31.6 in 1996 2000 and 36.8 in 2001-2005. The prevalence of hypertension decreased from 1981 1985 to 1991-1995, and plateaued thereafter for men and women. The age-adjusted prevalence of current smoking for men decreased while that of diabetes mellitus increased for both sexes from 1981-1985 to 2001-2005. CONCLUSIONS: The incidence of SCD decreased from 1981 to 1995 but was unchanged from 1996 to 2005. Continuous surveillance is necessary to clarify future trends in SCD in Japan because of an increasing incidence of diabetes mellitus. PMID- 22446989 TI - Validation of a questionnaire for the assessment of pain following ventral hernia repair--the VHPQ. AB - PURPOSE: The aim of this study was to create and evaluate the validity and reliability of a novel ventral hernia pain questionnaire (VHPQ) to assess pain following surgery for ventral hernia. METHODS: The questionnaire was constructed using focus groups and patient interviews. Validity was tested on 51 patients who responded to the VHPQ and brief pain inventory (BPI) 1 and 4 weeks following surgery. Reliability and internal consistency was tested on 74 patients who had surgery 3 years earlier and received the VHPQ and BPI on two separate occasions. Pain not related to surgery was examined on one occasion using the VHPQ on 100 non-operated people. RESULTS: For pain intensity items, a significant decrease was seen from week 1 to week 4 postoperative (p < 0.05). Spearman rank correlations were significant between the pain intensity items of the VHPQ and the BPI, tested 1 week postoperative (p < 0.05). Kappa levels for test-retest of items for interference with daily activities were higher than 0.5 for all items except one. Intra-class correlation was significant for pain intensity items (p < 0.05) in the test-retest group. Three years after surgery, the operated group stated more pain in the pain intensity items (p < 0.05) and more interference with daily activities (p < 0.05) than a non-operated group from the general population. CONCLUSION: The validity and reliability of the VHPQ make it a useful tool in assessing postoperative pain and patient satisfaction. PMID- 22446990 TI - Coagulation Day 2010: an Austrian survey on the routine of thromboprophylaxis in intensive care. AB - PURPOSE: Venous thromboembolism (VTE) is a common but often overlooked life threatening complication of critical illness. The aim of this cross-sectional survey was to assess current practice of thromboprophylaxis as well as adherence to international guidelines. METHODS: After ethics committee approval, all intensive care units in Austrian hospitals treating adult patients were invited to participate in this web-based survey. Anonymized data on each patient treated at the participating intensive care units on Coagulation Day 2010 were collected using an electronic case report form. Risk assessment, choice and monitoring of anticoagulants, means of mechanical prophylaxis, and demographic data were recorded. RESULTS: Data from 325 critically ill patients were collected. Patients had a median of four risk factors for thrombosis and 6 % suffered from VTE. Of the 325 patients, 80 % received low molecular weight heparins subcutaneously, 10 % received unfractionated heparin intravenously, 1 % received alternative anticoagulants and 9 % received no pharmacological prophylaxis. Mechanical prophylaxis was used in 49 % with a predominant use of graduated compression stockings. In 39 % a combination of pharmacological and mechanical prophylaxis was applied and 5 % received no prophylaxis at all. Overall guideline adherence was 40 % on Coagulation Day 2010. CONCLUSION: Current practice of thromboprophylaxis is predominantly based on the administration of low molecular weight heparins prescribed at rather arbitrary doses without a discernible relationship to drug monitoring, thromboembolic risk factors, vasopressor use or fluid balance. The use of mechanical prophylaxis, evaluation of risk scores and overall guideline adherence must be further encouraged by education, training and communication. PMID- 22446991 TI - Determination of macrolide antibiotics using dispersive liquid-liquid microextraction followed by surface-assisted laser desorption/ionization mass spectrometry. AB - A novel method for the determination of macrolide antibiotics using dispersive liquid-liquid microextraction coupled to surface-assisted laser desorption/ionization mass spectrometric detection was developed. Acetone and dichloromethane were used as the disperser solvent and extraction solvent, respectively. A mixture of extraction solvent and disperser solvent were rapidly injected into a 1.0 mL aqueous sample to form a cloudy solution. After the extraction, macrolide antibiotics were detected using surface-assisted laser desorption/ionization mass spectrometry (SALDI/MS) with colloidal silver as the matrix. Under optimum conditions, the limits of detection (LODs) at a signal-to noise ratio of 3 were 2, 3, 3, and 2 nM for erythromycin (ERY), spiramycin (SPI), tilmicosin (TILM), and tylosin (TYL), respectively. This developed method was successfully applied to the determination of macrolide antibiotics in human urine samples. PMID- 22446992 TI - Treatment update in multiple sclerosis. AB - Multiple sclerosis is the most common cause of disability in young people in the Western world. Reduced life expectancy and worsening quality of life due to increasing disability later in the disease course have significant personal and societal costs. Changes in treatment strategies and newly available treatments hope to improve the outlook for our often young patients. This paper details currently available treatments and some that are expected to reach the market shortly. PMID- 22446993 TI - Layered Na(0.71)CoO(2): a powerful candidate for viable and high performance Na batteries. AB - The present study reports on the synthesis and the electrochemical behavior of Na(0.71)CoO(2), a promising candidate as cathode for Na-based batteries. The material was obtained in two different morphologies by a double-step route, which is cheap and easy to scale up: the hydrothermal synthesis to produce Co(3)O(4) with tailored and nanometric morphology, followed by the solid-state reaction with NaOH, or alternatively with Na(2)CO(3), to promote Na intercalation. Both products are highly crystalline and have the P2-Na(0.71)CoO(2) crystal phase, but differ in the respective morphologies. The material obtained from Na(2)CO(3) have a narrow particle length (edge to edge) distribution and 2D platelet morphology, while those from NaOH exhibit large microcrystals, irregular in shape, with broad particle length distribution and undefined exposed surfaces. Electrochemical analysis shows the good performances of these materials as a positive electrode for Na-ion half cells. In particular, Na(0.71)CoO(2) thin microplatelets exhibit the best behavior with stable discharge specific capacities of 120 and 80 mAh g( 1) at 5 and 40 mA g(-1), respectively, in the range 2.0-3.9 V vs. Na(+)/Na. These outstanding properties make this material a promising candidate to construct viable and high-performance Na-based batteries. PMID- 22446994 TI - Potential synergism of Bim with p53 in mice with Myc-induced lymphoma in a mouse lymphoma model. AB - We report that Bim has an apoptotic function through Bax/mitochondrial apoptosis signaling in the p53-independent mode, which is somewhat additive to the effects of p53. Bim-deficient mouse embryonic fibroblast (MEF) cells were resistant to the apoptotic effects of Myc, while loss of Bim accelerated lymphoma development. Furthermore, Bim was overexpressed at the same frequency in Myc-initiated lymphomas, irrespective of p53 status, suggesting that Bim resides in a pathway separate from p53. Loss of Bim further augmented resistance to apoptosis in p53-/ MEFs. Mice with p53 knockdown exhibited exacerbated malignancies in the absence of Bim. The combined loss of these proteins promoted more severe spontaneous tumorigenesis. Thus, Myc-induced apoptotic signals through Bim and p53 must bifurcate to activate Bax, suggesting that the activation of Bim and p53 significantly contribute to apoptosis. Our results, therefore, establish that p53 and Bim are effective key initiators of apoptosis in lymphoma cells, particularly when combined. PMID- 22446995 TI - Resistance training can improve fine manual dexterity in essential tremor patients: a preliminary study. AB - OBJECTIVE: To determine if a short-term resistance training (RT) program of the upper limb can improve strength, fine manual dexterity, and quality of life in individuals with essential tremor (ET). DESIGN: Single group, dual pretest posttest intervention study. SETTING: General community. PARTICIPANTS: Participants (N=6; mean age +/- SD, 74+/-7y) clinically diagnosed as having ET (mean years diagnosed +/- SD, 19+/-7y) were recruited into the study. INTERVENTION: A 6-week RT program involving unilateral dumbbell bicep curls, wrist flexion, and wrist extension exercises twice a week. MAIN OUTCOME MEASURES: Upper limb strength determined from five-repetition maximum; fine manual dexterity determined from the Purdue Pegboard Test (PPT) for the hand of the most affected limb, the hand of the least affected limb, both hands, and a bilateral assembly task; and quality of life determined from the Medical Outcomes Study 36 Item Short-Form Health Survey and the ET specific Quality of Life in Essential Tremor questionnaire. RESULTS: The RT program resulted in significant increases in 4 of the 6 upper limb strength measures. Significant improvements in the PPT were observed for the single hand components of this test. PPT performance improved immediately after RT when using the most affected limb, but these changes took longer to be observed for the least affected limb. CONCLUSIONS: Overall, fine manual dexterity improved in ET patients after a simple RT program. The findings of this preliminary study provide clear evidence that RT is worthy of further investigation as a therapy for improving functionality in ET patients. PMID- 22446996 TI - Elevated concentration of placental growth factor (PlGF) and long term risk in patients with acute coronary syndrome in the PROVE IT-TIMI 22 trial. AB - Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, acts via the flt-1 receptor and promotes endothelial activation and macrophage recruitment into atherosclerotic lesions. We investigated the relationship of PlGF with cardiovascular outcomes in a large cohort of patients presenting across the spectrum of ACS. PlGF was measured at baseline (n = 3,761) and at four-months (n = 3,369) in patients randomized to atorvastatin 80 mg or pravastatin 40 mg after ACS in the PROVE IT-TIMI 22 trial. The primary endpoint was death, myocardial infarction (MI), unstable angina, revascularization or stroke (mean follow-up 24 months). Elevated baseline PlGF was associated with a higher incidence of the primary endpoint through 2 years (Q1 vs. Q5: 18.7 vs. 29.3%, p < 0.0001). The risk of death or MI was also higher in patients with elevated baseline PlGF (Q1 vs. Q5: 7.0 vs. 11.6%, p = 0.029). Adjusting for baseline characteristics and risk factors, elevated baseline PlGF was independently associated with the risk of the primary endpoint (adjusted-HR for Q5 vs. Q1 1.45; 95% CI 1.16-1.83; p = 0.001). Elevated PlGF at four months was associated with higher risk of death or MI (Adjusted HR Q5 vs. Q1 2.79, 95% CI: 1.37-5.68; p = 0.005), and higher risk of the primary endpoint (Adjusted HR Q5 vs. Q1 1.78, 95% CI: 1.26-2.51; p = 0.001). Higher concentration of PlGF after ACS is associated with long-term risk of recurrent cardiovascular events independent of traditional risk factors. This association is present early after ACS and appears to be stronger at four months. PMID- 22446997 TI - Diagnostic evaluation of the MRP-8/14 for the emergency assessment of chest pain. AB - Elevated levels of myeloid-related protein (MRP)-8/14 (S100A8/A9) are associated with first cardiovascular events in healthy individuals and worse prognosis in patients with acute coronary syndrome (ACS). The diagnostic utility of MRP-8/14 in patients presenting to the emergency room with symptoms concerning for ACS is uncertain. MRP-8/14 was measured in serial serum and plasma samples in a single center prospective cohort-study of patients presenting to the emergency room with non-traumatic chest pain concerning for ACS. Final diagnosis was adjudicated by an endpoint committee. Of patients with baseline MRP-8/14 results (n = 411), the median concentration in serum was 1.57 MUg/ml (25th, 75th: 0.87, 2.68) and in plasma was 0.41 MUg/ml (<0.4, 1.15) with only moderate correlation between serum and plasma (rho = 0.40). A final diagnosis of MI was made in 106 (26%). Peak serum MRP-8/14 was higher in patients presenting with MI (p < 0.001). However, the overall diagnostic performance of MRP-8/14 was poor: sensitivity 28% (95% CI 20-38), specificity 82% (78-86), positive predictive value 36% (26-47), and negative predictive value 77% (72-81). The area under the ROC curve for diagnosis of MI with MRP-8/14 was 0.55 (95% CI 0.51-0.60) compared with 0.95 for cTnI. The diagnostic performance was not improved in early-presenters, patients with negative initial cTnI, or using later MRP-8/14 samples. Patients presenting with MI had elevated levels of serum MRP-8/14 compared to patients with non-cardiac chest pain. However, overall diagnostic performance of MRP-8/14 was poor and neither plasma nor serum MRP-8/14 offered diagnostic utility comparable to cardiac troponin. PMID- 22446998 TI - The effects of QEEG-informed neurofeedback in ADHD: an open-label pilot study. AB - In ADHD several EEG biomarkers have been described before, with relevance to treatment outcome to stimulant medication. This pilot-study aimed at personalizing neurofeedback treatment to these specific sub-groups to investigate if such an approach leads to improved clinical outcomes. Furthermore, pre- and post-treatment EEG and ERP changes were investigated in a sub-group to study the neurophysiological effects of neurofeedback. Twenty-one patients with ADHD were treated with QEEG-informed neurofeedback and post-treatment effects on inattention (ATT), hyperactivity/impulsivity (HI) and comorbid depressive symptoms were investigated. There was a significant improvement for both ATT, HI and comorbid depressive complaints after QEEG-informed neurofeedback. The effect size for ATT was 1.78 and for HI was 1.22. Furthermore, anterior individual alpha peak frequency (iAPF) demonstrated a strong relation to improvement on comorbid depressive complaints. Pre- and post-treatment effects for the SMR neurofeedback sub-group exhibited increased N200 and P300 amplitudes and decreased SMR EEG power post-treatment. This pilot study is the first study demonstrating that it is possible to select neurofeedback protocols based on individual EEG biomarkers and suggests this results in improved treatment outcome specifically for ATT, however these results should be replicated in further controlled studies. A slow anterior iAPF at baseline predicts poor treatment response on comorbid depressive complaints in line with studies in depression. The effects of SMR neurofeedback resulted in specific ERP and EEG changes. PMID- 22446999 TI - Emotional intelligence and electro-dermal activity. AB - Emotional intelligence (EI) is a promising concept in our understanding of emotional regulation, related behaviors and pathologies. However, research linking EI to underlying physiological and biological structure and responses is meager. This study explored potential associations of EI with electro-dermal activity (EDA) responses to emotionally arousing visual stimuli. It was hypothesized that higher levels of EI will associate with more efficient emotional regulation as reflected by EDA. Eighty-four healthy participants were exposed to stimuli consisting of a series of 12 images designed to evoke positive or negative emotional responses, presented in a counterbalanced order. A self report questionnaire and a computer based test of EI were administered along with a demographic questionnaire. EDA measures were taken during the exposure to the above stimuli using BIOPACK MP150. EI test scores (Beta = .35, .32; p < .001) and age (Beta = -.24, -.31; p < .03) associated with EDA delta (stimulus response baseline) scores, while the self-report measure of EI and other demographics (e.g., gender. ethnicity) did not show any associations with the outcome measures. The results support the relevance of the concept to our understanding of emotional responses and regulation. The findings are briefly discussed within the context of underlying mechanisms of EI as well as measure validity and relevance. PMID- 22447000 TI - Neovascularization and angiogenic factors in advanced human carotid artery stenosis. AB - BACKGROUND: Most atherosclerotic lesions are vascularized, so neovessels may also contribute to plaque progression and vulnerability, but their precise role of neovessels in atherosclerosis is still unknown. The aim of this study was to analyze the possible relationships among neovascularization, relevant angiogenic factors, and plaque vulnerability in patients with advanced carotid artery stenosis. METHODS AND RESULTS: The study group comprised 56 patients (stable: n=28, unstable: n=28) with advanced carotid artery stenosis (>70%). Immunohistochemistry was performed for smooth muscle, endothelial, and inflammatory cells, macrophages, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), platelet-derived growth factor (PDGF), and angiopoietin-1, 2 (Ang-1,-2). Furthermore, the concentrations of angiogenic factors were measured in serum. Quantitative expression analysis was performed by SYBR-Green-based real time polymerase chain reaction. Compared with stable carotid lesions, unstable carotid lesions showed 1.8-fold increase in neovascularization (P=0.013), which significantly correlated with accumulation of inflammatory cells (factor 1.9, P<0.001). In unstable lesions, compared with stable lesions, VEGF was 1.7-fold increased (P=0.032) and Ang-1 was 1.9-fold reduced (P=0.029). Furthermore, VEGF was higher in the blood of patients with unstable plaques than in stable plaques (0.32 +/- 0.22 vs. 0.22 +/- 0.16 ng/ml; P=0.002). Significant correlations were observed between plaque vulnerability, VEGF, neovascularization and inflammatory cells. CONCLUSIONS: Our results show a close association between neovascularization, expression of angiogenic factors, inflammation, and plaque vulnerability in patients with advanced carotid stenosis. PMID- 22447001 TI - Detection of attenuated plaque in stable angina with 64-multidetector computed tomography: a comparison with intravascular ultrasound. AB - BACKGROUND: To clarify multidetector computed tomography (MDCT) findings of attenuated plaque detected by intravascular ultrasound (IVUS). METHODS AND RESULTS: One hundred and fifty-four patients with stable angina underwent MDCT before IVUS. The attenuated plaque was identified in the targeted artery with IVUS, and the same artery was analyzed with MDCT for the presence of a high density area (HDA) >130 Hounsfield units (HU), and a low density area (LDA) <30 HU. A HDA in attenuated plaque was compared with that in calcified plaque. Ten attenuated plaques and 15 calcified plaques were identified in 9 of 154 patients (males=9, 66.2 +/- 9.5 years). Eight of the 10 attenuated plaques and all 15 calcified plaques were accompanied with a HDA on MDCT. The HDA ranged from 174 to 667 HU (mean 389.0 +/- 148.3 HU) in the 8 attenuated plaques, and from 545 to 1,205 HU (mean 920.9 +/- 215.9 HU) in 15 calcified plaques. There was a significant difference in CT density of the HDA between the attenuated and calcified plaque (P<0.001). All attenuated plaques contained LDA <30 HU in the portions without HDA. CONCLUSIONS: MDCT has the ability to demonstrate attenuated plaque as the combination of HDA (approximately 400 HU on average) and LDA <30 HU. The HDA can be differentiated from calcified plaque by its lower CT density value. PMID- 22447002 TI - Extracorporeal shock wave therapy improves the walking ability of patients with peripheral artery disease and intermittent claudication. AB - BACKGROUND: Despite the recent advances in bypass surgery and catheter interventional therapy for peripheral artery disease (PAD), the long-term outcome of revascularization therapy for infrapopliteal lesions remains unsatisfactory. We have previously demonstrated that low-energy extracorporeal shock wave (SW) therapy effectively induces neovascularization through upregulation of angiogenic factors and improves myocardial ischemia in pigs and humans and in hindlimb ischemia in rabbits. In this study, we thus examined whether our SW therapy also improves the walking ability of patients with PAD and intermittent claudication. METHODS AND RESULTS: We treated 12 patients (19 limbs) in Fontaine II stage (males/females, 10/2; 60-86 years old) with low-energy SW therapy to their ischemic calf muscle 3 times/week for 3 consecutive weeks. After 24 weeks, the pain and distance subscale scores of the walking impairment questionnaire were significantly improved (33+/-25 vs. 64+/-26, 27+/-16 vs. 64+/-23, respectively, both P<0.01). Maximum walking distance was also significantly improved at 4 weeks (151+/-37% from baseline, P<0.01) and was maintained at 24 weeks (180+/-74% from baseline, P<0.01). Moreover, the recovery time of the tissue oxygenation index in the calf muscle during a treadmill test, which reflects local O2 supply, was significantly shortened (295+/-222s vs. 146+/-137s, P<0.01). Importantly, no adverse effects were noted. CONCLUSIONS: Non-invasive SW therapy improves the walking ability of PAD patients. PMID- 22447003 TI - Pulsatile cardiopulmonary bypass with intra-aortic balloon pump improves organ function and reduces endothelial activation. AB - BACKGROUND: We aimed to evaluate if the use of an intra-aortic balloon pump (IABP) during cardioplegic arrest improves organ function and reduces endothelial activation in patients undergoing coronary artery bypass graft (CABG). METHODS AND RESULTS: Five-hundred and one CABG patients were randomized into 2 groups: (Group A n=270) linear cardiopulmonary bypass (CPB); and (Group B n=231) automatic 80 beats/min IABP-induced pulsatile CPB. We evaluated hemodynamic response, coagulation and fibrinolysis, transaminase, bilirubin, amylase, lactate, renal function (estimated glomerular filtration rate [eGFR], creatinine and any possibility of renal insufficiency or failure), respiratory function and endothelial markers (vascular endothelial growth factor [VEGF] and monocyte chemotactic protein-1 [MCP-1]). IABP, which induced surplus hemodynamic energy, was 21,387 +/- 4,262 ergs/cm(3). Group B showed lower chest drainage, transfusions, international normalized ratio, and antithrombin III, together with higher platelets, activated partial thromboplastin time, fibrinogen and D-dimer. Transaminases, bilirubin, amylase, lactate were lower in Group B; there were better results for eGFR in Group B from ICU-arrival to 48 h, resulting in lower creatinine from ICU-arrival to 48 h. The necessity for renal replacement therapy was lower in Group B Stage-3. Group B P(a)O(2)/F(i)O(2) and lung compliance improved with aortic de-clamping on the first day with shorter intubation time. Group B showed lower VEGF and MCP-1. CONCLUSIONS: Pulsatile flow by IABP improves whole-body perfusion and reduces endothelial activation during CPB. PMID- 22447004 TI - Assessment of doxorubicin cardiac toxicity using gated 99mTc-hexakis-2 methoxyisobutylisonitrile myocardial single photon emission computed tomography: wall thickening and motion abnormalities can be an early sign of cardiac involvement. AB - BACKGROUND: Advancement in chemotherapy has significantly improved the prognosis of cancer patients. However, many anticancer drugs have serious cardiovascular side effects. We assessed doxorubicin-induced cardiac toxicity (DCT) during and after preoperative chemotherapy using gated (99m)Tc-hexakis-2 methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) in patients with malignant bone and soft tissue tumors. METHODS AND RESULTS: Gated (99m)Tc-MIBI SPECT was performed before, and after the middle and final courses of preoperative chemotherapy. Gated (99m)Tc-MIBI SPECT was quantitatively analyzed with QGS/QPS software. We also assessed the reproducibility of measurements of global and regional functions from gated SPECT images. Twenty-eight patients (19 males and 9 females), eligible for preoperative chemotherapy, were included. All patients had normal myocardial perfusion images based on QPS during preoperative chemotherapy. Wall thickening (WT) and motion (WM) decreased after the middle course of preoperative chemotherapy compared to baseline. After the final course of preoperative chemotherapy, significant decreases of ejection fraction, WT and WM, and one-third mean filling rate were observed compared to baseline. By regression analysis, correlation coefficients of inter- and intra-observer reproducibility of global and regional functions were excellent (r >= 0.95). CONCLUSIONS: Gated (99m)Tc-MIBI SPECT can monitor the deterioration of cardiac function in asymptomatic patients with possible DCT. WT and WM might be useful as early markers of ventricular dysfunction due to DCT. PMID- 22447005 TI - Heparin bridging vs. uninterrupted oral anticoagulation in patients with Atrial Fibrillation undergoing Coronary Artery Stenting. Results from the AFCAS registry. AB - BACKGROUND: The anti-thrombotic strategy during coronary stenting is challenging in patients on long-term oral anticoagulation (OAC) because of atrial fibrillation (AF). Uninterrupted OAC (UAC) is increasingly used, but bridging therapy (BT) is still in common use. METHODS AND RESULTS: Management of patients with Atrial Fibrillation undergoing Coronary Artery Stenting (AFCAS) is a prospective multicenter European registry that recruited 963 patients with AF undergoing coronary stenting. To compare the safety of UAC and BT, bleeding complications and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, target vessel revascularization, stent thrombosis and stroke) were assessed in 290 patients treated with UAC and 161 patients with BT during a 30-day follow-up period. In the BT group, OAC was interrupted for a median of 5 days. Overall bleeding complications tended to be more common in the BT group (18.6% vs. 12.1%, P=0.07), with no significant difference in the rate of major bleeding (2.5% vs. 1.4%) or MACCE (6.2% vs. 3.8%). After adjustment for propensity score, BT was not associated with bleeding complications (odds ratio [OR], 1.38; 95% confidence interval [CI]: 0.77-2.48, P=0.28) or MACCE (OR, 1.16; 95%CI: 0.44-3.05, P=0.76). Periprocedural international normalized ratio was not associated with bleeding or MACCE. CONCLUSIONS: UAC does not increase perioperative complications during coronary stenting and is a simple and cost effective alternative to conventional heparin bridging. PMID- 22447006 TI - Estimation of left atrial pump function by mitral annular velocity. AB - BACKGROUND: Estimation of left atrial (LA) pump function is important for the management of cardiac patients. The purpose of this study is to elucidate the role of mitral annular late diastolic velocity (A') determined by transthoracic echocardiography as a parameter to predict LA pump function. METHODS AND RESULTS: One hundred and four consecutive patients that were scheduled for paroxysmal atrial fibrillation (AF) ablation, in whom both multi-detector computed tomography (MDCT) and echocardiography during sinus rhythm prior to ablation were performed, were enrolled in this study. To determine the echocardiographic parameters that most accurately represent LA pump function, the relationship between LA emptying fraction (LAEF) obtained by MDCT and echocardiographic parameters including A' were examined. A' was the only echocardiographic parameter that was significantly correlated with LAEF (r=0.59, P<0.0001). Receiver-operating characteristic curve analysis showed that when impaired LA booster pump performance was defined as an LAEF <30%, an A' cutoff value of 7.4 cm/s had a sensitivity of 93%, specificity of 81%, predictive accuracy of 83%, positive predictive value of 43% and a negative predictive value of 99%. CONCLUSIONS: A' is a simple, non-invasive and reliable method to estimate LA pump function in patients with paroxysmal AF. PMID- 22447007 TI - Outcome of patients with profound cardiogenic shock after cardiopulmonary resuscitation and prompt extracorporeal membrane oxygenation support. A single center observational study. AB - BACKGROUND: The in-hospital outcome of patients with profound cardiogenic shock (CS) undergoing extracorporeal membrane oxygenation (ECMO) and prognostic predictors were analyzed. METHODS AND RESULTS: Between 2003 and 2010, 134 patients with profound CS undergoing 10-15 min of cardiopulmonary cerebral resuscitation (CPCR) and ECMO were prospectively recruited, including 27.6% (37) with ST-elevation myocardial infarction (STEMI), 11.9% (16) with non-STEMI, 22.4% (30) with post-surgery pump failure, 10.5% (14) with refractory congestive heart failure, 19.4% (26) with fulminant acute myocarditis, 2.2% (3) with pediatric congenital diaphragmatic hernia, and 6.0% (8) with percutaneous coronary intervention-related complications. The mean systolic pressure was 49.8 mmHg and 91.8% of patients required ventilatory support prior to ECMO. The Post-ECMO Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score and peak creatine kinase level were 26.2 and 5,311 IU/L, respectively. In-hospital mortality was 57.5%. Sixty-eight patients (50.7%) were successfully weaned from ECMO and 57 (42.5%) were discharged alive. Univariate analysis identified the APACHE II score as the strongest predictor of in-hospital mortality (P<0.0001) with respiratory failure, smoking, and male gender also related (all P<0.03). Multivariate analysis identified an APACHE II score >=22 and successful ECMO weaning as the only independent predictor for in-hospital mortality and a determinant of survival, respectively (P=0.0003). CONCLUSIONS: Profound CS was associated with high mortality. Both successful weaning from ECMO and an APACHE II score might serve as outcome predictors for risk stratification. PMID- 22447008 TI - Prior cardiac and thoracic aortic surgery as a complication risk factor for abdominal aortic aneurysm repair. AB - BACKGROUND: Patients with both cardiothoracic lesions and abdominal aortic aneurysm (AAA) are increasing in Japan. The objective of this study was to clarify the effect of 2-staged surgery on complication rates. METHODS AND RESULTS: Three hundred and forty-six patients who underwent elective surgery for infrarenal AAA were entered. History of cardiac and thoracic aortic surgery within 1 year before AAA repair was recorded. A retrospective study regarding perioperative complications was performed. Operative mortality and complication rates were 0.6% and 10.7%, respectively. Seventy patients (20.2%) underwent prior cardiac and thoracic aortic surgery before AAA repair. There was no significant difference in preoperative characteristics between the group with prior cardiac and thoracic aortic surgery and the group without prior surgery. Significant risk factors for postoperative morbidity were: (1) prior cardiac and thoracic aortic surgery (odds ratio [OR] 2.5; 95%CI 1.1-5.1); (2) open aneurysm repair (OAR) (OR 2.7; 95%CI 1.3-5.1); and (3) VSG-CRI score >=6 (OR 2.9; 95%CI 1.2-6.8). Subanalysis revealed that, although prior cardiac and thoracic aortic surgery was still a risk within patients undergoing OAR, it was not a risk factor for patients undergoing endovascular aneurysm repair (EVAR). CONCLUSIONS: Prior cardiac and thoracic aortic surgery carries high risk for AAA repair. To lower complication rates, we propose to perform EVAR on these patients if they are anatomically suitable. PMID- 22447009 TI - Effects of intravenous nicorandil on the mid-term prognosis of patients with acute heart failure syndrome. AB - BACKGROUND: Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect of intravenous nicorandil on the mid-term prognosis of AHFS. METHODS AND RESULTS: A total of 402 consecutive patients who were hospitalized for AHFS were divided into 2 groups according to the use of intravenous nicorandil: 78 patients in the Nicorandil group and 324 patients in the Control group. During the 180-day follow up, death or rehospitalization for heart failure occurred in 7 patients in the Nicorandil group (9.0%) and in 75 patients (23.2%) in the Control group. Event free survival rates were significantly higher in the Nicorandil group than in the Control group (P=0.006). Multivariate Cox hazard analysis revealed that age (hazard ratio (HR)=1.066, P<0.0001), systolic blood pressure (HR=0.983, P=0.0023), New York Heart Association class III/IV (HR=6.550, P<0.0001), log creatinine (HR=3.866, P=0.0106), and use of intravenous nicorandil (HR=0.179, P<0.0001) were significant predictive factors for the occurrence of death or rehospitalization for heart failure. CONCLUSIONS: Intravenous nicorandil treatment from the urgent phase of AHFS may improve the prognosis. PMID- 22447010 TI - Platelet level as a new prognostic factor for idiopathic pulmonary arterial hypertension in the era of combination therapy. AB - BACKGROUND: The recent development of various effective drugs, such as epoprostenol, sildenafil, and bosentan, has improved the prognosis for patients with idiopathic pulmonary arterial hypertension (IPAH). This study sought to determine survival rates and to identify predictive prognostic factors in patients with IPAH in the current era of combination therapy with new and more effective vasodilators. METHODS AND RESULTS: In 65 consecutive IPAH patients treated from 2004 to 2009, hemodynamic parameters were significantly improved and brain natriuretic peptide was significantly decreased by combination therapy (observation period: 35+/-18 months). The Kaplan-Meier survival curves were determined, and 22 prognostic variables, including 9 hemodynamic variables and 6 biomarkers, were evaluated to obtain the best variables. The 1-year and 3-year survival rates were 98% and 86%, respectively. Only the platelet level was correlated with death (P<0.05), and the platelet level was significantly correlated with mean pulmonary arterial pressure (P<0.01). Patients with a lower platelet level (<20*10(4)/ul (median value)) before treatment had a higher mortality rate compared to the other patients (78% vs. 95% for 3-year survival, P<0.01). CONCLUSIONS: Combination therapy contributed to an improvement in the prognosis of IPAH patients. Platelet level is a significant prognostic predictor in this new treatment era. PMID- 22447011 TI - Disrupted regulation of ghrelin production under antihypertensive treatment in spontaneously hypertensive rats. AB - BACKGROUND: Ghrelin is an acylated peptide hormone mainly secreted from the stomach. When administrated externally it modulates vascular tone mainly through the regulation of autonomic nerve activity. However, the effects of blood pressure (BP) on the production and secretion of ghrelin remain to be clarified. METHODS AND RESULTS: We examined the stomach and plasma levels of ghrelin in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats after a 4-week intervention with antihypertensive agents (candesartan-cilexetil [ARB], doxazosin [DZN], metoprolol [MP], reserpine [RES]) to clarify the influence of BP on the secretion of ghrelin. The effect of these agents on ghrelin production and secretion were examined by comparing vehicle-treated controls (WKY-Intact, SHR Intact). Treatment with the 4 antihypertensive drugs all yielded a significant decline in systolic BP in both SHR and WKY. Under these conditions, significantly lower levels of stomach and plasma ghrelin were detected in WKY treated with ARB (P<0.05), DZN (P<0.05), MP (P<0.05) and RES (P<0.05) compared with WKY-Intact, whereas no significant change in the ghrelin levels in the stomach and plasma were detected in SHR under the same treatments. CONCLUSIONS: The findings imply that the production and secretion of ghrelin are controlled by the ambient vascular tone and vice versa in normotensive WKY. This inter-relationship between ghrelin and BP seems to be disrupted in SHR. PMID- 22447013 TI - Left ventricular dysfunction assessed by cardiac time interval analysis among different geometric patterns in untreated hypertension. AB - BACKGROUND: Left ventricular (LV) hypertrophy is a powerful independent predictor of morbidity and mortality in hypertensive patients. Abnormal LV geometric patterns are also associated with hypertensive complications, and concentric hypertrophy is associated with the highest mortality in hypertensive patients. However, the relationship between geometric patterns and cardiac dysfunction is not fully established. We hypothesized that the Tei index, which is a measure of global cardiac function, is a feasible parameter for estimating cardiac dysfunction among the different LV geometric patterns in hypertensive patients. METHODS AND RESULTS: We enrolled 60 consecutive patients with untreated essential hypertension. Subjects were divided into 4 groups: normal geometry, concentric remodeling, eccentric hypertrophy and concentric hypertrophy. We measured ejection fraction, mitral E/A ratio, Tei index, ejection time, and isovolumic contraction and relaxation times. There were significant correlations between LV mass index and systolic blood pressure (P<0.01), ejection fraction (P<0.05), mitral E/A ratio (P<0.05) and Tei index (P<0.0001). In multiple regression analysis, only the Tei index independently correlated with LV mass index (P<0.01). Concentric hypertrophy significantly increased the Tei index compared with the other 3 groups. CONCLUSIONS: The Tei index provides a better marker for LV dysfunction by hypertensive hypertrophy than conventional parameters. LV function in concentric hypertrophy was most impaired among all the geometric patterns in untreated hypertensive patients. PMID- 22447012 TI - Intensity of statin therapy, achieved low-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after coronary revascularization. Perspectives from the CREDO-Kyoto registry cohort-2. AB - BACKGROUND: Association of the type of statin and the achieved level of low density lipoprotein cholesterol (LDL-C) with cardiovascular outcome has not been fully elucidated. METHODS AND RESULTS: The study included 14,866 patients who underwent a first coronary revascularization in 2005-2007. We identified 7,299 patients with statin therapy at discharge (so-called strong statins [atorvastatin, rosuvastatin, and pitavastatin]: 4,742 patients; standard statins [pravastatin, simvastatin, and fluvastatin]: 2,557 patients). Unadjusted 3-year incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stroke) was significantly lower (7.5% vs. 9.6%, P=0.0008) in the strong statin group, and there was a trend in adjusted risk of MACE favoring strong statins (hazard ratio [HR] 0.87, [95% confidence interval (CI) 0.73-1.04], P=0.13). Among 4,846 patients with follow-up LDL-C data available, outcomes were evaluated according to achieved LDL-C level (<80, 80-99 [reference], 100-119, >=120 mg/dl). Compared with the reference group, the risk for MACE was significantly higher in the >=120 mg/dl group (adjusted HR 1.74 [95%CI 1.11-2.71], P=0.01), although it was comparable in the 100-119 mg/dl group (adjusted HR 1.23 [95%CI 0.78-1.94], P=0.38) and in the <80 mg/dl group (adjusted HR 1.15 [95%CI 0.75-1.75], P=0.52). CONCLUSIONS: Strong statin therapy was associated with a trend toward lower cardiovascular risk compared with standard statin therapy. When LDL-C <120 mg/dl was achieved, risks for cardiovascular events were comparable irrespective of achieved LDL-C level. PMID- 22447015 TI - Clinical characteristics of patients with coronary slow flow. PMID- 22447014 TI - Does a combination pill of antihypertensive drugs improve medication adherence in Japanese? A randomized controlled trial. AB - BACKGROUND: In order to achieve target blood pressure levels to prevent cardiovascular disease, combination therapy of antihypertensive drugs is often required, although it is thought that requiring a patient to take many different pills would reduce adherence to the medication regimen. Whether antihypertensive treatment with a single pill combining antihypertensive drugs would improve medication adherence and blood pressure control was investigated. METHODS AND RESULTS: A total of 207 hypertensive subjects were randomly assigned to a combination pill group (losartan 50mg/hydrochlorothiazide 12.5mg; n=103) or a control group (an angiotensin receptor blocker and a thiazide diuretic; n=104). Medication adherence was evaluated by pill counts at 1, 3, and 6 months after randomization. The mean adherence rates over 6 months were not different between the 2 groups: 98% in the combination pill group and 98% in the control group. Moreover, the 2 groups included similar numbers of subjects with relatively poor adherence rates (<90%) in each treatment period. The mean blood pressures over the 6-month treatment period were not different between the groups: 131/75 mmHg in the combination pill group and 130/75 mmHg in the control group (P=0.84/0.96). CONCLUSIONS: There were no appreciable effects of the combination pill of antihypertensive drugs on medication adherence or blood pressure control in Japanese patients over a 6-month period. PMID- 22447017 TI - The Cardiac Society of Australia and New Zealand. PMID- 22447018 TI - The Israel Heart Society. PMID- 22447019 TI - Aspirin reduces cerebrovascular events in type 2 diabetic patients with poorly controlled blood pressure. Subanalysis from the JPAD trial. AB - BACKGROUND: There are few data that demonstrate a significant effect of aspirin therapy for diabetic patients. To clarify the effect of the primary prevention of aspirin therapy in diabetic patients, the relationship between blood pressure (BP) and the incidence of atherosclerotic events was investigated in participants in the Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial. METHODS AND RESULTS: We divided the JPAD participants according to their systolic (SBP) and diastolic (DBP) BPs at enrollment (SBP >=140 mmHg and/or DBP >=90 mmHg: unattained group, SBP <140 mmHg and DBP <90 mmHg: attained group). The incidence of the primary atherosclerotic events, especially cerebrovascular events, was higher in the unattained group than in the attained group. The incidence of cerebrovascular events was higher in the unattained group than in the attained group in patients without aspirin therapy; however, the incidence of cerebrovascular events in the unattained group was as low as the incidence in the attained group in patients undergoing aspirin therapy. Cox proportional hazards analysis revealed that BP level was an independent predictor for cerebrovascular events in diabetic patients. CONCLUSIONS: Aspirin therapy may reduce cerebrovascular events in diabetic patients with higher BP. Aspirin therapy could be an additional strategy as primary prevention for diabetic patients with higher BP. PMID- 22447021 TI - Anti-beta-adrenoceptors autoimmunity causing 'idiopathic' arrhythmias and cardiomyopathy. AB - BACKGROUND: To determine the prevalence of anti-beta-adrenoceptors autoantibodies (abetaAA) in patients with idiopathic arrhythmias (IA) and to assess whether abetaAA are predictive markers for concealed cardiomyopathy in such patients. METHODS AND RESULTS: Sixty-seven patients (group 1) with IA [25 supraventricular (SVA) and 42 ventricular (VA)]; 14 patients (group 2) with suspected cardiomyopathy, 12 patients with definite cardiomyopathy (group 3); and 19 healthy controls (group 4) were tested with an enzyme immunoassay, using synthetic peptides corresponding to the second extracellular loop of the human beta1-and beta2-adrenoceptors. Endomyocardial biopsy was performed in 29 patients. As compared with group 4 [3/19 (15.7%)], anti-beta1-adrenoceptor autoantibodies (abeta1AA) were more frequent in group-1 patients [38/67 (56.7%; P<0.01): 27/42 (64.2%; P<0.001) with VA and 11/25 (44%; P<0.05) with SVA]. 3 of the group 1 patients also had anti-beta2-adrenoceptor autoantibodies (abeta2AA). 4 were positive for abeta2AA only. Biopsy performed in 11/67 group 1 patients was abnormal in all. Of them, 7/8 (87.5%) with VA and 3/3 (100%) with SVA were positive for abeta1AA. PCR analysis from paraffin blocks of the 11 group 1 biopsied patients was negative for EV, EBV, HCV, AV, PVB19, INF A/B,HSV1/2, HHV6 and HHV8 viral genomes. CONCLUSIONS: The second extracellular loop of the beta adrenoceptor is the molecular target of specific autoantibodies. Positivity for abeta1AA predicts abnormal histological findings in 90% of IA patients and suggests that autoimmunity might play an arrhythmogenic role. PMID- 22447020 TI - Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-beta1. AB - BACKGROUND: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca(i)) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor beta1 (TGF beta1). METHODS AND RESULTS: MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-beta1. We studied membrane potential and Ca(i)transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca(i) transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca(2+)-ATPase 2a. CONCLUSIONS: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca(i) transient, EAD and triggered activity. Inhibition of Ca(2+) release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-beta1 Tx atria. PMID- 22447022 TI - MUolecular impact of bone morphogenetic protein 7, on lung cancer cells and its clinical significance. AB - The aim of this study was to investigate the expression of bone morphogenetic protein 7 (BMP7), in human pulmonary cancer tissues/cells and to evaluate the cellular impact of bone morphogenetic proteins on pulmonary cancer cells. BMP7 expression was determined in human lung cancer cell lines. The invasiveness and growth of cells transfected with BMP7, in vitro, were evaluated using the in vitro invasion assay and in vitro tumour models. Cellular migration was analysed using wounding assays. BMP7-positive tumours correlated with the absence of bone metastasis (P=0.040). In this analysis, we identified that 4 of 4 small cell lung cancer (SCLC) tissue specimens had no BMP7 expression, which illustrated that BMP7 may have no role in SCLC. BMP7 expression was not correlated with the overall survival time in lung cancer patients. Downregulation of BMP7 expression significantly inhibited the invasiveness of SPC-A1 cells (P<0.001) and forced expression of BMP7 dramatically increased the motility of A549 cells. Overexpression of BMP7 in A549 cells and its knockdown in SPC-A1 cells did not significantly alter proliferation compared with the control cells (P>0.5 respectively). In conclusion, we have demonstrated that BMP7 has an important role in controlling lung cancer cell motility and invasiveness, without affecting the growth process, cell proliferation and cell apoptosis. A higher BMP7 expression may be an indicator for bone metastasis. The therapeutic role of BMP7 warrants further investigation. PMID- 22447023 TI - MDP up-regulates the gene expression of type I interferons in human aortic endothelial cells. AB - Muramyldipeptide (MDP), the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear binding oligomerization domain 2 (NOD2). Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs) with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF) 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1beta, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti infection immune response and in the induction of innate immunity. PMID- 22447024 TI - Effect of the molecular mass of tremella polysaccharides on accelerated recovery from cyclophosphamide-induced leucopenia in rats. AB - The body of tremella were decocted with water, and hydrolyzed with 0.1 mol/L hydrochloric acid for different times, giving tremella polysaccharides with six molecular mass values. The structures of all the tremella polysaccharides had non reducing terminals of beta-D-pyranglucuronide, the backbone was composed of (1 -> 3)-linked beta-D-manno-pyranoside, and the side chain composed of (1 -> 6)-linked beta-D-xylopyranoside was attached to the C(2) of the backbone mannopyranoside. Immunomodulatory effect studies indicated that tremella polysaccharides increased the counts of leukocytes in the peripheral blood which were significantly lowered by cyclophosphamide, and the lower the molecular mass of the tremella polysaccharide, the better this effect was. PMID- 22447025 TI - Response surface modeling and optimization of accelerated solvent extraction of four lignans from fructus schisandrae. AB - A new method based on accelerated solvent extraction (ASE) combined with response surface methodology (RSM) modeling and optimization has been developed for the extraction of four lignans in Fructus Schisandrae (the fruits of Schisandra chinensis Baill). The RSM method, based on a three level and three variable Box Behnken design (BBD), was employed to obtain the optimal combination of extraction condition. In brief, the lignans schizandrin, schisandrol B, deoxyschizandrin and schisandrin B were optimally extracted with 87% ethanol as extraction solvent, extraction temperature of 160 degrees C, static extraction time of 10 min, extraction pressure of 1,500 psi, flush volume of 60% and one extraction cycle. The 3D response surface plot and the contour plot derived from the mathematical models were applied to determine the optimal conditions. Under the above conditions, the experimental value of four lignans was 14.72 mg/g, which is in close agreement with the value predicted by the model. PMID- 22447026 TI - Screening of anti-obesity agent from herbal mixtures. AB - Globally, one in three of the World's adults are overweight and one in 10 is obese. By 2015, World Health Organization (WHO) estimates the number of chubby adults will balloon to 2.3 billion--Equal to the combined populations of China, Europe and the United States. The discovery of bioactive compounds from herbs is one possible way to control obesity and to prevent or reduce the risks of developing various obesity-related diseases. In this study, we screened anti obesity agents such as methyl gallate from the herbal composition known as HemoHIM that actively inhibits lipid formation as evidenced by Oil Red O staining and triglyceride (TG) contents in 3T3-L1 adipocytes, suggesting their use as an anti-obesity agent. Furthermore, the amount of glycerol released from cells into the medium had increased by treatment of methyl gallate in a concentration dependent manner. The present study suggests that a promising anti-obesity agent like methyl gallate might be of therapeutic interest for the treatment of obesity. PMID- 22447027 TI - Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases. AB - To kill invading bacteria, neutrophils must interpret spatial cues, migrate and reach target sites. Although the initiation of chemotactic migration has been extensively studied, little is known about its termination. Here we found that two mitogen-activated protein kinases (MAPKs) had opposing roles in neutrophil trafficking. The extracellular signal-regulated kinase Erk potentiated activity of the G protein-coupled receptor kinase GRK2 and inhibited neutrophil migration, whereas the MAPK p38 acted as a noncanonical GRK that phosphorylated the formyl peptide receptor FPR1 and facilitated neutrophil migration by blocking GRK2 function. Therefore, the dynamic balance between Erk and p38 controlled neutrophil 'stop' and 'go' activity, which ensured that neutrophils reached their final destination as the first line of host defense. PMID- 22447028 TI - The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. AB - Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases. PMID- 22447029 TI - Combined topical and intracameral anesthesia for Descemet's stripping automated endothelial keratoplasty. AB - To evaluate the use of combined topical and intracameral anesthesia for Descemet's stripping automated keratoplasty (DSAEK). This was a retrospective comparative cohort analysis consisting of 10 eyes in 10 consecutive patients undergoing DSAEK surgery with combined topical and intracameral anesthesia. These cases were compared with 21 randomly selected controls during the same time period undergoing DSAEK surgery performed under retrobulbar anesthesia. Incidence of intraoperative and postoperative complications, and endothelial cell counts were compared. In all cases, DSAEK was completed without intraoperative complications. All patients tolerated the procedure well. There were 6 cases of postoperative graft dislocation requiring rebubbling, and no cases of primary failure or endophthalmitis. No significant difference in endothelial cell counts was found at final follow-up. Short-term results suggest that combined topical and intracameral anesthesia is as safe and effective for DSAEK in cooperative patients when compared to retrobulbar anesthesia. It may thereby be an alternative anesthetic modality for patients in whom retrobulbar or peribulbar anesthesia may be risky or contraindicated. PMID- 22447030 TI - Ophthalmologic outcome of direct and indirect carotid cavernous fistulas. AB - Carotid cavernous fistulas (CCFs) can be classified as direct and indirect, depending on their flow rates and their etiology. Both forms can cause the same characteristic ophthalmological symptoms and signs. We analyzed these ocular characteristics and determined the prognostics factors associated with treatment outcome. Forty-seven patients with an angiographically confirmed diagnosis of CCF, a preoperative ophthalmic evaluation and at least one ophthalmic sign or symptom at the initial presentation were retrospectively evaluated. The patients were followed-up ophthalmically until the end of treatment, and the complications and the remaining ophthalmological signs and symptoms were then recorded. The patients' ages ranged from 13 to 89 years, with an average of 55.78 (+/-20.73) years, and a predominance of 28 female (57.8 %) patients. The patients with a direct CCF had a lower average age (p = 0.02). The most common symptoms were blurred vision in 17 (36.2 %) and proptosis in 37 (78.7 %) patients. Elevated intraocular pressure (IOP) was more prevalent in patients with an indirect CCF (p = 0.02). Thrill was more prevalent in patients with direct CCF (p = 0.01). The presence of an initial decrease of visual acuity at the first ophthalmic evaluation was significantly associated with the persistence of ocular symptoms after fistula treatment (odds ratio 3.33). In conclusion our study shows a slight difference in ophthalmic symptoms among patients with different types of fistula. Elevated IOP was significantly associated with indirect fistulas, whereas thrill was significantly associated with direct fistulas. The presence of an initial decrease of visual acuity was significantly associated with a worse ophthalmic prognosis. PMID- 22447031 TI - Post-synthetic modification of isomorphic coordination layers: exchange dynamics of metal ions in a single crystal to single crystal fashion. AB - A diverse set of guest molecules template the consistent formation of fifteen iso structural layered structures containing a pyridine based tripodal ligand, divalent metal ions and anions. These materials have shown a remarkable ability to interconvert from Zn(II) to Cu(II), Cd(II) to Cu(II), Cu(II) to Cd(II) complexes in a SCSC (single crystal-to-single crystal) fashion. PMID- 22447032 TI - Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis. AB - Acute disseminated encephalomyelitis (ADEM) is a monophasic, immune-mediated demyelinating disorder that can appear after either immunizations or, more often, infections. Magnetic resonance imaging of patients shows inflammatory lesions in the brain and spinal cord. An immune-mediated mechanism may play a role in this disease, although its precise pathogenesis remains unclear. In this study, a 2 year-old boy presented with ADEM, and he showed improvement on treatment with high-dose intravenous corticosteroids. At the age of 3 years, the presence of recurrent bronchitis, bronchiectasia, and lymphopenia suggested that the patient was suffering from combined immunodeficiency. The patient was finally diagnosed with delayed onset adenosine deaminase deficiency. Delayed onset adenosine deaminase deficiency is frequently associated with autoimmune diseases, including thyroiditis and cytopenia, both of which were observed in the patient. The ADEM in this patient may be a presentation of delayed onset adenosine deaminase deficiency. PMID- 22447033 TI - One dimensional nanostructure/nanoparticle composites as photoanodes for dye sensitized solar cells. AB - Dye-sensitized solar cells (DSCs) show potential as a low cost alternative to silicon solar cells. Power conversion efficiencies exceeding 12% have been achieved for DSCs. Typical DSCs are based on TiO(2) nanoparticle photoanodes, which have numerous grain boundaries, surface defects and trap states as electrons transport from one particle to the other. Such defects and trap states increase back charge transfer (charge recombination) from the photoanode to electrolyte. One dimensional (1D) nanostructures such as nanofibers, nanorods, nanowires, and nanotubes can offer direct and fast electron transport to the electron collecting electrode. However, these 1D nanostructures have a major disadvantage of having insufficient surface area and inefficient dye attachment. To solve this challenge, mixtures of TiO(2) nanoparticles and 1D nanostructures (e.g. nanofibers, nanorods, nanowires, and nanotubes) are used to take advantage of the large surface area of nanoparticles and efficient charge transport of 1D nanostructures. In this article, we review the recent developments in using mixtures of 1D nanostructures and nanoparticles as photoanodes for efficient DSCs. Various randomly oriented and vertically aligned 1D nanostructures and their composites with nanoparticles are discussed. Future increase of efficiency in DSCs using 1D nanostructure/nanoparticle composites will rely on the optimization of diameters of 1D nanostructures, control of ratios of 1D nanostructures and nanoparticles, increase of crystallinity, and reduction of surface defects on the 1D nanostructures. This work will provide guidance for designing and growing appropriate 1D nanostructures, and combining them with nanoparticles at an optimal ratio for efficient DSCs. PMID- 22447034 TI - The extremely high level expression of human serum albumin in the milk of transgenic mice. AB - The recombinant production of human serum albumin has been challenging due to the low unit price and huge amount needed, for the commercial production of rhSA at an economically feasible level, It will be well worth the effort to exploit new method for the extremely high level expression of rhSA. To this end, here a hybrid gene locus strategy was employed, a 37 Kb mWAP-hSA hybrid gene locus was constructed and used as mammary gland specific expression vector, in which the 3 Kb genomic coding sequence in the 24 Kb mouse whey acidic protein (mWAP) gene locus was substituted by the 16 Kb genomic coding sequence of human serum albumin (hSA), exactly from the start codon to the end codon. Corresponding transgenic mice were generated and rhSA was secreted into the milk at an extremely high level of 11.9 g/L. Our transgenic mice carrying the mWAP-hSA hybrid gene locus represent a model system for the cost-effective production of human serum albumin. PMID- 22447035 TI - Work ability of employees in changing social services and health care organizations in Finland. AB - OBJECTIVES: In this study, we examined the connection between organizational changes and employees own evaluations of their work ability. MATERIALS AND METHODS: In early 2010, we asked employees (n = 2429) working in the Finnish social services and health care industry to identify all the organizational changes that had occurred at their workplaces over the previous two years, and to evaluate their own work ability and whether different statements related to the elements of work ability were true or false at the time of the survey. For our method of analysis, we used logistical regression analysis. RESULTS: In models adjusted for gender, age, marital status, professional education and managerial position, the respondents who had encountered organizational changes were at a higher risk of feeling that their work ability had decreased (OR = 1.49) than the respondents whose workplaces had not been affected by changes. Those respondents who had encountered organizational changes were also at a higher risk of feeling that several elements related to work ability had deteriorated. The risk of having decreased self-evaluated work ability was in turn higher among the respondents who stated they could not understand the changes than among those respondents who understood the changes (OR = 1.99). This was also the case among respondents who felt that their opportunities to be involved in the changes had been poor in comparison to those who felt that they had had good opportunities to be involved in the process (OR = 2.16). CONCLUSIONS: Our findings suggest that the organizational changes in social and health care may entail, especially when poorly executed, costs to which little attention has been paid until now. When implementing organizational changes, it is vital to ensure that the employees understand why the changes are being made, and that they are given the opportunity to take part in the implementation of these changes. PMID- 22447036 TI - Prevalence and socio-demographic correlates of daily cigarette smoking in Poland: results from the Global Adult Tobacco Survey (2009-2010). AB - OBJECTIVES: The aim of the study was to evaluate the prevalence and socio demographic correlates of daily cigarette smoking among adults in Poland. MATERIALS AND METHODS: A nationally representative household study was implemented between 2009 and 2010 to explore smoking pattern among the population aged 15 years and older. The smoking status and socio-demographic data were determined based on the Global Adult Tobacco Survey (GATS) questionnaire. Out of the 14000 households selected for the survey, 7840 sampled persons completed the interviews, including 2162 respondents who declared daily smoking of cigarettes. Logistic regression models were applied to assess factors related to daily cigarette smoking. RESULTS: Over 33% of men and 21% of women (p < 0.01) reported tobacco smoking on a daily basis. The significantly higher risk of smoking on a daily basis was observed among the male and female 20-59 years of age compared to the 60 or older population (p < 0.05). For men and women with the lower educational (primary/vocational/secondary) level, the risk of smoking was significantly higher than for the subjects with university degree (p < 0.05). The unemployed men smoked daily significantly more frequently than the employed ones (OR = 1.8; 95% CI: 1.4-2.4). This association was not observed among women (p > 0.05). The residents of urban areas smoked significantly more frequently than people living in rural settings (p < 0.05). CONCLUSIONS: Actions to tackle socio economic inequalities in smoking need to be intensified. The antismoking efforts should be focused on the population of Poles at large and people with lower educational levels, unemployed men, and residents of large urban settings in particular. The tobacco control interventions should also address the population of women at reproductive age. PMID- 22447037 TI - Factors associated with exposure of transvaginally placed polypropylene mesh for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: This study evaluates potential risk factors for mesh exposure following transvaginal placement of polypropylene mesh for pelvic organ prolapse requiring reoperation. METHODS: We performed a case-control study. Cases had mesh exposure requiring surgical revision; controls had no mesh exposures and were chosen for similar surgical date and type of mesh. RESULTS: We identified 48 cases and 48 controls. The adjusted odds ratio of having a bleeding complication at the time of mesh implantation was 7.25 [95% confidence interval (CI) 1.47 35.66], smokers versus nonsmokers was 3.17 (95% CI 0.59-17.12), and being 1 year older was 0.96 (95% CI 0.92-1.0), among women with mesh exposure. CONCLUSIONS: We identified bleeding complications at the time of mesh implantation as a risk factor for mesh exposure requiring reoperation. Despite being one of the largest studies on this topic, our data were inconclusive regarding the impact of other possible factors on mesh exposure. PMID- 22447038 TI - Highly enantioselective intermolecular carbene insertion to C-H and Si-H bonds catalyzed by a chiral iridium(III) complex of a D4-symmetric Halterman porphyrin ligand. AB - The chiral iridium porphyrin [Ir((-)-D(4)-Por*)(Me)(EtOH)] displays excellent reactivity and stereoselectivity towards carbene insertion to C-H and Si-H bonds, affording corresponding products in high yields (up to 96%) and high enantioselectivities (up to 98% ee). PMID- 22447039 TI - Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. AB - Breast cancer is a disease in which cancer cells form in the tissues of the breast. The present study aimed to explore the effect of the flavonoid compound quercetin on the growth and apoptosis of human breast cancer cells. Varying concentrations (12.5, 25, 50, 100, 200 uM) of quercetin were applied to cultured MCF-7 human breast cancer cells for defined lengths of time. At 50 to 200 uM doses, quercetin significantly inhibited the proliferation of MCF-7 cells assessed by MTT colorimetry, in both dose- and time-dependent manners (P<0.05). The compound also increased apoptosis after 48 h of exposure (P<0.05). Furthermore, following quercetin treatment Bcl-2 expression decreased significantly while Bax expression increased significantly (P<0.05). In brief, quercetin inhibits cell growth and induces apoptosis in MCF-7 human breast cancer cells. The mechanisms behind these effects may stem from the downregulation of Bcl-2 protein expression and upregulation of Bax expression. PMID- 22447040 TI - Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells. AB - PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The present study aimed to assess the synergistic effect of bufalin and TRAIL and elucidate the underlying mechanisms in breast cancer cells. METHODS: Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. The expression of proteins was assayed by flow cytometry and/or Western blotting. Transfection studies were used to determine the involvement of DR4, DR5 and Cbl-b in the synergistic effect of bufalin and TRAIL. RESULTS: MCF-7 and MDA-MB-231 cells were resistant to TRAIL. Both cell lines were dramatically sensitized to TRAIL-induced apoptosis by bufalin. Further experiments indicated that bufalin up-regulated DR4 and DR5, activated ERK, JNK and p38 MAPK and down-regulated Cbl-b. Blocking the up-regulation of DR4 and DR5 by siRNA rendered cells less sensitive to apoptosis induced by the combination of bufalin and TRAIL. Inhibition of the activation of ERK, JNK and p38 MAPK by specific inhibitors attenuated DR4 and DR5 up regulation. Moreover, down-regulation of Cbl-b by shRNA led to stronger activation of ERK, JNK and p38 MAPK, more up-regulation of DR4 and DR5, and a stronger synergistic effect of bufalin and TRAIL. CONCLUSIONS: Bufalin enhanced TRAIL-induced apoptosis by up-regulating the expression of DR4 and DR5. Bufalin induced down-regulation of Cbl-b contributed to the up-regulation of DR4 and DR5, which might be partially mediated by the activation of ERK, JNK and p38 MAPK. PMID- 22447041 TI - Resistance to acaricides in Italian strains of Tetranychus urticae: toxicological and enzymatic assays. AB - Problems with Tetranychus urticae are frequently reported in protected crops in Italy, particularly in roses where many introduced acaricides show a progressive loss of effectiveness. We have conducted bioassays to assess the response of some Italian strains of T. urticae to a number of acaricides. These include compounds that were widespread and frequently used in the past, but also some recently registered compounds. We investigated two T. urticae strains collected from rose growers where control failures were reported (SAN and PSE), together with a strain collected from unsprayed vegetables (BOSA). Adult females of the rose strains (SAN and PSE) were resistant to tebufenpyrad (Resistant Ratio-RR, RR(50) = 48.4 and 163.6) and fenpyroximate (RR(50) = 74.1 and 25.9) when compared to the susceptible BOSA strain. Lethal concentrations for these products were higher than the registered field rate. The PSE strain proved to be highly resistant to abamectin (RR(50) = 1,294.1). Variation in bifenazate susceptibility was detected amongst strains, but LC(90) values of SAN and PSE were still in the range of the registered field rate. In egg bioassays, the SAN and PSE strains exhibited high resistance levels to clofentezine (RR(50) = 66,473 and 170,714), hexythiazox (RR(50) = 70,244 and 159,493) and flufenoxuron (RR(50) = 61.9 and 117.9). But the recently introduced ovi/larvicides etoxazole and spirodiclofen exhibited high activity on all strains. The activity of detoxifying enzymes such as esterases, glutathione-S-transferases (GSTs) and cytochrome P450 monooxygenases (MFOs) was determined in these strains as a preliminary attempt to identify potential resistance mechanisms. Enzymatic assays showed that the rose strains exhibited 2.66 and 1.95-fold increased MFOs activity compared to the susceptible strain. Assays for GSTs revealed that only the SAN strain exhibited a significantly higher activity. In contrast, only the PSE strain showed a significant higher hydrolysis of 1-naphthyl acetate. PMID- 22447042 TI - Cardiac and pericardial tumors. AB - Primary cardiac tumors of the heart present often as a clinical dilemma and need to be considered in the differential diagnosis of other cardiovascular diseases. They are infrequent and often asymptomatic. Occasionally, the tumors may be life threatening. Secondary involvement of the heart by extracardiac tumors is much more common. Benign tumors constitute 80% of primary cardiac neoplasms, with myxomas as the most common type. This review describes the pathology, clinical presentation, and treatment of both benign and malignant tumors of both the heart and the pericardium. PMID- 22447043 TI - The J-curve revisited: a therapeutic dilemma. AB - The J-curve in hypertension treatment refers to the relationship between achieved diastolic blood pressure (BP) and cardiovascular morbidity and mortality, specifically related to coronary heart disease (CHD). As diastolic BP decreases below a certain threshold or nadir, the risk of cardiovascular events increases. This phenomenon was first described over 30 years ago and its significance has been debated ever since. We review in detail the literature for and against the existence of this J-curve and discuss its purported pathophysiology. Most notably, recent post hoc analyses of large contemporary randomized trials in patients with documented CHD strongly support its existence. Given the current emphasis on strict BP control, especially in high-risk patients like those with CHD, diabetes, and chronic kidney disease, we discuss the implications this J curve may have for treating hypertension in the individual patient. PMID- 22447044 TI - Protein kinase CK2 mediates peroxynitrite-induced heme oxygenase-1 expression in articular chondrocytes. AB - Heme oxygenase-1 (HO-1) is induced as an adaptive mechanism against oxidative stress in chondrocytes, which play an important role in the maintenance and degradation of cartilage. In the present study, we examined the role of protein kinase casein kinase (CK2) on peroxynitrite-induced expression of HO-1 in primary articular chondrocytes. 3-MUorpholinosydnonimine hydrochloride (SIN-1) has been shown to mediate cell death by activating apoptosis-related molecules in cells. In this study, we used a low concentration of SIN-1 that did not induce apoptosis to elucidate the mechanism by which SIN-1 upregulates HO-1 expression. In chondrocytes, SIN-1 induced HO-1 expression with spontaneous downregulation in a different manner than with high concentrations of SIN-1. Importantly, SIN-1 treatment of chondrocytes increased CK2 activation. Additionally, inhibition of CK2 with 4,5,6,7-tetrabromobenzotriazole (TBB) or siRNA did not induce HO-1 expression and reduced NF-E2-related factor 2 (Nrf2) accumulation in chondrocytes. Therefore, we examined whether CK2 directly regulates Nrf2, which is a transcription factor that regulates the expression of HO-1. Indeed, TBB treatment inhibited phosphorylation and nuclear translocation of Nrf2 in SIN-1 treated cells. Moreover, using an immunoprecipitation assay, we confirmed that SIN-1 treatment enhanced the interaction between CK2 and Nrf2. Taken together, our findings suggest that peroxynitrite activates Nrf2 via CK2 signaling, leading to the upregulation of HO-1 in primary chondrocytes. PMID- 22447045 TI - Comparison of neutron fluxes in an 18-MeV unshielded cyclotron room and a 16.5 MeV self-shielded cyclotron room. AB - Some medical compact cyclotrons have self-shielding to reduce neutron fluxes. Thermal neutron fluxes in an 18-MeV unshielded cyclotron room and in a 16.5-MeV self-shielded cyclotron room were evaluated. In addition, the radioactivities in concrete and metals due to thermal neutrons in the cyclotron rooms for 30 years were calculated of operation such that the sum of the ratio of the nuclide concentration to the nuclide clearance level was equal to 1. The thermal neutron flux from the unshielded cyclotron was approximately 10(2) cm(-2) s(-1), whereas that from the self-shielded cyclotron was approximately 10(2) cm(-2) s(-1). The thermal neutron fluxes for concrete, stainless steel, vessel steel, and aluminum that reached their clearance levels were 9.80 * 10(4), 2.17 * 10(3), 1.87 * 10(4), and 2.41 * 10(5) cm(-2) s(-1), respectively. The specific activities in the cyclotron room were found to be sufficiently below the clearance level when the self-shield was employed. PMID- 22447046 TI - Zbtb7 suppresses the expression of CDK2 and E2F4 in liver cancer cells: implications for the role of Zbtb7 in cell cycle regulation. AB - Zbtb7, a member of the POK protein family, is involved in tumorigenesis and cellular differentiation by acting as a crucial transcription factor, but its role in cell cycle modulation remains uncharacterized. In the present study, CDK2 and E2F4, two cell cycle regulators, are shown to be downregulated at the mRNA and protein levels by Zbtb7 in HepG2 and QGY7703 cells. Moreover, we demonstrate that the activities of CDK2 and E2F4 promoters were suppressed by the modulation of Zbtb7 levels and that Zbtb7 represses promoter activities through a mechanism involving direct binding of Zbtb7 to the promoters. Furthermore, it was identified that the site at -259 to -252 within the CDK2 promoter is responsible for Zbtb7-induced repression of the promoter activity. It was found that siRNA induced knockdown of Zbtb7 resulted in the suppression of cell cycle progression in HepG2 and QGY7703 cells. Collectively, these data indicate that CDK2 and E2F4 are the downstream targets of Zbtb7, and Zbtb7 may be a cell cycle modulator by regulating the expression of cell cycle-associated genes in liver cancer cells. PMID- 22447047 TI - Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. AB - OBJECTIVES: To evaluate the association between restless legs syndrome (RLS) and incident cardiovascular disease (CVD). DESIGN: Prospective cohort study. SETTING: Women's Health Study (WHS) and Physicians' Health Study (PHS), USA. PARTICIPANTS: 29 756 female health professionals aged >=45 years and 19 182 male physicians aged >=40 years at baseline. MAIN OUTCOME MEASURES: Main outcome was incidence of major CVD; secondary outcomes were first incidence of myocardial infarction, stroke, death due to CVD or coronary revascularisation. RESULTS: 3487 (11.7%) women and 1373 (7.2%) men met International Restless Legs Study Group criteria for RLS. In the WHS 450 major CVD events occurred and 1064 major CVD events were confirmed in the PHS. In both cohorts, RLS was not associated with increased risk of major CVD, stroke, myocardial infarction, CVD death or coronary revascularisation. After adjustment for major vascular risk factors, the HRs (95% CI) for major CVD were 1.15 (0.88 to 1.50) in women and 1.01 (0.81 to 1.25) in men. Highest multivariable-adjusted HRs were 1.29 (0.91 to 1.82) for total stroke in women and 1.22 (0.87 to 1.70) for CVD death in men. Excluding participants with comorbidities potentially leading to RLS did not substantially change the effect estimates. CONCLUSIONS: In these large prospective studies of female and male health professionals, RLS was not associated with an increased risk of any incident CVD event. The data do not support the hypothesis that RLS is a marker of increased risk of vascular disease. PMID- 22447048 TI - A 2 : 2 stilbeneboronic acid-gamma-cyclodextrin fluorescent ensemble highly selective for glucose in aqueous solutions. AB - By designing a long and hydrophobic stilbeneboronic acid (STDBA) and allowing it to be included within the cavity of gamma-cyclodextrin (gamma-CyD) we succeeded in developing a fluorescent 2 : 2 STDBA-gamma-CyD ensemble that shows a selective and sensitive response toward glucose in aqueous solutions, with satisfactory application in artificial urine samples. PMID- 22447049 TI - A three-dimensional finite element analysis of the effects of restorative materials and post geometry on stress distribution in mandibular molar tooth restored with post-core crown. AB - This study investigated the effects of crown material, post material, and post geometry on stress distribution in molar tooth restored with post-core crown. A three-dimensional solid model consisting of the mandibular second molar tooth, periodontal ligament, cortical bone, and spongy bone was generated. Finite element analysis results showed that prefabricated posts with a composite resin core increased stress concentration at the cementoenamel junction (CEJ), while cast posts induced high stress at post-dentin interface. Increase in the elastic modulus of crown material also increased the stress concentration, especially at CEJ. PMID- 22447050 TI - Effect of air abrasion and thermocycling on resin adaptation and shear bond strength to dentin for an etch-and-rinse and self-etch resin adhesive. AB - This study examined the effect of air abrasion and thermocycling on the adaptation and shear bond strength, of composite resin bonded to dentin using etch-and-rinse and self-etch resin adhesives. Confocal microscopy showed both adhesives closely adapted to dentin and a significantly (p<0.001) greater number of resin tags were observed for the etch-and-rinse adhesive. Air abrasion significantly increased resin tag length (p<0.05) for the etch-and-rinse adhesive and significantly increased the number (p<0.001), length (p<0.001) and thickness (p<0.01) of tags for the self-etch adhesive. However, air abrasion resulted in defect formation within the hybrid layer and thermocycling caused separation of the hybrid layer from adjacent dentin containing resin tags. A significant (p<0.05) reduction in shear bond strength was observed for the etch-and-rinse adhesive following thermocycling. Both adhesive systems adapted well to dentin in vitro and shear bond strengths were similar. The area of tag penetration into dentin was significantly (p<0.0001) enhanced following air abrasion. PMID- 22447051 TI - Effects of mechanical properties of adhesive resin cements on stress distribution in fiber-reinforced composite adhesive fixed partial dentures. AB - Using finite element analysis (FEA), this study investigated the effects of the mechanical properties of adhesive resin cements on stress distributions in fiber reinforced resin composite (FRC) adhesive fixed partial dentures (AFPDs). Two adhesive resin cements were compared: Super-Bond C&B and Panavia Fluoro Cement. The AFPD consisted of a pontic to replace a maxillary right lateral incisor and retainers on a maxillary central incisor and canine. FRC framework was made of isotropic, continuous, unidirectional E-glass fibers. Maximum principal stresses were calculated using finite element method (FEM). Test results revealed that differences in the mechanical properties of adhesive resin cements led to different stress distributions at the cement interfaces between AFPD and abutment teeth. Clinical implication of these findings suggested that the safety and longevity of an AFPD depended on choosing an adhesive resin cement with the appropriate mechanical properties. PMID- 22447052 TI - Preparation of Sr-containing carbonate apatite as a bone substitute and its properties. AB - Sr-containing carbonate apatite (SrCAp) specimens of varied Sr contents, ranging from 0 to 13.3 mol%, were prepared through a phosphate treatment of set gypsum and-carbonate mixture at 100 degrees C for 7 days. Effects of Sr content in SrCAp on microstructure, osteoblast-like cell (MC3T3-E1) attachment and proliferation, and alkaline phosphatase (ALP) activity were evaluated. Sr(2+) ion substituted Ca(2+) ion in the apatite lattice. Carbonate content was about 9-13.6 wt%, increasing in content level as Sr content increased. Sr addition benefited cell attachment but had no significant influence on cell proliferation, although the latter was inhibited at the highest Sr content. ALP activity reached a peak in specimen containing 3.4 mol% of Sr. The present study revealed that SrCAp is a promising candidate for use as a bone substitute material with good resorbabilty and osteoconductivity. PMID- 22447053 TI - Effects of different types of adhesive systems on the microleakage of compomer restorations in Class V cavities prepared by Er,Cr:YSGG laser in primary teeth. AB - The aim of this in vitro study was to evaluate the effects of different types of adhesive systems on the microleakage of compomer restorations in Class V cavities prepared by erbium, chromium: yttrium scandium gallium garnet (Er,Cr:YSGG) laser. There were five test groups according to the type of adhesive applied to the cavities: Adper Single Bond 2 (Group 1), Scotchbond Multi-Purpose Plus (Group 2), Xeno III (Group 3), Clearfil Protect Bond (Group 4), Prime&Bond NT (Group 5). Dye penetration was evaluated under a stereomicroscope, and data were statistically analyzed by Kruskal-Wallis and Wilcoxon Signed Ranks tests. Gingival margins showed significantly higher microleakage than occlusal margins in all the test groups (p<0.05). Groups 1 and 2 showed significantly less microleakage than Group 5 (p<0.05), and there were no statistically significant differences among Groups 3, 4, and 5 (p>0.05). None of the dentin bonding agents eliminated microleakage completely, and higher microleakage scores were observed along the gingival margin than the occlusal margin. PMID- 22447054 TI - Chemical properties of 1,3-bis(3-methacryloxypropyl)-1,1,3,3 tetramethyldisiloxane-methyl methacrylate copolymer. AB - This study evaluated the chemical properties such as water sorption, water solubility and solvent resistance of a new resin material consisting of 1,3-bis(3 methacryloxypropyl)-1,1,3,3-tetramethyldisiloxane (BMPMS) and methyl methacrylate (MMA). Water sorption was evaluated by immersing the specimens in water at 37+/-1 degrees C for 1 week, water solubility was evaluated by keeping the specimens in a desiccator under dry conditions at 37+/-1 degrees C until the weight became constant, and solvent resistance was evaluated by immersing the specimens in acetone for 1 week and measuring the dissolved weight of acetone volatilized from those liquids. The water sorption and solvent resistance of the new resin were improved with increasing amount of BMPMS, whereas the water solubility remained the same value and did not depend on the amount of BMPMS. PMID- 22447055 TI - Cytotoxic effects of acrylic acid, methacrylic acid, their corresponding saturated carboxylic acids, HEMA, and hydroquinone on fibroblasts derived from human pulp. AB - The purpose of this study was to evaluate the cytotoxicity of acrylic and methacrylic acid (AA and MA), propanoic acid and isobutylic acid (PRA and IBA) which were the corresponding saturated carboxylic acids, 2-hydroxylethyl methacrylate and acrylate (HEMA and HEA), and hydroquinone (HQ). The growth of the fibroblast when exposed to AA decreased with increase of the acid, and was less than when exposed to MA. The growth when exposed to their corresponding saturated acids, PRA and IBA, showed a similar tendency to AA and MA. The growth of fibroblasts exposed to 5 mmol/L HEMA after 4 days and 3 mmol/L HEMA after 6 days was significantly different compared with that without HEMA. The growth in 1, 3, and 5 mmol/L of HEA after 2 days was markedly decreased compared with that without HEA, and the cells were probably lifeless. The growth when exposed to HQ was extremely lower than their acids. PMID- 22447056 TI - Influence of Ankaferd Blood Stopper on shear bond strength of bonding systems. AB - This study investigated the effect of Ankaferd Blood Stopper (ABS) contamination on bond strength of total- and self-etching systems. Seventy mandibular third molars sectioned in a mesio-distal direction were mounted in acrylic resin, and flat dentin surfaces were exposed. The specimens were randomly assigned to seven groups (n=20), according to the surface treatment: Group I, ABS contamination+37% phosphoric acid+Solobond M; Group II, ABS contamination+Clearfil SE Bond; Group III, ABS contamination+All Bond SE; Group VI, 37% phosphoric acid+ABS contamination+Solobond M; Group V, Solobond M; Group VI, Clearfil SE Bond; and Group VII, All Bond SE. Next, a resin composite (Grandio) was built up using a plastic apparatus and polymerized. The specimens were tested in shear mode at a crosshead speed of 1 mm/min. There were significant differences in bond strengths between the control and ABS-contaminated samples. These findings suggest that ABS contamination reduced bond strength of total- and self-etching adhesives. PMID- 22447057 TI - Morphological categorization of acid-base resistant zones with self-etching primer adhesive systems. AB - This study investigated the influence of the composition of self-etching primer adhesive systems on the morphology of acid-base resistant zones (ABRZs). One-step self-etching primer systems (Clearfil Tri-S Bond, G-Bond, and One-Up Bond F Plus) and two-step self-etching primer systems (Clearfil SE Bond, Clearfil Protect Bond, UniFil Bond, and Mac Bond II) were used in this study. Each adhesive was applied on prepared dentin disk surfaces, and a resin composite was placed between two dentin disks. All resin-bonded specimens were subjected to acid-base challenge. Observation under a scanning electron microscope (SEM) revealed the creation of an ABRZ adjacent to the hybrid layer for all the self-etch primer adhesive systems, even when non-fluoride releasing adhesives were used. The presence of fluoride in two-step self-etching adhesive significantly increased the thickness of ABRZ created. Results suggested that an ABRZ was created with the use of self-etching primer adhesive systems, but its morphology differed between one-and two-step self-etching primer adhesive systems and was influenced by fluoride release activity. PMID- 22447058 TI - BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer. AB - This study aimed to compare the effects of bone morphogenetic protein BMP2/7 heterodimer and BMP homodimers on bone regeneration in bone defects model. Identical peri-implant bone defects model were created using proper controls on the frontal skull in 18 minipigs. Collagen sponges with low-dose (30 ng/mL) BMP2/7 heterodimer, BMP2 or BMP7 homodimer were filled in the defects. New bone formation and the expression of type I collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) were evaluated after 2, 3, and 6 weeks of implantation. BMP2/7 resulted in significantly higher new bone areas percentage in the defect region than BMP2 and BMP7 (p<0.05). Immunohistochemical staining of Col1, ALP and OCN was stronger in BMP2/7 group than BMP2, BMP7 and control group (p<0.05). These results demonstrate that BMP2/7 heterodimer is a stronger inducer of osteoblastogenesis and could be applied at low dose to reduce the cost and side effects of BMP homodimers. PMID- 22447059 TI - Effect of sandblasting conditions on alumina retention in representative dental alloys. AB - This study determined the effect of grit size and application pressure on alumina fragment retention after sandblasting in representative dental alloys. Plastic rectangular patterns (25*3*0.6 mm, n=240) were divided equally into four groups and cast with Au-Pt, Ni-Cr, Co-Cr alloys and grade-II cp-Ti. The specimens from each alloy were then divided into 12 subgroups. Each subgroup was then sandblasted with one of the 12 possible combinations of grit size (50, 100 and 250 microns) and propulsion pressure (0.15, 0.30, 0.45 and 0.60 MPa), and their surfaces imaged and analyzed using SEM/EDS analysis. The Al composition was statistically analyzed by two-way ANOVA with Tukey's post-test. Materials tested showed a substantial amount of retained alumina fragments, the extent of which was dependent on the grit size and propulsion pressure applied for tested alloys except cp-Ti. Importantly, sandblasting conditions different from those proposed by the manufacturers achieved lower levels of retained alumina fragments. PMID- 22447060 TI - Degradation of dental ZrO2-based materials after hydrothermal fatigue. Part I: XRD, XRF, and FESEM analyses. AB - The aim was to investigate the effect of simulated low-temperature degradation (s LTD) and hydrothermal fatigue on the degradation of three ZrO(2)-based dental materials. Lava, IPS, and NanoZr discs were randomly assigned to (1) Control Storage in distilled water at 37 degrees C; (2) Aging at 134 degrees C for 5 h (s LTD); (3) Thermocycling in saliva for 30,000 cycles (TF). XRD revealed that ZrO(2) m phase was identified in all groups but TF increased the m phase only for Lava. Under the FESEM, Lava showed no alterations under s-LTD, but displayed corrosion areas up to 60 um wide after TF. We conclude that TF accelerated the degradation of Lava through an increase in the m phase and grain pull-out from the material surface. PMID- 22447061 TI - Influence of inorganic filler content on the radiopacity of dental resin cements. AB - Digital radiography was used to measure the radiopacity of 18 resin cements to determine the influence of inorganic filler content on radiopacity. Four disk specimens (n=4) of each light-curing cement were digitally radiographed alongside an aluminum step wedge using an intraoral sensor (XIOS Plus, Sirona, Germany), and their mean gray value measured. Percentage of filler by weight was determined using an analytical combustion furnace. Data were statistically analyzed using one-way ANOVA and Tukey's test (alpha=0.05). All materials were more radiopaque than dentin and 12 materials were more radiopaque than enamel. Filler percentage ranged between 17.36 to 53.56 vol% and radiopacity between 1.02 to 3.40 mm Al. There were no statistically significant differences in inorganic filler percentage and radiopacity among the different shades of the same material (p>0.05), but the highest radiopacity was measured for the material which contained a higher percentage of filler. PMID- 22447062 TI - Chitosan whiskers from shrimp shells incorporated into dimethacrylate-based dental resin sealant. AB - A resin-based sealant containing chitosan whiskers was developed for use as a pit and fissure sealer. Chitosan whiskers were synthesized and then characterized using Fourier transform infrared spectrometry and transmission electron microscopy. The whiskers were next incorporated into dimethacrylate monomer at various ratios by weight and subsequently analyzed for their antimicrobial and physical properties. The dimethacrylate-based sealant containing chitosan whiskers had a greater antimicrobial activity than control sealant and they were comparable with antimicrobial commercial resin sealants. The inclusion of the whiskers did not reduce the curing depth or degree of double bond conversion and the reduction in hardness was minimal. In conclusion, a resin-based sealant containing chitosan whiskers can be considered an effective antimicrobial pit and fissure sealant. PMID- 22447063 TI - Effect of immersion disinfection of alginate impressions in sodium hypochlorite solution on the dimensional changes of stone models. AB - This study investigated the effect of the immersion of alginate impressions in 0.5% sodium hypochlorite solution for 15 min on the dimensional changes of stone models designed to simulate a sectional form of a residual ridge. Five brands of alginate impression materials, which underwent various dimensional changes in water, were used. A stone model made with an impression that had not been immersed was prepared as a control. The immersion of two brands of alginate impressions that underwent small dimensional changes in water did not lead to serious deformation of the stone models, and the differences in the dimensional changes between the stone models produced with disinfected impressions and those of the control were less than 15 um. In contrast, the immersions of three brands of alginate impressions that underwent comparatively large dimensional changes in water caused deformation of the stone models. PMID- 22447064 TI - Influence of surface treatment on bond strength of veneering ceramics fused to zirconia. AB - In all-ceramic restorations involving a zirconia framework, surface treatment of the zirconia surface is required to enhance bonding strength with the veneering ceramics and thus prevent chipping. The purpose of the present study was to investigate the influence of surface roughness and heat treatment of the zirconia and use of liner porcelain on bond strength between veneering ceramics and a zirconia framework. Debonding/crack-initiation strength (taub) was determined according to ISO 9693. No significant difference was observed among conditions, except with use of a liner under heat treatment, which yielded a taub of 26.0+/ 2.9-28.9+/-1.7 MPa. Electron probe microanalysis revealed that components of the veneering ceramics remained on the zirconia surface after debonding, suggesting that fractures occur in the veneering ceramics and that improving the strength of the veneering ceramics themselves might increase bond strength. PMID- 22447065 TI - Three-dimensional finite element stress analysis: the technique and methodology of non-linear property simulation and soft tissue loading behavior for different partial denture designs. AB - The purpose of this study was to develop and report upon a methodology for a non linear capacity 3D modeling finite element analysis evaluating the loading behavior of different partial denture designs. A 3D finite element model using human CT data was constructed. An original material constant conversion program was implemented in the data simulation of non-linear tissue behavior. The finite element method material properties of residual ridge mucosa were found to have seven material constants and six conversion points of stress values. Periodontal tissues were found to have three constants, and two conversion points. Three magnetic attachment partial denture designs with different bracing elements were evaluated. Technical procedures for finite element model simulation of nonlinear tissue behavior properties evaluating the oral behavior of prosthetic device designs are reported for prosthodontic testing. The use of horizontal cross-arch bracing positively impacts upon the comparative stability of the partial denture designs tested. PMID- 22447066 TI - Enhanced osteoblast response to electrical discharge machining surface. AB - The purpose of this study is to investigate the surface characteristics and biocompatibility of titanium (Ti) surfaces modified by wire electrical discharge machining (EDM). EDM surface characteristics were evaluated by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), thin-film X-ray diffractometry (XRD) and contact angle measurements. MC3T3-E1 cell morphology, attachment and proliferation, as well as analysis of osteoblastic gene expressions, on machined surfaces and EDM surfaces were also evaluated. EDM surfaces exhibited high super hydrophilicity, due to high surface energy. XPS and XRD revealed that a passive oxide layer with certain developing thickness onto. EDM surfaces promoted cell attachment, but restrained proliferation. Counted cell numbers increased significantly on the machined surfaces as compared to the EDM surfaces. Real-time PCR analyses showed significantly higher relative mRNA expression levels of osteoblastic genes (ALP, osteocalcin, Runx2, Osterix) in cells cultured on the EDM surfaces as compared to cells cultured on the machined surfaces. PMID- 22447067 TI - Effects of argon gas flow rate on laser-welding. AB - The purpose of this study was to evaluate the effects of the rate of argon gas flow on joint strength in the laser-welding of cast metal plates and to measure the porosity. Two cast plates (Ti and Co-Cr alloy) of the same metal were abutted and welded together. The rates of argon gas flow were 0, 5 and 10 L/min for the Co-Cr alloy, and 5 and 10 L/min for the Ti. There was a significant difference in the ratio of porosity according to the rate of argon gas flow in the welded area. Argon shielding had no significant effect on the tensile strength of Co-Cr alloy. The 5 L/min specimens showed greater tensile strength than the 10 L/min specimens for Ti. Laser welding of the Co-Cr alloy was influenced very little by argon shielding. When the rate of argon gas flow was high, joint strength decreased for Ti. PMID- 22447068 TI - The role of angiotensin II receptors in stroke protection. AB - The hypothesis that angiotensin II (Ang II) might have a stroke-protective role was first proposed by Brown and Brown about 25 years ago. Their hypothesis was generated from the results of the first Medical Research Council trial in patients with mild to moderate hypertension, which showed that patients treated with the diuretic bendrofluazide had a 70% decrease in strokes compared with those treated with the beta-blocker propranolol for similar blood pressure reduction. This hypothesis, which remained dormant for many years, was recently resurrected by several experimental studies that showed that the brain possesses its own renin-angiotensin system (RAS) similar to the one existing in the systemic circulation. These studies also showed that the brain RAS plays an important role in stroke prevention and neuronal protection through its active peptide Ang II. In addition, these studies demonstrated that the beneficial effects of Ang II are mediated through stimulation of its subtype 2 receptors, and possibly through stimulation of the subtype 4 receptors by Ang IV, a metabolite of Ang II. Drugs that selectively block the Ang II subtype 1 receptors, such as the angiotensin receptor blockers, have shown superior protection against strokes and neuronal damage than drugs that decrease the generation of Ang II, such as the angiotensin-converting enzyme inhibitors and beta-blockers. In this review, the role of the Ang II receptors and their mechanism of action regarding stroke prevention are discussed in view of the evidence from experimental and clinical studies. PMID- 22447069 TI - Highly efficient asymmetric anti-Mannich reactions of carbonyl compounds with N carbamoyl imines catalyzed by amino-thiourea organocatalysts. AB - A series of pyrrolidine-based organocatalysts which bear three synergistic features, i.e. secondary amino group, various H-bond donor groups at the 4 position and a stereocontrol silyl ether group at the alpha-position of the pyrrolidine nitrogen atom, were developed. They were screened in anti-Mannich reactions of carbonyl compounds with preformed or in situ generated N-protected alpha-imino ethylglyoxylate and aldehydes with preformed or in situ generated N carbamoyl imines. The influence of H-bond donor ability at the 4-position was also investigated. Among all the catalysts, 2a was identified as a general efficient organocatalyst suitable for various types of anti-Mannich reactions and broad substrate scope. Excellent results (up to 98% yield, >99% ee and >99 : 1 dr) were achieved with 5 mol% catalyst load. Sulfones with ortho substituents or very strong withdrawing groups on the aromatic ring, which have been regarded as challenging substrates in the direct anti-Mannich reactions of aldehydes with in situ generated N-carbamoyl imines, also worked well. The optimization of our catalytic system also offered alternative and easily operational protocols to access anti-Mannich products with orthogonal N-Boc or N-Cbz protecting groups. PMID- 22447070 TI - Total synthesis and absolute configuration of nocardioazine B. AB - The first total synthesis of the indole alkaloid nocardioazine B was accomplished in 10 steps with an overall yield of 11.8%, establishing the absolute stereochemistry of the natural product. PMID- 22447071 TI - Implicit social learning in relation to autistic-like traits. AB - We investigated if variation in autistic traits in the typically-developed population (using the Autism-spectrum Quotient, AQ) influenced implicit learning of social information. In the learning phase, participants repeatedly observed two identities whose gaze and expression conveyed either a pro- or antisocial disposition. These identities were then employed in a gaze-cueing paradigm. Participants made speeded responses to a peripheral target that was spatially pre cued by a non-predictive gaze direction. The low AQ group (n = 50) showed a smaller gaze-cueing effect for the antisocial than for the prosocial identity. The high AQ group (n = 48) showed equivalent gaze-cueing for both identities. Others' intentions/dispositions can be learned implicitly and affect subsequent responses to their behavior. This ability is impaired with increasing levels of autistic traits. PMID- 22447073 TI - Hypertrophied cruciate ligament in high performance weightlifters observed in magnetic resonance imaging. AB - PURPOSE: In a group of high performance weightlifters increased values of the cruciate ligaments (CLs) cross-sectional areas were observed. The purpose of this research was to investigate if repeated heavy workouts increase the volume of those structures. METHODS: The knee examinations were performed with an 1,5T MRI system. The area of the anterior cruciate ligament (ACL) and the posterior cruciate ligament (PCL) midsubstance cross-section were evaluated in T1-weighted images with administration of contrast medium in a group of nine athletes. A control group of 19 participants was also examined using the same protocol. RESULTS: Significant differences of the ACL and the PCL midsubstance cross sectional areas were observed between groups. The area of the CLs' midsubstance and the onset of training were strongly negatively correlated and the PCL cross sectional area was strongly positively correlated with the duration of training. CONCLUSION: This research is the first description of the CLs hypertrophy, which is probably caused by heavy training that was started about the age of puberty. The age of training onset seems to have a greater impact on the hypertrophy process than the training duration. Knowledge of the phenomenon of cruciate ligament overgrowth is vital for orthopaedics because, possible changes of the CLs mechanical properties and three-dimensional orientation, may affect the incidence of trauma and reconstruction procedures technique. PMID- 22447074 TI - Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. AB - Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease. PMID- 22447075 TI - Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. AB - Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da. Using genome wide linkage analyses, we discovered an association between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain. PMID- 22447076 TI - NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy. AB - It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32 dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans. PMID- 22447077 TI - Why schizophrenia genetics needs epigenetics: a review. AB - Schizophrenia (SZ) is a highly heritable disorder, with about 80% of the variance attributable to genetic factors. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SZ. On the other hand, rare and large copy number variants (CNVs) with high but incomplete penetrance, variable in different individual, could explain about additional 30% of SZ cases. Although these rare CNVs frequently develop de novo, it is not clear whether they affect risk independently or via interaction with a polygenic liability in the background. Finally, the role of environmental risk factors has been well established in SZ. Environmental factors are rarely sufficient to cause SZ independently, but act in parallel or in synergy with the underlying genetic liability. Epigenetic misregulation of the genome and direct CNS injury are probably the main mechanism to mediate prenatal environmental effects (e.g., viruses, ethanol, or nutritional deficiency) whereas postnatal risk factors (e.g., stress, urbanicity, cannabis use) may also affect risk via use-based potentiation of vulnerable CNS pathways implicated in SZ. In this review, we outline a general theoretical background of epigenetic mechanisms involved in GxE interactions, and then discuss epigenetic and neurodevelopmental features of SZ based on available information from genetics, epigenetics, epidemiology, neuroscience, and clinical research. We argue that epigenetic model of SZ provides a framework to integrate a variety of diverse empirical data into a powerful etiopathogenetic synthesis. The promising future of this model is the possibility to develop truly specific prevention and treatment strategies for SZ. PMID- 22447078 TI - Epigenetic and genetic complexity of psychosis: invited commentary on 'why schizophrenia genetics needs epigenetics'. PMID- 22447079 TI - Schizophrenia: Searching for the causes through many layers of complexity. PMID- 22447080 TI - Epigenetics in schizophrenia: more than an epiphenomenon. PMID- 22447081 TI - Why schizophrenia genetics needs epigenetics: a review. PMID- 22447082 TI - From genes to mental representations: a comment to "why schizophrenia genetics needs epigenetics". PMID- 22447083 TI - A phenomenological perspective on subjective well-being: from myth to science. AB - This paper summarizes the concept of subjective well-being, from ancient philosophical reflection to the first psychological, empirical research on the construct of positive psychology. The author examined the different conceptual definitions of subjective well-being throughout history as well as the dominant themes in the philosophical theories, concluded with some contemporary philosophical trends in Western culture of the 20th and 21st century. This framework also touches upon the dynamics of the relationship between philosophical and psychological thoughts on subjective well-being. PMID- 22447084 TI - Reproductive rights of mentally retarded persons. AB - Mental retardation denotes sub-average intellectual functioning, based on IQ, i.e. the inability of normal learning, accompanied by behavioral and developmental disorders. Persons with impairments (cognitive, motor, sensory or psychiatric) have often been, both through human history and today victims of discrimination and deprived of their basic human rights, both in the public and the private life spheres. Since the end of the 20th century, throughout the developed world, many disabled persons can accomplish their dreams and rights. However, the issue of sexuality is still an obstacle in realizing oneself as a whole person, of course in accordance with personal psychophysical abilities. The greatest problem is present in persons with severe disablement, considered not apt enough for information on sexuality and for expressing themselves as persons with their own sexual needs. Thus it is desirable to observe each disabled person individually and flexibly enough in order to establish parameters for the functioning of an intimate affair on the level of understanding and assent. The legal system must protect the most vulnerable and ensure for them the right of choice and consent, as well as the possibility of fulfilling their sexual needs, so that they could love and be loved. Naturally, the system must be built on foundations that satisfy the needs of its users, but also of persons engaged in work with them. Sex education should contain information regarding biological, socio-cultural and spiritual dimensions of sexuality, including cognitive, affective and behavioral domains. Unfortunately, very few educational programs with such aims provide sex education, not only for the disabled young population but also for the healthy. This review article is based on international investigations and Croatian legislative postulates. Its aim is to focus the attention of both professionals and non-professionals on this delicate problem. PMID- 22447085 TI - Various effects of antipsychotics on P50 sensory gating in Chinese schizophrenia patients: a meta-analysis. AB - BACKGROUND: The aim of this study was to conduct a meta-analysis so we could evaluate the impact of antipsychotics on the P50 ratio in Chinese schizophrenia patients. METHODS: Data were collected from the following databases: PubMed, China Biological Medicine Database, China National Knowledge Infrastructure, Cochrane Library and Elsevier Science Direct, with the latest report up to May 2011. An effect size with a 95% confidence interval (CI) was used to assess the strength of various effects of antipsychotics on P50 ratio in the patients. RESULTS: A total of six studies including 315 and 285 schizophrenia patients at the baseline and endpoint, respectively. Overall, no significant effect of these medicines on the P50 ratio was found (overall effect z=1.03, p=0.30; heterogeneity: Chi2=2.81, df=8, p=0.95, I2=0%). In subgroup analysis by drug, we did not find any significant effects on P50 ratio in either first-generation antipsychotics (effect z=0.92, p=0.36; heterogeneity: Chi2=0.00, df=1, p=0.98, I2=0%) or second-generation antipsychotics (effect z=0.55, p=0.58; heterogeneity: Chi2=2.38, df=5, p=0.79, I2=0%). CONCLUSION: Our meta-analysis suggests that neither the first-generation nor the second-generation antipsychotics had any significant effects on P50 ratio in Chinese patients with schizophrenia. PMID- 22447089 TI - Verbal and spatial functions during different phases of the menstrual cycle. AB - BACKGROUND: It has been reported that high levels of sex hormones improve the efficiency in tasks which are usually better performed by females. In contrast, in tasks which are usually better performed by males, the best efficiency corresponds to low levels of sex hormones. The aim of this study was to examine changes of efficiency in tasks of verbal fluency and mental rotations, as well as changes in masculinity and femininity during the menstrual cycle. SUBJECTS AND METHODS: Seventeen female subjects with a regular menstrual cycle took part in the study. For assesssments of masculinity and femininity, the subjects filled the Bem's Sex Roles Inventory. Endler's Anxiety Scale was used for determining the autonomic-emotional and cognitive-worry components of anxiety. Subjects performed the verbal fluency task and mental rotations tasks during the menstrual and the early follicular phase, as well as during the pre-ovulation and the midluteal phase. RESULTS: The results showed the best performance in mental rotation tasks which included rotations of three-dimensional objects along x and y axis during the phases of menstrual cycle, which are characterized by a low level of sex hormones. The most pronounced during these phases was also the masculinity. Furthermore, the best performance in verbal fluency task occurred during the menstrual and midluteal phase. Anxiety and femininity did not change across the menstrual cycle. CONCLUSION: Low levels of sex hormones potentiated the typical male cognitive profile. PMID- 22447090 TI - Comorbidity and multimorbidity in patients with schizophrenia and bipolar disorder: similarities and differencies. AB - BACKGROUND: There is a need for better understanding and research of the comorbidity structure in schizophrenia and bipolar disorder. OBJECTIVE: To assess the prevalence of somatic and psychiatric comorbidity in schizophrenia and bipolar affective disorder treated at the University Hospital Centre Zagreb. METHOD: This retrospective study compares the prevalence of comorbid diagnosis of somatic and psychiatric disorders in 192 patients with schizophrenia and 97 patients with bipolar disorder. The diagnoses were established according to ICD 10 criteria. The data were collected from hospital medical documentation. RESULTS: Patients with bipolar disorder had more both somatic (67.1% vs. 50.6%) and psychiatric (29.9% vs. 10.9%) comorbidity than patients with schizophrenia. The three most prevalent somatic comorbidites in patients with bipolar disorders were cardiovascular (22.6%), endocrinological (22.6%), and gastrointestinal (16.4%) disorders while neurological (11.4%), gastrointestinal (10.9%) and endocrinological (9.3%) disorders were the most frequent in patients with schizophrenia. CONCLUSION: The exact prevalence and nature of the somatic and psychiatric comorbidity in patients with schizophrenia and bipolar disorder is still unclear and further research is needed. PMID- 22447093 TI - Citalopram-induced major depression in a patient with panic disorder - a case report. PMID- 22447088 TI - Can the big five factors of personality predict lymphocyte counts? AB - BACKGROUND: Psychological stress is known to affect the immune system. The Limbic Hypothalamic Pituitary Adrenal (LHPA) axis has been identified as the principal path of the bidirectional communication between the immune system and the central nervous system with significant psychological activators. Personality traits acted as moderators of the relationship between life conflicts and psychological distress. This study focuses on the relationship between the Big Five factors of personality and immune regulation as indicated by Lymphocyte counts. SUBJECTS AND METHODS: Our study included 32 professional soldiers from the Slovenian Army that completed the Big Five questionnaire (Goldberg IPIP-300). We also assessed their white blood cell counts with a detailed lymphocyte analysis using flow cytometry. The correlations between personality variables and immune system parameters were calculated. Furthermore, regression analyses were performed using personality variables as predictors and immune parameters as criteria. RESULTS: The results demonstrated that the model using the Big Five factors as predictors of Lymphocyte counts is significant in predicting the variance in NK and B cell counts. Agreeableness showed the strongest predictive function. CONCLUSIONS: The results offer support for the theoretical models that stressed the essential links between personality and immune regulation. Further studies with larger samples examining the Big five factors and immune system parameters are needed. PMID- 22447087 TI - Pathways linking early life stress, metabolic syndrome, and the inflammatory marker fibrinogen in depressed inpatients. AB - BACKGROUND: Previous research has shown that metabolic syndrome as well as early life stress can account for immunoactivation (e.g. in the form of altered fibrinogen levels) in patients with major depression. This study aims at assessing the relationship between components of metabolic syndrome, early life stress and fibrinogen levels, taking the severity of depression into consideration. SUBJECTS AND METHODS: Measures of early life stress and signs of metabolic syndrome were collected in 58 adult inpatients diagnosed with depression. The relationships between the factors were assessed by means of path analyses. Two main models were tested: the first model with metabolic syndrome mediating between early life stress and fibrinogen levels and the second model without the mediating effect of metabolic syndrome. RESULTS: The first model was not supported by our data (chi2=7.02, df=1, p=0.008, CFI=0.00, NNFI=-9.44, RMSEA=0.50). The second model however provided an excellent fit for the data (chi2=0.02, df=1, p=0.90, CFI=1.00, NNFI=2.71, RMSEA=0.00). Extending the models by introducing severity of depression into them did not yield good indices of fit. CONCLUSIONS: The developmental trajectory between early life stress and inflammation appears not to be mediated by metabolic syndrome associated factors in our sample. Possible reasons including severity and type of early life stress, as well as potential epigenetic influences are discussed. PMID- 22447086 TI - Some QEEG parameters and gender differences in schizophrenia patients. AB - BACKGROUND: Gender issues are extensively explored in schizophrenia. A mounting body of research evidence suggests that there are gender differences in the age at onset, duration of untreated psychosis and presented psychopathology. In recent years, in order to obtain neurophysiologic explanation for the disturbed behavior and thinking in schizophrenia, numerous studies have been performed focusing on the QEEG parameters. However, the results were inconclusive. The aim of this study was to investigate the gender differences in some clinical and QEEG parameters in schizophrenia patients. SUBJECTS AND METHODS: Thirty schizophrenia patients were enrolled in the study (M/F ratio 13/17; mean age 34 years). The QEEG parameters which were analyzed were amplitude, mean frequency and relative power of the main bands of the basic activity. Clinical assessment was performed using the PANSS, BPRS and CGI scales. RESULTS: QEEG parameters demonstrating statistically significant difference were amplitude and relative power in beta activity and lower mean theta frequency over left frontal, temporal and parietal regions in female patients who also had statistically significant differences in PANSS and BPRS scores. CONCLUSION: Differences in amplitude and relative power in the beta bands in female schizophrenic patients are associated with more severe actual psychopathology. Considering the relatively small sample, the current results must be replicated with a larger group of drug-free patients to confirm the findings. PMID- 22447091 TI - Electroconvulsive therapy on Hungarian websites. AB - BACKGROUND: Although there are several similarities in terms of their equipment and the way they are performed, the social perception and public attitudes towards electroconvulsive therapy (ECT) and electric cardioversion (ECV) is entirely different. The aim of this study was to assess and compare the information on Hungarian Internet sites on ECT and ECV with respect to their depiction and acceptance by the public. SUBJECTS AND METHODS: An Internet search was undertaken with the Google search engine using the terms "ECT", "electroconvulsive therapy", "electroshock", "defibrillator" and "electric cardioversion". The search was restricted to information published in the Hungarian language from 1 January 2000 to 31 December 2010. All communications were classified into negative, neutral and positive groups depending on their attitude towards the aforementioned treatment methods. Professional or non professional categories were also distinguished. RESULTS: The total number of communications, which appeared between 2000 and 2010 and contained one of the search words for ECT was 66. The majority of them portrayed ECT in a negative (24; 36.4%) or neutral (25; 37.9%) fashion. Most of the websites (139; 95.2%) related to ECV were reflected positive (120; 82.2%) and neutral opinions (19; 13.0%). CONCLUSIONS: Hungarian-language Internet sites mainly view ECT as negative or neutral in contrast to ECV cardioversion, which has almost entirely a positive reputation. Although the effectiveness of both therapies is equally well established, their public image as manifested on the Internet differs significantly. This may have a major impact on the frequency of their use. PMID- 22447092 TI - Association between online social networking and depression in high school students: behavioral physiology viewpoint. AB - BACKGROUND: Frequent use of Facebook and other social networks is thought to be associated with certain behavioral changes, and some authors have expressed concerns about its possible detrimental effect on mental health. In this work, we investigated the relationship between social networking and depression indicators in adolescent population. SUBJECTS AND METHODS: Total of 160 high school students were interviewed using an anonymous, structured questionnaire and Back Depression Inventory - second edition (BDI-II-II). Apart from BDI-II-II, students were asked to provide the data for height and weight, gender, average daily time spent on social networking sites, average time spent watching TV, and sleep duration in a 24-hour period. RESULTS: Average BDI-II-II score was 8.19 (SD=5.86). Average daily time spent on social networking was 1.86 h (SD=2.08 h), and average time spent watching TV was 2.44 h (SD=1.74 h). Average body mass index of participants was 21.84 (SD=3.55) and average sleep duration was 7.37 (SD=1.82). BDI-II-II score indicated minimal depression in 104 students, mild depression in 46 students, and moderate depression in 10 students. Statistically significant positive correlation (p<0.05, R=0.15) was found between BDI-II-II score and the time spent on social networking. CONCLUSIONS: Our results indicate that online social networking is related to depression. Additional research is required to determine the possible causal nature of this relationship. PMID- 22447094 TI - Suicidal behavior in schizophrenia and its relationship to the quality of psychotic symptoms and insight - a case report. PMID- 22447096 TI - Emotional side effects after high-frequency rTMS of the right dorsolateral prefrontal cortex in an adult patient with ADHD and comorbid depression. PMID- 22447097 TI - Construction and expression of humanized chimeric T cell receptor specific for chronic myeloid leukemia cells. AB - Chimeric T cell receptors (chTCRs), composed of the single-chain variable fragments (scFv) of murine antibodies and human signaling molecules, are used to redirect the specificity of autologous or allogeneic T lymphocytes. To develop novel therapeutic agents for treatment of chronic myeloid leukemia (CML), we engineered a scFv from the hybridoma cell line CMA1 which produces monoclonal antibody specific against CML. The genes encoding the heavy and light chain variable regions were amplified from CMA1 cDNA and a humanized chTCR was constructed. Expression of the novel hchTCR was verified in NIH3T3 cells transduced with retroviral vectors. The results demonstrated that hchTCR can be expressed and presented on cell surface normally. These results suggest that retroviral vectors expressing hchTCR specific for CML cells may be used to redirect human T lymphocytes. PMID- 22447099 TI - Isolation of high quality and yield of RNA from Agaricus bisporus with a simple, inexpensive and reliable method. AB - A method for isolating high purity and quantity RNA from Agaricus bisporus which is rich in proteins, carbohydrate, fiber and secondary metabolites, is described. RNA was extracted from mycelium, primordia, sporophores at two development stages and two post-harvest storage stages as well as from pileipellis, inner cap, gill and stipe of the mature sporophore. The A(260)/A(230) and A(260)/A(280) ratios of isolated RNA from fruiting bodies were both ~2 and the yield was about 200 MUg/g fresh wt (FW). The yield of RNA from mycelium was approx. 100 MUg/g FW. High quality RNA was also extracted from fruiting body tissues of Lentinus edodes, Pleurotus ostreatus, Flammulina velutipes and Pleurotus eryngii with yields from 130 to 225 MUg/g FW. RNA extracted from all samples was intact, as demonstrated by gel electrophoresis and was suitable for downstream molecular applications, including RT-PCR and qPCR. PMID- 22447095 TI - Does aripiprazole protect from serotonin syndrome? PMID- 22447098 TI - Combination therapy with BMP-2 and BMSCs enhances bone healing efficacy of PCL scaffold fabricated using the 3D plotting system in a large segmental defect model. AB - The three-dimensional (3D) plotting system is a rapidly-developing scaffold fabrication method for bone tissue engineering. It yields a highly porous and inter-connective structure without the use of cytotoxic solvents. However, the therapeutic effects of a scaffold fabricated using the 3D plotting system in a large segmental defect model have not yet been demonstrated. We have tested two hypotheses: whether the bone healing efficacy of scaffold fabricated using the 3D plotting system would be enhanced by bone marrow-derived mesenchymal stem cell (BMSC) transplantation; and whether the combination of bone morphogenetic protein 2 (BMP-2) administration and BMSC transplantation onto the scaffold would act synergistically to enhance bone regeneration in a large segmental defect model. The use of the combined therapy did increase bone regeneration further as compared to that with monotherapy in large segmental bone defects. PMID- 22447100 TI - Progress in palladium-based catalytic systems for the sustainable synthesis of annulated heterocycles: a focus on indole backbones. AB - A survey highlighting the most recent palladium catalytic systems produced and their performances for progress in direct synthesis of indole backbones by heterocarbocyclization of reactive substrates is provided. The discussion is developed in relation with the principles of sustainable chemistry concerning atom and mass economy. In this respect, the general convergent character of the syntheses is of particular interest (one-pot, domino, cascade or tandem reactions), and the substrates accessibility and reactivity, together with the final waste production, are also important. This critical review clearly indicates that the development of ligand chemistry, mainly phosphines and carbenes, in the last few decades gave a significant impetus to powerful functionalization of indoles at virtually all positions of this ubiquitous backbone (118 references). PMID- 22447101 TI - Gallium(III), cobalt(III) and copper(II) protoporphyrin IX exhibit antimicrobial activity against Porphyromonas gingivalis by reducing planktonic and biofilm growth and invasion of host epithelial cells. AB - Porphyromonas gingivalis acquires heme for growth, and initiation and progression of periodontal diseases. One of its heme acquisition systems consists of the HmuR and HmuY proteins. This study analyzed the antimicrobial activity of non-iron metalloporphyrins against P. gingivalis during planktonic growth, biofilm formation, epithelial cell adhesion and invasion, and employed hmuY, hmuR and hmuY-hmuR mutants to assess the involvement of HmuY and HmuR proteins in the acquisition of metalloporphyrins. Iron(III) mesoporphyrin IX (mesoheme) and iron(III) deuteroporphyrin IX (deuteroheme) supported planktonic growth of P. gingivalis cells, biofilm accumulation, as well as survival, adhesion and invasion of HeLa cells in a way analogous to protoheme. In contrast, cobalt(III), gallium(III) and copper(II) protoporphyrin IX exhibited antimicrobial activity against P. gingivalis, and thus represent potentially useful antibacterial compounds with which to target P. gingivalis. P. gingivalis hmuY, hmuR and hmuY hmuR mutants showed decreased growth and infection of epithelial cells in the presence of all metalloporphyrins examined. In conclusion, the HmuY protein may not be directly involved in transport of free metalloporphyrins into the bacterial cell, but it may also play a protective role against metalloporphyrin toxicity by binding an excess of these compounds. PMID- 22447102 TI - Stimulus control in multiple temporal discriminations. AB - In multiple fixed interval (FI) schedules, rats are trained to discriminate different FIs that are signaled by different stimuli. After extensive training, the different stimuli often acquire control over performance, observed by an earlier increase in responding for stimuli that signal shorter FIs, as compared with stimuli that signal longer FIs. The order in which the different FIs are trained, either intermixed across cycles or in blocks of several cycles, may seem irrelevant given that average performance at asymptote may be similar. In this study, rats were trained in two procedures with multiple FIs presented intermixed within sessions or in blocks of one interval per session. Similar performance was observed at asymptote, but an inspection of early cycles in each session revealed that different stimuli acquired control over performance only when trained intermixed within each session. Although the stimuli reliably signaled the upcoming FI, when trained in successive blocks of 60 cycles, rats rapidly adjusted performance early in the sessions on the basis of the temporal aspects of the task, and not on the basis of the stimulus presented in the current cycle. These results are discussed in terms of overshadowing of the stimuli by temporal cues and in terms of conditions under which a stimulus acquires control over performance. PMID- 22447103 TI - Molecular variation and recombination in RNA segment 10 of rice black-streaked dwarf virus isolated from China during 2007-2010. AB - Rice black-streaked dwarf virus (RBSDV) is the causal agent of rice black streaked dwarf and maize rough dwarf diseases in China. The only open reading frame encoding the viral outer capsid protein on S10 RNA of 21 RBSDV isolates was sequenced for phylogenetic and recombination analysis. Four natural recombinants were detected, and the recombinant breakpoints were identified. In addition, the distribution of synonymous and non-synonymous nucleotide changes revealed that the virus had been evolving under purifying selection. PMID- 22447108 TI - Involvement of NF-kappaB-mediated expression of galectin-3-binding protein in TNF alpha-induced breast cancer cell adhesion. AB - Galectin-3-binding protein (G3BP) is highly expressed in various types of cancer and is thought to be involved in cancer malignancy; however, the role of G3BP in breast cancer cells is not fully understood. In this study, we investigated the role of NF-kappaB in the adhesion of breast cancer cells to a substrate by using (-)-DHMEQ, a specific inhibitor of NF-kappaB. (-)-DHMEQ inhibited both TNF-alpha induced G3BP expression and cell adhesion in human breast cancer cell lines. We also found that knockdown of G3BP suppressed the adhesion, while its overexpression increased the adhesion. These data reveal that (-)-DHMEQ suppresses breast cancer cell adhesion by inhibiting NF-kappaB-regulated G3BP expression. PMID- 22447107 TI - C2-symmetric proline-derived tetraamine as highly effective catalyst for direct asymmetric Michael addition of ketones to chalcones. AB - A C(2)-symmetric tetraamine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding adducts 1,5-dicarbonyl compounds were obtained in good chemical yields with high levels of diastereo- and enantioselectivities (up to >99 : 1 dr and 93% ee) under mild conditions. By studying the ESI-MS of the intermediates, a proposed mechanism was disclosed. PMID- 22447105 TI - A resin-buffered nutrient solution for controlling metal speciation in the algal bottle assay. AB - Metal speciation in solution is uncontrolled during algal growth in the traditional algal bottle assay. A resin-buffered nutrient solution was developed to overcome this problem and this was applied to test the effect of chloride (Cl ) on cadmium (Cd) uptake. Standard nutrient solution was enriched with 40 mM of either NaNO3 or NaCl, and was prepared to contain equal Cd2+ but varying dissolved Cd due to the presence of CdCl(n)(2-n) complexes. Both solutions were subsequently used in an algal assay in 100 mL beakers that contained only the solution (designated "-R") or contained the solution together with a cation exchange sulfonate resin (2 g L-1, designated "+R") as a deposit on the bottom of the beaker. Pseudokirchneriella subcapitata was grown for 72 h (1.4 * 105-1.4 * 106 cells mL-1) in stagnant solution and shaken three times a day. Growth was unaffected by the presence of the resin (p>0.05). The Cd concentrations in solution of the -R devices decreased with 50-58% of initial values due to Cd uptake. No such changes were found in the +R devices or in abiotic controls. Cd uptake was unaffected by either NaNO3 or NaCl treatment in the +R device, confirming that Cd2+ is the preferred Cd species in line with the general concept of metal bioavailability. In contrast, Cd uptake in the -R devices was two-fold larger in the NaCl treatment than in the NaNO3 treatment (p<0.001), suggesting that CdCl(n)(2-n) complexes are bioavailable in this traditional set-up. However this bioavailability is partially, but not completely, an apparent one, because of the considerable depletion of solution 109Cd in this set-up. Resin-buffered solutions are advocated in the algal bottle assay to control trace metal supply and to better identify the role of metal complexes on bioavailability. PMID- 22447110 TI - Role of arachidonoylethanolamine in blood pressure regulation in volume-resistant patients on peritoneal dialysis. AB - In this study we explored the possible role of arachidonoylethanolamine (AEA) in regulating blood pressure in patients on continuous ambulatory peritoneal dialysis (CAPD). One hundred and five patients on CAPD were enrolled. Volume status was evaluated by the overhydration (OH) value obtained by bioimpedance analysis. OH<2.0 kg was defined as normal volume (NV) and OH>=2.0 kg as high volume (HV). Home mean systolic blood pressure<130 mmHg was defined as controlled hypertension (CHT) and >=130 mmHg as uncontrolled hypertension (UHT). The patients were divided into four subgroups: (1) controlled hypertension with normal volume (CHT-NV), (2) controlled hypertension with high volume (CHT-HV), (3) uncontrolled hypertension with normal volume (UHT-NV), and (4) uncontrolled hypertension with high volume (UHT-HV). AEA was measured by ultra performance liquid chromatography-tandem mass spectrometry. AEA was significantly higher in the HV group as compared with the NV group (P<0.05). In addition, AEA was also significantly higher in the CHT-HV group as compared with the UHT-NV group (P<0.05). These results may suggest a compensatory function of AEA and TRPV1 pathway to lower blood pressure during volume expansion in CAPD patients. PMID- 22447113 TI - A super-oscillatory lens optical microscope for subwavelength imaging. AB - The past decade has seen an intensive effort to achieve optical imaging resolution beyond the diffraction limit. Apart from the Pendry-Veselago negative index superlens, implementation of which in optics faces challenges of losses and as yet unattainable fabrication finesse, other super-resolution approaches necessitate the lens either to be in the near proximity of the object or manufactured on it, or work only for a narrow class of samples, such as intensely luminescent or sparse objects. Here we report a new super-resolution microscope for optical imaging that beats the diffraction limit of conventional instruments and the recently demonstrated near-field optical superlens and hyperlens. This non-invasive subwavelength imaging paradigm uses a binary amplitude mask for direct focusing of laser light into a subwavelength spot in the post-evanescent field by precisely tailoring the interference of a large number of beams diffracted from a nanostructured mask. The new technology, which--in principle- has no physical limits on resolution, could be universally used for imaging at any wavelength and does not depend on the luminescence of the object, which can be tens of micrometres away from the mask. It has been implemented as a straightforward modification of a conventional microscope showing resolution better than lambda/6. PMID- 22447104 TI - Application of CT-PSF-based computer-simulated lung nodules for evaluating the accuracy of computer-aided volumetry. AB - With the wide dissemination of computed tomography (CT) screening for lung cancer, measuring the nodule volume accurately with computer-aided volumetry software is increasingly important. Many studies for determining the accuracy of volumetry software have been performed using a phantom with artificial nodules. These phantom studies are limited, however, in their ability to reproduce the nodules both accurately and in the variety of sizes and densities required. Therefore, we propose a new approach of using computer-simulated nodules based on the point spread function measured in a CT system. The validity of the proposed method was confirmed by the excellent agreement obtained between computer simulated nodules and phantom nodules regarding the volume measurements. A practical clinical evaluation of the accuracy of volumetry software was achieved by adding simulated nodules onto clinical lung images, including noise and artifacts. The tested volumetry software was revealed to be accurate within an error of 20 % for nodules >5 mm and with the difference between nodule density and background (lung) (CT value) being 400-600 HU. Such a detailed analysis can provide clinically useful information on the use of volumetry software in CT screening for lung cancer. We concluded that the proposed method is effective for evaluating the performance of computer-aided volumetry software. PMID- 22447109 TI - Potent inhibitory effect of Foeniculum vulgare Miller extract on osteoclast differentiation and ovariectomy-induced bone loss. AB - Inhibition of osteoclast differentiation and bone resorption is considered an effective therapeutic approach to the treatment of postmenopausal bone loss. To find natural compounds that may inhibit osteoclastogenesis, we screened herbal extracts on bone marrow cultures. In this study, we found that an aqueous extract of Foeniculum vulgare Miller seed (FvMs) at low concentration, which has traditionally been used as a treatment for a variety of ailments, inhibits the osteoclast differentiation and bone resorptive activity of mature osteoclasts. We further investigated the effects of FvMs on ovariectomy (OVX)-induced bone loss using microcomputed tomography, biomechanical tests and serum marker assays for bone remodeling. Oral administration of FvMs (30 mg or 100 mg/kg/day) for 6 weeks had an intermediary effect on the prevention of femoral bone mineral density (BMD), bone mineral content (BMC), and other parameters compared to OVX controls. In addition, FvMs slightly decreased bone turnover markers that were accelerated by OVX. The bone-protective effects of FvMs may be due to suppression of an OVX induced increase in bone turnover. Collectively, our findings indicate that FvMs have potential in preventing bone loss in postmenopausal osteoporosis by reducing both osteoclast differentiation and function. PMID- 22447111 TI - Serum osteocalcin levels are useful as a predictor of cardiovascular events in maintenance hemodialysis patients. AB - BACKGROUNDS: Osteocalcin (OC) is a known bone metabolic marker and a regulator of glucose and fat metabolisms. Although bone and energy metabolisms are known risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients, few studies have examined the correlation between OC and CVD. The purpose of this study was to investigate the impact of serum OC levels on the emergence of new CVD events in HD patients. METHODS: We designed a longitudinal, observational cohort study in which the study patients were divided into low- and high-serum OC groups based on a median serum OC level of 71.5 ng/ml. RESULTS: Cardiovascular disease events were observed in 29 of 126 patients (23.0 %). The number of cumulative CVD events in the low-serum OC group was significantly higher than that in the high-serum OC group, as evaluated by the Kaplan-Meier method (p = 0.0021, log-rank test). Multivariate Cox proportional hazards analysis demonstrated that a low level of serum OC is a significant predictor of a higher incidence of CVD events [hazard ratio, 2.925; 95 % confidence interval, 1.048 9.066; p = 0.0401] after adjustment. CONCLUSION: Serum OC level is a significant, independent prognostic factor for CVD events in maintenance HD patients. OC may be useful in predicting new CVD events in HD patients. PMID- 22447118 TI - Detection of a novel single nucleotide polymorphism of the human thiopurine s methyltransferase gene in a Chinese individual. AB - A 62-year-old Chinese patient with recurrent pompholyx submitted his blood sample for pre-treatment thiopurine S-methyltransferase (TPMT) pharmacogenetic profiling, and it was found to harbour a novel single nucleotide polymorphism (SNP). The novel SNP, detected by mRNA sequencing, was a c.2T>C (g.11018T>C) transition in the start codon, causing a Met1Thr amino acid change. This finding was confirmed on a subsequent blood sample from the same patient by DNA sequencing. The patient was genotyped as TPMT*1/*29, sequentially named as such following the latest TPMT SNP (TPMT*1/*28) at the time of writing. The novel SNP is expected to result in complete lack of protein translation, similar to the impact exerted by TPMT*14, another start codon SNP of the TPMT gene. PMID- 22447116 TI - Role of P-glycoprotein in intestinal absorption of FB2, a promising Abl/Src dual tyrosine kinase inhibitor. AB - FB2 is a promising Abl/Src dual tyrosine kinase inhibitor which is designed to overcome imatinib resistance. The present study aims to investigate the role of P glycoprotein (P-gp) in intestinal absorption of FB2 with an in vitro Caco-2 and MDCK-MDR1 cell model, single-pass intestinal perfusion model and in vivo pharmacokinetics with a selective inhibitor in rats. The results from Caco-2 cells indicated that P(appB-A) of FB2 and its metabolites (FB7 and FB10) were much higher than P(appA-B), and the efflux ratio (P(appB-A)/P(appA-B)) of FB2, FB7 and FB10 were decreased with P-gp inhibitor LSN335984; FB2 was further confirmed to be the substrate of P-gp in MDCK-MDR1 cells. In addition, P(blood) of FB2 and the cumulative amount of metabolites in mesenteric blood were elevated in a concentration-dependent manner in rat intestinal perfusion, while both of them were remarkably increased when P-gp inhibitor was added. The F(oral) of FB2 was increased to 24.52% when orally coadministrated with verapamil (25 mg/kg), which was significantly higher than that (5.7%) by FB2 (18 mg/kg) alone in rats. The AUC and Cmax of FB2 metabolites (FB7 and FB10) were also increased in the presence of verapamil. In conclusion, the low bioavailability of FB2 is believed to be partially due to the P-gp mediated active efflux and first-pass metabolism in the rat intestine. PMID- 22447117 TI - Effects of time culture and prototypical cytochrome P450 3A (CYP3A) inducers on CYP2B22, CYP2C, CYP3A and nuclear receptor (NR) mRNAs in long-term cryopreserved pig hepatocytes (CPHs). AB - In the present study, transcriptional and post-translational effects of culturing time and prototypical cytochrome P450 3A (CYP3A) inducers on principal nuclear receptors (NRs), CYP2B22, 2C and 3A were investigated in long-term stored (~10 years) cryopreserved pig hepatocytes (CPHs). In the time-course study, a crush and rise effect was observed for pregnane X receptor (NR1I2) and constitutive androstane receptor (NR1I3) mRNAs, while a time-dependent increase of retinoid X receptor alpha (NR2B1) was noticed. Cytochrome P450 gene expression profiles were down-regulated as a function of time. In the induction study, an increase of NR1I2, NR1I3 and NR2B1 mRNAs was observed in dexamethasone-exposed CPHs. About CYPs, an overall up-regulation was seen in CPHs exposed to phenobarbital, while dexamethasone and rifampicin up-regulated only CYP3A. In both studies, transcriptional CYP results were confirmed at the post-translational level (immunoblotting and enzyme activities), except for CYP2B immunoblotting in the induction study. The present data demonstrate that long-term stored CPHs may be used to investigate mechanisms involved in CYPs regulation, expression and function; provide further info about NR regulation of CYPs, and confirm species differences in these mechanisms of regulation; finally, they suggest the usefulness and relevance of gene expression profiling to early detect any modulation of CYP expression and bioactivity. PMID- 22447112 TI - Epidermal growth factor receptor mediates injury in rapidly progressive glomerular disease. PMID- 22447115 TI - Increased expression of drug-metabolizing enzymes in human hepatocarcinoma FLC-4 cells cultured on micro-space cell culture plates. AB - Human hepatocellular carcinoma cell lines cultured in a monolayer show negligible activities of drug-metabolizing enzymes such as cytochrome P450s (CYPs) and UDP glucuronosyltransferases (UGTs). Here, we show that culture of human hepatocellular carcinoma FLC-4 cells on 24-well plates arrayed with uniform micro sized compartments on the bottom of the plates (micro-space cell culture plates) resulted in increased expression of drug-metabolizing enzymes (CYP1A2, CYP2C9, CYP3A4, UGT1A1, etc.) and nuclear receptors (pregnane X receptor, constitutive androstane receptor, etc.). When cells were treated with a typical CYP3A substrate (triazolam), CYP2C9 substrate (diclofenac) or UGT1A1 substrate (SN-38), large amounts of their metabolites were detected in the medium of cells cultured on micro-space cell culture plates. The formation of metabolites from triazolam, diclofenac and SN-38 was strongly inhibited by co-treatment with a CYP3A inhibitor (ketoconazole), CYP2C9 inhibitor (sulfaphenazole) and UGT1A1 inhibitor (ketoconazole), respectively. On the other hand, formation of metabolites was not observed in the medium of cells cultured in a monolayer. Finally, the cytotoxic effect of aflatoxin B1 was more potent in cells cultured on micro-space cell culture plates than in cells cultured in a monolayer. The results suggest that FLC-4 cells cultured on micro-space cell culture plates are useful for studying drug metabolism and drug-induced hepatotoxicity. PMID- 22447119 TI - Active DNA demethylation in mammalian preimplantation embryos: new insights and new perspectives. AB - DNA methylation and demethylation are crucial for modulating gene expression and regulating cell differentiation. Functions and mechanisms of DNA methylation/demethylation in mammalian embryos are still far from being understood clearly. In this review we firstly describe new insights into DNA demethylation mechanisms, and secondly introduce the differences in active DNA methylation patterns in zygotes and early embryos in various mammalian species. Thirdly, we attempt to clarify the functions of DNA demethylation in early embryos. Most importantly we summarize the importance of active DNA demethylation and its possible relevance to human IVF clinics. Finally research perspectives regarding DNA demethylation are also discussed. PMID- 22447106 TI - USP22 nuclear expression is significantly associated with progression and unfavorable clinical outcome in human esophageal squamous cell carcinoma. AB - PURPOSE: To detect the expression levels of ubiquitin-specific protease 22 (USP22) in human esophageal squamous cell carcinoma (ESCC) and to correlate it with clinicopathologic and prognostic data. METHODS: The immunoreactivity of USP22 protein was analyzed in 157 pathologically characterized ESCC tissues by immunohistochemistry. All statistical analyses were performed with SPSS statistical software to evaluate the association of USP22 protein with clinicopathologic factors and survival. RESULTS: High expression of USP22 protein was detected in 50.96 % of 157 ESCC tissues and significantly associated with invasion depth, lymph node metastasis, pathologic stage and tumor relapse (P < 0.05, respectively). Univariate survival analysis showed that patients with high expression of USP22 protein had a significantly poorer 5-year disease-specific survival (P = 0.002), and multivariate survival analysis showed that high expression of USP22 protein was an independent prognosticator for unfavorable disease-specific survival (P = 0.039). Further survival analysis stratified by pathologic stage demonstrated that high expression of USP22 protein significantly predicted unfavorable clinical outcome (P = 0.029) among patients with pathologic stage II(b)-III diseases. CONCLUSION: USP22 protein plays an essential role in ESCC progression and has clinical potentials not only as a promising biomarker to identify the subgroup of patients with more aggressive tumors and poor prognostic potential but also as an attractively therapeutic target for ESCC. PMID- 22447121 TI - Recent advances in organic mechanofluorochromic materials. AB - Mechanofluorochromic materials, which are dependent on changes in physical molecular packing modes, have attracted considerable interest over the past ten years. In this review, recent progress in the area of pure organic mechanofluorochromism is summarized, and majority of the reported organic mechanofluorochromic systems are discussed, along with their derived structure property relationships. The existence of a structural relationship between aggregation-induced emission compounds and mechanofluorochromism is recognized based on our recent results, which considered aggregation-induced emission compounds as a well of mechanofluorochromic materials. The established structure property relationship will guide researchers in identifying and synthesizing more mechanofluorochromic materials. PMID- 22447123 TI - Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. AB - The outcomes of acute myocardial infarction, trauma, and stroke have improved by implementing processes that provide early diagnosis and aggressive interventions at the most proximal point of disease presentation. A common feature in these conditions is the implementation of early intervention strategies. One decade ago, a similar approach to sepsis began when a prospective randomized trial compared early goal-directed therapy (EGDT) to standard care using specific criteria for the early identification of high risk patients with infection. The components of EGDT were derived from expert consensus opinion to produce a protocol to reverse the hemodynamic perturbations of hypovolemia, vasodysregulation, myocardial suppression and increased metabolic demands for patients with severe sepsis in the intensive care unit (ICU). However, EGDT was provided at the most proximal phase of disease presentation in the Emergency Department (ED). With EGDT, a reduction in mortality of over 16% was shown over standard care. Since the EGDT study was published a decade ago, significant emphasis worldwide has been placed on a comprehensive approach to the first 6 hours of sepsis management which is commonly referred to as the resuscitation bundle (RB). The RB consists of early diagnosis, risk stratification using lactate levels, hemodynamic response after a fluid challenge, antibiotics, source control and hemodynamic optimization or EGDT. This review will examine one decade of evidence for the components of the RB examining its impact on systemic inflammation, the progression of organ failure, health care resource consumption and mortality in severe sepsis and septic shock. PMID- 22447125 TI - Improved hydrogen production from formic acid on a Pd/C catalyst doped by potassium. AB - The rate of hydrogen production from vapour-phase formic acid decomposition can be increased by 1-2 orders of magnitude by doping a Pd/C catalyst with potassium ions. Surface potassium formate and/or bicarbonate species could be involved in the rate-determining step of this reaction. PMID- 22447122 TI - Confocal Raman microscopy and SEM/EDS investigations of the interface between the zirconia core and veneering ceramic: the influence of a liner and regeneration firing. AB - The aim of this study was to evaluate the changes in the transition layer at the interface between yttria partial stabilized tetragonal zirconia polycrystalline (Y-TZP) core and veneering feldspathic ceramic (VITA VM((r))9), under different manufacturing methods. Confocal Raman microscopy and energy dispersive X-ray spectroscopy (EDS) analyses were carried out on tapered veneered cross sections of the interface. For some samples, an additional firing of the core was used, as the application of an optional liner material between the core and veneer. Single Raman spectra were distinguishable between Y-TZP and the veneering materials. VM((r))9 and liner spectra were broadly superimposable. No substantial differences appeared in their chemical elemental composition. 2D Raman images and EDS analysis emphasized changes in the interdiffusion thickness; the additional firing of the core decreased the interdiffusion zone, and the highest firing temperature of the liner increased the interdiffusion zone. These results, which will help us understand the changes in this transition layer, are discussed. PMID- 22447124 TI - Blockade of p53 by HIF-2alpha, but not HIF-1alpha, is involved in arsenite induced malignant transformation of human bronchial epithelial cells. AB - Hypoxia-inducible factors (HIFs), which consist of alpha and beta subunits, are transcription factors involved in regulation of a variety of cellular functions. By blocking the function of the tumor suppressor p53, over-expressions of HIFs are linked to carcinogenesis and tumor progression. Inorganic arsenic, a ubiquitous environmental contaminant, is associated with an increased risk of cancer. Although there are several hypotheses regarding arsenic-induced carcinogenesis, the mechanism of action remains obscure. We have shown that long term exposure of human bronchial epithelial (HBE) cells to a low level of arsenite increases their proliferation rate and anchorage-independent growth. When introduced into nude mice, the transformed cells are tumorigenic. The present report demonstrates that, with increased time of exposure to arsenite, there is more increased expression of HIF-2alpha, but not HIF-1alpha. These factors are known to have different functions, and, in some cases, opposite effects. Arsenite induces accumulation of HIF-2alpha by inhibiting its degradation through the ubiquitin-mediated proteasome pathway. HIF-2alpha knockdown, but not HIF-1alpha knockdown, increases the activation of p53. Finally, inhibition of HIF-2alpha blocks arsenite-induced proliferation and malignant transformation. Thus, our studies show that blockade of p53 function by inhibiting the ubiquitin-mediated proteasome degradation of HIF-2alpha, but not that of HIF-1alpha, is involved in arsenite-induced proliferation and neoplastic transformation of HBE cells. PMID- 22447126 TI - Transcriptomic response of Enterococcus faecalis to iron excess. AB - Iron is an essential nutrient for sustaining bacterial growth; however, little is known about the molecular mechanisms that govern gene expression during the homeostatic response to iron availability. In this study we analyzed the global transcriptional response of Enterococcus faecalis to a non-toxic iron excess in order to identify the set of genes that respond to an increment of intracellular iron. Our results showed an up-regulation of transcriptional regulators of the Fur family (PerR and ZurR), the cation efflux family (CzcD) and ferredoxin, while proton-dependent Mn/Fe (MntH) transporters and the universal stress protein (UspA) were down-regulated. This indicated that E. faecalis was able to activate a transcriptional response while growing in the presence of an excess of non toxic iron, assuring the maintenance of iron homeostasis. Gene expression analysis of E. faecalis treated with H(2)O(2) indicated that a fraction of the transcriptional changes induced by iron appears to be mediated by oxidative stress. A comparison of our transcriptomic data with a recently reported set of differentially expressed genes in E. faecalis grown in blood, revealed an important fraction of common genes. In particular, genes associated to oxidative stress were up-regulated in both conditions, while genes encoding the iron uptake system (feo and ycl operons) were up-regulated when cells were grown in blood. This suggested that blood cultures mimic an iron deficit, and was corroborated by measuring feo and ycl expression in E. faecalis treated with the iron chelating agent 2,2-dipyridil. In summary, our group identified an adaptive transcriptional mechanism in response to metal ion stress in E. faecalis, providing a foundation for future in-depth functional studies of the iron-activated regulatory network. PMID- 22447128 TI - Visible light mediated homo- and heterocoupling of benzyl alcohols and benzyl amines on polycrystalline cadmium sulfide. AB - The oxidative coupling of sp(3) hybridized carbon atoms by photocatalysis is a valuable synthetic method as stoichiometric oxidation reagents can be avoided and dihydrogen is the only byproduct of the reaction. Cadmium sulfide, a readily available semiconductor, was used as a visible light heterogeneous photocatalyst for the oxidative coupling of benzyl alcohols and benzyl amines by irradiation with blue light. Depending on the structure of the starting material, good to excellent yields of homocoupling products were obtained as mixtures of diastereomers. Cross-coupling between benzyl alcohols and benzyl amines gave product mixtures, but was selective for the coupling of tetrahydroisoquinolines to nitromethane. The results demonstrate that CdS is a suitable visible light photocatalyst for oxidative bond formation under anaerobic conditions. PMID- 22447130 TI - EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians. AB - Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians. PMID- 22447129 TI - [Do female medical graduates have different views on professional work and workload compared to their male colleagues? Results of a multicenter postal survey in Germany]. AB - BACKGROUND AND AIM: This study investigated the career preferences of medical graduates with regard to discipline, final position, preferred area of work, and work load after the completion of postgraduate according to gender in Germany. METHODS: Standardized postal survey among all last year medical students in the medical faculties of Erlangen, Giessen, Hamburg, Heidelberg, Cologne, Leipzig and Magdeburg in 2009. 2017 persons were contacted and 1012 (48 %) participated. Descriptive statistics and regression analysis were performed. Qualitative interviews with graduates completed data collection. RESULTS: Overall, graduates prefer the hospital over private practice as their workplace after postgraduate training. However, 50 % of male graduates but only 29 % of female graduates aspire a leading position in the hospital. Male graduates often prefer careers in surgical disciplines, specialized internal medicine whereas female graduates orient themselves towards gynecology, pediatrics and smaller clinical disciplines like dermatology. 80 % of male but only 40 % of female graduates prefer a full time position after completion of postgraduate training, whereas 16 % of female graduates aim at a part-time position only. CONCLUSION: The results demonstrate the persistence of traditional role models among medical graduates. Men aim at leading positions in the hospital whereas women prefer lower hospital positions or outpatient practices. Women look for part-time jobs, at least temporarily for child rearing whereas men continue to prefer full-time jobs. PMID- 22447127 TI - Sorting nexins 1 and 2a locate mainly to the TGN. AB - The subcellular localization of the sorting nexins (SNXs) in higher plants is a matter of controversy. Previous confocal laser scanning microscopy (CLSM studies on root cells from a transgenic Arabidopsis line expressing SNX1-GFP have suggested that this SNX is present on an endosome having characteristics of both the trans-Golgi network (TGN) and the multivesicular body (MVB). In contrast, SNX2a locates exclusively to the TGN when transiently expressed in tobacco mesophyll protoplasts. By performing immunogold electron microscopy on cryofixed Arabidopsis roots, we have tried to clarify the situation. Both SNX1-GFP and endogenous SNX2a locate principally to the TGN. Labeling of MVBs could not be confirmed with any certainty. PMID- 22447120 TI - Licensing of myeloid cells promotes central nervous system autoimmunity and is controlled by peroxisome proliferator-activated receptor gamma. AB - During central nervous system autoimmunity, interactions between infiltrating immune cells and brain-resident cells are critical for disease progression and ultimately organ damage. Here, we demonstrate that local cross-talk between invading autoreactive T cells and auto-antigen-presenting myeloid cells within the central nervous system results in myeloid cell activation, which is crucial for disease progression during experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. This T cell-mediated licensing of central nervous system myeloid cells triggered astrocytic CCL2-release and promoted recruitment of inflammatory CCR2(+)-monocytes, which are the main effectors of disease progression. By employing a cell-specific knockout model, we identify the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) in myeloid cells as key regulator of their disease-determining interactions with autoreactive T cells and brain-resident cells, respectively. LysM-PPARgamma(KO) mice exhibited disease exacerbation during the effector phase of experimental autoimmune encephalomyelitis characterized by enhanced activation of central nervous system myeloid cells accompanied by pronounced local CCL2 production and inflammatory monocyte invasion, which finally resulted in increased demyelination and neuronal damage. Pharmacological PPARgamma activation decreased antigen specific T cell-mediated licensing of central nervous system myeloid cells, reduced myeloid cell-mediated neurotoxicity and hence dampened central nervous system autoimmunity. Importantly, human monocytes derived from patients with multiple sclerosis clearly responded to PPARgamma-mediated control of proinflammatory activation and production of neurotoxic mediators. Furthermore, PPARgamma in human monocytes restricted their capacity to activate human astrocytes leading to dampened astrocytic CCL2 production. Together, interference with the disease-promoting cross-talk between central nervous system myeloid cells, autoreactive T cells and brain-resident cells represents a novel therapeutic approach that limits disease progression and lesion development during ongoing central nervous system autoimmunity. PMID- 22447131 TI - Molecular characterization of distinct bipartite begomovirus infecting bhendi (Abelmoschus esculentus L.) in India. AB - Yellow vein mosaic disease of okra is a whitefly transmitted begomovirus causing heavy economic loss in different parts of India. The okra isolate (OY131) of this virus from a bhendi plant [(Abelmoschus esculentus L.) Moench] showing yellow vein mosaic, vein twisting, reduced leaves, and a bushy appearance in the Palem region, New Delhi, India, was characterized in the present study. The complete DNA-A and DNA-B sequences have been determined and are comprised of 2,746 and 2,703 nucleotides, respectively. The betasatellite (DNA-beta) component was absent in the sample. The genome organization was typically of biparite begomoviruses, which were characterized earlier. Comparison of DNA-A component with other known begomoviruses suggest that this virus, being only distantly related (<85.9% similarity with its nearest relative, BYVMV) to other known begomoviruses, is a new species. We have tentatively assigned the genome to a novel geminivirus species Bhendi yellow vein mosaic Delhi virus [BYVDV-IN (India: Delhi: okra)]. DNA-B showed highest sequence identity (87.8% identical) to that of a ToLCNDV (AY158080). The phylogenetic analysis of the present isolate is distinct from all other viruses; however clusters with ToLCNDV group infect different crops. The recombination analysis revealed that this isolate has sequences originated from ToLCNDV. This is the first known bhendi yellow vein mosaic disease associated bipartite begomovirus from India. PMID- 22447134 TI - Characterization of hepatocellular carcinoma cell lines based on cell adhesion molecules. AB - Many studies which focus on the molecules and mechanisms related to the characteristics of the cancer have been performed. In particular, cell adhesion molecules (CAMs) are known to play a central role in the adhesion of cancer cells to vascular endothelial cells. In this study, the expression of CAMs in hepatocellular carcinoma (HCC) cell lines was analyzed and correlated with the characteristics of various HCC cell lines. Eight human HCC cell lines were used in this study. We analyzed the expression of ICAM-1, E-selectin and the integrin subunits of HCC cell lines by western blot analysis and ELISA kit. We estimated the expression of integrin-alpha5 using western blot analysis and RT-PCR to compare the expression at the gene level with the protein level. In addition, we determined the expression of TGF-beta1, as one of the markers for the cellular activity compared to the levels of expression with the expression of integrin alpha3 and -alpha5. ICAM-1 was highly expressed in all of the cell lines except SNU398 and Hep3B, which exhibit a more aggressive nature among the studied HCC cell lines. E-selectin and integrin subunits varied in all HCC cell lines. In particular, integrin-beta2 was highly expressed on all HCC cell lines. In conclusion, the levels of expression of the CAMs may not affect cellular activity, morphology or tumorigenicity. However, most HCC cell lines show various expressions of CAMs, suggesting that HCC cell lines expressing the major CAMs remain candidates for molecular targeted therapy, which may need to be patient tailored for therapy according to the molecular profile. PMID- 22447133 TI - Derivation, expansion and differentiation of induced pluripotent stem cells in continuous suspension cultures. AB - We describe derivation of induced pluripotent stem cells (iPSCs) from terminally differentiated mouse cells in serum- and feeder-free stirred suspension cultures. Temporal analysis of global gene expression revealed high correlations between cells reprogrammed in suspension and cells reprogrammed in adhesion-dependent conditions. Suspension culture-reprogrammed iPSCs (SiPSCs) could be differentiated into all three germ layers in vitro and contributed to chimeric embryos in vivo. SiPSC generation allowed for efficient selection of reprogramming factor-expressing cells based on their differential survival and proliferation in suspension culture. Seamless integration of SiPSC reprogramming and directed differentiation enabled scalable production of beating cardiac cells in a continuous single cell- and small aggregate-based process. This method is an important step toward the development of robust PSC generation, expansion and differentiation technology. PMID- 22447132 TI - The bowel and migraine: update on celiac disease and irritable bowel syndrome. AB - This article explores possible relationships between migraine, irritable bowel syndrome (IBS), celiac disease (CD), and gluten sensitivity. These seemingly distinct medical entities curiously share many common epidemiological, psychosocial, and pathophysiological similarities. Considerable evidence is emerging to support a concept that experiencing significant threatening adverse events creates a state of hypervigilance in the nervous system, which associates with exaggerated response to future threats and episodic attacks of migraine and IBS. While this sensitizing response is generally considered to reside in the central nervous system, it may be possible that the initiation resides in the enteric nervous system as well. What appears to link migraine, IBS, and CD is a disease model of a genetically sensitive nervous system transformed into one that is hypervigilant, and that over time can often develop disabling and pervasive disease. PMID- 22447136 TI - ZnT8 and type 1 diabetes. AB - Zinc is essential for the proper storage, secretion, and the action of insulin and is transported from cytoplasm to insulin secretory granules in the pancreatic beta-cells by SLC30A zinc transporters (ZnT). ZnT8 is specifically expressed in the pancreatic beta-cells and has been identified as a novel target autoantigen in patients with type 1 diabetes. Autoantibodies to ZnT8 (ZnT8A) are detected in 50-60% of Japanese patients with acute-onset and 20% with slow-onset type 1 diabetes. Furthermore, humoral autoreactivity to ZnT8 is unique in terms of a key determinant, which is not reported on other islet autoantigens such as insulin, glutamic acid decarboxylase, or the protein tyrosine phosphatase-related molecules IA-2. Type 2 diabetes-associated nonsynonymous single nucleotide polymorphism in SLC30A8 (the gene of ZnT8), rs13266634 (Arg325Trp), modulates ZnT8A specificities thereby indicating that this amino acid substitution has the critical role in antibody binding. The humoral autoreactivity to ZnT8 depends on the clinical phenotype, which may provide clues to understand the role of this protein in the pathogenesis of type 1 diabetes. PMID- 22447137 TI - Investigation of the prognosis of patients with papillary thyroid carcinoma by tumor size. AB - In papillary thyroid carcinoma (PTC), extrathyroid extension (Ex) and clinical lymph node metastasis (N) significantly affect the prognosis. We investigated the prognosis of patients with PTC 1 cm or less (1,220 patients), 1.1-2 cm (2,101 patients), 2.1-3 cm (1,249 patients), 3.1-4 cm (645 patients), and larger than 4 cm (563 patients). We classified N factor into three categories: N0, no clinical node metastasis: N1, clinical node metastasis smaller than 3 cm and without extranodal tumor extension requiring at least partial excision of adjacent organs for node dissection: and N2, clinical node metastasis 3 cm or larger or showing extranodal tumor extension. N2 markedly affected lymph node and distant recurrence-free survivals and cause-specific survival, regardless of the tumor size. N1 also adversely affected lymph node and distant recurrence-free survival but not cause-specific survival. Ex did not affect patients' prognosis with PTC 1 cm or less. It became a prognostic factor with PTC larger than 1 cm, and worsened lymph node and distant recurrence-free survival not only for N0 but also for N1 PTC larger than 3 cm and larger than 2 cm, respectively. However, its influence is limited for N2 PTC patients. Furthermore, Ex worsened the CSS with PTC larger than 2 cm in combination with N2. We have to note that the prognostic significance for lymph node and distant recurrence-free and cause-specific survival of Ex and N varies according to the tumor size in order to accurately predict the clinical outcomes and establish therapeutic strategies for PTC patients. PMID- 22447138 TI - Polyuric-polydipsic syndrome in a pediatric case of non-glucocorticoid remediable familial hyperaldosteronism. AB - Familial hyperaldosteronism (FH) encompasses 3 types of autosomal dominant hyperaldosteronisms leading to inheritable hypertension. FH type II (FH-II), undistinguishable from sporadic hyperaldosteronism, represents the most frequent cause of inheritable hypertension and is believed to only manifest in adults. FH III is a severe variety of PA resistant to pharmacotherapy and recently demonstrated to be caused by mutations in the gene encoding the potassium channel KCNJ5. In this report, we describe a FH pediatric patient, remarkable both for age at onset and unusual presentation: a two-years old girl with polyuric polydipsic syndrome and severe hypertension, successfully treated with canrenone and amiloride. The girl had severe hypertension, hypokalemia, hypercalciuria, suppressed renin activity, high aldosterone, and unremarkable adrenal imaging. FH type I was ruled out by glucocorticoid suppression test, PCR test for CYP11B1/CYP11B2 gene, and urinary 18-oxo-cortisol and 18-hydroxy-cortisol excretion, which was in FH-II range. In spite of a clear-cut FH-II phenotype, the girl and her mother were found to harbor a FH-III genotype with KCNJ5 mutation (c.452G>A). Treatment with canrenone was started, resulting in prompt normalization of electrolytes and remission of polyuric-polydypsic syndrome. The addition of amiloride led to a complete normalization of blood pressure. This report expands the phenotypic spectrum of FH-III to a milder end, mimiking FH-II phenotype demonstrating that pharmacotherapy may be effective. This also implies that FH-II/III should be considered in the differential diagnosis of hypertensive children and, perhaps, that the offspring of patients with hyperaldosteronism should be screened for hypertension. PMID- 22447139 TI - Use of molecular markers in samples obtained from preoperative aspiration of thyroid. AB - Several experiments have been carried out in order to find molecular markers that increase the diagnose accuracy of the Fine-Needle Aspiration (FNA), especially for thyroid lesions of undetermined significance. The growing number of published experiments on one or more of the different types of markers has started to justify the need to gather the pieces of information as a way to add evidence and guide the development of future research in the area. From the search arguments and criteria previously defined, 95 articles were selected from the electronic databases PUBMED, MEDLINE, SCOPUS and LILACS. From the 36 markers submitted to analysis and identified in preoperative FNA thyroid samples, only 10 (GAL3, CK-19, HBME-1, TPO, CD44, Telomerase, DAP IV, RAS, RET and BRAF) were assessed in more than two investigations, be it either in panel or individually. The minimum, medium and maximum values of sensibility, specificity, positive predictive value, negative predictive value and diagnose accuracy were obtained from the group of investigation, as well as the limitations and advantages of the use of each marker were identified. The BRAF mutation, for its unquestionable specificity, and the GAL3, for its regularity of average results obtained here, found in several locations in the cell as well as out of the cell, suggesting multiple functions of this molecule, were observed as holders of more expressive evidence in the effort of reducing the uncertainty of the diagnose in preoperative FNA of thyroid. PMID- 22447140 TI - Effect of triptolide on estradiol release from cultured rat granulosa cells. AB - Triptolide, a major active component of Tripterygium wilfordii Hook F (TWHF), is known to have multiple pharmacological activities. However, studies have also shown that triptolide is highly toxic to the reproductive system by disrupting normal androgen and estrogen signaling. In the present study, we investigated the effect of triptolide (5, 10, or 20 nM for 24 h) on estradiol production by rat granulosa cells. Triptolide inhibited basal and human chorionic gonadotropin (HCG)- or 8-bromo-cAMP-stimulated estradiol production as revealed by RIA assay. Furthermore, the HCG-evoked increase in cellular cAMP content was also inhibited by triptolide, indicating that disruption of the cAMP/PKA signaling pathway may mediate the deleterious effects of triptolide on steroid hormone regulation. In addition, (3)H(2)O tests showed that aromatase activity was significantly inhibited by triptolide in granulosa cells. Western blot and quantitative real time PCR (qRT-PCR) assays further revealed that triptolide decreased protein and mRNA expression of aromatase in granulosa cells. Moreover, mRNA expression of luteinizing hormone receptor (LHR) was induced by triptolide also using qRT-PCR method. In contrast, cell viability tests using Cell Counting Kit-8 (CCK-8) and 3 (4,5-dimethyl-thiazol-2-yl)-2,5- diphenyl-tetrazolium bromide (MTT) method indicated that triptolide did not cause measurable cell death at doses that suppressed steroidogenesis. The reproductive toxicity of triptolide may be mainly caused by disruption of cAMP/PKA-mediated expression of estrogen synthesis enzymes, leading to reduced estradiol synthesis and reproductive dysfunction. PMID- 22447141 TI - Association of alcohol consumption with the impaired beta-cell function independent of body mass index among Chinese men. AB - Alcohol consumption is associated with type 2 diabetes. However, the relationship between alcohol consumption and beta-cell function is still unclear. The aim of this study is to investigate the association between them. 675 Chinese men aged 20-75 years were recruited. The subjects were first classified into never drinkers, abstainers, light drinkers (0.1-19.9 g/day) , moderate drinkers (20.0 39.9 g/day) and heavy drinkers (>= 40.0 g/day) and then, were further divided into two subgroups according to body mass index (BMI) (BMI<25kg/m2 and BMI >= 25kg/m2). Analysis procedure was adjusted by the confounders including age, smoking status, BMI, waist circumference (WC), blood pressure, lipids and blood uric acid. Compared with never drinkers, alcohol consumption was associated with decreased homeostasis model assessment of beta-cell function (HOMA-beta) independent of BMI. The homeostasis model assessment of insulin resistance (HOMA IR) was significantly correlated with alcohol consumption history in the group of BMI<25kg/m2 and was significantly correlated with alcohol consumption in the group of BMI >= 25kg/m2. The results suggest that alcohol consumption is associated with the beta-cell dysfunction independent of BMI in Chinese community dwelling men. PMID- 22447142 TI - Should we use ultrasound features associated with papillary thyroid cancer in diagnosing medullary thyroid cancer? AB - In thyroid nodule management, ultrasound (US) features, such as hypoechogenicity of the lesion, irregular margins, microcalcifications, and intralesional vascular signal, alone or combined, have to be considered as suggestive for malignancy. Because of the low prevalence of medullary thyroid cancer (MTC), a few papers analyzed US characteristics associated with this cancer in small series, with controversial results. Aim of this study was to evaluate in MTC the US risk factors of thyroid nodule. In this order, a series of nodules histologically proven as MTC and a group of nodules with histology of papillary cancer (PTC) were retrospectively compared with a control group of benign nodule. Fifty percent MTC were solid hypoechoic and 16% showed microcalcifications with significant difference with respect to the benign group (p<0.05 for both parameters), while no significant difference was recorded regarding margins nor nodular vascularization. The presence of at least one US risk feature was almost equal in MTC (58.3%) and controls (55.5%). On the contrary, at least one US risk factor was significantly (p<0.001) more frequent in PTC than in benign group or MTC series. This study showed low frequency of ultrasound features associated to PTC when analyzed in medullary cancer. Because of the poor literature focusing on this topic, and the herein used design, these data contribute to the knowledge about presentation of MTC at US. We advice for further prospective studies on larger series to define the US presentation of this cancer type. PMID- 22447143 TI - The relationship of epicardial adipose tissue thickness to clinical and biochemical features in women with polycystic ovary syndrome. AB - The amount of epicardial adipose tissue (EAT), a component of body visceral adiposity, has been linked to the presence and severity of cardiovascular disease through multiple mechanisms. Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and subclinical inflammation, which participate in the mechanism of atherosclerosis. We searched if the patients with PCOS have increased EAT thickness (EATT), along with its relation to the measures of adiposity and insulin sensitivity. A total of 41 subjects with PCOS and 46 age and body mass index (BMI) matched healthy controls were enrolled. EAT was measured by echocardiography above the free wall of the right ventricle. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) formula, and plasma adiponectin level was measured by ELISA. Compared to healthy controls EATT and HOMA-IR score were significantly higher (p=0.0001 for both) while plasma adiponectin concentration was significantly lower (p=0.048) in women with PCOS. EATT correlated positively with total cholesterol, triglyceride, luteinizing hormone (LH) and negatively with sex hormon binding globuline (p<0.05 for all), whereas it displayed no correlation to plasma adiponectin level (p=0.924). Triglyceride level was the significant determinant of EATT in logistic regression analysis (p=0.035). Thickness of the EAT is increased in patients with PCOS in conjunction with hyperandrogenity. Prospective studies are required to identify the relation of EAT and cardiovascular risk in patients with PCOS. PMID- 22447144 TI - Thyroid cancer in children: a 20-year study at a Romanian oncology institute. AB - Thyroid carcinoma (TC) has an increasing incidence in the last decade and continues to represent the most frequent form of endocrine tumor. The aim of the study was to analyze the pediatric files of TC from the registry of "Prof. Dr. Ion Chiricuta" Institute of Oncology Cluj-Napoca, Romania (IOCN) and to provide the data related to the impact of nuclear fallout of Chernobyl on this pathology. We studied 72 children with TC treated between 1991 and 2010. The mean age was 15.3 years; the ratio female/male was 6.2:1. Twenty-nine children (40.2%) revealed metastasis in regional lymph nodes or lungs at the initial diagnostic. There were 63 differentiated thyroid carcinoma (DTC), 6 cases with medullary cancer (MC), 1 case with anaplastic carcinoma (AC), and 2 mixed cases. All patients underwent total thyroidectomy and the radioiodine was administered in 64 cases (activities between 1.1 - 28.1 GBq I-131). Fifty-two children (80.5%) are free of disease, 8 are in partial remission and 4 children are in evolution of the disease at minimum 12 months of follow-up. The incidence of TC was significantly increased 10 years after the accident. In the years after, the increasing trendline was stopped and at 25 years, the number of cases is stationary. The diagnosis of pediatric TC is made frequently in metastatic disease and the therapies must be conducted for many years till complete remission. A more clear strategy adapted to children is needed in the future. PMID- 22447145 TI - Usefulness of HbA1c to diagnose diabetes among Japanese children detected by a urine glucose screening program in the Tokyo Metropolitan Area. AB - We examined the correlation between plasma glucose (PG) and hemoglobin A1c (HbA1c) to evaluate the usefulness and limitations of applying the new diagnostic criteria for diabetes to Japanese pediatric patients. Data were collected from 298 school children who took an oral glucose tolerance test (OGTT) at a school based urinary glucose screening program in the Tokyo Metropolitan Area between 1988 and 2009. Mean (SD) age of the children was 11.9 (2.5) years. Male-to-female ratio was 1:1.1. Children were diagnosed with renal glucosuria (n=146), diabetes mellitus (n=133), or the Japan Diabetes Society (JDS) "borderline type" (n=19). Median (range) values of fasting plasma glucose (FPG), 2-h plasma glucose in an OGTT (OGTT-2h), and HbA1c were 101 (76-378) mg/dL, 146.5 (57-563) mg/dL, and 6.05 (4.7-14.1) %. The correlation between PG and HbA1c was analyzed using least squares regression, and HbA1c was found to highly correlate with PG. From estimated regression equations, mean values of FPG and OGTT-2h corresponding to an HbA1c of 6.5% were calculated to be 111.4 mg/dL and 170.4 mg/dL. The mean values of HbA1c corresponding to an FPG of 126 mg/dL and OGTT-2h of 200 mg/dL were calculated to be 7.5% and 7.8%. The mean values of PG corresponding to HbA1c of 6.5% were lower than found in adults as analyzed by JDS. The mean values of HbA1c corresponding to diabetic type PG were higher than found in adults. PMID- 22447146 TI - A novel splice site mutation of the MEN1 gene identified in a patient with primary hyperparathyroidism. AB - Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome characterized by pituitary, parathyroid and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and its incomplete forms often manifested as familial isolated hyperparathyroidism and apparently sporadic parathyroid tumor. Mutation analysis of the MEN1 gene is a powerful tool for the early diagnosis of MEN1; however, the clinical significance of the identified mutations is not always obvious. In this study, a previously unreported missense MEN1 mutation, c.824G>T was identified in a patient with primary hyperparathyroidism and evaluated for its pathogenicity. This mutation was predicted to generate a putative missense menin protein, R275M. A stability test of the menin protein demonstrated that the stability of R275M mutant was reduced only slightly as compared with wild type menin, and therefore could not preclude the possibility that it was a rare benign polymorphism. However, further analysis of leukocyte mRNA and minigene experiments indicated that the mutant c.824G>T allele gives rise to abnormally spliced menin mRNA, and thereby confirmed that c.824G>T mutation is causative for MEN1. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene. PMID- 22447147 TI - A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher. AB - Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog. PMID- 22447148 TI - In reference to The increasing incidence of small thyroid cancers: Where are the cases coming from? PMID- 22447149 TI - Lantibiotics biosynthesis genes and bacteriocinogenic activity of Lactobacillus spp. isolated from raw milk and cheese. AB - Lactobacillus species are usually used as starters for the production of fermented products, and some strains are capable of producing antimicrobial substances, such as bacteriocins. Because these characteristics are highly desirable, research are continually being performed for novel Lactobacillus strains with bacteriocinogenic potential for use by food industries. The aim of this study was to characterise the bacteriocinogenic potential and activity of Lactobacillus isolates. From a lactic acid bacteria culture collection obtained from raw milk and cheese, 27 isolates were identified by 16S rDNA as Lactobacillus spp. and selected for the detection of lantibiotics biosynthesis genes, bacteriocin production, antimicrobial spectra, and ideal incubation conditions for bacteriocin production. Based on the obtained results, 21 isolates presented at least one of the three lantibiotics biosynthesis genes (lanB, lanC or lamM), and 23 isolates also produced antimicrobial substances with sensitivity to at least one proteinase, indicating their bacteriocinogenic activity. In general, the isolates had broad inhibitory activity, mainly against Listeria spp. and Staphylococcus spp. strains, and the best antimicrobial performance of the isolates occurred when they were cultivated at 25 degrees C for 24 or 48 h or at 35 degrees C for 12 h. The present study identified the bacteriocinogenic potential of Lactobacillus isolates obtained from raw milk and cheese, suggesting their potential use as biopreservatives in foods. PMID- 22447150 TI - 1,000 consecutive cases of laser-assisted liposuction and suction-assisted lipectomy managed with local anesthesia. AB - BACKGROUND: Advances in suction-assisted lipectomy (SAL) include improved instrumentation, better understanding of fluid dynamics, and an improved concept of appropriate indications. The tumescent technique uses subcutaneous injection of isotonic fluid containing vasoconstrictive and analgesic agents and is proved to be safe, with low morbidity and mortality rates. Laser-assisted liposuction (LAL) using local infiltration of an anesthetic and no general anesthesia or sedation has been developed, with claims of fat destruction and skin tightening. This study aimed to review 1,000 consecutive cases of LAL and SAL performed with the patient under local anesthesia and to determine whether this represents a safe technique with few complications. METHODS: During a period of 22 months, 581 consecutive patients (486 females and 95 males) underwent 1,000 LAL/SAL operations, 545 of whom had multiple procedures performed. None of the patients had a body mass index (BMI) higher than 30 kg/m2. The patients ranged in age from 18 to 62 years. The fat aspirate ranged from 50 to 1,400 ml. Patients were given an oral sedative, an antibiotic, and an analgesic. Ringer's lactate solution containing lidocaine and epinephrine was injected into the subcutaneous space. The 1,064-nm and/or 1,320-nm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used for laser lipolysis followed by SAL using standard and/or power-assisted liposuction (PAL) cannulas. The treated areas included the neck, triceps, male breast, midback, flanks, axilla, abdomen, mons pubis, thighs, presacrum, and knees. No patient was administered intravenous sedation or general anesthesia. RESULTS: The average number of areas treated was 1.8, and no major complications or mortalities were observed. There were three burns, two infections, one hematoma, and one seroma. A total of 73 secondary procedures were performed (7.3%). No tertiary procedures were required. CONCLUSION: For appropriately selected patients, comparable results can be obtained with an excellent safety profile and short recovery period using LAL and SAL with the patient under local anesthesia. The awake patient is able to participate in body positioning and to provide physiologic monitoring. No major complications occurred in this series. The burn and hematoma complications occurred in the first 25 cases and may have been related to a learning curve. One case of cellulitis occurred in the triceps region, and a second infection occurred in the abdomen. Both responded to antibiotics. Altogether, 73 touch-up procedures (7.3%) were performed. The amounts of fat removal were comparable with the volumes obtained using traditional liposuction. In conclusion, this series demonstrated that LAL/SAL using local anesthesia is a safe procedure for selected patients, with acceptably low morbidity and revision rates. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22447151 TI - FLZ, synthetic squamosamide cyclic derivative, attenuates memory deficit and pathological changes in mice with experimentally induced aging. AB - The aim of this study was to investigate the protective effects of N-[2-(4 hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl) acrylamide (FLZ), a synthetic squamosamide cyclic derivative, on senescent mice induced by D: -galactose/NaNO(2) (120/90 mg/kg, i.p.) once daily for 60 days. FLZ (75 and 150 mg/kg) was orally administered once daily for 30 days after D: galactose/NaNO(2) treatment for 30 days. The cognitive function of mice was evaluated with step-down task. The brain biomarkers including monoamine oxidase B (MAO-B), glutathione peroxidase (GSH-px), and malondialdehyde (MDA) were determined according to the manufacturer's instructions. The expression of acetylcholinesterase (ACh-E) and choline acetyltransferase (ChAT) protein in the CA1 region of hippocampus were counted by immunohistochemical staining. The results showed that the cognitive function, GSH-px activity in the brain, and the expression of ACh-E and ChAT in the CA1 region of hippocampus were significantly decreased, while MAO-B activity and MDA level in the brain were increased in senescent mice compared with the control mice. FLZ treatment prolonged the step down latency and decreased the number of step-down errors in the senescent mice. In addition, FLZ treatment increased the GSH-px activity and the expression of ACh-E and ChAT in the hippocampus and decreased the MDA level and MAO-B activity compared with the senescent mice without drug administration. These findings suggested that FLZ improves the performance in the step-down task and the pathological alternations in senescent mice. PMID- 22447152 TI - Living situation, occupation and health-related quality of life in adult patients with classic galactosemia. AB - BACKGROUND: Galactose-1-phosphate uridyltransferase deficiency is well known as the underlying defect in classic galactosemia. However, little is known about the consequences of this defect beyond physical disease. AIM: To evaluate psychosocial, educational and occupational outcome as well as health-related quality of life (HRQOL) in adult German patients with galactosemia and to compare information with data from patients with phenylketonuria as well as the general German population. METHODS: Members of the German patient support group for galactosemia received invitation, informed consent form and questionnaires by regular mail from the patient support group. Participation was voluntary. RESULTS: Forty-one out of 66 invited patients participated in this study. Nearly 2/3 of the patients were singles, and the majority of patients were still living with their parents. Frequently, patients had no school leaving certificate, and 30% of the patients had never started or never completed an apprenticeship. Getting along with galactosemia was rated as 'very good' or 'good' although following the diet was a burden. Social well-being and social functioning was lower compared to patients with PKU. DISCUSSION: Patients with galactosemia need a multi-professional team not only focusing on physical and/or biochemical aspects of disease but including also psycho-social dimensions of life. PMID- 22447153 TI - Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation. AB - X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane. ALDP deficiency results in impaired peroxisomal beta oxidation and the subsequent accumulation of very long-chain fatty acids (VLCFA; > C22:0) in plasma and tissues. VLCFA are primarily derived from endogenous synthesis by ELOVL1. Therefore inhibiting this enzyme might constitute a feasible therapeutic approach. In this paper we demonstrate that bezafibrate, a PPAR pan agonist used for the treatment of patients with hyperlipidaemia reduces VLCFA levels in X-ALD fibroblasts. Surprisingly, the VLCFA-lowering effect was independent of PPAR activation and not caused by the increase in either mitochondrial or peroxisomal fatty acid beta-oxidation capacity. In fact, our results show that bezafibrate reduces VLCFA synthesis by decreasing the synthesis of C26:0 through a direct inhibition of fatty acid elongation activity. Taken together, our data indicate bezafibrate as a potential pharmacotherapeutic treatment for X-ALD. A clinical trial is currently ongoing to evaluate the effect in patients with X-ALD. PMID- 22447154 TI - In vivo catecholaminergic metabolism in the medial prefrontal cortex of ENU2 mice: an investigation of the cortical dopamine deficit in phenylketonuria. AB - OBJECTIVE: Phenylketonuria (PKU) is an inherited metabolic disease characterized by plasma hyperphenylalaninemia and several neurological symptoms that can be controlled by rigorous dietetic treatment. The cellular mechanisms underlying impaired brain functions are still unclear. It has been proposed, however, that phenylalanine interference in cognitive functions depends on impaired dopamine (DA) transmission in the prefrontal cortical area due to reduced availability of the precursor tyrosine. Here, using Pah(enu2) (ENU2) mice, the genetic murine model of PKU, we investigated all metabolic steps of catecholamine neurotransmission within the medial preFrontal Cortex (mpFC), availability of the precursor tyrosine, synthesis and release, to find an easy way to reinstate normal cortical DA neurotransmission. METHODS AND RESULTS: Analysis of blood and brain levels of tyrosine showed reduced plasma and cerebral levels of tyrosine in ENU2 mice. Western blot analysis demonstrated deficient tyrosine hydroxylase (TH) protein levels in mpFC of ENU2 mice. Cortical TH activity, determined in vivo by measuring the accumulation of l-3,4-dihydroxyphenylalanine (L-DOPA) in mpFC after inhibition of L-aromatic acid decarboxylase with NSD-1015, was reduced in ENU2 mice. Finally, a very low dose of L-DOPA, which bypasses the phenylalanine inhibited metabolic steps, restored DA prefrontal transmission to levels found in healthy mice. CONCLUSION: The data suggests that a strategy of using tyrosine supplementation to treat PKU is unlikely to be effective, whereas small dose L DOPA administration is likely to have a positive therapeutic effect. PMID- 22447155 TI - UVR8 mediates UV-B-induced Arabidopsis defense responses against Botrytis cinerea by controlling sinapate accumulation. AB - Light is emerging as a central regulator of plant immune responses against herbivores and pathogens. Solar UV-B radiation plays an important role as a positive modulator of plant defense. However, since UV-B photons can interact with a wide spectrum of molecular targets in plant tissues, the mechanisms that mediate their effects on plant defense have remained elusive. Here, we show that ecologically meaningful doses of UV-B radiation increase Arabidopsis resistance to the necrotrophic fungus Botrytis cinerea and that this effect is mediated by the photoreceptor UVR8. The UV-B effect on plant resistance was conserved in mutants impaired in jasmonate (JA) signaling (jar1-1 and P35S:JAZ10.4) or metabolism of tryptophan-derived defense compounds (pen2-1, pad3-1, pen2 pad3), suggesting that neither regulation of the JA pathway nor changes in levels of indolic glucosinolates (iGS) or camalexin are involved in this response. UV-B radiation, acting through UVR8, increased the levels of flavonoids and sinapates in leaf tissue. The UV-B effect on pathogen resistance was still detectable in tt4-1, a mutant deficient in chalcone synthase and therefore impaired in the synthesis of flavonoids, but was absent in fah1-7, a mutant deficient in ferulic acid 5-hydroxylase, which is essential for sinapate biosynthesis. Collectively, these results indicate that UVR8 plays an important role in mediating the effects of UV-B radiation on pathogen resistance by controlling the expression of the sinapate biosynthetic pathway. PMID- 22447156 TI - Effects of bisphosphonates on osteoclastogenesis in RAW264.7 cells. AB - Bisphosphonates are used as therapeutic agents for the management of osteoporosis and other bone diseases. However, the precise effects and mechanisms of bisphosphonates on osteoclastogenesis are unclear, as previous studies have reported contradictory findings and no studies have circumstantially assessed the effects of bisphosphonates on osteoclastogenesis. Therefore, the aim of this study was to determine the effects of bisphosphonates on osteoclastogenesis in RAW264.7 (RAW) cells. To examine the direct effects of bisphosphonates on osteoclast differentiation via receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL), RAW cells were cultured with bisphosphonates. Addition of bisphosphonates to RAW cells led to a significant decrease in the number of osteoclasts and large osteoclasts (>= 8 nuclei) in a bisphosphonate concentration dependent and time-dependent manner. The cytotoxicity of non-nitrogen-containing bisphosphonates was specific to osteoclasts, while nitrogen-containing bisphosphonates were cytotoxic and induced cell death in both osteoclasts and RAW cells. Resorption activity was significantly diminished by treatment with bisphosphonates, thus confirming that bisphosphonates impair the absorptive activity of osteoclasts. We also investigated the effects of bisphosphonates on the mRNA expression of genes associated with osteoclastogenesis, osteoclast specific markers and apoptosis-related genes using quantitative real-time PCR. The results suggest that bisphosphonates suppress osteoclast differentiation and infusion, and induce osteoclast apoptosis. With regard to osteoclast apoptosis induced by bisphosphonates, we further investigated the detection of DNA fragmentation and Caspase-Glo 3/7 assay. DNA fragmentation was confirmed after treatment with bisphosphonates, while caspase-3/7 activity increased significantly when compared with controls. In conclusion, bisphosphonates directly inhibited RANKL-stimulated osteoclast differentiation and fusion in RAW cells. It was confirmed that bisphosphonates impair osteoclast resorption activity and induce apoptosis. The effects of non-nitrogen-containing bisphosphonates were also specific to osteoclasts, while nitrogen-containing bisphosphonates were cytotoxic and induced cell death in both osteoclasts and RAW cells. PMID- 22447157 TI - Design and characterization of alkoxy-wrapped push-pull porphyrins for dye sensitized solar cells. AB - Three alkoxy-wrapped push-pull porphyrins were designed and synthesized for dye sensitized solar cell (DSSC) applications. Spectral, electrochemical, photovoltaic and electrochemical impedance spectroscopy properties of these porphyrin sensitizers were well investigated to provide evidence for the molecular design. PMID- 22447158 TI - Synthesis of 3-alkyl enol mimics inhibitors of type II dehydroquinase: factors influencing their inhibition potency. AB - Several 3-alkylaryl mimics of the enol intermediate in the reaction catalyzed by type II dehydroquinase were synthesized to investigate the effect on the inhibition potency of replacing the oxygen atom in the side chain by a carbon atom. The length and the rigidity of the spacer was also studied. The inhibitory properties of the reported compounds against type II dehydroquinase from Mycobacterium tuberculosis and Helicobacter pylori are also reported. The binding modes of these analogs in the active site of both enzymes were studied by molecular docking using GOLD 5.0 and dynamic simulations studies. PMID- 22447159 TI - Fundamental physics: Molecules star in quantum movie. PMID- 22447160 TI - Observation of quantum interference in molecular charge transport. AB - As the dimensions of a conductor approach the nanoscale, quantum effects begin to dominate, and it becomes possible to control the conductance through direct manipulation of the electron wavefunction. Such control has been demonstrated in various mesoscopic devices at cryogenic temperatures, but it has proved to be difficult to exert control over the wavefunction at higher temperatures. Molecules have typical energy level spacings (~eV) that are much larger than the thermal energy at 300 K (~25 meV), and are therefore natural candidates for such experiments. Previously, phenomena such as giant magnetoresistance, Kondo effects and conductance switching have been observed in single molecules, and theorists have predicted that it should also be possible to observe quantum interference in molecular conductors, but until now all the evidence for such behaviour has been indirect. Here, we report the observation of destructive quantum interference in charge transport through two-terminal molecular junctions at room temperature. We studied five different rigid pi-conjugated molecular wires, all of which form self-assembled monolayers on a gold surface, and find that the degree of interference can be controlled by simple chemical modifications of the molecular wire. PMID- 22447161 TI - Stable cycling of double-walled silicon nanotube battery anodes through solid electrolyte interphase control. AB - Although the performance of lithium ion-batteries continues to improve, their energy density and cycle life remain insufficient for applications in consumer electronics, transport and large-scale renewable energy storage. Silicon has a large charge storage capacity and this makes it an attractive anode material, but pulverization during cycling and an unstable solid-electrolyte interphase has limited the cycle life of silicon anodes to hundreds of cycles. Here, we show that anodes consisting of an active silicon nanotube surrounded by an ion permeable silicon oxide shell can cycle over 6,000 times in half cells while retaining more than 85% of their initial capacity. The outer surface of the silicon nanotube is prevented from expansion by the oxide shell, and the expanding inner surface is not exposed to the electrolyte, resulting in a stable solid-electrolyte interphase. Batteries containing these double-walled silicon nanotube anodes exhibit charge capacities approximately eight times larger than conventional carbon anodes and charging rates of up to 20C (a rate of 1C corresponds to complete charge or discharge in one hour). PMID- 22447162 TI - Molecular junctions: Interference comes into view. PMID- 22447163 TI - Real-time single-molecule imaging of quantum interference. AB - The observation of interference patterns in double-slit experiments with massive particles is generally regarded as the ultimate demonstration of the quantum nature of these objects. Such matter-wave interference has been observed for electrons, neutrons, atoms and molecules and, in contrast to classical physics, quantum interference can be observed when single particles arrive at the detector one by one. The build-up of such patterns in experiments with electrons has been described as the "most beautiful experiment in physics". Here, we show how a combination of nanofabrication and nano-imaging allows us to record the full two dimensional build-up of quantum interference patterns in real time for phthalocyanine molecules and for derivatives of phthalocyanine molecules, which have masses of 514 AMU and 1,298 AMU respectively. A laser-controlled micro evaporation source was used to produce a beam of molecules with the required intensity and coherence, and the gratings were machined in 10-nm-thick silicon nitride membranes to reduce the effect of van der Waals forces. Wide-field fluorescence microscopy detected the position of each molecule with an accuracy of 10 nm and revealed the build-up of a deterministic ensemble interference pattern from single molecules that arrived stochastically at the detector. In addition to providing this particularly clear demonstration of wave-particle duality, our approach could also be used to study larger molecules and explore the boundary between quantum and classical physics. PMID- 22447164 TI - The cytotoxic effect of TGF-beta1 on mesothelial cells via apoptosis in early peritoneal carcinomatosis. AB - Peritoneal dissemination is one of the main causes of death in gastric cancer patients. We have previously reported that gastric cancer cells can induce peritoneal apoptosis, lead to damage of peritoneum integrity, and therefore promote peritoneal metastasis. However, the soluble factors secreted by cancer cells to trigger the damaging cascade remain unclear. TGF-beta1, a cytokine known for its capacity to induce proliferative and transformative changes of cells is found in significantly higher quantities correlated with peritoneal metastasis and TNM stages of gastric cancer. High levels of TGF-beta1 in the subperitoneal milieu may affect the morphology and function of mesothelial cells, so that the resulting environment becomes favorable for peritoneal metastases. We observed apoptosis induced by TGF-beta1 in mesothelial cells in peritoneal carcinomatosis. Knockdown of the smad2 gene by siRNA silencing can partially inhibit these effects. TGF-beta1 could upregulate the expressions of Bax and suppress Bcl-2 in mesothelial cells. We conclude that TGF-beta1 could induce apoptosis of mesothelial cells, which involves the smad2 signaling pathway in peritoneal carcinomatosis. Bcl-2 and Bax may contribute to this phenomenon. PMID- 22447166 TI - Visual photoreceptor subtypes in the chicken retina: melatonin-synthesizing activity and in vitro differentiation. AB - The chicken retina contains five visual photoreceptor subtypes, based on the specific opsin gene they express. In addition to the central role they play in vision, some or all of these photoreceptors translate photoperiodic information into a day-night rhythm of melatonin production. This indolic hormone plays an important role in the photoperiodic regulation of retinal physiology. Previous studies have stopped short of establishing whether melatonin synthesis takes place in all the photoreceptor spectral subtypes. Another issue that has been left unsettled by previous studies is when during development are retinal precursor cells committed to a specific photoreceptor subtype and to a melatoninergic phenotype? To address the first question, in situ hybridization of the five opsins was combined with immunofluorescent detection of the melatonin synthesizing enzyme hydroxyindole O-methyltransferase (HIOMT, EC.2.1.1.4). Confocal microscopy clearly indicated that all photoreceptor spectral subtypes are involved in melatonin synthesis. To tackle the second question, retinal precursor cells were dissociated between embryonic day 6 (E6) and E13 and cultured in serum-free medium for 4 days to examine their ability to autonomously activate the expression of opsins and HIOMT. Real-time PCR on cultured precursors indicated that red-, green- and violet-sensitive cones are committed at E6, rods at E10 and blue-sensitive cones at E12. HIOMT gene expression was programmed at E6, probably reflecting the differentiation of early cones. The present study provides a better characterization of photoreceptor subtypes in the chicken retina and describes a combination of serum-free culture and real-time PCR that should facilitate further developmental studies. PMID- 22447167 TI - Recellularization of decellularized human adipose-tissue-derived extracellular matrix sheets with other human cell types. AB - Decellularized human extracellular matrices (ECMs) are an extremely appealing biomaterial for tissue engineering and regenerative medicine. In this study, we decellularized human adipose tissue, fabricated a thin ECM sheet and explored the potential of this human adipose-derived ECM sheet as a substrate to support the formation of tissues other than adipose tissue. Acellular ECM sheets were fabricated from human adipose tissue through successive physical and chemical treatments: homogenization, centrifugation, casting, freeze-drying and sodium dodecyl sulfate treatment. The ECM sheets exhibited good mechanical properties, despite their porous structure. They degraded quickly in the presence of collagenase and the degradation rate increased with the collagenase concentration in phosphate-buffered saline. Five different human cell types, covering a broad range of cells and applications (normal human dermal fibroblasts, human aortic smooth muscle cells, human chondrocytes, human umbilical vein endothelial cells and human adipose-derived stem cells), were seeded onto the ECM sheets. All the human cell types spread well, proliferated and were successfully integrated into the decellularized ECM sheet. Overall, the results suggest that recellularized ECM sheets are a promising substitute for defective or damaged human tissues. PMID- 22447168 TI - Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration. AB - Mesenchymal stem cells (MSCs) are multipotent cells with the capacity for self renewal and differentiation and have a broad tissue distribution. These characteristics make them candidate cells for wound healing and regeneration in a variety of disorders. Endogenous MSCs or exogenously delivered MSCs can traffic and migrate to injured tissue and participate in the healing of this tissue. The concentrated conditioned medium from MSCs can modulate wound repair without MSCs being present in the wound. The therapeutic effects of MSCs might be attributable to their ability to differentiate and transdifferentiate into tissue-specific cells, to fuse with the resident cells, to secrete a wide array of paracrine factors in order to stimulate the survival and functional recovery of the resident cells, or to regulate the local microenviroment or niche and immune response. These mechanisms are probably independent but not mutually exclusive. In many circumstances, a combination of these protective mechanisms might work together to affect cutaneous wound healing. This review gives a brief overview and discusses the mechanisms by which MSCs promote skin repair and regeneration, although the specific mechanisms in each type of cutaneous wound are still unclear and controversial. A comprehensive understanding of the mechanisms should allow us to find advanced and better treatment strategies for various skin diseases, even those that are currently incurable. PMID- 22447169 TI - Variations in elemental compositions of rat hippocampal formation between acute and latent phases of pilocarpine-induced epilepsy: an X-ray fluorescence microscopy study. AB - There is growing experimental evidence that tracing the elements involved in brain hyperexcitability, excitotoxicity, and/or subsequent neurodegeneration could be a valuable source of data on the molecular mechanisms triggering or promoting further development of epilepsy. The most frequently used experimental model of the temporal lobe epilepsy observed in clinical practice is the one based on pilocarpine-induced seizures. In the frame of this study, the elemental anomalies occurring for the rat hippocampal tissue in acute and silent periods after injection of pilocarpine in rats were compared. X-ray fluorescence microscopy was applied for the topographic and quantitative elemental analysis. The differences in the levels of elements such as P, S, K, Ca, Fe, Cu, and Zn between the rats 3 days (SE72) and 6 h (SE6) after pilocarpine injection as well as naive controls were examined. Comparison of SE72 and control groups showed, for specific areas of the hippocampal formation, lower levels of P, K, Cu, and Zn, and an increase in Ca accumulation. These results as well as further analysis of the differences between the SE72 and SE6 groups confirmed that seizure-induced excitotoxicity as well as mossy fiber sprouting are the mechanisms involved in the neurodegenerative processes which may finally lead to spontaneous seizures in the chronic period of the pilocarpine model. Moreover, in the light of the results obtained, Cu seems to play a very important role in the pathogenesis of epilepsy in this animal model. For all areas analyzed, the levels of this element recorded in the latent period were not only lower than those for controls but were even lower than the levels found in the acute period. The decreased hippocampal accumulation of Cu in the phase of behavior and EEG stabilization, a possible inhibitory effect of this element on excitatory amino acid receptors, and enhanced seizure susceptibility in Menkes disease (an inherited Cu transport disorder leading to Cu deficiency in the brain) suggest a neuroprotective role rather than neurodegenerative and proconvulsive roles of Cu in pilocarpine induced epilepsy. PMID- 22447170 TI - Effect of Telmisartan on local cardiovascular oxidative stress in mouse under chronic intermittent hypoxia condition. AB - OBJECTIVE: The objective of this study is to explore the protective effect of an angiotensin receptor blocker (ARB) on local cardiovascular angiotensin II (AngII) and oxidative stress markers such as malondialdehyde (MDA), NADPH oxydase p47(phox), and 8-hydroxy-2'-deoxyguanosine/8-hydroxyguanosine (8-OHdG/8-OHG) of mice that had chronic intermittent hypoxia (CIH). METHODS: Thirty-two healthy male C57B6J mice were randomly divided into four groups: CIH (12 weeks of CIH), ARB (CIH+Telmisartan), air control (room air delivery), and blank control (no treatment). AngII, p47(phox), and 8-OHdG/8-OHG were detected in mouse cardiocytes by immunohistochemistry. MDA was measured with the thiobarbituric acid method. MEASUREMENTS AND RESULTS: The highest AngII levels occur in the ARB treatment group (P < 0.05), followed by the CIH group (which was higher than the two control groups; P = 0.000). The levels of p47(phox) were statistically higher in the CIH group than in the other groups (P = 0.000) and lower in the ARB group (but still higher than in the two control groups, P = 0.000). The levels of 8 OHdG/8-OHG were the highest in the CIH group (P < 0.05), followed by the ARB group (which was higher than the two control groups, P = 0.000). The levels of MDA in the myocardial homogenate of mice were the highest in the CIH group (P = 0.000). CONCLUSIONS: Based on the above results, it can be concluded that Telmisartan may protect mouse cardiocytes from oxidative stress damage due to CIH. PMID- 22447171 TI - Validation of ApneaLink OxTM for the diagnosis of obstructive sleep apnea. AB - OBJECTIVE: The aim of the study was to validate the automatic and manual analysis of ApneaLink OxTM (ALOX) in patients with suspected obstructive sleep apnea (OSA). METHODS: All patients with suspected OSA had a polysomnography (PSG) and an ALOX performed in the sleep laboratory. For automatic analysis, hypopnea was defined as a decrease in airflow >=30 % of baseline for at least 10 s plus oxygen desaturation >=3 or 4 %. While for the manual analysis, hypopnoea was considered when a reduction of airflow >=30 % of >=10 s plus oxygen desaturation >=3 % or increase in cardiac rate >=5 beats/min were identified or, when only a reduction of airflow >=50 % was observed. OSA was defined as a respiratory disturbance index (RDI) >=5. The apnea/hypopnea automatic index (AHI3-a, AHI4-a) and manual index were estimated. Receiver operating characteristics (ROC) analysis and the agreement between ALOX and PSG were performed. RESULTS: Fifty-five patients were included (38 men; mean age, 48.2; median, RDI 15.1; median BMI, 30 Kg/m(2)). The automatic analysis of ALOX under-estimated the RDI from PSG, mainly for the criterion of oxygen desaturation >=4 % (AHI3-a-RDI, -3.6 +/- 10.1; AHI4-a-RDI, 6.5 +/- 10.9, p < 0.05). The autoscoring from ALOX device showed a better performance when it was set up to identify hypopneas with an oxygen desaturation criterion of >=3 % than when it was configured with an oxygen desaturation criterion of >=4 % (area under the receiver operator curves, 0.87 vs. 0.84). Also, the manual analysis was found to be better than the autoscoring set up with an oxygen desaturation of >=3 % (0.923 vs. 0.87). The manual analysis showed a good interobserver agreement for the classification of patients with or without OSA (k = 0.81). CONCLUSION: The AHI obtained automatically from the ApneaLink OxTM using oxygen desaturation >=3 % as a criterion of hypopnea had a good performance to diagnose OSA. The manual scoring from ApneaLink OxTM was better than the automatic scoring to discriminate patients with OSA. PMID- 22447172 TI - Comparison of three actigraphic algorithms used to evaluate sleep in patients with obstructive sleep apnea. AB - PURPOSE: Actigraphy is a non-invasive and valid method to detect sleep/wake status. However, the technique lacks reliability in patients with sleep disordered breathing and its results may depend on the algorithm employed. METHODS: We compared three currently used algorithms (the Cole-Kripke, Sadeh, and University of California San Diego [UCSD]) and determined which is the most reliable in patients with obstructive sleep apnea (OSA) assessing total sleep time. After identification of the most reliable algorithm, we compared total sleep time with the severity of obstructive sleep apnea. RESULTS: The mean total sleep time was not significantly different from that yielded by polysomnography when the UCSD algorithm was employed (p = 0.798) and UCSD algorithm was associated with the smallest bias. The correlation levels (with polysomnographic data) were mild-to-modest when the results yielded by all algorithms were evaluated, but were highest when the UCSD algorithm was employed (UCSD, r = 0.498, p < 0.001; Cole-Kripke, r = 0.389, p < 0.01; Sadeh, r = 0.272, p = 0.057). Actigraphic measures of mean total sleep time underestimated sleep in patients with severe obstructive sleep apnea (apnea-hypopnea index [AHI] >=30), and the correlation was low (r = 0.317, p = 0.116), but overestimated sleep, with high correlations, in patients with mild (5 <= AHI < 15) and moderate OSA (15 <= AHI < 30; r = 0.859, p < 0.001; r = 0.842, p < 0.001, respectively). CONCLUSIONS: Among the three actigraphic algorithms tested in this study, sleep duration estimated by the UCSD algorithm was the most correlated with polysomnography data in an OSA population. However, none of them was reliable enough for estimating sleep time in patients with sleep-disordered breathing, especially in patients with severe OSA. PMID- 22447173 TI - Personality profiles in patients with obstructive sleep apnea. AB - OBJECTIVE: The Minnesota Multiphasic Personality Inventory (MMPI) responses between snorers and obstructive sleep apnea (OSA) may be different. Thus, we compared the MMPI responses between snorers and OSA. DESIGN: A clinical-based cross-sectional survey. PARTICIPANTS: This is a survey of 94 treatment-naive sleep-disordered breathing (SDB) subjects. METHOD: Clinical information, body mass index (BMI), 36-item Short Form Health Survey, the Turkish version of the MMPI, Epworth sleepiness scale (ESS), fatigue scale, attention-deficit scale, and polysomnography were collected. All patients with OSA and snorers was accepted as individuals with SDB (AHI > 0 events/h). The threshold of five apnea and hypopnea per hour of sleep was chosen to define both OSA and snorers. Disability profile is consisting of four or more MMPI clinical scale elevations. RESULTS: OSA patients compared to snorers have significantly higher absolute scores on hypochondriasis (Hs) (65.0 +/- 12.0 vs 58.4 +/- 7.9, p = 0.01, respectively). OSA patients compared to snorers have significantly higher rate of clinical elevation on both psychopathic deviance (13.0 vs 0 %, p = 0.03, respectively) and Hs (26.1 vs 3.3 %, p = 0.01, respectively). People with disability profile has lower the quality of life, a higher score for inattention, a higher fatigue scores, and higher sleepiness scores. The quality of life and attention deficit and daytime sleepiness scores were associated with total MMPI absolute score in individuals with SDB in bivariate analyses. CONCLUSION: Present study indicated that patients with OSAS compared to snorers displayed significantly more hyopchondriasis and psychopathic deviance personality characteristics. The daytime functions in individuals with sleep-disordered breathing may be influenced by the severity of psychopathology. PMID- 22447174 TI - Evaluation of MAGE A1 in oral squamous cell carcinoma. AB - MAGE A1 is a cancer testis antigen (CTA) described in a variety of human cancers. CTAs exhibit a highly restricted tissue expression and by virtue of their immunogenic potential, these genes are promising target molecules for cancer vaccines. DNA hypomethylation is associated with gene regulation in several types of tumours. The aim of this project was to identify the presence of MAGE A1 in oral squamous cell carcinoma (OSCC) samples and to investigate the hypomethylation profile of CpG islands situated in the promoter region of this gene. The expression of MAGE A1 in OSCC and healthy oral mucosal samples was determined by real-time quantitative and conventional endpoint PCR and also by immunohistochemistry staining. In addition, to investigate the hypomethylation profile of promoter MAGE A1 CpG islands, we performed bisulphite sequencing. Real time quantitative and endpoint PCR assays demonstrated a lower level of MAGE A1 transcription. Endpoint PCR showed expression of MAGE A1 in 10% (2/20) of OSCCs. Sodium bisulphite sequencing analysis of MAGE A1 CpG islands did not reveal a difference between OSCC and normal oral mucosal samples. We further assessed MAGE A1 protein immunoexpression and found 80% (16/20) of immunopositivity in OSCCs. We did not observe a correlation between the presence of MAGE A1 protein and lower levels of transcripts. Identification of MAGE A1 protein in OSCCs and absence of immunoexpression in normal oral mucosa support the idea that this protein can be used as a biomarker for detection of OSCC; however, it is not associated with hypomethylation or high expression of the MAGE A1 gene. PMID- 22447175 TI - Diabetes self-management activities for Latinos living in non-metropolitan rural communities: a snapshot of an underserved rural state. AB - The Latino community continues to grow in the rural Midwest, and diabetes is a pertinent disease for research in this demographic. Patient self-management is an important aspect of comprehensive care for diabetes and may mitigate complications. A cross-sectional survey assessed various activities including self-monitoring of blood glucose, personal foot inspection, diet adherence, and diabetes self-management education. Less than half of the sample performed self monitoring of blood glucose daily (40 %), adhered strictly to special diabetes diet recommendations (44 %), or attended a diabetes self-management education class (48 %). Participants advised on personal foot inspection were three times more likely to perform the self-care activity. Improvements are indicated in these self-management activities. Further research is needed to discern disparities and barriers in self-monitoring of blood glucose among this target population. An increased emphasis on enrollment in diabetes self-management classes should target foreign-born Latinos with lower levels of education. PMID- 22447176 TI - Acute viral hepatitis in the United States-Mexico border region: data from the Border Infectious Disease Surveillance (BIDS) Project, 2000-2009. AB - Little is known about the characteristics of acute viral hepatitis cases in the United States (US)-Mexico border region. We analyzed characteristics of acute viral hepatitis cases collected from the Border Infectious Disease Surveillance Project from January 2000-December 2009. Over the study period, 1,437 acute hepatitis A, 311 acute hepatitis B, and 362 acute hepatitis C cases were reported from 5 Mexico and 2 US sites. Mexican hepatitis A cases most frequently reported close personal contact with a known case, whereas, US cases most often reported cross-border travel. Injection drug use was common among Mexican and US acute hepatitis B and C cases. Cross-border travel during the incubation period was common among acute viral hepatitis cases in both countries. Assiduous adherence to vaccination and prevention guidelines in the US is needed and strategic implementation of hepatitis vaccination and prevention programs south of the border should be considered. PMID- 22447177 TI - Pap testing, awareness, and acceptability of a human papillomavirus (HPV) vaccine among Chinese American women. AB - Little is known about the knowledge and opinions of human papillomavirus (HPV) vaccine among Chinese immigrants, nor the impact of framing HPV as a sexually transmitted infection in this population. A cross-sectional survey was conducted focusing on knowledge and experience with HPV, HPV vaccine, cervical cancer and Pap testing, and attitudes toward HPV vaccine in response to different message frames. Chinese American women were recruited in a community setting (n = 162). Only 19 % had heard of HPV and 38 % had had a Pap test in the last 3 years. Multivariate logistic regression showed that English proficiency was associated with vaccination acceptance and insurance status was associated with HPV awareness; there was no observed correlation with message framing. Chinese American women with limited English proficiency have low HPV awareness. Community based, culturally appropriate education about cervical cancer and HPV vaccine should be directed toward limited-English proficient Chinese American women. PMID- 22447178 TI - Achieving smoke-free apartment outdoor area policies in Asian/Pacific islander neighborhoods of central Los Angeles. AB - Attempting to achieve non-smoking outdoor area policies in apartment complexes of Central Los Angeles Asian/Pacific Islander neighborhoods, People's CORE, a community based organization, partnered with a professional evaluator for a three year campaign. Focus group discussion results with residents showed readiness as well as hesitation towards non-smoking policies. Through community organizing, focus group discussions with tenants and one-on-one education outreach activities to apartment managers, the organization managed to have 20 apartment complexes adopt and implement policies for smoking restrictions in their common outdoor areas. Pre- and post observations at 52 apartment complexes showed statistically significant reduction of tobacco litter in parking areas/garages, entrance ways, courtyards, and balcony/walkway/community rooms. The authors attribute the success of the project in part to the long-standing good reputation of People's CORE as a community mobilizer and organizer. PMID- 22447179 TI - The biological correlates of macroscopic breast tumour structure measured using fractal analysis in patients undergoing neoadjuvant chemotherapy. AB - Breast cancers are evolving, multi-scale systems that are characterized by varied complex spatial structures. In this study, we measured the structural characteristics of 33 breast tumours in patients who were to receive neoadjuvant chemotherapy using dynamic contrast enhanced MRI and fractal geometry. The results showed a significant association between fractal measurements and tumour characteristics. The fractal dimension was associated with receptor status (ER and PR) and the fractal fit was associated with response to chemotherapy, measured using a validated pathological response scale, tumour grade and size. This study describes structure measures that may be a consequence of known prognostic factors during the initial and/or maturation phase of tumour growth. These results suggest that measuring tumour structure in this way can predict an individual's response to neoadjuvant therapy and may identify those who will benefit least from neoadjuvant chemotherapy, allowing alternative treatment options to be selected in those patients. PMID- 22447180 TI - Soil properties predict plant community development of mitigation wetlands created in the Virginia Piedmont, USA. AB - The study investigated vegetative and soil properties in four created mitigation wetlands, ranging in age from three to ten years, all created in the Virginia Piedmont. Vegetation attributes included percent cover, richness (S), diversity (H'), floristic quality assessment index (FQAI), prevalence index (PI), and productivity [i.e., peak above-ground biomass (AGB) and below-ground biomass]. Soil attributes included soil organic matter (SOM), gravimetric soil moisture (GSM), pH, and bulk density (D(b)) for the top 10 cm. Species dominance (e.g., Juncus effusus, Scirpus cyperinus, Arthraxon hispidus) led to a lack of differences in vegetative attributes between sites. However, site-based differences were found for GSM, pH, and SOM (P < 0.001). Soil attributes were analyzed using Euclidean cluster analysis, resulting in four soil condition (SC) categories where plots were grouped based on common attribute levels (i.e., SC1 > SC2 > SC3 > SC4, trended more to less developed). When vegetation attributes were compared between SC groups, greater SOM, lower D(b), more circumneutral pH, and higher GSM, all indicative of maturation, were associated with higher H' (P < 0.05), FQAI (P < 0.05), and total and volunteer percent cover (P < 0.05), and lower AGB (P < 0.001), PI (P < 0.05), and seeded percent cover (P < 0.05). The outcome of the study shows that site age does not necessarily equate with site development with soil and vegetation developmental rates varying both within and among sites. The inclusion of soil attributes in post-construction monitoring should be required to enhance our understanding and prediction of developmental trajectory of created mitigation wetlands. PMID- 22447181 TI - Early trends in landcover change and forest fragmentation due to shale-gas development in Pennsylvania: a potential outcome for the Northcentral Appalachians. AB - Worldwide shale-gas development has the potential to cause substantial landscape disturbance. The northeastern U.S., specifically the Allegheny Plateau in Pennsylvania, West Virginia, Ohio, and Kentucky, is experiencing rapid exploration. Using Pennsylvania as a proxy for regional development across the Plateau, we examine land cover change due to shale-gas exploration, with emphasis on forest fragmentation. Pennsylvania's shale-gas development is greatest on private land, and is dominated by pads with 1-2 wells; less than 10 % of pads have five wells or more. Approximately 45-62 % of pads occur on agricultural land and 38-54 % in forest land (many in core forest on private land). Development of permits granted as of June 3, 2011, would convert at least 644-1072 ha of agricultural land and 536-894 ha of forest land. Agricultural land conversion suggests that drilling is somewhat competing with food production. Accounting for existing pads and development of all permits would result in at least 649 km of new road, which, along with pipelines, would fragment forest cover. The Susquehanna River basin (feeding the Chesapeake Bay), is most developed, with 885 pads (26 % in core forest); permit data suggests the basin will experience continued heavy development. The intensity of core forest disturbance, where many headwater streams occur, suggests that such streams should become a focus of aquatic monitoring. Given the intense development on private lands, we believe a regional strategy is needed to help guide infrastructure development, so that habitat loss, farmland conversion, and the risk to waterways are better managed. PMID- 22447182 TI - Revisiting CB1 receptor as drug target in human melanoma. AB - Previous studies have indicated the antitumoral effect of human melanocytes, human melanoma cell lines expressing CB1 receptor (CB1), and of the peritumoral administration of endocannabinoids. In the present study, we systematically screened several human melanoma cell lines for the expression of CNR1 and demonstrated transcription of the authentic gene. The product of CNR1, the CB1 protein, was found localized to the cell membrane as well as to the cytoskeleton. Further, the studied human melanoma cell lines expressed functional CB1 since physiological and synthetic ligands, anandamide (AEA), Met-F-AEA, ACEA and AM251 showed a wide range of biological effects in vitro, for example anti proliferative, proapoptotic and anti-migratory. More importantly, our studies revealed that systemic administration of a stable CB1 agonist, ACEA, into SCID mice specifically inhibited liver colonization of human melanoma cells. Since therapeutic options for melanoma patients are still very limited, the endocannabinoid-CB1 receptor system may offer a novel target. PMID- 22447184 TI - Multiplexed immunoassay to detect anabolic androgenic steroids in human serum. AB - A multianalyte enzyme-linked immunosorbent assay (ELISA) has been developed for the simultaneous detection of anabolic androgenic steroids (AAS) in human serum. The multiplexed method was developed according to a planar strategy in which the analytes are identified by their location in the microtiter plate. In the immunochemical procedure established here, human serum samples are mixed with a cocktail of antibodies and added to the distinct sections of a microplate biofunctionalized with different haptenized biomolecules. The cocktail of antibodies consists of a mixture of polyclonal antibodies raised against stanozolol (ST), boldenone (B), and tetrahydrogestrinone (THG). The whole immunochemical analytical procedure takes around 2 h including sample preparation, and many samples can be processed simultaneously to screen for the presence of the three AAS in a single run. Using this ELISA, ST, B, and THG can be detected and quantified individually. When used as a screening method, due to the cross-reactivity profiles of the immunoreagents used, the presence of up to 11 AAS can be detected simultaneously. The detectabilities achieved by this method in human serum are below the MRPLs (minimum required performance limits) proposed by WADA (World Anti-Doping Agency) and reference laboratories of the European Community. PMID- 22447186 TI - Robotically controlled ablation for atrial fibrillation: the first real-world experience in Africa with the Hansen robotic system. AB - BACKGROUND: We report the first single-centre experience in Africa with the Sensei X robotic navigation system in an unselected subset of patients with atrial fibrillation (AF). METHODS: Data were recorded prospectively of all consecutive patients who underwent robotically assisted catheter ablation therapy using the Sensei X robotic navigation system at the Christiaan Barnard Memorial Hospital, Cape Town, South Africa, from July 2009 to July 2010. Outcomes were defined at one and nine months. RESULTS: A total of 95 patients were included: 63% had only AF and 37% had AF plus atrial flutter. AF was of the persistent type in 81% of patients. The mean procedure, fluoroscopy and ablation times were 220.6 +/- 89.6 min, 31.0 +/- 20.4 min, and 61.3 +/- 28.1 min, respectively. Both fluoroscopy and procedure times were significantly longer for the first 19 patients compared with the remaining 76 patients (43.5 +/- 22.7 vs 27.8 +/- 18.5 min and 274.7 +/- 90.2 vs 207.1 +/- 84.7 min, respectively, p = 0.002). The procedural endpoint of the study was successfully achieved in all patients. After one attempt, 27% were discharged from hospital off anti-arrhythmic drugs (AADs). At a median of nine months' follow up, 74% were AF-free off AADs, and 11% were AF free on AADs, yielding a total freedom from AF of 84% without any redo procedures. Freedom from relapse after 1.12 procedures was 88%. CONCLUSION: The Sensei X robotic navigation system offers a safe and effective approach for the treatment of AF. There was a learning curve with regard to fluoroscopy and procedure time, after which point reduction in radiation exposure and operator strain, as well as improvement in procedure throughputs were even more pronounced. PMID- 22447185 TI - Rapid molecular detection of metastatic head and neck squamous cell carcinoma as an intraoperative adjunct to sentinel lymph node biopsy. AB - OBJECTIVES/HYPOTHESIS: Clinical staging of early head and neck squamous cell carcinoma (SCCHN) is often inaccurate, leading to elective neck dissection to detect the 30% of patients with micrometastatic disease. Sentinel node biopsy accurately stages the regional lymphatics, but intraoperative pathology is only moderately sensitive, and final pathology takes several days to complete. To facilitate immediate neck dissection where necessary, we have identified several promising marker genes of SCCHN metastasis and developed a rapid, accurate, and automated quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) assay for intraoperative use. STUDY DESIGN: Prospective tissue collection, retrospective pathologic correlation with qRT-PCR. METHODS: From a 40-gene marker screen, we quantified expression of 11 potential tumor genes using a test set of primary tumors (n = 32) and metastatic (n = 19) and benign (n = 10) lymph nodes. Eight patients' paired primary tumor and metastatic nodes were included. A validation set of 442 grossly tumor-negative nodes was evaluated for expression of the most promising markers, comparing metastasis detection by qRT-PCR with pathologic analysis (hematoxylin and eosin and immunohistochemistry). A novel multiplexed, automated, single-tube qRT-PCR assay was used to analyze more than 100 lymph nodes using a two-marker, 35-minute assay to determine its negative predictive value. RESULTS: Based on expression of 11 tumor-associated genes from the marker screen, the two most promising markers of SCCHN metastasis in the test set, pemphigus vulgaris antigen (PVA) and tumor-associated calcium signal transducer 1 (TACSTD1), also known as epithelial cell adhesion molecule (EpCAM), were selected. Development of a multiplexed qRT-PCR assay for the detection of metastasis compared favorably with pathologic analysis in the additional 442-node set. A rapid, multiplexed assay using PVA and TACSTD1 demonstrated excellent reproducibility, linearity, and accuracy (~96% negative predictive value) for identifying positive (n = 40) and negative (n = 62) nodes in a validation subset. CONCLUSIONS: Detection of metastatic SCCHN using multiplexed qRT-PCR can be rapid, accurate, and automated and may enable sentinel node biopsy to be used for intraoperative decision-making. PCR amplification of tumor marker genes is an effective method of intraoperative molecular staging of SCCHN and could more appropriately guide application of neck dissection in pN+ SCCHN patients, sparing 60% to 70% of pN0 patients from unnecessary neck dissection. This technique may also be used for identifying residual neck disease posttreatment, using outpatient fine-needle aspiration biopsy specimens. PMID- 22447188 TI - Synergistic association of serum albumin and globulin with coronary heart disease. AB - AIM: Serum albumin and globulin have important roles in atherosclerosis development; however, separate studies exploring the relationship between albumin or globulin and coronary heart disease (CHD) have been conducted. We explored whether there was a synergistic effect of albumin and globulin on the presence of CHD. METHODS: A total of 395 patients aged 50-74 years with angiographically documented CHD were recruited, and 596 age- and sex-matched controls without CHD were randomly selected from the general population. The association of albumin and globulin with CHD was analyzed using conditional logistic regression after adjusting for traditional CHD risk factors. RESULTS: Mean values of serum albumin and globulin were significantly lower in cases than in controls (p<0.001). In the fully adjusted model, compared with participants whose albumin (>=47.3 g/L) and globulin (>=25.6 g/L) levels were both higher than the median levels in these participants, the odds ratio for CHD was 1.59 (p= 0.048) for participants with higher albumin (>=47.3 g/L) but lower globulin (<25.6 g/L), 2.79 (p<0.001) for participants with lower albumin (<47.3 g/L) but higher globulin (>=25.6 g/L), and 16.03 (p<0.001) for participants with lower levels of both albumin (<47.3 g/L) and globulin (<25.6 g/L). CONCLUSIONS: Low serum albumin and globulin are independently associated with CHD. The synergistic association of both low albumin and low globulin with CHD is greater than either one alone. The synergistic effect deserves further investigation. PMID- 22447189 TI - Link between lipoprotein-associated phospholipase A2 gene expression of peripheral-blood mononuclear cells and prognostic outcome after acute ischemic stroke. AB - AIM: To evaluate the potential of the lipoprotein-associated phospholipase A(2) (Lp-PLA(2) level as a biomarker in the prediction of prognostic outcome in patients with acute ischemic stroke (IS). METHODS: From October 2008 to March 2010, 130 patients with acute IS were prospectively enrolled in the study and their medical records were reviewed. A blood sample was collected from each patient 48 hours after acute IS, as well as from 20 healthy volunteers as controls. Messenger-RNA (mRNA) expression of Lp-PLA(2) of peripheral-blood mononuclear cells (PBMNCs) relative to that of beta actin was measured using quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Patients with acute IS exhibited significantly higher Lp-PLA(2) mRNA expression of PBMNCs than the control group (p <0.0001). Lp-PLA(2) mRNA expression of PBMNCs in patients with a major adverse clinical outcome (MACO) (defined as recurrent stroke or death) within 90 days was significantly higher than in patients without MACO (p=0.006). Furthermore, elevated Lp-PLA(2) mRNA expression was strongly associated with old age, diabetes mellitus, a positive history of significant coronary arterial disease and significant stenosis of the extra-cranial carotid arteries (all p <0.04), and positively correlated with the body mass index, leukocyte count, and serum levels of total cholesterol and low-density lipoprotein cholesterol. Multivariate analysis revealed that Lp-PLA(2) mRNA expression of PBMNCs was a significant independent predictor of MACO within 90 days (p= 0.011). CONCLUSION: Elevated Lp-PLA(2) mRNA expression of PBMNCs seems to be a potential biomarker for predicting an unfavorable outcome in patients with acute IS. PMID- 22447190 TI - An evaluation of chemical pretreatment methods for improving enzymatic saccharification of chili postharvest residue. AB - Residue of chili plants left in the field after harvesting is a major lignocellulosic resource that is underexploited. India has over 0.6 million tons of this residue available as surplus annually which projects it as a potent feedstock for conversion to bioethanol. The cellulose, hemicellulose and lignin content of the chili residues are subject to variations with type of cultivar, geographical region and the season of cultivation, and the composition is critical in developing strategies for its conversion to bioalcohol(s). As with any lignocellulosic biomass, this feedstock needs pretreatment to make it more susceptible to hydrolysis by enzymes which is the most efficient method for generating sugars which can, then, be fermented to alcohol. Pretreatment of chili postharvest residue (CPHR) is, therefore, important though very little study has addressed this challenge. Similarly, enzymatic saccharification of pretreated chili biomass is another area which needs dedicated R&D because the combination of enzyme preparations and the conditions for saccharification are different in different biomass types. The present study was undertaken to develop an optimal process for pretreatment and enzymatic saccharification of CPHR that will yield high amount of free sugars. Dilute acid and alkali pretreatment of the biomass was studied at high temperatures (120-180 degrees C), with mixing (50-200 rpm) in a high pressure reactor. The holding time was adjusted between 15 and 60 min, and the resultant biomass was evaluated for its susceptibility to enzymatic hydrolysis. Similarly, the conditions for hydrolysis including biomass and enzyme loadings, mixing and incubation time were studied using a Taguchi method of experimentation and were optimized to obtain maximal yield of sugars. Efficiency of pretreatment was gauged by observing the changes in composition and the physicochemical properties of native and pretreated biomass which were analyzed by SEM and XRD analyses. The studies are expected to provide insights into the intricacies of biomass conversion leading to better processes that are simpler and more efficient. PMID- 22447191 TI - Comparison of immunohistochemistry, DNA sequencing and allele-specific PCR for the detection of IDH1 mutations in gliomas. AB - Previous studies have identified mutations of the isocitrate dehydrogenase 1 (IDH1) gene in more than 70% of World Health Organization (WHO) grade II and III gliomas. The most frequent mutation leads to a specific amino acid change from arginine to histidine at codon 132 (c.395G>A, p.R132H). IDH1 mutated tumors have a better prognosis than IDH1 non-mutated tumors. The aim of our study was to evaluate and compare the methods of mIDH1 R132H immunohistochemistry, allele specific PCR and DNA sequencing for determination of IDH1 status. We performed a retrospective study of 91 patients with WHO grade II (n=43) and III (n=48) oligodendrogliomas. A fragment of exon 4 spanning the sequence encoding the catalytic domain of IDH1, including codon 132, was amplified and sequenced using standard conditions. Allele-specific amplification was performed using two forward primers with variations in their 3' nucleotides such that each was specific for the wild-type or the mutated variant, and one reverse primer. Immunohistochemistry was performed with mouse monoclonal mIDH1 R132H. DNA was extracted from FFPE sections following macrodissection. IDH1 mutations were found in 55/90 patients (61.1%) by direct sequencing. R132H mutations were found in 47/55 patients (85.4%). The results of the allele-specific PCR positively correlated with those from DNA sequencing. Other mutations (p.R132C, p.R132S and pR132G) were found by DNA sequencing in 3, 3 and 2 tumors, respectively (8/55 patients, 14.6%). mIDH1 R132H immunostaining was found in the 47 patients presenting the R132H mutation (sensitivity 47/47, 100% for this mutation). None of the tumors presenting a wild-type IDH1 gene were stained (specificity 35/35, 100%). Our results demonstrate that immunohistochemistry using the mIDH1 R132H antibody and allele-specific amplification are highly sensitive techniques to detect the most frequent mutation of the IDH1 gene. PMID- 22447192 TI - DNA damage induced by micro- and nanoparticles--interaction with FPG influences the detection of DNA oxidation in the comet assay. AB - Reliable methods for evaluation of toxicity from particles, such as manufactured nanoparticles, are needed. One promising tool is the comet assay, often used to measure DNA breaks (strand breaks and alkali-labile sites) as well as oxidatively damaged DNA, the latter by addition of specific DNA repair enzymes such as formamidopyrimidine DNA glycosylase (FPG). The aim of this study was to investigate the use of the comet assay for analysis of DNA oxidation by a range of micro- and nanoparticles in the lung cell lines A549 and BEAS-2B and to test the hypothesis that nanoparticles present in the cells during the assay performance may interact with FPG. This was done by investigating the ability of micro- and nanoparticles (stainless steel, subway particles, MnO(2), Ag, CeO(2), Co(3)O(4), Fe(3)O(4), NiO and SiO(2)) to induce DNA breaks, oxidatively damaged DNA (FPG sites, dominantly 8-oxoguanine), intracellular production of reactive oxygen species (ROS) and non-cellular oxidation of the DNA base guanine, as well as by studying interactions of the particles and their released ions with FPG. Several particles caused DNA breaks, but low levels of FPG sites. The ability of FPG to detect DNA oxidation induced by a photosensitiser was however shown. An oxidative capacity of the particles was indicated by increased levels of intracellular ROS, and especially Ag and subway particles caused non-cellular oxidation of guanine. Incubation of FPG with the particles led to less FPG activity, particularly with nanoparticles of Ag but also with CeO(2), Co(3)O(4) and SiO(2). Further investigations of these particles revealed that for Ag, the decreased activity was mainly due to released Ag ions, whereas for CeO(2) and Co(3)O(4), FPG interactions were due to the particles. We conclude that measurement of oxidatively damaged DNA in cells exposed to nanoparticles may be underestimated in the comet assay due to interactions with FPG. PMID- 22447194 TI - Indoor air quality in Virginia waterpipe cafes. AB - INTRODUCTION: A revised indoor air quality law has been implemented in Virginia to protect the public from the harmful effects of secondhand smoke exposure. This legislation contains exemptions that include allowances for smoking in a room that is structurally separated and separately ventilated. The objective of the current study was to examine the impact of this law on air quality in waterpipe cafes, as well as to compare the air quality in these cafes to restaurants that allow cigarette smoking and those where no smoking is permitted. METHODS: Indoor air quality in 28 venues (17 waterpipe cafes, five cigarette smoking-permitted restaurants and six smoke-free restaurants (five with valid data)) in Virginia was assessed during 4 March to 27 May 2011. Real-time measurements of particulate matter (PM) with 2.5 MUm aerodynamic diameter or smaller (PM2.5) were obtained and occupant behaviour/venue characteristics were assessed. RESULTS: The highest mean PM2.5 concentration was observed for waterpipe cafe smoking rooms (374 MUg/m(3), n=17) followed by waterpipe cafe non-smoking rooms (123 MUg/m(3), n=11), cigarette smoking-permitted restaurant smoking rooms (119 MUg/m(3), n=5), cigarette smoking-permitted restaurant non-smoking rooms (26 MUg/m(3), n=5) and smoke-free restaurants (9 MUg/m(3), n=5). Smoking density was positively correlated with PM2.5 across smoking rooms and the smoke-free restaurants. In addition, PM2.5 was positively correlated between smoking and non-smoking rooms of venues. CONCLUSIONS: The PM2.5 concentrations observed among the waterpipe cafes sampled here indicated air quality in the waterpipe cafe smoking rooms was worse than restaurant rooms in which cigarette smoking was permitted, and state required non-smoking rooms in waterpipe cafes may expose patrons and employees to PM2.5 concentrations above national and international air quality standards. Reducing the health risks of secondhand smoke may require smoke-free establishments in which tobacco smoking sources such as water pipes are, like cigarettes, prohibited. PMID- 22447195 TI - Epidemiology and nature of self-harm in children and adolescents: findings from the multicentre study of self-harm in England. AB - We examined epidemiology and characteristics of self-harm in adolescents and impact of national guidance on management. Data were collected in six hospitals in three centres between 2000 and 2007 in the Multicentre Study of Self-harm in England. Of 5,205 individuals (7,150 episodes of self-harm), three-quarters were female. The female:male ratio in 10-14 year-olds was 5.0 and 2.7 in 15-18 year olds. Rates of self-harm varied somewhat between the centres. In females they averaged 302 per 100,000 (95 % CI 269-335) in 10-14 year-olds and 1,423 (95 % CI 1,346-1,501) in 15-18 year-olds, and were 67 (95 % CI 52-82) and 466 (95 % CI 422 510), respectively, in males. Self-poisoning was the most common method, involving paracetamol in 58.2 % of episodes. Presentations, especially those involving alcohol, peaked at night. Repetition of self-harm was frequent (53.3 % had a history of prior self-harm and 17.7 % repeated within a year). Relationship problems were the predominant difficulties associated with self-harm. Specialist assessment occurred in 57 % of episodes. Self-harm in children and adolescents in England is common, especially in older adolescents, and paracetamol overdose is the predominant method. National guidance on provision of psychosocial assessment in all cases of self-harm requires further implementation. PMID- 22447196 TI - Efficacy and safety of aripiprazole in child and adolescent patients. AB - Aripiprazole (APZ) has a unique pharmacological profile, as a partial agonist at the dopamine D2 and serotonin 5HT1A receptors and an antagonist at the serotonin 5HT2A receptor; this drug has few side effects (such as extrapyramidal syndrome, hyperprolactinemia, weight gain, metabolic disorders, and sedation) which are typical problems with other antipsychotic drugs. Due to its high tolerability, it is possible to safely administer it to children and adolescents. Efficacy and tolerability of APZ in children and adolescents have been well demonstrated in many clinical studies, which supported approvals granted by the US Food and Drug Administration (FDA) for schizophrenia, bipolar diseases, and irritability associated with autistic disorder in children and adolescents. APZ is expected to exert sedative, anti-depressive, and anti-anxiety effects, and stabilize emotion. APZ is an antipsychotic drug which could be useful for a wider spectrum of psychiatric disorders in children and adolescents. There is little risk of deterioration (such as disinhibition and acting out) and rapid stabilization is easy to achieve in children and adolescents without definitive diagnoses or with a combination of more than one spectrum of disorders. The effectiveness of APZ in children and adolescents is reviewed and discussed, given its pharmacological profile and the outcomes of various clinical studies. However, randomized or blind studies are still limited, and the majority of reports referenced here are open-label studies and case reports. Conclusions drawn from such studies must be evaluated with caution, and a further accumulation of controlled studies is thus needed. PMID- 22447197 TI - The characteristics of waste Saccharomyces cerevisiae biosorption of arsenic(III). AB - PURPOSE: The potential of using waste Saccharomyces cerevisiae as adsorbent for the adsorption of As(III) from aqueous solution was assessed. METHODS: The biosorbent was characterized by Fourier transform infrared (FTIR) spectroscopy analysis. Various parameters including pH, biosorbent dosage, contact time, and temperature were systematically investigated. RESULTS AND CONCLUSIONS: The FTIR results of S. cerevisiae biomass showed that biomass has different functional groups, and these functional groups are able to react with metal ion in aqueous solution. Several biosorption isotherms were used to fit the equilibrium data, showing sorption to be monolayer on the heterogeneous surface of the biosorbent. The maximum biosorption capacity calculated using Langmuir model was found to be 62.908 MUg/g at pH 5.0, biosorbent dosage 5 g/L, contact time 240 min, and temperature 35 degrees C. The kinetic studies indicated that the biosorption process of the As(III) followed well the pseudo-second-order equation. The intraparticle diffusion and Richenberg models were applied to the data, and we found that the biosorption of As(III) was governed by film diffusion followed by intraparticle diffusion. The thermodynamics constants indicated that the biosorption of As(III) onto S. cerevisiae was spontaneous and endothermic under examined conditions. Biosorbent could be regenerated using 0.5 M NaOH solution, with up to 75 % recovery. PMID- 22447198 TI - Coral recovery may not herald the return of fishes on damaged coral reefs. AB - The dynamic nature of coral reefs offers a rare opportunity to examine the response of ecosystems to disruption due to climate change. In 1998, the Great Barrier Reef experienced widespread coral bleaching and mortality. As a result, cryptobenthic fish assemblages underwent a dramatic phase-shift. Thirteen years, and up to 96 fish generations later, the cryptobenthic fish assemblage has not returned to its pre-bleach configuration. This is despite coral abundances returning to, or exceeding, pre-bleach values. The post-bleach fish assemblage exhibits no evidence of recovery. If these short-lived fish species are a model for their longer-lived counterparts, they suggest that (1) the full effects of the 1998 bleaching event on long-lived fish populations have yet to be seen, (2) it may take decades, or more, before recovery or regeneration of these long-lived species will begin, and (3) fish assemblages may not recover to their previous composition despite the return of corals. PMID- 22447199 TI - Multiple sclerosis and sexual dysfunction. AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by episodic and progressive neurologic dysfunction resulting from inflammatory and autoimmune reactions. The underlying pathogenesis of MS remains largely unclear. However, it is currently accepted as a T cell-mediated autoimmune disease. Among other clinical manifestations, sexual dysfunction (SD) is a painful but still underreported and underdiagnosed symptom of the disorder. SD in MS patients may result from a complex set of conditions and may be associated with multiple anatomic, physiologic, biologic, medical and psychological factors. SD arises primarily from lesions affecting the neural pathways involved in physiologic function. In addition, psychological factors, the side effects of medications and physical symptoms such as fatigue, muscular weakness, menstrual changes, pain and concerns about bladder and bowel incontinence may also be involved. Since MS primarily affects young people, SD secondary to MS may have a great impact on quality of life. Thus, maintaining a healthy sexual life with MS is an important priority. The treatment of SD requires multidisciplinary teamwork and cooperation among specialists, individual patients, partners and the society. PMID- 22447200 TI - Effectiveness and adverse effects of hormonal therapy for prostate cancer: Japanese experience and perspective. AB - Recently, novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of mechanisms of castration resistance of prostate cancer. We believe that these new developments will improve hormonal therapy. On the other hand, there has been an increase in criticism of hormonal therapy, because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease. In this review, we have introduced the Japanese experience of hormonal therapy, because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy. First, we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought. Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer. Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy. We showed that the death from cardiovascular diseases in Japanese patients receiving hormonal therapy was not higher than that in the general population. However, efforts should be made to decrease the adverse effects of hormonal therapy, because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan. Managements of endocrine and metabolic dysfunction, such as diabetes mellitus, are essential. New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed. PMID- 22447201 TI - Prolonged C1 inhibitor administration improves local healing of burn wounds and reduces myocardial inflammation in a rat burn wound model. AB - In a previous study, the authors found persistent presence of acute inflammation markers such as C-reactive protein and complement factors locally in burn wounds. This persistence of acute inflammation may not only delay local burn wound healing but also have a systemic effect, for instance on the heart. Here, the effects of C1 esterase inhibitor (C1inh), an inhibitor of complement activation, on burn wound progression and the heart were analyzed in rats. Dorsal full thickness burn wounds (2 * 4 cm) were induced on female Wistar rats (n = 14). The rats were divided into two groups (n = 7): a control group (just burns) and a C1inh group. C1inh was administered daily intravenously for 14 days. The burn wound, healthy skin from the hind leg (internal control), and the heart were then fixed in formalin. Tissues were analyzed for granulation tissue formation, reepithelialization, amount and type of infiltrating inflammatory cells (granulocytes and macrophages), and inflammatory markers (complement factors C3 and C4). C1inh treatment significantly reduced the amount of granulation tissue and significantly increased reepithelialization. C1inh also significantly reduced macrophage infiltration. Burns induced infiltration of macrophages into the ventricles of the heart and remarkably also into the atria of the heart. This effect could be counteracted by C1inh. These data show that systemic treatment with C1inh acts at different levels resulting in improved healing locally in burn wounds and systemically reduced inflammation in the heart. Therefore, C1inh might be a possible therapeutic intervention for burn wound patients. PMID- 22447202 TI - Security analysis of standards-driven communication protocols for healthcare scenarios. AB - The importance of the Electronic Health Record (EHR), that stores all healthcare related data belonging to a patient, has been recognised in recent years by governments, institutions and industry. Initiatives like the Integrating the Healthcare Enterprise (IHE) have been developed for the definition of standard methodologies for secure and interoperable EHR exchanges among clinics and hospitals. Using the requisites specified by these initiatives, many large scale projects have been set up for enabling healthcare professionals to handle patients' EHRs. The success of applications developed in these contexts crucially depends on ensuring such security properties as confidentiality, authentication, and authorization. In this paper, we first propose a communication protocol, based on the IHE specifications, for authenticating healthcare professionals and assuring patients' safety. By means of a formal analysis carried out by using the specification language COWS and the model checker CMC, we reveal a security flaw in the protocol thus demonstrating that to simply adopt the international standards does not guarantee the absence of such type of flaws. We then propose how to emend the IHE specifications and modify the protocol accordingly. Finally, we show how to tailor our protocol for application to more critical scenarios with no assumptions on the communication channels. To demonstrate feasibility and effectiveness of our protocols we have fully implemented them. PMID- 22447203 TI - Smooth muscle actin-expressing stromal fibroblasts in head and neck squamous cell carcinoma: increased expression of galectin-1 and induction of poor prognosis factors. AB - Tumor stroma is an active part influencing the biological properties of malignancies via molecular cross-talk. Cancer-associated fibroblasts play a significant role in this interaction. These cells frequently express smooth muscle actin and can be classified as myofibroblasts. The adhesion/growth regulatory lectin galectin-1 is an effector for their generation. In our study, we set the presence of smooth muscle actin-positive cancer-associated fibroblasts in relation to this endogenous lectin and an in vivo competitor (galectin-3). In squamous cell carcinomas of head and neck, upregulation of galectin-1 presence was highly significantly correlated to presence of smooth muscle actin-positive cancer-associated fibroblasts in the tumor (p = 4 * 10(-8)). To pinpoint further correlations on the molecular level, we applied microarray analyses to the transcription profiles of the corresponding tumors. Significant correlations of several transcripts were detected with the protein level of galectin-1 in the cancer-associated fibroblasts. These activated genes (MAP3K2, TRIM23, PTPLAD1, FUSIP1, SLC25A40 and SPIN1) are related to known squamous-cell-carcinoma poor prognosis factors, NF-kappaB upregulation and splicing downregulation. These results provide new insights into the significance of presence of myofibroblasts in squamous cell carcinoma. PMID- 22447204 TI - Porphyrin-LEGO(r): synthesis of a hexafullereno-diporphyrin using porphyrins programmed for [4+2]-cycloaddition. AB - A hexafullereno-diporphyrinoid was obtained in a sequence of cycloaddition steps using porphyrins programmed for [4+2]-cycloaddition reactions and C(60) fullerene. PMID- 22447205 TI - Evaluation of the appendicitis inflammatory response score for patients with acute appendicitis. AB - BACKGROUND: Acute appendicitis is still a difficult diagnosis. Scoring systems are designed to aid in the clinical assessment of patients with acute appendicitis. The Alvarado score is the most well known and best performing in validation studies. The purpose of the present study was to externally validate a recently developed appendicitis inflammatory response (AIR) score and compare it to the Alvarado score. METHODS: The present study selected consecutive patients who presented with suspicion of acute appendicitis between 2006 and 2009. Variables necessary to evaluate the scoring systems were registered. The diagnostic performance of the two scores was compared. RESULTS: The present study included 941 consecutive patients with suspicion of acute appendicitis. There were 410 male patients (44%) and 531 female patients (56%). The area under the receiver operating characteristic curve of the AIR score was 0.96 and significantly better than the area under the curve of 0.82 of the Alvarado score (p < 0.05). The AIR score also outperformed the Alvarado score when analyzing the more difficult patients, including women, children, and the elderly. CONCLUSIONS: This study externally validates the AIR Score for patients with acute appendicitis. The scoring system has a high discriminating power and outperforms the Alvarado score. PMID- 22447206 TI - Optical coherence tomography-based evaluation of malapposed strut coverage after drug-eluting stent implantation. AB - Minimal data exist regarding the use of optical coherence tomography (OCT) to evaluate malapposed strut coverage following implantation of drug-eluting stents (DESs). Follow-up OCT examination after DES implantation was performed in 368 patients with 406 lesions at our institute. We assessed the status of malapposed strut coverage that was identified via OCT in 92 (23 %) lesions. An absence of uncovered struts among malapposed struts was defined as completely covered (CC) malapposition; the presence of uncovered struts was defined as incompletely covered (IC) malapposition. Among the 92 lesions with malapposed DES struts, CC malapposition was detected in 47 lesions (51 %). Compared to lesions with IC malapposition (n = 45, 49 %), lesions with CC malapposition showed a significantly lower percentage of uncovered struts among all the struts (14.9 +/- 14.5 vs. 4.4 +/- 8.5 %, respectively, p < 0.001) and among the other well-apposed struts without malapposition (12.7 +/- 12.8 vs. 4.5 +/- 8.7 %, respectively, p = 0.001). The degree of malapposed strut coverage was significantly different according to the type of DES; new-generation DESs such as everolimus- or zotarolimus-eluting stents showed a higher incidence of CC malapposition, compared to first-generation DESs such as sirolimus- or paclitaxel-eluting stents (82 vs. 34 %, respectively, p < 0.001). This study showed the complete coverage in about 50 % of the lesions with malapposed DES struts on follow-up OCT. The degree of malapposed DES strut coverage was strongly affected by the type of implanted DESs. PMID- 22447207 TI - Management of chylous fistula after neck dissection using negative-pressure wound therapy: A preliminary report. AB - Chylous fistula is a distressing complication resulting from thoracic duct injury during neck dissections. We have successfully managed chylous fistula using negative-pressure wound therapy (NPWT) in a case where all conservative treatments failed. A 60-year-old man with tongue cancer underwent subtotal glossectomy and bilateral neck dissections. On postoperative day 4, a chylous fistula with large drainage developed in the right neck. Conservative treatments were not effective, therefore, NPWT was started from postoperative day 9. The drainage volume then began to decrease, and the chylous fistula was closed 6 days after starting NPWT. In our case, the effects of wound shrinkage and fluid removal by NPWT were considered to contribute to early closure. Although preliminary, NPWT can be an important treatment choice for the management of a chylous fistula after neck dissections. PMID- 22447208 TI - Implications of cleaved caspase 3 and AIF expression in colorectal cancer based on patient age. AB - A high incidence of colorectal cancer (CRC) has been established in the elderly population. Apoptosis is a key event in maintaining colon homeostasis, both in aging as well as in cancer prevention. Here, we report that colon morphology is affected during the aging process: crypt loss (P=0.045) and increasing distances between crypts (P=0.0001678) were observed, associated with a tendency for mucosa reduction (P=0.083). In addition, our results show that apoptosis plays a determining role on the effect of aging during CRC. Increased expression of cleaved caspase 3 (the key factor implicated in the caspase-dependent pathway; P=0.026 for non-tumor tissues, P=0.0013 for tumor tissues) and AIF (implicated in the caspase-independent pathway; P=0.037) in tissue from elderly patients has been observed. Furthermore, elderly patients respond better to chemotherapy than younger ones (P=9.27 x 10(-5)). These results suggest that patient age should be taken into account to adapt treatment of CRC. PMID- 22447209 TI - Age-period-cohort analysis of chronic obstructive pulmonary disease mortality in Japan, 1950-2004. AB - BACKGROUND: We examined trends in chronic obstructive pulmonary disease (COPD) mortality in Japan. METHODS: An age-period-cohort model was used to examine trends in COPD mortality by age, time period, and birth cohort among adults aged 40 years or older from 1950 to 2004. RESULTS: During the study period, the age standardized rate of COPD mortality substantially decreased from 71.3 per 100,000 to 19.7 in men and from 41.7 to 4.3 in women. The period effects rapidly declined during the early period in both sexes. They have increased in recent years in men but have continued to decrease in women. The cohort effects began increasing in the 1865-1869 birth cohort, peaked in the 1880-1889 cohort, and decreased thereafter among the recent cohorts. CONCLUSIONS: An early decrease in the period effects might have been associated with changes in disease structure and misclassification of COPD in the early period. Changes in cohort effects might have been mostly associated with changes in cigarette consumption and smoking prevalence in the Japanese population. Changes in those effects may also be a proxy for other social changes over time. PMID- 22447210 TI - Self-reported snoring frequency and incidence of cardiovascular disease: the Circulatory Risk in Communities Study (CIRCS). AB - BACKGROUND: Although associations between snoring and cardiovascular disease have been reported in several prospective studies, there is limited evidence from Asian populations. The objective of this study was to determine if there is an association between self-reported snoring frequency and the incidence of cardiovascular disease in Japanese. METHODS: The subjects were 2350 men and 4163 women aged 40 to 69 years who lived in 3 communities in Japan. All subjects were participants in the Circulatory Risk in Communities Study (CIRCS) and were followed for 6 years. Incidence of cardiovascular disease during the follow-up period comprised events of myocardial infarction, angina pectoris, sudden cardiac death and stroke. RESULTS: During the 6-year follow-up period, 97 participants (56 men and 41 women) had cardiovascular events. After adjustment for potential confounding factors, self-reported snoring frequency was associated with an increased risk of cardiovascular events among women but not men. The hazard ratios (95% CI) for cardiovascular events were 0.9 (0.4-2.0) for sometimes snoring and 2.5 (1.0-6.1) for everyday snoring in women and 0.7 (0.3-1.3) and 1.0 (0.5-2.1), respectively, in men. Further adjustment for body mass index attenuated the association in women; the respective hazard ratios for cardiovascular events were 0.9 (0.4-1.9) and 2.1 (0.9-5.4). CONCLUSIONS: Self reported habitual snoring was associated with increased risk of cardiovascular events among Japanese women. Overweight may partly mediate this association. PMID- 22447211 TI - Epidemiologic features of Kawasaki disease in Japan: results of the 2009-2010 nationwide survey. AB - BACKGROUND: Although the number of patients and incidence rate of Kawasaki disease (KD) are increasing in Japan, the most recent epidemiologic features of KD are not known. METHODS: The 21st nationwide survey of KD was conducted in 2011 and included patients treated for the disease in 2009 and 2010. Hospitals specializing in pediatrics, and hospitals with a total of 100 or more beds and a pediatric department, were asked to report all patients with KD during the 2 survey years. RESULTS: A total of 1445 departments and hospitals reported 23,730 KD patients (10,975 in 2009 and 12,755 in 2010): 13,515 boys and 10 215 girls. The annual incidence rates were 206.2 and 239.6 per 100,000 children aged 0 to 4 years in 2009 and 2010, respectively; the 2010 rate was the highest ever reported in Japan. Monthly number of patients peaked during winter to spring months; lower peaks were noted during summer months. However, the seasonal patterns in 2009 and 2010 differed from those of previous years. The age-specific incidence rate had a monomodal distribution, with a peak during the latter half of the year of birth. The prevalences of cardiac lesions during acute KD and cardiac sequelae were higher among infants and older age groups. Despite a decrease in prevalence, the proportion of patients with giant coronary aneurysms-the most severe sequela of KD-did not substantially decrease. CONCLUSIONS: The incidence rate and number of patients with KD continue to increase in Japan. PMID- 22447212 TI - Social capital and health: a review of prospective multilevel studies. AB - BACKGROUND: This article presents an overview of the concept of social capital, reviews prospective multilevel analytic studies of the association between social capital and health, and discusses intervention strategies that enhance social capital. METHODS: We conducted a systematic search of published peer-reviewed literature on the PubMed database and categorized studies according to health outcome. RESULTS: We identified 13 articles that satisfied the inclusion criteria for the review. In general, both individual social capital and area/workplace social capital had positive effects on health outcomes, regardless of study design, setting, follow-up period, or type of health outcome. Prospective studies that used a multilevel approach were mainly conducted in Western countries. Although we identified some cross-sectional multilevel studies that were conducted in Asian countries, including Japan, no prospective studies have been conducted in Asia. CONCLUSIONS: Prospective evidence from multilevel analytic studies of the effect of social capital on health is very limited at present. If epidemiologic findings on the association between social capital and health are to be put to practical use, we must gather additional evidence and explore the feasibility of interventions that build social capital as a means of promoting health. PMID- 22447213 TI - A randomized controlled trial of short and standard-length consent forms for a genetic cohort study: is longer better? AB - BACKGROUND: Although the amount of detail in informed consent documents has increased over time and the documents have therefore become very long, there is little research on whether longer informed consent documents actually result in (1) better informed research subjects or (2) higher consent rates. We therefore conducted an add-on randomized controlled trial to the Takashima Study, a prospective Japanese population-based genetic cohort study, to test the hypothesis that a shorter informed consent form would satisfy both of the above goals. METHODS: Standard (10 459 words, 11 pages) and short (3602 words, 5 pages) consent forms in Japanese were developed and distributed using cluster randomization to 293 potential cohort subjects living in 9 medico-social units and 288 subjects in 8 medico-social units, respectively. RESULTS: Few differences were found between the 2 groups with regard to outcome measures, including participants' self-perceived understanding, recall of information, concerns, voluntariness, trust, satisfaction, sense of duty, and consent rates. CONCLUSIONS: A short informed consent form was no less valid than a standard form with regard to fulfilling ethical requirements and securing the scientific validity of research. PMID- 22447214 TI - Analysis of colorectal adenocarcinoma tissue by desorption electrospray ionization mass spectrometric imaging. AB - Negative ion desorption electrospray ionization (DESI) was used for the analysis of an ex vivo tissue sample set comprising primary colorectal adenocarcinoma samples and colorectal adenocarcinoma liver metastasis samples. Frozen sections (12 MUm thick) were analyzed by means of DESI imaging mass spectrometry (IMS) with spatial resolution of 100 MUm using a computer-controlled DESI imaging stage mounted on a high resolution Orbitrap mass spectrometer. DESI-IMS data were found to predominantly feature complex lipids, including phosphatidyl-inositols, phophatidyl-ethanolamines, phosphatidyl-serines, phosphatidyl-ethanolamine plasmalogens, phosphatidic acids, phosphatidyl-glycerols, ceramides, sphingolipids, and sulfatides among others. Molecular constituents were identified based on their exact mass and MS/MS fragmentation spectra. An identified set of molecules was found to be in good agreement with previously reported DESI imaging data. Different histological tissue types were found to yield characteristic mass spectrometric data in each individual section. Histological features were identified by comparison to hematoxylin-eosin stained neighboring sections. Ions specific to certain histological tissue types (connective tissue, smooth muscle, healthy mucosa, healthy liver parenchyma, and adenocarcinoma) were identified by semi-automated screening of data. While each section featured a number of tissue-specific species, no potential global biomarker was found in the full sample set for any of the tissue types. As an alternative approach, data were analyzed by principal component analysis (PCA) and linear discriminant analysis (LDA) which resulted in efficient separation of data points based on their histological types. A pixel-by-pixel tissue identification method was developed, featuring the PCA/LDA analysis of authentic data set, and localization of unknowns in the resulting 60D, histologically assigned LDA space. Novel approach was found to yield results which are in 95% agreement with the results of classical histology. KRAS mutation status was determined for each sample by standard molecular biology methods and a similar PCA/LDA approach was developed to assess the feasibility of the determination of this important parameter using solely DESI imaging data. Results showed that the mutant and wild-type samples fully separated. DESI-MS and molecular biology results were in agreement in 90% of the cases. PMID- 22447215 TI - Rapid detection and quantification of 35 benzodiazepines in urine by GC-TOF-MS. AB - A rapid and sensitive method for the screening and quantification of 35 benzodiazepines in human urine by gas chromatography/time-of-flight mass spectrometry was developed and validated. Target analytes were isolated from 1 ml urine by solid-phase extraction using Oasis MCX extraction columns (extraction recovery between 35 and 99%). With a supported liquid-liquid extraction method, a new modification of conventional liquid-liquid-extraction, a less time intensive alternative for benzodiazepine extraction is presented. The sample pretreatment entails the derivatization of the benzodiazepines with N,O bis(trimethylsilyl)trifluoroacetamide plus 1% trimethylchlorosilane. Separation of all benzodiazepines was done within 9.5 min, and detection was based on full mass spectra for each analyte. A deconvolution algorithm was used for unresolved chromatographic peaks to identify coeluted substances. The subsequent quantification was done using significant masses. The limit of quantification is 10 ng/ml for most of the compounds. Linearity is in the range between 10 and 350 ng/ml. Reproducibility was observed with coefficients of variation below 2% at concentrations of 50 and 200 ng/ml. The accuracy is between 88 and 108% depending on the respective analyte and the concentration. PMID- 22447216 TI - Au:CdHgTe quantum dots for in vivo tumor-targeted multispectral fluorescence imaging. AB - Near-infrared gold-doped CdHgTe quantum dots (QDs) with improved photoluminescence and biocompatibility were developed using an aqueous solution route with L-glutathione and L-cysteine as stabilizers. As-prepared Au:CdHgTe QDs were covalently linked to arginine-glycine-aspartic acid (RGD) peptide, anti epidermal growth factor receptor (EGFR) monoclonal antibody (MAb), and anti- carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) MAb separately. Three Au:CdHgTe QD bioconjugates (QD800-RGD, QD820-anti-CEACAM1, and QD840-anti-EGFR) were successfully used as probes for in vivo tumor-targeted multispectral fluorescence imaging of xenografts. Fluorescence signals from the QD bioconjugates used to detect three tumor markers were spectrally unmixed, and their co-localization was analyzed. The results indicate that multiple tumor markers could be simultaneously detected by multispectral fluorescence imaging in vivo using QD bioconjugates as probes. This approach has excellent potential as an imaging method for the noninvasive exploration and detection of multiple tumor markers in vivo, thereby substantially aiding the diagnosis of cancer. PMID- 22447217 TI - Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography/tandem mass spectrometry and their effects on endothelial ROS production. AB - Cardiovascular disease (CVD) is prevalent in patients with chronic kidney disease (CKD). In hemodialysis (HD) patients, some protein-bound uremic toxins are considered to be associated with CVD. However, it is not yet known which uremic toxins are important in terms of endothelial toxicity. Serum samples were obtained from 45 HD patients before and after HD. Total and free serum concentrations of indoxyl sulfate, indoxyl glucuronide, indoleacetic acid, p cresyl sulfate, p-cresyl glucuronide, phenyl sulfate, phenyl glucuronide, phenylacetic acid, phenylacetyl glutamine, hippuric acid, 4-ethylphenyl sulfate, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) were simultaneously measured by liquid chromatography/electrospray ionization-mass spectrometry/mass spectrometry (LC/ESI-MS/MS). The effects of these solutes at their pre-HD mean and maximum serum concentrations on reactive oxygen species (ROS) production in human umbilical vein endothelial cells (HUVEC) were measured with a ROS probe. Serum levels of 11 of the solutes (all except 4-ethylphenyl sulfate) were significantly increased in HD patients compared to healthy subjects. All 12 solutes showed changes in their protein-binding ratios. In particular, indoxyl sulfate, p-cresyl sulfate, CMPF, and 4-ethylphenyl sulfate showed high protein binding ratios (>95 %) and low reduction rates by HD (<35 %). Indoxyl sulfate at its mean and maximum pre-HD serum concentrations-even with 4 % albumin-stimulated ROS production in HUVEC most intensely, followed by CMPF. In conclusion, the serum levels of 11 protein-bound uremic toxins were increased in HD patients. Indoxyl sulfate, p-cresyl sulfate, and CMPF could not be removed efficiently by HD due to their high protein-binding ratios. Indoxyl sulfate most intensely induced endothelial ROS production, followed by CMPF. PMID- 22447218 TI - Characterisation of historic plastics using terahertz time-domain spectroscopy and pulsed imaging. AB - Terahertz (THz) time-domain spectroscopy and 3D THz pulsed imaging have been explored with regard to polymer materials, both commodity and historic polymers. A systematic spectroscopic study of a wide range of different polymer materials showed significant differences in their spectra. Polyolefins and polystyrenes generally exhibit lower absorption than other examined polymers, various cellulose derivates, poly(vinyl chloride), poly(methyl methacrylate), polyamide, hard rubber and phenol formaldehyde resin, the last of these exhibiting the most intense absorption over the entire range, 0.15-4.2 THz. It was also examined how the presence of plasticisers in poly(vinyl chloride), the presence of fillers in polypropylene, and the degree of branching in polyethylene and polystyrene affect the spectra; inorganic fillers in polypropylene affected the absorption most. With 3D THz pulsed imaging, features in polymer objects were explored, appearing either as integral parts of the material (coatings and pores in foams) or as a consequence of physical deterioration (cracks, delamination). All of these features of various complexities can be successfully imaged in 3D. Terahertz technology is thus shown to have significant potential for both chemical and structural characterisation of polymers, which will be of interest to heritage science, but also to the polymer industry and development of analytical technologies in general. PMID- 22447219 TI - Towards a human proteomics atlas. AB - Proteomics research has taken up an increasingly important role in life sciences over the past few years. Due to a strong push from publishers and funders alike, the community has also started to freely share its data in earnest, making use of public repositories such as the highly popular PRIDE database at EMBL-EBI. Reuse of these publicly available data has so far been confined to rather specific, targeted reanalyses, but this limited reuse is set to expand dramatically as repositories continue to grow exponentially. Examples of large-scale reuse are readily found in other omics disciplines, where more comprehensive public data have already accumulated over longer periods. Here, a typical example of integrative data reuse is provided by the construction of so-called expression atlases. We here therefore investigate the issues involved in using the human data currently stored in the PRIDE database to construct a robust, tissue specific protein expression atlas from tandem-MS based label-free quantification. PMID- 22447220 TI - Isolation and characterization of dimethyl sulfide (DMS)-degrading bacteria from soil and biofilter treating waste gas containing DMS from the laboratory and pulp and paper industry. AB - Dimethyl sulfide (DMS) is one of the sulfurous pollutants present in the waste gas generated from the pulp and paper industry. DMS has environmental health implications; therefore, it is necessary to treat the waste gas containing DMS prior to discharge into the environment. A bench-scale biofilter was operated in the laboratory as well as in a pulp and paper industry for the treatment of DMS. Both the biofilters were packed with pre-sterilized wood chips and cow dung/compost of the same origin seeded with biomass developed from garden soil enriched with DMS. The biofilters were operated for the generation of process parameters, and the potential microorganisms isolated from both the biofilters have been purified and characterized for degradation of DMS. Further, these cultures were purified on a basal medium using DMS as a sole carbon source for the growth. Further, the purified cultures were characterized through standard fatty acid methyl esters (FAME)-gas chromatography method, and the isolates were found to be mesophilic, aerobic microbes. These microbes were identified as Bacillus sphaericus-GC subgroup F, Paenibacillus polymyxa, B. sphaericus-GC subgroup F, B. sphaericus-GC subgroup F, and Bacillus megaterium-GC subgroup A, respectively. The potential culture for degradation of DMS was identified as B. sphaericus by 16s rRNA molecular analysis. PMID- 22447221 TI - Biodegradation of a keratin waste and the concomitant production of detergent stable serine proteases from Paecilomyces lilacinus. AB - Paecilomyces lilacinus (LPS 876) efficiently degraded keratin in chicken feather during submerged cultivation producing extracellular proteases. Characterization of crude protease activity was done including its compatibility in commercial detergents. Optimum pH and temperature were 10.0 and 60 degrees C, respectively. Protease activity was enhanced by Ca2+ but was strongly inhibited by PMSF and by Hg2+ suggesting the presence of thiol-dependent serine proteases. The crude protease showed extreme stability toward non-ionic (Tween 20, Tween 85, and Triton X-100) and anionic (SDS) surfactants, and relative stability toward oxidizing agent (H2O2 and sodium perborate). In addition, it showed excellent stability and compatibility with various solid and liquid commercial detergents from 30 to 50 degrees C. The enzyme preparation retained more than 95% of its initial activity with solid detergents (ArielTM and DriveTM) and 97% of its original activity with a liquid detergent (AceTM) after pre-incubation at 40 degrees C. The protective effect of polyols (propylene glycol, PEG 4000, and glycerol) on the heat inactivation was also examined and the best results were obtained with glycerol from 50 to 60 degrees C. Considering its promising properties, P. lilacinus enzymatic preparation may be considered as a candidate for use in biotechnological processes (i.e., as detergent additive) and in the processing of keratinous wastes. PMID- 22447222 TI - Chronic cardiotoxicity of doxorubicin involves activation of myocardial and circulating matrix metalloproteinases in rats. AB - AIM: To investigate the role of matrix metalloproteinases (MMPs) in the responses of rats to a prolonged doxorubicin (DOX) treatment. METHODS: Male Wistar rats were used. DOX was administered by intraperitoneal injections of seven doses (cumulative dose was 15 mg/kg). Control animals were treated with saline. Tissue or plasma samples were collected at four and eight weeks after the application of the last dose. Protein levels were determined by immunoblot assay, and MMP activities were measured by gelatin zymography. Superoxide content was analyzed using a lucigenin chemiluminescence assay and superoxide dismutase (SOD) activities with a SOD assay kit. Qualitative structural alterations of the heart were characterized by transmission electron microscopy. RESULTS: Systolic blood pressure was higher in DOX-treated rats as compared with the control rats at 8 weeks after treatment. In contrast, there were no differences in the heart rate between the control and DOX-treated rats. DOX treatment caused marked heterogeneous subcellular alterations of cardiomyocytes and structural disorganizations of the cardiac extracellular space. The effects of DOX were linked to a stimulation of plasma MMP-2 and MMP-9 activities that had already increased by 4 weeks after the end of the treatment. In the left ventricle, however, DOX only led to increased MMP-2 activation at 8 weeks after the end of treatment. These changes in tissue MMP-2 were connected with stimulation of Akt kinase activation, inhibition of SOD, an increase in superoxide levels, induction of iNOS protein expression and caspase-3 activation. CONCLUSION: Our results show that MMPs are involved in the chronic cardiotoxicity of DOX in rats. The data also suggest that reactive oxygen species (superoxide), NO production (iNOS) and the Akt kinase pathway can modulate MMP-2 activities in rat hearts influenced by DOX. PMID- 22447223 TI - Sirt1 overexpression protects murine osteoblasts against TNF-alpha-induced injury in vitro by suppressing the NF-kappaB signaling pathway. AB - AIM: Sirtuin 1 (Sirt1) is the class III histone/protein deacetylase that interferes with the NF-kappaB signaling pathway, thereby has anti-inflammatory function. This study was undertaken to investigate whether Sirt1 could protect osteoblasts against TNF-alpha-induced injury in vitro. METHODS: Murine osteoblastic cell line, MC3T3-E1, was used. Overexpress of Sirt1 protein in MC3T3 E1 cells was made by transfection the cells with Sirt1-overexpressing adenovirus. The levels of mRNAs and proteins were determined with qRT-PCR and Western blotting, respectively. The activity of NF-kappaB was examined using NF-kappaB luciferase assay. The NO concentration was measured using the Griess method. RESULTS: Treatment of MC3T3-E1 cells with TNF-alpha (2.5-10 ng/mL) suppressed Sirt1 protein expression in a concentration-dependent manner. TNF-alpha (5 ng/mL) resulted in an increase in apoptosis and a reduction in ALP activity in the cells. Overexpression of Sirt1 in the cells significantly attenuated TNF-alpha induced injury through suppressing apoptosis, increasing ALP activity, and increasing the expression of Runx2 and osteocalcin mRNAs. Furthermore, overexpression of Sirt1 in the cells significantly suppressed TNF-alpha-induced NF-kappaB activation, followed by reducing the expression of iNOS and NO formation. Sirt1 activator resveratrol (10 MUmol/L) mimicked the protection of the cells by Sirt1 overexpression against TNF-alpha-induced injury, which was reversed by the Sirt1 inhibitor EX-527 (5 MUmol/L). CONCLUSION: Overexpression of Sirt1 protects MC3T3-E1 osteoblasts aganst TNF-alpha-induced cell injury in vitro, at least in part, via suppressing NF-kappaB signaling. Sirt1 may be a novel therapeutic target for treating rheumatoid arthritis-related bone loss. PMID- 22447224 TI - Chronic ethanol consumption increases the levels of chemerin in the serum and adipose tissue of humans and rats. AB - AIM: Chemerin is a new adipokine involved in adipogenesis and insulin resistance. Since ethanol affects the insulin sensitivity that is closely associated with adipokines. The aim of this study was to investigate the effects of ethanol on chemerin in humans and rats. METHODS: In the human study, 148 men who consumed alcohol for more than 3 years and 55 men who abstained from alcohol were included. Based on ethanol consumption per day, the drinkers were classified into 3 groups: low-dose (<15 g/d), middle-dose (15-47.9 g/d) and high-dose (>=48 g/d). Anthropometric measurements and serum parameters were collected. In the rat study, 27 male Wistar rats were randomly divided into 4 groups administered water or ethanol (0.5, 2.5, or 5 g.kg(-1).d(-1)) for 22 weeks. The chemerin levels in the sera, visceral adipose tissue (VAT) and liver were measured using ELISA. RESULTS: In the high-dose group of humans and middle- and high-dose groups of rats, chronic ethanol consumption significantly increased the serum chemerin level. Both the middle- and high-dose ethanol significantly increased the chemerin level in the VAT of rats. In humans, triglyceride, fasting glucose, insulin and HOMA-IR were independently associated with chemerin. In rats, the serum chemerin level was positively correlated with chemerin in the VAT after adjustments for the liver chemerin (r=+0.768). High-dose ethanol significantly increased the body fat in humans and the VAT in rats. CONCLUSION: Chronic ethanol consumption dose-dependently increases the chemerin levels in the serum and VAT. The serum chemerin level is associated with metabolic parameters in humans. The increased serum chemerin level is mainly attributed to an elevation of chemerin in the VAT after the ethanol treatment. PMID- 22447225 TI - Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate induced cognitive deficits in mice and apoptosis in SH-SY5Y cells. AB - AIM: To investigate whether asiatic acid (AA), a pentacyclic triterpene in Centella asiatica, exerted neuroprotective effects in vitro and in vivo, and to determine the underlying mechanisms. METHODS: Human neuroblastoma SH-SY5Y cells were used for in vitro study. Cell viability was determined with the MTT assay. Hoechst 33342 staining and flow cytometry were used to examine the apoptosis. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured using fluorescent dye. PGC-1alpha and Sirt1 levels were examined using Western blotting. Neonatal mice were given monosodium glutamate (2.5 mg/g) subcutaneously at the neck from postnatal day (PD) 7 to 13, and orally administered with AA on PD 14 daily for 30 d. The learning and memory of the mice were evaluated with the Morris water maze test. HE staining was used to analyze the pyramidal layer structure in the CA1 and CA3 regions. RESULTS: Pretreatment of SH-SY5Y cells with AA (0.1-100 nmol/L) attenuated toxicity induced by 10 mmol/L glutamate in a concentration-dependent manner. AA 10 nmol/L significantly decreased apoptotic cell death and reduced reactive oxygen species (ROS), stabilized the mitochondrial membrane potential (MMP), and promoted the expression of PGC-1alpha and Sirt1. In the mice models, oral administration of AA (100 mg/kg) significantly attenuated cognitive deficits in the Morris water maze test, and restored lipid peroxidation and glutathione and the activity of SOD in the hippocampus and cortex to the control levels. AA (50 and 100 mg/kg) also attenuated neuronal damage of the pyramidal layer in the CA1 and CA3 regions. CONCLUSION: AA attenuates glutamate-induced cognitive deficits of mice and protects SH-SY5Y cells against glutamate-induced apoptosis in vitro. PMID- 22447226 TI - FoxM1 mediated resistance to gefitinib in non-small-cell lung cancer cells. AB - AIM: Gefitinib is effective in only approximately 20% of patients with non-small cell lung cancer (NSCLC), and the underlying mechanism remains unclear. FoxM1 is upregulated in NSCLC and associated with a poor prognosis in NSCLC patients. In this study, we examined the possible role of FoxM1 in gefitinib resistance and the related mechanisms. METHODS: Gefitinib resistant human lung adenocarcinoma cell line SPC-A-1 and gefitinib-sensitive human lung mucoepidermoid carcinoma cell line NCI-H292 were used. mRNA and protein expression of FoxM1 and other factors were tested with quantitative RT PCR and Western blot analysis. RNA interference was performed to suppress FoxM1 expression in SPC-A-1 cells, and lentiviral infection was used to overexpress FoxM1 in H292 cells. MTT assay and flow cytometry were used to examine the proliferation and apoptosis of the cells. RESULTS: Treatment of SPC-A-1 cells with gefitinib (1 and 10 MUmol/L) upregulated the expression of FoxM1 in time- and concentration-dependent manners, while gefitinib (1 MUmol/L) downregulated in H292 cells. In SPC-A-1 cells treated with gefitinib (1 MUmol/L), the expression of several downstream targets of FoxM1, including survivin, cyclin B1, SKP2, PLK1, Aurora B kinase and CDC25B, were significantly upregulated. Overexpression of FoxM1 increased the resistance in H292 cells, while attenuated FoxM1 expression restored the sensitivity to gefitinib in SPC-A-1 cells by inhibiting proliferation and inducing apoptosis. CONCLUSION: The results suggest that FoxM1 plays an important role in the resistance of NSCLC cells to gefitinib in vitro. FoxM1 could be used as a therapeutic target to overcome the resistance to gefitinib. PMID- 22447228 TI - Evaluation of endoscopic harmonic diverticulostomy. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study is to review a consecutive series of patients with Zenker's diverticulum who were treated with endoscopic diverticulostomy using either the endoscopic stapler (ENDO GIA 30 Autosuture; Covidien, Dublin, Ireland) or Harmonic Ultrasonic Surgical Instrumentation (Ethicon Endo-Surgery, Cincinnati, OH) to evaluate the safety and optimal application of Harmonic technology to the treatment of patients with Zenker's diverticulum. STUDY DESIGN: This is a retrospective review at a tertiary academic hospital with institutional review board approval. METHODS: All patients undergoing endoscopic repair of Zenker's diverticulum between April 1, 2009 and December 1, 2010 at a single institution were studied. RESULTS: A total of 65 endoscopic diverticulostomies were performed: 24 Harmonic assisted, 41 stapler assisted. Average diverticulum size was 3.46 cm. There were two complications with staple-assisted (pharyngeal leak and recurrence) and six complications with Harmonic-assisted diverticulostomies (two pharyngeal leaks, two chest pains, one recurrence, and one subcutaneous emphysema). There was a statistically significant difference in the complication rates between the staple-assisted (4.88%) and Harmonic-assisted (25%) cohorts (P = .04). There were no complications with diverticula <2 cm. CONCLUSIONS: Endoscopic Harmonic esophagodiverticulostomy has been reported for the treatment of Zenker's diverticula. However, our data demonstrate a significantly higher complication rate with use of the Harmonic technology compared to the staple-assisted method (P = .04). Additional evaluations are warranted to validate these findings and before Harmonic diverticulostomy can be recommended as treatment for the majority of cases. PMID- 22447229 TI - Arterial stiffness: basic concepts and measurement techniques. AB - Arterial stiffness is highly relevant to cardiovascular disease. Arterial stiffness is central to the pathogenesis of isolated systolic hypertension and directly impacts left ventricular afterload, pressure pulsatility in the arterial tree, and its penetration into the microvasculature of target organs such as the brain and kidney. Arterial stiffness is affected by various risk factors and biologic processes. Measurements of arterial stiffness may therefore not only provide information about prevalent processes, but also valuable information regarding the cumulative history of risk factor exposure. Available studies consistently demonstrate that large artery stiffness, measured via carotid femoral pulse wave velocity, independently predicts the risk of incident cardiovascular events in clinical and community-based cohorts. Understanding the basic principles and definitions related to arterial stiffness is therefore desirable for cardiovascular clinicians and researchers. This introductory paper reviews basic physical principles and definitions regarding arterial stiffness and the most important non-invasive methods for its quantification in vivo. PMID- 22447230 TI - Haptoglobin genotype and its role in diabetic cardiovascular disease. AB - Over the past decade, several longitudinal epidemiological studies have brought attention to the haptoglobin genotype and its importance in determining diabetic vascular disease risk. This manuscript presents an overview of the biology of the haptoglobin genotype and reviews the literature concerning its role in the development of cardiovascular disease among individuals with diabetes mellitus. PMID- 22447231 TI - Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma. AB - Ovarian clear cell carcinoma (OCCC) has several significant characteristics based on molecular features that are distinct from those of ovarian high-grade serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature of OCCC and in the present study its metabolic mechanism was investigated. The amount of glycogen in cells cultured under hypoxia increased significantly and approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions. Periodic acid-Schiff positive staining also demonstrated intracellular glycogen storage. Western blot analysis revealed that HIF1alpha, which was overexpressed and stabilized under hypoxic conditions, led to an increase in the levels of cellular glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme activity, and glycogen synthase kinase 3 beta (GSK3beta) phosphorylated at Ser9, which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme activity. By contrast, the level of PYGM-b decreased. These results indicated that the glycogen accumulation under a hypoxic environment resulted in the promotion of glycogen synthesis, but did not lead to inhibition of glycogen degradation and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic subunit p110alpha of PI3K. The resulting activation of AKT (phosphoSer473) also plays a role as a central enhancer in glycogen synthesis through suppression of GSK3beta via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin and doxorubicin to various degrees. In conclusion, the hypoxic conditions together with HIF1 expression and stabilization increased the intracellular glycogen contents and resistance to the anticancer drugs. PMID- 22447232 TI - Current concepts in MR and CT arthrography. PMID- 22447233 TI - MR and CT arthrography of the shoulder. AB - The combined use of shoulder arthrography with MR and CT imaging offers distinct advantages over conventional nonarthrographic imaging techniques. The improved contrast and joint distension afforded by direct arthrography optimize evaluation of various intra-articular structures and help to define subtle abnormalities and distinguish normal variants from true shoulder pathology. In this article, we review the rationale and basic approaches to shoulder arthrography as well as the imaging appearance of the normal shoulder, anatomical variants, and pathology highlighted by this technique. PMID- 22447234 TI - MR and CT arthrography of the elbow. AB - Magnetic resonance (MR) arthrography has, to a great extent, replaced conventional and CT arthrography as the standard of care imaging tool for indications including medial elbow pain in the throwing athlete, chondral and osteochondral lesions in the elbow, and intra-articular bodies. There are still rare specific incidences where CT arthrography is indicated. This article reviews elbow arthrography, with a greater emphasis placed on MR arthrography, including indications, technique, potential complications, contraindications, equipment, and MR arthrographic pathologies. PMID- 22447235 TI - MR and CT arthrography of the wrist. AB - The study of the wrist represents a major diagnostic challenge because of its complex anatomy and the small size of individual structures. Recent advances in imaging techniques have increased our diagnostic capabilities. However, 3T magnets, multichannel specific wrist coils, and new MRI sequences have not restricted the indications of arthrographic imaging techniques (CT arthrography and MR arthrography). Distension of the different wrist compartments at CT arthrography and MR arthrography significantly improves the diagnostic accuracy for triangular fibrocartilage (TFC) complex injuries and carpal instability. Dedicated multichannel wrist coils are essential for an adequate study of the wrist, but the placement of these coils and the positioning of the wrist are also important for proper diagnosis. The development of dynamic multislice CT studies allows a diagnostic approach that combines dynamic information and the accurate assessment of ligaments and the TFC complex. New advances in arthroscopy have changed the anatomical description of the TFC with a functional division in the proximal and distal TFC complex, and they have allowed a better characterization of lesions of the TFC complex with subclassification of Palmer 1B and 1D lesions and description of new lesions not included in the Palmer classification, such as capsular injuries. PMID- 22447236 TI - MR and CT arthrography of the hip. AB - CT arthrography (CTa) and MR arthrography (MRa) are useful tools for the investigation of intra-articular hip disease. They are minimally invasive techniques with a very low rate of complications and can be performed safely. CTa or MRa can be performed after an intra-articular injection of diluted contrast, but both techniques can also be performed after a single injection. As radiologists we should be able to address the surgeon's questions and work together to standardize terminology and classifications systems for accurate reporting. This update emphasizes radiological findings with a clinical perspective. CTa and MRa allow the precise diagnosis of labral tears, loose bodies, and intra-articular ligaments (capsular and ligamentum teres). The use of careful technique and a tailored protocol has improved our ability to detect and describe cartilage lesions. This is essential because knowledge of the status of the cartilage may dictate a specific surgical approach, and when cartilage lesions are extensive, they are a negative prognostic indicator for arthroscopic treatment. PMID- 22447237 TI - MR and CT arthrography of the knee. AB - MR and CT arthrography are important imaging modalities for the assessment of the knee in certain situations. Indications for MR arthrography of the knee include assessment of the postoperative meniscus, the presence of chondral and osteochondral lesions, and the presence of intra-articular bodies. The major indication for CT arthrography is evaluating suspected internal derangement in patients who are unable to undergo MRI. In addition to reviewing the established clinical indications for MR and CT arthrography of the knee, the commonly used techniques, normal variants that can simulate disease, and the most commonly found pathologies that can be diagnosed with these modalities are discussed. Potential indications that are not currently well established in the literature including the evaluation of anterior cruciate ligament injury and autologous chondrocyte implants are examined. Where appropriate, the literature on controversial topics or diagnoses is reviewed. The use of conventional imaging versus CT and MR arthrography is also compared. PMID- 22447238 TI - Computational and experimental studies of the electronic excitation spectra of EDTA and DTPA substituted tetraphenylporphyrins and their Lu complexes. AB - Ethylendiaminetetraacetic acid (EDTA) substituted and diethylenetriaminopentaacetic acid (DTPA) substituted aminated free-base tetraphenylporphyrins (H2ATPP) and the corresponding lutetium(III) complexes have been studied computationally at the density functional theory (DFT) and second order algebraic diagrammatic construction (ADC(2)) levels using triple-xi basis sets augmented with polarization functions. The molecular structures were optimized using Becke's three-parameter hybrid functional (B3LYP). The electronic excitation spectra in the range of 400-700 nm were calculated using the ADC(2) and the linear-response time-dependent DFT methods. The calculated spectra are compared to those measured in ethanol solution. The calculated excitation energies agree well with those deduced from the experimental spectra. The excitation energies for the Qx band calculated at the B3LYP and ADC(2) level are 0.20-0.25 eV larger than the experimental values. The excitation energies for the Qy band calculated at the B3LYP level are 0.10-0.20 eV smaller than the ADC(2) ones and are thus in good agreement with experiment. The calculated excitation energies corresponding to the Bx and By bands are 0.10-0.30 eV larger than the experimental values. The excitation energies of the Bx and By bands calculated at the B3LYP level are in somewhat better agreement with experiment than the ADC(2) ones. The calculated and measured band strengths largely agree. PMID- 22447239 TI - CYP450-dependent biotransformation of the insecticide fipronil into fipronil sulfone can mediate fipronil-induced thyroid disruption in rats. AB - In rats, the widely used insecticide fipronil increases the clearance of thyroxine (T(4)). This effect is associated with a high plasma concentration of fipronil sulfone, the fipronil main metabolite in several species including rats and humans. In sheep, following fipronil treatment, fipronil sulfone plasma concentration and thyroid disruption are much lower than in rats. We postulated that fipronil biotransformation into fipronil sulfone by hepatic cytochromes P450 (CYP) could act as a potential thyroid disruptor. The aim of this study was to determine if fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and CYP induction in rats. Fipronil and fipronil sulfone treatments (3.4 MUmol/kg/day per os, 14 days) increased total and free T(4) clearances to the same extent in THX + T(3), euthyroid-like rats. Both treatments induced a 2.5-fold increase in Ugt1a1 and Sult1b1 messenger RNA (mRNA) expressions and a twofold increase in UGT1A activity suggesting that T(4) elimination was mediated, at least in part, by hepatic uridine 5'-diphospho glucuronosyltransferases (UGT) and/or sulfotransferases (SULT) induction. Both treatments induced a 10-fold increase in Cyp3a1 and Cyp2b2 mRNA expressions concomitant with a threefold increase in CYP3A immunoreactivity and a 1.7-fold increase in antipyrine clearance, a biomarker of CYP3A activity. All these results showed that fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and hepatic enzyme induction in rats. The potential of fipronil sulfone to act as a thyroid disruptor is all the more critical because it persists much longer in the organism than fipronil itself. PMID- 22447240 TI - Effortful swallowing training combined with electrical stimulation in post-stroke dysphagia: a randomized controlled study. AB - We tested the effect of effortful swallow combined with surface electrical stimulation used as a form of resistance training in post-stroke patients with dysphagia. Twenty post-stroke dysphagic patients were randomly divided into two groups: those who underwent effortful swallow with infrahyoid motor electrical stimulation (experimental group, n = 10) and effortful swallow with infrahyoid sensory electrical stimulation (control group, n = 10). In the experimental group, electrical stimulation was applied to the skin above the infrahyoid muscle with the current was adjusted until muscle contraction occurred and the hyoid bone was depressed. In the control group, the stimulation intensity was applied just above the sensory threshold. The patients in both groups were then asked to swallow effortfully in order to elevate their hyolaryngeal complex when the stimulation began. A total of 12 sessions of 20 min of training for 4 weeks were performed. Blinded biomechanical measurements of the extent of hyolaryngeal excursion, the maximal width of the upper esophageal sphincter (UES) opening, and the penetration-aspiration scale before and after training were performed. In the experimental group, the maximal vertical displacement of the larynx was increased significantly after the intervention (p < 0.05). The maximal vertical displacement of the hyoid bone and the maximal width of the UES opening increased but the increase was not found to be significant (p = 0.066). There was no increase in the control group. Effortful swallow training combined with electrical stimulation increased the extent of laryngeal excursion. This intervention can be used as a new treatment method in post-stroke patients with dysphagia. PMID- 22447241 TI - Management of acute coronary syndrome in South Africa: insights from the ACCESS (Acute Coronary Events - a Multinational Survey of Current Management Strategies) registry. AB - BACKGROUND: The burden of cardiovascular diseases is predicted to escalate in developing countries. While many studies have reported the descriptive epidemiology, practice patterns and outcomes of patients hospitalised with acute coronary syndromes (ACS), these have largely been confined to the developed nations. METHODS: In this prospective, observational registry, 12 068 adults hospitalised with a diagnosis of ACS were enrolled between January 2007 and January 2008 at 134 sites in 19 countries in Africa, Latin America and the Middle East. Data on patient characteristics, treatment and outcomes were collected. RESULTS: Of the 642 patients from South Africa in the registry, 615 had a confirmed ACS diagnosis and form the basis of this report; 41% had a discharge diagnosis of ST-segment elevation myocardial infarction (STEMI) and 59% a diagnosis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS), including 32% with non-ST-segment elevation myocardial infarction (NSTEMI) and 27% with unstable angina (UA). During hospitalisation, most patients received aspirin (94%) and a lipid-lowering medication (91%); 69% received a beta-blocker, and 66% an ACE inhibitor/angiotensin receptor blocker. Thrombolytic therapy was used in only 18% of subjects (36% of STEMI patients and 5.5% of NSTE-ACS patients). Angiography was undertaken in 93% of patients (61.3% on the first day), of whom 53% had a percutaneous coronary intervention (PCI) and 14% were referred for coronary artery bypass surgery. Drug-eluting stents were used in 57.9% of cases. Clopidogrel was prescribed at discharge from hospital in 62.2% of patients. All-cause death at 12 months was 5.7%, and was higher in patients with STEMI versus non-ST-elevation ACS (6.7 vs 5.0%, p < 0.0001). Clinical factors associated with higher risk of death at 12 months included age >= 70 years, presence of diabetes mellitus on admission, and a history of stroke/transient ischaemic attack (TIA). CONCLUSIONS: In this observational study of ACS patients, the use of evidence-based pharmacological therapies for ACS was quite high. Interventional rates were high compared to international standards, and in particular the use of drug-eluting stents, yet the clinical outcomes (mortality, re-admission rates and severe bleeding episodes at one year) were favourable, with low rates compared with other studies. PMID- 22447242 TI - Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation. AB - ATP-binding cassette (ABC) transporters shuttle a wide variety of molecules across cell membranes by alternating between inward- and outward-facing conformations, harnessing the energy of ATP binding and hydrolysis at their nucleotide binding domains (NBDs). Here we present the 2.9-A crystal structure of the heterodimeric ABC transporter TM287-TM288 (TM287/288) from Thermotoga maritima in its inward-facing state. In contrast to previous studies, we found that the NBDs only partially separate, remaining in contact through an interface involving conserved motifs that connect the two ATP hydrolysis sites. We observed AMP-PNP binding to the degenerate catalytic site, which deviates from the consensus sequence in the same positions as the eukaryotic homologs CFTR and TAP1 TAP2 (TAP1/2). The TM287/288 structure provides unprecedented insights into the mechanism of heterodimeric ABC exporters and will enable future studies on this large transporter superfamily. PMID- 22447243 TI - Structure of the ternary initiation complex aIF2-GDPNP-methionylated initiator tRNA. AB - Eukaryotic and archaeal translation initiation factor 2 (e/aIF2) is a heterotrimeric GTPase that has a crucial role in the selection of the correct start codon on messenger RNA. We report the 5-A resolution crystal structure of the ternary complex formed by archaeal aIF2 from Sulfolobus solfataricus, the GTP analog GDPNP and methionylated initiator tRNA. The 3D model is further supported by solution studies using small-angle X-ray scattering. The tRNA is bound by the alpha and gamma subunits of aIF2. Contacts involve the elbow of the tRNA and the minor groove of the acceptor stem, but not the T-stem minor groove. We conclude that despite considerable structural homology between the core gamma subunit of aIF2 and the elongation factor EF1A, these two G proteins of the translation apparatus use very different tRNA-binding strategies. PMID- 22447244 TI - Heavy metals of the Tibetan top soils: level, source, spatial distribution, temporal variation and risk assessment. AB - OBJECTIVE: Due to its high elevation, rare human activities and proximity to south Asia where industries are highly developed, it is required to investigate the fragile environment of the Tibetan Plateau. We are aiming to obtain the concentration level, source, spatial distribution, temporal variation and potential environmental risk of Tibetan soils. METHODS: A total of 128 surf ace soil samples were collected and analyzed f or V, Cr, Mn, Co, Ni, Cu, Zn, As, Cd and Pb, and an additional 111 samples were analyzed f or Hg and total organic carbon. Concentration comparisons coupled with multivariate statistics were used to analysis the sources of elements of soils. We also carried out Risk assessment on the soils. RESULTS: Concentrations of Hg, Cr, Ni, Cd and Pb are slightly higher than those of the late 1970s. Concentrations of Cr and Ni are higher than averaged world background values. Tibetan soils present a high natural As concentration level. DISCUSSION: Anthropogenic sources may partly contribute to the elevated Hg, Cd and Pb concentrations. Cr and Ni are mainly originated from soil parent materials. Soil elements in Anduo and Qamdo regions may threaten the health of local people. CONCLUSION: Heavy metal elements of Tibetan Plateau are mainly from the natural source. Arsenic present a high background level. Soil elements in Anduo and Qamdo regions may threaten the health of local people, which should be of concern to scientists and the government. PMID- 22447245 TI - Endocrine disrupting, mutagenic, and teratogenic effects of upper Danube River sediments using effect-directed analysis. AB - Effect-directed analysis (EDA) can be useful in identifying and evaluating potential toxic chemicals in matrixes. Previous investigations of extracts of sediments from the upper Danube River in Germany revealed acute nonspecific and mechanism-specific toxicity as determined by several bioassays. In the present study, EDA was used to further characterize these sediments and identify groups of potentially toxic chemicals. Four extracts of sediments were subjected to a novel fractionation scheme coupled with identification of chemicals to characterize their ability to disrupt steroidogenesis or cause mutagenic and/or teratogenic effects. All four whole extracts of sediment caused significant alteration of steroidogenesis and were mutagenic as well as teratogenic. The whole extracts of sediments were separated into 18 fractions and these fractions were then subjected to the same bioassays as the whole extracts. Fractions 7 to 15 of all four extracts were consistently more potent in both the Ames fluctuation and H295R assays. Much of this toxicity could be attributed to polycyclic aromatic hydrocarbons, sterols, and in fraction 7-naphthoic acids. Because the fraction containing polychlorinated biphenyls, polychlorodibenzodioxin/furan, dichlorodiphenyltrichloroethane, and several organophosphates did not cause any observable effects on hormone production or a mutagenic response, or were not detected in any of the samples, these compounds could be eliminated as causative agents for the observed effects. These results demonstrate the value of using EDA, which uses multiple bioassays and new fractionation techniques to assess toxicity. Furthermore, to our knowledge this is the first study using the recently developed H295R assay within EDA strategies. PMID- 22447246 TI - Cancer incidence among Nordic airline cabin crew. AB - Airline cabin crew are occupationally exposed to cosmic radiation and jet lag with potential disruption of circadian rhythms. This study assesses the influence of work-related factors in cancer incidence of cabin crew members. A cohort of 8,507 female and 1,559 male airline cabin attendants from Finland, Iceland, Norway and Sweden was followed for cancer incidence for a mean follow-up time of 23.6 years through the national cancer registries. Standardized incidence ratios (SIRs) were defined as ratios of observed and expected numbers of cases. A case control study nested in the cohort (excluding Norway) was conducted to assess the relation between the estimated cumulative cosmic radiation dose and cumulative number of flights crossing six time zones (indicator of circadian disruption) and cancer risk. Analysis of breast cancer was adjusted for parity and age at first live birth. Among female cabin crew, a significantly increased incidence was observed for breast cancer [SIR 1.50, 95% confidence interval (95% CI) 1.32 1.69], leukemia (1.89, 95% CI 1.03-3.17) and skin melanoma (1.85, 95% CI 1.41 2.38). Among men, significant excesses in skin melanoma (3.00, 95% CI 1.78-4.74), nonmelanoma skin cancer (2.47, 95% CI 1.18-4.53), Kaposi sarcoma (86.0, 95% CI 41.2-158) and alcohol-related cancers (combined SIR 3.12, 95% CI 1.95-4.72) were found. This large study with complete follow-up and comprehensive cancer incidence data shows an increased incidence of several cancers, but according to the case-control analysis, excesses appear not to be related to the cosmic radiation or circadian disruptions from crossing multiple time zones. PMID- 22447247 TI - A simple method to detect human intraosseous vascular structures: using the calcaneus as an example. AB - BACKGROUND: Intraosseous vessels play an important role in regeneration of bone. However, the anatomy of the intraosseous vessels in humans has not been clearly delineated due to inadequate method of stereoscopically investigating vessels surrounded by bone tissues. PURPOSE: This study was to investigate the feasibility of simple CT scanning with barium sulphate perfusion to detect intraosseous vessels in humans. METHODS: Two freshly obtained feet from a patient who required a double amputation were used in this study. One foot was perfused with barium sulfate and then scanned by CT (CT method). The other foot was processed using vascular corrosion casting (traditional method). Intraosseous vessels in both specimens were compared. RESULTS: The anatomical distributions of the calcaneal intraosseous vessels were similar as assessed by the CT and traditional methods. However, in comparison to traditional method, the CT method allows the preservation of the surrounding bone tissue, which is important for analyzing the relationship between intraosseous vessels and the surrounding bone structures, and the visualization of a special vascular structure called the sinusoid cluster. CONCLUSION: Simple CT scanning with barium sulfate perfusion may be a practical and adequate method for stereoscopically detecting the morphology and distribution of the intraosseous vessels. PMID- 22447248 TI - Antioxidant and prooxidant effects of lanthanum ions on Vicia faba L. seedlings under cadmium stress, suggesting ecological risk. AB - The present study combined chemical analyses and biological measurements to investigate biphasic effects of La on Cd stress in leaves of Vicia faba seedlings, which were hydroponically cultivated for 15 d in the combination of 6 uM CdCl(2) and 2 to 480 uM La(NO(3))(3), respectively. The results showed that contents of Cd first elevated above and then declined below the 6 uM single Cd treatment when 2 to 30 uM extraneous La were combined. Contents of mineral nutrients altered differentially and became imbalanced. No distinct band was observed in catalase (CAT), guaiacol peroxidase (GPX), or ascorbate peroxidase (APX) patterns, but in superoxide dismutase (SOD) isozymes by the supplementation with 8 to 480 uM of extraneous La. Superoxide dismutase and APX activities changed as a U-shaped curve; however, CAT and GPX changed as an inverted U-shaped curve along with increasing La. Moreover, heat shock protein 70 (HSP 70) production was reduced below the single treatment of Cd at 2 to 8 uM of extraneous La and enhanced thereafter. Thus, La at lower concentrations promoted antioxidation against Cd stress; La at higher concentrations turned to prooxidant effects, implicating potential ecological risk. Heat shock protein 70, combined with the antioxidant enzymes, constitutes an integrative defense system, which can be used to estimate the degree of antioxidation or prooxidation of extraneous La to Cd-induced oxidative stress in the seedlings. PMID- 22447249 TI - Interactions between the spatial and temporal stimulus factors that influence multisensory integration in human performance. AB - In natural environments, human sensory systems work in a coordinated and integrated manner to perceive and respond to external events. Previous research has shown that the spatial and temporal relationships of sensory signals are paramount in determining how information is integrated across sensory modalities, but in ecologically plausible settings, these factors are not independent. In the current study, we provide a novel exploration of the impact on behavioral performance for systematic manipulations of the spatial location and temporal synchrony of a visual-auditory stimulus pair. Simple auditory and visual stimuli were presented across a range of spatial locations and stimulus onset asynchronies (SOAs), and participants performed both a spatial localization and simultaneity judgment task. Response times in localizing paired visual-auditory stimuli were slower in the periphery and at larger SOAs, but most importantly, an interaction was found between the two factors, in which the effect of SOA was greater in peripheral as opposed to central locations. Simultaneity judgments also revealed a novel interaction between space and time: individuals were more likely to judge stimuli as synchronous when occurring in the periphery at large SOAs. The results of this study provide novel insights into (a) how the speed of spatial localization of an audiovisual stimulus is affected by location and temporal coincidence and the interaction between these two factors and (b) how the location of a multisensory stimulus impacts judgments concerning the temporal relationship of the paired stimuli. These findings provide strong evidence for a complex interdependency between spatial location and temporal structure in determining the ultimate behavioral and perceptual outcome associated with a paired multisensory (i.e., visual-auditory) stimulus. PMID- 22447250 TI - Linear and angular control of circular walking in healthy older adults and subjects with cerebellar ataxia. AB - Linear and angular control of trunk and leg motion during curvilinear navigation was investigated in subjects with cerebellar ataxia and age-matched control subjects. Subjects walked with eyes open around a 1.2-m circle. The relationship of linear to angular motion was quantified by determining the ratios of trunk linear velocity to trunk angular velocity and foot linear position to foot angular position. Errors in walking radius (the ratio of linear to angular motion) also were quantified continuously during the circular walk. Relative variability of linear and angular measures was compared using coefficients of variation (CoV). Patterns of variability were compared using power spectral analysis for the trunk and auto-covariance analysis for the feet. Errors in radius were significantly increased in patients with cerebellar damage as compared to controls. Cerebellar subjects had significantly larger CoV of feet and trunk in angular, but not linear, motion. Control subjects also showed larger CoV in angular compared to linear motion of the feet and trunk. Angular and linear components of stepping differed in that angular, but not linear, foot placement had a negative correlation from one stride to the next. Thus, walking in a circle was associated with more, and a different type of, variability in angular compared to linear motion. Results are consistent with increased difficulty of, and role of the cerebellum in, control of angular trunk and foot motion for curvilinear locomotion. PMID- 22447251 TI - The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo. AB - SNX-2112 is a selective heat shock protein 90 (Hsp90) inhibitor which can exert a potent anticancer activity. In this study, we investigated the effects of SNX 2112 on B16 melanoma cells in vitro and in vivo. The 3-(4,5-dimetrylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis demonstrated that SNX-2112 dose-dependently inhibited the growth of B16 cells, and induced G0/G1 cell cycle arrest and apoptosis. Western blotting revealed that SNX-2112 lead to the degradation of Hsp90 client proteins including Akt, IKKalpha, NF-kappaB, B-Raf and GSK3beta. Furthermore, we assessed the antitumor effect of SNX-2112 in vivo, using a xenograft model in C57BL/6 mice. Oral administration of SNX-2112 significantly inhibited the growth of B16 tumors in mice, with a 47% inhibition observed at dose of 80 mg/kg/day for 15 days, compared to control tumors. Hematoxylin-eosin (H&E) staining of xenograft tissues showed that SNX-2112 also inhibited angiogenesis and lead to a lower blood vessel density in the tumors, compared to the control group. These findings demonstrate that SNX-2112 can exhibit a potent anticancer activity against B16 melanoma cells both in vitro and in vivo, by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis in a mechanism dependent on the degradation of Hsp90 client proteins. PMID- 22447252 TI - Mutation screening of the EYA1, SIX1, and SIX5 genes in an East Asian cohort with branchio-oto-renal syndrome. AB - OBJECTIVES/HYPOTHESIS: To explore the genetic characteristics of branchio-oto renal (BOR) syndrome in an East Asian population. STUDY DESIGN: Prospective clinical genetic study. METHODS: Twelve families (total of 18 patients) who fulfilled the criteria for BOR syndrome were enrolled in this study. Mutation screening of the EYA1, SIX1, and SIX5 genes was performed by direct sequencing and quantitative polymerase chain reaction, and genotype-phenotype correlation was investigated. RESULTS: Two novel EYA1 variants, c.466C>T (p.Q156X) and c.1735delG (p.D579fs), were identified in two multiplex families. The c.466C>T variant resulted in a truncated EYA1 protein, whereas the c.1735delG variant was predicted to encode an EYA1 protein with an abnormal C terminal. Neither variant was identified in a panel of 100 normal controls, and both were cosegregated with the BOR phenotype in the pedigrees, indicating that they were pathogenic mutations. No SIX1 and SIX5 mutations were detected in members of the remaining 10 families. Analysis of the genotype-phenotype correlation revealed a high phenotypic variability between and within BOR families. CONCLUSIONS: Two novel EYA1 mutations (c.466C>T and c.1735delG) were identified in two families with BOR syndrome. SIX1 and SIX5 mutations were not detected in the present study. Further investigation is warranted regarding the contribution of SIX1 and SIX5 mutations to BOR syndrome in East Asian populations. PMID- 22447253 TI - Two novel trivacant Keggin-type polytungstates supported manganese carbonyl derivatives synthesized by degradation of metastable [gamma-XW10O36]8- (X = Ge(IV), Si(IV)). AB - Two novel trivacant Keggin-type polyoxometallate-based manganese carbonyl derivatives K(8)[(OC)(3)Mn(A-alpha-H(2)GeW(9)O(34))].10H(2)O (1) and K(8)[(OC)(3)Mn(A-alpha-H(2)SiW(9)O(34))].11H(2)O (2) have been synthesized by degradation of the metastable [gamma-XW(10)O(36)](8-) (X = Ge(IV), Si(IV)) in CH(3)CN-H(2)O solvent (1 : 2, vol.) and structurally characterized by elemental analyses, IR spectra, thermogravimetric analysis, and single-crystal X-ray diffraction. X-ray diffraction analyses indicate that 1 and 2 are isomorphic and consist of a [(OC)(3)Mn](+) group and a trivacant [A-alpha-H(2)XW(9)O(34)](8-) fragment, which exhibit the first examples of trivacant Keggin-type metal carbonyl derivatives. Additionally, the electrocatalytic properties of both for NO(2)(-) oxidation have been investigated. PMID- 22447254 TI - Pulmonary and critical care considerations in hepatic disease. PMID- 22447255 TI - Hepatic hydrothorax. AB - Hepatic hydrothorax is defined as a transudative pleural effusion, usually greater than 500 mL, in patients with portal hypertension without any other underlying primary cardiopulmonary cause. It develops most likely because of diaphragmatic defects that allow for passage of fluid from the peritoneal space to the pleural space. Because of the mechanical constraints of the thoracic cavity, this complication of portal hypertension can be challenging to treat because patients will become symptomatic when as little as 500 mL of fluid is present in the pleural space. Treatments include salt restriction, diuretics, thoracentesis, transjugular intrahepatic portosystemic shunt, video-assisted thoracoscopy, and pleurodesis. It is important to note that a chest tube is not a potential treatment option; a hepatic hydrothorax should not be treated with a chest tube unless there is frank pus in the pleural fluid or a pneumothorax is present. The ultimate treatment is a liver transplant; the development of a hepatic hydrothorax thus warrants a referral to a liver transplant center. PMID- 22447256 TI - Hepatopulmonary syndrome. AB - Hepatopulmonary syndrome (HPS) is characterized by an oxygenation defect induced by pulmonary vascular dilatation in the setting of liver cirrhosis or portal hypertension. It is defined by an alveolar-arterial gradient > 15 mm Hg measured at sea level. This syndrome is seen in 15 to 30% of cirrhotic patients and has been associated with worse survival. Most HPS patients are either asymptomatic or develop the insidious onset of dyspnea. The key event in its pathogenesis is the development of intrapulmonary vascular dilatation (IPVD), which has been linked to increased pulmonary levels of nitric oxide. Pulse oximetry is a useful screening test for HPS, which can guide subsequent use of arterial blood gases. Contrast-enhanced transthoracic echocardiography is the most effective test to demonstrate IPVD. Another method for detecting IPVD is the radionuclide lung perfusion scanning, using technetium-labeled macroaggregated albumin particles. Liver transplantation is the only available treatment for HPS, resulting in complete resolution or significant improvement in gas exchange in over 85% of patients. PMID- 22447257 TI - Portopulmonary hypertension. AB - Portopulmonary hypertension (POPH) refers to the presence of pulmonary arterial hypertension (PAH) in patients with portal hypertension. Pulmonary hypertension in patients with liver disease or portal hypertension can be due to multiple mechanisms, including hyperdynamic (high-flow) state, increased pulmonary venous congestion, and vascular constriction or obstruction of the pulmonary arterial bed. Vascular obstruction to pulmonary arterial flow, reflected by increased pulmonary vascular resistance (PVR), is a key parameter that defines POPH. Among patients with portal hypertension, reported incidence rates of POPH range from 2 to 9%. Long-term survival in cases of POPH is poor. Favorable responses to pulmonary vasodilator/vasomodulatory therapy have been observed, but prospective, randomized trials are lacking. Severe POPH with right ventricular failure despite vasodilator therapy is associated with poor outcomes in the setting of liver transplantation (LT) and is considered a contraindication to LT. The post-LT course of patients with moderate POPH is unpredictable, but most patients can be weaned from PAH-specific therapy over time. PMID- 22447258 TI - Sleep disorders in chronic liver disease. AB - Sleep-related complaints and disturbances are increasingly recognized in the setting of chronic liver disease and have recently been shown to be an important prognostic factor in patients with advanced chronic liver disease. This article reviews the literature surrounding sleep disturbances and disorders in a variety of types of chronic liver disease. This includes the association of sleep disturbances with hepatitis C and antiviral therapy, primary biliary cirrhosis, and Wilson disease as well as the circadian rhythm abnormalities present in cirrhosis and hepatic encephalopathy. The association between chronic liver disease, particularly nonalcoholic fatty liver disease, and sleep-disordered breathing is also reviewed in detail. PMID- 22447259 TI - Acute liver failure. AB - Acute liver failure (ALF) (sometimes referred to as fulminant hepatic failure) is a clinical syndrome from a variety of causes resulting from rapid loss in hepatocyte function, typically associated with coagulopathy and encephalopathy in a patient without preexisting liver disease or cirrhosis. Cerebral edema is a cardinal feature and may produce uncal herniation, yielding brain stem compression and death. The typical interval from onset of symptoms to onset of encephalopathy is 1 to 2 weeks, but cases evolving more slowly, up to 6 months, may still be included in the definition. ALF is rare, affecting 2000 patients annually in the United States, and comprises ~7% of liver transplants annually. Currently, in the United States, acetaminophen accounts for ~50% of all cases of ALF, but other etiologies include hepatitis, drug-induced liver injury, autoimmune hepatitis. Prior to the availability of liver transplantation (LT), mortality of ALF was extremely high, often exceeding 90%; most common causes of death were multiorgan failure, hemorrhage, infection, and cerebral edema. Fortunately, survival has improved considerably in the last 3 decades (overall survival now exceeds 60%). In large part, this improved survival reflects the option of LT but also reflects the high frequency of acetaminophen toxicity as a cause of ALF. In fact, most patients with ALF are not candidates for LT. Critical care of patients with ALF is key to their survival, and decisions must sometimes be made with inadequate information. We review standard practices (medical, pharmacological, and LT) and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient. PMID- 22447260 TI - Acute variceal bleeding. AB - Bleeding from gastroesophageal varices is a frequent complication of cirrhosis. Mortality from a variceal bleeding episode has decreased in the last 2 decades from 40% to 15 to 20% due to the implementation of effective treatments and improvement in the general medical care. Initial treatment should include adequate fluid resuscitation and transfusion to maintain hemoglobin around 7 to 8 g/dL, and prophylactic antibiotics (norfloxacin or ceftriaxone). It is currently recommended that a vasoactive drug be started as soon as variceal bleeding is suspected. Vasoactive therapy should be maintained for up to 5 days to prevent early rebleeding. Where available, terlipressin, a vasopressin derivative, is the preferred agent because of its safety profile; it represents the only drug with proven efficacy in improving survival. Somatostatin and octreotide are used and are as effective as terlipressin in control of bleeding but have not been shown to reduce mortality. Endoscopic therapy must be performed within the first 12 hours after admission when the patient is stable. Variceal band ligation is the recommended endoscopic treatment, but injection sclerotherapy is an alternative if band ligation is technically difficult. Despite this standard of care, 10 to 20% of patients may still exhibit initial failure to control bleeding or early rebleeding within the first 5 days. In failures to control bleeding the use of rescue transjugular intrahepatic portosystemic shunt (TIPS) using covered stents is the best alternative. In mild early rebleeding a second course of endoscopic therapy may be attempted. If rebleeding is severe, placement of TIPS using covered stents is the first-choice rescue treatment. In refractory variceal bleeding episodes, balloon tamponade may be used as a temporary bridge to TIPS. Identification of patients that are at high risk of treatment failure may guide new strategies to improve outcomes. Indeed, a recent trial has shown that placement of TIPS, using covered stents, within 72 hours of admission in patients at high risk of treatment failure (i.e., those Child B with active bleeding or Child C less than 14 points) markedly decreased rebleeding and improved survival. PMID- 22447261 TI - Hepatorenal syndrome: a critical update. AB - Acute kidney injury (AKI) is common in cirrhotic patients with ascites. Although not the primary etiology of AKI in cirrhotic patients, hepatorenal syndrome (HRS) is a unique form of AKI that develops only in cirrhotic patients. Intense renal vasoconstriction is the hallmark of HRS. Different mechanisms contribute to renal vasoconstriction, with splanchnic vasodilatation and reduced effective blood volume playing a central role. Diagnostic criteria for HRS have been developed and were recently modified, but diagnosing HRS and differentiating it from other causes of AKI in cirrhotic patients continues to be a difficult task in some patients. Given its overall dismal prognosis, strategies to prevent HRS have been developed and proved to be effective in reducing HRS prevalence among cirrhotic patients. Liver transplantation is the ultimate treatment, but more than one treatment modality can be utilized as a bridge to transplantation. This review provides an update on our current understanding of HRS with emphasis on the underlying pathophysiological mechanisms involved, difficulties in diagnosis, and different treatment modalities. PMID- 22447262 TI - Liver replacement therapy. AB - The realization of a support device able to effectively replace liver function in patients with hepatic failure has thus far been an elusive goal. The complexity of liver metabolic, synthetic, detoxifying, and excretory functions make artificial hepatic support extremely challenging. Currently, no specific treatment is available to reverse acute or acute-on-chronic liver failure, and morbidity and mortality of these syndromes are still high. Present management strategies are supportive, while waiting for spontaneous liver regeneration or liver transplant. Because of the scarcity of donor organs, liver support strategies are needed for patients with inadequate liver function until an appropriate organ becomes available for transplantation or until their liver recovers from injury. Currently available liver support systems comprise nonbiological systems (e.g., hemodiafiltration, albumin dialysis, and plasma exchange) and bioartificial systems utilizing viable liver cells. The role for these novel systems and their impact on survival or other clinically important outcomes are controversial. Development and use of bioartificial systems are limited by the inherent cost. PMID- 22447263 TI - Infectious complications of acute and chronic liver disease. AB - Acute and chronic liver diseases are frequently complicated by infections, which result in increased morbidity and mortality and place an economic burden on health care systems. This review discusses the epidemiology and the impact on prognosis of infections in liver cirrhosis, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, acute liver failure, and post-liver transplantation. Possible mechanisms for this increased susceptibility are innate immune dysfunction (Kupffer cells, neutrophils, monocytes), genetic predisposition, and intrinsic cellular defects. The causes for innate immune dysfunction may lie in increased gut permeability, the occurrence of endotoxemia, albumin and lipoprotein dysfunction, or toll-like receptor expression. From a clinical viewpoint this article discusses problems in diagnosing infection. Established (vaccination, antibiotic prophylaxis, antiviral prophylaxis, and nutrition) and experimental (probiotic) prophylactic strategies as well as established (antibiotics) and experimental (liver support, albumin, toll-like receptor antagonists) strategies are also reviewed. PMID- 22447264 TI - Acute respiratory failure complicating advanced liver disease. AB - Advanced liver disease is associated with hypoxemia and respiratory failure by various mechanisms. Patients with cirrhosis are especially prone to episodes of decompensation requiring intensive care unit admission and management. Such patients may already be in acute liver failure or have decompensated due to a concurrent illness such as spontaneous bacterial peritonitis, sepsis, encephalopathy, varices, or hepatorenal syndrome. Acute respiratory distress syndrome is one of the main reasons for intensive care unit admission and mortality. Overall, critically ill cirrhotic patients frequently progress to multiorgan failure requiring mechanical ventilation. Caring for such patients is therefore understandably complex and extremely challenging. Patients with end stage liver disease are especially at risk for developing acute respiratory failure and hypoxemia secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. They should therefore be screened for these conditions because failure to recognize and adequately treat these serious complications of cirrhosis may have devastating consequences. This article is based on a review of the current literature on how to approach and manage acute respiratory failure in advanced liver disease, which is important to intensivists, anesthesiologists, and physicians as a whole. PMID- 22447265 TI - Infectious complications after orthotopic liver transplantation. AB - Advances in surgical technique, critical care, immunosuppression, donor and recipient screening, and prophylactic strategies have contributed to the evolving microbiology and epidemiology of infectious complications after liver transplantation. Although decreased overall, infections continue to be a major contributor to graft loss and patient morbidity. Bacterial and candidal infections are less frequent, but antimicrobial resistance has become more common and can potentially limit successful treatment of health care-acquired and surgical site infections. As the transplant population grows, intensivists and pulmonologists are more likely to evaluate liver transplant recipients with infections. Presentations of opportunistic respiratory infections may be atypical in the setting of immunosuppression. Although novel noninvasive diagnostic tools are available for some pathogens, bronchoscopic evaluation may be increasingly helpful in differentiating between certain respiratory pathogens when empirical therapy is plagued by drug interactions and drug toxicities. Knowledge about common postoperative infections and opportunistic respiratory pathogens such as cytomegalovirus and fungi is essential to improving the global care of the liver transplant recipient. PMID- 22447266 TI - Imaging sequences in cardiovascular magnetic resonance: current role, evolving applications, and technical challenges. AB - Cardiovascular magnetic resonance (CMR) has been established as a powerful and comprehensive imaging modality for studying the cardiovascular (CV) system. Shortly after invention of magnetic resonance imaging, CMR applications and developments started to emerge, and they continue to evolve up to the present day. CMR has the advantages of high spatial resolution, enhanced tissue contrast, superior safety profile, and the plethora of physiological parameters that can be obtained. In the near future, CMR is expected to be the gold standard modality for comprehensive CV imaging. Specifically, CMR imaging sequences are increasingly growing in parallel with advancements in scanner hardware. Not only do CMR imaging sequences provide detailed anatomical information, but they also provide functional, perfusion, viability, hemodynamic, and metabolic information about the CV system. In this article, an up-to-date review of different CMR imaging sequences is presented. Each sequence is described along with typical imaging parameters, necessary image processing steps, derived CV parameters, and potential applications. The article then addresses advanced CMR imaging techniques and emerging applications. Finally, the challenges facing CMR imaging are discussed along with its expected future role. PMID- 22447273 TI - Effect of copper chloride exposure on the membrane potential and cytosolic free calcium in primary cultured chicken hepatocytes. AB - This study was conducted to examine the effects of copper on membrane potential and cytosolic free calcium in isolated primary chicken hepatocytes which were exposed to different concentration of Cu(2+) (0, 10, 50, 100 MUM) or a mixture of Cu(2+) and vitamin C (50 and 50 MUM, respectively). Viability, membrane potential, and cytosolic free Ca(2+) of monolayer cultured hepatocytes were investigated at the indicated time point. Results showed that, among the different concentrations of Cu(2+) exposure, the viability of hepatocytes treated with 100 MUM Cu(2+) was the worst at the 12th and 24th hours. The effects of Cu(2+) on viability and proliferation were time and dose dependent. Further investigation indicated that Cu(2+) exposure significantly enhanced cytosolic free Ca(2+) in hepatocytes, compared to that in control group, at the 24th hour. Meanwhile, membrane potential was noticeably reduced in hepatocytes increasing concentration of Cu(2+). Taking these results together, we have shown that Cu(2+) can cause toxicity to primary chicken hepatocytes in excessive dose and the effect of Cu(2+) exposure on membrane potential is not site specific, which is probably mediated by the changes of cytosolic free Ca(2+). PMID- 22447274 TI - Shoulder arthroplasty in alkaptonuric arthropathy: a clinical case report and literature review. AB - Alkaptonuria is a rare hereditary metabolic disease of autosomal recessive inheritance, resulting from deficiency of the enzyme homogentisic acid oxidase. The term "alkaptonuria" was first used in 1859 by Boedeker to describe a patient's urinary reducing compound, and in 1866, Virchow coined the term "ochronosis" due to typical yellow pigmentation. Deposition of this pigment in articular cartilage leads to ochronotic arthropathy, the most incapacitating complication of alkaptonuria. We report a rare case of shoulder ochronotic arthritis, treated with total shoulder arthroplasty, achieving a successful long term clinical and radiological outcomes. PMID- 22447275 TI - Realization of variable three-dimensional terahertz metamaterial tubes for passive resonance tunability. PMID- 22447276 TI - Employees sick-listed with mental disorders: who returns to work and when? AB - PURPOSE: To investigate return to work (RTW) in employees sick-listed with mental disorders classified according to the International Classification of Diseases (ICD). METHODS: Sickness absences (SA) medically certified as emotional disturbance (ICD-10 R45) or mental and behavioral disorders (ICD-10 F00-F99) were retrieved from an occupational health service register. RTW was associated with age, gender, and socioeconomic position (SEP) by parametric survival analysis. RESULTS: Emotional, neurotic, somatoform, stress-related, and mood disorders encompassed 94 % of all mental SA. Employees with emotional disturbance had the highest RTW rates: after 1 year 95 % had resumed work and after 2 years 98 % compared to 89 and 96 % of employees with neurotic, somatoform and stress-related disorders, and 70 and 86 % of employees with mood disorders. The probability of RTW decreased after 1 month of SA due to emotional disturbance, 2 months of SA with neurotic, somatoform and stress-related disorders, and 3 months of SA with mood disorders. Women resumed their work later than men. Young employees presenting with emotional disturbance, neurotic, somatoform, and stress-related disorders had earlier RTW than older employees and low-SEP employees had earlier RTW than high-SEP employees. CONCLUSIONS: RTW rates and probabilities differed across categories of mental disorders. Age and SEP were associated with RTW of employees with emotional, neurotic, somatoform, and stress-related disorders, but not with RTW of employees experiencing mood disorders. To maximize the likelihood of RTW, a focus on RTW is important in the first months after reporting sick with mental disorders. PMID- 22447277 TI - Rapid salivary pepsin test: blinded assessment of test performance in gastroesophageal reflux disease. AB - OBJECTIVE/HYPOTHESIS: Pepsin lateral flow device (LFD) is a rapid noninvasive test to detect salivary pepsin as a surrogate marker for gastroesophageal reflux disease (GERD). We aimed to establish the test sensitivity, specificity, positive and negative predictive values (PPV, NPV) in patients with symptomatic and objective evidence of GERD compared to healthy controls. STUDY DESIGN: Prospective, blinded, controlled cohort study. METHODS: A total of 230 samples were analyzed. In vitro bench testing was conducted on 52 gastric juice and 54 sterile water samples to assess test sensitivity and specificity. Saliva was collected from 58 patients with GERD and 51 controls. All patients with GERD underwent esophagogastroduodenoscopy (EGD) and wireless 48-hour pH monitoring off acid suppressive therapy. PPV and NPV were calculated based on disease definition of esophagitis and/or abnormal pH monitoring. RESULTS: Receiver operating characteristics analysis of in vitro samples found assay sensitivity and a specificity of 87%. There were 6/51 (12%) control subjects and 13/58 (22%) patients with GERD who tested positive for salivary pepsin (P = .25). There was a step-wise increase in the prevalence of positive salivary pepsin: esophagitis (55%), abnormal pH monitoring (43%), GERD symptoms only (24%) (P < .001). Salivary pepsin test showed a PPV of 81% and NPV of 78% for those with objective evidence of GERD (abnormal pH and/or esophagitis). CONCLUSIONS: Rapid LFD for salivary pepsin has acceptable test characteristics in patients with GERD. A positive salivary pepsin test in this group may obviate the need for more expensive diagnostic testing by EGD or pH monitoring. PMID- 22447278 TI - Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells. AB - Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis. Recently, it has been demonstrated that cancer cells that undergo EMT acquire a CD44+/CD24-/low basal cancer stem cell-like phenotype and are characterized by activation of HER-2/Neu and TGFbeta oncogenic signaling pathways with increased capacity of self-renewal, drug resistance, invasion and distant metastases. Following metastatic dissemination, cancer cells re-activate certain epithelial properties through mesenchymal to epithelial transition (MET) to establish neoplastic lesions at secondary sites, although the molecular mechanisms regulating MET remain elusive. In this study we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading to the development of distant metastases in ERalpha+ MCF-7 breast cancer xenografts. Importantly, development of distant metastases in xenograft models was linked to activation of the MET pathway characterized by reduced expression of EMT inducer genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family of transcription factors. In summary, our results demonstrate for the first time that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition. PMID- 22447279 TI - Induced pluripotent stem cells in cardiovascular research. AB - The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSC) by overexpression of a combination of transcription factors bears the potential to spawn a wealth of new applications in both preclinical and clinical cardiovascular research. Disease modeling, which is accomplished by deriving iPSC lines from patients affected by heritable diseases and then studying the pathophysiology of the diseases in somatic cells differentiated from these patient-specific iPSC lines, is the so far most advanced of these applications. Long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia are two heart rhythm disorders that have been already successfully modeled by several groups using this approach, which will likely serve to model other mono- or polygenetic cardiovascular disorders in the future. Test systems based on cells derived from iPSC might prove beneficial to screen for novel cardiovascular drugs or unwanted drug side effects and to individualize medical therapy. The application of iPSC for cell therapy of cardiovascular disorders, albeit promising, will only become feasible if the problem of biological safety of these cells will be mastered. PMID- 22447280 TI - Fusing three perylenebisimide branches and a truxene core into a star-shaped chromophore with strong two-photon excited fluorescence and high photostability. AB - A novel star-shaped chromophore, Tr-PBI, was constructed by fusing three perylenebisimide branches and a truxene core. Tr-PBI exhibits high photostability and excellent two-photon properties: the maximum of delta(TPA) is 11,000 GM at 990 nm and fluorescence quantum efficiency Phi is 0.40 in THF. PMID- 22447281 TI - Introduction of moribund category to OECD fish acute test and its effect on suffering and LC50 values. AB - It has become common practice in many laboratories in Europe to introduce the criterion "moribund" to reduce the suffering in fish acute lethality tests. Fish with severe sublethal symptoms might be declared moribund and are removed from the test as soon as this occurs (premature discontinuation of experiment). Moribund fish affect main study outcomes as the median lethal concentration (LC50) derived on fish declared as moribund may be lower than the conventional LC50. This was evaluated by a retrospective analysis of 328 fish acute toxicity tests of an industry laboratory based on five different definitions of moribund, and of 111 tests from 10 other laboratories from Europe and the United States. Using the criterion of moribund 10 to 23% of the fish were being declared as moribund in 49 to 79% of the studies. In 36 to 52% of the studies, the LC50(moribund) was lower than the conventional LC50 depending on the definitions of moribund. An inclusion of the moribund criterion in an updated Organisation for Economic Cooperation and Development guideline for the acute fish toxicity test would reduce the period of suffering by up to 92 h, lowering the value of the main toxicity endpoint by a factor of approximately 2, and maximal by a factor of approximately 16. PMID- 22447282 TI - Phenylethanoid and flavone glycosides from Ruellia tuberosa L. AB - A new phenylethanoid glycoside, isocassifolioside (8), and two new flavone glycosides, hispidulin 7-O-alpha-L-rhamnopyranosyl-(1'" -> 2")-O-beta-D glucuronopyranoside (11) and pectolinaringenin 7-O-alpha-L-rhamnopyranosyl-(1'" > 2")-O-beta-D-glucuronopyranoside (12) were isolated from the aerial portions of Ruellia tuberosa L., together with verbascoside (1), isoverbascoside (2), nuomioside (3), isonuomioside (4), forsythoside B (5), paucifloside (6), cassifolioside (7), hispidulin 7-O-beta-D-glucuronopyranoside (9) and comanthoside B (10). The structure elucidations were based on analyses of chemical and spectroscopic data including 1D- and 2D-NMR. The isolated compounds 1-12 exhibited radical scavenging activity using ORAC assay. PMID- 22447283 TI - Transpiration sensitivity of urban trees in a semi-arid climate is constrained by xylem vulnerability to cavitation. AB - Establishing quantitative links between plant hydraulic properties and the response of transpiration to environmental factors such as atmospheric vapor pressure deficit (D) is essential for improving our ability to understand plant water relations across a wide range of species and environmental conditions. We studied stomatal responses to D in irrigated trees in the urban landscape of Los Angeles, California. We found a strong linear relationship between the sensitivity of tree-level transpiration estimated from sap flux (m(T); slope of the relationship between tree transpiration and ln D) and transpiration at D=1 kPa (E(Tref)) that was similar to previous surveys of stomatal behavior in natural environments. In addition, m(T) was significantly related to vulnerability to cavitation of branches (P(50)). While m(T) did not appear to differ between ring- and diffuse-porous species, the relationship between m(T) and P(50) was distinct by wood anatomy. Therefore, our study confirms systematic differences in water relations in ring- versus diffuse-porous species, but these differences appear to be more strongly related to the relationship between stomatal sensitivity to D and vulnerability to cavitation rather than to stomatal sensitivity per se. PMID- 22447284 TI - The hepatorenal reflex contributes to the induction of oliguria during pneumoperitoneum in the rat. AB - BACKGROUND: Hepatic blood flow is known to decrease during pneumoperitoneum. Studies have shown that such changes affect kidney urinary output through the sympathetic pathway known as the hepatorenal reflex. This study investigated the potential role of the hepatorenal reflex in pneumoperitoneum-induced oliguria. The authors hypothesized that oliguria detectable during pneumoperitoneum is caused by activation of the hepatorenal reflex. METHODS: Denervation of the sympathetic nervous structure was performed in 15 rats by applying 1 ml of 90 % aqueous phenol solution circumferentially to the portal vein and vena cava area at their entrance to the liver. The same was applied to only the peritoneum in 15 nondenervated rats. After 2 weeks, the rats were divided into three subgroups (5 rats per subgroup) that were exposed respectively to carbon dioxide-induced pneumoperitoneum at 0, 10, and 15 mmHg for 2 h. Statistical analysis was performed using Student's t test and analyses of variance. RESULTS: Denervation did not affect the preinsufflation parameters. The denervated and the nondenervated 0-mmHg subgroups presented with similar parameters. The postinsufflation mean urine output was significantly lower in the nondenervated than in the denervated 10- and 15-mmHg subgroups (p = 0.0097). The denervated rats had a final creatinine clearance 29 % lower than the preinsufflation value (p = 0.83), whereas the nondenervated animals presented a 79 % drop in creatinine clearance (p = 0.02). CONCLUSION: The study findings indicate that the hepatorenal reflex plays an important role in the pathophysiology of oliguria that occurs during pneumoperitoneum in the rat. PMID- 22447285 TI - Safety and efficacy of new integrated bipolar and ultrasonic scissors compared to conventional laparoscopic 5-mm sealing and cutting instruments. AB - BACKGROUND: Hemostasis is a central issue in laparoscopic surgery. Ultrasonic scissors and bipolar clamps are commonly used, with known advantages with each technique. METHODS: The prototype of new surgical scissors, delivering ultrasonically generated frictional heat energy and bipolar heat energy simultaneously (THUNDERBEAT((r)) [TB]), was compared to ultrasonic scissors (Harmonic ACE((r)) [HA]) and an advanced bipolar device (LigaSure((r)) [LS]) using a pig model. As safety parameters, temperature profiles after single activation and after a defined cut were determined. As efficacy parameters, seal failures and the maximum burst pressure (BP) were measured after in vivo sealing of vessels of various types and diameters (categories 2-4 and 5-7 mm). Moreover, the vertical width of the tissue seal was measured on serial histological slices of selected arteries. The cutting speed was measured during division of isolated arteries and during dissection of a defined length of compound tissue (10 cm of mesentery). Burst-pressure measurement and histological analysis were performed by investigators blinded to the used sealing device. RESULTS: Using the TB, the burst pressure in larger arteries was significantly higher (734 +/- 64 mmHg) than that of the HA (453 +/- 50 mmHg). No differences in the rate of seal failures were observed. The cutting speed of the TB was significantly higher than that of all other devices. Safety evaluation revealed temperatures below 100 degrees C in the bipolar device. The maximum temperature of the HA and the TB was significantly higher. No relevant differences were observed between the HA and the TB. CONCLUSIONS: The ultrasonic and bipolar technique of the TB has the potential to surpass the dissection speed of ultrasonic devices with the sealing efficacy of bipolar clamps. However, heat production that is comparable to conventional ultrasonic scissors should be minded for clinical use. PMID- 22447286 TI - A novel extra-glissonian approach for totally laparoscopic left hepatectomy. AB - INTRODUCTION: We describe a novel extra-glissonian approach (EGA) for totally laparoscopic left hepatectomy. Published techniques for totally laparoscopic left hepatectomy generally involve the selective ligation of the vascular and biliary elements of the left pedicle. The laparoscopic dissection of these structures can be tedious, difficult, and dangerous. The EGA has proven useful in open surgery for major hepatectomies. We feel that this approach could be even more useful in the laparoscopic context. METHODS: We describe an extra-glissonian laparoscopic technique in which the left pedicle is isolated extraparenchymally, detaching the left hilar plate, with particular attention to preserving the branch for segment I. The left portal triad is encircled with a cotton tape and transected with an endostapler. This is performed totally extraparenchymally without damaging the surrounding parenchyma. RESULTS: This EGA technique for laparoscopic left hepatectomy follows by laparoscopy the same steps and recommendations that make the EGA safe and effective in open surgery. CONCLUSIONS: The EGA for LLH can be performed as described in open surgery, therefore offering the same advantages. PMID- 22447287 TI - Apoptosis induced by 7-difluoromethoxyl-5,4'-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells. AB - Genistein, 5,7,4'-trihydroxylisoflavone, a major component of soybean products, has been reported to possess anticancer activities. We examined the antitumor effects of 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), a novel synthetic genistein derivative, on human ovarian cancer cells as well as the molecular mechanism. The growth-inhibitory effects of genistein and DFOG were determined using MTT assay and clonogenic assay in CoC1 and SKOV3 human ovarian cancer cells. Apoptotic activities of DFOG were observed using histone/DNA ELISA assay and flow cytometry with propidium iodide (PI) staining. Multiple molecular techniques, such as RT-PCR, western blot analysis, siRNA and cDNA transfection were used to explore the molecular mechanism. We demonstrated that nine of the genistein derivatives had a more effective antitumor activity than genistein. Among the afore-mentioned derivatives, DFOG presented with the strongest activity against CoC1 and SKOV3 cells in vitro. DFOG and genistein inhibited the growth of CoC1 and SKOV3 cells, accompanied by cell cycle arrest in the G2/M phase. DFOG caused apoptotic cell death with concomitant attenuation of Forkhead box protein M1 (FoxM1) and its downstream genes, such as survivin, cdc25B, cyclin B, and increased p27KIP1. Downregulation of FoxM1 by siRNA followed by DFOG treatment resulted in enhanced cell growth inhibition and induction of apoptosis. Upregulation of FoxM1 by cDNA transfection attenuated DFOG-induced cell growth inhibition and apoptotic cell death. Our results show that the molecular role of FoxM1 in mediating the biological effects of DFOG and genistein in human ovarian cancer cells suggests that FoxM1 could be a novel target for the treatment of human ovarian cancer. PMID- 22447288 TI - A comparative study of the bactericidal activity and daily disinfection housekeeping surfaces by a new portable pulsed UV radiation device. AB - Daily cleaning and disinfecting of non-critical surfaces in the patient-care areas are known to reduce the occurrence of health care-associated infections. However, the conventional means for decontamination of housekeeping surfaces of sites of frequent hand contact such as manual disinfection using ethanol wipes are laborious and time-consuming in daily practice. This study evaluated a newly developed portable pulsed ultraviolet (UV) radiation device for its bactericidal activity in comparison with continuous UV-C, and investigated its effect on the labor burden when implemented in a hospital ward. Pseudomonas aeruginosa, Multidrug-resistant P. aeruginosa, Escherichia coli, Acinetobacter baumannii, Amikacin and Ciprofloxacin-resistant A. baumannii, Staphylococcus aureus, Methicillin-resistant S. aureus and Bacillus cereus were irradiated with pulsed UV or continuous UV-C. Pulsed UV and continuous UV-C required 5 and 30 s of irradiation, respectively, to attain bactericidal activity with more than 2Log growth inhibition of all the species. The use of pulsed UV in daily disinfection of housekeeping surfaces reduced the working hours by half in comparison to manual disinfection using ethanol wipes. The new portable pulsed UV radiation device was proven to have a bactericidal activity against critical nosocomial bacteria, including antimicrobial-resistant bacteria after short irradiation, and was thus found to be practical as a method for disinfecting housekeeping surfaces and decreasing the labor burden. PMID- 22447289 TI - Loss-of-function mutations in MC4R are very rare in the Greek severely obese adult population. AB - Melanocortin-4 receptor (MC4R) loss-of-function mutations are the commonest genetic cause of human monogenic obesity, so far. The contribution of MC4R coding mutations to severe obesity in the high-obesity prone Greek population has not been investigated to date. We determined the MC4R coding sequence of 510 obese and 469 lean control subjects of Greek origin, and we estimated the prevalence and the penetrance on obesity of MC4R loss-of-function mutations. The functional impact of novel nonsynonymous variants detected was investigated in vitro. We found two novel synonymous mutations (L23L and I102I), four nonsynonymous mutations (T112M, S127L, N274S, and S295L), and two polymorphisms (V103I and I251L) previously described in literature. We also detected a novel mutation (L207V) in a severely obese 69-year-old female patient, although the mutation did not cosegregate with obesity in the corresponding pedigree and had no functional consequences on MC4R protein function. Loss-of-function mutations represented 75% of all nonsynonymous rare mutations identified among lean carriers and only 25% among obese subjects (P = 0.0001). The prevalence of loss-of-function mutations was lower in the obese group than in lean control subjects (0.20 vs. 0.64%) but this difference was not significant. Therefore, the estimated penetrance of deleterious MC4R mutations was very low (6.3%) in heterozygous Greek carriers of MC4R loss-of-function mutations. Our data suggest that MC4R loss-of-function mutations are rare in the Greek population. MC4R genetic deficiency is unlikely to explain the high propensity to develop severe obesity in this specific population. PMID- 22447290 TI - A diurnal rhythm in glucose uptake in brown adipose tissue revealed by in vivo PET-FDG imaging. AB - Using a micro-positron emission tomography (PET)/computerized tomography scanner, we have measured (18)F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (iBAT) in C57Bl/6 mice at intervals across a 24-h light-dark cycle. Our data reveal a strong 24-h profile of glucose uptake of iBAT, peaking at ~9 h into the light phase of the 12-h light, 12-h dark day. BAT is increasingly gaining attention as being involved in metabolic phenotypes and obesity, where BAT, as observed by PET analysis, negatively correlates with obesity and age. Conversely, animals that show perturbations in circadian clocks, behavior, and physiology show metabolic phenotypes. The observation of a 24-h rhythm in glucose uptake in iBAT makes this tissue a candidate site of interaction between metabolic and circadian systems. PMID- 22447292 TI - Single crystal X-ray structure study of the Li(2-x)Na(x)Ni[PO4]F system. AB - The new compounds Li(2-x)Na(x)Ni[PO(4)]F (x = 0.7, 1, and 2) have been synthesized by a solid state reaction route. Their crystal structures were determined from single-crystal X-ray diffraction data. Li(1.3)Na(0.7)Ni[PO(4)]F crystallizes with the orthorhombic Li(2)Ni[PO(4)]F structure, space group Pnma, a = 10.7874(3), b = 6.2196(5), c = 11.1780(4) A and Z = 8, LiNaNi[PO(4)]F crystallizes with a monoclinic pseudomerohedrally twinned structure, space group P2(1)/c, a = 6.772(4), b = 11.154(6), c = 5.021(3) A, beta = 90 degrees and Z = 4, and Na(2)Ni[PO(4)]F crystallizes with a monoclinic twinned structure, space group P2(1)/c, a = 13.4581(8), b = 5.1991(3), c = 13.6978(16) A, beta = 120.58(1) degrees and Z = 8. For x = 0.7 and 1, the structures contain NiFO(3) chains made up of edge-sharing NiO(4)F(2) octahedra, whereas for x = 2 the chains are formed of dimer units (face-sharing octahedra) sharing corners. These chains are interlinked by PO(4) tetrahedra forming a 3D framework for x = 0.7 and different Ni[PO(4)]F layers for x = 1 and 2. A sodium/lithium disorder over three atomic positions is observed in Li(1.3)Na(0.7)Ni[PO(4)]F structure, whereas the alkali metal atoms are well ordered in between the layers in the LiNaNi[PO(4)]F and Na(2)Ni[PO(4)]F structures, which makes both compounds of great interest as potential positive electrodes for sodium cells. PMID- 22447293 TI - The metastatic microenvironment: Brain-derived soluble factors alter the malignant phenotype of cutaneous and brain-metastasizing melanoma cells. AB - The working hypothesis of this study is that the interactions between the brain microenvironment and melanoma cells determine metastasis formation at this organ site. The aim of the study was to evaluate the contribution of such interactions to the formation of brain metastasis in nude mice xenografted with human melanoma cells. An insight into these interactions is an essential prerequisite for the development of effective targeted therapy for melanoma brain metastasis. We assessed the effects of soluble factors present in supernatants of short-term cultures of normal mouse brain (referred here after as brain-derived soluble factors) on several characteristics linked to melanoma brain metastasis. It was found that brain-derived soluble factors affect differentially cutaneous and brain-metastasizing melanoma cells variants in vitro. Such factors enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain-metastasizing cells. Brain-derived soluble factors enhanced migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors upregulated the expression of the chemokine receptor CCR4 in both cutaneous and brain-metastasizing melanoma cells. It is not unlikely that CCR4 ligands expressed in the brain interact with the CCR4-expressing melanoma cells thereby directing them to the brain. Brain derived soluble factors enhanced the transmigration, across human brain endothelial cells of cutaneous but not of brain-metastasizing melanoma variants. This activity could promote the capacity of the cutaneous cells to metastasize to the brain. PMID- 22447294 TI - Upper abdominal cysts in first trimester fetuses. AB - Cystic abdominal structures in first trimester fetuses are rare. In order to elucidate the clinical significance of first trimester abdominal cysts, we present three cases of the ultrasonographic detection of upper abdominal cysts in first trimester fetuses with spontaneous regression until birth. Cysts with maximum diameters of 20, 15 and 21 mm were diagnosed in the first scan at 12 + 3 weeks of gestation and two times at 13 + 0 weeks of gestation, respectively. They had echogenic walls, a longish shape and were all located in the upper part of the abdomen. Further anomalies, relevant maternal infections, the most frequent cystic fibrosis mutations and fetal chromosomal abnormalities were excluded. In all three cases follow-up scans showed similar characteristics: The relatively large intraabdominal cyst resolved during the early second trimester. A hyperdense structure of up to 24 mm close to the liver capsule was the sole prenatally detectable remnant. During the first months after birth, development of all three children was normal. Pediatric ultrasound examination reported subcapsular liver calcifications. In conclusion, these cases demonstrate that first trimester upper abdominal cysts with spontaneous resolution until birth are associated with a favorable outcome, if infections and additional anatomical or chromosomal anomalies are ruled out. Nevertheless, one should be aware that postnatal gastrointestinal complications have been described in a few cases, even if the cyst had resolved spontaneously in utero. PMID- 22447295 TI - Rodent models of HAND and drug abuse: exogenous administration of viral protein(s) and cocaine. AB - Humans and chimpanzees are the natural hosts for HIV. Non-human primate models of SIV/SHIV infection in rhesus, cynomologus and pigtail macaques have been used extensively as excellent model systems for pathogenesis and vaccine studies. However, owing to the variability of disease progression in infected macaques, a phenomenon identical to humans, coupled with their prohibitive costs, there exists a critical need for the development of small-animal models in which to study the untoward effects of HIV-1 infection. Owing to the fact that rodents are not the natural permissive hosts for lentiviral infection, development of small animal models for studying virus infection has used strategies that circumvent the steps of viral entry and infection. Such strategies involve overexpression of toxic viral proteins, SCID mice engrafted with the human PBLs or macrophages, and EcoHIV chimeric virus wherein the gp120 of HIV-1 was replaced with the gp80 of the ecotropic murine leukemia virus. Additional strategy that is often used by investigators to study the toxic effect of viral proteins involves direct stereotactic injection of the viral protein(s) into specific brain regions. The present report is a compilation of the applications of direct administration of Tat into the striatum to mimic the effects of the viral neurotoxin in the CNS. Added advantage of this model is that it is also amenable to repeated intraperitoneal cocaine injections, thereby allowing the study of the additive/synergistic effects of both the viral protein and cocaine. Such a model system recapitulates aspects of HAND in the context of drug abuse. PMID- 22447296 TI - Pulmonary complications after major head and neck surgery: A retrospective cohort study. AB - OBJECTIVES/HYPOTHESIS: Postoperative pulmonary complications (PPCs) following head and neck surgery are common. Patients undergoing tracheostomy, free tissue transfer reconstruction, and postoperative ventilation in an intensive care unit (ICU) have a high incidence of PPCs. We sought to define the incidence of PPCs in this cohort and to determine what factors PPCs correlate with. STUDY DESIGN: Retrospective cohort study. METHODS: Following institutional research ethics board approval, a retrospective review of patients undergoing major head and neck surgery at a Canadian tertiary care center was conducted. The development of PPCs was the outcome of interest. Quality assurance parameters including ICU and hospital lengths of stay, and mortality were also recorded. RESULTS: There were 105 patients enrolled, of which 47 (44.8%) sustained one or more PPCs. The most frequent PPC was respiratory failure, accounting for 39 of 94 PPCs observed. Hypertension was the only comorbidity that correlated with development of a PPC (P = .031). Those who sustained PPCs were older than those who did not (median age, 65.6 vs. 58.7 years; P = .005). Development of PPCs correlated with longer ICU and hospital stays. There was increased mortality among patients with PPCs compared to those without (12.8% vs. 1.7%, P = .04). CONCLUSIONS: Patients undergoing major head and neck surgery are at high risk of PPCs. Advanced age and hypertension significantly correlated with PPCs. PPCs correlate with prolonged ICU and hospital stays, and increased mortality. Further research is needed to define risk factors, useful investigations, and effective optimization strategies to mitigate PPCs. PMID- 22447297 TI - Potentially inappropriate prescribing and cost outcomes for older people: a cross sectional study using the Northern Ireland Enhanced Prescribing Database. AB - PURPOSE: We sought to estimate the prevalence of potentially inappropriate prescribing (PIP) in the Northern Ireland (NI) population aged >=70 years, to investigate factors associated with PIP and to calculate total gross cost of PIP. METHODS: A retrospective cross-sectional population study was carried out in those aged >=70 years in 2009/2010 who were in primary care in NI. Data were extracted from the Enhanced Prescribing Database, which provides details of prescribed and dispensed medications for each individual registered with a general practitioner. Twenty-eight PIP indicators from the Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) criteria were applied to these data. PIP prevalence according to individual STOPP criteria and the overall prevalence of PIP were estimated. The relationship between PIP and polypharmacy, age and gender was examined using logistic regression. Gross cost of PIP was ascertained. RESULTS: The overall prevalence of PIP in the study population (n = 166,108) was 34 %. The most common examples of PIP identified were proton pump inhibitors at maximum therapeutic dose for >8 weeks (17,931 patients, 11 %), non-steroidal anti-inflammatory drugs >3 months (14,545 patients, 9 %) and long-term long-acting benzodiazepines (10,147 patients, 6 %). PIP was strongly associated with polypharmacy, with those receiving seven different medications being fivefold more likely to be exposed to PIP than those on zero to three medications (odds ratio 5.04, 95 % confidence interval 4.84 5.25) The gross cost of PIP was estimated to be 6,098,419 CONCLUSIONS: Consistent with other research, the prevalence of PIP was high among the study cohort, increased with polypharmacy and was associated with significant cost. PMID- 22447299 TI - Spinal mechanism underlying the antiallodynic effect of gabapentin studied in the mouse spinal nerve ligation model. AB - We studied the antiallodynic effect of gabapentin (GBP) in the mouse model of neuropathic pain, aiming at clarifying the underlying mechanism. The L5 spinal nerve ligation induced tactile allodynia, an increase of CD11b expression, and an increase in the protein expression level of the voltage-dependent Ca(2+) channel alpha(2)/delta-1 subunit in the spinal dorsal horn on the injured side. The chronic intrathecal administration of GBP (100 ug/body per day) as well as omega conotoxin MVIIA, an N-type Ca(2+)-channel blocker, completely suppressed allodynia, but did not attenuate the CD11b expression. The antiallodynic effect of GBP lasted for several days after the termination of the drug, while that of omega-conotoxin MVIIA disappeared immediately after the termination. GBP suppressed the elevation of the protein level of the alpha(2)/delta-1 subunit in the spinal dorsal horn, although it did not affect its mRNA level in the L5 DRG. These results suggest that GBP inhibits the development of allodynia by suppressing the up-regulation of N-type Ca(2+) channels, through normalization of the protein level of the alpha(2)/delta-1 subunit at the primary afferent nerve terminal via the inhibition of its anterograde transport. In addition, we propose that the nerve injury enhances the expression level of alpha(2)/delta-1 in the downstream of the activation of microglia. PMID- 22447298 TI - Pharmacokinetics of fondaparinux 1.5 mg once daily in a real-world cohort of patients with renal impairment undergoing major orthopaedic surgery. AB - PURPOSE: Fondaparinux, a selective activator factor X (factor Xa) inhibitor, is effective and safe for preventing venous thromboembolism after major orthopaedic surgery (MOS) at the once-daily subcutaneous dose of 2.5 mg. As the drug is mainly eliminated by the kidneys, a reduced dosage (1.5 mg once daily) was developed for patients with renal impairment. METHODS: We studied the pharmacokinetics (PK) of this dosage regimen using data from a real-world cohort of 442 patients with renal impairment (creatinine clearance 20-50 ml/min) undergoing MOS. Data were analysed using NON-linear Mixed Effect Modelling software (NONMEM) software. Fondaparinux PK was modelled using a two-compartment model with first-order absorption. RESULTS: This analysis confirmed the relationship between renal function and fondaparinux PK profiles. The mean predicted steady-state area under the plasma concentration time curve, peak and trough plasma concentrations of fondaparinux were lower by 15.6 %, 13.0 % and 10.3 %, respectively, in patients with renal impairment treated with 1.5 mg compared with patients with normal renal function treated with 2.5 mg (p < 0.01). CONCLUSION: Although administration of 1.5 mg fondaparinux in patients with renal impairment resulted in a predicted exposure slightly lower than that achieved with 2.5 mg in patients with normal renal function, fondaparinux 1.5 mg is a valuable thromboprophylactic option in MOS patients with renal impairment who are at risk of bleeding. PMID- 22447300 TI - Contrasting dose-effects of multi-glycoside of Tripterygium wilfordii HOOK. f. on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis. AB - Multi-glycoside, one of the extracted compounds from Tripterygium wilfordii HOOK. f. (GTW), has been shown to be clinically effective in suppressing glomerular inflammation in chronic kidney disease. However, its clinical application is often limited by its cytotoxic actions on the liver. This study was performed to contrast the dose-effects of GTW on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis (GN). Rats with acute or chronic anti Thy1.1 GN were either left untreated (the Vehicle group) or treated with a high or low dose of GTW and sacrificed on day 7 or day 45. GTW was administrated 3 days before or at the same time as the antibody injection and lasted until sacrifice. GTW at high dose ameliorated glomerular macrophage accumulation, mesangial proliferation, proteinuria, and interleukin-2 expression in the acute anti-Thy1.1 GN model, but caused structural and functional lesions in the liver. In contrast, GTW at low dose improved activated macrophage and T lymphocyte infiltration, mesangial injury, proteinuria, and interleukin-2 and interferon gamma expressions without hepatic toxicity in the chronic model of GN induced by anti-Thy1.1 antibody. In conclusion, GTW at low dose not only effectively inhibits glomerular inflammation but also avoids severe injuries to the liver. PMID- 22447301 TI - New 2-aryl-1,4-naphthoquinone-1-oxime methyl ether compound induces microtubule depolymerization and subsequent apoptosis. AB - In this study, we describe the antitumor activity of QO-1, one of the new 2-aryl 1,4-naphthoquinone-1-oxime methyl ether derivatives. QO-1 is a derivative of macarpine, a natural occurring product from Rutaceae plant. It could potently inhibit cell growth when tested on 19 cancer cell lines. To investigate its mechanism, two cell lines (HeLa and MCF-7) sensitive to QO-1 were selected. Based on flow cytometry, it was found to induce G(2)/M-phase arrest. Moreover, it could cause microtubule depolymerization both in vitro and in vivo. On the other hand, QO-1 activated spindle assembly checkpoint (SAC) proteins. Expression of Bub1, one of the SAC, was gradually increased, reaching a peak after 16 - 20 h, and then gradually decreased. Instead, QO-1 increased the sub-G(1) population, which suggested a cell death population. Actually, expression of Bcl-2 family proteins and activation of caspase-3/7 were evidences of apoptosis. Consistent with these results, cells with DNA fragmentation and multinucleated cells were increased time-dependently after QO-1 exposure. In conclusion, QO-1 has promising antitumor effects via microtubule depolymerization. PMID- 22447302 TI - Regulations of astrocytic functions by endothelins: roles in the pathophysiological responses of damaged brains. AB - The receptors for endothelins (ETs) are classified into the ET(A) and ET(B) types. ET(B) receptors are highly expressed in astrocytes, but pharmacological usages of this receptor are not clarified. In this article, recent studies on the pathophysiological roles of astrocytic ET(B) receptors in the brain are reviewed. The administration of ET(B) agonists and antagonists in nerve injury models showed that several astrocytic functions are regulated by ET(B) receptors. The activation of ET(B) receptors causes morphological alterations and proliferation of cultured astrocytes. Astrocytes produce various bio-active substances that can affect damage to nerve tissues. ETs stimulate the production of neurotrophic factors by astrocytes. This action improves impaired brain functions. On the other hand, the production of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), which induce brain edema, also are stimulated by ETs. These findings indicate that astrocytic functions are effectively regulated by modulations of ET(B) receptors. In brain insults and neurodegenerative diseases, these functions of astrocytes affect the protection and repair of damaged nerve tissues. Thus, astrocytic ET(B) receptors could be a target for novel types of neuroprotective drugs. PMID- 22447303 TI - Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK2 antagonists. AB - We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK(2) receptor (NK(2)-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK(2)-R agonist, betaAla(8)-neurokinin A(4-10) (betaA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of betaA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK(2)-R antagonists in dose- and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) values calculated in the PD model were highly correlated (r(2) = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK(2)-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK(2)-R with in vivo therapeutic efficacy. PMID- 22447304 TI - Impulsive behavior and nicotinic acetylcholine receptors. AB - Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; alpha4beta2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior. PMID- 22447305 TI - Effect of prenatal valproic acid exposure on cortical morphology in female mice. AB - We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPA-induced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits. PMID- 22447306 TI - The coffee diterpene kahweol prevents osteoclastogenesis via impairment of NFATc1 expression and blocking of Erk phosphorylation. AB - Osteoclasts (OCLs) are multinucleated bone resorbing cells whose differentiation is regulated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). It is known that inflammatory cytokines and oxidative stress stimulate differentiation of OCLs. Here we evaluated the effects of kahweol, a coffee-specific diterpene, which has been reported to possess anti-oxidant and anti-inflammatory properties, on the differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D cells into OCLs. Kahweol dose-dependently inhibited the formation of tartrate-resistant acid phosphatase staining-positive OCLs from both BMMs and RAW-D cells. In addition, kahweol prevented the bone resorbing activity of OCLs. Kahweol completely abolished RANKL-stimulated phosphorylation of extracellular signal-regulated kinase and impaired phosphorylation of Akt. Moreover, the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator for OCL differentiation; and OCL markers transcriptionally regulated by NFATc1 such as Src and cathepsin K were down-regulated by kahweol treatment. As one of the molecular mechanisms for the inhibitory effects of kahweol, we also showed that kahweol up-regulated heme oxygenase-1 and inhibited high mobility group box 1 release. Thus, kahweol in coffee is a useful constituent for inhibition of OCL differentiation. PMID- 22447307 TI - beta-arrestin-mediated signaling improves the efficacy of therapeutics. AB - beta-Arrestins (beta-arrestin-1 and beta-arrestin-2) were first identified as proteins that have the ability to desensitize G protein-coupled receptors (GPCRs). However, it has recently been found that beta-arrestins can activate signaling pathways independent of G protein activation. The diversity of these signaling pathways has also been recognized. This leads to an appreciation of beta-arrestin-biased agonists, which is a new class of drugs that selectively activate beta-arrestin-mediated signaling without G protein activation. In this review, we will discuss the recent advance of beta-arrestin-mediated signaling pathways, including a brief account of different biased agonists, their pharmacological applications, and novel beta-arrestin research. PMID- 22447308 TI - Fabrication of microlens arrays with well-controlled curvature by liquid trapping and electrohydrodynamic deformation in microholes. PMID- 22447309 TI - Insulin resistance and acne: a new risk factor for men? AB - The purpose of this study is to investigate the relationship between acne and insulin resistance as well as other metabolic impairment in young males. Acne is a skin disease that can be influenced by endocrine abnormalities. In females, it is associated with polycystic ovary syndrome, with peripheral insulin resistance and hyperinsulinemia, whereas few data are available in males. For investigating this, 22 young males with acne have been compared to 22 controls of comparable age and gender. Acne was scored using the global acne grading system score. Clinical as well as biochemical parameters of glucose and lipid metabolism, circulating levels of androgens, and IGF-1 were evaluated. Oral glucose tolerance test was performed and homeostasis model assessment of insulin resistance was calculated. The results thus obtained are as follows, patients had higher BMI (p = 0.003), WC (p = 0.002), WHR (p = 0.02), SBP (p = 0.0001), DBP (p = 0.001), basal (p = 0.01) and 120 min. oGTT serum insulin concentrations (p = 0.002), basal glucose concentrations (p = 0.03), HOMA-IR (p = 0.016), and lower HDL cholesterol than controls (p = 0.001). Among the subgroup of subjects with BMI <24.9, HDL-cholesterol (p = 0.05) and 120 min. oGTT serum insulin concentrations (p = 0.009) resulted to be independent predictors of acne at multivariate analysis. In conclusion, these findings highlight a metabolic imbalance in young males affected with acne. Insulin resistance seems to play the main role for the development of acne in these subjects. Insulin resistance could represent an effective target for therapy in male acne. PMID- 22447310 TI - Diagnostic performance of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay in obese and overweight patients referred to exclude Cushing's syndrome. AB - This study estimates diagnostic performance of late-night salivary cortisol (LNSC) as measured by automated electrochemiluminescence immunoassay (ECLIA), evaluates the clinical implication of two consecutive LNSC measurements, and compares its accuracy with enzyme-linked immunosorbent assay (ELISA) and serum cortisol after low-dose dexamethasone suppression test (DST) in obese and overweight patients referred for suspected Cushing's syndrome (CS). One hundred twenty three consecutive obese and overweight referred patients and 98 healthy volunteers provided two saliva samples collected at 23:00 using a Salivette (Sarstedt, Germany), assayed by ECLIA (Cobas e601) and ELISA. The patients underwent DST and were further evaluated until CS was pathologically confirmed (n = 45) or excluded. Diagnostic performance of LNSC was evaluated by receiver operating characteristic (ROC) analysis. The total areas under the curve (AUC) were calculated to compare the different tests. We found that a cut-off value of 9.4 nmol/l can differentiate CS among obese and overweight patients with sensitivity of 84.4 % (95% CI 71.2-92.2), specificity of 92.3 % (95% CI 84.2 96.4), and diagnostic odds ratio of 65.1 (95% CI 20.4-207.6). No difference was found between AUCs from the first, second, and the mean from the two LNSC measurements (ECLIA), LNSC (ELISA), or DST. The single LNSC (ECLIA) and DST improved the sensitivity and specificity for concordant results up to 100 and 97.4 %, respectively. In conclusion, due to its automation and its comparable diagnostic performance, ECLIA is preferable as a first-line LNSC screening test for CS. The initial use of single LNSC followed by DST provides better diagnostic performance for concordant results. PMID- 22447311 TI - Management of long term sickness absence: a systematic realist review. AB - PURPOSE: The increasing impact and costs of long term sickness absence have been well documented. However, the diversity and complexity of interventions and of the contexts in which these take place makes a traditional review problematic. Therefore, we undertook a systematic realist review to identify the dominant programme theories underlying best practice, to assess the evidence for these theories, and to throw light on important enabling or disabling contextual factors. METHOD: A search of the scholarly literature from 1950 to 2011 identified 5,576 articles, of which 269 formed the basis of the review. RESULTS: We found that the dominant programme theories in relation to effective management related to: early intervention or referral by employers; having proactive organisational procedures; good communication and cooperation between stakeholders; and workplace-based occupational rehabilitation. Significant contextual factors were identified as the level of support for interventions from top management, the size and structure of the organisation, the level of financial and organisational investment in the management of long-term sickness absence, and the quality of relationships between managers and staff. CONCLUSIONS: Consequently, those with responsibility for managing absence should bear in mind the contextual factors that are likely to have an impact on interventions, and do what they can to ensure stakeholders have at least a mutual understanding (if not a common purpose) in relation to their perceptions of interventions, goals, culture and practice in the management of long term sickness absence. PMID- 22447312 TI - Comparison of earthworm and chemical assays of the bioavailability of aged 1,1 dichloro-2,2-bis(p-chlorophenyl)ethylene, 1,1,1-trichloro-2,2-bis(p chlorophenyl)ethane, and heavy metals in orchard soils. AB - Orchard soils can contain elevated concentrations of 1,1-dichloro-2,2-bis(p chlorophenyl)ethylene (p,p'-DDE), 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT), and heavy metals as a result of historical agrichemical applications. The bioavailability of p,p'-DDE, p,p'-DDT, As, Cd, Cu, and Pb from five field aged New Zealand orchards and three grazing soils was assessed by using a 28-d bioassay with Aporrectodea caliginosa and chemical assays. Significant relationships were found between total soil and earthworm tissue concentrations for p,p'-DDE (p < 0.001), p,p'-DDT (p < 0.001), Cu (p < 0.001), and Pb (p < 0.01). Two neutral salt solutions, 0.01 M CaCl(2) and 1 M NH(4)NO(3), were used as surrogate measures of the bioavailability of heavy metals. Copper was the only heavy metal for which significant correlations were found between neutral-salt extractable and earthworm tissue concentrations (p < 0.001). Up to 28% of the aged DDT residues were released from the soils by Tenax over a 24-h extraction period. Significant relationships (p < 0.01) between the Tenax-extractable and earthworm tissue concentrations for p,p'-DDE and p,p'-DDT showed that Tenax provides a good surrogate measure of the bioavailability of these compounds to A. caliginosa. Surprisingly, there was a similarly significant relationship (p < 0.001) between the total soil and earthworm tissue concentrations for p,p'-DDE and p,p'-DDT, suggesting that total soil concentrations alone were sufficient to predict uptake by A. caliginosa. These results demonstrate that the aged agrichemical residues in orchard soils, and particularly p,p'-DDE and p,p'-DDT, remain highly bioavailable to A. caliginosa despite decades of weathering and continue to present an environmental risk. PMID- 22447313 TI - Hemodynamic differences between the awake and anesthetized conditions in normal calves. AB - There is insufficient information in the literature about baseline circulatory parameters in normal calves in the anesthetized versus postoperative awake conditions under which a large volume of medical research is conducted. Eleven calves (mean body weight, 78.1 +/- 14.3 kg) were implanted with a flow probe and fluid-filled pressure lines to measure cardiac output (CO), aortic (AoP), central venous (CVP), pulmonary arterial (PAP), and left atrial pressures (LAP). Systemic (SVR) and pulmonary vascular resistance (PVR) were also calculated. We obtained the above hemodynamic data (n = 11) and epicardial echocardiography (n = 7) during open-chest surgery under isoflurane anesthesia. After full recovery from surgery, animals were evaluated in the awake condition on postoperative days 6-9 using transthoracic echocardiography (n = 7) and the hemodynamic monitoring lines and probes noted (n = 11). CO, AoP, and PAP levels in the anesthetized condition were significantly lower than in the awake condition. Other hemodynamic parameters (CVP, LAP, SVR, and PVR) were not significantly different. In conclusion, data from this study quantify changes in CO, AoP, and PAP in anesthetized calves that may affect the hemodynamic response to experimental therapeutics such as new cardiac assist devices, prosthetic valves, and surgical interventions. Our study also provides baseline data for the translation of the hemodynamic data obtained in acute in vivo calf studies to that of an awake subject. PMID- 22447314 TI - Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria. AB - BACKGROUND: Inborn errors of cobalamin (Cbl) absorption and metabolism form a large group of rare diseases that include Cbl-C disorder. Among the renal complications of Cbl-C disorder, atypical hemolytic uremic syndrome (HUS) is the least common and has been described only in a small number of cases. CASE DIAGNOSIS/TREATMENT: Four patients were admitted to our clinic after 15-30 days of life with vomiting associated with poor sucking, failure to thrive, lethargy and hypotonia. Examinations showed thrombocytopenia and microangiopathic hemolytic anemia associated with renal damage. The neonates had high blood homocysteine levels, increased urinary levels of both homocystine and methylmalonic acid, increased propionylcarnitine (C3) levels and an increased C3/acetylcarnitine ratio. Homozygosity for c.271-272dupA (p.Arg91LysfsX14) of the MMACHC gene was detected in three patients, and heterozygosity for c.271-272dupA and c.666C > A(p.Tyr222X) in one patient, which confirmed the diagnosis of Cbl-C disorder. Treatment with parenteral hydroxycobalamin in combination with folic acid and betaine gradually normalized the metabolic test findings and hematological and renal parameters after about 1 week. CONCLUSIONS: Atypical HUS in neonates with Cbl-C disorder may be associated with mild to moderate renal involvement also in early-onset disease, and early adequate therapy can reverse renal damage. PMID- 22447315 TI - A zinc gable phthalocyanine and a derived planar bis-phthalocyanine containing a shared anthracene unit. AB - A gable-type zinc phthalocyanine and a derived planar bis-phthalocyanine containing a shared anthracene unit have been synthesized and their spectroscopic properties examined. The former showed a split Q band, while the latter exhibited a red-shifted but unsplit Q band, as explained by exciton coupling theory and molecular orbital calculations. PMID- 22447316 TI - The tumor microenvironment in hepatocellular carcinoma (review). AB - The tumor microenvironment has been largely studied as a dynamic system orchestrated by inflammatory cells, including cancer cells, stroma as well as the extracellular matrix. It is useful to describe and predict the phenotypic characteristics of cancer. Furthermore, a better understanding of its interplay with the various aspects of the tumor cells may be utilized for the discovery of novel molecular targets. Liver cancer is considered a model of the relation occurring between the tumor micro-environment and tumor development. The chronic inflammatory status of the liver, sustained by the infection of hepatitis viruses, as well as the production of cytokines and growth factors within the parenchyma, lead to an intricate microenvironment. The identification of novel molecular therapeutic targets may improve the outcome of patients with liver cancer as it remains the third leading cause of cancer death worldwide. In the present study, the tumor microenvironment in hepatocellular carcinoma (HCC) was explored by a review of the literature. Studies on hepatitis virus infections and the consequent chronic inflammatory status were examined. In this context, immune mediated and/or virus-related molecular mechanisms have been hypothesized as being responsible for liver cancer development. The interlink among HCC microenvironment components, comprising cellular elements, cytokines, growth factors and several proteins is also described together with the role of matrix metalloproteinases in HCC development. Finally, the rationale for targeting tumor stromal interface is summarized in the context of new therapeutic opportunities. PMID- 22447317 TI - Changes in carotid blood flow after unilateral perinatal arterial ischemic stroke. AB - INTRODUCTION: Little is known about changes in carotid blood flow after perinatal arterial ischemic stroke (PAIS). The aim of this study was to assess the blood flow in the internal carotid arteries (ICAs) after unilateral PAIS. METHODS: The carotid flow (ml/min) was measured noninvasively by means of two-dimensional phase-contrast magnetic resonance angiography (2D PC-MRA) in 25 full-term infants who had unilateral PAIS within 10 d after birth. In 17 infants a second 2D PC-MRA was carried out at the age of 3 mo. Asymmetry of carotid blood flow was calculated at both time points, and the circle of Willis (CoW) was assessed with a three-dimensional (3D) time-of-flight MRA. RESULTS: On the early magnetic resonance imaging (MRI), a significant increase in ipsilateral blood flow was observed (7.7%, 95% confidence interval (CI) 3.0-14.9%), which persisted after correcting for CoW configuration. At 3 mo, this asymmetry was no longer observed. No relationship was found between the asymmetry in blood flow and either stroke size or postnatal age at scan. DISCUSSION: A higher blood flow in the ipsilateral ICA was observed during the acute phase after unilateral PAIS, and this disappeared after 3 mo. Further research into the role of hyperperfusion after PAIS may suggest new approaches to neuroprotection. PMID- 22447318 TI - Prediction of neurodevelopmental outcome after hypoxic-ischemic encephalopathy treated with hypothermia by diffusion tensor imaging analyzed using tract-based spatial statistics. AB - INTRODUCTION: Objective biomarkers are needed to assess neuroprotective therapies after perinatal hypoxic-ischemic encephalopathy (HIE). We tested the hypothesis that, in infants who underwent therapeutic hypothermia after perinatal HIE, neurodevelopmental performance was predicted by fractional anisotropy (FA) values in the white matter (WM) on early diffusion tensor imaging (DTI) as assessed by means of tract-based spatial statistics (TBSS). METHODS: We studied 43 term infants with HIE. Developmental assessments were carried out at a median (range) age of 24 (12-28) mo. RESULTS: As compared with infants with favorable outcomes, those with unfavorable outcomes had significantly lower FA values (P < 0.05) in the centrum semiovale, corpus callosum (CC), anterior and posterior limbs of the internal capsule, external capsules, fornix, cingulum, cerebral peduncles, optic radiations, and inferior longitudinal fasciculus. In a second analysis in 32 assessable infants, the Griffiths Mental Development Scales (Revised) (GMDS-R) showed a significant linear correlation (P < 0.05) between FA values and developmental quotient (DQ) and all its component subscale scores. DISCUSSION: DTI analyzed by TBSS provides a qualified biomarker that can be used to assess the efficacy of additional neuroprotective therapies after HIE. PMID- 22447319 TI - Plasma midregional proadrenomedullin in newborn infants: impact of prematurity and perinatal infection. AB - INTRODUCTION: Adrenomedullin (ADM) is one of the strongest endogenous vasodilating hormones. Its stable by-product midregional-proADM (MR-proADM) is an established indicator of systemic infection and cardiovascular compromise in adult patients. METHODS: A prospective cross-sectional study was performed to investigate the perinatal factors affecting MR-proADM plasma concentrations in 328 newborn infants with a gestational age (GA) between 24 and 41 wk. RESULTS: Blood samples were obtained in 270 infants from umbilical veins (with additional 108 paired samples from umbilical arteries), and at 2-3 d of life in 183 infants. Paired venous and arterial umbilical cord MR-proADM concentrations were closely related (Spearman's rank order correlation coefficient (R(s)) = 0.825, P < 0.001). MR-proADM concentrations at birth and at 2-3 d were inversely related to GA (R(s) = -0.403 and R(s) = -0.541, respectively) and birth weight (BW; R(s) = 0.421 and R(s) = -0.530, respectively; all P < 0.001). On stepwise regression analysis, clinical chorioamnionitis and umbilical arterial blood base excess retained a significant impact on MR-proADM cord venous blood concentrations. At 2 3 d of life, histologic chorioamnionitis and GA at delivery were significantly associated with MR-proADM levels. DISCUSSION: As compared with adults, MR-proADM concentrations are elevated in neonates, especially those born very preterm. Immaturity and infection, which both feature low systemic vascular resistance, are related to increased MR-proADM concentrations. PMID- 22447320 TI - Dietary fish oil increases fat absorption and fecal bile acid content without altering bile acid synthesis in 20-d-old weanling rats following massive ileocecal resection. AB - INTRODUCTION: Dietary fish oil (FO) was reported to lower fecal fat excretion in a weanling rat model of short bowel syndrome (SBS) after ileocecal resection (ICR), and to induce changes in secretion and synthesis of bile acid (BA) in adults. We hypothesized that dietary FO, as compared with corn oil (CO), increases intestinal fat absorption in weanling SBS rats in part due to increased hepatic BA synthesis and luminal BA concentrations. METHODS: After undergoing ICR, 20-d-old rats were fed ad lib for 7 d with a CO or FO diet containing 5% sucrose polybehenate (SPB), a marker for dietary fat absorption. Fecal fatty acid, fecal and intestine luminal BA, liver mRNA expressions of cholesterol 7alpha-hydroxylase (Cyp7alpha1) and sterol-12alpha-hydroxylase (Cyp8beta1), and serum 7alpha-hydroxy-4-cholesten-3-1 (7alphaC4) levels were determined. RESULTS: As compared with CO-ICR rats, FO-ICR rats had higher intestinal absorption of total fat and most individual fatty acids. Although the BA content per gram of dry stool was increased in FO-ICR rats, there were no differences between groups for the BA content in remnant jejunum, liver mRNA expression of BA biosynthetic enzymes, Cyp7alpha1 and Cyp8beta1, or serum 7alphaC4, a marker for BA synthesis. CONCLUSION: Dietary FO increases dietary fat absorption without increasing hepatic BA synthesis in weanling SBS rats. PMID- 22447321 TI - Bidirectional solid phase synthesis of a model oligoglycine bolaamphiphile and purification by rapid self-assembly. AB - We utilised a simple bidirectional (N->C and C->N) solid phase synthesis strategy entailing conventional solid phase peptide synthesis and fragment condensation with a water-soluble carbodiimide to synthesise a model anionic glycylglycine bolaamphiphile containing a suberic acid linker moiety, namely N,N' suberoyldiglycylglycine. The synthetic suberoyldiglycylglycine was purified using its inherent ability to rapidly self-assemble in an aqueous acidic solution (0.1% trifluoroacetic acid). Monitoring of the rapid assembly process corroborated our visual observation and confirmed packing-directed self-assembly rather than non specific aggregation or precipitation. The progress of suberoyldiglycylglycine self-assembly was observed to be via the formation of oligomers in the solution, which then self-assembled to form layered beta-sheet type macrostructures. Within 24 h, nanotubes grew from these macrostructures and eventually combined to formed microtubes, which we isolated after 5-7 days. PMID- 22447322 TI - Trichocyst ribbons of a cryptomonads are constituted of homologs of R-body proteins produced by the intracellular parasitic bacterium of Paramecium. AB - Trichocysts are ejectile organelles found in cryptomonads, dinoflagellates, and peniculine ciliates. The fine structure of trichocysts differs considerably among lineages, and their evolutionary relationships are unclear. The biochemical makeup of the trichocyst constituents has been studied in the ciliate Paramecium, but there have been no investigations of cryptomonads and dinoflagellates. Furthermore, morphological similarity between the contents of cryptomonad trichocysts and the R-bodies of the endosymbiotic bacteria of Paramecium has been reported. In this study, we identified the proteins of the trichocyst constituents in a red cryptomonad, Pyrenomonas helgolandii, and found their closest relationships to be with rebB that comprises the R-bodies of Caedibacter taeniospiralis (gammaproteobacteria), which is an endosymbiont of Paramecium. In addition, the biochemical makeups of the trichocysts are entirely different between cryptomonads and peniculine ciliates, and therefore, cryptomonad trichocysts have an evolutionary origin independent from the peniculine ciliate trichocysts. PMID- 22447323 TI - Tex 19 paralogs exhibit a gonad and placenta-specific expression in the mouse. AB - We have previously suggested that TEX19, a mammalian-specific protein of which two paralogs exist in rodents, could be implicated in stem cell self-renewal and pluripotency. We have established here the expression profiles of Tex19.1 and Tex19.2 during mouse development and adulthood. We show that both genes are coexpressed in the ectoderm and then in primordial germ cells (PGCs). They are also coexpressed in the testis from embryonic day 13.5 to adulthood, whereas only Tex19.1 transcripts are detected in the developing and adult ovary as well as in the placenta and its precursor tissue, the ectoplacental cone. The presence of both Tex19.1 and Tex19.2 in PGCs, gonocytes and spermatocytes opens the possibility that these two genes could play redundant functions in male germ cells. Furthermore, the placental expression of Tex19.1 can explain why Tex19.1 knockout mice show embryonic lethality, in addition to testis defects. PMID- 22447324 TI - Mycotoxin alpha-zearalenol impairs the quality of preimplantation porcine embryos. AB - Alpha-Zearalenol (alpha-ZEA) is one of derivatives from Zearalenone (ZEA) which impacts mammalian reproduction and development. Previous studies have shown that pigs are sensitive to the estradiol-like effects of alpha-ZEA. However, the effect of alpha-ZEA for the early embryonic development has not been fully studied. The objective of this study was to identify the direct toxicity of alpha ZEA on porcine preimplantation embryonic development, embryo quality and expression of developmentally important genes. Presumptive zygotes were cultured in porcine zygote medium 3 (PZM-3) in the presence of alpha-ZEA (n=2,957) or 17beta-estradiol (E2) (n=1,333) dissolved in 0.1% Dimethyl Sulfoxide (DMSO) from 24 to 84 h post insemination followed by determination of apoptotic cell numbers and transcript levels of BAX, BCL2L1 and POU5F1 in blastocysts. Cleavage rates on day 2 were significantly decreased in 10, 30 and 60 uM alpha-ZEA groups; whereas blastocyst rates on day 6 were significantly decreased in the 30 and 60 uM of alpha-ZEA groups. Only the 100 uM E2 group significantly decreased cleavage and blastocyst rates. Total cell numbers (TCN) in blastocysts were significantly lower in the 10 uM alpha-ZEA group, but no differences in apoptotic cell rates were found. The expression levels of POU5F1 and BCL2L1 transcripts were similar; however, levels of BAX transcripts and the BAX/BCL2L1 ratio were increased in both alpha-ZEA groups. Since alpha-ZEA and E2 did not elicit similar effects, results suggest that alpha-ZEA might impact porcine preimplantation embryonic development through pathways other than estrogen receptor binding. PMID- 22447325 TI - Prediction of superovulatory response in Japanese Black cattle using ultrasound, plasma anti-Mullerian hormone concentrations and polymorphism in the ionotropic glutamate receptor AMPA1/GRIA1. AB - The aim of this study was to improve the reliability of predicting the superovulatory response in Japanese Black cattle. Follicle counts and plasma anti Mullerian hormone concentrations were analyzed within four days prior to the initiation of superovulation. The single nucleotide polymorphism (guanine or adenine) of the ionotropic glutamate receptor AMPA1 was determined. The plasma anti-Mullerian hormone concentration was positively correlated (P<0.001) with the numbers of all follicles and small (<5 mm) follicles and with the numbers of ova/embryos (P<0.001), fertilized embryos (P<0.001) and transferable embryos (P=0.005). There was no significant difference in follicle counts and superovulatory responses between donor cows bearing guanine/adenine or guanine/guanine alleles of AMPA1. Donor cows with a high plasma anti-Mullerian hormone concentration and homozygous for the guanine-containing allele of AMPA1 were most responsive to superovulation. The results suggest that physiological and genetic markers of superovulation have a synergistic effect on the accuracy of predictions of responsiveness. PMID- 22447326 TI - Influence of intergeneric/interspecies mitochondrial injection; parthenogenetic development of bovine oocytes after injection of mitochondria derived from somatic cells. AB - Interspecies/intergeneric mitochondrial heteroplasmy can occur in interspecies/intergeneric hybrid embryos or following nuclear transfer. In the present study, intergeneric buffalo (Bubalus bubalis) mitochondria (WB-mt) or interspecies murine (Mus spretus) mitochondria (M-mt) were injected into bovine (Bos taurus) oocytes, and the subsequent embryonic development was characterized. Fibroblast mitochondria (WB-mt or M-mt) were microinjected into in vitro matured bovine oocytes followed by oocyte activation by a combination of electrical stimulation and 6-dimethylaminopurine treatment. After seven days of culture, embryo development was evaluated. The copy number of specific mtDNA populations (introduced and native mtDNA) from heteroplasmic oocytes was estimated using real time PCR. The results illustrated that oocytes injected with either WB-mt or M-mt can develop to the blastocyst stage (20.6% and 19.6%). Cleavage division rates and development to the morula stage in oocytes injected with WB-mt were lower (76.2% and 45.9%, respectively) in comparison with uninjected oocytes (89.2% and 59.1%, respectively) (P<0.05). However, no differences were found in comparing M mt injected oocytes and controls (P>0.05). An increase in bovine mtDNA copy number was observed at the expanded blastocyst stage of injected embryos (P<0.01), while the number of injected mtDNA was stable throughout development. This study demonstrates that interspecies/intergeneric mitochondrial injected bovine oocytes have the ability to develop to the blastocyst stage after parthenogenetic activation and that injected mtDNA was neither selectively destroyed nor enhanced through development. Moreover, injected intergeneric mitochondria had a demonstrated influence on bovine parthenogenetic development and mtDNA replication. PMID- 22447327 TI - Seasonal changes in morphology and immunoreactivity of PDGF-A and its receptor PDGFR-alpha in the epididymis of wild ground squirrels (Citellus dauricus Brandt). AB - The platelet-derived growth factor (PDGF) system is expressed and can exert its biological role in the male reproductive system including the maintenance of morphological structure and function of the epididymis. The aim of this study was to clarify the relationship between the PDGF system and seasonal changes in morphology of the wild ground squirrel epididymis during the breeding and nonbreeding seasons. Hematoxylin-eosin (HE) staining was used to observe the epididymal morphology and histology. Immunohistochemistry and Western blotting were performed to detect the immunoreactivities of PDGF-A and B and PDGFR-alpha. Significant seasonal changes in epididymal morphology were observed in the breeding and nonbreeding seasons. The proportions of the three compartments (interstitial tissue, epithelium and lumen of the duct) revealed distinct variances. Strong immunostaining of PDGF-A was present in the myoid cell and on the sperm in the breeding season, whereas there was a faint signal in the myoid cell in the nonbreeding season. PDGFR-alpha was expressed in all cell types of the epithelium throughout the whole seasonal cycle, and immunostaining of PDGFR alpha in the breeding season was significantly stronger compared with that of the nonbreeding season. PDGF-B was not detected in the epididymis of wild ground squirrels. These results suggested that seasonal morphological changes in epididymis were correlated with immunoreactivities of PDGF-A and its receptor PDGFR-alpha and that PDGF-A and PDGFR-alpha might function as paracrine, autocrine or apocrine factors in wild ground squirrels. PMID- 22447328 TI - Comparative risk assessment of carcinogens in alcoholic beverages using the margin of exposure approach. AB - Alcoholic beverages have been classified as carcinogenic to humans. As alcoholic beverages are multicomponent mixtures containing several carcinogenic compounds, a quantitative approach is necessary to compare the risks. Fifteen known and suspected human carcinogens (acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, cadmium, ethanol, ethyl carbamate, formaldehyde, furan, lead, 4 methylimidazole, N-nitrosodimethylamine, ochratoxin A and safrole) occurring in alcoholic beverages were identified based on monograph reviews by the International Agency for Research on Cancer. The margin of exposure (MOE) approach was used for comparative risk assessment. MOE compares a toxicological threshold with the exposure. MOEs above 10,000 are judged as low priority for risk management action. MOEs were calculated for different drinking scenarios (low risk and heavy drinking) and different levels of contamination for four beverage groups (beer, wine, spirits and unrecorded alcohol). The lowest MOEs were found for ethanol (3.1 for low risk and 0.8 for heavy drinking). Inorganic lead and arsenic have average MOEs between 10 and 300, followed by acetaldehyde, cadmium and ethyl carbamate between 1,000 and 10,000. All other compounds had average MOEs above 10,000 independent of beverage type. Ethanol was identified as the most important carcinogen in alcoholic beverages, with clear dose response. Some other compounds (lead, arsenic, ethyl carbamate, acetaldehyde) may pose risks below thresholds normally tolerated for food contaminants, but from a cost effectiveness point of view, the focus should be on reducing alcohol consumption in general rather than on mitigative measures for some contaminants that contribute only to a limited extent (if at all) to the total health risk. PMID- 22447329 TI - Septic versus inflammatory arthritis: discriminating the ability of serum inflammatory markers. AB - Early diagnosis of septic arthritis is very important. Few studies showed diagnostic accuracy of serum inflammatory markers in septic arthritis. The aim of our study was to compare the serum and synovial fluid markers [procalcitonin, serum IL-6, TNF-alpha, C-reactive protein, erythrocyte sedimentation rate, synovial fluid white blood cell counts and PMN percentage] in septic and inflammatory arthritis. Seventy-five patients, including 25 and 50 septic and non septic arthritis, were enrolled in the study. The serum and synovial fluid markers [procalcitonin, serum IL-6, TNF-alpha, C-reactive protein, erythrocyte sedimentation rate, synovial fluid white blood cell counts, and PMN percentage] were compared in septic and inflammatory arthritis. Patients with septic arthritis had significantly elevated levels of procalcitonin, serum TNF-alpha, C reactive protein, erythrocyte sedimentation rate, synovial fluid white blood cell counts, and PMN percentage in comparison with the inflammatory arthritis group (P < 0.00). Serum IL-6 level does not differ among the two groups. In a receiver operating characteristic curve analysis, synovial fluid WBC counts, PMN percentage, TNF-alpha, ESR, and serum PCT preformed best in distinguishing between septic and non-septic arthritis. Our study suggests that PCT can be used to diagnose the septic arthritis, but more studies warranted in order to determine the specificity and sensitivity of the test. PMID- 22447330 TI - Rheumatic disease presenting as septic arthritis: a report of 10 cases. AB - To determine the forms and characteristics of rheumatic diseases whose initial presentation mimics septic arthritis. Retrospective study of 398 patients hospitalized between 1979 and 2005 for arthritis diagnosed and treated as septic. In 10 cases, initial presentation of a rheumatic disease was highly suggestive of septic arthritis, and the patient was treated as such. Three had rheumatoid arthritis, 3 spondyloarthropathies, 2 unclassified rheumatic diseases, 1 Wegener granulomatosis and 1 cytosteatonecrosis. Mean time to diagnosis of rheumatic arthritis was 6 months. There were 7 males and 3 females aged from 15 to 77 years. Six had fever, and 3 had leucocytosis. Average ESR was 68 mm/1 h, and C reactive protein was above 100 mg/l in 6 patients. Five patients had radiological signs suggestive of septic arthritis. Joint fluid count was above 100,000 WBCs/mm(3) in 2/5. Synovial biopsy suggested septic arthritis in 5 out of 6. These cases of pseudoseptic arthritis were indistinguishable from true septic arthritis. Follow-up is required in septic arthritis with negative culture findings to exclude rheumatic disease. PMID- 22447331 TI - Tacrolimus treatment increases bone formation in patients with rheumatoid arthritis. AB - Tacrolimus is a calcineurin inhibitor, and it is used for the treatment of rheumatoid arthritis (RA). It works by inhibiting nuclear factor of activated T cells and inducting immunosuppression. This study aims to evaluate the influence of tacrolimus on the bone metabolism of patients with RA. Twenty-eight RA patients in three centers received tacrolimus 3 mg once daily for 24 weeks. Blood samples for evaluating bone metabolism and cytokines were collected at Weeks 0 and 24. We measured the serum C-telopeptide of type I collagen (sCTx-I), osteocalcin and inflammatory cytokines. We analyzed the data using the Kruskal Wallis test and Spearman's correlation. IL-2 and IL-6 were significantly decreased after the administration of tacrolimus (p = 0.027 and p = 0.024). There was no significant difference in the serum level of sCTx-I before and after treatment. The level of serum osteocalcin at Week 24 was significantly increased compared to the level at Week 0 (p = 0.002). The increase of osteocalcin was correlated with the reductions of IL-2 and IFN-gamma (r = 0.405, p = 0.033 and r = 0.380, p = 0.046, respectively). Tacrolimus treatment increased bone formation markers in RA patients. This suggests that tacrolimus may play a role to inhibit bone erosion by increasing bone formation as well as improving the clinical symptoms of RA. PMID- 22447332 TI - Ameliorative effect of p-coumaric acid, a common dietary phenol, on adjuvant induced arthritis in rats. AB - p-Coumaric acid (3-(4-hydroxyphenyl)-2-propenoic acid), a common dietary polyphenol, is widely distributed in cereals, fruits and vegetables with antioxidant property. Numerous studies have enlightened the ability of dietary phenols to be considered as potential therapeutics against arthritis. In this study, we aimed to investigate the ameliorative effect of plant phenolic p coumaric acid on adjuvant-induced arthritis in rats. The reference drug indomethacin was used for comparison purposes. Arthritis was induced in rats by a single intradermal injection of complete freund's adjuvant (0.1 mL) into the foot pad of right hind paw. p-Coumaric acid (100 mg/kg b wt) and indomethacin (3 mg/kg b wt) were administered intraperitoneally for 8 days from day 11 to 18 after adjuvant injection. An increase in the activities/levels of lysosomal enzymes, tissue marker enzymes, glycoproteins and paw thickness was observed in the arthritic rats, on the contrary, the body weight was found to be reduced in arthritic rats when compared to normal control rats. Administration of p-coumaric acid (100 mg/kg b wt) to the arthritic rats reverted back the altered physical and biochemical parameters to near normal levels comparable to indomethacin treatment. Histopathological evaluation of ankle joints in arthritic rats also revealed the anti-inflammatory effect of p-coumaric acid by the reduction in leukocytes infiltration. Thus, the present study clearly demonstrates the anti inflammatory potential of the p-coumaric acid against adjuvant-induced arthritis in rats. PMID- 22447333 TI - Poly(ethylene glycol) cross-linked hemoglobin with antioxidant enzymes protects pancreatic islets from hypoxic and free radical stress and extends islet functionality. AB - The objective of this study was to investigate the efficiency of multifunctional poly(ethylene glycol)-based hemoglobin conjugates crosslinked with antioxidant enzymes for their ability to protect an oxygen carrier (hemoglobin) and insulin secreting islets from the combination of hypoxic and free radical stress under simulated transplantation conditions. In this study, RINm5F cells and isolated pancreatic islets were challenged with oxidants (H(2)O(2) or xanthine and xanthine oxidase) and incubated with conjugates (hemoglobin-hemoglobin or superoxide dismutase-catalase-hemoglobin) in normoxia (21% oxygen) or hypoxia (6% or 1% oxygen). Hemoglobin protection, intracellular free radical activity and cell viability in RINm5F cells measured by methemoglobin, dichlorofluorescein diacetate, and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, respectively, showed that cells were better protected by conjugates containing antioxidant enzymes. Insulin secretion from islets and qualitative confocal evaluation of viability showed beta cells were protected by conjugates containing antioxidant enzymes when exposed to induced stress. Our study suggested that antioxidant enzymes play a significant role in hemoglobin protection and thus extended cell protection. PMID- 22447334 TI - A general strategy to layered transition-metal hydroxide nanocones: tuning the composition for high electrochemical performance. AB - A general and facile strategy for the synthesis of a large family of monometallic (Co, Ni) and bimetallic (Co-Ni, Co-Cu and Co-Zn) hydroxide nanocones (NCs) intercalated with DS ions is demonstrated. The basal spacing of the NCs can be varied by adjusting the intercalated DS amount. Especially, electrochemical characterizations reveal that bimetallic Co-Ni hydroxide NCs have a higher specific capacitance than their monometallic counterpart. These results suggest the importance of rational designing layered hydroxide NCs with tuned transition metal composition for high-performance energy storage devices. PMID- 22447335 TI - JPH3 repeat expansions cause a progressive akinetic-rigid syndrome with severe dementia and putaminal rim in a five-generation African-American family. AB - We report the clinical, neuropsychological, genetic, and radiological features of a large five-generation African-American kindred from the southern USA presenting with a progressive akinetic-rigid syndrome and severe dementia, but clinically insignificant chorea, due to mutations in junctophillin 3 (JPH3). Overt disease onset was in the mid-20s to late 30s with cognitive decline, REM sleep disturbance, or psychiatric features, followed by development of a levodopa unresponsive akinetic-rigid motor syndrome. Dystonia and myoclonus were present in some subjects. A bedridden, nonverbal severely akinetic-rigid state developed within 10 to 15 years after onset. CTG repeat expansions ranged from 47 to 53. Imaging revealed generalized cerebral atrophy with severe striatal involvement and putaminal rim hyperintensity. Analysis of our kindred indicates that JPH3 mutations should be considered in the differential diagnosis of early-onset dementia and hypokinetic-rigid syndromes in individuals of African descent. Moreover, chorea may not be overtly manifest at presentation or during significant parts of the disease course. PMID- 22447336 TI - Approaches to sensitizing glioblastoma to radiotherapy: use of lentiviral vectors. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumour and extirpation followed by radio- and chemotherapy has had minimal impact on the median survival of patients which is still less than one year. Hence, a novel therapeutic modality is required if the survival of patients with this disease is to be improved. ATM, mutated in the human genetic disorder ataxia-telangiectasia (A-T), plays a central role in the response to DNA double strand breaks and patients with this disorder are characterised by extreme sensitivity to radiation, increased risk of cancer and neurodegeneration. Thus, ATM represents a potential target for radiosensitization of brain tumour cells. A safe, non replicating lentivirus is used to abrogate ATM in GBM through the antisense and RNAi approaches for radiosensitization. With either techniques, ATM protein was reduced by >90% and there was a 3-fold sensitization of GBM cells to radiation. ATM protein activation as well as ATM pS1981 foci formation were defective and downstream signalling determined by Ser15 phosphorylation on p53 was reduced. Success in the approaches provides a novel and exciting strategy for the treatment of GBM and thus improving the survival of patients with these tumours. PMID- 22447337 TI - Perfluoroalkyl contaminants in plasma of five sea turtle species: comparisons in concentration and potential health risks. AB - The authors compared blood plasma concentrations of 13 perfluoroalkyl contaminants (PFCs) in five sea turtle species with differing trophic levels. Wild sea turtles were blood sampled from the southeastern region of the United States, and plasma was analyzed using liquid chromatography tandem mass spectrometry. Mean concentrations of perfluorooctane sulfonate (PFOS), the predominant PFC, increased with trophic level from herbivorous greens (2.41 ng/g), jellyfish-eating leatherbacks (3.95 ng/g), omnivorous loggerheads (6.47 ng/g), to crab-eating Kemp's ridleys (15.7 ng/g). However, spongivorous hawksbills had surprisingly high concentrations of PFOS (11.9 ng/g) and other PFCs based on their trophic level. These baseline concentrations of biomagnifying PFCs demonstrate interesting species and geographical differences. The measured PFOS concentrations were compared with concentrations known to cause toxic effects in laboratory animals, and estimated margins of safety (EMOS) were calculated. Small EMOS (<100), suggestive of potential risk of adverse health effects, were observed for all five sea turtle species for immunosuppression. Estimated margins of safety less than 100 were also observed for liver, thyroid, and neurobehavorial effects for the more highly exposed species. These baseline concentrations and the preliminary EMOS exercise provide a better understanding of the potential health risks of PFCs for conservation managers to protect these threatened and endangered species. PMID- 22447338 TI - Review of toxicological effects caused by episodic stressor exposure. AB - Water quality monitoring tools that rely on data from stress-response tests with continuous exposure at constant concentrations are not always appropriately protective when stressor exposure in the field is episodic in nature. The present study identifies various approaches that have attempted to account for episodic stressor exposure, describes the development of a toxicological effects database of episodic stressor exposure collated from published scientific literature, and discusses whether any discernible trends are evident when these data are reviewed. The episodic stressor exposure literature indicated that few generalizations can be made regarding associated biological responses. Instead, when attempting to characterize the hazard of a certain episodic pollution event, the following situation-specific information is required: the specific species affected and its age, the specific stressor and its concentration, the number of exposures to the stressor, the duration of exposure to the stressor, and the recovery time after each exposure. The present study identifies four main challenges to the inclusion of episodic toxicity data in environmental water quality management: varying stressor concentration profiles, defining episodic stressor concentration levels, variation resulting from routes of exposure and modes of action, and species-specific responses to episodic stressor exposure. The database, available at http://iwr.ru.ac.za/iwr/download, could be particularly useful for site-specific risk assessments related to episodic exposures. PMID- 22447339 TI - A survey of the sedation practice of Portuguese palliative care teams. AB - AIM: The purpose of this study is to study the practice of sedation by Portuguese palliative care teams. METHODS: The teams included on the website of the Portuguese Association for Palliative Care were invited to participate. Data from all the patients sedated between April and June 2010 were recorded. Sedation was defined as the intentional administration of sedative drugs for symptom control, except insomnia, independently of the consciousness level reached. RESULTS: Of the 19 teams invited only 4 actually participated. During the study period, 181 patients were treated: 171 (94 %) were cancer patients and 10 non-cancer patients. Twenty-seven (16 %) patients were sedated: 13 intermittently, 11 continuously, and 3 intermittently at first then continuously. The rate of sedation varied substantially among the teams. Delirium was the most frequent reason for sedation. Midazolam was the drug used in most cases. In 21 cases of sedation, the decision was made unilaterally by the professionals; in 16 (76 %) of those, the situation was deemed to be emergent. From the patients on continuous sedation, 9 (64 %) patients maintained oxygen, 13 (93 %) hydration, and 6 (43 %) nutrition. Two patients who had undergone intermittent sedation were discharged home and one was transferred to another institution; the reason for sedation in the three cases was delirium. CONCLUSION: There is a substantial variation in the sedation rate among the teams. One of the most important aspects was the decision-making process which should be object of reflection and discussion in the teams. PMID- 22447340 TI - Two highly homologous methionine sulfoxide reductase A from tomato (Solanum lycopersicum), exhibit distinct catalytic properties. AB - E4, which is a fruit-ripening gene that is strongly induced by ethylene, has been reported to be a member of the methionine sulfoxide reductase A (MSRA) gene. In the present study, we determined for the first time the enzymatic activity and delineated the catalytic mechanism of the E4 protein via site-directed mutagenesis. The disulfide intermolecular cross-linking, kinetics parameter, thiol content titration analysis of wild-type and mutated E4 proteins revealed that the cysteine at position 37 (Cys-37) was the key catalytic residue, and Cys 194, but not Cys-180 served as the first recycling Cys in the thioredoxin (Trx) dependent regeneration system. In addition, the SlMSRA2 protein, which was encoded by another MSRA gene, shared high similarity with the E4 protein and was truncated at the C-terminus. The wild-type and mutated SlMSRA2 enzymes had similar activities compared to the E4 protein using DTT as a reductant, but showed extremely low activities in the Trx-dependent reduction system. Our results indicated that E4 and SlMSRA2 proteins might exhibit distinct catalytic mechanisms. PMID- 22447341 TI - Bevacizumab nasal spray: Noninvasive treatment of epistaxis in patients with Rendu-Osler disease. AB - OBJECTIVES/HYPOTHESIS: To evaluate the efficacy and safety of bevacizumab administered at a concentration of 50 mg as an intranasal spray in the treatment of epistaxis in patients suffering from Rendu-Osler disease. STUDY DESIGN: Prospective. METHODS: A preliminary, prospective, review board-approved study was conducted on six patients with Rendu-Osler disease who received 10 treatment courses of 50 mg bevacizumab. Monthly follow-up was based on the epistaxis severity score (ESS), with adverse effects being reported. RESULTS: Ten treatment courses were administered to six patients, with a mean follow-up period of 2.8 months. A statistically significant decrease in mean ESS was observed at 1 month (P < .001) and 2 months (P < .005), whereas a nonsignificant decrease was found at 3 months (P = .07). A nonsignificant decline in mean ESS was detected at 1 month in patients with ESS >=7 at baseline. No adverse effects were reported. CONCLUSIONS: The intranasal spray application of 50 mg bevacizumab was found to be an effective symptomatic treatment over a period of 2 months for patients with a pretreatment ESS of <7, with no adverse effects being noted. PMID- 22447343 TI - Suicidality and associated factors in pregnant women in Brazil. AB - Is important to evaluate suicidal potential and related factors during pregnancy among women who have attended public health services. To determine the suicidal potential, question 10 from Edinburgh Postnatal Depression Scale (EPDS) was used. In this sample (N = 1,334), 8.1% of pregnant women demonstrated suicidal potential. The potential risk factors for suicide in depressed pregnant women were being single, divorced or widowed, thinking about having an abortion, and having anxiety symptoms; in nondepressed pregnant women were lower age, low education level, low socioeconomic class, thoughts about having an abortion and anxiety symptoms. PMID- 22447344 TI - Meeting unmet needs of families of persons with mental illness: evaluation of a family peer support helpline. AB - Family members of persons with mental illness experience multiple stressors stemming from the burdens of caring for the ill family member. A potential source of help for this population is a family peer support helpline. Knowledge, however, is lacking about the types of help offered in such a service and its benefit for this population. In a study conducted in Israel, 800 calls made by family members of persons with mental illness to a family peer support helpline were analyzed utilizing an instrument developed for the family peers' evaluation of the calls. In addition, researchers conducted 77 follow-up interviews with callers who agreed to be interviewed. The findings indicate the importance of the life experience, flexibility and anonymity of the family peers in providing types of help that are complementary to the help provided by formal services. The most frequent categories of support provided were emotional support, information and advice. This help could assist family members of persons with mental illness with their care-giving role, as well as provide them with an alternative source of help if they experience difficulties with professionals. It could also serve as a catalyst in encouraging them to establish and maintain contact with the formal mental health services. Recognizing and supporting the contribution of a family peer support helpline would encourage its development within the range of services available for this population. PMID- 22447346 TI - Can we address the shortage of psychiatrists in the correctional setting with exposure during residency training? AB - Psychiatry residents at the University of Texas Southwestern Medical Center were surveyed to investigate their attitudes towards inmates, towards various aspects of correctional psychiatry and whether rotating at the local jail is associated with these attitudes. The overall opinion towards correctional psychiatry was fairly neutral though significantly more negative than towards inpatient psychiatry. While citing a high need for psychiatrists at correctional facilities, residents reported they are not likely to work there when they complete residency. No statistical differences were found between those residents who had rotated at the local jail and those who had not. Given the severe shortage of mental health providers in correctional facilities it is important to expose residents to this and understand ways to promote correctional psychiatry as a career. PMID- 22447345 TI - Implementation of a weight loss program for Latino outpatients with severe mental illness. AB - To determine feasibility of implementation of a weight loss program for overweight Latinos with severe mental illness. In this quasi-experimental study, a 14-week behavioral weight loss course (extended) was implemented at one clinic. A one-time nutrition class (brief) was given at a sister clinic. Implementation feasibility was assessed by consent and participation rates. Weight was followed for 6 months. Consent rates were high [77 % (49/64) extended; 68 % (39/57) brief], and 88 % (43/49) of extended subjects participated and 88 % (38/43) completed follow-up. Weight loss did not differ between groups. A behavioral weight loss course is feasible to implement for this population. PMID- 22447347 TI - Influence of the shape of intracellular potentials on the morphology of single fiber extracellular potentials in human muscle fibers. AB - Attention of the investigators is usually pointed to the peak-to-peak characteristics of single-fiber action potentials (SFAPs) that are mainly determined by the depolarizing phase of the intracellular action potential (IAP). However, the final portion of the SFAP has often specific shape that has to be related to peculiarities of the repolarization phase of IAP and the duration of its spike. A novel piecewise SFAP model is proposed to achieve greater insight into the nature of declining portion of the negative phase and of the third phase of SFAP. It was found that the SFAP third phase is essentially determined by the specific profile of the transition of the IAP falling phase toward the resting voltage, whereas the SFAP declining negative phase is more dependent upon the width of the corresponding IAP spike. We tentatively suggest that the duration of the spike of human IAPs should be over approximately 0.75 ms. PMID- 22447348 TI - A CAD/CAM-prototyped anatomical condylar prosthesis connected to a custom-made bone plate to support a fibula free flap. AB - This paper describes a new protocol for mandibular reconstruction. Computer-aided design/computer-aided manufacturing (CAD/CAM) technology was used to manufacture custom-made cutting guides for tumor ablation and reconstructive plates to support fibula free flaps. CT scan data from a patient with an odontogenic keratocyst on the left mandibular ramus were elaborated to produce a virtual surgical plan of mandibular osteotomy in safe tissue for complete ramus resection. The CAD/CAM procedure was used to construct a customized surgical device composed of a cutting guide and a titanium reconstructive bone plate. The cutting guide allowed the surgeon to precisely transfer the virtual planned osteotomy into the surgical environment. The bone plate, including a custom-made anatomical condylar prosthesis, was designed using the outer surface of the healthy side of the mandible to obtain an ideal contour and avoid the bone deformities present on the side affected by the tumor. Operation time was reduced in the demolition and reconstruction phases. Functional and aesthetic outcomes allowed patients to immediately recover their usual appearance and functionality. This new protocol for mandibular reconstruction using CAD/CAM to construct custom made guides and plates may represent a viable way to reproduce the patient's anatomical contour, give the surgeon better procedural control, and reduce operation time. PMID- 22447349 TI - Is it possible to detect dendrite currents using presently available magnetic resonance imaging techniques? AB - The action currents of a dendrite, peripheral nerve or skeletal muscle create their own magnetic field. Many investigators have attempted to detect neural and dendritic currents directly using magnetic resonance imaging that can cause the phase of the spins to change. Our goal in this paper is to use the calculated magnetic field of a dendrite to estimate the resulting phase shift in the magnetic resonance signal. The field produced by a dense collection of simultaneously active dendrites may be just detectable under the most ideal circumstances, but in almost every realistic case the field cannot be detected using current MRI technology. PMID- 22447350 TI - Cross-roads in the lung: immune cells and tissue interactions as determinants of allergic asthma. AB - Allergic asthma is a chronic disease of the lung characterized by underlying Th2- and IgE-mediated inflammation, structural alterations of the bronchial wall, and airway hyperresponsiveness. Initial allergic sensitization and later development of chronic disease are determined by close interactions between lung structural cells and the resident and migratory immune cells in the lung. Epithelial cells play a crucial role in allergic sensitization by directly influencing dendritic cells induction of tolerant or effector T cells and production of type 2 cytokines by innate immune cells. During chronic disease, the bronchial epithelium, stroma, and smooth muscle become structurally and functionally altered, contributing to the perpetuation of tissue remodeling. Thus, targeting tissue-driven pathology in addition to inflammation may increase the effectiveness of asthma treatment. PMID- 22447351 TI - The influence of pregnancy on systemic immunity. AB - Adaptations in maternal systemic immunity are presumed to be responsible for observed alterations in disease susceptibility and severity as pregnancy progresses. Epidemiological evidence as well as animal studies have shown that influenza infections are more severe during the second and third trimesters of pregnancy, resulting in greater morbidity and mortality, although the reason for this is still unclear. Our laboratory has taken advantage of 20 years of experience studying the murine immune response to respiratory viruses to address questions of altered immunity during pregnancy. With clinical studies and unique animal model systems, we are working to define the mechanisms responsible for altered immune responses to influenza infection during pregnancy and what roles hormones such as estrogen or progesterone play in these alterations. PMID- 22447352 TI - Mucosal immunology of tolerance and allergy in the gastrointestinal tract. AB - The mucosal immune system typically exists in a state of active tolerance to food antigens and commensal bacteria. Tolerance to food proteins is induced in part by dendritic cells residing in the intestinal mucosa and implemented by regulatory T cells. Food allergy occurs when immune tolerance is disrupted and a sensitizing immune response characterized by food-specific IgE production occurs instead. Experimental food allergy in mice requires use of adjuvant or exploitation of alternate routes of sensitization to induce allergic sensitization, and can aid in understanding the mechanisms of sensitization to food allergens and the pathophysiology of gastrointestinal manifestations of food allergy. Recent work in the understanding of mucosal immunology of tolerance and allergy in the gastrointestinal tract will be discussed. PMID- 22447353 TI - The health-promotion perspective in public-health plans in a Swedish region over three decades. AB - The trend away from a health and medical care-based policy to a healthy public policy has taken place in Sweden rather later than in other West European countries. One of the first county councils to establish health-promotion plans was Vasternorrland. The aims of this study are to describe the contents of and analyze the changes over time in the five public-health plans in the county. The object of study for the policy analysis consists in these plans between 1978 and 2004. A deductive thematic content analysis was performed for each plan on the basis of the central determinants of health promotion. The positioning of the plans was determined using a theoretical framework (Beattie's modified model) founded in the dimensions of power (individual and collective) and governance (local, i.e. the municipalities, and central, i.e. the county council). The results show that the value attributed to good health was consistently high, but the means for attaining this goal have varied over time. The policy focus of the measures in the plans have taken a cyclical path--from individual empowerment to empowerment from a societal perspective, and back prioritizing of actions at an individual level. On the governance dimension, there has been a corresponding positional change over time--from regional to local and then back to regional. Promoting the health of a population requires mutual interaction between the regional and local levels, in which both societal and individually oriented actions are prioritized. PMID- 22447354 TI - Kinetic and functional characterisation of the heparin-binding peptides from human transglutaminase 2. AB - Transglutaminase 2 (TG2) is an autoantigen in celiac disease (CD) and it has multiple biologic functions including involvement in cell adhesion through interactions with integrins, fibronectin (FN), and heparan sulfate proteoglycans. We aimed to delineate the heparin-binding regions of human TG2 by studying binding kinetics of the predicted heparin-binding peptides using surface plasmon resonance method. In addition, we characterized immunogenicity of the TG2 peptides and their effect on cell adhesion. The high-affinity binding of human TG2 to the immobilized heparin was observed, and two TG2 peptides, P1 (amino acids 202-215) and P2 (261-274), were found to bind heparin. The amino acid sequences corresponding to the heparin-binding peptides were located close to each other on the surface of the TG2 molecule as part of the alpha-helical structures. The heparin-binding peptides displayed increased immunoreactivity against serum IgA of CD patients compared with other TG2 peptides. The cell adhesion reducing effect of the peptide P2 was revealed in Caco-2 intestinal epithelial cell attachment to the FN and FN-TG2 coated surfaces. We propose that TG2 amino acid sequences 202-215 and 261-274 could be involved in binding of TG2 to cell surface heparan sulfates. High immunoreactivity of the corresponding heparin-binding peptides of TG2 with CD patient's IgA supports the previously described role of anti-TG2 autoantibodies interfering with this interaction. PMID- 22447355 TI - Obscure gastrointestinal bleeding: difficulties in comparing CT enterography and video capsule endoscopy. AB - A paper reports the results of a retrospective study that was designed to evaluate the potential role of video capsule endoscopy (VCE) in elucidating the cause of bleeding in patients with obscure gastrointestinal bleeding (OGIB) for whom CT enterography was negative. The authors highlight the limitations of dual phase CT enterography for the detection of flat lesions of the small bowel such as ulcers, angiodysplasias or arteriovenous malformations, and confirm the superiority of VCE for the detection of this category of lesions. This commentary discusses some of the issues raised. KEY POINTS: * Video capsule endoscopy surpasses CT enterography in detecting flat small bowel lesions. * Retrospective VCE and CT enterography findings in obscure bleeding need further evaluation. * A fair and unbiased comparison of the two investigations is still needed. PMID- 22447356 TI - Toxicity of major cations and anions (Na+, K+, Ca2+, Cl-, and SO4(2-)) to a macrophyte and an alga. AB - In many freshwater systems around the world, the concentrations of major ions (Na(+), K(+), Ca(2+), Mg(2+), Cl(-), HCO(3)(-), CO(3)(2-), and SO(4)(2-)) are exhibiting increasing trends, approaching the concentrations historically found mainly in estuaries. The objectives of the present study were to determine at what concentrations these salts are toxic to an aquatic plant and a green alga, to investigate two potential mechanisms of toxicity, and to determine the usefulness of conductivity as an indicator of salt toxicity. In a series of laboratory trials, Lemna minor and Pseudokirchneriella subcapitata were exposed to a range of concentrations of five different salts. Conductivity levels that caused 10 or 50% reductions in growth-related traits (EC10 and EC50, respectively) were determined, using conductivity of the test solutions as the independent variable. The EC10 values ranged from 0.44 to 2.67 mS/cm for P. subcapitata and from 1.3 to >19 mS/cm for L. minor. The EC50 values ranged from 1.7 to 5.8 mS/cm for P. subcapitata and from 4.2 to >27 mS/cm for L. minor. For both species the EC values varied dramatically among the salts. Pseudokirchneriella subcapitata was most sensitive to KCl and NaCl, whereas L. minor was most sensitive to Na(2)SO(4). The mechanism of toxicity does not appear to be related to production of reactive oxygen species, nor to reduction in chlorophyll concentrations. Because toxicity was strongly influenced by salt composition, regulation and management of specific ions may be preferable to conductivity. PMID- 22447357 TI - Polyaspartamide-polylactide electrospun scaffolds for potential topical release of Ibuprofen. AB - In this work, the production and characterization of electrospun scaffolds of the copolymer alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide-graft-polylactic acid (PHEA-g-PLA), proposed for a potential topical release of Ibuprofen (IBU), are reported. The drug has been chemically linked to PHEA-g-PLA and/or physically mixed to the copolymer before electrospinning. Degradation studies have been performed as a function of time in Dulbecco phosphate buffer solution pH 7.4, for both unloaded and drug-loaded scaffolds. By using an appropriate ratio between drug physically blended to the copolymer and drug-copolymer conjugate, a useful control of its release can be obtained. MTS assay on human dermal fibroblasts cultured onto these scaffolds, showed the absence of toxicity as well as their ability to allow cell adhesion. PMID- 22447358 TI - Extreme clinical variability of dilated cardiomyopathy in two siblings with Alstrom syndrome. AB - Alstrom syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report two brothers, 3 and 4 years of age and diagnosed with ALMS, who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intrafamilial variability. Although cardiomyopathy in the older sibling has mainly resolved thus allowing for the discontinuation of medical therapy, heart function in the younger sibling continues to deteriorate despite maximal drug support with furosemide, carvedilol, captopril, and aldospirone. Genetic analysis revealed homozygous mutations, c.8008C>T (R2670X), in ALMS1 resulting in premature protein truncation. This report further emphasizes the exceptional intrafamilial variability of ALMS, mainly during the natural course of cardiac disease. PMID- 22447359 TI - An angiographic predictor of pulmonary artery stenosis after the Norwood-Sano operation for hypoplastic left heart syndrome. AB - The objective of this study was to determine angiographic predictors of future pulmonary artery stenosis (PS) in patients with hypoplastic left heart syndrome (HLHS) at the time of pre-stage 2 cardiac catheterization (PS2C). The Sano modification of the Norwood operation (NSO) for HLHS includes placement of a right ventricle-to-pulmonary artery (RV-PA) conduit. Branch PS is a recognized complication. Data from patients with HLHS who underwent NSO from 2005 to 2009 and who underwent PS2C were reviewed retrospectively. Nakata and McGoon indices were calculated in the traditional fashion, and modified Nakata and McGoon indices were calculated using the narrowest branch PA diameters. Thirty-three patients underwent NSO and 28 patients underwent PS2C. Mean follow-up was 35.8 +/ 7.5 months. Ten (36 %) patients had significant left branch PS, with two requiring balloon angioplasty and eight requiring stent placement, a median of 15.2 months after PS2C (interquartile range 1.2, 32.8). The modified Nakata index was predictive of future intervention for left PS (receiver operating characteristic curve area under the curve 0.811), with a cut-off of 135 mm(2)/m(2) and a sensitivity of 100 % and specificity of 72.2 %. A modified Nakata index <135 mm(2)/m(2) at PS2C predicts future need for intervention on left-branch PS in patients with HLHS after the NSO. Surgical pulmonary arterioplasty at the time of stage 2 surgical palliation may obviate the need for future interventions. PMID- 22447360 TI - Gait measures with a triaxial accelerometer among patients with neurological impairment. AB - The purpose of the present study is to evaluate accelerometric parameters of gait in different neurological conditions with pathological gait impairment compared to healthy subjects. We studied 17 patients affected by Parkinson's disease, 24 with ataxic gait due to different diseases and 24 healthy subjects supplied with a triaxial accelerometer with a portable datalogger which measures acceleration and deceleration on an anterior-posterior, mediolateral and vertical plane at an approximate level of the center of mass (back sacral localization) and in other two positions (sternal and frontal sacral region) during a steady-state walking. Analyses of the basic accelerometric parameters associated with a jerk analysis allowed us to differentiate between the population groups. We observed a significant reduction of acceleration parameters in neurological patients when compared with healthy subjects, with a reduction of the mean acceleration of 0.30 m/s(2) for ataxic and 0.64 m/s(2) for parkinsonian patients (t test, p < 0.01). The root-mean square of the accelerations was used to quantify the attenuations of accelerations. This study suggests that a triaxial accelerometer is a good practical and an economic tool for assessing the alteration of perambulation. Moreover, it is plausible to use these data to obtain objective parameters in the evaluation of the progression of the disease and the efficacy of therapeutic tools. PMID- 22447361 TI - Longitudinal extensive transverse myelitis and optic neuritis: the elements for the diagnosis of neuromyelitis optica. PMID- 22447362 TI - Insulin-like growth factor 2 hypomethylation of blood leukocyte DNA is associated with gastric cancer risk. AB - To determine whether or not the methylation status of blood leukocyte DNA can be used as a surrogate marker of the risk for cancer, we quantitatively determined the methylation levels of insulin-like growth factor 2 (IGF2) and TUSC3 in 299 gastric cancer cases, and 299 age- and gender-matched controls. The IGF2 methylation levels in blood leukocyte DNA of the cases were lower than those of the healthy controls and there was a significant trend of increasing gastric cancer risk with decreasing methylation level of IGF2. Patients with hypermethylated IGF2 in blood leukocyte DNA showed a significantly better survival rate than those with hypomethylated IGF2, indicating that the IGF2 methylation level in blood leukocyte DNA can be a possible marker not only of the risk for but also of the prognosis of gastric cancer. In contrast, the TUSC3 methylation level in blood leukocyte DNA was higher in the cases than in the healthy controls, but the difference was not significant. The past lifestyle and clinicopathological characteristics of the participants were analyzed for any relationship with the methylation level. With aging and smoking, methylation of IGF2 and TUSC3 decreased and increased in blood leukocyte DNA, respectively. These results indicate that the methylation level of IGF2 in blood leukocyte DNA may be used as an important surrogate marker of the risk for gastric cancer. PMID- 22447363 TI - Continuous modeling of metabolic networks with gene regulation in yeast and in vivo determination of rate parameters. AB - A continuous model of a metabolic network including gene regulation to simulate metabolic fluxes during batch cultivation of yeast Saccharomyces cerevisiae was developed. The metabolic network includes reactions of glycolysis, gluconeogenesis, glycerol and ethanol synthesis and consumption, the tricarboxylic acid cycle, and protein synthesis. Carbon sources considered were glucose and then ethanol synthesized during growth on glucose. The metabolic network has 39 fluxes, which represent the action of 50 enzymes and 64 genes and it is coupled with a gene regulation network which defines enzyme synthesis (activities) and incorporates regulation by glucose (enzyme induction and repression), modeled using ordinary differential equations. The model includes enzyme kinetics, equations that follow both mass-action law and transport as well as inducible, repressible, and constitutive enzymes of metabolism. The model was able to simulate a fermentation of S. cerevisiae during the exponential growth phase on glucose and the exponential growth phase on ethanol using only one set of kinetic parameters. All fluxes in the continuous model followed the behavior shown by the metabolic flux analysis (MFA) obtained from experimental results. The differences obtained between the fluxes given by the model and the fluxes determined by the MFA do not exceed 25% in 75% of the cases during exponential growth on glucose, and 20% in 90% of the cases during exponential growth on ethanol. Furthermore, the adjustment of the fermentation profiles of biomass, glucose, and ethanol were 95%, 95%, and 79%, respectively. With these results the simulation was considered successful. A comparison between the simulation of the continuous model and the experimental data of the diauxic yeast fermentation for glucose, biomass, and ethanol, shows an extremely good match using the parameters found. The small discrepancies between the fluxes obtained through MFA and those predicted by the differential equations, as well as the good match between the profiles of glucose, biomass, and ethanol, and our simulation, show that this simple model, that does not rely on complex kinetic expressions, is able to capture the global behavior of the experimental data. Also, the determination of parameters using a straightforward minimization technique using data at only two points in time was sufficient to produce a relatively accurate model. Thus, even with a small amount of experimental data (rates and not concentrations) it was possible to estimate the parameters minimizing a simple objective function. The method proposed allows the obtention of reasonable parameters and concentrations in a system with a much larger number of unknowns than equations. Hence a contribution of this study is to present a convenient way to find in vivo rate parameters to model metabolic and genetic networks under different conditions. PMID- 22447364 TI - Biocompatible magnetite nanoparticles with varying silica-coating layer for use in biomedicine: physicochemical and magnetic properties, and cellular compatibility. AB - Magnetic nanoparticles (MNPs) are considered highly useful in therapeutic and diagnostic applications. However, MNPs require surface modification to promote dispersibility in aqueous solutions and thus biocompatibility. In this article, the authors modified MNPs with inorganic silica layer to create silica-coated magnetite nanoparticles (MNP@Si) via sol-gel process. Synthesis involves hydrolysis and condensation steps using tetraethylorthosilicate (TEOS) in methanol/ polyethylene glycol (PEG) solution and ammonia catalyst. Nanoparticles were characterized in terms of morphology, particle size, crystalline phase, chemical-bond structure, surface charge and magnetic properties: in particular, the MNP@Si size was easily tunable through alteration of the Fe(3) O(4) -to-TEOS ratio. As this ratio increased, the MNP@Si size decreased from 270 to 15 nm whilst maintaining core 12-nm MNP particle size, indicating decrease in thickness of the silica coating. All MNP@Si, in direct contrast to uncoated MNPs, showed excellent stability in aqueous solution. The particles' physicochemical and magnetic properties systematically varied with size (coating thickness), and the zeta potential diminished toward negative values, while magnetization increased as the coating thickness decreased. 15-nm MNP@Si showed excellent magnetization (about 64.1 emu/g), almost comparable to that of uncoated MNPs (70.8 emu/g). Preliminary in vitro assays confirmed that the silica layer significantly reduced cellular toxicity as assessed by increase in cell viability and reduction in reactive oxygen species production during 48 h of culture. Newly-developed MNP@Si, with a high capacity for magnetization, water-dispersibility, and diminished cell toxicity, may be potentially useful in diverse biomedical applications, including delivery of therapeutic and diagnostic biomolecules. PMID- 22447365 TI - Correlates of peer support in a clubhouse setting. AB - The purpose of this study was to examine the social support characteristics and correlates of peer networks for Clubhouse members. A random sample of 126 members from one Clubhouse was requested to nominate social network members and asked a series of questions about characteristics of supports provided by each network member. Respondents with both peers and non-peers in their network, three fifths of the sample, had more frequent contacts with peers than with non-peers and were more satisfied with peer relationships than with non-peer relationships. Those respondents also reported that peers were less critical than non-peers. Among all respondents, being Caucasian and having better quality of social life were correlated with having a peer network while higher degree of reliance on others and more Clubhouse visits were correlated with having a Clubhouse network. Longitudinal studies are needed to further investigate the relationship between quality and benefits of peer support. PMID- 22447366 TI - Acupuncture for the treatment of cancer pain: a systematic review of randomised clinical trials. AB - PURPOSE: Controlling cancer-related pain is an important component in the palliative care of cancer patients. The objective of this review was to assess the effectiveness of acupuncture for treating cancer pain. METHODS: Fourteen databases were searched from their inception through April 2011. Randomised clinical trials (RCTs) were included if acupuncture was used as the sole treatment or as a part of a combination therapy for cancer pain. Studies were included if they were controlled with a placebo or controlled against a drug therapy or no-treatment group. The Cochrane criteria were used to assess the risk of bias. RESULTS: A total of 15 RCTs met our inclusion criteria. All of the included RCTs were associated with a high risk of bias. The majority of acupuncture treatments or combination therapies with analgesics exhibited favourable effects compared with conventional treatments in individual studies. However, a meta-analysis suggested that acupuncture did not generate a better effect than drug therapy (n = 886; risk ratio (RR), 1.12; 95% CI 0.98 to 1.28; P = 0.09). The comparison between acupuncture plus drug therapy and drug therapy alone demonstrated a significant difference in favour of the combination therapy (n = 437; RR, 1.36; 95% CI 1.13 to 1.64; P = 0.003). The results of this systematic review provide no strong evidence for the effectiveness of acupuncture in the management of cancer pain. CONCLUSION: The total number of RCTs included in the analysis and their methodological quality were too low to draw firm conclusions. Future rigorous RCTs will be necessary to assess the clinical efficacy of acupuncture in this area. PMID- 22447367 TI - Outcomes of therapy vancomycin-resistant enterococcal bacteremia in hematology and bone marrow transplant patients. PMID- 22447368 TI - GPU-based real-time detection and analysis of biological targets using solid state nanopores. AB - The emergence of nanoscale devices has provided robust interfaces to biomolecules that faithfully transduce and define fundamental interactions of living systems. Measuring single-event behavior of important targets like DNA, and diseased cells has been achieved with a number of devices and systems. An important dimension to these systems, often discounted, is real-time computational decision-making from measured data. This paper describes an adaptive approach that can record single molecule or single-cell events in real-time and automatically analyze patterns from the measured data. The automated analysis of measured data is done using a static threshold technique and two variations of a dynamic threshold technique: baseline-tracker and moving average filtering. Dynamic techniques for threshold detection enable noise suppression in the measured data and precise detection of patterns, but at the cost of more complex software as compared to static technique. To mitigate the computational overhead, a real-time system is implemented that uses advanced I/O techniques to minimize the execution stalls, thus enabling the system to process data significantly faster than the electrical measurement setup. Furthermore, the algorithms are implemented on programmable graphics processing units for parallel pattern detection. Our implementation provides five times faster data acquisition and pattern detection than the maximum sampling rate of the electrical measurement setup. PMID- 22447369 TI - Non-linear separation of pressure, velocity and wave intensity into forward and backward components. AB - Separating pressure, flow/velocity and wave intensity signals into forward and backward components provide insights about arterial wave propagation and reflection. A linear wave separation is normally used, but ignores the pressure dependence of wave speed. While a non-linear separation could incorporate this pressure-dependence, no such method exists for wave intensity decomposition. Moreover, although linear separation errors for pressure (5-10 %) have been quantified previously, errors for velocity and wave intensity have not. Accordingly, we describe a non-linear wave separation technique based on the method of characteristics. Data from a computer model suggest that the percentage linear separation errors for velocity and wave intensity are approximately one half and twice that for pressure, respectively. Although comparable to measurement uncertainty in many instances, linear separation errors may become more significant: (1) if wave speed varies substantially over the cardiac cycle, e.g. if pulse pressure or vessel compliance is high, (2) if the degree of wave reflection in the arterial system is large, or (3) if the constant wave speed used for the linear separation is closer to the minimum or maximum pressure dependent value rather than the mean. Consideration of linear separation errors may therefore be important in some physiological settings. PMID- 22447370 TI - The elite sport and Christianity debate: shifting focus from normative values to the conscious disregard for health. AB - Scholars and theologians continue to debate whether or not God's intended purpose of elite sport violates the creational normativity for elite sport. However, while it is important to be aware of the contradictions between elite sport and Christianity, there is a need for more deep-seated discussions about emotions and health problems in elite sport and why so many Christian athletes continue to train for their sport at the expense of their health. This paper summaries the present debate regarding elite sport and Christianity and then shifts the reader to an exploration of the normalization of emotion, and the consequence of emotional suppression on athletes health. In doing so, the author presents the disregard of health problems as a more concrete measure of how far athletes should push themselves in elite sport. The author makes recommendations for emotion education and suggests directions for future research and practice. PMID- 22447371 TI - Do existential variables mediate between religious-spiritual facets of functionality and psychological wellbeing. AB - Religiosity has been related to psychological wellbeing outcomes. Although this relationship is primarily based on studies of church attendance or prayer and wellbeing, more recent work has focused on the potential mechanisms that may mediate the religion-wellbeing findings. One of the major function of religion is finding of meaning of life and improving hope. Recent studies have indicated that hope and meaning of life are the potential variables mediate between religion and wellbeing. It was hypothesized that one pathway through which religiosity may exert its positive influence on psychological wellbeing is through finding meaning of life and improving hope. One study was conducted examining the relationships among spiritual experiences, hope, meaning of life and psychological wellbeing operationalized as satisfaction with life, positive affect and negative affect. The following research tools were used: Daily Spiritual Experiences Scale, Purpose in Life Test, Hearth Hope Index, Cantril Ladder, Positive and Negative Affect Schedule. Meaning of life and hope were noticed to mediate between spiritual experiences and satisfaction with life as well as between spiritual experiences and positive affect. Spiritual experiences were not related to negative affect. Both meaning of life and hope predicted negative affect. This study found meaning of life and hope to be an important factors in the religion-wellbeing relationship and related to positive psychological outcomes, including improved satisfaction with life and positive affect as well as reduced negative affect. PMID- 22447372 TI - C-H activation of isobutylene using frustrated Lewis Pairs: aluminum and boron sigma-allyl complexes. PMID- 22447373 TI - Modification and comparison of minimally invasive cochleostomy techniques: A pilot study. AB - OBJECTIVES/HYPOTHESIS: Bimodal stimulation may offer improved auditory function following cochlear implantation. Modification of technique during cochleostomy may minimize trauma and maximize residual hearing. We hypothesize that CO(2) laser use during cochleostomy is useful and may decrease intracochlear trauma. This study examines the utility of CO(2) laser to perform cochleostomy and compares intracochlear sound and temperature levels during laser and drill usage. STUDY DESIGN: Experimental (30 cadaveric temporal bones). METHODS: A CO(2) laser at 3 W (four bones) and 6 W (four bones) and otologic drill (six bones) were utilized to perform a cochleostomy while recording operative time. Subsequently, 16 bones were used to simultaneously record intracochlear sound (in decibels) and temperature (in degrees Fahrenheit) during CO(2) laser (eight bones) and drill cochleostomies (eight bones). RESULTS: Average cochleostomy time for CO(2) laser was 15.5 minutes (3 W) and 7.75 minutes (6 W); it was 8 minutes for the drill. Average intracochlear sound level was 54.9 dB during laser use and 89.9 dB during drill use (P < .001), whereas maximal levels were 75 to 118 dB during laser use and 95 to 136 dB during drill use (P = .018). Average temperature was 63.4 degrees F during laser use and 61.5 degrees F during drill use (P = .151), whereas maximum temperatures ranged from 66 to 120 degrees F during laser use and 62 to 70 degrees F during drill use (P = .045). CONCLUSIONS: CO(2) laser can create cochleostomies comparable in operative time and intracochlear temperature to drilling while decreasing intracochlear sound levels. Further investigation is warranted to minimize trauma and maximize auditory function during cochleostomy. PMID- 22447374 TI - Bioanalytical method development, pharmacokinetics, and toxicity studies of paromomycin and paromomycin loaded in albumin microspheres. AB - Intracellular location of leishmania parasite in macrophages protects them from both hosts defence system as well as from antibiotics like paromomycin (PM) acting against them, thus there is a need of a formulation targeting intracellular parasites. Considering this, PM-loaded albumin microspheres (PM-MS) were prepared to target PM to macrophages where leishmania parasites resides and evaluated for their safety profile. A new bioanalytical method for quantitative determination of PM in rat plasma was developed by pre-column derivatization with 9-fluorenylmethyl chloroformate. The developed bioanalytical method was validated and applied for pharmacokinetic studies of PM administered by intramuscular and intravenous routes as well as for developed PM-MS which were administered by intravenous route. Comparative acute and subacute toxicity studies were also carried out for these formulations. The developed method was found to be very sensitive with a quantification limit of 40 ng/ml. Pharmacokinetic studies demonstrated nearly 80% reduction in C(max) of PM when administered as PM-MS, compared to other formulations at equivalent dose. Toxicity studies indicated increased level of blood urea and blood urea nitrogen in PM intramuscular injection at 90 mg/kg dose, whereas at the same dose level PM-MS showed no symptoms of toxicity. Results obtained suggest that developed PM-MS formulation is a promising alternative to the presently marketed PM intramuscular injection for the treatment of visceral leishmaniasis. PMID- 22447375 TI - MALT Lymphoma of the Gastric Remnant After Roux-en-Y Gastric Bypass. PMID- 22447376 TI - Pulmonary carcinoid tumor in a patient on adalimumab for Crohn's disease. PMID- 22447377 TI - Observer training for computer-aided detection of pulmonary nodules in chest radiography. AB - OBJECTIVES: To assess whether short-term feedback helps readers to increase their performance using computer-aided detection (CAD) for nodule detection in chest radiography. METHODS: The 140 CXRs (56 with a solitary CT-proven nodules and 84 negative controls) were divided into four subsets of 35; each were read in a different order by six readers. Lesion presence, location and diagnostic confidence were scored without and with CAD (IQQA-Chest, EDDA Technology) as second reader. Readers received individual feedback after each subset. Sensitivity, specificity and area under the receiver-operating characteristics curve (AUC) were calculated for readings with and without CAD with respect to change over time and impact of CAD. RESULTS: CAD stand-alone sensitivity was 59 % with 1.9 false-positives per image. Mean AUC slightly increased over time with and without CAD (0.78 vs. 0.84 with and 0.76 vs. 0.82 without CAD) but differences did not reach significance. The sensitivity increased (65 % vs. 70 % and 66 % vs. 70 %) and specificity decreased over time (79 % vs. 74 % and 80 % vs. 77 %) but no significant impact of CAD was found. CONCLUSION: Short-term feedback does not increase the ability of readers to differentiate true- from false-positive candidate lesions and to use CAD more effectively. KEY POINTS: * Computer-aided detection (CAD) is increasingly used as an adjunct for many radiological techniques. * Short-term feedback does not improve reader performance with CAD in chest radiography. * Differentiation between true- and false-positive CAD for low conspicious possible lesions proves difficult. * CAD can potentially increase reader performance for nodule detection in chest radiography. PMID- 22447379 TI - Polystannanes: synthesis, properties, and outlook. AB - Polystannanes are characterized by a main chain which consists of covalently bound tin atoms. Characteristic absorption maxima in UV-vis spectra of poly(dialkylstannane)s are due to sigma-delocalization and of poly(diarylstannane)s to sigma-pi delocalization. Poly(diorganostannane)s are thermally stable with decomposition commencing above 200 degrees C. Poly(dialkylstannane)s can show liquid-crystalline behavior around room temperature. They can be oriented by various procedures, whereby orientation of the polystannane main chain depends on the orientation procedure and the length of the alkyl side groups. Some of the oriented systems showed a pronounced dichroism. Polystannanes degrade under the action of light, in particular when in solution. PMID- 22447378 TI - The role of cardiac magnetic resonance imaging following acute myocardial infarction. AB - BACKGROUND: Advances in the management of myocardial infarction have resulted in substantial reductions in morbidity and mortality. METHODS: However, after acute treatment a number of diagnostic and prognostic questions often remain to be answered, whereby cardiac imaging plays an essential role. RESULTS: For example, some patients will sustain early mechanical complications after infarction, while others may develop significant ventricular dysfunction. Furthermore, many individuals harbour a significant burden of residual coronary disease for which clarification of functional ischaemic status and/or viability of the suspected myocardial territory is required. CONCLUSION: Cardiac magnetic resonance (CMR) imaging is well positioned to fulfil these requirements given its unparalleled capability in evaluating cardiac function, stress ischaemia testing and myocardial tissue characterisation. This review will focus on the utility of CMR in resolving diagnostic uncertainty, evaluating early complications following myocardial infarction, assessing inducible ischaemia, myocardial viability, ventricular remodelling and the emerging role of CMR-derived measures as endpoints in clinical trials. KEY POINTS: Cardiac magnetic resonance (CMR) imaging identifies early complications after myocardial infarction. * Adenosine stress CMR can reliably assess co-existing disease in non-culprit arteries. * Assessment of infarct size and microvascular obstruction a robust prognostic indicator. * Assessment of myocardial viability is important to guide revascularisation decision-making. PMID- 22447380 TI - Hemodynamic assessment in patients with one-and-a-half ventricle repair revealed by four-dimensional flow magnetic resonance imaging. AB - We report hemodynamic findings in two patients with pulmonary atresia and intact ventricular septum (PAIVS) after "one-and-a-half ventricle repair" and placement of a bidirectional Glenn shunt using four-dimensional (4D) flow magnetic resonance imaging. Quantification of flow and analysis of flow patterns revealed the hemodynamic "battle" between the right ventricle (RV) and the Glenn shunt. Moreover, with a novel approach we calculated during Glenn anastomosis the flow distribution from the superior vena cava (SVC) to the pulmonary arteries. Our results showed a highly asymmetric flow distribution, with most of the flow from the SVC toward the RV and not to the lungs. The evidence provided by 4D flow demonstrates poor efficiency of this system and suggests that both patients might benefit from adding an artificial pulmonary valve to avoid right heart failure. PMID- 22447381 TI - Comparison of the laboratory data between Kawasaki disease and enterovirus after intravenous immunoglobulin treatment. AB - Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. The laboratory findings before and after intravenous immunoglobulin (IVIG) in KD have been discussed, but the characteristics of IVIG therapy still are unclear. This study aimed to compare laboratory data from patients with KD and enterovirus (EV) infection to evaluate the differences after IVIG therapy. The study enrolled 171 KD patients and 38 EV patients treated with a single dose of IVIG from 2003 to 2010. Laboratory data including total white blood cell counts (WBC) and hemoglobin (Hb), platelet, segment, lymphocyte, eosinophil, and monocyte levels were analyzed. Compared with the KD patients, the EV patients had higher Hb, lymphocyte, and monocyte levels and lower eosinophil levels before IVIG treatment (p < 0.05). After IVIG treatment, the KD patients had lower Hb and segment levels but higher platelet, lymphocyte, and eosinophil levels than the EV patients (p < 0.05). In the KD patients, the platelet, eosinophil, and monocyte levels increased after IVIG treatment, whereas Hb, WBC, and segment levels decreased significantly (p < 0.001). In the EV patients, eosinophil levels increased after IVIG treatment, whereas WBC and Hb levels decreased significantly (p < 0.05). The study results provide evidence that eosinophilia may be related to IVIG therapy in KD and EV patients. The KD patients had higher eosinophil levels both before and after IVIG therapy than the EV patients, which may have been due to the inflammatory mechanism of KD. The KD patients had higher platelet levels than the EV patients, suggesting that platelets are involved in the inflammatory response to KD. PMID- 22447382 TI - Isolated left ventricular noncompaction in a newborn with Pierre-Robin sequence. AB - Pierre-Robin sequence or syndrome (PRS) (OMIM #261800) is characterized by a small mandible (micrognathia), posterior displacement/retraction of the tongue (glossoptosis), and upper airway obstruction. It has an incidence varying from 1 in 8,500 to 1 in 30,000 births. Congenital heart defects (CHDs) occur in 20 % of the patients with PRS. Ventricular septal defect, patent ductus arteriosus, and atrial septal defects are the most common lesions. Noncompaction of the ventricular myocardium is a rare cardiomyopathy characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses. It is thought to be caused by arrest of the normal endomyocardial morphogenesis. Isolated left ventricular noncompaction (LVNC) in patients with PRS has not been reported previously. This report describes a newborn with PRS and isolated LVNC. Previously, LVNC has been reported in association with mitochondrial disorders, Barth syndrome hypertrophic cardiomyopathy, zaspopathy, muscular dystrophy type 1, 1p36 deletion, Turner syndrome, Ohtahara syndrome, distal 5q deletion, mosaic trisomy 22, trisomy 13, DiGeorge syndrome, and 1q43 deletion with decreasing frequency. Karyotype analysis of the reported patient showed normal chromosomes (46, XX), and a fluorescent in situ hybridization study did not show chromosome 22q11.2 deletion. This is the first clinical report of a patient with isolated LVNC and PRS. Noncompaction of the ventricular myocardium is a rare and unique disorder with characteristic morphologic features that can be identified by echocardiography. Long-term follow-up evaluation for development of progressive LV dysfunction and cardiac arrhythmias is indicated for these patients. PMID- 22447383 TI - Neonatal midaortic syndrome and renal artery atresia presenting as malignant hypertension. AB - We report a case of congenital midaortic syndrome with bilateral renal artery atresia in a premature female neonate born by way of caesarean section secondary to acute onset of decreased fetal movement and polyhydramnios. The infant required cardiopulmonary resuscitation at birth, and initial echocardiogram exhibited normal intracardiac anatomy and mildly depressed left-ventricular systolic function. Within 24 h, the neonate developed severe systemic arterial hypertension and acute renal failure. Ultrasound demonstrated hyperechoic kidneys and a hypoplastic abdominal aorta. Angiography revealed severe suprarenal hypoplasia of the abdominal aorta with bilateral renal artery atresia. Medical support was withdrawn, and the patient died shortly thereafter. PMID- 22447384 TI - Short-term result of ductus arteriosus stent implantation compared with surgically created shunts. AB - This report aims to compare the researchers' early experience with the safety, efficacy, short-term outcomes, and complications of patent ductus arteriosus (PDA) stents in neonates having duct-dependent pulmonary circulation with those of surgically created shunts. Between April 2009 and April 2011, 18 infants with duct-dependent pulmonary circulation underwent cardiac catheterization for PDA stenting as the first palliative procedure in a referral center. For comparison, 20 infants who underwent surgical aortopulmonary shunt placement in another center were used. Follow-up assessment included clinical examination, echocardiography, oxygen saturation, and cardiac catheterization studies. Access and stenting for the PDA were successful in 15 patients (83.3 %). The mean procedure time was 58.43 +/- 41.25 min, and the mean fluoroscopy time was 18.81 +/- 5.64 min. Three patients (20 %) in the stented group and 6 patients (30 %) in the surgical group died (P = 0.09). After a 6-month follow-up period, none of the patients had significant stent stenosis requiring reintervention. The oxygen saturation increase did not differ significantly between the two groups either immediately after the procedure or 6 months later (P > 0.5). The left pulmonary artery diameter, McGoon ratio, and Nakata index did not differ significantly between the two groups (P > 0.05), but the right pulmonary diameter was larger in the stented group (5.01 +/- 0.45 vs 4.1 +/- 0.49 mm; P = 0.0001). Stenting for the PDA is an appropriate alternative to surgical shunt creation in many patients with duct-dependent circulation. In our sample, the two groups did not differ significantly in terms of outcome or mortality. PMID- 22447385 TI - Fibrolamellar hepatocellular carcinoma with cardiac spread causing severe inferior vena cava obstruction in a 9-year-old child. PMID- 22447386 TI - In vitro biocompatibility assessment of functionalized magnetite nanoparticles: biological and cytotoxicological effects. AB - In the biomedical field, nanomaterials have the potential for use in the targeted delivery of drugs in the human body and in the diagnosis and therapy of certain diseases. In the category of targeted delivery, magnetite (Fe(3)O(4)) nanoparticles have received much attention. As with any similar new therapy, when such nanoparticles are functionalized with chemical groups designed to permit the specific attachment of drugs, cytotoxicological testing is necessary before moving to animal models. Here, we consider several variously functionalized magnetite nanoparticles, including those prepared with (1) a monolayer of oleic acid (Fe(3)O(4)@OA), which is subsequently converted to (2) a shell of amine containing silane (Fe(3)O(4)@NH(2)), (3) a shell of silica (Fe(3)O(4)@SiO(2)), and (4) a shell of amine-containing silane over a shell of silica (Fe(3)O(4)@SiO(2)@NH(2)). These latter three functionalities were evaluated for biocompatibility, cellular morphology, mitochondrial function (MTT assay), lactate dehydrogenase membrane leakage (LDH assay), and proinflammatory potential through enzyme linked immunosorbent assay (ELISA) for interleukin 6 (IL-6). Controlled tests were performed over a period of 72 h, with results showing LDH leakage and abnormal Il-6 secretion at high concentrations (>50 MUg/mL). The tests showed that, in addition to the surface characteristics of the nanoparticles, both the nutrient medium and the time of suspension before exposure to cells also contribute to nanoparticle cytotoxicity. PMID- 22447387 TI - Using electron balances and molecular techniques to assess trichoroethene-induced shifts to a dechlorinating microbial community. AB - This study demonstrated the utility in correlating performance and community structure of a trichloroethene (TCE)-dechlorinating microbial consortium; specifically dechlorinators, fermenters, homoacetogens, and methanogens. Two complementary approaches were applied: predicting trends in the microbial community structure based on an electron balance analysis and experimentally assessing the community structure via pyrosequencing and quantitative polymerase chain reaction (qPCR). Fill-and-draw reactors inoculated with the DehaloR^2 consortium were operated at five TCE-pulsing rates between 14 and 168 umol/10-day SRT, amended with TCE every 2 days to give peak concentrations between 0.047 and 0.56 mM (6-74 ppm) and supplied lactate and methanol as sources of e(-) donor and carbon. The complementary approaches demonstrated the same trends: increasing abundance of Dehalococcoides and Geobacter and decreasing abundance of Firmicutes with increasing TCE pulsing rate, except for the highest pulsing rate. Based on qPCR, the abundance of Geobacter and Dehalococcoides decreased for the highest TCE pulsing rate, and pyrosequencing showed this same trend for the latter. This deviation suggested decoupling of Dehalococcoides growth from dechlorination. At pseudo steady-state, methanogenesis was minimal for all TCE pulsing rates. Pyrosequencing and qPCR showed suppression of the homoacetogenic genera Acetobacterium at the two highest pulsing rates, and it was corroborated by a decreased production of acetate from lactate fermentation and increased propionate production. Suppression of Acetobacterium, which can provide growth factors to Dehalococcoides, may have contributed to the decoupling for the highest TCE-pulsing rate. PMID- 22447388 TI - Genitourinary dysfunction in male rats after bilateral neurectomy of the motor branch of the sacral plexus. AB - AIMS: To determine the contribution of the striated musculature anatomically related to the urethra on urinary continence in conscious male rats. We tested whether the bilateral neurectomy of the motor branch of the sacral plexus (MBSP), a nerve that innervates the bulbospongiosus, ischiocavernosus, and external urethral sphincter, is a reliable procedure to induce changes in voiding pattern that can be used as indicators of urinary incontinence in unanesthetized male rats. METHODS: Micturition behavior was videotaped and urinary parameters measured 24 h before and at day 2 and 10 after surgery. RESULTS: Intact animals have a stereotyped behavior of micturition consisting in urination in the corner of the cage. Neurectomized animals lost place preference for voiding demonstrated by leakage of urine throughout the cage while eating, walking, or sleeping. Voiding frequency was double and voiding duration was triple the amount before surgery. Urine flow rate and voiding volume were also significantly decreased. Necropsy showed that 10 days post-denervation semen material was accumulated in the urethra and in the bladder. CONCLUSION: In male rats the perineal striated muscles are crucial to maintaining normal urinary continence, preventing retrograde ejaculation, and to expelling urine and seminal secretions. Bilateral neurectomy of the MBSP may not be appropriate for long term survival urinary studies because effects on urinary parameters can be contaminated and/or masked by impaired seminal fluid expulsion, as a consequence of impairment of striated urethral muscle function. PMID- 22447389 TI - Impairment of prostate cancer cell growth by a selective and reversible lysine specific demethylase 1 inhibitor. AB - Post-translational modifications of histones by chromatin modifying enzymes regulate chromatin structure and gene expression. As deregulation of histone modifications contributes to cancer progression, inhibition of chromatin modifying enzymes such as histone demethylases is an attractive therapeutic strategy to impair cancer growth. Lysine-specific demethylase 1 (LSD1) removes mono- and dimethyl marks from lysine 4 or 9 of histone H3. LSD1 in association with the androgen receptor (AR) controls androgen-dependent gene expression and prostate tumor cell proliferation, thus highlighting LSD1 as a drug target. By combining protein structure similarity clustering and in vitro screening, we identified Namoline, a gamma-pyrone, as a novel, selective and reversible LSD1 inhibitor. Namoline blocks LSD1 demethylase activity in vitro and in vivo. Inhibition of LSD1 by Namoline leads to silencing of AR-regulated gene expression and severely impairs androgen-dependent proliferation in vitro and in vivo. Thus, Namoline is a novel promising starting compound for the development of therapeutics to treat androgen-dependent prostate cancer. PMID- 22447390 TI - Xanthoria elegans (Link) (lichen) extract counteracts DNA damage and oxidative stress of mitomycin C in human lymphocytes. AB - Several lichen species have been used for medicinal purposes throughout the ages, and they are reported to be effective in the treatment of different disorders including ulcer and cancer. It is revealed that lichens may be easily accessible sources of natural drugs and possible food supplements after their safety evaluations. The main objective in this study was to evaluate the roles of aqueous extracts of Xanthoria elegans (at 25, 50 and 100 MUg/ml) upon mitomycin C (MMC; at 10(-7) M) induced genotoxic and oxidative damages in cultured human lymphocytes. X. elegans were collected from the Erzurum and Artvin provinces (in Turkey) during August 2010. After the application of MMC and X. elegans extract (XEE), separate and together, human whole blood cultures were assessed by four genotoxicity end-points including chromosomal aberration, micronucleus, sister chromatid exchange (SCE) and 8-oxo-2-deoxyguanosine (8-OH-dG) assays. In addition, biochemical parameters [total antioxidant capacity (TAC) and total oxidative stress (TOS)] were examined to determine oxidative effects. According to our results, the frequencies of cytogenetic endpoints and 8-OH-dG levels were significantly increased by MMC compared with controls in human peripheral lymphocytes. MMC caused oxidative stress by altering TAC and TOS levels. On the contrary, XEE led to increases of TAC level without changing TOS level. XEE had no genotoxic effect. Furthermore, our findings revealed that MMC induced increases in the mean frequencies of four genotoxic indices were diminished by XEE in dose dependent manner, indicating its protective role towards cells from MMC exerted injury. In conclusion, the results obtained in the present study indicate for the first time that XEE is a potential source of natural antigenotoxicants. PMID- 22447391 TI - Watching nanoparticles form: an in situ (small-/wide-angle X-ray scattering/total scattering) study of the growth of yttria-stabilised zirconia in supercritical fluids. AB - Understanding nanoparticle-formation reactions requires multi-technique in situ characterisation, since no single characterisation technique provides adequate information. Here, the first combined small-angle X-ray scattering (SAXS)/wide angle X-ray scattering (WAXS)/total-scattering study of nanoparticle formation is presented. We report on the formation and growth of yttria-stabilised zirconia (YSZ) under the extreme conditions of supercritical methanol for particles with Y(2)O(3) equivalent molar fractions of 0, 4, 8, 12 and 25 %. Simultaneous in situ SAXS and WAXS reveals a quick formation (seconds) of sub-nanometre amorphous material forming larger agglomerates with subsequent slow crystallisation (minutes) into nanocrystallites. The amount of yttria dopant is shown to strongly affect the crystallite size and unit-cell dimensions. At yttria-doping levels larger than 8 %, which is known to be the stoichiometry with maximum ionic conductivity, the strain on the crystal lattice is significantly increased. Time resolved nanoparticle size distributions are calculated based on whole-powder pattern modelling of the WAXS data, which reveals that concurrent with increasing average particle sizes, a broadening of the particle-size distributions occur. In situ total scattering provides structural insight into the sub-nanometre amorphous phase prior to crystallite growth, and the data reveal an atomic rearrangement from six-coordinated zirconium atoms in the initial amorphous clusters to eight-coordinated zirconia atoms in stable crystallites. Representative samples prepared ex situ and investigated by transmission electron microscopy confirm a transformation from an amorphous material to crystalline nanoparticles upon increased synthesis duration. PMID- 22447392 TI - The effects of a group visit program on outcomes of diabetes care in an urban family practice. AB - Diabetes mellitus is a prevalent chronic health condition associated with significant morbidity and mortality. Those with diabetes must acquire self efficacy in the tasks necessary for them to successfully manage their disease. In this study, a controlled pre- and post-design was used to determine the effect of an adult support and education group visit program embedded in an urban academic family medicine practice on weight and the achievement of treatment goals for hemoglobin A1C, low-density lipoprotein (LDL) blood concentration, and blood pressure (BP) several months after it was implemented. Participants in the program were matched to a comparison group based on age, gender, race/ethnicity, and zip code group, a surrogate marker for socioeconomic status. The distribution of demographic characteristics and co-morbidities was similar between the groups. Significant increases occurred in the proportion of participants achieving both an A1C concentration <7% (CMH=4.6613, p = 0.0309) while controlling for baseline AIC concentration, and a BP<140/90 mm Hg (CMH=5.61, p = 0.018) controlling for baseline BP compared to the comparison group. The hemoglobin A1C concentration declined in 76.9% of the participants in the group visit program compared to 54.3% in the comparison group (CMH=8.9911, p = 0.0027). The increase in the proportion of group visit participants achieving the target LDL concentrations did not achieve statistical significance. The proportion of participants who lost weight was similar to that in the comparison group. Early experience with the program was encouraging and suggested it may improve patients' management of their diabetes mellitus in an urban, predominantly African American population. PMID- 22447393 TI - Natural colloids are the dominant factor in the sedimentation of nanoparticles. AB - Estimating the environmental exposure to manufactured nanomaterials is part of risk assessment. Because nanoparticles aggregate with each other (homoaggregation) and with other particles (heteroaggregation), the main route of the removal of most nanoparticles from water is aggregation, followed by sedimentation. The authors used water samples from two rivers in Europe, the Rhine and the Meuse. To distinguish between small (mainly natural organic matter [NOM]) particles and the remainder of the natural colloids present, both filtered and unfiltered river water was used to prepare the particle suspensions. The results show that the removal of nanoparticles from natural river water follows first-order kinetics toward a residual concentration. This was measured in river water with less than 1 mg L(-1) CeO(2) nanoparticles. The authors inferred that the heteroaggregation with or deposition onto the solid fraction of natural colloids was the main mechanism causing sedimentation in relation to homoaggregation. In contrast, the NOM fraction in filtered river water stabilized the residual nanoparticles against further sedimentation for up to 12 d. In 10 mg L(-1) and 100 mg L(-1) CeO(2) nanoparticle suspensions, homoaggregation is likely the main mechanism leading to sedimentation. The proposed model could form the basis for improved exposure assessment for nanomaterials. PMID- 22447394 TI - Eating regulation styles, appearance schemas, and body satisfaction predict changes in body fat for emerging adults. AB - Obesity and high body fat percentages are a major public health issue. The percentage of obese and overweight Americans has increased over the past 30 years. On average, overweight individuals with higher percent body fat than normal weight individuals are at increased risk for numerous negative outcomes both physically and mentally. A prime time to investigate changes in body composition and associated psychological influences on decision making is during the emerging adulthood period. The first few years of college are a time when adolescents begin to regulate for themselves their own eating behaviors. Previous research shows that freshmen gain weight and increase in percent body fat during their first year of college. The current study addresses the limitations of previous research by investigating (1) individual growth in percent body fat over a longer period of time in college than previous available research and (2) important psychological and sex differences in this growth. This study measures percent body fat across the first 3 years of college at 8 time points for 542 undergraduates (351 females, 65 %; 191 males, 35 %). Longitudinal data analysis was conducted to identify changes in percent body fat, psychological predictors of those changes, and how changes differ for males and females. Our study found that significant increases exist in percent body fat during undergraduates' college years and that change differs for males and females. In addition, through the use of nested hierarchical models, eating regulation style (autonomous or controlled regulation), appearance schema (self-evaluative salience or motivational salience), and body satisfaction were identified as influential predictors of change in percent body fat. For example, young females, who do not feel in control of their physical appearance yet spend a great deal of time maintaining their appearance, have the highest initial body fat percentage and the steepest increase in percent body fat. Overall, males and females with high autonomous regulation and high motivational salience are likely to maintain (instead of increase) percent body fat over the college years. Knowing the influence of these predictors can be useful for promoting health and intervening with young adults in the college setting and other emerging adults who are not enrolled in postsecondary institutions. PMID- 22447395 TI - Early menarcheal age and risk for later depressive symptomatology: the role of childhood depressive symptoms. AB - Previous research has investigated the relationship between pubertal timing and depression in girls, with most results suggesting that earlier menarche predicts more depression in adolescence. However, few studies have controlled for the potentially confounding effects of childhood depressive symptoms. The current study uses a prospective, longitudinal sample of 1,185 girls (47.8 % Caucasian) to examine the relationships between pubertal timing, childhood depressive symptoms, and adolescent depressive symptomatology. Using multiple linear regression analyses, our results suggest that higher levels of childhood depressive symptoms and earlier menarche have independent effects on adolescent depressive symptoms. Surprisingly, childhood depressive symptomatology predicted later age of menarche, although the magnitude of this effect was small. Taken together, the results suggest that early childhood depressive symptoms and early menarche represent independent pathways to later depressive symptoms. PMID- 22447396 TI - Common NOD2 risk variants in African Americans with Crohn's disease are due exclusively to recent Caucasian admixture. AB - BACKGROUND: Crohn's disease (CD) is highly heritable. NOD2 has emerged as the main susceptibility gene among individuals of European ancestry; however, NOD2 does not appear to contribute to CD susceptibility among many non-European populations. Today's African American (AA) population represents an admixture of West African (80%) and European (20%) ancestry. Since genotype-based tools are becoming increasingly available for CD, it is important that we validate the risk variants in different populations, such as admixed AAs. METHODS: We analyzed the NOD2 variants among admixed AAs (n = 321, 240 with CD and 111 healthy controls [HCs]) and nonadmixed West Africans (n = 40) by genotyping four known disease causing NOD variants. We extracted the publicly available 1000 Genomes data on NOD2 variants from 500 subjects of West African origin. Association with disease was evaluated by logistic regression. RESULTS: An association with CD was found for the classical single nucleotide polymorphism (SNP) 1007fs (2.6% CD, 0% HC, P = 0.012); there was no association when the genotypic and allelic frequencies of the risk alleles were compared for SNPs R702W and G908R. No known NOD2 risk alleles were seen in either the West African cohort or in subjects of African ancestry from the 1000 Genomes project. CONCLUSIONS: The NOD2 gene is a risk for CD in AAs, although the allele frequencies and the attributable risk are much lower compared with Caucasians. The risk alleles are not seen in the West African population, suggesting that the risk for CD contributed by NOD2 among AAs is due exclusively to recent European admixture. PMID- 22447397 TI - Downstaging to non-invasive urothelial carcinoma is associated with improved outcome following radical cystectomy for patients with cT2 disease. AB - INTRODUCTION: Pathologic stage is a critically important prognostic factor after radical cystectomy (RC) that is used to guide the use of secondary therapies. However, the risk of disease recurrence, for patients clinically diagnosed with muscle-invasive tumors who are found not to have muscle-invasive disease at RC are poorly defined. Therefore, we reviewed the long-term outcomes in patients who were downstaged to non-invasive urothelial carcinoma at time of RC. METHODS: We identified 1,177 consecutive patients with muscle-invasive urothelial carcinoma of the bladder who underwent radical cystectomy at our institution between 1980 and 1999 without neoadjuvant therapy. Postoperative disease recurrence and survival were estimated using the Kaplan-Meier method and compared using the log rank test. Cox proportional hazard regression models were used to analyze the impact of pathologic stage on survival. RESULTS: Pathologic downstaging to non muscle invasive disease was identified in 538 (45.7 %) patients. The 10-year cancer-specific survival was 84.1, 77.4, 71.1 and 58.5 % for those with pT0, pTis, pT1 and pT2 tumors, respectively. On multivariate analysis, the risk of cancer-specific mortality was significantly decreased for patients with non muscle invasive disease than those with organ-confined muscle invasion (RR-0.39; p = 0.002). There was no difference in disease-specific mortality among patients who had non-invasive (pT0, pTa, or pTis) disease (p = 0.19). CONCLUSIONS: Downstaging from clinical muscle-invasive bladder cancer to non-muscle invasive disease at RC is associated with a significant reduction in cancer-specific mortality. However, even patients with residual non-muscle invasive disease may suffer disease recurrence and require continued surveillance after surgery. PMID- 22447398 TI - Will a crushed concha bullosa form again? AB - OBJECTIVES/HYPOTHESIS: This study endoscopically and radiologically evaluated whether a surgically crushed concha bullosa (CB) can form again. STUDY DESIGN: Prospective study. METHODS: This study included 14 adults who underwent CB surgery between March 2010 and February 2011. The middle turbinate was examined endoscopically and classified pre- and postoperatively into four groups according to size. The CB volume of all patients was measured using pre- and postoperative paranasal sinus computed tomography (CT). The pre- and postoperative measurements were compared using the paired t test. RESULTS: This study included 22 CB in 11 men and 3 women with a mean age of 35.85 (range, 20-47) years. The mean follow-up period was 4.42 (range, 2-10) months. The middle turbinates were significantly smaller postoperatively (P < .0005), as was the CB volume measured using paranasal sinus CT (P < .0005). CONCLUSIONS: The CB crushing technique is an easy, conservative treatment modality. As the CB does not appear to reform after crushing, this technique can be considered a definitive treatment. Nevertheless, these patients should be followed for the long term. PMID- 22447399 TI - Comparison of urine and hair testing for drugs of abuse in the control of abstinence in driver's license re-granting. AB - The purpose of the study was to compare the detection rate of illicit drugs in urine and hair specimens. The samples were taken from subjects trying to regain their revoked driver's license after a drug- or alcohol-related traffic offence. In 2010, we screened 14 000 urine and 3900 hair samples for amphetamines, methamphetamines, cannabinoids, cocaine, opiates, methadone, and benzodiazepines as well as for ethylglucuronide. We used the low threshold values of the new German guidelines for Medical Psychological Assessment (MPA). Positive screening tests were confirmed with gas chromatography-mass spectrometry (GC-MS), gas chromatography-tandem mass spectrometry (GC-MS/MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS). The results show that positivity rates for methamphetamines, MDMA, cocaine, and monoacetylmorphine were 1.7-, 5.7-, 3.8- and 9.3-fold higher in hair than in urine. In contrast, the detection rate for benzodiazepines was higher in urine than in hair (oxazepam, 0.21% versus 0%, nordiazepam 0.10% versus 0.03%). The positivity rate in hair for ethylglucuronide was 6-fold (12.7%) that for urine testing (2.1%). The study reveals that in the control of abstinence in the context of driving license re-granting there are in part large differences of positivity rates for some drugs or metabolites between hair and urine samples. These differences should be kept in mind by physicians and psychologists in traffic medicine who are ordering the drug testing. PMID- 22447400 TI - Modulation of dopaminergic neuronal differentiation from sympathoadrenal progenitors. AB - The capacity of sympathoadrenal progenitors from adrenal medulla to generate dopaminergic neurons in vitro makes them an attractive source for replacement therapies of neurodegenerative diseases such as Parkinson's disease. Dopaminergic cells constitute one percent of the adult adrenal medulla only. Thus, isolation of sympathoadrenal progenitors and enhancement of their capacity to derive dopaminergic neurons is a strategy to be considered. Here, we summarize data on the characterization and isolation of sympathoadrenal progenitors from adult adrenal medulla capable to give rise to functional dopaminergic neurons, in vitro. Pretransplantation treatment of these cells with pharmacological means is an important prerequisite to improve dopaminergic differentiation and efficient engraftment of sympathoadrenal progenitors. Treatment of these cells with retinoic and ascorbic acids significantly increased dopamine secretion from derived neurons. Furthermore, inhibition of Notch signaling activated molecular mechanisms involved in the determination of dopaminergic neuronal subtype. Taken together, somatic adrenomedullary sympathoadrenal progenitor cells are a valid cell source for replacement therapies with a high potential for dopaminergic neuronal differentiation. PMID- 22447401 TI - A cationic calcium hydride cluster stabilized by cyclen-derived macrocyclic N,N,N,N ligands. PMID- 22447402 TI - Effects of low-level laser irradiation on proliferation and osteoblastic differentiation of human mesenchymal stem cells seeded on a three-dimensional biomatrix: in vitro pilot study. AB - Mesenchymal stem cells (MSCs) from bone marrow are a recent source for tissue engineering. Several studies have shown that low-level laser irradiation has numerous biostimulating effects. The purpose of this trial was to evaluate the effects of Nd:Yag laser irradiation on proliferation and differentiation of MSCs induced into the osteoblastic lineage. MSCs were collected from adult human bone marrow, isolated, and cultured in complete medium (alpha-MEM). Subsequently, they were treated with osteogenic medium, seeded in three-dimensional collagen scaffolds, and incubated. We used six scaffolds, equally divided into three groups: two of these were irradiated with Nd:Yag laser at different power levels (15 Hz, 100 mJ, 1.5 W, and one with a power level of 15 Hz, 150 mJ, 2.25 W), and one was left untreated (control group). Evaluations with specific staining were performed at 7 and 14 days. After 7 days, proliferation was significantly increased in scaffolds treated with laser, compared with the control scaffold. After 14 days, however, laser irradiation did not appear to have any further effect on cell proliferation. As concerns differentiation, an exponential increase was observed after 14 days of laser irradiation, with respect to the control group. However, this was a pilot study with very limited sample size, we conclude, that low-level laser irradiation might lead to a reduction in healing times and potentially reduces risks of failure. PMID- 22447403 TI - Tensile bond strength of silicone-based soft denture liner to two chemically different denture base resins after various surface treatments. AB - This study evaluated the effect of various surface treatments on the tensile bond strength of a silicone-based soft denture liner to two chemically different denture base resins, heat-cured polymethyl methacrylate (PMMA), and light activated urethane dimethacrylate or Eclipse denture base resin. PMMA test specimens were fabricated and relined with a silicone-based soft denture liner (group AC). Eclipse test specimens were prepared according to the manufacturer's recommendation. Before they were relined with a silicone-based soft denture liner, each received one of three surface treatments: untreated (control, group EC), Eclipse bonding agent applied (group EB), and laser-irradiated (group EL). Tensile bond strength tests (crosshead speed = 5 mm/min) were performed for all specimens, and the results were analyzed using the analysis of variance followed by Tukey's test (p = 0.05). Eclipse denture base and PMMA resins presented similar bond strengths to the silicone-based soft denture liner. The highest mean force was observed in group EL specimens, and the tensile bond strengths in group EL were significantly different (p < 0.05) from those in the other groups. PMID- 22447404 TI - Influence of three laser wavelengths on human fibroblasts cell culture. AB - Although experimental studies in vitro and vivo have been numerous, the effect of laser wavelength irradiation on human fibroblast cell culture is poorly understood. This emphasizes the need of additional cellular and molecular research into laser influence with low energy and power. The aim of this study was to assess the influence of three different laser wavelengths on the human skin fibroblasts cell culture. We wanted to evaluate if near infrared lasers had any influence in healing of wounds by stimulating mitochondrial activity of fibroblasts. The cells were irradiated using 830-, 980- and 2,940-nm laser wavelengths. The irradiated cells were incubated and their mitochondrial activity was assessed by the MTT assay at 24, 48 and 72 h. Simultaneously, an apoptosis assay was assessed on the irradiated fibroblasts. It can be concluded that laser light of the near-infrared region (830 and 980 nm) influences fibroblasts mitochondrial activity compared to the 2,940-nm wavelength which produces apoptosis. PMID- 22447405 TI - Monocyte proliferation and differentiation to osteoclasts is affected by density of collagen covalently bound to a poly(dimethyl siloxane) culture surface. AB - Osteoclast differentiation is affected by substrate characteristics and environmental conditions; these parameters are therefore of interest for understanding bone remodeling. As a step toward osteoclast mechanotransduction experiments, we aimed to optimize conditions for osteoclast differentiation on extendable poly(dimethylsiloxane) (PDMS) substrates. Because cells attach poorly on PDMS alone, chemical modification by covalent attachment of collagen type I was performed. Effects of collagen surface concentrations on monocyte fusion and osteoclast differentiation were examined. Osteoclasts differentiated on modified PDMS were fewer in number (by ~50%) than controls on polystyrene physically modified by nonspecific attachment of collagen, and exhibited somewhat different morphologies. Nevertheless, for certain choices of the chemical modification procedures, appropriate differentiation on PDMS was still evident by qRT-PCR analysis for tartrate-resistant acid phosphate (TRAP) and cathepsin K (CTSK) gene expression, positive TRAP staining, fluorescent phalloidin staining showing actin ring formation and bone resorption assays. At relatively high collagen surface densities, monocyte clumps appeared on PDMS suggesting substrate-induced alterations to monocyte fusion. Covalently bound collagen can therefore be used to promote osteoclast differentiation on extendable PDMS substrates. Under appropriate conditions osteoclasts retain similar functionality as on polystyrene, which will enable future studies of osteoclast interactions with microstructured surfaces and mechanostimulation. PMID- 22447406 TI - Adenoviral transduction supports matrix expression of alginate cultured articular chondrocytes. AB - The present study examines the effects of adenoviral (Ad) transduction of human primary chondrocyte on transgene expression and matrix production. Primary chondrocytes were isolated from healthy articular cartilage and from cartilage with mild osteoarthritis (OA), transduced with an Ad vector and either immediately cultured in alginate or expanded in monolayer before alginate culture. Proteoglycan production was measured using dimethylmethylene blue (DMMB) assay and matrix gene expression was quantified by real-time PCR. Viral infection of primary chondrocytes results in a stable long time transgene expression for up to 13 weeks. Ad transduction does not significantly alter gene expression and matrix production if chondrocytes are immediately embedded in alginate. However, if expanded prior to three dimension (3D) culture in alginate, chondrocytes produce not only more proteoglycans compared to non-transduced controls, but also display an increased anabolic and decreased catabolic activity compared to non transduced controls. We therefore suggest that successful autologous chondrocyte transplantation (ACT) should combine adenoviral transduction of primary chondrocytes with expansion in monolayer followed by 3D culture. Future studies will be needed to investigate whether the subsequent matrix production can be further improved by using Ad vectors bearing genes encoding matrix proteins. PMID- 22447407 TI - Cost-effectiveness of conservative treatments for neck pain: a systematic review on economic evaluations. AB - PURPOSE: Various conservative interventions have been used for the treatment of non-specific neck pain. The aim of this systematic review was to investigate the cost-effectiveness of conservative treatments for non-specific neck pain. METHODS: Clinical and economic electronic databases, reference lists and authors' databases were searched up to 13 January 2011. Two reviewers independently selected studies for inclusion, performed the risk of bias assessment and data extraction. RESULTS: A total of five economic evaluations met the inclusion criteria. All studies were conducted alongside randomised controlled trials and included a cost-utility analysis, and four studies also conducted a cost effectiveness analysis. Most often, the economic evaluation was conducted from a societal or a health-care perspective. One study found that manual therapy was dominant over physiotherapy and general practitioner care, whilst behavioural graded activity was not cost-effective compared to manual therapy. The combination of advice and exercise with manual therapy was not cost-effective compared to advice and exercise only. One study found that acupuncture was cost effective compared to a delayed acupuncture intervention, and another study found no differences on cost-effectiveness between a brief physiotherapy intervention compared to usual physiotherapy. Pooling of the data was not possible as heterogeneity existed between the studies on participants, interventions, controls, outcomes, follow-up duration and context related socio-political differences. CONCLUSION: At present, the limited number of studies and the heterogeneity between studies warrant no definite conclusions on the cost effectiveness of conservative treatments for non-specific neck pain. PMID- 22447408 TI - Could clinical ultrasound improve the fitting of spinal orthosis for the patients with AIS? AB - PURPOSE: This study aimed to improve the effectiveness of orthotic treatment for the patients with AIS using the three-dimensional clinical ultrasound (3D CUS) method in which the optimal location of pressure pad of spinal orthosis was determined with the assistance of ultrasound image analysis. METHODS: By means of 3D CUS method, the spinous process angle (SPA) could be traced and used as a clinical parameter to estimate the Cobb's angle in order to determine the location of pressure pad. Twenty-one patients (test group) and 22 patients (control group) were recruited to the ultrasound-assisted fitting method and the conventional fitting method, respectively. All the measurements were done by a blinded observer. RESULTS: The intra-rater reliability of using 3D CUS to measure SPA was found >0.9 [ICC (3,3) = 0.91, p < 0.05]. In the test group, 13 out of 21 patients were required to adjust the location of pressure pad in order to achieve the largest curvature correction. The mean immediate in-brace corrections (Cobb's angle measured from radiographs) of the test group (mean thoracic curve correction: 10.3 degrees , mean lumbar curve correction: 10.1 degrees ) were found significantly higher (p < 0.005) than that of the control group (mean thoracic curve correction: 4.6 degrees , mean lumbar curve correction: 6.0 degrees ). The results showed that the ultrasound-assisted fitting method of spinal orthosis was effective and beneficial to 62 % of the patients in this study. CONCLUSIONS: The 3D CUS could be considered as an effective, non-invasive and fast assessment method to scoliosis, especially in enhancing the effectiveness of orthotic treatment and its applications could also be further extended to other spinal deformities. PMID- 22447409 TI - Froin's syndrome: an uncommon mimicker of Guillain-Barre syndrome. PMID- 22447410 TI - Vertebral deformity arising from an accelerated "creep" mechanism. AB - INTRODUCTION: Vertebral deformities often occur in patients who recall no trauma, and display no evident fracture on radiographs. We hypothesise that vertebral deformity can occur by a gradual creep mechanism which is accelerated following minor damage. "Creep" is continuous deformation under constant load. MATERIALS AND METHODS: Forty-five thoracolumbar spine motion segments were tested from cadavers aged 42-92 years. Vertebral body areal BMD was measured using DXA. Specimens were compressed at 1 kN for 30 min, while creep in each vertebral body was measured using an optical MacReflex system. After 30 min recovery, each specimen was subjected to a controlled overload event which caused minor damage to one of its vertebrae. The creep test was then repeated. RESULTS: Vertebral body creep was measurable in specimens with BMD <0.5 g/cm(2). Creep was greater anteriorly than posteriorly (p < 0.001), so that vertebrae gradually developed a wedge deformity. Compressive overload reduced specimen height by 2.24 mm (STD 0.77 mm), and increased vertebral body creep by 800 % (anteriorly), 1,000 % (centrally) and 600 % (posteriorly). In 34 vertebrae with complete before-and after data, anterior wedging occurring during the 1st creep test averaged 0.07 degrees (STD 0.17 degrees ), and in the 2nd test (after minor damage) it averaged 0.79 degrees (STD 1.03 degrees ). The increase was highly significant (P < 0.001). Vertebral body wedging during the 2nd creep test was proportional to the severity of damage, as quantified by specimen height loss during the overload event (r (2) = 0.51, p < 0.001, n = 34). CONCLUSIONS: Minor damage to an old vertebral body, even if it is barely discernible on radiographs, can accelerate creep to such an extent that it makes a substantial contribution to vertebral deformity. PMID- 22447411 TI - Diagnosis of potential stressors adversely affecting benthic communities in New Bedford Harbor, MA (USA). AB - Diagnosing the causes of impaired ecosystems in the marine environment is critical for effective management action. When ecological impairment is based on toxicological or biological criteria (i.e., degraded benthic community composition or toxicity test results), managers are faced with the additional problem of diagnosing the cause of impairment before plans can be initiated to reduce the pollutant loading. We evaluated a number of diagnostic tools to determine their ability to identify pollutants in New Bedford Harbor (NBH), Massachusetts (USA), using a modified version of the US Environmental Protection Agency's (USEPA) stressor identification (SI) guidance. In this study, we linked chemical sources and toxic chemicals in the sediment with spatial concentration studies; we also linked toxic chemicals in the sediment with toxicity test results using toxicity identification and evaluation (TIE) studies. We used geographical information systems (GIS) maps to determine sources and to aid in determining spatially integrated inorganic nitrogen (SIIN). The SIIN values of reference and test estuaries were quantified and compared. Using this approach, we determined that toxic chemicals continue to be active stressors in NBH and that a moderate nutrient stress exists, but we were unable to link the nutrient stressor with a source. Also excess sedimentation was evaluated, but it does not appear to be an active stressor in this harbor. The research included an evaluation of the effectiveness of tools under development that may be used to evaluate stressors in water bodies. We found that the following tools were useful in diagnosing active stressors: toxicity tests, toxicity identification and evaluation (TIE) methods, comparison of grain size-normalized total organic carbon (TOC) ratios with reference sites, and comparison of SIIN with reference sites. This approach allowed us to successfully evaluate stressors in NBH retrospectively; however, a limitation in using retrospective data sets is that the approach may underestimate current or newly emerging stressors. PMID- 22447412 TI - Nicotinic modulation of therapeutic response in vitro and in vivo. AB - Tobacco use significantly increases the risk of developing cancer. Moreover, there is growing evidence that tobacco use decreases survival in cancer patients. Nicotine, a systemically available component of tobacco, is associated with tumor promotion and decreased apoptosis in cell culture; however, the role of nicotine on response to radiotherapy (RT) or chemoradiotherapy (CRT) in vivo has not been evaluated. Our study evaluated the effects of nicotine administration on cancer cell survival in cell culture and mouse models. Nicotine increased survival in two cell lines following RT in vitro. Nicotine administration in mice during fractionated RT or CRT increased xenograft regrowth as compared to RT or CRT alone. Nicotine increased hypoxia-inducible factor 1-alpha (HIF-1alpha) expression in tumor xenografts without altering expression of carbonic-anhydrase, a clinical marker of tumor hypoxia. The effects of nicotine on HIF-1alpha expression were transient, returning to baseline levels within 2-3 days after nicotine removal. Further mechanistic studies indicated that inhibition of phosphoinositide-3-kinase (PI3K) prevented nicotine-mediated increases in HIF 1alpha expression as well as the prosurvival effects of nicotine on RT. These findings imply that during tobacco use, nicotine may function as a systemic agent through acute and reversible regulation of HIF-1alpha expression and a decreased therapeutic response. PMID- 22447413 TI - Nitrogen-doped carbon capsules via poly(ionic liquid)-based layer-by-layer assembly. AB - Layer-by-layer (LbL) assembly technique is applied for the first time for the preparation of nitrogen-doped carbon capsules. This approach uses colloid silica as template and two polymeric deposition components, that is, poly(ammonium acrylate) and a poly (ionic liquid) poly(3-cyanomethyl-1-vinylimidazolium bromide), which acts as both the carbon precursor and nitrogen source. Nitrogen doped carbon capsules are prepared successfully by polymer wrapping, subsequent carbonization and template removal. The as-synthesized carbon capsules contain ~7 wt% of nitrogen and have a structured specific surface area of 423 m(2) g(-1). Their application as supercapacitor has been briefly introduced. This work proves that LbL assembly methodology is available for preparing carbon structures of complex morphology. PMID- 22447414 TI - Percutaneous transtracheal needle insufflation: A useful emergency airway adjunct simply constructed from common items found on your anesthesia cart. AB - Using material already available in the operating room, we describe the construction and application of a percutaneous transtracheal needle insufflation device to be used in pediatric airway emergencies. Our technique of percutaneous needle insufflation using common materials found in the operating room can be a helpful adjunct in a time of need. Quickly constructed and at a minimal cost, the device can be just one of the many useful tools found in the otolaryngologist's airway armamentarium. PMID- 22447415 TI - Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial. AB - AIMS: The primary objective was to investigate the efficacy of desmopressin orally disintegrating tablet versus placebo in patients with nocturia. Pharmacodynamics, safety and patient-reported quality of life (QoL) outcomes were also evaluated. One of several benefits of the new formulation is increased bioavailability. Exploring lower doses allows for a better evaluation of therapeutic effect versus tolerability. METHODS: This was a 4-week, randomized, double-blind study comparing 10, 25, 50, or 100 ug desmopressin versus placebo in adults with defined nocturia. RESULTS: The intent to treat population comprised 757 patients experiencing ~3 voids/night and a high prevalence of nocturnal polyuria (~90%). Increasing doses of desmopressin were associated with decreasing numbers of nocturnal voids and voided volume, greater proportions of subjects with >33% reduction in nocturnal voids, and increased duration of first sleep period. The lowest dose reaching statistical significance (P < 0.05 vs. placebo) varied by endpoint. Improvements were clinically meaningful, meaning that patients actually had fewer nightly voids. Post hoc analyses by gender suggested a lower minimum effective dose for women. Desmopressin was generally well tolerated. Reductions in serum sodium to <125 mmol/L in six women (taking >25 ug desmopressin) and two men (aged 67 and 82) taking 100 ug, support lower and gender-specific dosing to reduce the small but clinically significant risk of hyponatraemia. Each void reduced/hour of sleep gained was associated with significant improvements in QoL. CONCLUSIONS: Desmopressin orally disintegrating tablet is an effective and well-tolerated treatment for patients with nocturia. Further exploration of the lower dose range is warranted. PMID- 22447416 TI - [Der Ophthalmologe - digital options are a sensible supplement to the Journal]. PMID- 22447417 TI - [Ophthalmological treatment during pregnancy. Healthy balance between treatment and safety]. PMID- 22447418 TI - [Ophthalmic agents during pregnancy and breastfeeding]. AB - Ocular therapy is necessary even during pregnancy but the use of pharmaceutical substances bears the risk of side effects on mother and child. The article reflects current knowledge on how to treat the most important eye diseases during pregnancy and breastfeeding. The review covers the diagnostics (tonometry, mydriasis, angiography) as well as treatment of infections of the eyes, glaucoma, allergies, diabetic retinopathy, pain and inflammation. PMID- 22447419 TI - [Influence of mode of delivery on pre-existing eye diseases]. AB - Many ophthalmologists and obstetricians recommend either an assisted vaginal delivery with forceps or vacuum extraction, or a Caesarean section in cases of pre-existing eye diseases, such as myopia, retinal detachment, glaucoma or diabetic retinopathy. This is mainly based on the increase of intraocular pressure during the final stage of labor. These recommendations, however, are not evidence-based. None of the published trials have reported any retinal changes after vaginal delivery. This report provides information on the influence of physiological changes on eye diseases during the final stage of delivery. In general eye disease is not an indication for an instrumental or operative delivery provided regular eye examinations (once each trimester) have been performed. PMID- 22447420 TI - [Management of patients with ocular diseases during pregnancy. Diabetes, glaucoma and uveitis]. AB - Many ocular diseases require treatment even during pregnancy. Some conditions, such as diabetic retinopathy tend to worsen during pregnancy but others, such as uveitis may benefit from the physiological changes occurring during pregnancy. But generally even a favorable development is not sufficient to obtain a steady state without treatment. Each medication applied during pregnancy should only be given after thorough consideration of the pros and cons and discussion of these with the patient. There are sufficient medications for ocular diseases that can be given when indicated following published guidelines and experiences. This review focuses on the course and therapy of glaucoma, diabetic retinopathy and uveitis during pregnancy. PMID- 22447421 TI - [Biometry of the anterior eye segment for implantation of phakic anterior chamber lenses. A comparison of current measurement devices]. AB - BACKGROUND: Implantation of phakic intraocular lenses (pIOL) is gaining in importance. Exact measurement of the anterior chamber is important to assure safe and effective pIOL implantation. In this study six currently available diagnostic devices were tested in order to compare accuracy of measurements (anterior chamber depth and diameter) and ease of handling. PATIENTS AND METHODS: In this study 100 eyes from 50 healthy patients were enrolled. All measurements were done by the same operator (L. K.) on the same day and under the same lighting conditions. The following devices were used to measure anterior chamber depth and diameter: IOLMaster 500, Visante OCT, UBM Vumax II, Galilei, Pentacam Classic und Orbscan IIz. Correlations between each method were assessed using Pearson's correlation. Bland Altman plots were composed to evaluate the range of agreement between two methods. RESULTS: The mean epithelial anterior chamber depth was 3.45 +/- 0.38 mm with IOLMaster 500, 3.69 +/- 0.33 mm with Visante OCT, 3.59 +/- 0.35 mm with Pentacam, 3.67 +/- 0,36 mm with Galilei, 3.48 +/- 0.38 mm with Orbscan IIz and 3.52 +/- 0.34 mm with UBM VumaxII. The mean white-to-white measurements were 11.98 +/- 0.37 mm with IOLMaster 500 and 11.71 +/- 0.36 mm with Orbscan IIz. The mean angle-to-angle distances were 11.83 +/- 0. 43 mm with Visante OCT, 10.73 +/- 0.38 mm with Pentacam, 12.30 +/- 0.45 mm with Galilei, and 11.15 +/- 0.52 mm with UBM Vumax II. In the Bland Altman plots the range of agreement was 0.5 mm between Visante OCT and IOLMaster 500, regarding anterior chamber depth as well as anterior chamber diameter. CONCLUSION: The IOLMaster 500 provides exact measurement of the anterior chamber depth and diameter and is easy to handle in the daily clinical routine. PMID- 22447422 TI - [Color Doppler sonography of retrobulbar vessels and hypercapnia in normal tension glaucoma]. AB - PURPOSE: The aim of the study was to investigate retrobulbar flow velocities during hypercapnia in patients with normal tension glaucoma (NTG) without systemic vasospasm and jn controls. METHODS: A total of 16 NTG patients (mean age 58 +/- 14 years) and 16 control subjects (mean age 50 +/- 13 years, p = 0.10) were enrolled in this study. Flow velocities, peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive indices (RI) of the ophthalmic (OA) and central retinal arteries (CRA) were assessed using color Doppler imaging. Blood flow velocities were measured under normocapnic and hypercapnic conditions (increasing the end-tidal pCO(2) by 15%). Blood pressure, ventilation rate and oxygen saturation were monitored simultaneously. RESULTS: During hypercapnia, velocity responses of the PSV (p = 0.044) and EDV (p = 0.037) of the CRA were significantly different in NTG patients and healthy controls, showing a greater increase of flow velocities in control subjects. Flow velocities of the OA increased significantly in both groups (PSV p = 0.039, EDV p = 0.003) during hypercapnia. Blood pressure, oxygen saturation and intraocular pressure changed similarly in both study groups with carbon dioxide provocation. CONCLUSIONS: Velocity response to hypercapnia was reduced in the CRA of NTG patients compared to controls. This may indicate a faulty vasodilatory response in NTG patients without vasospastic disease. PMID- 22447423 TI - [Investigation of the theoretical image quality of aspheric intraocular lenses by decentration. Hoya AF-1 iMics1 und Zeiss ASPHINA(TM) (Invent ZO)]. AB - BACKGROUND: The image quality of aberration correcting aspherical intraocular lenses (IOLs) depends on the centration in the eye. Aberration correcting IOLs of the second generation are claimed to be more robust to decentration. In this study the image quality of such IOLs was analyzed with decentration values of up to 1 mm. MATERIALS AND METHODS: In this study two aberration correction IOLs of the second generation were compared in a model eye. The IOLs were decentered for two pupil diameters (3.0 and 4.5 mm) in a range of +/- 1 mm relative to the line of sight in 50 um steps and the modulation transfer function was calculated. The results were compared for different spatial frequencies and visual acuities. RESULTS: The analyzed IOLs are superior to the spherical IOL in a decentration range from -0.45 mm to 0.60 mm (30 CPD, cycles per degree) for both pupil diameters. Especially for the greater pupil diameter the lenses show tolerance of image quality to lens decentration. CONCLUSIONS: Both IOLs show only a slight decrease in image quality with decentration and the range of tolerable decentration is increased compared to aspherical IOLs of the first generation. PMID- 22447424 TI - [Glaucoma diseases in Rhineland-Palatine 2010. Epidemiology and utilization of healthcare]. AB - BACKGROUND AND PURPOSE: Data on the epidemiology of glaucoma are sparse for Germany. Case registries from the Association of Statutory Health Insurance Physicians (Kassenarztliche Vereinigung) can be used to estimate disease prevalence rates for different types of glaucoma and to illustrate the utilization of glaucoma healthcare. METHODS: Analysis of healthcare data for suspected glaucoma cases and open angle, angle closure, secondary and other types of glaucoma was carried on the basis of case registries from the Association of Statutory Health Insurance Physicians in Rhineland-Palatine for the year 2010. Glaucoma cases were registered quarterly according to the ICD-10 classification for different glaucoma types (H40.0-H40.9). For the purpose of calculating the prevalence data were adjusted to the population size and compared in different age strata. RESULTS: The estimated prevalence of suspected glaucoma, open angle, angle closure, secondary and other types of glaucoma were 0.55%, 0.97%, 0.06%, 0.10% and 0.64%, respectively, with a higher prevalence in older age groups and women. Most glaucoma cases were diagnosed in the age group between 70 and 79 years and up to 15% of the population within this age group sought glaucoma care. In more than 50% of the glaucoma cases unspecific types of glaucoma diagnosis (suspected glaucoma /other glaucoma) were used. CONCLUSIONS: The data from the Association of Statutory Health Insurance Physicians can provide information about the utilization of ophthalmic healthcare and allow estimation of the underlying glaucoma prevalence in the population. The data illustrate weaknesses in the practice of glaucoma diagnosis and indicate the lack of a widely accepted glaucoma definition. PMID- 22447425 TI - [Ocular signs of a mitochondrial trifunctional protein defect. A long-term follow up]. AB - A 13-year-old boy presented with a defect of the mitochondrial trifunctional protein (MTP). The MTP complex catalyses beta-oxidation of long chain fatty acids. Disorders of this multienzyme complex result in accumulation of hydroxylated long chain fatty acids which leads to chorioretinopathy. Ophthalmoscopic findings in these patients include fine hyperpigmentation while autofluorescence reveals hyperfluorescent granules at the posterior pole. Visual acuity, visual fields and electroretinography are within the normal range. A special long chain fatty acid-reduced diet seems to delay the progression of chorioretinopathy. PMID- 22447426 TI - [Therapy-resistant purulent keratoconjunctivitis]. AB - The cause of keratoconjunctivitis could be either infectious or non-infectious in etiology. The case of a 79-year-old female patient with chronic, purulent bilateral keratoconjunctivitis which was totally resistant to therapy is presented. The patient also suffered from non-specific collagenosis resulting in severe Sicca symptoms. Over the years none of the many antibiotic or lubricant therapies that were administered could alleviate the symptoms and corneal scars resulted. After a long search the focus was localized. On everting the eyelids a pair of nearly fully decomposed therapeutic contact lenses adhering to each other were found and removed from both eyes. The pathogenic agent was identified as Stenotrophomonas maltophilia which was successfully treated by cotrimoxazol eye drops and immediately caused a dramatic improvement and total relief of the symptoms. PMID- 22447427 TI - [Botulinum toxin for ocular complications after facial palsy]. AB - Sequelae of facial palsy are often underdiagnosed. The ophthalmologist plays a pivotal role in the acute, subacute and chronic treatment of this condition. Goals are to provide corneal protection, restoration of facial asymmetry and facial movements and the treatment of crocodile tears. Botulinum toxin is the first line treatment for sequelae due to aberrant regeneration. The indications and techniques for treatment with botulinum toxin in patients with facial palsy are presented. PMID- 22447428 TI - [Migraine myths]. AB - Migraine is the most frequent cause of headache in patients seeking medical advice. Even ophthalmologists are frequently confronted with this diagnosis. In many cases a diagnosis can be easily established by a targeted patient history. Accompanying symptoms deserve attention, especially the aura which often leads patients directly to the ophthalmologist. Concerning migraine therapy well established guidelines exist but despite this many patients remain undiagnosed and inadequately treated. Many myths and half-truths are associated with migraine headache. This article aims to give an overview for ophthalmologists. PMID- 22447429 TI - Gene expression of solute carrier family 9 (sodium/hydrogen exchanger) 3, (SLC9A3) is downregulated in patients with ulcerative colitis. PMID- 22447430 TI - Structurally diverse polyamides obtained from monomers derived via the ugi multicomponent reaction. AB - The combination of the Ugi four-component reaction (Ugi-4CR) with acyclic diene metathesis (ADMET) or thiol-ene polymerization led to the formation of poly-1 (alkylcarbamoyl) carboxamides, a new class of substituted polyamides with amide moieties in the polymer backbone, as well as its side chains. 10-Undecenoic acid, obtained by pyrolysis of ricinoleic acid, the main fatty acid of castor oil, was used as the key renewable building block. The use of different primary amines, as well as isonitriles (isocyanides) for the described Ugi reactions provided monomers with high structural diversity. Furthermore, the possibility of versatile post-modification of functional groups in the side chains of the corresponding polymers should be of considerable interest in materials science. The obtained monomers were polymerized by ADMET, as well as thiol-ene, chemistry and all polymers were fully characterized. Finally, ortho-nitrobenzylamide containing polyamides obtained by this route were shown to be photoresponsive and exhibited a dramatic change of their properties upon irradiation with light. PMID- 22447431 TI - Coupling of kinesin ATP turnover to translocation and microtubule regulation: one engine, many machines. AB - The cycle of ATP turnover is integral to the action of motor proteins. Here we discuss how variation in this cycle leads to variation of function observed amongst members of the kinesin superfamily of microtubule associated motor proteins. Variation in the ATP turnover cycle among superfamily members can tune the characteristic kinesin motor to one of the range of microtubule-based functions performed by kinesins. The speed at which ATP is hydrolysed affects the speed of translocation. The ratio of rate constants of ATP turnover in relation to association and dissociation from the microtubule influence the processivity of translocation. Variation in the rate-limiting step of the cycle can reverse the way in which the motor domain interacts with the microtubule producing non motile kinesins. Because the ATP turnover cycle is not fully understood for the majority of kinesins, much work remains to show how the kinesin engine functions in such a wide variety of molecular machines. PMID- 22447432 TI - Infliximab for early endoscopic recurrence in patients with Crohn's disease. PMID- 22447433 TI - An ex vivo bacteriologic study comparing antiseptic techniques for natural orifice translumenal endoscopic surgery (NOTES) via the gastrointestinal tract. AB - BACKGROUND: NOTES via the gastrointestinal tract raises the specter of intra peritoneal infection. Various anti-microbial techniques have been employed in animal and human survival studies, including saline lavage, intravenous and topical antibiotics, and povidone-iodine, although there is a paucity of data regarding their general effectiveness. AIM: To assess the effectiveness of existing sterilization techniques for NOTES by quantifying and speciating colony forming units (CFUs) before and after treatment. DESIGN: Ex vivo animal studies; bacteriological study. METHODS: Stomachs and distal colons were harvested en bloc from ten fasted adult white pigs following euthanasia. Half received cefazolin 1 g intravenously prior to killing. Multiple tissue samples were obtained from each resected organ. Each tissue sample was then assigned to one of five treatment arms: (1) normal saline, (2) Betadine, (3) cefazolin/metronidazole suspension, (4) chlorhexidine, (5) no treatment. Fifteen samples were used per arm. After treatment, the mucosal surface of each sample was swabbed and inoculated in normal saline, followed by serial dilutions, which were then plated onto sheep's blood agar plates and incubated under aerobic and anaerobic conditions. CFUs were quantified and speciated. RESULTS: Median bacterial density was estimated to be 8.0 * 10(5) CFUs/ml (stomach) and 1.9 * 10(6) CFUs/ml (colon). The predominant organisms were Escherichia coli (stomach) and both E. coli and Enterococcus sp. (colon). Saline and antibiotic suspension lavages caused a 1-log reduction in stomach and colon. Betadine/chlorhexidine lavage resulted in a 4-log reduction. Intravenous antibiotics alone resulted in a 4-log reduction. Combining intravenous antibiotics and either Betadine or chlorhexidine decreased counts to the 10(1) level. By Kruskal-Wallis method, differences were statistically significant (p = 0.001). CONCLUSIONS: The use of intravenous antibiotics in addition to topical Betadine or chlorhexidine effectively reduced microbial burden in both gastric and colonic mucosa in this porcine model to the 10(1) level. PMID- 22447434 TI - Prenatal and perinatal characteristics associated with pediatric-onset inflammatory bowel disease. AB - BACKGROUND: The majority of studies that report early life risk factors for pediatric-onset inflammatory bowel disease (IBD) do not account for potential confounding, which can lead to spurious associations and incorrect inferences. AIMS: To assess the relationship between prenatal and perinatal characteristics and the risk of pediatric-onset IBD accounting for potential confounding. METHODS: We conducted a nested case-control study of 189 cases aged <=18 years and 3,080 age- and membership-matched controls born at a Kaiser Permanente Northern California facility between 1984 and 2006. The cases were diagnosed with IBD between 1996 and 2006 and diagnosis was confirmed by chart review. We obtained prenatal and perinatal characteristics from the electronic clinical records of the mother and child. Conditional logistic regression was used to assess the associations between these factors and risk of incident IBD, Crohn's disease, and ulcerative colitis. RESULTS: In analyses accounting for confounding, maternal IBD (odds ratio [OR] 5.1, 95 % confidence interval [CI] 2.0-12.9) and white race (OR 2.3, 95 % CI 1.6-3.2) were the only factors statistically associated with pediatric-onset IBD. Maternal respiratory infection during pregnancy (OR 2.0, 95 % CI 1.0-4.0), age < 20 years (OR 2.0, 95 % CI 0.8-4.7) and gestational hypertension (OR 1.7, 95 % CI 1.0-2.7) were associated with pediatric onset IBD, but did not achieve statistical significance. CONCLUSIONS: Maternal history of IBD and race were the only characteristics of those that we examined that were associated with the development of pediatric IBD in this well documented population of cases and matched controls. PMID- 22447435 TI - Validation of a hybrid Doppler ultrasound vessel-based registration algorithm for neurosurgery. AB - PURPOSE: We describe and validate a novel hybrid nonlinear vessel registration algorithm for intra-operative updating of preoperative magnetic resonance (MR) images using Doppler ultrasound (US) images acquired on the dura for the correction of brain-shift and registration inaccuracies. We also introduce an US vessel appearance simulator that generates vessel images similar in appearance to that acquired with US from MR angiography data. METHODS: Our registration uses the minimum amount of preprocessing to extract vessels from the raw volumetric images. This prevents the removal of important registration information and minimizes the introduction of artifacts that may affect robustness, while reducing the amount of extraneous information in the image to be processed, thus improving the convergence speed of the algorithm. We then completed 3 rounds of validation for our vessel registration method for robustness and accuracy using (i) a large number of synthetic trials generated with our US vessel simulator, (ii) US images acquired from a real physical phantom made from polyvinyl alcohol cryogel, and (iii) real clinical data gathered intra-operatively from 3 patients. RESULTS: Resulting target registration errors (TRE) of less than 2.5 mm are achieved in more than 90 % of the synthetic trials when the initial TREs are less than 20 mm. TREs of less than 2 mm were achieved when the technique was applied to the physical phantom, and TREs of less than 3 mm were achieved on clinical data. CONCLUSIONS: These test trials show that the proposed algorithm is not only accurate but also highly robust to noise and missing vessel segments when working with US images acquired in a wide range of real-world conditions. PMID- 22447436 TI - Community-acquired methicillin-resistant Staphylococcus aureus skull base osteomyelitis with occipital condylar cerebrospinal fluid leak in an immunocompetent patient. AB - Community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is emerging as an important pathogen in paranasal sinus disease. However, sinonasal CA-MRSA has not been reported as a source of central skull base osteomyelitis. We report an unusual case of a previously healthy and immunocompetent adult who developed meningitis, central skull base osteomyelitis, and occipital condylar cerebrospinal fluid rhinorrhea from CA-MRSA sphenoid sinusitis requiring endoscopic surgical repair. This case clearly demonstrates the expanding spectrum of severe infections caused by CA-MRSA, which requires prompt diagnosis, a high level of suspicion, and appropriate medical and/or surgical management. PMID- 22447437 TI - Increased relative wall thickness is a marker of subclinical cardiac target organ damage in African diabetic patients. AB - OBJECTIVE: To assess the prevalence and covariates of abnormal left ventricular (LV) geometry in diabetic outpatients attending Muhimbili National Hospital in Dar es Salaam, Tanzania. METHODS: Echocardiography was performed in 61 type 1 and 123 type 2 diabetes patients. LV hypertrophy was taken as LV mass/height(2.7) > 49.2 g/m(2.7) in men and > 46.7 g/m(2.7) in women. Relative wall thickness (RWT) was calculated as the ratio of LV posterior wall thickness to end-diastolic radius and considered increased if >= 0.43. LV geometry was defined from LV mass index and RWT in combination. RESULTS: The most common abnormal LV geometries were concentric remodelling in type 1 (30%) and concentric hypertrophy in type 2 (36.7%) diabetes patients. Overall, increased RWT was present in 58% of the patients. In multivariate analyses, higher RWT was independently associated with hypertension, longer isovolumic relaxation time, lower stress-corrected midwall shortening and circumferential end-systolic stress, both in type 1 (multiple R(2) = 0.73) and type 2 diabetes patients (multiple R(2) = 0.66), both p < 0.001. These associations were independent of gender, LV hypertrophy or renal dysfunction. CONCLUSION: Increased RWT is common among diabetic sub-Saharan Africans and is associated with hypertension and LV dysfunction. PMID- 22447438 TI - Hydrogen-driven collapse of C60 inside single-walled carbon nanotubes. PMID- 22447439 TI - Spy1 is frequently overexpressed in malignant gliomas and critically regulates the proliferation of glioma cells. AB - Spy1, a member of the Speedy/RINGO family, is a novel activator of cyclin dependent kinases known to mediate cell cycle progression and cell survival in response to DNA damage. This study focused on the role of Spy1 in glioma oncogenesis. Immunohistochemistry and western blot analysis were performed to examine the expression of Spy1 in human glioma tissues and cell lines. Spy1 was frequently overexpressed in tumor tissues and cultured cells. Our data suggested that Spy1 expression positively correlated with the malignancy of gliomas. Altered expression of Spy1 led to changes in cell cycle processes, cyclin dependent kinase 2 activity, and p27kip1 protein stabilization, ultimately disrupting cell growth rate. More importantly, high expression of Spy1 was associated with poor prognosis in patients with glioma, suggesting that Spy1 may be a novel independent prognostic predictor of survival for glioma patients. Collectively, this is the first report that Spy1 may play an essential role in the growth processes of human glioma. PMID- 22447440 TI - Urgent MRI with MR cholangiopancreatography (MRCP) of acute cholecystitis and related complications: diagnostic role and spectrum of imaging findings. AB - Acute cholecystitis, which is usually associated with gallstones, is one of the commonest surgical causes of emergency hospital admission and may be further complicated by mural necrosis, perforation, and abscess formation. Magnetic resonance imaging (MRI) is increasingly available in the emergency setting. Technically improved equipment and faster acquisition protocols allow excellent tissue contrast and MRI is now an attractive modality for imaging acute abdominal disorders. The use of MRI with MR cholangiopancreatography in the emergency setting provides rapid, noninvasive, and confident diagnosis or exclusion of acute cholecystitis and of coexistent choledocholithiasis. To familiarize the reader with these cross-sectional imaging appearances, this paper reviews MRI findings consistent with uncomplicated cholecystitis. These include gallbladder distension, intraluminal sludge and gallstones, impacted stones obstructing the gallbladder neck or cystic duct, thickening of the gallbladder wall, abnormal signal intensity and edematous stratification, and pericholecystic and perihepatic fluid, plus increased enhancement of the gallbladder wall and adjacent liver parenchyma when intravenous paramagnetic contrast is used. Furthermore, MRI allows prompt detection and comprehensive visualization and characterization of cholecystitis-related complications such as gangrene, perforation, pericholecystic abscess, and intrahepatic fistulization. Some previous literature reports, and our experience, suggest that, when available, MRI should be recommended to provide prompt and efficient triage of patients with suspected cholecystitis and inconclusive clinical, laboratory, and sonographic findings. It facilitates appropriate therapeutic planning, including the timing of surgery (emergency or delayed), approach (laparoscopic or laparotomic), and need for preoperative or intraoperative removal of stone(s) in the common bile duct. PMID- 22447441 TI - Open reduction and internal fixation of radial head fractures. AB - This study examines 32 patients operated for radial head fractures, mean age 48.7 years (range 26-76 years), Mason type II in 25 cases and Mason type III with 3 main fragments in 7 cases. Fractures were surgically reduced and fixed with Herbert's (12 cases) or Osteomed (20 cases) cannulated screws. The latter have a head that is <1 mm high and are only threaded distally. Both types of screw provide compression across the fracture. In Mason type II cases, the mean MEPS score was 98.4 and the DASH score 6.8. In Mason type III cases, MEPS was 99.3 and DASH 9.5. We believe that fixation can be carried out with screws alone, which are less invasive, and that the screw heads should preferably be completely buried, to avoid stiffness in prono-supination. In addition, suturing of the annular ligament and the joint capsule is made easier by the reduced invasiveness of screws. Screw treatment is effective in non-comminuted fractures of the radial head. PMID- 22447442 TI - Short-term macroinvertebrate recruitment and sediment accumulation: a novel field chamber approach. AB - Stream-deposited sediment is one of the major stressors affecting stream biota. Several methods exist to quantify stream sediment embeddedness, but they are relatively qualitative and operationally defined. The authors developed a short term in situ embeddedness chamber method to measure aquatic insect recruitment and associated sediment accumulation in a more quantitative, better replicated manner. With sediment accumulation and aquatic insect recruitment as endpoints, three exposure periods were evaluated (4, 7, and 14 d) on a low-order stream (Honey Creek, New Carlisle, Ohio, USA) and a medium-order stream (Stillwater River, Covington, Ohio, USA). Chamber results show significant positive correlations between newly deposited fine sediment and insect recruitment. Embeddedness was also measured using the more conventional techniques of the Burns method and the U.S. Geological Survey National Water Quality Assessment Program method. This in situ chamber method allows for increased experimental options for assessing the stress of embeddedness and siltation on benthic communities and may prove useful for investigating the resilience of benthic communities after disturbances. PMID- 22447443 TI - Study on the aconitine-type alkaloids of Radix Aconiti Lateralis and its processed products using HPLC-ESI-MSn. AB - The type and content change of alkaloids of Radix Aconiti Lateralis (Lateral root of Aconitum carmichaeli Debx, an important and popular medicinal herb in Traditional Chinese Medicine) in processing were studied using high performance liquid chromatography-electrospray ionization-multi-stage mass spectrometry (HPLC ESI-MS(n)). Extract containing alkaloids, which were known to be the main bioactive components of the herb, was prepared by 1% (v/v) hydrochloric acid solution. An HPLC method which can simultaneously separate these alkaloids was established with gradient elution mode. Forty-eight compounds were structurally identified by employing LC-MS(n) techniques; the MS(n) spectra of most alkaloids displayed a characteristic behaviour of loss of CH(3)COOH (60 u), CH(3)OH (32 u), C(6)H(5)COOH (122 u), CO (28 u) and H(2)O (18 u). Among them, the fragmentation ion C6H5COOH (122 u) was reported for the first time. By comparison, 22 compounds were found both in the crude materials and the processed products; 17 alkaloids were only found in the processed products and 9 alkaloids,which existed in crude material, could not be detected after processing. In the process of identification, we found new kinds of alkaloids, with protonated molecules at m/z 452, 468, and 482. We called these compounds dehydra-hypaconine, dehydra mesaconine, and dehydra-aconine, respectively. PMID- 22447444 TI - Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase. AB - 7-Ketocholesterol (7KC) is a cytotoxic oxysterol that plays a role in many age related degenerative diseases. 7KC formation and accumulation often occurs in the lysosome, which hinders enzymatic transformations that reduce its toxicity and increase the sensitivity to lysosomal membrane permeabilization. We assayed the potential to mitigate 7KC cytotoxicity and enhance cell viability by overexpressing 7KC-active enzymes in human fibroblasts. One of the enzymes tested, a cholesterol oxidase engineered for lysosomal targeting, significantly increased cell viability in the short term upon treatment with up to 50 uM 7KC relative to controls. These results suggest targeting the lysosome for optimal treatment of oxysterol-mediated cytotoxicity, and support the use of introducing novel catalytic function into the lysosome for therapeutic and research applications. PMID- 22447445 TI - Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit. AB - The bacterial homologue of C4orf14, YqeH, has been linked to assembly of the small ribosomal subunit. Here, recombinant C4orf14 isolated from human cells, co purified with the small, 28S subunit of the mitochondrial ribosome and the endogenous protein co-fractionated with the 28S subunit in sucrose gradients. Gene silencing of C4orf14 specifically affected components of the small subunit, leading to decreased protein synthesis in the organelle. The GTPase of C4orf14 was critical to its interaction with the 28S subunit, as was GTP. Therefore, we propose that C4orf14, with bound GTP, binds to components of the 28S subunit facilitating its assembly, and GTP hydrolysis acts as the release mechanism. C4orf14 was also found to be associated with human mitochondrial nucleoids, and C4orf14 gene silencing caused mitochondrial DNA depletion. In vitro C4orf14 is capable of binding to DNA. The association of C4orf14 with mitochondrial translation factors and the mitochondrial nucleoid suggests that the 28S subunit is assembled at the mitochondrial nucleoid, enabling the direct transfer of messenger RNA from the nucleoid to the ribosome in the organelle. PMID- 22447446 TI - Interactions between DNA, transcriptional regulator Dreb2a and the Med25 mediator subunit from Arabidopsis thaliana involve conformational changes. AB - Mediator is a multiprotein coregulatory complex that conveys signals from DNA bound transcriptional regulators to the RNA polymerase II transcription machinery in eukaryotes. The molecular mechanisms for how these signals are transmitted are still elusive. By using purified transcription factor Dreb2a, mediator subunit Med25 from Arabidopsis thaliana, and a combination of biochemical and biophysical methods, we show that binding of Dreb2a to its canonical DNA sequence leads to an increase in secondary structure of the transcription factor. Similarly, interaction between the Dreb2a and Med25 in the absence of DNA results in conformational changes. However, the presence of the canonical Dreb2a DNA-binding site reduces the affinity between Dreb2a and Med25. We conclude that transcription regulation is facilitated by small but distinct changes in energetic and structural parameters of the involved proteins. PMID- 22447447 TI - Mixture of differentially tagged Tol2 transposons accelerates conditional disruption of a broad spectrum of genes in mouse embryonic stem cells. AB - Among the insertional mutagenesis techniques used in the current international knockout mouse project (KOMP) on the inactivation of all mouse genes in embryonic stem (ES) cells, random gene trapping has been playing a major role. Gene targeting experiments have also been performed to individually and conditionally knockout the remaining 'difficult-to-trap' genes. Here, we show that transcriptionally silent genes in ES cells are severely underrepresented among the randomly trapped genes in KOMP. Our conditional poly(A)-trapping vector with a common retroviral backbone also has a strong bias to be integrated into constitutively transcribed genome loci. Most importantly, conditional gene disruption could not be successfully accomplished by using the retrovirus vector because of the frequent development of intra-vector deletions/rearrangements. We found that one of the cut and paste-type DNA transposons, Tol2, can serve as an ideal platform for gene-trap vectors that ensures identification and conditional disruption of a broad spectrum of genes in ES cells. We also solved a long standing problem associated with multiple vector integration into the genome of a single cell by incorporating a mixture of differentially tagged Tol2 transposons. We believe our strategy indicates a straightforward approach to mass-production of conditionally disrupted alleles for genes in the target cells. PMID- 22447448 TI - Interaction between Escherichia coli DNA polymerase IV and single-stranded DNA binding protein is required for DNA synthesis on SSB-coated DNA. AB - DNA polymerase IV (Pol IV) is one of three translesion polymerases in Escherichia coli. A mass spectrometry study revealed that single-stranded DNA-binding protein (SSB) in lysates prepared from exponentially-growing cells has a strong affinity for column-immobilized Pol IV. We found that purified SSB binds directly to Pol IV in a pull-down assay, whereas SSBDeltaC8, a mutant protein lacking the C terminal tail, failed to interact with Pol IV. These results show that the interaction between Pol IV and SSB is mediated by the C-terminal tail of SSB. When polymerase activity was tested on an SSBDeltaC8-coated template, we observed a strong inhibition of Pol IV activity. Competition experiments using a synthetic peptide containing the amino acid sequence of SSB tail revealed that the chain elongating capacity of Pol IV was greatly impaired when the interaction between Pol IV and SSB tail was inhibited. These results demonstrate that Pol IV requires the interaction with the C-terminal tail of SSB to replicate DNA efficiently when the template ssDNA is covered with SSB. We speculate that at the primer/template junction, Pol IV interacts with the tail of the nearest SSB tetramer on the template, and that this interaction allows the polymerase to travel along the template while disassembling SSB. PMID- 22447449 TI - Inference of modules associated to eQTLs. AB - Cataloging the association of transcripts to genetic variants in recent years holds the promise for functional dissection of regulatory structure of human transcription. Here, we present a novel approach, which aims at elucidating the joint relationships between transcripts and single-nucleotide polymorphisms (SNPs). This entails detection and analysis of modules of transcripts, each weakly associated to a single genetic variant, together exposing a high confidence association signal between the module and this 'main' SNP. To explore how transcripts in a module are related to causative loci for that module, we represent such dependencies by a graphical model. We applied our method to the existing data on genetics of gene expression in the liver. The modules are significantly more, larger and denser than found in permuted data. Quantification of the confidence in a module as a likelihood score, allows us to detect transcripts that do not reach genome-wide significance level. Topological analysis of each module identifies novel insights regarding the flow of causality between the main SNP and transcripts. We observe similar annotations of modules from two sources of information: the enrichment of a module in gene subsets and locus annotation of the genetic variants. This and further phenotypic analysis provide a validation for our methodology. PMID- 22447450 TI - Germline ablation of SMUG1 DNA glycosylase causes loss of 5-hydroxymethyluracil- and UNG-backup uracil-excision activities and increases cancer predisposition of Ung-/-Msh2-/- mice. AB - Deamination of cytosine (C), 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) occurs spontaneously in mammalian DNA with several hundred deaminations occurring in each cell every day. The resulting potentially mutagenic mispairs of uracil (U), thymine (T) or 5-hydroxymethyluracil (hmU) with guanine (G) are substrates for repair by various DNA glycosylases. Here, we show that targeted inactivation of the mouse Smug1 DNA glycosylase gene is sufficient to ablate nearly all hmU-DNA excision activity as judged by assay of tissue extracts from knockout mice as well as by the resistance of their embryo fibroblasts to 5 hydroxymethyldeoxyuridine toxicity. Inactivation of Smug1 when combined with inactivation of the Ung uracil-DNA glycosylase gene leads to a loss of nearly all detectable uracil excision activity. Thus, SMUG1 is the dominant glycosylase responsible for hmU-excision in mice as well as the major UNG-backup for U excision. Both Smug1-knockout and Smug1/Ung-double knockout mice breed normally and remain apparently healthy beyond 1 year of age. However, combined deficiency in SMUG1 and UNG exacerbates the cancer predisposition of Msh2(-/-) mice suggesting that when both base excision and mismatch repair pathways are defective, the mutagenic effects of spontaneous cytosine deamination are sufficient to increase cancer incidence but do not preclude mouse development. PMID- 22447451 TI - Replication regulation of Vibrio cholerae chromosome II involves initiator binding to the origin both as monomer and as dimer. AB - The origin region of Vibrio cholerae chromosome II (chrII) resembles plasmid origins that have repeated initiator-binding sites (iterons). Iterons are essential for initiation as well as preventing over-initiation of plasmid replication. In chrII, iterons are also essential for initiation but over initiation is prevented by sites called 39-mers. Both iterons and 39-mers are binding sites of the chrII specific initiator, RctB. Here, we have isolated RctB mutants that permit over-initiation in the presence of 39-mers. Characterization of two of the mutants showed that both are defective in 39-mer binding, which helps to explain their over-initiation phenotype. In vitro, RctB bound to 39-mers as monomers, and to iterons as both monomers and dimers. Monomer binding to iterons increased in both the mutants, suggesting that monomers are likely to be the initiators. We suggest that dimers might be competitive inhibitors of monomer binding to iterons and thus help control replication negatively. ChrII replication was found to be dependent on chaperones DnaJ and DnaK in vivo. The chaperones preferentially improved dimer binding in vitro, further suggesting the importance of dimer binding in the control of chrII replication. PMID- 22447452 TI - Local tissue reaction after the application of topical hemostatic agents in a rat partial nephrectomy model. AB - Various hemostatics are used for renal surgical procedures. We investigated the hemostatic efficacy of cellulose derivatives on the model of partial nephrectomy in rats focusing on the local reaction of renal parenchyma. A total of 50 Wistar rats were divided into five groups of 10 animals each. Partial nephrectomy of the caudal pole without hilar vascular control was performed. Oxidized cellulose (OC), sodium salt of oxycellulose (OCN), carboxymethyl cellulose (CMC), dialdehyde cellulose (DAC), and gelatin-based hemostatic (C) were applied to the bleeding wounds. The time to hemostasis was monitored. Half of the animals were euthanized after 3 days, the second half 30 days from the experiment start date. The left kidney was excised and subjected to histopathological examination. The biochemical data was subjected to statistical analysis. The time to hemostasis in all groups was significantly less than in the C group (in OC p = 0.0057, OCN p = 0.0039, CMC and DAC p = 0.0001). In the C group, massive hemorrhages and necrosis did occur. In the OC and OCN groups, there were regenerative changes, a receding inflammatory reaction and hemorrhage. DAC caused an immune reaction and massive interstitial hemorrhages with biochemical signs of liver damage. Parenchyma in CMC revealed a reduction of necrosis and interstitial hemorrhages with regenerative processes. The most effective hemostatics were CMC and OC, achieving the best results both in the time to hemostasis, and for histopathological evaluation. PMID- 22447453 TI - Specific environmental release categories--A tool for improving chemical safety assessment in the EC--report of a multi-stakeholder workshop. AB - In April 2011, experts from industry and authorities met for a workshop to discuss experience and future developments regarding the use of specific environmental release categories (SPERCs) in chemicals safety assessment (CSA) under the European Chemicals Regulation Registration, Evaluation and Authorization of Chemicals (REACH). This article provides a summary of the workshop. It briefly explains what a SPERC is, why SPERCs are needed, where the challenges of the concept are, and what improvements are needed to make SPERCs a useful tool for assessments under REACH. PMID- 22447454 TI - Surgical results of pancreatoduodenectomy in elderly patients. AB - PURPOSE: To assess the safety and feasibility of pancreatoduodenectomy (PD) in elderly patients, we investigated the clinical characteristics of patients aged >=75 years, who underwent this procedure at our hospital. METHODS: Between November 2005 and December 2010, 84 patients underwent PD at Tokushima University Hospital. We analyzed the clinicopathological data and outcomes after PD in patients aged >=75 years compared with those in patients <75 years. RESULTS: The preoperative characteristics of the elderly group (n = 28) were similar to those of the younger group (n = 56). The hemoglobin and albumin levels were significantly lower in the elderly patients (P < 0.05), who also had a higher rate of preoperative pulmonary dysfunction (P < 0.05). The operation time and intraoperative blood loss did not differ significantly between the groups, but the incidence of pneumonia was higher in the elderly group (P < 0.05). The overall survival rate did not differ significantly between the groups. CONCLUSION: Advanced age alone does not have an adverse effect on surgical outcomes, including postoperative complications and long-term prognosis. Therefore, PD may be justified for selected elderly patients. PMID- 22447455 TI - MC1R, ASIP, TYR, and TYRP1 gene variants in a population-based series of multiple primary melanomas. AB - Allelic variants of the low-penetrance melanoma gene MC1R increase the risk of both melanoma and non-melanoma skin cancer. Common variants of the genes ASIP, TYR, and TYRP1, which regulate the melanogenic pathway, have also been shown to associate with melanoma. In this population-based study, we investigated SNPs of MC1R, ASIP, TYR, and TYRP1 as risk factors for development of multiple primary melanomas (MPM) in 388 Norwegian cases. The MPM patients had a significantly higher likelihood of carrying any MC1R variant than the control group of 420 blood donors [86.8 vs. 78.3%, OR = 1.73, and confidence intervals (CI) 1.18 2.52]. When MC1R variants were analyzed individually, Asp84Glu and Arg151Cys were significantly more frequent among the MPM cases than among the controls (OR = 5.77, CI 1.97-16.90, and OR = 1.80, CI 1.36-2.37, respectively). In addition, there was an allele dose-dependent increase in MPM risk for carriers of red hair color (RHC) MC1R variants. The AH haplotype of ASIP was also a significant risk factor for MPM development (OR = 1.72 and CI 1.12-2.49), whereas no association was observed for previously reported risk variants of the TYR and TYRP1 genes. In summary, by using a population-based material of high-risk melanoma cases, we demonstrate a significant effect of both MC1R RHC variants and an ASIP haplotype, but could not replicate an association with postulated risk SNPs of TYR and TYRP1. PMID- 22447456 TI - Use of acellular aortic matrix for reconstruction of abdominal hernias in buffaloes. PMID- 22447457 TI - Recovery of staphylococci from computer keyboards in a veterinary medical centre and the effect of routine cleaning. AB - Computers play a vital role in veterinary clinics for grading, examining results, updating records, giving discharge instructions and maintaining billing information. Few studies have documented the degree of contamination or practical methods to disinfect computer equipment within the veterinary clinic setting. The intent of the present study was to characterise the frequency of recovery of Staphylococcus species from computer keyboards from a veterinary teaching hospital setting and to evaluate the effect of daily cleaning. From three keyboards in a treatment area, three in a dermatology area and one in office 70 environmental samples were cultured for Staphylococcus. As an indirect measure to assess cleanliness, samples were collected and tested using the 3M Clean-Trace Luminometer (relative light units [RLU]). Of the 25 Staphylococcus recovered 13 were Staphylococcus species, seven Staphylococcus pseudintermedius, four Staphylococcus aureus and one mixed colony of both Staphylococcus species and S pseudintermedius. The median RLU was 2098 (range 132 to 11,590). Routine cleaning decreased the recovering of Staphylococcus and the RLU values. In summary, the study results demonstrate the value of routine cleaning of keyboards and the need for on-going and regular education of staff and students about good hand hygiene. PMID- 22447458 TI - Pneumonia caused by influenza A H1N1 2009 virus in farmed American mink (Neovison vison). PMID- 22447459 TI - Pop hole use by hens with different keel fracture status monitored throughout the laying period. AB - The aim of this work was to study the effect of keel fractures on the extent to which free-range hens access the range through pop holes. Over two consecutive laying periods (two production years) a total of 1100 individual birds from one half of a house, divided into four separated flocks, were caught at 25, 35, 45, 55 and 65 weeks, palpated to assess the prevalence and severity of keel fractures and tagged with RFID transponders. Their use of pop holes was subsequently monitored in some cases from week 25 to end of lay at 68 to 70 weeks. At regular intervals (every 10 weeks), the tagged birds were re-caught to assess changes in keel fracture prevalence and severity. The average percentage of birds with fractured keels at 25, 35, 45, 55, 65 and at end of lay (68 to 70 weeks of age) was 5.5, 25.5, 49, 63, 66.5 and 78.5, respectively, across both production years. The effect of keel score on pop hole use was modelled statistically, adjusting for weather conditions and age of the birds. There were significant effects of most of the weather variables recorded, as well as age of the bird, on use of pop holes and also a significant effect of keel score. Higher keel scores resulted in a reduction in pop hole use. A significant statistical interaction between keel score and ambient temperature revealed an accelerated reduction in use as the temperature decreased and keel score increased. It is concluded that the occurrence of keel fractures may affect the birds' ability or willingness to utilise the outdoor range provided by free-range housing systems, thereby reducing the potential welfare advantages of this type of housing. PMID- 22447460 TI - Activation procedures in the electroencephalograms of healthy and epileptic cats under propofol anaesthesia. AB - The current study evaluated the diagnostic value of electroencephalographic recordings (EEG) in cats with epilepsy under special consideration of photic stimulation and hyperventilation. EEGs in six healthy cats were recorded under light (mean dose of 0.23 mg/kg/min) and deep (mean dose of 0.7 mg/kg/min) propofol anaesthesia, whereas EEGs in 13 diseased cats were recorded under a propofol anaesthesia which was kept as light as possible (mean dose of 0.39 mg/kg/min). Paroxysmal discharges were detected in six of 13 cats suffering from seizures (two cats with idiopathic epilepsy and four cats with symptomatic epilepsy). Activation techniques did not enhance the diagnostic value of the EEGs. Photic driving was detected in one of six healthy cats under light, in five of six healthy cats under deep propofol anaesthesia and in 11 of 13 cats with seizures. Systematic use of activation techniques does not seem to increase the diagnostic yield of the recorded EEGs and should not be used in a clinical setting until future studies indicate value. Further investigations into the origin of photic driving under propofol anaesthesia are needed and could lead to the development of a reliable animal model to research into drug effects on the EEG. PMID- 22447461 TI - 18F-FDG-PET evaluation of treatment response to neo-adjuvant therapy in patients with locally advanced rectal cancer: a meta-analysis. AB - The purpose of this meta-analysis was to evaluate the utility of positron emission tomography (PET) using fluor-18-deoxyglucose (FDG) to predict the response of rectal cancer to neo-adjuvant therapy. All previously published studies on the role of FDG-PET in predicting the response of rectal cancer to neo adjuvant therapy were collected. Pooled sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated using statistical software. A total of 28 studies, comprising 1,204 patients with rectal cancer, were included in the meta-analysis. Pooled sensitivity, specificity, PPV and NPV for FDG-PET predicting the response to therapy was 78% [95% confidence interval (CI): 75-82%], 66% (95% CI: 62-69%), 70% (95% CI; 66 73%) and 75% (95% CI: 71-0.79%), respectively. The included studies were of a relatively high methodological quality according to the QUADAS (quality assessment of studies of diagnostic accuracy included in systematic reviews) criteria. Based on the subgroup analyses, there was no significant difference between the response index, the standardized uptake value and the visual response score in predicting the therapy response. However, the accuracy of the group that underwent PET scanning during therapy showed significantly higher values (sensitivity 86% and specificity 80%) than the group that was scanned after completion of the therapy. Therefore, FDG-PET is valuable for predicting the response of rectal carcinoma to neo-adjuvant therapy, and early evaluation of response during the therapy may be more promising. However, additional studies using prospective clinical trials will be required to assess the clinical benefit of this strategy. PMID- 22447462 TI - Juvenile homosexual homicide. AB - Limited information exists on juvenile homosexual homicide (JHH), that is, youths who perpetrate sexual homicides against same-sex victims. Only a handful of cases from the United States and internationally have been described in the literature. This study, the first of its kind, examines the epidemiology, victimology, victim offender relationship, and weapon-use patterns in JHH offenders using a large U.S. database on homicide spanning three decades. The data for this study were derived from the Federal Bureau of Investigation's Supplementary Homicide Reports (SHRs) for the years 1976 through 2005. A total of 93 cases of JHH were identified. On average, three of these crimes occurred annually in the U.S., and there was a marked decline in its incidence over the study period. Ninety-five percent were male offender-male victim cases and 5% were female offender-female victim cases. JHH offenders were over-represented amongst all juvenile sexual murderers, similar to their adult counterparts. The majority of these boys were aged 16 or 17 and killed adult victims. They were significantly more likely to kill adult victims than other age groups, to be friends or acquaintances of the victims, and to use contact/edged weapons or firearms. Most offenders killed same race victims, although Black offenders were significantly more likely than White offenders to kill interracially. A case report is provided to illustrate JHH. Further research is needed to promote our understanding of the pathogenesis, etiology, and associated risk factors for this aberrant form of murder by children. PMID- 22447463 TI - Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy. AB - BACKGROUND: Lipid modification therapy (LMT) produces cardiovascular benefits principally through reductions in low density lipoprotein cholesterol. While recent evidence, using data from 454 participants in the Framingham Offspring Study, has suggested that increases in high density lipoprotein cholesterol (HDL C) are also associated with a reduction in cardiovascular outcomes, independently of changes in low density lipoprotein cholesterol, replication of this finding is important. The authors therefore present further results using data from the EPIC Norfolk (UK) and Rotterdam (The Netherlands) prospective cohort studies. METHODS: A total of 1148 participants, 446 from the EPIC-Norfolk and 702 from the Rotterdam study, were assessed for lipids before and after starting LMT. Subsequent risk of cardiovascular events, ascertained through linkage with mortality records and hospital databases, was investigated using Cox proportional hazards regression. Random effects meta-analysis was used to combine results across studies. RESULTS: Based on combined data from the EPIC-Norfolk and Rotterdam studies there was some evidence that change in HDL-C resulting from LMT was associated with reduced cardiovascular risk (HR per pooled SD (=0.34 mmol/l) increase=0.74, 95% CI 0.56 to 0.99, adjusted for age, sex and baseline HDL-C). However, this association was attenuated and was not (statistically) significant with further adjustments for non-HDL-C and for cigarette smoking history, prevalent diabetes, systolic blood pressure, body mass index, use of antihypertensive medication, previous myocardial infarction, prevalent angina and previous stroke (0.92, 0.701.20). CONCLUSIONS: Following adjustment for conventional non-lipid risk factors of cardiovascular disease, this study provides no evidence to support a significant benefit from increasing HDL-C independent of the effect of lowering non-HDL-C. PMID- 22447464 TI - Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy. AB - OBJECTIVE: To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). DESIGN: Clinical study. SETTING: Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. SUBJECTS: Twenty-four patients with a single HCM-causing mutation D175N in the alpha-tropomyosin gene and 17 control subjects. MAIN OUTCOME MEASURES: Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected. RESULTS: Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF kappaB) activation. Levels of hsCRP and interleukins (IL-1beta, IL-1RA, IL-6, IL 10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor alpha and IL 1RA levels had significant correlations with LGE in CMRI. CONCLUSIONS: A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response. PMID- 22447465 TI - Left ventricular apical mechanics during ectopy in an asymptomatic athlete. PMID- 22447466 TI - A transoral highly flexible robot: Novel technology and application. AB - OBJECTIVES/HYPOTHESIS: Organ preservation surgery is a major focus in head and neck oncology. Current approaches are aimed toward improving quality of life and decreasing treatment-related morbidity. Transoral robotic surgery was developed to overcome the limitations of traditional surgical approaches. The most widely used robotic system is the da Vinci Surgical System. Although the da Vinci offers clear surgical advantages over traditional approaches, its rigid operative arms prevent complex maneuverability in three-dimensional space. The ideal surgical robot would configure to the anatomy of the patient and maneuver in narrow spaces. We present the first cadaveric trials of the use of a highly flexible robot able to traverse the nonlinear upper aerodigestive tract and gain physical and visual access to important anatomical landmarks without laryngeal suspension. STUDY DESIGN: Feasibility. METHODS: Using human cadavers, we investigated the feasibility of visualizing the endolarynx transorally with a highly flexible robot without performing suspension of the larynx. Two fresh and four preserved human specimens were used. RESULTS: Unhampered visualization of the endolarynx was achieved in all specimens without performing laryngeal suspension. Standard mouth retractors facilitated the delivery of the robot into the endolarynx. CONCLUSIONS: The flexible robot technology mitigates laryngeal suspension and the limitations of current robotic surgery with rigid line-of-sight-directed instruments. Having demonstrated the feasibility of physical and visual access to the endolarynx, future work will study the feasibility of using the highly flexible robot in transoral robotic procedures with flexible instrumentation placed in the robot's available working ports. PMID- 22447467 TI - Low dose of hydrochlorothiazide, in combination with angiotensin receptor blocker, reduces blood pressure effectively without adverse effect on glucose and lipid profiles. AB - Previous studies have shown highly effective lowering of blood pressure with thiazide diuretics in combination with angiotensin receptor blockers. However, thiazide diuretics may cause the development of diabetes and abnormal lipid metabolism. Little is known as to whether dysmetabolic potential of thiazide diuretics could be neutralized when adding angiotensin receptor blockers. This study consisted of 26 patients with essential hypertension. Patients were randomized to 24 weeks of treatment with either candesartan, 12 mg monotherapy (n = 13, group A), or hydrochlorothiazide (HCTZ), 6.25 mg in combination with candesartan, 8 mg (n = 13, group B). Before and after treatment, we assessed glucose and lipid profiles including adiponectin, resistin, and active glucagon like peptide-1 (GLP-1) levels. At baseline, there were no differences in age, body mass index, systolic blood pressure (SBP), and diastolic blood pressure (DBP), as well as plasma levels of hemoglobin A1c, insulin, low-density lipoprotein cholesterol, triglycerides, adiponectin, resistin, and active GLP-1 between the two groups. There were significant reductions in SBP (from 152 +/- 10 mmHg at baseline to 134 +/- 12 mmHg after treatment) and DBP (from 84 +/- 5 mmHg at baseline to 71 +/- 8 mmHg after treatment) in group A. There were also significant reductions in SBP (from 148 +/- 10 at baseline to 128 +/- 7 mmHg after treatment) and DBP (from 90 +/- 9 at baseline to 74 +/- 12 mmHg after treatment) in group B. There were no differences in reduction of SBP or DBP after 24 weeks of treatment between the two groups. There were no changes of the glucose and lipid profiles, including adiponectin, resistin, insulin, and active GLP-1 levels after 24 weeks of treatment in both groups. A low dose of HCTZ in combination with candesartan reduces blood pressure effectively without adverse effects on the glucose and lipid profiles. Therefore, the combination of thiazide diuretics and angiotensin receptor blockers could assist patients in achieving long-term control of blood pressure with good tolerability. PMID- 22447468 TI - A high tender point count is associated with the presence of multiple idiopathic pain disorders: results from a population study. AB - BACKGROUND/AIMS: To test whether mechanical hyperalgesia is associated with multiple idiopathic pain disorders (IPDs) and whether this relationship is independent of the confounding effects of psychosocial factors. METHODS: One hundred eighteen subjects with chronic orofacial pain (COFP) were identified from their questionnaire responses to a population study in North West England. All subjects had a tender point examination according to the American College of Rheumatology classification. Validated tools on the questionnaire were used to identify presence of other IPDs (irritable bowel syndrome and chronic widespread pain) and psychosocial factors (anxiety, depression, health anxiety, sleep disturbance and reporting of somatic symptoms and adverse life events). RESULTS: Of the 118 subjects, 47.6% (n = 56) had COFP, 34.7% (n = 41) had COFP plus one IPD and 17.8% (n = 21) had all three IPDs. Univariate analysis revealed a dose response relationship between number of tender points (TPs) and number of IPDs [2 6 TPs (OR 2.6, 95% CI 1.0-7.3), >= 7 TPs (OR 10.5, 95% CI 3.8-29.3)] and number of IPDs and psychological distress [anxiety (OR 2.8, 95% CI 1.2-6.4), depression (OR 4.3, 95% CI 1.7-10.6), sleep disturbance (OR 4.8, 95% CI 1.6-14.6)]. The relationship between IPDs and TPs persisted after adjusting for psychosocial factors in multivariate analyses [2-6 TPs (OR 2.5, 95% CI 0.8-7.8) >= 7 TPs (OR 10.7, 95% CI 3.4-33.7)]. CONCLUSION: The dose-response relationship between TPs and IPDs needs further investigation to determine the temporal nature of these relationships and to disentangle the complex gene-environment relationships that may influence the occurrence of multiple IPDs. PMID- 22447469 TI - Cox regression for mixed case interval-censored data with covariate errors. AB - Covariate measurement error problems have been extensively studied in the context of right-censored data but less so for interval-censored data. Motivated by the AIDS Clinical Trial Group 175 study, where the occurrence time of AIDS was examined only at intermittent clinic visits and the baseline covariate CD4 count was measured with error, we describe a semiparametric maximum likelihood method for analyzing mixed case interval-censored data with mismeasured covariates under the proportional hazards model. We show that the estimator of the regression coefficient is asymptotically normal and efficient and provide a very stable and efficient algorithm for computing the estimators. We evaluate the method through simulation studies and illustrate it with AIDS data. PMID- 22447470 TI - Lethal effect of imidacloprid on the coccinellid predator Serangium japonicum and sublethal effects on predator voracity and on functional response to the whitefly Bemisia tabaci. AB - Neonicotinoid insecticides are widely used for controlling sucking pests, and sublethal effects can be expected in beneficial arthropods like natural enemies. Serangium japonicum is an important predator in many agricultural systems in China, and a potential biological control agent against Bemisia tabaci. We evaluated the toxicity of imidacloprid to S. japonicum and its impact on the functional response to B. tabaci eggs. S. japonicum adults exposed through contact to dried residues of imidacloprid at the recommended field rate on cotton against B. tabaci (4 g active ingredient per 100 l, i.e. 40 ppm [part per million]), and reduced rates (25, 20, 15 and 10 ppm) for 24 h showed high mortality rates. The mortality induced by a lowest rate, 5 ppm, was not significantly different than the control group and thus it was considered as a sublethal rate. The lethal rate 50 and hazard quotient (HQ) were estimated to be 11.54 ppm and 3.47 respectively, indicating a risk for S. japonicum in treated fields (HQ > 2). When exposed to dried residues of imidacloprid at the sublethal rate (5 ppm) on cotton leaves, functional response of S. japonicum to B. tabaci eggs was affected with an increase in handling time and a reduction in peak consumption of eggs. Imidacloprid residues also disturbed predator voracity, the number of B. tabaci eggs consumed on treated leaves being significantly lower than on untreated leaves. All effects disappeared within a few hours after transfer to untreated cotton leaves. Imidacloprid systemically applied at the recommended field rate (for cotton) showed no toxicity to S. japonicum, nor affected the functional response of the predator. Sublethal effects of imidacloprid on S. japonicum observed in our study likely negatively affect S. japonicum development and reproductive capacity and may ultimately reduce predator population growth. These results hint at the importance of assessing potential effects of imidacloprid on S. japonicum for developing effective integrated pest management programs of B. tabaci in China. PMID- 22447471 TI - Rodenticide exposure in wood mouse and house mouse populations on farms and potential secondary risk to predators. AB - We compared capture rates and exposure to SGARs of wood mice (Apodemus sylvaticus) and house mice (Mus domesticus) in autumn/winter on farms that currently used, had previously used, and never used SGARs. 6-10 weeks after baiting programmes began, 15 % of 55 wood mice and 33 % of 12 house mice had detectable liver SGAR residues. Wood mice with residues occurred on farms not using rodenticides, reflecting the high mobility of these animals, and four had multiple liver residues, possibly due to cross-contamination of baits. The winter decline in wood mouse numbers was similar on farms that did and did not use SGARs, suggesting little long-term impact of SGARs on populations on farms. Our results indicate residual levels of rodenticides will be ever present in small mammal prey across the agricultural landscape unless all farms in a locality cease application. The implications for secondary exposure and poisoning of predators are discussed. PMID- 22447472 TI - New antithrombotic drugs: a revolution in stroke management. PMID- 22447473 TI - Effect of sequential coronary artery bypass venous grafting on right ventricular functions assessed by tissue Doppler echocardiography. AB - BACKGROUND: Coronary artery bypass graft surgery is a well-known and proven method of treatment for coronary artery disease. A modification of this method is complete revascularisation of the right ventricle by sequential bypass grafting of the right coronary artery, the effects of which on ventricular function need to be clarified. We sought to determine the effect of the sequential bypass graft method on right ventricular (RV) function utilising tissue Doppler echocardiography. METHODS: A total of 35 coronary artery disease patients (group A: 20 sequential grafts; group B: 15 individual grafts) were enrolled. Patients were examined pre-operatively with tissue Doppler echocardiography for RV function, and again postoperatively after the first month. RESULTS: Pre operatively, there were no significant differences with regard to demographics or basal echocardiographic findings. On the other hand, postoperative right ventricular diastolic function was found to have improved significantly as the right ventricular E wave and E/A increased (9.5 +/- 1.6 vs 7.6 +/- 2.7 cm/s, p = 0.009 and 1.4 +/- 0.2 vs 0.9 +/- 0.2, p <= 0.01, respectively), while the A wave and isovolumic relaxation times (6.8 +/- 2.1 vs 8.3 +/- 3.4 cm/s, p < 0.03 and 55.2 +/- 11.9 vs 87.2 +/- 16.2 ms, p < 0.001, respectively) decreased. Although the S-wave peak amplitude decreased in group A patients, it did not reach statistical significance. CONCLUSIONS: Sequential, but not single, complete revascularisation of the right coronary artery appeared to improve the diastolic function of the right ventricle. PMID- 22447474 TI - Heart rate variability in physically active individuals: reliability and gender characteristics. AB - PURPOSE: To evaluate the reliability of short-term recordings (five minutes) of heart rate variability (HRV) and the association between HRV and gender. METHODS: HRV time- and frequency-domain parameters were calculated in 44 physically active students (21 males and 23 females) over four consecutive days. A Suunto t6 heart rate monitor was used to obtain inter-beat intervals (IBIs) that were then transferred to Kubios HRV analysis software. The relative reliability [intra class correlation (ICC)] and absolute reliability, [typical error of measurement (TEM) and typical error of measurement as a percentage (TEM%)] of the HRV parameters were then calculated for day 2 versus day 3 and day 3 versus day 4, with day 1 being a familiarisation day. The following HRV parameters were calculated: (1) time domain: resting heart rate (RHR), R-R intervals (IBI), standard deviation of normal-to-normal intervals (SDNN), root mean square differences of the standard deviation (RMSSD), percentage of beats that changed more than 50 ms from the previous beat (pNN50); and (2) frequency domain: low frequency normalised units (LFnu), high-frequency normalised units (HFnu), low frequency to high-frequency ratio in normalised units (LF/HFnu). An analysis of variance (ANOVA) with Tukey post-hoc testing was performed to compare HRV parameters in males and females. Significance was set at p <= 0.05. RESULTS: The ICCs for both relationship 1 and 2 indicated primarily good to excellent (> 0.8) relative reliability. The lowest value was found in the LF/HFnu ratio (ICC = 0.36) for males. Absolute reliability was low with TEM% greater than 10% for all HRV parameters, except IBIs. Females demonstrated better relative (higher ICCs) and absolute reliability (lower TEM and TEM% ) compared to males for the frequency domain. The relative and absolute reliability for the time domains were similar except for SDNN where the absolute reliability was higher in males. ANOVA illustrated significant gender differences for the LF/HFnu ratio (41% higher in males, p = 0.003), HFnu (12% higher in females, p = 0.02) and IBI (21% higher in females, p < 0.0001). CONCLUSIONS: Short-term recordings of HRV over three consecutive days demonstrated a high relative reliability. However, a low absolute reliability indicated large day-to-day random variation in HRV, which would make the detection of intervention effects using HRV difficult in individual participants. Females were shown to have a higher parasympathetic modulation of HRV, which may indicate an underlying cardioprotective mechanism in females compared to males. PMID- 22447475 TI - Left ventricular hypertrophy and geometry in type 2 diabetes patients with chronic kidney disease. An echocardiographic study. AB - OBJECTIVE: We assessed left ventricular structural alterations associated with chronic kidney disease (CKD) in Congolese patients with type 2 diabetes. METHODS: This was a cross-sectional study of a case series. We obtained anthropometric, clinical, biological and echocardiographic measurements in 60 consecutive type 2 diabetes patients (37 females, 62% ) aged 20 years or older from the diabetes outpatient clinic, University of Kinshasa Hospital, DRC. We computed creatinine clearance rate according to the MDRD equation and categorised patients into mild (CrCl > 60 ml/min per 1.73 m(2)), moderate (CrCl 30-60 ml/min per 1.73 m(2)) and severe CKD (< 30 ml/min per 1.73 m(2)). Left ventricular hypertrophy (LVH) was indicated by a LV mass index (LVMI) > 51 g/m(2.7) and LV geometry was defined as normal, or with concentric remodelling, eccentric or concentric hypertrophy, using relative wall thickness (RWT) and LVMI. RESULTS: Compared to patients with normal kidney function, CKD patients had higher uric acid levels (450 +/- 166 vs 306 +/- 107 umol/l; p <= 0.001), a greater proportion of LVH (37 vs 14%; p <= 0.05) and longstanding diabetes (13 +/- 8 vs 8 +/- 6 years; p <= 0.001). Their left ventricular internal diameter, diastolic (LVIDD) was (47.00 +/- 6.00 vs 43.00 +/- 7.00 mm; p <= 0.001), LVMI was (47 +/- 19 vs 36.00 +/- 15 g/m2.7; p <= 0.05) and proportions of concentric (22 vs 11%; p <= 0.05) or eccentric (15 vs 3%; p <= 0.05) LVH were also greater. Severe CKD was associated with increased interventricular septum, diastolic (IVSD) (12.30 +/- 3.08 vs 9.45 +/- 1.94 mm; p <= 0.05), posterior wall thickness, diastolic (PWTD) (11.61 +/- 2.78 vs 9.52 +/- 1.77 mm; p <= 0.01), relative wall thickness (RWT) (0.52 +/- 0.17 vs 0.40 +/- 0.07; p <= 0.01) rate of LVH (50 vs 30%; p <= 0.05), and elevated proportions of concentric remodelling (25 vs 15%; p <= 0.05) and concentric LVH (42 vs 10%; p <= 0.05) in comparison with patients with moderate CKD. In multivariable adjusted analysis, hyperuricaemia emerged as the only predictor of the presence of LVH in patients with CKD (adjusted OR 9.10; 95% CI: 2.40-33.73). CONCLUSION: In keeping with a higher rate of cardiovascular events usually reported in patients with impaired renal function, CKD patients exhibited LVH and abnormal LV geometry. PMID- 22447476 TI - The relationship between cortisol, C-reactive protein and hypertension in African and Causcasian women: the POWIRS study. AB - Research on the roles that C-reactive protein (CRP) and other risk factors such as cortisol and obesity play in the diagnosis of cardiovascular disease (CVD) in African and Caucasian women has become increasingly imperative when one considers the prevalence of hypertension in these groups. CRP and cortisol have been associated with an increased prevalence of hypertension and obesity. Cortisol has also been linked with both hypertension and the hypothalamic-pituitary-adrenal (HPA) response. African women have previously presented with an increased vascular reactivity. Conversely, Caucasian women have displayed an increased central cardiac reactivity. We included African (n = 102) and Caucasian (n = 115) women in the study, matched for age and body mass index. Elevated CRP levels were observed in African women compared to Caucasian women. A trend of hypocortisolism was exhibited in both hypertensive ethnic groups. Systolic blood pressure (SBP) and a vascular marker, arterial compliance (Cw), predicted hypertension in African women. Conversely, in Caucasian women, only SBP predicted hypertension. These results suggest the apparently diverse roles that dysregulation by the HPA axis, in conjunction with the respective cardiac and vascular responses in both Caucasian and African women, can play in future cardiovascular risk for these groups. PMID- 22447477 TI - End digit preference in blood pressure measurement in a hypertension specialty clinic in southwest Nigeria. AB - BACKGROUND: One of the observer errors associated with blood pressure (BP) measurement using a mercury sphygmomanometer is end digit preference (EDP) which refers to the occurrence of a particular end digit more frequently than would be expected by chance alone. Published reports, mainly from outside Africa, have shown a high prevalence ranging from 22 to 90% of end digit zero in BP readings taken by healthcare workers (HCWs). This study examined the prevalence of EDP and patients' and physicians' characteristics influencing the occurrence of EDP. METHODS: A retrospective review was undertaken of BP readings of 114 patients seen over a two-month period at our hypertension specialty clinic. RESULTS: Nurses and physicians displayed a high frequency of preference for end digit zero in systolic blood pressure (SBP) and diastolic blood pressure (DBP) readings. The preference for end digit zero was, however, higher for nurses than for physicians (SBP: 98.5 vs 51.2%, p < 0.001; DBP: 98.5 vs 64.3%, p < 0.001). Among the physicians, the consultant staff displayed the least preference for end digit zero compared to resident doctors. There was no statistically significant difference in gender, age, weight, height and BMI of those with BP readings with end digit zero compared with those with non-zero end digits. CONCLUSION: The high prevalence of EDP for zero argues for the training, retraining and certification of HCWs in BP measurement and the institution of a regular monitoring and feedback system on EDP in order to minimise this observer error. PMID- 22447478 TI - Sudden cardiac death due to beta2-agonist therapy: is a genetic basis overlooked? PMID- 22447479 TI - Experimental malaria: the in vitro and in vivo blood pressure paradox. AB - OBJECTIVE: Malaria causes more deaths worldwide than any other parasitic disease. Many aspects of the biology that governs the pathogenesis of this parasite are still unclear. Therefore insight into the complexity of the pathogenesis of malaria is vital to understand the disease, particularly as it relates to blood pressure. METHODS: In vivo and in vitro experimental models were used for this study. In the in vivo study, mean arterial pressure, pulse rates and heart rates were recorded by cannulation of the carotid artery of rats. In the in vitro study, ring preparations of blood vessels from the rat aorta were studied using standard organ bath techniques. Dose-response curves for phenylepherine (PE) - and acetylcholine (Ach) -induced relaxation were constructed for rings pre contracted with PE. RESULTS: Our results showed a significant (p < 0.05) reduction in the mean arterial pressure and pulse rates, while the heart rates remained unaltered in rats with malaria parasites, compared with the controls. Incubation of rat aortic rings with parasitised blood resulted in a significant (p < 0.05) increase in maximum contractile response to phenylephrine in the rat aortic rings but there was no effect on the baseline. The dose-response curve showed a significant (p < 0.05) leftward shift following the addition of parasitised blood and the EC(70) (M) values increased from 7 * 10(- 7) to 5 * 10( 6) M. Following exposure to parasitised blood, the magnitude of Ach-induced relaxation responses reduced significantly (p < 0.05) from 73 +/- 3.6 to 24.75 +/ 7.25% in the rat aortic rings. CONCLUSIONS: The results suggest that malaria parasitaemia caused in vivo reduction in blood pressure, and enhanced the responses to contractile agents and reduced relaxation responses to acetylcholine in vitro. This appears to be a paradox but is explainable by the complex cardiovascular control mechanisms in vivo. This may be independent of direct action on vascular smooth muscle. PMID- 22447480 TI - The diabetologist/cardiologist debate: a meeting of the minds. PMID- 22447481 TI - New ESC/EASD lipid guidelines empahsises need to expand cholesterol screening and treating to target in clinical practice. PMID- 22447482 TI - Recruitment of pulmonary hypertension patients for PATENT trial with Riociguat [corrected] completed Sub-Saharan pulmonary hypertension study launched. PMID- 22447483 TI - Serum creatine kinase increase in patients treated with tyrosine kinase inhibitors for solid tumors. AB - Regarding the frequency of muscular complains with the use of tyrosine kinase inhibitors (TKIs), we hypothesize that creatine kinase (CK) elevation may be more frequent than usually reported. We conducted a prospective study on patients treated with TKIs for solid tumors, to assess the incidence of CK increase on treatment. Most of the patients (105/155) had a gastrointestinal stromal tumor. Treatments were carried out with the following drugs: imatinib (87 cases); sunitinib (21 cases); HER antagonists (14 cases), other TKIs (15 cases); and imatinib-based combinations (2 cases). Myalgias were found in 50/155 patients (32%). Fifty-four patients (35%; 95%CI, 27-42%) had elevated CK. According to NCI CTC grading, there was 49/54 (31%) grade 1 and 5/54 (3%) grade 2 (2.5 to 5 times ULN). CK elevation was more frequent with imatinib than with other TKIs (39 cases, 45% vs. 14 cases, 21%, respectively; chi-squared test: P=0.003), and CK was more likely to be abnormal in patients treated with any TKI for more than 6 months. We found increased CK in about one-third of patients under TKIs for solid tumors, including 3% of patients with CK as high as 2.5-5 times ULN. PMID- 22447484 TI - Circulating microRNA expression is associated with genetic subtype and survival of multiple myeloma. AB - Circulating microRNAs (miRNAs) have shown potential as non-invasive prognostic biomarkers in cancer. Here, we investigated whether miRNAs present in the plasma of multiple myeloma (MM) patients have prognostic utility. We evaluated global miRNA expression profiles in the plasma of 12 multiple myeloma patients and 8 healthy controls using TaqMan Low-Density Arrays. Six miRNAs (miR-148a, miR-181a, miR-20a, miR-221, miR-625, and miR-99b) that were significantly upregulated in MM were selected and further quantified independently by quantitative reverse transcription PCR in plasma from 28 MM patients and 12 healthy controls. Moreover, within the patient group, the expression levels of miR-99b and miR-221 were associated with chromosomal abnormalities t(4; 14) and del(13q), respectively. High levels of miR-20a and miR-148a were related to shorter relapse free survival. In summary, we have identified aberrant expression of particular circulating miRNAs that are associated with the genetic subtype and survival of MM. These plasma miRNAs have potential as clinical biomarkers in MM. PMID- 22447485 TI - Expression and clinical significance of NEDD9 in lung tissues. AB - Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) acts as a scaffold protein and belongs to a family of CAS (Crk-associated substrate) that regulates protein complexes controlling invasion and differentiation. Preclinical research for this gene was predominantly reported in melanomas, glioblastoma, and lymphoma. So we investigated the expression and significance of NEDD9 mRNA and protein in lung tissues. Specifically, we immunohistochemically compared NEDD9 expression and localization in 24 formalin-fixed and paraffin-embedded lung adenocarcinoma tissues with that of surrounding nonneoplastic tissue and five microscopically normal lungs. NEDD9 mRNA levels were quantitatively analyzed by fluorescent quantitative reverse transcription-polymerase chain reaction (FQ-PCR) in frozen tissue specimens of all tumors and 24 matched nonneoplastic lung parenchymas, and protein expression in 16 homogenates of matched neoplastic/nonneoplastic specimens was evaluated by Western blotting. The three techniques showed that NEDD9 is weakly expressed in nonneoplastic lung parenchyma and upregulated in lung adenocarcinoma. Moreover, FQ-PCR indicated a statistically significant correlation between NEDD9 upregulation and higher disease stages (I+II versus III+IV, p=0.001; high and middle versus low differentiation, p<0.001). Our results provide evidence that NEDD9 is upregulated in lung adenocarcinoma, and overexpression of NEDD9 protein has been strongly correlated with staging and differentiation grade and tumor size in lung adenocarcinoma, which demonstrated a poor prognosis. PMID- 22447486 TI - Segmentation of iodine brachytherapy implants in fluoroscopy. AB - PURPOSE: In prostate brachytherapy, intraoperative dosimetry would allow for evaluation of the implant quality while the patient is still in treatment position. Such a mechanism, however, requires 3-D visualization of the deposited seeds relative to the prostate. It follows that accurate and robust seed segmentation is of critical importance in achieving intraoperative dosimetry. METHODS: Implanted iodine brachytherapy seeds are segmented via a region-based implicit active contour model. Overlapping seed groups are then resolved using a template-based declustering technique. RESULTS: Ground truth seed coordinates were obtained through manual segmentation. A total of 57 clinical C-arm images from 10 patients were used to validate the proposed algorithm. This resulted in two failed images and a 96.0% automatic detection rate with a corresponding 2.2% false-positive rate in the remaining 55 images. The mean centroid error between the manual and automatic segmentations was 1.2 pixels. CONCLUSIONS: Robust and accurate iodine seed segmentation can be achieved through the proposed segmentation workflow. PMID- 22447487 TI - Porous polycaprolactone/nanohydroxyapatite tissue engineering scaffolds fabricated by combining NaCl and PEG as co-porogens: structure, property, and chondrocyte-scaffold interaction in vitro. AB - In this study, porous polycaprolactone/nanohydroxyapatite (PCL/nHA) composite scaffolds were fabricated using a modified melt-molding/leaching technique, by the combination of salt particulate (NaCl) and water-soluble polymer (PEG) as co porogens. The porogens were kept at a constant proportion of 70% in the blends but varied in the NaCl/PEG ratio and the PEG variety to generate PCL/nHA scaffolds with various pore architectures. The resultant composite scaffolds were investigated on their morphologies, physicochemical properties, mechanical properties, and in vitro degradation. The cell-scaffold interactions were evaluated in vitro using chondrocyte. Generally, the PCL/nHA scaffolds exhibited multimodal pore morphologies consisting of macropores and interconnected micropores, created by the extraction of NaCl particulate and continuous PEG phase. The evolution of porogens led to much effect on the overall pore architecture of the scaffolds; subsequently, their physiochemical and mechanical properties and degradation behaviors, as well as the cell binding and proliferation. The PCL/nHA scaffold prepared from NaCl/PEG 4000 (20/50) presented more macropores (>50 MUm) with interconnectivity and showed higher strength and improved bioactivity than the others. All of these results suggest promising potentials of PCL/nHA scaffolds developed in this study desired for cartilage tissue engineering. PMID- 22447488 TI - Significantly improved analytical sensitivity of lateral flow immunoassays by using thermal contrast. PMID- 22447489 TI - Bolsterless management for recurrent auricular hematomata. AB - OBJECTIVES/HYPOTHESIS: The objectives were to describe our experience with a bolsterless technique for the management of auricular hematomata and discuss the management options for auricular hematomata and the comparative benefits of the bolsterless technique. STUDY DESIGN: Retrospective case series. METHODS: Patients presented with recurrent auricular hematomata following traditional treatment with incision and drainage and bolster placement. Revision incision and drainage were performed, and then auricular skin was stabilized using through-and-through absorbable horizontal mattress sutures. Patients were seen in follow-up to evaluate for recurrence and assess cosmetic results. RESULTS: Twenty-eight patients were treated for recurrent auricular hematomata using the bolsterless technique. There were no recurrences in follow-up, and cosmetic results were judged to be excellent by both patient and surgeon. CONCLUSIONS: Bolsterless management for auricular hematomata using absorbable mattress sutures has been described intermittently in the otolaryngology literature since 1991 but is not widely utilized. In this series, patients presenting with recurrent auricular hematomata following failure of traditional bolster management were effectively managed with the bolsterless technique. This technique is well tolerated by patients and allows for early return to athletic activity. PMID- 22447490 TI - The clinical features and surgical outcomes of pediatric patients with primary spinal cord tumor. AB - BACKGROUND: Primary spinal cord tumors (PSCTs) in pediatric patients are rare, with a reported overall incidence rate of 1-2.6 per one million children. We reviewed our experience of surgically treated 27 pediatric patients with PSCT and discussed the clinical features, radiological findings, surgical outcomes, and prognostic factors. METHODS: Between March 1999 and March 2010, a total of 27 pediatric patients with PSCT were surgically treated in a single institution. We retrospectively analyzed their data. RESULTS: There were 13 females and 14 males, and their ages ranged from 6 months to 19 years (mean age, 12.1 years). The most common presenting symptom was motor weakness, and the histologic type of the tumors were mainly schwannoma, astrocytoma, and ependymoma. The tumor was completely resected in 17 patients, subtotally resected in 7 patients, and partial resection or biopsy was performed in 3 patients. Adjuvant chemotherapy was performed in 9 patients, and radiotherapy in 12 patients, respectively. The average follow-up period was 33.5 months (1.17-129). Five patients experienced the progression of disease, and three of them expired. The mean time for disease progression was 19.0 months (4.5-48.7). CONCLUSIONS: PSCT in pediatric patients can be surgically removed with an acceptable low surgical morbidity. Progression free survival was found to be related to the grade of tumor and the extent of tumor resection. Early diagnosis and treatment anticipate good functional neurologic outcome. PMID- 22447491 TI - Brain volume and shape in infants with deformational plagiocephaly. AB - PURPOSE: Infants with deformational plagiocephaly (DP) have been shown to exhibit developmental delays relative to unaffected infants. Although the mechanisms accounting for these delays are unknown, one hypothesis focuses on underlying differences in brain development. In this study, we used MRI to examine brain volume and shape in infants with and without DP. METHODS: Participants included 20 infants with DP (mean age = 7.9 months, SD = 1.2; n = 12 male) and 21 controls (mean age = 7.9 months, SD = 1.3; n = 11 male). Measures included volumes of the total brain and cerebellum; midsagittal areas of the corpus callosum and cerebellar vermis; and linear distance measures used to quantify the shape of selected brain structures. We also evaluated the association between shape measures and developmental scores on the Bayley Scales of Infant and Toddler Development-III (BSID-III). RESULTS: Brain volume did not distinguish cases and controls (p = .214-.976). However, cases exhibited greater asymmetry and flattening of the posterior brain (p < .001-.002) and cerebellar vermis (p = .035), shortening of the corpus callosum (p = .012), and differences in the orientation of the corpus callosum (p = .005). Asymmetry and flattening of brain structures were associated with worse developmental outcomes on the BSID-III. CONCLUSIONS: Infants with DP show differences in brain shape, consistent with the skull deformity characteristic of this condition, and shape measures were associated with infant development. Longitudinal studies, beginning in the neonatal period, are needed to clarify whether developmental effects precede or follow brain deformation. PMID- 22447492 TI - Homogeneous human complex-type oligosaccharides in correctly folded intact glycoproteins: evaluation of oligosaccharide influence on protein folding, stability, and conformational properties. AB - The N-glycosylation of proteins is generated at the consensus sequence NXS/T (where X is any amino acid except proline) by the biosynthetic process, and occurs in the endoplasmic reticulum and Golgi apparatus. In order to investigate the influence of human complex-type oligosaccharides on counterpart protein conformation, crambin and ovomucoide, which consist of 46 and 56 amino acid residues, respectively, were selected for synthesis of model glycoproteins. These small glycoproteins were intentionally designed to be glycosylated at the alpha helix (crambin: 8 position), beta-sheet (crambin: 2 position) and loop position between the antiparallel beta-sheets (ovomucoide: 28 position), and were synthesized by using a peptide-segment coupling strategy. After preparation of these glycosylated polypeptide chains, protein folding experiments were performed under redox conditions by using cysteine-cystine. Although the small glycoproteins bearing intentional glycosylation at the alpha-helix and beta-sheet exhibited a suitable folding process, glycosylation at the loop position between the antiparallel beta-strands caused multiple products. The conformational differences in the isolated homogeneous glycoproteins compared with non glycosylated counterparts were evaluated by circular dichroism (CD) and NMR spectroscopy. These analyses suggested that this intentional N-glycosylation did not result in large conformational changes in the purified protein structures, including the case of glycosylation at the loop position between the antiparallel beta-strands. In addition to these experiments, the conformational properties of three glycoproteins were evaluated by CD spectroscopy under different temperatures. The oligosaccharides on the protein surface fluctuated considerably; this was dependent on the increase in the solution temperature and was thought to disrupt the protein tertiary structure. Based on the measurement of the CD spectra, however, the glycoproteins bearing three disulfide bonds did not exhibit any change in their protein tertiary structure. These results suggest that the oligosaccharide conformational fluctuations were not disruptive to protein tertiary structure, and the tertiary structure of glycoproteins might be stabilized by the disulfide bond network. PMID- 22447493 TI - A novel mechanism of gall midge resistance in the rice variety Kavya revealed by microarray analysis. AB - The Asian rice gall midge [Orseolia oryzae (Wood-Mason)] is an important rice pest causing an annual average yield loss of about US $80 million in India. Rice varieties possess several discrete resistance (R) genes conferring resistance against the pest in two distinct ways, i.e., with (HR+ type) or without (HR- type) the expression of hypersensitive reaction (HR). The aim of the present work is to understand the molecular basis of compatible and incompatible (HR- type) rice gall midge interactions between the rice variety Kavya and the two gall midge biotypes: the virulent GMB4M and the avirulent GMB1 using transcriptional microarray gene expression analysis. A large number of differentially expressed genes (602genes in incompatible interaction and 1,330 genes in compatible interaction with at least twofold changes, p value <0.05) was obtained from the microarray analysis that could be grouped into six clusters based on their induction during both or either of the interactions. MapMan software was used for functional characterization of these genes into 13 categories (BINs). Real-time polymerase chain reaction validation of 26 genes selected through the analysis revealed four genes viz. NADPH oxidase, AtrbohF, cinnamoyl-CoA reductase, and von Willebrand factor type A domain containing protein coding genes to be significantly upregulated during the incompatible interaction. But most of the signature genes related to HR+ type resistance like salicylic acid pathway related genes and disease resistance protein coding genes were downregulated. On the other hand, during the compatible interaction, genes related to primary metabolism and nutrient transport were upregulated and genes for defense and signaling were downregulated. We propose a hypothesis that HR- type of resistance in the rice variety Kavya against gall midge could be due to the constitutive expression of an R gene and a case of extreme resistance which is devoid of cell death. Compatible interaction, however, modulated a large number of differentially expressed transcripts to reprogram cell organization, cell remodeling, and relocation of nutrients through transport to support insect growth. PMID- 22447494 TI - Serum interleukin-16 levels in patients with nasal polyposis. AB - OBJECTIVE/HYPOTHESIS: Several inflammatory and allergic disorders have been reported to correlate with interleukin-16 (IL-16). IL-16 is a highly potent chemotactic and chemoattractant molecule for eosinophils. Nasal polyposis (NP) has an inflammatory basis, and eosinophilia is a common finding in polyp tissue. In this study, we aimed to determine serum IL-16 levels in NP patients. STUDY DESIGN: Prospective controlled study in a tertiary academic hospital. METHODS: Peripheral blood samples were obtained and used for serologic studies with enzyme linked immunosorbent assay kits to determine IL-16 levels. RESULTS: The study and the control groups consisted of 17 and 10 patients, respectively. Mean serum IL 16 levels were significantly higher in the study group when compared to the control group (447.9 pg/mL vs. 260.2 pg/mL) (P < .001). CONCLUSIONS: Serum IL-16 levels are significantly elevated in NP patients. This finding may represent identification of a valuable serum biomarker and potential therapeutic target in NP patients. PMID- 22447495 TI - Experimental investigation of targeting responsibility versus danger in cognitive therapy of obsessive-compulsive disorder. AB - BACKGROUND: Cognitive therapy (CT) for obsessive-compulsive disorder (OCD) has shown to be effective in diminishing OCD symptoms, but there is little known about the individual contributions of the specific treatment targets to CTtreatment outcome. Two of the treatment targets of CTare overestimations of danger and inflated beliefs of personal responsibility. No studies to date have investigated the relative efficacy of targeting inflated beliefs of personal responsibility compared to the overestimation of danger in the treatment of OCD. The aim of the present study was to experimentally investigate the relative efficacy of targeting inflated beliefs of responsibility (CT-R) versus targeting overestimations of danger (CT-D) in the cognitive treatment of DSM-III/DSM-IV OCDwith overt compulsions. METHODS: We conducted a randomized trial of CT-D (N = 38) versus CT-R (N = 40). Outcomes were change in OCDsymptoms and behavior, cognitions, and general psychopathology. RESULTS: The results showed that patients in both conditions improved significantly on all measures. Overall improvement effect sizes were large, percentages of clinically improved patients moderate. No differences between conditions were found. CONCLUSIONS: These initial results suggest that both treatment targets are of value to the cognitive treatment of OCD. PMID- 22447496 TI - Differential distribution of cobalt, chromium, and nickel between whole blood, plasma and urine in patients after metal-on-metal (MoM) hip arthroplasty. AB - Evidence shows that raised cobalt (Co), chromium (Cr), and nickel (Ni) whole blood concentrations correlate with poor device outcome in patients following metal-on-metal (MoM) hip arthroplasty. To understand the local and systemic pathological effects of these raised metal concentrations it is important to define their distribution between whole blood, plasma, and urine. The metals were measured by Inductively Coupled Plasma Mass Spectrometry (ICPMS). Two hundred and five plasma, 199 whole blood, and 24 sets of urine samples were analyzed from 202 patients with Co-Cr alloy MoM hip prostheses implanted between 8 months to 12 years (mean 6.0 years) prior to analysis. Plasma Co (median 39.1 nmol/L) showed significantly positive 1:1 correlation with whole blood Co (median 45.9 nmol/L; R(2) = 0.98, p < 0.001, slope = 1.0). Plasma Cr (median 53.8 nmol/L) and whole blood Cr (median 40.3 nmol/L) were also correlated; however, concentrations were significantly higher in plasma indicating relatively little blood cell uptake (R(2) = 0.96, p < 0.001, slope = 1.6). Urinary Co was up to threefold higher than Cr (median 334.0 vs. 97.3 nmol/L respectively). Nickel concentrations in whole blood, plasma, and urine were low relative to Co and Cr. The analysis shows fundamental differences in the physiological handling of these metals: Co is distributed approximately equally between blood cells and plasma, whereas Cr is mainly in plasma, despite which, Cr had far less renal excretion than Co. PMID- 22447497 TI - Quantitative detection of inhaled formoterol in human urine and relevance to doping control analysis. AB - Formoterol is a frequently prescribed beta(2)-agonist used for the treatment of asthma. Due to performance-enhancing effects of some beta(2) -agonists, formoterol appears on the prohibited list, published by the World Anti-doping Agency (WADA). Its therapeutic use is allowed but restricted to inhalation. Since the data on urinary concentrations originating from therapeutic use is limited, no discrimination can be made between use and misuse when a routine sample is found to contain formoterol. Therefore the urinary excretion of six volunteers after inhalation of 18 ug of formoterol was investigated. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of formoterol in urine samples. Sample preparation consists of an enzymatic hydrolysis of the urine samples, followed by a liquid-liquid extraction at pH 9.5 with diethyl ether/isopropanol (5/1, v/v). Analysis was performed using selected reaction monitoring after electrospray ionization. The method was linear in the range of 0.5-50 ng/ml. The limit of quantification (LOQ) was 0.5 ng/ml. The bias ranged between -1.0 and -6.8 %. Results for the urinary excretion show that formoterol could be detected for 72 h. The maximum urinary concentration detected was 8.5 ng/ml without and 11.4 ng/ml after enzymatic hydrolysis. Cumulative data showed that maximum 11.5% and 23% of the administered dose is excreted as parent drug within the first 12 h, respectively, non-conjugated and conjugated. Analysis of 82 routine doping samples, declared positive for formoterol during routine analysis, did not exhibit concentrations which could be attributed to misuse. PMID- 22447498 TI - Utilization of tyrosine- and histidine-containing dipeptides to enhance productivity and culture viability. AB - Adequate supply of nutrients, especially providing a sufficient level of specific amino acids, is essential for cell survival and production. Complex raw materials such as soy hydrolysates or yeast extracts are the source for both free amino acids and peptides. However, typical chemically defined (CD) media provide amino acids only in free form. While most amino acids are highly soluble in media and can be provided at fairly high concentrations, certain amino acids such as tyrosine have poor solubility and thus, only a limited amount can be added as a media component. The limited solubility of amino acids in media can raise the risk of media precipitation and instability, and could contribute to suboptimal culture performance due to insufficient nutrient levels to meet cellular demands. In this study, we examine the use of chemically synthesized dipeptides as an alternative method for delivering amino acids to various monoclonal antibody producing cell lines. In particular, we focus on tyrosine-containing dipeptides. Due to their substantially higher solubility (up to 250-fold as compared with free tyrosine), tyrosine-containing dipeptides can efficiently provide large amounts of tyrosine to cultured cells. When tested in fed-batch processes, these supplemental dipeptides exerted positive effects, including enhanced culture viability and titer. Moreover, dipeptide-supplemented cultures displayed improved metabolic profiles including lower lactate and NH 4(+) production, and better pH maintenance. In bioreactor studies using two-sided pH control, a lactate spike occurring on Day 10 and the concomitant high levels of base addition could be prevented with dipeptide supplementation. These beneficial effects could be obtained by one-time addition of dipeptides during inoculation, and did not require further feeds during the entire 11-15-day process. Non-tyrosine containing dipeptides, such as His-Gly, also showed improved productivity and viability over control cultures. PMID- 22447499 TI - Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. AB - Alveolar rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of the myogenic lineage with frequent chromosomal translocations involving the PAX3 or PAX7 and FOXO1 genes. Based on previous studies indicating that the fusion genes are amplified in a subset of these cancers, we conducted a comprehensive molecular and clinical investigation of these amplification events. Using oligonucleotide arrays to localize amplicons, we found that the minimal 1p36 amplicon measured 0.13 Mb and only contained PAX7 whereas the minimal 13q14 amplicon measured 0.53 Mb and contained FOXO1 and the poorly characterized LOC646982 gene. Application of a fluorescence in situ hybridization assay to over 100 fusion-positive cases revealed that the fusion gene is amplified in 93% of PAX7-FOXO1-positive and 9% of PAX3-FOXO1-positive cases. While most cells in amplified PAX7-FOXO1-positive cases contained the amplicon, only a fraction of cells in the amplified PAX3 FOXO1-positive cases contained the amplicon. Expression studies demonstrated that the fusion transcripts were generally expressed at higher levels in amplified cases, and that the PAX7-FOXO1 fusion transcript was expressed at higher levels than the PAX3-FOXO1 fusion transcript. Finally, fusion gene amplification and PAX7-FOXO1 fusion status were each associated with significantly improved outcome; a multivariate analysis demonstrated that this predictive value was independent of other standard prognostic parameters. These findings therefore provide further evidence for a novel good prognosis subset of fusion-positive RMS. PMID- 22447500 TI - Does a medical home influence the effect of low birthweight on health outcomes? AB - The objective of this study was to investigate the possible modifying effect of medical home on the association between low birthweight and children's health outcomes. The analytic sample included children 5 years and under from the 2007 National Survey of Children's Health whose mothers were the primary respondents and who had non-missing covariate information (n = 19,356). Controlling for sociodemographic factors, logistic and ordinal regression models estimated the presence of developmental, mental/behavioral or physical health outcomes, condition severity, and health status by birthweight, medical home, and their interaction. Prevalence estimates of physical, developmental, mental/behavioral and severe conditions among those with any conditions as well as fair/poor overall health were 8.9, 6.8, 2.4, 41.6, and 2.5 %, respectively. Overall, low compared to normal birthweight children had a higher prevalence of physical and developmental conditions and fair/poor health (15.2 vs. 8.3 %, 11.1 vs. 6.4 %, 4.5 vs. 2.3 %, respectively). Medical home did not significantly modify the effect of birthweight on health outcomes; however, prevalence of all outcomes was higher for children without a medical home. Adjusted models indicated that low birthweight children were almost twice as likely as normal birthweight children to have a physical or developmental condition and poorer overall health, regardless of having a medical home. Having a medical home was associated with equally improved health outcomes among normal and low birthweight children. Adequacy and frequency of medical home care should be investigated further, especially among low birthweight children. PMID- 22447501 TI - Traditional versus internet bullying in junior high school students. AB - To examine the prevalence of traditional and Internet bullying and the personal, family, and school environment characteristics of perpetrators and victims. Students (12-14 years old) in 35 junior high schools were randomly selected from the Jerusalem Hebrew (secular and religious) and Arab educational system (n = 2,610). Students answered an anonymous questionnaire, addressing personal, family, and school characteristics. Traditional bullying and Internet bullying for perpetrators and victims were categorized as either occurring at least sometimes during the school year or not occurring. Twenty-eight percent and 8.9 % of students were perpetrators of traditional and Internet bullying, respectively. The respective proportions of victims were 44.9 and 14.4 %. Traditional bullies presented higher Odds Ratios (ORs) for boys, for students with poor social skills (those who had difficulty in making friends, were influenced by peers in their behavior, or were bored), and for those who had poor communication with their parents. Boys and girls were equally likely to be Internet bullies and to use the Internet for communication and making friends. The OR for Internet bullying victims to be Internet bullying perpetrators was 3.70 (95 % confidence interval 2.47-5.55). Victims of traditional bullying felt helpless, and victims of traditional and Internet bullying find school to be a frightening place. There was a higher OR of Internet victimization with reports of loneliness. Traditional bully perpetrators present distinctive characteristics, while Internet perpetrators do not. Victims of traditional and Internet bullying feel fear in school. Tailored interventions are needed to address both types of bullying. PMID- 22447502 TI - Molecular responses differ between sensitive silver carp and tolerant bighead carp and bigmouth buffalo exposed to rotenone. AB - Some species of fish are more tolerant of rotenone, a commonly used non-specific piscicide, than others. This species-specific tolerance to rotenone has been thought to be associated with the uptake and the efficiency at which the chemical is detoxified. However, rotenone stimulates oxidative stress and superoxides, which are also toxic. Understanding the modes in which fish physiologically respond to rotenone is important in developing improved protocols for its application in controlling aquatic nuisance species. Using a molecular approach, we investigated the physiological and molecular mechanisms of rotenone resistance. Species-specific responses were observed when rotenone-sensitive silver, Hypophthalmichthys molitrix, and both rotenone-resistant bighead carp, Hypophthalmichthys nobilis, and bigmouth buffalo, Ictiobus cyprinellus, were exposed to rotenone. Rotenone levels in plasma were highest 90 min after exposure in both silver carp and bigmouth buffalo, but bigmouth buffalo tolerated over twice the burden (ng mL(-1) g(-1)) than silver carp. Expression of genes related with detoxification (cyp1a and gst) increased in silver carp, but either decreased or remained the same in bighead carp. Genes linked with oxidative stress in the cytosol (gpx, cat and sod1) and hsp70 increased only in silver carp after a 6-h exposure. Expression of genes associated with oxidative stress in the mitochondria (sod2 and ucp2) differed between silver carp and bighead carp. Expression of sod2 changed minimally in bighead carp, but expression of ucp2 linearly increased to nearly 85-fold of the level prior to exposure. Expression of sod2 and ucp2 did not change until 6 h in silver carp. Use of sod1 and sod2 to combat oxidative stress results in hydrogen peroxide production, while use of ucp2 produces nitric oxide, a chemical known to inhibit apoptosis. We conclude that the mechanism at which a fish handles oxidative stress plays an important role in the tolerance to rotenone. PMID- 22447503 TI - A phase II trial of temsirolimus in second-line metastatic urothelial cancer. AB - This phase II trial assessed temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), as second-line therapy in patients with metastatic transitional carcinoma of the urothelium (TCCU) after failure of platinum containing therapy. From June/2009 to June/2011, we enrolled 15 patients in this trial. Primary endpoint was overall survival, as secondary endpoints we defined time to disease progression, safety and QoL along treatment. Patients with progressive TCCU after prior platinum-based chemotherapy received weekly 25 mg of temsirolimus for 8 weeks. Evaluation for response was accomplished every 8 weeks according to the RECIST criteria, QoL assessment was done every 4 weeks using the QLQ-C30 questionnaire, adverse events (AEs) were recorded and graded using NCI-CTC criteria. Fifteen patients were enrolled in this study, of whom 14 (93%) were available for activity, safety and QoL assessment. We treated 10 (71%) male and 4 female (29%) patients. Median age was 64,7 years (45-76). Patients received on average 13 (3-15) infusions of temsirolimus. As per protocol, no sufficient benefit on overall survival was observed, we early stopped the study after 14 patients. Median time to progression was 2.5 months (77 days), median overall survival was 3.5 months (107 days). Four patients with stable disease were observed. QoL assessment along treatment revealed a reduction of EORTC-QLQ-C30, Global Health Status subscale, from initial 7.86 to 5.00. Temsirolimus was well tolerated. As Grade 3-4 adverse events, we observed fatigue (n=2), leukopenia (n=2) and thrombopenia (n=2). All other adverse events were graded 1-2 in nature. Temsirolimus seems to have poor activity in patients with progressive metastasized TCCU after failure of platinum containing first-line therapy. PMID- 22447504 TI - Pediatric primary lung adenocarcinoma in the absence of congenital pulmonary airway malformation. AB - Primary lung adenocarcinoma is a rare entity in the pediatric population, especially in the absence of an underlying congenital pulmonary airway malformation. Primary lung malignancies in pediatric patients are rare and constitute 0.2% of all childhood malignancies. EGFR mutations and congenital airway malformations have been identified as etiological factors in the development of precancerous lesions that eventually progress to malignancy. The availability of genome sequencing and advanced imaging has made it possible to associate primary lung adenocarcinoma with mutations and structural malformations. Early diagnosis with the help of these techniques may result in surgical resection during early stages of the disease and possibly provide definitive treatment. Development of lung adenocarcinoma in pediatric patients in the absence of the above factors has been recorded anecdotally. It is possible that these patients may harbor a yet unknown set of mutations and recording this cases and preserving their tissues is of vital importance in the detection of these yet unknown etiologies. PMID- 22447505 TI - Establishing a new methodology for genome mining and biosynthesis of polyketides and peptides through yeast molecular genetics. AB - Fungal genome sequencing has revealed many genes coding for biosynthetic enzymes, including polyketide synthases and nonribosomal peptide synthetases. However, characterizing these enzymes and identifying the compounds they synthesize remains a challenge, whether the genes are expressed in their original hosts or in more tractable heterologous hosts, such as yeast. Here, we developed a streamlined method for isolating biosynthetic genes from fungal sources and producing bioactive molecules in an engineered Saccharomyces cerevisiae host strain. We used overlap extension PCR and yeast homologous recombination to clone desired fungal polyketide synthase or a nonribosomal peptide synthetase genes (5 20 kb) into a yeast expression vector quickly and efficiently. This approach was used successfully to clone five polyketide synthases and one nonribosomal peptide synthetase, from various fungal species. Subsequent detailed chemical characterizations of the resulting natural products identified six polyketide and two nonribosomal peptide products, one of which was a new compound. Our system should facilitate investigating uncharacterized fungal biosynthetic genes, identifying novel natural products, and rationally engineering biosynthetic pathways for the production of enzyme analogues possessing modified bioactivity. PMID- 22447506 TI - Multiple coronary cameral fistulae: a rare anomaly and cause of ischaemia. AB - An 82-year-old hypertensive, diabetic woman was admitted to our department for pre-operative cardiac evaluation. A myocardial perfusion scan revealed apicoseptal and inferior segment hypoperfusion. Coronary angiography exhibited extensive multiple coronary cameral fistulae draining into the left ventricle in a homogeneous and circular way. PMID- 22447507 TI - The perils of pharmacological treatment for obesity: a case of sibutramine associated cardiomyopathy and malignant arrhythmias. AB - A 58-year-old woman presented with severe left ventricular dysfunction and malignant arrhythmias after taking combination drug treatment for weight loss. The combination treatment included sibutramine, liothyronine, hydrochlorothiazide diuretic, metformin and fucus. The effect of these drugs individually and in combination is discussed, with particular reference to it being a malignant combination. The patient showed reversability of the left ventricular dysfunction and negative ventricular stimulation studies after cessation of the drug concoction. PMID- 22447508 TI - Rare cardiac defect in Holt-Oram syndrome. AB - Holt-Oram syndrome is an autosomal dominant condition associated with skeletal malformations of the upper limbs, and congenital heart disease. Approximately 40% of cases represent new mutations. Defective development of the embryonic radial ray (e.g. aplasia, hypoplasia, fusion, other anomalous development) results in a wide spectrum of phenotypes, including triphalangeal or absent thumbs, foreshortened arms and phocomelia. The syndrome is associated with defective development of cardiac structures that results in atrial septal defect (ASD), most commonly the secundum type, heart block of varying degrees, or both. We report a rare cardiac defect patent ductus arteriosus (PDA) and ventricular septal defect (VSD) in a case of Holt-Oram syndrome. PMID- 22447509 TI - Infective endocarditis and spondylodiscitis due to posterior nasal packing in a patient with a bioprosthetic aortic valve. AB - Infective endocarditis (IE) is a severe form of heart valve disease and is associated with a poor prognosis and high risk of mortality. We report the first known case of bioprosthetic aortic valve endocarditis associated with spondylodiscitis as a result of posterior nasal packing coated with antibiotics but without systemic antibiotic prophylaxis. PMID- 22447510 TI - Total correction in tetralogy of Fallot with anomalous major coronary artery: an alternative method to conduit use. AB - INTRODUCTION: A coronary artery anomaly precludes the use of a trans-annular patch in right ventricular outflow tract (RVOT) reconstruction. Herein we present three patients with coronary artery anomalies who underwent total corrective operations without using a conduit. METHODS: Between 2007 and 2010, 84 patients with tetralogy of Fallot (TOF) were operated on. Nine (9.4%) of them had a coronary artery anomaly. Three (3.1%) of the patients were operated on using the double-outflow technique and two had a Blalock-Taussig shunt before the total corrective operation. In two patients, the left anterior descending artery (LAD) and in one, the right coronary artery (RCA) crossed the RVOT. RESULTS: Postoperatively, the right-to-left ventricular pressure ratios were 0.45, 0.59 and 0.60 after cardiopulmonary bypass. No gradient was detected in the RVOT in postoperative echocardiographical measurements (< 15 mmHg gradient). In all three patients, there were moderate pulmonary insufficiencies. All were discharged home on the sixth day postoperatively. Mean follow-up duration was 9.8 +/- 8 months. In the follow up of all three patients, there were moderate pulmonary insufficienciencies but no right ventricular dysfunction. CONCLUSION: The 'double outflow' technique is appropriate for TOF patients with a major coronary artery anomaly since it can easily be performed without the need of a conduit. PMID- 22447511 TI - Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats. AB - The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism based inhibition (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX-female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX-female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX-female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration-time curve of MDZ and decreased the total clearance in DEX-female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX female rats can serve as an in vivo model for assessing this DDI in humans. PMID- 22447512 TI - Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model. AB - Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting ~3 in 100 000 individuals in Caucasian populations. It is caused by intronic GAA repeat expansions that hinder the expression of the FXN gene, resulting in defective levels of the mitochondrial protein frataxin. Sensory neurons in dorsal root ganglia (DRG) are particularly damaged by frataxin deficiency. There is no specific therapy for FRDA. Here, we show that frataxin levels can be upregulated by interferon gamma (IFNgamma) in a variety of cell types, including primary cells derived from FRDA patients. IFNgamma appears to act largely through a transcriptional mechanism on the FXN gene. Importantly, in vivo treatment with IFNgamma increases frataxin expression in DRG neurons, prevents their pathological changes and ameliorates the sensorimotor performance in FRDA mice. These results disclose new roles for IFNgamma in cellular metabolism and have direct implications for the treatment of FRDA. PMID- 22447513 TI - The impact of exposure to interpersonal violence on gender differences in adolescent-onset major depression: results from the National Comorbidity Survey Replication (NCS-R). AB - BACKGROUND: Beginning in adolescence, females are at significantly higher risk for depression than males. Despite substantial efforts, gaps remain in our understanding of this disparity. This study tested whether gender differences in adolescent-onset depression arise because of female's greater exposure or sensitivity to violence. METHODS: Data came from 5,692 participants in the National Comorbidity Survey Replication. Trained interviewers collected data about major depression and participants' exposure to four types of interpersonal violence (physical abuse, sexual assault, rape, and witnessing violence) using a modified version of the Composite International Diagnostic Interview. We used discrete time survival analysis to investigate gender differences in the risk of adolescent onset depression. RESULTS: Of the entire sample, 5.7% met DSM-IV criteria for depression by age 18; 5.8% of the sample reported being physically abused, 11.7% sexually assaulted, 8.5% raped, and 13.2% witnessed violence by age 18. Females had 1.51 times higher odds of depression by age 18 than males. Exposure to all types of violence was associated with an increased odds of depression in both the past year and the years following exposure. Adjusting for exposure to violence partially attenuated the association between gender and depression, especially for sexual assault (odds ratio [OR] attenuated = 1.28; 15.23%) and rape (OR attenuated = 1.32; 12.59%). There was no evidence that females were more vulnerable to the effects of violence than males. DISCUSSION: Gender differences in depression are partly explained by females' higher likelihood of experiencing interpersonal violence. Reducing exposure to sexual assault and rape could therefore mitigate gender differences in depression. PMID- 22447514 TI - From the editors' desk: Growing old in America: lessons from our Japanese obaachan. PMID- 22447515 TI - Brave silence. PMID- 22447516 TI - Desmotropy, polymorphism, and solid-state proton transfer: four solid forms of an aromatic o-hydroxy Schiff base. AB - The Schiff base derived from salicylaldehyde and 2-amino-3-hydroxypyridine affords a diversity of solid forms, two polymorphic pairs of the enol-imino (D1 a and D1 b) and keto-amino (D2 a and D2 b) desmotropes. The isolated phases, identified by IR spectroscopy, X-ray crystallography, and (13)C cross polarization/magnetic angle spinning (CP/MAS) NMR spectroscopy, display essentially planar molecular conformations characterized by strong intramolecular hydrogen bonds of the O-H???N (D1) or N-H???O (D2) type. A change in the position of the proton within this O???H???N system is accompanied by substantially different molecular conformations and, subsequently, by divergent supramolecular architectures. The appearance and interconversion conditions for each of the four phases have been established on the basis of a number of solution and solvent free experiments, and evaluated against the results of computational studies. Solid phases readily convert into the most stable form (D1 a) upon exposure to methanol vapor, heating, or by mechanical treatment, and these transformations are accompanied by a change in the color of the sample. The course of thermally induced transformations has been monitored in detail by means of temperature resolved powder X-ray diffraction and infrared spectroscopy. Upon dissolution, all forms equilibrate immediately, as confirmed by NMR and UV/Vis spectroscopy in several solvents, with the equilibrium shifted far towards the enol tautomer. This study reveals the significance of peripheral groups in the stabilization of metastable tautomers in the solid state. PMID- 22447517 TI - Effect of deposition parameters on the photocatalytic activity and bioactivity of TiO2 thin films deposited by vacuum arc on Ti-6Al-4V substrates. AB - This article evaluates the influence of the main parameters in a cathodic arc deposition process on the microstructure of titanium dioxide thin coatings and correlates these to the photocatalytic activity (PCA) and in vitro bioactivity of the coatings. Bioactivity of all as deposited coatings was confirmed by the growth of uniform layers of hydroxyapatite (HA) after 7 days in phosphate buffered saline at 37 degrees C. Comparison of the HA growth after 24 h indicated enhanced HA formation on coatings with small titanium dioxide grains of rutile and anatase phase. The results from the PCA studies showed that coatings containing a mixed microstructure of both anatase and rutile phases, with small grain sizes in the range of 26-30 nm and with a coating thickness of about 250 nm, exhibited enhanced activity as compared with other microstructures and higher coating thickness. The results of this study should be valuable for the development of new bioactive implant coatings with photocatalytically induced on demand antibacterial properties. PMID- 22447518 TI - Biomechanical characterization of aortic valve tissue in humans and common animal models. AB - Aortic valve disease develops in an escalating fashion in elderly patients. Current treatments including total valve replacement and valve repair techniques are still suboptimal. A thorough understanding of the animal and human valve tissue properties, particularly their differences, is crucial for the establishment of preclinical animal models and strategies for evaluating new valve treatment techniques, such as transcatheter valve intervention and tissue engineered valves. The goal of this study was to characterize and compare the biomechanical properties and histological structure of healthy ovine, porcine, and human aortic valve leaflets. The biaxial mechanical properties of the aortic valve leaflets of 10 ovine (~1 year), 10 porcine (6-9 months), and 10 aged human (80.6 +/- 8.34) hearts were quantified. Tissue microstructure was analyzed via histological techniques. Aged human aortic valve leaflets were significantly less compliant than both ovine and porcine leaflets, with the ovine leaflets being the most compliant. Histological analysis revealed structural differences between the species: the human and porcine leaflets contained more collagen and elastin than the ovine leaflets. Significant mechanical and structural differences in the aortic valve tissues of 6- to 9-month-old porcine models and 1-year-old ovine models with respect to those of aged humans, suggest that these animal models may not be representative of the typical patient undergoing aortic valve replacement. PMID- 22447519 TI - FGF23 and PTH--double agents at the heart of CKD. PMID- 22447520 TI - Molecular genetic analysis of the hepatocyte growth factor/MET signaling pathway in pediatric medulloblastoma. AB - The hepatocyte growth factor (HGF)/MET pathway plays a critical role in the development of the nervous system and has been implicated in medulloblastoma pathogenesis. Recent studies have shown a role for gene amplification of activators of this pathway, as well as silencing of its inhibitors in medulloblastoma pathogenesis. We analyzed exon array data from a cohort of 103 primary medulloblastomas to show that HGF/MET pathway elements are dysregulated in tumors compared to normal cerebellum. To determine if mutation of HGF/MET pathway genes is a mechanism for pathway dysregulation, we conducted a mutational analysis by exon resequencing of three key components of this pathway, including serine protease inhibitor Kunitz-type 1 (SPINT1), serine protease inhibitor Kunitz-type 2 (SPINT2), and MET, in 32 primary human medulloblastoma specimens. From this analysis, we identified multiple coding synonymous and nonsynonymous single nucleotide polymorphisms in these genes among the 32 tumor samples. Interestingly, we also discovered two unreported sequence variants in SPINT1 and SPINT2 in two tumors that resulted in Arginine to Histidine amino acid substitutions at codons 418 and 233, respectively. However, conservation assessment and functional assays of these two variants indicate that they involve nonconserved residues and that they do not affect the function of SPINT1 and SPINT2 as tumor suppressor genes. In conclusion, our data suggest that mutation alone plays a minor role in causing aberrancies of the HGF/MET pathway in medulloblastoma in comparison with other malignancies such as breast, hepatocellular, renal, and lung carcinomas. PMID- 22447521 TI - The effects of vasopressin and oxytocin on methamphetamine-induced place preference behaviour in rats. AB - Methamphetamine is a highly addictive stimulant drug whose illicit use and resultant addiction has become an alarming global phenomenon. The mesolimbic dopaminergic pathway has been shown to be fundamental to the establishment of addictive behaviour. This pathway, as part of the reward system of the brain, has also been shown to be important in classical conditioning, which is a learnt response. Within the modulation of learning and memory, the neurohypophyseal hormones vasopressin and oxytocin have been reported to play a vital role, with vasopressin exerting a long- term facilitatory effect and oxytocin exerting an inhibitory effect. Therefore we adopted a conditioned place preference model to investigate whether vasopressin V1b receptor antagonist SSR 149415 or oxytocin treatment would cause a decrease in the seeking behaviour in a reinstatement paradigm. Behavioural findings indicated that methamphetamine induced a change in the place preference in the majority of our animals. This change in place preference was not seen when vasopressin was administered during the extinction phase. On the other hand the methamphetamine-induced change in place preference was enhanced during the reinstatement phase in the animals that were treated with oxytocin. Striatal dopamine levels were determined, as methamphetamine is known to increase dopamine transmission in this area. Significant changes in dopamine levels were observed in some of our animals. Rats that received both methamphetamine and oxytocin had significantly higher striatal dopamine than those that received oxytocin alone. Western blot analysis for hippocampal cyclic AMP response element binding protein (CREB) was also conducted as a possible indicator of glutamatergic NMDA receptor activity, a pathway that is important for learning and memory. The Western blot analysis showed no changes in hippocampal pCREB expression. Overall our data led us to conclude that methamphetamine treatment can change place preference behaviour in rats and that this change may be partially restored by vasopressin antagonism, but exaggerated by oxytocin. PMID- 22447522 TI - Serum amyloid A (SAA) induces pentraxin 3 (PTX3) production in rheumatoid synoviocytes. AB - OBJECTIVE: Pentraxin 3 (PTX3) is an acute-phase reactant that is involved in amplification of the inflammatory response and innate immunity. In the present study, we evaluated the relationship between PTX3 and serum amyloid A (SAA), another acute-phase reactant, in rheumatoid synoviocytes. METHODS: PTX3 mRNA expression was examined by reverse transcription polymerase chain reaction, and PTX3 protein was measured by enzyme-linked immunosorbent assay. RESULTS: SAA induced PTX3 mRNA and PTX3 protein expression in rheumatoid synoviocytes. SAA induced PTX3 expression was attenuated when rheumatoid synoviocytes were nucleofected with N-formyl peptide receptor ligand-1 (FPRL-1)-specific siRNA, suggesting the involvement of FPRL-1. Furthermore, SAA-induced PTX3 expression was inhibited by NF-kappaB or mitogen-activated protein kinase-specific inhibitors. Neither soluble TNF receptor (etanercept) nor recombinant IL-1 receptor antagonist affected PTX3 production by SAA-stimulated synoviocytes, suggesting that SAA directly induces PTX3. CONCLUSION: Our data suggest that SAA plays a role in the proinflammatory and immune responses in rheumatoid synovium by inducing PTX3. We provide the first evidence that the acute-phase reactant SAA, which is produced systemically by hepatocytes, perpetuates the rheumatoid inflammatory processes by inducing another proinflammatory molecule, PTX3, locally in rheumatoid synovial tissues. PMID- 22447523 TI - Frequency of enthesitis in apparently healthy Japanese subjects detected by (18)F FDG-PET/CT. PMID- 22447524 TI - Cell study of the three areas of the meniscus: effect of growth factors in an experimental model in sheep. AB - Meniscus had two areas with different vascular supply. Cells of the two areas and the synovium were monolayer cultivated. We analyzed the expression of genes of Col1, Col 2A, MMP-2, MMP-13, and aggrecan in a baseline state and after incubation with VEGF, TGF-beta, FGF, and IGF. We found that the growth factors used produced a major increase in the MMP-13 in all three areas. In the vascular area, the stimulation of MMP-3 was produced by FGF, while in the synovial and avascular areas, it was caused by TGF-beta. MMP-2 was only stimulated in the synovial area by IGF. Col 2A was stimulated in the synovial area by VEGF, and in the avascular area by TGF-beta, FGF, and IGF, whereas Col 1 was stimulated in the avascular area by IGF, FGF, and VEGF. The vascular or avascular areas of the meniscus, behave differently in terms of repair, and their cells express different factors. The growth factors act in a different way in each meniscal area. PMID- 22447525 TI - Validation of an operating room immersive microlaryngoscopy simulator. AB - OBJECTIVES/HYPOTHESIS: To assess the face and construct validity of two assessment tools for a microlaryngoscopy simulator-a Checklist Assessment for Microlaryngeal Surgery and Global Rating Assessment for Microlaryngeal Surgery. STUDY DESIGN: Blinded experimental simulator-based study. METHODS: There were 15 candidates divided into a novice (<=50 procedures performed) or experienced (>50 procedures) group depending on their previous microlaryngoscopy experience. Each candidate undertook a 10-minute simulation of a microlaryngoscopy and excision biopsy, and two blinded experts rated their performance live on each of the two assessment tools. To assess face validity, each candidate subsequently completed a questionnaire about the simulator. RESULTS: The model demonstrated good face validity across all levels of experience. The global rating assessment demonstrated excellent interrater reliability (0.9) compared to the checklist assessment (0.7). The checklist assessment was able to differentiate experienced and novice candidates and therefore demonstrated construct validity. The global rating tool, however, was unable to differentiate candidates. There was a significant correlation between the two assessment tools (correlation coefficient = 0.624). CONCLUSIONS: This study is the first reported study of a high-fidelity microlaryngoscopy simulator with task-specific rating tools. Use of these tools is recommended within otolaryngology training programs, with the global rating assessment for use as a frequently used feedback tool, and the checklist assessment as a confirmatory evaluation of competency at transitions of professional training. PMID- 22447526 TI - Changing trends in sinus and septal surgery, 2007 to 2009. AB - BACKGROUND: Sinus surgery remains one of the most commonly performed procedures in the United States, with more than 600,000 patients undergoing sinus operations each year. Advances in our understanding of chronic rhinosinusitis (CRS), as well as the technology used to treat it, has resulted in significant changes in surgical management. The aim of this study was to identify recent changes in the performance and coding of certain endoscopic sinus surgical procedures (ESS) in the hope of generating further discussion and research in this area. METHODS: The MarketScan Research Database was used to query health insurance claims for all rhinological procedures performed between 2007 and 2009. Current Procedural Terminology (CPT) codes for sinonasal procedures that are endorsed by the American Medical Association were analyzed and compared to general otolaryngological procedures in an attempt to identify trends in the performance and coding of certain ESS procedures. RESULTS: Compared to general otolaryngological procedures such as adenotonsillectomy, there was a statistically significant increase in the use of CPT codes for all ESS procedures between 2007 and 2009. The most marked interval changes were seen in the use of the CPT codes for procedures previously considered more complex, namely frontal sinusotomy (75%), sphenoidotomy (33%), and maxillary antrostomy with tissue removal (31%). CONCLUSION: The performance of certain ESS procedures previously considered more complex due to anatomy, access, and proximity to vital structures has increased dramatically in the past few years, whereas increases in basic procedures have mirrored anticipated changes similar to those seen in general otolaryngological procedures. PMID- 22447528 TI - The ever expanding spinocerebellar ataxias. Editorial. AB - The spinocerebellar ataxias (SCAs) are a clinically, genetically, and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and non-cerebellar symptoms that, in many cases,defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its relay connexions. The current identification of at least 43 SCA subtypes and the causative molecular defects in 27 of them refine the clinical diagnosis,provide molecular testing of at risk, a/pre-symptomatic, prenatal or pre-implantation and facilitate genetic counselling. The recent discovery of new causative SCA genes along with the respective scientific advances is uncovering high complexity and altered molecular pathways involved in the mechanisms by which the mutant gene products cause pathogenesis. Fortunately, the intensive ongoing clinical and neurogenetic research together with the applied molecular approaches is sure to yield scientific advances that will be translated into developing effective treatments for the spinocerebellar ataxias and other similar neurological conditions. PMID- 22447527 TI - Genetic and cytogenetic analysis of the American cherry fruit fly, Rhagoletis cingulata (Diptera: Tephritidae). AB - The American eastern cherry fruit fly, Rhagoletis cingulata, a pest of cherries in the western hemisphere, invaded Europe in 1983, and since then dispersed to several European countries. Information on the genetics and cytogenetics of this pest is very scarce. The mitotic karyotype and detailed photographic maps of the salivary gland polytene chromosomes of R. cingulata are presented here. The mitotic metaphase complement consists of six pairs of chromosomes with the sex chromosomes being very small and similar in size. The analysis of the salivary gland polytene complement shows a total number of five long chromosomes (10 polytene arms), which correspond to the five autosomes of the mitotic nuclei and an extrachromosomal heterochromatic mass, which corresponds to the sex chromosomes. The banding patterns and the most characteristic features and prominent landmarks of each polytene chromosome are presented and discussed. Chromosomal homologies between R. cingulata, R. completa and R. cerasi are also proposed, based on the comparison of chromosome banding patterns. Furthermore, the detection and characterization of Wolbachia pipientis in the R. cingulata population studied is presented and the potential correlation with the asynaptic phenomena found in its polytene complement is discussed. In addition, 10 out of 24 microsatellite markers developed for other Rhagoletis species are cross amplified, evaluated and proposed as useful markers for population and genetic studies in R. cingulata. PMID- 22447529 TI - Noncovalent PEGylation: different effects of dansyl-, L-tryptophan-, phenylbutylamino-, benzyl- and cholesteryl-PEGs on the aggregation of salmon calcitonin and lysozyme. AB - Protein aggregation is a major instability that can occur during all stages of protein drug production and development. Protein aggregates may compromise the safety and efficacy of the final protein formulation. In this paper, various new excipients [phenylbutylamino-, benzyl-, and cholesteryl-polyethylene glycols (PEGs)] and their use for the reduction of aggregation of salmon calcitonin (sCT) and hen egg-white lysozyme (HEWL) by noncovalent PEGylation are presented. The ability to suppress aggregation of sCT in various buffer systems at a 1:1 molar ratio was assessed by following changes in protein conformation and aggregation state over time. The results are compared with that of dansyl- and L-tryptophan (Trp)-PEGs described in earlier publications. Furthermore, the influence of the different PEG-based excipients on the aggregation of HEWL was measured. HEWL aggregation was completely suppressed in the presence of cholesteryl-PEGs (2 and 5 kDa), whereas deterioration was observed using benzyl-methoxy polyethylene glycols (mPEGs; 2 and 5 kDa). Phenylbutylamino- and Trp-mPEG (2 kDa), as well as dansyl-PEGs of different molecular weight prolonged the lag phase of aggregation and reduced the aggregation velocity of HEWL. PMID- 22447530 TI - Gender differences in pharmacokinetics of lumefantrine and its metabolite desbutyl-lumefantrine in rats. AB - Lumefantrine has been reported to be mainly bio-transformed by cytochrome P450 isozyme 3A4 to desbutyl-lumefantrine (DLF) in human liver microsomes. Since CYP3A is expressed in a sex specific manner in rats, it could be expected that the pharmacokinetics of lumefantrine would be changed in male rats compared with those in female rats. The pharmacokinetics of lumefantrine and its active metabolite DLF were evaluated after intravenous (0.5 mg/kg) and oral (20 mg/kg) administration of lumefantrine to male and female Sprague-Dawley rats. The quantitative bioanalysis was carried out by the liquid chromatography tandem mass spectrometry method. After intravenous and oral administration of lumefantrine the area under the curve (AUC) of lumefantrine was significantly higher in female rats than that in male rats, whereas the AUC of DLF was significantly lower in female rats in comparison with male rats. This lower AUC of DLF in female rats could have been due to reduced metabolism of lumefantrine in female rats. The bioavailability (%F) of lumefantrine was 1.66 times higher in male rats than that in female rats. PMID- 22447531 TI - Statistical methods for cost-effectiveness analyses that use observational data: a critical appraisal tool and review of current practice. AB - Many cost-effectiveness analyses (CEAs) use data from observational studies. Statistical methods can only address selection bias if they make plausible assumptions. No quality assessment tool is available for appraising CEAs that use observational studies. We developed a new checklist to assess statistical methods for addressing selection bias in CEAs that use observational data. The checklist criteria were informed by a conceptual review and applied in a systematic review of economic evaluations. Criteria included whether the study assessed the 'no unobserved confounding' assumption, overlap of baseline covariates between the treatment groups and the specification of the regression models. The checklist also considered structural uncertainty from the choice of statistical approach. We found 81 studies that met the inclusion criteria: studies tended to use regression (51%), matching on individual covariates (25%) or matching on the propensity score (22%). Most studies (77%) did not assess the 'no observed confounding' assumption, and few studies (16%) fully considered structural uncertainty from the choice of statistical approach. We conclude that published CEAs do not assess the main assumptions behind statistical methods for addressing selection bias. This checklist can raise awareness about the assumptions behind statistical methods for addressing selection bias and can complement existing method guidelines for CEAs. PMID- 22447532 TI - Preparation, characterization, and release behavior of aspirin-loaded poly(2 hydroxyethyl acrylate)/silica hydrogels. AB - Poly(2-hydroxyethyl acrylate) (PHEA) is a polymer hydrogel that can be used as a biomaterial. In this study, PHEA/silica composites containing aspirin as a model drug were prepared, and their drug release behaviors were tested. 2-Hydroxyethyl acrylate (HEA) was first copolymerized with 3-(trimethoxysilyl) propyl methacrylate (MSMA) in the presence of ammonium persulphate and then condensed with silicic acid oligomer. The composites were characterized with Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). In addition, water uptake and matrix erosion of PHEA/silica of different weight ratios were also investigated. The results indicated that the silica particles were well dispersed in PHEA hydrogels. The in vitro drug release test revealed that the release rate of aspirin decreased with the increasing content of silica. The drug release behaviors were analyzed by employing the power law, which showed that the release profiles were governed either by Case II diffusion or by anomalous diffusion. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay of rabbit chondrocytes revealed that adding silica can improve the biocompatibility of PHEA to some extent. PMID- 22447533 TI - An integrative genomic analysis of the superior fecundity phenotype in QSi5 mice. AB - Laboratory inbred mouse models are a valuable resource to identify quantitative trait loci (QTL) for complex reproductive performance traits. Advances in mouse genomics and high density single nucleotide polymorphism mapping has enabled genome-wide association studies to identify genes linked with specific phenotypes. Gene expression profiles of reproductive tissues also provide potentially useful information for identifying genes that play an important role. We have developed a highly fecund inbred strain, QSi5, with accompanying genotyping for comparative analysis of reproductive performance. Here we analyzed the QSi5 phenotype using a comparative analysis with fecundity data derived from 22 inbred strains of mice from the Mouse Phenome Project, and integration with published expression data from mouse ovary development. Using a haplotype association approach, 400 fecundity-associated regions (FDR < 0.05) with 499 underlying genes were identified. The most significant associations were located on Chromosomes 14, 8, and 6, and the genes underlying these regions were extracted. When these genes were analyzed for expression in an ovarian development profile (GSE6916) several distinctive co-expression patterns across each developmental stage were identified. The genetic analysis also refined 21 fecundity associated intervals on Chromosomes 1, 6, 9, 13, and 17 that overlapped with previously reported reproductive performance QTL. The combined use of phenotypic and in silico data with an integrative genomic analysis provides a powerful tool for elucidating the molecular mechanisms underlying fecundity. PMID- 22447534 TI - Self-assembled organic nanotubes through instant gelation and universal capacity for guest molecule encapsulation. AB - Loyal gelling: a C(3) symmetrical L-glutamic acid based gelator was found to instantly form hexagonal nanotubes through anti-solvent gelation in a wide range of mixed solvents at room temperature. Guest molecules, including simple dyes and biological macromolecules, could be entrapped in the nanotubes. This method provides a general and efficient way for the encapsulation of guest compounds in organic nanotubes. PMID- 22447535 TI - Anxiety sensitivity in adolescence and young adulthood: the role of stressful life events, 5HTTLPR and their interaction. AB - BACKGROUND: Cognitive biases have long been hypothesized to influence the development and maintenance of symptoms of internalizing problems. Anxiety sensitivity represents one such bias and refers to sensitivity to the physical and emotional symptoms of anxiety and the belief that these are harmful. Twin studies indicate a role for both environmental and genetic influences on anxiety sensitivity. However, little work has been done specifying environments or genes involved in this phenotype. In light of this, we looked at the association between stressful life events, the serotonin transporter gene polymorphism (5HTTLPR), and anxiety sensitivity in a longitudinal sample of adolescents. METHODS: Stressful life events and anxiety sensitivity were measured in over 1,500 individuals at three time points (mean ages 15, 17, and 20 years). 5HTTLPR was genotyped in 1,109 participants. RESULTS: There was consistent evidence for an association between stressful life events and both anxiety sensitivity and change in anxiety sensitivity over time. Although the effect of independent stressful life events was relatively short lived, dependent stressful life events were associated with anxiety sensitivity over time. There was no evidence for a main effect of 5HTTLPR on anxiety sensitivity. 5HTTLPR genotype did not moderate the effect of stressful life events on anxiety sensitivity. CONCLUSIONS: The current study extends previous work by showing that stressful life events, independent of the individual, explained change in cognitions associated with anxiety and depression. This effect does not, however, appear to be moderated by genotype. PMID- 22447536 TI - The UDP glucose: flavonoid-3-O-glucosyltransferase (UFGT) gene regulates anthocyanin biosynthesis in litchi (Litchi chinesis Sonn.) during fruit coloration. AB - We analyzed a litchi cultivar that included three phenotypes for pericarp color, ranging from green, indicating the absence of anthocyanins, to yellow, and red. Anthocyanins, chlorophylls, carotenoids, and flavonoids were measured in the three stages. Fruit coloration of red-skinned litchi was mainly due to higher flavonols, and anthocyanin pigments, lower chlorophyll (higher chlorophyll degradation). Expression of four genes of the anthocyanin pathway coding for phenylalanine ammonialyase, chalcone synthase, flavanone-3-hydroxylase, and the UDP-glucose: flavonoid-3-O-glucosyltransferase (UFGT), was analyzed by RT-PCR at three developmental stages from before the onset of ripening to full maturity. Gene expression patterns were compared to anthocyanin metabolites. The contents of anthocyanins and flavonols in the pericarps were consistent with the higher mRNA levels of UFGT, while, transcription of the other gene was not expected to follow the anthocyanin content. We suggest that UFGT might play an important role in anthocyanin biosynthesis in the pericarp of litchi. Thus, UFGT expression strongly influences fruit coloration in litchi. PMID- 22447537 TI - Sevoflurane postconditioning attenuates reperfusion-induced ventricular arrhythmias in isolated rat hearts exposed to ischemia/reperfusion injury. AB - Sevoflurane postconditioning has been proven to protect the hearts against ischemia/reperfusion injury, manifested mainly by improved cardiac function, reduced myocardial specific biomarker release, and decreased infarct size. This study is to observe the effects of sevoflurane postconditioning on reperfusion induced ventricular arrhythmias and reactive oxygen species generation in Langendorff perfused rat hearts. Compared with the unprotected hearts subjected to 25 min of global ischemia followed by 30 min of reperfusion, exposure of 3% sevoflurane during the first 15 min of reperfusion significantly improved cardiac function, reduced cardiac troponin I release, decreased infarct size and attenuated reperfusion-induced ventricular arrhythmia. Further analysis on arrhythmia during the 30 min of reperfusion showed that, sevoflurane postconditioning decreased both the duration and incidence of ventricular tachycardia and ventricular fibrillation. In the meantime, intracellular malondialdehyde and reactive oxygen species levels were also reduced. These above results demonstrate that sevoflurane postconditioning protects the hearts against ischemia/reperfusion injury and attenuates reperfusion-induced arrhythmia, which may be associated with the regulation of lipid peroxidation and reactive oxygen species generation. PMID- 22447538 TI - Overexpressing transcriptional regulator in Aspergillus oryzae activates a silent biosynthetic pathway to produce a novel polyketide. AB - Fungal genomes carry many gene clusters seemingly capable of natural product biosynthesis, yet most clusters remain silent. This places a major constraint on the conventional approach of cloning these genes in more amenable heterologous host for the natural product biosynthesis. One way to overcome this difficulty is to activate the silent gene clusters within the context of the target fungus. Here, we successfully activated a silent polyketide biosynthetic gene cluster in Aspergillus oryzae by overexpressing a transcriptional regulator found within the cluster from a plasmid. This strategy allowed us to isolate a new polyketide product and to efficiently decipher its biosynthetic pathway. Through this exercise, we also discovered unexpected activities of the biosynthetic enzymes found in the cluster. These results indicate that our approach would be valuable for isolating novel natural products and engineering analogues of comparable, if not more potent, bioactivity. PMID- 22447539 TI - Videolaryngoscopic assessment of laryngeal edema after arytenoid adduction. AB - OBJECTIVES/HYPOTHESIS: Arytenoid adduction (AA) as surgical treatment for unilateral vocal fold paralysis (UVFP) is associated with higher morbidity from airway complications due to postoperative laryngeal edema compared with other laryngeal framework surgeries. The aim of this study was to evaluate postoperative laryngeal edema after AA using a new videolaryngoscopic (VL) scoring assessment. STUDY DESIGN: Prospective case series. METHODS: Nineteen patients with UVFP (14 males and five females; mean age, 56 years) who were treated with AA alone or combined with ansa cervicalis (AA/AC) nerve anastomosis or nerve-muscle pedicle (AA/NMP) flap implantation were evaluated. Laryngeal edema was assessed by VL scoring for 10 days postoperatively. Degree of edema was scored in three subsites: the membranous vocal fold, arytenoid mound, and pyriform sinus on the operated side. Statistical significance was defined as P < .05. RESULTS: No patient experienced postoperative airway compromise. Interexaminer reliability was generally high (Spearman r > 0.75). The mean degree of edema increased steadily from postoperative day (POD) 1 to 3, peaking on POD 3 at all subsites. It then declined significantly from POD 3 to 7 (P < .05) and gradually through POD 10. The maximum degree of edema, maximum edema time, and operative time were not correlated significantly at any subsite. Maximum edema time and surgery type (AA vs. AA/AC or AA/NMP) were not correlated at any subsite. CONCLUSIONS: Inter-rater reliability for the proposed VL scoring was significant at all subsites. The VL findings suggest that AA alone or AA combined with reinnervation showed maximum laryngeal edema on POD 3 but added no significant morbidity. PMID- 22447540 TI - Improvement of FISH-FCM enumeration performance in filamentous yeast species in activated sludge by snailase partial digestion. AB - This paper developed a novel strategy to improve the fluorescence in situ hybridization-flow cytometry (FISH-FCM) enumeration performance in filamentous yeast species in activated sludge by snailase partial digestion to fully disaggregate filamentous yeast chains into single cells. A 2 h 2% snailase partial digestion liberated more rod-shaped yeast single cells from intertwined filamentous yeast samples than did sonication disaggregation, based on an optical microscopic observation and the forward-light-scatter frequency histogram of FCM analysis. However, adding snailase resulted in a fluorescence-quenching phenomenon of the hybridized filamentous yeast cells, which was minimized by lowering the snailase concentration. An approximately 3 h 0.5% snailase partial digestion conducted between sonication and hybridization significantly improved the FISH-FCM enumeration performance for filamentous yeast species by 37%. The results presented here will facilitate the rapid detection, identification and exact enumeration of specific filamentous fungal species in environmental samples. PMID- 22447541 TI - Public health, tuberculosis, and the continuing fight against infections. PMID- 22447542 TI - The importance of definition in diagnosing obesity: a review of studies of children in China. AB - The prevalence of childhood overweight and obesity in China has increased in recent decades. However, studies reported from China use several different definitions and growth references, making it difficult to compare the rates of obesity from different regions. It also makes it difficult to establish the extent of secular trends in obesity and to make international comparisons. This article reviews the definitions of childhood obesity used in Chinese studies published over the past 10 years. The majority (79%) of the Chinese studies used a definition of >120% of the mean value of the National Center for Health Statistics reference population to diagnose childhood obesity. Only 7 studies (9%) conducted in China measured childhood obesity using age-specific and sex specific body mass index (BMI) cutoffs, including International Obesity Task Force cutoffs, Centers for Disease Control 2000 and World Health Organization 2006 BMI curves, and Chinese BMI curves. It is important that a consistent and applicable definition is used and all studies accurately define the obesity with growth reference, cutoff criteria, sample selection, and age distribution. The use of sex-specific and age-specific BMI cutoffs should be considered when undertaking future studies of obesity in Chinese children. PMID- 22447543 TI - Dr Marcus Liveris, OBE: (15 May 1931 - 19 December 2011). PMID- 22447544 TI - Development of clinical visual physiology in China during the past fifty years. AB - In the past 50 years, China has experienced a valuable development stage of clinical visual physiology and made substantial progresses in the aspects. It not only contributes to ophthalmology development, but also cultivates the precious visual physiology scientist and researcher groups in China and will advance Chinese ophthalmology toward a glorious future. PMID- 22447545 TI - Comparison on visual function after implantation of an apodized diffractive aspheric multifocal or monofocal intraocular lens. AB - PURPOSE: To evaluate visual outcomes after implantation of an aspheric multifocal/ intraocular lens (MIOL) or an aspheric monofocal intraocular lens (IOL). METHODS: This was a prospective nonrandomized study. During 3-months of post-operative follow-up, the following outcomes for SN6AD1 MIOL (multifocal group) and SN60WF IOL (monofocal group) were compared: uncorrected (UDVA) and corrected (CDVA) distance visual acuity, uncorrected (UNVA) and distance corrected (DCNVA) near visual acuity, Chinese character near visual acuity, uncorrected intermediate visual acuity (UIVA) under high (100% contrast) and low contrast (10% contrast), UIVA for different IOL powers, and a quality-of-life questionnaire. RESULTS: UNVA, DCNVA, and UIVA under high contrast in the multifocal group were significantly better than those in the monofocal group (P<0.05). UDVA, CDVA and UIVA under low contrast did not differ between groups at 63 cm and 100 cm (P>0.05). In most of the cases, Chinese character near visual acuity was significantly better in the multifocal group (P<0.05). UNVA and UIVA at 63cm were improved 3 months post-operatively. Better UIVA was found in emmetropic and mild myopic eyes as compared to hyperopic ones. The patients in the multifocal group had a higher degree of satisfaction and performed better on near and intermediate tasks, although with greater complaints of visual disturbance. CONCLUSION: The SN6AD1 MIOL provides significantly better UNVA, DCNVA and UIVA under high contrast conditions, and better Chinese character near visual acuity. Patients receiving the SN6AD1 MIOL reported a better quality of vision in spite of more serious visual disturbances. Better UIVA was observed in emmetropic and mildly myopic eyes. PMID- 22447546 TI - Plateau iris in Whites versus Asians. AB - PURPOSE: To evaluate the prevalence of plateau iris diagnosed by ultrasound biomicroscopy after laser peripheral iridotomy in Whites as compared to Asians in a U.S. clinic setting. METHODS: This was a prospective, observational study of narrow angle patients (n=55) who underwent laser peripheral iridotomy. Ultrasound biomicroscopy was performed in 4 quadrants of only one eye of each patient 4~6 weeks before and after surgery. The images were randomized and interpreted qualitatively by a single observer. Plateau iris was diagnosed in eyes with persistent appositional angles after laser peripheral iridotomy when at least 2 quadrants fulfilled the following criteria: 1. The ciliary process was directed anteriorly. 2. The ciliary sulcus was absent. 3. The central iris plane was flat. RESULTS: Twenty eight subjects (50.1%) were Whites, and 27 subjects (49.0%) were Asians. Plateau iris was assessed in 18 subjects (32.7%): 9 of 28 Whites (32.1%) and 9 of 27 Asians (33.3%). The proportion of plateau iris did not differ between Whites and Asians (P>0.99) CONCLUSION: The prevalence of plateau iris did not differ between Whites and Asians. Both groups had a substantial proportion of narrow angle patients with this clinical entity. PMID- 22447547 TI - Complications of fibrin glue in pterygium surgery with amniotic membrane transplant. AB - PURPOSE: To compare the complications and the recurrence rate between fibrin glue (TISSEEL) and Vicryl 8-0 sutures in amniotic membrane transplant during pterygium surgery. METHODS: Patients who underwent pterygium surgery with amniotic membrane transplant (AMT) in the Wang Eye Clinic (Doraville, USA) were randomly categorized into two groups: one group received TISSEEL and the other group received Vicryl 8-0 sutures. All procedures for both groups were performed by one ophthalmologist. Twenty-four patients (24 eyes) participated in the TISSEEL group (22 eyes with primary surgery and 2 eyes with surgery for recurrence) and 19 patients (19 eyes) took part in the suture group (18 primary eyes and 1 recurrence). The patients with recurrent pterygium in both groups had not received AMT previously. Post-operatively, patients were followed up for one week and then one year to check for any signs of complications and recurrence. RESULTS: Conjunctival inflammation occurred in 3 eyes (12.5%) in the TISSEEL group, and 6 eyes (31.6%) in the suture group (P<0.05, Chi-square test). In the TISSEEL group, 1 eye (4.2%) showed recurrence, while there were no recurrences in the sutures group. There were 3 dry eyes (15.8%) in the suture group and 2 dry eyes (8.3%) in the TISSEEL group (P>0.05). No dislocated conjunctival grafts, Dellen, inflammation, infection, bleeding, pyogenic granuloma, or scleromalacia was observed in either group. CONCLUSION: Pterygium surgery with AMT had less conjunctival inflammation and dry eye in patients receiving fibrin glue than those with Vicryl 8-0 sutures. PMID- 22447548 TI - Efficacy of phacovitrectomy combined with internal limiting membrane peeling for macular diseases. AB - PURPOSE: To observe the efficacy of vitrectomy with internal limiting membrane (ILM) peeling combined with phacoemulsification with intraocular lens (IOL) implantation in the treatment of cataract with co-existing macular diseases. METHODS: A total of 28 cataract patients (28 eyes) with co-existing macular diseases were admitted to Aier Eye Hospital between May 2008 and May 2011. The clinical characteristics were analyzed in this study. Subjects included 6 men and 22 women, aged from 56 to 77 years (mean 64 years), with duration of disease ranging from 2 to 36 months (mean 9.3 months). All patients underwent phacoemulsification with implantation of a hydrophobic acrylic IOL into the capsular bag and pars plana vitrectomy with ILM peeling. RESULTS: Postoperatively, patients underwent 3- to 18-months of follow-up (mean 7.2 months). Only one eye had macular hole failing to close. Normal macular structure was restored in the other 27 eyes. The presenting visual acuity and best corrected visual acuity (BCVA) did not differ significantly (t=-1.724, P=0.096), with the BCVA in 27 eyes (96.4%) improving by 2 lines or more. The improvement in minimum angle of resolution (MAR) was > 0.3 in 21 eyes, >= 0.1 in 6 eyes and < 0.1 in 1 eye. The mean spherical equivalent (SE) was -4.67+/-5.98D preoperatively and -0.38+/-0.69D postoperatively (t=4.157, P<0.005). CONCLUSION: Combined phacovitrectomy surgery is a reliable and safe procedure in the treatment of cataract complicated by macular disease. PMID- 22447549 TI - Relationship between the alignment of a non-mydriatic fundus camera, anterior chamber depth and axial length. AB - PURPOSE: To evaluate the relationship between the position of the focal adjustment knob of a fundus camera and refractive error and biometric data as measured in the same eye. METHODS: Normal eyes of patients presenting to clinics at the Beijing Tongren Hospital were examined with a non-mydriatic fundus camera. The position on the focal scale of a knob adjusting the distance between the camera lens and film plane, used to adjust focus the image of the patients fundus relative to the refractive power of the eye, was recorded in degrees. Ocular biometry and refractometry were performed on the same eyes. RESULTS: The study included 136 subjects with a mean age of 36.5+/-19.6 years and a mean refractive error of -1.31 +/- 2.77 diopters. In univariate analysis, the position of the adjustment knob was significantly associated with refractive error (P<0.001; correlation coefficient r= -0.77), axial length (P<0.001; r= 0.65) and anterior chamber depth (P<0.001; r= 0.48). After adjustment for age, anterior chamber depth decreased by 0.01 mm (95% confidence interval: 0.003, 0.017) for change per degree in the position of the adjustment knob. CONCLUSION: A fundus camera can be used to estimate anterior chamber depth, axial length and refractive error. In a screening setting, a fundus camera operated by a technician may be helpful to detect a shallow anterior chamber and evaluate a potential risk factor for primary angle closure. PMID- 22447550 TI - Efficacy of removing dislocated lens using intravitreal phacoemulsification. AB - PURPOSE: To evaluate the efficacy of intravitreal phacoemulsification in the removal of dislocated crystalline lenses. METHODS: Twenty-two cases (22 eyes) with posterior dislocated lens induced by ocular trauma or capsule rupture during phacoemulsification between January 2008 and December 2010 were retrospectively analyzed in this study. Total vitrectomy was first performed through standard closed three-port incisions at the pars plana, and dislocated lenses were removed using the phacoemulsification tip without the silicone sleeve. Extraction of intraocular foreign body, endolaser retinal photocoagulation and intraocular lens implantation were performed simultaneously. Visual acuity, intraocular pressure (IOP) and postoperative complications were assessed over 1 to 3 months of follow up. RESULTS: All dislocated lenses were extracted without severe complication. The final corrected visual acuity was >= 6/15 in 7 cases, 6/100-6/18 in 5 cases and <= 6/120 in 10 cases, a significant improvement over preoperative values (P <0.05). The IOP in 10 cases (10 eyes) with secondary glaucoma was < 21 mmHg post operatively. Intraocular foreign bodies in 3 eyes were removed. Nine patients (9 eyes) underwent intraocular lens implantation. No instances of retinal detachment, retinal hemorrhage or scleral wound burn were observed after surgery. CONCLUSION: Intravitreal phacoemulsification combined with vitrectomy yielded good efficacy and safety in the treatment of posteriorly dislocated lens. It may be an alternative to phacofragmentation in the treatment of posteriorly dislocated lenses. PMID- 22447551 TI - Efficacy of cytidine-5'-diphosp-bocholine combined with compound anisodine in the treatment of early optic nerve contusion. AB - PURPOSE: To investigate the efficacy of anisodine combined with cytidine-5' diphosp-bocholine (citicoline) in the treatment of early optic nerve contusion. METHODS: A total of 33 subjects eligible for inclusion were selected from 105 patients clinically diagnosed with optic nerve contusion. These patients were subsequently divided into the control group (n=16) and the intervention group (n=17). In the control group, the participants received therapy consisting of glucocorticoids, mannitol, vasodilators and vitamin B. The patients in the intervention group additionally received anisodine in combination with citicoline. The visual acuity was graded on a scale from 0 to 8. RESULTS: Prior to treatment, the 25th, 50th and 75th percentiles of visual acuity grade were 3, 4 and 6.75 for the controls, and 3, 4 and 6.5 for the patients in the intervention group. (P=0.97). After treatment, the 25th, 50th and 75th percentiles of visual acuity grade were 4, 6 and 7.75 in the control group, and 7, 7 and 8 in the intervention group. (P=0.046). A significant difference was observed in both control (P=0.005) and intervention groups (P=0.001) when comparing presenting visual acuity before and after treatment. CONCLUSION: The combination of anisodine and citicoline with standard steroid and mannitol therapy appears to be effective in the treatment of early optic nerve contusion. PMID- 22447552 TI - Comparison of corneal thickness of young people with middle and high myopia between Shantou and Zhengzhou. AB - PURPOSE: To compare the corneal thickness of young subjects (aged 13 to 30 years) with moderate and high myopia living in Shantou and Zhengzhou. METHODS: One hundred and forty myopic subjects from Shantou (Guangdong, southern China) and 101 from Zhengzhou (Henan, central China) were selected and divided into 2 groups (moderate-myopic group and high-myopic group). The participants were sex-and age matched. The central corneal thickness (CCT) and thinnest corneal thickness (TCT) were measured by Orbscan and compared between the two groups. RESULTS: In the high-myopic group, CCT (515.47+/-40.39 MUm) and TCT (510.22+/-40.95 MUm) of the Shantou subjects (mean spherical equivalent [SE] -7.56+/-1.35), were thinner than those of their Zhengzhou counterparts (mean SE -7.47+/-0.88). In the moderate myopic group (Shantou mean SE -4.52+/-0.83; Zhengzhou -4.67+/- 0.77), CCT and TCT did not differ between the two cities. CONCLUSION: The corneal thickness of high myopic eyes may differ between Shantou and Zhengzhou. PMID- 22447553 TI - Eyelid basal cell carcinoma arising on the site of a congenital port wine hemangioma. AB - PURPOSE: Only one previous case of eyelid basal cell carcinoma arising in a facial port wine stain without previous local radiotherapy has been reported. We now report a second case. METHODS: A 42-year-old female patient with eyelid basal cell carcinoma developing within a facial port wine stain underwent incisional biopsy, surgical excision and repair. RESULTS: The patient had a mass at the inner canthus of the left eye for two years. She had a left facial congenital port wine hemangioma involving the left eyelid, for which no topical treatment had been given. Clinical examination disclosed a 1.5*1.2 cm ulcerated skin mass with irregular borders in the medial canthal region involving the medial aspect of both upper and lower left eyelids. Incisional biopsy revealed basal cell carcinoma. She underwent surgical excision by Mohs' technique and subsequent reconstructive eyelid surgery. The wound healed well postoperatively. At 2 years of follow up the patient showed no recurrence. CONCLUSION: Patients with congenital facial port wine stain may develop basal cell carcinoma, and should be regularly monitored. PMID- 22447554 TI - Late-onset lens particle glaucoma as a consequence of posterior capsule rupture after pars plana vitrectomy. AB - PURPOSE: To report the treatment of late-onset lens particle glaucoma associated with posterior capsule rupture during pars plana vitrectomy. METHODS: Case report. RESULTS: A 33-year-old man had severe pain and impaired vision in the left eye after vitrectomy, associated with white fleck-like particles circulating in the anterior chamber. The intraocular pressure (IOP) was 38 mmHg. The anterior lens capsule was intact, however, lens particle glaucoma was diagnosed by the slit-lamp examination, B-mode ultrasonography and ultrasound biomicroscopy (UBM). The lens material was removed by irrigation-aspiration after the patient remained face down for two hours to facilitate precipitation of the lens material from the vitreous into the anterior chamber. IOP after the procedure was 21 mmHg. CONCLUSION: Posterior lens capsule may be disrupted during vitrectomy. Although the anterior lens capsule is intact, lens particle glaucoma should be considered when IOP increases with particulate matter circulating in the anterior chamber. Surgical removal of this material may be sufficient to control IOP without the need for additional glaucoma surgery. PMID- 22447555 TI - New applications of femtosecond laser in cataract surgery. AB - The high prevalence of blindness associated with cataract is an urgent public health issue. Femtosecond (FS) laser offers several advantages over conventional laser, such as high penetration, short pulse-duration and micro-precision. Since 2009, several types of FS laser systems have been applied to cataract surgery, offering novel approaches to the three steps of clear corneal incision (CCI) construction, anterior capsulotomy and lens fragmentation. Superior accuracy, predictability, reproducibility and safety have been achieved with use of this innovative technology. However, certain problems remain unresolved. More studies are needed to clarify the optimal utilization of FS in cataract surgery. The purpose of this review is to outline the features, applications, benefits and risks of FS in cataract surgery, and to discuss current scientific evidence and relevant commercial issues. PMID- 22447556 TI - Atypical severe central serous chorioretinopathy in a patient with systemic lupus erythematosus improved with a rapid reduction in glucocorticoid. AB - A 36-year-old woman was diagnosed with systemic lupus erythematosus (SLE). Seven days after beginning glucocorticoid treatment, she developed reduced visual acuity, and atypical severe central serous chorioretinopathy (CSC) was confirmed. Since glucocorticoid use is an important risk factor for CSC, the PSL was reduced, tacrolimus was added, and the visual acuity improved rapidly. Reduction in glucocorticoid combined with the use of immunosuppressive agents is one option for preventing a deterioration in atypical severe CSC while still controlling SLE. PMID- 22447557 TI - Mycophenolate mofetil versus intravenous cyclophosphamide for induction treatment of proliferative lupus nephritis in a Japanese population: a retrospective study. AB - OBJECTIVES: Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC. METHODS: The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity. RESULTS: The primary endpoint was achieved in nine (81.8 %) patients receiving MMF and in four (40.0 %) receiving IVC, with no significant difference between the two groups (p = 0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group. CONCLUSIONS: MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients. PMID- 22447558 TI - Human chorionic gonadotropin interactions with immobilized anti-hCG studied by quartz-crystal microbalance with dissipation monitoring. AB - Previous studies have found that commercial human pregnancy tests are often too insensitive to function to their advertised >99% accuracy. Improper orientation of proteins used for recognition of ligands in sensors can often prevent the binding site from being available to the ligand, thereby decreasing sensor sensitivity. We have developed a simple method for the immobilization of anti human chorionic gonadotropin on a sensor surface that maximizes its sensitivity by ensuring ligand binding sites are exposed and densely packed. This surface also has an improved regenerative capacity over previously reported human chorionic gonadotropin sensors, retaining 99% of initial sensitivity after six regeneration cycles with 8M urea. PMID- 22447559 TI - In ovo exposure to nonylphenol and bisphenol A resulted in dose-independent feminization of male gonads in Japanese quail (Coturnix japonica) embryos. AB - Sex reversal effects of nonylphenol and bisphenol A on the gonads in F(1) (AWE * WE) Japanese quail (Coturnix japonica) embryos were investigated using an in vivo screening model developed previously. The F(1) (AWE * WE) Japanese quail are a useful avian model because sex differentiation is confirmed by the plumage color before hatching, ruled by a criss-cross inheritance. The nonylphenol at 200, 2,000, 20,000, and 200,000 ng/egg and bisphenol A at 20, 200, 2,000, and 20,000 ng/egg were injected into the egg white just before incubation. At 16 d of incubation, embryos were subjected to a complete necropsy, and their gonads were both grossly observed and examined histopathologically and morphometrically. Grossly, genetic sex was confirmed because plumage color coincided completely with the external sex phenotype of the gonads in all embryos. Histopathologically, feminization of the male gonad, called ovotestis, developed in the left testis in all nonylphenol- and bisphenol A-treated groups. The incidence of the lesion in all treated groups was significantly higher than that in the control group, whereas there were no dose-dependent changes in the incidence and area of the ovotestis in both nonylphenol- and bisphenol A-treated groups. The present study revealed that nonylphenol and bisphenol A have a dose independent potential of ovotestis induction in the Japanese quail embryo. PMID- 22447560 TI - Infectious crystalline keratopathy associated with Klebsiella oxytoca. AB - PURPOSE: The purpose of this study is to report a novel case of a Klebsiella oxytoca-associated infectious crystalline keratopathy METHODS: This is a case report study. RESULTS: An 80-year-old woman presented with complaint of noticing a white spot in the left eye for 2 to 3 days, as well as mild soreness and discharge. Past ocular history was notable for a failed left corneal transplant for which she was taking prednisolone acetate 1 % twice per day. On slit-lamp examination, there was an extensive stromal ulcer and infiltrate in the inferior half of the transplant. Extending superiorly in the graft were branching, needle like deep stromal opacities, characteristic of infectious crystalline keratopathy. Diagnostic scrapings revealed Gram-negative bacilli, subsequently identified on culture as K. oxytoca. There was also light growth of Staphylococcus species. The patient was placed on double topical antibiotic therapy with moxifloxacin and fortified tobramycin. After 2 months of treatment there was gradual resolution of the infection. CONCLUSIONS: K. oxytoca is a microorganism which can be associated with clinical infectious crystalline keratopathy, presenting as a mixed infection along with Staphylococcus species. PMID- 22447561 TI - Potential role for magnetoencephalography in distinguishing low- and high-grade gliomas: a preliminary study with histopathological confirmation. AB - Gliomas are the most common form of tumor in the CNS and are exceptionally heterogeneous. Accurately characterizing gliomas, in terms of grade and type, is essential for predicting the rate of tumor progression. Histopathological grading and analysis based on biopsied tissue remains the gold standard, but non- and semi-invasive neuroimaging also plays a key role. Neuroimaging has been used to guide and optimize biopsies for several decades, but more recently molecular imaging and variants of MRI have shown promise in independently predicting glioma grade. Here we evaluated whether magnetoencephalographic (MEG) measurements of population-level physiology within the glioma space were predictive of the inherent grade of the tissue, based on definitive histopathological analyses. High-density MEG data were recorded from 11 patients who were undergoing functional mapping in preparation for resective surgery. The primary results indicated that glioma grade was positively correlated with the local amplitude of activity within the glioma space in the theta (4-7 Hz), alpha (8-14 Hz), and beta bands (14-30 Hz). Additionally, activity within the glioma was significantly elevated relative to the nonaffected homologue area in the same frequency bands. These results indicate that pathological levels of synchronization exist within the tumor space and that MEG may be a viable tool for noninvasively differentiating gliomas by their grade. Although these results should be considered preliminary and are only correlative in nature, these data suggest that MEG can potentially detect neurophysiological signatures or markers that predict the inherent grade of a glial tumor. PMID- 22447562 TI - Severe outbreaks of polyarthritis in kids caused by Mycoplasma mycoides subspecies capri in Sicily. PMID- 22447563 TI - Parvovirus enteritis in Eurasian badgers (Meles meles). PMID- 22447564 TI - Heart and respiratory rates and adrenal response to propofol or alfaxalone in rabbits. PMID- 22447565 TI - Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for conditioned overgeneralization. AB - The past two decades have brought dramatic progress in the neuroscience of anxiety due, in no small part, to animal findings specifying the neurobiology of Pavlovian fear-conditioning. Fortuitously, this neurally mapped process of fear learning is widely expressed in humans, and has been centrally implicated in the etiology of clinical anxiety. Fear-conditioning experiments in anxiety patients thus represent a unique opportunity to bring recent advances in animal neuroscience to bear on working, brain-based models of clinical anxiety. The current presentation details the neural basis and clinical relevance of fear conditioning, and highlights generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of clinical anxiety. Studies testing such generalization across a variety of anxiety disorders (panic, generalized anxiety disorder, and social anxiety disorder) with systematic methods developed in animals will next be presented. Finally, neural accounts of overgeneralization deriving from animal and human data will be described with emphasis given to implications for the neurobiology and treatment of clinical anxiety. PMID- 22447566 TI - Indomethacin-loaded polymer nanocarriers based on poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane): preparation, in vitro and in vivo evaluation. AB - The study is focused on the development of copolymers based on poly(2 hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]-undecane). The macromolecular compounds were synthesized by dispersion polymerization in the presence of the radical initiator 4,4'-azobis(cyanopentanoic acid) and using sodium lauryl sulfate as tensioactive compound and poly(aspartic acid) (PAS) as protective colloid. PAS presents biocompatibility and biodegradability, and assures the increase of the absorbent character for the new synthesized network, and also, can supplement the hydrogen bonds contributing to the stability of the achieved complexes. The prepared polymeric networks were characterized by FTIR, SEM, and thermogravimetric analyses. The dependence on the pH of the swelling degree equilibrium was also evaluated correlated also with different temperature values. The poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10 tetraoxaspiro [5.5]-undecane) copolymers were evaluated as matrix for indomethacin (INN) as model drug loaded onto these polymeric networks. The evaluation of the homogeneity distribution of the INN drug in polymeric network was made by near infrared chemical imaging (NIR-CI) and correspondingly statistical analysis. The pharmacokinetic profile was achieved performing the in vitro release of the INN drug from the polymeric network. The data resulted from the in vivo experimental studies, respectively the biocompatibility tests, somatic nociceptive experimental model (Tail flick test) and visceral nociceptive experimental model (Writhing test)-are also reported in the study. PMID- 22447567 TI - Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. AB - PARP inhibitors are currently being used in clinical trials to treat BRCA1- or BRCA2-defective tumors, based on the synthetic lethal interaction between PARP1 and BRCA1/2-mediated homologous recombination (HR). However, the molecular mechanisms that drive this synthetic lethality remain unclear. Here, we show increased levels of Mre11, a key component of MRN (Mre11-Rad50-Nbs1) complex that plays a role in the restart of stalled replication forks and enhanced resection at stalled replication forks in BRCA2-deficient cells. BRCA2-deficient cells also showed hypersensitivity to the Mre11 inhibitor mirin. Interestingly, PARP1 activity was required to protect stalled forks from Mre11-dependent degradation. Resistance to PARP inhibition in BRCA2-mutant cells led to reduced levels of Mre11 foci and also rescued their sensitivity to mirin. Taken together, our findings not only show that Mre11 activity is required for the survival of BRCA2 mutant cells but also elucidate roles for both the BRCA2 and PARP1 proteins in protecting stalled replication forks, which offers insight into the molecular mechanisms of the synthetic lethality between BRCA2 and PARP1. PMID- 22447568 TI - Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. AB - Antiangiogenic therapy leads to devascularization that limits tumor growth. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. In this study, we explored the hypothesis that hypoxia caused by antiangiogenic therapy induces tumor cell autophagy as a cytoprotective adaptive response, thereby promoting treatment resistance. Hypoxia-induced autophagy was dependent on signaling through the hypoxia-inducible factor-1alpha (HIF-1alpha)/AMPK pathway, and treatment of hypoxic cells with autophagy inhibitors caused a shift from autophagic to apoptotic cell death in vitro. In glioblastomas, clinically resistant to the VEGF-neutralizing antibody bevacizumab, increased regions of hypoxia and higher levels of autophagy mediating BNIP3 were found when compared with pretreatment specimens from the same patients. When treated with bevacizumab alone, human glioblastoma xenografts showed increased BNIP3 expression and hypoxia-associated growth, which could be prevented by addition of the autophagy inhibitor chloroquine. In vivo targeting of the essential autophagy gene ATG7 also disrupted tumor growth when combined with bevacizumab treatment. Together, our findings elucidate a novel mechanism of resistance to antiangiogenic therapy in which hypoxia-mediated autophagy promotes tumor cell survival. One strong implication of our findings is that autophagy inhibitors may help prevent resistance to antiangiogenic therapy used in the clinic. PMID- 22447569 TI - Mechanisms of ploidy increase in human cancers: a new role for cell cannibalism. AB - Aneuploidy is a hallmark of human cancers originating from abnormal mitoses. Many aneuploid cancer cells also have greater-than-diploid DNA content, suggesting that polyploidy is a common precursor to aneuploidy during tumor progression. Polyploid cells can originate from cell fusion, endoreplication, and cytokinesis failure. Recently we found that cell cannibalism by entosis, a form of cell engulfment involving live cells, also leads to polyploidy, as internalized cells disrupt cytokinesis of their engulfing cell hosts. By this mechanism, cannibalistic cell behavior could promote tumor progression by leading to aneuploidy. Here, we discuss cell cannibalism in cancer and other mechanisms that result in the formation of polyploid cancer cells. PMID- 22447570 TI - Slow motion picture of protein inactivation during single-droplet drying: a study of inactivation kinetics of L-glutamate dehydrogenase dried in an acoustic levitator. AB - A novel technique is presented to allow measurement of the kinetics of protein inactivation during drying of an acoustically levitated single droplet. Droplets/particles are removed from the acoustic field after various times during drying, and the state of the protein within them is analyzed. The influence of drying air temperature, relative humidity, buffer concentration, and the presence of a substrate on the inactivation of glutamate dehydrogenase is described. The kinetics of inactivation showed three distinct phases. The first phase of constant drying rate demonstrated little protein inactivation in the solution droplet. After the critical point of drying, a second phase was distinguishable when the surface temperature has risen sharply, but there is still only little inactivation of the protein in the solid particle. An onset point of rapid inactivation of the protein marked the start of the third phase that proceeded with approximately first-order rate kinetics. In the case of L-glutamate dehydrogenase, the evidence suggests that the residual moisture content of the solid and not the temperature alone determines the point of onset of protein inactivation. PMID- 22447571 TI - Pretreatment with low-dose beta-adrenergic antagonist therapy does not affect severity of Takotsubo cardiomyopathy. AB - BACKGROUND: Takotsubo cardiomyopathy is a syndrome of transient left ventricular dysfunction following acute emotional or physical stress without obstructive coronary artery disease. The leading hypothesis for the etiology is stress induced catecholamine surge. HYPOTHESIS: People taking outpatient beta-adrenergic receptor antagonist therapy have less-severe presentation and clinical course of Takotsubo cardiomyopathy. METHODS: We identified patients diagnosed with Takotsubo cardiomyopathy from October 2005 to January 2011 by analyzing our cardiac-catheterization database. Clinical records and angiograms were reviewed by 2 experienced observers independently to confirm the diagnosis. We collected clinical, demographic, laboratory, and angiographic data for the identified patients. We then compared the severity of myocardial dysfunction or damage (cardiac enzymes, left ventricular end diastolic pressure, and left ventricular ejection fraction) between patients taking outpatient beta-adrenergic antagonist therapy upon admission vs those who were not. Arrival and peak values for cardiac enzymes were analyzed when available. Analysis of parameters related to the severity of myocardial dysfunction or damage was conducted using the Mann-Whitney U test. Means for age were compared using the Student t test. Statistical significance was set at P < 0.05 (2-tailed). RESULTS: Out of 64 patients identified, 16 (25%) were on one of 3 beta-adrenergic antagonists on presentation: metoprolol succinate, metoprolol tartrate, or atenolol, with mean doses of 75 mg daily, 52.5 mg twice daily, and 37.5 mg daily, respectively. Patients on beta-blockers were older (mean age 73.1 years vs 66 years; P < 0.05). There was no statistically significant difference in levels of cardiac enzymes, left ventricular end diastolic pressure, or left ventricular ejection fraction between the 2 groups. CONCLUSION: Prior therapy with low-dose beta-adrenergic antagonists does not affect the severity of presentation and clinical course of Takotsubo cardiomyopathy as measured by common markers of myocardial dysfunction. PMID- 22447572 TI - Isolated beta-turn model systems investigated by combined IR/UV spectroscopy. AB - The functionality of bioactive molecules sensitively depends on their structure. For the investigation of intrinsic structural properties, molecular beam experiments combined with laser spectroscopy have proven to be a suitable tool. Herein we present an analysis of the two isolated tripeptide model systems Ac-Phe Tyr(Me)-NHMe and Boc-Phe-Tyr(Me)-NHMe. For this purpose, mass-selective combined IR/UV spectroscopy is applied to both substances in a molecular beam experiment. The comparison of the experimental data with DFT calculations, including different functionals as well as dispersion corrections, allows an assignment of both tripeptide models to beta-turns formed independently from the protection groups and supported by the interaction of the two aromatic chromophores. PMID- 22447573 TI - A robust porous metal-organic framework with a new topology that demonstrates pronounced porosity and high-efficiency sorption/selectivity properties of small molecules. AB - A robust porous metal-organic framework (MOF), [Co(3)(ndc)(HCOO)(3)(MU(3) OH)(H(2)O)](n) (1) (H(2)ndc=5-(4-pyridyl)-isophthalic acid), was synthesized with pronounced porosity. MOF 1 contained two different types of nanotubular channels, which exhibited a new topology with the Schlafli symbol of {4(2).6(5).8(3)}{4(2).6}. MOF 1 showed high-efficiency for the selective sorption of small molecules, including the energy-correlated gases of H(2), CH(4), and CO(2), and environment-correlated steams of alcohols, acetone, and pyridine. Gas sorption experiments indicated that MOF 1 exhibited not only a high CO(2)-uptake (25.1 wt % at 273 K/1 bar) but also the impressive selective sorption of CO(2) over N(2) and CH(4). High H(2)-uptake (2.04 wt % at 77 K/1 bar) was also observed. Moreover, systematic studies on the sorption of steams of organic molecules displayed excellent capacity for the sorption of the homologous series of alcohols (C(1)-C(5)), acetone, pyridine, as well as water. PMID- 22447574 TI - Acacetin attenuates neuroinflammation via regulation the response to LPS stimuli in vitro and in vivo. AB - Under normal conditions in the brain, microglia play roles in homeostasis regulation and defense against injury. However, over-activated microglia secrete proinflammatory and cytotoxic factors that can induce progressive brain disorders, including Alzheimer's disease, Parkinson's disease and ischemia. Therefore, regulation of microglial activation contributes to the suppression of neuronal diseases via neuroinflammatory regulation. In this study, we investigated the effects of acacetin (5,7-dihydroxy-4'-methoxyflavone), which is derived from Robinia pseudoacacia, on neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells and in animal models of neuroinflammation and ischemia. Acacetin significantly inhibited the release of nitric oxide (NO) and prostaglandin E(2) and the expression of inducible NO synthase and cyclooxygenase 2 in LPS-stimulated BV-2 cells. The compound also reduced proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, and inhibited the activation of nuclear factor-kappaB and p38 mitogen-activated protein kinase. In an LPS-induced neuroinflammation mouse model, acacetin significantly suppressed microglial activation. Moreover, acacetin reduced neuronal cell death in an animal model of ischemia. These results suggest that acacetin may act as a potential therapeutic agent for brain diseases involving neuroinflammation. PMID- 22447575 TI - Optimization of culture medium composition for manganese peroxidase and tyrosinase production during Reactive Black 5 decolourization by the yeast Trichosporon akiyoshidainum. AB - Decolourization and degradation of the diazo dye Reactive Black 5 was carried out by the yeast Trichosporon akiyoshidainum. A nine-factor Plackett-Burman design was employed for the study and optimization of the decolourization process and production of manganese peroxidase (MnP) and tyrosinase activities. In the present study, 26 individual experiments were conducted and three responses were evaluated. Raising yeast extract concentration significantly enhanced decolourization and MnP production. Carbon and nitrogen sources, glucose and (NH4)2 SO4, showed no significant effect on any response over the concentration range tested. Other culture medium components, such as CaCl2 or MgSO4, could be excluded from the medium formula, as they had no effect on the evaluated responses. Metal ions (Fe, Cu and Mn) showed different effects on decolourization and enzymatic activities. Addition of copper significantly enhanced MnP activity and decreased dye decolourization. On the contrary, iron had a positive effect on decolourization and no effect on enzyme production. Oddly, increasing manganese concentration had a positive effect on tyrosinase production without affecting decolourization or MnP activity. These results strongly suggest that dye decolourization should be regarded as a complex multi-enzymatic process, where optimal medium composition should arise as a compromise between those optimal for each implied enzyme production. PMID- 22447576 TI - Modulation of gene expression using electrospun scaffolds with templated architecture. AB - The fabrication of biomimetic scaffolds is a critical component to fulfill the promise of functional tissue-engineered materials. We describe herein a simple technique, based on printed circuit board manufacturing, to produce novel templates for electrospinning scaffolds for tissue-engineering applications. This technique facilitates fabrication of electrospun scaffolds with templated architecture, which we defined as a scaffold's bulk mechanical properties being driven by its fiber architecture. Electrospun scaffolds with templated architectures were characterized with regard to fiber alignment and mechanical properties. Fast Fourier transform analysis revealed a high degree of fiber alignment along the conducting traces of the templates. Mechanical testing showed that scaffolds demonstrated tunable mechanical properties as a function of templated architecture. Fibroblast-seeded scaffolds were subjected to a peak strain of 3 or 10% at 0.5 Hz for 1 h. Exposing seeded scaffolds to the low strain magnitude (3%) significantly increased collagen I gene expression compared to the high strain magnitude (10%) in a scaffold architecture-dependent manner. These experiments indicate that scaffolds with templated architectures can be produced, and modulation of gene expression is possible with templated architectures. This technology holds promise for the long-term goal of creating tissue-engineered replacements with the biomechanical and biochemical make-up of native tissues. PMID- 22447577 TI - Audiometric asymmetry and tinnitus laterality. AB - OBJECTIVES/HYPOTHESIS: To identify an optimal audiometric asymmetry index for predicting tinnitus laterality. STUDY DESIGN: Retrospective medical record review. METHODS: Data from adult tinnitus patients (80 men and 44 women) were extracted for demographic, audiometric, tinnitus laterality, and related information. The main measures were sensitivity, specificity, positive predictive value (PPV), and receiver operating characteristic (ROC) curves. RESULTS: Three audiometric asymmetry indices were constructed using one, two, or three frequency elements to compute the average interaural threshold difference (aITD). Tinnitus laterality predictive performance of a particular index was assessed by increasing the cutoff or minimum magnitude of the aITD from 10 to 35 dB in 5-dB steps to determine its ROC curve. Single frequency index performance was inferior to the other two (P < .05). Double and triple frequency indices were indistinguishable (P > .05). Two adjoining frequency elements with aITD >= 15 dB performed optimally for predicting tinnitus laterality (sensitivity = 0.59, specificity = 0.71, and PPV = 0.76). Absolute and relative magnitudes of hearing loss in the poorer ear were uncorrelated with tinnitus distress. CONCLUSIONS: An optimal audiometric asymmetry index to predict tinnitus laterality is one whereby 15 dB is the minimum aITD of two adjoining frequencies, inclusive of the maximal ITD. Tinnitus laterality dependency on magnitude of interaural asymmetry may inform design and interpretation of neuroimaging studies. Monaural acoustic tinnitus therapy may be an initial consideration for asymmetric hearing loss meeting the criterion of aITD >= 15 dB. PMID- 22447578 TI - Impact of comorbidity on medication use in elderly patients with cardiovascular diseases: the OCTOCARDIO study. AB - BACKGROUND: Recommended medications are under-prescribed in elderly patients with atrial fibrillation (AF), coronary artery disease (CAD), and congestive heart failure (CHF). The relationship between under-prescribing and comorbidity is unclear. DESIGN: Single-day observational study. METHODS: Analysis of medications taken by patients aged 80 years or over at the time of their admission to cardiology units of 32 French hospitals. Comorbidity was measured using the Charlson comorbidity index (CCI). RESULTS: The study included 510 patients (57% men, mean age 85 years). History of AF, CHF, and CAD was present in 213 (42%), 199 (39%), and 187 (37%) patients, respectively. CCI was 0 in 110 (22%), 1-2 in 215 (42%), and >=3 in 185 (36%) patients. Vitamin K antagonists (VKA) were prescribed to 105 (49%) and aspirin to 86 (40%) patients with AF. CCI did not influence VKA prescription but influenced aspirin use, with lower prescription rates in patients with CCI 1-2 than CCI 0 or CCI >=3 (p = 0.02). In CHF, angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers were prescribed to 80 (40%) and 96 (48%) patients, respectively. Rates of prescription of ACEI, beta-blockers, statins, and aspirin in patients with CAD were 43%, 56%, 56%, and 66%, respectively. CCI level did not influence any medication use in CHF and CAD. CONCLUSION: Even in the absence of comorbidity, elderly patients with major cardiovascular diseases are denied from indicated medical treatments probably because of their age alone. Implementing measures to enhance awareness of treatment benefits and promote appropriate prescribing is necessary. PMID- 22447579 TI - Group cognitive and behavioral therapy and bibliotherapy for hoarding: a pilot trial. AB - BACKGROUND: Group cognitive behavioral treatments (GCBTs) for hoarding have produced modest benefits. The current study examined whether the outcomes of a specialized GCBT improve upon bibliotherapy (BIB) for hoarding, as part of a stepped care model. We also explored whether additional home assistance enhanced GCBT outcomes. METHODS: Hoarding patients (n = 38) were randomized and completed one of three conditions: (1) GCBT with nonclinician home assistants (GCBT+HA; N = 11), (2) GCBT without HA (CGBT; N = 14), and (3) BIB (N = 13). All GCBT participants received 20 weekly group sessions and four home visits by a group co therapist. GCBT+HA groups received four additional visits by a nonclinician coach. BIB participants were assigned a self-help book describing specific skills to reduce hoarding over the 20-week period. All participants were assessed by self-report at baseline, mid-treatment, and posttreatment. The sample averaged 57 years old and was mainly female, White, highly educated, employed, and living alone. RESULTS: GCBT+HA and GCBT participants showed significant reductions on hoarding and depression symptoms, whereas BIB did not. GCBT+HA and GCBT benefited substantially and similarly on the saving inventory-revised (reductions of 29.9 and 23.3%, respectively) and SI-R (Saving Inventory-Revised) (reductions of 26.5 and 25.4%), whereas BIB participants showed very limited improvement (9% reduction) on both measures. CONCLUSION: This study provides support for the efficacy of GCBT for hoarding. The effect of adding nonclinician home assistance was not significant in this small sample. BIB was not sufficient to improve hoarding symptoms. The findings have implications for a stepped care model for treating hoarding (e.g., the benefits of psycho-education via BIB, added benefits of extra in-home visits) and suggest the need to further examine the role of in home hoarding coaches. PMID- 22447580 TI - Nanoscale surface characterization and miscibility study of a spray-dried injectable polymeric matrix consisting of poly(lactic-co-glycolic acid) and polyvinylpyrrolidone. AB - Injectable controlled-release formulations are of increasing interest for the treatment of chronic diseases. This study aims to develop and characterize a polymeric matrix for intramuscular or subcutaneous injection, consisting of two biocompatible polymers, particularly suitable for formulating poorly soluble drugs. For this matrix, the water-insoluble polymer poly(lactic-co-glycolic acid) (PLGA) is combined with the water-soluble polymer polyvinylpyrrolidone (PVP). Microparticles of these two polymers were prepared by spray drying. The phase behavior of the samples was studied by means of modulated differential scanning calorimetry and the results showed that phase separation occurred in the bulk sample through evidence of two mixed amorphous phases, namely, a PLGA-rich phase and a PVP-rich phase. Characterization of the samples by scanning electron microscopy demonstrated that the spray-dried particles were hollow with a thin shell. Because of the importance in relation to stability and drug release, information about the surface of the microparticles was collected by different complementary surface analysis techniques. Atomic force microscopy gathered information about the morphology and phase behavior of the microparticle surface. Time-of-flight secondary ion mass spectrometry analysis of the particles revealed that the surface consisted mainly of the PLGA-rich phase. This was confirmed by X ray photoelectron spectroscopy at an increased sampling depth (~ 10 nm). Nanothermal analysis proved to be an innovative way to thermally detect the presence of the PLGA-dominated surface layer and the underlying PVP phase. Taken together, this information provides a rational basis for predicting the likely drug release behavior this formulation will display. PMID- 22447581 TI - Effects of Mucuna pruriens protease inhibitors on Echis carinatus venom. AB - The medicinal plant Mucuna pruriens, with reputed anti-snake venom properties has been reported to contain a kunitz-type trypsin inhibitor. This study was undertaken to further evaluate the protease inhibitory potential of gpMuc, a multiform glycoprotein, and other protein fractions from M. pruriens seeds against trypsin, chymotrypsin, Echis carinatus snake venom, ecarin and thrombin. The results showed that gpMuc inhibited both trypsin and chymotrypsin activities and was thermally stable, maintaining its trypsin inhibitory activity at temperatures of up to 50 degrees C. Its structural conformation was also maintained at pH ranges of 4-7. Immunoreactivity study confirms that it contains protease-recognizing epitope on one of its isoforms. The whole protein extract of M. pruriens seeds inhibited prothrombin activation by ecarin and whole E. carinatus venom, and also thrombin-like activity using chromogenic assay. PMID- 22447582 TI - Synthesis and characterization of antibacterial dental monomers and composites. AB - The objective of this study is to synthesize antibacterial methacrylate and methacrylamide monomers and formulate antibacterial fluoride-releasing dental composites. Three antibacterial methacrylate or methacrylamide monomers containing long-chain quaternary ammonium fluoride, 1,2-methacrylamido-N,N,N trimethyldodecan-1-aminium fluoride (monomer I), N-benzyl-11-(methacryloyloxy) N,N-dimethylundecan-1-aminium fluoride (monomer II), and methacryloxyldecylpyridinium fluoride (monomer III) have been synthesized and analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The cytotoxicity test and bactericidal test against Streptococcus mutans indicate that antibacterial monomer II is superior to monomers I and III. A series of dental composites containing 0-6% of antibacterial monomer II have been formulated and tested for degree of conversion (DC), flexure strength, water sorption, solubility, and inhibition of S. mutans biofilms. An antibacterial fluoride-releasing dental composite has also been formulated and tested for flexure strength and fluoride release. The dental composite containing 3% of monomer II has a significant effect against S. mutans biofilm formation without major adverse effects on its physical and mechanical properties. The new antibacterial monomers can be used together with the fluoride-releasing monomers containing a ternary zirconiun-fluoride chelate to formulate a new antibacterial fluoride-releasing dental composite. Such a new dental composite is expected to have higher anticaries efficacy and longer service life. PMID- 22447583 TI - Some evidence for the formation of an azo bond during the electroreduction of diazonium salts on Au substrates. AB - Molecular films obtained by electrochemical reduction of diazoniuim tetrafluoroborate salts [4-carboxybenzene (PhCOOH) and 4-amino-(2,3,5,6 tetrafluoro)-carboxybenzene (PhF(4)COOH)] on Au substrates and post functionalization with an osmium pyridil-bipyridine complex are studied by a combination of X-ray photoelectron (XPS) and polarization-modulation infrared reflection absorption spectroscopy (PM-IRRAS). The spectroscopic evidence suggests the formation of N=N bonds tethering the complexes to Au. The surface coverage of the azo-bonded osmium complexes strongly depends on the electrode potential. The resulting tethered osmium redox centres were characterized by cyclic voltammetry and impedance spectroscopy. Similar electron transfer-rate constants were measured for both fluorinated and non fluorinated benzene-linked Os complexes. PMID- 22447584 TI - Role of extracellular transaldolase from Bifidobacterium bifidum in mucin adhesion and aggregation. AB - The ability of bifidobacteria to establish in the intestine of mammals is among the main factors considered to be important for achieving probiotic effects. The role of surface molecules from Bifidobacterium bifidum taxon in mucin adhesion capability and the aggregation phenotype of this bacterial species was analyzed. Adhesion to the human intestinal cell line HT29 was determined for a collection of 12 B. bifidum strains. In four of them-B. bifidum LMG13195, DSM20456, DSM20239, and A8-the involvement of surface-exposed macromolecules in the aggregation phenomenon was determined. The aggregation of B. bifidum A8 and DSM20456 was abolished after treatment with proteinase K, this effect being more pronounced for the strain A8. Furthermore, a mucin binding assay of B. bifidum A8 surface proteins showed a high adhesive capability for its transaldolase (Tal). The localization of this enzyme on the surface of B. bifidum A8 was unequivocally demonstrated by immunogold electron microscopy experiments. The gene encoding Tal from B. bifidum A8 was expressed in Lactococcus lactis, and the protein was purified to homogeneity. The pure protein was able to restore the autoaggregation phenotype of proteinase K-treated B. bifidum A8 cells. A recombinant L. lactis strain, engineered to secrete Tal, displayed a mucin- binding level more than three times higher than the strain not producing the transaldolase. These findings suggest that Tal, when exposed on the cell surface of B. bifidum, could act as an important colonization factor favoring its establishment in the gut. PMID- 22447585 TI - A loss-of-function mutation in the PAS kinase Rim15p is related to defective quiescence entry and high fermentation rates of Saccharomyces cerevisiae sake yeast strains. AB - Sake yeast cells have defective entry into the quiescent state, allowing them to sustain high fermentation rates. To reveal the underlying mechanism, we investigated the PAS kinase Rim15p, which orchestrates initiation of the quiescence program in Saccharomyces cerevisiae. We found that Rim15p is truncated at the carboxyl terminus in modern sake yeast strains as a result of a frameshift mutation. Introduction of this mutation or deletion of the full-length RIM15 gene in a laboratory strain led to a defective stress response, decreased synthesis of the storage carbohydrates trehalose and glycogen, and impaired G(1) arrest, which together closely resemble the characteristic phenotypes of sake yeast. Notably, expression of a functional RIM15 gene in a modern sake strain suppressed all of these phenotypes, demonstrating that dysfunction of Rim15p prevents sake yeast cells from entering quiescence. Moreover, loss of Rim15p or its downstream targets Igo1p and Igo2p remarkably improved the fermentation rate in a laboratory strain. This finding verified that Rim15p-mediated entry into quiescence plays pivotal roles in the inhibition of ethanol fermentation. Taken together, our results suggest that the loss-of-function mutation in the RIM15 gene may be the key genetic determinant of the increased ethanol production rates in modern sake yeast strains. PMID- 22447587 TI - Intramolecular regulation of the sequence-specific mRNA interferase activity of MazF fused to a MazE fragment with a linker cleavable by specific proteases. AB - The genomes of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) consist of single-stranded RNA encoding polyproteins, which are processed to individual functional proteins by virus-encoded specific proteases. These proteases have been used as targets for drug development. Here, instead of targeting these proteases to inhibit viral infection, we utilized the protease activity to activate a toxic protein to prevent viral infection. We engineered the MazE-MazF antitoxin-toxin system of Escherichia coli to fuse a C-terminal 41 residue fragment of antitoxin MazE to the N-terminal end of toxin MazF with a linker having a specific protease cleavage site for either HIV PR (HIV-1 protease), NS3 protease (HCV protease), or factor Xa. These fusion proteins formed a stable dimer (instead of the MazF(2)-MazE(2)-MazF(2) heterohexamer in nature) to inactivate the ACA (sequence)-specific mRNA interferase activity of MazF. When the fusion proteins were incubated with the corresponding proteases, the MazE fragment was cleaved from the fusion proteins, releasing active MazF, which then acted as an ACA-specific mRNA interferase cleaving single-stranded MS2 phage RNA. The intramolecular regulation of MazF toxicity by proteases as demonstrated may provide a novel approach for preventive and therapeutic treatments of infection by HIV-1, HCV, and other single-stranded RNA viruses. PMID- 22447588 TI - Denitrification and nitrogen fixation dynamics in the area surrounding an individual ghost shrimp (Neotrypaea californiensis) burrow system. AB - Bioturbated sediments are thought of as areas of increased denitrification or fixed-nitrogen (N) loss; however, recent studies have suggested that not all N may be lost from these environments, with some N returning to the system via microbial dinitrogen (N(2)) fixation. We investigated denitrification and N(2) fixation in an intertidal lagoon (Catalina Harbor, CA), an environment characterized by bioturbation by thalassinidean shrimp (Neotrypaea californiensis). Field studies were combined with detailed measurements of denitrification and N(2) fixation surrounding a single ghost shrimp burrow system in a narrow aquarium (15 cm by 20 cm by 5 cm). Simultaneous measurements of both activities were performed on samples taken within a 1.5-cm grid for a two dimensional illustration of their intensity and distribution. These findings were then compared with rate measurements performed on bulk environmental sediment samples collected from the lagoon. Results for the aquarium indicated that both denitrification and N(2) fixation have a patchy distribution surrounding the burrow, with no clear correlation to each other, sediment depth, or distance from the burrow. Field denitrification rates were, on average, lower in a bioturbated region than in a seemingly nonbioturbated region; however, replicates showed very high variability. A comparison of denitrification field results with previously reported N(2) fixation rates from the same lagoon showed that in the nonbioturbated region, depth-integrated (10 cm) denitrification rates were higher than integrated N(2) fixation rates (~9 to 50 times). In contrast, in the bioturbated sediments, depending on the year and bioturbation intensity, some (~6.2%) to all of the N lost via denitrification might be accounted for via N(2) fixation. PMID- 22447586 TI - Community structure analysis of methanogens associated with rumen protozoa reveals bias in universal archaeal primers. AB - The diversity of protozoan-associated methanogens in cattle was investigated using five universal archaeal small-subunit (SSU) rRNA gene primer sets. Methanobrevibacter spp. and rumen cluster C (distantly related to Thermoplasma spp.) were predominant. Significant differences in species composition among libraries indicate that some primers used previously to characterize rumen methanogens exhibit biased amplification. PMID- 22447589 TI - Influence of substrate mineralogy on bacterial mineralization of calcium carbonate: implications for stone conservation. AB - The influence of mineral substrate composition and structure on bacterial calcium carbonate productivity and polymorph selection was studied. Bacterial calcium carbonate precipitation occurred on calcitic (Iceland spar single crystals, marble, and porous limestone) and silicate (glass coverslips, porous sintered glass, and quartz sandstone) substrates following culturing in liquid medium (M 3P) inoculated with different types of bacteria (Myxococcus xanthus, Brevundimonas diminuta, and a carbonatogenic bacterial community isolated from porous calcarenite stone in a historical building) and direct application of sterile M-3P medium to limestone and sandstone with their own bacterial communities. Field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), powder X-ray diffraction (XRD), and 2-dimensional XRD (2D-XRD) analyses revealed that abundant highly oriented calcite crystals formed homoepitaxially on the calcitic substrates, irrespective of the bacterial type. Conversely, scattered spheroidal vaterite entombing bacterial cells formed on the silicate substrates. These results show that carbonate phase selection is not strain specific and that under equal culture conditions, the substrate type is the overruling factor for calcium carbonate polymorph selection. Furthermore, carbonate productivity is strongly dependent on the mineralogy of the substrate. Calcitic substrates offer a higher affinity for bacterial attachment than silicate substrates, thereby fostering bacterial growth and metabolic activity, resulting in higher production of calcium carbonate cement. Bacterial calcite grows coherently over the calcitic substrate and is therefore more chemically and mechanically stable than metastable vaterite, which formed incoherently on the silicate substrates. The implications of these results for technological applications of bacterial carbonatogenesis, including building stone conservation, are discussed. PMID- 22447590 TI - Comparative analysis of eukaryotic marine microbial assemblages from 18S rRNA gene and gene transcript clone libraries by using different methods of extraction. AB - Eukaryotic marine microbes play pivotal roles in biogeochemical nutrient cycling and ecosystem function, but studies that focus on the protistan biogeography and genetic diversity lag-behind studies of other microbes. 18S rRNA PCR amplification and clone library sequencing are commonly used to assess diversity that is culture independent. However, molecular methods are not without potential biases and artifacts. In this study, we compare the community composition of clone libraries generated from the same water sample collected at the San Pedro Ocean Time Series (SPOTs) station in the northwest Pacific Ocean. Community composition was assessed using different cell lysis methods (chemical and mechanical) and the extraction of different nucleic acids (DNA and RNA reverse transcribed to cDNA) to build Sanger ABI clone libraries. We describe specific biases for ecologically important phylogenetic groups resulting from differences in nucleic acid extraction methods that will inform future designs of eukaryotic diversity studies, regardless of the target sequencing platform planned. PMID- 22447591 TI - Apparent loss of Vibrio vulnificus from North Carolina oysters coincides with a drought-induced increase in salinity. AB - Despite years of successful isolation of Vibrio vulnificus from estuarine waters, beginning in 2007, it was extremely difficult to culture V. vulnificus from either North Carolina estuarine water or oyster samples. After employing culture based methods as well as PCR and quantitative PCR for the detection of V. vulnificus, always with negative results, we concluded that this pathogen had become nearly undetectable in the North Carolina estuarine ecosystem. We ensured that the techniques were sound by seeding North Carolina oysters with V. vulnificus and performing the same tests as those previously conducted on unadulterated oysters. V. vulnificus was readily detected in the seeded oysters using both classes of methods. Furthermore, oysters were obtained from the Gulf of Mexico, and V. vulnificus was easily isolated, confirming that the methodology was sound but that the oysters and waters of North Carolina were lacking the V. vulnificus population studied for decades. Strikingly, the apparent loss of detectable V. vulnificus coincided with the most severe drought in the history of North Carolina. The drought continued until the end of 2009, with an elevated water column salinity being observed throughout this period and with V. vulnificus being nearly nonexistent. When salinities returned to normal after the drought abated in 2010, we were again able to routinely isolate V. vulnificus from the water column, although we were still unable to culture it from oysters. We suggest that the oysters were colonized with a more salt-tolerant bacterium during the drought, which displaced V. vulnificus and may be preventing recolonization. PMID- 22447592 TI - Indole-3-glycerol-phosphate synthase is recognized by a cold-inducible group II chaperonin in Thermococcus kodakarensis. AB - Thermococcus kodakarensis optimally grows at 85 degrees C and possesses two chaperonins, cold-inducible CpkA and heat-inducible CpkB. Gene disruptants DA1 (DeltacpkA) and DB1 (DeltacpkB) showed decreased cell growth at 60 degrees C and 93 degrees C, respectively. The DB2 mutant (DeltacpkAcpkB DeltacpkB), whose cpkB gene was expressed under the control of the cpkA promoter, did not grow at 60 degrees C, and the DB3 mutant [DeltacpkA(1-524)cpkB(1-524) DeltacpkB], whose CpkA amino acid residues 1 to 524 were replaced with corresponding CpkB residues that maintained the C-terminal region intact, grew at 60 degrees C, implying that the CpkA C-terminal region plays a key role in cell growth at 60 degrees C. To screen for specific CpkA target proteins, comparative pulldown studies with anti-Cpk were performed using cytoplasmic fractions from DA1 cells cultivated at 93 degrees C and DB1 cells cultivated at 60 degrees C. Among the proteins coprecipitated with anti-Cpk, TK0252, encoding indole-3-glycerol-phosphate synthase (TrpC), showed the highest Mascot score. Counter-pulldown experiments were also performed on DA1 and DB1 extracts using anti-TrpC. CpkA coimmunoprecipitated with anti-TrpC while CpkB did not. The results obtained indicate that TrpC is a specific target for CpkA. The effects of Cpks on denatured TrpC were then examined. The refolding of partially denatured TrpC was accelerated by the addition of CpkA but not by adding CpkB. DA1 cells grew optimally in minimal medium only in the presence of tryptophan but hardly grew in the absence of tryptophan at 60 degrees C. It has been suggested that a lesion of functional TrpC is caused by cpkA disruption, resulting in tryptophan auxotrophy. PMID- 22447593 TI - Feasibility of quantitative environmental surveillance in poliovirus eradication strategies. AB - The progress of the Global Polio Eradication Initiative is monitored by acute flaccid paralysis (AFP) surveillance supplemented with environmental surveillance in selected areas. To assess the sensitivity of environmental surveillance, stools from (re)vaccinated elderly persons with a low seroprevalence and from wastewater were concurrently collected and analyzed in the Netherlands over a prolonged period of time. A total number of 228 healthy individuals with different levels of immunity were challenged with monovalent oral polio vaccine serotype 1 or 3. Poliovirus concentrations were determined by the titration of fecal suspensions on poliovirus-sensitive L20B cells and of sewage concentrates by L20B monolayer plaque assay. Almost half of the individuals (45%) shed poliovirus on day 3 after challenge, which peaked (57%) on day 8 with an average poliovirus excretion of 1.3 * 10(5) TCID(50) per g of feces and gradually decreased to less than 5% on day 42. The virus concentrations in sewage peaked on days 6 to 8 at approximately 100 PFU per liter, remained high until day 14, and subsequently decreased to less than 10 PFU per liter on day 29. The estimated poliovirus concentration in sewage approximated the measured initial virus excretion in feces, within 1 log(10) variation, resulting in a sensitivity of detection of 100 infected but mostly asymptomatic individuals in tens of thousands of individuals. An additional second peak observed in sewage may indicate secondary transmission missed by enterovirus or AFP surveillance in patients. This enables the detection of circulating poliovirus by environmental surveillance, supporting its feasibility as an early warning system. PMID- 22447594 TI - Direct conversion of xylan to ethanol by recombinant Saccharomyces cerevisiae strains displaying an engineered minihemicellulosome. AB - Arabinoxylan is a heteropolymeric chain of a beta-1,4-linked xylose backbone substituted with arabinose residues, representing a principal component of plant cell walls. Here we developed recombinant Saccharomyces cerevisiae strains as whole-cell biocatalysts capable of combining hemicellulase production, xylan hydrolysis, and hydrolysate fermentation into a single step. These strains displayed a series of uni-, bi-, and trifunctional minihemicellulosomes that consisted of a miniscaffoldin (CipA3/CipA1) and up to three chimeric enzymes. The miniscaffoldin derived from Clostridium thermocellum contained one or three cohesin modules and was tethered to the cell surface through the S. cerevisiae a agglutinin adhesion receptor. Up to three types of hemicellulases, an endoxylanase (XynII), an arabinofuranosidase (AbfB), and a beta-xylosidase (XlnD), each bearing a C-terminal dockerin, were assembled onto the miniscaffoldin by high-affinity cohesin-dockerin interactions. Compared to uni- and bifunctional minihemicellulosomes, the resulting quaternary trifunctional complexes exhibited an enhanced rate of hydrolysis of arabinoxylan. Furthermore, with an integrated d-xylose-utilizing pathway, the recombinant yeast displaying the bifunctional minihemicellulosome CipA3-XynII-XlnD could simultaneously hydrolyze and ferment birchwood xylan to ethanol with a yield of 0.31 g per g of sugar consumed. PMID- 22447595 TI - New sequence types and multidrug resistance among pathogenic Escherichia coli isolates from coastal marine sediments. AB - The spread of antibiotic-resistant microorganisms is widely recognized, but data about their sources, presence, and significance in marine environments are still limited. We examined 109 Escherichia coli strains from coastal marine sediments carrying virulence genes for antibiotic susceptibility, specific resistance genes, prevalence of class 1 and 2 integrons, and sequence type. Antibiotic resistance was found in 35% of strains, and multiple resistances were found in 14%; the resistances detected most frequently were against tetracycline (28%), ampicillin (16.5%), trimethoprim-sulfamethoxazole (13%), and streptomycin (7%). The highest prevalence of resistant strains was in phylogenetic group A, whereas phylogroup B2 exhibited a significantly lower frequency than all the other groups. Sixty percent of multiresistant strains harbored class 1 or 2 integrase genes, and about 50% carried resistance genes (particularly dfrA and aadA) linked to a class 1 integron. Multilocus sequence typing of 14 selected strains identified eight different types characteristic of extraintestinal pathogens and three new allelic combinations. Our data suggest that coastal marine sediment may be a suitable environment for the survival of pathogenic and antimicrobial resistant E. coli strains capable of contributing to resistance spread via integrons among benthic bacteria, and they highlight a role for these strains in the emergence of new virulent genotypes. PMID- 22447596 TI - Novel Phakopsora pachyrhizi extracellular proteins are ideal targets for immunological diagnostic assays. AB - Phakopsora pachyrhizi, the causal agent of Asian soybean rust (ASR), continues to spread across the southeast and midsouth regions of the United States, necessitating the use of fungicides by producers. Our objective in this research was to identify ASR proteins expressed early during infection for the development of immunodiagnostic assays. We have identified and partially characterized a small gene family encoding extracellular proteins in the P. pachyrhizi urediniospore wall, termed PHEPs (for Phakopsora extracellular protein). Two highly expressed protein family members, PHEP 107 and PHEP 369, were selected as ideal immunodiagnostic targets for antibody development, after we detected PHEPs in plants as early as 3 days postinfection (dpi). Monoclonal antibodies (MAbs; 2E8E5-1 and 3G6H7-3) generated against recombinant PHEP 369 were tested for sensitivity against the recombinant protein and extracts from ASR-infected plants and for specificity against a set of common soybean pathogens. These antibodies should prove applicable in immunodiagnostic assays to detect infected soybeans and to identify ASR spores from sentinel surveillance plots. PMID- 22447597 TI - Genetic analysis of the Cronobacter sakazakii O4 to O7 O-antigen gene clusters and development of a PCR assay for identification of all C. sakazakii O serotypes. AB - The Gram-negative bacterium Cronobacter sakazakii is an emerging food-borne pathogen that causes severe invasive infections in neonates. Variation in the O antigen lipopolysaccharide in the outer membrane provides the basis for Gram negative bacteria serotyping. The O-antigen serotyping scheme for C. sakazakii, which includes seven serotypes (O1 to O7), has been recently established, and the O-antigen gene clusters and specific primers for three C. sakazakii serotypes (O1, O2, and O3) have been characterized. In this study, the C. sakazakii O4, O5, O6, and O7 O-antigen gene clusters were sequenced, and gene functions were predicted on the basis of homology. C. sakazakii O4 shared a similar O-antigen gene cluster with Escherichia coli O103. The general features and anomalies of all seven C. sakazakii O-antigen gene clusters were evaluated and the relationship between O-antigen structures and their gene clusters were investigated. Serotype-specific genes for O4 to O7 were identified, and a molecular serotyping method for all C. sakazakii O serotypes, a multiplex PCR assay, was developed by screening against 136 strains of C. sakazakii and closely related species. The sensitivity of PCR-based serotyping method was determined to be 0.01 ng of genomic DNA and 10(3) CFU of each strain/ml. This study completes the elucidation of C. sakazakii O-antigen genetics and provides a molecular method suitable for the identification of C. sakazakii O1 to O7 strains. PMID- 22447598 TI - Presence and persistence of Salmonella enterica serotype typhimurium in the phyllosphere and rhizosphere of spray-irrigated parsley. AB - Salmonella enterica is one of the major food-borne pathogens associated with ready-to-eat fresh foods. Although polluted water might be a significant source of contamination in the field, factors that influence the transfer of Salmonella from water to the crops are not well understood, especially under conditions of low pathogen levels in water. The aim of this study was to investigate the short- and long-term (1 h to 28 days) persistence of Salmonella enterica serotype Typhimurium in the phyllosphere and the rhizosphere of parsley following spray irrigation with contaminated water. Plate counting and quantitative real-time PCR (qRT-PCR)-based methods were implemented for the quantification. By applying qRT PCR with enrichment, we were able to show that even irrigation with water containing as little as ~300 CFU/ml resulted in the persistence of S. Typhimurium on the plants for 48 h. Irrigation with water containing 8.5 log CFU/ml resulted in persistence of the bacteria in the phyllosphere and the rhizosphere for at least 4 weeks, but the population steadily declined with a major reduction in bacterial counts, of ~2 log CFU/g, during the first 2 days. Higher levels of Salmonella were detected in the phyllosphere when plants were irrigated during the night compared to irrigation during the morning and during winter compared to the other seasons. Further elucidation of the mechanisms underlying the transfer of Salmonella from contaminated water to crops, as well as its persistence over time, will enable the implementation of effective irrigation and control strategies. PMID- 22447599 TI - Antimicrobial resistance in Escherichia coli isolates from raccoons (Procyon lotor) in Southern Ontario, Canada. AB - We conducted a cross-sectional study to determine the prevalence of antimicrobial resistance (AMR) in fecal Escherichia coli isolates from raccoons (Procyon lotor) living in Ontario, Canada. From June to October 2007, we trapped raccoons in three areas: one primarily urban site around Niagara, one primarily rural site north of Guelph, and one at the Toronto Zoo. In addition, we conducted a longitudinal study at the Toronto Zoo site to investigate the temporal dynamics of fecal E. coli and AMR in raccoons. Reduced susceptibility to >=1 antimicrobial agent was detected in E. coli isolates from 19% of 16 raccoons at the urban site, 17% of 29 raccoons from the rural site, and 42% of 130 samples collected from 59 raccoons at the zoo site. Raccoons from the zoo site were significantly more likely to shed E. coli with reduced susceptibility to >=1 antimicrobial agent than animals from the rural site (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.17 to 12.09; P = 0.02). Resistance to expanded-spectrum cephalosporins (and the associated bla(CMY-2) gene) was detected in two animals from the zoo site and one animal from the rural site. Serotyping and pulsed-field gel electrophoresis analysis show that raccoons on the zoo grounds harbor a diverse assemblage of E. coli, with rapid bacterial turnover within individuals over time. Our study indicates that raccoons may shed resistant bacteria of public health significance and that raccoons have the potential to disseminate these bacteria throughout their environment. PMID- 22447600 TI - Specific binding of radiolabeled Cry1Fa insecticidal protein from Bacillus thuringiensis to midgut sites in lepidopteran species. AB - Cry1Fa insecticidal protein was successfully radiolabeled with (125)I-Na. Specific binding to brush border membrane vesicles was shown for the lepidopteran species Ostrinia nubilalis, Spodoptera frugiperda, Spodoptera exigua, Helicoverpa armigera, Heliothis virescens, and Plutella xylostella. Homologous competition assays were performed to obtain equilibrium binding parameters (K(d) [dissociation constant] and R(t) [concentration of binding sites]) for these six insect species. PMID- 22447601 TI - Iodide oxidation by a novel multicopper oxidase from the alphaproteobacterium strain Q-1. AB - Alphaproteobacterium strain Q-1 is able to oxidize iodide (I(-)) to molecular iodine (I(2)) by an oxidase-like enzyme. One of the two isoforms of the iodide oxidizing enzyme (IOE-II) produced by this strain was excised from a native polyacrylamide gel, eluted, and purified. IOE-II appeared as a single band (51 kDa) and showed significant in-gel iodide-oxidizing activity in sodium dodecyl sulfate-polyacrylamide gel electrophoresis without heat treatment. However, at least two bands with much higher molecular masses (150 and 230 kDa) were observed with heat treatment (95 degrees C, 3 min). IOE-II was inhibited by NaN(3), KCN, EDTA, and a copper chelator, o-phenanthroline. In addition to iodide, IOE-II showed significant activities toward phenolic compounds such as syringaldazine, 2,6-dimethoxy phenol, and p-phenylenediamine. IOE-II contained copper atoms as prosthetic groups and had UV/VIS absorption peaks at 320 and 590 nm. Comparison of several internal amino acid sequences obtained from trypsin-digested IOE-II with a draft genome sequence of strain Q-1 revealed that the products of two open reading frames (IoxA and IoxC), with predicted molecular masses of 62 and 71 kDa, are involved in iodide oxidation. Furthermore, subsequent tandem mass spectrometric analysis repeatedly detected peptides from IoxA and IoxC with high sequence coverage (32 to 40%). IoxA showed homology with the family of multicopper oxidases and included four copper-binding regions that are highly conserved among various multicopper oxidases. These results suggest that IOE-II is a multicopper oxidase and that it may occur as a multimeric complex in which at least two proteins (IoxA and IoxC) are associated. PMID- 22447602 TI - Polymorphisms in rpoS and stress tolerance heterogeneity in natural isolates of Cronobacter sakazakii. AB - Significant phenotypic diversity was observed when we examined the abilities of a number of Cronobacter sakazakii natural isolates to cope with various sublethal stress conditions (acid, alkaline, osmotic, oxidative, or heat stress). Levels of catalase activity and use of acetate as a carbon source, phenotypes commonly used as indirect assays to predict RpoS function, revealed a high correlation between predicted RpoS activity and tolerance to acid, alkaline, osmotic, and oxidative treatments. The rpoS genes were sequenced and analyzed for polymorphisms. Loss-of function mutations were found in two strains; C. sakazakii DPC 6523 and the genome-sequenced strain C. sakazakii ATCC BAA-894. The complementation of these strains with a functional rpoS gene resulted in an increase in bacterial tolerance to acid, osmotic, and oxidative stresses. The pigmentation status of strains was also assessed, and a high variability in carotenoid content was observed, with a functional rpoS gene being essential for the production of the characteristic yellow pigment. In conclusion, the evidence presented in this study demonstrates that rpoS is a highly polymorphic gene in C. sakazakii, and it supports the importance of RpoS for the tolerance under stress conditions that C. sakazakii may encounter in the food chain and in the host during infection. PMID- 22447603 TI - Impact of respiration on resistance of Lactobacillus plantarum WCFS1 to acid stress. AB - This study shows that growth under respiration conditions has a negative impact on the survival of stationary-phase cultures of Lactobacillus plantarum WCFS1 at low pHs and that viability loss at critical values is associated with the formation of radicals and loss of membrane integrity. PMID- 22447604 TI - Listeria monocytogenes grown at 7 degrees C shows reduced acid survival and an altered transcriptional response to acid shock compared to L. monocytogenes grown at 37 degrees C. AB - Survival of the food-borne pathogen Listeria monocytogenes in acidic environments (e.g., in the human stomach) is vital to its transmission. Refrigerated, ready-to eat foods have been sources of listeriosis outbreaks. The purpose of this study was to determine whether growth at a low temperature (i.e., 7 degrees C) affects L. monocytogenes survival or gene transcription after exposure to a simulated gastric environment (i.e., acid shock at 37 degrees C). L. monocytogenes cells grown at 7 degrees C were less resistant to artificial gastric fluid (AGF) or acidified brain heart infusion broth (ABHI) than bacteria grown at higher temperatures (i.e., 30 degrees C or 37 degrees C). For L. monocytogenes grown at 7 degrees C, stationary-phase cells were more resistant to ABHI than log-phase cells, indicating that both temperature and growth phase affect acid survival. Microarray transcriptomic analysis revealed that the number and functional categories of genes differentially expressed after acid shock differed according to both growth temperature and growth phase. The acid response of L. monocytogenes grown to log phase at 37 degrees C involved stress-related transcriptional regulators (i.e., sigma(B), sigma(H), CtsR, and HrcA), some of which have been implicated in adaptation to the intracellular environment. In contrast, for bacteria grown at 7 degrees C to stationary phase, acid exposure did not result in differential expression of the stress regulons examined. However, two large operons encoding bacteriophage-like proteins were induced, suggesting lysogenic prophage induction. The adaptive transcriptional response observed in 37 degrees C-grown cells was largely absent in 7 degrees C-grown cells, suggesting that temperatures commonly encountered during food storage and distribution affect the ability of L. monocytogenes to survive gastric passage and ultimately cause disease. PMID- 22447605 TI - Real-time PCR detection of Phaeomoniella chlamydospora and Phaeoacremonium aleophilum. AB - Phaeomoniella chlamydospora and Phaeoacremonium aleophilum are the two main fungal causal agents of Petri disease and esca. Both diseases cause significant economic losses to viticulturalists. Since no curative control measures are known, proactive defensive measures must be taken. An important aspect of current research is the development of sensitive and time-saving protocols for the detection and identification of these pathogens. Real-time PCR based on the amplification of specific sequences is now being used for the identification and quantification of many infective agents. The present work reports real-time PCR protocols for identification of P. chlamydospora and P. aleophilum. Specificity was demonstrated against purified DNA from 60 P. chlamydospora isolates or 61 P. aleophilum isolates, and no amplification was obtained with 54 nontarget DNAs. The limits of detection (i.e., DNA detectable in 95% of reactions) were around 100 fg for P. chlamydospora and 50 fg for P. aleophilum. Detection was specific and sensitive for P. chlamydospora and P. aleophilum. Spores of P. chlamydospora and P. aleophilum were detected without the need for DNA purification. The established protocols detected these fungi in wood samples after DNA purification. P. chlamydospora was detectable without DNA purification and isolation in 67% of reactions. The detection of these pathogens in wood samples has great potential for use in pathogen-free certification schemes. PMID- 22447606 TI - Modular glucuronoxylan-specific xylanase with a family CBM35 carbohydrate-binding module. AB - Xyn30D from the xylanolytic strain Paenibacillus barcinonensis has been identified and characterized. The enzyme shows a modular structure comprising a catalytic module family 30 (GH30) and a carbohydrate-binding module family 35 (CBM35). Like GH30 xylanases, recombinant Xyn30D efficiently hydrolyzed glucuronoxylans and methyl-glucuronic acid branched xylooligosaccharides but showed no catalytic activity on arabinose-substituted xylans. Kinetic parameters of Xyn30D were determined on beechwood xylan, showing a K(m) of 14.72 mg/ml and a k(cat) value of 1,510 min(-1). The multidomain structure of Xyn30D clearly distinguishes it from the GH30 xylanases characterized to date, which are single domain enzymes. The modules of the enzyme were individually expressed in a recombinant host and characterized. The isolated GH30 catalytic module showed specific activity, mode of action on xylan, and kinetic parameters that were similar to those of the full-length enzyme. Computer modeling of the three dimensional structure of Xyn30D showed that the catalytic module is comprised of a common (beta/alpha)(8) barrel linked to a side-associated beta-structure. Several derivatives of the catalytic module with decreasing deletions of this associated structure were constructed. None of them showed catalytic activity, indicating the importance of the side beta-structure in the catalysis of Xyn30D. Binding properties of the isolated carbohydrate-binding module were analyzed by affinity gel electrophoresis, which showed that the CBM35 of the enzyme binds to soluble glucuronoxylans and arabinoxylans. Analysis by isothermal titration calorimetry showed that CBM35 binds to glucuronic acid and requires calcium ions for binding. Occurrence of a CBM35 in a glucuronoxylan-specific xylanase is a differential trait of the enzyme characterized. PMID- 22447607 TI - Zoonotic agents in small ruminants kept on city farms in southern Germany. AB - Sheep and goats are popular examples of livestock kept on city farms. In these settings, close contacts between humans and animals frequently occur. Although it is widely accepted that small ruminants can carry numerous zoonotic agents, it is unknown which of these agents actually occur in sheep and goats on city farms in Germany. We sampled feces and nasal liquid of 48 animals (28 goats, 20 sheep) distributed in 7 city farms and on one activity playground in southern Germany. We found that 100% of the sampled sheep and 89.3% of the goats carried Shiga toxin-producing Escherichia coli (STEC). The presence of Staphylococcus spp. in 75% of both sheep and goats could be demonstrated. Campylobacter spp. were detected in 25% and 14.3% of the sheep and goats, respectively. Neither Salmonella spp. nor Coxiella burnetii was found. On the basis of these data, we propose a reasonable hygiene scheme to prevent transmission of zoonotic agents during city farm visits. PMID- 22447608 TI - Effects of airflow and changing humidity on the aerosolization of respirable fungal fragments and conidia of Botrytis cinerea. AB - The purpose of this study was to investigate the aerosolization of particles (micro- and macroconidia and fragments) from Botrytis cinerea cultures in relation to potential human inhalation in indoor environments. The influence of the following factors on the aerosolization of B. cinerea particles was studied: exposure to airflow, relative humidity (rh), changing rh, and plant or building materials. The aerodynamic diameter (d(a)) and the respirable fraction of the aerosolized particles were determined. Conidia and fragments of B. cinerea were not aerosolized as a response to a decrease in the rh. In contrast, both micro- and macroconidia and fungal fragments were aerosolized when exposed to an airflow of 1.5 m s(-1) or 0.5 m s(-1). Significantly more particles of microconidial size and fragment size were aerosolized at a low rh (18 to 40% rh) than at a higher rh (60 to 80% rh) when cultures were exposed to airflow. The size of the respirable fraction of the aerosolized particles was dependent on the rh but not on the growth material. At high rh, about 30% of the aerosolized particles were of respirable size, while at low rh, about 70% were of respirable size. During low rh, more fungal (1->3)-beta-d-glucan and chitinase were aerosolized than during high rh. In conclusion, exposure to external physical forces such as airflow is necessary for the aerosolization of particles from B. cinerea. The amount and size distribution are highly affected by the rh, and more particles of respirable sizes were aerosolized at low rh than at high rh. PMID- 22447609 TI - New range of vectors with a stringent 5-fluoroorotic acid-based counterselection system for generating mutants by allelic replacement in Staphylococcus aureus. AB - We have developed a range of vectors for allelic replacements in Staphylococcus aureus to facilitate genetic work in this opportunistic pathogen. The central feature of the vector range is a selection/counterselection system that takes advantage of the 5-fluoroorotic acid (FOA) resistance and pyrimidine prototrophy caused by the loss and gain, respectively, of the pyrF and pyrE genes. This system allows for stringent counterselection of the vectors during the second homologous recombination of a classic allelic replacement. The basic vector pRLY2, which contains the pyrFE genes from Bacillus subtilis, was combined with chloramphenicol, erythromycin, and tetracycline resistance genes and four different versions of nonreplicative or conditionally replicative origins of replication. The choice between these 12 different pRLY vectors allows for high versatility and ensures that the vectors can be used in virtually any genetic background. Finally, as proof of concept, we present six deletions or modifications of components in the S. aureus degradosome as well as the operon containing the cshB DEAD box helicase. PMID- 22447610 TI - Stability of and attachment to lettuce by a culturable porcine sapovirus surrogate for human caliciviruses. AB - Human noroviruses (HuNoVs) are the leading cause of food-borne illness, accounting for 58% of U.S. cases. Because HuNoVs are unculturable, surrogates are needed to investigate transmission routes and evaluate disinfection methods. However, the current surrogates, feline calicivirus (FCV) and murine NoV (MNV), are less tolerant than HuNoVs to acid and chlorine, respectively. Porcine sapovirus (SaV) is the only culturable enteropathogenic calicivirus. In this study, the resistance of SaV to physicochemical treatments was compared to that of HuNoVs (by reverse transcription-PCR), FCV, and MNV (by infectivity assays). Sapovirus and HuNoV (viral RNA) showed similar resistances to heat (56 degrees C) and to different concentrations of chlorine. However, SaV was more resistant than HuNoVs to ethanol treatment (60% and 70%). Like HuNoVs, SaV was stable at pH 3.0 to 8.0, with a <1.0 log(10) 50% tissue culture infective dose (TCID(50)) reduction at pH 3.0 compared to the value for pH 4.0 to 8.0. SaV and MNV showed similar resistances, and both were more resistant than FCV to heat inactivation (56 degrees C). FCV was more resistant than MNV and SaV to ethanol, and all three viruses showed similar resistances to treatment with low concentrations of chlorine for 1 min. Those results indicate that SaV is a promising surrogate for HuNoVs. Next, we used SaV as a surrogate to examine virus attachment to lettuce at different pHs. Sapovirus attached to lettuce leaves significantly at its capsid isoelectric point (pH 5.0), and the attached viral particles remained infectious on lettuce after 1 week of storage at 4 degrees C. The culturable SaV is a good surrogate for studying HuNoV contamination and transmission in leafy greens and potential disinfectants. PMID- 22447611 TI - Phospholipase A2 inhibitors synthesized by two entomopathogenic bacteria, Xenorhabdus nematophila and Photorhabdus temperata subsp. temperata. AB - The entomopathogenic bacteria Xenorhabdus nematophila and Photorhabdus temperata subsp. temperata suppress insect immune responses by inhibiting the catalytic activity of phospholipase A(2) (PLA(2)), which results in preventing biosynthesis of immune-mediating eicosanoids. This study identified PLA(2) inhibitors derived from culture broths of these two bacteria. Both X. nematophila and P. temperata subsp. temperata culture broths possessed significant PLA(2)-inhibitory activities. Fractionation of these bacterial metabolites in the culture broths using organic solvent and subsequent chromatography purified seven potent PLA(2) inhibitors, three of which (benzylideneacetone [BZA], proline-tyrosine [PY], and acetylated phenylalanine-glycine-valine [FGV]) were reported in a previous study. Four other compounds (indole, oxindole, cis-cyclo-PY, and p-hydroxyphenyl propionic acid) were identified and shown to significantly inhibit PLA(2). X. nematophila culture broth contained these seven compounds, while P. temperata subsp. temperata culture broth contained three compounds (BZA, acetylated FGV, and cis-cyclo-PY). BZA was detected in the largest amount among these PLA(2) compounds in both bacterial culture broths. All seven bacterial metabolites also showed significant inhibitory activities against immune responses, such as phenoloxidase activity and hemocytic nodulation; BZA was the most potent. Finally, this study characterized these seven compounds for their insecticidal activities against the diamondback moth, Plutella xylostella. Even though these compounds showed relatively low toxicities to larvae, they significantly enhanced the pathogenicity of Bacillus thuringiensis. This study reports bacterial-origin PLA(2) inhibitors, which would be applicable for developing novel insecticides. PMID- 22447612 TI - Production of L-ribose from L-ribulose by a triple-site variant of mannose-6 phosphate isomerase from Geobacillus thermodenitrificans. AB - A triple-site variant (W17Q N90A L129F) of mannose-6-phosphate isomerase from Geobacillus thermodenitrificans was obtained by combining variants with residue substitutions at different positions after random and site-directed mutagenesis. The specific activity and catalytic efficiency (k(cat)/K(m)) for L-ribulose isomerization of this variant were 3.1- and 7.1-fold higher, respectively, than those of the wild-type enzyme at pH 7.0 and 70 degrees C in the presence of 1 mM Co(2+). The triple-site variant produced 213 g/liter l-ribose from 300 g/liter L ribulose for 60 min, with a volumetric productivity of 213 g liter(-1) h(-1), which was 4.5-fold higher than that of the wild-type enzyme. The k(cat)/K(m) and productivity of the triple-site variant were approximately 2-fold higher than those of the Thermus thermophilus R142N variant of mannose-6-phosphate isomerase, which exhibited the highest values previously reported. PMID- 22447613 TI - Persistence of nasal colonization with livestock-associated methicillin-resistant Staphylococcus aureus in pig farmers after holidays from pig exposure. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is frequently transmitted from pigs to farmers. This study analyzed whether an absence from direct contact with pigs during holidays had an impact on nasal MRSA colonization rates of pig farmers. Overall, 59% of the farmers did not clear MRSA colonization during their leave. PMID- 22447614 TI - Repetitive angioscopic observations of a sirolimus-eluting stent deployed in a patient with silent chronic thrombotic occlusion. AB - In the era of the drug-eluting stent, very late stent thrombosis has been the most serious issue in the field of interventional cardiology. A sirolimus-eluting stent (SES) was implanted in an in-stent restenotic lesion in the left circumflex artery of a 69-year-old man. Repetitive coronary angiography and angioscopy revealed that stent struts were covered with yellow neointima at 2 years after the SES deployment. At 4 years after the deployment, coronary angiography revealed the total occlusion of the SES. Angioscopy showed massive mural thrombi and yellow atherosclerotic plaques. Dual anti-platelet therapy (DAPT), ticlopidine and aspirin, had been continued since the SES deployment. Interventional cardiologists should heed the risk of silent chronic thrombotic occlusion even if struts of SES are fully covered with neointima under continued DAPT. PMID- 22447615 TI - Preparation, characterization, and in vitro enzymatic degradation of chitosan gelatine hydrogel scaffolds as potential biomaterials. AB - The crosslinking of chitosan (CHT) and gelatin (GEL) accomplished with N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N hydroxysuccinimide (NHS) was investigated and optimized in relation to hydrogels stability by varying the CHT/GEL mass ratio and the EDC/NHS molar ratio at different and constant EDC concentrations. Hydrogels were also fabricated in the presence of alpha-tocopherol to assess the release mechanism of a lipophilic drug from a highly-hydrophilic CHT/GEL hydrogel network. Alterations in the physico chemical properties of hydrogels were characterized by differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FTIR), and their biostability was studied within a simulated body-fluid solution (PBS of pH 7.4) at 37 degrees C for 24 h by evaluating the degree of swelling, followed by topography and morphology characterization using scanning electron microscopy (SEM). The analysis confirmed the formation of a modulated hydrogels porosity using different freezing temperatures prior to lyophilization. The in vitro degradation behaviors of the hydrogels were investigated for up to 5 weeks using collagenase, lysozyme, and N-acetyl-beta-D-glucosaminidase by monitoring the weight-losses of hydrogels and their degradation products, being identified by UV Vis spectroscopy and high-performance liquid chromatography (HPLC) as well as the pH monitoring of degraded solutions. It was observed that an inner morphological hydrogel structure influences their swelling and degradation behavior, which is additionally reduced by in-gel-embedded alpha-tocopherol because of hydrophobic interactions with their constituents, and hindering the effect on collagenase activity. PMID- 22447616 TI - Tissue distribution and histopathological effects of titanium dioxide nanoparticles after intravenous or subcutaneous injection in mice. AB - Nanoparticles can be formed following degradation of medical devices such as orthopedic implants. To evaluate the safety of titanium alloy orthopedic materials, data are needed on the long-term distribution and tissue effects of injected titanium nanoparticles in experimental animals. In this study, we evaluated the tissue distribution and histopathological effects of titanium dioxide (TiO(2)) nanoparticles (approximately 120 nm diameter) in mice after intravenous (i.v.; 56 or 560 mg kg(-1) per mouse) or subcutaneous (s.c.; 560 or 5600 mg kg(-1) per mouse) injection on two consecutive days. Animals were examined 1 and 3 days, and 2, 4, 12 and 26 weeks after the final injection. When examined by light microscopy, particle agglomerates identified as TiO(2) were observed mainly in the major filtration organs - liver, lung and spleen - following i.v. injection. Particles were still observed 26 weeks after injection, indicating that tissue clearance is limited. In addition, redistribution within the histological micro-compartments of organs, especially in the spleen, was noted. Following s.c. injection, the largest particle agglomerates were found mainly in the draining inguinal lymph node, and to a lesser extent, the liver, spleen and lung. With the exception of a foreign body response at the site of s.c. injection and the appearance of an increased number of macrophages in the lung and liver, there was no histopathological evidence of tissue damage observed in any tissue at any time point. PMID- 22447617 TI - Analysis of short stature cases referred for genetic evaluation. AB - OBJECTIVE: To retrospectively analyze the profile of patients who presented with chief complaint of short stature to Medical Genetics OPD of SGPGIMS, Lucknow, India. METHODS: Medical Genetics OPD records were searched for cases presenting with short stature, from January 2008 through December 2010. Short stature was defined as height less than -2 SD from mean for the corresponding age and sex for the Indian population. The workup done for the cases was analyzed, following which they were placed in one of the etiological categories of short stature. RESULTS: A total of 137 cases were analyzed. The number of female and male patients was 92 and 45 respectively. The evaluation done in majority of cases included anthropometry, calculation of mid-parental height, medical history, routine biochemistry and hematology, bone age assessment, thyroid function tests, antiendomysial antibody testing, karyotyping and other appropriate investigations as required. The percentages of cases in the various diagnostic categories were- skeletal dysplasia (32.1 %), turner syndrome (16.7 %), endocrine deficiencies (8 %), genetic syndromes (7.3 %), chronic diseases (5.8 %). Twenty one (15.3 %) cases grouped as idiopathic short stature consisted of 9 familial and 12 non familial cases. Twenty (14.6 %) cases were found to be incompletely evaluated. CONCLUSIONS: Skeletal dysplasias and turner syndrome accounted for majority of cases of short stature. Cause remains unidentified in 15.3 % cases and these idiopathic cases need further workup especially for the molecular defects in the pituitary GH-IGF1 axis. A detailed evaluation and good follow up of cases of short stature is required. PMID- 22447618 TI - Kawasaki disease masquerading as jaundice. AB - While the myriad manifestations of Kawasaki disease are increasingly being recognized, there are still many instances where this diagnosis can come as a surprise to the clinician. The authors report one such child who appeared to have acute infective hepatitis at presentation but went on to develop the full clinical picture of Kawasaki disease. This is a rarely reported presentation of Kawasaki disease. PMID- 22447619 TI - Haplotypes in candidate genes related to nitric oxide pathway and vascular permeability associated with migraine and aura. PMID- 22447620 TI - Minimally invasive surgery for parapharyngeal space tumors. AB - OBJECTIVES/HYPOTHESIS: Parapharyngeal space (PS) tumors are surrounded by critical anatomical structures. Resection is often challenging due to limited surgical exposure. Herein, we report a novel transcervical, minimally invasive, video-assisted technique that facilitates the resection of PS lesions. STUDY DESIGN: Case series and review of literature. METHODS: Description of surgical technique with analysis of four cases and literature review. RESULTS: The technique combines a transcervical approach to the PS and skull base with video assisted and image-guided dissection of tumor. Four cases of benign PS tumors resected with this technique are reported. The size of the tumor excised varied between 0.9 cm and 5 cm. Estimated blood losses were minimal. The average length of hospital stay was 1.5 days. No permanent complications were encountered. CONCLUSIONS: Excision of PS tumor abutting the skull base using a novel minimally invasive, video-assisted, image-guided, transcervical approach is feasible and safe. The short hospitalization stay and low morbidity makes it well suited for the resection of benign PS lesions. PMID- 22447621 TI - An improved methodology for multidimensional high-throughput preformulation characterization of protein conformational stability. AB - The empirical phase diagram (EPD) technique is a vector-based multidimensional analysis method for summarizing large data sets from a variety of biophysical techniques. It can be used to provide comprehensive preformulation characterization of a macromolecule's higher-order structural integrity and conformational stability. In its most common mode, it represents a type of stimulus-response diagram using environmental variables such as temperature, pH, and ionic strength as the stimulus, with alterations in macromolecular structure being the response. Until now, EPD analysis has not been available in a high throughput mode because of the large number of experimental techniques and environmental stressor/stabilizer variables typically employed. A new instrument has been developed that combines circular dichroism, ultraviolet absorbance, fluorescence spectroscopy, and light scattering in a single unit with a six position, temperature-controlled cuvette turret. Using this multifunctional instrument and a new software system, we have generated EPDs for four model proteins. Results confirm the reproducibility of the apparent phase boundaries and protein behavior within the boundaries. This new approach permits two EPDs to be generated per day using only 0.5 mg of protein per EPD. Thus, the new methodology generates reproducible EPDs in high-throughput mode and represents the next step in making such determinations more routine. PMID- 22447622 TI - Statistical support for subtypes in posttraumatic stress disorder: the how and why of subtype analysis. AB - A number of researchers have argued for the existence of different subtypes of posttraumatic stress disorder (PTSD). In the current paper we present criteria by which to assess these putative subtypes, clarify potential pitfalls of the statistical methods employed to determine them, and propose alternative methods for such determinations. Specifically, three PTSD subtypes are examined: (1) complex PTSD, (2) externalizing/internalizing PTSD, and (3) dissociative/nondissociative PTSD. In addition, three criteria are proposed for subtype evaluation, these are the need for (1) reliability and clarity of definition, (2) distinctions between subtypes either structurally or by mechanism, and (3) clinical meaningfulness. Common statistical evidence for subtyping, such as statistical mean difference and cluster analysis, are presented and evaluated. Finally, more robust statistical methods are suggested for future research on PTSD subtyping. PMID- 22447623 TI - REM sleep behavior disorder: motor manifestations and pathophysiology. AB - Patients with REM sleep behavior disorder (RBD) enact violent dreams during REM sleep in the absence of normal muscle atonia. This disorder is highly frequent in patients with synucleinopathies (60%-100% of patients) and rare in patients with other neurodegenerative disorders. The disorder is detected by interview plus video and sleep monitoring. Abnormal movements expose the patients and bed partners to a high risk of injury and sleep disruption. The disorder is usually alleviated with melatonin and clonazepam. Limb movements are mainly minor, jerky, fast, pseudohallucinatory, and repeated, with a limp wrist during apparently grasping movements, although body jerks and complex violent (fights) and nonviolent culturally acquired behaviors are also observed. Notably, parkinsonism disappears during RBD-associated complex behaviors in patients with Parkinson's disease and with multiple system atrophy, suggesting that the upper motor stream bypasses the basal ganglia during REM sleep. Longitudinal studies show that idiopathic RBD predisposes patients to later develop Parkinson's disease, dementia with Lewy bodies, and, more rarely, multiple system atrophy, with a rate of conversion of 46% within 5 years. During this time window, patients concomitantly develop nonmotor signs (decreased olfaction and color vision, orthostatic hypotension, altered visuospatial abilities, increased harm avoidance) and have abnormal test results (decreased putamen dopamine uptake, slower EEG). Patients with idiopathic RBD have higher and faster risk for conversion to Parkinson's disease and dementia with Lewy bodies if abnormalities in dopamine transporter imaging, transcranial sonography, olfaction, and color vision are found at baseline. They constitute a highly specific target for testing neuroprotective agents. PMID- 22447624 TI - BDNF Val66Met polymorphism is associated with Stage III-IV endometriosis and poor in vitro fertilization outcome. AB - BACKGROUND The recently identified human brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was found to be associated with altered susceptibility to some neuropsychiatric disorders. Interestingly, BDNF together with its receptors TrkB and p75 are extensively expressed in female reproduction system. The aim of this study is to investigate whether the BDNF Val66Met polymorphism plays a role in endometriosis, endometriosis-related infertility and the outcomes of IVF and embryo transfer (IVF-ET). METHODS A case-control study included 425 endometriosis patients and 244 control Chinese Han women. The genotyping of the BDNF Val66Met polymorphism was performed by the fluorescence resonance energy transfer method. The plasma and follicular fluid concentrations of BDNF on the day of oocyte retrieval were measured by ELISA. The general clinical data from the endometriosis-related and tubal obstructed infertile patients treated with IVF-ET were analyzed. RESULTS There was no association between the BDNF Val66Met polymorphism and overall endometriosis (P> 0.05), whereas higher genotype and allele frequencies of the BDNF(Met) polymorphism were found in the Stage III-IV endometriosis (both P< 0.01) and endometriosis-related infertile patients (both P< 0.05). Moreover, during IVF and embryo transfer (IVF-ET) treatment, fewer mature oocytes (P< 0.05) and lower fertilization rate (P< 0.01) were found in BDNF(Met/Met) carriers compared with those in BDNF(Val/Val) carriers with infertility. Follicular-fluid BDNF concentration in BDNF(Met/Met) carriers was lower compared with that in BDNF(Val/Val) individuals (P< 0.01). CONCLUSIONS Our results suggest that the BDNF(Met) single-nucleotide polymorphism might contribute to the increased susceptibility to the Stage III-IV endometriosis and endometriosis-related infertility. Moreover, infertile patients with the BDNF(Met/Met) genotype had a poorer IVF outcome compared with the BDNF(Val/Val) genotype individuals, which might in part be due to the decreased BDNF levels in follicular fluids after controlled ovarian hyperstimulation. PMID- 22447625 TI - Sperm gene expression profile is related to pregnancy rate after insemination and is predictive of low fecundity in normozoospermic men. AB - BACKGROUND: Assessment of male fertility is traditionally based on microscopic evaluation of semen. However, the classical semen parameters do not adequately reflect sperm function, and their clinical value in predicting fertility is limited. We hypothesize that the sperm expression profile could reflect the fertilizing quality of spermatozoa and could be more informative for predicting the in vivo reproductive fitness of men with normal semen parameters. METHODS: Sperm gene expression patterns of 68 normozoospermic donors (43 Phase I and 25 Phase II), used for therapeutic IUI, were analysed via TaqMan Arrays. RESULTS: Significant differences in the expression of individual genes were observed between groups of donors with the lowest and highest pregnancy rates (PRs) after IUI. Additionally, we have developed a molecular means to classify the fertility status of semen donors for IUI based on the expression signature of four genes. In the Phase I study, this model had 90% sensitivity and 97% specificity for discriminating donors resulting in low PRs (cut-off value: <13.6%), far better than that obtained from the combination of sperm parameters. The translation of the model was validated in Phase II donors resulting in a sensitivity of 71.5% and a specificity of 78%. CONCLUSIONS: Our findings contribute to the search for the most valuable genetic markers which are potentially useful as tools for predicting pregnancy. Our expression model could complement classical semen analysis in order to identify sperm donors with a less favourable IUI reproductive outcome despite having normal semen parameters. It may also be useful for the study of sperm function in couples with unexplained infertility. PMID- 22447626 TI - Xanthohumol inhibits growth and vascularization of developing endometriotic lesions. AB - BACKGROUND: Xanthohumol is a prenylated flavonoid isolated from hops, which is known to act as a pleiotropic cancer chemopreventive agent owing to its anti proliferative, anti-inflammatory and anti-angiogenic properties. In the present study, we analyzed, for the first time, whether this dietary compound may also be used for the treatment of endometriosis. METHODS: Peritoneal and mesenteric endometriotic lesions were surgically induced in BALB/c mice by uterine tissue transplantation into the abdominal cavity. The animals were treated daily with 100 uM xanthohumol (n= 8) or vehicle (control, n= 8) via the drinking water, starting 3 days before tissue transplantations. Lesion growth, cyst formation and vascularization were subsequently analyzed by means of high-resolution ultrasound imaging (at Day 0 and then once per week for 28 days), caliper measurements, western blotting, histology and immunohistochemistry over 4 weeks. RESULTS: In the treatment and control groups, uterine grafts developed typical endometriotic lesions with cyst-like dilated glands surrounded by a vascularized endometrial stroma. However, xanthohumol efficiently decreased the size of these lesions at Day 28, independent of their localization within the peritoneal cavity, compared with control (peritoneal: P =0.041; mesenteric: P =0.038). This was associated with a reduced level of phosphoinositide 3-kinase protein. Moreover, vascularization of xanthohumol-treated lesions was suppressed, as indicated by a significantly lower microvessel density at Day 28 when compared with vehicle treated controls (peritoneal: P =0.026; mesenteric: P =0.004). Additional analyses revealed that treatment with xanthohumol did not affect the histomorphology, proliferation and vascularization of the uterine horns and ovaries. CONCLUSIONS: Taken together, these experimental findings suggest that xanthohumol inhibits the development of endometriotic lesions in mice without inducing serious side effects in the reproductive organs. Thus, xanthohumol represents a promising dietary phytochemical that, after further testing, may be considered for the use in the selective treatment of endometriotic lesions. PMID- 22447627 TI - Pregnancy outcome in women with endometriomas achieving pregnancy through IVF. AB - BACKGROUND: There is a growing consensus that ovarian endometriomas should not be systematically removed in women selected for IVF. However, some recent evidence suggested that the presence of these cysts may negatively affect the course of pregnancy. METHODS: We set up a multicenter retrospective cohort study, including two infertility units. We analyzed data from patients achieving singleton clinical pregnancies through IVF comparing the pregnancy outcome between 78 pregnant women with endometriomas at the time of IVF and 156 patients who achieved pregnancy through IVF without endometriomas. RESULTS: The number of live births in women with and without endometriomas were 61 (78%) and 130 (83%), respectively (P = 0.39). The adjusted odds ratio (OR) of live birth in affected cases was 0.79 [95% confidence interval (CI): 0.38-1.68]. No differences were observed in late pregnancy and neonatal outcomes between the two groups. In particular, the rate of preterm birth and small-for-gestational age (SGA) was similar. The adjusted ORs were 0.47 (95% CI: 0.14-1.54) and 0.56 (95% CI: 0.12 2.56), respectively. CONCLUSIONS: Women with endometriomas achieving pregnancy through IVF do not seem to be exposed to a significant increased risk of obstetrical complications. PMID- 22447628 TI - Chemerin inhibits IGF-1-induced progesterone and estradiol secretion in human granulosa cells. AB - BACKGROUND: Chemerin is a novel adipokine involved in the regulation of adipocyte development, inflammation and metabolic functions. To date, no role of this adipokine in reproductive functions has been described. In the present study, we identified chemerin and its receptor, CMKLR1 (chemokine-like receptor 1), in primary human granulosa cells (hGCs) and in a human ovarian granulosa-like tumour cell line (KGN). We also investigated the effects of recombinant human chemerin (rhChem) on steroid production and on various signalling pathways. METHODS AND RESULTS: By RT-PCR immunoblotting and immunohistochemistry, we showed that chemerin and CMKLR1 are expressed in hGCs and KGN cells. By ELISA, we also found chemerin in human follicular fluid and we observed that in 8 of 10 women the chemerin level was at least 2-fold higher in follicular fluid than in plasma. rhChem (10 or 100 ng/ml) significantly decreased insulin-like growth factor-1 (IGF-1) (10(-8) M)-induced secretion of progesterone and estradiol (as determined by radioimmunoassay) but did not affect basal-or FSH (10(-8) M)-induced steroid secretion in hGCs and KGN cells. In parallel, it also decreased IGF-1-induced p450 aromatase protein levels without affecting the protein levels of other factors involved in steroidogenesis (steroidogenic acute regulatory protein, 3 beta-hydroxysteroid dehydrogenase and p450 side-chain cleavage enzyme) in hGCs cells. All these changes were associated with a decrease in the IGF-1-induced tyrosine phosphorylation of IGF-1 receptor beta subunit and phosphorylation of mitogen-activated protein kinase extracellular signal-regulated kinases 1/2 (MAPK ERK1/2) and Akt. In hGCs and KGN cells, rhChem also decreased IGF-1-induced thymidine incorporation. Finally, we showed that rhChem rapidly activates MAPK ERK1/2, MAPK P38 and Akt phosphorylation and more slowly AMP-activated protein kinase phosphorylation under basal conditions (no IGF-1 or FSH) in primary hGC cells. CONCLUSIONS: Taken together, chemerin and its receptor (CMKLR1) are present and active in hGCs. Chemerin reduces IGF-1-induced steroidogenesis and cell proliferation through a decrease in the activation of IGF-1R signalling pathways in primary hGCs. PMID- 22447629 TI - Temporal compliance trends in a cluster randomization with crossover trial of out of-hospital cardiac arrest. AB - BACKGROUND: Low compliance to randomized nondrug interventions can affect treatment estimates of clinical trials. Cluster-randomized crossover may be appropriate for increasing compliance in the out-of-hospital cardiac arrest setting. PURPOSE: The purpose was to determine whether the elapsed time from start of a nonblinded treatment period to episode enrollment date in a cluster randomized crossover trial is associated with compliance to either a period of brief cardiopulmonary resuscitation (CPR) with electrocardiogram (ECG) rhythm analysis or a period of longer CPR with a delayed ECG rhythm analysis in patients with out-of-hospital cardiac arrest. METHODS: The Resuscitation Outcomes Consortium PRIMED Analyze Late (AL) versus Analyze Early (AE) trial was a cluster randomized crossover trial at 10 North American regional sites. Clusters were created based on local service preference with treatment periods varying from 3 to 12 months depending on the expected enrollment rate of each randomizing unit. Episodes on the AL arm had a target of 180 s from CPR start to shock assessment and were deemed compliant if total time was between 150 and 210 s. Episodes on the AE arm had a target of <30 s from CPR start to shock assessment and were deemed compliant if total time was <60 s. We used logistic regression to examine the association between compliance (yes/no) and the elapsed number of days from the start of the treatment period to the episode in the framework of generalized estimating equations, controlling for randomized treatment (Late, reference = Early) and treatment period length (reference = 3, 4-5, 6, 7-11, and 12 months). RESULTS: We had 8769 episodes in our analysis population. Overall compliance to the randomized arm was 63.5%. After adjusting for treatment arm and treatment period length, the odds of compliance for episodes occurring >300 days from treatment period start were 33% lower (odds ratio (OR): 0.67; 95% confidence interval (CI): 0.52, 0.86) than for those <60 days from treatment period start. There was no significant difference in compliance between episodes before and immediately after a cluster crossed over to the opposite arm (OR: 0.81; 95% CI: 0.57, 1.16). LIMITATIONS: A major challenge was the lack of synchronicity between training cycles and agency crossover dates. CONCLUSION: We found a significant decrease in compliance to the AL versus AE cardiac arrest intervention as the elapsed time from start of treatment period increased. We did not find a difference in compliance immediately before and after a crossover. While these results suggest that future cluster with crossover trials in the out-of-hospital setting be designed with short treatment periods and frequent crossovers, provider logistical concerns must also be considered. PMID- 22447630 TI - Electrochemistry of carbon nanotubes: reactive processes, dual sensing-actuating properties and devices. AB - Single-walled carbon nanotubes (SWCNT) embedded in a non-electroactive polymer are electrochemically characterized. The increasing voltammetric maximums obtained with rising temperature or electrolyte concentration point to a chemical nature of the processes. The chemical kinetic control of the processes is corroborated by its empirical chemical kinetics: the initial reaction rates are obtained from the chronoamperometric responses to potential steps. The activation energy of the reaction includes information about the structural state of the SWCNT before the potential step. Under constant current the potential evolution (chronopotentiometric response) and consumed electrical energy at any time change as a function of (are sensors of) the experimental temperature or the electrolyte concentration. The reactive material, or any device based on this material, senses these working variables, and shows dual and simultaneous actuating-sensing properties. PMID- 22447631 TI - Damnacanthal from the Congolese medicinal plant Garcinia huillensis has a potent preferential cytotoxicity against human pancreatic cancer PANC-1 cells. AB - Screening of eight Congolese medicinal plants showed that the CHCl(3) and MeOH extracts of Aframomum melegueta (PC(50) = 47.8 ug/mL and 13.8 ug/mL, respectively) and CHCl(3) extracts of Garcinia huillensis (PC(50) = 17.8 ug/mL) and Securidaca longepedunculata (PC(50) = 23.4 ug/mL) had preferential cytotoxicity against human pancreatic cancer PANC-1 cells under nutrient-deprived conditions. The active constituents of the CHCl(3) extract of G. huillensis were examined and 12 known anthraquinones were identified. Among them, damnacanthal (1) caused preferential necrotic cell death of PANC-1 and PSN-1 cells under nutrient-deprived and serum-sensitive conditions (PC(50) = 4.46 um and 3.77 um, respectively). PMID- 22447632 TI - Early detection of impending physiologic deterioration among patients who are not in intensive care: development of predictive models using data from an automated electronic medical record. AB - BACKGROUND: Ward patients who experience unplanned transfer to intensive care units have excess morbidity and mortality. OBJECTIVE: To develop a predictive model for prediction of unplanned transfer from the medical-surgical ward to intensive care (or death on the ward in a patient who was "full code") using data from a comprehensive inpatient electronic medical record (EMR). DESIGN: Retrospective case-control study; unit of analysis was a 12-hour patient shift. Shifts where a patient experienced an unplanned transfer were event shifts; shifts without a transfer were comparison shifts. Hospitalization records were transformed into 12-hour shift records, with 10 randomly selected comparison shifts identified for each event shift. Analysis employed logistic regression and split validation. SETTING: Integrated healthcare delivery system in Northern California. PATIENTS: Hospitalized adults at 14 hospitals with comprehensive inpatient EMRs. MEASUREMENTS: Predictors included vital signs, laboratory test results, severity of illness scores, longitudinal chronic illness burden scores, transpired hospital length of stay, and care directives. Patients were also given a retrospective, electronically (not manually assigned) Modified Early Warning Score, or MEWS(re). Outcomes were transfer to the intensive care unit (ICU) from the ward or transitional care unit, or death outside the ICU among patients who were "full code". RESULTS: We identified 4,036 events and 39,782 comparison shifts from a cohort of 102,422 patients' hospitalizations. The MEWS(re) had a c statistic of 0.709 in the derivation and 0.698 in the validation dataset; corresponding values for the EMR-based model were 0.845 and 0.775. LIMITATIONS: Using these algorithms requires hospitals with comprehensive inpatient EMRs and longitudinal data. CONCLUSIONS: EMR-based detection of impending deterioration outside the ICU is feasible in integrated healthcare delivery systems. PMID- 22447633 TI - Influence of drug use on morbidity and mortality in heatstroke. AB - Numerous medications and illicit drugs can predispose an individual to heat illness, primarily by altering thermoregulation by either increasing endogenous heat production or impairing heat dissipation. This study sought to determine if use of such drugs was associated with more severe illness in patients presenting with heatstroke. A case control study was conducted on adult patients (age, >=14 years) admitted to an intensive care unit with an admitting diagnosis of heatstroke at two academic teaching hospitals in Phoenix, AZ, between 31 August 2005 through 31 July 2010. Subjects were classified as "users" if they admitted to taking a drug on a pre-defined list of drugs associated with abnormal thermal homeostasis, or if a urine test for drugs of abuse revealed the presence of an amphetamine or cocaine. Similarly, subjects who did not take such drugs were considered "non-users." Seventy-eight patients were identified, with complete medication histories available for 74 of 78 subjects. The overall prevalence of drug utilization was 41.9 % (31 of 74). The median length of stay was 3.0 days for the non-users compared with 9.0 days for "users." There was no difference between users and non-users with regard to mortality. Drugs that impair thermoregulation are frequently encountered in patients admitted for heatstroke. Patients taking such drugs may experience increased morbidity over those patients not taking such drugs. PMID- 22447634 TI - Welfare-related health inequality: does the choice of measure matter? AB - Using representative microdata from the German Socio-Economic Panel Study (SOEP), we show that the welfare measure choice has a substantial impact on the degree of welfare-related health inequality. To assess the sensitivity of welfare-related health inequality measures, we combine a unique set of income and wealth measures with different subjective, cardinalized, and (quasi-)objective health measures. The influence of the welfare measure is more pronounced when using subjective health measures than when using (quasi-)objective health measures. PMID- 22447635 TI - Student award for outstanding research winner in the Ph.D. category for the 9th World Biomaterials Congress, Chengdu, China, June 1-5, 2012: synthesis and application of photodegradable microspheres for spatiotemporal control of protein delivery. AB - In this study, the authors present a photodegradable microparticle system that can be used to entrap and deliver bioactive proteins to cells during culture. By using a photosensitive delivery system, experimenters can achieve a wide variety of spatiotemporally regulated release profiles with a single microparticle formulation, thereby, enabling one to probe many questions as to how protein presentation can be manipulated to regulate cell function. Photodegradable microparticles were synthesized via inverse suspension polymerization with a mean diameter of 22 MUm, and degradation was demonstrated upon exposure to several irradiation conditions. The protein-loaded depots were incorporated into cell cultures and release of bioactive protein was quantified during the photodegradation process. This phototriggered release allowed for the delivery of TGF-beta1 to stimulate PE25 cells and for the delivery of fluorescently labeled Annexin V to assay apoptotic 3T3 fibroblasts during culture. By incorporating these photoresponsive protein delivery depots into cell culture, new types of experiments are now possible to test hypotheses about how individual or multiple soluble factors might affect cell function when presented in a uniform, temporally varying, or gradient manner. PMID- 22447636 TI - Efficacy of intratympanic steroid administration on idiopathic sudden sensorineural hearing loss in comparison with hyperbaric oxygen therapy. AB - OBJECTIVES/HYPOTHESIS: The efficacy of intratympanic steroid administration was examined in comparison with hyperbaric oxygen (HBO) therapy in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Retrospective study. METHODS: Two hundred seventy-six consecutive patients with ISSNHL (average hearing levels at 250, 500, 1,000, 2,000, and 4,000 Hz >= 40 dB; time from onset to treatment <=30 days) were enrolled. All the patients were given intravenous hydrocortisone (400 mg/day) followed by tapered doses. In addition, 174 patients underwent HBO therapy (HBO group), and 102 patients received intratympanic dexamethasone injection (IT group). The hearing outcomes were evaluated by six indices; the cure rate, marked-recovery rate (percent of patients with hearing gains >=30 dB), recovery rate (percent of patients with hearing gains >=10 dB), hearing gain, hearing level after treatment, and hearing improvement rate compared to the unaffected contralateral ear. RESULTS: There was no significant difference in the cure rate, marked-recovery rate, hearing gain, hearing level after treatment, or hearing improvement rate between the two groups; however, the recovery rate was significantly higher in the IT group than in the HBO group (79.4% vs. 68.4%; P = .048). Multiple logistic regression analysis also showed that patients in the IT group were significantly more likely to recover than those in the HBO group (odds ratio: 2.045; 95% confidence interval: 1.097-3.812; P = .024). CONCLUSIONS: Systemic plus intratympanic steroid administration is more effective than systemic steroids plus HBO therapy, and can be a useful first-choice treatment for ISSNHL. PMID- 22447638 TI - Review: extrapyramidal side effects vary between different second-generation antipsychotic drugs. PMID- 22447637 TI - Impact of childhood trauma on the outcomes of a perinatal depression trial. AB - BACKGROUND: Childhood abuse and neglect have been linked with increased risks of adverse mental health outcomes in adulthood and may moderate or predict response to depression treatment. In a small randomized controlled trial treating depression in a diverse sample of nontreatment-seeking, pregnant, low-income women, we hypothesized that childhood trauma exposure would moderate changes in symptoms and functioning over time for women assigned to usual care (UC), but not to brief interpersonal psychotherapy (IPT-B) followed by maintenance IPT. Second, we predicted that trauma exposure would be negatively associated with treatment response over time and at the two follow-up time points for women within UC, but not for those within IPT-B who were expected to show remission in depression severity and other outcomes, regardless of trauma exposure. METHODS: Fifty-three pregnant low-income women were randomly assigned to IPT-B (n = 25) or UC (n = 28). Inclusion criteria included >= 18 years, >12 on the Edinburgh Postnatal Depression Scale, 10-32 weeks gestation, English speaking, and access to a phone. Participants were evaluated for childhood trauma, depressive symptoms/diagnoses, anxiety symptoms, social functioning, and interpersonal problems. RESULTS: Regression and mixed effects repeated measures analyses revealed that trauma exposure did not moderate changes in symptoms and functioning over time for women in UC versus IPT-B. Analyses of covariance showed that within the IPT-B group, women with more versus less trauma exposure had greater depression severity and poorer outcomes at 3-month postbaseline. At 6-month postpartum, they had outcomes indicating remission in depression and functioning, but also had more residual depressive symptoms than those with less trauma exposure. CONCLUSIONS: Childhood trauma did not predict poorer outcomes in the IPT-B group at 6-month postpartum, as it did at 3-month postbaseline, suggesting that IPT including maintenance sessions is a reasonable approach to treating depression in this population. Since women with more trauma exposure had more residual depressive symptoms at 6 month postpartum, they might require longer maintenance treatment to prevent depressive relapse. PMID- 22447639 TI - Rapamycin inhibits the invasive ability of thyroid cancer cells by down regulating the expression of VEGF-C in vitro. AB - The aim of this study was to observe the effects of rapamycin on proliferation, apoptosis and invasion of SW579 in vitro. The proliferation and apoptosis of SW579 cells were detected by methyl thiazolyl tetrazolium and flow cytometry. Transwell assay was used to observe the changes of invasive ability of SW579 cells after being treated with rapamycin. The effects of rapamycin on the expression of mammalian target of rapamycin (mTOR) signalling and vascular endothelial growth factor C (VEGF-C) were observed by Western blot. The inhibition and apoptosis rates increased obviously when the concentration of rapamycin was 20 nm. When the rapamycin concentration was 10 nm, the invasive ability of SW579 cells changed significantly than when it was 5 nm. Our data showed that when the concentrations of rapamycin were over 20 nm, the expression of mTOR and p70S6K decreased significantly, and the expression of PTEN increased notably. There were no remarkable variations observed when we detected the expression of Akt. We found the expression of VEGF-C was high in SW579 cells and decreased slightly when the cells were treated with 5 nm rapamycin. When the concentration of rapamycin was over 5 nm, significant changes were observed. Rapamycin could inhibit the proliferation and induce the apoptosis of human thyroid cancer cells in vitro by mTOR inhibition. No obvious changes observed in the expression of AKT indicated that there might be a feedback loop effect by the mTOR inhibition induced by rapamycin. Rapamycin could inhibit the invasive ability of SW579 cells by down-regulating the expression of VEGF-C. PMID- 22447640 TI - Influence of an unnatural amino acid side chain on the conformational dynamics of peptides. AB - In this work, a non-natural amino acid, H-propargylglycine-OH (Pra), is chosen to examine the side-chain effect on the backbone conformation of small peptides. The conformations of two synthesized Pra-containing tripeptides, Ac-Pra-Pra-NH(2) (PPTP) and Ac-Pra-Ala-NH(2) (PATP), are examined by infrared (IR) spectroscopy in combination with molecular dynamics (MD) simulations and quantum chemical computations. By analyzing the joint distributions of backbone torsional angles, several significant conformations can be identified for the two tripeptides solvated in D(2)O. At room temperature, 44 % of PPTP exists in the alpha-alpha conformation and 33 % of PATP exists in the alpha-polyproline-II conformation. Larger structural inhomogeneity is seen in both cases by MD simulations at elevated temperatures. Thus even a small side chain, such as the propargyl group can significantly alter the peptide backbone conformations. The results suggest that there is no overwhelming conformational propensity of the Pra residue in short peptides. IR spectra simulated in the amide-I region using two different methods, reasonably reproduce the experimental IR spectra and their temperature dependence. PMID- 22447641 TI - Potential antidepressant activity of Areca catechu nut via elevation of serotonin and noradrenaline in the hippocampus of rats. AB - The current study was aimed at investigating the potential antidepressant activity of Areca catechu nut ethanol extract and its various fractions using behavioral (acute and sub-chronic forced swim tests) and biochemical (monoamines and their metabolite levels using high performance liquid chromatography) tests. The areca nut ethanol extract and its aqueous fraction exhibited antidepressant activity in both acute and sub-chronic forced swim tests (IC50 ~ 50 and 20 mg/kg, respectively), which was further confirmed by unaltered locomotor (horizontal and vertical) activities of rats in the activity cage. Phytochemical analysis revealed that saponins of areca nut may be the active component in its antidepressant action. The rats treated sub-chronically with areca nut extract displayed toxic effects, whereas its active aqueous fraction was non-toxic, indicating the presence of different constituents for antidepressant and toxic effects. In the hippocampus of rats, the areca nut extract (50 mg/kg) and aqueous fraction (20 mg/kg) caused a significant elevation of serotonin (around 35%) and noradrenaline (around 30%) compared with the control (261 +/- 25 and 512 +/- 29 ng/g, respectively). In conclusion, the areca nut possesses potential antidepressant effect via the elevation of serotonin and noradrenaline. PMID- 22447642 TI - Hidden effectiveness? Results of hand-searching Italian language journals for occupational health interventions. AB - OBJECTIVE: To compare the yield of hand-searching with optimised electronic search strategies in retrieving occupational health (OH) intervention studies published in a language other than English. METHODS: The authors systematically hand-searched and screened reports of OH intervention studies published in Italian in peer-reviewed scientific journals between 1990 and 2008. The authors evaluated how many of them met the Cochrane Occupational Safety and Health Review Groups (OSHRG) definition of being an OH intervention study and how many potentially relevant studies retrieved by hand-searching would not be found by PubMed alone using the OSHRG's most specific and most sensitive search strings. RESULTS: Hand-searching retrieved 25 articles (reporting 27 studies), including nine not indexed in MEDLINE. Most studies (81%, 22/27) had a before-after design and only one was a randomised trial. The OSHRG's most sensitive search string retrieved all 16 articles published in the Italian language journals that were indexed in MEDLINE, while the most specific search strategy retrieved nine articles (56%, 9/16). The most specific search string showed a lower 'number needed to read' value than the most sensitive one (60 vs 132). CONCLUSIONS: These findings suggest that a sensitive electronic search strategy may be able to find most of the OH interventions published in languages other than English that are indexed in MEDLINE. Hand-searching of important national journals not indexed in MEDLINE should be considered when conducting particularly in-depth research. PMID- 22447643 TI - Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts. AB - OBJECTIVES: Though toxicological experiments demonstrate the teratogenicity of organic solvents in animal models, epidemiologic studies have reported inconsistent results. Using data from the population-based National Birth Defects Prevention Study, the authors examined the relation between maternal occupational exposure to aromatic solvents, chlorinated solvents and Stoddard solvent during early pregnancy and neural tube defects (NTDs) and orofacial clefts (OFCs). METHODS: Cases of NTDs (anencephaly, spina bifida and encephalocoele) and OFCs (cleft lip +/- cleft palate and cleft palate alone) delivered between 1997 and 2002 were identified by birth defect surveillance registries in eight states; non malformed control infants were selected using birth certificates or hospital records. Maternal solvent exposure was estimated by industrial hygienist review of self-reported occupational histories in combination with a literature-derived exposure database. ORs and 95% CIs for the association between solvent class and each birth defect group and component phenotype were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, folic acid supplement use and smoking. RESULTS: The prevalence of exposure to any solvent among mothers of NTD cases (n = 511), OFC cases (n = 1163) and controls (n = 2977) was 13.1%, 9.6% and 8.2%, respectively. Exposure to chlorinated solvents was associated with increased odds of NTDs (OR = 1.96, CI 1.34 to 2.87), especially spina bifida (OR = 2.26, CI 1.44 to 3.53). No solvent class was strongly associated with OFCs in these data. CONCLUSIONS: The findings suggest that maternal occupational exposure to chlorinated solvents during early pregnancy is positively associated with the prevalence of NTDs in offspring. PMID- 22447644 TI - Determinants of early-stage hearing loss among a cohort of young workers with 16 year follow-up. AB - OBJECTIVES: The authors had a unique opportunity to study the early impacts of occupational and recreational exposures on the development of noise-induced hearing loss (NIHL) in a cohort of 392 young workers. The objectives of this study were to estimate strength of associations between occupational and recreational exposures and occurrence of early-stage NIHL and to determine the extent to which relationships between specific noise exposures and early-stage NIHL were mitigated through the use of hearing protection. METHODS: Participants were young adults who agreed to participate in a follow-up of a randomised controlled trial. While the follow-up study was designed to observe long-term effects (up to 16 years) of a hearing conservation intervention for high school students, it also provided opportunity to study the potential aetiology of NIHL in this worker cohort. Study data were collected via exposure history questionnaires and clinical audiometric examinations. RESULTS: Over the 16-year study period, the authors documented changes to hearing acuity that exceeded 15 dB at high frequencies in 42.8% of men and 27.7% of women. Analyses of risk factors for NIHL were limited to men, who comprised 68% of the cohort, and showed that risks increased in association with higher levels of the most common recreational and occupational noise sources, as well as chemical exposures with ototoxic potential. Use of hearing protection and other safety measures, although not universal and sometimes modest, appeared to offer some protection. CONCLUSIONS: Early-stage NIHL can be detected in young workers by measuring high frequency changes in hearing acuity. Hearing conservation programmes should focus on a broader range of exposures, whether in occupational or non-occupational settings. Priority exposures include gunshots, chainsaws, power tools, smoking and potentially some chemical exposures. PMID- 22447645 TI - Basal ganglia intensity indices and diffusion weighted imaging in manganese exposed welders. AB - OBJECTIVES: Manganese exposure leads to diffuse cerebral metal deposition with the highest concentration in the globus pallidus associated with increased T1 weighted MRI signal. T1 signal intensity in extra-pallidal basal ganglia (caudate and putamen) has not been studied in occupationally exposed workers. Diffusion weighted imaging is a non-invasive measure of neuronal damage and may provide a quantification of neurotoxicity associated with welding and manganese exposure. This study investigated extra-pallidal T1 basal ganglia signal intensity as a marker of manganese exposure and basal ganglia diffusion weighted imaging abnormalities as a potential marker of neurotoxicity. METHODS: A 3T MR case:control imaging study was performed on 18 welders and 18 age- and gender matched controls. Basal ganglia regions of interest were identified for each subject. T1-weighted intensity indices and apparent diffusion coefficients were generated for each region. RESULTS: All regional indices were higher in welders than controls (p <= 0.05). Combined basal ganglia (rho = 0.610), caudate (rho = 0.645), anterior (rho = 0.595) and posterior putamen (rho = 0.511) indices were more correlated with exposure than pallidal (rho = 0.484) index. Welder apparent diffusion coefficient values were lower than controls for globus pallidus (p = 0.03) and anterior putamen (p = 0.004). CONCLUSIONS: Welders demonstrated elevated T1 indices throughout the basal ganglia. Combined basal ganglia, caudate and putamen indices were more correlated with exposure than pallidal index suggesting more inclusive basal ganglia sampling results in better exposure markers. Elevated indices were associated with diffusion weighted abnormalities in the pallidum and anterior putamen suggesting neurotoxicity in these regions. PMID- 22447646 TI - Online evaluation programs: benefits and limitations. AB - Patient navigation programs are increasing throughout the USA, yet some evaluation measures are too vague to determine what and how navigation functions. Through collaborative efforts an online evaluation program was developed. The goal of this evaluation program is to make data entry accurate, simple, and efficient. This comprehensive program includes major components on staff, mentoring, committees, partnerships, grants/studies, products, dissemination, patient navigation, and reports. Pull down menus, radio buttons, and check boxes are incorporated whenever possible. Although the program has limitations, the benefits of having access to current, up-to-date program data 24/7 are worth overcoming the challenges. Of major benefit is the ability of the staff to tailor summary reports to provide anonymous feedback in a timely manner to community partners and participants. The tailored data are useful for the partners to generate summaries for inclusion in new grant applications. PMID- 22447647 TI - Cell membrane integrity and internalization of ingested TiO(2) nanoparticles by digestive gland cells of a terrestrial isopod. AB - The present study was motivated by the paucity of reports on cellular internalization of ingested titanium dioxide (TiO(2)) nanoparticles (nano TiO(2)). The model invertebrate (Porcellio scaber, Isopoda, Crustacea) was exposed to food dosed with nano-TiO(2) containing 100, 1,000, 3,000, or 5,000 ug nano-TiO(2) per gram of food. After 14 d of exposure, the amount of Ti in the entire body was analyzed by inductively coupled plasma-mass spectrometry, and elemental analyses of tissue cross sections were performed by particle induced X ray emission. In addition, a series of toxicological markers including feeding parameters, weight change, and survival, as well as cytotoxic effects such as digestive gland cell membrane stability, were monitored. Internalization of ingested nano-TiO(2) by the isopod's digestive gland epithelial cells was shown to depend on cell membrane integrity. Cell membranes were found to be destabilized by TiO(2) particles, and at higher extracellular concentrations of nano-TiO(2), the nanoparticles were internalized. PMID- 22447648 TI - Comparability of protein therapeutics: quantitative comparison of second derivative amide I infrared spectra. AB - Comparability determination for protein therapeutics requires an assessment of their higher order structure, usually by using spectroscopic methods. One of the most common techniques used to determine secondary structure composition of proteins is analysis of the second derivative of the amide I region of Fourier transform infrared (FTIR) spectra. A number of algorithms have been described for quantitative comparison of second-derivative amide I FTIR spectra, but no systematic evaluation has been conducted to assess these approaches. In this study, the two most common methods, spectral correlation coefficient and area of overlap (AO), are compared for their ability to determine spectral comparability of a protein as a function of changes in pH or temperature. Two other algorithms were considered as well. Recently, a QC compare similarity function found in OMNIC software has been reported as being useful in comparing amide I FTIR spectra. In addition, a new algorithm, termed modified AO, is described herein. These four methods were evaluated for their ability to determine comparability for second-derivative amide I FTIR spectra of four model proteins. The result is a framework for quantitative determination of whether any two spectra differ significantly. PMID- 22447649 TI - "Can we just stop and talk?" patients value verbal communication about discharge care plans. AB - BACKGROUND: Studies show that hospitalized patients often do not understand their postdischarge care plan. There are few studies about patients' preferences regarding the content of discharge care plans. OBJECTIVE: To identify what patients view as essential elements of a post-hospitalization plan. DESIGN: Anonymous written survey distributed on the second day of admission to internal medicine wards. SETTING: An academic tertiary care hospital and an academic county hospital in Seattle, Washington. PATIENTS: Two hundred English-speaking adult inpatients >= 18 years or their proxies. RESULTS: The majority of patients (64.5%) surveyed wanted verbal discharge instructions, with only 10.5% requesting written instructions (P < 0.0001). One hundred percent of patients valued the following discharge instructions as essential: "when you need to follow-up with [primary care provider] PCP," "warning signs to call PCP," and "medicines to continue post-hospitalization." One hundred percent of patients wanted "a lot of information about my condition" and "test results," but only 39% wanted "a lot of information about my medications" (P < 0.0001). When asked to choose the most important piece of discharge instruction related to their disease, 67.5% of patients chose "lifestyle changes." One hundred percent of patients thought that personal communication between the inpatient provider and the outpatient primary care provider was "extremely important" or "essential." CONCLUSION: Patients uniformly placed high value on: 1) verbal communication about discharge care plans; 2) information about lifestyle changes for improved health; and 3) personal communication between inpatient and outpatient providers. PMID- 22447650 TI - Computational investigation of the HIV-1 Rev multimerization using molecular dynamics simulations and binding free energy calculations. AB - The HIV Rev protein mediates the nuclear export of viral mRNA, and is thereby essential for the production of late viral proteins in the replication cycle. Rev forms a large organized multimeric protein-protein complex for proper functioning. Recently, the three-dimensional structures of a Rev dimer and tetramer have been resolved and provide the basis for a thorough structural analysis of the binding interaction. Here, molecular dynamics (MD) and binding free energy calculations were performed to elucidate the forces thriving dimerization and higher order multimerization of the Rev protein. It is found that despite the structural differences between each crystal structure, both display a similar behavior according to our calculations. Our analysis based on a molecular mechanics-generalized Born surface area (MM/GBSA) and a configurational entropy approach demonstrates that the higher order multimerization site is much weaker than the dimerization site. In addition, a quantitative hot spot analysis combined with a mutational analysis reveals the most contributing amino acid residues for protein interactions in agreement with experimental results. Additional residues were found in each interface, which are important for the protein interaction. The investigation of the thermodynamics of the Rev multimerization interactions performed here could be a further step in the development of novel antiretrovirals using structure based drug design. Moreover, the variability of the angle between each Rev monomer as measured during the MD simulations suggests a role of the Rev protein in allowing flexibility of the arginine rich domain (ARM) to accommodate RNA binding. PMID- 22447651 TI - Aging of porous silicon in physiological conditions: cell adhesion modes on scaled 1D micropatterns. AB - The surface properties of porous silicon (PSi) evolve rapidly in phosphate buffered saline. X-ray photoelectron spectra indicate the formation of a Si-OH and C-O enriched surface, which becomes increasingly hydrophilic with aging time. Multiscale stripe micropatterns of Si and PSi have been fabricated by means of a high-energy ion-beam irradiation process. These micropatterns have been aged in physiological conditions and used to analyze human mesenchymal stem cell (hMSC) adhesion. The actin cytoskeleton of hMSCs orients following the uniaxial micropatterns. In the wider Si stripes, hMSCs are dominantly located on Si areas. However, for reduced Si widths, adhesion is avoided on PSi by a split assembly of the actin cytoskeleton on two parallel Si areas. These results confirm that nanostructured Si-OH/C-O-rich surfaces with hydrophilic character are specially adapted for the creation of cell adhesion surface contrasts. PMID- 22447652 TI - Effect of passive smoking on the ultrastructure of the nasal mucosa in children. AB - OBJECTIVES/HYPOTHESIS: Passive exposure to cigarette smoke has been implicated in a number of respiratory childhood disorders. Most studies concerning smoking were directed to its carcinogenic effect on the lungs. However, the effects of smoking on nasal respiratory mucosa have not been widely studied. The aim of the present study was, therefore, to study the ultrastructural changes in the nasal mucosa of a pediatric population exposed to passive smoking. STUDY DESIGN: The study included 20 children between the ages of 5 and 11 years, who were scheduled for tonsillectomy and at the same time had a positive history of prolonged exposure to household passive smoke. Another 10 children with a negative household smoking history were included as a control group. All children were nonatopic and with a negative family history of allergy. None of them had adenoids or infective rhinosinusitis. METHODS: At the time of surgery, a 1-mm(3) biopsy was taken was taken from the lower border of the inferior turbinate. The specimens were processed and examined with electron microscopy RESULTS: Examination of the nasal mucosa showed several ultrastructural changes. These included patchy loss of cilia, generalized loss of cilia, squamous metaplasia, hyperplasia of goblet cells and seromucinous acini, and vascular congestion. More severe changes were observed with longer passive exposures to cigarette smoke. The study did not disclose any evidence of ongoing allergic reaction or neoplastic transformations. CONCLUSIONS: Children exposed to passive cigarette smoke may develop several structural changes in the respiratory nasal mucosa with subsequent negative effects on its ciliary activity and mucociliary function. As a result of these effects, defense mechanisms of the nose may be ruined or lost, and those children may develop persistent sinonasal infections. Exposure of these children to passive smoking for longer periods of time may also induce other significant changes that were not detected in the present study. PMID- 22447654 TI - Flushing of intravenous locks in neonates: no evidence that heparin improves patency compared with saline. PMID- 22447653 TI - Quantitative analysis of photoactivated localization microscopy (PALM) datasets using pair-correlation analysis. AB - Pointillistic based super-resolution techniques, such as photoactivated localization microscopy (PALM), involve multiple cycles of sequential activation, imaging, and precise localization of single fluorescent molecules. A super resolution image, having nanoscopic structural information, is then constructed by compiling all the image sequences. Because the final image resolution is determined by the localization precision of detected single molecules and their density, accurate image reconstruction requires imaging of biological structures labeled with fluorescent molecules at high density. In such image datasets, stochastic variations in photon emission and intervening dark states lead to uncertainties in identification of single molecules. This, in turn, prevents the proper utilization of the wealth of information on molecular distribution and quantity. A recent strategy for overcoming this problem is pair-correlation analysis applied to PALM. Using rigorous statistical algorithms to estimate the number of detected proteins, this approach allows the spatial organization of molecules to be quantitatively described. PMID- 22447655 TI - Design rules for nanogap-based hydrogen gas sensors. AB - Nanoscale gaps, which enable many research applications in fields such as chemical sensors, single-electron transistors, and molecular switching devices, have been extensively investigated over the past decade and have witnessed the evolution of related technologies. Importantly, nanoscale gaps employed in hydrogen-gas (H(2)) sensors have been used to reversibly detect H(2) in an On-Off manner, and function as platforms for enhancing sensing performance. Herein, we review recent advances in nanogap design for H(2) sensors and deal with various strategies to create these gaps, including fracture generation by H(2) exposure, deposition onto prestructured patterns, island formation on a surface, artificial manipulation methods, methods using hybrid materials, and recent approaches using elastomeric substrates. Furthermore, this review discusses a new nanogap design that advances sensing capabilities in order to meet the diverse needs of academia and industry. PMID- 22447656 TI - Crystal structure of agkisacucetin, a Gpib-binding snake C-type lectin that inhibits platelet adhesion and aggregation. AB - Agkisacucetin is a snake C-type lectin isolated from the venom of Agkistrodon acutus (A. acutus). It binds specifically to the platelet glycoprotein (GP) Ib and prevents the von Willebrand factor (VWF) accessing it. We determined the crystal structure of agkisacucetin to 1.9A resolution. The structure of agkisacucetin has an (alphabeta) fold similar to another GPIb-binding protein, flavocetin-A, but lacks the C-terminal cysteine in the beta-subunit, does not form (betaalpha)(4) tetramers, and does not cluster GPIbs, like flavocetin-A. PMID- 22447657 TI - Dexamethasone and postoperative bleeding after tonsillectomy and adenotonsillectomy in children: A meta-analysis of prospective studies. AB - OBJECTIVES/HYPOTHESIS: Tonsillectomy and adenotonsillectomy are common pediatric surgical procedures. Although perioperative administration of dexamethasone is common, recent data indicate a possible association between dexamethasone and increased risk of postoperative hemorrhage. STUDY DESIGN: Meta-analysis of prospective studies. METHODS: Meta-analysis using MEDLINE and EMBASE, including all placebo-controlled prospective studies with perioperative dexamethasone as the intervention and postoperative bleeding as the outcome, in children age <18 years undergoing tonsillectomy or adenotonsillectomy. The association between any dexamethasone dose and bleeding outcomes was quantified. Dexamethasone dose analyses were performed using meta-regression and stratified dose analysis models. Individuals were pooled using the random effects model, and Mantel Haenszel odds ratios (OR) were used to assess the associations. All P values were two-sided. RESULTS: Twelve studies with 1,180 total participants were included in the meta-analysis. There was no significant association between dexamethasone at any dose and odds of bleeding compared to placebo (OR = 1.07; 95% confidence interval [CI], 0.58-1.98; P = .82). There was no significant association between increasing dexamethasone dose and bleeding (regression slope = -1.47, P = .10). Stratifying by dose ranges, studies comparing dexamethasone doses in 0.4 to 0.6 mg/kg range to placebo showed significantly increased odds of bleeding (OR = 3.14; 95% CI, 1.14-8.65; P = .03). Higher or lower doses were not associated with a difference in bleeding. CONCLUSIONS: There was no overall association between dexamethasone administration and postoperative bleeding in children undergoing tonsillectomy or adenotonsillectomy. However, this study cannot exclude the possibility of an association between specific dexamethasone doses and increased odds of bleeding. The results underscore the need for more dedicated prospective studies of this very common intervention. PMID- 22447658 TI - Polo-like kinase 1, on the rise from cell cycle regulation to prostate cancer development. AB - Polo-like kinase 1 (Plk1), a well-characterized member of serine/threonine kinases Plk family, has been shown to play pivotal roles in mitosis and cytokinesis in eukaryotic cells. Recent studies suggest that Plk1 not only controls the process of mitosis and cytokinesis, but also, going beyond those previously described functions, plays critical roles in DNA replication and Pten null prostate cancer initiation. In this review, we briefly summarize the functions of Plk1 in mitosis and cytokinesis, and then mainly focus on newly discovered functions of Plk1 in DNA replication and in Pten-null prostate cancer initiation. Furthermore, we briefly introduce the architectures of human and mouse prostate glands and the possible roles of Plk1 in human prostate cancer development. And finally, the newly chemotherapeutic development of small molecule Plk1 inhibitors to target Plk1 in cancer treatment and their translational studies are also briefly reviewed. PMID- 22447659 TI - Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis. AB - Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima. The formation of macrophage derived foam cells in a plaque is a hallmark of the development of atherosclerosis. Lipid homeostasis, especially cholesterol homeostasis, plays a crucial role during the formation of foam cells. Recently, lipid droplet associated proteins, including PAT and CIDE family proteins, have been shown to control the development of atherosclerosis by regulating the formation, growth, stabilization and functions of lipid droplets in macrophage-derived foam cells. This review focuses on the potential mechanisms of formation of macrophage derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins. Understanding the process of foam cell formation will aid in the future discovery of novel therapeutic interventions for atherosclerosis. PMID- 22447660 TI - Duration of last depressive episode may influence serum BDNF levels in remitted patients with major depression. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) may have an important role in the pathophysiology of depression. Previous studies indicate that serum BDNF levels were lower in patients with depression and increased after treatment with antidepressants. However, results of studies on serum BDNF levels in remitted patients with depression have been inconsistent. The purpose of the present study was to determine which factors influence the alteration of serum BDNF levels in depression in the remitted state. METHODS: Serum BDNF levels were evaluated in 75 remitted inpatients with major depressive disorder (MDD) and 108 controls. Multiple regression analyses were conducted using serum BDNF levels as the dependent variable; and the number of episodes, Hamilton Rating Scale for Depression score at admission, or duration of last depressive episode as independent variables. RESULTS: Serum BDNF levels were lower in remitted patients with MDD than in controls (P < .001). Multiple regression analysis showed a significant effect between the duration of the last depressive episode and serum BDNF levels (P < .022). CONCLUSIONS: Serum BDNF levels in remitted patients with MDD did not recover to the level of healthy controls, and lower serum BDNF levels were influenced by a longer duration of last depressive episode. It is possible that persistent hippocampal reduction in remitted depression may be caused by lower BDNF levels associated with a longer duration of the last depressive episode. PMID- 22447661 TI - Atomic structural analysis of nanowire defects and polytypes enabled through cross-sectional lattice imaging. AB - Correlated transmission electron microscopy imaging, electron diffraction, and Raman spectroscopy are used to investigate the structure of Si nanowires with planar defects. In addition to plan-view imaging, individual defective nanowires are imaged in axial cross-section at specific locations selected in plan-view imaging. This correlated characterization approach enables definitive identification of complex defect structures that give rise to diffraction patterns that have been misinterpreted in the literature. Conclusive evidence for the 9R Si polytype is presented, and the atomic structure of this phase is correlated with kinematically-forbidden reflections in Si diffraction patterns. Despite striking similarities between imaging and diffraction data from twinned nanowires and the 9R polytype, clear distinctions between the structures can be made. Finally, the structural origins of 1/3{422} reflections in Si [111] diffraction patterns are identified. PMID- 22447662 TI - Effects of the total alkaloidal extract of Murraya koenigii leaf on oxidative stress and cholinergic transmission in aged mice. AB - Alzheimer's disease (AD) is characterized by signs of major oxidative stress and the loss of cholinergic cells. The present study was designed to investigate the role of the total alkaloidal extract from Murraya koenigii (MKA) leaves on age related oxidative stress and the cholinergic pathway in aged mice. Ascorbic acid (100 mg/kg, p.o.) was used as a standard drug. The MKA improved the level of protective antioxidants such as glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase (GRD), superoxide dismutase (SOD) and catalase (CAT) in brain homogenate at higher doses (20 and 40 mg/kg, p.o.). Moreover, a dose dependent decline was noted in lipid peroxidation (LPO) and the nitric oxide assay (NO) at all doses of MKA (10, 20 and 40 mg/kg, p.o.). Interestingly, significant progress was noted with the supplementation of MKA by an improvement of the acetylcholine (ACh) levels and a reduction in the acetylcholinesterase (AChE) activity in aged mouse brain. In addition, a significant elevation of serum albumin (ALBU), alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and total protein as well as a decline in creatinine, total cholesterol, urea nitrogen and glucose levels with MKA also ameliorated the hepatic and renal functions in normal ageing process. The results showed the possible utility of Murraya koenigii leaves in neuroprotection against neurodegenerative disorders such as Alzheimer's disease. PMID- 22447664 TI - Enhancement of bony in-growth to metal implants by combining controlled hydroxyapatite coating and heat treatment. AB - The rate of bony in-growth to heat-treated and controlled hydroxyapatite metal implants made of either titanium alloy (Ti-6Al-4V) or stainless steel (SS) 316L inserted to the medullar canal of the femur in rats was investigated. It was found that while partial coverage of hydroxyapatite (HA) did not cause a significant elevation of their bonding strength when compared with nonheated implants, HA, and heat treatment caused a significant (p < 0.01) elevation of 3.1 fold in the bonding strength of the implants to the host bone. A similar phenomenon to that found for the titanium alloy implants was found to be true for the SS implants as well. It is concluded that the novel approach presented in this article, that is, to heat treat implants as well as controlled partial coating of them by HA, prior to their insertion to host bone, produce an enhancement of bone growth to metal implants greater than utilization of each method alone. Our findings may be used to further enhance bony in-growth to metal implants in several clinical settings, producing avid implants with superior integration capabilities. PMID- 22447665 TI - Bilateral inverted papilloma of the middle ear with intracranial involvement and malignant transformation: first reported case. AB - Inverted (Schneiderian) papilloma (IP) is a benign but locally aggressive tumor that is typically located in the sinonasal tract. Middle ear involvement and intracranial extension are rare. We present a patient with a history of a completely resected right nasal cavity IP that returned 7 months later with hearing loss, bilateral aural fullness, and right-sided facial weakness. Work-up revealed middle ear IP, and the patient underwent bilateral mastoidectomies. On both sides, the disease caused erosion of the tegmen and was adherent to the underlying dura. There was dehiscence of the carotid canal wall on the left. On the right, the tumor was discovered to have recurred 3 months after initial resection, resulting in complete facial nerve paralysis and trigeminal paresthesias. A right temporal bone resection was undertaken along with neurosurgery. The IP was discovered to have invaded through the dura of the temporal lobe, incase the internal carotid artery, and infiltrate the trigeminal nerve. The facial and vestibulocochlear nerves were sacrificed on the right. Pathology of the right temporal bone revealed malignant transformation to squamous carcinoma. The patient was referred to radiation oncology for postoperative therapy. To our knowledge, this is the first case of bilateral IP of the middle ear with intracranial involvement and malignant transformation. Discussion points include: 1) management of middle ear IP, 2) carotid canal wall dehiscence in erosive middle ear disease, 3) aggressive surgical excision in locally destructive middle ear tumors, and 4) the role of radiation therapy in malignant transformation of IP. PMID- 22447666 TI - A model of knowledge translation in health: the Active Healthy Kids Canada Report Card on physical activity for children and youth. AB - The health of Canadian children and youth has deteriorated in the past few decades and physical inactivity is a powerful contributor. Active Healthy Kids Canada (AHKC; www.activehealthykids.ca) is a national not-for-profit organization with a mission to inspire the nation to engage all children and youth in physical activity by providing expertise and direction to policy makers and the public on how to increase and effectively allocate resources and attention toward physical activity for Canadian children and youth. Annually, for the past 7 years, the AHKC Report Card has consolidated and translated research knowledge to drive social action for policy change relating to physical activity among children and youth. Original published articles and key surveillance data from national and regional surveys are reviewed. A group of content experts from across Canada meet semiannually to review the evidence and assign letter grades. The AHKC Report Card has played a key role in informing discussions that have led to action on physical inactivity in Canada. Further evidence of the Report Card's influence is in the replication of the model in several other jurisdictions, including Saskatchewan and Ontario, Canada; Louisiana, United States; South Africa; Mexico; and Kenya. PMID- 22447667 TI - Voices from the trenches: facilitators' perspectives on HIV risk reduction interventions. AB - Experienced HIV prevention group facilitators have a unique perspective on sexual risk reduction interventions; however, their views are rarely reported in the research literature. To address this gap, the authors solicited input from four men and four women who served as facilitators in a randomized controlled trial of HIV risk reduction interventions. During focus groups or individual interviews, these facilitators commented on issues related to facilitation training and supervision, key facilitator characteristics, and challenges associated with intervention delivery. Facilitators reported that they valued training that was specific to the HIV context, the opportunity to observe workshops and to facilitate a mock workshop before facilitating themselves, and ongoing peer supervision. They recognized several important facilitator characteristics, including being open and nonjudgemental, being flexible, and being culturally competent. Finally, facilitators mentioned that facilitating workshops was made more difficult by the many psychosocial problems many low-income participants experienced, and that facilitating workshops with men was more difficult than with women. Observations such as these, provided by experienced facilitators, can help to improve intervention training and delivery, and may increase the likelihood that interventions will be adopted in community settings. PMID- 22447668 TI - Is health promotion the starting point of primary cardiovascular care in low- and middle-income countries like Nepal? AB - BACKGROUND: Cardiovascular diseases (CVDs) are on the rise in low- and middle income countries (LMICs) but have not received adequate priority. With a lack of concrete policy and programs, the present emphasis of CVD management in most LMICs is on curative aspects. Nepal is a prototype in this trend as it is treatment centric, particularly in urban areas. A major drawback of cure-centrism is that it requires both larger funds and more skilled manpower--both of which are limited in Nepal and other LMICs. AIMS: In this article, the authors suggest a possible role of health promotion as starting point for tackling the rising burden of CVDs in LMICs with Nepal as example. CONCLUSIONS: Health promotion is practiced in Nepal in connection with many health care programs and could be used to include CVD preventive strategies. The authors believe this to be a first step to increase health literacy toward CVD in the general population which may help bridge limited funds and manpower that the current curative-centric CVD strategy requires. Thus, health promotion strategies should be a tempting option for many LMICs and deserve further explorative attention. PMID- 22447669 TI - "Thinking outside the pack": examining physically active smokers and implications for practice among Ontario residents. AB - INTRODUCTION: It is estimated that tobacco use kills more than 5 million people annually; it is the leading cause of preventable deaths. Recent public health interventions have likely contributed to a steady decline in rates of smoking over the past decade. Nevertheless, innovative and cost-effective approaches to smoking cessation remain a public health priority. The purpose of this study was to profile physically active smokers. METHOD: Data from the Canadian Community Health Survey 2007-2008-Ontario Sharing File were used. Responses from 41,800 persons aged 12 years and older were assessed to compare (a) the sociodemographic characteristics of physically active smokers to physically active nonsmokers in Ontario and (b) the types of leisure-time physical activities that are more commonly practiced among active Ontario smokers to active nonsmokers. RESULTS: Pearson chi(2) and independent samples t tests revealed that active smokers were more likely to be male, younger, single, and less educated and to have lower income than active nonsmokers. Active smokers were also more likely to report inexpensive, low-intensity, and solitary leisure-time physical activities. CONCLUSION: Our findings have important implications for physical activity promotion among smokers. Physical activity interventions for smokers need to be tailored differently than for nonsmokers. PMID- 22447670 TI - Demyelination affects temporal aspects of perception: an optic neuritis study. AB - OBJECTIVE: Visual Evoked Potentials (VEPs) following optic neuritis (ON) remain chronically prolonged, although standard visual tests indicate full recovery. We hypothesized that dynamic visual processes, such as motion perception, may be more vulnerable to slowed conduction in the optic nerve, and consequently be better associated with projection rates. METHODS: Twenty-one patients with acute unilateral, first-ever ON were studied during 1 year. Static visual functions (visual acuity, color perception, visual field, and contrast sensitivity), dynamic visual functions (motion perception), and VEPs were assessed repeatedly. RESULTS: Visual and electrophysiological measurements reached maximal performance 4 months following the acute phase, with no subsequent improvement. Whereas VEP amplitude and static visual functions recovered, VEP latency remained significantly prolonged, and motion perception remained impaired throughout the 12-month period. A strong correlation was found between VEP latencies and motion perception. Visual performance at 1 month was strongly predictive of visual outcome. For static functions, patients who showed partial recovery at 1 month subsequently achieved full recovery. For dynamic functions, the rate of improvement was constant across patients, independent of the initial deficit level. INTERPRETATION: Conduction velocity in the visual pathways correlated closely with dynamic visual functions, implicating the need for rapid transmission of visual input to perceive motion. Motion perception level may serve as a tool to assess the magnitude of myelination in the visual pathways. The constancy across patients may serve as a baseline to assess the efficacy of currently developing neuroprotective and regenerative therapeutic strategies, targeting myelination in the central nervous system. PMID- 22447671 TI - An AT-rich region in the APC gene may cause misinterpretation of familial adenomatous polyposis molecular screening. AB - Familial adenomatous polyposis (FAP) is an autosomal-dominant condition mainly due to a mutation of the adenomatous polyposis coli (APC) gene. The present study reports evidence of a technical issue occurring during the mutational analysis of APC exon 4. Genetic conventional direct sequence analysis of a repetitive AT-rich region in the splice acceptor site of APC intron 3 could be misinterpreted as a pathogenetic frameshift result. However, this potential bias may be bypassed adopting a method for random mutagenesis of DNA based on the use of a triphosphate nucleoside analogues mixture. Using this method as a second-level analysis, we also demonstrated the nonpathogenic nature of the variant in the poly A trait in APC exon 4 region (c.423-4delA) that do not result in aberrant splicing of APC exons 3-4; conversely, we did not find a previously reported T deletion/insertion polymorphism. PMID- 22447672 TI - Primary fragmentation pathways of gas phase [M(uracil-H)(uracil)]+ complexes (M=Zn, Cu, Ni, Co, Fe, Mn, Cd, Pd , Mg, Ca, Sr, Ba, and Pb): loss of uracil versus HNCO. AB - Complexes formed between metal dications, the conjugate base of uracil, and uracil are investigated by sustained off-resonance irradiation collision-induced dissociation (SORI-CID) in a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Positive-ion electrospray spectra show that [M(Ura-H)(Ura)](+) (M=Zn, Cu, Ni, Co, Fe, Mn, Cd, Pd, Mg, Ca, Sr, Ba, or Pb) is the most abundant ion even at low concentrations of uracil. SORI-CID experiments show that the main primary decomposition pathway for all [M(Ura-H)(Ura)](+) , except where M=Ca, Sr, Ba, or Pb, is the loss of HNCO. Under the same SORI-CID conditions, when M is Ca, Sr, Ba, or Pb, [M(Ura-H)(Ura)](+) are shown to lose a molecule of uracil. Similar results were observed under infrared multiple-photon dissociation excitation conditions, except that [Ca(Ura-H)(Ura)](+) was found to lose HNCO as the primary fragmentation product. The binding energies between neutral uracil and [M(Ura-H)](+) (M=Zn, Cu, Ni, Fe, Cd, Pd ,Mg, Ca, Sr Ba, or Pb) are calculated by means of electronic-structure calculations. The differences in the uracil binding energies between complexes which lose uracil and those which lose HNCO are consistent with the experimentally observed differences in fragmentation pathways. A size dependence in the binding energies suggests that the interaction between uracil and [M(Ura-H)](+) is ion-dipole complexation and the experimental evidence presented supports this. PMID- 22447673 TI - Crystal structure of a Cas6 paralogous protein from Pyrococcus furiosus. PMID- 22447674 TI - Ultrafast dynamics of exciton formation in semiconductor nanowires. AB - The dynamics of free electron-hole pairs and excitons in GaAs-AlGaAs-GaAs core shell-skin nanowires is investigated using femtosecond transient photoluminescence spectroscopy at 10 K. Following nonresonant excitation, a bimolecular interconversion of the initially generated electron-hole plasma into an exciton population is observed. This conducting-to-insulating transition appears to occur gradually over electron-hole charge pair densities of 2-4 * 10(16) cm(-3) . The smoothness of the Mott transition is attributed to the slow carrier-cooling during the bimolecular interconversion of free charge carriers into excitons and to the presence of chemical-potential fluctuations leading to inhomogeneous spectral characteristics. These results demonstrate that high quality nanowires are model systems for investigating fundamental scientific effects in 1D heterostructures. PMID- 22447675 TI - Subchronic microcystin-LR exposure increased hepatic apoptosis and induced compensatory mechanisms in mice. AB - Acute lethal cytotoxicity of microcystin-LR (MC-LR), a toxin produced by fresh water cyanobacteria, has been attributed to protein phosphatases type 1 and type 2A (PP1/PP2A) inhibition and reactive oxygen species (ROS) generation. However, the effects and molecular mechanisms of prolonged, sublethal MC-LR exposure are less known. We studied mice intraperitonealy injected with saline or 25 MUg MC LR/kg for 28 days (every 2 days). MC-LR induced apoptosis in liver and not in kidneys or heart of treated animals. Liver also showed decreased alpha-tubulin levels (45.56% +/- 7.65% of controls) and activation of p38-MAPK and CaMKII pathways (137.93% +/- 11.64% and 419.35% +/- 67.83% of the control group, respectively). PP1/PP2A activity decreased from 1.82 +/- 0.23 (controls) to 0.91 +/- 0.98 mU/mg (MC-LR-treated mice); however, no difference in total Ser/Thr phosphatase activity was found between both the groups. The results demonstrated that apoptosis and cytoskeleton disruption contributed to the hepatic cytotoxic effects of subchronic MC-LR administration. These effects occurred in association with sustained activation of signaling cascades and development of compensatory mechanisms to maintain total Ser/Thr phosphatase activity. PMID- 22447676 TI - Bacopa monnieri increases cerebral blood flow in rat independent of blood pressure. AB - Bacopa monnieri (L.) Wettst. (Brahmi in India and Thailand) is an ayurvedic dementia treatment, but its effect on cerebral blood flow (CBF) is still unknown. We sought to test its chronic and acute effects on CBF compared with Ginkgo biloba and donepezil. CBF was measured by laser Doppler from rat cerebral cortex after 8 weeks of daily oral dosing of these drugs. Systolic blood pressure was also measured using the tail cuff method or via arterial cannulation. In rats treated with B. monnieri (40 mg/kg), CBF was 25% increased [2927 +/- 123 perfusion units, (PU)] compared with shams (2337 +/- 217 PU, p < 0.05, nine rats). G. biloba (60 mg/kg) also increased CBF (by 29% to 3019 +/- 208 PU, p < 0.05, nine rats). No clear effect was obtained with donepezil (1 mg/kg). Chronic administration of the preparations had no effect on blood pressure. In contrast, intravenous acute infusion of these herbals (20-60 mg/kg) had marked dose dependent hypotensive actions (diastolic ~31 mmHg lower with 40 mg/kg of either extract), which correspondingly reduced CBF by ~15%. Likewise, CBF fell slightly with acute intravenous sodium nitroprusside and rose with noradrenaline. Donepezil (1 mg/kg) was slightly hypotensive without affecting CBF. Increased CBF with B. monnieri may account for its reported procognitive effect, and its further exploration as an alternative nootropic drug is worthwhile. PMID- 22447677 TI - Miller Fisher variant of Guillain-Barre syndrome masquerading as acute sphenoid sinusitis with orbital apex syndrome. AB - Miller Fisher syndrome (MFS), a variant of Guillain-Barre syndrome, is a rare disorder typically characterized by a triad of ataxia, areflexia, and ophthalmoplegia, which may have a highly variable clinical presentation. We report a case of MFS in a 45-year-old female presenting with sphenoid sinusitis and sixth nerve palsy. She underwent endoscopic sphenoid sinusotomy without improvement, had postoperative deterioration, was diagnosed with MFS, and was treated with intravenous immunoglobulin with complete response. Because of the potential severity of Guillain-Barre syndrome, great vigilance should be taken when examining sixth nerve palsies to prevent misdiagnosis and delay in treatment of the MFS variant of this disease. PMID- 22447678 TI - Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. AB - OBJECTIVE: The most common neurological symptom of tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) is early life refractory epilepsy. As previous studies have shown enhanced excitatory glutamatergic neurotransmission in TSC and FCD brains, we hypothesized that neurons associated with these lesions may also express altered gamma-aminobutyric acid (GABA)(A) receptor (GABA(A)R) mediated inhibition. METHODS: Expression of the GABA(A)R subunits alpha1 and alpha4, and the Na(+)-K(+)-2Cl(-) (NKCC1) and the K(+)-Cl(-) (KCC2) transporters, in human TSC and FCD type II specimens were analyzed by Western blot and double label immunocytochemistry. GABA(A) R responses in dysplastic neurons from a single case of TSC were measured by perforated patch recording and compared to normal-appearing cortical neurons from a non-TSC epilepsy case. RESULTS: TSC and FCD type IIb lesions demonstrated decreased expression of GABA(A)R alpha1, and increased NKCC1 and decreased KCC2 levels. In contrast, FCD type IIa lesions showed decreased alpha4, and increased expression of both NKCC1 and KCC2 transporters. Patch clamp recordings from dysplastic neurons in acute slices from TSC tubers demonstrated excitatory GABA(A)R responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABA(A)R-mediated currents in normal neurons from non-TSC cortical slices. INTERPRETATION: Expression and function of GABA(A)Rs in TSC and FCD type IIb suggest the relative benzodiazepine insensitivity and more excitatory action of GABA compared to FCD type IIa. These factors may contribute to resistance of seizure activity to anticonvulsants that increase GABAergic function, and may justify add-on trials of the NKCC1 inhibitor bumetanide for the treatment of TSC and FCD type IIb-related epilepsy. PMID- 22447679 TI - Preparation, characterization, and evaluation of a heparin-benzalkonium chloride graphite oxide/polymethylvinyl siloxane nanocomposite. AB - A heparin (Hep)-benzalkonium chloride (C12)-graphite oxide (GO)/polymethylvinyl siloxane (PMVS) nancomposite was prepared via melting intercalation at different temperatures. Scanning electron microscopy images showed the Hep-C12-GO was well dispersed into PMVS processed at 100 degrees C. Mechanical properties measurement demonstrated that the addition of Hep-C12-GO maintained its strength. XRD data indicated that Hep-C12-GO lost its layer structure completely. FTIR results suggested that Hep-C12-GO interacted with PMVS strongly. Antibacterial activity of resulting nanocomposite was evaluated using zone of inhibition and bacteria adhesion methods. The results demonstrated that Hep-C12-GO/PMVS had a good capability against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Antithrombogenic properties were assessed using platelet adhesion experiment and the results showed that Hep-C12-GO/PMVS was blood-compatible. PMID- 22447680 TI - Acene-modified triphenylamine dyes for dye-sensitized solar cells: a computational study. AB - A series of metal-free acene-modified triphenylamine dyes (benzene to pentacene, denoted as TPA-AC1 to TPA-AC5) are investigated as organic sensitizers for application in dye-sensitized solar cells (DSSCs). A combination of density functional theory (DFT), density functional tight-binding (DFTB), and time dependent DFT (TDDFT) approaches is employed. The effects of acene units on the spectra and electrochemical properties of the acene-modified TPA organic dyes are demonstrated. The dye/(TiO(2))(46) anatase nanoparticle systems are also simulated to show the electronic structures at the interface. The results show that from TPA-AC1 to TPA-AC5 with increasing sizes of the acenes, the absorption and fluorescence spectra are systematically broadened and red-shifted, but the oscillator strength and electron injection properties are reduced. The molecular orbital contributions show increasing localization on the bridging acene units from TPA-AC1 to TPA-AC5. From the theoretical examination of some key parameters including free enthalpy related to the electron injection, light-harvesting efficiency, and the shift of semiconductor conduction band, TPA-AC3 with an anthracene moiety demonstrates a balance of the above crucial factors. TPA-AC3 is expected to be a promising dye with desirable energetic and spectroscopic parameters in the DSSC field, which is consistent with recent experimental work. This study is expected to deepen our understanding of TPA-based organic dyes and assist the molecular design of new metal-free dyes for the further optimization of DSSCs. PMID- 22447682 TI - RNA biology in a test tube--an overview of in vitro systems/assays. AB - In vitro systems have provided a wealth of information in the field of RNA biology, as they constitute a superior and sometimes the unique approach to address many important questions. Such cell-free methods can be sorted by the degree of complexity of the preparation of enzymatic and/or regulatory activity. Progress in the study of pre-mRNA processing has largely relied on traditional in vitro methods, as these reactions have been recapitulated in cell-free systems. The pre-mRNA capping, editing, and cleavage/polyadenylation reactions have even been reconstituted using purified components, and the enzymes responsible for catalysis have been characterized by such techniques. In vitro splicing using nuclear or cytoplasmic extracts has yielded clues on spliceosome assembly, kinetics, and mechanisms of splicing and has been essential to elucidate the function of splicing factors. Coupled systems have been important to functionally connect distinct processes, like transcription and splicing. Extract preparation has also been adapted to cells from a variety of tissues and species, revealing general versus species-specific mechanisms. Cell-free assays have also been applied to newly discovered pathways such as those involving small RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs), and Piwi interacting RNAs (piRNAs). The first two pathways have been well characterized largely by in vitro methods, which need to be developed for piRNAs. Finally, new techniques, such as single-molecule studies, are continuously being established, providing new and important insights into the field. Thus, in vitro approaches have been, are, and will continue being at the forefront of RNA research. PMID- 22447681 TI - The effects of a low vitamin E diet on dichloroacetate- and trichloroacetate induced oxidative stress in the livers of mice. AB - Groups of mice were fed either a standard (Std) diet or a diet not supplemented with vitamin E (Low-E) and were divided into three subgroups that were treated subchronically by gavage, with water (control), dichloroacetate (DCA), or trichloroacetate (TCA). The livers of the animals were assayed for various biomarkers of oxidative stress (OS), antioxidant enzyme activities, and total glutathione (GSH). In general, livers from the low-E diet group expressed lower levels of biomarkers of OS associated with greater increases in various antioxidant enzymes activities and GSH when compared with the corresponding treatments in the Std diet group. These results suggest that vitamin E supplementation to the diet, while essential to maintain certain body functions, can compromise the effectiveness of the hepatic antioxidant enzymes and GSH resulting in an increase in DCA- and TCA-induced OS and a possible increase in the compounds-induced hepatotoxic/hepatocarcinogenic effects in mice. PMID- 22447683 TI - Golli myelin basic proteins stimulate oligodendrocyte progenitor cell proliferation and differentiation in remyelinating adult mouse brain. AB - Golli myelin basic proteins are necessary for normal myelination, acting via voltage and store-dependent Ca(2+) entry at multiple steps during oligodendrocyte progenitor cell (OPC) development. To date nothing is known regarding the role of golli proteins in demyelination or remyelination events. Here the effects of golli ablation and overexpression in myelin loss and recovery were examined using the cuprizone (CPZ) model of demyelination/remyelination. We found severe demyelination in the corpus callosum (CC) of golli-overexpressing mice (JOE) during the CPZ treatment, which was accompanied by an increased number of reactive astrocytes and activation of microglia/macrophages. During demyelination of JOE brains, a significant increase in the number of proliferating OPCs was found in the CC as well as in the subventricular zone, and our data indicate that these progenitors matured and fully remyelinated the CC of JOE animals after CPZ withdrawal. In contrast, in the absence of golli (golli-KO mice) delayed myelin loss associated with a smaller immune response, and a lower number of OPCs was found in these mice during the CPZ treatment. Furthermore, incomplete remyelination was observed after CPZ removal in large areas of the CC of golli-KO mice, reflecting irregular recovery of the oligodendrocyte population and subsequent myelin sheath formation. Our findings demonstrate that golli proteins sensitize mature oligodendrocytes to CPZ-induced demyelination, while at the same time stimulate the proliferation/recruitment of OPCs during demyelination, resulting in accelerated remyelination. PMID- 22447684 TI - Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes. AB - To understand the molecular mechanisms underlying the influence of quercetin on the physiological effects of hyperlipidemia, we investigated its role in the prevention of high-fat diet (HFD)-induced obesity and found that it regulated hepatic gene expression related to lipid metabolism. Quercetin supplementation in mice significantly reduced the HFD-induced gains in body weight, liver weight, and white adipose tissue weight compared with the mice fed only with HFD. It also significantly reduced HFD-induced increases in serum lipids, including cholesterol, triglyceride, and thiobarbituric acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic lipid accumulation and the size of lipid droplets in the epididymal fat pads were also reduced by quercetin supplementation. To further investigate how quercetin may reduce obesity, we analyzed lipid metabolism-related genes in the liver. Quercetin supplementation altered expression profiles of several lipid metabolism related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Acaca, Cd36, Fdft1, and Fasn, relative to those in HFD control mice. The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Collectively, our results indicate that quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be related to the regulation of lipogenesis at the level of transcription. PMID- 22447685 TI - Sulfamethazine suppresses epigenetic silencing in Arabidopsis by impairing folate synthesis. AB - DNA methylation is a critical, dynamically regulated epigenetic mark. Small chemicals can be valuable tools in probing cellular processes, but the set of chemicals with broad effects on epigenetic regulation is very limited. Using the Arabidopsis thaliana repressor of silencing1 mutant, in which transgenes are transcriptionally silenced, we performed chemical genetic screens and found sulfamethazine (SMZ) as a chemical suppressor of epigenetic silencing. SMZ treatment released the silencing of transgenes as well as endogenous transposons and other repetitive elements. Plants treated with SMZ exhibit substantially reduced levels of DNA methylation and histone H3 Lys-9 dimethylation, but heterochromatic siRNA levels were not affected. SMZ is a structural analog and competitive antagonist to p-aminobenzoic acid (PABA), which is a precursor of folates. SMZ decreased the plant folate pool size and caused methyl deficiency, as demonstrated by reductions in S-adenosylmethionine levels and in global DNA methylation. Exogenous application of PABA or compounds downstream in the folate biosynthesis pathway restored transcriptional silencing in SMZ-treated plants. Together, our results revealed a novel type of chemical suppressor of epigenetic silencing, which may serve as a valuable tool for studying the roles and mechanisms of epigenetic regulation and underscores an important linkage between primary metabolism and epigenetic gene regulation. PMID- 22447686 TI - A previously unknown oxalyl-CoA synthetase is important for oxalate catabolism in Arabidopsis. AB - Oxalate is produced by several catabolic pathways in plants. The best characterized pathway for subsequent oxalate degradation is via oxalate oxidase, but some species, such as Arabidopsis thaliana, have no oxalate oxidase activity. Previously, an alternative pathway was proposed in which oxalyl-CoA synthetase (EC 6.2.1.8) catalyzes the first step, but no gene encoding this function has been found. Here, we identify acyl-activating enzyme3 (AAE3; At3g48990) from Arabidopsis as a gene encoding oxalyl-CoA synthetase. Recombinant AAE3 protein has high activity against oxalate, with K(m) = 149.0 +/- 12.7 MUM and V(max) = 11.4 +/- 1.0 MUmol/min/mg protein, but no detectable activity against other organic acids tested. Allelic aae3 mutants lacked oxalyl-CoA synthetase activity and were unable to degrade oxalate into CO(2). Seeds of mutants accumulated oxalate to levels threefold higher than the wild type, resulting in the formation of oxalate crystals. Crystal formation was associated with seed coat defects and substantially reduced germination of mutant seeds. Leaves of mutants were damaged by exogenous oxalate and more susceptible than the wild type to infection by the fungus Sclerotinia sclerotiorum, which produces oxalate as a phytotoxin to aid infection. Our results demonstrate that, in Arabidopsis, oxalyl-CoA synthetase encoded by AAE3 is required for oxalate degradation, for normal seed development, and for defense against an oxalate-producing fungal pathogen. PMID- 22447687 TI - A global view of hybrid vigor: DNA methylation, small RNAs, and gene expression. PMID- 22447688 TI - Arabidopsis WD repeat domain55 Interacts with DNA damaged binding protein1 and is required for apical patterning in the embryo. AB - CUL4-RING ubiquitin E3 ligases (CRL4s) were recently shown to exert their specificity through the binding of various substrate receptors, which bind the CUL4 interactor DNA damaged binding protein1 (DDB1) through a WDxR motif. In a segregation-based mutagenesis screen, we identified a WDxR motif-containing protein (WDR55) required for male and female gametogenesis and seed development. We demonstrate that WDR55 physically interacts with Arabidopsis thaliana DDB1A in planta, suggesting that WDR55 may be a novel substrate recruiter of CRL4 complexes. Examination of mutants revealed a failure in the fusion of the polar cells in embryo sac development, in addition to embryo and endosperm developmental arrest at various stages ranging from the zygote stage to the globular stage. wdr55-2 embryos suggest a defect in the transition to bilateral symmetry in the apical embryo domain, further supported by aberrant apical embryo localization of DORNROESCHEN, a direct target of the auxin response factor protein monopteros. Moreover, the auxin response pattern, as determined using the synthetic auxin-responsive reporter ProDR5:green fluorescent protein, was shifted in the basal embryo and suspensor but does not support a strong direct link to auxin response. Interestingly, the observed embryo and endosperm phenotype is reminiscent of CUL4 or DDB1A/B loss of function and thus may support a regulatory role of a putative CRL4(WDR55) E3 ligase complex. PMID- 22447689 TI - Impedance and extraesophageal manifestations of reflux in pediatrics. AB - OBJECTIVES/HYPOTHESIS: Extraesophageal manifestations of gastroesophageal reflux (GER) include such signs and symptoms as cough, asthma, respiratory symptoms, hoarseness, and laryngoscopic findings. We reviewed the role of MII-pH monitoring in the evaluation of these findings in children to determine whether there is an association with pathological acid or nonacid reflux. STUDY DESIGN: Retrospective chart review. METHODS: We retrospectively reviewed charts from patients who underwent MII-pH. Inclusion criteria were ages 0 to 21 years with extraesophageal signs or symptom. Data were analyzed using dedicated software and manually reviewed. Reflux composite score was calculated based on DeMeester criteria. Impedance scores were calculated based on adult criteria. Symptom indexes were calculated. RESULTS: A total of 119 MII-pH studies were performed. Of those, 63 studies met inclusion criteria. There were 39 males and 24 females with mean age 7.32 +/- 4.1 years. The most common indication was cough. Six children had pathological GER based on DeMeester score. Using impedance criteria, only 10 of 63 patients had an abnormal evaluation (mean reflux episodes 107). Seven patients (15.2%) were found to have an association between symptom and reflux event. CONCLUSIONS: No association was demonstrated between the extraesophageal signs and symptoms and pathological GER based on DeMeester score or the number of reflux events based on impedance testing. PMID- 22447690 TI - Improving cellular function and immune protection via layer-by-layer nanocoating of pancreatic islet beta-cell spheroids cocultured with mesenchymal stem cells. AB - Islet transplantation as a therapy for type 1 diabetes is currently limited by lack of primary transplant material from human donors and post-transplantation loss of islets caused by adverse immune and nonimmune reactions. This study aimed to develop a novel strategy to create microenvironment for islets via integration of nanoencapsulation with cell cocultures, thereby enhancing their survival and function. The nanoencapsulation was achieved via layer-by-layer deposition of phosphorycholine-modified poly-L-lysine/heparin leading to the formation of nanometer-thick multilayer coating on islets. Spheroids formed by coculturing MIN6 beta-cells with mesenchymal stem cells in suspension were used as the tool for testing encapsulation. Coculturing MSCs with MIN6 cells allowed the cell constructs to enhance structural and morphologic stability with improved insulin secretory function and render them less susceptible to inflammatory cytokine induced apoptosis. Combining nanoencapsulation with coculture of MSCs/MIN6 resulted in higher glucose responsiveness, and lower antibody binding and apoptosis-inducing effects of cytokines. This strategy of nanoencapsulating islet cocultures appears promising to improve cellular delivery of insulin for treating type 1 diabetes. PMID- 22447691 TI - Intracerebral hemorrhage and COL4A1 and COL4A2 mutations, from fetal life into adulthood. PMID- 22447692 TI - Rationalization of solvation and stabilization of palladium nanoparticles in imidazolium-based ionic liquids by DFT and vibrational spectroscopy. AB - A combined DFT/vibrational spectroscopy approach is used to determine the interactions of the 1,3-dimethylimidazolium ([Mmim](+)) and 1-ethyl-3 methylimidazolium ([Emim](+)) cations and [BF(4)](-) anions with each other in the liquid state and with Pd nanoparticles (NPs) immersed in ionic liquids (ILs) composed of these ions. Formation of aggregates of the counter-ions in the liquid does not have a strong influence on the interaction energy of the IL components with the palladium clusters used to model NPs, which is smaller than the energy of addition of a Pd atom to the cluster. Stronger Pd-Pd interactions in comparison to the interactions of the palladium cluster with the IL suggest kinetic stabilisation of Pd-NPs in 1,3-dialkylimidazolium tetrafluoroborates rather than thermodynamic stabilisation. Moreover, the palladium clusters interact more strongly with the anions than with the cations, and this suggests an important role of the anions in formation and stabilisation of Pd-NP in ILs. At the same time, binding between an isolated Pd atom and [Mmim](+) cation is stronger than Pd-[BF(4)](-) binding. IR and Raman spectral simulations reveal that surface-enhanced Raman spectroscopy is much less sensitive to interactions of Pd-NPs with the [BF(4)](-) anion compared to interactions with [Mmim](+) cations. In contrast, IR spectroscopy is better suited to study the anion-metal interactions, whereas IR spectral manifestations of the cation-metal interactions are rather modest. The splitting of the strong nu(as)(BF(4)(-)) IR band into three components appears to be a convenient spectroscopic marker for Pd-[BF(4)]( ) interactions, which is confirmed by actual spectra of Pd-NPs stabilised by [Emim][BF(4)]. The IR spectra and their assignment with quantum chemical computations suggest that both the anions and cations of [Emim][BF(4)] interact with the Pd-NP surface in the IL. The cation ring orientation close to the surface normal appears to be the dominant interaction. The anion is bound to the surface through either two or three fluorine atoms. PMID- 22447693 TI - Proteomics Clinical Applications: serving the field. PMID- 22447694 TI - Proteomics Clinical Applications reviews 2012. PMID- 22447695 TI - Dynamic proteome in enigmatic preeclampsia: an account of molecular mechanisms and biomarker discovery. AB - The coevolution of genomics and proteomics has led to advancements in the field of diagnosis and molecular mechanisms of disease. Proteomics is now stepping into the field of obstetrics, where early diagnosis of pregnancy complication such as preeclampsia (PE) is imperative. PE is a multifactorial disease characterized by hypertension with proteinuria, which is a leading cause of maternal and neonatal morbidity and mortality occurring in 5-7% of pregnancies worldwide. This review discusses the probable molecular mechanisms that lead to PE and summarizes the proteomics research carried out in understanding the pathogenicity of PE, and for identifying the candidate biomarker for diagnosis of the disease. PMID- 22447697 TI - Microbacterium neimengense sp. nov., isolated from the rhizosphere of maize. AB - A Gram-positive, non-motile, non-spore-forming, rod-shaped bacterium, strain 7087(T), was isolated from rhizosphere of maize in China. The strain grew at 4-50 degrees C and at pH 4-10, with optima of 37 degrees C and pH 7.0, respectively. Phylogenetic analysis based on the full-length 16S rRNA gene sequence revealed that strain 7087(T) was a member of the genus Microbacterium. High levels of 16S rRNA gene similarities were found between strain 7087(T) and Microbacterium binotii DSM 19164(T) (99.8 %). However, the DNA-DNA hybridization value between strain 7087(T) and Microbacterium binotii DSM 19164(T) was 24.2 %. The DNA G+C content of strain 7087(T) was 69.9 mol%. The major fatty acids were anteiso-C(17 : 0) (36.45 %), anteiso-C(15 : 0) (36.08 %) and iso-C(16 : 0) (16.11 %). The predominant menaquinones were MK-10 (28.1 %), MK-11 (54.8 %) and MK-12 (17.1 %). The diagnostic diamino acid in the cell-wall peptidoglycan was ornithine. The major polar lipids are diphosphatidylglycerol, unknown phospholipids, an unknown glycolipid and unknown amino lipids. On the basis of these results, strain 7087(T) is considered to represent a novel species of the genus Microbacterium, for which the name Microbacterium neimengense sp. nov. is proposed. The type strain is 7087(T) ( = ACCC 03008(T) = DSM 24985(T)). PMID- 22447698 TI - Kwoniella shandongensis sp. nov., a basidiomycetous yeast isolated from soil and bark from an apple orchard. AB - Four basidiomycetous yeast strains (Y13-1(T), Y2-1, Y6-3 and Y8-2) were isolated from soil and bark collected from an apple orchard in Tai'an, Shandong province, PR China. Phylogenetic analysis based on 26S rRNA gene D1/D2 domains and ITS regions revealed that these novel strains were located in the Kwoniella clade in the class Tremellomycetes and were closely related to Cryptococcus cuniculi and Kwoniella heveanensis, but were clearly distinct from these species. Therefore, it is proposed that the new strains represent a novel species, Kwoniella shandongensis sp. nov., with the type strain Y13-1(T)(=CGMCC 2.04458(T)=CBS 12478(T)). The MycoBank number for the novel species is MB 564868. PMID- 22447699 TI - Streptococcus troglodytae sp. nov., from the chimpanzee oral cavity. AB - Six strains, TKU 25, TKU 28, TKU 30, TKU 31(T), TKU 33 and TKU 34, were isolated from the oral cavity of a chimpanzee (Pan troglodytes). Colonies of strains grown on Mitis-Salivarius agar were similar in morphology to that of Streptococcus mutans. The novel strains were Gram-stain-positive, facultatively anaerobic cocci that lacked catalase activity. Analysis of the partial 16S rRNA gene sequences of these isolates showed that the most closely related strain was the type strain of S. mutans (96.4 %). The next closely related strains to the isolates were the type strains of Streptococcus devriesei (94.5 %) and Streptococcus downei (93.9 %). These isolates could be distinguished from S. mutans by inulin fermentation and alkaline phosphatase activity (API ZYM system). The peptidoglycan type of the novel isolates was Glu-Lys-Ala(3). Strains were not susceptible to bacitracin. On the basis of phenotypic characterization, partial 16S rRNA gene and two housekeeping gene (groEL and sodA) sequence data, we propose a novel taxon, Streptococcus troglodytae sp. nov.; the type strain is TKU 31(T) ( = JCM 18038(T) = DSM 25324(T)). PMID- 22447700 TI - Saliterribacillus persicus gen. nov., sp. nov., a moderately halophilic bacterium isolated from a hypersaline lake. AB - A novel Gram-positive, moderately halophilic bacterium, designated strain X4B(T), was isolated from soil around the hypersaline lake Aran-Bidgol in Iran and characterized taxonomically using a polyphasic approach. Cells of strain X4B(T) were motile rods and formed ellipsoidal endospores at a terminal or subterminal position in swollen sporangia. Strain X4B(T) was a strictly aerobic bacterium, catalase- and oxidase-positive. The strain was able to grow at NaCl concentrations of 0.5-22.5 % (w/v), with optimum growth occurring at 7.5 % (w/v) NaCl. The optimum temperature and pH for growth were 35 degrees C and pH 7.0. Analysis of 16S rRNA gene sequence revealed that strain X4B(T) is a member of the family Bacillaceae, constituting a novel phyletic lineage within this family. Highest sequence similarities were obtained with the 16S rRNA gene sequences of the type strains of Sediminibacillus albus (96.0 %), Paraliobacillus ryukyuensis (95.9 %), Paraliobacillus quinghaiensis (95.8 %) and Sediminibacillus halophilus (95.7 %), respectively. The DNA G+C content of this novel isolate was 35.2 mol%. The major cellular fatty acids of strain X4B(T) were anteiso-C(15 : 0) and anteiso-C(17 : 0) and its polar lipid pattern consisted of diphosphatidylglycerol, phosphatidylglycerol, two aminolipids, an aminophospholipid and an unknown phospholipid. The isoprenoid quinones were MK-7 (89 %) and MK-6 (11 %). The peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid. On the basis of 16S rRNA gene sequence analysis in combination with chemotaxonomic and phenotypic data, strain X4B(T) represents a novel species in a new genus in the family Bacillaceae, order Bacillales for which the name Saliterribacillus persicus gen. nov., sp. nov. is proposed. The type strain of the type species (Saliterribacillus persicus) is X4B(T) ( = IBRC-M 10629(T) = KCTC 13827(T)). PMID- 22447701 TI - Herminiimonas contaminans sp. nov., isolated as a contaminant of biopharmaceuticals. AB - A Gram-staining-negative, rod-shaped, non-spore-forming bacterium isolated as a contaminant from a biopharmaceutical process (strain CCUG 53591(T)) was studied for its taxonomic allocation. On the basis of 16S rRNA gene sequence similarity data, this strain was clearly allocated to the genus Herminiimonas. Herminiimonas saxobsidens was shown to be the most closely related species on the basis of 16S rRNA gene sequence similarity (99.9 %), followed by Herminiimonas glaciei (99.6 %) and Herminiimonas arsenicoxydans (98.8 %). Strain ND5, previously reported as H. glaciei, but showing 100 % 16S rRNA gene sequence similarity to strain CCUG 53591(T), was included in the comparative study. Similarities to all other species of the genus Herminiimonas were below 98.0 %. Chemotaxonomic data (major ubiquinone, Q-8; major polar lipids, phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol; and major fatty acids, C(17 : 0) cyclo, C(19 : 0) cyclo omega8c and C(16 : 0,) with C(10 : 0) 3-OH as hydroxylated fatty acid) supported the affiliation of the isolate to the genus Herminiimonas. DNA-DNA hybridization results (mean values) for strain CCUG 53591(T) with H. saxobsidens CCUG 59860(T) (34 %), H. glaciei DSM 21140(T) (57 %), H. arsenicoxydans DSM 17148(T) (17 %) and Herminiimonas fonticola S-94(T) (11 %) clearly supported the separate taxonomic position of this strain. Strain ND5 showed DNA-DNA similarities of 78, 56 and 52 % to strain CCUG 53591(T), H. glaciei DSM 21140(T) and H. saxobsidens CCUG 59860(T), respectively. Phenotypic differentiation of the isolate from the most closely related species was possible by various features. Hence, strain CCUG 53591(T) represents a novel species, for which the name Herminiimonas contaminans sp. nov. is proposed, with the type strain CCUG 53591(T) ( = CCM 7991(T)). Strain ND5 is a second strain of this species. PMID- 22447702 TI - Survey of 150 strains belonging to the Mycobacterium terrae complex and description of Mycobacterium engbaekii sp. nov., Mycobacterium heraklionense sp. nov. and Mycobacterium longobardum sp. nov. AB - A thorough phenotypic and genotypic analysis of 150 strains belonging to the Mycobacterium terrae complex resulted in the identification of a number of previously unreported sequevars (sqvs) within the species known to belong to the complex. For the species Mycobacterium arupense, three sqvs were detected in the 16S rRNA gene, six sqvs in the hsp65 gene and 15 sqvs in the rpoB gene; in Mycobacterium senuense two sqvs were present in each of the three genetic regions; in Mycobacterium kumamotonense four, two and nine sqvs were found, respectively, and in M. terrae three, four and six sqvs were found, respectively. The inappropriate inclusion of Mycobacterium triviale within the M. terrae complex was confirmed. The limited utility of biochemical tests and of mycolic acid analyses for the differentiation of the members of M. terrae complex was also confirmed. The survey allowed the recognition of three previously undescribed species that were characterized by unique sequences in the 16S rRNA, hsp65 and rpoB genes. Mycobacterium engbaekii sp. nov. (proposed previously 40 years ago but never validly published) was characterized by pink photochromogenic pigmentation and rapid growth; phylogenetically it was related to Mycobacterium hiberniae. The type strain of this species, of which eight strains were investigated, is ATCC 27353(T) ( = DSM 45694(T)). A cluster of 24 strains was the basis for the description of Mycobacterium heraklionense sp. nov., which has an intermediate growth rate and is unpigmented; nitrate reductase activity is typically strong. Closely related to M. arupense with respect to the 16S rRNA gene, M. heraklionense sp. nov. could be clearly differentiated from the latter species in the other genetic regions investigated. The type strain is NCTC 13432(T) ( = LMG 24735(T) = CECT 7509(T)). Mycobacterium longobardum sp. nov., represented in the study by seven strains, was characterized by a unique phylogenetic location within the M. terrae complex, clearly divergent from any other species. The type strain is DSM 45394(T) ( = CCUG 58460(T)). PMID- 22447703 TI - Massilia namucuonensis sp. nov., isolated from a soil sample. AB - A Gram-staining-negative, rod-shaped and non-spore-forming bacterium, designated strain 333-1-0411(T), was isolated from a soil sample collected from Namucuo, Tibet Autonomous Region, China and characterized in a taxonomic study using a polyphasic approach. The major fatty acid components of strain 333-1-0411(T) were summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c) and C(16 : 0); its major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. Q-8 was the dominant ubiquinone, and the G+C content of the genomic DNA was 66.7 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain 333-1-0411(T) fell within the evolutionary radiation encompassed by the genus Massilia. The 16S rRNA gene sequence similarities between strain 333-1-0411(T) and recognized species of the genus Massilia ranged from 95.4 % to 97.2 %, and the most closely related strains were Massilia flava Y9(T) (97.2 %) and Massilia albidiflava 45(T) (97.0 %). However, the DNA-DNA relatedness values between strain 333-1-0411(T) and M. flava Y9(T) and M. albidiflava 45(T) were 20.2 % and 27.2 %, respectively. Based on the phenotypic, chemotaxonomic and phylogenetic properties, strain 333-1-0411(T) is considered to represent a novel species of the genus Massilia, for which the name Massilia namucuonensis sp. nov. is proposed. The type strain is 333-1-0411(T) (= CGMCC 1.11014(T) = DSM 25159(T)). PMID- 22447704 TI - Antioxidant capacity and environmentally friendly synthesis of dihydropyrimidin (2H)-ones promoted by naturally occurring organic acids. AB - The Biginelli reaction is a multicomponent reaction involving the condensation between an aldehyde, a beta-ketoester, and urea or thiourea, in the presence of an acid catalyst, producing dihydropyrimidinones (DHPMs). Owing to their important pharmacological properties, the DHPMs have been studied by many authors. However, most of the methodologies used for the synthesis of these compounds require drastic reaction conditions. In the current study, we report an efficient and clean procedure for preparing DHPMs by the use of citric acid or tartaric acid as a promoter of the Biginelli synthesis in ethanol as solvent. In addition, we have evaluated the antioxidant capacity of the compounds synthesized by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and the thiobarbituric acid-reactive species test. Two compounds presented antioxidant activity and also reduced lipid peroxidation at concentrations of 200 and 300 uM. In summary, we report an environmentally friendly procedure for the preparation of DHPMs and demonstrate the antioxidant capacity of some of the compounds. PMID- 22447705 TI - Focused search and retrieval: the impact of technology on our brains. PMID- 22447706 TI - Assessing patient management plans of doctors and medical students: an illness script perspective. AB - INTRODUCTION: Illness script theory offers explanations for expert-novice differences in clinical reasoning. However, it has mainly focused on diagnostic (Dx) performance, while patient management (Mx) has been largely ignored. The aim of the present study was to show the role of Mx knowledge in illness script development and how it relates to diagnostic knowledge in the course of development toward expertise. METHODS: The participants were 10 fourth-year and 10 sixth-year medical students, and 10 experienced physicians (ie, internists). Participants were asked to study 4 written clinical cases and provide management plans. Based on propositional analysis the management plans were examined for accuracy and elaborateness as well as the number of Mx and Dx items. RESULTS: Providing accurate Mx plans that concurrently pay attention to Dx and Mx was a characteristic of doctors' performance. The Mx plans of sixth-year students were as accurate as fourth-year students, but the format and the size of sixth-year students' plans was more similar to those of doctors. While sixth-year students generated plans with an Mx focus, the plans of fourth-year students were characterized by a Dx focus. DISCUSSION: The experienced physicians' accurate management plans are characterized by a high number of the Mx and Dx items. For sixth-year students the management plans are still incomplete, which leads to generic as well as inaccurate Mx orders. For fourth-year students, the Mx focus is lacking, and hence they seem to treat an Mx task as if it were a Dx task. PMID- 22447707 TI - Revisiting the educationally influential physician: development of a simplified nomination form. AB - INTRODUCTION: An educationally influential (EI) physician is one to whom colleagues look for informal clinical advice. The original nomination form created to identify EI physicians among general practitioners was published in 1978. The present research developed an updated and simplified nomination form based on a survey of specialists. METHODS: A mailed questionnaire asked specialists treating neuromuscular disease to consider traits they might look for in colleagues when seeking clinical advice and rate them on a 6-point Likert-type scale. Based on study hypotheses, the traits were categorized a priori as representing one of four categories: approachability, declarative knowledge, practice-based procedural knowledge, and translational ability. The response rate among the approximately 500 specialists surveyed was 45%. RESULTS: Practice-based procedural knowledge items were most highly rated, followed by translational ability, approachability, then declarative items. Women specialists selected a slightly different constellation of traits, including less emphasis on approachability. Performing, publishing, and even reading current research were not, on average, considered essential in an informal clinical advisor. DISCUSSION: Colleagues identified as informal clinical advisors (ICAs) by neuromuscular specialists cannot be assumed to possess knowledge of, or be practicing according to, research evidence. Participants indicated that when they made changes in their treatment of patients, they often did so on the basis of research evidence obtained in other ways, but they did not choose ICAs on the basis of their advisor's familiarity with research-based knowledge. PMID- 22447708 TI - Using speed dating sessions to foster collaboration in continuing interdisciplinary education. AB - INTRODUCTION: There are numerous examples of care gaps that could be reduced through enhanced knowledge exchange and practice collaboration between medical specialist physicians. In this paper, we report preliminary results on using speed-dating sessions (SDSs) to stimulate the development of continuing interdisciplinary education (CIDE) activities. METHODS: In 2007, a 35-minute SDS was carried out during a 2-hour faculty development workshop to provide continuing medical education (CME) directors of Quebec's 35 medical specialist associations with a formal opportunity to quickly share clinical issues and goals. A post-workshop survey was used to assess participants' satisfaction and whether they had met new colleagues, learned about interdisciplinary issues, and discovered opportunities for collaboration. CME accreditation files were audited to assess the occurrence of CIDE activities in the year prior and the 2 years that followed the workshop. CME directors were called to assess whether the development of these activities was directly attributable to their participation in the SDS. RESULTS: CME directors of 26 specialist physician associations attended the faculty development workshop. The vast majority of survey respondents (n = 18/20) were satisfied with the SDS and believed that this method was a stimulating and efficient way to meet new colleagues, quickly share clinical issues and goals, learn about unexpected but important interdisciplinary issues, and identify opportunities for CIDE collaboration. Sixty percent (12/20) reported having identified at least 1 opportunity for collaboration that was worth pursuing in the near future, and 19% of attending CME directors (5/26) developed a CIDE activity within 2 years, as compared with none in the previous year and for the 9 nonparticipating associations. DISCUSSION: Results suggest that SDSs enhanced networking, knowledge exchange, and collaboration in continuing education among CME providers who participated in a faculty development activity on CIDE. PMID- 22447709 TI - The relationship between continuing education and perceived competence, professional support, and professional value among clinical psychologists. AB - INTRODUCTION: Continuing education is one of the means by which professionals maintain and increase their level of competence. However, the relationship between continuing education and the professional's sense of personal competence and other practice-related variables remains unclear. This study examined practicing psychologists' continuing education activities and how these relate to feelings of perceived competence, professional value, and professional support. METHODS: Psychologists (n = 418) licensed to practice in Quebec were surveyed by pencil-and-paper mail-in survey concerning their continuing education activities, as well as their perceptions of their competence in practice, and their feelings of being professionally valued and professionally supported. RESULTS: Results indicated that feelings of competence in practice were related to professional reading, taking courses/workshops, years being licensed, and attending psychology conferences/conventions. Feelings of professional value were related to age and participating in psychology networking groups, and feelings of professional support were related to participating in case discussion groups, supervision groups, and psychology networking groups. DISCUSSION: The results showcase the complexity of professional development. Although relationships were found between continuing education activities and the 3 factors of interest, these relationships were moderate. Findings are discussed in the context of their value to individual psychologists, as well as to psychology licensing and regulatory boards, such as promoting participation in those activities related to feelings of competence and support. PMID- 22447710 TI - Obstetrician/gynecologists and postpartum mental health: differences between CME course takers and nontakers. AB - INTRODUCTION: Continuing medical education (CME) courses are an essential component of professional development. Research indicates a continued need for understanding how and why physicians select certain CME courses, as well as the differences between CME course takers and nontakers. PURPOSE: Obstetrician gynecologists (OB-GYNs) are health care providers for women, and part of their purview includes mental health, such as postpartum depression (PPD) and psychosis (PPP). This study evaluated OB-GYNs' knowledge, attitudes, and behavior (KAB) regarding PPD/PPP, and compared characteristics of CME course takers and nontakers. METHOD: A survey was sent to 400 OB-GYNs. RESULTS: Response rate was 56%. One-third had taken a CME course on PPD/PPP. Those who consider themselves a "specialist" were less likely to have taken a CME course on postpartum mental health than those who consider themselves "both primary care provider and specialist." Non-CME course takers rely on clinical judgment more. They also are less likely to track patients' psychiatric histories and they utilize validated assessments less frequently. However, CME course takers and nontakers did not differ on knowledge or belief items. CONCLUSION: CME courses on PPD/PPP were associated with increased screening and utilization of validated assessments. There was no association between having taken a course and several knowledge questions. It is unclear if CME courses are effective in disseminating information and altering KAB. PMID- 22447711 TI - Critically reflective work behavior of health care professionals. AB - INTRODUCTION: Better understanding of critically reflective work behavior (CRWB), an approach for work-related informal learning, is important in order to gain more profound insight in the continuing development of health care professionals. METHODS: A survey, developed to measure CRWB and its predictors, was distributed to veterinary professionals. The authors specified a model relating CRWB to a Perceived Need for Lifelong Learning, Perceived Workload, and Opportunities for Feedback. Furthermore, research utilization was added to the concept of CRWB. The model was tested against the data, using structural equation modeling (SEM). RESULTS: The model was well represented by the data. Four factors that reflect aspects of CRWB were distinguished: (1) individual CRWB; (2) being critical in interactions with others; (3) cross-checking of information; and (4) openness to new findings. The latter 2 originated from the factor research utilization in CRWB. The Perceived Need for Lifelong Learning predicts CRWB. Neither Perceived Workload nor Opportunities for Feedback of other practitioners was related to CRWB. DISCUSSION: The results suggest that research utilization, such as cross checking information and openness to new findings, is essential for CRWB. Furthermore, perceptions of the need for lifelong learning are more relevant for CRWB of health care professionals than qualities of the workplace. PMID- 22447712 TI - Assessment of Interprofessional Team Collaboration Scale (AITCS): development and testing of the instrument. AB - INTRODUCTION: Many health professionals believe they practice collaboratively. Providing insight into their actual level of collaboration requires a means to assess practice within health settings. This chapter reports on the development, testing, and refinement process for the Assessment of Interprofessional Team Collaboration Scale (AITCS). There is a paucity of literature and measurement tools addressing interprofessional collaborative team performance and the nature of effective teamwork processes and patient roles within collaborative teams. These gaps limit our knowledge about how health care teams form and function. Instruments are therefore needed to assess collaborative relationships. METHODS: The AITCS, with its 47 items within 4 subscales (partnership, cooperation, coordination, and shared decision making) and assessed on a 5-point Likert scale, was administered to a total of 125 practitioners from 7 health care teams practicing within a variety of settings, in 2 provinces in Canada. RESULTS: Principal components and factor analysis of data resulted in 37 items loading onto 3 factors, explaining 61.02% of the variance. The internal consistency estimates for reliability of each subscale ranged from 0.80 to 0.97, with an overall reliability of 0.98. Thus, the AITCS is a reliable and valid instrument. DISCUSSION: The psychometric analysis of this instrument supports its value in measuring collaboration within teams and when patients are included as team members. The AITCS can be applied to continuing professional education interventions to determine change over time. It has limitations to the Canadian context and within the settings where participants practiced. Further test and retest reliability and longitudinal study application is needed. PMID- 22447713 TI - Educating doctors on evaluation of fitness to drive: impact of a case-based workshop. AB - INTRODUCTION: In 2004, faced with demographic data predicting large increases in the number of older drivers within a relatively short period combined with the realization that screening for driver fitness was largely dependent on health professionals, principally physicians, the Societe de l'assurance automobile du Quebec (SAAQ) initiated measures to achieve better cooperation with the health professionals performing the screening. A continuing medical education (CME) program was initiated to improve the health professionals' understanding of road safety considerations. This article describes the program and its impact. METHODS: A 90-minute workshop combining presentation and discussion methods and centering on five case studies was developed and delivered to 824 participants. Outcomes were evaluated at the levels of satisfaction and performance. RESULTS: Participants reported a high level of satisfaction with the workshop. Data suggest that there was an increase in the number of reports submitted by physicians. The quality of physician reports also improved. DISCUSSION: SAAQ statistics show the benefit of its CME program. Informed physicians appear more willing to report drivers with medical problems affecting driver fitness, especially when they are asked to provide functional evaluations and not make decisions about fitness to drive. We believe that the success of this program was due to several factors: (1) its clinical rather than administrative orientation, (2) the use of physicians to deliver the workshop, and (3) formal recognition of the program by the authority responsible for licensing physicians. PMID- 22447715 TI - The role of iron as a mediator of oxidative stress in Alzheimer disease. AB - Iron is both essential for maintaining a spectrum of metabolic processes in the central nervous system and elsewhere, and potent source of reactive oxygen species. Redox balance with respect to iron, therefore, may be critical to human neurodegenerative disease but is also in need of better understanding. Alzheimer disease (AD) in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD. PMID- 22447716 TI - Cellular attachment and osteoblast differentiation of mesenchymal stem cells on natural cuttlefish bone. AB - The purpose of this study was to describe an approach that aims to provide fundamental information for the application of natural cuttlefish bone. Before applying cuttlefish bone as a bone defect filling material, we evaluated proliferation, adhesion, and cell viability of human mesenchymal stem cells (hMSCs) cultured on cuttlefish bone. Cuttlefish bone was separated into two parts (dorsal shield and lamellar region) and each part was used. Cell proliferation and viability were assessed using the MTS assay and live/dead fluorescence staining method. The morphology was observed using scanning electron microscopy (SEM). hMSCs were stimulated with osteogenic medium and osteoblast differentiation was evaluated. The fluorescence images showed that the seeded cells grew well and that cell distribution was in accordance with the surface morphology of the cuttlefish bone. Compared with the dorsal shield, cells penetrated deeper into the three-dimensional inner space of the lamellar part. Furthermore, under osteogenic differentiation conditions, alkaline phosphatase activity increased and the mRNA expression of ALP, runt-related transcription factor 2, and collagen type I alpha1 was increased in hMSCs cultured on both the dorsal shield and lamellar block. These results indicate the potential of cuttlefish bone as an ideal scaffold for bone regenerative materials. PMID- 22447717 TI - Mutations in CIZ1 cause adult onset primary cervical dystonia. AB - OBJECTIVE: Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia. METHODS: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation. High throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult onset cervical dystonia and matching controls for sequence variants in this mutant gene. RESULTS: Exome sequencing led to the identification of an exonic splicing enhancer mutation in exon 7 of CIZ1 (c.790A>G, p.S264G), which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified 2 additional CIZ1 missense mutations (p.P47S and p.R672M). INTERPRETATION: Mutations in CIZ1 may cause adult onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system. PMID- 22447718 TI - Photoelectrochemical energy conversion. PMID- 22447719 TI - Ca(2+) conduction by an amino acid-gated ion channel related to glutamate receptors. PMID- 22447721 TI - Effect of tin and lead chlorotriphenyl analogues on fruit fly Drosophila hydei and liposomes membrane. AB - This article presents the results of a study investigating the biological activity of triphenyltin chloride (TPhT) and two metalloorganic compounds, triphenyllead chloride (TPhL) and triphenylmethane chloride (TPhC), in their interaction with model membranes and the living organisms of fruit flies Drosophila hydei. The study of model membranes (sonicated liposomes) was conducted using the electron spin resonance (ESR) spin probe technique, whereas the experiment on fruit flies involved investigating their viability on media containing the studied compounds. The test results clearly demonstrate that TPhT affects fruit flies more actively than TPhL (complete lethality after 7 days of culture with a TPhT-containing medium). No toxic effect of TPhC on fruit flies was shown. The results of the biological experiment were reflected in the physical experiment involving an ESR study of liposomes: TPhT activity manifested itself as a considerable increase in fluidity of the central region of the liposome lipid bilayer. PMID- 22447722 TI - Metal-polymer-metal split-dipole nanoantennas. PMID- 22447723 TI - A potential role for zinc alterations in the pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD), one of the major causes of disability and mortality in Western societies, is a progressive age-related neurodegenerative disorder. Increasing evidence suggests that the etiology of AD may involve disruptions of zinc (Zn) homeostasis. This review discusses current evidence supporting a potential role of Zn and zinc transporters (ZnTs) in processing of the amyloid beta protein precursor (APP) and amyloid beta (Abeta) peptide generation and aggregation. PMID- 22447724 TI - Carbon nanotubes induce bone calcification by bidirectional interaction with osteoblasts. AB - Multi-walled carbon nanotubes (MWCNTs) promote calcification during hydroxyapatite (HA) formation by osteoblasts. Primary cultured osteoblasts are incubated with MWCNTs or carbon black. After culture for 3 weeks, the degree of calcification is very high in the 50 MUg mL(-1) MWCNT group. Transmission electron microscopy shows needle-like crystals around the MWCNTs, and diffraction patterns reveal that the peak of the crystals almost coincides with the known peak of HA. PMID- 22447725 TI - Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. AB - OBJECTIVE: Anti-Tr is among the better described autoantibodies in paraneoplastic cerebellar degeneration (PCD) combined with Hodgkin lymphoma (HL); however, the Tr antigen remains unidentified. METHODS: We used immunoprecipitation of total rat brain extract followed by mass spectrometry to identify the antigen recognized by anti-Tr-positive sera. By Western blotting and cell-based assays, we tested a total of 12 anti-Tr-positive and 246 control sera and determined the region of the epitope recognized by the anti-Tr antibodies. Deletion and mutant constructs were generated to further map the antigenic region. RESULTS: Mass spectrometry analysis of immunopurified rat brain extract using 4 different anti Tr-positive sera led to the identification of Delta/Notch-like epidermal growth factor-related receptor (DNER) as the Tr antigen. All but 1 of 246 control samples were negative in the HeLa cell-based screening assay, whereas 12 of the 12 anti-Tr-positive sera stained hemagglutinin-tagged DNER-expressing cells. Only 1 control subject with HL but no ataxia was found to be both DNER and Tr positive. Using deletion constructs, we pinpointed the main epitope to the extracellular domain. Knockdown of endogenous DNER in hippocampal and N glycosylation mutations abolished the anti-Tr staining, indicating that glycosylation of DNER is required for it to be recognized by anti-Tr antibodies. INTERPRETATION: DNER is the antigen detected by anti-Tr-positive sera. Presence of anti-Tr antibodies in patients with PCD and HL or HL only can now be screened quickly and reliably by using a cell-based screening assay. PMID- 22447726 TI - Developmental toxicity study of lersivirine in mice. AB - Lersivirine is a second-generation nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. An embryo-fetal developmental toxicity study was performed to evaluate the maternal and developmental toxicity of lersivirine in pregnant mice. Mated Crl:CD1(ICR) mice were administered 0, 150, 350, and 500 mg/kg lersivirine once daily by oral gavage on gestation days 6 to 17, followed by cesarean section on gestation day 18. The first 2 days of dosing for the high-dose group were done at 250 mg/kg to allow induction of hepatic metabolizing enzymes, after which the dose was increased to 500 mg/kg/day. This dosing paradigm allowed for maintenance of exposure in the high-dose group despite the considerable autoinduction that occurs in rodents following lersivirine treatment. Lersivirine did not cause an increase in external, visceral, or skeletal malformations. Intrauterine growth retardation, demonstrated by reduced fetal body weights and increased variations associated with delayed skeletal ossification, was noted at 350 and 500 mg/kg/day. The results of these studies indicate that lersivirine is not teratogenic in mice. PMID- 22447727 TI - Beta-tricalcium phosphate particles as a controlled release carrier of osteogenic proteins for bone tissue engineering. AB - Beta-tricalcium phosphate (beta-TCP) has been widely used as bone substitutes and delivery carriers of osteogenic proteins. However, low protein carrying capacity and agent burst release profiles of beta-TCP limit their usage. This study investigates strategies to enhance protein carrying capacity of beta-TCP particles with reduced initial burst by surface etching in citric acid solution or by creating apatite coatings with the simulate body fluid immersion approach. The release kinetics of protein from the modified beta-TCP particles was investigated using Nel-like molecule-1 (Nell-1), a novel osteogenic protein, as a model protein. Although chemical etching treatments reduced the initial burst release of protein from the particles, a rapid burst release was observed with high protein dose. In contrast, the burst release of protein was significantly reduced by the apatite coating and a high protein dose was successfully delivered over a prolonged period from the apatite-coated particles. Protein release was further modulated by simultaneously delivering proteins from two different substrates: acid-etched and apatite-coated particles. The bioactivity of the protein was preserved during the loading procedure onto the particles. In addition, protein-loaded particles maintained biological activity in the lyophilized state over 4 weeks. These findings suggest that the protein carrying capacity of beta-TCP can be modulated by surface modification, which has a potential for use as a protein carrier with controlled release. PMID- 22447728 TI - An enhanced protocol for expression and purification of heat-stable enterotoxin of enterotoxigenic Escherichia coli. AB - We present an improved protocol for expression and purification of heat-stable enterotoxin (STa) of enterotoxigenic Escherichia coli (ETEC). In this protocol, controlled growth conditions at different pHs (7.4, 8.0, and 8.6) were adopted using a bioreactor. In addition, specific adsorbent resins, methacrylate, were used for STa purification. The bioreactor provided optimal ETEC growth at pH 7.4 with high STa production. Furthermore, methacrylate bounded specifically to STa and dramatically enhanced the purification process of STa. The STa-specific activity was high (8.9 * 10(6) units/mg protein), and the minimal effective dose of STa required for production of gut weight to remaining body weight ratio >= 0.083 was recorded as less than 0.2 ng in 2-3 days old suckling mice. The protocol presented, produces highly purified STa as documented by matrix-assisted laser desorption ionization-time of flight mass spectroscopy/. Also, as compared with the traditional methods, this procedure is trouble-free and practical for scale-up production and purification of STa peptides. PMID- 22447729 TI - Perceptual and neural response to affective tactile texture stimulation in adults with autism spectrum disorders. AB - Autism spectrum disorders (ASD) are associated with differences in sensory sensitivity and affective response to sensory stimuli, the neural basis of which is still largely unknown. We used psychophysics and functional magnetic resonance imaging (fMRI) to investigate responses to somatosensory stimulation with three textured surfaces that spanned a range of roughness and pleasantness in a sample of adults with ASD and a control group. While psychophysical ratings of roughness and pleasantness were largely similar across the two groups, the ASD group gave pleasant and unpleasant textures more extreme average ratings than did controls. In addition, their ratings for a neutral texture were more variable than controls, indicating they are less consistent in evaluating a stimulus that is affectively ambiguous. Changes in brain blood oxygenation level-dependent (BOLD) signal in response to stimulation with these textures differed substantially between the groups, with the ASD group exhibiting diminished responses compared to the control group, particularly for pleasant and neutral textures. For the most unpleasant texture, the ASD group exhibited greater BOLD response than controls in affective somatosensory processing areas such as the posterior cingulate cortex and the insula. The amplitude of response in the insula in response to the unpleasant texture was positively correlated with social impairment as measured by the Autism Diagnostic Interview-Revised (ADI-R). These results suggest that people with ASD tend to show diminished response to pleasant and neutral stimuli, and exaggerated limbic responses to unpleasant stimuli, which may contribute to diminished social reward associated with touch, perpetuating social withdrawal, and aberrant social development. PMID- 22447730 TI - Lectin-binding pattern of the Senegalese sole Solea senegalensis oogenesis. AB - The glycoconjugate pattern of developing ovarian follicles in wild and cultured Senegalese sole Solea senegalensis was investigated by means of lectin histochemistry. Ovaries from cultured fish contained oocytes up to the late vitellogenic stage, whereas they reached the hydration stage in wild specimens. The follicular cells bound MAL II, SBA, HPA, DBA, Con A, KOH-sialidase (K-s)-WGA, GSA I-B(4) in the late vitellogenic stage, and in wild fish also SNA and K-s-PNA, whereas in the hydration stage SBA, HPA, DBA, and GSA I-B(4) only. The zona radiata reacted with SBA, HPA, DBA, Con A, and GSA I B(4) in the late vitellogenic stage and in cultured fish also with UEA I, whereas in the hydration stage it stained with SBA only. The cortical alveoli bound SBA, HPA, RCA(120) during the late vitellogenic stage, also SNA, PNA, K-s-PNA, GSA I-B(4) in cultured fish, DBA, and K-s-WGA in wild ones which stained with SBA, HPA, and GSA I-B(4) in the hydrated stage. The yolk reacted with Con A in the late vitellogenic oocytes, and also with MAL II, SNA, K-s-PNA, SBA, HPA, K-s-WGA, GSA I-B(4), UEA I in the hydrated ones. From perinucleolus to late vitellogenic stages, the oocyte nucleoplasm bound Con A, GSA I-B(4), GSA II, UEA I, and in wild fish also MAL II, SNA, LTA but only GSA I-B(4) reactivity in the early maturation stage. These findings demonstrate that the glycan pattern of fish ovarian follicles changes during the maturative stages and that it is affected by culture-rearing conditions. PMID- 22447731 TI - Oral manganese as an MRI contrast agent for the detection of nociceptive activity. AB - The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity. PMID- 22447732 TI - In vivo MRI of olfactory ensheathing cell grafts and regenerating axons in transplant mediated repair of the adult rat optic nerve. AB - The purpose of the present study was to use magnetic resonance imaging (MRI) as a tool for monitoring transplant-mediated repair of the adult rat visual pathway. We labelled rat olfactory ensheathing cells (OECs) using micron-sized particles of iron oxide (MPIO) and transplanted them by: i) intravitreal injection (ivit) and ii) intra-optic nerve (ON) injection (iON) in adult rats with ON crush (ONC) injury. We applied T(2)-weighted MRI and manganese-enhanced MRI (MEMRI) to visualise transplanted cells and ON axons at specific times after injury and cell engraftment. Our findings demonstrate that ivit MPIO-labelled OECs are unequivocally detected by T(2)-weighted MRI in vivo and that the T(1)-weighted 3D FLASH sequence applied for MEMRI facilitates simultaneous visualisation of Mn(2+ ) enhanced regenerating retinal ganglion cell (RGC) axons and MPIO-labelled OEC grafts. Furthermore, analysis of MRI data and ultrastructural findings supports the hypothesis that iON OEC transplants mediate regeneration and remyelination of RGC axons post injury. PMID- 22447734 TI - Hypertension and longitudinal changes in cerebral blood flow: the SMART-MR study. AB - OBJECTIVE: Cerebral hypoperfusion is among the mechanisms that may explain the association of high blood pressure (BP) with dementia. However, few data are available on the longitudinal association of hypertension and cerebral perfusion. METHODS: We examined the longitudinal association of hypertension, BP, and antihypertensive drugs with change in parenchymal cerebral blood flow (pCBF) in 575 patients with manifest atherosclerotic disease (mean age, 57 +/- 10 years) from the SMART-MR study. Total CBF was measured at baseline and at follow-up with magnetic resonance (MR) angiography and was expressed per 100ml brain volume as an indicator of cerebral perfusion. Automated brain segmentation was used to quantify brain tissue volumes and cerebrospinal fluid on MR imaging. RESULTS: Mean (standard deviation [SD]) baseline pCBF was 52.3 (9.8) ml/min/100ml and after 3.9 years (range, 3.0-5.8 years) of follow-up declined to 50.7 (10.3) ml/min/100ml. Regression analyses adjusted for age, sex, follow-up time, and vascular risk showed that untreated and poorly controlled hypertension and higher levels of systolic and diastolic BP (per SD) were significantly associated with a decline in pCBF; mean differences in decline (95% confidence interval) were -2.2 (-4.4 to 0.0), -1.0 (-1.8 to -0.1), and -1.0 (-1.8 to -0.2) ml/min/100ml. In addition, within hypertensive patients (n = 469), patients using angiotensin receptor blockers (ARBs) did not show a decline in pCBF, whereas patients using other antihypertensive drugs did show a decline in pCBF. INTERPRETATION: Untreated hypertension, poorly controlled hypertension, and high BP levels are associated with a decline in pCBF. In addition, treatment with ARBs might result in less decline in pCBF than other antihypertensive treatment. PMID- 22447735 TI - Block copolymer as a nanostructuring agent for high-efficiency and annealing-free bulk heterojunction organic solar cells. AB - The addition of a block copolymer to the polymer/fullerene blend is a novel approach to the fabrication of organic solar cells. The block copolymer (P3HT-b P4VP) is used as nanostructuring agent in the active layer. A significant enhancement of the cell efficiency is observed, in correlation with morphology control, both before (as-cast) and after the annealing process. PMID- 22447736 TI - Developmental sensitivity to the induction of great vessel malformations by N-(2 aminoethyl)ethanolamine. AB - N-(2-Aminoethyl)ethanolamine (AEEA) induced malformations of the great vessels in the offspring of rats treated during gestation and early lactation (Schneider et al., 2012. Birth Defects Res B Dev Reprod Toxicol [in press]). The aim of this study was to determine if in utero exposure alone was sufficient to induce these malformations or whether a peri-postnatal exposure or physiological component was required. Three groups of five time-mated female Wistar Han rats were administered AEEA (250 mg/kg/day) by gavage from gestation day (GD) 6 to GD 19 (groups 1 and 2) or from GD 6 to postnatal day 3 (group 3). Animals were euthanized on GD 21 (group 1) or postnatal day 4 (groups 2 and 3), and the hearts of the offspring were examined for changes to the great vessels. The incidence of malformations in group 1 was 91.1%, and primarily consisted of high aortic arch and abnormal carotid course. One fetus had an aortic aneurysm. All fetuses in groups 2 and 3 were malformed, primarily exhibiting abnormal carotid course and aneurysms, which mainly affected the aorta, ductus arteriosus, and pulmonary trunk. The incidence of high aortic arch was lower relative to group 1. Aneurysms were more prevalent in group 3 compared to group 2. These findings indicate that exposure to AEEA during gestation alone was sufficient to induce malformations of the great vessels and aneurysms, which may be triggered by physiological changes that occur during or after birth, but that the critical period of susceptibility to AEEA-induced aneurysms in the rat extends beyond gestation into the early postnatal period. PMID- 22447737 TI - Biomagnification of mercury through the benthic food webs of a temperate estuary: Masan Bay, Korea. AB - The authors examined food web magnification factors of total mercury (THg) and methylmercury (MeHg) for the benthic organisms in Masan Bay, a semiclosed, temperate estuary located on the southeastern coast of Korea. For benthic invertebrates, concentrations of THg and MeHg (%MeHg) ranged from 9.57 to 195 and 2.56 to 111 ng/g dry weight (12.2-85.6%), respectively. Benthic fish THg and MeHg (%MeHg) concentrations ranged widely from 10.8 to 618 and 2.90 to 529 ng/g dry weight (22.9-93.9%), respectively. The linear regression slopes of log [Hg] relative to delta(15)N (i.e., food web magnification factors) found for the Masan Bay benthic organisms were 0.119 for THg and 0.168 for MeHg. These values are similar to the food web magnification factors of benthic organisms and lower than those of pelagic organisms of various coastal marine environments. It suggests that pelagic organisms might be at greater risk of THg and MeHg accumulation than benthic biota. PMID- 22447738 TI - A dynamically programmed DNA transporter. PMID- 22447739 TI - A novel rotating electrochemically anodizing process to fabricate titanium oxide surface nanostructures enhancing the bioactivity of osteoblastic cells. AB - Titanium oxide (TiO(2) ) surface layers with various surface nanostructures (nanotubes and nanowires) have been developed using an anodizing technique. The pore size and length of TiO(2) nanotubes can be tailored by changing the anodizing time and applied voltage. We developed a novel method to transform the upper part of the formed TiO(2) nanotubes into a nanowire-like structure by rotating the titanium anode during anodizing process. The transformation of nanotubes contributed to the preferential chemical dissolution of TiO(2) on the areas with intense interface tension stress. Furthermore, we further compared the effect of various TiO(2) surface nanostructures including flat, nanotubes, and nanowires on bioactive applications. The MG-63 osteoblastic cells cultured on the TiO(2) nanowires exhibited a polygonal shape with extending filopodia and showed highest levels of cell viability and alkaline phosphatase activity (ALP). The TiO(2) nanowire structure formed by our novel method can provide beneficial effects for MG-63 osteoblastic cells in attachment, proliferation, and secretion of ALP on the TiO(2) surface layer. PMID- 22447740 TI - Isotope labeling experiments in metabolomics and fluxomics. AB - Metabolomics, the study of all the small molecules in and outside a cell and fluxomics, comprising all conversion rates in a cell, are increasingly used in fundamental and applied sciences to unravel structures and activities of cellular networks and their regulation, to investigate mechanisms of diseases and toxicity, and to improve producing strains among other applications. For both fluxomics and metabolomics the application of isotopes became almost indispensable. Their use in these techniques is discussed, focusing primarily on studies applying stable isotopes and using mass spectrometry. This includes the underlying principles, experimental and computational methods used, and examples of application. PMID- 22447741 TI - Parkinson's U.K.: pushing the search for a cure to new levels. PMID- 22447742 TI - Wellcome Trust: a long-term perspective. PMID- 22447743 TI - Exposure to green tea extract alters the incidence of specific cyclophosphamide induced malformations. AB - BACKGROUND: Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxygen species. Cyclophosphamide (CP) produces reactive oxidative species, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice. METHODS: From gestation days (GD) 6-13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS: The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 and/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure. CONCLUSIONS: Exposure of a developing mammal to moderate doses of GTE can modulate the effects of exposure to CP during development, possibly by affecting biotransformation, while a higher GTE dose tended to exacerbate the developmental toxicity of CP. GTE alone appeared to cause an adverse effect on eyelid development. PMID- 22447744 TI - Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. AB - OBJECTIVE: Anticoagulation with dabigatran etexilate (DE) has a favorable risk-to benefit profile for the prevention of ischemic events in patients with atrial fibrillation compared to warfarin. Whereas warfarin constitutes a strong contraindication for thrombolysis, it is unclear whether patients anticoagulated with DE can be thrombolysed. We compared the risk of thrombolysis-associated hemorrhagic transformation (HT) after pretreatment with DE or warfarin in a mouse model of ischemic stroke. METHODS: Thirty-nine C57BL/6 mice were pretreated orally with 75 mg/kg DE, 112.5mg/kg DE, 2mg/kg warfarin, or saline. We performed right middle cerebral artery occlusion for 3 hours, administered recombinant tissue plasminogen activator (rt-PA) directly before reperfusion, and assessed neurological deficit and HT blood volume after 24 hours. RESULTS: Warfarin anticoagulation increased HT secondary to rt-PA treatment as compared to nonanticoagulated controls (6.9 +/- 5.5 MUl vs 0.8 +/- 0.6 MUl, p < 0.05). In contrast, the rate of HT after pretreatment with 75 mg/kg DE, which led to plasma levels comparable to the highest plasma levels observed in participants of the RE LY trial, did not differ significantly from controls (1.6 +/- 0.8; p > 0.05 vs control). However, a high-dose group receiving 112.5mg/kg DE showed a considerable extent of HT (9.2 +/- 5.6 MUl, p < 0.01). INTERPRETATION: Our experimental data suggest that the risk of thrombolysis-associated HT may not be increased under DE pretreatment with standard doses leading to plasma levels of up to 400 ng/ml, a concentration that was not exceeded in the majority of DE trial patients. At higher DE plasma levels, however, the risk of severe HT rises considerably, emphasizing the need for a readily available assay of DE anticoagulant activity. PMID- 22447745 TI - In vitro assessment of Staphylococcus epidermidis and Staphylococcus aureus adhesion on TiO2 nanotubes on Ti-6Al-4V alloy. AB - The aim of this study was to evaluate Staphylococcus sp. adhesion to modified surfaces of titanium alloy (Ti-6Al-4V). Specimens of Ti-6Al-4V alloy 6-4 ELI grade 23 that meets the requirements of ASTM F136 2002A (AMS 2631B class A1) were anodized in a mixture of sulfuric/hydrofluoric acid at 20 V for 5 and 60 min to form nanoporous (NP) and nanotubular (NT) oxide layers with pore diameter of 20 and 100 nm, respectively. The amount of fluorine incorporated in the oxide films from the electrolyte was 6 and 4 wt %, respectively. Bacterial adherence was studied using laboratory strains and six clinical strains each of Staphylococcus aureus and Staphylococcus epidermidis. Lower adherence of laboratory strains was demonstrated on fluoride nanostructured surfaces in comparison with the fluoride free surfaces. Significant differences between clinical strains and laboratory strains were also found (p < 0.0001, Kruskal-Wallis test) when NP and NT specimens were compared with chemically polished (CP) surfaces. The results of the tests using multiple clinical strains confirmed a decrease in bacterial adherence on F-containing titanium oxide surfaces, suggesting a potential applicability of this surface, with a confirmed added value of decreasing clinical staphylococci adherence, for medical prosthetic devices. PMID- 22447746 TI - Application of U.S. EPA guidelines in a bioavailability-based assessment of ambient water quality criteria for zinc in freshwater. AB - The United States Environmental Protection Agency's (U.S. EPA) current ambient water quality criteria (AWQC) for zinc in freshwater are hardness-based and were last updated in 1995. The acute and chronic freshwater toxicity databases have since expanded substantially and the U.S. EPA's minimum phylogenetic diversity requirements for chronic zinc toxicity are now met (an acute:chronic ratio was previously required). Additionally, several acute and chronic biotic ligand models (BLMs) for zinc have since been developed and validated for freshwater organisms. Using the expanded toxicity database and existing BLMs, we developed a unified zinc BLM that could efficiently predict both acute and chronic toxicity over a wide range of zinc bioavailabilities. The unified BLM, developed by objectively averaging the biotic ligand binding constants for zinc (Zn(2+)) and competing cations (Ca(2+), Mg(2+), Na(+), H(+)) from existing BLMs, performed better in predicting toxicity to a diverse set of organisms than any individual existing BLM. Performance of the unified BLM was further improved by optimizing the biotic ligand binding constant for the ZnOH(+) species. The updated freshwater zinc toxicity database and unified BLM were then used to estimate the fifth percentiles of the acute and chronic species sensitivity distributions following the U.S. EPA guidelines for AWQC development. PMID- 22447747 TI - Introduction: Bioethics and intellectual disability--scientific promise, social context and policy. PMID- 22447748 TI - Genetic testing for autism spectrum disorders. AB - Children with autism spectrum disorders (ASD) have unique developmental and behavioral phenotypes, and they have specific challenges with communication, social skills, and repetitive behaviors. At this time, no single etiology for ASD has been identified. However, evidence from family studies and linkage analyses suggests that genetic factors play a pivotal role in the etiology of ASD. However, ASD appear to be influenced by complex genetic and environmental factors, and evidence suggests that this is not a single gene disorder. In particular, ASD has a complex behavioral phenotype, and this variation reflects complex genotypes under the influence of external factors. With these considerations in mind, it is important to recognize that genetic testing is a vital component of the diagnostic evaluation of children with ASD. For example, children with ASD who have definitive etiologies may be able to access more specific resources, they may be spared long, emotionally and financially exhausting diagnostic journeys, and associated medical conditions and comorbidities can be managed proactively. Most importantly, children with disabilities of unknown origin should have an ongoing evaluation of potential etiologies for their symptoms (Crocker, 1987). Our purpose is to describe current trends in genetic testing for ASD, potential genetic etiologies of ASD, known genetic disorders associated with ASD, and recommendations for genetic testing in ASD. We will also emphasize the importance of access to informed health professionals, especially in the contexts of stigma and community supports. PMID- 22447749 TI - Expanding newborn screening for lysosomal disorders: opportunities and challenges. AB - Newborn screening (NBS), since its implementation in the 1960s, has traditionally been successful in reducing mortality and disability in children with a range of different conditions. Lysosomal storage disorders (LSD) are a heterogeneous group of inherited metabolic diseases that result from lysosomal dysfunction. Based on available treatment and suitable screening methods, the LSDs that are considered for NBS generally include Fabry, Gaucher, Krabbe, MPSI, MPSII, MPSV, Metachromatic leukodystrophy, Niemann-Pick, and Pompe. Utilizing traditional and expanded criteria for consideration of NBS leads to a set of fundamental questions that need to be explored when considering the opportunities and challenges of adding LSDs to NBS panels. PMID- 22447750 TI - Dangerous and expensive screening and treatment for rare childhood diseases: the case of Krabbe disease. AB - Public policy surrounding newborn screening is in flux. New technology allows more screening for more diseases at lower cost. Traditional criteria for target diseases have been criticized by leading health policymakers. The example of newborn screening for Krabbe disease highlights many of the dilemmas associated with population-based screening programs. Krabbe is difficult to diagnose, variable in its natural history, and does not always respond to treatment. The only available treatment is hematopoietic stem cell transplantation, which is expensive, risky, and of uncertain efficacy. This article analyzes the debate about Krabbe as an example of the sorts of debates that will likely arise for many more diseases over the next decade. I conclude that pilot programs in pioneer states should be carefully evaluated before testing for Krabbe is universalized. PMID- 22447751 TI - Responding to requests of families for unproven interventions in neurodevelopmental disorders: hyperbaric oxygen "treatment" and stem cell "therapy" in cerebral palsy. AB - Faced with the limitations of currently available mainstream medical treatments and interventions, parents of children with neurodevelopmental disorders often seek information about unproven interventions. These interventions frequently have undetermined efficacy and uncertain safety profiles. In this article, we present a general background and case vignettes that highlight the use of hyperbaric oxygen chambers and stem cells in cerebral palsy, the leading cause of pediatric physical disability. We then review the current evidence about these interventions as exemplars of unproven therapies. Building on the background and cases, we explore and review two important questions related to unproven interventions: (1) How should clinicians respond to requests for innovative and alternative interventions? (2) What should clinicians keep in mind when such requests come from online sources? PMID- 22447752 TI - Prenatal testing for intellectual disability: misperceptions and reality with lessons from Down syndrome. AB - Down syndrome is the most common cause of intellectual disability. In the United States, it is recommended that prenatal testing for Down syndrome be offered to all women. Because of this policy and consequent public perception, having Down syndrome has become a disadvantage in the prenatal period. However, in the postnatal period, there may be some advantage in having Down syndrome. To help parents make informed decisions about screening and testing, it is crucial to reconcile divergent prenatal and postnatal perspectives. Advancements in genetic technologies will also impact the informed consent process and need to be considered. PMID- 22447753 TI - Health disparities and intellectual disabilities: lessons from individuals with Down syndrome. AB - Individuals with intellectual disabilities experience health disparities and disparities in accessing health care services compared to individuals within the general population. In order to eliminate these disparities the contributors to them must be understood. In this article, we aim to describe a recent reconceptualization of health and disability (Krahn, et al. [2006] Mental. Retard. Dev. Disabilities Res. Rev. 12:70-82) to further understand the health disparities between individuals with Down syndrome, the most common identified cause of intellectual disability in the United States, and the general population. We also detail known health disparities between individuals with Down syndrome of different races and discuss the possible reasons for these disparities, as well as potential actions to address them. PMID- 22447754 TI - How do we assess family supports and fairness in early intervention? AB - Public Law 99-457 extended the landmark Public Law 94-142 legislation to include early intervention for infants and toddlers with or at-risk for development of developmental disabilities. Currently over 300,000 infants and toddlers and their families in the United States receive services through Part C of the Individuals with Disabilities Education legislation. The law fostered interagency collaborations and included the child's parent or caregiver as an integral part of the intervention team. This article reviews the 26 years of legislation associated with educating young children with disabilities and the resulting early intervention service delivery system. Analyses and review of studies of Part C services are offered to inform policies that enhance early identification, family engagement, and intervention delivery. PMID- 22447755 TI - Health policy and the community safety net for individuals with intellectual disability. AB - This article explores social policy developments in the arena of intellectual and developmental disabilities. It begins by summarizing the challenges facing persons with intellectual disabilities and their caregivers in 1945. Families depended on a patchwork of over-crowded and under-funded large state institutions. Children with intellectual disabilities were marginalized from education and public services. Shame and stigma, along with the lack of community based services, led many parents to institutionalize a child. The federal government provided almost no specific assistance for disabled individuals or to their families. Postwar America provided fertile ground for parents to act collectively through the emergence of the National Association of Retarded Children (NARC). Partly as a consequence of such organizing, the 1950s marked a surprising turning-point, in which the federal government expanded income support to disabled persons through measures such as Social Security's "Disabled Adult Child" program and, by the early 1970s, the advent of Supplemental Security Income (SSI). It also reviews the growth of Medicaid as the dominant payer of medical and social services at the boundaries between personal medical services, case management, education, and other social services. The article ends by summarizing current challenges in intellectual disability policy. It notes that the size, complexity, and expense of I/DD services poses inherent challenges, particularly to state and local governments in the current recession. Adjusting for inflation, 23 states actually reduced real spending on I/DD services between 2008 and 2009. Controlling for local conditions, politically conservative states enacted deeper cuts and spent a smaller fraction of state income on intellectual disability services than other states. PMID- 22447756 TI - Do people with intellectual disability require special human subjects research protections? The interplay of history, ethics, and policy. AB - People with intellectual disability (ID) have a long history of discrimination and stigmatization, and a more recent history of pride and self-advocacy. The early history suggests that people with ID are a vulnerable population and deserve special research protections as do some other groups; the disability rights movement of the late 20th century aligns people with ID more closely with the principle of autonomy that has guided clinical and research ethics for the last 40 years. In examining the history of people with ID and the prevailing framework of human subjects research protections in the United States, we conclude that people with ID do not require special protection in human subjects research. The protections that have already been put in place for all individuals, if conscientiously and effectively implemented, achieve the right balance between safeguarding the interest of human research subjects and empowering individuals who choose to do so to participate in research. PMID- 22447757 TI - Collagen-infiltrated porous hydroxyapatite coating and its osteogenic properties: in vitro and in vivo study. AB - Bone-implant interface is critical for the early fixation of orthopedic implants. In this study, porous hydroxyapatite (HA) coatings were prepared through a liquid precursor plasma spraying process and were infiltrated with the collagen, alone and with the additional incorporation of recombinant human bone morphogenetic protein-2 (rhBMP-2) and RGD peptide (RGD). The results showed significantly improved mesenchymal stem cell (MSC) adhesion, proliferation, and differentiation on collagen-modified HA coatings, partially benefited from the formation of a fibrous network due to the self-reconstitution of collagen on the HA surface. Further enhancements on MSC proliferation and differentiation were generally observed through the additional incorporation of bone morphogenetic protein (BMP) and RGD. The osteoinductive and osteoconductive properties of the collagen/BMP modified HA coatings were studied in vivo. Clear ectopic bone formation and significantly accelerated bone growth rate (29% increase, p < 0.05) have been observed after 1-month implantation of HA-collagen/rhBMP-2-coated Ti alloy samples into the rabbit muscle and dog femora, respectively. Overall, our results suggest that collagen-modified HA coating surface is a far superior substrate for cell attachment, proliferation, and differentiation, and collagen can be used an efficient carrier for BMP in vivo. Therefore, modification of HA coating with collagen is a simple but effective biomimetic approach to enhancing the osteointegration and early fixation of bone-implant interface. PMID- 22447758 TI - Clenbuterol - regional food contamination a possible source for inadvertent doping in sports. AB - The misuse of the sympathomimetic and anabolic agent clenbuterol has been frequently reported in professional sport and in the livestock industry. In 2010, a team of athletes returned from competition in China and regular doping control samples were taken within the next two days. All urine samples contained low amounts (pg/ml) of clenbuterol, drawing the attention to a well-known problem: the possibility of an unintended clenbuterol intake with food. A warning that Chinese meat is possibly contaminated with prohibited substances according to international anti-doping regulations was also given by Chinese officials just before the Bejing Olympic Games in 2008. To investigate if clenbuterol can be found in human urine, a study was initiated comprising 28 volunteers collecting urine samples after their return from China. For the quantification of clenbuterol at a low pg/ml level, a very sensitive and specific isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed using liquid/liquid re-extraction for clean-up with a limit of detection and quantification of 1 and 3 pg/ml, respectively. The method was validated demonstrating good precision (intra-day: 2.9-5.5 %; inter-day: 5.1-8.8%), accuracy (89.5-102.5%) and mean recovery (81.4%). Clenbuterol was detectable in 22 (79%) of the analyzed samples, indicating a general food contamination problem despite an official clenbuterol prohibition in China for livestock. PMID- 22447759 TI - The agony of choice: how to find a suitable CPP for cargo delivery. AB - Successful and effective cellular delivery remains a main obstacles in the medical field. The use of cell-penetrating peptides (CPPs) has become one of the most important tools for the internalisation of a wide range of molecules including pharmaceuticals. It is still difficult to choose one CPP for one biological application because there is no ubiquitous CPP meeting the diverse requirements. In our case, we are looking for a suitable CPP to deliver the pro apoptotic KLA peptide (KLAKLAKKLAKLAK) by a simple co-incubation strategy. For that reason, we selected three different cell lines (fibroblastic, cancerous and macrophagic cells) and studied the uptake and subcellular localisation of six different CPPs alone as well as mixed with the KLA peptide. Furthermore, we used the CPPs with a carboxyamidated or a carboxylated C-terminus and analysed the impact of the C-termini on internalisation and cargo delivery. We could clearly showed that the cellular CPP uptake is not only dependent on the used CPP and cell line but also highly affected by its chemical nature of the C-terminus (uptake: carboxyamidated CPPs > carboxylated CPPs) and can influence its cellular localisation. We successfully delivered the KLA peptide in the three cell lines and learned that here as well, the C-terminus is crucial for an effective peptide delivery. Finally, we induced apoptosis in mouse leukaemic monocyte macrophage (RAW 264.7) and in human breast adenocarcinoma (MCF-7) cells using the mixture of amidated MPG peptide : KLA and in african green monkey kidney fibroblast (Cos-7) cells using carboxylated integrin peptide : KLA. PMID- 22447768 TI - Influence of nanometer smoothness and fibronectin immobilization of titanium surface on MC3T3-E1 cell behavior. AB - The aim of the present study was to evaluate the influence of mechanical treatment, namely, nanometer smoothing (Ra: approximately 2.0 nm) and sandblasting (Ra: approximately 1.0 MUm), as well as biochemical treatment, namely, fibronectin immobilization, of a titanium surface on osteoblast-like cell behavior. Cell proliferation was monitored by measurements of DNA content and ALP activity; osteocalcin production and mineralization behavior were also evaluated, in addition to morphological observation of attached cells. Fibronectin could be immobilized by the tresyl chloride-activation method. A sandblasted surface resulted in significantly more DNA than a nanometer-smooth surface, but fibronectin immobilization did not result in a significant increase of DNA at 52 days of cell culture. The nanometer-smooth surface showed highest ALP activity and osteocalcin production. FN immobilization decreased ALP activity for the nanometer-smooth surface, but increased it for the sandblasted surface. The nanometer-smooth surface also showed the highest osteocalcin production. Scanning electron microscopy showed interesting phenomena of the attached cells. Attached cell area was more rapidly increased on the nanometer-smooth surface than on the sandblasted surface. It was suggested that cultured cells on the nanometer-smooth surface began to spread earlier and that the proportion of spreading cells among total attached cells increased sooner on the nanometer-smooth surface than on the sandblasted rough surface. It appeared that FN immobilization influenced the arrangement of attached cells. In conclusion, the nanometer-smooth surface employed in the present study was beneficial for the differentiation of MC3T3-E1 cells. FN immobilization influenced the morphologies of attached cells. PMID- 22447769 TI - Electrospinning adipose tissue-derived extracellular matrix for adipose stem cell culture. AB - Basement membrane-rich extracellular matrices, particularly murine sarcoma derived Matrigel, play important roles in regenerative medicine research, exhibiting marked cellular responses in vitro and in vivo, although with limited clinical applications. We find that a human-derived matrix from lipoaspirate fat, a tissue rich in basement membrane components, can be fabricated by electrospinning and used to support cell culture. We describe practical applications and purification of extracellular matrix (ECM) from adipose tissue (At-ECM) and its use in electrospinning scaffolds and adipose stem cell (ASC) culture. The matrix composition of this purified and electrospun At-ECM was assessed histochemically for basement membrane, connective tissue, collagen, elastic fibers/elastin, glycoprotein, and proteoglycans. Each histochemical stain was positive in fat tissue, purified At-ECM, and electrospun At-ECM, and to some extent positive in a 10:90 blend with polydioxanone (PDO). We also show that electrospun At-ECM, alone and blended with PDO, supports ASC attachment and growth, suggesting that electrospun At-ECM scaffolds support ASC cultivation. These studies show that At-ECM can be isolated and electrospun as a basement membrane-rich tissue engineering matrix capable of supporting stem cells, providing the groundwork for an array of future regenerative medicine advances. PMID- 22447770 TI - Responses of microbial community from northern Gulf of Mexico sandy sediments following exposure to Deepwater Horizon crude oil. AB - In the present study, microbial community responses to exposure to unweathered Macondo Well crude oil and conventional diesel in a sandy beach environment were determined. Biodegradation was assessed in mesocosm experiments with differing fuel amounts (2,000 and 4,000 mg/kg) and with or without inorganic nutrient amendment. Carbon dioxide production was measured daily for 42 d. Aerobic alkane, total hydrocarbon, and polycyclic aromatic hydrocarbon (PAH) degraders were enumerated in treated and control mesocosms and changes in their abundances were measured weekly. Hydrocarbon mineralization occurred in all treatments. In the inorganic nutrient-amended treatments, the degradation rates were 2.31 and 2.00 times greater in the 2,000 mg/kg diesel and crude oil treatments, respectively, and 3.52 (diesel) and 4.14 (crude) times higher for the fuel types at the 4,000 mg/kg fuel concentrations compared to unamended treatments. Microbial lag phases were short (<3 d) and alkane and total hydrocarbon degrader numbers increased by five orders of magnitude compared to the uncontaminated treatments within 7 d in most treatments. Hydrocarbon degrader numbers in diesel and in crude oil treatments were similar; however, the PAH degraders were more abundant in the crude oil relative to diesel treatment. These findings indicate that hydrocarbon degradation by extant microbial populations in the northern Gulf of Mexico sandy beach environments can be stimulated and enhanced by inorganic nutrient addition. PMID- 22447771 TI - New ureteral scaffold constructed with composite poly(L-lactic acid)-collagen and urothelial cells by new centrifugal seeding system. AB - A tissue-engineered ureteral scaffold was constructed with composited poly L lactic acid (PLLA)-collagen endoluminal stent and uroepithelial cells (UECs) using a new seeding system. The electrospun PLLA-collagen nanofibrous mesh was seeded efficiently with human ureteral epithelial cells using a modified centrifugal seeding device. The cellular nanofibrous mesh was then wound around a spiral endoluminal stent to form a cellular composited PLLA-collagen ureteral scaffold. The cellular ureteral scaffold was subcutaneously implanted into nude mice. Cell attachment, distribution, and viability in vitro were investigated along with the cell fate in vivo. (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay showed that scaffolds seeded with centrifugal method had higher cellular activity than scaffolds seeded with static method (p < 0.05), and the metabolic activity per cell had no significant differences between the two methods (p > 0.05). Histologic analysis showed that the entrapped UECs remained in the scaffolds after 2 wk of implantation. The results of the study indicated that the composited PLLA-collagen endoluminal stent could serve as alternative cell carrier for tissue engineering ureter. In addition, the new modified centrifugal seeding system allowed rapid homogeneous distribution of cells onto the nanofibrous mesh, which will be useful to ureteral reconstruction. PMID- 22447772 TI - Development of a highly sensitive assay for enzyme-mediated reductive degradation of polychlorinated dibenzo-p-dioxin. AB - The degradation of 2-chloro-4,5-O-(4'-methyl-7', 8'-diphenyl)ether (CMDPE), an analog of 2,7-dichlorodibenzo-p-dioxin (2,7-DCDD), mediated by Geobacillus sp. UZO 3 cell-free extract was monitored. Ethyl acetate extracts of a complete reaction mixture incubated at 65 degrees C for 18 h were analyzed either by thin layer chromatography (TLC) fractionation coupled with spectrometric detection or by gas chromatography-mass spectrometry (GC-MS). The reaction product 4 methylumbelliferone (4MU) was successfully isolated by TLC and visualized by a transilluminator at 450 nm. The 4MU, 4-chlorophenol, and reaction intermediate 6 chlorophenoxy-4-methylumbelliferone were all successfully detected by GC-MS. The presence of these compounds suggest that Geobacillus sp. UZO 3 cell-free extract also catalyzes the reductive cleavage of the diaryl ether bonds of CMDPE in a similar mechanism previously reported in 2,7-DCDD. In the present study, the authors describe a simple and highly sensitive fluorescent assay for a new dioxin degrading enzyme(s). PMID- 22447773 TI - Making sense out of massive data by going beyond differential expression. AB - With the rapid growth of publicly available high-throughput transcriptomic data, there is increasing recognition that large sets of such data can be mined to better understand disease states and mechanisms. Prior gene expression analyses, both large and small, have been dichotomous in nature, in which phenotypes are compared using clearly defined controls. Such approaches may require arbitrary decisions about what are considered "normal" phenotypes, and what each phenotype should be compared to. Instead, we adopt a holistic approach in which we characterize phenotypes in the context of a myriad of tissues and diseases. We introduce scalable methods that associate expression patterns to phenotypes in order both to assign phenotype labels to new expression samples and to select phenotypically meaningful gene signatures. By using a nonparametric statistical approach, we identify signatures that are more precise than those from existing approaches and accurately reveal biological processes that are hidden in case vs. control studies. Employing a comprehensive perspective on expression, we show how metastasized tumor samples localize in the vicinity of the primary site counterparts and are overenriched for those phenotype labels. We find that our approach provides insights into the biological processes that underlie differences between tissues and diseases beyond those identified by traditional differential expression analyses. Finally, we provide an online resource (http://concordia.csail.mit.edu) for mapping users' gene expression samples onto the expression landscape of tissue and disease. PMID- 22447774 TI - Second genesis of a plastid organelle. PMID- 22447775 TI - The protein expression landscape of the Arabidopsis root. AB - Because proteins are the major functional components of cells, knowledge of their cellular localization is crucial to gaining an understanding of the biology of multicellular organisms. We have generated a protein expression map of the Arabidopsis root providing the identity and cell type-specific localization of nearly 2,000 proteins. Grouping proteins into functional categories revealed unique cellular functions and identified cell type-specific biomarkers. Cellular colocalization provided support for numerous protein-protein interactions. With a binary comparison, we found that RNA and protein expression profiles are weakly correlated. We then performed peak integration at cell type-specific resolution and found an improved correlation with transcriptome data using continuous values. We performed GeLC-MS/MS (in-gel tryptic digestion followed by liquid chromatography-tandem mass spectrometry) proteomic experiments on mutants with ectopic and no root hairs, providing complementary proteomic data. Finally, among our root hair-specific proteins we identified two unique regulators of root hair development. PMID- 22447776 TI - Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation. AB - Decoupling of transcription and translation during postmeiotic germ cell differentiation is critical for successful spermatogenesis. Here we establish that the interaction between microRNAs and actin-associated protein Arpc5 sets the stage for an elaborate translational control mechanism by facilitating the sequestration of germ cell mRNAs into translationally inert ribonucleoprotein particles until they are later translated. Our studies reveal that loss of microRNA-dependent regulation of Arpc5, which controls the distribution of germ cell mRNAs between translationally active and inactive pools, results in abnormal round spermatid differentiation and impaired fertility. Interestingly, Arpc5 functions as a broadly acting translational suppressor, as it inhibits translation initiation by blocking 80S formation and facilitates the transport of mRNAs to chromatoid/P bodies. These findings identify a unique role for actin associated proteins in translational regulation, and suggest that mRNA-specific and general translational control mechanisms work in tandem to regulate critical germ cell differentiation events and diverse somatic cell functions. PMID- 22447777 TI - A perfect (geochemical) storm yielded exceptional fossils in the early ocean. PMID- 22447778 TI - Imaging of protein synthesis with puromycin. PMID- 22447781 TI - BVA clarifies eye scheme examinations. PMID- 22447779 TI - Vaccination, not badger culling, to help control bovine TB in Wales. PMID- 22447782 TI - Reporting suspicions of badger baiting. PMID- 22447783 TI - Update on Kennel Club initiatives to improve dog health. PMID- 22447785 TI - Tackling challenges both existing and emerging. PMID- 22447786 TI - New rabies virus found in Tanzania. PMID- 22447787 TI - RCVS disciplinary structure and Defra's proposals for change. PMID- 22447788 TI - A vaccine against myxomatosis and RHD: a step forward for rabbit health. PMID- 22447789 TI - Independent veterinary checks at Crufts. PMID- 22447790 TI - Spotty liver syndrome in poultry in Great Britain. PMID- 22447791 TI - Best use of taxpayers' money? PMID- 22447793 TI - Relationship of in vitro susceptibility to moxifloxacin and in vivo clinical outcome in bacterial keratitis. AB - BACKGROUND: For bacterial infections, the susceptibility to antibiotics in vitro has been associated with clinical outcomes in vivo, although the importance of minimum inhibitory concentration (MIC) has been debated. In this study, we analyzed the association of MIC on clinical outcomes in bacterial corneal ulcers, while controlling for organism and severity of disease at presentation. METHODS: Data were collected as part of a National Eye Institute-funded, randomized, controlled trial (the Steroids for Corneal Ulcers Trial [SCUT]). All cases enrolled in SCUT had a culture-positive bacterial corneal ulcer and received moxifloxacin. The MIC to moxifloxacin was measured by E test. Outcomes included best spectacle-corrected visual acuity, infiltrate/scar size, time to re epithelialization, and corneal perforation. RESULTS: Five hundred patients with corneal ulcers were enrolled in the trial, and 480 were included in this analysis. The most commonly isolated organisms were Streptococcus pneumoniae and Pseudomonas aeruginosa. A 2-fold increase in MIC was associated with an approximately 0.02 logMAR decrease in visual acuity at 3 weeks, approximately 1 letter of vision loss on a Snellen chart (0.019 logMAR; 95% confidence interval [CI], .0040-.033; P = .01). A 2-fold increase in MIC was associated with an approximately 0.04-mm larger infiltrate/scar size at 3 weeks (0.036 mm; 95% CI, .010-.061; P = .006). After controlling for organism, a higher MIC was associated with slower time to re-epithelialization (hazards ratio, 0.92; 95% CI, .86-.97; P = .005). CONCLUSIONS: In bacterial keratitis, a higher MIC to the treating antibiotic is significantly associated with worse clinical outcomes, with approximately 1 line of vision loss per 32-fold increase in MIC. CLINICAL TRIALS REGISTRATION: NCT00324168. PMID- 22447794 TI - How hidden can malaria be in pregnant women? Diagnosis by microscopy, placental histology, polymerase chain reaction and detection of histidine-rich protein 2 in plasma. AB - BACKGROUND: Accurate diagnosis of malaria infection during pregnancy remains challenging because of low parasite densities and placental sequestration of Plasmodium falciparum. The performance of different methods to detect P. falciparum in pregnancy and the clinical relevance of undetected infections were evaluated. METHODS: P. falciparum infections were assessed in 272 Mozambican women at delivery by microscopy, placental histology, quantitative polymerase chain reaction (qPCR) and detection of histidine-rich protein 2 (HRP2) in plasma by enzyme-linked immunosorbent assay (ELISA) and a rapid diagnostic test (RDT). Association between infection and delivery outcomes was determined. RESULTS: Among the 122 women qPCR-positive for P. falciparum in peripheral and/or placental blood samples, 87 (71.3%) did not receive a positive diagnosis by peripheral microscopy, 75 (61.5%) by HRP2 ELISA, and 74 (60.7%) by HRP2 RDT in plasma. Fifty-seven of the 98 qPCR-positive placental infections (58.2%) were not detected by histology. Women who were qPCR-positive but negative in their peripheral blood by microscopy or HRP2 RDT in plasma (n = 62) were at increased risk of anemia, compared with negative women (n = 141; odds ratio, 2.03; 95% confidence interval, 1.07-3.83; P = .029). CONCLUSIONS: Microscopy, placental histology and HRP2-based plasma diagnostic methods fail to identify the majority of the P. falciparum infections detected by qPCR in peripheral and placental blood. Undetected infections were associated with maternal anemia, highlighting the urgent need for more accurate malaria diagnostic tools for pregnant women to avoid the negative clinical impact that hidden infections can have during pregnancy. CLINICAL TRIALS REGISTRATION: NCT00209781. PMID- 22447796 TI - What I've learned from BMJ case reports: excellent learning points. PMID- 22447797 TI - What I've learned from clinical evidence: peculiar treatments for gastroenteritis in children. PMID- 22447799 TI - Serum prolactin levels and the acute-phase efficacy in drug-naive schizophrenia treated with ziprasidone and olanzapine (translated version). AB - OBJECTIVES. To study the efficacy and associated serum prolactin levels of ziprasidone and olanzapine treatment in drug-naive schizophrenia patients. METHODS. All 78 inpatients with drug-naive schizophrenia were recruited from the Department of Psychology, The Third Affiliated Hospital of Sun Yat-sen University. They were divided into either olanzapine group (n = 49 [24 men, 25 women]; mean [standard deviation] age, 24 [6] years) or ziprasidone group (n = 29 [14 men, 15 women]; mean [standard deviation] age, 23 [7] years), all of whom were treated for 4 weeks. The serum prolactin level, the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement scores were measured before and at the end of treatment. RESULTS. In the olanzapine group, the respective mean (standard deviation) PANSS and CGI-S scores after the treatment (62 +/- 15 and 3 +/- 1) were significantly lower than those before the treatment (104 +/- 14 and 6 +/- 1) [p < 0.01]. In the ziprasidone group, the corresponding scores after the treatment (75 +/- 20 and 4 +/- 1) were also significantly lower than those before the treatment (104 +/- 17 and 6 +/- 1) [p < 0.01]. The decreases in mean (standard deviation) PANSS total (42 +/- 17) and PANSS positive scores (12 +/- 6) in the olanzapine group were significantly higher than those in the ziprasidone group (29 +/- 12 and 6 +/- 4, respectively) [p < 0.01]. The increase of serum prolactin in the ziprasidone female group (47 +/- 51 ug/L) was significantly higher than that in the ziprasidone male group (17 +/- 11 ug/L), the olanzapine male group (5 +/- 16 ug/L), and the olanzapine female group (21 +/- 34 ug/L) [p < 0.05]. CONCLUSIONS. Both ziprasidone and olanzapine are effective for treating drug-naive acute schizophrenia, but olanzapine was superior to ziprasidone in terms of positive and general psychopathological symptoms. In women, ziprasidone was associated with greater changes in prolactin level than olanzapine. PMID- 22447800 TI - Cognitive function, functional performance and severity of depression in Chinese older persons with late-onset depression. AB - OBJECTIVES. The relationship between cognitive status and depressive symptoms and their liability to cause functional decline are of clinical and public health importance as it appears to be common, frequently coexists, and may be treatable. This study examined the relationship of depression severity and cognitive performance and the impact of such an interaction on functional ability in Chinese elderly subjects with late-onset depression. METHODS. A total of 105 non demented elderly patients with late-onset depression were recruited. Impairment in instrumental activities of daily living and severity of depression were respectively assessed with the Disability Assessment for Dementia scale and the 24-item Hamilton Depression Rating Scale. Various cognitive domains were assessed including global cognitive function, delayed episodic memory, and executive functions. The relationship between specific cognitive impairment and mood symptom severity was assessed. The clinical correlates of functional performance were also examined. RESULTS. Increasingly severe depression was associated with lower scores in the Mini-Mental State Examination, delayed recall, and poorer performance in the Trail Making Test-Part A (after adjusting for the effect of age and education). The severity of apathy correlated negatively with the Mini Mental State Examination scores only. Among the depressed subjects, greater levels of depression and apathy, poorer performance in Trail Making Test-Part B, and mild parkinsonian signs were associated with lower functional scores. CONCLUSIONS. Lack of interest and motivation, depressive mood, compounded by behavioural abnormalities resulting from executive dysfunction, accounted for functional disability in elderly subjects with late-onset depression. These relationships may provide the background for developing interventions targeting functional deficits associated with specific cognitive dysfunctions and depression. PMID- 22447801 TI - A questionnaire survey on attitudes and understanding towards mental disorders. AB - OBJECTIVES. To obtain information about basic knowledge towards mental disorders and to evaluate public attitudes towards mental disorders in the Hong Kong Chinese population. METHODS. Questionnaires which collected basic demographic information, opinions about potential stigmas and myths, and knowledge on case vignettes depicting fictional characters with symptoms of mental illness were delivered to subjects in a secondary school, 2 homes for the elderly, a private housing estate, and a public housing estate in Hong Kong. RESULTS. Completed questionnaires were collected from 1035 subjects. In general, the participants' acceptance of mental illness was good. Regular contacts with such patients were associated with better knowledge (t = -2.71, p < 0.01) and better acceptance (t = 2.77, p < 0.01) of mental illness. Younger participants aged 15 to 19 years had a lower level of knowledge about mental health problems compared with other age groups (p < 0.001). CONCLUSIONS. Personal contact with people with mental illness may help to improve knowledge and acceptance. Younger people in secondary school should be the target and prioritised group for mental health education. Apart from the delivery of mental health knowledge, strategies to increase social contact of the public with people having mental illness could be considered in the design and implementation of anti-stigma programmes. PMID- 22447802 TI - Cognitive and functional impairment in Chinese elderly with late-onset depression. AB - OBJECTIVES. To investigate cognitive and functional impairment in Chinese elderly subjects with late-onset depression. METHODS. Subjects with late-onset depression and who were clinically non-demented were recruited. Their cognitive and functional scores were compared with those of cognitively normal elderly controls and elderly persons with mild cognitive impairment. Functional ability was assessed by the Disability Assessment for Dementia score. Various cognitive domains were assessed including global cognitive function, delayed episodic memory, working memory, and categorical verbal fluency test. RESULTS. A total of 105 depressed subjects and 324 non-depressed controls (149 normal elderly controls and 175 with mild cognitive impairment) were recruited. The depression group had significantly poorer performance in all cognitive assessments compared to the normal elderly control group. The depression group had a similar cognitive profile to those with mild cognitive impairment, except that its subjects had slightly better performance in the Categorical Verbal Fluency Test, delayed recall testing, and the Chinese version of the Alzheimer's Disease Assessment Scale-Cognitive subscale test. Depressed subjects had significantly lower functional scores in instrumental activities of daily living than the non depressed, normal elderly controls, and those with mild cognitive impairment. CONCLUSIONS. Our results demonstrate that Chinese elderly with late-onset depression had cognitive impairments in multiple domains similar to those encountered in the age- and sex-matched non-depressed controls with mild cognitive impairment. However, their functional performance was significantly poorer than that in these controls. This study provided extensive characterisation of the range and depth of cognitive and functional impairments in elderly patients with late-onset depression. PMID- 22447803 TI - Acute mental disturbance caused by synthetic cannabinoid: a potential emerging substance of abuse in Hong Kong. AB - Synthetic cannabinoids are hybrid herbal/chemical products which mimic the effects of cannabis. They are usually marketed as incense or 'herbal smoking blend', and best known by the brand names 'K2' and 'Spice'. Their popularity among recreational drug abusers has grown rapidly due to their easy availability, relatively low cost, non-detection by conventional drug tests, and ease of concealing their use from family and authorities. They took Europe and later North America by storm in the late 2000s, yet limited medical literature exists detailing their adverse effects. They began to emerge in the Hong Kong drug scene in 2009. We report on a man who developed acute mental disturbance after 4 weeks of daily K2 abuse. This is the first case report of mental disorder caused by synthetic cannabinoid abuse in a Chinese. PMID- 22447804 TI - Disruption of the X-loop turn of the prion protein linked to scrapie resistance. AB - The prion diseases are a class of neurodegenerative diseases caused by the misfolding and aggregation of the prion protein (PrP(C)) into toxic and infectious oligomers (PrP(Sc)). These oligomers are critical to understanding and combating these diseases. Differences in the sequence of PrP affect disease susceptibility, likely by shifting the tolerance of the protein for adaptation to PrP(Sc) conformations and/or the recognition event between PrP(Sc) and PrP(C) prior to conversion of the PrP(C). We selected two sets of PrP(Sc)-resistant mutant sequences for solvated atomistic molecular dynamics simulation to investigate the structural basis of resistance. The first group involved mutation in the X-loop (residues 164-171) resulting from selective breeding of sheep. The second group included eight mutants in mice identified by random mutagenesis targeting helix C followed by screening in cell cultures. Multiple simulations were performed of 14 different mutant and control constructs under different pH conditions for a total of 3.6 MUs of simulation time. The X-loop formed a stable turn at neutral pH in wild-type PrP from both species. PrP(Sc)-resistant mutations disrupted this turn even though only one of the mutants is in the X loop. The X-loop is compact and buried in our previously described spiral models of PrP(Sc)-like oligomers. On the basis of the findings presented here and in the context of the spiral oligomer model, we propose that expansion of the X-loop disrupts protofibril packing, providing a structural basis for resistance. PMID- 22447805 TI - Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. AB - AIMS: The efficacy of durable polymer drug-eluting stents (DES) is delivered at the expense of delayed healing of the stented vessel. Biodegradable polymer DES aim to avoid this shortcoming and may potentially improve long-term clinical outcomes, with benefit expected to accrue over time. We sought to compare long term outcomes in patients treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES). METHODS AND RESULTS: We pooled individual patient data from three large-scale multicentre randomized clinical trials (ISAR TEST 3, ISAR-TEST 4, and LEADERS) comparing biodegradable polymer DES with durable polymer SES and assessed clinical outcomes during follow-up through 4 years. The efficacy endpoint of interest was target lesion revascularization and the safety endpoint of interest was definite stent thrombosis. Out of 4062 patients included in the present analysis, 2358 were randomly assigned to treatment with biodegradable polymer DES (sirolimus-eluting, n= 1501; biolimus eluting, n= 857) and 1704 patients to durable polymer SES. No heterogeneity across the trials was observed in analyses of the primary and secondary endpoints. At 4 years, the risk of target lesion revascularization was significantly lower among patients treated with biodegradable polymer DES vs. durable polymer SES (hazard ratio 0.82, 95% CI 0.68-0.98, P= 0.029). In addition, the risk of stent thrombosis was significantly reduced with biodegradable polymer DES vs. durable polymer SES (hazard ratio 0.56, 95% CI 0.35-0.90, P= 0.015), driven by a lower risk of very late stent thrombosis (hazard ratio 0.22, 95% CI 0.08-0.61, P= 0.004). In keeping with this, in landmark analysis between 1 and 4 years, the incidence of myocardial infarction was lower for patients treated with biodegradable polymer DES vs. durable polymer SES (hazard ratio 0.59, 95% CI 0.73 0.95, P= 0.031). CONCLUSION: Biodegradable polymer DES improve safety and efficacy compared with durable polymer SES during long-term follow-up to 4 years. PMID- 22447806 TI - Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension. AB - BACKGROUND: Functional tricuspid regurgitation (FTR) with structurally normal valve is of poorly defined mechanisms. Prevalence and clinical context of idiopathic FTR (Id-FTR) (without overt TR cause) are unknown. METHODS AND RESULTS: To investigate prevalence, clinical context, and mechanisms specific to FTR types, Id-FTR versus pulmonary hypertension-related (PHTN-FTR, systolic pulmonary pressure >=50 mm Hg), we analyzed 1161 patients with prospectively quantified TR. Id-FTR (prevalence 12%) was associated with aging and atrial fibrillation. For mechanistic purposes, we measured valvular and right ventricular (RV) remodeling in 141 Id-FTR matched to 140 PHTN-FTR and to 99 controls with trivial TR for age, sex, atrial fibrillation, and ejection fraction. PHTN-FTR and Id-FTR were also matched for TR effective-regurgitant orifice (ERO). Id-FTR valvular alterations (versus controls) were largest annular area (3.53+/-0.6 versus 2.74+/-0.4 cm(2), P<0.0001) and lowest valvular/annular coverage ratio (1.06+/-0.1 versus 1.45+/-0.2, P<0.0001) but normal valve tenting height. PHTN-FTR had mild annular enlargement but excessive valve tenting height (0.8+/-0.3 versus 0.35+/-0.1 cm, P<0.0001). Valvular changes were linked to specific RV changes, largest basal dilatation, and normal length (RV conical deformation) in Id-FTR versus longest RV with elliptical/spherical deformation in PHTN-FTR. With increasing FTR severity (ERO >=40 mm(2)), changes specific to each FTR type were accentuated, and RV function (index of myocardial performance) was consistently reduced. CONCLUSIONS: Id-FTR is frequent, linked to aging and atrial fibrillation, can be severe, and is of unique mechanism. In Id-FTR, excess annular and RV-basal enlargement exhausts valvular/annular coverage reserve, and RV conical deformation does not cause notable valvular tenting. Conversely, PHTN FTR is determined by valvular tethering with tenting linked to RV elongation and elliptical/spherical deformation. These specific FTR-mechanisms may be important in considering surgical correction in FTR. PMID- 22447807 TI - Computed tomography myocardial perfusion imaging with 320-row detector computed tomography accurately detects myocardial ischemia in patients with obstructive coronary artery disease. AB - BACKGROUND: Computed tomography coronary angiography (CTA) has been shown to be accurate in detecting anatomic coronary arterial obstruction, but is limited for the detection of myocardial ischemia. The primary aim of this study was to assess the accuracy of 320-row computed tomography perfusion imaging (CTP) to detect atherosclerosis causing myocardial ischemia. METHODS AND RESULTS: Fifty symptomatic patients with recent single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) underwent a comprehensive cardiac computed tomography (CT) protocol that included 320-CTA, followed by adenosine stress CTP. CTP images were analyzed quantitatively for the presence of subendocardial perfusion deficits. All analyses were blinded to imaging and clinical results. CTA alone was a limited predictor of myocardial ischemia compared with SPECT, with a sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of 56%, 75%, 56%, and 75%, and the area under the receiver operator characteristic curve (AUC) was 0.65 (95% CI, 0.51-0.78, P=0.07). CTP was a better predictor of myocardial ischemia, with a sensitivity, specificity, PPV, and NPV of 72%, 91%, 81%, and 85%, with an AUC of 0.81 (95% CI, 0.68-0.91, P<0.001), and was an excellent predictor of myocardial ischemia on SPECT-MPI in the presence of stenosis (>=50% on CTA), with a sensitivity, specificity, PPV, and NPV of 100%, 81%, 50%, and 100%, with an AUC of 0.92 (95% CI, 0.80-0.97, P<0.001). The radiation dose for the comprehensive cardiac CT protocol and SPECT were 13.8+/-2.9 and 13.1+/-1.7; respectively (P=0.15). CONCLUSIONS: Computed tomography perfusion imaging with rest and adenosine stress 320-row CT is accurate in detecting obstructive atherosclerosis causing myocardial ischemia. PMID- 22447808 TI - Systematic mediastinal nodal dissection and video-assisted thoracic surgery. PMID- 22447809 TI - Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis. AB - BACKGROUND: Pressure overload resulting from aortic stenosis causes maladaptive ventricular and vascular remodeling that can lead to pulmonary hypertension, heart failure symptoms, and adverse outcomes. Retarding or reversing this maladaptive remodeling and its unfavorable hemodynamic consequences has the potential to improve morbidity and mortality. Preclinical models of pressure overload have shown that phosphodiesterase type 5 inhibition is beneficial; however, the use of phosphodiesterase type 5 inhibitors in patients with aortic stenosis is controversial because of concerns about vasodilation and hypotension. METHODS AND RESULTS: We evaluated the safety and hemodynamic response of 20 subjects with severe symptomatic aortic stenosis (mean aortic valve area, 0.7 +/- 0.2 cm(2); ejection fraction, 60 +/- 14%) who received a single oral dose of sildenafil (40 or 80 mg). Compared with baseline, after 60 minutes, sildenafil reduced systemic (-12%; P<0.001) and pulmonary (-29%; P=0.002) vascular resistance, mean pulmonary artery (-25%; P<0.001) and wedge (-17%; P<0.001) pressures, and increased systemic (13%; P<0.001) and pulmonary (45%; P<0.001) vascular compliance and stroke volume index (8%; P=0.01). These changes were not dose dependent. Sildenafil caused a modest decrease in mean systemic arterial pressure (-11%; P<0.001) but was well tolerated with no episodes of symptomatic hypotension. CONCLUSIONS: This study shows for the first time that a single dose of a phosphodiesterase type 5 inhibitor is safe and well tolerated in patients with severe aortic stenosis and is associated with improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of phosphodiesterase type 5 inhibition as adjunctive medical therapy in patients with aortic stenosis. PMID- 22447810 TI - Long-term results of mitral repair for functional mitral regurgitation in idiopathic dilated cardiomyopathy. AB - OBJECTIVES: While the results of mitral repair in ischaemic mitral regurgitation have been repeatedly reported, less data are available about the outcome of surgical repair of functional mitral regurgitation (FMR) in idiopathic dilated cardiomyopathy (iDCM) which represents the topic of this study. METHODS: Fifty four iDCM patients (mean age 63 +/- 10.5 years) underwent mitral valve repair for severe FMR. Coronary angiography confirmed the absence of coronary disease in all patients. Most of the patients (77.7%) were in New York Heart Association (NYHA) class III-IV. Pre-operative ejection fraction (EF) was 30.4 +/- 8.5%, left ventricle end-diastolic diameter (LVEDD) 67.5 +/- 7.8 mm, left ventricle end systolic diameter (LVESD) diameter 53.9 +/- 8.3 mm. Concomitant procedures were atrial fibrillation (AF) ablation (19 patients) and tricuspid repair (17 patients). Follow-up was 100% complete (mean 4.2 +/- 2.5 years, median 4.2 years, range 3.3 months-11.1 years). RESULTS: In-hospital mortality was 5.6%. Actuarial survival at 6.5 years was 69 +/- 8.8%. Patients submitted to successful AF ablation and/or cardiac resynchronization therapy (CRT) had a significantly better survival (91 +/- 7.9 vs 67 +/- 9.5%, P = 0.01). Freedom from MR>=3+/4+ was 89.1 +/- 5.7% at 6.5 years. Follow-up echocardiography showed a reduction in LVEDD (P < 0.0001) and LVESD (P = 0.0003). Mean EF increased to 38.7 +/- 12.4% (P < 0.0001). Multivariate analysis identified successful ablation of AF and/or CRT (P = 0.01) and higher preoperative EF (0.03) as predictors of overall survival. Successful ablation of AF and/or CRT (P = 0.02) and lower preoperative systolic pulmonary artery pressure (0.04) were identified as independent predictors of reverse LV remodelling at follow-up. At last follow-up, 86.2% of the patients were in NYHA II or less. CONCLUSIONS: Mitral repair for FMR in well-selected iDCM patients is associated with low hospital mortality and significant clinical benefit at late follow-up. Concomitant successful AF ablation and/or CRT provide a major symptomatic and prognostic advantage and should be associated to mitral surgery whenever indicated. PMID- 22447811 TI - Advancing understanding of racial and ethnic inequalities in injury research. PMID- 22447812 TI - Strengthening capacity for the prevention of family violence in low-income and middle-income countries. PMID- 22447813 TI - Ultrasound-guided percutaneous microwave ablation of benign thyroid nodules: experimental and clinical studies. AB - PURPOSE: To obtain the treatment parameters of internally cooled microwave antenna and to evaluate the feasibility of ultrasound-guided percutaneous microwave ablation (MWA) for benign thyroid nodules. MATERIALS AND METHODS: MWAs were performed by microwave antenna (16G) in ex vivo porcine liver. The lesion diameters achieved in different groups (20, 25, and 30 W for 3, 5, 7, 10, and 12 min) were compared. The clinical study was approved by the ethics committee. Written informed consent was obtained from all patients. MWA was performed in 11 patients (male to female ratio=1:10; mean age, 50+/-7 years) with 11 benign thyroid nodules. Ultrasound scan, laboratory data, and clinical symptoms were evaluated before and 1 day and 1, 3, 6, 9, and 12 months after the procedure. RESULTS: In ex vivo study, the ablation lesion at 30 W 12 min tended to have appropriate scope and spherical shape. In clinical study, the follow-up periods ranged from 1 to 9 months. At the last follow-up, the largest diameter decreased from 2.9+/-1.0 (range, 1.6-4.1) to 1.9+/-0.7 (range, 0.4-3.0) cm (P<0.01), and the volume decreased from 5.30+/-4.88 (range, 0.89-14.81) to 2.40+/-2.06 (range, 0.02-6.35) ml (P<0.01). The volume reduction ratio was 45.99+/-29.90 (range, 10.56-98.15) %. The cosmetic grading score was reduced from 3.20+/-0.79 to 2.30+/ 0.95 (P<0.05). One patient experienced temporary nerve palsy and was recovered within 2 months after treatment. CONCLUSION: The internally cooled microwave antenna can yield ideal ablation lesions, and ultrasound-guided percutaneous MWA is a feasible technique for benign thyroid nodules. PMID- 22447814 TI - Combined treatment with GH and anastrozole in a pubertal boy with Cushing's disease and postsurgical GH deficiency. AB - Growth failure is a characteristic manifestation of pediatric Cushing's disease. Catch-up growth is usually incomplete after cure of the disease, and final height is often compromised. Possible mechanisms for this phenomenon include postoperative persistence of GH hyposecretion and absence of retardation of bone maturation in spite of GH deficiency. This report describes the outcome in the case of a boy with Cushing's disease for whom GH replacement therapy was combined with anastrozole, an aromatase inhibitor, in order to delay skeletal maturation and extend the available time for linear growth. The case of a 14 years 4-months old pubertal male (Tanner stage III) with GH deficiency after successful surgical treatment of Cushing's disease is presented. His height was 147.2 cm (-2.34 SDS), and his midparental target height 171.2 cm (-0.95 SDS). Bone age was 13.5 years and predicted adult height 163.2 cm (-2.2 SDS). Combined treatment was administered for 2.5 years. GH was maintained up to age 18 years. Anastrozole induced a substantial deceleration of bone age. Near-final height at 18 years was 169.5 cm (-1.07 SDS). Puberty progressed normally. Compared with population reference data, bone mineral density before GH plus anastrozole treatment was 4.07 SDS in the lumbar spine and -1.85 SDS in the femoral neck. These measures increased to -1.95 and -0.89 SDSs respectively, at 18 years, when GH was discontinued. Combined treatment with GH and aromatase inhibitors could be a therapeutic alternative to improve the stature of pubertal boys with Cushing's disease and postsurgical GH deficiency. PMID- 22447815 TI - Inflammation and type one diabetes. AB - Type one diabetes (T1D) is a complex T cell-mediated autoimmune disease, the defining feature of which is the destruction of the insulin-secreting beta- (beta)- cell. Both genetic and environmental factors combine to precipitate disease, and the outcome of the pathological process is dependent on multiple inter-related factors. In this review, the mechanisms behind the initiation and propagation of the autoimmune response are analysed, and the contribution of differing T-helper (T(h)) subsets--in particular T(h)1- and T(h)17-related cytokines--to the disease process are discussed. An argument is then synthesized that proposes that the beta-cell's response to stress and inflammation is the critical determinant in predicting disease outcome and that, immunologically, a delicate balance exists between regulation and inflammation at the site of islet infiltration. Strategies for disease intervention, therefore, will not only require the induction of T-cell tolerance by tipping the balance towards regulation but will also need to contain approaches that result in the scavenging of inflammatory mediators, in order to facilitate repair. Ultimately, given that clinical diabetes presents late in the autoimmune process, strategies for beta cell regeneration must now be addressed. There is thus a requirement for an increased, collaborative effort between stem cell biologists and immunologists in order to tailor an optimal therapeutic strategy for the treatment of this debilitating disease. PMID- 22447816 TI - Geriatric consultation service in emergency department: how does it work? AB - BACKGROUND: Hong Kong is having a significant prevalence of geriatric patients who usually require admission after presentation to the hospital through emergency departments. The geriatric consultation programme 'We Care' aims at lowering acute geriatric medical admission. OBJECTIVES: The study aims at analysing the impact of the geriatric consultation service on the acute medical admission, and to study the characteristics and outcome of geriatric patients. METHODS: Retrospective study. Patients who received geriatric consultations during 1 January 2009 to 1 March 2011 were enrolled. The demographic information, diseases case mix, venue of discharge, clinical severity, community nursing service referrals and adverse outcomes were retrieved and analysed. The incidence of adverse outcomes under the presence of each factor was studied. RESULTS: 2202 geriatric patients were referred. Their age ranged from 45 to 99 (mean 79.91, SD 7.45, median 80). These cases were categorised into: (1) chronic pulmonary disease (n=673; 30.6%), (2) debilitating cardiac disease (n=526; 23.9%), (3) geriatric syndromes (n=147; 6.7%), (4) neurological problems (n=416; 18.9%), (5) diabetes-related problems (n=146; 6.6%), (6) terminal malignancy (n=39; 1.8%), (7) electrolyte or input/output disturbance (n=137; 6.2%), (8) non-respiratory infections (n=36, 1.6%) and (9) others (n=82; 3.7%). Acute medical admission was evaded in 84.7% of all consultations with 1039 (47.2%) patients discharged home and 825 patients (37.5%) admitted to convalescent hospital. The incidence rate of adverse outcomes was 1.6%. CONCLUSION: Programme 'We Care' provided comprehensive geriatric assessment to suitable geriatric patients, resulting in an effective reduction of acute geriatric hospital admission. PMID- 22447817 TI - Refocusing quality measurement to best support quality improvement: local ownership of quality measurement by clinicians. PMID- 22447818 TI - Self-reported violations during medication administration in two paediatric hospitals. AB - CONTENT: Violations of safety protocols are paths to adverse outcomes that have been poorly addressed by existing safety efforts. This study reports on nurses' self-reported violations in the medication administration process. OBJECTIVE: To assess the extent of violations in the medication administration process among nurses. DESIGN, SETTING AND PARTICIPANTS: Participants were 199 nurses from two US urban, academic, tertiary care, free-standing paediatric hospitals who worked in a paediatric intensive care unit (PICU), a haematology-oncology-transplant (HOT) unit or a medical-surgical (Med/Surg) unit. In a cross-sectional survey, nurses were asked about violations in routine or emergency situations in three steps of the medication administration process. MAIN OUTCOME MEASURE: Self reported violations of three medication administration protocols were made using a seven-point 0-6 scale from 'not at all' to 'a great deal'. RESULTS: Analysis of variance identified that violation reports were highest for emergency situations, rather than for routine operations, highest by HOT unit nurses, followed by PICU nurses and then Med/Surg unit nurses, and highest during patient identification checking, followed by matching a medication to a medication administration record, and then documenting an administration. There was also a significant three-way interaction among violation situation, step in the process, and unit. CONCLUSIONS: Protocol violations occur throughout the medication administration process and their prevalence varies as a function of hospital unit, step in the process, and violation situation. Further research is required to determine whether these violations improve or worsen safety, and for those that worsen safety, how to redesign the system of administration to reduce the need to violate protocol to accomplish job tasks. PMID- 22447819 TI - Failure mode and effects analysis: too little for too much? AB - Failure mode and effects analysis (FMEA) is a structured prospective risk assessment method that is widely used within healthcare. FMEA involves a multidisciplinary team mapping out a high-risk process of care, identifying the failures that can occur, and then characterising each of these in terms of probability of occurrence, severity of effects and detectability, to give a risk priority number used to identify failures most in need of attention. One might assume that such a widely used tool would have an established evidence base. This paper considers whether or not this is the case, examining the evidence for the reliability and validity of its outputs, the mathematical principles behind the calculation of a risk prioirty number, and variation in how it is used in practice. We also consider the likely advantages of this approach, together with the disadvantages in terms of the healthcare professionals' time involved. We conclude that although FMEA is popular and many published studies have reported its use within healthcare, there is little evidence to support its use for the quantitative prioritisation of process failures. It lacks both reliability and validity, and is very time consuming. We would not recommend its use as a quantitative technique to prioritise, promote or study patient safety interventions. However, the stage of FMEA involving multidisciplinary mapping process seems valuable and work is now needed to identify the best way of converting this into plans for action. PMID- 22447820 TI - Building information for systematic improvement of the prevention of hospital acquired pressure ulcers with statistical process control charts and regression. AB - OBJECTIVES: To demonstrate complementary results of regression and statistical process control (SPC) chart analyses for hospital-acquired pressure ulcers (HAPUs), and identify possible links between changes and opportunities for improvement between hospital microsystems and macrosystems. METHODS: Ordinary least squares and panel data regression of retrospective hospital billing data, and SPC charts of prospective patient records for a US tertiary-care facility (2004-2007). A prospective cohort of hospital inpatients at risk for HAPUs was the study population. RESULTS: There were 337 HAPU incidences hospital wide among 43 844 inpatients. A probit regression model predicted the correlation of age, gender and length of stay on HAPU incidence (pseudo R(2)=0.096). Panel data analysis determined that for each additional day in the hospital, there was a 0.28% increase in the likelihood of HAPU incidence. A p-chart of HAPU incidence showed a mean incidence rate of 1.17% remaining in statistical control. A t-chart showed the average time between events for the last 25 HAPUs was 13.25 days. There was one 57-day period between two incidences during the observation period. A p-chart addressing Braden scale assessments showed that 40.5% of all patients were risk stratified for HAPUs upon admission. CONCLUSION: SPC charts complement standard regression analysis. SPC amplifies patient outcomes at the microsystem level and is useful for guiding quality improvement. Macrosystems should monitor effective quality improvement initiatives in microsystems and aid the spread of successful initiatives to other microsystems, followed by system-wide analysis with regression. Although HAPU incidence in this study is below the national mean, there is still room to improve HAPU incidence in this hospital setting since 0% incidence is theoretically achievable. Further assessment of pressure ulcer incidence could illustrate improvement in the quality of care and prevent HAPUs. PMID- 22447821 TI - Poverty amid plenty. PMID- 22447822 TI - Nature and timing of incidents intercepted by the SURPASS checklist in surgical patients. AB - INTRODUCTION: More than half of in-hospital adverse events can be attributed to a surgical discipline. Checklists can effectively decrease errors and adverse events. However, the mechanisms by which checklists lead to increased safety are unclear. This study aimed to assess the number, nature and timing of incidents intercepted by use of the Surgical Patient Safety System (SURPASS) checklist, a patient-specific multidisciplinary checklist that covers the entire surgical patient pathway. METHODS: The checklist was implemented in two academic hospitals and four teaching hospitals in the Netherlands. Users of the checklist had three options for each item that was checked: 'not applicable', 'yes' and 'intercepted by checklist'. In each hospital, the first 1000 completed checklists were entered into an online central database. RESULTS: In six participating hospitals, 6313 checklists were collected. One or more incidents were intercepted in 2562 checklists (40.6%). In total, 6312 incidents were intercepted. After correction for the number of items and the extent of adherence in each part of the checklist, the number of intercepted incidents was highest in the preoperative and postoperative stages. CONCLUSIONS: The checklist intercepts many potentially harmful incidents across all stages of the surgical patient pathway. The majority of incidents were intercepted in the preoperative and postoperative stages of the pathway. The degree to which these incidents would have been intercepted by a single checklist in the operating room only, compared with a checklist for the entire surgical pathway, remains a subject for future study. PMID- 22447823 TI - What gets published: the characteristics of quality improvement research articles from low- and middle-income countries. AB - OBJECTIVES: Reports of quality improvement (QI) research from low- and middle income countries (LMICs) remain sparse in the scientific literature. The authors reviewed the published literature to describe the characteristics of such reports. METHODS: The authors conducted a systematic search for QI research articles from LMICs catalogued in the PubMed databases prior to December 2011, complemented by recommendations from experts in the field. Articles were categorised based on bibliometric and research characteristics. Twenty papers were randomly selected for narrative analysis regarding strategies used to present the methods and results of interventions. RESULTS: Seventy-six articles met the inclusion criteria. Publication rate accelerated over time, particularly among observational studies. Most studies did not use a concurrent control group; pre-/post-study designs were most common overall. Four papers were published in top-tier journals, 17 in journals at the top of their specialty and 20 in quality specific journals. Among the papers selected for narrative analysis, four distinct components were observed in most: a description of the problem state, a description of the improvement processes and tools, a separate description of the interventions tested and a description of the evaluation methods. DISCUSSION: The small number of articles identified by this review suggests that publication of QI research from LMICs remains challenging. However, recent increases in publication rates, especially among observational studies, may attest to greater interest in the topic among scientific audiences. Though the authors are not able to compare this sample with unpublished papers, the four components observed by them in the narrative analysis seem to strengthen QI research reports. PMID- 22447824 TI - Medical emergencies in medical imaging. PMID- 22447825 TI - Biologic effects of SMF and paclitaxel on K562 human leukemia cells. AB - In this study, we evaluated the ability of 8.8 mT static magnetic fields (SMF) to enhance the in vitro action of a chemotherapeutic agent, paclitaxel, against K562 human leukemia cells. We analyzed the cell proliferation, cell cycle distribution, DNA damage and alteration of cell surface and cell organelle ultrastructure after K562 cells were exposed to paclitaxel in the presence or absence of 8.8 mT SMF. The results showed that in the presence of SMF, the efficient concentration of paclitaxel on K562 cells was decreased from 50 to 10 ng/ml. Cell cycle analysis indicated that K562 cells treated with SMF plus paclitaxel were arrested at the G2 phase, which was mainly induced by paclitaxel. Through comet assay, we found that the cell cycle arrest effect of paclitaxel with or without SMF on K562 cells was correlated with DNA damage. The results of atomic force microscopy and transmission electron microscopy observation showed that the cell ultrastructure was altered in the group treated with the combination of SMF and paclitaxel, holes and protuberances were observed, and vacuoles in cytoplasm were augmented. Our data indicated that the potency of the combination of SMF and paclitaxel was greater than that of SMF or paclitaxel alone on K562 cells, and these effects were correlated with DNA damage induced by SMF and paclitaxel. Therefore, the alteration of cell membrane permeability may be one important mechanism underlying the effects of SMF and paclitaxel on K562 cells. PMID- 22447826 TI - Changes in cellular response to the damage induced in PC-3 prostate cancer cells by proton microbeam irradiation. AB - The aim of this research was to find out whether the passage number effect may influence on the PC-3 cells (the human prostate cancer line derived from bone metastases) response to proton radiation. 2 MeV horizontally focused proton microbeam was used as a radiation source. The cells were treated with a counted number of H(+) ions (50-8000) corresponding to doses of 1.3-209 Gy/cell. For comparison, cell death was also induced by UVC radiation. All cells were stained with Hoechst 33342 and propidium iodide and visualized under a fluorescence microscope. Necrosis was observed at: a) 8000 protons per cell (corresponding to ~209 Gy/cell) after 2-4 passages, b) 3200 protons per cell (corresponding to ~84 Gy/cell) for cells after 11-14 passages and c) only 800 protons per cell (corresponding to ~2 Gy/cell ) after 47-50 passages. Apoptosis was efficiently induced, by protons, only in cells after 50 passages. The results showed that the laboratory conditions affected cellular response of PC-3 cell line to the proton irradiation. The cellular response to the radiation treatment strongly depends on number of passages. PMID- 22447827 TI - Electroporation-induced changes in normal immature rat myoblasts (H9C2). AB - Application of a high electric field causes an electric shock to the heart. This is utilized in defibrillation to reestablish normal contraction rhythms during dangerous arrhythmias or in cardiac arrest. If shock-induced transmembrane potentials are large enough, they can cause tissue destruction due to irreversible electroporation (EP). Also electrochemotherapy of nearby tissues may have an adverse effect on the heart. Herein, we present experimental data on effects of electroporation in culture of cardiac cells (H9C2). The electric field was applied in short pulses of 25-3250 V/cm, 50 us each. The viability of cells was tested by MTT assay after 24 hours. For detection of DNA fragmentation, associated with apoptosis, alkaline and neutral comet assays were performed after EP. Additionally phase contrast images of cells obtained directly after EP were analyzed. Although cell images indicated disruption of cell membranes after EP with high intensities, only a few percent of apoptotic cells and no necrotic effects in the cell nucleus could be observed in comet assay tests performed 2 hours post EP. MTT viability test showed that pulse intensities above 375 V/cm are destructive for myocytes viability. PMID- 22447828 TI - Neither inhalative nor intravenous application of carbon monoxide modifies gastric mucosal oxygenation. AB - This study was designed to compare the effects of different ways of administering carbon monoxide (intravenous and inhalative) on gastric mucosal oxygenation in a canine model of hemorrhage. Six chronically instrumented dogs were repeatedly anesthetized and randomized to each of the following protocols: In a first series the animals were ventilated either with 100 ppm carbon monoxide (CO) or without followed by hemorrhage and re-transfusion. In a second series a saturated CO solution was infused, compared to normal saline, again followed by hemorrhage and re-transfusion. In a control series, animals received either CO-saline or saline without any further intervention. Microvascular oxygenation of the gastric mucosa (uHbO2) was assessed continuously by tissue reflectance spectrophotometry. Cardiac output was measured intermittently and oxygen delivery (DO2) was calculated. The application of CO, inhalative and intravenous, increased carboxyhemoglobin levels without effect on uHbO2. Hemorrhage reduced uHbO2 in all groups, paralleled by a reduction in DO2 without any differences between groups related to the application of CO. Neither intravenous nor inhalative application of CO alters uHbO2 during physiological conditions or during hemorrhage. Thus, independent of the application way, low dose CO does not seem to modulate regional mucosal oxygenation in cytoprotective concentrations. PMID- 22447829 TI - Characteristic induction of steroidogenic factor 1 (SF-1) and DAX-1 and enhanced expression of glucocorticoid synthesis-related genes in adrenals from spontaneously hypertensive rats. AB - To gain insight into the molecular mechanism of hyper-glucocorticoidism in spontaneously hypertensive rats (SHR), this study investigated the expression of genes related to glucocorticoid synthesis, melanocortin 2 receptor (MC2R), steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage enzyme (P450scc) and 11beta-hydroxylase (P450c11), and the transcription factors of steroidogenic factor 1 (SF-1), which stimulates expression of the above gene, and DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1), which negatively regulates the transcriptional activity of SF-1, in adrenals from SHR. On quantitative real time RT-PCR analysis, gene expression levels of MC2R, StAR, P450scc and P450c11 in SHR were high compared with those in normotensive Wistar Kyoto rats (WKY). The gene expression level of SF-1 was not different between the two rats. However, the expression level of DAX-1 in SHR was markedly lower than that in WKY. Furthermore, the protein levels of StAR, SF-1 and DAX-1 determined by Western blot analysis coincided well with the gene expressions in both rats. These results suggest that the low level of DAX-1 may enhance the transcriptional activity of SF-1 and expression of genes related to glucocorticoid synthesis, which are targeted by SF-1, in adrenals from SHR. PMID- 22447830 TI - Quercetin and epigallocatechin gallate effects on the cell membranes biophysical properties correlate with their antioxidant potential. AB - Quercetin and epigallocatechin gallate are two of the most abundant polyphenols in dietary plants, including apples, onions, red wine and green tea. The bioactivity of polyphenols is linked to their ability to interact with cell membranes without being internalized. The aim of the present study was to assess the short-time effect of these polyphenols on membrane anisotropy and transmembrane potential of U937 monocytes and Jurkat T lymphoblasts. Results showed that quercetin and epigallocatechin gallate induced, after 20 minutes cell exposure, a dose-dependent increase of membrane anisotropy and polarization. Anisotropy increase was correlated with the reduction of lipid peroxidation. Our results could indicate that the antioxidant capacity of the tested polyphenols is due to their stabilizing effect on the cell membranes, thus contributing to cell protection in various pathologies and as adjuvant therapy in highly toxic treatment regimens. PMID- 22447831 TI - Free-radical degradation of high-molar-mass hyaluronan induced by ascorbate plus cupric ions: testing of stobadine and its two derivatives in function as antioxidants. AB - Stobadine.2HCl and its two hydrophilic derivatives SM1dM9dM10.2HCl and SME1i ProC2.HCl were tested in the function of antioxidants on hyaluronan (HA) degradation induced by the Weissberger oxidative system [ascorbate plus Cu(II)]. As a primary method, rotational viscometry was applied, where the substance tested was added before or 1 h after the initiation of HA degradation. The most effective scavengers of *OH and peroxy-type radicals were recorded to be stobadine.2HCl and SME1i-ProC2.HCl, respectively. The most effective scavenger, determined by applying the ABTS assay, was stobadine.2HCl. PMID- 22447832 TI - Pancreatic islets from dexamethasone-treated rats show alterations in global gene expression and mitochondrial pathways. AB - Chronic administration of glucocorticoids (GC) leads to characteristic features of type 2 diabetes in mammals. The main action of dexamethasone in target cells occurs through modulation of gene expression, although the exact mechanisms are still unknown. We therefore investigated the gene expression profile of pancreatic islets from rats treated with dexamethasone using a cDNA array screening analysis. The expression of selected genes and proteins involved in mitochondrial apoptosis was further analyzed by PCR and immunoblotting. Insulin, triglyceride and free fatty acid plasma levels, as well as glucose-induced insulin secretion, were significantly higher in dexamethasone-treated rats compared with controls. Out of 1176 genes, 60 were up-regulated and 28 were down regulated by dexamethasone treatment. Some of the modulated genes are involved in apoptosis, stress response, and proliferation pathways. RT-PCR confirmed the cDNA array results for 6 selected genes. Bax alpha protein expression was increased, while Bcl-2 was decreased. In vivo dexamethasone treatment decreased the mitochondrial production of NAD(P)H, and increased ROS production. Concluding, our data indicate that dexamethasone modulates the expression of genes and proteins involved in several pathways of pancreatic-islet cells, and mitochondria dysfunction might be involved in the deleterious effects after long-term GC treatment. PMID- 22447833 TI - Cytotoxicity and genotoxicity evaluation of antidote oxime HI-6 tested on eight cell lines of human and rodent origin. AB - Oxime HI-6 is an efficient reactivator of the acetylcholinesterase inhibited by organophosphorous nerve agents. In this study we have estimated cytotoxicity of HI-6 by the colony forming assay and genotoxicity by the comet assay on human and rodent cell lines. IC50 of HI-6 assessed by the colony forming capacity was 3.59 mM for HeLa cells and 5.18 mM for a mouse cell line L929. Small difference in cytotoxicity was found among other cell lines tested: IC50 was 1.61 mM for human A549 cells, 1.14 mM for UROtse line, 1.96 mM and 1.71 mM for Chinese hamster cells AA8 and UV-20, respectively. The A549 cell viability measured with the MTT test was 5 times decreased comparing 2 and 24 hours of HI-6 oxime treatment. The 5 mM HI-6 concentration reduced the viability within 2 hours to 95% only, however, it induced a significant number of DNA breaks in mouse cells L929, and also in human UROtse and HepG2 cells. 1-beta-D-arabinofuranosylcytosine (10(-4) M) and hydroxyurea (10(-2) M), supplemented to the cultivation medium, did not cause any significant accumulation of DNA breaks during treatment, which indicated that the nucleotide excision repair was not acting on the induced DNA damage. PMID- 22447834 TI - Alleviation of genotoxic effects of cyclophosphamide using encapsulation into liposomes in the absence or presence of vitamin C. AB - Cyclophosphamide (CP) is a widely used anticancer and immunosuppressant that induces oxidative stress. To ameliorate the side effects resulted from CP treatment, liposomes were tested as an efficient drug delivery system with or without vitamin C as an antioxidant. CP resulted in clastogenic and cytotoxic effects that significantly increased for the total chromosomal aberrations as well as the numerical ones in the CP group (150.8 and 6, respectively) than the control group (6.6 and 0.0) as mean values at p < 0.05. Micronucleus assay showed a significant increased micronucleated polychromatic erythrocytes percentage (MNPCEs% = 11.7%) and a significant decrease of polychromatic to normochromatic erythrocytes ratio (0.551) when compared to the group treated with liposomised CP and vitamin C (3.44%; 0.795, respectively) at p < 0.05. Also, the total glutathione S-transferase activity as a body antioxidant enzyme was decreased from 52.2 in the control to 16.09 nmol/min/mg protein in CP group at p < 0.05, while the highly significant amelioration results were observed in the liposomised vitamin C and CP group (40.88 nmol/min/mg protein). Our findings support the potential use of CP in a liposomal formulation doped with vitamin C to diminish the potential side effects of the agent. PMID- 22447835 TI - Glutamate receptors and the airways hyperreactivity. AB - It is proposed the link between the hyperactivity of NMDA receptors and airway hyperresponsiveness. We investigated the effect of agents modulating the activity of NMDA receptors in the ovalbumin-induced airway hyperreactivity in guinea pigs. The airways hyperreactivity was influenced by the agonist (NMDA) and selective antagonist - competitive (AP-5) and non-competitive (MK-801) of NMDA receptors. Airway responsiveness to histamine or acetylcholine was evaluated in in vitro conditions. NMDA administration caused the increase of tracheal smooth muscle response in ovalbumin-induced hyperreactivity to acetylcholine. MK 801 as well as AP-5 provoked the decrease of reactivity mainly to acetylcholine in tracheal smooth muscle, while the former, non-competitive antagonist was more effective. We recorded more pronounced response in tracheal than in lung tissue smooth muscle with more considerable response to acetylcholine than to histamine. The results of experiments show the modification of airway smooth muscles responses by agents modulating the activity of NMDA receptors. They confirm the possibility of NMDA receptors participation in experimental airway hyperreactivity. The results enlarge information regarding the link of the inflammatory diseases and glutamatergic system. PMID- 22447836 TI - Proton magnetic resonance spectroscopy and its diagnostically important metabolites in the brain. AB - This review provides a brief summary of the physical basis of magnetic resonance spectroscopy ((1)H MRS) and its application in the human brain. We discuss the chemical structure, signal properties, biological function, normal spatial distribution and diagnostic potential of the more significant metabolites detectable in brain tissue: N-acetylaspartate, N-acetylaspartylglutamate, choline containing substances, creatine, phosphocreatine, myo-inositol, glutamine and glutamate. We also present a few notes on the importance of proper spectral quantification and contemporary trends in 1H MRS. [corrected]. PMID- 22447837 TI - Estimation of rate constants of drug binding to open channels of cardiac transient outward current. AB - An improved approach to the evaluation of the rate constants of drugs binding to the open channel underlying the transient outward potassium current I(t0) is described. It is based on an analysis of a quantitative model formulated by a set of twelve differential equations. The rate constants are calculated from the time constants resulting from an approximation of the time course of apparent inactivation of the recorded I(t0) by two exponentials in the absence and by three exponentials in the presence of a blocking agent. The model study confirmed significantly higher accuracy in comparison with the existing electrophysiological method. PMID- 22447838 TI - Vigorous intensity physical activity is related to the metabolic syndrome independent of the physical activity dose. AB - BACKGROUND: Current physical activity guidelines imply that, by comparison with moderate physical activity (MPA), the benefits of engaging in vigorous physical activity (VPA) are attributed to the greater energy expenditure dose per unit of time and do not relate to intensity per se. The purpose of this study was to determine whether VPA influences the metabolic syndrome (MetS) independent of its influence on the energy expenditure dose of moderate-to-vigorous physical activity (MVPA). METHODS: Participants consisted of 1841 adults from the 2003-06 National Health and Nutrition Examination Survey, a representative cross sectional study. MPA and VPA were measured objectively over 7 days using Actigraph accelerometers. MetS was determined using an established clinical definition. Associations between physical activity and the MetS were determined using logistic regression and controlled for relevant covariates. RESULTS: Analyses revealed that VPA remained a meaningful predictor of the MetS after controlling for the total energy expenditure dose of MVPA such that the relative odds of the MetS was 0.28 (95% confidence interval 0.17-0.46) in the group with the highest VPA compared with the group with no VPA. VPA had a greater influence on the MetS than an equivalent energy expenditure dose of MPA. For instance, between 0 and 500 MET min/week of MPA the adjusted prevalence of the MetS decreased by 15.5%, whereas between 0 and 500 MET min/week of VPA the prevalence decreased by 37.1%. CONCLUSION: These cross-sectional findings suggest that VPA per se has an important role in cardiometabolic disease prevention. PMID- 22447840 TI - Tunable optical transition in polymeric carbon nitrides synthesized via bulk thermal condensation. AB - Polymeric derivatives of dicyandiamide were synthesized via a bulk thermal condensation method, using a range of process temperatures between 400 and 610 degrees C. The obtained carbon nitride powders exhibit an optical transition in the UV-green range that has been assigned to the direct bandgap of a semiconductor-like material. Within this context, the apparent bandgap is linearly tunable with increasing process temperatures, showing a temperature coefficient of - 1.7(1) meV K(-1) between 2.5 and 3.0 eV. The obtained results show a predominant optical transition within the tri-s-triazine unit of the polymer, with a bathochromic shift originating from a gradually increasing degree of polymerization. PMID- 22447839 TI - Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma. AB - Diffuse Large B cell lymphomas (DLBCL) are the most prevalent of the non-Hodgkin lymphomas and are currently initially treated fairly successfully, but frequently relapse as refractory disease, resulting in poor salvage therapy options and short survival. The greatest challenge in improving survival of DLBCL patients is overcoming chemo-resistance, whose basis is poorly understood. Among the potential mediators of DLBCL chemo-resistance is the thioredxoin (Trx) family, primarily because Trx family members play critical roles in the regulation of cellular redox homeostasis, and recent studies have indicated that dysregulated redox homeostasis also plays a key role in chemoresistance. In this study, we showed that most of the DLBCL-derived cell lines and primary DLBCL cells express higher basal levels of Trx-1 than normal B cells and that Trx-1 expression level is associated with decreased patients survival. Our functional studies showed that inhibition of Trx-1 by small interfering RNA or a Trx-1 inhibitor (PX-12) inhibited DLBCL cell growth, clonogenicity, and also sensitized DLBCL cells to doxorubicin-induced cell growth inhibition in vitro. These results indicate that Trx-1 plays a key role in cell growth and survival, as well as chemoresistance, and is a potential target to overcome drug resistance in relapsed/refractory DLBCL. PMID- 22447841 TI - Microplates, assay reagents, screening consumables, and kits. PMID- 22447842 TI - Magnetic superspace groups and symmetry constraints in incommensurate magnetic phases. AB - Superspace symmetry has been for many years the standard approach for the analysis of non-magnetic modulated crystals because of its robust and efficient treatment of the structural constraints present in incommensurate phases. For incommensurate magnetic phases, this generalized symmetry formalism can play a similar role. In this context we review from a practical viewpoint the superspace formalism particularized to magnetic incommensurate phases. We analyse in detail the relation between the description using superspace symmetry and the representation method. Important general rules on the symmetry of magnetic incommensurate modulations with a single propagation vector are derived. The power and efficiency of the method is illustrated with various examples, including some multiferroic materials. We show that the concept of superspace symmetry provides a simple, efficient and systematic way to characterize the symmetry and rationalize the structural and physical properties of incommensurate magnetic materials. This is especially relevant when the properties of incommensurate multiferroics are investigated. PMID- 22447843 TI - Modulating the bandgaps of graphdiyne nanoribbons by transverse electric fields. AB - The effect of external transverse electric fields on the bandgaps of graphdiyne nanoribbons is investigated from first-principles calculations. The giant Stark effect is observed in the ribbons. When the field is applied, the valence and conduction band edge states are found to be strongly localized at low and high potential edges of the ribbon, respectively. Due to the wavefunction localization, the bandgap decreases with increasing field strength, and a semiconductor-metal transition occurs below a threshold field value. It is also shown that the bandgap decreasing rate depends linearly on the ribbon width. The tunable bandgap of a graphdiyne nanoribbon under an electric field would be helpful for practical applications. PMID- 22447844 TI - Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet derived growth factor receptor alpha and bcr-abl oncogene addiction in malignant hematologic cells. AB - PURPOSE: The "gate-keeper" mutations T674I platelet-derived growth factor receptor alpha (PDGFRalpha) in hypereosinophilic syndrome (HES) and T315I Bcr-Abl in chronic myeloid leukemia (CML) are resistant to imatinib and the second generation small-molecule tyrosine kinase inhibitors (TKI). However, to combat acquired resistance to imatinib, an alternative approach is to decrease the expression of the addicted gene to efficiently kill resistant malignant hematologic cells. The purpose of this study was to evaluate the strategy of shutting down the transcription and expression of FIP1-like-1 (FIP1L1)-PDGFRalpha and Bcr-Abl with SNS-032, an inhibitor of cyclin-dependent kinase 7 (CDK7) and CDK9 in phase I clinical trials. EXPERIMENTAL DESIGN: The effects of SNS-032 on PDGFRalpha and Bcr-Abl signaling pathways, apoptosis, and cell cycling were analyzed in TKI-resistant cells of HES and CML. The in vivo antitumor activity of SNS-032 was assessed with xenografted BaF3-T674I FIP1L1-PDGFRalpha and KBM5-T315I Bcr-Abl cells in nude mouse models. RESULTS: SNS-032 inhibited the phosphorylation on Ser5 and Ser2 of RNA polymerase II. SNS-032 decreased both the mRNA and protein levels of FIP1L1-PDGFRalpha and Bcr-Abl and inhibited the proliferation of malignant cells expressing FIP1L1-PDGFRalpha or Bcr-Abl. It also decreased the phosphorylation of downstream molecules. It induced apoptosis by triggering both the mitochondrial pathway and the death receptor pathway. CONCLUSIONS: This CDK7/9 inhibitor potently inhibits FIP1L1-PDGFRalpha-positive HES cells and Bcr-Abl-positive CML cells regardless of their sensitivity to imatinib. SNS-032 may have potential in treating hematologic malignancy by abrogating oncogene addiction. PMID- 22447845 TI - Boron nitride nanotubes as templates for half-metal nanowires. AB - We investigate by means of a GGA + U implementation of density functional theory the electronic and structural properties of magnetic nanotubes composed of an iron oxide monolayer and (n,0) boron nitride (BN) nanotubes, with n ranging from 6 to 14. The formation energy per FeO molecule of FeO covered tubes is smaller than the formation energy of small FeO nanoparticles, which suggests that the FeO molecules may cover the BN nanotubes rather than aggregating locally. Both GGA (PBE) and Van der Waals functionals predict an optimal FeO-BN interlayer distance of 2.94 A. Depending on the diameter of the tube, novel electronic properties for the FeO covered BN nanotubes were found. They can be semiconductors, intrinsic half-metals or semi-half-metals that can become half-metals if charged with either electrons or holes. Such results are important in the spintronics context. PMID- 22447846 TI - Accessing escalators: a central vestibular disorder after posterior fossa tumor removal. AB - About 20% of childhood tumors originate within the central nervous system. Progress in assessment and treatment of these lesions has led to improved survival rates. We describe a patient with a posterior fossa ependymoma who despite a remarkable recovery following treatment has been frustrated by difficulty in using escalators. Such symptom selectivity is explained by specific vertical visuomotor and high-frequency vestibular deficits disrupting the execution of this complex motor act. PMID- 22447847 TI - A review of pediatric palliative care service utilization in children with a progressive neuromuscular disease who died on a palliative care program. AB - Recent studies and consensus statements have expressed the need to involve palliative care services in the care of children with progressive neuromuscular diseases (PMD), yet there have been no reviews of the utilization of palliative care services by children who died on a palliative care program. We conducted a retrospective chart review of all children who had a PMD who died on a single center palliative care program. Twenty cases were identified. Services utilized by these patients included respite care, transition services, pain and symptom management, and end-of-life care. Prominent symptoms in the last 24 hours of life included respiratory distress, pain, nausea/vomiting, and anxiety; however, symptom management was very good. Utilization of services differed depending on the disease trajectory, with respite playing a critical role in the care of children with PMD. Good symptom management can be achieved. PMID- 22447848 TI - Benign neonatal sleep myoclonus: an autosomal dominant form not allelic to KCNQ2 or KCNQ3. AB - Benign neonatal sleep myoclonus is an uncommon, nonepileptic disorder characterized by myoclonic jerks appearing in the neonatal period that occur predominantly during sleep. Although self-limiting, the disorder is frequently confused with epileptic neonatal seizures. A few familial cases have been reported; however the genetics has not been studied. We ascertained 3 families with 2 or more affected individuals and analyzed the pedigrees. We used microsatellite markers to determine if the disorder was possibly linked to KCNQ2 or KCNQ3, the 2 genes that cause most cases of benign familial neonatal seizures, a disorder that it could be easily confused with. The 3 pedigrees, including one with 4 affected individuals, were suggestive of autosomal dominant inheritance. The loci for KCNQ2 and KCNQ3 were excluded in the 2 larger families. We conclude that benign neonatal sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures. PMID- 22447849 TI - Current practice and views of neurologists on the transition from pediatric to adult care. AB - To describe the current practice and views of neurologists on transitioning patients from pediatric to adult care, a cross-sectional study of all pediatric and adult neurologists in the province of Quebec, Canada, was conducted. The response rate was 73% for pediatric and 49% for adult neurologists. Most pediatric neurologists do not have a patient transition program or policy in place. Although a transfer summary is commonly provided, critical information is often lacking. Nearly half of neurologists believed that patients experience a gap in care during the transition process, and most agreed that the transition process is often poorly coordinated, highlighting patient, family, and health care factors. Current practice does not follow existing consensus statements for transition of care with respect to timing, communication, and preparation, and many pediatric neurologists experience difficulty in finding an appropriate adult health care provider for their patients. Neurologists reported many challenges in the current transition of care process. PMID- 22447850 TI - Using the test of variables of attention to determine the effectiveness of modafinil in children with attention-deficit hyperactivity disorder (ADHD): a prospective methylphenidate-controlled trial. AB - The efficacy of modafinil in comparison with methylphenidate in treatment of pediatric attention-deficit hyperactivity disorder (ADHD) has not been thoroughly investigated. This study compared the effect of modafinil versus methylphenidate on continuous attention task in children with ADHD, using the Test of Variables of Attention. Twenty-eight participants completed a baseline test followed by administration of a single dose of either methylphenidate or modafinil, after which the test was repeated. The test was performed a third time, after each subject received a dose of the medication not previously administered. Comparison of scores showed mean baseline, postmethylphenidate, and postmodafinil scores of 2.04, 0.017, and 0.09, respectively. No difference was found between improvements observed with either medication (P < .05). Adverse events for both agents were mild and self-limited, including abdominal pain, diarrhea, and hyposomnia. The authors conclude that modafinil is as effective as methylphenidate; however, a larger scale long-term study is required to confirm these results. PMID- 22447851 TI - Suberoylanilide hydroxamic acid enhances odontoblast differentiation. AB - Previous studies have shown that histone deacetylase (HDAC) inhibitors stimulate osteoblast differentiation in vitro and bone formation in vivo. However, the effects of HDAC inhibitors on odontoblasts have not been elucidated. Therefore, in this study, we examined the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on odontoblast differentiation using an MDPC23 odontoblast like cell line. SAHA significantly enhanced matrix mineralization and the expression levels of odontoblast marker genes. SAHA increased the expression levels of nuclear factor I/C (Nfic) and dentin sialophosphoprotein (Dspp). Nfic bound directly to the Dspp promoter and stimulated Dspp transcription. SAHA increased both basal and Nfic-induced Dspp promoter activity. SAHA-induced Dspp promoter activity disappeared when mutations were introduced within the Nfic binding element of the Dspp promoter. Nfic knockdown by siRNA blocked SAHA stimulation of Dspp expression. These results indicate that SAHA enhances odontoblast differentiation and that SAHA increases Dspp expression, at least in part, by increasing the expression level of Nfic. PMID- 22447852 TI - Extrahepatic bile duct cancer: invasion of the posterior hepatic plexuses- evaluation using multidetector CT. AB - PURPOSE: To assess the utility of axial and coronal reformatted multidetector computed tomographic (CT) images in the evaluation of the invasion of posterior hepatic plexuses by extrahepatic bile duct cancer. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. Forty-three patients (22 men, 21 women; age range, 40-80 years; mean age, 65 years) with surgically resected cancer involving the extrahepatic bile duct between December 2004 and September 2010 were included. Posterior hepatic plexus 1 runs from the superior and middle bile duct to the right celiac ganglion, and posterior hepatic plexus 2 runs between the lower bile duct and right celiac ganglion behind the portal vein. Invasion of the posterior hepatic plexuses was elucidated by using pathologic and postoperative multidetector CT findings. Three radiologists independently evaluated the preoperative axial and coronal reformatted images with a separate viewing session for the invasion of posterior hepatic plexuses that was detected on the basis of the presence of increased attenuation of fat tissue along the nerve routes. Receiver operating characteristic analysis was performed to compare the diagnostic performance of the two image interpretations. RESULTS: Invasion of posterior hepatic plexus 1 and of posterior hepatic plexus 2 was recognized in 10 (23%) and nine (21%) of 43 patients, respectively. The diagnostic performance of coronal reformatted image interpretation was significantly greater than that for axial image interpretation (mean area under the curve, 0.99 vs 0.89, P = .04; mean accuracy, 95% vs 82%, P = .003). In all reviewers, one false-positive diagnosis of the invasion of posterior hepatic plexus occurred on axial and/or coronal image display types because of fibrosis and inflammatory cell infiltration along these plexus routes. CONCLUSION: Coronal reformatted images can be useful for accurate diagnosis of the invasion of posterior hepatic plexuses and may facilitate surgical decision making in regard to the resection of celiac ganglion. PMID- 22447853 TI - Anterior cruciate ligament reconstruction: MR imaging signs of anterior knee laxity in the presence of an intact graft. AB - PURPOSE: To determine the accuracy of secondary magnetic resonance (MR) imaging signs of anterior cruciate ligament (ACL) insufficiency in predicting clinical anterior translational knee laxity, in the presence of an intact graft, after ACL reconstruction. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirement to obtain informed consent was waived. Fifty-two patients with ACL reconstruction and no injury to the contralateral knee were included. Three patients with visible ACL graft tears at MR imaging were excluded. All patients underwent MR imaging of the affected knee, functional assessment with use of the International Knee Documentation Committee (IKDC) score, and arthrometric testing of both the affected and uninjured knee. A side to-side difference of more than 3 mm at 133 N was considered to be indicative of knee laxity. Two radiologists independently evaluated all MR images for seven signs of anterior knee laxity. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated for each MR imaging sign. RESULTS: Ten patients demonstrated knee laxity at arthrometric testing. Patients with knee laxity at arthrometric testing had significantly lower IKDC scores (P < .03). Sensitivities for all signs were low (0%-50%). Anterior translation of the tibia of more than 7 mm, a posterior cruciate ligament (PCL) angle of less than 100 degrees , and a PCL curvature ratio of more than 0.39 demonstrated high specificity (range, 82%-90%). Uncovering of the posterior horn of the lateral meniscus and the posterior femoral line had a specificity of 97%-100% and a sensitivity of 0%. All signs had a low PPV and high NPV for laxity. All MR imaging signs demonstrated near-perfect interobserver agreement. CONCLUSION: Although MR imaging signs of knee laxity in the presence of an intact ACL graft have a high specificity, the low PPV means that MR imaging is of little value in predicting anterior knee laxity as demonstrated with mechanical testing. PMID- 22447854 TI - Salivary gland tumors: use of intravoxel incoherent motion MR imaging for assessment of diffusion and perfusion for the differentiation of benign from malignant tumors. AB - PURPOSE: To prospectively evaluate the intravoxel incoherent motion (IVIM) parameters (microvascular volume fraction, f; pure diffusion coefficient, D; and perfusion-related incoherent microcirculation, D*) for differentiating between benign and malignant salivary gland tumors. MATERIALS AND METHODS: All participants in this prospective institutional review board-approved study provided written informed consent. The perfusion and diffusion of 20 (65%) benign (12 pleomorphic adenomas and eight Warthin tumors) and 11 (35%) malignant salivary gland tumors were assessed on the basis of the IVIM theory. Diffusion weighted magnetic resonance imaging was performed by using 11 b values (0-800 sec/mm(2)). The IVIM parameters of the salivary gland tumors were determined by a radiologist, and significant differences between the tumor types were assessed by using the Steel-Dwass test. RESULTS: The f values of Warthin tumors (0.156 +/- 0.039 [standard deviation]) were significantly larger than those of pleomorphic adenomas (0.066 +/- 0.031) (P = .003). The D values of malignant tumors (0.96 * 10(-3) mm(2)/sec +/- 0.22) were significantly different from those of benign tumors (pleomorphic adenomas, 1.38 * 10(-3) mm(2)/sec +/- 0.30 [P = .002]; Warthin tumors, 0.61 * 10(-3) mm(2)/sec +/- 0.11 [P = .005]). The D* values of malignant tumors (21.99 * 10(-3) mm(2)/sec +/- 19.01) were significantly smaller than those of Warthin tumors (42.64 * 10(-3) mm(2)/sec +/- 20.17) (P = .022). The combination of D and D* criteria provided the best diagnostic accuracy (100%) for differentiation among the three tumor types. CONCLUSION: IVIM imaging may be helpful for differentiation between benign and malignant salivary gland tumors. PMID- 22447855 TI - Ubiquitin-specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11beta-hydroxysteroid dehydrogenase 1. AB - Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11beta-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis. PMID- 22447856 TI - Transgenerational glucose intolerance with Igf2/H19 epigenetic alterations in mouse islet induced by intrauterine hyperglycemia. AB - Gestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved and the possibilities of transgenerational transmission are still unclear. We intercrossed male and female adult control and first-generation offspring of GDM (F1-GDM) mice to obtain the second-generation (F2) offspring in four groups: C? C?, C?-GDM?, GDM?-C?, and GDM?-GDM?. We found that birth weight significantly increased in F2 offspring through the paternal line with impaired glucose tolerance (IGT). Regardless of birth from F1-GDM with or without IGT, high risk of IGT appeared as early as 3 weeks in F2 offspring and progressed through both parental lineages, especial the paternal line. IGT in male offspring was more obvious than that in females, with parental characteristics and sex-specific transmission. In both F1 and F2 offspring of GDM, the expression of imprinted genes Igf2 and H19 was downregulated in pancreatic islets, caused by abnormal methylation status of the differentially methylated region, which may be one of the mechanisms for impaired islet ultrastructure and function. Furthermore, altered Igf2 and H19 gene expression was found in sperm of adult F1-GDM, regardless of the presence of IGT, indicating that changes of epigenetics in germ cells contributed to transgenerational transmission. PMID- 22447857 TI - The WNT inhibitor Dickkopf 1 and bone morphogenetic protein 4 rescue adipogenesis in hypertrophic obesity in humans. AB - Overweight characterized by inappropriate expansion of adipose cells (hypertrophic obesity) is associated with the metabolic syndrome and is caused by an inability to recruit and differentiate new precursor cells. We examined the role of bone morphogenetic protein 4 (BMP4) and WNT activation in the regulation of human adipose cell differentiation. Cluster of differentiation (CD)14(+)/45(+) and CD31(+) cells were first removed before the remaining stromal vascular cells of human subcutaneous biopsy specimens were differentiated with/without different WNT inhibitors and/or BMP4. Inhibition of WNT and induction of Dickkopf 1 (DKK1) were markers of precursor cells undergoing excellent differentiation. The addition of DKK1 inhibited WNT activation and promoted adipogenesis in cells with a low degree of differentiation. The positive effect of DKK1, inhibiting cellular WNT activation by binding to the Kremen/LDL receptor-related protein receptors, was not seen with inhibitors of secreted WNT ligands. BMP4 increased differentiation, and BMP4 in the presence of DKK1 produced an additive effect. There was an apparent cross-talk between differentiation and commitment because BMP4 expression increased in differentiating adipocytes, and the addition of the BMP4 inhibitor, Noggin, reduced precursor cell differentiation. Thus, differentiated human adipose cells can promote adipogenesis via endogenous BMP4 activation, and the impaired adipogenesis in hypertrophic obesity is mainly due to an inability to suppress canonical WNT and to induce DKK1. PMID- 22447858 TI - The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. AB - PURPOSE: We noted an unexpected inheritance pattern of lesions in several strains of gene-manipulated mice with ocular phenotypes. The lesions, which appeared at various stages of backcross to C57BL/6, bore resemblance to the rd8 retinal degeneration phenotype. We set out to examine the prevalence of this mutation in induced mutant mouse lines, vendor C57BL/6 mice and in widely used embryonic stem cells. METHODS: Ocular lesions were evaluated by fundus examination and histopathology. Detection of the rd8 mutation at the genetic level was performed by PCR with appropriate primers. Data were confirmed by DNA sequencing in selected cases. RESULTS: Analysis of several induced mutant mouse lines with ocular disease phenotypes revealed that the disease was associated 100% with the presence of the rd8 mutation in the Crb1 gene rather than with the gene of interest. DNA analysis of C57BL/6 mice from common commercial vendors demonstrated the presence of the rd8 mutation in homozygous form in all C57BL/6N substrains, but not in the C57BL/6J substrain. A series of commercially available embryonic stem cells of C57BL/6N origin and C57BL/6N mouse lines used to generate ES cells also contained the rd8 mutation. Affected mice displayed ocular lesions typical of rd8, which were detectable by funduscopy and histopathology as early as 6 weeks of age. CONCLUSIONS: These findings identify the presence of the rd8 mutation in the C57BL/6N mouse substrain used widely to produce transgenic and knockout mice. The results have grave implications for the vision research community who develop mouse lines to study eye disease, as presence of rd8 can produce significant disease phenotypes unrelated to the gene or genes of interest. It is suggested that researchers screen for rd8 if their mouse lines were generated on the C57BL/6N background, bear resemblance to the rd8 phenotype, or are of indeterminate origin. PMID- 22447859 TI - Effect of the synthetic NC-1059 peptide on diffusion of riboflavin across an intact corneal epithelium. AB - PURPOSE: To investigate the effect of the peptide NC-1059 on riboflavin (RF) diffusion across an intact corneal epithelium into the stroma. METHODS: NC-1059 peptide was synthesized by solid-phase synthesis with 9-fluorenylmethoxycarbonyl chemistry, characterized by reversed-phase HPLC, and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy. The diffusion of RF across embryonic day 18 chick corneal epithelium ex vivo was monitored using confocal microscopy. The depth distributions of RF in the corneal stroma were calculated using a group of linear equations based on the relationship between RF fluorescence intensity and concentration. RESULTS: Data presented in this study demonstrate that the NC-1059 peptide can transiently open the intact epithelial barrier to allow the permeation of RF into the stroma. The effect of NC-1059 peptide on RF diffusion across the corneal epithelium was concentration and time dependent. The amount of RF reaching a 50-MUm depth of chick corneal stoma increased dramatically after exposure to NC-1059 for 10 minutes, reaching a plateau by 30 minutes. The concentrations of RF in the presence of NC-1059 at corneal stromal depths of 50, 100, and 150 MUm were significantly higher than in the absence of the peptide, and almost as high as in corneas in which the epithelium first had been physically removed. In addition, a cell viability assay indicated that the NC-1059 peptide did not kill corneal epithelial cells. CONCLUSIONS: NC-1059 peptide significantly enhances the diffusion of RF across intact corneal epithelium into the stroma. PMID- 22447860 TI - A comparison of HLA genotype with inflammation in uveal melanoma. AB - PURPOSE: Human leukocyte antigen (HLA) polymorphisms have been associated with the development of autoimmune diseases. In uveal melanoma, a high expression of HLA classes I and II, and infiltration with lymphocytes and macrophages are associated with a bad prognosis. Inflammation has an important role in this malignancy. The goal of our study was to determine whether specific HLA alleles are associated with increased inflammation. METHODS: Records were analyzed of 45 patients who underwent enucleation for uveal melanoma. HLA typing, tumor HLA expression and tumor macrophage infiltration were determined in each case. RESULTS: Before correction for multiple testing, macrophage infiltration was less in HLA-A2 positive patients. Patients with HLA-DR6 had a higher tumor cell expression of HLA-DR. After correction for the number of analyses, no associations remained statistically significant. CONCLUSION: The results before correction suggest that the HLA genotype may influence inflammation as indicated by HLA expression and macrophage infiltration in uveal melanoma. However, after correction this association did not prove significant. PMID- 22447861 TI - Laser-mediated activation of human retinal pigment epithelial cells and concomitant release of matrix metalloproteinases. AB - PURPOSE: To investigate cellular dynamics and associated matrix metalloproteinase (MMP) release patterns of human retinal pigment epithelium (RPE) cells subsequent to irradiation by nanosecond pulsed laser at energy levels below visual threshold. METHODS: Following a stabilization period, human RPE-Bruch's-choroid explants were irradiated with a nanosecond laser system (Q-switched, frequency doubled YAG laser, 532 nm), using a 400 MUm spot size with a discontinuous energy distribution and total irradiance of 240 mJ/cm2, and returned to the incubator for a further 14 days. RPE cellular dynamics were assessed using confocal laser scanning, conventional microscopy, cell viability, and proliferation assays. MMPs were quantified by gelatine zymography and densitometry. RESULTS: Within 4 hours of laser intervention, 47% +/- 8% (mean +/- SEM, n = 6) of the RPE cells within the treatment zone showed clear signs of injury. By posttreatment days 10 to 14, most of the injured beds were repopulated by migrating RPE cells from regions surrounding the lesion. Release of inactive MMP-2 was little altered over the 2 week experimental period, whereas levels of inactive MMP-9 increased 1.3-fold by day 1 to reach a 2.8-fold threshold by day 7 (n = 4; P < 0.05). However, changes in activated MMP-2 and MMP-9 were much more profound with levels increasing 6.7 +/- 2.6-fold (mean +/- SEM, n = 6; P < 0.001) and 4.4 +/- 1.1-fold (mean +/- SEM, n = 5; P < 0.01), respectively, above controls at day 7 post laser. CONCLUSIONS: The nanosecond laser pulse modality provides an avenue for transiently increasing the RPE-mediated release of active MMP enzymes. The likely impact of this enzymatic release on the structural and functional aspects of aging Bruch's membrane requires further evaluation. PMID- 22447862 TI - The role of RASSF1A in uveal melanoma. AB - PURPOSE: RASSF1A inactivation in uveal melanoma (UM) is common and methylation induced. We investigated the effect of RASSF1A re-expression on the UM phenotype in vivo and in vitro. METHODS: The phenotypic effect of methylation-induced inactivation of RASSF1A in UM was explored using a stable RASSF1A-expressing UM 15 clone. RASSF1A expression was assessed using QRT-PCR. Proliferation was evaluated in vitro using MTT assays. Additionally, athymic NOD/SCID mice were injected subcutaneously or intraocularly with RASSF1A-expressing and -non expressing UM-15 clones, and euthanized when tumors reached a volume of 1500 mm(3), or at 56 or 46 days, respectively. Tumor tissues, eyes, and livers were analyzed histologically. RESULTS: In vitro analysis confirmed the lack of RASSF1A expression and full methylation of the RASSF1A promoter region in the UM-15 cell line, which was reversible following treatment with 5-Aza-2-deoxycytidine. Cells expressing exogenous RASSF1A showed slower proliferation than controls and regained sensitivity to cisplatin. Compared to mice injected with control cells, mice treated with UM-15 cells expressing exogenous RASSF1A did not acquire intraocular tumors, and their subcutaneous tumors were relatively delayed and small. Neither group had liver metastases. CONCLUSIONS: UM cells reduced tumorigenicity in the presence of activated RASSF1A. RASSF1A apparently has an important role in the development of UM, and its reactivation might be applied in the development of new treatments. PMID- 22447863 TI - Temporal properties of visual perception on electrical stimulation of the retina. AB - PURPOSE: To investigate the elementary temporal properties of electrically evoked percepts in blind patients chronically implanted with an epiretinal prosthesis. METHODS: Nine subjects were presented with isolated stimuli of variable duration and pulse rate. Stimulation amplitude was set to the upper comfortable level and a group of 2 * 2 adjacent electrodes was simultaneously activated. First, subjects were asked to verbally describe their visual perception paying particular attention to the time-course of brightness. Then, in subsequent trials, they described the brightness time dependence using a joystick while auditory feedback of joystick position was provided. RESULTS: All subjects described a bright, well-localized percept at stimulus onset. Only one subject reported such a bright, well-localized visual sensation during an entire 10 second stimulation trial. For the remaining eight subjects, it faded more or less rapidly (in four cases <0.5 second) and was often followed by a percept described as less bright, poorly localized, and having different color. Only initial percepts at stimulation onset seemed bright and localized enough to reconstruct a patterned image. Changing stimulation pulse rate influenced the time course of perception only in some cases but the effect was not systematic. CONCLUSIONS: Percepts differed considerably across subjects, probably because of the considerable variations in the progression and remodeling processes associated with the disease. Appropriate coding of a patterned image under such conditions appears challenging. Further research of the underlying mechanisms of visual perception upon electrical stimulation of the retina is required to optimize stimulation paradigms and to better establish patient selection criteria. PMID- 22447864 TI - Evaluation of the Adult Strabismus-20 (AS-20) questionnaire using Rasch analysis. AB - PURPOSE: To further refine the Adult Strabismus 20 (AS-20) health-related quality of life (HRQOL) questionnaire using Rasch analysis. METHODS: Rasch analysis was performed independently on the original AS-20 using the following steps: dimensionality, response ordering, local dependence, infit and outfit analyses, differential item functioning, subject targeting, and confirmatory dimensionality. RESULTS: Two subscales were present in each of the original AS-20 subscales, for a total of 4 subscales, which were labeled "self-perception," "interaction," "reading function," and "general function." Response ordering was appropriate for 3 of the subscales but required reduction to 4 response options for the fourth subscale. No notable local dependence was found for any subscale. As a result of fit analysis, 2 items were removed, 1 each from 2 subscales. No significant differential item functioning was seen for sex or age. The resulting 5-item self-perception subscale and 4-item reading function subscale are reliable and target the adult strabismus patient cohort appropriately. The resulting 5 item interaction subscale and 4-item general function subscale have less than optimal reliability. CONCLUSIONS: The AS-20 benefits from reduction to 4 subscales (self-perception, interaction, reading function, and general function) and reducing the response options in the general function subscale from 5 to 4 options. The refined AS-20 may prove to be even more responsive to HRQOL changes in adult strabismus following treatment or changes over time. PMID- 22447865 TI - Relationship among visual field, blood flow, and neural structure measurements in glaucoma. AB - PURPOSE: To determine the relationship among visual field, neural structural, and blood flow measurements in glaucoma. METHODS: Case-control study. Forty-seven eyes of 42 patients with perimetric glaucoma were age-matched with 27 normal eyes of 27 patients. All patients underwent Doppler Fourier-domain optical coherence tomography to measure retinal blood flow and standard glaucoma evaluation with visual field testing and quantitative structural imaging. Linear regression analysis was performed to analyze the relationship among visual field, blood flow, and structure, after all variables were converted to logarithmic decibel scale. RESULTS: Retinal blood flow was reduced in glaucoma eyes compared to normal eyes (P < 0.001). Visual field loss was correlated with both reduced retinal blood flow and structural loss of rim area and retinal nerve fiber layer (RNFL). There was no correlation or paradoxical correlation between blood flow and structure. Multivariate regression analysis revealed that reduced blood flow and structural loss are independent predictors of visual field loss. Each dB decrease in blood flow was associated with at least 1.62 dB loss in mean deviation (P <= 0.001), whereas each dB decrease in rim area and RNFL was associated with 1.15 dB and 2.56 dB loss in mean deviation, respectively (P <= 0.03). CONCLUSIONS: There is a close link between reduced retinal blood flow and visual field loss in glaucoma that is largely independent of structural loss. Further studies are needed to elucidate the causes of the vascular dysfunction and potential avenues for therapeutic intervention. Blood flow measurement may be useful as an independent assessment of glaucoma severity. PMID- 22447866 TI - Muller cell expression of genes implicated in proliferative vitreoretinopathy is influenced by substrate elastic modulus. AB - PURPOSE: Matrix stiffness is recognized increasingly as a significant factor in cell and tissue function. To understand better the mechanosensitivity of Muller cells and its association with vitreoretinal disorders, we examined morphology, propagation, and expression of genes in Muller cells that were cultured on substrates of varying elastic moduli. METHODS: A conditionally immortalized mouse Muller cell line was cultured on laminin-coated polyacrylamide substrates with calibrated Young's moduli. Glass was used as a control. Phase contrast, fluorescence, and atomic force microscopy were used to study cell morphology and propagation. Expression of extracellular matrix (ECM) genes was analyzed using quantitative reverse-transcription PCR. RESULTS: The adherent area, stiffness, and propagation of Muller cells all are affected by matrix stiffness, but to different extents and with different ranges of sensitivity. Of 85 ECM genes tested 11 showed a continuous >4-fold increase or decrease in mRNA expression as a function of the substrate elastic modulus. The changes were statistically significant in four genes: connective tissue growth factor (Ctgf, P = 0.04), tenascin C (Tnc, P = 0.035), Collagen Ialpha1 (Col1a1, P = 0.0001), and Collagen IValpha3 (Col4a3, P = 0.05), with all showing increased expression on softer substrates. CONCLUSIONS: There are significant changes in morphology, cytoskeletal integrity, and gene regulation in Muller cells as a function of the stiffness of the substrate. Changes in local tissue elastic modulus may have a role in vitreoretinal disorders. These findings also may have implications for strategies for improved integration of retinal prosthetics, and for stem cell therapies, particularly targeting the transcriptional regulators YAP and TAZ. PMID- 22447867 TI - Quantification of visual orienting responses to coherent form and motion in typically developing children aged 0-12 years. AB - PURPOSE: Brain damage or brain development disorders can affect (the maturation of) visual processing functions, such as form and motion detection. The aim of our study was to investigate visual orienting responses of children to a coherent form and motion stimulus as a measure for maturation of visual information processing. METHODS: The 213 typically developing children aged 0-12 years included in this study were shown a 100% coherent form and motion expansion stimulus on a remote eye tracking monitor. Orienting eye movements were quantified in terms of ocular motor reaction time to fixation (RTF). Children were divided in age groups, and their performance was compared to 30 healthy adults with a mean age of 24.49 years (SD 3.62 years). RESULTS: The RTF values of coherent form in children up to six years old were significantly higher compared to the adult group (P < 0.05, Dunnett post-hoc test). For motion, mature levels were reached at eight years old. RTF values depended on stimulus type (F(1,168) = 240.8, P < 0.001) and age (F(11,168) = 25.8, P < 0.001), and there was a significant age by stimulus type interaction (F(11,168) = 2.2, P < 0.05). CONCLUSIONS: Remote eye tracking may provide objective insight into the maturation of visual information processing of coherent form and motion without complex instructions or active cooperation. The quantification of typical visual orienting behavior in childhood may be used as a reference for children with brain dysfunction. PMID- 22447868 TI - Fluorescent protein-labeled glucocorticoid receptor alpha isoform trafficking in cultured human trabecular meshwork cells. AB - PURPOSE: To characterize the roles of the cytoskeleton and heat shock protein 90 (HSP90) in steroid-induced glucocorticoid receptor alpha (GRalpha) translocation in cultured human trabecular meshwork cells. METHODS: Stably transfected red fluorescent protein (RFP)-GRalpha NTM5 cell lines were developed. Nuclear localization of RFP-GRalpha in NTM5 cells treated with vehicle (ethanol), dexamethasone (DEX), or RU486 was measured in cytosolic and nuclear fractions by western blotting and laser confocal microscopy. Cytochalasin D, colchicine, and 17-demethoxygeldanamycin (17AAG, an HSP90 inhibitor), were tested for their abilities to affect GRalpha trafficking. Nuclear export of RFP-GRalpha was studied using confocal microscopy following DEX or RU486 removal. RESULTS: NTM5 cells transfected with RFP-GRalpha showed a clear cytosolic localization of receptor that underwent nuclear localization after DEX treatment. RFP-GRalpha translocation was temperature sensitive, occurring at 37 degrees C but not at room temperature. Neither cytochalasin D nor colchicine blocked DEX-induced or RU486-induced RFP-GRalpha nuclear translocation; however, 17AAG prevented DEX induced RFP-GRalpha nuclear translocation. Both nuclear import and export of DEX induced RFP-GRalpha were faster than RU-486-induced nuclear shuttling. CONCLUSIONS: RFP-GRalpha receptor behaves similarly to the wild-type GRalpha with its cytosolic localization and shuttling to nucleus after DEX or RU486 treatment. HSP90 is required for nuclear translocation, but the disruption of cytoskeleton had no effect on nuclear translocation of RFP-GRalpha. PMID- 22447869 TI - Structure-function relationships between spectral-domain OCT and standard achromatic perimetry. AB - PURPOSE: To explore structure-function relationships in early glaucoma with spectral-domain optical coherence tomography (SD-OCT) and standard achromatic perimetry. METHODS: One hundred thirty-six eyes of 97 patients with suspected or early glaucoma were enrolled from the clinical database at UCLA's Glaucoma Division. All patients had good-quality peripapillary retinal nerve fiber layer (RNFL)/optic disc measurements and a reliable 24-2 SITA-Standard Humphrey visual field (VF) within a 6-month period. Correlations of global and sectoral RNFL thickness and rim area (RA) measurements, with corresponding global and regional VF sensitivities (both in logarithmic [dB] and 1/Lambert scales [1/L]), were investigated with components of variance models. RESULTS: The average RNFL thickness, RA, and mean deviation (MD) were 85.6 +/- 5.7 MU, 1.0 +/- 0.3 mm(2), and -1.3 +/- 1.9 dB, respectively. Global RA demonstrated a stronger correlation with MD compared to average RNFL thickness (P = 0.002). The highest correlations were observed between superonasal VF cluster (in dB scale) and inferotemporal RA (R(2) = 0.26, 95% CI: 0.15-0.40) or inferotemporal RNFL thickness (R(2) = 0.24, 95% CI: 0.13-0.37). In glaucoma suspects, the highest correlations were seen between superonasal VF cluster and inferotemporal RA (R(2) = 0.16) in dB scale or RNFL thickness (R(2) = 0.10) in 1/L scale. Correlations were slightly greater with dB scale than 1/L scale and tended to be linear with both scales. CONCLUSIONS: Structure-function relationships can be detected in early glaucoma with SD-OCT. Correlations of RA with VF thresholds tended to be higher compared to those of RNFL. Structure-function relationships were well described with a linear model. PMID- 22447870 TI - MicroRNA-328 may influence myopia development by mediating the PAX6 gene. AB - PURPOSE: We showed previously that single nucleotide polymorphism (SNP) rs662702 in PAX6 may be located in a microRNA-328 binding site that causes susceptibility to high myopia. Our study was done to elucidate the role of PAX6 and its relationship with microRNA-328 in myopia. METHODS: A luciferase assay was used to confirm microRNA-328 binding to the PAX6 locus. Clones containing each allele of rs662702 were created and tested for their binding affinity to microRNA-328. Because a low level of PAX6 is a risk factor for myopia, we tested whether knockdown of PAX6 affects retinal pigment epithelial (RPE) cells and scleral cells, as well as expression of myopia-related genes. We also tested for the effect of retinoic acid (RA) on microRNA-328 expression, since RA-responsive elements are predicted to lie in the microRNA-328 promoter. RESULTS: MicroRNA-328 was shown to bind to the wild-type, but not mutant 3' untranslated region (UTR) of PAX6. The risk C allele of rs644242 had strong response to microRNA-328 but the protective T allele did not respond to microRNA-328. Down-regulation of PAX6 in RPE increased RPE proliferation, but reduced scleral cell proliferation. In addition, transforming growth factor (TGF)-beta3 in the RPE and matrix malleoproteinase-2 (MMP2) in the sclera were increased, while collagen I and integrin beta1 in the sclera were decreased. RA dose-dependently increased microRNA-328 expression and, in turn, suppressed PAX6 expression. CONCLUSIONS: We elaborated the relationship among myopia development, SNP rs662702, microRNA-328 and RA. The data imply that reduction of miR-328 and/or RA can be potential strategies for myopia prevention or treatment. PMID- 22447871 TI - Depletion of SLC4A11 causes cell death by apoptosis in an immortalized human corneal endothelial cell line. AB - PURPOSE: To investigate the effects of SLC4A11 gene depletion in human corneal endothelial cells. METHODS: To achieve stable downregulation of SLC4A11 gene expression in immortalized human corneal endothelial cells (HCECs), short-hairpin RNA (shRNA) targeted against SLC4A11 was used. Cell growth and viability were determined using the real-time cell analyzer and trypan blue staining respectively. Apoptosis was investigated by Annexin V and TUNEL assays. Alterations in apoptotic gene expression following SLC4A11 silencing were determined using the RT(2)Profiler PCR array for human apoptosis while activation of the apoptotic pathway was ascertained by western analysis. RESULTS: SLC4A11 silencing in HCECs could be achieved by stable expression of shRNA targeted against SLC4A11. SLC4A11 knockdown suppressed HCEC growth and reduced HCEC viability compared to the control. This reduction in cell growth is associated with increased apoptosis in SLC4A11-silenced cells. CONCLUSIONS: Our data suggest that the reduction of cell number with time in SLC4A11-depleted HCECs is due to an increase in cell death by apoptosis. This suggests that SLC4A11 is necessary for cell survival and may explain the pathologic corneal endothelial cell loss in endotheliopathies due to SLC4A11 mutations. PMID- 22447872 TI - A validated risk calculator to assess risk and rate of visual field progression in treated glaucoma patients. AB - PURPOSE: The purpose of our study is to develop and validate a model to predict visual field (VF) outcomes in patients with treated glaucoma. METHODS: Data from 587 eyes with treated glaucoma evaluated in a cohort were used to develop two equations to predict VF outcomes, one estimating the risk of progression (%) and another estimating the global rate of VF sensitivity change (decibels [dB]/year). These equations, which included variables associated with VF progression in a multivariable model, then were tested in another cohort (n = 62 eyes) followed for at least 4 years. Agreement, discrimination, and calibration of the model in the validation sample were assessed as main outcome measures. RESULTS: The mean difference between observed and predicted global rates of sensitivity change was 0.13 dB/year (95% confidence interval [CI] = 0.06 to 0.18 dB/year) and the mean difference between observed and predicted final VF mean deviation (MD) values was 0.37 dB (95% CI = 0.00 to 0.75 dB). The predictive model had moderate discriminative ability to estimate VF progression in the independent sample (c index of 0.78, 95% CI = 0.59 to 0.97). CONCLUSIONS: To our knowledge, this is the first attempt to generate and validate a risk model for patients with treated glaucoma. The prediction model showed moderate accuracy in estimating future VF outcomes in an independent glaucoma population, and may be useful for the objective assessment of risk of progressive VF loss. PMID- 22447873 TI - The accuracy of real-time procedure coding by theatre nurses: a comparison with the central national system. AB - Accurate and timely clinical data are required for clinical and organisational purposes and is especially important for patient management, audit of surgical performance and the electronic health record. The recent introduction of computerised theatre management systems has enabled real-time (point-of-care) operative procedure coding by clinical staff. However the accuracy of these data is unknown. The aim of this Scottish study was to compare the accuracy of theatre nurses' real-time coding on the local theatre management system with the central Scottish Morbidity Record (SMR01). Paired procedural codes were recorded, qualitatively graded for precision and compared (n = 1038). In this study, real time, point-of-care coding by theatre nurses resulted in significant coding errors compared with the central SMR01 database. Improved collaboration between full-time coders and clinical staff using computerised decision support systems is suggested. PMID- 22447874 TI - Evidence-based practice and related information literacy skills of nurses in Singapore: an exploratory case study. AB - Increased demand for medical or healthcare services has meant that nurses are to take on a more proactive and independent role intending to patients, providing basic treatment and deciding relevant clinical practice. This, in turn, translates into the need for nurses to be able to translate research and evidence into their practice more efficiently and effectively. Hence, competencies in looking for, evaluating, synthesizing and applying documented information or evidence-based practice becomes crucial. This article presents a quantitative study that involved more than 300 nurses from a large government hospital in Singapore. A self-reporting questionnaire was developed to collect data pertaining to evidence-based practice and activities, including those that demonstrate information literacy competencies. Results seem to suggest that the nurses preferred to use print and human information sources compared to electronic information sources; were not proactive in looking up research or evidence-based information and, instead, preferred such information to be fed to them; and that they perceived they lacked the ability to evaluate research papers or effectively search electronic information related to nursing or evidence-based practice. It was also found that more than 80% of the nurses have not had any training related to evidence-based practice. PMID- 22447875 TI - Proof of concept for the role of glycemic control in the early detection of infections in diabetics. AB - The relationship of infections and glycemic control in diabetes has been previously investigated but no solid findings have been described. Meanwhile, the detection of any infection at the early stages of disease progression, i.e. during the incubation period, is critical. In order to study this topic, we used the infection evidence and the daily glycemic control data of 248 type-2 diabetics who participated in a large telemedicine study. The results showed that morning blood glucose was significantly elevated and that diabetics performed the measurements at a later time when infected. A simple model for predicting the occurrence of infection based on the glycemic control variables showed good performance (sensitivity: 56%, specificity: 92%). A set of variables that synthesize a diabetic's profile could be included in a dedicated model and facilitate the early detection of infections; other aspects, such as continuous self-monitoring and personalized medical records, should be examined in this direction. PMID- 22447876 TI - Functional safety of health information technology. AB - In an effort to improve patient safety and reduce adverse events, there has been a rapid growth in the utilisation of health information technology (HIT). However, little work has examined the safety of the HIT systems themselves, the methods used in their development or the potential errors they may introduce into existing systems. This article introduces the conventional safety-related systems development standard IEC 61508 to the medical domain. It is proposed that the techniques used in conventional safety-related systems development should be utilised by regulation bodies, healthcare organisations and HIT developers to provide an assurance of safety for HIT systems. In adopting the IEC 61508 methodology for HIT development and integration, inherent problems in the new systems can be identified and corrected during their development. Also, IEC 61508 should be used to develop a healthcare-specific standard to allow stakeholders to provide an assurance of a system's safety. PMID- 22447877 TI - The quality of English-language websites offering falls-prevention advice to older members of the public and their families. AB - Falls among older people are a major public health issue. Increasing numbers of older people are accessing the internet for health-related information, including information on falls risk and prevention. However, we are aware of no study that has assessed the quality of such websites. Using techniques for conducting systematic literature reviews, we evaluated English-language websites offering falls-related advice to members of the public. Forty-two websites were identified using popular search engines; these were assessed using evidence-based guidelines and codes of conduct on coverage of falls-related information, credibility and senior friendliness. Overall, scores were poor for coverage of falls information and credibility, although they were higher for senior friendliness. Few of the websites had been recently updated and none provided individually-tailored advice. We conclude that websites have fallen short of their potential to provide accessible, evidence-based information on the risks of falls and their prevention. PMID- 22447878 TI - Understanding public health informatics competencies for mid-tier public health practitioners: a web-based survey. AB - The literature suggests that there is a need for measuring public health informatics (PHI) competency to further understand whether current educational modules and modalities meet the needs of PHI practitioners and researchers to perform their jobs more effectively, particularly for mid-tier practitioners that constitute the majority of public health workers in the USA. The present study seeks to update current knowledge of the perceptions and experiences of PHI competencies proposed by the U.S. Council on Linkage in Public Health specifically for mid-tier PH practitioners and researchers. The results were collected and analyzed by using a Web-based survey (WBS) method administered among both practitioners and researchers. Researchers first compiled a draft list of candidate competency set by incorporating existing competency areas provided by: 1) the Council on Linkage; and by 2) those proposed by the USA's Centers for Disease Control CDC Public Health Informatics Work Group. Nine sets of competency statements with 120 competency items and demographic information of respondents were included in the WBS. The online survey instruments were pilot-tested accordingly to incorporate feedback from respondents of the pilot. Fifty-six subjects were recruited from PH experts who were: 1) members of the Health Informatics Information Technology (HIIT) group of American Public Health Association; and, 2) members from the Community of Science (COS) Website who were the first authors published in the PHI field from PubMed. The sample included diverse backgrounds of PHI workers. They expressed an increased need for training to improve their PHI competencies. Respondents agreed that four competency sets should be adequately represented, including Leadership and System Thinking Skills (82%), followed by Financial Planning and Management Skills (79%), Community Dimensions of Practice Skills (77%), and Policy Development/Program Planning Skills (63%). The findings parallel current literature indicating that there exists an expressed need for clarification of the public health practitioner's job-specific informatics competency. Findings of expressed needs for basic computer literacy training and community-based practice were consistent with those of the literature. Additional training and resources should be allocated to address the competency of leadership, management, community-based practice and policy advocacy skills for mid-tier public health practitioners to perform their jobs more effectively. Only when healthcare organizations properly identify PHI competency needs will public health practitioners likely improve their overall informatics skills while improving diversification for contribution across multiple settings. PMID- 22447879 TI - Molecular epidemiology of carbapenem-non-susceptible Acinetobacter baumannii in Japan. AB - OBJECTIVES: Acinetobacter baumannii presents a clinical challenge when it is non susceptible to carbapenems. The prevalence of carbapenem-non-susceptible A. baumannii in Japan is unclear, as previous studies have been limited in scope. We investigated the spread of carbapenem-non-susceptible A. baumannii in Japan and performed a comparison with findings from overseas. METHODS: A total of 305 non duplicate clinical isolates of Acinetobacter spp. from 176 medical facilities in all geographical regions of Japan were tested for susceptibility to antimicrobial agents by the agar dilution method. Isolates with MICs of imipenem >= 4 mg/L underwent PCR analysis of OXA-type beta-lactamase gene clusters and metallo-beta lactamase genes. These isolates were further analysed by sequencing of OXA-type beta-lactamases and by multilocus sequence typing (MLST). RESULTS: Fifty-five of the 305 clinical isolates had MICs of imipenem >= 4 mg/L. The OXA-51-like carbapenemase gene was detected in 52 of these 55 isolates. Within the OXA-51 like gene cluster, OXA-66 was found in 43 (82.7%) of the 52 isolates. MLST identified the following sequence types (STs): ST74, ST76, ST92, ST106, ST188 and ST195 in 2 (3.8%), 2 (3.8%), 40 (76.9%), 5 (9.6%), 2 (3.8%) and 1 (1.9%) of the isolates, respectively. In particular, ST92 was found in 31 (91.2%) of the 34 A. baumannii isolates with MICs of imipenem >= 16 mg/L. CONCLUSIONS: This is the first report on the molecular epidemiology of A. baumannii with MICs of imipenem >= 4 mg/L in Japan. OXA-66 and ST92 were dominant among these isolates. PMID- 22447881 TI - Survival is improving in systemic sclerosis: true or false? PMID- 22447880 TI - Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. AB - CONTEXT: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized double blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00824005. PMID- 22447882 TI - Aberrant expression of the negative costimulator PD-1 on T cells in granulomatosis with polyangiitis. AB - OBJECTIVE: Persistent T-cell activation is frequently observed in granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis). T-cell activation is usually balanced by negative costimulatory molecules. The negative costimulator programmed death receptor-1 (PD-1) and its relevance to T-cell immunity have not been studied so far in GPA. Thus it is the aim of the study to characterize the role of PD-1 in GPA. METHODS: Thirty-two patients suffering from GPA and 19 age-matched healthy controls (HCs) were enrolled. T-lymphocyte subsets from peripheral blood were analysed by flow cytometry for the expression of PD-1. The frequency of memory T cells and T cells producing pro-inflammatory cytokines was determined. Renal biopsies from GPA patients were stained for CD3 and PD-1. RESULTS: PD-1 expression was increased on T-helper cells (Th cells) from GPA patients as compared with HCs. In addition, parameters of persistent T-cell activation and production of pro-inflammatory cytokines were positively associated with numbers of PD-1(+) Th cells in patients but not in HCs. Latent infection with CMV seemed to enhance PD-1 expression on CD4(+) and CD4(+)CD25(-) T cells. Interestingly, expression of PD-1 on CD4(+)CD25(+)T cells was inversely correlated with relapse rate. Importantly, lesional T cells were mostly lacking PD-1. CONCLUSIONS: The expression of the negative costimulator PD-1 is altered in GPA and might counterbalance persistent T-cell activation. PMID- 22447883 TI - Effects of glucocorticoid treatment on CD25-FOXP3+ population and cytokine producing cells in rheumatoid arthritis. AB - OBJECTIVES: To investigate CD25(-)FOXP3(+) cells in RA patients and their possible relationship with disease features and response to glucocorticoids (GCs). METHODS: Peripheral blood mononuclear cells were collected from 147 RA patients, 29 healthy controls and 75 SLE patients as disease controls. The proportion of CD4(+)FOXP3(+) cells with negative, low or high CD25 expression and the levels of IL-10-, TNF-alpha-, IL-17- and IFNgamma-producing cells were assessed by flow cytometry. The presence of the high IL-10 genotype (-1082GG), associated with good response to GC, was determined by PCR amplification and hybridization with allele-specific fluorescently labelled probes. Data were related to treatment and clinical parameters. RESULTS: The CD25(-)FOXP3(+) population was significantly increased in RA patients and negatively correlated with DAS-28 and other disease parameters. The IL-10 genotype did not influence the frequency of these cells in controls or the entire RA group; however, GC treated patient carriers of the high IL-10 genotype presented significantly higher levels of this population in addition to an increased percentage of IL-10 secreting cells and relatively low amounts of TNF-alpha-, IFN-gamma- and IL-17 positive cells. Finally, a prospective study confirmed that genetically high IL 10 producers significantly increase CD25(-)FOXP3(+) cells after 6 months of GC treatment. CONCLUSION: The present study provides the first evidence of increased CD25(-)FOXP3(+) cells in RA patients, which were associated with disease activity and with GC treatment in carriers of the high IL-10 genotype, suggesting that this population plays a role in the clinical response to prednisone in RA. PMID- 22447884 TI - Immunity 12 years after alemtuzumab in RA: CD5+ B-cell depletion, thymus dependent T-cell reconstitution and normal vaccine responses. AB - OBJECTIVES: Lymphocyte depleting therapies have been used to treat refractory autoimmune disease, including RA, but treatment may be associated with long-term lymphopenia. It is unclear whether delayed reconstitution preferentially affects lymphocyte subsets, how this modulates immune challenges and whether thymic function influences the outcome. These questions are now addressed in a detailed analysis of RA patients 12 years after alemtuzumab (anti-CD52) treatment. METHODS: Blood was obtained from 20 RA patients 12 years after alemtuzumab treatment. Lymphocyte subsets were enumerated by flow cytometry. T-cell receptor excision circles (TRECs)/ml were determined to quantify thymic function, and serological responses to neoantigens and recall antigens were assessed. RESULTS: RA patients remained lymphopenic 12 years after their first dose of alemtuzumab. CD5(+) B cells, which may be associated with autoantibody production, were significantly reduced in alemtuzumab-treated patients compared with age-matched disease controls. In addition, naive and memory CD4(+) T-cell subsets were present in altered proportions in patients who had received alemtuzumab, with increased effector memory CD4(+) T cells, and decreased naive and central memory CD4(+) T cells. TRECs were detectable in alemtuzumab-treated patients and correlated with CD4(+) lymphocyte counts. Vaccine responses to neoantigens and recall antigens fell within the normal range for an ageing population. CONCLUSIONS: Alemtuzumab therapy resulted in long-term alterations in lymphocyte subsets. The significance of these changes remains uncertain but patients respond normally to antigenic challenges. Thymic function remains an important determinant of T-cell reconstitution even several years after lymphocytotoxic therapy. PMID- 22447885 TI - Long-term outcome of patients with JIA treated with etanercept, results of the biologic register JuMBO. AB - OBJECTIVE: To assess the outcome of adult patients with JIA who received etanercept (ETA) during childhood. METHODS: JuMBO (Juvenile arthritis MTX/Biologics long-term Observation) is an ongoing prospective cohort study. It follows adult JIA patients who were formerly included in the national JIA biologic register. In JuMBO, clinical status, therapy and the occurrence of adverse events are documented every 6 months by physicians; additionally, patient derived data are included [e.g. functional capacity and health-related quality of life (HRQoL)]. Here, data from the last available visit of patients were analysed. RESULTS: Until December 2010, 346 patients with a median age of 21 years were included in JuMBO. The majority of them had polyarthritis. Seventy eight per cent of them were still on DMARDs, 45% on ETA. The disease was inactive in about one in five patients. A restricted functional capacity was reported by 51% of participants and fatigue by 76%. The patients judged their HRQoL to be lower than a reference group from the general population, but only with regard to physical health. HRQoL correlated with the patient's perceived fatigue. Most frequently observed comorbidities in the young adults with JIA were disease related and included uveitis, IBDs and psoriasis. During the observation period, 2.1 severe infections and 1.5 new-onset autoimmune events per 100 patient-years were reported in patients on ETA, respectively. CONCLUSION: The first data from the JuMBO register indicate an improved long-term outcome of patients with severe JIA treated in the biologic era and an acceptable safety profile of ETA. PMID- 22447886 TI - Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative. AB - OBJECTIVE: To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA). METHODS: A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008-09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice. RESULTS: A total of 49,242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice. CONCLUSIONS: Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice. PMID- 22447887 TI - Musculoskeletal research--opportunities for all? PMID- 22447890 TI - Sialocele after parotid surgery: assessing the risk factors. AB - OBJECTIVE: To assess possible factors contributing to the occurrence of a sialocele after parotid surgery. STUDY DESIGN: Case series with chart review. SETTING: Secondary otolaryngology service. METHODS: One hundred two consecutive parotid operations by 1 surgeon were recorded. A high rate of sialocele formation was addressed by identifying possible contributing factors, sequentially introducing changes, and then analyzing the effect of such changes. RESULTS: Twenty patients developed a sialocele (19.6%). Demographic variables of those who developed a sialocele were similar to those who did not. Factors examined included partial versus complete superficial parotidectomy, use of Surgicel, vacuum drain pressure, and postoperative duration for surgical drain. The only significant factor on regression analysis for increasing the risk of a sialocele development was the use of Surgicel (P = .023). Once the use of Surgicel stopped, the rate of sialocele formation diminished markedly (from 28.6% to 11.3%). CONCLUSIONS: Sialocele can cause significant problems for the patient and surgeon in terms of delayed wound healing and increased clinic resources and frustration. This study suggests that the use of products such as Surgicel increases the risk of postoperative sialocele formation. PMID- 22447888 TI - Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. AB - CONTEXT: Thrombus embolization during percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) is common and results in suboptimal myocardial perfusion and increased infarct size. Two strategies proposed to reduce distal embolization and improve outcomes after primary PCI are bolus intracoronary abciximab and manual aspiration thrombectomy. OBJECTIVE: To determine whether bolus intracoronary abciximab, manual aspiration thrombectomy, or both reduce infarct size in high-risk patients with STEMI. DESIGN, SETTING, AND PATIENTS: Between November 28, 2009, and December 2, 2011, 452 patients presenting at 37 sites in 6 countries within 4 hours of STEMI due to proximal or mid left anterior descending artery occlusion undergoing primary PCI with bivalirudin anticoagulation were randomized in an open-label, 2 x 2 factorial design to bolus intracoronary abciximab delivered locally at the infarct lesion site vs no abciximab and to manual aspiration thrombectomy vs no thrombectomy. INTERVENTIONS: A 0.25-mg/kg bolus of abciximab was administered at the site of the infarct lesion via a local drug delivery catheter. Manual aspiration thrombectomy was performed with a 6 F aspiration catheter. MAIN OUTCOME MEASURES: Primary end point: infarct size (percentage of total left ventricular mass) at 30 days assessed by cardiac magnetic resonance imaging (cMRI) in the abciximab vs no abciximab groups (pooled across the aspiration randomization); major secondary end point: 30-day infarct size in the aspiration vs no aspiration groups (pooled across the abciximab randomization). RESULTS: Evaluable cMRI results at 30 days were present in 181 and 172 patients randomized to intracoronary abciximab vs no abciximab, respectively, and in 174 and 179 patients randomized to manual aspiration vs no aspiration, respectively. Patients randomized to intracoronary abciximab compared with no abciximab had a significant reduction in 30-day infarct size (median, 15.1%; interquartile range [IQR], 6.8%-22.7%; n = 181, vs 17.9% [IQR, 10.3%-25.4%]; n = 172; P = .03). Patients randomized to intracoronary abciximab also had a significant reduction in absolute infarct mass (median, 18.7 g [IQR, 7.4-31.3 g]; n = 184, vs 24.0 g [IQR, 12.1-34.2 g]; n = 175; P = .03) but not abnormal wall motion score (median, 7.0 [IQR, 2.0-10.0]; n = 188, vs 8.0 [IQR, 3.0-10.0]; n = 184; P = .08). Patients randomized to aspiration thrombectomy vs no aspiration had no significant difference in infarct size at 30 days (median, 17.0% [IQR, 9.0%-22.8%]; n = 174, vs 17.3% [IQR, 7.1%-25.5%]; n = 179; P = .51), absolute infarct mass (median, 20.3 g [IQR, 9.7-31.7 g]; n = 178, vs 21.0 g [IQR, 9.1-34.1 g]; n = 181; P = .36), or abnormal wall motion score (median, 7.5 [IQR, 2.0-10.0]; n = 186, vs 7.5 [IQR, 2.0-10.0]; n = 186; P = .89). CONCLUSION: In patients with large anterior STEMI presenting early after symptom onset and undergoing primary PCI with bivalirudin anticoagulation, infarct size at 30 days was significantly reduced by bolus intracoronary abciximab delivered to the infarct lesion site but not by manual aspiration thrombectomy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00976521. PMID- 22447891 TI - Risk factors for vagal palsy following cerebellopontine angle surgery. AB - OBJECTIVE: Describe the incidence, risk factors, and outcomes of postoperative vagal palsy in patients undergoing surgical excision of cerebellopontine angle (CPA) tumors. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care center. SUBJECTS AND METHODS: One hundred eighty-one consecutive patients undergoing surgical excision of CPA pathology from January 1, 2008, to December 31, 2010, at Johns Hopkins Hospital. Postoperative unilateral vagal palsy was identified by laryngoscopy or videofluoroscopy, and clinical variables were collected from medical records. RESULTS: Postoperative unilateral vagal palsy was identified in 19 of 181 (10%) patients. Vocal fold motion impairment (VFMI) in combination with pharyngeal palsy was more common than VFMI or pharyngeal palsy alone. Those with vagal palsy had a larger mean tumor size (30 mm) than those without vagal palsy (20 mm, P = .0002) and a significantly longer mean hospital stay (9 vs 5 days, P < .0001). Vagal palsy was not associated with tumor pathology, prior treatment (stereotactic radiation or prior surgery), or surgical approach (suboccipital craniotomy vs translabyrinthine approach). Significant rates of aspiration were observed in patients with vagal palsy (67%). CONCLUSION: Voice and swallowing function can be affected by surgical excision of pathology of the CPA. Tumor size is an independent risk factor for postoperative vagal palsy, which in turn has important consequences for prolonged hospital stay, aspiration, and voice and swallowing impairment. PMID- 22447892 TI - Food hypersensitivity and otolaryngologic conditions in young children. AB - OBJECTIVES/HYPOTHESIS: To explore the relationship between food hypersensitivity and common upper aerodigestive disorders found in children younger than 2 years. STUDY DESIGN: Case control study. SETTING: Tertiary pediatric gastroenterology/otolaryngology clinics. METHODS: Two-year retrospective chart review of a common cohort of children younger than 2 years with suspected cow's milk protein allergy (CMPA). Patients were managed in both a tertiary pediatric gastroenterology and otolaryngology clinic and compared with a control study group. RESULTS: One hundred ninety-one children with CMPA were reviewed. One hundred forty-one had aerodigestive complaints, with 101 having sufficient follow up to participate in the study. Ninety-one percent of this final patient group demonstrated improved symptoms following dairy elimination. Twenty-five patients (27%) had associated otolaryngologic (ear, nose, and throat [ENT]) issues that had been refractory to maximal gastroesophageal reflux therapy. The most common associated upper aerodigestive conditions were persistent upper airway congestion (72%) and oropharyngeal dysphagia (80%). Sixty percent of ENT disease improved with elimination diet. Eosinophilic esophagitis was noted in 36% of the cohort who had mucosal biopsies performed. Otolaryngology intervention was much more common in the cohort of children with CMPA compared with controls (odds ratio, 33.78; 95% confidence interval, 7.55, 151.03). CONCLUSIONS: CMPA is difficult to diagnose because of limited accurate diagnostic tools, especially in young children. This study suggests a relationship between CMPA and otolaryngologic conditions in children younger than 2 years. Some patients in this study showed symptom improvement via an elimination diet. Early recognition of otolaryngologic manifestations of CMPA may help manage this condition in young children. PMID- 22447893 TI - Endoscopic surgery for fronto-ethmoidal mucoceles: a 15-year experience. AB - OBJECTIVE: To add to the existing knowledge of endoscopic surgery for fronto ethmoidal mucoceles and to determine factors that influence the outcomes of endoscopic surgery. STUDY DESIGN: Case series with chart review. SETTING: University adult tertiary care institution. SUBJECTS AND METHODS: A database of patients treated surgically for mucoceles of the paranasal sinus has been kept by the senior author since 1995. It was used to identify those who have had endoscopic surgery for fronto-ethmoidal mucoceles from 1995 to 2010. All adult patients with 6 months or more of follow-up were included. The database was reviewed and assessed for variables that may affect outcome after surgery. RESULTS: Forty patients underwent 44 endoscopic procedures for treatment of fronto-ethmoidal mucoceles and the complications of surgery. The mean age was 46.3 years, and mean follow-up time was 74.9 months. Two patients had a history of head trauma. A total of 28 Draf IIa procedures, 13 Draf IIb, and 3 Draf III procedures were performed. Three patients had combined open approaches. Two patients had bilateral surgery, and 2 patients required revision surgery: 1 for restenosis after a Draf IIa procedure (1/28) and 1 for disease recurrence. Stenosis was found in a further 3 patients who had Draf IIb surgery (3/13). CONCLUSION: The current series represents one of the largest for the endoscopic management of fronto-ethmoidal mucoceles. Endoscopic approaches are suitable for most mucoceles. The most common complication, restenosis of the frontal recess, was more likely following Draf IIb procedures (23%) than Draf IIa (3.6%) procedures. PMID- 22447894 TI - Venolymphatic vascular malformation in the parapharyngeal space. PMID- 22447895 TI - Association study of PARD3 gene polymorphisms with neural tube defects in a Chinese Han population. AB - Partitioning defective 3 homolog (PARD3) is an attractive candidate gene for screening neural tube defect (NTD) risk. To investigate the role of genetic variants in PARD3 on NTD risk, a case-control study was performed in a region of China with a high prevalence of NTDs. Total 53 single-nucleotide polymorphisms (SNPs) in PARD3 were genotyped in 224 fetuses with NTDs and in 253 normal fetuses. We found that 6 SNPs (rs2496720, rs2252655, rs3851068, rs118153230, rs10827337, and rs12218196) were statistically associated with NTDs (P < .05). After stratifying participants by NTD phenotypes, the significant association only existed in cases with anencephaly rather than spina bifida. Further haplotype analysis confirmed the association between PARD3 polymorphisms and NTD risk (global test P = 3.41e-008). Our results suggested that genetic variants in PARD3 were associated with susceptibility to NTDs in a Chinese Han population, and this association was affected by NTD phenotypes. PMID- 22447896 TI - Structural determinants of Actinomyces sortase SrtC2 required for membrane localization and assembly of type 2 fimbriae for interbacterial coaggregation and oral biofilm formation. AB - As a pioneer colonizer of the oral cavity, Actinomyces oris expresses proteinaceous pili (also called fimbriae) to mediate the following two key events in biofilm formation: adherence to saliva deposits on enamel and interbacterial associations. Assembly of type 2 fimbriae that directly facilitate coaggregation with oral streptococci and Actinomyces biofilm development requires the class C sortase SrtC2. Although the general sortase-associated mechanisms have been elucidated, several structural attributes unique to the class C sortases require functional investigation. Mutational studies reported here suggest that the N terminal transmembrane (TM) region of SrtC2, predicted to contain a signal peptide sequence, is cleaved off the mature protein and that this processing is critical for the proper integration of the enzyme at the cytoplasmic membrane, which is mediated by the extended hydrophobic C terminus containing a TM domain and a cytoplasmic tail. Deletion of this putative TM or the entire cytoplasmic domain abolished the enzyme localization and functionality. Alanine substitution of the conserved catalytic Cys-His dyad abrogated the SrtC2 enzymatic activity. In contrast, mutations designed to alter a "lid" domain that covers the catalytic pocket of a class C sortase showed no effect on enzyme activity. Finally, each of the deleterious mutations that affected SrtC2 activity or membrane localization also eliminated Actinomyces species biofilm development and bacterial coaggregation with streptococci. We conclude that the N terminus of SrtC2, which contains the signal sequence, is required for proper protein translocation and maturation, while the extended C-terminal hydrophobic region serves as a stable membrane anchor for proper enzyme functionality. PMID- 22447897 TI - Functional dissection of N-acetylglutamate synthase (ArgA) of Pseudomonas aeruginosa and restoration of its ancestral N-acetylglutamate kinase activity. AB - In many microorganisms, the first step of arginine biosynthesis is catalyzed by the classical N-acetylglutamate synthase (NAGS), an enzyme composed of N-terminal amino acid kinase (AAK) and C-terminal histone acetyltransferase (GNAT) domains that bind the feedback inhibitor arginine and the substrates, respectively. In NAGS, three AAK domain dimers are interlinked by their N-terminal helices, conforming a hexameric ring, whereas each GNAT domain sits on the AAK domain of an adjacent dimer. The arginine inhibition of Pseudomonas aeruginosa NAGS was strongly hampered, abolished, or even reverted to modest activation by changes in the length/sequence of the short linker connecting both domains, supporting a crucial role of this linker in arginine regulation. Linker cleavage or recombinant domain production allowed the isolation of each NAGS domain. The AAK domain was hexameric and inactive, whereas the GNAT domain was monomeric/dimeric and catalytically active although with ~50-fold-increased and ~3-fold-decreased K(m)(glutamate) and k(cat) values, respectively, with arginine not influencing its activity. The deletion of N-terminal residues 1 to 12 dissociated NAGS into active dimers, catalyzing the reaction with substrate kinetics and arginine insensitivity identical to those for the GNAT domain. Therefore, the interaction between the AAK and GNAT domains from different dimers modulates GNAT domain activity, whereas the hexameric architecture appears to be essential for arginine inhibition. We proved the closeness of the AAK domains of NAGS and N acetylglutamate kinase (NAGK), the enzyme that catalyzes the next arginine biosynthesis step, shedding light on the origin of classical NAGS, by showing that a double mutation (M26K L240K) in the isolated NAGS AAK domain elicited NAGK activity. PMID- 22447898 TI - Molecular structure of isolated MvspI, a variable surface protein of the fish pathogen Mycoplasma mobile. AB - Mycoplasma mobile is a parasitic bacterium that causes necrosis in the gills of freshwater fishes. This study examines the molecular structure of its variable surface protein, MvspI, whose open reading frame encodes 2,002 amino acids. MvspI was isolated from mycoplasma cells by a biochemical procedure to 92% homogeneity. Gel filtration and analytical ultracentrifugation suggested that this protein is a cylinder-shaped monomer with axes of 66 and 2.7 nm. Rotary shadowing transmission electron microscopy of MvspI showed that the molecule is composed of two rods 30 and 45 nm long; the latter rod occasionally features a bulge. Immuno electron microscopy and epitope mapping showed that the bulge end of the molecular image corresponds to the C terminus of the amino acid sequence. Partial digestion by various proteases suggested that the N-terminal part, comprised of 697 amino acids, is flexible. Analysis of the predicted amino acid sequence showed that the molecule features a lipoprotein and 16 repeats of about 90 residues; 15 positions exist between residues 88 and 1479, and the other position is between residues 1725 and 1807. The amino acid sequence of MvspI was mapped onto a molecular image obtained by electron microscopy. The present study is the first to elucidate the molecular shape of a variable surface protein of mycoplasma. PMID- 22447899 TI - Type I signal peptidase and protein secretion in Staphylococcus aureus. AB - Staphylococcus aureus is an important human pathogen whose virulence relies on the secretion of many different proteins. In general, the secretion of most proteins in S. aureus, as well as other bacteria, is dependent on the type I signal peptidase (SPase)-mediated cleavage of the N-terminal signal peptide that targets a protein to the general secretory pathway. The arylomycins are a class of natural product antibiotics that inhibit SPase, suggesting that they may be useful chemical biology tools for characterizing the secretome. While wild-type S. aureus (NCTC 8325) is naturally resistant to the arylomycins, sensitivity is conferred via a point mutation in its SPase. Here, we use a synthetic arylomycin along with a sensitized strain of S. aureus and multidimensional protein identification technology (MudPIT) mass spectrometry to identify 46 proteins whose extracellular accumulation requires SPase activity. Forty-four possess identifiable Sec-type signal peptides and thus are likely canonically secreted proteins, while four also appear to possess cell wall retention signals. We also identified the soluble C-terminal domains of two transmembrane proteins, lipoteichoic acid synthase, LtaS, and O-acyteltransferase, OatA, both of which appear to have noncanonical, internal SPase cleavage sites. Lastly, we identified three proteins, HtrA, PrsA, and SAOUHSC_01761, whose secretion is induced by arylomycin treatment. In addition to elucidating fundamental aspects of the physiology and pathology of S. aureus, the data suggest that an arylomycin-based therapeutic would reduce virulence while simultaneously eradicating an infection. PMID- 22447900 TI - Growth of flagellar filaments of Escherichia coli is independent of filament length. AB - Bacterial flagellar filaments grow at their distal ends, from flagellin that travels through a central channel ~2 nm in diameter. The flagellin is extruded from the cytoplasm by a pump powered by a proton motive force (PMF). We measured filament growth in cells near the mid-exponential-phase with flagellin bearing a specific cysteine-for-serine substitution, allowing filaments to be labeled with sulfhydryl-specific fluorescent dyes. We labeled filaments first with a green maleimide dye and then, following an additional period of growth, with a red maleimide dye. The contour lengths of the green and red segments were measured. The average lengths of red segments (~2.3 MUm) were the same regardless of the lengths of the green segments from which they grew (ranging from less than 1 to more than 9 MUm in length). Thus, flagellar filaments do not grow at a rate that decreases exponentially with length, as formerly supposed. If flagellar filaments were broken by viscous shear, the broken filaments continued to grow. Identical results were obtained whether flagellin was expressed from fliC on the chromosome under the control of its native promoter or on a plasmid under the control of the arabinose promoter. PMID- 22447901 TI - Structural characterization of CFA/III and Longus type IVb pili from enterotoxigenic Escherichia coli. AB - The type IV pili are helical filaments found on many Gram-negative pathogenic bacteria, with multiple diverse roles in pathogenesis, including microcolony formation, adhesion, and twitching motility. Many pathogenic enterotoxigenic Escherichia coli (ETEC) isolates express one of two type IV pili belonging to the type IVb subclass: CFA/III or Longus. Here we show a direct correlation between CFA/III expression and ETEC aggregation, suggesting that these pili, like the Vibrio cholerae toxin-coregulated pili (TCP), mediate microcolony formation. We report a 1.26-A resolution crystal structure of CofA, the major pilin subunit from CFA/III. CofA is very similar in structure to V. cholerae TcpA but possesses a 10-amino-acid insertion that replaces part of the alpha2-helix with an irregular loop containing a 3(10)-helix. Homology modeling suggests a very similar structure for the Longus LngA pilin. A model for the CFA/III pilus filament was generated using the TCP electron microscopy reconstruction as a template. The unique 3(10)-helix insert fits perfectly within the gap between CofA globular domains. This insert, together with differences in surface-exposed residues, produces a filament that is smoother and more negatively charged than TCP. To explore the specificity of the type IV pilus assembly apparatus, CofA was expressed heterologously in V. cholerae by replacing the tcpA gene with that of cofA within the tcp operon. Although CofA was synthesized and processed by V. cholerae, no CFA/III filaments were detected, suggesting that the components of the type IVb pilus assembly system are highly specific to their pilin substrates. PMID- 22447902 TI - CcrR, a TetR family transcriptional regulator, activates the transcription of a gene of the Ethylmalonyl coenzyme A pathway in Methylobacterium extorquens AM1. AB - The ethylmalonyl coenzyme A (ethylmalonyl-CoA) pathway is one of the central methylotrophy pathways in Methylobacterium extorquens involved in glyoxylate generation and acetyl-CoA assimilation. Previous studies have elucidated the operation of the ethylmalonyl-CoA pathway in C(1) and C(2) assimilation, but the regulatory mechanisms for the ethylmalonyl-CoA pathway have not been reported. In this study, a TetR-type activator, CcrR, was shown to regulate the expression of crotonyl-CoA reductase/carboxylase, an enzyme of the ethylmalonyl-CoA pathway involved in the assimilation of C(1) and C(2) compounds in Methylobacterium extorquens AM1. A ccrR null mutant strain was impaired in its ability to grow on C(1) and C(2) compounds, correlating with the reduced activity of crotonyl-CoA reductase/carboxylase. Promoter fusion assays demonstrated that the activity of the promoter required for ccr expression (the katA-ccr promoter) decreased as much as 50% in the absence of ccrR compared to wild-type M. extorquens AM1. Gel mobility shift assays confirmed that CcrR directly binds to the region upstream of the katA-ccr promoter. A palindromic sequence upstream of katA at positions 334 to -321 with respect to the predicted translational start site was identified, and mutations in this region eliminated the gel retardation of the katA-ccr promoter region by CcrR. CcrR does not appear to regulate the expression of other ethylmalonyl-CoA pathway genes, suggesting the existence of additional regulators. PMID- 22447903 TI - Anaerobic metabolism of indoleacetate. AB - The anaerobic metabolism of indoleacetate (indole-3-acetic acid [IAA]) in the denitrifying betaproteobacterium Azoarcus evansii was studied. The strain oxidized IAA completely and grew with a generation time of 10 h. Enzyme activities that transformed IAA were present in the soluble cell fraction of IAA grown cells but were 10-fold downregulated in cells grown on 2-aminobenzoate or benzoate. The transformation of IAA did not require molecular oxygen but required electron acceptors like NAD(+) or artificial dyes. The first products identified were the enol and keto forms of 2-oxo-IAA. Later, polar products were observed, which could not yet be identified. The first steps likely consist of the anaerobic hydroxylation of the N-heterocyclic pyrrole ring to the enol form of 2 oxo-IAA, which is catalyzed by a molybdenum cofactor-containing dehydrogenase. This step is probably followed by the hydrolytic ring opening of the keto form, which is catalyzed by a hydantoinase-like enzyme. A comparison of the proteome of IAA- and benzoate-grown cells identified IAA-induced proteins. Owing to the high similarity of A. evansii with strain EbN1, whose genome is known, we identified a cluster of 14 genes that code for IAA-induced proteins involved in the early steps of IAA metabolism. These genes include a molybdenum cofactor-dependent dehydrogenase of the xanthine oxidase/aldehyde dehydrogenase family, a hydantoinase, a coenzyme A (CoA) ligase, a CoA transferase, a coenzyme B(12) dependent mutase, an acyl-CoA dehydrogenase, a fusion protein of an enoyl-CoA hydratase and a 3-hydroxyacyl-CoA dehydrogenase, a beta-ketothiolase, and a periplasmic substrate binding protein for ABC transport as well as a transcriptional regulator of the GntR family. Five predicted enzymes form or act on CoA thioesters, indicating that soon after the initial oxidation of IAA and possibly ring opening, CoA thioesters are formed, and the carbon skeleton is rearranged, followed by a CoA-dependent thiolytic release of another CoA thioester. We propose a scheme of an anaerobic IAA metabolic pathway that ultimately leads to 2-aminobenzoyl-CoA or benzoyl-CoA. PMID- 22447904 TI - Conserved terminal organelle morphology and function in Mycoplasma penetrans and Mycoplasma iowae. AB - Within the genus Mycoplasma are species whose cells have terminal organelles, polarized structures associated with cytadherence and gliding motility. Mycoplasma penetrans, found mostly in HIV-infected patients, and Mycoplasma iowae, an economically significant poultry pathogen, are members of the Mycoplasma muris phylogenetic cluster. Both species have terminal organelles that interact with host cells, yet the structures in these species, or any in the M. muris cluster, remain uncharacterized. Time-lapse microcinematography of two strains of M. penetrans, GTU-54-6A1 and HF-2, and two serovars of M. iowae, K and N, show that the terminal organelles of both species play a role in gliding motility, with differences in speed within and between the two species. The strains and serovars also differed in their hemadsorption abilities that positively correlated with differences in motility speeds. No morphological differences were observed between M. penetrans and M. iowae by scanning electron microscopy (SEM). SEM and light microscopy of M. penetrans and M. iowae showed the presence of membranous filaments connecting pairs of dividing cells. Breaking of this filament during cell division was observed for M. penetrans by microcinematography, and this suggests a role for motility during division. The Triton X-100-insoluble fractions of M. penetrans and M. iowae consisted of similar structures that were unique compared to those identified in other mycoplasma species. Like other polarized mycoplasmas, M. penetrans and M. iowae have terminal organelles with cytadherence and gliding functions. The difference in function and morphology of the terminal organelles suggests that mycoplasmas have evolved terminal organelles independently of one another. PMID- 22447905 TI - Stressed by a Lov triangle. PMID- 22447906 TI - Organizational requirements of the SaeR binding sites for a functional P1 promoter of the sae operon in Staphylococcus aureus. AB - In Staphylococcus aureus, the SaeRS two-component system controls the expression of multiple virulence factors. Of the two promoters in the sae operon, P1 is autoinduced and has two binding sites for the response regulator SaeR. In this study, we examined the organizational requirements of the SaeR binding sites in P1 for transcription activation. Mutational studies showed that both binding sites are essential for binding to phosphorylated SaeR (P-SaeR) and transcription activation. When the 21-bp distance between the centers of the two SaeR binding sites was altered to 26 bp, 31 bp, 36 bp, or 41 bp, only the 31-bp mutant retained approximately 40% of the original promoter activity. When the -1-bp spacing (i.e.,1-bp overlap) between the primary SaeR binding site and the -35 promoter region was altered, all mutant P1 promoters failed to initiate transcription; however, when the first nucleotide of the -35 region was changed from A to T, the mutants with 0-bp or 22-bp spacing showed detectable promoter activity. Although P-SaeR was essential for the binding of RNA polymerase to P1, it was not essential for the binding of the enzyme to the alpha-hemolysin promoter. When the nonoptimal spacing between promoter elements in P1 or the coagulase promoter was altered to the optimal spacing of 17 bp, both promoters failed to initiate transcription. These results suggest that SaeR binding sites are under rather strict organizational restrictions and provide clues for understanding the molecular mechanism of sae-mediated transcription activation. PMID- 22447907 TI - EscA is a crucial component of the type III secretion system of enteropathogenic Escherichia coli. AB - The virulence of many Gram-negative pathogens is associated with type III secretion systems (T3SSs), which deliver virulence effector proteins into the cytoplasm of host cells. Components of enteropathogenic Escherichia coli (EPEC) T3SS are encoded within the locus of enterocyte effacement (LEE). While most LEE encoded T3SS proteins in EPEC have assigned names and functions, a few of them remain poorly characterized. Here, we studied a small LEE-encoded protein, Orf15, that shows no homology to other T3SS/flagellar proteins and is only present in attaching and effacing pathogens, including enterohemorrhagic E. coli and Citrobacter rodentium. Our findings demonstrated that it is essential for type III secretion (T3S) and that it is localized to the periplasm and associated with the inner membrane. Membrane association was driven by the N-terminal 19 amino acid residues, which were also shown to be essential for T3S. Consistent with its localization, Orf15 was found to interact with the EPEC T3SS outer membrane ring component, EscC, which was previously shown to be embedded within the outer membrane and protruding into the periplasmic space. Interestingly, we found that the predicted coiled-coil structure of Orf15 is critical for the protein's function. Overall, our findings suggest that Orf15 is a structural protein that contributes to the structural integrity of the T3S complex, and therefore we propose to rename it EscA. PMID- 22447908 TI - Regulation of ykrL (htpX) by Rok and YkrK, a novel type of regulator in Bacillus subtilis. AB - Expression of ykrL of Bacillus subtilis, encoding a close homologue of the Escherichia coli membrane protein quality control protease HtpX, was shown to be upregulated under membrane protein overproduction stress. Using DNA affinity chromatography, two proteins were found to bind to the promoter region of ykrL: Rok, known as a repressor of competence and genes for extracytoplasmic functions, and YkrK, a novel type of regulator encoded by the gene adjacent to ykrL but divergently transcribed. Electrophoretic mobility shift assays showed Rok and YkrK binding to the ykrL promoter region as well as YkrK binding to the ykrK promoter region. Comparative bioinformatic analysis of the ykrL promoter regions in related Bacillus species revealed a consensus motif, which was demonstrated to be the binding site of YkrK. Deletion of rok and ykrK in a PykrL-gfp reporter strain showed that both proteins are repressors of ykrL expression. In addition, conditions which activated PykrL (membrane protein overproduction, dissipation of the membrane potential, and salt and phenol stress) point to the involvement of YkrL in membrane protein quality control. PMID- 22447909 TI - Analyses of MbtB, MbtE, and MbtF suggest revisions to the mycobactin biosynthesis pathway in Mycobacterium tuberculosis. AB - The production of mycobactin (MBT) by Mycobacterium tuberculosis is essential for this bacterium to access iron when it is in an infected host. Due to this essential function, there is considerable interest in deciphering the mechanism of MBT assembly, with the goal of targeting select biosynthetic steps for antituberculosis drug development. The proposed scheme for MBT biosynthesis involves assembly of the MBT backbone by a hybrid nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) megasynthase followed by the tailoring of this backbone by N(6) acylation of the central l-Lys residue and subsequent N(6) hydroxylation of the central N(6)-acyl-l-Lys and the terminal caprolactam. A complete testing of this hypothesis has been hindered by the inability to heterologously produce soluble megasynthase components. Here we show that soluble forms of the NRPS components MbtB, MbtE, and MbtF are obtained when these enzymes are coproduced with MbtH. Using these soluble enzymes we determined the amino acid specificity of each adenylation (A) domain. These results suggest that the proposed tailoring enzymes are actually involved in precursor biosynthesis since the A domains of MbtE and MbtF are specific for N(6)-acyl-N(6)-hydroxy-l-Lys and N(6)-hydroxy-l-Lys, respectively. Furthermore, the preference of the A domain of MbtB for l-Thr over l-Ser suggests that the megasynthase produces MBT derivatives with beta-methyl oxazoline rings. Since the most prominent form of MBT produced by M. tuberculosis lacks this beta-methyl group, a mechanism for demethylation remains to be discovered. These results suggest revisions to the MBT biosynthesis pathway while also identifying new targets for antituberculosis drug development. PMID- 22447910 TI - High normal plasma triglycerides are associated with preserved cognitive function in Chinese oldest-old. AB - OBJECTIVE: to explore the relationship between blood lipids/lipoproteins and cognitive function in the Chinese oldest-old. DESIGN: multivariate statistical analysis using cross-sectional data. SETTING: community-based setting in longevity areas in China. SUBJECTS: eight hundred and thirty-six subjects aged 80 and older were included in the sample. METHODS: plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure and fasting plasma glucose were measured and information about demographics and lifestyle was collected. Cognitive status was assessed using the Mini-Mental State Examination (MMSE). RESULTS: cumulative logit model analysis showed that triglyceride was significantly negatively associated with cognitive impairment. By general linear modelling, there was a significant linear trend of MMSE scores with the level of triglyceride, but not with levels of cholesterol after adjustment. The odds ratio (OR) of cognitive impairment (MMSE score < 18) was significantly reduced for the highest quartile of plasma triglyceride concentration (OR: 0.52, 95% CI: 0.33-0.84), but not for the second or third quartile, compared with the lowest quartile (adjusted models). There were no significant associations between cognitive impairment and cholesterol. CONCLUSION: we concluded that high normal plasma triglyceride was associated with preservation of cognitive function while lower concentrations were not in the Chinese oldest-old. PMID- 22447911 TI - Primary aldosteronism takes (KCNJ)five! PMID- 22447913 TI - Trainers' perceptions of the direct observation of practical skills assessment in histopathology training: a qualitative pilot study. AB - AIMS: This pilot study of the direct observation of practical skills (DOPS) assessment of histopathology trainees is needed in the absence of existing information on histopathology in the UK. The aim of the study was to explore the experiences and perceptions of trainers in using the DOPS tool with histopathology trainees. METHODS: A qualitative approach was taken using paper based questionnaires to consultants in a single teaching hospital histopathology department. RESULTS: DOPS was perceived by all trainers as a valid form of assessment. There was a spread of opinion regarding its feasibility, with some respondents raising concern about its impact on time. 28% of respondents were doubtful about the formative nature of DOPS. All stated the assessment was fair. CONCLUSIONS: Themes that have emerged include concerns about impact on trainer time, whether DOPS is used in a formative manner and concerns about the amount of guidance provided to trainers. Further research is required to expand on these points. PMID- 22447914 TI - Utility of multispectral imaging in automated quantitative scoring of immunohistochemistry. AB - BACKGROUND: Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining. METHODS: Immunohistochemistry for the membranous marker alpha catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin embedded tissue comprising 471 (alpha-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. RESULTS: Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted. CONCLUSION: Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry. PMID- 22447915 TI - Observer agreement comparing the use of virtual slides with glass slides in the pathology review component of the POSH breast cancer cohort study. AB - AIMS: (1) To compare the use of scanned virtual slide images (virtual microscopy) with glass slides (conventional microscopy) in the assessment of morphological characteristics of breast cancers within the setting of the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH), involving a cohort of women under 40 years of age, presenting with breast cancer. (2) To assess the acceptability to histopathologists of the use of virtual slide images. METHODS: 13 histopathologists from the UK and Australia participated in the POSH pathology review. The observers were asked to assess multiple morphological features such as tumour grade and type. Comparisons were made for a single observer using both virtual images and glass slides. Intra- and inter-observer variability was calculated using the kappa statistic and a comparison was made between the use of each image modality. RESULTS: Diagnostic performance with virtual slides was comparable to conventional microscopic assessment, with the measurement of agreement best for vascular invasion, necrosis and the presence of a central scar (kappa=0.37-0.78), and poor for more subjective parameters such as pleomorphism, stroma, the nature of the tumour border and the degree of lymphocytic infiltrate (kappa=0.1). CONCLUSION: Virtual slides represent an acceptable methodology for central review of breast cancer histopathology and can circumvent the need for either travel to view material, or the potential problems of sending it by post. PMID- 22447916 TI - Ectopic prostatic tissue in the uterine cervix. Report of a case and brief overview of basaloid cervical glandular lesions. PMID- 22447917 TI - Prognostic value of nuclear factor kappa B expression in patients with advanced cervical cancer undergoing radiation therapy followed by hysterectomy. AB - AIMS: The nuclear factor kappa B (NF-kappaB) family comprises transcription factors that promote the development and progression of cancer. The NF-kappaB pathway is induced by radiation therapy and may be related to tumour radioresistance. The aim of this study was to evaluate the expression of NF kappaB as a predictor of the response to radiotherapy and its value as a prognostic marker. METHODS: A retrospective analysis was performed in a series of 32 individuals with stage IB2 and IIB cervical cancer who underwent radiotherapy, followed by radical hysterectomy, from January 1992 to June 2001. NF-kappaB-p65 and NF-kappaB-p50 expression was examined by immunohistochemistry in biopsies from all patients before radiotherapy and in 12 patients with residual tumours after radiotherapy. RESULTS: 16 (50%) patients had residual disease after radical hysterectomy. The median follow-up time was 73.5 months, and the 5-year overall survival was 66.5%. Before radiotherapy, cytoplasmic expression of NF-kappaB-p65 and NF-kappaB-p50 was noted in 91% and 97% of cases, respectively, versus 59% of cases with nuclear expression of these subunits. Cytoplasmic expression of NF kappaB-p65 and NF-kappaB-p50 in the residual tumours after radiotherapy was observed in 50% of cases; 75% of cases with residual tumours had nuclear expression of NF-kappaB-p50 versus none with NF-kappaB-p65. NF-kappaB-p65 and NF kappaB-p50 did not correlate with the risk of residual tumours after radiotherapy or recurrence or death. CONCLUSIONS: These data suggest that NF-kappaB does not predict the response to radiotherapy and does not correlate with poor outcomes in advanced cervical cancer. PMID- 22447918 TI - Human homologue for Caenorhabditis elegans CUL-4 protein overexpression is associated with malignant potential of epithelial ovarian tumours and poor outcome in carcinoma. AB - BACKGROUND: CUL-4 plays a critical role in DNA replication in Caenorhabditis elegans, and interacts with p53 and p21 proteins in cell cycle regulation and response to genomic instability. However, the role of CUL-4 in human carcinomas is widely unknown. AIMS: To investigate the expression of CUL-4 protein and its association with p53 and p21, and to determine its prognostic relevance in invasive ovarian carcinoma. METHODS: CUL-4, p53 and p21 protein expression was determined retrospectively by immunohistochemistry in 140 specimens of human epithelial ovarian tumours (98 invasive carcinomas and 42 tumours of low malignant potential; LMP). RESULTS: Overexpression of CUL-4 was observed in 41 (41.8%) of carcinoma samples and in 10 (23.8%) LMP tumours. CUL-4 was significantly more often overexpressed in invasive carcinomas compared with LMP tumours (p=0.042, chi(2) test, OR 2.302, 95% CI 1.018 to 5.203). In invasive carcinoma, CUL-4 overexpression was found to be a prognostic factor for overall (p=0.017, Cox regression, HR 2.387, 95% CI 1.17 to 4.869) and disease-free survival (p=0.005, Cox regression, HR 3.5, 95% CI 1.465 to 8.365), respectively. In subgroup analysis, CUL-4 was only of prognostic relevance in carcinomas without p53 expression. CONCLUSION: These data indicate for the first time that CUL-4 might play a relevant role in the development and progression of ovarian carcinoma, warranting further investigations. Degradation of wild-type p53 might be a key mechanism to explain why CUL-4 leads to more aggressive clinical behaviour. Not only CUL-4 itself, but also its associated proteins might represent targets for novel, selective therapeutic strategies. PMID- 22447919 TI - Vacuolation in hepatocyte nuclei is a marker of senescence. AB - Hepatocyte nuclear vacuolation is considered benign and associated with non alcohol-related fatty liver disease. Vacuolated hepatocyte nuclei were compared with non-vacuolated hepatocyte nuclei in eight patients with advanced fibrosis and a spectrum of liver disease to explore the hypothesis that such nuclei represent senescence. Age- and sex-matched liver donors served as normal tissue. In normal liver <0.01% hepatocytes showed nuclear vacuolation. In contrast, nuclear vacuolation was present in all patients with liver disease, ranging from 0.1% to 11.7% hepatocytes, irrespective of the aetiology of liver disease and independent of insulin resistance. There was a close association between nuclear vacuolation and increased nuclear area, p21 expression, gamma H(2)AX expression and the absence of Mcm-2, consistent with senescence and cell cycle arrest. Nuclear vacuolation in hepatocytes is a marker of senescence and likely to be a consequence of liver injury, unrelated to insulin resistance. PMID- 22447920 TI - The prognostic value of Ki-67 expression in penile squamous cell carcinoma. AB - AIMS: To determine whether Ki-67 immunoexpression in penile squamous cell carcinoma (PSCC) has a prognostic value and correlates with lymph node metastasis, human papillomavirus (HPV) infection and patient survival. METHODS: 148 formalin-fixed paraffin-embedded PSCC samples were tissue-microarrayed, including 97 usual-type SCCs, 17 basaloid, 15 pure verrucous carcinomas, 2 warty and 17 mixed-type tumours. All samples were immunostained for Ki-67 protein. HPV DNA was detected with INNO-LiPA assay. Follow-up data were available for 134 patients. RESULTS: Ki-67 was strongly expressed in 57/148 (38.5%) of PSCCs. Different cancer subtypes showed significant difference in Ki-67 expression (p<0.0001) with highest positivity in basaloid, 16/17 (94%), followed by usual type, 38/97 (39%) and lack of Ki-67 positive cases within verrucous tumours, 0/15. Ki-67 positively correlated with high-risk HPV (p<0.0001) and showed good specificity (84%) but low sensitivity (61%) for high-risk HPV detection. Ki-67 protein strongly positively correlated with tumour grade (p<0.0001) but not with stage (p=0.2193), or lymph node status (p=0.7366). Ki-67 showed no prognostic value for cancer-specific survival (HR=1.00, 95%, CI 0.99 to 1.02, p=0.54) or overall survival (HR=1.00, 95%, CI 0.99 to 1.02, p=0.45). High tumour stage, lymph node metastasis, high tumour grade and age at diagnosis were all independent prognostic factors for cancer-specific survival and overall survival. CONCLUSIONS: Ki-67 is only a moderate surrogate marker for HPV infection in PSCC. It does not show prognostic value for cancer-specific survival and overall survival in PSCC. PMID- 22447921 TI - Infantile haemangioma expresses embryonic stem cell markers. AB - BACKGROUND: The origin of infantile haemangioma (IH) remains enigmatic. A primitive mesodermal phenotype origin of IH with the ability to differentiate down erythropoietic and terminal mesenchymal lineages has recently been demonstrated. AIMS: To investigate the expression of human embryonic stem cell (hESC) markers in IH and to determine whether IH-derived cells have the functional capacity to form teratoma in vivo. METHODS: Immunohistochemical staining and quantitative reverse transcription PCR were used to investigate the expression of hESC markers in IH biopsies. The ability of cells derived from proliferating IH to form teratomas in a mouse xenograft model was investigated. RESULTS: The hESC markers, Oct-4, STAT-3 and stage-specific embryonic antigen 4 were collectively expressed on the endothelium of proliferating IH lesions, whereas Nanog was not. Nanog was expressed by cells in the interstitium and these cells did not express Oct-4, stage-specific embryonic antigen 4 or STAT-3. Proliferating IH-derived cells were unable to form teratomas in severely compromised immunodeficient/non-obese diabetic mice. CONCLUSION: The novel expression of hESC on two different populations of cells in proliferating IH and their inability to form teratomas in vivo infer the presence of a primitive cellular origin for IH downstream from hESC. PMID- 22447922 TI - Comparison of the RNA-based EndoPredict multigene test between core biopsies and corresponding surgical breast cancer sections. AB - AIM: This study compared the perfomance of the RNA-based EndoPredict multigene test on core biopsies and surgical breast cancer specimens and analysed the influence of biopsy-induced tissue injuries on the test result. METHODS: 80 formalin-fixed paraffin-embedded samples comprising paired biopsies and surgical specimens from 40 ER-positive, HER2-negative patients were evaluated. Total RNA was extracted and the EndoPredict score was determined. RESULTS: RNA yield was considerably lower in core biopsies, but sufficient to measure the assay in all samples. The EndoPredict score was highly correlated between paired samples (Pearson r=0.92), with an excellent concordance of classification into a low or high risk of metastasis (overall agreement 95%). CONCLUSIONS: The measurements are comparable between core biopsies and surgical sections, which suggest that the EndoPredict assay can be performed on core biopsy tissue. Inflammatory changes induced by presurgical biopsies had no significant effect on the RNA based risk assessment in surgical specimens. PMID- 22447923 TI - Secretory pathway-dependent localization of the Saccharomyces cerevisiae Rho GTPase-activating protein Rgd1p at growth sites. AB - Establishment and maintenance of cell polarity in eukaryotes depends upon the regulation of Rho GTPases. In Saccharomyces cerevisiae, the Rho GTPase activating protein (RhoGAP) Rgd1p stimulates the GTPase activities of Rho3p and Rho4p, which are involved in bud growth and cytokinesis, respectively. Consistent with the distribution of Rho3p and Rho4p, Rgd1p is found mostly in areas of polarized growth during cell cycle progression. Rgd1p was mislocalized in mutants specifically altered for Golgi apparatus-based phosphatidylinositol 4-P [PtdIns(4)P] synthesis and for PtdIns(4,5)P(2) production at the plasma membrane. Analysis of Rgd1p distribution in different membrane-trafficking mutants suggested that Rgd1p was delivered to growth sites via the secretory pathway. Rgd1p may associate with post-Golgi vesicles by binding to PtdIns(4)P and then be transported by secretory vesicles to the plasma membrane. In agreement, we show that Rgd1p coimmunoprecipitated and localized with markers specific to secretory vesicles and cofractionated with a plasma membrane marker. Moreover, in vivo imaging revealed that Rgd1p was transported in an anterograde manner from the mother cell to the daughter cell in a vectoral manner. Our data indicate that secretory vesicles are involved in the delivery of RhoGAP Rgd1p to the bud tip and bud neck. PMID- 22447924 TI - Hypoxia and fungal pathogenesis: to air or not to air? AB - Over the last 3 decades, the frequency of life-threatening human fungal infections has increased as advances in medical therapies, solid-organ and hematopoietic stem cell transplantations, an increasing geriatric population, and HIV infections have resulted in significant rises in susceptible patient populations. Although significant advances have been made in understanding how fungi cause disease, the dynamic microenvironments encountered by fungi during infection and the mechanisms by which they adapt to these microenvironments are not fully understood. As inhibiting and preventing in vivo fungal growth are main goals of antifungal therapies, understanding in vivo fungal metabolism in these host microenvironments is critical for the improvement of existing therapies or the design of new approaches. In this minireview, we focus on the emerging appreciation that pathogenic fungi like Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are exposed to oxygen-limited or hypoxic microenvironments during fungal pathogenesis. The implications of these in vivo hypoxic microenvironments for fungal metabolism and pathogenesis are discussed with an aim toward understanding the potential impact of hypoxia on invasive fungal infection outcomes. PMID- 22447925 TI - CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant. AB - Regardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering C-C chemokine receptor type 5 (CCR5) antagonists as attractive agents not only for antiretroviral therapy but also for prevention. Here, we report the specificity, potency, and underlying mechanism of action of a novel small molecule CCR5 antagonist, TD-0680. TD-0680 displayed the greatest potency against a diverse group of R5-tropic HIV-1 and SIV strains when compared with its prodrug, TD-0232, the Food and Drug Administration-approved CCR5 antagonist Maraviroc, and TAK-779, with EC(50) values in the subnanomolar range (0.09-2.29 nm). Importantly, TD-0680 was equally potent at blocking envelope mediated cell-cell fusion and cell-mediated viral transmission as well as the replication of a TAK-779/Maraviroc-resistant HIV-1 variant. Interestingly, TD 0232 and TD-0680 functioned differently despite binding to a similar transmembrane pocket of CCR5. Site-directed mutagenesis, drug combination, and antibody blocking assays identified a novel mechanism of action of TD-0680. In addition to binding to the transmembrane pocket, the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 (ECL2) region of CCR5, thereby interrupting the interaction between virus and its co-receptor more effectively. This mechanism of action was supported by the observations of similar TD-0680 potency against CD4-dependent and -independent SIV strains and by molecular docking analysis using a CCR5 model. TD-0680, therefore, merits development as an anti-HIV-1 agent for therapeutic purposes and/or as a topical microbicide for the prevention of sexual transmission of R5 tropic HIV-1. PMID- 22447926 TI - Cyclic AMP-induced conformational changes in mycobacterial protein acetyltransferases. AB - The activities of a number of proteins are regulated by the binding of cAMP and cGMP to cyclic nucleotide binding (CNB) domains that are found associated with one or more effector domains with diverse functions. Although the conserved architecture of CNB domains has been extensively studied by x-ray crystallography, the key to unraveling the mechanisms of cAMP action has been protein dynamics analyses. Recently, we have identified a novel cAMP-binding protein from mycobacteria, where cAMP regulates the activity of an associated protein acetyltransferase domain. In the current study, we have monitored the conformational changes that occur upon cAMP binding to the CNB domain in these proteins, using a combination of bioluminescence resonance energy transfer and amide hydrogen/deuterium exchange mass spectrometry. Coupled with mutational analyses, our studies reveal the critical role of the linker region (positioned between the CNB domain and the acetyltransferase domain) in allosteric coupling of cAMP binding to activation of acetyltransferase catalysis. Importantly, major differences in conformational change upon cAMP binding were accompanied by stabilization of the CNB and linker domain alone. This is in contrast to other cAMP-binding proteins, where cyclic nucleotide binding has been shown to involve intricate and parallel allosteric relays. Finally, this powerful convergence of results from bioluminescence resonance energy transfer and hydrogen/deuterium exchange mass spectrometry reaffirms the power of solution biophysical tools in unraveling mechanistic bases of regulation of proteins in the absence of high resolution structural information. PMID- 22447927 TI - Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. AB - ICA69 (islet cell autoantigen 69 kDa) is a protein implicated in type 1 diabetes mellitus in both the non-obese diabetic (NOD) mouse model and humans. ICA69 is encoded by the Ica1 gene on mouse chromosome 6 A1-A2. We previously reported reduced ICA69 expression in the thymus of NOD mice compared with thymus of several non-diabetic mouse strains. We propose that reduced thymic ICA69 expression could result from variations in transcriptional regulation of the gene and that polymorphisms within the Ica1 core promoter may partially determine this transcriptional variability. We characterized the functional promoter of Ica1 in NOD mice and compared it with the corresponding portions of Ica1 in non-diabetic C57BL/6 mice. Luciferase reporter constructs demonstrated that the NOD Ica1 promoter region exhibited markedly reduced luciferase expression in transiently transfected medullary thymus epithelial (mTEC(+)) and B-cell (M12)-derived cell lines. However, in a non-diabetic strain, C57BL/6, the Ica1 promoter region was transcriptionally active when transiently transfected into the same cell lines. We concomitantly identified five single nucleotide polymorphisms within the NOD Ica1 promoter. One of these single nucleotide polymorphisms increases the binding affinity for the transcription factor AIRE (autoimmune regulator), which is highly expressed in thymic epithelial cells, where it is known to play a key role regulating self-antigen expression. We conclude that polymorphisms within the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in medullary thymic epithelial cells, thus providing a novel mechanistic explanation for the loss of immunologic tolerance to this self antigen in autoimmunity. PMID- 22447928 TI - TRAF6 protein couples Toll-like receptor 4 signaling to Src family kinase activation and opening of paracellular pathway in human lung microvascular endothelia. AB - Gram-negative bacteria release lipopolysaccharide (LPS) into the bloodstream. Here, it engages Toll-like receptor (TLR) 4 expressed in human lung microvascular endothelia (HMVEC-Ls) to open the paracellular pathway through Src family kinase (SFK) activation. The signaling molecules that couple TLR4 to the SFK-driven barrier disruption are unknown. In HMVEC-Ls, siRNA-induced silencing of TIRAP/Mal and overexpression of dominant-negative TIRAP/Mal each blocked LPS-induced SFK activation and increases in transendothelial [(14)C]albumin flux, implicating the MyD88-dependent pathway. LPS increased TRAF6 autoubiquitination and binding to IRAK1. Silencing of TRAF6, TRAF6-dominant-negative overexpression, or preincubation of HMVEC-Ls with a cell-permeable TRAF6 decoy peptide decreased both LPS-induced SFK activation and barrier disruption. LPS increased binding of both c-Src and Fyn to GST-TRAF6 but not to a GST-TRAF6 mutant in which the three prolines in the putative Src homology 3 domain-binding motif (amino acids 461 469) were substituted with alanines. A cell-permeable decoy peptide corresponding to the same proline-rich motif reduced SFK binding to WT GST-TRAF6 compared with the Pro -> Ala-substituted peptide. Finally, LPS increased binding of activated Tyr(P)(416)-SFK to GST-TRAF6, and preincubation of HMVEC-Ls with SFK-selective tyrosine kinase inhibitors, PP2 and SU6656, diminished TRAF6 binding to c-Src and Fyn. During the TRAF6-SFK association, TRAF6 catalyzed Lys(63)-linked ubiquitination of c-Src and Fyn, whereas SFK activation increased tyrosine phosphorylation of TRAF6. The TRAF6 decoy peptide blocked both LPS-induced SFK ubiquitination and TRAF6 phosphorylation. Together, these data indicate that the proline-rich Src homology 3 domain-binding motif in TRAF6 interacts directly with activated SFKs to couple LPS engagement of TLR4 to SFK activation and loss of barrier integrity in HMVEC-Ls. PMID- 22447929 TI - Ail protein binds ninth type III fibronectin repeat (9FNIII) within central 120 kDa region of fibronectin to facilitate cell binding by Yersinia pestis. AB - The Yersinia pestis adhesin molecule Ail interacts with the extracellular matrix protein fibronectin (Fn) on host cells to facilitate efficient delivery of cytotoxic Yop proteins, a process essential for plague virulence. A number of bacterial pathogens are known to bind to the N-terminal region of Fn, comprising type I Fn (FNI) repeats. Using proteolytically generated Fn fragments and purified recombinant Fn fragments, we demonstrated that Ail binds the centrally located 120-kDa fragment containing type III Fn (FNIII) repeats. A panel of monoclonal antibodies (mAbs) that recognize specific epitopes within the 120-kDa fragment demonstrated that mAb binding to (9)FNIII blocks Ail-mediated bacterial binding to Fn. Epitopes of three mAbs that blocked Ail binding to Fn were mapped to a similar face of (9)FNIII. Antibodies directed against (9)FNIII also inhibited Ail-dependent cell binding activity, thus demonstrating the biological relevance of this Ail binding region on Fn. Bacteria expressing Ail on their surface could also bind a minimal fragment of Fn containing repeats (9-10)FNIII, and this binding was blocked by a mAb specific for (9)FNIII. These data demonstrate that Ail binds to (9)FNIII of Fn and presents Fn to host cells to facilitate cell binding and delivery of Yops (cytotoxins of Y. pestis), a novel interaction, distinct from other bacterial Fn-binding proteins. PMID- 22447930 TI - Activated protein C inhibits pancreatic islet inflammation, stimulates T regulatory cells, and prevents diabetes in non-obese diabetic (NOD) mice. AB - Activated protein C (aPC) is a natural anticoagulant with strong cyto-protective and anti-inflammatory properties. aPC inhibits pancreatic inflammation and preserves functional islets after intraportal transplantation in mice. Whether aPC prevents the onset or development of type 1 diabetes (T1D) is unknown. In this study, when human recombinant aPC was delivered intraperitoneally, twice weekly for 10 weeks (from week 6 to 15) to non-obese diabetic (NOD) mice, a model for T1D, the incidence of diabetes was reduced from 70% (saline control) to 7.6% by 26 weeks of age. Islets of aPC-treated mice exhibited markedly increased expression of insulin, aPC/protein C, endothelial protein C receptor, and matrix metalloproteinase (MMP)-2 when examined by immunostaining. The insulitis score in aPC-treated mice was 50% less than that in control mice. T regulatory cells (Tregs) in the spleen, pancreatic islets, and pancreatic lymph nodes were increased 37, 53, and 59%, respectively, in NOD mice following aPC treatment. These Tregs had potent suppressor function and, after adoptive transfer, delayed diabetes onset in NOD.severe combined immunodeficiency mice. The culture of NOD mouse spleen cells with aPC reduced the secretion of inflammatory cytokines interleukin (IL)-1beta and interferon-gamma but increased IL-2 and transforming growth factor-beta1, two cytokines required for Treg differentiation. In summary, our results indicate that aPC prevents T1D in the NOD mouse. The aPC mechanism of action is complex, involving induction of Treg differentiation, inhibition of inflammation, and possibly direct cyto-protective effects on beta cells. PMID- 22447931 TI - Megakaryocytes regulate expression of Pyk2 isoforms and caspase-mediated cleavage of actin in osteoblasts. AB - The proliferation and differentiation of osteoblast (OB) precursors are essential for elaborating the bone-forming activity of mature OBs. However, the mechanisms regulating OB proliferation and function are largely unknown. We reported that OB proliferation is enhanced by megakaryocytes (MKs) via a process that is regulated in part by integrin signaling. The tyrosine kinase Pyk2 has been shown to regulate cell proliferation and survival in a variety of cells. Pyk2 is also activated by integrin signaling and regulates actin remodeling in bone-resorbing osteoclasts. In this study, we examined the role of Pyk2 and actin in the MK mediated increase in OB proliferation. Calvarial OBs were cultured in the presence of MKs for various times, and Pyk2 signaling cascades in OBs were examined by Western blotting, subcellular fractionation, and microscopy. We found that MKs regulate the temporal expression of Pyk2 and its subcellular localization. We also found that MKs regulate the expression of two alternatively spliced isoforms of Pyk2 in OBs, which may regulate OB differentiation and proliferation. MKs also induced cytoskeletal reorganization in OBs, which was associated with the caspase-mediated cleavage of actin, an increase in focal adhesions, and the formation of apical membrane ruffles. Moreover, BrdU incorporation in MK-stimulated OBs was blocked by the actin-polymerizing agent, jasplakinolide. Collectively, our studies reveal that Pyk2 and actin play an important role in MK-regulated signaling cascades that control OB proliferation and may be important for therapeutic interventions aimed at increasing bone formation in metabolic diseases of the skeleton. PMID- 22447932 TI - Cellular prion protein regulates its own alpha-cleavage through ADAM8 in skeletal muscle. AB - The ubiquitously expressed cellular prion protein (PrP(C)) is subjected to the physiological alpha-cleavage at a region critical for both PrP toxicity and the conversion of PrP(C) to its pathogenic prion form (PrP(Sc)), generating the C1 and N1 fragments. The C1 fragment can activate caspase 3 while the N1 fragment is neuroprotective. Recent articles indicate that ADAM10, ADAM17, and ADAM9 may not play a prominent role in the alpha-cleavage of PrP(C) as previously thought, raising questions on the identity of the responsible protease(s). Here we show that, ADAM8 can directly cleave PrP to generate C1 in vitro and PrP C1/full length ratio is greatly decreased in the skeletal muscles of ADAM8 knock-out mice; in addition, the PrP C1/full-length ratio is linearly correlated with ADAM8 protein level in myoblast cell line C2C12 and in skeletal muscle tissues of transgenic mice. These results indicate that ADAM8 is the primary protease responsible for the alpha-cleavage of PrP(C) in muscle cells. Moreover, we found that overexpression of PrP(C) led to up-regulation of ADAM8, suggesting that PrP(C) may regulate its own alpha-cleavage through modulating ADAM8 activity. PMID- 22447933 TI - Cell surface trafficking of TLR1 is differentially regulated by the chaperones PRAT4A and PRAT4B. AB - The subcellular localization of Toll-like receptors (TLRs) is critical to their ability to function as innate immune sensors of microbial infection. We previously reported that an I602S polymorphism of human TLR1 is associated with aberrant trafficking of the receptor to the cell surface, loss of responses to TLR1 agonists, and differential susceptibility to diseases caused by pathogenic mycobacteria. Through an extensive analysis of receptor deletion and point mutants we have discovered that position 602 resides within a short 6 amino acid cytoplasmic region that is required for TLR1 surface expression. This short trafficking motif, in conjunction with the adjacent transmembrane domain, is sufficient to direct TLR1 to the cell surface. A serine at position 602 interrupts this trafficking motif and prevents cell surface expression of TLR1. Additionally, we have found that ER-resident TLR chaperones, PRAT4A and PRAT4B, act as positive and negative regulators of TLR1 surface trafficking, respectively. Importantly, either over-expression of PRAT4A or knock-down of PRAT4B rescues cell surface expression of the TLR1 602S variant. We also report that IFN-gamma treatment of primary human monocytes derived from homozygous 602S individuals rescues TLR1 cell surface trafficking and cellular responses to soluble agonists. This event appears to be mediated by PRAT4A whose expression is strongly induced in human monocytes by IFN-gamma. Collectively, these results provide a mechanism for the differential trafficking of TLR1 I602S variants, and highlight the distinct roles for PRAT4A and PRAT4B in the regulation of TLR1 surface expression. PMID- 22447934 TI - Action of multiple endoplasmic reticulum chaperon-like proteins is required for proper folding and polarized localization of Kre6 protein essential in yeast cell wall beta-1,6-glucan synthesis. AB - Saccharomyces cerevisiae Kre6 is a type II membrane protein essential for cell wall beta-1,6-glucan synthesis. Recently we reported that the majority of Kre6 is in the endoplasmic reticulum (ER), but a significant portion of Kre6 is found in the plasma membrane of buds, and this polarized appearance of Kre6 is required for beta-1,6-glucan synthesis. An essential membrane protein, Keg1, and ER chaperon Rot1 bind to Kre6. In this study we found that in mutant keg1-1 cells, accumulation of Kre6 at the buds is diminished, binding of Kre6 to Keg1 is decreased, and Kre6 becomes susceptible to ER-associated degradation (ERAD), which suggests Keg1 participates in folding and transport of Kre6. All mutants of the calnexin cycle member homologues (cwh41, rot2, kre5, and cne1) showed defects in beta-1,6-glucan synthesis, although the calnexin chaperon system is considered not functional in yeast. We found synthetic defects between them and keg1-1, and Cne1 co-immunoprecipitated with Keg1 and Kre6. A stronger binding of Cne1 to Kre6 was detected when two glucosidases (Cwh41 and Rot2) that remove glucose on N glycan were functional. Skn1, a Kre6 homologue, was not detected by immunofluorescence in the wild type yeast, but in kre6Delta cells it became detectable and behaved like Kre6. In conclusion, the action of multiple ER chaperon-like proteins is required for proper folding and localization of Kre6 and probably Skn1 to function in beta-1,6-glucan synthesis. PMID- 22447935 TI - Phosphatidylinositol 4,5-bisphosphate increases Ca2+ affinity of synaptotagmin-1 by 40-fold. AB - Synaptotagmin-1 is the main Ca(2+) sensor of neuronal exocytosis. It binds to both Ca(2+) and the anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP(2)), but the precise cooperativity of this binding is still poorly understood. Here, we used microscale thermophoresis to quantify the cooperative binding of PIP(2) and Ca(2+) to synaptotagmin-1. We found that PIP(2) bound to the well conserved polybasic patch of the C2B domain with an apparent dissociation constant of ~20 MUM. PIP(2) binding reduced the apparent dissociation constant for Ca(2+) from ~250 to <5 MUM. Thus, our data show that PIP(2) makes synaptotagmin-1 >40-fold more sensitive to Ca(2+). This interplay between Ca(2+), synaptotagmin-1, and PIP(2) is crucial for neurotransmitter release. PMID- 22447936 TI - The C-terminal kinase and ERK-binding domains of Drosophila S6KII (RSK) are required for phosphorylation of the protein and modulation of circadian behavior. AB - A detailed structure/function analysis of Drosophila p90 ribosomal S6 kinase (S6KII) or its mammalian homolog RSK has not been performed in the context of neuronal plasticity or behavior. We previously reported that S6KII is required for normal circadian periodicity. Here we report a site-directed mutagenesis of S6KII and analysis of mutants, in vivo, that identifies functional domains and phosphorylation sites critical for the regulation of circadian period. We demonstrate, for the first time, a role for the S6KII C-terminal kinase that is independent of its known role in activation of the N-terminal kinase. Both S6KII C-terminal kinase activity and its ERK-binding domain are required for wild-type circadian period and normal phosphorylation status of the protein. In contrast, the N-terminal kinase of S6KII is dispensable for modulation of circadian period and normal phosphorylation of the protein. We also show that particular sites of S6KII phosphorylation, Ser-515 and Thr-732, are essential for normal circadian behavior. Surprisingly, the phosphorylation of S6KII residues, in vivo, does not follow a strict sequential pattern, as implied by certain cell-based studies of mammalian RSK protein. PMID- 22447937 TI - Ksp1 kinase regulates autophagy via the target of rapamycin complex 1 (TORC1) pathway. AB - Macroautophagy (hereafter autophagy) is a bulk degradation system conserved in all eukaryotes, which engulfs cytoplasmic components within double-membrane vesicles to allow their delivery to, and subsequent degradation within, the vacuole/lysosome. Autophagy activity is tightly regulated in response to the nutritional state of the cell and also to maintain organelle homeostasis. In nutrient-rich conditions, Tor kinase complex 1 (TORC1) is activated to inhibit autophagy, whereas inactivation of this complex in response to stress leads to autophagy induction; however, it is unclear how the activity of TORC1 is controlled to allow precise adjustments in autophagy activity. In this study, we performed genetic analyses in Saccharomyces cerevisiae to identify factors that regulate TORC1 activity. We determined that the Ksp1 kinase functions in part as a negative regulator of autophagy; deletion of KSP1 facilitated dephosphorylation of Atg13, a TORC1 substrate, which correlates with enhanced autophagy. These results suggest that Ksp1 down-regulates autophagy activity via the TORC1 pathway. The suppressive function of Ksp1 is partially activated by the Ras/cAMP dependent protein kinase A (PKA), which is another negative regulator of autophagy. Our study therefore identifies Ksp1 as a new component that functions as part of the PKA and TORC1 signaling network to control the magnitude of autophagy. PMID- 22447938 TI - Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat. AB - Angiotensin II contributes to myocardial tissue remodeling and interstitial fibrosis through NADPH oxidase-mediated generation of oxidative stress in the progression of heart failure. Recent data have suggested that nebivolol, a third generation beta-blocker, improves diastolic dysfunction by targeting nitric oxide (NO) and metabolic pathways that decrease interstitial fibrosis. We sought to determine if targeting NO would improve diastolic function in a model of tissue renin-angiotensin system overactivation. We used the transgenic (TG) (mRen2)27 rat, which overexpresses the murine renin transgene and manifests insulin resistance and left ventricular dysfunction. We treated 6- to 7-wk-old TG (mRen2)27 rats and age-matched Sprague-Dawley control rats with nebivolol (10 mg.kg(-1).day(-1)) or placebo via osmotic minipumps for a period of 21 days. Compared with Sprague-Dawley control rats, TG (mRen2)27 rats displayed a prolonged diastolic relaxation time and reduced initial filling rate associated with increased interstitial fibrosis and left ventricular hypertrophy. These findings were temporally related to increased NADPH oxidase activity and subunits p47(phox) and Rac1 and increased total ROS and peroxynitrite formation in parallel with reductions in the antioxidant heme oxygenase as well as the phosphorylation/activation of endothelial NO synthase and PKB/Akt. Treatment with nebivolol restored diastolic function and interstitial fibrosis through increases in the phosphorylation of 5'-AMP-activated protein kinase, Akt, and endothelial NO synthase and reductions in oxidant stress. These results support that targeting NO with nebivolol treatment improves diastolic dysfunction through reducing myocardial oxidative stress by enhancing 5'-AMP-activated protein kinase and Akt activation of NO biosynthesis. PMID- 22447939 TI - Regional increase in extracellular potassium can be arrhythmogenic due to nonuniform muscle contraction in rat ventricular muscle. AB - In the ischemic myocardium, extracellular potassium ([K(+)](o)) increases to >=20 mmol/l. To determine how lethal arrhythmias occur during ischemia, we investigated whether the increased spatial pattern of [K(+)](o), i.e., a regional or a global increase, affects the incidence of arrhythmias. Force, sarcomere length, membrane potential, and nonuniform intracellular Ca(2+) ([Ca(2+)](i)) were measured in rat ventricular trabeculae. A "regional" or "global" increase in [K(+)](o) was produced by exposing a restricted region of muscle to a jet of 30 mmol/l KCl or by superfusing trabeculae with a solution containing 30 mmol/l KCl, respectively. The increase in [Ca(2+)](i) (Ca(CW)) during Ca(2+) waves was measured (24 degrees C, 3.0 mmol/l [Ca(2+)](o)). A regional increase in [K(+)](o) caused nonuniform [Ca(2+)](i) and contraction. In the presence of isoproterenol, the regional increase in [K(+)](o) induced sustained arrhythmias in 10 of 14 trabeculae, whereas the global increase did not induce such arrhythmias. During sustained arrhythmias, Ca(2+) surged within the jet-exposed region. In the absence of isoproterenol, the regional increase in [K(+)](o) increased Ca(CW), whereas the global increase decreased it. This increase in Ca(CW) with the regional increase in [K(+)](o) was not suppressed by 100 MUmol/l streptomycin, whereas it was suppressed by 1) a combination of 10 MUmol/l cilnidipine and 3 MUmol/l SEA0400; 2) 20 mmol/l 2,3-butanedione monoxime; and 3) 10 MUmol/l blebbistatin. A regional but not a global increase in [K(+)](o) induces sustained arrhythmias, probably due to nonuniform excitation-contraction coupling. The same mechanism may underlie arrhythmias during ischemia. PMID- 22447940 TI - Roles of sarcoplasmic reticulum Ca2+ cycling and Na+/Ca2+ exchanger in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models. AB - To elucidate the roles of sarcoplasmic reticulum (SR) Ca(2+) cycling and Na(+)/Ca(2+) exchanger (NCX) in sinoatrial node (SAN) pacemaking, we have applied stability and bifurcation analyses to a coupled-clock system model developed by Maltsev and Lakatta (Am J Physiol Heart Circ Physiol 296: H594-H615, 2009). Equilibrium point (EP) at which the system is stationary (i.e., the oscillatory system fails to function), periodic orbit (limit cycle), and their stability were determined as functions of model parameters. The stability analysis to detect bifurcation points confirmed crucial importance of SR Ca(2+) pumping rate constant (P(up)), NCX density (k(NCX)), and L-type Ca(2+) channel conductance for the system function reported in previous parameter-dependent numerical simulations. We showed, however, that the model cell does not exhibit self sustained automaticity of SR Ca(2+) release at any clamped voltage and therefore needs further tuning to reproduce oscillatory local Ca(2+) release and net membrane current reported experimentally at -10 mV. Our further extended bifurcation analyses revealed important novel features of the pacemaker system that go beyond prior numerical simulations in relation to the roles of SR Ca(2+) cycling and NCX in SAN pacemaking. Specifically, we found that 1) NCX contributes to EP instability and enhancement of robustness in the full system during normal spontaneous action potential firings, while stabilizing EPs to prevent sustained Ca(2+) oscillations under voltage clamping; 2) SR requires relatively large k(NCX) and subsarcolemmal Ca(2+) diffusion barrier (i.e., subspace) to contribute to EP destabilization and enhancement of robustness; and 3) decrementing P(up) or k(NCX) decreased the full system robustness against hyperpolarizing loads because EP stabilization and cessation of pacemaking were observed at the lower critical amplitude of hyperpolarizing bias currents, suggesting that SR Ca(2+) cycling contributes to enhancement of the full system robustness by modulating NCX currents and promoting EP destabilization. PMID- 22447941 TI - Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction. AB - We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction. PMID- 22447943 TI - Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training. AB - The impact of cancer therapies on adult cardiac function is becoming a concern as more children survive their initial cancer. Cardiovascular disease is now a significant problem to adult survivors of childhood cancer. Specifically, doxorubicin (DOX) may be particularly harmful in young girls. The objective of this study was to characterize DOX damage and determine the ability of dexrazoxane (DEX) to reduce DOX-mediated cardiac damage in sedentary and swim trained female rats. Female Sprague-Dawley rats were left intact or ovariectomized (OVX) at weaning then injected with DEX (60 mg/kg) before DOX (3 mg/kg), DOX alone, or PBS. Rats were separated into sedentary and swim cohorts. Body weight was reduced in DOX:DEX- but not PBS- or DOX-treated rats. Echocardiographic parameters were similar in sedentary rats. Swim training revealed greater concentric remodeling in DOX-treated rats and reduced fractional shortening in DOX:DEX-treated rats. Calsequestrin 2 was reduced with DOX and increased with DOX:DEX postswim. Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a was reduced and calsequestrin 2 reduced further by swim training only in intact rats. OVX rats were heavier and developed eccentric remodeling post-swim with DOX and eccentric hypertrophy with DOX:DEX. Changes in SERCA2a and calsequestrin 2 expression were not observed. Ovariectomized DOX- and DOX:DEX-treated rats stopped growing during swim training. DEX coinjection did not relieve DOX mediated cardiotoxicity in intact or hormone-deficient rats. DOX-mediated reductions in growth, cardiac function, and expression of calcium homeostasis proteins were exacerbated by swim. DEX coadministration did not substantially relieve DOX-mediated cardiotoxicity in young female rats. Ovarian hormones reduce DOX-induced cardiotoxicity. PMID- 22447944 TI - A novel, minimally invasive, segmental myocardial infarction with a clear healed infarct borderzone in rabbits. AB - Ventricular arrhythmias in the setting of a healed myocardial infarction have been studied to a much lesser degree than acute and subacute infarction, due to the pericardial scarring, which results from the traditional open-chest techniques used for myocardial infarction (MI) induction. We sought to develop a segmental MI with low perioperative mortality in the rabbit that allows optimal visualization and therefore improved study of the infarction borderzone. Rabbits underwent MI using endovascular coil occlusion of the first obtuse marginal artery. Three weeks postprocedure, we evaluated our model by echocardiography and electrophysiology studies, optical mapping of isolated hearts, and histological studies. Seventeen rabbits underwent the protocol (12 MI and 5 sham) with a 92% survival to completion of the study (11 MI and 5 sham). MI rabbits demonstrated wall motion abnormalities on echocardiography while shams did not. At electrophysiological study, two MI rabbits had inducible ventricular tachycardia and one had inducible ventricular fibrillation. Isolated hearts demonstrated no pericardial scarring with a smooth, easily identifiable infarct borderzone. Optical mapping of the borderzone region showed successful mapping of peri infarct reentry formation, with ventricular fibrillation inducible in 11 of 11 MI hearts and 1 of 5 sham hearts. We demonstrate successful high resolution mapping in the borderzone, showing delayed conduction in this region corresponding to late deflections in the QRS on ECG. We report the successful development of a minimally invasive MI via targeted coil delivery to the obtuse marginal artery with an exceptionally high rate of procedural survival and an arrhythmogenic phenotype. This model mimics human post-MI on echocardiography, gross pathology, histology, and electrophysiology. PMID- 22447942 TI - Inositol trisphosphate receptors in smooth muscle cells. AB - Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are a family of tetrameric intracellular calcium (Ca(2+)) release channels that are located on the sarcoplasmic reticulum (SR) membrane of virtually all mammalian cell types, including smooth muscle cells (SMC). Here, we have reviewed literature investigating IP(3)R expression, cellular localization, tissue distribution, activity regulation, communication with ion channels and organelles, generation of Ca(2+) signals, modulation of physiological functions, and alterations in pathologies in SMCs. Three IP(3)R isoforms have been identified, with relative expression and cellular localization of each contributing to signaling differences in diverse SMC types. Several endogenous ligands, kinases, proteins, and other modulators control SMC IP(3)R channel activity. SMC IP(3)Rs communicate with nearby ryanodine-sensitive Ca(2+) channels and mitochondria to influence SR Ca(2+) release and reactive oxygen species generation. IP(3)R-mediated Ca(2+) release can stimulate plasma membrane-localized channels, including transient receptor potential (TRP) channels and store-operated Ca(2+) channels. SMC IP(3)Rs also signal to other proteins via SR Ca(2+) release-independent mechanisms through physical coupling to TRP channels and local communication with large conductance Ca(2+)-activated potassium channels. IP(3)R-mediated Ca(2+) release generates a wide variety of intracellular Ca(2+) signals, which vary with respect to frequency, amplitude, spatial, and temporal properties. IP(3)R signaling controls multiple SMC functions, including contraction, gene expression, migration, and proliferation. IP(3)R expression and cellular signaling are altered in several SMC diseases, notably asthma, atherosclerosis, diabetes, and hypertension. In summary, IP(3)R-mediated pathways control diverse SMC physiological functions, with pathological alterations in IP(3)R signaling contributing to disease. PMID- 22447945 TI - Nitric oxide synthase, ADMA, SDMA, and nitric oxide activity in the paraventricular nucleus throughout the etiology of renal wrap hypertension. AB - Within the paraventricular nucleus (PVN), there is a balance between the excitatory and inhibitory neurotransmitters that regulate blood pressure; in hypertension, the balance shifts to enhanced excitation. Nitric oxide (NO) is an atypical neurotransmitter that elicits inhibitory effects on cardiovascular function. We hypothesized that reduced PVN NO led to elevations in blood pressure during both the onset and sustained phases of hypertension due to decreased NO synthase (NOS) and increased asymmetrical dimethylarginine (ADMA; an endogenous NOS inhibitor) and symmetric dimethylarginine (SDMA). Elevated blood pressure, in response to PVN bilateral microinjections of a NO inhibitor, nitro-L-arginine methyl ester, was blunted in renal wrapped rats during the onset of hypertension (day 7) and sustained renal wrap hypertension (day 28) compared with sham operated rats. Adenoviruses (Ad) encoding endothelial NOS (eNOS) or LacZ microinjected into the PVN [1 * 10(9) plaque-forming units, bilateral (200 nl/site)] reduced mean arterial pressure compared with control (Day 7, Ad LacZ wrap: 144 +/- 7 mmHg and Ad eNOS wrap: 117 +/- 5 mmHg, P <= 0.05) throughout the study (Day 28, Ad LacZ wrap: 123 +/- 1 mmHg and Ad eNOS wrap: 108 +/- 4 mmHg, P <= 0.05). Western blot analyses of PVN NOS revealed significantly lower PVN neuronal NOS during the onset of hypertension but not in sustained hypertension. Reduced SDMA was found in the PVN during the onset of hypertension; however, no change in ADMA was observed. In conclusion, functional indexes of NO activity indicated an overall downregulation of NO in renal wrap hypertension, but the mechanism by which this occurs likely differs throughout the development of hypertension. PMID- 22447946 TI - TGF-beta and Smad3 modulate PI3K/Akt signaling pathway in vascular smooth muscle cells. AB - Transforming growth factor-beta (TGF-beta) is upregulated at the time of arterial injury; however, the mechanism through which TGF-beta enhances the development of intimal hyperplasia is not clear. Recent studies from our laboratory suggest that in the presence of elevated levels of Smad3, TGF-beta stimulates smooth muscle cell (SMC) proliferation. This is a novel phenomenon in that TGF-beta has traditionally been known as a potent inhibitor of cellular proliferation. In these studies we explore the signaling pathways through which TGF-beta mediates its proliferative effect in vascular SMCs. We found that TGF-beta phosphorylates and activates Akt in a time-dependent manner, and this effect is significantly enhanced by overexpression of Smad3. Furthermore, both chemical and molecular inhibition of Smad3 can reverse the effect of TGF-beta on Akt. Although we found numerous signaling pathways that might function as intermediates between Smad3 and Akt, p38 appeared the most promising. Overexpression of Smad3 enhanced p38 phosphorylation and inhibition of p38 with a chemical inhibitor or a small interfering RNA blocked TGF-beta-induced Akt phosphorylation. Moreover, TGF beta/Smad3 enhancement of SMC proliferation was blocked by inhibition of p38. Phosphorylation of Akt by TGF-beta/Smad3 was not dependent on gene expression or protein synthesis, and immunoprecipitation studies revealed a physical association among p38, Akt, and Smad3 suggesting that activation requires a direct protein-protein interaction. Our findings were confirmed in vivo where overexpression of Smad3 in a rat carotid injury model led to enhancement of p p38, p-Akt, as well as SMC proliferation. Furthermore, inhibition of p38 in vivo led to decreased Akt phosphorylation and SMC proliferation. In summary, our studies reveal a novel pathway whereby TGF-beta/Smad3 stimulates SMC proliferation through p38 and Akt. These findings provide a potential mechanism for the substantial effect of TGF-beta on intimal hyperplasia and suggest new targets for chemical or molecular prevention of vascular restenosis. PMID- 22447947 TI - Inflammation and metabolic dysfunction: links to cardiovascular diseases. AB - Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF kappaB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-alpha, adipocyte fatty acid binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets. PMID- 22447948 TI - Flow mechanotransduction regulates traction forces, intercellular forces, and adherens junctions. AB - Endothelial cells respond to fluid shear stress through mechanotransduction responses that affect their cytoskeleton and cell-cell contacts. Here, endothelial cells were grown as monolayers on arrays of microposts and exposed to laminar or disturbed flow to examine the relationship among traction forces, intercellular forces, and cell-cell junctions. Cells under laminar flow had traction forces that were higher than those under static conditions, whereas cells under disturbed flow had lower traction forces. The response in adhesion junction assembly matched closely with changes in traction forces since adherens junctions were larger in size for laminar flow and smaller for disturbed flow. Treating the cells with calyculin-A to increase myosin phosphorylation and traction forces caused an increase in adherens junction size, whereas Y-27362 cause a decrease in their size. Since tugging forces across cell-cell junctions can promote junctional assembly, we developed a novel approach to measure intercellular forces and found that these forces were higher for laminar flow than for static or disturbed flow. The size of adherens junctions and tight junctions matched closely with intercellular forces for these flow conditions. These results indicate that laminar flow can increase cytoskeletal tension while disturbed flow decreases cytoskeletal tension. Consequently, we found that changes in cytoskeletal tension in response to shear flow conditions can affect intercellular tension, which in turn regulates the assembly of cell-cell junctions. PMID- 22447949 TI - Unexpected and rapid recovery of left ventricular function in patients with peripartum cardiomyopathy: impact of cardiac resynchronization therapy. AB - Aim Peripartum cardiomyopathy (PPCM) is a rare cause of dilated cardiomyopathy responsible for heart failure toward the end of pregnancy, which can lead to chronic heart failure in 50% of cases. In this short report, we assessed the benefit of cardiac resynchronization in patients with PPCM and chronic systolic dysfunction despite optimal medical treatment. METHODS AND RESULTS: For the last 10 years, we managed eight patients diagnosed with PPCM. Two of them presented severe systolic dysfunction, and medical treatment resulted in limited improvement from 10% to 25% and from 25% to 28% despite optimal treatment for 9 and 6 years, respectively. These two patients were porposed to receive an implantatable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). Six months after ICD-CRT treatment, we observed a significant improvement in systolic function from 25% to 45% and 28% to 50%, respectively, and positive remodelling with reduction of left ventricular end-diastolic volume from 216 to 144 mL and from 354 to 105 mL, which represent a 34% and a 70% reduction, respectively. CONCLUSIONS: Physicians in charge of patients with PPCM should offer the opportunity of CRT for patients whose cardiac function has not significantly improved under standard medical treatment. PMID- 22447950 TI - Peritoneal dialysis relieves clinical symptoms and is well tolerated in patients with refractory heart failure and chronic kidney disease. AB - AIMS: The aim of the study was to evaluate the efficacy and clinical outcome of peritoneal dialysis (PD) treatment in patients with severe refractory heart failure (HF) and chronic kidney disease (CKD). METHODS AND RESULTS: The PD treatment was performed in 118 patients [49.2% New York Heart Association (NYHA) III and 50.8% NYHA IV] with a mean age of 73.2 +/- 11.4 years as an in-centre based and intermittent automated PD at least three times per week for 12 h per session and followed up for 1.11 +/- 1.17 years. The functional status of those surviving for 6 months improved (P < 0.0001): 18 (32.1%) of all 60 patients with NYHA IV at baseline died within 6 months, 3 (5.4%) converted to NYHA III, 33 (58.9%) to NYHA II, and 2 (3.6%) to NYHA I. In all 58 patients with NYHA III at baseline, 14 (25.0%) died within 6 months, 27 (48.2%) converted to NYHA II, 12 (21.4%) to NYHA I, and 3 (5.4%) showed no improvement. In those surviving for 6 months, fluid overload was significantly reduced as body weight decreased, from 78.7 [95% confidence interval (CI) 75.8-81.7] to 74.7 (71.5-77.9) after 6 months after multiple imputation (P < 0.001). The overall survival rates after 3, 6, and 12 months were 77% (95% CI 70-85), 71% (95% CI 62-79), and 55% (95% CI 45-64). In the multivariate analyses, age, diabetes mellitus, serum urea, and brain natriuretic peptide were significantly associated with mortality. The incidence of peritonitis and catheter dysfunction was 0.053 (95% CI 0.014-0.093) and 0.084 (95% CI 0.034-0.133), respectively. CONCLUSION: The data suggest that PD is a safe, efficient, and well tolerated therapeutic tool for patients with refractory chronic HF and CKD. PMID- 22447951 TI - Editorial: MMP-2 and MMP-9 in lymph-node-positive bladder cancer. PMID- 22447952 TI - Efficacy of an incident-reporting system in cellular pathology: a practical experience. AB - BACKGROUND AND AIMS: Incident reporting (IR) refers to systematic documentation of adverse incidents to facilitate their appropriate investigation and institution of corrective or remedial actions, and provide data to identify risk trends for recurrent problems. Minimisation of errors and reduction in process variation is recognised as an important goal of quality management and is an essential part of continuous quality improvement. Published data on the role IR plays in cellular pathology remains scanty. METHODS: In this study, the authors collected and analysed all incidents and adverse events reported in their department over a 2-year period. RESULTS: 584 incidents were reported (0.5% of all cases processed). The majority (59%) occurred in the pre-analytical phase of the laboratory process with 23% in the analytical and 18% in the post-analytical phases. Booking-in and specimen labelling-related incidents were the largest single group (56% of all incidents), prompting further root cause analysis, but no other obvious patterns or trends were identified, and most incidents were followed by corrective actions on an individual basis. Most incidents (79%) posed potential harm, as opposed to causing actual harm to the service or patients. Only 78 cases (14%) posed a major risk to patients, such as specimen loss or mix up, whereas 27% were associated with moderate risk and 59% with minor or insignificant risk. CONCLUSION: Major risk incidents are relatively rare in the cellular pathology laboratory. IR should be included as an important component of a risk management strategy and clinical governance framework. PMID- 22447953 TI - Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia. AB - The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-beta were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR alpha remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed. PMID- 22447955 TI - Withdrawal of 'Xigris' from the market: old and new lessons. PMID- 22447954 TI - Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in ApoE-deficient mice. AB - Smokers with airflow obstruction have an increased risk of atherosclerosis, but the relationship between the pathogenesis of these diseases is not well understood. To determine whether hypercholesterolemia alters lung inflammation and emphysema formation, we examined the lung phenotype of two hypercholesterolemic murine models of atherosclerosis at baseline and on a high fat diet. Airspace enlargement developed in the lungs of apolipoprotein E deficient (Apoe(-/-)) mice exposed to a Western-type diet for 10 wk. An elevated number of macrophages and lymphocytes accompanied by an increase in matrix metalloproteinase-9 (MMP-9) activity and MMP-12 expression was observed in the lungs of Apoe(-/-) mice on a Western-type diet. In contrast, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice did not exhibit lung destruction or inflammatory changes. Most importantly, we revealed augmented expression of the downstream targets of the Toll-like receptor (TLR) pathway, interleukin-1 receptor-associated kinase 1, and granulocyte colony-stimulating factor, in the lungs of Apoe(-/-) mice fed with a Western-type diet. In addition, we demonstrated overexpression of MMP-9 in Apoe(-/-) macrophages treated with TLR4 ligand, augmented with the addition of oxidized LDL, suggesting that emphysema in these mice results from the activation of the TLR pathway secondary to known abnormal cholesterol efflux. Our findings indicate that, in Apoe(-/-) mice fed with an atherogenic diet, abnormal cholesterol efflux leads to increased systemic inflammation with subsequent lung damage and emphysema formation. PMID- 22447956 TI - Cardiac autonomic disturbances in patients with vasovagal syndrome: comparison between iodine-123-metaiodobenzylguanidine myocardial scintigraphy and heart rate variability. AB - AIMS: The aim of this study was to examine autonomic disorders in patients with different types of vasovagal syndrome by performing both a cardiac sympathetic innervation evaluation and a head-up tilt-test with heart rate variability (HRV) analysis. METHODS AND RESULTS: We enrolled 60 patients with vasovagal syncope (32 women, mean age 40 +/- 16 years), and 20 age-matched controls. We assessed the integrity and function of the myocardial pre-synaptic nerve endings and in the sympathovagal activity, using (123)I-metaiodobenzylguanidine (MIBG) scintigraphy and time-domain indexes of HRV. A significantly lower heart/mediastinum ratio was found in the syncopal patients compared with the control group, both at 10 min (1.9 +/- 0.25 vs. 3.6 +/- 1.7, P = 0.02) and at 4 h (1.79 +/- 0.12 vs. 2.07 +/- 0.19, P = 0.04), whereas washout rate was significantly greater in syncopal patients (5.5 +/- 3.7 vs. 2 +/- 0.19, P = 0.04). There were no significant differences in any of the above parameters between patients with different types of syncope. In addition, the majority of the patients showed multiple adrenergic innervation defects in the left ventricular myocardium. No significant difference was found in any of the HRV time-domain indexes. However, a correlation was found between root-mean-square of the difference between successive RRs and washout rate in syncopal patients (r = -0.256, P = 0.48). CONCLUSION: Patients with vasovagal syncope induced by tilt testing reveal a high degree of disturbance of myocardial adrenergic innervation and multiple adrenergic innervation defects. This suggests a possible predominance of cardiac adrenergic activity in those with abnormal cardiac MIBG scintigraphy. PMID- 22447957 TI - Characteristics of recurrent clockwise atrial flutter after previous radiofrequency catheter ablation for counterclockwise isthmus-dependent atrial flutter. AB - AIMS: Isthmus-dependent (ID) clockwise (CW) atrial flutters (AFl) are rare in comparison with counterclockwise (CCW) AFl. Little is known about clinical and electrophysiological characteristics of CW AFl occurring after previous radiofrequency (RF) catheter ablation of CCW AFl. We sought to compare CW AFl de novo vs. CW AFl occurring after previous CCW AFl RF ablation. METHODS AND RESULTS: A total of 246 procedures of RF catheter ablation for AFl from January 2009 to January 2011 were reviewed. Clinical and electrophysiological data were analysed. Patients were excluded if they were in sinus rhythm at the beginning of the procedure, if they had concomitant/previous atrial fibrillation ablation, or if AFl was not ID. Twenty-seven patients presented CW AFl (10.9% of all ID AFl), including 10 CW AFl occurring after a previous RF catheter ablation for CCW AFl. Mean time for recurrence after the previous procedure of CCW AFl RF ablation was 3.5 years. They were younger (61.6 +/- 11 years) than patients with CW AFl de novo (74.0 +/- 7.2 years; P = 0.005). Bidirectional isthmus block was obtained in all patients. There was a significant difference in terms of double potential separation after ablation (155 +/- 31 ms for CW AFl de novo vs. 111 +/- 7 ms for recurrent CW AFl; P = 0.028). No differences were observed concerning CHADS score, AFl cycle length, and electrocardiogram typical pattern for CW AFl between the two groups. CONCLUSION: Patients with CW AFl occurrence after CCW AFl RF catheter ablation are younger than patients with CW AFl de novo. They also have a smaller interspike interval after block completion. PMID- 22447959 TI - The persistence of irregular treatment of hypertension in the former Soviet Union. AB - BACKGROUND: Hypertension is one of the leading causes of avoidable mortality in the former Soviet Union (fSU). In previous work, the authors described patterns of irregular hypertension treatment in eight countries of the fSU in 2001. This paper presents new data on changes in the use of hypertension treatment in the same countries. METHODS: Using household survey data from 18 420 (2001) and 17 914 (2010) respondents from Armenia, Azerbaijan (2010 only), Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia and Ukraine, the authors describe changes in rates of irregular treatment use (less than daily) between 2001 and 2010. Multivariate logistic regression was also used to analyse the characteristics associated with irregular treatment. RESULTS: Irregular treatment was extremely high at 74% in 2001 and only fell to 68% in 2010 (all countries combined). Irregular treatment remained particularly high in 2010 in Armenia (79%), Kazakhstan (73%) and Moldova (73%). Recurring characteristics associated with irregular treatment included gender (men), younger age, higher fitness levels, and consuming alcohol and tobacco. CONCLUSIONS: Irregular hypertension treatment continues to be a major problem in the countries of the fSU and requires an urgent response. PMID- 22447958 TI - Heart failure in patients with sick sinus syndrome treated with single lead atrial or dual-chamber pacing: no association with pacing mode or right ventricular pacing site. AB - AIMS: Previous studies indicate that ventricular pacing may precipitate heart failure (HF). We investigated occurrence of HF during long-term follow-up among patients with sick sinus syndrome (SSS) randomized to AAIR or DDDR pacing. Furthermore, we investigated effects of percentage of ventricular pacing (%VP) and pacing site in the ventricle. METHODS AND RESULTS: We analysed data from 1415 patients randomized to AAIR (n = 707) or DDDR pacing (n = 708). Ventricular pacing leads were recorded as located in either an apical or a non-apical position. The %VP and HF hospitalizations were recorded during follow-up. Patients were classified with new HF, if in New York Heart Association (NYHA) functional class IV or if presence of >=2 of: oedema; dyspnoea; NYHA functional class III. Mean follow-up was 5.4 +/- 2.4 years. Heart failure hospitalizations did not differ between groups. In the AAIR group, 170 of the 707 (26%) patients developed HF vs. 169 of the 708 (26%) patients in the DDDR group, hazard rate ratio (HR) 1.00, 95% confidence interval (CI) 0.79-1.22, P = 0.87. In DDDR patients, 146 of the 512 patients (29%) with ventricular leads in an apical position developed HF vs. 28 of the 161 patients (17%) with the leads in a non apical position, HR 0.67, CI 0.45-1.00, P = 0.05. After adjustments this difference was non-significant. The incidence of HF was not associated with %VP (P = 0.57). CONCLUSION: In patients with SSS, HF was not associated with pacing mode, %VP, or ventricular lead localization. This suggests that DDDR pacing is safe in patients with SSS without precipitating HF. PMID- 22447960 TI - Impact of an electronic, computer-delivered questionnaire, with or without postal reminders, on survey response rate in primary care. PMID- 22447961 TI - Smoke-free movies: an important component of a comprehensive ban on tobacco advertising, promotion and sponsorship. PMID- 22447962 TI - Are health inequalities evident at all ages? An ecological study of English mortality records. AB - BACKGROUND: Inequalities in mortality are often presumed to exist at all ages. Here we examine whether this is true. METHODS: We conducted an ecological study of mortality in England for 1997-99 using routinely collected public records. We used a (smoothed) single year of age rate of mortality for males and females by the multiple deprivation quintile of their ward of residence, for all and specific causes to assess if inequalities varied by age. RESULTS: For most ages, a greater mortality risk exists for those living in the most deprived compared with the least deprived quintile of wards. However, during late adolescence there is equality. The equalization occurs at the age of 17-19 years. There is a longer period of 10 years for females and 20 years for males of convergence and then divergence centred on late adolescence and young adulthood. The equalization is driven principally through a heightened exposure to the risk of land transport accidents and a resulting higher than expected rate of mortality for the least deprived rather than a decrease in risk for the most deprived. CONCLUSIONS: It seems likely that an increase in risk taking associated with late adolescence combined with exposure to a relatively dangerous transport environment leads to large increases in risk for young people in the least deprived parts of England. As a result mortality inequality disappears at this age. PMID- 22447963 TI - Enhanced pulmonary arteriopathy in simian immunodeficiency virus-infected macaques exposed to morphine. AB - RATIONALE: HIV-associated pulmonary arterial hypertension (PAH) is likely a more prevalent noninfectious complication of AIDS than previously recognized. Furthermore, the majority of HIV-PAH cases occur in individuals with a history of intravenous drug use. In this study we used a simian immunodeficiency (SIV) macaque model and a primary cell-culture system to investigate the association between drug abuse and HIV infection in HIV-PAH development. METHODS: The archival lung tissues from macaques previously used to study the effect of morphine on SIV infection-associated neuropathogenesis were analyzed for pulmonary vascular changes. The direct effect of HIV proteins and illicit drugs was investigated on oxidative stress, survival, and proliferation of human pulmonary microvascular endothelial cells. MEASUREMENTS AND MAIN RESULTS: SIVmacR71/17E-infected rhesus macaques treated with morphine (VM group) demonstrated significant pulmonary vascular remodeling, including the presence of early and advanced complex (plexiform) lesions, when compared with either the SIV infected (V group) or morphine-treated uninfected (M group) macaques. However, both the V (two of five) and VM (two of six) groups included some animals with Pneumocystis jirovecii pneumonia. The endothelial cells lining the vessels with medial hypertrophy or initial-stage intimal lesions in lung sections from VM macaques demonstrated an increase in positivity for both terminal dUTP nick-end labeling and Ki67. Oxidative stress-mediated enhanced apoptosis followed by enhanced proliferation of endothelial cells was observed on simultaneous treatment with viral proteins and drugs of abuse compared with either treatment alone. CONCLUSIONS: Our findings suggest that SIV/HIV protein(s) and morphine interact to cause the proliferation of apoptosis-resistant endothelial cells leading to angio-obliteration. PMID- 22447964 TI - Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. AB - RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES: Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS: Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and <= 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS: There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS: The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required. PMID- 22447965 TI - Pulmonary complications of sickle cell disease. AB - Sickle cell disease (SCD) is a common monogenetic disorder with high associated morbidity and mortality. The pulmonary complications of SCD are of particular importance, as acute chest syndrome and pulmonary hypertension have the highest associated mortality rates within this population. This article reviews the pathophysiology, diagnosis, and treatment of clinically significant pulmonary manifestations of SCD, including acute chest syndrome, asthma, and pulmonary hypertension in adult and pediatric patients. Clinicians should be vigilant in screening and treating such comorbidities to improve patient outcomes. PMID- 22447966 TI - AtACDO1, an ABC1-like kinase gene, is involved in chlorophyll degradation and the response to photooxidative stress in Arabidopsis. AB - ABC1 (activity of bc1 complex) is a newly discovered atypical kinase in plants. Here, it is reported that an ABC1 protein kinase-encoded gene, AtACDO1 (ABC1-like kinase related to chlorophyll degradation and oxidative stress), located in chloroplasts, was up-regulated by methyl viologen (MV) treatment. AtACDO1 RNAi (RNA interference) plants showed developmental defects, including yellow-green leaves and reduced contents of carotenoids and chlorophyll; the chlorophyll reduction was associated with a change in the numbers of chlorophyll-binding proteins of the photosynthetic complexes. Chlorophyllide (Chlide) a the first product of chlorophyll degradation, and pheophorbide a, a subsequent intermediate of Chlide a degradation, were increased in AtACDO1 RNAi plants. The AtACDO1 RNAi plants were more sensitive to high light and MV than wild-type plants. The AtACDO1 RNAi plants had lower transcript levels of the oxidative stress response genes FSD1, CSD1, CAT1, and UTG71C1 after MV treatment compared with wild-type or 35S::AtACDO1 plants. Taken together, the results suggest that the chloroplast AtACDO1 protein plays important roles in mediating chlorophyll degradation and maintaining the number of chlorophyll-binding photosynthetic thylakoid membranes, as well as in the photooxidative stress response. PMID- 22447967 TI - The pathway of auxin biosynthesis in plants. AB - The plant hormone auxin, which is predominantly represented by indole-3-acetic acid (IAA), is involved in the regulation of plant growth and development. Although IAA was the first plant hormone identified, the biosynthetic pathway at the genetic level has remained unclear. Two major pathways for IAA biosynthesis have been proposed: the tryptophan (Trp)-independent and Trp-dependent pathways. In Trp-dependent IAA biosynthesis, four pathways have been postulated in plants: (i) the indole-3-acetamide (IAM) pathway; (ii) the indole-3-pyruvic acid (IPA) pathway; (iii) the tryptamine (TAM) pathway; and (iv) the indole-3-acetaldoxime (IAOX) pathway. Although different plant species may have unique strategies and modifications to optimize their metabolic pathways, plants would be expected to share evolutionarily conserved core mechanisms for auxin biosynthesis because IAA is a fundamental substance in the plant life cycle. In this review, the genes now known to be involved in auxin biosynthesis are summarized and the major IAA biosynthetic pathway distributed widely in the plant kingdom is discussed on the basis of biochemical and molecular biological findings and bioinformatics studies. Based on evolutionarily conserved core mechanisms, it is thought that the pathway via IAM or IPA is the major route(s) to IAA in plants. PMID- 22447968 TI - Pharmacologic agents elevating cAMP prevent arginase II expression and proliferation of pulmonary artery smooth muscle cells. AB - Arginase II has been shown to be involved in the hypoxia-induced proliferation of human pulmonary artery smooth muscle cells (hPASMCs). The signal transduction pathways responsible for the induction of arginase II are poorly understood. Cyclic AMP is involved in many intracellular processes, and cAMP levels are regulated by a balance between production via adenylate cyclases and degradation via phosphodiesterases. The purpose of this study was to determine the effects of cAMP on hypoxia-induced arginase expression, activity, and proliferation in hPASMCs. We found that the cAMP analog 8-Bromo-cAMP (8-Br-cAMP), the adenylate cyclase activator forskolin, and the phosphodiesterase 3 inhibitor cilostamide prevented the hypoxic induction of arginase II mRNA and protein expression in hPASMCs. The inhibition of arginase II protein was found to be mediated by exchange protein directly activated by cAMP. Arginase activity was decreased by 8 Br-cAMP, as evidenced by significantly lower V(max) for arginase in normoxia and hypoxia. The hypoxia-induced hPASMC proliferation was completely prevented by the addition of 8-Br-cAMP, forskolin, or cilostamide. These data are the first to describe the inhibitory effect of cAMP on arginase activity, expression, and resultant proliferation of hypoxic hPASMCs. PMID- 22447969 TI - Mycobacterium tuberculosis chaperonin 60.1 inhibits leukocyte diapedesis in a murine model of allergic lung inflammation. AB - Chaperonin 60.1 from Mycobacterium tuberculosis suppressed allergic lung inflammation and bronchial hyperresponsiveness in mice by a mechanism that is yet to be clarified. To investigate the possible antiinflammatory mechanism(s) of action of Cpn60.1 in a model of allergic lung inflammation, ovalbumin (OVA) allergic mice were pretreated with Cpn60.1 intranasally 20 minutes before each OVA aerosol challenge in a total of three treatments. Readouts were performed 24 hours after last challenge. Pretreatment with Cpn60.1 (1.0-0.001 MUg) significantly inhibited the number of eosinophils in bronchoalveolar lavage fluid (OVA, 49.2 +/- 12.3 versus Cpn60.1 [1 MUg dose], 90.4 +/- 2.3 * 10(4) cells/ml) and IL-5 release (OVA, 43 +/- 8.5 versus Cpn60.1 [1 MUg dose], 3 +/- 11 pg/ml) but increased IL-12 levels (OVA, 50 +/- 24 versus Cpn60.1 [1 MUg dose], 103 +/- 13 pg/ml). The effect of Cpn60.1 on cell recruitment and IL-5, but not IL-12, release was abolished in TLR-4 knockout mice. Intravital microscopy demonstrated that Cpn60.1 reduced chemokine-mediated leukocyte rolling and transmigration across the vessel wall (rolling cells: eotaxin, 11.7 +/- 1.1 versus Cpn60.1 [1 MUg dose], 2.8 +/- 1 cells in 30 s). Similarly, Cpn60.1 reduced eotaxin-induced leukocyte migration in vitro (eotaxin, 17.3 +/- 3.3 versus Cpn60.1 [0.1 MUg dose], 3.3 +/- 0.4 cells * 10(4)/ml). Immunostaining demonstrated that Cpn60.1 inhibits VCAM-1 and increases vascular endothelial-cadherin expression in lung vascular tissue, suggesting that the antiinflammatory effect of Cpn60.1 is partly mediated by altering the expression of adhesion molecules. This study shows that Cpn60.1 inhibits leukocyte diapedesis by a TLR-4 and an adhesion molecule dependent mechanism in allergic inflammation in mice. PMID- 22447970 TI - Integrative assessment of chlorine-induced acute lung injury in mice. AB - The genetic basis for the underlying individual susceptibility to chlorine induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using >= 10% allelic frequency and >= 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4. PMID- 22447971 TI - Transcriptional targeting in the airway using novel gene regulatory elements. AB - The delivery of cystic fibrosis transmembrane conductance regulator (CFTR) to airway epithelia is a goal of many gene therapy strategies to treat cystic fibrosis. Because the native regulatory elements of the CFTR are not well characterized, the development of vectors with heterologous promoters of varying strengths and specificity would aid in our selection of optimal reagents for the appropriate expression of the vector-delivered CFTR gene. Here we contrasted the performance of several novel gene-regulatory elements. Based on airway expression analysis, we selected putative regulatory elements from BPIFA1 and WDR65 to investigate. In addition, we selected a human CFTR promoter region (~ 2 kb upstream of the human CFTR transcription start site) to study. Using feline immunodeficiency virus vectors containing the candidate elements driving firefly luciferase, we transduced murine nasal epithelia in vivo. Luciferase expression persisted for 30 weeks, which was the duration of the experiment. Furthermore, when the nasal epithelium was ablated using the detergent polidocanol, the mice showed a transient loss of luciferase expression that returned 2 weeks after administration, suggesting that our vectors transduced a progenitor cell population. Importantly, the hWDR65 element drove sufficient CFTR expression to correct the anion transport defect in CFTR-null epithelia. These results will guide the development of optimal vectors for sufficient, sustained CFTR expression in airway epithelia. PMID- 22447972 TI - Concomitant activation of functionally opposing prostacyclin and thromboxane prostanoid receptors by cyclo-oxygenase-1-mediated prostacyclin synthesis in mouse arteries. AB - This study aimed to determine whether cyclo-oxygenase-1 (COX-1) mediates dilatation of mouse arteries via synthesis of prostacyclin (PGI(2)) and, if so, how PGI(2) (IP) receptors contribute and whether thromboxane prostanoid (TP) receptors are implicated in the process. Mesenteric arteries were isolated from wild-type mice or mice with COX-1 deficiency (COX-1(-/-)). The vasomotor reaction to the COX substrate arachidonic acid (AA) was determined with isometric force measurement, while the in vitro production or the plasma level of the PGI(2) metabolite 6-keto-PGF(1alpha) was analysed with high-performance liquid chromatography-mass spectroscopy or enzyme immunoassay, respectively. Results showed that AA, which evoked endothelium-dependent 6-keto-PGF(1alpha) production, elicited relaxation that was inhibited or enhanced by antagonizing IP or TP receptors, respectively. Also, IP receptor blockade resulted in contraction in response to AA (following NO synthase inhibition), which was prevented by a concomitant TP receptor antagonism. Meanwhile, COX-1(-/-) or COX-1 inhibition abolished the in vitro 6-keto-PGF(1alpha) production and reduced the relaxation or contraction observed with AA. Real-time PCR showed that whereas TP receptor mRNAs were detected at similar levels, IP receptor mRNAs were present at higher levels in the branches than in the main stem of the mesenteric artery. In addition, antagonizing the IP receptors enhanced the contraction evoked by PGI(2) in the carotid artery. Also, we noted that COX-1(-/-) mice had a reduced basal plasma 6-keto-PGF(1alpha) level. These results demonstrate an explicit vasodilator role for COX-1-mediated endothelial PGI(2) synthesis and suggest that the functionally opposing IP and TP receptors concomitantly mediate the vasomotor reaction to PGI(2), with the dilator activity of IP receptors being compromised by the vasoconstrictor effect of TP receptors and vice versa. PMID- 22447974 TI - Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart. AB - The steep slope of the rate adaptation of ventricular action potential duration (APD) is thought to indicate profibrillatory tendency. In cardiac patients, APD restitution is commonly assessed by extrasystolic (S(1)-S(2)) stimulations rather than dynamic pacing, because the latter may provoke myocardial ischaemia. In this study, ventricular APD and effective refractory period (ERP) were measured in perfused guinea-pig hearts to determine whether S(1)-S(2) stimulations and dynamic pacing may have similar value in APD restitution assessments aimed to predict arrhythmic risk. The maximal restitution slope was greater upon S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), 1.2 +/- 0.08; dynamic, 0.72 +/- 0.06; P = 0.0004) and endocardium (S(1)-S(2), 1.45 +/- 0.08; dynamic, 0.95 +/- 0.06; P = 0.0003). This difference was partly accounted for by an effect of the previous pacing history, as evidenced by flattening of APD restitution upon reductions in the regular beating interval prior to S(2) application. Furthermore, shorter ERP than APD relationships enabled ventricular capture at shorter diastolic intervals during S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), -1 +/- 3 ms; dynamic, 35 +/- 3 ms; P < 0.0001) and endocardium (S(1)-S(2), -1 +/- 7 ms; dynamic, 38 +/- 3 ms; P < 0.0001), thereby contributing to greater maximal restitution slope values. Flecainide, a Na(+) channel blocker, increased the ERP-to-APD ratio and eliminated early premature beats (diastolic interval of ~0 ms), thereby flattening the S(1)-S(2) restitution curve, but had no effect on dynamic restitution. In hypokalaemia-induced arrhythmogenicity, a reduction in ventricular fibrillation threshold was paralleled by increased steepness of dynamic APD restitution, while no change in the maximal restitution slope was revealed by S(1)-S(2) stimulations. In summary, changes in electrical restitution obtained from extrasystolic stimulations may dissociate from those revealed by dynamic pacing. These findings therefore challenge the value of electrical restitution assessments based on extrasystolic stimulation alone, as commonly performed in the clinical setting. PMID- 22447975 TI - Surgical optimization and characterization of a minimally invasive aortic banding procedure to induce cardiac hypertrophy in mice. AB - Left ventricular pressure overload in response to aortic banding is an invaluable model for studying progression of cardiac hypertrophy and transition to heart failure. Traditional aortic banding has recently been superceded by minimally invasive transverse aortic banding (MTAB), which does not require ventilation so is less technically challenging. Although the MTAB approach is superior, few laboratories have documented success, and minimal information on the model is available. The aim of this study was to optimize conditions for MTAB and to characterize the development and progression of cardiac hypertrophy. Isofluorane proved the most suitable anaesthetic for MTAB surgery in mice, and 1 week after surgery the MTAB animals showed significant increases in systolic blood pressure (MTAB 110 +/- 6 mmHg versus sham 78 +/- 3 mmHg, n = 7, P < 0.0001) and heart weight to body weight ratio (MTAB 6.2 +/- 0.2 versus sham 5.1 +/- 0.1, n = 12, P < 0.001), together with systolic (e.g. fractional shortening, MTAB 31.7 +/- 1% versus sham 36.6 +/- 1.4%, P = 0.01) and diastolic dysfunction (e.g. left ventricular end-diastolic pressure, MTAB 12.7 +/- 1.0 mmHg versus sham 6.7 +/- 0.8 mmHg, P < 0.001). Leucocyte infiltration to the heart was evident after 1 week in MTAB hearts, signifying an inflammatory response. More pronounced remodelling was observed 4 weeks postsurgery (heart weight to body weight ratio, MTAB 9.1 +/- 0.6 versus sham 4.6 +/- 0.04, n = 10, P < 0.0001) and fractional shortening was further decreased (MTAB 24.3 +/- 2.5% versus sham 43.6 +/- 1.7%, n = 10, P = 0.003), together with a significant increase in cardiac fibrosis and further cardiac inflammation. Our findings demonstrate that MTAB is a relevant experimental model for studying development and progression of cardiac hypertrophy, which will be highly valuable for future studies examining potential novel therapeutic interventions in this setting. PMID- 22447976 TI - Differential roles for RIG-I-like receptors and nucleic acid-sensing TLR pathways in controlling a chronic viral infection. AB - The necessity for pathogen recognition of viral infection by the innate immune system in initiating early innate and adaptive host defenses is well documented. However, little is known about the role these receptors play in the maintenance of adaptive immune responses and their contribution to resolution of persistent viral infections. In this study, we demonstrate a nonredundant functional requirement for both nucleic acid-sensing TLRs and RIG-I-like receptors in the control of a mouse model of chronic viral infection. Whereas the RIG-I-like receptor pathway was important for production of type I IFNs and optimal CD8(+) T cell responses, nucleic acid-sensing TLRs were largely dispensable. In contrast, optimal anti-viral Ab responses required intact signaling through nucleic acid sensing TLRs, and the absence of this pathway correlated with less virus-specific Ab and deficient long-term virus control of a chronic infection. Surprisingly, absence of the TLR pathway had only modest effects on Ab production in an acute infection with a closely related virus strain, suggesting that persistent TLR stimulation may be necessary for optimal Ab responses in a chronic infection. These results indicate that innate virus recognition pathways may play critical roles in the outcome of chronic viral infections through distinct mechanisms. PMID- 22447977 TI - IL-15 can signal via IL-15Ralpha, JNK, and NF-kappaB to drive RANTES production by myeloid cells. AB - IL-15 plays many important roles within the immune system. IL-15 signals in lymphocytes via trans presentation, where accessory cells such as macrophages and dendritic cells present IL-15 bound to IL-15Ralpha in trans to NK cells and CD8(+) memory T cells expressing IL-15/IL-2Rbeta and common gamma chain (gamma(c)). Previously, we showed that the prophylactic delivery of IL-15 to Rag2(-/-)gamma(c)(-/-) mice (mature T, B, and NK cell negative) afforded protection against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma cells. In this study, we demonstrated that in vivo delivery of an adenoviral construct optimized for the secretion of human IL-15 to Rag2(-/-)gamma(c)(-/-) mice resulted in significant increases in spleen size and cell number, leading us to hypothesize that IL-15 signals differently in myeloid immune cells compared with lymphocytes, for which IL-15/IL-2Rbeta and gamma(c) expression are essential. Furthermore, treatment with IL-15 induced RANTES production by Rag2(-/ )gamma(c)(-/-) bone marrow cells, but the presence of gamma(c) did not increase bone marrow cell sensitivity to IL-15. This IL-15-mediated RANTES production by Rag2(-/-)gamma(c)(-/-) bone marrow cells occurred independently of the IL-15/IL 2Rbeta and Jak/STAT pathways and instead required IL-15Ralpha signaling as well as activation of JNK and NF-kappaB. Importantly, we also showed that the trans presentation of IL-15 by IL-15Ralpha boosts IL-15-mediated IFN-gamma production by NK cells but reduces IL-15-mediated RANTES production by Rag2(-/-)gamma(c)(-/ ) myeloid bone marrow cells. Our data clearly show that IL-15 signaling in NK cells is different from that of myeloid immune cells. Additional insights into IL 15 biology may lead to novel therapies aimed at bolstering targeted immune responses against cancer and infectious disease. PMID- 22447978 TI - CD8 T cells recruited early in mouse polyomavirus infection undergo exhaustion. AB - Repetitive Ag encounter, coupled with dynamic changes in Ag density and inflammation, imparts phenotypic and functional heterogeneity to memory virus specific CD8 T cells in persistently infected hosts. For herpesvirus infections, which cycle between latency and reactivation, recent studies demonstrate that virus-specific T cell memory is predominantly derived from naive precursors recruited during acute infection. Whether functional memory T cells to viruses that persist in a nonlatent, low-level infectious state (smoldering infection) originate from acute infection-recruited naive T cells is not known. Using mouse polyomavirus (MPyV) infection, we previously showed that virus-specific CD8 T cells in persistently infected mice are stably maintained and functionally competent; however, a sizeable fraction of these memory T cells are short-lived. Further, we found that naive anti-MPyV CD8 T cells are primed de novo during persistent infection and contribute to maintenance of the virus-specific CD8 T cell population and its phenotypic heterogeneity. Using a new MPyV-specific TCR transgenic system, we now demonstrate that virus-specific CD8 T cells recruited during persistent infection possess multicytokine effector function, have strong replication potential, express a phenotype profile indicative of authentic memory capability, and are stably maintained. In contrast, CD8 T cells recruited early in MPyV infection express phenotypic and functional attributes of clonal exhaustion, including attrition from the memory pool. These findings indicate that naive virus-specific CD8 T cells recruited during persistent infection contribute to preservation of functional memory against a smoldering viral infection. PMID- 22447979 TI - C-reactive protein testing in patients with acute rhinosinusitis leads to a reduction in antibiotic use. AB - OBJECTIVE: To evaluate the effect of C-reactive protein (CRP) testing on the antibiotic prescribing in patients with acute rhinosinusitis. METHODS: Audit based study carried out in primary care centres in Spain. GPs registered episodes of rhinosinusitis during 3-week period before and after an intervention. Two types of intervention were considered: full intervention group (FIG) consisting in individual feedback based on results from the first registry, courses in rational antibiotic prescribing, guidelines, patient information leaflets, workshops on rapid tests and use of the CRP test. GPs in the partial intervention group (PIG) underwent all the above intervention except for the workshop and they did not have access to CRP. Multilevel logistic regression analysis was performed considering the prescription of antibiotics as the dependent variable. RESULTS: Two hundred and ten physicians were assigned to FIG and 71 to PIG. In 2009, 59 new physicians were included as a control group. Two hundred and sixty-seven GPs visited contacts with rhinosinusitis (78.5%) registering a total of 836 cases. In the group of GPs with access to CRP rapid test, 207 patients with rhinosinusitis (75.3%) were tested and antibiotics were prescribed in 156 patients (56.7%). Antibiotics were prescribed in 87 patients (82.9%) in the group of GPs exposed to PIG and in 52 patients (86.7%) in the control group (P < 0.001). Antibiotic prescription was significantly reduced after the intervention among physicians assigned to FIG, with an odds ratio of antibiotic prescribing of 0.12 (95% confidence interval: 0.01-0.32). CONCLUSION: Physicians with access to CRP tests significantly reduced antibiotic prescription in patients with rhinosinusitis. PMID- 22447980 TI - Molecular mechanisms in the dramatic enhancement of HIV-1 Tat transduction by cationic liposomes. AB - Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) protein possesses a unique membrane-transduction property. Interestingly, Tat transduction could be dramatically increased 1000-fold based on LTR transactivation assay when complexed with cationic liposomes (lipo-Tat), compared with Tat alone. Therefore, underlining mechanisms were explored further. Microscopy and flow cytometry showed that this effect was associated with enhanced membrane binding, large particle formation (1-2 MUm) and increased intracellular uptake of Tat fluorescent proteins. Using pharmacological assays and immune colocalizations, it was found that lipid raft-dependent endocytosis and macropinocytosis were major pathways involved in lipo-Tat uptake, and actin filaments played a major role in intracellular trafficking of lipo-Tat to the nucleus. Furthermore, we found that the Tat hydrophobic domain (aa 36-47) mediated formation of two positively charged molecules into lipo-Tat complexes via hydrophobic bonds, based on LTR-transactivation inhibition assay. Thus, the hydrophobic domain may play an important role in Tat protein uptake and be useful for intracellular delivery of biomacromolecules if coupled together with Tat basic peptide, a cell-penetrating peptide. PMID- 22447981 TI - Glucocorticoid receptor mediates the gluconeogenic activity of the farnesoid X receptor in the fasting condition. AB - The glucocorticoid receptor (GR) is a master gene orchestrating the activation of gluconeogenic genes in the liver in response to food withdrawal. Mechanisms of GR regulation by other nuclear receptors, however, are poorly defined. Here, we report that the farnesoid X receptor (FXR), a bile acid sensor, activates gluconeogenic pathways in the liver and regulates GR expression and activity. FXR null mice are hypoglycemic in the unfed state and exhibit both a reduced hepatic production of glucose in response to the pyruvate challenge and a decreased expression of two rate-limiting enzymes involved in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), along with blunted liver expression of GR. Treating wild-type mice with a semisynthetic FXR ligand (6E-CDCA) increases the liver expression of GR, PEPCK, and G6Pase. This effect was lost in fed animals, as well as in FXR(-/-) mice. The human and mouse GR promoters contain a conserved FXR-responsive element (an ER-8 sequence) whose activation by FXR ligation leads to GR transcription. GR silencing by siRNA in vitro or its pharmacological antagonism in vivo with mifepristone reverses the effect of FXR activation on expression of gluconeogenic genes. These findings demonstrate that an FXR-GR pathway regulates the activation of hepatic gluconeogenesis in the transition from the unfed to the fed state. PMID- 22447982 TI - Herbarium specimens, photographs, and field observations show Philadelphia area plants are responding to climate change. AB - PREMISE OF THE STUDY: The global climate is changing rapidly and is expected to continue changing in coming decades. Studying changes in plant flowering times during a historical period of warming temperatures gives us a way to examine the impacts of climate change and allows us to predict further changes in coming decades. The Greater Philadelphia region has a long and rich history of botanical study and documentation, with abundant herbarium specimens, field observations, and botanical photographs from the mid-1800s onward. These extensive records also provide an opportunity to validate methodologies employed by other climate change researchers at a different biogeographical area and with a different group of species. METHODS: Data for 2539 flowering records from 1840 to 2010 were assessed to examine changes in flowering response over time and in relation to monthly minimum temperatures of 28 Piedmont species native to the Greater Philadelphia region. KEY RESULTS: Regression analysis of the date of flowering with year or with temperature showed that, on average, the Greater Philadelphia species studied are flowering 16 d earlier over the 170-yr period and 2.7 d earlier per 1 degrees C rise in monthly minimum temperature. CONCLUSIONS: Of the species studied, woody plants with short flowering duration are the best indicators of a warming climate. For monthly minimum temperatures, temperatures 1 or 2 mo prior to flowering are most significantly correlated with flowering time. Studies combining herbarium specimens, photographs, and field observations are an effective method for detecting the effects of climate change on flowering times. PMID- 22447983 TI - Isolation and characterization of microsatellites in the lichen Buellia frigida (Physciaceae), an Antarctic endemic. AB - PREMISE OF THE STUDY: Microsatellite markers were characterized for an Antarctic endemic, Buellia frigida, to investigate population structure and origin of Antarctic lichens. METHODS AND RESULTS: Five primer sets were characterized. All loci were polymorphic with eight to 16 alleles per locus in a sample of 59 lichens. CONCLUSIONS: The microsatellite markers potentially provide insight into population structure and gene flow of B. frigida. PMID- 22447984 TI - Development of microsatellite markers for Anadenanthera colubrina (Leguminosae), a neotropical tree species. AB - PREMISE OF THE STUDY: We developed and characterized nuclear microsatellite markers for Anadenanthera colubrina, a tropical tree species widely distributed in South America. METHODS AND RESULTS: Leaf samples of mature A. colubrina trees, popularly called "angico," were collected from an area that is greatly impacted by agricultural practices in the region of Ribeirao Preto in Sao Paulo State in southeastern Brazil. Twenty simple sequence repeat (SSR) markers were developed, 14 of which had polymorphic loci. A total of 96 alleles were detected with an average of 6.86 alleles per polymorphic locus. The expected heterozygosity, calculated at polymorphic loci, ranged from 0.18 to 0.83. Finally, we demonstrated that 18 loci were cross-amplified in A. peregrina. CONCLUSIONS: A total of 14 polymorphic markers suggest a high potential for genetic diversity, gene flow, and mating system analyses in A. colubrina. PMID- 22447985 TI - Isolation and characterization of 15 microsatellite loci in four endangered Amentotaxus species (Taxaceae). AB - PREMISE OF THE STUDY: Fifteen microsatellite loci were developed in an endangered species, Amentotaxus formosana, and were tested in an additional three species, A. argotaenia, A. yunnanensis, and A. poilanei, to evaluate the population structure for conservation efforts and reconstruct the phylogeographic patterns of this ancient lineage. METHODS AND RESULTS: Polymorphic primer sets were developed from A. formosana; the number of alleles ranged from two to 10, with an observed heterozygosity ranging from 0 to 0.60. All of the loci were found to be interspecifically amplifiable. CONCLUSIONS: These polymorphic and transferable loci will be potentially useful for future studies that will focus on identifying distinct genetic units within species and establishing the phylogeographic patterns and the process of speciation among closely related species. PMID- 22447986 TI - Development and characterization of 41 novel EST-SSR markers for Pisum sativum (Leguminosae). AB - PREMISE OF THE STUDY: Expressed sequence tag (EST)-derived simple sequence repeat (SSR) markers were developed in Pisum sativum for further use in genetic studies and breeding programs. METHODS AND RESULTS: Forty-one novel EST-SSR primers were developed and characterized for size polymorphism in 32 Pisum sativum individuals from four populations from China. In each population, the number of alleles per locus ranged from one to seven, with observed heterozygosity and expected heterozygosity ranging from 0 to 0.8889 and 0 to 0.8400, respectively. Furthermore, 53.7% of these markers could be transferred to the related species, Vicia faba. CONCLUSIONS: The developed markers have potential for application in the study of genetic diversity, germplasm appraisal, and marker-assisted breeding in pea and other legume species. PMID- 22447987 TI - Development of microsatellite markers in Fosterella rusbyi (Bromeliaceae) using 454 pyrosequencing. AB - PREMISE OF THE STUDY: Polymorphic microsatellite markers were developed for Fosterella rusbyi (Bromeliaceae) to evaluate the population genetic structure and genetic diversity of natural populations of F. rusbyi and other Fosterella species in Bolivia. METHODS AND RESULTS: 454 pyrosequencing technology was used to generate 73027 sequence reads from F. rusbyi DNA, which together contained 2796 perfect simple sequence repeats (SSRs). Primer pairs were designed for 30 loci, of which 15 were used to genotype 30 F. rusbyi plants from two geographical areas in Bolivia. All markers were polymorphic, with two to nine alleles in the overall sample. Cross-species amplification was tested in 10 additional Fosterella species. Seven loci showed consistent amplification in six or more species. CONCLUSIONS: The 15 SSR markers developed for F. rusbyi are promising candidates for population genetic analyses within F. rusbyi and other species of Fosterella. PMID- 22447988 TI - Organ volume measurements: comparison between MRI and autopsy findings in infants following sudden unexpected death. AB - OBJECTIVE: To assess the accuracy of a semiautomated 3D volume reconstruction method for organ volume measurement by postmortem MRI. METHODS: This prospective study was approved by the institutional review board and the infants' parents gave their consent. Postmortem MRI was performed in 16 infants (1 month to 1 year of age) at 1.5 T within 48 h of their sudden death. Virtual organ volumes were estimated using the Myrian software. Real volumes were recorded at autopsy by water displacement. The agreement between virtual and real volumes was quantified following the Bland and Altman's method. RESULTS: There was a good agreement between virtual and real volumes for brain (mean difference: -0.03% (-13.6 to +7.1)), liver (+8.3% (-9.6 to +26.2)) and lungs (+5.5% (-26.6 to +37.6)). For kidneys, spleen and thymus, the MRI/autopsy volume ratio was close to 1 (kidney: 0.87+/-0.1; spleen: 0.99+/-0.17; thymus: 0.94+/-0.25), but with a less good agreement. For heart, the MRI/real volume ratio was 1.29+/-0.76, possibly due to the presence of residual blood within the heart. The virtual volumes of adrenal glands were significantly underestimated (p=0.04), possibly due to their very small size during the first year of life. The percentage of interobserver and intraobserver variation was lower or equal to 10%, but for thymus (15.9% and 12.6%, respectively) and adrenal glands (69% and 25.9%). CONCLUSIONS: Virtual volumetry may provide significant information concerning the macroscopic features of the main organs and help pathologists in sampling organs that are more likely to yield histological findings. PMID- 22447989 TI - Withdrawal of artificial nutrition and hydration in the neonatal intensive care unit: parental perspectives. AB - OBJECTIVE: To review the experience of the practice of withdrawal of artificial nutrition and hydration (WANH) and to describe parental perspectives on the process. DESIGN: A retrospective chart review and parental survey. SETTING: Tertiary level Neonatal Intensive Care Unit (NICU). PARTICIPANTS: Infants who had WANH after withdrawal of other life-sustaining treatment, and their parents. MAIN OUTCOME MEASURE: Parental perspectives on the care and process were obtained through a survey administered 1 to 4 years after the death of their infant. RESULTS: Fifteen cases (5.5% of all mortality and 0.5% of all admissions) of WANH were identified, and 10 parents participated in the survey. The median (range) gestational age was 40 weeks (31-42) and birth weight was 3409 g (2000-4640). The reason for WANH was predicted poor outcome due to severe neurological injury/disease. The median (range) time between WANH and death was 16 days (2 37). All parents reported favourable perceptions of preparation, support, communication and care. Seven parents reported concerns regarding pain experienced by their infant. Parents reported the ability to spend quality time, creating tangible memories and the virtues and professional qualities of the caregivers to be helpful, but identified that consistency and continuity of care could be improved. CONCLUSION: Within the spectrum of palliative care in neonates, WANH can be a tenable, justifiable and humane practice in the NICU. PMID- 22447990 TI - Listeria monocytogenes: generalised maculopapular rash may be the clue. PMID- 22447991 TI - Transfusion-associated necrotising enterocolitis in neonates. AB - OBJECTIVE: To evaluate the association between blood transfusion in previous 2 days and necrotising enterocolitis (NEC) in infants admitted to neonatal intensive care units in Canada. PATIENTS AND METHODS: Using the Canadian Neonatal Network database of admissions to neonatal intensive care units from 2003 to 2008, cases with NEC were matched with controls by gestational age (GA) at birth. Exposure to transfusion within 2 days of NEC (for cases) or 2 days before the median age of NEC diagnosis among cases of the same GA (for controls) was determined. After controlling for confounders, the differences in characteristics and neonatal outcomes of transfusion-associated NEC (TANEC) and NEC not associated with transfusion (non-TANEC) were compared. RESULTS: NEC cases (n=927) were matched with 2781 controls. Transfusion in previous 2 days was significantly higher in NEC cases than in controls (15.5 vs 7.7%; adjusted OR (AOR) 2. 44; 95% CI 1.87 to 3.18). TANEC cases versus non-TANEC cases had a lower mean GA (25.8 vs 29.3 weeks), a lower mean birthweight (885 vs 1373 grams), and a higher proportion of infants with SNAPII score >20 (52.1 vs 22.9%). After adjustment for confounders, no significant differences in mortality (AOR 1.28, 95% CI 0.82 to 2.01), severe retinopathy (AOR 1.15, 95% CI 0.71 to 1.87), or severe neurological injury (AOR 0.83, 95% CI 0.43 to 1.60) were identified. CONCLUSIONS: Exposure to transfusion in previous 2 days was an independent risk factor for NEC. After controlling for confounders, no significant differences in mortality and morbidities were observed between infants who had transfusion-associated NEC and those with NEC not associated with transfusion. PMID- 22447993 TI - The danger of biopsy in fibrodysplasia ossificans progressiva. PMID- 22447994 TI - Checking pregnancy status in adolescent girls before procedures under general anaesthesia. AB - OBJECTIVE: Surgery, ionising radiation and anaesthesia in the presence of an undetected pregnancy could be harmful. British guidelines state that female patients of 'childbearing age' should have their pregnancy status established before surgery. Approaching this topic with an adolescent girl can be challenging. DESIGN: The authors conducted an observational study and a survey in their institution and a national survey of Association of Paediatric Anaesthetists (APA) linkmen. SETTING: Local: Southampton. National: UK. RESULTS: Both surveys demonstrate widespread concerns about inconsistent and informal practices. Only 45% of respondents in the authors' institution stated they ask adolescent girls if they could be pregnant. 40% of APA linkmen were unaware of national guidelines. CONCLUSIONS: This work illustrates the need for consistent national guidance. We propose that all girls who have reached menarche should be routinely offered a urine pregnancy test before any procedure under general anaesthesia. PMID- 22447992 TI - Genotypic differences in pod wall and seed growth relate to invertase activities and assimilate transport pathways in asparagus bean. AB - BACKGROUND AND AIMS: Coordination of sugar transport and metabolism between developing seeds and their enclosing fruit tissues is little understood. In this study the physiological mechanism is examined using two genotypes of asparagus bean (Vigna unguiculata ssp. sesquipedialis) differing in pod wall and seed growth rates. Pod growth dominates over seed growth in genotype 'Zhijiang 121' but not in 'Zhijiang 282' in which a 'bulging pod' phenotype is apparent from 8 d post-anthesis (dpa) onward. METHODS: Seed and pod wall growth rates and degree of pod-bulging were measured in the two genotypes together with assays of activities of sucrose-degrading enzymes and sugar content in pod wall and seed and evaluation of cellular pathways of phloem unloading in seed coat using a symplasmic fluorescent dye, 5(6)-carboxyfluorescein (CF). KEY RESULTS: Activities of cell wall, cytoplasmic and vacuolar invertases (CWIN, CIN and VIN) were significantly smaller in pod walls of '282' than in '121' at 10 dpa onwards. Low INV activities were associated with weak pod wall growth of '282'. In seed coats, CF was confined within the vasculature in '282' but moved beyond the vasculature in '121', indicating apoplasmic and symplasmic phloem unloading, respectively. Higher CWIN activity in '282' seed coats at 6-8 dpa correlated with high hexose concentration in embryos and enhanced early seed growth. However, CWIN activity in '282' decreased significantly compared with '121' from 10 dpa onwards, coinciding with earlier commencement of nuclei endoreduplication in their embryos. CONCLUSIONS: The study shows genotypic differences between 'bulging pod' and 'non-bulging' phenotypes of asparagus bean in sucrose metabolism in relation to the pathway of phloem unloading in developing seed coats, and to pod and seed growth. Low INV activity in pod wall corresponds to its shortened and weak growth period; by contrast, the apoplasmic path in the seed coat is associated with high CWIN activity and strong early seed growth. PMID- 22447995 TI - Severe hyperlipidaemia complicating diabetic ketoacidosis. PMID- 22447996 TI - Investigation and management of hypercalcaemia in children. AB - Hypercalcaemia is a far less common finding in children than in adults. It may present with characteristic symptoms or may be identified as a coincidental finding in children investigated for a variety of complaints. Assessment of hypercalcaemia requires an understanding of the normal physiological regulation of plasma calcium by the combined actions of parathyroid hormone, 1,25 dihydroxyvitamin D(3) and the calcium sensing receptor. Hypercalcaemia will usually require treatment using a number of different modalities but occasionally it can be due to a benign asymptomatic condition that requires no intervention. This article presents a logical approach to the investigation and subsequent management of this condition. PMID- 22447997 TI - Neuromuscular electrical stimulation for children with cerebral palsy: a review. AB - The aim of this review paper is to consider the application of neuromuscular electrical stimulation (NMES) to improve gait or upper limb function in children with cerebral palsy (CP). Although most NMES research has been directed at adults with neurological conditions, there is a growing body of evidence supporting its use in children with CP. In line with a recent meta-analysis, the use of electrical stimulation to minimise impairment and activity limitations during gait is cautiously advocated. A detailed commentary on one of the most common lower limb NMES applications, tibialis anterior stimulation (either with or without gastrocnemius stimulation) is given. Although there is a lack of randomised controlled trials and a predominance of mainly small studies, this review further concludes that the balance of available evidence is in favour of upper limb exercise NMES offering benefits such as increased muscle strength, range of motion and function in children with CP. The use of dynamic splinting with NMES has been shown to be more effective than either treatment on its own in improving function and posture. There is at present little published work to support the application of botulinum toxin type A to temporarily reduce muscle tone as an adjunct intervention to NMES in this population, although the presence of parallel applications to manage similar symptoms in other muscular disorders is noted. PMID- 22447999 TI - Towards evidence based medicine for paediatricians. Question 1. Does anti-reflux therapy improve symptoms in infants with laryngomalacia? PMID- 22448000 TI - Towards evidence based medicine for paediatricians. Question 2. What is the ideal dose of vitamin D supplementation for term neonates? PMID- 22448001 TI - Towards evidence based medicine for paediatricians. Question 3. Does the administration of glucagon improve the rate of radiological reduction in children with acute intestinal intussusception? PMID- 22448002 TI - Extravaginal reservoirs of vaginal bacteria as risk factors for incident bacterial vaginosis. AB - BACKGROUND: Bacterial vaginosis (BV) represents shifts in microbiota from Lactobacillus spp. to diverse anaerobes. Although antibiotics relieve symptoms and temporarily eradicate BV-associated bacteria (BVAB), BV usually recurs. We investigated the role of extravaginal BVAB reservoirs in recurrence. METHODS: Risks for BV acquisition over the course of 1 year were defined. DNA in vaginal, anal, and oral swab samples from enrollment was subjected to quantitative polymerase chain reaction assays targeting 16S ribosomal RNA genes of Gardnerella vaginalis, Lactobacillus crispatus, BVAB1, BVAB2, BVAB3, Megasphaera spp., Lactobacillus jensenii, and Leptotrichia/Sneathia spp. A case-control approach analyzed BVAB detection at enrollment for case patients (BV acquisition) versus controls (none). RESULTS: Of 239 women enrolled without BV, 199 were seen in follow-up, and 40 experienced BV; 15 had all samples for analysis. Detection of G. vaginalis in oral cavity or anal samples and Leptotrichia/Sneathia spp. in anal samples was more common at enrollment among case patients, who also had higher concentrations of these bacteria and Megasphaera relative to 30 controls at each site. In contrast, L. crispatus was detected more frequently in anal samples among controls. CONCLUSIONS: Women who acquire BV are more likely have previous colonization of extravaginal reservoirs with some BVAB, and less likely to have L. crispatus, suggesting that BVAB may be acquired vaginally from extravaginal reservoirs. PMID- 22448003 TI - Second-line antiretroviral treatment successfully resuppresses drug-resistant HIV 1 after first-line failure: prospective cohort in Sub-Saharan Africa. AB - Little is known about the effect of human immunodeficiency virus type 1 (HIV-1) resistance mutations present at time of regimen switch on the response to second line antiretroviral therapy in Africa. In adults who switched to boosted protease inhibitor-based regimens after first-line failure, HIV-RNA and genotypic resistance testing was performed at switch and after 12 months. Factors associated with treatment failure were assessed using logistic regression. Of 243 participants, 53% were predicted to receive partially active second-line regimens due to drug resistance. The risk of treatment failure was, however, not increased in these participants. In this African cohort, boosted protease inhibitors successfully resuppressed drug-resistant HIV after first-line failure. PMID- 22448004 TI - Targeting pan-resistant bacteria with antibodies to a broadly conserved surface polysaccharide expressed during infection. AB - BACKGROUND: New therapeutic targets for antibiotic-resistant bacterial pathogens are desperately needed. The bacterial surface polysaccharide poly-beta-(1-6)-N acetyl-glucosamine (PNAG) mediates biofilm formation by some bacterial species, and antibodies to PNAG can confer protective immunity. By analyzing sequenced genomes, we found that potentially multidrug-resistant bacterial species such as Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, and the Burkholderia cepacia complex (BCC) may be able to produce PNAG. Among patients with cystic fibrosis patients, highly antibiotic-resistant bacteria in the BCC have emerged as problematic pathogens, providing an impetus to study the potential of PNAG to be targeted for immunotherapy against pan-resistant bacterial pathogens. METHODS: The presence of PNAG on BCC was assessed using a combination of bacterial genetics, microscopy, and immunochemical approaches. Antibodies to PNAG were tested using opsonophagocytic assays and for protective efficacy against lethal peritonitis in mice. RESULTS: PNAG is expressed in vitro and in vivo by the BCC, and cystic fibrosis patients infected by the BCC species B. dolosa mounted a PNAG-specific opsonophagocytic antibody response. Antisera to PNAG mediated opsonophagocytic killing of BCC and were protective against lethal BCC peritonitis even during coinfection with methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Our findings raise potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogens. PMID- 22448005 TI - Sequence analysis of Kaposi sarcoma-associated herpesvirus (KSHV) microRNAs in patients with multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome. AB - BACKGROUND: Kaposi sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs that yield 25 mature microRNAs. We previously reported phylogenetic analysis of the microRNA-coding region of KSHV from Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD) patients. We observed a high level of conservation for most sequences but also a divergent cluster of 5 KSHV sequences, including 2 from MCD patients. METHODS: KSHV microRNA sequences from 23 MCD patients and 7 patients with a newly described KSHV-associated inflammatory cytokine syndrome (KICS) were examined by amplification, cloning, and sequencing of a 646-bp fragment of K12/T0.7 encoding microRNA-K12-10 and microRNA-K12-12 and a 2.8-kbp fragment containing the remaining 10 pre-microRNAs. RESULTS: Phylogenetic analysis showed a distinct variant cluster consisting exclusively of MCD and KICS patients in all trees. Pearson chi(2) analysis revealed that 40 single-nucleotide polymorphisms (SNPs) at various loci were significantly associated with MCD and KICS risk. Cluster analysis of these SNPs generated several combinations of 3 SNPs as putative indicators of MCD and KICS risk. CONCLUSIONS: These findings show that MCD and KICS patients frequently have unusual KSHV microRNA sequences and suggest an association between the observed sequence variation and risk of MCD and KICS. PMID- 22448006 TI - Combination antiviral therapy for influenza: predictions from modeling of human infections. AB - Emergence of resistance is a major concern in influenza antiviral treatment and prophylaxis. Combination antiviral therapy might overcome this problem. Here, we estimate that all possible single mutants and a sizeable fraction of double mutants are generated during an uncomplicated influenza infection. While most of them may sustain a fitness cost, some variants may confer drug resistance and be selected during therapy. We argue that a triple combination regimen would markedly reduce the risk of antiviral resistance emergence in seasonal and pandemic influenza viruses, especially in seriously ill or immunocompromised hosts. PMID- 22448007 TI - Waning intestinal immunity after vaccination with oral poliovirus vaccines in India. AB - BACKGROUND: The eradication of wild-type polioviruses in areas with efficient fecal-oral transmission relies on intestinal mucosal immunity induced by oral poliovirus vaccine (OPV). Mucosal immunity is thought to wane over time but the rate of loss of protection has not been examined. METHODS: We examined the degree and duration of intestinal mucosal immunity in India by measuring the prevalence of vaccine poliovirus in stool samples collected 4-28 days after a "challenge" dose of OPV among 47 574 children with acute flaccid paralysis reported during 2005-2009. RESULTS: Previous vaccination with OPV was protective against excretion of vaccine poliovirus after challenge, but the odds of excretion increased significantly with the time since the child was last exposed to an immunization activity (odds ratio, 1.39 [95% confidence interval .99-1.97], 2.04 [1.28-3.25], and 1.31 [1.00-1.70] comparing >=6 months with 1 month ago for serotypes 1, 2, and 3, respectively). Vaccine administered during the high season for enterovirus infections (April-September) was significantly less likely to result in excretion, especially in northern states (odds ratio, 0.57 [95% confidence interval, .50-.65], 0.58 [.41-.81], and 0.48 [.40-.57] for serotypes 1, 2, and 3). CONCLUSIONS: Infection with OPV (vaccine "take") is highly seasonal in India and results in intestinal mucosal immunity that appears to wane significantly within a year of vaccination. PMID- 22448008 TI - Epigenetic dysregulation of virulence gene expression in severe Plasmodium falciparum malaria. AB - Chronic infections with the human malaria parasite Plasmodium falciparum depend on antigenic variation. P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major erythrocyte surface antigen mediating parasite sequestration in the microvasculature, is encoded in parasites by a highly diverse family of var genes. Antigenic switching is mediated by clonal variation in var expression, and recent in vitro studies have demonstrated a role for epigenetic processes in var regulation. Expression of particular PfEMP1 variants may result in parasite enrichment in different tissues, a factor in the development of severe disease. Here, we study in vivo human infections and provide evidence that infection induced stress responses in the host can modify PfEMP1 expression via the perturbation of epigenetic mechanisms. Our work suggests that severe disease may not be the direct result of an adaptive virulence strategy to maximize parasite survival but that it may indicate a loss of control of the carefully regulated process of antigenic switching that maintains chronic infections. PMID- 22448009 TI - The recombinant hepatitis B surface antigen vaccine in persons with HIV: is seroconversion sufficient for long-term protection? AB - A cohort of human immunodeficiency virus (HIV)-infected individuals with documented vaccine-induced hepatitis B surface antibody (HBsAb) seroconversion was evaluated retrospectively to determine factors associated with loss of protective levels of HBsAb. After a median follow-up of 43 months, 111 of the 152 participants (73%) maintained protective levels of HBsAb. HIV RNA suppression at vaccination was associated with persistence of protective levels of HBsAb (odds ratio, 3.83; P < .01). Booster doses were provided for those with loss of protective antibody levels, and hepatitis B virus-specific immune memory, as evaluated with T-cell proliferation assays, was poor despite the observation that boosters successfully reinduced protective levels of HBsAb. PMID- 22448010 TI - CD28-negative CD4+ and CD8+ T cells in antiretroviral therapy-naive HIV-infected adults enrolled in adult clinical trials group studies. AB - BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) have higher risk than HIV-negative individuals for diseases associated with aging. T cell senescence, characterized by expansion of cells lacking the costimulatory molecule CD28, has been hypothesized to mediate these risks. METHODS: We measured the percentage of CD28(-)CD4(+) and CD8(+) T cells from HIV-infected treatment naive adults from 5 Adult Clinical Trials Group (ACTG) antiretroviral therapy (ART) studies and the ALLRT (ACTG Longitudinal Linked Randomized Trials) cohort, and from 48 HIV-negative adults. Pretreatment and 96-week posttreatment %CD28(-) cells were assessed using linear regression for associations with age, sex, race/ethnicity, CD4 count, HIV RNA, ART regimen, and hepatitis C virus (HCV) infection. RESULTS: In total, 1291 chronically HIV-infected adults were studied. Pretreatment, lower CD4 count was associated with higher %CD28(-)CD4(+) and %CD28(-)CD8(+) cells. For CD8(+) cells, younger age and HCV infection were associated with a lower %CD28(-). ART reduced %CD28(-) levels at week 96 among virally suppressed individuals. Older age was strongly predictive of higher %CD28(-)CD8(+). Compared to HIV-uninfected individuals, HIV-infected individuals maintained significantly higher %CD28(-). CONCLUSIONS: Effective ART reduced the proportion of CD28(-) T cells. However, levels remained abnormally high and closer to levels in older HIV-uninfected individuals. This finding may inform future research of increased rates of age-associated disease in HIV-infected adults. PMID- 22448011 TI - A computationally optimized hemagglutinin virus-like particle vaccine elicits broadly reactive antibodies that protect nonhuman primates from H5N1 infection. AB - BACKGROUND: Highly pathogenic H5N1 avian influenza viruses continue to spread via waterfowl, causing lethal infections in humans. Vaccines can prevent the morbidity and mortality associated with pandemic influenza isolates. Predicting the specific isolate that may emerge from the 10 different H5N1 clades is a tremendous challenge for vaccine design. METHODS: In this study, we generated a synthetic hemagglutinin (HA) on the basis of a new method, computationally optimized broadly reactive antigen (COBRA), which uses worldwide sequencing and surveillance efforts that are specifically focused on sequences from H5N1 clade 2 human isolates. RESULTS: Cynomolgus macaques vaccinated with COBRA clade 2 HA H5N1 virus-like particles (VLPs) had hemagglutination-inhibition antibody titers that recognized a broader number of representative isolates from divergent clades as compared to nonhuman primates vaccinated with clade 2.2 HA VLPs. Furthermore, all vaccinated animals were protected from A/Whooper Swan/Mongolia/244/2005 (WS/05) clade 2.2 challenge, with no virus detected in the nasal or tracheal washes. However, COBRA VLP-vaccinated nonhuman primates had reduced lung inflammation and pathologic effects as compared to those that received WS/05 VLP vaccines. CONCLUSIONS: The COBRA clade 2 HA H5N1 VLP elicits broad humoral immunity against multiple H5N1 isolates from different clades. In addition, the COBRA VLP vaccine is more effective than a homologous vaccine against a highly pathogenic avian influenza virus challenge. PMID- 22448012 TI - Aging population and future burden of pneumococcal pneumonia in the United States. AB - Pneumococcal pneumonia is concentrated among the elderly. Using a decision analytic model, we projected the future incidence of pneumococcal pneumonia and associated healthcare utilization and costs accounting for an aging US population. Between 2004 and 2040, as the population increases by 38%, pneumococcal pneumonia hospitalizations will increase by 96% (from 401 000 to 790 000), because population growth is fastest in older age groups experiencing the highest rates of pneumococcal disease. Absent intervention, the total cost of pneumococcal pneumonia will increase by $2.5 billion annually, and the demand for healthcare services for pneumococcal pneumonia, especially inpatient capacity, will double in coming decades. PMID- 22448014 TI - Local immune responses in human tuberculosis: learning from the site of infection. AB - Host-pathogen interactions in tuberculosis should be studied at the disease site because Mycobacterium tuberculosis is predominately contained in local tissue lesions. Although M. tuberculosis infection involves different clinical forms of tuberculosis, such as pulmonary tuberculosis, pleural tuberculosis, and lymph node tuberculosis, most studies of human tuberculosis are performed using cells from the peripheral blood, which may not provide a proper reflection of the M. tuberculosis-specific immune responses induced at the local site of infection. A very low proportion of M. tuberculosis-specific effector T cells are found in the blood compared with the infected tissue, and thus there may be considerable differences in the cellular immune response and regulatory mechanisms induced in these diverse compartments. In this review, we discuss differences in the immune response at the local site of infection compared with the peripheral circulation. The cell types and immune reactions involved in granuloma formation and maintenance as well as the in situ technologies used to assess local tuberculosis pathogenesis are also described. We need to strengthen and improve the exploratory strategies used to dissect immunopathogenesis in human tuberculosis with the aim to accelerate the implementation of relevant research findings in clinical practice. PMID- 22448013 TI - Associations between phylogenetic clustering and HLA profile among HIV-infected individuals in San Diego, California. AB - BACKGROUND: Specific sequence changes of human immunodeficiency virus type 1 (HIV 1) in the presence of specific HLA molecules may alter the composition and processing of viral peptides, leading to immune escape. Persistence of these mutations after transmission may leave the genetic fingerprint of the transmitter's HLA profile. Here, we evaluated the associations between HLA profiles and the phylogenetic relationships of HIV sequences sampled from a cohort of recently infected individuals in San Diego, California. METHODS: We identified transmission clusters within the study cohort, using phylogenetic analysis of sampled HIV pol genotypes at a genetic distance of <1.5%. We then evaluated the association of specific HLA alleles, HLA homozygosity, HLA concordance, race and ethnicity, and mutational patterns within the clustering and nonclustering groups. RESULTS: From 350 cohort participants, we identified 162 clustering individuals and 188 nonclustering individuals. We identified trends for enrichment of particular alleles within individual clusters and evidence of viral escape within those clusters. We also found that discordance of HLA alleles was significantly associated with clustering individuals. CONCLUSIONS: Some transmission clusters demonstrate HLA enrichment, and viruses in these HLA-associated clusters often show evidence of escape to enriched alleles. Interestingly, HLA discordance was associated with clustering in our predominantly MSM population. PMID- 22448015 TI - Tuberculosis and HIV control in sub-Saharan African prisons: "thinking outside the prison cell". AB - Tuberculosis is one of the fastest-growing epidemics in prison populations in sub Saharan Africa (SSA), constituting a threat to both inmates and the wider community. Various factors have contributed to the breakdown of tuberculosis control in prison facilities in SSA, including slow and insensitive diagnostics, failing prison infrastructure, inadequate funding, and weak prevention and treatment interventions for human immunodeficiency virus (HIV). In this article, we describe the challenges inherent in current approaches to tuberculosis control in prisons and consider the alternatives. We argue that although improved implementation of conventional tuberculosis control activities is necessary, considerable investment in a broader range of public health interventions, including infrastructure and staffing upgrades, cutting-edge tuberculosis diagnostics, and combination prevention for HIV, will be equally critical. This combination response to tuberculosis in prisons will be essential for tackling existing and nascent prison tuberculosis epidemics and will require high-level political support and financing. PMID- 22448016 TI - Strategies and challenges involved in the discovery of new chemical entities during early-stage tuberculosis drug discovery. AB - There is an increasing flow of new antituberculosis chemical entities entering the tuberculosis drug development pipeline. Although this is encouraging, the current number of compounds is too low to meet the demanding criteria required for registration, shorten treatment duration, treat drug-resistant infection, and address pediatric tuberculosis cases. More new chemical entities are needed urgently to supplement the pipeline and ensure that more drugs and regimens enter clinical practice. Most drug discovery projects under way exploit enzyme systems deemed essential in a specific Mycobacterium tuberculosis biosynthetic pathway or develop chemical scaffolds identified by phenotypic screening of compound libraries, specific pharmacophores or chemical clusters, and natural products. Because the development of a compound for treating tuberculosis is even longer than for treating other infection indications, the identification of selective, potent, and safe chemical entities early in the drug development process is essential to ensure that the pipeline is filled with new candidates that have the best chance to reach the clinic. PMID- 22448017 TI - Rational development of adjunct immune-based therapies for drug-resistant tuberculosis: hypotheses and experimental designs. AB - The poor treatment outcomes for extensively drug-resistant and multidrug resistant tuberculosis and the slow progress in development and evaluation of new tuberculosis drugs gave rise to development of several potential immune-based therapies for adjunct use with drug treatment. However, none of these therapies have been shown to be of benefit in controlled clinical trials in humans. There is an urgent need to rethink the immunology of Mycobacterium tuberculosis infection and to ascertain protective immune mechanisms that could be exploited to develop more effective adjunct immune therapies. T cells obtained from the peripheral blood circulation may not reflect the biologically relevant recognition of anti-M. tuberculosis T-cell responses in situ. Thus, T cells that mediate protective anti-M. tuberculosis immune responses recognize an as-yet undiscovered set of M. tuberculosis antigens that require definition. The biologically and clinically relevant M. tuberculosis targets that elicit protective immune responses may have yet to be discovered. The entire M. tuberculosis proteome is now accessible for screening by antibody recognition and can therefore be used to identify specific T-cell M. tuberculosis target antigens. Inhibitory cytokines and lymphocytosis present in chronic tuberculosis inflammation may be deleterious in mounting an effective M. tuberculosis T-cell response. Consequently, aberrant and noneffective immune responses could be refocused with anticytokine or cellular therapy. Epigenetic changes due to chronic inflammation may be responsible, in part, for impaired immune responses in tuberculosis and these changes could be reversed. We present feasible experimental designs to test these hypotheses; the results of which may guide and refocus development of novel immune-based therapies for adjunct treatment of drug resistant tuberculosis. Insights from cancer immunology will cross-fertilize tuberculosis immunology and help to devise more effective adjunct treatment and vaccination strategies. PMID- 22448018 TI - Prevention, diagnosis, and treatment of tuberculosis in children and mothers: evidence for action for maternal, neonatal, and child health services. AB - Tuberculosis affected an estimated 8.8 million people and caused 1.4 million deaths globally in 2010, including a half-million women and at least 64 000 children. It also results in nearly 10 million cumulative orphans due to parental deaths. Moreover, it causes 6%-15% of all maternal mortality, which increases to 15%-34% if only indirect causes are considered. Increasingly, more women with tuberculosis are notified than men in settings with a high prevalence of human immunodeficiency virus (HIV), and maternal tuberculosis increases the vertical transmission of HIV. Tuberculosis prevention, diagnosis, and treatment services should be included as key interventions in the integrated management of pregnancy and child health. Tuberculosis screening using a simple clinical algorithm that relies on the absence of current cough, fever, weight loss, and night sweats should be used to identify eligible pregnant women living with HIV for isoniazid preventive therapy or for further investigation for tuberculosis disease as part of services for prevention of vertical HIV transmission. While implementing these simple, low-cost, effective interventions as part of maternal, neonatal, and child health services, the unmet basic and operational tuberculosis research needs of children, pregnant, and breastfeeding women should be addressed. National policy makers, program managers, and international stakeholders (eg, United Nations bodies, donors, and implementers) working on maternal, neonatal, and child health, especially in HIV-prevalent settings, should give due attention and include tuberculosis prevention, diagnosis, and treatment services as part of their core functions and address the public health impacts of tuberculosis in their programs and services. PMID- 22448019 TI - Eliminating tuberculosis and tuberculosis-HIV co-disease in the 21st century: key perspectives, controversies, unresolved issues, and needs. PMID- 22448020 TI - The immunological footprint of Mycobacterium tuberculosis T-cell epitope recognition. AB - Aerosols containing Mycobacterium tuberculosis (MTB) generated from the cough of patients with active pulmonary tuberculosis are the source of MTB infection. About 70% of individuals exposed to infected aerosols do not get infected, depending on the intensity and duration of MTB exposure. Only 40% of the rest of the individuals (about 10% of those originally exposed) develop primary tuberculosis, whereas the remaining 60% contain the infection with generation of a robust immune response leading to latent tuberculosis, which is regarded as a spectrum rather than a single entity. The mechanisms involved in this natural protection are not yet well understood. There is an increasing need to integrate all disparate observations into a coherent systems biology approach for a comprehensive understanding: we need to decipher the nature of success and failure in MTB infection in humans. New advances in cellular immunology will aid in achieving that goal. We review here the nature of MTB peptide generation, antigen presentation, and detection of major histocompatibility complex class I and II-presented T-cell epitopes. Cross-sectional thinking from lessons learned in the context of the major efforts to develop vaccines will help to dissect biologically relevant mechanisms that need to be translated into the clinical context of MTB infection with the aim to (1) better understand clinically relevant T-cell responses in individuals protected from tuberculosis disease and develop markers of immune protection and vaccine take, (2) characterize the nature of the immune response in individuals who are not able to contain MTB infection, and ultimately (3) characterize markers to gauge response to therapy. PMID- 22448021 TI - Viewpoint: Challenges and opportunities in tuberculosis research. PMID- 22448022 TI - New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future. AB - For the first time in 40 years, a portfolio of promising new compounds for the treatment of tuberculosis is on the horizon. The introduction of new drugs in combination treatment for all forms of tuberculosis raises several issues related to patients' access to novel treatments, programmatic feasibility, cost effectiveness, and implications for monitoring and surveillance, particularly with regard to the development of drug resistance. Particular attention should be given to the identification of optimal drug combination(s) for the treatment of all forms of tuberculosis, particularly in high-risk and vulnerable groups, such as human immunodeficiency virus-coinfected persons and children, and to the rational use of new drugs. Addressing these issues adequately requires the establishment of clear guidelines to assist countries in the development of policies for the proper use of tuberculosis drugs in a way that guarantees access to best treatments for all those in need and avoids inappropriate use of new drugs. After a description of these various challenges, we present activities that will be carried out by the World Health Organization in collaboration with key stakeholders for the development of policy guidelines for optimal treatment of tuberculosis. PMID- 22448023 TI - Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel. AB - There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis. PMID- 22448024 TI - Tuberculosis and tuberculosis/HIV/AIDS-associated mortality in Africa: the urgent need to expand and invest in routine and research autopsies. AB - Frequently quoted statistics that tuberculosis and human immunodeficiency virus (HIV)/AIDS are the most important infectious causes of death in high-burden countries are based on clinical records, death certificates, and verbal autopsy studies. Causes of death ascertained through these methods are known to be grossly inaccurate. Most data from Africa on mortality and causes of death currently used by international agencies have come from verbal autopsy studies, which only provide inaccurate estimates of causes of death. Autopsy rates in most sub-Saharan African countries have declined over the years, and actual causes of deaths in the community and in hospitals in most sub-Saharan African countries remain unknown. The quality of cause-specific mortality statistics remains poor. The effect of various interventions to reduce mortality rates can only be evaluated accurately if cause-specific mortality data are available. Autopsy studies could have particular relevance to direct public health interventions, such as vaccination programs or preventive therapy, and could also allow for study of background levels of subclinical tuberculosis disease, Mycobacterium tuberculosis-HIV coinfection, and other infectious and noncommunicable diseases not yet clinically manifest. Autopsies performed soon after death may represent a unique opportunity to understand the pathogenesis of M. tuberculosis and the pathogenesis of early deaths after initiation of antiretroviral therapy. The few autopsies performed so far for research purposes have yielded invaluable information and insights into tuberculosis, HIV/AIDS, and other opportunistic infections. Accurate cause-specific mortality data are essential for prioritization of governmental and donor investments into health services to reduce morbidity and mortality from deadly infectious diseases such as tuberculosis and HIV/AIDS. There is an urgent need for reviving routine and research autopsies in sub-Saharan African countries. PMID- 22448025 TI - Controversies and unresolved issues in tuberculosis prevention and control: a low burden-country perspective. AB - Despite declining incidence in most high-income countries, tuberculosis shows no signs of disappearing in the near future. Although surveillance data from most Western European countries show relatively stable declines in the rate of tuberculosis over the past several decades, some have reported either an increasing rate or a decelerating pace of reduction in recent years. The burden of disease now disproportionately affects high-risk groups such as migrants, homeless persons, and prisoners. In view of the concentration of cases in urban areas and high-risk deprived groups, interventions that may not be efficient when applied to the general population may be highly cost effective when targeted at high-risk groups. In this article, we examine some controversial elements of tuberculosis prevention and control in low-burden countries and recommend issues for further research. In particular, we assess current evidence on the duration of protection by BCG vaccine, the screening of migrants and hard-to-reach groups, and the use of preventive therapy for contacts of cases of infectious multidrug resistant tuberculosis. This analysis is presented from the perspective of low tuberculosis-burden, high-income countries attempting to eliminate tuberculosis. PMID- 22448026 TI - Global fund financing of tuberculosis services delivery in prisons. AB - INTRODUCTION: Despite concerted efforts to scale up tuberculosis control with large amounts of international financing in the last 2 decades, tuberculosis continues to be a social issue affecting the world's most marginalized and disadvantaged communities. This includes prisoners, estimated at about 10 million globally, for whom tuberculosis is a leading cause of mortality and morbidity. The Global Fund to Fight AIDS, Tuberculosis and Malaria has emerged as the single largest international donor for tuberculosis control, including funding support in delivering tuberculosis treatment for the confined population. METHODS: The Global Fund grants database, with an aggregate approved investment of $21.7 billion in 150 countries by the end of 2010, was reviewed to identify tuberculosis and human immunodeficiency virus/tuberculosis grants and activities that monitored the delivery of tuberculosis treatment and support activities in penitentiary settings. The distribution and trend of number of countries with tuberculosis prison support was mapped by year, geographic region, tuberculosis or multidrug-resistant tuberculosis burden, and prison population rate. We examined the types of grant recipients managing program delivery, their performance, and the nature and range of services provided. RESULTS: Fifty-three of the 105 countries (50%) with Global Fund-supported tuberculosis programs delivered services within prison settings. Thirty-two percent (73 of 228) of tuberculosis grants, representing $558 million of all disbursements of Global Fund tuberculosis support by the end of 2010, included output indicators related to tuberculosis services delivered in prisons. Nearly two-thirds (64%) of these grants were implemented by governments, with the remaining by civil society and other partners. In terms of services, half (36 of 73) of grants provided diagnosis and treatment and an additional 27% provided screening and monitoring of tuberculosis for prisoners. The range of services tracked was limited in scope and scale, with 69% offering only 1 type of service and less than one-fifth offering 2 types of service. CONCLUSIONS: This study is a preliminary attempt to examine Global Fund investments in the fight against tuberculosis in prison settings. Tuberculosis services delivered in prisons have increased in the last decade, but systematic information on funding levels and gaps, services provided, and cost-effective delivery models for delivering tuberculosis services in prisons are lacking. PMID- 22448027 TI - Innovative trial designs are practical solutions for improving the treatment of tuberculosis. AB - A growing number of new drugs for the treatment of tuberculosis are in clinical development. Confirmatory phase 3 trials are expensive and time-consuming and the question of whether one particular drug combination can be used to treat tuberculosis is less important from a public health perspective than the question of which are the shortest, simplest, most effective, and safest regimens. While preclinical and phase 1 studies provide some guidance in the selection of combinations for clinical evaluation, a large number of combinations will require phase 2 testing to ensure that only the best regimens advance to phase 3. The multi-arm multi-stage trial design is an example of a treatment selection adaptive design where multiple experimental arms are each simultaneously compared with a common control and interim analyses allow for poor performing arms to be dropped early. Such designs, if designed and implemented correctly, require fewer patients, can be completed in a shorter time frame, and answer more relevant questions without any loss in statistical validity or scientific integrity. There are, however, practical issues that must be considered in applying this in tuberculosis treatment trials. More innovative trials designs should be considered to speed drug and regimen development for the treatment of tuberculosis. PMID- 22448028 TI - Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24. AB - Protein farnesyltransferase (FTase) inhibitors, generally called "FTIs," block the farnesylation of prelamin A, inhibiting the biogenesis of mature lamin A and leading to an accumulation of prelamin A within cells. A recent report found that a GGTI, an inhibitor of protein geranylgeranyltransferase-I (GGTase-I), caused an exaggerated accumulation of prelamin A in the presence of low amounts of an FTI. This finding was interpreted as indicating that prelamin A can be alternately prenylated by GGTase-I and that inhibiting both protein prenyltransferases leads to more prelamin A accumulation than blocking FTase alone. Here, we tested an alternative hypothesis-GGTIs are not specific for GGTase-I, and they lead to prelamin A accumulation by inhibiting ZMPSTE24 (a zinc metalloprotease that converts farnesyl-prelamin A to mature lamin A). In our studies, commonly used GGTIs caused prelamin A accumulation in human fibroblasts, but the prelamin A in GGTI-treated cells exhibited a more rapid electrophoretic mobility than prelamin A from FTI-treated cells. The latter finding suggested that the prelamin A in GGTI-treated cells might be farnesylated (which would be consistent with the notion that GGTIs inhibit ZMPSTE24). Indeed, metabolic labeling studies revealed that the prelamin A in GGTI-treated fibroblasts is farnesylated. Moreover, biochemical assays of ZMPSTE24 activity showed that ZMPSTE24 is potently inhibited by a GGTI. Our studies show that GGTIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. Thus, caution is required when interpreting the effects of GGTIs on prelamin A processing. PMID- 22448029 TI - Role of leptin in the pancreatic beta-cell: effects and signaling pathways. AB - Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic beta-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the beta-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, beta-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the beta cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic beta-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of beta-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic beta-cell. PMID- 22448030 TI - Methylation of human papillomavirus type 16 genome and risk of cervical precancer in a Costa Rican population. AB - BACKGROUND: Previous studies have suggested an association between human papillomavirus type 16 (HPV16) genome methylation and cervical intraepithelial neoplasia grade 3 (CIN3) (ie, cervical precancer) and cancer, but the results have been inconsistent. METHODS: We designed a case-control study within a large prospective cohort of women who underwent multiple screenings for cervical cancer in Guanacaste, Costa Rica. Diagnostic specimens were collected at the time of CIN3 diagnosis (n = 30 case subjects) and persistent HPV16 infection (persistence; n = 35 case subjects), prediagnostic specimens at the first HPV16 positive screening visit (n = 20 CIN3 case subjects; n = 35 persistence case subjects), and control specimens from women with infection clearance within 2 years (n = 34 control subjects). DNA extracted from specimens (cervical cells) was analyzed for methylation levels at 67 CpG sites throughout the HPV16 genome using pyrosequencing. Benjamini-Hochberg method was used to account for multiple testing. Associations between methylation levels and risk of CIN3 or persistence were assessed using logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Increased methylation in diagnostic vs control specimens at nine CpG sites, three in each L1, L2, and E2/E4 genomic regions, was associated with an increased risk of CIN3 (third tertile [high] vs first and second tertiles combined [low], OR = 3.29 [95% CI = 1.16 to 9.34] to 11.12 [95% CI = 2.29 to 76.80]) and persistence. High methylation at three of these CpG sites was associated with a much higher risk when combined compared with low methylation at these sites (OR = 52, 95% CI = 4.0 to 670). In prediagnostic vs control specimens, increased methylation at a CpG site (nucleotide position 4261) in L2 was associated with an increased risk of CIN3. CONCLUSION: In this HPV16-infected cohort, increased methylation of CpG sites within the HPV16 genome before diagnosis and at the time of diagnosis was associated with cervical precancer. PMID- 22448031 TI - Relationship between movement disorders and obsessive-compulsive disorder: beyond the obsessive-compulsive-tic phenotype. A systematic review. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) and symptoms (OC symptoms) are associated with tic disorders and share an aetiological relationship. The extent to which OCD/OC symptoms are correlated with other hyperkinetic movement disorders is unclear. The aim of this review was to investigate this co occurrence and the extent to which OCD/OC symptoms and hyperkinetic movement disorders share a neurobiological basis. METHODS: A systematic review was performed, specifically searching for OCD/OC symptom comorbidity in hyperkinetic movement disorders using case control studies, longitudinal studies and family based studies. The literature search was conducted using PubMed and PsycINFO databases. RESULTS: Heterogeneity of measurement instruments to detect OCD diagnosis and OC symptoms decreased comparability between studies. The most convincing evidence for a relationship was found between the choreas (Huntington's disease and Sydenham's chorea) and OCD/OC symptoms. Furthermore, elevated frequencies of OC symptoms were found in small case control series of dystonias. Small family based studies in dystonia subtypes modestly suggest shared familial/genetic relationships between OC symptoms and dystonia. CONCLUSION: Current data indicate a relationship between OCD/OC symptoms and the choreas. As OCD and the choreas have been associated with dysfunctional frontal striatal circuits, the observed relationships might converge at the level of dysfunctions of these circuits. However, paucity of longitudinal and family studies hampers strong conclusions on the nature of the relationship. IMPLICATIONS: The relationship between OCD and movement disorders needs further elaboration using larger family based longitudinal studies and sound instruments to characterise OC symptomatology. This could lead to better understanding of the shared pathology between OCD and hyperkinetic movement disorders. PMID- 22448032 TI - Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. AB - The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested. PMID- 22448033 TI - Impact of 18F-FDG PET used after initial treatment of cancer: comparison of the National Oncologic PET Registry 2006 and 2009 cohorts. AB - Since 2006, the National Oncologic PET Registry has collected prospective data on (18)F-FDG PET performed for cancer indications in Medicare beneficiaries under the coverage-with-evidence-development (CED) policy of the Centers for Medicare & Medicaid Services. In April 2009, coverage for PET performed to inform the initial treatment strategy of most solid tumors was expanded by the Centers for Medicare & Medicaid Services, but they continued to require CED for subsequent treatment strategy evaluations for many cancers. METHODS: For all years, we assessed National Oncologic PET Registry data for bladder, kidney, pancreas, prostate, stomach, small cell lung, uterine, and all other cancers that required CED. We compared clinical profiles and changes in intended management by interval (before or after April 2009, designated as the 2006 and 2009 cohorts) for PET scans performed for restaging or suspected recurrence (2006, n = 30,911; 2009, n = 54,747) or for chemotherapy monitoring (2006, n = 10,234; 2009, n = 15,611). RESULTS: There were slight differences between time periods but little difference by cancer type or patient age within a time period. For restaging or suspected recurrence, comparing the 2006 and 2009 cohorts, total change in intended management for all cancer types was about 33% in those younger than 65 y and about 35% in those older than 65 y (range by cancer type, 31%-41%). The referring physician impression of disease extent (restaging) or prognosis (chemotherapy monitoring) after PET was similar between cohorts. In the 2009 cohort, PET for chemotherapy monitoring was associated with a 25% increase in plans to continue therapy and a complementary decline in plans to adjust therapy. The greatest management impact of PET was during chemotherapy monitoring in the 2009 cohort, where a post-PET prognosis judged to be worse than before PET was associated with a plan to discontinue that therapy in 90% and to change to a different therapy in 65%. CONCLUSION: Our data demonstrate a similar impact of PET on planned management of cancer patients before and after the 2009 expansion of coverage. These results strongly suggest it is unlikely that new useful information will be obtained by extending the coverage of certain cancer types and indications only under CED. Future research on advanced imaging in the management of patients with cancer should focus on optimal sequencing and frequency of PET and other imaging modalities. PMID- 22448035 TI - PINK1- and Parkin-mediated mitophagy at a glance. PMID- 22448036 TI - Mitochondrial redox signalling at a glance. PMID- 22448037 TI - Mitochondria and cell signalling. AB - Mitochondria have long been considered as crucial organelles, primarily for their roles in biosynthetic reactions such as ATP synthesis. However, it is becoming increasingly apparent that mitochondria are intimately involved in cell signalling pathways. Mitochondria perform various signalling functions, serving as platforms to initiate cell signalling, as well as acting as transducers and effectors in multiple processes. Here, we discuss the active roles that mitochondria have in cell death signalling, innate immunity and autophagy. Common themes of mitochondrial regulation emerge from these diverse but interconnected processes. These include: the outer mitochondrial membrane serving as a major signalling platform, and regulation of cell signalling through mitochondrial dynamics and by mitochondrial metabolites, including ATP and reactive oxygen species. Importantly, defects in mitochondrial control of cell signalling and in the regulation of mitochondrial homeostasis might underpin many diseases, in particular age-related pathologies. PMID- 22448038 TI - Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2-Cul3-Rbx1 complex to allow normal Nrf2 activation and repression. AB - INrf2 (Keap1) serves as a negative regulator of the cytoprotective transcription factor Nrf2. At basal levels, INrf2 functions as a substrate adaptor to sequester Nrf2 into the Cul3-Rbx1 E3 ligase complex for ubiquitylation and proteasomal degradation. In response to antioxidants, Nrf2 is released from the INrf2-Cul3 Rbx1 complex and translocates into the nucleus, where it activates ARE-mediated cytoprotective gene expression. The present studies demonstrate that INrf2, Cul3 and Rbx1 export out of the nucleus and are degraded during the early or pre induction response to antioxidants. Mutation of Tyr85 in INrf2 stymied the nuclear export of INrf2, suggesting that tyrosine phosphorylation controls the pre-induction nuclear export and degradation in response to antioxidants. The nuclear export of Cul3-Rbx1 were also blocked when INrf2Tyr85 was mutated, suggesting that INrf2-Cul3-Rbx1 undergo nuclear export as a complex. INrf2 siRNA also inhibited the nuclear export of Cul3-Rbx1, confirming that Cul3-Rbx1 requires INrf2 for nuclear export. Newly synthesized INrf2-Cul3-Rbx1 is imported back into the nucleus during the post-induction period to ubiquitylate and degrade Nrf2. Mutation of INrf2Tyr85 had no effect on activation of Nrf2 but led to nuclear accumulation of Nrf2 during the post-induction period owing to reduced export and degradation of Nrf2. Our results also showed that nuclear export and degradation followed by the new synthesis of INrf2-Cul3-Rbx1 controls the cellular abundance of the proteins during different phases of antioxidant responses. In conclusion, the early or pre-induction nuclear export of INrf2 in response to antioxidants is controlled by tyrosine phosphorylation, whereas the nuclear export of Cul3 and Rbx1 is controlled by INrf2, allowing normal activation or repression of Nrf2. PMID- 22448039 TI - Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents. AB - In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses ("the nanomolar rule"). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed. PMID- 22448040 TI - Characteristics of general practices associated with numbers of elective admissions. AB - BACKGROUND: In England both emergency (unplanned) and non-emergency (elective) hospital admissions have been increasing. Some elective admissions are potentially avoidable. AIM: to identify the characteristics of general practices and patients associated with elective admissions. METHODS: A cross-sectional study, in Leicestershire, England, was conducted using admission data (2006-07 and 2007-08). Practice characteristics (list size, distance from principal hospital, quality and outcomes framework score and general practitioner (GP) patient access survey data) and patient characteristics (age, ethnicity and deprivation and gender) were used as predictors of elective hospital admissions in a negative binomial regression model. RESULTS: Practices with a higher proportion of patients aged 65 years or greater and of white ethnicity had higher rates of elective hospital admissions. Practices with more male patients and with more patients reporting being able to consult a particular GP had fewer elective hospital admissions. For 2007-08 practices with a larger list size were associated with higher elective hospital admissions. Quality and outcomes framework performance did not predict admission numbers. CONCLUSIONS: As for unplanned admissions, elective admissions increase as being able to consult a particular GP declines. Interventions to improve continuity should be investigated. Practices face major problems in managing the increased need for planned care as the population ages. PMID- 22448041 TI - Socioeconomic inequalities in childhood exposure to secondhand smoke before and after smoke-free legislation in three UK countries. AB - BACKGROUND: Secondhand smoke (SHS) exposure is higher among lower socioeconomic status (SES) children. Legislation restricting smoking in public places has been associated with reduced childhood SHS exposure and increased smoke-free homes. This paper examines socioeconomic patterning in these changes. METHODS: Repeated cross-sectional survey of 10 867 schoolchildren in 304 primary schools in Scotland, Wales and Northern Ireland. Children provided saliva for cotinine assay, completing questionnaires before and 12 months after legislation. RESULTS: SHS exposure was highest, and private smoking restrictions least frequently reported, among lower SES children. Proportions of saliva samples containing <0.1 ng/ml (i.e. undetectable) cotinine increased from 31.0 to 41.0%. Although across the whole SES spectrum, there was no evidence of displacement of smoking into the home or increased SHS exposure, socioeconomic inequality in the likelihood of samples containing detectable levels of cotinine increased. Among children from the poorest families, 96.9% of post-legislation samples contained detectable cotinine, compared with 38.2% among the most affluent. Socioeconomic gradients at higher exposure levels remained unchanged. Among children from the poorest families, one in three samples contained >3 ng/ml cotinine. Smoking restrictions in homes and cars increased, although socioeconomic patterning remained. CONCLUSIONS: Urgent action is needed to reduce inequalities in SHS exposure. Such action should include emphasis on reducing smoking in cars and homes. PMID- 22448042 TI - The Black Queen Hypothesis: evolution of dependencies through adaptive gene loss. AB - Reductive genomic evolution, driven by genetic drift, is common in endosymbiotic bacteria. Genome reduction is less common in free-living organisms, but it has occurred in the numerically dominant open-ocean bacterioplankton Prochlorococcus and "Candidatus Pelagibacter," and in these cases the reduction appears to be driven by natural selection rather than drift. Gene loss in free-living organisms may leave them dependent on cooccurring microbes for lost metabolic functions. We present the Black Queen Hypothesis (BQH), a novel theory of reductive evolution that explains how selection leads to such dependencies; its name refers to the queen of spades in the game Hearts, where the usual strategy is to avoid taking this card. Gene loss can provide a selective advantage by conserving an organism's limiting resources, provided the gene's function is dispensable. Many vital genetic functions are leaky, thereby unavoidably producing public goods that are available to the entire community. Such leaky functions are thus dispensable for individuals, provided they are not lost entirely from the community. The BQH predicts that the loss of a costly, leaky function is selectively favored at the individual level and will proceed until the production of public goods is just sufficient to support the equilibrium community; at that point, the benefit of any further loss would be offset by the cost. Evolution in accordance with the BQH thus generates "beneficiaries" of reduced genomic content that are dependent on leaky "helpers," and it may explain the observed nonuniversality of prototrophy, stress resistance, and other cellular functions in the microbial world. PMID- 22448043 TI - The chitin connection. AB - Chitin, a polymer of N-acetylglucosamine, is an essential component of the fungal cell wall. Chitosan, a deacetylated form of chitin, is also important in maintaining cell wall integrity and is essential for Cryptococcus neoformans virulence. In their article, Gilbert et al. [N. M. Gilbert, L. G. Baker, C. A. Specht, and J. K. Lodge, mBio 3(1):e00007-12, 2012] demonstrate that the enzyme responsible for chitosan synthesis, chitin deacetylase (CDA), is differentially attached to the cell membrane and wall. Bioactivity is localized to the cell membrane, where it is covalently linked via a glycosylphosphatidylinositol (GPI) anchor. Findings from this study significantly enhance our understanding of cryptococcal cell wall biology. Besides the role of chitin in supporting structural stability, chitin and host enzymes with chitinase activity have an important role in host defense and modifying the inflammatory response. Thus, chitin appears to provide a link between the fungus and host that involves both innate and adaptive immune responses. Recently, there has been increased attention to the role of chitinases in the pathogenesis of allergic inflammation, especially asthma. We review these findings and explore the possible connection between fungal infections, the induction of chitinases, and asthma. PMID- 22448044 TI - Visualization of an alphaherpesvirus membrane protein that is essential for anterograde axonal spread of infection in neurons. AB - Pseudorabies virus (PRV), an alphaherpesvirus with a broad host range, replicates and spreads in chains of synaptically connected neurons. The PRV protein Us9 is a small membrane protein that is highly conserved among alphaherpesviruses and is essential for anterograde axonal spread in neurons. Specifically, the Us9 protein is required for the sorting of newly assembled PRV particles into axons. However, the molecular details underlying the function of Us9 are poorly understood. Here we constructed PRV strains that express functional green fluorescent protein (GFP)-Us9 fusion proteins in order to visualize axonal transport of viral particles in infected rat superior cervical ganglion neurons. We show that GFP Us9-labeled structures are transported exclusively in the anterograde direction within axons. Additionally, the vast majority of anterograde-directed capsids (labeled with VP26-monomeric red fluorescent protein) and a viral membrane protein (labeled with glycoprotein M fused to mCherry) are cotransported with GFP Us9 in the anterograde direction. In contrast, during infection with PRV strains that express nonfunctional mutant GFP-Us9 proteins, cotransport of mutant GFP-Us9 with capsids in axons is abolished. These findings show that axonal sorting of progeny viral particles is dependent upon the association of viral structures with membranes that contain functional Us9 proteins. This association is required for anterograde spread of infection in neurons. IMPORTANCE: Alphaherpesviruses, such as pseudorabies virus (PRV), are parasites of the mammalian nervous system. These viruses spread over long distances in chains of synaptically connected neurons. PRV encodes several proteins that mediate directed virion transport and spread of infection. Us9 is a highly conserved viral membrane protein that is essential for anterograde neuronal spread of infection. In the absence of Us9, newly replicated viral particles are assembled in the cell body but are not sorted into or transported within axons. Here, we constructed and characterized novel PRV strains that express functional green fluorescent protein (GFP)-Us9 fusion proteins in order to visualize its localization in living neurons during infection. This enabled us to better understand the function of Us9 in facilitating the spread of infection. We show that all viral particles moving in the anterograde direction are labeled with GFP-Us9, suggesting that the presence of Us9 determines the capacity for directed transport within axons. PMID- 22448046 TI - Diet of wolves Canis lupus returning to Hungary. AB - At the end of the nineteenth century, the wolf Canis lupus was extinct in Hungary and in recent decades has returned to the northern highland area of the country. The diet of wolves living in groups in Aggteleki National Park was investigated using scat analysis (n = 81 scats) and prey remains (n = 31 carcasses). Throughout the year wolves (average, minimum two wolves per year) consumed mostly wild-living ungulates (mean percent of biomass consumed, B% 97.2%; relative frequency of occurrence, %O 74.0%). The wild boar Sus scrofa was the most common prey item found in wolf scat (%B 35.6%) and is also the most commonly occurring ungulate in the study areas. The second most commonly occurring prey item in wolf scat was red deer Cervus elaphus (B% 32.8%). Conversely, prey remain analyses revealed wild boar as the second most commonly utilised prey species (%O 16.1%) after red deer (%O 67.7%). The roe deer Capreolus capreolus that occurs at lower population densities was the third most commonly utilised prey species. The importance of low population density mouflon Ovis aries, livestock and other food types was low. The results are similar to those found in the northern part of the Carpathian Mountains. PMID- 22448045 TI - Cells lacking beta-actin are genetically reprogrammed and maintain conditional migratory capacity. AB - Vertebrate nonmuscle cells express two actin isoforms: cytoplasmic beta- and gamma-actin. Because of the presence and localized translation of beta-actin at the leading edge, this isoform is generally accepted to specifically generate protrusive forces for cell migration. Recent evidence also implicates beta-actin in gene regulation. Cell migration without beta-actin has remained unstudied until recently and it is unclear whether other actin isoforms can compensate for this cytoplasmic function and/or for its nuclear role. Primary mouse embryonic fibroblasts lacking beta-actin display compensatory expression of other actin isoforms. Consistent with this preservation of polymerization capacity, beta actin knockout cells have unchanged lamellipodial protrusion rates despite a severe migration defect. To solve this paradox we applied quantitative proteomics revealing a broad genetic reprogramming of beta-actin knockout cells. This also explains why reintroducing beta-actin in knockout cells does not restore the affected cell migration. Pathway analysis suggested increased Rho-ROCK signaling, consistent with observed phenotypic changes. We therefore developed and tested a model explaining the phenotypes in beta-actin knockout cells based on increased Rho-ROCK signaling and increased TGFbeta production resulting in increased adhesion and contractility in the knockout cells. Inhibiting ROCK or myosin restores migration of beta-actin knockout cells indicating that other actins compensate for beta-actin in this process. Consequently, isoactins act redundantly in providing propulsive forces for cell migration, but beta-actin has a unique nuclear function, regulating expression on transcriptional and post translational levels, thereby preventing myogenic differentiation. PMID- 22448047 TI - Response to Letter to the Editor Regarding: Comparison of Several Methods of Chromatographic Baseline Removal with a New Approach Based on Quantile Regression. PMID- 22448048 TI - Tuberculosis of the spine. PMID- 22448049 TI - Treatment of displaced intraarticular calcaneal fractures with or without bone grafts: A systematic review of the literature. AB - BACKGROUND: The necessity of bone grafts in the treatment of intraarticular calcaneal fractures continues to be one of the most debated topics in foot and ankle surgery. The purpose of this study was to determine whether there are sufficient objective cumulative data in the literature to compare the two methods and if the bone graft was needed in surgical treatment of intraarticular calcaneal fractures. MATERIALS AND METHODS: A comprehensive search of all relevant articles from 1990 to 2010 was conducted. Two reviewers evaluated each study to determine its suitability for inclusion and collected the data of interest. Meta-analytic pooling of group results across studies was performed for the two treatment methods. RESULTS: The systematic review identified 32 primary studies with 1281 fractures, which contained 4 comparative studies, 13 with bone grafts, and 15 without bone grafts in treatment methods. The infection rate in bone graft group was higher through statistically insignificant than in non-graft group (8.3% vs. 6.3%) No significant difference was found between good reduction rate, postoperative osteoarthritis rate, and subtalar fusion rate. The average full weight-bearing time in bone graft group was significantly lower (5.4 months) than in non-graft group (10.5 months). The mean postoperative Bohler's angle was significantly higher in bone graft group (lose due to collapse was significancy less). For the efficacy outcomes, the bone graft group had a lower American Orthopaedic Foot and Ankle Society Score (AOFAS) (71.4 points vs. 80.5 points) but a higher Creighton score (89.9 points vs. 81.0 points) compared with non graft group. Pooled mean results showed 35% of the patients in bone graft group had an excellent result, 40% had a good result, 21% had a fair result, and 4% had a poor result. In the non-graft group, the corresponding values were 34, 42, 14, and 10%, respectively. CONCLUSIONS: The operative treatment of intraarticular calcaneal fractures with bone grafts could restore the Bohler's angle better and the patients could return to full weight bearing earlier. However, the functional and efficacy outcomes appear to be similar between the two treatment groups. There were more joint depression and comminuted fractures in the bone graft group, and the mean followup time was shorter. Large sample comparative studies are still needed. PMID- 22448050 TI - Efficacy of directly observed treatment short-course intermittent regimen in spinal tuberculosis. AB - BACKGROUND: Most important cause of treatment failure and emergence of drug resistance in the treatment of tuberculosis is noncompliance. Compliance can be improved by direct observation of drug intake, intermittent therapy, and short course treatment. The efficacy of Directly Observed Treatment Short Course (DOTS) strategy advocated by World Health Organization (WHO) in spinal tuberculosis is not yet proven. We conducted a prospective clinical study on a consecutive series of patients with spinal tuberculosis treated by Category I Revised National Tuberculosis Control Programme (RNTCP) regimen based on DOTS strategy of WHO from 2004 to 2007 to evaluate the efficacy. MATERIALS AND METHODS: Forty-nine consecutive patients of spinal tuberculosis were treated with short-course intermittent chemotherapy under Category I RNTCP/DOTS strategy. Patients were followed up for a minimum period of 2 years. Surgery was done if the patient presented with significant neurologic deficit or when the drug treatment failed. Outcome was assessed by clinical, radiologic, and laboratory criteria, and graded into excellent, good, fair, and poor based on various parameters. RESULTS: 63.4% (n=26) of the patients had excellent results. 14.6% (n=6) of the patients had good and fair results. Three patients (7.3%) had poor results 48.7% (n=20) of the patients had but only one of them was severe enough to warrant change of drug. CONCLUSIONS: Efficacy of DOTS was comparable with other standard regimens. There was a significant reduction in adverse side effects when compared with daily regimens. Study showed that the outcome was better in those treated early. PMID- 22448051 TI - The role of debridement and reconstruction of sagittal balance in tuberculous spondylitis. AB - BACKGROUND: An accepted comprehensive clinical approach to the deformed spine with tuberculous infection is still lacking. We aimed to determine the usage of a staged algorithm in the treatment of kyphotic spine with tuberculous infection and to present the clinical results of the patients treated with the help of this protocol. MATERIALS AND METHODS: 54 patients (28 females, 26 males) with a mean age of 39.2 (22-76) years. Preoperative, early postoperative, and followup clinical and radiologic results were evaluated retrospectively. The patients were classified into Kaplan A (kyphotic deformity <30 degrees ), Kaplan B (kyphotic deformity 30 degrees -60 degrees ) and Kaplan C (kyphotic deformity >60 degrees ). They were operated by posterior instrument with anterior debridment (Kaplan A), debridment with anterior bone grafting (Kaplan B) and anterior column resection and bone grafting in Kaplan C. RESULTS: Tuberculous involvement were seen at more than one level in 40 patients and paraspinal abscess were detected in 31. Preoperative focal kyphotic deformity was reconstructed with an average of 19 (9-38) degrees. Twenty-six patients had neurologic compromise with different severities and 12 of them improved after the surgical intervention. Improvement in work ability and pain status was detected in 52% and 61% of the patients, respectively. Wound complications responding to medical care were detected in nine patients. Initial kyphotic deformity was found as an important parameter in selecting the surgical procedure. CONCLUSION: Regarding resected amount of infected osseous material, as planned preoperatively, have resulted with better concordance between anterior and posterior column heights and better sagittal alignment. We could correct kyphosis and improve sagittal balance with staged algorithm as used by us. PMID- 22448052 TI - Spinal tuberculosis in children: Retrospective analysis of 124 patients. AB - BACKGROUND: There is a paucity of report on spinal tuberculosis in children. We report a retrospective analysis of 124 children with TB spine treated over 30 years. MATERIALS AND METHODS: We retrospectively reviewed 124 children; of cervical (n=36), cervicothoracic (n=4), thoracic (n=53), and lumbar and lumbosacral tuberculosis (n=31) with no skip or multifocal lesions treated between 1971-2004. The age ranged from 2 to 15 years of age with 28 children less than 5 years of age, 58 were between 6 and 10 years, and 38 were over 10 years, 18 had paraplegia of various degrees. Ninety-one children were treated conservatively, while 33 children were subjected to surgery for focal debridement (n=23), posterior interspinous wiring and cementation (n=4), and posterior instrumentation with rods and segmental wiring (n=14). Triple chemotherapy (isoniazid, streptomycin, and PAS) was given for 18 months (3HSPa, 15Hpa) between 1971 and 1975, and triple or quadruple chemotherapy (isoniazid, rifampicin, ethambutol, or pyrazinamide) after 1976 to 2004 for 12 months (12RHZ or 12 RHZE). Some of the children in the current series belonged to the British MRC conservative study patients. The average duration of followup was 5 years and 8 months (range 1.6-20 years). RESULTS: All children attained healed status and showed neural recovery (n=18). The patients attained healed status at 18 months in the first series and at 12 months in the second series after chemotherapy. Spontaneous intercorporal fusion occurred only in 10 (8.06%) of 124 children. Sagittal curve during growth showed three different patterns: Unchanged, decreased, and increased curves. The residual kyphosis was unavoidable in cases with growth plate damage. Kyphosis increased in cases with wedged monovertebra and fused wedged block vertebra, though it was different at different level. CONCLUSION: The vertebral reformation and curve correction were possible only through the growth plates. The posterior instrumented stabilization alone could correct and/or prevent progress of the kyphosis. However, for active tuberculosis, posterior instrumented stabilization combined with anterior radical surgery should be reserved only for the advanced tuberculosis with instability, rapid progress of kyphosis, and/or unacceptable pre-existing kyphosis, though there is a new trend of prophylactic posterior instrumentation even for the early tuberculosis. PMID- 22448053 TI - Outcome of minimally invasive surgery in the management of tuberculous spondylitis. AB - INTRODUCTION: With the advancement of instrumentation and minimally access techniques in the field of spine surgery, good surgical decompression and instrumentation can be done for tuberculous spondylitis with known advantage of MIS (minimally invasive surgery). The aim of this study was to assess the outcome of the minimally invasive techniques in the surgical treatment of patients with tuberculous spondylodiscitis. MATERIALS AND METHODS: 23 patients (Group A) with a mean age 38.2 years with single-level spondylodiscitis between T4-T11 treated with video-assisted thoracoscopic surgery (VATS) involving anterior debridement and fusion and 15 patients (Group B) with a mean age of 32.5 years who underwent minimally invasive posterior pedicle screw instrumentation and mini open posterolateral debridement and fusion were included in study. The study was conducted from Mar 2003 to Dec 2009 duration. The indication of surgery was progressive neurological deficit and/or instability. The patients were evaluated for blood loss, duration of surgery, VAS scores, improvement in kyphosis, and fusion status. Improvement in neurology was documented and functional outcome was judged by oswestry disability index (ODI). RESULTS: The mean blood loss in Group A (VATS category) was 780 ml (330-1180 ml) and the operative time averaged was 228 min (102-330 min). The average preoperative kyphosis in Group A was 38 degrees which was corrected to 30 degrees . Twenty-two patients who underwent VATS had good fusion (Grade I and Grade II) with failure of fusion in one. Complications occurred in seven patients who underwent VATS. The mean blood loss was 625 ml (350-800 ml) with an average duration of surgery of 255 min (180-345 min) in the percutaneous posterior instrumentation group (Group B). The average preoperative segmental (kyphosis) Cobb's angle of three patients with thoracic TB in Group B was 41.25 degrees (28-48 degrees ), improved to 14.5 degrees (11 degrees - 21 degrees ) in the immediate postoperative period (71.8% correction). The average preoperative segmental kyphosis in another 12 patients in Group B with lumbar tuberculosis of 20.25 degrees improved to -12.08 degrees of lordosis with 32.33 degrees average correction of deformity. Good fusion (Grade I and Grade II) was achieved in 14 patients and Grade III fusion in 1 patient in Group B. One patient suffered with pseudoarthrosis/doubtful fusion with screw loosening in the percutaneous group. CONCLUSION: Good fusion rate with encouraging functional results can be obtained in caries spine with minimally invasive techniques with all the major advantages of a minimally invasive procedures including reduction in approach-related morbidity. PMID- 22448054 TI - Anterior versus posterior procedure for surgical treatment of thoracolumbar tuberculosis: A retrospective analysis. AB - BACKGROUND: Approach for surgical treatment of thoracolumbar tuberculosis has been controversial. The aim of present study is to compare the clinical, radiological and functional outcome of anterior versus posterior debridement and spinal fixation for the surgical treatment of thoracic and thoracolumbar tuberculosis. MATERIALS AND METHODS: 70 patients with spinal tuberculosis treated surgically between Jan 2005 and Dec 2009 were included in the study [corrected]. Thirty four patients (group I) with mean age 34.9 years underwent anterior debridement, decompression and instrumentation by anterior transthoracic, transpleural and/or retroperitoneal diaphragm cutting approach. Thirty six patients (group II) with mean age of 33.6 years were operated by posterolateral (extracavitary) decompression and posterior instrumentation. Various parameters like blood loss, surgical time, levels of instrumentation, neurological recovery, and kyphosis improvement were compared. Fusion assessment was done as per Bridwell criteria. Functional outcome was assessed using Prolo scale. Mean followup was 26 months. RESULTS: Mean surgical time in group I was 5 h 10 min versus 4 h 50 min in group II (P>0.05). Average blood loss in group I was 900 ml compared to 1100 ml in group II (P>0.05). In group I, the percentage immediate correction in kyphosis was 52.27% versus 72.80% in group II. Satisfactory bony fusion (grades I and II) was seen in 100% patients in group I versus 97.22% in group II. Three patients in group I needed prolonged immediate postoperative ICU support compared to one in group II. Injury to lung parenchyma was seen in one patient in group I while the anterior procedure had to be abandoned in one case due to pleural adhesions. Functional outcome (Prolo scale) in group II was good in 94.4% patients compared to 88.23% patients in group I. CONCLUSION: Though the anterior approach is an equally good method for debridement and stabilization, kyphus correction is better with posterior instrumentation and the posterior approach is associated with less morbidity and complications. PMID- 22448055 TI - Tuberculosis spine: Therapeutically refractory disease. AB - BACKGROUND: India ranks second amongst the high-burden multi drug resistant tuberculosis (MDR-TB) countries, with an estimated incidence of 2.3% MDR-TB cases amongst the new cases and 17.2% amongst the previously treated cases. The diagnosis and treatment protocol for MDR-TB of the spine are not clearly established. We report outcome of a series of 15 cases of TB spine who were suspected to be therapeutically refractory cases (MDR-TB) on the basis of clinicoradiological failures of initial treatment. MATERIALS AND METHODS: Fifteen cases of TB spine from C2 to L5 spine were suspected to be the cases of MDR-TB (therapeutically refractory cases) on the basis of failures of adequate clinicoradiological healing response at 5 months or more on antitubercular treatment (ATT). None of the patient was immunocompromised. Thirteen out of 15 patients had tissue samples sent for histopathology, culture and sensitivity, smear, BACTEC, and polymerase chain reaction (PCR). All patients were put on second line ATT and followed up fortnightly with regular liver and kidney function tests, erythrocyte sedimentation rate (ESR), and plain X-ray. Healing was documented as subjective improvement of symptoms, reduction in ESR, and observations on contrast enhanced magnetic resonance imaging (MRI) such as resolution of marrow edema, fatty replacement of bone marrow and resolution of abscesses. Ambiguous MRI observations in a few patients were resolved on positron emission tomography (PET) scan. Patients were monitored continuously for 2 years after stopping ATT. RESULTS: We could demonstrate a positive culture in three cases. Two of them had multi drug resistance. We could achieve healing status in 13 out of 14 patients after starting second line drugs, one patient is still on treatment while other patient with no drug resistance is responding well on ATT. CONCLUSIONS: The suspicion of therapeutically refractory case is of paramount importance. Once suspected, surgery to procure tissue for diagnosis and culture is to be undertaken. The demonstration of drug resistance on culture may not be achieved in all TB spine cases and empiric drug regimen for MDR-TB is to be started. We have achieved the healed status with immunomodulation and second line ATT. The length of treatment needs to be monitored with MRI and PET scan. PMID- 22448056 TI - Short term analysis of healed post-tubercular kyphosis in younger children based on principles of congenital kyphosis. AB - BACKGROUND: The patients with healed severe progressive tubercular kyphosis may develop late-onset paraplegia. A particular subgroup of these children (Type IB progression) may benefit from the management principles of congenital kyphosis. Self-correction may be observed by selective continued growth of anterior vertebral epiphyseal end-plates over the posterior fused mass. We report a series of cases with posterior fusion of progressive post-tubercular kyphosis with an aim to prevent further progression of kyphosis and to assess if any gradual self correction is seen in followup. MATERIALS AND METHODS: Twelve children fulfilling inclusion criteria of clinicoradiological, hematological diagnosis of healed spine TB having no or <2 spine at risk signs having documented progression of kyphosis and neural deficit underwent posterior fusion in situ without instrumentation, using autogenous iliac crest grafts as well as allograft donor bone graft. They were followed up to maximum of 5 years. RESULTS: All 12 children had a progressive increase in angle preoperatively. Mean followup was 3.6 years. Post surgery, 66% showed a clinical improvement and correction, 25% had static angle, and worsening in one patient. Thus, overall 91% have a favorable result. CONCLUSION: The mechanism of correction of deformity in presence of posterior fusion is continued growth of the anterior epiphyseal end plates and hence this leads to selective differential anterior column growth giving gradual correction of kyphosis. This avoids anterior, technically demanding and complex, internal gibbus surgeries. This procedure is simple, safe, and less morbid with good results, avoiding long term disability to the patients in selected group of patients. PMID- 22448057 TI - Magnetic resonance imaging findings in spinal tuberculosis: Comparison of HIV positive and negative patients. AB - BACKGROUND: There is an increasing incidence of Human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection. This has led to an increasing number of atypical features on magnetic resonance imaging (MRI). We postulated that the type 4 hypersensitivity response causing granulomatous inflammation may be disrupted by the HIV resulting in less vertebral body destruction. This study compares the MRI features of spinal tuberculosis in HIV positive and negative patients. MATERIALS AND METHODS: Fifty patients with confirmed spinal tuberculosis, HIV status and available MRI scans at a single institution from 2003-2009 were identified. HIV status was positive in 20 and negative in 30. Females were predominant (34:16). The HIV positive group was younger at 32.4 versus 46 years (P=0.008). Blood parameters (WCC, ESR, Hb, Lymphocyte count) were not significantly different between the HIV groups. MRI scans were reviewed by a radiologist who was blinded to the HIV status. Site, extent of disease, body collapse, abscess location and volume, kyphotic deformity and cord signal were reported. RESULTS: There was no difference between the number of vertebral bodies affection with TB involvement, presence of cord signal or incidence of non contiguous lesions. The HIV negative group had significantly more total vertebral collapse (P=0.036) and greater kyphosis (P=0.002). The HIV positive group had a trend to larger anterior epidural pus collection (P=0.2). CONCLUSION: HIV negative patients demonstrate greater tuberculous destruction in terms of total percentage body collapse and resultant kyphosis. There is no difference in the incidence of cord signal or presence of non-contiguous lesions. HIV positive patients show a trend to a greater epidural abscess volume. This difference may be explained by the reduced autoimmune response of the type 4 hypersensitivity reaction caused by the HIV infection. PMID- 22448058 TI - Tuberculosis of hip in children: A retrospective analysis. AB - BACKGROUND: Tuberculosis (TB) of hip constitutes nearly 15% of all cases of osteoarticular tuberculosis. We report a retrospective study carried out on 43 children with hip TB. MATERIALS AND METHODS: Forty-three children of TB hip treated between 1971 and 2000 were analysed. Twenty-four children of the early series were treated with streptomycin (S), isoniazid (H) and PAS (Pa) for 18 months (3HPaS, 15 HPa), while 19 children in the later series were treated with isoniazid (H), rifampicin (R) and ethambutol (E) or pyrazinamide (Z) for 12 months [(12 RHE(Z)]. Five out of 18 children with radiologically normal appearing type hip TB were treated with chemotherapy alone and 38 children were subjected to surgery; simple synovectomy alone in 31 hips, joint debridement in six hips, and proximal femoral varisation osteotomy in one. After surgery hips were immobilized in cast for one to three months according to the severity of the disease and patients pain tolerance, and then were mobilized under leg traction in bed gradually till pain subsided completely. RESULTS: TB of hip healed with minimum sequelae in all children. In 18 Type one hip TB, normal hip (synovial form) anatomy was maintained, and in 25 patients with advanced lesions some defect in the femoral head and acetabulum was noticed, though painless good hip motion was maintained. Excellent to good results were obtained in 31 children (73.1%), fair in eight (18.6%), and poor in four (9.3%). In four patients with poor results, there was some residual morphological defect in the hip. None developed ankylosis of hip. CONCLUSION: We achieved good outcome with minimum sequelae in this series. The management goal should be aimed not only to heal the disease but also to maintain a painless mobile hip and anatomical cephalocotyloid relationship until maturity, and retard the development of secondary osteoarthritis. PMID- 22448059 TI - Tuberculosis of the elbow: A clinicoradiological analysis. AB - BACKGROUND: The incidence of Tuberculosis (TB) of elbow is 2-5% of all skeletal locations. Most reports of TB elbow have focused attention on the diagnosis. The management options and classification has been missing. We present a retrospective clinicoradiological analysis of 38 cases (40 elbows) of TB of elbow joint. MATERIALS AND METHODS: The patients presented with pain, swelling and loss of motion. Two cases had bilateral involvement. The average delay between onset of symptoms and presentation was 8 months. The elbows were classified according to modified Martini's radiological classification, which distinguishes between osseous lesions close to joint line (e.g. coronoid, condyles) and lesions away from the joint line (e.g. epicondyles, olecranon). We modified the classification to subdivide into para-articular bony lesions that had invaded the joint and those that were threatening to invade joint. All patients received antitubercular chemotherapy and immobilization in above-elbow plaster slab for 4-8 weeks. Twenty patients underwent surgical interventions (synovectomy, intraarticular debridement). RESULTS: The average followup period was 5.3 years (range 1.5-14.2 years). The range of movement at final followup averaged 107 degrees for stage 2, 90 degrees for stage 3A, 47 degrees for stage 3B and 32 degrees for stage 4. Range of supination and pronation was less satisfactory as compared to flexion and extension and all elbows with bony involvement had less than 90 degrees arc of supination and pronation. CONCLUSION: Surgical intervention could appreciably alter the outcome especially in patients with extra-articular involvement close to the joint. We have classified this subgroup separately. PMID- 22448060 TI - Tuberculosis of the foot: An osteolytic variety. AB - BACKGROUND: Foot involvement in osteoarticular tuberculosis is uncommon and isolated bony involvement of foot bones with an osteolytic defect is even more rare; diagnostic and therapeutic delays can occur, worsening the prognosis. We present a retrospective series of osteolytic variety of foot tuberculosis. MATERIALS AND METHODS: We present 24 osteolytic variety of foot tuberculosis (Eleven calcaneus, four cuboid, two cunieforms, one talus, three metatarsals, three phalanges) out of 92 foot TB cases collected over last 20 years. There were 16 adults and eight children. Tissue diagnosis was established in 23 of 24 cases based on PCR AFB staining, culture, and histopathology. Surgical intervention was reserved for patients with either a juxtaarticular focus threatening to involve a joint or an impending collapse of a midfoot bone with cystic destruction. RESULTS: Fifteen cases had an osteolytic lesion on the radiographs resembling a space-occupying lesion, five had patchy osteolysis, while four showed coke like sequestra; one patient had a lesion in two bones. Antitubercular chemotherapy after biopsy was sufficient to heal the lesion in 19 cases, while in five cases surgical debridement needed to be done. The lesions healed eventually. At an average followup of 8.3 years, (range 2-15 years) there were no recurrences and all patients were free from pain, with no restriction of movements. Six patients complained of occasional pain during walking on uneven ground. CONCLUSION: When tuberculous pathology is limited to the bone, the prognosis is better than in articular disease, as there is less deformity, and hence, less residual pain and disability. PMID- 22448061 TI - Femoral head-neck offset in the Indian population: A CT based study. AB - BACKGROUND: Femoroacetabular impingement has been postulated as the important cause of primary osteoarthritis in non dysplastic hips. We postulated that the rarity of primary osteoarthritis of hip in Indian population could be attributable to morphological differences, specifically to a lower prevalence of abnormal head-neck morphology. We conducted an anthropometric study to evaluate the prevalence of abnormal head-neck offset in Indian population and to correlate it with the low prevalence of primary osteoarthrosis in the Indian population. MATERIALS AND METHODS: The computed tomography (CT) images of 85 apparently normal hips were analysed. An axial image was created parallel to the central axis of the femoral neck and passing through the center of the femoral head using coronal scout view. This image was then used to calculate alpha and beta angles and the head-neck offset ratio. The measurements were made by two independent observers on two different occasions. RESULTS: The prevalence of abnormal head neck offset ratio was 11.7% and the mean alpha and beta angles were 45.6 degrees and 40.6 degrees , respectively. Pearson correlation coefficients for intra observer and inter-observer agreement were, respectively, 0.84 and 0.80 for alpha angle, 0.80 and 0.77 for beta angle and 0.78 and 0.75 for head-neck offset ratio. The values were similar to those reported in the western population. CONCLUSION: The differences in the prevalence of hip osteoarthritis in Indian and western populations are not attributable to variation in the prevalence of abnormal head neck offset. PMID- 22448062 TI - Functional outcome of closed fractures of proximal humerus managed by Joshi's external stabilizing system. AB - BACKGROUND: Proximal humeral fractures account for 4-5% of all fractures; most of them involving elderly and osteoporotic people. 1 51% of such fractures are displaced. Two Fractures with minimal displacement, regardless of the number of fracture lines, can be treated with closed reduction and early mobilization, but anatomical reduction in displaced fractures is difficult to obtain and the incidence of pseudarthrosis is high 3-5. We evaluated the functional results of closed Neer's 2- and 3-part proximal humerus fractures treated by Joshi's external stabilizing system. MATERIALS AND METHODS: Sixteen patients with proximal humeral fractures were managed from 2008 to 2010 by Joshi's stabilizing external fixation. They were 10 males and 6 females, with a mean age of 57.5 years. Based on Neer's classification, there were eleven 3-part fractures and five 2-part fractures. The mechanism of injuries included seven road traffic accidents and nine fall. Shoulder mobilization exercises were started within 1 week after stabilization with JESS. External fixation was removed after the evidence of union (6-8 weeks). Pain was evaluated by visual analogue scale (VAS) and shoulder range of motion was evaluated by Constant Scoring System. Followup was done at 4 weeks, 8 weeks, 12 weeks, and then at every 4 weeks. RESULTS: Mean followup was of 20.5 months (range 9-30 months). Postoperative mean VAS score and Constant Score of patients was 2.1 (+/-0.73) and 78.1 (+/-9.61) at an average followup of 6 months. Mean duration for union was 6.5 (+/-1.18) weeks. One case of K-wire loosening and one case of pin tract infection were the complications noted. CONCLUSION: External fixation by JESS is an alternative option to treat Neer's 2 and 3 part proximal humerus fractures with good results. PMID- 22448063 TI - Supracondylar femoral extension osteotomy and patellar tendon advancement in the management of persistent crouch gait in cerebral palsy. AB - BACKGROUND: Severe crouch gait in adolescent cerebral palsy is a difficult problem to manage. The patients develop loading of patellofemoral joint, leading to pain, gait deviation, excessive energy expenditure and progressive loss of function. Patella alta and avulsion of patella are the other complications. Different treatment options have been described in the literature to deal with this difficult problem. We evaluated outcome of supracondylar femoral extension osteotomy (SCFEO) and patellar tendon advancement (PTA) in the treatment of crouch gait in patients with cerebral palsy. MATERIALS AND METHODS: Fourteen adolescents with crouch gait were operated by SCFEO and PTA. All subjects were evaluated pre and postoperatively. Clinical, radiographic, observational gait analysis and functional measures were included to assess the changes in knee function. RESULTS: Cases were followed up to 3 years. The patients walked with increased knee extension and improvement in quadriceps muscle strength. Knee pain was decreased and improvements in functional mobility and radiologic improvement were found. CONCLUSION: SCFEO and PTA for adolescent crouch gait is effective in improving knee extensor strength, reducing knee pain and improving function. PMID- 22448064 TI - Radiography and sonography of clubfoot: A comparative study. AB - BACKGROUND: Congenital talipes equinovarus is a common foot deformity afflicting children with reported incidence varying from 0.9/1000 to 7/1000 in various populations. The success reported with Ponseti method when started at an early age requires an imaging modality to quantitate the deformity. Sonography being a radiation free, easily available non-invasive imaging has been investigated for this purpose. Various studies have described the sonographic anatomy of normal neonatal foot and clubfoot and correlated the degree of severity with trends in sonographic measurements. However, none of these studies have correlated clinical, radiographic and sonographic parameters of all the component deformities in clubfoot. The present study aims to compare the radiographic and sonographic parameters in various grades of clubfoot. MATERIALS AND METHODS: Thirty-one children with unilateral clubfoot were examined clinically and graded according to the Demeglio system of classification of clubfoot severity. Antero posterior (AP) and lateral radiographs of both normal and affected feet were obtained in maximum correction and AP talo-calcaneal (T-C), AP talo-first metatarsal (TMT) and lateral T-C angles were measured. Sonographic examination was done in medial, lateral, dorsal and posterior projections of both feet in static neutral position and after Ponseti manouever in the position of maximum correctability in dynamic sonography. Normal foot was taken as control in all cases. The sonographic parameters measured were as follows : Medial malleolar- navicular distance (MMN) and medial soft tissue thickness (STT) on medial projection, calcaneo-cuboid (C-C) distance, calcaneo-cuboid (C-C) angle and maximum length of calcaneus on lateral projection, length of talus on dorsal projection; and tibiocalcaneal (T-C) distance, posterior soft tissue thickness and length of tendoachilles on posterior projection. Also, medial displacement of navicular relative to talus, mobility of talonavicular joint (medial view); reducibility of C-C mal alignment (lateral view); talonavicular relation with respect to dorsal/ ventral displacement of navicular (dorsal view) and reduction of talus within the ankle mortise (posterior view) were subjectively assessed while performing dynamic sonography. Various radiographic and sonographic parameters were correlated with clinical grades. RESULTS: MMN distance and STT measured on medial view, C-C distance and C-C angle measured on lateral view and tibiocalcaneal distance measured on posterior view showed statistically significant difference between cases and controls. A significant correlation was evident between sonographic parameters and clinical grades of relevant components of clubfoot. All radiographic angles except AP T-C angle were significantly different between cases and controls. However, they did not show correlation with clinical degree of severity. CONCLUSION: All radiographic angles except AP T-C angle and sonographic parameters varied significantly between cases and controls. However, radiographic parameters did not correlate well with clubfoot severity. In contrast, sonography not only assessed all components of clubfoot comprehensively but also the sonographic parameters correlated well with the severity of these components. Thus, we conclude that sonography is a superior, radiation free imaging modality for clubfoot. PMID- 22448065 TI - Chronic triceps insufficiency managed with extensor carpi radialis longus and palmaris longus tendon grafts. AB - Chronic triceps insufficiency, causing prolonged disability, occurs due to a missed diagnosis of an acute rupture. We report a 25 year old male with history of a significant fall sustaining multiple injuries. Since then, he had inability in extending his right elbow for which he sought intervention after a year. Diagnosis of triceps rupture was made clinicoradiologically and surgery was planned. Intraoperative findings revealed a deficient triceps with a fleck of avulsed bone from olecranon. Ipsilateral double tendon graft including extensor carpi radialis longus and palmaris longus were anchored to triceps and secured with the olecranon. Six-months follow revealed a complete active extension of elbow and a full function at the donor site. PMID- 22448066 TI - Bilateral multiligament injury of knee caused by entangled dupatta. AB - We report a rare case of bilateral multiligament knee injury in an 18-year-old female employed in garment industry. Patient was wearing salwar kameez and dupatta while operating an electric laundry machine. In this case we discuss a peculiar mechanism of injury caused due to wearing dupatta near working site and suggest simple preventive measures. PMID- 22448067 TI - Trochleoplasty and medial patellofemoral ligament reconstruction for recurrent patellar dislocation. AB - We report a case of recurrent patellar dislocation with high-grade trochlear dysplasia which persisted despite two previous operations. We did a Dejour's sulcus deepening trochleoplasty, medial patellofemoral ligament reconstruction, and lateral retinacular release. Trochleoplasty and medial patellofemoral ligament reconstruction is required in patients with high grade trochlear dysplasia. PMID- 22448068 TI - Aspergillus vertebral osteomyelitis in immunocompetent patients. AB - Fungal infections are one of the important cause of morbidity and mortality in immunocompromised patients. Aspergillus vertebral osteomyelitis is extremely rare. We report two cases of aspergillus vertebral osteomyelitis in immunocompetent men in the absence of an underlying disorder. The clinical and radiological findings were suggestive of Pott's spine. The absolute CD4, CD8 counts and their ratio were normal. The HIV status was negative in both patients. Both patients underwent surgical decompression. The histopathology of tissue obtained were suggestive of aspergillus osteomyelitis. One patient had antifungal treatment for 3 months and was doing well at 1 year followup, whereas other patient did not turnup after 2 months. PMID- 22448069 TI - Closed retrograde retrieval of the distal broken segment of femoral cannulated intramedullary nail using a ball-tipped guide wire: A comment. PMID- 22448070 TI - Author's reply. PMID- 22448071 TI - Evaluation of the syndesmotic-only fixation for Weber-C ankle fractures with syndesmotic injury: A comment. PMID- 22448072 TI - Author's reply. PMID- 22448073 TI - Subtrochanteric valgus osteotomy in developmental coxa vara: A comment. PMID- 22448074 TI - Author's reply. PMID- 22448075 TI - Gender and Material Transfers between Older Parents and Children in Ismailia, Egypt. AB - In Egypt, kin relations have been governed by a patriarchal contract, which defines expectations for intergenerational support along gendered lines. Social changes may be disrupting these customs and bringing attention to the ways gender may influence intergenerational support in rapidly changing contexts. Using data from 4,465 parent-child dyads in Ismailia, Egypt, we examined whether intergenerational material transfers favored women over men and whether gaps in needs and endowments accounted for gender differences in transfers. Fathers gave children money and goods more often than did mothers; mothers received material transfers from children more often than did fathers. Compared to sons, daughters made transfers to parents less often and received transfers from parents more often. We found residual advantages to mothers and daughters, even adjusting for differential needs and endowments. Findings corroborate persistent norms of gender complementarity, patrilocal endogamy, and reciprocation for women's caregiving, despite changes that have threatened patriarchal rules of exchange. PMID- 22448076 TI - Modification of the Two-Point Scaling Theory for the Description of the Phase Transition in Solution. Analysis of Sodium Octanoate Aqueous Solutions. AB - On the basis of conventional scaling theory, the two-point scaling theory was modified in order to describe the influence of composition on the partial molar heat capacity and volume during the micellization process. To verify the theory, isobaric heat capacities and densities of aqueous sodium octanoate solutions were measured over wide composition and temperature ranges and the modified approach was used to analyze the calculated partial molar heat capacities and volumes of the surfactant in water. The results obtained indicate that the micellization process is subject to the scaling laws. The results were compared with those for other systems. Peculiar behavior of the critical indices was observed and correlated with the structure of the micelles. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10953-012-9795-6) contains supplementary material, which is available to authorized users. PMID- 22448077 TI - The role of the amygdala in face perception and evaluation. AB - Faces are one of the most significant social stimuli and the processes underlying face perception are at the intersection of cognition, affect, and motivation. Vision scientists have had a tremendous success of mapping the regions for perceptual analysis of faces in posterior cortex. Based on evidence from (a) single unit recording studies in monkeys and humans; (b) human functional localizer studies; and (c) meta-analyses of neuroimaging studies, I argue that faces automatically evoke responses not only in these regions but also in the amygdala. I also argue that (a) a key property of faces represented in the amygdala is their typicality; and (b) one of the functions of the amygdala is to bias attention to atypical faces, which are associated with higher uncertainty. This framework is consistent with a number of other amygdala findings not involving faces, suggesting a general account for the role of the amygdala in perception. PMID- 22448078 TI - Cross-frequency coupling of brain oscillations in studying motivation and emotion. AB - Research has shown that brain functions are realized by simultaneous oscillations in various frequency bands. In addition to examining oscillations in pre specified bands, interactions and relations between the different frequency bandwidths is another important aspect that needs to be considered in unraveling the workings of the human brain and its functions. In this review we provide evidence that studying interdependencies between brain oscillations may be a valuable approach to study the electrophysiological processes associated with motivation and emotional states. Studies will be presented showing that amplitude amplitude coupling between delta-alpha and delta-beta oscillations varies as a function of state anxiety and approach-avoidance-related motivation, and that changes in the association between delta-beta oscillations can be observed following successful psychotherapy. Together these studies suggest that cross frequency coupling of brain oscillations may contribute to expanding our understanding of the neural processes underlying motivation and emotion. PMID- 22448079 TI - Testosterone, cortisol, and serotonin as key regulators of social aggression: A review and theoretical perspective. AB - In human and non-human animals the steroid hormones cortisol and testosterone are involved in social aggression and recent studies suggest that these steroids might jointly regulate this behavior. It has been hypothesized that the imbalance between cortisol and testosterone levels is predictive for aggressive psychopathology, with high testosterone to cortisol ratio predisposing to a socially aggressive behavioral style. In this review, we focus on the effects of cortisol and testosterone on human social aggression, as well as on how they might modulate the aggression circuitry of the human brain. Recently, serotonin is hypothesized to differentiate between impulsive and instrumental aggression, and we will briefly review evidence on this hypothesis. The aim of this article is to provide a theoretical framework for the role of steroids and serotonin in impulsive social aggression in humans. PMID- 22448080 TI - Association of Religious Participation With Mortality Among Chinese Old Adults. AB - This research examines the association of religious participation with mortality using a longitudinal data set collected from 9,017 oldest-old aged 85+ and 6,956 younger elders aged 65 to 84 in China in 2002 and 2005 and hazard models. Results show that adjusted for demographics, family/social support, and health practices, risk of dying was 24% (p < 0.001) and 12% (p < 0.01) lower among frequent and infrequent religious participants than among nonparticipants for all elders aged 65+. After baseline health was adjusted, the corresponding risk of dying declined to 21% (p < 0.001) and 6% (not significant), respectively. The authors also conducted hazard models analysis for men versus women and for young-old versus oldest-old, respectively, adjusted for single-year age; the authors found that gender differentials of association of religious participation with mortality among all elderly aged 65+ were not significant; association among young-old men was significantly stronger than among oldest-old men, but no such significant young-old versus oldest-old differentials in women were found. PMID- 22448081 TI - Foreword. PMID- 22448082 TI - A Passive Monitoring System in Assisted Living Facilities: 12-Month Comparative Study. AB - The GE QuietCare(r) passive monitoring system uses advanced motion sensor technology that learns the daily living patterns of senior community residents and sends alerts when certain out-of-the-ordinary events occur. This study compared falls, hospitalizations, care level changes, and resident attrition between two similar assisted living facilities where one facility adopted the QuietCare(r) monitoring system and the other did not over a 12-month period. Average falls per week were significantly lower in the QuietCare(r) facility than the control facility. There was also a trend toward fewer weekly hospitalizations in the QuietCare(r) facility. There was higher resident retention at the QuietCare(r) facility. This study provides evidence of direct benefits to both the resident and the facility for the use of QuietCare(r). There was a significant reduction in the number of falls, as well as a general facility performance improvement measured by care level consistency and higher resident retention rates. PMID- 22448083 TI - Simultaneous genome sequencing of symbionts and their hosts. AB - Second-generation sequencing has made possible the sequencing of genomes of interest for even small research groups. However, obtaining separate clean cultures and clonal or inbred samples of metazoan hosts and their bacterial symbionts is often difficult. We present a computational pipeline for separating metazoan and bacterial DNA in silico rather than at the bench. The method relies on the generation of deep coverage of all the genomes in a mixed sample using Illumina short-read sequencing technology, and using aggregate properties of the different genomes to identify read sets belonging to each. This inexpensive and rapid approach has been used to sequence several nematode genomes and their bacterial endosymbionts in the last year in our laboratory and can also be used to visualize and identify unexpected contaminants (or possible symbionts) in genomic DNA samples. We hope that this method will enable researchers studying symbiotic systems to move from gene-centric to genome-centric approaches. PMID- 22448084 TI - Calling the roll on Laxus oneistus immune defense molecules. PMID- 22448085 TI - Mating skew in Barbary macaque males: the role of female mating synchrony, female behavior, and male-male coalitions. AB - A fundamental question of sexual selection theory concerns the causes and consequences of reproductive skew among males. The priority of access (PoA) model (Altmann, Ann NY Acad Sci 102:338-435, 1962) has been the most influential framework in primates living in permanent, mixed-sex groups, but to date it has only been tested with the appropriate data on female synchrony in a handful of species. In this paper, we used mating data from one large semi-free ranging group of Barbary macaques: (1) to provide the first test of the priority-of access model in this species, using mating data from 11 sexually active females (including six females that were implanted with a hormonal contraceptive but who showed levels of sexual activity comparable to those of naturally cycling females) and (2) to determine the proximate mechanism(s) underlying male mating skew. Our results show that the fit of the observed distribution of matings with sexually attractive females to predictions of the PoA model was poor, with lower ranking males mating more than expected. While our work confirms that female mating synchrony sets an upper limit to monopolization by high-ranking individuals, other factors are also important. Coalitionary activity was the main tactic used by males to lower mating skew in the study group. Coalitions were expressed in a strongly age-related fashion and allowed subordinate, post-prime males to increase their mating success by targeting more dominant, prime males. Conversely, females, while mating promiscuously with several males during a given mating cycle, were more likely to initiate their consortships with prime males, thus reducing the overall effectiveness of coalitions. We conclude that high ranking Barbary macaque males have a limited ability to monopolize mating access, leading to a modest mating skew among them. PMID- 22448086 TI - Declining extra-pair paternity with laying order associated with initial incubation behavior, but independent of final clutch size in the blue tit. AB - Although functional explanations for female engagement in extra-pair copulation have been studied extensively in birds, little is known about how extra-pair paternity is linked to other fundamental aspects of avian reproduction. However, recent studies indicate that the occurrence of extra-pair offspring may generally decline with laying order, possibly because stimulation by eggs induces incubation, which may suppress female motivation to acquire extra-pair paternity. Here we tested whether experimental inhibition of incubation during the laying phase, induced by the temporary removal of eggs, resulted in increased extra-pair paternity, in concert with a later cessation of laying, in blue tits (Cyanistes caeruleus). As expected, experimental females showed a more gradual increase in nocturnal incubation duration over the laying phase and produced larger clutches than controls. Moreover, incubation duration on the night after the first egg was laid predicted how extra-pair paternity declined with laying order, with less incubation being associated with more extra-pair offspring among the earliest eggs in the clutch. However, incubation duration on this first night was unrelated to our experimental treatment and independent of final clutch size. Consequently, the observed decline in extra-pair paternity with laying order was unaffected by our manipulation and larger clutches included proportionally fewer extra-pair offspring. We suggest that female physiological state prior to laying, associated with incubation at the onset of laying, determines motivation to acquire extra-pair paternity independent of final clutch size. This decline in proportion of extra-pair offspring with clutch size may be a general pattern within bird species. PMID- 22448087 TI - An Internet-Based Computer-Tailored Intervention to Promote Responsible Drinking: Findings from a Pilot Test with Employed Adults. AB - This paper describes pilot test findings of an Internet-based, Transtheoretical Model-based, computer tailored intervention for adults who exceed national guidelines for low-risk drinking. In a pilot test, 166 adults recruited from worksites completed one session and evaluated the program. Pre and post assessments indicate intention to make behavioral changes. Importantly, 94.3% of participants indicated that they would recommend the program. Ratings were positive with the majority of participants 'agreeing' or 'strongly agreeing' with all 14 evaluation items. Feasibility was demonstrated by recruiting and engaging employed adults. This program is a cost-effective prevention program promoting responsible drinking to adults. PMID- 22448088 TI - Predicting the Risk of Intimate Partner Violence: The Chinese Risk Assessment Tool for Victims. AB - The present study reports the development and validation of the Chinese Risk Assessment Tool for Victims (CRAT-V), an actuarial instrument for the prediction of intimate partner violence (IPV) victimization in a Chinese population. Data were collected from a representative sample of 2,708 Chinese women who were married or cohabiting in Hong Kong. All participants were interviewed with a questionnaire assessing their experience of IPV victimization and personal or family factors related to IPV. As measured by the Revised Conflict Tactics Scale (CTS 2), the base rates of preceding-year physical and sexual IPV victimization were 4.6 % and 3.6 %, respectively. Using a cross-validation procedure, the present study developed a 5-factor instrument with one half of the randomly split sample and validated the resulting tool with the other half. The CRAT-V had a sensitivity of 74.0 %, a specificity of 68.3 %, an overall accuracy of 68.7 %, and an area under the receiver operating characteristic (ROC) curve of 0.75 when administered on the second half of sample. Overall, the CRAT-V may serve as a straightforward, systematic, and easy-to-administer instrument tailor-made for Chinese populations for the assessment of risk of IPV victimization against women. PMID- 22448090 TI - Oligomerized lychee fruit extract (OLFE) and a mixture of vitamin C and vitamin E for endurance capacity in a double blind randomized controlled trial. AB - Antioxidant supplementations are commonly used as an ergogenic aid for physical exercise despite its limited evidence. The study aimed to investigate the effects of a polyphenol mixture and vitamins on exercise endurance capacity. Seventy regularly exercising male participants were randomly assigned to receive oligomerized lychee fruit extract, a mixture of vitamin C (800 mg) and E (320 IU), or a placebo for 30 consecutive days. The study results showed that oligomerized lychee fruit extract significantly elevated the submaximal running time (p = 0.01). The adjusted mean change was 3.87 min (95% CI: 1.29, 6.46) for oligomerized lychee fruit extract, 1.33 (-1.23, 3.89) for the vitamins, and 1.60 (-1.36, 4.56) for the placebo (p = 0.33 in between groups). Oligomerized lychee fruit extract significantly increased the anaerobic threshold by 7.4% (1.8, 13.0). On the other hand, vitamins significantly attenuated VO(2)max by -3.11 ml/kg/m (-5.35, -0.87). Their effects on plasma free radical amount, however, were similar. Our results suggest that a polyphenol-containing supplement and typical antioxidants may have different mechanisms of action and that the endurance-promoting effect of oligomerized lychee fruit extract may not directly come from the scavenging of free radicals but may be attributed to other non antioxidant properties of polyphenols, which requires further investigation. PMID- 22448089 TI - Novel roles of peroxiredoxins in inflammation, cancer and innate immunity. AB - Peroxiredoxins possess thioredoxin or glutathione peroxidase and chaperone-like activities and thereby protect cells from oxidative insults. Recent studies, however, reveal additional functions of peroxiredoxins in gene expression and inflammation-related biological reactions such as tissue repair, parasite infection and tumor progression. Notably, peroxiredoxin 1, the major mammalian peroxiredoxin family protein, directly interacts with transcription factors such as c-Myc and NF-kappaB in the nucleus. Additionally, peroxiredoxin 1 is secreted from some cells following stimulation with TGF-beta and other cytokines and is thus present in plasma and body fluids. Peroxiredoxin 1 is now recognized as one of the pro-inflammatory factors interacting with toll-like receptor 4, which triggers NF-kappaB activation and other signaling pathways to evoke inflammatory reactions. Some cancer cells release peroxiredoxin 1 to stimulate toll-like receptor 4-mediated signaling for their progression. Interestingly, peroxiredoxins expressed in protozoa and helminth may modulate host immune responses partly through toll-like receptor 4 for their survival and progression in host. Extracellular peroxiredoxin 1 and peroxiredoxin 2 are known to enhance natural killer cell activity and suppress virus-replication in cells. Peroxiredoxin 1-deficient mice show reduced antioxidant activities but also exhibit restrained tissue inflammatory reactions under some patho-physiological conditions. Novel functions of peroxiredoxins in inflammation, cancer and innate immunity are the focus of this review. PMID- 22448091 TI - Pancreatic insulin release in vitamin C-deficient senescence marker protein 30/gluconolactonase knockout mice. AB - We recently identified senescence marker protein-30 as the lactone-hydrolyzing enzyme gluconolactonase, which is involved in vitamin C biosynthesis. In this study, we investigated the effects of vitamin C on insulin secretion from pancreatic beta-cells using senescence marker protein-30/gluconolactonase knockout mice. In intraperitoneal glucose tolerance tests, vitamin C-deficient senescence marker protein-30/gluconolactonase knockout mice demonstrated impaired glucose tolerance with significantly lower blood insulin levels at 30 and 120 min post-challenge than in wild type mice (p<0.01-0.05). In contrast, vitamin C sufficient senescence marker protein-30/gluconolactonase knockout mice demonstrated significantly higher blood glucose and lower insulin only at the 30 min post-challenge time point (p<0.05). Senescence marker protein 30/gluconolactonase knockout mice showed enhanced insulin sensitivity regardless of vitamin C status. Static incubation of islets revealed that 20 mM glucose stimulated insulin secretion and islet ATP production were significantly decreased at 60 min only in vitamin C-deficient SMP30/GNL knockout mice relative to wild type mice (p<0.05). These results indicate that the site of vitamin C action lies between glycolysis and mitochondrial oxidative phosphorylation, while SMP30 deficiency itself impairs the distal portion of insulin secretion pathway. PMID- 22448092 TI - Ubiquinol affects the expression of genes involved in PPARalpha signalling and lipid metabolism without changes in methylation of CpG promoter islands in the liver of mice. AB - Coenzyme Q(10) is an essential cofactor in the respiratory chain and serves as a potent antioxidant in biological membranes. Recent studies in vitro and in vivo provide evidence that Coenzyme Q(10) is involved in inflammatory processes and lipid metabolism via gene expression. To study these effects at the epigenomic level, C57BL6J mice were supplemented for one week with reduced Coenzyme Q(10) (ubiquinol). Afterwards, gene expression signatures and DNA promoter methylation patterns of selected genes were analysed. Genome-wide transcript profiling in the liver identified 1112 up-regulated and 571 down-regulated transcripts as differentially regulated between ubiquinol-treated and control animals. Text mining and GeneOntology analysis revealed that the "top 20" ubiquinol-regulated genes play a role in lipid metabolism and are functionally connected by the PPARalpha signalling pathway. With regard to the ubiquinol-induced changes in gene expression of about +3.14-fold (p<=0.05), +2.18-fold (p<=0.01), and -2.13 fold (p<=0.05) for ABCA1, ACYP1, and ACSL1 genes, respectively, hepatic DNA methylation analysis of 282 (sense orientation) and 271 (antisense) CpG units in the respective promoter islands revealed no significant effect of ubiquinol. In conclusion, ubiquinol affects the expression of genes involved in PPARalpha signalling and lipid metabolism without changing the promoter DNA methylation status in the liver of mice. PMID- 22448093 TI - Oxygen radical absorbance capacity (ORAC) of cyclodextrin-solubilized flavonoids, resveratrol and astaxanthin as measured with the ORAC-EPR method. AB - Recently, we proposed an oxygen radical absorbance capacity method that directly quantifies the antioxidant's scavenging capacity against free radicals and evaluated the radical scavenging abilities for water soluble antioxidant compounds. In this study, we determined the radical scavenging abilities of lipophilic antioxidants which were solubilized by cyclodextrin in water. Commonly employed fluorescence-based method measures the antioxidant's protection capability for the fluorescent probe, while we directly quantify free-radical level using electron paramagnetic resonance spin trapping technique. In addition, the spin trapping-based method adopted controlled UV-photolysis of azo-initiator for free radical generation, but in fluorescence-based method, thermal decomposition of azo-initiator was utilized. We determined the radical scavenging abilities of seven well-known lipophilic antioxidants (five flavonoids, resveratrol and astaxanthin), using methylated beta-cyclodextrin as a solubilizer. The results indicated that the agreement between spin trapping-based and fluorescence-based values was only fair partly because of a large variation in the previous fluorescence-based data. Typical radical scavenging abilities in trolox equivalent unit are: catechin 0.96; epicatechin 0.94; epigallocatechin gallate 1.3; kaempferol 0.37; myricetin 3.2; resveratrol 0.64; and astaxanthin 0.28, indicating that myricetin possesses the highest antioxidant capacity among the compounds tested. We sorted out the possible causes of the deviation between the two methods. PMID- 22448094 TI - Protective effect of theaflavins on neuron against 6-hydroxydopamine-induced apoptosis in SH-SY5Y cells. AB - Theaflavins, the oxidation products of tea polyphenols are important biologically active components of black tea. 6-hydroxydopamine is a pro-parkinsonian neurotoxin. Theaflavins could inhibit the auto-oxidation of 6-hydroxydopamine in a dose-dependent manner from 0.5 ug/ml to 25 ug/ml. Here we investigated the protective effect of theaflavins on 6-hydroxydopamine induced SH-SY5Y cells against apoptosis (within this concentration range). It was found that pretreating SH-SY5Y cells with 0.5 ug/ml of theaflavins prevented 6 hydroxydopamine-induced loss of cell viability, condensed nuclear morphology, attenuated 6-hydroxydopamine-induced apoptosis, decrease of mitochondrial membrane potential and the increase of intracellular nitric oxide levels. Our results indicated that theaflavins had protective effect against 6 hydroxydopamine induced apoptosis at low concentrations, possibly through inhibition of reactive oxygen species and nitric oxide production. PMID- 22448095 TI - Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats. AB - Mulberry is commonly used as silkworm diet and an alternative medicine in Japan and China, has recently reported to contain many antioxidative flavanoid compounds and having the free radical scavenging effects. Antioxidants reduce cardiac oxidative stress and attenuate cardiac dysfunction in animals with pacing induced congestive heart failure. Hence we investigated the cardioprotective effect of mulberry leaf powder in rats with experimental autoimmune myocarditis. Eight-week-old Lewis rats immunized with cardiac myosin were fed with either normal chow or a diet containing 5% mulberry leaf powder and were examined on day 21. ML significantly decreased oxidative stress, myocyte apoptosis, cellular infiltration, cardiac fibrosis, mast cell density, myocardial levels of sarco/endo-plasmic reticulum Ca(2+) ATPase2, p22(phox), receptor for advanced glycation end products, phospho-p38 mitogen activated protein kinase, phospho-c Jun NH(2)-terminal protein kinase, glucose regulated protein78, caspase12 and osteopontin levels in EAM rats. These results may suggest that mulberry diet can preserve the cardiac function in experimental autoimmune myocarditis by modulating oxidative stress induced MAPK activation and further afford protection against endoplasmic reticulum stress mediated apoptosis. PMID- 22448096 TI - Effects of coenzyme Q10 and alpha-lipoic acid supplementation in fructose fed rats. AB - This study was conducted to investigate the effects of alpha-lipoic acid and coenzyme Q10 on plasma levels of lipids, asymmetric dimethylarginine, oxidative stress in fructose fed rats which provide a model of dietary-induced insulin resistance and to evaluate vascular changes developing in these rats by histologically. Male Sprague Dawley rats were used in this study. The animals were divided into 4 groups. Group 1 did not receive any medication and served as a control. Group 2 received a regular diet and water ad libitum and fructose was administered as % 10 solution in drinking water. Group 3 received alpha-lipoic acid (100 mg/kg/day) i.p. for 5 weeks and Group 4 received coenzyme Q10 (10 mg/kg/day) i.p. for 5 weeks. For determination of plasma asymmetric dimethylarginine, glutathione and malondialdehyde levels, high-performance liquid chromatography system was used. Homeostatic model assessment as a measure of insulin resistance was calculated. Lipid profile measurements were determined using enzymatic assay on an Auto analyzer. The high fructose diet was significantly associated with an increase in levels of plasma LDL, VLDL and total cholesterol and decrease in level of HDL cholesterol. Plasma asymmetric dimethylarginine, malondialdehyde and glutathione levels were also increase in these rats. alpha-lipoic acid or coenzyme Q10 supplementation was found to have some positive effect on these parameters. These findings were also demonstrated by morphological observation of the aorta. We demonstrated that administration of alpha-lipoic acid and coenzyme Q10 notably suppresses oxidative and nitrative stress, hyperinsulinemia, insulin resistance developing in fructose fed rats, a model of metabolic syndrome (MS). These positive effects of alpha-lipoic acid or coenzyme Q10 can be attributed to its antioxidant activity. PMID- 22448097 TI - Atopic dermatitis causes lipid accumulation in the liver of NC/Nga mouse. AB - Various factors have been reported to influence lipid metabolism and cause metabolic syndrome. However, the influence of allergy on the liver that plays important role of lipid metabolism has not been clarified. The aim of this study was to examine the influence of allergy on lipid metabolism of liver. A model of atopic dermatitis was developed in the NC/Nga mouse using picryl chloride to induce allergy. Lipid metabolism parameters were measured and the mechanism of changes in these parameters was examined using DNA microarray analysis and quantitative reverse transcriptase PCR. Triacylglycerol accumulation was promoted in the liver in the mouse atopic dermatitis model despite reductions in food intake, body weight gain, and serum glucose. As this mechanism, it was thought that atopic dermatitis caused the suppression of fatty acid beta-oxidation. These results suggest that atopic dermatitis causes lipid accumulation in the liver. PMID- 22448098 TI - The 90-day oral toxicity of d-psicose in male Wistar rats. AB - d-Psicose is a rare sugar present in small quantities in natural products. In a previous study, we showed that d-psicose suppresses increase in plasma glucose and reduces body fat accumulation in rats. Based on acute toxicity testing in rats, d-psicose is classified as an ordinary substance (LD(50) = 16 g/kg). Elucidating the effects of sub-chronic feeding of d-psicose in rats is essential before it can be utilized as a physiologically functional food. In this study, male Wistar rats (3 weeks old) were fed diets containing 3% d-psicose or sucrose for 90 days. The body weight gain and intra-abdominal adipose tissue weight did not differ between the sucrose and the d-psicose groups. The weights of the liver and kidneys were significantly higher in the d-psicose group than in the sucrose group. However, no gross pathological findings were evident at dietary doses of 3% d-psicose or were correlated with hypertrophy of the liver and kidney. In a clinical chemistry analysis, the erythrocyte and leukocyte courts were significantly higher in the d-psicose group, but that was not considered to be toxicologically significant. Therefore, the present study found no adverse effects of d-psicose in rats fed a diet containing 3% d-psicosefor 90 days. PMID- 22448099 TI - Amino acid and vitamin supplementation improved health conditions in elderly participants. AB - The purpose of this study was to investigate the effects of supplementation with amino acids and vitamins on health conditions in unhealthy older people. One bedridden inpatient group (n = 10; mean age, 79.8 +/- 8.5 y) and one outpatient group (n = 9; mean age, 72.9 +/- 12.2 y) participated in this study. A mixture supplementation with amino acids containing arginine (500 mg/day), glutamine (600 mg/day), and leucine (1200 mg/day), and 11 kinds of vitamins was daily administrated for 8 weeks. In both groups, general blood biomarkers such as white blood cell count, natural killer cell activity, and C-reactive protein levels were measured. All measurements were taken before (baseline), at 4 weeks (mid point), and after each trial (post-point). At mid-point, natural killer cell activity in the outpatient group increased significantly compared to baseline. At post-point, natural killer cell activity in the outpatient and inpatient groups increased significantly compared to baseline. The other blood biomarkers did not show any significant change throughout the trial. This pilot study suggested that a mixture of arginine, glutamine, leucine, and vitamins is useful to support innate immunity in unhealthy older people, even if their diseases, symptoms, and prescribed medicines are different. PMID- 22448100 TI - Different gastoroesophageal reflux symptoms of middle-aged to elderly asthma and chronic obstructive pulmonary disease (COPD) patients. AB - Symptomatic differences and the impact of gastroesophageal reflux disease (GERD) have not been clarified in patients with asthma and chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the differences of GERD symptoms among asthma, COPD, and disease control patients, and determine the impact of GERD symptoms on exacerbation of asthma or COPD by using a new questionnaire for GERD. A total of 120 subjects underwent assessment with the frequency scale for the symptoms of GERD (FSSG) questionnaire, including 40 age matched patients in each of the asthma, COPD, and disease control groups. Asthma and control patients had more regurgitation-related symptoms than COPD patients (p<0.05), while COPD patients had more dysmotility-related symptoms than asthma patients (p<0.01) or disease control patients (p<0.01). The most distinctive symptom of asthma patients with GERD was an unusual sensation in the throat, while bloated stomach was the chief symptom of COPD patients with GERD, and these symptoms were associated with disease exacerbations. The presence of GERD diagnosed by the total score of FSSG influences the exacerbation of COPD. GERD symptoms differed between asthma and COPD patients, and the presence of GERD diagnosed by the FSSG influences the exacerbation of COPD. PMID- 22448101 TI - From Scribbles to Scrabble: Preschool Children's Developing Knowledge of Written Language. AB - The purpose of this study was to concurrently examine the development of written language across several writing tasks and to investigate how writing features develop in preschool children. Emergent written language knowledge of 372 preschoolers was assessed using numerous writing tasks. The findings from this study indicate that children possess a great deal of writing knowledge before beginning school. Children appear to progress along a continuum from scribbling to conventional spelling, and this progression is linear and task dependent. There was clear evidence to support the claim that universal writing features develop before language-specific features. Children as young as 3 years possess knowledge regarding universal and language-specific writing features. There is substantial developmental continuity in literacy skills from the preschool period into early elementary grades. Implications of these findings on writing development are discussed. PMID- 22448102 TI - Speech production deficits in early readers: predictors of risk. AB - Speech problems and reading disorders are linked, suggesting that speech problems may potentially be an early marker of later difficulty in associating graphemes with phonemes. Current norms suggest that complete mastery of the production of the consonant phonemes in English occurs in most children at around 6-7 years. Many children enter formal schooling (kindergarten) around 5 years of age with near-adult levels of speech production. Given that previous research has shown that speech production abilities and phonological awareness skills are linked in preschool children, we set out to examine whether this pattern also holds for children just beginning to learn to read, as suggested by the critical age hypothesis. In the present study, using a diverse sample, we explored whether expressive phonological skills in 92 5-year-old children at the beginning and end of kindergarten were associated with early reading skills. Speech errors were coded according to whether they were developmentally appropriate, position within the syllable, manner of production of the target sounds, and whether the error involved a substitution, omission, or addition of a speech sound. At the beginning of the school year, children with significant early reading deficits on a predictively normed test (DIBELS) made more speech errors than children who were at grade level. Most of these errors were typical of kindergarten children (e.g., substitutions involving fricatives), but reading-delayed children made more of these errors than children who entered kindergarten with grade level skills. The reading-delayed children also made more atypical errors, consistent with our previous findings about preschoolers. Children who made no speech errors at the beginning of kindergarten had superior early reading abilities, and improvements in speech errors over the course of the year were significantly correlated with year-end reading skills. The role of expressive vocabulary and working memory were also explored, and appear to account for some of these findings. PMID- 22448103 TI - MtsslWizard: In Silico Spin-Labeling and Generation of Distance Distributions in PyMOL. AB - MtsslWizard is a computer program, which operates as a plugin for the PyMOL molecular graphics system. MtsslWizard estimates distances between spin labels on proteins quickly with user-configurable options through a simple graphical interface. In default mode, the program searches for ensembles of possible MTSSL conformations that do not clash with a static model of the protein. Once conformations are assigned, distance distributions between two or more ensembles are calculated, displayed, and can be exported to other software. The program's use is evaluated in a number of challenging test cases and its strengths and weaknesses evaluated. The benefits of the program are its accuracy and simplicity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00723-012-0314-0) contains supplementary material, which is available to authorized users. PMID- 22448104 TI - Early Numerical Competencies of Students with Different Forms of Mathematics Difficulty. AB - The purpose of the study was to examine differences in early numerical competencies, as well as subtraction skill, as a function of children's mathematics difficulty (MD) status: computational difficulty (CD), word problem solving difficulty (PD), concurrent difficulty (CDPD), or neither difficulty (i.e., typically developing; TYP). Based on measures of addition and word-problem skill, second grade students (N = 332) were classified in terms of MD status. Then, students were assessed on three early numerical competency measures (Number Line Estimation, Number Sets Test, and Counting Knowledge) as well as a measure of subtraction. On Number Line Estimation and Number Sets Test, students with CD and those with PD scored comparably, but both outperformed students with CDPD. On Counting Knowledge-Double First, students with CDPD scored lower than the three contrasting groups. On subtraction, students with CD outperformed those with PD, and students with PD and those with CDPD performed comparably. Findings are discussed in terms of differential performance as a function of difficulty status and implications for understanding and teaching subtypes of MD. PMID- 22448105 TI - 2,4-Diacetylphloroglucinol suppresses zoosporogenesis and impairs motility of Peronosporomycete zoospores. AB - 2,4-Diacetylphloroglucinol (DAPG) produced by Pseudomonas fluorescens, shows toxicity to many microorganisms including fungi, bacteria, and peronosporomycetes. Zoosporogenesis and motility of zoospores are critical for a complete disease cycle and pathogenicity of the peronosporomycete phytopathogens. The aim of this study was to test the effects of DAPG and its derivatives on zoosporogenesis and motility of zoospores of a downy mildew pathogen, Plasmopara viticola, and a damping-off pathogen, Aphanomyces cochlioides. In both cases, DAPG inhibited zoosporogenesis (5 MUg/ml) and the motility of zoospores (10 MUg/ml) in a dose-dependent manner. Generally, zoospores became immotile shortly after exposure to DAPG followed by lysis. However, a fraction of DAPG treated A. cochlioides zoospores formed round cystospores instead of lysis and then germinated with excessively-branched germ tubes. All derivatives of DAPG had similar inhibitory activities but at varying doses. Among them, 2,4 dipropylphloroglucinol exerted the highest inhibitory activity against both zoosporogenesis and motility of zoospores. This revealed that the degree of hydrogen atoms substitution in the benzene ring by acyl groups and the length of substituted acyl groups were related to the level of bioactivity. This is the first report of inhibitory activities of DAPG and its derivatives against zoosporogenesis and motility of zoospores of two important peronosporomycete phytopathogens. PMID- 22448106 TI - Behavior Problems in Relation to Sustained Selective Attention Skills of Moderately Preterm Children. AB - Attention skills may form an important developmental mechanism. A mediation model was examined in which behavioral problems of moderately preterm and term children at school age are explained by attention performance. Parents and teachers completed behavioral assessments of 348 moderately preterm children and 182 term children at 8 years of age. Children were administered a test of sustained selective attention. Preterm birth was associated with more behavioral and attention difficulties. Gestational age, prenatal maternal smoking, and gender were associated with mothers', fathers', and teachers' reports of children's problem behavior. Sustained selective attention partially mediated the relationship between birth status and problem behavior. Development of attention skills should be an important focus for future research in moderately preterm children. PMID- 22448107 TI - Parenting After a Natural Disaster: A Qualitative Study of Norwegian Families Surviving the 2004 Tsunami in Southeast Asia. AB - How do parents support their children after a high-impact disaster? To answer this question, face-to-face interviews were conducted with 51 Norwegian parents. These parents and children were all severely exposed to the trauma of the tsunami disaster. The analyses show how parents interpret their children's signs of distress, as well as their own strategies of support in the aftermath. The main strategies described by the parents were watchful waiting, careful monitoring of the children's reactions and a sensitive timing when providing support. Such monitoring, and interpretation of signs of distress, served as an aid for the parents in determining what needs their children had and what support they therefore needed to provide. A range of support strategies were employed, including re-establishing a sense of safety, resuming normal roles and routines, and talking to their children. Parents who were themselves severely impacted by the disaster reported a reduced ability to assess their children's reactions and thereby were unable to provide optimal care in the aftermath. Interestingly, the parents' support strategies mirror the early intervention recommendations put forward in the NICE guidelines and in the Psychological First Aid guidelines which is a well accepted and promising practice for helping children after disasters. PMID- 22448108 TI - Unique Roles of Mothering and Fathering in Child Anxiety; Moderation by Child's Age and Gender. AB - We examined the associations between the parenting dimensions autonomy granting, over control, and rejection and children's anxiety, in relation to parent and child gender and child age. Elementary school-aged children (n = 179, M(age) = 10.27, SD = 1.30), adolescents (n = 127, M(age) = 15.02, SD = 1.54) and both their parents completed questionnaires on parenting and children's anxiety. Parenting was more strongly related to child anxiety in elementary school children than in adolescents. Maternal over control was uniquely related to elementary school-aged children's anxiety whereas paternal over control was more important during adolescence. Opposite to our expectations, we found higher levels of parental autonomy granting to be related to higher levels of anxiety for younger elementary school-aged children (age < 10). For adolescents, the association between paternal over control and anxiety was stronger for older adolescents (age > 15), with higher levels of over control related to higher levels of anxiety. For both elementary school-aged children and adolescents, the associations between parenting and child anxiety did not differ as a function of the child's gender. If we are to understand the associations between parenting and children's anxiety, it is important to distinguish parental autonomy granting from parental over control and to consider the role of parent gender and the age of the child. PMID- 22448109 TI - Mifepristone 2.5 mg versus 5 mg daily in the treatment of leiomyoma before surgery. AB - OBJECTIVES: To evaluate the efficacy and safety of 2.5 mg and 5 mg mifepristone during 3 months for the treatment of uterine fibroids before surgery. DESIGN: Multicenter randomized clinical trial. LOCATIONS: Eusebio Hernandez Hospital, Havana, Cuba and the Aleman Hospital, Managua, Nicaragua. SUBJECTS: Included in the study were 146 women with symptomatic uterine fibroids. TREATMENT: GROUP I: half a tablet of 5 mg (2.5 mg) mifepristone taken orally every 24 hours, and Group II: one tablet of 5 mg mifepristone taken orally every 24 hours over a period of 3 months in both groups. Two endometrial biopsies were performed. VARIABLES TO EVALUATE EFFICACY: Increase in average hemoglobin, changes in fibroid and uterine volume, and symptomatic improvement. RESULTS: The average hemoglobin at the end of treatment was 0.6 g/dL greater in the 5 mg mifepristone group (P = 0.033). In both groups there were similar reductions in fibroid volumes. Clinical improvement was more significant in the 5 mg group. CONCLUSION: The dose to be used should be 5 mg. PMID- 22448110 TI - Laparoendoscopic single-site surgery (LESS) versus conventional laparoscopic surgery for adnexal preservation: a randomized controlled study. AB - OBJECTIVE: To compare the operative outcomes, postoperative pain, and subsequent convalescence after laparoendoscopic single-site surgery (LESS) or conventional laparoscopic surgery for adnexal preservation. STUDY DESIGN: From December 2009 to September 2010, 63 patients underwent LESS (n = 33) or a conventional laparoscopic surgery (n = 30) for cyst enucleation. The overall operative outcomes including postoperative pain measurement using the visual analog scale (VAS) were evaluated (time points 6, 24, and 24 hours). The convalescence data included data obtained from questionnaires on the need for analgesics and on patient-reported time to recovery end points. RESULTS: The preoperative characteristics did not significantly differ between the two groups. The postoperative hemoglobin drop was higher in the LESS group than in the conventional laparoscopic surgery group (P = 0.048). Postoperative pain at each VAS time point, oral analgesic requirement, intramuscular analgesic requirement, and the number of days until return to work were similar in both groups. CONCLUSION: In adnexa-preserving surgery performed in reproductive-age women, the operative outcomes, including satisfaction of the patients and convalescence after surgery, are comparable for LESS and conventional laparoscopy. LESS may be a feasible and a promising alternative method for scarless abdominal surgery in the treatment of young women with adnexal cysts. PMID- 22448111 TI - Remote prognosis after primary cesarean delivery: the association of VBACs and recurrent cesarean deliveries with maternal morbidity. AB - PURPOSE: To determine the effects of vaginal birth after cesarean (VBAC) versus repeated cesarean sections (RCS) after a primary cesarean section (CS), on the rate of intraoperative and postpartum maternal morbidity. PATIENTS AND METHODS: This is a retrospective population-based cohort study. During the study period (1988-2005) there were 200,012 deliveries by 76,985 women at our medical center; 16,365 of them had a primary CS, of which 7429 women delivered a singleton infant after the primary CS, met the inclusion criteria, were included in our study, and were followed for four consecutive deliveries. Patients were divided into three study groups according to the outcome of their consecutive delivery after the primary CS: VBAC (n = 3622), elective CS (n = 1910), or an urgent CS (n = 1897). Survival analysis models were used to investigate the effect of the urgency of CS and the numbers of pregnancy predating the primary CS on peripartum complications. RESULTS: Women who failed a trial of labor had a higher rate of uterine rupture than those who had a VBAC. Patients who delivered by CS had a higher rate of endometritis than those giving birth vaginally. The rate of cesarean hysterectomy and transfer to other departments increased significantly at the fourth consecutive surgery (P = 0.02 and P = 0.003, respectively). VBAC was associated with a 55% reduction in the risk of intrapartum complications in comparison to a planned CS (hazard ratio [HR] 0.45; 95% confidence interval [CI]: 0.22-0.89. A greater maternal parity at the time of primary CS was associated with lower intrapartum and postpartum morbidities (HR 0.44; 95% CI: 0.24-0.79; HR 0.54; 95% CI: 0.47-0.62, respectively). CONCLUSIONS: (1) A successful VBAC is associated with a reduction in the intrapartum complications; and (2) maternal morbidity increases substantially from the fourth consecutive cesarean delivery. PMID- 22448112 TI - Next-generation NovaSure device for endometrial ablation: assessing ease-of-use among physicians. AB - OBJECTIVE: To compare physician assessment of the next-generation NovaSure((r)) device to the original NovaSure device. DESIGN: Prospective open-label, unblinded survey utilizing Likert scales. SETTING: Community-based obstetrician and gynecology practices. PATIENTS: There were 270 evaluations completed by 168 physicians for women undergoing endometrial ablation with the next-generation NovaSure device compared to the previous model. INTERVENTIONS: Physician survey across multiple community-based obstetrician and gynecology practices. MEASUREMENTS AND MAIN RESULTS: In general, 53.7% of women had a normal uterus, with an average cavity length of 5.3 cm +/- 0.9 cm, and 44.7% of women had a normal cervix. Overall, 98.7% of physicians agreed or strongly agreed that they were satisfied with the performance of the next-generation NovaSure device compared with the previous device. Additionally, 89% of physicians rated the next generation NovaSure device as superior to the previous device. The best rated features were the SureFitTM Cervical Seal, Smooth AccessTM Tips, and the thumb pusher. No adverse events were reported in this study. CONCLUSION: Community based physicians rated the next-generation NovaSure device as superior to the previous model in a general population of women. PMID- 22448113 TI - A new species and new record of the leafhopper genus Seriana Dworakowska (Hemiptera, Cicadellidae, Typhlocybinae) from China. AB - Seriana menglaensissp. n. (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini) is described and illustrated from Southwest China. Seriana equata (Singh, 1969) is recorded for the first time from China. PMID- 22448114 TI - Review of Australasian spider flies (Diptera, Acroceridae) with a revision of Panops Lamarck. AB - The Australasian spider flies (Diptera: Acroceridae) are reviewed, with all eight currently recognized genera diagnosed and figured. The panopine genus Panops Lamarck, 1804 from Australia and Indonesia is revised with four new species described, increasing the total number of species in the genus to nine: Panops aurumsp. n., Panops danielsisp. n., Panops jadesp. n. and Panops schlingerisp. n. Five species of Panops are redescribed: Panops austrae Neboiss, 1971, Panops baudini Lamarck, 1804, Panops boharti (Schlinger, 1959), comb. n., Panops conspicuus (Brunetti, 1926) and Panops grossi (Neboiss, 1971), comb. n. The monotypic genera Neopanops Schlinger, 1959 and Panocalda Neboiss, 1971 are synonymized with Panops. Keys to genera of Australasian Acroceridae and species of Panops, Helle Osten Sacken, 1896 and Australasian Pterodontia Gray, 1832 are included. PMID- 22448115 TI - A new species of Geotrigona Moure from the Caribbean coast of Colombia (Hymenoptera, Apidae). AB - A new species of the Neotropical stingless bee genus Geotrigona Moure from the Caribbean coast of Colombia is described and figured. Geotrigona joearroyoisp. n. belongs to the fulvohirta species group and is distinguished on the basis of color and type of pubescence on the metasomal terga. New geographical records and an updated key to the species of Geotrigona are provided. PMID- 22448116 TI - A new wild, pollinating bee species of the genus Tetraloniella from the Arabian Peninsula (Hymenoptera, Apidae). AB - A new species of the eucerine bee genus Tetraloniella Ashmead (Apinae: Eucerini) is described and figured from central Saudi Arabia and Qatar. Tetraloniella (Tetraloniella) persiciformissp. n. is distinguished on the basis of coloration, integumental sculpturing, male metafemoral structure, and male terminalia. A floral record of Pulicaria undulata (L.) C.A. Mey. (Compositae) is noted for some of the material. Females superficially resemble those of Tarsalia persica (Warncke) (Ancylaini) in overall coloration but can be distinguished by the typical generic and tribal characters. PMID- 22448117 TI - A new species of Halacarsantia Wolff, 1989 (Crustacea, Isopoda, Asellota, Santiidae) from Wistari Reef, southern Great Barrier Reef, Australia. AB - Halacarsantia acutasp. n. is described from Wistari Reef, Capricorn Group, southern Great Barrier Reef, the first record of the genus from Australia. The new species differs from its congeners in having antenna flagellum composed of 8 articles; epipod apically acute, without setae, broad maxilliped endite and pereopod 1 basis with a short projection. A key to species of the genus is provided. PMID- 22448118 TI - Commensal Leucothoidae (Crustacea, Amphipoda) of the Ryukyu Archipelago, Japan. Part III: coral rubble-dwellers. AB - Commensal leucothoid amphipods have been collected from coral rubble samples throughout the Ryukyu Archipelago, Japan. Seven new species are described in two generawith valuable location data. A new locality is presented for Paranamixis misakiensis Thomas, 1997. An identification key to all described Leucothoidae of the Ryukyu Archipelago is provided. PMID- 22448119 TI - Description of a new species of Haemogamasus (Mesostigmata, Laelapidae, Haemogamasinae) from Chubut, Rio Negro and Neuquen Provinces, Argentina. AB - A new species of Haemogamasus mites is described from Chubut, Neuquen and Rio Negro Provinces, Argentina. It was collected primarily from rodents of the genus Abrothrix (65 of 77 collections): Abrothrix longipilis (63), Abrothrix olivaceus olivaceus (1) and Abrothrix olivaceus xanthorhinus (1). Additional collections were made from Geoxus valdivianus (5) and Loxdomtomys micropus (5). Possibly incidental or contaminate collections were recorded from Oligoryzomys longicaudatus (1) and Dromiciops gliroides (1). Most collections came from Rio Negro Province (36), with 22 from Neuquen and 19 from Chubut. An identification key is provided to distinguish ?s of this new species from ?s of species from the western hemisphere, based on morphological characters. PMID- 22448120 TI - Achrysocharoides Girault (Hymenoptera, Eulophidae) new to tropical America, with eight new species. AB - The genus Achrysocharoides Girault is here reported for the first time from tropical America. Included are ten species, eight newly described: Achrysocharoides asperulus, Achrysocharoides callisetosus, Achrysocharoides cuspidatus, Achrysocharoides foveatus, Achrysocharoides infuscus, Achrysocharoides mediocarinatus, Achrysocharoides purpureus, Achrysocharoides sulcatus, and two already known: Achrysocharoides ecuadorensis (Hansson) and Achrysocharoides gliricidiae (Hansson & Cave). All species are included in an identification key, diagnosed, described and illustrated. Only one of the species, Achrysocharoides gliricidiae, has a host record, an endoparasitoid in a leafmining Gracillariidae (Lepidoptera) on Gliricidia sepium (Fabaceae), thus conforming to the biology of extralimital Achrysocharoides species. The genus Kratoysma Boucek is here established as a junior synonym of Achrysocharoides, and the following species previously in Kratoysma are here recombined to Achrysocharoides: Kratoysma citri Boucek, Kratoysma ecuadorensis Hansson, Kratoysma gliricidiae Hansson & Cave, Kratoysma longifacies Hansson, Kratoysma nepalensis Hansson, Derostenus usticrus Erdos. PMID- 22448121 TI - Classification, molecular characterization, and the significance of pten alteration in leiomyosarcoma. AB - Leiomyosarcoma is a malignant smooth muscle neoplasm with a complicated histopathologic classification scheme and marked differences in clinical behavior depending on the anatomic site of origin. Overlapping morphologic features of benign and borderline malignant smooth muscle neoplasms further complicate the diagnostic process. Likewise, deciphering the complex and heterogeneous patterns of genetic changes which occur in this cancer has been challenging. Preliminary studies suggest that reproducible molecular classification may be possible in the near future and new prognostic markers are emerging. Robust recapitulation of leiomyosarcoma in mice with conditional deletion of Pten in smooth muscle and the simultaneous discovery of a novel role for Pten in genomic stability provide a fresh perspective on the mechanism of leiomyosarcomagenesis and promise for therapeutic intervention. PMID- 22448122 TI - Giant cell tumors of the axial skeleton. AB - Background. We report on 19 cases of giant cell tumor of bone (GCT) affecting the spine or sacrum and evaluate the outcome of different treatment modalities. Methods. Nineteen patients with GCT of the spine (n = 6) or sacrum (n = 13) have been included in this study. The mean followup was 51.6 months. Ten sacral GCT were treated by intralesional procedures of which 4 also received embolization, and 3 with irradiation only. All spinal GCT were surgically treated. Results. Two (15.4%) patients with sacral and 4 (66.7%) with spinal tumors had a local recurrence, two of the letter developed pulmonary metastases. One local recurrence of the spine was successfully treated by serial arterial embolization, a procedure previously described only for sacral tumors. At last followup, 9 patients had no evidence of disease, 8 had stable disease, 1 had progressive disease, 1 died due to disease. Six patients had neurological deficits. Conclusions. GCT of the axial skeleton have a high local recurrence rate. Neurological deficits are common. En-bloc spondylectomy combined with embolization is the treatment of choice. In case of inoperability, serial arterial embolization seems to be an alternative not only for sacral but also for spinal tumors. PMID- 22448123 TI - Molecular alterations associated with osteosarcoma development. AB - Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases which is the main cause of death. Unfortunately, the conventional chemotherapy is not fully effective on osteosarcoma metastases. The progression of a primary tumor to metastasis requires multiple processes, which are neovascularization, proliferation, invasion, survival in the bloodstream, apoptosis resistance, arrest at a distant organ, and outgrowth in secondary sites. Consequently, recent studies have revealed new insights into the molecular mechanisms of metastasis development. The understanding of the mechanism of molecular alterations can provide the identification of novel therapeutic targets and/or prognostic markers for osteosarcoma treatment to improve the clinical outcome. PMID- 22448124 TI - Putative multifunctional signature of lung metastases in dedifferentiated chondrosarcoma. AB - Chondrosarcomas are among the most malignant skeletal tumors. Dedifferentiated chondrosarcoma is a highly aggressive subtype of chondrosarcoma, with lung metastases developing within a few months of diagnosis in 90% of patients. In this paper we performed comparative analyses of the transcriptomes of five individual metastatic lung lesions that were surgically resected from a patient with dedifferentiated chondrosarcoma. We document for the first time a high heterogeneity of gene expression profiles among the individual lung metastases. Moreover, we reveal a signature of "multifunctional" genes that are expressed in all metastatic lung lesions. Also, for the first time, we document the occurrence of massive macrophage infiltration in dedifferentiated chondrosarcoma lung metastases. PMID- 22448125 TI - Cytotoxicity and ion release of alloy nanoparticles. AB - It is well-known that nanoparticles could cause toxic effects in cells. Alloy nanoparticles with yet unknown health risk may be released from cardiovascular implants made of Nickel-Titanium or Cobalt-Chromium due to abrasion or production failure. We show the bio-response of human primary endothelial and smooth muscle cells exposed to different concentrations of metal and alloy nanoparticles. Nanoparticles having primary particle sizes in the range of 5-250 nm were generated using laser ablation in three different solutions avoiding artificial chemical additives, and giving access to formulations containing nanoparticles only stabilized by biological ligands. Endothelial cells are found to be more sensitive to nanoparticle exposure than smooth muscle cells. Cobalt and Nickel nanoparticles caused the highest cytotoxicity. In contrast, Titanium, Nickel Iron, and Nickel-Titanium nanoparticles had almost no influence on cells below a nanoparticle concentration of 10 MUM. Nanoparticles in cysteine dissolved almost completely, whereas less ions are released when nanoparticles were stabilized in water or citrate solution. Nanoparticles stabilized by cysteine caused less inhibitory effects on cells suggesting cysteine to form metal complexes with bioactive ions in media. PMID- 22448126 TI - Bioremediation of agro-based pulp mill effluent by microbial consortium comprising autochthonous bacteria. AB - Small-scale agro-based pulp and paper mills are characterized as highly polluting industries. These mills use Kraft pulping process for paper manufacturing due to which toxic lignified chemicals are released into the environment. Lack of infrastructure, technical manpower, and research and development facilities restricts these mills to recover these chemicals. Therefore, the chemical oxygen demand (COD) of the emanating stream is quite high. For solving the above problem, four bacteria were isolated from the premises of agro-based pulp and paper mill which were identified as species of Pseudomonas, Bacillus, Pannonibacter, and Ochrobacterum. These bacteria were found capable of reducing COD up to 85%-86.5% in case of back water and 65-66% in case of back water : black liquor (60:40), respectively, after acclimatization under optimized conditions (pH 6.8, temperature 35 degrees C, and shaking 200 rpm) when the wastewater was supplemented with nitrogen and phosphorus as trace elements. PMID- 22448127 TI - Quantification and classification of corn and sunflower oils as adulterants in olive oil using chemometrics and FTIR spectra. AB - Commercially, extra virgin olive oil (EVOO) is subjected to be adulterated with low-price oils having similar color to EVOO. Fourier transform infrared (FTIR) spectroscopy combined with chemometrics has been successfully used for classification and quantification of corn (CO) and sunflower oils (SFOs) in EVOO sets. The combined frequency regions of 3027-3000, 1076-860, and 790-698 cm(-1) were used for classification and quantification of CO in EVOO; meanwhile, SFO was analyzed using frequency regions of 3025-3000 and 1400-985 cm(-1). Discriminant analysis can make classification of pure EVOO and EVOO adulterated with CO and SFO with no misclassification reported. The presence of CO in EVOO was determined with the aid of partial least square calibration using FTIR normal spectra. The calibration and validation errors obtained in CO's quantification are 0.404 and 1.13%, respectively. Meanwhile, the first derivative FTIR spectra and PLS calibration model were preferred for quantification of SFO in EVOO with high coefficient of determination (R(2)) and low errors, either in calibration or in validation sample sets. PMID- 22448128 TI - Conservation of nucleosome positions in duplicated and orthologous gene pairs. AB - Although nucleosome positions tend to be conserved in gene promoters, whether they are conserved in duplicated and orthologous genes is unknown. In order to elucidate how nucleosome positions are conserved between duplicated and orthologous gene pairs, I performed 2 comparative studies. First, I compared the nucleosome position profiles of duplicated genes in the filamentous ascomycete Aspergillus fumigatus. After identifying 63 duplicated gene pairs among 9630 protein-encoding genes, I compared the nucleosome position profiles of the paired genes. Although nucleosome positions are conserved more in gene promoters than in gene bodies, their profiles were diverse, suggesting evolutionary changes after gene duplication. Next, I examined the conservation of nucleosome position profiles in 347 A. fumigatus orthologs of S. cerevisiae genes that showed notably high conservation of nucleosome positions between the parent strain and 2 deletion mutants. In only 11 (3.2%) of the 347 gene pairs, the nucleosome position profile was highly conserved (Spearman's rank correlation coefficient > 0.7). The absence of nucleosome position conservation in promoters of orthologous genes suggests organismal specificity of nucleosome arrangements. PMID- 22448129 TI - Transcriptional profiling of ESTs from the biocontrol fungus Chaetomium cupreum. AB - Comparative analysis was applied to two cDNA/ESTs libraries (C1 and C2) from Chaetomium cupreum. A total of 5538 ESTs were sequenced and assembled into 2162 unigenes including 585 contigs and 1577 singletons. BlastX analysis enabled the identification of 1211 unigenes with similarities to sequences in the public databases. MFS monosaccharide transporter was found as the gene expressed at the highest level in library C2, but no expression in C1. The majority of unigenes were library specific. Comparative analysis of the ESTs further revealed the difference of C. cupreum in gene expression and metabolic pathways between libraries. Two different sequences similar to the 48-KDa endochitinase and 46-KDa endochitinase were identified in libraries C1 and C2, respectively. PMID- 22448130 TI - Mentoring nurse scientists to meet nursing faculty workforce needs. AB - Research indicates that mentoring has been highly effective in promoting faculty success. Strong mentors in the area of scholarship are extremely valuable for junior faculty, not only because of their research and academic expertise but also for their role modeling behaviors. This paper highlights key components of research mentoring used by a senior nursing faculty member. The senior faculty mentor and junior faculty mentee developed a common vision, relating to research interests in health promotion for vulnerable populations. Impact at the individual, school, university, and society level is discussed, and benefits of mentoring to meet nursing faculty workforce needs are emphasized. PMID- 22448131 TI - Oxidative stress level in the testes of mice and rats during nickel intoxication. AB - The genotioxic and carcinogenic effect of nickel probably results from its capacity to produce reactive oxygen species (ROS) and disturb the redox balance. The aim of the study was to find out if rats lacking spermatic protamine 2 are less susceptible to Ni(II) than mice. Consequently, the levels of malondialdehyde + 4 hydroxynonenal (MDA+4HDA) - markers of lipid peroxidation, as well as the level of reduced glutathione (GSH) were measured within the rat and mouse testes. Our results showed that the levels of lipid peroxidation markers were elevated in testicular homogenates of intoxicated mice without any changes in rats. GSH level was lower in the group of intoxicated mice comparing to the control without statistically significant changes in rats' homogenates. Moreover, the level of GSH in the testes of intoxicated mice was lower than in rats. On the basis of our results, it appears that Ni(II) can initiate oxidative stress in the testes of mice but not of rats and can reduce GSH level. Consequently, the antioxidative defense of the testes is reduced. Ni(II) that causes oxidative stress in the testes may also contribute to infertility. PMID- 22448132 TI - Tuberculosis in sheltered homeless population of Rome: an integrated model of recruitment for risk management. AB - The authors show the results of an integrated model for risk management of tuberculosis in a sample of sheltered homeless in Rome. Tuberculin skin test (TST) was used for evaluating the prevalence of latent infection (LTBI). In TST positives, expectorate was collected and chest X-ray was achieved. Multiple logistic regression analysis was performed to investigate determinants of infection. Out of 288 recruited subjects, 259 returned for the TST reading; 45.56% were positive and referred to a specialized center; 70 accessed the health facility and completed the clinical pathway. The risk factors associated to LTBI were male gender (OR = 3.72), age over 60 years (OR = 3.59), immigrant status (OR = 3.73), and obesity (OR = 2.19). This approach, based on an integrated social network, guarantees high adherence to screening (89.93%), allowing patients testing positive for latent tuberculosis infection to be diagnosed and rapidly referred to a specialized center. PMID- 22448133 TI - Vesiculation from Pseudomonas aeruginosa under SOS. AB - Bacterial infections can be aggravated by antibiotic treatment that induces SOS response and vesiculation. This leads to a hypothesis concerning association of SOS with vesiculation. To test it, we conducted multiple analyses of outer membrane vesicles (OMVs) produced from the Pseudomonas aeruginosa wild type in which SOS is induced by ciprofloxacin and from the LexA noncleavable (lexAN) strain in which SOS is repressed. The levels of OMV proteins, lipids, and cytotoxicity increased for both the treated strains, demonstrating vesiculation stimulation by the antibiotic treatment. However, the further increase was suppressed in the lexAN strains, suggesting the SOS involvement. Obviously, the stimulated vesiculation is attributed by both SOS-related and unrelated factors. OMV subproteomic analysis was performed to examine these factors, which reflected the OMV-mediated cytotoxicity and the physiology of the vesiculating cells under treatment and SOS. Thus, SOS plays a role in the vesiculation stimulation that contributes to cytotoxicity. PMID- 22448134 TI - Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications. AB - The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120 injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB. PMID- 22448135 TI - Diversity of catechin in northeast Indian tea cultivars. AB - Tea (Camellia sinensis L.) leaf contains a large amount of catechins (a group of very active flavonoids) which contribute to major quality attributes of black tea. Based on morphological characters tea plants were classified as Assam, China, and Cambod varieties. The present study is an attempt for biochemical fingerprinting of the tea varieties based on catechin composition in green leaf of cultivars grown in Northeast India. Assam variety cultivars contained the highest level of catechins followed by Cambod and China. The average catechin contents were 231 +/- 7 mg g(-1), 202 +/- 5 mg g(-1), and 157 +/- 4 mg g(-1) of dry weight of green leaf for Assam, Cambod, and China cultivars, respectively. Among the individual catechins the variations in epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were the most prominent among the varieties. High EGC content was found to be a characteristic of Assam variety which was further corroborated through multivariate analysis. PMID- 22448136 TI - Thyroid function after subtotal thyroidectomy in patients with Graves' hyperthyroidism. AB - BACKGROUND: Subtotal thyroidectomy is a surgical procedure, in which the surgeon leaves a small thyroid remnant in situ to preserve thyroid function, thereby preventing lifelong thyroid hormone supplementation therapy. AIM: To evaluate thyroid function after subtotal thyroidectomy for Graves' hyperthyroidism. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of all patients (n = 62) who underwent subtotal thyroidectomy for recurrent Graves' hyperthyroidism between 1992 and 2008 in our hospital. Thyroid function was defined according to plasma TSH and free T4 values. RESULTS: Median followup after operation was 54.6 months (range 2.1-204.2 months). Only 6% of patients were euthyroid after surgery. The majority of patients (84%) became hypothyroid, whereas 10% of patients had persistent or recurrent hyperthyroidism. Permanent recurrent laryngeal nerve palsy and permanent hypocalcaemia were noted in 1.6% and 3.2% of patients, respectively. CONCLUSION: In our series, subtotal thyroidectomy for Graves' hyperthyroidism was associated with a high risk of postoperative hypothyroidism and a smaller, but significant, risk of persistent hyperthyroidism. Our data suggest that subtotal thyroidectomy seems to provide very little advantage over total thyroidectomy in terms of postoperative thyroid function. PMID- 22448137 TI - Porous collagen scaffold reinforced with surfaced activated PLLA nanoparticles. AB - Porous collagen scaffold is integrated with surface activated PLLA nanoparticles fabricated by lyophilizing and crosslinking via EDC treatment. In order to prepare surface-modified PLLA nanoparticles, PLLA was firstly grafted with poly (acrylic acid) (PAA) through surface-initiated polymerization of acrylic acid. Nanoparticles of average diameter 316 nm and zeta potential -39.88 mV were obtained from the such-treated PLLA by dialysis method. Porous collagen scaffold were fabricated by mixing PLLA nanoparticles with collagen solution, freeze drying, and crosslinking with EDC. SEM observation revealed that nanoparticles were homogeneously dispersed in collagen matrix, forming interconnected porous structure with pore size ranging from 150 to 200 MUm, irrespective of the amount of nanoparticles. The porosity of the scaffolds kept almost unchanged with the increment of the nanoparticles, whereas the mechanical property was obviously improved, and the degradation was effectively retarded. In vitro L929 mouse fibroblast cells seeding and culture studies revealed that cells infiltrated into the scaffolds and were distributed homogeneously. Compared with the pure collagen sponge, the number of cells in hybrid scaffolds greatly increased with the increment of incorporated nanoparticles. These results manifested that the surface-activated PLLA nanoparticles effectively reinforced the porous collagen scaffold and promoted the cells penetrating into the scaffold, and proliferation. PMID- 22448138 TI - Clinical characteristics of recurrent nasopharyngeal carcinoma in high-incidence area. AB - BACKGROUND: To describe the clinical characteristics of the patients who suffered from relapse after conventional irradiation for nasopharyngeal carcinoma (NPC). METHODS: Three hundred and fifty-one consecutive patients with first-time recurrent NPC between January 1999 and July 2005 were included. The patients' clinical data were reviewed, including recurrent interval time, symptoms, signs, imaging characteristics, pathologic features, and restaging. RESULTS: The median interval of relapse was 26.0 months. The most common symptoms in symptomatic patients were nasal bloody discharge (37.9%) and headache (31.1%). Local recurrence alone accounted for 73.5%. Most patients were restaged as stage III (23.1%) and stage IV (51.1%). Subgroup analysis suggested a significantly higher proportion of the long-latent relapses originated from early primary. A series of postreirradiation complications were more frequent in patients with longer latency at reception. CONCLUSIONS: Most recurrent nasopharyngeal carcinoma is advanced disease. Patients with different recurrent interval time show different nature behavior. PMID- 22448139 TI - Biomass estimation of dry tropical woody species at juvenile stage. AB - Accurate characterization of biomass in different forest components is important to estimate their contribution to total carbon stock. Due to lack of allometric equations for biomass estimation of woody species at juvenile stage, the carbon stored in this forest component is ignored. We harvested 47 woody species at juvenile stage in a dry tropical forest and developed regression models for the estimation of above-ground biomass (AGB). The models including wood-specific gravity (rho) exhibited higher R(2) than those without rho. The model consisting of rho, stem diameter (D), and height (H) not only exhibited the highest R(2) value but also had the lowest standard error of estimate. We suggest that rho based regression model is a viable option for nondestructive estimation of biomass of forest trees at juvenile stage. PMID- 22448140 TI - Skin and soft tissue infections in patients with solid tumours. AB - BACKGROUND: Skin and soft tissue infections (SSTIs) in cancer patients represent a diagnostic challenge, as etiologic diagnosis is often missing, and clinical assessment of severity is difficult. Few studies have described (SSTIs) in patients with solid tumours (STs). PATIENTS AND METHODS: Records of patients with ST and SSTI, cared for at the University Hospital of Heraklion, from 2002 to 2006 were retrospectively studied. Results. A total of 81 episodes of SSTIs, occurring in 71 patients with ST, have been evaluated. Their median age was 65 years (34 82). The most common underlying malignancy was breast cancer in 17 patients (24%). Most episodes (89%) occurred in nonneutropenics. Cellulitis/erysipelas was the most common clinical presentation (56; 69%). Bacterial cultures were possible in 29 (36%) patients. All patients received antimicrobial therapy, while in 17 episodes (21%) an incision and drainage was required. Treatment failure occurred in 20 episodes (25%). Five patients (7%) died due to sepsis. None was neutropenic. Severe sepsis on admission (P = 0.002) and prior blood transfusion (P = 0.043) were independent predictors of treatment failure. CONCLUSION: SSTIs can be life threatening among patients with ST. Early diagnosis and appropriate treatment are of the utmost importance, since sepsis was proven a significant factor of unfavourable outcome. PMID- 22448141 TI - A meta-analysis of tea drinking and risk of Parkinson's disease. AB - BACKGROUND: Many studies have reported an association between tea drinking and Parkinson's disease (PD). Our purpose is to summarize the available information and evaluate the risk of PD associated with tea drinking. METHODS: We searched all publications in English language on the association of tea drinking and PD risk published up to December 2010. The pooled analysis was performed with Review Manager 5.0. RESULTS: In total, eight articles including 1418 cases and 4250 controls were included in the meta-analysis. The pooled odds ratio (95% CI) was 0.85 (0.74-0.98), which suggests the protective effect of tea drinking in PD risks. Moreover, the summary OR (OR: 0.83, 95% CI = 0.69-0.99) for drinkers of <= 1 cup of tea per day versus nonconsumers and that (OR: 0.96, 95% CI = 0.73-1.27) for drinkers of >1 cups of tea per day versus nonconsumers showed that there was not an apparent dose-response relationship. No indication for publication bias was found. CONCLUSIONS: This meta-analysis showed that tea drinking can lower the risk of PD, while no apparent dose-response relationship was found. Further effort is needed to fully understand the mechanism underlying the beneficial effect of tea consumption in lowering PD risk. PMID- 22448142 TI - DWI-MRI: single, informative, and noninvasive technique for prostate cancer diagnosis. AB - AIM: To evaluate diffusion weighted image-MRI (DWI) as a single diagnostic noninvasive MRI technique for prostate cancer (PCa) diagnosis. MATERIAL AND METHODS: A prospective study was conducted between July 2008 and July 2009. Candidates patients were equal or more than 40 years old, with suspicious digital rectal examination (more than clinical T2) or PSA >4 ng/mL. Informed consent was signed. DWI-MRI was performed at 1.5 T with a body coil combined with a spine coil in consecutive 100 cases. The histopathology of biopsies has been used as reference standard. Two examiners were evaluating MRI and TRUS, both of them were blinded regarding pathological findings. Accuracy, specificity, and sensitivity were statistically analyzed. RESULTS: Based on pathological diagnosis: group A (cancerous); 75 cases and group B (non-cancerous); 25 cases. Mean age was 65.3 and 62.8 years in groups A and B, respectively. Mean PSA was 30.7 and 9.2 ng/mL in groups A and B, respectively. Sensitivity of DWI was 58.3% while specificity was 83.8%. Accuracy of lesion detection was 52.4-77.8% (P < 0.05). Moreover, DWI at ADC value 1.2 * 10(-3) mL/sec could determine 82.4% of true positive cases (P < 0.05). ADC values were lower with Gleason score >= 7 (P < 0.05). CONCLUSION: DWI could represent a non invasive single diagnostic tool not only in detection and localization but also in prediction of Gleason score whenever DWI is used prior to invasive TRUS biopsy. Furthermore, targeted single biopsy could be planned after DWI to minimize patient morbidity by invasive techniques. PMID- 22448143 TI - New and Evolving Management Paradigms for Hepatitis C after Liver Transplantation. AB - Hepatitis-C induced liver failure is the leading indication for liver transplantation in the United States, and the burden of hepatitis C virus (HCV) induced liver disease is not expected to peak for at least another decade. 2011 will usher in a new era of directly acting antiviral therapies and personalized medicine that will assist patients and clinicians in choosing the best drug regimen. Specific markers to predict sustained virologic response (SVR) in the posttransplant setting are under development, and the role of graft genetic markers like interleukin-28B and interferon-gamma inducible protein-10 have yet to be fully defined. Lessons and experiences from treating the pretransplant population will be applied to patients with recurrent posttransplant HCV while studies specific to this population proceed. New paradigms for HCV treatment give promise to reducing the pretransplant burden of disease and improving SVR rates in the posttransplant population. PMID- 22448144 TI - Maternal xNorrin, a canonical Wnt signaling agonist and TGF-beta antagonist, controls early neuroectoderm specification in Xenopus. AB - Dorsal-ventral specification in the amphibian embryo is controlled by beta catenin, whose activation in all dorsal cells is dependent on maternal Wnt11. However, it remains unknown whether other maternally secreted factors contribute to beta-catenin activation in the dorsal ectoderm. Here, we show that maternal Xenopus Norrin (xNorrin) promotes anterior neural tissue formation in ventralized embryos. Conversely, when xNorrin function is inhibited, early canonical Wnt signaling in the dorsal ectoderm and the early expression of the zygotic neural inducers Chordin, Noggin, and Xnr3 are severely suppressed, causing the loss of anterior structures. In addition, xNorrin potently inhibits BMP- and Nodal/Activin-related functions through direct binding to the ligands. Moreover, a subset of Norrin mutants identified in humans with Norrie disease retain Wnt activation but show defective inhibition of Nodal/Activin-related signaling in mesoderm induction, suggesting that this disinhibition causes Norrie disease. Thus, xNorrin is an unusual molecule that acts on two major signaling pathways, Wnt and TGF-beta, in opposite ways and is essential for early neuroectoderm specification. PMID- 22448145 TI - Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. AB - An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS), and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL) patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats met mutants. PMID- 22448146 TI - Neuroscience, ethics, and national security: the state of the art. AB - National security organizations in the United States, including the armed services and the intelligence community, have developed a close relationship with the scientific establishment. The latest technology often fuels warfighting and counter-intelligence capacities, providing the tactical advantages thought necessary to maintain geopolitical dominance and national security. Neuroscience has emerged as a prominent focus within this milieu, annually receiving hundreds of millions of Department of Defense dollars. Its role in national security operations raises ethical issues that need to be addressed to ensure the pragmatic synthesis of ethical accountability and national security. PMID- 22448147 TI - Guidance for evidence-informed policies about health systems: assessing how much confidence to place in the research evidence. AB - In the third paper in a three-part series on health systems guidance, Simon Lewin and colleagues explore the challenge of assessing how much confidence to place in evidence on health systems interventions. PMID- 22448148 TI - Better guidance is welcome, but without blinders. PMID- 22448149 TI - Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. AB - BACKGROUND: Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy. METHODS AND FINDINGS: FDA Drug Approval Packages for eight second-generation antipsychotics aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone--were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant. CONCLUSIONS: The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs. PMID- 22448151 TI - Absorption Enhancement in Peridinin-Chlorophyll-Protein Light-Harvesting Complexes Coupled to Semicontinuous Silver Film. AB - We report on experimental and theoretical studies of plasmon-induced effects in a hybrid nanostructure composed of light-harvesting complexes and metallic nanoparticles in the form of semicontinuous silver film. The results of continuous-wave and time-resolved spectroscopy indicate that absorption of the light-harvesting complexes is strongly enhanced upon coupling with the metallic film spaced by 25 nm of a dielectric silica layer. This conclusion is corroborated by modeling, which confirms the morphology of the silver island film. PMID- 22448152 TI - The Roots of Linguistic Organization in a New Language. AB - It is possible for a language to emerge with no direct linguistic history or outside linguistic influence. Al-Sayyid Bedouin Sign Language (ABSL) arose about 70 years ago in a small, insular community with a high incidence of profound prelingual neurosensory deafness. In ABSL, we have been able to identify the beginnings of phonology, morphology, syntax, and prosody. The linguistic elements we find in ABSL are not exclusively holistic, nor are they all compositional, but a combination of both. We do not, however, find in ABSL certain features that have been posited as essential even for a proto-language. ABSL has a highly regular syntax as well as word-internal compounding, also highly regular but quite distinct from syntax in its patterns. ABSL, however, has no discernable word-internal structure of the kind observed in more mature sign languages: no spatially organized morphology and no evident duality of phonological patterning. PMID- 22448150 TI - CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. AB - BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/ul and ending with either a measurement >500 copies/ul, the first of two consecutive measurements between 50-500 copies/ul, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/ul (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/ul, 0.81 (0.71-0.92) for counts 200 to <350 cells/ul, 0.74 (0.66-0.83) for counts 350 to <500 cells/ul, and 0.96 (0.92-0.99) for counts >=500 cells/ul. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/ul. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/ul but still some slight benefit for those with a CD4 cell count >=500 cells/ul. PMID- 22448153 TI - Transgressive segregation of primary and secondary metabolites in F(2) hybrids between Jacobaea aquatica and J. vulgaris. AB - Hybridization between plant species can have a number of biological consequences; interspecific hybridization has been tied to speciation events, biological invasions, and diversification at the level of genes, metabolites, and phenotypes. This study aims to provide evidence of transgressive segregation in the expression of primary and secondary metabolites in hybrids between Jacobaeavulgaris and J. aquaticus using an NMR-based metabolomic profiling approach. A number of F(2) hybrid genotypes exhibited metabolomic profiles that were outside the range encompassed by parental species. Expression of a number of primary and secondary metabolites, including jacaronone analogues, chlorogenic acid, sucrose, glucose, malic acid, and two amino acids was extreme in some F(2) hybrid genotypes compared to parental genotypes, and citric acid was expressed in highest concentrations in J. vulgaris. Metabolomic profiling based on NMR is a useful tool for quantifying genetically controlled differences between major primary and secondary metabolites among plant genotypes. Interspecific plant hybrids in general, and specifically hybrids between J. vulgaris and J. aquatica, will be useful for disentangling the ecological role of suites of primary and secondary metabolites in plants, because interspecific hybridization generates extreme metabolomic diversity compared to that normally observed between parental genotypes. PMID- 22448154 TI - Metabolomics of cerebrospinal fluid reveals changes in the central nervous system metabolism in a rat model of multiple sclerosis. AB - Experimental Autoimmune Encephalomyelitis (EAE) is the most commonly used animal model for Multiple Sclerosis (MScl). CSF metabolomics in an acute EAE rat model was investigated using targetted LC-MS and GC-MS. Acute EAE in Lewis rats was induced by co-injection of Myelin Basic Protein with Complete Freund's Adjuvant. CSF samples were collected at two time points: 10 days after inoculation, which was during the onset of the disease, and 14 days after inoculation, which was during the peak of the disease. The obtained metabolite profiles from the two time points of EAE development show profound differences between onset and the peak of the disease, suggesting significant changes in CNS metabolism over the course of MBP-induced neuroinflammation. Around the onset of EAE the metabolome profile shows significant decreases in arginine, alanine and branched amino acid levels, relative to controls. At the peak of the disease, significant increases in concentrations of multiple metabolites are observed, including glutamine, O phosphoethanolamine, branched-chain amino acids and putrescine. Observed changes in metabolite levels suggest profound changes in CNS metabolism over the course of EAE. Affected pathways include nitric oxide synthesis, altered energy metabolism, polyamine synthesis and levels of endogenous antioxidants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306 011-0306-3) contains supplementary material, which is available to authorized users. PMID- 22448155 TI - Development of quantitative metabolomics for Pichia pastoris. AB - Accurate, reliable and reproducible measurement of intracellular metabolite levels has become important for metabolic studies of microbial cell factories. A first critical step for metabolomic studies is the establishment of an adequate quenching and washing protocol, which ensures effective arrest of all metabolic activity and removal of extracellular metabolites, without causing leakage of metabolites from the cells. Five different procedures based on cold methanol quenching and cell separation by filtration were tested for metabolomics of Pichia pastoris regarding methanol content and temperature of the quenching solution as key parameters. Quantitative evaluation of these protocols was carried out through mass balance analysis, based on metabolite measurements in all sample fractions, those are whole broth, quenched and washed cells, culture filtrate and quenching and washing solution. Finally, the optimal method was used to study the time profiles of free amino acid and central carbon metabolism intermediates in glucose-limited chemostat cultures. Acceptable recoveries (>90%) were obtained for all quenching procedures tested. However, quenching at -27 degrees C in 60% v/v methanol performed slightly better in terms of leakage minimization. We could demonstrate that five residence times under glucose limitation are enough to reach stable intracellular metabolite pools. Moreover, when comparing P. pastoris and S. cerevisiae metabolomes, under the same cultivation conditions, similar metabolite fingerprints were found in both yeasts, except for the lower glycolysis, where the levels of these metabolites in P. pastoris suggested an enzymatic capacity limitation in that part of the metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0308-1) contains supplementary material, which is available to authorized users. PMID- 22448156 TI - Plasma metabolomics and proteomics profiling after a postprandial challenge reveal subtle diet effects on human metabolic status. AB - We introduce the metabolomics and proteomics based Postprandial Challenge Test (PCT) to quantify the postprandial response of multiple metabolic processes in humans in a standardized manner. The PCT comprised consumption of a standardized 500 ml dairy shake containing respectively 59, 30 and 12 energy percent lipids, carbohydrates and protein. During a 6 h time course after PCT 145 plasma metabolites, 79 proteins and 7 clinical chemistry parameters were quantified. Multiple processes related to metabolism, oxidation and inflammation reacted to the PCT, as demonstrated by changes of 106 metabolites, 31 proteins and 5 clinical chemistry parameters. The PCT was applied in a dietary intervention study to evaluate if the PCT would reveal additional metabolic changes compared to non-perturbed conditions. The study consisted of a 5-week intervention with a supplement mix of anti-inflammatory compounds in a crossover design with 36 overweight subjects. Of the 231 quantified parameters, 31 had different responses over time between treated and control groups, revealing differences in amino acid metabolism, oxidative stress, inflammation and endocrine metabolism. The results showed that the acute, short term metabolic responses to the PCT were different in subjects on the supplement mix compared to the controls. The PCT provided additional metabolic changes related to the dietary intervention not observed in non-perturbed conditions. Thus, a metabolomics based quantification of a standardized perturbation of metabolic homeostasis is more informative on metabolic status and subtle health effects induced by (dietary) interventions than quantification of the homeostatic situation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0320-5) contains supplementary material, which is available to authorized users. PMID- 22448157 TI - Displaced distal forearm fractures in children with an indication for reduction under general anesthesia should be percutaneously fixated. AB - PURPOSE: Worldwide, many displaced distal forearm fractures in children are treated by closed reduction under local anesthesia and cast immobilization. If mal-alignment of the fracture persists after initial reduction attempt, final fracture reduction will be performed under general anesthesia, followed by cast immobilization. The purpose of this study was to analyze the results of minimally invasive fixation with K-Wire or ESIN after fracture reduction in children under general anesthesia, compared with the results of closed reduction and plaster immobilization. We hypothesize that primary percutaneous fixation prevents secondary redisplacement and reduces the number of secondary interventions. METHODS: All skeletally immature children who sustained a distal forearm fracture, and treated under general anesthesia in the operation room (OR), were included. The patients were analyzed according to three treatment groups and fracture type. The primary outcome measure was the number of patients who required a second procedure of fracture reduction after initial treatment. RESULTS: A considerable amount of children with displaced distal forearm fractures treated by closed reduction and cast immobilization show loss of reduction and require secondary reduction (43.7%). After closed reduction with primary internal fixation, with minimally invasive techniques such as K-wires or ESIN, secondary loss of reduction did not occur. CONCLUSIONS: Additional internal fixation after reduction of a forearm fracture minimizes the secondary displacement risk and the subsequent risk of a re-intervention. Therefore, primary minimal invasive fixation of displaced distal forearm fractures after closed reduction under general anesthesia seems preferable to closed reduction only and is strongly recommended as the preferred treatment strategy. PMID- 22448158 TI - Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions. AB - Hematopoietic stem cells (HSCs) differentiate and generate all blood cell lineages while maintaining self-renewal ability throughout life. Systemic responses to stressful insults, either psychological or physical exert both stimulating and down-regulating effects on these dynamic members of the immune system. Stress-facilitated division and re-oriented differentiation of progenitor cells modifies hematopoietic cell type composition, while enhancing cytokine production and promoting inflammation. Inversely, stress-induced increases in the neurotransmitter acetylcholine (ACh) act to mitigate inflammatory response and regain homeostasis. This signaling process is terminated when ACh is hydrolyzed by acetylcholinesterase (AChE). Alternative splicing, which is stress-modified, changes the composition of AChE variants, modifying their terminal sequences, susceptibility for microRNA suppression, and sub-cellular localizations. Intriguingly, the effects of stress and AChE variants on hematopoietic development and inflammation in health and disease are both subject to small molecule as well as oligonucleotide-mediated manipulations in vitro and in vivo. The therapeutic agents can thus be targeted to the enzyme protein, its encoding mRNA transcripts, or the regulator microRNA-132, opening new venues for therapeutic interference with multiple nervous and immune system diseases. PMID- 22448159 TI - Spike sorting of heterogeneous neuron types by multimodality-weighted PCA and explicit robust variational Bayes. AB - This study introduces a new spike sorting method that classifies spike waveforms from multiunit recordings into spike trains of individual neurons. In particular, we develop a method to sort a spike mixture generated by a heterogeneous neural population. Such a spike sorting has a significant practical value, but was previously difficult. The method combines a feature extraction method, which we may term "multimodality-weighted principal component analysis" (mPCA), and a clustering method by variational Bayes for Student's t mixture model (SVB). The performance of the proposed method was compared with that of other conventional methods for simulated and experimental data sets. We found that the mPCA efficiently extracts highly informative features as clusters clearly separable in a relatively low-dimensional feature space. The SVB was implemented explicitly without relying on Maximum-A-Posterior (MAP) inference for the "degree of freedom" parameters. The explicit SVB is faster than the conventional SVB derived with MAP inference and works more reliably over various data sets that include spiking patterns difficult to sort. For instance, spikes of a single bursting neuron may be separated incorrectly into multiple clusters, whereas those of a sparsely firing neuron tend to be merged into clusters for other neurons. Our method showed significantly improved performance in spike sorting of these "difficult" neurons. A parallelized implementation of the proposed algorithm (EToS version 3) is available as open-source code at http://etos.sourceforge.net/. PMID- 22448160 TI - Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens. AB - The autoimmune regulator (Aire)-directed ectopic expression of tissue-specific antigens (TSAs) by mature medullary thymic epithelial cells (mTECs) has been viewed as an essential mechanism in the induction of central tolerance. Recent data suggest that the survival of mTECs extends beyond the Aire+ cell population to form the post-Aire mTEC population and Hassall's corpuscles (HCs). The nature and function of these post-Aire epithelial cells and structures, however, have remained unidentified. In this study, we characterized in detail the end-stage development of mTECs and HCs in both Aire-sufficient and Airedeficient mice. In addition, using a transgenic mouse model in which the LacZ reporter gene is under the control of the endogenous Aire promoter, we purified and analyzed the post Aire mTECs to characterize their function. We showed that the end-stage maturation of mTECs closely resembles that of keratinocytes and that the lack of Aire results in a marked block of mTEC differentiation, which is partially overcome by ligands for RANK and CD40. We also provide evidence that, during mTEC development, Aire is expressed only once and during a limited 1-2 day period. The following loss of Aire expression is accompanied by a quick downregulation of MHC class II and CD80, and of most of the Aire-dependent and Aire-independent TSAs, with the exception of keratinocyte-specific genes. In the final stage of maturation, the mTECs lose their nuclei to become HCs and specifically express desmogleins (DGs) 1 and 3, which, via cross-presentation by APCs, may contribute to tolerance against these pemphigus vulgaris-related TSAs. PMID- 22448161 TI - P53 binding sites in transposons. PMID- 22448162 TI - Bacterial Magnetosome: A Novel Biogenetic Magnetic Targeted Drug Carrier with Potential Multifunctions. AB - Bacterial magnetosomes (BMs) synthesized by magnetotactic bacteria have recently drawn great interest due to their unique features. BMs are used experimentally as carriers for antibodies, enzymes, ligands, nucleic acids, and chemotherapeutic drugs. In addition to the common attractive properties of magnetic carriers, BMs also show superiority as targeting nanoscale drug carriers, which is hardly matched by artificial magnetic particles. We are presenting the potential applications of BMs as drug carriers by introducing the drug-loading methods and strategies and the recent research progress of BMs which has contributed to the application of BMs as drug carriers. PMID- 22448163 TI - Rosiglitazone affects nitric oxide synthases and improves renal outcome in a rat model of severe ischemia/reperfusion injury. AB - Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60 min). Following 24 h of reperfusion, inulin- and PAH clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NO(x)-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NO(x) plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury. PMID- 22448164 TI - The Impact of PPARgamma Genetic Variants on IBD Susceptibility and IBD Disease Course. AB - PPARgamma is a nuclear receptor that regulates numerous pathways including cytokine expression and immune responses and plays an important role in controlling colon inflammation. We aimed at determining the occurring PPARgamma SNPs, at predicting the haplotypes, and at determining the frequency outcome in inflammatory bowel disease (IBD) patients in comparison with healthy controls. We determined genetic variants in the coding exons and flanking intronic sequences of the NR1C3 gene in 284 IBD patients and 194 controls and predicted NR1C3 haplotypes via bioinformatic analysis. We investigated whether certain NR1C3 variants are associated with susceptibility to IBD or its disease course. None of the detected 22 NR1C3 variants were associated with IBD. Two variants with allelic frequencies over 1% were included in haplotype/diplotype analyses. None of the NR3C1 haplotypes showed association with IBD development or disease course. We conclude that NR1C3 haplotypes are not related to IBD susceptibility or IBD disease activity. PMID- 22448165 TI - The renoprotective actions of peroxisome proliferator-activated receptors agonists in diabetes. AB - Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes. PMID- 22448166 TI - Altered peroxisome-proliferator activated receptors expression in human endometrial cancer. AB - Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear hormone receptors acting as transcriptional factors, recently involved also in carcinogenesis. Present study was undertaken to evaluate the presence and subcellular localization of different PPAR isoforms (alpha, beta, gamma) in healthy endometrial tissue (n = 10) and endometrial carcinoma (FIGO I, endometrioides type, G1, n = 35). We sought to analyze PPARs mRNA content as well as protein immunohistochemical expression that was further quantified by Western Blot technique. For both PPARalpha and PPARbeta, protein expression was significantly higher in endometrial cancers compared to normal endometrial mucosa. In opposite, PPARgamma protein expression was lower in endometrial cancer cells. In each case, immunohistochemical reaction was confined to the perinuclear and/or nuclear region. At the transcriptional level, the content of mRNA of all PPAR subunits did not follow the protein pattern of changes. These results provide evidence for altered PPAR's protein expression and disregulation of posttranslational processes in endometrial cancers. PMID- 22448167 TI - Role of PPARs in Trypanosoma cruzi Infection: Implications for Chagas Disease Therapy. AB - Chagas disease, which is caused by Trypanosoma cruzi (T. cruzi), remains a substantial public health concern and an important cause of morbidity and mortality in Latin America. T. cruzi infection causes an intense inflammatory response in diverse tissues by triggering local expression of inflammatory mediators, which results in the upregulation of the levels of cytokines and chemokines, and important cardiac alterations in the host, being one of the most characteristic damages of Chagas disease. Therefore, controlling the inflammatory reaction becomes critical for the control of the proliferation of the parasite and of the evolution of Chagas disease. The nuclear receptors known as peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of lipid metabolism and inflammation. The precise role of PPAR ligands in T. cruzi infection or in Chagas disease is poorly understood. This review summarizes our knowledge about T. cruzi infection as well as about the activation of PPARs and the potential role of their ligands in the resolution of inflammation, with the aim to address a new pharmacological approach to improve the host health. PMID- 22448168 TI - Peroxisome Proliferator-Activated Receptor-gamma-Mediated Polarization of Macrophages in Leishmania Infection. AB - Infection is the outcome of a contest between a pathogen and its host. In the disease leishmaniasis, the causative protozoan parasites are harbored inside the macrophages. Leishmania species adapt strategies to make the infection chronic, keeping a balance between their own and the host's defense so as to establish an environment that is favorable for survival and propagation. Activation of peroxisome proliferator-activated receptor (PPAR) is one of the tactics used. This ligand-activated nuclear factor curbs inflammation to protect the host from excessive injuries by setting a limit to its destructive force. In this paper, we report the interaction of host PPARs and the pathogen for visceral leishmaniasis, Leishmania donovani, in vivo and in vitro. PPAR expression is induced by parasitic infection. Leishmanial activation of PPARgamma promotes survival, whereas blockade of PPARgamma facilitates removal of the parasite. Thus, Leishmania parasites harness PPARgamma to increase infectivity. PMID- 22448169 TI - The PPAR Gamma Agonist Troglitazone Regulates Erk 1/2 Phosphorylation via a PPARgamma-Independent, MEK-Dependent Pathway in Human Prostate Cancer Cells. AB - Thiazolidinediones (TZDs) dramatically reduce the growth of human prostate cancer cells in vitro and in vivo. To determine whether the antitumor effects of TZDs were due in part to changes in the MEK/Erk signaling pathway, we examined the regulation of Erk phosphorylation by the TZD troglitazone within the PC-3 and C4 2 human prostate cancer cell lines. Western blot analysis revealed troglitazone induced phosphorylation of Erk in both PC-3 and C4-2 cells. Troglitazone-induced increases in Erk phosphorylation were suppressed by the MEK inhibitor U0126 but not by the PPARgamma antagonist GW9662. Pretreatment with U0126 did not alter the ability of troglitazone to regulate expression of two proteins that control cell cycle, p21, and c-Myc. Troglitazone was also still effective at reducing PC-3 proliferation in the presence of U0126. Therefore, our data suggest that troglitazone-induced Erk phosphorylation does not significantly contribute to the antiproliferative effect of troglitazone. PMID- 22448170 TI - Adult-brain-derived neural stem cells grafting into a vein bridge increases postlesional recovery and regeneration in a peripheral nerve of adult pig. AB - We attempted transplantation of adult neural stem cells (ANSCs) inside an autologous venous graft following surgical transsection of nervis cruralis with 30 mm long gap in adult pig. The transplanted cell suspension was a primary culture of neurospheres from adult pig subventricular zone (SVZ) which had been labeled in vitro with BrdU or lentivirally transferred fluorescent protein. Lesion-induced loss of leg extension on the thigh became definitive in controls but was reversed by 45-90 days after neurosphere-filled vein grafting. Electromyography showed stimulodetection recovery in neurosphere-transplanted pigs but not in controls. Postmortem immunohistochemistry revealed neurosphere derived cells that survived inside the venous graft from 10 to 240 post-lesion days and all displayed a neuronal phenotype. Newly formed neurons were distributed inside the venous graft along the severed nerve longitudinal axis. Moreover, ANSC transplantation increased CNPase expression, indicating activation of intrinsic Schwann cells. Thus ANSC transplantation inside an autologous venous graft provides an efficient repair strategy. PMID- 22448171 TI - Stem cell niche dynamics: from homeostasis to carcinogenesis. AB - The stem cell microenvironment is involved in regulating the fate of the stem cell with respect to self-renewal, quiescence, and differentiation. Mathematical models are helpful in understanding how key pathways regulate the dynamics of stem cell maintenance and homeostasis. This tight regulation and maintenance of stem cell number is thought to break down during carcinogenesis. As a result, the stem cell niche has become a novel target of cancer therapeutics. Developing a quantitative understanding of the regulatory pathways that guide stem cell behavior will be vital to understanding how these systems change under conditions of stress, inflammation, and cancer initiation. Predictions from mathematical modeling can be used as a clinical tool to guide therapy design. We present a survey of mathematical models used to study stem cell population dynamics and stem cell niche regulation, both in the hematopoietic system and other tissues. Highlighting the quantitative aspects of stem cell biology, we describe compelling questions that can be addressed with modeling. Finally, we discuss experimental systems, most notably Drosophila, that can best be used to validate mathematical predictions. PMID- 22448172 TI - Optimising human mesenchymal stem cell numbers for clinical application: a literature review. AB - Adult mesenchymal stem cells (MSCs) are being investigated further for their use in stem cell therapies. However, as they are found in very low numbers in adult tissue, expansion in vitro is required to produce desired MSC numbers for clinical application. The need for effective cell-based therapies is increasing due to a rise in the ageing population, increasing the prevalence of musculoskeletal disorders. This review investigates how factors, age and gender of donor, as well as seeding density can affect MSC expansion. Age and gender of donor have received mixed results from studies, whereas seeding density studies have produced consistent results for numerous MSC sources, favouring lower seeding densities. Further research is required to reduce the risk of infection, loss of cell characterisation in cell culture, and making cell-based therapies more cost effective through creating rapid expansion of MSCs regardless of patient factors. PMID- 22448173 TI - Prospect of induced pluripotent stem cell genetic repair to cure genetic diseases. AB - In genetic diseases, where the cells are already damaged, the damaged cells can be replaced by new normal cells, which can be differentiated from iPSC. To avoid immune rejection, iPSC from the patient's own cell can be developed. However, iPSC from the patients's cell harbors the same genetic aberration. Therefore, before differentiating the iPSCs into required cells, genetic repair should be done. This review discusses the various technologies to repair the genetic aberration in patient-derived iPSC, or to prevent the genetic aberration to cause further damage in the iPSC-derived cells, such as Zn finger and TALE nuclease genetic editing, RNA interference technology, exon skipping, and gene transfer method. In addition, the challenges in using the iPSC and the strategies to manage the hurdles are addressed. PMID- 22448174 TI - Stem cell applications in tendon disorders: a clinical perspective. AB - Tendon injuries are a common cause of morbidity and a significant health burden on society. Tendons are structural tissues connecting muscle to bone and are prone to tearing and tendinopathy, an overuse or degenerative condition that is characterized by failed healing and cellular depletion. Current treatments, for tendon tear are conservative, surgical repair or surgical scaffold reconstruction. Tendinopathy is treated by exercises, injection therapies, shock wave treatments or surgical tendon debridement. However, tendons usually heal with fibrosis and scar tissue, which has suboptimal tensile strength and is prone to reinjury, resulting in lifestyle changes with activity restriction. Preclinical studies show that cell therapies have the potential to regenerate rather than repair tendon tissue, a process termed tenogenesis. A number of different cell lines, with varying degrees of differentiation, have being evaluated including stem cells, tendon derived cells and dermal fibroblasts. Even though cellular therapies offer some potential in treating tendon disorders, there have been few published clinical trials to determine the ideal cell source, the number of cells to administer, or the optimal bioscaffold for clinical use. PMID- 22448175 TI - Mesenchymal stem cells as a potent cell source for bone regeneration. AB - While small bone defects heal spontaneously, large bone defects need surgical intervention for bone transplantation. Autologous bone grafts are the best and safest strategy for bone repair. An alternative method is to use allogenic bone graft. Both methods have limitations, particularly when bone defects are of a critical size. In these cases, bone constructs created by tissue engineering technologies are of utmost importance. Cells are one main component in the manufacture of bone construct. A few cell types, including embryonic stem cells (ESCs), adult osteoblast, and adult stem cells, can be used for this purpose. Mesenchymal stem cells (MSCs), as adult stem cells, possess characteristics that make them good candidate for bone repair. This paper discusses different aspects of MSCs that render them an appropriate cell type for clinical use to promote bone regeneration. PMID- 22448181 TI - Comprehension of Linguistic Dependencies: Speed-Accuracy Tradeoff Evidence for Direct-Access Retrieval From Memory. AB - Comprehenders can rapidly and efficiently interpret expressions with various types of non-adjacent dependencies. In the sentence The boy that the teacher warned fell, boy is readily interpreted as the subject of the verb fall despite the fact that a relative clause, that the teacher warned, intervenes between the two dependent elements. We review research investigating three memory operations proposed for resolving this and other types of non-adjacent dependencies: serial search retrieval, in which the dependent constituent is recovered by a search process through representations in memory, direct-access retrieval in which the dependent constituent is recovered directly by retrieval cue operations without search, and active maintenance of the dependent constituent in focal attention. Studies using speed-accuracy tradeoff methodology to examine the full timecourse of interpreting a wide range of non-adjacent dependencies indicate that comprehenders retrieve dependent constituents with a direct-access operation, consistent with the claim that representations formed during comprehension are accessed with a cue-driven, content-addressable retrieval process. The observed timecourse profiles are inconsistent with a broad class of models based on several search operations for retrieval. The profiles are also inconsistent with active maintenance of a constituent while concurrently processing subsequent material, and suggest that, with few exceptions, direct-access retrieval is required to process non-adjacent dependencies. PMID- 22448182 TI - A fresh look at preoperative body washing. AB - National guidelines do not support preoperative body washing to reduce surgical site infections, instead recommending bathing or showering with soap. Yet preoperative body washing continues to be widely used in many hospitals across Europe. This paper suggests that existing trials of preoperative body washing, upon which guidelines are based, are dated and proposes a new investigation of preoperative body washing using modern definitions of surgical site infection with standardised patient follow up, modern surgical techniques and well designed trials. This paper provides a critique of existing guidelines and describes a randomised trial with 60 participants to compare the effect of soap and two antiseptic washing products on colony forming units (CFUs) for up to six hours. Chlorhexidine gluconate and octenidine were significantly more effective than soap in reducing CFUs in the underarm, and chlorhexidine was significantly more effective than soap in reducing CFUs in the groin. PMID- 22448183 TI - Micro channels within chronic total occlusion: a true way. PMID- 22448184 TI - Over-the-counter kaolin and morphine: two hazards in one. AB - A 56-year-old woman, who was admitted with hypokalaemia, hypertension and metabolic alkalosis, was found to be dependent on kaolin and morphine, a common agent used for the treatment of diarrhoea. This case report highlights the problems of an over-the-counter (OTC) medicine such as kaolin and morphine when it can be purchased in large quantities. PMID- 22448185 TI - A new category for chronic sclerosing sialadenitis as an IgG4 related syndrome. AB - This report presents three cases of IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. The clinical, radiographic and pathologic findings later suggested that the patients had chronic sclerosing sialadenitis. The submandibular gland tumour regressed in two patients. These patients were suspected to have Mikulicz's disease or Sjogren's syndrome, but the diagnostic criteria were not satisfied. The workup for chronic sclerosing sialadenitis revealed a significantly elevated value of serum IgG4. The patient was then diagnosed with IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. After administering prednisolone to these patients, the serum IgG4 values decreased after 4 weeks. The current cases may represent a new category for Mikulicz's disease or Sjogren's syndrome as an IgG4 related sclerosing disease. PMID- 22448186 TI - Obscure gastrointestinal bleeding as first symptom of eosinophilic jejunitis in a liver transplant recipient: diagnosis and treatment with single balloon enteroscopy. AB - The small bowel is only partially accessible to traditional endoscopic techniques. The recently introduced push-and-pull enteroscopy technique allows endoscopists to examine the small bowel in its entirety and enables them to take biopsy specimens and administer treatment. We report the case of a liver transplant recipient presenting with obscure gastrointestinal bleeding, whose diagnosis of eosinophilic enteritis was achieved following a single balloon enteroscopy examination. The patient was discharged 3 days after endoscopic treatment. Eosinophilic enteritis is still not a well known disease. The modality of treatment was suggested by our endoscopic experience and not from codified guidelines. The patient's haemoglobin value was normal 12 months after treatment. PMID- 22448187 TI - Outcome in a patient with systemic lupus erythematosus and concurrent chronic hepatitis B infection. AB - A 35-year-old Caucasian woman with proven systemic lupus erythematosus (SLE) had been effectively managed with hydroxychloroquine and methylprednisolone for many years. In 2005 she was admitted to the rheumatology clinic with a flare up of the disease and with proteinuria of 3.2 g/24 h. Renal biopsy was performed and revealed diffuse proliferative nephritis. Before the renal biopsy a positive HB(s)Ag was found with high virus replication (hepatitis B virus (HBV)-DNA-4 170 000 copies/ml). Liver biopsy revealed chronic hepatitis with minimal activity (TAIS=1). Lamivudine was administered with concomitant maintenance corticosteroid treatment, but without antimalarials. Pulsed methylprednisolone treatment for diffuse lupus nephritis was begun on the background of lamivudine therapy. The liver enzymes returned to normal values, HBV replication was suppressed, and the proteinuria disappeared. At present the patient is not being treated with lamivudine and there are no objective signs of nephritis and hepatitis, or HBV activation. PMID- 22448188 TI - An unusual case of unequal chest expansion. PMID- 22448189 TI - The role of postmortem study in the diagnosis of the cause of death in a young man: a rare case of Ehlers-Danlos syndrome type IV. AB - Diagnosis of the cause of death in young people is a challenge to both the clinician and the pathologist. Ehlers-Danlos syndrome (EDS) type IV is an inherited connective tissue disorder. It is characterised by thin translucent skin, abnormal fragility of blood vessels, and a typical facial appearance. The cause of death is usually due to large arterial rupture. We describe an unusual case of a 23-year-old man clinically diagnosed with myocarditis, who suffered from recurrent pulmonary haemorrhage and died of massive myocardial haemorrhage and ischaemia without coronary artery disease. Diagnosis of EDS type IV was made by autopsy. To our knowledge, this is the first such report in the literature. Delay in diagnosing this syndrome is common even when clinical features are typical, and the condition often goes unrecognised until necropsy. The diagnosis of EDS should be considered in young people who seek medical attention because of arterial rupture. PMID- 22448190 TI - Acute myocardial infarction following ingestion of a non-selective non-steroidal anti-inflammatory drug. AB - While selective non-steroidal anti-inflammatory drugs, namely cyclo-oxygenase-2 (COX 2) inhibitors, are known to be associated with acute myocardial infarction, little is known about the cardiovascular safety of the non-selective non steroidal anti-inflammatory drugs. We report the case of a 44-year-old man who developed anaphylactic reaction and acute inferior myocardial infarction following ingestion of a non-selective anti-inflammatory drug, diclofenac sodium. Coronary angiography revealed a large thrombus in the right coronary artery which was partially removed by intracoronary catheter aspiration. Complete resolution of the remaining thrombus was achieved after treatment with an oral anticoagulant. PMID- 22448191 TI - Healthcare quality in systemic lupus erythematosus: using Donabedian's conceptual framework to understand what we know. AB - Healthcare quality improvement has the potential to reduce the striking disparities in health outcomes among patients with systemic lupus erythematosus (SLE). Donabedian's framework for assessment of healthcare quality, which divides factors impacting quality into structures, processes and outcomes, provides a theoretical framework for research and interventions in quality improvement. This review applies Donabedian's model to current research describing quality of care in SLE, highlighting structures and processes that may lead to improved outcomes. Work remains to be done to develop meaningful metrics to assess quality and to understand the structures and processes that improve outcomes. Quality indicators have emerged as an important tool to measure quality, but further validation is required to define their validity and feasibility in clinical practice, as well as their association with improved outcomes. Implementation science also shows promise as a means to create meaningful systematic improvements in healthcare quality for patients with SLE. PMID- 22448192 TI - DYNAMIC OPTICAL COHERENCE ELASTOGRAPHY: A REVIEW. AB - With the development of optical coherence tomography, the application optical coherence elastography (OCE) has gained more and more attention in biomechanics for its unique features including micron-scale resolution, real-time processing, and non-invasive imaging. In this review, one group of OCE techniques, namely dynamic OCE, are introduced and discussed including external dynamic OCE mapping and imaging of ex vivo breast tumor, external dynamic OCE measurement of in vivo human skin, and internal dynamic OCE including acoustomotive OCE and magnetomotive OCE. These techniques overcame some of the major drawbacks of traditional static OCE, and broadened the OCE application fields. Driven by scientific needs to engineer new quantitative methods that utilize the high micron-scale resolution achievable with optics, results of biomechanical properties were obtained from biological tissues. The results suggest potential diagnostic and therapeutic clinical applications. Results from these studies also help our understanding of the relationship between biomechanical variations and functional tissue changes in biological systems. PMID- 22448193 TI - Nano-carbons as theranostics. AB - Nano-carbons, including fullerenes, carbon nanoparticles, carbon nanotubes, graphene, and nano-diamonds, are an important class of nanostructures attracting tremendous interests in the past two decades. In this special issue, seven review articles and research reports are collected, to summarize and present the latest progress in the exploration of various nano-carbons for theranostic applications. PMID- 22448194 TI - Carbon nanotube thin film biosensors for sensitive and reproducible whole virus detection. AB - Here, we report the label-free, sensitive, and real-time electrical detection of whole viruses using carbon nanotube thin film (CNT-TF) field effect devices. Selective detection of approximately 550 model viruses, M13-bacteriophage, is demonstrated using a simple two-terminal (no gate electrode) configuration. Chemical gating through specific antibody-virus binding on CNT surface is proposed to be the sensing mechanism. Compared to electrical impedance sensors with identical microelectrode dimensions (no CNT), the CNT-TF sensors exhibit sensitivity 5 orders higher. We believe the reported approach could lead to a reproducible and cost-effective solution for rapid viral identification. PMID- 22448195 TI - Biomedical applications of graphene. AB - Graphene exhibits unique 2-D structure and exceptional phyiscal and chemical properties that lead to many potential applications. Among various applications, biomedical applications of graphene have attracted ever-increasing interests over the last three years. In this review, we present an overview of current advances in applications of graphene in biomedicine with focus on drug delivery, cancer therapy and biological imaging, together with a brief discussion on the challenges and perspectives for future research in this field. PMID- 22448196 TI - Competitive performance of carbon "quantum" dots in optical bioimaging. AB - Carbon-based "quantum" dots or carbon dots are surface-functionalized small carbon nanoparticles. For bright fluorescence emissions, the carbon nanoparticles may be surface-doped with an inorganic salt and then the same organic functionalization. In this study, carbon dots without and with the ZnS doping were prepared, followed by gel-column fractionation to harvest dots of 40% and 60% in fluorescence quantum yields, respectively. These highly fluorescent carbon dots were evaluated for optical imaging in mice, from which bright fluorescence images were obtained. Of particular interest was the observed competitive performance of the carbon dots in vivo to that of the well-established CdSe/ZnS QDs. The results suggest that carbon dots may be further developed into a new class of high-performance yet nontoxic contrast agents for optical bioimaging. PMID- 22448197 TI - Clinical Indications of C-Choline PET/CT in Prostate Cancer Patients with Biochemical Relapse. AB - Several studies investigated the potential role of imaging modalities in prostate cancer patients in case of biochemical recurrence. However, the role of molecular imaging has not been well established yet. Considering the results of the literature and of our own experience, we tried to summarize the potential applications of (11)C-choline PET/CT in prostate cancer patients in case of biochemical relapse for the detection of lymph node and distant recurrence. PMID- 22448198 TI - Choline PET and PET/CT in Primary Diagnosis and Staging of Prostate Cancer. AB - PET and PET/CT using [(11)C]- and [(18)F]-labelled choline derivates is increasingly being used for imaging of primary and recurrent prostate cancer. While PET and PET/CT with [(11)C]- and [(18)F]-labelled choline derivates in patients suffering from biochemical recurrence of prostate cancer has been examined in many studies that demonstrate an increasing importance, its role in the primary staging of prostate cancer is still a matter of debate.Morphological and functional imaging techniques such as CT, MRI and TRUS have demonstrated only limited accuracy for the diagnosis of primary prostate cancer. Molecular imaging with PET and PET/CT could potentially increase accuracy to localize primary prostate cancer. A considerable number of studies have examined the value of PET/CT with [(11)C]- and [(18)F]- labelled choline derivates for the diagnosis of primary prostate cancer with mixed results. Primary prostate cancer can only be detected with moderate sensitivity using [(11)C]- and [(18)F]choline PET and PET/CT. The detection rate depends on the tumour configuration. Detection is also limited by a considerable number of microcarcinomas that cannot be detected due to partial volume effects. Therefore small and in part rind-like tumours can often not be visualized. Furthermore, the differentiation between benign changes like prostatitis, high-grade intraepithelial neoplasia (HGPIN) or prostatic hyperplasia is not always possible. Therefore, at the present time, the routine use of PET/CT with [(11)C]- and [(18)F]-labelled choline derivates cannot be recommended as a first-line screening procedure for primary prostate cancer in men at risk. A potential application of choline PET and PET/CT may be to increase the detection rate of clinically suspected prostate cancer with multiple negative prostate biopsies, for example in preparation of a focused re-biopsy and may play a role in patient stratification with respect to primary surgery and radiation therapy in the future. PMID- 22448199 TI - Can Choline PET Tackle the Challenge of Imaging Prostate Cancer? AB - Positron emission tompography with radiolabeled (with 11C- or 18F-) choline has received much attention, particularly in Europe and Japan, over the past several years. While monitoring cellular membrane lipogenesis with radiolabeled choline is nonspecific for cancer, the malignancy-induced increased demand for cellular membrane synthesis can be a useful feature for imaging-based diagnosis and treatment evaluation. Many choline PET(/CT) studies have focused on prostate cancer given that 18F-flurodeoxyglucose appears to be primarily useful in progressive metastatic disease and is overall limited in the initial staging of disease or for evaluation of men with biochemical recurrence. The current evidence suggests that choline PET(/CT), particularly the 18F- label, may become routinely available, initially in many European countries, for the clinical imaging evaluation of men with prostate cancer. PMID- 22448200 TI - JOCB Bulletin. PMID- 22448201 TI - Approximation for Cooperative Interactions of a Spatially-Detailed Cardiac Sarcomere Model. AB - We developed a novel ordinary differential equation (ODE) model, which produced results that correlated well with the Monte Carlo (MC) simulation when applied to a spatially-detailed model of the cardiac sarcomere. Configuration of the novel ODE model was based on the Ising model of myofilaments, with the "co-operative activation" effect introduced to incorporate nearest-neighbor interactions. First, a set of parameters was estimated using arbitrary Ca transient data to reproduce the combinational probability for the states of three consecutive regulatory units, using single unit probabilities for central and neighboring units in the MC simulation. The parameter set thus obtained enabled the calculation of the state transition of each unit using the ODE model with reference to the neighboring states. The present ODE model not only provided good agreement with the MC simulation results but was also capable of reproducing a wide range of experimental results under both steady-state and dynamic conditions including shortening twitch. The simulation results suggested that the nearest neighbor interaction is a reasonable approximation of the cooperativity based on end-to-end interactions. Utilizing the modified ODE model resulted in a reduction in computational costs but maintained spatial integrity and co-operative effects, making it a powerful tool in cardiac modeling. PMID- 22448203 TI - Computer-Aided Patient-Specific Coronary Artery Graft Design Improvements Using CFD Coupled Shape Optimizer. AB - This study aims to (i) demonstrate the efficacy of a new surgical planning framework for complex cardiovascular reconstructions, (ii) develop a computational fluid dynamics (CFD) coupled multi-dimensional shape optimization method to aid patient-specific coronary artery by-pass graft (CABG) design and, (iii) compare the hemodynamic efficiency of the sequential CABG, i.e., raising a daughter parallel branch from the parent CABG in patient-specific 3D settings. Hemodynamic efficiency of patient-specific complete revascularization scenarios for right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex artery (LCX) bypasses were investigated in comparison to the stenosis condition. Multivariate 2D constraint optimization was applied on the left internal mammary artery (LIMA) graft, which was parameterized based on actual surgical settings extracted from 2D CT slices. The objective function was set to minimize the local variation of wall shear stress (WSS) and other hemodynamic indices (energy dissipation, flow deviation angle, average WSS, and vorticity) that correlate with performance of the graft and risk of re-stenosis at the anastomosis zone. Once the optimized 2D graft shape was obtained, it was translated to 3D using an in-house "sketch-based" interactive anatomical editing tool. The final graft design was evaluated using an experimentally validated second-order non-Newtonian CFD solver incorporating resistance based outlet boundary conditions. 3D patient-specific simulations for the healthy coronary anatomy produced realistic coronary flows. All revascularization techniques restored coronary perfusions to the healthy baseline. Multi-scale evaluation of the optimized LIMA graft enabled significant wall shear stress gradient (WSSG) relief (~34%). In comparison to original LIMA graft, sequential graft also lowered the WSSG by 15% proximal to LAD and diagonal bifurcation. The proposed sketch-based surgical planning paradigm evaluated the selected coronary bypass surgery procedures based on acute hemodynamic readjustments of aorta-CA flow. This methodology may provide a rational to aid surgical decision making in time critical, patient-specific CA bypass operations before in vivo execution. PMID- 22448202 TI - Vascular disruption and the role of angiogenic proteins after spinal cord injury. AB - Spinal cord injuries (SCI) can result in devastating paralysis, for which there is currently no robustly efficacious neuroprotective/neuroregenerative treatment. When the spinal cord is subjected to a traumatic injury, the local vasculature is disrupted and the blood-spinal cord barrier is compromised. Subsequent inflammation and ischemia may then contribute to further secondary damage, exacerbating neurological deficits. Therefore, understanding the vascular response to SCI and the molecular elements that regulate angiogenesis has considerable relevance from a therapeutic standpoint. In this paper, we review the nature of vascular damage after traumatic SCI and what is known about the role that angiogenic proteins-angiopoietin 1 (Ang1), angiopoietin 2 (Ang2) and angiogenin-may play in the subsequent response. To this, we add recent work that we have conducted in measuring these proteins in the cerebrospinal fluid (CSF) and serum after acute SCI in human patients. Intrathecal catheters were installed in 15 acute SCI patients within 48 h of injury. CSF and serum samples were collected over the following 3-5 days and analysed for Ang1, Ang2 and angiogenin protein levels using a standard ELISA technique. This represents the first description of the endogenous expression of these proteins in an acute human SCI setting. PMID- 22448204 TI - Self-management of chronic pain in Malaysian patients: effectiveness trial with 1 year follow-up. AB - Self-management of chronic illnesses has been widely recognised as an important goal on quality of life, health service utilisation and cost grounds. This study describes the first published account on the application of this approach to people suffering from chronic pain conditions in a Southeast Asian country, Malaysia. A heterogeneous sample of chronic pain patients in Malaysia attended a 2-week cognitive-behavioural pain management programme (PMP) aimed at improving daily functional activities and general psychological well-being. Complete datasets from 70 patients out of 102 patients who attended 11 programmes conducted from 2002 to 2007, as well as the 1-month and 1-year follow-up sessions at the hospital clinic, are reported. The pre- to post-treatment results on self report measures indicate that significant gains were achieved on the dimensions of pain, disability and psychological well-being. These gains were maintained at both 1-month and 1-year follow-ups. The results mirror those reported from similar interventions in Europe and North America and indicate the concept of self-management of a chronic illness is acceptable and meaningful to Asian patients. Importantly, the achieved outcomes were independent of gender and ethnic group status. PMID- 22448205 TI - Interactive voice response technology for symptom monitoring and as an adjunct to the treatment of chronic pain. AB - Chronic pain is a medical condition that severely decreases the quality of life for those who struggle to cope with it. Interactive voice response (IVR) technology has the ability to track symptoms and disease progression, to investigate the relationships between symptom patterns and clinical outcomes, to assess the efficacy of ongoing treatments, and to directly serve as an adjunct to therapeutic treatment for chronic pain. While many approaches exist toward the management of chronic pain, all have their pitfalls and none work universally. Cognitive behavioral therapy (CBT) is one approach that has been shown to be fairly effective, and therapeutic interactive voice response technology provides a convenient and easy-to-use means of extending the therapeutic gains of CBT long after patients have discontinued clinical visitations. This review summarizes the advantages and disadvantages of IVR technology, provides evidence for the efficacy of the method in monitoring and managing chronic pain, and addresses potential future directions that the technology may take as a therapeutic intervention in its own right. PMID- 22448206 TI - Endoplasmic Reticulum (ER) Stress Enhances Tip60 (A Histone Acetyltransferase) Binding to the Concanavalin A. AB - Herein, we report that the concanavalin A binding of Tip60 (a target of the human immunodeficiency virus type 1-encoded transactivator Tat interacting protein 60 KD; a histone acetyltransferase; HAT) is enhanced as the result of endoplasmic reticulum (ER) stress. The cell expression of Tip60 combined with site-directed mutagenesis analysis was used to identify the glutamine 324 residue as the lecithin binding (Concanavalin A; Con A) site. The Tip60 N324A mutant strain, which seems to be the Con A binding-deficient, was attenuated the protein-protein interactions with FE65 and its protein stability, but its ability of G0-G1 cell cycle arrest was not interrupted. Interestingly, both HAT activity and the nuclear localization of Tip60 N324A mutant were enhanced than those of Tip60 WT. Thus, our results indicate that the Con A binding deficient of Tip60 seems to be one of the most pivotal posttranslational modifications (such as N-glycosylation) for its functional regulation signal, which is generated in response to ER stress. PMID- 22448207 TI - The epidemiology, genetics and future management of syndactyly. AB - Syndactyly is a condition well documented in current literature due to it being the most common congenital hand defect, with a large aesthetic and functional significance.There are currently nine types of phenotypically diverse non syndromic syndactyly, an increase since the original classification by Temtamy and McKusick(1978). Non-syndromic syndactyly is inherited as an autosomal dominant trait, although the more severe presenting types and sub types appear to have autosomal recessive and in some cases X-linked hereditary.Gene research has found that these phenotypes appear to not only be one gene specific, although having individual localised loci, but dependant on a wide range of genes and subsequent signalling pathways involved in limb formation. The principal genes so far defined to be involved in congenital syndactyly concern mainly the Zone of Polarizing Activity and Shh pathway.Research into the individual phenotypes appears to complicate classification as new genes are found both linked, and not linked, to each malformation. Consequently anatomical, phenotypical and genotypical classifications can be used, but are variable in significance, depending on the audience.Currently, management is surgical, with a technique unchanged for several decades, although future development will hopefully bring alternatives in both earlier diagnosis and gene manipulation for therapy. PMID- 22448208 TI - The influence of dopamine receptor d4 polymorphism on resting EEG in healthy young females. AB - The polymorphism of variable number of tandem repeat (VNTR) in dopamine receptor D4 (DRD4) gene exon III has been linked to various neuro-psychiatric conditions with disinhibition/impulsivity as one of the core features. This study examined the modulatory effects of long-allele variant of DRD4 VNTR on the regional neural activity as well as inter-regional neural interactions in a young female population. Blood sample and resting state eyes-closed EEG signals were collected in 233 healthy females, stratified into two groups by polymerase chain reaction: long-allele carriers (>4- repeat) and non-carriers (<=4-repeat/<=4-repeat). The values of mean power of 18 electrodes and mutual information of 38 channel pairs across theta, alpha, and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group differences of regional power and connectivity strength were quantified by independent t-test, while between group differences in global trends were examined by non-parametric analyses. We noticed that DRD4 VNTR long-allele was associated with decreased global connectivity strength (from non-parametric analysis), especially over bi-frontal, biparietal and right fronto-parietal and right fronto-temporal connections (from independent t-tests). The between-group differences in regional power were not robust. Our findings fit with the networks of response inhibition, providing evidence bridging DRD4 long-allele and disinhibition/impulsivity in neuropsychiatric disorders. We suggest future DRD4 studies of imaging genetics incorporate connectivity analysis to unveil its impact on cerebral network. PMID- 22448211 TI - Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease. AB - BACKGROUND: Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART. METHODS: Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels. RESULTS: Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95%CI 1.4 4.9) for D-dimer, and 3.8 (95% CI: 1.8-7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001). CONCLUSIONS: Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted. TRIAL REGISTRATION: Parent study: ClinicalTrials.gov NCT00342355. PMID- 22448212 TI - Age at menarche, the leg length to sitting height ratio, and risk of diabetes in middle-aged and elderly Chinese men and women. AB - AIMS: To evaluate the associations of age at menarche and the leg length-to sitting-height ratio, markers of adolescent growth, with risk of diabetes in later life. MATERIALS AND METHODS: Information from 69,385 women and 55,311 men, aged 40-74 years from the Shanghai Women's Health Study and Shanghai Men's Health Study, were included in the current analyses. Diabetes status was ascertained through biennial in person follow-up. Cox models, with age as the time scale, were used. RESULTS: There were 2369 cases of diabetes (1831 women; 538 men) during an average of 7.3 and 3.6 years of follow-up of the women and men, respectively. In females, menarche age was inversely associated with diabetes risk after adjustment for birth cohort, education, and income (HR = 0.95, 0.92 0.98). In both genders, leg length-to-sitting-height ratio was inversely related to diabetes (HR = 0.88, 0.80-0.97 for men; HR = 0.91, 0.86-0.96 for women) after adjustment for birth cohort, education, and income. Further adjustment for adult BMI at study enrollment completely eliminated the associations of age at menarche (HR = 0.99, 0.96-1.02) and the leg length-to-sitting-height ratio (HR = 1.00, 0.91-1.10 for men; HR = 1.01, 0.96-1.07 for women) with diabetes risk. CONCLUSIONS: Our study suggests that markers of an early age at peak height velocity, i.e. early menarche age and low leg-length-to-sitting height ratio, may be associated with diabetes risk later in life and this association is likely to be mediated through obesity. PMID- 22448213 TI - 5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection. AB - 5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung. The fungal susceptibility of 5-LO(-/-) mice correlated with a lower rate of macrophage ingestion of IgG-H. capsulatum relative to WT macrophages. Conversely, exogenous LTB4 and LTC4 restored macrophage phagocytosis in 5-LO deficient mice. Our results demonstrate that leukotrienes are required to control chronic fungal infection by amplifying both the innate and adaptive immune response during histoplasmosis. PMID- 22448214 TI - Factors associated with sexual violence against men who have sex with men and transgendered individuals in Karnataka, India. AB - OBJECTIVES: There is a lack of information on sexual violence (SV) among men who have sex with men and transgendered individuals (MSM-T) in southern India. As SV has been associated with HIV vulnerability, this study examined health related behaviours and practices associated with SV among MSM-T. DESIGN: Data were from cross-sectional surveys from four districts in Karnataka, India. METHODS: Multivariable logistic regression models were constructed to examine factors related to SV. Multivariable negative binomial regression models examined the association between physician visits and SV. RESULTS: A total of 543 MSM-T were included in the study. Prevalence of SV was 18% in the past year. HIV prevalence among those reporting SV was 20%, compared to 12% among those not reporting SV (p = .104). In multivariable models, and among sex workers, those reporting SV were more likely to report anal sex with 5+ casual sex partners in the past week (AOR: 4.1; 95%CI: 1.2-14.3, p = .029). Increased physician visits among those reporting SV was reported only for those involved in sex work (ARR: 1.7; 95%CI: 1.1-2.7, p = .012). CONCLUSIONS: These results demonstrate high levels of SV among MSM-T populations, highlighting the importance of integrating interventions to reduce violence as part of HIV prevention programs and health services. PMID- 22448215 TI - Communication in the third dimension: song perch height of rivals affects singing response in nightingales. AB - Many animals use long-range signals to compete over mates and resources. Optimal transmission can be achieved by choosing efficient signals, or by choosing adequate signalling perches and song posts. High signalling perches benefit sound transmission and reception, but may be more risky due to exposure to airborne predators. Perch height could thus reflect male quality, with individuals signalling at higher perches appearing as more threatening to rivals. Using playbacks on nightingales (Luscinia megarhynchos), we simulated rivals singing at the same height as residents, or singing three metres higher. Surprisingly, residents increased song output stronger, and, varying with future pairing success, overlapped more songs of the playback when rivals were singing at the same height than when they were singing higher. Other than expected, rivals singing at the same height may thus be experienced as more threatening than rivals singing at higher perches. Our study provides new evidence that territorial animals integrate information on signalling height and thus on vertical cues in their assessment of rivals. PMID- 22448216 TI - Genome expression profile analysis of the immature maize embryo during dedifferentiation. AB - Maize is one of the most important cereal crops worldwide and one of the primary targets of genetic manipulation, which provides an excellent way to promote its production. However, the obvious difference of the dedifferentiation frequency of immature maize embryo among various genotypes indicates that its genetic transformation is dependence on genotype and immature embryo-derived undifferentiated cells. To identify important genes and metabolic pathways involved in forming of embryo-derived embryonic calli, in this study, DGE (differential gene expression) analysis was performed on stages I, II, and III of maize inbred line 18-599R and corresponding control during the process of immature embryo dedifferentiation. A total of ~21 million cDNA tags were sequenced, and 4,849,453, 5,076,030, 4,931,339, and 5,130,573 clean tags were obtained in the libraries of the samples and the control, respectively. In comparison with the control, 251, 324 and 313 differentially expressed genes (DEGs) were identified in the three stages with more than five folds, respectively. Interestingly, it is revealed that all the DEGs are related to metabolism, cellular process, and signaling and information storage and processing functions. Particularly, the genes involved in amino acid and carbohydrate transport and metabolism, cell wall/membrane/envelope biogenesis and signal transduction mechanism have been significantly changed during the dedifferentiation. To our best knowledge, this study is the first genome-wide effort to investigate the transcriptional changes in dedifferentiation immature maize embryos and the identified DEGs can serve as a basis for further functional characterization. PMID- 22448217 TI - Dynamic 5-HT2C receptor editing in a mouse model of obesity. AB - The central serotonergic signalling system has been shown to play an important role in appetite control and the regulation of food intake. Serotonin exerts its anorectic effects mainly through the 5-HT(1B), 5-HT(2C) and 5-HT(6) receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT(2C) receptor has the distinctive ability to be modified by posttranscriptional RNA editing on 5 nucleotide positions (A, B, C, D, E), having an overall decreased receptor function. Recently, it has been shown that feeding behaviour and fat mass are altered when the 5-HT(2C) receptor RNA is fully edited, suggesting a potential role for 5-HT(2C) editing in obesity. The present studies investigate the expression of serotonin receptors involved in central regulation of food intake, appetite and energy expenditure, with particular focus on the level of 5-HT(2C) receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob), we show increased hypothalamic 5-HT(1A) receptor expression as well as increased hippocampal 5-HT(1A), 5-HT(1B), and 5-HT(6) receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT(2C) expression, depending on time of day, as well as differences in 5-HT(2C) receptor editing were found, independent of changes in total 5-HT(2C) receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite suppressing effects of the 5-HT(2C) receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT(1A), 5 HT(1B) and 5-HT(6) receptor expression and altered 5-HT(2C) receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies. PMID- 22448218 TI - Temperature- and touch-sensitive neurons couple CNG and TRPV channel activities to control heat avoidance in Caenorhabditis elegans. AB - BACKGROUND: Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding ~35 degrees C and also senses changes in its environmental temperature in the range between 15 and 25 degrees C. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. METHODOLOGY/PRINCIPAL FINDINGS: We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicin-sensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. CONCLUSIONS/SIGNIFICANCE: Our results identify distinct thermal responses mediated by a single neuron, but also show that parallel nociceptor circuits and molecules may be used as back-up strategies to guarantee fast and efficient responses to potentially detrimental stimuli. PMID- 22448219 TI - Prioritisation of clinical research by the example of type 2 diabetes: a caregiver-survey on perceived relevance and need for evidence. AB - BACKGROUND: The Cochrane Collaboration aims at providing the best available evidence for interventions in health care. We wished to examine to which extent treatments considered relevant by caregivers in type 2 diabetes are covered by Cochrane systematic reviews. METHODOLOGY/PRINCIPAL FINDINGS: 130 different interventions in type 2 diabetes were identified based on a review of clinical practice guidelines and expert opinion (Table S1). 459 members of the German Diabetes Society (diabetologists, general practitioners, diabetic nurses, nutritionists, podologists, others) were surveyed via e-mail-list to rank a) the perceived clinical relevance and b) the perceived need for evidence of interventions, based on an internet survey. In the Cochrane Library, there were, at the time of this evaluation, 56 reviews on interventions in diabetes. Generally, coverage of topics by Cochrane reviews reflected the perceived clinical relevance and perceived need for evidence. As an example, highly ranked treatments such as lifestyle changes or oral antidiabetics were well covered, while low rank treatments such as complementary approaches were not covered. Discrepancies occurred with new treatments such as amylin-analogues (low relevance, high need for evidence, review not yet completed) and interventions with immediate and dramatic effects such as treating hypoglycemia (high relevance, low need for evidence, no review). Also, there was a relative scarcity of reviews concerning specific problems, in particular, treatment of late diabetic complications. CONCLUSIONS/SIGNIFICANCE: For most interventions, perceived relevance and perceived need for evidence are reflected by the evidence already available. Prioritizing should aim at improving immediacy and consideration of the treatment of complications. PMID- 22448220 TI - By any other name: heterologous replacement of the Escherichia coli RNase P protein subunit has in vivo fitness consequences. AB - Bacterial RNase P is an essential ribonucleoprotein composed of a catalytic RNA component (encoded by the rnpB gene) and an associated protein moiety (encoded by rnpA). We construct a system that allows for the deletion of the essential endogenous rnpA copy and for its simultaneous replacement by a heterologous version of the gene. Using growth rate as a proxy, we explore the effects on fitness of heterologous replacement by increasingly divergent versions of the RNase P protein. All of the heterologs tested complement the loss of the endogenous rnpA gene, suggesting that all existing bacterial versions of the rnpA sequence retain the elements required for functional interaction with the RNase P RNA. All replacements, however, exact a cost on organismal fitness, and particularly on the rate of growth acceleration, defined as the time required to reach maximal growth rate. Our data suggest that the similarity of the heterolog to the endogenous version--whether defined at the sequence, structure or codon usage level--not predict the fitness costs of the replacement. The common assumption that sequence similarity predicts functional similarity requires experimental confirmation and may prove to be an oversimplification. PMID- 22448221 TI - Modelling the regulation of thermal adaptation in Candida albicans, a major fungal pathogen of humans. AB - Eukaryotic cells have evolved mechanisms to sense and adapt to dynamic environmental changes. Adaptation to thermal insults, in particular, is essential for their survival. The major fungal pathogen of humans, Candida albicans, is obligately associated with warm-blooded animals and hence occupies thermally buffered niches. Yet during its evolution in the host it has retained a bona fide heat shock response whilst other stress responses have diverged significantly. Furthermore the heat shock response is essential for the virulence of C. albicans. With a view to understanding the relevance of this response to infection we have explored the dynamic regulation of thermal adaptation using an integrative systems biology approach. Our mathematical model of thermal regulation, which has been validated experimentally in C. albicans, describes the dynamic autoregulation of the heat shock transcription factor Hsf1 and the essential chaperone protein Hsp90. We have used this model to show that the thermal adaptation system displays perfect adaptation, that it retains a transient molecular memory, and that Hsf1 is activated during thermal transitions that mimic fever. In addition to providing explanations for the evolutionary conservation of the heat shock response in this pathogen and the relevant of this response to infection, our model provides a platform for the analysis of thermal adaptation in other eukaryotic cells. PMID- 22448222 TI - High fidelity processing and activation of the human alpha-defensin HNP1 precursor by neutrophil elastase and proteinase 3. AB - The azurophilic granules of human neutrophils contain four alpha-defensins called human neutrophil peptides (HNPs 1-4). HNPs are tridisulfide-linked antimicrobial peptides involved in the intracellular killing of organisms phagocytosed by neutrophils. The peptides are produced as inactive precursors (proHNPs) which are processed to active microbicides by as yet unidentified convertases. ProHNP1 was expressed in E. coli and the affinity-purified propeptide isolated as two species, one containing mature HNP1 sequence with native disulfide linkages ("folded proHNP1") and the other containing non-native disulfide linked proHNP1 conformers (misfolded proHNP1). Native HNP1, liberated by CNBr treatment of folded proHNP1, was microbicidal against Staphylococcus aureus, but the peptide derived from misfolded proHNP1 was inactive. We hypothesized that neutrophil elastase (NE), proteinase 3 (PR3) or cathepsin G (CG), serine proteases that co localize with HNPs in azurophil granules, are proHNP1 activating convertases. Folded proHNP1 was converted to mature HNP1 by both NE and PR3, but CG generated an HNP1 variant with an N-terminal dipeptide extension. NE and PR3 cleaved folded proHNP1 to produce a peptide indistinguishable from native HNP1 purified from neutrophils, and the microbicidal activities of in vitro derived and natural HNP1 peptides were equivalent. In contrast, misfolded proHNP1 conformers were degraded extensively under the same conditions. Thus, NE and PR3 possess proHNP1 convertase activity that requires the presence of the native HNP1 disulfide motif for high fidelity activation of the precursor in vitro. PMID- 22448223 TI - Layer-specific fMRI reflects different neuronal computations at different depths in human V1. AB - Recent work has established that cerebral blood flow is regulated at a spatial scale that can be resolved by high field fMRI to show cortical columns in humans. While cortical columns represent a cluster of neurons with similar response properties (spanning from the pial surface to the white matter), important information regarding neuronal interactions and computational processes is also contained within a single column, distributed across the six cortical lamina. A basic understanding of underlying neuronal circuitry or computations may be revealed through investigations of the distribution of neural responses at different cortical depths. In this study, we used T(2)-weighted imaging with 0.7 mm (isotropic) resolution to measure fMRI responses at different depths in the gray matter while human subjects observed images with either recognizable or scrambled (physically impossible) objects. Intact and scrambled images were partially occluded, resulting in clusters of activity distributed across primary visual cortex. A subset of the identified clusters of voxels showed a preference for scrambled objects over intact; in these clusters, the fMRI response in middle layers was stronger during the presentation of scrambled objects than during the presentation of intact objects. A second experiment, using stimuli targeted at either the magnocellular or the parvocellular visual pathway, shows that laminar profiles in response to parvocellular-targeted stimuli peak in more superficial layers. These findings provide new evidence for the differential sensitivity of high-field fMRI to modulations of the neural responses at different cortical depths. PMID- 22448224 TI - Discovery of defense- and neuropeptides in social ants by genome-mining. AB - Natural peptides of great number and diversity occur in all organisms, but analyzing their peptidome is often difficult. With natural product drug discovery in mind, we devised a genome-mining approach to identify defense- and neuropeptides in the genomes of social ants from Atta cephalotes (leaf-cutter ant), Camponotus floridanus (carpenter ant) and Harpegnathos saltator (basal genus). Numerous peptide-encoding genes of defense peptides, in particular defensins, and neuropeptides or regulatory peptide hormones, such as allatostatins and tachykinins, were identified and analyzed. Most interestingly we annotated genes that encode oxytocin/vasopressin-related peptides (inotocins) and their putative receptors. This is the first piece of evidence for the existence of this nonapeptide hormone system in ants (Formicidae) and supports recent findings in Tribolium castaneum (red flour beetle) and Nasonia vitripennis (parasitoid wasp), and therefore its confinement to some basal holometabolous insects. By contrast, the absence of the inotocin hormone system in Apis mellifera (honeybee), another closely-related member of the eusocial Hymenoptera clade, establishes the basis for future studies on the molecular evolution and physiological function of oxytocin/vasopressin-related peptides (vasotocin nonapeptide family) and their receptors in social insects. Particularly the identification of ant inotocin and defensin peptide sequences will provide a basis for future pharmacological characterization in the quest for potent and selective lead compounds of therapeutic value. PMID- 22448225 TI - A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. AB - BACKGROUND AND AIMS: Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians. METHODS: Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235). RESULTS: The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9-13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6-11.1; p = 0.31). In contrast, HLA DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4-1.9; p = 1). CONCLUSIONS: A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches. PMID- 22448226 TI - Examining the incidence of human papillomavirus-associated head and neck cancers by race and ethnicity in the U.S., 1995-2005. AB - BACKGROUND: Head and neck cancer (HNC) incidence, mortality and survival rates vary by sex and race, with men and African Americans disproportionately affected. Risk factors for HNC include tobacco and alcohol exposure, with a recent implication of human papillomavirus (HPV) in the pathogenesis of HNC. This study describes the epidemiology of HNC in the United States, examining variation of rates by age, sex, race/ethnicity and potential HPV-association. METHODS: We used the North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CINA) Deluxe Analytic Data to analyze HNC incidence for 1995-2005 from forty population-based cancer registries. We calculated age-adjusted incidence rates and incidence trends using annual percent change by age, sex, race/ethnicity and HPV-association. RESULTS: Males and Non-Hispanic Blacks experienced greater HNC incidence compared to women and other race/ethnicity groupings. A significant overall increase in HNC incidence was observed among HPV associated sites during 1995-2005, while non HPV-associated sites experienced a significant decline in HNC incidence. Overall, younger age groups, Non-Hispanic Whites and Hispanics experienced greater increases in incidence for HPV associated sites, while HNC incidence declined for Non-Hispanic Blacks independent of HPV-association. In particular, for HPV-associated sites, HNC incidence for Non-Hispanic White males aged 45-54 increased at the greatest rate, with an APC of 6.28% (p<0.05). Among non HPV-associated sites, Non-Hispanic Black males aged 0-44 years experienced the greatest reduction in incidence (APC, 8.17%, p<0.05), while a greater decline among the older, 55-64 year age group (APC, -5.44%, p<0.05) occurred in females. CONCLUSIONS: This study provides evidence that HPV-associated tumors are disproportionately affecting certain age, sex and race/ethnicity groups, representing a different disease process for HPV associated tumors compared to non HPV-associated tumors. Our study suggests that HPV tumor status should be incorporated into treatment decisions for HNC patients to improve prognosis and survival. PMID- 22448227 TI - The passive yet successful way of planktonic life: genomic and experimental analysis of the ecology of a free-living polynucleobacter population. AB - BACKGROUND: The bacterial taxon Polynucleobacter necessarius subspecies asymbioticus represents a group of planktonic freshwater bacteria with cosmopolitan and ubiquitous distribution in standing freshwater habitats. These bacteria comprise <1% to 70% (on average about 20%) of total bacterioplankton cells in various freshwater habitats. The ubiquity of this taxon was recently explained by intra-taxon ecological diversification, i.e. specialization of lineages to specific environmental conditions; however, details on specific adaptations are not known. Here we investigated by means of genomic and experimental analyses the ecological adaptation of a persistent population dwelling in a small acidic pond. FINDINGS: The investigated population (F10 lineage) contributed on average 11% to total bacterioplankton in the pond during the vegetation periods (ice-free period, usually May to November). Only a low degree of genetic diversification of the population could be revealed. These bacteria are characterized by a small genome size (2.1 Mb), a relatively small number of genes involved in transduction of environmental signals, and the lack of motility and quorum sensing. Experiments indicated that these bacteria live as chemoorganotrophs by mainly utilizing low-molecular-weight substrates derived from photooxidation of humic substances. CONCLUSIONS: Evolutionary genome streamlining resulted in a highly passive lifestyle so far only known among free living bacteria from pelagic marine taxa dwelling in environmentally stable nutrient-poor off-shore systems. Surprisingly, such a lifestyle is also successful in a highly dynamic and nutrient-richer environment such as the water column of the investigated pond, which was undergoing complete mixis and pronounced stratification in diurnal cycles. Obviously, metabolic and ecological versatility is not a prerequisite for long-lasting establishment of abundant bacterial populations under highly dynamic environmental conditions. Caution should be exercised when generalizing the obtained insights into the ecology and adaptation of the investigated lineage to other Polynucleobacter lineages. PMID- 22448228 TI - The adaptor molecule Nck localizes the WAVE complex to promote actin polymerization during CEACAM3-mediated phagocytosis of bacteria. AB - BACKGROUND: CEACAM3 is a granulocyte receptor mediating the opsonin-independent recognition and phagocytosis of human-restricted CEACAM-binding bacteria. CEACAM3 function depends on an intracellular immunoreceptor tyrosine-based activation motif (ITAM)-like sequence that is tyrosine phosphorylated by Src family kinases upon receptor engagement. The phosphorylated ITAM-like sequence triggers GTP loading of Rac by directly associating with the guanine nucleotide exchange factor (GEF) Vav. Rac stimulation in turn is critical for actin cytoskeleton rearrangements that generate lamellipodial protrusions and lead to bacterial uptake. PRINCIPAL FINDINGS: In our present study we provide biochemical and microscopic evidence that the adaptor proteins Nck1 and Nck2, but not CrkL, Grb2 or SLP-76, bind to tyrosine phosphorylated CEACAM3. The association is phosphorylation-dependent and requires the Nck SH2 domain. Overexpression of the isolated Nck1 SH2 domain, RNAi-mediated knock-down of Nck1, or genetic deletion of Nck1 and Nck2 interfere with CEACAM3-mediated bacterial internalization and with the formation of lamellipodial protrusions. Nck is constitutively associated with WAVE2 and directs the actin nucleation promoting WAVE complex to tyrosine phosphorylated CEACAM3. In turn, dominant-negative WAVE2 as well as shRNA mediated knock-down of WAVE2 or the WAVE-complex component Nap1 reduce internalization of bacteria. CONCLUSIONS: Our results provide novel mechanistic insight into CEACAM3-initiated phagocytosis. We suggest that the CEACAM3 ITAM like sequence is optimized to co-ordinate a minimal set of cellular factors needed to efficiently trigger actin-based lamellipodial protrusions and rapid pathogen engulfment. PMID- 22448229 TI - Ginkgo biloba responds to herbivory by activating early signaling and direct defenses. AB - BACKGROUND: Ginkgo biloba (Ginkgoaceae) is one of the most ancient living seed plants and is regarded as a living fossil. G. biloba has a broad spectrum of resistance or tolerance to many pathogens and herbivores because of the presence of toxic leaf compounds. Little is known about early and late events occurring in G. biloba upon herbivory. The aim of this study was to assess whether herbivory by the generalist Spodoptera littoralis was able to induce early signaling and direct defense in G. biloba by evaluating early and late responses. METHODOLOGY/PRINCIPAL FINDINGS: Early and late responses in mechanically wounded leaves and in leaves damaged by S. littoralis included plasma transmembrane potential (Vm) variations, time-course changes in both cytosolic calcium concentration ([Ca(2+)](cyt)) and H(2)O(2) production, the regulation of genes correlated to terpenoid and flavonoid biosynthesis, the induction of direct defense compounds, and the release of volatile organic compounds (VOCs). The results show that G. biloba responded to hebivory with a significant Vm depolarization which was associated to significant increases in both [Ca(2+)](cyt) and H(2)O(2). Several defense genes were regulated by herbivory, including those coding for ROS scavenging enzymes and the synthesis of terpenoids and flavonoids. Metabolomic analyses revealed the herbivore-induced production of several flavonoids and VOCs. Surprisingly, no significant induction by herbivory was found for two of the most characteristic G. biloba classes of bioactive compounds; ginkgolides and bilobalides. CONCLUSIONS/SIGNIFICANCE: By studying early and late responses of G. biloba to herbivory, we provided the first evidence that this "living fossil" plant responds to herbivory with the same defense mechanisms adopted by the most recent angiosperms. PMID- 22448230 TI - Deleterious GRM1 mutations in schizophrenia. AB - We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1 signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies. PMID- 22448231 TI - Chemical mechanism of UDP-galactopyranose mutase from Trypanosoma cruzi: a potential drug target against Chagas' disease. AB - UDP-galactopyranose mutase (UGM) is a flavoenzyme that catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, the precursor of galactofuranose (Galf). Galf is found in several pathogenic organisms, including the parasite Trypanosoma cruzi, the causative agent of Chagas' disease. Galf) is important for virulence and is not present in humans, making its biosynthetic pathway an attractive target for the development of new drugs against T. cruzi. Although UGMs catalyze a non-redox reaction, the flavin must be in the reduced state for activity and the exact role of the flavin in this reaction is controversial. The kinetic and chemical mechanism of TcUGM was probed using steady state kinetics, trapping of reaction intermediates, rapid reaction kinetics, and fluorescence anisotropy. It was shown for the first time that NADPH is an effective redox partner of TcUGM. The substrate, UDP-galactopyranose, protects the enzyme from reacting with molecular oxygen allowing TcUGM to turnover ~1000 times for every NADPH oxidized. Spectral changes consistent with a flavin iminium ion, without the formation of a flavin semiquinone, were observed under rapid reaction conditions. These data support the proposal of the flavin acting as a nucleophile. In support of this role, a flavin-galactose adduct was isolated and characterized. A detailed kinetic and chemical mechanism for the unique non-redox reaction of UGM is presented. PMID- 22448232 TI - Breast cancer exosome-like microvesicles and salivary gland cells interplay alters salivary gland cell-derived exosome-like microvesicles in vitro. AB - Saliva is a useful biofluid for the early detection of disease, but how distal tumors communicate with the oral cavity and create disease-specific salivary biomarkers remains unclear. Using an in vitro breast cancer model, we demonstrated that breast cancer-derived exosome-like microvesicles are capable of interacting with salivary gland cells, altering the composition of their secreted exosome-like microvesicles. We found that the salivary gland cells secreted exosome-like microvesicles encapsulating both protein and mRNA. We also showed that the interaction with breast cancer-derived exosome-like microvesicles communicated and activated the transcriptional machinery of the salivary gland cells. Thus, the interaction altered the composition of the salivary gland cell derived exosome-like microvesicles on both the transcriptomically and proteomically. PMID- 22448233 TI - Measuring multi-joint stiffness during single movements: numerical validation of a novel time-frequency approach. AB - This study presents and validates a Time-Frequency technique for measuring 2 dimensional multijoint arm stiffness throughout a single planar movement as well as during static posture. It is proposed as an alternative to current regressive methods which require numerous repetitions to obtain average stiffness on a small segment of the hand trajectory. The method is based on the analysis of the reassigned spectrogram of the arm's response to impulsive perturbations and can estimate arm stiffness on a trial-by-trial basis. Analytic and empirical methods are first derived and tested through modal analysis on synthetic data. The technique's accuracy and robustness are assessed by modeling the estimation of stiffness time profiles changing at different rates and affected by different noise levels. Our method obtains results comparable with two well-known regressive techniques. We also test how the technique can identify the viscoelastic component of non-linear and higher than second order systems with a non-parametrical approach. The technique proposed here is very impervious to noise and can be used easily for both postural and movement tasks. Estimations of stiffness profiles are possible with only one perturbation, making our method a useful tool for estimating limb stiffness during motor learning and adaptation tasks, and for understanding the modulation of stiffness in individuals with neurodegenerative diseases. PMID- 22448234 TI - Massively parallel RNA sequencing identifies a complex immune gene repertoire in the lophotrochozoan Mytilus edulis. AB - The marine mussel Mytilus edulis and its closely related sister species are distributed world-wide and play an important role in coastal ecology and economy. The diversification in different species and their hybrids, broad ecological distribution, as well as the filter feeding mode of life has made this genus an attractive model to investigate physiological and molecular adaptations and responses to various biotic and abiotic environmental factors. In the present study we investigated the immune system of Mytilus, which may contribute to the ecological plasticity of this species. We generated a large Mytilus transcriptome database from different tissues of immune challenged and stress treated individuals from the Baltic Sea using 454 pyrosequencing. Phylogenetic comparison of orthologous groups of 23 species demonstrated the basal position of lophotrochozoans within protostomes. The investigation of immune related transcripts revealed a complex repertoire of innate recognition receptors and downstream pathway members including transcripts for 27 toll-like receptors and 524 C1q domain containing transcripts. NOD-like receptors on the other hand were absent. We also found evidence for sophisticated TNF, autophagy and apoptosis systems as well as for cytokines. Gill tissue and hemocytes showed highest expression of putative immune related contigs and are promising tissues for further functional studies. Our results partly contrast with findings of a less complex immune repertoire in ecdysozoan and other lophotrochozoan protostomes. We show that bivalves are interesting candidates to investigate the evolution of the immune system from basal metazoans to deuterostomes and protostomes and provide a basis for future molecular work directed to immune system functioning in Mytilus. PMID- 22448235 TI - Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high CRP levels (DIATOR trial). AB - BACKGROUND: A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin. METHODOLOGY/PRINCIPAL FINDINGS: The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r(2) = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin. CONCLUSIONS/SIGNIFICANCE: Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators. TRIAL REGISTRATION: ClinicalTrials.gov NCT00974740. PMID- 22448236 TI - Multi-scale sampling to evaluate assemblage dynamics in an oceanic marine reserve. AB - To resolve the capacity of Marine Protected Areas (MPA) to enhance fish productivity it is first necessary to understand how environmental conditions affect the distribution and abundance of fishes independent of potential reserve effects. Baseline fish production was examined from 2002-2004 through ichthyoplankton sampling in a large (10,878 km(2)) Southern Californian oceanic marine reserve, the Cowcod Conservation Area (CCA) that was established in 2001, and the Southern California Bight as a whole (238,000 km(2) CalCOFI sampling domain). The CCA assemblage changed through time as the importance of oceanic pelagic species decreased between 2002 (La Nina) and 2003 (El Nino) and then increased in 2004 (El Nino), while oceanic species and rockfishes displayed the opposite pattern. By contrast, the CalCOFI assemblage was relatively stable through time. Depth, temperature, and zooplankton explained more of the variability in assemblage structure at the CalCOFI scale than they did at the CCA scale. CalCOFI sampling revealed that oceanic species impinged upon the CCA between 2002 and 2003 in association with warmer offshore waters, thus explaining the increased influence of these species in the CCA during the El Nino years. Multi-scale, spatially explicit sampling and analysis was necessary to interpret assemblage dynamics in the CCA and likely will be needed to evaluate other focal oceanic marine reserves throughout the world. PMID- 22448237 TI - Selective reduction of post-selection CD8 thymocyte proliferation in IL-15Ralpha deficient mice. AB - Peripheral CD8(+) T cells are defective in both IL-15 and IL-15Ralpha knock-out (KO) mice; however, whether IL-15/IL-15Ralpha deficiency has a similar effect on CD8 single-positive (SP) thymocytes remains unclear. In this study, we investigated whether the absence of IL-15 transpresentation in IL-15Ralpha KO mice results in a defect in thymic CD8 single positive (SP) TCR(hi) thymocytes. Comparison of CD8SP TCR(hi) thymocytes from IL-15Ralpha KO mice with their wild type (WT) counterparts by flow cytometry showed a significant reduction in the percentage of CD69(-) CD8SP TCR(hi) thymocytes, which represent thymic premigrants. In addition, analysis of in vivo 5-bromo-2-deoxyuridine (BrdU) incorporation demonstrated that premigrant expansion of CD8SP TCR(hi) thymocytes was reduced in IL-15Ralpha KO mice. The presence of IL-15 transpresentation dependent expansion in CD8SP TCR(hi) thymocytes was assessed by culturing total thymocytes in IL-15Ralpha-Fc fusion protein-pre-bound plates that were pre incubated with IL-15 to mimic IL-15 transpresentation in vitro. The results demonstrated that CD8SP thymocytes selectively outgrew other thymic subsets. The contribution of the newly divided CD8SP thymocytes to the peripheral CD8(+) T cell pool was examined using double labeling with intrathymically injected FITC and intravenously injected BrdU. A marked decrease in FITC(+) BrdU(+) CD8(+) T cells was observed in the IL-15Ralpha KO lymph nodes. Through these experiments, we identified an IL-15 transpresentation-dependent proliferation process selective for the mature CD8SP premigrant subpopulation. Importantly, this process may contribute to the maintenance of the normal peripheral CD8(+) T cell pool. PMID- 22448238 TI - Evolution of opinions on social networks in the presence of competing committed groups. AB - Public opinion is often affected by the presence of committed groups of individuals dedicated to competing points of view. Using a model of pairwise social influence, we study how the presence of such groups within social networks affects the outcome and the speed of evolution of the overall opinion on the network. Earlier work indicated that a single committed group within a dense social network can cause the entire network to quickly adopt the group's opinion (in times scaling logarithmically with the network size), so long as the committed group constitutes more than about 10% of the population (with the findings being qualitatively similar for sparse networks as well). Here we study the more general case of opinion evolution when two groups committed to distinct, competing opinions A and B, and constituting fractions pA and pB of the total population respectively, are present in the network. We show for stylized social networks (including Erdos-Renyi random graphs and Barabasi-Albert scale-free networks) that the phase diagram of this system in parameter space (pA,pB) consists of two regions, one where two stable steady-states coexist, and the remaining where only a single stable steady-state exists. These two regions are separated by two fold-bifurcation (spinodal) lines which meet tangentially and terminate at a cusp (critical point). We provide further insights to the phase diagram and to the nature of the underlying phase transitions by investigating the model on infinite (mean-field limit), finite complete graphs and finite sparse networks. For the latter case, we also derive the scaling exponent associated with the exponential growth of switching times as a function of the distance from the critical point. PMID- 22448239 TI - Investigation of polyurea-crosslinked silica aerogels as a neuronal scaffold: a pilot study. AB - BACKGROUND: Polymer crosslinked aerogels are an attractive class of materials for future implant applications particularly as a biomaterial for the support of nerve growth. The low density and nano-porous structure of this material combined with large surface area, high mechanical strength, and tunable surface properties, make aerogels materials with a high potential in aiding repair of injuries of the peripheral nervous system. however, the interaction of neurons with aerogels remains to be investigated. METHODOLOGY: In this work the attachment and growth of neurons on clear polyurea crosslinked silica aerogels (PCSA) coated with: poly-L-lysine, basement membrane extract (BME), and laminin1 was investigated by means of optical and scanning electron microscopy. After comparing the attachment and growth capability of neurons on these different coatings, laminin1 and BME were chosen for nerve cell attachment and growth on PCSA surfaces. The behavior of neurons on treated petri dish surfaces was used as the control and behavior of neurons on treated PCSA discs was compared against it. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that: 1) untreated PCSA surfaces do not support attachment and growth of nerve cells, 2) a thin application of laminin1 layer onto the PCSA discs adhered well to the PCSA surface while also supporting growth and differentiation of neurons as evidenced by the number of processes extended and b3-tubulin expression, 3) three dimensional porous structure of PCSA remains intact after fixing protocols necessary for preservation of biological samples and 4) laminin1 coating proved to be the most effective method for attaching neurons to the desired regions on PCSA discs. This work provides the basis for potential use of PCSA as a biomaterial scaffold for neural regeneration. PMID- 22448240 TI - Infection-associated nuclear degeneration in the rice blast fungus Magnaporthe oryzae requires non-selective macro-autophagy. AB - BACKGROUND: The rice blast fungus Magnaporthe oryzae elaborates a specialized infection structure called an appressorium to breach the rice leaf surface and gain access to plant tissue. Appressorium development is controlled by cell cycle progression, and a single round of nuclear division occurs prior to appressorium formation. Mitosis is always followed by programmed cell death of the spore from which the appressorium develops. Nuclear degeneration in the spore is known to be essential for plant infection, but the precise mechanism by which it occurs is not known. METHODOLOGY/PRINCIPAL FINDINGS: In yeast, nuclear breakdown requires a specific form of autophagy, known as piecemeal microautophagy of the nucleus (PMN), and we therefore investigated whether this process occurs in the rice blast fungus. Here, we report that M. oryzae possesses two conserved components of a putative PMN pathway, MoVac8 and MoTsc13, but that both are dispensable for nuclear breakdown during plant infection. MoVAC8 encodes a vacuolar membrane protein and MoTSC13 a peri-nuclear and peripheral ER protein. CONCLUSIONS/SIGNIFICANCE: We show that MoVAC8 is necessary for caffeine resistance, but dispensable for pathogenicity of M. oryzae, while MoTSC13 is involved in cell wall stress responses and is an important virulence determinant. By functional analysis of DeltaMoatg1 and DeltaMoatg4 mutants, we demonstrate that infection-associated nuclear degeneration in M. oryzae instead occurs by non selective macroautophagy, which is necessary for rice blast disease. PMID- 22448241 TI - Condom negotiations among female sex workers in the Philippines: environmental influences. AB - BACKGROUND: Social and structural influences of condom negotiation among female sex workers (FSWs) remain understudied. This study assesses environmental and individual factors associated with condom negotiation among FSWs at high risk for acquiring HIV in a large urban setting of Metro Manila, Philippines. METHODS: Female bar/spa workers (N = 498), aged 18 and over, underwent interview-led surveys examining their sexual health practices in the context of their risk environments. Data were collected from April 2009-January 2010 from 54 venues. Multiple logistic regressions were conducted to assess socio-behavioral factors (e.g., age, education, length of time employed as an entertainer, and alcohol/drug use) and socio-structural factors (e.g., venue-level peer/manager support, condom rule/availability, and sex trafficking) associated with condom negotiation, adjusting for individuals nested within venues. RESULTS: Of 142 FSWs who traded sex in the previous 6 months (included in the analysis), 24% did not typically negotiate condom use with venue patrons. Factors in the physical environment--trafficked/coerced into work (AOR = 12.92, 95% CI = 3.34-49.90), economic environment--sex without a condom to make more money (AOR = 1.52, 95% CI 1.01-2.30), policy environment--sex without a condom because none was available (AOR = 2.58, 95% CI = 1.49-4.48), and individual risk--substance use (AOR = 2.36, 95% CI = 1.28-4.35) were independently associated with FSWs' lack of condom negotiation with venue patrons. CONCLUSIONS: Factors in the physical, economic, and policy environments, over individual (excepting substance use) and social level factors, were significantly associated with these FSWs' condom negotiations in the Philippines. Drawing upon Rhodes' risk environment framework, these results highlight the need for policies that support safer sex negotiations among sex workers in the context of their risk environments. Interventions should reduce barriers to condom negotiation for FSWs trafficked/coerced into their work, substance using, and impacted by economic conditions and policies that do not support condom availability. PMID- 22448242 TI - Involvement of Wnt signaling pathways in the metamorphosis of the bryozoan Bugula neritina. AB - In this study, we analyzed the metamorphosis of the marine bryozoan Bugula neritina. We observed the morphogenesis of the ancestrula. We defined three distinct pre-ancestrula stages based on the anatomy of the developing polypide and the overall morphology of pre-ancestrula. We then used an annotation based enrichment analysis tool to analyze the B. neritina transcriptome and identified over-representation of genes related to Wnt signaling pathways, suggesting its involvement in metamorphosis. Finally, we studied the temporal-spatial gene expression studies of several Wnt pathway genes. We found that one of the Wnt ligand, BnWnt10, was expressed spatially opposite to the Wnt antagonist BnsFRP within the blastemas, which is the presumptive polypide. Down-stream components of the canonical Wnt signaling pathway were exclusively expressed in the blastemas. Bnbetacatenin and BnFz5/8 were exclusively expressed in the blastemas throughout the metamorphosis. Based on the genes expression patterns, we propose that BnWnt10 and BnsFRP may relate to the patterning of the polypide, in which the two genes served as positional signals and contributed to the polarization of the blastemas. Another Wnt ligand, BnWnt6, was expressed in the apical part of the pre-ancestrula epidermis. Overall, our findings suggest that the Wnt signaling pathway may be important to the pattern formation of polypide and the development of epidermis. PMID- 22448243 TI - Altered trabecular bone structure and delayed cartilage degeneration in the knees of collagen VI null mice. AB - Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1(-/-) mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP). Col6a1(-/-) mice showed significant differences in trabecular bone structure, with lower bone volume, connectivity density, trabecular number, and trabecular thickness but higher structure model index and trabecular separation compared to Col6a1(+/+) mice. Subchondral bone thickness and mineral content increased significantly with age in Col6a1(+/+) mice, but not in Col6a1(-/-) mice. Col6a1(-/-) mice had lower cartilage degradation scores, but developed early, severe osteophytes compared to Col6a1(+/+) mice. In both groups, cartilage roughness increased with age, but neither the frictional coefficient nor compressive modulus of the cartilage changed with age or genotype, as measured by AFM. Cartilage diffusivity, measured via SCAMP, varied minimally with age or genotype. The absence of type VI collagen has profound effects on knee joint structure and morphometry, yet minimal influences on the physical properties of the cartilage. Together with previous studies showing accelerated hip osteoarthritis in Col6a1(-/-) mice, these findings suggest different roles for collagen VI at different sites in the body, consistent with clinical data. PMID- 22448244 TI - Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. AB - BACKGROUND: A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. Our objective was to enhance the precision of estimates of the effect of metformin on the risk of any-site and site-specific cancers in patients with diabetes. METHODS/PRINCIPAL FINDINGS: We performed a search of MEDLINE, EMBASE, ISI Web of Science, Cochrane Library, and ClinicalTrials.gov for pertinent articles published as of October 12, 2011, and included them in a systematic review and meta-analysis. We calculated pooled risk ratios (RRs) for overall cancer mortality and cancer incidence. Of the 21,195 diabetic patients reported in 6 studies (4 cohort studies, 2 RCTs), 991 (4.5%) cases of death from cancer were reported. A total of 11,117 (5.3%) cases of incident cancer at any site were reported among 210,892 patients in 10 studies (2 RCTs, 6 cohort studies, 2 case-control studies). The risks of cancer among metformin users were significantly lower than those among non-metformin users: the pooled RRs (95% confidence interval) were 0.66 (0.49-0.88) for cancer mortality, 0.67 (0.53-0.85) for all-cancer incidence, 0.68 (0.53-0.88) for colorectal cancer (n = 6), 0.20 (0.07-0.59) for hepatocellular cancer (n = 4), 0.67 (0.45-0.99) for lung cancer (n = 3). CONCLUSION/SIGNIFICANCE: The use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence. However, this analysis is mainly based on observational studies and our findings underscore the more need for long-term RCTs to confirm this potential benefit for individuals with diabetes. PMID- 22448245 TI - Transient and microscale deformations and strains measured under exogenous loading by noninvasive magnetic resonance. AB - Characterization of spatiotemporal deformation dynamics and material properties requires non-destructive methods to visualize mechanics of materials and biological tissues. Displacement-encoded magnetic resonance imaging (MRI) has emerged as a noninvasive and non-destructive technique used to quantify deformation and strains. However, the techniques are not yet applicable to a broad range of materials and load-bearing tissues. In this paper, we visualize transient and internal material deformation through the novel synchrony of external mechanical loading with rapid displacement-encoded MRI. We achieved deformation measurements in silicone gel materials with a spatial resolution of 100 um and a temporal resolution (of 2.25 ms), set by the repetition time (TR) of the rapid MRI acquisition. Displacement and strain precisions after smoothing were 11 um and 0.1%, respectively, approaching cellular length scales. Short (1/2 TR) echo times enabled visualization of in situ deformation in a human tibiofemoral joint, inclusive of multiple variable T(2) biomaterials. Moreover, the MRI acquisitions achieved a fivefold improvement in imaging time over previous technology, setting the stage for mechanical imaging in vivo. Our results provide a general approach for noninvasive and non-destructive measurement, at high spatial and temporal resolution, of the dynamic mechanical response of a broad range of load-bearing materials and biological tissues. PMID- 22448246 TI - Low prevalence of transmitted drug resistance in patients newly diagnosed with HIV-1 infection in Sweden 2003-2010. AB - Transmitted drug resistance (TDR) is a clinical and epidemiological problem because it may contribute to failure of antiretroviral treatment. The prevalence of TDR varies geographically, and its prevalence in Sweden during the last decade has not been reported. Plasma samples from 1,463 patients newly diagnosed with HIV-1 infection between 2003 and 2010, representing 44% of all patients diagnosed in Sweden during this period, were analyzed using the WHO 2009 list of mutations for surveillance of TDR. Maximum likelihood phylogenetic analyses were used to determine genetic subtype and to investigate the relatedness of the sequences. Eighty-two patients showed evidence of TDR, representing a prevalence of 5.6% (95% CI: 4.5%-6.9%) without any significant time trends or differences between patients infected in Sweden or abroad. Multivariable logistic regression showed that TDR was positively associated with men who have sex with men (MSM) and subtype B infection and negatively associated with CD4 cell counts. Among patients with TDR, 54 (68%) had single resistance mutations, whereas five patients had multi-drug resistant HIV-1. Phylogenetic analyses identified nine significantly supported clusters involving 29 of the patients with TDR, including 23 of 42 (55%) of the patients with TDR acquired in Sweden. One cluster contained 18 viruses with a M41L resistance mutation, which had spread among MSM in Stockholm over a period of at least 16 years (1994-2010). Another cluster, which contained the five multidrug resistant viruses, also involved MSM from Stockholm. The prevalence of TDR in Sweden 2003-2010 was lower than in many other European countries. TDR was concentrated among MSM, where clustering of TDR strains was observed, which highlights the need for continued and improved measures for targeted interventions. PMID- 22448247 TI - Depleting components of the THO complex causes increased telomere length by reducing the expression of the telomere-associated protein Rif1p. AB - Telomere length is regulated mostly by proteins directly associated with telomeres. However, genome-wide analysis of Saccharomyces cerevisiae mutants has revealed that deletion of Hpr1p, a component of the THO complex, also affects telomere length. The THO complex comprises four protein subunits, namely, Tho2p, Hpr1p, Mft1p, and Thp2p. These subunits interplay between transcription elongation and co-transcriptional assembly of export-competent mRNPs. Here we found that the deletion of tho2 or hpr1 caused telomere lengthening by ~50-100 bps, whereas that of mft1 or thp2 did not affect telomere length. Since the THO complex functions in transcription elongation, we analyzed the expression of telomere-associated proteins in mutants depleted of complex components. We found that both the mRNA and protein levels of RIF1 were decreased in tho2 and hpr1 cells. RIF1 encodes a 1917-amino acid polypeptide that is involved in regulating telomere length and the formation of telomeric heterochromatin. Hpr1p and Tho2p appeared to affect telomeres through Rif1p, as increased Rif1p levels suppressed the telomere lengthening in tho2 and hpr1 cells. Moreover, yeast cells carrying rif1 tho2 or rif1 hpr1 double mutations showed telomere lengths and telomere silencing effects similar to those observed in the rif1 mutant. Thus, we conclude that mutations of components of the THO complex affect telomere functions by reducing the expression of a telomere-associated protein, Rif1p. PMID- 22448248 TI - A sensitive and quantitative polymerase chain reaction-based cell free in vitro non-homologous end joining assay for hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic homeostasis and regeneration after injury for the entire lifespan of an organism. Maintenance of genomic stability is crucial for the preservation of HSCs, which depends on their efficient repair of DNA damage, particularly DNA double strand breaks (DSBs). Because of the paucity of HSCs and lack of sensitive assays, directly measuring the ability of HSCs to repair DSBs has been difficult. Therefore, we developed a sensitive and quantitative cell free in vitro non homologous end joining (NHEJ) assay using linearized plasmids as the substrates and quantitative polymerase chain reaction (qPCR) technique. This assay can sensitively detect DSB repair via NHEJ in less than 1 ug 293T cell nuclear proteins or nuclear extracts from about 5,000 to 10,000 human BM CD34(+) hematopoietic cells. Using this assay, we confirmed that human bone marrow HSCs (CD34(+)CD38(-) cells) are less proficient in the repair of DSBs by NHEJ than HPCs (CD34(+)CD38(+) cells). In contrast, mouse quiescent HSCs (Pyronin-Y(low) LKS(+) cells) and cycling HSCs (Pyronin-Y(hi) LKS(+) cells) repaired the damage more efficiently than HPCs (LKS(-) cells). The difference in the abilities of human and mouse HSCs and HPCs to repair DSBs through NHEJ is likely attributed to their differential expression of key NHEJ DNA damage repair genes such as LIG4. These findings suggest that the qPCR-based cell free in vitro NHEJ assay can be used to sensitively measure the ability of human and mouse HSCs to repair DSBs. PMID- 22448249 TI - In vivo imaging of macrophages during the early-stages of abdominal aortic aneurysm using high resolution MRI in ApoE mice. AB - BACKGROUND: Angiotensin II (ANG II) promotes vascular inflammation and induces abdominal aortic aneurysm (AAA) in hyperlipidemic apolipoprotein E knock-out (apoE(-/-)) mice. The aim of the present study was to detect macrophage activities in an ANG II-induced early-stage AAA model using superparamagnetic iron oxide (SPIO) as a marker. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-six male apoE(-/-) mice received saline or ANG II (1000 or 500 ng/kg/min) infusion for 14 days. All animals underwent MRI scanning following administration of SPIO with the exception of three mice in the 1000 ng ANG II group, which were scanned without SPIO administration. MR imaging was performed using black-blood T2 to proton density -weighted multi-spin multi-echo sequence. In vivo MRI measurement of SPIO uptake and abdominal aortic diameter were obtained. Prussian blue, CD68,alpha-SMC and MAC3 immunohistological stains were used for the detection of SPIO, macrophages and smooth muscle cells. ANG II infusion with 1000 ng/kg/min induced AAA in all of the apoE(-/-) mice. ANG II infusion exhibited significantly higher degrees of SPIO uptake, which was detected using MRI as a distinct loss of signal intensity. The contrast-to-noise ratio value decreased in proportion to an increase in the number of iron-laden macrophages in the aneurysm. The aneurysmal vessel wall in both groups of ANG II treated mice contained more iron-positive macrophages than saline-treated mice. However, the presence of cells capable of phagocytosing haemosiderin in mural thrombi also induced low-signal-intensities via MRI imaging. CONCLUSIONS/SIGNIFICANCE: SPIO is taken up by macrophages in the shoulder and the outer layer of AAA. This alters the MRI signaling properties and can be used in imaging inflammation associated with AAA. It is important to compare images of the aorta before and after SPIO injection. PMID- 22448250 TI - Disruption of murine mp29/Syf2/Ntc31 gene results in embryonic lethality with aberrant checkpoint response. AB - Human p29 is a putative component of spliceosomes, but its role in pre-mRNA is elusive. By siRNA knockdown and stable overexpression, we demonstrated that human p29 is involved in DNA damage response and Fanconi anemia pathway in cultured cells. In this study, we generated p29 knockout mice (mp29(GT/GT)) using the mp29 gene trap embryonic stem cells to study the role of mp29 in DNA damage response in vivo. Interruption of mp29 at both alleles resulted in embryonic lethality. Embryonic abnormality occurred as early as E6.5 in mp29(GT/GT) mice accompanied with decreased mRNA levels of alpha-tubulin and Chk1. The reduction of alpha tubulin and Chk1 mRNAs is likely due to an impaired post-transcriptional event. An aberrant G2/M checkpoint was found in mp29 gene trap embryos when exposed to aphidicolin and UV light. This embryonic lethality was rescued by crossing with mp29 transgenic mice. Additionally, the knockdown of zfp29 in zebrafish resulted in embryonic death at 72 hours of development postfertilization (hpf). A lower level of acetylated alpha-tubulin was also observed in zfp29 morphants. Together, these results illustrate an indispensable role of mp29 in DNA checkpoint response during embryonic development. PMID- 22448251 TI - Mutation accumulation in a selfing population: consequences of different mutation rates between selfers and outcrossers. AB - Currently existing theories predict that because deleterious mutations accumulate at a higher rate, selfing populations suffer from more intense genetic degradation relative to outcrossing populations. This prediction may not always be true when we consider a potential difference in deleterious mutation rate between selfers and outcrossers. By analyzing the evolutionary stability of selfing and outcrossing in an infinite population, we found that the genome-wide deleterious mutation rate would be lower in selfing than in outcrossing organisms. When this difference in mutation rate was included in simulations, we found that in a small population, mutations accumulated more slowly under selfing rather than outcrossing. This result suggests that under frequent and intense bottlenecks, a selfing population may have a lower risk of genetic extinction than an outcrossing population. PMID- 22448252 TI - Interaction between NANOS2 and the CCR4-NOT deadenylation complex is essential for male germ cell development in mouse. AB - Nanos is one of the evolutionarily conserved proteins implicated in germ cell development and we have previously shown that it interacts with the CCR4-NOT deadenylation complex leading to the suppression of specific RNAs. However, the molecular mechanism and physiological significance of this interaction have remained elusive. In our present study, we identify CNOT1, a component of the CCR4-NOT deadenylation complex, as a direct factor mediating the interaction with NANOS2. We find that the first 10 amino acids (AAs) of NANOS2 are required for this binding. We further observe that a NANOS2 mutant lacking these first 10 AAs (NANOS2-DeltaN10) fails to rescue defects in the Nanos2-null mouse. Our current data thus indicate that the interaction with the CCR4-NOT deadenylation complex is essential for NANOS2 function. In addition, we further demonstrate that NANOS2 DeltaN10 can associate with specific mRNAs as well as wild-type NANOS2, suggesting the existence of other NANOS2-associated factor(s) that determine the specificity of RNA-binding independently of the CCR4-NOT deadenylation complex. PMID- 22448253 TI - Competition-colonization trade-offs, competitive uncertainty, and the evolutionary assembly of species. AB - We utilize a standard competition-colonization metapopulation model in order to study the evolutionary assembly of species. Based on earlier work showing how models assuming strict competitive hierarchies will likely lead to runaway evolution and self-extinction for all species, we adopt a continuous competition function that allows for levels of uncertainty in the outcome of competition. We then, by extending the standard patch-dynamic metapopulation model in order to include evolutionary dynamics, allow for the coevolution of species into stable communities composed of species with distinct limiting similarities. Runaway evolution towards stochastic extinction then becomes a limiting case controlled by the level of competitive uncertainty. We demonstrate how intermediate competitive uncertainty maximizes the equilibrium species richness as well as maximizes the adaptive radiation and self-assembly of species under adaptive dynamics with mutations of non-negligible size. By reconciling competition colonization tradeoff theory with co-evolutionary dynamics, our results reveal the importance of intermediate levels of competitive uncertainty for the evolutionary assembly of species. PMID- 22448254 TI - Role of trehalose in salinity and temperature tolerance in the model halophilic bacterium Chromohalobacter salexigens. AB - The disaccharide trehalose is considered as a universal stress molecule, protecting cells and biomolecules from injuries imposed by high osmolarity, heat, oxidation, desiccation and freezing. Chromohalobacter salexigens is a halophilic and extremely halotolerant gamma-proteobacterium of the family Halomonadaceae. In this work, we have investigated the role of trehalose as a protectant against salinity, temperature and desiccation in C. salexigens. A mutant deficient in the trehalose-6-phosphate synthase gene (otsA::Omega) was not affected in its salt or heat tolerance, but double mutants ectoine- and trehalose-deficient, or hydroxyectoine-reduced and trehalose-deficient, displayed an osmo- and thermosensitive phenotype, respectively. This suggests a role of trehalose as a secondary solute involved in osmo- (at least at low salinity) and thermoprotection of C. salexigens. Interestingly, trehalose synthesis was osmoregulated at the transcriptional level, and thermoregulated at the post transcriptional level, suggesting that C. salexigens cells need to be pre conditioned by osmotic stress, in order to be able to quickly synthesize trehalose in response to heat stress. C. salexigens was more sensitive to desiccation than E. coli and desiccation tolerance was slightly improved when cells were grown at high temperature. Under these conditions, single mutants affected in the synthesis of trehalose or hydroxyectoine were more sensitive to desiccation than the wild-type strain. However, given the low survival rates of the wild type, the involvement of trehalose and hydroxyectoine in C. salexigens response to desiccation could not be firmly established. PMID- 22448255 TI - Cost-effectiveness of peer-delivered interventions for cocaine and alcohol abuse among women: a randomized controlled trial. AB - AIMS: To determine whether the additional interventions to standard care are cost effective in addressing cocaine and alcohol abuse at 4 months (4 M) and 12 months (12 M) from baseline. METHOD: We conducted a cost-effectiveness analysis of a randomized controlled trial with three arms: (1) NIDA's Standard intervention (SI); (2) SI plus a Well Woman Exam (WWE); and, (3) SI, WWE, plus four Educational Sessions (4ES). RESULTS: To obtain an additional cocaine abstainer, WWE compared to SI cost $7,223 at 4 M and $3,611 at 12 M. Per additional alcohol abstainer, WWE compared to SI cost $3,611 and $7,223 at 4 M and 12 M, respectively. At 12 M, 4ES was dominated (more costly and less effective) by WWE for abstinence outcomes. CONCLUSIONS: To our knowledge, this is the first cost effectiveness analysis simultaneously examining cocaine and alcohol abuse in women. Depending on primary outcomes sought and priorities of policy makers, peer delivered interventions can be a cost-effective way to address the needs of this growing, underserved population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01235091. PMID- 22448256 TI - Identification and analysis of conserved cis-regulatory regions of the MEIS1 gene. AB - Meis1, a conserved transcription factor of the TALE-homeodomain class, is expressed in a wide variety of tissues during development. Its complex expression pattern is likely to be controlled by an equally complex regulatory landscape. Here we have scanned the Meis1 locus for regulatory elements and found 13 non coding regions, highly conserved between humans and teleost fishes, that have enhancer activity in stable transgenic zebrafish lines. All these regions are syntenic in most vertebrates. The composite expression of all these enhancer elements recapitulate most of Meis1 expression during early embryogenesis, indicating they comprise a basic set of regulatory elements of the Meis1 gene. Using bioinformatic tools, we identify a number of potential binding sites for transcription factors that are compatible with the regulation of these enhancers. Specifically, HHc2:066650, which is expressed in the developing retina and optic tectum, harbors several predicted Pax6 sites. Biochemical, functional and transgenic assays indicate that pax6 genes directly regulate HHc2:066650 activity. PMID- 22448257 TI - Evaluation of a rapid immunochromatographic ODK-0901 test for detection of pneumococcal antigen in middle ear fluids and nasopharyngeal secretions. AB - Since the incidence of penicillin-resistant Streptococcus pneumoniae has been increasing at an astonishing rate throughout the world, the need for accurate and rapid identification of pneumococci has become increasingly important to determine the appropriate antimicrobial treatment. We have evaluated an immunochromatographic test (ODK-0901) that detects pneumococcal antigens using 264 middle ear fluids (MEFs) and 268 nasopharyngeal secretions (NPSs). A sample was defined to contain S. pneumoniae when optochin and bile sensitive alpha hemolytic streptococcal colonies were isolated by culture. The sensitivity and specificity of the ODK-0901 test were 81.4% and 80.5%, respectively, for MEFs from patients with acute otitis media (AOM). In addition, the sensitivity and specificity were 75.2% and 88.8%, respectively, for NPSs from patients with acute rhinosinusitis. The ODK-0901 test may provide a rapid and highly sensitive evaluation of the presence of S. pneumoniae and thus may be a promising method of identifying pneumococci in MEFs and NPSs. PMID- 22448258 TI - Vocal responses to perturbations in voice auditory feedback in individuals with Parkinson's disease. AB - BACKGROUND: One of the most common symptoms of speech deficits in individuals with Parkinson's disease (PD) is significantly reduced vocal loudness and pitch range. The present study investigated whether abnormal vocalizations in individuals with PD are related to sensory processing of voice auditory feedback. Perturbations in loudness or pitch of voice auditory feedback are known to elicit short latency, compensatory responses in voice amplitude or fundamental frequency. METHODOLOGY/PRINCIPAL FINDINGS: Twelve individuals with Parkinson's disease and 13 age- and sex-matched healthy control subjects sustained a vowel sound (/alpha/) and received unexpected, brief (200 ms) perturbations in voice loudness (+/-3 or 6 dB) or pitch (+/-100 cents) auditory feedback. Results showed that, while all subjects produced compensatory responses in their voice amplitude or fundamental frequency, individuals with PD exhibited larger response magnitudes than the control subjects. Furthermore, for loudness-shifted feedback, upward stimuli resulted in shorter response latencies than downward stimuli in the control subjects but not in individuals with PD. CONCLUSIONS/SIGNIFICANCE: The larger response magnitudes in individuals with PD compared with the control subjects suggest that processing of voice auditory feedback is abnormal in PD. Although the precise mechanisms of the voice feedback processing are unknown, results of this study suggest that abnormal voice control in individuals with PD may be related to dysfunctional mechanisms of error detection or correction in sensory feedback processing. PMID- 22448259 TI - Semaphorin 3A suppresses tumor growth and metastasis in mice melanoma model. AB - BACKGROUND: Recent understanding on cancer therapy indicated that targeting metastatic signature or angiogenic switch could be a promising and rational approach to combat cancer. Advancement in cancer research has demonstrated the potential role of various tumor suppressor proteins in inhibition of cancer progression. Current studies have shown that axonal sprouting inhibitor, semaphorin 3A (Sema 3A) acts as a potent suppressor of tumor angiogenesis in various cancer models. However, the function of Sema 3A in regulation of melanoma progression is not well studied, and yet to be the subject of intense investigation. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using multiple in vitro and in vivo approaches we have demonstrated that Sema 3A acts as a potent tumor suppressor in vitro and in vivo mice (C57BL/6) models. Mouse melanoma (B16F10) cells overexpressed with Sema 3A resulted in significant inhibition of cell motility, invasiveness and proliferation as well as suppression of in vivo tumor growth, angiogenesis and metastasis in mice models. Moreover, we have observed that Sema 3A overexpressed melanoma clone showed increased sensitivity towards curcumin and Dacarbazine, anti-cancer agents. CONCLUSIONS: Our results demonstrate, at least in part, the functional approach underlying Sema 3A mediated inhibition of tumorigenesis and angiogenesis and a clear understanding of such a process may facilitate the development of novel therapeutic strategy for the treatment of cancer. PMID- 22448260 TI - Drought-adaptation potential in Fagus sylvatica: linking moisture availability with genetic diversity and dendrochronology. AB - BACKGROUND: Microevolution is essential for species persistence especially under anticipated climate change scenarios. Species distribution projection models suggested that the dominant tree species of lowland forests in Switzerland, European beech (Fagus sylvatica L.), might disappear from most areas due to expected longer dry periods. However, if genotypes at the moisture boundary of the species climatic envelope are adapted to lower moisture availability, they can serve as seed source for the continuation of beech forests under changing climates. METHODOLOGY/PRINCIPAL FINDINGS: With an AFLP genome scan approach, we studied neutral and potentially adaptive genetic variation in Fagus sylvatica in three regions containing a dry and a mesic site each (n(ind.) = 241, n(markers) = 517). We linked this dataset with dendrochronological growth measures and local moisture availabilities based on precipitation and soil characteristics. Genetic diversity decreased slightly at dry sites. Overall genetic differentiation was low (F(st) = 0.028) and Bayesian cluster analysis grouped all populations together suggesting high (historical) gene flow. The Bayesian outlier analyses indicated 13 markers with three markers differing between all dry and mesic sites and the others between the contrasting sites within individual regions. A total of 41 markers, including seven outlier loci, changed their frequency with local moisture availability. Tree height and median basal growth increments were reduced at dry sites, but marker presence/absence was not related to dendrochronological characteristics. CONCLUSION AND THEIR SIGNIFICANCE: The outlier alleles and the makers with changing frequencies in relation to moisture availability indicate microevolutionary processes occurring within short geographic distances. The general genetic similarity among sites suggests that 'preadaptive' genes can easily spread across the landscape. Yet, due to the long live span of trees, fostering saplings originating from dry sites and grown within mesic sites might increase resistance of beech forests during the anticipated longer dry periods. PMID- 22448261 TI - Control of gastric H,K-ATPase activity by cations, voltage and intracellular pH analyzed by voltage clamp fluorometry in Xenopus oocytes. AB - Whereas electrogenic partial reactions of the Na,K-ATPase have been studied in depth, much less is known about the influence of the membrane potential on the electroneutrally operating gastric H,K-ATPase. In this work, we investigated site specifically fluorescence-labeled H,K-ATPase expressed in Xenopus oocytes by voltage clamp fluorometry to monitor the voltage-dependent distribution between E(1)P and E(2)P states and measured Rb(+) uptake under various ionic and pH conditions. The steady-state E(1)P/E(2)P distribution, as indicated by the voltage-dependent fluorescence amplitudes and the Rb(+) uptake activity were highly sensitive to small changes in intracellular pH, whereas even large extracellular pH changes affected neither the E(1)P/E(2)P distribution nor transport activity. Notably, intracellular acidification by approximately 0.5 pH units shifted V(0.5), the voltage, at which the E(1)P/E(2)P ratio is 50?50, by 100 mV. This was paralleled by an approximately two-fold acceleration of the forward rate constant of the E(1)P->E(2)P transition and a similar increase in the rate of steady-state cation transport. The temperature dependence of Rb(+) uptake yielded an activation energy of ~90 kJ/mol, suggesting that ion transport is rate-limited by a major conformational transition. The pronounced sensitivity towards intracellular pH suggests that proton uptake from the cytoplasmic side controls the level of phosphoenzyme entering the E(1)P->E(2)P conformational transition, thus limiting ion transport of the gastric H,K-ATPase. These findings highlight the significance of cellular mechanisms contributing to increased proton availability in the cytoplasm of gastric parietal cells. Furthermore, we show that extracellular Na(+) profoundly alters the voltage-dependent E(1)P/E(2)P distribution indicating that Na(+) ions can act as surrogates for protons regarding the E(2)P->E(1)P transition. The complexity of the intra- and extracellular cation effects can be rationalized by a kinetic model suggesting that cations reach the binding sites through a rather high-field intra- and a rather low-field extracellular access channel, with fractional electrical distances of ~0.5 and ~0.2, respectively. PMID- 22448262 TI - Cadmium induces p53-dependent apoptosis in human prostate epithelial cells. AB - Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC 3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl(2) and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl(2) concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis. PMID- 22448263 TI - A relationship between carotenoid accumulation and the distribution of species of the fungus Neurospora in Spain. AB - The ascomycete fungus Neurospora is present in many parts of the world, in particular in tropical and subtropical areas, where it is found growing on recently burned vegetation. We have sampled the Neurospora population across Spain. The sampling sites were located in the region of Galicia (northwestern corner of the Iberian peninsula), the province of Caceres, the city of Seville, and the two major islands of the Canary Islands archipelago (Tenerife and Gran Canaria, west coast of Africa). The sites covered a latitude interval between 27.88 degrees and 42.74 degrees . We have identified wild-type strains of N. discreta, N. tetrasperma, N. crassa, and N. sitophila and the frequency of each species varied from site to site. It has been shown that after exposure to light Neurospora accumulates the orange carotenoid neurosporaxanthin, presumably for protection from UV radiation. We have found that each Neurospora species accumulates a different amount of carotenoids after exposure to light, but these differences did not correlate with the expression of the carotenogenic genes al-1 or al-2. The accumulation of carotenoids in Neurospora shows a correlation with latitude, as Neurospora strains isolated from lower latitudes accumulate more carotenoids than strains isolated from higher latitudes. Since regions of low latitude receive high UV irradiation we propose that the increased carotenoid accumulation may protect Neurospora from high UV exposure. In support of this hypothesis, we have found that N. crassa, the species that accumulates more carotenoids, is more resistant to UV radiation than N. discreta or N. tetrasperma. The photoprotection provided by carotenoids and the capability to accumulate different amounts of carotenoids may be responsible, at least in part, for the distribution of Neurospora species that we have observed across a range of latitudes. PMID- 22448264 TI - Mutations in radial spoke head genes and ultrastructural cilia defects in East European cohort of primary ciliary dyskinesia patients. AB - Primary ciliary dyskinesia (PCD) is a rare (1/20,000), multisystem disease with a complex phenotype caused by the impaired motility of cilia/flagella, usually related to ultrastructural defects of these organelles. Mutations in genes encoding radial spoke head (RSPH) proteins, elements of the ciliary ultrastructure, have been recently described. However, the relative involvement of RSPH genes in PCD pathogenesis remained unknown, due to a small number of PCD families examined for mutations in these genes. The purpose of this study was to estimate the involvement of RSPH4A and RSPH9 in PCD pathogenesis among East Europeans (West Slavs), and to shed more light on ultrastructural ciliary defects caused by mutations in these genes. The coding sequences of RSPH4A and RSPH9 were screened in PCD patients from 184 families, using single strand conformational polymorphism analysis and sequencing. Two previously described (Q109X; R490X) and two new RSPH4A mutations (W356X; IVS3_2-5del), in/around exons 1 and 3, were identified; no mutations were found in RSPH9. We estimate that mutations in RSPH4A, but not in RSPH9, are responsible for 2-3% of cases in the East European PCD population (4% in PCD families without situs inversus; 11% in families preselected for microtubular defects). Analysis of the SNP-haplotype background provided insight into the ancestry of repetitively found mutations (Q109X; R490X; IVS3_2-5del), but further studies involving other PCD cohorts are required to elucidate whether these mutations are specific for Slavic people or spread among other European populations. Ultrastructural defects associated with the mutations were analyzed in the transmission electron microscope images; almost half of the ciliary cross-sections examined in patients with RSPH4A mutations had the microtubule transposition phenotype (9+0 and 8+1 pattern). While microtubule transposition was a prevalent ultrastructural defect in cilia from patients with RSPH4A mutations, similar defects were also observed in PCD patients with mutations in other genes. PMID- 22448265 TI - A marine stem-tetrapod from the Devonian of western North America. AB - The origin of terrestrial vertebrates represents one of the major evolutionary and ecological transformations in the history of life, and the established timing and environment of this transition has recently come under scrutiny. The discovery and description of a well-preserved fossil sarcopterygian (fleshy limbed vertebrate) from the Middle Devonian of Nevada helps to refine and question aspects of the temporal and anatomical framework that underpins the tetrapod condition. This new taxon, Tinirau clackae, demonstrates that substantial parallelism pervaded the early history of stem-tetrapods, raises additional questions about when digited sarcopterygians first evolved, and further documents that incipient stages of the terrestrial appendicular condition began when sarcopterygians still retained their median fins and occupied aquatic habitats. PMID- 22448266 TI - Acidic digestion in a teleost: postprandial and circadian pattern of gastric pH, pepsin activity, and pepsinogen and proton pump mRNAs expression. AB - Two different modes for regulation of stomach acid secretion have been described in vertebrates. Some species exhibit a continuous acid secretion maintaining a low gastric pH during fasting. Others, as some teleosts, maintain a neutral gastric pH during fasting while the hydrochloric acid is released only after the ingestion of a meal. Those different patterns seem to be closely related to specific feeding habits. However, our recent observations suggest that this acidification pattern could be modified by changes in daily feeding frequency and time schedule. The aim of this study was to advance in understanding the regulation mechanisms of stomach digestion and pattern of acid secretion in teleost fish. We have examined the postprandial pattern of gastric pH, pepsin activity, and mRNA expression for pepsinogen and proton pump in white seabream juveniles maintained under a light/dark 12/12 hours cycle and receiving only one morning meal. The pepsin activity was analyzed according to the standard protocol buffering at pH 2 and using the actual pH measured in the stomach. The results show how the enzyme precursor is permanently available while the hydrochloric acid, which activates the zymogen fraction, is secreted just after the ingestion of food. Results also reveal that analytical protocol at pH 2 notably overestimates true pepsin activity in fish stomach. The expression of the mRNA encoding pepsinogen and proton pump exhibited almost parallel patterns, with notable increases during the darkness period and sharp decreases just before the morning meal. These results indicate that white seabream uses the resting hours for recovering the mRNA stock that will be quickly used during the feeding process. Our data clearly shows that both daily illumination pattern and feeding time are involved at different level in the regulation of the secretion of digestive juices. PMID- 22448267 TI - Automated counting of bacterial colony forming units on agar plates. AB - Manual counting of bacterial colony forming units (CFUs) on agar plates is laborious and error-prone. We therefore implemented a colony counting system with a novel segmentation algorithm to discriminate bacterial colonies from blood and other agar plates.A colony counter hardware was designed and a novel segmentation algorithm was written in MATLAB. In brief, pre-processing with Top-Hat-filtering to obtain a uniform background was followed by the segmentation step, during which the colony images were extracted from the blood agar and individual colonies were separated. A Bayes classifier was then applied to count the final number of bacterial colonies as some of the colonies could still be concatenated to form larger groups. To assess accuracy and performance of the colony counter, we tested automated colony counting of different agar plates with known CFU numbers of S. pneumoniae, P. aeruginosa and M. catarrhalis and showed excellent performance. PMID- 22448268 TI - Canonical A-to-I and C-to-U RNA editing is enriched at 3'UTRs and microRNA target sites in multiple mouse tissues. AB - RNA editing is a process that modifies RNA nucleotides and changes the efficiency and fidelity of the central dogma. Enzymes that catalyze RNA editing are required for life, and defects in RNA editing are associated with many diseases. Recent advances in sequencing have enabled the genome-wide identification of RNA editing sites in mammalian transcriptomes. Here, we demonstrate that canonical RNA editing (A-to-I and C-to-U) occurs in liver, white adipose, and bone tissues of the laboratory mouse, and we show that apparent non-canonical editing (all other possible base substitutions) is an artifact of current high-throughput sequencing technology. Further, we report that high-confidence canonical RNA editing sites can cause non-synonymous amino acid changes and are significantly enriched in 3' UTRs, specifically at microRNA target sites, suggesting both regulatory and functional consequences for RNA editing. PMID- 22448269 TI - The plastid genome of Eutreptiella provides a window into the process of secondary endosymbiosis of plastid in euglenids. AB - Euglenids are a group of protists that comprises species with diverse feeding modes. One distinct and diversified clade of euglenids is photoautotrophic, and its members bear green secondary plastids. In this paper we present the plastid genome of the euglenid Eutreptiella, which we assembled from 454 sequencing of Eutreptiella gDNA. Comparison of this genome and the only other available plastid genomes of photosynthetic euglenid, Euglena gracilis, revealed that they contain a virtually identical set of 57 protein coding genes, 24 genes fewer than the genome of Pyramimonas parkeae, the closest extant algal relative of the euglenid plastid. Searching within the transcriptomes of Euglena and Eutreptiella showed that 6 of the missing genes were transferred to the nucleus of the euglenid host while 18 have been probably lost completely. Euglena and Eutreptiella represent the deepest bifurcation in the photosynthetic clade, and therefore all these gene transfers and losses must have happened before the last common ancestor of all known photosynthetic euglenids. After the split of Euglena and Eutreptiella only one additional gene loss took place. The conservation of gene content in the two lineages of euglenids is in contrast to the variability of gene order and intron counts, which diversified dramatically. Our results show that the early secondary plastid of euglenids was much more susceptible to gene losses and endosymbiotic gene transfers than the established plastid, which is surprisingly resistant to changes in gene content. PMID- 22448270 TI - Developmental characterization of the microRNA-specific C. elegans Argonautes alg 1 and alg-2. AB - The genes alg-1 and alg-2 (referred to as "alg-1/2") encode the Argonaute proteins affiliated to the microRNA (miRNA) pathway in C. elegans. Bound to miRNAs they form the effector complex that effects post-transcriptional gene silencing. In order to define biological features important to understand the mode of action of these Argonautes, we characterize aspects of these genes during development. We establish that alg-1/2 display an overlapping spatio-temporal expression profile and shared association to a miRNAs set, but with gene-specific predominant expression in various cells and increased relative association to defined miRNAs. Congruent with their spatio-temporal coincidence and regardless of alg-1/2 drastic post-embryonic differences, only loss of both genes leads to embryonic lethality. Embryos without zygotic alg-1/2 predominantly arrest during the morphogenetic process of elongation with defects in the epidermal-muscle attachment structures. Altogether our results highlight similarities and specificities of the alg-1/2 likely to be explained at different cellular and molecular levels. PMID- 22448271 TI - Assessment of gastroenteric viruses frequency in a children's day care center in Rio De Janeiro, Brazil: a fifteen year study (1994-2008). AB - This 15-year study aimed to determine the role of the main viruses responsible for acute infantile gastroenteritis cases in a day care center in the city of Rio de Janeiro, Brazil. From 1994 to 2008, 539 fecal samples were obtained from 23 outbreaks as well as sporadic cases that occurred in this period. The detection of Rotavirus group A (RVA), norovirus (NoV) and astrovirus (AstV) was investigated both by classical and molecular methods of viral detection. RVA was detected by enzymatic immune assay and/or polyacrylamide gel electrophoresis and genotyped by using semi-nested multiplex PCR. NoV and AstV were subsequently tested by real time PCR in all RVA-negative samples and genotyped throughout genome sequencing. Three protocols for molecular characterization of NoV nucleotide sequencing were performed with the partial nucleotide sequencing of genomic regions known as region B (polymerase gen), C and D (capsid gen).Viruses were identified in 47.7% (257/539) of the cases, and the detection rates of RVA, NoV and AstV in16.1% (87/539), 33.4% (151/452), and 6.3% (19/301), respectively. Most gastroenteritis cases were reported in autumn and winter, although NoV presented a broader monthly distribution. Viruses' detection rates were significantly higher among children aged less than 24 months old, although NoV cases were detected in all age groups. RVA genotypes as G1P[8], G9P[8], G2P[4], G3P[8] and G1+G3P[8] and RVA was no longer detected after 2005. NoV characterization revealed genotypes variability circulating in the period as GI.2, GI.3, GI.8 GII.2, GII.3, GII.4, GII.4 variants 2001 and 2006b, GII.6, GII.7, GII.12 and GII.17. AstV genotypes 1, 2, 4 and 5 were also characterized. Those data demonstrate the impact of NoV infection in cases of infantile gastroenteritis, surpassing RVA infection responsible for high morbidity rate in children under five years old. PMID- 22448272 TI - Genetic diversity of the ORF5 gene of porcine reproductive and respiratory syndrome virus isolates in southwest China from 2007 to 2009. AB - To gain insight into the molecular epidemiology and possible mechanisms of genetic variation of porcine reproductive and respiratory syndrome (PRRS) in Yunnan Province of China, the ORF5 gene of 32 PRRSV isolates from clinical samples collected from 2007 to 2009 were sequenced and analyzed. Nucleotide and amino acid analyses were carried out on 32 isolates and representative strains of the North American genotype, European genotype and two representative Chinese isolates. Results revealed that these isolates share 86.9-99.0% nucleotide and 87.5-98.0% amino acid identity with VR-2332 the prototypical North American PRRSV, 61.7-62.9% and 54.3-57.8% with Lelystad virus (LV) the representative strain of European genotype, 91.2-95.4% and 90.0-94.5% with CH-1a that was isolated in mainland China in 1996, 88.1-99.3% and 85.5-99.0% with JX-A1 the representative strain of High pathogenic PRRSV in China, and 86.2-99.8% and 85.5 100.0% between isolated strains of different years, respectively. Phylogenetic analysis revealed that all 32 PRRSV isolates belonged to the North American genotype and were further divided into two different subgenotypes. Subgenotype 1 comprised twenty two Yunnan isolates which divided into two branches. Subgenotype 2 comprised ten isolates which closely related to the RespPRRS vaccine and its parent strain VR-2332. The functional domains of GP5 such as the signal peptide, ectodomain, transmembrane regions and endodomain were identified and some motifs in GP5 with known functions, such as primary neutralizing epitope (PNE) and decoy epitope were also further analyzed. Our study shown the great genetic diversity of PRRSV in southwest China, rendering the guide for control and prevention of this disease. PMID- 22448273 TI - High-density transcriptional initiation signals underline genomic islands in bacteria. AB - Genomic islands (GIs), frequently associated with the pathogenicity of bacteria and having a substantial influence on bacterial evolution, are groups of "alien" elements which probably undergo special temporal-spatial regulation in the host genome. Are there particular hallmark transcriptional signals for these "exotic" regions? We here explore the potential transcriptional signals that underline the GIs beyond the conventional views on basic sequence composition, such as codon usage and GC property bias. It showed that there is a significant enrichment of the transcription start positions (TSPs) in the GI regions compared to the whole genome of Salmonella enterica and Escherichia coli. There was up to a four-fold increase for the 70% GIs, implying high-density TSPs profile can potentially differentiate the GI regions. Based on this feature, we developed a new sliding window method GIST, Genomic-island Identification by Signals of Transcription, to identify these regions. Subsequently, we compared the known GI-associated features of the GIs detected by GIST and by the existing method Islandviewer to those of the whole genome. Our method demonstrates high sensitivity in detecting GIs harboring genes with biased GI-like function, preferred subcellular localization, skewed GC property, shorter gene length and biased "non-optimal" codon usage. The special transcriptional signals discovered here may contribute to the coordinate expression regulation of foreign genes. Finally, by using GIST, we detected many interesting GIs in the 2011 German E. coli O104:H4 outbreak strain TY-2482, including the microcin H47 system and gene cluster ycgXEFZ-ymgABC that activates the production of biofilm matrix. The aforesaid findings highlight the power of GIST to predict GIs with distinct intrinsic features to the genome. The heterogeneity of cumulative TSPs profiles may not only be a better identity for "alien" regions, but also provide hints to the special evolutionary course and transcriptional regulation of GI regions. PMID- 22448274 TI - High through-put sequencing of the Parhyale hawaiensis mRNAs and microRNAs to aid comparative developmental studies. AB - Understanding the genetic and evolutionary basis of animal morphological diversity will require comparative developmental studies that use new model organisms. This necessitates development of tools for the study of genetics and also the generation of sequence information of the organism to be studied. The development of next generation sequencing technology has enabled quick and cost effective generation of sequence information. Parhyale hawaiensis has emerged as a model organism of choice due to the development of advanced molecular tools, thus P. hawaiensis genetic information will help drive functional studies in this organism.Here we present a transcriptome and miRNA collection generated using next generation sequencing platforms. We generated approximately 1.7 million reads from a P. hawaiensis cDNA library constructed from embryos up to the germ band stage. These reads were assembled into a dataset comprising 163,501 transcripts.Using the combined annotation of Annot8r and pfam2go, Gene Ontology classifications was assigned to 20,597 transcripts. Annot8r was used to provide KEGG orthology to our transcript dataset. A total of 25,292 KEGG pathway assignments were defined and further confirmed with reciprocal blast against the NCBI nr protein database. This has identified many P. hawaiensis gene orthologs of key conserved signalling pathways involved in development. We also generated small RNA sequences from P. hawaiensis, identifying 55 conserved miRNAs. Sequenced small RNAs that were not annotated by stringent comparison to mirBase were used to search the Daphnia pulex for possible novel miRNAs. Using a conservative approach, we have identified 51 possible miRNA candidates conserved in the Daphnia pulex genome, which could be potential crustacean/arthropod specific miRNAs. Our study presents gene and miRNA discovery in a new model organism that does not have a sequenced genome. The data provided by our work will be valuable for the P. hawaiensis community as well as the wider evolutionary developmental biology community. PMID- 22448275 TI - Phosphatidylinositol 3-kinase plays a vital role in regulation of rice seed vigor via altering NADPH oxidase activity. AB - Phosphatidylinositol 3-kinase (PI3K) has been reported to be important in normal plant growth and stress responses. In this study, it was verified that PI3K played a vital role in rice seed germination through regulating NADPH oxidase activity. Suppression of PI3K activity by inhibitors wortmannin or LY294002 could abate the reactive oxygen species (ROS) formation, which resulted in disturbance to the seed germination. And then, the signal cascades that PI3K promoted the ROS liberation was also evaluated. Diphenylene iodonium (DPI), an NADPH oxidase inhibitor, suppressed most of ROS generation in rice seed germination, which suggested that NADPH oxidase was the main source of ROS in this process. Pharmacological experiment and RT-PCR demonstrated that PI3K promoted the expression of Os rboh9. Moreover, functional analysis by native PAGE and the measurement of the 2, 3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazo-lium-5- carboxanilide (XTT) formazan concentration both showed that PI3K promoted the activity of NADPH oxidase. Furthermore, the western blot analysis of OsRac-1 demonstrated that the translocation of Rac-1 from cytoplasm to plasma membrane, which was known as a key factor in the assembly of NADPH oxidase, was suppressed by treatment with PI3K inhibitors, resulting in the decreased activity of NADPH oxidase. Taken together, these data favored the novel conclusion that PI3K regulated NADPH oxidase activity through modulating the recruitment of Rac-1 to plasma membrane and accelerated the process of rice seed germination. PMID- 22448276 TI - Prevalence and associated factors of elder mistreatment in a rural community in People's Republic of China: a cross-sectional study. AB - BACKGROUND: Current knowledge about elder mistreatment is mainly derived from studies done in Western countries, which indicate that this problem is related to risk factors such as a shared living situation, social isolation, disease burden, and caregiver strain. We know little about prevalence and risk factors for elder mistreatment and mistreatment subtypes in rural China where the elder population is the most vulnerable. METHODS: In 2010, we conducted a cross-sectional survey among older adults aged 60 or older in three rural communities in Macheng, a city in Hubei province, China. Of 2245 people initially identified, 2039 were available for interview and this was completed in 2000. A structured questionnaire was used to collect data regarding mistreatment and covariates. Logistic regression analysis was used to identify factors related to elder mistreatment and subtypes of mistreatment. RESULTS: Elder mistreatment was reported by 36.2% (95% CI: 34.1%-38.3%) of the participants. Prevalence rates of psychological mistreatment, caregiver neglect, physical mistreatment, and financial mistreatment were 27.3% (95% CI: 25.3%-29.2%), 15.8% (95% CI: 14.2% 17.4%), 4.9% (95% CI: 3.9%-5.8%) and 2.0% (95% CI: 1.3%-2.6%), respectively. The multivariate logistic regression analysis revealed that depression, being widowed/divorced/single/separated, having a physical disability, having a labor intensive job, depending solely on self-made income, and living alone were risk factors for elder mistreatment. Different types of elder mistreatment were associated with different risk factors, and depression was the consistent risk factor for the three most common mistreatment subtypes. CONCLUSION: Older adults in rural China self-report a higher rate of mistreatment than their counterparts in Western countries. Depression is a main risk factor associated with most subtypes of mistreatment. Our findings suggest that prevention and management of elder mistreatment is a challenge facing a rapidly aging Chinese population. PMID- 22448277 TI - Inhaled NO contributes to lung repair in piglets with acute respiratory distress syndrome via increasing circulating endothelial progenitor cells. AB - BACKGROUND: Nitric oxide (NO) plays an important role in mobilization of endothelial progenitor cells (EPCs). We hypothesized that inhaled NO (iNO) would induce EPC mobilization and therefore promote lung repair in acute respiratory distress syndrome (ARDS). METHODOLOGY/PRINCIPAL FINDINGS: Healthy piglets were randomized into four groups (n = 6): Control (Con; mechanical ventilation only); ARDS (established by oleic acid infusion and mechanical ventilation); ARDS plus granulocyte-colony stimulating factor (G-CSF; 10 ug/kg/d subcutaneously); ARDS plus NO inhalation (iNO; 10 ppm). EPCs and mobilizing cytokines were assayed at different time points (baseline, 0, 24, 72 and 168 h) and injury reparation was assessed at 168 h. Compared to the Con group, the levels of EPCs were increased in bone marrow but not in blood in the ARDS group at 24 h. Compared to the ARDS group, inhaled NO induced a rapid elevation in the number of CD34(+)KDR(+), KDR(+)CD133(+) and CD34(+)KDR(+)CD133(+) EPCs in blood (2163+/-454 vs. 1094+/ 416, 1302+/-413 vs. 429+/-244, 1140+/-494 vs. 453+/-273 cells/ml, respectively, P<0.05), and a reduction in the percentage of KDR(+)CD133(+) cells in bone marrow. Lung CD34, CD133, VEGF, VEGF receptor 2, endothelial NO synthase mRNA, and VEGF and VEGF receptor 2 protein expression levels were augmented in the iNO group, but not in the G-CSF group, compared to ARDS. Furthermore, iNO treatment reduced vascular permeability, increased pulmonary vessel density, and alleviated pulmonary edema and inflammation compared to ARDS treatment. Plasma VEGF, stromal cell-derived factor-1 (SDF-1) and bone marrow NO(2)(-)/NO(3)(-) were significantly higher in the iNO group compared to the ARDS group at 72 h. CONCLUSIONS: These results suggest that iNO induces mobilization of EPCs from bone marrow into circulation, contributes to vascular repair, and thereby alleviates lung damage. PMID- 22448278 TI - Understanding communication signals during mycobacterial latency through predicted genome-wide protein interactions and boolean modeling. AB - About 90% of the people infected with Mycobacterium tuberculosis carry latent bacteria that are believed to get activated upon immune suppression. One of the fundamental challenges in the control of tuberculosis is therefore to understand molecular mechanisms involved in the onset of latency and/or reactivation. We have attempted to address this problem at the systems level by a combination of predicted functional protein:protein interactions, integration of functional interactions with large scale gene expression studies, predicted transcription regulatory network and finally simulations with a boolean model of the network. Initially a prediction for genome-wide protein functional linkages was obtained based on genome-context methods using a Support Vector Machine. This set of protein functional linkages along with gene expression data of the available models of latency was employed to identify proteins involved in mediating switch signals during dormancy. We show that genes that are up and down regulated during dormancy are not only coordinately regulated under dormancy-like conditions but also under a variety of other experimental conditions. Their synchronized regulation indicates that they form a tightly regulated gene cluster and might form a latency-regulon. Conservation of these genes across bacterial species suggests a unique evolutionary history that might be associated with M. tuberculosis dormancy. Finally, simulations with a boolean model based on the regulatory network with logical relationships derived from gene expression data reveals a bistable switch suggesting alternating latent and actively growing states. Our analysis based on the interaction network therefore reveals a potential model of M. tuberculosis latency. PMID- 22448279 TI - Clinically isolated syndromes suggestive of multiple sclerosis: an optical coherence tomography study. AB - BACKGROUND: Optical coherence tomography (OCT) is a simple, high-resolution technique to quantify the thickness of retinal nerve fiber layer (RNFL), which provides an indirect measurement of axonal damage in multiple sclerosis (MS). This study aimed to evaluate RNFL thickness in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. METHODOLOGY: This was a cross-sectional study. Twenty-four patients with CIS suggestive of MS (8 optic neuritis [ON], 6 spinal cord syndromes, 5 brainstem symptoms and 5 with sensory and other syndromes) were prospectively studied. The main outcome evaluated was RNFL thickness at CIS onset. Secondary objectives were to study the relationship between RNFL thickness and MRI criteria for disease dissemination in space (DIS) as well as the presence of oligoclonal bands in the cerebrospinal fluid. PRINCIPAL FINDINGS: Thirteen patients had decreased RNFL thickness in at least one quadrant. Mean RNFL thickness was 101.67+/-10.72 um in retrobulbar ON eyes and 96.93+/-10.54 in unaffected eyes. Three of the 6 patients with myelitis had at least one abnormal quadrant in one of the two eyes. Eight CIS patients fulfilled DIS MRI criteria. The presence of at least one quadrant of an optic nerve with a RNFL thickness at a P<5% cut-off value had a sensitivity of 75% and a specificity of 56% for predicting DIS MRI. CONCLUSIONS: The findings from this study show that axonal damage measured by OCT is present in any type of CIS; even in myelitis forms, not only in ON as seen up to now. OCT can detect axonal damage in very early stages of disease and seems to have high sensitivity and moderate specificity for predicting DIS MRI. Studies with prospective long-term follow-up would be needed to establish the prognostic value of baseline OCT findings. PMID- 22448280 TI - Adjuvant effect of killed Propionibacterium acnes on mouse peritoneal B-1 lymphocytes and their early phagocyte differentiation. AB - B-1 lymphocytes are the predominant cells in mouse peritoneal cavity. They express macrophage and lymphocyte markers and are divided into B-1a, B-1b and B 1c subtypes. The role of B-1 cells is not completely clear, but they are responsible for natural IgM production and seem to play a regulatory role. An enriched B-1b cell population can be obtained from non-adherent peritoneal cell cultures, and we have previously demonstrated that these cells undergo differentiation to acquire a mononuclear phagocyte phenotype upon attachment to the substrate in vitro. Nevertheless, the B-1 cell response to antigens or adjuvants has been poorly investigated. Because killed Propionibacterium acnes exhibits immunomodulatory effects on both macrophages and B-2 lymphocytes, we analyzed whether a killed bacterial suspension or its soluble polysaccharide (PS) could modulate the absolute number of peritoneal B-1 cells in BALB/c mice, the activation status of these cells and their ability to differentiate into phagocytes in vitro. In vivo, P. acnes treatment elevated the absolute number of all B-1 subsets, whereas PS only increased B-1c. Moreover, the bacterium increased the number of B-1b cells that were positive for MHC II, TLR2, TLR4, TLR9, IL-4, IL-5 and IL-12, in addition to up-regulating TLR9, CD80 and CD86 expression. PS increased B-1b cell expression of TLR4, TLR9, CD40 and CD86, as well as IL-10 and IL-12 synthesis. Both of the treatments decreased the absolute number of B-1b cells in vitro, suggesting their early differentiation into B-1 cell-derived phagocytes (B-1CDP). We also observed a higher phagocytic activity from the phagocytes that were derived from B-1b cells after P. acnes and PS treatment. The adjuvant effect that P. acnes has on B-1 cells, mainly the B-1b subtype, reinforces the importance of B-1 cells in the innate and adaptive immune responses. PMID- 22448281 TI - Volume navigation with contrast enhanced ultrasound and image fusion for percutaneous interventions: first results. AB - OBJECTIVE: Assessing the feasibility and efficiency of interventions using ultrasound (US) volume navigation (V Nav) with real time needle tracking and image fusion with contrast enhanced (ce) CT, MRI or US. METHODS: First an in vitro study on a liver phantom with CT data image fusion was performed, involving the puncture of a 10 mm lesion in a depth of 5 cm performed by 15 examiners with US guided freehand technique vs. V Nav for the purpose of time optimization. Then 23 patients underwent ultrasound-navigated biopsies or interventions using V Nav image fusion of live ultrasound with ceCT, ceMRI or CEUS, which were acquired before the intervention. A CEUS data set was acquired in all patients. Image fusion was established for CEUS and CT or CEUS and MRI using anatomical landmarks in the area of the targeted lesion. The definition of a virtual biopsy line with navigational axes targeting the lesion was achieved by the usage of sterile trocar with a magnetic sensor embedded in its distal tip employing a dedicated navigation software for real time needle tracking. RESULTS: The in vitro study showed significantly less time needed for the simulated interventions in all examiners when V Nav was used (p<0.05). In the study involving patients, in all 10 biopsies of suspect lesions of the liver a histological confirmation was achieved. We also used V Nav for a breast biopsy (intraductal carcinoma), for a biopsy of the abdominal wall (metastasis of ovarial carcinoma) and for radiofrequency ablations (4 ablations). In 8 cases of inflammatory abdominal lesions 9 percutaneous drainages were successfully inserted. CONCLUSION: Percutaneous biopsies and drainages, even of small lesions involving complex access pathways, can be accomplished with a high success rate by using 3D real time image fusion together with real time needle tracking. PMID- 22448282 TI - Cannabinoid receptor 2-mediated attenuation of CXCR4-tropic HIV infection in primary CD4+ T cells. AB - Agents that activate cannabinoid receptor pathways have been tested as treatments for cachexia, nausea or neuropathic pain in HIV-1/AIDS patients. The cannabinoid receptors (CB(1)R and CB(2)R) and the HIV-1 co-receptors, CCR5 and CXCR4, all signal via Galphai-coupled pathways. We hypothesized that drugs targeting cannabinoid receptors modulate chemokine co-receptor function and regulate HIV-1 infectivity. We found that agonism of CB(2)R, but not CB(1)R, reduced infection in primary CD4+ T cells following cell-free and cell-to-cell transmission of CXCR4-tropic virus. As this change in viral permissiveness was most pronounced in unstimulated T cells, we investigated the effect of CB(2)R agonism on to CXCR4 induced signaling following binding of chemokine or virus to the co-receptor. We found that CB(2)R agonism decreased CXCR4-activation mediated G-protein activity and MAPK phosphorylation. Furthermore, CB(2)R agonism altered the cytoskeletal architecture of resting CD4+ T cells by decreasing F-actin levels. Our findings suggest that CB(2)R activation in CD4+ T cells can inhibit actin reorganization and impair productive infection following cell-free or cell-associated viral acquisition of CXCR4-tropic HIV-1 in resting cells. Therefore, the clinical use of CB(2)R agonists in the treatment of AIDS symptoms may also exert beneficial adjunctive antiviral effects against CXCR4-tropic viruses in late stages of HIV-1 infection. PMID- 22448283 TI - Genotyping performance between saliva and blood-derived genomic DNAs on the DMET array: a comparison. AB - The Affymetrix Drug Metabolism Enzymes and Transporters (DMET) microarray is the first assay to offer a large representation of SNPs conferring genetic diversity across known pharmacokinetic markers. As a convenient and painless alternative to blood, saliva samples have been reported to work well for genotyping on the high density SNP arrays, but no reports to date have examined this application for saliva-derived DNA on the DMET platform. Genomic DNA extractions from saliva samples produced an ample quantity of genomic DNA for DMET arrays, however when human amplifiable DNA was measured, it was determined that a large percentage of this DNA was from bacteria or fungi. A mean of 37.3% human amplifiable DNA was determined for saliva-derived DNAs, which results in a significant decrease in the genotyping call rate (88.8%) when compared with blood-derived DNAs (99.1%). More interestingly, the percentage of human amplifiable DNA correlated with a higher genotyping call rate, and almost all samples with more than 31.3% human DNA produced a genotyping call rate of at least 96%. SNP genotyping results for saliva derived DNA (n = 39) illustrated a 98.7% concordance when compared with blood DNA. In conclusion, when compared with blood DNA and tested on the DMET array, saliva-derived DNA provided adequate genotyping quality with a significant lower number of SNP calls. Saliva-derived DNA does perform very well if it contains greater than 31.3% human amplifiable DNA. PMID- 22448284 TI - Foxp3+ regulatory T cells control persistence of viral CNS infection. AB - We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+) CD25(+) Foxp3(+) Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+) T cells predominantly recognising the H-2D(b)-presented viral hemagglutinin epitope MV-H(22-30) (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8(+) effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS. PMID- 22448285 TI - Expression of PRB, FKBP52 and HB-EGF relating with ultrasonic evaluation of endometrial receptivity. AB - BACKGROUND: To explore the molecular basis of the different ultrasonic patterns of the human endometrium, and the molecular marker basis of local injury. METHODOLOGY/PRINCIPAL FINDINGS: The mRNA and protein expression of FKBP52, progesterone receptor A (PRA), progesterone receptor B (PRB), and HB-EGF were detected in different patterns of the endometrium by real-time RTPCR and immunohistochemistry. There were differences in the mRNA and protein expression of FKBP52, PRB, and HB-EGF in the triple line (Pattern A) and homogeneous (Pattern C) endometrium in the window of implantation. No difference was detected in PRA expression. After local injury, the mRNA expression of HB-EGF significantly increased. In contrast, there was no difference in the mRNA expression of FKBP52, PRB, or PRA. The protein expression of FKBP52, PRB, and HB EGF increased after local injury. There was no difference in the PRA expression after local injury. CONCLUSIONS: PRB, FKBP52, and HB-EGF may be the molecular basis for the classification of the ultrasonic patterns. HB-EGF may be the molecular basis of local injury. Ultrasonic evaluation on the day of ovulation can be effective in predicting the outcome of implantation. PMID- 22448286 TI - Phylogeography and demographic history of Babina pleuraden (Anura, Ranidae) in southwestern China. AB - Factors that determine genetic structure of species in southwestern China remain largely unknown. In this study, sequences of two mitochondrial genes (COI and cyt b) were determined to investigate the phylogeography and demography of Babina pleuraden, a pond frog endemic to southwestern China. A total of 262 individuals from 22 populations across the entire range of the species were collected. Our results indicate that B. pleuraden comprises five well-supported mitochondrial lineages roughly corresponding to five geographical areas. The phylogeographic structure of B. pleuraden has been shaped primarily by the unique regional responses of the Yunnan Plateau to the rapid uplift of the Qinghai-Tibetan Plateau occurred c. 2.5 Mya (B phrase of Qingzang Movement) and climatic oscillation during middle Pleistocene (c. 0.64-0.36 Mya), rather than by the paleo-drainage systems. The present wide distribution of the species has resulted from recent population expansion (c. 0.053-0.025 Mya) from multiple refugia prior to the Last Glacial Maximum, corresponding to the scenario of "refugia within refugia". PMID- 22448287 TI - Different host exploitation strategies in two zebra mussel-trematode systems: adjustments of host life history traits. AB - The zebra mussel is the intermediate host for two digenean trematodes, Phyllodistomum folium and Bucephalus polymorphus, infecting gills and the gonad respectively. Many gray areas exist relating to the host physiological disturbances associated with these infections, and the strategies used by these parasites to exploit their host without killing it. The aim of this study was to examine the host exploitation strategies of these trematodes and the associated host physiological disturbances. We hypothesized that these two parasite species, by infecting two different organs (gills or gonads), do not induce the same physiological changes. Four cellular responses (lysosomal and peroxisomal defence systems, lipidic peroxidation and lipidic reserves) in the host digestive gland were studied by histochemistry and stereology, as well as the energetic reserves available in gonads. Moreover, two indices were calculated related to the reproductive status and the physiological condition of the organisms. Both parasites induced adjustments of zebra mussel life history traits. The host exploitation strategy adopted by P. folium would occur during a short-term period due to gill deformation, and could be defined as "virulent." Moreover, this parasite had significant host gender-dependent effects: infected males displayed a slowed-down metabolism and energetic reserves more allocated to growth, whereas females displayed better defences and would allocate more energy to reproduction and maintenance. In contrast, B. polymorphus would be a more "prudent" parasite, exploiting its host during a long-term period through the consumption of reserves allocated to reproduction. PMID- 22448288 TI - Manipulation of life-history decisions using leptin in a wild passerine. AB - Seasonal timing of reproduction and the number of clutches produced per season are two key avian life-history traits with major fitness consequences. Female condition may play an important role in these decisions. In mammals, body condition and leptin levels are correlated. In birds, the role of leptin remains unclear. We did two experiments where we implanted female great tits with a pellet releasing leptin evenly for 14 days, to manipulate their perceived body condition, or a placebo pellet. In the first experiment where females were implanted when feeding their first brood offspring we found, surprisingly, that placebo treated females were more likely to initiate a second brood compared to leptin treated females. Only one second brood fledged two chicks while five were deserted late in the incubation stage or when the first egg hatched. No difference was found in female or male return rate or in recruitment rate of fledglings of the first brood, possibly due to the desertion of the second broods. In our study population, where there is selection for early egg laying, earlier timing of reproduction might be hampered by food availability and thus nutritional state of the female before egg laying. We therefore implanted similar leptin pellets three weeks before the expected start of egg laying in an attempt to manipulate the laying dates of first clutches. However, leptin treated females did not initiate egg laying earlier compared to placebo treated females, suggesting that other variables than the perceived body condition play a major role in the timing of reproduction. Also, leptin treatment did not affect body mass, basal metabolic rate or feeding rates in captive females. Manipulating life history decisions using experimental protocols which do not alter individuals' energy balance are crucial in understanding the trade-off between costs and benefits of life history decisions. PMID- 22448289 TI - Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner. AB - BACKGROUND: During mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling. METHODOLOGY/PRINCIPAL FINDINGS: We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAG(CreER+); Rosa26 NICD(loxp/+) mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICD-negative). CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additional pathways that could synergistically interact with Notch1 pathway to produce HCs at postnatal ages. PMID- 22448290 TI - Prophylactic application of CpG oligonucleotides augments the early host response and confers protection in acute melioidosis. AB - Prophylactic administration of CpG oligodeoxynucleotides (CpG ODNs) is known to confer protection against lethal sepsis caused by Burkholderia pseudomallei in the mouse model. The mechanisms whereby CpG regulates the innate immune response to provide protection against B. pseudomallei, however, are poorly characterized. In the present study, we demonstrate that intranasal treatment of mice with Class C CpG, results in recruitment of inflammatory monocytes and neutrophils to the lung at 48 h post-treatment. Mice infected with B. pseudomallei 48 h post-CpG treatment had reduced organ bacterial load and significantly altered cytokine and chemokine profiles concomitant with protection as compared to control animals. CpG administration reduced the robust production of chemokines and pro inflammatory cytokines in blood, lung and spleen, observed following infection of non-treated animals. Death of control animals coincided with the time of peak cytokine production (day 1-3), while a moderate; sustained cytokine production in CpG-treated animals was associated with survival. In general, CpG treatment resulted in diminished expression of cytokines and chemokines post-infection, though IL-12p40 was released in larger quantities in CpG treated animals. In contrast to CpG-treated animals, the lungs of infected control animals were infiltrated with leukocytes, especially neutrophils, and large numbers of necrotic lesions were observed in lung sections. Therapeutic treatment of B. pseudomallei-infected animals with CpG at 24 h post-infection did not impact survival compared to control animals. In summary, protection of CpG-treated animals was associated with recruitment of inflammatory monocytes and neutrophils into the lungs prior to infection. These responses correspond with early control of bacterial growth, a dampened inflammatory cytokine/chemokine response, reduced lung pathology, and greatly increased survival. In contrast, a delay in recruitment of inflammatory cell populations, despite a robust production of pro inflammatory cytokines, was associated with poorly controlled bacterial growth, severe lung pathology, and death of control animals. PMID- 22448291 TI - Recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in nonhuman primates. AB - The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses an individual filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). The main concern with all replication competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV) GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV) GP; three animals received rVSV-wild type (wt) vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use. PMID- 22448292 TI - Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans. AB - The four serotypes of dengue virus (DENV) cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Severe disease has been associated with heterotypic secondary DENV infection, mediated by cross-reactive antibodies (Abs) and/or cross-reactive T cells. The role of cross-reactive immunity in mediating enhanced disease versus cross-protection against secondary heterotypic DENV infection is not well defined. A better understanding of the cross-reactive immune response in natural infections is critical for development of safe and effective tetravalent vaccines. We studied the B cell phenotype of circulating B cells in the blood of pediatric patients suspected of dengue during the 2010-2011 dengue season in Managua, Nicaragua (n = 216), which was dominated by the DENV-3 serotype. We found a markedly larger percentage of plasmablast/plasma cells (PB/PCs) circulating in DENV-positive patients as compared to patients with Other Febrile Illnesses (OFIs). The percentage of DENV specific PB/PCs against DENV-3 represented 10% of the circulating antibody producing cells (ASCs) in secondary DENV-3 infections. Importantly, the cross reactive DENV-specific B cell response was higher against a heterotypic serotype, with 46% of circulating PB/PCs specific to DENV-2 and 10% specific to DENV-3 during acute infection. We also observed a higher cross-reactive DENV-specific IgG serum avidity directed against DENV-2 as compared to DENV-3 during acute infection. The neutralization capacity of the serum was broadly cross-reactive against the four DENV serotypes both during the acute phase and at 3 months post onset of symptoms. Overall, the cross-reactive B cell immune response dominates during secondary DENV infections in humans. These results reflect our recent findings in a mouse model of DENV cross-protection. In addition, this study enabled the development of increased technical and research capacity of Nicaraguan scientists and the implementation of several new immunological assays in the field. PMID- 22448293 TI - Glycotope sharing between snail hemolymph and larval schistosomes: larval transformation products alter shared glycan patterns of plasma proteins. AB - Recent evidence supports the involvement of inducible, highly diverse lectin-like recognition molecules in snail hemocyte-mediated responses to larval Schistosoma mansoni. Because host lectins likely are involved in initial parasite recognition, we sought to identify specific carbohydrate structures (glycans) shared between larval S. mansoni and its host Biomphalaria glabrata to address possible mechanisms of immune avoidance through mimicry of elements associated with the host immunoreactivity. A panel of monoclonal antibodies (mABs) to specific S. mansoni glycans was used to identify the distribution and abundance of shared glycan epitopes (glycotopes) on plasma glycoproteins from B. glabrata strains that differ in their susceptibilities to infection by S. mansoni. In addition, a major aim of this study was to determine if larval transformation products (LTPs) could bind to plasma proteins, and thereby alter the glycotopes exposed on plasma proteins in a snail strain-specific fashion. Plasma fractions (< 100 kDa/> 100 kDa) from susceptible (NMRI) and resistant (BS-90) snail strains were subjected to SDS-PAGE and immunoblot analyses using mAB to LacdiNAc (LDN), fucosylated LDN variants, Lewis X and trimannosyl core glycans. Results confirmed a high degree of glycan sharing, with NMRI plasma exhibiting a greater distribution/abundance of LDN, F-LDN and F-LDN-F than BS-90 plasma (< 100 kDa fraction). Pretreatment of blotted proteins with LTPs significantly altered the reactivity of specific mABs to shared glycotopes on blots, mainly through the binding of LTPs to plasma proteins resulting in either glycotope blocking or increased glycotope attachment to plasma. Many LTP-mediated changes in shared glycans were snail-strain specific, especially those in the < 100 kDa fraction for NMRI plasma proteins, and for BS-90, mainly those in the > 100 kDa fraction. Our data suggest that differential binding of S. mansoni LTPs to plasma proteins of susceptible and resistant B. glabrata strains may significantly impact early anti-larval immune reactivity, and in turn, compatibility, in this parasite-host system. PMID- 22448294 TI - Implementing preventive chemotherapy through an integrated National Neglected Tropical Disease Control Program in Mali. AB - BACKGROUND: Mali is endemic for all five targeted major neglected tropical diseases (NTDs). As one of the five 'fast-track' countries supported with the United States Agency for International Development (USAID) funds, Mali started to integrate the activities of existing disease-specific national control programs on these diseases in 2007. The ultimate objectives are to eliminate lymphatic filariasis, onchocerciasis and trachoma as public health problems and to reduce morbidity caused by schistosomiasis and soil-transmitted helminthiasis through regular treatment to eligible populations, and the specific objectives were to achieve 80% program coverage and 100% geographical coverage yearly. The paper reports on the implementation of the integrated mass drug administration and the lessons learned. METHODOLOGY/PRINCIPAL FINDINGS: The integrated control program was led by the Ministry of Health and coordinated by the national NTD Control Program. The drug packages were designed according to the disease endemicity in each district and delivered through various platforms to eligible populations involving the primary health care system. Treatment data were recorded and reported by the community drug distributors. After a pilot implementation of integrated drug delivery in three regions in 2007, the treatment for all five targeted NTDs was steadily scaled up to 100% geographical coverage by 2009, and program coverage has since been maintained at a high level: over 85% for lymphatic filariasis, over 90% for onchocerciasis and soil-transmitted helminthiasis, around 90% in school-age children for schistosomiasis, and 76-97% for trachoma. Around 10 million people have received one or more drug packages each year since 2009. No severe cases of adverse effects were reported. CONCLUSIONS/SIGNIFICANCE: Mali has scaled up the drug treatment to national coverage through integrated drug delivery involving the primary health care system. The successes and lessons learned in Mali can be valuable assets to other countries starting up their own integrated national NTD control programs. PMID- 22448295 TI - Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection. AB - Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice or guinea pigs were given MAbs i.p. in various doses individually or as pools of 3-4 MAbs to test their protection against a lethal challenge with mouse- or guinea pig-adapted EBOV. Each of the 8 MAbs (100 ug) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven MAbs were effective 2 days post-infection (dpi), with 1 MAb demonstrating partial protection 3 dpi. In the guinea pigs each MAb showed partial protection at 1 dpi, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 MAbs completely protected the majority of animals, while administration at 2-3 dpi achieved 50-100% protection. This data suggests that the MAbs generated are capable of protecting both animal species against lethal Ebola virus challenge. These results indicate that MAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection. PMID- 22448296 TI - Azithromycin mass treatment for trachoma control: risk factors for non participation of children in two treatment rounds. AB - BACKGROUND: Persistent non-participation of children in mass drug administration (MDAs) for trachoma may reduce program impact. Risk factors that identify families where participation is a problem or program characteristics that foster non-participation are poorly understood. We examined risk factors for households with at least one child who did not participate in two MDAs compared to households where all children participated in both MDAs. METHODS/PRINCIPAL FINDINGS: We conducted a case control study in 28 Tanzanian communities. Cases included all 152 households with at least one child who did not participate in the 2008 and 2009 MDAs with azithromycin. Controls consisted of a random sample of 460 households where all children participated in both MDAs. A questionnaire was asked of all families. Random-intercept logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), control for clustering, and adjust for community size. In total, 140 case households and 452 control households were included in the analyses. Compared to controls, guardians in case households had higher odds of reporting excellent health (OR 4.12 (CI 95% 1.57-10.86)), reporting a burden due to family health (OR 3.15 (95% CI 1.35 7.35)), reduced ability to rely on others for assistance (OR 1.66 (95% CI 1.01 2.75)), being in a two (versus five) days distribution program (OR 3.31 (95% CI 1.68-6.50)) and living in a community with < 2 community treatment assistants (CTAs)/1000 residents (OR 2.07 (95% CI 1.04-4.12). Furthermore, case households were more likely to have more children, younger guardians, unfamiliarity with CTAs, and CTAs with more travel time to their assigned households (p-values < 0.05). CONCLUSIONS/SIGNIFICANCE: Compared to full participation households, households with persistent non-participation had a higher burden of familial responsibility and seemed less connected in the community. Additional distribution days and lessening CTAs' travel time to their furthest assigned households may prevent non-participation. PMID- 22448297 TI - Analysing spatio-temporal clustering of meningococcal meningitis outbreaks in Niger reveals opportunities for improved disease control. AB - BACKGROUND: Meningococcal meningitis is a major health problem in the "African Meningitis Belt" where recurrent epidemics occur during the hot, dry season. In Niger, a central country belonging to the Meningitis Belt, reported meningitis cases varied between 1,000 and 13,000 from 2003 to 2009, with a case-fatality rate of 5-15%. METHODOLOGY/PRINCIPAL FINDINGS: In order to gain insight in the epidemiology of meningococcal meningitis in Niger and to improve control strategies, the emergence of the epidemics and their diffusion patterns at a fine spatial scale have been investigated. A statistical analysis of the spatio temporal distribution of confirmed meningococcal meningitis cases was performed between 2002 and 2009, based on health centre catchment areas (HCCAs) as spatial units. Anselin's local Moran's I test for spatial autocorrelation and Kulldorff's spatial scan statistic were used to identify spatial and spatio-temporal clusters of cases. Spatial clusters were detected every year and most frequently occurred within nine southern districts. Clusters most often encompassed few HCCAs within a district, without expanding to the entire district. Besides, strong intra district heterogeneity and inter-annual variability in the spatio-temporal epidemic patterns were observed. To further investigate the benefit of using a finer spatial scale for surveillance and disease control, we compared timeliness of epidemic detection at the HCCA level versus district level and showed that a decision based on threshold estimated at the HCCA level may lead to earlier detection of outbreaks. CONCLUSIONS/SIGNIFICANCE: Our findings provide an evidence-based approach to improve control of meningitis in sub-Saharan Africa. First, they can assist public health authorities in Niger to better adjust allocation of resources (antibiotics, rapid diagnostic tests and medical staff). Then, this spatio-temporal analysis showed that surveillance at a finer spatial scale (HCCA) would be more efficient for public health response: outbreaks would be detected earlier and reactive vaccination would be better targeted. PMID- 22448298 TI - Protective human leucocyte antigen haplotype, HLA-DRB1*01-B*14, against chronic Chagas disease in Bolivia. AB - BACKGROUND: Chagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8-10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA) regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms. METHODOLOGY: Two hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG), and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region) mainly through Sequence based and LABType SSO typing test using LUMINEX Technology. PRINCIPAL FINDINGS: The frequencies of HLA-DRB1*01 and HLA B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD), and the HLA-DRB1*01-B*14-MICA*011 haplotype was associated with resistance against chronic Chagas disease. CONCLUSIONS: This is the first report of HLA haplotype association with resistance to chronic Chagas disease. PMID- 22448299 TI - Processing of Body Odor Signals by the Human Brain. AB - Brain development in mammals has been proposed to be promoted by successful adaptations to the social complexity as well as to the social and non-social chemical environment. Therefore, the communication via chemosensory signals might have been and might still be a phylogenetically ancient communication channel transmitting evolutionary significant information. In humans, the neuronal underpinnings of the processing of social chemosignals have been investigated in relation to kin recognition, mate choice, the reproductive state and emotional contagion. These studies reveal that human chemosignals are probably not processed within olfactory brain areas but through neuronal relays responsible for the processing of social information. It is concluded that the processing of human social chemosignals resembles the processing of social signals originating from other modalities, except that human social chemosignals are usually communicated without the allocation of attentional resources, that is below the threshold of consciousness. Deviances in the processing of human social chemosignals might be related to the development and maintenance of mental disorders. PMID- 22448300 TI - The inhibitory effect of cerulenin to yeasts is fungicidal. AB - Fatty acid biosynthesis plays a significant role in the growth and survival of diverse organisms. In yeasts, the de novo fatty acid synthesis (FAS) pathway produces and regulates essential fatty acid species such as saturated (SFA) and unsaturated (UFA) fatty acids that are required for generation and maintenance of cell membranes. Inhibition of enzymes in this pathway, such as fatty acid synthase and fatty acid desaturase, impede yeast cell growth unless appropriate exogenous fatty acids are provided.(1,2 )Although, the fatty acid biosynthesis pathway is essential to yeast cells, exploration of this pathway for combating fungal infections has been largely neglected. We and others have shown that deletion of a fatty acid synthase dramatically attenuates the virulence of the yeast Candida parapsilosis 2 and Candida albicans.(1) Significantly, our data has revealed that inhibition of FAS enzymes results in the hypersensitivity of the yeast to serum, indicating that targeting this pathway is potentially an ideal way to combat systemic yeast infections.(2) We demonstrated that using the minimal inhibitory concentration of cerulenin, a fatty acid synthase inhibitor, we could kill the wild type yeast cells in serum.(2) Thus, the inhibitory effect of cerulenin (ie. blockade of the FAS pathway) on the yeast cells is fungicidal. PMID- 22448301 TI - Internet addiction: Neuroimaging findings. AB - The Internet has so radically changed the way we conduct our lives for a long time. However, maladaptive use of the internet has resulted in impairment of the individual's psychological well-being, academic failure and reduced work performance. While not yet officially codified within a psychopathological framework, Internet addiction disorder (IAD) is growing both in prevalence and within the public consciousness as a potentially problematic condition with many parallels to existing recognized disorders. Neuroimaging is a noninvasive way to reveal altered regional cerebral activity and structural changes. As there has been a recent rise in IAD, here, we review some of the neuroimaging IAD studies and discuss these findings. PMID- 22448302 TI - A new theoretical approach to the functional meaning of sleep and dreaming in humans based on the maintenance of 'predictive psychic homeostasis'. AB - Different theories have been put forward during the last decade to explain the functional meaning of sleep and dreaming in humans. In the present paper, a new theory is presented which, while taking advantage of these earlier theories, introduces the following new and original aspects: * Circadian rhythms relevant to various organs of the body affect the reciprocal interactions which operate to maintain constancy of the internal milieu and thereby also affect the sleep/wakefulness cycle. Particular attention is given to the constancy of natraemia and osmolarity and to the permissive role that the evolution of renal function has had for the evolution of the central nervous system and its integrative actions. * The resetting of neuro-endocrine controls at the onset of wakefulness leads to the acquisition of new information and its integration within previously stored memories. This point is dealt with in relation to Moore Ede's proposal for the existence of a 'predictive homeostasis'. * The concept of 'psychic homeostasis' is introduced and is considered as one of the most important states since it is aimed at the well-being, or eudemonia, of the human psyche. Sleep and dreaming in humans are discussed as important functions for the maintenance of a newly proposed composite state: that of 'predictive psychic homeostasis'. On the basis of these assumptions, and in accordance with the available neurobiological data, the present paper puts forward the novel hypothesis that sleep and dreaming play important functions in humans by compensating for psychic allostatic overloads. Hence, both consolatory dreams and disturbing nightmares can be part of the vis medicatrix naturae, the natural healing power, in this case, the state of eudemonia. PMID- 22448303 TI - Interactive brains, social minds. AB - To reveal the neural and behavioral dynamics of social interaction, single-person studies are increasingly complemented by research designs that simultaneously assess two or more interacting individuals. In this article, we review studies on neural mechanisms and markers of social interactions that use multi-person functional magnetic resonance imaging and electrophysiological recordings. We propose a terminology for investigating social interaction dynamics, show how forward models of action regulation may serve as a framework for investigating interpersonal action coordination and discuss different methodological approaches to studying functional brain connectivity. PMID- 22448304 TI - Multiple Tyrosine Residues Contribute to GABA Binding in the GABA(C) Receptor Binding Pocket. AB - The ligand binding site of Cys-loop receptors is dominated by aromatic amino acids. In GABA(C) receptors, these are predominantly tyrosine residues, with a number of other aromatic residues located in or close to the binding pocket. Here we examine the roles of these residues using substitution with both natural and unnatural amino acids followed by functional characterization. Tyr198 (loop B) has previously been shown to form a cation-pi interaction with GABA; the current data indicate that none of the other aromatic residues form such an interaction, although the data indicate that both Tyr102 and Phe138 may contribute to stabilization of the positively charged amine of GABA. Tyr247 (loop C) was very sensitive to substitution and, combined with data from a model of the receptor, suggest a pi-pi interaction with Tyr241 (loop C); here again functional data show aromaticity is important. In addition the hydroxyl group of Tyr241 is important, supporting the presence of a hydrogen bond with Arg104 suggested by the model. At position Tyr102 (loop D) size and aromaticity are important; this residue may play a role in receptor gating and/or ligand binding. The data also suggest that Tyr167, Tyr200, and Tyr208 have a structural role while Tyr106, Trp246, and Tyr251 are not critical. Comparison of the agonist binding site "aromatic box" across the superfamily of Cys-loop receptors reveals some interesting parallels and divergences. PMID- 22448305 TI - Agonist-antagonist combinations in opioid dependence: a translational approach. AB - The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID- 22448306 TI - Preventing sport injuries: improving performance. PMID- 22448307 TI - What are the next steps in designing an orthosis for paraplegic subjects? AB - BACKGROUND: Over the years, various types of orthoses have been designed to assist subjects with spinal cord injury (SCI) to stand and walk. However, the functional performance of the orthoses has not been adequate, that is, patients experience stability problems, consume excessive energy during ambulation, and generally require assistance in donning and doffing the devices. This research is aimed at categorizing the available orthoses designed specifically for SCI patients and to compare the available orthoses according to the energy consumption, stability analysis, and gait parameters. METHODS: An electronic search was done in PubMed, Embase, and ISI Web of Knowledge databases to extract data related to 1960 - 2010. The available orthoses were characterized based on the level of stabilization they provided and the source of power used. The orthoses were compared based on the stability, energy consumption, and gait performance parameters, according to the results of various studies collected from the literature review. RESULTS: Among various orthoses designed for paraplegic subjects, the mechanical orthoses seemed to have a better performance. Moreover, donning and doffing of the mechanical orthosis was easier for the subjects. CONCLUSION: Although the HGO has better functional performance than other available orthoses, the subjects are more willing to use the RGO. The new design of orthoses must allow easy donning and doffing by the users, have enough stability during walking and standing, and enable the patients to change the alignment of the orthosis to suit their needs. PMID- 22448308 TI - LDL Particle Size and Reactive Oxygen Metabolites in Dyslipidemic Patients. AB - OBJECTIVES: Small dense low-density lipoprotein (sdLDL) which has a small LDL particle size with greater susceptibility to oxidation is regarded as a risk marker for cardiovascular disease. The diacron reactive oxygen metabolites (d ROMs) test has recently been introduced as an oxidative stress-related marker in the clinic. The aim of the present study was to investigate the correlation between the mean LDL particle size and the oxidative stress status as evaluated by the d-ROMs in dyslipidemic patients. METHODS: The study included 278 dyslipidemic patients (121 male and 157 female, mean age, 60 years). Clinical data including the conventional atherosclerotic risk factors in addition to the mean LDL particle size measured with the gel electrophoresis and the d-ROMs were collected. RESULTS: Male patients had a significantly smaller mean LDL particle size than females (262.2 +/- 7.5 [SD] vs. 264.3 +/- 6.7 A, P<0.05), while female patients had a significantly higher d-ROMs level than males (318 +/- 68 vs. 350 +/- 72 U. Carr., P<0.01). A multiple regression analysis revealed that there was an independent, significant, and inverse correlation between the mean LDL particle size and the d-ROMs (beta=-0.19, P<0.05). CONCLUSIONS: These findings of the co-existence of both markers suggest that sdLDL and oxidative stress can be cooperative in atherogenesis, possibly leading to the incidence of CVD, in dyslipidemic patients. PMID- 22448309 TI - Should We Look for Celiac Disease among all Patients with Liver Function Test Abnormalities? AB - BACKGROUND: Celiac disease (CD) has been found in up to 10% of the patients presenting with unexplained abnormal liver function tests (LFT). As there is no precise data from our country in this regard, we investigated the prevalence of CD in patients presenting with abnormal LFT. METHODS: From 2003 to 2008, we measured IgA anti-tissue transglutaminase (t-TG) antibody (with ELISA technique) within the first-level screening steps for all patients presenting with abnormal LFT to three outpatient gastroenterology clinics in Isfahan, IRAN. All subjects with an IgA anti-tTG antibody value of >10 MU/ml (seropositive) were undergone upper gastrointestinal endoscopy and duodenal biopsy. Histopathological changes were assessed according to the Marsh classification. CD was defined as being seropositive with Marsh I or above in histopathology and having a good response to gluten free diet (GFD). RESULTS: During the study, 224 patients were evaluated, out of which, 10 patients (4.4%) were seropositive for CD. Duodenal biopsies were performed in eight patients and revealed six (2.7%) cases of Marsh I or above (four Marsh IIIA, two Marsh I), all of them had good response to GFD. The overall prevalence of CD among patients with hypertransaminasemia, autoimmune hepatitis, and cryptogenic cirrhosis was determined as 10.7% (3/28), 3.4% (2/59), and 5.3% (1/19), respectively. CONCLUSION: Serological screening with IgA anti tTG antibody test should be routinely performed in patients presenting with abnormal LFT and especially those with chronic liver diseases including hypertransaminasemia, autoimmune hepatitis, and cryptogenic cirrhosis. PMID- 22448310 TI - Establishment of Health Clinics as Mass Screening and Referral Systems for Chronic Non-communicable Diseases in Primary Health Care. AB - BACKGROUND: This study aimed to establish a comprehensive screening and referral system for chronic non-communicable diseases (CNCD) in the routine primary health care, and to determine the prevalence of diabetes, pre-diabetes, metabolic syndrome, and dyslipidemia in adult population invited by public announcement to the Health clinics in Isfahan, Iran. METHODS: This survey was conducted from March 2010, and the current paper presents data obtained until November 2011. To provide health services for prevention and control of CNCDs, with priority of type2 diabetes mellitus, Health clinics were established in different parts of Isfahan city with a population of approximately 2,100,000 in Iran. The general populations aged 30 years and above were invited to the Health clinics by public announcement. RESULTS: A total of 198972 participants were screened. The mean age of participants was 47.8 years (48.5 men, 47.3 women), with a range of 1 to 95 years old and standard deviation of 12.3 years (12.7 men, 12.1 women). Overall, 22% of participants had impaired fasting glucose, 25% had hypercholesterolemia, 31% had hypertriglyceridemia, and 20% had metabolic syndrome. CONCLUSION: The high prevalence of dysglycemia and diabetes in our survey may serve as confirmatory evidence about the importance of mass screening and early diagnosis of CNCDs' risk factors. Our model of establishing Health clinics, as a comprehensive referral system in the routine primary health care can be adopted by Middle Eastern countries, where CNCDs notably diabetes are an emerging health problem. PMID- 22448311 TI - Socioeconomic Status and Incidence of Traffic Accidents in Metropolitan Tehran: A Population-based Study. AB - BACKGROUND: Population-based estimates of traffic accidents (TAs) are not readily available for developing countries. This study examined the contribution of socioeconomic status (SES) to the risk of TA among Iranian adults. METHODS: A total of 64,200people aged >=18years were identified from 2008 Urban Health Equity Assessment and Response Tool (Urban HEART) survey. 22,128 households were interviewed to estimate the overall annual incidence, severity and socioeconomic determinants of TAs for males and females in Iranian capital over the preceding year. Wealth index and house value index were constructed for economic measurement. Weighted estimates were computed adjusting for complex survey design. Logistic regression models were used to examine individual and SES measures as potential determinants of TAs in adults. RESULTS: The overall incidence of traffic accident was 17.3(95% CI 16.0, 18.7) per 1000 per year. TA rate in men and women was 22.6(95% CI 20.6, 24.8) and 11.8(95% CI 10.4, 13.2), respectively. The overall TA mortality rate was 26.6(95% CI 13.4, 39.8) per 100,000 person-years, which was almost three times higher in men than that for women (40.4 vs. 12.1 per 100,000person-years). Lower economic level was associated with increased incidence and mortality of TA. Association between SES and incidence, and severity and mortality of TA were identified. CONCLUSION: TAs occur more in lower socioeconomic layers of the society. This should be taken seriously into consideration by policy makers, so that preventive programs aimed at behavioral modifications in the society are promoted to decrease the health and economic burden imposed by TAs. PMID- 22448312 TI - The estimation of direct medical costs of treating patients with chronic hepatitis B and C in iran. AB - BACKGROUND: The objective of this study is to estimate the average diagnosis and treatment costs of chronic hepatitis B and C, with respect to different therapeutic strategies in Iran. METHODS: This is a descriptive, analytical, and cross-sectional study carried out on patients with hepatitis B and C, who were referred to the Liver Disease Research Center for Prevention and Treatment of Hepatitis, Isfahan University of Medical Sciences, in 2011. We have estimated the direct medical costs including doctors' fees, cost of para-clinical tests, medical treatments, and liver biopsy, in different treatment strategies. FINDINGS: The results of this study showed that the total cost of diagnostic services for hepatitis B virus (HBV) and hepatitis C virus (HCV) patients, with state medical tariffs, was US$ 1499.07 and US$ 2084.89, respectively. The patients' profiles showed that there were currently seven therapeutic strategies available to treat HBV patients. The total cost of treatment strategies varied significantly from US$ 73 to US$ 8256. There were also four main strategies for HCV patients, each of these could be applied in two periods of time. The total cost of these treatment strategies showed a high discrepancy from US$ 242 to US$ 8256. CONCLUSION: The results confirmed that the total direct medical cost for an HBV patient in Iran exceeded US$ 5.5 Milliard in 2011. The results implied that the market price of direct medical cost of HBV and HCV patients in Iran is much higher than the estimated state costs. These costs would likely be saved or reduced by effective disease management and early prevention. PMID- 22448313 TI - Aphorisms and short phrases as pieces of knowledge in the pedagogical framework of the andalusian school of public health. AB - BACKGROUND: Bearing in mind the philosophical pedagogical significance of short phrases for the training of researchers in the health care ambit, we hence have studied the aphorisms and striking phrases expressed during the epidemiology course at the Andalusian School of Public Health. METHODS: Belonging to the qualitative type and applied through the establishment of a multidisciplinary focus group made up of ten post-graduated students, where one of them acted as a moderator. The collection of information lasted four months. Information was classified in two ways: Firstly, aphorisms and short phrases with a pedagogical impact; and secondly, data with statistical, epidemiological, epistemological, pragmatic, or heuristic component, and for scientific diffusion. It was decided to perform a triangulation that included a descriptive presentation and a basic categorical analysis. The two teachers with a highest interpretative load have been identified . RESULTS: A total of 127 elements, regarded as of interest by the focus group, were collected. Forty-four of them (34.6%) were aphorisms, and 83 were short phrases with a pedagogical load (65.3%). Most of all them were classified as statistical elements (35.4%) followed by epistemological (21.3%) and epidemiological (15.7%) elements. There was no tendency towards aphorisms or short phrases (P > 0.05) among the teachers with more informative representation. CONCLUSION: There has been a tilt in the contents towards the statistical area to the detriment of the epidemiological one. Concept maps have visualized classifications. This sort of qualitative analysis helps the researcher review contents acquired during his/her training process. PMID- 22448314 TI - Body Mass Index or Microalbuminuria, Which One is More Important for the Prediction and Prevention of Diastolic Dysfunction in Non-diabetic Hypertensive Patients? AB - BACKGROUND: Numerous studies have now demonstrated that heart failure with a normal ejection fraction (HFnlEF) is common. Hypertension is also the most commonly associated cardiac condition in patients with HFnlEF. Despite the observed link between microalbuminuria, obesity, and cardiovascular disorders, this question has remained - 'Which is more important for the prediction and prevention of diastolic dysfunction in non-diabetic hypertensive patients?' METHODS: The current study was a cross-section study conducted on a total of 126 non-diabetic hypertensive patients screened to identify those with hypertension. Urine creatinine was measured by the picric acid method and urine albumin content was measured by a sensitive, nephelometric technique. The urinary albumin/creatinine ratio (UACR) was determined as an indicator of microalbuminuria. Complete two-dimensional, doppler, and tissue-doppler echocardiography was performed and the recording of the diastolic function parameters was carried out. RESULTS: High body mass index and high systolic blood pressure were positively correlated with the appearance of left ventricular hypertrophy, whereas, the UACR index had no significant relationship with hypertrophy. Multivariable analysis also showed that advanced age and systolic blood pressure were significantly associated with the E/E annulus parameter. CONCLUSION: According to our investigation obesity is more important than microalbuminuria for the prediction and prevention of diastolic dysfunction in non-diabetic hypertensive patients. PMID- 22448315 TI - Vitamin and mineral supplements: do we really need them? AB - In the United States, 40 - 50% of the men and women 50 years of age or older regularly use multivitamin/mineral (MVM) supplements, making the annual sales of these supplements over $11 billion. However, the question remains whether using MVM supplements is beneficial to health. This article reviews the results of randomized studies of MVM supplements and individual vitamins/mineral supplements in relation to overall mortality and incidence of chronic diseases, particularly cancer and ischemic heart disease. The results of large-scale randomized trials show that, for the majority of the population, there is no overall benefit from taking MVM supplements. Indeed, some studies have shown increased risk of cancers in relation to using certain vitamins. PMID- 22448316 TI - N-heterocyclic carbene-catalyzed rearrangements of vinyl sulfones. AB - N-heterocyclic carbenes catalyze the rearrangement of 1,1 bis(arylsulfonyl)ethylene to the corresponding trans-1,2-bis(phenylsulfonyl) under mild conditions. Tandem rearrangement/cycloadditions have been developed to capitalize on this new process and generate highly substituted isoxazolines and additional heterocyclic compounds. Preliminary mechanistic studies support a new conjugate addition/Umpolung process involving the ejection and subsequent unusual re-addition of a sulfinate ion. PMID- 22448317 TI - Extreme chemical sensitivity of nonlinear conductivity in charge-ordered LuFe(2)O(4). AB - Nonlinear transport behaviors are crucial for applications in electronic technology. At the nonlinear critical turning point, the nonequilibrium states cause rich physics responses to environment. The corresponding study in this field is crucial for physics and industry application. Here nonlinear conductivity in charge-ordered (CO) LuFe(2)O(4 )has been demonstrated. Remarkable resistivity switching behavior was observed and the gas-sensing property can be reversibly tuned by a small alternation of partial pressure and/or chemical components of the environment. These facts allow us to use LuFe(2)O(4) materials as a sensitive chemical gas sensor in technological applications. Careful analysis of the gas sensing process in LuFe(2)O(4) suggests a novel sensing mechanism in sharp contrast with that discussed for the conventional gas sensors which depend fundamentally on surface chemical reactions. PMID- 22448318 TI - Different inhibitory potency of febuxostat towards mammalian and bacterial xanthine oxidoreductases: insight from molecular dynamics. AB - Febuxostat, a drug recently approved in the US, European Union and Japan for treatment of gout, inhibits xanthine oxidoreductase (XOR)-mediated generation of uric acid during purine catabolism. It inhibits bovine milk XOR with a K(i) in the picomolar-order, but we found that it is a much weaker inhibitor of Rhodobacter capsulatus XOR, even though the substrate-binding pockets of mammalian and bacterial XOR are well-conserved as regards to catalytically important residues and three-dimensional structure, and both permit the inhibitor to be accommodated in the active site, as indicated by computational docking studies. To clarify the reason for the difference of inhibitory potency towards the two XORs, we performed molecular dynamics simulations. The results indicate that differences in mobility of hydrophobic residues that do not directly interact with the substrate account for the difference in inhibitory potency. PMID- 22448319 TI - Aspirin prophylaxis for the prevention of thrombosis: expectations and limitations. AB - Platelets play a very important role in the pathogenesis of acute vascular events leading to thrombosis of the coronary and cerebral arteries. Blockage of these arteries leading to regional ischemia of heart and brain tissues precipitate heart attacks and stroke. Acetyl salicylic acid (Aspirin) has been the drug of choice for over half a century for the primary and secondary prophylaxis of thrombotic events. In spite of its extensive use as an antiplatelet drug for the prevention of vascular thrombosis, there is considerable concern about the degree of protection it offers, to patients under aspirin therapy. In this paper, we explain the phenomenon of aspirin resistance, discuss the limitations of aspirin therapy, and suggest methods to monitor "at-risk" individuals. Ability to monitor and determine at risk patients will provide opportunities for the clinicians to customize antiplatelet therapies. PMID- 22448320 TI - The avantgarde carbostent in patients scheduled for undelayable noncardiac surgery. AB - Background. Treatment of patients who need coronary revascularization before undelayable non-cardiac surgery is challenging. Methods. We assessed the safety and efficacy of percutaneous coronary interventions (PCI) using the Avantgarde( TM) Carbostent (CID, Italy) in patients undergoing PCI before undelayable non cardiac surgery. The Multiplate analyzer point-of-care was used to assess residual platelet reactivity. One major cardiac events (MACE, defined as death, myocardial infarction, and stent thrombosis and major bleeding) were assessed. Results. 42 consecutive patients were analyzed. Total stent length >=25 mm was observed in 16 (37%) patients. Multivessel stenting was performed in 11 (31.5%) patients. Clopidogrel was interrupted 5 days before surgery in 35 patients, whereas it was stopped the day of the surgery in 7 patients. Surgery was performed after 27 +/- 9 (7-42) days from PCI. MACE occurred in one patient (2.4%; 95% confidence interval: 0.01-13%), who had fatal acute myocardial infarction 3 days after abdominal aortic aneurysm surgery and 12 days after stent implantation. No case of major bleeding in the postoperative phase was observed. Conclusions. The present pilot study suggests that, although at least 10-14 days of dual antiplatelet therapy remain mandatory, the Avantgarde( TM) stent seems to have a role in patients requiring undelayable surgery. PMID- 22448321 TI - The role of dermcidin isoform 2: a two-faceted atherosclerotic risk factor for coronary artery disease and the effect of acetyl salicylic Acid on it. AB - Hypertension and diabetes mellitus are considered to be two major atherosclerotic risk factors for coronary artery disease (CAD). A stress-induced protein identified to be dermcidin isoform 2 of Mr. 11 kDa from blood plasma of hypertensive persons when injected (0.1 MUM) in rabbits increased the systolic pressure by 77% and diastolic pressure by 45% over the controls within 2 h. Ingestion of acetyl salicylic acid (150 mg/70 kg) by these subjects reduced systolic (130 mm Hg) and diastolic pressures (80 mm Hg) with reduction of plasma dermcidin level to normal ranges (9 nM). The protein was found to be a potent activator of platelet cyclooxygenase and inhibited insulin synthesis. Aspirin was found to reduce hypertension by reduction of plasma dermcidin level, neutralized the effect of cyclooxygenase, and restored the pancreatic insulin synthesis through NO synthesis. These results indicated that dermcidin could be a novel atherosclerotic risk factor for its hypertensive and diabetogenic effects. PMID- 22448322 TI - Postoperative pain trajectories in cardiac surgery patients. AB - Poorly controlled postoperative pain is a longstanding and costly problem in medicine. The purposes of this study were to characterize the acute pain trajectories over the first four postoperative days in 83 cardiac surgery patients with a mixed effects model of linear growth to determine whether statistically significant individual differences exist in these pain trajectories, and to compare the quality of measurement by trajectory with conventional pain measurement practices. The data conformed to a linear model that provided slope (rate of change) as a basis for comparing patients. Slopes varied significantly across patients, indicating that the direction and rate of change in pain during the first four days of recovery from surgery differed systematically across individuals. Of the 83 patients, 24 had decreasing pain after surgery, 24 had increasing pain, and the remaining 35 had approximately constant levels of pain over the four postoperative days. PMID- 22448323 TI - Interspinous spacer implant in patients with lumbar spinal stenosis: preliminary results of a multicenter, randomized, controlled trial. AB - A prospective, randomized, controlled trial was conducted to compare clinical outcomes in patients treated with an investigational interspinous spacer (Superion) versus those treated with an FDA-approved spacer (X-STOP). One hundred sixty-six patients with moderate lumbar spinal stenosis (LSS) unresponsive to conservative care were treated randomly with the Superion (n = 80) or X-STOP (n = 86) interspinous spacer. Study subjects were followed through 6 months posttreatment. Zurich Claudication Questionnaire (ZCQ) symptom severity scores improved 30% with Superion and 25% with X-STOP (both P < 0.001). Similar changes were noted in ZCQ physical function with improvements of 32% with Superion and 27% with X-STOP (both P < 0.001). Mean ZCQ patient satisfaction score ranged from 1.7 to 2.0 in both groups at all follow-up visits. The proportion of subjects that achieved at least two of three ZCQ clinical success criteria at 6 months was 75% with Superion and 67% with X-STOP. Axial pain decreased from 55 +/- 27 mm at pretreatment to 22 +/- 26 mm at 6 months in the Superion group (P < 0.001) and from 54 +/- 29 mm to 32 +/- 31 mm with X-STOP (P < 0.001). Extremity pain decreased from 61 +/- 26 mm at pretreatment to 18 +/- 27 mm at 6 months in the Superion group (P < 0.001) and from 64 +/- 26 mm to 22 +/- 30 mm with X-STOP (P < 0.001). Back function improved from 38 +/- 13% to 21 +/- 19% with Superion (P < 0.001) and from 40 +/- 13% to 25 +/- 16% with X-STOP (P < 0.001). Preliminary results suggest that the Superion interspinous spacer and the X-STOP each effectively alleviate pain and improve back function in patients with moderate LSS who are unresponsive to conservative care. PMID- 22448324 TI - Airway Remodelling in Asthma and COPD: Findings, Similarities, and Differences Using Quantitative CT. AB - Airway remodelling is a well-established feature in asthma and chronic obstructive lung disease (COPD), secondary to chronic airway inflammation. The structural changes found on pathological examination of remodelled airway wall have been shown to display similarities but also differences. Computed tomography (CT) is today a remarkable tool to assess airway wall morphology in vivo since submillimetric acquisitions over the whole lung volume could be obtained allowing 3D evaluation. Recently, CT-derived indices extracted from CT images have been described and are thought to assess airway remodelling. This may help understand the complex mechanism underlying the remodelling process, which is still not fully understood. This paper summarizes the various methods described to quantify airway remodelling in asthma and COPD using CT, and similarities and differences between both diseases will be emphasized. PMID- 22448325 TI - Lipid-Laden Alveolar Macrophages and pH Monitoring in Gastroesophageal Reflux Related Respiratory Symptoms. AB - Lipid-laden alveolar macrophages and pH monitoring have been used in the diagnosis of chronic aspiration in children with gastroesophageal reflux (GER). This study was conducted to prove a correlation between the detection of alimentary pulmonary fat phagocytosis and an increasing amount of proximal gastroesophageal reflux. It was assumed that proximal gastroesophageal reflux better correlates with aspiration than distal GER. Patients from 6 months to 16 years with unexplained recurrent wheezy bronchitis and bronchial hyperreactivity, or recurrent pneumonia with chronic cough underwent 24-hour double-channel pH monitoring and bronchoscopy with bronchoalveolar lavage (BAL). Aspiration of gastric content was determined by counting lipid laden alveolar macrophages from BAL specimens. There were no correlations between any pH-monitoring parameters and counts of lipid-laden macrophages in the whole study population, even when restricting analysis to those with abnormal reflux index expressing clinically significant GER. Quantifying lipid-laden alveolar macrophages from BAL in children with gastroesophageal-related respiratory disorders does not have an acceptable specificity to prove chronic aspiration as an underlying etiology. Therefore, research for other markers of pulmonary aspiration is needed. PMID- 22448326 TI - Pleural fluid analysis: standstill or a work in progress? AB - Pleural fluid analysis yields important diagnostic information in pleural effusions in combination with clinical history, examination, and radiology. For more than 30 years, the initial and most pragmatic step in this process is to determine whether the fluid is a transudate or an exudate. Light's criteria remain the most robust in separating the transudate-exudate classification which dictates further investigations or management. Recent studies have led to the evaluation and implementation of a number of additional fluid analyses that may improve the diagnostic utility of this method. This paper discusses the current practice and future direction of pleural fluid analysis in determining the aetiology of a pleural effusion. While this has been performed for a few decades, a number of other pleural characteristics are becoming available suggesting that this diagnostic tool is indeed a work in progress. PMID- 22448327 TI - Pulmonary bacterial communities in surgically resected noncystic fibrosis bronchiectasis lungs are similar to those in cystic fibrosis. AB - Background. Recurrent bacterial infections play a key role in the pathogenesis of bronchiectasis, but conventional microbiologic methods may fail to identify pathogens in many cases. We characterized and compared the pulmonary bacterial communities of cystic fibrosis (CF) and non-CF bronchiectasis patients using a culture-independent molecular approach. Methods. Bacterial 16S rRNA gene libraries were constructed from lung tissue of 10 non-CF bronchiectasis and 21 CF patients, followed by DNA sequencing of isolates from each library. Community characteristics were analyzed and compared between the two groups. Results. A wide range of bacterial diversity was detected in both groups, with between 1 and 21 bacterial taxa found in each patient. Pseudomonas was the most common genus in both groups, comprising 49% of sequences detected and dominating numerically in 13 patients. Although Pseudomonas appeared to be dominant more often in CF patients than in non-CF patients, analysis of entire bacterial communities did not identify significant differences between these two groups. Conclusions. Our data indicate significant diversity in the pulmonary bacterial community of both CF and non-CF bronchiectasis patients and suggest that this community is similar in surgically resected lungs of CF and non-CF bronchiectasis patients. PMID- 22448328 TI - Smoking and idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology with considerable morbidity and mortality. Cigarette smoking is one of the most recognized risk factors for development of IPF. Furthermore, recent work suggests that smoking may have a detrimental effect on survival of patients with IPF. The mechanism by which smoking may contribute to the pathogenesis of IPF is largely unknown. However, accumulating evidence suggests that increased oxidative stress might promote disease progression in IPF patients who are current and former smokers. In this review, potential mechanisms by which cigarette smoking affects IPF, the effects of cigarette smoking on accelerated loss of lung function in patients with IPF, key genetic studies evaluating the potential candidate genes and gene-environment (smoking) interaction, diagnosis, and treatment with emphasis on recently closed and ongoing clinical trials are presented. PMID- 22448329 TI - Imaging diagnosis of interstitial pneumonia with emphysema (combined pulmonary fibrosis and emphysema). AB - Based on clinical and radiological findings, Cottin defined combined pulmonary fibrosis and emphysema (CPFE) as pulmonary emphysema in the upper lungs and interstitial pneumonia in the lower lungs with various radiological patterns. Pathologic findings of CPFE probably corresponded with diffuse interstitial pneumonia with pulmonary emphysema, emphysema with fibrosis, and the combination of both. We described reported radiological findings of CPFE. PMID- 22448330 TI - Near fatal asthma: clinical and airway biopsy characteristics. AB - Background. Inflammation and remodeling are integral parts of asthma pathophysiology. We sought to describe the clinical and pathologic features of near fatal asthma exacerbation (NFE). Methods. Bronchial biopsies were collected prospectively from NFE I subjects. Another NFE II group and a moderate severity exacerbation control group (ME II) were retrospectively identified-no biopsies obtained. Results. All NFE II (n = 9) subjects exhibited remodeling and significant inflammation (eosinophilic, neutrophilic). NFE II group (n = 37) had a significant history of prior intubation and inhaled corticosteroids usage compared to ME II group (n = 41). They also exhibited leukocytosis, eosinophilia, and longer hospitalization days. Conclusions. Remodeling, eosinophilic, and neutrophilic inflammation were observed in NFE. NFE is associated with prior intubation and inhaled corticosteroids usage. PMID- 22448331 TI - Combined Pulmonary Fibrosis and Emphysema Syndrome: A New Phenotype within the Spectrum of Smoking-Related Interstitial Lung Disease. AB - Combined pulmonary fibrosis and emphysema (CPFE) is a recently defined syndrome, in which centrilobular and/or paraseptal emphysemas in upper lung zones coexist with pulmonary fibrosis in lower lobes in individuals. These patients have a characteristic lung function profile, with unexpected subnormal dynamic and static lung volumes, contrasting with a significant reduction of carbon monoxide transfer (DL(co)) and exercise hypoxemia. Pulmonary hypertension is highly prevalent in CPFE and is the leading determinant of death. Tobacco smoking has been proposed as the main factor in its etiology, though the pathophysiology and its natural history remain to be determined. High-resolution computed axial tomography is the mandatory tool to confirm the diagnosis. Currently, there is no consensus about its treatment since those published to date on this issue are limited to well-characterised series of cases; hence, a better understanding of this entity may help in the development of future therapeutic approaches. PMID- 22448332 TI - Bronchoscopy in rural areas? AB - Quality of bronchoscopy performed by one single pulmonologist in a scarcely populated subarctic area was compared to the guidelines provided by the British Thoracic Society (BTS). 103 patients underwent bronchoscopy. Diagnostic yield was increased to 76.6% when the first bronchoscopy was supplemented by bronchial washing fluid and brush cytology and to 86.7% (BTS guidelines >80%) after a second bronchoscopy. Median time from referral to bronchoscopy was 10 days and 8 days from positive bronchoscopy to operative referral to another hospital. 1% of patients that underwent transbronchial lung biopsy had minor complications. One pulmonologist had rate of correct diagnosis based on visible endobronchial tumors that was comparable to the rates of numerous pulmonologists at larger centers performing the same procedure. Time delay was short. Rate of complications was comparable. Bronchoscopy performed by one pulmonologist alone could, in organized settings, be carried out at local hospitals in areas of scattered settlement. PMID- 22448333 TI - Working with mild traumatic brain injury: voices from the field. AB - Mild traumatic brain injury (mTBI), also known as concussion, is an emerging public health issue in the United States. The estimated annual 1.2 million individuals who sustain this injury face a range of cognitive, psychological, and physical consequences for which rehabilitation protocols are being developed and implemented. On the frontlines of this developing area of rehabilitation work are professionals in a range of therapeutic settings whose practice wisdom has yet to be shared in the professional literature. This qualitative study aimed to fill this gap by exploring the experiences and insights of rehabilitation professionals serving mTBI patients in outpatient, civilian settings. An analysis of the qualitative data revealed five themes common in mTBI work, providing an in depth look at this often challenging field of rehabilitation. PMID- 22448334 TI - Driving difficulties and adaptive strategies: the perception of individuals having sustained a mild traumatic brain injury. AB - Introduction. After a mild traumatic brain injury (mTBI), individuals quickly resume driving. However, relatively little is known about the impact of mTBI on driving ability and, notably, on the perceived influence of postconcussive symptoms on driving. Hence, the objective of this study was to document the perception of driving abilities in individuals with mTBI. Method. Twenty-seven drivers with mTBI were interviewed to document their perception regarding their driving abilities. Both driving-related difficulties and compensatory strategies used to increase driving safety were documented. A mixed quantitative and qualitative analysis of the data was completed. Results. 93% of participants reported at least one difficulty perceived as having an impact on everyday activities. Most frequently named problems affecting driving were fatigue and reduced concentration. In addition, 74% of participants had adapted their driving or developed strategies to compensate for driving difficulties. Discussion/Conclusion. Postconcussive symptoms have repercussions on driving ability. However, people with mTBI tend to be aware of their difficulties and develop, over time, adaptive strategies. Preventive measures are thus warranted to increase health care professionals' awareness of the potential consequences of mTBI on driving ability and to promote guidelines for the safe resumption of driving after injury. PMID- 22448335 TI - Internal Quality Assurance Program for ERBB2 (HER2) Testing Improves the Selection of Breast Cancer Patients for Treatment with Trastuzumab. AB - International guidelines for ERBB2 (HER2) testing procedures in breast cancer patients highlight the importance of external quality control. In contrast, internal quality assurance programs have been poorly defined, and their clinical significance has not yet been investigated. We developed a quality assurance scheme by performing HER2 FISH on 724 patients randomly selected out of 1996 patients with breast cancer presenting at our institute. We collected samples monthly for tissue microarray analysis and correlated HER2 gene status with IHC scores. The concordance was excellent (kappa = 0.92, P < 0.0001). HER2 amplification characterized 25% of score 2+ but also 13% of score 1+, thus expanding the number of patients eligible for trastuzumab. Based on these findings, the FISH test is now recommended at our institution for score 1+ and 2+ patients. Adherence to internal assurance program improves patient selection and may lead to the definition of in-house tailored diagnostic algorithms different from those proposed in international guidelines. PMID- 22448336 TI - Automated measurement of immature granulocytes: performance characteristics and utility in routine clinical practice. AB - The granulocytic "shift to left" reflects marrow response to bacterial infection, and this may be quantified as band count or immature granulocyte count (IGC). The former value, used widely in neonatal sepsis, has been notoriously difficult to measure accurately and precisely. A reproducible, precise, and accurate counting of immature granulocyte counts may be possible with automation. This study of 200 febrile patients aimed at analysing the performance characteristics of automated immature granulocytes (AIGs) in predicting blood culture and their clinical utility. The absolute (IGC) and relative IG count (IG%) had area under curve (AUC) of 0.69 and 0.66. Moreover, the means of IGC and IG% between culture positive and negative groups were statistically significant suggesting that they are potential markers for bacteremia. IGC of 0.03 * 10(3) cu.mm and IG% of 0.5% offered sensitivity of 86.3% and 92.2%, respectively, and may be used for screening for bacteremia. Higher values, IGC > 0.3, and IG% > 3 had specificity greater than 90%, although the values were infrequent. It may not be long before that these automated hemograms are put into regular diagnostic use. PMID- 22448337 TI - Effect of multiple stresses (thermal, nutritional, and walking stress) on the reproductive performance of malpura ewes. AB - A study was conducted to assess the effect of multiple stresses (thermal, nutritional, and walking stress) on the reproductive performance of Malpura ewes. The study was conducted for a period of 35 days covering two estrous cycles during summer season (April-May). The ewes were randomly allocated into two groups of twelve animals each namely, GI (n=12; Control), and GII (n=1 2; Multiple stresses). GI ewes were maintained in the shed, while GII ewes were subjected to multiple stresses (thermal, nutritional, and walking stress). The estrus % differed significantly (P< 0.05) between the groups. Estrus duration also showed similar trend to that of estrus %. Both conception and lambing rate also differed significantly (P< 0.05) between the control and multiple-stress group. In addition plasma estradiol and progesterone also showed significant difference between the groups. The study proved the detrimental effects of multiple-stresses on various reproductive parameters studied. Hence it is very pertinent to conclude that when two or more than two stressors occur simultaneously, the total impact may be severe on reproductive functions of the animals. PMID- 22448338 TI - Effects of high-mobility group a protein application on canine adipose-derived mesenchymal stem cells in vitro. AB - Multipotency and self-renewal are considered as most important features of stem cells to persist throughout life in tissues. In this context, the role of HMGA proteins to influence proliferation of adipose-derived mesenchymal stem cell (ASCs) while maintaining their multipotent and self-renewal capacities has not yet been investigated. Therefore, extracellular HMGA1 and HMGA2 application alone (10-200 ng/mL) and in combination with each other (100, 200 ng/mL each) was investigated with regard to proliferative effects on canine ASCs (cASCs) after 48 hours of cultivation. Furthermore, mRNA expression of multipotency marker genes in unstimulated and HMGA2-stimulated cASCs (50, 100 ng/mL) was analyzed by RT qPCR. HMGA1 significantly reduced cASCs proliferation in concentrations of 10-200 ng/mL culture medium. A combination of HMGA1 and HMGA2 protein (100 and 200 ng/mL each) caused the same effects, whereas no significant effect on cASCs proliferation was shown after HMGA2 protein application alone. RT-qPCR results showed that expression levels of marker genes including KLF4, SOX2, OCT4, HMGA2, and cMYC mRNAs were on the same level in both HMGA2-protein-stimulated and unstimulated cASCs. Extracellular HMGA protein application might be valuable to control proliferation of cASCs in context with their employment in regenerative approaches without affecting their self-renewal and multipotency abilities. PMID- 22448339 TI - Separation of cis- and trans-Asarone from Acorus tatarinowii by Preparative Gas Chromatography. AB - A preparative gas chromatography (pGC) method was developed for the separation of isomers (cis- and trans-asarone) from essential oil of Acorus tatarinowii. The oil was primarily fractionated by silica gel chromatography using different ratios of petroleum ether and ethyl acetate as gradient elution solvents. And then the fraction that contains mixture of the isomers was further separated by pGC. The compounds were separated on a stainless steel column packed with 10% OV 101 (3 m * 6 mm, i.d.), and then the effluent was split into two gas flows. One percent of the effluent passed to the flame ionization detector (FID) for detection and the remaining 99% was directed to the fraction collector. Two isomers were collected after 90 single injections (5 uL) with the yield of 178 mg and 82 mg, respectively. Furthermore, the structures of the obtained compounds were identified as cis- and trans-asarone by (1)H- and (13)C-NMR spectra, respectively. PMID- 22448340 TI - Effects of iron concentration level in extracting solutions from contaminated soils on the determination of zinc by flame atomic absorption spectrometry with two background correctors. AB - Zinc and iron concentrations were determined after digestion, water, and three step sequential extractions of contaminated soils. Analyses were carried out using flame absorption spectrometry with two background correctors: a deuterium lamp used as the continuum light source (D(2) method) and the high-speed self reversal method (HSSR method). Regarding the preliminary results obtained with synthetic solutions, the D(2) method often emerged as an unsuitable configuration for compensating iron spectral interferences. In contrast, the HSSR method appeared as a convenient and powerful configuration and was tested for the determination of zinc in contaminated soils containing high amounts of iron. Simple, fast, and interference-free method, the HSSR method allows zinc determination at the ppb level in the presence of large amounts of iron with high stability, sensitivity, and reproducibility of results. Therefore, the HSSR method is described here as a promising approach for monitoring zinc concentrations in various iron-containing samples without any pretreatment. PMID- 22448341 TI - Gas-purged headspace liquid phase microextraction system for determination of volatile and semivolatile analytes. AB - In order to achieve rapid, automatic, and efficient extraction for trace chemicals from samples, a system of gas-purged headspace liquid phase microextraction (GP-HS-LPME) has been researched and developed based on the original HS-LPME technique. In this system, semiconductor condenser and heater, whose refrigerating and heating temperatures were controlled by microcontroller, were designed to cool the extraction solvent and to heat the sample, respectively. Besides, inert gas, whose gas flow rate was adjusted by mass flow controller, was continuously introduced into and discharged from the system. Under optimized parameters, extraction experiments were performed, respectively, using GP-HS-LPME system and original HS-LPME technique for enriching volatile and semivolatile target compounds from the same kind of sample of 15 PAHs standard mixture. GC-MS analysis results for the two experiments indicated that a higher enrichment factor was obtained from GP-HS-LPME. The enrichment results demonstrate that GP-HS-LPME system is potential in determination of volatile and semivolatile analytes from various kinds of samples. PMID- 22448342 TI - Contribution to the Study of the Relation between Microstructure and Electrochemical Behavior of Iron-Based FeCoC Ternary Alloys. AB - This work deals with the relation between microstructure and electrochemical behavior of four iron-based FeCoC ternary alloys. First, the arc-melted studied alloys were characterized using differential thermal analyses and scanning electron microscopy. The established solidification sequences of these alloys show the presence of two primary crystallization phases (delta(Fe) and graphite) as well as two univariante lines : peritectic L + delta(Fe)<->gamma(Fe) and eutectic L<->gamma(Fe) + C(graphite). The ternary alloys were thereafter studied in nondeaerated solution of 10(-3) M NaHCO3 + 10(-3) M Na(2)SO(4), at 25 degrees C, by means of the potentiodynamic technique. The results indicate that the corrosion resistance of the FeCoC alloys depends on the carbon amount and the morphology of the phases present in the studied alloys. PMID- 22448343 TI - Sequential determination of total arsenic and cadmium in concentrated cadmium sulphate solutions by flow-through stripping chronopotentiometry after online cation exchanger separation. AB - Flow-through stripping chronopotentiometry with a gold wire electrode was used for the determination of total arsenic and cadmium in cadmium sulphate solutions for cadmium production. The analysis is based on the online separation of arsenic as arsenate anion from cadmium cations by means of a cation exchanger. On measuring arsenate in the effluent, the trapped cadmium is eluted by sodium chloride solution and determined in a small segment of the effluent by making use of the same electrode. The elaborated protocol enables a full automatic measurement of both species in the same sample solution. The accuracy of the results was confirmed by atomic absorption spectrometry. The LOD and LOQ for Arsenic were found to be 0.9 MUg dm(-3) and 2.7 MUg dm(-3), respectively. A linear response range was observed in the concentration range of 1 to 300 MUg dm( 3) for sample volumes of 4 mL. The repeatability and reproducibility were found to be 2.9% and 5.2%, respectively. The linear response range for cadmium was found to be 0.5 to 60 g/L. The method was tested on samples from a cadmium production plant. PMID- 22448344 TI - EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. AB - BRAF mutations occur in 10-15% of colorectal cancers (CRCs) and confer adverse outcome. While RAF inhibitors such as vemurafenib (PLX4032) have proven effective in BRAF mutant melanoma, they are surprisingly ineffective in BRAF mutant CRCs, and the reason for this disparity remains unclear. Compared to BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRCs expressed higher levels of phospho-EGFR than BRAF mutant melanomas, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells and markedly improved efficacy in vitro and in vivo. These findings support evaluation of combined RAF and EGFR inhibition in BRAF mutant CRC patients. SIGNIFICANCE: BRAF valine 600 (V600) mutations occur in 10% to 15% of colorectal cancers, yet these tumors show a surprisingly low clinical response rate (~5%) to selective RAF inhibitors such as vemurafenib, which have produced dramatic response rates (60%-80%) in melanomas harboring the identical BRAF V600 mutation. We found that EGFR-mediated MAPK pathway reactivation leads to resistance to vemurafenib in BRAF-mutant colorectal cancers and that combined RAF and EGFR inhibition can lead to sustained MAPK pathway suppression and improved efficacy in vitro and in tumor xenografts. PMID- 22448345 TI - Predisposition to Obesity: Should We Target Those Most Susceptible? AB - Obesity prevention should remain a priority, even if there is some suggestion that the epidemic may presently have reached a stable level. However, previous interventions have not been effective in preventing overweight and obesity, and at the same time studies suggest that some subgroups are more predisposed to future obesity. The purpose of this paper is to review interventions on obesity prevention published during the past year, and to examine if interventions targeting predisposed groups or individuals seem more efficient in preventing obesity than studies targeting general populations. Among 15 identified studies, 7 targeted predisposed children or adolescents. More of the studies targeting predisposed individuals were able to show significant effects than the studies targeting general populations. Most studies targeting predisposed defined the predisposition based on ethnicity or socioeconomic status. Thus, we may be more successful in preventing obesity when targeting predisposed individuals, but more studies are needed before a firm conclusion can be drawn. PMID- 22448346 TI - Memory Training Interventions: What has been forgotten? AB - Memory training for older adults often produces gains that are limited to the particular memory tasks encountered during training. We suggest that memory training programs may be misguided by an implicit "generalist" assumption-memory training on a couple of memory tasks will have a positive benefit on memory ability in general. One approach to increase memory-training benefits is to target training for the everyday memory tasks for which older adults struggle. Examples include training retrieval strategies, prospective memory strategies, and strategies for learning and remembering names. Another approach is to design training to foster transfer. Possible elements to improve transfer are increasing the variation that is experienced during the course of training at the level of stimuli and tasks, incorporating "homework" that guides the older adult to become attuned to situations in which the strategies can be applied, and providing older adults with a better understanding of how memory works. Finally, incorporating aerobic exercise into memory training programs may potentiate the acquisition and maintenance of the trained cognitive strategies. PMID- 22448347 TI - Contribution of splanchnic and musculocutaneous vascular compartments to the formation of blood flow volume in the vena cava posterior during catecholamine treatment. AB - Studies by electromagnetic flowmetry in acute experiments on cats under conditions of the open thoracic cage and artificial ventilation of the lungs showed that 64% of venous return via the vena cava posterior was realized at the expense of the splanchnic and 36% due to the musculocutaneous vessels (abdominal basin of the caudal vein). Epinephrine (20 MUg/kg) increased the contribution of the splanchnic venous blood flow to the increase in the blood flow in the vena cava posterior and reduced the contribution of the musculocutaneous veins throughout the entire duration of systemic reactions: 84% of the blood flow increase in the vena cava posterior was due to the splanchnic and just 16% due to the musculocutaneous blood flow. Norepinephrine (10 MUg/kg) resulted in a phase wise involvement of the studied compartments in blood flow increase in the vena cava posterior. During the initial period of systemic reactions (coinciding with the maximum systemic BP rise) the contribution of the musculocutaneous compartment was 13% higher, while later (by the time of the maximum elevation of venous blood flow in the studied compartments) the contribution of splanchnic veins predominated constituting 89% of venous blood flow in the vena cava posterior. These results indicate that venous blood flow increase in the splanchnic vessels largely determined the formation of changes in the vena cava posterior blood flow in response to catecholamines. PMID- 22448348 TI - Structure of microvascular networks in the lungs and peculiarities of blood circulation in them. AB - Microvessels and their relationship with alveoli in the lungs of albino rats under physiological condition in the thorax were studied by intravital microscopy. The structure of a network of large microvessels 20-30 MU in diameter surrounding each alveolus along the perimeter from all sides was demonstrated. Blood flow was investigated by video. PMID- 22448349 TI - Age-related peculiarities in steroid hormone secretion and behavior in prenatally stressed female rats in novel environment. AB - We studied the effects of immobilization of female rat during days 15-18 of pregnancy on the behavior in novel environment (open field test) and blood level of steroid hormones in their female offspring depending on the cycle phase and age. The rats were tested at the age of 3, 12, and 24 months. Locomotor and exploratory activity and anxiety of control rats depended on the phase of estrous cycle. Age-related changes in the studied parameters were noted: locomotor and exploratory activity decreased and anxiety increased against the background of reduced secretion of the main ovarian hormones with age. In addition, blood estradiol level and behavior in novel environment virtually did not depend on age and estrous cycle phase in prenatally stressed females. Our findings suggest that maternal stress has a modulatory effect on relationship between behavioral type and estrous cycle stage, as well as on age-related pattern of behavioral reactions. PMID- 22448350 TI - Modulating effect of interleukin-4 on free radical processes in the brain of rats during emotional stress. AB - We studied the effect of anti-inflammatory cytokine IL-4 on the intensity of free radical processes in emotiogenic brain structures (hypothalamus, sensorimotor cortex, and amygdala) in rats with different prognostic emotional resistance. One hour immobilization of animals with simultaneous electrocutaneous stimulation was used as a model of acute stress. The stress was accompanied by accumulation of MDA (LPO end-product) in the sensorimotor cortex and amygdala of passive rats. Intraperitoneal administration of IL-4 (5 MUg/kg) increased MDA content in the amygdala and hypothalamus of non-stressed rats with different behavioral activity. In the sensorimotor cortex of passive and, especially, active rats, a decrease in MDA level was observed after injection of this cytokine. Preliminary administration of IL-4 prevented LPO activation in the sensorimotor cortex of behaviorally passive animals observed after stress against the background of saline injection. Regional peculiarities of LPO under the influence of this cytokine can be determined by differences in both biochemical processes in the brain tissue and specific involvement of different emotiogenic structures in the formation of the stress response. The revealed differences in the effects of IL-4 on free radical processes in active and passive rats indicate peculiarities of immune mechanisms in animals with different resistance to the same type of stress. PMID- 22448351 TI - Pecularities of prolonged use of moxonidine in patients with hypertension associated with metabolic syndrome. AB - A 6-month clinical study with active therapeutic intervention was carried out to evaluate the efficacy of moxonidine for the correction of arterial hypertension in 30 patients with metabolic syndrome. Along with the metabolic neutrality for the lipid and purine metabolism, the drug demonstrated a distinct antihypertensive effect, which against the background of pronounced sympatholytic action after 3 months of therapy tends to disappear, which can be prevented by dosage correction. It was shown that the efficacy of moxonidine in reducing insulin resistance in patients with metabolic syndrome directly depends on the severity of hypersympathicotonia manifesting in heart rate over 80 bpm at rest. PMID- 22448352 TI - Rhythmic oscillations of human penile bioimpedance in healthy individuals and in patients with vascular erectile dysfunction. AB - Small variations of electric impedance (bioimpedance) of human penis were examined in healthy volunteers and in patients with vascular erectile dysfunction (ED). The harmonic analysis revealed rhythmic oscillations of penile bioimpedance at frequencies corresponding to the heart and respiration rates and Mayer wave (0.1 Hz) and to multiple frequencies (harmonics) of the respiratory and cardiac oscillations. In normal penile bioimpedance spectrum, the Mayer and respiratory peaks were several times higher than the first cardiac (pulsatile) harmonic indicating neurogenic origin of rhythmic bioimpedance variations in the whole penis. The most of healthy individuals (78%) demonstrated the cardiac harmonics at the frequency range of 4-7 Hz that violated the monotone decrement of the pulsatile harmonic series suggesting the resonant character of oscillations of the penile arteries at this "near" frequency range. In contrast to stable 1-4 cardiac harmonics, the amplitudes of the near-range resonant harmonics could vary during few minutes suggesting a causal relation of the corresponding bioimpedance oscillations with the varying vascular tone in penile arteries. The most patients (89%) with vascular ED demonstrated not only the first 1-4 monotonically decrementing harmonics and the near-resonant ones, but also the stable cardiac harmonics at the "far" frequency range of 8-14 Hz that also disturbed the monotonic character of the cardiac harmonic series indicating the sclerotic alterations in regional arteries. In ED patients, insignificant decrease of the initial cardiac harmonics C1-C3 in comparison with the norm was accompanied by pronounced and significant decrease of the respiratory R1 and Mayer M1 peaks. The study showed that the far-frequency bioimpedance resonances at the range of 8-14 Hz and dramatic drop of Mayer and respiratory peaks are the diagnostic signs of vascular ED independent on the accompanying hormonal or neurogenic disorders. PMID- 22448353 TI - Cell cycle arrest in the thymus and spleen in male mice under conditions of chronic social defeat stress: effects of diazepam. AB - The effects of chronic social defeat stress on the percentage of cells in different phases of the cell cycle and in apoptosis in the thymus and spleen of male mice were studied by the method of flow cytofluorometry. In stressed males, thymus weight decreased, the percent of proliferating thymocytes was significantly lower, and the percentage of G0-G1 cells was higher than in intact males. Stress substantially reduced the percentage of splenocytes in the G0-G1 phase and apoptotic cells, but the percentage of S and G2-M cells and proliferation index significantly increased. Chronic administration of anxiolytic diazepam prevented the majority of the changes in the percentage of cells in different phases of the cell cycle, but apoptosis in the thymus increased under these conditions. Possible association between cell cycle disorders, impairment of cell immunity, and chronic anxiety developing under conditions of long-term social defeat stress is considered. PMID- 22448354 TI - Immobilization of lipase on poly(N-vinyl pyrrolidone). AB - Immobilization of lipase from Rhizopus niveus on poly(N-vinyl pyrrolidone) was carried out and optimal conditions for manifestation of catalytic activity of this enzyme were determined. Kinetic aspects of substrate hydrolysis by free and immobilized lipase were studied. PMID- 22448355 TI - Kinetic characteristics of myosin ATPase in dog skeletal muscles after shin bone fracture. AB - Kinetic characteristics of myosin from dog anterior tibial and gastrocnemius muscles after shin bone fracture were studied. Myosin affinity for ATP increased in muscles of the injured and contralateral limbs. PMID- 22448356 TI - Effect of meadowsweet (Filipendula vulgaris) extract on bioenergetics of the brain during experimental posthypoxic encephalopathy. AB - We studied the effect of Filipendula vulgaris aqueous extract on mitochondrial energy production system in the brain of rats with posthypoxic encephalopathy developing 19 days after hypoxic injury. Filipendula extract more effectively than valerian extract improved kinetic characteristics of respiratory activity of mitochondria, increased substrate oxidation-phosphorylation coupling, and inhibited LPO. PMID- 22448357 TI - Antidepressant activity of diterpene alkaloids of Aconitum baicalense Turcz. AB - Course treatment with diterpene alkaloids of Aconitum baicalense in mice reduced the time of immobilization in the tail suspension test and produced an antiexudative effect in mouse model of serotonin-induced edema. In the open field test, application of alkaloids did not change the total motor activity, orientation and exploratory behavior, and emotional reactions of animals. Experimental data suggest that diterpene alkaloids of Aconitum baicalensis exhibit antidepressant properties, possibly due to modulation of sensitivity to serotonin. PMID- 22448358 TI - Effects of Pro-Gly-Pro tripeptide on the dopamine system. AB - Tripeptide Pro-Gly-Pro interacted with dopamine receptors in vitro and reduced behavioral manifestations of apomorphine-induced hyperfunction of the dopamine system in verticalization, stereotypy, and yawning tests. Presumably, the behavioral effects of Pro-Gly-Pro tripeptide were mediated through post- and presynaptic D(2)and D(3)receptors. PMID- 22448359 TI - Effects of NF-kappaB blocker curcumin on oogenesis and immunocompetent organ cells in immune ovarian injury in mice. AB - Immunization of CBA mice with extracts from the ovaries of outbred albino mouse led to disorders in meiotic maturation of oocytes, enhanced death of immunocompetent cells in the thymus, spleen, and lymph nodes mainly by necrosis, and promoted the development of inflammatory reaction, as was shown by complete blood count. Treatment with activation inhibitor NF-kappaB curcumin against the background of immunization significantly reduced disorders in meiotic maturation of oocytes, decreased the number of cells dying by necrosis in immunocompetent organs, and attenuated the inflammatory reaction. PMID- 22448360 TI - Immunostimulatory effect of gold nanoparticles conjugated with transmissible gastroenteritis virus. AB - Animals were immunized with transmissible gastroenteritis virus conjugated with gold nanoparticles. The resultant antibodies had a higher titer than antibodies produced in response to native virus. Immunization with the antigen-colloidal gold complex led to a significant increase of the peritoneal macrophages respiratory activity and of plasma IFN-gamma level in immunized animals. PMID- 22448361 TI - Viability of postmortal epididymal mouse spermatozoa during long-term hypothermic storage and cryopreservation. AB - The study examined the effect of long-term hypothermic (4 degrees C) storage of mouse carcasses on motility, cell membrane damage, in vitro survival and capacitation of epididymal spermatozoa before and after cryopreservation. It was shown that the number of spermatozoa with rectilinear forward motion decreased with increasing storage time. There were no significant changes in the total sperm motility and integrity of their plasmalemma. Pronounced effects of hypothermia and long-term storage of the mouse carcasses on cryocapacitation of spermatozoa during cryoconservation were demonstrated. PMID- 22448362 TI - Effects of CYP1A2 gene polymorphisms on antipyrine CYP1A2-dependent metabolism. AB - The distribution of two CYP1A2 gene polymorphisms, CYP1A2*F and CYP1A2*D, was studied in a group of 38 men. Antipyrine elimination test was carried out and urinary cotinine was measured. The contribution of these CYP1A2 gene polymorphisms, age, and tobacco smoking to accumulation of three main antipyrine metabolites in the urine was evaluated by regression analysis. The impact of both studied polymorphisms was essential for urinary levels of 3 hydroxymethylantipyrine (metabolite most dependent on cytochrome P-4501A2) and hence, for functional activity of this isoform of the enzyme. PMID- 22448363 TI - Relationship between the expression of VEGF signal components and matrix metalloproteinases in ovarian tumors. AB - The content of vascular endothelium growth factor is significantly increased, while the level of matrix metalloproteinase-2 is 2-fold reduced in ovarian cancer tissue compared to benign tumors. A trend to an increase in the levels of matrix metalloproteinases 7 and 9 and reduction of vascular endothelial growth factor type 2 receptors in tumor tissue was also detected. A highly significant negative correlation between the levels of vascular endothelial growth factor and matrix metalloproteinase 2 and positive correlations between vascular endothelial growth factor and matrix metalloproteinase 7, vascular endothelial growth factor and matrix metalloproteinase 9, matrix metalloproteinase 2 and vascular endothelial growth factor type 2 receptors were revealed. In the tumors assayed after preoperative therapy, relative normalization of the studied parameters was observed: the level of vascular endothelial growth factor decreased significantly, while the levels of matrix metalloproteinase 2 and vascular endothelial growth factor type 2 receptors increased. The levels of the markers differed significantly in ovarian tumors of different histological types, and the levels of vascular endothelial growth factor type 2 receptors were higher in patients with stage III compared to stage I and the content of matrix metalloproteinase 7 was higher in stage III compared to stage II cancer. PMID- 22448364 TI - Prospects of using pancragen for correction of metabolic disorders in elderly people. AB - We examined two groups of older persons: 30 healthy and 33 patients with type 2 diabetes mellitius. Nocturnal melatonin production was significantly reduced by 70% in patients with DM2 compared to healthy individuals of the corresponding age. In patients with DM2, pancragen significantly decreased glucose level on an empty stomach and in standard glucose tolerance test and reduced plasma concentrations of insulin and insulin resistance index. In patients receiving no pancragen, no changes in carbohydrate metabolism indices were observed. Thus, disturbances in the melatonin-producing function of the pineal gland in elderly individuals contribute to the development of insulin resistance. Administration of the tetrapeptide pancragen is a promising approach to the correction of insulin resistance in elderly individuals. PMID- 22448365 TI - Role of dendritic cells in the formation of subpopulation of cytotoxic T lymphocytes in the thymus during its aging. AB - The counts of dendritic cells and cytotoxic T-lymphocytes in the thymus decrease during its aging. The counts of dendritic cells decrease in senile age, while low counts of cytotoxic T-cells are observed only in long-living individuals. Presumably, reduction of the counts of thymic dendritic cells causes disorders in the differentiation of T-cells, particularly of cytotoxic ones, which can represent a mechanism of thymus involution during its aging. PMID- 22448366 TI - Interrelation of cell apoptosis and proliferation in the thymus during its involution. AB - In people over 60 years, thymocytes contain proliferation protein Ki67 and proapoptotic protein P53. During aging, apoptosis of thymus cell prevails over proliferation, though thymocytes retain proliferative capacity even in long livers. PMID- 22448367 TI - Effects of amino acid combinations on the development of organotypic culture of the myocardium from young and old rats. AB - Effects of 20 L-amino acids in concentration of 0.05 ng/ml on the development of myocardium of young (3-month-old) and old (24-month-old) rats in organotypic tissue culture were investigated. Stimulation of cell proliferation in the myocardium of young animals appeared under the influence of asparagine, histidine, serine, lysine, arginine, glutamic acid, and isoleucine. In the myocardium of old rats, proliferative effects remained only for two amino acids, lysine and arginine. Combinations of one stimulating and one inactive amino acids effectively increase the stimulating effect in both young and old rats. Modulating properties of amino acids and their combinations provide the basis for the synthesis of peptides regulating regenerative processes in the myocardium, particularly during aging. PMID- 22448368 TI - Markers of inflammation and intracellular metabolism of neutrophils in patients with acute coronary syndrome and normal troponin T levels. AB - Markers of inflammation and intracellular metabolism of neutrophils were studied in 58 patients with acute coronary syndrome with different levels of troponin T. In patients with repeated coronary events within a year, more pronounced endothelial dysfunction associated with activation of oxygen-dependent metabolism of neutrophils and lipid peroxidation process was revealed at admission to the hospital. PMID- 22448369 TI - Modulation of oxygen-dependent and oxygen-independent metabolism of neutrophilic granulocytes by quantum points. AB - Inhibition of neutrophilic granulocyte metabolism under the effect of semiconductor quantum points was demonstrated. The status of the oxidative system was evaluated by the NBT test, nonoxidative status by the lysosomal cationic test. It was found that quantum points in a dose of 0.1 mg/ml irrespective of their core and composition of coating significantly inhibited oxygen-dependent and oxygen-independent metabolism of neutrophilic granulocytes. PMID- 22448370 TI - Structural and functional state of the bone marrow during its in vitro interaction with ferromagnetic nanoparticles. AB - Hemopoietic islets, associations of stromal (macrophages, fibroblasts) and blood (including stem) cells, are structural and functional units of the bone marrow. We studied cellular and molecular processes developing following short-term (1 h) contact of hemopoietic islets with ferromagnetic nanoparticles in a multicellular system of the bone marrow in vitro. It was established that nanodispersions of magnetite (Fe(3)O(4), mean particle diameter 18 nm) and iron coated with carbon (Fe(C), particle diameter 5-10 nm) in a dose of 3 mg/liter had a minor effect on processes of necrotic and apoptotic cell death. Nanodispersion of carbon-coated iron (Fe(C)) most mildly stimulated oxidizing processes recorded by intracellular levels of reactive oxygen species. These nanoparticles, in contrast to magnetite, did not reduce the amount of hemopoietic islets in the bone marrow cell suspension. PMID- 22448371 TI - Experimental study of relationship between biological hazards of low-dose radiofrequency exposure and energy flow density in Spirostomum ambiguum infusoria exposed at a mobile connection frequency (1 GHz). AB - Radiofrequency exposure at the mobile connection frequency (1 GHz) at different energy flow densities, 5 MUW/cm(2)(2-fold below the maximum permissible level) and 50 MUW/cm(2)(5-fold surpassing this level), caused a reduction of motor activity in unicellular hydrobionts Spirostomum ambiguum Ehrbg infusoria. In all cases, the effect was similar by the intensity and developed in a jump-wise manner after exposure of a certain duration, after which did not increase with prolongation of the exposure. The duration of radiofrequency exposure safe for the object varied significantly: 8-9 h and 10 min at 5 and 50 MUW, respectively. These innovation data on harmful biological effects of very low radiofrequency exposure (5 MUW/cm(2)), the threshold form of biological reaction, presence of "safe" periods of exposure, and the data demonstrating a clear-cut relationship between these periods and energy flow density are interesting from theoretical viewpoint and in connection with the problem of evaluating permissible levels of radiofrequency exposure of biological objects. PMID- 22448372 TI - Cellular composition of the thymus in Wistar rats in experimental intracerebral hemorrhage. AB - The time course of changes in cellular composition of the thymus after experimental intracerebral hemorrhage was studied in rats with various prognostic resistance to emotional stress. Increased migration of T lymphocyte precursors to the subcapsular zone, activation of T lymphocyte differentiation in the thymus, reduced number of mitotic cells, destruction and intensive migration of thymocytes from the thymus were observed. The severity of changes in cell composition in all layers of the thymus after experimental intracerebral hemorrhage was different in rats resistant and predisposed to emotional stress. Predisposition to emotional stress and stress before surgical modeling of intracerebral hemorrhage affected the severity of changes in the thymus. It is shown that autoimmune and adaptation mechanisms, which are closely interrelated, play an important role in the pathogenesis of the intracerebral hemorrhage. PMID- 22448373 TI - Morphological changes in rat tracheal wall in experimental hemorrhagic stroke. AB - Structure of the tracheal wall of male Wistar rats was studied by histological methods on days 1, 3, and 7 after experimental hemorrhagic stroke. Signs of impaired microcirculation and lymphatic drainage were revealed at all stages of the experiment. In the acute phase of stroke (day 1), these disturbances lead to destruction of epithelial cells and their extensive desquamation, edema of the submucosa, and hemorrhages in the tracheal wall. On days 3 and 7 of the experiment, destructive changes in the mucosa membrane were still present, but swelling of mucosa lamina propria and submucosa of the tracheal wall greatly decreased, probably due to evacuation of tissue fluid excess into the lumen. We can assume that changes in the structure of the tracheal wall in experimental hemorrhagic stroke impair the barrier function of the wall, which can contribute to the development of pneumonia, a serious inflammatory complications of stroke. PMID- 22448374 TI - Comparative characteristics of the morphology of rabbit lymph nodes after implantation of porous titanium with composite nanocoating and hydroxyapatite particles embedded into pores. AB - We studied changes of microarchitectonics of lymph nodes in mature rabbits in response to introduction of bioimplants based on porous titanium with carbon containing nanocoating or nanocoating with hydroxyapatite embedded into pores. Moderate local reactivity of the lymphoid system was observed in animals with implants coated with carbon-containing films within 30 days after surgery. In animals with nanocoated implants containing hydroxyapatite, the immune response was more pronounced. Introduction of implants led to activation of cellular and humoral mechanisms of immunity in animals of both groups. PMID- 22448375 TI - Morphological features of peri-implant tissue after placement of dental implants into the extraction socket. AB - In experiments on pigs, bone regeneration was studied after implantation of implants with four cylindrical roots and support cone and laminar crest-shaped implants with shape memory effect. The implants were placed to the extraction socket (mandibular canine) and through the socket immediately after tooth extraction using osteoplastic material or without using collapan-L. The use of collapan-L accelerated regeneration of peri-implant tissue and provided stable fixation of dental construct in the bone over 3 months after surgery, which can be relevant for determining timing of prosthodontic therapy and constructional features of prosthesis. PMID- 22448376 TI - Statistical analysis of clone formation in cultures of human stem cells. AB - We performed a statistical analysis of clone formation from aneuploid cells (chromosomes 6, 8, 11, X) in cultures of bone marrow-derived human multipotent mesenchymal stromal cells by spontaneous level of aneuploidy at different terms of culturing (from 2 to 19 cell cycles). It was found that the duration of cell cycle increased from 65.6 h at passages 2-3 to 164.5 h at passage 12. The expected ratio of aneuploid cells was calculated using modeled 5, 10, 20 and 30% selective preference in reproduction. The size of samples for detecting 10, 25, and 50% increased level of aneuploidy was calculated. The presented principles for evaluation of aneuploid clone formation may be used to distinguish clones of any abnormal cells. PMID- 22448377 TI - Activin A suppresses induced formation of neuroectoderm in colonies of parthenogenetic stem cells in vitro. AB - We studied the effect of recombinant human activin A on induced neuroectoderm formation in colonies of human parthenogenetic SC in the absence of feeder cells. It was found that pretreatment of human parthenogenetic SC with activin A suppressed subsequent neural induction. Activin A in a concentration of 10 ng/ml significantly decreased transcriptional activity of genes required for neuroectoderm formation. At the same time, activin A in a concentration of 20 ng/ml increased the expression of pluripotency genes and completely inhibited the formation of structures in vitro reproducing the neural tube of the developing embryo. These findings attest to prolonged effect of activin A as an inhibitor of neuroectodermal differentiation. PMID- 22448378 TI - Phenotypic plasticity of retinal pigment epithelial cells from adult human eye in vitro. AB - Phenotypic plasticity of retinal pigment epithelial cells from adult human eye was studied by immunohistochemical methods under different culturing conditions. It was found that retinal pigment epithelium in adult human eye is a heterogeneous population of cells demonstrating different behavior in vitro. Some cells retain epithelial morphology for a long time in culture, while others are rapidly transformed into fibroblast-like cells and synthesize proteins typical of proneural, neural, glial, and photoreceptor cells. However, irrespective of initial morphological features differentiation of retinal pigment cells can be modulated by varying culturing conditions. PMID- 22448379 TI - Mesenchymal cells in the treatment of focal brain injury induced by venous circulation disturbances in rats. AB - We studied the efficiency of bone marrow multipotent mesenchymal stem cells for correction of neurological deficit in rats with experimental sustained focal brain injury caused by venous outflow disturbances. It was found that neurological deficit in animals with transplantation of multipotent mesenchymal stromal cells decreased by 54-75% (vs. 14-17% in the control group) by day 21. The efficiency of mesenchymal stromal cell transplantation (intravenous or local) on day 1 of postoperation period was significantly higher than on day 7. This manifested in more pronounced decrease in the severity of neurological disorders (according to modified neurological severity score) and more rapid recovery of autonomic feeding. Moreover, transplantation of multipotent mesenchymal stromal cells on day 1 abolished the need in antiedematous therapy, while in animals receiving cell therapy on day 7, administration of glucocorticoids was necessary. Comparison of two regimens of cell administration at early terms revealed no advantages of local transplantation of multipotent mesenchymal stromal cells over intravenous injection. PMID- 22448380 TI - Location of chromosomes in the nucleus of human mesenchymal stem cells. AB - For evaluation of the spatial structure of chromatin in nuclei of mesenchymal SC we determined the position of centromeres and individual chromosomes in interphase nucleus of mesenchymal SC. More than 300 nuclei in 7 cultures of mesenchymal SC were analyzed. Centromeres of chromosomes 6, 8, and 11 lie at a longer (0.68, 0.67, 0.7), while centromere of chromosome 18 at a shorter radial distance (0.49). Homologues of each chromosome had different radial distances. No differences in radial distances of centromeres were detected between mesenchymal SC from the adipose tissue and BM. After passage 8, distal displacement of chromosome 6 centromere (from 0.66 to 0.72) was observed, which probably indicates aging or spontaneous differentiation of cells. PMID- 22448381 TI - Low-fluence photodynamic treatment modifies functional properties of vascular cell wall. AB - We studied the effect of low-fluence photodynamic treatment with Photosence preparation on functional properties of macrophages and endothelium in vitro. It was shown that low-intensity photodynamic treatment did not affect viability of these cells. Exposure (0.25 J/cm(2)) of endothelial cells loaded with Photosence did not change the expression of adhesion molecules, but reduced adhesion of peripheral blood mononuclears to these cells. The same low-intensity exposure inhibited phagocytic activity of macrophages and reduced activity of matrix metalloproteinase-9 produced by them. PMID- 22448382 TI - Immunosuppressive effects of multipotent mesenchymal stromal cells in cultures with different O2 content in the medium. AB - We studied the effects of multipotent mesenchymal stromal cells isolated from the adipose tissue on proliferation and viability of immunocompetent cells at different concentration of O(2) (5 and 20%) in culture medium. It was shown that co-culturing with multipotent mesenchymal stromal cells 3-fold reduced proliferative index of phytohemagglutinin-activated lymphocytes, while their viability remained unchanged and did not depend on partial oxygen pressure in the medium. These findings suggest that low O(2)concentration in tissues will not affect immunosuppressive properties of multipotent mesenchymal stromal cells, which is very important for their application in regenerative medicine. PMID- 22448383 TI - Peptides from the pituitary gland and cortex stimulate differentiation of polypotent embryonic tissue. AB - We studied the effects of synthetic peptides from the pituitary gland and brain cortex on differentiation of polypotent ectodermal tissue of the early gastrula of Xenopus laevis. It was shown that the pituitary gland peptide stimulates differentiation of polypotent tissue into epidermis and nerve tissue, while brain cortex peptide induces the development of mesenchyma and epidermis. Differentiation of polypotent tissue under the effect of the peptide is a mechanism of their geroprotective effect and suggests that they are promising as preparations for the treatment of neurodegenerative diseases. PMID- 22448384 TI - Effect of cell therapy on metabolite content in brain structures of children with consequences of severe brain injury: 1H magnetic resonance spectroscopy study. AB - The effect of intravenous injection of human umbilical cord blood cells on the levels of N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, glutamine and glutamate, and myoinositol in morphologically intact areas of the cortex, white matter, and hippocampus of children with consequences of traumatic brain injury was studied by single voxel 1H magnetic resonance spectroscopy. It was shown that cell therapy increases the content of N acetylaspartate, a marker of functional integrity of neurons, in the white matter and in the cortex at the boundary between the frontotemporal and parietal lobes and reduces neurological deficit. PMID- 22448385 TI - Fluorescent microscopic study of endocytosis of nanoparticles by platelets. AB - We propose a method of precise measurement of the content of nanoparticles carrying a fluorescent label in platelets. Examination under a broadband filter does not allow distinguishing platelets containing and not containing nanoparticles despite different staining of platelets and nanoparticles. Print Screen image of the sample made at the moment of sample motion divides the colors of nanoparticles and platelets and yields two clear-cut spots of different colors on the monitor indicating the presence of nanoparticles in platelets. PMID- 22448386 TI - The use of catalytic carbon deposits as 3D carriers for human bone marrow stromal cells. AB - We studied the possibility of using 3D structures based on carbon catalytic deposits as carriers for human bone marrow stromal cells. It was found that carbon catalytic deposits obtained by gas deposition method using FeCl(3) * 6H(2)O as the catalyst are a biocompatible material for human bone marrow stromal cells promoting adhesion, proliferation, and distribution of cells within the 3D carrier, and therefore can be used for tissue engineering. PMID- 22448387 TI - Economical technology of creation of cell-free matrix of animal and human arterial vessels. AB - We present a technology of creation of blood vessel connective tissue framework by 2-3-h vessel perfusion with detergents. The technology ensures effective removal of vascular cells without damaging collagen and elastic fibers. The connective tissue frameworks prepared by this method can the used for restoring blood flow in various vascular pathologies. The presented approach attenuates the damaging effect of treatment on the vascular framework due to maximum simplification and shortening of the duration of treatment and is universal for human and animal vessels. PMID- 22448388 TI - Comparative characteristics of platelet lysates from different donors. AB - We studied the effect of platelet lysates from different donors on fibroblast growth in culture. In most samples (40 of 50), the growth-stimulating characteristics were greater than in 10% FCS, but every ninth sample exhibited low mitogenic activity. A weak dependence between platelet concentration and total protein content was noted, but no correlation was found between these parameters and fibroblast growth in culture. PMID- 22448389 TI - Assessment of DNA damage in human bone marrow cells and multipotent mesenchymal stromal cells. AB - We carried out a comparative analysis of DNA damage (percentage of DNA in comet tail) and frequencies of comets in apoptotic cells in BM samples and cultures of BM multipotent mesenchymal stromal cells at different terms of culturing (passages 3-11). The levels of DNA damage in mesenchymal stromal cells remained unchanged during culturing (3.5 +/- 0.9 and 4.4 +/- 1.2%) and did not differ from those in BM cells (3.6 +/- 0.8%). In BM samples, 10-28% atypical cells with high level of DNA damage were detected. In mesenchymal stromal cells, 2.8 +/- 0.9 and 3.6 +/- 1.8% apoptotic cells were detected at early and late passages, respectively. PMID- 22448390 TI - Microwave high performance liquid chromatography with UV-visible detection. Application to vitamins determination. AB - The present work describes the first attempt to use microwave reversed phase high performance liquid chromatography (MW-HPLC) to carry out the separation of organic compounds. Biotin and riboflavin were selected for the characterization of the new separation technique. Additional vitamins (nicotinamide, pyridoxine and thiamine) were used as reference compounds. In order to perform the separation, a chromatographic column was placed inside a domestic microwave oven in a hanging position. The column particular location was an extremely critical point, since it precluded the actual power absorbed by the sample. In order to avoid magnetron damage, a heat well (i.e., water vessels) was used. Vitamins were detected using a UV-VIS detector. Results obtained showed that the application of microwave radiation, even at low power levels, gave rise to a significant modification in the characteristics of the chromatograms. It was found that retention times for biotin and riboflavin shortened as the power increased. Furthermore, the peak shape also changed, with the modification being more significant for the former vitamin than for the latter one. Furthermore, sensitivity also increased as the column was exposed to the action of microwave. Comparatively speaking, MW-HPLC was more efficient in terms of compound separation than when performed at room temperature or thermostatted at 45 degrees C HPLC. This was likely due to the combined action of a moderate and quick heating of the mobile phase with an increase in the analytes diffusivity caused by the radiation. PMID- 22448391 TI - Editorial--Future electroanalytical developments. PMID- 22448392 TI - Unexpected stereomutation dependence on the chemical structure of helical vinyl glycopolymers. AB - A small change in chemical structure causes a remarkable influence on the stereostructure stability and mutarotational rate of helical vinyl polymers bearing laterally attached p-terphenyl pendants with an achiral butoxy terminal and a chiral galactosyloxy terminal. PMID- 22448393 TI - Metal ion-binding properties of DNA duplexes containing thiopyrimidine base pairs. AB - Thiopyrimidine pairs in DNA duplexes were unexpectedly largely stabilized by complexation with two equivalents of Ag(I) ions and their binding properties were evaluated. The metal ion-binding properties of the thiopyrimidine base pairs differed significantly from those of unpaired bases. PMID- 22448394 TI - Testing for altruism and social pressure in charitable giving. AB - Every year, 90% of Americans give money to charities. Is such generosity necessarily welfare enhancing for the giver? We present a theoretical framework that distinguishes two types of motivation: individuals like to give, for example, due to altruism or warm glow, and individuals would rather not give but dislike saying no, for example, due to social pressure. We design a door-to-door fund-raiser in which some households are informed about the exact time of solicitation with a flyer on their doorknobs. Thus, they can seek or avoid the fund-raiser. We find that the flyer reduces the share of households opening the door by 9% to 25% and, if the flyer allows checking a Do Not Disturb box, reduces giving by 28% to 42%. The latter decrease is concentrated among donations smaller than $10. These findings suggest that social pressure is an important determinant of door-to-door giving. Combining data from this and a complementary field experiment, we structurally estimate the model. The estimated social pressure cost of saying no to a solicitor is $3.80 for an in-state charity and $1.40 for an out-of-state charity. Our welfare calculations suggest that our door-to-door fund-raising campaigns on average lower the utility of the potential donors. PMID- 22448395 TI - [GMP production.Shaping the future]. PMID- 22448396 TI - Q-Monitoring of ambulatory care in Switzerland - with the participation of the SRS! PMID- 22448397 TI - Family physicians sue to shine light on RUC deliberations, claim specialists skew reimbursement against primary care. PMID- 22448398 TI - Blinded by the Brandeisian light: the HRSA/Bavley database case. PMID- 22448399 TI - Bridging with glycoprotein IIb/IIIa inhibitors for periprocedural management of antiplatelet therapy in patients with drug eluting stents. AB - OBJECTIVE: To describe outcomes when glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors are used as bridging antiplatelet therapy for surgical procedures in patients with drug eluting stents (DES). BACKGROUND: The optimal management of patients with DES who require surgical procedures prior to completion of antiplatelet therapy is unclear. In high risk patients, the use of GP IIb/IIIa inhibitors as bridging therapy while antiplatelet therapy is held has been described, but safety and efficacy data remain sparse. METHODS: A pharmacy database was used to identify GP IIb/IIIa inhibitor orders at our hospital between January 1, 2007 and July 31, 2009. Indication for GP IIb/IIIa inhibitor administration and other clinical data were gathered through retrospective review of medical records. End points assessed were stent thrombosis, major bleeding, minor bleeding, postoperative acute coronary syndrome, and death within 30 days. RESULTS: Four thousand one hundred seventy-six separate orders for GP IIb/IIIa inhibitors were identified (January 1, 2007 to July 31, 2009). Six patients underwent non-cardiac and thirteen underwent cardiac surgery. Clopidogrel was discontinued a median of 6 days before surgery and 2 days prior to initiating GP IIb/IIIa inhibitor. All bridging patients were treated with eptifibatide infusion prior to procedure. There were no stent thromboses, deaths, or acute coronary syndrome events. Major bleeding occurred in 7 (53.9%) cardiac surgery patients and none of the non-cardiac surgery patients, while minor bleeding occurred in 1 (7.7%) and 1 (16.6%) patients, respectively. CONCLUSIONS: In patients with DES, who require cessation of clopidogrel before surgery, bridging with GP IIb/IIIa inhibitors appears effective in preventing adverse cardiac outcomes but may be associated with bleeding in patients undergoing cardiac surgery. PMID- 22448400 TI - Sensing in nature. Preface. PMID- 22448401 TI - Marrow noncaseating granulomas: sarcoidosis. PMID- 22448403 TI - AIDS vaccine research. PMID- 22448402 TI - Antiapoptotic function of Toso (Faim3) in death receptor signaling. PMID- 22448404 TI - PROCARE: what is on the agenda? PMID- 22448405 TI - Structure of D-ribulose-l,5-bisphosphate carboxylase/oxygenase from Alcaligenes eutrophyus H16. AB - RuBPcase, D-ribulose-1,5-bisphosphate carboxylase/oxygenase (EC4.1.1.39) is the key enzyme of the reductive pentose phosphate cycle. Because of its biological significance, many structural studies on a number of plant and bacterial RuBPCases have been undertaken, including the enzyme isolated from the autotrophic hydrogen-oxidizing bacterium Alcaligenes eutrophus H16 (refs 2-6). Although both the higher plant enzyme and the A. eutrophus enzyme consist of eight large and eight small subunits (L(8)S(8)), no model describing the quaternary structure is generally accepted. Here we present a model for the A. eutrophus RuBPCase derived from X-ray crystallography of three-dimensional (3D) crystals, and electron microscopy and image analysis of two-dimensional (2D) crystals of the enzyme. The X-ray electron density of RuBPCase in the presence of HCO(-)(3), Mg(2+), and the transition state analogue 2-carboxyarabinitol-1,5 bisphosphate (CABP) shows an L(8)S(8) molecule in which the L(4)S(4) half molecules have local 4-fold symmetry (C4). The local 4-fold axes of the two L(4)S(4) halves do not coincide but are shifted by 36 A and are related by a crystallographic 2-fold axis perpendicular to and between the local 4-fold axes. Electron microscope data of the enzyme without CABP, which can be perfectly modelled using the X-ray densities, do not show this shift and the low-resolution point group of the molecules in the 2D crystals is D4. Both structures are presented. PMID- 22448406 TI - Progressive myoclonic epilepsies. PMID- 22448407 TI - [Disbiosis in oral mucosa pathology]. PMID- 22448408 TI - [Clinical and immunological features of oral health in children with juvenile rheumatoid arthritis]. PMID- 22448409 TI - [Matrix metalloproteinases in periodontal disease]. PMID- 22448410 TI - [Electric and manual tooth brushes-comparative characteristics and an efficiency estimation]. PMID- 22448411 TI - [Relationship between maintaining whole-body homeostasis and dental diseases]. PMID- 22448412 TI - Management and health issues in women with epilepsy - a review. AB - Although epilepsy affects men and women equally, there are special implications for women, especially during their childbearing years, and particularly when pregnancy is contemplated. This review summarisesthe complexity and multifaceted nature of health issues affecting women with epilepsy (WWE) in general and epilepsy in women beyond childbearing age. The female sex hormones and their cyclic as well as age-related variations certainly influence seizure activity and epilepsy in women. Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. There are special concerns for women of child bearing years with regard to contraception, pregnancy and teratogenicity that should be considered during counseling and selection of appropriate treatment.Although the majority of pregnant WWE experience normal pregnancies and deliveries, their children have a higher risk of birth defects. Individualised treatment coupling antiepileptic drug use (AED) and the specific phase of impact of the reproductive cycle must be considered in treatment selection. As the number of available treatment options for epilepsy increases, the optimal goal for the general practitioner is to work as a team with obstetricians and gynaecologists, and neurologists in an effort to ensure the best treatment of WWE PMID- 22448413 TI - [Posterior capsule opacification in long-term follow-up of patients after implantation of hydrophilic/hydrophobic intraocular lens Acri.Smart]. AB - AIM: The aim of the retrospective study was to establish the frequency of the posterior lens capsule opacification after the cataract surgery and artificial intraocular lens (IOL) Acri.Smart 46S (Acri.Tech Zeiss) implantation. MATERIAL AND METHODS: The study group consisted of 72 eyes (30 men and 28 women), their average age was 65.4 +/- 8.4 years, with performed cataract surgery and implanted IOL Acri.Smart 46S (Acri.Tech Zeiss). After the average period of 32.4 +/- 7.3 months after the surgery, the patients underwent the examination with refractive error measurement, uncorrected and best-corrected visual acuity for for, and posterior lens capsule transparency examination with dilated pupils and with retroillumination photography taken by NIDEK EAS-100 device. RESULTS: After the average follow-up period of 32.4 +/- 7.3 months after the surgery, the refractive error was -0.32 +/- 0.8 diopters and average cylindrical error -0.8 +/- 0.6 Dcyl. The uncorrected visual acuity (UCVA) was 0.72 +/- 0.3, and the best-corrected visual acuity (BCVA) 0.95 +/- 0.2. The average diameter of the examined posterior capsule was 5.89 +/- 2.1 mm, and the transparency of the posterior capsule was 98.41 +/- 8.5%. In two eyes (2.7%) only, the YAG capsulotomy was performed. CONCLUSION: The IOL Acri.Smart is safe, easy to implant IOL, which meets the requirements of the microincision surgery. The IOL had very low incidence of posterior lens capsule opacification, and in two eyes (2.7%) only the YAG capsulotomy was performed. PMID- 22448414 TI - [AquaLase method--influence to the secondary cataract appearance and its safety]. AB - PURPOSE: To study effect of AquaLase method used for final management of posterior capsule during cataract surgery on the posterior capsule opacification (PCO) and to verify safety of this method for the eye tissue. METHODS: The prospective clinical study involving 50 patients (100 eyes) with bilateral cataract having lens removal at the Department of Ophthalmology, University Hospital Hradec Kralove in the period from September 2007 to March 2009. During the surgery was lens removed using torsional phacoemulsification and bimanual irrigation/aspiration. Cleaning of the posterior capsule of the right eye was performed using AquaLase method. All patients were examined pre-operatively and 3, 6 and 12 months after surgery. Each examination covered best corrected visual acuity (BCVA), endothelial cell count (ECC), corneal pachymetry and digital retroillumination photographs of the anterior segment focused on the posterior capsule were obtained. The Evaluation of Posterior Capsule Opacification (EPCO 2000) software and the Open-Access Systematic Capsule Assessment (OSCA) system were used for PCO evaluation. RESULTS: BCVA was 0.8 in all patients. Average value for PCO index was in 3, 6 and 12 months postoperatively for right eye 0.260 +/- 0.198; 0.259 +/- 0.173; 0.308 +/- 0.191; for left eye 0.279 +/- 0.170; 0.280 +/- 0.153; 0.333 +/- 0.197. Average value for OSCA score was for right eye 0.599 +/- 0.240; 0.605 +/- 0.333; 0.598 +/- 0.256; for left eye 0.627 +/- 0.403; 0.635 +/- 0.357; 0.541 +/- 0.328. Nd-YAG capsulotomy was performed in one right eye one year after surgery. Pachymetry and ECC results show that the method AquaLase is safe for corneal endothelium. CONCLUSION: One year after surgery, most cases of PCO were graded as minimal by both software's of analysis. The results were not statistically significant. Pachymetry and ECC results show that the AquaLase method is safe for corneal endothelium. PMID- 22448415 TI - [Correlation of intraocular pressure measured by applanation tonometry, noncontact tonometry and TonoPen with central corneal thickness]. AB - The purpose of the study was to determine the dependence of intraocular pressure (IOP) measured by Goldmann applanation tonometer (AT), non-contact tonometer (BT) and Tone-Pen (TP) on central corneal thickness (CCT) as well as the respective comparison in relation to the central corneal thickness. METHODS: CCT and IOP were assessed in 106 eyes of 106 subjects aged 7-77 years (mean 34.3 +/- 17.1 years). IOP was measured with BT, TP and AT. Central corneal thickness was assessed using ultrasound pachymetry. The obtained data were statistically analyzed. RESULTS: The mean CCT in 106 eyes was 572 +/- 46 microm (range 455-701 microm). A positive correlation between IOP and CCT was found in all types of tonometry. The change in measured IOP for a 100 microm of CCT was 2.0, 2.5 and 5.6 mmHg for TP, AT and BT, respectively. CONCLUSION: IOP measurement by all three methods is affected by CCT. The BT is influenced by CCT significantly more than are AT and TP. PMID- 22448416 TI - [Contribution to the investigation macular function for the surgical treatment of idiopathic macular holes]. AB - We evaluate annual anatomical and functional results of standard 20G pars plana vitrectomy for idiopathic macular hole, with peeling MLI (membrana limitans interna) and instillation of gas tamponade (20% SF6 - sulfur hexafluoride). The observed group consisted of 32 eyes of 32 patients (3 men and 29 women), mean age 69 years (range 59-76). There was no other ocular pathology besides idiopathic macular holes (IMD). Objectification of ocular anatomy was done with: anterior segment slit lamp, the biomicroscopy in artificial mydriasis and optical coherence tomography (Stratus OCT, Carl Zeiss). For examination of the central area of the retina was evaluated: the best corrected visual acuity in the distance (BCVA) with ETDRS optotype, BCVA in the near (Jaeger charts), multifocal electroretinography (MfERG) and pattern reversal electroretinography (PERG). For the statistical processing of results we used non-parametric Wilcoxon paired test. ANATOMICAL RESULTS: The primary closure of the IMD occurred in 29 (90%), the IMD was not closed, but it's edges were flattened in 2 eyes (6%), and once time the edges of the IMD were not flattened (3%). FUNCTIONAL RESULTS: The initial BCVA ranged from 0.1 to 0.5 (1.0 to 0.3 LogMAR). After one year of operations the visual acuity improved by 2 or more lines in 27 eyes (84%), of 3 or more lines in 18 eyes (56%), and 4 or more lines in 5 eyes (16%). PERG amplitudes (N95) in all eyes were between 4 to 9 microV (within the normal range of the laboratory), and was not found statistically significant difference between the values before surgery and 12 months after. Statistically significant difference (improvement) was found in the first and the second central ring of the MfERG. Improvement involved the values of P1 wave amplitude before surgery and 12 months after (Wilcoxon p < 0.01). The difference between the values of N1 and P1 latencies before surgery and month 12 was not statistically significant, as well as changes between the values of the amplitudes of waves N1 preoperatively and 12 months later. Due to the favorable anatomical and functional results we consider surgical treatment of macular holes through PPV with peeling MLI as a safe technique. When the indication to perform peeling is considered, there is a need to think about other factors, especially duration IMD, disease stage, type of intraocular tamponade and the patient's cooperation. PMID- 22448417 TI - [Minimal ocular findings in a patient with Best disease caused by the c.653G>A mutation in BEST1]. AB - PURPOSE: To describe the phenotype in an asymptomatic 64-year-old patient with family history of Best disease and to identify the disease causing variant in the BEST1 gene. METHODS: Detailed ocular examination of the proband including spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography and electrooculography was performed. Direct sequencing approach was used to screen the whole coding sequence of 11 exons of BEST1. RESULTS: An early vitelliform stage of Best disease presenting as a small yellowish spot in the macula was observed in the right eye. The fundus appearance in the left eye was normal. SD-OCT of the right macula revealed hypodense space between the retinal pigment epithelium and the neuroretinal layer. Arden ratio was bilaterally mildly reduced; 1.36 in the right and 1.3 in the left eye. Molecular genetic analysis identified a heterozygous change c.653G>A (p.Arg218His) as the disease-causing variant. CONCLUSION: Here we report for the first time a phenotype-genotype correlation in a Czech patient with Best disease. SD-OCT is a fast method that may show the presence of small pathological changes. The screening of BEST1 gene enables identification of disease-causing variants in asymptomatic individuals with normal fundus appearance and thus improves counseling to the affected families. PMID- 22448418 TI - [Suprachoroid hemorrhage without the connection to the surgical procedure]. AB - The aim of our report is to present 2 cases of patients with suprachoroidal hemorrhage (SH). Suprachoroidal hemorrhage occur relatively infrequently and in our cases are not associated with the surgery or postoperative period. The first case was a patient with suprachoroidal hemorrhage following spontaneous corneal penetration after corneal ulcer. The second case was a patient with a suprachoroidal hemorrhage after severe contusion of the eye globe. The most important is rapid diagnosis of disease, differentiation from other eye diseases and initiation of therapy. We discuss clinical symptomatology, diagnostic and treatment of suprachoroidal hemorrhage. PMID- 22448419 TI - [Transcaruncular medial orbitotomy--a case report]. AB - Transcaruncular medial orbitotomy is a tissue preserving, time sparing and cosmetically acceptable approach, which is appropriate for treatment of various pathological conditions, as fractures of the medial orbital wall, inflammatory expansions and tumours of adjacent part of the orbit, but also the orbital endokrinopathy and correction of the medial palpebral ligament. Surgical technique and authors' first experience with this approach in female with orbital haemangioma is presented. PMID- 22448420 TI - [Comparison of keratometric values and corneal eccentricity of myopia, hyperopia and emmetropia]. AB - PURPOSE: The aim of this work is to compare the findings of keratometric values and their differences at various ametropias. The eccentricity of the cornea in the sense compared to the possible influence of refraction of the eye is topographically observed. Groups of myopia, hyperopia and emmetropia are always represented 100 subjects, i.e. 600 eyes. The results of these measurements are mutually compared and statistically processed. METHODS: The studied cohort a total of 300 clients enrolled. To measure the steepest (r1) and flattest meridian (r2) and to determine corneal eccentricity was used autorefraktokeratometer with Placido disc (KR 8100P, Topcon, Japan). The obtained data were processed with appropriate software and statistically evaluated. RESULTS: Group A consisted of 100 myopes (n = 200), 35 men and 65 women, average age 37.3 +/- 18.7 years (min. 10 years, max. 87 years). Objective refractive error - sphere: - 2.9 +/- 2.27 D (min.-0.25 D, -14.5 D max), cylinder: -0.88 +/- 0.75 D (min. -0.25 D, up to -5.0 D). Keratametry in this group is as follows: radius of curvature of the cornea in the front area of the steepest meridian 7.62 +/- 0.28 mm (min. 6.96 mm, max. 8.44 mm) and the flattest meridian is 7.76 +/- 0.3 mm (min. 7.08 mm, max 8.75 mm). The mean eccentricity was 0.37 +/- 0.12 (min 0.00, max. 0.79). Group B consisting of 100 hyperopic subjects (n = 200), 40 men and 60 women, average age 61.6 +/- 15 years (min. 21 years, max 88 years). Objective refraction in this group -sphere: +2.71 +/- 1.6 D (at least +0.25 D, up to +9.0 D), cylinder: -1.0 +/- 0.9 D (min. 0.25 D, max. -5.75 D).Corneal surface curvature in two main sections according keratometric measurement looks as follows: the steepest meridian is 7.67 +/- 0.29 mm (min. 6.99 mm, max. 8.62 mm), the flattest meridian then 7.81 +/- 0.29 mm (min. 7.10 mm, max. 8.70 mm). The value of the median eccentricity for these hundred hyperopes is 0.37 +/- 0.14 (min. 0.00; max 0.86). The third group C consists of 100 emetropic subjects (n = 200), then clients without refractive errors who achieve without corrective aids Vmin = 1.0. This group is composed of 42 men and 58 women, mean age 41.4 +/- 17.8 years (min. 3 years, max. 82 years). Measured values of objective refraction - sphere: +0.32 +/- 0.47 D (at least 1.75 D, up to +1.5 D), cylinder: -0.28 +/- 0.45 D (min. -1.25 D, up to +1.25 D). Keratometry values measured at the corneal surface in two perpendicular cross section are: steepest meridian corresponds to the radius of curvature of 7.72 +/- 0.26 mm (min. 6.91 mm, max. 8.32 mm), the flattest meridian reaches values 7.83 +/- 0.25 mm (min. 7.10 mm, max. 8.53 mm). The median eccentricity is represented by the observed values of 0.36 +/- 0.11 (min 0.00; max. 0.57). Due to the validity of the results from the groups as unsuitable respondents with corneal astigmatism greater than -1.0 D were subsequently eliminated. CONCLUSION: Keratometry as well as topography is one of the fundamental methods of measuring corneal front surface. Their proportions are essential for the proper parameters selection, especially with contact lenses as one of the possible means intended to correct refractive errors. The study subjects were not included in any load condition cornea, purulent conjunctivitis, blepharitis, after refractive surgery or other eye symptoms. PMID- 22448421 TI - [Results of the IOP decrease after application of some mixtures of amino acids and antiglaucomatics in rabbits (a review of experimental publications)]. AB - OBJECTIVE: To summarise of experimental results performed on rabbit eyes focused to influence the physiological intraocular pressure (lOP) after application of some amino acids mixture with some regularly used antiglaucomatics. MATERIAL AND METHODS: The experiments were performed on adult rabbits (female of the New Zealand White species). The applicated substances were: 10% solution of amino acids (L-lysin.2HCl.2H2O, L-arginine.HCL or L-glycine.HCL) in antiglau-comatics 0.5% timolol (Timoptol) or 0.005% latanoprost (Xalatan). This mixture was applicated to the left eye; right eye was used as control. The measurement of IOP and pupil diameter was performed before instillation, in 15th, 30th, 60th, 180th, 240th minute and 24 hours after application. RESULTS: Functional bioactivity of the used antiglaucomatics in case of decreased lOP is rising after interaction with the relevant specific amino acid. Glycine in timolol showed the highest effect on average decrease of the lOP physiological values (lOP decrease reached 5,5 torr) followed by arginine in timolol (lOP decrease reached - 3,3 torr). The lOP decrease after other combinations of amino acids and antiglaucomatics was in average lower or nonsignificant. CONCLUSIONS: Through interaction between in vitro prepared mixture free amino acids and antiglaucomatics a new, biologically active substance (metabolite) is created. After instillation in experimental condition achieving stronger and longer decrease of the lOP compared with a single antiglaucomatic or amino acid. PMID- 22448422 TI - Safety net Denver Health System improves revenue cycle performance. PMID- 22448423 TI - Clinical documentation improvement supports the revenue cycle. PMID- 22448424 TI - Insights into 5010-related payer rejections. PMID- 22448425 TI - [Claudette Foucault: knowing how to care. Aware of the fragility and strength of life, she has that quality of being and listening that we see in those who have witnessed death]. PMID- 22448426 TI - [The CHU Sainte-Justine publications --a window to pediatrics knowledge in Quebec]. PMID- 22448427 TI - [Lymphedema --an association to improve its recognition]. PMID- 22448428 TI - [The ROCQLD --together against school dropouts]. PMID- 22448429 TI - [The ACFAS-Desjardins prize: Simon Grenier-Michaud. Interview by Dalila Benhaberou-Brun]. PMID- 22448430 TI - [Telenursing in wound care]. PMID- 22448431 TI - [Mobile phones: at the service of nursing care]. PMID- 22448432 TI - [Informatics competency in nursing care. Perceptions of future nurses]. PMID- 22448433 TI - [Reemergence of measles. Current operation "vaccination" in our schools]. PMID- 22448434 TI - [Home oxygen therapy. New guidelines and a new reference framework currently applied in Quebec]. PMID- 22448435 TI - [Living with a stoma. Part 4. Choosing a collecting device]. PMID- 22448436 TI - [Motivational interview]. PMID- 22448438 TI - [Helping her to choose a contraceptive]. PMID- 22448437 TI - [Brain concussions in young athletes. Respecting the rules of the game]. PMID- 22448439 TI - [Chronic lumbago --no reason to suffer in silence]. PMID- 22448440 TI - [Preventing infections. Chlorhexidine gauze given to patients]. PMID- 22448441 TI - [Canadians affected by income gaps. Risk of early death in the cities with the deepest gaps]. PMID- 22448442 TI - [Keeping the cognitive functions. Excessive salt and no exercise affect the cognitive functions in the elderly]. PMID- 22448443 TI - [Insulin in the era of the wireless. Management of type 1 diabetes]. PMID- 22448444 TI - [Botox --against chronic migraine]. PMID- 22448445 TI - [Metastatic breast cancer. Everolimus --a drug delays the progression of the tumor]. PMID- 22448447 TI - [Budget surplus? Making wise investments]. PMID- 22448446 TI - [Kalifa and malaria. Chronicle of a nurse in Ethiopia]. PMID- 22448448 TI - Local and systemic safety of intranasal corticosteroids. AB - The safety and efficacy of intranasal corticosteroids (INCs) are well established for the management of allergic rhinitis, rhinosinusitis, and nasal polyps. As seen in numerous studies, INCs demonstrate markedly reduced systemic bioavailability compared with oral and even inhaled corticosteroids and have shown an excellent safety profile over 3 decades of use. Nonetheless, concerns remain among some prescribers and patients that these agents may reach the systemic circulation in sufficient concentration to produce adverse effects (AEs). Available evidence does not support these concerns. A review of the published literature indicates that the side effect profiles of INCs consist primarily of a low incidence of mostly mild and often transient local AEs, such as nasal irritation and epistaxis.The second-generation INC agents currently in use (mometasone furoate nasal spray, fluticasone propionate, ciclesonide, and fluticasone furoate) have favorable pharmacokinetic characteristics that further minimize systemic bioavailability (< 1%) compared with older INCs and compared with oral agents, thereby limiting the risk for systemic adverse events. PMID- 22448449 TI - Diagnostic utility of components in allergy to Anisakis simplex. AB - BACKGROUND: In our region, Anisakis allergy is responsible for 8% of acute urticarial reactions, 25% of which progress to anaphylactic shock. The poor specificity of skin tests and in vitro specific immunoglobulin (Ig) E means that Anisakis allergy is frequently overdiagnosed. OBJECTIVE: We studied the diagnostic value of 2 Anisakis allergens: rAni s 1 and rAni s 3. METHODS: Skin tests, the basophil activation test (BAT), and specific IgE determination were performed with rAni s 1 and 3 in 25 patients allergic to Anisakis, 17 atopic controls, and 10 controls with acute urticaria and positive skin test and sIgE results for Anisakis, but no allergy to Anisakis. RESULTS: For rAni s1, skin tests had a sensitivity and specificity of 100% and specific IgE had a sensitivity and specificity of 100% in the atopic control group and 90% in the urticaria control group. BAT had a sensitivity of 96.8% and a specificity of 100% in the atopic control group and 66.7% in the urticaria control group. For rAni s 3, only 1 patient had positive specific IgE results to rAni s 3. All other techniques gave negative results in patients and controls CONCLUSIONS: rAni s 1 is the major allergen of Anisakis and the target allergen when diagnosing allergy to Anisakis, rAni s 3 is not relevant when attempting to explain false-positive results. PMID- 22448450 TI - Preliminary study of the cellular characteristics of primary bronchial fibroblasts in patients with asthma: expression of alpha-smooth muscle actin, fibronectin containing extra type III domain A, and smoothelin. AB - BACKGROUND: The relationship between fibroblasts, myofibroblasts, and smooth muscle cells within the airway wall remains poorly understood. OBJECTIVE: The cellular characteristics of primary bronchial fibroblasts from patients with asthma were investigated by evaluating the expression of 3 proteins: alpha-smooth muscle actin (SMA), fibronectin containing extra type III domain A (EDAcFN), and smoothelin. METHODS: Expression of SMA, EDAcFN, and smoothelin was evaluated in primary fibroblasts from 3 patients with asthma of varying symptom severity, embryonic fibroblasts, and a healthy control. In addition, primary bronchial fibroblasts from patients with asthma were assessed for SMA at various incubation times (4 hours to 76 hours) and with different extracellular matrices (ECMs). Immunofluorescence was assessed by manually counting cells that stained positively as fine filamentous structures under a fluorescence microscope. RESULTS: Expression of filamentous SMA tended to increase with the length of incubation. The positive to total cell ratio for filamentous cells did not differ significantly between the various kinds of ECMs onto which cells were plated (P > .05). Primary bronchial fibroblasts from asthma patients produced more prominent expression of EDAcFN than control fibroblasts. Smoothelin was not expressed in any fibroblasts. CONCLUSIONS: More than 50% of primary bronchial fibroblasts were defined as myofibroblasts. Primary bronchial fibroblasts in patients with asthma had more potential for tissue fibrosis than control fibroblasts. No mature smooth muscle cells were observed in primary bronchial fibroblasts in patients with asthma. PMID- 22448451 TI - Clinical efficacy of web-based versus standard asthma self-management. AB - BACKGROUND: Guided self-management is an important component of asthma care. Most trials have evaluated paper-based strategies. The effectiveness of new communication technologies remains uncertain. OBJECTIVES: To compare the feasibility and clinical outcomes of a standard paper-based asthma self management strategy with web-based strategies. METHODS: In a crossover trial, 21 patients using inhaled corticosteroids and long-acting B2-agonists (mean [SD] age 29 [10] years) were randomly assigned to use a sequence of web-based and paper based diary and action plan. Quality of life, asthma control, lung function, and airway inflammation were assessed using the Asthma Life Quality Questionnaire (ALQ), Asthma Control Questionnaire (ACQ-5), Mini Asthma Quality of Life Questionnaire (Mini AQLQ), and office spirometry. The ratio of forced expiratory volume in the first second of expiration (FEV1) to peak expiratory flow (PEF) rate (PiKo-1) and fraction of exhaled nitric oxide (FE(NO)) were monitored. The main clinical outcomes were asthma control and FE(NO). Quality of data and adherence to monitoring tools were the main process outcomes. RESULTS: Significant improvements were observed in the AQL and ACQ scores, although lung function did not change. FE(NO) was significantly reduced only after a web-based strategy but a significant period effect occurred (P = .006). There were no differences in clinical outcomes between web-based and paper-based management. No intervention-related adverse effects were observed. Adherence seemed higher with the paper-based strategy (P < .001). However, paper data were unreliable when compared to automatic daily electronic FEV1/PEF records. Twelve patients were very interested in continuing self-management with the web-based approach compared with 2 in using paper tools (P = .002). CONCLUSIONS: Web-based management was feasible, safe, and preferred by patients. Short-term outcomes were at least as good, and data quality was improved. PMID- 22448452 TI - Immunogenicity of Phleum pratense depigmented allergoid vaccines: experimental study in rabbits. AB - BACKGROUND: Immunogenicity studies are based on accurate preclinical and clinical assessment of pharmaceutical products. The immunogenicity of modified allergen vaccines has not been fully elucidated, and the mechanisms involved are not well understood. Animal and human models have recently shown that depigmented allergoids induce specific immunoglobulin (Ig) G against individual allergens, thus supporting the clinical efficacy of these vaccines. OBJECTIVE: The aim of this study was to investigate the production of specific IgG against individual antigens and their isoforms in rabbits injected with depigmented allergoid extracts of Phleum pratense pollen. METHODS: Two New Zealand rabbits were immunized with depigmented-polymerized extracts adsorbed onto aluminum hydroxide (Depigoid) of P pratense. Rabbits were injected 3 times (35 microg Phl p 5). Specific IgG titers against native, depigmented, and depigmented-polymerized extracts and individual allergens (rPhl p 1 and rPhl p 5a) were analyzed by direct enzyme-linked immunosorbent assay. The capacity of these synthesized antibodies to recognize individual native and depigmented allergens and different isoforms was evaluated by immunoblot and 2-D analysis. RESULTS: All rabbits produced high titers of specific IgG against the 3 extracts. Rabbits injected with depigmented allergoids produced similar specific antibody titers against native, depigmented, and depigmented-polymerized extracts. Serum samples recognized individual allergens and their isoforms in the nonmodified extracts. CONCLUSION: Vaccines containing depigmented allergoid extracts of P pratense induce immunogenicity in vivo. The antibodies produced after injection of these extracts clearly recognized allergens and different isoforms in their native configuration. PMID- 22448453 TI - Diagnosis of patients with immediate hypersensitivity to beta-lactams using retest. AB - BACKGROUND: beta-Lactams are the drugs most frequently involved in hypersensitivity reactions mediated by immunoglobulin (Ig) E. OBJECTIVE: To evaluate a population of patients with suspected B-lactam allergy using a validated algorithm that includes specific IgE antibodies, skin testing, and/or a drug provocation test. METHODS: A total of 1032 patients with symptoms compatible with B-lactam allergy were evaluated by means of their clinical history, specific immunoglobulin (Ig) E antibody determinations (benzylpenicillin, ampicillin, and amoxicillin), and skin tests with major determinants (penicilloyl-polylysine) and minor determinants (minor determinant mixture) of benzylpenicillin, penicillin G, ampicillin, and amoxicillin-clavulanic acid. Patients whose skin test results were negative were challenged with amoxicillin-clavulanic acid. Only immediate hypersensitivity reactions were evaluated. All patients with negative study results and for whom a reaction occurred more than 1 year before were retested using the same protocol. RESULTS: A total of 170 patients (16.4%) were finally confirmed as having immediate allergic reactions to beta-lactams (62.3% by skin testing, 16.5% by specific IgE, and 21.2% by drug provocation test). The mean age of these patients was 43.3 years, and the drug most frequently involved in the reaction was amoxicillin (41.1%), followed by the combination amoxicillin clavulanic acid (36.4%). In the remaining 22.5%, different beta-lactams were involved or the culprit drug was not known. Only mild reactions were observed after the drug provocation test. A retest was required in 23% of patients in order to confirm their hypersensitivity. CONCLUSIONS: These results indicate that a diagnostic protocol based on the combination of skin testing and in vitro determination of specific IgE antibodies plus, if required, drug provocation testing is an appropriate procedure for evaluating immediate hypersensitivity reactions to beta-lactams. Because the sensitivity of skin testing and in vitro IgE assays is not optimal and a considerable proportion of patients are tolerant, drug provocation tests are necessary to achieve the diagnosis or confirm tolerance. A large percentage of patients (23%) were diagnosed using retest. PMID- 22448454 TI - Umbilical artery pH values at birth and risk of asthma at 5 to 6 years of age. AB - BACKGROUND: Intrapartum factors may have a role in the development of asthma and allergic diseases among offspring. OBJECTIVE: To investigate the association between umbilical arterial pH values at birth and asthma, allergic rhinitis, and atopic eczema in children. METHODS: We performed a case-control study of 222 asthmatic children and 183 control children aged 5 to 6 years with umbilical artery pH values recorded at birth. Associations were evaluated using logistic regression analysis. RESULTS: Asthmatic children had significantly lower umbilical artery pH values at birth than nonasthmatics, even after adjusting. Children who were born with pH values of 7.20-7.25 had a 2.62-fold (95% confidence interval [CI], 1.31-5.23) higher risk of asthma and children who were born with umbilical arterial pH values < or = 7.19 had a 3.22-fold (95% CI, 1.51 6.87) higher risk of asthma than children who were born with umbilical arterial pH values of 7.26-7.30. In contrast, children who were born with umbilical arterial pH values > or = 7.30 had a 0.41-fold lower risk of atopic eczema than children who were born with umbilical arterial pH values of 7.26-7.30. No such association was detected between umbilical artery pH values and allergic rhinitis. CONCLUSIONS: Stressful events at birth may play an important role in the development of asthma during early childhood. In contrast, higher umbilical arterial pH values were associated with a decreased risk of parent-reported atopic eczema at 5-6 years. PMID- 22448455 TI - Genetic variant rs4982958 at 14q11.2 is associated with allergic rhinitis in a Chinese Han population running title: 14q11.2 is a susceptibility locus for allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) is one of the most common diseases caused by the combined effects of intrinsic factors (susceptibility genes and immunological status) and the external environment. Analyses of ascendant family history of atopic disease suggest that AR and atopic dermatitis might share a similar genetic background. OBJECTIVE: To conduct a case-control study in a Chinese Han population to evaluate the potential influence of single nucleotide polymorphisms (SNPs) at FLG, 5q22.1, 11q13.5, 14q11.2 and 20q13.33 on AR. METHODS: Ten SNPs- rs11204971 and rs3126085 at FLG, rs10067777, rs7701890, rs13360927, and rs13361382 at 5q22.1, rs6010620 at 20q13.33, rs7936562 and rs7124842 at 11q13.5, and rs4982958 at 14q11.2 were genotyped in 363 cases and 668 controls using the Sequenom MassArray system. Data were analyzed with PLINK 1.07 software. RESULTS: The T allele of rs4982958 at 14q11.2 was observed to be significantly associated with AR (P = .002, OR = 0.73, P(Bonferront) = .02). Genotype-based association testing revealed that the recessive model might provide the best fit for rs4982958 (P(Bonferroni) = .01). In subphenotype analyses, the rs4982958 T allele was also significantly associated with persistent AR (P = .01) and more than 2 positive skin prick tests (P = .038). CONCLUSION: We identified a novel susceptibility locus 14q11.2 for AR that might bear candidate genes conferring susceptibility to AR and affecting disease phenotypes. PMID- 22448456 TI - AAT polymorphisms in intron 20 of NOS1 confer vulnerability to mite-induced allergic rhinitis in Chinese patients. PMID- 22448457 TI - Glatiramer acetate anaphylaxis: detection of antibodies and basophil activation test. PMID- 22448458 TI - Azathioprine-induced Sweet's syndrome. PMID- 22448459 TI - SCID-like phenotype associated with an inhibitory autoreactive immunoglobulin. PMID- 22448460 TI - Bronchospasm induced selectively by paracetamol. PMID- 22448461 TI - Oral desensitization to egg enables CD4+FoxP3+ cells to expand in egg-stimulated cells. PMID- 22448462 TI - Atopic manifestations in patients with ulcerative colitis: a report from Chile. PMID- 22448463 TI - Specific oral tolerance induction (SOTI) to egg: our experience with 19 children. PMID- 22448464 TI - Severe primary antibody deficiency due to a novel mutation of mu heavy chain. PMID- 22448465 TI - [School shooting in statu nascendi]. AB - In the last few years, amok-like killings and especially so-called "school shootings" have received a great deal of public attention both in the Old and the New world. Meanwhile, criminal psychological research has gained a thorough insight into this dangerous development in young people. Thus, the possibility to assess the concrete threat of such a multiple killing before it is carried out has been considerably improved, as many prognostic criteria have been worked out in the meantime. The case report presented shows that it is possible to exercise a favourable influence on this critical negative trend. PMID- 22448466 TI - [Illness and death of the violin virtuoso Nicolo Paganini--interpretation based on new hair investigations]. AB - The violin virtuoso Paganini died at Nice in 1840 after a long, severe illness. It is undisputed that Paganini was treated with mercury for suspected syphilis and lost all his teeth in 1828 because of that treatment. In the comprehensive literature published on this topic, most authors assume that the terminal complaints and his death were caused by tuberculosis. On the other hand, the hypothesis that he may have died from mercury poisoning was rejected, because there was no information available supporting this assumption. The authors performed morphological investigations using light microscopy and raster electron microscopy (REM). The examined hairs corresponded to a growth phase of > 1 year and < 3 years before death. Structural damage to the hairs indicate heavy metal intoxication in that phase of life; compatible results were supplied by the complex investigations using ICP mass spectrometry and TXRF, which revealed high concentrations of mercury. Using ICP-MS, the mean value for mercury found in the hair sample was 15.4 microg/g with a standard deviation of 0.7 microg/g. The values obtained when investigating segments of single hairs showed high dispersion, but overlapped with the values from the area investigated using ICP MS. Information not yet considered in the literature support the diagnosis of syphilis and provide a complete and unambiguous explanation for Paganini's death on the basis of the mercury concentrations found. PMID- 22448467 TI - [Identification of a corpse using autosomal and gonosomal STR markers]. AB - The identification of unidentified corpses poses an exceptional challenge in the field of forensic medicine, because visual traits are often unspecific. Forensic genetics offer a reliable means to determine the identity of a corpse unambiguously. In the process, Y and X chromosomal markers play an important role. Here, we report about a case out of the ordinary where a corpse was properly identified using forensic genetic methods. PMID- 22448468 TI - [Puppe's rule--a literature review]. AB - As early as 1903, it was pointed out by Puppe that it is possible to determine the sequence of injuries in skull fractures caused by blows to the head: the second fracture ends at the point where a break in cohesion is already present. This finding was confirmed by tests carried out by other forensic pathologists. It soon became clear that the rule also applies to gunshot fractures. In the case of gunshot injuries, it is even possible to make more detailed statements. However, the applicability of Puppe's rule is limited by incomplete ossification or ossification disorders. The priority rule is also found in English-language literature, but without the name of the author who first described it. PMID- 22448469 TI - [Pregabalin--a drug with abuse potential?]. AB - A case of pregabalin misuse associated with delusional ideas in a drug addict is reported. Pregabalin has been approved as an adjunct therapy for epilepsy, but also for neuropathic pain and generalized anxiety disorders and is widely used today. It has also been used in clinical trials to study its potential utility as a treatment for tobacco, alcohol and benzodiazepine addiction. Web sites, case reports and an epidemiological study (Swedish National Register of Adverse Drug Reactions) suggest that the drug may be abused, especially by substance-dependent individuals. Pregabalin was analyzed by LC/MS/MS following precipitation of serum proteins. Vigabatrin was used as internal standard. The concentration of 25 pg pregabalin/mL serum determined in the present case is the second highest value published so far after misuse of the substance. Due to paradoxical agitation, anxiety attacks and abnormal thinking, the man was exculpated. Further studies are required to assess the actual abuse potential of pregabalin. PMID- 22448470 TI - [Suffocation due to foreign body aspiration visualized by post-mortem CT]. AB - The aspiration of a foreign body is a high-risk event in the life of an infant or toddler, which needs fast clinical diagnosis and therapy. If the respiratory tract is massively obstructed, the aspiration can be fatal, as shown in the case of an 18-month-old child. The little boy choked on a fragment of a hazelnut shell. Besides radiography and bronchoscopy, a CT scan can be of special value to visualize the foreign body. Based on the data obtained, a virtual bronchoscopy can be calculated. Compared with conventional radiography, the advantages of computed tomography are better image quality, higher indicative value and the possibility to exactly localize the foreign body in the respiratory tract. In the presented case, the nutshell could be visualized in the larynx before autopsy. PMID- 22448471 TI - [The role of examination of lower urinary tract function in choice of treatment policy in patients with chronic cystitis and chronic nonobstructive pyelonephritis]. AB - The latest investigations evidence for growing number of women with urination disorders in the absence of pathological changes in the urine. This fact suggests the conclusion that dysuria may be caused by neuroendocrine disorders in such women. Besides hemodynamic disorders, urodynamic ones are also involved in pyelonephritis pathogenesis. Our investigations show that chronic non-obstructive pyelonephritis and chronic cystitis can be both a cause and a result of functional disorders of the lower urinary tract related to defects in nervous regulation. Long-term dysfunction of the lower urinary tract may provoke progressive inflammation. In this case antibacterial and anti-inflammatory treatment of chronic cystitis and chronic non-obstructive pyelonephritis may be low effective without normalization of functional condition of the urinary bladder and urethra. PMID- 22448472 TI - [Vaginoplasty with inverted penile skin in male-to-female sex reassignment surgery]. AB - The article presents the results of vaginoplasty in male-to-female sex reassignment surgery, technique of this operation, complications, long-term consequences, functional and social changes. PMID- 22448473 TI - [Etiological structure and antibiotic sensitivity of uropathogens in chronic recurrent infection of the lower urinary tract]. AB - While acute infections of the lower urinary tract (UT) have been studied in detail and antibiotic therapy of such infections is well known, etiology and choice of antibacterial treatment in recurrent chronic UT infection are not so clear. In our trial we aimed at elucidation of etiological structure of chronic cystitis recurrences by means of microbiological investigation of urine samples from 72 women on extended spectrum of nutrient media. In all the cases urine was infected with both aerobic and non-clostridial anaerobic bacteria. We determined prevalent pathogens and their antibiotic sensitivity and compared them with standard pathogens and their sensitivity in acute lower UT infection. We came to the conclusion that it is necessary to develop new recommendations on antibiotic treatment of recurrent chronic cystitis in women. PMID- 22448474 TI - [Diagnosis and treatment of pelvic disorders in patients with multiple sclerosis]. AB - Pelvic dysfunction is a frequent severe manifestation of multiple sclerosis (MS). Basing on the experience in management of 70 MS patients with pelvic affection, we developed an algorithm of outpatient care for such patients which involves neurological, urological and gastroenterological assistence. PMID- 22448475 TI - [Clinicobiochemical and immunological assessment of polyoxidonium efficacy in the treatment of patients with chronic calculous pyelonephritis]. AB - Of 59 patients with chronic calculous pyelonephritis (CCP) taking preparation therapy for extracorporeal lithotripsy, 29 patients received combined basic treatment (antibacterial drugs, phytotherapy, physiotherapy) plus polyoxidonium (a course of 10 intramuscular 6 mg injections each other day). The rest 30 patients (controls) received basic therapy alone. Polyoxidonium efficacy was assessed by the results of clinical, device and immunological investigations, content of the main phospholipid fractions and cholesterol in red cell membranes. The results of the tests show that polyoxidonium has anti-inflammatory and immunomodulating effects, exhibits activity of peroxidation processes, contributes to normalization of a lipid phase of cell membranes and can be recommended as a component of combined treatment of patients with chronic pyelonephritis and urolithiasis. PMID- 22448476 TI - [Panavir in combined treatment of chronic cystitis with hyperplastic changes in urinary bladder mucosa]. AB - Human papilloma virus was detected by polymerase chain reaction in patients suffering from chronic cystitis with hyperplastic changes in urinary bladder mucosa. In most of the examinees (90%) it was HPV of highly oncogenic type 16. Panavir added to combined treatment of such patients produced a significant positive result in long-term period. Improvement was observed both in subjective assessment and the absence of dysuria episodes. PMID- 22448477 TI - [Correction of erectile dysfunction in patients with chronic abacterial prostatitis]. AB - A total of 76 patients with chronic abacterial prostatitis (CAP) in combination with erectile dysfunction were divided into two groups. Clinical symptoms of CAP and severity of erectile dysfunction were the same in both groups. Patients of the study group (n = 36) received pathogenetic treatment (vitaprost plus physiotherapy) and impase. The control group (n = 40) received vitaprost and physiotherapy. The results of the treatment showed that impase addition to combined treatment of CAP patients with erectile dysfunction significantly improves erectile function: 80.6% patients given impase raised their score by International Index of Erectile Function Scale to normal (26 points and higher). Impase efficacy increased with prolongation of the treatment from 4 to 12 weeks. PMID- 22448478 TI - [Effect of herpes simplex virus on spermatogenesis]. AB - To investigate the effect of Herpes Simplex virus (HSV) on spermatogenesis, HSV in ejaculate was detected by a rapid cultural method in 268 infertile males and 47 healthy ones. The number of mobile spermatozoa in HSV infected samples was less than in non-infected samples (21 mln/mlversus 40 mln/ml, p = 0.0001). The relative number of morphologically normal gametes was 13% versus 19% (p = 0.002), respectively. The quantitative karyological test discovered that males with HSV infected ejaculate have more degenerating sex cells while in high virus contamination (more than 10 virus particles in 1 ml) the number of spermatides and spermatocytes of the 1 order at diploten stage is low. Organic testicular culture was used for more detailed study of pathogenetic mechanisms of HSV impact on spermatogenesis. Testicular explants infection was associated with reduction in the number of spermatogones, spermatocytes and spermatides on culturing week 2. The above findings reveal some pathogenetic mechanisms underling fertility disorders in males with HSV infection: a gametotoxic effect of the virus reducing populations of spermatogones, spermatocytes and spermatide; affected mobility and morphological characteristics of spermatozoa. Detection of the mechanisms of HSV action on spermatogenesis opens a perspective of antivirus drug administration in combined treatment of male infertility. PMID- 22448479 TI - [Clinicopathophysiological aspects of utilization of local physiotherapy device mavit in combined treatment of patients with chronic prostatitis and symptomatic prostatic adenoma]. AB - Clinical efficacy of combined treatment with application of MAVIT device was studied in 45 patients with chronic prostatitis. By the results of examination the patients were divided into two groups: group 1 consisted of 25 patients with the diagnosis of prostatic adenoma of stage I-II complicated with chronic prostatitis; group 2 - of 20 patients with chronic prostatitis. Biotissue effect of MAVIT on prostatic blood circulation was studied in 10 patients of group 2 who were examined with transrectal ultrasound (color Doppler mapping) before and after the physiotherapeutic session. The ultrasound examination assessed linear peak blood flow velocity, index of peripheral vascular resistance, intensity of organic vascular net. The treatment results were followed up in both groups for 3 12 months. Positive changes were registered: reduction or disappearance of dysuria, subjective improvement of urination, alleviation of genital pain. Thus, combined conservative treatment of chronic prostatitis in patients with symptomatic prostatic adenoma has a pathogenetic significance and provides adequate preparation for surgery. MAVIT device can be recommended for treatment of chronic prostatitis including patients with prostatic adenoma. PMID- 22448480 TI - [A comparative study of efficacy of 2-, 3- and 4-glass tests in patients with chronic prostatitis]. AB - To compare informative value of three tests (2-, 3- and 4-glass) in diagnosis ofprostatitis we examined 177 patients with chronic prostatitis (CP) who were randomized into 4 groups. Group 1 patients (n = 33) were examined with standard 4 glass test (Mearls and Stamey), patients of subgroup 2a (n = 42) were examined with 2-glass test before finger rectal test (FRT), FRT was made in subgroup 2b (n = 45) before urine collection (2 portions), group 3 (n = 57) was examined by an original technique proposed by the authors. While performing the latter test special focus was given to urination continuity, then the secretion obtained at FRT was studied. Efficacy of each of the tests was assessed by comfort of the procedure for the patient and the doctor, a proportion of false-positive results. The 3-glass test proved most informative and significant. Also, it is sensitive in detection of urogenital tuberculosis. The 4-glass test is not comfortable for both the patient and the doctor. The 2-glass test often produced false-positive results. PMID- 22448481 TI - [Combined treatment of patients with prostatic adenoma and overactive bladder]. AB - Of late, we observe a trend to a progressive rise of overactive bladder (OB) morbidity with age. M-cholinolytic drugs are most effective in management of OB but old patients with prostatic adenoma (PA) and comorbid pathology have a risk of acute urinary retention and serious side effects. We have the experience in combined treatment of 30 old patients with PA and OB with M-cholinolytic and alpha-adrenoblocker. The results of the treatment show its efficacy and absence of complications in the control of residual urine for 3 months. Combination of M cholinolytic with alpha-adreboblocker significantly reduced daily diuresis, improved an accumulation function of the bladder and life quality. PMID- 22448482 TI - [Effects of immunocorrective therapy on immunological indices in patients with chronic bacterial prostatitis]. AB - A total of 57 patients with chronic bacterial prostatitis were divided into two groups. The control group (n = 28) received standard treatment, the study group (n = 29) received treatment including immunomodulator likopid. The tests for IgA, IgM, IgG, compliment components C3, C4, circulating immune complexes were made, immunophenotyping of peripheral blood lymphocytes was performed, chemiluminescence parameters of whole blood and plasma, content of IL-10, TNF alpha, IL-lbeta in seminal fluid were assessed. The detected abnormalities in parameters of systemic and mucose-associated immunity give ground for inclusion of immunomodulators in combined treatment of patients with chronic bacterial prostatitis. PMID- 22448483 TI - [Vitaprost-forte in the treatment of patients with prostatic adenoma]. AB - Our study included 50 patients aged 48-67 years with moderate symptoms of prostatic adenoma (PA). Thirty patients received vitaprost-forte in the form of rectal suppositories for 60 days and alpha-adrenoblocker. A positive effect of the drug on PA symptoms and improvement of life quality by IPSS and QoL questionnaires was observed in 93.3% patients. Relief of infravesical obstruction led to a 43% reduction of residual urine. The effect was stable on day 30 after the treatment. Our findings evidence that vitaprost forte can be successfully and safely used in the treatment of PA in combination with alpha-adrenoblockers. PMID- 22448484 TI - [Nebido in the treatment of hypogonadism syndrome and its complications in men]. AB - The article presents original experience with use of undecanoate (nebido, BayerHealthcare Pharmaceuticals, Germany) in androgenic testosteron replacement therapy in males with hypogonadism. Prospective studies of nebido efficacy were made in males with vein-occlusive erectile dysfunction (n = 20), chronic pelvic pain syndrome (n = 77), metabolic syndrome (n = 170). Retrospective studies assessed efficacy of nebido monotherapy in patients with erectile dysfunction and hypogonadism (n = 34), hematological and urological safety of the drug (n = 40). Laboratory monitoring was performed in all the studies according to ISSAM recommendations. The patients were not included in contraindications to androgenic therapy. Nebido treatment significantly improved libido and erectile function, efficacy of phosphodiesterase of type 5 inhibiors used in moderate and severe erectile dysfunction. Depressive, asthenic, pain symptoms declined in males with chronic pelvic pain. Body fat reduced in metabolic syndrome with alleviation of its other components. Insignificant rise of hemoglobin level and packed cell volume was observed in some patients while a PSA level increase was clinically significant in 10% patients who had initial PSA > 2.5 ng/ml and acromegalia. Also, nebido depressed production of gonadotropins and spermatogenesis. Thus, nebido is highly effective in sexual dysfunction and other somatic disorders caused by hypogonadism. Nebido does not induce severe side effects, but clinically significant rise of PSA level requires treatment discontinuation and more careful urological examination. In view of nebido ability to suppress spermatogenesis, the drug should not be used in reproductively active men. PMID- 22448485 TI - [Iliac neobladder - 10-year experience]. AB - Surgeons of the clinic of P.V. Mandryka Central Military Hospital have rich 10 year experience in creation of neobladders after cystectomy. So, from 2000 to 2009 a total of 90 cystectomies were made for different diseases of the urinary bladder and prostatic gland as well as in cancer of the other pelvic organs. Vesicoplasty, both heterotopic and orthotopic, was performed from an iliac segment by an original technique with creation of antireflux bypass with the ureters. The examination of the patients in different terms after operation (up to 10 years later) provided information about changes in the neobladder under the influence of urine and systemic changes in the body. The analysis of the results show that creation of the iliac neobladder in our modification is perspective, while side effects are rare. Further long-term follow-up will give new arguments for and against this procedure. PMID- 22448486 TI - [Kidney transplantation in recipients with renal carcinoma]. AB - Transplantation of the kidney in patients with renal carcinoma is disputable. The article presents the results of kidney transplantation in different cancer lesions of the patient's kidneys. Seven case histories of patients with primary renal tumors are retrospectively analysed. A clinical case of development of the tumor of own kidney in a patient after transplantation is reported. A time factor of kidney transplantation after tumor removal in a recipient is discussed. PMID- 22448487 TI - [The role of mutation of gene cyp1A1 and benzapilene in cytogenetic changes of urinary tract epitheliocytes in oil industry workers employed in the oil fields of the North of West Siberia]. AB - The examination of 477 oil industry workers and office personnel (control) employed in the oil fields of the North of Tomsk and Tyumen regions has detected increased number of epithelyocytes with micronuclei and an elevated urine level ofbenzapilene in workers employed in oil production. Especially pronounced changes of the above parameters were observed in men with mutant alleles Val of CYP1A1 gene. An enhanced mutation process in oil production workers may be due to a resultant action of different factors on human genome. Involved may be both mutagens and factors of comutagenic nature. The results obtained in this study suggest a conclusion about urgent need of introduction of new scientifically validated criteria of selection of personnel for oil production in the North of the West Siberia. Health examination of the applicants must include genotyping. PMID- 22448488 TI - [Combined endoscopic treatment of patients with prostatic adenoma]. AB - We studied efficacy of combined surgical treatment of patients with prostatic adenoma (PA) including laser vaporization (LV) and transurethral electroresection (TUER). A total of 294 PA patients entered the trial. Photoselective LV was made with GreenLight PVP laser (80 W) in 180 patients and Dornier Urobeam laser on the basis of diode laser (940 nm) in 34 patients. The other 60 and 20 patients after photoselective LV (GreenLight PVP 80-W laser) and (Dornier Urobeam laser), respectively, have undergone TUER of coagulative-necrotic scab after vaporization. The analysis of the treatment results show that laser vaporization on both lasers is followed with dysuria in 26.6 and 32.4% patients, respectively, while in combination of LV with TUER - in 11.25% patients. Thus, the above combined endoscopic treatment can be recommended as most effective as it rapidly improves quality of life of the patients. PMID- 22448489 TI - [Laparoscopic and microsurgical varicocelectomy: comparison of the results]. AB - Laparoscopic and microsurgical varicocelectomy were compared by clinical and cost efficacy results. Microsurgical subinguinal varicocelectomy was performed in 129 patients, laparoscopic - 167 patients. Median of the patients' age was 27 years (16-38 years). Median of follow-up in microsurgical operation was 26 months (13 60 months), in laparoscopic method - 62 months (28-71 months). By clinical criteria (time of surgical intervention, amount of analgetic drugs in the postoperative period, stay in hospital, rate of varicocele recurrence and postoperative complications), the results of microsurgical varicocelectomy proved significantly better than those of laparoscopic operations. The rate of all complications after microsurgical ligation of the testicular veins was 8 times less than after laparoscopic intervention, the rate of varicocele recurrence - 2.4 times less. Microsurgical operations were financially more effective (by 20%) than laparoscopic varicocelectomy. Thus, microsurgical varicocelectomy is more effective than laparoscopic one both clinically and financially. PMID- 22448490 TI - [Radiodiagnosis of early-stage nephroangiopathy in children with arterial hypertension]. AB - A total of 115 children aged 13-17 years (mean age 15.77 +/- 1.89 years, 98 boys and 17 girls) with essential arterial hypertension (EAH) were examined. Of them, 70 children had stable arterial hypertension (SAH), 45 children - labile arterial hypertension (LAH). 24-h monitoring of blood pressure, triplex ultrasound study of the renal vessels were performed in all the patients. The assessment of renal hemodynamics showed that blood flow was more active in SAH patients. The clinostatic test revealed inhibition of circulation at the level of the basic trunk (by 26% in SAH and by 22% in LAH) and segmentary renal arteries (by 28% in SAG), IR ( < 0.52). The above findings confirm the action of arterioveinous bypass blood flow mechanism and provide diagnosis of nephroangiopathy at early stages of EAH. PMID- 22448491 TI - [Intravesical electrostimulation and magnetotherapy in chronic pyelonephritis and cystitis in children with urodynamic disorders]. AB - The results of the treatment of 38 children (6 boys and 32 girls, age 6-14 years) with chronic pyelonephritis and/or cystitis complicated with neurogenic dysfunction of the urinary bladder (NDUB) and/or vesicoureteral reflux (VUR) of the first-third degree demonstrate efficacy of intravesical electrostimulation (IVES) and adrenal magnetotherapy. IVES was conducted with high-frequency current impulses (2.2 kHz) by means of INTRASTIM attachment to the device AMUS-01 INTRAMAG in the region of the urethrovesical anastomosis via solution of the drugs for instillation. As the result of exposure to both physical factors in the presence of standard medication, NDUB symptoms alleviated (by E.L. Vishnevsky's criteria) by 59.5% against 38.1% in the control group. Dopplerographic examination of renal vessels stated a 24.3% increase in blood flow in the major renal artery in the study group against 10.5% in the control. The proposed complex pharmacological plus physiotherapeutic treatment of chronic pyelonephritis and cystitis in abnormal urodynamics resulted in a 2.2-fold decrease in the number of recurrences compared to the standard treatment. PMID- 22448492 TI - [Cranberry preparations in urological practice: view of a clinical pharmacologist]. AB - Cranberry has been used in various urological problems from ancient times but only now cranberry preparations were studied clinically and pharmacologically in terms of prophylaxis of urinary tract infections. The active component of cranberry are protoantocianides which have no antibacterial activity but inhibit adhesion of uropathogenic E.coli due to block of P-fimbria and thus inhibit development of biofilms. When cranberry preparations are taken per os, proantocianides accumulate in high doses in urine. Efficacy of cranberry in prophylaxis of recurrent urinary infection was demonstrated in randomized clinical trials. Administration of standard cranberry preparations containing not less than 36 mg of proantocianides such as monurel is recommended by European Urological Association (EUA). Cranberry preparations are well tolerated, especially in capsules. However, they can contribute to nephrolithiasis progression and enhance anticoagulation action of indirect anticoagulant drugs. PMID- 22448493 TI - [Operative treatment of a patient with tuberous sclerosis in suspected renal carcinoma]. PMID- 22448494 TI - [Eetiological hypotheses of renal carcinoma onset]. PMID- 22448495 TI - [Analysis of the use of field medical units in the armies of NATO and Russian Armed Forces]. AB - An analysis of medical services of NATO and the Medical Service of the Armed Forces of the Russian Federation of modern technology deployment stages of medical evacuation (tents, inflatable structures, shelters, containers, medical armored vehicles, cars, etc.) is presented. Examples of their usage in isolated employment, usage in the group as a mobile medical stations and field hospitals in various conditions, the prospects and directions of development of technical means deployment of medical service are given. PMID- 22448496 TI - [Status and problems of postgraduate training of medical staff of Disaster Medicine Service]. AB - An analysis of the postgraduate training of doctors of Disaster Medicine Service in the central and local training bases in the federal districts of Russian Federation in 2010 is performed. It was concluded that the existing Department of Emergency Medicine and mobilization training and health education can not reach those who need further training. It was proposed to create on the basis of a FSI VTSMK "Protection" Institute of Emergency Medicine to improve the training of doctors, training and methodological support of teaching and training of the teaching staff. PMID- 22448497 TI - [Bifurcation coronary stenting guided by intravascular diagnostic tools]. AB - Results of coronary bifurcation stenting guided by intravascular diagnostic tools were searched. 85 patients took part in the study, there were generated two groups. In the research group intravascular ultrasound of main vessel has revealed stent malapposition in 97.6%. Fractional flow reserve of jailed side branch ostium is less then 0.75 in 7.1% only, despite of the average 78 +/- 4% narrowing. Severe cardiac events in research group during long-term clinical follow-up were better in research group: 6.9% vs 32.5% (p < 0.05). PMID- 22448498 TI - [About the improvement of urologic care for soldiers with erectile dysfunction]. AB - Organizational concepts of improvement of urological aid given to military men with erectile dysfunction. The reasons for insufficiency of urological aid rendered to military men with erectile dysfunction were established. The algorithm of its diagnostics was developed. Complete and reduced volume of urological aid with reference to the existing medical and diagnostic capacities of military medical and preventive treatment facilities has been developed. Organizational concepts of improvement of urological aid given to the patients with erectile dysfunction have been determined. PMID- 22448499 TI - [Military activities of outpatient clinics to ensure the sanitary-epidemiological welfare of the population]. AB - The article describes the experience of the military outpatient institutions in providing sanitary-epidemiological welfare of the attached troops and medical staff. The list of activities implemented in practice of this trend is lead up, suggestions for the improvement are given. PMID- 22448500 TI - [Lessons from the organization of medical support during the Battle for Moscow]. AB - Covered and analyzed the state of medical support during the Battle for Moscow. The problems of organizing of medical support for troops during all stages of this war--defensive operations and counter-offensive strategic operations are considered. Analyzed errors and mistakes made in the course of medical support of combat operations of the fronts that participated in the battle for Moscow. The article traces the solutions of the problems encountered and assess the results of translating these decisions into practice. Particular attention is paid to problems of organization of work as a hospital base fronts and armies, and the medical units and divisional managers, as well as management of medical service, evacuate the wounded and sick, the dynamics of formation of the provision of specialized medical care and anti security forces. PMID- 22448501 TI - [Front roads of Professor M. K. Kuzmin (the 70th anniversary of the Battle for Moscow]. AB - The article is a biographical sketch about the veteran and invalid of Great Patriotic War, the holder of many military decorations, honorary citizen of several cities in the battles for which he was involved, a prominent historian of medicine, doctor of medical sciences, professor Mikhail Kuzmin (1920-2010). Over the years of scientific and teaching life professor M. K. Kuzmin published over 300 scientific publications, including 9 monographs, textbook of the history of medicine, published lectures, and manuals. PMID- 22448502 TI - [Ivan Stepanovich Kolesnikov--"general of surgery" (the 110th anniversary of his birth)]. AB - The article is devoted to the 110th anniversary of outstanding surgeon, scientist and educator, academician of the USSR Ivan Stepanovich Kolesnikov. During the Great Patriotic War--he was an army surgeon on the Central Front, and then--in Leningrad. As one of the pioneers of thoracic surgery, the first in the Soviet Union began to apply the resection of pulmonary tuberculosis, cancer, and acute and chronic suppurative diseases of the lung and pleura, reflecting the experience of more than 4,000 thousand operations in numerous monographs and published in 1960, major work, "Resection lights". On his initiative in 1961 was the first in the Soviet Union an independent chair of the thermal lesions, and in 1964--the country's first intensive care unit and intensive care. He published over 200 papers on topical issues of surgery, including 28 monographs. Under his leadership were trained 25 Ph.D. and 43 master's theses. PMID- 22448503 TI - [Contribution of Academician V. D. Belyakov to the development of epidemiological science and medical education]. AB - The paper analyzes life and scientific legacy of academician and professor of Natural Sciences, Major-General of the Medical Service Vitaly Dmitrievich Belyakov (1921-1996). The outstanding epidemiologist made a valuable contribution to the training of personnel for the military medical service and health of the country, as well as the improvement of anti-epidemic support for the troops and the navy and the country's population. Academician V. D. Belyakov is considered as one of the giants of the domestic medicine dedicated their lives to the development of epidemiological science and preventive work in Russia. PMID- 22448504 TI - Health assessment of free-ranging and captive Matschie's tree kangaroos (Dendrolagus matschiei) in Papua New Guinea. AB - Medical evaluations were performed on free-ranging and captive Matschie's tree kangaroos (Dendrolagus matschiei) in Papua New Guinea. The health assessment included physical examination, morphometrics, cloacal swab; and blood, hair, and feces collection. Radio-collars were placed on free-ranging tree kangaroos to determine home range and forest habitat use. The free-ranging tree kangaroos were lightly anesthetized with tiletamine/zolazepam for the data collection. A total of nine free-ranging and seven captive tree kangaroos were evaluated; medical samples were collected from six and five animals, respectively. Results of physical examination, anesthetic monitoring, serum vitamin, mineral, trace nutrient, and electrolytes, whole blood heavy metal analysis, mycobacterial screening, and fecal examinations are presented. Free-ranging tree kangaroos had significantly lower values for beta carotene, copper, selenium, molybdenum, lead, and arsenic and significantly higher values for vitamin E than captive individuals. Cloacal swabs were all negative for Mycobacterium avium via polymerase chain reaction. Some free-ranging and captive individuals had positive coprologic exams revealing Eimeria spp. oocysts and strongyle spp. type ova. These are the first medical and anesthetic data published on Matschie's tree kangaroos from Papua New Guinea. PMID- 22448505 TI - Standing sedation in captive zebra (Equus grevyi and Equus burchellii). AB - Nine Grevy's zebras (Equus grevyi) and three Burchell's zebras (Equus burchellii) were immobilized in a standing position a total of 70 times for minor, nonpainful procedures over a 9-yr period. Standing sedation was successfully obtained with a combination of detomidine and butorphanol on 47 occasions (67.1%). Detomidine i.m. (median 0.10 mg/kg; range: 0.07-0.21) was administered by dart, followed 10 min later by butorphanol i.m. (median 0.13 mg/kg; range 0.04-0.24). The dosages were varied depending on the initial demeanor of the animal. On 23 occasions (32.9%), small amounts of etorphine (median 2.5 microg/kg; range 1.1-12.3 microg/kg) plus acepromazine (median 10 microg/kg; range 4.4-50 microg/kg) (as in Large Animal-Immobilon) had to be administered i.m. to gain sufficient sedation. In these latter cases, the animals were either excited or known for their aggressive character. The zebras were sufficiently immobilized for the length of most procedures (<45 min) without supplementation. At the end of the procedure, the animals were given atipamezole (2 mg per 1 mg detomidine used) and naltrexone (0.1 mg/kg) to reverse the sedative effects, irrespective of whether etorphine was used or not. Standing sedation, using the combination of the alpha-2 agonist detomidine and the partial agonist-antagonist opioid butorphanol (in some cases supplemented with etorphine + acepromazine), proved to be a very efficacious and safe method to be used in zebras under zoo conditions for short-lasting, nonpainful procedures. PMID- 22448506 TI - Propagation method of saving valuable strains from a Mycobacterium liflandii infection in Western clawed frogs (Silurana tropicalis). AB - Mycobacterium liflandii has been responsible for an emerging infection reported in the international trade of Western clawed frogs (Silurana tropicalis). This study shows that this mycolactone-producing Mycobacterium (MPM) has expanded its distribution range to France. The results of this study suggest that the use of in vitro fertilization to maintain genetic lines could be a temporary solution for valuable S. tropicalis propagation. PMID- 22448507 TI - Evaluation of exertion and capture stress in serum of wild dugongs (Dugong dugon). AB - Seven hundred fifty-one dugongs (Dugong dugon) were pursued, captured, and handled for up to 20 min for population sampling. Fifty of these dugongs were then removed from the water for up to 55 min for comprehensive medical examination. Fifty whole blood and separated serum samples were analyzed for potassium, sodium, chloride, creatinine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), urea, creatinine, glucose, anion gap, and total blood CO2. Serum biochemical variables of the dugong were compared with those obtained in previous studies of the related West Indian manatee, a mammal that does not appear to experience capture myopathy based on available data. Differences between these species included higher blood sodium and chloride in dugongs, which may reflect differences in salt balance and renal function, and higher blood lactate and CO2. Some biochemical analytes such as CK and AST, which may be indicative of rhabdomyolysis associated with capture stress myopathy (a potentially fatal condition for which dugongs have been thought to be highly susceptible) were high compared with levels previously measured in wild West Indian manatees (Trichechus latirostris). One of the 50 dugongs had marked elevations of CK and AST but showed no other clinical indications of rhabdomyolysis associated with capture myopathy such as hyperthermia. Rather, generally high levels of lactate, CK, and AST most probably reflect metabolic acidosis resulting from the exertion involved in the pursuit prior to capture. Earlier observations suggesting that dugongs were probably susceptible to capture stress myopathy (based on high serum potassium levels) were not supported by this study. Capture and handling methods currently used on dugongs in this research program do not appear to result in acute capture stress. PMID- 22448508 TI - Evaluation of two-dimensional and three-dimensional ultrasound in the assessment of thyroid volume of the Indo-Pacific bottlenose dolphin (Tursiops aduncus). AB - The assessment of thyroid volume plays an indispensable role in the diagnosis and management of different thyroid diseases. The present study evaluates the accuracy of dolphin thyroid volume measurement as determined by four two dimensional (2D) ultrasound methods (A-D), with a standard of reference using three-dimensional (3D) ultrasound. The measurement accuracy for different recognized thyroid configuration is also evaluated. Inter- and intraoperator variability of the measurement methods was determined. Thyroid ultrasound examinations were conducted in 16 apparently healthy Indo-Pacific bottlenose dolphins (Tursiops aduncus) with 2D and 3D ultrasound under identical scanning conditions. All 2D ultrasound measurement methods yielded high accuracies (79.9 81.3%) when compared with the 3D ultrasound measurement, and had high measurement reproducibility (77.6-86.2%) and repeatability (78.1-99.7%). For 2D ultrasound measurements, Methods A and B were more accurate and reliable than Methods C and D, regardless of thyroid configuration. Ultrasound is useful in the measurement of thyroid volume in bottlenose dolphins. For the first time, a reliable ultrasound scanning protocol for measuring dolphin thyroid volume was developed, which provides a means to establish a normative reference for the diagnosis of thyroid pathologies and to monitor the thyroid volume during the course of treatment in living dolphins. Key words: 3D ultrasound, Indo-Pacific bottlenose dolphin, thyroid volume measurement, Tursiops aduncus. PMID- 22448509 TI - Neoplasia of captive yellow sea horses (Hippocampus kuda) and weedy sea dragons (Phyllopteryx taeniolatus). AB - Syngnathidae is the family of fish that includes sea horses, pipefish, and sea dragons. To date, only a single publication has described neoplasia in syngnathids, a fibrosarcoma of the brood pouch in an aquarium-reared lined sea horse (Hippocampus erectus). From 1998 until 2010, the Toronto Zoo submitted 172 syngnathids for postmortem; species included the spotted or yellow sea horse (Hippocampus kuda), the pot-bellied sea horse (Hippocampus abdominalis) and the weedy sea dragon (Phyllopteryx taeniolatus). Seven neoplasms and two neoplastic like lesions were identified from these cases. Under light microscopy, the neoplasms had morphological characteristics of a cardiac rhabdomyosarcoma, renal adenocarcinoma, renal adenoma, renal round cell tumors, which were likely lymphomas, exocrine pancreatic carcinoma, and intestinal carcinoma. Of these neoplasms, four had clear evidence of metastasis: the pancreatic and intestinal carcinomas and both round cell tumors. As syngnathids are highly fastidious animals, they can be difficult to maintain in captivity. In order to improve their husbandry, preventative and palliative care, as well as treatment, it is important to investigate and document the types of diseases affecting syngnathids. PMID- 22448510 TI - Comparison of intraosseous and peripheral venous fluid dynamics in the desert tortoise (Gopherus agassizii). AB - The efficacy of intraosseous catheterization has not been described previously in the desert tortoise (Gopherus agassizii). The goal of this study was to describe and compare the efficacy of four intraosseous catheter sites (humerus, femur, plastocarapacial junction [bridge], and gular region of the plastron) to jugular catheterization. Five adult tortoises were catheterized in each of the sites at least once. The distribution of a bolus injection of radiopharmaceutical (technetium-99m-diethylenetriaminepentaacidic acid [99mTc -DTPA]) was monitored via gamma camera over 2-min periods at five time intervals over 24 min. Compared to jugular catheterization, the humerus and femur sites provided the next best vascular access, with 84.4 and 61.8% of activity reaching the systemic circulation by 7 min, respectively. The bridge and gular catheter sites were less effective with only 41.9 and 40.8% systemic activity, respectively. Intraosseous catheters were no more technically difficult to place than jugular catheters and were less commonly dislodged, making them a viable option for vascular access in tortoises. PMID- 22448511 TI - Efficacy of a portable oxygen concentrator with pulsed delivery for treatment of hypoxemia during anesthesia of wildlife. AB - Portable battery-driven oxygen concentrators provide an alternative to the use of oxygen cylinders for treatment of hypoxemia during field anesthesia. The aim of this study was to evaluate the use of the EverGo Portable Oxygen Concentrator (Respironics, Murrysville, Pennsylvania 15668, USA) with pulse-dose delivery for improvement of arterial oxygenation during anesthesia of wildlife. This concentrator delivers oxygen in a pulsed flow with pulse volumes from 12 to 70 ml, up to a maximum capacity of 1.05 L/min. The pulse-dose setting shall be adjusted according to the respiratory rate of the animal, e.g., setting 6 for a respiratory rate < or = 15/min. The study included 16 free-ranging brown bears (Ursus arctos), 18 free-ranging bighorn sheep (Ovis canadensis), and five captive reindeer (Rangifer tarandus). Oxygen was administered via two nasal lines that were inserted through the nostrils to the level of the medial canthus of the eyes. Arterial blood samples were collected before, during, and after oxygen therapy and immediately analyzed. When providing oxygen from the portable concentrator, the arterial oxygenation markedly improved in all brown bears and some reindeer, whereas no or minor improvement was seen in the bighorn sheep. The mean +/- SD (range) PaO2 during oxygen supplementation was 134 +/- 29 (90-185) mmHg in the brown bears, 52 +/- 11 (32-67) mmHg in the bighorn sheep, and 79 +/- 19 (61-110) mmHg in the reindeer. The efficacy of the evaluated method may be influenced by ambient temperature, altitude, pulse-dose setting on the concentrator, the animal's respiratory rate, and species-specific physiology during anesthesia. Advantages of the portable oxygen concentrator included small size and low weight, ease of operate, and rechargeablity. PMID- 22448512 TI - Venous blood gas and lactate values of mourning doves (Zenaida macroura), boat tailed grackles (Quiscalus major), and house sparrows (Passer domesticus) after capture by mist net, banding, and venipuncture. AB - Blood gas partial pressures, pH, and bicarbonate and lactate concentrations were measured from the basilic vein of mourning doves (Zenaida macroura) and the jugular vein of boat-tailed grackles (Quiscalus major) and house sparrows (Passer domesticus) to assess immediate impacts of mist net capture and handling for banding and venipuncture. Mourning doves and house sparrows exhibited mild acidemia (median [minimum-maximum] venous blood pH(41 degrees C) = 7.394 [7.230 7.496] and 7.395 [7.248-7.458], respectively), relative to boat-tailed grackles (Quiscalus major; 7.452 [7.364-7.512]), but for different reasons. Mourning doves exhibited relative metabolic acidosis (lower venous blood pH, higher lactate concentrations, lower bicarbonate, and no significant differences in partial pressure of CO2 (pCO2) or partial pressure of O2 (pO2) compared with boat-tailed grackles). House sparrows exhibited relative respiratory acidosis (lower venous blood pH, higher pCO2, lower pO2, and no significant differences in bicarbonate and lactate concentrations compared with boat-tailed grackles). All birds captured by mist net and handled for banding and venipuncture experienced some degree of lactic acidemia; and values were greater in mourning doves (lactate, 7.72 [3.94-14.14] mmol/L) than in boat-tailed grackles (5.74 [3.09-8.75] mmol/L) and house sparrows (4.77 [2.66-12.03] mmol/L), despite mourning doves resisting least and being easiest to disentangle from the mist net. House sparrows were more susceptible to respiratory acidosis, warranting particular care in handling birds <30 g to minimize interference with ventilation. The different sample collection site for mourning doves may have affected results in comparison with the other two species, due to activity of the wing muscles. However, despite the higher lactate concentrations, pCO2 was relatively low in doves. The metabolic, respiratory, and acid-base alterations observed in this study were minor in most cases, indicative of the general safety of these important field ornithology techniques. The effect of other adverse conditions, however, could be additive. PMID- 22448513 TI - Occurrence of antibodies to Toxoplasma gondii and Lepstospira spp. in manatees (Trichechus inunguis) of the Brazilian Amazon. AB - The presence of Toxoplasma gondii and Leptospira spp. antibodies was investigated in 74 manatees (Trichechus inunguis [Mammalia: Sirenia]) kept in captivity in two rescue units in the northern region of Brazil. Antibodies to T. gondii were detected in 29 (39.2%) of 74 animals by using the modified agglutination test (titer, 1:25). For antibodies against Leptospira spp., sera were diluted 1:50 and tested against 24 strains ofleptospires by microscopic agglutination microtechnique, and positive samples were end titrated. Twenty-three (31.1%) of 74 animals were reactive to four serovars (Patoc 21/23, Castellonis 2/23, Icterohaemorrhagiae 1/23, and Butembo 1/ 23), with titers ranging from 100 to 1,600. This is the first report of antibodies against T. gondii and Leptospira spp. in T. inunguis from the Brazilian Amazon. PMID- 22448514 TI - A retrospective and prospective study of megaesophagus in the parma wallaby (Macropus parma) at the San Diego Zoo, California, USA. AB - At the San Diego Zoo (California, USA), 22 cases of megaesophagus were diagnosed in the parma wallaby (Macropus parma); a prevalence of 21.1%. Parma wallabies often have no clinical signs until severe and chronic dilation of the esophagus is present. Clinical signs of advanced disease include weight loss, swelling of the cervical region, regurgitation without reswallowing of ingesta, short flight distance, depression, collapse, dyspnea, and sudden death. Retrospective and prospective studies at the San Diego Zoo and a multi-institutional survey in the United States were used to try to determine the cause of megaesophagus. The retrospective study did not identify an etiology. The prospective study revealed megaesophagus and severely delayed esophageal transit time in eight of eight animals. Myasthenia gravis, lead toxicosis, toxoplasmosis, and thyroid disease were eliminated as possible causes. Of 286 living and dead parma wallabies surveyed at other institutions, three cases of esophageal diverticulum and one case of megaesophagus were reported. The cause of megaesophagus in parma wallabies was not determined. PMID- 22448515 TI - Cystic endometrial hyperplasia and pyometra in three captive African hunting dogs (Lycaon pictus). AB - Pyometra and cystic endometrial hyperplasia are common in domestic canids and are suspected to develop as a consequence of elevated progesterone levels. Reports of uterine pathology in exotic canids are limited, with some speculating of association with contraception. This report describes pyometra, cystic endometrial hyperplasia, and ovariohysterectomy in three African hunting dogs (Lycaon pictus). Ovarian corpora lutea were detected in two of the dogs, suggesting endogenous progesterone production. One dog had a uterine adenocarcinoma and two had ovarian granulosa cell tumors. Clinical signs included anorexia, lethargy, vulvar discharge, polyuria, polydipsia, and abdominal distention. Diagnosis was based on clinical signs, physical examination, bloodwork, radiography, and ultrasonography, with confirmation through histopathologic evaluation of tissues. Cystic endometrial hyperplasia, pyometra, and uterine neoplasia have rarely been diagnosed in exotic canids; however, they should be considered as differential diagnoses in intact bitches that present with suspected reproductive disease. PMID- 22448516 TI - Treatment of ureteral calculus obstruction with laser lithotripsy in an Atlantic bottlenose dolphin (Tursiops truncatus). AB - An adult female bottlenose dolphin (Tursiops truncatus) presented with acute anorexia secondary to progressive azotemia (blood urea nitrogen = 213 mg/dl, creatinine [Cr] = 9.5 mg/dl) and electrolyte abnormalities (K = 7.4 mEq/L). It was later diagnosed with postrenal obstruction secondary to bilaterally obstructing ureteral calculi seen on ultrasound. Treatment of the obstruction required two endoscopic procedures, cystoscopy for ureteral stent placement and ureteroscopy to perform intracorporeal lithotripsy on the obstructing calculi. Before the first procedure, the dolphin's azotemia was stabilized with aggressive fluid therapy, peritoneal dialysis, and treatment for acidosis. Diuresis subsequent to the fluid therapy enabled passage of the right obstructing urolith. For both endoscopic procedures, the dolphin was placed in left lateral recumbency due to the peritoneal dialysis catheter in the right retroperitoneal region. For the first procedure, a 12-French (Fr) flexible cystoscope was inserted retrograde into the bladder via the urethra, whereupon a calculus was seen obstructing the left ureteral orifice. A 4.8-Fr, 26-cm double-pigtail ureteral stent was placed up the left ureter to relieve the postrenal obstruction. Inadvertent proximal migration of the left ureteral stent occurred during the procedure. However, renal parameters (serum Cr = 5.8, K = 5.4) improved significantly by the next day. For the second procedure, 28 hr later, ureteroscopy was performed to treat the calculus and replace the existing stent with a longer stent. The left ureteral calculus was pulverized into tiny fragments by using a holmium:yttrium aluminum-garnet laser inserted through a 6.9-Fr semirigid ureteroscope. The migrated stent was visualized in the distal left ureter and replaced with a 90-cm single-pigtail ureteral stent that was sutured exterior to the urogenital slit and removed 3 days later. Renal function normalized over the next several days, and the dolphin recovered over the next 2 mo. PMID- 22448517 TI - Multicentric neurofibromatosis with rectal prolapse in a California sea lion (Zalophus californianus). AB - An approximately 31-yr-old California sea lion (Zalophus californianus) with a history of chronic visual impairment and corneal disease presented with slow onset, progressive neurologic deficits. Treatment for rear flipper paresis was not effective and the animal was euthanatized. Histopathologic findings included hepatocellular and biliary neoplasia, ocular amyloidosis, adrenal adenoma and pheochromocytoma, and spinal cord changes consistent with multicentric neurofibromatosis. This is the first documentation of these conditions in a California sea lion. PMID- 22448518 TI - Serial temperature monitoring and comparison of rectal and muscle temperatures in immobilized free-ranging black rhinoceros (Diceros bicornis). AB - Control of body temperature is critical to a successful anesthetic outcome, particularly during field immobilization of wild animals. Hyperthermia associated with exertion can lead to serious and potentially life-threatening complications such as organ damage (including myopathy) and death. Methods for monitoring core body temperature must accurately reflect the physiologic status of the animal in order for interventions to be effective. The goal of this preliminary study was to compare serial rectal and muscle temperatures in field-immobilized black rhinoceros (Diceros bicornis) and evaluate a possible association. Twenty-four free-ranging black rhinoceros were immobilized between February and March of 2010 in Ethosha National Park, Namibia. Pairwise comparisons showed a correlation of 0.73 (95% CI; 0.70-0.75) between rectal and muscle temperature measurements. Results from a multivariable model indicate that muscle temperature readings were, on average, 0.46 degrees C (95% CI; 0.36-0.57 degrees C) higher than rectal temperatures while adjusting for repeated measurements on the same rhinoceros, effect of duration of immobilization, and effect of ambient temperature on rhinoceroses' temperature readings. As immobilization time increased, muscle and rectal temperature values within an individual rhinoceros tended to equilibrate. The overall temperatures decreased by an average of 0.00059 degrees C/min (95% CI; -0.0047 to -0.0035 degrees C/min; P = 0.779). As the ambient temperature at time of immobilization increased by 1 degree C, the average rhinoceros temperature increased by 0.09 degrees C (95% CI; 0.06-0.11 degrees C, P < 0.0001). Higher body temperature creates a potential for cellular damage leading to complications that include myopathy. Methods for monitoring rectal, muscle, and ambient temperatures should be incorporated into anesthetic monitoring protocols for large ungulates, particularly under field conditions. PMID- 22448519 TI - Strangulating intestinal obstructions in four captive elephants (Elephas maximus and Loxodonta africana). AB - Three captive-born (5-day-old, 8-day-old, and 4-yr-old) Asian elephants (Elephas maximus) and one captive-born 22-yr-old African elephant (Loxodonta africana) from three private elephant facilities and one zoo in the United States presented with depression, anorexia, and tachycardia as well as gastrointestinal signs of disease including abdominal distention, decreased borborygmi, tenesmus, hematochezia, or diarrhea. All elephants showed some evidence of discomfort including agitation, vocalization, or postural changes. One animal had abnormal rectal findings. Nonmotile bowel loops were seen on transabdominal ultrasound in another case. Duration of signs ranged from 6 to 36 hr. All elephants received analgesics and were given oral or rectal fluids. Other treatments included warm water enemas or walking. One elephant underwent exploratory celiotomy. Three animals died, and the elephant taken to surgery was euthanized prior to anesthetic recovery. At necropsy, all animals had severe, strangulating intestinal lesions. PMID- 22448520 TI - Proliferative thyroid lesions in three diplodactylid geckos: Nephrurus amyae, Nephrurus levis, and Oedura marmorata. AB - Over a 5-mo period, three diplodactylid geckos housed at the National Aquarium were diagnosed with proliferative thyroid lesions: a rough knob-tail gecko (Nephrurus amyae), a smooth knob-tail gecko (Nephrurus levis), and a marbled velvet gecko (Oedura marmorata). Clinical signs included an intraoral mass or ventral throat swelling (or both), oral bleeding, and weight loss. Both of the knob-tail geckos died. The histologic diagnosis for the rough knob-tail gecko was thyroid carcinoma with metastases to the liver and lungs, and thyroid carcinoma with no metastases was reported in the smooth knob-tail gecko. A thyroidectomy was performed on the marbled velvet gecko with a histologic diagnosis of adenomatous hyperplasia. Postoperative weight loss and bradycardia resolved following oral supplementation with levothyroxine. The animal is in normal health 10 mo post-surgery. Five other diplodactylid geckos in the collection remain unaffected, giving a 38% prevalence of proliferative thyroid lesions (3/8). The etiology remains undetermined. This is the first report of a cluster of proliferative thyroid lesions in geckos. PMID- 22448521 TI - Eradication of elephant ear mites (Loxoanoetus bassoni) in two African elephants (Loxodonta africana). AB - Elephant ear mites, not previously described in North America, were eradicated in two African elephants (Loxodonta africana) after six otic instillations of ivermectin at 2-wk intervals. The microscopic examination of a clear, mucoid discharge collected from the external ear canals of two wild-born African elephants housed in a New York State zoo for 25 yr revealed live mites (Loxoaneotus bassoni). The cytologic examination demonstrated no evidence of inflammation or infection. Both elephants were asymptomatic with normal hemograms and serum chemistry panels. A diagnosis of otoacariasis was made. Each elephant was treated six times with 5 ml of 1% ivermectin syrup instilled in each ear canal once every 2 wk. Microscopic examinations of clear mucus collected from each elephant's ear canals 9 days after the first instillation of ivermectin were negative for any life stages of ear mites. Microscopic examinations of mucus collected from both elephants' ear canals at 6, 11, and 16 wk, as well as annually post-treatment for 7 yr, confirmed eradication of the ear mites. The L. bassoni ear mite was first identified in the external ear canals of wild, asymptomatic, lesion-free, African elephants culled in Kruger National Park in South Africa. However, a new species in the same genus of mites (Loxoanoetus lenae) was identified at the necropsy of an 86-yr-old Asian elephant (Elephas maximus) living in a circus in Australia. The autopsy revealed a marked, ballooning distension of bone around the left external acoustic meatus, suggestive of mite-induced otitis externa, as seen in cattle infested with ear mites (Raillieta auris). Elephant health care providers should identify the prevalence of, and consider treatment of, elephants in their care infested with ear mites, given the possible risk for adverse health effects. PMID- 22448522 TI - Systemic mycosis in a California sea lion (Zalophus californianus) with detection of cystofilobasidiales DNA. AB - A 6-yr-old, intact male California sea lion (Zalophus californianus) with a systemic mycosis died after 5 wk of antifungal drug therapy. Antemortem clinical findings included hind flipper swelling, ring-lesions on skin of the flippers, and dermal nodules that increased in size and number spreading from the hind flippers and ventral abdomen to the foreflippers and muzzle. Lesions were accompanied by severe lymphadenopathy and development of systemic clinical signs despite therapy using itraconazole and later voriconazole. Histopathologic evaluation of biopsies revealed granulomatous dermatitis due to infection by fungus-producing yeast cells in tissue. Isolation attempts, using biopsied skin and tissue samples collected at necropsy, failed to yield growth of a fungus producing yeast cells like those in histologic section. Consensus polymerase chain reaction (PCR) tests of biopsied skin for fungal DNA produced an amplicon having significant sequence identity with a Cystofilobasidiales, a fungus belonging to a subclade that includes several Cryptococcus spp. Histopathologic evaluation of necropsy tissues revealed a systemic mycosis with yeast cells disseminated throughout subcutis, lymph nodes, and viscera. Hepatic necrosis was identified associated with acute liver failure, possibly from the voriconazole administration. This is the first report documenting the clinical presentation, treatment, and pathologic findings of infection associated with Cystofilobasidiales in a marine mammal and serves to expand the understanding of mycoses in pinnipeds. PMID- 22448523 TI - Dilated ureters, renal dysplasia, and chronic renal failure in an African elephant (Loxodonta africana). AB - An ultrasonographic reproductive health examination of a 26-yr-old female African elephant (Loxodonta africana) revealed bilateral ureteral wall thickening and dilatation. On ultrasonographic examination, the bladder and both ureters were normal near the trigone; however, the cranial-most aspect of each ureter was dilated and thickened for a length of 30-50 cm. The same month, elevated blood creatinine (3.0 mg/dl), and urine protein-creatinine ratio (4.0) were observed. Chronic renal failure was diagnosed based on these abnormalities, and the persistent ureteral dilatation was seen on subsequent ultrasound examinations. Complete blood cell counts, serum chemistries, and urinalyses remained relatively unchanged until 24 mo after diagnosis, at which time azotemia, hypophosphatemia, and hypercalcemia (including elevated ionized calcium) developed. Hydronephrosis of both kidneys and prominent sacculation of the left ureter were noted on ultrasonographic examination. Lethargy, ventral edema, and oral mucosal ulceration acutely developed 30 mo after diagnosis. Although blood urea nitrogen remained elevated, creatinine, total calcium, and ionized calcium returned to within reference ranges at that time. Due to rapid clinical decline and grave prognosis, humane euthanasia was elected. Bilateral ureteral dilatation, dysplasia of the right kidney, and chronic nephritis of the left kidney were identified postmortem. PMID- 22448524 TI - Prevalence of methicillin-resistant Staphylococcus aureus in mammals of the Royal Zoological Society of Antwerp, Belgium. AB - Contrary to the numerous reports on methicillin-resistant Staphylococcus aureus (MRSA) in domestic animals, only three articles concerning zoo animals are documented in the literature. A skin infection of an African elephant (Loxodonta africana) calf was most likely acquired from an infected caretaker. Another zoo detected MRSA in the rumen content of a mouflon (Ovis aries), and, in a third facility, it was reported in a fistulous wound at the coronary band of a digit of an Indian rhinoceros (Rhinoceros unicornis). In the present study, which lasted 13 months and involved 93 different individual mammals that belonged to 40 species and 19 families housed in the Royal Zoological Society of Antwerp, Belgium, this study reports the absence of MRSA in swabs of nostrils, skins, conjunctiva, vulva, abscess, and arm rests in public spaces. Samples were enriched overnight and inoculated on a selective chromogenic medium. PMID- 22448525 TI - Severe anemia caused by babesiosis in a maned wolf (Chrysocyon brachyurus). AB - An 8-yr-old, captive, spayed, female maned wolf (Chrysocyon brachyurus) developed progressive lethargy and weakness over a 24-hr period. Clinical signs included vomiting, recumbency, horizontal nystagmus, possible blindness, pale icteric mucus membranes, and port-wine colored urine. A complete blood cell count revealed severe anemia (packed cell volume [PCV], 6%) and intraerythrocytic piroplasms consistent with a Babesia species. Polymerase chain reaction testing later confirmed babesiosis. The wolf was treated with imidocarb dipropionate, antibiotics, and fluid therapy. A whole-blood transfusion from a sibling maned wolf also was performed. Despite aggressive treatment, the wolf failed to improve and was euthanized. To the authors' knowledge, this is the first documented case of babesiosis in a captive maned wolf in North America. Surveillance of infectious diseases in captive and wild maned wolf populations should be expanded to include screening for Babesia species. Tick control also should be implemented to prevent and decrease transmission of the disease to this endangered species. PMID- 22448526 TI - Role of nonmigratory mottled ducks (Anas fulvigula) as sentinels for avian influenza surveillance. AB - The objective of this study was to evaluate the mottled duck (Anas fulvigula), a nonmigratory dabbling duck, as a sentinel species for avian influenza virus (AIV) surveillance. A total of 235 cloacal swabs from 147 live-captured and 88 hunter harvested mottled ducks during summer (June-August 2007) and winter (November 2007 to January 2008), respectively, were collected along the upper Texas coast. Samples were screened for AIV using real-time reverse transcription polymerase chain reaction (rRT-PCR); all rRT-PCR-positive samples were processed for virus isolation. Three samples were positive for AIV by AIV-matrix rRT-PCR. One of these samples also was positive for H5 by rRT-PCR, and a low pathogenic H5N2 AIV was isolated. Although isolation of AIVs from mottled ducks during the winter has been reported previously, to the authors' knowledge, this is the first H5 isolate from mottled ducks. Interestingly, this isolation was made during the same season that other H5N2 viruses were obtained from migratory waterfowl on the Texas coast, which suggests AIV transmission among waterfowl on the wintering grounds and the potential role of mottled ducks as a naturally occurring sentinel species for AIV surveillance. PMID- 22448527 TI - Severe idiopathic hypocalcemia in a juvenile western lowland gorilla, Gorilla gorilla gorilla. AB - A 6-mo-old, male western lowland gorilla (Gorilla gorilla gorilla) was evaluated because of tetany of both hands. The gorilla had alternating periods of constipation, diarrhea, and bloating since birth. A diagnosis of idiopathic hypocalcemia was based on severe hypocalcemia, a normal vitamin D level, response to oral calcium and vitamin D therapy, and eventual resolution. Idiopathic hypocalcemia, an uncommon disease in neonatal humans, should be considered in young gorillas with persistent gastrointestinal problems or acute tetany. PMID- 22448528 TI - Detection of antibodies against the rabies virus in Korean raccoon dogs (Nyctereutes procyonoides koreensis). AB - Rabies has been reported in dogs, cattle, and raccoon dogs in Korea, especially in the provinces of Gyeonggi and Gangwon. The aim of this study was to investigate the seroprevalence of the rabies in wild Korean raccoon dogs by using 50 blood samples collected in Gyeonggi and Gangwon provinces. Antibodies against rabies were measured by using a fluorescent antibody virus neutralization test. Of the 50 blood samples tested, 20 raccoon dogs (40%) tested positive. Seropositive animals were distributed in Paju, Yangpyeong, Goyang, Yangju, Yanggu, and Hoengseong cities. PMID- 22448529 TI - Serum protein electrophoresis values for free-ranging and zoo-based koalas (Phascolarctos cinereus). AB - In a clinical setting, especially with species of special interest, it is important to use all clinical pathology testing options for general health monitoring and diagnosis. Protein electrophoresis (EPH) has previously been shown to be an important adjunct tool in veterinary medicine. Serum samples from 18 free-ranging and 12 zoo-based koalas (Phascolarctos cinereus) were subject to EPH analysis. Significant differences were found between the two groups for the following values: total protein, albumin, beta globulins, and albumin-globulin ratio (P < 0.05). By using the combined data, the minimum-maximum values for the EPH fractions were as follows: total protein 5.0-7.8 g/dl, albumin 2.8-4.7 g/dl, alpha-1 globulins 0.5-1.1 g/dl, alpha-2 globulins 0.3-0.7 g/dl, beta globulins 0.4-1.0 g/dl, gamma globulins 0.2-1.0 g/dl, and albumin-globulin ratio 1.0-2.1. PMID- 22448530 TI - Idiopathic systemic AA-amyloidosis in a skunk (Mephitis mephitis). AB - This report describes a case of systemic amyloidosis in a captive striped skunk. At necropsy, bilateral alopecia, as well as reno-, hepato-, and splenomegaly were present. Congo red staining and immunohistochemistry revealed depositions of AA amyloid in different organs. The lack of a predisposing disease is suggestive of idiopathic systemic AA-amyloidosis. PMID- 22448531 TI - Vesiculobullous skin reaction temporally related to firocoxib treatment in a white rhinoceros (Ceratotherium simum). AB - A 40 yr-old female white rhinoceros (Ceratotherium simum) suffered from chronic nail-bed abscesses. Due to worsening of clinical signs, the animal's nonsteroidal anti-inflammatory treatment was switched to firocoxib. Approximately 7 days after this change, the animal developed multifocal vesicles and bullae along the lateral aspects of the thorax and abdomen, the dorsum, and the proximal limbs. Cytology and culture did not identify an infectious etiology. Histologically, the lesions consisted of a severe, subacute vesiculobullous dermatitis with intraepidermal to subepidermal clefting with areas of individual keratinocyte necrosis and minor neutrophilic epidermal infiltrates. These findings are similar to those seen in some drug reactions in people; therefore an adverse drug reaction to the firocoxib was suspected. PMID- 22448532 TI - Low sensitivity of antemortem gill biopsies for the detection of subclinical Pseudodactylogyrus bini infestations in American eels (Anguilla rostrata). AB - The objectives of this study were twofold: to determine the sensitivity of gill biopsies used for the screening of Pseudodactylogyrus bini in subclinically infested American eels (Anguilla rostrata) and to evaluate the effect of bath anesthesia on the proportion of infested eels. Fifty-four eels were euthanized following either intracoelomic injection of T61 or deep anesthesia with tricaine methanesulfonate. Proportions of eels infested by P. bini diagnosed by gill biopsies taken through the gill slit and by microscopic examination of the entire gill arches were compared. The euthanasia protocol had no significant effect on parasite abundance. The prevalence of monogeneans detected by examination of nonterminal antemortem gill biopsies and by complete gill examinations was 20% and 70%, respectively. The sensitivity of gill biopsies (29%) to detect P. bini in subclinically infested eels is therefore low, and should be used for group screening rather than individual screening. PMID- 22448533 TI - Management of twin pregnancy and perinatal concerns in a Beluga (Delphinapterus leucas). AB - A 22-yr-old multiparous beluga, Delphinapterus leucas, with consistently elevated serum progesterone concentrations post-artificial insemination was diagnosed with viable twins at 149 days postconception. Twins were of similar size at least until day 264, the last point when ultrasound measurements of both twins were made. However, ultrasound was used to determine the viability of both fetuses on days 365, 393, and 400. After 90% of normal gestation, or 434 days, steroids were administered to encourage fetal lung maturation. Seven days later a 40.9-kg live female calf was delivered headfirst. A second 22.7-kg stillborn calf was delivered in fluke-first presentation 8 hr later. Immediately after birth, the live calf was administered surfactant intratracheally. The next day, it was given beluga immunoglobulin intramuscularly, and started on oral antibiotics and provided nutritional support via an oral gastric tube. The calf started nursing voluntarily on day 3. Antibiotic and nutritional support was discontinued on day 10. Bimonthly weight and length measurements demonstrated that after an initial increased growth rate, the calf has grown within normal parameters after birth. This calf represents the first known successful surviving twin of any cetacean species and sets an important precedent for treatment modalities that may be available to assist the premature cetacean neonate. PMID- 22448535 TI - Did plaintiff's nurse expert witness have necessary qualifications to testify? Springhill Hospitals, Inc. v. Dinitrios Critopoulos, 1090946 ALSC, (11/18/2011) S.3d-AL. PMID- 22448534 TI - Disseminated coccidoidomycosis in a koala (Phascolarctos cinereus). AB - A16-yr-old male koala (Phascolarctos cinereus) presented for nonspecific signs of illness and weight loss. Despite 2 mo of diagnostics and supportive care, the koala's health declined and euthanasia was elected. On histopathologic examination, lesions containing fungal organisms morphologically consistent with coccidioidomycosis were found in the lung, liver, spleen, kidney, lymph node, heart, eye, and bone marrow. Although disseminated infection was present, the koala was IgM and IgG seronegative for Coccidioides spp. 1 mo prior to euthanasia. PMID- 22448536 TI - Can RNs give expert testimony as to whether bills are reasonable? Case on point: State Farm Auto. Ins. Co. v. Bowling, 2D10-1505 FLCA2 (2/10/2012)-FL. PMID- 22448537 TI - NY: RN and heart center prevail in suit: lack of sufficient evidence to avoid judgment. Barrett v. Hudson Valley Cardiovascular Associates, P.C., 2012-00317 NYAPP2 (1/17/2012)-NY. PMID- 22448538 TI - NY: RN made error in administration of meds.: court ruled punitive damages could be awarded. Marsh v. Arnot Ogden Medical Center, 2012-00154, NYAPP3 (1/12/2012) NY. PMID- 22448539 TI - Failure to monitor coumadin: pt. died from hematoma of brain. Case on point: Frazier v. Gillis, 2100101AL CIV (8/5/2011)-AL. PMID- 22448540 TI - The making of an entrepreneurial science: biotechnology in Britain, 1975-1995. AB - Monoclonal antibodies played a key role in the development of the biotechnology industry of the 1980s and 1990s. Investments in the sector and commercial returns have rivaled those of recombinant DNA technologies. Although the monoclonal antibody technology was first developed in Britain, the first patents were taken out by American scientists. During the first Thatcher government in Britain, blame for the missed opportunity fell on the scientists involved as well as on the National Research and Development Corporation, which had been put in place after World War II to avoid a repeat of the penicillin story, when patent rights were not sought. Instead of apportioning the blame, this essay suggests that despite past experiences and despite the new channels that were in place, Britain was not in a "patent culture" in the 1970s. It traces the long and painful process that made a commercial attitude among publicly funded British research scientists and in a civil service institution like the Medical Research Council both possible and desirable. In this process the meaning of the term "public science" also changed dramatically. PMID- 22448541 TI - The paradoxes of patenting at General Electric: Isador Ladoff's journey from Siberian exile to the heart of corporate capitalism. AB - Isador Ladoff (1857-1918) worked briefly in the General Electric Company Research Laboratory, from 1901 to 1903. Since he was not employed to invent, Ladoff maintained that he, not the company, owned his invention of a new arc lamp electrode, eventually winning his case on appeal in 1911. The conduct and course of this patent litigation are examined in the light of Ladoff's remarkable life as a prisoner of the czar in Siberia before his escape to the United States in 1891 and as a socialist activist and writer thereafter. In showing that Ladoff's socialist principles activated his struggle with GE, the essay brings out the ironies of his defense of individualism against the incipient socialism of the laboratory supposedly espoused by officials of the company. The case is interesting in relation to the shift from the ideology, and the reality, of heroic individual invention to that of corporate invention in U.S. industrial research. That shift in turn was a crucial landmark in the longer history of the place of science in negotiation and contest about the relationship between creativity and intellectual property. PMID- 22448542 TI - From rodent utopia to urban hell: population, pathology, and the crowded rats of NIMH. AB - In a series of experiments at the National Institute of Mental Health, the animal ecologist John B. Calhoun offered rats everything they needed, except space. The resulting population explosion was followed by a series of "social pathologies"- violence, sexual deviance, and withdrawal. This essay examines the influence of Calhoun's experiments among psychologists and sociologists concerned with the effects of the built environment on health and behavior. Some saw evidence of the danger of the crowd in Calhoun's "rat cities" and fastened on a method of analysis that could be transferred to the study of urban man. Others, however, cautioned against drawing analogies between rodents and humans. The ensuing dispute saw social scientists involved in a careful negotiation over the structure and meaning of Calhoun's experimental systems and, with it, over the significance of the crowd in the laboratory, institution, and city. PMID- 22448543 TI - Introduction: Reengaging with instruments. AB - Over the past twenty years or so, historians of science have become increasingly sensitized to issues involved in studying and interpreting scientific and medical instruments. The contributors to this Focus section are historians of science who have worked closely with museum objects and collections, specifically instruments used in scientific and medical contexts. Such close engagement by historians of science is somewhat rare, provoking distinctive questions as to how we define and understand instruments, opening up issues regarding the value of broken or incomplete objects, and raising concerns about which scientific and medical artifacts are displayed and interpreted in museums and in what manner. It is hoped that these essays point historians of science in new directions for reengaging with scientific objects and collections. PMID- 22448544 TI - Early modern mathematical instruments. AB - In considering the appropriate use of the terms "science" and "scientific instrument," tracing the history of "mathematical instruments" in the early modern period is offered as an illuminating alternative to the historian's natural instinct to follow the guiding lights of originality and innovation, even if the trail transgresses contemporary boundaries. The mathematical instrument was a well-defined category, shared across the academic, artisanal, and commercial aspects of instrumentation, and its narrative from the sixteenth to the eighteenth century was largely independent from other classes of device, in a period when a "scientific" instrument was unheard of. PMID- 22448545 TI - Easily cracked: scientific instruments in states of disrepair. AB - There has been much scholarly attention to definitions of the term "scientific instrument." Rather more mundane work by makers, curators, and users is devoted to instruments' maintenance and repair. A familiar argument holds that when a tool breaks, its character and recalcitrance become evident. Much can be gained from historical study of instruments' breakages, defects, and recuperation. Maintenance and repair technologies have been a vital aspect of relations between makers and other users. Their history illuminates systems of instruction, support, and abuse. These systems were, for example, evident in the development of astronomical instruments around 1800 within and beyond the European sphere. Episodes from that milieu are used to explore how instrument users sought autonomy, how instruments' mutable character was defined, and how judgments of instruments' failure or success were ever secured. PMID- 22448546 TI - Medical instruments in museums: immediate impressions and historical meanings. AB - This essay proposes that our understanding of medical instruments might benefit from adding a more forthright concern with their immediate presence to the current historical focus on simply decoding their meanings and context. This approach is applied to the intriguingly tricky question of what actually is meant by a "medical instrument." It is suggested that a pragmatic part of the answer might lie simply in reconsidering the holdings of medical museums, where the significance of the physical actuality of instruments comes readily to hand. PMID- 22448548 TI - [Malaria vaccine--reality or illusion?]. AB - Although attempts to develop an effective malaria vaccine have been made already for decades, they have met little success. The malarial parasite is able to avoid the body's immune defense in various ways, which complicates vaccine development. A number of vaccines are, however, being developed. The RTS,S vaccine, furthest along in the development process, has undergone part of phase III clinical trials and according to initial results has provided an approximately 50% protection for children of 5 to 17 months of age. PMID- 22448549 TI - [Traumatic pseudoaneurysm of the superficial temporal artery]. AB - Pseudoaneurysms of the superficial temporal artery (STA) are uncommon vascular lesions. Approximately 75% of them result from blunt trauma. Other etiological factors include penetrating wounds, iatrogenic trauma such as hair grafting and neurosurgical procedures. Thorough history and physical examination are often sufficient to make the diagnosis. Imaging studies are recommended for closer morphology and to rule out intracranial vascular communications and other possibilities in the differential diagnosis. We present successful treatment of a traumatic STA pseudoaneurysm with ultrasound-guided percutaneuous thrombin injection. PMID- 22448550 TI - [Update on current care guidelines: atrial fibrillation]. AB - According to the update of the Finnish guidelines for management of patients with atrial fibrillation (AF) dronedarone should be used only in patients with non permanent AF as a second line medication. It is recommended to monitor the patients regularly and stop dronedarone if permanent AF, heart failure or other adverse events are detected. Dabigatran and rivaroxaban can be used as an alternative to warfarin in patients requiring oral anticoagulation therapy. The selection between warfarin and the new anticoagulants should be based on careful evaluation of the benefits and disadvantages of the drugs in a given patient. PMID- 22448551 TI - [Current treatment of distal radius fractures]. AB - Most fractures of the distal radius are treated with closed reduction and casting. Locking plates are the most common method of fixation. In young persons and in elderly persons with functional activity above that of their age level, a <10 degrees dorsal or <20 degrees volar angle of tilt, a radial shortening of <2 mm, a radial inclination of >15 degrees and an intra-articular step-off or gap of <1 to 2 mm are regarded as an acceptable limit of position of the radius. In persons over 65 years of age the functioning of the hand can usually be restored with casting. PMID- 22448552 TI - [Fingertip injuries]. AB - Hands are used to interpret and shape the environment. The highly specialized structures of the fingertip enable tasks requiring precision, strength and endurance. Therefore injuries on fingertips have an effect to the entire hand. Thorough study of medical history and clinical examination are required to determine the correct treatment. The goal is to restore the function of the fingertip as well as possible. A good fingertip is pain free, has adequate sensation and is stable. As well as being aesthetically important, the nail adds to the stability and precision of the distal fingertip. Therefore, the structures of the nail should be repaired when possible. Different treatment options of the fingertip injuries range from conservative to operative, including flaps from adjacent areas. In selected cases, reattachment of an amputated fingertip yields best results. PMID- 22448553 TI - [Sore wrist]. AB - A patient with a sore, stiff and swollen wrist should be referred to basic examination at the first consultation visit. Nontraumatic causes such as joint inflammation, tumors and avascular necrosis require urgent treatment. Symptomatic treatment and follow-up observation can be considered, if the anamnesis does not reveal anything indicative of severe joint disease or significant injury, and no clear-cut abnormalities are found in the wrist. Triangular fibrocartilage complex injuries and scaphoid/lunate ligament tear are the most common ligament injuries requiring surgical treatment. PMID- 22448554 TI - [Surgery of the upper limbs can improve functional ability of a tetraplegic patient]. AB - A tetraplegic patient loses most of the muscle function and sensation, although some recovery often takes place after the acute stage. Better functioning of the upper limbs has proved to be the greatest desire of these patients. Procedures restoring and improving upper limb functions have developed over the past decades. New surgical techniques and procedural combinations enable reconstructions allowing significant improvement of functional capacity and independence in daily life. The surgical operation is planned on the basis of the patient's remaining muscles with function and strength. Needs of the patient for upper limb function are considered individually. PMID- 22448555 TI - [Dupuytren's contracture]. AB - Dupuytren's contracture forms nodules and fibril bundles causing the fingers to contract. The pathological tissue contains myofibroblasts exhibiting properties of fibrocytes and smooth muscle cell myoblasts. The disease has a clear-cut family predisposition, but its etiology remains unclear. Diabetes, smoking, heavy drinking and mechanical irritation of the palm are regarded as predisposing factors. Dupuytren's contracture is treated surgically in cases with the limitation of extension in the metacarpophalangeal joints over 30 degrees and 20 degrees in the proximal interphalangeal joints. PMID- 22448556 TI - [Osteoarthritis of the thumb and fingers]. AB - Most commonly affected joints of the hand in osteoarthritis include the carpometacarpal joint of the thumb (CMC 1) and the distal (DIP) and proximal (PIP) interphalangeal joints. Ageing, female gender, genotype, heavy work causing pressure on the hands, and injuries predispose to osteoarthritis in the hand. The pain is likely to be due to secondary synovitis caused by molecules released from the joint cartilage. Initial treatment of osteoarthritis is always conservative: analgesic medication, splint and physiotherapy. Surgery is considered for severe symptoms. The most common procedures include arthrodeses and arthroplasties with autogenous grafts or implants. PMID- 22448557 TI - [Children with thalidomide injuries are still being born]. PMID- 22448558 TI - [Surgery is needed in low and middle income countries. Highly cost-effective public health intervention]. PMID- 22448559 TI - [Swedish iodination of salt has decreased the incidence of goiter. But low use of iodinated salt in the schools raises concerns for the future]. PMID- 22448560 TI - [The Swedish child vaccination program also reaches the children born abroad. Serologic samples show good protection compared to Swedish-born]. PMID- 22448561 TI - [Hereditary angioedema--difficult disease with new therapeutic options]. PMID- 22448562 TI - [Ear thermometers can be used in children from the age of 1 year--comparison of methods for temperature measurement in children up to 6 years]. PMID- 22448563 TI - [Introduce emergency medicine in the medical education]. PMID- 22448564 TI - [New European guidelines for the specialist education in interventional neuroradiology]. PMID- 22448565 TI - [Curt Franksson--the father of Swedish transplantation surgery]. PMID- 22448594 TI - PM2.5 monitoring and mitigation in the cities of China. PMID- 22448595 TI - The therapeutic potential of the endocannabinoid system for Alzheimer's disease. AB - INTRODUCTION: Dementia currently affects over 35 million people worldwide. The most common form of dementia is Alzheimer's disease (AD). Currently, treatments for AD do not stop or reverse the progression of the disease and they are accompanied by side effects. AREAS COVERED: The main features of AD pathology, treatment options currently available, the endocannabinoid system and its functionality in general and its role in AD pathology in detail will be outlined. A particular focus will be on the therapeutic potential of the phytocannabinoid cannabidiol. EXPERT OPINION: Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy. The cannabinoid receptor 2 appears to be a promising candidate but its role in AD has to be investigated cautiously. Furthermore, the phytocannabinoid cannabidiol is of particular interest as it lacks the psychoactive and cognition-impairing properties of other cannabinoids. In conclusion, future research should focus on the evaluation of the effects of manipulations to the endocannabinoid system in established animal models for AD, combined with early-phase studies in humans. PMID- 22448596 TI - Corrigendum: Enterococcus hirae-associated endocarditis outbreaks in broiler flocks: clinical and pathological characteristics and molecular epidemiology. PMID- 22448597 TI - Prognostic value of molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer risk scores in primary T1 bladder cancer. AB - What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over-treatment of non-progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head-to-head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub-stage according to a new system (micro-invasive [T1m] and extensive-invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub-group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub-stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision-making in T1 BC. OBJECTIVE: To evaluate the prognostic significance of four molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette Guerin. PATIENTS AND METHODS: The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed. T1 sub staging was done in two separate rounds, using a new system that identifies micro invasive (T1m) and extensive-invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c). The EORTC risk scores for recurrence and progression were calculated. Uni- and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub-stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki-67, P53, P27 expression). RESULTS: The median follow-up was 6.5 years. Forty-two patients remained recurrence-free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients. In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub-stage (T1m/T1e) and carcinoma in situ (CIS) were significant. Molecular markers were significant in univariable and in multivariable analyses for recurrence. EORTC risk scores were not significant. CONCLUSIONS: CIS, female gender and sub-stage (T1m/T1e) were the most important variables for progression. The additional value of molecular markers was modest. Sub-stage (T1m/T1e) could potentially be incorporated in future tumour-node metastasis classifications. PMID- 22448598 TI - Off-label use of atypical antipsychotics: cause for concern? AB - Licensed indications for medicines were designed to regulate the claims that can be made about a medicine by a pharmaceutical company. Off-label prescribing (i.e. prescribing a drug for an indication outside of that for which it is licensed) is legal and an integral part of medical practice. In psychiatry, off-label prescribing is common and gives clinicians scope to treat patients who are refractory to standard therapy or where there is no licensed medication for an indication. However, efficacy or safety of such off-label use may not be established. There is a growing list of licensed indications for atypical antipsychotics (AAP) beyond schizophrenia and bipolar affective disorder, and also more evidence for other indications where pharmaceutical companies have not obtained a license. Pharmaceutical companies have promoted AAPs for off-label indications to increase sales and consequently have been fined by the US FDA for this. Since the 1990s, AAP use has expanded considerably, for example, the off label use of quetiapine alone accounted for an estimated 17% of the AAP spend in New Zealand in 2010. There are a number of potential problems with the expanded use of AAPs outside of schizophrenia and related psychoses. A larger population will be exposed to their adverse effects, which include weight gain, type 2 diabetes mellitus, sudden cardiac death and increased mortality rates in the elderly with dementia. There are also concerns with the abuse of these agents, in particular quetiapine. Given that an increasing percentage of the population is being treated with these agents, off-label prescribing of AAPs is a cause for concern; they have a propensity to cause significant side effects and their efficacy and long-term safety for most off-label indications remains largely unknown, and therefore the risks and benefits of their use should be carefully weighed up prior to prescribing these agents off-label. PMID- 22448599 TI - Evaluation of the cross section of elongated micelles by static and dynamic light scattering. AB - We describe simultaneous static (SLS) and dynamic light scattering (DLS) measurements on dilute solutions of a series of poly(ferrocenyldimethylsilane-b isoprene) (PFS(50)-PI(1000)) block copolymer micelles of uniform length in tert butyl acetate (tBA) and in decane. The subscripts in the term PFS(50)-PI(1000) refer to the mean degree of polymerization of each block. The SLS experiments show that in both solvents the micelles formed are elongated and rigid. We also observed that the large length of the PI block (1000 units) contributes to the SLS signal. From the SLS data, we calculated the mass per unit length (linear aggregation number), as well as the cross section of the micelles in both solvents. Interestingly, the linear aggregation number and the micelle cross sections, as deduced by SLS, were the same in decane and in tBA. However, the fitting of DLS data indicates that the hydrodynamic cross section of the micelles in tBA is much larger than that in decane, and both values are larger than the values determined by SLS. We hypothesize that the difference between cross sections deduced from SLS and DLS data fitting is related to the shape of the segment density profile of the corona. In tBA, the PI chains are more stretched than in decane, increasing the hydrodynamic radius of the micelle cross section. PMID- 22448600 TI - Inter-species sequence comparison of Brachypodium reveals how transposon activity corrodes genome colinearity. AB - Intergenic sequences evolve rapidly in plant genomes through a process known as genomic turnover. To investigate the influence of DNA transposons on genomic turnover, we compared 1 Mbp of orthologous genomic sequences from Brachypodium distachyon and Brachypodium sylvaticum. We found that B. distachyon and B. sylvaticum diverged approximately 1.7-2.0 million years ago. Of a total of 219 genes identified on the analyzed sequences, 211 were colinear. However, only 24 transposable elements of a total of 451 were orthologous (i.e. inserted in the common ancestor). We characterized in detail 59 insertions and 60 excisions of DNA transposons in one or other species, which altered 17% of the intergenic space. The DNA transposon excision sites showed complex and highly diagnostic sequence motifs for double-strand break (DSB) repair. DNA transposon excisions can lead to extensive deletions of hundreds of base pairs of flanking sequence if the DSB is repaired by 'single-strand annealing', or insertions of up to several hundred base pairs of 'filler DNA' if the DSB is repaired by 'synthesis-dependent strand annealing'. In some cases, DSBs were repaired by a combination of both methods. We present a model for the evolution of intergenic sequences in which repair of DSBs upon DNA transposon excision is a major factor in the rapid turnover and erosion of intergenic sequences. PMID- 22448601 TI - Inaugural editorial for Personality Disorders: Theory, Research, and Treatment. PMID- 22448602 TI - Introduction to the Commentaries and Online Forum of Personality Disorders: Theory, Research, and Treatment. PMID- 22448603 TI - Comparing factor analytic models of the DSM-IV personality disorders. AB - There is little agreement about the latent factor structure of the Diagnostic and Statistical Manual of Mental Disorders (DSM) personality disorders (PDs). Factor analytic studies over the past 2 decades have yielded different results, in part reflecting differences in factor analytic technique, the measure used to assess the PDs, and the changing DSM criteria. In this study, we explore the latent factor structure of the DSM (4th ed.; IV) PDs in a sample of 1200 psychiatric outpatients evaluated with the Structured Interview for DSM-IV PDs (B. Pfohl, N. Blum, & M. Zimmerman, 1997). We first evaluated 2 a priori models of the PDs with confirmatory factor analysis (CFA), reflecting their inherent organization in the DSM-IV: a 3-factor model and a 10-factor model. Fit statistics did not suggest that these models yielded an adequate fit. We then evaluated the latent structure with exploratory factor analysis (EFA). Multiple solutions produced more statistically and theoretically reasonable results, as well as providing clinically useful findings. On the basis of fit statistics and theory, 3 models were evaluated further--the 4-, 5-, and 10-factor models. The 10-factor model, which did not resemble the 10-factor model of the CFA, was determined to be the strongest of all 3 models. Future research should use contemporary methods of evaluating factor analytic results in order to more thoroughly compare various factor solutions. PMID- 22448604 TI - A multimethod analysis of impulsivity in nonsuicidal self-injury. AB - Impulsivity has been proposed as an important construct in nonsuicidal self injury (NSSI). Yet, research on the relationship of impulsivity to NSSI has been mixed. The present study clarified this relationship using a multifaceted measure of impulsivity (i.e., UPPS Impulsive Behavior Scale), and a computer-based behavioral measure of inhibitory control (i.e., a stop-signal task). Participants were 82 confirmed self-injurers and 86 controls recruited from a college population. Self-injurers and controls performed similarly on the stop-signal task. On the UPPS, self-injurers were best distinguished by Urgency (committing rash decisions when faced with negative emotions), and distinguished to a lesser degree by lack of Premeditation (inability to delay action in order to plan) and Sensation Seeking (seeking excitement and adventure). Among self-injurers, lack of Perseverance (inability to stay with a task through completion) predicted more recent and frequent NSSI. Conceptual and clinical implications are discussed. PMID- 22448605 TI - Fluoroscopic imaging of needle position in the tension-free vaginal mesh procedure for pelvic organ prolapse: two case reports. AB - The tension-free vaginal mesh (TVM) procedure has become one of the commonly used treatments for pelvic organ prolapse (POP) due to good clinical outcome. However, there are several technical difficulties associated with this procedure. We performed fluoroscopy for imaging of the surgical procedure on the TVM to resolve the technical problems regarding needle penetration. Fluoroscopic imaging with rectogram and cystogram demonstrated the positions of the needle, pelvic organs and index finger for needle guidance in the TVM procedure. Fluoroscopic imaging may be useful to understand the movement of surgical devices in the blind space, objectively evaluate the surgeon's skill, avoid injury to the pelvic organs, and detect any such injury immediately should it occur. PMID- 22448608 TI - Canadian Physical Activity Guidelines for the Early Years (aged 0-4 years). AB - The Canadian Society for Exercise Physiology (CSEP), with assistance from multiple partners, stakeholders, and researchers, developed the first Canadian Physical Activity Guidelines for the Early Years (aged 0-4 years). These national guidelines were created in response to an urgent call from public health, health care, child care, and fitness practitioners for healthy active living guidance for the early years. The guideline development process was informed by the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument and the evidence assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The recommendations are informed by evidence from a systematic review that examined the relationships between physical activity and health indicators (healthy body weight, bone and skeletal health, motor skill development, psychosocial health, cognitive development, and cardio-metabolic disease risk factors) for three age groups (infants aged <1 year; toddlers aged 1 2 years; preschoolers aged 3-4 years). The new guidelines include a preamble to provide context, followed by the specific recommendations. The final guidelines benefitted from an extensive on-line consultation process with input from over 900 domestic and international stakeholders, end-users, and key informants. The final guideline recommendations state that for healthy growth and development, infants (aged <1 year) should be physically active several times daily - particularly through interactive floor-based play. Toddlers (aged 1-2 years) and preschoolers (aged 3-4 years) should accumulate at least 180 min of physical activity at any intensity spread throughout the day, including a variety of activities in different environments, activities that develop movement skills, and progression toward at least 60 min of energetic play by 5 years of age. More daily physical activity provides greater benefits. PMID- 22448609 TI - Canadian Sedentary Behaviour Guidelines for the Early Years (aged 0-4 years). AB - The Canadian Society for Exercise Physiology (CSEP), with assistance from multiple partners, stakeholders, and researchers, developed the first Canadian Sedentary Behaviour Guidelines for the Early Years (aged 0-4 years). These national guidelines are in response to a call from health and health care professionals, child care providers, and fitness practitioners for guidance on sedentary behaviour in the early years. The guideline development process followed the Appraisal of Guidelines for Research Evaluation (AGREE) II framework. The recommendations are informed by evidence from a systematic review that examined the relationships between sedentary behaviour (predominantly screen time) and health indicators (healthy body weight, bone and skeletal health, motor skill development, psychosocial health, cognitive development, and cardio metabolic disease risk factors) for three age groups (infants aged <1 year; toddlers aged 1-2 years; preschoolers aged 3-4 years). Evidence from the review was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The new guidelines include a preamble to provide context, followed by the specific recommendations. The final guidelines benefitted from extensive on-line consultations with input from >900 domestic and international stakeholders, end-users, and key informants. The final guidelines state: for healthy growth and development, caregivers should minimize the time infants (aged <1 year), toddlers (aged 1-2 years), and preschoolers (aged 3-4 years) spend being sedentary during waking hours. This includes prolonged sitting or being restrained (e.g., stroller, high chair) for more than 1 h at a time. For those under 2 years, screen time (e.g., TV, computer, electronic games) is not recommended. For children 2-4 years, screen time should be limited to under 1 h per day; less is better. PMID- 22448610 TI - Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. AB - BACKGROUND: In 2009 the Uterine Bleeding and Pain Women's Research Study (UBP WRS) was conducted interviewing 21,479 women across 8 countries in order to gain patient-based prevalence data on uterine pain and bleeding indications and investigate uterine symptoms and women's treatment experiences. This article shows relevant results of the study for the indication uterine fibroids providing data on self-reported prevalence, symptomatology and management of uterine fibroids. METHODS: 2,500 women (USA: 4,500 women) in each country (Brazil, Canada, France, Germany, Italy, South Korea, the UK, the USA) completed an online survey. Women included were in their reproductive age (age group 15-49 years; USA: 18-49 years) and had ever experienced menstrual bleedings. Quotas were applied for age, region, level of education and household income of respondents. Variables have been analyzed descriptively and exploratory statistical tests have been performed. RESULTS: The self-reported prevalence of uterine fibroids ranged from 4.5% (UK) to 9.8% (Italy), reaching 9.4% (UK) to 17.8% (Italy) in the age group of 40-49 years. Women with a diagnosis of uterine fibroids reported significantly more often about bleeding symptoms than women without a diagnosis: heavy bleedings (59.8% vs. 37.4%), prolonged bleedings (37.3% vs. 15.6%), bleeding between periods (33.3% vs. 13.5%), frequent periods (28.4% vs. 15.2%), irregular and predictable periods (36.3% vs. 23.9%). Furthermore women with diagnosed uterine fibroids reported significantly more often about the following pain symptoms: pressure on the bladder (32.6% vs. 15.0%), chronic pelvic pain (14.5% vs. 2.9%), painful sexual intercourse (23.5% vs. 9.1%) and pain occurring mid-cycle, after and during menstrual bleeding (31.3%, 16.7%, 59.7%, vs. 17.1%, 6.4%, 52.0%). 53.7% of women reported that their symptoms had a negative impact on their life in the last 12 month, influencing their sexual life (42.9%), performance at work (27.7%) and relationship & family (27.2%). CONCLUSIONS: Uterine fibroid is a common concern in women at fertile age causing multiple bleeding and pain symptoms which can have a negative impact on different aspects in women's life. PMID- 22448611 TI - Eye care in Fiji: a population-based study of use and barriers. AB - PURPOSE: To determine the use of medical services for eye problems in Fiji, and barriers to seeking that care. METHODS: An interview-based questionnaire was administered as part of a population-based cross-sectional survey of adults selected by multistage random sampling from those aged >=40 years living on Fiji's main island. RESULTS: Participation rate was 73.0% (n = 1381). A current vision or eye problem was reported by 931 participants, and a further 235 recalled a previous difficulty. Urban dwellers (P = 0.002) and those aged >=50 years (P = 0.017) were more likely to report a problem. Gender was not predictive (P = 0.215). "Blurred/poor vision" was the most common complaint (78.5%). Over half (53.3%) had not sought care for the problem most important to them. For current problems, being younger (P < 0.001) and from a household without paid income (P = 0.007) were predictive of being less likely to seek treatment. Gender was not (P = 0.416). The most frequently cited principal reason for not seeking care was "able to manage/accept the problem" (66.5%; of whom 84.7% claimed vision problems). Direct and indirect costs were mentioned as deterrents. "Thought nothing could be done" (P = 0.032) and "lack of awareness of service availability" (P = 0.026) were more common among rural dwellers. Of participants who sought care, 75.6% used government services. Most participants requiring spectacles or medication incurred costs for these. Satisfaction with overall care was independent of provider (P = 0.062) and user gender (P = 0.851). CONCLUSION: With expanding service delivery, increased eye health promotion, and attention to the financing of treatments, improved service use ought to be possible in Fiji. PMID- 22448612 TI - Compliance with follow-up after cataract surgery in rural China. AB - PURPOSE: To evaluate reasons for non-compliance with post-cataract surgical follow-up in rural China, and assess the impact of incentives on improving compliance. METHODS: Patients having undergone cataract surgery more than 3 months previously at cataract surgery training hospitals in Guangdong were invited by telephone and advertisements to a hospital-based study examination, with compensation for travel costs (US$7). Information on prior post-surgical follow up was collected by questionnaire at the hospital or by telephone. Logistic regression was used to assess predictors of post-operative attendance with or without compensation. RESULTS: Among 518 eligible patients, 426 (82.2%) underwent interviews and 342 (66.0%) attended the compensated study examination. Ninety nine participants (23.2%) reported previously returning for uncompensated follow-up >= 3 months post-operatively, and 225 (52.8%) had returned for any prior post-operative examination. Uncompensated follow-up at >= 3 months was associated with higher income (P = 0.037), and recalling instruction by a doctor to follow-up (P = 0.001), while age, gender, travel cost, and post-operative satisfaction and vision were not associated. Younger (P = 0.002) patients and those reporting being instructed to follow up (P = 0.008) were more likely to return for the compensated research examination. Among all interviewed subjects, only 170 (39.9%) reported knowing they were to return to hospital. CONCLUSIONS: Modest compensation, advertisements and telephone contact can increase medium term follow-up rates after cataract surgery by three-fold. Better communication of specific targets for follow-up may improve follow-up compliance. PMID- 22448614 TI - Biofilm formation of Klebsiella pneumoniae on urethral catheters requires either type 1 or type 3 fimbriae. AB - Urinary catheters are standard medical devices utilized in both hospital and nursing home settings, but are associated with a high frequency of catheter associated urinary tract infections (CAUTI). In particular, biofilm formation on the catheter surface by uropathogens such as Klebsiella pneumoniae causes severe problems. Here we demonstrate that type 1 and type 3 fimbriae expressed by K. pneumoniae enhance biofilm formation on urinary catheters in a catheterized bladder model that mirrors the physico-chemical conditions present in catheterized patients. Furthermore, we show that both fimbrial types are able to functionally compensate for each other during biofilm formation on urinary catheters. In situ monitoring of fimbrial expression revealed that neither of the two fimbrial types is expressed when cells are grown planktonically. Interestingly, during biofilm formation on catheters, both fimbrial types are expressed, suggesting that they are both important in promoting biofilm formation on catheters. Additionally, transformed into and expressed by a nonfimbriated Escherichia coli strain, both fimbrial types significantly increased biofilm formation on catheters compared with the wild-type E. coli strain. The widespread occurrence of the two fimbrial types in different species of pathogenic bacteria stresses the need for further assessment of their role during urinary tract infections. PMID- 22448615 TI - Omega-3 index and smoking in patients with acute ST-elevation myocardial infarction taking statins: a case-control study in Korea. AB - BACKGROUND: n-3 fatty acids and lifestyle also are closely related to risk of CVD. Most Koreans have higher fish consumption than people of Western populations. However, little is known about the recommended value of omega-3 index in Korean patients with acute ST-elevation myocardial infarction (STEMI) taking statins. Here, we tested the hypothesis that lower omega-3 fatty acids and/or smoking are associated with acute STEMI, even though patients with dyslipidemia who were taking statins and who attained their LDL-C goals. METHODS: We conducted a case-control study in which omega-3 fatty acids and lifestyle factors were determined in 24 consecutive Korean patients taking statins with angiographically confirmed acute STEMI and 68 healthy controls without acute STEMI. The omega-3 index was calculated by the sum of eicosapentaenoic acid and docosahexaenoic acid in erythrocyte membranes. Multivariable adjusted regression analysis was used to assess independent associations between acute STEMI, omega-3 index, and lifestyle factors after adjusting for age, sex, and body mass index (BMI). RESULTS: The mean age of total subjects was 59.9 years, and 57.6% of the subjects were male. The omega-3 index was significantly lower in cases (8.83%) than controls (11.13%; P < 0.001); however, total trans-fatty acids were not different between the two groups. The omega-3 index was inversely associated with odds for being a case (OR 0.16 (95% CI 0.03-1.14); P = 0.047), while smoking was positively associated with odds for being a case (OR 6.67 (95% CI 1.77-25.23); P = 0.005) after adjusting for all confounding variables. CONCLUSION: This study shows that relative to controls, acute STEMI cases are more likely to be smokers and to have a lower omega-3 index, even though the cases were taking statins. An omega-3 index of at least 11% and abstinence from smoking are associated with cardioprotection for Koreans. PMID- 22448616 TI - Feasibility and reliability of measuring strength, sprint power, and aerobic capacity in athletes and non-athletes with cerebral palsy. AB - AIM: The aim of this study was to analyse the feasibility and reliability of the tests used to determine muscle strength, sprint power, and aerobic capacity in athletes and non-athletes with cerebral palsy (CP). METHODS: Twenty individuals with spastic CP (four females, 16 males; age range 18-49y; Gross Motor Function Classification System level I, n=15; II, n=5; unilateral CP, n=10; bilateral CP, n=10; athletes, n=12; non-athletes, n=8) participated in the study. Isometric and isokinetic knee flexor and extensor strength, sprint power, and aerobic capacity were determined, using, respectively an isokinetic dynamometer, a Wingate cycling test, and a graded maximal bicycle exercise test, on three occasions. Intraclass correlation coefficients (ICC), standard error of measurements, and smallest detectable differences (SDD) were calculated. RESULTS: The feasibility of the isometric strength test, Wingate test, and graded exercise test was good; the isokinetic strength test was difficult to perform for five participants. The strength parameters showed moderate to good ICCs (isometric, 0.74-0.94; isokinetic, 0.88-0.93) but high SDDs (isometric, 25-45%; isokinetic, 30-45%). Sprint power (ICC 0.98; SDD 24%) and aerobic capacity (ICC 0.98-0.99; SDD 16-21%) showed good ICCs and moderate SDDs. INTERPRETATION: All tests, except for the isokinetic strength test, seemed to be feasible for almost all participants. All tests are suitable for evaluating changes in a group; however, only large improvements (16-45%) can be detected when monitoring individual changes. PMID- 22448617 TI - Innate immunity and hepatitis C virus infection: a microarray's view. AB - Hepatitis C virus (HCV) induces a chronic infection in more than two-thirds of HCV infected subjects. The inefficient innate and adaptive immune responses have been shown to play a major pathogenetic role in the development and persistence of HCV chronic infection. Several aspects of the interactions between the virus and the host immune system have been clarified and, in particular, mechanisms have been identified which underlie the ability of HCV to seize and subvert innate as well as adaptive immune responses. The present review summarizes recent findings on the interaction between HCV infection and innate immune response whose final effect is the downstream inefficient development of antigen-specific adaptive immunity, thereby contributing to virus persistence. PMID- 22448618 TI - The complete mitogenome of Cylindrus obtusus (Helicidae, Ariantinae) using Illumina next generation sequencing. AB - BACKGROUND: This study describes how the complete mitogenome of a terrestrial snail, Cylindrus obtusus (Draparnaud, 1805) was sequenced without PCRs from a collection specimen that had been in 70% ethanol for 8 years. The mitogenome was obtained with Illumina GAIIx shot gun sequencing. Although the used specimen was collected relatively recently and kept in a DNA-friendly preservative (not formalin as frequently used with old museum specimens), we believe that the exclusion of PCRs as facilitated by NGS (Next Generation Sequencing) removes a great obstacle in DNA sequencing of collection specimens. A brief comparison is made between our Illumina GAIIx approach and a similar study that made use of the Roche 454-FLX platform. RESULTS: The mtDNA sequence of C. obtusus is 14,610 bases in length (about 0.5 kb larger than other stylommatophoran mitogenomes reported hitherto) and contains the 37 genes (13 protein coding genes, two rRNAs and 22 tRNAs) typical for metazoans. Except for a swap between the position of tRNA-Pro and tRNA-Ala, the gene arrangement of C. obtusus is identical to that reported for Cepaea nemoralis. The 'aberrant' rearrangement of tRNA-Thr and COIII compared to that of other Sigmurethra (and the majority of gastropods), is not unique for C. nemoralis (subfamily Helicinae), but is also shown to occur in C. obtusus (subfamily Ariantinae) and might be a synapomorphy for the family Helicidae. CONCLUSIONS: Natural history collections potentially harbor a wealth of information for the field of evolutionary genetics, but it can be difficult to amplify DNA from such specimens (due to DNA degradation for instance). Because NGS techniques do not rely on primer-directed amplification (PCR) and allow DNA to be fragmented (DNA gets sheared during library preparation), NGS could be a valuable tool for retrieving DNA sequence data from such specimens. A comparison between Illumina GAIIx and the Roche 454 platform suggests that the former might be more suited for de novo sequencing of mitogenomes. PMID- 22448620 TI - Gender differences in autonomic indicators of antisocial personality disorder features. AB - We investigated the autonomic indicators of antisocial personality disorder (APD) features in a mixed gender student sample. One hundred college students (50 men, 50 women) were administered an interview of APD and self-report measures of aggression and psychopathy. Participants completed a passive coping task and viewed emotionally valenced slideshows while their electrodermal activity (EDA), pre-ejection period (PEP), and respiratory sinus arrhythmia (RSA) were measured. Associations between APD features and autonomic reactivity were examined, controlling for aggression and psychopathy. APD features were associated with EDA hyporeactivity in men, but not women, during passive coping. While viewing threatening slides, APD features were associated with RSA hyperreactivity in women and with PEP hyperreactivity in men. APD features were associated with RSA hyperreactivity in women, but not men, while viewing slides of others in distress. These findings suggest that APD features are characterized by parasympathetic nervous system dysfunction in women but sympathetic nervous system dysfunction in men. PMID- 22448619 TI - Impact of obesity on drug metabolism and elimination in adults and children. AB - The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown. In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes. This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults. Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology. PMID- 22448621 TI - Personality traits and the classification of mental disorders: toward a more complete integration in DSM-5 and an empirical model of psychopathology. AB - Personality trait dimensions are related to a wide variety of important life outcomes, such as mortality, physical and mental health, and interpersonal relationships. Nevertheless, the diagnostic system with arguably the most influence in mental health settings (Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) formally includes personality primarily in the form of 10 putatively categorical personality disorders. We advocate a more complete and extensive integration of personality in future DSMs, via the explicit inclusion of an empirically based, dimensional personality trait model. To justify this position, we provide a broad review of the ways in which personality traits have proven useful in the description and conceptualization of personality disorders and other mental disorders, as well as in the prediction of key clinical phenomena. We also discuss the importance of constructing a comprehensive quantitative model of psychopathology based on data, an endeavor that is motivated and informed by the close conceptual and empirical parallels between personality and psychopathology. PMID- 22448622 TI - Commentary on "Personality traits and the classification of mental disorders: toward a more complete integration in DSM-5 and an empirical model of psychopathology". AB - This article develops the larger theme that the fundamental quantitatively developed architecture of personality provides a sound base for classifying all areas of psychopathology and, more specifically, should underlie the current effort to revise the classification of personality disorders (PDs) in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). My commentary is organized around what I perceive to be four significant problems with the proposed change to a trait-based system: (1) unfamiliarity to clinicians (and possibly unfeasibility), (2) lack of clinical utility, (3) the preliminary quality of the science upon which the proposed change is based, and (4) harmful effects on the diagnosis of borderline personality disorder (BPD). PMID- 22448623 TI - Commentary on Krueger and Eaton's "Personality traits and the classification of mental disorders: toward a more complete integration in DSM-5 and an empirical model of psychopathology": real-world considerations in implementing an empirically based dimensional model of personality in DSM-5. AB - In their article, Krueger and Eaton (pp. 97-118, this issue) advocate for a "more complete and extensive integration of personality traits in future DSMs [Diagnostic and Statistical Manuals of Mental Disorders], via the explicit inclusion of an empirically based, dimensional personality trait model" (p. 97) and review the "diverse ways in which the inclusion of an empirically based personality trait model could constitute a critical innovation in the transition from DSM-IV to DSM-5" (p. 113). Krueger and Eaton's proposal that (DSM-5) adopt a dimensional personality trait approach exemplifies the difficulties of devising a classification scheme that satisfies the needs of the both the clinical and research communities. In this instance, the challenge is adapting a complex dimensional trait scheme developed and utilized almost exclusively by the research community, for clinical use. PMID- 22448624 TI - Bridging the gap with the five-factor model. AB - Comments on the original article Personality traits and the classification of mental Disorders: Toward a more complete integration in DSM-5 and an empirical model of psychopathology by Robert F. Krueger and Nicholas R. Eaton (see record 2010-13810-003). Some researchers had hoped the forthcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) would ask psychiatrists (and the clinical psychologists and researchers who are also tied to the DSM) to leap the gap and embrace a trait-based taxonomy of personality pathology (Widiger & Trull, 2007). Krueger and Eaton (pp. 97-118, this issue) take a more pragmatic stance: They hope to coax psychiatrists across by introducing personality dimensions as an adjunct to familiar PD types; they envision that DSM-5 might serve "as a bridge" (p. 110, this issue) to a fully dimensional Diagnostic and Statistical Manual of Mental Disorders, Sixth Edition (DSM-6). We acknowledge the wisdom of this strategy and suggest ways to strengthen it. PMID- 22448625 TI - Quantitative methods in psychiatric classification: the path forward is clear but complex: commentary on Krueger and Eaton (2010). AB - Comments on the original article Personality traits and the classification of mental Disorders: Toward a more complete integration in DSM-5 and an empirical model of psychopathology by Robert F. Krueger and Nicholas R. Eaton (see record 2010-13810-003). Krueger and Eaton (pp. 97-118, this issue) have provided a trenchant argument for greater use of dimensional approaches in the classification of personality disorders (PDs) in future iterations of the psychiatric nomenclature, and their explication of the importance of personality constructs in models of psychopathology more generally is commendably lucid. We agree that the division of PDs in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) into 10 categorical diagnoses with arbitrary thresholds does not match existing data and requires significant retooling, and we view the inclusion of dimensional traits as an important component of the provisional Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) proposal. PMID- 22448626 TI - A personality trait model for the Diagnostic and Statistical Manual of Mental Disorders (DSM): the challenges ahead. AB - We were sincerely flattered to discover that John Gunderson, Michael First, Paul Costa, Robert McCrae, Michael Hallquist, and Paul Pilkonis provided commentaries on our target article. In this brief response, we cannot hope to discuss the myriad points raised by this august group. Such a task would be particularly daunting given the diversity of the commentaries. Indeed, the diversity of the commentaries provides a kind of "metacommentary" on the state of personality and psychopathology research. That is, the intellectual diversity contained in the commentaries underlines the substantial challenges that lie ahead of us, in terms of articulating a model of personality and psychopathology with both scientific validity and clinical applicability. PMID- 22448627 TI - Hydrogen sulfide as a therapeutic target for inflammation. AB - INTRODUCTION: The view of hydrogen sulfide has changed from a toxic by-product to a crucial signaling molecule, with enormous potential as a pharmacological target for diseases ranging from heart disease to sepsis. Despite this progression of ideas, there is still a large amount that is unknown about this gaseous signaling molecule. Hydrogen sulfide has been implicated as a tissue protectant in many pathological conditions, the mechanisms of tissue protection is a point of controversy, particularly distinguishing the direct actions from the indirect downstream effects of hydrogen sulfide. This point of controversy is particularly pertinent in inflammation research. AREAS COVERED: Current research into the pathways in which hydrogen sulfide can act as a pro-inflammatory molecule and as an anti-inflammatory molecule. EXPERT OPINION: How controversies regarding hydrogen sulfide may have occurred is discussed. Addressed are the direct and indirect pathways of hydrogen sulfide on inflammation, the effects of different concentrations of hydrogen sulfide and how the effects of hydrogen sulfide on the immune system vary with different delivery mechanisms. Furthermore, there is a discussion on what key gaps exist in current knowledge and must be addressed before hydrogen sulfide can be considered a valid pharmacological target. PMID- 22448628 TI - A novel strategy for retrospective exposure assessment in the Norwegian silicon carbide industry. AB - The objective was to construct a retrospective job-exposure matrix (JEM) for the Norwegian silicon carbide industry. More than 3300 historical total dust measurements were available (1967-2005); however, there were few measurements of other agents. Total dust measurements were therefore used as the basis for the JEM, and a novel method was developed to estimate exposure to other agents. Multiple linear regression models were developed to describe historical exposure to total dust. Exposure estimates were extrapolated backward to periods without exposure data by adjustments for process and work-hour related changes. An exposure assessment study was performed where total dust was sampled in parallel with fibers or respirable dust. The respirable dust was analyzed for the content of quartz, cristobalite, and silicon carbide. Mixed-effect models were developed to estimate the exposure to these agents from total dust exposure, plant, and job group. Exposure to asbestos and polycyclic aromatic hydrocarbons was assigned qualitatively. Multiple linear regression models of total dust described historical exposure best in the furnace department (R(2) (adj) = 0.49-0.74). Models in the other departments explained less variance (R(2) (adj) = 0.12-0.32). Exposure determinants and total dust explained a substantial proportion of the between- (70-100%) and within-worker (8.0-54%) variance in the mixed-effect models. The relative bias between available historical measurements and the estimated exposure to dust components varied between -39% (fiber) and 40% (quartz). However, corrections were not considered necessary due to limitations in the historical data. The component-specific metrices were sufficiently different from each other (r(Pearson) < 0.7), with the exception of total and respirable dust (r(Pearson) = 0.84) and total dust and cristobalite (r(Pearson) = 0.72), and will enable component-specific epidemiologic analyses in the future. Improved and less correlated estimates of exposure levels for the different components in the dust were obtained with the updated exposure assessment. Due to limitations in the measurement data, assumptions had to be made, especially in the period before 1967. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file containing tables outlining multiple linear regression models for prediction of total dust exposure in the processing departments of Norwegian SiC producing plants, evaluation of the predictive abilities of the reduced total dust models, and mixed models for pedicting exposure to fibers and respirable quartz, cristobalite, non-fibrous silicon carbide and respirable dust from total dust exposure.]. PMID- 22448629 TI - Knee extension strength in obese and nonobese male adolescents. AB - The aim of the present study was to compare "absolute" and "relative" knee extension strength between obese and nonobese adolescents. Ten nonobese and 12 severely obese adolescent boys of similar chronological age, maturity status, and height were compared. Total body and regional soft tissue composition were determined using dual-energy X-ray absorptiometry (DXA). Knee extensors maximum voluntary contraction (MVC) torque was measured using an isometric dynamometer at a knee angle of 60 degrees (0 degrees is full extension). Absolute MVC torque was significantly higher in obese adolescents than in controls. However, although MVC torque expressed per unit of body mass was found to be significantly lower in obese adolescent boys, no significant difference in MVC torque was found between groups when normalized to fat-free mass. Conversely, when correcting for thigh lean mass and estimated thigh muscle mass, MVC torque was significantly higher in the obese group (17.9% and 22.2%, respectively; P <0.05). To conclude, our sample of obese adolescent boys had higher absolute and relative knee extension strength than our nonobese controls. However, further studies are required to ascertain whether or not relative strength, measured with more accurate in vivo methods such as magnetic resonance imaging, is higher in obese adolescents than in nonobese controls. PMID- 22448630 TI - Dispersions of nanocrystalline cellulose in aqueous polymer solutions: structure formation of colloidal rods. AB - The steady-state shear and linear viscoelastic deformations of semidilute suspensions of rod-shaped nanocrystalline cellulose (NCC) particles in 1.0% hydroxyethyl cellulose and carboxymethyl cellulose solutions were investigated. Addition of NCC at the onset of semidilute suspension concentration significantly altered the rheological and linear viscoelastic properties of semidilute polymer solutions. The low-shear viscosity values of polymers solutions were increased 20 490 times (depending on polymer molecular weight and functional groups) by the presence of NCC. NCC suspensions in polymer solutions exhibited yield stresses up to 7.12 Pa. Viscoelasticity measurements also showed that NCC suspended polymer solutions had higher linear elastic moduli than the loss moduli. All of those results revealed the gel formation of NCC particles and presence of internal structures. The formation of a weak gel structure was due to the nonadsorbing macromolecules which caused the depletion-induced interaction among NCC particles. A simple interaction energy model was used to show successfully the flocculation of NCC particles in the presence of nonadsorbing polymers. The model is based on the incorporation of the depletion interaction term between two parallel plates into the DLVO theory for cubic prismatic rod shaped NCC particles. PMID- 22448631 TI - Borderline personality features moderate the effect of a fear induction on impulsivity. AB - This study examined the effects of laboratory-induced fear on impulsivity among participants who were high (n = 28) or low (n = 44) in borderline personality (BP) features. Participants were randomly assigned to complete a laboratory measure of impulsivity (passive avoidance learning task) following either a neutral mood induction or a fear induction. BP features moderated the association of the emotion condition (fear vs. neutral) with impulsivity: High-BP participants, but not low-BP participants, committed a greater number of impulsive responses in the fear condition compared with the neutral condition. Findings indicated that impulsivity among persons with BP features may not be a trait-like deficit, but rather, depends on emotional context. These findings suggest that future research should examine impulsivity under differing emotional conditions, and that clinical interventions to reduce impulsivity among persons with BP features should focus on responses to emotional contexts. PMID- 22448632 TI - Psychopathy in a noninstitutional sample: differences in primary and secondary subtypes. AB - Early theoretical conceptualizations suggest psychopathy is a heterogeneous construct whereby psychopathic individuals are found in diverse populations. The current study examined male and female psychopathy subtypes in a large sample of undergraduate students (n = 1229). Model-based cluster analysis of the Psychopathic Personality Inventory-Short Form (PPI-SF) revealed two clusters in both male and female students. In males, the primary subtype evidenced greater psychopathic personality traits (i.e., Social Potency, Fearlessness, and Impulsive Nonconformity) and lower anxiety (i.e., higher Stress Immunity), whereas the secondary subtype displayed fewer psychopathic personality traits (i.e., Machiavellian Egocentricity and Blame Externalization) and higher anxiety (i.e., lower Stress Immunity). In females, the primary subtype exhibited higher scores across all PPI-SF subscales and lower anxiety whereas the secondary subtype reported lower PPI-SF subscale scores and higher anxiety. Across a diverse array of personality, affective, and behavioral external correlates, differences between the subtypes and with nonpsychopaths emerged. Implications for psychopathy in noninstitutional populations with respect to theory, research, and gender are discussed. PMID- 22448633 TI - Pain perception and nonsuicidal self-injury: a laboratory investigation. AB - People who engage in self-injurious behaviors such as cutting and burning may have altered pain perception. Using a community sample, we examined group differences in pain threshold and pain endurance between participants who self injured and control participants who were exposed to pressure pain applied to the finger. Participants who self-injured had higher pain thresholds (time to report pain) and endured pain for longer than control participants. Among participants who self-injured, those with longer histories of self-injury had higher pain thresholds. Duration of self-injury was unrelated to pain endurance. Instead, greater pain endurance was predicted by higher levels of introversion and neuroticism and by more negative beliefs about one's self-worth. A highly self critical cognitive style was the strongest predictor of prolonged pain endurance. People who self-injure may regard suffering and pain as something that they deserve. Our findings also have implications for understanding factors that might be involved in the development and maintenance of self-injury. PMID- 22448634 TI - The case for using research on trait narcissism as a building block for understanding narcissistic personality disorder. AB - The empirical literature on narcissistic personality disorder (NPD) is quite sparse with only a small number of studies singularly devoted to this important construct. Of the published articles on NPD, the majority (approximately 80%) are either of a theoretical nature or present data from a case study perspective. There is, however, a thriving and growing literature on trait narcissism. In comparison to NPD, trait narcissism is viewed as a continuous construct in which no attempt is made to make dichotomous decisions of a clinical nature. Recent data suggest that research on trait narcissism is relevant to NPD as self-report scores are substantially correlated with the Diagnostic and Statistical Manual of Mental Disorders (4th ed., American Psychiatric Association, 1994) interviews of NPD and generate a five-factor model personality profile that is congruent with expert ratings of prototypical NPD. We review the literature on trait narcissism in relation to implicit and explicit aspects of self-esteem, self-presentation, decision making, relationships, work performance, and externalizing behavior (e.g., aggression). Ultimately, we argue that this literature might be used as a stepping stone toward the development of a better empirical understanding of NPD and its nomological network. PMID- 22448636 TI - In defense of narcissistic personality traits. AB - Comments on the article by Miller and Campbell (see record 2010-17135-004), in which they provide an informative discussion of the importance of considering narcissistic personality trait research when attempting to understand narcissistic personality disorder. Their arguments might seem so straightforward and compelling that they are hardly worth presenting. However, it does seem that this considerable body of literature is at times neglected, if not ignored. PMID- 22448637 TI - Personality pathology is dimensional, so what shall we do with the DSM-IV personality disorder categories? The case of narcissistic personality disorder: Comment on Miller and Campbell (2010). AB - What is narcissism? Is it a dimensional personality trait? Is it the core element of a categorical form of psychopathology? Miller and Campbell (see record 2010 17135-004) present a thoughtful, scholarly, and well-written review of a substantial literature aimed at synthesizing research on trait narcissism and contemplating its relevance to the category of narcissistic personality disorder (NPD). They also present an argument that research on trait narcissism should be used to help propel research on NPD, as explicated in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994). This latter argument is somewhat surprising in the context of the rest of Miller and Campbell's article and it is the focus of my commentary. PMID- 22448638 TI - Toward an integrative study of narcissism. AB - Comments on the article by Miller and Campbell (see record 2010-17135-004). The expression of narcissism spans the continuum from normal to pathological and has meaningful correlates in clinical and nonclinical populations. There is growing speculation that narcissism also contributes to major societal concerns (e.g., terrorism and corporate malfeasance). Improving our understanding of the psychological, interpersonal, and social expressions of narcissism should be one of the most important areas in behavioral science research. Unfortunately, the study of narcissism is fragmented and underpursued. Pathological narcissism (PN), primarily narcissistic personality disorder (NPD; American Psychiatric Association, 1994), has been studied mainly through clinical case reports and psychodynamic theory (Ronningstam, 2005), whereas the study of trait narcissism has utilized more empirical methods. Miller and Campbell contend that the current understanding of PN is speculative and empirically lacking. His proposed remedy is for psychiatric and clinical researchers to incorporate the strategies and tools used to study trait narcissism. Although research on PN should be more empirically based, the uncritical adoption of the trait narcissism paradigm seems ill advised. Rather, an integrative research perspective incorporating knowledge and methodologies across disciplines would seem more promising. PMID- 22448640 TI - Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models. AB - BACKGROUND: Chemotherapy of cholangiocarcinoma (CCA), a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed. METHODS/DESIGN: The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR), the crude ethanolic extracts of rhizomes of Zingiber officinale Roscoe (Ginger: ZO) and Atractylodes lancea thung. DC (Khod-Kha-Mao: AL), fruits of Piper chaba Hunt. (De Plee: PC), and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF) were investigated in animal models. Anti cholangiocarcinoma (anti-CCA) was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification. RESULTS: Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight) as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively). PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL), analgesic (CUR and PPF), antipyretic (CUR and AL), antihypertensive (ZO and AL), and anti-ulcer (CUR, ZO, and AL) activities. CONCLUSION: Plants used in Thai traditional medicine for the treatment of various ailments may provide reservoirs of promising candidate chemotherapeutics for the treatment of CCA. PMID- 22448641 TI - Are micelles needed to form methane hydrates in sodium dodecyl sulfate solutions? AB - The possibility that methane hydrates form in sodium dodecyl sulfate (SDS) water solutions without the help of micelles formation has been investigated. To asses whether micelles are needed for the hydrate to form only one SDS molecule has been considered. To figure out the possible mechanism through which the SDS promotes the formation of methane clathrate the dynamics of CH(4) solvation in the presence and absence of the surfactant molecule is monitored. To carry out the dynamical calculations, the SDS-H(2)O, SDS-CH(4), and CH(4)-H(2)O interactions were described using a recently proposed model potential. The adopted model leverages both on the decomposition of the molecular polarizability in effective components associated with the interaction centers distributed on the molecular frame and on the use of an improved Lennard-Jones functional form to represent the effective pair interaction energies. Molecular dynamics simulations performed on such potential, contrary to some earlier assumptions, do not support mechanisms requiring the formation of micelles as suggested by the findings of more recent experiments. PMID- 22448642 TI - Malignant transformation arising from mature cystic teratoma of the ovary: a report of six cases. AB - AIM: Malignant transformation of mature cystic teratoma (MCT) is an uncommon complication. Preoperative diagnosis is difficult because of the lack of specific symptoms and signs indicating malignancy. Thus, we retrospectively analyzed the clinical characteristics of patients and the role of surgery in their management. MATERIAL AND METHODS: During a 9-year period (2002-2010), six patients with malignant transformation arising from ovarian MCT were treated at the Gynecologic Oncology Unit of Bakirkoy Woman and Children's Training and Research Hospital. A retrospective chart review and analysis of the patients' data were conducted. RESULTS: Malignant transformation arising from ovarian MCT accounted for 1.9% of all ovarian MCT (6/321). Three cases were stage IA and the other three were stage IC. Histologically, three of six cases had squamous cell carcinoma (50%), two had a carcinoid tumor (33%), and one had mucinous adenocarcinoma (17%). All patients underwent comprehensive surgical staging. Two patients received adjuvant chemotherapy and one received adjuvant chemoradiation. Five of six patients were observed for 16-104 months and no recurrence was detected. One patient with a carcinoid tumor in stage IC died of disease within 34 months following the surgery. CONCLUSION: Early detection of malignant transformation arising from MCT is mandatory for treating patients, but in most patients malignancy was detected intraoperatively. Surgical cytoreduction with a complete staging procedure and adjuvant treatment may be reasonable for stage IC. Additionally, prognosis is better when the tumor is completely excised and does not extend beyond the capsule. PMID- 22448643 TI - PCV2-DNA in formalin-fixed and paraffin embedded lymph nodes of wild boar (Sus scrofa ssp. scrofa): one sampling approach for two laboratory techniques. AB - Superficial inguinal lymph nodes from 72 wild boars examined in a previous immunohistochemical (IHC) study on porcine circovirus type 2 (PCV2) were selected for a PCV2 polymerase chain reaction (PCR) analysis. Four of these lymph nodes were PCV2-IHC strongly positive with PMWS histological lesions (outcome 1), 6 weak to mild PCV2-IHC positive without PMWS histological lesions (outcome 2) and 62 PCV2-IHC negative. Considering IHC the gold standard for diagnosis, the aims of the study were to evaluate the suitability of the PCV2-DNA extraction from formalin-fixed and paraffin-embedded (FFPE) tissue and the sensitivity and specificity of PCR under two IHC interpretations criteria: (A) the sample was considered positive if the result was outcome 1; (B) the sample was considered positive if the result was outcome 1 or 2. Under (A) criteria, sensitivity and specificity of PCR were 100% and 89.7%, respectively; the Cohen's Kappa coefficient was 0.49. Under (B) criteria, sensitivity and specificity of PCR were 80.0% and 95.2%, respectively; the Cohen's Kappa coefficient was 0.72. The high Cohen's Kappa coefficient under the (B) interpretative criteria indicates good agreement between the two methods. In conclusion, 1) DNA extracted from FFPE specimens of wild boar is suitable for PCR and further represents a screening test for PCV2/PCVD (PCV2 Diseases) investigations in wild boar as well; 2) routine histological sampling can also be useful for PCV2 virological studies in wild boar. PMID- 22448644 TI - Clinicopathological characteristics and prognostic factors of advanced colorectal mucinous adenocarcinoma. AB - AIMS: Mucinous adenocarcinoma (MUC) is a histological variant of colorectal adenocarcinoma. The aim of the present study was to characterize clinicopathological features and identify prognostic factors of MUCs. METHODS AND RESULTS: A total of 181 patients with MUC who underwent surgery between 1975 and 2003 were reviewed. The clinicopathological features of these patients were compared with those of 4125 non-MUC patients. Univariate and multivariate analyses were conducted to identify significant prognostic factors in 102 patients with pT3 or pT4 tumour who underwent curative surgery. Patients with MUCs tended to present with more advanced clinical stages. The overall 5-year survival rate of MUC patients was lower than that of non-MUC patients; however, no prognostic difference was found when patients with the same clinical stages were compared. Multivariate analysis revealed male sex, bowel obstruction and infiltrating growth type as independent prognostic factors. Five-year cancer specific survival rates for MUC patients with <=1, 2 and 3 risk factors identified by multivariate analysis were 95.5%, 52.1% and 0.0%, respectively (P < 0.001). CONCLUSIONS: Mucinous adenocarcinoma represents a distinct clinicopathological entity. Sex, bowel obstruction and growth patterns might be useful prognostic factors to identify patients with a high risk of recurrence after curative resection of advanced MUCs. PMID- 22448645 TI - Biochemical and pharmacological study of N-linked glycosylation of the human serotonin 5-HT7a receptor. AB - The 5-hydroxytryptamine (5-HT)(7(a)) receptor is a G-protein-coupled receptor critically involved in human psychiatric and neurological disorders. In the present study, we evaluate the presence and the functional role of N glycosylation of the human 5-HT(7) receptor. Western blot analysis of HEK293T cells transiently expressing the 5-HT(7(a)) receptor in the presence of tunicamycin gave rise to a band shift, indicating the existence of an N glycosylated form of the 5-HT(7(a)) receptor. To further investigate this, we mutated the two predicted N-glycosylation sites (N5Q and N66Q) and compared the molecular mass of the immunoreactive bands with those of the wild-type receptor, indicating that both asparagines were N-glycosylated. The mutant receptors had the same binding affinity for [(3) H]5-CT and the same potency and efficacy with regard to 5-HT-induced activation of adenylyl cyclase. However, there was a reduction in maximal ligand binding for the single and double mutants compared to the wild-type receptor. Next, membrane labelling and immunocytochemical studies demonstrated that the N-glycosylation mutants were expressed at the cell surface. We conclude that N-glycosylation is not important for cell surface expression of the 5-HT(7) receptor. PMID- 22448646 TI - A high normal TSH level is associated with an atherogenic lipid profile in euthyroid non-smokers with newly diagnosed asymptomatic coronary heart disease. AB - BACKGROUND: Serum lipid profiles may be influenced by thyroid function, but the detailed mechanism remains unclear. Increasing evidence suggests that thyrotropin (TSH) may exert extra-thyroidal effects. The goal of this study was to evaluate the relationship between serum TSH levels and the lipid profiles in euthyroid non smokers with newly diagnosed asymptomatic coronary heart disease (CHD). METHODS: This was a retrospective study of 406 euthyroid non-smokers (187 males and 219 females) with newly diagnosed asymptomatic CHD from 2004 to 2010 in Jinan, China. Lipid parameters and the levels of TSH, FT3, and FT4 were determined. Multiple linear regression analysis and Logistic regression analysis were used to assess the influence of TSH on the lipid profiles and the risks of dyslipidemia. RESULTS: The TSH level, even within the normal range, was positively and linearly correlated with total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C) and triglycerides (TG) (Beta = 0.173, 0.181 and 0.103, respectively, P < 0.01 in all). With 1 mIU/L rise of TSH, the levels of TC, TG and non-HDL-C will increase by 1.010, 1.064, and 1.062 mmol/L, respectively. The odds ratio of hypercholesterolemia and hypertriglyceridemia with respect to the serum TSH level was 1.640 (95% CI 1.199-2.243, P = 0.002) and 1.349 (95% CI 1.054-1.726, P = 0.017), respectively. CONCLUSIONS: TSH levels were correlated in a positive linear manner with the TC, non-HDL-C and TG levels in euthyroid non-smokers with newly diagnosed asymptomatic CHD. TSH in the upper limits of the reference range might exert adverse effects on lipid profiles and thus representing as a risk factor for hypercholesterolemia and hypertriglyceridemia in the context of CHD. PMID- 22448647 TI - Unpredictability of nectar nicotine promotes outcrossing by hummingbirds in Nicotiana attenuata. AB - Many plants use sophisticated strategies to maximize their reproductive success via outcrossing. Nicotiana attenuata flowers produce nectar with nicotine at concentrations that are repellent to hummingbirds, increasing the number of flowers visited per plant. In choice tests using native hummingbirds, we show that these important pollinators learn to tolerate high-nicotine nectar but prefer low-nicotine nectar, and show no signs of nicotine addiction. Nectar nicotine concentrations, unlike those of other vegetative tissues, are unpredictably variable among flowers, not only among populations, but also within populations, and even among flowers within an inflorescence. To evaluate whether variations in nectar nicotine concentrations increase outcrossing, polymorphic microsatellite markers, optimized to evaluate paternity in native N. attenuata populations, were used to compare outcrossing in plants silenced for expression of a biosynthetic gene for nicotine production (Napmt1/2) and in control empty vector plants, which were antherectomized and transplanted into native populations. When only exposed to hummingbird pollinators, seeds produced by flowers with nicotine in their nectar had a greater number of genetically different sires, compared to seeds from nicotine-free flowers. As the variation in nectar nicotine levels among flowers in an inflorescence decreased in N. attenuata plants silenced in various combinations of three Dicer-like (DCL) proteins, small RNAs are probably involved in the unpredictable variation in nectar nicotine levels within a plant. PMID- 22448648 TI - Biofilm building capacity of Salmonella enterica strains from the poultry farm environment. AB - The Biofilm (BF) building capacity of different serotypes of Salmonella enterica derived from the poultry farm environment was investigated. Starting point for the investigation was the question if farm-isolated Salmonella serotypes with high importance for poultry meat and egg production are capable of forming a BF under defined laboratory conditions. Several isolates from different stages of the production cycle were chosen and compared to laboratory grown strains of the same serotype. BF building capacity was analyzed in a 96-well format during a time period of 2 days. Pulse field gel electrophoresis was used to establish a relationship between different isolates. The BF building capacity of a monospecies BF was strongly dependent on the temperature used for incubation. Results indicated further that certain farm isolates were capable of forming BF under laboratory conditions, whereas laboratory grown strains were not. Considerable differences between different field serovars and within one serovar exist. In conclusion, the BF building capacity of poultry-derived isolates is a function of adaptation to their host environment. Thus, the control of BF as a reservoir for Salmonella in the farm environment is of crucial importance for the overall improvement of food safety. Mechanical and substance-based approaches for this control exist in several variations, but overall decontamination success is difficult to achieve and needs to be especially adapted to the farm environment. PMID- 22448649 TI - Prostate-specific antigen testing in older men in the USA: data from the behavioral risk factor surveillance system. AB - OBJECTIVE: To examine the frequency of PSA testing in men aged >=75 years before and after the 2008 US Preventive Services Task Force (USPSTF) recommendation to stop prostate-specific antigen (PSA) screening at age 75. MATERIALS AND METHODS: Data were obtained from the Behavioral Risk Factor Surveillance System (BRFSS) surveys completed in 2006, 2008 and 2010. Men aged >= 76 years at the time of survey and without a prostate cancer diagnosis were included in the study. The percentage of men who had a PSA test in the year before the survey was computed separately for survey years 2006, 2008 and 2010. RESULTS: The estimated percentages of men with a PSA test in the year before the survey were 60% (95% CI: 58-62%), based on 9033 respondents interviewed in 2006, 63% (95% CI: 62-65%), based on 12,063 respondents interviewed in 2008, and 60% (95% CI: 59-61%), based on 14,782 respondents interviewed in 2010. CONCLUSION: No substantial reduction in the frequency of PSA testing was observed in the BRFSS 2010 survey data compared with the earlier years, suggesting that the USPSTF 2008 recommendation had no major impact on the frequency of PSA testing in older men in the USA. PMID- 22448650 TI - Expanding the measures of physical capacity in cerebral palsy. PMID- 22448651 TI - Transcriptome landscape of the human placenta. AB - BACKGROUND: The placenta is a key component in understanding the physiological processes involved in pregnancy. Characterizing genes critical for placental function can serve as a basis for identifying mechanisms underlying both normal and pathologic pregnancies. Detailing the placental tissue transcriptome could provide a valuable resource for genomic studies related to placental disease. RESULTS: We have conducted a deep RNA sequencing (RNA-Seq) study on three tissue components (amnion, chorion, and decidua) of 5 human placentas from normal term pregnancies. We compared the placental RNA-Seq data to that of 16 other human tissues and observed a wide spectrum of transcriptome differences both between placenta and other human tissues and between distinct compartments of the placenta. Exon-level analysis of the RNA-Seq data revealed a large number of exons with differential splicing activities between placenta and other tissues, and 79% (27 out of 34) of the events selected for RT-PCR test were validated. The master splicing regulator ESRP1 is expressed at a proportionately higher level in amnion compared to all other analyzed human tissues, and there is a significant enrichment of ESRP1-regulated exons with tissue-specific splicing activities in amnion. This suggests an important role of alternative splicing in regulating gene function and activity in specific placental compartments. Importantly, genes with differential expression or splicing in the placenta are significantly enriched for genes implicated in placental abnormalities and preterm birth. In addition, we identified 604-1007 novel transcripts and 494-585 novel exons expressed in each of the three placental compartments. CONCLUSIONS: Our data demonstrate unique aspects of gene expression and splicing in placental tissues that provide a basis for disease investigation related to disruption of these mechanisms. These data are publicly available providing the community with a rich resource for placental physiology and disease-related studies. PMID- 22448652 TI - A novel WD-repeat protein, WDR26, inhibits apoptosis of cardiomyocytes induced by oxidative stress. AB - WD40 repeat proteins have a variety of functions, such as signal transduction, transcription regulation, cell cycle control, autophagy and apoptosis. WDR26 is a novel protein of WD40 repeat proteins and up-regulated during myocardial cells ischemic preconditioning (IPC) but its role in myocardial cell apoptosis induced by oxidative stress and its subcellular localisation are not clear. So we investigated the subcellular localisation of WDR26 and WDR26 expression in rat myocardial ischaemia-reperfusion injury model and H9c2 cells stimulated by H(2)O(2). The results showed that WDR26 can be located at mitochondria and induced by ischaemia-reperfusion injury and H(2)O(2). Then we examined the effects induced by H(2)O(2) in H9c2 cells WDR26 expression. The results showed that WDR26 expression can inhibit apoptosis induced by H(2)O(2). Further, we demonstrated that WDR26 inhibit cytochrome c release from mitochondria. These founding indicate that WDR26 protects myocardial cells against oxidative stress. PMID- 22448653 TI - Surface ultrastructure of the eggs of Malacopsylla grossiventris and Phthiropsylla agenoris (Siphonaptera: Malacopsyllidae). AB - The fleas of the Malacopsyllidae are known only by their adults. In this study, we describe the eggs of Malacopsylla grossiventris and Phthiropsylla agenoris and compare their surface ultrastructure using scanning electron microscopy. Eggs of both flea species are similar in their general appearance, i.e., the presence of disks and absence of lateral aeropyles, but they differ in size, texture of the surface, and number of micropyles and aeropyles. In addition, the eggs of M. grossiventris and P. agenoris are larger (719-800 um) than most of the flea eggs known (<600 um), and the length/width ratio is 2.0, while it varies between 1.6 and 1.8 in other species. As opposed to other large species, malacopsyllids have expandable (telescoping) abdomens that display growth. It is possible that a clutch of eggs has more than 2 eggs. Females of M. grossiventris were observed fixed with their mouthparts to the skin of their hosts. Indeed, some of these specimens were observed copulating on the venter of their hosts. These results contribute to the knowledge about the biology of malacopsyllids. PMID- 22448654 TI - Borrelia burgdorferi serosurvey in wild deer in England and Wales. AB - Lyme disease is the most common vector-borne disease in the United Kingdom and its incidence has been increasing in recent years. However, limited information is available on its epidemiology and dynamics in the U.K. A survey in wild deer to investigate the presence of antibodies reactive to Borrellia burgdorferi was conducted to obtain initial information on the distribution pattern of the spirochete in England and Wales. Samples from roe deer (n=604) and red deer (n=80) were collected in eight different locations. An ELISA protocol was developed to identify antibodies reactive to B. burgdorferi s.l. Seropositivity was investigated by location of sampling, over time, and in relation to the level of deer tick infestation. Twenty-three percent of animals had a positive serology. Seroprevalence varied according to location with the southern forestry districts showing higher seroprevalence rates. One northern location showed an unexpectedly high proportion of positive deer. Variations in the proportion of positive animals were also observed over time. Tick load was higher from spring through autumn, and its relation to seroprevalence was compatible with higher tick infectivity during the spring and summer months. This study represents the first assessment of distribution of Borrelia antibodies in deer in the U.K. and identifies areas that are potential hot spots for human Lyme borreliosis. Targeted epidemiological studies should be conducted to evaluate the actual disease risk for humans. PMID- 22448655 TI - Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review. AB - BACKGROUND: Traumatic brain injury (TBI) is a major source of death and severe disability worldwide. Raised Intracranial pressure (ICP) is an important predictor of mortality in patients with severe TBI and aggressive treatment of elevated ICP has been shown to reduce mortality and improve outcome. The acute post-injury period in TBI is characterized by several pathophysiologic processes that start in the minutes to hours following injury. All of these processes are temperature-dependent; they are all aggravated by fever and inhibited by hypothermia. METHODS: This study reviewed the current clinical evidence in support of the use of therapeutic hypothermia (TH) for the treatment of intracranial hypertension (ICH) in patients with severe TBI. RESULTS: This study identified a total of 18 studies involving hypothermia for control of ICP; 13 were randomized controlled trials (RCT) and five were observational studies. TH (32-34 degrees C) was effective in controlling ICH in all studies. In the 13 RCT, ICP in the TH group was always significantly lower than ICP in the normothermia group. In the five observational studies, ICP during TH was always significantly lower than prior to inducing TH. CONCLUSIONS: Pending results from large multi centre studies evaluating the effect of TH on ICH and outcome, TH should be included as a therapeutic option to control ICP in patients with severe TBI. PMID- 22448656 TI - Iron nanoparticles catalyzing the asymmetric transfer hydrogenation of ketones. AB - Investigation into the mechanism of transfer hydrogenation using trans [Fe(NCMe)CO(PPh(2)C(6)H(4)CH?NCHR-)(2)][BF(4)](2), where R = H (1) or R = Ph (2) (from R,R-dpen), has led to strong evidence that the active species in catalysis are iron(0) nanoparticles (Fe NPs) functionalized with achiral (with 1) and chiral (with 2) PNNP-type tetradentate ligands. Support for this proposition is given in terms of in operando techniques such as a kinetic investigation of the induction period during catalysis as well as poisoning experiments using substoichiometric amounts of various poisoning agents. Further support for the presence of Fe(0) NPs includes STEM microscopy imaging with EDX analysis, XPS analysis, and SQUID magnetometry analysis of catalytic solutions. Further evidence of Fe NPs acting as the active catalyst is given in terms of a polymer supported substrate experiment whereby the NPs are too large to permeate the pores of a functionalized polymer. Final support is given in terms of a combined poisoning/STEM/EDX experiment whereby the poisoning agent is shown to be bound to the Fe NPs. This paper provides evidence of a rare example of asymmetric catalysis with nonprecious metal, zerovalent nanoparticles. PMID- 22448657 TI - Study of antibacterial activity by capillary electrophoresis using multiple UV detection points. AB - A new methodology for an antibacterial assay based on capillary electrophoresis with multiple UV detection points has been proposed. The possible antibacterial activity of cationic molecules on bacteria (Gram-positive and Gram-negative) is studied by detecting the bacteria before, during, and after their meeting with the cationic antibacterial compound. For that, a UV area imaging detector having two loops and three detection windows was used with a 95 cm *100 MUm i.d. capillary. In the antibacterial assay, the bacteria (negatively charged) and the cationic molecules were injected separately from each end of the capillary. The bacteria were mobilized by anionic ITP mode while cationic molecules migrate in the opposite direction under conditions close to CZE. The cationic molecules were injected into the capillary as a broad band (injected volume about 16% of the volume of the capillary) to prevent dilution of the sample during the electrophoretic process. Bacteriolytic activity, as well as strong interactions between the small antibacterial molecules and the bacteria, can be investigated within a few minutes. The assay was used to study the antibacterial activity of dendrigraft poly-L-lysines on Micrococcus luteus and Erwinia carotovora. Because dendrigraft poly-L-lysines are nonimmunogenic and have low toxicity, this new class of dendritic biomacromolecules is very promising for antibacterial applications. PMID- 22448658 TI - "What do they want me to say?" The hidden curriculum at work in the medical school selection process: a qualitative study. AB - BACKGROUND: There has been little study of the role of the essay question in selection for medical school. The purpose of this study was to obtain a better understanding of how applicants approached the essay questions used in selection at our medical school in 2007. METHODS: The authors conducted a qualitative analysis of 210 essays written as part of the medical school admissions process, and developed a conceptual framework to describe the relationships, ideas and concepts observed in the data. RESULTS: Findings of this analysis were confirmed in interviews with applicants and assessors. Analysis revealed a tension between "genuine" and "expected" responses that we believe applicants experience when choosing how to answer questions in the admissions process. A theory named "What do they want me to say?" was developed to describe the ways in which applicants modulate their responses to conform to their expectations of the selection process; the elements of this theory were confirmed in interviews with applicants and assessors. CONCLUSIONS: This work suggests the existence of a "hidden curriculum of admissions" and demonstrates that the process of selection has a strong influence on applicant response. This paper suggests ways that selection might be modified to address this effect. Studies such as this can help us to appreciate the unintended consequences of admissions processes and can identify ways to make the selection process more consistent, transparent and fair. PMID- 22448660 TI - A patient presenting with concha bullosa in another concha bullosa: a case report. AB - INTRODUCTION: Anatomic variations of the paranasal sinuses are very common. The paranasal sinus anatomy should be carefully examined prior to performing endoscopic sinus surgery in terms of both existent pathologies and anatomic variations. The anatomy of the paranasal sinuses and its variations have gained importance, along with advances in coronal paranasal sinus computed tomography and extensive use of endoscopic sinus surgery. CASE PRESENTATION: A 53-year-old Caucasian woman was admitted to our clinic with complaints of nasal breathing difficulties and headache persisting for a long time. Another concha bullosa was detected in the middle concha bullosa on preoperative paranasal computed tomography examination. It is known that the paranasal sinuses have a number of anatomical variations. CONCLUSION: Herein we report a rare case, along with a review of the literature, to emphasize that a concha bullosa inside another concha bullosa should not be ignored. PMID- 22448661 TI - Valsartan: in children and adolescents with hypertension. AB - Valsartan is an oral angiotensin II subtype 1 receptor antagonist with well established antihypertensive efficacy in adults. It is now approved in the EU and the US for the treatment of hypertension in children and adolescents. In two, randomized, double-blind trials, a once-daily regimen of valsartan reduced the blood pressure (BP) of children and adolescents with hypertension. In one trial in hypertensive children and adolescents aged 6-16 years, significant dose dependent reductions from baseline in mean sitting systolic BP (msSBP) were observed for recipients of valsartan following 2 weeks' treatment (primary endpoint). There were corresponding dose-dependent and significant reductions in mean sitting diastolic BP. Following 2 further weeks of treatment, the reduction in msSBP was maintained in patients who were re-randomized to continue receiving the same dosage of valsartan but not in those re-randomized to placebo. In the other trial in hypertensive children and adolescents aged 6-17 years, valsartan was no less effective than enalapril in reducing BP. Following 12 weeks' treatment, the least square mean reduction from baseline in msSBP (primary endpoint) in recipients of valsartan was noninferior to that in recipients of enalapril. In addition, the proportion of patients achieving an msSBP <95th percentile for age, sex, and height at week 12 was not significantly different between recipients of valsartan and enalapril (67% vs 70%). Treatment with valsartan for up to 52 weeks was well tolerated in children and adolescents with hypertension. PMID- 22448662 TI - Diagnostic utility of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 in malignant germ cell tumors of the ovary. AB - AIM: Primary ovarian malignant germ cell tumors (OMGCTs) are rare and difficult to diagnose. Immunohistochemistry can help in the diagnosis and development of new management strategies. The aim of this study was to investigate the frequency of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 marker expression in OMGCTs. MATERIAL AND METHODS: We examined the expression of six markers in 87 (85 pure and two mixed OMGCTs) cases of OMGCT using immunohistochemical staining. Staining was graded in a semiquantitative manner as follows: negative (no staining), 1+ (1 30% staining), 2+ (31-60% staining), or 3+ (>60% staining). RESULTS: All 27 dysgerminomas and all 31 YSTs showed CD117 expression, with only nine (29%) positively stained in immature teratomas. SALL4 and glypican-3 were strongly positive in 100 and 79.3%, respectively, of YSTs. All dysgerminomas were positive for OCT4, whereas all YSTs and immature teratomas were negative. 100% of dysgerminomas were positive for TCL1, but all immature teratomas were negative. CD133 expression showed generally the same tendency in the 3 OMGCTs. CONCLUSION: CD117 can be used as a diagnostic marker for dysgerminoma and YST. SALL4 is a more sensitive and specific marker for YSTs than glypican-3. SALL4 and OCT4 are useful in distinguishing YST from dysgerminoma. PMID- 22448663 TI - Developing best practice for fungal specimen submission--fungal audit of general practice. AB - The objective of this study was to investigate the management of suspected fungal nail infections by general practitioners (GPs) and determine whether guidance is sought when submitting specimens for investigation or treating cases. Questionnaires were sent to all GPs (n = 2420) served by five Health Protection Agency (HPA) collaborating laboratories in the South West of England. A total of 769 GPs responded - topical and oral antifungals were never used by 29% and 16% of GPs respectively. When antifungals were prescribed, topicals were normally given because of the severity of infection (32%); Amorolofine (53%) was the preferred choice. Oral antifungals were most often prescribed after receipt of a laboratory report (77%); Terbinafine was the preferred choice (86%). Seventy percent of GPs would only treat a suspected nail infection with oral antifungals after sending a sample for investigation, yet 27% never waited for a microscopy report before prescribing oral antifungal treatment. GPs routinely send specimens from suspected fungal nail infections for microbiological investigation, yet treatment is often prescribed before a result is received. With clinical signs of fungal infections often non-specific, GPs should rely on laboratory results before prescribing expensive and lengthy antifungal treatments. Laboratories could further reduce antifungal use by including guidance on microscopy and culture reports. PMID- 22448664 TI - Syntheses of chiral beta- and gamma-amino ethers, morpholines, and their homologues via nucleophilic ring-opening of chiral activated aziridines and azetidines. AB - Lewis acid catalyzed quaternary ammonium salt mediated highly regioselective ring opening of chiral activated aziridines and azetidines with alcohols to nonracemic beta- and gamma-amino ethers has been developed. The reaction mainly proceeds via an S(N)2 pathway, and the partial racemization of the starting substrate was effectively controlled by using quaternary ammonium salts. beta- and gamma-amino ethers are obtained with high enantio- and diastereospecificity (ee up to >99%, de up to 99%). The methodology was further extended to synthesize morpholines and their homologues with high enantiospecificity (ee up to 90%) when halo alcohols were employed as the nucleophiles. PMID- 22448665 TI - Evidence for deficits in reward responsivity in antisocial youth with callous unemotional traits. AB - This study investigated reward responsivity in youth with high levels of callous unemotional (CU) traits using a cross-sectional design. Whereas deficits in responding to punishment cues are well established in youth with CU traits, it is unclear whether responsivity to rewarding stimuli is impaired as well. Participants were 148 predominantly Caucasian, adjudicated adolescents between the ages of 11 and 17 (M = 15.1, SD = 1.4) who completed the Balloon Analogue Risk Task as part of a larger battery investigating aggression and social information processing. A Reward Responsivity variable was created to capture changes in participants' responding after receiving a reward. A hierarchical regression analysis indicated that higher levels of CU traits significantly predicted less reward responsivity, above and beyond gender, sensation seeking, and impulsivity. Results support Blair's (2004) Integrated Emotion Systems model that proposes individuals with CU traits are impaired in their responsivity to both appetitive and aversive stimuli. PMID- 22448666 TI - Personality-related problems in living: an empirical approach. AB - A proposal for the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-V) is to separate the diagnosis of mental disorder from the assessment of impairment or disability. A separation of the assessment of traits and impairment is consistent with the five-factor model (FFM) procedure for the diagnosis of a personality disorder, which first assesses for the presence of personality traits, followed by an assessment of impairments associated with a particular trait elevation. The current study tested the hypothesis that the FFM has specific implications with respect to the 3 fundamental components of personality disorder as provided in the American Psychiatric Association's (2000) diagnostic manual, concerning social impairment, occupational impairment, and distress. These hypotheses were confirmed in a sample of 79 persons who were currently or recently in psychological treatment. Implications of the findings for a conceptualization of personality disorder and future research are discussed. PMID- 22448667 TI - Refining behavioral dysregulation in borderline personality disorder using a sample of women with anorexia nervosa. AB - One of the primary facets of borderline personality disorder (BPD) is behavioral dysregulation, a wide array of behaviors that are difficult to control and harmful to the individual. The purpose of this study was to explore the association between BPD and a variety of dysregulated behaviors, some of which have received little empirical attention. Using a large sample of individuals diagnosed with anorexia nervosa, 41 individuals diagnosed with BPD were compared to the rest of the sample on the presence of dysregulated behaviors using logistic regression analyses. Anorexia nervosa subtypes, age, and other Cluster B personality disorders were used as covariates. Results support an association between BPD and alcohol misuse, hitting someone/breaking things, provoking fights/arguments, self-injury, overdosing, street drug use, binge-eating, impulsive spending, shoplifting/stealing, and risky sexual behaviors. Differences between dichotomous and continuous measures of BPD yielded somewhat different results. Information on co-occurring anorexia nervosa and BPD was generated. PMID- 22448669 TI - Berry fruits modulated endothelial cell migration and angiogenesis via phosphoinositide-3 kinase/protein kinase B pathway in vitro in endothelial cells. AB - Polyphenolic-rich berry fruits are known to activate redox-sensitive cellular signaling molecules such as phosphatidylinositol-3-kinase (PI3 kinase)/kinase B (Akt), resulting in a cascade of downstream signaling pathways. This study investigated the ability of strawberry (SB), wild blueberry (WBB), and cranberry (CB) extracts to induce the activation of PI3 kinase/Akt signaling in vitro in human umbilical endothelial cells (HUVECs) and whether this activation would enhance cell migration and angiogenesis. Anthocyanin profiles of the extracts were characterized using HPLC-ESI/MS, and Akt activation was investigated using the Alpha Screen SureFire assay. The total anthocyanin contents of SB, WBB, and CB extracts were 81.7, 82.5, and 83.0 mg/100 g fresh weight, respectively. SB, WBB, and CB extracts activated Akt in a dose-dependent manner via PI3 kinase and induced cell migration and angiogenesis in vitro in HUVECs. The results from this study suggest that polyphenolics in berry fruits may play a role in promoting vascular health. PMID- 22448670 TI - Pronounced microheterogeneity in a sorbitol-water mixture observed through variable temperature neutron scattering. AB - In this study, the structure of concentrated d-sorbitol-water mixtures is studied by wide- and small-angle neutron scattering (WANS and SANS) as a function of temperature. The mixtures are prepared using both deuterated and regular sorbitol and water at a molar fraction of sorbitol of 0.19 (equivalent to 70% by weight of regular sorbitol in water). Retention of an amorphous structure (i.e., absence of crystallinity) is confirmed for this system over the entire temperature range, 100-298 K. The glass transition temperature, Tg, is found from differential scanning calorimetry to be approximately 200 K. WANS data are analyzed using empirical potential structure refinement, to obtain the site-site radial distribution functions (RDFs) and coordination numbers. This analysis reveals the presence of nanoscaled water clusters surrounded by (and interacting with) sorbitol molecules. The water clusters appear more structured compared to bulk water and, especially at the lowest temperatures, resemble the structure of low density amorphous ice (LDA). Upon cooling to 100 K the peaks in the water RDFs become markedly sharper, with increased coordination number, indicating enhanced local (nanometer-scale) ordering, with changes taking place both above and well below the Tg. On the mesoscopic (submicrometer) scale, although there are no changes between 298 and 213 K, cooling the sample to 100 K results in a significant increase in the SANS signal, which is indicative of pronounced inhomogeneities. This increase in the scattering is partly reversed during heating, although some hysteresis is observed. Furthermore, a power law analysis of the SANS data indicates the existence of domains with well-defined interfaces on the submicrometer length scale, probably as a result of the appearance and growth of microscopic voids in the glassy matrix. Because of the unusual combination of small and wide scattering data used here, the present results provide new physical insight into the structure of aqueous glasses over a broad temperature and length scale, leading to an improved understanding of the mechanisms of temperature- and water-induced (de)stabilization of various systems, including proteins, pharmaceuticals, and biological objects. PMID- 22448671 TI - Real-time three-dimensional transthoracic echocardiography in daily practice: initial experience. AB - AIM OF THE WORK: To evaluate the feasibility and possible additional value of transthoracic real-time three-dimensional echocardiography (RT3D-TTE) for the assessment of cardiac structures as compared to 2D-TTE. METHODS: 320 patients (mean age 45 +/- 8.4 years, 75% males) underwent 2D-TTE and RT3D-TTE using 3DQ-Q lab software for offline analysis. Volume quantification and functional assessment was performed in 90 patients for left ventricle and in 20 patients for right ventricle. Assessment of native (112 patients) and prosthetic (30 patients) valves morphology and functions was performed. RT3D-TTE was performed for evaluation of septal defects in 30 patients and intracardiac masses in 52 patients. RESULTS: RT3D-TTE assessment of left ventricle was feasible and reproducible in 86% of patients while for right ventricle, it was (55%). RT3D-TTE could define the surface anatomy of mitral valve optimally (100%), while for aortic and tricuspid was (88% and 81% respectively). Valve area could be planimetered in 100% for the mitral and in 80% for the aortic. RT3D-TTE provided a comprehensive anatomical and functional evaluation of prosthetic valves. RT3D TTE enface visualization of septal defects allowed optimal assessment of shape, size, area and number of defects and evaluated the outcome post device closure. RT3D-TTE allowed looking inside the intracardiac masses through multiple sectioning, valuable anatomical delineation and volume calculation. CONCLUSION: Our initial experience showed that the use of RT3D-TTE in the assessment of cardiac patients is feasible and allowed detailed anatomical and functional assessment of many cardiac disorders. PMID- 22448672 TI - Combining semiquantitative measures of fibrosis and qualitative features of parenchymal remodelling to identify fibrosis regression in hepatitis C: a multiple biopsy study. AB - AIMS: A fall in hepatic fibrosis stage may be observed in patients with chronic hepatitis C (CHC); however, parenchymal architectural changes may also signify hepatic remodelling associated with fibrosis regression. The aim of this study was to utilize semiquantitative and qualitative methods to report the prevalence and factors associated with fibrosis regression in CHC. METHODS AND RESULTS: Paired liver biopsies were scored for fibrosis (Ishak), and for the presence of eight qualitative features of parenchymal remodelling, to derive a qualitative regression score (QR score). Combined fibrosis regression was defined as >=2 stage fall in Ishak stage (Reg-I) or <2-stage fall in Ishak stage with a rise in QR score (Reg-Qual). Among 159 patients (biopsy interval 5.4 +/- 3.1 years), Reg I was observed in 12 (7.5%) and Reg-Qual in 26 (16.4%) patients. The combined diagnostic criteria increased the diagnosis rate for fibrosis regression (38 patients, 23.9%) compared with use of Reg-I alone (P < 0.001). Combined fibrosis regression was observed in nine patients (50%) who achieved sustained virological response (SVR), and in 29 of 141 (21%) patients despite persistent viraemia. SVR was the only clinical factor associated independently with combined fibrosis regression (odds ratio 3.05). CONCLUSIONS: The combination of semiquantitative measures and qualitative features aids the identification of fibrosis regression in CHC. PMID- 22448673 TI - Genetic basis of rifampicin resistance in methicillin-resistant Staphylococcus aureus suggests clonal expansion in hospitals in Cape Town, South Africa. AB - BACKGROUND: Since 2001, several studies have reported high rifampicin resistance rates (45 - 100%) among methicillin-resistant Staphylococcus aureus (MRSA) isolates from South Africa. The authors previously characterised 100 MRSA isolates from hospitals in Cape Town, South Africa; forty-five percent of these isolates were rifampicin-resistant. The majority (44/45) corresponded to ST612 MRSA-IV, which is prevalent in South Africa, but has not been reported frequently elsewhere. The remaining rifampicin-resistant isolate corresponded to ST5-MRSA-I. The aim of this study was to investigate further the prevalence and genetic basis of rifampicin-resistance in MRSA isolates from hospitals in Cape Town. RESULTS: Between July 2007 and June 2011, the prevalence of rifampicin-resistant MRSA in hospitals in Cape Town ranged from 39.7% to 46.4%. Based on the results of the aforementioned study, nine ST612-MRSA-IV isolates, the rifampicin-resistant ST5 MRSA-I isolate, and two rifampicin-susceptible MRSA isolates were investigated. Four previously described ST612-MRSA-IV isolates, including two each from South Africa and Australia, were also included.The ST5-MRSA-I isolate carried a single mutational change, H481Y, commonly associated with high-level rifampicin resistance. All ST612-MRSA-IV isolates carried an uncommon double amino acid substitution in RpoB, H481N, I527M, whilst one of the Australian ST612-MRSA-IV isolates carried an additional mutation within rpoB, representing a novel rpoB genotype: H481N, I527M, K579R. All ST612-MRSA-IV isolates also shared a unique silent single nucleotide polymorphism (SNP) within rpoB. CONCLUSIONS: That local ST612-MRSA-IV isolates described here share an uncommon rpoB genotype and a unique silent SNP suggests this clone may have undergone clonal expansion in hospitals in Cape Town. Further, the data suggest that these isolates may be related to rifampicin-resistant ST612-MRSA-IV previously described in South Africa and Australia. PMID- 22448674 TI - A new experimental rat model of erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: the testosterone supplemented spontaneously hypertensive rat. AB - What's known on the subject? and What does the study add? Lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common problems in the aging male population. Moreover, several recent studies have shown that ED is closely associated with the presence and severity of LUTS independently of co-morbidities. However, the pathophysiological mechanisms linking LUTS/BPH and ED remain largely unexplored. The major difficulty in studying such relationships between ED and LUTS/BPH, and of exploring the impact of new therapeutic approaches for both LUTS/BPH and ED, is the lack of experimental model combining ED, prostate enlargement and bladder dysfunction all at once. The present study describes a new model of BPH, the SHR supplemented with testosterone which is the first animal model which displays all at once the key features of BPH: prostate enlargement and an increased sympathetic tone of bladder outlet mimicking the static and the dynamic components of voiding symptoms of BPH, a significant impairment of bladder function which reflects the storage symptoms of BPH and finally, ED. This model could be very relevant to better characterize the close relationship that exists between BPH/LUTS and ED, and to evaluate new therapeutic strategies for BPH together with their side effect profile on sexual function on the same animal, thus allowing a reduction of the number of animals to be used in such studies. Study Type - Aetiology (case control) Level of Evidence 3b. OBJECTIVE: * To design a new experimental model combining erectile dysfunction, prostate enlargement and urodynamic impairment characteristic of lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). MATERIALS AND METHODS: * Three groups of animals (12-week-old; n= 7/group) were considered: Wistar Kyoto (control) rats (WKY), untreated spontaneously hypertensive rats (SHR) and SHR treated with testosterone (SHR-T, 3 mg/kg/day) for 3 weeks. * Cystometry experiments and evaluation of erectile function were performed. Prostate enlargement was evaluated. RESULTS: * SHR displayed a significant decrease in the intercontraction interval (ICI) and in the voided volume (VV) whereas non-voiding contractions (NVC) were increased. SHR-T exhibited a further decreased ICI and VV and an increased frequency of NVC. * Erectile responses to electrical stimulation of the cavernous nerve were significantly impaired in both SHR (-66%) and SHR-T (-58%). * The prostate weight was similar in WKY and SHR, but significantly increased in SHR-T. CONCLUSIONS: * The testosterone supplemented SHR represents an experimental model for urodynamic impairment combining both static and dynamic components of voiding symptoms with erectile dysfunction and prostate enlargement. * This model is suitable for the assessment of sexual side effects of LUTS/BPH treatments and efficacy of new therapeutic agents in LUTS/BPH and associated erectile dysfunction. PMID- 22448675 TI - DNA barcoding of schistosome cercariae reveals a novel sub-lineage within Schistosoma rodhaini from Ngamba Island Chimpanzee Sanctuary, Lake Victoria. AB - While Schistosoma rodhaini is typically considered a parasite of small mammals and is very scantly distributed in the Lake Victoria basin, it is known to hybridize with the more widespread Schistosoma mansoni, the causative agent of intestinal schistosomiasis. As part of broader parasitological and malacological surveys for S. mansoni across Lake Victoria, schistosome cercariae were harvested from a field-caught Biomphalaria choanomphala taken on Ngamba Island Chimpanzee Sanctuary, Uganda. Upon DNA barcoding, these cercariae were found to be a mixture of both S. rodhaini and S. mansoni, with further phylogenetic analysis revealing a hitherto unknown sub-lineage within S. rodhaini. Despite repeated sampling for eggs and miracidia from both chimpanzees and staff on Ngamba Island Sanctuary, detection of S. rodhaini within local definitive hosts awaits additional efforts, which should be mindful of a potential host role of spotted-necked otters. PMID- 22448676 TI - Unraveling the ecological complexities of tick-associated Crimean-Congo hemorrhagic fever virus transmission: a gap analysis for the western Palearctic. AB - This review aims to summarize the current knowledge of the eco-epidemiology of Crimean-Congo hemorrhagic fever (CCHF) virus transmission reviewing the most recent scientific advances in the last few decades of epidemic and non-epidemic ("silent") periods. We explicitly aim to highlight the dynamics of transmission that are still largely unknown. Recent knowledge gathered from research in Africa and Europe explains the very focal nature of the virus, and indicates that research on the ecology of the virus in the inter-epidemic periods of the disease has not yet been addressed. Hyalomma spp. ticks have been incriminated in the transmission of the virus under field conditions, but the role of other ticks found infected in nature remains to be tested under experimental conditions. Published evidence suggests that the increase in human cases reported in the Balkans, Turkey, and Russia is perhaps less due to the effect of changes in climate, but rather result from the impact of yet unexplored mechanisms of amplification that might be supported by wild animal hosts. Assessment of the available data suggests that epidemics in Eastern Europe are not the result of a spreading viral wave, but more likely are due to a combination of factors, such as habitat abandonment, landscape fragmentation, and proliferation of wildlife hosts that have exacerbated prevalence rates in tick vectors. There is an urgent need to empirically demonstrate these assumptions as well as the role of birds in introducing infected ticks, and also to evaluate the potential for survival of introduced ticks. Either a replacement of the pathogenic virus in the western Mediterranean or a lack of westward dissemination of infected tick populations may explain the absence of the virus in Western Europe. PMID- 22448677 TI - Development of real-time polymerase chain reaction for detection of Borrelia burgdorferi sensu lato in China. AB - Universal primers and probes were selected on the basis of the 16S rRNA gene sequence of Borrelia burgdorferi in GenBank(r), and a real-time polymerase chain reaction (PCR) method for detection of B. burgdorferi was established. The results showed that this method could specifically detect the B31 strain (Borrelia burgdorferi sensu stricto), the BO23 strain (Borrelia afzelii), and the SZ strain (Borrelia garinii), without cross-reaction with genome DNA of Theileria (T. luwenshuni, T. uilenbergi, T. sinensis, T. annulata, T. sergenti, T. annulata), Babesia (B. bigemina, B. ovate, B. sp. (Xinjiang)), Anaplasma (A. marginale, A. ovis), Mycoplasma mycoides subsp. capri, and Chlamydia psittaci, which are the infective pathogens to yak and/or sheep. The sensitivity of this real-time PCR is 104 times greater than that of a conventional PCR. The real-time PCR was able to amplify 16S rRNA gene from as few as 22.88 fg genomic DNA of B. burgdorferi sensu lato. Tick DNAs from 369 field samples collected from Shangzhi City of Heilongjiang Province were tested, resulting in an infection rate of 42.80%, and a total of 332 genomic DNAs from the blood of 186 yaks and 146 sheep in the Gannan Tibetan Autonomous Prefecture of Gansu Province were tested, resulting in 24.19% positive rate for the yaks and 39.04% positive rate for the sheep. PMID- 22448678 TI - Detection of murine toxoplasmosis using magnetic bead-based serum peptide profiling by MALDI-TOF MS. AB - Establishment of a rapid, highly specific, and accurate method for diagnosis of Toxoplasma gondii infection is essential to control and prevent zoonotic toxoplasmosis. In this study, a novel diagnostic strategy using magnetic bead based serum peptide profiling by matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS) was developed. The serum peptides (samples I, II, and III) from T. gondii RH strain-infected mice at days 3, 6, and 9 post-infection (p.i.), and healthy mice were enriched by the optimized magnetic bead-based hydrophobic interaction (MB-HIC8). The mass spectrograms were acquired by MALDI-TOF MS, and analyzed by ClinProTools bioinformatics software from Bruker Daltonics. The diagnostic models from T. gondii RH-infected serum peptide profiling of samples I, II, and III were produced by genetic algorithms, and verified by cross-validation. The sample II model could correctly recognize T. gondii RH strain infection in mice at days 3, 6, and 9 p.i. with a sensitivity of 91.1% and a specificity of 96.7%., and also detect T. gondii ME49 strain-infected serum samples at days 3, 6, 9, and 12 p.i. with a sensitivity of 91.7%. The results of the present study suggest that serum peptide profiling by MALDI-TOF MS is a novel potential tool for the clinical diagnosis of acute T. gondii infection. PMID- 22448679 TI - Toscana virus infections in northern Italy: laboratory and clinical evaluation. AB - Toscana virus (TOSv) is a neurotropic arthropod-borne virus that causes meningitis in the Mediterranean basin during the summer months. A total of 120 patients suffering from acute aseptic meningitis between July 1 and October 31, 2010 in northern Italy were evaluated. Eighteen of them (15%) were in the acute stage of TOSv disease. PMID- 22448680 TI - An assessment of the distribution and spread of the tick Hyalomma marginatum in the western Palearctic under different climate scenarios. AB - We applied a process-driven model to evaluate the impact of climate scenarios for the years 2020, 2050, and 2080 on the life cycle of Hyalomma marginatum ticks in the western Palearctic. The net growth rate of the tick populations increased in every scenario tested compared to the current climate baseline. These results support the expectations of increased tick survival and increased population turnover in future climate scenarios. We included a basic evaluation of host movement based on rules connected to altitude, slope, size of the near patches, and inter-patch distances in the real landscape over the target area. Data on landscape were obtained from medium-resolution MODIS satellite imagery, which allowed us to test the potential spread of the populations. Such a model of host dispersal linked to the process-driven life cycle model demonstrated that eastern (Turkey, Russia, and Balkans) populations of H. marginatum currently are well separated and have little mixing with western (Italy, Spain, and northern Africa) populations. The northern limit is marked by the cold areas in the Balkans, Alps, and Pyrenees. Under the warmer conditions predicted by the climate scenarios, the exchange of ticks throughout new areas, previously free of the vector, is expected to increase, mainly in the Balkans and southern Russia, over the limit of the mountain ranges. Therefore, the northern limit of the tick range would increase. Additional studies are necessary to understand the implications of host changes in range and abundance for H. marginatum and Crimean-Congo hemorrhagic fever virus. PMID- 22448681 TI - A null mutation of ROS1a for DNA demethylation in rice is not transmittable to progeny. AB - Genes that promote DNA methylation and demethylation in plants have been characterized mainly in Arabidopsis. Arabidopsis DNA demethylation is mediated by bi-functional DNA enzymes with glycosylase activity that removes 5-methylcytosine and lyase activity that nicks double-stranded DNA at an abasic site. Homologous recombination-promoted knock-in targeting of the ROS1a gene, the longest of six putative DNA demethylase genes in the rice genome, by fusing its endogenous promoter to the GUS reporter gene, led to reproducibly disrupted ROS1a in primary (T(0)) transgenic plants in the heterozygous condition. These T(0) plants exhibited no overt morphological phenotypes during the vegetative phase, and GUS staining showed ROS1a expression in pollen, unfertilized ovules and meristematic cells. Interestingly, neither the maternal nor paternal knock-in null allele, ros1a-GUS1, was virtually detected in the progeny; such an intransmittable null mutation is difficult to isolate by conventional mutagenesis techniques that are usually used to identify and isolate mutants in the progeny population. Even in the presence of the wild-type paternal ROS1a allele, the maternal ros1a-GUS1 allele caused failure of early-stage endosperm development, resulting in incomplete embryo development, with embryogenesis producing irregular but viable embryos that failed to complete seed dormancy, implying non-equivalent maternal and paternal contribution of ROS1a in endosperm development. The paternal ros1a GUS1 allele was not transmitted to progeny, presumably because of a male gametophytic defect(s) prior to fertilization. Thus, ROS1a is indispensable in both male and female gametophytes, and DNA demethylation must plays important roles in both gametophytes. PMID- 22448682 TI - Novel use of a Weerda laryngoscope for transoral excision of a cervical ganglioneuroma: a case report. AB - INTRODUCTION: A ganglioneuroma is a benign neoplasm arising from neural crest cells of the sympathetic nerve fibers and is most commonly seen in the posterior mediastinum or retroperitoneum. Although very uncommon, ganglioneuromas must be included in the differential diagnosis of neck masses. In young adult women, neck incisions made for excision of these benign tumors should be avoided whenever possible. CASE PRESENTATION: We herein describe the case of a 19-year-old Japanese woman with a ganglioneuroma. The tumor was found in the parapharyngeal space, an unusual location. A fine-needle aspiration biopsy was performed but was considered inadequate to make a definitive diagnosis, so the asymptomatic lesion was surgically excised using a Weerda laryngoscope. The lesion measured 4 * 3 cm in size and was encapsulated. A pathological analysis showed the presence of two distinct cell types, ganglion cells and Schwann cells, embedded in a loose myxoid stroma. The final diagnosis was a ganglioneuroma. CONCLUSION: A complete excision was made possible by using a transoral approach with a novel use of the Weerda laryngoscope. Although its applicability to specific cases depends on the location, size and nature of the tumor, we believe that the Weerda laryngoscope will continue to be useful for performing transoral surgery for cervical tumors. PMID- 22448684 TI - Effect of the H-bonding on aromaticity of purine tautomers. AB - Four tautomers of purine (1-H, 3-H, 7-H, and 9-H) and their equilibrium H-bonded complexes with F(-) and HF for acidic and basic centers, respectively, were optimized by means of the B3LYP/6-311++G(d,p) level of theory. Purine tautomer stability increases in the following series: 1-H < 3-H < 7-H < 9-H, consistent with increasing aromaticity. Furthermore, the presence of a hydrogen bond with HF does not change this order. For neutral H-bonded complexes, the strongest and the weakest intermolecular interactions occur (-14.12 and -10.49 kcal/mol) for less stable purine tautomers when the proton acceptor is located in the five- and six membered rings, respectively. For 9-H and 7-H tautomers the order is reversed. The H-bond energy for the imidazole complex with HF amounts to -14.03 kcal/mol; hence, in the latter case, the fusion of imidazole to pyrimidine decreases its basicity. The ionic H-bonds of N(-)...HF type are stronger by ~10 kcal/mol than the neutral N...HF intermolecular interactions. The hydrogen bond N(-)...HF energies in pyrrole and imidazole are -32.28 and -30.03 kcal/mol, respectively, and are substantially stronger than those observed in purine complexes. The aromaticity of each individual ring and of the whole molecule for all tautomers in ionic complexes is very similar to that observed for the anion of purine. This is not the case for neutral complexes and purine as a reference. The N...HF bonds perturb much more the pi-electron structure of five-membered rings than that of the six-membered ones. The H-bonding complexes for 7-H and 9-H tautomers are characterized by higher aromaticity and a much lower range of HOMA variability. PMID- 22448685 TI - Candida esophagitis with fever alone in a patient with stroke. AB - BACKGROUND: Candida esophagitis is a rare disease, but its incidence is higher in patients with impaired immunity due to an underlying disease. Patients with candida esophagitis usually present with lower retrosternal pain or dysphagia, but they are sometimes asymptomatic. Several risk factors, including diabetes mellitus, malignancies, chronic obstructive pulmonary disease (COPD) and steroid therapy, have been shown to be associated with candida esophagitis. Candida esophagitis may mimic other disease processes and can thus be misdiagnosed. CASE STUDY: This study describes a case of candida esophagitis with fever alone in the patient with stroke. After a stroke attack, a 53-year-old man was hospitalized for rehabilitation. He had a fever unexpectedly, but the cause could not be found for 2 weeks. Esophagogastroduodenoscopy (EGD) was performed to find the cause of the fever and it was diagnosed as candida eosphagitis. Fever decreased respectively 4 days after anti-fungal therapy begun. CONCLUSION: Dysphagia, unexplained anaemia, loss of appetite and dyspepsia may require EGD to make a confirmative diagnosis. If unexplained fever is persistent without any of these symptoms, it is advisable to consider EGD in patients with stroke. PMID- 22448686 TI - Personality and personality disorders in the DSM-5: introduction to the special issue. AB - In this introduction to the special section on Personality and Personality Disorders in DSM-5, the editors briefly describe the major changes proposed by the Work Group on Personality Disorders for DSM-5. They then introduce and describe the key points in the target articles by the Work Group as well as in the commentaries. The aim of this section is to present an arena for the articulation and discussion of the rationale of the proposed changes and the logic and evidence for these proposed changes. Special attention is paid to points of contention, debate, and controversy with regard to the proposed changes. It is the editors' goal to facilitate an open discussion of these issues in an effort to promote a scientifically based and clinically useful product. PMID- 22448687 TI - Proposed changes in personality and personality disorder assessment and diagnosis for DSM-5 Part I: Description and rationale. AB - A major reconceptualization of personality psychopathology has been proposed for DSM-5 that identifies core impairments in personality functioning, pathological personality traits, and prominent pathological personality types. A comprehensive personality assessment consists of four components: levels of personality functioning, personality disorder types, pathological personality trait domains and facets, and general criteria for personality disorder. This four-part assessment focuses attention on identifying personality psychopathology with increasing degrees of specificity, based on a clinician's available time, information, and expertise. In Part I of this two-part article, we describe the components of the new model and present brief theoretical and empirical rationales for each. In Part II, we will illustrate the clinical application of the model with vignettes of patients with varying degrees of personality psychopathology, to show how assessments might be conducted and diagnoses reached. PMID- 22448688 TI - Proposed changes in personality and personality disorder assessment and diagnosis for DSM-5 Part II: Clinical application. AB - The four-part assessment of personality psychopathology proposed for DSM-5 focuses attention on identifying personality psychopathology with increasing degrees of specificity, based on a clinician's available time, information, and expertise. In Part I of this two-part article, we described the components of the new model and presented brief rationales for them. In Part II, we illustrate the clinical application of the model with vignettes of patients with varying degrees of personality psychopathology, selected from the DSM-IV-TR Casebook, to show how assessments might be conducted and diagnoses reached. PMID- 22448689 TI - Some comments on nomology, diagnostic process, and narcissistic personality disorder in the DSM-5 proposal for personality and personality disorders. AB - I comment on the DSM-5 proposal for personality disorders (PDs), including discussion of the proposal's nomological revisions and their implications, the development and prioritization of a set of general criteria for PD, the shift to prototype matching of narrative descriptions for assessment of personality impairments and prominent PD types, and the recommendation to delete five PD diagnoses. Although the general criteria for PD are promising, implementation of prototype ratings for both functional impairments and PD types remains psychometrically questionable. In addition, revising the format and content of the diagnostic criteria while simultaneously deleting five diagnoses confounds evaluation of the revisions for the purposes indicated in the proposal. Finally, the performance of prior DSM criteria sets should not be the primary basis for considering the ontological status of prominent types because of construct definition problems with the criteria sets and criterion problems with DSM-based PD research. These concerns were highlighted in the case of Narcissistic PD-a diagnosis slated for deletion despite significant evidence for its clinical utility and validity when data beyond DSM criteria is considered. Changes of this magnitude are needed, but rigorous scientific evaluation is necessary before evolving from a proposal to the officially published DSM-5. PMID- 22448690 TI - A shaky future for personality disorders. AB - The major accomplishment of the fourth edition of the American Psychiatric Association's diagnostic manual was not in the development of surprising new content but rather in the careful, cautious, and systematic method with which it was constructed. The authors of the forthcoming fifth edition may have reversed the priorities, instead emphasizing radical changes without first conducting careful, systematic, thorough, or objective reviews of the scientific literature. Of particular concern are the proposals to cut half of the diagnoses from the manual, to abandon diagnostic criterion sets, and to include a dimensional model that lacks empirical support, fails to be integrated with normal personality functioning, and will lack official recognition. PMID- 22448691 TI - Patterns of biomedical science production in a sub-Saharan research center. AB - BACKGROUND: Research activities in sub-Saharan Africa may be limited to delegated tasks due to the strong control from Western collaborators, which could lead to scientific production of little value in terms of its impact on social and economic innovation in less developed areas. However, the current contexts of international biomedical research including the development of public-private partnerships and research institutions in Africa suggest that scientific activities are growing in sub-Saharan Africa. This study aims to describe the patterns of clinical research activities at a sub-Saharan biomedical research center. METHODS: In-depth interviews were conducted with a core group of researchers at the Medical Research Unit of the Albert Schweitzer Hospital from June 2009 to February 2010 in Lambarene, Gabon. Scientific activities running at the MRU as well as the implementation of ethical and regulatory standards were covered by the interview sessions. RESULTS: The framework of clinical research includes transnational studies and research initiated locally. In transnational collaborations, a sub-Saharan research institution may be limited to producing confirmatory and late-stage data with little impact on economic and social innovation. However, ethical and regulatory guidelines are being implemented taking into consideration the local contexts. Similarly, the scientific content of studies designed by researchers at the MRU, if local needs are taken into account, may potentially contribute to a scientific production with long-term value on social and economic innovation in sub-Saharan Africa. CONCLUSION: Further research questions and methods in social sciences should comprehensively address the construction of scientific content with the social, economic and cultural contexts surrounding research activities. PMID- 22448692 TI - [Diagnostic methods to predict response to cardiac resynchronization therapy]. PMID- 22448693 TI - [Diagnosis of the light chain deposition disease in the kidney biopsy samples]. PMID- 22448694 TI - [Septic shock due to infective reserve in patients with resynchronization therapy]. PMID- 22448695 TI - [The importance of contractile reserve in patients with resynchronization therapy]. AB - INTRODUCTION: Contractile reserve of the myocardium is a strong prognostic factor in patients with heart failure. The presence of a significant amount of myocardial fibrosis might lead to insufficient response to resynchronization therapy We assumed that pre-implantation examination of global contractile reserve will allow prediction of the response to resynchronization treatment. METHODS: 25 symptomatic patients (NYHA III) with severe systolic dysfunction [ejection fraction (EF) 28.9 +/- 6.9%] with signs of electric asynchrony (QRS 120 ms) went through dobutamine echocardiography prior to resynchronization treatment. The global contractile reserve was determined from the change to EF at rest and at the peak of pharmacological burden (40 MUg/kg/min). Patients with a rise in EF of more than 5% and/or endsystolic volume reduction of more than 15% after three months of resynchronization treatment were considered responders. RESULTS: Compared to non-responders, responders had higher increase in EF during dobutamine stress echocardiography (Delta 12.8 +/- 7.4 % vs. Delta 3.4 +/- 7.1 %, p = 0.0042). Three months from the initiation of resynchronization therapy, the global myocardial contractile reserve also significantly correlated with EF increase (r = 0.67, p = 0.007). The 6% increase in EF during dobutamin stress echocardiography predicted responders to resynchronization therapy with 83% sensitivity and 75% specificity. CONCLUSION: The global contractile reserve may play an important role in prediction of a response to resynchronization therapy. PMID- 22448696 TI - [A detailed study of colon polyps]. AB - INTRODUCTION, STUDY AIM: Colorectal carcinoma is one of the most frequent malignancies. Most frequently, neoplasms, including malignant precursors, are in the form of polyps, although these might be of a non-tumour origin. The aim of this prospective multicentre study was to provide an overview of coloscopic identification and biological nature of polyps. RESULTS: 3,400 consecutive coloscopies performed between 2009 and 2010 were analyzed. At different centres, the top of the cecum was reached in 89% to 93% and terminal ileum in 73% to 87% of cases. In the above 40 age group, 26.6% were screening coloscopies. The mean age of the above 40 patients was 56 years. The incidence of potential neoplastic lesions (polyps, carcinomas), advanced adenomas and carcinomas were: 7.8 %, 0.8 % and 0.16 %, respectively, in the above 40 age group, 41.5 %, 9.8 % and 1.6 %, respectively, in the 40-50 years age group and 70.5 %, 31.3 % and 6.8 %, respectively, in the above 50 age group. The incidence of tubular adenoma and hyperplastic polyps was 23.9% and 66.2%, respectively, in the below 40 age group and 53.1% and 26.1% in the above 50 age group. 57.8% of advances neoplasms were located in the rectosigmoid a descendent colon. The incidence ratio for adenomas and hyperplastic polyps was 76.6% and 14%, respectively, for rectosigmoid colon, 63.6 and 17.4 %, respectively, for descendent colon, 63.6 and 11.4 % for traverse colon and 63,4 a 17,9 %, respectively, for cecum and ascendant colon. The incidence of tubulovillous adenomas and hyperplastic polyps in pedunculated polyps larger than 1 cm was 19.4 % and 20.4 %, respectively, and 34.2 % and 13.1 %, respectively, in other polyps. The incidence of potential lesions (polyps and carcinomas), advanced adenomas, carcinomas and advanced neoplasms was 66.7 %, 23.1 %, 5.8 % and 28.9 %, respectively, in women and 63.1 %, 30.0 %, 5.7 % and 34.7 %, respectively, in men. CONCLUSION: The top of the cecum was reached in a higher proportion of cases than required, although this was lower than in the majority of other recent studies. Terminal ileum was reached in high number of cases. The incidence of polyps and neoplasms rose sharply from 40 years of age. Therefore, the screening threshold should be extended to the below 50 age group. Hyperplastic polyps predominated in younger age and adenomas in the above 40 age group. Histological profile was similar and did not suggest importantly different pathogenesis with respect to localization. There were relatively fewer adenomas and more hyperplastic polyps in pedunculated polyps and vice verse in other types of polyps, suggesting a higher risk associated with non-pedunculated lesions. Both sexes differed less than suggested based on epidemiological statistics. PMID- 22448697 TI - [Endocrine changes in liver disease]. AB - Liver diseases have an influence on function and morphology of all endocrine glands. Knowledge of these specific changes is important in correct interpretation of pathological clinical and laboratory hormonal symptoms and signs induced by liver disease. We analyze the influence on the thyroid, bone metabolism, adrenocorticotropic axis, gonadal hormones, prolactin and growth hormone. PMID- 22448698 TI - [Common, standardized and recommended approaches in the diagnosis and monitoring of paroxysmal nocturnal haemoglobinuria using flow cytometry]. AB - Paroxysmal nocturnal hemoglobinuria is an acquired clonal disease characterized by proliferation of stem cells, deficient of proteins linked to the membrane via glycophosphatidylinositol (GPI) anchors. PNH cell characterization by flow cytometry was introduced in 1986, since 1996 is considered as method of choice for PNH diagnosis. Flow cytometry PNH analysis is nowadays crucial for disease monitoring in terms of progression, regression, remission or response to therapy and screening for small PNH clones (< 1.0%) in patients with aplastic anemia or myelodysplastic syndrome. Flow cytometry is unfortunately still poorly standardized, there is a variety of different methodological approaches for PNH evaluation and results from external quality assurances schemes reveal heterogeneous results. The aim of this work is to review the applicability of flow cytometry for the diagnosis and monitoring of PNH with respect to our experience and in the context of the recent trends and guidelines for PNH evaluation by flow cytometry. PMID- 22448699 TI - [Light chain deposition disease]. AB - The aim of the study is to put forward the recent knowledge about a relatively rare clinical condition caused by the deposition of immunoglobulin light chains kappa or lambda into the parenchyme of kidneys and other vital organs, leading to a progressive loss of their function with terminal organ failure. The paper focuses on the etiopathogenesis of light chain deposition disease, and the differentiation of idiopatic form of the disease from multiple myeloma associated conditions and other B lymphoproliferative disorders. We concentrate on the issue of clinical manifestation, contemporary diagnostic possibilities and differential diagnosis of the disease. Finally, we summarize recent therapeutic approaches using chemo-immunotherapy (bortezomib) and high-dosed chemotherapy with support of autologous peripheral stem cell transplantation that lead to a substantial improvement of the prognosis of this prognostically unfavorable disorder. PMID- 22448700 TI - [Modes of tissue blood perfusion assessment by microdialysis - a review of current knowledge]. AB - Microdialysis is a dynamically evolving method utilized for monitoring of tissue metabolism and barrier function, pharmacological studies and to estimate local blood perfusion in situ. The present review summarizes current knowledge of the last of the aforementioned applications on a characterization and comparison of two approaches used - microdialysis flow-indicator dilution technique and continuous metabolic monitoring. Currently, the use of metabolic indicators, which enable sensitive and complex evaluation of perfusion-induced changes in the tissue, is preferred. Despite the methods numerous advantages the measurement of tissue blood perfusion by microdialysis remains centralized in the area of clinical research, for the present. For wider acceptance and exercise in the routine clinical practice, more validating studies ought to be conducted and situations identified, where microdialysis could replace the current methods. PMID- 22448701 TI - [Hyponatraemia associated with the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) - options for treatment]. AB - Hyponatremia is the most common electrolyte imbalance in outpatients and hospital inpatients and the syndrom of inappropriate secretion of antidiuretic hormone (SIADH) is one of the common causes of euvolemic hyponatremia. Recent studies showed significantly higher mortality and morbidity of hyponatriemic patients compared to normonatriemic controls. Moreover the morbidity and mortality of hyponatremic patients significantly increases in nontreated in comparison to those with the therapy. Clinical consequences of hyponatremia in SIADH could be devided according to stage of the disorder. The cerebral oedema with its symptoms (letargy, weakness, nausea, coma) is the most dangerous clinical feature. Clinical symptoms of hyponatremia also depend on how rapid the change of natremia is. Therefore the early diagnosis of disturbance and treatment are necessary. Not only acute but also chronic hyponatriemia must be treated. In the correction the restriction of water intake, loop diuretics (together with hypertonic solution of NaCl), demeclocyclin, urea and litium can be used. The blockers of vasopresin receptors - vaptans are perspective in treatment of patients with hyponatremia. PMID- 22448702 TI - [A recommended approach to evaluate cardiovascular risk and to prevent cardiovascular diseases and type 2 diabetes mellitus in women with polycystic ovary syndrome]. AB - Polycystic ovary syndrome is one of the most common endocrinopathy in women of fertile age. It is commnoly accompanied by an increased occurence of cardiovascular risk factors. This association led to a consensus statement of Androgen Excess Society for screening of cardiovascular risk factors. We present the recommendations of Czech Endocrine and Czech Diabetological Societies for the screening and primary prevention of cardiovascular diseases and diabetes mellitus. PMID- 22448703 TI - [Septic shock due to infective endocarditis of stimulation system of implantable cardioverter-defibrillator]. AB - We present a case of a 60-year old patient hospitalized at the Department of Infectious Diseases and Travel Medicine, Medical faculty of UPJS and L. Pasteurs University Hospital in Kosice with suspected gastroenteritis. The patient was admitted to an intensive care unit because of the signs of septic shock. Within one hour from admission, the patient was administered early goal directed therapy for septic shock. Subsequently, infectious endocarditis of stimulation electrodes and tricuspid valve was identified as the origin of the infection. The stimulation system was then explanted from a stabilized and afebrile patient at the Department of cardiac Surgery of Eastern Slovak Institute of Cardiac and Vascular Diseases in Kosice. This case should emphasise frequently atypical course of this serious disease and the need for early identification of severe sepsis to enable timely management to affect mortality. PMID- 22448704 TI - [Lenalidomide induced therapeutic response in a patient with aggressive multi system Langerhans cell histiocytosis resistant to 2-chloro-deoxyadenosine and early relapsing after high-dose BEAM chemotherapy with autologous peripheral blood stem cell transplantation]. AB - Adult Langerhans cell histiocytosis (LCH) usually follows a favorable course. Very rarely, however, multi-system (multi-organ) LCH difficult to manage either with traditional first line treatment (vinblastine, mercaptopurine, prednisone or etoposide) or 2-chlorodeoxyadenosine occurs. In these patients, other treatment modalities have to be used. We describe a patient with LCH manifesting with generalized lymphadenopathy and infiltrating the pulmonary parenchyma and skin. The disease activity was always associated with B-symptoms (weight loss, subfebrile states, night sweats). Histological investigations repeatedly showed higher proliferation activity than that usual in adult patients with LCH. Expression of Ki-67 proliferation marker was up to 30% and there were 8-10 cells in mitosis in the microscope viewing field. Therefore, therapy started with the application of stimulation regimen (cyclophosphamide 2 g/m2 on day 1 and etoposide 200 mg/m2 on days 1-3) followed by collection of peripheral blood stem cells. Then, treatment with 2-chlorodeoxyadenosine, the first 3 cycles as monotherapy of 5 mg/m2 SC on days 1-5 in 28-day cycles, the next 3 cycles in combination with cyclophosphamide 150 mg/m2 on days 1-5 and methylprednisolone 250 mg on days 1-5, was used. However, the disease relapsed 2 months after completion of the therapy. This early relapse was treated with 4 cycles of CHOEP chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone). Following the 4th cycle of CHOEP, high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, melphalan) with autologous stem cell transplantation were administered. According to the follow-up PET-CT examination, this treatment resulted in complete disease remission. However, the disease relapsed again in the lymph nodes, lungs, skin and bones 5 months after the high-dose chemotherapy. The progression was documented on PET-CT scanning. Lenalidomide 25 mg daily for 21 days in 28-day cycles with dexamethasone 20 mg once a week were administered as the 4th line treatment. After the 4th cycle of lenalidomide, PET-CT was performed, where the CT component suggested a significant reduction (more than 50%) in the size of the lymph nodes and the PET component showed substantial reduction in fluorodeoxyglucose accumulation in the affected lymph nodes as well as in the bone lesions. HRCT showed disappearance of pulmonary nodules. During the treatment, CRP levels declined and hemoglobin rose from 110 to 141 g/l, i.e. partial remission was achieved after 4 cycles. Etoposide (100 mg IV) was added to lenalidomide and dexamethasone on days 22, 23 and 24 of the above mentioned 28 day cycle. The added etoposide further intensified treatment response. In all, 11 cycles of this chemotherapy were given, resulting in complete remission confirmed by follow-up PET-CT. The achieved remission was consolidated using allogeneic bone marrow transplantation after FLAMSA reduced intensity conditioning without amsacrine. Four months after allogeneic transplantation, the patient has been relapse free. Herein we presented treatment response of highly aggressive LCH to lenalidomide. The used four cycles led to partial remission only and with the combination of lenalidomide, dexamethasone and etoposide the treatment response was further intensified to complete remission. PMID- 22448705 TI - [Hyponatremia - carbamazepine medication complications]. AB - Hyponatremia can be defined like the low sodium concentration, lower that 135 mmol/l. It becomes really serious when the concentration is lower than 120 mmol/l. The most frequent causes of hyponatremia are: the extrarenal loss (GIT, skin, bleeding, sequestration), the renal loss (diuretics, nephritis with the salt loss, osmotical diuresis, the Addison disease), hypothyroidism, the lack of glucocorticoids, emotional stress, pain, pseudohyponatremia (incorrect taking, dyslipoproteinemia). There is fatigue, exhaustion, headache and vertigoes dominating in the clinical record file. By the deficit increasing a patient becomes delirious, comatose even with the shock development. It is necessary to separate sufficient supply of sodium from much more often reason, which is loss of sodium which can be caused by: excessive sweating, vomitting with the metabolical alkalosis development, diarrhoea with the metabolical acidosis development, renal losses (a phase of renal failure). Treatment of hyponatremia: intensive treatment starts at the level of plasmatic concentration of sodium under 120 mmol/l or when neurological symptoms of brain oedema are present. In the therapy it is necessary to avoid fast infusions of hypertonic saline solutions (3-5% NaCl solutions) because of the danger of the development of serious CNS complications (intracranial bleeding, etc.). It is recommended to adjust the plasmatic concentration of sodium up to 120 mmol/l during the first four hours and a subsequent correction should not be higher than 2 mmol per an hour. Treatment of the basic illness is very important. We present 2 case histories: a 74-year old female patient and a 69-year old female patient both with the hyponatremia caused by taking of carbamazepine. We want to inform and warn about not only a well known side effect during long-term treatment but about hyponatremia that arose within 48 hours after the start of taking medicine as well. PMID- 22448706 TI - Neonatal invasive candidiasis in Tunisian hospital: incidence, risk factors, distribution of species and antifungal susceptibility. AB - The aim of our study was to assess epidemiological features of neonatal invasive candidiasis in Farhat Hached hospital of Sousse, Tunisia, including incidence, risk factors, mortality, species distribution and antifungal susceptibility. Laboratory data from 1995 to 2010 and medical records of 127 invasive candidiasis cases were reviewed. We tested the susceptibility of 100 Candida sp isolates by using ATB fungus((r)) 3 and to fluconazole by using E-test((r)) strips. A total of 252 cases of neonatal invasive candidiasis occurred over the study period. The incidence increased 1.8-fold from 1995 to 2006 and decreased fourfold from 2007 to 2010. Candida albicans was the predominant species up to 2006 and a shift in the species spectrum was observed with increase of the non-albicans species mainly C. parapsilosis. The agreement between the ATB Fungus((r)) and the E test((r)) for determining fluconazole susceptibility was high. All tested isolates were susceptible to fluconazole, flucytosine, amphotericine B and voriconazole and the itraconazole resistance rate was 5%. The mortality rate was 63%. The invasive candidiasis incidence increased from 1995 to 2006 and decreased from 2007 to 2010. The spectrum of Candida species and the lack of fluconazole resistant strains argue for the usefulness of fluconazole as an empiric treatment. PMID- 22448707 TI - Distinctions in early stage unwinding mechanisms of zwitterionic, capped, and neutral forms of different alpha-helical homopolymeric peptides. AB - Molecular dynamics simulations of alpha-helical polyalanine, polyleucine, polylysine, and poly(glutamic acid) with different forms of terminal groups in water at 300 K showed sharp distinctions in their unwinding mechanisms. Zwitterionic, capped, and neutral forms of polyalanine, polyleucine, and polylysine have been explored to elucidate their unwinding mechanism at very early stage, e.g., initial time window. Role of water in the unwinding mechanisms of the various helices has been envisaged. Also, it is evident from our calculations that the short- and long-range nonbonded interactions among the side chains is an important factor determining the unwinding mechanisms of the various homopolymeric alpha-helices. These findings can be helpful in constructing predictive models for understanding of the unwinding of alpha-helical proteins and peptides. PMID- 22448708 TI - Doxorubicin-induced neurotoxicity is attenuated by a 43-kD protein from the leaves of Cajanus indicus L. via NF-kappaB and mitochondria dependent pathways. AB - Doxorubicin (Dox) is an effective anthracycline antitumour drug although its clinical efficacy is restricted because of several acute and chronic side effects. It has been suggested that Dox-induced anticancer effect and neurotoxicity do not follow identical mechanism. The present study has been carried out to investigate the neuroprotecive role of a 43-kD protein (Cajanus indicus (CI) protein) against Dox-induced oxidative impairment and brain tissue damage. Administration of Dox (25 mg/kg body weight) increased reactive oxygen species (ROS) production, altered neuro antioxidant status, activities of brain specific coenzymes (like acetyl coenzyme, monoamine oxidase, etc.), ATPases (like Na(+)/K(+), Ca(2+), etc.) and brain biogenic amines levels. Signal transduction studies showed that Dox markedly decreased mitochondrial membrane potential, disturbed Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased levels of Apaf1, caspase-9/3, cleaved PARP protein and ultimately led to apoptotic cell death. In addition, Dox markedly increased nuclear factor kappa B (NF-kappaB) nuclear translocation in association with IKKalpha/beta phosphorylation and IkappaBalpha degradation. Post-treatment with CI protein (3 mg/kg body weight, once daily for next 4 days), however, reduced Dox-induced oxidative stress, attenuated the nuclear translocation of NF-kappaB and protected the brain tissue from Dox-induced apoptotic death. Histological studies also support these experimental findings. Results suggest that CI protein might act as a beneficial agent against Dox-induced neuronal dysfunctions. PMID- 22448709 TI - Posterior urethral valves and adult sexual function. AB - OBJECTIVES: To evaluate sexual function and fertility in adult patients treated for posterior urethral valves (PUV) in childhood and to compare these patients with the normal population. To examine if patient characteristics such as chronic renal failure (CRF), history of cryptorchidism and bladder neck incision in childhood have an impact on sexual function. PATIENTS AND METHODS: Information on sexual function was assessed using questions from the International Index of Erectile Function (IIEF). In addition, the patients were asked if they had had children or been treated for CRF. Out of 108 adult patients with PUV, 67 (62%) returned the questionnaires. Sexual function in these patients was compared with 201 controls and paternity rates were compared with a national database. RESULTS: The mean (sd) age of the patients and controls was 38 (9) and 38 (7) years, respectively. Six percent of the patients and 9% of the controls reported problems in achieving erection during sexual stimulation and 9% of the patients and 10% of the controls reported problems with the hardness of erection (P = nonsignificant). Ejaculation was absent in 1/61 sexually active patients (2%). The only significant risk factor in patients for erectile dysfunction (ED) was increasing age. Thirty-three (49%) of all 67 patients and four (57%) of the seven patients with kidney transplantation had had children. The paternity rates were similar to those in corresponding age groups of the general Finnish population. Eight patients (12%) had attempted to have children without success. CONCLUSIONS: Men treated for PUV have a similar prevalence of ED and similar paternity rates to men without PUV. Erectile function and paternity rates can be satisfactory in spite of CRF. PMID- 22448710 TI - An open trial of self-help behaviours of clients with eating disorders in an online programme. AB - AIM: The aim of this study was to evaluate the self-help behaviour of individuals with eating disorders in an Internet-based self-help programme developed in the Asia-Pacific region and to determine their compliance with the programme. BACKGROUND: Eating disorders represent a growing health problem affecting both Western and Asian countries. Without timely and adequate treatment, individuals with eating disorders are at risk of premature death. Self-help approaches for treating eating disorders offer therapeutic promise. DESIGN: An open trial design was used. METHOD: This study, conducted from August 2006-July 2011, included 280 participants recruited from outpatient eating disorder clinics and treatment units and through a university student newspaper and Internet websites. This open trial evaluated an Internet-based self-help programme, which included components on healthy eating, family education, health assessment, motivation enhancement, self-help strategies, and psychological health promotion. The progress of participants was followed up via monthly e-mails. A tracking system was implemented to determine their compliance with the programme. FINDINGS: A small majority of the participants (56.9%) were already undergoing treatment for their eating disorders. About 63% (n = 176) demonstrated self-help behaviour, as manifested by their completion of health assessment questionnaires, involvement in motivation enhancement exercises, or the use of self-help strategies such as monitoring, normalizing eating behaviour, and stress management. Improvements were observed in their eating disorder psychopathology, motivational stage of change and psychological health from baseline to the 1-month follow up. CONCLUSION: Internet-based self-help programmes for eating disorders are helpful adjuncts to professional treatment. PMID- 22448711 TI - Twists in views on RB functions in cellular signaling, metabolism and stem cells. AB - One-quarter of a century ago, identification of the human retinoblastoma gene (RB) loci proved Knudson's 'two-hit theory' that tumor suppressor genes exist. Since then, numerous works delineated crucial roles for the RB protein (pRB)-E2F transcription factor complex in G1-S phase transition. In addition, discovering the relationship between pRB and tissue-specific transcription factors enabled a better understanding of how cell cycle exit and terminal differentiation are coupled. Recent works provoked many exciting twists in views on pRB functions during cancer initiation and progression beyond its previously well-appreciated roles. Various mitogenic and cytostatic cellular signals appeared to modulate pRB functions and thus affect a wide variety of effector molecules. In addition, genetic studies in mice as well as other creatures incessantly force us to revise our views on pRB functions. This review will focus particularly on the roles of pRB in regulating intracellular signaling, cell metabolism, chromatin function, stem cells and cancer stem cells. PMID- 22448712 TI - A new genus and species of Philopteridae (Phthiraptera: Ischnocera) from the trumpeters (Aves: Gruiformes: Psophiidae). AB - A new chewing louse genus and species belonging to the Philopteridae, namely, Palmaellus inexpectatus n. gen., n. sp., is described. The new genus is distinguished from the other ischnoceran genera hitherto described by its peculiar characters of the dorsal anterior head plate with 2 postero-lateral projections, pterothorax and abdomen with scarce chaetotaxy, male genitalia with simple mesomere and paramere lacking inner digitiform projection, and the genital region of female with postero-vulvar plates bearing setae. It is a parasite of the trumpeters, an avian family endemic to South America's Amazon Basin. PMID- 22448713 TI - Deposition of latex colloids at rough mineral surfaces: an analogue study using nanopatterned surfaces. AB - Deposition of latex colloids on a structured silicon surface was investigated. The surface with well-defined roughness and topography pattern served as an analogue for rough mineral surfaces with half-pores in the submicrometer size. The silicon topography consists of a regular pit pattern (pit diameter = 400 nm, pit spacing = 400 nm, pit depth = 100 nm). Effects of hydrodynamics and colloidal interactions in transport and deposition dynamics of a colloidal suspension were investigated in a parallel plate flow chamber. The experiments were conducted at pH ~ 5.5 under both favorable and unfavorable adsorption conditions using carboxylate functionalized colloids to study the impact of surface topography on particle retention. Vertical scanning interferometry (VSI) was applied for both surface topography characterization and the quantification of colloidal retention over large fields of view. The influence of particle diameter variation (d = 0.3 2 MUm) on retention of monodisperse as well as polydisperse suspensions was studied as a function of flow velocity. Despite electrostatically unfavorable conditions, at all flow velocities, an increased retention of colloids was observed at the rough surface compared to a smooth surface without surface pattern. The impact of surface roughness on retention was found to be more significant for smaller colloids (d = 0.3, 0.43 vs. 1, 2 MUm). From smooth to rough surfaces, the deposition rate of 0.3 and 0.43 MUm colloids increased by a factor of ~2.7 compared to a factor of 1.2 or 1.8 for 1 and 2 MUm colloids, respectively. For a substrate herein, with constant surface topography, the ratio between substrate roughness and radius of colloid, Rq/rc, determined the deposition efficiency. As Rq/rc increased, particle-substrate overall DLVO interaction energy decreased. Larger colloids (1 and 2 MUm) beyond a critical velocity (7 * 10(-5) and 3 * 10(-6) m/s) (when drag force exceeds adhesion force) tend to detach from the surface irrespective of the impact of roughness. For polydisperse solutions, an increase in the polydispersity and flow velocity resulted in a reduction of colloid deposition efficiency due to the resulting enhanced double-layer repulsion. Quantification of surface topography variations of two endmembers of natural grain surfaces showed that half-pore depths and roughness of sedimentary quartz grains are mainly in the micrometer range. Grains with diagenetically formed quartz overgrowths, however, show surface roughness mainly in the submicrometer range. Thus, surface topography features applied in the here presented analogue study and resulting variation in particle retention can serve as quantitative analogue for particle reactions in diagenetically altered quartz sands and sandstones. The reported impact of particle polydispersity can have an important application for quantitative prediction of retention of varying types of minerals, such as different clay minerals in the environment under prevailing unfavorable conditions. PMID- 22448714 TI - EuroSCORE and neutrophil adhesion molecules predict outcome post-cardiac surgery. AB - BACKGROUND: This study tested the hypothesis that surgical stress and the host response to this trauma trigger an inflammatory cascade in which the neutrophil plays a central role. We hypothesised that pre-operative neutrophil migratory responses will correlate with post-operative clinical outcome in our shock model of open-heart surgery patients. We also tested the hypothesis that surface expression of adhesion molecules involved in the migratory process - CD11b, CD47 and CD99 - could be used to predict outcome. We believe that combining neutrophil migratory response, CD11b, CD47 and CD99 with the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) will strengthen the power of the EuroSCORE not only in predicting post-operative mortality but also other clinical endpoints. MATERIALS AND METHODS: Neutrophils were isolated pre-operatively from n = 31 patients undergoing open-heart surgery and allowed to migrate across endothelial monolayers in response to N-formyl-methionine-leucine-phenylalanine (fMLP). Isolated neutrophils were also assessed for surface expression of CD11b, CD47 and CD99 in response to fMLP by flow cytometry. Post-operative clinical parameters collected included days 1-5 white cell count and creatinine levels as well as intensive care unit (ICU) and post-operative hospital stay. RESULTS: Pre operative surface expression of CD99 and CD47 correlates with post-operative creatinine levels (P < 0.05), a measurement of renal injury. We also show that while the logistic EuroSCORE alone can be used as a predictor of ICU stay, when combined with pre-operative CD99 surface expression, it improves its AUC value (0.794). CONCLUSION: Immunological markers, specifically the ability of the neutrophil to migrate, combined with the logistic EuroSCORE lead to improved sensitivity and specificity to predict patient outcome. PMID- 22448715 TI - Parainfluenza virus infection associated with posterior reversible encephalopathy syndrome: a case report. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome is a clinical and radiological entity. The most accepted theory of posterior reversible encephalopathy syndrome is a loss of autoregulation in cerebral blood flow with a subsequent increase in vascular permeability and leakage of blood plasma and erythrocytes, producing vasogenic edema. In infection-associated posterior reversible encephalopathy syndrome, a clinical pattern consistent with systemic inflammatory response syndrome develops. Parainfluenza virus has not been reported in the medical literature to be associated with posterior reversible encephalopathy syndrome. CASE PRESENTATION: We report herein the case of a 54 year-old Caucasian woman with posterior reversible encephalopathy syndrome associated with parainfluenza virus infection who presented with generalized headache, blurring of vision, new-onset seizure and flu-like symptoms. CONCLUSION: Infection-associated posterior reversible encephalopathy syndrome as well as hypertension-associated posterior reversible encephalopathy syndrome favor the contribution of endothelial dysfunction to the pathophysiology of this clinicoradiological syndrome. In view of the reversible nature of this clinical entity, it is important that all physicians are well aware of posterior reversible encephalopathy syndrome in patients presenting with headache and seizure activity. A detailed clinical assessment leading to the recognition of precipitant factors in posterior reversible encephalopathy syndrome is paramount. PMID- 22448716 TI - Acute regional improvement of myocardial function after interventional transfemoral aortic valve replacement in aortic stenosis: a speckle tracking echocardiography study. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a promising therapy for patients with severe aortic stenosis (AS) and high perioperative risk. New echocardiographic methods, including 2D Strain analysis, allow the more accurate measurement of left ventricular (LV) systolic function. The goal of this study was to describe the course of LV reverse remodelling immediately after TAVI in a broad spectrum of patients with symptomatic severe aortic valve stenosis. METHODS: Thirty consecutive patients with symptomatic aortic valve stenosis and preserved LVEF underwent transfemoral aortic valve implantation. We performed echocardiography at baseline and one week after TAVI. Echocardiography included standard 2D and Doppler analysis of global systolic and diastolic function as well as 2D Strain measurements of longitudinal, radial and circumferential LV motion and Tissue Doppler echocardiography. RESULTS: The baseline biplane LVEF was 57 +/- 8.2%, the mean pressure gradient was 46.8 +/- 17.2 mmHg and the mean valve area was 0.73 +/- 0.27 cm(2). The average global longitudinal 2D strain of the left ventricle improved significantly from -15.1 (+/- 3.0) to -17.5 (+/- 2.4) % (p < .001). This was reflected mainly in improvement in the basal and medial segments while strain in the apex did not change significantly [-11.6 (+/- 5.2) % to -15.1 (+/- 5.5) % (p < .001), -13.9 (+/- 5.1) % to -16.8 (+/- 5.6) % (p < .001) and -19.2 (+/- 7.0) % to -20.0 (+/- 7.2) % (p = .481) respectively]. While circumferential strain [-18.1 (+/- 5.1) % vs. -18.9 (+/- 4.2) %, p = .607], radial strain [36.5 (+/- 13.7) % vs. 39.7 (+/- 17.2) %, p = .458] and the LVEF remained unchanged after one week [57.0 (+/- 8.2) % vs. 59.1 (+/- 8.1) %, p = .116]. CONCLUSION: There is an acute improvement of myocardial longitudinal systolic function of the basal and medial segments measured by 2D Strain analysis immediately after TAVI. The radial, circumferential strain and LVEF does not change significantly in all patients acutely after TAVI. These data suggest that sensitive new echo methods can reliably detect early regional changes of myocardial function after TAVI before benefits in LVEF are detectable. PMID- 22448717 TI - High recovery of cell-free methylated DNA based on a rapid bisulfite-treatment protocol. AB - BACKGROUND: Detection of cell-free methylated DNA in plasma is a promising tool for tumour diagnosis and monitoring. Due to the very low amounts of cell-free DNA in plasma, analytical sensitivity is of utmost importance. The vast majority of currently available methods for analysing DNA methylation are based on bisulfite mediated deamination of cytosine. Cytosine is rapidly converted to uracil during bisulfite treatment, whereas 5-methylcytosine is only slowly converted. Hence, bisulfite treatment converts an epigenetic modification into a difference in sequence, amenable to analysis either by sequencing or PCR based methods. However, the recovery of bisulfite-converted DNA is very poor. RESULTS: Here we introduce an alternative method for the crucial steps of bisulfite treatment with high recovery. The method is based on an accelerated deamination step and alkaline desulfonation in combination with magnetic silica purification of DNA, allowing preparation of deaminated DNA from patient samples in less than 2 hours. CONCLUSIONS: The method presented here allows low levels of DNA to be easily and reliably analysed, a prerequisite for the clinical usefulness of cell-free methylated DNA detection in plasma. PMID- 22448718 TI - Intravenous oxycodone for pain relief in the first stage of labour--maternal pharmacokinetics and neonatal exposure. AB - Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open-labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1 mg i.v., up to a cumulative dose of 5 mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half-life of 2.6 hr (range, 1.8-2.8). Oxycodone concentrations in the umbilical plasma 2.7 MUg/l (0.3-14.5) were similar as in maternal plasma 2.4 (0.1 14.8) MUg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half-life of i.v. oxycodone was significantly shorter than that reported in non-pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure. PMID- 22448719 TI - Tick-borne encephalitis in Slovenia: data from a questionnaire survey. AB - There has been a marked increase in the incidence of tick-borne encephalitis (TBE) in the last two decades, with new foci of the disease evolving. TBE is endemic in Slovenia, and the incidence rate is one of the highest in the European Union. A survey of notified TBE cases started in 1999, aiming to collect additional epidemiological data that are not available through the usual notification system. From 1999 to 2009, a short, anonymous, self-administered questionnaire was sent to 2779 notified TBE cases. The response rate was 69.5%. The willingness to respond was higher in those over 60 years of age, but did not differ by gender. In all, 1564 (82.3%) of the responders had a tick bite on one or multiple sites on the body. Age and gender influenced the location of the tick bite: males patients most often had the tick located on the torso, and females had them on the legs. Ticks located on the head and neck were significantly higher in preschool children compared to school children and adults. The estimated duration of tick attachment was less than 6 h in 23.5% of TBE cases. Long attachments (more than 24 h) were reported by only 10% of the patients. The tick bite occurred while the TBE patients were engaged in leisure time activities (sports or camping, 32.8%), mushroom or berry picking (30.2%), or farming (23.3%). Almost two-thirds of TBE patients reported that they had practiced at least one of the recommended preventive measures, most frequently self inspection, and least often repellent use. The patients were asked to disclose the most probable geographical location of the TBE viral (TBEV) infection. Maps were created on a county level and showed that the risk of TBE is widespread, with few counties unaffected. The counties located in the northern and the central areas had the highest risk of TBEV infection. PMID- 22448720 TI - Phylogeography and demographic history of Amblyomma variegatum (Fabricius) (Acari: Ixodidae), the tropical bont tick. AB - The genetic diversity of Amblyomma variegatum (Fabricius) from four Caribbean islands and five African countries was compared by analyzing the sequences of three gene fragments, two mitochondrial (12SrDNA and D-Loop-DL), and one nuclear (intergenic transcribed spacer 2 [ITS2]). Genetic variability of the ITS2 DNA fragment consisted of only uninformative single nucleotide mutations, and therefore this gene was excluded from further analyses. Mitochondrial gene divergences among African populations and between Caribbean and African populations were very low. Nevertheless, the data suggest that A. variegatum is divided into distinct East and West African groups, the western group including all Caribbean samples. Phylogenetic analyses of the 12SrDNA and DL gene sequences showed that the West African A. variegatum clustered in a well-supported monophyletic clade, distinct from eastern paraphyletic lineages. Sequences of A. variegatum from the Caribbean were embedded in the West African clade, which supports the known West African historical origin for these ticks. PMID- 22448721 TI - Brucella suis Biovar 1 isolated from a hepatic abscess drainage. AB - Positive cultures from hepatic abscess drainage are extremely rare, and in this case the infection would have remained undiagnosed if Brucella suis had not been isolated. Failure to correctly diagnose this zoonosis delays patient treatment and is dangerous, as in this case that could have been a laboratory-acquired disease. This type of infection is preventable if proper safety protocols are established and followed. PMID- 22448722 TI - Detection of Dirofilaria immitis and Ehrlichia species in coyotes (Canis latrans), from rural Oklahoma and Texas. AB - There is a lack of knowledge regarding the prevalence of Dirofilaria immitis and Ehrlichia spp. in coyotes in Oklahoma and Texas. Documenting the prevalence of these vector-borne disease agents in coyotes from Oklahoma and Texas underscores the importance of wild canids as reservoir hosts that infect companion animals and humans. To learn more about the sylvatic cycle of D. immitis and Ehrlichia spp. in coyotes from Oklahoma and Texas, we tested for infection with and exposure to, respectively, these disease agents. Coyote carcasses were collected opportunistically from animal control experts and hunters in seven counties in Oklahoma and Texas from January to March, 2010. Serum samples from 77 coyotes were tested with a commercial ELISA test. Five (6.5%) coyotes had D. immitis antigens, and four (5.2%) had antibodies to Ehrlichia spp. The overall prevalence of D. immitis was low relative to studies from the eastern United States. Little is known about the prevalence of Ehrlichia spp. throughout the United States, but coyotes from rural Oklahoma in the current study had a higher exposure rate than those reported from California, and a lower rate than data from an earlier study from Oklahoma. PMID- 22448723 TI - Foxes as a potential wildlife reservoir for mecA-positive Staphylococci. AB - Methicillin-resistant staphylococci (MRS), and methicillin-resistant Staphylococcus aureus (MRSA) in particular, have become a public and veterinary health concern. The search for MRS reservoirs outside human hospitals is needed in order to understand the reasons for their persistence and to control their spread. MRS have been isolated from rats, but little is known about their occurrence in foxes. In view of the perceived increasing proximity between people and foxes in the U.K. and the well-documented potential of foxes as hosts for zoonotic pathogens, this study examined whether foxes can be a reservoir for MRS. This study examined the carriage of staphylococci and their antimicrobial resistance patterns in 38 foxes (Vulpes vulpes) from rural and semirural areas in the U.K. Staphylococci were isolated by enrichment culture from nasal, oral, axillary, and perineal swabs and speciated by standard bacteriological tests and API ID32 STAPH (bioMerieux, Marcy l'Etoile, France). Antimicrobial resistance was investigated by disc diffusion tests and identification of mecA. Thirty-seven staphylococcal isolates were identified from 35 of the 38 foxes. All isolates were coagulase-negative and most frequently included species from the S. sciuri group (35%), S. equorum (27%), and S. capitis (22%). All were phenotypically resistant to methicillin, and mecA was detected in 33 (89%) of isolates, but only 10 (27%) showed broad beta-lactam antibiotic resistance. Methicillin-resistant S. aureus was not identified. These results indicate that foxes are a potential wildlife reservoir for mecA-positive staphylococci. Selection pressure from environmental contamination with antimicrobials should be considered. PMID- 22448724 TI - A review of the invasive mosquitoes in Europe: ecology, public health risks, and control options. AB - There has been growing interest in Europe in recent years in the establishment and spread of invasive mosquitoes, notably the incursion of Aedes albopictus through the international trade in used tires and lucky bamboo, with onward spread within Europe through ground transport. More recently, five other non European aedine mosquito species have been found in Europe, and in some cases populations have established locally and are spreading. Concerns have been raised about the involvement of these mosquito species in transmission cycles of pathogens of public health importance, and these concerns were borne out following the outbreak of chikungunya fever in Italy in 2007, and subsequent autochthonous cases of dengue fever in France and Croatia in 2010. This article reviews current understanding of all exotic (five introduced invasive and one intercepted) aedine species in Europe, highlighting the known import pathways, biotic and abiotic constraints for establishment, control strategies, and public health significance, and encourages Europe-wide surveillance for invasive mosquitoes. PMID- 22448725 TI - Copper-catalyzed azide-alkyne cycloaddition reaction in water using cyclodextrin as a phase transfer catalyst. AB - 1,4-Disubstituted-1,2,3-triazoles were obtained in excellent yields from azides and terminal alkynes in H(2)O in the presence of catalytic amount of beta cyclodextrin as a phase transfer catalyst. Also, a one-pot CuAAC reaction was carried out successfully, affording 1,4-disubstituted-1,2,3-triazoles in good to high yields starting from an alkyl bromide, sodium azide, and terminal alkyne. PMID- 22448726 TI - Influence of the carboxy terminus of serum amyloid A on protein oligomerization, misfolding, and fibril formation. AB - The fibrillar deposition of serum amyloid A (SAA) has been linked to the disease amyloid A (AA) amyloidosis. We have used the SAA isoform, SAA2.2, from the CE/J mouse strain, as a model system to explore the inherent structural and biophysical properties of SAA. Despite its nonpathogenic nature in vivo, SAA2.2 spontaneously forms fibrils in vitro, suggesting that SAA proteins are inherently amyloidogenic. However, whereas the importance of the amino terminus of SAA for fibril formation has been well documented, the influence of the proline-rich and presumably disordered carboxy terminus remains poorly understood. To clarify the inherent role of the carboxy terminus in the oligomerization and fibrillation of SAA, we truncated the proline-rich final 13 residues of SAA2.2. We found that unlike full-length SAA2.2, the carboxy-terminal truncated SAA2.2 (SAA2.2DeltaC) did not oligomerize to a hexamer or octamer, but formed a high molecular weight soluble aggregate. Moreover, SAA2.2DeltaC also exhibited a pronounced decrease in the rate of fibril formation. Intriguingly, when equimolar amounts of denatured SAA2.2 and SAA2.2DeltaC were mixed and allowed to refold together, the mixture formed an octamer and exhibited rapid fibrillation kinetics, similar to those for full-length SAA2.2. These results suggest that the carboxy terminus of SAA, which is highly conserved among SAA sequences in all vertebrates, might play important structural roles, including modulating the folding, oligomerization, misfolding, and fibrillation of SAA. PMID- 22448727 TI - The psychological assessment of candidates for reconstructive hand transplantation. AB - Standardized psychological assessment of candidates for reconstructive hand transplantation (RHT) is a new approach in transplantation medicine. Currently, international guidelines and standardized criteria for the evaluation are not established. Patients suffering from the loss of a hand or an upper extremity have to cope with multiple challenges. For a selected group of patients, RHT represents an option for restoring natural function and for regaining daily living independence. The identification of at-risk patients and those requiring ongoing counseling due to poor coping or limited psychological resources are the primary focus of the psychological assessment. We have developed the 'Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT-PSP)' which utilizes a semi-structured interview and standardized psychological screening procedures and continuous follow-up ratings. Between January 2011 and October 2011, four candidates were evaluated using the iRT-PSP. Psychological impairments including social withdrawal, embarrassment, reduced self-esteem, and a depressive coping style were identified and poor quality of life was reported. The motivation for transplantation was diverse, depending on many factors such as bi- or unilateral impairment, native or accidental loss of hand, and social integration. PMID- 22448728 TI - Factors predicting hospital length-of-stay and readmission after colorectal resection: a population-based study of elective and emergency admissions. AB - BACKGROUND: The impact of developments in colorectal cancer surgery on length-of stay (LOS) and re-admission have not been well described. In a population-based analysis, we investigated predictors of LOS and emergency readmission after the initial surgery episode. METHODS: Incident colorectal cancers (ICD-O2: C18-C20), diagnosed 2002-2008, were identified from the National Cancer Registry Ireland, and linked to hospital in-patient episodes. For those who underwent colorectal resection, the associated hospital episode was identified. Factors predicting longer LOS (upper-quartile, > 24 days) for elective and emergency admissions separately, and whether LOS predicted emergency readmission within 28 days of discharge, were investigated using logistic regression. RESULTS: 8197 patients underwent resection, 63% (n = 5133) elective and 37% (n = 3063) emergency admissions. Median LOS was 14 days (inter-quartile range (IQR) = 11-20) for elective and 21 (15-33) for emergency admissions. For both emergency and elective admissions, likelihood of longer LOS was significantly higher in patients who were older, had co-morbidities and were unmarried; it was reduced for private patients. For emergency patients only the likelihood of longer LOS was lower for patients admitted to higher-volume hospitals. Longer LOS was associated with increased risk of emergency readmission. CONCLUSIONS: One quarter of patients stay in hospital for at least 25 days following colorectal resection. Over one third of resected patients are emergency admissions and these have a significantly longer median LOS. Patient- and health service-related factors were associated with prolonged LOS. Longer LOS was associated with increased risk of emergency readmission. The cost implications of these findings are significant. PMID- 22448729 TI - Intraoperative stereoscopic 3D video imaging: pushing the boundaries of surgical visualisation and applications for neurosurgical education. AB - OBJECTIVE: In the past decades, we have witnessed waves of interest in three dimensional (3D) stereoscopic imaging. Previously, the complexity associated with 3D technology led to its absence in the operating room. But recently, the public's resurrection of interest in this imaging modality has revived its exploration in surgery. Technological advances have also paved the way for incorporation of 3D stereoscopic imaging in neurosurgical education. METHODS: Herein, the authors discuss the advantages of intraoperative 3D recording and display for neurosurgical learning and contemplate its future directions based on their experience with 3D technology and a review of the literature. RESULTS: Potential benefits of stereoscopic displays include an enhancement of subjective image quality, proper identification of the structure of interest from surrounding tissues and improved surface detection and depth judgment. Such benefits are critical during the intraoperative decision-making process and proper handling of the lesion (specifically, for surgery on aneurysms and tumours), and should therefore be available to the observers in the operating room and residents in training. Our trainees can relive the intraoperative experience of the primary surgeon by reviewing the recorded stereoscopic 3D videos. CONCLUSION: Proper 3D knowledge of surgical anatomy is important for operative success. 3D stereoscopic viewing of this anatomy may accelerate the learning curve of trainees and improve the standards of surgical teaching. More objective studies are relevant in further establishing the value of 3D technology in neurosurgical education. PMID- 22448730 TI - Recurrence of MDD: a prospective study of personality pathology and cognitive distortions. AB - Major depressive disorder (MDD) is characterized by a high risk of recurrence, especially among individuals whose initial episode occurs during adolescence. Identifying predictors of recurrence of MDD among young samples is therefore of paramount clinical importance. Survival analytic models were used to evaluate the effects of dysfunctional cognitions and Axis II personality pathology on MDD recurrence in a sample of 130 previously, but not currently, depressed young adults. Participants were initially assessed for depression, dysfunctional attitudes, and personality pathology during their first semester in college and then reevaluated via the Longitudinal Interval Follow-up Evaluation interview every 6 months for 18 months. Baseline level of depressive symptoms significantly (HR-1.07, p = .002) predicted recurrence of MDD. In the survival analyses with baseline level of depression serving as a current mood state covariate, overall personality pathology (HR-1.04, p < .05), but not cognitive distortions, uniquely predicted MDD recurrence. In similar analyses, none of the specific DSM-IV personality disorder cluster scores uniquely predicted recurrence. We discussed the theoretical, empirical, and clinical implications of these findings, and we noted the limitations of the study. PMID- 22448731 TI - Parallel syndromes: two dimensions of narcissism and the facets of psychopathic personality in criminally involved individuals. AB - Little research has examined different dimensions of narcissism that may parallel psychopathy facets in criminally involved individuals. In this study, we examined the pattern of relationships between grandiose and vulnerable narcissism, assessed using the Narcissistic Personality Inventory-16 and the Hypersensitive Narcissism Scale, respectively, and the four facets of psychopathy (interpersonal, affective, lifestyle, and antisocial) assessed via the Psychopathy Checklist: Screening Version. As predicted, grandiose and vulnerable narcissism showed differential relationships to psychopathy facets, with grandiose narcissism relating positively to the interpersonal facet of psychopathy and vulnerable narcissism relating positively to the lifestyle facet of psychopathy. Paralleling existing psychopathy research, vulnerable narcissism showed stronger associations than grandiose narcissism to (a) other forms of psychopathology, including internalizing and substance use disorders, and (b) self- and other-directed aggression, measured with the Life History of Aggression and the Forms of Aggression Questionnaire. Grandiose narcissism was nonetheless associated with social dysfunction marked by a manipulative and deceitful interpersonal style and unprovoked aggression. Potentially important implications for uncovering etiological pathways and developing treatment interventions for these disorders in externalizing adults are discussed. PMID- 22448732 TI - Impulsivity and risk-taking in borderline personality disorder with and without substance use disorders. AB - Impulsivity and risk taking propensity were assessed in participants with borderline personality disorder (BPD-only; n = 19), BPD and a current or past substance use disorder (BPD-SUD; n = 32), and a matched comparison group (MC; n = 28). Participants were administered behavioral measures of two facets of the multidimensional construct of impulsivity [GoStop, delay discounting task (DDT)], one measure of risk-taking propensity [Balloon Analog Risk Task (BART)], and two self-report measures of impulsivity (i.e., Barrett Impulsiveness Scale, Eysenck Impulsiveness Scale). The BPD-SUD group, but not the BPD-only group, discounted delayed rewards faster than the MC group on the DDT, suggesting that the BPD SUD/MC group difference may be because of the SUD rather than BPD. In contrast, both the BPD-SUD and BPD-only groups exhibited poorer behavioral response inhibition compared with the MC group, but the two BPD groups did not differ from one another. This finding suggests that the differences in behavioral response inhibition may be because of BPD rather than SUD and that behavioral response disinhibition may be a core feature of BPD. None of the groups differed on the measure of risk-taking propensity (i.e., BART). On self-report questionnaires, the BPD-SUD group reported more impulsivity than the BPD-only group and both BPD groups reported more impulsivity than the MC group. Data from the DDT and self report measures provide partial support for the hypothesis that BPD individuals with a SUD are more impulsive than BPD individuals without a SUD on some facets of impulsivity (e.g., desire to obtain a smaller immediate reward rather than wait to obtain a larger reward in the future). Results suggest that behavioral response inhibition may be a novel treatment outcome variable for BPD treatment studies. PMID- 22448733 TI - Relationships between depressive rumination, anger rumination, and borderline personality features. AB - We examined relationships between depressive rumination, anger rumination, and features of borderline personality disorder in a sample of 93 students with a wide range of borderline symptoms. All completed self-report measures of borderline features; trait-level negative affect; depressive and anger rumination; and current symptoms of depression, anxiety, and stress. Depressive and anger rumination were strongly associated with borderline features after controlling for comorbid symptoms of depression, anxiety, and stress. Both types of rumination showed significant incremental validity over trait-level sadness, anger, and general negative affect in predicting borderline features. Relationships with borderline features were stronger for anger rumination than for depressive rumination. Relationships between trait-level negative affect and borderline features were substantially reduced when anger rumination was included in regression models, suggesting the need for longitudinal analyses of mediation. Findings suggest that severity of borderline symptoms is influenced by ruminative thinking in response to negative affect, especially anger. PMID- 22448734 TI - Estimation of the mutual orientation and intermolecular interaction of C12Ex from molecular dynamics simulations. AB - Nonionic surfactants, such as poly(ethylene glycol) alkyl ethers (abbreviated as CyEx) show a rich phase behavior in aqueous solution, i.e., they form micellar, lamellar, cubic, and so forth phases depending on experimental parameters such as the hydrophobic and hydrophilic chain lengths, temperature, or concentration. The aim of the present study is to determine the nature of the preaggregates, which are inferred to exist before the actual self-assembly process in aqueous solution, and to assess the aptitude to their formation. The target molecules are C12E3, C12E4 and C12E5, surfactants of moderate water solubility. Coarse-grained and all-atom molecular dynamics simulations (NPT/293 K) of two molecules of each species with explicit water in periodic boundary conditions are carried out to estimate the mutual orientation and the interaction between the surfactants in their dimers. The force fields are MARTINI and Amber99, the latter with self derived parameters for the ether groups. The change in the orientation and distance between the molecules in the dimers are discussed based on different structural parameters. In addition, the interaction between the surfactants is evaluated from quantum chemistry calculations in terms of binding energy for the average structures from the cluster analysis. The solvent-solute interaction is quantified by the mean number of hydrogen bonds formed between them. On the basis of combined analysis, a series of different structures for subsequent study of the possible self-assembly patterns of C12E3, C12E4, and C12E5 is outlined. PMID- 22448735 TI - Development of a rule-based method for the assessment of protein druggability. AB - Target selection is a critical step in the majority of modern drug discovery programs. The viability of a drug target depends on two components: biological relevance and chemical tractability. The concept of druggability was introduced to describe the second component, and it is defined as the ability of a target to bind a drug-like molecule with a therapeutically useful level of affinity. To investigate the rules that govern druggability, we developed an algorithm to isolate and characterize the binding pockets of protein targets. Using this algorithm, we performed a comparative analysis between the relevant pockets of 60 targets of approved drugs and a diverse set of 440 ligand-binding pockets. As a result, we defined a preferred property space for druggable pockets based on five key properties (volume, depth, enclosure, percentage of charged residues and hydrophobicity), and we represented it with a set of simple rules. These rules may be applicable in the future to evaluate the chemical tractability of prospective targets. PMID- 22448736 TI - Comparison of infectious and noninfectious intracranial caseating granulomas. AB - Although caseating granulomas are classically associated with infectious processes, a subgroup of intracranial caseating granulomas without identifiable infectious pathology (ICGN) is described. We aimed to identify clinical, laboratory, radiological and histological markers with potential to distinguish patients with ICGN from those with intracranial caseating granulomas with infectious etiology (ICGI) on tissue microbiological examinations. In a referral hospital setting, we identified 11 patients with ICGNs and 6 patients with ICGI over an 11-year period. The two groups had similar demographics (other than higher infection risk factors in ICGIs), clinical presentation, serology, location of lesions and cellular composition of the inflammatory infiltrate. Significant differences were the homogenous vs. ring pattern of enhancement on neuroimaging and small (<1 mm) vs. large (>1 mm) area of necrosis on histological examination, in ICGNs and ICGIs, respectively. The dichotomy was best reflected in the response of ICGNs to immunomodulatory and not antimicrobial treatment and the reverse pattern in ICGIs. Based on these findings, we suggest a scheme for the diagnosis of ICGN: (i) caseating granulomas with areas of necrosis predominantly <1 mm in diameter; (ii) absence of an identifiable infectious agent in extensive tissue examinations; and (iii) no clinical and radiological response within 2 months of appropriate antimicrobial treatment. PMID- 22448737 TI - Body temperature modulates the antioxidant and acute immune responses to exercise. AB - The aim of this study was to determine the effects of whole body heat in combination with exercise on the oxidative stress and acute phase immune response. Nine male endurance-trained athletes voluntarily performed two running bouts of 45 minutes at 75-80% of VO(2max) in a climatic chamber in two conditions: cold and hot humid environment. Leukocyte, neutrophil and basophil counts significantly rose after exercise in both environments; it was significantly greater in the hot environment. Lymphocyte and neutrophil antioxidant enzyme activities and carbonyl index significantly increased or decreased after exercise only in the hot environment, respectively. The lymphocytes expression of catalase, Hsp72 and CuZn-superoxide dismutase was increased in the hot environment and Sirt3 in the cold environment, mainly during recovery. In conclusion, the increased core body temperature results in the acute phase immune response associated to intense exercise and in the immune cell adaptations to counteract the oxidative stress situation. PMID- 22448738 TI - Efficacy and safety of avanafil for treating erectile dysfunction: results of a multicentre, randomized, double-blind, placebo-controlled trial. AB - Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED). Preclinical and clinical phase I studies showed that avanafil had enhanced selectivity, faster onset of action and a favourable side-effect profile relative to currently available PDE5 inhibitors. As the result of phase III clinical trial for the efficacy and safety of avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED, avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity. OBJECTIVE: * To evaluate the efficacy and safety of avanafil, a new potent selective phosphodiesterase type 5 (PDE5) inhibitor, in patients with erectile dysfunction (ED). PATIENTS AND METHODS: * The present study was a multicentre, randomized, double-blind, placebo-controlled, fix-dosed phase three clinical trial involving 200 patients with ED. * The subjects were treated with placebo or avanafil (100 or 200 mg) for 12 weeks and were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ). * The primary outcome variable was the change from baseline for IIEF erectile function domain (EFD) score. * The secondary outcome variables were SEP Q2 and Q3, the shift to normal rate (EFD >= 26), and response to the GAQ. RESULTS: * Compared with placebo, patients who took 100 or 200 mg of avanafil had significantly improved IIEF-EFD score. * There were similar results when comparing Q2 and Q3 in the SEP diary and the GAQ. * Flushing was the most common treatment-related adverse event. * Most adverse events were transient and mild or moderate in severity. CONCLUSION: * Avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity. PMID- 22448739 TI - Repair of an inguinoscrotal hernia containing the urinary bladder: a case report. AB - INTRODUCTION: Cases of patients with inguinoscrotal hernia containing the urinary bladder are very rare. These patients usually present with frequent episodes of urinary tract infection, difficulty in walking, pollakisuria and difficulty in initiating micturition because of incarceration of the urinary bladder into the scrotum. CASE PRESENTATION: We describe the case of an 80-year-old Caucasian man with an incarcerated urinary bladder into the scrotum who underwent surgical repair with mesh. CONCLUSIONS: Diagnosis of such cases often requires not only clinical examination but also specialized radiological examinations to show the ectopic position of the urinary bladder. Surgical repair in these patients is a real challenge for surgeons. PMID- 22448740 TI - The hierarchical structure of DSM-5 pathological personality traits. AB - A multidimensional trait system has been proposed for representing personality disorder (PD) features in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to address problematic classification issues such as comorbidity. In this model, which may also assist in providing scaffolding for the underlying structure of major forms of psychopathology more generally, 25 primary traits are organized by 5 higher order dimensions: Negative Affect, Detachment, Antagonism, Disinhibition, and Psychoticism. We examined (a) the generalizability of the structure proposed for DSM-5 PD traits, and (b) the potential for an integrative hierarchy based upon DSM-5 PD traits to represent the dimensions scaffolding psychopathology more generally. A large sample of student participants (N = 2,461) completed the Personality Inventory for DSM-5, which operationalizes the DSM-5 traits. Exploratory factor analysis replicated the initially reported 5-factor structure, as indicated by high factor congruencies. The 2-, 3-, and 4-factor solutions estimated in the hierarchy of the DSM-5 traits bear close resemblance to existing models of common mental disorders, temperament, and personality pathology. Thus, beyond the description of individual differences in personality disorder, the trait dimensions might provide a framework for the metastructure of psychopathology in the DSM-5 and the integration of a number of ostensibly competing models of personality trait covariation. PMID- 22448741 TI - General personality and psychopathology in referred and nonreferred children and adolescents: an investigation of continuity, pathoplasty, and complication models. AB - This study investigated the continuity, pathoplasty, and complication models as plausible explanations for personality-psychopathology relations in a combined sample of community (n = 571) and referred (n = 146) children and adolescents. Multivariate structural equation modeling was used to examine the structural relations between latent personality and psychopathology change across a 2-year period. Item response theory models were fitted as an additional test of the continuity hypothesis. Even after correcting for item overlap, the results provided strong support for the continuity model, demonstrating that personality and psychopathology displayed dynamic change patterns across time. Item response theory models further supported the continuity conceptualization for understanding the association between internalizing problems and emotional stability and extraversion as well as between externalizing problems and benevolence and conscientiousness. In addition to the continuity model, particular personality and psychopathology combinations provided evidence for the pathoplasty and complication models. The theoretical and practical implications of these results are discussed, and suggestions for future research are provided. PMID- 22448742 TI - Ontogenetic and evolutionary effects of predation and competition on nine-spined stickleback (Pungitius pungitius) body size. AB - 1. Individual- and population-level variation in body size and growth often correlates with many fitness traits. Predation and food availability are expected to affect body size and growth as important agents of both natural selection and phenotypic plasticity. How differences in predation and food availability affect body size/growth during ontogeny in populations adapted to different predation and competition regimes is rarely studied. 2. Nine-spined stickleback (Pungitius pungitius) populations originating from habitats with varying levels of predation and competition are known to be locally adapted to their respective habitats in terms of body size and growth. Here, we studied how different levels of perceived predation risk and competition during ontogeny affect the reaction norms of body size and growth in (i) marine and pond populations adapted to different levels of predation and competition and (ii) different sexes. We reared nine-spined stickleback in a factorial experiment under two levels of perceived predation risk (present/absent) and competition (high/low food supply). 3. We found divergence in the reaction norms at two levels: (i) predation-adapted marine stickleback had stronger reactions to predatory cues than intraspecific competition-adapted pond stickleback, the latter being more sensitive to available food than the marine fish and (ii) females reacting more strongly to the treatments than males. 4. The repeated, habitat-dependent nature of the differences suggests that natural selection is the agent behind the observed patterns. Our results suggest that genetic adaptation to certain environmental factors also involves an increase in the range of expressible phenotypic plasticity. We found support for this phenomenon at two levels: (i) across populations driven by habitat type and (ii) within populations driven by sex. PMID- 22448743 TI - Hexadecadienyl monolayers on hydrogen-terminated Si(111): faster monolayer formation and improved surface coverage using the enyne moiety. AB - To further improve the coverage of organic monolayers on hydrogen-terminated silicon (H-Si) surfaces with respect to the hitherto best agents (1-alkynes), it was hypothesized that enynes (H-C=C-HC?CH-R) would be even better reagents for dense monolayer formation. To investigate whether the increased delocalization of beta-carbon radicals by the enyne functionality indeed lowers the activation barrier, the kinetics of monolayer formation by hexadec-3-en-1-yne and 1 hexadecyne on H-Si(111) were followed by studying partially incomplete monolayers. Ellipsometry and static contact angle measurements indeed showed a faster increase of layer thickness and hydrophobicity for the hexadec-3-en-1-yne derived monolayers. This more rapid monolayer formation was supported by IRRAS and XPS measurements that for the enyne show a faster increase of the CH2 stretching bands and the amount of carbon at the surface (C/Si ratio), respectively. Monolayer formation at room temperature yielded plateau values for hexadec-3-en-1-yne and 1-hexadecyne after 8 and 16 h, respectively. Additional experiments were performed for 16 h at 80 degrees to ensure full completion of the layers, which allows comparison of the quality of both layers. Ellipsometry thicknesses (2.0 nm) and contact angles (111-112 degrees ) indicated a high quality of both layers. XPS, in combination with DFT calculations, revealed terminal attachment of hexadec-3-en-1-yne to the H-Si surface, leading to dienyl monolayers. Moreover, analysis of the Si2p region showed no surface oxidation. Quantitative XPS measurements, obtained via rotating Si samples, showed a higher surface coverage for C16 dienyl layers than for C16 alkenyl layers (63% vs 59%). The dense packing of the layers was confirmed by IRRAS and NEXAFS results. Molecular mechanics simulations were undertaken to understand the differences in reactivity and surface coverage. Alkenyl layers show more favorable packing energies for surface coverages up to 50-55%. At higher coverages, this packing energy rises quickly, and there the dienyl packing becomes more favorable. When the binding energies are included the difference becomes more pronounced, and dense packing of dienyl layers becomes more favorable by 2-3 kcal/mol. These combined data show that enynes provide the highest-quality organic monolayers reported on H-Si up to now. PMID- 22448744 TI - Seroepidemiology of Toxoplasma gondii infection in elderly people in a northern Mexican city. AB - Whereas it is well-known that the seroprevalence of infection with Toxoplasma gondii increases with age, details of the seroepidemiology of infection in elderly people are largely unknown. Anti-T. gondii IgG and IgM antibody levels were determined in 483 subjects aged >=60 years old in Durango City, Mexico, using enzyme-linked immunosorbent assays. Socio-demographic, clinical, and behavioral characteristics from each participant were also obtained. In total, 58 (12%) of 483 participants (mean age 70.35+/-6.63 years) had anti-T. gondii IgG antibodies, and 14 (2.9%) also had anti-T. gondii IgM antibodies. Seroprevalence of infection varied significantly with age, birthplace, and educational level. Seroprevalence increased with age, especially in women (p=0.01), and was higher in subjects born outside of Durango State than those born within Durango State (p=0.008). Seroprevalence was higher in men with up to 12 years of education than in men with more than 12 years of education (p=0.01). Multivariate analysis of behavioral data showed a positive association of T. gondii infection with the presence of cats in the neighborhood, as well as consumption of boar, pigeon, iguana, and armadillo meats, and chorizo. Gender-specific analysis showed the described associations in women but not in men. In contrast, consumption of beef showed a negative association with T. gondii infection. This is the first report of the seroprevalence and contributing factors for T. gondii infection in elderly people, and of an association of the consumption of armadillo and iguana meats with T. gondii infection. Our results will provide the basis for the design of optimal preventive measures against T. gondii infection. PMID- 22448745 TI - Identification of Rickettsia africae and Wolbachia sp. in Ceratophyllus garei fleas from Passerine birds migrated from Africa. AB - The aim of the study was to reveal new aspects of the role of flea vector taken from migratory birds by screening of specimens with molecular biological methods. A field study was done in fishponds in Slovakia. Actually, 47 fleas were collected from reed warblers (Acrocephalus scirpaceus) and their nests. DNA was extracted and analyzed for representatives of the orders Rickettsiales. A rickettsia that shares 99.7% of identity by gltA gene with Rickettsia africae was identified in Ceratophyllus garei collected from A. scirpaceus. Moreover, two Wolbachia sp. were also detected in fleas. This is the first record of R. africae and Wolbachia sp. identified so far in Central Europe in fleas collected from migratory bird returning from Africa. This molecular study extends the geographic range and vector spectrum of arthropod-borne agents. PMID- 22448746 TI - Experimental West Nile virus infection in Gyr-Saker hybrid falcons. AB - West Nile disease (WND) has become a major public and veterinary health concern since the appearance of West Nile virus (WNV) in New York in 1999. The following panzootic spread in the U.S. and the recent WNV outbreaks in Europe and the Mediterranean Basin have increased interest in WND. Despite considerable investigation of WNV infection in birds, the effects of WNV on avian populations are still largely unknown. In Europe, raptors have been found to be particularly susceptible to WNV infection, but studies in birds of prey are lacking. To our knowledge, the present study is the first to report an experimental infection with WNV in Gyr-Saker hybrid falcons. We show that 10-week-old captive-reared Gyr Saker (Falco rusticolus * Falco cherrug) hybrid falcons are susceptible to WNV infection. Neither morbidity nor mortality was observed after subcutaneous WNV inoculation with mixed extracts of non-infected mosquito salivary glands. Both the macroscopic and microscopic lesions observed were similar to those previously reported in naturally and experimentally infected North American raptors. The results obtained in the present study demonstrate that although Gyr-Saker hybrid falcons do not seem to be a good reservoir for WNV transmission via mosquito, they can become infected with WNV, develop viremia and antibodies, and are able to shed the virus. PMID- 22448747 TI - Stimulation of TLR4 by recombinant HSP70 requires structural integrity of the HSP70 protein itself. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is activated by bacterial endotoxin, a prototypical pathogen-associated molecular pattern (PAMP). It has been suggested that TLR4 can also be activated by damage-associated molecular pattern (DAMP) proteins such as HSP70. It remains a challenge to provide unequivocal evidence that DAMP proteins themselves play a role in TLR4 activation, as the DAMP proteins used are often contaminated with endotoxin and other TLR ligands introduced during protein expression and/or purification. RESULTS: Here we report that the activation of TLR4 on primary human macrophage cultures by recombinant HSP70 is not solely due to contaminating endotoxin. Polymyxin B pretreatment of HSP70 preparations to neutralize contaminating endotoxin caused significant reductions in the amount of TNF-alpha induced by the recombinant protein as determined by ELISA. However, digestion of HSP70 with Proteinase K-agarose beads also dramatically reduced the TNF-alpha response of macrophages to HSP70, while leaving levels of contaminating endotoxin largely unchanged relative to controls. CONCLUSIONS: These results indicate that the stimulatory effect of recombinant HSP70 requires both the presence of endotoxin and structural integrity of the heat shock protein itself. PMID- 22448748 TI - Crop to wild introgression in lettuce: following the fate of crop genome segments in backcross populations. AB - BACKGROUND: After crop-wild hybridization, some of the crop genomic segments may become established in wild populations through selfing of the hybrids or through backcrosses to the wild parent. This constitutes a possible route through which crop (trans)genes could become established in natural populations. The likelihood of introgression of transgenes will not only be determined by fitness effects from the transgene itself but also by the crop genes linked to it. Although lettuce is generally regarded as self-pollinating, outbreeding does occur at a low frequency. Backcrossing to wild lettuce is a likely pathway to introgression along with selfing, due to the high frequency of wild individuals relative to the rarely occurring crop-wild hybrids. To test the effect of backcrossing on the vigour of inter-specific hybrids, Lactuca serriola, the closest wild relative of cultivated lettuce, was crossed with L. sativa and the F(1) hybrid was backcrossed to L. serriola to generate BC(1) and BC(2) populations. Experiments were conducted on progeny from selfed plants of the backcrossing families (BC(1)S(1) and BC(2)S(1)). Plant vigour of these two backcrossing populations was determined in the greenhouse under non-stress and abiotic stress conditions (salinity, drought, and nutrient deficiency). RESULTS: Despite the decreasing contribution of crop genomic blocks in the backcross populations, the BC(1)S(1) and BC(2)S(1) hybrids were characterized by a substantial genetic variation under both non-stress and stress conditions. Hybrids were identified that performed equally or better than the wild genotypes, indicating that two backcrossing events did not eliminate the effect of the crop genomic segments that contributed to the vigour of the BC(1) and BC(2) hybrids. QTLs for plant vigour under non stress and the various stress conditions were detected in the two populations with positive as well as negative effects from the crop. CONCLUSION: As it was shown that the crop contributed QTLs with either a positive or a negative effect on plant vigour, we hypothesize that genomic regions exist where transgenes could preferentially be located in order to mitigate their persistence in natural populations through genetic hitchhiking. PMID- 22448749 TI - Intra-operative management of low portal vein flow in pediatric living donor liver transplantation. AB - For pediatric living donor liver transplantation, portal vein complications cause significant morbidity and graft failure. Routine intra-operative Doppler ultrasound is performed after graft reperfusion to evaluate the flow of portal vein. This retrospective study reviewed 65 children who had undergone living donor liver transplantation. Seven patients were detected with suboptimal portal vein flow velocity following vascular reconstruction and abdominal closure. They underwent immediate on-table interventions to improve the portal vein flow. Both surgical and endovascular modalities were employed, namely, graft re-positioning, collateral shunt ligation, thrombectomy, revision of anastomosis, inferior mesenteric vein cannulation, and endovascular stenting. The ultrasonographic follow-up assessment for all seven patients demonstrated patent portal vein and satisfactory flow. We reviewed our experience on the different modalities and proposed an approach for our future intra-operative management to improve portal vein flow at the time of liver transplantation. PMID- 22448750 TI - SirT1 regulates radiosensitivity of hepatoma cells differently under normoxic and hypoxic conditions. AB - Intratumoral hypoxic cells are more resistant to radiotherapy due to a reduction in lifespan of DNA-damaging free radicals and augmentation of post-irradiation molecular restoration. SirT1, a member of the mammalian sirtuin family, deacetylates various transcription factors to trigger cell defense and survival in response to stresses and DNA damage. In this study, we provide new evidence indicating that overexpression of SirT1 in hepatoma HepG2 cells allowed the cells to become much more resistant to irradiation under hypoxia than under normoxia. When SirT1 was knocked down in both HepG2 and SK-Hep-1 cells, the radiosensitivity was increased, especially under hypoxia. But this enhanced radiosensitivity in SirT1-deficient cells was extensively decreased by infecting cells with c-Myc siRNA. Furthermore, the expression of c-Myc protein and its acetylation were increased in the SirT1 knockdown cells and these increments under hypoxic conditions were much more notable than under normoxia. In addition, c-Myc interference significantly suppressed phosphorylated p53 protein expression after irradiation, especially under hypoxic conditions. The current findings indicate that SirT1 confers a higher radioresistance in hypoxic cells than in normoxic cells due to the decreased levels of c-Myc protein and its acetylation, and that a c-Myc-dependent radiation-induced phosphorylated p53 may be involved. SirT1 could serve as a novel target of radiation damage and thus as a potential strategy to advance the efficiency of radiotherapy in hepatoma entities. PMID- 22448751 TI - Redescription and new host record of Capsala laevis (Monogenoidea: Capsalidae: Capsalinae) from gill of roundscale spearfish, Tetrapturus georgii (Perciformes: Istiophoridae) in the northwestern Atlantic Ocean. AB - Specimens of a capsalid collected from the gill arches of 2 roundscale spearfish, Tetrapturus georgii Lowe, 1840, (Perciformes: Istiophoridae), captured in the northwestern Atlantic Ocean were identified as Capsala laevis (Verrill, 1875) Johnston, 1929 by having the combination of papillae on the ventral surface of haptor, dorsomarginal body sclerites in a single column extending the entire body length, haptoral accessory sclerites, conical papillae distributing over the ventral body surface, and an anterior attachment organ with a fimbriated posterior margin. The new specimens plus the holotype were used to conduct a taxonomic redescription of C. laevis using light and scanning electron microscopy. We documented that the holotype (USNPC No. 7179) and the new specimens of C. laevis from roundscale spearfish each had papillae on the ventral surface of the anterior attachment organs and sensory papillae on the dorsal body surface. Although data are insufficient at this time to justify proposal of a new species, the new specimens differed from the holotype and published accounts of C. laevis by having a sinistral dorsomarginal patch comprising 27-35 sclerites whereas the holotype has a dorsomarginal patch comprising 60 sclerites. Capsala laevis morphologically most closely resembles Capsala ovalis (Goto, 1894) Price, 1938 , but can be most easily differentiated from it by having dorsomarginal body sclerites. This represents the first record of any parasite from the recently taxonomically resurrected roundscale spearfish, long considered by some as a junior subjective synonym of white marlin, Tetrapturus albidus Poey, 1860 and, concomitantly, a new host record for Capsalidae Baird, 1853. An updated list of host records for C. laevis is provided. A perusal of that literature reveals that the identity of the type host for C. laevis is indeterminate beyond Istiophoridae species and that subsequent reports of the type host as ' T. albidus ' are presumptuous (originally reported in 1875 by Verrill as "bill-fish" only). Our results indicated that 2 records of C. laevis from the swordfish, Xiphias gladius Linnaeus, 1758, (Perciformes: Xiphiidae) are dubious, i.e., study of the museum voucher USNPC No. 8154 indicates that Linton's 1940 record from the northwestern Atlantic Ocean likely represents a new species of Capsala Bosc, 1811 and that the Kayis et al. 2010 record from the Aegean Sea likely depicts a species of Capsaloides Price, 1938. PMID- 22448752 TI - Data-driven assessment of the association of polymorphisms in 5-Fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer. AB - A major challenge in the assessment of medicines, treatment options, etc., is to establish a framework for the comparison of risks and benefits of many different types and magnitudes, a framework that at the same time allows a clear distinction between the roles played by the statistical analyses of data and by judgements based on personal experience and expertise. The purpose of this study was to demonstrate how clinical data can be weighted, scored and presented by the use of an eight-step data-driven benefit-risk assessment method, where two genetic profiles are compared. Our aim was to present a comprehensive approach that is simple to apply, allows direct comparison of different types of risks and benefits, quantifies the clinical relevance of data and is tailored for the comparison of different options. We analysed a cohort of 302 patients with colorectal cancer treated with 5-Fluorouracil (5-FU). Endpoints were cure rate, survival rate, time-to-death (TTD), time-to-relapse (TTR) and main adverse drug reactions. Multifactor dimensionality reduction (MDR) was used to identify genetic interaction profiles associated with outcome. We have been able to demonstrate that a specific MDR-derived combination (the MDR-1 group) of dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms is associated with increased and clinically significant difference for cure and survival rates, TTD and probably also for TTR, which are seen as the most important endpoints. An inferior profile was observed for severe myocardial ischaemia. A probably inferior profile was seen for severe arthralgia/myalgia and severe infections. A clear superior profile was seen for severe mucositis/stomatitis. The proposed approach offers comprehensive, data-driven assessment that can facilitate decision processes, for example, in a clinical setting. It employs descriptive statistical methods to highlight the clinically relevant differences between options. PMID- 22448753 TI - Unexpected electronic properties of micrometer-thick supracrystals of Au nanocrystals. AB - We investigated the electronic properties of highly ordered three-dimensional colloidal crystals of gold nanocrystals (7 +/- 0.4 nm), called supracrystals. Two kinds of Au supracrystals with typical thicknesses of 300 nm and 5 MUm, respectively, are probed for the first time with scanning tunneling microscopy/spectroscopy at 5 K revealing similar power law behavior and showing homogeneous conductance with the fingerprint of isolated nanocrystal. Potential applications evading the size-related risks of nanocrystals could be then considered. PMID- 22448754 TI - 1,5-Stereoinduction in boron-mediated aldol reactions of beta,delta-bisalkoxy methylketones containing cyclic protecting groups. AB - A study of the aldol reactions of boron enolates from methylketones that are protected with dimethylacetonide or di-tert-butylsilyl groups and that possess a trans or cis relationship between the chiral centers is presented. The main objective of this work was to evaluate the influence of the relative stereochemistry between the chiral centers and the steric and electronic influences of the cyclic protecting groups on the aldol reactions. The aldol adducts were obtained with moderate to high 1,5-anti stereoselectivity that was dependent on both the identity of the protecting group on the beta,delta-oxygen stereocenters and the relative stereochemistry between the beta and delta chiral centers. A theoretical analysis of the transition states involving these aldol reactions was performed utilizing DFT (density functional theory). PMID- 22448755 TI - Discrepancies between the medical record and the reports of patients with acute coronary syndrome regarding important aspects of the medical history. AB - BACKGROUND: Many critical treatment decisions are based on the medical history of patients with an acute coronary syndrome (ACS). Discrepancies between the medical history documented by a health professional and the patient's own report may therefore have important health consequences. METHODS: Medical histories of 117 patients with an ACS were documented. A questionnaire assessing the patient's health history was then completed by 62 eligible patients. Information about 13 health conditions with relevance to ACS management was obtained from the questionnaire and the medical record. Concordance between these two sources and reasons for discordance were identified. RESULTS: There was significant variation in agreement, from very poor in angina (kappa < 0) to almost perfect in diabetes (kappa = 0.94). Agreement was substantial in cerebrovascular accident (kappa = 0.76) and hypertension (kappa = 0.73); moderate in cocaine use (kappa = 0.54), smoking (kappa = 0.46), kidney disease (kappa = 0.52) and congestive heart failure (kappa = 0.54); and fair in arrhythmia (kappa = 0.37), myocardial infarction (kappa = 0.31), other cardiovascular diseases (kappa = 0.37) and bronchitis/pneumonia (kappa = 0.31). The odds of agreement was 42% higher among individuals with at least some college education (OR = 1.42; 95% CI, 1.00 - 2.01, p = 0.053). Listing of a condition in medical record but not in the questionnaire was a common cause of discordance. CONCLUSION: Discrepancies in aspects of the medical history may have important effects on the care of ACS patients. Future research focused on identifying the most effective and efficient means to obtain accurate health information may improve ACS patient care quality and safety. PMID- 22448756 TI - Effect of nanochannel dimension on the transport of water molecules. AB - From the perspectives of biological applications and material sciences, it is essential to understand the transport properties of water molecules through nanochannels. Although considerable effort and progress has been made in recent years, a systematic understanding of the effect of nanochannel dimension is still lacking. In this paper, we use molecular dynamics (MD) simulations to study the transport of water molecules through carbon nanotubes (CNTs) with various dimensions under pressure differences. We find an exponential decay describing the relation of the water flow and CNT lengths (L) for different pressures. The average translocation time of individual water molecules yields to a power law relation with L. We also exploit these results by comparing with the single-file transport, where some interesting relations were figured. Meanwhile, for a given CNT length, the water flow vs CNT diameters (R) can be depicted by a power law, which is found to be relevant to the water occupancy inside the nanochannel. In addition, we compare our MD results with predictions from the no-slip Hagen Poisseuille (HP) relation. The dependence of the enhancement of the simulated water flux over the HP prediction on the CNT length and diameter supports previous MD and experimental studies. Actually, the effect of nanotube dimension is not only originated from the motion of water molecules inside the CNT but also related to thermal fluctuations in the bulk water outside the CNT. These results enrich our knowledge about the channel size effect on the water transportation, which should have deep implications for the design of nanofluidic devices. PMID- 22448757 TI - Comparative structural effects of HIV-1 Gag and nucleocapsid proteins in binding to and unwinding of the viral RNA packaging signal. AB - The major RNA binding region of the HIV-1 Gag polyprotein is the nucleocapsid (NC) domain, which is responsible for the specific capture of the genomic RNA genome during viral assembly. The Gag polyprotein has other RNA chaperone functions, which are mirrored by the isolated NC protein after physiological cleavage from Gag. Gag, however, is suggested to have superior nucleic acid chaperone activity. Here we investigate the interaction of Gag and NC with the core RNA structure of the HIV-1 packaging signal (Psi), using 2-aminopurine substitution to create a series of modified RNAs based on the Psi helix loop structure. The effects of 2-aminopurine substitution on the physical and structural properties of the viral Psi were characterized. The fluorescence properties of the 2-aminopurine substitutions showed features consistent with the native GNAR tetraloop. Dissociation constants (K(d)) of the two viral proteins, measured by fluorescence polarization (FP), were similar, and both NC and Gag affected the 2-aminopurine fluorescence of bases close to the loop binding region in a similar fashion. However, the influence of Gag on the fluorescence of the 2 aminopurine nucleotides at the base of the helix implied a much more potent helix destabilizing action on the RNA stem loop (SL) versus that seen with NC. This was further supported when the viral Psi SL was tagged with a 5' fluorophore and 3' quencher. In the absence of any viral protein, minimal fluorescence was detected; addition of NC yielded a slight increase in fluorescence, while addition of the Gag protein yielded a large change in fluorescence, further suggesting that, compared to NC, the Gag protein has a greater propensity to affect RNA structure and that Psi helix unwinding may be an intrinsic step in RNA encapsidation. PMID- 22448758 TI - Intracranial hypertension with polyradiculopathy--early CSF diversion to optimize neurological recovery. AB - Cerebral venous sinus thrombosis (CVST) and idiopathic intracranial hypertension (IIH) are common considerations in young patients presenting with isolated intracranial hypertension. We report two patients with progressive visual failure and polyradiculopathy with areflexic quadriparesis, secondary to raised intracranial pressure (ICP). Both underwent cerebrospinal fluid diversion with complete recovery. Such a fulminant presentation of raised ICP with an excellent outcome has rarely been reported in the literature. PMID- 22448759 TI - Single-lead percutaneous peripheral nerve stimulation for the treatment of hemiplegic shoulder pain: a case series. AB - OBJECTIVE: Previous studies demonstrated the efficacy of Intramuscular Nerve (IMN) therapy with a 4-lead percutaneous, peripheral nerve stimulation (PNS) system in reducing hemiplegic shoulder pain (HSP). This case series investigates the feasibility of a less complex, single-lead approach in reducing HSP. METHODS: Eight participants received one percutaneous intramuscular lead in the hemiparetic deltoid muscle and were then treated 6 hours/day for 3 weeks. The primary outcome measure was the Brief Pain Inventory (Short-Form) Question 3 (BPI3), which queries worst pain in the last week on a 0 to 10 numeric rating scale. Secondary outcomes included pain interference (BPI9) and Medical Outcomes Study Short-Form 36 (SF-36v2). Primary and secondary outcomes were assessed at the end of treatment (EOT) and 1 and 4 weeks after the EOT. RESULTS: All participants tolerated the treatment well with 96% compliance. All leads remained infection-free and were removed intact at the EOT. On average, participants exhibited 70% reduction in BPI3 at the EOT and 61% reduction at 4 weeks after the EOT. All participants satisfied the success criterion of at least a 2-point reduction in BPI3 at the EOT. Longitudinal analysis revealed significant treatment effect for BPI3 (F = 14.0, P < 0.001), BPI9 (F = 5.9, P < 0.01), and the bodily pain domain of SF-36v2 (F = 12.8, P < 0.001). CONCLUSION: This case series demonstrates the feasibility of a single-lead, 3-week IMN therapy for the treatment of chronic HSP. Additional studies are needed to further demonstrate safety, efficacy, and long-term benefit, define optimal prescriptive parameters and dose, and expand clinical indications. PMID- 22448760 TI - Peri-orbital foreign body: a case report. AB - INTRODUCTION: Foreign bodies inside the orbital cavity are rare. They can cause more or less serious complications, depending on their nature and size. CASE PRESENTATION: We report a case of a work-related accident involving a peri orbital foreign body. The patient was a 50-year-old Caucasian man whose face was injured on the right side while he was working with an agricultural machine. On admission, he was fully conscious and did not have any neurological deficits. He had no loss of vision or ocular motility, but had a laceration of the lateral side of his right upper eyelid. A computed tomographic scan revealed a 6-cm-long bended metal object lodged in the lateral bulbar space of the right orbit. The patient recovered well after surgery and a course of antibiotic therapy. CONCLUSION: The original aspects of this case are the singularity of the foreign body and its relative harmlessness in spite of its large size. PMID- 22448761 TI - Streptococcus cristatus ArcA interferes with Porphyromonas gingivalis pathogenicity in mice. AB - BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis has been implicated as one of the major pathogens in chronic periodontitis, an infectious disease affecting the majority of the adult population. We have previously demonstrated that a surface protein, arginine deiminase (ArcA), of Streptococcus cristatus represses production of P. gingivalis long fimbriae and interrupts the formation of P. gingivalis biofilms in vitro. Our in vivo studies have also shown that the distribution of P. gingivalis and S. cristatus in human subgingival plaque is negatively correlated. The objective of this study was to determine if S. cristatus ArcA inhibits P. gingivalis colonization and attenuates its subsequent pathogenesis in alveolar bone loss in the murine oral cavity. MATERIAL AND METHODS: A wild-type strain of S. cristatus (CC5A) and its arcA knockout mutant (ArcAE) were used as initial colonizers in the oral cavity of BALB/cByJ mice. Colonization of P. gingivalis on the existing S. cristatus biofilms was assessed by quantitative PCR, and P. gingivalis-induced alveolar bone loss was measured 6 wk after P. gingivalis infection. RESULTS: The presence of S. cristatus CC5A, but not its arcA mutant, attenuated P. gingivalis colonization in the murine oral cavity. In addition, P. gingivalis-induced alveolar bone loss was significantly lower in mice initially infected with S. cristatus CC5A than in those infected with the arcA mutant. CONCLUSION: This study provides direct evidence that S. cristatus ArcA has an inhibitory effect on P. gingivalis colonization, which may in turn attenuate the pathogenicity of P. gingivalis. PMID- 22448762 TI - Correlates of alcohol-related regretted sex among college students. AB - The prevalence of alcohol-related regretted sex in college students warrants a better understanding of the characteristics of students who report such experiences. Therefore, the present study examined correlates of regretted sexual experiences involving alcohol use among 2 specific high-risk college student samples: students mandated to alcohol intervention (n = 522) and volunteer 1st year students transitioning to college (n = 481). Results indicated that alcohol related regretted sex occurred at similar rates in mandated and volunteer students, with approximately 25% of the students reporting at least 1 occurrence in the past month. Women were more likely to report alcohol-related regretted sex compared with men. The belief that alcohol use would result in "liquid courage" was associated with alcohol-related regretted sex among college students, even after accounting for greater alcohol use and problem alcohol use behaviors. These findings have significant implications for intervention efforts and future research. PMID- 22448763 TI - Hazardous alcohol use and intimate partner violence in the military: understanding protective factors. AB - Hazardous alcohol use is a well-established risk factor for men's intimate partner violence (IPV), with dozens of studies demonstrating the association. The current study extends understanding of the hazardous alcohol use-IPV link by examining what factors moderate this association in a more systematic and broader way that has been done in past studies. Individual, family, workplace, community, and developmental factors were tested as moderators of the hazardous alcohol use and IPV link in a large, representative sample of active duty service members (the 2006 Community Assessment), and the results were tested for replicability in a hold-out sample. Two family variables (relationship satisfaction and parent child satisfaction), 1 community variable (community safety), and 3 developmental variables (years in the military, marital length, and family income/pay grade) cross-validated as significant moderators of the association between men's hazardous alcohol use and IPV. Across the significant moderators, the association between hazardous alcohol use and men's IPV was weakened by maturation/development, improved community safety, and better relationship functioning. No individual or workplace variables were significant moderators for men, and there were no significant moderators found for women. The results support the importance of a developmental and relational perspective to understanding the hazardous alcohol use-IPV link, rather than solely an individual coping perspective. PMID- 22448764 TI - Efficient RNA interference in patients' acute lymphoblastic leukemia cells amplified as xenografts in mice. AB - BACKGROUND: Signaling studies in cell lines are hampered by non-physiological alterations obtained in vitro. Physiologic primary tumor cells from patients with leukemia require passaging through immune-compromised mice for amplification. The aim was to enable molecular work in patients' ALL cells by establishing siRNA transfection into cells amplified in mice. RESULTS: We established delivering siRNA into these cells without affecting cell viability. Knockdown of single or multiple genes reduced constitutive or induced protein expression accompanied by marked signaling alterations. CONCLUSION: Our novel technique allows using patient-derived tumor cells instead of cell lines for signaling studies in leukemia. PMID- 22448765 TI - Conscientiousness and obsessive-compulsive personality disorder. AB - A dimensional perspective on personality disorder hypothesizes that the current diagnostic categories represent maladaptive variants of general personality traits. However, a fundamental foundation of this viewpoint is that dimensional models can adequately account for the pathology currently described by these categories. While most of the personality disorders have well established links to dimensional models that buttress this hypothesis, obsessive-compulsive personality disorder (OCPD) has obtained only inconsistent support. The current study administered multiple measures of 1) conscientiousness-related personality traits, 2) DSM-IV OCPD, and 3) specific components of OCPD (e.g., compulsivity and perfectionism) to a sample of 536 undergraduates who were oversampled for elevated OCPD scores. Six existing measures of conscientiousness-related personality traits converged strongly with each other supporting their assessment of a common trait. These measures of conscientiousness correlated highly with scales assessing specific components of OCPD, but obtained variable relationships with measures of DSM-IV OCPD. More specifically, there were differences within the conscientiousness instruments such that those designed to assess general personality functioning had small to medium relationships with OCPD, but those assessing more maladaptive variants obtained large effect sizes. These findings support the view that OCPD does represent a maladaptive variant of normal-range conscientiousness. PMID- 22448766 TI - An examination of the structure of self-report psychopathy measures and their relations with general traits and externalizing behaviors. AB - Self-report assessment of psychopathy is plagued by inconsistencies among the relations of the various psychopathy factors. We examined the factor structure of 3 prominent self-report measures of psychopathy-the Self-Report Psychopathy Scale III (SRP-III; Williams, Paulhus, & Hare, 2007), the Levenson Self-Report Psychopathy Scale (LSRP; Levenson, Kiehl, & Fitzpatrick, 1995), and the Psychopathic Personality Inventory-R (PPI-R; Lilienfeld & Widows, 2005). A coherent 4-factor structure resulted from conducting an exploratory factor analysis (EFA) of the psychopathy subscales along with the domains from the five factor model. Two of these factors were consistent with traditional conceptualizations of a 2-factor structure of psychopathy (i.e., Factor 1, which loaded negatively with Agreeableness; Factor 2, which loaded negatively with Conscientiousness), while 2 additional factors emerged, 1 of which emphasized low Neuroticism and 1 of which emphasized traits related to novelty/reward-seeking and dominance-related personality traits (high Extraversion). We also investigated the relations of these factors with a variety of externalizing behaviors (EB). The psychopathy scales indicative of interpersonal antagonism (i.e., Factor 1) were most consistently and strongly related to EB. Our findings are discussed in terms of the importance of a trait-based perspective in the assessment of psychopathy. PMID- 22448767 TI - Exploring associations between borderline personality disorder, crack/cocaine dependence, gender, and risky sexual behavior among substance-dependent inpatients. AB - Engagement in self-destructive and impulsive behaviors is considered to be a cardinal symptom of borderline personality disorder (BPD), and many of the behaviors enumerated in this criterion have been the focus of extensive empirical research. However, very few studies have examined risky sexual behavior (RSB) in particular in BPD. Given evidence that BPD patients with a co-occurring substance use disorder (SUD) may be at increased risk for RSB relative to BPD patients without a SUD, the present study examined the association between BPD and past year engagement in RSB (particularly, penetrative sex and nonuse of condoms with casual and commercial partners) within a mixed-gender sample of 94 SUD patients in residential treatment, as well as the moderating role of gender in this association. Given past findings of an association between crack/cocaine use and RSB, we also examined the moderating role of lifetime crack/cocaine dependence on the relationship between BPD and RSB. Results demonstrated a significant main effect of BPD on past-year penetrative sex with casual and commercial partners. Significant 3-way interactions between BPD status, lifetime crack/cocaine dependence, and gender were also found for past-year penetrative sex with casual and commercial partners, as well as the likelihood of not using a condom during sex with a casual partner. Post hoc analyses indicated that women with co occurring BPD and lifetime crack/cocaine dependence were at greatest risk for RSB. Findings replicate extant findings pertaining to the association between BPD and RSB and extend research by identifying relevant factors that may moderate this association. PMID- 22448768 TI - Affective instability, family history of mood disorders, and neurodevelopmental disturbance. AB - The association between affective instability and both family history of mood disorders and signs of neurodevelopmental disturbance was examined in a sample of 303 adults. Affective instability was measured using the borderline personality disorder "affective instability due to a marked reactivity of mood" diagnostic criterion as assessed dimensionally using the Personality Disorder Interview--IV. Participants were interviewed concerning family history of mood disorders, with family history coded using the Family History Research Diagnostic Criteria. Minor physical anomalies, inconsistent hand use, and dermatoglyphic asymmetries were used to index neurodevelopmental disturbance. Affective instability was associated with elevated rates of family history of mood disorders, particularly among individuals who exhibited inconsistent hand use and greater minor physical anomalies. These associations could not be accounted for by shared variance with age, gender, negative affect, or personal history of mood disorders. PMID- 22448769 TI - Functional imaging of emotion reactivity in opiate-dependent borderline personality disorder. AB - Opiate dependence (OD) and borderline personality disorder (BPD), separately and together, are significant public health problems with poor treatment outcomes. BPD is associated with difficulties in emotion regulation, and brain-imaging studies in BPD individuals indicate differential activation in prefrontal cingulate cortices and their interactions with limbic regions. Likewise, a similar network is implicated in drug cue responsivity in substance abusers. The present, preliminary study used functional MRI to examine activation of this network in comorbid OD/BPD participants when engaged in an "oddball" task that required attention to a target in the context of emotionally negative distractors. Twelve male OD/BPD participants and 12 male healthy controls participated. All OD/BPD participants were taking the opiate replacement medication Suboxone, and a subset of participants was positive for substances of abuse on scan day. Relative to controls, OD/BPD participants demonstrated reduced activation to negative stimuli in the amygdala and anterior cingulate. Unlike previous studies that demonstrated hyperresponsivity in neural regions associated with affective processing in individuals with BPD versus healthy controls, comorbid OD/BPD participants were hyporesponsive to emotional cues. Future studies that also include BPD-only and OD-only groups are necessary to help clarify the individual and potentially synergistic effects of these two conditions. PMID- 22448770 TI - Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors. AB - The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 MUM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure antidengue activity relationship studies. Among the series of 2,4 diaminoquinazoline derivative probed, 4o was observed to display both the highest antiviral potency (EC(50) = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile. PMID- 22448771 TI - Comparison of synthetic oviductal fluid and G1/G2 medium under low-1 oxygen atmosphere on embryo production and pregnancy rates in Nelore (Bos indicus) cattle. AB - In this work, we evaluated whether embryo development and pregnancy rates would be affected by culturing bovine Bos indicus embryos in Synthetic Oviductal Fluid with amino acids (SOFaa) or G1/G2 sequential medium under a low-oxygen atmosphere. Using Ovum Pick Up, we obtained 1,538 oocytes, divided into G1/G2 (n = 783) and SOFaa (n = 755). No difference was observed for blastocyst development among the groups (27.8% +/- 14.6 and 34.9% +/- 20.0 for G1/G2 and SOFaa respectively, p > 0.05). Transferring the embryos (n = 450) from both groups to recipients resulted in similar pregnancy rates for the G1/G2 (38.4% n = 78/203) compared to the SOFaa (39.7% n = 98/247). Our findings confirm that Bos indicus embryos cultured in SOFaa and G1/G2 under low-oxygen atmosphere have similar in vitro (blastocyst rate) and in vivo (pregnancy rate) developmental capacity. However, embryos cultured in G1/G2 medium have higher cleavage than those cultured in SOFaa medium. PMID- 22448772 TI - Perceptions of hypertension treatment among patients with and without diabetes. AB - BACKGROUND: Despite the availability of a wide selection of effective antihypertensive treatments and the existence of clear treatment guidelines, many patients with hypertension do not have controlled blood pressure. We conducted a qualitative study to explore beliefs and perceptions regarding hypertension and gain an understanding of barriers to treatment among patients with and without diabetes. METHODS: Ten focus groups were held for patients with hypertension in three age ranges, with and without diabetes. The topic guides for the groups were: What will determine your future health status? What do you understand by "raised blood pressure"? How should one go about treating raised blood pressure? RESULTS: People with hypertension tend to see hypertension not as a disease but as a risk factor for myocardial infarction or stroke. They do not view it as a continuous, degenerative process of damage to the vascular system, but rather as a binary risk process, within which you can either be a winner (not become ill) or a loser. This makes non-adherence to treatment a gamble with a potential positive outcome. Patients with diabetes are more likely to accept hypertension as a chronic illness with minor impact on their routine, and less important than their diabetes. Most participants overestimated the effect of stress as a causative factor believing that a reduction in levels of stress is the most important treatment modality. Many believe they "know their bodies" and are able to control their blood pressure. Patients without diabetes were most likely to adopt a treatment which is a compromise between their physician's suggestions and their own understanding of hypertension. CONCLUSION: Patient denial and non adherence to hypertension treatment is a prevalent phenomenon reflecting a conscious choice made by the patient, based on his knowledge and perceptions regarding the medical condition and its treatment. There is a need to change perception of hypertension from a gamble to a disease process. Changing the message from the existing one of "silent killer" to one that depicts hypertension as a manageable disease process may have the potential to significantly increase adherence rates. PMID- 22448773 TI - A quantitative approach to hepatic clearance prediction of metabolism by aldehyde oxidase using custom pooled hepatocytes. AB - We describe the usability of human pooled hepatocytes for non-CYP metabolism evaluation and an in vivo-in vitro correlation analysis for aldehyde oxidase (AO) substrate compounds using pooled hepatocytes. By comparing intrinsic clearance values of 18 compounds primarily metabolized by AO, UDP-glucuronosyltransferase, carbonyl/aldo-keto reductase, flavin-containing monooxygenase, and monoamineoxidase in individual hepatocytes and pooled hepatocytes from the same individual donors, intrinsic clearance in the pooled hepatocytes was +/- 30% of the average clearance value in individuals for 15 of 18 compounds, suggesting that pooled hepatocytes maintained the average activity of the individual hepatocytes. Although the results of an in vivo-in vitro correlation analysis for AO substrate compounds showed a trend toward under-prediction, the underestimation ratios for all AO substrates were nevertheless comparable (7.2- to 14.9-fold), suggesting that hepatic clearance prediction for these compounds can be quantified using empirical scaling. These observations enabled us to obtain specific pooled hepatocytes that showed the expected non-CYP enzyme activities by pre-characterization and to quantify hepatic clearance prediction for AO compounds using an empirical scaling factor. PMID- 22448774 TI - Reactions of benzene oxide, a reactive metabolite of benzene, with model nucleophiles and DNA. AB - 1. Reactivity of benzene oxide (BO), a reactive metabolite of benzene, was studied in model reactions with biologically relevant S- and N-nucleophiles by LC ESI-MS. 2. Reaction with N-acetylcysteine (NAC) in aqueous buffer solutions gave N-acetyl-S-(6-hydroxycyclohexa-2,4-dien-1-yl)cysteine (pre-phenylmercapturic acid, PPhMA), which was easily dehydrated in acidic solutions to phenylmercapturic acid (PhMA). The yield of PPhMA + PhMA increased exponentially with pH up to 11% in the pH range from 5.5 to 11.4. 3. Primary 6-hydroxycyclohexa 2,4-dien-1-yl (HC) adducts were detected also in reactions of purine nucleosides and nucleotides under physiological conditions. After a vigorous acidic hydrolysis, all HC adducts were converted to corresponding phenyl purines, which were identified as 7-phenylguanine (7-PhG), 3-phenyladenine (3-PhA) and N(6) phenyladenine (6-PhA). The yield of 7-PhG amounted to 14 +/- 5 and 16 +/- 7 ppm for 2'-deoxyguanosine and 2'-deoxyguanosine-5'-monophosphate, respectively, that of 6-PhA was 500 +/- 70 and 455 +/- 75 ppm with 2'-deoxyadenosine and 2' deoxyadenosine-5'-phosphate, respectively, with only traces of 3-PhA. 4. Reactions with the DNA followed by acidic hydrolysis yielded 26 +/- 11 ppm (mean +/- SD; n = 9) of 7-PhG as the sole adduct detected. 5. In contrast to the reactions with S-nucleophiles, the reactivity of BO with nucleophilic sites in the DNA is very low and can therefore hardly account for a significant DNA damage caused by benzene. PMID- 22448775 TI - Reduction of renal uptake of 111In-DOTA-labeled and A700-labeled RAFT-RGD during integrin alphavbeta3 targeting using single photon emission computed tomography and optical imaging. AB - Integrin alpha(v)beta(3) expression is upregulated during tumor growth and invasion in newly formed endothelial cells in tumor neovasculature and in some tumor cells. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin alpha(v)beta(3) in vitro and in vivo. When labeled with indium-111, the RAFT-RGD is partially reabsorbed and trapped in the kidneys, limiting its use for further internal targeted radiotherapy and imaging investigations. We studied the effect of Gelofusine on RAFT-RGD renal retention in tumor-bearing mice. Mice were imaged using single photon emission computed tomography and optical imaging 1 and 24 h following tracer injection. Distribution of RAFT-RGD was further investigated by tissue removal and direct counting of the tracer. Kidney sections were analyzed by confocal microscopy. Gelofusine significantly induced a >50% reduction of the renal reabsorption of (111)In-DOTA-RAFT-RGD and A700-RAFT-RGD, without affecting tumor uptake. Injection of Gelofusine significantly reduced the renal retention of labeled RAFT-RGD, while increasing the tumor over healthy tissue ratio. These results will lead to the development of future therapeutic approaches. PMID- 22448776 TI - Regional anesthesia in children: the future. AB - Pediatric regional anesthesia continues to evolve. Education and attention to anatomical detail remain key elements to successful outcomes. New techniques, some adapted from adult practice, provide analgesia for pediatric surgical procedures such cleft palate or congenital hip dysplasia. Despite technological advances a number of controversial issues remain unresolved. PMID- 22448777 TI - Plagiorchis elegans (Trematoda) induces immune response in an incompatible snail host Biomphalaria glabrata (Pulmonata: Planorbidae). AB - Plagiorchis elegans has been shown to decrease the fecundity and survivorship of the incompatible snail host Biomphalaria glabrata. Furthermore, a prior infection with P. elegans was shown to render the snails resistant to the compatible parasite Schistosoma mansoni. Here, we test the hypothesis that infection with P. elegans stimulates the immune system of B. glabrata. Our findings indicate that infection by P. elegans significantly increased the number of free hemocytes in the hemolymph of B. glabrata by an average of ~60%. Furthermore, this immuno stimulated state lasted from the first day post-infection (PI) to some time between 7 and 21 days PI. This is one of the few reported examples of a parasite stimulating the immune response of an incompatible host. PMID- 22448778 TI - Pronounced effects of anisotropy on plasmonic properties of nanorings fabricated by electron beam lithography. AB - Gold nanoring dimers were fabricated via EBL with dimensions of 127.6 +/- 2.5 and 57.8 +/- 2.3 nm for the outer and inner diameters, respectively, with interparticle separations ranging from 17.8 +/- 3.4 to 239.2 +/- 3.7 nm. The coupling between the inner and outer surfaces of a single nanoring renders it very sensitive to any anisotropy. We found that anisotropy in the particle geometry and anisotropy introduced by the substrate combine to create very unique spectral features in this system. PMID- 22448779 TI - Formation of self-assembled monolayers of pi-conjugated molecules on TiO2 surfaces by thermal grafting of aryl and benzyl halides. AB - We demonstrate the formation of molecular monolayers of pi-conjugated organic molecules on nanocrystalline TiO(2) surfaces through the thermal grafting of benzyl and aryl halides. X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy were used to characterize the reactivity of aryl and benzyl chlorides, bromides, and iodides with TiO(2) surfaces, along with controls consisting of nonhalogenated compounds. Our results show that benzyl and aryl halides follow a similar reactivity trend (I > Br > Cl >> H). While the ability to graft benzyl halides is consistent with the well-known Williamson ether synthesis, the grafting of aryl halides has no similar precedent. The unique reactivity of the TiO(2) surface is demonstrated using nuclear magnetic resonance spectroscopy to compare the surface reactions with the liquid-phase interactions of benzyl and aryl iodides with tert-butanol and -butoxide anion. While the aryl iodides show no detectable reactivity with a tert-butanol/tert-butoxide mixture, they react with TiO(2) within 2 h at 50 degrees C. Atomic force microscopy studies show that grafting of 4-iodo-1-(trifluoromethyl)benzene onto the rutile TiO(2)(110) surface leads to a very uniform, homogeneous molecular layer with a thickness of ~0.45 nm, demonstrating formation of a self-terminating molecular monolayer. Thermal grafting of aryl iodides provides a facile route to link pi conjugated molecules to TiO(2) surfaces with the shortest possible linkage between the conjugated electron system and the TiO(2). PMID- 22448780 TI - Induction of Cr(VI) reduction activity in an Anoxybacillus strain under heat stress: a biochemical and proteomic study. AB - A bacterial strain, designated as TSB-6, was isolated from the sediments of a Tantloi (India) hot spring at 65 degrees C. The strain showed 98% 16S rRNA gene sequence similarity with Anoxybacillus kualawohkensis strain KW12 and was found to grow optimally at 37 degrees C. However, growing cells, cell suspensions, and cell-free extracts from 65 degrees C cultures showed higher Cr(VI) reduction activities when assayed at either 37 or 65 degrees C than those obtained from 37 degrees C cultures. On fractionation of extracts from cells grown at 65 degrees C, the chromate reductase activity assayed at 65 degrees C was found mostly in the soluble fraction. When log-phase cells growing at 37 degrees C were shifted to 65 degrees C, the stressed cells produced larger quantities of reactive oxygen species. Consequently, growth of the cells was retarded, but specific Cr(VI) reduction activity increased. 2D gel electrophoresis followed by MALDI-TOF MS/MS identified the proteins whose expression level changed as a result of heat stress. The upregulated set included proteins involved in cellular metabolism of sugar, nucleotide, amino acids, lipids and vitamins, oxidoreductase activity, and protein folding. The downregulated proteins are also involved in cellular metabolism, DNA binding, and environmental signal processing. PMID- 22448781 TI - Predicting the demand of physician workforce: an international model based on "crowd behaviors". AB - BACKGROUND: Appropriateness of physician workforce greatly influences the quality of healthcare. When facing the crisis of physician shortages, the correction of manpower always takes an extended time period, and both the public and health personnel suffer. To calculate an appropriate number of Physician Density (PD) for a specific country, this study was designed to create a PD prediction model, based on health-related data from many countries. METHODS: Twelve factors that could possibly impact physicians' demand were chosen, and data of these factors from 130 countries (by reviewing 195) were extracted. Multiple stepwise-linear regression was used to derive the PD prediction model, and a split-sample cross validation procedure was performed to evaluate the generalizability of the results. RESULTS: Using data from 130 countries, with the consideration of the correlation between variables, and preventing multi-collinearity, seven out of the 12 predictor variables were selected for entry into the stepwise regression procedure. The final model was: PD = (5.014 - 0.128 * proportion under age 15 years + 0.034 * life expectancy)2, with R2 of 80.4%. Using the prediction equation, 70 countries had PDs with "negative discrepancy", while 58 had PDs with "positive discrepancy". CONCLUSION: This study provided a regression-based PD model to calculate a "norm" number of PD for a specific country. A large PD discrepancy in a country indicates the needs to examine physician's workloads and their well-being, the effectiveness/efficiency of medical care, the promotion of population health and the team resource management. PMID- 22448782 TI - Synthesis of FeS and FeSe nanoparticles from a single source precursor: a study of their photocatalytic activity, peroxidase-like behavior, and electrochemical sensing of H2O2. AB - Nanocrystalline FeS and FeSe compounds were prepared by solvothermal decomposition of a precursor complex [Fe(3)(MU(3)-O)(MU(2) O(2)CCH(2)Cl)(6)(H(2)O)(3)]NO(3).H(2)O in the presence of thiourea and sodium selenite, respectively. The as-obtained products were characterized by X-ray diffraction analysis (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and UV-vis spectroscopic techniques. Structural analyses revealed that the FeS and FeSe nanoparticles (NPs) are composed of needle-like and spherical particles, respectively. The FeS and FeSe NPs showed photocatalytic activity for the decomposition of rose bengal (RB) and methylene blue (MB) dyes under white light illumination. They also showed good catalytic activity toward oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H(2)O(2) and followed Michaelis-Menten kinetics. In addition, both FeS and FeSe NPs exhibited electrocatalytic activity toward reduction of hydrogen peroxide, which on immobilization on glassy carbon (GC) electrodes perform as amperometric sensors for detection of H(2)O(2). At pH 7.0, the FeS/GC showed a linear range for detection of H(2)O(2) from 5 to 140 MUM, while for FeSe/GC the range was 5 to 100 MUM. PMID- 22448783 TI - The clinical pharmacokinetics of Lu AA21004 and its major metabolite in healthy young volunteers. AB - Lu AA21004 is a novel multimodal antidepressant that is currently in phase 3 development. The objective of this report was to detail the clinical pharmacokinetics of Lu AA21004 and its major but inactive metabolite Lu AA34443 (3-methyl-4-(2-piperazine-1-yl-phenylsulfanyl)-benzoic acid) in healthy men and women aged between 18 and 53 years. Data from two single-dose and one multiple dose study were combined; the total number of volunteers was 97 (64 men, 33 women). Blood and urine samples were collected after p.o. and i.v. administrations to determine the content of Lu AA21004 and Lu AA34443 performed with a validated method. Standard pharmacokinetic parameters were estimated with non-compartmental analysis. The absolute bioavailability was 75%. After oral administration, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution resulting in late t(max) values and a mean elimination half-life of 57 hr. The exposure of Lu AA21004 showed a linear relationship with dose in the dose ranges studied (up to 75-mg single dosing and 60-mg multiple dosing). After weight correction, no differences in exposure for Lu AA21004 and Lu AA34443 were observed between men and women. The renal clearance of Lu AA21004 was negligible. The major metabolite Lu AA34443 had a half-life similar to that of Lu AA21004 but a lower accumulation ratio at steady state, indicating formation-rate-limited elimination. In conclusion, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution. PMID- 22448784 TI - Stereoselective synthesis of the C5-C18 fragment of halichomycin. AB - An efficient and convergent synthesis of the C(5)-C(18) fragment of halichomycin is reported. Butanolide fragment 6 was readily prepared stereoselectively from (R)-Roche ester through catalyst control; dienylic bromide domain 7 was synthesized from (S)-serine by substrate control. C(5)-C(18) fragment 2 was rapidly assembled through a stereoselective alkylation of the butanolide with the dienylic bromide, followed by functional group transformations. PMID- 22448785 TI - alphaC helix as a switch in the conformational transition of Src/CDK-like kinase domains. AB - One mechanism of regulating the catalytic activity of protein kinases is through conformational transitions. Despite great diversity in the structural changes involved in the transitions, a certain set of changes within the kinase domain (KD) has been observed for many kinases including Src and CDK2. We investigated this conformational transition computationally to identify the topological features that are energetically critical to the transition. Results from both molecular dynamics sampling and transition path optimization highlight the displacement of the alphaC helix as the major energy barrier, mediating the switch of the KD between the active and down-regulated states. The critical role of the alphaC helix is noteworthy by providing a rationale for a number of activation and deactivation mechanisms known to occur in cells. We find that kinases with the alphaC helix displacement exist throughout the kinome, suggesting that this feature may have emerged early in evolution. PMID- 22448786 TI - The interferon family as biomarkers of disease: renaissance of the innate immune system. PMID- 22448787 TI - Type I interferons as biomarkers in autoimmune diseases. PMID- 22448788 TI - The interferon signaling pathway genes as biomarkers of hepatitis C virus disease progression and response to treatment. AB - Hepatitis C virus is an ever-increasing worldwide health problem with over 350,000 individuals succumbing to hepatitis C virus-related liver diseases each year. The ability to determine the outcome of an acute-phase illness may be useful in terms of implementing treatment strategies; however, to date, the predictive associations in the literature have centered around candidate gene analysis. Much greater advancements have been made in describing biomarkers from the activation of the host innate immune response, such as the interferon system, for prediction of treatment outcome in chronic hepatitis C with the advent of genome-wide association studies. Recent times has seen a major breakthrough in the field with the description of the IL28B genotype as an independent association factor for pegylated IFN-alpha2b/ribavirin treatment response. The ability to couple this with other easily measured biomarkers such as the interferon-stimulated gene CXCL10, serum concentration may make this predictive marker set very useful in the clinical setting. PMID- 22448789 TI - IFN-lambda and IgE-mediated allergic disease: a potential future role? AB - Reduced early microbial exposure has become a leading candidate to explain the rise in allergic disease, and research has focused on studying the interaction between the developing immune system and the microbial environment. However, despite intense interest, the pathways that lead to dysregulation of the immune system in allergic disease are still poorly understood. The newly described type III IFN-lambda molecules were initially shown to exhibit antiviral activity, but these molecules are also likely to have an important role to play in the immune epithelial interface, given their immunomodulatory functions and restricted receptor expression to immune and epithelial cells. Previous studies on the role of IFN-lambda in allergic disease have been limited to allergic asthma. More recently, a genetic variation flanking IL28B encoding IFN-lambda3 has been associated with allergic disease. Here, we examine this family and suggest how IFN-lambda may be an important player in allergic disease. PMID- 22448790 TI - Interferons as biomarkers and effectors: lessons learned from animal models. AB - Interferons (IFNs) comprise type I, II and III families with multiple subtypes. Via transcription of IFN-stimulated genes (ISGs), IFNs can exert multiple biological effects on the cell. In infectious and chronic inflammatory diseases, the IFNs and their ISG sets can be potentially utilized as biomarkers of disease outcome. Animal models allow investigations into disease pathogenesis and gene knockout models have proved cause and effect relationships of molecules related to the IFN response. Sets of IFN subtypes and their ISG products provide immunological signature patterns for different viral and other diseases. In this article, we give an overview of IFNs in several virus infection models and autoimmune diseases of medical relevance. Lessons learned from animal models inform us of IFN system parameters as indicators of disease outcome and whether clinical research is warranted. Moreover, validated IFN biomarkers for prognosis enhance our understanding of therapeutic and vaccine development. PMID- 22448791 TI - MIGRAs: are they the new IGRAs? Development of monokine-amplified IFN-gamma release assays. AB - IFN-gamma release by antigen-specific T cells can be used to track immune responses to infections and vaccines. In recent years, there have been substantial advances in the techniques available to measure IFN-gamma release and a generation of such assays are now available for clinical use, as well as in a research setting. Interferon release leads to subsequent release of interferon responsive chemokines such as MIG and IP-10, thus amplifying the original signal. A number of investigators have assessed whether measurement of these chemokines might provide a sensitive platform for detection of infection and antigen specific T-cell responses. In this article, we assess the potential of these new approaches. We have termed the new antigen-specific T-cell assays monokine amplified IFN-gamma release assays (MIGRAs). Overall, it seems likely that improvements in the detection threshold could be made by analysis of antigen triggered chemokines and potentially of other molecules in the future, although whether MIGRAs will provide additional clinical utility still remains to be determined. PMID- 22448792 TI - Proteomic biomarkers for psychiatric disorders: a progress update. PMID- 22448794 TI - Signaling molecule c-Met is a biomarker for favorable prognostic in Hodgkin lymphoma. PMID- 22448795 TI - An aromatase polymorphism (g.132810C>T) predicts risk of bisphosphonate-related osteonecrosis of the jaw. AB - BACKGROUND: Bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) is an unpredictable, debilitating adverse effect. Recently, genetic polymorphisms have arisen as promising tools to identify patients with a higher risk of drug-related adverse events. AIM: We aimed to examine the association between the aromatase polymorphism g.132810C>T, and the estrogen receptor polymorphisms g.156705T>C and g.156751A>G, and the risk of BP-related ONJ. METHODS: Eighty-three subjects were included in the study. A clinical and radiological examination was conducted on oncologic subjects treated with zoledronic acid. Subjects with histologically confirmed ONJ were included in the test group (n = 30) whereas subjects with good oral health were included in control group (n = 53). Aromatase and estrogen receptor polymorphisms from blood samples were analyzed. RESULTS: The aromatase g.132810C>T polymorphism displayed an over-representation of the TT genotype in the test group (36.67 vs 16.98%; p < 0.05). There was no significant difference in either estrogen receptor polymorphism genotype frequency between the test and control groups. CONCLUSION: Our data suggest a role for the g.132810C>T polymorphism in predicting ONJ risk. These results can pave the way to the personalization of BP therapy, based on individual genotype. PMID- 22448796 TI - Efficacy and pharmacogenomic biomarkers in breast cancer. AB - In patients with breast cancer, a number of biomarkers, such as estrogen receptor, progesterone receptor and HER2, are part of routine work-up and used to guide endocrine, cytotoxic and HER2-targeted treatment. Interaction among these markers may also impact on treatment response and is being investigated. Multigene assays have reached varying levels of validation and clinical use as predictive biomarkers of cytotoxic therapy in specific clinical situations. A number of pharmacogenomic biomarkers based on germline polymorphisms have reached some degree of validation for predicting variation in treatment response and treatment-associated adverse effects. The challenge of validating biomarkers will be exacerbated as the cost of nucleic acid sequencing rapidly declines and more potential biomarkers emerge. New, carefully designed approaches will be needed to address this issue and realize the potential of biomarkers in breast cancer. PMID- 22448797 TI - Gilbert syndrome: the UGT1A1*28 promoter polymorphism as a biomarker of multifactorial diseases and drug metabolism. AB - Gilbert syndrome belongs to the group of the most common human metabolic disorders and is characterized by an elevated level of bilirubin in blood serum. A polymorphism of the 5' end of the UGT1A1 gene promoter, a homozygous insertion of TA pairs (genotype UGT1A1*28/*28), results in a decrease in bilirubin glucuronidation activity and therefore leads to an increase in the level of unconjugated bilirubin (hyperbilirubinemia). Genotyping the UGT1A1 promoter is an important step in the determination of the etiology of free hyperbilirubinemia of unknown origin. Molecular diagnosis enables avoiding invasive diagnostic procedures, such as liver biopsy, in establishing the appropriate diagnosis and prognosis, as well as in establishing the correct therapeutic procedures in a variety of diseases (e.g., chemotherapy or bone marrow transplantation). Moreover, the UGT1A1*28/*28 genotype has emerged as an important element in drug tolerance, as well as in multifactorial diseases, such as cancer. However, the role of this polymorphism is still not completely understood. In this review we have summarized current knowledge and attempted to propose directions for further research. PMID- 22448798 TI - Monitoring early response to taxane therapy in advanced breast cancer with circulating tumor cells and [(18)F] 3'-deoxy-3'-fluorothymidine PET: a pilot study. AB - AIM: Early markers of response to chemotherapy, measured by blood markers and imaging, may ultimately lead to tailored therapies that avoid cumulative toxicity. MATERIALS & METHODS: We performed a small pilot study to compare early changes in levels of circulatory tumor cells (CTCs) with changes in tumor proliferation, using metabolic imaging with [(18)F] 3'-deoxy-3'-fluorothymidine PET (FLT-PET) in women with advanced breast cancer, before and during docetaxel therapy. RESULTS: In those individuals in whom we could detect CTCs, a decrease in CTC count correlated with a decrease in FLT-PET signal, within 2 weeks. CONCLUSION: Combined, these two technologies are likely to provide a powerful, albeit expensive, tool to assess immediate responses to therapy. PMID- 22448800 TI - Leaf temperatures in glasshouses and open-top chambers. AB - Climate manipulation experiments are of key importance in identifying possible responses of plant communities and ecosystems to climate change. Experiments for warming the air under sunlit conditions are carried out in (partial) enclosures. These inevitably alter the energy balance inside, potentially altering tissue temperatures which affect metabolism and growth. Using an empirically validated energy balance model, we investigate effects of two widely used warming methods, climate-controlled glasshouses and passively warmed open-top chambers (OTCs), on leaf temperatures. The model applies standard energy balance formulas, supplemented with data on optical properties of glasshouse materials and wind conditions inside OTCs. Results show that the different radiation environment inside glasshouses did not produce large leaf temperature deviations compared with outside. Poor glasshouse design with significant radiation blockage by the structure or with insufficient ventilation did affect tissue temperatures more significantly. The drastic wind speed reduction inside OTCs approximately doubled the actual (canopy) warming compared with earlier reported increases in air temperature provided by this technique - an effect that was inflated if the plants' stomates closed. These results demonstrate that leaf temperatures were higher than previously considered in OTCs but not in climate-controlled glasshouses. PMID- 22448801 TI - Too upset to think: the interplay of borderline personality features, negative emotions, and social problem solving in the laboratory. AB - Borderline personality disorder (BPD) is associated with poor social problem solving and problems with emotion regulation. In this study, the social problem solving performance of undergraduates with high (n = 26), mid (n = 32), or low (n = 29) levels of BPD features was assessed with the Social Problem-Solving Inventory-Revised and using the means-ends problem-solving procedure before and after a social rejection stressor. The high-BP group, but not the low-BP group, showed a significant reduction in relevant solutions to social problems and more inappropriate solutions following the negative emotion induction. Increases in self-reported negative emotions during the emotion induction mediated the relationship between BP features and reductions in social problem-solving performance. In addition, the high-BP group demonstrated trait deficits in social problem solving on the Social Problem-Solving Inventory-Revised. These findings suggest that future research must examine social problem solving under differing emotional conditions, and that clinical interventions to improve social problem solving among persons with BP features should focus on responses to emotional contexts. PMID- 22448802 TI - The structure of personality disorders in individuals with posttraumatic stress disorder. AB - Research on the structure of personality disorders (PDs) has relied primarily on exploratory analyses to evaluate trait-based models of the factors underlying the covariation of these disorders. This study used confirmatory factor analysis to evaluate whether a model that included both PD traits and a general personality dysfunction factor would account for the comorbidity of the PDs better than a trait-only model. It also examined if the internalizing/externalizing model of psychopathology, developed previously through research on the structure of Axis I disorders, might similarly account for the covariation of the Axis II disorders in a sample of 245 veterans and nonveterans with posttraumatic stress disorder. Results indicated that the best fitting model was a modified bifactor structure composed of nine lower-order common factors. These factors indexed pathology ranging from aggression to dependency, with the correlations among them accounted for by higher-order Internalizing and Externalizing factors. Further, a general factor, reflecting a construct that we termed boundary disturbance, accounted for additional variance and covariance across nearly all the indicators. The Internalizing, Externalizing, and Boundary Disturbance factors evidenced differential associations with trauma-related covariates. These findings suggest continuity in the underlying structure of psychopathology across DSM-IV Axes I and II and provide empirical evidence of a pervasive, core disturbance in the boundary between self and other across the PDs. PMID- 22448803 TI - Personality constellations in incarcerated psychopathic men. AB - Advances in the operationalization of psychopathy have led to an increased understanding of the boundaries, structure, and nomological network of this construct, although significant questions remain. The empirical identification of replicable and theoretically meaningful psychopathy subtypes may help to improve the classification and diagnosis of this condition. We conducted a classification study of 91 incarcerated men who met conventional criteria for high levels of psychopathy using the Psychopathy Checklist-Revised. We expanded on the methodology of previous research on psychopathy subtypes by utilizing a comprehensive personality assessment instrument and a prototype matching approach to classification. The analyses revealed a primary (narcissistic) subtype and a secondary (hostile and dysregulated) subtype that were broadly consistent with the previous literature. External validation analyses, statistical controls, and incremental validity analyses provided substantial support for the primary and secondary subtypes. PMID- 22448804 TI - Extending research on the utility of an adjunctive emotion regulation group therapy for deliberate self-harm among women with borderline personality pathology. AB - Deliberate self-harm (DSH) is a clinically important behavior commonly associated with borderline personality disorder (BPD). Despite the clinical relevance and associated negative consequences of this behavior, however, there are few empirically supported treatments for DSH among individuals with BPD, and those that exist are difficult to implement in many clinical settings (due to their duration and intensity). To address this limitation, Gratz and Gunderson (2006) examined the efficacy of a 14-week, adjunctive emotion regulation group therapy (ERGT) for DSH among women with BPD. Although the results of this initial trial were promising (indicating positive effects of this treatment on DSH, emotion dysregulation, experiential avoidance, and psychiatric symptoms), they require replication and extension. Thus, the purpose of this study was to further develop this ERGT by examining its utility across other settings, a more diverse group of patients, a wider range of outcomes, and group leaders other than the principal investigator. Twenty-three women received this ERGT in addition to their ongoing treatment in the community. Self-report and interview-based measures of DSH and other self-destructive behaviors, psychiatric symptoms, adaptive functioning (including social and vocational impairment and quality of life), and the proposed mechanisms of change (emotion dysregulation and experiential avoidance) were administered pre- and posttreatment. Results indicate significant changes over time (accompanied by large effect sizes) on all outcome measures except quality of life and self-destructive behaviors (although the latter was a large sized effect). Further, 55% of participants reported abstinence from DSH during the last two months of the group. PMID- 22448805 TI - Speed and accuracy of facial expression classification in avoidant personality disorder: a preliminary study. AB - The aim of this preliminary study was to examine whether individuals with avoidant personality disorder (APD) could be characterized by deficits in the classification of dynamically presented facial emotional expressions. Using a community sample of adults with APD (n = 17) and non-APD controls (n = 16), speed and accuracy of facial emotional expression recognition was investigated in a task that morphs facial expressions from neutral to prototypical expressions (Multi-Morph Facial Affect Recognition Task; Blair, Colledge, Murray, & Mitchell, 2001). Results indicated that individuals with APD were significantly more likely than controls to make errors when classifying fully expressed fear. However, no differences were found between groups in the speed to correctly classify facial emotional expressions. The findings are some of the first to investigate facial emotional processing in a sample of individuals with APD and point to an underlying deficit in processing social cues that may be involved in the maintenance of APD. PMID- 22448806 TI - Opioid-free perioperative analgesia for hemicolectomy in a patient with opioid induced delirium: a case report and review of the analgesic efficacy of the alpha 2 agonist agents. AB - Surgical pain in patients with documented opioid-induced delirium can be difficult to treat. We present a case of a patient undergoing laparoscopic hemicolectomy effectively treated with an opioid-free, alpha-2 adrenoreceptor agonist analgesic regimen. CASE REPORT: A 21-year-old woman with persistent abdominal pain presented to the operating room for laparoscopic hemicolectomy for redundant right colon. Her medical history included a recently diagnosed postoperative opioid-induced delirium. Epidural infusion with local anesthetic offered partial pain relief with sensory levels of T9-L2. With the addition of dexmedetomidine infusion in the immediate postoperative period, the patient was comfortable with pain scores of 1 to 2/10 on Numerical Rating Scale (NRS). On postoperative day 1, the infusion was discontinued and the clonidine, 12 MUg/hours was added to the epidural bupivacaine. With increased sedation 48 hours later, neuraxial clonidine was discontinued in favor to transdermal clonidine 0.1 mg/week, which was maintained until hospital discharge. Pain scores were maintained at 2 to 3/10 on NRS for the next 3 days when increased abdominal distention because of abscess formation rendered a new surgical intervention. The analgesia for the exploratory laparoscopy was maintained using epidural clonidine and bupivacaine infusion as well as intravenous dexmedetomidine, which were maintained another 2 days. Pain scores remained minimal until discharged home 3 day later. DISCUSSION: Nonopioid analgesic regimens are beneficial in patients at risk of postoperative cognitive dysfunction attributable to opioids. Successful postoperative analgesia was achieved in our patient by alternating various routes of administration of alpha-2 adrenoreceptor agonists. PMID- 22448807 TI - Post-warming competence of in vivo matured rabbit oocytes treated with cytoskeletal stabilization (Taxol) and cytoskeletal relaxant (Cytochalasin B) before vitrification. AB - The aim of this study was to investigate the effect of Taxol and Cytochalasin B on the spindle, chromosome configuration and development to blastocyst stage after parthenogenesis activation of in vivo matured rabbit oocytes after vitrification. Oocytes were randomized into four groups: oocytes treated with Cytochalasin B or Taxol before vitrification, oocytes without treatment before vitrification and fresh oocytes. Oocytes were vitrified using Cryotop method, and meiotic spindle and chromosomal distribution were assessed with a confocal laser scanning microscopy. To determine oocyte competence, in vitro development of oocytes was assessed with parthenogenesis activation. There were no significant differences in the frequencies of normal spindle (33.0%, 31.0% and 32.6%, for non treated, Taxol-treated and Cytochalasin B-treated oocytes, respectively) and chromosome (48.3%, 46.6% and 34.8%, for non-treated, Taxol-treated oocytes and Cytochalasin B-treated oocytes respectively) in vitrified groups, but significantly lower than those of fresh group (89.7% and 90.2%, for normal spindle and chromosome organization, respectively). No statistical differences were found in the cleavage and blastocyst development rates between non-treated and Taxol-treated oocytes (7.7% and 1.5% and 13.7% and 4.6%, for non-treated and Taxol-treated oocytes, respectively), although they were significantly lower than in the fresh group (42.3% and 32.1%, for cleavage and blastocyst development, respectively). Oocytes treated with Cytochalasin B failed to reach blastocyst stage. Normal spindle, chromosome configuration and blastocyst development of in vivo matured rabbit oocytes were damaged in vitrification, which was not improved by Taxol and Cytochalasin B pre-treatment before vitrification. Moreover, a detrimental effect on blastocyst development of Cytochalasin B pre-treatment before vitrification was observed. PMID- 22448808 TI - Catch me if I fall! Enacted uncertainty avoidance and the social safety net as country-level moderators in the job insecurity-job attitudes link. AB - Job insecurity is related to many detrimental outcomes, with reduced job satisfaction and affective organizational commitment being the 2 most prominent reactions. Yet, effect sizes vary greatly, suggesting the presence of moderator variables. On the basis of Lazarus's cognitive appraisal theory, we assumed that country-level enacted uncertainty avoidance and a country's social safety net would affect an individual's appraisal of job insecurity. More specifically, we hypothesized that these 2 country-level variables would buffer the negative relationships between job insecurity and the 2 aforementioned job attitudes. Combining 3 different data sources, we tested the hypotheses in a sample of 15,200 employees from 24 countries by applying multilevel modeling. The results confirmed the hypotheses that both enacted uncertainty avoidance and the social safety net act as cross-level buffer variables. Furthermore, our data revealed that the 2 cross-level interactions share variance in explaining the 2 job attitudes. Our study responds to calls to look at stress processes from a multilevel perspective and highlights the potential importance of governmental regulation when it comes to individual stress processes. PMID- 22448809 TI - Structural analysis of the hexasome, lacking one histone H2A/H2B dimer from the conventional nucleosome. AB - Genomic DNA is packaged into chromatin in eukaryotes, and the nucleosome is the fundamental unit of chromatin. The canonical nucleosome is the octasome, which is composed of two H2A/H2B dimers and two H3/H4 dimers. During transcription elongation, one of the H2A/H2B dimers is removed from the octasome. The depletion of the H2A/H2B dimer is also suggested to occur during DNA replication and repair. The remaining histone components are believed to maintain a nucleosomal structure called a "hexasome", which is probably important for the regulation of gene expression, DNA replication, and repair in chromatin. However, hexasomes are currently poorly understood, due to the lack of in vivo and in vitro studies. Biochemical and structural studies of hexasomes have been hampered by the difficulty of preparing purified hexasomes. In the present study, we successfully reconstituted hexasomes, using recombinant human histones. A micrococcal nuclease treatment and in vitro reconstitution assays revealed that the hexasome tightly wraps approximately 110 base-pairs of DNA, about 40 base-pairs shorter than the length of the DNA wrapped within the canonical nucleosome. A small-angle X-ray scattering analysis revealed that the global structure of the hexasome is similar to that of the canonical nucleosome. Our studies suggest that octasomes can be converted into hexasomes by the eviction of one of the H2A/H2B dimers, and the release of about 40 base-pairs of DNA, without involving large structural changes in the nucleosome core particle. PMID- 22448810 TI - Early effect of oral administration of omeprazole with mosapride as compared with those of omeprazole alone on the intragastric pH. AB - BACKGROUND: The ideal medication for acid-related diseases should have a rapid onset of action to promote hemostasis and cause efficient resolution of symptoms. The aim of our study was to comparatively investigate the inhibitory effect on gastric acid secretion of a single oral administration of omeprazole plus mosapride with that of omeprazole alone. METHODS: Ten Helicobacter pylori negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 hours after a single oral administration of omeprazole 20 mg or that of omeprazole 20 mg plus mosapride 5 mg (the omeprazole being administered one hour after the mosapride). Each administration was separated by a 7-days washout period. RESULTS: The average pH during the 6-hour period after administration of omeprazole 20 mg plus mosapride 5 mg was higher than that after administration of omeprazole 20 mg alone (median: 3.22 versus 4.21, respectively; p = 0.0247). CONCLUSIONS: In H. pylori -negative healthy male subjects, an oral dose of omeprazole 20 mg plus mosapride 5 mg increased the intragastric pH more rapidly than omeprazole 20 mg alone. PMID- 22448811 TI - Expression of fatty acid synthesis genes and fatty acid accumulation in haematococcus pluvialis under different stressors. AB - BACKGROUND: Biofuel has been the focus of intensive global research over the past few years. The development of 4th generation biofuel production (algae-to biofuels) based on metabolic engineering of algae is still in its infancy, one of the main barriers is our lacking of understanding of microalgal growth, metabolism and biofuel production. Although fatty acid (FA) biosynthesis pathway genes have been all cloned and biosynthesis pathway was built up in some higher plants, the molecular mechanism for its regulation in microalgae is far away from elucidation. RESULTS: We cloned main key genes for FA biosynthesis in Haematococcus pluvialis, a green microalga as a potential biodiesel feedstock, and investigated the correlations between their expression alternation and FA composition and content detected by GC-MS under different stress treatments, such as nitrogen depletion, salinity, high or low temperature. Our results showed that high temperature, high salinity, and nitrogen depletion treatments played significant roles in promoting microalgal FA synthesis, while FA qualities were not changed much. Correlation analysis showed that acyl carrier protein (ACP), 3 ketoacyl-ACP-synthase (KAS), and acyl-ACP thioesterase (FATA) gene expression had significant correlations with monounsaturated FA (MUFA) synthesis and polyunsaturated FA (PUFA) synthesis. CONCLUSIONS: We proposed that ACP, KAS, and FATA in H. pluvialis may play an important role in FA synthesis and may be rate limiting genes, which probably could be modified for the further study of metabolic engineering to improve microalgal biofuel quality and production. PMID- 22448812 TI - Does the FDA have regulatory authority over adult autologous stem cell therapies? 21 CFR 1271 and the emperor's new clothes. AB - FDA has recently asserted that many autologous cell therapies once considered the practice of medicine are in fact drugs. These changes began with the creation of new sections of 21 CFR 1271 and a subsequent one word change where the FDA, without public commentary, altered a single word in its regulatory language regarding cell and tissue based therapies that asserted the authority to classify autologous tissue as drugs. The bright line between medical care and drug production can be delineated in many ways, but a simple metric that defines the dichotomy is the consent status of the patient. In healthcare, a patient can either be consented individually for a medical procedure or exposed to an unconsented risk where regulatory assurances are already in place. These new FDA policies apply rules meant to keep drugs safe in a drug factory (unconsented mass production risks) to individually consented surgical procedures. We argue that there is little societal benefit to these changes and that they are already stifling medical innovation. PMID- 22448813 TI - Wild great apes as sentinels and sources of infectious disease. AB - Emerging zoonotic infectious diseases pose a serious threat to global health. This is especially true in relation to the great apes, whose close phylogenetic relationship with humans results in a high potential for microorganism exchange. In this review, we show how studies of the microorganisms of wild great apes can lead to the discovery of novel pathogens of importance for humans. We also illustrate how these primates, living in their natural habitats, can serve as sentinels for outbreaks of human disease in regions with a high likelihood of disease emergence. Greater sampling efforts and improvements in sample preservation and diagnostic capacity are rapidly improving our understanding of the diversity and distribution of microorganisms in wild great apes. Linking non invasive diagnostic data with observational health data from great apes habituated to human presence is a promising approach for the discovery of pathogens of high relevance for humans. PMID- 22448814 TI - Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. AB - BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (>=2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 +/- 884, 4608 +/- 1030, and 4596 +/- 939 ng*h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation. PMID- 22448815 TI - Subgroup decomposition of plasmonic resonances in hybrid oligomers: modeling the resonance lineshape. AB - Plasmonic resonances with a Fano lineshape observed in metallic nanoclusters often arise from the destructive interference between a dark, subradiant mode and a bright, super-radiant one. A flexible control over the Fano profile characterized by its linewidth and spectral contrast is crucial for many potential applications such as slowing light and biosensing. In this work, we show how one can easily but significantly tailor the overall spectral profile in plasmonic nanocluster systems, for example, quadrumers and pentamers, by selectively altering the particle shape without a need to change the particle size, interparticle distance, or the number of elements of the oligomers. This is achieved through decomposing the whole spectrum into two separate contributions from subgroups, which are efficiently excited at their spectral peak positions. We further show that different strengths of interference between the two subgroups must be considered for a full understanding of the resulting spectral lineshape. In some cases, each subgroup is separately active in distinct frequency windows with only small overlap, leading to a simple convolution of the subspectra. Variation in particle shape of either subgroup results in the tuning of the overall spectral lineshape, which opens a novel pathway for shaping the plasmonic response in small nanoclusters. PMID- 22448816 TI - Evaluation of physicians' professional performance: an iterative development and validation study of multisource feedback instruments. AB - BACKGROUND: There is a global need to assess physicians' professional performance in actual clinical practice. Valid and reliable instruments are necessary to support these efforts. This study focuses on the reliability and validity, the influences of some sociodemographic biasing factors, associations between self and other evaluations, and the number of evaluations needed for reliable assessment of a physician based on the three instruments used for the multisource assessment of physicians' professional performance in the Netherlands. METHODS: This observational validation study of three instruments underlying multisource feedback (MSF) was set in 26 non-academic hospitals in the Netherlands. In total, 146 hospital-based physicians took part in the study. Each physician's professional performance was assessed by peers (physician colleagues), co-workers (including nurses, secretary assistants and other healthcare professionals) and patients. Physicians also completed a self-evaluation. Ratings of 864 peers, 894 co-workers and 1960 patients on MSF were available. We used principal components analysis and methods of classical test theory to evaluate the factor structure, reliability and validity of instruments. We used Pearson's correlation coefficient and linear mixed models to address other objectives. RESULTS: The peer, co-worker and patient instruments respectively had six factors, three factors and one factor with high internal consistencies (Cronbach's alpha 0.95 - 0.96). It appeared that only 2 percent of variance in the mean ratings could be attributed to biasing factors. Self-ratings were not correlated with peer, co worker or patient ratings. However, ratings of peers, co-workers and patients were correlated. Five peer evaluations, five co-worker evaluations and 11 patient evaluations are required to achieve reliable results (reliability coefficient >= 0.70). CONCLUSIONS: The study demonstrated that the three MSF instruments produced reliable and valid data for evaluating physicians' professional performance in the Netherlands. Scores from peers, co-workers and patients were not correlated with self-evaluations. Future research should examine improvement of performance when using MSF. PMID- 22448817 TI - Electrochemistry-assisted top-down characterization of disulfide-containing proteins. AB - Covalent disulfide bond linkage in a protein represents an important challenge for mass spectrometry (MS)-based top-down protein structure analysis as it reduces the backbone cleavage efficiency for MS/MS dissociation. This study presents a strategy for solving this critical issue via integrating electrochemistry (EC) online with a top-down MS approach. In this approach, proteins undergo electrolytic reduction in an electrochemical cell to break disulfide bonds and then undergo online ionization into gaseous ions for analysis by electron-capture dissociation (ECD) and collision-induced dissociation (CID). The electrochemical reduction of proteins allows one to remove disulfide bond constraints and also leads to increased charge numbers of the resulting protein ions. As a result, sequence coverage was significantly enhanced, as exemplified by beta-lactoglobulin A (24 vs 75 backbone cleavages before and after electrolytic reduction, respectively) and lysozyme (5 vs 66 backbone cleavages before and after electrolytic reduction, respectively). This methodology is fast and does not need chemical reductants, which would have an important impact in high-throughput proteomics research. PMID- 22448818 TI - Computational studies on the resistance of penicillin-binding protein 2B (PBP2B) of wild-type and mutant strains of Streptococcus pneumoniae against beta-lactam antibiotics. AB - Mutations within transpeptidase domain of penicillin-binding protein 2B of the strains of Streptococcus pneumoniae leads to resistance against beta-lactam antibiotics. To uncover the important residues responsible for sensitivity and resistance, the recently determined three dimensional structures of penicillin binding protein 2B of both wild-type R6 (sensitive) and mutant 5204 (resistant) strains along with the predicted structures of other mutant strains G54, Hungary19A-6 and SP195 were considered for the interaction study with beta-lactam antibiotics using induced-fit docking of Schrodinger. Associated binding energies of the complexes and their intermolecular interactions in the binding site clearly show that the wild-type R6 as sensitive, mutant strains 5204 and G54 as highly resistant, and the mutant strains Hungary19A-6 and SP195 as intermediate resistant. The study also reveals that the mutant strains Hungary19A-6 and SP195 exhibit intermediate resistant because of the existence of mutations till the intermediate 538th and 516th positions, respectively, and not till the end of the C-terminus. Furthermore, our investigations show that if the mutations are extended till the end of the C terminus, then the antibiotic resistance of induced-mutated strains increases from intermediate to high as in the strains 5204 and G54. The binding patterns obtained in the study are useful in designing potential inhibitors against multidrug resistant S. pneumoniae. PMID- 22448819 TI - Insights into the structure of the supramolecular amphiphile formed by a sulfonated calix[6]arene and alkyltrimethylammonium surfactants. AB - In this work, we have studied the interactions between the water-soluble p sulfonatocalix[6]arene and cationic surfactants octyltrimethylammonium bromide below the cmc and dodecyltrimethylammonium bromide above the cmc, by saturation transfer difference (STD) NMR spectroscopy. From the STD build-up curves, we have obtained the T1 independent cross relaxation rates, and the results show that the interactions established between the cationic headgroup of the surfactant and the OMe group of the macrocycle play an important role in the stabilization of the complex, both below and above the cmc. PMID- 22448820 TI - The crowded environment of a reverse micelle induces the formation of beta-strand seed structures for nucleating amyloid fibril formation. AB - A hallmark of Alzheimer's disease is the accumulation of insoluble fibrils in the brain composed of amyloid beta (Abeta) proteins with parallel in-register cross beta-sheet structure. It has been suggested that the aggregation of monomeric Abeta proteins into fibrils is promoted by "seeds" that form within compartments of the brain that have limited solvent due to macromolecular crowding. To characterize these seeds, a crowded macromolecular environment was mimicked by encapsulating Abeta40 monomers into reverse micelles. Fourier-transform infrared spectroscopy revealed that monomeric Abeta proteins form extended beta-strands in reverse micelles, while an analogue with a scrambled sequence does not. This is a remarkable finding, because the formation of extended beta-strands by monomeric Abeta proteins suggests a plausible mechanism whereby the formation of amyloid fibrils may be nucleated in the human brain. PMID- 22448821 TI - Is the evidence behind platelet-rich plasma therapies strong enough? PMID- 22448822 TI - Evaluation of new version of Mecbio hip resurfacing prosthesis. AB - OBJECTIVES: The aim of this preliminary study was to compare clinical outcomes of the modern version of the Mecbio resurfacing arthroplasty prosthesis which is custom-designed for each patient with the older prototype which has three sizes. PATIENTS AND METHODS: Between 2003 and 2008, 20 patients with hip disorders who underwent a total of 21 arthroplasties with the modern version or prototype prosthesis were included in the study. The prototype was used for the first 15 procedures, while the modern version was used for the last six procedures. The modified lateral approach was performed on all patients. Clinical and radiological examination were also performed by two experienced surgeons. Cortical changes of the calcar were evaluated by comparison of the thinner layer of the medial cortex with thickened one within 5 cm below the lesser trochanter. The patients were also clinically evaluated by the Harris Hip Score. The mean follow-up was three years (range, 2 to 5 years). RESULTS: There was a significant improvement in the Harris Hip Score following surgery compared to baseline between the groups (p<0.05). There was a significant increase in the prototype group (0.14+/-0.06 to 0.23+/-0.07, p<0.0001) and modern version group (0.15+/ 0.07 to 0.25+/-0.03, p=0.0020) in terms of the thinner cortex and thickened cortex in the prototype group (0.21+/-0.06 to 0.28+/-0.06 p<0.0001) and modern version group (0.25+/-0.07 to 0.29+/-0.05, p=0.0156). There was no significant difference in terms of radiological measurements between the groups. CONCLUSION: The results suggest that excellent clinical and radiological outcomes can be obtained with both the prototype and modern version prosthesis. PMID- 22448823 TI - [Functional status, patient satisfaction and quality of life in patients with arthroscopic partial meniscectomy]. AB - OBJECTIVES: This study aims to investigate the effects of clinical and demographic variables on functional status, patient satisfaction and quality of life following arthroscopic partial meniscectomy. PATIENTS AND METHODS: Between January 2001 and December 2010, 98 patients (44 males, 54 females; mean age 52.1+/-12.5 years; range 18 to 88 years) who underwent arthroscopic partial meniscectomy in our clinic and were eligible for the study. Demographic and clinical data of patients and surgical characteristics were recorded. Preoperative activity levels of patients were measured. Severity of activity pain and patient satisfaction following surgery were evaluated using Visual Analog Scale (VAS). Functional status was evaluated by Lysholm knee score and WOMAC (Osteoarthritis Index Western Ontario and McMaster Universities), while quality of life was evaluated by Short Form-36 (SF-36). RESULTS: Postoperative mean time from surgery was 62.5+/-26.1 (8-120) months, GAS score at rest was 1.7+/-2.6 (0 10), GAS activity score was 3.4+/-3.3 (0-10) and GAS patient satisfaction score was 7.0+/-3.0 (0-10). It was found that 68 of the patients (69.4%) were evaluated themselves as excellent or better than preoperative period with a mean Lysholm knee score of 73.8+/-17.4 (24-95). Significant influences of body mass index and preoperative symptom duration on evaluation parameters were not detected. Male gender, less than five years after surgery, less intraoperative joint degeneration and moderate to severe activity level before the onset of symptoms had a positive influence on the severity of pain, patient satisfaction and functional status. CONCLUSION: Our study provided critical data for optimal patient selection during the preoperative period to predict which patients may have better results in the mid-term follow-up after arthroscopic partial meniscectomy. PMID- 22448824 TI - [Is bone microstructure different between osteopenic and osteoporotic patients with femoral neck fracture?]. AB - OBJECTIVES: This study aims to investigate whether bone microstructure is different between osteopenic and osteoporotic patients with femoral neck fracture. PATIENTS AND METHODS: Fourteen patients (5 males, 9 females) with proximal femoral fracture following low energy trauma were included in the study. Patients with secondary osteoporosis and who received antiosteoporotic treatment prior to trauma were excluded. The patients were divided into two groups based on the bone mineral density measurement, including osteopenic group (n=7, mean age 69 years; range 63-74 years) and osteoporotic group (n=7, mean age 74.1 years; range 67-78 years). Cortical bone specimens for biopsy obtained from the patients who underwent endoprosthesis during partial hip arthroplasty and were evaluated using light microscope. RESULTS: Mean cortical bone thickness was 3622.14 MUM in osteopenic group, and 2323.14 MUM in osteoporotic group (p<0.005). However, light microscope revealed similar characteristics for both groups. CONCLUSION: Although a significant difference was found between the groups in terms of cortical thickness, bone microstructure showed similar characteristics in osteopenic and osteoporotic patients with low energy femoral neck fracture. PMID- 22448825 TI - Adolescent Blount disease in obese children treated by eight-plate hemiepiphysiodesis. AB - OBJECTIVES: The aim of this study is to evaluate the outcomes of eight-plate (Orthofix) use during hemiepiphyseodesis operation for growth modulation in obese children with adolescent Blount disease. PATIENTS AND METHODS: Six limbs of five consecutive patients who underwent lateral proximal tibial eight-plate (Orthofix) hemiepiphysiodesis were evaluated. The body mass index (BMI) was >30 and the severity of the deformity was in Zone III according to the Mielke and Stevens definition. The mechanical medial proximal tibial angle (MPTA) and the mechanical axis deviation (MAD) were measured preoperatively, postoperatively, and at last follow-up. The outcome of the procedure was established by the degree of tibia vara correction degree at final plate removal or skeletal maturity. RESULTS: Mean age of the patients and mean BMI at the time of surgery was 13 years (range 12 to 14) and 33.5 kg/m2 (range 31 to 36), respectively. Patients were followed for an average of 22 months (range 13 to 31). Preoperative and last follow-up mean values for MPTA were 81 and 80 degrees, respectively. Outcome of the procedure showed two extremities demonstrated progression of the tibia vara (mean of 6.5 degrees), two extremities had no correction of the deformity, and the remaining two extremities showed minimally improvement (mean 3 degrees). The procedure failed to correct the tibia vara in all extremities and all patients were scheduled for an osteotomy to treat the deformity. CONCLUSION: We do not recommend the use of a tension band plate hemiepiphyseodesis (eight-plate, Orthofix) to treat severe adolescent Blount disease in obese children. PMID- 22448826 TI - [The long-term results of brace treatment in Perthes disease]. AB - OBJECTIVES: We evaluated the long-term radiological outcomes of the patients with Perthes disease who were conservatively treated with brace. PATIENTS AND METHODS: Thirty-three hips of 27 skeletally mature patients (21 males, 6 females; mean age 25.2+/-3.4 years; range 20 to 32 years) treated with modified Thomas splint were included in this study. The results were evaluated according to the Stulberg classification. RESULTS: The mean age of the patients was 6.3+/-2.2 (range 3-12) years at the onset of the disease and the mean follow-up was 18.6+/-3.2 (range 7.2-24.1) years. According to onset of the disease, good results were obtained for the patients who were less than six-years-old as 77.7%, between 6-9 years old as 84.2%, after nine years old as 40%. However, 100% of the Herring group A hips, 79.2% of the group B hips and 50% of the group C hips were healed with Stulberg class I or II results. CONCLUSION: We obtained satisfactory results after conservative treatment with Thomas splint in patients who were between 6-9 years old at onset of the disease with Herring group B involvement. It is hard to say whether the good results were stemmed from having good prognosis of these patients, or stemmed from positive effect of using brace on treatment. PMID- 22448827 TI - Outcomes of posterior titanium spinal instrumentation in neuromuscular scoliosis patients. AB - OBJECTIVES: In this study, we aimed to characterize the outcomes of posterior spinal fusion (PSF) using titanium instrumentation in neuromuscular scoliosis (NMS) patients with a special focus on deformity correction and correction maintenance. PATIENTS AND METHODS: Between 2002 and 2004, nine patients (5 girls and 4 boys; mean age 14.9+/-2.3 years; range 11 to 19 years) with NMS who underwent PSF using titanium instrumentation were retrospectively analyzed. The mean height at surgery was 154.6+/-14.2 cm (range, 136-173 cm) and the mean weight was 59.4+/-19.2 kg (range, 26-114 kg). The mean follow-up duration was 3.7 years (range, 2-5 years). Preoperative data included demographics, curve type, and surgical indication. Rod size, fusion levels, duration of the operation (min), estimated blood loss (cc), and length of stay in hospital (day) were also evaluated intraoperatively. Postoperative data included correction of deformity, maintenance of correction, and complications. Radiographic measurements were obtained from standing posterior-anterior and lateral spinal radiographs at preoperative, postoperative (at first week after standing; i.e. first erect) and last follow-up visits. The data obtained were analyzed using descriptive statistic methods (mean, standard deviation, median, frequency and percentage). RESULTS: Dramatic improvements in the spinal deformities were observed in the patients with NMS who underwent PSF using titanium instrumentation. Mean preoperative Cobb angle was reduced from 69.7 degrees to 16.2 degrees at first erect following surgery (at first week; 77% correction). Two-year follow-up revealed that this correction sustained (mean 14.8 degrees). However, moderate to severe postoperative complications requiring careful monitoring were reported. CONCLUSION: Our study results showed that PSF with titanium instrumentation in pediatric NMS patients demonstrated satisfactory outcomes during the follow-up period. However, further large-scale studies with a long-term follow-up results are required to generalize the results regarding PSF using titanium instrumentation in these patients. PMID- 22448828 TI - Treatment of chronic lateral instability of the ankle with the Colville technique: a prospective analysis with minimum five years of follow-up. AB - OBJECTIVES: This study aims to prospectively analyze of the long-term results of the Colville's technique for the treatment of chronic lateral ankle instabilities. PATIENTS AND METHODS: Twenty-eight ankles of 28 male patients (mean age 24.6 years; range 20 to 35 years) which were treated using Colville's technique were evaluated with a mean follow-up of 76.1 months (range 60 to 106 months). Ankle instability, ankle functions and outcomes in the last visit were assessed and statistically compared. Stress radiographs with the TELOS device were repeated at six-months and five-years after surgery and compared with the stability of the uninjured ankle. RESULTS: Twenty-three of the results were excellent and five were good according to the criteria of Chrisman and Snook. All patients returned to normal daily activity levels at an average of eight months following surgery. Radiographic analysis revealed the significant preservation of stability at least five years after surgery with no sign of arthritis. The difference between preoperative and sixth-months postoperative values of both the talar tilt and the anterior draw tests were found statistically significant, indicating significant correction of the laxity. On contrary, difference between sixth months and five year values were not statistically significant, indicating the preservation of the correction. CONCLUSION: Anatomical augmented reconstruction procedure of Colville's is a long-lasting and good alternative compared to other more complex techniques of reconstruction with minimum long term complications. PMID- 22448829 TI - Snapping scapula syndrome caused by subscapular osteochondroma. AB - OBJECTIVES: This study aims to evaluate the results of surgical excisions of subscapular exostoses which caused snapping scapula syndrome. PATIENTS AND METHODS: Between September 1980 and January 2010 30 patients with scapular osteochondromas which caused snapping, were treated surgically in our clinic. Fifteen patients (9 males, 6 females; mean age 15.6 years; range 6 to 29 years) in whom we were able to contact following treatment were clinically evaluated. The mean follow-up was 13.7 years (range 1 to 31 years). The initial examination included radiographs and computed tomography. The clinical results were evaluated with a simple shoulder test at their last follow-up. RESULTS: The preoperatively most common complaint was winging of the scapula in all patients (100%), followed by pain in 12 patients (80%), and crepitus with scapulothoracic motion in 10 patients (66.6%). None of the patients had any clue in favor of snapping after surgical treatment. According to the responses to the simple shoulder test, none of the patients had any restriction of motion on their operated shoulders. They didn't give us a history about recurrence of the lesion. CONCLUSION: Excision is an appropriate treatment for osteochondromas. In this retrospective analysis, complete relief following excision of the exostosis was achieved in all patients. No patient had any complaint or recurrence. PMID- 22448830 TI - Cefazolin-sodium has no adverse effect on fracture healing in an experimental rabbit model. AB - OBJECTIVES: This study aims to investigate whether cefazolin-sodium has any adverse effect on fracture healing in an experimental rabbit model. MATERIALS AND METHODS: The study was performed on 50 male New-Zealand white rabbits. Under general anesthesia, closed double fracture of middle one-third of the tibia fibula of the left lower extremity of the subjects was produced by manual compression followed by closed reduction of fracture and long leg circular cast was applied. Subjects were divided randomly into five groups including 10 rabbits in each group. The first and second group were administered ciprofloxacin 50 mg/kg SC bid and cefazolin-sodium 50 mg/kg IM on the seventh day of fracture. The third group was applied a single high-dose of vitamin D (50.000 IU/kg) IM following fracture. The fourth group was applied daily vitamin E (alpha tocopherol) 20 mg/kg IM for five days from one hour before the production of fracture. Control group did not receive any treatment before and after fracture. Initial and control X-ray examinations were performed immediately and four weeks after production of fracture, respectively. At the end of the fourth week, animals were sacrificed and a histological examination of the fracture site was performed. RESULTS: Histological evaluation showed that the histological grade of the fracture healing was significantly lower in the ciprofloxacin group, while it was significantly higher in the cefazolin-sodium, vitamin D and vitamin E groups, compared to control group (p<0.005). CONCLUSION: Significantly improved histological grade of the fracture healing in subjects treated with cefazolin sodium than controls suggest that it may be reasonable to choose cefazolin-sodium as an antibiotic therapy for the treatment of infection in patients with bone fractures. PMID- 22448831 TI - The greater trochanter located in the acetabulum in a girl with developmental dysplasia of the hip: an unusual complication after redislocation. AB - Unstable closed reduction often leads to unsatisfied function. Abnormal force transmission after unstable closed reduction can cause pain, episodes of instability and restriction of range of movement. There is a limited number of literature data which suggests overgrown greater trochanteric located in the acetabulum as a false femoral head without any functional deterioration. In this article, we reported a five-year-old girl with developmental dysplasia of the left hip redislocated following closed reduction. After five-years of follow-up, overgrown greater trochanter was located in the left acetabulum and it unexpectedly resulted in a satisfied function. The unforeseen overgrown greater trochanteric as a false femoral head may lead to a satisfactory function at five years after reduction. However, long-term follow is required, as its role in early-onset degenerative osteoarthritis remains inconclusive. PMID- 22448832 TI - A lipoma causing separation of toes in the second web space of the foot. AB - Lipomas are common and benign soft tissue neoplasms which are composed of fat cells. These tumors often develop where adipose tissue is present; however, they can be rarely found in the foot. In this article, we present a 55-year-old male case with a lipoma leading to separating toes in the second web space of the foot and mechanical discomfort. PMID- 22448833 TI - Treatment of capitellar osteochondritis dissecans with a tendon graft: a case report. AB - A 14-year-old girl who was engaged in farming was admitted with the complaints of right elbow pain and limited range of motion in the elbow joint. Plain radiograph revealed capitellar osteochondritis dissecans. After the loose fragment was removed from the capitellum and the defect was curetted, a palmaris longus tendon graft harvested from the same hand was implanted into the capitellar defect. Elbow joint was immobilized for three weeks. Magnetic resonance imaging showed that tendon graft was successfully adapted into defect. The range of motion was preserved and she had no pain in the elbow joint. In conclusion, we suggest that tendon autograft can be used in the treatment of capitellar osteochondritis dissecans. PMID- 22448834 TI - Scapular manipulation for reduction of anterior shoulder dislocation; with or without analgesia: comment. PMID- 22448836 TI - Willed action and its impairments. AB - Actions are goal-directed behaviours that usually involve movem ent. There is evidence that intentional self-generated actions (willed actions) are controlled differently from routine, stereotyped actions that are externally triggered by environmental stimuli. We review evidence from investigations using positron emission tomography (PET), recordings of movement-related cortical potentials (MRCPs) or transcranial magnetic stimulation (TMS), and conclude that willed actions are controlled by a network of frontal cortical (dorsolateral prefrontal cortex, supplementary motor area, anterior cingulate) and subcortical (thalamus and basal ganglia) areas. We also consider evidence suggesting that some of the cognitive and motor deficits of patients with frontal lesions, Parkinson's disease, or schizophrenia as well as apathy and abulia and rarer phenomena such as primary obsessional slowness can be considered as reflecting im pairment of willed actions. We propose that the concept of a willed action system based on the frontostriatal circuits provides a useful framework for integrating the cognitive, motor, and motivational deficits found in these disorders. Problems remaining to be resolved include: identification of the component processes of willed actions; the specific and differential role played by each of the frontal cortical and subcortical areas in the control of willed actions; the specific mechanisms of impairm ent of willed actions in Parkinson's disease, schizophrenia, and frontal damage; and the precise role of the neurotransmitter dopamine in the willed action system. PMID- 22448837 TI - The visual perception of human locomotion. AB - To function adeptly within our environment, we must perceive and interpret the movements of others. What mechanisms underlie our exquisite visual sensitivity to human m ovement? To address this question, a set of psychophysical studies was conducted to ascertain the temporal characteristics of the visual perception of human locomotion. Subjects viewed a computer-generated point-light walker presented within a mask under conditions of apparent motion. The temporal delay between the display frames as well as the motion characteristics of the mask were varied. With sufficiently long trial durations, performance in a direction discrimination task remained fairly constant across inter-stimulus interval (ISI) when the walker was presented within a random motion mask but increased with ISI when the mask motion duplicated the motion of the walker. This pattern of results suggests that both low-level and high-level visual analyses are involved in the visual perception of human locomotion. These findings are discussed in relation to recent neurophysiological data suggesting that the visual perception of human movement may involve a functional linkage between the visual and motor systems. PMID- 22448838 TI - Top down effect of strategy on the perception of human biological motion: a pet investigation. AB - This experiment was designed to investigate the neural network engaged by the perception of human movements using positron emission tomography. Perception of meaningful and of meaningless hand actions without any purpose was contrasted with the perception of the same kind of stimuli with the goal to imitate them later. A condition that consisted of the perception of stationary hands served as a baseline level. Perception of meaningful actions and meaningless actions without any aim was associated with activation of a common set of cortical regions. In both hemispheres, the occipito-temporal junction (Ba 37/19) and the superior occipital gyrus (Ba 19) were involved. In the left hemisphere, the middle temporal gyrus (Ba 21) and the inferior parietal lobe (Ba 40) were found to be activated. These regions are interpreted as related to the analysis of hand movements. The precentral gyrus, within the area of hand representation (Ba 4), was activated in the left hemisphere. In addition to this common network, meaningful and meaningless movements engaged specific networks, respectively: meaningful actions were associated with activations mainly located in the left hemisphere in the inferior frontal gyrus (Ba 44/45) and the fusiform gyrus (Ba 38/20), whereas meaningless actions involved the dorsal pathway (inferior parietal lobe, Ba 40 and superior parietal lobule, Ba 7) bilaterally and the right cerebellum. In contrast, meaningful and meaningless actions shared almost the same network when the aim of the perception was to im itate. Activations were located in the right cerebellum and bilaterally in the dorsal pathway reaching the prem otor cortex. Additional bilateral activations were located in the SMA and in the orbitofrontal cortex during observation of meaningful actions. PMID- 22448839 TI - Ideational apraxia and naturalistic action. AB - It is frequently claimed that ideational apraxia, an impairm ent of the performance of complex actions with objects, is a left-hemisphere syndrome. We assessed the consequences of lefthemisphere damage for naturalistic action performance in two studies. In Study 1, we compared the action errors of left hemisphere stroke patients (LCVA) to previously reported patients with right hemisphere stroke (RCVA) and closed head injury (CHI), and found that LCVA were no more vulnerable to errors of action than the other patient groups once differences in severity were controlled. In Study 2, we compared the naturalistic action performance of a patient with severe ideational apraxia and left hemisphere damage to that of two RCVA patients of equal clinical severity. There was considerable quantitative and qualitative similarity in the errors of the three patients. From these and other findings, we argue that deficits in left-hem isphere systems do not compromise com plex action in a unique or transparent manner. We offer an alternative account based on nonspecific resource limitations that accommodates the data from all patient groups. PMID- 22448840 TI - Visual affordances direct action: neuropsychological evidence from manual interference. AB - We report an experimental study of the factors that elicit manual interference in a patient with so-called "anarchic hand" behaviour in everyday life (Della Sala, Marchetti, & Spinnler, 1991, 1994) due to corticobasilar degeneration. The patient, ES, showed problems with both hands. We used tests in which ES had to respond to a left-side object with her left hand and to a right-side object with her right hand; manual interference responses occurred when she used the left hand to respond to the right-side object and the right hand to respond to left side objects. In reaching tasks, interference responses were determined by stimulus familiarity and by the spatial relations between the hand of response and the part of the object used for action (the handle of the cup). In pointing tasks interference responses were affected by both effector and spatial uncertainty. Right hand responses were affected particularly by familiarity, and left hand responses by effector and spatial uncertainty. The results demonstrate that visual affordances (determined by object-hand compatibility) and visual familiarity can directly activate motor responses. Hand differences are discussed in terms of hemispheric specialisation for different components of motor action. PMID- 22448841 TI - Dyssynchronous apraxia: failure to combine simultaneous preprogrammed movements. AB - Limb apraxia, a defect in skilled, learned purposive movement, may be related to impairment of either representational or innervatory components of praxis processing. Innervatory motor patterns, in turn, may involve on-line motor programs (visual feedback-controlled) or prepared movement programs (independent of continuous visual feedback). We evaluated movement abilities ofthe innervatory pattern system in TB,a 26-year-old patient with apraxia from a left dorsolateral frontal stroke. TB and four controls performed nonmeaningful single and multi joint movements to command, with multi-joint movements combined sequentially (e.g. "open and close your hand and then bend your elbow") or simultaneously (e.g. "open and close your hand; keep doing that while bending your elbow"). TB showed no difference between single-joint (71.5% correct) and multi-joint movements in sequential combinations (68% correct), but she was significantly worse at simultaneous movement combinations (28.6% correct; P < .02). Controls performed consistently at > 90% mean accuracy. TB and four normals also performed the Fitts (1954) task, in which they alternately tapped with a pen between two target circles of varying size. TB was proportionately slower than controls on the larger Fitts circles, which call predominantly on prepared movement programs; her performance on the smaller circles (involving more on-line programs) was comparable to normals. We conclude that functional synchrony of one innervatory pattern subtype, prepared movement programs, may require late-level frontal processing, and that failure at this level can result in both apraxia and defective programming of nonmeaningful movements. PMID- 22448842 TI - The perception of spatial relations in a patient with visual form agnosia. AB - It is generally believed that neuropsychological patients presenting with visual agnosia, a deficit on object perception/recognition, have suffered damage to the ventral visual cortical pathway (Milner & Goodale, 1995). Rarely has the ability of such patients to perceive the spatial location of objects been investigated perhaps because "spatial vision" is thought by some researchers to be mediated exclusively by the dorsal visual cortical pathway. Here we present data on spatial perception in a patient DF, who has a profound visual form agnosia. DF and two control subjects were required to make a copy of the spatial arrangement of a target display of five differently coloured circular tokens using a duplicate set of the same tokens. Spatial performance was analysed in two ways: (1) relative location measured the ability to reconstruct the relative spatial relations between the tokens such as left versus right, above versus below, and nearer versus farther; (2) absolute location measured the exact displacement in millimetres of each token's copied position relative to its true location. DF was able to copy some of relative location relations between the tokens although her abilityto do so was not nearly as accurate as that of the control subjects. Nevertheless, DF's limited appreciation of relative location was enough to enable her to discriminate rather well between spatial patterns of tokens. She could not, however, reconstruct the absolute distance relations between the tokens and showed large displacements of token position compared to the control subjects. Interestingly, although Df was not "normal" in her ability to appreciate the allocentric spatial relations between the locations of the tokens relative to one another, she could accurately process token location egocentrically (i.e. relative to her own body and hand position). Thus, like controls, she was perfectly able to point to and touch all the tokens in an array. These results demonstrate deficits in the ability to perceive spatial relations between objects in a patient with visual form agnosia and suggest that the ventral steam also plays a functional role in spatial vision, particularly allocentric spatial vision. PMID- 22448843 TI - Evidence for movement preprogramming and on line control in differentially impaired patients with Parkinson's disease. AB - Investigated were those aspects of motor planning and execution underlying movem ent dysfunction in patients with Parkinson's disease (PD). Specifically examined was the effect of disease severity on these processes. An experiment is reported that dissociates preprogramm ing processes from on-line programming processes in a simple motor task that varies in movement complexity. Dependent m easures included reaction time, movement time, as well as kinematic measures of peak velocity, peak acceleration, peak deceleration, and their respective time values, plus inter-trial variability and EMG activation. While PD patients as a whole were able to pre-program movem ents, inter-trial variability for these measures was increased for more severely affected PD patients. Nonetheless, evidence for on-line programm ing occurred for all PD patients in later intervals of more complex movements. Further, EMG impulses correspond with acceleration trace deviations. The data as a whole support the hypothesis that disrupted basal ganglia function influences the consistency of cortical activation and the selection of motor program com ponents. PMID- 22448844 TI - Gesture imitation in autism I: nonsymbolic postures and sequences. AB - This study investigated the ability of children and adolescents with autism to imitate nonsymbolic manual postures and sequences. The controls were children with receptive language delays (matched to the autistic group for age and language level), and typically developing children (matched for language level). Control tasks assessed gesture memory and manual dexterity. Imitation tasks were videotaped for blind scoring of overall accuracy and specific errors. Children with autism performed relatively poorly on posture imitation, but not imitation of simple posture sequences. Reduced manual dexterity contributed to, but did not entirely account for the autistic im itative deficit. An error that was significantly more common in the autistic group suggests that their difficulty in assuming another's perspective may be apparent at the level of simple actions. PMID- 22448845 TI - Identification of the region required for maintaining pHW126 in its monomeric form. AB - The pHW126-like plasmids are a recently discovered small group of cryptic plasmids replicating by the rolling circle mode. The replication origin of pHW126 consists of a conserved stretch, four perfect direct repeats and a so-called accessory region. The latter increases plasmid stability but is not absolutely necessary for replication. Here, we report that deletion of the accessory region causes rapid multimerization of pHW126. While the number of pHW126-units per cell remains constant, the number of physically independent plasmid molecules is reduced by approximately 40%, rendering random distribution to daughter cells less effective. A conserved inverted repeat within the accessory region could be identified as a sequence necessary for maintaining pHW126 in its monomeric form. A mutant version of pHW126 lacking this inverted repeat could be rescued by placing the single-strand initiation site (ssi) of pHW15 on the plus strand, while including the ssi in the opposite direction had no effect. Thus, our data provide evidence that multimer formation is, besides copy number reduction and ssDNA accumulation, an additional means how loss of a mechanism ensuring efficient lagging strand synthesis may cause destabilization of rolling circle plasmids. PMID- 22448846 TI - Equally increased hypercoagulability irrespective of using minimized or conventional ECC systems. AB - OBJECTIVE: Minimized extracorporeal circulation systems in coronary artery bypass may have less impairing effect on hematological parameters and bleeding compared to conventional systems. The aim of this study was to investigate whether the use of mini systems does result in an increased postoperative hypercoagulative status. METHODS: Patients with increased risk of postoperative blood transfusion were randomly allocated to coronary bypass surgery using conventional or minimized extracorporeal circulation. Serial thrombelastographic analysis was performed preoperatively, at day 1 and 5. RESULTS: Forty-six patients were included. In 56% of the patients in the experimental and in 62% in the control group an activated coagulation system, measured as maximal amplitude above normal reference was found preoperatively. This was normalized the day after operation. At day 5 a significant number of patients in the experimental group (p = 0.03) overshooted the preoperative maximal clot strength compared to the control group (p = 0.15); however, a direct intergroup analysis showed no difference. In both groups, hemoglobin levels and platelet counts decreased at day one after surgery. At day 5, hemoglobin was partly and platelets completely normalized. No differences were found with respect to transfusion needs. CONCLUSION: Mini systems seem to induce at least an equal increased state of hypercoagulability after coronary surgery. No clinical relevant differences could be demonstrated. This could indicate that patients after using mini systems are not protected against a postoperative state of increased hypercoagulability. PMID- 22448847 TI - fSUB: normal mode analysis with flexible substructures. AB - In this paper, we report a novel normal-mode analysis for supramolecular complexes, named fSUB. The method models a complex as a group of flexible substructures. The low-frequency substructure modes are first determined with substructures in isolation, and the motions of the whole complex are then calculated on the basis of substructure modes and substructure-substructure interactions. The calculation of modes in fSUB requires modal analysis without initial energy minimization, which is essential for maintaining energetic and structural consistency between substructures and whole complex. Compared with other coarse-grained methods, such as the RTB method, fSUB delivers much more accurate modes for the complex and allows for the choice of much larger substructures. The method can also accommodate any type of substructure arrangement including covalent bonds across the interface. In tests on molecular chaperonin GroEL (7350 residues) and HK97 capsid complex (118,092 residues), fSUB was shown to be much more efficient in terms of combined accuracy and demand of computing resources. Our results clearly demonstrated the vital importance of including substructure flexibility in complex modal analysis, as the deformational patterns of substructures were found to play an important role even in the lowest frequency modes of the whole complex. PMID- 22448848 TI - In situ assembly of raspberry- and mulberry-like silica nanospheres toward antireflective and antifogging coatings. AB - Raspberry- and mulberry-like hierarchically structured silica particulate coatings were fabricated via facile in situ layer-by-layer assembly with monodisperse silica nanoparticles (NPs) of two different sizes followed by calcination. Raspberry-like and mulberry-like silica particulate coatings were achieved when the size ratio of two silica particles was 20/200 and 20/70 nm, respectively. The latter coating exhibited good antireflective property. Its maximum transmittance reached as high as 97%, whereas that of the glass substrate is only 91%. The morphologies of the coatings were observed by scanning electron microscopy and atom force microscopy. The surface properties of these coatings were investigated by measuring their water contact angles and the spreading time of water droplet. The results showed that such hierarchically structured coatings had superhydrophilic and antifogging properties. PMID- 22448849 TI - Yoga spinal flexion positions and vertebral compression fracture in osteopenia or osteoporosis of spine: case series. AB - OBJECTIVE: The objective of this report is to raise awareness of the effect of strenuous yoga flexion exercises on osteopenic or osteoporotic spines. We previously described subjects with known osteoporosis in whom vertebral compression fractures (VCFs) developed after spinal flexion exercise (SFE) and recommended that SFEs not be prescribed in patients with spinal osteoporosis. METHODS: This report describes 3 healthy persons with low bone mass and yoga induced pain or fracture. RESULTS: All 3 patients had osteopenia, were in good health and pain-free, and had started yoga exercises to improve their musculoskeletal health. New pain and fracture areas occurred after participation in yoga flexion exercises. CONCLUSIONS: The development of pain and complications with some flexion yoga positions in the patients with osteopenia leads to concern that fracture risk would increase even further in osteoporosis. Although exercise has been shown to be effective for improving bone mineral density and decreasing fracture risk, our subjects had development of VCFs and neck and back pain with yoga exercises. This finding suggests that factors other than bone mass should be considered for exercise counseling in patients with bone loss. The increased torque pressure applied to vertebral bodies during SFEs may be a risk. Exercise is effective and important for treatment of osteopenia and osteoporosis and should be prescribed for patients with vertebral bone loss. Some yoga positions can contribute to extreme strain on spines with bone loss. Assessment of fracture risk in older persons performing SFEs and other high-impact exercises is an important clinical consideration. PMID- 22448850 TI - The hypothalamic-neurohypophyseal system: from genome to physiology. AB - The elucidation of the genomes of a large number of mammalian species has produced a huge amount of data on which to base physiological studies. These endeavours have also produced surprises, not least of which has been the revelation that the number of protein coding genes needed to make a mammal is only 22 333 (give or take). However, this small number belies an unanticipated complexity that has only recently been revealed as a result of genomic studies. This complexity is evident at a number of levels: (i) cis-regulatory sequences; (ii) noncoding and antisense mRNAs, most of which have no known function; (iii) alternative splicing that results in the generation of multiple, subtly different mature mRNAs from the precursor transcript encoded by a single gene; and (iv) post-translational processing and modification. In this review, we examine the steps being taken to decipher genome complexity in the context of gene expression, regulation and function in the hypothalamic-neurohypophyseal system (HNS). Five unique stories explain: (i) the use of transcriptomics to identify genes involved in the response to physiological (dehydration) and pathological (hypertension) cues; (ii) the use of mass spectrometry for single-cell level identification of biological active peptides in the HNS, and to measure in vitro release; (iii) the use of transgenic lines that express fusion transgenes enabling (by cross-breeding) the generation of double transgenic lines that can be used to study vasopressin (AVP) and oxytocin (OXT) neurones in the HNS, as well as their neuroanatomy, electrophysiology and activation upon exposure to any given stimulus; (iv) the use of viral vectors to demonstrate that somato dendritically released AVP plays an important role in cardiovascular homeostasis by binding to V1a receptors on local somata and dendrites; and (v) the use of virally-mediated optogenetics to dissect the role of OXT and AVP in the modulation of a wide variety of behaviours. PMID- 22448851 TI - A multilevel layout algorithm for visualizing physical and genetic interaction networks, with emphasis on their modular organization. AB - BACKGROUND: Graph drawing is an integral part of many systems biology studies, enabling visual exploration and mining of large-scale biological networks. While a number of layout algorithms are available in popular network analysis platforms, such as Cytoscape, it remains poorly understood how well their solutions reflect the underlying biological processes that give rise to the network connectivity structure. Moreover, visualizations obtained using conventional layout algorithms, such as those based on the force-directed drawing approach, may become uninformative when applied to larger networks with dense or clustered connectivity structure. METHODS: We implemented a modified layout plug in, named Multilevel Layout, which applies the conventional layout algorithms within a multilevel optimization framework to better capture the hierarchical modularity of many biological networks. Using a wide variety of real life biological networks, we carried out a systematic evaluation of the method in comparison with other layout algorithms in Cytoscape. RESULTS: The multilevel approach provided both biologically relevant and visually pleasant layout solutions in most network types, hence complementing the layout options available in Cytoscape. In particular, it could improve drawing of large-scale networks of yeast genetic interactions and human physical interactions. In more general terms, the biological evaluation framework developed here enables one to assess the layout solutions from any existing or future graph drawing algorithm as well as to optimize their performance for a given network type or structure. CONCLUSIONS: By making use of the multilevel modular organization when visualizing biological networks, together with the biological evaluation of the layout solutions, one can generate convenient visualizations for many network biology applications. PMID- 22448852 TI - Thermodynamic origins of monovalent facilitated RNA folding. AB - Cations have long been associated with formation of native RNA structure and are commonly thought to stabilize the formation of tertiary contacts by favorably interacting with the electrostatic potential of the RNA, giving rise to an "ion atmosphere". A significant amount of information regarding the thermodynamics of structural transitions in the presence of an ion atmosphere has accumulated and suggests stabilization is dominated by entropic terms. This work provides an analysis of how RNA-cation interactions affect the entropy and enthalpy associated with an RNA tertiary transition. Specifically, temperature-dependent single-molecule fluorescence resonance energy transfer studies have been exploited to determine the free energy (DeltaG degrees ), enthalpy (DeltaH degrees ), and entropy (DeltaS degrees ) of folding for an isolated tetraloop receptor tertiary interaction as a function of Na(+) concentration. Somewhat unexpectedly, increasing the Na(+) concentration changes the folding enthalpy from a strongly exothermic process [e.g., DeltaH degrees = -26(2) kcal/mol at 180 mM] to a weakly exothermic process [e.g., DeltaH degrees = -4(1) kcal/mol at 630 mM]. As a direct corollary, it is the strong increase in folding entropy [Delta(DeltaS degrees ) > 0] that compensates for this loss of exothermicity for the achievement of more favorable folding [Delta(DeltaG degrees ) < 0] at higher Na(+) concentrations. In conjunction with corresponding measurements of the thermodynamics of the transition state barrier, these data provide a detailed description of the folding pathway associated with the GAAA tetraloop-receptor interaction as a function of Na(+) concentration. The results support a potentially universal mechanism for monovalent facilitated RNA folding, whereby an increasing monovalent concentration stabilizes tertiary structure by reducing the entropic penalty for folding. PMID- 22448854 TI - Bidirectional optical sorting of gold nanoparticles. AB - We present a generic technique allowing size-based all-optical sorting of gold nanoparticles. Optical forces acting on metallic nanoparticles are substantially enhanced when they are illuminated at a wavelength near the plasmon resonance, as determined by the particle's geometry. Exploiting these resonances, we realize sorting in a system of two counter-propagating evanescent waves, each at different wavelengths that selectively guide nanoparticles of different sizes in opposite directions. We validate this concept by demonstrating bidirectional sorting of gold nanoparticles of either 150 or 130 nm in diameter from those of 100 nm in diameter within a mixture. PMID- 22448853 TI - Thrombus aspiration during primary percutaneous coronary intervention is associated with reduced myocardial edema, hemorrhage, microvascular obstruction and left ventricular remodeling. AB - BACKGROUND: Thrombus aspiration (TA) has been shown to improve microvascular perfusion during primary percutaneous coronary intervention (PCI) for patients with ST-segment elevation myocardial infarction (STEMI). The objective of our study was to assess the relationship between TA and myocardial edema, myocardial hemorrhage, microvascular obstruction (MVO) and left ventricular remodeling in STEMI patients using cardiovascular magnetic resonance (CMR). METHODS: Sixty patients were enrolled post primary PCI and underwent CMR on a 1.5 T scanner at 48 hours and 6 months. Patients were retrospectively stratified into 2 groups: those that received TA (35 patients) versus that did not receive thrombus aspiration (NTA) (25 patients). Myocardial edema and myocardial hemorrhage were assessed by T2 and T2* quantification respectively. MVO was assessed via a contrast-enhanced T1-weighted inversion recovery gradient-echo sequence. RESULTS: At 48 hours, infarct segment T2 (NTA 57.9 ms vs. TA 52.1 ms, p = 0.022) was lower in the TA group. Also, infarct segment T2* was higher in the TA group (NTA 29.3 ms vs. TA 37.8 ms, p = 0.007). MVO incidence was lower in the TA group (NTA 88% vs. TA 54%, p = 0.013).At 6 months, left ventricular end-diastolic volume index (NTA 91.9 ml/m2 vs. TA 68.3 ml/m2, p = 0.013) and left ventricular end systolic volume index (NTA 52.1 ml/m2 vs. TA 32.4 ml/m2, p = 0.008) were lower and infarct segment systolic wall thickening was higher in the TA group (NTA 3.5% vs. TA 74.8%, p = 0.003). CONCLUSION: TA during primary PCI is associated with reduced myocardial edema, myocardial hemorrhage, left ventricular remodeling and incidence of MVO after STEMI. PMID- 22448855 TI - Differential involvement of the medial prefrontal cortex in the expression of learned fear across development. AB - Studies have shown that in adult animals the medial prefrontal cortex (mPFC) is a critical brain region involved in fear regulation, with the prelimbic (PL) subregion being important for fear expression. However, few studies have examined whether the PL cortex is also involved in fear expression in infant animals. Five experiments, using immunohistochemical and temporary inactivation procedures, assessed the role of the PL in the expression of learned fear in postnatal day (PND) 18 (infant) and PND25 (juvenile) rats. We found that in juvenile rats expressing fear (measured through freezing) there was an increase in the number of phosphorylated mitogen-activated protein kinase (pMAPK)-labeled neurons in the PL; this increase was not observed in the infralimbic cortex. Furthermore, inactivation of the PL at test, using muscimol, decreased freezing in the juvenile rat. In contrast, expression of learned fear in infant rats did not require the PL, as there was neither an increase in the number of pMAPK-labeled cells in the PL nor was there any effect of PL inactivation on freezing levels. Taken together, these experiments suggest that a different neural circuitry underlies fear regulation early in life and that the lack of mPFC involvement may reflect a less flexible emotional regulation system in infant animals. PMID- 22448856 TI - Sustaining high acetylcholine levels in the frontal cortex, but not retrosplenial cortex, recovers spatial memory performance in a rodent model of diencephalic amnesia. AB - Although the thalamus and/or mammillary bodies are the primary sites of neuropathology in cases of diencephalic amnesia such as Wernicke Korsakoff Syndrome (WKS), there is also functional deactivation of certain cortical regions that contribute to the cognitive dysfunction. Acetylcholine (ACh) is a key neurotransmitter that modulates neural processing within the cortex and between the thalamus and cortex. In the pyrithiamine-induced thiamine deficiency (PTD) rat model of WKS, there are significant reductions in cholinergic innervation and behaviorally stimulated ACh efflux in the frontal (FC) and retrosplenial (RSC) cortices. In the present study, ACh released levels were site-specifically amplified with physostigmine (0.5 MUg, 1.0 MUg) in the FC and the RSC, which was confirmed with in vivo microdialysis. Although physostigmine sustained high ACh levels in both cortical regions, the effects on spatial memory, assessed by spontaneous alternation, were different as a function of region (FC, RSC) and treatment (PTD, pair-fed [PF]). Higher ACh levels in the FC recovered the rate of alternation in PTD rats as well as reduced arm-reentry perseverative errors. However, higher ACh levels within the FC of PF rats exacerbated arm-reentry perseverative errors without significantly affecting alternation rates. Maintaining high ACh levels in the RSC had no procognitive effects in PTD rats, but rather impaired alternation behavior in PF rats. These results demonstrate that diverse cortical regions respond differently to intensified ACh levels-and the effects are dependent on thalamic pathology. Thus, pharmacotherapeutics aimed at enhancing cognitive functions must account for the unique features of cortical ACh stimulation and the connective circuitry with the thalamus. PMID- 22448857 TI - The effects of basolateral amygdala lesions on unblocking. AB - Prior reinforcement of a neutral stimulus often blocks subsequent conditioning of a new stimulus if a compound of the original and new cues is paired with the same reinforcer. However, if the value of the reinforcer is altered when the compound is presented, the new cue typically acquires conditioning, a result called unblocking. Blocking, unblocking, and related phenomena have been attributed to variations in processing of either the reinforcer, for example, the Rescorla Wagner (1972) model, or cues, for example, the Pearce-Hall (1980) model. Here, we examined the effects of lesions of the basolateral amygdala on the occurrence of unblocking when the food reinforcer was increased in quantity at the time of introduction of the new cue. The lesions had no effects on unblocking in a simple design (Experiment 1), which did not distinguish between unblocking produced by variations in reward or cue processing. However, in a procedure that distinguished between unblocking due to direct conditioning by the added reinforcer, consistent with the Rescorla-Wagner (1972) model, and that due to increases in conditioning to the original reinforcer, consistent with the Pearce Hall (1980) and other models of learning, the lesions prevented unblocking of the latter type. These results were discussed in the context of roles of the basolateral amygdala in coding and using reward prediction error information in associative learning. PMID- 22448858 TI - An expert consensus approach to relating the proposed DSM-5 types and traits. AB - Although personality disorders (PDs) have been defined categorically throughout the history of psychiatric nomenclatures, the DSM-5 Personality and Personality Disorders Work Group proposed a substantial shift to a dimensional conceptualization and diagnosis of personality pathology. This proposal included the adoption of a trait model with 37 specific traits that fell within six higher order domains. In addition, they specified that half of the current diagnoses be recast as types defined by narrative description, with the other half deleted. Instead, the deleted categories would be diagnosed through ratings on specifically assigned traits. The Work Group also specified a number of traits that are relevant to each of the five DSM-5 types. However, these assignments for the types and deleted DSM-IV PDs lack empirical justification. The current study examined the relations between the DSM-5 traits and PDs slated for inclusion and exclusion using an expert consensus approach. Researchers with expertise on specific PDs provided descriptions of either the DSM-5 type narratives or a prototypic case of DSM-IV PDs in terms of the trait model. The ratings by experts in the current study demonstrated moderate agreement with the Work Group's assignments, but also identified notable discrepancies between how these types were described by the Work Group and how they were perceived by other PD researchers. These results hold promise for improving the currently proposed system and will help inform researchers and clinicians who will ultimately use the DSM-5 model. PMID- 22448859 TI - Development and construct validation of MMPI-2-RF indices of global psychopathy, fearless-dominance, and impulsive-antisociality. AB - This paper reports on three psychopathy indices derived from scores on the MMPI-2 Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008). In Study 1, we describe the development of such indices referenced to the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996) and its two distinguishable facets, Fearless-Dominance and Impulsive-Antisociality. We estimated psychopathy scores by regressing PPI scores onto conceptually selected MMPI-2-RF scales in a combined sample of 825 college students and correctional inmates. In Study 2, we explored the construct validity of these psychopathy measures in college student and correctional samples. The measures demonstrated conceptually expected patterns of associations with other established psychopathy inventories, and with psychopathy-related traits including narcissism, sensation seeking, antisociality, and impulsivity as well as broad personality and temperament factors. In Study 3, we used data from a large sample of outpatient mental health clients to establish the validity of the MMPI-2-RF psychopathy measures in relation to legal and mental health variables and therapist ratings of antisociality, narcissism, aggression, and internalizing problems. Theoretical implications of findings from these three studies for the psychopathy construct (including for DSM-5) are discussed. PMID- 22448860 TI - Deliberate self-harm among underserved adolescents: the moderating roles of gender, race, and school-level and association with borderline personality features. AB - Despite increasing research on the correlates and functions of deliberate self harm (DSH) among community youth, less is known about the subsets of youth most at-risk for DSH or the relevance of borderline personality (BP) pathology to DSH within this population. This study sought to extend research on the characteristics associated with DSH by examining the ways in which gender, racial/ethnic background, and school-level interact to influence DSH among ethnically diverse youth in a relatively poor and underserved area, as well as the extent to which levels of BP features account for differences in rates of DSH across subsets of youth. Middle- and high-school students (N = 1931) from six public schools in Mississippi completed self-report measures of DSH and BP features. Consistent with past research, 39% of the youth in our sample reported engaging in DSH. However, rates of DSH varied as function of gender, racial/ethnic background, and school-level (as well as their interactions), with African American boys reporting higher rates of most DSH behaviors than their peers (particularly in middle-school). One notable exception to this pattern pertains to the specific behavior of cutting, for which both White girls and African American boys reported the highest rates. Further, although BP features were reliably associated with DSH status (above and beyond these demographic characteristics), they did not account for the interactive effect of gender and race on rates of DSH. Findings highlight the importance of continuing to examine DSH and its correlates among more diverse groups of youth. PMID- 22448861 TI - Parental personality disorder symptoms are associated with dysfunctional parent child interactions during early childhood: a multilevel modeling analysis. AB - Personality disorders (PDs) have been linked to impaired functioning in important interpersonal domains. The present study examined the effects of parental PD symptoms on observationally assessed parent-child interaction behaviors in a community sample of 145 mothers, fathers, and their 3- to 6-year-old children. As expected, parents who endorsed more PD symptoms generally demonstrated more negative parenting; effects were also found for children's interaction behaviors. Some effects on parent-child interaction were pervasive across PD constructs, whereas others were specific to particular PDs; several moderating effects of parent sex and child age were also found. Our results provide further evidence that personality pathology reflects pervasive dysfunction that is manifested across situational and interpersonal contexts, including the parent-child relationship, even within a community sample of participants with relatively mild levels of PD symptoms. PMID- 22448862 TI - Associations among childhood abuse and psychopathy facets in male sexual offenders. AB - In the search for causes of psychopathy, the literature historically focuses on biological and temperamental differences. In comparison, this literature overshadows that of psychosocial risk factors for the development of psychopathy, namely childhood maltreatment. The current study examines the association between specific types of maltreatment (i.e., physical, emotional, sexual abuse, neglect) and PCL-R total and facet scores among a sample of 223 adult men convicted of sexual offenses and evaluated for civil commitment. Results indicate that childhood sexual abuse is associated with higher PCL-R total scores and facets tapping a grandiose and manipulative interpersonal style, impulsive-irresponsible lifestyle, and antisocial behavior. Also, childhood physical abuse and neglect are associated with antisocial behavior. Emotional detachment traits of psychopathy (i.e., lack of empathy, shallow affect) are associated with childhood neglect for child molesters, although rapists scored higher on these traits irrespective of neglect history. Theoretical and practical implications are discussed. PMID- 22448863 TI - Risk factors affecting children of mothers with borderline personality disorder: Comment on Stepp, Whalen, Pilkonis, Hipwell, and Levine (2011). AB - Comments on an article Children of mothers with borderline personality disorder: Identifying parenting behaviors as potential targets for intervention by Stepp, Whalen, Pilkonis, Hipwell, and Levine (see record 2011-05873-001). Despite both a limited empirical literature and the muddy problem of borderline personality disorder (BPD) classification, the authors have significantly clarified the risk factors relevant to children of mothers with BPD and have outlined important and reasonable skill-based interventions likely to mitigate these risks. Not only have they sensibly connected the dots among the extant studies (which included very different samples, ages of children, criterion behaviors, etc.), they have identified the few key points of agreement across studies and translated these into a blueprint for early intervention. This commentary (a) further elaborates on some of the parameters of BPD that make risk assessment for children of mothers with BPD complicated, including both diagnostic heterogeneity and myriad other problems that reduce the specificity of BPD as a classification tool for these purposes and (b) identifies direct, indirect, and general mechanisms of transmission of difficulties from a mother (or parent or caregiver) with BPD to her child. PMID- 22448864 TI - Methodological challenges in identifying parenting behaviors as potential targets for intervention: commentary on Stepp et al. (2011). AB - Comments on an article Children of mothers with borderline personality disorder: Identifying parenting behaviors as potential targets for intervention by Stepp, Whalen, Pilkonis, Hipwell, and Levine (see record 2011-05873-001). The authors have offered us an extremely timely paper, given the surge of interest in borderline psychopathology in general, and its parenting correlates in particular. This is an ambitious overview that assesses the current state of knowledge concerning the parenting of mothers with borderline personality disorder (BPD). The authors also grapple with what we can make of this literature in setting directions for prevention/intervention strategies for children of parents with BPD. This was a comprehensive and thoughtful review. This commentary elaborate on three issues brought to the fore by the current paper. PMID- 22448865 TI - Do mothers with borderline personality disorder oscillate in their behavior towards their children? Implications for interventions: commentary on Stepp, Whalen, Pilkonis, Hipwell, and Levine's article "Children of mothers with borderline personality disorder: identifying parenting behaviors as potential targets for intervention". AB - Comments on an article Children of mothers with borderline personality disorder: Identifying parenting behaviors as potential targets for intervention by Stepp, Whalen, Pilkonis, Hipwell, and Levine (see record 2011-05873-001). Maternal borderline personality disorder (BPD) may present a challenge for children's development (Macfie, 2009). Although the fertility rate for women with BPD is relatively low (McGlashan, 1986; Stone, 1990), BPD affects women exclusively during their childbearing years: from adolescence (Ludolph et al., 1990) through middle age (Paris, 1993). Stepp and her colleagues provide a rich introduction to the need for interventions for offspring of women with BPD. They also provide a wide range of suggestions. PMID- 22448866 TI - Extending research on parenting in mothers diagnosed with BPD: commentary on Stepp et al. AB - Comments on an article Children of mothers with borderline personality disorder: Identifying parenting behaviors as potential targets for intervention by Stepp, Whalen, Pilkonis, Hipwell, and Levine (see record 2011-05873-001). With this review, Stepp and colleagues have advanced our understanding of parenting and child development within the context of maternal borderline personality disorder (BPD). It is commendable that these authors have initiated the first theoretical description of how a diagnosis of BPD may affect the quality of parenting. At the same time, this article highlights the disheartening lack of research in this area. Given the paucity of prior theoretical and empirical work exploring parenting in mothers diagnosed with BPD, advances in this area could be buttressed by current conceptualizations of parenting and empirical evidence from related parenting research. In this commentary, we highlight two main concerns and provide suggestions for moving the research in this area forward. First, we raise questions about how some of the identified parenting deficits thought to be specific to mothers with BPD will be operationalized in future basic research. Second, we suggest that the use of a behavioral approach to examining parenting in this population will facilitate both basic research and future intervention work. PMID- 22448868 TI - The Open Facilities for Training in European Neurology (OFTEN): an emerging pan European exchange programme for junior neurologists. PMID- 22448869 TI - Unraveling the mechanism of catalytic reduction of O2 by microperoxidase-11 adsorbed within a transparent 3D-nanoporous ITO film. AB - Nanoporous films of indium tin oxide (ITO), with thicknesses ranging from 250 nm to 2 MUm, were prepared by Glancing Angle Deposition (GLAD) and used as highly sensitive transparent 3D-electrodes for quantitatively interrogating, by time resolved spectroelectrochemistry, the reactivity of microperoxidase-11 (MP-11) adsorbed within such films. The capacitive current densities of these 3D electrodes as well as the amount of adsorbed MP-11 were shown to be linearly correlated to the GLAD ITO film thickness, indicating a homogeneous distribution of MP-11 across the film as well as homogeneous film porosity. Under saturating adsorption conditions, MP-11 film concentration as high as 60 mM was reached. This is equivalent to a stack of 110 monolayers of MP-11 per micrometer film thickness. This high MP-11 film loading combined with the excellent ITO film conductivity has allowed the simultaneous characterization of the heterogeneous one-electron transfer dynamics of the MP-11 Fe(III)/Fe(II) redox couple by cyclic voltammetry and cyclic voltabsorptometry, up to a scan rate of few volts per second with a satisfactory single-scan signal-to-noise ratio. The potency of the method to unravel complex redox coupled chemical reactions was also demonstrated with the catalytic reduction of oxygen by MP-11. In the presence of O(2), cross correlation of electrochemical and spectroscopic data has allowed us to determine the key kinetics and thermodynamics parameters of the redox catalysis that otherwise could not be easily extracted using conventional protein film voltammetry. On the basis of numerical simulations of cyclic voltammograms and voltabsorptograms and within the framework of different plausible catalytic reaction schemes including appropriate approximations, it was shown possible to discriminate between different possible catalytic pathways and to identify the relevant catalytic cycle. In addition, from the best fits of simulations to the experimental voltammograms and voltabsorptograms, the partition coefficient of O(2) for the ITO film as well as the values of two kinetic rate constants could be extracted. It was finally concluded that the catalytic reduction of O(2) by MP 11 adsorbed within nanoporous ITO films occurs via a 2-electron mechanism with the formation of an intermediate Fe(III)-OOH adduct characterized by a decay rate of 11 s(-1). The spectroelectroanalytical strategy presented here opens new opportunities for characterizing complex redox-coupled chemical reactions not only with redox proteins, but also with redox biomimetic systems and catalysts. It might also be of great interest for the development and optimization of new spectroelectrochemical sensors and biosensors, or eventually new photoelectrocatalytic systems or biofuel cells. PMID- 22448870 TI - No evidence for an open vessel effect in centrifuge-based vulnerability curves of a long-vesselled liana (Vitis vinifera). AB - Vulnerability to cavitation curves are used to estimate xylem cavitation resistance and can be constructed using multiple techniques. It was recently suggested that a technique that relies on centrifugal force to generate negative xylem pressures may be susceptible to an open vessel artifact in long-vesselled species. Here, we used custom centrifuge rotors to measure different sample lengths of 1-yr-old stems of grapevine to examine the influence of open vessels on vulnerability curves, thus testing the hypothesized open vessel artifact. These curves were compared with a dehydration-based vulnerability curve. Although samples differed significantly in the number of open vessels, there was no difference in the vulnerability to cavitation measured on 0.14- and 0.271-m-long samples of Vitis vinifera. Dehydration and centrifuge-based curves showed a similar pattern of declining xylem-specific hydraulic conductivity (K(s)) with declining water potential. The percentage loss in hydraulic conductivity (PLC) differed between dehydration and centrifuge curves and it was determined that grapevine is susceptible to errors in estimating maximum K(s) during dehydration because of the development of vessel blockages. Our results from a long-vesselled liana do not support the open vessel artifact hypothesis. PMID- 22448871 TI - Complete monosaccharide analysis by high-performance anion-exchange chromatography with pulsed amperometric detection. AB - Monosaccharide analysis is a critical way to profile the composition of complex carbohydrates. Methods to analyze neutral and amino sugars have been established for a long time, but methods for acidic sugars are rare. The acidic sugars, including uronic acids and sialic acids, are also important components in some complex carbohydrates. In this report, a high-performance anion-exchange chromatography method with pulsed amperometric detection was initially developed to analyze acidic sugars including different uronic acids and sialic acids. Subsequently, a method to profile complete monosaccharides, including most neutral, amino, and acidic sugars, was developed. This method has a limit of quantitation of ~12.5 * 10(-3) nmol for each sugar as well as good linearity over a wide range. This is a convenient procedure because it avoids additional derivatization of monosaccharides and has a broad application to a wide range of complex carbohydrates. The monosaccharide compositions of a variety of complex carbohydrates such as different glycosaminoglycans, alginate, fucoidan, and glycans were profiled by this comprehensive method. In addition, the hydrolysis patterns of these complex carbohydrates are discussed. PMID- 22448872 TI - Study protocol for prevention of falls: a randomized controlled trial of effects of vitamin D and exercise on falls prevention. AB - BACKGROUND: Falls are the leading cause of unintentional injury and injury related death among older people. In addition to physical activity, vitamin D also may affect balance and neuromuscular function. Low serum 25-hydroksivitamin D level increases the risk of bone loss, falls and fractures. Thus, an appropriate exercise program and sufficient vitamin D intake may significantly improve not only functional balance, but also balance confidence. Balance represents a complex motor skill determined by reaction time, muscle strength, and speed and coordination of movement. METHODS/DESIGN: A 2-year randomized double-blind placebo-controlled vitamin D and open exercise trial of 409 home dwelling women 70 to 80 years of age comprising four study arms: 1) exercise + vitamin D (800 IU/d), 2) exercise + placebo, 3) no exercise + vitamin D (800 IU/d), 4) no exercise + placebo. In addition to monthly fall diaries, general health status, life style, bone health, physical functioning, and vitamin D metabolism will be assessed. The primary outcomes are the rate of falls and fall related injuries. Secondary outcomes include changes in neuromuscular functioning (e.g. body balance, muscle strength), ADL- and mobility functions, bone density and structure, cardiovascular risk factors, quality of life and fear of falling. DISCUSSION: The successful completion of this trial will provide evidence on the effectiveness of exercise and vitamin D for falls reduction. TRIAL REGISTRATION: ClinicalTrial.gov -register (NCT00986466). PMID- 22448873 TI - Magnetic DNA vector constructed from PDMAEMA polycation and PEGylated brush-type polyanion with cross-linkable shell. AB - A novel magnetic-responsive complex composed of polycation, DNA, and polyanion has been constructed via electrostatic interaction. The magnetic nanoparticles (MNPs) were first coated with a polycation, poly[2-(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety (Chol-PDMAEMA(30)), and then binded with DNA through electrostatic interaction; the complexes were further interacted with the brush-type polyanion, namely poly[poly(ethylene glycol)methyl ether methacrylate]-block-poly[methacrylic acid carrying partial mercapto groups] (PPEGMA-b-PMAA(SH)). The resulting magnetic particle/DNA/polyion complexes could be stabilized by oxidizing the mercapto groups to form cross-linking shell with bridging disulfide (S-S) between PPEGMA-b-PMAA(SH) molecular chains. The interactions among DNA, Chol-PDMAEMA coated MNPs, and PPEGMA-b-PMAA(SH) were studied by agarose gel retardation assay. The complexes were fully characterized by means of zeta potential, transmission electron microscopy (TEM), dynamic light scattering (DLS) measurements, cytotoxicity assay, antinonspecific protein adsorption, and in vitro transfection tests. All these results indicate that this kind of magnetic-responsive complex has potential applications for gene vector. PMID- 22448874 TI - A novel family of bacterial dioxygenases that catalyse the hydroxylation of free L-amino acids. AB - L-isoleucine-4-hydroxylase (IDO) is a recently discovered member of the Pfam family PF10014 (the former DUF 2257 family) of uncharacterized conserved bacterial proteins. To uncover the range of biochemical activities carried out by PF10014 members, eight in silico-selected IDO homologues belonging to the PF10014 were cloned and expressed in Escherichia coli. L-methionine, L-leucine, L isoleucine and L-threonine were found to be catalysed by the investigated enzymes, producing L-methionine sulfoxide, 4-hydroxyleucine, 4-hydroxyisoleucine and 4-hydroxythreonine, respectively. An investigation of enzyme kinetics suggested the existence of a novel subfamily of bacterial dioxygenases within the PF10014 family for which free L-amino acids could be accepted as in vivo substrates. A hypothesis regarding the physiological significance of hydroxylated l-amino acids is also discussed. PMID- 22448875 TI - Relapse of imported vivax malaria despite standard-dose primaquine therapy: an investigation with molecular genotyping analyses. AB - Taiwan CDC investigated four cases of recurrent imported vivax malaria during 2003-2010. Molecular genotyping results and the lack of inter-episodes travel history indicated that two of the patients, who acquired vivax malaria in Indonesia and the Solomon Islands, respectively, suffered relapses after an interval of 3-4 months, despite completing standard-dose primaquine therapy (30 mg/day for 14 days) for the first episode. Treatment with a higher dose of primaquine (60 mg/day for 14 days) prevented further relapse in both patients. This finding calls for further monitoring of the therapeutic efficacy of primaquine in treating Plasmodium vivax acquired in southeast Asia and Oceania. PMID- 22448876 TI - How do small rural primary health care services sustain themselves in a constantly changing health system environment? AB - BACKGROUND: The ability to sustain comprehensive primary health care (PHC) services in the face of change is crucial to the health of rural communities. This paper illustrates how one service has proactively managed change to remain sustainable. METHODS: A 6-year longitudinal evaluation of the Elmore Primary Health Service (EPHS) located in rural Victoria, Australia, is currently underway, examining the performance, quality and sustainability of the service. Threats to, and enablers of, sustainability have been identified from evaluation data (audit of service indicators, community surveys, key stakeholder interviews and focus groups) and our own observations. These are mapped against an overarching framework of service sustainability requirements: workforce organisation and supply; funding; governance, management and leadership; service linkages; and infrastructure. RESULTS: Four years into the evaluation, the evidence indicates EPHS has responded effectively to external and internal changes to ensure viability. The specific steps taken by the service to address risks and capitalise on opportunities are identified. CONCLUSIONS: This evaluation highlights lessons for health service providers, policymakers, consumers and researchers about the importance of ongoing monitoring of sentinel service indicators; being attentive to changes that have an impact on sustainability; maintaining community involvement; and succession planning. PMID- 22448877 TI - Autoantibodies against cardiac beta(1)-adrenoceptor do not affect the low affinity state beta(1)-adrenoceptor-mediated inotropy in rat cardiomyocytes. AB - Circulating autoantibodies directed against the 2nd extracellular loop (EL-2) of beta(1)-adrenoceptors (beta(1)-AABs) have been detected in the serum of patients with various cardiovascular pathologies. beta(1)-AABs induce agonistic, positive inotropic effects via beta(1)-adrenoceptors (beta(1)ARs). In the mammalian heart, beta(1)-AR can exist in 2 distinct activated configurations (the so-called high- and low-affinity states). The aim of the present study was to investigate whether the action of beta(1)-AAB is dependent on the affinity state of beta(1)AR in isolated ventricular cardiomyocytes of adult Wistar rats. Immunoglobulin G (IgG) containing beta(1)-AAB obtained from animals immunized with a peptide corresponding to the EL-2 of human beta(1)-AR, caused a dose-dependent increase in cell shortening. Isoproterenol-induced inotropy was significantly reduced in cardiomyocytes that had been preincubated with IgG containing beta(1)-AAB and in cardiomyocytes isolated from immunized rats. The negative effects of preincubation with IgG containing beta(1)-AAB on the response to isoproterenol was inhibited in the presence of bisoprolol. CGP 12177A and pindolol-induced inotropy was not affected by IgG preincubation or immunization. No detectable inotropic effect of cell shortening was obtained with IgG containing beta(1)-AAB in the presence of propranolol and 3-isobutyl-1-methylxanthine. The present study demonstrates that beta(1)-AABs have no agonist/antagonist-like effects upon low affinity state beta(1)-ARs. This result indicates that beta(1)-AABs recognize and stabilize the high-affinity state, but are unable to stabilize and (or) induce the low-affinity state receptor. PMID- 22448878 TI - Solvent-induced infrared frequency shifts in aromatic nitriles are quantitatively described by the vibrational Stark effect. AB - The physical properties of solvents strongly affect the spectra of dissolved solutes, and this phenomenon can be exploited to gain insight into the solvent solute interaction. The large solvatochromic shifts observed for many dye molecules in polar solvents are due to variations in the solvent reaction field, and these shifts are widely used to estimate the change in the dye's dipole moment upon photoexcitation, which is typically on the order of ~1-10 D. In contrast, the change in dipole moment for vibrational transitions is approximately 2 orders of magnitude smaller. Nonetheless, vibrational chromophores display significant solvatochromism, and the relative contributions of specific chemical interactions and electrostatic interactions are debated, complicating the interpretation of vibrational frequency shifts in complex systems such as proteins. Here we present a series of substituted benzonitriles that display widely varying degrees of vibrational solvatochromism. In most cases, this variation can be quantitatively described by the experimentally determined Stark tuning rate, coupled with a simple Onsager-like model of solvation, reinforcing the view that vibrational frequency shifts are largely caused by electrostatic interactions. In addition, we discuss specific cases where continuum solvation models fail to predict solvatochromic shifts, revealing the necessity for more advanced theoretical models that capture local aspects of solute-solvent interactions. PMID- 22448881 TI - Immobilization of Co-Al layered double hydroxides on graphene oxide nanosheets: growth mechanism and supercapacitor studies. AB - Layered double hydroxides (LDHs) are generally expressed as [M(2+)(1-x)M(3+)(x) (OH)(2)] [A(n-)(x/n).mH(2)O], where M(2+) and M(3+) are divalent and trivalent metal cations respectively, and A is n-valent interlayer guest anion. Co-Al layered double hydroxides (LDHs) with different sizes have been grown on graphene oxide (GO) via in situ hydrothermal crystallization. In the synthesis procedure, the GO is partially reduced in company with the formation of Co-Al LDHs. The morphology and structure of LDHs/GO hybrids are characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy. The growth mechanism of LDHs on GO nanosheets is discussed. Moreover, both LDHs and LDHs/graphene nanosheets (GNS) hybrids are further used as electrochemical supercapacitor materials and their performance is evaluated by cyclic voltammetry (CV) and galvanostatic charge/discharge measurements. It is shown that the specific capacitances of LDHs are significantly enhanced by the hybridization with GNS. PMID- 22448884 TI - High-resolution intravascular magnetic resonance quantification of atherosclerotic plaque at 3T. AB - BACKGROUND: The thickness of fibrous caps (FCT) of atherosclerotic lesions is a critical factor affecting plaque vulnerability to rupture. This study tests whether 3 Tesla high-resolution intravascular cardiovascular magnetic resonance (CMR) employing tiny loopless detectors can identify lesions and accurately measure FCT in human arterial specimens, and whether such an approach is feasible in vivo using animal models. METHODS: Receive-only 2.2 mm and 0.8 mm diameter intravascular loopless CMR detectors were fabricated for a clinical 3 Tesla MR scanner, and the absolute signal-to-noise ratio determined. The detectors were applied in a two-step protocol comprised of CMR angiography to identify atherosclerotic lesions, followed by high-resolution CMR to characterize FCT, lesion size, and/or vessel wall thickness. The protocol was applied in fresh human iliac and carotid artery specimens in a human-equivalent saline bath. Mean FCT measured by 80 MUm intravascular CMR was compared with histology of the same sections. In vivo studies compared aortic wall thickness and plaque size in healthy and hyperlipidemic rabbit models, with post-mortem histology. RESULTS: Histology confirmed plaques in human specimens, with calcifications appearing as signal voids. Mean FCT agreed with histological measurements within 13% on average (correlation coefficient, R = 0.98; Bland-Altman analysis, -1.3 +/- 68.9 MUm). In vivo aortic wall and plaque size measured by 80 MUm intravascular CMR agreed with histology. CONCLUSION: Intravascular 3T CMR with loopless detectors can both locate atherosclerotic lesions, and accurately measure FCT at high resolution in a strategy that appears feasible in vivo. The approach shows promise for quantifying vulnerable plaque for evaluating experimental therapies. PMID- 22448885 TI - Do immigration and acculturation have an impact on hyperemesis gravidarum? Results of a study in Berlin/Germany. AB - QUESTION: How large is the number of immigrant women being treated for hyperemesis gravidarum (HG) among the in-patients in a University hospital in Germany? Does migration have an impact on the psychosocial state of HG patients? Does acculturation have an impact on psychosocial distress in HG patients? METHODS: The following methods were used: retrospective evaluation of all in patients with HG from 1/1997 to 11/2009, inquiry of a consecutively surveyed group (from 2007 to 2009) of HG in-patients with a questionnaire set: socio demographic data, questionnaire on psychic distress (SCL-90-R) questionnaire on migration/acculturation, and comparison of German patients and patients with immigration backgrounds as well as among immigrant groups. RESULTS: During the 13 year study period, there were 4.5 times more immigrants treated for HG than native German patients. Compared to the age standardized resident population, the number of women with immigration backgrounds is over-proportionally high. The HG patients scored high in the SCL-90-R scale "somatization" without showing a higher level of psychic distress than the native patients. CONCLUSIONS: Experience of migration is an etiological cofactor for HG. The grade of acculturation does not have a significant influence on the psychic well-being of HG patients. PMID- 22448886 TI - Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy. AB - BACKGROUND: P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma. METHODS: Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted. RESULTS: Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT. CONCLUSIONS: Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population. PMID- 22448887 TI - Transdermal opioid patches for pain treatment in ancient Greece. AB - Pain treatment in ancient Greece, and through the middle ages in Europe, was to a great extent based on the expertise of the Greek physician Galen (c. 129-200 A.D.). Galen makes particular reference to "Olympic Victor's Dark Ointment" (OVDO), which is listed with a number of collyria. Galen states that OVDO can be useful for treating extreme pain and swellings, forming one of the best eye salves. Olympic Victor's Dark Ointment, an opium-based treatment, forms a "patch" when applied externally as an ointment, because it quickly dries to cover a localized region but still retains its elastic properties. This study has recreated OVDO and applied the ointment to abdominal mouse skin, in vitro. To assess the efficacy of OVDO, the transdermal transfer of morphine was measured when given as OVDO and compared to morphine administered in the form of a solution of Opium + PBS (ringer). Olympic Victor's Dark Ointment showed a transdermal transfer of morphine over time comparable to 25% of the most efficient modern transdermal opioid patches, while hardly any morphine was able to penetrate the skin when applied mixed in PBS. We conclude that OVDO is very efficient in its composition and may carry some forgotten abilities in terms of drug delivery, which could be transferred to modern medicine. Indeed, this may lead to a better choice of morphine use and controlled management in individual patient cases, taking both pain relief and anti-inflammatory aspects into account. PMID- 22448888 TI - Changing beliefs and behavior through experience-taking. AB - The present research introduces the concept of experience-taking-the imaginative process of spontaneously assuming the identity of a character in a narrative and simulating that character's thoughts, emotions, behaviors, goals, and traits as if they were one's own. Six studies investigated the degree to which particular psychological states and features of narratives cause individuals, without instruction, to engage in experience-taking and investigated how the merger between self and other that occurs during experience-taking produces changes in self-judgments, attitudes, and behavior that align with the character's. Results from Studies 1-3 showed that being in a reduced state of self-concept accessibility while reading a brief fictional work increased-and being in a heightened state of self-concept accessibility decreased-participants' levels of experience-taking and subsequent incorporation of a character's personality trait into their self-concepts. Study 4 revealed that a first-person narrative depicting an ingroup character elicited the highest levels of experience-taking and produced the greatest change in participants' behavior, compared with versions of the narrative written in 3rd-person voice and/or depicting an outgroup protagonist. The final 2 studies demonstrated that whereas revealing a character's outgroup membership as a homosexual or African American early in a narrative inhibited experience-taking, delaying the revelation of the character's outgroup identity until later in the story produced higher levels of experience taking, lower levels of stereotype application in participants' evaluation of the character, and more favorable attitudes toward the character's group. The implications of these findings in relation to perspective-taking, self-other overlap, and prime-to-behavior effects are discussed. PMID- 22448889 TI - Stereotyping by omission: eliminate the negative, accentuate the positive. AB - Communicators, motivated by strategic self-presentation, selectively underreport negative content in describing their impressions of individuals and stereotypes of groups, particularly for targets whom they view ambivalently with respect to warmth and competence. Communicators avoid overtly inaccurate descriptions, preferring to omit negative information and emphasize positive information about mixed individual targets (Study 1). With more public audiences, communicators increasingly prefer negativity omission to complete accuracy (Study 2), a process driven by self-presentation concerns (Study 3) and moderated by bidimensional ambivalence. Similarly, in an extension of the Princeton Trilogy studies, reported stereotypes of ethnic and national outgroups systematically omitted negative dimensions over 75 years--as anti-prejudice norms intensified--while neutral and positive stereotype dimensions remained constant (Study 4). Multiple assessment methods confirm this stereotyping-by-omission phenomenon (Study 5). Implications of negativity omission for innuendo and stereotype stagnation are discussed. PMID- 22448890 TI - Identification of genes transcribed by Pasteurella multocida in rabbit livers through the selective capture of transcribed sequences. AB - Pasteurella multocida, a Gram-negative nonmotile coccobacillus, is the causative agent of fowl cholera in poultry, hemorrhagic septicemia in cattle, atropic rhinitis in swine, and snuffles in rabbits. The differentially expressed gene profile of P. multocida in infected rabbit livers was identified and compared with that from in vitro culture by selective capture of transcribed sequences. A total of 31 genes were identified, of which 28 encoded enzymes for amino acid biosynthesis and metabolism, intermediary metabolism, and energy metabolism, or proteins for regulatory adaptive responses, general microbial stress response, transport proteins, and secreted proteinases. Three were unknown, novel genes. Five genes representing different categories were chosen randomly and verified by real-time reverse transcriptase-polymerase chain reaction analysis. All were upregulated by P. multocida in infected rabbit livers, with changes ranging from 1.61- to 13.55-fold when compared with in vitro cultures. This study has identified genes of P. multocida that are upregulated during infection of rabbit livers when compared with in vitro growth conditions. The genes will provide a molecular basis for further study of the pathogenesis of P. multocida. PMID- 22448891 TI - Raman spectroscopic analysis of gunshot residue offering great potential for caliber differentiation. AB - Near-infrared (NIR) Raman microspectroscopy combined with advanced statistics was used to differentiate gunshot residue (GSR) particles originating from different caliber ammunition. The firearm discharge process is analogous to a complex chemical reaction. The reagents of this process are represented by the chemical composition of the ammunition, firearm, and cartridge case. The specific firearm parameters determine the conditions of the reaction and thus the subsequent product, GSR. We found that Raman spectra collected from these products are characteristic for different caliber ammunition. GSR particles from 9 mm and 0.38 caliber ammunition, collected under identical discharge conditions, were used to demonstrate the capability of confocal Raman microspectroscopy for the discrimination and identification of GSR particles. The caliber differentiation algorithm is based on support vector machines (SVM) and partial least squares (PLS) discriminant analyses, validated by a leave-one-out cross-validation method. This study demonstrates for the first time that NIR Raman microspectroscopy has the potential for the reagentless differentiation of GSR based upon forensically relevant parameters, such as caliber size. When fully developed, this method should have a significant impact on the efficiency of crime scene investigations. PMID- 22448892 TI - Prior exercise training alleviates the lung inflammation induced by subsequent exposure to environmental cigarette smoke. AB - AIM: Environmental cigarette smoke (CS) contains many compounds that are harmful to the respiratory system and lead to chronic lung inflammation and other lung diseases. Exercise training is known to confer protection against diseases with chronic inflammation by reducing inflammatory response in human or experimental animals. In this study, we investigated the preventive effect of exercise training against lung inflammation induced by environmental CS. METHODS AND RESULTS: In this study, two groups of mice received air exposure with (the exercise group) or without (the control group) exercise training for 8 weeks and another two groups received air exposure for the first 4 weeks and CS exposure for the following 4 weeks with (the exercise+CS group) or without (the CS group) exercise training for 8 weeks. As compared with lung tissues of control and exercise groups, those of the CS group showed significantly increased bronchoalveolar-capillary permeability, inflammatory cell infiltration, epithelial thickening, expression of proliferating cell nuclear antigen, mucin 2, cytokines, chemokines, adhesion molecules and activation of NF-kappaB. These CS induced pathophysiologic consequences were largely prevented in the exercise + CS group. CONCLUSION: Collectively, prior exercise training may protect against lung inflammation induced by environmental CS in mice by attenuating the activation of NF-kappaB and the production of inflammatory mediators. PMID- 22448893 TI - Surface plasmon polariton amplification upon electrical injection in highly integrated plasmonic circuits. AB - We propose a very efficient approach for amplification of surface plasmon polaritons (SPPs) in a nanoscale waveguiding geometry with strong (~lambda/10) mode confinement. The implemented scheme of electric pumping is based on a single heterostructure Schottky-barrier diode and has been numerically shown to ensure full compensation of the SPP propagation losses at wavelengths around 3 MUm and, moreover, to provide net SPP gain. The presented concept creates the backbone for the implementation of highly integrated large-scale hybrid electronic-plasmonic circuits operating at extremely high speeds and opens the prospects for the realization of integrated coherent SPP sources. PMID- 22448894 TI - Surface chemistry of isopropoxy tetramethyl dioxaborolane on Cu(111). AB - The surface chemistry of isopropoxy tetramethyl dioxaborolane (ITDB), tetramethyl dioxaborolane (TDB), and 2-propanol is studied on a clean Cu(111) single crystal using temperature-programmed desorption (TPD). 2-Propanol is found to have two competing reactions on the copper surface. Dehydration results in water and propene formation, and dehydrogenation results in the formation of acetone and hydrogen. ITDB directly adsorbed on the surface reacts completely and does not molecularly desorb. TDB and 2-propanol decompose desorbing mainly 2,3-dimethyl 2 butene and acetone, respectively. Both of those products desorb above room temperature and are present in TPDs of ITDB. An additional acetone desorption peak was observed for ITDB at higher temperatures than acetone desorption from 2 propanol. This higher temperature peak at ~391 K was attributed to two acetone molecules forming from the tetramethyl end group resulting from a stronger bound surface species in ITDB compared to TDB despite their identical end groups. The copper surface seems to be reactive enough toward ITDB at room temperature that a potential boron-containing tribofilm could be produced for copper-copper sliding contacts. Despite their similarities, ITDB and TDB have different surface species present at room temperature, so their tribological properties will be investigated in the future. PMID- 22448895 TI - Manipulation of liquid filaments on photoresponsive microwrinkles. AB - Microwrinkle grooves serve as open microchannel capillaries, where the capillary action depends on the wettability of a liquid on the groove surface. Here, we report the photoinduced capillary action of a liquid in such microwrinkle grooves. The wettability is changed through the irradiation of a photoresponsive microwrinkle surface. By utilizing micropattern light-projection apparatus, we prepare liquid filaments that fill only the microgrooves prescribed by the patterned light, with micrometer-scale spatial resolution. This new technology enables the precise spatial control of liquids on a solid surface, and thus, is applicable in the fields of micropatterning and open-channel microfluidics. PMID- 22448896 TI - Activation of 11R-lipoxygenase is fully Ca(2+)-dependent and controlled by the phospholipid composition of the target membrane. AB - Activation of some lipoxygenases (LOX) is found to be related to the selective membrane binding upon cell stimulation. In this study, a systematic analysis of the effect of the lipid composition on the membrane binding efficiency, Ca(2+) affinity, and enzymatic activity of 11R-LOX was performed. The analysis of the membrane targeting by fluorometric and surface plasmon resonance measurements in the absence of Ca(2+) showed an exclusive binding of 11R-LOX to the anionic phospholipids (phosphatidylinositol < phosphatidylglycerol ~ phosphatidylserine) containing model membranes. The presence of Ca(2+) enhanced the rate of interaction and influenced its mode. The modulation of the activity of 11R-LOX indicated that (i) Ca(2+) binding is a prerequisite for productive membrane association, (ii) the reaction of 11R-LOX with arachidonic acid coincided with and was driven by its Ca(2+)-mediated membrane association, and (iii) phosphatidylethanolamine and anionic phospholipids had a synergistic effect on the Ca(2+) affinity, in line with a target-activated messenger affinity mechanism [Corbin, J. A., et al. (2007) Biochemistry 46, 4322-4336]. According to the mechanism proposed in this report, 11R-LOX can bind to the membranes in two different modes and the efficiency of productive membrane binding is determined by a concerted association of Ca(2+) and lipid headgroups. PMID- 22448897 TI - WAVOS: a MATLAB toolkit for wavelet analysis and visualization of oscillatory systems. AB - BACKGROUND: Wavelets have proven to be a powerful technique for the analysis of periodic data, such as those that arise in the analysis of circadian oscillators. While many implementations of both continuous and discrete wavelet transforms are available, we are aware of no software that has been designed with the nontechnical end-user in mind. By developing a toolkit that makes these analyses accessible to end users without significant programming experience, we hope to promote the more widespread use of wavelet analysis. FINDINGS: We have developed the WAVOS toolkit for wavelet analysis and visualization of oscillatory systems. WAVOS features both the continuous (Morlet) and discrete (Daubechies) wavelet transforms, with a simple, user-friendly graphical user interface within MATLAB. The interface allows for data to be imported from a number of standard file formats, visualized, processed and analyzed, and exported without use of the command line. Our work has been motivated by the challenges of circadian data, thus default settings appropriate to the analysis of such data have been pre selected in order to minimize the need for fine-tuning. The toolkit is flexible enough to deal with a wide range of oscillatory signals, however, and may be used in more general contexts. CONCLUSIONS: We have presented WAVOS: a comprehensive wavelet-based MATLAB toolkit that allows for easy visualization, exploration, and analysis of oscillatory data. WAVOS includes both the Morlet continuous wavelet transform and the Daubechies discrete wavelet transform. We have illustrated the use of WAVOS, and demonstrated its utility for the analysis of circadian data on both bioluminesence and wheel-running data. WAVOS is freely available at http://sourceforge.net/projects/wavos/files/ PMID- 22448898 TI - Phase transformation of colloidal In2O3 nanocrystals driven by the interface nucleation mechanism: a kinetic study. AB - The kinetics of phase transformation of colloidal In(2)O(3) nanocrystals (NCs) during their synthesis in solution was explored by a combination of structural and spectroscopic methods, including X-ray diffraction, transmission electron microscopy, and extended X-ray absorption fine structure spectroscopy. Johnson Mehl-Avrami-Erofeyev-Kholmogorov (JMAEK) and the interface nucleation models were used to analyze the isothermal kinetic data for the phase transformation of NCs in the temperature range of 210-260 degrees C. The results show that NCs are initially stabilized in the metastable corundum (rh-In(2)O(3)) phase. The phase transformation occurs via nucleation of cubic bixbyite (bcc-In(2)O(3)) phase at the interface between contacting rh-In(2)O(3) NCs, and propagates rapidly throughout the NC volume. The activation energy of the phase transformation was determined from the Arrhenius expression to be 152 +/- 60 kJ/mol. The interface nucleation rate is maximal at the beginning of the phase transformation process, and decreases over the course of the reaction due to a decrease in the concentration of rh-In(2)O(3) NCs in the reaction mixture. In situ high temperature XRD patterns collected during nonisothermal treatment of In(2)O(3) NCs reveal that phase transformation of smaller NCs occurs at a faster rate and lower temperature, which is associated with their higher packing density and contact formation probability. Because NC surfaces and interfaces play a key role in phase transformation, their control through the synthesis conditions and reaction kinetics is an effective route to manipulate NC structure and properties. PMID- 22448899 TI - Molecular dynamics study of the interaction of arginine with phosphatidylcholine and phosphatidylethanolamine bilayers. AB - In this work, the differential interaction of zwitterionic arginines with fully hydrated dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) bilayers was analyzed by molecular dynamics simulations. In both systems, arginine binds to lipids with the carboxylate moiety oriented toward the aqueous phase, in agreement with previous experimental determinations of zeta potential of DMPC and DMPE liposomes. The guanidinium groups are found at different depths within the bilayers indicating that some arginines are buried, especially in DMPE. We observe, in the DMPE system, that the strongest interaction occurs between the guanidinium group and the carbonyl oxygen of the lipid. In the case of DMPC membranes, the strongest interaction is found between the guanidinium groups of the arginines and the phosphate groups of the lipids. Unexpectedly, arginine zwitterions are stabilized through the creation of hydrogen bonds (HB), either with water or with polar groups of the lipids. The mechanisms of interaction seem to be different in both membranes. In DMPE bilayers, arginines insert by breaking the inner HB network of the polar head groups, consequently increasing the occupied area per lipid molecule. In the DMPC bilayers the arginines insert by replacing the already present water molecules within the membrane, without significant effects on the area per lipid. PMID- 22448900 TI - Cysteine-induced modifications of zero-valent silver nanomaterials: implications for particle surface chemistry, aggregation, dissolution, and silver speciation. AB - The persistence of silver nanoparticles in aquatic environments and their subsequent impact on organisms depends on key transformation processes, which include aggregation, dissolution, and surface modifications by metal-complexing ligands. Here, we studied how cysteine, an amino acid representative of thiol ligands that bind monovalent silver, can alter the surface chemistry, aggregation, and dissolution of zero-valent silver nanoparticles. We compared nanoparticles synthesized with two coatings, citrate and polyvinylpirrolidone (PVP), and prepared nanoparticle suspensions (approximately 8 MUM total Ag) containing an excess of cysteine (400 MUM). Within 48 h, up to 47% of the silver had dissolved, as indicated by filtration of the samples with a 0.025-MUm filter. Initial dissolution rates were calculated from the increase of dissolved silver concentration when particles were exposed to cysteine and normalized to the available surface area of nanoparticles in solution. In general, the rates of dissolution were almost 3 times faster for citrate-coated nanoparticles relative to PVP-coated nanoparticles. Rates tended to be slower in solutions with higher ionic strength in which the nanoparticles were aggregating. X-ray absorption spectroscopy analysis of the particles suggested that cysteine adsorbed to silver nanoparticles surfaces through the formation of Ag(+I)--sulfhydryl bonds. Overall, the results of this study highlight the importance of modifications by sulfhydryl-containing ligands that can drastically influence the long-term reactivity of silver nanoparticles in the aquatic environment and their bioavailability to exposed organisms. Our findings demonstrate the need to consider multiple interlinked transformation processes when assessing the bioavailability, environmental risks, and safety of nanoparticles, particularly in the presence of metal-binding ligands. PMID- 22448901 TI - Transcranial direct current stimulation of the affected hemisphere does not accelerate recovery of acute stroke patients. AB - BACKGROUND AND PURPOSE: Transcranial direct current stimulation (TDCS) is a potential tool to improve motor deficits in chronic stroke patients. Safety and efficacy of this procedure in acute stroke patients have not yet been addressed. METHODS: We performed in our stroke unit a single-centre randomized, double blind, sham-controlled study to investigate safety and efficacy of anodal TDCS of the affected hemisphere in acute stroke patients. The second day from stroke onset, 50 acute stroke patients received either five-daily sessions of anodal (n=25) at 2mA for 20min or sham TDCS (n=25) to the ipsilesional primary motor cortex (M1). Motor deficit was assessed by the short form of the Fugl-Meyer motor scale (FM) and overall neurological deficit by the National Institute of Health Stroke Scale (NIHSS) at onset, at 5days after stroke and after 3months. RESULTS: No side effects were detected during either TDCS or sham. In both groups, there was a significant improvement in NIHSS and FM scores, which did not significantly differ when comparing TDCS and sham. CONCLUSIONS: Five-daily sessions of anodal TDCS to the ipsilesional M1 appear to be safe in acute stroke patients but do not improve clinical outcome. PMID- 22448902 TI - USA300 abroad: global spread of a virulent strain of community-associated methicillin-resistant Staphylococcus aureus. AB - The epidemic of USA300-0114 methicillin-resistant Staphylococcus aureus (MRSA) in the USA has been remarkable for its virulence and for its ability to cause infections in both the community and healthcare settings. Although it has mainly been associated with skin and soft tissue infections, particularly furunculosis, it has also caused severe life-threatening conditions such as necrotizing pneumonia, osteomyelitis, and septic arthritis. This strain or a closely related Latin American variant has now spread to multiple countries on five continents, where associated clinical and epidemiological features have been in keeping with those seen in the USA. Furthermore, it has become the dominant community associated MRSA strain in five countries. It is now a major international epidemic strain, but whether it will supplant established community-associated strains in other countries remains to be seen. PMID- 22448903 TI - The impact of processing time on the bizarreness and orthographic distinctiveness effects. AB - The bizarreness effect and the orthographic distinctiveness effect (OD effect) are typical cases of secondary-distinctiveness-based effects. This study tested the simple attentional account or processing time hypothesis as a possible explanation of the bizarreness effect and the OD effect. In the bizarreness effect literature, this hypothesis gained support by some studies but was also discredited by other research. In light of these conflicting results, Experiment 1 was devised to test the processing time hypothesis in the bizarreness effect by using black-and-white concrete images and manipulating the time allotted for processing the stimuli (500 ms, 1000 ms, 3000 ms). Concerning the OD effect, no research has directly investigated the impact of processing time by examining the effect under varying amounts of study time. Experiment 2 was thus devised to investigate this same hypothesis in the OD effect and time allotted for processing the stimuli was manipulated (250 ms, 500 ms, 1000 ms, 3000 ms). Results did not support the processing time hypothesis since the magnitude of the bizarreness effect and of the OD effect was not modulated by the amount of time allotted for processing the stimuli. We refer to alternative explanations to account for these two secondary-distinctiveness-based effects. PMID- 22448904 TI - European outbreaks of atypical myopathy in grazing equids (2006-2009): spatiotemporal distribution, history and clinical features. AB - REASONS FOR PERFORMING STUDY: Improved understanding of the epidemiology of atypical myopathy (AM) will help to define the environmental factors that permit or support the causal agent(s) to exert toxicity. OBJECTIVES: This European survey of AM aimed to describe spatiotemporal distribution, survival, clinical signs, circumstances in which AM develops and its different expressions between countries and over time. METHODS: The spatiotemporal distribution, history and clinical features of AM cases reported to the Atypical Myopathy Alert Group from 2006 to 2009 were described. Comparisons of data from the most severely affected countries and from the large outbreaks were made with Fisher's exact and Welch's tests with Bonferroni correction. RESULTS: Of 600 suspected cases, 354 met the diagnostic criteria for confirmed or highly probable AM. The largest outbreaks occurred during the autumns of 2006 and 2009 in Belgium, France and Germany. For the first time, donkeys, zebras and old horses were affected, and clinical signs such as gastrointestinal impaction, diarrhoea, penile prolapse, buccal ulceration and renal dysfunction were observed. Affected horses spent >6 h/day on pastures that almost always contained or were surrounded by trees. The latency period was estimated at up to 4 days. Overall survival rate was 26%. Although differences between countries in affected breeds, body condition, horse management and pasture characteristics were recognised, the common presenting clinical signs and mortality were similar between countries. CONCLUSIONS AND POTENTIAL RELEVANCE: This study describes new data on case details, history and clinical course of AM that is of preventive, diagnostic and therapeutic value. However, the true impact of the findings of this study on the development of or severity of AM should be tested with case-control studies. PMID- 22448905 TI - Theoretical investigation of the mechanisms for the reaction of fused tricyclic dimetallenes containing highly strained E?E (E = C, Si, Ge, Sn, and Pb) double bonds. AB - The potential energy surfaces for the reactions of fused tricyclic dimetallenes that feature a highly strained E?E double bond, Rea-E?E, where E = C, Si, Ge, Sn, and Pb, were studied using density functional theory (B3LYP/LANL2DZ). Three types of chemical reactions (i.e., a self-isomerization reaction, a [2 + 2] cycloaddition with a ketone and a methanol 1,2-addition reaction) were used to determine the reactivity of the Rea-E?E molecules. The theoretical findings reveal that the smaller the singlet-triplet splitting of the Rea-E?E, the lower are its activation barriers and, in turn, the more rapid are its chemical reactions with other chemical molecules. Theoretical observations suggest that the relative reactivity increases in the following order: C?C ? Si?Si < Ge?Ge < Sn?Sn < Pb?Pb. Namely, the smaller the atomic weight of the group 14 atom (E), the smaller is the atomic radius of E and the more stable is its fused tricyclic Rea-E?E to chemical reaction. It is thus predicted that the fused tricyclic Rea C?C and Rea-Si?Si molecules should be stable and readily synthesized and isolated at room temperature. The computational results show good agreement with the available experimental observations. The theoretical results obtained from this work allow a number of predictions to be made. PMID- 22448906 TI - EHD2 shuttles to the nucleus and represses transcription. AB - EHD {EH [Eps15 (epidermal growth factor receptor substrate 15) homology]-domain containing} proteins participate in several endocytic events, such as the internalization and the recycling processes. There are four EHD proteins in mammalian cells, EHD1-EHD4, each with diverse roles in the recycling pathway of endocytosis. EHD2 is a plasma-membrane-associated member of the EHD family that regulates internalization. Since several endocytic proteins have been shown to undergo nucleocytoplasmic shuttling and have been assigned roles in regulation of gene expression, we tested the possibility that EHD proteins also shuttle to the nucleus. Our results showed that, among the three EHD proteins (EHD1-EHD3) that were tested, only EHD2 accumulates in the nucleus under nuclear export inhibition treatment. Moreover, the presence of a NLS (nuclear localization signal) was essential for its entry into the nucleus. Nuclear exit of EHD2 depended partially on its NES (nuclear export signal). Elimination of a potential SUMOylation site in EHD2 resulted in a major accumulation of the protein in the nucleus, indicating the involvement of SUMOylation in the nuclear exit of EHD2. We confirmed the SUMOylation of EHD2 by employing co-immunoprecipitation and the yeast two-hybrid system. Using GAL4-based transactivation assay as well as a KLF7 (Kruppel-like factor 7)-dependent transcription assay of the p21WAF1/Cip1 [CDKN1A (cyclin-dependent kinase inhibitor 1A)] gene, we showed that EHD2 represses transcription. qRT-PCR (quantitative real-time PCR) of RNA from cells overexpressing EHD2 or of RNA from cells knocked down for EHD2 confirmed that EHD2 represses transcription of the p21WAF1/Cip1 gene. PMID- 22448907 TI - Splint: the efficacy of orthotic management in rest to prevent equinus in children with cerebral palsy, a randomised controlled trial. AB - BACKGROUND: Range of motion deficits of the lower extremity occur in about the half of the children with spastic cerebral palsy (CP). Over time, these impairments can cause joint deformities and deviations in the children's gait pattern, leading to limitations in moblity. Preventing a loss of range of motion is important in order to reduce secondary activity limitations and joint deformities. Sustained muscle stretch, imposed by orthotic management in rest, might be an effective method of preventing a decrease in range of motion. However, no controlled study has been performed. METHODS: A single blind randomised controlled trial will be performed in 66 children with spastic CP, divided over three groups with each 22 participants. Two groups will be treated for 1 year with orthoses to prevent a decrease in range of motion in the ankle (either with static or dynamic knee-ankle-foot-orthoses) and a third group will be included as a control group and will receive usual care (physical therapy, manual stretching). Measurements will be performed at baseline and at 3, 6, 9 and 12 months after treatment allocation. The primary outcome measure will be ankle dorsiflexion at full knee extension, measured with a custom designed hand held dynamometer. Secondary outcome measures will be i) ankle and knee flexion during gait and ii) gross motor function. Furthermore, to gain more insight in the working mechanism of the orthotic management in rest, morphological parameters like achilles tendon length, muscle belly length, muscle fascicle length, muscle physiological cross sectional area length and fascicle pennation angle will be measured in a subgroup of 18 participants using a 3D imaging technique. DISCUSSION: This randomised controlled trial will provide more insight into the efficacy of orthotic management in rest and the working mechanisms behind this treatment. The results of this study could lead to improved treatments. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR2091. PMID- 22448908 TI - Upregulation of platelet (L)-arginine: nitric oxide pathway after exercise training in hypertension. AB - We investigated whether physical exercise can affect platelet L-arginine - nitric oxide pathway in spontaneously hypertensive rats (SHR). Sixteen male SHR and 16 Wistar Kyoto rats (WKY) were divided among exercise (EX) and sedentary (SED) groups. After 20 weeks of treadmill training, systolic blood pressure (mm Hg) was significantly lower in exercised spontaneously hypertensive rats (SHR/EX; 138 +/- 8) than in sedentary spontaneously hypertensive rats (SHR/SED; 214 +/- 9). Exercise significantly increased platelet L-arginine transport (pmol L arginine.(10(9) cells)(-1).min(-1)), assessed by incubation with L-[(3)H] arginine, in both WKY (SED, 0.196 +/- 0.054 compared with EX, 0.531 +/- 0.052) and SHR (SED, 0.346 +/- 0.076 compared with EX, 0.600 +/- 0.049). Nitric oxide synthase (NOS) activity (pmol L-citrulline.(10(8) cells)(-1)), measured by the conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline, was significantly increased in SHR/EX (0.072 +/- 0.007) compared with SHR/SED (0.038 +/- 0.007), but no changes were observed in WKY. The iNOS and eNOS protein levels assessed by Western blot were not affected by exercise. This upregulation of the platelet L arginine-NO pathway may attenuate the risk of thromboembolic events, supporting the role of exercise in hypertension management. PMID- 22448909 TI - B2A as a positive BMP receptor modulator. AB - B2A (B2A2-K-NS) is a synthetic multi-domain peptide that in vitro augments bone morphogenetic protein (BMP)-2-induced cell responsiveness and osteodifferentiation. Augmentation of endogenous BMP-2 is thought to ultimately improve bone repair, and has led to clinical evaluation of B2A in orthopedic applications. In this study, we show that B2A binds to BMP receptor (BMPR)-IB, BMPR-II, and BMPR-IA. B2A reduces the EC50 of rh-BMP-2, thus shifting the response curve to the left. B2A enhances the osteogenic activity of BMP-2, but not growth and differentiation factor-5, BMP-7, or BMP-9, indicating its action is highly BMP-2 selective. Additionally, B2A did not augment Wnt-3a- and retinoic acid-induced differentiation. All three functional domains (receptor-binding domain, hydrophobic-linker domain, heparin-binding domain) of B2A are required for optimal bioactivity. Collectively, the results suggest that B2A, via its unique sequence, acts in a manner consistent with a positive receptor modulator to selectively enhance BMP-2 osteodifferentiation, and yet in the absence of BMP 2, B2A is without cooperative effect. PMID- 22448910 TI - An electrochemical immunosensor based on chemical assembly of vertically aligned carbon nanotubes on carbon substrates for direct detection of the pesticide endosulfan in environmental water. AB - A glassy carbon substrate was covalently modified with a mixed layer of 4 aminophenyl and phenyl via in situ electrografting of their aryldiazonium salts in acidic solutions. Single-walled carbon nanotubes (SWNTs) were covalently and vertically anchored on the electrode surface via the formation of amide bonds from the reaction between the amines located on the modified substrate and the carboxylic groups at the ends of the nanotubes. Ferrocenedimethylamine (FDMA) was subsequently attached to the ends of SWNTs through amide bonding followed by the attachment of an epitope, i.e., endosulfan hapten to which an antibody would bind. Association or dissociation of the antibody with the sensing interface causes a modulation of the ferrocene electrochemistry. Antibody-complexed electrodes were exposed to samples containing spiked endosulfan (unbound target analyte) in environment water and interrogated using the square wave voltammetry (SWV) technique. The modified sensing surfaces were characterized by atomic force microscopy, XPS, and electrochemistry. The fabricated electrochemical immunosensor can be successfully used for the detection of endosulfan over the range of 0.01-20 ppb by a displacement assay. The lowest detection limit of this immunosensor is 0.01 ppb endosulfan in 50 mM phosphate buffer at pH 7.0. PMID- 22448911 TI - Feed restriction and a diet's caloric value: The influence on the aerobic and anaerobic capacity of rats. AB - BACKGROUND: The influence of feed restriction and different diet's caloric value on the aerobic and anaerobic capacity is unclear in the literature. Thus, the objectives of this study were to determine the possible influences of two diets with different caloric values and the influence of feed restriction on the aerobic (anaerobic threshold: AT) and anaerobic (time to exhaustion: Tlim) variables measured by a lactate minimum test (LM) in rats. METHODS: We used 40 adult Wistar rats. The animals were divided into four groups: ad libitum commercial Purina(r) diet (3028.0 Kcal/kg) (ALP), restricted commercial Purina(r) diet (RAP), ad libitum semi-purified AIN-93 diet (3802.7 Kcal/kg) (ALD) and restricted semi-purified AIN-93 diet (RAD). The animals performed LM at the end of the experiment, 48 h before euthanasia. Comparisons between groups were performed by analysis of variance (p < 0,05). RESULTS: At the end of the experiment, the weights of the rats in the groups with the restricted diets were significantly lower than those in the groups with ad libitum diet intakes. In addition, the ALD group had higher amounts of adipose tissue. With respect to energetic substrates, the groups subjected to diet restriction had significantly higher levels of liver and muscle glycogen. There were no differences between the groups with respect to AT; however, the ALD group had lower lactatemia at the AT intensity and higher Tlim than the other groups. CONCLUSIONS: We conclude that dietary restriction induces changes in energetic substrates and that ad libitum intake of a semi-purified AIN-93 diet results in an increase in adipose tissue, likely reducing the density of the animals in water and favouring their performance during the swimming exercises. PMID- 22448912 TI - Cognition, action, and object manipulation. AB - Although psychology is the science of mental life and behavior, little attention has been paid to the means by which mental life is translated into behavior. One domain in which links between cognition and action have been explored is the manipulation of objects. This article reviews psychological research on this topic, with special emphasis on the tendency to grasp objects differently depending on what one plans to do with the objects. Such differential grasping has been demonstrated in a wide range of object manipulation tasks, including grasping an object in a way that reveals anticipation of the object's future orientation, height, and required placement precision. Differential grasping has also been demonstrated in a wide range of behaviors, including 1-hand grasps, 2 hand grasps, walking, and transferring objects from place to place as well as from person to person. The populations in which the tendency has been shown are also diverse, including nonhuman primates as well as human adults, children, and babies. The tendency is compromised in a variety of clinical populations and in children of a surprisingly advanced age. Verbal working memory is compromised as well if words are memorized while object manipulation tasks are performed; the recency portion of the serial position curve is reduced in this circumstance. In general, the research reviewed here points to rich connections between cognition and action as revealed through the study of object manipulation. Other implications concern affordances, Donders' law, naturalistic observation, and the teaching of psychology. PMID- 22448913 TI - An inconvenienced youth? Ageism and its potential intergenerational roots. AB - Age is the only social category identifying subgroups that everyone may eventually join. Despite this and despite the well-known growth of the older population, age-based prejudice remains an understudied topic in social psychology. This article systematically reviews the literature on ageism, highlighting extant research on its consequences and theoretical perspectives on its causes. We then identify a crucial gap in the literature, potential intergenerational tensions, speculating how a growing-older population-and society's efforts to accommodate it-might stoke intergenerational fires, particularly among the younger generation. Presenting both sides of this incipient issue, we review relevant empirical work that introduces reasons for both optimism and pessimism concerning intergenerational relations within an aging society. We conclude by suggesting future avenues for ageism research, emphasizing the importance of understanding forthcoming intergenerational dynamics for the benefit of the field and broader society. PMID- 22448914 TI - Elementary visual hallucinations and their relationships to neural pattern forming mechanisms. AB - An extraordinary variety of experimental (e.g., flicker, magnetic fields) and clinical (epilepsy, migraine) conditions give rise to a surprisingly common set of elementary hallucinations, including spots, geometric patterns, and jagged lines, some of which also have color, depth, motion, and texture. Many of these simple hallucinations fall into a small number of perceptual geometries-the Kluver forms-that (via a nonlinear mapping from retina to cortex) correspond to even simpler sets of oriented stripes of cortical activity (and their superpositions). Other simple hallucinations (phosphenes and fortification auras) are linked to the Kluver forms and to pattern-forming cortical mechanisms by their spatial and temporal scales. The Kluver cortical activity patterns are examples of self-organized pattern formation that arise from nonlinear dynamic interactions between excitatory and inhibitory cortical neurons; with reasonable modifications, this model accounts for a wide range of hallucinated patterns. The Kluver cortical activity patterns are a subset of autonomous spatiotemporal cortical patterns, some of which have been studied with functional imaging techniques. Understanding the interaction of these intrinsic patterns with stimulus-driven cortical activity is an important problem in neuroscience. In line with this, hallucinatory pattern formation interacts with physical stimuli, and many conditions that induce hallucinations show interesting interactions with one another. Both types of interactions are predictable from neural and psychophysical principles such as localized processing, excitatory-inhibitory neural circuits, lateral inhibition, simultaneous and sequential contrast, saccadic suppression, and perceptual opponency. Elementary hallucinations arise from familiar mechanisms stimulated in unusual ways. PMID- 22448916 TI - Future-oriented emotions in the prediction of binge-drinking intention and expectation: the role of anticipated and anticipatory emotions. AB - The Theory of Planned Behavior (TPB) offers a parsimonious explanation of purposive behavior, but in the study of healthy and risk behaviors its sufficiency may be questioned. Working with binge-drinking, a very common risk behavior in Spanish undergraduate students, we used two strategies for improving predictions from TPB: using behavioral intention (BI) and behavioral expectation (BE) as proximal antecedents of behaviors and adding as new predictors two future oriented emotions (anticipated and anticipatory). Hierarchical regression analyses show that while anticipated emotions improved TPB explanations of BI, anticipatory emotions improved the explanations of BE. The present results show the influence of future emotions in the prediction of behavioral intention and behavioral expectation. PMID- 22448915 TI - De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology. AB - Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild industrial strains. PMID- 22448917 TI - MicroRNA-297b-5p/3p target Mllt3/Af9 to suppress lymphoma cell proliferation, migration and invasion in vitro and tumor growth in nude mice. AB - Mllt3/Af9 is a proto-oncogene capable of deregulating the expression of genes critical for leukemia. However, the regulation of its expression remains incompletely elucidated. Herein, we show that the microRNAs miR-297b-5p/3p are capable of regulating Mllt3/Af9 expression negatively by binding to its 3' untranslated region. Overexpression of miR-297b-5p/3p also led to altered expression of p27(Kip1) and proliferating cell nuclear antigen, abnormal cell cycle arrest, decreased cell proliferation, migration and invasion in vitro in cell cultures, and suppressed xenograft tumor growth in vivo in the nude mouse. These data demonstrate that miR-297b-5p/3p and Mllt3/Af9 might be critical regulators of lymphoma cell proliferation or carcinogenesis. Together our findings suggest that miR-297b-5p/3p might be useful molecular targets for diagnosis or treatment of cancers associated with abnormal expression of Mllt3/Af9. PMID- 22448918 TI - Front-line immunochemotherapy for aggressive non-Hodgkin lymphoma using dose dense rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone plus granulocyte-macrophage colony stimulating factor and pegfilgrastim as support. AB - Granulocyte-macrophage colony stimulating factor (GM-CSF) has been associated with multiple immune effects, which could enhance the outcome of chemotherapy. For this reason we decided to explore the combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) given every 14 days with pegfilgrastim (Neulasta) and GM-CSF (Leukine). A total of 59 HIV negative patients with aggressive-histology non-Hodgkin lymphoma were accrued. The median age was 56 years (range 25-87). Lactate dehydrogenase (LDH) was high in 36 patients (61%); performance status was 0-1 in 48 patients; International Prognostic Index (IPI) was 0-1 in 30 and 2-3 in 24 patients; and disease was stage I-II in 46% and III-IV in 56% of patients. Diffuse large B-cell lymphoma was the most common lymphoma type. Response rates were: complete remission (CR) in 51 (86%), partial remission (PR) in five (8%) and failure in three patients (5%). At a median follow-up of 26 months, the overall survival (OS) at 3 years was 76% and the 3-year failure-free survival (FFS) was 73%. No patient relapsed beyond 18 months. Patients with IPI >= 3 had a 3-year progression-free survival (PFS) of 54% versus 82% in those with IPI < 3 (p = 0.038). Patients aged < 60 years had a FFS of 77% while those aged >= 60 years had a FFS of 69% (p = 0.29). Both the CR rate and the quality of CRs were satisfactory, with only 5/51 (10%) of complete responders having lost their remissions to date. Of interest is that age >= 60, an important adverse prognostic factor, appeared to have lost some of its importance, since the difference between those aged < 60 and >= 60 years was minimal in our study. The results with R-CHOP-GM-CSF every 14 days are encouraging, and merit a prospective comparative clinical trial against R-CHOP-14 in order to elucidate the contribution of GM-CSF. PMID- 22448919 TI - Diffuse large B-cell lymphoma: is there a place for autologous hematopoietic stem cell transplant in first remission in the era of chemo-immunotherapy? AB - While rituximab-based chemo-immunotherapy has improved response and long-term survival rates in diffuse large B-cell non-Hodgkin lymphoma (DLBCL), relapse and death from recurrent disease is still the eventual outcome in a significant proportion of patients, especially those with high-risk disease. Autologous hematopoietic stem cell transplant (AHSCT) in first remission, which was studied mainly before the advent of rituximab, has lost its appeal due to several small negative trials. However, definitive data do not exist to determine the role of AHSCT in first remission. In this review, we critically evaluate studies investigating AHSCT in DLBCL in first remission. Most available studies have shortcomings that limit the applicability of their findings. AHSCT in first remission may have a role in selected patients with high-risk DLBCL, but a carefully designed prospective study is required to appropriately evaluate this concept. PMID- 22448920 TI - Impact of fluorine-18 fluorodeoxyglucose positron emission tomography on diagnosis and antimicrobial utilization in patients with high-risk febrile neutropenia. AB - Early and targeted antimicrobial therapy improves outcomes in patients with febrile neutropenia (FN). We evaluated the impact of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) on antimicrobial utilization in the management of FN. A cohort of patients with FN and hematological malignancy was identified. Cases (in whom FDG-PET was performed, n = 37) were compared with controls (in whom conventional investigations excluding FDG-PET were performed, n = 76). An underlying cause for FN was determined in 94.6% of cases, compared to 69.7% of controls. FDG-PET had a significant impact on antimicrobial utilization compared to conventional imaging (35.1% vs. 11.8%; p = 0.003), and was associated with shorter duration of liposomal amphotericin-B therapy for systemic fungal infection (median 4.0 days cases vs. 10.0 days controls; p = 0.001). Cases had a longer length of hospitalization (p = 0.016). In the management of patients with high-risk FN, FDG-PET improves diagnostic yield and allows rationalization of antifungal therapy. The impact upon healthcare costs associated with antimicrobial therapy for FN requires further evaluation. PMID- 22448921 TI - Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia. AB - The outcome for patients with refractory or relapsed acute lymphoblastic leukemia (ALL) treated with conventional therapy is poor. Immunoconjugates present a novel approach and have recently been shown to have efficacy in this setting. Combotox is a mixture of two ricin-conjugated monoclonal antibodies (RFB4 and HD37) directed against CD19 and CD22, respectively, and has shown activity in pediatric and adult ALL. We created a murine xenograft model of advanced ALL using the NALM/6 cell line to explore whether the combination of Combotox with the cytotoxic agent cytarabine (Ara-C) results in better outcomes. In our model the combination of both low- and high-dose Combotox and Ara-C resulted in significantly longer median survival. Sequential administration of Ara-C and Combotox, however, was shown to be superior to concurrent administration. These findings have led to a phase I clinical trial exploring this combination in adults with relapsed or refractory B-lineage ALL (ClinicalTrials.gov identifier NCT01408160). PMID- 22448922 TI - Outcome of childhood relapsed or refractory mature B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia. AB - Patients with childhood relapsed and refractory mature B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukemia (B-ALL) are rare and have a dismal prognosis. The previous UK national analysis of 26 children over a 7-year period prior to 1996 had highlighted the poor outcome, with only three survivors. This 10-year multicenter study evaluated recent data, since 2000. Of 33 children, nine survived (27.3%), with a median follow-up of 4.3 years. On exclusion of six children treated with palliative intent, the survival was one-third (nine of 27; 33.3%). All patients with primary refractory disease (n = 7) and all except one with early relapse (n = 11) died. Administration of four doses of 375 mg/m(2) of rituximab was associated with a longer survival (p = 0.006). Response to reinduction (p < 0.001) and autologous hematopoietic stem cell transplant (auto HSCT) (p = 0.003) were significant on multivariate analysis. Patients with a time to relapse of at least 6 months are potentially curable and must be offered intensive treatment with salvage chemotherapy, rituximab and auto-HSCT. PMID- 22448924 TI - Psychodynamic psychotherapy of ADHD: a review of the literature. AB - Contributions of psychodynamic psychotherapy to the treatment of children with attention deficit hyperactivity disorder (ADHD) have been sparse. However, mixed results of other interventions, including behavior therapy and medication, call for a systematic examination of psychodynamic contributions to treatment of ADHD children. A systematic review of the literature on psychodynamic psychotherapy with ADHD children yielded a combination of 23 case studies, research reports, and theoretical writings. Questions relevant to the practice of psychodynamic psychotherapy were the focus and included a review of psychodynamic diagnosis of ADHD, theoretical orientations of psychodynamic psychotherapy, identification of core treatment issues, clinical examples, and theoretical perspectives on therapeutic change as well as practice techniques. A review of 231 abstracts resulted from key word searches including ADHD, Psychotherapy, Psychodynamic, and Psychoanalytic. Once inclusion criteria were met, the information from the literature was organized according to categories reflecting the review's focus. Findings of the review are provided to guide psychodynamic psychotherapists in their treatment of ADHD children. Recommendations for future individual and group studies are discussed. PMID- 22448923 TI - Multifaceted actions of 8-amino-adenosine kill BCR-ABL positive cells. AB - Survival of chronic myelogenous leukemia (CML) cells is dependent on BCR-ABL kinase, the activity of which is contingent on the level of BCR-ABL protein and the availability of adenosine triphosphate (ATP). We hypothesized that 8-amino adenosine (8-amino-Ado)-mediated reduction in cellular ATP level and inhibition of mRNA synthesis leading to a decrease in protein level would result in a multifaceted targeting of BCR-ABL. Using K562 cells, we demonstrated that there was a dose- and time-dependent increase in 8-amino-ATP accompanied by a > 95% decline in the endogenous ATP pool. In parallel, 8-amino-Ado inhibited RNA synthesis and resulted in a depletion of BCR-ABL transcript. Consistent with this, BCR-ABL and ABL protein levels were also decreased. These effects were associated with the initiation of cell death as visualized by poly(ADP-ribose) polymerase (PARP) cleavage, decreased clonogenicity and greater than additive interaction with imatinib. In imatinib-sensitive and -resistant KBM5 cells, 8 amino-Ado treatment augmented the imatinib effect on growth inhibition. PMID- 22448925 TI - Redox-induced conformational change in mercaptoalkanoic acid multilayer films. AB - We discuss the assembly, structure, and stability of multilayer molecular films formed from multiple mercaptoalkanoic acid monolayers ligated via carboxyl and thiol interactions with divalent copper ions. Using dual-polarization interferometry to study the assembly of multilayer films in real time, we observe a clear linear relationship between the number of layers within a film and the overall average film thickness. Unexpectedly, however, we find a restructuring of the lower monolayer upon association of the Cu(2+) ions to form the Cu carboxylate surface. In particular, the thickness of the lower monolayer was found to decrease significantly, accompanied by an increase in the film density. The conformation of the monolayer subsequently recovered to that observed originally following the reduction of the Cu ion to Cu(+) upon chemisorption of the adlayer. Comparable restructuring was also observed in molecular dynamics simulations of a bilayer film assembled on a gold surface. Our combined experimental and theoretical study suggests that the observed restructuring is a result of charge-charge interactions between adjacent Cu ions that exist in the +2 oxidation state in the copper carboxylate surface and in the +1 oxidation state following chemisorption of the adlayer. PMID- 22448926 TI - Semaphorin 7A inhibits platelet production from CD34+ progenitor cells. AB - BACKGROUND: The multifunctional protein semaphorin 7A (Sema7A) may have regulatory effects on blood cell differentiation via its receptors beta1-integrin and plexin C1. As thrombocytopenia can be treated with transfusion of ex vivo CD34(+) cell-derived megakaryocytes, we investigated the effect of Sema7A on differentiation of CD34(+) progenitor cells into megakaryocytes and platelets. METHODS: Megakaryocytes and platelets were differentiated with a specific cytokine cocktail (CC) from CD34(+) progenitor cells in the presence or absence of Sema7A. Expression of cell markers CD41, CD42a and CD61 or detection of the activation of the signal mediator focal adhesion kinase (FAK) was performed by flow cytometry, cytokine secretion by Luminex technology, and megakaryocyte cell density and morphology by microscopic studies. Sema7A levels in vivo were assessed by real-time PCR and ELISA in hematological patients undergoing chemotherapy. RESULTS: CD34(+) progenitor cells expressed the receptors for Sema7A. Expression of CD41, CD42a and CD61 was markedly reduced in the presence of Sema7A, after CC-dependent platelet production from CD34(+) progenitor cells. As revealed by microscopic analysis, megakaryocyte cell density was significantly lower in the presence of Sema7A as compared with controls. Blocking of CD29 abrogated the Sema7A-mediated inhibition. Sema7A activated FAK in CD34(+) progenitor cells and significantly increased secretion of the proinflammatory cytokines IL-6, IL-8 and GM-CSF. Finally, Sema7A levels were up-regulated in 50% of patients after chemotherapy. CONCLUSIONS: Sema7A markedly reduces the production rates of megakaryocytes and platelets from CD34(+) progenitor cells. Hence, up-regulation of Sema7A may be a major risk factor for a reduced platelet repopulation after hematopoietic stem cell transplantation. PMID- 22448927 TI - A constitutively active Galpha subunit provides insights into the mechanism of G protein activation. AB - The activation of Galpha subunits of heterotrimeric G proteins by G protein coupled receptors (GPCRs) is a critical event underlying a variety of biological responses. Understanding how G proteins are activated will require structural and biochemical analyses of GPCRs complexed to their G protein partners, together with structure-function studies of Galpha mutants that shed light on the different steps in the activation pathway. Previously, we reported that the substitution of a glycine for a proline at position 56 within the linker region connecting the helical and GTP-binding domains of a Galpha chimera, designated alphaT*, yields a more readily exchangeable state for guanine nucleotides. Here we show that GDP-GTP exchange on alphaT*(G56P), in the presence of the light activated GPCR, rhodopsin (R*), is less sensitive to the beta1gamma1 subunit complex than to wild-type alphaT*. We determined the X-ray crystal structure for the alphaT*(G56P) mutant and found that the G56P substitution leads to concerted changes that are transmitted to the conformationally sensitive switch regions, the alpha4-beta6 loop, and the beta6 strand. The alpha4-beta6 loop has been proposed to be a GPCR contact site that signals to the TCAT motif and weakens the binding of the guanine ring of GDP, whereas the switch regions are the contact sites for the beta1gamma1 complex. Collectively, these biochemical and structural data lead us to suggest that alphaT*(G56P) may be adopting a conformation that is normally induced within Galpha subunits by the combined actions of a GPCR and a Gbetagamma subunit complex during the G protein activation event. PMID- 22448928 TI - Long acting risperidone in Australian patients with chronic schizophrenia: 24 month data from the e-STAR database. AB - BACKGROUND: This observational study was designed to collect treatment outcomes data in patients using the electronic Schizophrenia Treatment Adherence Registry (e-STAR). METHODS: Patients with schizophrenia or schizoaffective disorder in Australia who were prescribed risperidone long-acting injection (RLAI) between 2003 and 2007 were assessed 12-months retrospectively, at baseline and 24-months prospectively at 3-monthly intervals. The intent-to-treat population, defined as all patients who received at least one dose of RLAI at baseline, was used for the efficacy and safety analyses. RESULTS: At total of 784 patients (74% with schizophrenia, 69.8% male) with a mean age of 37.1 +/- 12.5 years and 10.6 +/- 9.5 years since diagnosis were included in this Australian cohort. A significant improvement in mean Clinical Global Impression - severity score was observed at 24-months (4.52 +/- 1.04 at baseline, 3.56 +/- 1.10 at 24-months). Most of this improvement was seen by 3-months and was also reflected in mean Global Assessment of Functioning score, which improved significantly at 24-months (42.9 +/- 14.5 at baseline, 59 +/- 15.4 at 24-months). For patients still receiving RLAI at 24 months there was an increase from a mean baseline RLAI dose of 26.4 +/- 5 mg to 43.4 +/- 15.7 mg. Sixty-six percent of patients discontinued RLAI before the 24 month period--this decreased to 46% once patients lost to follow-up were excluded. CONCLUSION: Over the 24-month period, initiation of RLAI was associated with improved patient functioning and illness severity in patients with schizophrenia or schizoaffective disorder. Improved outcomes were observed early and sustained throughout the study. TRIAL REGISTRATION: Clinical Trials Registration Number, NCT00283517. PMID- 22448929 TI - Ultrasoft 100 nm thick zero Poisson's ratio film with 60% reversible compressibility. AB - About a 100 nm thick multilayer film of nanoparticle monolayers and polymer layers is shown to behave like cellular-foam with a modulus below 100 KPa. The 1.25 cm radius film adhered to a rigid surface can be compressed reversibly to 60% strain. The more than 4 orders of magnitude lower modulus compared to its constituents is explained by considering local bending in the (nano)cellular structure, similar to cork and wings of beetles. As the rigidity of the polymer backbone is increased in just four monolayers, the modulus of the composite increases by over 70%. Electro-optical map of the strain distribution over the area of compression and increase in modulus with thickness indicates the films have zero Poisson's ratio. PMID- 22448930 TI - Evidence for a link between locus R-R sequence type and outcome of infection with Entamoeba histolytica. AB - The results of Entamoeba histolytica infections range from asymptomatic colonization to variable disease outcomes. However, markers that may predict infection outcomes are not known. Here, we investigated sequence types of a non coding tRNA-linked locus R-R to identify surrogate markers that may show association with infection outcomes. Among 112 clinical samples--21 asymptomatic, 20 diarrhoea/dysentery and 71 liver abscesses--we identified 11 sequence types. Sequence type 5RR was mostly associated with asymptomatic samples, and sequence type 10RR was predominantly associated with the symptomatic (diarrhoea/dysentery and liver abscess) samples. This is the first report that identifies markers that may predict disease outcomes in E. histolytica infection. PMID- 22448931 TI - Fast, high peak capacity separations in gas chromatography-time-of-flight mass spectrometry. AB - Peak capacity production (i.e., peak capacity per separation run time) is substantially improved for gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) and applied to the fast separation of complex samples. The increase in peak capacity production is achieved by selecting appropriate experimental conditions based on theoretical modeling of on-column band broadening, and by reducing the injection pulse width. Modeling to estimate the on-column band broadening from experimental parameters provided insight for the potential of achieving GC separations in the absence of off-column band broadening, i.e., the additional band broadening not due to the on-column separation process. To optimize GC-TOFMS separations collected with a commercial instrumental platform, off-column band broadening from injection and detection needed to be significantly reduced. Specifically for injection, a commercially available thermal modulator is adapted and applied (referred to herein as thermal injection) to provide a narrow injection pulse, while the TOFMS provided a data collection rate of 500 Hz, initially averaged to 100 Hz for data storage. The use of long, relatively narrow open tubular capillary columns and a 30 degrees C/min programming rate were explored for GC-TOFMS, specifically a 20 m, 100 MUm inner diameter (i.d.) capillary column with a 0.4 MUm film thickness to benefit column capacity, operated slightly below the optimal average linear gas velocity (at ~2 mL/min, due to the flow rate constraint of the TOFMS). Standard autoinjection with a 1:100 split resulted in an average peak width of ~1.2 s, hence a peak capacity production of 50 peaks/min. Metabolites in the headspace of urine were sampled by solid-phase microextraction (SPME), followed by thermal injection and a ~7 min GC separation (with a ~6 min separation time window), producing ~660 ms peak widths on average, resulting in a total peak capacity of ~550 peaks (at unit resolution) and a peak capacity production of ~90 peaks/min (~2-fold improvement relative to standard autoinjection with the 1:100 split). This total peak capacity production achieved is equivalent to, or greater than, that currently utilized in metabolomics studies using GC/MS, but with much slower separations, on the order of 40 to 60 min, corresponding to a 5-fold or greater GC/MS analysis throughput rate. PMID- 22448932 TI - Dimerization of the full-length Alzheimer amyloid beta-peptide (Abeta42) in explicit aqueous solution: a molecular dynamics study. AB - In this study, the mechanism of dimerization of the full-length Alzheimer amyloid beta (Abeta42) peptide and structural properties of the three most stable dimers have been elucidated through 0.8 MUs classical molecular dynamics (MD) simulations. The Abeta42 dimer has been reported to be the smallest neurotoxic species that adversely affects both memory and synaptic plasticity. On the basis of interactions between the distinct regions of the Abeta42 monomer, 10 different starting configurations were developed from their native folded structures. However, only six of them were found to form dimers and among them the three most stable (X(P), C-C(AP), and N-N(P)) were chosen for the detailed analysis. The structural properties of these dimers were compared with the available experimental and theoretical data. The MD simulations show that hydrophobic regions of both monomers play critical roles in the dimerization process. The high content of the alpha-helical structure in all the dimers is in line with its experimentally proposed role in the oligomerization. The formation of a zipper like structure in X(P) is also in accordance with its existence in the aggregates of several short amyloidogenic peptides. The computed values of translational (D(T)) and rotational (D(R)) diffusion constants of 0.63 * 10(-6) cm(2)/s and 0.035 ns(-1), respectively, for this dimer are supported by the corresponding values of the Abeta42 monomer. These simulations have also elucidated several other key structural properties of these peptides. This information will be very useful to design small molecules for the inhibition and disruption of the critical Abeta42 dimers. PMID- 22448934 TI - Working with policy makers. PMID- 22448935 TI - Opioid overdose deaths: reactions and overreactions. PMID- 22448936 TI - Different mechanisms for the short-term effects of real versus sham transcutaneous electrical nerve stimulation (TENS) in patients with chronic pain: a pilot study. AB - Transcutaneous electrical nerve stimulation (TENS) has existed since the early 1970s. However, randomized placebo controlled studies show inconclusive results in the treatment of chronic pain. These results could be explained by assuming that TENS elicits a placebo response. However, in animal research TENS has been found to decrease hyperalgesia, which contradicts this assumption. The aim of this study is to use quantitative sensory testing to explore changes in pain processing during sham versus real TENS in patients with chronic pain. Patients with chronic pain (N = 20) were randomly allocated to real TENS or sham TENS application. Electrical pain thresholds (EPTs) were determined inside and outside the segment stimulated, before and after the first 20 minutes of the intervention, and after a period of 10 days of daily real/sham TENS application. Pain relief did not differ significantly for real versus sham TENS. However, by comparing time courses of EPTs, it was found that EPT values outside the segment of stimulation increased for sham TENS, whereas for real TENS these values decreased. There were, however, no differences for EPT measurements inside the segment stimulated. These results illustrate the importance of including mechanism-reflecting parameters in addition to symptoms when conducting pain research. PMID- 22448937 TI - Topical delivery of nonsteroidal anti-inflammatory drugs for osteoarthritis. AB - Osteoarthritis (OA) is one of the most commonly reported chronic pain syndromes experienced in the United States. Treatment guidelines for OA recommend acetaminophen for first-line pharmacotherapy for these patients; however, this strategy is rarely effective as monotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the next step in therapy and have accumulated a large body of data to support their efficacy for OA. Unfortunately, this class of agents is not without the potential for significant adverse effects. In an effort to capture the efficacy of NSAIDs while decreasing their side effect burden, many clinicians are turning to the topical administration of these agents. Localized pain and smaller, superficial joints may be especially amenable to the topical administration of NSAIDs. Numerous commercially available topical NSAID formulations have been shown to be efficacious in patients with OA. This review focuses on the topical delivery of NSAIDs for the treatment of OA. PMID- 22448938 TI - Oral morphine effectiveness in Nigerian patients with advanced cancer. AB - Oral morphine elixir in the immediate release form became available in Nigeria in the year 2006 after decades of use in the treatment of cancer pain in many other countries. In order to determine the effectiveness of oral morphine in Nigerian patients, 182 patients presenting with severe cancer pain at the Radiotherapy Clinic, University College Hospital (UCH), Ibadan, Nigeria, were recruited in a prospective descriptive observational study. Information on patient's demography, diagnosis, baseline intensity and character of pain, morphine dosages, and effects were collected using a semistructured questionnaire administered at recruitment and biweekly in the follow-up period. Mean (+ SD) age of the patients was 47 (+ 14.6) years and the most common types of cancer diagnosed in the study participants included cancer of the breast and uterine cervix. The pretreatment pain intensity score mean (+ SD) was 8.09 (+ 1.51). Of the 166 patients whose data were analyzed, 84.3% (95% confidence interval [CI] 77.8-89.5%) achieved a 3 point reduction in pain intensity using the 11-point Numerical Rating Scale at the end of the first week of treatment. Twenty-six patients (15.7%) required adjuvant therapy. The reduction in pain intensity was maintained throughout the 3 months follow-up period, with the mean 24-hour morphine consumption of 55.54 mg in the first month and 61.54 mg in the third month. Oral morphine significantly reduced cancer pain in Nigerian patients (P < .01). Increasing dose as required was found to enhance the effectiveness of oral morphine. PMID- 22448939 TI - Review of palliative sedation and its distinction from euthanasia and lethal injection. AB - Palliative sedation evolved from within the practice of palliative medicine and has become adopted by other areas of medicine, such as within intensive care practice. Clinician's usually come across this practice for dying patients who are foregoing or having life support terminated. A number of intolerable and intractable symptom burdens can occur during the end of life period that may require the use of palliative sedation. Furthermore, when patients receive palliative sedation, the continued use of hydration and nutrition becomes an issue of consideration and there are contentious bioethical issues involved in using or withholding these life-sustaining provisions. A general understanding of biomedical ethics helps prevent abuse in the practice of palliative sedation. Various sedative drugs can be employed in the provision of palliative sedation that can produce any desired effect, from light sedation to complete unconsciousness. Although there are some similarities in the pharmacotherapy of palliative sedation, euthanasia, physician-assisted suicide, and lethal injection, there is a difference in how the drugs are administered with each practice. There are some published guidelines about how palliative sedation should be practiced, but currently there is not any universally accepted standard of practice. PMID- 22448940 TI - IOM calls for transformation of attitudes toward pain and its prevention and management. AB - The Institute of Medicine (IOM), the most influential health policy body in the United States, has published an extensive report calling for a cultural transformation of attitudes toward pain and its prevention and management. This report summarizes the IOM publication. PMID- 22448941 TI - Opioid overdoses in the United States. AB - The November 2011 issue of the online bulletin CDC Vital Signs posted by the Centers for Disease Control and Prevention of the U.S. Public Health Service entitled "Prescription Painkiller Overdoses in the U.S." addressed epidemiologic aspects of drug overdose deaths in the United States due to opioids. A subsequent blog posting on the CDC Directors Blog entitled "Prescription Drug Overdose in the United States: Blog Q&A" also addresses this important issue. Statistics on overdose deaths and strategies for improvement by all stakeholders are provided. PMID- 22448942 TI - Prescription monitoring programs: pitfalls and opportunities. AB - Prescription monitoring programs for controlled substances are increasingly common. Pitfalls and opportunities resulting from the data generated by these programs are discussed. PMID- 22448944 TI - The importance of saying goodbye to a loved one in a pain-free environment. AB - When a loved one is diagnosed with a terminal illness, it's devastating to everyone close to them. At these moments creating a pain free environment is essential, not just to the person receiving the medication, but also to those who love and care for them. In these situations pain is not just physical, it's emotional, and when people have to watch a loved one suffer, it amplifies the emotional pain they are already experiencing at the realization of losing them. As for the patient who is dying, they are experiencing pain and emotions on so many levels. They are watching their loved ones experience their emotional turmoil, but they are also coming to grips with having to say goodbye to everyone who ever meant anything to them. The physical pain is the most immediate and the easiest to understand and it also happens to be the simplest type of pain to deal with. PMID- 22448945 TI - A journey towards hospice care. AB - Fulfilling information needs is one of the keys to success in palliative care. A comprehensive palliative care offered in continuity not only helps people in coping with the illness but also relieves pain and other distresses. Primary physician or any doctor on whom the patient rely should be in the care team for effective management. This is the gist of the narrative shared by a family member in a continuity of cancer care workshop. Perhaps the hospice team offered more than enough to adjust and accept dying in a safe environment, for which the family remained grateful forever. PMID- 22448948 TI - The consequences of chronic pain. AB - Questions from patients about analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self advocates. The topic addressed in this issue is untreated/undertreated chronic pain and the physical, emotional, and social consequences that can profoundly affect a patient's quality of life. Chronic pain is no longer considered a symptom; it is a disease entity itself. Anxiety and depression often coexist with chronic pain. Chronic pain is the enemy of happiness. Further, chronic pain can activate the sympathetic nervous system, leading to the fight-or-flight response. PMID- 22448949 TI - Medical marijuana use for chronic pain: risks and benefits. AB - Questions from patients about medical marijuana use for chronic pain are becoming more common. The information in this report will help patients understand the potential risks and benefits of using this substance for painful conditions. PMID- 22448957 TI - Thrombolysis in cervical artery dissection--data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. AB - OBJECTIVE: To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeAD(Stroke) ) affects outcome and major haemorrhage rates. METHODS: We used a multicentre CeAD(Stroke) database to compare CeAD(Stroke) patients treated with and without thrombolysis. Main outcome measures were favourable 3-month outcome (modified Rankin Scale 0-2) and 'major haemorrhage' [any intracranial haemorrhage (ICH) and major extracranial haemorrhage]. Adjusted odds ratios [OR (95% confidence intervals)] were calculated on the whole database and on propensity-matched groups. RESULTS: Among 616 CeAD(Stroke) patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups [OR(adjusted) 0.95 (95% CI 0.45-2.00)]. The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non-thrombolyzed-matched CeAD(Stroke) patients [OR 1.00 (0.49-2.00)]. Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non-thrombolysis group, 3 (0.6%) patients had major haemorrhages [asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1)]. CONCLUSION: As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeAD(Stroke) patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies. PMID- 22448958 TI - Characterising visual deficits in children of an urban elementary school in Taiwan. AB - PURPOSE: The aim was to screen children from Grades 1 to 6 in an urban elementary school in Central Taiwan for visual deficits and associated parameters and, as an extension, to examine the acceptance of cycloplegic therapy as well as the lag in optimal vision correction. METHODS: Of 900 students in one school, 731 participated in the study, with parental consent. Data from 694 students, who had also completed a vision correction history were analysed. In addition to body height and weight, the screening included vision, non-cycloplegic autorefraction and distance retinoscopy, axial length and functional testing. RESULTS: There was a decrease in students with vision of 1.0 or better from 55.8 per cent in Grade 1 to 20.0 per cent in Grade 6. The decreases between Grades 2 and 3 and Grades 5 and 6 were significant. These trends were in general agreement with those based on refractive error and axial length. The students had abnormal functional findings including: stereoscopic vision, 9.2 per cent; cover tests, 14.1 per cent; pupillary responses, 13.8 per cent; and less commonly in extraocular muscular functions (3.0 per cent) and colour vision (5.2 per cent). A full 40 per cent of students received cycloplegic therapy with 25 per cent dropping out for various reasons. These cases were generally associated with lower vision and higher myopia. A lag between subnormal vision and optical correction was also observed with 55.1 per cent apparently not optimally corrected. Other parameters, including body height, weight and body mass index were not correlated with vision or refractive error. CONCLUSIONS: Age-dependent increase in the prevalence of myopia appears to continue despite the common practice of topical cycloplegic therapy in Taiwan. Timely correction of the refractive error is also lacking. While maintaining a visual acuity of 1.0 or better for all students at all times is not possible, this lag might be shortened by more frequent screening and/or direct provision of optical aids. PMID- 22448959 TI - Exploring the construct validity of the social cognition and object relations scale in a clinical sample. AB - The Social Cognition and Object Relations Scale-Global rating method (SCORS-G; Stein, Hilsenroth, Slavin-Mulford, & Pinsker, 2011; Westen, 1995) measures the quality of object relations in narrative material. This study employed a multimethod approach to explore the structure and construct validity of the SCORS G. The Thematic Apperception Test (TAT; Murray, 1943) was administered to 59 patients referred for psychological assessment at a large Northeastern U.S. hospital. The resulting 301 TAT narratives were rated using the SCORS-G method. The 8 SCORS variables were found to have high interrater reliability and good internal consistency. Principal components analysis revealed a 3-component solution with components tapping emotions/affect regulation in relationships, self-image, and aspects of cognition. Next, the construct validity of the SCORS-G components was explored using measures of intellectual and executive functioning, psychopathology, and normal personality. The 3 SCORS-G components showed unique and theoretically meaningful relationships across these broad and diverse psychological measures. This study demonstrates the value of using a standardized scoring method, like the SCORS-G, to reveal the rich and complex nature of narrative material. PMID- 22448960 TI - A facile chemical conversion synthesis of Sb2S3 nanotubes and the visible light driven photocatalytic activities. AB - We report a simple chemical conversion and cation exchange technique to realize the synthesis of Sb2S3 nanotubes at a low temperature of 90 degrees C. The successful chemical conversion from ZnS nanotubes to Sb2S3 ones benefits from the large difference in solubility between ZnS and Sb2S3. The as-grown Sb2S3 nanotubes have been transformed from a weak crystallization to a polycrystalline structure via successive annealing. In addition to the detailed structural, morphological, and optical investigation of the yielded Sb2S3 nanotubes before and after annealing, we have shown high photocatalytic activities of Sb2S3 nanotubes for methyl orange degradation under visible light irradiation. This approach offers an effective control of the composition and structure of Sb2S3 nanomaterials, facilitates the production at a relatively low reaction temperature without the need of organics, templates, or crystal seeds, and can be extended to the synthesis of hollow structures with various compositions and shapes for unique properties. PMID- 22448961 TI - Real-Time PCR in faecal samples of Triatoma infestans obtained by xenodiagnosis: proposal for an exogenous internal control. AB - BACKGROUND: The polymerase chain reaction (PCR) has proved to be a sensitive technique to detect Trypanosoma cruzi in the chronic phase of Chagas disease, which is characterized by low and fluctuating parasitemia. Another technique proposed for parasitological diagnosis in this phase of infection combines a microscopic search for motile trypomastigote forms in faecal samples (FS) obtained by xenodiagnosis (XD) with conventional PCR (XD-PCR). In this study we evaluate the use of human blood DNA as an exogenous internal control (EIC) for real time PCR (qPCR) combined with XD (XD-qPCR) using chromosome 12 (X12) detection. FINDINGS: None of the FS-XD evaluated by qPCR amplified for X12. Nevertheless, all the EIC-FS-XD mixtures amplified for X12. CONCLUSIONS: We determined that X12 is useful as an EIC for XD-qPCR because we showed that the FS XD does not contain human DNA after 30 or more days of XD incubation. This information is relevant for research on T. cruzi by XD-qPCR since it allows ruling out inhibition and false negative results due to DNA loss during the process of extraction and purification. PMID- 22448962 TI - Fluoxetine protects against monocrotaline-induced pulmonary arterial remodeling by inhibition of hypoxia-inducible factor-1alpha and vascular endothelial growth factor. AB - The selective serotonin re-uptake inhibitor fluoxetine has been shown to protect against monocrotaline (MCT)-induced pulmonary hypertension in rats. To investigate the possible role of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in mediating this protective effect, MCT-treated rats were administered fluoxetine by gavage, at doses of 2 mg/kg body mass or 10 mg/kg once daily for 3 weeks. Changes in pulmonary hemodynamic parameters, pulmonary artery morphologies, and expressions of HIF-1alpha and VEGF were assessed. Fluoxetine at the 10 mg/kg dose, but not at the 2 mg/kg dose, attenuated the effects of MCT on pulmonary artery pressure, right ventricle index, and medial wall thickness. In addition, 10 mg/kg fluoxetine mitigated the MCT-induced up-regulation of HIF-1alpha and VEGF protein and reactive oxygen species (ROS) in the lungs. This dosage also decreased pERK1/2 levels and inhibited proliferation of pulmonary arterial smooth muscle cells in MCT-treated rats. In conclusion, fluoxetine can protect against MCT-induced pulmonary arterial remodeling, which linked to reduced ROS generation and decreased HIF 1alpha and VEGF protein levels via the ERK1/2 phosphorylation pathway. PMID- 22448963 TI - Electronic spin transition in nanosize stoichiometric lithium cobalt oxide. AB - A change in the electronic spin state of the surfaces relevant to Li (de)intercalation of nanosized stoichiometric lithium cobalt oxide LiCo(III)O(2) from low-spin to intermediate and high spin is observed for the first time. These surfaces are the ones that are relevant for Li (de)intercalation. From density functional theory calculations with a Hubbard U correction, the surface energies of the layered lithium cobalt oxide can be significantly lowered as a consequence of the spin change. The crystal field splitting of Co d orbitals is modified at the surface due to missing Co-O bonds. The electronic spin transition also has a significant impact on Co(III)-Co(IV) redox potential, as revealed by the change in the lithium (de)intercalation voltage profile in a lithium half cell. PMID- 22448964 TI - Kinetics and mechanisms of the tropospheric reactions of menthol, borneol, fenchol, camphor, and fenchone with hydroxyl radicals (OH) and chlorine atoms (Cl). AB - Relative kinetic techniques have been used to measure the rate coefficients for the reactions of oxygenated terpenes (menthol, borneol, fenchol, camphor, and fenchone) and cyclohexanol with hydroxyl radicals (OH) and chlorine atoms (Cl) at 298 +/- 2 K and atmospheric pressure. The rate coefficients obtained for the reactions of the title compounds with OH are the following (in units of 10(-11) cm(3) molecule(-1) s(-1)): (1.48 +/- 0.31), (2.65 +/- 0.32), (2.49 +/- 0.30), (0.38 +/- 0.08), (0.39 +/- 0.09) for menthol, borneol, fenchol, camphor, and fenchone, respectively. For the corresponding reactions with Cl atoms the rate coefficients are as follows (in units of 10(-10) cm(3) molecule(-1) s(-1)): (3.21 +/- 0.26), (3.40 +/- 0.28), (2.72 +/- 0.13), (2.93 +/- 0.17), (1.59 +/- 0.10), and (1.86 +/- 0.29) for cyclohexanol, menthol, borneol, fenchol, camphor, and fenchone, respectively. The reported error is twice the standard deviation. Product studies of the reactions were performed using multipass in situ FTIR (Fourier transform infrared spectroscopy) and solid-phase microextraction (SPME) with analysis by GC-MS (gas chromatography-mass spectrometry). A detailed mechanism is proposed to justify the observed reaction products. PMID- 22448965 TI - Searching for new chemotherapies for tropical diseases: ruthenium-clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells. AB - Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[Ru(II)Cl(2)(DMSO)(3)(CTZ)] (1), cis,cis,trans-[Ru(II)Cl(2)(DMSO)(2)(CTZ)(2)] (2), Na[Ru(III)Cl(4)(DMSO)(CTZ)] (3), Na[trans-Ru(III)Cl(4)(CTZ)(2)] (4), [Ru(II)(eta(6)-p-cymene)Cl(2)(CTZ)] (5), [Ru(II)(eta(6)-p-cymene)(bipy)(CTZ)][BF(4)](2) (6), [Ru(II)(eta(6)-p cymene)(en)(CTZ)][BF(4)](2) (7), and [Ru(II)(eta(6)-p-cymene)(acac)(CTZ)][BF(4)] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4-8 are described. Complexes 1-8 are active against promastigotes of Leishmania major and epimastigotes of Trypanosoma cruzi. Most notably, complex 5 increases the activity of CTZ by factors of 110 and 58 against L. major and T. cruzi, with no appreciable toxicity to human osteoblasts, resulting in nanomolar and low micromolar lethal doses and therapeutic indexes of 500 and 75, respectively. In a high-content imaging assay on L. major-infected intraperitoneal mice macrophages, complex 5 showed significant inhibition on the proliferation of intracellular amastigotes (IC(70) = 29 nM), while complex 8 displayed some effect at a higher concentration (IC(40) = 1 MUM). PMID- 22448966 TI - Permanent genetic resources added to Molecular Ecology Resources Database 1 December 2011-31 January 2012. AB - This article documents the addition of 473 microsatellite marker loci and 71 pairs of single-nucleotide polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Barteria fistulosa, Bombus morio, Galaxias platei, Hematodinium perezi, Macrocentrus cingulum Brischke (a.k.a. M. abdominalis Fab., M. grandii Goidanich or M. gifuensis Ashmead), Micropogonias furnieri, Nerita melanotragus, Nilaparvata lugens Stal, Sciaenops ocellatus, Scomber scombrus, Spodoptera frugiperda and Turdus lherminieri. These loci were cross-tested on the following species: Barteria dewevrei, Barteria nigritana, Barteria solida, Cynoscion acoupa, Cynoscion jamaicensis, Cynoscion leiarchus, Cynoscion nebulosus, Cynoscion striatus, Cynoscion virescens, Macrodon ancylodon, Menticirrhus americanus, Nilaparvata muiri and Umbrina canosai. This article also documents the addition of 116 sequencing primer pairs for Dicentrarchus labrax. PMID- 22448967 TI - Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. AB - BACKGROUND: Thrombotic events (TEs) are rare but often serious adverse events that could occur after administration of immune globulin (IG) products. Our study objective was to assess occurrence of recorded TEs after administration of different US-licensed IG products and investigate potential risk factors using a large administrative database. STUDY DESIGN AND METHODS: This is a retrospective claims-based cohort study of individuals exposed to IG products from January 1, 2008, through September 30, 2010, using HealthCore's Integrated Research Database, a longitudinal health care database. IG products were identified by recorded Healthcare Common Procedure Coding System codes. TEs were ascertained via International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for same-day TEs by IG product, while controlling for confounders. RESULTS: Of 11,785 individuals exposed to IG products in the study period, 122 (1%) had TE(s) recorded on the same day as IG administration. TE rates per 1000 persons exposed ranged from 6.1 to 20.5 for different IG product groups. Vivaglobin users had an increased same-day TE risk compared to reference Gammagard Liquid users (OR, 3.56; 95% CI, 1.54-8.23). An increased TE risk was also found with older age (>= 45 years), prior TE(s), and hypercoagulable state(s). CONCLUSION: The study suggests potentially elevated TE rates for different IG products, including subcutaneous. It also identifies important recipient TE risk factors and suggests that risk-benefit profiles should be weighed before IG administration. The observed differences may be due to various factors such as dosage, administration rates, and product manufacturing processes that warrant further evaluation. PMID- 22448968 TI - The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase. AB - BACKGROUND: GSAO (4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid) and PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) are tumour metabolism inhibitors that target adenine nucleotide translocase (ANT) of the inner-mitochondrial membrane. Both compounds are currently being trialled in patients with solid tumours. The trivalent arsenical moiety of GSAO and PENAO reacts with two matrix facing cysteine residues of ANT, inactivating the transporter. This leads to proliferation arrest and death of tumour and tumour supporting cells. RESULTS: The two reactive ANT cysteine residues have been identified in this study by expressing cysteine mutants of human ANT1 in Saccharomyces cerevisiae and measuring interaction with the arsenical moiety of GSAO and PENAO. The arsenic atom of both compounds cross-links cysteine residues 57 and 257 of human ANT1. CONCLUSIONS: The sulphur atoms of these two cysteines are 20 A apart in the crystal structures of ANT and the optimal spacing of cysteine thiolates for reaction with As (III) is 3-4 A. This implies that a significant conformational change in ANT is required for the organoarsenicals to react with cysteines 57 and 257. This conformational change may relate to the selectivity of the compounds for proliferating cells. PMID- 22448969 TI - The recombinant bifunctional protein alphaCD133-GPVI promotes repair of the infarcted myocardium in mice. AB - BACKGROUND: Bone-marrow-derived progenitor cells are important in myocardial repair mechanisms following prolonged ischemia. Cell-based therapy of diseased myocardium is limited by a low level of tissue engraftment. OBJECTIVES: The aim of this study was the development of the bifunctional protein alphaCD133 glycoprotein (GP)VI as an effective treatment for supporting vascular and myocardial repair mechanisms. RESULTS: We have generated and characterized a bifunctional molecule (alphaCD133-GPVI) that binds both to the subendothelium of the injured microvasculature and to CD133(+) progenitor cells with high affinity. alphaCD133-GPVI enhances progenitor cell adhesion to extracellular matrix proteins and differentiation into mature endothelial cells. In vivo studies showed that alphaCD133-GPVI favors adhesion of circulating progenitor cells to the injured vessel wall (intravital microscopy). Also, treatment of mice undergoing experimental myocardial infarction with alphaCD133-GPVI-labeled progenitor cells reduces infarction size and preserves myocardial function. CONCLUSIONS: The bifunctional trapping protein alphaCD133-GPVI represents a novel and promising therapeutic option for limiting heart failure of the ischemic myocardium. PMID- 22448970 TI - Marathon of eponyms: 25 Yersiniosis. AB - The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Yersiniosis. PMID- 22448971 TI - Tunable spin polarization in bismuth ultrathin film on Si(111). AB - We performed a spin- and angle-resolved photoemission spectroscopy of bismuth ultrathin film on Si(111) with various film thickness d. We found that the spin polarization of spin-split Rashba surface states near the Brillouin-zone boundary, which is high (0.7) at d = 40 BL (bilayers), is gradually reduced on decreasing d and almost vanishes at d = 8 BL. This finding provides a novel method to generate spin-polarized electrons with tunable spin-polarization. PMID- 22448972 TI - Structural influences on preferential oxazolone versus diketopiperazine b(2+) ion formation for histidine analogue-containing peptides. AB - Studies of peptide fragment ion structures are important to aid in the accurate kinetic modeling and prediction of peptide fragmentation pathways for a given sequence. Peptide b(2)(+) ion structures have been of recent interest. While previously studied b(2)(+) ions that contain only aliphatic or simple aromatic residues are oxazolone structures, the HA b(2)(+) ion consists of both oxazolone and diketopiperazine structures. The structures of a series of histidine-analogue containing Xxx-Ala b(2)(+) ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy, fragment ion hydrogen-deuterium exchange (HDX), and density functional theory (DFT) calculations to systematically probe the influence of different side chain structural elements on the resulting b(2)(+) ion structures formed. The b(2)(+) ions studied include His-Ala (HA), methylated histidine analogues, including pi-methyl-HA and tau-methyl-HA, pyridylalanine (pa) analogues, including 2-(pa)A, 3-(pa)A, and 4-(pa)A, and linear analogues, including diaminobutanoic acid-Ala (DabA) and Lys-Ala (KA). The location and accessibility of the histidine pi-nitrogen, or an amino nitrogen on an aliphatic side chain, were seen to be essential for diketopiperazine formation in addition to the more typical oxazolone structure formation, while blocking or removal of the tau-nitrogen did not change the b(2)(+) ion structures formed. Linear histidine analogues, DabA and KA, formed only diketopiperazine structures, suggesting that a steric interaction in the HisAla case may interfere with the complete trans-cis isomerization of the first amide bond that is necessary for diketopiperazine formation. PMID- 22448973 TI - BK virus nephropathy in simultaneous pancreas kidney transplant: a potentially preventable cause of kidney allograft loss. AB - More than half of the simultaneous pancreas kidney transplant (SPK) patients afflicted with BK virus nephropathy (BKVN) lose their kidney allograft. Fear of pancreatic rejection limits the ability to reduce immunosuppression; this may result in inadequate treatment of BKVN. This single-center retrospective review included 138 SPK patients who underwent periodic BKV screening and were managed with IS reduction alone as a treatment of choice for BKVN. All patients underwent rabbit anti-thymocyte globulin (rATG) induction and were maintained on tacrolimus/sirolimus or mycophenolate. The incidence of BKVN was 4.4%. BKVN was diagnosed at a median of 11 months; mean serum creatinine 2.1 mg/dL and the geometric mean BK serum viral load at diagnosis 1,758,000 DNA copies/mL. Median time to BKV clearance was 5.6 months; there was 96% reduction in the mycophenolate dose, 100% reduction in sirolimus, and 40% reduction in the tacrolimus blood level at BKVN clearance. No BKVN-related kidney failure was noted, and patients retained excellent kidney and pancreatic allograft function till last follow-up (43 months). BKVN in SPK is a potentially preventable cause of end-stage kidney disease, and IS reduction alone is an acceptable treatment modality in SPK without a higher risk of kidney/pancreas allograft loss as long as close monitoring can be ensured. PMID- 22448974 TI - Involvement of parathyroid hormone-related protein in vascular calcification of chronic haemodialysis patients. AB - AIMS: To investigate the role of parathyroid hormone-related protein (PTHrP) in vascular calcification of patients with chronic hemodialysis. METHODS: The inferior epigastric arteries were obtained from 23 patients on chronic haemodialysis and 16 patients with renal carcinoma as control. Haematoxylin-eosin staining, elastic fibre staining, Alizarin Red calcium staining and immunohistochemical staining of PTHrP, bone morphogenetic protein-2 (BMP-2), Cbfa1/Runx2 were performed. Real-time polymerase chain reaction (PCR) was used to examine mRNA expressions of PTHrP, BMP-2 and Cbfa1/Runx2. Western blot and real time PCR were used to detect the effects of PTHrP-siRNA and rh-PTHrP-1-34 on the expressions of PTHrP, BMP-2 and Cbfa1/Runx2 in human aortic smooth muscle cells (HASMC). Alkaline phosphatase (ALP) activities and intracellular calcium content in HASMCs were assessed after treatment with 10 mmol/L beta-glycerol phosphoric acid for 48 h. RESULTS: Vascular calcification was confirmed in 78.2% of patients on chronic haemodialysis, and the expressions of PTHrP, BMP-2 and Cbfa1 in the arteries were significantly upregulated. PTHrP-siRNA could downregulate the expression of PTHrP by 60%, BMP-2 by 25% and Cbfa1 by 25% at 24 h (P < 0.05). Exogenous rh-PTHrP-1-34 could upregulate the expressions of BMP-2 and Cbfa1 by 1.37-fold and 1.46-fold, respectively, at 24 h in a time-independent manner (P < 0.05), which were attenuated by PTHrP-siRNA. Moreover, it could promote intracellular calcium deposition and increase ALP activities, which were partially blocked by PTHrP-siRNA (P < 0.05). CONCLUSIONS: Vascular calcification was common in patients with chronic haemodialysis, to which PTHrP might contribute by activating BMP-2/ Cbfa1 signalling pathway. PMID- 22448975 TI - Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site directed mutagenesis. AB - The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. Site-directed mutagenesis (SDM) and domain exchange (chimera) studies have provided important insight into key features of the OX1 and OX2 binding sites. However, the precise determinants of antagonist binding and selectivity are still not fully known. In this work, we used homology modeling of OX receptors to direct further SDM studies. These SDM studies were followed by molecular dynamics (MD) simulations to rationalize the full scope of the SDM data and to explain the role of each mutated residue in the binding and selectivity of a set of OX antagonists: Almorexant (dual OX1 and OX2 antagonist), SB-674042 (OX1 selective antagonist), EMPA (OX2 selective antagonist), and others. Our primary interest was focused on transmembrane helix 3 (TM3), which is identified as being of great importance for the selectivity of OX antagonists. These studies revealed conformational differences between the TM3 helices of OX1 and OX2, resulting from differences in amino acid sequences of the OX receptors that affect key interhelical interactions formed between TM3 and neighboring TM domains. The MD simulation protocol used here, which was followed by flexible docking studies, went beyond the use of static models and allowed for a more detailed exploration of the OX structures. In this work, we have demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors. The MD simulations allowed refinement of the OX receptor models to a degree that was not possible with static homology modeling alone and provided a deeper rationalization of the SDM data obtained. To validate these findings and to demonstrate that they can be usefully applied to the design of novel, very selective OX antagonists, we show here two examples of antagonists designed in house: EP-109-0092 (OX1 selective) and EP-009-0513 (OX2 selective). PMID- 22448976 TI - Personality assessment inventory (PAI) profiles of offenders and their relationship to institutional misconduct and risk of reconviction. AB - This article investigates whether particular scales of the personality assessment inventory (PAI; Morey, 1991 ) are associated with institutional misconduct and risk of reconviction among 268 offenders in a therapeutic community prison. A moderate positive correlation was found between the Antisocial Behavior subscale of the PAI and general institutional misconduct. Moderate positive correlations were also found between the antisocial features, aggression, and drug problems scales and risk of reconviction as measured by the offender group reconviction scale (Francis, Soothill, & Humphries, 2007; Taylor, 1999 ). In addition, receiver operating characteristic analyses showed that certain PAI cut scores had utility in identifying prisoners who had engaged in institutional misconduct and who posed a high risk of reconviction. PMID- 22448977 TI - Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics. AB - GKAs (glucokinase activators) are promising agents for the therapy of Type 2 diabetes, but little is known about their effects on hepatic intermediary metabolism. We monitored the fate of (13)C-labelled glucose in both a liver perfusion system and isolated hepatocytes. MS and NMR spectroscopy were deployed to measure isotopic enrichment. The results demonstrate that the stimulation of glycolysis by GKA led to numerous changes in hepatic metabolism: (i) augmented flux through the TCA (tricarboxylic acid) cycle, as evidenced by greater incorporation of (13)C into the cycle (anaplerosis) and increased generation of (13)C isotopomers of citrate, glutamate and aspartate (cataplerosis); (ii) lowering of hepatic [Pi] and elevated [ATP], denoting greater phosphorylation potential and energy state; (iii) stimulation of glycogen synthesis from glucose, but inhibition of glycogen synthesis from 3-carbon precursors; (iv) increased synthesis of N-acetylglutamate and consequently augmented ureagenesis; (v) increased synthesis of glutamine, alanine, serine and glycine; and (vi) increased production and outflow of lactate. The present study provides a deeper insight into the hepatic actions of GKAs and uncovers the potential benefits and risks of GKA for treatment of diabetes. GKA improved hepatic bioenergetics, ureagenesis and glycogenesis, but decreased gluconeogenesis with a potential risk of lactic acidosis and fatty liver. PMID- 22448978 TI - Whey protein coating bead improves the survival of the probiotic Lactobacillus rhamnosus CRL 1505 to low pH. AB - AIMS: To evaluate the efficacy of a novel microencapsulation procedure using whey protein and pectin to improve the survival rate of Lactobacillus rhamnosus CRL 1505 to low pH and bile. METHODS AND RESULTS: Lactobacillus rhamnosus CRL 1505 was encapsulated by ionotropic gelation using pectin (PE) and pectin-whey protein (PE-WP). Both types of beads (MC(PE/WP) and MC(PE-WP/WP)) were covered with a layer of whey protein by complex coacervation. The noncapsulated lactobacilli were not sensitive to bile salts but to acid. Both microparticles protected Lact. rhamnosus CRL 1505 at pH 2.0, but only MC(PE/WP) was effective at pH 1.2. CONCLUSIONS: The combination of ionotropic gelation and complex coacervation techniques is efficient to obtain microcapsules of pectin covered with whey proteins. The MC(PE/WP) beads were more stable than the MC(PE-WP/WP) beads in simulated gastric conditions, thus offering better protection to Lact. rhamnosus CRL 1505 at low pH. SIGNIFICANCE AND IMPACT OF THE STUDY: Pectin beads with a whey protein layer (MC(PE/WP)) could be used as probiotic carrier in functional foods of low pH (e.g. apple juice), thus protecting Lact. rhamnosus CRL 1505 against the stressful conditions of the gastric tract. PMID- 22448979 TI - Fine needle aspiration of a lingual thyroid with Hashimoto's thyroiditis. PMID- 22448981 TI - Patterns of developmental change in infants' nighttime sleep awakenings from 6 through 36 months of age. AB - Nighttime sleep awakenings and infant and family characteristics were measured longitudinally in more than 1,200 infants when the infants were 6, 15, 24, and 36 months old. By 6 months of age, the majority of children slept through the night, awakening their mothers only about once or twice per week. However, not all children followed this predominant developmental pattern. Using growth mixture modeling, we identified 2 distinct developmental patterns. One group, labeled Sleepers, included 66% of the children. These children showed a flat trajectory of sleep awakenings from 6 through 36 months, with mothers reporting their infant awakening from sleep about 1 night per week. The second group, labeled Transitional Sleepers, included 34% of the infants. These children had 7 reported nights of awakenings per week at 6 months, dropping to 2 nights per week at 15 months and to 1 night per week by 24 months. Compared with Sleepers, Transitional Sleepers were more likely to be boys, score higher on the 6-month difficult temperament assessment, be breastfed at 6 and 15 months old, and have more depressed mothers at 6 months old. Using 2-group structural equation modeling, we examined individual differences at different points on the individual infants' sleep trajectories. For infants in both groups, reported sleep awakenings were associated with difficult temperament measured at 6 months, breastfeeding, infant illness, maternal depression, and greater maternal sensitivity. Infant-mother attachment measures were not related to these sleep awakenings. PMID- 22448982 TI - The legacy of early experiences in development: formalizing alternative models of how early experiences are carried forward over time. AB - Psychologists have long debated the role of early experience in social and cognitive development. However, traditional approaches to studying this issue are not well positioned to address this debate. The authors present simulations that indicate that the associations between early experiences and later outcomes should approach different asymptotic values across time, given alternative assumptions about the developmental significance of early experience. To test the predictions of alternative developmental models, the authors examine data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (SECCYD) on maternal sensitivity in the first 3 years of life and its association with social competence and academic skills through age 15. Across multimethod, multi-informant outcome data, results suggest that there may be enduring effects of early caregiving experiences in both of these domains. PMID- 22448983 TI - When familiar is not better: 12-month-old infants respond to talk about absent objects. AB - Three experiments that demonstrate a novel constraint on infants' language skills are described. Across the experiments it is shown that as babies near their 1st birthday, their ability to respond to talk about an absent object is influenced by a referent's spatiotemporal history: familiarizing infants with an object in 1 or several nontest locations before the study interferes with their ability to respond to talk about the object when it is out of view. Familiarity with an object may not always strengthen infants' object representations and therefore facilitate their ability to appropriately react to the mention of absent objects. On the contrary, early in development, irrelevant information about prior location may be bound to representations of familiar objects and thus interfere with infants' ability to respond to talk about absent things. PMID- 22448984 TI - Developmental trajectories of part-based and configural object recognition in adolescence. AB - Three experiments assessed the development of children's part and configural (part-relational) processing in object recognition during adolescence. In total, 312 school children aged 7-16 years and 80 adults were tested in 3-alternative forced choice (3-AFC) tasks. They judged the correct appearance of upright and inverted presented familiar animals, artifacts, and newly learned multipart objects, which had been manipulated either in terms of individual parts or part relations. Manipulation of part relations was constrained to either metric (animals, artifacts, and multipart objects) or categorical (multipart objects only) changes. For animals and artifacts, even the youngest children were close to adult levels for the correct recognition of an individual part change. By contrast, it was not until 11-12 years of age that they achieved similar levels of performance with regard to altered metric part relations. For the newly learned multipart objects, performance was equivalent throughout the tested age range for upright presented stimuli in the case of categorical part-specific and part-relational changes. In the case of metric manipulations, the results confirmed the data pattern observed for animals and artifacts. Together, the results provide converging evidence, with studies of face recognition, for a surprisingly late consolidation of configural-metric relative to part-based object recognition. PMID- 22448985 TI - The life course in the making: gender and the development of adolescents' expected timing of adult role transitions. AB - Adolescents' expectations about the timing of adult role transitions have the potential to shape their actual transitions, setting the stage for their adult lives. Although expectations about timing emerge by early adolescence, little is known about how these expectations develop across adolescence. This longitudinal study examined developmental trajectories of adolescents' anticipated ages of school completion, job entry, marriage, and parenthood over the high school years, focusing on gender differences. Latent growth curve analysis of data from 411 rural youths followed from Grades 9 through 12 (age at Grade 9: M = 14.35, SD = 0.77) indicated a significant increase in adolescents' anticipated ages of entry into work and parenthood as well as gender differences in the trajectory of the expected age of marriage. Gender role attitudes, school performance, romantic relationships, and expected educational and occupational attainment were associated with the anticipated timing of role transitions, with significant variations by gender. Adolescents' expected ages of entry into adult family roles predicted their educational attainment and family role transitions in early adulthood. The findings provide insights into the process through which adolescent boys and girls construct their expectations regarding the transition to adulthood and, in turn, their future life course. PMID- 22448986 TI - Marital conflict and growth in children's internalizing symptoms: the role of autonomic nervous system activity. AB - We assessed trajectories of children's internalizing symptoms, indexed through anxiety and depression, with a focus on the role of interactions between interparental marital conflict, children's sympathetic nervous system activity indexed by skin conductance level (SCL), and parasympathetic nervous system activity indexed by respiratory sinus arrhythmia (RSA) as predictors of growth. Children participated in 3 waves of data collection with a 1-year lag between each wave. At T1, 128 girls and 123 boys participated (M age = 8.23 years; SD = 0.73). The most important findings reveal that girls with either low RSA in conjunction with low SCL (i.e., coinhibition) at baseline or with increasing RSA and decreasing SCL in response to a challenging task (i.e., reciprocal parasympathetic activation) are susceptible to high or escalating anxiety and depression symptoms, particularly in the context of marital conflict. Findings support the importance of concurrent examinations of environmental risk factors and physiological activity for better prediction of the development of anxiety and depression symptoms. PMID- 22448987 TI - Perceived parenting style and adolescent adjustment: revisiting directions of effects and the role of parental knowledge. AB - In the present research on parenting and adolescent behavior, there is much focus on reciprocal, bidirectional, and transactional processes, but parenting-style research still adheres to a unidirectional perspective in which parents affect youth behavior but are unaffected by it. In addition, many of the most cited parenting-style studies have used measures of parental behavioral control that are questionable because they include measures of parental knowledge. The goals of this study were to determine whether including knowledge items might have affected results of past studies and to test the unidirectional assumption. Data were from 978 adolescents participating in a longitudinal study. Parenting-style and adolescent adjustment measures at 2 time points were used, with a 2-year interval between time points. A variety of internal and external adjustment measures were used. Results showed that including knowledge items in measures of parental behavioral control elevated links between behavioral control and adjustment. Thus, the results and conclusions of many of the most highly cited studies are likely to have been stronger than if the measures had focused strictly on parental behavior. In addition, adolescent adjustment predicted changes in authoritative and neglectful parenting styles more robustly than these styles predicted changes in adolescent adjustment. Adolescent adjustment also predicted changes in authoritativeness more robustly than authoritativeness predicted changes in adjustment. Thus, parenting style cannot be seen as independent of the adolescent. In summary, both the theoretical premises of parenting-style research and the prior findings should be revisited. PMID- 22448988 TI - Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold. AB - Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 MUM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K(i) < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC(50) values of 60-90 nM, and induces robust cell death in the H146 cancer cell line at 30-100 nM. PMID- 22448989 TI - A multilayered approach of Si/SiO to promote carrier transport in electroluminescence of Si nanocrystals. AB - The electroluminescence (EL) and photoluminescence of Si nanocrystals (Si-nc) from multilayered samples of Si/SiO are investigated. Si-nc are formed within Si and SiO layers after furnace annealing. It is found that the presence of Si interlayers creates extra carrier paths for EL emission. A comparative study is further performed on a multilayered Si/SiO sample and a single-layered one with Si and SiO homogeneously mixed. Both samples have the same ratio of Si to O and the same contents of Si and O. The multilayered sample is found to have higher EL intensity, less turn-on voltage, lower resistance, and higher current efficiency than the single-layered one. The results indicate that Si interlayers in Si/SiO may act as carrier channels, which promote carrier transport and enhance the EL emission of Si-nc. PMID- 22448990 TI - Seeking relevance to diversity: Australian occupational therapy's promise. PMID- 22448991 TI - Examining construct validity of a new naturalistic observational assessment of hand skills for preschool- and school-age children. AB - BACKGROUND/AIM: The Assessment of Children's Hand Skills is a new assessment that utilises a naturalistic observational method to capture children's real-life hand skill performance when engaged at various types of daily activities in everyday living contexts. The Assessment of Children's Hand Skills is designed for use with 2- to 12-year-old children with a range of disabilities or health conditions. The study aimed to investigate construct validity of the Assessment of Children's Hand Skills in Australian children. METHODS: Rasch analysis was used to examine internal construct validity of the Assessment of Children's Hand Skills in a mixed sample of 53 children with disabilities (including autism spectrum disorder, developmental/genetic disorders and physical disabilities) and 85 typically developing children. External construct validity was examined by correlating with three questionnaires evaluating daily living skills and hand skills. RESULTS: Rasch goodness-of-fit analysis suggested that all 22 activity items and 19 of 20 hand skill items in the Assessment of Children's Hand Skills measured a single construct. The Assessment of Children's Hand Skills items were placed in a clinically meaningful hierarchy from easy to hard, and the difficulty range of the items also matched the majority of children with disabilities and typically developing preschool-aged children. Moderate to high correlations (0.59 <= Spearman's rho coefficients <= 0.89, P < 0.01) were found with the assessments of daily living and fine motor skills. CONCLUSION: This study provided preliminary evidence supporting the construct validity of the Assessment of Children's Hand Skills for its clinical application in assessing children's real life hand skill performance in Australian contexts. PMID- 22448992 TI - Retrospective analysis of factors that affect driving assessment outcomes after stroke. AB - INTRODUCTION: More than 50% of people do not resume driving post-stroke. Potential disincentives include limited knowledge about assessment, access to services, cost and fear of failure. Factors contributing to a successful return to driving have been the focus of limited research. AIM: To determine the proportion of people with stroke who successfully pass their first on-road occupational therapy driving assessment, and factors associated with a successful assessment outcome. METHODS: A retrospective cohort study design was used. The primary data collection method was a review of 441 consecutive occupational therapy driving assessment reports from one Australian metropolitan centre. Participants had a diagnosis of stroke, a driving licence pre-stroke and completed a driving assessment between 1999 and 2010. RESULTS: Of the 441 records analysed, the mean age of drivers was 65.4 years (SD: 15.4). The majority (53.7%) passed their first assessment (pass/conditional pass); only 8.8% failed. A weak relationship was found between initial driving assessment outcome and time post stroke (r(s) = 0.19), but a fair relationship with younger age (r(s) = 0.31) and higher scores on three off-road assessments (r(s) = -0.26 to -0.28). The strongest predictors of initial driving assessment outcome were off-road assessment scores, age, gender and time post-stroke (R(2) = 19.7%, P < 0.01). CONCLUSIONS: Data on stroke severity are required to confirm these preliminary predictors of driving assessment outcome. Stroke severity should be routinely documented by driving assessment services for use in future research. PMID- 22448993 TI - Framework for describing community integration for people with acquired brain injury. AB - BACKGROUND/AIM: Community integration is the ultimate goal of rehabilitation of adults with acquired brain injury which has a high incidence in the Australian population. The literature shows a need for a more comprehensive framework for community integration. This study developed a descriptive community integration framework drawn from views of five stakeholder groups and was compared with four similar frameworks. METHODS: Thirty-seven experts in acquired brain injury, including practitioners, researchers, policy makers, people with acquired brain injury and family members participated. Using a Delphi method, an iterative process of surveys, interviews, and focus groups sought their views on community integration. Responses were analysed in three stages systematically to reduce a large quantity of raw data into a core set of descriptive themes. A final member checking process rated participants' agreement with the importance of each theme. RESULTS: Seven themes were identified and described: Relationships, Community Access, Acceptance, Occupation, Being at Home, Picking up Life Again, and Heightened Risks and Vulnerability. Themes were congruent with elements of the frameworks from the literature. CONCLUSIONS: Rich data came from the diverse stakeholders in the participant groups. Two unique themes reflected the importance of re-integration and recovering important aspects of previous lives, and identifying risks and vulnerabilities and providing safeguards. The framework reflected emphases that may be specific to acquired brain injury. It can be used as a basis for development of community integration programmes and outcome measures. PMID- 22448994 TI - Feedback interventions for improving self-awareness after brain injury: a protocol for a pragmatic randomised controlled trial. AB - BACKGROUND: Occupational therapists working in brain injury rehabilitation use functional tasks as a means of providing feedback to improve self-awareness of people who have a brain injury and ultimately improve their occupational performance. PURPOSE: To compare the effectiveness of video, verbal and experiential feedback for improving self-awareness in people with traumatic brain injury. METHODS: A randomised controlled trial will be conducted to compare the efficacy of video and verbal feedback during occupational therapy. Fifty-four participants with traumatic brain injury will be randomly allocated into three intervention groups: (i) video plus verbal feedback, (ii) verbal feedback and (iii) experiential feedback (control condition). Participants will receive the allocated intervention based on performance of a meal preparation task. The intervention sessions will occur four times during a two-week period. Blinded assessment will occur at baseline, post-intervention, and two months follow up. The primary outcome will be a measure of on-line self-awareness (number of self corrected and therapist corrected errors). Secondary outcomes to be assessed include levels of intellectual self-awareness, emotional distress, and acceptance of disability. Data will be analysed using an intention to treat approach. Linear mixed effects models will be used to investigate the intervention effects. FINDINGS AND IMPLICATIONS: Results will contribute to evidence-based guidelines to support therapists to choose the most effective form of feedback for people with decreased self-awareness after traumatic brain injury. PMID- 22448995 TI - Collaboration with teachers: a survey of South Australian occupational therapists' perceptions and experiences. AB - BACKGROUND/AIM: Early intervention and the development of integrated coordinated services in schools has created a greater need for effective collaboration between health and education professionals. The present study aimed to explore South Australian occupational therapists' perceptions and experiences of collaboration with school teachers in providing services to kindergarten and school-aged children. METHODS: A survey was employed to capture the perceptions and experiences of 45 occupational therapists, working with kindergarten and school-aged children in South Australia. Descriptive exploratory statistical analysis of the data obtained was performed using SPSS version 17, followed by thematic analysis for extended text responses to compile and identify predominant themes. RESULTS: The results indicated a high level of consensus among participants for what constitutes collaborative practice, low levels of implementation indicated that differences exist between perceptions and experiences of best practice. Participants showed ambivalence about the success of, and satisfaction with, their own collaborative practice. CONCLUSIONS: The present study has confirmed consistency with existing literature that the best practice principles for collaboration are not implemented in the field. The findings have implications for current practice to address the challenges of collaborative work. Further research into the efficacy of collaboration and investigation of appropriate models and systems, which support collaboration is proposed to facilitate best practice in South Australia. PMID- 22448996 TI - The impact of 'Generation Y' occupational therapy students on practice education. AB - BACKGROUND/AIM: Many occupational therapy students can be classified as 'Generation Y', a group whose characteristics are perceived as being confident, optimistic and 'techno-savvy'. This study aimed to explore practice educator perceptions of 'Generation Y' students. METHODS: A questionnaire survey was sent to all practice educators affiliated with the university. The survey contained fixed choice questions on demographics and educators' knowledge of the term 'Generation Y', followed by open-ended questions on practice educator perceptions of occupational therapy 'Generation Y' students and the educational strategies used in practice education. RESULTS: Anonymous responses were analysed using descriptive statistics, attribute coding and content analysis. Most educators considered that there was, in fact, a 'Generation Y student', describing them as confident with technology, over confident in their skill level and easily bored. Practice educators raised concerns regarding students' casual communication, poor professional behaviour, shallow professional reasoning and difficulty when receiving negative feedback. CONCLUSIONS: Overall, the results of this study suggest that 'Generation Y' students are having both a negative and a positive impact on practice education in occupational therapy. For educators, management of the overconfident student and professional reasoning development should be addressed in university practice education workshops. For students, the need for clarification of placement expectations on professional behaviour and communication was indicated. Students may also require 'listening to feedback' skill development prior to practice education. Universities and practice educators should consider the development of technological resources for practice education, including simulation, to meet the needs of the, now recognised 'Generation Y' student. PMID- 22448997 TI - Mental practice combined with task-specific practice improved arm ability but dosage remains inconclusive. PMID- 22448998 TI - Four weeks (10 sessions) of individual sensory discrimination training produced clinically important changes in upper limb sensation after stroke. PMID- 22449000 TI - Invisible vesicles swarm within the iceberg. PMID- 22449001 TI - A comparison of the construct validity of two alternative approaches to the assessment of psychopathy in the community. AB - This study compared the validity of 2 different self-report approaches to the assessment of psychopathy in nonforensic samples: the Psychopathy Resemblance Index (PRI), derived from a measure of normal personality functioning, and the Self-Report Psychopathy Scale (SRP), developed specifically to assess the maladaptive traits associated with psychopathy. In 2 adult samples (n (1) = 260, n(2) = 250), the PRI and the SRP were positively correlated with each other and with measures of maladaptive personality traits related to Machiavellianism and narcissism. However, unlike the SRP, the PRI was independent of trait empathy and general psychopathology and was positively associated with trait emotional intelligence. These results suggest that the PRI captures a more adaptive variant of psychopathy than does the SRP. PMID- 22449002 TI - Routine antenatal anti-D prophylaxis. PMID- 22449003 TI - Do individual characteristics explain variation in sanction risk updating among serious juvenile offenders? Advancing the logic of differential deterrence. AB - Recent theoretical and empirical research in deterrence has detected evidence of differential deterrability, or that the effect of sanctions is not uniform across persons. Important questions in this area remain to be explored, and this study considered a central question: Whether important across-individual variability in risk perceptions can be tied to important individual-level factors. This article extends the Bayesian risk updating model developed by Anwar and Loughran (2011) to determine whether the weight individuals place on new offending information differs across persons on the basis of individual characteristics. Using longitudinal data from a sample of serious youthful offenders, we found that the effect of an arrest on updated risk perceptions differs as a function of IQ and early behavioral problems. In particular, individuals low in verbal IQ and those who display early behavioral problems place greater weight on new information, suggesting that individuals who are traditionally viewed as being high in criminal propensity are more affected by arrest such that they are more likely to increase their perceived risk of getting caught when offending after experiencing an arrest. Findings support the idea that high-propensity offenders are more responsive to formal sanctions, and thus (potentially) more deterrable, than low propensity individuals. PMID- 22449004 TI - Radioprotective effect of hypothermia on cells - a multiparametric approach to delineate the mechanisms. AB - PURPOSE: Low temperature (hypothermia) during irradiation of cells has been reported to have a radioprotective effect. The mechanisms are not fully understood. This study further investigates the possible mechanisms behind hypothermia-mediated radioprotection. MATERIALS AND METHODS: Human lymphoblastoid TK6 cells were incubated for 20 min at 0.8 or 37 degrees C and subsequently exposed to 1 Gy of gamma- or X-rays. The influence of ataxia telangiectasia mutated (ATM)-mediated double-strand break signalling and histone deacetylase dependent chromatin condensation was investigated using the micronucleus assay. Furthermore, the effect of hypothermia was investigated at the level of phosphorylated histone 2AX (gammaH2AX) foci, clonogenic cell survival and micronuclei in sequentially-harvested cells. RESULTS: The radioprotective effect of hypothermia (called the temperature effect [TE]) was evident only at the level of micronuclei at a single fixation time, was not influenced by the inhibition of ATM kinase activity and completely abolished by the histone deacetylase inhibition. No TE was seen at the level of gammaH2AX foci and cell survival. CONCLUSIONS: We suggest that low temperature during irradiation can induce a temporary cell cycle shift, which could lead to a reduced micronucleus frequency. Future experiments focused on cell cycle progression are needed to confirm this hypothesis. PMID- 22449005 TI - DNA damage foci formation and decline in two-dimensional monolayers and in three dimensional human vessel models: differential effects according to radiation quality. AB - PURPOSE: To analyze the effect of different radiation qualities on the kinetics of p53 Binding Protein 1 (53BP1) formation and decline in human three-dimensional (3-D) vessel models. MATERIAL AND METHODS: Two-dimensional (2-D) and 3-D cultures of human umbilical vein cells were exposed to 80 cGy of Gamma radiation and high energy protons and Fe ions. 53BP1 antibodies were used for foci visualization via immunocytochemistry. Computer analysis was used to determine the number and the size of foci up to 48 hours after irradiation. RESULTS: DNA foci kinetics in 2-D and 3-D human vessel cultures show that foci formation and removal were the same in each type of culture. After 48 h, the number of foci induced by high-energy protons and gamma rays reduced to almost control levels while high linear energy transfer (LET) Fe particles produced more persistent damage. CONCLUSION: The kinetics of radiation-induced 53BP1 foci in 3-D vessel models is essentially the same as in 2-D monolayers. Since the basal level of spontaneous foci is low in these differentiated non-proliferating cultures, the persistence of radiation induced 53BP1 foci is detected longer than previously noted. Furthermore, analysis of foci sizes revealed that abnormal radiation-induced foci can persist even when foci frequencies are close to basal levels. The detection of these latent abnormalities could be useful for a more sensitive dosimetry. PMID- 22449006 TI - Design, synthesis, and structure-activity correlations of novel dibenzo[b,d]furan, dibenzo[b,d]thiophene, and N-methylcarbazole clubbed 1,2,3 triazoles as potent inhibitors of Mycobacterium tuberculosis. AB - A molecular hybridization approach is an emerging structural modification tool to design new molecules with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one molecular platform to prepare various novel clubbed 1,2,3-triazole hybrids using click chemistry. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogues revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Two of the most potent M. tuberculosis inhibitors 13h and 13q with MIC = 0.78 MUg/mL (~1.9 MUM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of molecular hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections. PMID- 22449007 TI - Orthogonal inactivation of influenza and the creation of detergent resistant viral aggregates: towards a novel vaccine strategy. AB - BACKGROUND: It has been previously shown that enveloped viruses can be inactivated using aryl azides, such as 1-iodo-5-azidonaphthalene (INA), plus UVA irradiation with preservation of surface epitopes in the inactivated virus preparations. Prolonged UVA irradiation in the presence of INA results in ROS species formation, which in turn results in detergent resistant viral protein fractions. RESULTS: Herein, we characterize the applicability of this technique to inactivate influenza. It is shown that influenza virus + INA (100 micromolar) + UVA irradiation for 30 minutes results in a significant (p < 0.05) increase in pelletablehemagglutinin after Triton X-100 treatment followed by ultracentrifugation. Additionally, characterization of the virus suspension by immunogold labeling in cryo-EM, and viral pellet characterization via immunoprecipitation with a neutralizing antibody, shows preservation of neutralization epitopes after this treatment. CONCLUSION: These orthogonally inactivated viral preparations with detergent resistant fractions are being explored as a novel route for safe, effective inactivated vaccines generated from a variety of enveloped viruses. PMID- 22449008 TI - Disposition of desfuroylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal tissues after administration of ceftiofur crystalline free acid (CCFA) to pony mares with placentitis. AB - The objective of this study was to determine the pharmacokinetics of CCFA in mares with placentitis and evaluate the disposition of the drug in fetal fluids, fetal membranes, colostrum, and serum of foals. A secondary objective was to obtain pilot data regarding the efficacy of CCFA for improving foal survival in mares with placentitis. Twelve pregnant pony mares were enrolled in the study, inoculated with Streptococcus zooepidemicus, intracervically and assigned to one of three groups: CEFT (n = 3; administered CCFA only; 6.6 mg/kg, i.m., q96h); COMBO (n = 6; administered combination therapy of CCFA, altrenogest, and pentoxifylline); UNTREAT (n = 3, no treatment). Treatment was initiated at the onset of clinical signs. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur metabolites, were measured using high-performance liquid chromatography. Maximum and minimum serum concentrations of DCA at steady state in treated mares were 2.40+/-0.40 MUg/mL and 1.06+/-0.29 MUg/mL, respectively. Concentration of DCA in colostrum was 1.51+/-0.60 MUg/mL. DCA concentrations in placenta and fetal tissues were very low (median = 0.03 MUg/mL) and below the minimum inhibitory concentration of relevant pathogens. DCA was not detected in amniotic fluid or foal serum. Treatment did not appear to improve foal survival (CEFT: 0/3; COMBO: 2/6; UNTREAT: 2/3). Bacteria were recovered from the uterus of most mares postpartum and from blood cultures of most foals regardless of treatment. PMID- 22449009 TI - Tissue factor pathway inhibitor is an inhibitor of factor VII-activating protease. AB - BACKGROUND: Factor VII-activating protease (FSAP) is a serine protease that circulates in plasma in its inactive single-chain form and can be activated upon contact with dead cells. When activated by apoptotic cells, FSAP leads to the release of nucleosomes. The serpins C1-inhibitor and alpha(2) -antiplasmin are reported to be the major inhibitors of FSAP. However, regulation of FSAP activity by Kunitz-type inhibitors is not well studied. OBJECTIVES: To compare the inhibition of FSAP activity and FSAP-induced nucleosome release from apoptotic cells by tissue factor pathway inhibitor (TFPI) with that of C1-inhibitor and alpha(2) -antiplasmin. METHODS: Apoptotic cells were incubated with plasma or FSAP in presence of the inhibitor, and nucleosome release was analyzed with flow cytometry. Monoclonal antibodies against TFPI and altered forms of TFPI were used to investigate which domains of TFPI contribute to FSAP inhibition. RESULTS AND CONCLUSIONS: We show that TFPI abrogates FSAP activity and nucleosome release from apoptotic cells. TFPI is a much more efficient inhibitor than C1-inhibitor or alpha(2) -antiplasmin. The active site of K2 is required for inhibition of FSAP. A direct binding interaction between FSAP and the C-terminal domain of TFPI is also required for efficient inhibition. Inhibition of FSAP-induced nucleosome release by recombinant TFPI might, in part, explain the anti-inflammatory effects of recombinant TFPI infusion observed in animal and human sepsis. PMID- 22449010 TI - Pornography use: who uses it and how it is associated with couple outcomes. AB - Very little is known about how pornography use is related to the quality of committed relationships. This study examined associations among pornography use, the meaning people attach to its use, sexual quality, and relationship satisfaction. It also looked at factors that discriminate between those who use pornography and those who do not. Participants were couples (N = 617 couples) who were either married or cohabiting at the time the data were gathered. Overall results from this study indicated substantial gender differences in terms of use profiles, as well as pornography's association with relationship factors. Specifically, male pornography use was negatively associated with both male and female sexual quality, whereas female pornography use was positively associated with female sexual quality. The study also found that meaning explained a relatively small part of the relationship between pornography use and sexual quality. PMID- 22449011 TI - Estimating the number of the people who inject drugs in Bali, 2010. AB - INTRODUCTION AND AIMS: A population estimation study was performed in 2009-2010 to understand the apparent decrease in people who inject drugs (PWID) attending needle syringe programs (NSPs) and to calculate the number of PWID in Bali for service planning. DESIGN AND METHODS: The multiplier method was applied to the results of a survey of 125 PWID using data from 16 institutions to calculate benchmarks for five events. Respondents were also asked to nominate other PWID and the services they used and to name PWID who had died in the previous 3 years. RESULTS: There was consistency in the estimates calculated using the multipliers for police arrests, voluntary counselling and testing and NSP which produced estimates of 700, 723 and 769 PWID, respectively. The nominator method identified 529 PWID. The number of reported PWID deaths had decreased over the past 3 years and may reflect a shrinking in the population of PWID in Bali. Police data revealed a dramatic shift in arrests for drug possession in 2002-2003 compared with arrests during 2009. Heroin possession was recorded in 37.4% of 2002-2003 arrests but decreased to 3.1% in 2009, whereas amphetamine possession increased from 11% to 30.9% in the same period. DISCUSSION AND CONCLUSIONS: Bali appears to have experienced a decrease in the number of PWID, which is likely to be related to death and to a pronounced shift to non-injected drug use. PMID- 22449012 TI - Personality and coping with professional demands: a behavioral genetics analysis. AB - Work-related mental health problems lead to individual ill-being but also absenteeism and early retirement from work. As such, it is desirable to diagnose strain and coping deficits before mental or physical symptoms occur in order to provide interventions early. Work engagement, resistance to stress, and occupational attitude toward life are three facets of coping with professional demands that are related to psychological health (Kieschke & Schaarschmidt, 2003). Personality, defined as characteristic patterns of thoughts, feelings, and behaviors over time and across situations, is also associated with health and well-being. To understand who becomes ill and why and to provide adequate interventions, we investigated the relations between personality and coping with professional demands, as well as the etiological basis of this relation. Personality and coping with professional demands (work engagement, resistance to stress, and occupational attitude toward life) were assessed in a sample of 302 monozygotic and dizygotic adult twin pairs. Correlations between personality and coping with professional demands were moderate (r range: -0.61 to 0.37). All scales except occupational attitude toward life showed significant heritabilities. Genetic and environmental influences on coping with professional demands were largely independent of genetic and environmental effects on personality. These findings suggest that interventions should focus on work engagement, resistance to stress, and occupational attitude toward life without specific considering of personality. PMID- 22449013 TI - Insufficient sleep predicts clinical burnout. AB - The present prospective study aimed to identify risk factors for subsequent clinical burnout. Three hundred eighty-eight working individuals completed a baseline questionnaire regarding work stress, sleep, mood, health, and so forth. During a 2-year period, 15 subjects (7 women and 8 men) of the total sample were identified as "burnout cases," as they were assessed and referred to treatment for clinical burnout. Questionnaire data from the baseline measurement were used as independent variables in a series of logistic regression analyses to predict clinical burnout. The results identified "too little sleep (< 6 h)" as the main risk factor for burnout development, with adjustment for "work demands," "thoughts of work during leisure time," and "sleep quality." The first two factors were significant predictors in earlier steps of the multivariate regression. The results indicate that insufficient sleep, preoccupation with thoughts of work during leisure time, and high work demands are risk factors for subsequent burnout. The results suggest a chain of causation. PMID- 22449015 TI - Social care and support for elderly men and women in an urban and a rural area of Nepal. AB - This study has aimed to describe the care and support for urban and rural elderly people of Bhaktapur district, Nepal. Efforts were made to identify the feeling of some features of general well-beings associated to mental health, person responsible for care and support, capability to perform daily routine activities, sources of finance and ownership to the property. More than half of the respondents were found having single or multiple features of loneliness, anxiety, depression and insomnia. The rate of point prevalence loneliness was found higher in the above 80 years of age, urban respondents. Almost 9 in 10 respondents were capable themselves to dress, walk and maintain personal hygiene and majority of them were assisted by spouse, son/daughter-in-laws. Family support was common sources of income and ownership to the property was absolutely high. PMID- 22449016 TI - Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: critical role of methoxylation in both inhibition potency and cytotoxicity. AB - ABCG2 plays a major role in anticancer-drug efflux and related tumor multidrug resistance. Potent and selective ABCG2 inhibitors with low cytotoxicity were investigated among a series of 44 chalcones and analogues (1,3-diarylpropenones), by evaluating their inhibitory effect on the transport of mitoxantrone, a known ABCG2 substrate. Six compounds producing complete inhibition with IC(50) values below 0.5 MUM and high selectivity for ABCG2 were identified. The number and position of methoxy substituents appeared to be critical for both inhibition and cytotoxicity. The best compounds, with potent inhibition and low toxicity, contained an N-methyl-1-indolyl (compound 38) or a 6'-hydroxyl-2',4'-dimethoxy-1 phenyl (compound 27) moiety (A-ring) and two methoxy groups at positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxy substitution contributed to inhibition at positions 3 and 5, but had a negative effect at position 4. Finally, methoxy groups at positions 3, 4, and 5 of the B-ring markedly increased cytotoxicity and, therefore, should be avoided. PMID- 22449017 TI - Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception. AB - BACKGROUND: Interstitial cystitis/painful bladder syndrome (IC/PBS), is a severely debilitating chronic condition that is frequently unresponsive to conventional pain medications. The etiology is unknown, however evidence suggests that nervous system sensitization contributes to enhanced pain in IC/PBS. In particular, central nervous system plasticity of glutamatergic signaling involving NMDA and metabotropic glutamate receptors (mGluRs) has been implicated in a variety of chronic pain conditions. Here, we test the hypothesis that mGluR5 mediates both non-inflammatory and inflammatory bladder pain or nociception in a mouse model by monitoring the visceromotor response (VMR) during graded bladder distention. RESULTS: Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5 dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice. CONCLUSIONS: Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain. PMID- 22449018 TI - Altered expression and activities of enzymes involved in thiamine diphosphate biosynthesis in Saccharomyces cerevisiae under oxidative and osmotic stress. AB - Thiamine diphosphate (TDP) serves as a cofactor for enzymes engaged in pivotal carbohydrate metabolic pathways, which are known to be modulated under stress conditions to ensure the cell survival. Recent reports have proven a protective role of thiamine (vitamin B(1)) in the response of plants to abiotic stress. This work aimed at verifying a hypothesis that also baker's yeast, which can synthesize thiamine de novo similarly to plants and bacteria, adjust thiamine metabolism to adverse environmental conditions. Our analyses on the gene expression and enzymatic activity levels generally showed an increased production of thiamine biosynthesis enzymes (THI4 and THI6/THI6), a TDP synthesizing enzyme (THI80/THI80) and a TDP-requiring enzyme, transketolase (TKL1/TKL) by yeast subjected to oxidative (1 mM hydrogen peroxide) and osmotic (1 M sorbitol) stress. However, these effects differed in magnitude, depending on yeast growth phase and presence of thiamine in growth medium. A mutant thi4Delta with increased sensitivity to oxidative stress exhibited enhanced TDP biosynthesis as compared with the wild-type strain. Similar tendencies were observed in mutants yap1Delta and hog1Delta defective in the signaling pathways of the defense against oxidative and osmotic stress, respectively, suggesting that thiamine metabolism can partly compensate damages of yeast general defense systems. PMID- 22449019 TI - Withholding negative feedback: is it about protecting the self or protecting others? AB - The reluctance to deliver negative feedback to someone's face is widely documented. This research disentangles the extent to which this reluctance is motivated by a desire to protect the self as opposed to others. Participants assessed an essay written by someone with high, medium, or low self-esteem. Assessment of the essay was most positive when the feedback was to be provided face-to-face, less positive when delivered anonymously, and least positive when it was not required to be delivered at all. This effect only emerged among participants low in self-liking (but was unrelated to self-competency). The self esteem of the essay writer had no effect on evaluations. The data lend support for a self-protection motive and modest support for an other-protection motive. PMID- 22449020 TI - The challenges of reducing tobacco use among prisoners. AB - ISSUE: The prevalence of smoking among prisoners is exceptionally high and is often comorbid with alcohol and drug problems, mental illness and other health problems. This review paper summarises the literature and available research related to smoking prevalence and smoking cessation initiatives among prisoners and identifies areas of need for further research and intervention. APPROACH: This paper highlights three studies conducted in the New South Wales prison system which attempt to address these high rates of smoking including a feasibility study, a focus group study and a randomised controlled trial. KEY FINDINGS: The challenges of making systems-level changes to address these high rates of smoking are discussed including a recent National Summit on Tobacco Smoking in Prisons. IMPLICATIONS: Dissemination of research findings has assisted in highlighting the importance of tobacco smoking among prisoners and the need to develop culturally and setting appropriate smoking cessation initiatives for prisoners. CONCLUSIONS: As one of the most marginalised and socially disadvantaged populations in Australia, prisoners represent an important population to target for smoking cessation programs and interventions. This paper highlights a number of initiatives undertaken to address this problem and suggests directions for the future. PMID- 22449021 TI - The moderating effects of contact with lesbian and gay friends on the relationships among religious fundamentalism, sexism, and sexual prejudice. AB - The purpose of this study was to examine the degree to which contact with lesbian and gay friends moderated the effects of religious fundamentalism and sexism on sexual prejudice. The authors gathered data from 269 heterosexual adults living in Texas. Results indicate that the effects of religious fundamentalism on sexual prejudice were reduced when contact was high. However, the positive association between modern sexism and sexual prejudice was not moderated by contact. The authors discuss theoretical and practical implications. PMID- 22449022 TI - 'If I buy the Kellogg's then he should [buy] the milk': young women's perspectives on relationship dynamics, gender power and HIV risk in Johannesburg, South Africa. AB - Ideals of masculinity and femininity may limit South African women's decision making power in relationships and increase their risk of HIV infection. We conducted 30 in-depth interviews with 18-24-year-old women in inner-city Johannesburg with the aim of understanding young women's expectations of intimate relationships with men, their perceptions of gender and power and how this influences HIV risk. We found that the majority of young women reported expectations of power in relationships that conform to a model of femininity marked by financial independence, freedom to make decisions, including over sexuality, and equality (resistant femininity). The majority of young women, however, were in relationships marked by intimate partner violence, infidelity or lack of condom use. In spite of this, more young women who subscribed to a resistant model of femininity were in less risky relationships than young women who subscribed to acquiescent models, in which power was vested in their male partners. Further, young women who subscribed to resistant femininity had more education than women who subscribed to an acquiescent model. The disconnect between expectations of relationships and young women's lived realities emphasises the need for structural changes that afford women greater economic and thus decision making power. PMID- 22449023 TI - Structure-activity relationship of nonacidic quinazolinone inhibitors of human microsomal prostaglandin synthase 1 (mPGES 1). AB - Microsomal prostaglandin E synthase 1 (mPGES-1) is a key enzyme of the arachidonic acid cascade. Its product PGE(2) plays an important role in various inflammatory processes, pain, fever, and cancer. Selective inhibition of mPGES-1 might be a promising step to avoid cyclooxygenase-related effects of NSAIDs. We studied a class of quinazolinone derivatives of the lead structure FR20 for their effects on the isolated human and murine enzymes, human HeLa cells, and in various settings of the whole blood assay. Novel compounds with direct enzyme inhibiting activity in the submicromolar range (IC(50): 0.13-0.37 MUM) were designed using a bioisosteric replacement strategy and proved to be effective in both cells and human whole blood. Furthermore, pharmacological profiling of toxicity and eicosanoid screening with LC/MS-MS was applied to characterize this new class of mPGES-1 inhibitors. PMID- 22449024 TI - Sodium channels and mammalian sensory mechanotransduction. AB - BACKGROUND: Members of the degenerin/epithelial (DEG/ENaC) sodium channel family are mechanosensors in C elegans, and Nav1.7 and Nav1.8 voltage-gated sodium channel knockout mice have major deficits in mechanosensation. beta and gammaENaC sodium channel subunits are present with acid sensing ion channels (ASICs) in mammalian sensory neurons of the dorsal root ganglia (DRG). The extent to which epithelial or voltage-gated sodium channels are involved in transduction of mechanical stimuli is unclear. RESULTS: Here we show that deleting beta and gammaENaC sodium channels in sensory neurons does not result in mechanosensory behavioural deficits. We had shown previously that Nav1.7/Nav1.8 double knockout mice have major deficits in behavioural responses to noxious mechanical pressure. However, all classes of mechanically activated currents in DRG neurons are unaffected by deletion of the two sodium channels. In contrast, the ability of Nav1.7/Nav1.8 knockout DRG neurons to generate action potentials is compromised with 50% of the small diameter sensory neurons unable to respond to electrical stimulation in vitro. CONCLUSION: Behavioural deficits in Nav1.7/Nav1.8 knockout mice reflects a failure of action potential propagation in a mechanosensitive set of sensory neurons rather than a loss of primary transduction currents. DEG/ENaC sodium channels are not mechanosensors in mouse sensory neurons. PMID- 22449025 TI - Age-related patterns of drug use initiation among polydrug using regular psychostimulant users. AB - INTRODUCTION AND AIMS: To determine age-related patterns of drug use initiation, drug sequencing and treatment entry among regular psychostimulant users. DESIGN AND METHODS: Cross-sectional study of 269 regular psychostimulant users, administered a structured interview examining onset of use for major licit and illicit drugs. RESULTS: The mean age at first intoxication was not associated with age or gender. In contrast, younger age was associated with earlier ages of onset for all of the illicit drug classes. Each additional year of age was associated with a 4 month increase in onset age for methamphetamine, and 3 months for heroin. By the age of 17, those born prior to 1961 had, on average, used only tobacco and alcohol, whereas those born between 1986 and 1990 had used nine different drug classes. The period between initial use and the transition to regular use, however, was stable. Age was also negatively correlated with both age at initial injection and regular injecting. Onset sequences, however, remained stable. Consistent with the age-related patterns of drug use, each additional year of age associated with a 0.47 year increase in the age at first treatment. DISCUSSION AND CONCLUSIONS: While the age at first intoxication appeared stable, the trajectory through illicit drug use was substantially truncated. The data indicate that, at least among those who progress to regular illicit drug use, younger users are likely to be exposed to far broader polydrug use in their teens than has previously been the case. PMID- 22449026 TI - Cognitive load privileges memory-based over data-driven processing, not group level over person-level processing. AB - In the current paper, we argue that categorization and individuation, as traditionally discussed and as experimentally operationalized, are defined in terms of two confounded underlying dimensions: a person/group dimension and a memory-based/data-driven dimension. In a series of three experiments, we unconfound these dimensions and impose a cognitive load. Across the three experiments, two with laboratory-created targets and one with participants' friends as the target, we demonstrate that cognitive load privileges memory-based over data-driven processing, not group- over person-level processing. We discuss the results in terms of their implications for conceptualizations of the categorization/individuation distinction, for the equivalence of person and group processes, for the ultimate 'purpose' and meaningfulness of group-based perception and, fundamentally, for the process of categorization, broadly defined. PMID- 22449027 TI - Age-related reduction of the confidence-accuracy relationship in episodic memory: effects of recollection quality and retrieval monitoring. AB - We investigated age-related reductions in episodic metamemory accuracy. Participants studied pictures and words in different colors and then took forced choice recollection tests. These tests required recollection of the earlier presentation color, holding familiarity of the response options constant. Metamemory accuracy was assessed for each participant by comparing recollection test accuracy with corresponding confidence judgments. We found that recollection test accuracy was greater in younger than older adults and also for pictures than font color. Metamemory accuracy tracked each of these recollection differences, as well as individual differences in recollection test accuracy within each age group, suggesting that recollection ability affects metamemory accuracy. Critically, the age-related impairment in metamemory accuracy persisted even when the groups were matched on recollection test accuracy, suggesting that metamemory declines were not entirely due to differences in recollection frequency or quantity, but that differences in recollection quality and/or monitoring also played a role. We also found that age-related impairments in recollection and metamemory accuracy were equivalent for pictures and font colors. This result contrasted with previous false recognition findings, which predicted that older adults would be differentially impaired when monitoring memory for less distinctive memories. These and other results suggest that age-related reductions in metamemory accuracy are not entirely attributable to false recognition effects, but also depend heavily on deficient recollection and/or monitoring of specific details associated with studied stimuli. PMID- 22449028 TI - Losing a dime with a satisfied mind: positive affect predicts less search in sequential decision making. AB - We investigated the contribution of cognitive ability and affect to age differences in sequential decision making by asking younger and older adults to shop for items in a computerized sequential decision-making task. Older adults performed poorly compared to younger adults partly due to searching too few options. An analysis of the decision process with a formal model suggested that older adults set lower thresholds for accepting an option than younger participants. Further analyses suggested that positive affect, but not fluid abilities, was related to search in the sequential decision task. A second study that manipulated affect in younger adults supported the causal role of affect: Increased positive affect lowered the initial threshold for accepting an attractive option. In sum, our results suggest that positive affect is a key factor determining search in sequential decision making. Consequently, increased positive affect in older age may contribute to poorer sequential decisions by leading to insufficient search. PMID- 22449029 TI - Synergistic activity of alphavbeta3 integrins and the elastin binding protein enhance cell-matrix interactions on bioactive hydrogel surfaces. AB - Engineering materials suitable for vascular prostheses has been a significant challenge, especially in promoting extracellular matrix (ECM) development within synthetic materials. Herein we have utilized two different elastin mimetic peptide sequences, EM-19 and EM-23, to provide a template for ECM deposition when covalently incorporated into scaffold materials. Both peptides contain the hexapeptide sequence VGVAPG, which interacts with the cell surface receptor known as the elastin binding protein (EBP). Additionally, EM-23 contains an RGDS sequence intended for the peptide's interaction with the alpha(v)beta(3) integrin. We first confirm that the presence of both peptides approximates the synergistic mechanism for elastic fiber assembly in vivo, a process that utilizes both the EBP and alpha(v)beta(3). Peptides were then grafted onto the surface of a poly(ethylene glycol) diacrylate (PEG-DA) hydrogel and their efficacy as templates for promoting cell adhesion, spreading, and elastin deposition was evaluated. Although both peptides were able to encourage smooth muscle cell (SMC) adhesion and elastin deposition over PEG-DA and PEG-RGDS controls, PEG-grafted EM 23 was proven to be the more promising motif for inclusion in synthetic substrates to be used in the engineering of vascular tissues, enhancing cell adhesion 60-fold and elastin content 2-fold compared with PEG-RGDS. PMID- 22449030 TI - Autophagy and the immune system. AB - Stressors ranging from nutrient deprivation to immune signaling can induce the degradation of cytoplasmic material by a process known as autophagy. Increasingly, research on autophagy has begun to focus on its role in inflammation and the immune response. Autophagy acts as an immune effector that mediates pathogen clearance. The roles of autophagy bridge both the innate and adaptive immune systems and include functions in thymic selection, antigen presentation, promotion of lymphocyte homeostasis and survival, and regulation of cytokine production. In this review, we discuss the mechanisms by which autophagy is regulated, as well as the functions of autophagy and autophagy proteins in immunity and inflammation. PMID- 22449031 TI - Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides. AB - Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or "tyrosine gate" (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections. PMID- 22449032 TI - Children with Usher syndrome: mental and behavioral disorders. AB - BACKGROUND: Mental and behavioral disorders among adults with Usher syndrome have been discussed and reported in some case studies but no research has been reported on children with Usher syndrome. METHODS: This article investigates the prevalence and characteristics of mental and behavioral disorders among 26 children, 3-17 years of age, with Usher syndrome. RESULTS: Six of the 26 children were diagnosed with a mental or behavioral disorder (1 with schizophrenia and mild mental retardation, 1 with atypical autism and severe mental retardation, 1 with atypical autism and mild mental retardation, 1 with mild mental retardation, and 2 with conduct disorder). Another 3 children had had a mental or behavioral disorder previously in their childhood. CONCLUSION: Even though vision impairment first manifests in late childhood, some children with Usher syndrome seem to develop mental and behavioral disorders during childhood. The aetiology and treatment of mental and behavioral disorders among children with Usher syndrome are discussed. Children with Usher syndrome and their parents may need clinical support during early childhood to prevent development of mental and behavioral disorders. PMID- 22449033 TI - Sticky plant captures prey for symbiotic bug: is this digestive mutualism? AB - Many plants capture and kill insects but, until relatively recently, only carnivorous plants with digestive enzymes were known to gain directly from the nutrients of those insects. Recent studies show that some carnivorous plants lack digestive enzymes and have evolved digestive mutualisms with symbiotic insects that digest their prey for them. Rhododendron macrosepalum, a plant with sticky leaves that captures insects, has an association with symbiotic Mirid bugs that consume the insects captured. Here, we determine what the nature of the relationship is between Mirid and plant. We find that R. macrosepalum has no digestive enzymes of its own but that it does not seem to have the ability to absorb hemipteran faeces through its leaf cuticle. Naturally occurring levels of (15) N and (14) N were used to determine that R. macrosepalum gains no nitrogen through its association with the Mirid bugs and that it obtains all of its nitrogen from the soil. The Mirids, on the other hand, seem to obtain nitrogen from insects captured by the plant, as well as from plant tissues. The relationship between plant and Mirid is not a digestive mutualism but more likely an antagonistic relationship. This study adds to our understanding of how digestive mutualisms evolve and shows that insect capture alone, or in combination with a symbiotic insect relationship does not necessarily make a plant 'carnivorous'. PMID- 22449034 TI - Multiple tender crusted plaques of sudden exacerbation. PMID- 22449035 TI - Using regression equations built from summary data in the psychological assessment of the individual case: extension to multiple regression. AB - Regression equations have many useful roles in psychological assessment. Moreover, there is a large reservoir of published data that could be used to build regression equations; these equations could then be employed to test a wide variety of hypotheses concerning the functioning of individual cases. This resource is currently underused because (a) not all psychologists are aware that regression equations can be built not only from raw data but also using only basic summary data for a sample, and (b) the computations involved are tedious and prone to error. In an attempt to overcome these barriers, Crawford and Garthwaite (2007) provided methods to build and apply simple linear regression models using summary statistics as data. In the present study, we extend this work to set out the steps required to build multiple regression models from sample summary statistics and the further steps required to compute the associated statistics for drawing inferences concerning an individual case. We also develop, describe, and make available a computer program that implements these methods. Although there are caveats associated with the use of the methods, these need to be balanced against pragmatic considerations and against the alternative of either entirely ignoring a pertinent data set or using it informally to provide a clinical "guesstimate." Upgraded versions of earlier programs for regression in the single case are also provided; these add the point and interval estimates of effect size developed in the present article. PMID- 22449036 TI - Using the Advanced Progressive Matrices (Set I) to assess fluid ability in a short time frame: an item response theory-based analysis. AB - This article is aimed at evaluating the possibility that Set I of the Advanced Progressive Matrices (APM-Set I) can be employed to assess fluid ability in a short time frame. The APM-Set I was administered to a sample of 1,389 primary and secondary school students. Confirmatory factor analysis attested to the unidimensionality of the scale. Item response theory analyses were applied to investigate the increasing level of item difficulty, test information function, and differential item functioning across gender and age. Additionally, validity measures are reported. Results provide evidence that the APM-Set I can be used as a reliable and valid short form of the Raven's Progressive Matrices in the assessment of fluid ability. PMID- 22449037 TI - Tuning multi/pluri-potent stem cell fate by electrospun poly(L-lactic acid) calcium-deficient hydroxyapatite nanocomposite mats. AB - In this study, we investigated whether multipotent (human-bone-marrow-derived mesenchymal stem cells [hBM-MSCs]) and pluripotent stem cells (murine-induced pluripotent stem cells [iPSCs] and murine embryonic stem cells [ESCs]) respond to nanocomposite fibrous mats of poly(L-lactic acid) (PLLA) loaded with 1 or 8 wt % of calcium-deficient nanohydroxyapatite (d-HAp). Remarkably, the dispersion of different amounts of d-HAp to PLLA produced a set of materials (PLLA/d-HAp) with similar architectures and tunable mechanical properties. After 3 weeks of culture in the absence of soluble osteogenic factors, we observed the expression of osteogenic markers, including the deposition of bone matrix proteins, in multi/pluripotent cells only grown on PLLA/d-HAp nanocomposites, whereas the osteogenic differentiation was absent on stem-cell-neat PLLA cultures. Interestingly, this phenomenon was confined only in hBM-MSCs, murine iPSCs, and ESCs grown on direct contact with the PLLA/d-HAp mats. Altogether, these results indicate that the osteogenic differentiation effect of these electrospun PLLA/d HAp nanocomposites was independent of the stem cell type and highlight the direct interaction of stem cell-polymeric nanocomposite and the mechanical properties acquired by the PLLA/d-HAp nanocomposites as key steps for the differentiation process. PMID- 22449038 TI - High-resolution measurements in plant biology. PMID- 22449039 TI - Cell type-specific transcriptional profiling: implications for metabolite profiling. AB - Plant development and survival is centered on complex regulatory networks composed of genes, proteins, hormone pathways, metabolites and signaling pathways. The recent advancements in whole genome biology have furthered our understanding of the interactions between these networks. As a result, numerous cell type-specific transcriptome profiles have been generated that have elucidated complex gene regulatory networks occurring at the cellular level, many of which were masked during whole-organ analysis. Modern technologies have also allowed researchers to generate multiple whole-organ metabolite profiles; however, only a limited number have been generated at the level of individual cells. Recent advancements in the isolation of individual cell populations have made cell type-specific metabolite profiles possible, enabling the enhanced detection and quantification of metabolites that were formerly unavailable when considering the whole organ. The comparison of metabolite and transcriptome profiles from the same cells has been a valuable resource to generate predictions regarding specific metabolite activity and function. In this review, we focus on recent studies that demonstrate the value of cell type-specific transcriptional profiles and their comparison with profiles generated from whole organs. Advancements in the isolation of single-cell populations will be highlighted, and the potential application towards generating detailed metabolic profiles will be discussed. PMID- 22449040 TI - Analysis of plant germline development by high-throughput RNA profiling: technical advances and new insights. AB - Reproduction is a crucial step in the life cycle of plants. The male and female germline lineages develop in the reproductive organs of the flower, which in higher plants are the anthers and ovules, respectively. Development of the germline lineage initiates from a dedicated sporophytic cell that undergoes meiosis to form spores that subsequently give rise to the gametophytes through mitotic cell divisions. The mature male and female gametophytes harbour the male (sperm cells) and female gametes (egg and central cell), respectively. Those unite during double fertilization to initiate embryo and endosperm development in sexually reproducing higher plants. While cytological changes involved in development of the germline lineages have been well characterized in a number of species, investigation of the transcriptional basis underlying their development and the specification of the gametes proved challenging. This is largely due to the inaccessibility of the cells constituting the germline lineages, which are enclosed by sporophytic tissues. Only recently, these technical limitations could be overcome by combining new methods to isolate the relevant cells with powerful transcriptional profiling methods, such as microarrays or high-throughput sequencing of RNA. This review focuses on these technical advances and the new insights gained from them concerning the transcriptional basis and molecular mechanisms underlying germline development. PMID- 22449041 TI - Metabolite analyses of single cells. AB - Single-cell analysis is a promising method for understanding not only cellular physiology but also biological mechanisms of multicellular organisms. Although neighboring cells in multicellular organisms originate from the same genomic information, different circumstances around cells or epigenetic differences have different influences on each cell, leading to differing expression of genes, and thus differing levels and dynamics of metabolites, in single cells. However, single-cell analysis is a tough challenge, even with recent technologies, because of the small size of single cells. Unlike genes, metabolites cannot be amplified, and therefore metabolite analysis is another issue. To analyze such a tiny quantity of metabolites in a single cell, various techniques have been tried and developed. Especially in mass spectrometry, marked improvements in both detection sensitivity and ionization techniques have opened up the challenge for the analysis of metabolites in single cells. In this review, we discuss the method for metabolite detection at the level of single cells and recent advancements in technology. PMID- 22449042 TI - High-resolution plant metabolomics: from mass spectral features to metabolites and from whole-cell analysis to subcellular metabolite distributions. AB - The main goal of metabolomics is the comprehensive qualitative and quantitative analysis of the time- and space-resolved distribution of all metabolites present in a given biological system. Because metabolite structures, in contrast to transcript and protein sequences, are not directly deducible from the genomic DNA sequence, the massive increase in genomic information is only indirectly of use to metabolomics, leaving compound annotation as a key problem to be solved by the available analytical techniques. Furthermore, as metabolites vary widely in both concentration and chemical behavior, there is no single analytical procedure allowing the unbiased and comprehensive structural elucidation and determination of all metabolites present in a given biological system. In this review the different approaches for targeted and non-targeted metabolomics analysis will be described with special emphasis on mass spectrometry-based techniques. Particular attention is given to approaches which can be employed for the annotation of unknown compounds. In the second part, the different experimental approaches aimed at tissue-specific or subcellular analysis of metabolites are discussed including a range of non-mass spectrometry based technologies. PMID- 22449043 TI - Glandular trichomes: what comes after expressed sequence tags? AB - Glandular trichomes cover the surface of many plant species. They exhibit tremendous diversity, be it in their shape or the compounds they secrete. This diversity is expressed between species but also within species or even individual plants. The industrial uses of some trichome secretions and their potential as a defense barrier, for example against arthropod pests, has spurred research into the biosynthesis pathways that lead to these specialized metabolites. Because complete biosynthesis pathways take place in the secretory cells, the establishment of trichome-specific expressed sequence tag libraries has greatly accelerated their elucidation. Glandular trichomes also have an important metabolic capacity and may be considered as true cell factories. To fully exploit the potential of glandular trichomes as breeding or engineering objects, several research areas will have to be further investigated, such as development, patterning, metabolic fluxes and transcription regulation. The purpose of this review is to provide an update on the methods and technologies which have been used to investigate glandular trichomes and to propose new avenues of research to deepen our understanding of these specialized structures. PMID- 22449044 TI - Use of mass spectrometry for imaging metabolites in plants. AB - We discuss and illustrate recent advances that have been made to image the distribution of metabolites among cells and tissues of plants using different mass spectrometry technologies. These technologies include matrix-assisted laser desorption ionization, desorption electrospray ionization, and secondary ion mass spectrometry. These are relatively new technological applications of mass spectrometry and they are providing highly spatially resolved data concerning the cellular distribution of metabolites. We discuss the advantages and limitations of each of these mass spectrometric methods, and provide a description of the technical barriers that are currently limiting the technology to the level of single-cell resolution. However, we anticipate that advances in the next few years will increase the resolving power of the technology to provide unprecedented data on the distribution of metabolites at the subcellular level, which will increase our ability to decipher new knowledge concerning the spatial organization of metabolic processes in plants. PMID- 22449045 TI - Fluorescent protein-based technologies: shedding new light on the plant endomembrane system. AB - Without doubt, GFP and spectral derivatives have revolutionized the way biologists approach their journey toward the discovery of how plant cells function. It is fascinating that in its early days GFP was used merely for localization studies, but as time progressed researchers successfully explored new avenues to push the power of GFP technology to reach new and exciting research frontiers. This has had a profound impact on the way we can now study complex and dynamic systems such as plant endomembranes. Here we briefly describe some of the approaches where GFP has revolutionized in vivo studies of protein distribution and dynamics and focus on two emerging approaches for the application of GFP technology in plant endomembranes, namely optical tweezers and forward genetics approaches, which are based either on the light or on genetic manipulation of secretory organelles to gain insights on the factors that control their activities and integrity. PMID- 22449046 TI - Quantitative imaging using genetically encoded sensors for small molecules in plants. AB - Quantitative imaging in live cells is a powerful method for monitoring the dynamics of biomolecules at an excellent spatio-temporal resolution. Such an approach, initially limited to a small number of substrates for which specific dyes were available, has become possible for a large number of biomolecules due to the development of genetically encoded, protein-based sensors. These sensors, which can be introduced into live cells through a transgenic approach, offer the benefits of quantitative imaging, with an extra advantage of non-invasiveness. In the past decade there has been a drastic expansion in the number of biomolecules for which genetically encoded sensors are available, and the functional properties of existing sensors are being improved at a dramatic pace. A number of technical improvements have now made the application of genetically encoded sensors in plants rather straightforward, and some of the sensors such as calcium indicator proteins have become standard analytical tools in many plant laboratories. The use of a handful of probes has already revealed an amazing specificity of cellular biomolecule dynamics in plants, which leads us to believe that there are many more discoveries to be made using genetically encoded sensors. In this short review, we will summarize the progress made in the past 15 years in the development in genetically encoded sensors, and highlight significant discoveries made in plant biology. PMID- 22449047 TI - High-resolution imaging of Ca2+ , redox status, ROS and pH using GFP biosensors. AB - Many plant response systems are linked to complex dynamics in signaling molecules such as Ca(2+) and reactive oxygen species (ROS) and to pH. Regulatory changes in these molecules can occur in the timeframe of seconds and are often limited to specific subcellular locales. Thus, to understand how Ca(2+) , ROS and pH form part of plants' regulatory networks, it is essential to capture their rapid dynamics with resolutions that span the whole plant to subcellular dimensions. Defining the spatio-temporal signaling 'signatures' of these regulators at high resolution has now been greatly facilitated by the generation of plants expressing a range of GFP-based bioprobes. For Ca(2+) and pH, probes such as the yellow cameleon Ca(2+) sensors (principally YC2.1 and 3.6) or the pHluorin and H148D pH sensors provide a robust suite of tools to image changes in these ions. For ROS, the tools are much more limited, with the GFP-based H(2) O(2) sensor Hyper representing a significant advance for the field. However, with this probe, its marked pH sensitivity provides a key challenge to interpretation without using appropriate controls to test for potentially coupled pH-dependent changes. Most of these Ca(2+) -, ROS- and pH-imaging biosensors are compatible with the standard configurations of confocal microscopes available to many researchers. These probes therefore represent a readily accessible toolkit to monitor cellular signaling. Their use does require appreciation of a minimal set of controls but these are largely related to ensuring that neither the probe itself nor the imaging conditions used perturb the biology of the plant under study. PMID- 22449048 TI - Surveying the plant's world by magnetic resonance imaging. AB - Understanding the way in which plants develop, grow and interact with their environment requires tools capable of a high degree of both spatial and temporal resolution. Magnetic resonance imaging (MRI), a technique which is able to visualize internal structures and metabolites, has the great virtue that it is non-invasive and therefore has the potential to monitor physiological processes occurring in vivo. The major aim of this review is to attract plant biologists to MRI by explaining its advantages and wide range of possible applications for solving outstanding issues in plant science. We discuss the challenges and opportunities of MRI in the study of plant physiology and development, plant environment interactions, biodiversity, gene functions and metabolism. Overall, it is our view that the potential benefit of harnessing MRI for plant research purposes is hard to overrate. PMID- 22449049 TI - The structure of the phloem--still more questions than answers. AB - Long-distance assimilate distribution in higher plants takes place in the enucleate sieve-tube system of the phloem. It is generally accepted that flow of assimilates is driven by an osmotically generated pressure differential, as proposed by Ernst Munch more than 80 years ago. In the period between 1960 and 1980, the pressure flow hypothesis was challenged when electron microscopic images suggested that sieve tubes contain obstructions that would prevent passive flow. This led to the proposal of alternative translocation mechanisms. However, most investigators came to the conclusion that obstructions in the sieve-tube path were due to preparation artifacts. New developments in bioimaging have vastly enhanced our ability to study the phloem. Unexpectedly, in vivo studies challenge the pressure-flow hypothesis once again. In this review we summarize current investigations of phloem structure and function and discuss their impact on our understanding of long-distance transport in the phloem. PMID- 22449050 TI - Composition, architecture and dynamics of the photosynthetic apparatus in higher plants. AB - The process of oxygenic photosynthesis enabled and still sustains aerobic life on Earth. The most elaborate form of the apparatus that carries out the primary steps of this vital process is the one present in higher plants. Here, we review the overall composition and supramolecular organization of this apparatus, as well as the complex architecture of the lamellar system within which it is harbored. Along the way, we refer to the genetic, biochemical, spectroscopic and, in particular, microscopic studies that have been employed to elucidate the structure and working of this remarkable molecular energy conversion device. As an example of the highly dynamic nature of the apparatus, we discuss the molecular and structural events that enable it to maintain high photosynthetic yields under fluctuating light conditions. We conclude the review with a summary of the hypotheses made over the years about the driving forces that underlie the partition of the lamellar system of higher plants and certain green algae into appressed and non-appressed membrane domains and the segregation of the photosynthetic protein complexes within these domains. PMID- 22449051 TI - Advances in plant genome sequencing. AB - The study of plant biology in the 21st century is, and will continue to be, vastly different from that in the 20th century. One driver for this has been the use of genomics methods to reveal the genetic blueprints for not one but dozens of plant species, as well as resolving genome differences in thousands of individuals at the population level. Genomics technology has advanced substantially since publication of the first plant genome sequence, that of Arabidopsis thaliana, in 2000. Plant genomics researchers have readily embraced new algorithms, technologies and approaches to generate genome, transcriptome and epigenome datasets for model and crop species that have permitted deep inferences into plant biology. Challenges in sequencing any genome include ploidy, heterozygosity and paralogy, all which are amplified in plant genomes compared to animal genomes due to the large genome sizes, high repetitive sequence content, and rampant whole- or segmental genome duplication. The ability to generate de novo transcriptome assemblies provides an alternative approach to bypass these complex genomes and access the gene space of these recalcitrant species. The field of genomics is driven by technological improvements in sequencing platforms; however, software and algorithm development has lagged behind reductions in sequencing costs, improved throughput, and quality improvements. It is anticipated that sequencing platforms will continue to improve the length and quality of output, and that the complementary algorithms and bioinformatic software needed to handle large, repetitive genomes will improve. The future is bright for an exponential improvement in our understanding of plant biology. PMID- 22449052 TI - Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. AB - Aurachin RE (1) is a strong antibiotic that was recently found to possess 1,4 dihydroxy-2-naphthoate prenyltransferase (MenA) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9' position. To identify selective MenA inhibitors against Mycobacterium tuberculosis , a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays, including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against nonreplicating M. tuberculosis. PMID- 22449053 TI - Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice. AB - Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNgamma ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T(reg)) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNgamma were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T(reg) and MDSC populations in tumor-bearing hosts. PMID- 22449054 TI - Seasonal variations of cough reflex sensitivity in elite athletes training in cold air environment. AB - BACKGROUND: Exercise-induced cough is common among athletes. Athletes training in cold air often report an increasingly troublesome cough during the winter season. Chronic airway irritation or inflammation may increase the sensory response of cough receptors. The aim of this study was to evaluate the seasonal variability of cough reflex sensitivity to capsaicin in elite athletes. METHODS: Fifty-three elite winter athletes and 33 sedentary subjects completed a respiratory questionnaire and a capsaicin provocation test during the summer, fall, and winter. Allergy skin prick tests, spirometry, eucapnic voluntary hyperpnea test (EVH), methacholine inhalation test (MIT), and induced sputum analysis were also performed. RESULTS: In athletes, the prevalence of cough immediately after exercise was high, particularly during winter. Athletes often showed a late occurrence of cough between 2-8 h after exercise. The cough reflex sensitivity to capsaicin was unchanged through the seasons in both athletes and non-athlete subjects. No significant correlations were found in groups between cough reflex sensitivity to capsaicin and the number of years in sport training, the number of hours of training per week, EVH response (% fall in FEV1), airway responsiveness to methacholine (PC20), airway inflammation or atopy. CONCLUSION: The prevalence of cough immediately and a few hours after exercise is high in athletes and more frequently reported during winter. However, cough does not seem to be associated with cough reflex hypersensitivity to capsaicin, bronchoconstriction, or airway inflammation in the majority of athletes. PMID- 22449055 TI - Chronic obstructive pulmonary disease and severe pneumonia. PMID- 22449056 TI - Repetitive pneumonia and wheezing in an elderly patient after radiation therapy. PMID- 22449057 TI - Necrotizing fasciitis following intra-articular steroid injection: case report and review of the literature. PMID- 22449058 TI - Unilateral iliopsoas hematoma in elderly patients with sudden back pain and severe anemia: report of two cases. PMID- 22449059 TI - Stroke and an unexplained dyspnea in an elderly patient: platypnea-orthodeoxia syndrome. PMID- 22449060 TI - Pink urine in an elderly woman. PMID- 22449061 TI - Dysphagia in older adults at high risk of requiring care. PMID- 22449062 TI - Toe clearance rehabilitative slipper for fall risk in institutionalized older people. PMID- 22449063 TI - Prevalence of resuscitation orders among residents from aged care facilities admitted to general medical units. PMID- 22449064 TI - A low-cost body inertial-sensing network for practical gait discrimination of hemiplegia patients. AB - Gait analysis is widely used in detecting human walking disorders. Current gait analysis methods like video- or optical-based systems are expensive and cause invasion of human privacy. This article presents a self-developed low-cost body inertial-sensing network, which contains a base station, three wearable inertial measurement nodes, and the affiliated wireless communication protocol, for practical gait discrimination between hemiplegia patients and asymptomatic subjects. Every sensing node contains one three-axis accelerometer, one three axis magnetometer, and one three-axis gyroscope. Seven hemiplegia patients (all were abnormal on the right side) and 7 asymptomatic subjects were examined. The three measurement nodes were attached on the thigh, the shank, and the dorsum of the foot, respectively (all on the right side of the body). A new method, which does not need to obtain accurate positions of the sensors, was used to calculate angles of knee flexion/extension and foot in the gait cycle. The angle amplitudes of initial contact, toe off, and knee flexion/extension were extracted. The results showed that there were significant differences between the two groups in the three angle amplitudes examined (-0.52+/-0.98 degrees versus 6.94+/-2.63 degrees , 28.33+/-11.66 degrees versus 47.34+/-7.90 degrees , and 26.85+/-8.6 degrees versus 50.91+/-6.60 degrees , respectively). It was concluded that the body inertial-sensing network platform provided a practical approach for wearable biomotion acquisition and was effective for discriminating gait symptoms between hemiplegia and asymptomatic subjects. PMID- 22449065 TI - Emotional processing in borderline personality disorder. AB - This study examines whether individuals with borderline personality disorder (BPD) would exhibit augmented emotional responses to picture stimuli after being challenged with an ideographic interpersonal conflict script. Participants were 24 adults diagnosed with BPD, 23 adults diagnosed with obsessive-compulsive personality disorder (OCPD), and 28 normal controls. Participants viewed emotionally evocative pictures before and after listening to the interpersonal script while a variety of physiological measures were recorded. Findings indicated that the interpersonal script was effective in eliciting enduring emotional responses from the BPD group relative to the control groups. However, despite the effectiveness of the interpersonal challenge task, there were no group differences in emotional responding to the affect eliciting stimuli. The findings underscore the complexities involved in examining emotional dysregulation in BPD in a laboratory setting. PMID- 22449066 TI - An item response theory analysis of DSM-IV diagnostic criteria for personality disorders: findings from the national epidemiologic survey on alcohol and related conditions. AB - The purpose of this study was to evaluate the psychometric properties of DSM-IV symptom criteria for assessing personality disorders (PDs) in a national population and to compare variations in proposed symptom coding for social and/or occupational dysfunction. Data were obtained from a total sample of 34,653 respondents from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). For each personality disorder, confirmatory factor analysis (CFA) established a 1-factor latent factor structure for the respective symptom criteria. A 2-parameter item response theory (IRT) model was applied to the symptom criteria for each PD to assess the probabilities of symptom item endorsements across different values of the underlying trait (latent factor). Findings were compared with a separate IRT model using an alternative coding of symptom criteria that requires distress/impairment to be related to each criterion. The CFAs yielded a good fit for a single underlying latent dimension for each PD. Findings from the IRT indicated that DSM-IV PD symptom criteria are clustered in the moderate to severe range of the underlying latent dimension for each PD and are peaked, indicating high measurement precision only within a narrow range of the underlying trait and lower measurement precision at lower and higher levels of severity. Compared with the NESARC symptom coding, the IRT results for the alternative symptom coding are shifted toward the more severe range of the latent trait but generally have lower measurement precision for each PD. The IRT findings provide support for a reliable assessment of each PD for both NESARC and alternative coding for distress/impairment. The use of symptom dysfunction for each criterion, however, raises a number of issues and implications for the DSM-5 revision currently proposed for Axis II disorders (American Psychiatric Association, 2010). PMID- 22449067 TI - Manipulation and control of molecular beams. PMID- 22449068 TI - Functional expression of PHO1 to the Golgi and trans-Golgi network and its role in export of inorganic phosphate. AB - Arabidopsis thaliana PHO1 is primarily expressed in the root vascular cylinder and is involved in the transfer of inorganic phosphate (Pi) from roots to shoots. To analyze the role of PHO1 in transport of Pi, we have generated transgenic plants expressing PHO1 in ectopic A. thaliana tissues using an estradiol inducible promoter. Leaves treated with estradiol showed strong PHO1 expression, leading to detectable accumulation of PHO1 protein. Estradiol-mediated induction of PHO1 in leaves from soil-grown plants, in leaves and roots of plants grown in liquid culture, or in leaf mesophyll protoplasts, was all accompanied by the specific release of Pi to the extracellular medium as early as 2-3 h after addition of estradiol. Net Pi export triggered by PHO1 induction was enhanced by high extracellular Pi and weakly inhibited by the proton-ionophore carbonyl cyanide m-chlorophenylhydrazone. Expression of a PHO1-GFP construct complementing the pho1 mutant revealed GFP expression in punctate structures in the pericycle cells but no fluorescence at the plasma membrane. When expressed in onion epidermal cells or in tobacco mesophyll cells, PHO1-GFP was associated with similar punctate structures that co-localized with the Golgi/trans-Golgi network and uncharacterized vesicles. However, PHO1-GFP could be partially relocated to the plasma membrane in leaves infiltrated with a high-phosphate solution. Together, these results show that PHO1 can trigger Pi export in ectopic plant cells, strongly indicating that PHO1 is itself a Pi exporter. Interestingly, PHO1 mediated Pi export was associated with its localization to the Golgi and trans Golgi networks, revealing a role for these organelles in Pi transport. PMID- 22449069 TI - Local knowledge of traditional fishermen on economically important crabs (Decapoda: Brachyura) in the city of Conde, Bahia State, Northeastern Brazil. AB - BACKGROUND: This article records the traditional knowledge of crab gatherers in the city of Conde, in the North Coast Region of Bahia State, Northeastern Brazil. METHODS: Data on biological and ecological aspects of economically important brachyuran crustaceans have been obtained from semi-structured interviews and in loco observations conducted from September 2007 to December 2009. A total of 57 fishermen of both genders, aged between 10 and 78 years have been interviewed (individually or collectively) in different contexts; interviewees were asked about aspects such as external morphology, life cycle, trophic ecology, and spatial and temporal distribution of the major economically important brachyuran crustaceans in the region. Seven fishing communities were visited: Siribinha, Sitio do Conde, Pocas, Ilha das Ostras, Cobo, Buri and Sempre Viva. Data were analyzed by comparing the information provided by participants with those from the specialized academic literature. RESULTS: The results show that artisanal fishermen have a wide ranging and well-grounded knowledge on the ecological and biological aspects of crustaceans. Crab gatherers of Conde know about growth and reproductive behavior of the animals they interact with, especially with regard to the three major biological aspects: "molt", "walking dance" and "spawning". CONCLUSION: This knowledge constitutes an important source of information that should be considered in studies of management and sustainable use of fishery resources in the North Coast Region of Bahia State. PMID- 22449070 TI - In this issue: Tec kinases in the crosshairs. AB - Tec family kinases are the second largest family of non-receptor tyrosine kinases, of critical importance to the biology of cells derived from the bone marrow. Significant progress in this area during the last decade revealed a role for several of these kinases in inflammatory and oncologic disorders. This led to the discovery and development of molecular targeted therapies against Tec kinases, most notably to date Btk, already showing promising clinical activity in B cell lymphoma and autoimmunity. As Btk does not carry oncogenic modifications, this also establishes a novel therapeutic paradigm, based on targeting ancillary pathways recruited by the pathogenic process to become pivotal to cancer cell's biology. This issue focuses on biology and translation of Tec kinases, at the cross-roads between immunology and cancer. PMID- 22449071 TI - Tec family kinases in inflammation and disease. AB - Over the last decade, the Tec family of nonreceptor tyrosine kinases (Btk, Tec, Bmx, Itk, and Rlk) have been shown to play a key role in inflammation and bone destruction. Bruton's tyrosine kinase (Btk) has been the most widely studied due to the critical role of this kinase in B-cell development and recent evidence showing that blocking Btk signaling is effective in ameliorating lymphoma progression and experimental arthritis. This review will examine the role of TFK in myeloid cell function and the potential of targeting these kinases as a therapeutic intervention in autoimmune disorders such as rheumatoid arthritis. PMID- 22449072 TI - The role of the tec kinase Bruton's tyrosine kinase (Btk) in leukocyte recruitment. AB - Recruitment of leukocytes into inflamed tissue is a key component of the immune system. The activation of integrins on leukocytes is required for their recruitment into the inflamed tissue. Btk is a cytoplasmic nonreceptor tyrosine kinase belonging to the Tec-kinase family. It plays a key role in B-cell development and function, and recently published studies revealed important roles of Btk in myeloid cells. Btk might be activated through a variety of receptors leading to activation of integrins as the pivotal element in leukocyte recruitment. This review focuses on the role of Btk in B-lymphocyte homing and in neutrophil recruitment. PMID- 22449073 TI - Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. AB - BTK is a kinase that functions downstream of multiple receptors in various hematologic cells. This review focuses on BTK-dependent pathways that are likely to be involved in maintaining the malignant phenotype in B-cell lymphomas and leukemias. Survival of various B-cell malignancies requires BTK-dependent signals from the B-cell antigen receptor. Survival is also dependent on malignant cells homing to and interacting with lymphoid microenvironments, and these interactions are also BTK-dependent due its role in signaling downstream of chemokine and innate immune receptors. The potential for therapeutic targeting of BTK is currently being tested in clinical settings. PMID- 22449074 TI - The role of Tec family kinases in the regulation of T-helper-cell differentiation. AB - ABSTRACT Members of the Tec kinase family (Tec, Btk, Itk, Rlk, and Bmx) play an important role during innate and adaptive immune responses, and mutations in Tec family kinases are linked with immunodeficiencies in humans and mice. Three members of the Tec kinase family are expressed in T cells (Tec, Itk, and Rlk), and biochemical and genetic studies have revealed important roles for Tec family kinases during T-cell development and in the control of T-cell function. Here the authors review the role of Tec family kinases in the regulation of T-helper-cell differentiation. PMID- 22449075 TI - Regulation of T-cell responses and disease by tec kinase Itk. AB - Itk is a member of the Tec family tyrosine kinases involved in T-cell receptor signaling. The authors review the background and most recent findings of the role of Itk T-cell activation and development of alphabeta T cells. They also discuss the role of Itk in development of nonconventional T cells, including CD8(+) innate memory phenotype T cells, different gammadelta T-cell populations, and invariant NKT cells. They close by reviewing the regulation of T helper differentiation and cytokine secretion, the immune response to infectious disease, and diseases such as allergic asthma and atopic dermatitis by Itk. PMID- 22449076 TI - BMX and its role in inflammation, cardiovascular disease, and cancer. AB - Bone marrow kinase on chromosome X (BMX) is a cytosolic tyrosine kinase and a member of the TEC kinase family. BMX is expressed in hematopoietic cells of the myeloid lineage where it participates in the immune response. It is also involved in the response to ischemia and pressure overload in the endocardium and the cardiac endothelium. Moreover, BMX is expressed in several types of cancers and very recently has been shown to mediate the survival and tumorigenicity of glioblastoma cancer stem cells. In the inflammatory response BMX regulates the secretion of proinflammatory cytokines induced by TNFalpha, IL-1beta, and TLR agonists. It is required for the activation of the MAP kinase and NFkappaB pathways and acts at the level of the essential TAK1/TAB complex. Cellular regulation of the IL-8 promoter by BMX is dependent on membrane localization mediated by its pleckstrin homology domain, as well as on BMX kinase activity. BMX deficiency confers protection from arthritis in a mouse model known to be dependent on macrophages and IL-1beta. Genetic replacement of BMX with a kinase inactive allele surprisingly restored susceptibility to arthritis, suggesting that in vivo BMX kinase activity can be dispensable. This review summarizes recent advances in the knowledge of BMX biology and their relevance for translational medicine. PMID- 22449077 TI - Isodesacetyluvaricin, an Annonaceous acetogenin, specifically inhibits gene expression of cyclooxygenase-2. AB - Cyclooxygenase-2 (COX-2) is an inducible isoform of the enzyme responsible for the synthesis of several inflammatory mediators. In a search for phytochemicals with anti-inflammatory activity, the COX-2 inhibitory activity of 15 typical Annonaceous acetogenins was examined. Isodesacetyluvaricin (1), from the Formosan tropical fruit tree Annona glabra, exhibited the most potent activity. Reverse transcription PCR was used to test the effect of 1 on epidermal growth factor stimulated expression of COX-2 in cultures of A431 human epidermoid carcinoma cells. Three hours after exposure to 1 (5 MUM), A431 cells had barely detectable levels of COX-2 mRNA. A corresponding but smaller decline in the COX-2 protein appeared on using Western blots. Lipopolysaccharide-stimulated expression of COX 2 in Raw 264.7 mouse leukemic monocyte-macrophages showed a similar decrease. Luciferase assays revealed that cells exposed to 1 had reduced activities of two COX-2 promoter-transcription factors: cAMP response element-binding factor and nuclear factor of activated T-cells. Compound 1 did not affect cell proliferation, as measured by a colorimetric assay, or intracellular store operated calcium influx, as determined by fluorescence imaging. Thus, 1 may serve as a lead compound for targeting inflammatory diseases as well as angiogenesis and cancer metastasis. PMID- 22449078 TI - A curve of thresholds governs plague epizootics in Central Asia. AB - A core concept of infectious disease epidemiology is the abundance threshold, below which an infection is unable to invade or persist. There have been contrasting theoretical predictions regarding the nature of this threshold for vector-borne diseases, but for infections with an invertebrate vector, it is common to assume a threshold defined by the ratio of vector and host abundances. Here, we show in contrast, both from field data and model simulations, that for plague (Yersinia pestis) in Kazakhstan, the invasion threshold quantity is based on the product of its host (Rhombomys opimus) and vector (mainly Xenopsylla spp.) abundances, resulting in a combined threshold curve with hyperbolic shape. This shape implies compensation between host and vector abundances in permitting infection, which has important implications for disease control. Realistic joint thresholds, supported by data, should promote improved understanding, prediction and management of disease occurrence in this and other vector-borne disease systems. PMID- 22449079 TI - How many treatment sessions and patients are needed to create a stable score of adherence and competence in the treatment of cocaine dependence? AB - The study utilized a generalizability theory analysis of adherence and competence ratings to evaluate the number of sessions and patients needed to yield dependable scores at the patient and therapist levels. Independent judges' ratings of supportive expressive therapy (n = 94), cognitive therapy (n = 103), and individual drug counseling (n = 98) were obtained on tapes of sessions from the NIDA Collaborative Cocaine Treatment Study. Generalizability coefficients revealed that, for all three treatments, ratings made on approximately five to 10 sessions per patient are needed to achieve sufficient dependability at the patient level. At the therapist level, four to 14 patients need to be evaluated (depending on the modality), to yield dependable scores. Many studies today use fewer numbers. PMID- 22449080 TI - Connecting the chemical and biological properties of nitric oxide. AB - Nitric oxide (NO(*); nitrogen monoxide) is known to be a critical regulator of cell and tissue function through mechanisms that utilize its unique physicochemical properties as a small and uncharged free radical with limited reactivity. Here, the basic chemistry and biochemistry of NO(*) are summarized through the description of its chemical reactivity, biological sources, physiological and pathophysiological levels, and cellular transport. The complexity of the interactions of NO(*) with biotargets, which vary from irreversible second-order reactions to reversible formation of nonreactive and reactive nitrosyl complexes, is noted. Emphasis is placed on the kinetics and physiological consequences of the reactions of NO(*) with its better characterized biotargets. These targets are soluble guanylate cyclase (sCG), oxyhemoglobin/hemoglobin (HbO(2)/Hb) and cytochrome c oxidase (CcOx), all of which are ferrous heme proteins that react with NO(*) with second-order rate constants approaching the diffusion limit (k(on) approximately 10(7) to 10(8) M( 1) s(-1)). Likewise, the biotarget responsible for the most described pathophysiological actions of NO(*) is the superoxide anion radical (O(2)(*-)), which reacts with NO(*) in a diffusion-controlled process (k approximately 10(10) M(-1) s(-1)). The reactions of NO(*) with proteins containing iron-sulfur clusters ([FeS]) remain little studied and the reported rate constants of the first steps of these reactions are considerable (k approximately 10(5) M(-1) s( 1)). Not surprisingly, the interactions of proteins containing iron-sulfur clusters with NO(*) remain ambiguous and have been associated with both physiological and pathophysiological effects. Overall, it is emphasized that any claimed biological action of NO(*) should be connected with its interaction with kinetically relevant biotargets. Although reactivity toward biotargets is only one of the factors contributing to cellular and tissue responses mediated by short-lived species, such as NO(*) and other oxygen-derived species, it is a critical factor. Therefore, taking reactivity into account is important to advancing our knowledge on redox signaling mechanisms. PMID- 22449081 TI - Permanent 125I-seed prostate brachytherapy: early prostate specific antigen value as a predictor of PSA bounce occurrence. AB - PURPOSE: To evaluate predictive factors for PSA bounce after 125I permanent seed prostate brachytherapy and identify criteria that distinguish between benign bounces and biochemical relapses. MATERIALS AND METHODS: Men treated with exclusive permanent 125I seed brachytherapy from November 1999, with at least a 36 months follow-up were included. Bounce was defined as an increase >= 0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Biochemical failure (BF) was defined using the criteria of the Phoenix conference: nadir +2 ng/ml. RESULTS: 198 men were included. After a median follow-up of 63.9 months, 21 patients experienced a BF, and 35.9% had at least one bounce which occurred after a median period of 17 months after implantation (4-50). Bounce amplitude was 0.6 ng/ml (0.2-5.1), and duration was 13.6 months (4.0-44.9). In 12.5%, bounce magnitude exceeded the threshold defining BF. Age at the time of treatment and high PSA level assessed at 6 weeks were significantly correlated with bounce but not with BF. Bounce patients had a higher BF free survival than the others (100% versus 92%, p = 0,007). In case of PSA increase, PSA doubling time and velocity were not significantly different between bounce and BF patients. Bounces occurred significantly earlier than relapses and than nadir + 0.2 ng/ml in BF patients (17 vs 27.8 months, p < 0.0001). CONCLUSION: High PSA value assessed 6 weeks after brachytherapy and young age were significantly associated to a higher risk of bounces but not to BF. Long delays between brachytherapy and PSA increase are more indicative of BF. PMID- 22449082 TI - Autopolyploidy differentially influences body size in plants, but facilitates enhanced accumulation of secondary metabolites, causing increased cytosine methylation. AB - Whole genome duplication leads to autopolyploidy and brings about an increase in cell size, concentration of secondary metabolites and enhanced cytosine methylation. The increased cell size offers a positive advantage to polyploids for cell-surface-related activities, but there is a differential response to change in body size across species and taxonomic groups. Although polyploidy has been very extensively studied, having genetic, ecological and evolutionary implications, there is no report that underscores the significance of native secondary metabolites vis-a-vis body size with ploidy change. To address this problem we targeted unique diploid-autotetraploid paired sets of eight diverse clones of six species of Cymbopogon- a species complex of aromatic grasses that accumulate qualitatively different monoterpene essential oils (secondary metabolite) in their vegetative biomass. Based on the qualitative composition of essential oils and the plant body size relationship between the diploid versus autotetraploid paired sets, we show that polyploidy brings about enhanced accumulation of secondary metabolites in all cases, but exerts differential effects on body size in various species. It is observed that the accumulation of alcohol-type metabolites (e.g. geraniol) does not inhibit increase in body size with ploidy change from 2* to 4* (r = 0.854, P < 0.01), but aldehyde-type metabolites (e.g. citral) appear to drastically impede body development (r = 0.895). Such a differential response may be correlated to the metabolic steps involved in the synthesis of essential oil components. When changed to tetraploidy, the progenitor diploids requiring longer metabolic steps in production of their secondary metabolites are stressed, and those having shorter metabolite routes better utilize their resources for growth and vigour. In situ immunodetection of 5-methylcytosine sites reveals enhanced DNA methylation in autopolyploids. It is underpinned that the qualitative composition of secondary metabolites found in the vegetative biomass of the progenitor diploid has a decisive bearing on the body size of the derived autotetraploids and brings about an enhancement in genome-wide cytosine methylation. PMID- 22449083 TI - Predictors of posttraumatic stress disorder and other psychological symptoms in trauma-exposed firefighters. AB - Firefighters are exposed to a range of potentially traumatic stressors, yet studies examining the impact of this exposure are equivocal. Although some studies suggest increased risk for mental health problems, others suggest unusual resilience. Type of assessment methodology may contribute to the lack of consistent findings. We assessed 142 trauma-exposed, professional firefighters utilizing a standardized clinical interview and self-report measures and found low rates of posttraumatic stress disorder (PTSD) diagnoses (4.2%), and depressive, anxiety, and alcohol-abuse symptoms. Frequency of trauma exposure did not predict psychological symptoms. Perceived social support, occupational stress, coping, as well as the interaction between perceived social support and self-blame were significant predictors of symptoms. Firefighters reporting low perceived social support and high self-blame demonstrated the highest levels of clinically significant symptoms. These findings may inform education, treatment, and resilience training for emergency personnel. PMID- 22449084 TI - Prolonged exposure therapy for combat-related posttraumatic stress disorder: comparing outcomes for veterans of different wars. AB - There is significant support for exposure therapy as an effective treatment for posttraumatic stress disorder (PTSD) across a variety of populations, including veterans; however, there is little empirical information regarding how veterans of different war theaters respond to exposure therapy. Accordingly, questions remain regarding therapy effectiveness for treatment of PTSD for veterans of different eras. Such questions have important implications for the dissemination of evidence based treatments, treatment development, and policy. The current study compared treatment outcomes across 112 veterans of the Vietnam War, the first Persian Gulf War, and the wars in Afghanistan and Iraq. All subjects were diagnosed with PTSD and enrolled in prolonged exposure (PE) treatment. Veterans from all three groups showed significant improvement in PTSD symptoms, with veterans from Vietnam and Afghanistan/Iraq responding similarly to treatment. Persian Gulf veterans did not respond to treatment at the same rate or to the same degree as veterans from the other two eras. Questions and issues regarding the effectiveness of evidence based treatment for veterans from different eras are discussed. PMID- 22449085 TI - Leadership as a predictor of stigma and practical barriers toward receiving mental health treatment: a multilevel approach. AB - The present research examined positive and negative leadership behaviors as predictors of stigma and practical barriers to mental health treatment. Soldiers completed measures of noncommissioned officer (NCO) and officer leadership, stigma, and practical barriers to getting mental health treatment at 2, 3, and 4 months following a 15-month deployment to Afghanistan. The results revealed that positive and negative NCO and officer leader behaviors were predictive of overall stigma and barriers to care (collapsed across the three time periods), with only NCO positive and negative behaviors being uniquely predictive of stigma when included in the same model with officer behaviors. In addition, negative and positive NCO leader behaviors were predictive of stigma within participants over the course of the three month time period, and positive NCO leader behaviors were inversely related to practical barriers to mental health treatment within participants across the same time period. The results are discussed in terms of how different leader behaviors may be linked to different factors influencing a soldier's decision to seek mental health treatment. PMID- 22449086 TI - Race differences in the receipt of mental health services among young adults. AB - This study investigates race and ethnic differences in the receipt of mental health services among young adults. Research has indicated that racial minorities receive treatment at a much lower rate than those with middle and upper incomes and whites. We use data from the National Longitudinal Study of Adolescent Health, a nationally representative study of young adults, first interviewed when in Grades 7 through 12. We find significant differences across race-ethnicity. Consistent with prior research, blacks are less likely to have received mental health services. Findings for gender and education differed from previous studies. The relationship of gender on services receipt is mediated by depression. The relationship of race-ethnicity on services receipt is moderated by levels of education and prior services use. Education is associated with greater services use for Whites, but less services use for blacks. Also, blacks who used services in the past are significantly less likely to be current users. The implications of these results are discussed. PMID- 22449087 TI - Pathways to vocational services: factors affecting entry by veterans enrolled in Veterans Health Administration mental health services. AB - The current study provides naturalistic data documenting the pathways-to-care to vocational services for 155 veterans who were receiving some form of mental health care from the Veterans Health Administration and had a vocational need but were not currently enrolled in vocational services. Of the participants, 94.2% had recognized their vocational need, 80.6% reported that they or someone else had sought help to alleviate the need, and 77.4% had previously received some form of vocational services. The median length of the participants' vocational need was more than 4.2 years. Delays associated with recognition, help-seeking, and treatment entry all contributed to the overall delay in entering appropriate care. Filtering factors associated with quicker recognition, seeking help, and receiving services included diagnosis, level of disability, type of vocational need, and support from primary providers, family, and friends. The results provide information for designing interventions to improve service entry by adults with mental health problems and vocational needs. PMID- 22449088 TI - Mental health experts' perspectives on barriers to dissemination of couples treatment for alcohol use disorders. AB - Despite evidence supporting the efficacy of couples-based approaches to treating alcohol problems, provision of such treatments has been limited. To better understand the limited use of this treatment, the current study explored barriers to the adoption of couples treatment for alcohol use disorders. Experts in alcohol treatment, couples treatment, and behavioral couples treatment for alcohol problems (n = 12) were interviewed on this topic; interview transcripts were analyzed using grounded theory qualitative procedures. All mental health experts endorsed the perspective that implementation and acceptance of couples treatment posed difficulties for providers. Four themes (logistical barriers at the provider level, logistical barriers at the system levels, provider treatment preferences, and lack of appropriate training) were identified. Results from the current study provide guidance in addressing barriers to the adoption of couples based treatments. PMID- 22449089 TI - Exploring the effect of therapists' treatment practices on client attendance in community-based care for children. AB - Sustained treatment attendance has been reported to be poor in publicly funded community-based clinic settings serving children and families. Several child and family characteristics have been shown to predict attendance in community-based care, but virtually no research has been conducted to examine how experiences in care, including psychotherapists' within-session practices, influence client attendance. The goal of this exploratory study was to examine how observed practice within sessions, in particular the extent to which therapists delivered elements consistent with evidence-based practices, impacts total number of sessions attended, while accounting for an array of other potential predictors. Participants include 181 children ages 4-13 and their parents entering a new episode of care for disruptive behavior problems in publicly funded clinics. Data sources include administrative billing records on treatment attendance; coded videotaped treatment sessions; and self-reports from children, parents, and therapists. Results indicate that parent education, service funding source, parent alliance with therapist, and therapist experience predicted number of sessions attended; intensity of evidence-based treatment techniques delivered to children was marginally associated with attendance (p = .059). Implications for improving engagement in community-based care are discussed. PMID- 22449090 TI - Provider, veteran, and family perspectives on family education in Veterans Affairs community-based outpatient facilities. AB - The Veterans Affairs (VA) healthcare system is dedicated to providing high quality mental health services to all veterans, including the nearly 40% of enrolled veterans living in rural areas. Family education programs regarding mental illness and posttraumatic stress disorder, mandated for delivery in all VA medical centers and some community-based outpatient clinics (CBOCs), have been developed and provided primarily in large, urban medical centers. This qualitative investigation involved interviews with CBOC providers and veterans and families who live in rural areas and/or seek care in CBOCs to ascertain their perceptions of the benefits, feasibility, structural and cultural barriers, and logistical preferences regarding family education. The perspectives and concerns that emerged in these interviews were combined with expert knowledge to identify the resources and considerations a VAMC would want to address when translating and implementing similar programming into CBOCs. Although institutional, logistic, and attitudinal challenges were described, all three stakeholder groups endorsed the need for family education, did not see the barriers as insurmountable, and provided creative solutions. Administrators and CBOC clinicians may benefit by anticipating and problem solving around the key issues raised when developing family programming. PMID- 22449091 TI - Payment schedules do not affect attendance/completion of group behavioral parent training. AB - Though previous research suggests that attendance at individual therapy is not impacted by amount or source of payment for services, such research is relatively sparse and clinician concerns remain. The present study explores the connection between payment of fees and attendance at group treatments--a previously unexplored area. Participants in a 10-week behavioral parent training (BPT) program varied in timing of payment of fees as well as amount of fees based on income. The varying payment schedules did not affect attendance to sessions at which payments were due nor did payment schedules affect completion of the program. A small relationship was found between income group and attendance. The results are discussed in their relation to the larger literature on fees and attendance at psychotherapy. PMID- 22449092 TI - Infant feeding practice and associated factors of HIV positive mothers attending prevention of mother to child transmission and antiretroviral therapy clinics in Gondar Town health institutions, Northwest Ethiopia. AB - BACKGROUND: It has been estimated that 430,000 children under 15 years of age were newly infected with HIV in 2008, and more than 71% are living in sub-Saharan Africa. In the absence of intervention to prevent mother-to-child transmission, 30-45% of infants born to HIV-positive mothers in developing countries become infected during pregnancy, delivery and breastfeeding. The aim of this study was to assess infant feeding practice and associated factors of HIV positive mothers attending prevention of mother to child transmission and antiretroviral therapy clinics of Northwest Ethiopia. METHODS: Institution based cross sectional study was conducted from January to May 2011 among all HIV positive mothers with less than two years old child attending prevention of mother to child transmission and antiretroviral therapy clinics in Gondar Town health institutions. A structured pre-tested questionnaire using interview technique was used for data collection. The data was entered and analyzed using SPSS version 16 statistical package. RESULTS: A total of 209 HIV positive mothers were included in the study. Of these, 187 (89.5%) had followed the recommended way of infant feeding practice while significant percentage (10.5%) had practiced mixed breast feeding. In multivariate analysis, disclosure of HIV status with their spouse, insufficient breast milk and occupational status were found to be independently associated (p value of < 0.05) with recommended infant feeding practice. Lack of resource, stigma of HIV/AIDS, and husband opposition were also obtained as factors that influenced choice of infant feeding options by respondents. CONCLUSIONS: Higher proportion of respondents used the recommended way of infant feeding practice by WHO as well as by Ethiopian Ministry of Health. However, mixed feeding in the first 6 months of age, an undesirable practice in infant feeding, were reported in this study. Infant feeding education that is aligned to national policy should be strengthened in primary health care, particularly in situations where prevention of mother to child transmission of HIV is prioritized. PMID- 22449093 TI - Novel tailormade Bi4MO4(PO4)2 structural type (M = Mg, Zn). AB - In the Bi(2)O(3)-MO-P(2)O(5) ternary system, the commonly observed sizable 1D ribbon-like units have been extended to their 2D infinite end member, leading to the novel tailormade Bi(4)MO(4)(PO(4))(2) compounds. It contains planar [Bi(2)O(2)](2+) derivatives, separated by two slabs of PO(4), which create channels hosting the M(2+) cations (M = Mg, Zn). For both compounds, supercell orderings occur comparatively to the predicted ideal crystal structure (V(Mg) = 2V(ideal) and V(Zn) = 8V(ideal)). In the Mg case a transition into the ideal lattice occurs above 450 degrees C. In spite of the conceptual assembly of 2D motifs, the final architecture is three-dimensional due to strong interbonds. Thus, our work gives new insights on the possibility for versatile organization of original secondary building units (SBUs) able to self-assemble into predicted structural edifices. Single-crystal and powder XRD versus temperature, high temperature (31)P NMR, as well as transmission electron microscopy were used for structural characterization. Preliminary electric characterization is also reported. PMID- 22449094 TI - Pure curcumin decreases the expression of WT1 by upregulation of miR-15a and miR 16-1 in leukemic cells. AB - BACKGROUND: Pure curcumin has been reported to down-regulate the expression of WT1 in leukemic cells. However, the molecular mechanism underlying the down regulation of WT1 by curcumin is not completely delineated. The purpose of this present study is to identify a new miRNA-mediated mechanism which plays an important role in the anti-proliferation effects of curcumin in leukemic cells. METHODS: K562 and HL-60 cells were treated with different concentrations of curcumin for 24 and 48 hours, the level of miR-15a/16-1 and WT1 were detected by qRT-PCR and Western blotting. WT1 expression and cell proliferation were detected by Western blotting and CCK-8, after curcumin treated-K562 and HL-60 cells were transfected with anti-miR-15a/16-1 oligonucleotides. RESULTS: We found that pure curcumin upregulated the expression of miR-15a/16-1 and downregulated the expression of WT1 in leukemic cells and primary acute myeloid leukemia (AML) cells. Overexpression of miR-15a/16-1 deduced the protein level of WT1 in leukemic cells, but downregulation of WT1 by siRNA-WT1 could not increase the expression of miR-15a/16-1 in leukemic cells. These results reveal that curcumin induced-upregulation of miR-15a/16-1 is an early event upstream to downregulation of WT1. Furthermore, anti-miR-15a/16-1 oligonucleotides (AMO) partly reversed the downregulation of WT1 induced by pure curcumin in leukemic cells and AMO promoted the growth of curcumin treated-K562 and HL-60 cells. CONCLUSION: Thus, these data suggest for the first time that pure curcumin downregulated the expression of WT1 partly by upregulating the expression of miR-15a/16-1 in leukemic cells. miR 15a/16-1 mediated WT1 downregulation plays an important role in the anti proliferation effect of curcumin in leukemic cells. PMID- 22449096 TI - Multimode resonances in silver nanocuboids. AB - A rich variety of dipolar and higher order plasmon resonances have been predicted for nanoscale cubes and parallopipeds of silver, in contrast to the simple dipolar modes found on silver nanospheres or nanorods. However, in general, these multimode resonances are not readily detected in experimental colloidal ensembles, due primarily to the usual variation of size and shape of the particles obscuring or blending the individual extinction peaks. Recently, methods have been found to prepare silver parallopipeds with unprecedented shape control by nucleating the silver onto a tightly controlled suspension of gold nanorods (Okuno, Y.; Nishioka, K.; Kiya, A.; Nakashima, N.; Ishibashi, A.; Niidome, Y. Uniform and Controllable Preparation of Au-Ag Core-Shell Nanorods Using Anisotropic Silver Shell Formation on Gold Nanorods. Nanoscale 2010, 2, 1489-1493). The optical extinction spectra of suspensions of such monodisperse particles are found to contain multiple extinction peaks, which we show here to be due to the multimode resonances predicted by theoretical studies. Control of the radius of the nanoparticle edges is found to be an effective way to turn some of these modes on or off. These nanoparticles provide a flexible platform for the excitation, manipulation, and exploration of higher order plasmon resonances. PMID- 22449095 TI - Vibrational analysis of mononitrosyl complexes in hemerythrin and flavodiiron proteins: relevance to detoxifying NO reductase. AB - Flavodiiron proteins (FDPs) play important roles in the microbial nitrosative stress response in low-oxygen environments by reductively scavenging nitric oxide (NO). Recently, we showed that FMN-free diferrous FDP from Thermotoga maritima exposed to 1 equiv NO forms a stable diiron-mononitrosyl complex (deflavo FDP(NO)) that can react further with NO to form N(2)O [Hayashi, T.; Caranto, J. D.; Wampler, D. A; Kurtz, D. M., Jr.; Moenne-Loccoz, P. Biochemistry 2010, 49, 7040-7049]. Here we report resonance Raman and low-temperature photolysis FTIR data that better define the structure of this diiron-mononitrosyl complex. We first validate this approach using the stable diiron-mononitrosyl complex of hemerythrin, Hr(NO), for which we observe a nu(NO) at 1658 cm(-1), the lowest nu(NO) ever reported for a nonheme {FeNO}(7) species. Both deflavo-FDP(NO) and the mononitrosyl adduct of the flavinated FPD (FDP(NO)) show nu(NO) at 1681 cm( 1), which is also unusually low. These results indicate that, in Hr(NO) and FDP(NO), the coordinated NO is exceptionally electron rich, more closely approaching the Fe(III)(NO(-)) resonance structure. In the case of Hr(NO), this polarization may be promoted by steric enforcement of an unusually small FeNO angle, while in FDP(NO), the Fe(III)(NO(-)) structure may be due to a semibridging electrostatic interaction with the second Fe(II) ion. In Hr(NO), accessibility and steric constraints prevent further reaction of the diiron mononitrosyl complex with NO, whereas in FDP(NO) the increased nucleophilicity of the nitrosyl group may promote attack by a second NO to produce N(2)O. This latter scenario is supported by theoretical modeling [Blomberg, L. M.; Blomberg, M. R.; Siegbahn, P. E. J. Biol. Inorg. Chem. 2007, 12, 79-89]. Published vibrational data on bioengineered models of denitrifying heme-nonheme NO reductases [Hayashi, T.; Miner, K. D.; Yeung, N.; Lin, Y.-W.; Lu, Y.; Moenne Loccoz, P. Biochemistry 2011, 50, 5939-5947 ] support a similar mode of activation of a heme {FeNO}(7) species by the nearby nonheme Fe(II). PMID- 22449097 TI - Evaluation of infrared-reflection absorption spectroscopy measurement and locally weighted partial least-squares for rapid analysis of residual drug substances in cleaning processes. AB - The usefulness of infrared-reflection absorption spectroscopy (IR-RAS) for the rapid measurement of residual drug substances without sampling was evaluated. In order to realize the highly accurate rapid measurement, locally weighted partial least-squares (LW-PLS) with a new weighting technique was developed. LW-PLS is an adaptive method that builds a calibration model on demand by using a database whenever prediction is required. By adding more weight to samples closer to a query, LW-PLS can achieve higher prediction accuracy than PLS. In this study, a new weighting technique is proposed to further improve the prediction accuracy of LW-PLS. The root-mean-square error of prediction (RMSEP) of the IR-RAS spectra analyzed by LW-PLS with the new weighting technique was compared with that analyzed by PLS and locally weighted regression (LWR). The RMSEP of LW-PLS with the proposed weighting technique was about 36% and 14% smaller than that of PLS and LWR, respectively, when ibuprofen was a residual drug substance. Similarly, LW-PLS with the weighting technique was about 39% and 24% better than PLS and LWR in RMSEP, respectively, when magnesium stearate was a residual excipient. The combination of IR-RAS and LW-PLS with the proposed weighting technique is a very useful rapid measurement technique of the residual drug substances. PMID- 22449098 TI - A prospective study to optimize insulin treatment by switching to insulin glargine in type 2 diabetic patients previously uncontrolled on premixed insulin: the optimization study. AB - OBJECTIVE: To evaluate the efficacy, safety and treatment satisfaction of insulin glargine plus oral antidiabetic drugs (OADs) in Chinese individuals with Type 2 diabetes inadequately controlled with premixed insulin plus OADs. METHODS: In this open-label, single-arm, 16-week, phase IV study, 313 subjects with Type 2 diabetes inadequately controlled with premixed insulin plus OADs were switched to insulin glargine plus OADs. Changes in glycaemic control, incidence of hypoglycaemia and treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were evaluated. RESULTS: Switching to insulin glargine was associated with significant reductions in levels of glycosylated haemoglobin (HbA(1c); 8.4 +/- 0.6 to 7.9 +/- 1.0%; p < 0.001) and fasting plasma glucose (FPG; 9.50 +/- 2.10 to 6.58 +/- 2.07 mmol/L; p < 0.001). A total of 32.9% of subjects experienced hypoglycaemia, including two cases of severe hypoglycaemia. Treatment satisfaction was improved with insulin glargine (DTSQ 8 item scores, all p < 0.001). Logistic regression analysis showed a significant association between baseline HbA(1c), disease duration, endpoint FPG and HbA(1c) < 7%. CONCLUSION: This single-arm study suggested that switching to insulin glargine plus OADs significantly improved glycaemic control, with a low incidence of hypoglycaemia, in patients with Type 2 diabetes uncontrolled on premixed insulin plus OADs. Switching to insulin glargine was also associated with better patient treatment satisfaction compared with previous treatment. The main limitations to this study are the open-label design and the lack of a control arm. PMID- 22449099 TI - Cleavage of ST6Gal I by radiation-induced BACE1 inhibits golgi-anchored ST6Gal I mediated sialylation of integrin beta1 and migration in colon cancer cells. AB - BACKGROUND: Previously, we found that beta-galactoside alpha2,6-sialyltransferase (ST6Gal I), an enzyme that adds sialic acids to N-linked oligosaccharides of glycoproteins and is frequently overexpressed in cancer cells, is up-regulated by ionizing radiation (IR) and cleaved to a form possessing catalytic activity comparable to that of the Golgi-localized enzyme. Moreover, this soluble form is secreted into the culture media. Induction of ST6Gal I significantly increased the migration of colon cancer cells via sialylation of integrin beta1. Here, we further investigated the mechanisms underlying ST6Gal I cleavage, solubilization and release from cells, and addressed its functions, focusing primarily on cancer cell migration. METHODS: We performed immunoblotting and lectin affinity assay to analyze the expression of ST6 Gal I and level of sialylated integrin beta1. After ionizing radiation, migration of cells was measured by in vitro migration assay. alpha2, 6 sialylation level of cell surface was analyzed by flow cytometry. Cell culture media were concentrated and then analyzed for soluble ST6Gal I levels using an alpha2, 6 sialyltransferase sandwich ELISA. RESULT: We found that ST6Gal I was cleaved by BACE1 (beta-site amyloid precursor protein-cleaving enzyme), which was specifically overexpressed in response to IR. The soluble form of ST6Gal I, which also has sialyltransferase enzymatic activity, was cleaved from the Golgi membrane and then released into the culture media. Both non-cleaved and cleaved forms of ST6Gal I significantly increased colon cancer cell migration in a sialylation-dependent manner. The pro-migratory effect of the non-cleaved form of ST6Gal I was dependent on integrin beta1 sialylation, whereas that of the cleaved form of ST6Gal I was not, suggesting that other intracellular sialylated molecules apart from cell surface molecules such as integrin beta1 might be involved in mediating the pro-migratory effects of the soluble form of ST6Gal I. Moreover, production of soluble form ST6Gal I by BACE 1 inhibited integrin beta1 sialylation and migration by Golgi-anchored form of ST6Gal I. CONCLUSIONS: Our results suggest that soluble ST6Gal I, possibly in cooperation with the Golgi bound form, may participate in cancer progression and metastasis prior to being secreted from cancer cells. PMID- 22449100 TI - Top papers of 2011: recognizing our finest. PMID- 22449101 TI - Visual perception and regulatory conflict: motivation and physiology influence distance perception. AB - Regulatory conflict can emerge when people experience a strong motivation to act on goals but a conflicting inclination to withhold action because physical resources available, or physiological potentials, are low. This study demonstrated that distance perception is biased in ways that theory suggests assists in managing this conflict. Participants estimated the distance to a target location. Individual differences in physiological potential measured via waist-to-hip ratio interacted with manipulated motivational states to predict visual perception. Among people low in physiological potential and likely to experience regulatory conflict, the environment appeared easier to traverse when motivation was strong compared with weak. Among people high in potential and less likely to experience conflict, perception was not predicted by motivational strength. The role of motivated distance perception in self-regulation is discussed. PMID- 22449102 TI - Unveiling structure-property relationships in Sr2Fe(1.5)Mo(0.5)O(6-delta), an electrode material for symmetric solid oxide fuel cells. AB - We characterize experimentally and theoretically the promising new solid oxide fuel cell electrode material Sr(2)Fe(1.5)Mo(0.5)O(6-delta) (SFMO). Rietveld refinement of powder neutron diffraction data has determined that the crystal structure of this material is distorted from the ideal cubic simple perovskite, instead belonging to the orthorhombic space group Pnma. The refinement revealed the presence of oxygen vacancies in the as-synthesized material, resulting in a composition of Sr(2)Fe(1.5)Mo(0.5)O(5.90(2)) (delta = 0.10(2)). DFT+U theory predicts essentially the same concentration of oxygen vacancies. Theoretical analysis of the electronic structure allows us to elucidate the origin of this nonstoichiometry and the attendant mixed ion-electron conductor character so important for intermediate temperature fuel cell operation. The ease with which SFMO forms oxygen vacancies and allows for facile bulk oxide ion diffusivity is directly related to a strong hybridization of the Fe d and O p states, which is also responsible for its impressive electronic conductivity. PMID- 22449103 TI - Organic vapor triggered repeatable on-off crystalline-state luminescence switching. AB - A nonporous crystalline solid consisting of an organoarsenic platinum(II) complex, i.e., a mononuclear diiodoplatinum(II) complex trans-PtI(2)(cis DHDAtBu)(2) (1) with cis-1,4-dihydro-1,4-dimethyl-2,3,5,6-tetrakis(tert butoxycarbonyl)-1,4-diarsinine (cis-DHDAtBu), shows on-off solid-state luminescence switching through reversible solvent vapor uptake and escape. The on off switching of solid-state luminescence was achieved without changing the structure or electronic state of the organoarsenic platinum(II) complex. PMID- 22449104 TI - Celiac disease in type 1 diabetes mellitus. AB - Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients. PMID- 22449106 TI - Introduction--bipolar illness: current understanding and future perspectives. PMID- 22449107 TI - Interpreting magnetic resonance imaging findings in bipolar disorder. AB - The episodic nature of bipolar disorder together with the ostensibly polar extremes of mania and depression have favored the acceptance of a functional model postulating regionally disturbed brain activity returning to normal with time or treatment. Seemingly contrary to that view, anatomical imaging studies have demonstrated abnormalities in brain structure which could reflect neurodegeneration or represent disturbed neuronal development. Resolution may come from an appreciation of adult neurogenesis, especially given the neuroprotective properties of drugs, such as lithium and their effects on brain volume. The brain regions vulnerable to structural changes also show evidence of dysfunction, giving rise to corticolimbic dysregulation interpretations of bipolar disorder. This article reviews the structural and functional magnetic resonance imaging data in bipolar disorder. Its focus is on the interpretation of findings in light of recent developments in the fields of neurobiology and image analysis, with particular attention paid to both the confounding effects of medication and the baseline energy state of the brain. PMID- 22449108 TI - Excessive autophagy contributes to neuron death in cerebral ischemia. AB - AIMS: To determine the extent to which autophagy contributes to neuronal death in cerebral hypoxia and ischemia. METHODS: We performed immunocytochemistry, western blot, cell viability assay, and electron microscopy to analyze autophagy activities in vitro and in vivo. RESULTS: In both primary cortical neurons and SH SY5Y cells exposed to oxygen and glucose deprivation (OGD)for 6 h and reperfusion (RP) for 24, 48, and 72 h, respectively, an increase of autophagy was observed as determined by the increased ratio of LC3-II to LC3-I and Beclin-1 (BECN1) expression. Using Fluoro-Jade C and monodansylcadaverine double-staining, and electron microscopy we found the increment in autophagy after OGD/RP was accompanied by increased autophagic cell death, and this increased cell death was inhibited by the specific autophagy inhibitor, 3-methyladenine. The presence of large autolysosomes and numerous autophagosomes in cortical neurons were confirmed by electron microscopy. Autophagy activities were increased dramatically in the ischemic brains 3-7 days postinjury from a rat model of neonatal cerebral hypoxia/ischemia as shown by increased punctate LC3 staining and BECN1 expression. CONCLUSION: Excessive activation of autophagy contributes to neuronal death in cerebral ischemia. PMID- 22449109 TI - High-sensitivity C-reactive protein is a strong risk factor for death after acute ischemic stroke among Chinese. AB - BACKGROUND AND PURPOSE: Elevated plasma C-reactive protein (CRP) has been suggested as a risk factor for ischemic stroke (IS) and coronary ischemic disease. Evidence has shown that high-sensitivity CRP (hs-CRP) is related to a worsening prognosis after IS, but hs-CRP was rare in a large-sample study in a Chinese population. We investigated the associations between hs-CRP and outcome of Chinese patients after acute IS. METHODS: Seven hundred and forty-one consecutive acute IS patients (74.9% male, mean age 60.9 years), with baseline characteristics and hs-CRP measured within 24 h after hospitalization, were admitted in this study. We also prospectively followed up for clinical outcome and death 3 months after disease onset. hs-CRP was divided into two categories: hs-CRP >3 mg/L and hs-CRP <=3 mg/L. Survival analysis using multivariable Cox regression was performed to analyze the association between hs-CRP and stroke outcomes after adjusting for potential confounding factors. RESULTS: Compared with low hs-CRP, patients with high hs-CRP (>3 mg/L) had a significantly higher rate of all-cause death (0.71% vs. 10.00%; P < 0.001) at 3 months after stroke onset. High hs-CRP was an independent risk factor for all-cause death (HR, 6.48; 95% CI, 1.41 to 29.8; P= 0.016), as well as history of atrial fibrillation (HR, 5.24; 95% CI, 1.83 to 15.0; P= 0.002), no statin therapy during hospitalization (HR, 4.56; 95% CI, 2.18 to 9.55; P < 0.001), high homocysteine (>15.1 mmol/L) (HR, 2.66; 95% CI, 1.26 to 5.60; P= 0.01); fasting glucose (>6.1 mmol/L) (HR, 9.14; 95% CI, 3.34 to 25.0; P < 0.001), NIHSS at admission (HR, 2.35; 95% CI, 1.35 to 4.09; P= 0.003) and history of coronary heart disease (CHD) (HR, 2.34; 95% CI, 1.06 to 5.17; P= 0.035). Kaplan-Meier survival curves showed a higher risk of death for patients with hs-CRP >3 mg/L (P= 0.016). CONCLUSION: Elevated plasma hs-CRP independently predicted risk of all-cause death within 3 months after acute IS in Chinese patients. PMID- 22449110 TI - Nicotinamide postpones stroke in stroke-prone spontaneously hypertensive rats. PMID- 22449111 TI - Pregabalin in the treatment of refractory bipolar disorders. PMID- 22449112 TI - Paroxysmal kinesigenic dyskinesia as the initial symptom of Hashimoto encephalopathy. PMID- 22449113 TI - Commentary on "Initial experience with aspirin use during robotic radical prostatectomy". PMID- 22449114 TI - Commentary on "A standard approach to expose the recurrent laryngeal nerve during endoscopic thyroidectomy". PMID- 22449115 TI - 10 years of experience with laparoscopic-assisted endorectal Soave pull-through procedure for Hirschsprung's disease in China. AB - OBJECTIVE: To report early and late results of laparoscopic-assisted endorectal Soave pull-through (LAEPT) with a short and V-shaped partial resection muscular cuff for Hirschsprung's disease (HD) over a 10-year period. METHODS: The clinical courses of 218 patients who underwent modified LAEPT for HD were reviewed. LAEPT was described by the Georgeson technique. The main modifications included less dissection of the bottom of the pelvis, rectal mucosa dissection with a long cuff, coloanal anastomosis with a short cuff, and a V-shaped partial resection in the posterior wall of the muscular cuff. RESULTS: From September 1999 to July 2009, 218 patients were operated on by the same surgeon. Ages ranged from 15 days to 12 years old. The aganglionic segment was located in the rectum or sigmoid colon in 176 patients, in the left colon in 38 children, and in the transverse colon in 4 patients. The median operating time was 176 minutes. Conversion to open surgery was required in 2 patients. Bleeding of the left iliac vein occurred in 1 patient, and a 180 degrees twist of the neorectum occurred in 2 cases. Median first bowel movement time was 23 hours, and median postoperative hospital stay was 10.4 days. Median daily defecation frequency was 4.6 within 2 weeks and 2.3 at 3 months postoperatively. The immediate postoperative complications included intestine herniation from the trocar site in 2 patients, perianal excoriation in 32 patients, and anastomotic leakage in 3 patients. Follow-up ranging from 6 to 120 months was obtained for 182 patients. Late postoperative complications included postoperative adhesive bowel obstruction (1.1%), enterocolitis (7.7%), anasomostic stenosis (2.2%), constipation (1.6%), and soiling (3.6%). Eighty-seven percent had excellent and good bowel function. CONCLUSION: LAEPT with a short muscular cuff with a V-shaped partial resection in the posterior wall is a safe and effective procedure for HD. PMID- 22449116 TI - Palladium-catalyzed ortho-arylation of benzamides via direct sp(2) C-H bond activation. AB - The palladium-catalyzed ortho-arylation of benzamides by aryl iodides has been demonstrated with the simplest amide CONH(2) as a directing group for the first time. This protocol can be applied to various benzamides and aryl iodides with both electron-donating and electron-withdrawing groups. In addition, the synthesized biphenyl-2-carboxamides can be further transformed to other biphenyl derivatives such as nitriles, carboxylic acids, carbamates, and amines. PMID- 22449117 TI - Study of amyloid beta-peptide (Abeta12-28-Cys) interactions with Congo red and beta-sheet breaker peptides using electrochemical impedance spectroscopy. AB - A surface-based approach is presented to study the interactions of Abeta12-28-Cys assembled on gold surfaces with Congo red (CR) and a beta-sheet breaker (BSB) peptide. The various aspects of the peptide film have been examined using different electrochemical and surface analytical techniques. Cyclic voltammetry and electrochemical impedance spectroscopy (EIS) results using redox probes [Fe(CN)(6)](3-/4-) show that Abeta12-28-Cys on gold forms a stable and reproducible blocking film. EIS analysis shows that CR and BSB have different effects on the electrochemical properties of Abeta12-28-Cys films, presumably due to changes in the interactions between the film and CR and BSB. EIS results indicate that in the case of CR film resistance decreases significantly presumably due to better penetration of the solution-based redox probe into the film, whereas in the case of BSB, the film resistance increases. We interpret this difference to BSB being able to interact with the Abeta12-28-Cys on the surface and presumably forming a film that presents a higher resistance for electron transfer from the redox probe to the solution. PMID- 22449118 TI - Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials. AB - OBJECTIVE: The randomized clinical trials, RE-LY, ROCKET-AF, and ARISTOTLE, demonstrate that the novel oral anticoagulants (NOACs) are effective options for stroke prevention among non-valvular atrial fibrillation (AF) patients. This study aimed to evaluate the medical cost reductions associated with the use of individual NOACs instead of warfarin from the US payer perspective. METHODS: Rates for efficacy and safety clinical events for warfarin were estimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE trials, and event rates for NOACs were determined by applying trial hazard ratios or relative risk ratios to such weighted averages. Incremental medical costs to a US health payer of an AF patient experiencing a clinical event during 1 year following the event were obtained from published literature and inflation adjusted to 2010 cost levels. Medical costs, excluding drug costs, were evaluated and compared for each NOAC vs warfarin. Sensitivity analyses were conducted to determine the influence of variations in clinical event rates and incremental costs on the medical cost reduction. RESULTS: In a patient year, the medical cost reduction associated with NOAC usage instead of warfarin was estimated to be -$179, -$89, and -$485 for dabigatran, rivaroxaban, and apixaban, respectively. When clinical event rates and costs were allowed to vary simultaneously, through a Monte Carlo simulation, the 95% confidence interval of annual medical costs differences ranged between $424 and +$71 for dabigatran, -$301 and +$135 for rivaroxaban, and -$741 and $252 for apixaban, with a negative number indicating a cost reduction. Of the 10,000 Monte-Carlo iterations 92.6%, 79.8%, and 100.0% were associated with a medical cost reduction >$0 for dabigatran, rivaroxaban, and apixaban, respectively. CONCLUSIONS: Usage of the NOACs, dabigatran, rivaroxaban, and apixaban may be associated with lower medical (excluding drug costs) costs relative to warfarin, with apixaban having the most substantial medical cost reduction. PMID- 22449119 TI - Priority setting of ICU resources in an influenza pandemic: a qualitative study of the Canadian public's perspectives. AB - BACKGROUND: Pandemic influenza may exacerbate existing scarcity of life-saving medical resources. As a result, decision-makers may be faced with making tough choices about who will receive care and who will have to wait or go without. Although previous studies have explored ethical issues in priority setting from the perspective of clinicians and policymakers, there has been little investigation into how the public views priority setting during a pandemic influenza, in particular related to intensive care resources. METHODS: To bridge this gap, we conducted three public town hall meetings across Canada to explore Canadian's perspectives on this ethical challenge. Town hall discussions group discussions were digitally recorded, transcribed, and analyzed using thematic analysis. RESULTS: Six interrelated themes emerged from the town hall discussions related to: ethical and empirical starting points for deliberation; criteria for setting priorities; pre-crisis planning; in-crisis decision-making; the need for public deliberation and input; and participants' deliberative struggle with the ethical issues. CONCLUSIONS: Our findings underscore the importance of public consultation in pandemic planning for sustaining public trust in a public health emergency. Participants appreciated the empirical and ethical uncertainty of decision-making in an influenza pandemic and demonstrated nuanced ethical reasoning about priority setting of intensive care resources in an influenza pandemic. Policymakers may benefit from a better understanding the public's empirical and ethical 'starting points' in developing effective pandemic plans. PMID- 22449120 TI - Is systems biology a promising approach to resolve controversies in cancer research? AB - At the beginning of the 21st century cancer research has reached an impasse similar to that experienced in developmental biology in the first decades of the 20th century when conflicting results and interpretations co-existed for a long time until these differences were resolved and contradictions were eliminated. In cancer research, instead of this healthy "weeding-out" process, there have been attempts to reach a premature synthesis, while no hypothesis is being rejected. Systems Biology could help cancer research to overcome this stalemate by resolving contradictions and identifying spurious data. First, in silico experiments should allow cancer researchers to be bold and a priori reject sets of data and hypotheses in order to gain a deeper understanding of how each dataset and each hypothesis contributes to the overall picture. In turn, this process should generate novel hypotheses and rules, which could be explored using these in silico approaches. These activities are significantly less costly and much faster than "wet-experiments". Consequently, Systems Biology could be advantageously used both as a heuristic tool to guide "wet-experiments" and to refine hypotheses and test predictions. PMID- 22449121 TI - Gravitational sedimentation induced blood delamination for continuous plasma separation on a microfluidics chip. AB - Continuous plasma separation will be greatly helpful for dynamic metabolite monitoring in kinetics research and drug development. In this work, we proposed a continuous on-chip plasma separation method based on the natural aggregating and sedimentation behavior of red blood cells at low shear rate. In this approach, a glass capillary was first used to realize quick and obvious delamination of blood cells from plasma. A novel "dual-elbow" connector was designed to change the direction of delamination. The blood was finally separated by laminar flow and bifurcation on the microchip. Results demonstrated that the present device can efficiently and stably separate plasma from blood in a continuous means, e.g., in a 4 h separation we did not observe clogging or a trend of clogging. In addition, the present approach can avoid the damage to cells which usually occurs in separation with high shear rate in a microchannel and possible contaminants to plasma. The proposed microchip device is robust, simple, and inexpensive for long time plasma separation with high plasma recovery and less sample consumption. The present work provides an effective tool for metabolite monitoring in pharmacokinetics research and drug development. PMID- 22449122 TI - Marital status: a gender-independent risk factor for poorer survival after radical cystectomy. AB - Study Type - Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Married individuals have lower morbidity and mortality rates for all major causes of death. Cancer-specific survival is better in married patients with testis cancer, prostate cancer, breast cancer, cervical cancer, as well as head and neck cancers. We have found the effect of marital status on outcomes after radical cystectomy to be variable, depending on gender and the outcome addressed. Being married is predictive of lower all-cause mortality for both men and women relative to their separated, divorced or widowed (SDW) or never-married counterparts. It is also predictive of lower bladder cancer-specific mortality relative to SDW individuals. Marriage also exerts a protective effect on men regarding non-organ-confined disease, with those never having married having significantly higher rates. OBJECTIVES: * To examine the effect of marital status (MS) on the rate of non-organ-confined disease (NOCD) at radical cystectomy (RC) * To assess the effect of MS on the rate of bladder cancer-specific mortality (BCSM) and all-cause mortality (ACM) after RC for urothelial carcinoma of the urinary bladder (UCUB). MATERIALS AND METHODS: * A total of 14 859 patients, who underwent RC for UCUB, were captured within the Surveillance, Epidemiology, and End Results database, between 1988 and 2006. * Logistic regression analysis was used to assess the rate of NOCD (T(3-4) /N(I-3) /M(0) ) at RC and Cox regression analyses were used to assess BCSM and ACM. * Analyses were stratified according to gender; covariates included socio-economic status, tumour stage, age, race, tumour grade and year of surgery. RESULTS: * Never-married males had a higher rate of NOCD at RC (odds ratio = 1.22, P= 0.004), an effect not found in never-married females. * Separated, divorced or widowed (SDW) males (hazard ratio [HR]= 1.18, P= 0.005) and females (HR = 1.16, P= 0.002) had higher rates of BCSM than their married counterparts. * SDW and never-married males had higher rates of ACM than their married counterparts (HR = 1.22, P < 0.001 and HR = 1.26, P < 0.001, respectively). * SDW and never-married females also had higher rates of ACM than married females (HR = 1.24, P < 0.001 and HR = 1.22, P= 0.01, respectively). CONCLUSIONS: * For both men and women, being SDW conveyed an increased risk of BCSM after RC. * SDW and never marrying had a deleterious effect on ACM. * Unfavourable stage at RC was also seen more commonly in never-married males. PMID- 22449123 TI - Nine-yr experience of 700 hand-assisted laparoscopic donor nephrectomies in Japan. AB - OBJECTIVE: We reviewed the introduction of a new, minimally invasive, live kidney donation program in our department. METHODS: The operating times of 700 consecutive hand-assisted laparoscopic donor nephrectomies (HALDN) conducted from February 2001 to April 2010 were examined. The risk factors for prolonging operating times were analyzed and major surgical barriers in HALDN investigated. RESULTS: All procedures were successfully performed without the requirement for conversion to open surgery or blood transfusion. The overall prevalence of perioperative complications was 3.0%, with no mortality, in this non-obese donor population with mean body mass index (BMI) as low as 23.2 +/- 3.2 kg/m(2) . After the initial learning curve, a second learning plateau was detected until around case 300. Multivariate analyses showed that the significant risk factors were male sex, graft weight, number of renal arteries, right nephrectomy, and previous epigastric surgery (p < 0.05). HALDN provided direct handling of the surgical field, secure vascular control, safe manipulation of adhesive tissues, and served to maintain surgical safety. Mean values of the BMI of donors had a significant positive correlation with the prevalence of complications between large studies (p = 0.042). CONCLUSIONS: Laparoscopic donor nephrectomy was safely introduced and established in a single institution with the help of the hand-assistance method. PMID- 22449124 TI - Cleft Lip and Palate in a Patient with 5q35.2-q35.3 Microdeletion: The Importance of Chromosomal Microarray Testing in the Craniofacial Clinic. AB - We report on a 31/2-year-old African American female with a 1.63 Mb microdeletion in 5q35.2-q35.3. This deletion includes NSD1, the gene that causes Sotos syndrome. The patient has unilateral cleft lip and palate (CLP) status postrepair, an unrepaired alveolar cleft, speech delay, global developmental delay, macrocephaly, mild cerebral palsy, and a patent ductus arteriosus status postrepair. Dysmorphic features include a prominent forehead and midface hypoplasia. This is one of the first cases of CLP associated with Sotos syndrome and emphasizes the utility of chromosomal microarray analysis in patients with more than isolated CLP in the Craniofacial Clinic. PMID- 22449125 TI - Identification of two new HLA-G alleles, G*01:01:03:03 and G*01:01:21, in Brazilian individuals. AB - Here we report two new non-classical class I HLA-G alleles found in the Brazilian population. PMID- 22449126 TI - Perceiving event dynamics and parsing Hollywood films. AB - We selected 24 Hollywood movies released from 1940 through 2010 to serve as a film corpus. Eight viewers, three per film, parsed them into events, which are best termed subscenes. While watching a film a second time, viewers scrolled through frames and recorded the frame number where each event began. Viewers agreed about 90% of the time. We then analyzed the data as a function of a number of visual variables: shot transitions, shot duration, shot scale, motion, luminance, and color across shots within and across events, and a code that noted changes in place or time. We modeled viewer parsings across all shots of each film and found that, as an ensemble, the visual variables accounted for about 30% of the variance in the data, even without considering the soundtrack. Adding a code recording place and/or time change increases this variance to about 50%. We conclude that there is ample perceptual information for viewers to parse films into events without necessarily considering the intentions and goals of the actors, although these are certainly needed to understand the story of the film. PMID- 22449127 TI - Stimulus-responsive light coupling and modulation with nanofiber waveguide junctions. AB - We report a systematic study of light coupling at junctions of overlapping SnO(2) nanofiber waveguides (WGs) as a function of gap separation and guided wavelength. The junctions were assembled on silica substrates using micromanipulation techniques and the gap separation was controlled by depositing thin self assembled polyelectrolyte coatings at the fiber junctions. We demonstrate that the coupling efficiency is strongly dependent on the gap separation, showing strong fluctuations (0.1 dB/nm) in the power transfer when the separation between nanofibers changes by as little as 2 nm. Experimental results correlate well with numerical simulations using three-dimensional finite-difference time-domain techniques. To demonstrate the feasibility of using coupled nanofiber WGs to modulate light, we encased the junctions in an environment-responsive matrix and exposed the junctions to gaseous vapor. The nanofiber junctions show an ~95% (or ~80%) modulation of the guided 450 nm (or 510 nm) light upon interaction with the gaseous molecules. The results reveal a unique nanofiber-based sensing scheme that does not require a change in the refractive index to detect stimuli, suggesting these structures could play important roles in localized sensing devices including force-based measurements or novel chemically induced light modulators. PMID- 22449128 TI - Porous double-walled metal triazolate framework based upon a bifunctional ligand and a pentanuclear zinc cluster exhibiting selective CO2 uptake. AB - The self-assembly of a custom-designed bifunctional ligand featuring both 1,2,3 triazolate and carboxylate donor groups with a pentanuclear zinc cluster generated in situ affords a double-walled metal triazolate framework (MTAF) material, MTAF-1 (Zn(5)(MU(3) O)(2)(C(9)N(3)H(5)O(2))(5)(H(+))(4)(H(2)O)(17)(C(3)H(7)NO)(10)), which exhibits a surface area of 2300 m(2)/g and demonstrates interesting selective CO(2) uptake performances. PMID- 22449129 TI - Utilization of photoinduced charge-separated state of donor-acceptor-linked molecules for regulation of cell membrane potential and ion transport. AB - The control of ion transport across cell membranes by light is an attractive strategy that allows targeted, fast control of precisely defined events in the biological membrane. Here we report a novel general strategy for the control of membrane potential and ion transport by using charge-separation molecules and light. Delivery of charge-separation molecules to the plasma membrane of PC12 cells by a membranous nanocarrier and subsequent light irradiation led to depolarization of the membrane potential as well as inhibition of the potassium ion flow across the membrane. Photoregulation of the cell membrane potential and ion transport by using charge-separation molecules is highly promising for control of cell functions. PMID- 22449130 TI - Exploiting the behaviour of wild malaria vectors to achieve high infection with fungal biocontrol agents. AB - BACKGROUND: Control of mosquitoes that transmit malaria has been the mainstay in the fight against the disease, but alternative methods are required in view of emerging insecticide resistance. Entomopathogenic fungi are candidate alternatives, but to date, few trials have translated the use of these agents to field-based evaluations of their actual impact on mosquito survival and malaria risk. Mineral oil-formulations of the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana were applied using five different techniques that each exploited the behaviour of malaria mosquitoes when entering, host seeking or resting in experimental huts in a malaria endemic area of rural Tanzania. RESULTS: Survival of mosquitoes was reduced by 39-57% relative to controls after forcing upward house-entry of mosquitoes through fungus treated baffles attached to the eaves or after application of fungus-treated surfaces around an occupied bed net (bed net strip design). Moreover, 68 to 76% of the treatment mosquitoes showed fungal growth and thus had sufficient contact with fungus treated surfaces. A population dynamic model of malaria-mosquito interactions shows that these infection rates reduce malaria transmission by 75 80% due to the effect of fungal infection on adult mortality alone. The model also demonstrated that even if a high proportion of the mosquitoes exhibits outdoor biting behaviour, malaria transmission was still significantly reduced. CONCLUSIONS: Entomopathogenic fungi strongly affect mosquito survival and have a high predicted impact on malaria transmission. These entomopathogens represent a viable alternative for malaria control, especially if they are used as part of an integrated vector management strategy. PMID- 22449131 TI - Rehabilitation of muscle after injury - the role of anti-inflammatory drugs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely consumed among athletes worldwide in relation to muscle injury and soreness. This review aims to provide an overview of studies investigating their effects on skeletal muscle, in particular the repair processes in injured muscle. Muscle injury occurs in diverse situations and the nature of muscle injuries varies significantly, complicating extrapolations between experimental models and "real life." Classical muscle strain injuries occur at the interphase between the muscle fibers and connective tissue, most often in the myotendinuous junction, whereas contusion or overload injury can damage both myofibers and intramuscular connective tissue. The role of NSAIDs in muscle repair is complicated by differences in injury models used, variables evaluated, and time point(s) selected for evaluations. While the temporal pattern of the influence of NSAIDs on muscle repair is difficult to settle on, it appears that a potential beneficial effect of NSAIDs in the early phase after injury is not maintained in the long term, or is even negated by a long-term repair deficit. At the cellular level, evidence exists for a negative influence of NSAIDs on the muscle stem cell population (satellite cells). At a structural level, it is known that muscle connective tissue undergoes significant remodeling during muscle regeneration, but the potential of NSAID exposure to alter this response in humans needs investigation. PMID- 22449132 TI - The place-value of a digit in multi-digit numbers is processed automatically. AB - The automatic processing of the place-value of digits in a multi-digit number was investigated in 4 experiments. Experiment 1 and two control experiments employed a numerical comparison task in which the place-value of a non-zero digit was varied in a string composed of zeros. Experiment 2 employed a physical comparison task in which strings of digits varied in their physical sizes. In both types of tasks, the place-value of the non-zero digit in the string was irrelevant to the task performed. Interference of the place-value information was found in both tasks. When the non-zero digit occupied a lower place-value, it was recognized slower as a larger digit or as written in a larger font size. We concluded that place-value in a multi-digit number is processed automatically. These results support the notion of a decomposed representation of multi-digit numbers in memory. PMID- 22449133 TI - Grouping and binding in visual short-term memory. AB - Findings of 2 experiments are reported that challenge the current understanding of visual short-term memory (VSTM). In both experiments, a single study display, containing 6 colored shapes, was presented briefly and then probed with a single colored shape. At stake is how VSTM retains a record of different objects that share common features: In the 1st experiment, 2 study items sometimes shared a common feature (either a shape or a color). The data revealed a color sharing effect, in which memory was much better for items that shared a common color than for items that did not. The 2nd experiment showed that the size of the color sharing effect depended on whether a single pair of items shared a common color or whether 2 pairs of items were so defined-memory for all items improved when 2 color groups were presented. In explaining performance, an account is advanced in which items compete for a fixed number of slots, but then memory recall for any given stored item is prone to error. A critical assumption is that items that share a common color are stored together in a slot as a chunk. The evidence provides further support for the idea that principles of perceptual organization may determine the manner in which items are stored in VSTM. PMID- 22449134 TI - Temporal dynamics of activation of thematic and functional knowledge during conceptual processing of manipulable artifacts. AB - The current research aimed at specifying the activation time course of different types of semantic information during object conceptual processing and the effect of context on this time course. We distinguished between thematic and functional knowledge and the specificity of functional similarity. Two experiments were conducted with healthy older adults using eye tracking in a word-to-picture matching task. The time course of gaze fixations was used to assess activation of distractor objects during the identification of manipulable artifact targets (e.g., broom). Distractors were (a) thematically related (e.g., dustpan), (b) related by a specific function (e.g., vacuum cleaner), or (c) related by a general function (e.g., sponge). Growth curve analyses were used to assess competition effects when target words were presented in isolation (Experiment 1) and embedded in contextual sentences of different generality levels (Experiment 2). In the absence of context, there was earlier and shorter lasting activation of thematically related as compared to functionally related objects. The time course difference was more pronounced for general functions than specific functions. When contexts were provided, functional similarities that were congruent with context generality level increased in salience with earlier activation of those objects. Context had little impact on thematic activation time course. These data demonstrate that processing a single manipulable artifact concept implicitly activates thematic and functional knowledge with different time courses and that context speeds activation of context-congruent functional similarity. PMID- 22449135 TI - Short-term forgetting without interference. AB - In the 1st reported experiment, we demonstrate that auditory memory is robust over extended retention intervals (RIs) when listeners compare the timbre of complex tones, even when active or verbal rehearsal is difficult or impossible. Thus, our tones have an abstract timbre that resists verbal labeling, they differ across trials so that no "standard" comparison stimulus is built up, and the spectral change to be discriminated is very slight and therefore does not shift stimuli across verbal categories. Nonetheless, performance in this nonverbal immediate memory task was better at short (1-, 2-, or 4-s) than long (8-, 16-, or 32-s) RIs, an outcome predicted by temporal distinctiveness theory whereby at long RIs, tones are closer in time to tones on previous trials. We reject this account in the 2nd experiment, where we demonstrate that the ratio of RI to intertrial interval makes absolutely no difference to performance. We suggest that steady forgetting is consistent with a psychoacoustically derived conception of an auditory memory (the timbre memory model) that embodies time-based forgetting in the absence of feature-specific interference. PMID- 22449136 TI - Slow continuous ultrafiltration in a patient with anomaly of a persistent left superior vena cava. AB - This paper describes an uncommon case of a patient with anomaly of a persistent left superior vena cava (PLSVC). A 54-year-old man with a history of chronic kidney disease, heart failure, diabetes mellitus and hypertension was admitted to the hospital for worsening dyspnoea. During his hospital stay, heart failure was further deteriorated and he became anuric. Renal replacement therapy was then required. After multiple unsuccessful attempts of right subclavian vein catheterisation, a catheter was placed in the left subclavian vein. Chest X-ray revealed the catheter in the left side of the thorax. Transthoracic cardiac ultrasound with agitated saline and chest MRI confirmed the diagnosis of PLSVC. The patient had nine sessions of slow continuous ultrafiltration. His heart and renal function were gradually improved. Nephrologists and health care professionals must be aware of this uncommon anatomic variant. Unnecessary manipulations can lead to serious complications, such as cardiac arrhythmias, cardiac arrest and venous sinus thrombosis. PMID- 22449137 TI - Adoption and use of social media among public health departments. AB - BACKGROUND: Effective communication is a critical function within any public health system. Social media has enhanced communication between individuals and organizations and has the potential to augment public health communication. However, there is a lack of reported data on social media adoption within public health settings. The purposes of this study were to assess: 1) the extent to which state public health departments (SHDs) are using social media; 2) which social media applications are used most often; and 3) how often social media is used interactively to engage audiences. METHODS: This was a non-experimental, cross sectional study of SHD social media sites. Screen capture software Snag It(r) was used to obtain screenshots of SHD social media sites across five applications. These sites were coded for social media presence, interactivity, reach, and topic. RESULTS: Sixty percent of SHDs reported using at least one social media application. Of these, 86.7% had a Twitter account, 56% a Facebook account, and 43% a YouTube channel. There was a statistically significant difference between average population density and use of social media (p = .01). On average, SHDs made one post per day on social media sites, and this was primarily to distribute information; there was very little interaction with audiences. SHDs have few followers or friends on their social media sites. The most common topics for posts and tweets related to staying healthy and diseases and conditions. Limitations include the absence of a standard by which social media metrics measure presence, reach, or interactivity; SHDs were only included if they had an institutionally maintained account; and the study was cross sectional. CONCLUSIONS: Social media use by public health agencies is in the early adoption stage. However, the reach of social media is limited. SHDs are using social media as a channel to distribute information rather than capitalizing on the interactivity available to create conversations and engage with the audience. If public health agencies are to effectively use social media then they must develop a strategic communication plan that incorporates best practices for expanding reach and fostering interactivity and engagement. PMID- 22449138 TI - Polymer-graphene nanocomposites as ultrafast-charge and -discharge cathodes for rechargeable lithium batteries. AB - Electroactive polymers are a new generation of "green" cathode materials for rechargeable lithium batteries. We have developed nanocomposites combining graphene with two promising polymer cathode materials, poly(anthraquinonyl sulfide) and polyimide, to improve their high-rate performance. The polymer graphene nanocomposites were synthesized through a simple in situ polymerization in the presence of graphene sheets. The highly dispersed graphene sheets in the nanocomposite drastically enhanced the electronic conductivity and allowed the electrochemical activity of the polymer cathode to be efficiently utilized. This allows for ultrafast charging and discharging; the composite can deliver more than 100 mAh/g within just a few seconds. PMID- 22449139 TI - Elastin-derived peptides induce inflammatory responses through the activation of NF-kappaB in human ligamentum flavum cells. AB - The formation of fibrotic tissue in the ligamentum flavum (LF) is usually preceded by breakdown of elastic fibers. Elastin-derived peptides (EDPs) from breakdown of elastic fibers display a wide range of biological activities in a variety of cells, but there is minimal information regarding the involvement in the processes of LF hypertrophy. The aim of this study is to elucidate the effects of EDPs on cultured human LF cells and to investigate their molecular and biochemical mechanisms. Human LF cells were obtained from 18 patients who underwent lumbar spine surgery. After treatment with different concentrations of EDPs with or without specific inhibitors in culture medium, the viability and proliferation of LF cells, genes expression, and the signaling pathways were evaluated and analyzed. It was found that 50 MUg/ml EDPs significantly increased cell proliferation and synthesis of prostaglandin E(2). The gene expression and protein production of proinflammatory cytokines, including interleukin-1alpha (IL 1alpha), IL-1beta, and IL-6, were also upregulated. The levels of p-ERK (extracellular signal-regulated kinase) and NF-kappaB increased immediately following EDP treatment and sustained up to 90 min. It was also found that NF kappaB inhibitor, but not ERK1/2 inhibitor, attenuated EDP-dependent induction of IL-1alpha, IL-1beta, and IL-6 expression, indicating that NF-kappaB pathways are required for EDP-induced IL-1alpha, IL-1beta, and IL-6 gene expression in human LF cells. The results of this in vitro experiment suggest that EDPs do induce inflammatory responses in human LF cells and plays the key role in the development of LF hypertrophy. PMID- 22449140 TI - Evaluation of high resolution magic-angle coil spinning NMR spectroscopy for metabolic profiling of nanoliter tissue biopsies. AB - High-resolution magic-angle sample spinning (HR-MAS) (1)H NMR spectroscopy of tissue biopsies combined with chemometric techniques has emerged as a valuable methodology for disease diagnosis and environmental assessments. However, the tissue mass required for such experiments is of the order of 10 mg, and this can compromise the metabolic evaluation because of tissue heterogeneity. Tissue availability is often a limitation for clinical studies due to histopathological requirements, which are currently the gold standard for diagnosis, for example, in the case of tumors. Here, we introduce the use of a rotating micro-NMR detector that optimizes the coil filling factor such that mass-limited samples can be measured. We show the results for measuring nanoliter volume tissue biopsies using a commercial HR-MAS probe for the first time. The method has been tested with bovine muscle and human gastric mucosal tumor tissue samples. The gain in mass sensitivity is approximate up to 17-fold, and the adequate spectral resolution (3 Hz) allows the measurement of the metabolite profiles in nanoliter volume samples, thereby limiting the ambiguity resulting from heterogeneous tissues; thus, the approach presents diagnostic potential for studies by metabonomics of mass-limited biopsies. PMID- 22449141 TI - Critical comparison of multidimensional separation methods for increasing protein expression coverage. AB - We present a comparison of two-dimensional separation methods and how they affect the degree of coverage of protein expression in complex mixtures. We investigated the relative merits of various protein and peptide separations prior to acidic reversed-phase chromatography directly coupled to an ion trap mass spectrometer. The first dimensions investigated were density gradient organelle fractionation of cell extracts, 1D SDS-PAGE protein separation followed by digestion by trypsin or GluC proteases, strong cation exchange chromatography, and off-gel isoelectric focusing of tryptic peptides. The number of fractions from each first dimension and the total data accumulation RP-HPLC-MS/MS time was kept constant and the experiments were run in triplicate. We find that the most critical parameters are the data accumulation time, which defines the level of under-sampling and the avoidance of peptides from high expression level proteins eluting over the entire gradient. PMID- 22449142 TI - Ba2(BO3)(1-x)(CO3)(x)Cl(1+x): a mixed borate and carbonate chloride crystallized from high-temperature solution. AB - A mixed borate and carbonate chloride Ba(2)(BO(3))(1-x)(CO(3))(x)Cl(1+x) was obtained by spontaneous crystallization from a high-temperature melt in open air. It crystallizes in the trigonal crystal system with space group of P3m1 and lattice constants of a = 5.4708(8) A and c = 10.640(2) A. The structure can be viewed as an intergrowth of trigonal Ba(2)Mg(BO(3))(2) (001) slab and (111) slab of the cubic fluorite BaCl(2). During Fourier analysis of the single-crystal X ray diffraction data, additional electron density was found locating at 1b (0, 0, 1/2) site and attributed to chlorine surplus, which was confirmed by chemical titration. Charge balance of the compound was found, unexpectedly in an acidic borate containing high-temperature melt, by partial CO(3)(2-) group substituting the BO(3)(3-) group. The existence of CO(3)(2-) anion in the crystal was detected by thermogravimetry-mass spectrum analysis and Raman spectrum. The transmittance spectrum shows that the crystal is transparent from ultraviolet to infrared with short-wavelength absorption edge at about 220 nm. PMID- 22449143 TI - Magnetic click colloidal assembly. AB - We introduce a new class of spherical colloids that reversibly self-assemble into well-defined nonlinear structures by virtue of "magnetic patches". This assembly is driven by tunable magnetostatic binding forces that originate from microscopic permanent magnets embedded underneath the surface of the particles. The resulting clusters form spontaneously in the absence of external magnetizing fields, and their geometry is determined by an interplay between magnetic, steric, and electrostatic interactions. Imposing an external magnetic field enables the clusters to unbind or change their geometry allowing, in principle, the creation of materials with a reconfigurable structural arrangement. PMID- 22449144 TI - Utilization and responsiveness of the asthma control test (ACT) at the initiation of therapy for patients with asthma: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to assess the responsiveness of the asthma control test (ACT) to detect changes at the initiation of therapy and its utilization in the initiation of asthma treatment. METHODS: This study was designed as a randomized clinical trial conducted in a primary care setting. The subjects were asthma patients who had not received controller therapy for at least two months. The patients were randomized into two groups: The Saudi Initiative for Asthma (SINA) group and the Global Initiative for Asthma (GINA) group. Treatment in the SINA group was initiated at step1 when the ACT scores >= 20, step 2 when the score between16-19, and step 3 when the score < 16 began at step 3. The GINA group patients were started on step 2 when they had persistent asthma symptoms or step 3 when they had severely uncontrolled disease. RESULTS: Forty-five patients were analyzed in each group. The improvement in ACT score after treatment initiation was significantly higher when the SINA approach was used (2.9 in the SINA group compared to 1.7 in the GINA group (p = 0.04)). The improvement in FEV1 was 5.8% in the SINA group compared to 3.4% in the GINA group (p = 0.46). The number of patients who achieved asthma control at the follow-up visit and required no treatment adjustment was 33 (73.3%) in the SINA group and 27 (60%) in the GINA group (p = 0.0125). CONCLUSION: The ACT was responsive to change at the initiation of asthma treatment and was useful for the initiation of asthma treatment. TRIAL REGISTRATION NUMBER: ISRCTN31998214. PMID- 22449145 TI - Association of total energy intake and macronutrient consumption with colorectal cancer risk: results from a large population-based case-control study in Newfoundland and Labrador and Ontario, Canada. AB - BACKGROUND: Diet is regarded as one of the most important environmental factors associated with colorectal cancer (CRC) risk. A recent report comprehensively concluded that total energy intake does not have a simple relationship with CRC risk, and that the data were inconsistent for carbohydrate, cholesterol and protein. The objective of this study was to identify the associations of CRC risk with dietary intakes of total energy, protein, fat, carbohydrate, fiber, and alcohol using data from a large case-control study conducted in Newfoundland and Labrador (NL) and Ontario (ON), Canada. METHODS: Incident colorectal cancer cases (n = 1760) were identified from population-based cancer registries in the provinces of ON (1997-2000) and NL (1999-2003). Controls (n = 2481) were a random sample of residents in each province, aged 20-74 years. Family history questionnaire (FHQ), personal history questionnaire (PHQ), and food frequency questionnaire (FFQ) were used to collect study data. Logistic regression was used to evaluate the association of intakes of total energy, macronutrients and alcohol with CRC risk. RESULTS: Total energy intake was associated with higher risk of CRC (OR: 1.56; 95% CI: 1.21-2.01, p-trend = 0.02, 5th versus 1st quintile), whereas inverse associations emerged for intakes of protein (OR: 0.85, 95%CI: 0.69-1.00, p-trend = 0.06, 5th versus 1st quintile), carbohydrate (OR: 0.81, 95%CI: 0.63-1.00, p-trend = 0.05, 5th versus 1st quintile) and total dietary fiber (OR: 0.84, 95% CI:0.67-0.99, p-trend = 0.04, 5th versus 1st quintile). Total fat, alcohol, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, and cholesterol were not associated with CRC risk. CONCLUSION: This study provides further evidence that high energy intake may increase risk of incident CRC, whereas diets high in protein, fiber, and carbohydrate may reduce the risk of the disease. PMID- 22449147 TI - Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood. AB - BACKGROUND: Mutations in LIPH are a cause of autosomal recessive woolly hair (ARWH). Homozygous c.736T>A (p.Cys246Ser), and compound heterozygous c.736T>A and c.742C>A (p.His248Asn) have been reported in 5 and 7 Japanese children with ARWH respectively. The severity of hypotrichosis is known to be able to change in the clinical course, and the mutation patterns of LIPH do not always correlate with the severity of hypotrichosis in ARWH caused by other mutation sites of LIPH. However, all 12 Japanese children previously reported to have ARWH have shown similar severity of hypotrichosis. OBJECTIVE: In this study, we investigated the clinical features and molecular basis of ARWH in patients including three adults (three adults and two children) from five non-related Japanese families. METHODS: Five families of Japanese origin that presented with woolly hair were studied. The phenotype was confirmed by clinical examination. Direct automated DNA sequencing of the LIPH gene was performed to identify the mutations in our probands. RESULTS: All patients had had woolly hair since birth. Homozygous c.736T>A mutations were found in four patients, including three adult cases, and compound heterozygous c.736T>A and c.742C>A mutations were found in one child patient. The two adults and two children had only sparse scalp hair, although one adult woman had mild hypotrichosis with long hairs. CONCLUSION: Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood. PMID- 22449146 TI - From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation. AB - Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct protein interaction between neurofibromin, the protein product of the NF1 gene, and VCP/p97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/p97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/p97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/p97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases. PMID- 22449148 TI - Brentuximab vedotin in anaplastic large cell lymphoma. AB - INTRODUCTION: Brentuximab vedotin , a novel anti-CD30 antibody-drug conjugate, delivers a cytotoxic agent into CD30(+) cells. CD30 expression is characteristic of anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL). AREAS COVERED: We reviewed data on brentuximab vedotin, focusing on ALCL and discuss pharmacology, clinical trials leading to approval and future research directions. Systemic ALCL, 3% of adult NHL, is characterized by large anaplastic CD30(+) cells. The fusion protein NPM-ALK, when present in systemic ALCL, confers better prognosis, although even ALK- patients with IPI score >= 3 are high-risk. For patients with systemic ALCL, 25 - 45% relapse after frontline therapy, and > 50% of patients will relapse following high-dose chemotherapy with autologous stem cell support. There has been no standard therapy for relapsed/refractory systemic ALCL. Brentuximab vedotin, combines a monoclonal antibody targeted to CD30 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen. EXPERT OPINION: Brentuximab vedotin provides targeted therapy to CD30(+) lymphomas, including ALCL and HL, with high response rates and manageable toxicity, predominantly myelosuppression and peripheral neuropathy. PMID- 22449149 TI - Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma. AB - We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony stimulating factor and harvest. Melphalan 100 mg/m(2) per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4.35 mg/l (range: 1.8-11.4); albumin was 37 g/l (range: 3.1-4.9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1.3 mg/m(2) was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (>=partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval (CI): 11-21] months and the median overall survival was 35 (95% CI: 22 43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0.0072) and FANCF (P = 0.0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma. PMID- 22449150 TI - Methylation in colorectal cancer. PMID- 22449151 TI - p16 gene methylation in colorectal cancer patients with long-term follow-up. AB - INTRODUCTION: p16 gene plays an important role in the cell cycle regulation and is considered an important tumor suppressor gene. Several mechanisms of gene inactivation have been described; in this study we have focused on p16 gene promoter methylation. In colorectal cancer p16 gene methylation is a frequent event. METHODS: 326 patients with sporadic colorectal cancer were included. DNA was extracted from tumor tissue samples obtained during the surgical procedure. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. Frequency of p16 methylation was analyzed and compared with other clinicopathological variables. RESULTS: p16 gene methylation was detected in 24.8% of patients. Methylation was associated with differentiation grade and with tumor location: methylation was frequent in poorly differentiated tumors and had low frequency in distal colon. The p16 promoter methylation discriminated a subgroup of patients with better prognosis in poorly differentiated tumors. CONCLUSIONS: p16 methylation was a frequent event in our population and was able to induce differences in the overall survival of patients with poorly differentiated tumors. PMID- 22449152 TI - Transit of radiopaque particles through the gastrointestinal tract: comparison between type 2 diabetes patients and healthy individuals. AB - BACKGROUND/AIMS: some studies have reported controversial results when comparing the gastrointestinal transit between diabetic and healthy individuals. Therefore, we compared the gastrointestinal transit of radiopaque particles between diabetic and non-diabetic healthy individuals. METHODS: abdominal radiographies were performed for 45 type 2 diabetes mellitus patients and 35 healthy individuals (gender and age similar for both groups) at 24 and 72 h after they ingested radiopaque particles. The mean number of particles in the colon was compared for both groups. The data were expressed as mean and standard deviation values. RESULTS: at 24 h, the total number of particles in the colon did not differ significantly for the diabetic and non-diabetic individuals. At 72 hours, the distribution in the diabetic and non-diabetic individuals was as follows: right colon, 0.44 +/- 0.88 and 0.26 +/- 0.7, respectively (p = 0.8); left colon, 2.6 +/ 4.2 and 0.49 +/- 1.3 (p < 0.003); and rectosigmoid colon, 2.65 +/- 3.8 and 0.80 +/- 1.5 (p < 0.005).The mean number of radiopaque particles in the entire colon was 5.7 +/- 7.1 and 1.5 +/- 2.7 for diabetic and non-diabetic individuals, respectively (p < 0.001). CONCLUSIONS: the number of radiopaque particles in the colon did not significantly differ for the diabetic and non-diabetic individuals at 24 h after ingestion but was significantly greater in diabetic individuals at 72 h after ingestion. At 72 h, the mean number of radiopaque particles in the left and rectosigmoid colon were significantly higher in the diabetics than in the non-diabetic individuals. PMID- 22449153 TI - Prospective analysis of clinician accuracy in the diagnosis of benign anorrectal pathology: the value of clinical information. AB - AIM: the prevalence of anorectal disorders in general population is high. The aim of this study was to analyze the influence of clinical symptoms on diagnostic accuracy for benign anorectal pathology among different specialists and evaluate the relationship between diagnostic accuracy and years of professional experience. METHODS: seven typical cases were selected. In a first interview, participants were shown images and asked to make a diagnosis. Afterwards, images with additional information (clinical symptoms) were used. Two groups (group 1 = general surgeons and group 2 = medical specialists who attended emergency department) completed both phases of the study to analyze the influence of clinical symptoms on the final diagnosis. RESULTS: forty four specialists were interviewed. The percentage of participants making a correct diagnosis in groups 1 and 2, respectively, was as follows: case 1 (perianal abscess): 100 vs. 80.6%, (p = 0.157); case 2 (fissure): 92.3 vs. 51.6% (p = 0.015); case 3 (thrombosed hemorrhoid): 92.3 vs. 74.2% (p = 0.321); case 4 (anal condyloma): 100 vs. 87.1% (p = 0.302); case 5 (rectal prolapse): 100 vs. 83.9% (p = 0.301); case 6 (prolapsed hemorrhoid): 92.3 vs. 29% (p = 0.001), and case 7 (fistula): 100 vs. 67.7% (p = 0.021). There were significant differences in the number of correctly diagnosed cases between groups (p < 0.001). Information about clinical symptoms significantly increased overall and specific accuracy. There was no correlation between experience and accuracy. CONCLUSIONS: clinical symptoms are important for diagnostic accuracy in anorectal pathology. Training in anorectal pathology in medical specialists is warranted. PMID- 22449154 TI - Gastrointestinal stromal tumors (GISTs): role of CD 117 and PDGFRA Golgi-like staining pattern in the recognition of mutational status. AB - AIMS: to determine whether potential correlations between CD117 and PDGFRA might serve as an indication for targeted therapies. MATERIAL AND METHODS: immunohistochemical expression of CD117 and PDGFRA was evaluated in 99 paraffin embedded GISTs in conjunction with KIT and PDGFRA mutational status. RESULTS: CD117-positive staining was noted in 93 out of 99 cases. The predominant staining pattern was cytoplasmic, either with or without membrane accentuation; in 44.5% of cases, a clear Golgi-like pattern was evident. Correlations were found between KIT mutation and both CD117 expression (p = 0.006) and Golgi-like pattern (p = 0.026). Cytoplasmic PDGFRA-positive staining was detected in 87% of cases, both with and without membrane accentuation; in 8% cases an evident Golgi-like staining pattern was observed. A significant correlation was noted between PDGFRA mutations and Golgi-like staining pattern (p = 0.001). Moreover, 95% of PDGFRA positive GISTs were also CD117-positive, suggesting that expression of the two markers is not mutually exclusive; most of these had mutations in KIT exon 11. PDGFRA-positive/CD117-negative tumors had mutations in PDGFRA, mainly in exon 18. PDGFRA-negative/CD117-negative staining was observed in 15% of cases, all of which displayed mutations in KIT exon 11. CD117-positive/PDGFRA-negative cases were characterized by mutations in KIT, mainly in exon 11. CONCLUSIONS: CD117 and PDGFRA staining are not exclusive, and the presence of a Golgi-like staining pattern for either, whilst not pathognomonic, is highly suggestive of KIT and PDGFRA mutated GISTs, respectively, and may be used with some reservations as an alternative indication for prescribing targeted therapies. PMID- 22449155 TI - Current management of gastric cancer. AB - Gastric cancer is a disease with high incidence and mortality in our population. The prognosis of patients with this disease is closely related to the neoplasm stage at diagnosis, including the following characteristics of the tumor: extension into the gastric wall thickness, spread to locoregional lymph nodes and the ability to generate distant metastases, as described by the TNM classification. For localized tumors characterized only by invasion of mucosa or submucosa at diagnosis, survival at 5 years is between 70 and 95% with exclusive surgical management; however, when extension into the gastric wall is higher and/or there is locoregional nodal involvement, survival decreases to 20-30% at 5 years. Currently, at high-volume centers, the extent of gastrectomy is individualized based on several parameters, which in an increasing number of cases allows a total gastrectomy with D2 lymphadenectomy and preservation of the spleen and pancreas. This improved procedure increases the chance of R0 surgery and improves the relationship between resected and affected lymph nodes, resulting in a decreased risk of the long-term locoregional recurrence. To improve these results, different therapeutic strategies combining chemotherapy or chemoradiotherapy with surgery have been tested. Previously, the Intergroup 0116 clinical trial, published in 2001, which changed clinical practice in the United States, showed that adjuvant chemoradiotherapy improved survival (from 26 to 37 months overall survival) of these patients. In Europe, perioperative chemotherapy has been considered the standard treatment, since the publication of two randomized phase III trials showed an increase at 5 years survival in the group treated with chemotherapy. PMID- 22449156 TI - [Mantle cell lymphoma with intestinal involvement]. PMID- 22449157 TI - Appendicular mucocele as cause of chronic abdominal pain. PMID- 22449158 TI - Multiple desmoid tumors in a patient with familial adenomatous polyposis caused by the novel W421X mutation. AB - Familial adenomatous polyposis (FAP) is a rare syndrome characterized by the presence of hundreds to thousands of colorectal adenomas and is responsible for less than 1% of all colorectal cancers. The syndrome is also characterized by extra-colorectal features including amongst others upper gastrointestinal tract polyps and desmoid tumors. The syndrome is inherited by an autosomal dominant gene, the adenomatous polyposis coli (APC) gene. We present the physical history, clinical presentation, diagnosis and treatment of a patient with a novel germline APC mutation, the W421X mutation, which resulted in FAP presenting with about a hundred colorectal polyps, gastric hyperplastic polyps and multiple aggressive intra-abdominal and extra-abdominal desmoid tumors. PMID- 22449159 TI - [Patient information. Dieulafoy's lesion]. PMID- 22449160 TI - Anticoagulation in a cirrhotic patient with acute portal vein thrombosis unrelated to malignancy. A case report. PMID- 22449161 TI - Gallbladder variceal bleeding in a patient with alcoholic cirrhosis: a rare entity. PMID- 22449162 TI - Unusual technique for caustic esophagitis. PMID- 22449163 TI - Clinical challenge: diverticulitis of third and fourth portion of the duodenum with perforation. PMID- 22449164 TI - Tuberculous monoarthritis after treatment with adalimumab in Crohn's disease. PMID- 22449165 TI - Uncommon cause of chronic diarrhea. PMID- 22449166 TI - Quantification of four major metabolites of embryotoxic N-methyl- and N-ethyl-2 pyrrolidone in human urine by cooled-injection gas chromatography and isotope dilution mass spectrometry. AB - N-Methyl- and N-ethyl-2-pyrollidone (NMP and NEP) are frequently used industrial solvents and were shown to be embryotoxic in animal experiments. We developed a sensitive, specific, and robust analytical method based on cooled-injection (CIS) gas chromatography and isotope dilution mass spectrometry to analyze 5-hydroxy-N ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI), two newly identified presumed metabolites of NEP, and their corresponding methyl counterparts (5-HNMP, 2-HMSI) in human urine. The urine was spiked with deuterium labeled analogues of these metabolites. The analytes were separated from urinary matrix by solid-phase extraction and silylated prior to quantification. Validation of this method was carried out by using both, spiked pooled urine samples and urine samples from 56 individuals of the general population with no known occupational exposure to NMP and NEP. Interday and intraday imprecision was better than 8% for all metabolites, while the limits of detection were between 5 and 20 MUg/L depending on the analyte. The high sensitivity of the method enables us to quantify NMP and NEP metabolites at current environmental exposures by human biomonitoring. PMID- 22449167 TI - Directional scattering and hydrogen sensing by bimetallic Pd-Au nanoantennas. AB - Nanoplasmonic sensing is typically based on quantification of changes in optical extinction or scattering spectra. Here we explore the possibility of facile self referenced hydrogen sensing based on angle-resolved spectroscopy. We found that heterodimers built from closely spaced gold and palladium nanodisks exhibit pronounced directional scattering, that is, for particular wavelengths, much more light is scattered toward the Au than toward the Pd particle in a dimer. The effect is due to optical phase shifts associated with the material asymmetry and therefore highly sensitive to changes in the permittivity of Pd induced by hydrogen loading. In a wider perspective, the results suggest that directional scattering from bimetallic antennas, and material asymmetry in general, may offer many new routes toward novel nanophotonic sensing schemes. PMID- 22449168 TI - Diverse closed cavities in condensed rare earth metal-chalcogenide matrixes: Cs[Lu7Q11] and (ClCs6)[RE21Q34] (RE = Dy, Ho; Q = S, Se, Te). AB - Two types of novel ordered chalcogenids Cs[Lu(7)Q(11)] (Q = S, Se) and (ClCs(6))[RE(21)Q(34)] (RE = Dy, Ho; Q = S, Se, Te) were discovered by high temperature solid state reactions. The structures were characterized by single crystal X-ray diffraction data. Cs[Lu(7)Q(11)] crystallize in the orthorhombic Cmca (no. 64) with a = 15.228(4)-15.849(7) A, b = 13.357(3)-13.858(6) A, c = 18.777(5)-19.509(8) A, and Z = 8. (ClCs(6))[RE(21)Q(34)] crystallize in the monoclinic C2/m (no. 12) with a = 17.127(2)-18.868(2) A, b = 19.489(2)-21.578(9) A, c = 12.988(9)-14.356(2) A, beta = 128.604(2)-128.738(4) degrees , and Z = 2. Both types of compounds feature 3D RE-Q network structures that embed with dual tricapped cubes Cs(2)@Se(18) in the former or unprecedented matryoshka nesting doll structure cavities of (ClCs(6))@Se(32) in the latter. The band gap, band structure, as well as a structure change trend of the majority of A/RE/Q compounds are presented. PMID- 22449169 TI - From detrimental to beneficial constituents in foods: tracking the publication trends in JAFC. AB - A large part of the research focus on food constituents in the 20th century was toward health-detrimental contaminants-pathogens, toxins, chemical residues, and some food additives. This is reflected in the publications in the Journal of Agricultural and Food Chemistry and other journals. This era witnessed the formation of the U.S. Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) and the rise and fall of DDT and other synthetic chemicals, as well as a number of artificial sweeteners, preservatives, and coloring/flavoring agents that attracted consumer and government attention. During the past 25 years or so, the emphasis in food chemistry and biochemistry has trended more toward health-beneficial chemicals in foods, as their examination yields information on naturally occurring components-polyphenolic antioxidants, unsaturated fatty acids, soluble fibers, and many other classes of constituents that may ward off chronic diseases. This perspective addresses the changes in emphases in published research to the present and trends that indicate the directions that food chemistry/biochemistry and related sciences might follow in the future. PMID- 22449170 TI - Effects and predictors of shoulder muscle massage for patients with posterior shoulder tightness. AB - BACKGROUND: Clinical approaches like mobilization, stretching, and/or massage may decrease shoulder tightness and improve symptoms in subjects with stiff shoulders. We investigated the effect and predictors of effectiveness of massage in the treatment of patients with posterior shoulder tightness. METHODS: A randomized controlled trial was conducted in a hospital-based outpatient practice (orthopedic and rehabilitation). Forty-three women and 17 men (mean age = 54 years, range 43-73 years) with posterior shoulder tightness participated and were randomized into massage and control groups (n = 30 per group). A physical therapist provided the massage on the posterior deltoid, infraspinatus, and teres minor of the involved shoulder for 18 minutes [about 6 minutes for each muscle] two times a week for 4 weeks. For the control group, one therapist applied light hand touch on the muscles 10 minutes two times a week for 4 weeks. Glenohumeral internal rotation ROM, functional status, and muscle tightness were the main outcomes. Additionally, the potential factors on the effectiveness of massage were analyzed by multivariate logistic regression. For this analysis, patients with functional score improvement at least 20% after massage were considered responsive, and the others were considered nonresponsive. RESULTS: Fifty-two patients completed the study (29 for the massage and 23 for the control). The overall mean internal rotation ROM increased significantly in the massage group compared to the control (54.9 degrees v.s. 34.9 degrees ; P <= 0.001). There were 21 patients in the responsive group and 8 in the nonresponsive group. Among the factors, duration of symptoms, functional score, and posterior deltoid tightness were significant predictors of effectiveness of massage. CONCLUSIONS: Massage was an effective treatment for patients with posterior shoulder tightness, but was less effective in patients with longer duration of symptoms, higher functional limitation, and less posterior deltoid tightness. TRIAL REGISTRATION: This clinical trial is registered at Trial Registration "Trial registration: Clinicaltrials.gov NCT01022827". PMID- 22449171 TI - Dietary meat and fat intake and prevalence of rhinoconjunctivitis in pregnant Japanese women: baseline data from the Kyushu Okinawa Maternal and Child Health Study. AB - BACKGROUND: Dietary fat exerts numerous complex effects on proinflammatory and immunologic pathways. Several epidemiological studies have examined the relationships between intake of fatty acids and/or foods high in fat and allergic rhinitis, but have provided conflicting findings. The current cross-sectional study investigated such relationships in Japan. METHODS: Study subjects were 1745 pregnant women. The definition of rhinoconjunctivitis was based on criteria from the International Study of Asthma and Allergies in Childhood. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for age; gestation; region of residence; number of older siblings; number of children; smoking; secondhand smoke exposure at home and at work; family history of asthma, atopic eczema, and allergic rhinitis; household income; education; and body mass index. RESULTS: The prevalence of rhinoconjunctivitis in the past 12 months was 25.9%. Higher meat intake was significantly associated with an increased prevalence of rhinoconjunctivitis: the adjusted odds ratio between extreme quartiles was 1.71 (95% confidence interval: 1.25-2.35, P for trend = 0.002). No measurable association was found between fish intake and rhinoconjunctivitis. Intake of total fat, saturated fatty acids, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, n-6 polyunsaturated fatty acids, linoleic acid, arachidonic acid, and cholesterol and the ratio of n-3 to n-6 polyunsaturated fatty acid intake were not evidently related to the prevalence of rhinoconjunctivitis. CONCLUSIONS: The current results suggest that meat intake may be positively associated with the prevalence of rhinoconjunctivitis in young adult Japanese women. PMID- 22449172 TI - The role of thrombomodulin lectin-like domain in inflammation. AB - Thrombomodulin (TM) is a cell surface glycoprotein which is widely expressed in a variety of cell types. It is a cofactor for thrombin binding that mediates protein C activation and inhibits thrombin activity. In addition to its anticoagulant activity, recent evidence has revealed that TM, especially its lectin-like domain, has potent anti-inflammatory function through a variety of molecular mechanisms. The lectin-like domain of TM plays an important role in suppressing inflammation independent of the TM anticoagulant activity. This article makes an extensive review of the role of TM in inflammation. The molecular targets of TM lectin-like domain have also been elucidated. Recombinant TM protein, especially the TM lectin-like domain may play a promising role in the management of sepsis, glomerulonephritis and arthritis. These data demonstrated the potential therapeutic role of TM in the treatment of inflammatory diseases. PMID- 22449173 TI - Basal cell carcinoma growth in patients waiting for Mohs surgery: a prospective study. PMID- 22449174 TI - Multiplex loop-mediated isothermal amplification detection by sequence-based barcodes coupled with nicking endonuclease-mediated pyrosequencing. AB - The loop-mediated isothermal amplification (LAMP) is a well-developed method for replicating a targeted DNA sequence with a high specificity, but multiplex LAMP detection is difficult because LAMP amplicons are very complicated in structure. To allow simultaneous detection of multiple LAMP products, a series of target specific barcodes were designed and tagged in LAMP amplicons by FIP primers. The targeted barcodes were decoded by pyrosequencing on nicked LAMP amplicons. To enable the nicking reaction to occur just near the barcode regions, the recognition sequence of the nicking endonuclease (NEase) was also introduced into the FIP primer. After the nicking reaction, pyrosequencing started at the nicked 3' end when the added deoxyribonucleoside triphosphate (dNTP) was complementary to the non-nicked strand. To efficiently encode multiple targets, the barcodes were designed with a reporter base and two stuffer bases, so that the decoding of a target-specific barcode only required a single peak in a pyrogram. We have successfully detected the four kinds of pathogens including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Treponema pallidum (TP), which are easily infected in blood, by a 4-plex LAMP in a single tube, indicating that barcoded LAMP coupled with NEase-mediated pyrosequencing is a simple, rapid, and reliable way in multiple target identification. PMID- 22449175 TI - Stimulated erythropoiesis with secondary iron loading leads to a decrease in hepcidin despite an increase in bone morphogenetic protein 6 expression. AB - The BMP/SMAD signalling pathway plays an important role in iron homeostasis, regulating hepcidin expression in response to body iron levels. However, the role of this pathway in the reduction in hepcidin associated with increased erythropoiesis (and secondary iron loading) is unclear. To investigate this, we established a mouse model of chronic stimulated erythropoiesis with secondary iron loading using the haemolytic agent phenylhydrazine. We then examined the expression of components of the BMP6/SMAD signalling pathway in these animals. We also examined this pathway in the Hbb(th3/+) mouse, a model of the iron loading anaemia beta-thalassaemia intermedia. Increasing doses of phenylhydrazine led to a progressive increase in both liver iron levels and Bmp6 mRNA expression, but, in contrast, hepatic Hamp expression declined. The increase in Bmp6 expression was not associated with a corresponding change in the phosphorylation of hepatic SMAD1/5/8, indicating that stimulated erythropoiesis decreases the ability of BMP6 to alter SMAD phosphorylation. Increased erythropoiesis also reduces the capacity of phosphorylated SMAD (pSMAD) to induce hepcidin, as Hamp levels declined despite no changes in pSMAD1/5/8. Similar results were seen in Hbb(th3/+) mice. Thus the erythroid signal probably affects some components of BMP/SMAD signalling, but also may exert some independent effects. PMID- 22449176 TI - Recruiting and retaining rural students: evidence from a faculty of dentistry in South Africa. AB - INTRODUCTION: There is a shortage internationally of adequately trained health professionals to service rural areas. Health professionals are more likely to practice in communities that are like the one in which they grew up. The WHO therefore suggests targeted university admission policies to facilitate the enrolment of students from rural areas. In South Africa, rural students have special needs with regard to university access and throughput because they come from the most economically disadvantaged communities and often are the first in their families to attend university. This descriptive study, the first in South Africa with a cohort of dentistry students, draws on data from undergraduates at a single faculty of dentistry in South Africa. It investigates the factors affecting rural students' access to university, their academic success, as well as their employment intentions. METHODS: A self-administered questionnaire was completed by 304 (70%) of the total number of 435 undergraduate dental students. Closed questions elicited information regarding students' year of study, academic performance, source and adequacy of funding, family history of university attendance, and area of origin. Responses were analyzed using MS Excel and Epi InfoTM. Qualitative data were used to support quantitative findings. Open-ended questionnaire questions, including employment intentions, and three focus group interviews generated examples to illustrate and elaborate the quantitative findings. RESULTS: Only 7% (n=22) of the cohort (n=304) were from rural areas. Rural students relied on assistance from those with university experience to apply and register, for course information and funding opportunities. Most rural students were funded by provincial bursaries (41%; n=9) and National Student Financial Scheme (NSFAS) funding (18%; n=4). Forty-four percent (n=4) of the rural students with provincial bursaries and 100% (n=4) of the rural students with NSFAS funding reported not having enough money for food. All NSFAS-funded rural students (n=4) reported not having enough money to buy the prescribed and recommended texts. Fifty percent (n=2) of the rural students with NSFAS funding had failed at least one academic year. Rural students were least likely to have family members who had attended university. Rural students were three times more likely than other students to want to work in rural areas. CONCLUSION: Only a minority of dentistry students came from rural areas, and rural schools did not adequately prepare these students academically for university. Rural students also lacked immediate access to people with insight into the academic and socio cultural aspects of higher education, including the process of independent learning. Despite financial and academic challenges, rural students had a significantly stronger commitment to rural employment than students from cities and towns. It is recommended that rural students should receive academic, financial, and mentoring support both before and during their studies. PMID- 22449177 TI - A homochiral luminescent 2D porous coordination polymer with collagen-type triple helices showing selective guest inclusion. AB - A homochiral luminescent porous coordination polymer, [Cd(L)(H(2)O)].3H(2)O, with interconnected collagen like triple-helical chains has been synthesized solvothermally by using cadmium(II) salt and a newly designed d-isosorbide-based, enantiomerically pure chiral ligand. The framework is a 2D porous material and forms a 1D channel along the a axis, with the channel dimensions ~6.2 * 4.4 A(2). The compound has high selectivity in the uptake of water and methanol over other solvents (e.g., tetrahydrofuran, ethanol, benzene, and cyclohexane) inside the channels. PMID- 22449178 TI - Mapping the social network: tracking lice in a wild primate (Microcebus rufus) population to infer social contacts and vector potential. AB - BACKGROUND: Studies of host-parasite interactions have the potential to provide insights into the ecology of both organisms involved. We monitored the movement of sucking lice (Lemurpediculus verruculosus), parasites that require direct host host contact to be transferred, in their host population of wild mouse lemurs (Microcebus rufus). These lemurs live in the rainforests of Madagascar, are small (40 g), arboreal, nocturnal, solitary foraging primates for which data on population-wide interactions are difficult to obtain. We developed a simple, cost effective method exploiting the intimate relationship between louse and lemur, whereby individual lice were marked, without removal from their host, with an individualized code, and tracked throughout the lemur population. We then tested the hypotheses that 1) the frequency of louse transfers, and thus interactions, would decrease with increasing distance between paired individual lemurs; 2) due to host polygynandry, social interactions and hence louse transfers would increase during the onset of the breeding season; and 3) individual mouse lemurs would vary in their contributions to the spread of lice. RESULTS: We show that louse transfers involved 43.75% of the studied lemur population, exclusively males. Louse transfers peaked during the breeding season, perhaps due to increased social interactions between lemurs. Although trap-based individual lemur ranging patterns are restricted, louse transfer rate does not correlate with the distance between lemur trapping locales, indicating wider host ranging behavior and a greater risk of rapid population-wide pathogen transmission than predicted by standard trapping data alone. Furthermore, relatively few lemur individuals contributed disproportionately to the rapid spread of lice throughout the population. CONCLUSIONS: Using a simple method, we were able to visualize exchanges of lice in a population of cryptic wild primates. This method not only provided insight into the previously unseen parasite movement between lemurs, but also allowed us to infer social interactions between them. As lice are known pathogen vectors, our method also allowed us to identify the lemurs most likely to facilitate louse-mediated epidemics. Our approach demonstrates the potential to uncover otherwise inaccessible parasite-host, and host social interaction data in any trappable species parasitized by sucking lice. PMID- 22449179 TI - The development of modulated, quasi-isothermal and ultraslow thermal methods as a means of characterizing the alpha to gamma indomethacin polymorphic transformation. AB - While polymorphism remains a key issue within the pharmaceutical and related industries, the understanding of the transformation process itself remains relatively poorly understood. In this study we use a combination of conventional and modulated temperature differential scanning calorimetry (MTDSC), quasi isothermal MTDSC (Qi-MTDSC) and ultraslow heating rate MTDSC as a novel means of investigating the temperature-induced alpha to gamma transformation in indomethacin, using hot stage microscopy and variable temperature attenuated total reflectance FTIR spectroscopy as supportive techniques. In particular, we utilize the ability of MTDSC to measure subtle heat capacity changes through the transformation, we examine the use of Lissajous analysis of the modulated heating signal itself (both scanning and quasi-isothermal) and finally we investigate the use of ultraslow heating rates (down to 0.04 degrees C/min) so as to facilitate examination of the melt-crystallization process at a scanning rate whereby kinetic hindrance becomes negligible. Indomethacin was prepared in the metastable alpha and stable gamma forms using standard approaches. Samples were studied using conventional DSC, Qi-MTDSC (involving holding and modulating the sample at a series of incremental temperature steps) and ultraslow MTDSC. All studies were conducted using a Q-1000 MTDSC using crimped pans, following standard calibration procedures. Conventional DSC at 10 degrees C/min showed the expected single melting responses for the alpha and gamma forms, while MTDSC at slower rates indicated the presence of a melt-crystallization process. Quasi-isothermal studies allowed the heat capacity to be estimated as a function of time, while the associated Lissajous analysis demonstrated distortion of the elliptical response as a result of the kinetic events involved. Ultraslow heating resulted in superimposition of the melting and crystallization processes, resulting in a discrete thermal event that was enthalpically equivalent to the difference between the two processes. It is suggested that these combined thermal methods allow the conversion to be profiled in a manner which facilitates both kinetic and thermodynamic analysis of the transformation. PMID- 22449180 TI - Chlamydia trachomatis, Mycoplasma genitalium and Ureaplasma urealyticum among students in northern Norway. AB - BACKGROUND: The prevalence of Mycoplasma genitalium and Ureaplasma genitalium in populations outside sexually transmitted infection clinics in Norway is unknown. OBJECTIVE: To assess the prevalence of potential sexually transmitted organisms in a non-clinical setting, among college students in Northern Norway. METHODS: In total 655 students, 449 men and 206 women, were tested for Chlamydia trachomatis, M. genitalium, and U. urealyticum by nucleic acid amplification testing of urine samples. All subjects completed questionnaires. RESULTS: Among the included men, the prevalences of C. trachomatis, M. genitalium, and U. urealyticum were 4.2%, 1.1% and 8.9%, respectively. Prevalence among included women was 1.9%, 1% and 8.2%, respectively. In men, the number of sexual partners in the preceding 6 months was associated with prevalence of U. urealyticum and C. trachomatis. CONCLUSIONS: U. urealyticum appeared more prevalent than C. trachomatis and increased number of sexual partners was associated with increased risk of a positive test. M. genitalium had a low prevalence. PMID- 22449181 TI - What changes in DNA methylation take place in individuals exposed to maternal smoking in utero? PMID- 22449182 TI - Longevity with systems medicine? Epigenome, genome and environment interactions network. PMID- 22449183 TI - Neuronal activation and insight into the plasticity of DNA methylation. PMID- 22449185 TI - Polycomb and DNA methyltransferase complexes participate in global and focal epigenetic alteration in cancer cells. PMID- 22449186 TI - Methylation of TFPI-2 is an early event of esophageal carcinogenesis. AB - AIMS: To explore the epigenetic changes and the function of TFPI-2 in esophageal cancer. MATERIALS & METHODS: Nine esophageal cancer cell lines, nine normal esophageal mucosa, 60 esophageal dysplasia and 106 advanced esophageal cancer samples were included in this study. TFPI-2 methylation was examined by methylation-specific PCR. TFPI-2 expression was evaluated by immunohistochemistry in tissue samples. The effect of TFPI-2 on proliferation, apoptosis, invasion and migration was analyzed by colony formation assay, western blot assay, transwell assay and flow cytometric analysis. RESULTS: TFPI-2 expression was regulated by promoter region hypermethylation in human esophageal cancer cell lines, and TFPI 2 expression is inversely correlated with methylation in primary cancer. Methylation was found in 28.2, 33.3 and 33.3% of grade 1, 2 and 3 esophageal dysplasia, and 67% of primary esophageal cancer, but no methylation was found in normal mucosa. Methylation is significantly related to tumor differentiation. Inhibition of invasion, migration, colony formation and proliferation, and induction of apoptosis occurred with the restoration of TFPI-2 expression in the KYSE70 cell line. CONCLUSION: TFPI-2 is frequently methylated in esophageal cancer with a progression tendency. TFPI-2 is a potential tumor suppressor in esophageal cancer. PMID- 22449187 TI - Epigenetics and genetics in endometrial cancer: new carcinogenic mechanisms and relationship with clinical practice. AB - Endometrial cancer is the seventh most common cancer worldwide among females. An increased incidence and a younger age of patients are also predicted to occur, and therefore elucidation of the pathological mechanisms is important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, epigenetic mechanisms have been examined. Silencing of genes by DNA hypermethylation, hereditary epimutation of DNA mismatch repair genes and regulation of gene expression by miRNAs may underlie carcinogenesis in endometrial cancer. New therapies include targeting epigenetic changes using histone deacetylase inhibitors. Some cases of endometrial cancer may also be hereditary. Thus, patients with Lynch syndrome which is a hereditary disease, have a higher risk for developing endometrial cancer than the general population. Identification of such disease-related genes may contribute to early detection and prevention of endometrial cancer. PMID- 22449188 TI - Histone-modifying enzymes: regulators of developmental decisions and drivers of human disease. AB - Precise transcriptional networks drive the orchestration and execution of complex developmental processes. Transcription factors possessing sequence-specific DNA binding properties activate or repress target genes in a step-wise manner to control most cell lineage decisions. This regulation often requires the interaction between transcription factors and subunits of massive protein complexes that bear enzymatic activities towards histones. The functional coupling of transcription proteins and histone modifiers underscores the importance of transcriptional regulation through chromatin modification in developmental cell fate decisions and in disease pathogenesis. PMID- 22449189 TI - Promoter CpG island methylation markers in colorectal cancer: the road ahead. AB - Despite increasing knowledge on the biology, detection and treatment of colorectal cancer (CRC), the disease is still a major health problem. Hypermethylation of promoter regions of genes has been studied extensively as a contributor in CRC carcinogenesis. In addition, it is the topic of many studies focusing on biomarkers for the early detection, prediction of prognosis and treatment outcome. Methylation markers may be preferred over current screening and test methods as they are stable and easy to detect. However, almost no methylation marker is currently being used in clinical practice, often due to a lack of sensitivity, specificity, or validation of the results. This review summarizes the current knowledge of hypermethylation biomarkers for CRC detection, progression and treatment outcome. PMID- 22449190 TI - Epigenomics of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Gene-expression profiling studies have taught us quite a bit about the biology of this fatal disease, but epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptome changes associated with the development of IPF. This review will begin with an introduction to the disease, followed by brief summaries of studies of gene expression in IPF and epigenetic marks associated with exposures relevant to IPF. The majority of the discussion will focus on epigenetic studies conducted so far in IPF, the limitations, challenges nd future directions in this field. PMID- 22449191 TI - Modeling the dynamic epigenome: from histone modifications towards self organizing chromatin. AB - Epigenetic mechanisms play an important role in regulating and stabilizing functional states of living cells. However, in spite of an increasing amount of experimental data, models of transcriptional regulation by epigenetic processes, in particular by histone modifications, are rather rare. In this article, we focus on epigenetic modes of transcriptional regulation based on histone modifications and their potential dynamical interplay with DNA methylation and higher-order chromatin structure. The main purpose of this article is to review recent formal modeling approaches to the dynamics and propagation of histone modifications and to relate them to available experimental data. We evaluate their assumptions with respect to recruitment of relevant modifiers, establishment and processing of modifications, and compare the emerging stability properties and memory effects. Theoretical predictions that await experimental validation are highlighted and potential extensions of these models towards multiscale models of self-organizing chromatin are discussed. PMID- 22449192 TI - MacroH2A in stem cells: a story beyond gene repression. AB - The importance of epigenetic mechanisms is most clearly illustrated during early development when a totipotent cell goes through multiple cell fate transitions to form the many different cell types and tissues that constitute the embryo and the adult. The exchange of a canonical H2A histone for the 'repressive' macroH2A variant is one of the most striking epigenetic chromatin alterations that can occur at the level of the nucleosome. Here, we discuss recent data on macroH2A in zebrafish and mouse embryos, in embryonic and adult stem cells and also in nuclear reprogramming. We highlight the role of macroH2A in the establishment and maintenance of differentiated states and we discuss its still poorly recognized function in transcriptional activation. PMID- 22449193 TI - Uropathogenic Escherichia coli infection: potential importance of epigenetics. AB - Patients suffering from recurrent urinary tract infections (UTIs) may be maintained on antibiotic prophylaxis, or even treated by surgery. However, there are no biological data on which to base such treatment selection for the individual patient. This highlights the need for a biological marker that might predict UTI recurrence risk. Infection of mammalian tissues with bacteria, viruses and other pathogens results in the modification of the host cell epigenome, particularly DNA methylation. We recently demonstrated that in vitro infection of bladder uroepithelial cells with uropathogenic Escherichia coli results in hypermethylation of the tumor suppressor gene CDKN2A, providing proof of-concept that uropathogenic E. coli infection modulates the host cell epigenome. If postinfection persistence of UTI-induced uroepithelial DNA hypermethylation were to be associated with subsequent UTI propensity, these epigenetic marks could act as a potential biomarker for UTI recurrence risk and could be used to rationalize and improve treatment of patients with infection associated uropathies. PMID- 22449194 TI - Analysis of miRNA market trends reveals hotspots of research activity. AB - We have conducted an analysis of the miRNA research marketplace by evaluating the publication trends in the field. In this article, we present the results of our analysis which reveals that hotspots exist in terms of research activities in the miRNA space--these hotspots illustrate the areas in the miRNA research space where specific miRNAs have been extensively studied, and other areas that represent new territory. We frame these data into the context of areas of opportunity for miRNA content harvest versus segments of opportunity for the development of research tools. Also presented in this article are the primary market data from online surveys we have performed with researchers involved in miRNA research around the world. Taken together, these data frame the current state of the miRNA marketplace and provide niches of opportunity for new entrants into this space. PMID- 22449196 TI - A new LMS algorithm for analysis of atrial fibrillation signals. AB - BACKGROUND: A biomedical signal can be defined by its extrinsic features (x-axis and y-axis shift and scale) and intrinsic features (shape after normalization of extrinsic features). In this study, an LMS algorithm utilizing the method of differential steepest descent is developed, and is tested by normalization of extrinsic features in complex fractionated atrial electrograms (CFAE). METHOD: Equations for normalization of x-axis and y-axis shift and scale are first derived. The algorithm is implemented for real-time analysis of CFAE acquired during atrial fibrillation (AF). Data was acquired at a 977 Hz sampling rate from 10 paroxysmal and 10 persistent AF patients undergoing clinical electrophysiologic study and catheter ablation therapy. Over 24 trials, normalization characteristics using the new algorithm with four weights were compared to the Widrow-Hoff LMS algorithm with four tapped delays. The time for convergence, and the mean squared error (MSE) after convergence, were compared. The new LMS algorithm was also applied to lead aVF of the electrocardiogram in one patient with longstanding persistent AF, to enhance the F wave and to monitor extrinsic changes in signal shape. The average waveform over a 25 s interval was used as a prototypical reference signal for matching with the aVF lead. RESULTS: Based on the derivation equations, the y-shift and y-scale adjustments of the new LMS algorithm were shown to be equivalent to the scalar form of the Widrow-Hoff LMS algorithm. For x-shift and x-scale adjustments, rather than implementing a long tapped delay as in Widrow-Hoff LMS, the new method uses only two weights. After convergence, the MSE for matching paroxysmal CFAE averaged 0.46 +/- 0.49 MUV(2)/sample for the new LMS algorithm versus 0.72 +/- 0.35 MUV(2)/sample for Widrow-Hoff LMS. The MSE for matching persistent CFAE averaged 0.55 +/- 0.95 MUV(2)/sample for the new LMS algorithm versus 0.62 +/- 0.55 MUV(2)/sample for Widrow-Hoff LMS. There were no significant differences in estimation error for paroxysmal versus persistent data. From all trials, the mean convergence time was approximately 1 second for both algorithms. The new LMS algorithm was useful to enhance the electrocardiogram F wave by subtraction of an adaptively weighted prototypical reference signal from the aVF lead. The extrinsic weighting over 25 s demonstrated that time-varying functions such as patient respiration could be identified and monitored. CONCLUSIONS: A new LMS algorithm was derived and used for normalization of the extrinsic features in CFAE and for electrocardiogram monitoring. The weighting at convergence provides an estimate of the degree of similarity between two signals in terms of x-axis and y-axis shift and scale. The algorithm is computationally efficient with low estimation error. Based on the results, proposed applications include monitoring of extrinsic and intrinsic features of repetitive patterns in CFAE, enhancement of the electrocardiogram F wave and monitoring of time-varying signal properties, and to quantitatively characterize mechanistic differences in paroxysmal versus persistent AF. PMID- 22449197 TI - T-cell replete fludarabine/cyclophosphamide reduced intensity allogeneic stem cell transplantation for lymphoid malignancies. AB - The relative merits of reduced-intensity allogeneic stem cell transplantation (RISCT) for high-risk indolent lymphoid malignancies are emerging, although the preferred conditioning regimen to manage the risks of graft-versus-host disease (GVHD) is not clearly defined. Here we report the outcome of 73 patients with lymphoid malignancies who received RISCT with a fludarabine/cyclophosphosphamide conditioning regimen and a median follow-up of 3 years. Median age was 54 years. Forty-eight per cent of patients had previously undergone autologous stem cell transplantation with a median of three prior therapies. Non-relapse mortality at 3 years was 19% but only 5% for patients with multiple myeloma (MM). Three-year overall survival and current progression-free survival was 67% and 63% respectively. Grade 2-4 acute GVHD occurred in 14% of patients while 49% had chronic GVHD requiring systemic immunosuppression. The preparatory regimen in this study has the advantage of reduced acute GVHD and low mortality, notably in patients with MM. In addition, this strategy provides long-term disease control in a significant proportion of patients with particular benefit in those with high-risk follicular lymphoma. PMID- 22449198 TI - Total synthesis of (+/-)-7-epi-nemorosone. AB - A concise total synthesis of (+/-)-7-epi-nemorosone is reported. Our synthetic approach establishes a viable route to polycyclic polyprenylated acylphloroglucinol natural products (PPAP's) bearing a C-7 endo prenyl side chain. Key steps include retro-aldol-vinyl cerium addition to a hydroxy adamantane core scaffold and palladium-mediated deoxygenation. PMID- 22449199 TI - The effectiveness of face to face education using catharsis education action (CEA) method in improving the adherence of private general practitioners to national guideline on management of tuberculosis in Bandung, Indonesia. AB - BACKGROUND: In many countries, private general practitioners are the first contact in health services for people with symptoms of tuberculosis. Targeting the private sector has been recommended in previous studies to improve tuberculosis control. A brief face-to-face intervention using Catharsis Education Action (CEA) method, repeated at periodic intervals, seems to change physicians' attitudes, beliefs and practice.The objective of the study was to determine the effectiveness of CEA method in improving the private general practitioners' (PPs) adherence to the national guideline on the management of tuberculosis patients in Bandung District, Indonesia. METHOD: A randomized controlled trial was done. For the intervention group, a session of the CEA method was delivered to PPs while brief reminder with provision of pamphlet was used for the comparative group. RESULTS: A total of 82 PPs were included in the analysis. The intervention group showed some positive trends in adherence especially in the use of sputum as first laboratory examination (RR = 1.24) and follow up (RR = 1.37), though not reaching statistical significance. After intervention PPs in CEA group maintained the adherence, but PPs in pamphlets group showed deterioration (score before to after: -12.5). CONCLUSION: Face to face education using CEA method seems to be as effective as brief reminder with provision of pamphlet in improving the adherence. CEA offers additional information that can be useful in designing intervention programs to improve the adherence to guideline. PMID- 22449200 TI - Tax gene characterization of human T-lymphotropic virus type 1 strains from Brazilian HIV-coinfected patients. AB - The tax gene of human T-lymphotropic virus type 1 (HTLV-1) diverges among isolates according to geographic regions and has been classified into two genotypes: taxA and taxB. In Brazil, taxA is the most prevalent genotype in symptomatic and asymptomatic carriers. Few studies have been conducted in HIV infected patients. The present study characterized the tax gene (1059 bp) in 13 Brazilian HIV-1/HTLV-1-coinfected patients from the south and southeast regions. The results confirmed the transcontinental HTLV-1 subgroup A of the Cosmopolitan subtype and showed high nucleotide similarity both among Brazilian sequences and in relation to the ATK prototype (99.5% and 99.2%, respectively). Six nucleotide substitutions were highly conserved among isolates, ranging from 76.9% to 100%: C7401T, T7914C, C7920T, C7982T, G8231A, and A8367C. The presence of the Brazilian molecular signature of genotype taxA was confirmed in all of the isolates, and they clustered into two Latin American clusters, which confirms the double introduction of HTLV-1 in Brazil. PMID- 22449201 TI - Nail penetration and predicted mycological efficacy of an innovative hydrosoluble ciclopirox nail lacquer vs. a standard amorolfine lacquer in healthy subjects. AB - BACKGROUND: In a previous study a new hydrosoluble nail lacquer (P-3051) containing 8% ciclopirox (CPX) showed higher nail penetration compared to a water insoluble 5% amorolfine (MRF) lacquer. To our knowledge, in vivo human data on a similar topic are not available. OBJECTIVES: To compare fingernail penetration of P-3051 with that of MRF reference in humans and to evaluate their predicted efficacy against Trichophyton rubrum and Candida parapsilosis. METHODS: Single centre, randomized, multiple dose, open label, within subjects study. Test and reference were self-applied to all fingernails of either hand for 28 days. At baseline and after 15 and 25 days, the nail free edge was collected for analysis. Efficiency coefficients were calculated for T. rubrum and C. parapsilosis as ratios of nail concentration/minimum inhibitory concentration. The coefficients were classified as very high, high or poor. RESULTS: Nail concentrations after 15 days were 2.82 +/- 0.58 MUg/mg for CPX and 0.64 +/- 0.11 MUg/mg for MRF. At day 25 there was a non-significant decline (1.85 +/- 0.31 MUg/mg, P = 0.077) for CPX and a highly significant (0.13 +/- 0.03 MUg/mg, P = 0.0002) 80% decline for MRF. Efficiency coefficients were very high/high in all subjects treated with P-3051 against both T. rubrum and C. parapsilosis; they were significantly lower for MRF reference against both pathogens at both observation points. CONCLUSIONS: P-3051 exhibited better penetration and higher predicted efficacy after in vivo multiple application to human fingernails when compared to MRF reference. These in vivo data are in good agreement with our previous in vitro study. PMID- 22449202 TI - Cationic amphiphilic drugs cause a marked expansion of apparent lysosomal volume: implications for an intracellular distribution-based drug interaction. AB - How a drug distributes within highly compartmentalized mammalian cells can affect both the activity and pharmacokinetic behavior. Many commercially available drugs are considered to be lysosomotropic, meaning they are extensively sequestered in lysosomes by an ion trapping-type mechanism. Lysosomotropic drugs typically have a very large apparent volume of distribution and a prolonged half-life in vivo, despite minimal association with adipose tissue. In this report we tested the prediction that the accumulation of one drug (perpetrator) in lysosomes could influence the accumulation of a secondarily administered one (victim), resulting in an intracellular distribution-based drug interaction. To test this hypothesis cells were exposed to nine different hydrophobic amine-containing drugs, which included imipramine, chlorpromazine and amiodarone, at a 10 MUM concentration for 24 to 48 h. After exposure to the perpetrators the cellular accumulation of LysoTracker Red (LTR), a model lysosomotropic probe, was evaluated both quantitatively and microscopically. We found that all of the tested perpetrators caused a significant increase in the cellular accumulation of LTR. Exposure of cells to imipramine caused an increase in the cellular accumulation of other lysosomotropic probes and drugs including LyosTracker Green, daunorubicin, propranolol and methylamine; however, imipramine did not alter the cellular accumulation of non-lysosomotropic amine-containing molecules including MitoTracker Red and sulforhodamine 101. In studies using ionophores to abolish intracellular pH gradients we were able to resolve ion trapping-based cellular accumulation from residual pH-gradient independent accumulation. Results from these evaluations in conjunction with lysosomal pH measurements enabled us to estimate the relative aqueous volume of lysosomes of cells before and after imipramine treatment. Our results suggest that imipramine exposure caused a 4 fold expansion in the lysosomal volume, which provides the basis for the observed drug interaction. The imipramine-induced lysosomal volume expansion was shown to be both time- and temperature-dependent and reversed by exposing cells to hydroxypropyl-beta-cyclodextrin, which reduced lysosomal cholesterol burden. This suggests that the expansion of lysosomal volume occurs secondary to perpetrator induced elevations in lysosomal cholesterol content. In support of this claim, the cellular accumulation of LTR was shown to be higher in cells isolated from patients with Niemann-Pick type C disease, which are known to hyperaccumulate cholesterol in lysosomes. PMID- 22449203 TI - Small molecule screening platform for assessment of cardiovascular toxicity on adult zebrafish heart. AB - BACKGROUND: Cardiovascular toxicity is a major limiting factor in drug development and requires multiple cost-effective models to perform toxicological evaluation. Zebrafish is an excellent model for many developmental, toxicological and regenerative studies. Using approaches like morpholino knockdown and electrocardiogram, researchers have demonstrated physiological and functional similarities between zebrafish heart and human heart. The close resemblance of the genetic cascade governing heart development in zebrafish to that of humans has propelled the zebrafish system as a cost-effective model to conduct various genetic and pharmacological screens on developing embryos and larvae. The current report describes a methodology for rapid isolation of adult zebrafish heart, maintenance ex vivo, and a setup to perform quick small molecule throughput screening, including an in-house implemented analysis script. RESULTS: Adult zebrafish were anesthetized and after rapid decapitation the hearts were isolated. The short time required for isolation of hearts allows dissection of multiple fishes, thereby obtaining a large sample size. The simple protocol for ex vivo culture allowed maintaining the beating heart for several days. The in house developed script and spectral analyses allowed the readouts to be presented either in time domain or in frequency domain. Taken together, the current report offers an efficient platform for performing cardiac drug testing and pharmacological screens. CONCLUSION: The new methodology presents a fast, cost effective, sensitive and reliable method for performing small molecule screening. The variety of readouts that can be obtained along with the in-house developed analyses script offers a powerful setup for performing cardiac toxicity evaluation by researchers from both academics and industry. PMID- 22449204 TI - Pregnancy loss and thrombophilia: the elusive link. AB - Recurrent pregnancy loss (RPL) affects 1% pregnancies and is multi-factorial in origin. The role of the acquired thrombophilia antiphospholipid syndrome (APS) as a common and potentially treatable cause of RPL is well established but this is less so for inherited thrombophilia. In obstetric APS the combination of aspirin and heparin has improved outcomes. By analogy, the use of low molecular weight heparin (LMWH) has become commonplace in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the pregnancy. This review will examine the pathophysiological role of thrombophilia in pregnancy loss, and the evidence for anticoagulant-based intervention. The limited data supporting the use of heparin for women with RPL and inherited thrombophilia suggests adoption of a more cautious and judicious approach in this setting. PMID- 22449205 TI - Addressing poverty through disease control programmes: examples from Tuberculosis control in India. AB - INTRODUCTION: Tuberculosis remains a major public health problem in India with the country accounting for one-fifth or 21% of all tuberculosis cases reported globally. The purpose of the study was to obtain an understanding on pro-poor initiatives within the framework of tuberculosis control programme in India and to identify mechanisms to improve the uptake and access to TB services among the poor. METHODOLOGY: A national level workshop was held with participation from all relevant stakeholder groups. This study conducted during the stakeholder workshop adopted participatory research methods. The data was elicited through consultative and collegiate processes. The research study also factored information from primary and secondary sources that included literature review examining poverty headcount ratios and below poverty line population in the country; and quasi-profiling assessments to identify poor, backward and tribal districts as defined by the TB programme in India. RESULTS: Results revealed that current pro-poor initiatives in TB control included collaboration with private providers and engaging community to improve access among the poor to TB diagnostic and treatment services. The participants identified gaps in existing pro-poor strategies that related to implementation of advocacy, communication and social mobilisation; decentralisation of DOT; and incentives for the poor through the available schemes for public-private partnerships and provided key recommendations for action. Synergies between TB control programme and centrally sponsored social welfare schemes and state specific social welfare programmes aimed at benefitting the poor were unclear. CONCLUSION: Further in-depth analysis and systems/policy/operations research exploring pro-poor initiatives, in particular examining service delivery synergies between existing poverty alleviation schemes and TB control programme is essential. The understanding, reflection and knowledge of the key stakeholders during this participatory workshop provides recommendations for action, further planning and research on pro-poor TB centric interventions in the country. PMID- 22449206 TI - A catalytic asymmetric reaction involving enolizable anhydrides. AB - In the presence of a highly efficient novel bifunctional organocatalyst at low loadings under mild conditions, enolizable homophthalic anhydrides can be added to a range of aromatic and aliphatic aldehydes to give dihydroisocoumarins, with excellent yields and diastereo- and enantiocontrol (up to 99% ee). PMID- 22449208 TI - Could estrogen protect younger menopausal women from stroke? PMID- 22449207 TI - Structural features based genome-wide characterization and prediction of nucleosome organization. AB - BACKGROUND: Nucleosome distribution along chromatin dictates genomic DNA accessibility and thus profoundly influences gene expression. However, the underlying mechanism of nucleosome formation remains elusive. Here, taking a structural perspective, we systematically explored nucleosome formation potential of genomic sequences and the effect on chromatin organization and gene expression in S. cerevisiae. RESULTS: We analyzed twelve structural features related to flexibility, curvature and energy of DNA sequences. The results showed that some structural features such as DNA denaturation, DNA-bending stiffness, Stacking energy, Z-DNA, Propeller twist and free energy, were highly correlated with in vitro and in vivo nucleosome occupancy. Specifically, they can be classified into two classes, one positively and the other negatively correlated with nucleosome occupancy. These two kinds of structural features facilitated nucleosome binding in centromere regions and repressed nucleosome formation in the promoter regions of protein-coding genes to mediate transcriptional regulation. Based on these analyses, we integrated all twelve structural features in a model to predict more accurately nucleosome occupancy in vivo than the existing methods that mainly depend on sequence compositional features. Furthermore, we developed a novel approach, named DLaNe, that located nucleosomes by detecting peaks of structural profiles, and built a meta predictor to integrate information from different structural features. As a comparison, we also constructed a hidden Markov model (HMM) to locate nucleosomes based on the profiles of these structural features. The result showed that the meta DLaNe and HMM-based method performed better than the existing methods, demonstrating the power of these structural features in predicting nucleosome positions. CONCLUSIONS: Our analysis revealed that DNA structures significantly contribute to nucleosome organization and influence chromatin structure and gene expression regulation. The results indicated that our proposed methods are effective in predicting nucleosome occupancy and positions and that these structural features are highly predictive of nucleosome organization.The implementation of our DLaNe method based on structural features is available online. PMID- 22449210 TI - Glatiramer acetate for treatment of relapsing-remitting multiple sclerosis. AB - Glatiramer acetate (GA; Copaxone((r)), Teva Pharmaceuticals Inc.), approved in the USA in 1996 and EU in 2001 as first-line treatment for relapsing-remitting multiple sclerosis, is now available in 51 countries and recently gained approval for delaying conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes. Over the last 10-15 years, abundant research has better characterized the immunomodulatory activities and clinical efficacy and safety of GA. Relapsing-remitting multiple sclerosis patients taking GA continuously for up to 22 years as disease-modifying monotherapy experience minimal disability progression, and more than 1 million patient-years of experience attest to GA safety and tolerability. GA does not generate neutralizing antibodies, has no known drug interactions - making it a good candidate for combination therapy - and new formulations under evaluation may reduce injection frequency and injection-site reactions. The place of GA in the growing multiple sclerosis armamentarium will depend on its demonstrated benefit risk ratio relative to that of newer investigational drugs. PMID- 22449211 TI - Clobazam for patients with Lennox-Gastaut syndrome and epilepsy. AB - Lennox-Gastaut syndrome (LGS) is a form of childhood epileptic encephalopathy that continues to be challenging to treat and manage. The available treatments have failed to provide good control for patients with this devastating epilepsy syndrome. Clobazam is a promising antiepileptic medication, given its effectiveness and relatively low rates of adverse effects. It has been studied and used in several countries for the treatment of refractory seizures, including those that occur with LGS. Clobazam (OnfiTM; Lundbeck Inc., IL, USA) has been studied in the USA to demonstrate its efficacy and safety for the treatment of seizures associated with LGS, and Phase II and III trials have recently been completed. This article will explore the use of clobazam in the treatment of LGS and present the results of Phase II and III studies, along with an overall summary of the treatment of LGS, as well as the possible role of clobazam in a treatment algorithm. We based this article on the most relevant reports with the term 'clobazam' found through a Medline search (1966-2011). PMID- 22449212 TI - Does soy-based infant formula cause ADHD? Update and public policy considerations. AB - An earlier article hypothesized a relationship between soy-based infant formulas, manganese (Mn) neurotoxicity and symptoms of ADHD. In this update, more recent literature on ADHD, Mn and Mn neurotoxicity is reviewed, as well as the risks of Mn toxicity that may accompany ingestion of soy-based infant formula. The results of several critical studies are described, including rodent and primate models that demonstrate an association between ingestion of relatively high levels of Mn and: overactivity, disinhibition and inattention; stereotypes and disturbances of social relatedness; and alterations of dopamine D1 and D2 receptors and dopamine transporter in critical brain regions. Similar deficits have been shown in children with ADHD. In addition, ADHD-like symptoms of behavioral disinhibition were found to be correlated with Mn content in tooth enamel, apparently deposited at or before the fifth gestational month. The results are discussed in terms of their weight as a risk factor in ADHD, vis-a-vis compelling evidence of genetic, epigenetic and other environmental risk factors associated with the disorder, as well as the appropriateness of additional public policy decisions regarding the safety of soy formula. PMID- 22449214 TI - A novel treatment for glioblastoma: integrin inhibition. AB - Glioblastoma (GBM) is the most common malignant primary brain tumor, which despite combined modality treatment, recurs and is invariably fatal. New therapies for GBM represent an unmet need in neuro-oncology. This review provides an overview of the epidemiology and molecular biology of GBM and focuses, in particular, on integrins, which are heterodimeric transmembrane surface proteins that, when activated, signal through several GBM-relevant pathways, including proliferation, motility, cytoskeleton organization, survival and angiogenesis pathways. Consequently, the potential effects of anti-integrin strategies in anti GBM therapeutics are threefold: antiangiogenesis; anti-invasion; and anti-tumor. Trials of anti-integrins are most mature in GBM, and this review summarizes the completed and future trials of integrin inhibitors in the treatment of both newly diagnosed and recurrent GBM. PMID- 22449213 TI - Need for a paradigm shift in therapeutic approaches to CNS injury. AB - Irreversible damage to the nervous system can result from many causes including trauma, disruption of blood supply, pathogen infection or neurodegenerative disease. Common features following CNS injury include a disruption of axons, neuron death and injury, local B-cell and microglial activation, and the synthesis of pathogenic autoantibodies. CNS injury results in a pervasive inhibitory microenvironment that hinders regeneration. Current approaches to eliminate the inhibitory environment have met with limited success. These results argue for a paradigm shift in therapeutic approaches to CNS injury. Targeting CNS cells (neurons, oligodendrocytes and astrocytes) themselves may drive CNS repair. For example, our group and others have demonstrated that autoreactive antibodies can participate in aspects of CNS regeneration, including remyelination. We have developed recombinant autoreactive natural human IgM antibodies with the therapeutic potential for CNS repair in several neurologic diseases. PMID- 22449215 TI - The past, present and future of Gamma Knife radiosurgery for brain tumors: the Pittsburgh experience. AB - Since Lars Leksell conceived of the Gamma Knife in the mid-20th century, it has become a fundamental strategy for managing intracranial tumors. The Gamma Knife harnesses around 200 focused beams of ionizing radiation that are directed stereotactically onto an intracranial target, destroying or inactivating it, all while sparing surrounding tissues. Today, a patient can have numerous intracranial tumors treated by radiosurgery in a minimally invasive fashion, during a single outpatient encounter, and return to usual activities the next day. Gamma Knife radiosurgery has found applications for nearly all intracranial tumors, either as a primary strategy or adjunctive therapy. In no area has Gamma Knife radiosurgery had a larger impact than in the treatment of brain metastases. In this article, we review the evolution of Gamma Knife radiosurgery, discuss current indications for the treatment of intracranial tumors and highlight how the future treatment of metastatic brain cancer may change. PMID- 22449216 TI - Neurofeedback in children with ADHD: validation and challenges. AB - Neurofeedback (NF), a type of neurobehavioral training, has gained increasing attention in recent years, especially concerning the treatment of children with ADHD. Promising results have emerged from recent randomized controlled studies, and thus, NF is on its way to becoming a valuable addition to the multimodal treatment of ADHD. In this review, we summarize the randomized controlled trials in children with ADHD that have been published within the last 5 years and discuss issues such as the efficacy and specificity of effects, treatment fidelity and problems inherent in placebo-controlled trials of NF. Directions for future NF research are outlined, which should further address specificity and help to determine moderators and mediators to optimize and individualize NF training. Furthermore, we describe methodological (tomographic NF) and technical ('tele-NF') developments that may also contribute to further improvements in treatment outcome. PMID- 22449217 TI - Psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorders. AB - We conducted a comprehensive review of studies assessing the efficacy and tolerability of psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorder (encompassing autism disorder, Asperger's syndrome and pervasive developmental disorders not otherwise specified). PubMed, Ovid, EMBASE, Web of Science, ERIC and CINHAL were searched through 3 January 2012. From a pool of 348 potentially relevant references, 12 citations (11 studies) were retained as pertinent. Four of the included studies had a randomized controlled design. Most of the studies assessed methylphenidate immediate release. Despite inter study heterogeneity, taken together, the results of the selected reports suggest that psychostimulants may be effective for ADHD-like symptoms in autism spectrum disorder individuals. The most common adverse events reported in the included trials were appetite reduction, sleep-onset difficulties, irritability and emotional outbursts. We discuss future directions in the field, including the need for trials assessing more ecological outcomes and combined treatment strategies tailored to the specific individual features. PMID- 22449218 TI - ADHD: an integration with pediatric traumatic brain injury. AB - This review examines the long-standing finding that ADHD is a common sequela of pediatric traumatic brain injury (PTBI) in light of the current conceptualization of ADHD as a dimensional, neuropsychologically heterogeneous disorder. The review contends that this conceptualization established the basis for concluding that frequently occurring symptoms caused by PTBI, such as slow processing speed, emotional dysregulation and disinhibition, are indicative of ADHD. Consequently, it concludes that ADHD following PTBI is even more common than the 30% rate the current literature suggests. It provides recommendations for the assessment and treatment of ADHD associated with PTBI. PMID- 22449219 TI - Current therapies and future perspectives in subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis is a progressive neurological disorder of children and young adults caused by a measles virus that became defective by persisting in the host. According to the results of clinical trials, antiviral and/or immunomodulatory therapy can slow the progression of the disease and improve life expectancy in patients. However, its long-term effects and eventual outcome remain debatable due to conflicting results and its lack of effect on the rapidly progressive form of the disease. Possible future therapies for subacute sclerosing panencephalitis are RNAi and antiapoptotic agents, which are currently in the hypothetical and experimental stages of research. PMID- 22449222 TI - Dermoscopy guided scalp biopsy in cicatricial alopecia. AB - BACKGROUND: Scalp biopsies are crucial for the diagnosis of cicatricial alopecia. However, the pathologic interpretation may not be diagnostic if biopsy is not obtained from the correct site. This is particularly relevant for cicatricial alopecia as the disease may be focal and disease activity difficult to appreciate by the naked eye. OBJECTIVE: To report a new simple technique to select the optimal biopsy site in cicatricial alopecia. METHODS: In the last 2 years we performed dermoscopy guided scalp biopsies using handled dermatoscopes in 80 patients with different forms of cicatricial alopecia. Biopsy site was selected based on presence of the following dermatoscopic features: perifollicular concentric white scales in lichen planopilaris, frontal fibrosing alopecia (FFA) and discoid lupus erythematosus (DLE); hair tufts in folliculitis decalvans, hairs surrounded by a peripilar grey-white halo in central centrifugal cicatricial alopecia and follicular red dots or keratotic plugs in DLE. RESULTS: The dermoscopy guided biopsies yielded a definitive pathological diagnosis in 95% of the cases. COMMENT: The advantage of this method is that it is a fast, precise way to identify even individually affected follicles in early or focal cicatricial alopecia. It also allows for the morphologic characterization of particular follicular structures. PMID- 22449223 TI - Visualizing internal stabilization in weakly bound systems using atomic energies: hydrogen bonding in small water clusters. AB - Atomic energies are used to visualize the local stabilizing and destabilizing energy changes in water clusters. Small clusters, (H(2)O)(n), from n = 2-5, at MP2/aug-cc-pVTZ geometries are evaluated using energies defined by the quantum theory of atoms in molecules (QTAIM). The atomic energies reproduce MP2 total energies to within 0.005 kcal mol(-1). Oxygen atoms are stabilized for all systems and hydrogen atoms are destabilized. The increased stability of the water clusters due to hydrogen bond cooperativity is demonstrated at an atomic level. Variations in atomic energies within the clusters are correlated to the geometry of the waters and reveal variations in the hydrogen bond strengths. The method of visualization of the energy changes applied here is especially suited for application to large biomolecules. PMID- 22449224 TI - Effectiveness of conventional versus virtual reality based vestibular rehabilitation in the treatment of dizziness, gait and balance impairment in adults with unilateral peripheral vestibular loss: a randomised controlled trial. AB - BACKGROUND: Unilateral peripheral vestibular loss results in gait and balance impairment, dizziness and oscillopsia. Vestibular rehabilitation benefits patients but optimal treatment remains unknown. Virtual reality is an emerging tool in rehabilitation and provides opportunities to improve both outcomes and patient satisfaction with treatment. The Nintendo Wii Fit Plus(r) (NWFP) is a low cost virtual reality system that challenges balance and provides visual and auditory feedback. It may augment the motor learning that is required to improve balance and gait, but no trials to date have investigated efficacy. METHODS/DESIGN: In a single (assessor) blind, two centre randomised controlled superiority trial, 80 patients with unilateral peripheral vestibular loss will be randomised to either conventional or virtual reality based (NWFP) vestibular rehabilitation for 6 weeks. The primary outcome measure is gait speed (measured with three dimensional gait analysis). Secondary outcomes include computerised posturography, dynamic visual acuity, and validated questionnaires on dizziness, confidence and anxiety/depression. Outcome will be assessed post treatment (8 weeks) and at 6 months. DISCUSSION: Advances in the gaming industry have allowed mass production of highly sophisticated low cost virtual reality systems that incorporate technology previously not accessible to most therapists and patients. Importantly, they are not confined to rehabilitation departments, can be used at home and provide an accurate record of adherence to exercise. The benefits of providing augmented feedback, increasing intensity of exercise and accurately measuring adherence may improve conventional vestibular rehabilitation but efficacy must first be demonstrated. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT01442623. PMID- 22449225 TI - CD44 expression in plexiform lesions of idiopathic pulmonary arterial hypertension. AB - Plexiform lesions in pulmonary arteries are a characteristic histological feature for idiopathic pulmonary arterial hypertension (IPAH). The pathogenesis of the plexiform lesion is not fully understood, although it may be related to endothelial cell dysfunction and local inflammation. CD44 is a cell adhesion molecule and it is also involved in angiogenesis, endothelial cell proliferation and migration. The expression of CD44 was examined in lung plexiform lesions obtained from patients with IPAH (IPAH group, n= 7) and pulmonary arterial hypertension associated with atrial septal defect (ASD-PAH group, n= 4). Expression of CD44 was detected in 49 out of 52 plexiform lesions (93%) from all patients in the IPAH group, whereas 31 plexiform lesions obtained from the ASD PAH group lacked CD44 positivity by immunohistochemistry. In the IPAH group, CD44 was localized in the endothelial cells of microvessels within plexiform lesions and activated T cells in and around the lesions. Furthermore, T cell infiltration and endothelial cell proliferation activity were prominent in the plexiform lesions of the IPAH group, compared to those of the ASD-PAH group. These findings suggest that CD44 and activated T cell infiltration play an important role in the development of plexiform lesions particularly in IPAH. PMID- 22449226 TI - A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma. AB - An evaluation of epidermal growth factor receptor (EGFR) phenotypic expression in malignant pleural and peritoneal mesothelioma was undertaken, using immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Thirty-eight malignant mesothelioma (MM) specimens were subjected to IHC staining and FISH to evaluate the expression of EGFR protein and gene status. Overall positive IHC reaction was detected in 20/38 (53%) cases, in 11/22 (50%) pleural MM, and in 9/16 (56%) peritoneal MM. Our study confirmed that EGFR membranous expression is a common feature in MM, but not in benign mesothelial lesion. Thirty-seven cases did not show a gene copy number gain. Only one case showed a copy number gain. The protein overexpression of EGFR was not related to a gene copy number gain. PMID- 22449227 TI - Differences of molecular expression mechanisms among neural cell adhesion molecule 1, synaptophysin, and chromogranin A in lung cancer cells. AB - Neural cell adhesion molecule 1 (NCAM1), synaptophysin (SYPT), and chromogranin A (CGA) are immunohistochemical markers for diagnosing lung neuroendocrine tumors (LNETs). However, the precise expression mechanisms have not been studied in enough detail. The purpose of the present study is to define the molecular mechanisms of NCAM1, SYPT, and CGA gene expressions, using cultivated lung cancer cells and focusing upon NeuroD1 (ND1), achaete-scute homolog-like 1 (ASCL1), and known transcription factors, repressor element 1 (RE1)-silencing transcription factor (REST) and c-AMP responsive element-binding protein (CREB). Promoter assays, chromatin immunoprecipitation, and transfection experiments revealed that ND1 activated NCAM1, that ASCL1 weakly upregulated SYPT expression, and that CGA expression was not regulated by ND1 or ASCL1. REST expression was restricted in non-small cell lung cancer (NSCLC) cells, and knockdown of REST could cause as much SYPT expression as in SCLC cells and weak CGA expression in NSCLC cells. However, CGA gene upregulation via CREB activation was not found in REST-lacking NSCLC cells, indicating the requirement of some additional mechanism for sufficient expression. These results suggest that NCAM1, SYPT and CGA expressions are differently regulated by neuroendocrine phenotype-specific transcription factors and provide a reason why NCAM1 and SYPT are frequently expressed in LNETs, irrespective of malignancy grade. PMID- 22449228 TI - Transient expression of cellular retinol-binding protein-1 during cardiac repair after myocardial infarction. AB - Retinoic acid (RA) is a vitamin A derivative that exerts pleiotropic biological effects. Intracellular transport and metabolism of RA are regulated by cellular retinol-binding proteins (CRBP). CRBP-1 is transiently expressed in granulation tissue fibroblasts during wound healing; however, its role in cardiac remodeling remains unknown. A rat myocardial infarction (MI) model was established by ligation of the left coronary artery, and hearts were obtained at 3, 6, 15, 30 and 45 days after operation. Heart sections were examined immunohistochemically using anti-vimentin, anti-alpha-smooth muscle actin (alpha-SMA), anti-matrix metalloproteinase (MMP)-2, anti-MMP-9 and anti-CRBP-1 antibodies. Infarction involved 48.8 +/- 3.6% of the left ventricle and was followed by an important cardiac remodeling. Vimentin-positive fibroblastic cells including alpha-SMA positive myofibroblasts expressed CRBP-1 at 3-, 6-, and 15-days after MI. Expression of CRBP-1 reached a maximum at 6-days after infarction. Thereafter, CRBP-1 expression was dramatically decreased, showing a similar tendency to MMP expression. Human heart specimens of individuals with a recent myocardial infarction demonstrated presence of CRBP-1-positive fibroblasts by immunohistochemistry. We have demonstrated that CRBP-1 is transiently expressed by fibroblasts during cardiac remodeling. Our results suggest that CRBP-1 plays a role in ventricular remodeling after MI allegedly through its RA binding activity. PMID- 22449229 TI - Tubular and endothelial chimerism in renal allografts using fluorescence and chromogenic in situ hybridization (FISH, CISH) technology. AB - The role of endothelial and tubular chimerism in renal allograft adaptation and rejection varies in different studies. We addressed the correlation between different clinico-pathological settings and sex-chromosomal endothelial and/or tubular chimerism in renal allografts. We examined the presence or absence of the X and Y chromosomes by fluorescence and chromogenic in situ hybridization (FISH, CISH) methodology on paraffin embedded kidney biopsies in 16 gender mismatched renal transplants (1 to 12 years post-transplantation). Twelve patients were male, four female. Four groups were selected: (i) Vascular calcineurin inhibitor toxicity without rejection; (ii) T-cell mediated vascular rejection; (iii) antibody mediated rejection; and (iv) C4d-positivity in AB0-incompatible transplants with or without rejection. Twelve non-transplant kidney biopsies (8 female, 4 male) were used as controls. Tubular chimerism was detected more frequently (69%) than endothelial chimerism (12%) in renal transplants. One of 12 control patients had tubular and endothelial chimeric cells (8%). The Y chromosome occurred in 8/12 male recipients (67%) in tubular epithelial cells and in 5/12 male recipients (42%) in endothelial cells. Double X chromosomes were detected in 3/4 female recipients in tubular epithelium. Tubular chimerism occurred more often with endothelial chimerism and capillaritis without correlation with other parameters, such as rejection. Combined Y chromosomal tubular and lymphatic endothelial chimerism correlated with T-cell mediated vascular rejection in two out of three patients (66%). Combined Y chromosomal tubular and peritubular capillary chimerism correlated with antibody mediated C4d+ rejection in one out of two patients (50%). Tubular and/or endothelial chimerism occur frequently in gender mismatched renal allografts and, when combined, this is associated with T-cell mediated rejection. PMID- 22449230 TI - Primary cutaneous CD30 positive T-cell lymphoproliferative disorders with aberrant expression of PAX5: report of three cases. AB - Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs. PMID- 22449231 TI - Mullerian adenosarcoma with a neuroectodermal component associated with an endometriotic cyst of the ovary: a case report. AB - Reported here is a case of Mullerian adenosarcoma of the ovary which contained a primitive neuroectodermal tissue component within the stroma. The adenosarcoma coexisted with clear cell adenocarcinoma in an endometriotic cyst. The patient was a 33-year-old woman with a large unilocular endometriotic cyst of the right ovary. On the internal wall of the cyst, both a plaque-like protrusion with a papillary surface and a dome-like mural nodule were noted. The former exhibited features of Mullerian adenosarcoma, and the latter showed those of clear cell adenocarcinoma. In the deeper portion of adenosarcoma, teratoma-like tissue which contained various tissue components including primitive neuroectodermal tissue was found. The presence of primitive neuroectodermal tissue in the stroma of adenosarcoma suggested the diagnosis of 'adenosarcoma with neuroectodermal differentiation' ('teratoid adenosarcoma'), although the possibility of the incidental occurrence of an immature teratoma could not be completely excluded. PMID- 22449232 TI - Malignant transformation of ovarian mature cystic teratoma with a predominant pulmonary type small cell carcinoma component. AB - A 68-year-old woman was diagnosed with mature cystic teratoma of the left ovary when she was 44 years old. The tumor recently enlarged rapidly, and abdominal magnetic resonance imaging revealed an intrapelvic cystic lesion, which measured 123 * 120 * 107 mm and contained a mural nodule. Under a clinical diagnosis of malignant transformation of mature cystic teratoma, bilateral salpingo oophorectomy with total hysterectomy and omentectomy were performed. The resected specimen showed a unilocular cystic lesion containing a well-demarcated mural nodule measuring 35 * 30 * 25 mm in the left ovary. A microscopic examination revealed various types of carcinoma in the mural nodule: pulmonary type small cell carcinoma (65%), adenocarcinoma (25%), squamous cell carcinoma (5%), and transitional cell carcinoma (5%). Small cell carcinoma was positive for CD56, synaptophysin, and chromogranin A. The adenocarcinoma component showed intestinal phenotypes; i.e. cytokeratin (CK) 7(-), CK20(+), CDX2(+), estrogen receptor(-), and progesterone receptor (-). Interestingly, CDX2 positivity was retained in all of the carcinomas. It was assumed that the adenocarcinoma had arisen from an intestinal epithelium in the mature cystic teratoma and then differentiated into the diverse histological types mentioned above. PMID- 22449233 TI - IgG4-related sclerosing mesenteritis: a rare mesenteric disease of unknown etiology. AB - Sclerosing mesenteritis is a rare inflammatory and fibrosing disorder of unknown etiology, while IgG4-related disease (IgG4-RD) consists of mass-forming, fibroinflammatory lesions characterized by high serum IgG4 levels and tissue infiltration of many IgG4-positive plasma cells; obliterative phlebitis is common. This report describes a case of sclerosing mesenteritis that was considered a manifestation of IgG4-RD. A 53-year-old man underwent right hemicolectomy because of an ileocecal mass that did not improve with conservative therapy. The ill-defined fibroinflammatory lesion extended in the mesentery with storiform fibrosis, obliterative phlebitis, and infiltration of many IgG4 positive plasma cells. The ratio of IgG4-positive/IgG-positive cells was 64%, and the ratio of forkhead box protein 3 (FOXP3)-positive/CD4-positive cells was elevated (13%). It is likely that at least some cases of sclerosing mesenteritis are a manifestation of IgG4-RD. It is important to investigate this relationship because steroid therapy may benefit such cases. PMID- 22449234 TI - Expression of beta-tubulin isotypes in classical Hodgkin's lymphoma. AB - Microtubules consist of heterodimers of alpha- and beta-tubulin. Aberrant expression of specific beta-tubulin isotype is associated with resistance to chemotherapy in malignant tumors. In this study, we examined the expressions of beta-tubulin isotypes in classical Hodgkin's lymphoma (cHL) by immunohistochemistry. Among the beta-tubulin isotypes, class II beta-tubulin (31/34, 91%) was most frequently overexpressed in the cytoplasm of almost all Hodgkin's and Reed-Sternberg (HRS) cells, followed by class I beta-tubulin (18/34, 53%) and class III beta-tubulin (12/34, 35%). Class IV beta-tubulin was not expressed in any cHL case. Class I beta-tubulin was expressed in the background lymphoid cells as well as the HRS cells. Thus, our results indicate that class II beta-tubulin may be very useful for immunohistochemical diagnosis of cHL, and provide valuable information for the potential application of beta tubulin isotype-specific targeting. PMID- 22449235 TI - Extra-renal clear cell renal cell carcinoma probably arising from mesodermal embryonic remnants. PMID- 22449236 TI - Cationic Pd(II)-catalyzed highly enantioselective arylative cyclization of alkyne tethered enals or enones initiated by carbopalladation of alkynes with arylboronic acids. AB - Cationic Pd(II)-catalyzed enantioselective arylative cyclization of alkyne tethered enals or enones initiated by carbopalladation of alkynes was developed without the necessity of a redox system. PMID- 22449237 TI - Understanding determinants of socioeconomic inequality in mental health in Iran's capital, Tehran: a concentration index decomposition approach. AB - BACKGROUND: Mental health is of special importance regarding socioeconomic inequalities in health. On the one hand, mental health status mediates the relationship between economic inequality and health; on the other hand, mental health as an "end state" is affected by social factors and socioeconomic inequality. In spite of this, in examining socioeconomic inequalities in health, mental health has attracted less attention than physical health. As a first attempt in Iran, the objectives of this paper were to measure socioeconomic inequality in mental health, and then to untangle and quantify the contributions of potential determinants of mental health to the measured socioeconomic inequality. METHODS: In a cross-sectional observational study, mental health data were taken from an Urban Health Equity Assessment and Response Tool (Urban HEART) survey, conducted on 22 300 Tehran households in 2007 and covering people aged 15 and above. Principal component analysis was used to measure the economic status of households. As a measure of socioeconomic inequality, a concentration index of mental health was applied and decomposed into its determinants. RESULTS: The overall concentration index of mental health in Tehran was -0.0673 (95% CI = 0.070 - -0.057). Decomposition of the concentration index revealed that economic status made the largest contribution (44.7%) to socioeconomic inequality in mental health. Educational status (13.4%), age group (13.1%), district of residence (12.5%) and employment status (6.5%) also proved further important contributors to the inequality. CONCLUSIONS: Socioeconomic inequalities exist in mental health status in Iran's capital, Tehran. Since the root of this avoidable inequality is in sectors outside the health system, a holistic mental health policy approach which includes social and economic determinants should be adopted to redress the inequitable distribution of mental health. PMID- 22449238 TI - The effect of mouse strain on herpes simplex virus type 1 (HSV-1) infection of the central nervous system (CNS). AB - BACKGROUND: Mice infected with HSV-1 can develop lethal encephalitis or virus induced CNS demyelination. Multiple factors affect outcome including route of infection, virus and mouse strain. When infected with a sub-lethal dose of HSV-1 strain 2 via the oral mucosa, susceptible SJL/J, A/J, and PL/J mice develop demyelinating lesions throughout the brain. In contrast, lesions are restricted to the brainstem (BST) in moderately resistant BALB/c mice and are absent in resistant BL/6 mice. The reasons for the strain differences are unknown. METHODS: In this study, we combine histology, immunohistochemistry, and in-situ hybridization to investigate the relationship between virus and the development of lesions during the early stage (< 24 days PI) of demyelination in different strains of mice. RESULTS: Initially, viral DNA and antigen positive cells appear sequentially in non-contiguous areas throughout the brains of BALB/c, SJL/J, A/J, and PL/J mice but are restricted to an area of the BST of BL/6 mice. In SJL/J, A/J, and PL/J mice, this is followed by the development of 'focal' areas of virus infected neuronal and non-neuronal cells throughout the brain. The 'focal' areas follow a hierarchical order and co-localize with developing demyelinating lesions. When antigen is cleared, viral DNA positive cells can remain in areas of demyelination; consistent with a latent infection. In contrast, 'focal' areas are restricted to the BST of BALB/c mice and do not occur in BL/6 mice. CONCLUSIONS: The results of this study indicate that susceptible mouse strains, infected with HSV-1 via the oral mucosa, develop CNS demyelination during the first 24 days PI in several stages. These include: the initial spread of virus and infection of cells in non-contiguous areas throughout the brain, the development of 'focal' areas of virus infected neuronal and non-neuronal cells, the co-localization of 'focal' areas with developing demyelinating lesions, and latent infection in a number of the lesions. In contrast, the limited demyelination that develops in BALB/c and the lack of demyelination in BL/6 mice correlates with the limited or lack of 'focal' areas of virus infected neuronal and non-neuronal cells in these two strains. PMID- 22449239 TI - The Bone Dysplasia Ontology: integrating genotype and phenotype information in the skeletal dysplasia domain. AB - BACKGROUND: Skeletal dysplasias are a rare and heterogeneous group of genetic disorders affecting skeletal development. Patients with skeletal dysplasias suffer from many complex medical issues including degenerative joint disease and neurological complications. Because the data and expertise associated with this field is both sparse and disparate, significant benefits will potentially accrue from the availability of an ontology that provides a shared conceptualisation of the domain knowledge and enables data integration, cross-referencing and advanced reasoning across the relevant but distributed data sources. RESULTS: We introduce the design considerations and implementation details of the Bone Dysplasia Ontology. We also describe the different components of the ontology, including a comprehensive and formal representation of the skeletal dysplasia domain as well as the related genotypes and phenotypes. We then briefly describe SKELETOME, a community-driven knowledge curation platform that is underpinned by the Bone Dysplasia Ontology. SKELETOME enables domain experts to use, refine and extend and apply the ontology without any prior ontology engineering experience--to advance the body of knowledge in the skeletal dysplasia field. CONCLUSIONS: The Bone Dysplasia Ontology represents the most comprehensive structured knowledge source for the skeletal dysplasias domain. It provides the means for integrating and annotating clinical and research data, not only at the generic domain knowledge level, but also at the level of individual patient case studies. It enables links between individual cases and publicly available genotype and phenotype resources based on a community-driven curation process that ensures a shared conceptualisation of the domain knowledge and its continuous incremental evolution. PMID- 22449240 TI - The first Caucasian patient with p.Val122Ile mutated-transthyretin cardiac amyloidosis treated with isolated heart transplantation. AB - Effective treatments for mutated transthyretin (TTR)-related cardiac amyloidosis are limited. Heart transplantation or combined liver-heart transplantation are the most successful options, although results rely on underline mechanism and systemic nature of the disease. In this report, we present the first case of a Caucasian patient with the p.Val122Ile mutated TTR-related cardiac amyloidosis treated with heart transplantation due to this gene mutation frequent in Afro Americans with a prevalent isolated heart involvement. The choice of isolated heart transplantation instead of combined heart and liver transplantations was based on (1) severe and progressive cardiac disease, (2) evidence of a gene mutation generally associated with isolated cardiac disease and (3) absence of relevant extra-cardiac involvement (with the possible exception of mild peripheral neuropathy). In any case, the very short post-transplant observation period of 10 months does not allow any conclusions on the long-term course of the presented strategy. Finally, it is the first European Caucasian family with the p.Val122Ile TTR mutation that has been described. Till now, very few Caucasian cases of p.Val122Ile mutated TTR-related cardiac amyloidosis have been reported. The patient and some members of his family also had mild peripheral neuropathy suggesting a regional phenotypic heterogeneity of European Caucasian TTR p.Val122Ile. PMID- 22449241 TI - Antibacterial activity of wine phenolic compounds and oenological extracts against potential respiratory pathogens. AB - AIMS: To investigate the effect of seven wine phenolic compounds and six oenological phenolic extracts on the growth of pathogenic bacteria associated with respiratory diseases (Pseudomonas aeruginosa, Staphylococcus aureus, Moraxella catarrhalis, Enterococcus faecalis, Streptococcus sp Group F, Streptococcus agalactiae and Streptococcus pneumoniae). METHODS AND RESULTS: Antimicrobial activity was determined using a microdilution method and quantified as IC(50) . Mor. catarrhalis was the most susceptible specie to phenolic compounds and extracts. Gallic acid and ethyl gallate were the compounds that showed the greatest antimicrobial activity. Regarding phenolic extracts, GSE (grape seed extract) and GSE-O (oligomeric-rich fraction from GSE) were the ones that displayed the strongest antimicrobial effects. CONCLUSIONS: Results highlight the antimicrobial properties of wine phenolic compounds and oenological extracts against potential respiratory pathogens. The antimicrobial activity of wine phenolic compounds was influenced by the type of phenolic compounds. Gram negative bacteria were more susceptible than Gram-positive bacteria to the action of phenolic compounds and extracts; however, the effect was species-dependent. SIGNIFICANCE AND IMPACT OF STUDY: The ability to inhibit the growth of respiratory pathogenic bacteria as shown by several wine phenolic compounds and oenological extracts warrants further investigations to explore the use of grape and wine preparations in oral hygiene. PMID- 22449242 TI - Cortisol suppression and hearing thresholds in tinnitus after low-dose dexamethasone challenge. AB - BACKGROUND: Tinnitus is a frequent, debilitating hearing disorder associated with severe emotional and psychological suffering. Although a link between stress and tinnitus has been widely recognized, the empirical evidence is scant. Our aims were to test for dysregulation of the stress-related hypothalamus-pituitary adrenal (HPA) axis in tinnitus and to examine ear sensitivity variations with cortisol manipulation. METHODS: Twenty-one tinnitus participants and 21 controls comparable in age, education, and overall health status but without tinnitus underwent basal cortisol assessments on three non-consecutive days and took 0.5 mg of dexamethasone (DEX) at 23:00 on the first day. Cortisol levels were measured hourly the next morning. Detection and discomfort hearing thresholds were measured before and after dexamethasone suppression test. RESULTS: Both groups displayed similar basal cortisol levels, but tinnitus participants showed stronger and longer-lasting cortisol suppression after DEX administration. Suppression was unrelated to hearing loss. Discomfort threshold was lower after cortisol suppression in tinnitus ears. CONCLUSIONS: Our findings suggest heightened glucocorticoid sensitivity in tinnitus in terms of an abnormally strong glucocorticoid receptor (GR)-mediated HPA-axis feedback (despite a normal mineralocorticoid receptor (MR)-mediated tone) and lower tolerance for sound loudness with suppressed cortisol levels. Long-term stress exposure and its deleterious effects therefore constitute an important predisposing factor for, or a significant pathological consequence of, this debilitating hearing disorder. PMID- 22449243 TI - Dynamic nanoparticle assemblies. AB - Although nanoparticle (NP) assemblies are at the beginning of their development, their unique geometrical shapes and media-responsive optical, electronic, and magnetic properties have attracted significant interest. Nanoscale assembly bridges multiple levels of hierarchy of materials: individual nanoparticles, discrete molecule-like or virus-like nanoscale agglomerates, microscale devices, and macroscale materials. The capacity to self-assemble can greatly facilitate the integration of nanotechnology with other technologies and, in particular, with microscale fabrication. In this Account, we describe developments in the emerging field of dynamic NP assemblies, which are spontaneously form superstructures containing more than two inorganic nanoscale particles that display the ability to change their geometrical, physical, chemical, and other attributes. In many ways, dynamic assemblies can represent a bottleneck in the "bottom-up" fabrication of NP-based devices because they can produce a much greater variety of assemblies, but they also provide a convenient tool for variation of geometries and dimensions of nanoparticle assemblies. Superstructures of NPs (and those held together by similar intrinsic forces)are classified into two groups: Class 1 where media and external fields can alter shape, conformation, and order of stable super structures with a nearly constant number of NPs or Class 2 where the total number of NPs changes, while the organizational motif in the final superstructure remains the same. The future development of successful dynamic assemblies requires understanding the equilibrium in dynamic NP systems. The dynamic nature of Class 1 assemblies is associated with the equilibrium between different conformations of a superstructure and is comparable to the isomerization in classical chemistry. Class 2 assemblies involve the formation or breakage of linkages between the NPs, which is analogous to the classical chemical equilibrium for the formation of a molecule from atoms. Finer classification of NP assemblies in accord with established conventions in the field may include different size dimensionalities: discrete assemblies (artificial molecules) and one-dimensional (spaced chains), two-dimensional (sheets), and three-dimensional (superlattices, twisted structures) assemblies. Notably, these dimensional attributes must be regarded as primarily topological in nature because all of these superstructures can acquire complex three-dimensional shapes. We discuss three primary strategies used to prepare NP superstructures: (1) anisotropy-based assemblies utilizing either intrinsic force field anisotropy around NPs or external anisotropy associated with templates or applied fields, (2) assembly methods utilizing uniform NPs with isotropic interactions, and (3) methods based on mutual recognition of biomolecules, such as DNA and antigen-antibody interactions. We consider optical, electronic, and magnetic properties of dynamic superstructures, focusing primarily on multiparticle effects in NP superstructures as represented by surface plasmon resonance, NP-NP charge transport, and multibody magnetization. Unique properties of NP superstructures are being applied to biosensing, drug delivery, and nanoelectronics. For both Class 1 and Class 2 dynamic assemblies, biosensing is the most dominant and well-developed area of dynamic nanostructures being successfully transitioned into practice. We can foresee the rapid development of dynamic NP assemblies toward applications in harvesting of dissipated energy, photonics, and electronics. The final part of this Account is devoted to the fundamental questions facing dynamic assemblies of NPs in the future. PMID- 22449244 TI - Infrared spectra at a conical intersection: vibrations of methoxy. AB - The J = 0 infrared spectrum of methoxy is theoretically calculated for the ground X(2)E state using a quartic potential energy force field, and the quadratic dipole moment expansion is calculated ab initio at the CCSD(T) level of theory and cc-pVTZ basis. Writing these expansions with vibronic operators whose symmetry properties are defined with respect to C(3v) rotation greatly simplifies these calculations. With minor adjustments to the force field, excellent agreement with experiment is found for both the transition energies of CH(3)O and those of CD(3)O. The role of Jahn-Teller and Fermi coupling is illustrated by scaling these terms by a parameter delta that varies from 0 to 1. Plotting the eigenvalues as a function of delta yields a correlation diagram connecting the harmonic eigenvalues to those of the fully coupled problem. The spectrum for CH(3)O is determined using a combination of Davidson and Lanczos iteration schemes. The spectral features are found to be dominated by Jahn-Teller effects, but direct Fermi coupling and indirect potential couplings have important roles. The origin of the complexities in the CH stretch region are discussed. PMID- 22449245 TI - MEF2C mutations are a rare cause of Rett or severe Rett-like encephalopathies. PMID- 22449246 TI - Health impact and toxicological effects of nanomaterials in the lung. AB - The manufacture, use and disposal of nanomaterials will result in increased human exposures to engineered nanoparticles (ENPs), potentially via the lung. ENPs differ physically and chemically from natural- or combustion-derived nanoparticles (NP) in important respects. While there are parallels with ultrafine aerosol particles in the atmosphere and colloids in water, there remain some unique issues and impacts of engineered materials on lung health that require consideration and urgent study. The study of toxicity of nanomaterials in biological systems--nanotoxicology--emerged from the observed effects of inhaled particulate matter (PM) and NP. Some engineered nanomaterials deserve special toxicological examination because of their unique properties in biological systems; novel toxicological approaches may be required for their assessment. Translocation in biological systems--a key feature of ENPs--is dependent on ENP size and surface interactions with macromolecules at the portal of entry, upstream of cellular interaction. Of particular significance is the agglomeration processes associated with macromolecule adsorption at ENP surfaces, which determine clearance rates and cellular response. ENP toxicity is therefore dominated by three linked physico-chemical factors: size-shape, surface and 'corona' (formed by adhering macromolecules from the suscipient host). Measuring and predicting ENP translocation and effects following lung entry have proven to be particularly challenging, but understanding ENP behaviour in vivo is fundamental for safe design for effective and targeted drug delivery. Human exposures via medical and dental applications appear important in terms of dose and toxicity, and may need to be assessed for risk on a case-by-case basis. PMID- 22449247 TI - Vitamin D receptor ligands: the impact of crystal structures. AB - INTRODUCTION: In the past years, the biologically active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), has received large appreciation due to the broad physiological impact of the hormone and its nuclear receptor, the transcription factor vitamin D receptor (VDR). Recently, the understanding of VDR actions has progressed greatly, due to VDR crystal structures with various ligands. AREAS COVERED: This review will present and discuss new synthetic agonistic and antagonistic 1alpha,25(OH)(2)D(3) analogs in the context of the recent insights provided by VDR crystal structures. EXPERT OPINION: During the last 5 years, a large number of new 1alpha,25(OH)(2)D(3) analogs, many of which have an interesting functional profile, have been patented. Moreover, for a surprisingly high number of 1alpha,25(OH)(2)D(3) analogs, the crystal structure data of their complex with the VDR is available. This structural information provides important insight into the functional potential of the VDR ligands and explains their agonistic and antagonistic action. However, so far, only for a few VDR ligands, a rational design, based on crystal structure information, has been applied. The design of future analogs may also take the specificity of co-factor interaction into account, in order to create selective VDR modulators. PMID- 22449248 TI - A practical preparation of highly versatile N-acylpyrroles from 2,4,4 trimethoxybutan-1-amine. AB - A novel method for the preparation of N-acylpyrrole is described. The method involves condensation of carboxylic acids with 2,4,4-trimethoxybutan-1-amine, followed by acid-mediated cyclization to form the pyrrole ring. The preparative procedure is highly tolerant of a variety of functional groups. PMID- 22449249 TI - Sensitivity pattern among bacterial isolates in neonatal septicaemia in port Harcourt. AB - BACKGROUND: The organisms responsible for neonatal sepsis vary across geographical boundaries and with the time of illness thus periodic bacteriologic surveillance is a neccessity. The present study was therefore carried out to determine the common bacterial pathogens in Port Harcourt and their sensitivity pattern. METHODS: Four hundred and six neonates were prospectively screened for sepsis over a 6 month period. Sensitivity of the bacterial isolates to different antibiotics was determined using Kirby-Bauer diffusion method. RESULTS: Gram negative organisms predominated (75.1%) with Klebsiella pneumonia (58.2%) being the commonest. The quinolones were the most sensitive antibiotics to the commonly isolated organisms. CONCLUSION: Klebsiella pneumonia is the commonest organism responsible for neonatal sepsis in Port Harcourt. There is an overall decline in the antibiotic susceptibility to the commonly isolated bacterial pathogens. PMID- 22449250 TI - Correction: Co-culture of Retinal and Endothelial Cells Results in the Modulation of Genes Critical to Retinal Neovascularization. PMID- 22449251 TI - Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B. AB - BACKGROUND: Combination antiviral therapy holds the promise of increasing response rates while decreasing antiviral resistance, but has yet to be shown to be beneficial or necessary in chronic hepatitis B. AIM: To evaluate the benefit of combination therapy with adefovir and lamivudine versus adefovir alone in maintaining virological, biochemical and histological responses. METHODS: Patients with chronic hepatitis B with and without previous lamivudine therapy were randomised to receive adefovir alone (10 mg/daily) or adefovir and lamivudine (100 mg/daily) for up to 192 weeks. Study endpoints were (i) maintained virological (HBV DNA <500 copies/mL), biochemical and histological response, (ii) loss of HBeAg and (iii) loss of HBsAg. RESULTS: A total of 41 patients were enrolled, including 31 HBeAg -positive and 31 treatment-naive subjects. 30 patients remained on assigned therapy at 192 weeks. The percentage of patients achieving a combined maintained response was higher in the combination than the monotherapy arm, both at week 48 (59% vs. 26%, P = 0.06) and 192 (68% vs. 31%, P = 0.03). At week 192, 76% of the combination vs. 36% of the monotherapy group had loss of HBeAg (P = 0.03). One patient receiving adefovir cleared HBsAg. Adefovir resistance developed in 6 of 19 (32%) monotherapy but none of 22 combination treated patients (P = 0.03). CONCLUSIONS: Extended combination therapy with lamivudine and adefovir is associated with a high rate of long-term virological and biochemical response. Adefovir monotherapy appears to be less effective mainly because of poor initial response and the ultimate development of antiviral resistance (www.Clinical. Trials.gov NCT00023309). PMID- 22449252 TI - Catalytic stereoselective synthesis of diverse oxindoles and spirooxindoles from isatins. AB - A strategy for the efficient two-step synthesis of triazole derivatives of oxindoles and spirooxindoles is presented. Using a common set of N-propargylated isatins, a series of mechanistically distinct stereoselective reactions with different combinations of nucleophiles and catalysts provide access to diverse hydroxy-oxindoles, spiroindolones, and spirocyclic oxazoline structures. The resulting N-propargylated oxindoles are then converted to triazoles using copper catalyzed azide-alkyne cycloaddition (CuAAC) reactions. Overall, this strategy affords a 64-member pilot-scale library of diverse oxindoles and spirooxindoles. PMID- 22449253 TI - Early increase in marker of neuronal integrity with antidepressant treatment of major depression: 1H-magnetic resonance spectroscopy of N-acetyl-aspartate. AB - Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time-course of any effect on neuronal integrity is unclear. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on N-acetyl-aspartate (NAA), a marker of neuronal integrity. Thirty-nine participants with major depression were randomly assigned to receive either 10 mg escitalopram or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30*30*20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were significantly higher in patients treated with escitalopram than in either placebo-treated patients (p<0.01) or healthy controls (p<0.01). Our findings are consistent with the proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity. PMID- 22449254 TI - Vitamin D deficiency and changes in serum vitamin D levels with treatment among tuberculosis patients in South Korea. AB - BACKGROUND AND OBJECTIVE: Vitamin D deficiency has been reported to be associated with the development of active tuberculosis (TB), but many discrepancies exist among studies. The aims of this study were to compare the frequency of vitamin D deficiency in a Korean population of TB patients and control subjects, and to monitor the changes in vitamin D levels during TB treatment. METHODS: Patients with newly diagnosed TB were prospectively enrolled. In addition, healthy volunteers or patients with diseases other than TB were enrolled as controls. Baseline serum 25-hydroxyvitamin D (25-OHD) levels were measured in both groups and compared. In the TB patients, measurements of serum 25-OHD were repeated 1 month after the initiation of treatment and again after completion of treatment. RESULTS: In total, 116 patients with TB and 86 control subjects were recruited. The median 25-OHD concentration was not different in TB patients at diagnosis (13.9 ng/mL; interquartile range (IQR) 8.80-21.8) compared with control subjects (13.2 ng/mL; IQR 9.6-19.3) (P = 0.97). The frequency of vitamin D deficiency (<= 10 ng/mL) was also not different in TB patients (36.2%) compared with controls (27.3%) (P = 0.21). In TB patients, the median 25-OHD concentration decreased significantly during treatment, to 12.5 ng/mL at 1 month and 11.0 ng/mL on completion of treatment (P = 0.01). CONCLUSIONS: Vitamin D levels do not appear to be associated with the development of TB in the Korean population. The median 25-OHD concentration decreased after treatment for TB. PMID- 22449255 TI - DNp73 improves generation efficiency of human induced pluripotent stem cells. AB - BACKGROUND: Recent studies have found that p53 and its' associated cell cycle pathways are major inhibitors of human induced pluripotent stem (iPS) cell generation. In the same family as p53 is p73, which shares sequence similarities with p53. However, p73 also has distinct properties of its own, such as two alternative promoters to express transactivation of p73 (TAp73) and N terminal deleted p73 (DNp73). Functionally, TAp73 acts similarly to p53 in tumor suppression. However, DNp73, on the other hand acts as an oncogene to suppress p53 and p73 induced apoptosis. Therefore, how can p73 have opposing roles in human iPS cell generation? RESULTS: Transcription factors, Oct4, Sox2, Klf4 and cMyc (4TF, Yamanaka factors) are used as basal conditions to generate iPS cells. In addition, the factor of DNp73(actually alpha splicing DNp73, DNp73alpha) is used to generate iPS cells. The experiment found that the addition of DNp73 gene increases human iPS cell generation efficiency by 12.6 folds in comparison to human fibroblast cells transduced with only the basal conditions. Also, iPS cells generated with DNp73 expression are more resistant to in vitro and in vivo differentiation. CONCLUSIONS: This study found DNp73, a family member of p53, is also involved in the human iPS cell generation. Specifically, that the involvement of DNp73 generates iPS cells that are more resistant to in vitro and in vivo differentiation. Therefore, this data may prove to be useful in future developmental studies and cancer researches. PMID- 22449256 TI - Ruthenium(0)-catalyzed sp3 C-H bond arylation of benzylic amines using arylboronates. AB - A Ru-catalyzed direct arylation of benzylic sp(3) carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient transformation can be performed with various combinations of N-(2-pyridyl) substituted benzylamines and arylboronates. Substitution of the pyridine directing group in the 3-position proved to be crucial in order to achieve high arylation yields. Furthermore, the pyridine directing group can be removed in high yields via a two-step protocol. PMID- 22449257 TI - The alterations of inducible nitric oxide synthase in the mouse brainstem during herpes simplex virus type 1-induced facial palsy. AB - OBJECTIVE: We sought to study the alterations of inducible nitric oxide synthase (iNOS) in the mouse brainstem during facial paralysis induced by herpes simplex virus type 1 (HSV-1) and the inhibitory effects of glucocorticoids. METHODS: HSV 1 was inoculated into the surface of posterior auricle of mouse to set up an animal model. The paralyzed mice were divided in three groups as detailed in text. Mice, in one group, were killed at different time points and, in other two groups, were injected daily for 2 days with methylprednisolone sodium succinate (MPSS) or with combined administration of MPSS and glucocorticoid receptor blocker (RU486). Morphological changes were evaluated by means of hematoxylin and eosin (H&E) staining and improved trichrome staining. The expression and location of iNOS in the facial nucleus of brainstem was detected by reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. RESULTS: After inoculated by HSV-1, 49.09% of mice developed unilateral facial paralysis. Injuries in response to HSV-1 infection in the facial nerves and facial nucleus of paralyzed mice were observed by morphological methods. Besides, we found that iNOS was present in normal glial cells and motor neurons at low levels and was upregulated dramatically after facial paralysis, which could be inhibited by MPSS. RU486, a glucocorticoid receptor inhibitor, could block the inhibitory effects of MPSS. DISCUSSION: The present study demonstrates that the enhanced activity of iNOS in the early phase represents an important mechanism in HSV-1-induced facial paralysis. MPSS can effectively attenuate HSV-1-mediated damages in nerve system, which is closely associated to its inhibitory effect on expression of iNOS. PMID- 22449258 TI - Inkjet-printed graphene electronics. AB - We demonstrate inkjet printing as a viable method for large-area fabrication of graphene devices. We produce a graphene-based ink by liquid phase exfoliation of graphite in N-methylpyrrolidone. We use it to print thin-film transistors, with mobilities up to ~95 cm(2) V(-1) s(-1), as well as transparent and conductive patterns, with ~80% transmittance and ~30 kOmega/? sheet resistance. This paves the way to all-printed, flexible, and transparent graphene devices on arbitrary substrates. PMID- 22449259 TI - Genetic variants of p27 and p21 as predictors for risk of second primary malignancy in patients with index squamous cell carcinoma of head and neck. AB - BACKGROUND: Cell cycle deregulation is common in human cancer, and alterations of p27 and p21, two critical cell cycle regulators, have been implicated in the development of many human malignancies. Therefore, we hypothesize that p27 T109G polymorphism individually or in combination with p21 (C98A and C70T) polymorphisms modifies risk of second primary malignancy (SPM) in patients with index squamous cell carcinoma of head and neck (SCCHN). METHODS: A cohort of 1,292 patients with index SCCHN was recruited between May 1995 and January 2007 at the M.D. Anderson Cancer Center and followed for SPM occurrence. Patients were genotyped for the three polymorphisms. A log-rank test and Cox proportional hazards models were used to compare SPM-free survival and SPM risk. RESULTS: We found that patients with p27 109 TG/GG, p21 98 CA/AA and p21 70 CT/TT variant genotypes had a worse SPM-free survival and an increased SPM risk than those with the corresponding p27109 TT, p21 98 CC, and p21 70 CC common genotypes, respectively. After combining the three polymorphisms, there was a trend for significantly increased SPM risk with increasing number of the variant genotypes (Ptrend = 0.0002). Moreover, patients with the variant genotypes had an approximately 2.4-fold significantly increased risk for SPM compared with those with no variant genotypes (HR, 2.4, 95% CI, 1.6-3.6). CONCLUSIONS: These results suggest that p27 T109G polymorphism individually or in combination with p21 (C98A and C70T) polymorphisms increases risk of SPM in patients with index SCCHN. PMID- 22449260 TI - Targeting RhoA/ROCK pathway in pulmonary arterial hypertension. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis. It is often associated with an increased vascular resistance, whilst in the more advanced stages there is a remodelling of the vascular walls. PAH has an intricate involvement of various signaling pathways, including the ras homolog family member A (RhoA)-Rho kinase (ROCK) axis. Currently, available therapies are not always able to significantly slow PAH progression. Therefore, newer approaches are needed. AREAS COVERED: In this review, areas covered include the role of the RhoA/ROCK in PAH pathogenesis and the plausibility of its therapeutic targeting. Furthermore, various inhibitory compounds are discussed, including Fasudil and SB-772077-B. EXPERT OPINION: Currently, specific RhoA/ROCK inhibition is the most promising therapeutic approach for PAH. Research has shown that it suppresses both the components of this axis and the upstream upregulating mediators. An inhaled RhoA/ROCK inhibitor may be a successful future therapy; however, further clinical trials are needed to support this approach. PMID- 22449261 TI - Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices. AB - BACKGROUND: In patients with oesophageal varices, the combination of endoscopic variceal ligation (EVL) and medical therapy is recommended as standard of care for prevention of rebleeding. The results of previous meta-analyses on this topic are equivocal. AIM: To assess the effects of EVL plus medical therapy vs. monotherapy (EVL or medical therapy alone) for secondary prevention in oesophageal varices. METHODS: Electronic and manual searches were combined. The primary outcome measures were overall rebleeding (variceal and nonvariceal) and mortality. Random-effects meta-analyses were performed with subgroup, sensitivity, regression and sequential analyses to identify sources of intertrial heterogeneity and the robustness of the results. RESULTS: Nine randomised trials were included. In total, 442 patients were randomised to combination therapy and 513 to monotherapy. Combination therapy reduced rebleeding (RR = 0.68; 95% CI = 0.54-0.85; number needed to treat eight patients). The result was confirmed in sequential and regression analyses, but not when limiting the analysis to trials with adequate selection bias control. No effect on overall mortality was identified (RR = 0.89; 95% CI = 0.65-1.21). Combination therapy reduced bleeding related mortality (RR = 0.52; 95% CI 0.27-0.99; number needed to treat 33 patients) and the risk of rebleeding from oesophageal varices. Combination therapy increased the risk of serious adverse events in fixed, but not in random effects meta-analyses. CONCLUSIONS: The combination of endoscopic variceal ligation and medical therapy reduce the risk of rebleeding, but not overall mortality. Additional research is needed to determine why reduced rebleeding rates do not lead to reduced mortality. PMID- 22449262 TI - Cannabinoids, working memory, and schizophrenia. PMID- 22449263 TI - Orbitofrontal cortex and neuromaturation: a gateway to risk? PMID- 22449264 TI - Herd-level risk factors associated with Leptospira Hardjo seroprevalence in Beef/Suckler herds in the Republic of Ireland. AB - BACKGROUND: The aim of the present study was to investigate risk factors for herd seropositivity to Leptospira Hardjo in Irish suckler herds. Herds were considered eligible for the study if they were unvaccinated and contained >= 9 breeding animals of beef breed which were >= 12 months of age. The country was divided into six regions using county boundaries. Herd and individual animal prevalence data were available from the results of a concurrent seroprevalence study. Herds were classified as either "Free from Infection" or "Infected" based on a minimum expected 40% within-herd prevalence.Questionnaires were posted to 320 farmers chosen randomly from 6 regions, encompassing 25 counties, of the Republic of Ireland. The questionnaire was designed to obtain information about vaccination; reproductive disease; breeding herd details; the presence of recognized risk factors from previous studies; and husbandry on each farm. Data collected from 128 eligible herds were subjected to statistical analysis. RESULTS: Following the use of Pearson's Chi-Square Test, those variables associated with a herd being "infected" with a significance level of P < 0.2 were considered as candidates for multivariable logistic regression modelling. Breeding herd size was found to be a statistically significant risk factor after multivariable logistic regression. The odds of a herd being positive for leptospiral infection were 5.47 times higher (P = 0.032) in herds with 14 to 23 breeding animals compared with herds with <= 13 breeding animals, adjusting for Region, and 7.08 times higher (P = 0.033) in herds with 32.6 to 142 breeding animals. CONCLUSIONS: Breeding herd size was identified as a significant risk factor for leptospiral infection in Irish suckler herds, which was similar to findings of previous studies of leptospirosis in dairy herds. PMID- 22449265 TI - Cochlear implantation in mitochondrial deafness due to A7445G mutation. AB - OBJECTIVE: This study aimed to determine if cochlear implantation (CI) improved speech discrimination in the New Zealand pedigree with the A7445G mitochondrial DNA (mtDNA) mutation and sensorineural hearing loss (SNHL). METHODS: Nine patients had their speech discrimination and pure tone audiograms evaluated. Pre- and post-implant results were compared. Type of CI and patient age at implantation was recorded. RESULTS: Speech discrimination testing shows greatly improved functional hearing after CI in this group of patients. DISCUSSION: Individuals with mtDNA-related SNHL should be identified by screening and offered assessment for CI suitability because functional hearing improves after CI. PMID- 22449266 TI - Twelve tips for facilitating successful teleconferences. AB - BACKGROUND: The work of medical education is increasingly collaborative across geographical sites, sometimes spanning international borders. The success of projects depends more strongly on how meetings are led and run than variables about the task itself; therefore, excellent communication using teleconferencing technology is required. However, we found no medical literature to assist with developing best practices in telecommunication. AIM: Using the organization and management literature, which has examined the use of telecommunication in optimizing work outcomes, we provide a guide for initiating and facilitating teleconferences. METHODS: We used Tuckman's framework for group development as a means of organizing guidelines that address practical issues in approaching communication on teleconferences and discuss important aspects of forming work groups using telecommunication, setting ground rules and norms, addressing conflict, and enhancing accountability and outcomes. RESULTS: We identified 12 tips for optimal teleconferencing and divided them into phases of formation, setting ground rules, managing conflict, and enhancing group performance. CONCLUSION: Successful work on teleconferences requires excellent attention to the group process, especially since full engagement by participants is not always assured. PMID- 22449267 TI - Licensing examinations for doctors graduated outside the European Economic Area. PMID- 22449268 TI - How we use social media to supplement a novel curriculum in medical education. AB - BACKGROUND: The millennial learner is reliant on technology to gain knowledge. Social media in the form of Twitter and Facebook provide a unique way to reach these learners. AIMS: To demonstrate a supplement to a curriculum using "push technology" via Twitter and Facebook to deliver educational content to mobile devices. METHODS: A curriculum consisting of high-yield ultrasound concepts was developed and posted to Twitter @EDUltrasound daily. Followers received tweets "pushed" directly to their mobile devices. Following the year-long program, followers were surveyed regarding the program's effectiveness. To determine the ways in which tweets were reaching users, followers were categorized demographically. RESULTS: Daily "tweets" were posted each morning beginning on July 1, 2010. By the end of the year, there were 87 followers on Twitter and 78 on Facebook. The majority of followers (55.6%) had not previously used Twitter. The majority of followers (88.9%) found Twitter user-friendly, while most (81.5%) found the information useful. CONCLUSIONS: Due to ease of use and widespread applicability, Twitter and Facebook are excellent applications of "push technology" as a means to deliver educational content. This pilot project demonstrates the potential of social media to both supplement and enhance traditional educational methods. PMID- 22449269 TI - Will next year's rise in UK tuition fees change the demographic of future medical and dental students? PMID- 22449270 TI - An assessment of stress in Irish interns. PMID- 22449271 TI - Twelve tips for writing educational research grant proposals. AB - BACKGROUND: The need to promote educational research and faculty development grants and assist medical educators with grant writing is well documented in the medical education literature. AIMS: To assist medical educators with writing educational research grant proposals, we propose a set of 12 tips for writing competitive grant proposals. METHODS: We distilled challenges and effective strategies and approaches from our experience in writing and assisting with education research grant proposals. We presented these challenges and approaches at faculty development workshops on writing educational research grant proposals conducted over the past 3 years and evaluated the outcomes of these presentations and the participant's experiences with educational research grant writing. RESULTS: Approximately 100 participating faculty provided feedback, affirming that these sessions were very useful for developing grant proposals and for reaching out to funding agencies and that these faculty development efforts in grant writing are much needed. CONCLUSIONS: Based on our experiences with education grants and workshop efforts, we propose a set of strategies for faculty to seek grant sources and write promising education research grant proposals. PMID- 22449272 TI - Development, implementation, and evaluation of a student-initiated undergraduate medical education elective in HIV care. AB - BACKGROUND: The literature indicates that medical students require more comprehensive HIV training. AIM: Medical students at the University of Toronto developed and implemented the preclerkship HIV elective (PHE) with the aim to increase trainee HIV knowledge, address important issues in HIV care, and prepare students to serve affected populations. METHODS: Developed in partnership with the Ontario HIV Treatment Network and in consultation with local AIDS service organizations and the University of Toronto Faculty of Medicine, the PHE was inaugurated in November 2008 as an elective supplement to medical curriculum content. Eighteen second-year medical students participated in the PHE, consisting of lectures, small group sessions, clinical observerships, community placements, reading assignments, and an HIV counseling and testing workshop. Participants completed a self-assessment of HIV knowledge prior to starting and after PHE completion. RESULTS: Self-assessment scores of HIV knowledge among PHE participants significantly increased from 78.1% (pre-PHE) to 90.2% (post-PHE) (p = 0.0016). Common themes from feedback on participant satisfaction included enthusiasm for small group sessions, clinical observerships, community agency placements, and the diversity of topics covered. CONCLUSIONS: Student-run initiatives can supplement medical curriculum content and program feedback may be used to advocate for curriculum changes. Factors influencing success include student leadership and interest, community partnerships, and faculty mentorship. PMID- 22449273 TI - Medical student-developed obesity education program uses modified team-based learning to motivate adolescents. AB - BACKGROUND: Childhood obesity is reaching epidemic proportions and requires intervention. AIMS: To educate high school (HS) students on the effects of obesity and implement small healthy changes. Train medical students to educate and motivate adolescents and utilize a modified team-based learning format. METHODS: A medical student-created HS-based module was developed to educate adolescents on obesity's effects on health. Over 2 years, 25 medical students from each semester were trained and presented to 1590 freshmen and sophomores at suburban HSs in Milwaukee, Wisconsin. The program included an interactive power point and a 30-day challenge to make small measurable changes in their current health behaviors. A modified team-based learning format was included to engage students and increase classroom interaction. RESULTS: Medical students reported the program improved their ability to communicate with adolescents and enhanced their training as future physicians. Teachers felt students had sustained retention of knowledge at the end of 30 days and the majority of students fulfilled their self-imposed challenge. CONCLUSION: A student-run HS obesity education module using a portion of team-based learning was successfully implemented into HS health science curriculums, exposed medical students to community advocacy while educating and motivating adolescents to improve health behaviors. PMID- 22449274 TI - Medical students' responses to their first clinical experiences. PMID- 22449275 TI - Interleukin-6 polymorphism and bronchopulmonary dysplasia risk in very low birthweight infants. AB - BACKGROUND: The aim of the present study was to evaluate the role of interleukin (IL)-6-634 polymorphism in neonatal disorders such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL) in very low-birthweight (VLBW) infants. METHODS: This prospective cohort study included 202 infants (gestational age at birth, 23-34 weeks; birthweight, 500-1499 g). Genotypic analysis (polymerase chain reaction-restriction fragment length polymorphism) was performed with DNA extracted from whole-blood samples. RESULTS: Genotype distribution (66.8% CC, 28.2% CG, 5.0% GG) was similar to that in the adult Japanese population. BPD occurred in 85 infants (42.1%) among 202 VLBW infants. The duration of O(2) therapy in infants with CG/GG genotypes was significantly longer than that in infants with the CC genotype (CG/GG vs CC: 40.3 +/- 52.2 days vs 28.4 +/- 32.6 days, P < 0.05), but the prevalence of BPD was not associated with the CG/GG genotype (CG/GG, 40.0%; CC, 46.3%, P= 0.24). Infants with CG/GG genotypes were more likely to have received postnatal corticosteroid therapy for BPD than those with the CC genotype (CG/GG vs CC: 20.9% vs 11.1%, P = 0.05). PVL occurred in six infants (3.0%). There was no significant difference in the prevalence of PVL among IL-6-634 polymorphisms (CG/GG, 3.0%; CC, 3.0%, P = 0.65). CONCLUSIONS: IL-6-634 polymorphism is associated with duration of oxygen therapy in VLBW infants. This suggests that the IL-6-634 polymorphism G allele is an aggravating factor of BPD. IL-6-634 polymorphism is not associated with PVL. PMID- 22449277 TI - Remote Raman spectroscopy for planetary exploration: a review. AB - In this review, we discuss the current state of standoff Raman spectroscopy as it applies to remote planetary applications, including standoff instrumentation, the technique's ability to identify biologically and geologically important analytes, and the feasibility to make standoff Raman measurements under various planetary conditions. This is not intended to be an exhaustive review of standoff Raman and many excellent papers are not mentioned. Rather it is intended to give the reader a quick review of the types of standoff Raman systems that are being developed and that might be suitable for astrospectroscopy, a look at specific analytes that are of interest for planetary applications, planetary measurement opportunities and challenges that need to be solved, and a brief discussion of the feasibility of making surface and plume planetary Raman measurements from an orbiting spacecraft. PMID- 22449276 TI - Genome-wide associations for milk production and somatic cell score in Holstein Friesian cattle in Ireland. AB - BACKGROUND: Contemporary dairy breeding goals have broadened to include, along with milk production traits, a number of non-production-related traits in an effort to improve the overall functionality of the dairy cow. Increased indirect selection for resistance to mastitis, one of the most important production related diseases in the dairy sector, via selection for reduced somatic cell count has been part of these broadened goals. A number of genome-wide association studies have identified genetic variants associated with milk production traits and mastitis resistance, however the majority of these studies have been based on animals which were predominantly kept in confinement and fed a concentrate-based diet (i.e. high-input production systems). This genome-wide association study aims to detect associations using genotypic and phenotypic data from Irish Holstein-Friesian cattle fed predominantly grazed grass in a pasture-based production system (low-input). RESULTS: Significant associations were detected for milk yield, fat yield, protein yield, fat percentage, protein percentage and somatic cell score using separate single-locus, frequentist and multi-locus, Bayesian approaches. These associations were detected using two separate populations of Holstein-Friesian sires and cows. In total, 1,529 and 37 associations were detected in the sires using a single SNP regression and a Bayesian method, respectively. There were 103 associations in common between the sires and cows across all the traits. As well as detecting associations within known QTL regions, a number of novel associations were detected; the most notable of these was a region of chromosome 13 associated with milk yield in the population of Holstein-Friesian sires. CONCLUSIONS: A total of 276 of novel SNPs were detected in the sires using a single SNP regression approach. Although obvious candidate genes may not be initially forthcoming, this study provides a preliminary framework upon which to identify the causal mechanisms underlying the various milk production traits and somatic cell score. Consequently this will deepen our understanding of how these traits are expressed. PMID- 22449278 TI - In situ Raman spectroscopy: a process analytical technology tool to monitor a de protection reaction carried out in aqueous solution. AB - The application of in situ Raman spectroscopy at small scale (maximum 80 mL) during the development of a manufacturing process is disclosed. The reaction was run in aqueous solution between ambient and 100 degrees C. Raman spectroscopy has proven to be a viable method to track the reaction. Three distinct phases could be followed: dissolution of the starting material, production of a reactive intermediate, and then subsequent conversion of that intermediate to form product. The objective of the work was to confirm the presence of a reactive intermediate and this could only be carried out via in situ spectroscopy as the intermediate was known to be unstable. Toward the end, the reaction passes though several neutralization points and these are consistent with changes in the spectra. Comparison of data obtained at an illumination wavelength of 998 nm with that obtained at 785 nm is also disclosed. The data obtained at shorter wavelength was contaminated by reasonably strong fluorescence, whereas the data obtained at 998 nm was free of fluorescence. An unexpected observation from this work was that the reaction time was much shorter than expected and this work was key in showing that a reduction in batch cycle time was possible during commercial manufacture. PMID- 22449279 TI - Single-molecule enzyme dynamics of monomeric sarcosine oxidase in a gold-based zero-mode waveguide. AB - The localization of optical fields is a powerful method of reducing spectroscopic background signals, enabling studies of single fluorescent molecules. Zero-mode waveguides (ZMWs) strongly confine optical fields to zeptoliter (zL, 10(-21) L) volumes and can be coupled with fluorescence microscopy to study the dynamics of single enzyme molecules due to their excellent optical confinement, precise positioning, and massive parallelism. The experiments described here exploit arrays of gold-based (Au-based) nanopores derivatized with single copies of the redox enzyme monomeric sarcosine oxidase (MSOX). MSOX contains a covalently bound flavin adenine dinucleotide (FAD) cofactor, which is highly fluorescent in the oxidized state and dark in the reduced state, thus producing a characteristic on off fluorescence signal synchronous with transitions between oxidation states. Although aluminum (Al) is the common choice for the metallic overlayer in ZMW construction, Au is used here to access its unique surface-binding chemistry. In particular, the signal-to-noise ratio is improved for Au-based ZMWs by selective Au passivation. For MSOX reactions involving both the nominal substrate (sarcosine) and an analogous substrate (proline), statistical analysis of single molecule temporal trajectories reveals the static heterogeneity of single-enzyme reaction rates, but no dynamic disorder. In addition, the single-molecule data confirm the independence of reduction and oxidation reactions. These structures open the way for systematic studies of the effect of molecular crowding on enzyme dynamics. PMID- 22449280 TI - Recognition of a C-C mismatch in a DNA duplex using a fluorescent small molecule with application for "off-on" discrimination of C/G mutation. AB - The fluorescent small molecule 2-amino-7-methyl-1,8-naphthyridine (AMND) can selectively bind to a cytosine (C) at a C-C mismatch in double-stranded DNA (dsDNA). The interactions between AMND and C-C mismatch-containing dsDNA were investigated by measuring ultraviolet (UV) absorption as a function of temperature to obtain melting curves as well as circular dichroism and fluorescence spectra. Results show that AMND strongly stabilizes C-C mismatch containing dsDNA, whereas fully matched duplexes are not stabilized under the same conditions. The fluorescence of AMND was efficiently quenched when it was bound to a C-C mismatch in dsDNA. Binding constants (K(11)), obtained by fluorescence titration, were 1.2 * 10(5) M(-1). Although sensing functions depend on the sequences flanking the mismatch site, the change in AMND fluorescence intensity can be utilized to detect the C-C mismatch-containing dsDNA. Accordingly, discrimination of the C/G mutation in the model sequence (PGR gene rs1255998) was achieved by visualizing fluorescence of AMND. A probe DNA molecule was designed to contain a C opposite the C/G base in the target DNA, and this probe was used to hybridize the target DNA. The fluorescence of AMND was "on" for a C-G match, while the fluorescence was "off" for a C-C mismatch. This assay is simple and does not require DNA labeling. PMID- 22449281 TI - Chemiluminescent identification and quantification of artemisinin and relevant sesquiterpene lactone derivatives. AB - A simple, sensitive, and rapid chemiluminescence method was developed for the detection and quantification of selected derivatives of artemisinin. It was found that the chemiluminescence (CL) signal resulting from the alkaline luminol reaction of the artemisinin derivatives in the presence of hematin was linear over a wide concentration range. We report results that suggest that a visual test or a test involving digital image capture may be used in addition to a field ready instrumental approach to combat drug counterfeiting of malarial therapies. PMID- 22449282 TI - Noise characterization in circular dichroism spectroscopy. AB - Circular dichroism (CD), defined as the difference in absorption between left and right circularly polarized light, is used to spectroscopically study the structures of chiral materials. In this article, various methodologies are presented for characterizing the performance of CD spectrometers to determine (1) experimental conditions for optimal data collection, (2) noise characteristics dependent on machine parameters, (3) the relative significance of spectral data as a function of detector gain, and (4) stray light and dark current as a function of wavelength. The results of case studies of two commercial CD spectrometers (specifically, Jasco J810 and J815) are described. The analyses show that the variation of CD signal is Poisson distributed and hence can be considered shot noise. Also, optimum scan parameters are established and a weighting function of CD data significance is produced so that wavelength dependent gain (as determined by the high tension, HT, voltage applied to the photomultiplier tube, PMT, detector) can be accommodated. Lastly, the amount of stray light and dark current for the photomultiplier tube is determined. Though specific to the Jasco CD spectrometers characterized in this study, it is expected that all CD spectrometers exhibit similar behavior and the methodology described here can be usefully applied to characterize CD spectrometers independent of manufacturer. PMID- 22449283 TI - Effects of metallic, semiconducting, and insulating substrates on the coupling involving radiative polaritons in thin oxide films. AB - Through simulations, this work explores the effects of conducting, semiconducting, and insulating substrates on the absorption of infrared radiation by radiative polaritons in oxide layers with thicknesses that range from 30 nm to 9 MUm. Using atomic layer deposition, oxide layers can be formed in the nanometer scale. Our results suggest that the chemistry and conductivity of the substrate determine the amount of absorption by radiative polaritons in oxide layers thinner than the skin depth. The effects of the chemistry and conductivity of the substrate are especially effective for oxide films thinner than about 250 nm, which we label as the substrate sensitive thickness of the oxide film. PMID- 22449284 TI - Characterization of attenuated total reflection infrared spectral intensity variations of immature and mature cotton fibers by two-dimensional correlation analysis. AB - Two-dimensional (2D) correlation analysis was applied to characterize the attenuated total reflection (ATR) spectral intensity fluctuations of immature and mature cotton fibers. Prior to 2D analysis, the spectra were leveled to zero at the peak intensity of 1800 cm(-1) and then were normalized at the peak intensity of 660 cm(-1) to subjectively correct the variations resulting from ATR sampling. Next, normalized spectra were subjected to principal component analysis (PCA), and two clusters of immature and mature fibers were confirmed on the basis of the first principal component (PC1) negative and positive scores, respectively. The normalized spectra clearly demonstrated the intensity increase or decrease of the bands ascribed to different C-O confirmations of primary alcohols in the 1050-950 cm(-1) region, which was not apparent from raw ATR spectra. The PC1 increasing induced 2D correlation analysis revealed remarkable differences between the immature and mature fibers. Of interest were that: (1) Both intensity increase of two bands at 968 and 956 cm(-1) and the shifting of 968 cm(-1) in immature fibers to 956 cm(-1) in mature fibers, together with the intensity decreasing and shifting of the 1048 and 1042 cm(-1) bands, are the characteristics of cotton fiber development and maturation. (2) Intensities of most bands in the 1800-1200 cm(-1) region decreased with the fiber growth, suggesting they are from either noncellulosic components or CH and OH fractions in amorphous celluloses. (3) The reverse sequence of intensity variations of the bands in the 1100-1000 cm(-1) and 1000-900 cm(-1) region of asynchronous spectra indicated a different mechanism of compositional and structural changes in developing cotton fibers at different growth stages. PMID- 22449285 TI - Concentration measurements in ionic liquid-water mixtures by mid-infrared spectroscopy and indirect hard modeling. AB - An analytical method for the quantitative characterization of binary mixtures of water and ionic liquids (ILs) is presented. Mid-infrared (mid-IR) spectroscopy in combination with indirect hard modeling (IHM) is employed to quantify the water content in 1-butyl-3-methylimidazolium chloride (BMIMCl), 1,3-dimethylimidazolium dimethylphosphate (DMIMDMP), and 1-ethyl-3-methylimidazolium acetate (EMIMAc). Despite significant nonlinear shifts of the spectral bands, a good spectral fit with calibration errors of less than 2.3 wt % can be achieved almost over the whole concentration range. A profound analysis of the spectral models including peak assignment substantiates the physico-chemical foundation of the spectral models. Furthermore, the shift of peak functions in the spectral models is shown to provide a measure of molecular interaction in IL-water mixtures, which can also be utilized quantitatively. The vibrational bands of the water dipole reveal differences in the strength of hydrogen bonding with water in the IL studied. These properties of the spectral hard models demonstrate their quantitative analytical potential and set the stage for multiway calibration in comprehensive reaction monitoring in these highly interacting mixtures of IL and water. PMID- 22449286 TI - An on-line near-infrared (NIR) transmission method for determining depth profiles of fatty acid composition and iodine value in porcine adipose fat tissue. AB - The present work describes a measurement method using spatially resolved near infrared (NIR) spectroscopy to determine porcine carcass fat quality as a function of the distance to the skin by estimating its iodine value (IV). The new method is capable of performing on-line carcass grading at full production speed (approximately 1000 carcasses per hour). The method is demonstrated in an experiment where 35 carcasses were sampled at an abattoir, selected from three feeding groups. The NIR transmission instrument was applied on the loin of each carcass, and a parallel reference sample was removed and processed into 1.8 mm thick disks, representing a depth-of-fat profile from the loin. The disks were analyzed for fatty acid composition using gas chromatography (GC) and for IV. A principal component analysis (PCA) of the obtained GC reference values clearly showed that the feeding regimes can be differentiated. Using interval partial least squares (iPLS) regression, a model was produced that can predict the IV of the fat at a given measured depth with a root mean square error of cross validation (RMSECV) of 1.44. The results show how the IV varies as a function of feeding regime and as a function of fat depth. The maximum variation found within a single depth profile was 10.1 IV from the skin to the innermost part of the fat layers. In the sample material investigated the average span in IV between the average values of the two porcine backfat layers was 6.4 IV (the maximum difference was 8.6 IV). The new method can provide the abattoir with new chemical information about fat quality and production quality that will open new possibilities of meat/carcass grading and product development. PMID- 22449287 TI - Femtosecond stimulated Raman spectroscopy using a scanning multichannel technique. AB - A scanning multichannel technique (SMT) has been implemented in femtosecond stimulated Raman spectroscopy (FSRS). By combining several FSRS spectra detected at slightly different positions of the spectrograph via SMT, we have eliminated the systematic noise patterns ("fixed pattern noise") due to the variation in sensitivity and noise characteristics of the individual charge-coupled device (CCD) pixels. In nonresonant FSRS, solvent subtraction can effectively remove the systematic noise pattern even without SMT. However, in the case of resonant FSRS, we show that a similar solvent subtraction procedure is ineffective at removing the noise patterns without SMT. Application of SMT results in averaged FSRS spectra with improved signal-to-noise ratios that approach the shot-noise limit. PMID- 22449288 TI - In situ high-pressure and high-temperature experiments on n-heptane. AB - The Raman spectroscopy of n-heptane was investigated in a moissanite anvil cell at ambient temperatures and a diamond anvil cell under pressures of up to ~2000 MPa and at temperature range from 298 to 588 K. The results show that at room temperature the vibration modes, assigned to the symmetric and antisymmetric stretching of CH(3) and CH(2) stretching, shifted to higher frequency according to quasi-linearity with increasing pressure, and a liquid-solid phase transition occurred at near 1150 MPa. The high-temperature solidus line of n-heptane follows a quadratic function of P = 0.00737T(2) + 5.27977T - 1195.76556. Upon phase change, fitting the experimental data obtained in the temperature range of 183~412 K to the Clausius-Clapeyron equation allows one to define the thermodynamic parameters of n-heptane of dP/dT = 0.01474T + 5.27977. PMID- 22449289 TI - Fungal sensitivity to and enzymatic deglycosylation of ginsenosides. AB - A ginseng pathogen, Cylindrocarpon destructans, and five nonpathogens were tested for their sensitivity to a total ginsenoside fraction (T-GF), a protopanaxadiol type ginsenoside fraction (PPD-GF) and a protopanaxatriol-type ginsenoside fraction (PPT-GF) from the roots of Panax ginseng C.A. Meyer. The results showed that T-GF inhibited growth of the five ginseng nonpathogens, while it promoted growth of the ginseng pathogen C. destructans. PPT-GF and PPD-GF both inhibited the growth of the five ginseng nonpathogens, although the activity of PPT-GF was higher than that of PPD-GF. PPT-GF and PPD-GF exhibited different activities on C. destructans: PPT-GF inhibited its growth, whereas PPD-GF significantly enhanced its growth. The subsequent analysis of enzymatic degradation of ginsenosides by the test fungi showed that C. destructans can consecutively hydrolyze the terminal monosaccharide units from the sugar chains attached at C3 and C20 in PPD-type ginsenosides by extracellular glycosidase activity to yield four major products, gypenoside XVII (G-XVII), compound O, compound Mb and the ginsenoside F(2). By contrast, the ginseng nonpathogens Aspergillus nidulans and Cladosporium fulvum have no extracellular glycosidase activity toward sugar chains attached to C3 in PPD-type ginsenosides. These results indicated that ginsenosides might act as host chemical defenses, while the ginseng root pathogenic fungi might counter their toxicity by converting PPD-type ginsenosides into growth or host recognition factors. The ability of ginseng root pathogens to deglycosylate PPD-type ginsenosides may be a pathogenicity factor. PMID- 22449290 TI - Emergence of spontaneous bacterial peritonitis due to enterococci - risk factors and outcome in a 12-year retrospective study. AB - BACKGROUND: Third-generation cephalosporins (TGC) constitute the empirical first line therapy for spontaneous bacterial peritonitis (SBP). Hospitalisation, invasive procedures and use of antibiotics may challenge this concept due to an increase in enterococci and other TGC-resistant microorganisms. AIM: To determine prevalence, risk factors and outcome of ascitic fluid infections caused by enterococci. METHODS: All independent episodes of culture-positive ascitic fluid between 2000 and 2011 in a German tertiary centre were analysed retrospectively. RESULTS: Out of 244 positive ascitic fluid cultures, 90 episodes of monomicrobial SBP and 25 episodes of monomicrobial bacterascites (BA) in patients with decompensated cirrhosis were identified. Enterococcus spp. were isolated in 32 (28%) episodes. We noticed a profound increase in the frequency of enterococcal infection over the study period from 11% to 35% (P = 0.007). Univariate risk factors for enterococcal SBP/BA included nosocomial infection (OR = 4.56; 95% CI 1.90-10.97), previous use of antibiotics (OR = 5.63; 95% CI 1.81-17.49) and recent gastrointestinal endoscopy (OR = 3.17; 95% CI 1.33-7.54). Nosocomial infection (OR = 3.29; P = 0.011) and recent antibiotic therapy (OR = 3.88; P = 0.025) remained independent risk factors for enterococcal infection in multivariate logistic regression and these factors contributed also to the model when only SBP cases were considered. In subjects with monomicrobial SBP who were treated with TGC or ciprofloxacin, the probability of 90-day survival was 12% in enterococcal infection compared to 50% in non-enterococcal SBP (P = 0.022 in log rank test). CONCLUSION: Because of the increasing prevalence of enterococcal spontaneous bacterial peritonitis and its poor prognosis when treated inappropriately, clinicians should consider empirical therapy with anti enterococcal antibiotics for patients with risk factors. PMID- 22449291 TI - Using smart phone video to supplement communication of radiology imaging in a neurosurgical unit: technical note. AB - BACKGROUND: The use of smart phones within medicine continues to grow at the same rate as mobile phone technology continues to evolve. One use of smart phones within medicine is in the transmission of radiological images to consultant neurosurgeons who are off-site in an emergency setting. In our unit, this has allowed quick, efficient, and safe communication between consultant neurosurgeon and trainees, aiding in rapid patient assessment and management in emergency situations. OBJECTIVE: To describe a new means of smart phone technology use in the neurosurgical setting, where the video application of smart phones allows transfer of a whole series of patient neuroimaging via multimedia messaging service to off-site consultant neurosurgeons. METHOD/TECHNIQUE: Using the video application of smart phones, a 30-second video of an entire series of patient neuroimaging was transmitted to consultant neurosurgeons. With this information, combined with a clinical history, accurate management decisions were made. RESULTS: This technique has been used on a number of emergency situations in our unit to date. Thus far, the imaging received by consultants has been a very useful adjunct to the clinical information provided by the on-site trainee, and has helped expedite management of patients. CONCLUSION: While the aim should always be for the specialist neurosurgeon to review the imaging in person, in emergency settings, this is not always possible, and we feel that this technique of smart phone video is a very useful means for rapid communication with neurosurgeons. PMID- 22449292 TI - Non-invasive assessment of fluid responsiveness by changes in partial end-tidal CO2 pressure during a passive leg-raising maneuver. AB - BACKGROUND: The passive leg-raising (PLR) maneuver provides a dynamic assessment of fluid responsiveness inducing a reversible increase in cardiac preload. Since its effects are sudden and transitory, a continuous cardiac output (CO) monitoring is required to appropriately assess the hemodynamic response of PLR. On the other hand, changes in partial end-tidal CO2 pressure (PETCO2) have been demonstrated to be tightly correlated with changes in CO during constant ventilation and stable tissue CO2 production (VCO2). In this study we tested the hypothesis that, assuming a constant VCO2 and under fixed ventilation, PETCO2 can track changes in CO induced by PLR and can be used to predict fluid responsiveness. METHODS: Thirty-seven mechanically ventilated patients with acute circulatory failure were monitored with the CardioQ-ODM esophageal Doppler. A 2 minutes PLR maneuver was performed. Fluid responsiveness was defined according to CO increase (responders >= 15%) after volume expansion. RESULTS: PLR-induced increases in CO and PETCO2 were strongly correlated (R2 = 0.79; P < 0.0001). The areas under the receiver-operating characteristics (ROC) curve for a PLR-induced increase in CO and PETCO2 (0.97 +/- 0.03 SE; CI 95%: 0.85 to 0.99 and 0.94 +/- 0.04 SE; CI 95%: 0.82 to 0.99; respectively) were not significantly different. An increase >= 5% in PETCO2 or >= 12% in CO during PLR predicted fluid responsiveness with a sensitivity of 90.5% (95% CI: 69.9 to 98.8%) and 95.2% (95% CI: 76.2 to 99.9%), respectively, and a specificity of 93.7% (95% CI: 69.8 to 99.8%). CONCLUSION: Induced changes in PETCO2 during a PLR maneuver could be used to track changes in CO for prediction of fluid responsiveness in mechanically ventilated patients with acute circulatory failure, under fixed minute ventilation and assuming a constant tissue CO2 production. PMID- 22449294 TI - Current status of off-pump coronary-artery bypass. PMID- 22449295 TI - CT angiography for safe discharge of patients with possible acute coronary syndromes. AB - BACKGROUND: Admission rates among patients presenting to emergency departments with possible acute coronary syndromes are high, although for most of these patients, the symptoms are ultimately found not to have a cardiac cause. Coronary computed tomographic angiography (CCTA) has a very high negative predictive value for the detection of coronary disease, but its usefulness in determining whether discharge of patients from the emergency department is safe is not well established. METHODS: We randomly assigned low-to-intermediate-risk patients presenting with possible acute coronary syndromes, in a 2:1 ratio, to undergo CCTA or to receive traditional care. Patients were enrolled at five centers in the United States. Patients older than 30 years of age with a Thrombolysis in Myocardial Infarction risk score of 0 to 2 and signs or symptoms warranting admission or testing were eligible. The primary outcome was safety, assessed in the subgroup of patients with a negative CCTA examination, with safety defined as the absence of myocardial infarction and cardiac death during the first 30 days after presentation. RESULTS: We enrolled 1370 subjects: 908 in the CCTA group and 462 in the group receiving traditional care. The baseline characteristics were similar in the two groups. Of 640 patients with a negative CCTA examination, none died or had a myocardial infarction within 30 days (0%; 95% confidence interval [CI], 0 to 0.57). As compared with patients receiving traditional care, patients in the CCTA group had a higher rate of discharge from the emergency department (49.6% vs. 22.7%; difference, 26.8 percentage points; 95% CI, 21.4 to 32.2), a shorter length of stay (median, 18.0 hours vs. 24.8 hours; P<0.001), and a higher rate of detection of coronary disease (9.0% vs. 3.5%; difference, 5.6 percentage points; 95% CI, 0 to 11.2). There was one serious adverse event in each group. CONCLUSIONS: A CCTA-based strategy for low-to-intermediate-risk patients presenting with a possible acute coronary syndrome appears to allow the safe, expedited discharge from the emergency department of many patients who would otherwise be admitted. (Funded by the Commonwealth of Pennsylvania Department of Health and the American College of Radiology Imaging Network Foundation; ClinicalTrials.gov number, NCT00933400.). PMID- 22449293 TI - Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. AB - BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.). PMID- 22449297 TI - Incidence and risk factors of parenteral nutrition-associated liver disease in newborn infants. AB - BACKGROUND: The aim of the present study was to determine the incidence and risk factors of parenteral nutrition-associated liver disease (PNALD) in neonates. METHODS: A 1 year prospective cohort study was carried out at the neonatal intensive care unit and sick neonatal wards, Chiang Mai University Hospital. Newborns >1000 g, receiving >7 days of parenteral nutrition (PN), were enrolled. Liver function tests were done by the end of first, second, and fourth week, and then every 4 weeks until the PN was discontinued and the jaundice resolved. The diagnosis of PNALD relied on a history of PN, direct bilirubin >2 mg/dL, and exclusion of other causes of neonatal cholestasis. Selected patient factors and PN compositions were analyzed to determine the risks for development of PNALD. RESULTS: A total of 24 infants with a mean gestational age and birthweight of 32.5 weeks and 1840 g were enrolled. Eight of the 24 developed PNALD. Compared to those without PNALD, gastrointestinal surgery, duration of enteral starvation, duration of PN, maximum PN caloric intake, and maximum carbohydrate intake were significantly associated with the development of liver disease. Despite the lack of statistical significance, there was a trend towards cholestasis in patients with sepsis. Elevation of direct bilirubin was the earliest biochemical change, observed in the first week after PN, followed by increased transaminases. CONCLUSION: Gastrointestinal surgery, duration of enteral starvation, duration of PN, maximum caloric and carbohydrate intake in PN were significant risks of PNALD in newborn infants. PMID- 22449299 TI - Current innovations: HTML and a new reference style. PMID- 22449298 TI - Effect of influenza vaccination on international normalized ratio during chronic warfarin therapy. AB - WHAT IS KNOWN AND OBJECTIVE: Warfarin is a widely used anticoagulant, well-known for its interactions with medications and foods. Vaccinations, particularly the influenza vaccine, have been thought to potentially interfere with anticoagulation response in those on chronic warfarin. Our objective was to systematically review the literature to assess the validity and clinical significance of this association. METHODS: A primary literature search was performed using MEDLINE (1966 - June 2011) and EMBASE (1980 - June 2011). Additional studies were obtained by performing a manual bibliographical review of literature from the initial results and by searching The Cochrane Database of Systematic Reviews. All English-language, peer-reviewed publications identified were evaluated. Reviews, case studies and trials reporting anticoagulation response using an unconverted prothrombin time ratio were excluded. RESULTS AND DISCUSSION: Thirty-one abstracts were initially reviewed, and seven studies were identified for inclusion in this review. Significant changes in mean INR post vaccination between the study and comparator groups were documented in one trial. Through subgroup analysis, another study noted that elderly patients spent more time in the subtherapeutic range post-vaccination when compared with baseline INR levels. No other significant changes in mean INR levels were documented following influenza vaccination. Adverse bleeding events reported after immunization were limited and minor in nature. WHAT IS NEW AND CONCLUSION: Overall, our review does not indicate a consistent, clinically relevant effect of influenza vaccines on INR of patients on chronic warfarin therapy. Isolated reports of variations in INR following influenza vaccination are likely due to other factors. PMID- 22449300 TI - A review of advances in deep-ocean Raman spectroscopy. AB - We review the rapid progress made in the applications of Raman spectroscopy to deep-ocean science. This is made possible by deployment of instrumentation on remotely operated vehicles used for providing power and data flow and for precise positioning on targets of interest. Early prototype systems have now been replaced by compact and robust units that have been deployed well over 100 times on an expeditionary basis over a very wide range of ocean depths without failure. Real-time access to the spectra obtained in the vehicle control room allows for expedition decision making. Quantification of some of the solutes in seawater or pore waters observed in the spectra is made possible by self-referencing to the ubiquitous nu(2) water bending peak. The applications include detection of the structure and composition of complex thermogenic gas hydrates both occurring naturally on the sea floor and in controlled sea floor experiments designed to simulate the growth of such natural systems. New developments in the ability to probe the chemistry of sediment pore waters in situ, long thought impossible candidates for Raman study due to fluorescence observed in recovered samples, have occurred. This permits accurate measurement of the abundance of dissolved methane and sulfide in sediment pore waters. In areas where a high gas flux is observed coming out of the sediments a difference of about *30 between in situ Raman measurement and the quantity observed in recovered cores has been found. New applications under development include the ability to address deep-sea biological processes and the ability to survey the sea floor chemical conditions associated with potential sub-sea geologic CO(2) disposal in abandoned oil and gas fields. PMID- 22449296 TI - Off-pump or on-pump coronary-artery bypass grafting at 30 days. AB - BACKGROUND: The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established. METHODS: At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization. RESULTS: There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01). CONCLUSIONS: There was no significant difference between off-pump and on pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.). PMID- 22449301 TI - Monitoring uranium, hydrogen, and lithium and their isotopes using a compact laser-induced breakdown spectroscopy (LIBS) probe and high-resolution spectrometer. AB - The development of field-deployable instruments to monitor radiological, nuclear, and explosive (RNE) threats is of current interest for a number of assessment needs such as the on-site screening of suspect facilities and nuclear forensics. The presence of uranium and plutonium and radiological materials can be determined through monitoring the elemental emission spectrum using relatively low-resolution spectrometers. In addition, uranium compounds, explosives, and chemicals used in nuclear fuel processing (e.g., tributyl-phosphate) can be identified by applying chemometric analysis to the laser-induced breakdown (LIBS) spectrum recorded by these spectrometers. For nuclear forensic applications, however, isotopes of U and Pu and other elements (e.g., H and Li) must also be determined, requiring higher resolution spectrometers given the small magnitude of the isotope shifts for some of these elements (e.g., 25 pm for U and 13 pm for Pu). High-resolution spectrometers will be preferred for several reasons but these must fit into realistic field-based analysis scenarios. To address the need for field instrumentation, we evaluated a previously developed field-deployable hand-held LIBS interrogation probe combined with two relatively new high resolution spectrometers (lambda/Deltalambda ~75,000 and ~44,000) that have the potential to meet field-based analysis needs. These spectrometers are significantly smaller and lighter in weight than those previously used for isotopic analysis and one unit can provide simultaneous wide spectral coverage and high resolution in a relatively small package. The LIBS interrogation probe was developed initially for use with low resolution compact spectrometers in a person-portable backpack LIBS instrument. Here we present the results of an evaluation of the LIBS probe combined with a high-resolution spectrometer and demonstrate rapid detection of isotopes of uranium and hydrogen and highly enriched samples of (6)Li and (7)Li. PMID- 22449302 TI - Feasibility of laser-induced breakdown spectroscopy (LIBS) for classification of sea salts. AB - We have investigated the feasibility of laser-induced breakdown spectroscopy (LIBS) as a fast, reliable classification tool for sea salts. For 11 kinds of sea salts, potassium (K), magnesium (Mg), calcium (Ca), and aluminum (Al), concentrations were measured by inductively coupled plasma-atomic emission spectroscopy (ICP-AES), and the LIBS spectra were recorded in the narrow wavelength region between 760 and 800 nm where K (I), Mg (I), Ca (II), Al (I), and cyanide (CN) band emissions are observed. The ICP-AES measurements revealed that the K, Mg, Ca, and Al concentrations varied significantly with the provenance of each salt. The relative intensities of the K (I), Mg (I), Ca (II), and Al (I) peaks observed in the LIBS spectra are consistent with the results using ICP-AES. The principal component analysis of the LIBS spectra provided the score plot with quite a high degree of clustering. This indicates that classification of sea salts by chemometric analysis of LIBS spectra is very promising. Classification models were developed by partial least squares discriminant analysis (PLS-DA) and evaluated. In addition, the Al (I) peaks enabled us to discriminate between different production methods of the salts. PMID- 22449303 TI - Multivariate statistical analysis of Raman images of a pharmaceutical tablet. AB - This paper describes the application of principal component analysis (PCA) and independent component analysis (ICA) to identify the reference spectra of a pharmaceutical tablet's constituent compounds from Raman spectroscopic data. The analysis shows, first with a simulated data set and then with data collected from a pharmaceutical tablet, that both PCA and ICA are able to identify most of the features present in the reference spectra of the constituent compounds. However, the results suggest that the ICA method may be more appropriate when attempting to identify unknown reference spectra from a sample. The resulting PCA and ICA models are subsequently used to estimate the relative concentrations of the constituent compounds and to produce spatial distribution images of the analyzed tablet. These images provide a visual representation of the spatial distribution of the constituent compounds throughout the tablet. Images associated with the ICA scores are found to be more informative and not as affected by measurement noise as the PCA based score images. The paper concludes with a discussion of the future work that needs to be undertaken for ICA to gain wider acceptance in the applied spectroscopy community. PMID- 22449304 TI - Application of Raman multivariate curve resolution to solvation-shell spectroscopy. AB - Raman spectroscopy and multivariate curve resolution (Raman-MCR) are combined to yield a powerful spectroscopic method for identifying solute-induced perturbations of solvent molecules. The principles and applications of the resulting solvation-shell spectroscopy are described and illustrated using both numerical model spectra and experimental Raman spectra, including water in acetone and aqueous OH(-), as well as of both neutral and ionic acetic acid solutions. The results illustrate the quantitative capabilities of Raman-MCR as a solvation-shell spectroscopy, including fundamental limitations arising from "intensity" and "rotational" ambiguities. PMID- 22449305 TI - Phosphorylation detection and characterization in ribonucleotides using Raman and Raman optical activity (ROA) spectroscopies. AB - Raman and Raman optical activity (ROA) spectra are presented for adenosine and seven of its derivative ribonucleotides. Both of these spectroscopic techniques are shown to be sensitive to the site and degree of phosphorylation, with a considerable number of marker bands being identified for these ribonucleotides. ROA spectra are shown to provide the most sensitive diagnostic tool for phosphorylation characterization and quantification. PMID- 22449306 TI - Silver nanoparticles deposited on porous silicon as a surface-enhanced Raman scattering (SERS) active substrate. AB - Silver nanoparticles were deposited spontaneously from their aqueous solution on a porous silicon (PS) layer. The PS acts both as a reducing agent and as the substrate on which the nanoparticles nucleate. At higher silver ion concentrations, layers of nanoparticle aggregates were formed on the PS surface. The morphology of the metallic layers and their SERS activity were influenced by the concentrations of the silver ion solutions used for deposition. Raman measurements of rhodamine 6G (R6G) and crystal violet (CV) adsorbed on these surfaces showed remarkable enhancement of up to about 10 orders of magnitude. PMID- 22449307 TI - An optical fiber sensor for remote pH sensing and imaging. AB - A fiber-optical probe for pH sensing and real-time imaging is successfully fabricated by connecting a polymer imaging fiber and a gradient index (GRIN) lens rod which was modified with a sensing film. By employing an improved metallographic microscope, an optical system is designed to cooperate with the probe. This novel technique has high-quality imaging capabilities for observing remote samples while measuring pH. The linear range of the probe is pH 1.2-3.5. This technique overcomes the difficulty that high-quality images cannot be obtained when directly using conventional imaging bundles for pH sensing and imaging. As preliminary applications, the corrosion behavior of an iron screw and the reaction process of rust were investigated in buffer solutions of pH 2.0 and 2.9, respectively. The experiment demonstrated that the pH values of the analytes' surface were higher than that of buffer solutions due to the chemical reaction. It provides great potential for applications in optical multifunctional detection, especially in chemical sensing and biosensing. PMID- 22449308 TI - Infrared microspectroscopy using prism-based spectrographs and focal plane array detection. AB - Several prism-based spectrographs employing a mercury cadmium telluride (MCT) focal plane array detector have been interfaced to an infrared microscope. In the combined system, the area-defining aperture of the microscope also served as the entrance slit to the spectrograph. This investigation considered the fundamental limits of diffraction for both the spectrograph and microscope in order to determine both the spatial and spectral resolution of the system as a whole. Experimental results for spectral resolution, spectral range, and peak-to-peak noise have been presented. Finally, the dynamic capabilities of one spectrograph/microscope combination were investigated. PMID- 22449309 TI - Detection of reversible nonlinear dynamic responses of polymer films by using time-resolved soft-pulse compression attenuated total reflection step-scan Fourier transform infrared spectroscopy. AB - An improved time-resolved soft-pulse dynamic compression attenuated total reflection (ATR) step-scan Fourier transform rheo-optical system has been developed. This system was used to observe reversible dynamic responses of poly(ethyleneterephthalate) (PET) and poly(p-phenylene biphenyltetracarboximide) (BPDA-PDA) films. In the case of PET, reversible nonlinear dynamic responses were observed in the C=O stretching vibration. The nonlinear responses decreased with decreasing compressive strain from 0.045 to 0.018. For the C-O stretching bands associated with the backbone structure of the PET, the nonlinear responses were very small. Characteristic burst-like reversible nonlinear dynamic responses can be seen in the in-phase and out-of-phase C=O stretching vibrations of cyclic imides, and phenyl ring deformation bands in the PDA parts of the BPDA-PDA. The results suggest the presence of inter-molecular interaction between C=O of cyclic imides and the phenyl ring groups of the PDA parts. The present method shows promise for characterizing a wide variety of polymeric materials, including polymer alloys, blends, composites, and copolymers and semicrystalline polymers. PMID- 22449310 TI - A study on the resolution of a terahertz spectrometer for the assessment of the porosity of pharmaceutical tablets. AB - In this study, the resolution of a time-domain terahertz spectrometer for tablet porosity measurements was estimated using two sets of pharmaceutical tablets. One set consisted of tablets with constant thickness and with porosity as a variable. The other set consisted of tablets with variable thickness and only a relatively small change in porosity. The set with constant thickness was used for the calibration of the terahertz (THz) spectrometer for the porosity measurements, and the resolution of the terahertz spectrometer was estimated using the set with different thicknesses and slightly different porosities. It was shown that a time domain THz spectrometer is a sensitive device that allows monitoring of minute changes in the porosity of pharmaceutical tablets by detecting the time delay of the THz pulse, which is attributable to different refractive indices within the tablet. PMID- 22449311 TI - Quantum cascade laser-based measurement of metal alkylamide density during atomic layer deposition. AB - An in situ gas-phase diagnostic for the metal alkylamide compound tetrakis(ethylmethylamido) hafnium (TEMAH), Hf[N(C(2)H(5))(CH(3))](4), was demonstrated. This diagnostic is based on direct absorption measurement of TEMAH vapor using an external cavity quantum cascade laser emitting at 979 cm(-1), coinciding with the most intense TEMAH absorption in the mid-infrared spectral region, and employing 50 kHz amplitude modulation with synchronous detection. Measurements were performed in a single-pass configuration in a research-grade atomic layer deposition (ALD) chamber. To examine the detection limit of this technique for use as a TEMAH delivery monitor, this technique was demonstrated in the absence of any other deposition reactants or products, and to examine the selectivity of this technique in the presence of deposition products that potentially interfere with detection of TEMAH vapor, it was demonstrated during ALD of hafnium oxide using TEMAH and water. This technique successfully detected TEMAH at molecular densities present during simulated industrial ALD conditions. During hafnium oxide ALD using TEMAH and water, absorbance from gas-phase reaction products did not interfere with TEMAH measurements while absorption by reaction products deposited on the optical windows did interfere, although interfering absorption by deposited reaction products corresponded to only ~4% of the total derived TEMAH density. With short measurement times and appropriate signal averaging, estimated TEMAH minimum detectable densities as low as ~2 * 10(12) molecules/cm(3) could be obtained. While this technique was demonstrated specifically for TEMAH delivery and hafnium oxide ALD using TEMAH and water, it should be readily applicable to other metal alkylamide compounds and associated metal oxide and nitride deposition chemistries, assuming similar metal alkylamide molar absorptivity and molecular density in the measurement chamber. PMID- 22449312 TI - Estimating probabilistic confidence for mixture components identified using a spectral search algorithm. AB - Providing a confidence measure associated with the substance(s) identified in an unknown mixture by a spectral search technique is critical for non-expert users of devices and techniques based on spectroscopy. In this work, a technique for estimating probabilities associated with substances identified by spectral searching is described. In the proposed approach, a mixture analysis algorithm processes the spectrum of an unknown sample using a spectral library to generate a list of substances that may be present in the sample. The partial correlation of each of the substances in the list is then computed. The estimation of the probability is accomplished through a generalized linear model that converts the partial correlation values to a probability measure for each of the mixture components. The statistical properties of partial correlation allow probability estimation irrespective of whether a substance is present in a pure form or within a mixture. The technique was evaluated using both simulated and real Raman spectra of multi-component mixtures, and adequate performance was demonstrated. PMID- 22449313 TI - A 5-kg time-resolved luminescence photometer with multiple excitation sources. AB - A luminescence photometer was developed based on lanthanide-sensitized luminescence to detect environmental pollutants and residues in foods including, in particular, two classes of antibiotics: tetracyclines and fluoroquinolones. Multiple excitation sources, a xenon flashlamp and ultraviolet light-emitting diodes (UV LEDs), were used to their advantages. A photomultiplier tube module, gated to reject time-domain interferences, was used as a photodetector. Using danofloxacin as a model analyte, luminescence signal was linear in more than three decades (0.5-2000 ng/mL) with R(2) > 0.998 in each decade. This photometer achieved a limit of detection of 2.0 ng/mL with 1.3% average relative standard deviation. It is field deployable at 4.6 kg and 15 W power consumption. PMID- 22449314 TI - Methods for identifying lipoxygenase producing microorganisms on agar plates. AB - Plate assays for lipoxygenase producing microorganisms on agar plates have been developed. Both potassium iodide-starch and indamine dye formation methods were effective for detecting soybean lipoxygenase activity on agar plates. A positive result was also achieved using the beta-carotene bleaching method, but the sensitivity of this method was lower than the other two methods. The potassium iodide-starch and indamine dye formation methods were also applied for detecting lipoxygenase production by Trichoderma reesei and Pichia pastoris transformants expressing the lipoxygenase gene of the fungus Gaeumannomyces graminis. In both cases lipoxygenase production in the transformants could be identified. For detection of the G. graminis lipoxygenase produced by Aspergillus nidulans the potassium iodide-starch method was successful. When Escherichia coli was grown on agar and soybean lipoxygenase was applied on the culture lipoxygenase activity could clearly be detected by the indamine dye formation method. This suggests that the method has potential for screening of metagenomic libraries in E. coli for lipoxygenase activity. PMID- 22449315 TI - Matrix metalloproteinase-9 concentration in the cerebral extracellular fluid of patients during the acute phase of aneurysmal subarachnoid hemorrhage. AB - OBJECTIVES: The pathogenesis of delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) is multi-factorial and not completely elucidated. Matrix metalloproteinase-9 (MMP-9) might participate in wall remodeling leading to luminal narrowing. The authors investigated MMP-9 concentration in brain extracellular fluid of aSAH patients and assessed whether this enzyme could have a predictive value for the risk of DCI. METHODS: Patients were classified according to the grading of the World Federation of Neurological Surgeons (WFNS) in low- and high-grade patients (WFNS = 1-3, n = 9 and WFNS = 4-5, n = 12, respectively). Cerebral microdialysis probes were placed in brain parenchyma of the respective vascular territory of the aneurysm in 21 consecutive aSAH patients, enrolled in a prospective study on inflammation. Microdialysis samples, collected daily from day 0 until day 8 after aSAH, were retrospectively analyzed for MMP-9 by zymography. RESULTS: Initial concentration of the MMP-9 proform (pro-MMP-9) was significantly higher in high-grade patients as compared to low-grade patients. Furthermore, initial pro-MMP-9 concentration in patients with DCI was seven-fold higher than in asymptomatic patients. Pro-MMP-9 values greater than or equal to 0.27 pg/MUl showed 83% sensitivity and 63% specificity in predicting vasospasm. The mature form of the MMP-9 could be preferentially detected in patients with DCI but was usually low. DISCUSSION: The pro and mature forms of MMP-9 were released locally in the brain after aSAH. Pro-MMP-9 release was related to WFNS grade severity. This protease, considered as playing a critical role in endothelial basal membrane damage, may contribute to the inflammatory processes leading to arterial narrowing. PMID- 22449316 TI - Cochlear implants and magnetic resonance scans: A case report and review. AB - OBJECTIVE AND IMPORTANCE: Traditionally, magnetic resonance imaging (MRI) was contraindicated for patients with cochlear implants (CIs), due to concern about device displacement, overheating of the device or tissues, or direct damage to the device electrode. In addition, image artifact from the device magnet gave poor imaging information in the cranial and upper cervical spine region. Today, MRI is increasingly required in patients who have undergone cochlear implantation, and CI design and MRI protocols have therefore changed to allow implanted patients to safely enter the MRI field, in some cases without removal of the CI internal magnet. CLINICAL PRESENTATION: We present a patient with bilateral CIs who required MRI to investigate new neurological symptoms. Despite tight head bandaging applied according to our protocol, MRI at 1.5 T led to bilateral skin reactions and displacement of the magnet on the left. Both magnets were subsequently removed to allow the skin reactions to settle and for further imaging without artifact. The functioning of the patient's implants was not affected. CONCLUSION: The final decision to recommend that a patient with a CI undergoes MRI, with or without removal of the internal magnet, requires close cooperation between the CI team, the physician requiring the scan, and the radiology team involved in the patient's care. The case study we present highlights the need for patients to be fully informed of the risks involved. PMID- 22449317 TI - Bariatric surgery versus conventional medical therapy for type 2 diabetes. AB - BACKGROUND: Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed. METHODS: In this single-center, nonblinded, randomized, controlled trial, 60 patients between the ages of 30 and 60 years with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or more, a history of at least 5 years of diabetes, and a glycated hemoglobin level of 7.0% or more were randomly assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of <100 mg per deciliter [5.6 mmol per liter] and a glycated hemoglobin level of <6.5% in the absence of pharmacologic therapy). RESULTS: At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P<0.001 for both comparisons). Age, sex, baseline BMI, duration of diabetes, and weight changes were not significant predictors of diabetes remission at 2 years or of improvement in glycemia at 1 and 3 months. At 2 years, the average baseline glycated hemoglobin level (8.65+/-1.45%) had decreased in all groups, but patients in the two surgical groups had the greatest degree of improvement (average glycated hemoglobin levels, 7.69+/-0.57% in the medical-therapy group, 6.35+/-1.42% in the gastric-bypass group, and 4.95+/-0.49% in the biliopancreatic-diversion group). CONCLUSIONS: In severely obese patients with type 2 diabetes, bariatric surgery resulted in better glucose control than did medical therapy. Preoperative BMI and weight loss did not predict the improvement in hyperglycemia after these procedures. (Funded by Catholic University of Rome; ClinicalTrials.gov number, NCT00888836.). PMID- 22449318 TI - Surgery or medical therapy for obese patients with type 2 diabetes? PMID- 22449319 TI - Bariatric surgery versus intensive medical therapy in obese patients with diabetes. AB - BACKGROUND: Observational studies have shown improvement in patients with type 2 diabetes mellitus after bariatric surgery. METHODS: In this randomized, nonblinded, single-center trial, we evaluated the efficacy of intensive medical therapy alone versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled type 2 diabetes. The mean (+/ SD) age of the patients was 49+/-8 years, and 66% were women. The average glycated hemoglobin level was 9.2+/-1.5%. The primary end point was the proportion of patients with a glycated hemoglobin level of 6.0% or less 12 months after treatment. RESULTS: Of the 150 patients, 93% completed 12 months of follow up. The proportion of patients with the primary end point was 12% (5 of 41 patients) in the medical-therapy group versus 42% (21 of 50 patients) in the gastric-bypass group (P=0.002) and 37% (18 of 49 patients) in the sleeve gastrectomy group (P=0.008). Glycemic control improved in all three groups, with a mean glycated hemoglobin level of 7.5+/-1.8% in the medical-therapy group, 6.4+/-0.9% in the gastric-bypass group (P<0.001), and 6.6+/-1.0% in the sleeve gastrectomy group (P=0.003). Weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group (-29.4+/-9.0 kg and -25.1+/-8.5 kg, respectively) than in the medical-therapy group (-5.4+/-8.0 kg) (P<0.001 for both comparisons). The use of drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients receiving medical therapy only. The index for homeostasis model assessment of insulin resistance (HOMA-IR) improved significantly after bariatric surgery. Four patients underwent reoperation. There were no deaths or life-threatening complications. CONCLUSIONS: In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone. Further study will be necessary to assess the durability of these results. (Funded by Ethicon Endo Surgery and others; ClinicalTrials.gov number, NCT00432809.). PMID- 22449320 TI - Role of epigenetics in pharmacotherapy, psychotherapy and nutritional management of mental disorders. AB - WHAT IS KNOWN AND OBJECTIVE: There is increasing evidence that epigenetics plays a major role in the pathogenesis of the idiopathic mental disorders. This article comments on the role of epigenetics in the pharmacotherapy, psychotherapy and nutritional management of these disorders. COMMENT: There are two classes of epigenetic drugs undergoing trials for treating the idiopathic mental disorders: DNA methyltransferase and histone deacetylase inhibitors. These drugs may fulfil the need for newer and more effective drugs for treating these disorders. Psychotherapy could exert its therapeutic effect in idiopathic mental disorders through epigenetic mechanisms. As nutrients like folic acid and vitamin B(12) can influence an individual's epigenome, especially early in life, abnormal intakes of such agents may be involved in the pathogenesis of the idiopathic mental disorders. Hence, adequate emphasis should be given to such factors in an individual's nutrition, especially early in life. Nutrients such as L methylfolate and S-adenosylmethionine may also be useful in nutritional therapy of these disorders. WHAT IS NEW AND CONCLUSION: Epigenetics plays a key role in the pathogenesis of the idiopathic mental disorders. Due emphasis should be given to epigenetic mechanisms in the pharmacotherapy, psychotherapy and nutritional management of these disorders. PMID- 22449322 TI - Laser-induced breakdown spectroscopy (LIBS), part II: review of instrumental and methodological approaches to material analysis and applications to different fields. AB - The first part of this two-part review focused on the fundamental and diagnostics aspects of laser-induced plasmas, only touching briefly upon concepts such as sensitivity and detection limits and largely omitting any discussion of the vast panorama of the practical applications of the technique. Clearly a true LIBS community has emerged, which promises to quicken the pace of LIBS developments, applications, and implementations. With this second part, a more applied flavor is taken, and its intended goal is summarizing the current state-of-the-art of analytical LIBS, providing a contemporary snapshot of LIBS applications, and highlighting new directions in laser-induced breakdown spectroscopy, such as novel approaches, instrumental developments, and advanced use of chemometric tools. More specifically, we discuss instrumental and analytical approaches (e.g., double- and multi-pulse LIBS to improve the sensitivity), calibration-free approaches, hyphenated approaches in which techniques such as Raman and fluorescence are coupled with LIBS to increase sensitivity and information power, resonantly enhanced LIBS approaches, signal processing and optimization (e.g., signal-to-noise analysis), and finally applications. An attempt is made to provide an updated view of the role played by LIBS in the various fields, with emphasis on applications considered to be unique. We finally try to assess where LIBS is going as an analytical field, where in our opinion it should go, and what should still be done for consolidating the technique as a mature method of chemical analysis. PMID- 22449323 TI - Elemental analyses and determination of lead content in kohl (stone) by laser induced breakdown spectroscopy. AB - Elemental analyses of kohl (stone) samples collected from three different parts of the world were performed using laser-induced breakdown spectroscopy (LIBS). The analyses indicated that lead (Pb), copper (Cu), silver (Ag), iron (Fe), calcium (Ca), aluminum (Al), silicon (Si), and sodium (Na) were present in all the kohl samples. In addition to these elements, the sample from Madina, Kingdom of Saudi Arabia (KSA), contained the elements tin (Sn), zirconium (Zr), and antimony (Sb). The sample from Mount Toor, Egypt, also contained Sn. Also, quantitative analysis for lead was carried out by the standard addition method using the LIBS technique. The result showed the presence of 14.12 +/- 0.28% by weight of Pb in the sample from Madina, which compares well with the measurement done using atomic absorption spectroscopy (AAS) (13.31 +/- 0.46%). The standard addition method used three calibration curves drawn for three emission lines of the LIBS spectra of Pb. The limits of detection (LoD) for these calibration curves varied from 0.27% to 1.16% by weight. The lead contents of the samples from Mount Toor and the local market of Bangladesh were also measured by the AAS technique, and the results were 14.61 +/- 0.48% and 8.98 +/- 0.35% by weight, respectively. The reason for determining only the lead content in kohl, which may be used as an eye cosmetic, is the adverse effect that lead has on health. PMID- 22449324 TI - Silica crystalline colloidal array deep ultraviolet narrow-band diffraction devices. AB - We developed a facile method to fabricate deep ultraviolet (UV) photonic crystal crystalline colloidal array (CCA) Bragg diffraction devices. The CCAs were prepared through the self-assembly of small, monodisperse, highly surface charged silica particles (~50 nm diameter) that were synthesized by using a modified Stober process. The particle surfaces were charged by functionalizing them with the strong acid, non-UV absorbing silane coupling agent 3-(trihydroxylsilyl)-1 propane-sulfonic acid (THOPS). These highly charged, monodisperse silica particles self assemble into a face-centered cubic CCA that efficiently Bragg diffracts light in the deep UV. The diffracted wavelength was varied between 237 nm to 227 nm by tilting the CCA orientation relative to the incident beam between glancing angles from 90 degrees to ~66 degrees . Theoretical calculations predict that the silica CCA diffraction will have a full width at half-maximum (FWHM) of 2 nm with a transmission of ~10(-11) at the band center. We demonstrate the utility of this silica CCA filter to reject the Rayleigh scattering in 229 nm deep UV Raman measurements of highly scattering Teflon. PMID- 22449325 TI - Hard- and soft-modeling approaches for resolution of complex formation of Co2+ and Ni2+ with glycine. AB - Principal component analysis (PCA) was used to obtain information about the number of components in the complex formation equilibria of Co(2+) and Ni(2+) with glycine (Gly). In order to obtain a clearer insight into these complex formation systems, multivariate curve resolution-alternating least squares (MCR ALS) was used. Using MCR-ALS as a soft-modeling method, well-defined concentration and spectral profiles were obtained under unimodality, non negativity, and closure constraints. Based on the obtained results, an equilibrium model was proposed and subsequently, a hard-modeling method was used to resolve the complex formation equilibria completely. Due to the presence of multiple equilibria, the resolution of such systems is very difficult. The Co-Gly system was best described by a model consisting of M(GlyH), M(Gly), M(Gly)(2), M(Gly)(2)H, and M(Gly)(3) (M = Co(2+)) with the overall stability constants determined to be 7.10 +/- 0.011, 5.14 +/- 0.006, 9.28 +/- 0.009, 13.75 +/- 0.016, and 11.10 +/- 0.010, respectively. On the other hand, the system of Ni-Gly was best fitted by a model containing M(GlyH), M(Gly), M(Gly)(2), M(Gly)(3), and M(Gly)(2)(OH) (M = Ni(2+)) with overall stability constants of 10.95 +/- 0.04, 6.41 +/- 0.03, 11.31 +/- 0.03, 15.39 +/- 0.06, and 14.32 +/- 0.02, respectively. PMID- 22449326 TI - Characterization of swellable molecularly imprinted polymer particles by surface plasmon resonance spectroscopy. AB - Surface plasmon resonance (SPR) has been used to investigate template binding at sites in theophylline-imprinted poly-[N-(N-propyl) acrylamide] particles. At concentrations as low as 10(-6) M theophylline, particle swelling is detected as a shift in the angle of minimum reflectance. The binding constant of theophylline estimated from the inflection point of the theophylline calibration curve is approximately 10,000. The imprinted polymer particles do not respond to caffeine or theobromine (which differs from theophylline by a single methyl group) at concentrations as high as 10(-2) M. Full-scale response of the imprinted polymer particles to theophylline (template) occurs in less than 15 minutes, and swelling is reversible. The immobilized imprinted polymer particles can undergo approximately 20 to 25 swelling and shrinking cycles before there is significant loss in functionality. A unique aspect of these imprinted polymer particles is that template binding causes the angle of minimum reflectance to decrease, not increase, in magnitude. Adsorption, which causes an increase in the angle of minimum reflectance, can be readily discriminated from template binding. PMID- 22449327 TI - Selection of haploid maize kernels from hybrid kernels for plant breeding using near-infrared spectroscopy and SIMCA analysis. AB - Samples of haploid and hybrid seed from three different maize donor genotypes after maternal haploid induction were used to test the capability of automated near-infrared transmission spectroscopy to individually differentiate haploid from hybrid seeds. Using a two-step chemometric analysis in which the seeds were first classified according to genotype and then the haploid or hybrid status was determined proved to be the most successful approach. This approach allowed 11 of 13 haploid and 25 of 25 hybrid kernels to be correctly identified from a mixture that included seeds of all the genotypes. PMID- 22449328 TI - Transmission fourier transform Raman spectroscopy of pharmaceutical tablet cores. AB - Transmission Fourier transform (FT) Raman spectroscopy of pharmaceutical tablet cores is demonstrated using traditional, unmodified commercial instrumentation. The benefits of improved precision over backscattering Raman spectroscopy due to increased sample volume are demonstrated. Self-absorption effects on analyte band ratios and sample probe volume are apparent, however. A survey of near-infrared (NIR) absorption spectra in the FT-Raman spectral range (approximately 0 to 3500 wavenumber shift from 1064 nm, or 1064 to 1700 nm) of molecules with a wide range of NIR-active functional groups shows that although absorption at the laser wavelength (1064 nm) is relatively small, some regions of the Raman spectrum coincide with NIR absorbances of 0.5 per cm or greater. Fortunately, the pharmaceutically important regions of the Raman shift spectrum from 0 to 600 cm( 1) and from 1400 to 1900 cm(-1) exhibit low self-absorption for most organic materials. A statistical analysis of transmission FT-Raman noise in spectra collected from different regions of a pharmaceutical tablet provides insight into both spectral distortion and reduced sampling volume caused by self-absorption. PMID- 22449329 TI - Minimizing the effect of extraneous spikes in open-path Fourier transform infrared interferograms. AB - Intense spikes caused by extraneous factors are sometimes found in the interferograms of open-path Fourier transform infrared (OP/FT-IR) measurements. Those spikes result in dominant oscillations in the corresponding spectra and make the true spectral features indistinguishable from the noise. Three techniques were designed to remove the spikes: replacing the affected region by zeroes; grafting the data from the corresponding region on the other side of the centerburst ("homografting"); and grafting the data from the same region on the same side of the centerburst from a neighboring interferogram ("heterografting"). Results showed that all three techniques were effective to remove the spikes, but at the cost of introducing more noise into the corresponding spectrum. The performance of the heterograft technique was the best in terms of noise reduction. The factors affecting the noise level of spectra computed from spike-removed interferograms were also explored. A procedure was proposed to minimize the effect of spikes on OP/FT-IR spectra, and a Matlab program with a graphical user interface is available upon request to facilitate the implementation. PMID- 22449330 TI - Characterization of the interaction between 4-(tetrahydro-2-furanmethoxy)-N octadecyl-1,8-naphthalimide and human serum albumin by molecular spectroscopy and its analytical application. AB - A novel 4-(tetrahydro-2-furanmethoxy)-N-octadecyl-1,8-naphthalimide (TNN) was synthesized as a spectrofluorimetric probe for the determination of proteins. The effect of different solvents on the spectral characteristics of TNN was investigated. The results showed that TNN displayed dependent solvent polarity properties due to the effect of internal charge transfer. The interactions between TNN and human serum albumin (HSA) were studied by fluorescence and absorption spectroscopy. Fluorescence data revealed that the fluorescence quenching of HSA by TNN was the result of the formation of TNN-HSA complex. The binding parameters of interactions between TNN and HSA at different temperatures were obtained according to the Stern-Volmer equation. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS), for the interactions were calculated to be -7.31 kJ mol(-1) and 72.75 J mol(-1) K(-1) according to the van't Hoff equation, indicating that the hydrogen bonds and hydrophobic interactions were the dominant intermolecular force in stabilizing the complex. The effect of TNN on the conformation of HSA was analyzed by circular dichroism and synchronous fluorescence spectroscopy. Furthermore, the results of displacement experiments using warfarin indicated that TNN could bind to site I of HSA. The fluorescence of TNN could be largely quenched by HSA, based on which a new fluorometric method for detecting HSA in the HCl-Tris buffer solution (pH = 7.4) was developed. The linear ranges of the calibration curves were 0.1~14.2 MUM for HSA, 0.1~13.0 MUM for bovine serum albumin (BSA), 0.2~9.7 MUM for gamma-globulin, and 0.3~11.3 MUM for hemoglobin (Hb), with detection limits (3sigma) of 1.37 * 10(-10) M for HSA, 1.84 * 10(-10) M for BSA, 3.14 * 10( 10) M for gamma-globulin, and 6.86 * 10(-10) M for Hb. The effect of metal cations on the fluorescence spectra of TNN in ethanol was also investigated. The method has been applied to the determination of total proteins in human serum samples collected from the hospital and the results were in good agreement with those reported by the hospital. PMID- 22449331 TI - Accelerated weathering-induced degradation of poly(lactic acid) fiber studied by near-infrared (NIR) hyperspectral imaging. AB - Hydrolysis degradation of a set of drawn poly(lactic acid) (PLA) fibers was induced by an accelerated weathering test, radiating ultraviolet (UV) light under a certain temperature and humidity. The fine features of the transient behavior of the PLA fibers were captured by near-infrared (NIR) hyperspectral imaging. The PLA fibers showed a gradual decrease in mechanical property (e.g., tensile strength), indicating hydrolysis degradation. Thus, the detailed analysis of the spectral variation, in turn, offers useful information on the molecular-level degradation behavior of the drawn PLA fibers. The variation of the spectral intensity as well as band position shift of the crystalline band of PLA was analyzed. The spectral intensity of the crystalline band of PLA showed gradual decrease, suggesting the decrease in molecular weight induced by the hydrolysis degradation. In addition, the crystalline band also exhibited a coinciding shift to the lower wavenumber direction with the weathering test, revealing cleavage induced crystallization of the PLA samples. Consequently, the hydrolysis degradation induced by the weathering test substantially accelerates predominant degradation of the amorphous structure of the PLA and such variation of the molecular structure, in turn, brings less ductility to the PLA fiber. PMID- 22449332 TI - Cotreatment with darbepoetin and granulocyte colony-stimulating factor is efficient to recruit proangiogenic cell populations in patients with acute myocardial infarction. AB - To determine whether newer combination cytokine treatment with granulocyte colony stimulating factor (G-CSF) and darbepoetin can improve efficacy of stem cell therapy, we evaluated safety and peripheral blood stem/progenitor cell (PBSC) mobilizing effects of combination cytokine in comparison with G-CSF alone in patients with acute myocardial infarction (AMI). We randomized 60 patients with AMI into two groups under 2:1 ratio; combination treatment with darbepoetin and G CSF (n = 41: Combicytokine group) and the G-CSF alone (n = 19: G-CSF group). After coronary angioplasty, G-CSF was treated for 3 days with dose of 10 MUg/kg/day in both groups. Only in the combicytokine group, additional single intravenous injection of 4.5 MUg/kg of darbepoetin was administrated immediate after coronary angioplasty. Combination cytokine treatment was well tolerated as was G-CSF alone. PBSCs were obtained by apheresis for intracoronary infusion after completion of cytokine treatment and were analyzed by flow cytometry. The purity of proangiogenic cells was higher in combination cytokine group than the G CSF group. Specifically, proportion of CD34(+)/KDR(+) endothelial progenitor cells, CD3(+)/CD31(+) angiogenic T cells and Tie2(+)/CXCR4(+) cells in apheresis products were higher in the combicytokine group. These meant that the combicytokine treatment recruited PBSCs in higher purity and fewer unwanted inflammatory cells than G-CSF alone in apheresis products. Combination treatment with darbepoetin and G-CSF is safe and more efficient to mobilize and recruit proangiogenic cells than G-CSF alone in patients with AMI. ( TRIAL REGISTRATION: www.ClinicalTrials. gov identifier: NCT00501917). PMID- 22449333 TI - Cortisol levels in hair reflect behavioural reactivity of dogs to acoustic stimuli. AB - Cortisol levels in hair samples were examined in fourteen domestic dogs and related to the dogs' responses to different acoustic stimuli. Stimuli were playbacks of species-typical vocalizations recorded during three different situations ("disturbance", "isolation" and "play" barks) and the sounds of a thunderstorm. Hair samples were collected at 9:00 h and 17:00 h two weeks after the behavioural tests. Results showed that behavioural reactivity to playback of the various stimuli correlates with cortisol levels in hair samples collected at 9:00 h, and the same was the case for the separate measures of behaviour (i.e. hiding, running away, seeking attention from the tester, panting and lowering of the body posture). Hence, levels of cortisol in hair appear to reflect the dog's chronic state of emotional reactivity, or temperament. PMID- 22449334 TI - Dyslipidemia and oxidative stress in sarcoidosis patients. AB - OBJECTIVES: Sarcoidosis is an inflammatory disease characterised by enhanced production of reactive oxygen species and alterations in the circulating lipid profile. Both attributes are thought to play a role in its pathogenesis. However, current knowledge regarding the significance of blood oxidative stress/anti oxidant defence as well as alterations in lipid status parameters in sarcoidosis is scarce. The aim of our study was to assess these parameters and their inter relationships, as well as their potential for patient-control discrimination. DESIGN AND METHODS: Oxidative stress status and anti-oxidant defence parameters were determined in serum and erythrocytes and lipid status parameters were assessed in the serum of 213 treated sarcoidosis patients and 90 controls. RESULTS: Malondialdehyde, superoxide anion, total oxidant status, prooxidant antioxidant balance and triglycerides were significantly higher whereas total anti-oxidant status, superoxide dismutase activity and HDL-cholesterol were significantly lower in sarcoidosis patients compared with controls. Total sulfhydryl group content was higher in patients compared with controls. Serum and erythrocyte malondialdehyde exhibited the strongest ability to predict disease presence. Elevated oxidative stress was characterised by higher clinical accuracy compared with lipid status abnormality. Some oxidative stress and lipid status markers were significantly associated in sarcoidosis. CONCLUSIONS: Sarcoidosis is characterised by increased oxidative stress, diminished overall anti-oxidative protection and alterations in the circulating lipid profile. Both oxidative stress and lipid status parameters demonstrated the potential to discriminate sarcoidosis from controls which was particularly evident from the point of view of oxidative stress status parameters. Association between these parameters may indicate an increased risk for atherosclerosis development. PMID- 22449335 TI - Association of MIF in serum and synovial fluid with severity of knee osteoarthritis. AB - OBJECTIVE: Recent evidences suggest that inflammation contributes to the development and progression of osteoarthritis (OA). This study aims to determine macrophage migration inhibitory factor (MIF) levels in serum and synovial fluid (SF) of patients with knee OA and to analyze the association of MIF levels with the radiographic severity of OA. DESIGN AND METHODS: 224 patients with knee OA and 186 healthy controls were enrolled in this study. RESULTS: Higher levels of serum MIF were found in knee OA patients compared with healthy controls. Knee OA patients with Kellgren and Lawrence (KL) grade 4 showed significantly elevated MIF levels in serum and SF compared with those with KL grade 2 and 3. MIF levels in serum and SF of knee OA patients were significantly related to disease severity evaluated by KL grading criteria. CONCLUSION: MIF levels in serum and SF were closely related to the radiographic severity of OA. PMID- 22449336 TI - Development of multiplex real-time quantitative PCR for simultaneous detection of Chlamydia trachomatis and Ureaplasma parvum. AB - OBJECTIVES: Chlamydia trachomatis and Ureaplasma urealyticum are common pathogens of sexually transmitted diseases. The majority of human ureaplasma isolates belong to the new species U. parvum. Clinically, C. trachomatis and U. parvum usually double infect in the nongonococcal urethritis patients. A novel method for simultaneous detection of C. trachomatis and U. parvum was set up in the present work. DESIGN AND METHODS: Multiple real-time quantitative PCR was developed to allow for rapid, sensitive, specific and quantitative detection of C. trachomatis and U. parvum, simultaneously. To evaluate the applicability of the multiplex real-time quantitative PCR assay to clinical specimens, 64 samples of cervical swabs collected were studied. RESULTS: Compared to the results obtained from single real-time quantitative PCR of C. trachomatis and U. parvum, the specificity, sensitivity and quantitative detection results of multiple real time quantitative PCR are approximately identical with those of the former. CONCLUSIONS: This assay will be of great value in the simultaneous and rapid diagnosis of C. trachomatis and U. parvum in the future. PMID- 22449337 TI - Association of follicle-stimulating hormone and sex hormone binding globulin with the metabolic syndrome in postmenopausal women. AB - OBJECTIVES: We compared the association of follicle-stimulating hormone (FSH) and sex hormone binding globulin (SHBG) with metabolic syndrome (MetS). DESIGN AND METHODS: We examined 320 postmenopausal women (148 with MetS and 172 without MetS). RESULTS: FSH was more strongly associated with MetS probability in the logistic regression model compared to SHBG. Receiver operating characteristic (ROC) curves comparison showed greater areas under the curve for FSH than SHBG concentrations. CONCLUSIONS: FSH exhibited a stronger coherence to MetS than SHBG in postmenopausal women. PMID- 22449338 TI - Long-term biological variation in cardiac troponin I. AB - OBJECTIVES: To determine the long-term biological variation (BV) of cardiac troponin I. DESIGN AND METHODS: Three samples separated by a mean of 8.7 +/- 2.8 months from 17 patients seen in an outpatient clinic. Tropoinin I was measured using a high sensitivity assay from Singulex, Inc. RESULTS: The long-term analytical, intra-assay and total variation were 15.2%, 27.9%, and 70.9%, respectively. The index of individuality (II) was 0.45, and the reference change value was +98% and -50%, respectively. CONCLUSION: The BV over 9 months was comparable to previously published results over 2 months using the same testing methodology. The II indicates that reference range values are of less value than serial testing. PMID- 22449339 TI - The renal amalgam: where renal pathology fits. PMID- 22449340 TI - The global role of kidney transplantation. PMID- 22449341 TI - Glomerular grievances and CKD. PMID- 22449342 TI - Renal biopsy in the elderly and very elderly: useful or not? AB - Longer life expectancy has led to a growing epidemic of kidney disease in the elderly (aged >= 65 years) and very elderly (aged >= 80 years). While much of the rising burden of kidney disease in these age-groups can be attributed to age associated decline and a high prevalence of comorbidities such as hypertension and diabetes mellitus, a significant proportion of kidney disease is due to potentially reversible causes of injury in the glomerular, tubulointerstitial, and vascular compartments. A renal biopsy is crucial not only to diagnose such potentially reversible lesions but also to provide prognostic information and guide therapeutic decisions. In this review, we survey the literature on renal biopsy in the elderly and very elderly, focusing on the utility and safety of this procedure. We report the most common histopathologic findings in these age groups and demonstrate that many of these lesions are associated with diseases that respond to appropriate therapies, regardless of age. We conclude that, in a variety of commonly encountered clinical situations, a renal biopsy is crucial for appropriate management of elderly and very elderly patients with kidney disease. PMID- 22449343 TI - Infection-related glomerulonephritis: changing demographics and outcomes. AB - Postinfectious glomerulonephritis (PIGN) is the classic form of immune-mediated infection-associated glomerulonephritis following a nonrenal infection. Its epidemiology has been changing over the past several decades, with recent data indicating a global decline, particularly in developed countries. This is owing to better and earlier treatment of infections, and improvements in living conditions and nutrition. The currently affected patient population tends to be older, with more adults developing the disease, especially those with comorbidities such as diabetes; approximately one-third of adults with PIGN will have at least one comorbid factor. Organisms causing PIGN are also changing, with fewer cases associated with Streptococcus and more cases owing to Staphylococcus. IgA-dominant PIGN has become more widely recognized as a lesion usually found in adult patients with diabetes or another form of chronic illness, with more severe clinical manifestations and a more guarded outcome. Children have the best prognosis and outcome followed by healthy adults, with adults having comorbid factors exhibiting more chronic renal injury following PIGN. It is important to be aware of these shifting features of PIGN, as the impacted patient population is at higher risk for poor renal outcome. PMID- 22449344 TI - Podocyte biology in segmental sclerosis and progressive glomerular injury. AB - During the past 2 decades, progress has been made in understanding the biology and mechanisms of podocyte injury and the relationship of these processes to glomerulosclerosis. In addition, studies of human biopsies and animal models have provided insights into the mechanisms of glomerular disease progression and repair. These new developments are critical for establishing better therapeutic guidelines that target specific pathways, which otherwise would lead to irreversible injury. PMID- 22449345 TI - Complement in glomerular disease. AB - The role of the complement system in renal disease has long been recognized, but there have been major advances in our understanding of its role over the past decade. Complement plays a critical role not only in host's defense against infection and preventing damage to "self" tissues but also mediates tissue injury, both in the glomerulus and tubulointerstitium. Although injury may originate in the glomerulus, resulting proteinuria and complement activation within the tubular lumen may lead to tubulointerstitial damage and progressive renal disease. Recent advances in our understanding of the mechanisms by which complement mediates renal injury have led to the development of promising strategies with which complement may be targeted to prevent renal injury and its associated complications. PMID- 22449346 TI - Novel insights into the relationship between glomerular pathology and progressive kidney disease. AB - Both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of nephropathy. Glomerular injury is associated with tubulointerstitial inflammation, and many studies show that tubulointerstitial changes correlate well with progressive renal functional decline. Strong evidence supports the concept that once established, proteinuric glomerular injury can cause tubular injury. This review briefly summarizes the pathophysiological consequences of glomerular damage that are responsible for tubulointerstitial injury. It further focuses on tubule-derived renal injury biomarkers that may be used to monitor the progression of kidney disease. This monitoring is predicted to become increasingly useful as novel therapeutic interventions preventing progressive renal damage are introduced. In particular, biomarkers of kidney dysfunction, such as urinary podocytes, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, hematopoietic growth factor-inducible neurokinin 1, or periostin, might be useful in the diagnosis or detection of early nephropathy and risk assessment of kidney disease. However, these biomarkers require further study before they are used in routine screening or in guiding patient therapy. PMID- 22449347 TI - Collagen Type III Glomerulopathies. AB - The 2 rare disorders characterized by the pathological accumulation of collagen type III in glomeruli are discussed. These are collagenofibrotic glomerulopathy, also known as collagen type III glomerulopathy, and the nail-patella syndrome. Although there are similarities in abnormal morphology, with type III collagen in mesangium and/or capillary walls, there is no genetic or pathogenic link to them. Collagenofibrotic glomerulopathy presents either in childhood, often with a family history suggesting autosomal recessive inheritance, or in adults as a sporadic occurrence. Proteinuria is the typical manifestation, with progression to ESRD in approximately 10 years. Although there is markedly elevated serum precursor collagen type III protein in the circulation, the usual manner of diagnosis is with kidney biopsy, which discloses type III collagen in subendothelial aspects of capillary walls and often in the mesangial matrix. Glomerular involvement in the nail-patella syndrome invariably presents in a patient with an established diagnosis of this multisystem disorder with orthopedic and cutaneous manifestations. It is owing to mutations in the gene LMX1B. Although the lesion may be asymptomatic, it is usually manifested by proteinuria. Structural lesions are of collagen type III within glomerular basement membranes, different in distribution to collagenofibrotic glomerulopathy. The clinical course is variable. PMID- 22449348 TI - Morphologic markers of progressive immunoglobulin A nephropathy. AB - The clinical outcome of patients with immunoglobulin A (IgA) nephropathy is highly variable, and immunosuppressive therapies used to treat progressive disease carry a high risk of toxicity. While the kidney biopsy remains essential for the diagnosis of IgA nephropathy, previous biopsy scoring systems have not been consistently integrated into clinical care. Recent rigorous efforts to describe and quantify clinically important morphologic measures of disease activity and injury have established that data gleaned from kidney biopsies provides independent prognostic information. In this article we review the recent derivation of a simplified scoring system for IgA nephropathy and discuss potential integration of pathology scores into routine clinical care. PMID- 22449349 TI - Recent advances and prognosis in idiopathic membranous nephropathy. AB - Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome. Recently, progress has been made in understanding the pathogenesis of idiopathic MN with the finding of M-type phospholipase A2 receptor (PLA2R) antibodies in the serum and immune complexes of glomeruli in the majority of adult idiopathic MN patients. In the future, the detection of M-type PLA2R antibodies may help distinguish patients with primary MN who require aggressive immunosuppressive therapy from those with secondary disease. Levels of circulating antibody to this receptor may help in monitoring disease activity and in gauging response to therapy, as changes in antibody levels may precede changes in proteinuria. The degree of renal dysfunction or change in renal function over time and the level of persistent proteinuria are key prognostic factors in the decision to initiate therapy in idiopathic MN patients. Although spontaneous remissions occur in ~30% of patients, partial and complete remissions help to define the clinical course of an individual patient. PMID- 22449351 TI - Commentary: Impaired driving: what is your responsibility as an emergency physician? PMID- 22449350 TI - Drowsy man with breathlessness and blurred vision. Methanol toxicity. PMID- 22449353 TI - Annals of Emergency Medicine Journal Club. Computed tomography imaging in the emergency department: benefits, risks and risk ratios. Answers to the November 2011 Journal Club questions. PMID- 22449354 TI - Man with confusion and resolved paralysis. Lightning strike injury. PMID- 22449355 TI - Clarification of funding sources in "Electronic control device exposures: a review of morbidity and mortality". PMID- 22449356 TI - Thrombolytic use in transient ischemic attack and stroke mimics. PMID- 22449358 TI - Lessons from the Glasgow Coma Scale. PMID- 22449359 TI - Acute vision loss. Keratoconus with acute corneal hydrops. PMID- 22449360 TI - Development of the ASE test battery for assessment of pitch perception in speech. AB - OBJECTIVES: The auditory speech sounds evaluation 2009 test battery for assessment of speech pitch perception is presented. It was designed to (a) assess perception of pitch in linguistic contexts without the confounds of secondary acoustic cues, (b) be usable with listeners from different language backgrounds, and (c) be suitable for use in a clinical setting. The need for this test battery arises from increased awareness of the importance of prosody in clinical practice, and the development of methods for improving pitch perception in listeners with profound hearing losses. METHODS: Identification and discrimination tasks based on linguistic contexts were developed to establish listeners' just noticeable differences (JNDs) for pitch changes. Stimuli were pseudosentences and pseudowords based on speech from a female speaker, overlain with stylized pitch contours. Target pitch excursions were varied from the 200 Hz baseline to a maximum of 349 Hz. Ninety normal-hearing listeners participated in test validation that assessed goals (a)-(c), established test-retest reliability, and gathered normative data. RESULTS: The JNDs on non-linguistic, control tasks were lower than on linguistic ones, showing that non-linguistic tasks may overestimate pitch perception in speech. Listeners from different language backgrounds scored comparably on most linguistic tasks, and test-retest differences were non-significant. Test usability as evidenced by task duration and subject experience seemed satisfactory for clinical use. PMID- 22449361 TI - Solitary fibrous tumor arising slowly in the vulva over 10 years: case report and review. AB - Solitary fibrous tumor (SFT), which was first described as a pleural lesion by Klemperer and Rabin in 1931, is a rare, slow-growing neoplasm characterized by the proliferation of fibroblast-like spindle cells arranged in a patternless manner with few nuclear atypia. Extrathoracic SFT have increasingly been recognized, but those in the genital tract are extremely rare. Gynecological SFT behave as tumors with low malignant potential to recur, metastasize, or affect nearby organs resulting in infertility. We report a case of vulvar SFT slowly growing for 10 years, and propose a strategy for the diagnosis and treatment of gynecological SFT. PMID- 22449364 TI - Hematological malignancies: a primer. PMID- 22449365 TI - Chronic lymphocytic leukemia. PMID- 22449366 TI - Chronic myelogenous leukemia for primary care physicians. PMID- 22449367 TI - Myeloproliferative neoplasms. PMID- 22449368 TI - Current concepts of clinical management of multiple myeloma. PMID- 22449369 TI - Overview of non-Hodgkin's lymphoma. PMID- 22449370 TI - Adult acute leukemia. PMID- 22449371 TI - Infections in hematological malignancies. PMID- 22449372 TI - Maturation of periodontal tissues following implantation of rhGDF-5/beta-TCP in one-wall intra-bony defects in dogs: 24-week histological observations. AB - OBJECTIVE: Although a previous study reported that recombinant human growth/differentiation factor-5 (rhGDF-5) coated onto a beta-tricalciumphosphate (beta-TCP) significantly enhanced periodontal regeneration, the long-term stability/maturation of the regenerated tissues has not been demonstrated. The objective of this study was to evaluate periodontal regeneration/maturation following application of rhGDF-5/beta-TCP using an established periodontal defect model and a 24-week healing interval. MATERIAL & METHODS: Unilateral, surgically created, 4 * 4 * 5 mm (length * width * height), one-wall, critical-size, intra bony periodontal defects at the mandibular second and fourth premolar teeth in five young adult Beagle dogs received rhGDF-5/beta-TCP. Bilateral sites at the fourth premolar in the other four dogs served as pristine controls receiving mucogingival flap surgery without defect induction. The animals were euthanized at 24 weeks for histological analysis. Unpublished data from the previous 8-week study were used to compare tissue maturation between 8 and 24 weeks. RESULTS: Linear histometric observations of cementum and alveolar regeneration showed no significant differences between the 8- and 24-week observation intervals. However, parameters of periodontal tissue maturation showed significant differences between the observation intervals including increased fraction mineralized tissue and lamellar bone (p < 0.05) and decreased osteocyte counts (p < 0.05) at 24 weeks compared with 8 weeks. Although the count inserting Sharpey's fibre did not significantly change, regenerated cementum remote from the intact periodontal ligament appeared more highly mineralized and thicker at 24 weeks compared with 8 weeks, and compared with the pristine cementum. Minimal beta-TCP remained. CONCLUSIONS: These 24-week observations suggest that regenerated periodontal tissues in sites receiving rhGDF-5/beta-TCP undergo progressive maturation without debilitating aberrant tissue reactions. PMID- 22449373 TI - Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation. AB - The present study was performed to examine whether paricalcitol may prevent the cisplatin-induced kidney injury. Furthermore, potential molecular mechanisms underlying the protective effect of paricalcitol were explored. Male Sprague Dawley rats were treated with vehicle (n=12), cisplatin (n=12, 6 mg/kg/day, i.p.), or cisplatin+paricalcitol (n=12, 0.2 MUg/kg/day, s.c.) for 4 days. In another series of experiment, HK-2 cells were treated with cisplatin (50 MUM), with or without paricalcitol (0.2 ng/ml). Paricalcitol counteracted the cisplatin induced decline in renal function. Paricalcitol also suppressed the expression of TGF-beta1, Smad signaling, and the subsequent epithelial-to-mesenchymal process in cisplatin-treated rats. The expression of P-p53 and p21 was increased in cisplatin-induced nephropathy. These changes were completely prevented or significantly attenuated with paricalcitol co-treatment. The expression of p27(kip1) was increased in cisplatin-treated rats, which was, however, further augmented by the paricalcitol co-treatment. In HK-2 cells, cisplatin increased the expression of p-ERK1/2 and P-p38. Cisplatin also increased the expression of fibronectin and CTGF. Cisplatin increased the expression of pro-apoptotic markers. The expression of CDK2 and Cyclin E as well as that of PCNA was increased. These changes were completely prevented or significantly attenuated by the paricalcitol pretreatment. In contrast, cisplatin increased the expression of p27(kip1), which was further augmented by the paricalcitol-pretreatment. These results suggest that paricalcitol may ameliorate cisplatin-induced renal injury by suppressing the fibrotic, apoptotic and proliferative factors. Its underlying mechanisms may include inhibition of TGF-beta1, mitogen-activated protein kinase signaling, p53-induced apoptosis, and augmentation of p27(kip1). PMID- 22449374 TI - Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d aspartate receptor antagonists in rats with neuropathic spinal cord injury pain. AB - Underlying below-level cutaneous hypersensitivity observed following spinal cord injury (SCI) is a concurrent loss of inhibition with an increase in excitation in the spinal dorsal horn. Thus, a dual pharmacological approach, increasing spinal gamma-aminobutyrate (GABA) inhibition and decreasing N-methyl-d-aspartate (NMDA) receptor-mediated excitation, could be more beneficial than either approach alone. The current study evaluated the antinociceptive effects of lumbar intrathecal (i.t.) administration of GABA receptor agonists and NMDA receptor antagonists alone and in combination in rats with neuropathic SCI pain. Rats developed markedly decreased hind paw withdrawal thresholds following an acute thoracic spinal cord compression, indicative of below-level hypersensitivity. Separately, i.t. GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen demonstrated dose-dependent antinociception, whereas i.t. NMDA receptor antagonist ketamine and the endogenous peptide [Ser1]histogranin, a putative NMDA receptor antagonist, demonstrated no efficacy. The combination of baclofen and ketamine resulted in a supra-additive (synergistic) antinociception whereas the combinations with muscimol were merely additive. Intrathecal pretreatment with the GABA(B) receptor antagonist CGP 35348 prevented the antinociceptive effect of the baclofen and ketamine combination. The data indicate that blocking spinal NMDA receptors alone is not sufficient to ameliorate SCI hypersensitivity, whereas a combined approach, simultaneous activation of spinal GABA(B) receptors and NMDA receptor blockade with ketamine, leads to significant antinociception. By engaging diverse pain modulating systems at the spinal level, combination drug treatment may be a useful approach in treating neuropathic SCI pain. PMID- 22449375 TI - Effect of ranolazine on rat intrarenal arteries in vitro. AB - Ranolazine is mainly used to treat patients with chronic stable angina in clinical practice. However, ranolazine does not lower significantly systemic blood pressure. The direct effect of ranolazine on vascular tone remains unknown. In the present study, we investigated the vascular effects and mechanisms of action of ranolazine in isolated rat intrarenal arteries. Rings of intrarenal arteries were mounted in a small vessel myography using two stainless steel wires for the measurement of isometric tension. L-type Ca2+ currents were recorded in isolated single renal arterial smooth muscle cells using patch clamp techniques in whole-cell mode. Ranolazine induced concentration-dependent relaxations in rings contracted with phenylephrine, but ranolazine failed to cause any relaxation in rings pre-contracted by U46619, 5-HT or endothelin-1. Ranolazine also induced relaxations in norepinephrine pre-contracted rings. Yohimbine failed to induce relaxation in rings pre-contracted by norepinephrine. Propranolol did not affect ranolazine-induced relaxation but the relaxant effect of ranolazine was much less than that of prazosin. Ranolazine-induced relaxations were slight but significantly attenuated by endothelial denudation. Partial inhibition was observed in endothelium-intact arteries exposed to a combination of iberiotoxin and apamin. Ranolazine at higher concentration (>30 MUM) inhibited Ca2+-induced contraction in a noncompetitive manner. Ranolazine reduced L-type Ca2+ currents at potentials between -30 and 50 mV in isolated renal artery myocytes. Therefore it can be said that ranolazine has significant alpha1-adrenergic receptor and weak calcium channel antagonistic effects in rat intrarenal arteries. PMID- 22449376 TI - Prevention of age-related memory deficit in transgenic mice by human choline acetyltransferase. AB - Choline acetyltransferase (ChAT, acetylCoA:choline O-acetyltransferase, EC 2.3.1.6) is the biosynthetic enzyme of neurotransmitter acetylcholine. Here we showed for the first time that transgenic mice with human ChAT kept excellent learning and memory ability during aging process. Transgenic mice were prepared through microinjection of human ChAT into mouse fertilized eggs, and PCR reaction was used to screen out the transgenic mice. The results of measurements of ChAT activity and acetylcholine level in mouse brain indicated that human ChAT gene was expressed throughout the life of the transgenic mice. The results of step through test and water maze test suggested that learning and memory ability was improved in transgenic mice compared to that of their age-matched littermates. The results support our idea that supplement of ChAT might serve as a potential therapeutic strategy for cognitive deficit. PMID- 22449377 TI - Montelukast abrogates rhabdomyolysis-induced acute renal failure via rectifying detrimental changes in antioxidant profile and systemic cytokines and apoptotic factors production. AB - In addition to antiasthmatic effect, the cysteinyl leukotriene receptor 1 (CysLT1) antagonist montelukast shows renoprotective effect during ischemia/reperfusion and cyclosporine-induced renal damage. Here, we proposed that montelukast protects against rhabdomyolysis-induced acute renal failure. Compared with saline-treated rats, at 48 h following the induction of rhabdomyolysis using intramuscular glycerol (10 ml 50% glycerol/kg), significant elevations in serum levels of urea, creatinine, phosphate and acute renal tubular necrosis were observed. This was associated with elevations in serum Fas, interleukin-10, tumor necrotic factor-alpha, and transforming growth factor-beta1 and renal malondialdehyde and nitrite and detrimental reductions in renal catalase and superoxide dismutase activities. The effects of rhabdomyolysis on renal functional, biochemical and structural integrity and the associated changes in cytokines and Fas levels were abolished upon concurrent administration of montelukast (10 mg/kg i.p.) for 3 days (1 day before and 2 days after induction of rhabdomyolysis). Alternatively, administration of the anti-oxidant, alpha tocopherol (400 mg/kg i.m.) for 3 days, succeeded in alleviating renal oxidative stress, but had no significant effect on the circulating levels of most cytokines and partially restored kidney functional and structural damage. Serum level of interleukin-6 was not altered by rhabdomyolysis but showed significant elevations in rats treated with montelukast or alpha-tocopherol. Collectively, motelukast abrogated functional and structural renal damage induced by rhabdomyolysis via ameliorating renal oxidative stress and modulation of systemic cytokines and apoptotic factors production. The results of this work are expected to open new avenues for early prevention of rhabdomyolysis-induced acute renal failure using selective CysLT1 antagonists such as montelukast. PMID- 22449378 TI - Effects of (+/-)-praeruptorin A on airway inflammation, airway hyperresponsiveness and NF-kappaB signaling pathway in a mouse model of allergic airway disease. AB - The root of Peucedanum praeruptorum Dunn is a traditional Chinese medicine commonly used to treat asthma in China. (+/-)-praeruptorin A (PA) is the most abundant constituent of P. praeruptorum Dunn, the effects of which on asthma were investigated using a murine model of allergic airway disease. BALB/c mice were sensitized and challenged by ovalbumin to induce airway inflammation. PA was administered intragastrically before every OVA challenge. Airway responsiveness was measured by a lung function analysis system. The number of total leukocytes in bronchoalveolar lavage fluid was counted using a hemocytometer, and differential cell counts were determined using Diff-Quick-stained smears. Histopathology of lung tissue was analyzed by hematoxylin-eosin and Congo red staining. Levels of inflammatory mediators in bronchoalveolar lavage fluid and immunoglobulins in serum were measured by enzyme-linked immunosorbent assay. The expression of pulmonary eotaxin was detected by immunohistochemistry and reverse transcription polymerase chain reaction. The activation of NF-kappaB was evaluated by electrophoretic mobility shift assay and western blot analysis. Compared with model group, PA significantly reduced airway hyperresponsiveness and airway eosinophilic inflammation, improved pathologic lesion of the lungs, reduced levels of interleukin (IL)-4, IL-5, IL-13 and LTC4 in bronchoalveolar lavage fluid and immunoglobulin (Ig) E in serum, and inhibited eotaxin protein and mRNA expression, IkappaBalpha degradation, NF-kappaB nuclear translocation, NF-kappaB DNA-binding activity and RelA/p65 phosphorylation in lung, which suggested that PA can significantly suppress OVA-induced airway inflammation and airway hyperresponsiveness in mice, showing great therapeutic potential for the treatment of allergic asthma. PMID- 22449379 TI - Tramadol antinociception is potentiated by clonidine through alpha2-adrenergic and I2-imidazoline but not by endothelin ET(A) receptors in mice. AB - Tramadol is a centrally acting analgesic that acts via MU-opioid agonism and by blocking the neuronal uptake of norepinephrine and serotonin. Clonidine potentiates the antinociceptive effects of tramadol; however the receptors involved in this potentiation have not been studied. Endothelin ET(A) receptor antagonists potentiate antinociceptive effects of morphine and oxycodone; however the effects of endothelin ET(A) receptor antagonists on tramadol antinociception have not been evaluated. This study was conducted to determine the effect of clonidine on tramadol antinociception; the role of opioid, alpha2-adrenergic and I2-imidazoline receptors in clonidine potentiation of tramadol antinociception; and the effect of endothelin ET(A) receptor antagonists in modulating tramadol antinociception. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with tramadol; clonidine plus tramadol; or antagonists plus tramadol. Mice were pretreated with naloxone (opioid antagonist), yohimbine (alpha2-adrenoceptor antagonist), idazoxan (alpha2 adrenoceptor/I2-imidazoline antagonist), BMS182874 or BQ123 (endothelin ET(A) receptor antagonists) to study the involvement of these receptors. Tramadol produced a dose dependent increase in antinociceptive latencies. Tramadol antinociception was partially blocked by naloxone but not by yohimbine or idazoxan. Clonidine potentiated tramadol antinociception; potentiation was blocked by naloxone, yohimbine and idazoxan. Idazoxan produced a more pronounced blockade of potentiation than yohimbine. BMS182874 or BQ123 had no effect on tramadol antinociception, indicating that endothelin ET(A) receptors are not involved in tramadol antinociception in mice. Results demonstrate the involvement of opioid but not alpha2-adrenergic/I2-imidazoline receptors in tramadol antinociception and that opioid, alpha2-adrenergic and I2-imidazoline receptors are involved in clonidine potentiation of tramadol antinociception. PMID- 22449380 TI - Somatostatin receptor subtype-4 agonist NNC 26-9100 decreases extracellular and intracellular Abeta1-42 trimers. AB - Soluble amyloid beta-protein (Abeta) oligomers are primary mediators of synaptic dysfunction associated with the progression of Alzheimer's disease. Such Abeta oligomers exist dependent on their rates of aggregation and metabolism. Use of selective somatostatin receptor-subtype agonists have been identified as a potential means to mitigate Abeta accumulation in the brain, via regulation of the enzyme neprilysin. Herein, we first evaluated the impact of the somatostatin receptor subtype-4 agonist 1-[3-[N-(5-Bromopyridin-2-yl)-N-(3,4 dichlorobenzyl)amino]propyl]-3-[3-(1H-imidazol-4-yl)propyl]thiourea (NNC 26-9100) on learning and memory in 12-month SAMP8 mice (i.c.v. injection). NNC 26-9100 (0.2 MUg-dose) was shown to enhance both learning (T-maze) and memory (object recognition) compared to vehicle controls. Cortical and hippocampal tissues were evaluated subsequent to NNC 26-9100 (0.2 MUg) or vehicle administration for changes in neprilysin activity, along with protein expression of amyloid precursor protein (APP), neprilysin, and Abeta1-42 oligomers within respective cellular fractions (extracellular, intracellular and membrane). NNC 26-9100 increased neprilysin activity in cortical tissue, with an associated protein expression increase in the extracellular fraction and decreased in the intracellular fraction. A decrease in intracellular APP expression was found with treatment in both cortical and hippocampal tissues. NNC 26-9100 also significantly decreased expression of Abeta1-42 trimers within both the extracellular and intracellular cortical fractions. No expression changes were found in membrane fractions for any protein. These finding suggest the potential use of selective SSTR4 agonists to mitigate toxic oligomeric forms of Abeta1-42 in critical regions of the brain identified with learning and memory decline. PMID- 22449381 TI - Neuronal nitric oxide synthase inhibition attenuates the development of L-DOPA induced dyskinesia in hemi-Parkinsonian rats. AB - Long-term treatment with the dopamine precursor levodopa (l-DOPA) frequently induces dyskinesia in Parkinson's disease patients, which is a major complication of this therapy. Previous studies using animal models show that repeated administration of l-DOPA results in alterations of some signaling molecules, including DeltaFosB, phospho-DARPP32 and phosoho-GluA1 (also referred to as GluR1 or GluR-A) AMPA receptor subunits. Moreover, an in vivo microdialysis study showed that l-DOPA increases nitric oxide (NO) production in the striatum. However, it is not known whether NO is involved in the development of dyskinesia. The present study examined the effects of NOS inhibitors on the development of l DOPA-induced dyskinesia in the rats. Dyskinesia symptoms were triggered by daily administration of l-DOPA for 3-4weeks in unilateral 6-hydroxydopamine lesioned rats. Repeated treatments, 30min prior l-DOPA administration, of the nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester, and the nNOS inhibitor 7 nitroindazole, but not the inducible NOS inhibitor aminoguanidine, attenuated the development of l-DOPA-induced dyskinesia. In agreement with the behavioral analysis, 7-nitroindazole reduced the l-DOPA-induced increases in DeltaFosB, phospho-DARPP32 and phospho-GluA1 AMPA receptor subunit levels in the striatum of 6-hydroxydopamine-lesioned rats. Furthermore, aminoguanidine did not affect DeltaFosB or phospho-GluA1 AMPA receptor subunit levels. These findings suggest that nNOS-derived NO is involved in the development of l-DOPA-induced dyskinesia through a post-synaptic mechanism. PMID- 22449382 TI - The mechanisms responsible for neuroprotective capacity of arylpiperazine dopaminergic ligands against cell death induced by sodium nitroprusside. AB - A group of sixteen arylpiperazines had been previously synthesized and evaluated for atypical antipsychotic activity. Here we examined these compounds for their neuroprotective capacity. The affinity and agonist/antagonist action of the arylpiperazines at dopamine hD(2S) receptors were determined in vitro on membranes from stably transfected CHO-hD(2S) cell line. The assays for cell viability and antioxidative capacity (total glutathione and total superoxide dismutase activity), amount of nitric oxide and superoxide radicals, as well as influence on prosurvival pathways (Akt and ERK), were performed on the human neuroblastoma cell line SH-SY5Y. Cell death was induced by oxidative or nitrosative stress, or by growing cells in the medium deprived of serum. Only four of the arylpiperazines exhibited notable neuroprotection against cell death induced by sodium nitroprusside. Two of these arylpiperazines induced elevations of pAkt, while two other compounds reduced the levels of pErk, whereas these actions are considered to support the cell survival. The benzimidazole heteroaryl group, that mimics catechol moiety of the dopamine molecule, might be the prerequisite structure for the neuroprotective action of these ligands. It is postulated that neuroprotection was acquired also by elevation of endogenous glutathione or total superoxide dismutase activity. PMID- 22449383 TI - Adenosine A1 receptors do not play a major role in the regulation of lipogenic gene expression in hepatocytes. AB - Activation of adenosine A1 receptors was reported to promote fatty acid synthesis in AML-12 cells, by increasing the expression of SREBP-(1c) (sterol regulatory binding protein 1c) and FAS (fatty acid synthase). Since these findings have important therapeutic implications for the discovery of adenosine A1 receptor agonists, further studies were undertaken to determine the expression and functional relevance of adenosine A1 receptor in the liver. To that end, we used two classes of distinct adenosine A1 receptor agonists: CPA (N6-cyclopentyl adenosine), a full agonist and GS-9667 (2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol), a partial agonist. Treatment of AML-12 cells, HepG2 cells and primary human hepatocytes with either CPA or GS-9667 did not increase the gene expression of SREBP-(1c) or FAS. Furthermore, in AML-12 and HepG2 cells, CPA did not antagonize forskolin-stimulated cAMP production, a characteristic of adenosine A1 receptor activation, indicating that these cells lack adenosine A1 receptor function. Consistent with this finding, adenosine A1 receptor gene expression was found to be very low and adenosine A1 receptor protein levels were hardly detectable by radioligand binding assays in hepatic cell lines such as AML-12 and HepG2 as well as in both mouse and human liver tissues. Finally, acute treatment with adenosine A1 receptor agonist GS-9667 had no significant effect on gene expression of both SREBP-(1c) and FAS in livers of Sprague Dawley rats. Taken together, our data suggest that the expression of adenosine A1 receptor is too low to play a major role in the regulation of lipogenic gene expression in hepatocytes. PMID- 22449384 TI - Nociceptin/orphanin FQ inhibition with SB612111 ameliorates dextran sodium sulfate-induced colitis. AB - Inflammatory bowel diseases, primarily Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. The majority of current therapeutic agents focus on controlling proinflammatory molecules. The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been described as a potential immunomodulator for inflammatory bowel diseases. In this study, we asked whether the small molecule N/OFQ antagonist (-)-cis-1-methyl 7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H benzocyclohepten-5-ol (SB612111) would inhibit the development of dextran sodium sulfate-induced colitis in C57BL/6 mice. Inhibition of the N/OFQ receptor (NOP) by SB612111 significantly ameliorated the clinical disease course in these animals, as indicated by reduced fecal bleeding, improved recovery from diarrhea and weight loss, and a reduction in histopathological alterations. In addition, the inflammatory response in the colon was diminished, as demonstrated by reduced cytokine protein and messenger RNA expression for CXCL1/keratinocyte-derived chemokine, interferon-gamma, interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, some of which are known targets for the treatment of this devastating disease. Our results strongly support a role for the receptor-ligand pair NOP-N/OFQ in the pathogenesis of colitis. We conclude that inhibition of NOP receptors with small molecule inhibitors may constitute a novel, urgently needed approach for the treatment of inflammatory bowel diseases. PMID- 22449385 TI - First and second generation H1 histamine receptor antagonists produce different sleep-inducing profiles in rats. AB - First generation H1 histamine receptor antagonists, such as d-chlorpheniramine (d CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H1 histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H1 histamine receptor antagonist which is more permeable to the brain than newer H1 histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H1 histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H1 histamine receptor antagonists may be mediated by H1 histamine receptor-independent actions. To further examine the tolerance of ketotifen induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention. PMID- 22449386 TI - Muscarinic regulation of SCA-9 cell proliferation via nitric oxide synthases, arginases and cyclooxygenases. Role of the nuclear translocation factor-kappaB. AB - The submandibular gland-derived tumor cell line SCA-9 is considered a useful tool to study the signaling pathways involved in proliferation, and their regulation, triggered by different stimuli. It is proposed that the non neuronal cholinergic system: acethylcholine, the enzymes that synthesize and degrade it, and the nicotinic and muscarinic receptors, play a key role in tumorigenesis. Here, we investigate the role of muscarinic receptors in SCA-9 cell proliferation, and the modulation of cholinergic signaling pathways exerted by the nuclear transcription factor kappaB (NF-kappaB). The activation of cholinergic receptors by carbachol (10-9M) increased cell proliferation (P<0.001). This was prevented by preincubating cells with the muscarinic antagonist atropine but not by mecamylamine, a nicotinic receptor blocker. Phospholipase C (PLC)/nitric oxide synthase (NOS)/arginase pathway is involved in this effect, since carbachol stimulated nitric oxide production, increased NOS2 and NOS3 expressions, urea production, and arginase II expression (P<0.001). Also, phospholipase A2 (PLA2)/cyclooxygenase (COX) pathway is up-regulated in carbachol-induced SCA-9 cell proliferation, because prostaglandin E2 liberation (P<0.001) is increased and COX-1 expression is turned up (P<0.001). Interactions between PLC/NOS/arginases and PLA2/COX pathways via its metabolites were detected. SCA-9 cells exhibit a constitutive activation of NF-kappaB, which regulates carbachol induced NOS2 and 3, arginase II and COX-1 expressions. In addition, protein kinase C is involved in the up-regulation of NOS2 and arginase II enzymes induced by carbachol via NF-kappaB. In conclusion, the activation of cholinergic receptors in SCA-9 tumor cells promotes proliferation via muscarinic effector enzymes, and reveals the participation of NF-kappaB at this step of tumorigenesis. PMID- 22449387 TI - Intraoperative tissue fluorescence using 5-aminolevolinic acid (5-ALA) is more sensitive than contrast MRI or amino acid positron emission tomography ((18)F-FET PET) in glioblastoma surgery. AB - OBJECTIVE: The sensitivity of 5-aminolevolinic acid (5-ALA) in detecting intraoperative glioblastoma (GBM) tissue compared to postoperative (18)F fluoroethyl-L-tyrosine and T1 contrast uptake of tumor cells in positron emission tomography (PET) and magnetic resonance imaging (MRI) scans was investigated in a retrospective image correlative study. METHODS: Ten patients with histological verified GBM in eloquent brain regions underwent 11 surgeries with neuronavigation and 5-ALA assisted tumor resection. Residual 5-ALA fluorescence was labeled intraoperatively on the navigation MRI scans and images were fused with postoperative (18)F-FET PET and T1 contrast MRI. RESULTS: Intraoperatively, at the end of save resection, in all patients 2-5 faint 5-ALA positive resection planes were detected (mean 3.6), compared to 0-4 (18)F-FET positive resection planes (mean 1.4) and 0-2 positive T1 contrast MRI resection planes in postoperative scans. The difference between the number of 5-ALA and (18)F-FET positive resection planes was statistically significant (P = 0.0002). The histological investigation of 5-ALA positive resection margins demonstrated infiltrative tumor in every case. Residual 5-ALA fluorescence on resection margins and postoperative (18)F-FET uptake areas or residual contrast T1 areas were colocalized in all cases, documented by pre-/postoperative image fusion. CONCLUSION: Residual faint 5ALA uptake is documented in large areas at the end of GBM resection and corresponds to tumor infiltration. These 5-ALA positive resection plans exceeded the (18)F-FET uptake areas in postoperative PET scans. Thus, intraoperative 5-ALA residual fluorescence seems to be a more sensitive marker than (18)F-FET PET for residual tumor in malignant gliomas. PMID- 22449388 TI - BF3.Et2O-induced stereoselective aldol reaction with benzaldehyde, and steroid sapogenins and its application to a convenient synthesis of dinorcholanic lactones. AB - Treatment of steroid sapogenins with benzaldehyde and BF(3).Et(2)O cleanly produces E-23(23')-benzylidenspirostanes in good yields in a reaction pathway which consists on an aldol reaction followed by a dehydration step. The obtained E-23(23')-benzylidenspirostanes can be easily converted to dinorcholanic lactones by treatment with CrO(3) in acetic acid. The synthetic sequence to dinorcholanic lactones is compatible with the presence of double bonds and carbonyl groups in the steroid framework. PMID- 22449389 TI - 3p deletion syndrome: implications for cochlear implantation. AB - OBJECTIVE AND IMPORTANCE: To describe the role of cochlear implantation in patients with 3p deletion syndrome. Additionally, this paper will review non mastoid approaches to the cochlea potentially used in cases of mastoid abnormalities. CLINICAL PRESENTATION: A 23-month-old child with 3p deletion syndrome (3pDS) presented with suspected hearing loss and characteristic craniofacial abnormalities. Bilateral sensorineural hearing loss (SNHL) was confirmed. Temporal bone computed tomography showed poorly developed mastoids bilaterally. INTERVENTION: Cochlear implantation was successfully undertaken using a retro-auricular transmeatal approach. CONCLUSION: SNHL is commonly encountered in patients with 3pDS and can be improved by cochlear implantation. In this patient population, particular attention must be given to pre-operative imaging and possible altered mastoid anatomy may exist. In doing so, intra operative complications can be avoided. PMID- 22449390 TI - Very rare cause of vaginal mass in pregnancy: cavernous hemangioma. AB - Vaginal cavernous hemangioma is a considerably rare condition during pregnancy. There has only been one reported case to date. A multiparous, 24-year-old woman in the 32nd week of pregnancy was admitted with a mass prolapsed from the vagina, which had suddenly increased in size over the previous few days. A necrotic mass obstructing the vaginal canal and originating from the posterior wall was observed in a pelvic physical examination and carefully excised. The patient had contractions after the intervention and was administered tocolytic treatment with bed-rest and fluids. Her obstetric clinical status was stable after treatment and she gave birth without complication at 37 weeks and 5 days from the vaginal canal. The main approach to these very rare tumors of pregnancy, especially in the presence of necrosis, infection and/or obstruction, should be excision. But the potential for increased blood loss that may occur due to the hypervascular structure of the tumor should be taken into account. PMID- 22449391 TI - New tools lead to new science. PMID- 22449393 TI - Azathioprine as monotherapy for scleritis in relapsing polychondritis. PMID- 22449394 TI - Psoriasiform pemphigus foliaceus: a report of two cases. AB - Pemphigus foliaceus (PF) represents an autoimmune blistering disease characterized by the disruption of epidermal intercellular adhesion proteins. Clinical findings include superficial crusted erosions in a seborrheic distribution; however, the disease can rarely present as an exfoliative erythroderma. Histopathologic findings include acantholysis with cleavage within the granular layer. Direct immunofluorescence studies show intercellular IgG and complement deposition. We present two patients, to our dermatology department, with a previous diagnosis of psoriasis, with an exfoliative erythroderma, which ultimately proved to be because of PF based on histopathological features, direct immunofluorescence results and levels of antibodies against desmoglein 1. Both patients responded well to oral prednisone and rituximab. This variant of PF should be entertained in both the clinical differential diagnosis of psoriasiform erythroderma and in the microscopic differential diagnosis of psoriasiform epidermal hyperplasia with focal acantholysis, particularly in patients for whom the clinical history is not classic for psoriasis or for whom conventional psoriasis therapies have not proven beneficial. PMID- 22449395 TI - Genomics, Proteomics & Bioinformatics (GPB) has a new start--open access. PMID- 22449396 TI - Distinct contributions of replication and transcription to mutation rate variation of human genomes. AB - Here, we evaluate the contribution of two major biological processes--DNA replication and transcription--to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes. PMID- 22449397 TI - The transcript-centric mutations in human genomes. AB - Since the human genome is mostly transcribed, genetic variations must exhibit sequence signatures reflecting the relationship between transcription processes and chromosomal structures as we have observed in unicellular organisms. In this study, a set of 646 ubiquitous expression-invariable genes (EIGs) which are present in germline cells were defined and examined based on RNA-sequencing data from multiple high-throughput transcriptomic data. We demonstrated a relationship between gene expression level and transcript-centric mutations in the human genome based on single nucleotide polymorphism (SNP) data. A significant positive correlation was shown between gene expression and mutation, where highly expressed genes accumulate more mutations than lowly-expressed genes. Furthermore, we found four major types of transcript-centric mutations: C->T, A >G, C->G, and G->T in human genomes and identified a negative gradient of the sequence variations aligning from the 5' end to the 3' end of the transcription units (TUs). The periodical occurrence of these genetic variations across TUs is associated with nucleosome phasing. We propose that transcript-centric mutations are one of the major driving forces for gene and genome evolution along with creation of new genes, gene/genome duplication, and horizontal gene transfer. PMID- 22449398 TI - Mining functional gene modules linked with rheumatoid arthritis using a SNP-SNP network. AB - The identification of functional gene modules that are derived from integration of information from different types of networks is a powerful strategy for interpreting the etiology of complex diseases such as rheumatoid arthritis (RA). Genetic variants are known to increase the risk of developing RA. Here, a novel method, the construction of a genetic network, was used to mine functional gene modules linked with RA. A polymorphism interaction analysis (PIA) algorithm was used to obtain cooperating single nucleotide polymorphisms (SNPs) that contribute to RA disease. The acquired SNP pairs were used to construct a SNP-SNP network. Sub-networks defined by hub SNPs were then extracted and turned into gene modules by mapping SNPs to genes using dbSNP database. We performed Gene Ontology (GO) analysis on each gene module, and some GO terms enriched in the gene modules can be used to investigate clustered gene function for better understanding RA pathogenesis. This method was applied to the Genetic Analysis Workshop 15 (GAW 15) RA dataset. The results show that genes involved in functional gene modules, such as CD160 (rs744877) and RUNX1 (rs2051179), are especially relevant to RA, which is supported by previous reports. Furthermore, the 43 SNPs involved in the identified gene modules were found to be the best classifiers when used as variables for sample classification. PMID- 22449399 TI - MotViz: a tool for sequence motif prediction in parallel to structural visualization and analyses. AB - Linking similar proteins structurally is a challenging task that may help in finding the novel members of a protein family. In this respect, identification of conserved sequence can facilitate understanding and classifying the exact role of proteins. However, the exact role of these conserved elements cannot be elucidated without structural and physiochemical information. In this work, we present a novel desktop application MotViz designed for searching and analyzing the conserved sequence segments within protein structure. With MotViz, the user can extract a complete list of sequence motifs from loaded 3D structures, annotate the motifs structurally and analyze their physiochemical properties. The conservation value calculated for an individual motif can be visualized graphically. To check the efficiency, predicted motifs from the data sets of 9 protein families were analyzed and MotViz algorithm was more efficient in comparison to other online motif prediction tools. Furthermore, a database was also integrated for storing, retrieving and performing the detailed functional annotation studies. In summary, MotViz effectively predicts motifs with high sensitivity and simultaneously visualizes them into 3D strucures. Moreover, MotViz is user-friendly with optimized graphical parameters and better processing speed due to the inclusion of a database at the back end. MotViz is available at http://www.fi-pk.com/motviz.html. PMID- 22449400 TI - SMS 2.0: an updated database to study the structural plasticity of short peptide fragments in non-redundant proteins. AB - The function of a protein molecule is greatly influenced by its three-dimensional (3D) structure and therefore structure prediction will help identify its biological function. We have updated Sequence, Motif and Structure (SMS), the database of structurally rigid peptide fragments, by combining amino acid sequences and the corresponding 3D atomic coordinates of non-redundant (25%) and redundant (90%) protein chains available in the Protein Data Bank (PDB). SMS 2.0 provides information pertaining to the peptide fragments of length 5-14 residues. The entire dataset is divided into three categories, namely, same sequence motifs having similar, intermediate or dissimilar 3D structures. Further, options are provided to facilitate structural superposition using the program structural alignment of multiple proteins (STAMP) and the popular JAVA plug-in (Jmol) is deployed for visualization. In addition, functionalities are provided to search for the occurrences of the sequence motifs in other structural and sequence databases like PDB, Genome Database (GDB), Protein Information Resource (PIR) and Swiss-Prot. The updated database along with the search engine is available over the World Wide Web through the following URL http://cluster.physics.iisc.ernet.in/sms/. PMID- 22449401 TI - Gene2DGE: a Perl package for gene model renewal with digital gene expression data. AB - For transcriptome analysis, it is critical to precisely define all the transcripts across the whole genome. More and more digital gene expression (DGE) scannings have indicated the presence of huge amount of novel transcripts in addition to the known gene models. However, almost all these studies still depend crucially on existing annotation. Here, we present Gene2DGE, a Perl software package for gene model renewal with DGE data. We applied Gene2DGE to the mouse blastomere transcriptome, and defined 98,532 read-enriched regions (RERs) by read clustering supported by more than four reads for each base pair. Taking advantage of this ab initio method, we refined 2,104 exonic regions (4% of a total of 48,501 annotated transcribed regions) with remarkable extension into un-annotated regions (>50 bp). For 5% of uniquely mapped reads falling within intron regions, we identified 13,291 additional possible exons. As a result, we renewed 4,788 gene models, which account for 39% of a total of 12,277 transcribed genes. Furthermore, we identified 12,613 intergenic RERs, suggesting the possible presence of novel genes outside the existing gene models. In this study, therefore, we have developed a suitable tool for renewal of known gene models by ab initio prediction in transcriptome dissection. The Gene2DGE package is freely available at http://bighapmap.big.ac.cn/. PMID- 22449402 TI - Carbon ion radiotherapy for recurrent malignant transformation from mature cystic teratoma of the ovary. AB - Mature cystic teratoma (MCT) is the most common tumor of the ovary; malignant transformation (MT) of squamous cell carcinoma is a rare disorder. A 78-year-old woman with stage IIc MT-MCT (squamous cell carcinoma [SCC]) underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy; there was residual tumor in the pelvis. The patient was treated with six courses of paclitaxel and carboplatin, but the recurrent tumor grew. The patient was then treated with carbon ion radiotherapy (CIRT). The recurrent tumor shrank and the patient has been free of clinical disease for 53 months. CIRT can be considered as a treatment for recurrent MT-MCT. PMID- 22449403 TI - An unusual finding after cardiac transplantation. PMID- 22449404 TI - Tributyltin induces oxidative stress and neuronal injury by inhibiting glutathione S-transferase in rat organotypic hippocampal slice cultures. AB - Tributyltin (TBT) has been used as a heat stabilizer, agricultural pesticide and antifouling agents on ships, boats and fish-farming nets; however, the neurotoxicity of TBT has recently become a concern. TBT is suggested to stimulate the generation of reactive oxygen species (ROS) inside cells. The aim of this study was to determine the mechanism of neuronal oxidative injury induced by TBT using rat organotypic hippocampal slice cultures. The treatment of rat hippocampal slices with TBT induced ROS production, lipid peroxidation and cell death. Pretreatment with antioxidants such as superoxide dismutase, catalase or trolox, suppressed the above phenomena induced by TBT, indicating that TBT elicits oxidative stress in hippocampal slices, which causes neuronal cell death. TBT dose-dependently inhibited glutathione S-transferase (GST), but not glutathione peroxidase or glutathione reductase in the cytosol of rat hippocampus. The treatment of hippocampal slices with TBT decreased the GST activity. Pretreatment with reduced glutathione attenuated the reduction of GST activity and cell death induced by TBT, indicating that the decrease in GST activity by TBT is involved in hippocampal cell death. When hippocampal slices were treated with sulforaphane, the expression and activity of GST were increased. Notably, TBT-induced oxidative stress and cell death were significantly suppressed by pretreatment with sulforaphane. These results indicate that GST inhibition could contribute, at least in part, to the neuronal cell death induced by TBT in hippocampal slices. This study is the first report to show the link between neuronal oxidative injury and the GST inhibition elicited by TBT. PMID- 22449405 TI - Aesthetic outcome in patients after polymethyl-methacrylate (PMMA) cranioplasty - a questionnaire-based single-centre study. AB - OBJECTIVES: Acquired skull deformities are common and most likely treated surgically by cranioplasty. Since data on patient aesthetic outcome after cranioplasty are rare in literature, we aimed to assess patient satisfaction after polymethyl-methacrylate (PMMA) cranioplasty in this study using a questionnaire. METHODS: A patient questionnaire was developed to evaluate the grade of satisfaction after surgery. After approval by the institutional ethical review board, we were allowed to send to all 115 patients, who received a cranioplasty from 2001 to 2008 at the University Hospital of Zurich, our questionnaire once to retrospectively analyze the patient response together with the patient hospital records. RESULTS: Out of 115 patients, 36 patients were lost to follow-up and our questionnaire was sent out once to 79 patients. Sixty-three of 79 patients replied to the questionnaire (79.7%) and 16 did not reply. Seventeen declined to participate in this study and out of the remaining 46 patients (58.2%, 18 women, mean age 54 years, range 20-83 years), who agreed to participate in this study, 22 (47.8%) judged their cranioplasty to be aesthetically 'excellent', 16 (34.8%) 'favorable' and 4 (8.7%) 'poor'. Another four patients (8.7%) were not satisfied, asking for a surgical revision. Patient age and gender was not related to the assessment of the aesthetic result. A higher satisfaction grade was found in patients with primary PMMA cranioplasty compared to PMMA cranioplasty implanted during a second surgery (Fisher's exact test, P = 0.031). A dent was strongly associated with absence of satisfaction (P<0.01, Fisher's exact test). CONCLUSION: Our questionnaire was suitable to assess patient satisfaction after cranioplasty. Localization of cranioplasty showed to be an important factor of aesthetic outcome, especially in the fronto temporal region where a carefully planned reconstruction should be performed to guarantee an excellent grade of satisfaction after surgery. PMID- 22449407 TI - A systems biological analysis links ROS metabolism to mitochondrial protein quality control. AB - The analyses of previously generated Podospora anserina strains in which the mitochondrial superoxide dismutase, PaSOD3, is increased in abundance, revealed unexpected results, which, at first glance, are contradictory to the 'free radical theory of aging' (FRTA). To re-analyze these results, we performed additional experiments and developed a mathematical model consisting of a set of differential equations describing the time course of various ROS (reactive oxygen species), components of the cellular antioxidant system (PaSOD3 and mitochondrial peroxiredoxin, PaPRX1), and PaCLPP, a mitochondrial matrix protease involved in protein quality control. Incorporating these components we could identify a positive feed-back loop and demonstrate that the role of superoxide as the primary ROS responsible for age-related molecular damage is more complicated than originally stated by the FRTA. Our study is a first step towards the integration of the various pathways known to be involved in the control of biological aging. PMID- 22449406 TI - Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study. AB - Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages >=65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD related death, particularly among women. PMID- 22449408 TI - Impairment of skeletal muscle insulin action with aging in Wistar rats: role of leptin and caloric restriction. AB - Insulin resistance develops with aging in rats in parallel to fat mass accretion, central leptin resistance and hyperleptinemia. Previous studies demonstrated that insulin resistance appears earlier in adipose tissue than in muscle during aging and pointed to a role of hyperleptinemia in the impairment of insulin action. Here we explored the evolution along aging of insulin sensitivity in soleus and EDL muscles by analyzing insulin signaling in vivo and insulin-dependent glucose transport ex vivo. A decrease in insulin action was observed in both muscles. Caloric restriction improves insulin sensitivity at early aging but not in older animals. We also tested the role of leptin on insulin action in skeletal muscle. Short-term pretreatment with leptin inhibits in vivo muscle insulin signaling and insulin-dependent glucose transport in isolated muscle strips. This effect is mediated by its action on early insulin signaling as well as by the inhibition of p38. In contrast, chronic central administration of leptin elicits an insulin sensitizing effect on soleus. These data suggest that leptin can act as muscle insulin sensitizer, when acting at central level, and as insulin antagonistic when interacting directly with soleus muscle. This effect may be relevant in situations of hyperleptinemia such as aging. PMID- 22449409 TI - Optimizing pneumococcal vaccination for paediatric cochlear implant recipients using the cochlear implant pneumococcal vaccination flowchart. AB - INTRODUCTION: Cochlear implant recipients are known to be at an increased risk of meningitis. It is routine practice to check that pneumococcal vaccinations have been received prior to surgery. Recent changes in United Kingdom national guidelines mean that children who were previously thought to be fully immunized may in fact not be optimally protected. We present a simple, robust audit tool that can be used in both primary care and tertiary centres to identify those children at risk. METHODS: The pneumococcal immunization status of 63 paediatric cochlear implant recipients was assessed using a unique and comprehensive flowchart-style audit tool. The data collected included age at implantation, details of previous immunizations, and whether or not further vaccinations were required. RESULTS: Fifty-four per cent of children were not optimally immunized prior to implantation. Seventy per cent of children required further vaccinations following surgery. The commonest reason for an incomplete immunization history was failure to administer the 23-valent vaccine after the second birthday. CONCLUSION: The pneumococcal immunization schedule for high-risk children is complicated and nationally available guidance can be difficult to interpret. There are multiple types of vaccines and their use is not standardized across the UK. Cochlear implant programmes may find that a large proportion of their patients are in fact not optimally vaccinated, particularly in light of recent changes in the national guidelines. Our audit tool allows health professionals, in both primary care and implant centres, to accurately assess the status and immunization requirements for both new and old patients. PMID- 22449410 TI - Prediction of the human oral bioavailability by using in vitro and in silico drug related parameters in a physiologically based absorption model. AB - Estimates of the human oral absolute bioavailability were made by using a physiological-based pharmacokinetic model of absorption and the drug solubility at the gastrointestinal pH range 1.5-7.5, the apparent permeability (P(app)) in Caco-2 cells and the intrinsic clearance (Cl(int)) in human hepatocytes suspensions as major drug related parameters. The predictive ability of this approach was tested in 164 drugs divided in four levels of input data: (i) in vitro data for both P(app) and Cl(int); (ii) in vitro data for Cl(int) only; (iii) in vitro data for P(app) only and (iv) in silico data for both P(app) and Cl(int). In all scenarios, solubility was estimated in silico. Excellent predictive abilities were observed when in vitro data for both P(app) and Cl(int) were used, with 84% of drugs with oral bioavailability predictions within a+/-20% interval of the correct value. This predictive ability is reduced with the introduction of the in silico estimated parameters, particularly when Cl(int) is used. Performance of the model using only in silico data provided 53% of drugs with bioavailability predictions within a+/-20% acceptance interval. However, 74% of drugs in the same scenario resulted in bioavailability predictions within a+/ 35% interval, which indicates that a qualitative prediction of the absolute bioavailability is still possible. This approach is a valuable way to estimate a fundamental pharmacokinetic parameter, using data typically collected in the drug discovery and early development phases, providing also mechanistic information of the limiting bioavailability steps of the drug. PMID- 22449411 TI - Bio-relevant media to assess drug permeability: sodium taurocholate and lecithin combination or crude bile? AB - The assessment of in vivo drug absorption with in vitro permeability models demands the use of transport media with surface acting compounds. With the aim to establish their influence on in vitro permeability of 30 drugs through Caco-2 monolayers, cell vitality/integrity and micellar drug entrapment, taurocholate/lecithin (NaTC/Leci) and pig crude bile were applied. Drug permeabilities were correlated to fraction of drugs absorbed and appropriate NaTC/Leci and bile concentrations were proposed to simulate fasted/fed conditions in vitro (bile in the concentration range 1-5 v/v% or 0.2/0.05mM NaTC/Leci for fasted; 10 v/v% bile or 3/0.75mM NaTC/Leci for fed conditions) without detrimental effects on monolayer integrity/vitality (NaTC/Leci was more toxic than bile). Surfactants exerted different affinities for drugs; free drug concentration (c(free)) of some was significantly lowered only by bile, while for the others NaTC/Leci and bile significantly diminished c(free). For some substances NaTC/Leci and bile significantly increased their permeabilities (i.e. more than 3-times) in spite of profound c(free) decrease indicating the existence of an alternative absorption mechanism. Based on these data, the impact of bile on in vitro drug permeability and micellar drug entrapment cannot be adequately simulated by NaTC/Leci, because their effects on drug absorption differ. PMID- 22449412 TI - Tracking of the viability of Stenotrophomonas maltophilia bacteria population in polyvinylalcohol nanofiber webs by positron annihilation lifetime spectroscopy. AB - Polyvinylalcohol (PVA) fiber web containing embedded bacteria was prepared by electrospinning technique. From the point of the complex functionality of such potential delivery systems, it will be of impact how bacteria can survive in such artificial biotopes. The present study suggests a possible fast method for the tracking of the viability of the embedded bacteria based on the changes of the supramolecular structure of the polymeric delivery system caused by the metabolic product of the bacteria. Positron annihilation lifetime spectroscopy (PALS) was applied to track the free volume changes of the system in the course of storage. The PALS method sensitively detected the free volume changes, thus the viability of the bacteria in the polymeric fiber web. PMID- 22449413 TI - Influence of primary crystallisation conditions on the mechanical and interfacial properties of micronised budesonide for dry powder inhalation. AB - Investigate the influence of primary crystallisation conditions on the mechanical properties and secondary processing behaviour of budesonide for dry powder inhaler (DPI) formulations. Young's modulus of two batches of budesonide crystals (samples A and B) produced using different anti-solvents was determined using nanoindentation. Physicochemical and surface interfacial properties via the cohesive-adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) of air-jet micronised budesonide crystals were also investigated. These data were correlated to in vitro aerosolization performance of carrier-based DPI formulations containing either budesonide samples A or B and lactose monohydrate. Young's modulus of budesonide samples A and B crystals was 0.95 and 4.04 GPa, respectively. Sample A crystals with low Young's modulus exhibited poorer micronisation efficiency than sample B. CAB analysis of micronised budesonide samples A and B, suggest that sample B budesonide had a greater adhesion to lactose than sample A. These data correlated with in vitro aerosolisation studies, which showed that the fine particle delivery of budesonide sample A was higher than that of sample B. In conclusion, crystallisation conditions may affect the mechanical properties of budesonide, and therefore secondary processing of the material and their interfacial properties and product performance in carrier based DPI formulations. PMID- 22449414 TI - Inhibition of collagen deposit in obstructed rat bladder outlet by transplantation of superparamagnetic iron oxide-labeled human mesenchymal stem cells as monitored by molecular magnetic resonance imaging (MRI). AB - Bladder outlet obstruction (BOO) caused by collagen deposit is one of the most common problems in elderly males. The present study is to investigate if human mesenchymal stem cells (MSCs) are capable of inhibiting collagen deposition and improve cystometric parameters in bladder outlet obstruction in rats. Human MSCs were labeled with nanoparticles containing superparamagnetic iron oxide (SPION), and transplanted in rat BOO lesion site. Forty 6-week-old female Sprague-Dawley rats were divided into four groups (group 1: control, group 2: sham operation, group 3: BOO, and group 4: BOO rats receiving SPION-hMSCs). Two weeks after the onset of BOO, 1 * 10(6) SPION-hMSCs were injected into the bladder wall. Serial T2-weighted MR images were taken immediately after transplantation of SPION labeled human MSCs and at 4 weeks posttransplantation. T2-weighted MR images showed a clear hypointense signal induced by the SPION-labeled MSCs. While the expression of collagen and TGF-beta protein increased after BOO, the expression of both returned to the original levels after MSC transplantation. Expression of HGF and c-met protein also increased in the group with MSC transplantation. Maximal voiding pressure and residual urine volume increased after BOO but they recovered after MSC transplantation. Human MSCs transplanted in rat BOO models inhibited the bladder fibrosis and mediated recovery of bladder dysfunction. Transplantation of MSC-based cell therapy could be a novel therapeutic strategy against bladder fibrosis in patients with bladder outlet obstruction. PMID- 22449415 TI - MMP-2 expression by fibroblasts is suppressed by the myofibroblast phenotype. AB - During wound healing, fibroblasts transition from quiescence to a migratory state, then to a contractile myofibroblast state associated with wound closure. We found that the myofibroblast phenotype, characterized by the expression of high levels of contractile proteins, suppresses the expression of the pro migratory gene, MMP-2. Fibroblasts cultured in a 3-D collagen lattice and allowed to develop tension showed increased contractile protein expression and decreased MMP-2 levels in comparison to a stress-released lattice. In 2-D cultures, factors that promote fibroblast contractility, including serum or TGF-beta, down regulated MMP-2. Pharmacologically inducing F-actin disassembly or reduced contractility increased MMP-2 expression, while conditions that promote F-actin assembly suppressed MMP-2 expression. In all cases, changes in MMP-2 levels were inversely related to changes in the contractile marker, smooth muscle alpha actin. To determine if the mechanisms involved in contractile protein gene expression play a direct role in MMP-2 regulation, we used RNAi-mediated knock down of the myocardin-like factors, MRTF-A and MRTF-B, which induced the down regulation of contractile protein genes by fibroblasts under both serum containing and serum-free conditions. In the presence of serum or TGF-beta, MRTF A/B knock-down resulted in the up-regulation of MMP-2; serum-free conditions prevented this increased expression. Together, these results indicate that, while MMP-2 expression is suppressed by F-actin formation, its up-regulation is not simply a consequence of contractile protein down-regulation. PMID- 22449416 TI - Laboratory based experiments to assess the use of green and food based compost to improve water quality in a Sustainable Drainage (SUDS) device such as a swale. AB - Many tonnes of compost are generated per year due to door step composting of both garden and kitchen waste. Whilst there are commercial outlets for the finer grade of compost (<10mm) in plant nurseries, there is little demand for the coarser material (>25 mm). This paper reports part of a WRAP-sponsored (Waste Resources Action Programme) study which investigated the potential for green (GC) and mixed green and food (MC) composts to be incorporated into Sustainable Drainage (SUDS) devices such as swales, and replace the topsoil (TS) onto which turf is laid or grass seed distributed. However, it is not known whether compost can replace TS in terms of pollutant remediation, both the trapping of polluted particulates and in dealing with hydrocarbons such as oil, but also from a biofilm development and activity perspective. Using laboratory based experiments utilising leaching columns and an investigation of microbiological development in the composts studied, it was found that many of the differences in performance between MC and GC were insignificant, whilst both composts performed better in terms of pollutant retention than TS. Mixed compost in particular could be used in devices where there may be oil spillages, such as the lorry park of a Motorway Service Area due to its efficiency in degrading oil. Samples of GC and MC were found to contain many of the bacteria and fungi necessary for an active and efficient biofilm which would be an argument in their favour for replacement of TS and incorporation in swales. PMID- 22449417 TI - Analysis of variance: variably complex. PMID- 22449418 TI - Ordinary least products: let's welcome back an old friend. PMID- 22449419 TI - Nabilone in inflammatory pain: to be or not to be. PMID- 22449420 TI - Spontaneous rupture of the dividing membrane in a monochorionic pregnancy resulting in a pseudo-monoamniotic pregnancy with cord entanglement. AB - During pregnancy spontaneous rupture of the dividing membrane of monochorionic diamniotic twins is extremely rare and difficult to diagnose prenatally. We report a case of pseudo-monoamniotic twins derived from monochorionic diamniotic twin gestation. A 37-year-old woman pregnant with monochorionic diamniotic twins initially confirmed by the first trimester ultrasonography, was suspected to have a dividing membrane not visualized on ultrasound examinations at 27 gestational weeks. The woman did not undergo any invasive procedure during pregnancy and did not have notable symptoms. We considered the possibility of spontaneous rupture of the dividing membrane and cord entanglement, and managed the rest of her gestational period as a monoamniotic twin gestation. Concordantly grown healthy male babies were born at 35 weeks and 1 day by elective cesarean section. The mother had complex entangled umbilical cords and a small trace of amniotic membrane in the placenta. PMID- 22449421 TI - Immunity to hepatitis A when outbreaks of infection in men who have sex with men (MSM) are rare. AB - BACKGROUND: Epidemics of hepatitis A among men who have sex with men (MSM) have decreased significantly in recent years although the level of immunity that is required to prevent epidemics has not been studied. Our aim was to determine the level of immunity to hepatitis A among MSM. METHODS: This was a retrospective study conducted using notifications of Hepatitis A in Victoria from 1991 to 2010, serological testing for hepatitis A among MSM attending Melbourne Sexual Health Centre (MSHC), and vaccination records among MSM attending MSHC. RESULTS: Hepatitis A notifications declined from 370 to 47 and the male to female ratio declined from 4.2 to 0.9 in Victoria between 1991 to 2010. Between 2002 and 2011, there were 12,064 individuals MSM seen at MSHC of whom 3055 (25%) were tested for hepatitis A antibodies and 1180 (39%) had antibodies. The proportion of MSM who were tested for hepatitis A rose significantly over time (P<0.01), but the proportion of these with hepatitis A antibodies did not (P=0.28). Hepatitis A antibodies were more common in MSM over 30 (54%) compared to those 30 or less (32%), (Crude Odds Ratio 2.5 (95% confidence interval 2.1-2.9)) and were uncommon in MSM under 20 (19%). Vaccination against hepatitis A was recorded in 49% of 660 clinical files of MSM who attended the centre between 2003 and 2011 and did not change over time (P=0.42) but was significantly more common in those over 30 years of age (P<0.005). CONCLUSION: Hepatitis A is rare in MSM in Victoria where levels of immunity are about 40-50%. As outbreaks have occurred when levels of immunity were around 30%, maintaining vaccination levels over 40-50% is important if outbreaks are to be prevented. The lower levels of immunity in younger MSM create the potential for outbreaks in this sub-group. PMID- 22449422 TI - Engineering temperature sensitive live attenuated influenza vaccines from emerging viruses. AB - The licensed live attenuated influenza A vaccine (LAIV) in the United States is created by making a reassortant containing six internal genes from a cold-adapted master donor strain (ca A/AA/6/60) and two surface glycoprotein genes from a circulating/emerging strain (e.g., A/CA/7/09 for the 2009/2010 H1N1 pandemic). Technologies to rapidly create recombinant viruses directly from patient specimens were used to engineer alternative LAIV candidates that have genomes composed entirely of vRNAs from pandemic or seasonal strains. Multiple mutations involved in the temperature-sensitive (ts) phenotype of the ca A/AA/6/60 master donor strain were introduced into a 2009 H1N1 pandemic strain rA/New York/1682/2009 (rNY1682-WT) to create rNY1682-TS1, and additional mutations identified in other ts viruses were added to rNY1682-TS1 to create rNY1682-TS2. Both rNY1682-TS1 and rNY1682-TS2 replicated efficiently at 30 degrees C and 33 degrees C. However, rNY1682-TS1 was partially restricted, and rNY1682-TS2 was completely restricted at 39 degrees C. Additionally, engineering the TS1 or TS2 mutations into a distantly related human seasonal H1N1 influenza A virus also resulted pronounced restriction of replication in vitro. Clinical symptoms and virus replication in the lungs of mice showed that although rNY1682-TS2 and the licensed FluMist((r))-H1N1pdm LAIV that was used to combat the 2009/2010 pandemic were similarly attenuated, the rNY1682-TS2 was more protective upon challenge with a virulent mutant of pandemic H1N1 virus or a heterologous H1N1 (A/PR/8/1934) virus. This study demonstrates that engineering key temperature sensitive mutations (PB1-K391E, D581G, A661T; PB2-P112S, N265S, N556D, Y658H) into the genomes of influenza A viruses attenuates divergent human virus lineages and provides an alternative strategy for the generation of LAIVs. PMID- 22449423 TI - Parental and societal values for the risks and benefits of childhood combination vaccines. AB - BACKGROUND: New combination vaccines reduce the number of injections needed for immunization. However, possible drawbacks include higher prices, extra doses of vaccine antigens and increased minor adverse events. Our objective was to measure parental and societal values for attributes of childhood combination vaccines. METHODS: We conducted a discrete choice experiment using an online survey of adults administered by Knowledge Networks. Values were measured for attributes of combination vaccines for a hypothetical child aged 6 months: (1) number of injections, (2) extra dose of hepatitis B vaccine, (3) 20% higher chance of fever, (4) community-level immunization coverage of 2-year-olds of 90% or 80%, and (5) cost per visit. Logistic regression with generalized estimating equations was used to analyze the value of different attributes and generate a marginal willingness-to-pay for a change in attribute level. RESULTS: The response rate was 64% (N=558). Most respondents were parents (63%) and most respondents agreed that combination vaccines were safe (77%). Respondents were willing to pay $7.68 to avoid an injection (compared to $9.94 when looking at parents only). However, respondents were willing to pay $41.57 to avoid higher risk of fever after one set of immunizations (10% versus 30%) and $65.42 for higher immunization coverage rates. These results were very similar for parents only. There was no significant preference to avoid an extra dose of hepatitis B vaccine. CONCLUSIONS: Respondents were willing to pay larger amounts to avoid increased risk of minor adverse events and to increase community-level immunization coverage than to avoid injections. These values should be taken into account when determining the risks and benefits of combination vaccines. PMID- 22449424 TI - Sortase-conjugation generates a capsule vaccine that protects guinea pigs against Bacillus anthracis. AB - Capsules protect bacteria against phagocytic clearance. Capsular polysaccharides or polyglutamates have evolved also to resist antigen presentation by immune cells, thereby interfering with the production of opsonophagocytic antibodies. Linking capsular material to a carrier protein stimulates its presentation to the immune system. For many conjugate vaccines this is achieved by a process of random chemical cross-linking. Here we describe a new technology, designated sortase-conjugation, which generates a single amide bond between the C-terminal end of a carrier protein and the capsular material. Sortase-conjugation was used to link the poly-D-gamma-glutamic acid (PDGA) capsule of Bacillus anthracis to the receptor binding domain (D4) of protective antigen (PagA). When used as a vaccine, PDGA-D4 conjugate elicited robust antibody responses against both capsule and D4. Immunization with PDGA-D4 afforded guinea pigs complete protection against anthrax challenge with wild-type or pagA mutant B. anthracis Ames. PMID- 22449425 TI - Immunogenicity and clinical protection against equine influenza by DNA vaccination of ponies. AB - Equine influenza A (H3N8) virus infection is a leading cause of respiratory disease in horses, resulting in widespread morbidity and economic losses. As with influenza in other species, equine influenza strains continuously mutate, often requiring the development of new vaccines. Current inactivated (killed) vaccines, while efficacious, only offer limited protection against diverse subtypes and require frequent boosts. Research into new vaccine technologies, including gene based vaccines, aims to increase the neutralization potency, breadth, and duration of protective immunity. Here, we demonstrate that a DNA vaccine expressing the hemagglutinin protein of equine H3N8 influenza virus generates homologous and heterologous immune responses, and protects against clinical disease and viral replication by homologous H3N8 virus in horses. Furthermore, we demonstrate that needle-free delivery is as efficient and effective as conventional parenteral injection using a needle and syringe. These findings suggest that DNA vaccines offer a safe, effective, and promising alternative approach for veterinary vaccines against equine influenza. PMID- 22449426 TI - Bacillus atrophaeus inactivated spores as a potential adjuvant for veterinary rabies vaccine. AB - Rabies is a viral encephalitis, nearly always fatal, but preventable through vaccines. Rabid animal bite is the prime transmission act, while veterinary vaccination is one of the best strategies for rabies general prevention. Aluminum compounds and saponin are the commercial adjuvants used for this vaccine nowadays. Nevertheless, aluminum compounds can provoke undesired side effects and saponin has a narrow activity range without toxicity. B. atrophaeus inactivated spores (BAIS), with or without saponin, were then used as an alternative to boost the inactivated rabies virus response. BAIS was as effective as saponin in augmenting antibody titers, but combination of both adjuvants doubled the titers raised by them individually. The combined adjuvant formulation maintained viability for 21 months when stored at 4-8 degrees C. Overall, BAIS was demonstrated as a viable alternative to commercial adjuvants, while its combination with saponin resulted in even higher vaccine potency with good stability. PMID- 22449427 TI - Efficacy of three candidate Rift Valley fever vaccines in sheep. AB - Rift Valley fever virus (RVFV) is a mosquito-transmitted Bunyavirus that causes high morbidity and mortality among ruminants and humans. The virus is endemic to the African continent and the Arabian Peninsula and continues to spread into new areas. The explosive nature of RVF outbreaks requires that vaccines provide swift protection after a single vaccination. We recently developed several candidate vaccines and here report their efficacy in lambs within three weeks after a single vaccination. The first vaccine comprises the purified ectodomain of the Gn structural glycoprotein formulated in a water-in-oil adjuvant. The second vaccine is based on a Newcastle disease virus-based vector that produces both RVFV structural glycoproteins Gn and Gc. The third vaccine comprises a recently developed nonspreading RVFV. The latter two vaccines were administered without adjuvant. The inactivated whole virus-based vaccine produced by Onderstepoort Biological Products was used as a positive control. Five out of six mock vaccinated lambs developed high viremia and fever and one lamb succumbed to the challenge infection. A single vaccination with each vaccine resulted in a neutralizing antibody response within three weeks after vaccination and protected lambs from viremia, pyrexia and mortality. PMID- 22449428 TI - The future is primary. PMID- 22449429 TI - Accidental injection of formalin into oral soft tissue: are medications the only treatment? PMID- 22449430 TI - Biomet Microfixation Temporomandibular Joint Replacement System: a 3-year follow up study of patients treated during 1995 to 2005. AB - PURPOSE: To assess the safety and efficacy of a stock alloplastic total temporomandibular joint (TMJ) implant system, the Biomet Microfixation TMJ Replacement System. MATERIALS AND METHODS: During a 10-year multicenter clinical trial from 1995 to 2005, 442 Biomet Microfixation TMJ Replacement Systems were implanted in 288 patients (154 bilaterally and 134 unilaterally). Patients were followed at landmark times, including the date of surgery and at 1 month, 3 months, 1 year, 1 year 6 months, and 3 years. The 3 major metrics that were evaluated were preoperative and postoperative pain, interference with eating, and maximal incisal opening. Paired t tests and comparison analyses were used to assess outcomes. RESULTS: There was statistically significant improvement in pain level (P = .0001), jaw function (P = .0001), and incisal opening (P = .0001). Although there were complications necessitating the removal of 14 of 442 implants (3.2%), there were no device-related mechanical failures. CONCLUSIONS: The clinical study presented supports the conclusion that a stock TMJ alloplastic replacement, based on sound orthopedic and biomedical principles, is a safe and efficacious option when alloplastic reconstruction of the TMJ is indicated. PMID- 22449432 TI - Failure in implant rehabilitation in a patient with severe congenital neutropenia (Kostmann syndrome). PMID- 22449433 TI - Relations between obstructive sleep apnea syndrome and specific cephalometric measurements, body mass index, and apnea-hypopnea index. AB - PURPOSE: To evaluate the relation of specific cephalometric landmarks, body mass index, and the apnea-hypopnea index in patients diagnosed with obstructive sleep apnea syndrome (OSAS) and treated with functional upper airway surgery. MATERIALS AND METHODS: This was a retrospective cohort analysis of 89 consecutive patients over a 3-year period diagnosed with overnight-attended polysomnogram-confirmed OSAS who underwent functional upper airway surgery. Five predetermined specific cephalometric parameters were analyzed: posterior airway space, soft palate length, hyoid to mandibular plane angle, sella-nasion to mandibular plane angle, and gonion to gnathion length. Simple and multiple linear regression analyses were used to establish a relation between independent and dependent variables. RESULTS: There were no statistically significant associations between the 5 specific cephalometric craniofacial structures in combination with other potential confounders, body mass index and apnea-hypopnea index, and the presence of OSAS. CONCLUSIONS: No one skeletal or soft tissue parameter can be directly linked to OSAS. PMID- 22449434 TI - Surgical prediction of skeletal and soft tissue changes in Class III treatment. AB - PURPOSE: The purpose of this study was to study the treatment outcomes and accuracy of the digital prediction using Dolphin Imaging Software and the actual postoperative outcome in subjects presenting Class III malocclusions. MATERIALS AND METHODS: Maxillary advancement surgery was performed in group 1, and maxillary advancement was combined with mandibular setback surgery in group 2. Predictive cephalometric tracings were made using Dolphin Imaging Software. RESULTS: Before surgery, the maxillary deficiency was significantly greater in group 1 than in group 2, and the mandibular length was significantly greater in group 2. Surgical reductions in mandibular length and angle were significantly greater 12 months after surgery than indicated by the predictive cephalometric tracings. CONCLUSION: In groups 1 and 2, maxillary advancement surgery was performed in accordance with the Dolphin Imaging Software. The mandibular setback surgery performed was beyond the established plan, but without clinical implications. Mandibular dentoskeletal measurements showed a greater correlation with the profile than the maxillary measurements. PMID- 22449435 TI - Delayed cerebrospinal fluid leakage: an unusual septoplasty complication. PMID- 22449436 TI - Intraperitoneal administration of CDP-choline or a combination of cytidine plus choline improves nerve regeneration and functional recovery in a rat model of sciatic nerve injury. AB - OBJECTIVE: Topical cytidine-5'-diphosphocholine (CDP-choline) improves functional recovery and promotes nerve regeneration in sciatic nerve injury in rats. The aims of this study were to test whether systemic treatment with CDP-choline was effective in improving the recovery of injured sciatic nerve, and to determine whether the cytidine and/or choline moieties of CDP-choline contribute to its beneficial actions. METHODS: Seventy Sprague-Dawley rats underwent a surgical procedure that involved transectioning and immediate surgical repairing of the right sciatic nerve. Rats were assigned to one of five groups and administered intraperitoneally 1 ml/kg of saline (control) or saline containing 600 MUmol/kg of each of CDP-choline, cytidine, choline, or cytidine+choline. RESULTS: Recovery in sciatic function index score was greater in rats treated with CDP-choline, choline, or cytidine+choline at 8 and 12 weeks after the interventions. Peripheral nerve regeneration evaluated by electromyography at 12 weeks was also greater in rats receiving CDP-choline (228% of control), choline (168% of control), or cytidine+choline (221% of control). Axon counts and axon density increased significantly following CDP-choline, choline, or cytidine+choline, respectively. Treatment with equivalent dose of cytidine failed to affect sciatic function index, electromyography, and axon counts. Treatment with CDP-choline, but not its metabolites improved nerve adherence and separability score. CONCLUSION: These data show that intraperitoneal CDP-choline, as well as the combination of its metabolites, cytidine+choline, improves functional recovery and promotes regeneration of injured sciatic nerves in rats. CDP-choline also improves nerve adherence and separability. PMID- 22449437 TI - Facilitating the transition from the pediatric to adult cochlear implant setting: perspectives of CI professionals. AB - OBJECTIVES: Over the last 20 years, the availability of cochlear implantation has resulted in a pediatric population with different health needs than adults who receive cochlear implants (CIs). These pediatric patients are now transitioning to adult hospital settings in significant numbers. This issue of transition is not unique to cochlear implant services: research in other chronic health conditions has documented a variety of challenges for youth and health care providers. The objectives of this study were to identify factors important in the transition from pediatric to adult CI services from the perspective of service providers and to make recommendations to improve transition practices in the future. METHODS: Focus groups were conducted with professionals providing specialized CI services in pediatric and adult hospitals, and specialized educators in the school setting. Qualitative research methodology was used to identify key themes. Data extracted from patient files allowed comparison of pediatric and adult CI recipients. RESULTS: Youth who had received CIs in the pediatric setting differed from other adult patients in the incidence of prelingual hearing losses, and age at CI surgery. Key focus group themes were related to service delivery models, communication between settings, and skills needed by the patients to effectively meet their own health needs. DISCUSSION: Factors identified by CI professionals were very similar to those identified in research for other health conditions. From the focus groups, as well as other literature, a number of recommendations are proposed to facilitate a positive transition of young people to adult health care. PMID- 22449438 TI - Sedative, antiepileptic and antipsychotic effects of Viscum album L. (Loranthaceae) in mice and rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Viscum album L. is claimed in traditional medical practice, to be useful in the treatment of epilepsy and insomnia in Himachal Pradesh, India. MATERIALS AND METHODS: The effect of Viscum album L. on epilepsy, psychosis and sedative activity was evaluated in mice and rats using standard procedure. RESULTS: The aqueous leaf extract of Viscum album L. prolonged the pentobarbital induced sleeping time and reduced the locomotor activity in actophotometer. This suggests that reduced locomotor activity facilitate GABAergic transmission. In addition the extract reduced MES, INH and PTZ-induced convulsions which suggest that there may be possibility of blocking Na(+) channels, opening of Cl(-) channels or enhancing the GABAergic system. The extract decreased the apomorphine-induced stereotyped behavior and potentiates the HAL-induced cataleptic score which suggests the extract possess antidopaminergic activity. CONCLUSION: The results obtained in present study suggested that title plant exhibited sedative, antiepileptic and antipsychotic activity in mice and rats. PMID- 22449439 TI - Effects of Tinospora cordifolia (Menispermaceae) on the proliferation, osteogenic differentiation and mineralization of osteoblast model systems in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ancient Indian ayurvedic literature prescribes Tinospora cordifolia as a remedy to rheumatoid arthritis, inflammatory and allied diseases of musculo skeletal system. AIM: To investigate the effects of the alcoholic extract of Tinospora cordifolia (TC) on the proliferation, differentiation and mineralization of bone like matrix on osteoblast model systems in vitro and hence its possible use as a potential anti-osteoporotic agent. MATERIALS AND METHODS: Two in vitro osteoblast model systems were used in the study viz., human osteoblast-like cells MG-63 and primary osteoblast cells isolated from femur of rats. Cell growth and viability was assessed by standard colorimetric assays like MTT assay. The cell differentiation into osteoblastic lineage was evaluated by the activities of bone marker alkaline phosphatase. The effect of the extract on matrix mineralization was assessed by alizarin red-s staining and Von kossa staining. Cell morphology was studied by phase contrast microscopy and light microscopy (Giemsa/crystal violet staining). RESULTS: Results indicate that the alcoholic extract of TC at a dosage of 25MUg/ml stimulated the growth of osteoblasts, increased the differentiation of cells into osteoblastic lineage and increased the mineralization of bone like matrix on both the osteoblast model systems used in the study. Cell morphology studies clearly indicated the increase in cell numbers and absence of adverse change in the cell morphology on treatment with the extract. CONCLUSION: TC extract has a potential influence on osteogenesis and hence its use could be explored as a potential anti osteoporotic agent. PMID- 22449440 TI - Standardized flavonoid-rich fraction of Artemisia princeps Pampanini cv. Sajabal induces apoptosis via mitochondrial pathway in human cervical cancer HeLa cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia princeps Pampanini is widely used in Eastern traditional medicine for the treatment of circulatory disorders, such as, dysmenorrhea, hematuria, hemorrhoids, and inflammation, and is also used to treat chronic conditions, such as, cancers, ulcers, and digestive disorders. AIM OF THE STUDY: The purpose of this study is to investigate the effect of a standardized flavonoid-rich fraction of Artemisia princeps Pampanini cv. Sajabal (FRAP) on the induction of apoptosis and the molecular mechanism involved in human cervical cancer HeLa cells. MATERIALS AND METHODS: Human cervical cancer HeLa cells were treated with FRAP and apoptosis was detected by cell morphologic observation, annexin-V-PI staning and western blot analysis on the expression of protein associated with cell death. RESULTS: FRAP led to the cleavages of caspase-3, -8, and -9 and the cleavage of poly (ADP-ribose) polymerase (PARP) in HeLa cells. Caspase-3 inhibitor (z-DEVD-fmk), caspase-8 inhibitor (z-IETD-fmk), caspase-9 inhibitor (z-LEHD), and broad caspase inhibitor (z-VAD-fmk) significantly suppressed the FRAP-induced accumulation of annexin V positive cells. Furthermore, it was found that FRAP caused a loss of mitochondrial membrane potential (MMP) and the release of cytochrome c to the cytosol. Furthermore, the overexpression of Bcl-xL significantly prevented FRAP-induced apoptosis, MMP changes, and the activations of caspase-3, -8, and -9. Interestingly, pretreatment with caspase-8 inhibitor significantly reduced the FRAP-induced activation of caspase-3 but not that of caspase-9, whereas the caspase-3 inhibitor, z-DEVD-fmk, markedly attenuated the FRAP-induced activation of caspase 8. In BALB/c(nu/nu) mice bearing a HeLa xenograft, FRAP dosed at 25 or 50mg/kg significantly inhibited tumor growth. CONCLUSION: Our results indicate caspase mediated activation of the mitochondrial death pathway plays a critical role in the FRAP-induced apoptosis of HeLa cells and that FRAP inhibits the in vivo tumor growth of HeLa xenograft mice. PMID- 22449441 TI - The hydroalcoholic extract of Cassia alata (Linn.) leaves and its major compound rhein exhibits antiallergic activity via mast cell stabilization and lipoxygenase inhibition. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Cassia alata (family: Caesalpiniaceae) are ethnomedically claimed as anti-asthmatic. In the current study we aimed to investigate the anti-allergic activities of hydro-methanolic extract of Cassia alata (Linn.) and its constituents rhein and kaempferol on triple antigen/sheep serum-induced mast-cell degranulation in rats. MATERIALS AND METHODS: Antiallergic activity of hydroalcoholic extract of Cassia alata along with its two components rhein and kaempferol was evaluated using in vivo mast cell stabilization assay. Inhibitory effect on lipoxygenase (LOX) enzyme was also evaluated in vitro. Further chemical standardization of Cassia alata extract was done using rhein and kaempferol by HPTLC-densitometric method. RESULTS: The hydroalcoholic extract of Cassia alata significantly inhibited mast cell degranulation at 200mg/kg dose. Both chemical constituents rhein and kaempferol also showed potent (>76%) inhibition of mast-cell degranulation at 5mg/kg. Extract and rhein inhibited LOX enzyme with IC(50) values of 90.2 and 3.9MUg/mL, respectively, whereas kaempferol was inactive. CONCLUSION: Our results suggest that Cassia alata exhibit anti-allergic activity through mast cell stabilization and LOX inhibition. Thus, Cassia alata or its active constituents could be potential alternative treatment for allergic diseases. PMID- 22449442 TI - Aquaporin 4 knockdown exacerbates streptozotocin-induced diabetic retinopathy through aggravating inflammatory response. AB - Diabetic retinopathy is a leading cause of reduced visual acuity and acquired blindness. Diabetes is known to alter the amount of retinal expression of the water-selective channels aquaporin 4 (AQP4). However, the function and impact of AQP4 in diabetic retinopathy is not well understood. In the present work, diabetes was induced by intraperitoneal injection of streptozotocin in Sprague Dawley rats. Two weeks later, AQP4 shRNA (r) lentiviral particles or negative lentiviral particles were delivered by intravitreal injection to the eyes. Gene delivery was confirmed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blotting analysis. Eight weeks later, BRB breakdown was measured using Evans blue dye. Images of retinal sections were obtained and the thicknesses of the retinas were determined. Retinal leukostasis measurement was performed using acridine orange leukocyte fluorography. The mRNA levels of IL-1beta, IL-6, intercellular adhesion molecule 1 (ICAM-1), glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) were determined using qRT-PCR method. AQP4 shRNA (r) lentiviral particles or negative lentiviral particles were transfected into rMC-1 cells to investigate its effect on inflammation induced by high glucose. Incubation with IL-1beta or IL-6 was performed to test their effect on AQP4 expression in rMC-1 cells. In the current work, it was found that AQP4 expression was enhanced in the retina of diabetic rats. AQP4 knockdown led to exacerbation of retinopathy including enhancing retinal vascular permeability, retinal thickness, pro-inflammatory factors expression, and VEGF and GFAP expression in retinas of diabetic rats. AQP4 knockdown enhanced the expression of pro-inflammatory cytokines induced by high glucose in rMC-1 cells. In addition, AQP4 knockdown enhanced the release of IL-6 and VEGF from rMC-1 cells into the medium. Moreover, it was found that incubation with IL-1beta or IL-6 suppressed AQP4 expression in rMC-1 cells. These results suggested that streptozotocin injection induced diabetes resulted in compensatory increases of AQP4 expression, and downregulation of AQP4 exacerbated diabetic retinopathy through aggravating inflammatory response, at last in part. Therefore, regulation of retinal function by AQP4 may attenuate diabetic retinopathy, offering a promising therapeutic strategy for diabetic retinopathy. PMID- 22449443 TI - Administration of a soluble activin type IIB receptor promotes the transplantation of human myoblasts in dystrophic mice. AB - Duchenne muscular dystrophy (DMD) is a recessive disease caused by a dystrophin gene mutation. Myoblast transplantation permits the introduction of the dystrophin gene into dystrophic muscle fibers. However, this strategy has so far produced limited results. Modulation of transforming growth factor-beta (TGF beta) superfamily signaling promotes skeletal muscle differentiation and growth and myogenic regeneration. We investigated the possibility that the combination of TGF-beta superfamily signaling inhibition with myoblast transplantation might be an effective therapeutic approach in dystrophin-deficient patients. In vitro, blocking myostatin and other ligands with a soluble form of the extracellular domain of the activin IIB receptor (ActRIIB/Fc) upregulated the expression of myogenic differentiation factors and increased human myoblast fusion. In vivo, systemic inhibition of activin IIB receptor signaling by delivery of ActRIIB/Fc increased the success of the myoblast transplantation. This effect was further increased by forcing the mice to swim weekly to induce cycles of muscle degeneration and regeneration. Treatment of dystrophic mice with ActRIIB/Fc led to increased body weight, increased skeletal muscle mass, and improved myoblast transplantation. Thus, ActRIIB/Fc represents an effective therapeutic strategy for muscular dystrophies, and its effects are enhanced when combined with muscle exercise. PMID- 22449444 TI - Testing strategies for embryo-fetal toxicity of human pharmaceuticals. Animal models vs. in vitro approaches: a workshop report. AB - Reproductive toxicity testing is characterized by high animal use. For registration of pharmaceutical compounds, developmental toxicity studies are usually conducted in both rat and rabbits. Efforts have been underway for a long time to design alternatives to animal use. Implementation has lagged, partly because of uncertainties about the applicability domain of the alternatives. The reproductive cycle is complex and not all mechanisms of development can be mimicked in vitro. Therefore, efforts are underway to characterize the available alternative tests with regard to the mechanism of action they include. One alternative test is the mouse embryonic stem cell test (EST), which has been studied since the late 1990s. It is a genuine 3R "alternative" assay as it is essentially animal-free. A meeting was held to review the state-of-the-art of various in vitro models for prediction of developmental toxicity. Although the predictivity of individual assays is improving, a battery of several assays is likely to have even higher predictivity, which is necessary for regulatory acceptance. The workshop concluded that an important first step is a thorough survey of the existing rat and rabbit studies, to fully characterize the frequency of responses and the types of effects seen. At the same time, it is important to continue the optimization of in vitro assays. As more experience accumulates, the optimal conditions, assay structure, and applicability of the alternative assays are expected to emerge. PMID- 22449445 TI - Functional characterization of normal and degraded bovine meniscus: rate dependent indentation and friction studies. AB - The menisci are known to play important roles in normal joint function and the development of diseases such as osteoarthritis. However, our understanding of meniscus' load bearing and lubrication properties at the tissue level remains limited. The objective of this investigation was to characterize the site- and rate-dependency of the compressive and frictional responses of the meniscus under a spherical contact load. Using a custom testing device, indentation tests with rates of 1, 10, 25, 50, and 100MUm/s were performed on bovine medial meniscus explants, which were harvested from five locations including the femoral apposing surface at the anterior, central, and posterior locations and the central portion at the deep layer and at the tibial apposing surface (n=5 per location). Sliding tests with rates of 0.05, 0.25, 1, and 5mm/s were performed on the central femoral aspect and central tibial aspect superficial samples (n=6 per location). A separate set of superficial samples were subjected to papain digestion and tested prior to and post treatment. Our findings are: i) the Hertz contact model can be used to fit the force responses of meniscus under the conditions tested; ii) the anterior region is significantly stiffer than the posterior region and tissue modulus does not vary with tissue depth at the central region; iii) the friction coefficient of the meniscus is on the order of 0.02 under migratory contacts and the femoral apposing surface tends to show lower friction than the tibial apposing surface; iv) the meniscus exhibits increased modulus and lubrication with increased indentation and sliding rates; v) matrix degradation impedes the functional load support and lubrication properties of the tissue. The site- and rate-dependent properties of the meniscus may be attributed to spatial variations of the tissue's biphasic structure. These properties substantiate the role of the meniscus as one of the important bearing surfaces of the knee. These data contribute to an improved understanding of meniscus function, and its role in degenerative joint diseases. In addition, the results provide functional metrics for developing engineered tissue replacements. This article is part of a Special Issue entitled Osteoarthritis. PMID- 22449446 TI - Age and sex differences in tibia morphology in healthy adult Caucasians. AB - Variability in peripheral Quantitative Computed Tomography (pQCT) measurement sites limits direct comparisons of results between studies. Further, it is unclear what estimates of bone strength are most indicative of changes due to aging, disease, or interventions. The purpose of this study was to examine age group and sex differences in tibia morphology. Additional purposes of this study were to determine which tibia site or sites are most sensitive for detecting age and sex differences. METHODS: Self-identifying Caucasian men (n=55) and women (n=59) ages 20-59 years and separated by decades had their non-dominant tibias measured with pQCT (Stratec XCT 3000) at every 10% of the limb length from 5% to 85% (distal to proximal). Volumetric BMD and BMC of the total, cortical and trabecular bone were determined, as well as periosteal (PeriC) and endosteal (EndoC) circumferences, and cortical thickness (CTh). RESULTS: There were significant (p<0.01) site effects for all BMC, vBMD, PeriC and EndoC measures. Large sex differences (men>women) in Tot.BMC (21-28%) were paralleled by differences in Cort.BMC (21-25%) (p<0.01). Site*sex interaction effects were significant (p<0.05) for BMC (peak sex difference: 5%, 15%, 25%, 85% sites) and circumference (peak sex difference: 65% site) variables. CTh and total vBMD were lowest (p<0.05) in 50-59 year group, and EndoC was highest in the 50-59 year group. Site*age interactions existed for Cort.vBMD, Tot.BMC (85% site), and EndoC (25%, 35%, 55%-85% sites). Correcting for bone free lean body mass (BFLBM) greatly reduced sex differences, eliminating sex*site interaction effects, but sex main effects remained significant. Correcting for BFLBM did not eliminate age effects. CONCLUSION: The magnitude of age and sex differences in tibia variables varied by measurement site demonstrating the need for standardization of measurement sites. PMID- 22449447 TI - Ultra-structural defects cause low bone matrix stiffness despite high mineralization in osteogenesis imperfecta mice. AB - Bone is a complex material with a hierarchical multi-scale organization from the molecule to the organ scale. The genetic bone disease, osteogenesis imperfecta, is primarily caused by mutations in the collagen type I genes, resulting in bone fragility. Because the basis of the disease is molecular with ramifications at the whole bone level, it provides a platform for investigating the relationship between structure, composition, and mechanics throughout the hierarchy. Prior studies have individually shown that OI leads to: 1. increased bone mineralization, 2. decreased elastic modulus, and 3. smaller apatite crystal size. However, these have not been studied together and the mechanism for how mineral structure influences tissue mechanics has not been identified. This lack of understanding inhibits the development of more accurate models and therapies. To address this research gap, we used a mouse model of the disease (oim) to measure these outcomes together in order to propose an underlying mechanism for the changes in properties. Our main finding was that despite increased mineralization, oim bones have lower stiffness that may result from the poorly organized mineral matrix with significantly smaller, highly packed and disoriented apatite crystals. Using a composite framework, we interpret the lower oim bone matrix elasticity observed as the result of a change in the aspect ratio of apatite crystals and a disruption of the crystal connectivity. PMID- 22449449 TI - Reconstruction of distal urethral strictures confined to the glans with circular buccal mucosa graft. AB - OBJECTIVE: To report our results with 1-stage reconstruction in short distal urethral strictures using circular buccal mucosa graft (cBMG). METHODS: The data of 19 patients (median age 41.8 years, range 25-58) operated between 2001 and 2010 were reviewed. Patients were evaluated with American Urological Association (AUA) symptom score, uroflowmetry, voiding cystourethrography (VCUG), and intraoperative urethroscopy. Stricture was limited to the glanular urethra (<= 2 cm.) in all cases and 16 patients had lichen sclerosus. Strictured urethra was resected 0.5 cm proximal to the healthy urethra and a rectangular BMG with 4-cm length and 1.5- to 2.5-cm width (depending on the length of the defect) was rolled on a 24-Fr sound that calibrated the urethra. Proximal and distal edges of the cBMG were anastomosed circumferentially to the healthy mucosa and meatus, respectively. Foley catheter was removed within 10-14 days. Voiding symptoms, uroflowmetric parameters, and cosmesis were assessed at 1, 3, and 6 months, and yearly thereafter. RESULTS: With a median follow-up of 38 months (range 12-96), 16 (84.2%) patients were cured. One patient developed early graft loss, and 2 patients developed stricture at proximal anastomotic site. Mean Q(max) (mL/s) increased from 7.8 +/- 5.4 preoperatively to 21.8 +/- 9.2 postoperatively (P = .001), and mean AUA score decreased from 26.7 +/- 3.9 preoperatively to 7.3 +/- 3.8 postoperatively (P < .001). CONCLUSION: Our results suggest cBMG as a feasible alternative in 1-stage reconstruction of distal strictures confined to the glanular urethra because the glans penis has a good blood supply, providing an efficient circumferential graft take. PMID- 22449450 TI - Editorial comment. PMID- 22449451 TI - A potential role for CPY17 as a parameter in differentiation between aldosterone producing adenoma and nodular hyperplasia in patients with hyperaldosteronism. AB - OBJECTIVE: To investigate CYP17 mRNA and protein expressions in aldosterone producing adenoma (APA), nodular hyperplasia (NH) and normal adrenal gland (NAG) and if CPY17 might be used as a potential marker to differentiate between APA and NH in patients with hyperaldosteronism. METHODS: Total RNA and protein were extracted from APA, 12 NH, and 15 NAG tissues. mRNA and protein expressions of CPY17 were examined by real-time polymerase chain reaction (PCR) and Western blot analysis. RESULTS: The relative expression levels of CPY17mRNA to glyceraldehyde 3-phosphate dehydrogenase in the APA, NH, and NAG groups are 0.94 +/- 0.09, 2.07 +/- 0.10, and 3.94 +/- 0.19, respectively, when evaluated by real-time PCR. This result was confirmed by the relative protein expression levels of CPY17 to beta actin, which are 117 +/- 13%, 274 +/- 19%, and 478 +/- 25%, respectively, when evaluated by Western blot analysis. There was a significant difference in mRNA and protein expression level of CYP17 between any two groups (P < .05). Thus, the sequence of the relative expression level of CPY17 is APA < NH < NAG. CONCLUSION: These results indicate that CPY17 was down-regulated in APA compared with that in NH, suggesting a potential role for CPY17 as a marker in differentiation between APA and NH in patients with hyperaldosteronism. Such a study might be helpful to improve the diagnosis and treatment of primary aldosteronism. PMID- 22449452 TI - Unsuccessful outcomes after posterior urethroplasty: definition, diagnosis, and treatment. AB - OBJECTIVE: To establish some guidelines for the definition, diagnosis, and treatment of failed posterior urethroplasty. METHODS: We identified 20 successive patients who required a secondary endoscopic or surgical procedure after anastomotic repair of a postpelvic fracture urethral injury from 1979 to 2010. Of the 20 patients, 18 had undergone perineal repair and 2 a perineo-abdominal procedure. Their medical records were reviewed with a focus on 6 postoperative items: symptoms, onset of unsuccessful result, urethral calibration, urethrocystography, urethroscopy, and treatment. Follow-up ranged from 1 to 25 years (mean 14). RESULTS: Of the 20 patients, 11 (55%) presented shortly after removal of the urethral stent with failure to void (n = 9) or incontinence (n = 2), and 9 (45%) presented 1 month to 12 years after surgery with a weak stream. Early failures resulted from obstruction at the site of repair in 5 patients, retraction of the bulbar urethra in 3, wrong anastomosis to a false tract in 1, and an open bladder neck in 2. Correction was accomplished by salvage urethroplasty in 8 patients and bladder neck repair in 2. Late failures resulted from narrowing of the anastomosis and were corrected by direct visual internal urethrotomy in 7 patients and surgery in 2. CONCLUSION: Unsuccessful outcomes can be encountered shortly after removal of the urethral stent or delayed for several months or years after surgery. Early cases present by an inability to void or incontinence and usually require salvage urethroplasty or bladder neck repair. Late cases present by a weak urinary stream, are due to narrowing of the anastomosis, and are usually corrected by direct visual internal urethrotomy. PMID- 22449453 TI - Outcomes of artificial urinary sphincter placement in men after radical cystectomy and orthotopic urinary diversions for the treatment of stress urinary incontinence: the University of Southern California experience. AB - OBJECTIVE: To examine the outcomes of male patients who have undergone artificial urinary sphincter (AUS), AMS-800 (American Medical Systems Minnetonka, MN) placement for iatrogenic stress urinary incontinence after radical cystectomy (RC) and orthotopic neobladder (ONB) diversion in a single institution. MATERIALS AND METHODS: From 2002-2009, patients were prospectively randomized to undergo RC and Studer vs T-pouch neobladder reconstruction. We received IRB- approval to retrospectively review the charts of patients who underwent AUS placement for symptoms of SUI. Patients were mailed 2 validated questionnaires, International Continence Society Male-Short Form, the Incontinence Symptom Severity Index, and a pad questionnaire. RESULTS: Twelve male patients were identified. Average age at time of AUS placement was 73.8 years (range 52-82). Mean time between RC/ONB and AUS placement was 1.53 years (range 1-4). Mean follow-up time after initial AUS placement was 21.7 months (range 12-72). Ten patients (10/12; 83.3%) returned the validated questionnaires. In comparing pre-AUS to post-AUS continence, 90% of patients reported improvement in continence. Three patients deactivated their AUS during the day and activated it at night. There were no erosions (0%) or any mechanical malfunctions of the device (0%) in our cohort. There were no complications or injuries to the ONB during placement of the AUS components. CONCLUSION: AUS is a safe, effective continence procedure for patients with ONB and SUI. Complication rate, urinary symptoms, and quality of life these patients have as determined by validated questionnaires is acceptable. PMID- 22449454 TI - Bladder metastasis from maxillary sinus undifferentiated carcinoma: a rare case. AB - We report the rare case of a 72-year-old woman with maxillary sinus undifferentiated carcinoma with metachronous metastasis localized to the bladder. Bladder metastases and maxillary sinus carcinoma are rare tumors. The bladder is not 1 of the usual sites of distant extension for parasinus tumors. To our knowledge, no data have been reported regarding bladder metastasis originating from a maxillary sinus carcinoma. PMID- 22449455 TI - Enhancing crystalline properties of a cardiovascular active pharmaceutical ingredient using a process analytical technology based crystallization feedback control strategy. AB - Pharmaceutical regulatory bodies require minimal presence of solvent in an active pharmaceutical ingredient (API) after crystallization. From a processing point of view bigger crystals with minimal agglomeration and uniform size distribution are preferred to avoid solvent inclusion and for improved downstream processing. The current work addresses these issues encountered during the production of the potential anti-arrhythmic cardiovascular drug, AZD7009. This paper demonstrates that by applying the automated direct nucleation control (ADNC) approach problems with agglomeration and solvent inclusion were resolved. This model free approach automatically induces temperature cycles in the system, with the number of cycles, temperature range and adaptive heating and cooling rates determined to maintain the number of particles in the system, as measured by a focused beam reflectance measurement (FBRM) probe, within a constant range during the crystallization. The ADNC approach was able to produce larger and more uniform crystals and also removed the residual solvent trapped between the crystals compared to the typical crystallization operation using linear cooling profile. The results illustrate the application of process analytical technologies, such as FBRM and ATR-UV-vis spectroscopy, for the design of optimal crystallization operating conditions for the production of pharmaceuticals, and demonstrate that the ADNC approach can be used for rapid crystallization development for APIs exhibiting problems with agglomeration and solvent inclusion. PMID- 22449456 TI - Bedside handover of critically ill patients. PMID- 22449457 TI - The effects of aging, physical training, and a single bout of exercise on mitochondrial protein expression in human skeletal muscle. AB - Aging results in a significant decline in aerobic capacity and impaired mitochondrial function. We have tested the effects of moderate physical activity on aerobic capacity and a single bout of exercise on the expression profile of mitochondrial biogenesis, and fusion and fission related genes in skeletal muscle of human subjects. Physical activity attenuated the aging-associated decline in VO2 max (p<0.05). Aging increased and a single exercise bout decreased the expression of nuclear respiratory factor-1 (NRF1), while the transcription factor A (TFAM) expression showed a strong relationship with VO(2max) and increased significantly in the young physically active group. Mitochondrial fission representing FIS1 was induced by regular physical activity, while a bout of exercise decreased fusion-associated gene expression. The expression of polynucleotide phosphorylase (PNPase) changed inversely in young and old groups and decreased with aging. The A2 subunit of cyclic AMP-activated protein kinase (AMPK) was induced by a single bout of exercise in skeletal muscle samples of both young and old subjects (p<0.05). Our data suggest that moderate levels of regular physical activity increases a larger number of mitochondrial biogenesis related gene expressions in young individuals than in aged subjects. Mitochondrial fission is impaired by aging and could be one of the most sensitive markers of the age-associated decline in the adaptive response to physical activity. PMID- 22449458 TI - Circulating progenitor cells and the elderly: a seven-year observational study. AB - Cardiovascular (CV) diseases and related complications are the main causes of morbidity and mortality in the elderly. CV progenitor cells, including CD34+ cells, play a role in delaying the progression of atherosclerosis. In the present study we observed 100 octogenarians for seven years, in order to address the question of whether CD34+ cell number is a predictor of longevity in selected survivors. We also checked for associations of cell expression of manganese superoxide dismutase (Mn-SOD), catalase (CAT), and glutathione peroxidase type-1 (GPx-1) antioxidative enzymes, with number of CD34+ progenitor cells and mortality. We found that in very old subjects the number of CD34+ cells at baseline were higher in subjects who reached older age at death or were still living at the end of observation period, with respect to subjects who died from all causes, including CV deaths. On the other hand, HDL-C plasma levels and, with the exception of diabetes, the classic CV risk factors (hypertension, smoking, hypercholesterolemia) showed a loss of their predictive power. A significant association between the redox system of CD34+ cells and mortality was also observed. These data suggest that, even in the elderly, CD34+ cells maintain their role in predicting mortality. CD34+ cells could thus be considered as a biomarker of longevity. PMID- 22449459 TI - Integration of ethics teaching within GP training. PMID- 22449460 TI - The Emperor's New Clothes revisited: learning styles in medical education. PMID- 22449461 TI - Training for independent practice, change and professional development. PMID- 22449462 TI - Mentoring for doctors in difficulty. PMID- 22449463 TI - Don't forget the learner: an essential aspect for developing effective hypermedia online learning in continuing medical education. AB - There is increasing use of hypermedia online learning in continuing medical education (CME) that presents the learner with a wide range of different learning resources, requiring the learner to use self-regulated learning (SRL) skills. This study is the first to apply an SRL perspective to understand how learners engage with hypermedia online learning in CME. We found that the main SRL skills used by learners were use of strategies and monitoring. The increasing use of strategies was associated with increasing interest in the topic and with increasing satisfaction with the learning experience. Further research is recommended to understand SRL processes and its impact on learning in other aspects of hypermedia online learning across the different phases of medical education. Research is also recommended to implement and evaluate the learning impact of a variety of approaches to develop the SRL skills of hypermedia online learners in CME. PMID- 22449464 TI - Do general practice selection scores predict success at MRCGP? An exploratory study. AB - BACKGROUND: Selection into general practice training is undertaken using a competency based approach. The clear advantage of this approach over traditional methods has been demonstrated through evaluation of its validity and reliability. However, the relationship between selection and performance in the Royal College of General Practitioner examinations (MRCGP) has yet to be explored. The MRCGP comprises of an applied knowledge test (AKT), a clinical skills assessment (CSA) and workplace-based assessments (WPBA). AIM: To explore the predictive validity of general practice selection scores using the AKT and CSA elements of the MRCGP as a final outcome measure. METHODS: This study carried out a retrospective analysis of 101 trainees from the Wales Deanery who were successfully selected on to general practice training in 2007. Selection data consisted of an overall selection score as well as scores from each individual stage of selection. Correlation was used to explore associations between selection scores and examination scores. RESULTS: The score for overall performance at selection achieved statistically significant correlation with examination performance (r = 0.491 for the AKT and r = 0.526 for the CSA, P <0.01). CONCLUSIONS: The general practice selection process is predictive of future performance in the MRCGP. PMID- 22449465 TI - Formative assessment of GP trainees' clinical skills. AB - BACKGROUND: Clinical skill assessment (CSA) has been an integral part of the Royal College of General Practitioners' membership examination (MRCGP) since 2008. It is an expensive, high-stakes examination with first time pass rates ranging from 76.4 to 81.3. In this paper we describe the South East Scotland Deanery, NHS Education Scotland, pilot of a formative clinical skills assessment (fCSA) using the principles of formative assessment and OSCE. The purpose of the study was to assess the acceptability of the fCSA and to examine whether trainees, identified during the fCSA as 'at risk of failing the MRCGP CSA exam', are more likely to fail the MRCGP CSA exam later on in the year. METHODS: Trainees were assessed in four clinical skills stations under exam conditions. After each station they were given verbal feedback and subsequently both trainee and their trainer received written feedback. We assessed the value of the exercise through written feedback from trainees and trainers. Each trainee's performance in fCSA was triangulated with trainer assessment to identify 'flagged trainees'. We compared flagged and non-flagged trainees' performance in MRCGP CSA. RESULTS: Both trainees and trainers highly rated the fCSA. Overall 97% of non-flagged trainees have passed the RCGP CSA exam by May of that year in comparison to 80% of flagged trainees who have passed the RCGP CSA (P = 0.005). Trainers and trainees rated the fCSA as excellent and useful. CONCLUSION: We were able to demonstrate that the fCSA can be used to identify those trainees likely to fail the RCGP CSA. Contrary to reservations about the potential to demoralise trainees, the fCSA was viewed as a useful and a positive experience by both trainees and trainers. In addition, we suggest that feedback from fCSA was useful in triggering appropriate educational interventions. Early intervention with trainees who are predicted to fail the CSA has the potential to reduce deaneries overall fail rate. Preventing one trainee failure could save over L30 000. PMID- 22449466 TI - Implementing evidence in practice: do action lists work? AB - BACKGROUND: Much continuing medical education is known to have a limited impact on subsequent clinical behaviour. An option to improve this is to ask participants to develop specific actions about their clinical behaviour changes. METHODS: We aimed to investigate the content and outcomes of GPs' action lists produced on a one-day continuing professional development (CPD) course. Actions were recorded during a one-day course, and followed up six months later. RESULTS: Of 1696 delegates attending the nine courses, 306 (18%) provided their action plan and 139 of these responded to the questionnaire at six months (response rate 45%). The 306 delegates recorded a total of 1443 actions (4.7 per delegate). Of these, 359 were subsequently explored by follow-up questionnaire at six months of which 147 (41%; 95% CI 36%-46%) were 'successful', an average of completed actions of 1.9 per GP. Four significant facilitators and four significant barriers to success were identified. CONCLUSIONS: Delegates attending the one-day CPD course recorded an average of 4.7 intended practice changes, and completed 41%. Further research is needed on how to increase the number of planned and completed actions. PMID- 22449467 TI - Needs assessment and reflection in a practice education accreditation scheme in the Southampton area: some questions. PMID- 22449468 TI - Encouraging GPs into the gene pool: designing a CPD course in genetics for primary care. PMID- 22449469 TI - The novel 'Prepare-Intensive Coaching-Compete (PICC)' model to learn research. PMID- 22449470 TI - Identify learning outcomes for learning agreements. PMID- 22449471 TI - The use of a workshop to encourage trainers to consider spiritual care. PMID- 22449472 TI - The evolution and establishment of a quality assured structure for education delivery in Severn. PMID- 22449473 TI - Technology-enhanced learning. PMID- 22449474 TI - Progress in untying the Gordian nodes of Ranvier in Guillain-Barre Syndrome. PMID- 22449475 TI - Olig1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) resulting in cumulative neurologic deficits associated with progressive myelin loss. We have previously shown that transplantation of neural progenitor cells (NPCs) into mice persistently infected with the JHM strain of mouse hepatitis virus (JHMV) results in enhanced differentiation into oligodendrocyte progenitor cells (OPCs) that is associated with remyelination and axonal sparing. The current study examines the contributions of the transcription factor Olig1 on NPC differentiation and remyelination. Under defined conditions, NPCs preferentially differentiate into oligodendroglia whereas NPCs isolated from Olig1-deficient (Olig1-/-) mice exhibit enhanced differentiation into astrocytes. Transplantation of Olig1-/- and Olig1+/+ NPCs into JHMV-infected mice resulted in similar cell survival, proliferation, and selective migration to areas of demyelination. However, only recipients of wild type NPCs exhibited extensive remyelination compared to mice receiving Olig1-/- NPCs. In vivo characterization of NPCs revealed that Olig1+/+ NPCs preferentially differentiated into NG2 positive OPCs and formed processes expressing myelin basic protein that encircled axons. In contrast, the majority of transplanted Olig1-/- NPCs differentiated into GFAP-positive cells consistent with the astrocyte lineage. These results indicate that exogenous NPCs contribute to improved clinical and histological outcome and this is associated with remyelination by this donor population. Further, these findings reveal that Olig1function is required for the remyelination potential of NPCs after transplant, through specification and/or maintenance of oligodendroglial identity. PMID- 22449476 TI - Adolescent hyperactivity and impaired coordination after neonatal hyperoxia. AB - In preterm infants, the risk to develop attention-deficit/hyperactivity disorder is 3 to 4-fold higher than in term infants. Moreover, preterm infants exhibit deficits in motor coordination and balance. Based on clinical data, higher oxygen levels in preterm infants lead to worse neurological outcome, and experimental hyperoxia causes wide-ranging cerebral changes in neonatal rodents. We hypothesize that hyperoxia in the immature brain may affect motor activity in preterm infants. We subjected newborn mice from P6 to P8 to 48 h of hyperoxia (80% O(2)) and tested motor activity in running wheels starting at adolescent age P30. Subsequently, from P44 to P53, regular wheels were replaced by complex wheels with variable crossbar positions to assess motor coordination deficits. MRI with diffusion tensor imaging was performed in the corpus callosum to determine white matter diffusivity in mice after hyperoxia at ages P30 and P53 in comparison to control animals. Adolescent mice after neonatal hyperoxia revealed significantly higher values for maximum velocity and mean velocity in regular wheels than controls (P<0.05). In the complex running wheels, however, maximum velocity was decreased in animals after hyperoxia, as compared to controls (P<0.05). Decreased fractional anisotropy and increased radial diffusion coefficient were observed in the corpus callosum of P30 and P53 mice after neonatal hyperoxia compared to control mice. Hyperoxia in the immature brain causes hyperactivity, motor coordination deficits, and impaired white matter diffusivity in adolescent and young adult mice. PMID- 22449477 TI - A novel trigeminal neuropathic pain model: compression of the trigeminal nerve root produces prolonged nociception in rats. AB - We demonstrate the establishment of a novel animal model for trigeminal neuropathic pain following compression of the trigeminal nerve root, which produces prolonged nociceptive behavior and demyelination of the trigeminal nerve root. Under anesthesia, male Sprague-Dawley rats (200-230 g) were mounted onto a stereotaxic frame and injections of a 4% agar solution (10 MUl) were given to achieve compression of the trigeminal nerve root. A sham operation was performed using identical procedures but without agar injections. Nociceptive behavior was examined 3 days before and then at 3, 7, 10, 14, 17, 21, 24, 30, 40, 55, and 70 days after the surgery. Compression of the trigeminal nerve root caused mechanical allodynia, hyperalgesia, and cold hypersensitivity. Mechanical allodynia was established within 3 days and recovered to preoperative levels on postoperative day (POD) 40. Mechanical hyperalgesia and cold hypersensitivity persisted until 55 days following compression. The compression produced focal demyelination in the trigeminal nerve root. In the medullary dorsal horn, phospho p38 (p-p38) mitogen-activated protein kinase (MAPK) was found to be exclusively expressed in the microglia on POD 14. Furthermore, intraperitoneal administration of carbamazepine (50mg/kg) significantly blocked mechanical allodynia and reduced p38 MAPK activation induced by the compression of the trigeminal nerve root. Our findings suggest that prolonged nociceptive behavior following compression of the trigeminal nerve root may mimic trigeminal neuralgia in this animal model and that the activation of p38 MAPK in the microglia contributes to pain hypersensitivity in rats that have undergone compression of the trigeminal nerve root. PMID- 22449478 TI - Decreased serum angiogenin level in Alzheimer's disease. AB - BACKGROUND: It has been suggested that Alzheimer's disease (AD) is mediated by pathological angiogenesis. Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), and tumor necrosis factor alpha (TNF alpha) may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization in AD pathogenesis. A few studies on the roles of VEGF in AD have been reported recently. But, the results were inconsistent. Angiogenin, which is suspected to have a similar function as VEGF, however, has not yet been studied in patients with AD. OBJECTIVE: This study was performed to investigate the levels of angiogenin and vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptorI (VEGFR I), and vascular endothelial growth factor receptor II (VEGFR II) in serums of patients with AD, to compare their levels with control subjects, and to determine whether serum angiogenin, VEGF, VEGFR I, and VEGFR II levels are associated with Alzheimer's disease (AD). METHODS: Serum angiogenin, VEGF, VEGFR I, and VEGFR II levels were quantified at the time of diagnosis in 20 patients with definite AD, and 18 healthy controls, using a commercial ELISA kit. RESULTS: Patients with AD exhibited lower serum angiogenin (p=0.003) and higher VEGF (p=0.008) levels than control subjects. No difference in serum VEGFR I and VEGFR II concentrations was observed between AD patients and controls. There was a correlation between serum levels of angiogenin and cognitive function (MMSE-KC and CDR) in AD patients. CONCLUSION: The increased serum level of VEGF and decreased serum angiogenin level were founded. Cognitive function was correlated with serum levels of angiogenin. Angiogenin may be involved in the pathogenesis of AD. Further study should be needed to evaluate the possibility of serum angiogenin as a biomarker of AD and as a predictor of disease progression. PMID- 22449479 TI - Differential effects of fluoxetine and venlafaxine on memory recognition: possible mechanisms of action. AB - Serotonin-specific reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are antidepressant drugs commonly used to treat a wide spectrum of mood disorders (Wong and Licinio, 2001). Although they have been clinically used for more than 50 years, the molecular and cellular basis for the action of SSRIs and SNRIs is not clear. Considering that the changes in gene expression involved in the action of antidepressant drugs on memory have not been identified, in this study we investigated the impact of chronic treatment with a SSRI (fluoxetine) and a SNRI (venlafaxine) on the mRNA expression of genes related to memory cascade in the mouse hippocampus, namely, alpha-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid (AMPA), nitric oxide synthase 1 (NOS1), neurotrophic tyrosine kinase receptor type 2 (TrKB), mitogen-activated protein kinases (MAPK/ERK) and serotonin transporter (SERT). Animals treated with fluoxetine 10 mg/Kg/day for 28 days showed a significant decrease in the percentage of time spent in the novel object recognition test (p<=0.005) and induced MAPK1/ERK2 down-regulation (p=0.005). Our results suggest that the effect on cognition could probably be explained by fluoxetine interference in the MAPK/ERK memory pathway. In contrast, chronic treatment with venlafaxine did not reduce MAPK1/ERK2 expression, suggesting that MAPK1/ERK2 down-regulation is not a common effect of all antidepressant drugs. Further studies are needed to examine the effect of chronic fluoxetine treatment on the ERK-CREB system, and to determine whether there is a causal relationship between the disruption of the ERK-CREB system and the effect of this antidepressant on memory performance. PMID- 22449480 TI - Commentary on 'No differences in perioperative outcome between symptomatic and asymptomatic AAAs after EVAR: an analysis from the ENGAGE Registry'. PMID- 22449481 TI - Healthcare-related correlates of recent HIV testing in New York City. AB - OBJECTIVE: To examine healthcare-related correlates of recent HIV testing among New York City (NYC) residents, controlling for socio-demographic and HIV-related risk factors. METHODS: Using the NYC 2007 Community Health Survey (population based telephone survey, n=8911), recent HIV testing was examined for its association with healthcare-related variables, including medical screening for other conditions, controlling for other HIV testing correlates using multiple logistic regression. RESULTS: Factors associated with a recent HIV test included: provider recommendation for an HIV test (adjusted odds ratio [AOR]: 10.1, 95% confidence interval [CI]:7.6-13.5), Medicaid versus private insurance (AOR: 1.6, 95% CI: 1.2-2.1), and having a personal doctor (AOR: 1.6, 95% CI: 1.3-2.1). The proportion of HIV tests attributed to each factor (attributable-fraction [AF]) was 49% for provider recommendation, 33% for having a personal doctor, and 8.3% for Medicaid insurance. Among subgroups eligible for other medical screening, factors associated with recent HIV testing included recent receipt of blood lipid testing (AOR: 2.2, 95% CI: 1.6-3.0; AF: 45%), and Pap smear (AOR: 2.7, 95% CI: 2.1-3.5; AF: 52%). Recent receipt of mammography and colonoscopy was not associated with recent HIV testing. CONCLUSIONS: A substantial proportion of recent HIV testing coverage among New Yorkers may be attributable to healthcare related factors. Joint medical screening may provide opportunities to increase population HIV testing coverage. PMID- 22449482 TI - Fairness and wellness incentives: what is the relevance of the process-outcome distinction? AB - OBJECTIVE: To determine whether the commonly drawn distinction between the fairness of incentives targeting behavioral processes (or effort) and those targeting outcomes (or achievement) provide suitable grounds for favoring either approach in healthcare research, policy and practice. METHODS: Conceptual analysis, literature review. RESULTS: A categorical distinction between process- and outcome-based incentives is less crisp than it seems. Both processes and outcomes involve targets, and both are subject to differences - across and within socio-economic groups - in circumstance and perspective. Thus, a spectrum view is more appropriate, in which the fairness of incentive programs increases with the extent of control that people have. The effectiveness of incentives is a further relevant consideration, and some available evidence suggests that incentives closer to the outcome-end of the spectrum can be more effective. CONCLUSIONS: Simple distinctions between processes and outcomes by themselves provide little assurance that programs are effective or fair. Effectiveness can and should be assessed empirically. Assessments of fairness should focus on the extent to which an activity or outcome might be feasible and under an individual's control, not on whether it targets a process or outcome. Rigid uniform targets for all are generally less desirable than those that reward person-specific improvement. PMID- 22449483 TI - Screen time and passive school travel as independent predictors of cardiorespiratory fitness in youth. AB - OBJECTIVE: The most prevalent sedentary behaviours in children and adolescents are engagement with small screen media (screen-time) and passive travel (by motorised vehicle). The objective of this research was to assess the independence of these behaviours from one another and from physical activity as predictors of cardiorespiratory fitness in youth. METHODS: We measured cardiorespiratory fitness in n=6819 10-16 year olds (53% male) who self-reported their physical activity (7-day recall) school travel and screen time habits. Travel was classified as active (walking, cycling) or passive; screen time as <2 h, 2-4 h or >4 h. RESULTS: The multivariate odds of being fit were higher in active travel (Boys: OR 1.32, 95% CI: 1.09-1.59; Girls: OR 1.46, 1.15-1.84) than in passive travel groups. Boys reporting low screen time were more likely to be fit than those reporting >4 h (OR 2.11, 95% CI: 1.68-2.63) as were girls (OR 1.66, 95% CI: 1.24-2.20). These odds remained significant after additionally controlling for physical activity. CONCLUSION: Passive travel and high screen time are independently associated with poor cardiorespiratory fitness in youth, and this relationship is independent of physical activity levels. A lifestyle involving high screen time and habitual passive school travel appears incompatible with healthful levels of cardiorespiratory fitness in youth. PMID- 22449484 TI - Associations between anxious-depressed symptoms and cardiovascular risk factors in a longitudinal childhood study. AB - OBJECTIVE: To examine the influence of anxious/depressed scores on cardiovascular risk factors throughout childhood. METHODS: Data from the Western Australian Pregnancy Cohort (Raine) Study, a study of 2900 pregnancies recruited between 1989 and 1991, were used. Anxious-depressed scores (derived from the Childhood Behavior Checklist), body mass index (BMI) and blood pressure were measured at 5 (n=1681), 8 (n=1697), 10 (n=1575) and 14 (n=1386) years. At age 14 depressive symptom scores (Beck Depression Inventory for Youth), anxious-depressed scores (Youth Self-Report (YSR) and Teacher Report Form (TRF)) and fasting lipid, glucose and insulin were also available. Cross sectional and longitudinal analyses were conducted. RESULTS: At age 14, girls with higher anxious-depressed scores had higher BMI (p<= 0.005) and homeostasis model assessment-estimated insulin resistance (p<= 0.0001). This equated to a difference of 0.6 kg/m(2) and 0.3 units in predicted BMI and HOMA-IR respectively (top 5% vs. score of zero). Boys with higher anxious-depressed scores had lower systolic blood pressure trajectories (p=0.024). CONCLUSION: Depressive scores appear to have differing influences on BMI, homeostasis model assessment-estimated insulin resistance and systolic blood pressure in boys and girls. Paradoxically boys with higher anxious depressed scores had lower blood pressure throughout childhood. PMID- 22449485 TI - Time course of neuroprotection induced by normobaric hyperoxia in focal cerebral ischemia. AB - BACKGROUND: The purpose of this study was to determine if normobaric hyperoxia (HO) preconditioning offers durable neuroprotection against cerebral ischemia and the role of reactive oxygen species in the ischemic tolerance mechanism. MATERIALS AND METHODS: Rats were divided into four experimental main groups. First main group which was comprised four subgroups, were exposed to 90% HO for 6 days, 4 hours per day and subjected to 60 minutes of right middle cerebral artery occlusion (MCAO) after 2, 5, 10, and 15 days. Second group acted as control, was exposed to 21% oxygen (RA; room air) in the same chamber, and subjected to 60 minutes of right MCAO. Third main group comprised two subgroups, were exposed to 90% HO for 6 days, 4 hours per day, received normal saline (NS; 2HO+NS) and dimethylthiourea (DT) just before inhaling 90% HO (2HO+DT). Forth main group was exposed to 21% oxygen (2RA) in the same chamber and received normal saline (2RA+NS) and DT just before inhaling 21% oxygen (2RA+DT). Last two main groups were subjected to 60 minutes of right MCAO after 2 days. After 24-hour reperfusion, neurological deficit score (NDS), infarct volume, brain water content, and Evans blue extravasations were assessed in all animals. RESULTS: First main group compared with the RA group, NDS, infarct volume, Brain water content, and Evans blue extravasations were reduced in 2, 5, and 10 days significantly, whereas there was no difference among groups 2HO+DT, 2RA+DT, and 2RA+NS. CONCLUSIONS: In the model of transient focal cerebral ischemia, hyperoxia preconditioning induced effective but transient neuroprotective effects. PMID- 22449486 TI - Allurin, an amphibian sperm chemoattractant having implications for mammalian sperm physiology. AB - Eggs of many species are surrounded by extracellular coats that emit ligands to which conspecific sperm respond by undergoing chemotaxis and changes in metabolism, motility, and acrosomal status in preparation for fertilization. Here we review methods used to measure sperm chemotaxis and focus on recent studies of allurin, a 21-kDa protein belonging to the Cysteine-RIch Secretory Protein (CRISP) family that has chemoattraction activity for both amphibian and mammalian sperm. Allurin is unique in being the first extensively characterized Crisp protein found in the female reproductive tract and is the product of a newly discovered amphibian gene within a gene cluster that has been largely conserved in mammals. Study of its expression, function, and tertiary structure could lead to new insights in the role of Crisp proteins in sperm physiology. PMID- 22449487 TI - New insights into the regulation of E-cadherin distribution by endocytosis. AB - Homeostasis of adherens junctions is achieved through complex regulatory mechanisms. The junctions are highly dynamic in contact establishment, in remodeling events during development, and during processes involving a loss of adhesion like epithelial-mesenchyme transition. It appeared recently that they are also dynamically renewed in mature, steady-state adhesions. Indeed, maintenance of a steady state must be integrated into a tight control of force equilibrium between a cell and its neighbors. Therefore, it appears that E cadherin dynamics allows to respond constantly to various biochemical and mechanical stimuli and to regulate the movement and shape of junctions in active remodeling processes. E-cadherin dynamics is mediated through several mechanisms (diffusion, trafficking) in function of the biological system. In mature junctions, membrane E-cadherin is quickly renewed by endocytosis in many cell types. E-cadherin endocytosis shows a complex regulation, depending on small G proteins, ubiquitination, cleavage events, actomyosin cytoskeleton, and other trans molecules in adherens junctions. It is modulated by growth factor stimulations and physical factors. Consequently, E-cadherin endocytosis tightly controls a number of functional processes: cell movements, junction maintenance, cell sorting, and polarity. Misregulated E-cadherin endocytosis is involved in many diseases, from cancerous processes to organogenesis defects. PMID- 22449488 TI - New insights into the role of the cortical cytoskeleton in exocytosis from neuroendocrine cells. AB - The cortical cytoskeleton is a dense network of filamentous actin (F-actin) that participates in the events associated with secretion from neuroendocrine cells. This filamentous web traps secretory vesicles, acting as a retention system that blocks the access of vesicles to secretory sites during the resting state, and it mediates their active directional transport during stimulation. The changes in the cortical cytoskeleton that drive this functional transformation have been well documented, particularly in cultured chromaffin cells. At the biochemical level, alterations in F-actin are governed by the activity of molecular motors like myosins II and V and by other calcium-dependent proteins that influence the polymerization and cross-linking of F-actin structures. In addition to modulating vesicle transport, the F-actin cortical network and its associated motor proteins also influence the late phases of the secretory process, including membrane fusion and the release of active substances through the exocytotic fusion pore. Here, we discuss the potential interactions between the F-actin cortical web and proteins such as SNAREs during secretion. We also discuss the role of the cytoskeleton in organizing the molecular elements required to sustain regulated exocytosis, forming a molecular structure that foments the efficient release of neurotransmitters and hormones. PMID- 22449489 TI - New insights into the mechanisms for photodynamic therapy-induced cancer cell death. AB - Photodynamic therapy (PDT) is a promising therapeutic modality for cancer treatment; however, a more detailed understanding is needed to improve the clinical use of this therapy. PDT induces cancer cell death by apoptosis, necrosis, and autophagy, and these mechanisms can be concurrently occurred. PDT destroys cancer cells by inducing apoptosis through diverse signaling pathways coupled with Bcl-2 family members, caspases, and apopotosis-inducing factor. When the apoptotic pathway is unavailable, PDT can cause cancer cell death through induction of a necrotic or autophagic mechanism. Autophagy is occurred in a Bax independent manner and can be stimulated in parallel with apoptosis. PDT directly destroys cancer cells by inducing either apoptotic or necrotic death. PDT also can induce autophagy as a death or a survival mechanism. These mechanisms are dependent on a variety of parameters including the nature of the photosensitizer, PDT dose, and cell genotype. Understanding the complex cross talk between these pathways may improve the effectiveness of PDT. Here, we discuss the interplay between these mechanisms based on recent evidence and suggest prospects with regard to advances in PDT. PMID- 22449490 TI - New insights into the role of angiogenin in actin polymerization. AB - Angiogenin is a potent stimulator of angiogenesis. It interacts with endothelial cells and induces a wide range of cellular responses initiating a process of blood vessel formation. One important target of angiogenin is endothelial cell surface actin, and their interaction might be one of crucial steps in angiogenin induced neovascularization. Recently, it was shown that angiogenin inhibits polymerization of G-actin and changes the physical properties of F-actin. These observations suggest that angiogenin may cause changes in the cell cytoskeleton. This chapter reviews the current state of the literature regarding angiogenin structure and function and discusses the relationship between the angiogenin and actin and possible functional roles of their interaction. PMID- 22449491 TI - Asymmetric cell divisions in the epidermis. AB - Generation of three-dimensional tissues with distinct cell types is required for the development of all organs. On its own, mitotic spindle orientation allows tissues to change in length or shape. In combination with intrinsic or extrinsic cues, this can also be coupled to the generation of diverse cell fates-a process known as asymmetric cell division (ACD). Understanding ACDs has been greatly aided by studies in invertebrate model systems, where genetics and live imaging have provided the basis for much of what we know. ACDs also drive the development and differentiation of the epidermis in mammals. While similar to the invertebrate models, the epidermis is distinct in balancing symmetric and asymmetric divisions to yield a tissue of the correct surface area and thickness. Here, we review the roles of spindle orientation in driving both morphogenesis and cell fate decisions. We highlight the epidermis as a unique model system to study not only basic mechanisms of ACD but also their regulation during development. PMID- 22449493 TI - Role of store-operated calcium entry during meiotic progression and fertilization of mammalian oocytes. AB - Calcium signaling is essential for many cellular events, including muscle contraction, secretion of hormones and neurotransmitters, and fertilization of oocytes. For the appropriate maturation and fertilization of mammalian oocytes, the influx of extracellular calcium through plasma membrane Ca(2+) channels is required. Although the molecular pathway of the Ca(2+) entry in other cell types has been reported, Ca(2+) channels involved in the regulation of Ca(2+) influx in oocytes have remained unknown for a long time. In this review, we summarize recent findings regarding the occurrence of store-operated calcium entry (SOCE) in mammalian oocytes and the expression and localization profiles of STIM1 and ORAI1, two important proteins that control SOCE. As we discuss here, STIM1, as an endoplasmic reticulum Ca(2+) sensor, and ORAI1, the major plasma Ca(2+) channel involved in SOCE, might help to explain the role of Ca(2+) entry in mammalian oocyte maturation and fertilization. PMID- 22449492 TI - New insights into the regulation of RNP granule assembly in oocytes. AB - In a variety of cell types in plants, animals, and fungi, ribonucleoprotein (RNP) complexes play critical roles in regulating RNA metabolism. These RNP granules include processing bodies and stress granules that are found broadly across cell types, as well as RNP granules unique to the germline, such as P granules, polar granules, sponge bodies, and germinal granules. This review focuses on RNP granules localized in oocytes of the major model systems, Caenorhabditis elegans, Drosophila, Xenopus, mouse, and zebrafish. The signature families of proteins within oocyte RNPs include Vasa and other RNA-binding proteins, decapping activators and enzymes, Argonaute family proteins, and translation initiation complex proteins. This review describes the many recent insights into the dynamics and functions of RNP granules, including their roles in mRNA degradation, mRNA localization, translational regulation, and fertility. The roles of the cytoskeleton and cell organelles in regulating RNP granule assembly are also discussed. PMID- 22449494 TI - A pressure cooking-based DNA extraction from archival formalin-fixed, paraffin embedded tissue. AB - As emerging novel DNA-based methodologies are adopted, nucleic acid-based assays depend critically on the quality and quantity of extracted DNA. Formalin-fixed, paraffin embedded (FFPE) tissue samples provide an invaluable resource for subsequent molecular studies of clinical phenotypes, but high-quality DNA extraction from archival FFPE tissue specimens remains complex and time consuming. To address this challenge, we have developed a reliable rapid DNA extraction method for FFPE tissue specimens. It is based on deparaffinization at high temperature coupled with relieving crosslink in a pressure cooker. The DNA yield by this rapid method resulted in an average 1.8-fold increase in comparison with the commercial kit and OD 260/280 ratios between 1.87 and 1.95. The DNA obtained by the rapid method was suitable for methylation analyses in colon cancer patients. These data suggest that this new DNA extraction method coupled with methylation-specific polymerase chain reaction can be used for epigenetic studies with the advantages of rapidity and high quality and may contribute to the development of biomarkers in clinical studies. PMID- 22449495 TI - Non-crosslinking gold nanoprobes for detection of nucleic acid sequence-based amplification products. AB - Lack of an appropriate detection method for isothermal RNA amplification technique, known as nucleic acid sequence-based amplification (NASBA), is considered as a major defect for its vast applications. In that regard, novel detection methods as fast, specific, and sensitive as the gold nanoprobe detection technique are highly demanded and non-crosslinking gold nanoprobes are regarded as the ideal choice. In this study, we attempted to integrate these two techniques (RNA amplification and nanoprobe detection) into a single detection associated amplification method. In that line, essential adjustments such as amplicon dilution, disturbing reagent extraction, ion adjustment, and modification of the hybridization protocol were needed due to the ribonucleic acid nature of NASBA products and the presence of some interfering reagents in the amplification reaction environment. The adjustments successfully resulted in the gold nanoparticle-based detection of NASBA products with naked eyes in a whole operational time of less than 3.5h (including nucleic acid extraction, amplification, and detection). Furthermore, the developed assay was successfully applied to detect dnaK messenger RNA of Salmonella typhimurium. The developed colorimetric method facilitated the detection step of NASBA leading to an ideal methodology for rapid assays and serves as an ideal alternative to the highly expensive reverse transcription polymerase chain reaction (RT-PCR) approach. PMID- 22449496 TI - Enzymatic fluorometric microplate assay for quantitative analysis of 3 hydroxybutyric acid in mouse plasma. AB - 3-Hydroxybutyric acid (3HB) is a ketone body and acts as an indicator of energy balance and a central regulator of energy homeostasis. We report the application of a sensitive fluorometric assay for the quantitative determination of 3HB. The assay is based on the oxidation of 3HB by 3HB dehydrogenase and on the diaphorase resazurin amplifying system. This simple assay enables the measurement of changes in 3HB levels in the blood of normal mice by very small volume sample collection. Therefore, this assay will be useful for in vivo studies of small animals. PMID- 22449497 TI - Scaling down the size and increasing the throughput of glycosyltransferase assays: activity changes on stem cell differentiation. AB - Glycosyltransferases (glycoTs) catalyze the transfer of monosaccharides from nucleotide-sugars to carbohydrate-, lipid-, and protein-based acceptors. We examined strategies to scale down and increase the throughput of glycoT enzymatic assays because traditional methods require large reaction volumes and complex chromatography. Approaches tested used (i) microarray pin printing, an appropriate method when glycoT activity was high; (ii) microwells and microcentrifuge tubes, a suitable method for studies with cell lysates when enzyme activity was moderate; and (iii) C(18) pipette tips and solvent extraction, a method that enriched reaction product when the extent of reaction was low. In all cases, reverse-phase thin layer chromatography (RP-TLC) coupled with phosphorimaging quantified the reaction rate. Studies with mouse embryonic stem cells (mESCs) demonstrated an increase in overall beta(1,3)galactosyltransferase and alpha(2,3)sialyltransferase activity and a decrease in alpha(1,3)fucosyltransferases when these cells differentiate toward cardiomyocytes. Enzymatic and lectin binding data suggest a transition from Lewis(x)-type structures in mESCs to sialylated Galbeta1,3GalNAc-type glycans on differentiation, with more prominent changes in enzyme activity occurring at later stages when embryoid bodies differentiated toward cardiomyocytes. Overall, simple, rapid, quantitative, and scalable glycoT activity analysis methods are presented. These use a range of natural and synthetic acceptors for the analysis of complex biological specimens that have limited availability. PMID- 22449498 TI - A dynamic real-time method for monitoring epithelial barrier function in vitro. AB - The intestinal epithelium functions as a physical barrier against the harmful environment of the lumen, which usually becomes impaired in the presence of intestinal diseases. In this work, we introduce an electronic impedance-based analysis using a real-time xCELLigence system to record the dynamic processes of ethanol-induced intestinal barrier dysfunction. In terms of analyzing morphological alterations in the paracellular junction complex and the organization of pericellular F-actin, this novel, real-time, cell-based technology shows considerable correlations with the standard transepithelial electrical resistance endpoint assay. In addition, monitoring barrier functions in real time allows unbiased screening and characterization of biochemical agents in the lumen that affect epithelial integrity. This functional assay further identifies the in vitro roles of the inducible nitric oxide synthase inhibitor, epithelial growth factor, tyrosine kinases, and phosphatases in regulating epithelial barrier function in response to ethanol administration. Taken together, our findings suggest that this novel, real-time, high-throughput method offers a promising tool for monitoring epithelial barrier functions in situations with more physiological relevance. PMID- 22449499 TI - Autologous mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-gamma, and indoleamine 2,3-dioxygenase. AB - Transplant arteriosclerosis (TA) remains the major limitation of long-term graft survival in heart transplantation despite the advances in immunosuppressants. Mesenchymal stem cells (MSCs) have been demonstrated to suppress allogeneic immune responses by numerous in vitro studies. However, the immunomodulatory effects of MSCs in vivo are controversial and the underlying molecular mechanisms are not conclusive. In this study, we investigated the therapeutic potential of autologous bone marrow-derived MSCs on TA in a porcine model of femoral artery transplantation. MSCs or saline were injected into the soft tissue surrounding the arterial grafts immediately postanastomosis. Four weeks after transplantation, neointimal formation increased significantly in untreated allografts compared with the MSC-treated grafts as assessed by intravascular ultrasound (maximum luminal area stenosis: 40 +/- 12% vs. 18 +/- 6%, p < 0.001). Grafts harvested at 4 weeks showed dense perivascular lymphocyte infiltration accompanied by significant intimal hyperplasia in the untreated but not in the MSC-treated allografts. Serial angiographic examination showed that all of the untreated allografts became occluded at the 8th week whereas the majority of the MSC-treated grafts remained patent at the 12th week posttransplantation (n = 12 each group, p < 0.001). Quantitative PCR analysis revealed that Foxp3 expression was comparable between the untreated and the MSC-treated groups. However, expression of interleukin-10 (IL-10), interferon-gamma (IFN-gamma), and indoleamine 2,3-dioxygenase (IDO) was increased significantly in the MSC-treated allografts compared with that in the allograft controls (p = 0.021 for IL-10, p = 0.003 for IFN-gamma, and p = 0.008 for IDO). In conclusion, local delivery of autologous MSCs alleviates TA by inducing allograft tolerance via enhanced expression of IL-10, IFN-gamma, and IDO but not Foxp3-positive cells in the vessel wall. These results suggest that MSCs induce immune tolerance by activating the type 1 regulatory T-like cells. PMID- 22449500 TI - After the storm: personal experiences following an EF4 tornado. AB - In April of 2011, an EF4 tornado ripped through the city of Tuscaloosa, AL, leaving in its wake thousands of destroyed homes and businesses. In the hours and days that followed, the health care community of this city, as well as the entire state of Alabama and the southeastern United States, came together to provide care to hundreds of victims, recovery workers, and volunteers. PMID- 22449501 TI - Risk factors and interventions for ventilator-associated pneumonia in pediatric patients. AB - Ventilator-associated pneumonia (VAP) is a leading nosocomial infection in pediatrics. Little research has investigated the risk factors or effectiveness of interventions for pediatric VAP prevention. The purposes of this study were to identify the risk factors associated with VAP in pediatric patients and describe current VAP prevention practices. Data were gathered retrospectively on ventilated patients admitted to the pediatric intensive care unit over 12 months. No variables were found to be predictive of VAP. Review of practices indicates that better documentation is needed of all interventions. Findings provide information to guide the implementation of VAP bundles. Implementation should focus on adequate documentation of VAP prevention efforts. PMID- 22449502 TI - Bonding efficacy of 1-step self-etch adhesives: effect of additional enamel etching and hydrophobic layer application. AB - PURPOSE: The purpose of this study was to analyze the effect of additional enamel etching and hydrophobic layer application on microleakage of 1-step self-etch adhesives. METHODS: Class V cavities were made on the buccal surfaces of 80 extracted human premolars. The teeth were divided into 2 test groups according to the 1-step self-etch adhesive used: Clearfil S(3) Bond and Xeno III. Each test group was subdivided into 4 groups (n=10) according to application mode of the adhesive: (1) Group 1=adhesive applied following manufacturer's directions; (2) Group 2=enamel etching prior to adhesive application; (3) Group 3=same as Group 1, plus application of an additional coat of hydrophobic resin layer; (4) Group 4=same as Group 2, plus application of an additional coat of hydrophobic resin layer. The adhesives were light cured, and the cavities were filled with resin composite. Specimens were thermocycled and analyzed for leakage using Kruskal Wallis and Mann-Whitney U test at a significance level of P=.05. RESULTS: Enamel etching significantly reduced leakage in both the adhesives. Hydrophobic resin layer application significantly reduced leakage in Xeno III. CONCLUSIONS: An additional acid etching step and hydrophobic resin layer application can improve the bonding of 1-step self-etched adhesives to enamel and dentin, respectively. PMID- 22449503 TI - Effects of amorphous calcium phosphate stabilized by casein phosphopeptides on enamel de- and remineralization in primary teeth: an in vitro study. AB - PURPOSE: Amorphous calcium phosphate, stabilized by casein phosphopeptides, has been found to enhance remineralization of subsurface lesions in permanent teeth. The purpose of the present in vitro study was to evaluate the potential of GC Tooth Mousse to enhance remineralization of initial demineralized enamel sites in primary teeth. METHODS: Forty-four demineralization sites were created in 22 extracted primary teeth. Samples were randomly assigned to 6 treatment groups (GC Tooth Mousse covering, GC Tooth Mousse covering and demineralization, and control groups). The mineral content of each sample was evaluated using energy dispersive X-ray analysis, performed from the enamel surface of each lesion inwards. The results were analyzed using analysis of variance, with a significance level P<.05. RESULTS: Samples treated with GC Tooth Mousse demonstrated an increase in the calcium-phosphate ratio by approximately 2% near the surface, a minimal increase of 1% at a depth over 60 MUm, and no change at a depth from 40 to 60 MUm, with no statistically significant differences (P>.05). CONCLUSION: This study demonstrates a minimal increase in the subsurface calcium-phosphate ratio following GC Tooth Mousse treatment, especially in demineralized enamel tissue. PMID- 22449504 TI - Multidisciplinary treatment approach in Treacher Collins syndrome. AB - Treacher Collins syndrome (TCS) is a common genetic disorder with high penetrance and phenotypic variability. First and second branchial arches are affected in TCS, resulting in craniofacial and intraoral anomalies such as: severe convex facial profile; mid-face hypoplasia; microtia; eyelid colobomas; mandibular retrognathism; cleft palate; dental hypoplasia; heterotopic teeth; maxillary transverse hypoplasia; anterior open bite; and Angle Class II molar relationship. A high incidence of caries is also a typical finding in TCS patients. Nonetheless, even simple dental restorative procedures can be challenging in this patient population due to other associated medical conditions, such as: congenital heart defects; decreased oropharyngeal airways; hearing loss; and anxiety toward treatment. These patients often require a multidisciplinary treatment approach, including: audiology; speech and language pathology; otorhinolaryngology; general dentistry; orthodontics; oral and maxillofacial surgery; and plastic and reconstructive surgeries to improve facial appearance. This paper's purpose was to present a current understanding of Treacher Collins syndrome etiology, phenotype, and current treatment approaches. PMID- 22449505 TI - Esthetic rehabilitation of severely decayed primary incisors using glass fiber reinforced composite: a case report. AB - Restoration of primary maxillary incisors severely damaged by caries or trauma is a clinical challenge in pediatric dental clinics. Early childhood caries is observed in approximately half the child population. In the past, the only treatment option would have been to extract the affected teeth and replace them with prosthetic substitutes. With the introduction of new adhesive systems and restorative materials, alternative approaches in treating these teeth have been proposed. The purpose of this paper was to describe the rehabilitation of primary anterior teeth in a 5-year-old patient using glass fiber reinforced composite resin as an intracanal post. PMID- 22449506 TI - Regional odontodysplasia: report of a case. AB - Regional odontodysplasia is an unusual nonhereditary dental anomaly of uncertain origin. It presents clinically as delayed or failed eruption, abscess formation, early exfoliation, and malformed teeth and radiographically as defective enamel and dentin formation, giving the teeth a fuzzy silhouette. Because teeth are essential for psychological and functional development of the child, appreciation and management of regional odontodysplasia is important for comprehensive dental care. The purpose of this paper was to present the case of a 12-year-old female who presented with an eruption disturbance affecting a single segment of her jaw and characteristic ghost teeth radiographic appearance. The approach toward management should be aimed at preserving the unerupted affected teeth for the development of the alveolar ridge, conserving the erupted teeth (if salvageable) or extraction followed by prosthetic rehabilitation. PMID- 22449507 TI - Management of an unerupted dilacerated maxillary central incisor after trauma to the primary predecessor. AB - The most common cause of permanent maxillary incisor dilaceration is usually trauma to the primary predecessor, such as avulsions, intrusions, or gross displacement of primary incisors. The purpose of this case report was to describe the surgical exposure and orthodontic traction of an unerupted dilacerated permanent maxillary central incisor performed on a young girl. During the surgical exposure, a hole was placed in the tooth crown, and elastic chains, inserted though the hole, were used for traction. The alignment and leveling of the impacted incisor were performed with sequential stainless steel wires. Good periapical and periodontal health, combined with adequate occlusion and a positive esthetic outcome, demonstrated the satisfactory results of this case. PMID- 22449508 TI - Clinical and radiographic evaluation and comparison of six cases of fusion involving the primary dentition. AB - Fusion occurs infrequently, but could cause esthetic, spacing, and periodontal problems. An understanding of fused teeth and their associated problems is important to provide prophylactic measures, thereby preventing or minimizing possible complications. The purpose of this case report was to highlight the infrequency of fused primary teeth by virtue of the number of such cases reported in the literature. Six cases of asymptomatic dental twinning anomalies in the primary dentition are reported in this study, and a clinical and radiographic presentation of the cases of fusion of primary incisor teeth is illustrated. This clinical entity has been found to appear with varied clinical and radiographic appearances. All cases are different from each other. This study's fourth patient is of particular interest because he is the second known case of bilateral fusion of the primary mandibular central and lateral incisors to be reported in the literature. An association of fusion of primary incisors with the number of succedaneous teeth was observed. PMID- 22449509 TI - Foreign bodies in primary molars: a report of 2 cases. AB - Foreign bodies can be found in the pulps of primary teeth during routine oral examinations. These foreign bodies can result in painful complications. A detailed case history and clinical and radiographic examinations are necessary to come to a conclusion about the nature, size, and location of the foreign body, and to determine the difficulty involved in its removal. The purpose of this paper was to discuss 2 clinical cases and the management of foreign bodies found lodged in primary molars. PMID- 22449510 TI - Ascaris: development of selected genotypes in mice. AB - Using nucleotide variation in the first internal transcribed spacer of nuclear ribosomal DNA, five different genotypes (designated G1-G5) have been identified and the preponderance of genotype G1 in humans and of genotype G3 in pigs led to the proposal that parasites bearing the two genotypes have an affinity for a particular host species. A subsequent study using eggs of genotype G1 from humans and G3 from pigs to infect pigs and mice indicated that there is a significant difference in the ability to infect and establish as larvae in mice and as adults in pigs between the two genotypes. Extending previous investigations, the present study investigated whether there are differences in development as designated by egg hatching, larvae migration and distribution in the mice between the Ascaris strains with known genotypes. Ascaris eggs of genotypes G1 (predominating in human-derived worms) and G3 (predominating in pig-derived worms) were used to infect C57BL/6 mice orally. Eggs/larvae were examined from the small and large intestines, thoracic and abdominal cavities, peripheral blood, livers and lungs at intervals of 2h until 12h post-infection, then periodically until 34 days of infection. Results showed distinct differences in egg hatching (the timing and location of hatching, and the numbers hatched), and in larvae migration and distribution (the means and constituent ratios, the time of peak recovery, and larvae reappearing in intestines) between the two strains. The results can explain the findings of significantly higher larval recovery of genotype G1 than G3 in the mice, and may shed some enlightenment to understand the difference in host affiliation of Ascaris of different genotypes. PMID- 22449511 TI - Leishmania amazonensis: inhibition of 3'-nucleotidase activity by Cu2+ ions. AB - Free Cu(2+) is toxic due to the capacity of free copper ions to catalyze the production of reactive oxygen species (ROS) that can modify the structure and/or function of biomolecules. In addition, non-specific binding to enzymes, which modifies their catalytic activities, can occur. In this work, the mechanisms underlying the ability of copper to inhibit 3'-nucleotidase from Leishmania amazonensis (La3'-nucleotidase) were investigated. To that end, La3'-nucleotidase activity was assayed with CuCl(2) in the presence of ascorbate or hydrogen peroxide to discriminate non-specific binding effects from pro-oxidant effects of copper. Copper inhibitory effects were greater at more acidic pH than at alkaline pH. The addition of enzyme substrate, adenosine 3'-monophosphate (3'AMP), prevented the inhibition of enzyme activity by copper. Thiol-containing compounds were able to protect the enzyme activity against inhibition due to copper. The specific copper chelating agent bathocuproine sulphonate (BCS) restored enzyme activity after pre-treatment of the enzyme with copper. La3'-nucleotidase activity was found to be resistant to ROS generated during oxidation reactions of ascorbate and hydrogen peroxide catalyzed by copper. Our results suggest that Cu(2+) ions exert their inhibitory effects by binding to specific motifs of the 3'-nucleotidase protein and that the enzyme appears to be extremely resistant to ROS. PMID- 22449512 TI - Obesity: "priming" the lung for injury. AB - Acute lung injury (ALI) is a severe inflammatory condition that develops in response to local and systemic lung challenges. To date, specific risk factors for development of ALI remain poorly defined. Recent epidemiological studies have reported obesity as an important predisposing factor in the development of this condition. Although the pathogenic mechanisms linking obesity and ALI have not been well-elucidated, emerging scientific evidence has described factors secreted by adipose tissue that have important biological activities in lung and has suggested that altered secretion of these factors during obesity contributes to increased ALI susceptibility. The objective of this manuscript is to highlight recent clinical evidence supporting the association between obesity and ALI and to discuss the posited role for adipose tissue-derived factors in the pathogenesis of this condition. PMID- 22449513 TI - Patterns of c-reactive protein RATIO response in severe community-acquired pneumonia: a cohort study. AB - INTRODUCTION: Community-acquired pneumonia (CAP) requiring intensive care unit (ICU) admission remains a severe medical condition, presenting ICU mortality rates reaching 30%. The aim of this study was to assess the value of different patterns of C-reactive protein (CRP)-ratio response to antibiotic therapy in patients with severe CAP requiring ICU admission as an early maker of outcome. METHODS: In total, 191 patients with severe CAP were prospectively included and CRP was sampled every other day from D1 to D7 of antibiotic prescription. CRP ratio was calculated in relation to D1 CRP concentration. Patients were classified according to an individual pattern of CRP-ratio response with the following criteria: fast response - when D5 CRP was less than or equal to 0.4 of D1 CRP concentration; slow response - when D5 CRP was > 0.4 and D7 less than or equal to 0.8 of D1 CRP concentration; nonresponse - when D7 CRP was > 0.8 of D1 CRP concentration. Comparison between ICU survivors and non-survivors was performed. RESULTS: CRP-ratio from D1 to D7 decreased faster in survivors than in non-survivors (p = 0.01). The ability of CRP-ratio by D5 to predict ICU outcome assessed by the area under the ROC curve was 0.73 (95% Confidence Interval, 0.64 0.82). By D5, a CRP concentration above 0.5 of the initial level was a marker of poor outcome (sensitivity 0.81, specificity 0.58, positive likelihood ratio 1.93, negative likelihood ratio 0.33). The time-dependent analysis of CRP-ratio of the three patterns (fast response n = 66; slow response n = 81; nonresponse n = 44) was significantly different between groups (p < 0.001). The ICU mortality rate was considerably different according to the patterns of CRP-ratio response: fast response 4.8%, slow response 17.3% and nonresponse 36.4% (p < 0.001). CONCLUSIONS: In severe CAP, sequential evaluation of CRP-ratio was useful in the early identification of patients with poor outcome. The evaluation of CRP-ratio pattern of response to antibiotics during the first week of therapy was useful in the recognition of the individual clinical evolution. PMID- 22449514 TI - Human cystic echinococcosis: epidemiologic, zoonotic, clinical, diagnostic and therapeutic aspects. AB - This review represents an updated scenario on the transmission cycle, epidemiology, clinical features and pathogenicity, diagnosis and treatment, and prevention and control measures of a cestode parasite Echincoccus granulosus (E. granulosus) infection causing cystic echinococcosis (CE) in humans. Human CE is a serious life-threatening neglected zoonotic disease that occurs in both developing and developed countries, and is recognized as a major public health problem. The life cycle of E. granulosus involves a definitive host (dogs and other canids) for the adult E. granulosus that resides in the intestine, and an intermediate host (sheep and other herbivores) for the tissue-invading metacestode (larval) stage. Humans are only incidentally infected; since the completion of the life cycle of E. granulosus depends on carnivores feeding on herbivores bearing hydatid cysts with viable protoscoleces, humans represent usually the dead end for the parasite. On ingestion of E. granulosus eggs, hydatid cysts are formed mostly in liver and lungs, and occasionally in other organs of human body, which are considered as uncommon sites of localization of hydatid cysts. The diagnosis of extrahepatic echinococcal disease is more accurate today because of the availability of new imaging techniques, and the current treatments include surgery and percutaneous drainage, and chemotherapy (albendazole and mebendazole). But, the wild animals that involve in sylvatic cycle may overlap and interact with the domestic sheep-dog cycle, and thus complicating the control efforts. The updated facts and phenomena regarding human and animal CE presented herein are due to the web search of SCI and non-SCI journals. PMID- 22449515 TI - Scrub typhus: pathophysiology, clinical manifestations and prognosis. AB - Scrub typhus is a zoonosis caused by the pathogen Orientia tsutsugamushi (O. tsutsugamushi). The disease has significant prevalence in eastern and Southeast Asia. Usually presenting as an acute febrile illness, the diagnosis is often missed because of similarities with other tropical febrile infections. Many unusual manifestations are present, and these are described in this review, together with an outline of current knowledge of pathophysiology. Awareness of these unusual clinical manifestations will help the clinician to arrive at an early diagnosis, resulting in early administration of appropriate antibiotics. Prognostic indicators for severe disease have not yet been clearly established. PMID- 22449516 TI - Effect of nalidixic acid on the morphology and protein expression of Pseudomonas aeruginosa. AB - OBJECTIVE: To determine the effect of nalidixic acid on the morphology and protein expression of Pseudomonas aeruginosa (P. aeruginosa). METHODS: Nalidixic acid solution of 1 600 MUg/mL was prepared. The minimum inhibitory concentration (MIC) for P. aeruginosa was determined with tube dilution test. The effect of nalidixic acid on the morphology of P. aeruginosa was studied using light microscope and scanning electron microscope. Changes in protein profile were studied using SDS-PAGE. RESULTS: The MIC of nalidixic acid was 700 MUg/mL against P. aeruginosa. The exposure of P. aeruginosa to different concentrations of nalidixic acid resulted in deformation of most of the growing cells. At the concentration of 600 MUg/mL most of the cells turned into elongated and adhere to each other while some of the cells were bulged. The intensity of protein bands were changed when they exposed to nalidixic acid. CONCLUSIONS: The present findings suggest that the morphology and protein expression of P. aeruginosa is greatly affected by nalidixic acid. PMID- 22449517 TI - Therapeutic effects of tender coconut water on oxidative stress in fructose fed insulin resistant hypertensive rats. AB - OBJECTIVE: To investigate whether tender coconut water (TCW) mitigates oxidative stress in fructose fed hypertensive rats. METHODS: Male Sprague Dawley rats were fed with fructose rich diet and treated with TCW (4 mL/100 g of body weight) for 3 subsequent weeks. Systolic blood pressure was measured every three days using the indirect tail cuff method. At the end of the experimental period, plasma glucose and insulin, serum triglycerides and free fatty acids, lipid peroxidation markers (MDA, hydroperoxides and conjugated dienes) and the activities of antioxidant enzymes were analyzed in all the groups. RESULTS: Treatment with TCW significantly lowered the systolic blood pressure and reduced serum triglycerides and free fatty acids. Plasma glucose and insulin levels and lipid peroxidation markers such as MDA, hydroperoxides and conjugated dienes were significantly reduced in fructose fed rats treated with TCW. Activities of antioxidant enzymes are up regulated significantly in TCW treated rats. Histopathological analysis of liver showed that TCW treatment reduced the lipid accumulation and inflammatory infiltration without any significant hepatocellular damage. CONCLUSIONS: The overall results suggest that, TCW treatment could prevent and reverse high blood pressure induced by high fructose diet probably by inhibition of lipid peroxidation, upregulation of antioxidant status and improved insulin sensitivity. PMID- 22449518 TI - Evaluation of the acute and sub acute toxicity of Annona senegalensis root bark extracts. AB - OBJECTIVE: To investigate the safety profile of Annona senegalensis (A. senegalensis). METHODS: Dried powdered root-bark of A. senegalensis was prepared by Sohxlet extraction using methanol-methylene chloride (1:1) solution and concentrated to obtain the methanol-methylene chloride extract (MME). MME was fractionated to obtain the n-hexane (HF), ethylacetate (EF) and methanol (MF) fractions. Acute toxicity (LD(50)) test was performed with MME, HF, EF and MF in mice by oral route. The sub acute toxicity studies were performed in rats after 14 days of MME administration while haematological and biochemical parameters were monitored. RESULTS: Medium lethal (LD(50)) values of 1,296, 3,808, 1,265 and 2,154 mg/kg were obtained for the MME, MF, HF and EF, respectively. The sub-acute toxicity studies indicated a significant (P<0.05) increase in the body weight of both the treated rats and the control. The haematological tests indicated no change in the packed cell volume values but a significant (P<0.05) increase in the total WBC count at 100 and 400 mg/kg doses. The differential analysis showed a decrease in the nutrophils and a non-significant increase in the lymphocyte counts. The liver transaminase enzymes, alanin transaminase and aspartate transaminase showed no significant increase compared to the control. Histopathological examination of the liver sections also indicted no obvious signs of hepatotoxicity except with the 400 mg/kg dose that showed degeneration and necrosis of the hepatocytes. CONCLUSIONS: These results indicated that the root bark extracts of A. Senegalensis are safe at the lower doses tested, and calls for caution in use at higher doses in treatment. PMID- 22449519 TI - Hepatoprotective potential of ethanolic extract of Ziziphus oenoplia (L.) Mill roots against antitubercular drugs induced hepatotoxicity in experimental models. AB - OBJECTIVE: To evaluate the hepatoprotective potential of ethanolic (50%) extract of Ziziphus oenoplia (L.) Mill (Z. oenoplia) root against isoniazid (INH) and rifampicin (RIF) induced liver damage in animal models. METHODS: Five groups of six rats each were selected for the study. Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin (100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups. The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), and bilirubin were estimated along with activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione peroxidase, and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver. RESULTS: The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards normal in a dose dependent manner after the treatment with ethanolic extract of Z. oenoplia roots. Meanwhile, the decreased activities of superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependently. In addition, ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections. CONCLUSIONS: The results of this study strongly indicate that ethanolic extract of Z. oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats. PMID- 22449520 TI - Phytochemical analysis, hepatoprotective and antioxidant activity of Alchornea cordifolia methanol leaf extract on carbon tetrachloride-induced hepatic damage in rats. AB - OBJECTIVE: To investigate the hepatoprotective and antioxidant activities of Alchornea cordifolia (A. cordifolia) leaf extract. METHODS: Various solvent fractions of the methanol extract of the leaf of the plant A. cordifolia Mull. Arg (Fam: Euphorbiaceae) were evaluated for hepatoprotective activity by carbon tetrachloride-induced liver damage in rats. The degree of protection was measured by using biochemical parameters such as serum glutamate oxalate transaminase (SGOT/AST), serum glutamate pyruvate transaminase (SGPT/ALT), alkaline phosphatase (ALP) and total bilirubin. The in vitro antioxidant activity of the extract was also evaluated by the 1, 1-diphenyl- 2-picrylhydrazyl (DPPH) free radical scavenging assay. The extract was subjected to preliminary phytochemical screening. RESULTS: The ethyl acetate and chloroform fractions, at a dose of 300 mg/kg, produced significant (P<0.05) hepatoprotection by decreasing the activities of the serum enzymes and bilirubin while there were marked scavenging of the DPPH free radicals by the fractions. The effects were comparable to those of the standard drugs used for the respective experiments, silymarin and ascorbic acid. Alkaloids, flavonoids, saponins and tannins were detected in the phytochemical screening. CONCLUSION: From this study, it was concluded that the plant of A. cordifolia possesses hepatoprotective as well as antioxidant activities and these activities reside mainly in the ethyl acetate and acetone fractions of methanol leaf extract. PMID- 22449521 TI - Antioxidant and antiangiogenic activities of the essential oils of Myristica fragrans and Morinda citrifolia. AB - OBJECTIVE: Toinvestigate the anti-angiogenic activity and antioxidant properties of Myristica fragrans (M. fragrans) (nutmeg) and Morinda citrifolia (M. citrifolia)(mengkudu) oils. METHODS: The nutmeg and megkudu essential oils were obtained by steam distillation. The antioxidant activities of both essential oils were determined by beta-carotene/linoleic acid bleaching assay and reducing power while the anti-angiogenic activity was investigated using rat aortic ring assay using various concentrations. RESULTS: The results showed that nutmeg oil has higher antioxidant activity than mengkudu oil. The nutmeg oil effectively inhibited the oxidation of linoleic acid with (88.68+/-0.1)% while the inhibition percentage of oxidation of linoleic acid of the mengkudu oil is (69.44+/-0.4)%. The nutmeg oil and mengkudu oil showed reducing power with an EC(50) value of 181.4 MUg/mL and 3 043.0 MUg/mL, respectively. The antiangiogenic activity of nutmeg oil showed significant antiangiogenic activity with IC(50) of 77.64 MUg/mL comparing to mengkudu oil which exhibits IC(50) of 109.30 MUg/mL. CONCLUSIONS: Bioactive compound(s) will be isolated from the nutmeg essential oil to be developed as antiangiogenic drugs. PMID- 22449522 TI - Mosquito larvicidal properties of Orthosiphon thymiflorus (Roth) Sleesen. (Family: Labiatae) against mosquito vectors, Anopheles stephensi, Culex quinquefasciatus and Aedes aegypti (Diptera: Culicidae). AB - OBJECTIVE: To determine the mosquito larvicidal activities of hexane, chloroform, ethyl acetate, acetone and methanol leaf extract of Orthosiphon thymiflorus (O. thymiflorus) against Anopheles stephensi (An. stephensi), Culex quinquefasciatus (Cx. quinquefasciatus) and Aedes aegypti (Ae. aegypti). METHODS: The larvicidal activity was assayed against three mosquito species at various concentrations ranging from (50-450 ppm) under the laboratory conditions. The LC(50) and LC(90) value of the O. thymiflorus leaf extract was determined by Probit analysis. RESULTS: The LC(50) values of hexane, chloroform, ethyl acetate, acetone and methanol extract of O. thymiflorus third instar larvae of An. stephensi were LC(50)= 201.39, 178.76, 158.06, 139.22 and 118.74 ppm; Cx. quinquefasciatus were LC(50)=228.13, 209.72, 183.35, 163.55 and 149.96 ppm and Ae. aegypti were LC(50)=215.65, 197.91, 175.05, 154.80 and 137.26 ppm, respectively. Maximum larvicidal activity was observed in the methanolic extract followed by acetone, ethyl acetate chloroform and hexane extract. The larval mortality was observed after 24 h exposure. No mortality was observed in control. CONCLUSIONS: The present results suggest that the effective plant crude extracts have potential to be used as an ideal eco-friendly approach for the control of mosquito vectors. This study provides the first report on the larvicidal activity of this plant crude solvent extract of against An. stephensi, Cx. quinquefasciatus and Ae. aegypti mosquitoes. PMID- 22449523 TI - Cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on QSG-7701 hepatocytes. AB - OBJECTIVE: To investigate the cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on cultured QSG-7701 cells lines. METHODS: Isoniazid, rifampicin, mixture of rifampicin and isoniazid, acetylhydrazine, hydrazine were added in cultural media of QSG-7701 cells and cultured for 48 hours. The survival rate of cells was determined by MTT method. The cultural media and cells were collected and the activity of lactate dehydrogenase was detected by chromatometry. RESULTS: Compared with control group, the survival rate decreased significantly and the lactate dehydrogenase released from cell increased significantly in cells treated with isoniazid, rifampicin, acetylhydrazine, hydrazine. Hydrazine, the metabolite of isoniazid produced significant damage on hepatocytes in low concentration. CONCLUSIONS: Rifampicin together with rifampicin and metabolites of isoniazid produce cellular toxic effects and hydrazine may be the most toxiferous metabolite. PMID- 22449524 TI - Effect of calcium citrate on bone integration in a rabbit femur defect model. AB - OBJECTIVE: To explore effect of calcium citrate on bone integration in a rabbit femur defect model, and to compare the bone formation with different sizes by radiological and histological study. METHODS: Twenty-four male Japanese white rabbits were randomly divided into three groups (Group A, B, C) in this study. Under anesthesia, defects of four sizes (1.2, 1.5, 2.0 and 2.5 mm) were created in each of the rabbits. Commercially pure calcium citrate powder was placed inside the medullary compartment of the femur (Experimental), while in the contralateral femur (Control) nothing was implanted. The defects were analyzed using radiography and histological analysis by using Imagepro-Plus 6.0 software after animal was sacrificed at 4th(Group A), 6th(Group B) and 8th(Group C) weeks postoperatively. Four samples were analyzed for each size of defect and each healing period. RESULTS: The histological and the radiologic evaluation were performed after sacrification of all rabbits on postoperative 4th and 6th weeks, It showed significant difference between the experimental group and the control group when these defects were less than or equal to 2.0 mm. No statistical difference was observed when these defects were larger than 2.0 mm at all healing periods except at the 4th week. CONCLUSIONS: Calcium citrate affects the early periods of bone defects healing mechanism in Japanese white rabbits positively, especially when the defect is not too large. We suggest further studies on calcium citrate to determine the effects of various dosages, administration ways and the experimental time on the bone defects. PMID- 22449525 TI - Concurrent dengue and malaria in an area in Kolkata. AB - OBJECTIVE: To establish the nature and extent of dual dengue and malaria infections in an endemic area through a longitudinal study. METHODS: A prospective study was conducted from August 2005 to December 2010 to document the nature and extent of concurrent dengue and malaria infections in an area in central Kolkata, endemic both for dengue and malaria. RESULTS: Of 2 971 suspected cases of dengue fever, in 605 (20.36%) persons dengue infection was detected, of whom 46 (7.60%, 46/605) patients (40 and 6 suffered from secondary and primary dengue fever respectively) were simultaneously suffering from malaria (28 and 18 were infected with Plasmodium vivax (P.vivax) and Plasmodium falciparum (P. falciparum) respectively, such dual infections of dengue and malaria were detected in all the years of the study period, except 2007, indicating intense transmission of both dengue and malaria in the study area, and the phenomenon was not an isolated one, the rate of concomitant infections ranged from 25% in 2009 to 4.9% in 2005. Out of total population surveyed, 1.54% (46/2 971) had concurrent dengue and malaria infection. CONCLUSIONS: These findings added a new dimension in diagnosis, treatment, epidemiology and control of dengue and malaria. The possible risk of concurrent dengue and malaria infections should always be kept in mind in endemic areas for early diagnosis employing modern technology and prompt and effective treatment to avoid serious complications. PMID- 22449526 TI - A preliminary study on the key factors contributing to the attractive lips of Chinese children. AB - OBJECTIVE: To explore the aesthetic characteristics of the Chinese children lips. METHODS: Frontal and profile photographs of 653 healthy children were categorized as the attractive and the unattractive by three laypersons and objectively measured for comparison. RESULTS: The attractive group tended to be smaller in the upper paramedian red lip height, the lower paramedian red lip height, the midline upper red lip height, the central bow angle, and the lip angle, while greater in the Cupid's bow width. CONCLUSIONS: Thinner lips seemed to be more attractive than full ones among Chinese children. PMID- 22449527 TI - Study on serum cytokine levels in posttraumatic stress disorder patients. AB - OBJECTIVE: To evaluate serum IL-2, IL-4, IL-6, IL-8, IL-10 and TNF-alpha levels in posttraumatic stress disorder (PTSD) patients. METHODS: We utilized ELISA technology to examine cytokines such as IL-2, IL-4, IL-6, IL-8, IL-10 and TNF alpha in serum from 50 well-characterized individuals with a primary DSM-IV PTSD diagnosis, and 50 age- and gender-matched healthy controls. We conservatively employed a Mann-Whitney U testing. RESULTS: Individuals with primary PTSD had significantly elevated peripheral cytokine levels for all 6 different cytokines compared to age- and gender-matched healthy controls (all P<0.01). CONCLUSIONS: These findings suggest that a generalized inflammatory state may be present in individuals with PTSD. PMID- 22449528 TI - Two cases of imported malaria in Western Romania, 2010-2011. AB - Malaria is a major problem for European travelers to endemic regions. In Romania during 1980-2007 approximately 20 imported cases were detected annually. The aim of our short communication is to present 2 interesting cases of imported malaria detected in Western Romania. The first patient was a 20-year female who traveled to India and acquired an infection with Plasmodium vivax (P. vivax). The second patient, a 60-year female, contracted an infection with Plasmodium falciparum (P. falciparum) during a trip to Ghana; the evolution of the disease was severe with many complications and the patient finally died. The cases presented revealed the difficulties in establishing a correct diagnosis of malaria in a non-endemic country, consequences of an incomplete taken anamnesis. Travel history should always represent a mandatory part of a well conducted investigation. At the same time, we must underline the importance of a correct and complete prophylaxis prior to every departure to tropical countries. PMID- 22449529 TI - Ceftazidime resistance in Burkholderia pseudomallei: first report from India. AB - Melioidosis, a disease of public health importance in Southeast Asia and Northern Australia, of late has shown an increasing trend in India, particularly Southern India. We describe a case of a 39-year-old diabetic patient with left elbow septic arthritis, multiple liver, splenic abscesses, pneumonia, pleural effusion, followed by sepsis syndrome. Blood cultures and culture of the joint aspirate yielded pure growth of Burkholderia pseudomallei (B. pesudomallei), sensitive to carbapenem, co-trimoxazole and resistant to ceftazidime. The patient was successfully treated with imipenem- cilastin. He was discharged on co-trimoxazole to complete the 24 weeks course and follow-up has continued to date. The patient continues to remain asymptomatic. The case re-emphasizes the need to monitor the trend of B. pseudomallei in India, particularly the development of ceftazidime resistance, which incidentally is the drug of choice. PMID- 22449530 TI - Overt gastrointestinal bleeding because of hookworm infection. AB - Hookworm infection is a relatively common cause of anemia in endemic areas. The most common hookworm species are Ancylostoma duodenale and Necator americanus. In this report we present a case of overt gastrointestinal bleeding because of hookworm infection. Capsule endoscopy revealed many hookworms in the lumen of proximal jejunum where active bleeding was seen. The patient was successfully treated with Albendazole. PMID- 22449531 TI - On the roads to H1N1 pandemic era: drive safe and fearless using colour-coded masks. AB - Notwithstanding the end of 2009 H1N1 pandemic, the threat for its revisit still persists and WHO has warned to remain vigilant. During that time the situation was more panicky than fatal. In this article, a suggestion to minimize the panic is provided by the usage of colour-coded masks and is proposed hereby as a "population segregation" approach in case of the revisit of H1N1 or similar threatening respiratory viral infections. PMID- 22449532 TI - NDM-1 in the Indian environment: hitherto the problem is not disquieting. PMID- 22449533 TI - Caffeine interferes embryonic development through over-stimulating serotonergic system in chicken embryo. AB - The potential harmful effects of caffeine in pregnant women aroused public interests due to its possibility to jeopardize fetal development. Monoamine neurotransmitters are thought to regulate neural development processes through maternal-fetal interactions, which may have long term impact on mental and behavioral effects. The current study focuses on investigating the effects of caffeine on the monoamine neurotransmitter system using developmental chicken embryos. The ED(50) value of caffeine toxicity was 27.3 MUmol/egg in chicken embryo. Administration of caffeine, with lower dosage than ED(50) (2.5, 5.0 and 10.0 MUmol/egg), caused failure of neural tube closure. In addition, contents of 5-HT and its metabolite 5-HIAA were increased under dosage of 10.0 MUmol/egg caffeine administration. Gene expression of TPH2 was also increased by caffeine treatment. Caffeine could result in defect of neural tube closure and induce disorder of serotonergic system development, which may increase teratogenic rate of embryos. Meanwhile, it is probably an underlying factor for inducing psychological and behavioral disorders in adult. Moreover, caffeine was found to be accumulated in the embryonic brain and not being metabolized, which may incur a magnification of adverse effects. This study may provide valuable data for further investigations on toxicology of caffeine during different stages of pregnancy. PMID- 22449534 TI - Fragrance material review on methyl dihydrojasmonate. AB - A toxicologic and dermatologic review of methyl dihydrojasmonate when used as a fragrance ingredient is presented. Methyl dihydrojasmonate is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for methyl dihydrojasmonate were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, photoallergy, toxicokinetics, repeated dose, reproductive toxicity, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (this issue) for an overall assessment of the safe use of this material. PMID- 22449535 TI - Toxic essential oils: anxiolytic, antinociceptive and antimicrobial properties of the yarrow Achillea umbellata Sibth. et Sm. (Asteraceae) volatiles. AB - Many plant species are used for medicinal purposes without the knowledge of their possible toxic effect. The ethnopharmacologically renowned genus Achillea L. (Asteraceae) is even more troublesome in this respect since different taxa are believed to have the same beneficial properties as A. millefolium. According to the median lethal i.p. dose (LD(50)=853 mg/kg, mice), the volatiles of Achillea umbellata Sibth. et Sm. are more toxic than the thujone-containing essential oils (LD(50)>960 mg/kg). A GC-MS analysis of A. umbellata oil revealed the presence of a series of fragranyl esters (six new natural products). The major constituents of this oil, the rare monoterpene alcohol fragranol and fragranyl acetate, and one more ester (benzoate), as well as the oil itself, showed antianxiety, analgesic and, in some instances, paralyzing properties at 50-150 mg/kg but these are very likely sign of intoxication and not of possible beneficial effects of the plant volatiles. Testing of antimicrobial activity demonstrated that the oil possesses moderate activity against pathogenic microorganisms, but the effect of the oil differs in pro- and eukaryotic cells. According to the results obtained, fragranol may be considered as the main active principle responsible for the observed activity/toxicity. PMID- 22449536 TI - Fragrance material review on 2-heptylidenecyclopentan-1-one. AB - A toxicologic and dermatologic review of 2-heptylidenecyclopentan-1-one when used as a fragrance ingredient is presented. 2-Heptylidenecyclopentan-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-heptylidenecyclopentan-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and repeated dose data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22449537 TI - Fragrance material review on methyl hexyl oxo cyclopentanone carboxylate. AB - A toxicologic and dermatologic review of methyl hexyl oxo cyclopentanone carboxylate when used as a fragrance ingredient is presented. Methyl hexyl oxo cyclopentanone carboxylate is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for methyl hexyl oxo cyclopentanone carboxylate were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, skin sensitization, and genotoxicity data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (this issue) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22449538 TI - Fragrance material review on hexenylcyclopentanone. AB - A toxicologic and dermatologic review of hexenylcyclopentanone when used as a fragrance ingredient is presented. Hexenylcyclopentanone is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for hexenylcyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, and skin sensitization data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22449539 TI - Fragrance material review on cyclotene propionate. AB - A toxicologic and dermatologic review of cyclotene propionate when used as a fragrance ingredient is presented. Cyclotene propionate is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for cyclotene propionate were evaluated then summarized and includes physical properties data. A safety assessment of the entire Ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Ketones Cyclopentanones and Cyclopentenones in fragrances. PMID- 22449540 TI - Fragrance material review on methyl 3-oxo-2-(pent-2-enyl)cyclopentaneacetate. AB - A toxicologic and dermatologic review of methyl 3-oxo-2-(pent-2 enyl)cyclopentaneacetate when used as a fragrance ingredient is presented. Methyl 3-oxo-2-(pent-2-enyl)cyclopentaneacetate is a member of the fragrance structural group Ketones Cyclopentanones and Cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for methyl 3-oxo-2-(pent-2 enyl)cyclopentaneacetate were evaluated then summarized and includes physical properties data. A safety assessment of the entire Ketones Cyclopentanones and Cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances. PMID- 22449541 TI - Synthesis of hypoallergenic derivatives of the major allergen Fag t 1 from tartary buckwheat via sequence restructuring. AB - Fag t 1, a legumin-type protein, is the major allergen in tartary buckwheat. In the current study, three recombinant derivatives of Fag t 1, designated as Fag t 1-rs1, Fag t 1-rs2, and Fag t 1-rs3, were constructed via rational design and genetic engineering. However, because of the loss of their native-like folds, the Fag t 1 derivatives failed to bind IgE, and their allergenic activities were reduced. The recombinant hypoallergenic variants are promising vaccine candidates for specific immunotherapy of buckwheat allergy. The unfolding of the Fag t 1 structure reduced its high resistance to gastrointestinal proteolysis and strongly reduced its IgE reactivity. The derivatives showed a more than 90% reduction in allergenic activity compared with rFag t 1. These results suggest that the structure-dependent stability of 11S seed storage proteins is directly related to digestive stability and allergenic potential. Therefore, the destruction of the native conformation is the appropriate strategy to reduce the allergenicity of the cupin family food allergens. PMID- 22449542 TI - Effect of Robusta (Coffea canephora P.) coffee cherries quantity put out for sun drying on contamination by fungi and ochratoxin A (OTA) under tropical humid zone (Cote d'Ivoire). AB - The effect of coffee cherries quantity put out for sun drying on the kinetics of the drying, chemical components variation, fungal growth and ochratoxin A production was evaluated. The results showed that the more coffee cherries quantity on the drying area was important, the slower they dried. Indeed, the drying durations were 12, 17, 21, 26, 31 and 32 days respectively for the lots of 10 kg, 20 kg, 30 kg, 40 kg, 50 kg and 60 kg of cherries by square meter of drying area. The slowness of the drying led to the increasing of fungal development and ochratoxin A production in the cherries. Indeed, samples more contaminated were those from the lots of 50 kg and 60 kg of cherries by square meter of drying area with between 10% and 100% of infected beans and with levels of ochratoxin A ranging from 0.92 to 118.47 and 1.4 to 131.33 MUg kg(-1) respectively. The slowness of the drying led also to the acidification of the cherries (pH=5.55 4.54) and the degradation of their chlorogenic acids content (13.03-11.69) while for their caffeine content (2.52-2.54), any significant difference was observed whatever the drying duration. PMID- 22449543 TI - Fragrance material review on methyl jasmonate. AB - A toxicologic and dermatologic review of methyl jasmonate when used as a fragrance ingredient is presented. Methyl jasmonate is a member of the fragrance structural group Ketones Cyclopentanones and Cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for methyl jasmonate were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, and photoallergy data. A safety assessment of the entire Ketones Cyclopentanones and Cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Ketones Cyclopentanones and Cyclopentenones in fragrances. PMID- 22449544 TI - Piperidine alkaloids: human and food animal teratogens. AB - Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure-activity relationships and their potential implications for human health. PMID- 22449545 TI - Further insights into chemical characterization through GC-MS and evaluation for anticancer potential of Dracaena draco leaf and fruit extracts. AB - The present study reports for the first time the amino acid and fatty acid compositions and the antitumoral activity of aqueous extracts obtained from Dracaena draco L. leaf and fruit. Metabolite profiles were determined by gas chromatography-ion trap-mass spectrometry (GC-IT-MS), with several amino acids, palmitic, linolenic and stearic acid being identified in the leaf extract, and only proline, oleic and stearic acid in the fruit extract. The in vitro antiproliferative activities of the extracts were tested against human colon (Caco-2), kidney (A-498), and liver (HepG2) cancer cell lines. In addition, primary cultures of normal and cancerous renal cells derived from kidney cancer patients were treated with D. draco extracts (0-400 MUg/mL). Antiproliferative and cytotoxic effects were determined by the MTT assay. D. draco extracts inhibited proliferation of human colon and renal tumor cells in vitro, whereas no or weak effect was observed in HepG2 cells. Compared to the fruit extract, D. draco leaf extract exhibited stronger antiproliferative activity against all cancer cells. Our results indicate that D. draco, particularly the leaf, may be useful as a cancer chemopreventive and/or chemotherapeutic agent for colon and kidney cancers. PMID- 22449546 TI - Elucidation of the metabolic pathway of S-equol in rat, monkey and man. AB - S-equol is a selective estrogen receptor beta (ERbeta) agonist which is produced in certain individuals after ingestion of its precursor daidzein, an isoflavone present in soy. S-equol is thought to provide certain health benefits, including reduced menopausal symptoms. The metabolic profile of S-equol was determined in vivo in Sprague-Dawley rats and cynomolgus monkeys, and in vitro using hepatocytes from rat, monkey, and human. High resolution MS fragmentation patterns indicated that the major metabolite of S-equol in rat plasma and urine was the 4'-glucuronide conjugate, with lesser amounts of unconjugated S-equol, the 7-sulfate conjugate, and the 4'-glucuronide-7-sulfate diconjugate. Monkeys also showed extensive metabolism, with the major species in plasma being the 4' glucuronide and the 7-sulfate-4'-glucuronide diconjugate; urine contained primarily the 4'-glucuronide, as seen in the rat. In vitro metabolism by hepatocytes was extensive and similar in all species, with fragmentation patterns also indicating that the 4'-glucuronide was the major metabolite. No oxidative metabolites of [(14)C] S-equol were detected in either in vivo or in vitro studies. These findings show that glucuronidation is the primary pathway for the metabolism of S-equol in rat, monkey and man, and that all metabolic routes of S equol observed in vitro were also observed in vivo. PMID- 22449547 TI - Steroid derivatives as pure antagonists of the androgen receptor. AB - BACKGROUND: While the androgens of testicular origin (representing about 50% of total androgens in men over 50 years) can be completely eliminated by surgical or medical castration with GnRH (gonadotropin-releasing hormone) agonists or antagonists, the antiandrogens currently available as blockers of androgen binding to the androgen receptor (AR), namely bicalutamide (BICA), flutamide (FLU) and nilutamide have too weak affinity to completely neutralize the other 50% of androgens made locally from dehydroepiandrosterone (DHEA) in the prostate cancer tissue by the mechanisms of intracrinology. MATERIALS AND METHODS: Series of steroid derivatives having pure and potent antagonistic activity on the human and rodent AR were synthesized. Assays of AR binding and activity in carcinoma mouse Shionogi and human LNCaP cells as well as in vivo bioavailability measurements and in vivo prostate weight assays in the rat were used. RESULTS: The chosen lead steroidal compound, namely EM-5854, has a 3.7-fold higher affinity than BICA for the human AR while EM-5855, an important metabolite of EM 5854, has a 94-fold higher affinity for the human AR compared to BICA. EM-5854 and EM-5855 are 14 times more potent than BICA in inhibiting androgen (R1881) stimulated prostatic specific antigen (PSA) secretion in human prostatic carcinoma LNCaP cells in vitro. MDV3100 has a potency comparable to bicalutamide in these assays. Depending upon the oral formulation, EM-5854 is 5- to 10-times more potent than BICA to inhibit dihydrotestosterone (DHT)-stimulated ventral prostatic weight in vivo in the rat while MDV3100 has lower activity than BICA in this in vivo model. These data are supported by respective 40-fold and 105-fold higher potencies of EM-5854 and EM-5855 compared to BICA to inhibit cell proliferation in the androgen-sensitive Shionogi carcinoma cell model. CONCLUSIONS: Although the present preclinical results data need evaluation in clinical trials in men, combination of the data obtained in vitro in human LNCaP cells as indicator of potency in the human prostate and the data on metabolism evaluated in vivo on ventral prostate weight in the rat, could suggest the possibility of a 70- to 140-fold higher potency of EM-5854 compared to bicalutamide (Casodex) for the treatment of prostate cancer in men. PMID- 22449548 TI - Organophosphorus compound effects on neurotrophin receptors and intracellular signaling. AB - Neurite outgrowth of SH-SY5Y neuroblastoma cells following the addition of spinal cord extracts from chickens exposed to a neuropathic organophosphorus (OP) compound suggests the presence of a growth factor during OP neuropathy. However, exposure of SH-SY5Y cells directly to neuropathic OP compounds results in apoptosis and/or decreased neurite outgrowth. These cellular effects may follow OP-induced interference with neurotrophin-receptor binding and/or intracellular signaling resulting from receptor binding. We hypothesized that sub-lethal concentrations of a neuropathic OP compound interferes with neurotrophin-receptor binding as well as specific intracellular signaling pathways in neuroblastoma cells which would not occur with a non-neuropathic OP compound. SH-SY5Y cells were exposed to a neuropathic OP compound (PSP; 0.01, 0.1, 1.0MUM), a neuropathic OP compound with nerve growth factor (1.0MUM PSP+1ng/ml NGF), a non-neuropathic OP compound (paraoxon; 100MUM), and medium only for 4, 8, 24, and 48h. Western blots indicate that cells exposed to a low dose of PSP or the high dose of PSP+NGF contained the phosphorylated form of a common neurotrophin receptor (pp75) that was four times greater than that of the phosphorylated form of the high-affinity NGF receptor (pTrkA) suggesting that p75 activation may contribute to early cell death after exposure to OP compounds. Furthermore, events in signaling pathways after exposure to PSP differed from those after exposure to paraoxon, with activation of the MEK1/2 protein increasing significantly only after exposure to paraoxon. Both types of OP compounds, however, caused significant activation of Akt in the PI-3K cell-survival pathway. These results suggest that exposure to a non-neuropathic OP compound causes increased activity of the MAPK pathway whereas exposure to neuropathic OP compounds prevented upregulation of the pathway. Since this pathway is integral to neurite outgrowth and cell survival, this study has revealed molecular mechanisms implicated in neuronal response after exposure to neuropathic OP compounds. PMID- 22449549 TI - Oxidative stress responses to carboxylic acid functionalized single wall carbon nanotubes on the human intestinal cell line Caco-2. AB - Carbon nanotubes (CNT) are among the more promising nanomaterials due to their potential applications. In this sense, the adverse effects that CNT can induce are of concern. In particular, carboxylic acid functionalized single wall carbon nanotubes (COOH-SWCNT) have shown to reduce cell viability and induce morphological effects on the human intestinal cell line Caco-2, but little is known about the toxic mechanisms involved. The aim of the present study was to investigate the oxidative stress responses of this cell line after 24h exposure to COOH-SWCNT. Biomarkers assayed included lipid peroxidation (LPO), reactive oxygen species (ROS) generation, and enzymatic and non-enzymatic antioxidant defences. Results showed an increase in ROS from 100MUg/mL reaching 5.2-fold the basal value at the highest concentration assayed. An induction of catalase, superoxide dismutase and glutathione peroxidase activities was also observed, meanwhile glutathione reductase showed a reduced activity at 1000MUg/mL. Glutathione (GSH) levels also decreased (2.5-fold) at the highest level of exposure. Therefore, the antioxidant defences could not overwhelm the oxidative insult caused by COOH-SWCNT and LPO products increased in a concentration dependent manner. We can conclude that oxidative stress plays a role in the pathogenicity induced by COOH-SWCNT on Caco-2 cells at the concentrations assayed. PMID- 22449550 TI - The role of microRNA-23b in the differentiation of MSC into chondrocyte by targeting protein kinase A signaling. AB - Chondrogenic differentiation of mesenchymal stem cells (MSCs) is critical for successful cartilage regeneration. Several methods have been developed to attempt to chondrogenic differentiation, because chondrogenic differentiated cells can form stable cartilage and induce expression of a cartilage-specific phenotype. In this study, we found that both H-89 and microRNA-23b induced differentiation into chondrocyte of hMSCs through down-regulation of protein kinase A (PKA) signaling. The small molecule, H-89, was identified by PCA analysis as a potential mediator of chondrogenic differentiation. H-89 induced the expression of the chondrocyte marker, aggrecan, as well as miR-23b. We searched that miR-23b regulates protein level of PKA. When miR-23b was transfected into hMSCs, chondrogenic differentiation was induced. We confirmed the target of miR-23b using a reporter gene assay. Furthermore, not only H-89 or miR-23b-treated cells, but also cell co treated with H-89 and miR-23b differentiated into chondrocytes. Our results indicate that H-89 induces the expression of endogenous miR-23b, thereby inducing chondrogenic differentiation by negatively inhibition of PKA signaling. PMID- 22449551 TI - Characterization of compensatory trunk movements during prosthetic upper limb reaching tasks. AB - OBJECTIVE: To characterize the compensatory movements of the trunk during functional reaching tasks performed by upper limb prosthesis users. DESIGN: Survey. SETTING: Clinical laboratory at a national rehabilitation hospital. PARTICIPANTS: Transhumeral and transradial prosthesis users (n=10) and uninjured control subjects (n=10). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Three-dimensional motion analysis data were collected during simulated reaching tasks, such as donning a cap, placing a nut, and sorting clothes. The metrics were range of motion of the trunk in the 3 anatomical directions and elbow and shoulder path distance. RESULTS: Prosthesis users had significantly larger truncal movements than controls during all 3 reaching tasks in all 3 directions (P<=.03). Shoulder path distance in persons with amputation was larger than in controls in all 3 tasks (P<.01). Elbow path distance in persons with amputation was larger than in controls in the nut and clothes tasks (P<=.02). The subgroup of transradial prosthesis users displayed these abnormal movements despite the presence of an intact elbow. CONCLUSIONS: The altered physiologic structure of the arm caused the individuals to develop a different motor control strategy than an intact arm. Functional limitations, such as the loss of distal degrees of freedom, required persons with amputation to use trunk displacement in place of arm/hand movement. These compensatory movements during reaching tasks may be a cause of prosthesis rejection and, in some cases, may be resolved with proper rehabilitative training. Analysis of compensatory trunk movements may also provide a useful endpoint for evaluating new prosthesis designs. PMID- 22449552 TI - Effect of topical anesthetics on needle insertion pain during botulinum toxin type A injections for limb spasticity. AB - OBJECTIVE: To compare pain perception using 3 anesthetics (eutectic mixture of local anesthetics [EMLA], vapocoolant spray, and ice) compared with a control (no anesthetic) during botulinum toxin type A (BTX-A) injections for lower limb spasticity. DESIGN: A placebo-controlled, single-blinded study where each study patient served as their own control. SETTING: Spasticity clinic. PARTICIPANTS: Subjects (N=30) with ankle spasticity who visited the clinic for BTX-A injections in the gastrocnemius muscle were consecutively sampled. INTERVENTION: The gastrocnemius muscle was divided into 4 quadrants and 1 of the 3 different anesthetic agents was applied to each quadrant with 1 quadrant using no anesthetic, control. MAIN OUTCOME MEASURES: Numerical Rating Scale (NRS) and the Wong-Baker FACES scale. RESULTS: Pain perception using the NRS and FACES scale was significantly lower using ice and EMLA compared with control and spray conditions (P<.05). Pain perception using EMLA and ice was similar. These results indicate that patients experience minimal to moderate pain during BTX-A injections. CONCLUSIONS: Pain relief offered by EMLA and ice was comparable, suggesting that ice is a more convenient option because of brief application time (compared with EMLA). Spray may have made the patients more sensitive to pain and alternative approaches for using vapocoolant should be considered. PMID- 22449553 TI - Antimicrobial drug concentrations and sampling techniques in the equine lung. AB - The distribution of antimicrobial drugs in the equine lung is important in designing optimal dosage regimens for the treatment of lower airway infections. Several studies in horses and other species have shown that the pharmacokinetics of a drug in the lung cannot necessarily be predicted by its behaviour in plasma, and influencing factors include the class of drug, the animal species and the chosen sampling technique. This review provides a description of the target site for bacterial lower airway infections and describes the penetration of antibiotics into lung matrices. It also offers an overview of published equine pulmonary pharmacokinetic studies and considers the different sampling methods used and the influence existing methodological problems can have on the interpretation of data. An awareness of these factors is important in establishing optimal dosage regimes to treat lower airway infections in horses. PMID- 22449554 TI - Variation in a locus linked to platelet aggregation phenotype predicts intraparenchymal hemorrhagic volume. AB - OBJECTIVE: Alteration in platelet aggregation has been shown to promote bleeding and affect outcome after intracerebral hemorrhage (ICH).We investigated the influence of genetic variants of platelet aggregation, and their effects on admission ICH volume and clinical outcome. METHODS: Our prospective study analyzed selected candidate single-nucleotide polymorphisms (SNPs) previously associated with platelet aggregation phenotype in previous genome-wide association studies, with regards to outcome and ICH volume. Patients were assessed at the Columbia University Medical Center Neuro-Intensive Care Unit. Exclusion criteria included age <18 years, ICH following trauma, hemorrhagic transformation, or tumor, no consent for genetic analysis, or incomplete data. Radiological variables (location and volume of acute ICH, presence of intraventricular extension, midline shift, and hydrocephalus) and clinical variables (mortality and modified Rankin score at discharge) were prospectively recorded. RESULTS: One hundred and twenty-two patients with spontaneous ICH between February 2009 and May 2011 diagnosed via clinical assessment and admission computed tomography scan were included. The median admission Glasgow coma scale score (GCS) was 11.5. Univariate predictors of mortality at discharge included systolic blood pressure, presence of intraventricular hemorrhage, anticoagulant use, and GCS, the only independent predictor of discharge mortality (P<0.001). Age, intraventricular hemorrhage, and GCS were associated with poor functional outcome; age (P = 0.001) and GCS (P<0.001) were significant in the multivariate model. Admission GCS (P<0.01), antiplatelet use, and rs342286 (PIK3CG; P = 0.04; R(2) = 0.247) had univariate associations with hematoma volume. DISCUSSION: We identified SNP rs342286 as an independent predictor of admission hematoma volume. Our findings suggest that PIK3CG function, which is previously linked to this SNP and affects platelet aggregation, impacts the severity of the intraparenchymal bleed. PMID- 22449555 TI - Mechanisms of immune complex-mediated experimental glomerulonephritis: possible role of the balance between endogenous TNF and soluble TNF receptor type 2. AB - In an experimental model of immune-complex-mediated glomerulonephritis, mice excreted increased levels of urinary protein starting three days after the induction. Mice lacking the TNF receptor type 2 (TNFR2) were protected from early proteinuria and enhanced mortality. Analysis of the molecular basis of the mechanisms of glomerulonephritis revealed that naive mice continuously excrete soluble TNF-neutralizing TNFR2 in urine. Mice kept in a specific pathogen-free environment did not go on to develop early proteinuria or enhanced mortality, following induction of glomerulonephritis. TNFR2-deficient mice were protected from early proteinuria and enhanced mortality only when housed conventionally. Mice producing human TNFR2 that can be activated by mouse TNF, in addition to mouse TNFR2, did not demonstrate enhanced susceptibility to the lethal effects of glomerulonephritis, indicating that pro-inflammatory signalling via TNFR2 does not account for a sensitizing effect. Finally, we suggest that the protective effect seen in mice lacking TNFR2 results rather from environment-induced attenuation by low dose bacterial endotoxins than from missing pro-inflammatory signalling via the TNFR2. PMID- 22449556 TI - Current applications of human pluripotent stem cells: possibilities and challenges. AB - Stem cells are self-renewable cells with the differentiation capacity to develop into somatic cells with biological functions. This ability to sustain a renewable source of multi- and/or pluripotential differentiation has brought new hope to the field of regenerative medicine in terms of cell therapy and tissue engineering. Moreover, stem cells are invaluable tools as in vitro models for studying diverse fields, from basic scientific questions such as developmental processes and lineage commitment, to practical application including drug screening and testing. The stem cells with widest differentiation potential are pluripotent stem cells (PSCs), which are rare cells with the ability to generate somatic cells from all three germ layers. PSCs are considered the most optimal choice for therapeutic potential of stem cells, bringing new impetus to the field of regenerative medicine. In this article, we discuss the therapeutic potential of human PSCs (hPSCs) including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), reviewing the current preclinical and clinical data using these stem cells. We describe the classification of different sources of hPSCs, ongoing research, and currently encountered clinical obstacles of these novel and versatile human stem cells. PMID- 22449557 TI - Identification of chronic rhinosinusitis phenotypes using cluster analysis. AB - BACKGROUND: The pathophysiology of chronic rhinosinusitis (CRS) is not fully understood. In Europe and the United States, major subsets of CRS classification are based on the presence or absence of polyps. Although nasal polyps (NPs) are a critical factor, many other factors also contribute to the pathogenesis of CRS. The aim of this study was to investigate diverse CRS phenotypes using cluster analysis. METHODS: This was a multicenter study examining clinical data from CRS patients treated at five hospitals. The study design was a retrospective analysis of prospectively collected data. Complete data were available for 425/496 patients. Data were subjected to k-means cluster analysis in an attempt to identify the different phenotypes involved in CRS. RESULTS: CRS was divided into four clusters. Cluster 1 (n = 180) and cluster 2 (n = 129) comprised patients with low peripheral eosinophil and mucosal eosinophil counts. However, polyp scores in cluster 2 were higher than cluster 1. Cluster 3 (n = 50) comprised patients with very high mucosal eosinophil counts but low polyp and symptom scores. Finally, subjects in cluster 4 (n = 66) showed severe polyposis. Polyp score and mucosal eosinophil count were the strongest predictors of clustering by discriminant analysis. CONCLUSION: The results of this study identified distinct clinical CRS phenotypes. CRS was classified into four phenotypes based on NPs and mucosal eosinophil counts. Cutoff points for these factors were identified by tree analysis. Additional studies are needed to establish clinical significance of the phenotypes. PMID- 22449558 TI - Essential psychiatric and substance use competencies for the registered nurse: crucial and complex knowledge, skills, and abilities. PMID- 22449559 TI - Predictors of eating attitudes and behaviors among gay Hispanic men. AB - Gay men are a vulnerable population at risk for a number of health disparities, but little is known about eating disorders among gay Hispanic men. The purpose of this study was to examine the relationship of eating attitudes and behaviors with alcohol abuse, body image, depression, self-esteem, and sexual behaviors to determine predictors of eating attitudes and behaviors in a community sample of gay Hispanic men. Significant numbers of the participants were at risk for eating disorders (13%), alcohol abuse (18%), body image disturbance (29%), depression (25%), low self-esteem (12%), and high-risk sexual behaviors (34%). Alcohol abuse, body image, depression, self-esteem, and sexual behaviors were significant predictors of eating attitudes and behaviors and accounted for 38% of the variance in eating attitudes and behaviors. Nurses providing care to this population of gay men must be aware of this cluster of related mental health conditions that are experienced by these men. Addressing and treating these health conditions as a group of related mental health conditions are necessary. More research is needed to further explore this cluster of health issues among gay Hispanic men. PMID- 22449560 TI - Depressive symptoms after a myocardial infarction and self-care. AB - This descriptive study examined depressive symptoms impacting the performance of self-care behaviors in patients (N = 62) who have experienced a myocardial infarction (MI). Having had a prior MI is inversely associated with decreased self-care behaviors at 30 days. Depressive symptoms of agitation and loss of energy significantly impacted self-care performance 30 days after discharge from the hospital. A variance of 21% (P < .05) in patients who experienced a prior MI and exhibited depressive symptoms of agitation and loss of energy at 30 days suggests patient vulnerability after discharge and a window for therapeutic interventions. PMID- 22449561 TI - The family-focused mental health practice questionnaire. AB - It is estimated that 1 in 5 children have a parent with a mental illness, and studies have shown that such children are more likely to develop mental health problems when compared with their peers. Research has demonstrated the benefits of mental health clinician family-sensitive practice to both parents and their children; however, a measure of clinician practice is not available. The psychometric properties of a questionnaire measuring family-focused practice in the psychiatric setting are reported here. There were 307 public adult mental health worker participants, predominantly from the nursing profession and working full time. Principal component analysis highlighted 14 subscales that summarize 49 items reflecting organizational and worker factors, such as skill/knowledge about the impact of parental mental illness on children and worker confidence. Subscales are discussed in relation to the literature and psychiatric policy. The measure appears a useful tool for evaluation, benchmarking for training and organizational improvement, and ultimately, for increasing quality services to parents, families, and particularly children associated with psychiatric services. PMID- 22449562 TI - Help-seeking behaviors of Turkish patients prior to accessing a psychiatric polyclinic. AB - Despite the high prevalence of mental illness worldwide, people often do not receive adequate care and treatment. This study determined the help-seeking behaviors, prior to attending a psychiatric outpatient clinic, among Turkish patients (N = 225) with mental illness. Prior to attending the clinic, 29.3% of patients surveyed indicated they used self-implementation techniques, 17.78% consulted someone other than a physician, and 9.3% visited special healing sites other than hospitals. More than 50% used alternative therapies rather than conventional treatment. Mental health nurses must be aware of these health seeking behaviors when planning individualized patient care and treatment. PMID- 22449563 TI - The influence of psychosomatic symptoms, physical and sexual abuse, and coping strategies on delinquent behavior among Korean adolescents. AB - PURPOSE: This cross-sectional study was undertaken to examine the contributing factors related to juvenile delinquency, as well as to identify the effect of psychosomatic symptoms, physical abuse, sexual abuse, and coping strategies on delinquent behavior among Korean adolescents. METHODS: To investigate the research problem, 2,146 adolescents, including 1,350 student adolescents and 796 delinquent adolescents, were assessed using a cross-sectional descriptive design study via anonymous, self-reporting questionnaires. Almost all research variables were measured using the Mental Health Questionnaire for Korean Adolescents. RESULTS: Our results revealed that delinquent adolescents showed a greater incidence of psychosomatic symptoms, higher levels of physical and sexual abuse, and a higher level of less effective coping strategies compared with student adolescents. Our path analysis revealed that the likelihood of delinquent behavior among adolescents appeared to be influenced mainly by sexual abuse, Psychosomatic Symptoms I, and physical abuse, with these three variables having the highest total effect. CONCLUSIONS: This study confirms the relationships previously identified among stress, somatic complaints, and ineffective coping. In addition, we demonstrated that these relationships cover a wide spectrum, ranging from psychosomatic symptoms to behavioral problems. Further implications of the results and research limitation were discussed. PMID- 22449564 TI - Moving to a recovery framework of care: focusing attention on process. PMID- 22449565 TI - Health-seeking behaviors of Native American Indians with persistent mental illness: completing the circle. AB - Nationally, disparity exists in the delivery of mental health services to minority groups, and an imperative exists that expects culturally responsive care. The purpose of this grounded theory study was to discover health-seeking practices used by Native American Indians (NAIs) with persistent mental illness (PMI). Eighteen interviews were examined using constant comparative analysis. Health-seeking practices emerged as two central categories: health engagement strategy and avoidant strategy. This research assists mental health caregivers in approaching the NAI with PMI in a culturally responsive manner by providing a NAI's perception of health and knowledge of their health-seeking behaviors/practices. PMID- 22449566 TI - Sixteen-month evaluation of depressive symptomatology in older adults. AB - We examined the prevalence of depressive symptoms over time in a sample of community-residing older adults at baseline, 2 months, 6 months, and 14 months. The nonprobability sample (N = 222) was 90% female, 87% Caucasian, 15% Hispanic, and 12% African American with an average age of 75 years. If depressive symptoms had been measured at only one time, 19% of the sample would have scored above the cutoff versus 39% scoring above the cutoff when measured at all 4 periods. The findings provide evidence that depressive symptoms in older adults are variable and fluctuate over time. The significance of this research was the longitudinal evaluation of depressive symptoms in community-residing elders. PMID- 22449567 TI - Oxidative stress-induced cytotoxic and genotoxic effects of nano-sized titanium dioxide particles in human HaCaT keratinocytes. AB - Since nano-sized particles (NPs) are increasingly used in various fields of innovative biomedicine and industrial technologies, it is of importance to identify their potential human health risk. We investigated whether ROS-induced mitochondrial DNA damage is the mode of action of titanium dioxide-NPs (TiO2-NPs; <=20 nm) to induce cytotoxic and genotoxic effects in human HaCaT keratinocytes in vitro. We showed that TiO2-NPs accumulate at the cell surface and are taken up by endocytosis. Micronucleus (MN) formation was found to be significantly maximal increased 24 h after treatment with 10 MUg/ml and 48 h after treatment with 5 MUg/ml TiO2-NPs about 1.8-fold respectively 2.2-fold of control. Mitochondrial DNA damage measured as "common deletion" was observed to be significantly 14-fold increased 72 h after treatment with 10 MUg/ml TiO2-NPs when compared to control. Four hours after treatment with 5 and 50 MUg/ml TiO2-NPs the level of ROS in HaCaT cells was found to be significantly increased about 7.5-fold respectively 16.7-fold of control. In conclusion, for the first time we demonstrate the induction of the mitochondrial "common deletion" in HaCaT cells following exposure to TiO2-NPs, which strongly suggests a ROS-mediated cytotoxic and genotoxic potential of NPs. However, the effects of the modification of TiO2-NPs, such as agglomeration, size distribution pattern and exposure time have to be further critically examined. PMID- 22449568 TI - 'Hop the skip' with extended segment intestinal biopsy in Hirschsprung's disease. AB - INTRODUCTION: Skip segment Hirschsprung's is an extremely rare condition, with only 25 reported cases in the English language literature. Diagnosis of skip segment Hirschsprung's may be missed as it is rarely suspected at initial surgery. PRESENTATION OF CASE: A case report of an infant with total colonic aganglionosis and a skip segment Hirschsprung's in the cecum is presented. A review of literature on current surgical practice is presented along with our suggested modification to the diagnostic and therapeutic algorithm of this rare condition. DISCUSSION: In our patient the initial leveling colostomy was incorrectly sited at the level of the first detected ganglionated segment. Subsequent recurrent episodes of enterocolitis led to a diagnosis of a long skip segment involving the ascending colon, cecum and terminal ileum. Correct leveling colostomy and a subsequent Duhamel procedure led to a good outcome. CONCLUSION: Determination of the transition zone in Hirschsprung's may be incorrect if intestinal biopsies are terminated at the first evidence of ganglion cells. Extended segment intestinal biopsies should be included in the algorithm for management of long segment Hirschsprung's disease and will enable the surgeon to correctly detect rare manifestations such as skip segment disease at the initial procedure. PMID- 22449569 TI - Metabolic engineering of the non-conventional yeast Pichia ciferrii for production of rare sphingoid bases. AB - The study describes the identification of sphingolipid biosynthesis genes in the non-conventional yeast Pichia ciferrii, the development of tools for its genetic modification as well as their application for metabolic engineering of P. ciferrii with the goal to generate strains capable of producing the rare sphingoid bases sphinganine and sphingosine. Several canonical genes encoding ceramide synthase (encoded by PcLAG1 and PcLAF1), alkaline ceramidase (PcYXC1) and sphingolipid C-4-hydroxylase(PcSYR2), as well as structural genes for dihydroceramide Delta(4)-desaturase (PcDES1) and sphingolipid Delta(8)-desaturase (PcSLD1) were identified, indicating that P. ciferrii would be capable of synthesizing desaturated sphingoid bases, a property not ubiquitously found in yeasts. In order to convert the phytosphingosine-producing P. ciferrii wildtype into a strain capable of producing predominantly sphinganine, Syringomycin E resistant mutants were isolated. A stable mutant almost exclusively producing high levels of acetylated sphinganine was obtained and used as the base strain for further metabolic engineering. A metabolic pathway required for the three step conversion of sphinganine to sphingosine was implemented in the sphinganine producing P. ciferrii strain and subsequently enhanced by screening for the appropriate heterologous enzymes, improvement of gene expression and codon optimization. These combined efforts led to a strain capable of producing 240mgL( 1) triacetyl sphingosine in shake flask, with tri- and diacetyl sphinganine being the main by-products. Lab-scale fermentation of this strain resulted in production of up to 890mgkg(-1) triacetyl sphingosine. A third by-product was unequivocally identified as triacetyl sphingadienine. It could be shown that inactivation of the SLD1 gene in P. ciferrii efficiently suppresses triacetyl sphingadienine formation. Further improvement of the described P. ciferrii strains will enable a biotechnological route to produce sphinganine and sphingosine for cosmetic and pharmaceutical applications. PMID- 22449570 TI - Cells and cell lysates: a direct approach for engineering antibodies against membrane proteins using yeast surface display. AB - Membrane proteins (MPs) are often desirable targets for antibody engineering. However, the majority of antibody engineering platforms depend implicitly on aqueous solubility of the target antigen which is often problematic for MPs. Recombinant, soluble forms of MPs have been successfully employed as antigen sources for antibody engineering, but heterologous expression and purification of soluble MP fragments remains a challenging and time-consuming process. Here we present a more direct approach to aid in the engineering of antibodies to MPs. By combining yeast surface display technology directly with whole cells or detergent solubilized whole-cell lysates, antibody libraries can be screened against MP antigens in their near-native conformations. We also describe how the platform can be adapted for antibody characterization and antigen identification. This collection of compatible methods serves as a basis for antibody engineering against MPs and it is predicted that these methods will mature in parallel with developments in membrane protein biochemistry and solubilization technology. PMID- 22449571 TI - Sperm DNA integrity in relation to exposure to environmental perfluoroalkyl substances - a study of spouses of pregnant women in three geographical regions. AB - Perfluoroalkyl substances (PFASs) can interfere with male reproductive function, but evidence in humans is limited. Six hundred four fertile men (199 from Greenland, 197 from Poland and 208 from Ukraine) were enrolled in the study. We measured four PFASs in serum (PFOS, PFOA, PFNA and PFHxS) and concurrent DNA damage in spermatozoa by sperm chromatin structure assay (SCSA) and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, apoptotic markers in semen (Fas-receptor and Bcl-xL), and reproductive hormones in serum. No association between PFASs and SCSA, apoptotic markers or reproductive hormones emerged. We observed a slight increase in SHBG and TUNEL positivity with increased PFOA exposure in men from Greenland. Thus, consistent evidence that PFAS exposure interferes with sperm DNA fragmentation, apoptosis or reproductive hormones was not found. PMID- 22449572 TI - Clinical and genetic characteristics of late-onset Stargardt's disease. AB - OBJECTIVE: To describe the genotype and phenotype of patients with a late-onset Stargardt's disease (STGD1). DESIGN: Retrospective case series. PARTICIPANTS: Twenty-one unrelated STGD1 patients with an age at onset of >=45 years and >=1 rare variant in the ABCA4 gene. METHODS: Ophthalmologic examination, including best-corrected visual acuity (VA), Amsler grid testing, fundus photography, fluorescein angiography (FA), spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, full-field electroretinography (ERG), multifocal ERG, and central visual field testing. Analysis of the ABCA4 gene was performed using microarray analysis, sequencing, and multiplex ligation-dependent probe amplification. In addition, the PRPH2 and CFH genes were sequenced. MAIN OUTCOME MEASURES: Age at onset, VA, fundus appearance, FA, FAF, and OCT findings; ABCA4 mutations; and genotype-phenotype correlation. RESULTS: The mean age at onset was 55 years (range, 45-72 years). Seven patients were diagnosed without visual symptoms (age range, 45-83 years). The VA was >=20/40 in 24 eyes of 14 patients (59%) owing to foveal sparing. On ophthalmoscopy, late-onset STGD1 showed flavimaculatus flecks (15 patients), small flecks surrounding mottled foveal changes (3 patients), extensive chorioretinal atrophy (2 patients), or small yellowish spots in the macula (1 patient). The fundus flecks showed increased autofluorescence on FAF. The choroidal background fluorescence on FA was obscured in 16 patients (80%). We found a single heterozygous ABCA4 variant in 11 patients (52%), 2 compound heterozygous variants in 8 patients (38%), and a homozygous variant in 2 patients (10%). No PRPH2 or CFH mutations were detected. CONCLUSIONS: Late-onset STGD1 is at the mild end of the spectrum of retinal dystrophies caused by ABCA4 mutations. The VA is frequently preserved in late onset STGD1 patients owing to foveal sparing. This phenotype may be caused by 1 or 2 ABCA4 variants. The differential diagnosis between late-onset STGD1 and age related macular degeneration may be challenging. A thorough clinical and genetic analysis makes a distinction possible, which is important for clinical and genetic counseling. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 22449573 TI - Restraints on backbone conformations in solid state NMR studies of uniformly labeled proteins from quantitative amide 15N-15N and carbonyl 13C-13C dipolar recoupling data. AB - Recent structural studies of uniformly (15)N, (13)C-labeled proteins by solid state nuclear magnetic resonance (NMR) rely principally on two sources of structural restraints: (i) restraints on backbone conformation from isotropic (15)N and (13)C chemical shifts, based on empirical correlations between chemical shifts and backbone torsion angles; (ii) restraints on inter-residue proximities from qualitative measurements of internuclear dipole-dipole couplings, detected as the presence or absence of inter-residue crosspeaks in multidimensional spectra. We show that site-specific dipole-dipole couplings among (15)N-labeled backbone amide sites and among (13)C-labeled backbone carbonyl sites can be measured quantitatively in uniformly-labeled proteins, using dipolar recoupling techniques that we call (15)N-BARE and (13)C-BARE (BAckbone REcoupling), and that the resulting data represent a new source of restraints on backbone conformation. (15)N-BARE and (13)C-BARE data can be incorporated into structural modeling calculations as potential energy surfaces, which are derived from comparisons between experimental (15)N and (13)C signal decay curves, extracted from crosspeak intensities in series of two-dimensional spectra, with numerical simulations of the (15)N-BARE and (13)C-BARE measurements. We demonstrate this approach through experiments on microcrystalline, uniformly (15)N, (13)C-labeled protein GB1. Results for GB1 show that (15)N-BARE and (13)C-BARE restraints are complementary to restraints from chemical shifts and inter-residue crosspeaks, improving both the precision and the accuracy of calculated structures. PMID- 22449574 TI - PI3-kinase and mTOR inhibitors differently modulate the function of the ABCG2 multidrug transporter. AB - The ATP-binding cassette (ABC) transporter ABCG2 plays an important role in tissue detoxification and confers multidrug resistance to cancer cells. Identification of expressional and functional cellular regulators of this multidrug transporter is therefore intensively pursued. The PI3-kinase/Akt signaling axis has been implicated as a key element in regulating various cellular functions, including the expression and plasma membrane localization of ABCG2. Here we demonstrate that besides inhibiting their respective target kinases, the pharmacological PI3-kinase inhibitor LY294002 and the downstream mTOR kinase inhibitor rapamycin also directly inhibit ABCG2 function. In contrast, wortmannin, another commonly used pharmacological inhibitor of PI3 kinase does not interact with the transporter. We suggest that direct functional modulation of ABCG2 should be taken into consideration when pharmacological agents are applied to dissect the specific role of PI3-kinase/Akt/mTOR signaling in cellular functions. PMID- 22449575 TI - Immortal person-time bias in relation to the use of nonsteroidal anti inflammatory drugs and statins in the prevention of esophageal cancer in patients with Barrett's esophagus. PMID- 22449577 TI - An unexpected explanation for exhaustion. PMID- 22449578 TI - Identifying hepatitis B carriers at low risk for hepatocellular carcinoma. PMID- 22449579 TI - Genotype-phenotype relationships in hepatocellular carcinoma: p53 inactivation promotes tumors with stem cell features. PMID- 22449580 TI - A mindful way through IBS: reducing abdominal pain and improving quality of life. PMID- 22449581 TI - Let's not jump to conclusions regarding low-grade dysplasia in Barrett's esophagus. PMID- 22449582 TI - Variants in autophagy genes affect susceptibility to both Crohn's disease and Helicobacter pylori infection. PMID- 22449583 TI - Recurrent pneumothoraces after diagnostic colonoscopy. PMID- 22449584 TI - An unusual complication of percutaneous biliary stenting. PMID- 22449585 TI - Was that last colonoscopy really negative? A surprising cause of rectal bleeding in a 75-year-old man. PMID- 22449586 TI - Detection of free-living amoebae by using multiplex quantitative PCR. AB - Free-living amoebae (FLA) are protozoa found worldwide in soil and aquatic environments, which are able to colonize man-made water networks. Some FLA have the potential to be pathogenic and others might harbour pathogenic bacteria. Indeed, FLA feed on bacteria, but some bacteria could resist phagocytosis and either survive in FLA or even multiply within FLA. These bacteria are collectively named amoeba resistant bacteria (ARB). The best characterized example is Legionella pneumophila, for which FLA is the main reservoir in the environment. Not only could FLA be a reservoir that protects ARB, some bacteria might become more resistant to treatment and be more virulent. Thus, it is of medical significance to quantify FLA populations in soil, water or the environment. The main limitation for the quantification of FLA is that classical culture is not efficient and reliable for many genera and 'strains'. Thus, several PCR-based quantification methods have been published for various FLA. However, thus far, no method has been published to simultaneously quantify the main FLA genera in the same PCR reaction. In this study, we developed a multiplex qPCR method to detect both Amoebozoan (i.e. Acanthamoeba, Hartmannella and Echinamoeba) and Vahlkampfiidae (i.e. Vahlkampfia and Naegleria) using 18S ribosomal RNA as the target gene. This method was shown to be specific, reliable and sensitive, could be used for the quantification of FLA and is likely to be useful to anticipate risks due to FLA or pathogenic bacteria, such as L. pneumophila. PMID- 22449587 TI - [Address from the previous president, January 13, 2012]. PMID- 22449588 TI - Inflammation augments the development of experimental glomerulonephritis by accelerating proteinuria and enhancing mortality. AB - Proteinuria represents a parameter for a damaged filtration capacity of the kidney. We investigated how inflammation influences the development of experimental, immune complex-mediated glomerulonephritis by monitoring proteinuria. Mice pre-treated with LPS or TNF, one day before induction of glomerulonephritis, excreted high levels of protein in the urine immediately after the induction of glomerulonephritis, in contrast to non-treated mice where proteinuria increased steadily after day 3. Protein levels in the urine of pre treated mice remained elevated over the 15-day observation time. The severity of proteinuria at later times correlated with the degree of tissue pathology and mortality in individual mice. Pre-treatment with inflammatory agents accelerated the development of proteinuria and induced more severe kidney damage. PMID- 22449589 TI - Chimeric fluorescent reporter as a tool for generation of transgenic Eimeria (Apicomplexa, Coccidia) strains with stage specific reporter gene expression. AB - Progress in transfection of Eimeria sporozoites leads to transformed oocysts, however the output of mutants after passages in the host animals is low. Further enrichment of transgenic oocysts was dependent on fluorescent activated cell sorting and could not be achieved by drug selection. In this study, we fused the Toxoplasma gondii DHFR-TSm2m3 pyrimethamine resistance gene with the yellow fluorescent protein (YFP) encoding sequence to provide continuous pyrimethamine resistance and fluorescence in the Eimeria parasite from a single transcript. The permanent YFP signal of transgenic parasites allows differentiating transgenic parasites from wild type parasites throughout the entire life cycle. The output of transformed oocysts increased up to more than 30% after initial transfection and completion of the life cycle in the host animal. Within three passages under pyrimethamine treatment, a strain with 100% transformed sporulated oocysts of the parasite could be isolated. This new method provides the potential to produce and monitor transgenic Eimeria strains without additional fluorescence activated cell sorting (FACS). The chimeric fluorescent reporter can be utilized as a continuous internal control for plasmids containing stage specific promoter. By this means we utilized an Eimeria tenella gamogony gene specific regulatory sequence to confer macrogamont specific tandem dimer tomato (tdtomato) reporter gene expression in Eimeria nieschulzi. PMID- 22449590 TI - Severity of alveolar cleft before palatoplasty affects vertical maxillofacial growth in 6-year-old patients with complete unilateral cleft lip and palate. AB - INTRODUCTION: In this study, we investigated the association between the severity of alveolar clefts in infants and the succeeding maxillofacial growth in patients affected by complete unilateral cleft lip and palate. METHODS: The subjects were 35 nonsyndromic patients affected by unilateral cleft lip and palate (n = 27) or bilateral cleft lip and palate (n = 8). Plaster models and lateral cephalograms taken at 6 years of age were analyzed and compared with the Japanese norms. In the unilateral cleft lip and palate patients, the relationship between the width of the alveolar cleft before palatoplasty and the skeletal characteristics was also explored. RESULTS: Significant deficiencies of the posterior maxilla and steep palatal planes were noted in both the unilateral and bilateral cleft lip and palate patients. However, they were not clearly observed in the unilateral cleft lip and palate patients born with a small alveolar cleft and were correlated with the severity of alveolar cleft in infancy. Neither cleft type nor the severity of the alveolar cleft was implicated in the maxillary arch form in childhood, but the growth of the alveolar height on the cleft side was less in the unilateral cleft lip and palate patients born with a large alveolar cleft. CONCLUSIONS: The severity of the alveolar cleft before palatoplasty affects the succeeding vertical maxillofacial growth in patients affected by unilateral cleft lip and palate; this suggests the necessity of a different diagnosis and treatment in unilateral cleft lip and palate patients according to the severity of the alveolar cleft in infancy. PMID- 22449591 TI - Orthodontic treatment of a patient with oral-facial-digital syndrome. AB - Oral-facial-digital syndrome is characterized by heterogeneous clinical features involving malformations of the face, oral cavity, and digits. The syndrome has been reported only in women, suggesting that it is lethal in males. Affected females have malformations of the oral cavity (cleft palate, lip and tongue, abnormal dentition, and hamartomas), face (hypertelorism and milia), and digits (syndactyly, brachydactyly, and polydactyly). In this article, we report the orthodontic treatment of a 21-year-old woman with oral-facial-digital syndrome. PMID- 22449592 TI - Orthodontic reconstruction with autotransplantation and bone grafting after a traffic accident. AB - This case report describes the orthodontic treatment with autotransplantation and bone grafting of the lost maxillary alveolus for a patient injured in a traffic accident. This patient had a severe skeletal Class III relationship because of the loss of 6 maxillary teeth and the adjacent alveolar bone. Autotransplantation of mandibular first premolars and bone grafting of the deficient alveolus were carried out to improve the occlusion and the profile. After orthodontic treatment, the transplanted premolars were reshaped and restored with composite as central incisors. Good occlusion and cosmetic improvement were obtained. Orthodontic treatment is useful for occlusal reconstruction after a traumatic injury, and autotransplantation is an effective option for these patients. PMID- 22449593 TI - Orthodontic and surgical treatment of a patient with hemifacial microsomia. AB - This article describes the surgical and orthodontic treatment of a 12-year-old boy with a significant deformity and functional involvement caused by hemifacial microsomia. The left mandibular ramus and condyle were hypoplastic and abnormal in form and location. The lower third of the face was increased, with mandibular retrusion and significant facial asymmetry. He had difficulties in speaking and chewing and problems related to his facial appearance, which caused severe psychosocial disturbances. The patient received orthodontic treatment and temporomandibular joint reconstruction with a costochondral graft on the left side while he was still growing. Three-year follow-up records are presented. PMID- 22449594 TI - Ideal treatment protocol for cleft lip and palate patient from mixed to permanent dentition. AB - A girl with an Angle Class III malocclusion, anterior and posterior crossbites, a concave profile, and cleft lip and palate sought orthodontic treatment. She was treated with a multidisciplinary therapeutic protocol including orthodontic and surgical procedures. The proposed objectives of occlusion, normal function, and balanced profile were achieved, and these results remained stable 4 years after the treatment. PMID- 22449595 TI - Interdisciplinary treatment of an adult with complete bilateral cleft lip and palate. AB - Interdisciplinary treatment was used for an adult patient born with complete bilateral cleft lip and palate. He had a severe maxillary deficiency with a wide cleft involving the alveolar and maxillary bone and palate. Reconstruction of the arches and occlusion in patients who missed the optimal treatment time is a difficult task for orthodontists. The clinical examination showed severe hypogenesis of the maxillary bone with a total crossbite. The maxillary dental arch was extremely narrow, and the maxillary incisors showed extensive caries caused by improper oral hygiene. Fixed and removable expansion appliances were used to improve the lateral crossbite. Alveolar bone grafting and unilateral LeFort I maxillary osteotomy were performed on the right side for alignment of the maxillary arch. Mandibular setback with bilateral sagittal split ramus osteotomy was also performed to correct the anteroposterior skeletal discrepancy. After postsurgical orthodontic treatment, prosthetic treatment was carried out for final reconstruction of esthetics and orthognathic function. Interdisciplinary treatment was necessary for this patient to achieve a proper occlusion and better esthetics. PMID- 22449596 TI - Patient with oculo-facio-cardio-dental syndrome treated with surgical orthodontics. AB - Oculo-facio-cardio-dental (OFCD) syndrome is a rare syndrome characterized by ocular, facial, cardiac, and dental disorders. Only about 20 cases have been reported to date. The most prominent of the various features of this syndrome is canine radiculomegaly. Other features include a long and narrow face, a high nasal bridge, a broad and pointed nose, a bifid nose, ear deformity, cleft palate or submucous cleft palate, maxillary growth retardation, a large gonial angle, open apices, delayed eruption, persistent deciduous teeth, extreme overbite, and constricted maxilla. Orthodontic and prosthodontic treatment has been reported for several patients, but surgical-orthodontic treatment for OFCD has not been reported. An 18-year-old woman with skeletal Class III malocclusion and OFCD syndrome was treated with edgewise appliance therapy combined with orthognathic surgery. We applied a light force during the treatment so as not to induce ankylosis. At the end of the surgical and orthodontic treatments, functional occlusion and an improved facial profile were achieved. After the retention period, stomatognathic function was improved. The results of this treatment suggest that surgical-orthodontic treatment is an effective method for improving skeletal disharmony, facial profile, occlusion, and stomatognathic function in patients with OFCD. PMID- 22449597 TI - Litigation and legislation. Referral liability and interdisciplinary craniofacial or dentofacial anomaly care. PMID- 22449598 TI - The craniofacial team. PMID- 22449599 TI - Ethics in orthodontics. When is enough enough? PMID- 22449601 TI - Parameters of care for craniosynostosis: dental and orthodontic perspectives. AB - INTRODUCTION: A multidisciplinary conference was convened in March 2010 with the charge to develop parameters of care for patients with craniosynostosis. The 52 participants represented 16 medical specialties and 16 professional societies. Herein, we present the dental, orthodontic, and surgical care recommendations for those with craniosynostosis, with special emphasis on craniosynostosis syndromes. METHODS: Plenary and small-group iterative discussions were held to draft specialty-specific parameters of care. All participants reviewed and discussed each specialty-specific document. Special care was taken to ensure cross discipline interactions, recognizing the importance of interdisciplinary team care. RESULTS: A unified document was produced delineating longitudinal care parameters from prenatal assessment and consultation to adulthood in all the represented specialty areas. The dental and orthodontic care parameters from infancy to adulthood are explained in terms of stages of development and coordinated with interdisciplinary assessments and interventions. CONCLUSIONS: The consensus document provides a detailed description of physical, functional, and cognitive development in persons with craniosynostosis and recommends staged team observations and interventions. The expectation is that the document will help to ensure state-of-the-art care for patients with craniosynostosis and provide a generally acceptable framework for collaborative studies. PMID- 22449602 TI - Team management and treatment outcomes for patients with hemifacial microsomia. AB - INTRODUCTION: Hemifacial microsomia is the most common congenital craniofacial anomaly after cleft lip and palate. The purpose of this study was to evaluate the final outcome of team care for patients with hemifacial microsomia after a protocol of growth management, orthodontic treatment, orthognathic surgery, and soft-tissue augmentation. METHODS: This was a retrospective study with chart reviews, radiographs, and photographs to document the treatment interventions and outcomes. Six patients, 2 in each of 3 mandibular types, who had recently completed treatment and had complete records available and were not previously reported, were included. Facial midlines and maxillary and mandibular deviations from the midline were measured. RESULTS: The maxillary deviation changed by 10.0 +/- 4.6 mm to a deviation from the midline of 1.1 +/- 0.6 mm. The chin deviation improved by 8.1 +/- 2.7 mm to a mean distance of 0.6 +/- 0.5 mm from the midline. The occlusal plane can't changed from 7.0 degrees +/- 4.2 degrees to 2.3 degrees +/- 1.4 degrees . All changes were significant. CONCLUSIONS: Facial asymmetry in patients with hemifacial microsomia can be significantly improved by stepwise orthodontic treatment, orthognathic and facial surgery, and soft-tissue augmentation. As for most craniofacial conditions, team care is essential. PMID- 22449603 TI - Craniofacial team management in Apert syndrome. AB - INTRODUCTION: Apert syndrome is one of the rarest of the craniosynostosis syndromes. Affected persons have extensive structural and functional impairments, some of which can be life threatening. Management requires team care from infancy to adulthood. The purposes of this article are to assess the outcomes in individuals with Apert syndrome after completion of treatment and to review current protocols for craniofacial team care and dental, orthodontic, and orthognathic surgical management. METHODS: This was a retrospective cohort study of 8 subjects with Apert syndrome. Cephalograms at 2 time points were compared: adolescence (before midface advancement) and at least 1 year after advancement. The cephalometric values were compared with paired t tests. Team protocols are delineated. RESULTS: Measurements indicating forward positioning of the maxilla increased significantly: SNA by 10.7 degrees (P = 0.002) and midface length by 9.6 mm (P = 0.002). Sagittal jaw relationship improved significantly as well: ANB by 14 degrees (P = 0.004) and the Wits appraisal by 8 mm (P = 0.003). Vertical dimensions also increased. CONCLUSIONS: All individuals had significantly improved and stable positions of the midface and normalized facial profiles after treatment. PMID- 22449604 TI - Mandibular widening in hemifacial microsomia: a roentgen stereometric study of 11 patients with the aid of metallic implants. AB - INTRODUCTION: Our objective was to study mandibular widening in untreated subjects with hemifacial microsomia. METHODS: From the 3-dimensional files at the Department of Plastic and Reconstructive Surgery, Skane University Hospital in Malmo, Sweden, data of 11 subjects (3 girls, 8 boys) with hemifacial microsomia were retrieved. Their age range was 9 years 2 months to 13 years 2 months at the first examination. The mean observation period was 5 years 2 months. Each subject was studied by roentgen stereophotogrammetry with the aid of metallic implants. RESULTS: A significant widening of the mandible was found, with a mean total change of 0.31 mm (range, 0.08-0.79 mm) and a mean annual change of 0.07 mm (range, 0.03-0.12 mm). In 2 subjects, narrowing of the mandible was found: -0.16 and - 0.23 mm. CONCLUSIONS: The mandible got wider during adolescence in 9 of our subjects with hemifacial microsomia but to a lesser extent than has been reported in subjects without hemifacial microsomia and from ordinary orthodontic clinics. Sex difference was not addressed. It was suggested that chewing (forces and patterns) was responsible for the mandibular widening in our subjects; this is in line with previous research. PMID- 22449605 TI - Three-dimensional analysis of the pharyngeal airway morphology in growing Japanese girls with and without cleft lip and palate. AB - INTRODUCTION: We evaluated the 3-dimensional craniofacial skeletal and pharyngeal airway morphology in growing patients with and without cleft lip and palate. METHODS: Our juvenile subjects consisted of 34 girls (ages, 9-12 years); 15 had cleft lip and palate, and 19 did not. The adolescent subjects consisted of 32 girls (ages, 13-17 years); 14 had cleft lip and palate, and 18 did not. Each subject was examined with cone-beam computed tomography. The dimensions of the craniofacial skeleton and pharyngeal airway were measured. The Scheffe method of multiple comparisons was used to identify relationships among skeletal and pharyngeal variables. RESULTS: The pharyngeal airway and mandibular size variables did not differ significantly between the juvenile and adolescent cleft lip and palate groups. Significant differences were observed between each cleft lip and palate group and its corresponding control group. FHN-A, FHN-B, FH-NA, FH NB, and Co-Me were significantly smaller in the cleft lip and palate groups than in the corresponding control groups. Anteroposterior and lateral widths, heights, and volumes of the superior oropharyngeal airway were significantly smaller in the adolescent cleft lip and palate group than in the adolescent controls. CONCLUSIONS: The mandible and the oropharyngeal airway were larger in the adolescent controls than in the juvenile controls without cleft lip and palate, but there were no significant differences between the adolescent and juvenile patients with cleft lip and palate. PMID- 22449606 TI - Noninvasive bioluminescence imaging of olfactory ensheathing glia and schwann cells following transplantation into the lesioned rat spinal cord. AB - In this study, we assess the feasibility of bioluminescence imaging to monitor the survival of Schwann cells (SCs) and olfactory ensheathing glia cells (OECs) after implantation in the lesioned spinal cord of adult rats. To this end, purified SCs and OECs were genetically modified with lentiviral vectors encoding luciferase-2 and GFP and implanted in the lesioned dorsal column. The bioluminescent signal was monitored for over 3 months, and at 7 and 98 days postsurgery, the signal was compared to standard histological analysis of GFP expression in the spinal cords. The temporal profile of the bioluminescent signal showed three distinct phases for both cell types. (I) A relatively stable signal in the first week. (II) A progressive decline in signal strength in the second and third week. (III) After the third week, the average bioluminescent signal stabilized for both cell types. Interestingly, in the first week, the peak of the bioluminescent signal after luciferin injection was delayed when compared to later time points. Similar to in vitro, our data indicated a linear relationship between the in vivo bioluminescent signal and the GFP signal of the SCs and OECs in the spinal cords when the results of both the 7 and 98 day time points are combined. This is the first report of the use of in vivo bioluminescence to monitor cell survival in the lesioned rat spinal cord. Bioluminescence could be a potentially powerful, noninvasive strategy to examine the efficacy of treatments that aim to improve the survival of proregenerative cells transplanted in the injured rat spinal cord. PMID- 22449607 TI - Memory formation: its changing face. PMID- 22449608 TI - The ever elusive permissive mismatch. PMID- 22449609 TI - Peripheral blood or marrow: is one better than the other? PMID- 22449610 TI - Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia. AB - Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS. PMID- 22449611 TI - Time to explore preventive and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. AB - Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is performed to treat otherwise incurable and fatal diseases, transplantation itself can lead to life-threatening complications due to organ damage. Pulmonary complications remain a significant barrier to the success of allo-HSCT. Lung injury, a frequent complication after allo-HSCT, and noninfectious pulmonary deaths account for a significant proportion of non-relapse mortality. Bronchiolitis obliterans syndrome (BOS) is a common and potentially devastating complication. BOS is now considered a diagnostic criterion of chronic graft-versus-host-disease (cGVHD), and National Institutes of Health (NIH) consensus has been published to establish guidelines for diagnosis and monitoring of BOS. It usually occurs within the first 2 years but may develop as late as 5 years after transplantation. Recent prevalence estimates suggest that BOS is likely underdiagnosed, and when severe BOS does occur, current treatments have been largely ineffective. Prevention and effective novel approaches remain the primary tools in the clinician's arsenal in managing BOS. This article provides an overview of the currently available and novel strategies for BOS, and we also discuss specific preventive interventions to reduce severe BOS after allo-HSCT. Therapeutic trials continue to be needed for this orphan disease. PMID- 22449612 TI - Description of two new species of the genus Thaparocleidus Jain, 1952 (Monogenea, Dactylogyridae) from freshwater fish in India: morphological and molecular phylogenetic evidence. AB - The present paper describes the taxonomy of two new monogeneans, namely, Thaparocleidus longiphallus sp. n. and T. siloniansis sp. n., based on morphological, morphometric and molecular biological analysis, collected from the fish Wallago attu (Bloch & Schn.) and Silonia silondia (Ham.), respectively, at Meerut, UP, India. Genetic characterization of the two new species is based on sequence analyses of the rDNA 28S gene using neighbour-joining and maximum parsimony techniques. These methods are congruent in depicting T. longiphallus sp. n. and T. siloniansis sp. n. as closely related species, but distinct from each other and forming a subclade with other species of the genus Thaparocleidus Jain, 1952. Secondary-structure models of the large subunit rDNA of the two species were also predicted using a combined comparative and thermodynamic approach. Molecular morphometric and phylogenetic relationships of the isolates of the Thaparocleidus species are discussed in detail. PMID- 22449613 TI - Chronic application of topiramate and carbamazepine differentially affects the EEG and penicillin-induced epileptiform activity in rats. AB - Carbamazepine (CBZ) and topiramate (TPM) are among commonly used antiepileptic drugs. The acute actions of these drugs are well known but the effects of long term use on partially induced epileptiform characteristics are yet to be clarified. The rats were received CBZ (154 mg/kg/day), TPM (10 mg/kg/day) or tap water by gavage. We investigated penicillin-induced cortical epileptiform activity and electroencephalogram spectral power of rats by using electrocorticogram recordings. Animals were anesthetized with i.p. urethane (1.25 g/kg). Analysis of electroencephalogram recordings prior to epileptiform activity revealed that 3-week treatment of CBZ significantly increased relative power of delta (P<0.01) while reduced alpha (P<0.017) and beta (P<0.017) relative power compared to both control group and TPM group. TPM had no effect on absolute power and relative power of any frequency band. TPM treatment of 21 days significantly reduced the spike frequency (P<0.01). This preventive effect was missing in CBZ-treated rats. Upon the application of the last dose of drugs during ongoing epileptiform activity, the drugs suppressed the epileptiform activity. However, TPM was more rapid and effective than CBZ. In conclusion, our in vivo electrophysiological data suggest that TPM is more effective in animal model of partial epilepsy at the applied doses in this study. PMID- 22449614 TI - Feasibility of in-office endoscopic sinus surgery with balloon sinus dilation. AB - BACKGROUND: Balloon sinus dilation (BSD) tools are increasingly used in endoscopic sinus surgery (ESS) and post maximal may cause less tissue trauma/bleeding, potentially enabling office-based ESS. We evaluate the feasibility of ESS performed in-office using BSD instrumentation. METHODS: All patients had a diagnosis with chronic rhinosinusitis. Because of symptom resolution failure postmaximal medical therapy (prolonged antibiotics, corticosteroids, and other adjuvant therapies), all patients were candidates for ESS. In-office ESS using BSD tools was performed on 37 subjects at nine sites. Procedure feasibility was assessed prospectively through technical success rate, procedure tolerability, quality of life, and radiographic outcomes. Subjects were followed at 1, 4, 24, and 52 weeks. RESULTS: In-office technical success by subject was 89% (33/37). There was one nonserious adverse event. In-office BSD was tolerable, with 93% (27/29) of patients reporting the procedure as tolerable or highly tolerable. Two in-office subjects (7%) indicated poor procedure tolerability. Intraprocedure pain was also well managed during in-office BSD, with 66% (24/36) of patients reporting no pain or pain of low intensity. While 33% (12/36) reported higher-scale pain, usually during balloon inflation, only 2 patients experienced intense pain. At 52 weeks, 95% of the subjects stated they would have procedure again. Sino-Nasal Outcome Test-20 scores revealed clinically and statistically significant treatment effects at all time points, comparable to previous balloon dilation studies conducted in an operating room setting. Lund Mackay scores revealed a statistically significant reduction at 24 weeks. CONCLUSION: Office-based ESS with BSD is feasible with demonstration of high technical success rate, meaningful patient symptom improvement, and high patient satisfaction. PMID- 22449615 TI - The role of the second and third extracellular loops of the adenosine A1 receptor in activation and allosteric modulation. AB - The adenosine A1 receptor is a member of the large membrane protein family that signals through G proteins, the G protein-coupled receptors (GPCRs). GPCRs consist of seven transmembrane domains connected by three intracellular and three extracellular loops. Their N-terminus is extracellular, the C-terminal tail is in the cytoplasm. The transmembrane domains in receptor subfamilies that bind the same endogenous ligand, such as dopamine or adenosine, tend to be highly similar. In contrast, the loop regions can vary greatly, both in sequence and in length, and the role these loops have in the activation mechanism of the receptors remains unclear. Here, we investigated the activating role of the second and third extracellular loop of the human adenosine A1 receptor. By means of an (Ala)3 mutagenic scan in which consecutive sets of three amino acids were mutated into alanine residues in EL2 and a classical alanine scan in EL3, we revealed a strong regulatory role for the second extracellular loop (EL2) of the human adenosine A1 receptor. Besides many residues in the second and the third extracellular loops important for adenosine A1 receptor activation, we also identified two residues in EL2, a tryptophan and a glutamate, that affect the influence of the allosteric modulator PD81,723. These results, combined with a comparison of the different receptor loop regions, provide insight in the activation mechanism of this typical class A GPCR and further emphasize the unique pharmacological profile the loops can provide to individual receptors, even within subfamilies of GPCRs. PMID- 22449616 TI - Genetics of adiponectin. AB - Anti-inflammatory, anti-atherogenic and anti-diabetic properties of adiponectin make this adipokine an attractive target in the metabolism research. Given its biological role, genetic variation in adiponectin affecting its function might consequently play a role in the pathophysiology of various metabolic disorders. In this light, genetic aspects of adiponectin including its gene structure, heritability of serum concentrations and the role of genetic variation have been addressed in multiple genetic studies. Here, we provide a brief summary of adiponectin genetics with focus on gene structure and genetic variation controlling circulating adiponectin levels. We summarize the main findings from genome-wide linkage and association studies that have revealed the major genetic determinants of serum adiponectin. Beside genetic variants in the adiponectin gene, several other genes/loci (ARL15, CDH13, KNG1, FER, ETV5) contributing to the variability in circulating adiponectin have been identified. The majority of these variants are significantly associated with metabolic phenotypes relevant to metabolic diseases (e.g. obesity or type 2 diabetes (T2D)). Considering the protective properties of adiponectin in diseases such as T2D, comprehensive analyses of genetic variants including rare as well as frequent polymorphisms might provide insights on the specific role of adiponectin in the pathophysiology of metabolic diseases. PMID- 22449617 TI - Plasma concentrations of Ang-1, Ang-2 and Tie-2 in gastric cancer. AB - BACKGROUND/AIM: Ang-1 and Ang-2 have both been identified as ligands for Tie-2, a receptor expressed on endothelial cells (EC). They play critical roles in angiogenesis, in concert with VEGF. Ang-1-binding to Tie-2 maintains and stabilizes mature vessels by promoting interactions between EC and the surrounding extra-cellular matrix. However, Ang-2 shows context-dependent, proangiogenic and antiangiogenic activities. Despite the rapidly accumulating histopathological data reporting differences in the expression of members of the Ang family on the surface of various normal and tumour cells, data for these growth factors in plasma from cancer patients, including gastric cancer, remain scarce. The aims of the present study were to measure the plasma concentrations of Ang-1, Ang-2 and Tie-2 in gastric cancer patients, and to assess the correlation between the concentrations of these factors and the stage of the tumor. PATIENTS AND METHODS: The study cohort consisted of 50 patients (33 male, 17 female) with gastric cancer, ranging in age from 38 to 74 years (mean age 55.3+/-12.4), and 50 sex- and age-matched, healthy controls. Determinations of Ang-1, Ang-2 and Tie-2 were performed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Concentrations of Ang-2 and Tie-2 were significantly higher in patients with gastric cancer than controls, while concentrations of Ang 1 were not statistically different between the groups. Concentrations of Ang-1, Ang-2 and Tie-2 were not statistically significantly different in gastric cancer patients with different stages of disease. CONCLUSION: Ang-2 and Tie-2 plasma concentrations might be useful, additional tumor markers in gastric cancer. PMID- 22449618 TI - Cortisol and corticosterone independence in cortisol-dominant wildlife. AB - Species have traditionally been defined as cortisol-dominant or corticosterone dominant, depending on the glucocorticoid that is reported. To assess the degree of covariance versus independence between cortisol and corticosterone, 245 serum samples belonging to 219 individuals from 18 cortisol-dominant, non-domesticated species (6 mammalian orders) were compared by mass spectrometry. In these samples, which were elevated above baseline, concentration ranges were overlapping for cortisol and corticosterone although cortisol was dominant in every sample except one of 17 bighorn sheep with a corticosterone-biased cortisol to-corticosterone ratio of 0.17. As expected, cortisol and corticosterone were strongly associated among species (r(2)=0.8; species with high absolute cortisol tend to have high absolute corticosterone concentrations), with wide variation in the species-average cortisol-to-corticosterone ratio (range 7.5-49) and an even wider ratio range across individuals (0.2-341). However, only 9 out of 13 species with >7 individuals showed a positive association between cortisol and corticosterone among individuals, and repeated measures of the cortisol-to corticosterone ratio within individuals were weakly associated (CV range 3-136%). We conclude that corticosterone, although at lower concentrations, has the potential to signal independently of cortisol, and should be included in integrated endocrine models of stress responses. PMID- 22449619 TI - Rapid stress-induced inhibition of plasma testosterone in free-ranging male rufous-winged sparrows, Peucaea carpalis: characterization, time course, and recovery. AB - Chronic stress generally inhibits the activity of the reproductive system. Acute stress also is often inhibitory, but the mechanism involved and its persistence of action once animals are no longer exposed to the stressor are poorly understood. We investigated the effect of capture and restraint stress on plasma testosterone (T), luteinizing hormone (LH), and corticosterone (CORT) in free ranging male rufous-winged sparrows, Peucaea carpalis. Stress decreased plasma T between 10 and 30 min after capture and restraint but did not influence plasma LH, the main hormone that controls T secretion, suggesting that stress did not decrease plasma T by inhibiting LH secretion. The stress-induced decrease in plasma T was associated with elevated plasma CORT, but there was no evidence that these effects were functionally related. Plasma stress-induced T was positively related to plasma initial T measured within 2 min of capture. This relationship was, however, complex as plasma T decreased proportionally more in response to stress in sparrows with high than low plasma initial T. The relative sensitivity to the same stressor was, therefore, individually variable and this variation was related to initial plasma T. Birds caught and restrained for 30 min, and then released on their breeding territory before recapture up to 6 h later, maintained depressed plasma T, indicating that the effect of acute stress on this hormone persists after the stressor removal. These studies provide new information on the effects of acute stress on plasma T in free-ranging birds. In particular, they are among the first to characterize the time course and to describe the persistence of these effects. The findings also contribute to identifying factors that are associated with individual differences in plasma hormone levels. PMID- 22449620 TI - Eosinophilia: introduction. PMID- 22449621 TI - Eosinophils and disease pathogenesis. AB - Eosinophils are granulocytic innate immune cells whose presence is conspicuous in a variety of disease states, including eosinophilic hyperproliferative and infiltrative processes, as well as conditions associated with maladaptive Th2 inflammation. This review discusses the role of eosinophils in disease pathogenesis, including a consideration of relevant eosinophil biology. Eosinophilic disease patterns of tissue infiltration are also detailed, as are candidate mechanisms by which eosinophils cause fibrosis and hypercoagulability and the importance of eosinophils in allergic inflammation. Eosinophils are unique cells in their spectrum of associated disease, with the promise of future discoveries in delineating the manner in which they contribute to disease pathogenesis. PMID- 22449622 TI - Eosinophilic myeloid disorders. AB - The discovery of therapeutically relevant mutations involving platelet-derived growth factor receptors alpha and beta (PDGFRA and PDGFRB) changed the way we evaluate and treat patients with clonal eosinophilia. Despite our improved understanding of the pathobiology of clonal eosinophilia, more than 50% of patients are diagnosed with idiopathic disease, 10% to 20% with a clonal myeloid disorder, and the remainder with a lymphocytic variant. The World Health Organization classification of tumors recognized the importance of a semi molecular classification of eosinophilic myeloid disorders and divided them into two major subgroups: (1) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or fibroblast growth factor receptor 1 (FGFR1); and (2) chronic eosinophilic leukemia, not otherwise specified. A key challenge remains the identification of tyrosine kinase responsive molecular lesions in patients in whom the pathogenesis of clonal eosinophilia remains unclear. PMID- 22449623 TI - Mast cells and eosinophils in mastocytosis, chronic eosinophilic leukemia, and non-clonal disorders. AB - Mast cells and eosinophils often travel in the same biologic circles. In non clonal states, such as allergic and inflammatory conditions, cell-to-cell contact and the pleiotropic actions of multiple cytokines and chemokines, derived from local tissues or mast cells themselves, foster the co-recruitment of these cells to the same geographic cellular niche. While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis, these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors. The dysregulated tyrosine kinases, D816V KIT and FIP1L1-PDGFRA, are the prototypic oncogenic lesions resulting in systemic mastocytosis (SM) and chronic eosinophilic leukemia, respectively. We review the pathobiology of these myeloproliferative neoplasms (MPNs) with a focus on the relationship between mast cells and eosinophils, and discuss murine models, which further elucidate how the phenotype of these diseases can be influenced by stem cell factor (SCF) and expression of the potent eosinophilopoietic cytokine, interleukin-5 (IL-5). Therapy of SM and FIP1L1-PDGFRA-positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed. PMID- 22449624 TI - Lymphoproliferative disorders associated with hypereosinophilia. AB - Hypereosinophilia, defined as peripheral blood eosinophil counts > 1,500/MUL, may complicate the course of various lymphoproliferative disorders. Among these, Hodgkin lymphoma (HL) and certain peripheral T-cell lymphomas (PTCLs) derived from CD4 cells, including Sezary syndrome (SS), adult T-cell leukemia/lymphoma (ATLL), and angioimmunoblastic T-cell lymphoma (AITL), are most commonly associated with increased reactive eosinophilopoiesis. Rarely, marked hypereosinophilia (HE) may occur in the setting of acute B-cell lymphoblastic leukemia, with a substantial impact on disease course. The mechanisms leading to blood and tissue eosinophilia in the setting of lymphoproliferative disorders, as well as the clinical complications and prognostic implications of hypereosinophilia, are discussed in this review. PMID- 22449625 TI - Evaluation and differential diagnosis of marked, persistent eosinophilia. AB - High-grade eosinophilia can be a diagnostic dilemma, as the etiologies are extensive and varied. Hypereosinophilic syndromes (HES) are a group of heterogeneous disorders, many of which remain poorly defined. By definition, HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, non-infectious causes must be considered, and include drug reactions, malignancies, and immunologic, inflammatory and allergic diseases. PMID- 22449626 TI - Therapeutic approaches to patients with hypereosinophilic syndromes. AB - Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders that range from asymptomatic eosinophilia > 1,500/mL to aggressive disease complicated by life-threatening end organ involvement, including endomyocardial fibrosis and thromboembolism. To complicate matters further, similar clinical manifestations can occur in the setting of marked eosinophilia due to helminth infection, drug hypersensitivity, and other causes. In the past, therapy was guided only by the exclusion of these secondary causes of eosinophilia and the severity of the clinical manifestations. More recently, the availability of novel targeted therapies and a better understanding of the etiologies of some subtypes of HES have necessitated a more structured approach. PMID- 22449627 TI - Controversies and open questions in the definitions and classification of the hypereosinophilic syndromes and eosinophilic leukemias. AB - Eosinophilia is frequently detectable in certain myeloid neoplasms and various reactive conditions, but it may also occur in the absence of an apparent underlying disease, or, rarely, as a paraneoplastic feature with solid tumors. In myeloid neoplasms, eosinophils are considered to belong to the malignant clone in most cases, whereas in all other conditions, eosinophilia is a reactive process triggered by eosinopoietic cytokines. Excessive accumulation of eosinophils, also termed hypereosinophilia (HE), is typically seen in eosinophilic leukemias, but it may also occur in other neoplasms and reactive disorders. HE-related end organ damage may develop in patients with reactive HE but also in those with hematologic malignancies. During the past few years, our knowledge about HE and HE-related organ damage in hematologic and nonhematologic disorders has improved considerably. Moreover, proposals for the definition and classification of eosinophil disorders have been generated by various expert groups and by the World Health Organization (WHO). However, several questions related to eosinophils and HE remain open, and many aspects of the definition and classification of eosinophil disorders and related pathologies remain controversial. In the current article, these open issues are discussed with special reference to the 2008 WHO classification of myeloid neoplasms and other classifications proposed by immunologists and various expert panels, as well as definitions and criteria recently proposed in a multidisciplinary consensus proposal. PMID- 22449628 TI - Treatment of hypereosinophilic syndromes--the first 100 years. AB - Treatment of the hypereosinophilic syndrome (HES) has advanced rapidly and prevention of end organ damage previously associated with the disorders is now possible in most patients who have had a timely diagnosis. Tried and true medications such as prednisone, hydroxyurea, and interferon-alpha (IFN-aalpha) continue to play a valuable role in treating HES and their cost is modest. Newer medications included pegylated forms of IFN-aalpha and IFN-alpha2b, first- and second-generation tyrosine kinase inhibitors (imatinib mesylate, nilotinib), and monoclonal antibodies to interleukin (IL)-5 and CD52. The combination of better understanding of HES and better medications now provide the clinician with an improved ability to control unregulated proliferation of eosinophils. PMID- 22449629 TI - Cytotoxicity and genotoxicity of nanosized and microsized titanium dioxide and iron oxide particles in Syrian hamster embryo cells. AB - Potential differences in the toxicological properties of nanosized and non nanosized particles have been notably pointed out for titanium dioxide (TiO(2)) particles, which are currently widely produced and used in many industrial areas. Nanoparticles of the iron oxides magnetite (Fe(3)O(4)) and hematite (Fe(2)O(3)) also have many industrial applications but their toxicological properties are less documented than those of TiO(2). In the present study, the in vitro cytotoxicity and genotoxicity of commercially available nanosized and microsized anatase TiO(2), rutile TiO(2), Fe(3)O(4), and Fe(2)O(3) particles were compared in Syrian hamster embryo (SHE) cells. Samples were characterized for chemical composition, primary particle size, crystal phase, shape, and specific surface area. In acellular assays, TiO(2) and iron oxide particles were able to generate reactive oxygen species (ROS). At the same mass dose, all nanoparticles produced higher levels of ROS than their microsized counterparts. Measurement of particle size in the SHE culture medium showed that primary nanoparticles and microparticles are present in the form of micrometric agglomerates of highly poly dispersed size. Uptake of primary particles and agglomerates by SHE exposed for 24 h was observed for all samples. TiO(2) samples were found to be more cytotoxic than iron oxide samples. Concerning primary size effects, anatase TiO(2), rutile TiO(2), and Fe(2)O(3) nanoparticles induced higher cytotoxicity than their microsized counterparts after 72 h of exposure. Over this treatment time, anatase TiO(2) and Fe(2)O(3) nanoparticles also produced more intracellular ROS compared to the microsized particles. However, similar levels of DNA damage were observed in the comet assay after 24 h of exposure to anatase nanoparticles and microparticles. Rutile microparticles were found to induce more DNA damage than the nanosized particles. However, no significant increase in DNA damage was detected from nanosized and microsized iron oxides. None of the samples tested showed significant induction of micronuclei formation after 24 h of exposure. In agreement with previous size-comparison studies, we suggest that in vitro cytotoxicity and genotoxicity induced by metal oxide nanoparticles are not always higher than those induced by their bulk counterparts. PMID- 22449630 TI - Biomonitoring Hexamethylene diisocyanate (HDI) exposure based on serum levels of HDI-specific IgG. AB - OBJECTIVES: Isocyanate chemicals essential for polyurethane production are widely used industrially, and are increasingly found in consumer products. Asthma and other adverse health effects of isocyanates are well-documented and exposure surveillance is crucial to disease prevention. Hexamethylene diisocyanate (HDI) specific serum immunoglobulin G (IgG) was evaluated as an exposure biomarker among workers at a US Air Force Air Logistics Center, which includes a large aircraft maintenance facility. METHODS: HDI-specific IgG (HDI-IgG) titers in serum samples (n = 74) were measured using an enzyme-linked immunosorbent assay based upon the biuret form of HDI conjugated to human albumin. Information on personal protective equipment (PPE), work location/tasks, smoking, asthma history, basic demographics, and HDI skin exposure was obtained through questionnaire. RESULTS: HDI-specific serum IgG levels were elevated in n = 17 (23%) of the workers studied. The prevalence and/or end-titer of the HDI-IgG was significantly (P < 0.05) associated with specific job titles, self-reported skin exposure, night-shift work, and respirator use, but not atopy, asthma, or other demographic information. The highest titers were localized to specific worksites (C-130 painting), while other worksites (generator painting) had no or few workers with detectable HDI-IgG. CONCLUSIONS: HDI-specific immune responses (IgG) provide a practical biomarker to aid in exposure surveillance and ongoing industrial hygiene efforts. The strategy may supplement current air sampling approaches, which do not assess exposures via skin, or variability in PPE use or effectiveness. The approach may also be applicable to evaluating isocyanate exposures in other settings, and may extend to other chemical allergens. PMID- 22449631 TI - The small heat shock proteins family: the long forgotten chaperones. AB - Small heat shock proteins are a rather heterogeneous family of ATP-independent chaperones, some of which have been proven to block protein aggregation and help the cells to survive stressful conditions. Although much less studied than high molecular weight HSPs like HSP70/HSPA or HSP90/HSPC, their implication in physio pathological processes and human diseases is now well evidenced, as it will be discussed in the different reviews of this special issue. In this mini-review we will just present a general introduction about the small heat shock proteins family. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22449632 TI - Genome-wide distribution of AdpA, a global regulator for secondary metabolism and morphological differentiation in Streptomyces, revealed the extent and complexity of the AdpA regulatory network. AB - AdpA is a global transcriptional activator triggering morphological differentiation and secondary metabolism in Streptomyces griseus. AdpA influences the expression of >1000 genes; however, the overall picture of the AdpA regulon remains obscure. Here, we took snapshots of the distribution of AdpA across the chromosome in living S. griseus cells using chromatin immunoprecipitation/chromatin affinity precipitation-seq analysis. In both liquid and solid cultures, AdpA bound to >1200 similar sites, which were located on not only in putative regulatory regions (65%), but also in regions (35%) that appeared not to affect transcription. Transcriptome analysis indicated that ~40% of the AdpA-binding sites in putative regulatory regions were involved in gene regulation. AdpA was indicated to act as a transcriptional repressor as well as an activator. Expression profiles of AdpA-target genes were very different between liquid and solid cultures, despite their similar AdpA-binding profiles. We concluded that AdpA directly controls >500 genes in cooperation with other regulatory proteins. A comprehensive competitive gel mobility shift assay of AdpA with 304 selected AdpA-binding sites revealed several unique characteristics of the DNA-binding property of AdpA. This study provides the first experimental insight into the extent of the AdpA regulon, indicating that many genes are under the direct control of AdpA. PMID- 22449633 TI - Evaluation of appropriate use of transthoracic echocardiography in 1,820 consecutive patients using the 2011 revised appropriate use criteria for echocardiography. AB - Revised Appropriate Use Criteria (AUC) for Echocardiography were published in 2011 and classify potential procedure indications as appropriate (score of 7 to 9), uncertain (score of 4 to 6), or inappropriate (score of 1 to 3). The appropriate utilization rate of transthoracic echocardiography in clinical practice using the revised AUC is unknown. The aim of the present study was to determine the appropriate utilization rate of echocardiography in a large number of consecutive studies in clinical practice and to determine the number of "unclassifiable" studies using the revised and expanded AUC. The clinical indication for transthoracic echocardiography (TTE) was determined on the basis of a detailed review of preprocedural clinical documentation. These clinical indications were further classified (when possible) into 1 of the 98 indications described in the 2011 AUC for echocardiography. From December 2010 to January 2011, 1,825 patients (mean age 63.2 years) underwent TTE for clinical reasons. Of the final study group of 1,820 patients, TTE was appropriate in 82%, inappropriate in 12.3%, and uncertain in 5.3%, and 0.4% studies were unclassifiable. The evaluation of symptoms potentially due to a cardiac etiology was the most common appropriate indication for TTE (27.5%). The most common inappropriate indication was routine surveillance (<1 year) of heart failure without a change in clinical status (2.5%). In conclusion, most TTE studies were appropriately ordered, and only a very small number of studies were unclassifiable. PMID- 22449634 TI - Relation among the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio, insulin resistance, and associated cardio-metabolic risk factors in men and women. AB - Results of recent studies using the ratio of plasma triglyceride (TG) to high density lipoprotein (HDL) cholesterol concentration to identify insulin-resistant patients at increased cardiometabolic risk have emphasized that the cut point used for this purpose will vary with race. Because TG and HDL cholesterol concentrations vary with gender, this analysis was initiated to define gender specific plasma TG/HDL cholesterol concentration ratios that best identified high risk subjects among women (n = 1,102) and men (n = 464) of primarily European ancestry. Insulin resistance was defined as the 25% of the population with the highest values for fasting plasma insulin concentration and homeostasis model assessment of insulin resistance. Using TG/HDL concentration ratios >2.5 in women and >3.5 in men identified subgroups of men and women that were comparable in terms of insulin resistance and associated cardiometabolic risk, with significantly higher values for fasting plasma insulin, homeostasis model assessment of insulin resistance, blood pressure, body mass index, waist circumference, and glucose and TG concentrations and lower HDL cholesterol concentrations than in women and men below these cut points. The sensitivity and specificity of these gender-specific cut points to identify insulin-resistant subjects were about 40% and about 80%, respectively. In conclusion, the plasma TG/HDL cholesterol concentration ratio that identifies patients who are insulin resistant and at significantly greater cardiometabolic risk varies between men and women. PMID- 22449635 TI - Saving lives: can we predict and prevent adolescent suicide? PMID- 22449636 TI - Developmental neuroscience and the courts: how science is influencing the disposition of juvenile offenders. PMID- 22449637 TI - Proposed criteria for autism spectrum disorder in the DSM-5. PMID- 22449638 TI - DSM-5's conceptualization of autistic disorders. PMID- 22449639 TI - Commentary from the DSM-5 Workgroup on Neurodevelopmental Disorders. PMID- 22449640 TI - Affectively charged: decision making in teenage suicide attempters. PMID- 22449641 TI - Joy returns last: anhedonia and treatment resistance in depressed adolescents. PMID- 22449642 TI - Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. AB - OBJECTIVE: This article aims to review basic and clinical studies outlining the roles of prefrontal cortical (PFC) networks in the behavior and cognitive functions that are compromised in childhood neurodevelopmental disorders and how these map into the neuroimaging evidence of circuit abnormalities in these disorders. METHOD: Studies of animals, normally developing children, and patients with neurodevelopmental disorders were reviewed, with focus on neuroimaging studies. RESULTS: The PFC provides "top-down" regulation of attention, inhibition/cognitive control, motivation, and emotion through connections with posterior cortical and subcortical structures. Dorsolateral and inferior PFC regulate attention and cognitive/inhibitory control, whereas orbital and ventromedial structures regulate motivation and affect. PFC circuitries are very sensitive to their neurochemical environment, and small changes in the underlying neurotransmitter systems, e.g. by medications, can produce large effects on mediated function. Neuroimaging studies of children with neurodevelopmental disorders show altered brain structure and function in distinctive circuits respecting this organization. Children with attention-deficit/hyperactivity disorder show prominent abnormalities in the inferior PFC and its connections to striatal, cerebellar, and parietal regions, whereas children with conduct disorder show alterations in the paralimbic system, comprising ventromedial, lateral orbitofrontal, and superior temporal cortices together with specific underlying limbic regions, regulating motivation and emotion control. Children with major depressive disorder show alterations in ventral orbital and limbic activity, particularly in the left hemisphere, mediating emotions. Finally, children with obsessive-compulsive disorder appear to have a dysregulation in orbito-fronto-striatal inhibitory control pathways, but also deficits in dorsolateral fronto-parietal systems of attention. CONCLUSIONS: Altogether, there is a good correspondence between anatomical circuitry mediating compromised functions and patterns of brain structure and function changes in children with neuropsychiatric disorders. Medications may optimize the neurochemical environment in PFC and associated circuitries, and improve structure and function. PMID- 22449643 TI - Sensitivity and specificity of proposed DSM-5 diagnostic criteria for autism spectrum disorder. AB - OBJECTIVE: This study evaluated the potential impact of proposed DSM-5 diagnostic criteria for autism spectrum disorder (ASD). METHOD: The study focused on a sample of 933 participants evaluated during the DSM-IV field trial; 657 carried a clinical diagnosis of an ASD, and 276 were diagnosed with a non-autistic disorder. Sensitivity and specificity for proposed DSM-5 diagnostic criteria were evaluated using field trial symptom checklists as follows: individual field trial checklist items (e.g., nonverbal communication); checklist items grouped together as described by a single DSM-5 symptom (e.g., nonverbal and verbal communication); individual DSM-5 criterion (e.g., social-communicative impairment); and overall diagnostic criteria. RESULTS: When applying proposed DSM 5 diagnostic criteria for ASD, 60.6% (95% confidence interval: 57%-64%) of cases with a clinical diagnosis of an ASD met revised DSM-5 diagnostic criteria for ASD. Overall specificity was high, with 94.9% (95% confidence interval: 92%-97%) of individuals accurately excluded from the spectrum. Sensitivity varied by diagnostic subgroup (autistic disorder = 0.76; Asperger's disorder = 0.25; pervasive developmental disorder-not otherwise specified = 0.28) and cognitive ability (IQ < 70 = 0.70; IQ >= 70 = 0.46). CONCLUSIONS: Proposed DSM-5 criteria could substantially alter the composition of the autism spectrum. Revised criteria improve specificity but exclude a substantial portion of cognitively able individuals and those with ASDs other than autistic disorder. A more stringent diagnostic rubric holds significant public health ramifications regarding service eligibility and compatibility of historical and future research. PMID- 22449644 TI - Deconstructing oppositional defiant disorder: clinic-based evidence for an anger/irritability phenotype. AB - OBJECTIVE: To examine risk factors and co-occurring symptoms associated with mother-reported versus teacher-reported anger/irritability symptoms (AIS) of oppositional defiant disorder (ODD) in a clinic-based sample of 1,160 youth aged 6 through 18 years. METHOD: Participants completed a background history questionnaire (mothers), school functioning questionnaire (mothers, teachers), and DSM-IV-referenced symptom checklists (mothers, teachers). Youth meeting AIS criteria for ODD were compared to youth with ODD who met criteria for noncompliant symptoms (NS) but not AIS and to clinic controls. RESULTS: Compared with NS youth, youth with AIS were rated as exhibiting higher levels of anxiety and mood symptoms for both mother- and teacher-defined groups, and higher levels of conduct disorder symptoms for mother-defined younger and older youth. The remaining group differences for developmental, psychosocial, and psychiatric correlates varied as a function of informant and youth's age. CONCLUSIONS: Evidence suggests that AIS may constitute a more severe and qualitatively different ODD clinical phenotype, but informant and age of youth appear to be important considerations. PMID- 22449645 TI - Impaired decision making in adolescent suicide attempters. AB - OBJECTIVE: Decision-making deficits have been linked to suicidal behavior in adults. However, it remains unclear whether impaired decision making plays a role in the etiopathogenesis of youth suicidal behavior. The purpose of this study was to examine decision-making processes in adolescent suicide attempters and never suicidal comparison subjects. METHOD: Using the Iowa Gambling Task, the authors examined decision making in 40 adolescent suicide attempters, 13 to 18 years old, and 40 never-suicidal, demographically matched psychiatric comparison subjects. RESULTS: Overall, suicide attempters performed significantly worse on the Iowa Gambling Task than comparison subjects. This difference in overall task performance between the groups persisted in an exact conditional logistic regression analysis that controlled for affective disorder, current psychotropic medication use, impulsivity, and hostility (adjusted odds ratio = 0.96, 95% confidence interval = 0.90-0.99, p < 0.05). A two-way repeated-measures analysis of variance revealed a significant group-by-block interaction, demonstrating that attempters failed to learn during the task, picking approximately the same proportion of disadvantageous cards in the first and final blocks of the task. In contrast, comparison subjects picked proportionately fewer cards from the disadvantageous decks as the task progressed. Within the attempter group, overall task performance did not correlate with any characteristic of the index attempt or with the personality dimensions of impulsivity, hostility, and emotional lability. CONCLUSIONS: Similar to findings in adults, impaired decision making is associated with suicidal behavior in adolescents. Longitudinal studies are needed to elucidate the temporal relationship between decision-making processes and suicidal behavior and to help frame potential targets for early identification and preventive interventions to reduce youth suicide and suicidal behavior. PMID- 22449646 TI - Anhedonia predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-resistant depression. AB - OBJECTIVE: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. METHOD: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication switch, or a medication switch plus CBT. This study examined five established symptom dimensions (Child Depression Rating Scale Revised) at baseline as they predicted recovery over 24 weeks of acute and continuation treatment. The two indices of recovery that were evaluated were time to remission and number of depression-free days. RESULTS: Multivariate analyses examining all five depression symptom dimensions simultaneously indicated that anhedonia was the only dimension to predict a longer time to remission, and also the only dimension to predict fewer depression-free days. In addition, when anhedonia and CDRS-total score were evaluated simultaneously, anhedonia continued to uniquely predict longer time to remission and fewer depression-free days. CONCLUSIONS: Anhedonia may represent an important negative prognostic indicator among treatment-resistant depressed adolescents. Further research is needed to elucidate neurobehavioral underpinnings of anhedonia, and to test treatments that target anhedonia in the context of overall treatment of depression. PMID- 22449647 TI - Promoting self-regulation and cooperation in pre-kindergarten children with conduct problems: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness and mechanisms of Hitkashrut, a "common elements" co-parent training (PT) program for early intervention with preschoolers (3-5 years of age) at risk for conduct problems (CP). METHOD: A randomized controlled trial with 140 participants in PT and 69 in a minimal intervention control group. The primary outcome (presence of CP) was assessed at pre-intervention, post-intervention, and 1-year follow-up. Callous-unemotional traits, effortful control, parental distress, negative/inconsistent parenting, and couple relationship quality were assessed at pre- and post-intervention, whereas callous-unemotional traits and effortful control were also assessed in the PT group at follow-up. Retention was 87.1% at post-intervention and 60% at follow-up. Hitkashrut incorporated evidence-based components of established PT programs into a culturally adapted protocol. The facilitators were trained and supervised psychologists working in Israel's Educational Psychology Services. RESULTS: Intervention effect (Cohen's d) was large at post-intervention (ES = .76, p < .001), and an additional medium effect was found at follow-up (ES = 0.63, p < .001). Parallel post-intervention and follow-up intervention effects were also found in the degree of clinically significant improvements. Effects of the intervention on callous-unemotional traits (ES = 0.85, p < .001) and effortful control (ES = 0.47, p < .001) were maintained at follow-up. Follow-up improvement in CP was mediated by improvements in parental practices and distress. CONCLUSIONS: Hitkashrut's implementation and subsequent dissemination in real-world settings demonstrates the potential effectiveness of common elements programs to promote innovations within service-delivery systems. Improvements in dispositional variables and the mediated follow-up effect support theoretical cascade models that emphasize early developmental malleability and the growing preventive effects of PT's facilitated parental changes on disruptive developmental trajectories. Clinical trial registration information - The effect of a "common elements" co-parent training program (called 'Hitkashrut') on conduct in preschoolers at risk for conduct problems; http://www.anzctr.org.au; ACTRN12612000148875. PMID- 22449648 TI - Leadership, innovation climate, and attitudes toward evidence-based practice during a statewide implementation. AB - OBJECTIVE: Leadership is important in practice change, yet there are few studies addressing this issue in mental health and social services. This study examined the differential roles of transformational (i.e., charismatic) leadership and leader-member exchange (i.e., the relationship between a supervisor and their direct service providers) on team innovation climate (i.e., openness to new innovations) and provider attitudes toward adopting evidence-based practice (EBP) during a statewide evidence-based practice implementation (EBPI) of an intervention to reduce child neglect. METHOD: Participants were 140 case-managers in 30 teams providing home-based services to families in a statewide child welfare system. Teams were assigned by region to EBPI or services as usual (SAU) conditions. Multiple group path analysis was used to examine associations of transformational leadership and leader-member exchange with innovation climate and attitudes toward adoption and use of EBP. RESULTS: Transformational leadership predicted higher innovation climate during implementation, whereas leader-member exchange predicted higher innovation climate during SAU. Innovation climate was, in turn, associated with more positive attitudes toward EBP for the EBPI group. CONCLUSIONS: Strategies designed to enhance supervisor transformational leadership have the potential to facilitate implementation efforts by promoting a strong climate for EBPI and positive provider attitudes toward adoption and use of EBP. PMID- 22449649 TI - Genome-wide association study of intelligence: additive effects of novel brain expressed genes. AB - OBJECTIVE: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. METHOD: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally homogeneous family sample of 656 individuals with at least one child affected by attention-deficit/hyperactivity disorder (ADHD). RESULTS: Haplotype trend regression analysis with sliding four-SNP windows identified haplotypes of genome-wide significance in genes involved in synaptic signaling (KIF16B; p = 1.27E-08) and neurodevelopment (PAX5; p = 3.58E-08), and highlight findings from a recent genetic study of cognitive ability (RXRA; p = 7.7E-08; GYPC; p = 2.5E-07). Further interrogation of SNPs within top haplotypes reveals that the minor alleles are associated with higher intelligence, whereas others are associated with relatively lower (but still average range) intelligence. Effects of the eight genes are additive, as a greater number of the associated genotypes in a given individual predict higher intelligence (p = 5.36E 08) and account for 8% of variance in intelligence. CONCLUSIONS: Analyses that examine additive genetic effects may be useful in identifying regions where the additive effects of SNPs have a significant effect on phenotype. These results describe novel variants and additive effects of genes involved in brain development on variability in intelligence within an ADHD sample. The precise mechanisms of these loci in relation to determining individual differences in general cognitive ability require further investigation. PMID- 22449650 TI - In defense of lumping (and splitting). PMID- 22449653 TI - Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: synthesis, cytotoxicity and antitubulin activity. AB - A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure-activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC(50) = 2-3 MUM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G(2)/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners. PMID- 22449654 TI - Prostaglandin A2 influences gene expression in an established insect cell line (BCIRL-HzAM1) cells. AB - Prostaglandins (PGs) and other eicosanoids are oxygenated metabolites of arachidonic acid and two other C(20) polyunsaturated fatty acids. While most well studied in mammals, PGs exert important actions in insects and virtually all other invertebrates. We have been researching the mechanisms of PG actions in established insect cell lines and reported earlier that two PGs, PGA(1) and PGE(1), influence gene and protein expression in HzAM1 cells. Here we report on further experiments with three 2-series PGs, PGA(2), PGE(2) and PGF(2alpha). In separate experiments we treated cells with each of the three PGs for 12 and 24h and then analyzed cell lysates by 2-D electrophoresis. Analysis of the gels by Delta2D software showed that PGA(2) influenced expression of 60 proteins while PGE(2) and PGF(2alpha) treatments led to expression changes for only a few proteins. All spots representing changes in protein expression were processed for analysis by MALDI TOF/TOF mass spectrometry. Bioinformatic analysis of the resulting sequences yielded in silico identifications of all proteins. The apparent changes in some proteins were confirmed by quantitative PCR, which demonstrated that changes in protein expression were parallel to changes in mRNA expression. We assorted the proteins into functional categories, including 1/cell structure and function; 2/cell protection and immunity; 3/energetics and metabolism; 4/nucleotide processing; 5/protein action and processing and 6/signal transduction. These findings substantially extend our idea that one mechanism of PG actions in insect cells is the modulation of gene and protein expression. PMID- 22449655 TI - Do males time their mate-guarding effort with the fertile phase in order to secure fertilisation in Cayo Santiago rhesus macaques? AB - In contrast to most mammalian species, female sexual activity is not limited to the fertile phase of the ovarian cycle in anthropoid primates, which has long been proposed to conceal the timing of ovulation to males. It is now generally believed that females are still most attractive during the fertile phase, leading to high-ranking males successfully mate-guarding them specifically during this period. While studies conducted in species exhibiting exaggerated sexual swellings (probabilistic signal of the fertile phase) have generally supported this hypothesis, mixed support comes from others. Here, we investigated whether high-ranking males timed mate-guarding effort towards female fertile phases in rhesus macaques (Macaca mulatta). In this species, adult females do not exhibit sexual swellings, but undergo facial skin colour variation, an alternative oestrogen-dependent graded-signal of female reproductive status. We collected behavioural, hormonal and genetic paternity data during two mating seasons for one group of the free-ranging population of Cayo Santiago. Our results show that mate-guarding by top-ranking males did not completely cover the entire female fertile phase and that this tactic accounted for only 30-40% of all fertilisations observed. Males tended to prolong mate-guarding into the luteal phase (null probability of fertilisation), which mirrors the pattern of male attraction to female facial colour reported in an earlier study. These findings suggest that males may have limited knowledge regarding the exact timing of females' fertile phase in rhesus macaques, which presumably allows females to gain more control over reproduction relative to other anthropoid primate species. PMID- 22449656 TI - Risk assessment and prevention of contrast-induced nephropathy in patients undergoing coronary angiography. PMID- 22449657 TI - Meta-analysis: total parenteral nutrition versus total enteral nutrition in predicted severe acute pancreatitis. AB - BACKGROUND: Total parenteral nutrition (TPN) as a traditional mode of treatment in severe acute pancreatitis was still used widely in clinical work. In addition, enteral nutrition treatment methods have developed; early enteral nutrition has already been highlighted for severe acute pancreatitis, but the therapeutic risks versus benefits need to be studied. AIMS AND OBJECTIVE: To compare total parenteral nutrition with total enteral nutrition (TEN) in patients with severe acute pancreatitis by performing a meta-analysis. MATERIALS AND METHODS: Electronic databases including PubMed, EMBASE, Science Citation Index, were searched to find relevant randomized controlled trials. Two reviewers independently identified relevant trials evaluating the effect of total parenteral nutrition and early enteral nutrion. Outcome measures were the mortality, hospital length of stay, infectious complications, duration of nutrition, organ failure and surgical intervention. RESULTS: Eight randomized controlled trials (RCTs) including 381 patients were identified. Meta-analysis demonstrated that TEN was significantly superior to TPN when considering mortality [p=0.001, 95%CI 0.37(0.21-0.68)], infectious complications [p=0.004, 95%CI 0.46(0.27-0.78)], organ failure [p=0.02, 95%CI 0.44(0.22-0.88)] and surgical intervention [p=0.003, 95%CI 0.41(0.23-0.74)].While no difference between TEN and TPN when considering the hospital length of stay [p=0.22, 95%CI 14.10(-36.48-8.26)] and as for duration of nutrition [p=0.72, 95%CI -1.50(-9.56 6.56)] there was not enough data to compare the differences. CONCLUSION: Total enteral nutritional support is associated with lower mortality, fewer infectious complications, decreased organ failure and surgical intervention rate compared to parenteral nutritional support. PMID- 22449658 TI - Prevention of contrast-induced nephropathy with ascorbic acid. AB - BACKGROUND: Some studies have shown that antioxidant ascorbic acid has renal protective effects, but the beneficial effects of contrast-induced nephropathy prevention remain to be clearly shown. Therefore, we aimed to determine whether ascorbic acid pretreatment reduces the risk of contrast-induced nephropathy in a high-risk population of patients with renal insufficiency undergoing coronary angiography. METHODS: We conducted a prospective, randomized, controlled trial, involving 156 consecutive patients with chronic renal insufficiency (calculated estimated glomerular filtration rate<60 mL/min/1.73 m(2) and/or serum creatinine>=1.1 mg/dL) undergoing coronary angiography. Patients were randomized to ascorbic acid (n=74, 3 g intravenous injection before the procedure and oral 1 g per day for 2 days after the procedure, ascorbic acid group) or sodium chloride alone (n=82, control group). All patients received pre-and postprocedure hydration. RESULTS: There was no difference between the ascorbic acid group and control group in mean peak increase in serum creatinine measured within 48 hours after coronary angiography, the primary study end point (0.012+/-0.146 vs 0.022+/ 0.212 mg/dL respectively, p=0.216). The incidence of contrast-induced nephropathy, a secondary end point defined as increase of either>=25% or >=0.5 mg/dL in serum creatinine, was 5.4% in ascorbic acid-treated patients (4/74) and 6.3% in control group patients (6/82), a nonsignificant difference (p=0.690). There were also no differences between the 2 groups in the inhospital clinical outcomes or length of hospital stay. CONCLUSION: Ascorbic acid pretreatment for short-term at high dose do not prevent renal function deterioration after administration of contrast medium in patients with baseline renal insufficiency undergoing coronary angiography. PMID- 22449659 TI - Relationship between brachial-ankle pulse wave velocity and cardiovascular risk factors: a multi-ethnic study. AB - OBJECTIVE: The objective of the present multi-ethnic study was to explore whether an association exists between brachial-ankle pulse wave velocity (baPWV) and cardiovascular risk factors in China. METHODS: Two hundred sixty-four adult subjects (152 subjects were of Han nationality, 70 subjects were from Uygur, 19 subjects were from Kazakh, 15 subjects were from Hui, and 8 subjects were of other nationalities.) aged 30-82 years were enrolled in the present study. The subjects' anthropometric, baPWV and laboratory measurements were recorded. RESULTS: Age (p=0.000), systolic blood pressure (p=0.000), diastolic blood pressure (p=0.002), fasting blood glucose (p=0.000), and hemoglobin (p=0.019) differed significantly among the subjects in the baPWV quartile. Spearman correlation analyses indicated that baPWV was significantly and positively associated with age (r=0.584, p=0.000), systolic blood pressure (r=0.396, p=0.000), diastolic blood pressure (r=0.217, p=0.000), and fasting blood glucose (r=0.231, p=0.000). baPWV was significantly and negatively associated with erythrocyte number (r=-0.181, p=0.003) and hemoglobin (r=-0.192, p=0.002) levels. Multiple regression analyses suggested that age (beta=0.573, p=0.000), systolic blood pressure (beta=0.181, p=0.003), triglycerides (beta=0.160, p=0.008), and cholesterol (beta=0.132, p=0.020) were independently associated with baPWV. CONCLUSION: Age, SBP, triglycerides, and cholesterol levels are independently and positively associated with baPWV. PMID- 22449660 TI - Serum glycerophosphate levels are increased in Japanese men with type 2 diabetes. AB - OBJECTIVE: To identify metabolites showing changes in serum levels among Japanese male with diabetes. METHODS: We performed metabolite profiling by coupling capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry using fasting serum samples from Japanese male subjects with diabetes (n=17), impaired glucose tolerance (IGT; n=5) and normal glucose tolerance (NGT; n=14). RESULTS: Other than the expected differences in characteristics related to abnormal glucose metabolism, the percent body fat was significantly different among subjects with diabetes, IGT and NGT (27.3+/-6.2, 22.2+/-4.5 and 19.2+/-6.0%, respectively, p=0.0022). Therefore, percent body fat was considered as a possible confounding factor in subsequent analyses. Of 560 metabolites detected using our platform, the levels of 74 metabolites were quantified in all of the serum samples. Significant differences between diabetes and NGT were observed for 24 metabolites. The top-ranked metabolite was glycerol 3-phophate (glycerophosphate), which was significantly higher in subjects with diabetes than in those with NGT, even after Bonferroni correction for multiple testing (11.7+/-3.6 vs. 6.4+/-1.9 uM, respectively; corrected p=0.0222). Stepwise multiple regression analyses revealed that serum glycerophosphate levels were significantly correlated with 2-h plasma glucose after a 75-g oral glucose tolerance test (r=0.553, p=0.0005), independently of other characteristics, including FPG and HbA1c. CONCLUSION: Serum glycerophosphate levels were found to be elevated in Japanese men with diabetes, and correlated with 2-h PG, independent of FPG and HbA1c. Namely, serum glycerophosphate level at fasting condition can be a marker for predicting glucose intolerance. These results warrant further studies to evaluate the relevance of glycerophosphate in the pathophysiology of diabetes. PMID- 22449661 TI - Visfatin may be a novel marker for identifying stages of essential hypertension in advanced age patients. AB - OBJECTIVE: Visfatin is a peptide that is secreted from visceral fat. It has been reported to be associated with inflammation and endothelial dysfunction. However, little is known about its function in hypertension. Therefore the aim of the present study was to evaluate visfatin levels in patients with hypertension. METHODS: We studied forty-six newly diagnosed hypertensive patients and 30 healthy participants. In accordance with blood pressure levels reported in the JNC 7 guidelines, hypertensive patients were divided into 2 groups: stage 1 and stage 2. The control group was divided into 2 groups: normal and prehypertensive. Blood pressure (BP) measurements were obtained from each patient. Serum lipid profile, glucose and visfatin levels were measured. RESULTS: The levels of fasting blood glucose (FBG), total cholesterol, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), BMI, waist circumference were significantly higher in the patient group than those in control subjects (p<0.05). The mean visfatin level was significantly higher in hypertensive patients. In the prehypertensive group, the serum visfatin levels were also significantly higher than in participants with normal blood pressure (p:0.043). There was a significantly positive correlation with visfatin and systolic BP, diastolic BP. CONCLUSION: We consider that visfatin may be a marker which may be used to illustrate damage even in prehypertensive stage caused by isolated essential HT. PMID- 22449662 TI - High serum thioredoxin levels are reduced after tonsillectomy in patients with IgA nephropathy. AB - OBJECTIVE: The role of oxidative stress in IgA nephropathy (IgAN), the most common type of primary glomerulonephritis, is unknown. We evaluated the clinical significance of serum levels of oxidative stress markers, thioredoxin (TRX) and manganese superoxide dismutase (MnSOD), in patients with IgAN. METHODS: Forty eight patients with histologically confirmed IgAN and 14 healthy subjects were enrolled in this study. Serum samples from 14 IgAN patients were obtained after tonsillectomy, a procedure hypothesized to be an effective treatment for IgAN. RESULTS: Serum TRX levels were significantly higher in patients with IgAN than in healthy subjects (mean [ng/mL]; 49.5 vs.14.4, p<0.001). Serum TRX levels are positively correlated with blood urea nitrogen, serum uric acid and proteinuria, and negatively with estimated glomerular filtration rate (eGFR). In addition, serum TRX levels gradually increased as the severity of renal histology increased. High levels of serum TRX were significantly decreased after tonsillectomy in patients with IgAN (mean [ng/mL]; 55.5 to 41.1, p=0.02). In contrast, serum MnSOD levels did not differ between IgAN patients and healthy subjects, and these levels did not change after tonsillectomy in IgAN patients. CONCLUSION: Serum TRX is associated with IgAN, and tonsillectomy may decrease oxidative stress in IgAN patients, leading to clinical improvement. PMID- 22449663 TI - Asthma control and management changes in Japan: questionnaire survey. AB - BACKGROUND: Despite the advances of asthma management and the accompanying improved asthma control, many problems related to asthma management still remain. The Niigata Asthma Treatment Study Group has been regularly collecting information via surveys since 1998 using a questionnaire, on problems related to asthma management; various studies on asthma management have been reported using data from the questionnaire. METHODS: The aim of this study was to investigate the changes in asthma control and management for every two-year period using the data from 1998 to 2008; future problems requiring resolution were extracted and discussed. RESULTS: The number of cases surveyed each year was about 3,000 (2,593 3,347 cases). The changes in the data from 1998 to 2008, including asthma attacks and symptoms rate, indicated the improvement of asthma control with the spread of medication according to the guidelines; of particular note, there was a 24.1% increase in the usage rate of inhaled corticosteroids during the study period. From 2002 to 2008, however, some asthmatic conditions seemed to show no improvement with regards to asthma control related to the rates of changes in peak flow meter use, leukotriene receptor antagonist use and oral sustained released theophylline use. Moreover, there was no decrease in the occurrence of emergency episodes related to asthma deaths. CONCLUSION: In the actual clinical setting, asthma control seems to be progressing well with the appropriate changes of medication according to the guidelines, and in part due to inhaled corticosteroid use. However, there were two problems which need to be addressed: 1) no improvement in some asthmatic conditions and 2) the occurrence of emergency episodes related to asthma deaths. In the future, it will be necessary to manage asthma in view of these points. PMID- 22449664 TI - Cardiac safety of donepezil in elderly patients with Alzheimer disease. AB - OBJECTIVE: Donepezil is a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease (AD), however its cholinergic adverse side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the adverse side effects caused by donepezil on cardiac rhythm and postural blood pressure changes in elderly patients with Alzheimer Disease. METHODS: The ECG parameters including heart rate, PR, QT, QTc interval and QRS duration and postural blood pressure changes were recorded at the baseline and at each donepezil dose level (5 and 10 mg/d). Patients Seventy-one consecutive patients who were referred by primary care centers to a Geriatric Clinic were enrolled and underwent comprehensive geriatric assessment. RESULTS: Fifty-two subjects completed the study. There were no significant changes relative to the baseline in any of the ECG parameters or arterial blood pressure at any of the investigated dosages of donepezil. CONCLUSION: It was demonstrated that donepezil was not associated with increased negative chronotropic, arrhythmogenic or hypotensive effects for elderly patients with Alzheimer's disease. PMID- 22449665 TI - Late-onset patients with sporadic amyotrophic lateral sclerosis in Japan have a higher progression rate of ALSFRS-R at the time of diagnosis. AB - OBJECTIVE: The population in Japan is aging at a faster rate than in other countries in the world. It is speculated that the number of patients with late onset amyotrophic lateral sclerosis (ALS) will increase even more in the future. However, few studies have been undertaken on the characteristics of patients with late-onset ALS in Japan. This study sought to investigate the clinical features of patients with late-onset ALS compared with those with early-onset ALS using the progression rate (DeltaFS). METHODS: Forty-five patients with sporadic ALS were divided into 2 groups: 23 patients with early-onset of ALS (<65 years; early onset) and 22 patients with late-onset ALS (>=65 years; late onset). Every patient was followed up from the time of initial diagnosis to the primary endpoint (death or time culminating in death without tracheostomy or ventilation assistance including noninvasive positive pressure ventilation) or for at least 48 months after initial diagnosis. RESULTS: DeltaFS in the patient group with late onset was significantly higher than that of the group with early onset (p=0.010). Survival of patients with late onset was significantly decreased compared to that of patients with early onset (p=0.031). CONCLUSION: Our finding suggested that patients with late-onset ALS showed more rapid disease progression than those with early-onset ALS using DeltaFS. PMID- 22449666 TI - Clinical features and the role of atypical pathogens in nursing and healthcare associated pneumonia (NHCAP): differences between a teaching university hospital and a community hospital. AB - OBJECTIVE: The Japan Respiratory Society documented a new category of guidelines for nursing and healthcare-associated pneumonia (NHCAP), which is distinct from community acquired pneumonia (CAP). The objective of this study was to determine the epidemiological differences between NHCAP patients in a teaching university hospital and a community hospital. In addition, to clarify the strategy for treatment of NHCAP, we investigated the role of atypical pathogens. METHODS: We analyzed 250 NHCAP and 421 CAP cases in a university hospital and 349 NHCAP and 374 CAP cases in a community hospital. RESULTS: Patient age and the incidences of poor general condition were significantly higher in the community hospital compared with those in the university hospital. The distribution and frequency of pathogens, especially multidrug-resistant (MDR) pathogens, were significantly different between the two hospitals. Central nervous system disorders, dementia and poor performance status, which was possibility related to aspiration pneumonia, were significantly more frequent in patients with NHCAP compared with those with CAP in both hospitals. Atypical pathogens were detected in a few cases in patients with NHCAP. CONCLUSION: There were many differences in the clinical characteristics between NHCAP patients in a university hospital and a community hospital even for hospitals located in the same area. Aspiration pneumonia was thought to be the main characteristic of NHCAP in both hospitals. Thus, all NHCAP patients did not need the same empiric therapy with a multidrug regimen directed against MDR pathogens. In addition, physicians rarely need to consider atypical pathogens in NHCAP treatment. PMID- 22449667 TI - Combination therapy with adalimumab plus intensive granulocyte and monocyte adsorptive apheresis induced clinical remission in a Crohn's disease patient with the loss of response to scheduled adalimumab maintenance therapy: a case report. AB - A 21-year-old Caucasian man with a diagnosis of Crohn's disease (CD) at the age of 14 was admitted to our hospital due to CD flare-up while under scheduled adalimumab (ADA) maintenance therapy. His symptoms remained virtually unchanged following high dose corticosteroid therapy. Seven days later, combination therapy with ADA plus intensive granulocyte/monocyte adsorptive apheresis (GMA) was initiated, which induced clinical remission. Therefore, combination therapy with ADA plus intensive GMA appears to be an effective therapeutic option for patients with severe CD while under scheduled ADA maintenance therapy. PMID- 22449668 TI - Warfarin-induced leukocytoclastic vasculitis: a case report and review of literature. AB - Warfarin is widely prescribed for patients with atrial fibrillation. In addition to unexpected bleeding, allergic skin reaction is one of its uncommon adverse effects. We herein report an 89-year-old man who, after taking warfarin for 4 years, suffered extensive skin eruptions. The skin biopsy disclosed leukocytoclastic vasculitis. The causal relationship between skin lesions and warfarin was confirmed after re-challenge of warfarin. A literature review revealed only 13 such cases reported from 1980 to 2011. Clinicians should be aware of this potential adverse effect of warfarin. PMID- 22449669 TI - A case of acute coronary artery occlusion associated with very rapid onset heparin-induced thrombosis without thrombocytopenia. AB - An 81-year-old woman was admitted to our hospital with acute heart failure. A coronary stent was implanted in the left circumflex artery (LCX) on day 3, and elective percutaneous coronary intervention for stenosis in the left anterior descending artery (LAD) was planned for day 10. However, 15 minutes after heparin administration, sudden thrombotic occlusion occurred first in the LAD and then in the LCX. Although anti-platelet factor 4/heparin antibody positivity was detected, there was no significant decrease in platelet counts. This suggests that in the event of unexplained thrombosis, heparin-induced thrombosis should be suspected irrespective of platelet counts and early onset. PMID- 22449670 TI - Dopamine-secreting carotid body paragangliomas-biochemical control with radiotherapy. AB - Head and neck paragangliomas that are exclusively or predominantly dopamine secreting are rare. Surgery and/or radiotherapy are modalities for locoregional tumoral control. Little is known about the efficacy of radiotherapy for biochemical control in such tumors. We report a 62-year-old Chinese man with bilateral carotid body tumors which were exclusively dopamine secreting. The left sided tumor invaded the skull base and encased the left carotid artery. Surgery was not performed due to high risk of morbidity and mortality. The patient received external beam radiotherapy to bilateral neck regions. Progressive decline and eventual normalization of urinary dopamine excretion was seen together with a slight reduction in tumor size. This is the first report demonstrating the efficacy of radiotherapy for both biochemical and locoregional control of functioning carotid body paragangliomas. PMID- 22449671 TI - A case of type 2 diabetes and metastatic liver cancer exhibiting hypercholesterolemia with abnormal lipoproteins. AB - Although the appearance of abnormal lipoproteins in liver diseases is well known, the precise analyses of abnormal lipoproteins remain elusive. Here, we report a 71-year-old woman with type 2 diabetes whose serum cholesterol levels were elevated to 560 mg/dL over a 4-month period. High-performance liquid chromatography demonstrated the presence of lipoprotein-X and lipoprotein-Y and sigmoid colon cancer and multiple liver metastases were found by colonoscopy and computed tomography. Remission of the primary colon cancer and liver lesions was achieved by chemotherapy with oxaliplatin and fluorouracil and her serum cholesterol went back to basal levels associated with the disappearance of abnormal lipoproteins. PMID- 22449672 TI - A case of nephrocalcinosis associated with primary aldosteronism. AB - Herein, we report a 37-year-old man presenting with nephrocalcinosis associated with primary aldosteronism. Primary hyperaldosteronism is reported to facilitate urinary calcium excretion; however, renal calculi or calcinosis in this disorder has been rarely reported. The patient had renal dysfunction and calcification in the renal medulla on both kidneys. A kidney biopsy was performed. His renal dysfunction seemed to be mainly caused by hypertension and tubulointerstitial damage. Furthermore, von Kossa-positive stones were seen in some tubules. X-ray element analysis revealed that the stones were composed of calcium phosphate. PMID- 22449673 TI - An adult case of fulminant Epstein-Barr virus infection with acute tubulointerstitial nephritis. AB - Epstein-Barr virus (EBV) infection is common in adolescence, but fulminant infection is very rare. A 40-year-old man presented with high fever and sore throat. Symptoms, including cervical lymphadenopathy, jaundice, atypical lymphocytosis, respiratory distress and oliguria, suggested infectious mononucleosis with multiple organ failure that required mechanical ventilation and renal replacement therapy. Virus markers were consistent with primary EBV infection. Renal function was gradually improved by corticosteroid therapy. Renal biopsy revealed acute tubulointerstitial nephritis. In situ hybridizaion EBV encoded RNA 1 did not show the presence of virus in the kidney, but acute kidney injury may be explained by cytotoxic/suppressor T lymphocyte infiltration. PMID- 22449674 TI - Interstitial pneumonia and nodular regenerative hyperplasia of the liver as initial manifestations of polyarteritis nodosa. AB - A 65-year-old man was admitted to our hospital because of progressive dyspnea. A laboratory examination and high-resolution computed tomography (HRCT) revealed that he had interstitial pneumonia (IP) with liver dysfunction. Myeloperoxidase ANCA (MPO-ANCA) was negative. Although his respiratory condition had become stable after initiation of steroid therapy, liver dysfunction had worsened with progressive portal hypertension. He died of hepatic insufficiency about three years after the first medical examination. Autopsy showed that he had vasculitis of medium and small blood vessels of the spleen, lungs, and liver. The final diagnosis was classical polyarteritis nodosa (PAN). Microscopically, non-specific interstitial pneumonia was identified in the autopsied lung. The pathological findings of the liver were consistent with nodular regenerative hyperplasia (NRH). We report a case of PAN with IP and NRH preceding findings of systemic vasculitis. PMID- 22449675 TI - Myopericytoma presenting as multiple pulmonary nodules. AB - Myopericytoma is a benign tumor composed of cells that show apparent differentiation towards putative perivascular myoid cells called myopericytes. To date, only a small number of series describing myopericytomas have been reported. Here, we report a case of pulmonary myopericytoma presenting as multiple nodules in a 26-year-old man. Clinical presentation, radiological features and histopathologic findings of the patient are also discussed. The result of the histology combined with the immunohistochemical analysis led to a diagnosis of myopericytomas. To our knowledge, this is the first report of myopericytoma showing pulmonary involvement. PMID- 22449676 TI - Diffuse large B-cell lymphoma arising primarily at the stoma after bladder reconstruction using ileal conduit. AB - A 76-year-old man suffered from swelling stoma for several weeks. A biopsy sample revealed the diffuse infiltration of large lymphoid cells which were positive for CD20, bcl-6, and MUM1. The patient was diagnosed with diffuse large B-cell lymphoma, with a non-germinal center B-cell pattern. A whole-body PET-CT scan revealed that the lymphoma was restricted to the stomal site. Bladder reconstruction was undertaken using the ileal conduit: this is the first reported case of lymphoma that developed primarily at the stoma. During the long-term maintenance after bladder reconstruction, clinicians should consider the possibility of lymphoma at the stomal site. PMID- 22449677 TI - Delayed recurrent ischemic stroke after initial good recovery from pneumococcal meningitis. AB - We describe unusual delayed recurrent episodes of ischemic stroke in a patient with initial good recovery from pneumococcal meningitis due to progressive arterial stenosis for over 3 months. We postulate that any of the following may have been responsible for his condition: widespread cerebral vasculopathy due to the effects of purulent material bathing the base of the brain, an immune mediated para-infectious condition, or a rebound effect of the primary inflammatory reaction that was initially suppressed by dexamethasone. This case demonstrates that progressive arterial stenosis can evolve months after bacterial meningitis and should be recognized as a potential vascular complication. PMID- 22449678 TI - Rectal ulcer in a patient with VZV sacral meningoradiculitis (Elsberg syndrome). AB - This report describes the case of a 55-year-old woman with varicella-zoster virus (VZV) sacral meningoradiculitis (Elsberg syndrome) who presented with herpes zoster in the left S2 dermatome area, urinary retention, and constipation. Lumbar magnetic resonance imaging showed the left sacral nerve root swelling with enhancement. Thereafter, she suddenly showed massive hematochezia and hemorrhagic shock because of a rectal ulcer. To elucidate the relation between Elsberg syndrome and rectal ulcer, accumulation of similar cases is necessary. To avoid severe complications, attention must be devoted to the possibility of rectal bleeding in the early stage of Elsberg syndrome. PMID- 22449679 TI - Hemophagocytic lymphohistiocytosis in a rheumatoid arthritis patient treated with infliximab. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report a case of a 74-year-old woman with rheumatoid arthritis who developed HLH secondary to pyelonephritis due to Escherichia coli infection following infliximab treatment. Bone marrow aspiration showed proliferation of histiocytes with hemophagocytosis. The patient died despite treatment with intravenous antibiotics intravenous methylprednisolone and intravenous immunoglobulin. Cytokine levels were measured and are discussed. PMID- 22449680 TI - Gefitinib for a poor performance status patient with squamous cell carcinoma of the lung harboring EGFR mutation. AB - Recent reports have shown gefitinib, epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) induced marked improvement in ECOG performance status (PS) as first-line therapy in EGFR mutation-positive patients with extremely poor PS. EGFR mutations frequently occur in east-Asian, female, non-smoking, adenocarcinoma patients, however they are occasionally detected in patients with non-adenocarcinomas or with a heavy smoking history. We describe a case in which EGFR mutation was detected in a male, current smoker, squamous cell carcinoma (SCC) patient with PS 4, who showed a marked response to the first-line gefitinib therapy. EGFR mutational analysis is recommended even for SCC patients especially in east-Asian populations. PMID- 22449681 TI - Gall bladder B-lymphoblastic lymphoma showing carcinoma-like appearance. PMID- 22449682 TI - Colon lymphoma causing intussusception. PMID- 22449683 TI - Dorsal pancreatic artery aneurysm with celiac trunk occlusion. PMID- 22449684 TI - Sinus Valsalva aneurysms in a patient with ankylosing spondilitis. PMID- 22449685 TI - Endovascular management of a giant celiac artery aneurysm. PMID- 22449686 TI - Thymic enlargement in two cases of Graves' disease. PMID- 22449687 TI - Distal renal tubular acidosis associated with Sjogren's syndrome. PMID- 22449688 TI - Massive tension pneumomediastinum. PMID- 22449689 TI - Varicella pneumonitis. PMID- 22449690 TI - Cervical Pott's disease revealed by diabetic ketoacidosis. PMID- 22449691 TI - Diffusion-weighted MRI findings in a patient with pituitary abscess. PMID- 22449692 TI - Diffuse metastases of lung adenocarcinoma with EGFR mutation. PMID- 22449693 TI - Progressive multicentric reticulohistiocytosis. PMID- 22449694 TI - Infected esophageal duplication cyst masquerading as pericarditis. PMID- 22449695 TI - Ligation with nucleic acid sequence-based amplification. AB - This work presents a novel method for detecting nucleic acid targets using a ligation step along with an isothermal, exponential amplification step. We use an engineered ssDNA with two variable regions on the ends, allowing us to design the probe for optimal reaction kinetics and primer binding. This two-part probe is ligated by T4 DNA Ligase only when both parts bind adjacently to the target. The assay demonstrates that the expected 72-nt RNA product appears only when the synthetic target, T4 ligase, and both probe fragments are present during the ligation step. An extraneous 38-nt RNA product also appears due to linear amplification of unligated probe (P3), but its presence does not cause a false positive result. In addition, 40 mmol/L KCl in the final amplification mix was found to be optimal. It was also found that increasing P5 in excess of P3 helped with ligation and reduced the extraneous 38-nt RNA product. The assay was also tested with a single nucleotide polymorphism target, changing one base at the ligation site. The assay was able to yield a negative signal despite only a single-base change. Finally, using P3 and P5 with longer binding sites results in increased overall sensitivity of the reaction, showing that increasing ligation efficiency can improve the assay overall. We believe that this method can be used effectively for a number of diagnostic assays. PMID- 22449696 TI - A method for measuring gene copy number in biological samples without using control samples of known copies. AB - Various human diseases are caused by gene copy number variants, underlining the importance of determining disease gene copy number for clinical diagnostics. In this study, we describe a method for determining gene copy number in a biological organism. In this method, both a target gene and an internal control gene were amplified from the organism by regular PCR. The PCR products were purified and quantified, and the target and internal control genes were mixed at different molar ratios. Real-time PCR was then used to measure the quantification cycle (Cq) values of both the target and internal control genes in the mixtures. A standard curve was constructed to correlate the differences between the Cq values and the logarithmic ratios of the target gene to the internal control gene. Real time PCR was then used to measure the Cq values of both the target and internal control genes in experimental samples; the copy number of the target gene in the sample can be calculated readily from the calculated standard curve. This method was validated by a set of internal control genes and a foreign gene in transgenic alfalfa, demonstrating the utility of this method in the determination of gene copy number for various applications. PMID- 22449697 TI - [Biotechnological cultivation of edible macrofungi: an alternative for obtaining nutraceutics]. AB - Macromycetes have been part of the human culture for thousand years, and have been reported as food in the most important civilizations in history. Many nutraceutical properties of macromycetes have been described, such as anti cancer, anti-tumour, cholesterol lowering, antiviral, antibacterial, or immunomodulatory, among others. Given that production of mushrooms by traditional cultivation and extraction of bioactive metabolites is very difficult in some cases, biotechnology is essential for the development of profitable and productive techniques for obtaining these metabolites. It is the development of this technology, and the ease in which it enables the use of its variables that has allowed mycelium to be cultivated in liquid medium of macrofungi, with a significant reduction in time and an increased production of metabolites. This increased production has led to the study of compounds that have medicinal, nutriceutical and quasi-farmaceutical potential, in the exhausted media and the mycelium. The aim of this review is to provide an overview of the use of liquid state fermentation as a technological tool for obtaining edible fungi, and the study of these and their metabolites, by describing the different cultivation conditions used in recent years, as well as the results obtained. The relevance of Agaricus, Flammulina, Grifola, Pleurotus and Lentinula genera, will also be discussed, with emphasis on the last one, since Shiitake has been always considered as the ultimate medicinal mushroom. PMID- 22449698 TI - Chimeric RNAs as potential biomarkers for tumor diagnosis. AB - Cancers claim millions of lives each year. Early detection that can enable a higher chance of cure is of paramount importance to cancer patients. However, diagnostic tools for many forms of tumors have been lacking. Over the last few years, studies of chimeric RNAs as biomarkers have emerged. Numerous reports using bioinformatics and screening methodologies have described more than 30,000 expressed sequence tags (EST) or cDNA sequences as putative chimeric RNAs. While cancer cells have been well known to contain fusion genes derived from chromosomal translocations, rearrangements or deletions, recent studies suggest that trans-splicing in cells may be another source of chimeric RNA production. Unlike cis-splicing, trans-splicing takes place between two pre-mRNA molecules, which are in most cases derived from two different genes, generating a chimeric non-co-linear RNA. It is possible that trans-splicing occurs in normal cells at high frequencies but the resulting chimeric RNAs exist only at low levels. However the levels of certain RNA chimeras may be elevated in cancers, leading to the formation of fusion genes. In light of the fact that chimeric RNAs have been shown to be overrepresented in various tumors, studies of the mechanisms that produce chimeric RNAs and identification of signature RNA chimeras as biomarkers present an opportunity for the development of diagnoses for early tumor detection. PMID- 22449699 TI - Anti-obesity and hypolipidemic effects of Rheum undulatum in high-fat diet-fed C57BL/6 mice through protein tyrosine phosphatase 1B inhibition. AB - Protein tyrosine phosphatase 1B (PTP1B) is important in the regulation of metabolic diseases and has emerged as a promising signaling target. Previously, we reported the PTP1B inhibitory activity of Rheum undulatum (RU). In the present study, we investigated the metabolic regulatory effects of RU in a high-fat diet (HFD) model. RU treatment significantly blocked body weight gain, which was accompanied by a reduction of feed efficiency. In addition, it led to a reduction of liver weight mediated by overexpression of PPARalpha and CPT1 in the liver, and an increase in the expression of adiponectin, aP2, and UCP3 in adipose tissue responsible for the reduction of total and LDL-cholesterol levels. Chrysophanol and physcion from RU significantly inhibited PTP1B activity and strongly enhanced insulin sensitivity. Altogether, our findings strongly suggest that 2 compounds are novel PTP1B inhibitors and might be considered as anti-obesity agents that are effective for suppressing body weight gain and improving lipid homeostasis. PMID- 22449700 TI - Oxidative modification of ferritin induced by methylglyoxal. AB - Methylglyoxal (MG) was identified as an intermediate in non-enzymatic glycation and increased levels were reported in patients with diabetes. In this study, we evaluated the effects of MG on the modification of ferritin. When ferritin was incubated with MG, covalent crosslinking of the protein increased in a time- and MG dose-dependent manner. Reactive oxygen species (ROS) scavengers, N-acetyl-(L) cysteine and thiourea suppressed the MG-mediated ferritin modification. The formation of dityrosine was observed in MG-mediated ferritin aggregates and ROS scavengers inhibited the formation of dityrosine. During the reaction between ferritin and MG, the generation of ROS was increased as a function of incubation time. These results suggest that ROS may play a role in the modification of ferritin by MG. The reaction between ferritin and MG led to the release of iron ions from the protein. Ferritin exposure to MG resulted in a loss of arginine, histidine and lysine residues. It was assumed that oxidative damage to ferritin caused by MG may induce an increase in the iron content in cells, which is deleterious to cells. This mechanism, in part, may provide an explanation or the deterioration of organs under diabetic conditions. PMID- 22449701 TI - Geft is dispensable for the development of the second heart field. AB - Geft is a guanine nucleotide exchange factor, which can specifically activate Rho family of small GTPase by catalyzing the exchange of bound GDP for GTP. Geft is highly expressed in the excitable tissue as heart and skeletal muscle and plays important roles in many cellular processes, such as cell proliferation, migration, and cell fate decision. However, the in vivo role of Geft remains unknown. Here, we generated a Geft conditional knockout mouse by flanking exons 5 17 of Geft with loxP sites. Cre-mediated deletion of the Geft gene in heart using Mef2c-Cre transgenic mice resulted in a dramatic decrease of Geft expression. Geft knockout mice develop normally and exhibit no discernable phenotype, suggesting Geft is dispensable for the development of the second heart field in mouse. The Geft conditional knockout mouse will be a valuable genetic tool for uncovering the in vivo roles of Geft during development and in adult homeostasis. PMID- 22449702 TI - The activation of CD99 inhibits cell-extracellular matrix adhesion by suppressing beta(1) integrin affinity. AB - CD99 is known to be involved in the regulation of cell-cell adhesion. However, it remains unclear whether CD99 controls cell-extracellular matrix adhesion. In this study, the effects of CD99 activation on cell-extracellular matrix adhesion were investigated. It was found that engagement of CD99 with the stimulating antibody YG32 downregulated the adhesion of MCF-7 cells to fibronectin, laminin and collagen IV in a dose-dependent manner. The CD99 effect on cell-ECM adhesion was inhibited by overexpression of the dominant negative form of CD99 or CD99 siRNA transfection. Treatment of cells with Mn(2+) or by beta(1) integrin-stimulating antibody restored the inhibitory effect of CD99 on cell-ECM adhesion. Cross linking CD99 inactivated beta(1) integrin through conformational change. CD99 activation caused dephosphorylation at Tyr-397 in FAK, which was restored by the beta(1) stimulating antibody. Taken together, these results provide the first evidence that CD99 inhibits cell-extracellular matrix adhesion by suppressing beta(1) integrin affinity. [BMB reports 2012; 45(3): 159-164]. PMID- 22449703 TI - Identification of anti-HIV and anti-reverse transcriptase activity from Tetracera scandens. AB - We report here that an ethanol extract of Tetracera scandens, a Vietnamese medicinal plant, has anti-HIV activity and possesses strong inhibitory activity against HIV-1 reverse transcriptase (RTase). Using a MT-4 cell-based assay, we found that the T. scandens extract inhibited effectively HIV virus replication with an IC(50) value in the range of 2.0-2.5 MUg/ml while the cellular toxicity value (CC50) was more than 40-50 MUg/ml concentration, thus yielding a minimum specificity index of 20-fold. Moreover, the anti-HIV efficacy of the T. scandens extract was determined to be due, in part, to its potent inhibitory activity against HIV-1 RTase activity in vitro. The inhibitory activity against the RTase was further confirmed by probing viral cDNA production, an intermediate of viral reverse transcription, in virus-infected cells using quantitative DNA-PCR analysis. Thus, these results suggest that T. scandens can be a useful source for the isolation and development of new anti- HIV-1 inhibitor(s). [BMB reports 2012; 45(3): 165-170]. PMID- 22449704 TI - Glutaredoxin2 isoform b (Glrx2b) promotes RANKL-induced osteoclastogenesis through activation of the p38-MAPK signaling pathway. AB - Receptor activator of NF-kappaB ligand (RANKL) triggers the differentiation of bone marrow-derived monocyte/macrophage precursor cells (BMMs) of hematopoietic origin into osteoclasts through the activation of mitogen-activated protein (MAP) kinases and transcription factors. Recently, reactive oxygen species (ROS) and antioxidant enzymes were shown to be closely associated with RANKL-mediated osteoclast differentiation. Although glutaredoxin2 (Glrx2) plays a role in cellular redox homeostasis, its role in RANKL-mediated osteoclastogenesis is unclear. We found that Glrx2 isoform b (Glrx2b) expression is induced during RANKLmediated osteoclastogenesis. Over-expression of Glrx2b strongly enhanced RANKL- mediated osteoclastogenesis. In addition, Glrx2b-transduced BMMs enhanced the expression of key transcription factors c-Fos and NFATc1, but pre-treatment with SB203580, a p38-specific inhibitor, completely blocked this enhancement. Conversely, down-regulation of Glrx2b decreased RANKL- mediated osteoclastogenesis and the expression of c-Fos and NFATc1 proteins. Also, Glrx2b down-regulation attenuated the RANKL-induced activation of p38. Taken together, these results suggest that Glrx2b enhances RANKL-induced osteoclastogenesis via p38 activation. PMID- 22449705 TI - Anti-inflammatory activity of Camellia japonica oil. AB - Camellia japonica oil (CJ oil) has been used traditionally in East Asia to nourish and soothe the skin as well as help restore the elasticity of skin. CJ oil has also been used on all types of bleeding instances. However, little is known about its anti-inflammatory effects. Therefore, the anti-inflammatory effects of CJ oil and its mechanisms of action were investigated. CJ oil inhibited LPS-induced production of NO, PGE(2), and TNF-alpha in RAW264.7 cells. In addition, expression of COX-2 and iNOS genes was reduced. To evaluate the mechanism of the anti-inflammatory activity of CJ oil, LPS-induced activation of AP-1 and NF-kappaB promoters was found to be significantly reduced by CJ oil. LPS induced phosphorylation of IkappaBalpha, ERK, p38, and JNK was also attenuated. Our results indicate that CJ oil exerts anti-inflammatory effects by downregulating the expression of iNOS and COX-2 genes through inhibition of NF kappaB and AP-1 signaling. [BMB reports 2012; 45(3): 177-182]. PMID- 22449706 TI - Human intersectin 2 (ITSN2) binds to Eps8 protein and enhances its degradation. AB - Participates in actin remodeling through Rac and receptor endocytosis via Rab5. Here, we used yeast two-hybrid system with Eps8 as bait to screen a human brain cDNA library. ITSN2 was identified as the novel binding factor of Eps8. The interaction between ITSN2 and Eps8 was demonstrated by the in vivo co immunoprecipitation and colocalization assays and the in vitro GST pull-down assays. Furthermore, we mapped the interaction domains to the region between amino acids 260-306 of Eps8 and the coiled-coil domain of ITSN2. In addition, protein stability assays and immunofluorescence analysis showed ITSN2 overexpression induced the degradation of Eps8 proteins, which was markedly alleviated with the lysosome inhibitor NH4Cl treatment. Taken together, our results suggested ITSN2 interacts with Eps8 and stimulates the degradation of Eps8 proteins. PMID- 22449707 TI - Mxi1 influences cyst formation in three-dimensional cell culture. AB - Cyst formation is a major characteristic of ADPKD and is caused by the abnormal proliferation of epithelial cells. Renal cyst formation disrupts renal function and induces diverse complications. The mechanism of cyst formation is unclear. mIMCD-3 cells were established to develop simple epithelial cell cysts in 3-D culture. We confirmed previously that Mxi1 plays a role in cyst formation in Mxi1 deficient mice. Cysts in Mxi1 transfectanted cells were showed by collagen or mebiol gels in 3-D cell culture system. Causative genes of ADPKD were measured by q RT-PCR. Herein, Mxi1 transfectants rarely formed a simple epithelial cyst and induced cell death. Overexpression of Mxi1 resulted in a decrease in the PKD1, PKD2 and c-myc mRNA relating to the pathway of cyst formation. These data indicate that Mxi1 influences cyst formation of mIMCD-3 cells in 3-D culture and that Mxi1 may control the mechanism of renal cyst formation. PMID- 22449708 TI - Sodium selenite-induced activation of DAPK promotes autophagy in human leukemia HL60 cells. AB - Autophagy has been suggested as a possible mechanism for non-apoptotic death despite evidence from many species that autophagy represents a survival strategy of cells under stress. From our previous findings that supranutritional doses of sodium selenite induced apoptosis in human leukemia cells, now we show autophagic cell death occurred after selenite exposure in HL60, suggested an alternative mechanism for the potential therapeutic properties of selenite. Additionally, Death-associated Protein Kinase (DAPK) performed a significantly increased expression during this process, concomitantly with gradually decreased phosphorylation at Ser(308). We further reveal that the up-regulation of DAPK which depends on selenite-activated ERK had no effect on autophagy. However, activation of DAPK via PP2A-mediated dephosphorylation at Ser(308) serves as a new strategy for autophagy induction. In conclusion, these results indicate that PP2A-mediated activated DAPK sensitizes HL60 cells to selenite, ultimately triggers autophagic cell death pathway to commit cell demise. PMID- 22449709 TI - Anti-inflammatory functions of purpurogallin in LPS-activated human endothelial cells. AB - Enzymatic oxidation of commercially available pyrogallol was efficiently transformed to an oxidative product, purpurogallin. Purpurogallin plays an important role in inhibiting glutathione S-transferase, xanthine oxidase, catechol O-methyltransferase activities and is effective in the cell protection of several cell types. However, the anti-inflammatory functions of purpurogallin are not well studied. Here, we determined the effects of purpurogallin on lipopolysaccharide (LPS)-mediated proinflammatory responses. The results showed that purpurogallin inhibited LPS-mediated barrier hyper-permeability, monocyte adhesion and migration and such inhibitory effects were significantly correlated with the inhibitory functions of purpurogallin on LPS-mediated cell adhesion molecules (vascular cell adhesion molecules, intracellular cell adhesion molecule, E-selectin). Furthermore, LPS-mediated nuclear factor-kappaB (NF kappaB) and tumor necrosis factor-alpha (TNF-alpha) releases from HUVECs were inhibited by purpurogallin. Given these results, purpurogallin showed its anti inflammatory activities and could be a candidate as a therapeutic agent for various systemic inflammatory diseases. [BMB reports 2012; 45(3): 200-205]. PMID- 22449710 TI - HSP27 modulates survival signaling networks in cells treated with curcumin and TRAIL. AB - The combination of curcumin and TRAIL and their role in enhancing apoptotic cell death has been reported by many studies. However, the exact molecular mechanism of apoptosis mediated by curcumin and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is not yet completely understood. In this study, we observed a close connection between dephosphorylated Akt and an increase in phosphorylated heat shock protein 27 (HSP27) during combined treatment with curcumin and TRAIL. Akt dephosphorylation was cumulatively regulated by protein phosphatase 1 (PP1), phosphoinositide-dependent kinase-1 (PDK1), and src. PP1 and PDK1 directly interacted with HSP27, whereas src indirectly interacted with HSP27 via the tumor necrosis factor receptor-associated factor 6 complex. In conclusion, HSP27 modulated cell survival by its interactions with various binding partners, depending on the level of phosphorylated HSP27. PMID- 22449711 TI - Increased determinism in brain electrical activity occurs in association with multiple sclerosis. AB - OBJECTIVE: Increased determinism (decreased complexity) of brain electrical activity has been associated with some brain diseases. Our objective was to determine whether a similar association occurred for multiple sclerosis (MS). METHODS: Ten subjects with a relapsing-remitting course of MS who were in remission were studied; the controls were age- and gender-matched clinically normal subjects. Recurrence plots were calculated using representative electroencephalogram (EEG) epochs (1-7 seconds) from six derivations; the plots were quantified using the nonlinear variables percent recurrence (%R) and percent determinism (%D). The results were averaged over all derivations for each participant, and the means were compared between the groups. As a linear control procedure the groups were also compared using spectral analysis. RESULTS: The mean+/-SD of %R for the MS subjects was 6.6+/-1.3%, compared with 5.1+/-1.3% in the normal group (P = 0.017), indicating that brain activity in the subjects with MS was less complex, as hypothesized. The groups were not distinguishable using %D or spectral analysis. DISCUSSION: Taken together with our earlier report that %R could be used to discriminate between MS and normal subjects based on the ability to exhibit evoked potentials, the evidence suggests that complexity analysis of the EEG has potential for development as a diagnostic test for MS. PMID- 22449712 TI - Macular lymphocytic arteritis in a patient with rheumatoid arthritis. PMID- 22449713 TI - Embryonic stem cells improve cardiac function in Doxorubicin-induced cardiomyopathy mediated through multiple mechanisms. AB - Doxorubicin (DOX) is an effective antineoplastic agent used for the treatment of a variety of cancers. Unfortunately, its use is limited as this drug induces cardiotoxicity and heart failure as a side effect. There is no report that describes whether transplanted embryonic stem (ES) cells or their conditioned medium (CM) in DOX-induced cardiomyopathy (DIC) can repair and regenerate myocardium. Therefore, we transplanted ES cells or CM in DIC to examine apoptosis, fibrosis, cytoplasmic vacuolization, and myofibrillar loss and their associated Akt and ERK pathway. Moreover, we also determined activation of endogenous c-kit(+ve) cardiac stem cells (CSCs), levels of HGF and IGF-1, growth factors required for c-kit cell activation, and their differentiation into cardiac myocytes, which also contributes in cardiac regeneration and improved heart function. We generated DIC in C57Bl/6 mice (cumulative dose of DOX 12 mg/kg body weight, IP), and animals were treated with ES cells, CM, or cell culture medium in controls. Two weeks post-DIC, ES cells or CM transplanted hearts showed a significant (p < 0.05) decrease in cardiac apoptotic nuclei and their regulation with Akt and ERK pathway. Cardiac fibrosis observed in the ES cell or CM groups was significantly less compared with DOX and cell culture medium groups (p < 0.05). Next, cytoplasmic vacuolization and myofibrillar loss was reduced (p < 0.05) following treatment with ES cells or CM. Moreover, our data also demonstrated increased levels of c-kit(+ve) CSCs in ES cells or CM hearts and differentiated cardiac myocytes from these CSCs, suggesting endogenous cardiac regeneration. Importantly, the levels of HFG and IGF-1 were significantly increased in ES cells or CM transplanted hearts. In conclusion, we reported that transplanted ES cells or CM in DIC hearts significantly decreases various adverse pathological mechanisms as well as enhances cardiac regeneration that effectively contributes to improved heart function. PMID- 22449714 TI - In vitro anthelmintic activity of crude extracts of selected medicinal plants against Haemonchus contortus from sheep. AB - Ethanol extracts of 25 plant species were screened for anthelmintic effects against Haemonchus contortus. Ethanol extracts of each plant were used at various concentrations (10, 20 and 30%) to treat 10-day faecal cultures, incubated at 27 degrees C with control cultures which were treated with ethanol for 48 h. Five plants with high efficacies (Ananas comosus, Aloe ferox, Allium sativum, Lespedeza cuneata and Warburgia salutaris) were selected from the first screening for further investigation using ethanol, dichloromethane and water extracts at four concentrations (2.5, 5, 10 and 20%). Ethanol was the most effective solvent. Larval counts decreased with increasing extract concentrations, of which 10 and 20% had similar effects. Lespedeza cuneata caused more than 70% mortality at all concentrations. However, there remains a need to assess in vivo efficacy of these plants. PMID- 22449715 TI - Factors associated with supportive care needs of patients under treatment for breast cancer. AB - PURPOSE: This study aimed at gaining insight into supportive care needs and cancer treatment-related symptoms, and to determine factors associated with supportive care needs. Breast cancer and its treatment cause emotional trauma and health complaints. These lead to supportive care needs in some patients, while others are more able to cope with these consequences themselves. To be able to address these needs, it is important to identify patients' needs at the time they arise. METHODS: Women (n = 175) with newly-diagnosed breast cancer, under treatment in two Swiss breast cancer clinics, participated in a cross-sectional survey. Standardized instruments were used: Supportive Care Needs Survey, Cancer- and Cancer Treatment-related Symptom Scale, Hospital Anxiety and Depression Scale, Distress Thermometer, and Interpersonal Relationship Inventory. RESULTS: The patients' most needed help with psychological issues. Many had treatment related symptoms like fatigue (87.7%), hot flashes (71.5%), and a changed body appearance (55.8%). The majority suffered from distress (56.2%), fewer from anxiety (24.1%) and depression (12.1%). Physical and social impairment, impaired body image, distress, anxiety and depression, a lack of social support and conflicts in their personal relationships were associated with supportive care needs. CONCLUSIONS: The findings can help to identify more vulnerable patients with unmet needs and a higher demand for support. Assessment of patients enables health care professionals to provide support and counselling. In these assessments, the patients' relationship to close relatives should also be addressed. PMID- 22449716 TI - Coadministration of 5% glucose solution has a decrease in bendamustine-related vascular pain grade. PMID- 22449718 TI - The non-genomic rapid acidification in peripheral T cells by progesterone depends on intracellular calcium increase and not on Na+/H+-exchange inhibition. AB - Progesterone is an endogenous immunomodulator that is able to suppress T cell activation during pregnancy. An increased intracellular free calcium concentration ([Ca(2+)](i)), acidification, and an inhibition of Na(+)/H(+) exchange 1 (NHE1) are associated with this progesterone rapid non-genomic response that involves plasma membrane sites. Such acidification, when induced by phytohemagglutinin, is calcium dependent in PKC down-regulated T cells. We investigated the relationship between this rapid response involving the [Ca(2+)](i) increase and various membrane progesterone receptors (mPRs). In addition, we explored whether the induction of acidification in T cells by progesterone is a direct result of the [Ca(2+)](i) increase. The results show that the intracellular calcium elevation caused by progesterone is inhibited by SKF96365, U73122, and 2-APB, but not by pertussis toxin or U73343. The elevation is enhanced by the protein tyrosine kinase inhibitor staurosporine and the protein kinase C inhibitors Ro318220 and Go6983. These findings suggest that progesterone does not stimulate the [Ca(2+)](i) increase via the Gi coupled mPR(alpha). Furthermore, progesterone-induced acidification was found to be dependent on Ca(2+) entry and blocked by the inorganic channel blocker, Ni(2+). However, BAPTA, an intracellular calcium chelator, was found to prevent progesterone-induced acidification but not the inhibition of NHE1. This implies that acidification by progesterone is a direct result of the [Ca(2+)](i) increase and does not directly involve NHE1. Taken together, further investigations are needed to explore whether one or more mPRs or PGRMC1 are involved in bringing about the T cell rapid response that results in the [Ca(2+)](i) increase and inhibition of NHE1. PMID- 22449719 TI - Translating standards into practice - one Semantic Web API for Gene Expression. AB - Sharing and describing experimental results unambiguously with sufficient detail to enable replication of results is a fundamental tenet of scientific research. In today's cluttered world of "-omics" sciences, data standards and standardized use of terminologies and ontologies for biomedical informatics play an important role in reporting high-throughput experiment results in formats that can be interpreted by both researchers and analytical tools. Increasing adoption of Semantic Web and Linked Data technologies for the integration of heterogeneous and distributed health care and life sciences (HCLSs) datasets has made the reuse of standards even more pressing; dynamic semantic query federation can be used for integrative bioinformatics when ontologies and identifiers are reused across data instances. We present here a methodology to integrate the results and experimental context of three different representations of microarray-based transcriptomic experiments: the Gene Expression Atlas, the W3C BioRDF task force approach to reporting Provenance of Microarray Experiments, and the HSCI blood genomics project. Our approach does not attempt to improve the expressivity of existing standards for genomics but, instead, to enable integration of existing datasets published from microarray-based transcriptomic experiments. SPARQL Construct is used to create a posteriori mappings of concepts and properties and linking rules that match entities based on query constraints. We discuss how our integrative approach can encourage reuse of the Experimental Factor Ontology (EFO) and the Ontology for Biomedical Investigations (OBIs) for the reporting of experimental context and results of gene expression studies. PMID- 22449720 TI - Lexical patterns, features and knowledge resources for coreference resolution in clinical notes. AB - Generation of entity coreference chains provides a means to extract linked narrative events from clinical notes, but despite being a well-researched topic in natural language processing, general-purpose coreference tools perform poorly on clinical texts. This paper presents a knowledge-centric and pattern-based approach to resolving coreference across a wide variety of clinical records from two corpora (Ontology Development and Information Extraction (ODIE) and i2b2/VA), and describes a method for generating coreference chains using progressively pruned linked lists that reduces the search space and facilitates evaluation by a number of metrics. Independent evaluation results give an F-measure for each corpus of 79.2% and 87.5%, respectively. A baseline of blind coreference of mentions of the same class gives F-measures of 65.3% and 51.9% respectively. For the ODIE corpus, recall is significantly improved over the baseline (p<0.05) but overall there was no statistically significant improvement in F-measure (p>0.05). For the i2b2/VA corpus, recall, precision, and F-measure are significantly improved over the baseline (p<0.05). Overall, our approach offers performance at least as good as human annotators and greatly increased performance over general purpose tools. The system uses a number of open-source components that are available to download. PMID- 22449721 TI - Patterns of [PSI (+) ] aggregation allow insights into cellular organization of yeast prion aggregates. AB - The yeast prion phenomenon is very widespread and mounting evidence suggests that it has an impact on cellular regulatory mechanisms related to phenotypic responses to changing environments. Studying the aggregation patterns of prion amyloids during different stages of the prion life cycle is a first key step to understand major principles of how and where cells generate, organize and turn over prion aggregates. The induction of the [PSI (+) ] state involves the actin cytoskeleton and quality control compartments such as the Insoluble Protein Deposit (IPOD). An initially unstable transitional induction state can be visualized by overexpression of the prion determinant and displays characteristic large ring- and ribbon-shaped aggregates consisting of poorly fragmented bundles of very long prion fibrils. In the mature prion state, the aggregation pattern is characterized by highly fragmented, shorter prion fibrils that form aggregates, which can be visualized through tagging with fluorescent proteins. The number of aggregates formed varies, ranging from a single large aggregate at the IPOD to multiple smaller ones, depending on several parameters discussed. Aggregate units below the resolution of light microscopy that are detectable by fluorescence correlation spectroscopy are in equilibrium with larger aggregates in this stage and can mediate faithful inheritance of the prion state. Loss of the prion state is often characterized by reduced fragmentation of prion fibrils and fewer, larger aggregates. PMID- 22449722 TI - Meta-analytic comparison of randomized and nonrandomized studies of breast cancer surgery. AB - BACKGROUND: Randomized controlled trials (RCTs) are thought to provide the most accurate estimation of "true" treatment effect. The relative quality of effect estimates derived from nonrandomized studies (nRCTs) remains unclear, particularly in surgery, where the obstacles to performing high-quality RCTs are compounded. We performed a meta-analysis of effect estimates of RCTs comparing surgical procedures for breast cancer relative to those of corresponding nRCTs. METHODS: English-language RCTs of breast cancer treatment in human patients published from 2003 to 2008 were identified in MEDLINE, EMBASE and Cochrane databases. We identified nRCTs using the National Library of Medicine's "related articles" function and reference lists. Two reviewers conducted all steps of study selection. We included studies comparing 2 surgical arms for the treatment of breast cancer. Information on treatment efficacy estimates, expressed as relative risk (RR) for outcomes of interest in both the RCTs and nRCTs was extracted. RESULTS: We identified 12 RCTs representing 10 topic/outcome combinations with comparable nRCTs. On visual inspection, 4 of 10 outcomes showed substantial differences in summary RR. The pooled RR estimates for RCTs versus nRCTs differed more than 2-fold in 2 of 10 outcomes and failed to demonstrate consistency of statistical differences in 3 of 10 cases. A statistically significant difference, as assessed by the z score, was not detected for any of the outcomes. CONCLUSION: Randomized controlled trials comparing surgical procedures for breast cancer may demonstrate clinically relevant differences in effect estimates in 20%-40% of cases relative to those generated by nRCTs, depending on which metric is used. PMID- 22449723 TI - Safety of thyroidectomy and cervical neck dissection without drains. AB - BACKGROUND: Many studies have reported that drainage after thyroidectomy does not decrease the rate of local postoperative complications. We sought to review the safety of thyroidectomy combined with cervical neck dissection (CND) without drainage. METHODS: The medical records of consecutive patients who underwent thyroidectomy without drainage were retrospectively reviewed. Two groups were defined depending on whether CND was or was not performed. The main outcome was identification of patients with cervical bleeding, hematoma or seroma. RESULTS: We included 1127 patients (139 who had CND and 988 who did not). Of these, 207 patients (18%) had transient postoperative hypocalcemia, 9 (0.8%) had permanent postoperative hypoparathyroidism, 56 (5%) had transient postoperative hoarseness and 7 (0.6%) had permanent vocal cord paralysis. A total of 44 patients (4%) experienced postoperative hematoma and/or seroma: 8 patients (6%) who had CND and 36 (4%) who did not. There was no major bleeding in the 2 groups; all patients had minor bleeding or seroma not requiring surgical intervention. The postoperative stay in hospital for both groups was 1 day in 92% of patients. Wound infection occurred in 0.8% of all patients: 1 (0.7%) who had CND and 8 (0.8%) who did not. There was no significant difference between the groups in overall perioperative complications or in time of hospital discharge. CONCLUSION: Thyroidectomy without drains is safe and effective, even in combination with CND. PMID- 22449724 TI - Variable impact of complications in general surgery: a prospective cohort study. AB - BACKGROUND: Registering complications is important in surgery, since complications serve as outcome measures and indicators of quality of care. Few studies have addressed the variation in severity and consequences of complications. We hypothesized that complications show much variation in consequences and severity. METHODS: We conducted a prospective observational cohort study to evaluate consequences and severity of complications in surgical practice. All recorded complications of patients admitted to our hospital between June 1, 2005, and Dec. 31, 2007, were prospectively recorded in an electronic database. Complications were classified according to the system of the Trauma Registry of the American College of Surgeons. We graded the severity of complications according to the system proposed by Clavien and colleagues, and the consequences of each complication were registered. RESULTS: During the study period, 3418 complications were recorded; consequences and severity were recorded in 89% of them. Of 3026 complications, 987 (33%) were grade I, 781 (26%) were grade IIa, 1020 (34%) were grade IIb, 150 (5%) were grade III and 88 (3%) were grade IV. The consequences and severity of identically registered complications showed a large degree of variation, best illustrated by wound infections, which were grade I in 50%, grade IIa in 22%, grade IIb in 28% and grade III and IV in 0.3% of patients. CONCLUSION: Severity should be routinely presented when reporting complications in clinical practice and surgical research papers to adequately compare quality of care and results of clinical trials. PMID- 22449725 TI - The dietary flavonoid luteolin inhibits Aurora B kinase activity and blocks proliferation of cancer cells. AB - In human, Aurora B is a chromosomal passenger protein that induces phosphorylation of histone and involves in spindle checkpoint and cytokinesis. Aberrant expression of Aurora B has been shown to correlate with genetic instability and carcinogenesis. In the past, Aurora B has been validated as a drug target by several studies. Here we report that the dietary flavonoid luteolin could inhibit recombinant Aurora B in radiometric activity assay (IC(50)=0.357 MUM) and bind to Aurora B with a high affinity (K(D)=5.85 MUM) measured by Biacore 3000. Dose-dependent down-regulation of phosphorylation on Ser10 of histone H3 was also observed in cancer cell lines after 24-h treatment, indicating that endogenous Aurora B activity was inhibited by luteolin. Furthermore, we evaluated the effects of luteolin on the survival of a panel of 23 cell lines, and found that luteolin blocked growth of HeLa cells and SW620 cells in an 8-day cell proliferation assay as well as in colony formation assay. Thus, we identified Aurora B as a novel direct target of luteolin, and our results demonstrated that targeting Aurora B by natural products may be a feasible strategy to develop low toxic anticancer agents. PMID- 22449726 TI - Hydroxysafflor yellow A induces apoptosis in activated hepatic stellate cells through ERK1/2 pathway in vitro. AB - A key feature in the molecular pathogenesis of liver fibrosis requires maintenance of the activated hepatic stellate cells (HSCs) phenotype by inhibition of apoptosis. The induction of apoptosis in activated HSCs has been proposed as an antifibrotic treatment strategy. This study aims at evaluating the effect of hydroxysafflor yellow A (HSYA) on apoptosis of culture-activated HSCs and further elucidating the underlying mechanisms. Primary HSCs were isolated from rats. The analysis of the cell cycle be performed by flow cytometry, detection of apoptosis by Annexin V-FITC/ PI staining, and the results were confirmed by DNA fragmentation, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). Real-time polymerase chain reaction and Western blotting were used to analyze the expression of genes. Our results revealed that HSYA significantly induced apoptosis in a dose- and time-dependent manner. HSYA suppresses the activation of ERK1/2 and ERK1/2-regulated gene expression, including Bcl-2, Cytochrome c, caspase-9, and caspase-3, leading to the enhancement of apoptosis. Pharmacological blockade of ERK1/2 kinase abrogation this action of HSYA. Our data provide a molecular basis for the anti-hepatic fibrosis activity of HSYA. PMID- 22449727 TI - High frequency oscillations in the intact brain. AB - High frequency oscillations (HFOs) constitute a novel trend in neurophysiology that is fascinating neuroscientists in general, and epileptologists in particular. But what are HFOs? What is the frequency range of HFOs? Are there different types of HFOs, physiological and pathological? How are HFOs generated? Can HFOs represent temporal codes for cognitive processes? These questions are pressing and this symposium volume attempts to give constructive answers. As a prelude to this exciting discussion, we summarize the physiological high frequency patterns in the intact brain, concentrating mainly on hippocampal patterns, where the mechanisms of high frequency oscillations are perhaps best understood. PMID- 22449728 TI - Comparison of the Adult Comorbidity Evaluation 27 and the Charlson Comorbidity indices in patients with laryngeal squamous cell carcinoma. AB - OBJECTIVE: This study aimed to compare the prognostic impact of comorbidity grading by the Adult Comorbidity Evaluation 27 index and the Charlson Comorbidity Index on the five-year overall and disease-specific survival in patients undergoing surgery for laryngeal squamous cell carcinoma. METHODS: The impact of comorbidity and other factors on survival was examined retrospectively in a group of 177 patients with previously untreated tumour stage one to four laryngeal squamous cell carcinoma surgically treated at the Clinic of Otorhinolaryngology and Maxillofacial Surgery, Clinical Centre of Serbia, between 2000 and 2003. The Cox proportional hazard model was used to identify independent prognostic factors. RESULTS: On univariate analysis, comorbidity had an impact on prognosis regardless of which index was used. On multivariate analysis, the significant predictors of patients' five-year overall and disease-specific survival were tumour-node-metastasis stage and comorbidity as graded by the Adult Comorbidity Evaluation 27 index. CONCLUSION: The Adult Comorbidity Evaluation 27 index is a more reliable predictor of survival than the Charlson Comorbidity Index in patients with laryngeal squamous cell carcinoma. PMID- 22449730 TI - The addition of Sunitinib to radiation delays tumor growth in a murine model of glioblastoma. AB - OBJECTIVES: Recent preclinical studies suggest that treating glioblastoma (GBM) with a combination of targeted chemotherapy and radiotherapy may enhance the anti tumor effects of both therapies. However, the effects of these treatments on glioma growth and progression are poorly understood. METHODS: In this study, we have tested the effects of combination therapy in a mouse glioma model that utilizes a PDGF-IRES-Cre-expressing retrovirus to infect adult glial progenitors in mice carrying conditional deletions of Pten and p53. This model produces tumors with the histological features of GBM with 100% penetrance, making it a powerful system to test novel treatments. Sunitinib is an orally active, small molecule inhibitor of multiple receptor tyrosine kinases critical for tumor growth and angiogenesis, including PDGF receptors. We investigate the addition of Sunitinib to radiotherapy, and use bioluminescence imaging to characterize the effects of treatment on glioma growth and progression. RESULTS: Treating our PDGF driven mouse model with either Sunitinib or high-dose radiation alone delayed tumor growth and had a modest but significant effect on survival, while treating with low-dose radiation alone failed to control glioma growth and progression. The addition of Sunitinib to low-dose radiation caused a modest, but significant delay in tumor growth. However, no significant survival benefit was seen as tumors progressed in 100% of animals. Histological analysis revealed a reduction in vascular proliferation and a marked increase in brain invasion. An additional study combining Sunitinib with high-dose radiation revealed a fatal toxicity despite individual monotherapies being well tolerated. DISCUSSION: These results show that the addition of Sunitinib to radiotherapy fails to significantly alter survival in GBM despite enhancement of the effects of radiation. Furthermore, an enhanced risk of toxicity associated with combined therapy must be considered in the design of future clinical studies. PMID- 22449731 TI - Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases. AB - BACKGROUND: The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown. PATIENTS AND METHODS: A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out. RESULTS: In the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was ?363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort. CONCLUSIONS: In this population of breast cancer patients with isolated tumor cells or micrometastases, ?36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis. PMID- 22449732 TI - Alcohol drinking and epithelial ovarian cancer risk. a systematic review and meta analysis. AB - OBJECTIVE: In order to provide an updated quantification of the association between alcohol drinking and epithelial ovarian cancer risk, we conducted a meta analysis of published observational studies. METHODS: Using PubMed, we performed a literature search of all case-control and cohort studies published as original articles in English up to September 2011. We included 27 observational studies, of which 23 were case-control studies, 3 cohort studies and one pooled analysis of prospective cohort studies, including a total of 16,554 epithelial ovarian cancer cases. We derived pooled meta-analytic estimates using random-effects models. RESULTS: The pooled relative risk (RR) for any alcohol drinking compared with non/occasional drinking was 1.00 [95% confidence interval (CI), 0.95-1.05]. The RRs were 0.97 (95% CI, 0.92-1.02), 1.03 (95% CI, 0.96-1.11) and 1.09 (95% CI, 0.80-1.50) for light (<= 1 drink/day), moderate (>1 to <3 drinks) and heavy drinking (>= 3 drinks/day), respectively. In particular, the pooled RR for invasive epithelial ovarian cancers was 1.00 (95% CI, 0.95-1.06), while for borderline cancers was 0.96 (95% CI, 0.74-1.26). Stratified analyses across cancer histotypes revealed a modest protective effect of alcohol on endometrioid epithelial ovarian tumors (RR=0.82, 95% CI, 0.70-0.96), while no association was found for serous (RR=1.00, 95% CI, 0.84-1.19), mucinous (RR=0.91, 95% CI, 0.78 1.08) and clear cell (RR=0.93, 95% CI, 0.76-1.14) cancers. There was no evidence of publication bias. CONCLUSIONS: This comprehensive meta-analysis provided no evidence of a material association between alcohol drinking and epithelial ovarian cancer risk. PMID- 22449733 TI - Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy. AB - OBJECTIVE: To determine factors associated with resistance to methotrexate treatment of low-risk gestational trophoblastic neoplasia (GTN). METHODS: We reviewed the records of 358 patients with low-risk GTN (FIGO stage I and stages II-III, score<7) treated initially with methotrexate 0.4 mg/kg (max 25mg) IV push daily * 5 days every 14 days between 1979 and 2009. Actinomycin D 0.5mg IV push daily * 5 days every 14 days was used in 64 patients who developed resistance or toxicity to initial methotrexate chemotherapy, and combination drug regimens were used in 20 patients who failed single-agent chemotherapy. Adjuvant surgery was used in 34 selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS: The complete response rate to initial methotrexate chemotherapy was 81% (290/358) and the complete response rate to actinomycin D as secondary therapy was 75% (48/64), for an overall complete response rate to sequential single-agent chemotherapy of 94% (338/358). The remaining 20 patients (6%) were all placed into permanent remission with the use of multiagent chemotherapy with or without surgery. Resistance to initial methotrexate chemotherapy was associated with increasing FIGO score (p<.0001), clinicopathologic diagnosis of choriocarcinoma (p=.028), higher pretreatment hCG (p=0.001) and presence of metastatic, disease (p=.018). CONCLUSIONS: Sequential single-agent chemotherapy with methotrexate (0.4 mg/kg max 25mg) followed by actinomycin D (0.5mg) each given IV push for 5 consecutive days every other week for treatment of low-risk GTN resulted in only 6% of patients requiring multiagent chemotherapy and a 100% survival rate. PMID- 22449734 TI - Re: "Pelvic exenteration with curative intent for recurrent uterine malignancies". PMID- 22449735 TI - External validation of a nomogram predicting overall survival of patients diagnosed with endometrial cancer. AB - OBJECTIVES: Nomograms are predictive models that provide the overall probability of a specific outcome. Nomograms have shown better individual discrimination than currently used staging systems in numerous tumor entities. Recently, a nomogram for predicting overall survival (OS) in women with endometrial cancer was introduced by Memorial Sloan-Kettering Cancer Center (MSKCC). The aim of this study was to test the validity of the MSKCC endometrial cancer nomogram using an independent, external patient cohort. METHODS: The MSKCC nomogram is based on five readily available clinical characteristics. A multi-institutional endometrial cancer database was used to test the nomogram's validity. All consecutive patients treated for endometrial cancer between December 1995 and May 2011 and who had all nomogram variables documented were identified for analysis. RESULTS: Seven hundred sixty-five eligible patients were identified and used for external validation analysis. In the Austrian patient cohort, median OS was 134 months, and 3-year and 5-year OS rates were 83.8% (95% CI, 80.6-86.5%) and 77.2% (95% CI, 43.5-80.5%), respectively. The nomogram concordance index was 0.71 (SE=0.017; 95% CI, 0.68-0.74). The correspondence between the actual OS and the nomogram predictions suggests a good calibration of the nomogram in the validation cohort. CONCLUSION: The MSKCC endometrial cancer nomogram was externally validated and was shown to be generalizable to a new and independent patient population. The nomogram provides a more individualized and accurate estimation of OS for patients diagnosed with endometrial cancer following primary therapy. The nomogram can be used for counseling patients more accurately and for better stratifying patients for clinical trials. PMID- 22449736 TI - Insulin resistance: a significant risk factor of endometrial cancer. AB - OBJECTIVE: To review the role played by insulin resistance in the development of endometrial cancer. METHODS: Relevant manuscripts and studies were searched on Medline using the terms endometrial cancer, insulin resistance, obesity, adipokine, C-peptide, leptin, adiponectin, plasminogen activator inhibitor-1, insulin, PI3K/Akt, Ras/MAPK and metformin alone or in combination. RESULTS: Epidemiological studies have shown that insulin resistance is an important potential risk factor of endometrial cancer, and several research studies have been undertaken to determine the mechanism underlying its link to this malignant disease. Risk factors of insulin resistance, such as the inflammatory mediators, adipokines adiponectin, leptin and plasminogen activator inhibitor-1 and excessive androgen are also risk factors of endometrial cancer. High levels of insulin induced by insulin resistance have been found to exert direct and indirect effects that contribute to the development of endometrial cancer. Insulin directly promotes cell proliferation and survival through the PI3K/Akt and Ras/MAPK pathways. Moreover, the network among insulin, estrogen and insulin like growth factor-1 also contributes to the development of endometrial cancer. Indirectly, insulin leads to changes in sex hormone levels, including increases in the levels of estrogen. Additionally, a small number of studies suggested that metformin, an insulin-sensitizing agent, has therapeutic potential for endometrial cancer. CONCLUSIONS: This evidence suggests that insulin resistance plays a central role in endometrial cancer development. Understanding the relationship between insulin resistance and endometrial cancer may supply new ideas to fight this malignancy. Furthermore, combating insulin resistance may be a useful preventive and therapeutic strategy for endometrial cancer. PMID- 22449737 TI - Refractory inappropriate sinus tachycardia successfully treated with radiofrequency ablation at the arcuate ridge. AB - Supraventricular tachycardias similar to sinus rhythm are difficult to evaluate and treat with catheter ablation. In addition to inappropriate sinus tachycardia (IST), curative ablation of atrial tachycardia arising from the crista terminalis is well described. We report the case of a 48-year-old woman with multiple failed ablation attempts for IST successfully ablated on the arcuate ridge. Ultrasound and fluoroscopy-guided mapping and ablation of this specific endocavitary anatomic site may be helpful in certain patients with the diagnosis of IST. PMID- 22449739 TI - Early repolarization and short QT interval in healthy subjects. AB - BACKGROUND: An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear. OBJECTIVE: The purpose of this study was to study the prevalence of ER and its morphological variants, and its association with the QTc interval in healthy subjects. METHODS: Digital ECGs from 1886 healthy subjects from Phase I clinical trials were analyzed by a central ECG laboratory. RESULTS: ER, defined as J-point elevation >=0.1 mV in >=2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V(4)-V(6)) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 +/- 13.3 bpm [mean difference +/- SD], P <.001) and shorter QTc intervals (QTcB = 20.2 +/- 25.6 ms, QTcF = 11.0 +/- 21.9 ms; P <.001). Four subjects in each group had a short QT interval (QTcF <350 ms). CONCLUSION: ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF <350 ms) is rare. PMID- 22449740 TI - Does atrial fibrillation burden measured by continuous monitoring during the blanking period predict the response to ablation at 12-month follow-up? AB - BACKGROUND: Recurrences are common within the first months following atrial fibrillation (AF) ablation. However, prior studies using only intermittent ECG recording have not shown a powerful correlation with ultimate response. OBJECTIVE: The purpose of this study was to use continuous AF monitoring with an implanted monitor to assess the AF burden measured continuously during the first months postablation and the relationship to subsequent AF recurrences. METHODS: Six hundred thirteen patients with symptomatic drug-refractory AF (17% with persistent AF) were part of this retrospective analysis. All patients underwent circumferential pulmonary vein isolation and were implanted with a subcutaneous AF monitor (Reveal XT, Medtronic) for collecting data on AF burden (AF%) during a 12-month follow-up period. AF freedom (responders) was defined as AF% <=0.5% during each monthly telemetric follow-up. A receiver operating characteristic curve analysis was performed to identify the value in AF% during the first months in the postablation blanking period that was predictive of later recurrence of AF. Sensitivity of 90% was selected as the target value. RESULTS: After the first ablation procedure, 396 of the 613 patients (65%) were responders (AF <=0.5%) at 12 months: 346 of 508 (68%) in the paroxysmal AF group and 50 of 105 (47%) in the persistent AF group. Using the receiver operating characteristic curve, the specificity corresponding to 90% sensitivity was 85% for AF% at 2 months. The corresponding threshold in the AF burden during the blanking period able to identify patients at risk for late recurrences was 4.5%, corresponding to a cumulative 65.9 hours (2.75 days) spent in AF during the first 2 months. In a multivariate analysis, AF% <4.5% during the first 2 months was highly significant (P <.001), and the odds ratio of responders/nonresponders was 39.8 (95% CI, 19.1 82.9). CONCLUSION: The AF burden measured during the blanking period can predict the response to catheter ablation at 12 months. AF% >=4.5% at 2 months assessed by continuous monitoring is a powerful predictor of subsequent AF recurrences after initial ablation, thus providing relevant clinical information to select patients for early reintervention. PMID- 22449741 TI - Deaths caused by the failure of Riata and Riata ST implantable cardioverter defibrillator leads. AB - BACKGROUND: Riata and Riata ST leads (St Jude Medical, Sylmar, CA) were recalled in 2011. These leads are prone to externalized conductors. However, it is electrical malfunctions that may result in serious adverse events, including death. OBJECTIVE: To assess the deaths of patients with Riata and Riata ST leads that have been reported to the Food and Drug Administration to determine whether they were due to lead malfunction. A similar analysis was performed for Quattro Secure leads (Medtronic, Inc, Minneapolis, MN). METHODS: In February 2012, we searched the Food and Drug Administration's Manufacturers and User Facility Device Experience database for deaths associated with Riata, Riata ST, and Quattro Secure leads. A lead-related death was a sudden or unexpected death accompanied by evidence of lead malfunction; an indeterminate death was a death that was nonsudden or evidence of lead malfunction was not provided; a not lead related death was a death that was nonsudden and/or there was no evidence that the lead contributed to the patient's demise. RESULTS: The Manufacturers and User Facility Device Experience database search found 133 deaths; of these, 22 were caused by Riata or Riata ST lead failure and 5 were caused by Quattro Secure lead failure. Riata and Riata ST lead failure deaths were typically caused by short circuits between high-voltage components. No death was due to externalized conductors. CONCLUSIONS: Riata and Riata ST implantable cardioverter defibrillator leads are prone to high-voltage failures that have resulted in death. These failures appeared to have been caused by insulation defects that resulted in short circuiting between high-voltage components. Externalized conductors were not a factor in these deaths. PMID- 22449742 TI - High prevalence of insulation failure with externalized cables in St. Jude Medical Riata family ICD leads: fluoroscopic grading scale and correlation to extracted leads. AB - BACKGROUND: Inside-out abrasion with externalization of sensing ring or high voltage cables in St Jude Medical Riata implantable cardioverter-defibrillator leads has been reported. The prevalence of extruded cables, rate of electrical abnormalities, and predictors of failure in Riata leads are unknown. OBJECTIVES: To estimate the incidence of lead failure in the St Jude Medical Riata implantable cardioverter-defibrillator leads and to propose a standard for the fluoroscopic assessment of insulation breakdown. METHODS: Patients undergoing cine-fluoroscopy on Riata implantable cardioverter-defibrillator leads at our institution before January 25, 2012, were included (n = 87). Leads were graded as types 0-3 (0 = normal, 1 = abnormal conductor spacing, 2 <=1 cm cable extrusion, 3 = >1 cm length extrusion). Comparison to extracted leads (n = 15) was documented. Device interrogation data were used for electrical analysis. RESULTS: The mean time from implant was 5.9 +/- 3.45 years. Structural lead failure with externalized cables was seen in 33.3% (29 of 87) of the patients. Thirty-one percent (9 of 29) of the leads with exposed cables showed electrical failure, and 29.7% (19 of 64) of the leads with normal electrical data contained externalized cables. Time from implant >=5 years predicted structural lead failure (P < 0.05). X-ray grade compared with extracted leads demonstrated a sensitivity and specificity of 86% and 100%, respectively. CONCLUSIONS: Cine-fluoroscopy using a simple scale correlated with the structural integrity of extracted Riata leads. A high percentage of leads with extrusion showed electrical failure. Leads >=5 years from implant showed a high rate of externalized cables. A large independent multicenter study to determine the prevalence and clinical sequelae of Riata lead failures is warranted. PMID- 22449743 TI - Focal cortical myoclonus in rolandic cortical dysplasia presenting as hemifacial twitching. AB - A 2-year-old girl presented with brief episodes of left hemifacial twitching. On ictal electroencephalography, repetitive focal spike discharges appeared at the right fronto-centro-temporal regions; these discharges preceded the onset of each twitch by 12 ms. Magnetic resonance imaging showed a linear abnormal signal intensity in the subcortical white matter at the right postcentral gyrus, where a cluster of dipole sources was detected by magnetoencephalography. These findings suggested that the patient had focal cortical myoclonus due to rolandic focal cortical dysplasia. PMID- 22449744 TI - Lateral medullary syndrome in a boy with hereditary dysfibrinogenemia. AB - A 9-year-old boy presented with sudden onset of nausea, vomiting and unsteady gait after a bread-eating game, which possibly caused neck hyperextension. Neurological examination revealed hemisensory loss of pain and temperature sensation in the right trunk and limbs along with left Horner's syndrome, suggesting lateral medullary syndrome (LMS). Magnetic resonance (MR) imaging of the brain revealed infarction at the left lateral medulla. MR angiography showed no sign of arterial dissection and no occlusion or stenosis of the intracranial, basilar or vertebral arteries or their branches. No evidence of cardioemboli or systemic inflammation was apparent. Repeated blood examination revealed low activity of fibrinogen. Genetic testing confirmed the presence of hereditary dysfibrinogenemia with a mutation in the FGB gene (BbetaGly15Cys). This fibrinogen variant has previously been found in Japanese patients with atherosclerosis obliterans or no symptoms. Under conservative treatment without anticoagulation and aspirin, the patient made a good recovery within a few months. We presume that microthrombosis may have been deposited within the vertebral system as a result of extension and rotation of the neck during sports activity, with a contribution from hereditary dysfibrinogenemia. PMID- 22449745 TI - Genetic transformation of Pseudochoricystis ellipsoidea, an aliphatic hydrocarbon producing green alga. AB - Pseudochoricystis ellipsoidea is a recently isolated unicellular green alga, which is classified within the family Trebouxiophyceae. This alga has a unique ability to synthesize and accumulate intracellularly a significant amount of aliphatic hydrocarbons. To elucidate molecular mechanisms of the hydrocarbon production in this organism, the development of genetic methods including DNA transformation methods are important. Towards the goal, we constructed several plasmids in which neomycin phosphotransferase II-encoding G418-resistant gene (nptII) is flanked by a P. ellipsoidea-derived promoter and terminator. These plasmids were introduced into P. ellipsoidea cells through particle-gun bombardment, and transformants were screened among G418-resistant cells by PCR amplification of plasmid-borne genes. Southern blot analysis demonstrated that the exogenous DNA was integrated into the genome of the transformants. Furthermore, the expression of nptII was confirmed at the transcript and protein levels by RT-PCR and immunoblot analyses, respectively. These results clearly indicated that a genetic transformation system was successfully established for P. ellipsoidea. PMID- 22449746 TI - Purification and characterization of two phospho-beta-galactosidases, LacG1 and LacG2, from Lactobacillus gasseri ATCC33323(T). AB - Lactobacillus gasseri ATCC33323(T) expresses four enzymes showing phospho-beta galactosidase activity (LacG1, LacG2, Pbg1 and Pbg2). We previously reported the purification and characterization of two phospho-beta-galactosidases (Pbg1 and Pbg2) from Lactobacillus gasseri JCM1031 cultured in lactose medium. Here we aimed to characterize LacG1 and LacG2, and classify the four enzymes into 'phospho-beta-galactosidase' or 'phospho-beta-glucosidase.' LacG1 and recombinant LacG2 (rLacG2), from Lb. gasseri ATCC33323(T), were purified to homogeneity using column chromatography. Kinetic experiments were performed using sugar substrates, o-nitrophenyl-beta-D-galactopyranoside 6-phosphate (ONPGal-6P) and o-nitrophenyl beta-D-glucopyranoside 6-phosphate (ONPGlc-6P), synthesized in our laboratory. LacG1 and rLacG2 exhibited high k(cat)/K(m) values for ONPGal-6P as compared with Pbg1 and Pbg2. The V(max) values for ONPGal-6P were higher than phospho-beta galactosidases previously purified and characterized from several lactic acid bacteria. A phylogenetic tree analysis showed that LacG1 and LacG2 belong to the phospho-beta-galactosidase cluster and Pbg1 and Pbg2 belong to the phospho-beta glucosidase cluster. Our data suggest two phospho-beta-galactosidase, LacG1 and LacG2, are the primary enzymes for lactose utilization in Lb. gasseri ATCC33323(T). We propose a reclassification of Pbg1 and Pbg2 as phospho-beta glucosidase. PMID- 22449747 TI - Isolation and application of Gordonia sp. JC11 for removal of boat lubricants. AB - Boat lubricants are continuously released into the marine environment and thereby cause chronic oil pollution. This study aims to isolate lubricant-degrading microorganisms from Thai coastal areas as well as to apply a selected strain for removal of boat lubricants. Ten microorganisms in the genera of Gordonia, Microbacterium, Acinetobacter, Pseudomonas, Brucella, Enterococcus and Candida were initially isolated by crude oil enrichment culture techniques. The lubricant removal activity of these isolates was investigated with mineral-based lubricants that had been manufactured for the 4-stroke diesel engines of fishing boats. Gordonia sp. JC11, the most effective strain was able to degrade 25-55% of 1,000 mg L(-1) total hydrocarbons in six tested lubricants, while only 0-15% of the lubricants was abiotically removed. The bacterium had many characteristics that promoted lubricant degradation such as hydrocarbon utilization ability, emulsification activity and cell surface hydrophobicity. For bioaugmentation treatment of lubricant contaminated seawater, the inoculum of Gordonia sp. JC11 was prepared by immobilizing the bacterium on polyurethane foam (PUF). PUF immobilized Gordonia sp. JC11 was able to remove 42-56% of 100-1,000 mg L(-1) waste lubricant No. 2 within 5 days. This lubricant removal efficiency was higher than those of free cells and PUF without bacterial cells. The bioaugmentation treatment significantly increased the number of lubricant-degrading microorganisms in the fishery port seawater microcosm and resulted in rapid removal of waste lubricant No. 2. PMID- 22449748 TI - Identification and characterization of filamentous fungi isolated from fermentation starters for Hong Qu glutinous rice wine brewing. AB - Hong Qu glutinous rice wine is one of the most popular traditional rice wines in China. Traditionally, this wine is brewed from glutinous rice with the addition of wine fermentation starters (Hong Qu (also called red yeast rice) and White Qu). The objective of this study was to investigate the variability of filamentous fungi associated with traditional fermentation starters through a traditional culture-dependent method and a molecular identification approach. In this study, forty-three filamentous fungi were separated by traditional culture dependent means (macro- and microscopic characteristics) from 10 fermentation starters and classified into 16 different species based on morphological examination and the internal transcribed spacer (ITS) sequences analysis. It was observed that the genus Aspergillus had the highest number (14 isolates) of isolates followed by Rhizopus (11 isolates), Monascus (5 isolates) and Penicillium (4 isolates). The species R. oryzae, A. niger, A. flavus and M. purpureus were frequently found in wine starter samples, among which R. oryzae was the most frequent species. The enzyme-producing properties (glucoamylase, alpha-amylase and protease) of all fungal isolates from different starters were also evaluated. A. flavus, R. oryzae and M. purpureus were found to be better glucoamylase producers. A. flavus, R. oryzae and A.oryzae exhibited higher activity of alpha-amylase. A. flavus and A. oryzae had higher protease activity. However, some fungal isolates of the same species exhibited a significant variability in the production levels for all determined enzyme activity. This study is the first to identify filamentous fungi associated with the starter of Hong Qu glutinous rice wine using both traditional and molecular methods. The results enrich our knowledge of liquor-related micro-organisms, and can be used to promote the development of the traditional fermentation technology. PMID- 22449749 TI - Morphology of mitochondrial nucleoids, mitochondria, and nuclei during meiosis and sporulation of the yeast Saccharomycodes ludwigii. AB - The morphology of mitochondrial nucleoids (mt-nucleoids), mitochondria, and nuclei was investigated during meiosis and sporulation of the diploid cells of the ascosporogenic yeast Saccharomycodes ludwigii. The mt-nucleoids appeared as discrete dots uniformly distributed in stationary-phase cells as revealed by 4',6 diamidino-2-phenylindole (DAPI) staining. Throughout first and second meiotic divisions, the mt-nucleoids moved to be located close to the dividing nuclei with the appearance of dots. On the other hand, mitochondria, which had tubular or fragmented forms in stationary-phase cells, increasingly fused with each other to form elongated mitochondria during meiotic prophase as revealed by 3,3' dihexyloxacarbocyanine iodide [DiOC(6)(3)] staining. Mitochondria assembled to be located close to dividing nuclei during first and second meiotic divisions, and were finally incorporated into spores. During the first meiotic division, nuclear division occurred in any direction parallel, diagonally, or perpendicular to the longitudinal axis of the cell. In contrast, the second meiotic division was exclusively parallel to the longitudinal axis of the cell. The behavior of dividing nuclei explains the formation of a pair of spores with opposite mating types at both ends of cells. In the course of this study, it was also found that ledges between two spores were specifically stained with DiOC(6)(3). PMID- 22449750 TI - Identification of growth-dependent transcripts in the haloalkaliphilic archaeon Natrialba magadii. PMID- 22449751 TI - Candida baotianensis sp. nov., an ascomycetous yeast species from forest soil in China. PMID- 22449752 TI - Characterization of a thermostable adenosine 5'-monophosphate deaminase gene in Streptomyces murinus. PMID- 22449753 TI - Cerebrospinal fluid substance P-like immunoreactivity correlates with aggression in personality disordered subjects. AB - BACKGROUND: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters; some seem to play an inhibitory role, whereas others seem to play a facilitory role in the modulation of aggression. Laboratory animal studies of substance P suggest a facilitory role for this undecapeptide in the modulation of aggression, but no studies of substance P have yet been reported with regard to human aggression. METHODS: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with personality disorder (PD) and substance P-like immunoreactivity was measured and correlated with measures of aggression and impulsivity. RESULTS: The cerebrospinal fluid substance P-like immunoreactivity levels were directly correlated with a composite measure of aggression and, more specifically, with Buss-Durkee Aggression. No correlation was seen with any measure of impulsivity or of general dimensions of personality. CONCLUSIONS: These data suggest a direct relationship between central nervous system substance P containing neural circuits and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of impulsive aggression in human subjects. PMID- 22449754 TI - Naphthoquinone-tyrptophan reduces neurotoxic Abeta*56 levels and improves cognition in Alzheimer's disease animal model. AB - An increasing body of evidence indicates a role for oligomers of the amyloid-beta peptide (Abeta) in the neurotoxicity of this peptide and the pathology of Alzheimer's disease (AD). Several neurotoxic oligomeric forms of Abeta have been noted ranging from the larger Amyloid beta-Derived Diffusible Ligands (ADDLs) to smaller trimers and dimers of Abeta. More recently a dodecameric form of Abeta with a 56 kDa molecular weight, denoted Abeta*56, was shown to cause memory impairment in AD model mice. Here, we present for the first time a potential therapeutic strategy for AD that targets the early stages in the formation of neurotoxic Abeta*56 oligomers using a modified quinone-Tryptophan small molecule N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-L-Tryptophan (Cl-NQTrp). Using NMR spectroscopy we show that this compound binds the aromatic recognition core of Abeta and prevents the formation of oligomers. We assessed the effect of Cl NQTrp in vivo in transgenic flies expressing Abeta(1-42) in their nervous system. When these flies were fed with Cl-NQTrp a marked alleviation of their Abeta engendered reduced life span and defective locomotion was observed. Finally, intraperitoneal injection of Cl-NQTrp into an aggressive AD mouse model reduced the level of the Abeta*56 species in their brain and reversed their cognitive defects. Further experiments should assess whether this is a direct effect of the drug in the brain or an indirect peripheral effect. This is the first demonstration that targeted reduction of Abeta*56 results in amelioration of AD symptoms. This second generation of tryptophan-modified naphthoquinones could therefore serve as potent disease modifying therapeutic for AD. PMID- 22449755 TI - Distinct and complementary roles of papillary and reticular fibroblasts in skin morphogenesis and homeostasis. AB - To study the biological properties of dermal fibroblast sub-populations, we used a reconstructed skin model with a dermal compartment populated with either papillary or reticular fibroblasts. The histological and immunohistological characterization of these reconstructed skins revealed distinct biological and structural differences, depending on the site-matched fibroblast population incorporated. Epidermal differentiation and maturation was favored and found optimum in the presence of papillary fibroblasts with little effect on ECM, as opposed to reticular fibroblasts, which had a significant positive effect on the production of the ECM molecules of the dermal epidermal junction and the dermis. In addition, the synthesis and release of MMPs and soluble factors like VEGF and KGF into the culture medium were influenced by the fibroblast population. MMP1 and VEGF were increased in the presence of papillary fibroblasts, whereas MMP3 and KGF levels were higher in the presence of reticular fibroblasts. Our results suggest that papillary and reticular fibroblasts exert distinct functions and activities in skin as revealed by the reconstructed skin model. These functional differences may have implications in wound healing and skin aging processes, considering the slow loss of papillary fibroblasts in human skin that occurs with age. PMID- 22449756 TI - Nasogastric tube insertion in difficult cases with the aid of a flexible nasendoscope. PMID- 22449757 TI - EOS 2D/3D X-ray imaging system: a systematic review and economic evaluation. AB - BACKGROUND: EOS is a biplane X-ray imaging system manufactured by EOS Imaging (formerly Biospace Med, Paris, France). It uses slot-scanning technology to produce a high-quality image with less irradiation than standard imaging techniques. OBJECTIVE: To determine the clinical effectiveness and cost effectiveness of EOS two-dimensional (2D)/three-dimensional (3D) X-ray imaging system for the evaluation and monitoring of scoliosis and other relevant orthopaedic conditions. DATA SOURCES: For the systematic review of EOS, electronic databases (MEDLINE, Allied and Complementary Medicine Database, BIOSIS Previews, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library, EMBASE, Health Management Information Consortium, Inspec, ISI Science Citation Index and PASCAL), clinical trials registries and the manufacturer's website were searched from 1993 to November 2010. REVIEW METHODS: A systematic review of studies comparing EOS with standard X-ray [film, computed radiography (CR) or digital radiography] in any orthopaedic condition was performed. A narrative synthesis was undertaken. A decision-analytic model was developed to assess the cost-effectiveness of EOS in the relevant indications compared with standard X-ray and incorporated the clinical effectiveness of EOS and the adverse effects of radiation. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the perspective of the NHS. RESULTS: Three studies met the inclusion criteria for the review. Two studies compared EOS with film X-ray and one study compared EOS with CR. The three included studies were small and of limited quality. One study used an earlier version of the technology, the Charpak system. Both studies comparing EOS with film X-ray found image quality to be comparable or better with EOS overall. Radiation dose was considerably lower with EOS: ratio of means for posteroanterior spine was 5.2 (13.1 for the study using the Charpak system); ratio of means for the lateral spine was 6.2 (15.1 for the study using the Charpak system). The study comparing EOS with CR found image quality to be comparable or better with EOS. Radiation dose was considerably lower with EOS than CR; ratio of means for the centre of the back was 5.9 and for the proximal lateral point 8.8. The lowest ratio of means was at the nape of the neck, which was 2.9. No other outcomes were assessed in the included studies, such as implications for patient management from the nature and quality of the image. Patient throughput is the major determinant of the cost-effectiveness of EOS. The average cost per procedure of EOS decreases with utilisation. Using estimates of patient throughput at national level from Hospital Episode Statistics data suggests that EOS is not cost-effective for the indications considered. Throughput in the region of 15,100 to 26,500 (corresponding to a workload of 60 to 106 patient appointments per working day) for EOS compared with a throughput of only 7530 for CR (30 patient appointments per working day) is needed to achieve an incremental cost-effectiveness ratio of L30,000 per QALY. EOS can be shown to be cost-effective only when compared with CR if the utilisation for EOS is about double the utilisation of CR. LIMITATIONS: The main limitation of the systematic review of the clinical effectiveness of EOS was the limited number and quality of the data available. In particular, there were no studies assessing the potential health benefits arising from the quality and nature of the image, over and above those associated with reduced radiation exposure. Uncertainty in the model inputs was not fully explored owing to a lack of reporting of standard deviations or confidence intervals in the published literature for most of the parameters. As a result, uncertainty in the cost-effectiveness results was not presented. CONCLUSIONS: Radiation dose is considerably lower with EOS than standard X-ray, whereas image quality remains comparable or better with EOS. However, the long-term health benefits from reduced radiation exposure with EOS are very small and there was a lack of data on other potential patient health benefits. The implications of any changes in the quality and nature of the EOS image compared with standard X-ray, for patient health outcomes, needs to be assessed. Given the higher cost of an EOS machine, utilisation is the major determinant of cost-effectiveness. Estimates of patient throughput at national level suggest that EOS is not cost-effective. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22449758 TI - Bead-based suspension array for simultaneous detection of antibodies against the Rift Valley fever virus nucleocapsid and Gn glycoprotein. AB - A multiplex bead-based suspension array was developed that can be used for the simultaneous detection of antibodies against the surface glycoprotein Gn and the nucleocapsid protein N of Rift Valley fever virus (RVFV) in various animal species. The N protein and the purified ectodomain of the Gn protein were covalently linked to paramagnetic Luminex beads. The performance of the resulting multiplex immunoassay was evaluated by testing a comprehensive and well characterized panel of sera from sheep, cattle and humans. The suitability of this multiplex immunoassay to differentiate infected from vaccinated animals (DIVA) was investigated by testing sera from lambs vaccinated with a paramyxovirus vaccine vector expressing the RVFV surface glycoproteins Gn and Gc. The results suggest that the bead-based suspension array can be used as a DIVA assay to accompany several recently developed experimental vaccines that are based on RVFV glycoproteins, and are devoid of the N protein. PMID- 22449759 TI - Comparison of the f-HPV typingTM and Hybrid Capture II(r) assays for detection of high-risk HPV genotypes in cervical samples. AB - Human papillomavirus genotyping is being considered in cervical screening programs and for monitoring the effectiveness of HPV vaccination. Both approaches require access to fast, easy and high-throughput technology. The aim of this study was to compare a new commercial assay (f-HPV typingTM) with the Hybrid Capture II(r) (HC2) to detect HPV infection. The F-HPV typing is a multiplex fluorescent PCR method recognizing E6 and E7 regions of 13 high-risk (HR) HPV types, the same set of HR-types targeted HC2 test. A subset of 157 cervical samples was tested with both assays. The percentage of positive HR-HPV DNA samples was 24% (37/155) by HC2 and 33% (49/155) by f-HPV typing. Concordant results were found in 133/155 (overall agreement, 85.8%; Cohen's kappa=0.65). The analytical sensitivity and specificity of f-HPV were 97.6 and 93, respectively. In conclusion, this study shows that the f-HPV assay provides a good alternative to HC2 to detect HPV infection, allowing simple and rapid HPV genotyping and detecting multiple infections. PMID- 22449760 TI - Overexpression of TIMP-1 in embryonic stem cells attenuates adverse cardiac remodeling following myocardial infarction. AB - Transplanted embryonic stem (ES) cells, following myocardial infarction (MI), contribute to limited cardiac repair and regeneration with improved function. Therefore, novel strategies are still needed to understand the effects of genetically modified transplanted stem cells on cardiac remodeling. The present study evaluates whether transplanted mouse ES cells overexpressing TIMP-1, an antiapoptotic and antifibrotic protein, can enhance cardiac myocyte differentiation, inhibit native cardiac myocyte apoptosis, reduce fibrosis, and improve cardiac function in the infarcted myocardium. MI was produced in C57BL/6 mice by coronary artery ligation. TIMP-1-ES cells, ES cells, or culture medium (control) were transplanted into the peri-infarct region of the heart. Immunofluorescence, TUNEL staining, caspase-3 activity, ELISAs, histology, and echocardiography were used to identify newly differentiated cardiac myocytes and assess apoptosis, fibrosis, and heart function. Two weeks post-MI, significantly (p < 0.05) enhanced engraftment and cardiac myocyte differentiation was observed in TIMP-1-ES cell-transplanted hearts compared with hearts transplanted with ES cells and control. Hearts transplanted with TIMP-1-ES cells demonstrated a reduction in apoptosis as well as an increase (p< 0.05) in p-Akt activity compared with ES cells or culture media controls. Infarct size and interstitial and vascular fibrosis were significantly (p< 0.05) decreased in the TIMP-1-ES cell group compared to controls. Furthermore, MMP-9, a key profibrotic protein, was significantly (p < 0.01) reduced following TIMP-1-ES cell transplantation. Echocardiography data showed fractional shortening and ejection fraction were significantly (p< 0.05) improved in the TIMP-1-ES cell group compared with respective controls. Our data suggest that transplanted ES cells overexpressing TIMP-1 attenuate adverse myocardial remodeling and improve cardiac function compared with ES cells that may have therapeutic potential in regenerative medicine. PMID- 22449761 TI - Clinical presentations and diagnostic issues in dual diagnosis disorders. AB - PURPOSE OF REVIEW: The co-occurrence of mental disorders and substance use disorders (SUDs) is very common, and associated with substantial psychiatric morbidity, functional and quality of life impairments, and societal costs. However, dual disorders are often underdetected, misdiagnosed and inadequately treated in both substance abuse and mental health settings. RECENT FINDINGS: Individuals with dual or multiple disorders generally have worse clinical features and long-term outcomes than those with single disorders. However, findings can vary depending on factors such as type(s) of psychiatric disorder(s) and substance(s) involved, and whether the mental disorder is primary or secondary, or substance-induced or independent. Underdiagnosis or misdiagnosis of dual disorders may occur due, in part, to the use of measurement instruments and diagnostic approaches that have uncertain clinical utility. SUMMARY: Routine, thorough, and integrated screening and diagnosis of dual disorders are needed to facilitate implementation of appropriate treatment. Results suggest that forthcoming revisions to the Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases should categorize and define mental and SUDs such that clinicians can more readily detect and diagnose all types of substance use and mental health comorbid conditions. Adoption and widespread use of appropriate screening, assessment and diagnostic instruments, and more thorough diagnostic (clinimetric) approaches are recommended. PMID- 22449762 TI - Genetic factors influencing outcome from neurotrauma. AB - PURPOSE OF REVIEW: Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors. There is converging evidence from genetic research that a number of genetic variants may contribute to this variability. This review provides recent data from human studies, published in the previous year, on genetic factors influencing outcome after neurotrauma. The bibliographic databases MEDLINE, EMBASE and PsycINFO were searched to identify relevant studies. RECENT FINDINGS: Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies. Genetic loci investigated include polymorphisms in APOE, MAO-A, BDNF, NOS3, IL-6, NEFH, SLC6A4, COMT, PPP3CC and KIBRA genes. The importance of these findings and future directions are discussed. SUMMARY: Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity. A better understanding of the underlying biological pathways and molecular mechanisms of an individual's response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome. PMID- 22449763 TI - Epidemiology of comorbid substance use and psychiatric disorders in Asia. AB - PURPOSE OF REVIEW: Studying comorbidities between substance use disorders (SUDs) and psychiatric disorders in different regions is important from public health and heuristic perspectives. In this study we review recent studies conducted in Asian countries on these comorbidities. RECENT FINDINGS: Comprehensive and methodologically sound studies conducted with focus on comorbidity between SUDs and psychiatric disorders are few and far between in Asian countries. Studies differ widely in their focus and methodological rigor. Some studies from China, Japan and Taiwan report fairly low rates of comorbidity of SUDs, particularly with illicit substances, among individuals with psychiatric disorders. Similar findings exist for rates of psychiatric disorders among those with SUDs. Recent research is lacking in several Asian countries on the issue of comorbidity. SUMMARY: Interesting regional differences exist in the rates of comorbidity both across the Asian countries and between these countries and the west. Genetic and socio-cultural differences may be responsible for these differences. Methodologically sound, multicenter studies, involving several Asian countries, specifically examining the epidemiology of comorbidity between SUDs and psychiatric disorders, will have the potential to provide useful insights in this regard. PMID- 22449764 TI - Evidence for the diagnostic criteria of delirium: an update. AB - PURPOSE OF REVIEW: Since the publication of DSM-III in 1980, the essential criteria for delirium have been reduced progressively through DSM-III-R to DSM IV. As the field moves toward DSM-V and ICD-11, new data can shed light on the nosological changes that are needed so that diagnostic criteria can reflect empirical data. In this study, we reassess the existing or potential criteria for delirium. RECENT FINDINGS: Phenomenological studies in recent years have informed the criteria for delirium, including the appropriateness of the term 'consciousness' as a core symptom of the diagnosis, additional symptoms of delirium that are frequent but are not currently part of the diagnostic criteria, subsyndromal delirium, motoric subtypes of delirium (hyperactive, hypoactive), and the association of delirium with dementia. SUMMARY: Recent studies suggest that motoric subtypes should be included as a subtype for delirium but that subsyndromal delirium, although a useful research construct, should not be included in clinical diagnostic criteria given the frequent fluctuation in symptoms over short periods. In addition, though the core symptoms are probably adequate to make the diagnosis, clinicians must be aware of the frequency of other symptoms, for symptoms such as profound sleep disturbance or psychotic symptoms may dominate the clinical picture. PMID- 22449765 TI - Clinical and epidemiological assessment of substance misuse and psychiatric comorbidity. AB - PURPOSE OF REVIEW: The purpose of our review was to select, summarize and express opinions on a range of research studies published in 2011 on the clinical assessment, screening and monitoring of patients with substance use and psychiatric comorbidity, together with epidemiological and other relevant studies. RECENT FINDINGS: There was a wide range of publications on many aspects of comorbidity. The research was carried out on different populations in different treatment settings, including an alcohol and drug treatment centre, an emergency medical department, a community mental health centre, a methadone maintenance programme and inpatient unit, and in the community. Several structured or semi-structured interviews and self-administered instruments were used for the assessments of psychiatric disorders, substance use disorders and related problems. Each study has its strengths and weaknesses, with some studies reporting interesting new methodology or results, and others confirming what was already known about the subject. SUMMARY: The results of most studies support a high prevalence of substance misuse among individuals with psychiatric disorders and vice versa. Various aspects of the relationship between the two conditions are discussed. PMID- 22449766 TI - Managing patients with dual diagnosis in psychiatric practice. AB - PURPOSE OF REVIEW: To focus on recent research that may influence clinical practice in relation to patients with dual diagnosis disorders. RECENT FINDINGS: Harmful substance use is a heightened risk with bipolar disorder. Self-medication with substances of abuse for anxiety is linked with greater risk of developing anxiety disorders, particularly social anxiety disorder. Antisocial and schizotypal personality disorders were particularly linked with chronicity in substance use disorders. There are sex differences in responses to psychological approaches for dual disorders involving alcohol. Integrated dual diagnosis treatment for youth is not conclusive but shows promise. Online therapy is viable for adult patients with dual diagnosis. Structured interventions reduce the risk of opioid misuse amongst those with chronic pain, who are identified as at high risk. SUMMARY: We have confirmation that clinicians should be particularly vigilant in monitoring for substance use problems early in anxiety disorders and mood disorders and that certain personality disorders are linked with substance use chronicity. Practitioners can incorporate specific therapy approaches for dual disorders that appear to have advantages over treatment as usual. PMID- 22449767 TI - Psychiatric comorbidity in injecting drug users in Asia and Africa. AB - PURPOSE OF REVIEW: The prevalence of psychiatric co-morbidity in injecting drug users (IDUs) in the Western countries is high and is associated with lower quality of life and reduces the effectiveness of treatment programs. The aim of this study is to provide a review about psychiatric comorbidity in IDUs in Asia and Africa, where HIV prevalence is high and still increasing. RECENT FINDINGS: Studies focusing on psychiatric comorbidity in Asia and Africa are scarce. The prevalence of psychiatric comorbidity is comparable with the prevalence in western countries. Psychiatric disorders can occur before or during drug abuse and are also associated with substance abuse and physical comorbidity and its treatments. Childhood trauma followed by post-traumatic disorders is a significant risk factor for substance abuse. Psychiatric co-occurring disorders influence the adherence to the physical and drug use treatment. Evidence-based treatment for psychiatric comorbidity in IDUs is still limited. SUMMARY: A better understanding of the prevalence of psychiatric disorders in IDUs and its impact on the overall treatments is growing. However, more studies focusing on the treatment for psychiatric comorbidity in IDUs in Asia and Africa are needed. PMID- 22449768 TI - The diagnostic accuracy of attention-deficit/hyperactivity disorder in adults with substance use disorders. AB - PURPOSE OF REVIEW: Adult attention deficit/hyperactivity disorder (ADHD) is a common comorbid condition to substance use disorder (SUD) and is associated with worse prognosis and quality of life. This review summarizes recent work assessing ADHD diagnosis reliability in SUD patients and provides arguments to enhance the accuracy of detecting this disorder. RECENT FINDINGS: Adequate diagnosis of ADHD in SUD patients is challenged by phenomenological aspects of addiction and frequently associated other psychiatric disorders that overlap with key symptoms of ADHD. A detailed comprehensive search for child and adult symptoms including the temporal relationship of ADHD, substance use and other psychiatric disorders should maximize the validity and the reliability of adult ADHD diagnosis in this population. Further, a follow-up evaluation of ADHD symptoms during treatment of SUD may reduce the likelihood of misdiagnosis. SUMMARY: Considering the high rate of ADHD comorbidity among SUD patients, it is crucial to promote a systematic diagnostic approach to this disorder in specialized addiction treatment settings. However, overlapping symptoms between disorders frequently challenge the accuracy of adult ADHD diagnosis. Areas in need of further investigations include the development of valid screening procedures, associated neuropsychological factors and effective treatment strategies for these populations. PMID- 22449769 TI - Recent progress in the understanding and treatment of nonepileptic seizures. AB - PURPOSE OF REVIEW: There has been a steady increase in the number of publications about (psychogenic) nonepileptic seizures (NES) over the past two decades. This review focuses on work published in the past 3 years. It summarizes the most important developments in terms of diagnosis, cause, clinical manifestations and treatment of NES. RECENT FINDINGS: Several recent studies demonstrate the scope and limitation of questionnaire-based and conversation analytic approaches to the differential diagnosis of epilepsy and NES. Experimental work has revealed that patients with NES have increased levels of physiological arousal at rest which are associated with abnormal mental processing. There is a growing understanding of the meaning and clinical significance of the heterogeneous manifestations of NES. Several studies document the therapeutic potential of an early and effective communication of the diagnosis of NES. A number of randomized controlled or uncontrolled long-term follow-up pilot studies suggest that different forms of psychotherapy are effective for NES. SUMMARY: Recent research has improved our understanding of NES as a biopsychosocial disorder. Clear diagnostic and management pathways for patients with NES are likely to emerge in the near future. PMID- 22449770 TI - Comorbidity of psychiatric and substance use disorders in the United States: current issues and findings from the NESARC. AB - PURPOSE OF REVIEW: The comorbidity between psychiatric and substance use disorders remains an important phenomenon to understand, and an active area of investigation. The purpose of this review is to highlight key 2011 issues and novel findings on psychiatric and substance disorders comorbidity from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large national survey of the US general population. RECENT FINDINGS: Topics of active investigation included the internalizing/externalizing meta-structure of common mental disorders; the 10 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) personality disorders; the 3-year incidence and persistence of disorders; treatment of major depression; and many other topics not as easily categorized. SUMMARY: Meta-structure may increasingly offer a parsimonious way of addressing comorbidity, although adding new disorders adds complexity and the value of etiologic analyses utilizing broad dimensions of psychopathology rather than individual disorders is not yet fully known. Expanding the range of personality disorders beyond antisocial personality disorder appears essential in understanding the incidence and persistence of substance use disorders. Substance use disorders have low rates of treatment relative to major depression, but increase the likelihood of depression treatment among comorbid cases, a phenomenon that needs to be understood. These comorbidity studies provide much novel information, and indicate many potentially fruitful directions for new research. PMID- 22449771 TI - Bartonella bacteria in nature: where does population variability end and a species start? AB - The application of new molecular approaches has permitted the differentiation of numerous strains belonging to the genus Bartonella and identification of new Bartonella species. However, the molecular typing of these organisms should be coupled with studies aimed at defining the biological properties of the newly described species. The long-history of co-adaptation between bartonella(1) bacteria and their mammalian hosts and possibly arthropod vectors provides a unique opportunity for applying this information for the sub-genus taxonomy. There can be a varying level of association between the bacteria and their hosts, ranging from animal species to animal genus to animal community. The commonality is that any level of association provides a certain degree of isolation for a given bartonella population that can mimic 'biological isolation'. Such an association defines a specific ecological niche and determines some specific characteristics, including sequence types that can be used as markers for demarcation of bacterial species. Usage of a combination of genetic markers and ecological information can delineate a number of species complexes that might combine several genospecies, named strains, and unique genotypes. The identification of such species complexes can be presented as (1) separate phylogenetic lineages distantly related to other species (e.g. Bartonella bacilliformis); (2) clusters of genetically similar strains associated with a specific mammalian group (e.g. Bartonella elizabethae species complex); and (3) clusters of genetically similar strains that combine a number of ecotypes (e.g. Bartonella vinsonii species complex). PMID- 22449772 TI - Inheritance of the Salmonella virulence plasmids: mostly vertical and rarely horizontal. AB - Salmonella virulence plasmids (VPs) contribute to pathogenesis during the systemic phase of infection. Only eight serovars have been found to contain VP, and the size of VP is unique to the host serovar, suggesting VPs are mainly transmitted vertically. According to this hypothesis, VPs should have the same phylogenetic relationships as the chromosomes among the bacteria that carry the VPs. To test this hypothesis, we sequenced VPs from the serovar Enteritidis and Pullorum, named pSENV and pSPUV, respectively, and compared them with VPs from other Salmonella serovars. The overall results supported our hypothesis with the exception of pSENV, which was more similar to VPs from the more distantly related serovars Typhimuirum, Choleraesuis and Paratyphi C than to those from the very closely related serovars Dublin and Gallinarum/Pullorum with regard to either gene content or nucleotide similarity. These findings demonstrate that Enteritidis acquired pSENV by horizontal transfer. PMID- 22449773 TI - Phylogenetic evidence based on Trypanosoma cruzi nuclear gene sequences and information entropy suggest that inter-strain intragenic recombination is a basic mechanism underlying the allele diversity of hybrid strains. AB - The diversity of Trypanosoma cruzi is categorized into six discrete typing units (DTUs) T. cruzi I to VI. Several studies indicate that T. cruzi I and II are ancestors of T. cruzi III-VI which are considered products of independent hybridization events. The individual haplotypes or alleles of these hybrids cluster in three groups, either closer to T. cruzi I or T. cruzi II or forming a midpoint clade between T. cruzi I and II in network phylogenies. To understand the origins of these different sets of haplotypes and test the hypothesis of a direct correlation between high entropy and positive selection, we analyzed four nuclear protein coding genes. We show that hybrid strains contain haplotypes that are mosaics probably originated by intragenic recombination. Accordingly, in phylogenies, the hybrid haplotypes are closer to one or both parentals (T. cruzi I and II) depending on the proportion of parental sequences composing the mosaics. In addition, Shannon entropy, used to measure sequence diversity, is highly correlated with positive selection in the four genes here analyzed. Our data on recombination patterns also support the hypothesis of two hybridization events in the hybrid structures of T. cruzi III-VI. Data presented and discussed here are consistent with a scenario where TcI and TcII are phylogenetically divergent forming a hybrid zone in between (T. cruzi III-VI). We predict that because of the quasi-random nature of T. cruzi I and II hybridization more DTUs, with different haplotype combinations, will be discovered in the hybrid zone. PMID- 22449774 TI - Detection of Trypanosoma lewisi from wild rats in Southern China and its genetic diversity based on the ITS1 and ITS2 sequences. AB - Trypanosoma lewisi has widely been considered as a non-pathogenic rat trypanosome. However, more and more cases of humans infected with T. lewisi have been reported around the world, indicating that it can infect humans in some undetermined circumstances. Quick and sensitive diagnosis of infection by T. lewisi is important for both treatment of patients and epidemiological studies of this parasite. In this paper, three methods i.e. wet blood smear (diagnosis by microscopy), PCR and LAMP were used to detect T. lewisi from 238 wild rats (Rattus norvegicus) collected from the field in Huadu, Guangdong province, China. Infection rates of these samples detected by the 3 methods was 6.7% (16/238), 12.6% (30/238), and 18.9% (45/238), respectively. LAMP could detect all samples shown positive by microscopical observation of wet smear and by single PCR indicating good potential for application in the detection of T. lewisi. So far as we know, this is the first report of the LAMP method being used to detect T. lewisi in wild rats. The specific T. lewisi LAMP primers were able to amplify the target fragment from the genomic DNA of 19 T. lewisi strains isolated from Huadu, Guangdong province (n=16), Changchun, Jilin province of China (n=1) and from Thailand (n=2). Based on the analyses of ITS1 (internal transcribed spacer 1) and ITS2 sequences, these 19 strains show a very close genetic relationship with over 96-97% similarity to the other corresponding sequences of T. lewisi published in Genbank. Phylogenetic trees of the species in the subgenus Herpetosoma were constructed, based on the ITS1 and ITS2 sequences, and these results also indicate that they are closely related and in the same clade. PMID- 22449775 TI - Vascular, electrophysiological, and metabolic consequences of cortical spreading depression in a mouse model of simulated neurosurgical conditions. AB - OBJECTIVES: Cortical spreading depression (CSD) is a metabolically taxing wave of cellular depolarization that propagates slowly across the brain. Though CSD is known to occur after brain injury in humans, it is unknown if CSD occurs during neurosurgical procedures. This study evaluates CSD in a mouse model of simulated neurosurgical conditions. METHODS: Mice were intubated and ventilated, maintained at ~37 degrees C, an arterial line placed to monitor mean arterial pressure and maintain pCO(2) ~30 mmHg. Mice were given simulated neuroanesthesia (fentanyl, propofol, and isofluorane). Burrholes and craniotomies were made to record the response to cortical bipolar cauterization. Separate sets of experiments (three animals each) examined electrocorticographic (ECoG) activity, optical measures of blood volume and vascular diameters (540 nm absorbance), and autofluorescence attributed to NADH (750 nm, two-photon excitation). RESULTS: Ipsilateral cauterization invariably resulted in a propagating CSD wave identified by slow DC potential shifts (2.8+/-0.2 mm/minute, n = 6) and suppression of ECoG activity (range 0.5-7.3 minutes, n = 10). Each CSD was associated with an initial arteriolar constriction and decreased blood volume, followed by a longer-lasting vasodilation and increased blood volume. Tissue oxygenation, assessed indirectly by NADH imaging, was consistent with demand on oxidative metabolism following each CSD. Repetitive SDs resulted in loss of tissue autofluorescence, suggestive of tissue compromise. CONCLUSIONS: CSD is consistently elicited by simulated neurosurgical stimuli under simulated intraoperative conditions in mice. These events caused ECoG depression, transient vasoconstriction, and metabolic demand that propagated from the manipulation site. It is likely that CSD occurs during neurosurgery and may contribute to surgical brain injuries otherwise poorly explained. PMID- 22449776 TI - Nucleic acid adjuvants: toward an educated vaccine. AB - Two striking facts surround the practice of vaccination: It is the sole medical approach to have fully annihilated a disease, yet the development of most effective vaccines took place without considering the intricate cellular processes they wish to effectuate. While extremely potent vaccines have been developed that can protect practically a lifetime after a single dose, numerous other vaccines have utterly failed or provide only marginal protection. Here, we aim to illustrate why this difference in efficacy exists, and underline why specific cytotoxic T cell-inducing vaccines could combat persistent major diseases. Moreover, we discuss how the combinatorial use of nucleic acid adjuvants in vaccines could aid the development of the latter and move vaccine design from the empirical stage into an era of "educated design." PMID- 22449777 TI - Structure-based design for high-hanging vaccine fruits. AB - Although vaccines have proven life saving against a myriad of infectious diseases, various pathogens have remained refractory to prophylaxis of their host by active immunization. New insights in the three dimensional (3D) structure, domain organization and dynamics of viral and bacterial surface proteins can guide the design of effective vaccines in several ways. In this review we highlight recent developments in structure-based vaccine design that are aimed at stabilization of native conformations and focusing immune response to conserved epitopes. Detailed 3D structures of pathogen surface proteins provide knowledge on how to minimize complex antigens or how to redesign the surface of an immunogen in order to induce only relevant neutralizing antibodies against a broad range of serotypes. Structure - based vaccines with reduced complexity and broad efficacy could greatly enhance the number of people that might benefit from the therapies that are developed. PMID- 22449778 TI - Mechanisms of peptide vaccination in mouse models: tolerance, immunity, and hyperreactivity. AB - The development of synthetic peptide vaccines capable of inducing strong and protective T-cell immunity has taken more than 20 years. Peptide vaccines come in many flavors and although their design is simple, their use is more complicated as the success of a particular peptide vaccine is influenced by many parameters. In fact, peptide vaccination may lead to tolerance, immunity or even hyper reactivity causing death of the animals. Here we systematically dissect the parameters that influence the final outcome of peptide vaccines as examined in mouse models and this will guide the rational design of new vaccines in the future. PMID- 22449779 TI - Experience with synthetic vaccines for cancer and persistent virus infections in nonhuman primates and patients. AB - Synthetic vaccines, in particular long synthetic peptides of approximately 25-50 amino acids in length, are attractive for HIV vaccine development and for induction of therapeutic immune responses in patients with (pre-)malignant disorders. In the case of preventive vaccine development against HIV, no major success has been achieved, but the possibilities are by no means exhausted. A long peptide vaccine consisting of 13 overlapping peptides, which together cover the entire length of the two oncogenic proteins E6 and E7 of high-risk human papilloma virus type 16 (HPV16), caused complete regression of all lesions and eradication of virus in 9 out of 20 women with high-grade vulvar intraepithelial neoplasia, a therapy-resistant preneoplastic disorder. The nature and strength of the vaccine-prompted T cell responses were significantly correlated with the clinical response. Synthetic peptide vaccines are attractive, because they allow rational improvement of vaccine design and detailed pharmacokinetic and pharmacodynamic studies not possible with conventional vaccines. Improvements are possible by addition or conjugation of adjuvants, notably TLR ligands, to the synthetic peptides. PMID- 22449780 TI - Malaria vaccine development using synthetic peptides as a technical platform. AB - The review covers the development of synthetic peptides as vaccine candidates for Plasmodium falciparum- and Plasmodium vivax-induced malaria from its beginning up to date and the concomitant progress of solid phase peptide synthesis (SPPS) that enables the production of long peptides in a routine fashion. The review also stresses the development of other complementary tools and actions in order to achieve the long sought goal of an efficacious malaria vaccine. PMID- 22449782 TI - TLR ligand-peptide conjugate vaccines: toward clinical application. AB - Approaches to treat cancer with therapeutic vaccination have made significant progress. In order to induce efficient antitumor immunity, a vaccine should target and activate antigen-presenting cells, such as the dendritic cell, while delivering the tumor-derived antigen of choice. Conjugates of synthetic peptides and ligands of pattern-recognition receptors (PRRs) combine these features and, given their synthetic nature, can be produced under GMP conditions. Therefore, conjugation of antigenic peptides to potent PRR ligands is a promising vaccination approach for the treatment of cancer. This review focuses on the different PRR families that can be exploited for the design of conjugates and explores the results obtained so far with PRR ligands conjugated to antigen. The uptake and processing of Toll-like receptor ligand-peptide conjugates are discussed in more detail, as well as future directions that may further enhance the immunogenicity of conjugates. PMID- 22449781 TI - Enhancing cancer immunotherapy by intracellular delivery of cell-penetrating peptides and stimulation of pattern-recognition receptor signaling. AB - The importance of T-cell-mediated antitumor immunity has been demonstrated in both animal models and human cancer immunotherapy. In the past 30 years, T-cell based immunotherapy has been improved with an objective clinical response rate of up to 72%. Identification of MHC class I- and II-restricted tumor antigens recognized by tumor-reactive T cells has generated a resurgence of interest in cancer vaccines. Although clinical trials with cancer peptide/protein vaccines have only met a limited success, several phase II/III clinical trials are either completed or ongoing with encouraging results. Recent advances in immunotherapy have led to the approval of two anticancer drugs (sipuleucel-T vaccine and anti CTLA-4 antibody) by the US FDA for the treatment of metastatic castration resistant prostate cancer and melanoma, respectively. Intracellular delivery of antigenic peptides into dendritic cells (DCs) prolongs antigen presentation of antigen-presenting cells to T cells, thus further improving clinical efficacy of peptide/protein cancer vaccines. Because innate immune responses are critically important to provide sensing and initiating of adaptive immunity, combined use of cell-penetrating peptide vaccines with stimulation of innate immune signaling may produce potent antitumor immune responses. We will discuss the recent progress and novel strategies in cancer immunotherapy. PMID- 22449783 TI - Behavior and function of tissue-resident memory T cells. AB - Our understanding of memory T cell function in mice and men is to date in large part restricted to the behavior of circulating memory T cells. Emerging evidence, however, suggests that in addition to such systemic memory T cell populations, a separate population of locally confined memory T cells is generated at former sites of antigen encounter. Here, we discuss the potential function of these long term tissue-resident memory T cells (T(TRM)), how such local T cell memory can be maintained for prolonged periods of time, and how the induction of long-term tissue-resident memory T cells may potentially be exploited during vaccination. PMID- 22449784 TI - Rational design of vaccines: learning from immune evasion mechanisms of persistent viruses and tumors. AB - The induction of adaptive immunity and prevention of tolerance is a critical component of vaccination and immunotherapy in order to prevent pathogen-related diseases and to eradicate malignant cells. Although many acute infections can be controlled by vaccination, the development of prophylactic and therapeutic vaccines against persistent viruses and tumors remains challenging. The diverse immune evasion strategies used by persistent DNA viruses such as herpesviruses contribute directly to their persistence and escape from immune control. Intriguingly, many tumors have also developed escape mechanisms to dismantle similar aspects of the host's immune system. Analogous targets of immune evasion mechanisms comprise suppression of antigen presentation and T cell costimulatory pathways, induction of immunosuppressive cytokines, and obstruction of interferon and chemokine functions, which emphasizes them not only as critical elements of T cell activation pathways but also as the potential "Achilles' heels" of the host immune system. The insight that immune evasion by viruses and tumors targets analogous host immune pathways might lead to cross-pollination of the viral and tumor immunology research fields, which could lead to new perspectives and appreciation of the intricacies and subtleties that arise from the merging of these fields. Accordingly, a rational and combinatorial manipulation of immune evasion pathways and their targets should aid in the development of safer and more effective vaccine strategies and immunotherapies for a wide range of infections and malignancies. PMID- 22449785 TI - Advances in Immunology. Synthetic vaccines. Preface. PMID- 22449786 TI - Repeated exposure of the posterior ventral tegmental area to nicotine increases the sensitivity of local dopamine neurons to the stimulating effects of ethanol. AB - Clinical evidence indicates a frequent co-morbidity of nicotine and alcohol abuse and dependence. The posterior ventral tegmental area (pVTA) appears to support the reinforcing and dopamine-stimulating effects of both drugs. The current study tested the hypothesis that repeated exposure of the pVTA to one drug would increase the sensitivity of local dopamine neurons to the stimulating effects of the other drug. Female Wistar rats received repeated daily microinjections of either 100 MUM nicotine or vehicle directly into the pVTA for 7 days. On the 8th day, rats received microinjections of either vehicle or ethanol (100 or 200 mg%) into the pVTA while extracellular dopamine samples were collected from the ipsilateral nucleus accumbens shell (NACsh) with microdialysis. Another experiment tested the effects of challenge microinjections of 200 MUM nicotine in the pVTA on extracellular dopamine levels in the NACsh following 7 daily pretreatments with 200 mg% ethanol in the pVTA. Nicotine pretreatments increased the dopamine-stimulating effects of ethanol in the pVTA (100 mg% ethanol: 115% vs 160% of baseline in the vehicle and nicotine groups, respectively, p < 0.05; 200 mg% ethanol: 145% vs 190% of baseline in the vehicle and nicotine groups, respectively, p < 0.05). In contrast, ethanol pretreatments did not alter the stimulating effects of nicotine in the pVTA. The results suggest that repeated exposure of the pVTA to nicotine increased the response of local dopamine neurons to the stimulating effects of ethanol, whereas repeated exposure of the pVTA to ethanol did not alter the responses of pVTA dopamine neurons to nicotine. PMID- 22449787 TI - The role of biogenic amine signaling in the bed nucleus of the stria terminals in alcohol abuse. AB - There is a growing body of evidence that suggests that stress and anxiety can influence the development of alcohol use disorders. This influence is believed to be due in part to persistent adaptations in discrete brain regions that underlie stress responsivity. One structure that has been proposed to be a site of important neuroadaptations underlying this behavior is the extended amygdala. The extended amygdala is a series of extensively inter-connected limbic structures including the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). These structures are critical regulators of behavioral and physiological activation associated with anxiety. Additionally, numerous reports have suggested that these regions are involved in increased drinking behavior associated with chronic alcohol exposure and withdrawal. The focus of this review will be to discuss the role of the BNST in regulation of behavior, to provide some insight in to the circuitry of the BNST, and to discuss the actions of the biogenic amines, serotonin, dopamine and norepinephrine, in the BNST. PMID- 22449788 TI - Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have received considerable importance in cancer chemoprevention over the last few years. They are now being considered as prospective candidates in cancer immunotherapy because of their striking immune-enhancing impact on various effector elements of anti-tumour immunity on one hand, and to augment the efficacy of different anti-cancer immunotherapeutic strategies on the other. This review specifically discusses the role of NSAIDs in anti-tumour immunity by describing their immunomodulatory effects on different immune cells including tumour-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, T effector cells, and T regulatory cells (Treg). Secondly, the therapeutic perspective of NSAIDs in combination with different anti-cancer immunotherapeutic approaches, in particular the cancer vaccines, tumour-specific monoclonal antibodies, and cytokine-based therapy, has been outlined. At the end, the impact of anti inflammatories other than NSAIDs on tumour immunity and immunotherapy, and the immunopharmacological potential of selective E-prostanoid (EP) receptor antagonists with respect to cancer immunity have also been discussed briefly. PMID- 22449789 TI - Virgin olive oil and nuts as key foods of the Mediterranean diet effects on inflammatory biomakers related to atherosclerosis. AB - Previous epidemiological and feeding studies have observed that adherence to Mediterranean diet (Med-Diet) is associated with reduced cardiovascular risk. However, the molecular mechanisms involved are not fully understood. Since atherosclerosis is nowadays considered a low-grade inflammatory disease, recent studies have explored the anti-inflammatory effects of a Med-Diet intervention on serum and cellular biomarkers related to atherosclerosis. In two sub-studies of the PREDIMED (PREvencion con DIeta MEDiterranea) trial, we analyzed the effects at 3 months of two Med-Diet interventions supplemented with either virgin olive oil (VOO) or nuts compared with a control low-fat diet (LFD). Both Med-Diets showed an anti-inflammatory effect reducing serum C-reactive protein, interleukin 6 (IL6) and endothelial and monocytary adhesion molecules and chemokines (P<0.05; all), whereas these parameters increased after the LFD intervention (P<0.05; all). In another substudy, we evaluated the long-term (1 year) effects of these interventions on vascular risk factors in 516 high-risk subjects, as well as the effect of different Med-Diet components in the reduction of these biomarkers. At 1 year, the Med-Diet groups had significant decreases in the plasma concentrations of IL6, tumor necrosis factor receptor (TNFR) 60 and TNFR80 (P<0.05), while intercellular adhesion molecule 1 (ICAM-1), TNFR60 and TNFR80 concentrations increased in the LFD group (P<0.002). In addition, those allocated in the highest tertile of VOO and vegetables consumption had a significant diminution of plasma TNFR60 concentration compared with those in tertile 1 (P<0.02). In conclusion, Med-Diet exerts an anti-inflammatory effect on cardiovascular system since it down-regulates cellular and circulating inflammatory biomarkers related to atherogenesis in subjects at high cardiovascular risk. PMID- 22449790 TI - Highly active antiretroviral therapy alone is an effective treatment for lymphadenopathic kaposi sarcoma demonstrated by a clinical and F-18 FDG positron emission tomography/computed tomography response. PMID- 22449791 TI - Successful pregnancy and delivery after concomitant temozolomide and radiotherapy treatment of glioblastoma multiforme. PMID- 22449792 TI - Interstitial granulomatous drug reaction to a Chinese herb extract. PMID- 22449793 TI - Up-front staging of suspected lung cancer with PET-CT - new horizon or false dawn? PMID- 22449794 TI - PICOT increases cardiac contractility by inhibiting PKCzeta activity. AB - Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT) has distinct anti-hypertrophic and inotropic functions. We have previously shown that PICOT exerts its anti-hypertrophic effect by inhibiting calcineurin-NFAT signaling through its C-terminal glutaredoxin domain. However, the mechanism underlying the inotropic effect of PICOT is unknown. The results of protein pull-down experiments showed that PICOT directly binds to the catalytic domain of PKCzeta through its N-terminal thioredoxin-like domain. Purified PICOT protein inhibited the kinase activity of PKCzeta in vitro, which indicated that PICOT is an endogenous inhibitor of PKCzeta. The inhibition of PKCzeta activity with a PKCzeta-specific pseudosubstrate peptide inhibitor was sufficient to increase the cardiac contractility in vitro and ex vivo. Overexpression of PICOT or inhibition of PKCzeta activity down-regulated PKCalpha activity, which led to the elevation of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) 2a activity, concomitant with the increased phosphorylation of phospholamban (PLB). Overexpression of PICOT or inhibition of PKCzeta activity also down-regulated protein phosphatase (PP) 2A activity, which subsequently resulted in the increased phosphorylation of troponin (Tn) I and T, key myofilament proteins associated with the regulation of contractility. PICOT appeared to inhibit PP2A activity through the disruption of the functional PKCzeta/PP2A complex. In contrast to the overexpression of PICOT or inhibition of PKCzeta, reduced PICOT expression resulted in up-regulation of PKCalpha and PP2A activities, followed by decreased phosphorylation of PLB, and TnI and T, respectively, supporting the physiological relevance of these events. Transgene- or adeno-associated virus (AAV)-mediated overexpression of PICOT restored the impaired contractility and prevented further morphological and functional deterioration of the failing hearts. Taken together, the results of the present study suggest that PICOT exerts its inotropic effect by negatively regulating PKCalpha and PP2A activities through the inhibition of PKCzeta activity. This finding provides a novel insight into the regulation of cardiac contractility. PMID- 22449795 TI - Kinetic effects of carbon monoxide inhalation on tissue protection in ventilator induced lung injury. AB - Mechanical ventilation causes ventilator-induced lung injury (VILI), and contributes to acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a disease with high morbidity and mortality among critically ill patients. Carbon monoxide (CO) can confer lung protective effects during mechanical ventilation. This study investigates the time dependency of CO therapy with respect to lung protection in animals subjected to mechanical ventilation. For this purpose, mice were ventilated with a tidal volume of 12 ml/kg body weight for 6 h with air in the absence or presence of CO (250 parts per million). Histological analysis of lung tissue sections was used to determine alveolar wall thickening and the degree of lung damage by VILI score. Bronchoalveolar lavage fluid was analyzed for total cellular influx, neutrophil accumulation, and interleukin-1beta release. As the main results, mechanical ventilation induced pulmonary edema, cytokine release, and neutrophil recruitment. In contrast, application of CO for 6 h prevented VILI. Although CO application for 3 h followed by 3-h air ventilation failed to prevent lung injury, a further reduction of CO application time to 1 h in this setting provided sufficient protection. Pre-treatment of animals with inhaled CO for 1 h before ventilation showed no beneficial effect. Delayed application of CO beginning at 3 or 5 h after initiation of ventilation, reduced lung damage, total cell influx, and neutrophil accumulation. In conclusion, administration of CO for 6 h protected against VILI. Identical protective effects were achieved by limiting the administration of CO to the first hour of ventilation. Pre-treatment with CO had no impact on VILI. In contrast, delayed application of CO led to anti-inflammatory effects with time dependent reduction in tissue protection. PMID- 22449796 TI - Notch signaling pathway and Cdx2 expression in the development of Barrett's esophagus. AB - Cdx2 expression in esophageal stem cells induced by reflux bile acids may be an important factor for development of Barrett's esophagus, whereas Notch signaling is a molecular signaling pathway that plays an important role in the determination of cell differentiation. ATOH1 (a factor associated with Notch signaling) plays an important role in differentiation of stem cells into goblet cells. However, the relationship between the Notch signaling pathway and Cdx2 expression in the development of Barrett's esophagus has not been explored. The aim of this study was to investigate the interrelationship between Notch signaling and Cdx2 in esophageal epithelial cells. The expressions of Cdx2, MUC2, and intracellular signaling molecules related to Notch signaling (Notch1, Hes1, and ATOH1) were examined using real-time polymerase chain reaction (PCR) and immunohistochemical staining with biopsy specimens obtained from esophageal intestinal metaplasia (IM) with goblet cells (IM+) and columnar epithelium not accompanied by goblet cells (IM-). For in vitro experiments, we employed human esophageal epithelial cell lines (OE33, OE19, and Het-1A). After forced Cdx2 expression by applying a Cdx2 expression vector to the cells, changes in the expressions of Notch1, Hes1, ATOH1, Cdx2, and MUC2 were analyzed by real-time PCR and western blot analysis. Changes in expressions of Notch1, Hes1, ATOH1, Cdx2, and MUC2 in cells were analyzed following stimulation with bile acids in the presence or absence of Cdx2 blocking with Cdx2-siRNA. Suppressed Hes1 and enhanced ATOH1 and MUC2 expressions were identified in IM+ specimens. Forced expression of Cdx2 in cells suppressed Hes1, and enhanced ATOH1 and MUC2 expressions, whereas bile acids suppressed Hes1, and enhanced ATOH1, Cdx2, and MUC2 expressions. On the other hand, these effects were blocked by siRNA-based Cdx2 downregulation. Enhanced expression of Cdx2 by stimulation with bile acids may induce intestinal differentiation of esophageal columnar cells by interaction with the Notch signaling pathway. PMID- 22449797 TI - NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. AB - In mouse models it has been shown that natural killer (NK) cells can attenuate liver fibrosis via killing of activated hepatic stellate cells (HSCs) in a NKG2D- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. However, only little data exist regarding interactions of human NK cells with HSCs and their potential role in hepatitis C virus (HCV)-associated fibrogenesis. Therefore, purified NK cells from untreated HCV RNA(+) patients (n=33), interferon-alpha (IFN-alpha)-treated patients (n=17) and healthy controls (n=18) were coincubated with activated primary HSCs, and were tested for degranulation (CD107a expression) and secretion of IFN-gamma and TNF-alpha, respectively. Induction of HSC apoptosis was analyzed using an active caspase-3 assay. We found that following coincubation with HSCs a significant increase in CD107a expression could be observed in both NK cells from HCV(+) patients and healthy controls, whereas only negligible secretion of IFN-gamma and TNF-alpha could be detected. More importantly, NK cells from untreated HCV RNA(+) patients were significantly more effective in induction of HSC apoptosis (17.8 +/- 9.2%) than NK cells from healthy controls (6.2 +/- 2.1%; P<0.0001). Additionally, we observed an inverse correlation of liver fibrosis stage and the ability of NK cells to induce HSC apoptosis. Induction of HSC apoptosis was contact dependent and could partly be blocked by antibodies specific for TRAIL, NKG2D and FasL, respectively. It is noteworthy that NK cells from IFN-alpha-treated HCV(+) patients displayed the highest capability to kill HSCs (27.6 +/- 10.5%). Accordingly, pre-stimulation of NK cells with recombinant IFN-alpha significantly increased the ability of NK cells to induce cell death in primary HSCs and was dependent on upregulated expression of TRAIL. Here we demonstrate that NK cells from HCV-infected patients are highly efficient in inducing apoptosis of activated HSCs. Thus, NK cells may have an important anti-fibrotic role in chronic hepatitis C. PMID- 22449798 TI - Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model. AB - Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8-/- and krt18-/- mice crossed into the same 129-ola genetic background were treated by acute and chronic administration of 3,5-diethoxy-carbonyl-1,4 dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8-/- and krt18-/- compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18-/- mice already at an early stage of intoxication in contrast to krt8-/- mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8-/-, krt18-/- and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18 /- and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8-/- mice, steatosis was less, ballooning, and MDBs were absent. krt18-/- mice developed MDBs whereas krt8-/- mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. They are independent of the genetic background as an intrinsic factor. By contrast, toxicity effects may depend on the genetic background. krt8-/- and krt18-/- mice on the same genetic background show similar sensitivity to DDC intoxication and almost resemble wt animals regarding survival, degree of porphyria, liver-to-body weight ratio, serum bilirubin and liver enzyme levels. This stands in contrast to previous work where krt8-/- and krt18-/- mice on different genetic backgrounds were investigated. PMID- 22449799 TI - Increased matrix metalloproteinase-9 activity and mRNA expression in lung injury following cardiopulmonary bypass. AB - To determine whether the presence of Matrix metalloproteinases (MMPs) is associated with acute lung injury following cardiopulmonary bypass (CPB), we evaluated the activity and gene expression of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) of lungs using rat model of CPB. Adult male Sprague-Dawley rats were randomly divided into three groups: Group I (underwent cannulation + heparinization only); group II (underwent 60 min of normothermic CPB); and group III (underwent 60 min of normothermic of CPB, which rats received doxycycline treat by filling stomach 1 week ahead of CPB). Lung injury was evaluated histologically. The enzyme activity of MMP-9 and TIMP-1 in the bronchoalveolar lavage fluid was detected by western-blot analysis. The expression of MMP-9 and TIMP-1 in lung tissue was assessed using reverse transcriptase-polymerase chain reaction method. We found there was significantly pulmonary edema and lung injury in groups II and III compared with group I, and the histological markers of pulmonary edema in the Group III were less pronounced in comparison with Group II. The MMP-9 activity and gene expression were increased significantly, but the TIMP-1 increased slowly in group II, and the ratio of MMP-9/TIMP-1 was imbalanced severely. More significantly, the MMP-9 decreased significantly and the TIMP-1 mRNA increased gradually in group III compared with group II, and the ratio of MMP-9/TIMP-1 was improved significantly. We concluded MMP-9 might have an important role in acute lung injury following CPB. TIMP-1 increased in the rats treated with doxycycline ahead and might compensate for the activity of MMP-9. The doxycycline might have the protective effect against acute lung injury following CPB. PMID- 22449800 TI - Curcumin eliminates the inhibitory effect of advanced glycation end-products (AGEs) on gene expression of AGE receptor-1 in hepatic stellate cells in vitro. AB - Diabetes is featured by hyperglycemia, which facilitates the formation of advanced glycation end-products (AGEs). AGEs are a causal factor in development of diabetic complications. AGE receptor-1 (AGE-R1) is responsible for detoxification and clearance of AGEs. Type 2 diabetes mellitus is commonly accompanied by non-alcoholic steatohepatitis, which could cause hepatic fibrosis. Little attention has been paid to effects of AGEs on hepatic fibrogenesis. Curcumin, a phytochemical from turmeric, has been reported to inhibit the activation of hepatic stellate cells (HSCs), the major effectors during hepatic fibrogenesis, and to protect against hepatic fibrogenesis in vitro and in vivo. The current study was designed to evaluate the effects of AGEs on inducing HSC activation, to assess the role of curcumin in diminishing the AGE effects, and to explore the underlying mechanisms. Our results showed that AGEs stimulated HSC activation by inducing cell proliferation and expression of genes relevant to HSC activation, which were abrogated by curcumin. Curcumin induced gene expression of AGE-R1 in passaged HSCs, which might facilitate the attenuation of the stimulatory effects of AGEs on the activation of HSCs. Further experiments revealed that curcumin inhibited the activity of extracellular signal-regulated kinase (ERK), and induced gene expression and the activity of peroxisome proliferator-activated receptor-gamma (PPARgamma), leading to the induction of the AGE-R1 gene expression. In summary, AGEs stimulated HSC activation. Curcumin eliminated the AGE effects at least partially by inducing the AGE-R1 gene expression. The process was mediated by inhibiting ERK activity, inducing gene expression of PPARgamma and stimulating its transactivity. PMID- 22449801 TI - Hyperglycemia and xerostomia are key determinants of tooth decay in type 1 diabetic mice. AB - Insulin-dependent type 1 diabetes mellitus (DM) and oral diseases are closely interrelated. Poor metabolic control in diabetics is associated with a high risk of gingivitis, periodontitis and tooth loss. Salivary flow declines in diabetics and patients suffer from xerostomia. Reduced saliva predisposes to enamel hypomineralization and caries formation; however, the mechanisms that initiate and lead to progression of tooth decay and periodontitis in type 1 DM have not been explored. To address this issue, we analyzed tooth morphology in Akita -/- mice that harbor a point mutation in the Ins2 insulin gene, which leads to progressive hyperglycemia. Mandibles from Akita -/- and wild-type littermates were analyzed by microCT, scanning EM and histology; teeth were examined for amelogenin (Amel) and ameloblastin (Ambn) expression. Mice were injected with pilocarpine to assess saliva production. As hyperglycemia may alter pulp repair, the effect of high glucose levels on the proliferation/differentiation of cultured MD10-F2 pulp cells was also analyzed. Results showed that Akita -/- mice at 6 weeks of age showed chalky white incisors that correlated with marked hyperglycemia and impaired saliva production. MicroCT of Akita -/- teeth revealed excessive enamel wearing and hypomineralization; immunostaining for Amel and Ambn was decreased. A striking feature was invasion of dentinal tubules with Streptococcus mitis and microabcesses that originated in the coronal pulp and progressed to pulp necrosis and periapical periodontitis. High levels of glucose also inhibited MD10-F2 cell proliferation and differentiation. Our findings provide the first evidence that hyperglycemia in combination with reduced saliva in a model of type1 DM leads to decreased enamel mineralization/matrix proteins and predisposes to excessive wearing and decay. Importantly, hyperglycemia adversely affects enamel matrix proteins and pulp repair. Early detection and treatment of hyperglycemia and hyposalivation may provide a useful strategy for preventing the dental complications of diabetes and promoting oral health in this population. PMID- 22449802 TI - Rapid Rhino versus Merocel nasal packs in septal surgery. PMID- 22449803 TI - Submitting an application for research ethics clearance. AB - BACKGROUND: Research involving human subjects requires approval by a research ethics committee before commencement. What appears to many researchers to be a daunting task can be relatively easy if approached sensibly. AIM: The aim of this paper is to offer advice to potential applicants for ethics approval of their research. METHOD: The paper provides practical information, based on years of experience, for novice and experienced applicants to a research ethics committee. PMID- 22449804 TI - Caries prevention with xylitol lozenges in children related to maternal anxiety. A demonstration project. AB - AIM: This was to compare the effect of a prevention program between children of anxious and non-anxious mothers. METHODS: Mothers (n=120) with high and low dental anxiety scores (DAS>15 and DAS <8, respectively), and with high levels of mutans streptococci (>10(5)cfu/mL) were recruited at a maternity clinic of Tartu, Estonia. Two groups: 30 highly anxious, and 30 non-anxious mothers used xylitol (6 g/day) for 33 months and a non-treatment group of 60 mothers, both highly and low anxious (30 in each sub-group), acted as controls. All mothers were interviewed for oral health habits and education, and their dental health was examined. Due to discontinued participation 75% of the children (n=90) were examined at 2 and at 3 years of age. RESULTS: Anxious mothers brushed less frequently (p=0.014), had a longer time since their last dental visit (p<0.0001), and a lower level of education (p<0.0001) than their non-anxious counterparts. However, maternal anxiety had no effect on children's dental health, contrary to the caries prevention program which was effective both at 2 and at 3 years of age (p<0.01; OR 6.6, 1.8-25.0 and OR 3.9, CI 1.5-10.0, respectively). CONCLUSION: Children benefited from the caries prevention program, irrespective of maternal anxiety. PMID- 22449805 TI - Maternal education is an independent determinant of cariogenic feeding practices in the first year of life. AB - AIM: To identify risk factors for cariogenic feeding practices in the first year of life. STUDY DESIGN: Cohort study. METHODS: 500 children born within the public health care system in Sao Leopoldo, Brazil, were recruited in a follow-up program. Anthropometric and demographic data were collected soon after birth; data on feeding practices were assessed at 12 months of age using a standardised questionnaire; clinical examination at 4 years of age allowed identification of cariogenic feeding practices in the first year of life and to quantify their relative risks. In the present study, the attributable risks of each child were summed, and the outcome was assessed for the upper quartile of scores for cariogenic feeding practices. STATISTICS: Adjusted relative risks for the outcome were estimated using robust Poisson regression models. RESULTS: A total of 327 children comprised the final study sample, i.e. were followed from birth to 4 years of age. Multivariate analysis showed that the risk of cariogenic feeding practices doubled in children from mothers with less than 5 years of education (RR 2.19, 95%CI 1.26-3.82) and was 70% higher in children from mothers with 5-8 years of education when compared with maternal education >8 years. The other independent variables were not associated with the outcome. CONCLUSIONS: Low maternal education is a risk factor for cariogenic feeding practices, independently of other factors. Mothers with low educational levels should be the focus of child health promotion interventions, especially those aimed at controlling dental caries. PMID- 22449806 TI - Parental knowledge, attitudes and cultural beliefs regarding oral health and dental care of preschool children in an Indian population: a quantitative study. AB - AIM: Preschool children are dependent upon their parents for their dental care. The aim of this study was to assess the knowledge, attitude and beliefs of parents towards oral health and dental care of their children aged 1-4 years in an Indian population. METHODS: Parents of 620 preschool children, who visited Krishna Dental College and Hospital, Ghaziabad, India for dental treatment were recruited into this study and completed a self administered questionnaire. RESULTS: It was revealed that the lack of knowledge and awareness of importance of the primary teeth, dental fear of the parents and the myths associated with dental treatment, created barriers to early preventive dental care of preschool children. The oral hygiene and feeding practices were found to be disappointing and the knowledge about the essential role of fluoride and transmission of Streptococcus mutans bacteria was found to be limited. The elders in the family, especially grandparents, highly influenced the decisions of the parents regarding dental treatment of their children. CONCLUSIONS: Parents' knowledge, attitudes and beliefs about the importance of dental health need to be improved. Coordinated efforts by paediatricians, paediatric dentists and other health professionals are required to impart dental health education about oral hygiene, feeding practices, importance of the primary dentition and to promote preventive dental programmes. PMID- 22449807 TI - Investigation of mothers' knowledge of dental trauma management in United Arab Emirates. AB - AIM: To assess, by means of a structured questionnaire, mothers' level of knowledge with regards to the immediate emergency management of dental trauma in the Emirate of Ajman, United Arab Emirates (UAE). METHODS: A cross-sectional study using anonymous structured questionnaires was employed for mothers chosen at random from child care centres. The questionnaire surveyed mothers' background, knowledge and management of tooth fracture, avulsion, and also investigated mothers' self-assessed knowledge of the availability and priority of emergency services of trauma in UAE. RESULTS: The sample consisted of 676 mothers (response rate 96.6%) who attended mother and child care centres in Ajman over a period of two months (January-February 2011). More than half of the mothers participated in this study were in their twenties and 69.4% had university qualifications. Around 61.5% of the mothers had previous direct or indirect experience of dental trauma. Mother's knowledge of dental trauma seemed to be inadequate. Chi-square test indicated that there was no significant difference in the number of correct responses in relation to age, level of education, or number of observed trauma cases. Most mothers were unaware of the availability of after working hours emergency services. They were dissatisfied with their level of knowledge of dental trauma and the majority were interested in having further education on the topic. CONCLUSIONS: The level of knowledge of dental trauma management (especially tooth avulsion) among mothers in Ajman was inadequate and education campaigns are necessary to improve the emergency management of dental injuries. Therefore it is important to educate the public of the availability of after hours dental emergency services to overcome any delay in seeking professional help in cases of dental trauma. PMID- 22449808 TI - A review of the reasons and sources of referral to a hospital paediatric dental service in Ireland. AB - AIM: To examine the reasons for referral to the Paediatric Dental Department, Cork University Dental School and Hospital, Ireland and to study the profile of these reasons in terms of the various sources of referral. STUDY DESIGN: Clinical review. METHODS: Consecutive clinical records for children attending the service were reviewed with regard to a child's age at initial attendance, the reason for referral and the source of referral. Reasons for referral were recorded based on a defined list of acceptance criteria and were categorised by their different sources of referral. RESULTS: Records were available for 612 children with a mean age at time of initial consultation was 9.13 (SD+/- 3.94) years. Reason for referral; children who had difficulty co-operating for dental treatment made up the largest group (36.1%). Children who only required treatment planning comprised 25.0% of the total. Source of referral: 56.0% of consultations were from the salaried public dental service and 31.2% from private dental practitioners. Forty seven patients (7.7%) were from emergency department, while 31 (5.1%) were from medical practitioners. From the public dental service, 51.0% of referrals were for children who had difficulty co-operating for dental treatment and 22.7% were for treatment planning only. Referrals from private dental practitioners were most commonly for treatment planning only (38.2%). The proportion of referrals from the public dental service for children who had difficulty cooperating for dental treatment was twice as high as from private dentists. The proportion of referrals for trauma and for extensive dental disease from private dental practitioners was twice as high as from the public dental service. Almost all attendances from an emergency hospital department were for dental trauma. The majority of attendances from medical doctors were for medically at risk patients. CONCLUSIONS: Children with difficulty cooperating for dental treatment made up the largest single group of children attending the service. The majority of children attending were referred from the salaried public dental service. PMID- 22449809 TI - Comparison of validation methods for the diagnosis of occlusal caries in primary molars. AB - AIM: To evaluate the reproducibility of 7 validation methods used for caries diagnosis in primary teeth. METHODS: Seventy-two occlusal sites were selected on 40 primary molars. The sites were evaluated independently by 3 experienced examiners using validation methods that involved direct assessment, i.e. by using a (1) magnifying glass (8*) and (2) stereomicroscope (35*), or indirect assessment i.e. by using (3) photographs, (4) slide projections of photographs, (5) stereomicroscope (35*) photographs, (6) stereomicroscope (35*) slide projections, and (7) projections of polarised light microscope slides. Cohen's kappa coefficients were calculated and subjected to the Kruskal-Wallis test at a significance level of 5%. RESULTS: The mean inter-examiner kappa values for the validation methods were 0.31-0.51. There were statistically significant differences (p<0.05) between methods 1 and 3, 1 and 4, 2 and 4, 4 and 5, 4 and 6, and 4 and 7. Moderate agreement was observed for all methods except methods 1 and 4, for which the agreement was fair. CONCLUSIONS: The inter-examiner agreement for all validation methods for caries diagnosis was moderate, except for the method based on indirect assessment by slide projection, which showed low agreement. PMID- 22449810 TI - The success rates of a glass ionomer cement and a resin-based fissure sealant placed by fifth-year undergraduate dental students. AB - AIM: To evaluate retention and caries prevention of a glass-ionomer cement (GIC) and a resin-based fissure sealant placed by fifth-year undergraduate dental students. METHODS: The study was conducted according to a split-mouth, randomised clinical trial. Children with at least one pair of caries-free permanent first molars with deep pits and fissures were included in the study. The children were selected from a population that had a high risk for dental caries. Sealant materials were applied by fifth-year undergraduate dental students on 346 fissures of the first permanent molars in 173 children. The ages of the children ranged from 7-15 years (mean 9.4). Two researchers at the clinics supervised all of the procedures. Intra-examiner reproducibility and inter-examiner reproducibility were 0.90 and 0.86, respectively, for the clinical assessment of sealant retention and caries evaluation. RESULTS: GIC sealants were completely lost in 31.9% and resin-based sealants in 16.6% (p<0.05). The total retention rates of GIC sealants and resin-based sealants were 13.8% and 20.8%, respectively. After 24 months, the caries increment was 3.4% for GIC sealants and 4.8% for resin-based sealants (p>0.05). CONCLUSIONS: The retention of GIC sealants was markedly inferior to the retention of resin-based sealants; however, GIC when used as a pit and fissure sealant was slightly more effective in preventing occlusal caries. PMID- 22449811 TI - Case report: idiopathic pre-eruptive coronal resorption of a maxillary permanent canine. AB - BACKGROUND: Coronal resorption is a coronal degeneration of enamel and dentine in which ultimately the crown is replaced by vascular connective tissue through a defect in the enamel organ of an unerupted tooth. This is also known as pre eruptive coronal resorption. However, the aetiology of resorption remains unclear. CASE REPORT: A 13 years 7 months old Caucasian boy who attended an orthodontic consultation for anterior crossbite correction presented with idiopathic pre-eruptive coronal resorption of an erupted right maxillary permanent canine (FDI 13). Clinically, the enamel remaining on the crown was extremely thin and had a shell-like appearance. There was erythematous soft tissue within the parameters of the crown that resembled pulp tissue. From the radiographs, the irregular radiolucency area within the crown portion extended widely into the enamel and dentine. TREATMENT: Following excisional biopsy, it was decided to retain the right maxillary canine and monitor its progress. FOLLOW UP: He has been reviewed at frequent appointments over 18-months since the time there was radiographic evidence of resorption. CONCLUSION: It is prudent to make an early diagnosis of this condition and to formulate short and long-term treatment plans, which may involve keeping the affected tooth to retain the alveolar bone height and width to allow for the option of planning for an implant. PMID- 22449812 TI - Atypical protein kinase C in cardiometabolic abnormalities. AB - PURPOSE OF REVIEW: To review the aberrations of insulin signaling to atypical protein kinase C (aPKC) in muscle and liver that generate cardiovascular risk factors, including obesity, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in type 2 diabetes mellitus (T2DM), and obesity-associated metabolic syndrome (MetSyn). RECENT FINDINGS: aPKC and Akt mediate the insulin effects on glucose transport in muscle and synthesis of lipids, cytokines and glucose in liver. In T2DM, whereas Akt and aPKC activation are diminished in muscle, and hepatic Akt activation is diminished, hepatic aPKC activation is conserved. Imbalance between muscle and hepatic aPKC activation (and expression of PKC-iota in humans) by insulin results from differential downregulation of insulin receptor substrates that control phosphatidylinositol-3 kinase. Conserved activation of hepatic aPKC in hyperinsulinemic states of T2DM, obesity and MetSyn is problematic, as excessive activation of aPKC-dependent lipogenic, gluconeogenic and proinflammatory pathways increases the cardiovascular risk factors. Indeed, selective inhibition of hepatic aPKC by adenoviral-mediated expression of kinase-inactive aPKC, or newly developed small molecule biochemicals, dramatically improves abdominal obesity, hepatosteatosis, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in murine models of obesity and T2DM. SUMMARY: Hepatic aPKC is a unifying target for treating multiple clinical abnormalities that increase the cardiovascular risk in insulin-resistant states of obesity, MetSyn and T2DM. PMID- 22449813 TI - The holy grail of metabolic disease: brown adipose tissue. AB - PURPOSE OF REVIEW: The finding that brown adipose tissue (BAT) is present in adults brought BAT physiology into the focus of many researchers interested in energy metabolism. Here, we review recent insight into how BAT develops, functions and might help to treat metabolic disorders in humans. RECENT FINDINGS: BAT is under control of the nervous system, and several pathways have been identified that allow direct manipulation of BAT biology. In addition, some brown adipocytes arise from a distinct subset of white adipocyte precursors and studies were performed that characterize the development of these 'brite' adipocytes. Importantly, progress has been made in understanding how BAT takes up and dissipates nutrients that in metabolic disorders are present in excess. Finally, as it seems that BAT activity declines with age and obesity, we review findings that might shed light on how humans could sustain or increase BAT activity, thus preventing or treating obesity, hyperlipidemia and type 2 diabetes. SUMMARY: BAT is a powerful organ that controls the development of metabolic disease. These powers are boosted by mechanisms that turn white into brown fat and enhance lipid flux into BAT. However, in humans, it remains unclear what was the first: metabolic disease or decreased BAT activity. PMID- 22449814 TI - Connecting mTORC1 signaling to SREBP-1 activation. AB - PURPOSE OF REVIEW: The implication of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) in promoting protein synthesis has been well described. Over the past years, several studies revealed that mTORC1 also plays a crucial role in promoting lipid biosynthesis and that such connection could be linked to diseases including obesity, nonalcoholic fatty liver disease (NAFLD), and cancer. Here, we review the mechanisms by which mTORC1 regulates lipid synthesis by focusing on the key signaling events that trigger hepatic de-novo lipogenesis in response to nutrients and insulin. RECENT FINDINGS: mTORC1 promotes lipid synthesis by activating the transcription factor sterol regulatory element binding protein 1 (SREBP-1). Recent studies indicate that mTORC1 regulates SREBP-1 activation at multiple levels. Although mTORC1 was originally shown to be necessary and sufficient to activate SREBP-1 in vitro, new studies indicate that hyperactivation of mTORC1 is insufficient to trigger SREBP-1 activation and lipid biogenesis in vivo. These findings reveal that the molecular connection between mTORC1 and SREBP-1 is more complex than originally envisioned. SUMMARY: The discovery of a connection between mTORC1 and SREBP-1 opens a new chapter in our understanding of the molecular mechanisms regulating de-novo lipogenesis. A better comprehension of these mechanisms is key for the development of new tools to treat NAFLD and its complications. PMID- 22449815 TI - [A comprehensive review of literature to investigate development of global knowledge and consensus on asbestos carcinogenicity: up to the report and recommendations by UICC Working Group in 1964]. AB - This author comprehensively reviewed the literature on asbestos carcinogenicity up to the Report and Recommendations by Union Internationale Contra Cancrum (UICC) Working Group on asbestos and cancer in 1964. The first cases of mesothelioma and lung cancer in necropsied patients with asbestosis were reported in 1933 and 1934, respectively. After that, various studies examining the association between each of the diseases and asbestos exposure had been carried out until the meeting of the UICC Working Group: case report studies, case series studies, prevalence studies, historical cohort studies, and case-control studies. Newly reported studies including experimental studies in that meeting all supported the association. These findings on asbestos and cancer correspond well with Hill's criteria, which were just then advocated for evaluating causality epidemiologically. The Report and Recommendations by the Working Group concluded, "There is evidence of an association between exposure to asbestos and malignant neoplasia." and "The types of tumors ... are ... (1) carcinoma of the lungs, and (2) diffuse mesothelioma of the pleura and peritoneum." This author considers that the causal association between lung cancer or mesothelioma and asbestos was established at the meeting of UICC Working Group in 1964, not by the report on asbestos carcinogenicity in ILO (International Labour Organization) or IARC (International Agency for Research on Cancer) expert meetings in 1972, as the Japanese government announced. The amount of asbestos import in Japan doubled from 130,000 to 280,000 tons annually from 1964 to 1972. The government should have recognized the global knowledge on asbestos carcinogenicity in 1964; the amount of asbestos import could have been reduced greatly. PMID- 22449816 TI - [Malnutrition of fetal age and the infant health]. PMID- 22449817 TI - [Relationship of maternal malnutrition caused by Di(2-ethylhexyl) phthalate exposure with lifestyle disease in offspring]. AB - The hypothesis that offspring growing up malnourished during their fetal period have a high risk of lifestyle diseases in later life has been attracting great attention. Although animal experiments and epidemiological studies have been reported, most of them focused on the deficiency of maternal malnutritional elements or starvation. We found that di(2-ethylhexyl) phthalate (DEHP) decreased maternal plasma triglyceride levels, which is a significant source of nutrients for fetuses, in mice. Therefore, we analyzed how offspring exposed to malnutritional status during their fetal period develop potential adverse effects in later life. Male and female wild-type (mPPARalpha), Pparalpha-null, and hPPARalpha mice were treated with diets containing 0 or 0.05% DEHP. After 4 weeks, males and females in the same genotype and dose group were mated. After continued exposure until weaning, each group was divided into two groups, and one of them was dissected. The remaining was further divided into two subgroups; one was fed normal feed (control-diet group), while the other was fed a high-fat diet (HFD group). After 8-week feeding, all the mice were dissected. In the control diet group, DEHP exposure at the fetal and pup stages increased food consumption in mPPARalpha and hPPARalpha mice, but not in Ppara-null mice. In contrast, DEHP exposure decreased plasma leptin levels in mPPARalpha and hPPARalpha mice at the weaning stage. In the HFD group, DEHP exposure at the fetal and pup stages influenced neither food consumption nor leptin levels. These findings suggest that maternal malnutrition may be caused by not only nutritional deficiency but also exposure to some chemicals such as DEHP, and the latter case may also influence feeding behavior in offspring. These effects may be related to hepatic PPARalpha and diminished by HFD feeding. Further study is warranted as to whether such feeding behavior influences the risk of lifestyle diseases such as obesity. PMID- 22449819 TI - [Parent-child relationships and mindfulness]. AB - Psychological approaches such as mindfulness-based stress reduction or mindfulness-based cognitive therapy could be effective for relieving a wide range of psychosocial stresses or frictions between parents and children. Several interventional approaches based on mindfulness have been shown to be useful for improving parent-child relationships not only among healthy families but also among those with difficult psychopathologies. Particularly in the relationships of parents with their children with developmental disorders such as autism or attention-deficit/hyperactivity disorders, these approaches may play an important role in that the motivations of both parents and children could be enhanced because they can actually feel that their mental condition improves through meaningful parent-child interactions that they experience in their daily lives. These approaches are also expected to improve communications between mothers and children through the development of a finely honed sensitivity. One practical example is shown for the mental growth of children by the mindfulness-based dietary education and the secondary effects of this education on the parents. We can also apply these effective methods to the improvement of general interpersonal relationships. PMID- 22449820 TI - [Evidence-based policy and strategic planning of health system: how to utilize databases]. PMID- 22449821 TI - [Effect of cardiovascular risk factors on individual and population medical expenditures: a 10-year cohort study of 4,535 National Health Insurance beneficiaries in Shiga]. AB - A 10-year follow-up cohort study of 4,535 National Health Insurance beneficiaries aged 40 to 69 years in Shiga was performed as part of a research project conducted by the Health Promotion Research Committee of the Shiga National Health Insurance Organizations in 2002. The relationship between cardiovascular risk factors and medical expenditures during the 10-year study period has been examined in this cohort. For example, there was a positively graded correlation between blood pressure and individual total medical expenditures per month. The odds ratio for cumulative hospitalization and hazard ratio for all-cause mortality in severe hypertensives were also higher than those in normotensives. However, from the viewpoint of the entire population, the excess medical expenditures attributable to hypertension within the total medical expenditures were higher for mild-to-moderate hypertensives than for severe hypertensives. On the other hand, although individual medical expenditures per month were 1.7-fold higher for participants with 2 or 3 risk factors and obesity, which was broadly equivalent to metabolic syndrome, than for those without these factors, the excess medical expenditures determined by risk clustering within the total medical expenditures were higher in normal-weight people than in obese people because of the higher prevalence of normal weight. These findings suggest that high-risk individuals are a good target of a high-risk approach, such as intensive health guidance, from the viewpoint of medical expenditures. However, another approach for the majority with a low-to-moderate cardiovascular risk should be considered, because they account for a greater proportion of the excess medical expenditures. Another way to solve this problem may be a population approach with an effective method of providing information to citizens. PMID- 22449822 TI - [Evaluation of health promotion programs using health checkup data and medical receipts]. AB - OBJECTIVES: In a research project on the evaluation of health promotion programs using a health dataset including health checkup data and medical receipts, which was supported by a research grant from the Ministry of Health, Labour and Welfare, the potential preventive factors that influence disease severity and medical expenditure were studied. METHODS: A dataset from a city with a population of 36,544 and a large elderly population (31.1%) was studied using 12 elementary school geographical areas as the basis of classification. A dataset from a company of 4,780 employees was analyzed to determine changes in health checkup data related to metabolic syndrome over 3 years. A simulation model to identify factors that are important for reducing the incidence of complications such as ischemic heart disease and stroke was developed. RESULTS: Geographical analyses showed a negative association between the rate of participation in health checkup and the prevalence of noncommunicable diseases. The percentage of new patients who started pharmaceutical treatment was lower in the health-advice intervention group (5.2%) than in the nonintervention group (29.6%). A simulation model to identify factors that are important for reducing the incidence of complications was developed using data on health checkup participation, percentage of those who undertook a lifestyle-modification program, and compliance with medical treatment among others. CONCLUSIONS: Various health data including those on health checkup participation, percentage of those who undertook a lifestyle modification program, and compliance under medical treatment over 3 years were helpful in evaluating health promotion programs. PMID- 22449823 TI - [Lifetime medical expenditures of smokers and nonsmokers]. AB - OBJECTIVES: The aim of this study was to examine which of the two groups have higher lifetime medical expenditures; male smokers or male nonsmokers. We conducted this investigation using a Japanese single cohort database to calculate long-term medical expenditures and 95% confidence intervals. METHODS: We first constructed life tables for male smokers and male nonsmokers from the age of 40 years after analyzing their mortality rates. Next, we calculated the average annual medical expenditures of each of the two groups, categorized into survivors and deceased. Finally, we calculated long-term medical expenditures and performed sensitivity analyses. RESULTS: The results showed that although smokers had generally higher annual medical expenditures than nonsmokers, the former's lifetime medical expenditure was slightly lower than the latter's because of a shorter life expectancy that resulted from a higher mortality rate. Sensitivity analyses did not reverse the order of the two lifetime medical expenditures. CONCLUSIONS: In conclusion, although smoking may not result in an increase in lifetime medical expenditures, it is associated with diseases, decreased life expectancy, lower quality of life (QOL), and generally higher annual medical expenditures. It is crucial to promote further tobacco control strategically by maximizing the use of available data. PMID- 22449824 TI - [Practical use of E-claim data for regional healthcare planning]. AB - Japanese E-claim data contain comprehensive medical procedures and are adapted nationwide. Almost 94% of hospitals and pharmacies claim medical records for payment electronically. Although the handling and analysis of E-claim data are not as easy as those of Diagnosis Procedure Combination (DPC) data, these data contain important and useful information for the next regional healthcare planning of local governments in Japan. In this paper, we explain some examples of a healthcare delivery system in each region and patients' behavior in Hokkaido obtained from the Joint Program for E-claim database of Hokkaido University Hospital and the Hokkaido local government. Differences between the E-claim data format and the DPC data format are also described in terms of data analysis. Some suggestions are provided for the E-claim data format of the next generation. PMID- 22449825 TI - [Readmission rate for health care delivery system assessment]. AB - OBJECTIVES: The health care system in Japan has undergone major changes, with increasing focus on specialization and continuity of care in its organization and delivery. Reducing the average length of stay is central to this plan. Readmission is often seen as an avoidable consequence of early discharges. And therefore, the readmission rate is used to assess the quality and efficiency of care. In this study, the main subjects in the implementation of readmission rate as an indicator are laid out and the framework for readmission in acute myocardial infarction (AMI) patients is applied. METHODS: Literature review concerning readmission in AMI patients was conducted to understand the key points of the framework of the readmission. We then used insurance claims data to implement readmission as an indicator. The study sample consisted of 2,332 patients hospitalized due to AMI in Kyoto Prefecture from April 2009 to March 2010. RESULTS: The 30-day readmission rate after AMI discharge was 3.7% (87/2,332), with the majority of these admissions due to coronary disease (38%). This rate was extremely low compared to the results reported in other countries, with readmission rates as high as 20% observed in the US. However, we observed that countries with high readmission rates had correspondingly short lengths of stay (LOS), and countries such as Germany and Japan with low readmission rates had long LOS. CONCLUSIONS: The readmission rate in Japan is low compared with those in other countries although mean LOS is long. The use of readmission rate may have applications in understanding trends in healthcare quality as Japan attempts to reduce LOS durations. PMID- 22449826 TI - [Changes in mental health index, serum biochemical parameters and neutrophil function after start of the wheelchair use at a nursing home in Korea]. AB - OBJECTIVES: In Korea, long-term care insurance has been provided to the elderly since 2008. We conducted a health survey of the elderly in a nursing home in Korea from 2007 to 2010. Since the introduction of the insurance system, many of the elderly have started using wheelchairs. We aimed to determine the effect of using wheelchairs on mental health index, serum biochemical parameters, and neutrophil function. METHODS: The subjects were 32 elderly persons (mean age: 74.44 +/- 5.79 years) who could walk unaided in 2007 and were not bedridden until 2010. We classified the subjects into the walking group (subjects could walk unaided or with a cane until 2010; 10 men, 9 women) and the wheelchair group (subjects required the use of a wheelchair from 2007 to 2010; 2 men, 11 women). We determined stress score, stress tolerance, subjective well-being score in accordance with the Philadelphia Geriatric Center Morale Scale, and serum biochemical parameters. We also analyzed oxidant production and phagocytosis by neutrophils and estimated the balance between oxidant production and phagocytosis by correlation analysis. RESULTS: Increases in the stress tolerance of the wheelchair group in 2008 and 2009 and the subjective well-being score in 2009 in the survey were observed. However, in 2010, the stress tolerance and the subjective well-being score decreased to the levels in 2007. In 2010, the levels of serum albumin and high-density lipoprotein cholesterol of the wheelchair group were significantly lower than those of the walking group, and the balance between phagocytosis and oxidant production in the wheelchair group improved. PMID- 22449827 TI - [DNA damage in human pleural mesothelial cells induced by exposure to carbon nanotubes]. AB - OBJECTIVES: Nanomaterials are currently used in electronics, industrial materials, cosmetics, and medicine because they have useful physicochemical properties, such as strength, conductivity, durability, and chemical stability. As these materials have become widespread, many questions have arisen regarding their effects on health and the environment. In particular, recent studies have demonstrated that carbon nanotubes (CNTs) cause significant inflammation and mesothelioma in vivo. In this study, we investigated the potential risk posed by singlewalled carbon nanotube (SWCNT) and multiwalled carbon nanotube (MWCNT) exposure in human pleural mesothelial cells. METHODS: CNT cytotoxicity was determined by a trypan blue exclusion assay, and DNA damage was detected by an alkaline comet assay. The concentration of 8-oxodeoxyguanosine (8-OHdG) in DNA was measured by high perhormance liquid chromatography with electrochemical detection. The expression of base excision repair enzymes in the cell was estimated by immunoblot analysis. RESULTS: We observed inhibitory effects on cell proliferation and the induction of DNA damage following exposure of cells to purified CNTs that were suspended in dispersion medium. However, accumulation of 8-OHdG in DNA was not found. In addition, the expression levels of base excision enzymes that are involved in hOGG1, hMTH1, and MYH in MeT-5A cells remained unchanged for 24 h after carbon nanotube exposure. CONCLUSIONS: CNTs significantly inhibit cell proliferation and decrease DNA damage in human pleural mesothelial cells. Our results indicate that the mechanism of CNT-induced genotoxicity is different from that following exposure to reactive oxygen species, which causes oxidative DNA modifications and 8-OHdG production. Further investigation is required to characterize the specific DNA mutations that occur following CNT exposure. PMID- 22449828 TI - [Recruitment officers' attitude toward smoking habits of applicants]. AB - OBJECTIVES: This study sought to determine the implications of smoking cessation/prevention policy in college students. METHODS: We conducted an internet survey to investigate the attitude of recruitment officers in a company concerning acceptance evaluation and smoking of applicants. RESULTS: Among 838 respondents, more than one-half had unfavorable impressions when they saw new employees or college students smoking. Among the respondents, 3.7% answered that their companies had already introduced the policy of considering smoking status during acceptance evaluation to be acceptance policies, and 14.3% answered that this introduction is under consideration. Among the remaining 687 respondents, 7.6% answered that it can be included in the acceptance policies in the future and 45.7% answered it will not be included in the policies but can be considered during acceptance evaluation itself. Regarding their personal impression, 30% have experienced the case in which smoking status might have affected acceptance and 48.7% answered that it might affect acceptance in the future. CONCLUSIONS: Our study clarified that smoking status affected acceptance evaluation by recruitment officers in not a little cases although smoking status is not included in formal acceptance policies. Considering that there are only a few countermeasures for smoking among college students, job hunting activities can be a good opportunity for smoking cessation/prevention among them in collaboration with companies, colleges, and policy makers. PMID- 22449829 TI - Polymorphisms in ADAR1 gene affect response to interferon alpha based therapy for chronic hepatitis B in Han Chinese. AB - Host genetic polymorphisms in interferon pathway genes are reported to be associated with response to interferon therapy. Five hundred and forty-eight alpha interferon treatment-naive chronic hepatitis B patients were enrolled in the retrospective nested case-control study. All patients received alpha interferon based treatment and were examined for therapy efficacy. We genotyped 115 polymorphisms from 16 interferon pathway genes using the MassArray system. We identified rs4845384 in ADAR1 gene is strongly associated with the outcome of interferon therapy allele dose-depended (P=0.0005), with decreased odds ratios of 0.69 and 0.27 for GA and AA genotypes, respectively (95% confidence interval, 0.47-0.99 for GA; 0.11-0.64 for AA). Our study suggested that rs4845384 in ADAR1 associates with treatment-induced clearance of chronic hepatitis B. PMID- 22449830 TI - The future of trauma care in a developing country: interest of medical students and interns in surgery and surgical specialties. AB - BACKGROUND: Attracting the best medical graduates to trauma-related specialties is pivotal for excellent injury management in future, especially with the rising global incidence of injuries. We sought to explore the interest of Nigerian medical students and interns in Orthopaedics, Cardiothoracic, Neurological, Burns and Plastic and General Surgery specialties. METHODS: A cross-sectional study was conducted using a self-administered questionnaire to assess interest in selected trauma-related specialties among 177 senior medical students and interns at the Lagos State University Teaching Hospital and Lagos University Teaching Hospital in Lagos, Nigeria. Stratified random sampling method was employed and Chi-square test was performed in data analysis using SPSS v15.0 statistical package. RESULTS: Majority (80%) showed interest in post-graduate specialization. Surgery topped the list of specialties chosen by participants while 55% were likely to choose one of the selected trauma-related specialties. Exposure to positive role models, male gender and being single were significantly associated with interest in trauma-related future career. Opportunities for career fulfilment, carrying out difficult procedures, research and discovery, intellectual challenges during practice, use of modern technology, financial remuneration of specialists, patient outcomes and previous theatre experience had significant positive influence on participants who had strong interest in trauma-related specialty. Lifestyle issues like workload, call schedules, stress and duration of residency, training conditions and facilities and time commitment to practice had negative influence on choice of specialty. CONCLUSION: Interest of medical students and interns in trauma-related specialties may be sustained and enhanced by practicing surgeons through mentoring and by serving as role models. Training programs in surgery should be revisited and made less stressful while lifestyle issues need to be made more favourable. PMID- 22449831 TI - Postoperative port-site pain after gall bladder retrieval from epigastric vs. umbilical port in laparoscopic cholecystectomy: a randomized controlled trial. AB - OBJECTIVE: To determine whether gall bladder (GB) retrieval from umbilical port is associated with more pain at port site as compared to GB retrieval from epigastric port in adult patients undergoing four port elective laparoscopic cholecystectomy at a tertiary care hospital. METHODS: Adult patients, who were undergoing elective laparoscopic cholecystectomy during a six month period in 2010 at our institute, were randomized to either group A (n = 60, GB retrieval through epigastric port) or group B (n = 60, GB retrieval through umbilical port). VAS for pain was assessed by a registered nurse at 1, 6, 12, 24 and 36 h after surgery. RESULTS: The VAS for pain at umbilical port was less than epigastric port at 1, 6, 12, 24 and 36 h after surgery (5.9 +/- 1.1 vs. 4.1 +/- 1.5, 4.6 +/- 0.94 vs. 3.5 +/- 1.05, 3.9 +/- 0.85 vs. 2.4 +/- 0.79, 3.05 +/- 0.87 vs. 2.15 +/- 0.87, respectively) and the difference was statistically significant (p-value < 0.001). Multiple linear regression was done for port site pain at 24 h and the VAS at umbilical port was less than epigastric port with VAS difference of 0.9 after adjusting for age, sex, duration of surgery and additional analgesia use (r2 = 0.253, p-value < 0.001). CONCLUSION: Gall bladder retrieval from umbilical port is associated with lower port site pain than GB retrieval from epigastric port in patients undergoing elective laparoscopic cholecystectomy. We recommend umbilical port for gall bladder retrieval. PMID- 22449832 TI - A meta-analysis examining the use of tacker fixation versus no-fixation of mesh in laparoscopic inguinal hernia repair. AB - OBJECTIVE: The objective of this article is to systematically analyse the randomised, controlled trials comparing tacker mesh fixation (TMF) versus no-mesh fixation (NMF) in laparoscopic inguinal hernia repair (LIHR). METHODS: Randomised, controlled trials comparing TMF versus NMF in LIHR were analysed systematically using RevMan((r)), and combined outcomes were expressed as risk ratio (RR) and standardised mean difference (SMD). RESULTS: Eight randomised, controlled trials encompassing 1386 patients were retrieved from the electronic databases. There were 691 patients in the TMF group and 695 patients in the NMF group. Statistically there was non-significant heterogeneity among trials. In random effects models, operating time (p = 0.15), post-operative pain (p = 0.45), post-operative complications (p = 0.55) and length of hospital stay (p = 0.11) were statistically comparable between two techniques of mesh fixation in LIHR. The risk of developing chronic groin pain (p = 0.67) and risk of hernia recurrence (p = 0.77) was also similar. CONCLUSION: NMF in LIHR does not increase the risk of hernia recurrence. It is comparable with TMF in terms of operation time, post-operative pain, post-operative complications, length of hospital stay and chronic groin pain. Therefore, based upon the results of this review NMF approach may be adopted routinely and safely in LIHR. PMID- 22449833 TI - Improving the future of surgical training and education: consensus recommendations from the Association of Surgeons in Training. AB - In the past decade surgical training in the United Kingdom (UK) has seen radical overhaul with the introduction of formal training curricula, competency based assessment, and a new Core Surgical Training programme. Despite this, and in common with many other countries, numerous threats remain to sustaining high quality surgical training and education in the modern working environment. These include service delivery pressures and the reduction in working hours. There are numerous areas for potential improvement and dissemination of best training practice, from incentivising training within the National Health Service (NHS) through top-down government initiatives, to individualised information and feedback for trainees at the front-line. This document sets out the current structure of surgical training in the UK, and describes the contribution to the current debate by the Association of Surgeons in Training. Highlighting areas for improvement at national, regional, local and individual levels, the Association proposes 34 action points to enhance surgical training and education. Adoption of these will ensure future practice continues to improve on, and learn from, the longstanding history of training provided under the guidance of the Royal Surgical Colleges. PMID- 22449834 TI - The utility of CT angiography in planning perineal flap reconstruction following radical pelvic surgery. AB - INTRODUCTION: Closure of the perineum following radical excision of pelvic tumours can prove to be a complex surgical problem. A number of pedicled flaps have been used for perineal reconstruction in order to reduce post-operative complications such as infection and abscess formation. The aim of this case series was to analyse the use of pre-operative computer tomography (CT) angiography to guide flap selection for perineal reconstruction following radical excision of pelvic tumours. METHODS: We conducted a retrospective review to identify all patients who underwent CT angiography prior to radical excision of pelvic tumours and planned flap reconstruction over an 18 month period. Six patients were identified and are presented in this case series. Patients' medical records, histology reports, pre-operative investigations and CT angiograms, complications and follow-up were reviewed. RESULTS: The mean patient age was 58.3 years, with a male to female ratio of 1:2. Four out of six patients (66.6%) underwent pre-operative radiotherapy. The deep inferior epigastric arteries (DIEA) were visualised in all six cases (100%) and the pre-operative CT angiography helped guide flap choice in all cases (100%). In one case, narrowing of the DIEA vessels was noted precluding the use of a DIEA-based flap. One patient had a minor superficial wound dehiscence. CONCLUSION: Pre-operative CT angiography allows accurate visualisation of the DIEA system including perforator vessels. CT angiography is a useful tool, providing the surgical team with significant additional information to aid pre-operative planning and optimise reconstructive choice and outcome. PMID- 22449835 TI - Longitudinal changes in semantic categorization performance after symptomatic remission from first-episode psychosis: a 3-year follow-up study. AB - Semantic categorization abnormalities have been observed in schizophrenia, but studies have rarely focused on the longitudinal trajectory. In this study, we consider semantic performance and the relationship with symptomatic changes during recovery from a first-episode of schizophrenia over a period of 3 years. Thirty-seven first-episode patients with schizophrenia were compared to thirty seven matched controls in a categorization task. Patients were assessed at first episode, after clinical stabilization, and annually for the subsequent 3 years. In the task, participants indicated whether a word belonged to a given category. Each category contained words of varying degrees of semantic relatedness: typical, atypical, borderline, related-but-outside, and unrelated. Reaction times and proportion of 'yes' responses were analyzed. At first assessment, semantic categorization abnormalities were observed in first-episode patients. Patients assigned more semantically-dissimilar words to the categories than controls. As patients stabilized from acute states, their semantic categorization performance improved and then remained stable throughout the entire follow up period of 3 years. Interestingly, semantic performance deficits, particularly a diminished typicality effect, correlated with negative symptoms in the initial episode, but not at stabilization when symptoms subsided. No significant associations between positive and negative symptoms, or pre-defined categorization measures were identified. The data demonstrated semantic memory abnormalities in first-episode schizophrenia. However, an improvement of semantic categorization performance was observed in stabilized schizophrenia patients. Overall, the data are suggestive of a state effect in semantic abnormalities rather than a trait effect. The correlation between degree of impairment and symptoms may explain previous inconsistent findings. PMID- 22449836 TI - Minority recruitment into clinical trials: experimental findings and practical implications. AB - Racial and ethnic minorities in the US suffer disproportionately from obesity and related comorbidities, yet remain underrepresented in health research. To date, research on practical strategies to improve minority reach and recruitment into clinical trials is primarily descriptive rather than experimental. Within a randomized behavioral weight management trial for obese women, this recruitment experiment examined whether two characteristics of direct mail letters, an ethnically-targeted statement and personalization, increased the response rate among minority women. The ethnically-targeted statement noted ethnic-specific information about health risks of obesity. Personalized letters included recipients' names/addresses in the salutation and a handwritten signature on high quality letterhead. Of women sent direct mail letters (N=30,000), those sent letters with the ethnically-targeted statement were more likely to respond than women sent letters with the generic statement, 0.8% (n=121) vs. 0.6% (n=90) respectively, p=.03, a 34.4% increase. Women sent personalized letters were no more likely to respond than women sent non-personalized letters, p=.53. In the weight management trial itself, of 267 women randomized into the trial, 33.7% (n=90) were minorities. Of minority women randomized into the trial, 68.9% (n=62) were recruited by direct mail letters: 75.8% (n=47) of those were sent a letter and 24.2% (n=15) were referred by friends/family who were sent a letter. The results indicate that a simple modification to a standard recruitment letter can have a meaningful impact on minority reach and recruitment rates. Practical implications include using ethnically-targeted, non-personalized direct mail letters and recruiting through friends/family at no additional cost. PMID- 22449837 TI - A randomized trial to assess the effect of a research informational pamphlet on telephone survey completion rates among older Latinos. AB - PURPOSE OF THE STUDY: To assess the effects of receiving a research informational pamphlet produced by the federal Office for Human Research Protections on telephone survey participation rates of older Latinos, and illustrate the feasibility of nesting recruitment studies within other funded studies when stand alone funding for recruitment studies is limited. DESIGN AND METHODS: Latino patients aged >=50 with >=1 visit during the preceding year (N=1314) were sampled from three community clinics and a multi-specialty medical group. Patients were randomly assigned to receive or not receive a pamphlet that contained information on research participation in the initial mailing for the telephone survey study. Survey participation rates were compared between the pamphlet and no pamphlet groups. RESULTS: In a multivariate model, women (OR=1.4; 95% CI 1.1, 1.8), and those with public insurance (vs. no insurance; OR=1.7; 95% CI 1.1, 2.5) were more likely to participate, while those age 65+ (vs. age 50-54; OR=0.6; 95% CI 0.4, 0.8) were less likely to participate; there was no significant difference by pamphlet group (OR=0.8; 95% CI 0.7, 1.1). Nesting of the randomized trial of the recruitment pamphlet within the funded study required minimal additional resources. IMPLICATIONS: Recruitment methods that are more intensive than a pamphlet may be needed to enhance survey participation rates among older Latinos. Nesting recruitment trials within funded studies is a promising and efficient approach for testing recruitment strategies. PMID- 22449838 TI - Current situation of clinical trials in Beijing, China. AB - PURPOSE: This study investigated the current quality of clinical trials conducted in China. METHODS: Questionnaires were administered to medical doctors belonging to institutes affiliated to Peking University in Beijing, China. The delivery and collection of questionnaires were conducted by a research team from China. Analysis and evaluation were conducted by research teams from both China and Japan. RESULTS: A total of 145 questionnaires were administered and 117 respondents included the name of the medical institution to which they belonged. A total of 56.3% of the respondents participated in audit and inspection by institutes and 50.5% of the respondents reported receipt of the audit findings. A further 23.6% participated in audits and inspections performed by an external authority and 20.2% reported the receipt of the audit findings. CONCLUSION: Our research suggests that clinical trials in Beijing are well conducted and are monitored by both institutions and external authorities. PMID- 22449839 TI - Life before Nkx2.5: cardiovascular progenitor cells: embryonic origins and development. AB - Development of the heart, like that of other organs, requires the specification of progenitor cell populations that will ultimately form the differentiated cell types of the functional organ. A relatively recent and exciting advance in cardiac research has been the identification of cardiovascular progenitor cells (CPCs), which have the potential to form the major cell types of the heart (cardiomyocytes, smooth muscle, and endothelium/endocardium). This suggests that a common progenitor is responsible for much of heart development and has spurred great interest in use of CPC-like cells for cardiac repair. In this review, CPC development is discussed, with a focus on early events prior to the initiation of cardiac gene expression. In particular, I discuss evidence that CPC fate is established during gastrulation, well before a time when heart development has typically been studied. Pathways regulating CPC specification are examined. The relationship between CPC specification and migration is further discussed. Finally, how CPCs may be related to efforts to promote cardiac development by approaches including reprogramming is discussed. PMID- 22449840 TI - The second heart field. AB - Ten years ago, a population of cardiac progenitor cells was identified in pharyngeal mesoderm that gives rise to a major part of the amniote heart. These multipotent progenitor cells, termed the second heart field (SHF), contribute progressively to the poles of the elongating heart tube during looping morphogenesis, giving rise to myocardium, smooth muscle, and endothelial cells. Research into the mechanisms of SHF development has contributed significantly to our understanding of the properties of cardiac progenitor cells and the origins of congenital heart defects. Here recent data concerning the regulation, clinically relevant subpopulations, evolution and lineage relationships of the SHF are reviewed. Proliferation and differentiation of SHF cells are controlled by multiple intercellular signaling pathways and a transcriptional regulatory network that is beginning to be elucidated. Perturbation of SHF development results in common forms of congenital heart defects and particular progenitor cell subpopulations are highly relevant clinically, including cells giving rise to myocardium at the base of the pulmonary trunk and the interatrial septum. A SHF has recently been identified in amphibian, fish, and agnathan embryos, highlighting the important contribution of these cells to the evolution of the vertebrate heart. Finally, SHF-derived parts of the heart share a lineage relationship with craniofacial skeletal muscles revealing that these progenitor cells belong to a broad cardiocraniofacial field of pharyngeal mesoderm. Investigation of the mechanisms underlying the dynamic process of SHF deployment is likely to yield further insights into cardiac development and pathology. PMID- 22449841 TI - An unauthorized biography of the second heart field and a pioneer/scaffold model for cardiac development. AB - The identification of subpharyngeal cardiac precursors has had a strong influence on the way we think about early cardiac development. From this discovery was born the concept of multiple heart fields. Early support for the concept came from gene expression, genetic retrospective fate mapping, and gene targeting studies, which collectively suggested the existence of a second heart field (SHF) on the basis of specific Islet-1 (Isl-1) expression, presence of two cardiac ancestral lineages, and compatible cardiac knockout phenotypes, respectively. A decade after the original studies, support for the SHF concept is dwindling. This is because in all bilaterian models studied, Isl expression in heart progenitors is not SHF-specific, because lineage data are best explained by alternative models including an older, truly ancestral, lineage of cardiac pioneers with unrestricted contribution to all cardiac segments and, finally, because the inflow-to-outflow segmental nature of the early vertebrate peristaltic heart has been reaffirmed with novel, less invasive, methodologies. Altogether, the paradigms derived from the discovery of subpharyngeal cardiac progenitors helped us shift from relatively simple models, which rely predominantly either on patterning, gene expression patterns or lineages, to a much more sophisticated body of knowledge in which all these parameters must be accounted. Thus, it is well possible that due consideration of the key elements contained in the inflow/outflow, pioneer/scaffold, ballooning, and SHF hypotheses may provide us with a unified framework of the early stages of cardiac development. Here, we advance into this direction by suggesting an intuitive model of early heart development based on the concept of an inflow/outflow scaffold erected by cardiac pioneers, one that is required to assemble all the subsequent cell contribution that emigrates from cardiac progenitor areas. PMID- 22449842 TI - Development and evolution of the ascidian cardiogenic mesoderm. AB - The heart and other blood pumping organs are close to being universally essential in the animal kingdom. These organs present a large anatomical, morphological, and cellular diversity, which is thought to have arisen by building developmental modules on a conserved core of ancestral heart regulatory units. In this context, studies using the ascidian model system Ciona intestinalis offer a distinctive set of theoretical and experimental advantages, which we herein discuss in details. Development of the heart and related muscles in Ciona has been analyzed with a cellular to subcellular resolution unprecedented in Chordate model systems. Unique derived developmental characters of the cardiogenic mesoderm appear to be shared between Ciona and vertebrates. Notably, accumulating evidence point to an early Chordate origin of the cardiopharyngeal population of mesoderm cells that may have provided the foundation for the emergence of the second heart field in higher vertebrates. PMID- 22449843 TI - Regulation of GATA4 transcriptional activity in cardiovascular development and disease. AB - Transcription factors regulate formation and function of the heart, and perturbation of transcription factor expression and regulation disrupts normal heart structure and function. Multiple mechanisms regulate the level and locus specific activity of transcription factors, including transcription, translation, subcellular localization, posttranslational modifications, and context-dependent interactions with other transcription factors, chromatin remodeling enzymes, and epigenetic regulators. The zinc finger transcription factor GATA4 is among the best-studied cardiac transcriptional factors. This review focuses on molecular mechanisms that regulate GATA4 transcriptional activity in the cardiovascular system, providing a framework to investigate and understand the molecular regulation of cardiac gene transcription by other transcription factors. PMID- 22449844 TI - Localized and temporal gene regulation in heart development. AB - The heart is a structurally complex and functionally heterogeneous organ. The repertoire of genes active in a given cardiac cell defines its shapes and function. This process of localized or heterogeneous gene expression is regulated to a large extent at the level of transcription, dictating the degree particular genes in a cell are active. Therefore, errors in the regulation of localized gene expression are at the basis of misregulation of the delicate process of heart development and function. In this review, we provide an overview of the origin of the different components of the vertebrate heart, and discuss our current understanding of the regulation of localized gene expression in the developing heart. We will also discuss where future research may lead to gain more insight into this process, which should provide much needed insight into the dysregulation of heart development and function, and the etiology of congenital defects. PMID- 22449845 TI - Heart valve development, maintenance, and disease: the role of endothelial cells. AB - Heart valves are dynamic structures that open and close during the cardiac cycle to maintain unidirectional blood flow throughout life. Insufficient valve function, commonly due to congenital malformations leads to disruptions in hemodynamics and eventual heart failure. Mature valve leaflets are composed of a heterogeneous population of interstitial cells and stratified extracellular matrix, surrounded by a layer of endothelial cells. This defined connective tissue "architecture" provides the valve with all the necessary biomechanical properties required to efficiently function while withstanding constant cyclic shear stress. Valvular endothelial cells (VECs) play essential roles in establishing the valve structures during embryonic development and are important for maintaining lifelong valve integrity and function. In contrast to a continuous endothelium over the surface of healthy valve leaflets, VEC disruption is commonly observed in malfunctioning valves and is associated with pathological processes that promote valve sclerosis and calcification. Increasing our understanding of the roles of VECs in development and disease has lead to promising advances in the development of endothelial cell-based therapies for treating valve disease. PMID- 22449846 TI - An epicardial floor plan for building and rebuilding the mammalian heart. AB - The epicardium is a mesothelial cell layer which contributes to the coronary vessels and myocardium and acts as an important source of trophic signals to maintain continued growth and differentiation of the developing heart. The precise lineage potential of the embryonic epicardium has come under recent scrutiny with notable questions around its capacity to give rise to derivative vascular endothelial cells and cardiomyocytes. The importance of the epicardium is not restricted to heart formation. Recent studies in the adult heart have highlighted a paracrine role in modulating injury and have begun to realize its potential as a source of progenitor cells (EPDCs) which may be reactivated toward facilitating neovascularization and myocardial repair after ischemic injury. Thus, the adult epicardium has an embryological origin and emerges as a prime exemplar of the paradigm of activated resident stem cell therapy in regenerative medicine, whereupon a major goal is to restore embryonic plasticity to otherwise dormant adult progenitors and facilitate organ repair. In this review, we will explore current thinking on the origins of the epicardium, its role as a signaling center, lineage heterogeneity, and controversy around epicardial potential within the developing heart. We will extrapolate to the adult injury setting, drawing on key studies in zebrafish and mouse which establish the basis for the adult epicardium as a target for cardiovascular regeneration. Finally, we will consider translation of this potential to the human lineage alongside the prospects for discovery of target cell-based therapeutics. PMID- 22449847 TI - Transcription factor pathways and congenital heart disease. AB - Congenital heart disease is a major cause of morbidity and mortality throughout life. Mutations in numerous transcription factors have been identified in patients and families with some of the most common forms of cardiac malformations and arrhythmias. This review discusses transcription factor pathways known to be important for normal heart development and how abnormalities in these pathways have been linked to morphological and functional forms of congenital heart defects. A comprehensive, current list of known transcription factor mutations associated with congenital heart disease is provided, but the review focuses primarily on three key transcription factors, Nkx2-5, GATA4, and Tbx5, and their known biochemical and genetic partners. By understanding the interaction partners, transcriptional targets, and upstream activators of these core cardiac transcription factors, additional information about normal heart formation and further insight into genes and pathways affected in congenital heart disease should result. PMID- 22449848 TI - MicroRNAs in heart development. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs of ~22nt in length which are involved in the regulation of gene expression at the posttranscriptional level by degrading their target mRNAs and/or inhibiting their translation. Expressed ubiquitously or in a tissue-specific manner, miRNAs are involved in the regulation of many biological processes such as cell proliferation, differentiation, apoptosis, and the maintenance of normal cellular physiology. Many miRNAs are expressed in embryonic, postnatal, and adult hearts. Aberrant expression or genetic deletion of miRNAs is associated with abnormal cardiac cell differentiation, disruption of heart development, and cardiac dysfunction. This chapter will summarize the history, biogenesis, and processing of miRNAs as well as their function in heart development, remodeling, and disease. PMID- 22449849 TI - Cardiac regeneration. AB - The heart is a pump that is comprised of cardiac myocytes and other cell types and whose proper function is critical to quality of life. The ability to trigger regeneration of heart muscle following injury eludes adult mammals, a deficiency of great clinical impact. Major research efforts are attempting to change this through advances in cell therapy or activating endogenous regenerative mechanisms that exist only early in life. In contrast with mammals, lower vertebrates like zebrafish demonstrate an impressive natural capacity for cardiac regeneration throughout life. This review will cover recent progress in the field of heart regeneration with a focus on endogenous regenerative capacity and its potential manipulation. PMID- 22449850 TI - The development of the embryonic heart. Preface. PMID- 22449851 TI - Inhibitory effect of andrographolide in 3T3-L1 adipocytes differentiation through the PPARgamma pathway. AB - Andrographolide (AG), an active compound found in Andrographis paniculate Nees, has been shown to exert anti-inflammatory, anticancer and anti-hyperglycemic effects. However, its biological activities against obesity have not been reported. The purpose of this study was to investigate the effect of AG on the differentiation of 3T3-L1 preadipocytes. We found AG significantly inhibited not only on adipocyte differentiation induced by standard adipogenic agents and MDI, but also on the adipogenesis-related transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), as well as the expressions of the PPARgamma targeted genes, such as CD36, LPL, FAS and other adiocyte markers. Taken together, our data showed AG inhibited the early stage of adipogenic differentiation, in part via the inhibition of PPARgamma-dependent mechanisms. PMID- 22449852 TI - Calcium sensing receptor activation elevates proinflammatory factor expression in human adipose cells and adipose tissue. AB - The proinflammatory status of adipose tissue has been linked to the metabolic and cardiovascular consequences of obesity. Human adipose cells express the calcium sensing receptor (CaSR), and its expression is elevated in inflammatory states, such as that associated with obesity. Given the CaSR's association with inflammation in other tissues, we evaluated its role elevating the adipose expression of inflammatory factors. The CaSR activation by the calcimimatic cinacalcet (5MUM) in adipose tissue and in vitro cultured LS14 adipose cells elicited an elevation in the expression of the proinflammatory cytokines IL6, IL1beta, TNFalpha, and the chemoattractant CCL2. This was in part reverted by SN50, an inhibitor of the inflammatory mediator nuclear factor kappa B (NFkappaB). Our observations suggest that CaSR activation elevates cytokine and chemokine production, partially mediated by NFkappaB. These findings support the relevance of the CaSR in the pathophysiology of obesity-induced adipose tissue dysfunction, with an interesting potential for pharmacological manipulation. PMID- 22449854 TI - Endoscopic endonasal resection of extensive anterior skull base sinonasal osteoblastoma. PMID- 22449853 TI - Probing the role of structural features of mouse PrP in yeast by expression as Sup35-PrP fusions. AB - The yeast Saccharomyces cerevisiae is a tractable model organism in which both to explore the molecular mechanisms underlying the generation of disease-associated protein misfolding and to map the cellular responses to potentially toxic misfolded proteins. Specific targets have included proteins which in certain disease states form amyloids and lead to neurodegeneration. Such studies are greatly facilitated by the extensive 'toolbox' available to the yeast researcher that provides a range of cell engineering options. Consequently, a number of assays at the cell and molecular level have been set up to report on specific protein misfolding events associated with endogenous or heterologous proteins. One major target is the mammalian prion protein PrP because we know little about what specific sequence and/or structural feature(s) of PrP are important for its conversion to the infectious prion form, PrP (Sc) . Here, using a study of the expression in yeast of fusion proteins comprising the yeast prion protein Sup35 fused to various regions of mouse PrP protein, we show how PrP sequences can direct the formation of non-transmissible amyloids and focus in particular on the role of the mouse octarepeat region. Through this study we illustrate the benefits and limitations of yeast-based models for protein misfolding disorders. PMID- 22449855 TI - Upper lip dermoid in a 13-month-old child. PMID- 22449856 TI - Riedel disease: report of extensive disease requiring a total laryngectomy. PMID- 22449857 TI - Laryngeal anisakiasis: an unusual cause of foreign-body sensation in the throat. PMID- 22449860 TI - Increased human herpes virus 6 DNA detected by real-time PCR in the saliva of two patients with drug-induced hypersensitivity syndrome. PMID- 22449861 TI - Microneurosurgical management of anterior choroidal artery aneurysms: a 16-year institutional experience of 102 patients. AB - OBJECTIVE: Surgical treatment of anterior choroidal artery aneurysms (AChAAs) continues to be challenging and technically demanding for vascular neurosurgeons. Ischemic stroke is the most common complication after surgical clipping of AChAAs. We retrospectively studied a series of 102 consecutive patients with AChAAs to evaluate the clinical outcomes and ischemic complications after surgical clipping. METHODS: Between January 1995 and December 2010, 102 patients presenting at West China Hospital, with a total of 106 AChAAs that were treated with surgical clipping were included in this study. There were 40 men (39%) and 62 women (61%) with an average age of 52 years (range 34-78 years). There were 62 small, 40 medium, and 4 large aneurysms. Clinical outcomes, treatment-related complications, follow-up results, and the factors influencing the clinical outcomes were evaluated. RESULTS: Eighty-three patients (81%) achieved a good outcome (Glasgow outcome scale score 4-5) at follow-up for a mean of 18.8 months (range 4-103 months). The surgical mortality rate was 7%, and the major surgical morbidity was 12%. Fifteen patients (15%) had clinical anterior choroidal artery (AChA) territory infarction confirmed by computerized tomography. In 36 patients, the AChAA was originated entirely or partially from the AChA itself, 10 (27.8%) of them had postoperative ischemic complication. None of the 95 followed patients had rebleeding or regrowth of residual aneurysm during this period. CONCLUSIONS: The surgery of AChAAs is not easy, surgical management of AChAAs carries with it a high risk of postoperative ischemic complications, especially for those aneurysms originating entirely or partially from the AChA itself. PMID- 22449862 TI - Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T. AB - Depression is a complex psychiatric disorder characterized by anhedonia and feeling of sadness and chronic mild stress (CMS) seems to be a valuable animal model of depression. CMS animal model was induced and validated using behavioral studies. In the present study we investigated the neuro-metabolite changes occurring in prefrontal cortex and hippocampus during the onset of depression, in CMS rat model using in vivo proton magnetic resonance spectroscopy ((1)H MRS) at field strength of 7 T. Results showed that CMS caused depression-like behavior in rats, as indicated by the decrease in sucrose consumption and locomotor activity. (1)H MRS was performed in both control and CMS rats (n=10, in each group) and the quantitative assessment of the neurometabolites was done using LC model. Relative concentrations of all the metabolites along with the macromolecules were calculated for analysis. The results revealed a significant decrease of glutamate (Glu), glutamine (Gln), NAA+NAAG, Glx and GABA levels in both hippocampus and prefrontal cortex of CMS animals and an elevated level of myo-ionisitol (mI) and taurine (Tau) was observed only in hippocampus. These metabolite fluctuations revealed by proton MRS indicate that there might be change in the neuronal integrity of the glial cells and neurons within prefrontal cortex and hippocampus in CMS model of depression. The present study also suggests that there may be a degenerative process concerning the brain morphology in the CMS rats. The overall finding using (1)H MRS suggests that, there might be a major role of the glia and neuron in the onset of depression. PMID- 22449863 TI - Prior action execution has no effect on corticospinal facilitation during action observation. AB - Transcranial magnetic stimulation (TMS) has been used widely in research investigating corticospinal (CS) excitability during action observation. Generally, this work has shown that observation of an action performed by others, in the absence of overt movement, modulates the excitability of the CS pathway in humans. Despite the extent of the literature exploring action observation effects, however, there has been little research to date that has compared observation with the combination of observation and execution directly. Here, we report a single-pulse TMS study that investigated whether CS excitability during action observation was modulated by actions performed by the observers prior to viewing a ball pinching action. The results showed that CS excitability during action observation increased when compared to observation of a static hand, but that there was no additional motor facilitation when participants performed the same action prior to observing it. Our findings highlight the importance of action observation and its consequences on the CS system, whilst also illustrating the limited effect of prior action execution on the CS pathway for a simple action task. PMID- 22449864 TI - Determinants of campylobacteriosis notifications in New Zealand. PMID- 22449865 TI - Ongoing measles outbreak in Elche, Spain, 29 January to 9 March 2012. AB - On 29 January 2012, the first case of measles in Elche, Spain, since 2001 was notified through the epidemiological surveillance system of the Valencian Community. As of 9 March, 109 cases have been notified. The outbreak started in a neighbourhood where the vaccination coverage of the population is inadequate. This report highlights the need to vaccinate the susceptible population and also points to the importance of developing coordinated measures between public health centres and hospital preventive services. PMID- 22449866 TI - Identification of OXA-23-producing Acinetobacter baumannii in Greece, 2010 to 2011. AB - We report on the sequence type and beta-lactamase content of 174 carbapenem resistant Acinetobacter baumannii isolates recovered from clinical specimens during 2010 and 2011 in a tertiary care hospital in central Greece. Carbapenem resistance was associated mainly with carriage of the bla(OXA-23) gene (in 72.4% of the isolates). To our knowledge, this is the first description of A. baumannii strains producing OXA-23 in Greece. During 2011, in our hospital they rapidly 'replaced' the previously predominant OXA-58- positive A. baumannii strains. PMID- 22449867 TI - Moderate influenza vaccine effectiveness in Victoria, Australia, 2011. AB - We used a sentinel general practitioner (GP) network to conduct surveillance for laboratory-confirmed influenza amongst patients presenting with influenza-like illness (ILI) in Victoria, Australia in 2011. The test negative variation of the case control study design was used to estimate effectiveness for seasonal trivalent influenza vaccine. Cases and controls were ILI patients that tested positive and negative for influenza, respectively. Vaccination status was recorded by GPs and vaccine effectiveness (VE) was calculated as (1-adjusted odds ratio)x100%. There were 529 patients included in the study, of which 29% were influenza positive. Twelve percent of study participants were reported as vaccinated, 6% of cases and 15% of controls. Adjusted VE against all influenza was 56%, but not statistically significant. There was generally little variation in VE estimates when stratified by virus type and subtype, which is consistent with good matches between circulating strains and the vaccine strains. The VE was higher among adults of working age than among children. PMID- 22449868 TI - Outbreak investigation of brucellosis in Thassos, Greece, 2008. AB - In spring 2008, the Hellenic Center for Disease Control and Prevention was notified about human brucellosis cases in Thassos, a Greek island that had been up to that point under a brucellosis eradication programme. Following the verification of the outbreak a 1:1 case- control study was conducted in the island. The study revealed that consumption of locally produced raw cheese was a risk factor for Brucella melitensis infection (odds ratio (OR): 15.1, 95% confidence interval (CI): 6.56-34.7). Brucella melitensis biotype 3 was identified in two clinical samples. As a result of the outbreak, the island is no longer officially considered as an area with farms free of brucellosis and is currently under a brucellosis control programme. The investigation of this outbreak demonstrated that control and eradication of brucellosis is not only a question of designing a strategy, but rather of ensuring its continuous, strict implementation. Furthermore, it revealed the lack of appropriate education of the public regarding the risks associated with raw, non heat-treated cheese consumption. PMID- 22449869 TI - Carbapenem-resistant Acinetobacter baumannii carrying the NDM-1 gene, Czech Republic, 2011. PMID- 22449872 TI - Proteomic analysis of the very low density lipoprotein (VLDL) transport vesicles. AB - The VLDL transport vesicle (VTV) mediates the transport of nascent VLDL particles from the ER to the Golgi and plays a key role in VLDL-secretion from the liver. The functionality of VTV is controlled by specific proteins; however, full characterization and proteomic profiling of VTV remain to be carried out. Here, we report the first proteomic profile of VTVs. VTVs were purified to their homogeneity and characterized biochemically and morphologically. Thin section transmission electron microscopy suggests that the size of VTV ranges between 100 nm to 120 nm and each vesicle contains only one VLDL particle. Immunoblotting data indicate VTV concentrate apoB100, apoB48 and apoAIV but exclude apoAI. Proteomic analysis based on 2D-gel coupled with MALDI-TOF identified a number of vesicle-related proteins, however, many important VTV proteins could only be identified using LC-MS/MS methodology. Our data strongly indicate that VTVs greatly differ in their proteome with their counterparts of intestinal origin, the PCTVs. For example, VTV contains Sec22b, SVIP, ApoC-I, reticulon 3, cideB, LPCAT3 etc. which are not present in PCTV. The VTV proteome reported here will provide a basic tool to study the mechanisms underlying VLDL biogenesis, maturation, intracellular trafficking and secretion from the liver. PMID- 22449873 TI - Right-to-left shunts and micro-embolization in migraine. AB - PURPOSE OF REVIEW: The present review covers the latest studies on right-to-left shunts (RLSs) in migraine patients and different types of emboli capable of triggering migraine. RECENT FINDINGS: Although three recent studies found no increased RLS prevalence in migraine with aura patients, there remains ample evidence that the prevalence of RLS is increased in migraine with aura. Introduced emboli in the carotid artery of mice have been shown to cause cortical spreading depression, which has been considered the pathophysiological mechanism of migraine aura. In humans, iatrogenic introduced (micro)-emboli can provoke migraine attacks; available evidence, however, is limited. SUMMARY: RLS and migraine with aura (but not without) are comorbid conditions, but the biological mechanism remains speculative. Specific emboli are probably able (although infrequently) to induce migraine symptoms. There is no convincing evidence that closure of a RLS alters migraine frequency; therefore, diagnosis or treatment of RLS in migraine has no place in daily clinical practice and should only take place in controlled studies. PMID- 22449874 TI - New preceptor benefit. PMID- 22449875 TI - The use of high-fidelity simulation for rapid response team training: a community hospital's story. AB - The authors describe how simulation training was used to improve rapid response team activation in a nonteaching, nonprofit community hospital. Goals were established, and a scenario was developed to educate the healthcare team on the importance of early activation of the rapid response ream. Organizing and implementing a large-scale simulation required a solid commitment from the staff development department. The education from the simulation has led to increased knowledge and comfort levels of clinical staff, resulting in an increased use of the rapid response team. PMID- 22449876 TI - Overcoming barriers to implementing evidence-based practice: a collaboration between academics and practice. AB - This article describes two collaborative paired student-preceptor efforts. One project resulted in the implementation of a hospital-wide oral care protocol, and the second enhanced the admission assessment process for adult patients at risk for respiratory compromise after sedation and/or receipt of narcotic analgesia. Recommendations for staff development are addressed. PMID- 22449877 TI - Needs assessment: blueprint for a nurse graduate orientation employer toolkit. AB - Southern Nevada nurse employers are resistant to hiring new graduate nurses (NGNs) because of their difficulties in making the transition into the workplace. At the same time, employers consider nurse residencies cost-prohibitive. Therefore, an alternative strategy was developed to assist employers with increasing the effectiveness of existing NGN orientation programs. A needs assessment of NGNs, employers, and nursing educators was completed, and the results were used to develop a toolkit for employers. PMID- 22449878 TI - Assessment of clinical judgment in nursing orientation: time well invested. AB - There is a correlation between patient safety and nursing orientation. The authors discuss a mixed-method study that supports the efficacy of using a competency-based process to assess knowledge and judgment skills of registered nurses in a community hospital. This assessment is the backbone of the competency based orientation. PMID- 22449879 TI - Using a professional writing retreat to enhance professional publications, presentations, and research development with staff nurses. AB - This article presents the outcomes of a structured writing retreat used with a group of professional nurses from a Magnet-designated hospital. The purpose of the retreat was to enhance nurses' ability to prepare poster presentations, develop manuscripts for peer-reviewed journal submissions, and design new research studies. This staff development retreat can serve as an exemplar for other hospitals desiring to increase dissemination of best practice. PMID- 22449880 TI - Infusing research into practice: a staff nurse evidence-based practice fellowship program. AB - This article describes the framework and dynamics of an evidence-based practice mentorship program for staff nurses. Staff development educators can be instrumental as leaders in an evidence-based practice fellowship program, as they foster a thirst for lifelong learning, assist with developing a questioning attitude, and inspire nurses to ask clinical questions. The program serves as a bridge to bring research into real-world patient care that results in improved patient outcomes. PMID- 22449881 TI - Quality of work life of novice nurses: a qualitative exploration. AB - This qualitative research study examines factors influencing the quality of work life of novice nurses (less than 2 years' experience) in the Eastern Regional Health Authority in St. John's, Newfoundland and Labrador, Canada. Although novice nurses are highly motivated to provide quality patient care, they encounter many sources of stress, including "difficult personalities," inadequate orientation and mentoring, and horizontal violence from nursing and medical colleagues. These stressors are compounded by staffing shortages and heavy workloads. Supportive mentoring and adequate orientation are key factors to successful transition. PMID- 22449882 TI - Nursing professional development: stories, tips, and techniques. PMID- 22449883 TI - Respect. PMID- 22449884 TI - NNSDO in Boston in 2012: revolutionizing healthcare education. PMID- 22449885 TI - Mentoring nurses in evidence-based projects. PMID- 22449886 TI - The professional portfolio--a tool to document nursing competency. PMID- 22449887 TI - Cardiac clinical skill assessments for registered nurses. AB - This article outlines a framework of clinical skill assessments that identify the knowledge and skills required for safe and competent care of cardiac patients. This framework categorizes identified cardiac skills into a logical sequence for assessment, aims to standardize the assessment process, and allows transportability of clinical skills. PMID- 22449889 TI - Preceptorship-making a difference. AB - A preceptor project at the Royal Brisbane and Women's Hospital in Queensland, Australia, explored existing levels of preceptorship support during the transition processes of newly employed or transferred nurses and midwives. Initiatives adopted have enhanced the implementation and maintenance of preceptorship principles and communication processes and defined accountability and responsibilities. Outcomes have contributed to enhanced role clarity, improved communication, increased support for teaching and learning, and infrastructure processes to facilitate the preceptor-preceptee relationship and increased retention. PMID- 22449890 TI - Evaluation of basic arrhythmia knowledge retention and clinical application by registered nurses. AB - The purpose of this descriptive study was to evaluate knowledge retention over time and clinical application of basic arrhythmia knowledge following exposure to an orientation program. Data showed significant differences in knowledge retention at 4 weeks and clinical application in rhythm identification using simulation at 3 months. PMID- 22449891 TI - Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. AB - Major depressive disorder (MDD) is the most common psychiatric disorder and the second overall cause of disability. Even though a significant amount of the variance in the MDD phenotype is explained by inheritance, specific genetic variants conferring susceptibility to MDD explain only a minimal proportion of MDD causality. Moreover, genome-wide association studies have only identified two small-sized effect loci that reach genome-wide significance. In this study, a group of Mexican-American patients with MDD and controls recruited for a pharmacogenetic study were genotyped for nonsynonymous single-nucleotide polymorphisms (nsSNPs) and used to explore the interactions of multiple functional genetic variants with risk-classification tree analysis. The risk classification tree analysis model and linkage disequilibrium blocks were used to replicate exploratory findings in the database of genotypes and phenotypes (dbGaP) for major depression, and pathway analysis was performed to explore potential biological mechanisms using the branching events. In exploratory analyses, we found that risk-classification tree analysis, using 15 nsSNPs that had a nominal association with MDD diagnosis, identified multiple increased-MDD genotype clusters and significant additive interactions in combinations of genotype variants that were significantly associated with MDD. The results in the dbGaP for major depression disclosed a multidimensional dependent phenotype constituted of MDD plus significant modifiers (smoking, marriage status, age, alcohol abuse/dependence and gender), which then was used for the association tree analysis. The reconstructed tree analysis for the dbGaP data showed robust reliability and replicated most of the genes involved in the branching process found in our exploratory analyses. Pathway analysis using all six major events of branching (PSMD9, HSD3B1, BDNF, GHRHR, PDE6C and PDLIM5) was significant for positive regulation of cellular and biological processes that are relevant to growth and organ development. Our findings not only provide important insights into the biological pathways underlying innate susceptibility to MDD but also offer a predictive framework based on interactions of multiple functional genetic variants and environmental factors. These findings identify novel targets for therapeutics and for translation into preventive, clinical and personalized health care. PMID- 22449892 TI - Rumination mediates the relationship between impaired cognitive control for emotional information and depressive symptoms: A prospective study in remitted depressed adults. AB - Impaired cognitive control may be an important vulnerability factor for depression. Moreover, impairments in cognitive control have been proposed as a crucial process underlying ruminative thinking. The present study investigates the influence of impaired cognitive control for emotional information on rumination and depressive symptoms in a prospective design with a 1 year follow up in a clinical sample. Thirty remitted depressed adults completed the Internal Shift Task (IST), a measure of cognitive control of emotional information, at baseline. Moreover, questionnaires measuring rumination (RRS) and depressive symptoms (BDI-II) were administered. One year later participants were contacted again and asked to complete the BDI-II and RRS. Mediation analyses showed a significant influence of impaired cognitive control for emotional information at baseline on depressive symptoms one year later, which was fully mediated by rumination. These findings underscore the importance of cognitive control abilities as a process underlying rumination and as a vulnerability factor for depression. They can stimulate translational research to improve the effectiveness of interventions that aim to decrease vulnerability by targeting cognitive control. PMID- 22449893 TI - Significance of overvaluation of shape and weight in an ethnically diverse sample of obese patients with binge-eating disorder in primary care settings. AB - Undue influence of shape or weight on self-evaluation--referred to as overvaluation--is a core feature across eating disorders, but is not a diagnostic requirement for binge-eating disorder (BED). This study examined overvaluation of shape/weight in ethnically diverse obese patients with BED seeking treatment in primary care. Participants were a consecutive series of 142 (105 female and 37 male) participants with BED; 43% were Caucasian, 37% were African-American, 13% were Hispanic-American, and 7% were of "other" ethnicity. Participants categorized with overvaluation (N=97; 68%) versus without clinical overvaluation (N=45; 32%) did not differ significantly in ethnicity/race, age, gender, body mass index, or binge-eating frequency. The overvaluation group had significantly greater levels of eating disorder psychopathology, poorer psychological functioning (higher depression, lower self-esteem), and greater anxiety disorder co-morbidity than the group who did not overvalue their shape/weight. The greater eating disorder and psychological disturbance levels in the overvaluation group relative to the non-overvaluation group persisted after controlling for psychiatric co-morbidity. Our findings, based on an ethnically diverse series of patients seeking treatment in general primary care settings, are consistent with findings from specialist clinics and suggest that overvaluation does not simply reflect concerns commensurate with being obese or with frequency of binge-eating, but is strongly associated with heightened eating-related psychopathology and psychological distress. Overvaluation of shape/weight warrants consideration as a diagnostic specifier for BED as it provides important information about severity. PMID- 22449894 TI - [Influence of b value on the measurement of contrast and apparent diffusion coefficient in 3.0 Tesla breast magnetic resonance imaging]. AB - Diffusion-weighted imaging (DWI) has been used to characterize not only the brain, but also the breast by implementation of faster imaging techniques and higher magnetic field strengths. However, the optimum b value, which is an important scan parameter for DW images contrast on 3 T breast magnetic resonance imaging (MRI) has not been established. The purpose of this study was to investigate the influence of different b value combinations on the image contrast and apparent diffusion coefficient (ADC) in patients with known invasive carcinoma, ductal carcinoma in situ (DCIS), and normal mammary gland in breast DWI. The analysis procedure consisted of the following methods: 1) T(2) correction of DW images with echo-planar imaging (EPI) T(2)-weighted images; 2) contrast measurement between normal mammary gland and tumor tissues; 3) ADC measurement of normal mammary gland and tumor tissues. In many cases, the highest contrast between normal mammary gland and tumor tissues was obtained using a b value of 1500 s/mm(2). Our results indicated that when only one b value is used, the b value in which signal intensities of normal mammary gland decreases down to noise level, and the contrast between normal mammary gland and tumor tissues is recommended. ADC value decreased with increasing b value. Therefore, when determining the ADC threshold level, it is important to perform the evaluation using ADC values calculated from DW images with the same b value in clinical studies. PMID- 22449895 TI - [A new method for measuring temporal resolution in electrocardiogram-gated reconstruction image with area-detector computed tomography]. AB - The purpose of this study was to design and construct a phantom for using motion artifact in the electrocardiogram (ECG)-gated reconstruction image. In addition, the temporal resolution under various conditions was estimated. A stepping motor was used to move the phantom over an arc in a reciprocating manner. The program for controlling the stepping motor permitted the stationary period and the heart rate to be adjusted as desired. Images of the phantom were obtained using a 320 row area-detector computed tomography (ADCT) system under various conditions using the ECG-gated reconstruction method. For estimation, the reconstruction phase was continuously changed and the motion artifacts were quantitatively assessed. The temporal resolution was calculated from the number of motion-free images. Changes in the temporal resolution according to heart rate, rotation time, the number of reconstruction segments and acquisition position in z-axis were also investigated. The measured temporal resolution of ECG-gated half reconstruction is 180 ms, which is in good agreement with the nominal temporal resolution of 175 ms. The measured temporal resolution of ECG-gated segmental reconstruction is in good agreement with the nominal temporal resolution in most cases. The estimated temporal resolution improved to approach the nominal temporal resolution as the number of reconstruction segments was increased. Temporal resolution in changing acquisition position is equal. This study shows that we could design a new phantom for estimating temporal resolution. PMID- 22449896 TI - [Comparison of absorbed and effective dose from two dental cone beam computed tomography scanners]. AB - OBJECTIVE: This research compared the field of view with the tissue absorbed dose and effective doses using the two dental cone beam computed tomography (CBCT) scanners. MATERIALS AND METHODS: Two CBCT devices, an Alphard VEGA and 3DX multi image micro CT MCT-1, were used. Measurements were made using an Alderson RANDO phantom and thermoluminescence dosimeters (TLDs). The calculation of the effective dose was carried out according to ICRP Publication 60 and 103. RESULTS: The effective doses for Alphard VEGA D mode, I mode, P mode, and C mode were 86, 238, 413, and 323 uSv, respectively. The effective doses using 3DX for the maxillary incisor, maxillary molar, mandibular incisor, mandibular molar, TMJ, and mandibular molar scout images were 27, 30, 48, 60, 14, and 1 uSv, respectively. CONCLUSIONS: Both Alphard VEGA and 3DX values revealed salivary gland and oral mucosa doses much higher than those required for other tissues. It is necessary to select a small mode suitable in order to realize optimization. PMID- 22449897 TI - [Assessment of the exposure dose value displayed on operator console in a computed tomography system deciding exposure dose from positioning image]. AB - The aim of this study was to assess the exposure dose value (DLP) displayed on the operator console in a computed tomography system with automatic exposure control (CT-AEC) which decides the exposure dose from a positioning image. We measured exposure dose with two kinds of CT systems and evaluated the error of the displayed DLP value on the operator console against the measured DLP value. The assessment was performed in three sites: head and neck, upper chest, and lower abdomen. As a result, the errors of displayed value with CT-AEC against the error without CT-AEC in system A (4.09%) were significantly different on two assessment sites (head and neck: -4.02%, upper chest: 6.60%). There is no significant difference on the third assessment site (lower abdomen: 0.06%). On the other hand, those values in system B (8.38%) were almost similar with no significant differences (head and neck: -1.12%, upper chest: -1.85%, lower abdomen: -0.64%). The results show that there were significant differences noted between the errors of displayed value with CT-AEC and without CT-AEC in system A for the head and neck and the upper chest. In conclusion, displayed value with CT AEC and without CT-AEC were about the same error. However, the possibility that the error depended on a model and the examination site of CT was shown. PMID- 22449898 TI - [Study of dynamic pituitary magnetic resonance imaging using three-dimensional turbo spin echo method at 3 Tesla MRI]. AB - Dynamic magnetic resonance (MR) imaging for pituitary microadenomas is usually performed in 2-dimensional (2D) multi-slice method which used coronal T(1) weighted imaging with turbo spin echo (SE) method. However, on MR images using 2D multi-slice method, the detectability of small lesions between slices may decrease. Therefore, the aim of our study is to investigate the influence that imaging parameters give to T(1)-weighted image with 3-dimensional (3D) turbo SE method, and to examine the use of 3D turbo SE method as the detection of pituitary microadenomas. We can plan the shortening of imaging time by shortening repetition time (TR), because the contrast to noise ratio (CNR) in the 3D turbo SE method was superior enough than that of the 2D turbo SE method. In addition, low refocusing flip angle induced the decrease of CNR, but it has the effect which decreases flow-induced artifacts. Dynamic MR imaging which used coronal T(1)-weighted imaging with 3D turbo SE method is feasible by utilizing the reduction of TR and low refocusing flip angle, as well as the combination of parallel imaging and radial sampling. PMID- 22449899 TI - [Method of measuring modulation transfer function in computed tomography using slit method with air gap phantom]. AB - There are several methods for measuring modulation transfer function (MTF) in computed tomography (CT) images. The aluminum slit method, scanning a phantom consisting of a thin aluminum foil sandwiched by flat plastic slabs, is a standard method for measuring field of view (FOV) in clinical CT scan. But this method requires extreme caution when handling metal foil of high precision. Therefore, we devised a more simple method named air gap slit (AS) method. This new technique is based on the aluminum slit method but use air gap instead of metal foil between phantoms. The MTF was calculated from a reversed profile curve of air slit which indicated minimum CT number. The aim of this study was to investigate a possibility of AS method evaluating MTF. We investigated fluctuation of MTF and FOV in clinical CT scan compared with the aluminum slit method. The result showed that the fluctuation of MTF was caused by statistics noise and is more affected by a bone kernel than standard kernel when reconstructing. Also, the MTF value in AS method was slightly higher than in aluminum slit method and did not correspond with. AS method is a useful method for measurement of MTF in clinical CT scan. When we use this method, we have to take into consideration the noise influence of data. PMID- 22449900 TI - [Examination of patient dose reduction in cardiovasucular X-ray systems with a metal filter]. AB - In interventional X-ray for cardiology of flat panel digital detector (FPD), the phenomenon that exposure dose was suddenly increased when a subject thickness was thickened was recognized. At that time, variable metal built-in filters in FPD were all off. Therefore, we examined whether dose reduction was possible without affecting a clinical image using metal filter (filter) which we have been conventionally using for dose reduction. About 45% dose reduction was achieved when we measured an exposure dose at 30 cm of acrylic thickness in the presence of a filter. In addition, we measured signal to noise ratio/contrast to noise ratio/a resolution limit by the visual evaluation, and there was no influence by filter usage. In the clinical examination, visual evaluation of image quality of coronary angiography (40 cases) using a 5-point evaluation scale by a physician was performed. As a result, filter usage did not influence the image quality (p=NS). Therefore, reduction of sudden increase of exposure dose was achieved without influencing an image quality by adding filter to FPD. PMID- 22449901 TI - [Impact on reproducibility of the treatment position by improving immobilization device in image guided radiation therapy]. AB - The immobilization device for treatment becomes important to obtain fixation and reproducibility of the treatment position. It was confirmed that reproducibility of the treatment position obtains higher accuracy by the method of using immobilization device. METHODS: We divided into three terms by the methods of immobilization. An infrared reflective marker performs the setup of a position at the start of treatment, and setup of the patient in a fixed implement is performed by ExacTrac. Difference between coordinates of the immobilization device and the patient position was calculated by the vector in three directions. We estimated the position error index (PE(index)) by using the square root of the sum of square of each vectors, and evaluated the amount of differences of patient position at three terms. RESULTS: Mean and standard deviation of index values were 9.53 +/- 7.21, 8.50 +/- 5.93, and 6.42 +/- 3.80 at each three terms. With every passing year, the amount of gap and difference of the patient fixation has decreased. CONCLUSION: By the improvement of the use of the immobilization device, gap and difference of fixation has decreased. Accordingly, we could obtain better accuracy of fixation. PMID- 22449902 TI - [The comparison between dose rates at the interventional reference point of the angiography systems in many facilities]. AB - The management of the radiation dose is very important in interventional radiology (IVR), especially in percutaneous coronary intervention (PCI). Therefore, we measured entrance surface doses at the interventional reference point of 27 cardiac intervention procedures in 22 cardiac catheterization laboratories around Hiroshima, and compared these doses. Recently, for cardiac interventional radiology, the X-ray machines using flat-panel detectors (FPD) instead of image intensifiers (I.I.) is increasing; 13 systems used FPD and 14 systems used I.I. For fluoroscopy rate, the difference between laboratories was 9 times. For cineangiography rate, the difference between laboratories was 7 times. In addition, between both devices, the I.I. group is bigger than the FPD group. When comparing by the same condition, for the dose at the interventional reference point, no significant difference was detected between the FPD group and the I.I. group. This study shows that FPD is not available for reducing the radiation dose simply. Therefore, it is necessary that we think of the balance with image quality and radiation dose. The optimization of the devices and cardiac intervention procedures becomes very important. PMID- 22449903 TI - [Determination of the optimal ROI setting position of the input function for the 99mTc-ethyl cysteinate dimmer brain uptake ratio method]. AB - Determination of the input function for the (99m)Tc-ethyl cysteinate dimmer brain uptake ratio ((99m)Tc-ECD BUR) method as a non-invasive quantitative measurement of cerebral blood flow measurement is of critical importance in order to improve the accuracy of this method. The input functions were experimentally obtained by setting the regions of interest (ROIs) in the ascending aorta, aortic arch, and descending aorta on the 49 chest RI-angio images. rCBFs by the BUR method with 3 input functions of the 6 cases were compared with those by the (123)I iodoamphetamine (IMP) continuous arterial blood sampling method in order to determine the best location for the ROI of the input function. The input function of the ascending aorta was higher than those of the aortic arch and the descending aorta. The input functions of the aortic arch and the descending aorta decreased due to the origin of the three branches of the right brachiocephalic artery, left subclavian artery, and left common carotid artery. A good correlation was found in the regional cerebral blood flow (rCBF) values between the (123)I-IMP continuous arterial blood sampling method and the (99m)Tc-ECD BUR method with the input function of the ascending aorta. Therefore, the ascending aorta is the best location for the ROI of the input function for the (99m)Tc-ECD BUR method. PMID- 22449904 TI - [Radioisotope decontamination of X-ray detector (photostimulable phosphor plate)]. AB - We tried to remove contamination of radioisotope (RI) for an X-ray detector (photostimulable phosphor plate; IP) and verified that our procedure suggested by Nishihara et al. was effective for decontamination. The procedure was as follows. First, the IP was kept for approximately twelve hours, and then it was processed [image (A)] as well as a clinical processing mode. Second, using a wet-type chemical wiper, we scavenged the IP to remove the adhered RI on its surface. Then, once again, the IP was kept for approximately fifteen hours and processed [image (B)] in order to check an effect of decontamination. Finally, the two images of (A) and (B) were analyzed using ImageJ, which can be downloaded as a free software, and a percentage of removal was calculated. The procedure was applied to two IPs using the FCR 5501 plus. In the present case, the percentage of removal was approximately 96%. The removed radioisotopes in the chemical wipers were analyzed by Ge detector. Then, (134)Cs and (137)Cs were found with activities of 2.9 4.3 Bq and 3.5 5.2 Bq, respectively. For three months after that, we cannot see black spots on the IPs owing to the contamination of the RI and there are no defects caused by decontamination using a wet-type chemical wiper. PMID- 22449905 TI - [Study of the voxel-based specific regional analysis system for Alzheimer's disease imaging sequence after magnetic resonance apparatus replacement]. AB - In our institute, an MR apparatus, MAGNETOM VISION (Siemens) was replaced by ECHELON Vega (HITACHI). Z-score data acquired by MPRAGE (VISION) was compared with those by radio frequency-spoiled steady-state acquisition with rewinded gradient echo (RSSG) and gradient echo inversion recovery (GEIR) (ECHELON). For this study, ten normal volunteers were recruited and their data ware obtained within two months using both apparatuses. In addition, the difference of the contrasts of the images of these apparatuses was compared. There was a significant difference between Z-scores of MPRAGE and RSSG while there was no difference between MPRAGE and GEIR. As for the contrast, data of MPRAGE were similar to those of GEIR. To compare Z-scores acquired with MAGNTOM VISION (Siemens), it seems appropriate to use GEIR in ECHELON Vega. PMID- 22449906 TI - [Intra-fractional set-up and organ motion errors in intensity-modulated radiation therapy for prostate cancer]. AB - PURPOSE: The aim of this study is to investigate various intra-fractional errors and to determine the appropriate planning target volume (PTV) margins in intensity modulated radiation therapy (IMRT) for prostate cancer. METHODS: Ten patients with prostate cancer treated with IMRT between July 2009 and March 2010 were analyzed. PTV was created by adding 4 mm posterior and 7 mm anterior and lateral margins to the clinical target volume (CTV) including prostate and proximal seminal vesicles. Intra-fractional set-up and organ motion errors were measured using cone beam computed tomography (CBCT) images before and after each irradiation. Systematic and random errors were calculated by van Herk and Stroom's models. RESULTS: Intra-fractional errors of set-up and organ motion were 0.70 +/- 0.84 mm and 0.88 +/- 0.95 mm in the left-right (L-R), 1.04 +/- 0.98 mm and 1.69 +/- 1.58 mm in the cranial-coudal (C-C), and 1.08 +/- 1.01 mm and 1.91 +/- 1.58 mm in the anterior-posterior (A-P) directions, respectively. The errors in the C-C and A-P were significantly larger than those in the L-R (p<0.01). The organ motion errors in the C-C and A-P were significantly larger than the set-up errors (p<0.01). The appropriate PTV margin estimated in this study was 4.73 mm. CONCLUSIONS: Intra-fractional errors in all directions were less than 2 mm and required PTV margin in the study was similar to actual posterior margin in our routine practice. It is important to determine intra-fractional errors as well as inter-fractional errors to deliver successful IMRT for prostate cancers. PMID- 22449907 TI - [Development of the software package of the nuclear medicine data processor for education and research]. AB - The objective of this study was to develop a personal computer-based nuclear medicine data processor for education and research in the field of nuclear medicine. We call this software package "Prominence Processor" (PP). Windows of Microsoft Corporation was used as the operating system of this PP, which have 1024 * 768 image resolution and various 63 applications classified into 6 groups. The accuracy was examined for a lot of applications of the PP. For example, in the FBP reconstruction application, there was visually no difference in the image quality as a result of comparing two SPECT images obtained from the PP and GMS 5500A (Toshiba). Moreover, Normalized MSE between both images showed 0.0003. Therefore the high processing accuracy of the FBP reconstruction application was proven as well as other applications. The PP can be used in an arbitrary place if the software package is installed in note PC. Therefore the PP is used to lecture and to practice on an educational site and used for the purpose of the research of the radiological technologist on a clinical site etc. widely now. PMID- 22449908 TI - [Development of a pin-hole camera using a phosphor plate, and visualization of the scattered X-ray distribution and optical image]. AB - In order to obtain an image of scattered X-ray in the diagnosis domain, we have newly developed a pin-hole camera. Because of the necessity of the X-ray shielding, the pin-hole part has a depth corresponding to that of the shielded material. As a result, efficiencies of obliquely incident X-rays are reduced. To decrease the descent of the efficiencies, we developed a large camera using a 10 * 12 inch size phosphor plate as an X-ray detector. A phantom was irradiated by X rays with conditions of 500 mAs and 5000 mAs, and images of scattered X-rays were obtained. The former image showed scattered X-rays from the phantom. The latter image showed those from the air of beam axis as well as from the phantom. Moreover, we made a new proposal to obtain an optical image using the fading effect. PMID- 22449909 TI - [JSRT member Mr. Hisashi Maekoshi, interview by Katsuhiro Ichikawa]. PMID- 22449910 TI - [Genitourinary applications of dual-energy CT]. PMID- 22449911 TI - [Tutorial review: Historical background for investigation of Wiener spectrum- beginning of quantum mottle research--]. PMID- 22449912 TI - [7. Measurement of nuclear medicine--radiation dosimetry in positron emission tomography--]. PMID- 22449913 TI - [Role and responsibility of radiotherapy quality manager]. PMID- 22449914 TI - [2. Mammography]. PMID- 22449915 TI - [Subject about the long view examination using flat panel detector (FPD)]. PMID- 22449916 TI - [2011 standardization committee activities]. PMID- 22449917 TI - [Background of establishment and future activities of radiation & dose committee]. PMID- 22449918 TI - Preparation, characterization, and cellular associations of silicon logic embedded vectors. AB - Logic-embedded vectors (LEVs) have been introduced as a means to overcome sequential, biological barriers that prevent particle-based drug delivery systems from reaching their targets. In this chapter, we address the challenge of fabricating and optimizing LEVs to reach non-endosomal targets. We describe the general preparation, characterization, and cellular association of porous silicon based LEVs. A specific example of LEV fabrication from start to finish, along with optimization and troubleshooting information, is presented to serve as a template for future designs. PMID- 22449919 TI - Postformulation peptide drug loading of nanostructures. AB - Cytolytic peptides have commanded attention for their anticancer potential because the membrane-disrupting function that produces cell death is less likely to be overcome by resistant mutations. Congruently, peptides that are involved in molecular recognition and biological activities become attractive therapeutic candidates because of their high specificity, better affinity, reduced immunogenicity, and reduced off target toxicity. However, problems of inadequate delivery, rapid deactivation in vivo, and poor bioavailability have limited clinical application. Therefore, peptide drug development for clinical use requires an appropriate combination of an effective therapeutic peptide and a robust delivery methodology. In this chapter, we describe methods for the postformulation insertion of peptide drugs into lipidic nanostructures, the physical characterization of peptide-nanostructure complexes, and the evaluation of their therapeutic effectiveness both in vitro and in vivo. PMID- 22449920 TI - Application of mesoporous silica nanoparticles in intracellular delivery of molecules and proteins. AB - Delivery of drugs and molecules to eukaryote animal and plant cells can be enhanced when mediated by mesoporous silica nanoparticle (MSN) materials. This chapter describes, in detail, the synthesis of several different MSN materials used for the transport of various hydrophilic and hydrophobic drug molecules, neurotransmitters, and macromolecules across the cell membrane, and in some cases, the cell wall of plant cells. In addition, the utility of MSN for mediating the delivery of cell-impermeable proteins is described in detail. Though the experimental descriptions are specifically detailed to research that has been completed, the procedures are applicable to additional drug and protein delivery experiments. Also summarized are several considerations that need to be addressed when utilizing MSN materials with biological systems to avoid complicating experiments. PMID- 22449921 TI - Multifunctional anticancer nanomedicine based on a magnetically responsive cyanoacrylate polymer. AB - The therapeutic effect of antitumor molecules (efficacy and safety) is severely limited by their poor pharmacokinetic characteristics. Recently, the use of colloids has been proposed for the delivery of anticancer drugs to tumor cells, thereby providing a significant advance toward new treatments with improved specificity. In this respect, magnetically responsive nanopolymers are probably one of the most promising materials. In this contribution, we describe the basic steps to be followed in the development of such composite nanoplatforms. Starting from the formulation procedure, we detail the physicochemical engineering of these nanomedicines for combined antitumor activities (anticancer drug delivery plus hyperthermia effect). The key features determining drug incorporation to the nanomaterial are analyzed. Such stimuli-sensitive nanoparticles have promising properties (e.g., blood compatibility, hyperthermia, magnetic targeting capabilities, high drug loading, and little burst drug release), which could be used for efficient multifunctional anticancer therapy. PMID- 22449922 TI - Development and use of ceramide nanoliposomes in cancer. AB - Integration of C6-ceramide into stealth pegylated nanoliposomes has led to the development of a promising preclinical therapeutic alone and in combination with other agents for treatment of cancer. Ceramide itself has been implicated as a bioactive lipid second messenger mediating cell senescence, cell cycle arrest, and apoptosis. Recent lipidomic analyses have demonstrated that specific ceramide species are differentially metabolized in individual cancers. Therapeutics that increase ceramide levels in cancer tissues have shown increased cell death and tumor inhibition. However, the use of ceramide itself as therapeutic has been problematic due to its inherent hydrophobicity and insolubility, therefore limiting the application for intravenous administration. Pegylated nanoliposomes eliminate this issue and are able to enhance the intracellular delivery of ceramide to cancer cells. PMID- 22449923 TI - Multistage nanoparticles for improved delivery into tumor tissue. AB - The enhanced permeability and retention (EPR) effect has been a key rationale for the development of nanoscale carriers to solid tumors. As a consequence of EPR, nanotherapeutics are expected to improve drug and detection probe delivery, have less adverse effects than conventional chemotherapy, and thus result in improved detection and treatment of tumors. Physiological barriers posed by the abnormal tumor microenvironment, however, can hinder the homogeneous delivery of nanomedicine in amounts sufficient to eradicate cancer. To effectively enhance the therapeutic outcome of cancer patients by nanotherapeutics, we have to find ways to overcome these barriers. One possibility is to exploit the abnormal tumor microenvironment for selective and improved delivery of therapeutic agents to tumors. Recently, we proposed a multistage nanoparticle delivery system as a potential means to enable uniform delivery throughout the tumor and improve the efficacy of anticancer therapy. Here, we describe the synthesis of a novel multistage nanoparticle formulation that shrinks in size once it enters the tumor interstitial space to optimize the delivery to tumors as well as within tumors. Finally, we provide detailed experimental methods for the characterization of such nanoparticles. PMID- 22449924 TI - Mitochondria-specific nanocarriers for improving the proapoptotic activity of small molecules. AB - The efficiency and efficacy of drug action depends largely on how well an unaided drug molecule is able to reach its intracellular target or even its target inside organelles such as mitochondria. Subsequently, the specific delivery of a drug to its site of action inside cells will dramatically improve its action. Mitochondria play a key role in apoptosis, and several clinically used, as well as experimental, drugs are known to trigger apoptosis by interacting directly with the target site at or inside mitochondria. During the past decade, a variety of mitochondria-specific pharmaceutical nanocarriers have been developed for the purpose of delivering therapeutic DNA or low-molecular weight compounds to mitochondria inside living mammalian cells. Here, the preparation of drug containing, mitochondria-targeted nanocarriers is described and protocols for their in vitro and in vivo assessment are given. PMID- 22449925 TI - Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles. AB - The destruction of the neovessels in solid tumors can cause the death of tumor cells resulting from the lack of oxygen and nutrients. Peculiarities of the tumor vasculature, however, also position angiogenic endothelial cells as obvious targets to address cytotoxic drugs into the tumor. In particular, the identification of a three-amino acids sequence, arginine-glycine-aspartate (RGD), as a fundamental recognition site for proliferating endothelial attachment to the extracellular matrix leads to the development of tumor-targeting ligands for nanoparticles. The RGD peptide can target the alpha(v)beta(3) integrin overexpressed by the tumor endothelium, and thereby increases the accumulation of drug-loaded RGD-grafted nanoparticles. RGD-nanoparticles may thus extravasate more efficiently and enter the tumor via the enhanced permeability and retention (EPR) effect. This combination of active and passive processes leads to the penetration of nanoparticles into the tumor tissue, followed by cellular uptake and intracellular delivery of the cytotoxic payload. Since cancer cells may also express alpha(v)beta(3) integrin, the entrapping of RGD-nanoparticles into the tumor interstitial fluid may yet be facilitated through direct binding to cancer cells. Here, we describe methods used for the preparation of RGD-nanoparticles and for the validation of their potential of tumor endothelium targeting both in vitro and in vivo. We also illustrate how RGD-nanoparticles may be more suited than nontargeted modalities for the tumor delivery of poorly soluble and/or highly cytotoxic drugs, using different mouse tumor xenograft models. PMID- 22449926 TI - Peptide nanofiber scaffold for brain tissue reconstruction. AB - Traumatic brain injury (TBI) and neurosurgical procedures commonly result in tissue loss within the cerebral parenchyma. Regeneration is limited by the anatomical tissue gaps and the hostile microenvironment created by the trauma. A search for novel biomaterials that are neuroprotective and conducive to healing and regeneration is needed. One approach is with the use of RADA16-I, a type I self-assembling peptide nanofiber scaffold. We review the current evidence on the use of RADA16-I and describe our experience with its use in rodent models of surgical brain injury. A cortical resection model is used to mimic the significant amount of tissue loss seen in TBI and clinical surgery. The use of RADA16-I as a carrier of transplantable neuroprogenitor cells and a potential topical hemostatic agent is described. RADA16-I can bridge tissue gaps and reduce surrounding reactive changes. Embedment of transplantable cells within the tissue scaffold is feasible. RADA16-I achieves hemostasis almost instantaneously and is associated with less tissue damage when compared with other conventional methods. There are, however, certain limitations with the application of RADA16-I mainly due to its intrinsically low pH and need for prebuffering. The use of peptide nanofiber scaffold is a promising approach for the reconstruction of the injured brain. New experimental models and research methods are required to fully explore its potential in minimizing secondary brain injuries and to promote neuronal regeneration. PMID- 22449927 TI - Detection and treatment of intravascular thrombi with magnetofluorescent nanoparticles. AB - Thrombosis, the formation of a clot within a blood vessel, underlies a number of life-threatening cardiovascular disorders such as heart attack, ischemic stroke, pulmonary embolism, and deep vein thrombosis. These conditions affect the lives of millions of people worldwide and result in significant morbidity and mortality. It is thus crucial to develop novel methodologies to enhance the detection and treatment of these disorders. Thrombolysis, or the dissolution of blood clots, relies upon the administration of exogenous plasminogen activators (PAs) that lyse fibrin. Yet, there are several drawbacks to the use of current PAs, including significant risks of uncontrolled bleeding and suboptimal efficacy and pharmacokinetics. Nanomaterials are well positioned to address these priority issues in thrombolysis, via the alteration of PA pharmacokinetics and biodistribution. Additionally, due to the multifunctional nature of nanoparticles, these thrombolytics may be targeted to the site of occlusion, effectively concentrating the drug where it is most needed. Herein, we describe the methodology associated with the synthesis of a novel thrombus-targeted fibrinolytic nanoagent. At each step of the synthesis, we analyze the nanomaterials, including their physical properties and their ability to bind to thrombosis targets of interest. The effect of the conjugation of tPA to the nanoparticle surface on the amidolytic and fibrinolytic activities of nanoagents is also investigated. Lastly, the in vivo binding of the targeted thrombolytic to intravascular thrombi is examined. PMID- 22449928 TI - Imaging the efficacy of anti-inflammatory liposomes in a rabbit model of atherosclerosis by non-invasive imaging. AB - Nanomedicine can provide a potent alternative to current therapeutic strategies for atherosclerosis. For example, the encapsulation of anti-inflammatory drugs into liposomes improves their pharmacokinetics and biodistribution, thereby enhancing bioavailability to atherosclerotic plaques and improving therapeutic efficacy. The evaluation of this type of experimental therapeutics can greatly benefit from in vivo evaluation to assess biological changes, which can be performed by non-invasive imaging techniques, such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Here, we will illustrate the methods for inducing atherosclerosis in a rabbit model, the production of anti-inflammatory liposomes and monitoring of therapeutic efficacy of experimental therapeutics with the above-mentioned imaging techniques. PMID- 22449929 TI - Lipid nanoparticles for drug targeting to the brain. AB - In this chapter, the main production methods of lipid nanostructures such as solid lipid nanoparticles and nanostructured lipid carriers, and their application are described. In particular, we describe the strategies commonly used to obtain lipid nanoparticles to overcome the blood-brain barrier (BBB) for the treatment of several brain diseases. The use of these carriers as targeted drug delivery systems is associated with many advantages that include excellent storage stability, easy production without the use of any organic solvent, the possibility of steam sterilization and lyophilization, and large scale production. They exhibit good stability during long-term storage, consist of physiologically well-tolerated ingredients often already approved for pharmaceutical applications in humans, and are generally recognized as safe. Under optimized conditions, they can be produced to incorporate several drugs and therapeutic proteins. Formulation in solid lipid nanostructures confers improved drug loading and protein stability, targeting, and sustained release of the incorporated molecules. Moreover, their lipophilic features lead them to the central nervous system by an endocytotic mechanism, overcoming the BBB. Many drugs have been incorporated into solid lipid nanosystems and several therapeutic applications may be foreseen, such as targeting with molecules useful for treatment of brain diseases. PMID- 22449930 TI - Transport of a caspase inhibitor across the blood-brain barrier by chitosan nanoparticles. AB - The current treatment of neurological and psychiatric diseases is far beyond being satisfactory. In addition to highly complex disease mechanisms, the blood brain barrier (BBB) also remains as a challenge by limiting the delivery of the majority of currently available therapeutics to the central nervous system. Several approaches taking advantage of molecular and physicochemical characteristics of the BBB have been developed recently to improve drug delivery to the brain. Here, we introduce a nanomedicine that can efficiently transport BBB-impermeable peptides to the brain. This nanomedicine is made of chitosan nanoparticles into which considerable amounts of a peptide can be incorporated. The nanoparticle surface is modified with polyethylene glycol to enhance the plasma residence time by preventing their capture by the reticuloendothelial system. Monoclonal antibodies against the transferrin receptor (TfR), which is highly expressed on the brain capillary endothelium, are conjugated to nanoparticles via biotin-streptavidin bonds. The activation of TfR by the nanoparticle-antibody complex induces transcytosis and thus delivers the loaded drug to the brain. Penetration of nanoparticles to the brain can be illustrated in vivo by intravital microscopy as well as ex vivo by fluorescence or electron microscopy. N-Benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK)-loaded nanoparticles rapidly release their contents within brain parenchyma, inhibit ischemia-induced caspase-3 activity, and thereby provide neuroprotection. PMID- 22449931 TI - Nanotechnology as a promising strategy for alternative routes of insulin delivery. AB - Since its discovery, insulin has been used as highly specific and effective therapeutic protein to treat type 1 diabetes and later was associated to oral antidiabetic agents in the treatment of type 2 diabetes. Generally, insulin is administered parenterally. Although this route is successful, it still has several limitations, such as discomfort, pain, lipodystrophy at the injection sites and peripheral hyperinsulinemia, which may be the cause of side effects and some complications. Thus, alternative routes of administration have been developed, namely, those based on nanotechnologies. Nanoparticles, made of synthetic or natural materials, have been shown to successfully overcome the inherent barriers for insulin stability, degradation, and uptake across the gastrointestinal tract and other mucosal membranes. This review describes some of the many attempts made to develop alternative and more convenient routes for insulin delivery. PMID- 22449932 TI - Chitosan-coated solid lipid nanoparticles for insulin delivery. AB - The delivery of therapeutic proteins like insulin, exploiting routes of administration different from the traditional injectable forms, has been investigated extensively, taking advantage of the nanotechnology tools available nowadays in the massive drug delivery system pipeline. In this chapter, we describe in detail the preparation of solid lipid nanoparticles (SLN), further coated with the mucoadhesive polymer chitosan, intended for intestinal absorption of insulin after oral administration. We give special focus on the characterization of the SLN and of the biomacromolecule by itself after encapsulation, because of the intrinsic labile properties of insulin during the manufacturing process. We also describe methods to determine the in vitro intestinal permeability of insulin that solid lipid and chitosan-coated SLN can afford, as well as in vivo models to evaluate the hypoglycemic effect in diabetic animals. PMID- 22449933 TI - Peptide nanomedicines for treatment of acute lung injury. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a heterogenous group of lung disease in critically ill patients. Despite the increased understanding of the molecular pathogenesis of ARDS, the mortality remains unacceptably high, ranging from 34% to 64%. Hence, ARDS represents an unmet medical need with an urgency to develop effective pharmacotherapies. Several promising targets that have been identified as potential therapies for ARDS have been limited because of difficulty with delivery. In particular, delivery of peptides and proteins to the lung is an ongoing challenge. Nanobiotechnology and nanoscience are the basis of innovative techniques to deliver drugs targeted to the site of inflamed organs, such as the lungs. Nanoscale drug delivery systems have the ability to improve the pharmacokinetics and pharmakodynamics of agents allowing an increase in the biodistribution of therapeutic agents to target organs, resulting in improved efficacy with reduction in drug toxicity. These systems are exploited for therapeutic purpose to carry the drug in the body in a controlled manner from the site of administration to the therapeutic target. Hence, it is an attractive strategy to test potential targets for ALI/ARDS using nanotechnology. To this end, we have identified several potential targets and proposed the delivery of these agents using nanomicelles to improve the drug delivery. PMID- 22449934 TI - Nanoparticle-mediated treatment of pulmonary arterial hypertension. AB - Nanomedicine is an emerging field with great opportunities to improve the treatment of diseases which are currently not curable. Pulmonary arterial hypertension (PAH) is one of these diseases treatable by inhalation of medicines that provide novel depots for drugs with short pharmacological half-lives to improve the quality of life for patients. In this context, nanostructured drug delivery systems such as liposomes and polymeric nanoparticles are depot forms that can also act as penetration enhancers and solubilizers of drugs. The pulmonary use of these drug carriers will improve the therapeutic effect of potent drugs that are currently not fully applicable. This review focuses on the design and characterization of drug delivery systems with the potential to improve the treatment options for hypertonic conditions (like PAH). Liposomes as well as polymeric nanoparticles based on lactic acid, proticles and nanocrystalline drugs have good potential to be developed toward clinical use. Preparation methods and characterization techniques of nanoparticles such as light scattering or microscopy are provided. PMID- 22449935 TI - Nanomedicines for inflammatory diseases. AB - Inflammation is the body's natural defense mechanism in response to many diseases including infection, cancer, and autoimmune disease. Since the birth of nanotechnology at the end of the twentieth century, scientists have been utilizing the pathophysiologic features of inflammation, mainly leaky vasculature and the overexpression of biomarkers, to design nanomedicines that can deliver drugs with passive and active targeting mechanisms to inflamed tissue sites and achieve effective therapy. Recent advances in nanomedicine research have provided scientists with nanocarriers of many unique and tunable properties to match the specific requirements for the treatment of different inflammatory disease conditions. In this chapter, we describe some of the materials and methods used in the preparation and characterization of these nanomedicines, approaches used for the evaluation of their efficacy on a cellular and organ level, as well as available animal models. We also show how safety and biodistribution studies using anti-inflammatory nanomedicines are conducted in our laboratory for the treatment of rheumatoid arthritis animal models. PMID- 22449936 TI - Polymeric nanoparticles for the selective therapy of inflammatory bowel disease. AB - The two main forms of inflammatory bowel disease (IBD) are Crohn's disease and ulcerative colitis. Both diseases are chronic relapsing inflammations of the gut. The challenge for drug carrier systems that are used for the therapy of IBD is the delivery of the active ingredient to the site of inflammation. A site directed targeting should lead to higher local drug concentrations, less systemic absorption, and therewith to less adverse effects. Because nanoparticulate drug carrier systems have the ability to accumulate in the inflamed regions, they offer a new targeting approach in IBD. We describe preparation techniques for polymeric nanoparticles and methods to characterize their physicochemical properties, their behavior in cell culture, and the therapeutic efficiency in murine experimental colitis models. PMID- 22449937 TI - Nanomedicine cancer, diabetes, and cardiovascular, central nervous system, pulmonary and inflammatory diseases. Preface. PMID- 22449938 TI - Iron levels in polarized macrophages: regulation of immunity and autoimmunity. AB - Although the hallmark of autoimmune diseases remains the generation of autoantigen-specific lynfocytic cell response, growing evidence is showing a key role for macrophages in a number of autoimmune diseases. Macrophages are characterized by phenotypical and functional heterogeneity. Different immunological signals, coming from systemic blood circulation or from microenvironment, polarize macrophages to classical (M1) or alternative (M2) phenotypes. Iron accumulation in M1 macrophages is a well known bacteriostatic mechanism and one of the mechanisms at the basis of anemia associated to chronic inflammation. Moreover, some recent data suggest that iron accumulation in macrophages can directly activate macrophages to pro-inflammatory M1 phenotype, highlighting a putative role of macrophage iron retention in the pathogenesis of chronic inflammatory and autoimmune diseases. Conversely, iron content is low in M2 macrophages, principally due to increased iron release, and increased availability of iron in the extracellular milieu supported by M2 macrophages could influence the growth rate of adjacent cell and thus play an important role in tumor growth and tissue remodeling. In this review we summarize the molecular mechanisms sustaining differential iron metabolism in polarized macrophages, discuss the relevance of this metabolic signature in chronic inflammatory and autoimmune diseases, and finally focus on potential therapeutic implications rising from a better understanding of underlying molecular mechanisms. PMID- 22449939 TI - Ephrin regulation of synapse formation, function and plasticity. AB - Synapses enable the transmission of information within neural circuits and allow the brain to change in response to experience. During the last decade numerous proteins that can induce synapse formation have been identified. Many of these synaptic inducers rely on trans-synaptic cell-cell interactions to generate functional contacts. Moreover, evidence now suggests that the same proteins that function early in development to regulate synapse formation may help to maintain and/or regulate the function and plasticity of mature synapses. One set of receptors and ligands that appear to impact both the development and the mature function of synapses are Eph receptors (erythropoietin-producing human hepatocellular carcinoma cell line) and their surface associated ligands, ephrins (Eph family receptor interacting proteins). Ephs can initiate new synaptic contacts, recruit and stabilize glutamate receptors at nascent synapses and regulate dendritic spine morphology. Recent evidence demonstrates that ephrin ligands also play major roles at synapses. Activation of ephrins by Eph receptors can induce synapse formation and spine morphogenesis, whereas in the mature nervous system ephrin signaling modulates synaptic function and long-term changes in synaptic strength. In this review we will summarize the recent progress in understanding the role of ephrins in presynaptic and postsynaptic differentiation, and synapse development, function and plasticity. PMID- 22449940 TI - Down-regulation of flavin reductase and alcohol dehydrogenase-1 (ADH1) in metronidazole-resistant isolates of Trichomonas vaginalis. AB - The microaerophilic parasite Trichomonas vaginalis is a causative agent of painful vaginitis or urethritis, termed trichomoniasis, and can also cause preterm delivery or stillbirth. Treatment of trichomoniasis is almost exclusively based on the nitroimidazole drugs metronidazole and tinidazole. Metronidazole resistance in T. vaginalis does occur and is often associated with treatment failure. In most cases, metronidazole-resistant isolates remain susceptible to tinidazole, but cross resistance between the two closely related drugs can be a problem. In this study we measured activities of thioredoxin reductase and flavin reductase in four metronidazole-susceptible and five metronidazole-resistant isolates. These enzyme activities had been previously found to be downregulated in T. vaginalis with high-level metronidazole resistance induced in the laboratory. Further, we aimed at identifying factors causing metronidazole resistance and compared the protein expression profiles of all nine isolates by application of two-dimensional gel electrophoresis (2DE). Thioredoxin reductase activity was nearly equal in all strains assayed but flavin reductase activity was clearly down-regulated, or even absent, in metronidazole-resistant strains. Since flavin reductase has been shown to reduce oxygen to hydrogen peroxide, its down-regulation could significantly contribute to the impairment of oxygen scavenging as reported by others for metronidazole-resistant strains. Analysis by 2DE revealed down-regulation of alcohol dehydrogenase 1 (ADH1) in strains with reduced sensitivity to metronidazole, an enzyme that could be involved in detoxification of intracellular acetaldehyde. PMID- 22449941 TI - Discovery of factors linked to antimony resistance in Leishmania panamensis through differential proteome analysis. AB - The rate of treatment failure to antileishmanial chemotherapy in Latin America is up to 64%. Parasite drug resistance contributes to an unknown proportion of treatment failures. Identification of clinically relevant molecular mechanisms responsible for parasite drug resistance is critical to the conservation of available drugs and to the discovery of novel targets to reverse the resistant phenotype. We conducted comparative proteomic-based analysis of Leishmania (Viannia) panamensis lines selected in vitro for resistance to trivalent antimony (Sb(III)) to identify factors associated with antimony resistance. Using 2 dimensional gel electrophoresis, two distinct sub-proteomes (soluble in NP 40/urea and Triton X-114, respectively) of promastigotes of WT and Sb(III) resistant lines were generated. Overall, 9 differentially expressed putative Sb resistance factors were detected and identified by mass spectrometry. These constituted two major groups: (a) proteins involved in general stress responses and (b) proteins with highly specific metabolic and transport functions, potentially directly contributing to the Sb-resistance mechanism. Notably, the sulfur amino acid-metabolizing enzymes S-adenosylmethionine synthetase (SAMS) and S-adenosylhomocysteine hydrolase (SAHH) were over-expressed in Sb(III)-resistant lines and Sb(III)-resistant clinical isolates. These enzymes play a central role in the upstream synthesis of precursors of trypanothione, a key molecule involved in Sb-resistance in Leishmania parasites, and suggest involvement of epigenetic regulation in response to drug exposure. These data re-enforce the importance of thiol metabolism in Leishmania Sb resistance, reveal previously unrecognized steps in the mechanism(s) of Sb tolerance, and suggest a cross-talk between drug resistance, metabolism and virulence. PMID- 22449942 TI - When elderly people give warning of suicide. AB - BACKGROUND: The study has a dual objective: (1) to investigate the extent to which, and how and to whom, elderly people gave warning (according to the definition of the term given by the American Association of Suicidology) prior to suicide; (2) to investigate how these warnings were perceived by the recipients of them, and what reactions the recipients had to the warnings. METHODS: This is a psychological autopsy study based on qualitative interviews. Sixty-three informants were interviewed about 23 suicides by individuals aged over 65 in Norway. The informants comprised relatives, general practitioners (GPs) and home based care nurses. In general, the analysis of the interviews follows the systematic text condensation method. RESULTS: The interviews contained four main themes regarding reactions to the warnings: "not taken seriously," "helplessness," "exhaustion," and "acceptance." A total of 14 of the 23 elderly people gave warning before the suicides occurred. The warnings were given to relatives (11), home-based care nurses (5), and GPs (2). CONCLUSIONS: Even though more than half of the elderly people had given warning (most frequently to relatives) before the suicide, the warnings did not initiate preventive measures. Together with passive attitudes, the lack of recognition of both the risk of suicide and the opportunities for treatment prevented possible measures being implemented. The paper discusses the grounds for the reactions as well as how suicide warnings given by elderly people can be taken seriously. PMID- 22449943 TI - The patellar reflex: does activity of quadriceps femoris muscles reflect leg movement? AB - OBJECTIVES: The assessment of spinal reflexes has traditionally been performed by clinicians with minimal need for recording equipment, where doctors rely on their training and may use established subjective reflex rating scales. With advances in technology, it is now possible to assess reflexes objectively. This study compared two objective methods of assessing patellar reflex magnitude, duration, and latency, namely electromyography (EMG) of the quadriceps muscles and kinematic assessment of the leg movement around the knee joint. METHODS: Reflexes of 24 healthy participants were assessed and seven variables were found to describe each reflex. These were the change in knee angle, the velocity of the reflex, the time to maximum knee angle, the biomechanical movement latency, the EMG maximum amplitude, the negative peak duration, and the EMG latency. Spearman's rank correlation tests were run in order to compare all of the variables. RESULTS: The results showed that there were positive correlations between EMG maximum amplitude and the change in knee angle (R(2) = 0.75; P < 0.0001) as well as the EMG maximum amplitude and the velocity of the reflex (R(2) = 0.30; P = 0.0058). There was also a negative correlation between EMG maximum amplitude and the biomechanical movement latency (R(2) = 0.35; P = 0.0024). DISCUSSION: The results show that there is a relationship between muscle activity and the actual visual movement of the leg assessed using kinematics. This relationship is closest between kinematic measurements and EMG measures of reflex amplitude. PMID- 22449944 TI - Advances in the use of multimarker panels for renal risk stratification. AB - PURPOSE OF REVIEW: This review discusses novel studies in the past year that have examined the use of combinations of multiple markers to improve risk prediction in the setting of chronic kidney disease (CKD). We will focus on multimarker panels to: improve prediction of CKD onset; improve classification of CKD and risk stratification of persons with CKD; and develop individual-level risk scores for progression to end-stage renal disease (ESRD). RECENT FINDINGS: One study reported that several novel circulation biomarkers may aid in predicting incident CKD and microalbuminuria. Second, our group has shown that the combination of creatinine, cystatin C, and albuminuria improves detection and risk stratification for death, heart failure, cardiovascular events, and ESRD compared with creatinine alone. Finally, a highly accurate individual risk score was developed to predict progression to ESRD using readily available clinical markers. SUMMARY: The combination of multiple markers improves detection and risk stratification in CKD. Future research is needed in understanding the use of a 'renal panel' for detection, classification, and risk stratification in kidney disease in diverse populations. The studies presented here represent the beginning of a paradigm shift to multimarker panels in nephrology. PMID- 22449946 TI - Recent advances in acute kidney injury epidemiology. AB - PURPOSE OF REVIEW: Expanding rates of acute kidney injury (AKI) coupled with increasing awareness of its short-term and long-term sequelae have focused efforts to identify patients at risk for this disease and its complications. This review details the recent attempts to identify novel risk factors for AKI, describes further refinements in the diagnostic and prognostic approach using biological markers of injury, and highlights the features of AKI that independently predict poor long-term outcomes. RECENT FINDINGS: The presence of proteinuria predicts the development of AKI independently of estimated glomerular filtration rate. Initial results from a large prospective study of AKI biomarkers in cardiac surgery indicate lower agreement with serum creatinine as an AKI standard than observed in early studies. AKI severity and duration are important predictors of chronic kidney disease and long-term mortality. A minority of patients surviving AKI with decreased kidney function is seen by a nephrologist. SUMMARY: Although the pathophysiologic link is unclear, proteinuria is an easily measurable risk factor for AKI worth considering before anticipated procedures or medication exposures carrying nephrologic risk. Investigation extending beyond agreement with serum creatinine is needed to fully understand the diagnostic and prognostic value of AKI biomarkers. Severity and duration are components of AKI that can help risk-stratify survivors in need of monitoring or nephrology referral. PMID- 22449945 TI - Renal interstitial fibrosis: mechanisms and evaluation. AB - PURPOSE OF REVIEW: Tubulointerstitial injury in the kidney is complex, involving a number of independent and overlapping cellular and molecular pathways, with renal interstitial fibrosis and tubular atrophy (IFTA) as the final common pathway. Furthermore, there are multiple ways to assess IFTA. RECENT FINDINGS: Cells involved include tubular epithelial cells, fibroblasts, fibrocytes, myofibroblasts, monocyte/macrophages, and mast cells with complex and still incompletely characterized cell-molecular interactions. Molecular mediators involved are numerous and involve pathways such as transforming growth factor (TGF)-beta, bone morphogenic protein (BMP), platelet-derived growth factor (PDGF), and hepatocyte growth factor (HGF). Recent genomic approaches have shed insight into some of these cellular and molecular pathways. Pathologic evaluation of IFTA is central in assessing the severity of chronic disease; however, there are a variety of methods used to assess IFTA. Most assessment of IFTA relies on pathologist assessment of special stains such as trichrome, Sirius Red, and collagen III immunohistochemistry. Visual pathologist assessment can be prone to intra and interobserver variability, but some methods employ computerized morphometery, without a clear consensus as to the best method. SUMMARY: IFTA results from on orchestration of cell types and molecular pathways. Opinions vary on the optimal qualitative and quantitative assessment of IFTA. PMID- 22449947 TI - Cartilage destruction in granulomatosis with polyangiitis (Wegener's granulomatosis) is mediated by human fibroblasts after transplantation into immunodeficient mice. AB - A key feature of granulomatosis with polyangiitis (GPA; or Wegener's granulomatosis) is the granulomatous inflammation of the upper respiratory tract, which leads to the subsequent destruction of adjacent tissues. The aim of our work was to study the histopathological and cellular components of tissue destruction of human GPA tissue transplanted into immunodeficient mice. Biopsy specimens from patients with active GPA (n = 10) or sinusitis (controls, n = 6) were s.c. co-implanted with healthy allogeneic human nasal cartilage into immunodeficient pfp/rag2(-/-) mice. Transplants were examined for their destructive capability of the allografted human cartilage. In addition, nasal fibroblasts from patients with GPA (n = 8) and control healthy nasal fibroblasts (n = 5) were cultured, and cell proliferation and apoptosis were quantified. mRNA and protein levels of matrix metalloproteinases and cytokines were evaluated at baseline and after proinflammatory stimulation. GPA implants showed massive destruction of the co-implanted human cartilage, whereas cartilage destruction was only marginal in control samples. Destruction was mediated by human fibroblasts and could be inhibited by corticoid treatment. The up-regulated production of matrix metalloproteinases 1, 3, and 13 and cytokines IL-6 and IL-8 was found in vivo and in vitro. Although proliferation of isolated fibroblasts was comparable between GPA and controls, GPA samples showed a significant delay of apoptosis. The destruction of nasal cartilage in GPA is mainly mediated by fibroblasts that can be blocked by corticosteroids, and this tissue destruction is not dependent on the influx of leukocytes. PMID- 22449948 TI - Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. AB - Resolution of acute inflammation is an active process that involves the biosynthesis of specialized proresolving lipid mediators. Among them, resolvin D1 (RvD1) actions are mediated by two G protein-coupled receptors (GPCRs), ALX/FPR2 and GPR32, that also regulate specific microRNAs (miRNAs) and their target genes in novel resolution circuits. We report the ligand selectivity of RvD1 activation of ALX/FPR2 and GPR32. In addition to RvD1, its aspirin-triggered epimer and RvD1 analogs each dose dependently and effectively activated ALX/FPR2 and GPR32 in GPCR-overexpressing beta-arrestin systems using luminescence and electric cell substrate impedance sensing. To corroborate these findings in vivo, neutrophil infiltration in self-limited peritonitis was reduced in human ALX/FPR2 overexpressing transgenic mice that was further limited to 50% by RvD1 treatment with as little as 10 ng of RvD1 per mouse. Analysis of miRNA expression revealed that RvD1 administration significantly up-regulated miR-208a and miR-219 in exudates isolated from ALX/FPR2 transgenic mice compared with littermates. Overexpression of miR-208a in human macrophages up-regulated IL-10. In comparison, in ALX/FPR2 knockout mice, RvD1 neither significantly reduced leukocyte infiltration in zymosan-induced peritonitis nor regulated miR-208a and IL-10 in these mice. Together, these results demonstrate the selectivity of RvD1 interactions with receptors ALX/FPR2 and GPR32. Moreover, they establish a new molecular circuit that is operative in the resolution of acute inflammation activated by the proresolving mediator RvD1 involving specific GPCRs and miRNAs. PMID- 22449949 TI - The F508del mutation in cystic fibrosis transmembrane conductance regulator gene impacts bone formation. AB - The F508del mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene is believed to be an independent risk factor for cystic fibrosis related bone disease. In this study, we evaluated the bone mineral density as well as the histomorphometric parameters of bone formation and bone mass in both F508del-Cftr homozygous mice (F508del Cftr(tm1Eur)) and Cftr(+/+) littermate controls at 6 (prepubertal), 10 (pubertal), and 14 (young adult) weeks of age in both sexes. The bone architecture of F508del Cftr(tm1Eur) and wild-type (WT) littermate mice was evaluated by bone densitometry, microcomputed tomography, and analysis of the dynamic parameters of bone formation. Serum levels of both insulin-like growth factor 1 and osteocalcin also were determined. Reduced bone mineral density, lower femoral bone mass, and altered trabecular bone architecture were observed in F508del Cftr(tm1Eur) mice compared with controls at 6, 10, and 14 weeks of age. A decrease in the bone formation rate in F508del Cftr(tm1Eur) mice was shown compared with control mice, independently of age and sex. In addition, we found lower insulin-like growth factor 1 levels in F508del Cftr(tm1Eur) mice compared with age-matched controls, whereas osteocalcin levels were normal. Severe osteopenia and altered bone architecture were found in young and mature adult F508del Cftr(tm1Eur) mice. Our findings show that the F508del mutation in CFTR impacts trabecular bone mass by reducing bone formation. PMID- 22449950 TI - A mouse model of Schwartz-Jampel syndrome reveals myelinating Schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking. AB - Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K(+) channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K(+) homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes. PMID- 22449951 TI - Nature versus nurture in glioblastoma: microenvironment and genetics can both drive mesenchymal transcriptional signature. PMID- 22449952 TI - PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21. AB - Prostate cancer development and progression are associated with alterations in expression and function of elements of cytokine networks, some of which can activate multiple signaling pathways. Protein inhibitor of activated signal transducers and activators of transcription (PIAS)1, a regulator of cytokine signaling, may be implicated in the modulation of cellular events during carcinogenesis. This study was designed to investigate the functional significance of PIAS1 in models of human prostate cancer. We demonstrate for the first time that PIAS1 protein expression is significantly higher in malignant areas of clinical prostate cancer specimens than in normal tissues, thus suggesting a growth-promoting role for PIAS1. Expression of PIAS1 was observed in the majority of tested prostate cancer cell lines. In addition, we investigated the mechanism by which PIAS1 might promote prostate cancer and found that down regulation of PIAS1 leads to decreased proliferation and colony formation ability of prostate cancer cell lines. This decrease correlates with cell cycle arrest in the G0/G1 phase, which is mediated by increased expression of p21(CIP1/WAF1). Furthermore, PIAS1 overexpression positively influences cell cycle progression and thereby stimulates proliferation, which can be mechanistically explained by a decrease in the levels of cellular p21. Taken together, our data reveal an important new role for PIAS1 in the regulation of cell proliferation in prostate cancer. PMID- 22449953 TI - Cathepsin E, maspin, Plk1, and survivin are promising prognostic protein markers for progression in non-muscle invasive bladder cancer. AB - Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. In this study, we investigated the prognostic value of the protein expression of cathepsin E, maspin, polo-like kinase 1 (Plk1), and survivin in patients with stage Ta and T1 urothelial carcinomas. Transcripts from the four genes encoding these proteins were previously included in gene expression signatures for outcome prediction for Ta/T1 bladder cancer. We used three different tissue microarrays with 693 non-muscle invasive urothelial carcinomas from Danish, Swedish, and Spanish patient cohorts with long-term follow-up. Protein expression was measured by immunohistochemistry, and antibody specificity was validated by Western blotting. In the Danish patient cohort, we found the expression of cathepsin E, maspin, Plk1, and survivin to be significantly associated with progression to stage T2 to T4 bladder cancer (for each marker: log-rank test; P < 0.001). Multivariate Cox regression analysis identified cathepsin E (P < 0.001), Plk1 (P = 0.021), maspin (P = 0.001), and survivin (P = 0.001) as independent prognostic markers. Furthermore, maspin, survivin, and cathepsin E expression significantly subgrouped patients already stratified by European Organization for Research and Treatment of Cancer risk scores. Finally, we successfully validated the results in tumors from 410 patients from both Sweden and Spain. We conclude that all four protein markers may have prognostic value in non-muscle invasive bladder cancer for guiding optimal treatment of patients. Additional prospective studies are needed for further validation of the clinical relevance of this marker panel. PMID- 22449954 TI - Sip carefully. PMID- 22449955 TI - Do cannabinoids reduce brain power? PMID- 22449956 TI - Sensing the long and the short of it. PMID- 22449957 TI - Dendritic architecture: form and function. PMID- 22449958 TI - One cell's poison is another cell's cure. PMID- 22449959 TI - Deep thinking. PMID- 22449960 TI - From circuits to behavior: a bridge too far? AB - Neuroscience seeks to understand how neural circuits lead to behavior. However, the gap between circuits and behavior is too wide. An intermediate level is one of neural computations, which occur in individual neurons and populations of neurons. Some computations seem to be canonical: repeated and combined in different ways across the brain. To understand neural computations, we must record from a myriad of neurons in multiple brain regions. Understanding computation guides research in the underlying circuits and provides a language for theories of behavior. PMID- 22449961 TI - Intracellular interactions between protein 4.1 and glycophorin C on transport vesicles, as determined by fluorescence correlation spectroscopy. AB - Interaction of protein 4.1 (4.1R) with the transmembrane protein glycophorin C (GPC) regulates the functions of erythrocyte membrane. Fluorescence correlation spectroscopy (FCS) was used to define the interaction of EGFP-4.1R with DsRed-GPC on transport vesicles (TVs) by measuring their fluctuation in living cells. DsRed GPC expressed in HeLa cells was delivered to the plasma membrane through slow vesicle transport. EGFP-4.1R, which freely diffused in the cytosol when expressed alone, diffused slowly when co-expressed with DsRed-GPC, indicating association of EGFP-4.1R with TVs. Fluorescence cross-correlation spectroscopy (FCCS) showed direct interaction of EGFP-4.1R with DsRed-GPC on TVs. The present study demonstrates that 4.1R binds to GPC on TVs in living cells. PMID- 22449962 TI - Interaction between relaxase MbeA and accessory protein MbeC of the conjugally mobilizable plasmid ColE1. AB - MbeA and MbeC are two key proteins in plasmid ColE1 conjugal mobilization. Isothermal titration calorimetry was used to detect and quantify an interaction between MbeA and MbeC. As a result of this interaction, the affinity of MbeA for single stranded DNA increased. The interaction was confirmed in vivo using a bacterial two-hybrid system, which revealed that MbeA-MbeC complexes are formed through the amino-terminal region of MbeA and the carboxy-terminal region of MbeC. To the best of our knowledge, this is the first report of direct interactions between conjugative proteins encoded by a mobilizable plasmid. PMID- 22449963 TI - Formation of amyloid fibrils from beta-amylase. AB - Fibril formation has been considered a significant feature of amyloid proteins. However, it has been proposed that fibril formation is a common property of many proteins under appropriate conditions. We studied the fibril formation of beta amylase, a non-amyloid protein rich in alpha-helical structure, because the secondary structure of beta-amylase is similar to that of prions. With the conditions for the fibril formation of prions, beta-amylase proteins were converted into amyloid fibrils. The features of beta-amylase proteins and fibrils are compared to prion proteins and fibrils. Furthermore, the cause of neurotoxicity in amyloid diseases is discussed. PMID- 22449964 TI - A peptide mimicking the C-terminal part of the reactive center loop induces the transition to the latent form of plasminogen activator inhibitor type-1. AB - Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of plasminogen activators (uPA and tPA) and thus plays a central role in fibrinolysis. The spontaneous insertion of its reactive centre loop (RCL) into beta-sheet A is responsible for its irreversible conversion into the inactive latent form. In this study, we used two peptides mimicking residues P14-P9 and P8-P3 of the RCL so as to understand this dynamic process. We show that both peptides inhibit the formation of PAI-1/uPA and PAI-1/tPA complexes via two different mechanisms. Targeting the N-terminal part of the loop induces the cleavage of PAI-1 by the proteases uPA/tPA while targeting its C-terminal part greatly favors the irreversible formation of latent PAI-1. PMID- 22449965 TI - A putative myristoylated 2C-type protein phosphatase, PP2C74, interacts with SnRK1 in Arabidopsis. AB - N-myristoylation is a lipid modification of many signaling proteins in which myristate is added to an N-terminal glycine residue. Here we show that PP2C74, a putative myristoylated 2C-type protein phosphatase (PP2C) in Arabidopsis, is transcribed in various tissues and has protein phosphatase activity. GFP-fused PP2C74 localized to the plasma membrane, but not when a glycine residue at position 2, which is the putative myristoylation site, was substituted with an alanine residue. Yeast two-hybrid analysis and GST pull-down analysis showed that PP2C74 interacts with AKIN10, the catalytic alpha subunit of the SnRK1 protein kinase complex, the beta subunits of which are known targets of myristoylation. PMID- 22449966 TI - Requirement for Pak3 in Rac1-induced organization of actin and myosin during Drosophila larval wound healing. AB - Rho-family small GTPases regulate epithelial cell sheet migration by organizing actin and myosin during wound healing. Here, we report that Pak3, but not Pak1, is a downstream target protein for Rac1 in wound closure of the Drosophila larval epidermis. Pak3-deficient larvae failed to close a wound hole and this defect was not rescued by Pak1 expression, indicating differential functions of the two proteins. Pak3 localized to the wound margin, which selectively required Rac1. Pak3-deficient larvae showed severe defects in actin-myosin organization at the wound margin and in submarginal cells, which was reminiscent of the phenotypes of Rac1-deficient larvae. These results suggest that Pak3 specifically mediates Rac1 signaling in organizing actin and myosin during Drosophila epidermal wound healing. PMID- 22449967 TI - Imprinted DNA methylation reprogramming during early mouse embryogenesis at the Gpr1-Zdbf2 locus is linked to long cis-intergenic transcription. AB - The paternally-expressed imprinted genes Gpr1 and Zdbf2 form a gene cluster wherein the imprinted-methylated regions of these two genes differ. We identified a novel, paternally expressed, long intergenic non-coding Zdbf2 variant (Zdbf2linc) transcribed from maternally methylated Gpr1 DMR during early embryogenesis in the mouse. While the Gpr1 DMR displayed biallelic hypermethylation, Zdbf2linc expression was rarely observed in the post gastrulation, despite a positive correlation between the methylation of Zdbf2 DMRs and the mono-allelic transcription of the original Zdbf2 coding variant. Furthermore, lack of the maternal methylation imprint resulted in the biallelic expression of both coding and non-coding Zdbf2 transcripts as well as complete methylation of Zdbf2 DMRs. Globally, our findings suggest the role of Zdbf2linc in the establishment of secondary epigenetic modifications after implantation. PMID- 22449968 TI - Kruppel-like factor 4 inhibits the expression of interleukin-1 beta in lipopolysaccharide-induced RAW264.7 macrophages. AB - RAW264.7 macrophages and human peripheral blood mononuclear cells were treated with LPS to determine the expression of KLF4 and release of IL-1beta. A full length cDNA or short interference RNA of KLF4 was transfected into RAW264.7 macrophages; the expression and release of IL-1beta were analyzed. The transcription and DNA binding activities of KLF4 to the IL-1beta promoter were detected further. The results showed LPS treatment resulted in the increase of KLF4 level and IL-1beta release; KLF4 overexpression decreased the expression of IL-1beta, while KLF4 inhibition increased the expression of IL-1beta; overexpression of KLF4 promoted the DNA binding activity of KLF4 to the IL-1beta promoter and attenuated the transcription of IL-1beta promoter, indicating an important role of KLF4 in regulating expression of IL-1beta. PMID- 22449969 TI - Localization of residues in a novel DNA-binding domain of DmSNAP43 required for DmSNAPc DNA-binding activity. AB - Transcription of snRNA genes depends upon the recognition of the proximal sequence element (PSE) by the snRNA activating protein complex SNAPc. In Drosophila melanogaster, all subunits of DmSNAPc (DmSNAP43, DmSNAP50, and DmSNAP190) are required for PSE-binding activity. Previous work demonstrated that a non-canonical DmSNAP43 domain bounded by residues 193-272 was essential for DmSNAPc to bind to the PSE. In this study, the contribution of amino acid residues within this domain to DNA binding by DmSNAPc was investigated by alanine scanning mutagenesis. The results have identified two clusters of residues within this domain required for the sequence-specific DNA-binding activity of DmSNAPc. PMID- 22449970 TI - Ycf1p attenuates basal level oxidative stress response in Saccharomyces cerevisiae. AB - Ycf1p function is regulated by casein kinase 2alpha, Cka1p, via phosphorylation of Ser251. Cka1p-mediated phosphorylation of Ycf1p is attenuated in response to high salt stress. Previous results from our lab suggest a role for Ycf1p in cellular resistance to salt stress. Here, we show that Ycf1p plays an important role in cellular resistance to salt stress by maintaining the cellular redox balance via glutathione recycling. Our results suggest that during acute salt stress increased Sod1p, Sod2p and Ctt1p activity is the main compensatory for the loss in Ycf1p function that results from reduced Ycf1p-dependent recycling of cellular GSH levels. PMID- 22449971 TI - The C-terminus of kinesin-14 Ncd is a crucial component of the force generating mechanism. AB - Ncd, a member of kinesin-14 family motors, uses the power stroke, a lever-like pivoting action of a long and stiff element, to exert force and generate movement. To better understand the role of the Ncd C-terminus in this process we produced four Ncd mutants in which this segment was altered or deleted. For these proteins we measured their affinity to the microtubule, steady-state ATPase and gliding velocity in multiple motor assays. The mutations had a dramatic effect on all three parameters measured, suggesting that the C-terminal residues of Ncd play an important role in modulating the interaction of the motor with the microtubule. PMID- 22449972 TI - Crystal structures of the Tudor domains of human PHF20 reveal novel structural variations on the Royal Family of proteins. AB - The human PHD finger protein 20 (PHF20) is a putative transcription factor. While little is known about its cognate cellular role, antibodies against PHF20 are present in sera from patients with hepatocellular carcinoma, glioblastoma and childhood medulloblastula. PHF20 comprises two N-terminal Tudor domains, a central C2H2-link zinc finger domain and a C-terminal zinc-binding PHD domain, and is a component of some MLL methyltransferase complexes. Here, we report the crystal structures of the N-terminal Tudor domains of PHF20 and highlight the novel structural features of each domain. We also confirm previous studies suggesting that the second Tudor domain of PHF20 exhibits preference for dimethylated histone substrates. PMID- 22449973 TI - Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6. AB - The discovery of sirtuins (SIRT), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, has indicated that intracellular NAD level is crucial for the hypertrophic response of cardiomyocytes. Nicotinamide mononucleotide adenylyltransferase (Nmnat) is a central enzyme in NAD biosynthesis. Here we revealed that Nmnat2 protein expression and enzyme activity were down-regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)-induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. Our results suggested that modulation of Nmnat2 activity may be beneficial in cardiac hypertrophy. PMID- 22449974 TI - The frpB1 gene of Helicobacter pylori is regulated by iron and encodes a membrane protein capable of binding haem and haemoglobin. AB - FrpB1 is a novel membrane protein of Helicobacter pylori that is capable of binding both haem and haemoglobin but consistently shows more affinity for haem. The mRNA levels of frpB1 were repressed by iron and lightly modulated by haem or haemoglobin. The overexpression of the frpB1 gene supported cellular growth when haem or haemoglobin were supplied as the only iron source. Three-dimensional modelling revealed the presence of motifs necessary to bind either haem or haemoglobin. Our overall results support the idea that FrpB1 is a membrane protein of H. pylori that allows this pathogen to survive in the human stomach. PMID- 22449975 TI - GSH threshold requirement for NO-mediated expression of the Arabidopsis AtFer1 ferritin gene in response to iron. AB - Iron treatment of Arabidopsis cultured cells promotes a rapid NO burst within chloroplasts, necessary for up-regulation of the AtFer1 ferritin gene expression. The same occurs in Arabidopsis leaf chloroplasts, and is dependent upon the GSH content of plants. A leaf GSH concentration threshold between 10 and 50 nmol GSHg(-1) FW is required for full induction of AtFer1 gene expression in response to iron. PMID- 22449976 TI - MiR-219-5p inhibits hepatocellular carcinoma cell proliferation by targeting glypican-3. AB - MicroRNAs (miRNAs) have been linked to the molecular pathogenesis of many cancers. In this study, we found that miR-219-5p was significantly downregulated in 83 HCC tissues and three HCC cell lines, compared to their non-tumor counterparts. MiR-219-5p expression correlated with tumor size, histological differentiation, and overall survival time in HCC patients. We also found that miR-219-5p could inhibit cell proliferation in vitro and arrest cell cycle at the G1 to S transition. Further studies identified that miR-219-5p reduced both the mRNA and protein levels of glypican-3 (GPC3). These findings indicate that miR 219-5p exerts tumor-suppressive effects in hepatic carcinogenesis through negative regulation of GPC3 expression. PMID- 22449977 TI - 17beta-estradiol induces both up-regulation and processing of cyclin E in a calpain-dependent manner in MCF-7 breast cancer cells. AB - In the current study, we investigated whether 17beta-estradiol (E2) induces cyclin E expression and triggers cyclin E processing via calpain in MCF-7 breast cancer cells. We found that E2 induced increased expression of cyclin E in a slow and persistent manner, and a rapid yet sustained processing of cyclin E. In addition, estrogenic ethanol was able to stimulate cyclin E truncation. Calpeptin or ALLN greatly suppressed the E2-triggered cyclin E processing and its expression, suggesting a calpain-mediated action for E2. Finally, the E2-induced effects could also be significantly suppressed by BAPTA or U0126, indicating involvement of calcium/ERK signaling. Taken together, these results show that estrogen may contribute to both up-regulation and proteolysis of cyclin E through calpain in MCF-7 cells. PMID- 22449978 TI - miR-20a promotes migration and invasion by regulating TNKS2 in human cervical cancer cells. AB - miR-20a is an important member of the miR-17-92 cluster, and its real function in cervical cancer cells is unknown. Our study demonstrated that miR-20a was upregulated in cervical cancer tissues. Overexpression of miR-20a in cervical cancer-derived cell lines, HeLa and C-33A, enhanced long-term cellular proliferation, migration and invasion, whereas inhibition of miR-20a suppressed those functions. We also confirmed that oncogenic TNKS2 is directly upregulated by miR-20a. Furthermore, suppression of TNKS2 expression could inhibit colony formation, migration and invasion of cervical cancer cells. Therefore, we concluded that miR-20a can promote migration and invasion of cervical cancer cells through the upregulation of TNKS2. PMID- 22449979 TI - Lysine degradation through the saccharopine pathway in bacteria: LKR and SDH in bacteria and its relationship to the plant and animal enzymes. AB - Lysine degradation through the saccharopine pathway has been shown only in plants and animals. Here, we show that bacteria possess the genes encoding lysine ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH). In Silicibacter, the contiguous lkr and sdh genes are interspersed, in another frame, by a polypeptide of unknown function. The bacterial enzyme does not contain the 110-amino-acid interdomain (ID) that intersperses the LKR and SDH domains of the plant enzyme. The ID was found in Cyanobacteria interspersing polypeptides without similarities and activities of LKR and SDH. The LKR/SDH bifunctional polypeptide of animals and plants may have arisen from a alpha proteobacterium with a configuration similar to that of Silicibacter, whereas the ID in the plant enzyme may have been inherited from Cyanobacteria. PMID- 22449980 TI - Crystal structure of a single-chain trimer of human adiponectin globular domain. AB - Adiponectin is increasingly recognized as a potential therapeutic agent for the treatment of diabetes and other metabolic diseases. It circulates in plasma as homotrimers and higher-order oliogomers of homotrimers. To facilitate the production of active recombinant adiponectin as a therapeutic tool, we designed a single-chain globular domain adiponectin (sc-gAd) in which three monomer sequences are linked together in tandem to form one contiguous polypeptide. Here, we present the crystal structure of human sc-gAd at 2.0A resolution. The structure reveals a similar trimeric topology to that of mouse gAd protein. Trimer formation is further rigidified by three calcium ions. PMID- 22449981 TI - Rational design of DNA sequence-specific zinc fingers. AB - We developed a rational scheme for designing DNA binding proteins. The scheme was applied for a zinc finger protein and the designed sequences were experimentally characterized with high DNA sequence specificity. Starting with the backbone of a known finger structure, we initially calculated amino acid sequences compatible with the expected structure and the secondary structures of the designed fingers were then experimentally confirmed. The DNA-binding function was added to the designed finger by reconsidering a section of the amino acid sequence and computationally selecting amino acids to have the lowest protein-DNA interaction energy for the target DNA sequences. Among the designed proteins, one had a gap between the lowest and second lowest protein-DNA interaction energies that was sufficient to give DNA sequence-specificity. PMID- 22449982 TI - Prediction of replication origins by calculating DNA structural properties. AB - In this study, we introduced two DNA structural characteristics, namely, bendability and hydroxyl radical cleavage intensity to analyze origin of replication (ORI) in the Saccharomyces cerevisiae genome. We found that both DNA bendability and cleavage intensity in core replication regions were significantly lower than in the linker regions. By using these two DNA structural characteristics, we developed a computational model for ORI prediction and evaluated the model in a benchmark dataset. The predictive performance of the jackknife cross-validation indicates that DNA bendability and cleavage intensity have the ability to describe core replication regions and our model is effective in ORI prediction. PMID- 22449983 TI - Crystal structure of Cmr2 suggests a nucleotide cyclase-related enzyme in type III CRISPR-Cas systems. AB - CRISPR RNAs (crRNAs) mediate sequence-specific silencing of invading viruses and plasmids in prokaryotes. The crRNA-Cmr protein complex cleaves complementary RNA. We report the crystal structure of Pyrococcus furiosus Cmr2 (Cas10), a component of this Cmr complex and the signature protein in type III CRISPR systems. The structure reveals a nucleotide cyclase domain with a set of conserved catalytic residues that associates with an unexpected deviant cyclase domain like dimeric cyclases. Additionally, two helical domains resemble the thumb domain of A-family DNA polymerase and Cmr5, respectively. Our results suggest that Cmr2 possesses novel enzymatic activity that remains to be elucidated. PMID- 22449985 TI - Neochloris oleoabundans grown in enriched natural seawater for biodiesel feedstock: evaluation of its growth and biochemical composition. AB - The freshwater microalga Neochloris oleoabundans was used to study algal lipid production in enriched natural seawater, in order to assess its suitability as biodiesel feedstock. Optimal and nitrogen-stress (N-stress) conditions were analyzed. Under optimal conditions, the strain's growth rate was 0.73 div day(-1) and the biomass concentration was 1.5 g L(-1), while it had a maximum lipid yield under N-stress conditions (lipid content: 26% of dry weigh and lipid productivity: 56 mg L(-1) day(-1)). Lipid accumulation was mainly due to a significant increase of triacylglycerol content. Neutral lipids were characterized by a dominance of monounsaturated fatty acids and displayed a fatty acid profile that is suitable for biodiesel. This work offers an interesting alternative for sustainable microalgal oil synthesis for biodiesel production without using freshwater resources. However, further studies are necessary in order to optimize the lipid productivities required for commercial biodiesel production. PMID- 22449984 TI - Regulation of amyloid-beta production by the prion protein. AB - Alzheimer disease (AD) is characterized by the amyloidogenic processing of the amyloid precursor protein (APP), culminating in the accumulation of amyloid-beta peptides in the brain. The enzymatic action of the beta-secretase, BACE1 is the rate-limiting step in this amyloidogenic processing of APP. BACE1 cleavage of wild-type APP (APPWT) is inhibited by the cellular prion protein (PrP (C) ). Our recent study has revealed the molecular and cellular mechanisms behind this observation by showing that PrP (C) directly interacts with the pro-domain of BACE1 in the trans-Golgi network (TGN), decreasing the amount of BACE1 at the cell surface and in endosomes where it cleaves APPWT, while increasing BACE1 in the TGN where it preferentially cleaves APP with the Swedish mutation (APPSwe). PrP (C) deletion in transgenic mice expressing the Swedish and Indiana familial mutations (APPSwe,Ind) failed to affect amyloid-beta accumulation, which is explained by the differential subcellular sites of action of BACE1 toward APPWT and APPSwe. This, together with our observation that PrP (C) is reduced in sporadic but not familial AD brain, suggests that PrP (C) plays a key protective role against sporadic AD. It also highlights the need for an APPWT transgenic mouse model to understand the molecular and cellular mechanisms underlying sporadic AD. PMID- 22449986 TI - Azo dye decolorization by Shewanella aquimarina under saline conditions. AB - Decolorization of azo dyes under saline conditions was studied with Shewanella aquimarina, which demonstrated good growth at up to 7% NaCl. No inhibition on acid red 27 (AR27) decolorization was caused by 1-3% NaCl. Additionally, 14.5% AR27 (0.2mM) could still be removed in 12h in the presence of 10% NaCl. The relationship between specific decolorization rate and AR27 concentration followed Michaelis-Menten kinetics (K(m)=0.34 mM, V(max)=6.44 MUmol mg cell(-1) h(-1)). Lactate and formate were efficient electron donors for AR27 decolorization. The initial decolorization rate was in direct proportion to biomass concentration (0.18-0.72 g l(-1)). Compared to NaCl, slighter inhibitive effects were found with Na(2)SO(4) whereas more severe inhibition was caused by NaNO(3). Lower NaCl concentration stimulated azoreductase, laccase and NADH-DCIP reductase activities of cell extracts. AR27 decolorization products were found to be aromatic amines, which were less phytotoxic than the untreated dye. PMID- 22449987 TI - Effects of micro-nano and non micro-nano MSWI ashes addition on MSW anaerobic digestion. AB - This study aims at investigating the effects of micro-nano municipal solid waste (MSW) incinerator (MSWI) fly ash (FA) and bottom ash (BA) on the MSW anaerobic digestion. Results showed that suitable micro-nano and non micro-nano MSWI ashes addition (FA/MSW 3, 6, 18 and 30 g g(-1) VS and BA/MSW 12, 36, 60 and 120 g g(-1) VS) could enhance the biogas production compared to the control. It was particularly found to have the highest biogas production at the micro-nano MSWI BA/MSW ratio of 36 g g(-1) VS (~193 mL g(-1) VS MSW, ~3.5 times to the control). Micro-nano MSWI FA and BA added bioreactors had the higher biogas production than the corresponding non micro-nano MSWI FA and BA added ones. Suitable MSWI ashes addition could improve the biogas production due to the released metals levels suitable for the MSW anaerobic digestion particularly found in the micro-nano added bioreactors. PMID- 22449988 TI - Diagnostic imaging in patients with retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a progressive inherited retinal disease, and patients with RP have reduced visual function caused by a degeneration of the photoreceptors and retinal pigment epithelium (RPE). At the end stage of RP, the degeneration of the photoreceptors in the fovea reduces central vision, and RP is one of the main causes of acquired blindness in developed countries. Therefore, morphological and functional assessments of the photoreceptors in the macula area can be useful in estimating the residual retinal function in RP patients. Optical coherence tomography (OCT) is a well-established method of examining the retinal architecture in situ. The photoreceptor inner/outer segment (IS/OS) junction is observed as a distinct, highly reflective line by OCT. The presence of the IS/OS junction in the OCT images is essential for normal visual function. Fundus autofluorescence (FAF) results from the accumulation of lipofuscin in the RPE cells and has been used to investigate RPE and retinal function. More than one half of RP patients have an abnormally high density parafoveal FAF ring (AF ring). The AF ring represents the border between functional and dysfunctional retina. In this review, we shall summarize recent progress on diagnostic imaging in eyes with RP. PMID- 22449989 TI - Androgen in postmenopausal women. AB - Menopausal symptoms, bone loss, changes in lipid profiles and reduction of insulin sensitivity due to an abrupt decrease in circulating estrogen level are well known in women during the menopausal transition. On the other hand, the effect of androgen on women's health has not been fully elucidated. Circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEA-S) gradually decrease with age in postmenopausal women, although transient increases have been observed during the menopausal transition. High testosterone level has been suggested to be associated with increased risk of cardiovascular disease, increased triglyceride, insulin resistance and increase in the risk of developing breast cancer in postmenopausal women. Circulating DHEA-S level does not affect the risk of cardiovascular disease, mortality or lipid profiles in women. Female androgen insufficiency, which is characterized by the presence of reduced androgen level in circulation, leads to an impairment in sexual drive, reduced libido, depressed mood, and signs and symptoms of limited androgen exposure such as decreased muscle mass, reduced bone density and decreased sense of well-being. An appropriate level of androgen may play important roles in metabolic, psychological and sexual functions in women. In addition, the roles of testosterone and DHEA-S in women's health may be different. PMID- 22449990 TI - Simulation-based medical education in clinical skills laboratory. AB - Clinical skills laboratories have been established in medical institutions as facilities for simulation-based medical education (SBME). SBME is believed to be superior to the traditional style of medical education from the viewpoint of the active and adult learning theories. SBME can provide a learning cycle of debriefing and feedback for learners as well as evaluation of procedures and competency. SBME offers both learners and patients a safe environment for practice and error. In a full-environment simulation, learners can obtain not only technical skills but also non-technical skills, such as leadership, team work, communication, situation awareness, decision-making, and awareness of personal limitations. SBME is also effective for integration of clinical medicine and basic medicine. In addition, technology-enhanced simulation training is associated with beneficial effects for outcomes of knowledge, skills, behaviors, and patient-related outcomes. To perform SBME, effectively, not only simulators including high-fidelity mannequin-type simulators or virtual-reality simulators but also full-time faculties and instructors as professionals of SBME are essential in a clinical skills laboratory for SBME. Clinical skills laboratory is expected to become an integrated medical education center to achieve continuing professional development, integrated learning of basic and clinical medicine, and citizens' participation and cooperation in medical education. PMID- 22449991 TI - Hydrogen peroxide inhibits insulin-induced ATP-sensitive potassium channel activation independent of insulin signaling pathway in cultured vascular smooth muscle cells. AB - Both reactive oxygen species (ROS) and insulin resistance have been reported to play essential pathophysiological roles in cardiovascular diseases, such as hypertension and atherosclerosis. However, the mechanistic link between ROS and insulin resistance in the vasculature remains unclear. Recently we have shown that insulin causes membrane hyperpolarization via ATP-sensitive potassium (K(ATP)) channel activation, which is mediated by phosphatidylinositol 3-kinase (PI3-K) in cultured vascular smooth muscle cells (VSMCs). K(ATP) channel in the vasculature is critical in the regulation of vascular tonus. Here we examined the effects of ROS induced by hydrogen peroxide (H(2)O(2)) on insulin-induced K(ATP) channel activities in cultured VSMCs, A10 cells. H(2)O(2) (10 uM) increased significantly intercellular ROS in A10 cells. By using a cell-attached patch clamp experiment, 10 uM H(2)O(2) suppressed significantly insulin-induced K(ATP) channel activation without inhibition of insulin receptor signal transduction component including IRS and Akt in A10 cells. Furthermore 10 uM H(2)O(2) suppressed significantly pinacidil-induced K(ATP) channel activation in A10 cells. These data suggest that H(2)O(2) might inhibit directly K(ATP) channel independent of insulin signaling pathway. This study may contribute to our understanding of mechanisms of insulin resistance-associated cardiovascular disease. PMID- 22449992 TI - Multi-channel near-infrared spectroscopy reveals reduced prefrontal activation in schizophrenia patients during performance of the kana Stroop task. AB - The purpose of the present study was to investigate the activity of frontal lobe of patients with schizophrenia during performance of two Japanese versions of the Stroop task (kana and kanji) by measuring changes in the concentration of oxygenated hemoglobin (oxyHb) with near-infrared spectroscopy (NIRS). Fourteen schizophrenia patients and 14 age- and gender-matched healthy control subjects participated in the study after giving consent. The relative changes of concentrations of oxyHb were measured by NIRS during performance of the Stroop task. Significant Stroop effects, as measured by the number of correct responses, were observed with both the kana and the kanji versions. Analysis of NIRS data revealed that the schizophrenia patients showed reduced activation in the prefrontal cortex compared to healthy controls during performance of the kana Stroop task, and that both schizophrenia patients and healthy controls showed lack of activity in the prefrontal cortex during performance of the kanji Stroop task. The results of the present study suggest the possibility that the kana Stroop task cause a greater Stroop effect than the kanji Stroop task, and schizophrenia patients show decreased prefrontal vascular reactivity associated with the inhibition required during the performance of the kana Stroop task. PMID- 22449993 TI - Sterilization effect of UV light on Bacillus spores using TiO(2) films depends on wavelength. AB - UV light and photocatalysts such as titanium dioxide (TiO(2)) and silver (Ag) are useful for disinfection of water and surfaces. However, the effect of UV wavelength on photocatalytic disinfection of spores is not well understood. Inactivation of Bacillus spores has been examined using different UV wavelengths and TiO(2) or TiO(2)/Ag composite materials. The level of UVA disinfection of Bacillus anthracis and Bacillus brevis vegetative cells increased with the presence of the TiO(2) and Ag photocatalysts, but had little effect on their spores. B. brevis spores were slightly more sensitive to UVB and UVC than the spores of B. atrophaeus. Photocatalytic sterilization against spores was strongest in UVC and UVB and weakest in UVA. The rate of inactivation of Bacillus spores was significantly increased by the presence of TiO(2), but was not markedly different from that induced by the presence of Ag. Therefore, TiO(2)/Ag plus UVA can be used for the sterilization of vegetative cells, while TiO(2) and UVC are effective against spores. PMID- 22449994 TI - Dissection of morphological and metabolic differentiation of ameloblasts via ectopic SP6 expression. AB - Tooth enamel is the hardest organ in the body. In rodent incisor, the enamel is exclusively produced by ameloblasts with yellowish-brown pigmentation, indicating normal enamel formation. However, the molecular mechanisms of ameloblast differentiation and amelogenesis are not fully understood. Specificity protein (Sp) 6 has been reported as one of the critical factors for tooth development. To explore SP6 function, we generated Sp6 transgenic (Tg) rats. Unexpectedly, the enamel surfaces of the incisors in Tg rats were discolored, even though enamel formation and serum iron concentrations were normal. Histological analysis of incisors from 6-week-old Tg rats demonstrated that the ameloblast layer at the pigmentation stage was elongated up to the gingival margin with ectopic SP6 expression in longitudinal incisor sections. In contrast, the incisors from 10 week-old Tg rats revealed that the pigmented ameloblasts were morphologically changed to those of the reduced stage, concomitant with the sporadic disappearance of ectopic SP6 expression. Here we report that morphological differentiation and metabolism of the iron-containing pigment in ameloblasts are independently regulated during amelogenesis by means of ectopic SP6 expression. PMID- 22449995 TI - Twenty five-gauge sutureless vitrectomy versus 20-gauge vitrectomy in epiretinal membrane surgery. AB - PURPOSE: To compare visual outcomes, intraoperative and postoperative complications of 25-gauge transconjunctival sutureless vitrectomy (25-G TSV) versus conventional 20-gauge vitrectomy in epiretinal membrane (ERM) surgery. METHODS: A retrospective comparative study was conducted on 200 eyes with idiopathic ERM who underwent either primary 20-gauge vitrectomy (n=95) or 25-G TSV (n=105) with 6 months follow up. The following parameters were collected and compared: age, gender, best corrected visual acuity (BCVA), intraocular pressure (IOP), postoperative anterior chamber inflammation, intraoperative and postoperative complications. RESULTS: Twenty-five gauge group achieved a significantly better vision at the 1(st) postoperative month (p=0.008) and a significantly higher incidence of visual improvement 6 months postoperatively (p=0.04) than 20-gauge group. Intraocular pressure was significantly higher at the 1(st), 3(rd) and 6(th) postoperative months compared with baseline in the 20 G group. However, in the 25-gauge group IOP remained near to the baseline at the same period. Twenty five-gauge group achieved a significantly lower anterior chamber inflammation and a lower incidence of postoperative cystoid macular edema (CME) (p=0.01), hyphema (p=0.000) and after cataract (p=0.000) than 20-gauge group. CONCLUSIONS: The 25-gauge sutureless vitrectomy achieves rapid and higher visual improvement, less postoperative inflammation and complications than the 20 gauge vitrectomy in ERM surgery. PMID- 22449996 TI - Characterization of a gene cluster for sialoglycoconjugate utilization in Bacteroides fragilis. AB - Recent analysis of the whole genome sequence of Bacteroides fragilis revealed extensive duplication of polysaccharide utilization genes in this anaerobe. Here we analyzed a unique 27-kb gene cluster (sgu) comprised of the 13 sialoglycoconjugates-utilization genes, which include the sialidase gene (nanH1) in B. fragilis strain YCH46. The genes were tightly organized and transcribed polycistronically. Comparative PCR scanning demonstrated that the sgu locus was conserved among the Bacteroides strains tested. Based on the transcriptional profiles generated by reverse transcriptase PCR, the sgu locus can be classified into at least three regulatory units: 1) sialic acid- or sialooligosaccharide inducible genes, 2) constitutively expressed genes that can be down-regulated by catabolite repression, and 3) constitutively expressed genes. In vitro comparison of the growth of a sgu locus deletion mutant (SGUM172941) with a wild type strain indicates that this locus is necessary for B. fragilis to efficiently utilize mucin as a carbon source. Furthermore, SGUM172941 was defective in colonization of the intestines of germ-free mice under competitive conditions. These data indicate that the sgu locus in B. fragilis plays a crucial role in the utilization of host-derived sialoglycoconjugates and the stable colonization of this anaerobe in the human gut. PMID- 22449997 TI - Decreased expression of MHC class II and cathepsin E in dendritic cells might contribute to impaired induction of antigen-specific T cell response in NC/Nga mice. AB - NC/Nga (NC) mice are an animal model for human atopic dermatitis. We found that induction of antigen (Ag)-specific T cell response is diminished in ovalbumin (OVA)-immunized NC mice. Ability of Ag presentation in NC mouse dendritic cells (DCs) was significantly weaker than that in BALB/c and DBA/2 mouse DCs. Expression levels of MHC class II molecules and cathepsin E in NC mouse DCs were significantly lower that those in BALB/c and DBA/2 mouse DCs. These results indicate that low expression levels of MHC class II and cathepsin E might contribute to the defect in induction of Ag-specific T cells in NC mice. PMID- 22449998 TI - Electrolyte-carbohydrate beverage prevents water loss in the early stage of high altitude training. AB - To prevent water loss in the early stage of high altitude training, we focused on the effect of electrolyte-carbohydrate beverage (EC). Subjects were 16 male university students who belonged to a ski club. They had ski training at an altitude of 1,800 m. The water (WT) group drank only water, and the EC group drank only an electrolyte-carbohydrate beverage. They arrived at the training site in the late afternoon. The study started at 7 pm on the day of arrival and continued until noon of the 4(th) day. In the first 12 hours, 1 L of beverages were given. On the second and third days, 2.5 L of beverages were given. All subjects ate the same meals. Each morning while in fasting condition, subjects were weighed and blood was withdrawn for various parameters (hemoglobin, hematocrit, sodium, potassium and aldosterone). Urine was collected at 12 hour intervals for a total 60 hours (5 times). The urine volume, gravity, sodium and potassium concentrations were measured. Peripheral oxygen saturation and heart rate were measured during sleep with a pulse oximeter. Liquid intakes in both groups were similar, hence the electrolytes intake was higher in the EC group than in the WT group. The total urine volume was lower in the EC group than in the WT group, respectively (p<0.05). Plasma volume decreased in the WT group and increased in the EC group but a significant difference was not observed in the final value. Aldosterone concentration tended to be less in the EC group than in the WT group. Electrolyte-carbohydrate beverage in the early stage of high altitude training may be effective in decreasing urinary output and preventing loss of blood plasma volume. PMID- 22449999 TI - Study on the necessary survey days for energy intake in school children assessed by 7 day survey. AB - Theoretically, the longer the period of a nutrition survey, the more reliable the results. However, a long survey can impose a burden on subjects and cause the results to become inaccurate. For adults, a 3 non-consecutive day survey is usually recommended; however, for school children, at least in Japan, it has not been determined whether this is necessary. In this study we conducted a survey of 7 days and tried to find the minimum number of days necessary to determine the energy intake. The subjects were about 300 children aged from 6 to 7, 10 to 11 and 13 to 14 years old in a city in the western part of Japan. The weighing method was used for the school lunch and other meals were surveyed by 24 recalling method. For the 6-7 year-old school children, guardians were asked to keep dietary records. The final number of subjects who were able to complete the 7-day survey was 139. Energy intakes for each weekday were not statistically different (p>0.05) and those for each weekend did not differ (p>0.05). Average energy intakes on weekdays were higher than those on weekend days in 10-11 and 13 14 year-old children. The average intakes of energy in 10-11 and 13-14 year-old children were lower than Japanese estimated energy requirements (EER). However, body weight of more than 90% of subjects was within the normal range. The results suggest that a survey of one weekday is reliable for all weekdays and that of one week-end day is reliable for any weekend day and also indicate the necessity of further studies of EER in rapidly growing children. PMID- 22450000 TI - Identification and functional analysis of a splice variant of mouse sodium dependent phosphate transporter Npt2c. AB - Mutations in the SLC34A3 gene, a sodium-dependent inorganic phosphate (Pi) cotransporter, also referred to as NaPi IIc, causes hereditary hypophosphatemic rickets with hypercalciuria (HHRH), an autosomal recessive disorder. In human and rodent, NaPi IIc is mainly localized in the apical membrane of renal proximal tubular cells. In this study, we identified mouse NaPi IIc variant (Npt2c-v1) that lacks the part of the exon 3 sequence that includes the assumed translation initiation site of Npt2c. Microinjection of mouse Npt2c-v1 cRNA into Xenopus oocytes demonstrated that Npt2c-v1 showed sodium-dependent Pi cotransport activity. The characterization of pH dependency showed activation at extracellular alkaline-pH. Furthermore, Npt2c-v1 mediated Pi transport activity was significantly higher at any pH value than those of Npt2c. In an in vitro study, the localization of the Npt2c-v1 protein was detected in the apical membrane in opossum kidney cells. The expression of Npt2c-v1 mRNA was detected in the heart, spleen, testis, uterus, placenta, femur, cerebellum, hippocampus, diencephalon and brain stem of mouse. Using mouse bone primary cultured cells, we showed the expression of Npt2c-v1 mRNA. In addition, the Npt2c protein was detected in the spermatozoa head. Thus, Npt2c-v1 was expressed in extra-renal tissues such as epididymal spermatozoa and may function as a sodium-dependent phosphate transporter. PMID- 22450001 TI - Interventional study for improvement of lung cancer screening rate. AB - The aim of this study is to evaluate whether leaflet distribution affects lung screening rate, and what factor affects the motivation of consultation. Men and women aged 40 to 59 were targeted to improve screening rate of ages for cancer screening, especially in their prime. Each 1,000 subject, a total of 2,000 were selected and divided into 8 groups in consideration of age group by random sampling method. This group was further divided into two groups, an intervention group including subjects distributed a leaflet and a non-intervention (control) group. A survey was conducted by postal self-administered survey forms. Collection rate was 21.6% for the intervention and 17.6% for the control group. The numbers of respondents who answered that this leaflet was effective for motivation of consulting lung cancer screening and the leaflet was ineffective, were 120 (60.0%) and 80 (40.0%), respectively. This indicated that the leaflet was clearly effective (p<0.01). Actual cancer screening rate was 38.8% for the intervention group and 37.7% for the control group. It was shown that distribution by mail of even a single leaflet made by National Cancer Center was effective for motivation of consultation of lung cancer screening. PMID- 22450002 TI - Efficacy of the Quickert procedure for involutional entropion: the first case series in Asia. AB - PURPOSE: To report the efficacy of the Quickert procedure in the first case series of involutional entropion in an elderly Asian population, and to introduce the technique to Asian ophthalmologists including general ophthalmologisits and ophthalmic trainees. METHODS: We conducted a retrospective review of 13 consecutive patients underwent the Quickert procedure for involutional entropion by occasional eyelid surgeons at Tokushima University Hospital or Mino Tanaka Hospital from September 2003 to April 2010. Demographic data, including gender, age, history of previous eyelid surgery, systemic disease, recurrence of entropion, postoperative complications, and symptoms were analyzed. RESULTS: There were 5 male (38.5%) and 8 female (61.5%) subjects with a mean age of 77.8 years. Three patients underwent previous surgery for entropion were included. Entropion was rectified in all patients by a single Quickert procedure, and no recurrence was observed for a maximum of 89 months after the surgery. Although notching of the eyelid margin and mild symblepharon were observed in one patient, no symptoms associated with these complications were reported. CONCLUSION: The Quickert procedure can be one of the surgical procedures of choice for involutional entropion and should be common surgical approach for occasional eyelid surgeons in Asia as well as in western countries. PMID- 22450003 TI - The evaluation of histo-blood group ABO typing by flow cytometric and PCR amplification of specific alleles analyses and their application in clinical laboratories. AB - ABO antigens are oligosaccharide antigens, and are widely distributed on red blood and tissue cells as well as in saliva and body fluid. Therefore, these antigens are important not only for blood transfusion, but also for tissue cell and organ transplantations. Also, blood, hair, and seminal fluid are important sources of evidence at crime scenes, and these antigens are some of the most important markers for personal identification in forensic investigations. Here, we describe the development and use of quantitative analysis of A, B, and H antigens on red blood cells by employing flow cytometric analysis and the ABO genotyping method based on PCR-amplification of specific alleles (PASA) within DNA, especially from blood and saliva. In this study, flow cytometric analysis could be used to compare the differences between the expression of A and/or B and H antigens on red blood cells with various phenotypes, and the PASA method was able to determine the genotype of the type cisA(2)B(3) pedigree using only DNA extracted from saliva. These analysis methods are simple and useful for judging the ABO blood group system and genotyping, and are used widely throughout research and clinical laboratories and forensic fields. PMID- 22450004 TI - Early postoperative evaluation of secondary bone grafting into the alveolar cleft and its effects on subsequent orthodontic treatment. AB - BACKGROUND: Alveolar bone grafting is a standard procedure used to achieve good occlusion for both functional and aesthetic purposes in patients with cleft lip and palate. At the past, main methods used to evaluate bone bridge formation after bone grafting are radiographs, such as dental, occlusal, and panoramic. PURPOSE: To evaluate bone bridge both qualitatively and quantitatively, we used CT scans (conventional and QCT). Quantitative computed tomography (QCT) has previously been used for measuring bone mineral density of the lumbar vertebrae. PATIENTS AND METHODS: The study comprised 26 male and 15 female patients who underwent alveolar bone grafting. We analyzed bone bridge with regard to four factors: marginal bone level, vertical height, anteroposterior bone width and bone mineral density using dental radiographs, and CT scans such as conventional and QCT. The clinical results of orthodontic treatment were evaluated more than 2 years postoperatively. RESULTS: Orthodontic treatment was considered to be successful when the bone bridge satisfied the following criteria: marginal bone level >= 3, vertical height >= 6.5 mm, anteroposterior bone width >= 5 mm, and bone mineral density < 350 mg Ca(5) (PO(4)) OH/mL. CONCLUSION: we could predict the prognosis of patients' orthodontic treatment in early stage after bone grafting. PMID- 22450005 TI - Effectiveness of metformin and lifestyle interventions as an initial treatment in Japanese patients with newly diagnosed type 2 diabetes: a prospective observational study. AB - Although global guidelines recommend metformin and lifestyle interventions as an initial treatment in patients with newly diagnosed type 2 diabetes (T2DM), few reports exist about its effectiveness in Japanese patients. To examine its effectiveness, we performed a prospective observational study within a routine clinical setting. We provided metformin (>=1,500 mg/day) and lifestyle interventions to 23 patients with newly diagnosed T2DM (20 men and 3 women, mean age 53 years, mean body mass index [BMI] 25.7 kg/m(2)). After 16 weeks, HbA1c levels significantly decreased from 9.1+/-2.1% (mean+/-SD) to 6.6+/-0.8% (p<0.001). Thirteen patients (56.5%) achieved a target HbA1c<6.5%. We did not find a significant correlation between baseline BMI and the changes in HbA1c (DeltaHbA1c) (r=-0.165, p=0.451). In contrast, we found a significant correlation between baseline fasting plasma glucose and DeltaHbA1c (r=-0.755, p<0.001). Body weight decreased from 73.3+/-13.3 kg to 69.8+/-11.6 kg (p<0.001). Total cholesterol, low density lipoprotein - cholesterol, non-high density lipoprotein cholesterol, and serum vitamin B-12 concentrations also significantly decreased. Adverse events included diarrhea (26.1%) and mild elevation of liver enzymes (8.7%). These results suggest that metformin and lifestyle interventions is effective and safe as an initial treatment in Japanese patients with newly diagnosed T2DM. PMID- 22450006 TI - Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats. AB - BACKGROUND: Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiation-induced lung disorders in an experimental model. METHODS: The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. RESULTS: Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro inflammatory cytokines (IL-6, IL-1beta), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. CONCLUSIONS: In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation. PMID- 22450007 TI - Simvastatin represses translocation of Pseudomonas aeruginosa across Madin-Darby canine kidney cell monolayers. AB - Pseudomonas aeruginosa causes both invasive (bacteremic) and chronic noninvasive infections. An increase in intestinal epithelial permeability is a characteristic of severe sepsis. Alterations in the normal barrier function of the gut mucosa may result in the translocation of microbial cells and products. On the otherhand, it has been demonstrated that statin use is associated with a lower risk of mortality from bloodstream infections. Therefore, we investigated the ability of P. aeruginosa PAO1 to translocate across the Madin-Darby canine kidney (MDCK) cell monolayers in the presence and absence of simvastatin. The bacteria readily translocated across MDCK cell monolayers after 3 h of infection irrespective of the presence or absence of the drug in the medium. However, the bacteria were less able to penetrate the MDCK monolayers in the presence of simvastatin than in its absence. A gentamicin survival assay demonstrated that simvastatin did not affect the bacteria's invasive behavior in the MDCK cells. PMID- 22450008 TI - Health behavior of elderly people engaged in agriculture in conjunction with information communication technology. AB - The aim of this study is to clarify the health behavior of elderly people engaged in agriculture and information communication technology (ICT). The participants were 61 people engaged in agriculture in conjunction with ICT systems (group A), and 49 people not engaged in this (group B) from among the people aged 65 years or over in village C, both living located in a mountain areas. Data were collected from August 2009 to June 2011 in two stages: interviews to members of group A through home visits, and a group survey of groups A and B through questionnaires. The results of the study were as follows: 1) members of group A lived with feelings of attachment to the land to which they were accustomed and showed gratitude to their ancestors; 2) in group A, the desire of participants to continue their life was sufficient motivation to look after their own health and maintain independence; and 3) they provided a new challenge and a sense of achievement. The results suggest that the health behavior in group A was behavior adopted voluntarily in order to maintain an independent lifestyle supported by working, and it is likely to be linked to the preservation of health. PMID- 22450009 TI - The effects measurement of hand massage by the autonomic activity and psychological indicators. AB - This study examined the effects of hand massage on autonomic activity, anxiety, relaxation and sense of affinity by performing it to healthy people before applying the technic in actual clinical practice. Findings were showed below: 1) the significant increase in the pNN50 and the significant decrease in the heart rate meant the intervention of massage increased the autonomic nervous activity, improved the parasympathetic nerve activity and reduced the sympathetic nerve activity. This means the subjects were considered to be in a state of relaxation. 2) Salivary alpha amylase has been reported as a possible indicator for sympathetic nerve activity. In this study, there was no significant difference in the salivary alpha amylase despite a decrease after massage. 3) State anxiety score is temporal situational reactions while being in the state of anxiety and this score decreased significantly after massage. 4) The level of willingness to communicate with other person and the sense of affinity toward the massage performer had a positive change of 70 percent. From this, it can be considered that a comfortable physical contact between a patient and a nursing profession, who are in a supported-supportive relationship, leads to an effect of shortening the gap in their psychological distance. PMID- 22450010 TI - Using ultrasonography in evaluating the intramuscular injection techniques used for administering drug treatments to schizophrenic patients in Japan. AB - This study was conducted with six patients with schizophrenia, four of whom received the atypical antipsychotic risperidone long-acting injectable (RLAI), and two patients receiving the typical depot injection (TDI). The purpose of this study was to determine the location (gluteus medius or maximus; deltoid muscles) and diffusion of typical and atypical antipsychotic medications administered intramuscularly using ultrasonography. When using the standardized depth of needle insertion, in some cases, the drug was injected into the gluteus maximus instead of the gluteus medius. Similarly, in some cases the TDI was not visible in the ultrasonographic images until sixteen days after the injection. This verifies how hard the injection site becomes when microspheres of RLAI is injected as compared to other muscle areas. These results confirmed that the gluteus muscle structure was the ideal muscle for depot injection as evidenced by the injection solution being dispersed and rendered not visible immediately after intramuscular injection (IM). With the use of ultrasonography, injection sites and drug dispersions were evaluated under a direct visual guidance, suggesting that ultrasonography is a useful method for establishing evidence for determining correct insertion of IM injection, diffusion of medications, and the effective administration of IM injections. PMID- 22450011 TI - Torsion of an accessory spleen with situs inversus in a child. AB - We present an unusual case of acute abdomen caused by torsion of an accessory spleen with situs inversus in a child. A three-year-old girl was admitted to our hospital with an 11-day history of right flank pain with fever. Her medical history revealed an operation of coarctation of the aorta with situs inversus at one month of age. Physical examination revealed a right flank mass and tenderness. A contrast-enhanced CT scan showed a normally enhanced small spleen in the right upper quadrant and a 7.0*6.0*3.5 cm, hypodense, marginal enhancing mass in the right midabdomen adjacent to the intestine. An emergency laparotomy was decided upon with a preoperative diagnosis as an acute abdomen. During surgery, a mass was found under the greater omentum and two accessory spleens of 1.5 cm in diameter were found surrounding the main spleen. Several loops of bowel were adherent to the mass. The loops of bowel were dissected away. A pediculated congested mass was observed as an accessory spleen emerging from the greater omentum. The mass was twisted on its vascular pedicle and strangulated. The necrotic mass was removed and the postoperative recovery was uneventful. Though torsion of an accessory spleen is extremely rare, it should be considered in the differential diagnosis of acute abdomen in childhood. PMID- 22450012 TI - Developmental changes in cold tolerance and ability to autoresuscitate from hypothermic respiratory arrest are not linked in rats and hamsters. AB - In adult mammals, severe hypothermia leads to respiratory and cardiac arrest, followed by death. Neonatal rats and hamsters can survive much lower body temperatures and, upon artificial rewarming, spontaneously recover from respiratory arrest (autoresuscitate), typically suffering no long-term effects. To determine developmental and species differences in cold tolerance (defined here as the temperature of respiratory arrest) and its relation to the ability to autoresuscitate, we cooled neonatal and juvenile Sprague-Dawley rats and Syrian hamsters until respiration ceased, followed by rewarming. Ventilation and heartbeat were continuously monitored. In rats, cold tolerance did not change throughout development, however the ability to autoresuscitate from hypothermic respiratory arrest did (lost between postnatal days, P, 14 and 20), suggesting that the mechanisms for maintaining breathing at low temperatures was retained throughout development while those initiating breathing on rewarming were altered. Hamsters, however, showed increased cold tolerance until P26-28 and were able to autoresuscitate into adulthood (provided the heart kept beating throughout respiratory arrest). Also, hamsters were more cold tolerant than rats. We saw no evidence of gasping to initiate breathing following respiratory arrest, contributing to the hypothesis that hypothermic respiratory arrest does not lead to anoxia. PMID- 22450013 TI - [Receiving the baton]. PMID- 22450014 TI - [Epidemiologic behavior of malignant digestive tract tumors over a five year period in Veracruz, Mexico]. AB - INTRODUCTION: Tumors of the digestive system are considered to be a public health problem because of their elevated mortality rate. In Mexico, gastric cancer and colon cancer rank fourth and fifth, respectively, following tracheal, bronchial, and lung cancer, and there has been an increase in their frequency in the last few years. However, there are no specific studies that have evaluated their epidemiologic behavior in Veracruz. OBJECTIVE: To determine the frequency of digestive system cancer in five health institutions in the city of Veracruz and to describe its epidemiologic behavior over a five-year period. MATERIAL AND METHODS: Annual statistics from the following hospitals were reviewed: the Instituto Mexicano del Seguro Social, the Secretaria de Salud, the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Petroleos Mexicanos, and the Secretaria de la Defensa Nacional within the time frame of January 2005 to December 2009. Diagnoses based on histopathology were recorded, along with patient age and sex. RESULTS: A total of 1803 cases of digestive tract cancers were detected: 52% were men and 48% were women. A yearly increase in the number of cases was observed with colon cancer being in first place, followed by stomach cancer and rectal cancer. CONCLUSIONS: The increase in digestive system cancer cases over the last five years in Veracruz underlines the need to evaluate the implementation of screening programs for the at-risk population and to study the different etiologic factors involved in its manifestation. PMID- 22450015 TI - [Effectiveness of intercostal nerve block with ropivacaine in analgesia of patients undergoing emergency open cholecystectomy under general anesthesia]. AB - INTRODUCTION: Postoperative pain after open cholecystectomy is associated with reduced respiratory function, longer recovery period before deambulation and oral food intake, and prolonged hospital stay. Intercostal nerve block provides satisfactory analgesia and ropivacaine is the most widely used local anesthetic agent in intercostal nerve block due to its excellent effectiveness, lower cardiovascular toxicity, and longer half-life. AIMS: To evaluate intercostal nerve block effectiveness with ropivacaine in patients undergoing emergency open cholecystectomy under general anesthesia compared with conventional management. MATERIAL AND METHODS: A controlled clinical trial was carried out on 50 patients undergoing open cholecystectomy, 25 patients without intercostal nerve block versus 25 patients with intercostal nerve block using ropivacaine at 0.5% combined with epinephrine. Intraoperative minimum alveolar concentration and inhalation anesthetic use were evaluated. Tramadol as rescue analgesic agent and pain were evaluated during immediate postoperative period by means of the Visual Analog Scale at 8, 16, and 24 hours. RESULTS: Mean inhalation anesthetic use was lower in the intercostal nerve block group with 13% vs 37% in the group without intercostal nerve block (p= 0.01). Rescue tramadol requirement was lower in the intercostal nerve block group than in the group without intercostal nerve block at 8 hours (8% vs 67%), 16 hours (0% vs 83%), and 24 hours (12% vs 79%) (p<0.0001). Visual Analog Scale for Pain results were similar in both groups. CONCLUSIONS: Intercostal nerve block reduces intraoperative inhalation anesthetic use, immediate postoperative pain, and tramadol intake as rescue analgesic agent in patients undergoing open cholecystectomy. PMID- 22450016 TI - [Laparoscopic Nissen fundoplication: results and prognostic factors]. AB - INTRODUCTION: Laparoscopic Nissen fundoplication is the technique of choice in the surgical treatment of gastroesophageal reflux disease. AIMS: To review the cases of laparoscopic Nissen fundoplication carried out at our hospital and to analyze the prognostic factors that influenced surgical outcome. MATERIAL AND METHODS: A total of 226 patients that underwent laparoscopic Nissen fundoplication within the time frame of 1996 to 2010 were retrospectively reviewed. Surgical results and prognostic factors were evaluated in 182 patients that had a follow-up longer than one year. RESULTS: The Nissen-Rossetti technique was carried out in 219 patients, without short gastric vessel division, and the "floppy"-Nissen technique was performed on seven patients. Intraoperative complication rate was 3.1%, conversion rate was 6.6%, and postoperative complication rate was 4%. Mortality was 0. After surgery, 19% of patients presented with dysphagia that was persistent in only 3.5%. Of the 182 patients with a follow-up longer than one year, 166 (91.2%) were satisfied with the surgical results. In the univariate analysis, esophagitis (OR=0.59) was a protective factor, while a DeMeester score >50 (OR=1.97) and medical treatment resistance (OR=1.75) were risk factors. In the multivariate analysis a DeMeester score >50 (OR=4.24) was the only independent prognostic factor associated with poor outcome. CONCLUSIONS: Our results with laparoscopic Nissen fundoplication are comparable to those found in the medical literature, with a high degree of patient satisfaction. Esophagitis is associated with good outcome, while massive reflux and medical treatment resistance are negative prognostic factors. PMID- 22450017 TI - [Deficient lactose digestion and intolerance in a group of patients with chronic nonspecific ulcerative colitis: a controlled, double-blind, cross-over clinical trial]. AB - INTRODUCTION: Despite the fact that the frequency of hypolactasia and lactose intolerance is similar in both chronic idiopathic ulcerative colitis patients and the general population, the elimination of dairy products from the patient's diet is a habitual recommendation. Hypolactasia is common in Mexico, but its relation to chronic idiopathic ulcerative colitis has not been established. AIMS: To evaluate lactose digestion and lactose intolerance in persons with chronic idiopathic ulcerative colitis. MATERIAL AND METHODS: Thirty-nine patients with confirmed chronic idiopathic ulcerative colitis diagnosis were included in the study (mean: 31 years, range: 15 to 38). Twenty-two patients presented with rectosigmoid involvement and the remaining patients with pancolitis. No patient showed inflammatory activity according to the Truelove-Witts criteria and all consumed dairy products before diagnosis. A prospective, controlled, double blind, cross-over study was designed. Patients randomly received 12.5 g of lactose or maltose in 250 cc water- each test 72 hours apart - and ydrogen was measured in exhaled air before disaccharide ingestion and then every 30 minutes for 3 hours. Digestion was considered deficient when there was an increase in hydrogen of at least 20 ppm. Symptom intensities were evaluated by Visual Analog Scales before, during, and after the hydrogen test. Differences between the groups were contrasted with the Mann-Whitney U and the Wilcoxon tests. RESULTS: Eighteen patients (46%) presented with deficient lactose digestion. No significant differences were found in the symptoms, extension, or progression of chronic idiopathic ulcerative colitis between patients that could digest and those that could not digest lactose. No patient had symptom exacerbation with the disaccharides used. CONCLUSIONS: Lactose digestion deficiency frequency is similar in subjects with chronic idiopathic ulcerative colitis and in healthy individuals in Mexico. We do not know whether higher doses could have some effect, but symptoms in patients with inactive chronic idiopathic ulcerative colitis were not modified using 12.5 g of lactose/day. PMID- 22450018 TI - [Endoscopic ultrasound-guided choledochoduodenostomy for relieving malignant distal biliary obstruction]. AB - Ultrasound-guided biliary drainage is a new and effective method for relieving obstructive lesions of the biliary tract. In the hands of experienced operators, ultrasound-guided diversion of the mid portion of the common bile duct and the duodenal bulb is a feasible strategy for the relief of jaundice secondary to distal obstruction (distal bile duct tumors, pancreatic head cancer, or major duodenal papillary tumor), with low morbidity and mortality rates. The technical aspects of the procedure and its indications are reviewed herein, emphasizing its performance in institutions equipped with experienced personnel adhering to strict study protocols. PMID- 22450019 TI - [Clinical image in gastroenterology. Mucocele of the appendix: an incidental finding]. PMID- 22450020 TI - Successful colonoscopic fecal transplant for severe acute Clostridium difficile pseudomembranous colitis. AB - Clostridium difficile-associated diarrhea has become one of the most common healthcare-associated infections, with significant morbidity and mortality, especially among the elderly in the inpatient setting. The standard approach with metronidazole and vancomycin is not very effective in treating patients with severe colitis and hence other alternatives have been explored. We herein describe the first successful experience of colonoscopic fecal transplant in a case of severe refractory C. difficile pseudomembranous colitis. PMID- 22450021 TI - Multiple hepatic abscesses secondary to chicken bone penetration of the colon: a case report. AB - Hepatic abscesses can result from foreign body perforation of the gastrointestinal tract. Although uncommon, reported cases often involve solitary hepatic abscess with no obvious etiology. We describe the case of a 65-year- old female with multiple hepatic abscesses occurring secondary to chicken bone perforation of the sigmoid colon identified on colonoscopy. With prompt diagnosis, the patient was successfully treated with endoscopic removal of the foreign body and broad spectrum antibiotic treatment. PMID- 22450022 TI - [Micronized lactulose + paraffin (gel) in constipation]. PMID- 22450024 TI - The role of insulin resistance in the development of muscle wasting during cancer cachexia. AB - BACKGROUND: Cancer cachexia is a complex syndrome associated with multiple metabolic abnormalities. Insulin resistance is present in many cancer patients and may be one mechanism through which muscle wasting occurs. METHODS AND RESULTS: The present review examines evidence in support of a role for insulin resistance in the development of muscle wasting during cancer cachexia and identifies areas for future research. Patients suffering from cancer cachexia tend to exhibit insulin resistance and improvements in insulin resistance have the potential to improve cachexia symptoms. In addition, evidence suggests that insulin resistance may occur prior to the onset of cachexia symptoms. CONCLUSIONS: Further investigation of the role of insulin resistance in cancer cachexia is needed. The use of translational research in this area is strongly encouraged, and has important implications for clinical research and the treatment and prevention of cancer cachexia. PMID- 22450025 TI - Role of interleukin-10 in the pathogenesis of necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature neonates. The pathogenesis of NEC is characterized by an intestinal epithelial injury caused by perinatal insults, leading to the activation of the mucosal innate immune system and exacerbation of the epithelial barrier damage. Cytokines play an important role in mucosal immunity. Interleukin 10 (IL-10) is an anti-inflammatory cytokine that has been shown to play a role in epithelial integrity and modulation of the mucosal immune system. We hypothesized that IL-10 may protect against the development of experimental NEC by blunting the inflammatory response in the intestine. METHODS: Wild-type and IL-10 -/- mice underwent a NEC-inducing regimen of formula feeding in combination with hypoxia and hypothermia (FF+HH). Integrity of the gut barrier was assessed through measurement of epithelial apoptosis, tight junction disruption, and inducible nitric oxide synthase. A total of 5 MUg of exogenous IL-10 was administered intraperitoneally to IL-10-/-mouse pups before the initiation of FF+HH to test dependence of gene knockout phenotype on IL-10. RESULTS: IL-10 -/- FF+HH showed more severe morphologic and histologic changes compared with controls as evidenced by increased epithelial apoptosis, decreased junctional adhesion molecule-1 localization, and increased intestinal inducible nitric oxide synthase expression. Administration of exogenous IL-10 alleviated the mucosal injury. CONCLUSIONS: We conclude that IL-10 plays a protective role in the pathogenesis of NEC by attenuating the degree of intestinal inflammation. PMID- 22450026 TI - Inhalation of carbon monoxide reduces skeletal muscle injury after hind limb ischemia-reperfusion injury in mice. AB - BACKGROUND: The purpose of this study was to determine if inhaled carbon monoxide (CO) can ameliorate skeletal muscle injury, modulate endogenous heme oxygenase-1 expression, and improve indexes of tissue integrity and inflammation after hind limb ischemia reperfusion. METHODS: C57BL6 mice inhaling CO (250 ppm) or room air were subjected to 1.5 hours of ischemia followed by limb reperfusion for either 3 or 6 hours (total treatment time, 4.5 or 7.5 h). After the initial period of reperfusion, all mice breathed only room air until 24 hours after the onset of ischemia. Mice were killed at either the end of CO treatment or at 24 hours' reperfusion. Skeletal muscle was subjected to histologic and biochemical analysis. RESULTS: CO treatment for 7.5 hours protected skeletal muscle from histologic and structural evidence of skeletal muscle injury. Serum and tissue cytokines were reduced significantly (P < .05) in mice treated with CO for 7.5 hours. Tubulin, heme oxygenase, and adenosine triphosphate levels were higher in CO-treated mice. CONCLUSIONS: Inhaled CO protected muscle from structural injury and energy depletion after ischemia reperfusion. PMID- 22450027 TI - Identifying best practice guidelines for debriefing in surgery: a tri-continental study. AB - BACKGROUND: Changes in surgical training have decreased opportunities for experiential learning in the operating room (OR). With this decrease, a commensurate increase in debriefing-dependent simulation-based activities has occurred. Effective debriefing could optimize learning from both simulated and real clinical encounters. METHODS: Thirty-three semistructured interviews with surgeons, anesthesiologists, and OR nurses from the United Kingdom, United States, and Australia identified the goals of debriefing, core components of an effective debrief, and solutions to its effective implementation. Interviews were audiotaped, transcribed, and coded using emergent theme analysis. RESULTS: Core components of an effective debrief include having the appropriate approach, establishing a learning environment, learner engagement, managing learner reaction, reflection, analysis, diagnosis, and application to real clinical practice. Solutions to enhance practice involve promotion of a debriefing culture within the surgical community with protected time to conduct a structured debriefing. CONCLUSIONS: A need exists to enhance surgical training through regular structured debriefing. Identifying the key components of an effective debrief is a first step toward improving practice and embedding a debriefing culture within the OR. PMID- 22450028 TI - The script concordance test as a measure of clinical reasoning: a national validation study. AB - INTRODUCTION: The script concordance test (SCT) is an innovative tool for clinical reasoning assessment. It has previously been shown to be a reliable and valid measure of clinical reasoning among general surgical residents. PURPOSE: To determine if the SCT maintained its validity and reliability when administered on a national level. METHODS: The test was administered to 202 residents (51 R1, 45 R2, 45 R3, 28 R4, and 33 R5) in 9 general surgery programs across Canada. RESULTS: The optimized version of the test had a reliability (Cronbach alpha) of .85. Scores increased progressively from R1 (64.5 +/- 7.6) to R2 (69.5 +/- 5.8) to R3 (69.9 +/- 6.7) to R4 (72.0 +/- 6.2) with a dip in the R5s (68.3 +/- 8.6). The test was able to differentiate junior (R1+ R2 = 66.8 +/- 7.2) from senior residents (R3 + R4 + R5 = 70.0 +/- 7.3, P = .001) across all the programs. CONCLUSIONS: The SCT maintained its reliability and validity as a measure of intraoperative clinical reasoning among general surgical residents when administered across multiple centers. We believe that the SCT can be developed to measure clinical reasoning in high-stakes national examinations. PMID- 22450029 TI - Use of absorbable hemostatic gauze with medical adhesive is effective for achieving hemostasis in presacral hemorrhage. AB - BACKGROUND: Management of presacral hemorrhage is always challenging. Herein we describe the use of an absorbable hemostatic gauze with alpha-cyanoacrylate medical adhesive to achieve hemostasis. METHODS: In this study, we conducted total mesorectal excision for the treatment of rectal cancer in 258 patients from March 2006 to May 2009. Intraoperative presacral hemorrhage developed in 5 (2%) patients during rectal mobilization. RESULTS: In these 5 patients, massive bleeding could not be controlled by pressure and pelvic packing with gauze. An absorbable hemostatic gauze spread with medical adhesive was compressed onto the bleeding vessel for at least 20 minutes. Hemostasis was achieved successfully and was maintained during the surgery. Patients recovered uneventfully and no postoperative events were noted. CONCLUSIONS: The use of an absorbable hemostatic gauze with medical adhesive is a simple and effective method for achieving hemostasis when massive presacral hemorrhage occurs. However, its effectiveness needs to be confirmed in a controlled study in a properly selected patient population. PMID- 22450030 TI - Cytosolic events involved in chloroplast protein targeting. AB - Chloroplasts are unique organelles that are responsible for photosynthesis. Although chloroplasts contain their own genome, the majority of chloroplast proteins are encoded by the nuclear genome. These proteins are transported to the chloroplasts after translation in the cytosol. Chloroplasts contain three membrane systems (outer/inner envelope and thylakoid membranes) that subdivide the interior into three soluble compartments known as the intermembrane space, stroma, and thylakoid lumen. Several targeting mechanisms are required to deliver proteins to the correct chloroplast membrane or soluble compartment. These mechanisms have been extensively studied using purified chloroplasts in vitro. Prior to targeting these proteins to the various compartments of the chloroplast, they must be correctly sorted in the cytosol. To date, it is not clear how these proteins are sorted in the cytosol and then targeted to the chloroplasts. Recently, the cytosolic carrier protein AKR2 and its associated cofactor Hsp17.8 for outer envelope membrane proteins of chloroplasts were identified. Additionally, a mechanism for controlling unimported plastid precursors in the cytosol has been discovered. This review will mainly focus on recent findings concerning the possible cytosolic events that occur prior to protein targeting to the chloroplasts. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 22450031 TI - Mitochondrial dynamics in heart disease. AB - Mitochondrial fission and fusion have been observed, and their importance revealed, in almost every tissue and cell type except adult cardiac myocytes. As each human heart is uniquely dependent upon mitochondria to generate massive amounts of ATP that fuel its approximately 38 million contractions per year, it seems odd that cardiac myocytes are the sole exception to the general rule that mitochondrial dynamism is important to function. Here, I briefly review the mechanisms for mitochondrial fusion and fission and examine current data that dispel the previous notion that mitochondrial fusion is dispensable in the heart. Rare and generally overlooked examples of cardiomyopathies linked either to naturally-occurring mutations or to experimentally-induced mutagenesis of mitochondrial fusion/fission genes are described. New findings from genetically targeted Drosophila and mouse models wherein mitochondrial fusion deficiency has specifically been induced in cardiac myocytes are discussed. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology. PMID- 22450032 TI - Control of protein synthesis in yeast mitochondria: the concept of translational activators. AB - Mitochondria contain their own genome which codes for a small number of proteins. Most mitochondrial translation products are part of the membrane-embedded reaction centers of the respiratory chain complexes. In the yeast Saccharomyces cerevisiae, the expression of these proteins is regulated by translational activators that bind mitochondrial mRNAs, in most cases to their 5'-untranslated regions, and each mitochondrial mRNA appears to have its own translational activator(s). Recent studies showed that these translational activators can be part of feedback control loops which only permit translation if the downstream assembly of nascent translation products can occur. In several cases, the accumulation of a non-assembled protein prevents further synthesis of this protein but not translation in general. These control loops prevent the synthesis of potentially harmful assembly intermediates of the reaction centers of mitochondrial enzymes. Since such regulatory feedback loops only work if translation occurs in the compartment in which the complexes of the respiratory chain are assembled, these control mechanisms require the presence of a translation machinery in mitochondria. This might explain why eukaryotic cells maintained DNA in mitochondria during the last two billion years of evolution. This review gives an overview of the mitochondrial translation system and summarizes the current knowledge on translational activators and their role in the regulation of mitochondrial protein synthesis. This article is part of a Special Issue entitled: Protein import and quality control in mitochondria and plastids. PMID- 22450033 TI - Gene network models robust to spatial scaling and noisy input. AB - Many biological systems are inherently noisy, yet demonstrate robustness to perturbations and changes in external influences. Such is the case in the Bicoid Hunchback (Bcd-Hb) system, which is critical to axis specification in the developing Drosophila embryo. We use this system as motivation to explore the larger problem of how precise patterning can be achieved under imprecise conditions. While evidence suggests Bicoid gradients are uncorrelated with respect to embryo length, downstream genes, such as Hb, are expressed in a precise manner with regard to position along the anterior-posterior (AP)-axis. In addition to precision under variability of embryo length, Hb also exhibits robustness to perturbations to the regulatory network, gene dosage, and temperature. Understanding the reduced variability of patterns in this system is of interest to both experimentalists and theoreticians, lending itself well to the field of mathematical modeling. In this paper, a class of reaction-diffusion models is presented, which produce precise patterns, despite receiving noisy input and other perturbations to the system. An essential property of the network includes the existence of a strong inhibitor for the Hb representative, where the strength of the inhibition is directly related to the amount of variation that can be tolerated. With a higher inhibitory effect, larger perturbations of Bcd can be made with relatively small changes to the location of the Hb boundary. Network topology and interaction strength are the essential properties of the minimal model giving rise to the robust features, and possible interpretations are made with regard to the Bcd-Hb system. PMID- 22450034 TI - Control measures for Chagas disease. AB - Chagas disease, also known as American trypanosomiasis, is a potentially life threatening illness caused by the protozoan parasite, Trypanosoma cruzi. The main mode of transmission of this disease in endemic areas is through an insect vector called triatomine bug. Triatomines become infected with T. cruzi by feeding blood of an infected person or animal. Chagas disease is considered the most important vector borne infection in Latin America. It is estimated that between 16 and 18 millions of persons are infected with T. cruzi, and at least 20,000 deaths each year. In this work we formulate a model for the transmission of this infection among humans, vectors and domestic mammals. Our main objective is to assess the effectiveness of Chagas disease control measures. For this, we do sensitivity analysis of the basic reproductive number R0 and the endemic proportions with respect to epidemiological and demographic parameters. PMID- 22450035 TI - Lifetime risk of suicidal behaviors and communication to a health professional about suicidal ideation. Results from a large survey of the French adult population. AB - BACKGROUND: There is presently a lack of information on the role of healthcare in suicidal ideation in adults. AIMS: To assess the frequencies, patterns, and factors associated with the communication of suicidal ideation toward a health professional. METHODS: Participants stem from a French cross-sectional survey of 22,133 randomly selected adults. Lifetime suicidal behaviors and 12-month mental disorder patterns were assessed using the short form of the Composite International Diagnostic Interview. Participants with suicidal ideation were asked whether they had talked about it and, if they had, to whom. RESULTS: Around 20% of people with suicidal ideation had talked about this distress to a health professional. It was more frequent for people with more severe suicidal behaviors (plan or a prior attempt), among women, those aged 30 or more, those suffering from major depressive episode, panic disorder, or drug use disorder. Above all, it was more frequent among those who had also talked to friends or relatives. CONCLUSIONS: Prevention strategies that encourage suicidal persons to seek help for their distress, whoever that is, may be the more important strategies to develop. PMID- 22450036 TI - Classification Algorithm for the Determination of Suicide Attempt and Suicide (CAD-SAS). Development and psychometric properties. AB - BACKGROUND: One methodological difficulty in research into suicide attempts and suicide is distinguishing these phenomena from nonsuicidal self-harming behaviors and accidents. This is problematic because a reliable assessment of the presence or absence of the outcome variable is fundamental for the validity of the findings. AIMS: To develop a standardized rating system, the Classification Algorithm for the Determination of Suicide Attempt and Suicide (CAD-SAS), and to investigate its psychometric properties. METHODS: To examine the test-retest reliability, one investigator rated 217 narratives of real-life self-harming incidents at initial assessment and 4 weeks later. To establish the interrater reliability, three independent raters assessed a random sample of 70 narratives using the CAD-SAS. To examine the validity, one investigator using the CAD-SAS compared ratings to clinical judgments made by a consultant psychiatrist without the CAD-SAS on the same random set of 70 narratives. RESULTS: Test-retest reliability was excellent (97.2% agreement) and interrater reliability was substantial (70.0% agreement, kappa = 0.70). Agreement in the classification of incidents with the "real-world" clinical judgments supports the validity of the CAD-SAS (64.3% agreement, kappa = 0.46). CONCLUSIONS: The reliability and validity of future studies can be enhanced through the standardized assessment and classification of incidents. PMID- 22450037 TI - Internet comments elicited by media portrayal of a familicide-suicide case. AB - BACKGROUND: Events of extraordinary violence attract media attention. Recently, much media reporting has moved to the Internet, giving readers the possibility to comment online. AIMS: To analyze the content of public cognitions and the emotional tonality of attitudes expressed in spontaneous Internet comments on a familicide-suicide case reported in the Estonian media. METHODS: A content analysis is based on the comments of 6,333 readers following media coverage. Descriptive statistics were used for quantitative data analysis. RESULTS: Of all comments, 27.6% were without manifest content. Manifest content categories were "value judgments" (35.2%), "risk and protective factors" (27.2%), and "critics of media portrayal" (10.0%). As to emotional tonality, the comments were most often angry (34.5%), ironic (24.7%), or neutral (23.3%). "Critics of media portrayal" had the most clearly pronounced emotional tonality, the majority being angry or approving. Comments about "value judgments" were most frequently anguished. CONCLUSIONS: An analysis of Internet comments can provide valuable information about value judgments and attitudes in society. From an ethical and preventive perspective, similar homicide and suicide stories should not be open for unmoderated public discussion. Nevertheless, the study represents an original methodological approach for such research and also provides some guidance for public relations campaigns. PMID- 22450038 TI - Effects of a comprehensive police suicide prevention program. AB - BACKGROUND: Police suicides are an important problem, and many police forces have high rates. Montreal police suicide rates were slightly higher than other Quebec police rates in the 11 years before the program began (30.5/100,000 per year vs. 26.0/100,000). AIMS: To evaluate Together for Life, a suicide prevention program for the Montreal police. METHODS: All 4,178 members of the Montreal police participated. The program involved training for all officers, supervisors, and union representatives as well as establishing a volunteer helpline and a publicity campaign. Outcome measures included suicide rates, pre-post assessments of learning, focus groups, interviews, and follow-up of supervisors. RESULTS: In the 12 years since the program began the suicide rate decreased by 79% (6.4/100,000), while other Quebec police rates had a nonsignificant (11%) increase (29.0/100,000). Also, knowledge increased, supervisors engaged in effective interventions, and the activities were highly appreciated. LIMITATIONS: Possibly some unidentified factors unrelated to the program could have influenced the observed changes. CONCLUSIONS: The decrease in suicides appears to be related to this program since suicide rates for comparable populations did not decrease and there were no major changes in functioning, training, or recruitment to explain the differences. Comprehensive suicide prevention programs tailored to the work environment may significantly impact suicide rates. PMID- 22450039 TI - Reporting of suicide by the New Zealand media. AB - BACKGROUND: Rates of suicide in New Zealand are high compared with those of other countries. International evidence suggests that the reporting of suicide may influence rates of suicidal behavior. No research exists, however, on the reporting of suicide by New Zealand media. AIMS: This study provides the first baseline picture of the reporting of suicide by New Zealand media. The overall objective was to use the findings to inform future development of media guidelines by the Ministry of Health. METHOD: Newspaper, Internet, television and radio news items on suicide were collected over 12 months. Descriptive statistical data on the nature and extent of the reporting of suicide were generated through content analysis of applicable items. A random sample of 10% was then subjected to a quality analysis to determine whether items aligned with the Ministry of Health's guideline for the reporting of suicide. RESULTS: A total of 3,483 items were extracted, most of which reported on an individual's attempted or completed suicide, while suicide methods were not often mentioned. Few items focused on people overcoming their difficulties or provided information to assist people struggling with suicidal ideation. CONCLUSIONS: The reporting of suicide by New Zealand media was extensive and generally of good quality. Better collaboration between the media and mental health professionals is needed, however, to increase information supplied within items on support services. More succinct guidelines and increased journalist awareness of their existence would also contribute to the quality of reporting on suicide. PMID- 22450040 TI - Understanding the risks of recent discharge: the phenomenological experiences: trying to survive while living under the proverbial "Sword of Damocles". AB - BACKGROUND: Evidence indicates that people whose mental health problems lead them to require psychiatric hospitalization are at a significantly increased risk of suicide, and the period of time immediately following discharge after such hospitalizations appears to be a particularly high-risk time. AIMS: This paper reports on phenomenological findings from a federally funded, mixed-methods study that sought to better understand the observed increased risk for suicide following discharge from an inpatient psychiatric service. METHODS: A purposive sample of 20 recently discharged former suicidal inpatients was obtained. Data were collected from the participants in hermeneutic interviews lasting between 1 h and 2 h and analyzed according to van Manen's (1997) interpretation of hermeneutic phenomenology. RESULTS: Two key themes were induced: "Existential Angst at the Prospect of Discharge" and "Trying to Survive While Living Under the Proverbial 'Sword of Damocles'." Each of these was comprised of five themes with the second key theme - the focus of this paper - encompassing the following: "Needing Postdischarge Support," "Feeling Lost, Uncertain and Disorientated," "Feeling Alone and Isolated," "Suicide Remains an Option," and "Engaging in Soothing, Comforting Behaviors." CONCLUSIONS: The authors conclude that early exploration of and reconciling patients' expectations regarding inpatient care for their suicidality would appear to be an empirically based intervention that could diminish the postdischarge risk for further suicide attempts. PMID- 22450042 TI - Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children. PMID- 22450041 TI - Suicide deaths and nonfatal hospital admissions for deliberate self-harm in the United States. Temporality by day of week and month of year. AB - BACKGROUND: No one knows whether the temporality of nonfatal deliberate self-harm in the United States mirrors the temporality of suicide deaths. AIMS: To analyze day- and month-specific variation in population rates for suicide fatalities and, separately, for hospital admissions for nonfatal deliberate self-harm. METHODS: For 12 states, we extracted vital statistics data on all suicides (n = 11,429) and hospital discharge data on all nonfatal deliberate self-harm admissions (n = 60,870) occurring in 1997. We used multinomial logistic regression to analyze the significance of day-to-day and month-to-month variations in the occurrence of suicides and nonfatal deliberate self-harm admissions. RESULTS: Both fatal and nonfatal events had a 6%-10% excess occurrence on Monday and Tuesday and were 5% 13% less likely to occur on Saturdays (p < .05). Males were more likely than females to act on Wednesdays and Saturdays. Nonfatal admission rates were 6% above the average in April and May (p < .05). In contrast, suicide rates were 6% above the average in February and March and 8% below it in November (p < .05). CONCLUSIONS: Suicides and nonfatal hospital admissions for deliberate self-harm have peaks and troughs on the same days in the United States. In contrast, the monthly patterns for these fatal and nonfatal events are not congruent. PMID- 22450043 TI - Delayed childbearing: effects on fertility and the outcome of pregnancy. AB - PURPOSE OF REVIEW: The proportion of women who are intentionally delaying pregnancy beyond the age of 35 years has increased greatly in the past few decades because of the clash between the optimal biological period for women to have children with obtaining additional education and building a career. This article highlights the effects of delayed childbearing on fertility and obstetric and perinatal outcome. RECENT FINDINGS: Demographic studies indicate that fertility rates are falling in many countries, Europe being the continent with lowest total fertility rate. Female employment and childrearing can be combined when the reduction in work-family conflict is facilitated by state of policy intervention. It has been traditionally accepted that fertility is more related to the age of the female than the male partner but recent literature suggests trends that increased paternal age is also associated with lower fertility, an increase in pregnancy-associated complications and an increase in adverse outcome in the offspring. Delayed childbearing is rarely a conscious choice and women are unaware that, at present, with the exception of egg donation, assisted reproductive technology has no answer yet to age-related decline of female fertility. There is no evidence of a beneficial effect of preimplantation genetic screening for women of advanced maternal age. Concerning perinatal outcomes, apart from the known effects of advanced maternal age on common fetal and obstetric complications, recent evidence increasingly points toward an independent association between maternal (and paternal age) and cerebral palsy, neurocognitive and psychiatric disorders. SUMMARY: The consequences of advancing maternal and paternal age are not only relevant for the risk of natural and assisted conception, but also for the outcome of pregnancy. Although the absolute rate of poor pregnancy outcomes may be low from an individual standpoint, the impact of delaying childbearing from a public health perspective cannot be overestimated and should be in the agenda of public health policies for the years to come. PMID- 22450044 TI - Circular dichroism and guanine quadruplexes. AB - Circular dichroism (CD) is remarkably sensitive to the conformational states of nucleic acids; therefore, CD spectroscopy has been used to study most features of DNA and RNA structures. Quadruplexes are among the significant noncanonical nucleic acids architectures that have received special attentions recently. This article presents examples on the contribution of CD spectroscopy to our knowledge of quadruplex structures and their polymorphism. The examples were selected to demonstrate the potential of this simple method in the quadruplex field. As CD spectroscopy detects only the global feature of a macromolecule, it should preferably be used in combination with other techniques. On the other hand, CD spectroscopy, often as a pioneering approach, can reveal the formation of particular structural arrangements, to search for the conditions stabilizing the structures, to follow the transitions between various structural states, to explore kinetics of their appearance, to determine thermodynamic parameters and also detect formation of higher order structures. This article aims to show that CD spectroscopy is an important complementary technique to NMR spectroscopy and X ray diffraction in quadruplex studies. PMID- 22450045 TI - Short-term regulation of the hypothalamic melanocortinergic system under fasting and defined glucose-refeeding conditions in rats: a laser capture microdissection (LMD)-based study. AB - It is well established that under fasting conditions the expression of the orexigenic neuropeptide agouti-related peptide (AGRP) is up-regulated in the hypothalamic arcuate nucleus (ARC), while inconsistent data exist regarding fasting regulation of the anorexigenic neurohormone proopiomelanocortin (POMC). Inconsistencies might have methodological reasons, especially concerning neuromorphological and/or experimental (nutritional) specificity. We analyzed the expression of both neuropeptides in ARC neurons, using lasercapture microdissection (LMD) and real-time PCR in 12h fasted vs. fed Wistar rats as well as after a standardized glucose load, i.e., under clinically relevant conditions in terms of diagnosing glucose intolerance in the human. Under fasting conditions, clear up-regulation of AGRP was observed, with increasing magnitude in ARC single neurons (SNP) as compared to ARC cell layers (+125% vs. +23%, resp.), closely correlated to hypoinsulinemia and hypoleptinemia. Surprisingly, in the fasting state POMC was not found to be down-regulated, neither in ARC cell layers nor in ARC single neurons (+9% vs. +6%). However, glucose-refeeding under diagnostically relevant conditions led to strong neuronal up-regulation of POMC expression in ARC SNP (+128%), and AGRP down-regulation (-50%). In conclusion, experimentally, topographically, and analytically specific and standardized conditions confirmed AGRP in ARC neurons as being neuronally up- and down regulated, resp., depending on the general nutritional state, while POMC was found to be (up-) regulated only after peripheral glucose load. Findings suggest that POMC in ARC neurons acts glucose-mediated as an "anti-orexigenic" neurohormone, specifically responding to hyperglycemia. PMID- 22450046 TI - The response of neuregulin 1 mutant mice to acute restraint stress. AB - Stress plays a role in the development and severity of psychotic symptoms and there may be a genetic component to stress vulnerability in schizophrenia. Using an established mouse model for schizophrenia, we investigated the behavioural and endocrine response of Nrg1 transmembrane domain mutant mice (Nrg1 HET) and wild type-like (WT) littermates to acute restraint stress. Animals were screened at 3 4 months and 6-7 months of age (before and after onset of hyperlocomotion) for open field behaviour and serum corticosterone levels. In younger mice, stress reduced locomotive and explorative measures and increased anxiety-like behaviour regardless of genotype. Older Nrg1 mutants were less susceptible to the effects of stress on anxiety-related behaviours. All mice responded to restraint stress with robust increases in serum corticosterone. Importantly, the stress-induced increase in corticosterone was more pronounced in Nrg1 mutant than WT mice at the younger but not the older age. Our results suggest that transmembrane domain Nrg1 has only a moderate effect on the acute stress response of mice. The behavioural differences detected between WT and Nrg1 HET mice at the older age were evident without parallel modifications to the glucocorticoid system. PMID- 22450047 TI - NMDA receptor/amyloid precursor protein interactions: a comparison between wild type and amyloid precursor protein mutations associated with familial Alzheimer's disease. AB - Two recent reports showed that amyloid precursor protein (APP) may contribute to postsynaptic mechanisms via the regulation of the surface trafficking of excitatory N-methyl-D-aspartate (NMDA) receptors. Here we have investigated the interactions and surface trafficking of NR1-1a/NR2A and NR1-1a/NR2B NMDA receptor subtypes with three APP mutations linked to familial Alzheimer's disease, APP695(Indiana), APP695(London) and APP695(Swedish). Flag-tagged mutated APP695s were generated and shown to be expressed at equivalent levels to wild-type APP695 in mammalian cells. Each APP mutant co-precipitated with NR1-1a/NR2A and NR1 1a/NR2B receptors following co-expression in mammalian cells. Further, as found for wild-type APP695, each enhanced NMDA receptor surface expression with no concomitant increase in total NR1-1a, NR2A or NR2B subunit expression. Thus these three familial APP mutations behave as wild-type APP695 with respect to their association with assembled NMDA receptors and their APP695-enhanced receptor cell surface trafficking. PMID- 22450048 TI - M1 muscarinic acetylcholine receptor interacts with BACE1 and regulates its proteosomal degradation. AB - A prime culprit in the pathogenesis of Alzheimer's disease (AD) is overproduction/aggregation of beta-amyloid (Abeta), which is derived from beta Amyloid Precursor Protein through sequential cleavages by beta-site APP cleaving protein 1 (BACE1) and gamma-secretase. The level/activity of BACE1 is elevated in sporadic AD and identification of proteins that affect BACE1 is important in AD research. Here we found that M1 Muscarinic acetylcholine receptor (M1 mAChR), an important G protein-coupled receptor involved in cholinergic neuronal activity, can interact with BACE1 and mediate its proteosomal degradation. Moreover, overexpression and downregulation of M1 mAChR can decrease and increase the levels of BACE1, as well as the generation of Abeta, respectively. These findings point to a novel coupling of BACE1 and M1 mAChR in AD and possibly schizophrenia. PMID- 22450049 TI - Face specific broadband electrocorticographic spectral power change in the rhinal cortex. AB - Recent studies have revealed additional face areas in the anterior temporal lobe in addition to the 'core' face areas (fusiform face area, occipital face area, and face area in the superior temporal sulcus). The electrocorticogram of a patient who underwent implantation of subdural grid electrodes in the right anterior ventral temporal lobe revealed a strong face-specific response both in event-related potentials (ERP) and in the induced broadband spectral power change at an electrode located on the anterior collateral sulcus, straddling the border between the perirhinal and entorhinal cortices. The ERP and induced broadband power changes were highly specific to facial stimuli, which was obvious even in a single trial analysis. The face-specific response was recorded in an area with perfect overlap of the 'anterior temporal face patch' in the anterior collateral sulcus, proposed based on human functional magnetic resonance imaging (fMRI) results. A recent fMRI study in monkeys reported a face-specific visual response in the rhinal cortex, suggesting that the basic structural configuration of face responsive areas are preserved across species. Although the rhinal cortex has long been regarded as part of the memory system, recent data suggest that it also plays a role in perception. The face-specific response in the present study might reflect visual processing based on complex conjunctions of visual features required for facial processing. PMID- 22450050 TI - Mechanical injured neurons stimulate astrocytes to express apolipoprotein E through ERK pathway. AB - To explore the possible cellular source and mechanism of apolipoprotein E (apoE) expression in mechanical injured neuronal cultures. Primary cultured mouse cortical neurons were subjected into mechanical injury by needle scratching. The conditioned medium of wild type (WT) primary mouse astrocytes was collected and added into cultured injured apoE knockout (KO) neurons. Separately, the conditioned medium of injured apoE KO neurons was collected and added into cultured WT astrocytes. We used a specific inhibitor of extracellular signal regulated kinase (ERK) to block the possible apoE-associated pathway between injured neurons and astrocytes. The apoE expression levels of the cells and secreted into medium were measured by Western blot, respectively. The apoE expression was increased in neurons after mechanically injury, and the injured neurons uptook the astrocyte-secreted apoE, as well. Furthermore, the injured neurons stimulated astrocytes to express more apoE through the ERK signaling pathway. Mechanical injury triggered the neurons to increasingly synthesized apoE and uptook exogenous apoE, while stimulators released from injured neurons elevated astrocytes in apoE expression and secretion. PMID- 22450051 TI - Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus. AB - The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. PMID- 22450052 TI - Synthesis and properties of a water soluble graft (chitosan-g-2 acrylamidoglycolic acid) copolymer. AB - The present paper reports the graft copolymerization of 2-acrylamidoglycolic acid onto chitosan by using potassium bromate/silver nitrate as an efficient redox initiator in an inert atmosphere. The effect of reaction conditions on grafting parameters i.e. grafting ratio, efficiency, conversion, add on, homopolymer and rate of grafting has been studied. Experimental results show that maximum grafting has been obtained at 0.4 g dm(-3) concentration of chitosan, 8.0*10(-2) mol dm(-3) concentration of 2-acrylamidoglycolic acid and 1.0*10(-3) mol dm(-3) concentration of hydrogen ion. It has also been observed that grafting ratio, add on, conversion, efficiency and rate of grafting increase up to 3.2*10(-3) mol dm( 3) of silver nitrate and 1.7*10(-2) mol dm(-3) of potassium bromate. Time (120 min) and temperature (40 degrees C) were kept constant during reaction. The physicochemical properties of graft copolymer synthesized have been performed in terms of water swelling, metal ion sorption, flocculation and resistance to biodegradability with respect to the chitosan as a parent polymer. The graft copolymer has been characterized by Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis. PMID- 22450053 TI - Adsorptive characteristics of phosphate from aqueous solutions by MIEX resin. AB - This study investigated the potential of MIEX resin as the adsorbent for the removal of phosphate from aqueous solutions. In our batch experiments, we studied the effect of some parameters on the removal of phosphate. It was observed that uptake of phosphate was mainly affected by initial phosphate concentration, adsorbent dosage, initial pH of solution, and coexistent anions. The adsorption equilibrium data at 288 K fitted well to Freundlich and Koble-Corrigan isotherm models. The kinetics studies displayed that the adsorption process followed the pseudo-second-order model. The diffusion studies showed that the intra-particle diffusion was not the only rate-controlling step and, the diffusion process of phosphate from solution to MIEX resin was controlled by film diffusion. The thermodynamics parameters were evaluated. The results showed that the adsorption process was spontaneous thermodynamically, endothermic, and entropy driven. These results have established a good potentiality for MIEX resin to be used as an adsorbent for the removal of phosphate from aqueous solutions. This work will deepen our understanding of the adsorptive characteristics of phosphate by MIEX resin and provide a better way to remove phosphate from wastewater. PMID- 22450054 TI - Sensitivity of cationic surfactant templates to specific anions in liquid interface crystallization. AB - We investigated the specific effects of potassium salts of various anions upon the interfacially templated crystal nucleation of K(2)SO(4). Previously, we have shown that the presence of several salts at low concentrations could induce changes in important crystallization characteristics templated by 1 octadecylamine at the liquid-liquid interface, and that these changes depended greatly on the specific identity of the salt. In this work we extend our surfactant monolayers to include dimethyldioctadecylammonium bromide (DODAB) and hexadecyltrimethylammonium bromide (CTAB). Addition of 10 mM of various potassium salts results in a diminution in efficiency of the templating capability of CTAB monolayer, as evidenced by higher C(onset) values and polycrystalline habit. The ability of the anions to perturb these values varied in a manner consistent with a Hofmeister series. However, DODAB maintained its templating effectiveness regardless of the nature of the salt or concentration. DODAB and CTAB are likely to be undergoing different reordering effects in the monolayer upon binding with chaotropic anions: a combined reduction in surface charge with different monolayer ordering results in a differing template ability. These studies have provided significant insights into the understanding of the interaction of ordered surfactant arrays with salts, and provide exciting possibilities for crystal engineering and materials design. PMID- 22450055 TI - Preparation of superhydrophobic Fe2O3 nanorod films with the tunable water adhesion. AB - We describe a simple and inexpensive method to prepare alpha-Fe(2)O(3) nanorods films on glass slides fabricated via a simple hydrothermal procedure at 120 degrees C. Such films exhibit a hierarchical microtexture, and after the surface modification, they show extraordinary superhydrophobicity and the controllable water adhesion. Such superhydrophobic surfaces of the ferric oxides imply wide industrial applications. PMID- 22450056 TI - Mechanism of gelation in the hydrogenated soybean lecithin (PC70)/hexadecanol/water system. AB - The crude phospholipid mixture (PC70) forms a homogeneous gel with hexadecanol (HD) in water, whereas the purified lipid does not. The fact that the crude material PC70 can be utilized for homogeneous gel preparation suits the cosmetic industry very well from the viewpoint of cost performance. In order to clarify the mechanism of the gelation, we investigated the structures and physicochemical properties of the PC70/HD/water system by rheometry, freeze-fracture electron microscopy, differential scanning calorimetry (DSC) and synchrotron X-ray diffraction. Our results suggested that the gelation is induced by change in bilayer morphology from closed vesicles to sheet-like structures with open edges covered by minor lipid components that are stiffened due to intercalation of HD molecules between phospholipids. The morphological change may give rise to homogeneous distribution of the bilayer sheets throughout the solution and formation of water continuum that may work as a network in the gel. PMID- 22450057 TI - Crystallization process of zeolite rho prepared by hydrothermal synthesis using 18-crown-6 ether as organic template. AB - There are many viewpoints on the formation mechanisms for zeolites, but the details are not clear. An understanding of the elementary steps for their formation is important for the development of large-scale membranes and efficient manufacturing processes. In this study, the effects of silicon, aluminum, and the incorporation of 18-crown-6 (18C6) ether, on the formation of zeolite rho, using 18C6 as the structure directing agent (SDA) have been investigated by using field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray fluorescence spectrometry (EDX), nuclear magnetic resonance spectroscopy (NMR), thermo gravimetric analysis (TGA), and the pH measurement. These results suggested that a zeolite rho has four synthesis steps; (1) 0-3 h, the dehydration and condensation reaction between the silica and alumina to form amorphous aluminosilicates; (2) 3-20 h, the particle growth and aggregation process for the amorphous aluminosilicates; (3) 20-48 h, the crystallization and crystal growth of zeolite rho, with the incorporation of 18C6; and (4) 48-96 h, gentle growth with an increase in Na/Si ratio and a change in rate for the bounding state between the silica- and the alumina-based species. We consider the above to reflect the four steps for the formation of zeolite rho. PMID- 22450058 TI - Relative value of transcatheter aortic valve replacement. PMID- 22450059 TI - The right thing to do with the wrong thing. PMID- 22450060 TI - Invited commentary. PMID- 22450061 TI - Invited commentary. PMID- 22450062 TI - Invited commentary. PMID- 22450063 TI - Invited commentary. PMID- 22450064 TI - Invited commentary. PMID- 22450065 TI - Comparative genomics of esophageal adenocarcinoma and squamous cell carcinoma. AB - BACKGROUND: Esophageal cancer consists of two major histologic types: esophageal squamous cell carcinoma (ESCC), predominant globally, and esophageal adenocarcinoma (EAC), which has a higher incidence in westernized countries. Five year overall survival is 15%. Clinical trials frequently combine histologic types although they are different diseases with distinct origins. In the evolving era of personalized medicine and targeted therapies, we hypothesized that ESCC and EAC have genomic differences important for developing new therapeutic strategies for esophageal cancer. METHODS: We explored DNA copy number abnormalities in 70 ESCCs with publicly available array data and 189 EACs from our group. All data was from single nucleotide polymorphism arrays. Analysis was performed using a segmentation algorithm. Log ratio thresholds for copy number gain and loss were set at +/-0.2 (approximately 2.3 and 1.7 copies, respectively). RESULTS: The ESCC and EAC genomes showed some copy number abnormalities with similar frequencies (eg, CDKN2A, EGFR, KRAS, MYC, CDK6, MET) but also many copy number abnormalities with different frequencies between histologic types, most of which were amplification events. Some of these regions harbor genes for which targeted therapies are currently available (VEGFA, ERBB2) or for which agents are in clinical trials (PIK3CA, FGFR1). Other regions contain putative oncogenes that may be targeted in the future. CONCLUSIONS: Using single nucleotide polymorphism arrays we compared genomic abnormalities in a large cohort of EACs and ESCCs. We report here the similar and different frequencies of copy number abnormalities in ESCC and EAC. These results may allow development of histology-specific therapeutic agents for esophageal cancer. PMID- 22450066 TI - Invited commentary. PMID- 22450067 TI - Invited commentary. PMID- 22450068 TI - Invited commentary. PMID- 22450069 TI - Invited commentary. PMID- 22450070 TI - Economic evaluation of endoscopic versus open vein harvest for coronary artery bypass grafting. AB - BACKGROUND: A short saphenous vein segment is commonly used as a conduit for coronary artery bypass grafting, and clinicians must decide whether to obtain it by performing open (OVH) or endoscopic vein harvest (EVH). We conducted a health economic evaluation, using data on resource usage collected alongside a randomized controlled trial, to investigate whether EVH is cost-effective compared with OVH. METHODS: Analyses were performed in accordance with international guidelines for health economic evaluations. We constructed 3 cost levels as the current literature is inconclusive as to which resource consumptions differ significantly between harvesting methods. Outcomes were measured as purulent infections avoided in the cost-effectiveness analysis and for the cost-utility analysis we estimated quality-adjusted life-years gained. Results were presented as incremental cost-effectiveness ratios: ie, the extra cost of obtaining one extra quality-adjusted life-year and the extra cost of avoiding one purulent infection. To handle uncertainties, we performed bias corrected bootstrap analyses on 5,000 resamples and constructed cost effectiveness acceptability curves. RESULTS: The incremental cost-effectiveness ratio was $79,391/quality-adjusted life-year and $1,970/purulent infection avoided when costs and outcomes within 35 days postoperatively were compared. Within 35 days postoperatively, EVH was less than 1% cost-effective at a willingness-to-pay threshold of $50,000/quality-adjusted life-year. CONCLUSIONS: The EVH was not cost-effective within 35 days postoperatively. Future studies should investigate long-term cost effectiveness. PMID- 22450071 TI - Invited commentary. PMID- 22450072 TI - Invited commentary. PMID- 22450073 TI - Invited commentary. PMID- 22450075 TI - Anvil extension technology in thoracic surgery. AB - PURPOSE: Endoscopic staplers are the dominant tools to divide tubular structures in thoracoscopic lobectomy. However, passing these devices can be challenging because of limitations in their design. DESCRIPTION: Two independent concepts were combined into one design aiming to overcome the limitation of passing the straight anvil of an endoscopic stapler through a tunnel typically created by a curved dissection instrument within the complex cluster of tubular structures that comprise the pulmonary hilum. EVALUATION: A library of 45 unedited advanced thoracoscopic lung resection videos containing a balance of all major anatomic resections (36 lobectomy and 9 pneumonectomy) spanning 2004 to 2011 were reviewed, and 220 hilar structure division times were measured along with the adjunctive techniques like catheter leaders or silicone slings. Prolonged passage times occurred throughout the series despite improved experience; however, early experience with 51 passes using the new design showed significant time savings (median 61 s versus 115 s, p = 0.005). CONCLUSIONS: Curved tip anvils for endoscopic linear cutting staplers appear useful to speed thoracoscopic lung resections. PMID- 22450074 TI - Contemporary Fontan operation: association between early outcome and type of cavopulmonary connection. AB - BACKGROUND: Extracardiac conduit and lateral atrial tunnel total cavopulmonary connection are both widely used in the management of functionally univentricular hearts. The effect of the type of connection on early outcomes after Fontan operation remains unclear. We evaluated the effect of Fontan type on early outcome in a large clinical database. METHODS: Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Fontan operation (2000 to 2009) were included. We used multivariable analysis to evaluate the effect of Fontan type (extracardiac conduit vs lateral tunnel) on in hospital death, Fontan takedown/revision, Fontan failure (in-hospital death or Fontan takedown/revision), postoperative length of stay, and complications, adjusting for patient, procedural, and center factors. RESULTS: The study included 2,747 patients (61% male) from 68 centers. A right-dominant ventricle was present in 45%. Extracardiac conduit Fontan (vs lateral atrial tunnel) was performed in 63%; in all, 65% were fenestrated. In multivariable analysis with adjustment for patient, procedural (including fenestration), and center factors (including Fontan volume), the extracardiac conduit Fontan was associated with significantly higher Fontan takedown/revision (odds ratio, 2.73; 95% confidence interval, 1.09 to 6.87) and Fontan failure (odds ratio, 2.28; 95% confidence interval, 1.13 to 4.59), and longer postoperative hospital stay (adjusted estimated difference in postoperative hospital stay: +1.4 days). CONCLUSIONS: These multicenter data suggest that of the two prevalent forms of Fontan connection in current use, the lateral atrial tunnel Fontan may be associated with superior early outcomes. PMID- 22450076 TI - Intraoperative electroanatomic mapping. AB - PURPOSE: An electroanatomic mapping system using an electromagnetic navigation technology constructs a 3-dimensional structure of the heart with high geometric accuracy of the data that provides a precise localization of the substrates of arrhythmias. The system was tested for the feasibility and efficacy in intraoperative mapping. DESCRIPTION: The strength of the magnetic field is measured by a location sensor with three different frequencies generated by a location pad placed beneath the operating table, and the spatial location of the sensor is determined. By roving the catheter on the heart while the local electrogram is recorded simultaneously, the 3-dimensional figure of the heart is reconstructed and an activation or voltage map is generated. EVALUATION: The system was used in 19 patients with ventricular tachycardia or other arrhythmias. The focus or reentrant circuit of the tachycardia was precisely located and a map guided procedure was successfully performed in all patients. Cardiopulmonary bypass allowed for the tachycardias to be mapped without any hemodynamic compromise. CONCLUSIONS: Intraoperative mapping using the electroanatomic mapping system enables a precise localization of the tachycardia substrate. PMID- 22450077 TI - Bilateral double free-flaps for reconstruction of extensive chest wall defect. AB - A 44-year-old woman presented with ulcerating stage IV breast cancer involving the chest wall. En bloc resection of the second to seventh ribs on the right side, parts of the second to eighth ribs on the left side, the sternum, the chest wall muscles, and skin was completed with immediate reconstruction using bilateral double free flaps consisting of anterior lateral thigh and tensor fascia latae elevated on the lateral circumflex femoral system and creating recipient vessels with an arteriovenous loop. PMID- 22450078 TI - Tracheal stenosis after metal stent insertion treated successfully with a T-tube. AB - Tracheal stenosis after intubation is a fairly common complication, and treatment of such cases can be difficult. A 52-year-old woman was admitted to our hospital because of severe dyspnea. Seven years previously, she had suffered tracheal stenosis after tracheal intubation and had undergone tracheal resection and placement of a self-expandable metal stent. In this case, tracheal restenosis had occurred and we successfully treated the patient by insertion of a silicone T tube after tracheotomy. Use of a T-tube is safe and effective for relief of tracheal restenosis after self-expandable metal stent placement. PMID- 22450079 TI - Use of cervicothoracic anatomy as a guide for directed drainage of descending necrotizing mediastinitis. AB - Descending necrotizing mediastinitis is a potentially lethal infection originating from the oropharynx. Adequate abscess drainage is crucial to successful treatment. We present novel management of descending necrotizing mediastinitis using a series of anterior mediastinal incisions adjoined by Penrose drains. The success of this treatment was dependent on radiographic documentation of infection confined to the anterior cervicothoracic plane. PMID- 22450080 TI - Concurrent metastatic thymic carcinoma and postirradiation sarcoma. AB - We present a case of concurrent metastatic thymic carcinoma and postirradiation sarcoma in the same lobe of the lung in a woman who had received partial resection of thymic carcinoma with chemoradiotherapy 11 years ago. One tumor showed similar histology to the previous carcinoma. The other tumor was a pleomorphic sarcoma, suggestive of a postirradiation sarcoma. Irradiation-induced sarcomas are rare and have not been reported in patients with thymic carcinoma. This case may serve as a model in considering the possibility of postirradiation sarcoma for patients encountering recurrent masses with the history of radiotherapy for thymic carcinoma several years ago. PMID- 22450081 TI - Direct transaortic CoreValve implantation through right minithoracotomy in patients with patent coronary grafts. AB - Transcatheter aortic valve implantation has rapidly gained credibility as a valuable alternative to conventional aortic valve replacement in patients with severe aortic stenosis, who are otherwise left untreated owing to the perceived high risk of operative mortality. However, these patients are often also affected by severe iliofemoral arteriopathy, rendering the transfemoral approach unfeasible. Different alternative access routes have been used in these patients, such the transapical and the subclavian routes. We report our experience of direct aortic access through a right anterior minithoractomy to implant a self expanding aortic valve bioprosthesis in two patients who had previously undergone coronary artery bypass graft surgery. PMID- 22450082 TI - Blood pressure measurements in patients with Takayasu arteritis: a work of caution. AB - Takayasu arteritis is a large vessel vasculitis among young women that affects the aorta and its branches. Disease-related subclavian or brachial obstructions can lead to hypotensive brachial blood pressure values. By contrast, arterial hypertension is also frequent in this disease, possibly unrecognized in case of solitary brachial blood pressure measurement. We present the case of a 28-year old woman with cerebral hypoperfusion related to Takayasu arteritis. Despite "pseudo-hypotensive" brachial blood pressure values of 70 mm Hg, Doppler measurement of the ankle revealed a systolic pressure of 220 mm Hg. In Takayasu vasculitis, additional ankle pressure measurement may represent the true cardiac load and blood pressure. PMID- 22450083 TI - Mycotic pseudoaneurysm of the aortic arch with purulent pericardial effusion. AB - A 67-year-old woman presented with dyspnea on exertion and a diminished left radial pulse in comparison with the right. She had signs and symptoms of cardiac tamponade. A computed tomographic (CT) angiogram of the chest revealed an aortic arch pseudoaneurysm along the lesser curvature and a large pericardial effusion with the density of blood. Upon pericardiotomy, a nonhemorrhagic thick purulent effusion (Streptococcus milleri) was discovered in the pericardial space. Replacement of the aortic arch was performed with a rifampin-soaked Dacron tube graft, with the patient under hypothermic circulatory arrest. PMID- 22450084 TI - Central extracorporeal life support in pheochromocytoma crisis. AB - Pheochromocytoma is a catecholamine-secreting tumor associated with clinical presentations ranging from paroxysmal hypertension to intractable cardiogenic shock. We report the use of central extracorporeal life support (ECLS) in a young woman admitted to the intensive care unit with cardiogenic shock. Her medical history included neurofibromatosis type I and pheochromocytoma. ECLS was needed because of severe left ventricular failure and inotropic therapy unresponsiveness. ECLS permitted full recovery of left ventricular function. Right adrenelectomy was performed 4 months later. In this case, central ECLS was used to treat pheochromocytoma-induced cardiogenic shock complicated by pulmonary edema. PMID- 22450085 TI - Long-term mechanical circulatory support of an adult patient with Down syndrome. AB - Destination therapy with the HeartMate II left-ventricular assist device (Thoratec Corp, Pleasanton, CA) was undertaken in an adult patient with Down syndrome and end-stage heart failure. The patient was bridged to the HeartMate II with extracorporeal membrane oxygenation followed by the Levitronix CentriMag (Levitronix, Waltham, MA). HeartMate II implantation was complicated by coagulopathy. The patient spent 44 postoperative days in hospital and is currently stable in the community. No infections were acquired. Compliance training was delivered primarily to the patient's family. Destination therapy with the HeartMate II may be successfully implemented in eligible, socially supported Down syndrome patients. PMID- 22450086 TI - Acute dysfunction of mechanical aortic valve as electrocardiographic mimic of acute left main coronary artery occlusion. AB - We report three patients with acute dysfunction of mechanical aortic valve prosthesis resulting in chest pain, concomitant cardiogenic shock, and electrocardiographic changes mimicking acute occlusion of the left main coronary artery whereas emergency coronary angiography revealed normal coronary arteries. During operation, abnormal proliferation of subvalvular pannus overgrowth on the inflow aspect of the prosthesis was found to impede normal prosthesis closure. We discuss the possible underlying mechanisms of electrocardiographic presentations. PMID- 22450087 TI - Colonic injury from temporary epicardial pacing wires. AB - A 72-year-old man who had undergone a three-vessel coronary artery bypass grafting, aortic valve replacement, and tricuspid valve repair became comatose 1 week after the procedure. Signs of intraabdominal sepsis developed 6 days later, leading to laparotomy on his 12th postoperative day. The Intraoperative finding was a perforating injury to the transverse colon caused by the ventricular temporary pacing wires. A defunctioning double-barreled transverse colostomy was performed, after which the patient started to recover. He was discharged home 2 weeks later. PMID- 22450088 TI - Reconstruction of pulmonary artery in a newborn using a porcine small intestinal submucosal patch. AB - In this case report, we evaluated cellular structure and the growth potential of a porcine small intestinal submucosal patch used for pulmonary artery augmentation in a 20-day-old newborn with pulmonary atresia. The patch was resected 2 months postoperatively due to apparent abnormal wall thickening and evaluated by histologic and immunohistologic staining. PMID- 22450089 TI - Severe cyanosis after Kawashima operation resulting from congenital portosystemic shunt. AB - We describe an unusual case of a patient with polysplenia, inferior vena cava (IVC) interruption, and unrecognized congenital portosystemic venous connection (CPVC) in whom severe cyanosis developed in the acute postoperative stage after a Kawashima operation and required urgent surgical division of the CPVC. It has been stressed recently that CPVCs and other abdominal venous abnormalities have been underdiagnosed in patients with polysplenia and IVC interruption, and we think that a routine evaluation of abdominal venous connections should be mandatory before considering the Kawashima operation for these patients. PMID- 22450090 TI - Multivessel intralobar pulmonary sequestration. PMID- 22450091 TI - Fibrous cyst arising from the cordae tendiniae of the mitral valve. PMID- 22450092 TI - Triple-barreled aortic dissection developing into quadruple-barreled dissection. PMID- 22450093 TI - Cervical video-assisted thoracoscopic surgery using a flexible endoscope for bilateral thoracoscopy. AB - Video-assisted thoracoscopic surgery (VATS) has become the standard of care for pleural evaluation, drainage, and pleurodesis. The major limitations to standard VATS techniques include intercostal pain and the unilateral nature of the procedure. We report on a cervical VATS approach for bilateral thoracoscopy, pleural biopsy, and talc pleurodesis using a flexible video endoscope without any intercostal incision. A 64-year old male with peritoneal carcinomatosis was noted to have significant bilateral pleural effusions. A cervical video-assisted thoracoscopic surgery (C-VATS) procedure was performed through a 2-cm cervical incision using a sterile flexible gastroscope. Bilateral thoracoscopy, pleural drainage, pleural biopsies, lung biopsy, and talc pleurodesis were performed. No thoracic intercostal incisions were performed. Total operative time was 48 minutes. The procedure was successful and the recovery was uneventful. The patient was discharged 4 days after the procedure. C-VATS is an extremely minimally invasive procedure. It avoids intercostal incisions and allows for bilateral pleural procedures through a single small cervical incision. PMID- 22450094 TI - Composite venous coronary grafts: construction made simple. AB - We describe an efficient, safe, and effective method for constructing a satisfactory composite venous conduit from 2 portions of saphenous vein, which by themselves would be inadequate in length to function as independent conduits. PMID- 22450095 TI - Use of an ultrasonic surgical aspirator to expose buried coronary arteries. AB - In coronary artery bypass grafting, the target arteries for grafting can be buried in thick adipose tissue or myocardium, and exposure may be difficult. We used an ultrasonic surgical aspirator to expose buried coronary arteries. Fat tissue or myocardium covering coronary arteries was removed, and target arteries were exposed with little bleeding. No arrhythmia or coronary spastic event occurred during its application, and bypass grafting could be completed. In postoperative angiography, no deformity or shrinkage of coronary arteries was observed at the sites at which the ultrasonic aspirator was applied. PMID- 22450096 TI - Loop-in-loop technique in mitral valve repair via minithoracotomy. AB - Although multiple neochordae creations with premeasured loops by polytetrafluoroethylene (PTFE) sutures is a feasible and effective technique for mitral valve repair by an endoscopic-assisted minithoracotomy approach, measuring the correct length of premeasured loops is difficult because of diversity of the distance between the papillary muscle and the prolapsed mitral leaflet. A new technique consisted of a premade primary loop set and a secondary loop to adjust the length of the neochordae was devised as a loop-in-loop technique. Facilitating tying a slippery PTFE suture as the secondary loop in a correct position, a knot fixation using a neurosurgical titanium clip was applied. PMID- 22450099 TI - The indications for uniportal video-assisted thoracic surgery. PMID- 22450100 TI - DualMesh 2-MM Gore-Tex and pectus excavatum repair. PMID- 22450101 TI - Blalock-Taussig shunts with and without closure of the ductus arteriosus. PMID- 22450102 TI - Aorto-GoreTex central shunt with side-to-side aortic anastomosis. PMID- 22450105 TI - Alternate method for hybrid Fontan completion. AB - A Fontan completion with a hybrid approach was performed on a 27-month-old girl with a univentricular heart. A large covered stent was placed between the inferior vena cava and the cavopulmonary anastomosis through a pericardial patch in the intracardiac fenestrated tunnel, circumventing the need for an occluder device for baffle closure. The child's progress has been good and she displays normal growth and acceptable clinical, ultrasonographic, and laboratory results. PMID- 22450106 TI - A Bjork-Shiley valve 40 years in action. PMID- 22450107 TI - Traumatic aneurysm of the right internal thoracic artery. PMID- 22450108 TI - Video-assisted cardiac myxoma resection: basket technique for complete and safe removal from the heart. AB - Video assistance can replace sternotomy in cardiac operations with excellent results. Because myxomas are very friable tumors, their removal from the heart and chest cavity through a working port in video-assisted or robotic procedures may be challenging. We used a laparoscopic basket to safely catch and remove these friable tumors in 10 patients undergoing video-assisted myxoma resection between December 2008 and June 2011. Complete excision and removal was achieved in all patients. No neurologic, vascular, or wound complications were observed. This minimally invasive myxoma technique gives excellent and reproducible results without a higher risk for the patient. PMID- 22450109 TI - Giant asymptomatic primary esophageal schwannoma. AB - Primary esophageal schwannomas are uncommon. We describe a case of a large asymptomatic primary esophageal schwannoma in a 65-year-old patient. Computed tomography and positron emission tomography revealed an (18)F-fluorodeoxyglucose avid 11-cm mass arising from the esophagus. A preoperative diagnosis was made via endoscopic ultrasound. The patient underwent a three-field esophagogastrectomy with cervical esophagogastric anastomosis. He remains well and free of recurrence 10 months after treatment. PMID- 22450110 TI - Penetrating injury of ascending aorta with arrow in situ. AB - Penetrating injuries of the aorta are rare and highly lethal; very few patients are able to reach the hospital alive. We report a case of penetrating injury into the ascending aorta with the arrow still in situ, shot by a bow in a tribal region of India. The wound of entry into the aorta was sealed by the arrow itself. The patient came to us walking and supporting the arrow with his left hand. He was operated on, and the arrow was successfully removed from the aorta. PMID- 22450111 TI - TAVI for pure aortic valve insufficiency in a patient with a left ventricular assist device. AB - We report transcatheter aortic valve implantation (TAVI) for pure aortic valve insufficiency in a patient with an otherwise normal aortic valve and a long-term left ventricular assist device (LVAD). An oversized 29-mm Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) was implanted in the 21-mm native aortic valve annulus. Despite the complete absence of aortic calcifications, the prosthesis remained stably anchored inside the annulus. The reported experience demonstrates that TAVI is feasible even in patients with pure aortic valve regurgitation and can be a reasonable option in patients with aortic regurgitation after LVAD implantation. PMID- 22450112 TI - Bartonella as a cause of mechanical prosthetic aortic root endocarditis. AB - Bartonella henselae infection is typically associated with cat scratch disease. This microorganism can also lead to culture-negative infective endocarditis in immunocompromised patients. We present a rare case of a previously healthy 65 year-old man with B. henselae-associated endocarditis of a prosthetic aortic root. All blood cultures, as well as cultures of the resected aortic valve vegetations, remained negative. Polymerase chain reaction with specific bacterial primers with DNA sequencing was used to identify B. henselae as the etiologic agent. This was successfully managed by an aortic root re-replacement using a mechanical conduit, reimplantation of coronaries ostia, and antibiotic therapy. PMID- 22450113 TI - Mitral valve repair for double-orifice mitral valve with flail leaflet: the usefulness of real-time three-dimensional transesophageal echocardiography. AB - We describe a 66-year-old man who required an operation for severe mitral regurgitation associated with a double-orifice mitral valve. Real-time 3 dimensional transesophageal echocardiography clearly demonstrated a double orifice mitral valve with a central fibrous bridge. A flail posterior leaflet was observed on the anterolateral mitral valve orifice. Mitral valve repair using P1 triangular resection, anterolateral commissure plication, and ring annuloplasty with Duran band (Medtronic, Minneapolis, MN) was successfully performed. Postoperative real-time 3-dimensional transesophageal echocardiography demonstrated a double-orifice mitral valve without regurgitation or stenosis. PMID- 22450114 TI - Secondary abdominal compartment syndrome causing failure to wean from cardiopulmonary bypass. AB - The abdominal compartment syndrome has been associated with trauma or primary abdominal procedures. The secondary abdominal compartment syndrome which is not associated with a primary abdominal process is seen in burns and other clinical situations where aggressive fluid resuscitation is needed. This case report describes a secondary abdominal compartment syndrome that occurred during an elective coronary revascularization which resulted in an inability to wean from cardiopulmonary bypass (CPB). After a decompressive laparotomy was done, the patient was successfully weaned from bypass. PMID- 22450115 TI - Innovations in humanitarian technologies working group-report of the proceedings, Humanitarian Action Summit 2011. PMID- 22450116 TI - Evidence-based mental health and psychosocial support in humanitarian settings: gaps and opportunities. PMID- 22450117 TI - Two-step biodiesel production from crude Jatropha curcas L. oil using ultrasonic irradiation assisted. AB - In this paper, the feasibility of crude Jatropha curcas L. oil (CJCO) as raw material to produce biodiesel under low-frequency ultrasonic irradiation (40 kHz) assisted is examined. A two-step transesterification process (acid catalyzed esterification followed by alkaline catalyzed transesterification) is employed to produce biodiesel. In the first step, the high level of free fatty acid (FFA), 12.5%, of CJCO is successfully reduced to less than 3% by acid catalyzed esterification with 15% w/w methanol to oil ratio, catalyst concentration 3.0% w/w, ultrasonic irradiation time 20 min at under reaction temperature 30 degrees C, which are selected as optimum conditions for the acid catalyzed esterification. Then, the second step, alkaline catalyzed transesterification is carried out as methanol to oil ratio 15% w/w, catalyst concentration 1% w/w, reaction temperature 30 degrees C and ultrasonic irradiation time 30 min. This results to high percentage of conversion to biodiesel about 98%. Comparing the results obtained under the ultrasonic irradiation in this study with those under conventional stirring conditions, ultrasonic irradiation technique significantly illustrated the higher efficiency than the conventional method, especially for the high FFA oil. PMID- 22450118 TI - Actual ratio of triacylglycerol positional isomers in milk and cheese. AB - Actual ratios of triacylglycerol (TAG) positional isomers in human, rat, and cow milk fat and cow, buffalo, goat, and sheep cheese fat were analyzed using HPLC-UV atmospheric pressure chemical ionization-MS/MS system equipped with an octacosyl silylation column or polymeric ODS column. We substituted cheese fats for milk fats in parts of our study because milks from ruminants, with the exception of cows, are difficult to get in Japan. The actual ratio of beta-PPC (the TAG consisting of two palmitic acids (P) and one capric acid (C), with the palmitic acid located at the beta position) and beta-PCP in human milk was different from those in ruminants, with more than half of the medium-chain fatty acids located at the beta position even though other fats possessed it mainly at the alpha position. Palmitic acid was mainly located at the beta position for human milk and rat milk; however, the location in ruminant cheese fat was mainly at the alpha position. The location of fatty acids is thought to be very important for infant nutrition. Particularly, the location of palmitic acid in case of human milk and of medium-chain fatty acids in case of ruminant milk was very characteristic and is considered to be very important to the fatty acids in milk fat. PMID- 22450119 TI - Effect of oil type and fatty acid composition on dynamic and steady shear rheology of vegetable oils. AB - In this study, effect of fatty acid composition on dynamic and steady shear rheology of oils was studied. For this aim, different types of vegetable oils (soybean, sunflower, olive, hazelnut, cottonseed and canola), were used. Rheological properties of oil samples were identified by rheometer (Thermo-Haake) at 25 degrees C and fatty acid composition of oils was determined by GC (Agilent 6890). Steady shear rheological properties of oil samples were measured at shear rate range of 0.1-100 s-1. Viscosity of olive, hazelnut, cottonseed, canola, soybean and sunflower was 61.2 mPa.s, 59.7 mPa.s, 57.3 mPa.s, 53.5 mPa.s, 48.7 mPa.s and 48.2 mPa.s, respectively. There was a significant difference between viscosity of oils except soybean and sunflower. As a result it was seen that there was a correlation between viscosity and monounsaturated (R=0.89), polyunsaturated (R=-0.97) fatty acid composition of oils, separately. Equation was found to predict viscosity of the oils based on mono and polyunsaturation composition of oils. In addition the dynamic rheological properties of oils were also examined. G', G'' and tan delta (G''/G') values were measured at 0.3 Pa (in viscoelastic region) and 0.1-1 Hz. As a result of multiple regression analysis another equations were found between tan delta, viscosity and polyunsaturated fatty acids. PMID- 22450120 TI - Copper extraction by fatty hydroxamic acids derivatives synthesized based on palm kernel oil. AB - Fatty hydroxamic acids derivatives based on palm kernel oil which are phenyl fatty hydroxamic acids (PFHAs), methyl fatty hydroxamic acids (MFHAs), isopropyl fatty hydroxamic acids (IPFHAs) and benzyl fatty hydroxamic acids (BFHAs) were applied as chelating agent for copper liquid-liquid extraction. The extraction of copper from aqueous solution by MFHAs, PFHAs, BFHAs or IPFHAs were carried out in hexane as an organic phase through the formation of copper methyl fatty hydroxamate (Cu-MFHs), copper phenyl fatty hydroxamate (Cu-PFHs), copper benzyl fatty hydroxamate (Cu-BFHs) and copper isopropyl fatty hydroxamate (Cu-IPFHs). The results showed that the fatty hydroxamic acid derivatives could extract copper at pH 6.2 effectively with high percentage of extraction (the percentages of copper extraction by MFHAs, PFHAs, IPFHs and BFHAs were found to be 99.3, 87.5, 82.3 and 90.2%, respectively). The extracted copper could be quantitatively stripped back into sulphuric acid (3M) aqueous solution. The obtained results showed that the copper recovery percentages from Cu-MFHs, Cu-PFHs, Cu-BFHs and Cu IPFHs are 99.1, 99.4, 99.6 and 99.9 respectively. The copper extraction was not affected by the presence of a large amount of Mg (II), Ni (II), Al (III), Mn (II) and Co (II) ions in the aqueous solution. PMID- 22450121 TI - Langmuir monolayer miscibility of perfluorocarboxylic acids with biomembrane constituents at the air-water interface. AB - Over the past two or three decades, Langmuir monolayers comprising various fluorinated amphiphiles such as perfluorinated, partially fluorinated, and fluorinated-hydrogenated hybrid molecules at the air-water interface, have been investigated to deepen the understanding of their characteristic phenomena and to explore the mutual interaction of these amphiphiles with biomembrane constituents. Langmuir monolayers of these fluorinated amphiphiles are potentially applicable in the fields of materials, biological and clinical science, where they may be utilized in two-dimensional protein crystallization, microelectronics, and for surfactant replacement in the lung. This review article focuses on the miscibility between perfluorinated long-chain carboxylic acids (CF3(CF2)(n-1)COOH, or FnCOOH) and phospholipids or fatty acids in biomembranes upon lateral compression, and describes how the chain-length mismatch between the fluorinated and the hydrogenated tails relates to the interfacial phase behavior from the thermodynamic and the morphological aspects at the micrometer and nanometer levels. PMID- 22450122 TI - Virucidal effects of bleach activators, sodium alkyl acyloxybenzene sulfonate and acyloxybenzoic acid, against Feline calicivirus. AB - Noroviruses (NVs) are major causative pathogens of gastroenteritis. The disinfection of contaminated clothing during common household washing is desirable. The virucidal effects of 2 bleach activators, sodium alkyl acyloxybenzene sulfonate (OBS) and alkyl acyloxybenzoic acid (OBC), were studied using Feline calicivirus (FCV) as a surrogate for NVs. FCV was added to solutions containing either OBS or OBC and sodium percarbonate at various temperatures and for varying lengths of time. OBS and OBC, which generate long carbon chain peroxy acids, enhanced the virucidal effect of sodium percarbonate (PC). In particular, sodium lauroyloxybenzene sulfonate (OBS-12) and decanoyloxybenzoic acid (OBC-10) showed superior virucidal effects. Although the virucidal effect of 38-200 mg/L OBS-12 was maintained with 2-5% (v/v) horse serum, there was less of an effect with the same concentration of available chlorine. OBS and OBC have been used as ingredients in some laundry products to increase bleaching activity. It is expected that the use of OBS and OBC is also effective for the inactivation of NVs under common household washing conditions. PMID- 22450123 TI - Removal of sulfa drugs by sewage treatment in aqueous solution systems: activated carbon treatment and ozone oxidation. AB - This study investigates the activated carbon (AC) treatment and ozone oxidation of the sulfa drugs--sulfamethoxazole (SMX), sulfamonomethoxine (SMM), sulfadimidine (SDD), and sulfadimethoxine (SDM)--in aqueous solution systems. Three AC samples were prepared from Shirasagi (AC1 and AC2) and coal (AC3), and the surface functional groups, solution pH, specific surface areas, pore volumes, and morphologies of the three samples were evaluated. The specific surface areas were in the following order: AC1 (1391 m2/g) > AC2 (1053 m2/g) > AC3 (807 m2/g). The pore volume and mean pore diameter of AC3 were greater than those of AC1 and AC2. The concentration of sulfa drugs adsorbed onto the AC samples reached equilibrium within 150 h. Experimental data of the adsorption rate were fitted to a pseudo-second-order model. The amount of sulfa drugs adsorbed onto the AC samples was in the order of SDM < SMM < SDD < SMX; the mechanism of adsorption of the sulfa drugs onto the AC samples depended on the hydrophobicity of the AC surface. The adsorption isotherm data were fitted to Freundlich and Langmuir models. Ozone was generated from oxygen gas using an A-27 ozone generator, and the complete degradation of the sulfa drugs by ozone treatment at 60 mL/min was achieved within 50 min. Ozone treatment caused the structure of the sulfa drugs to decompose via ozone oxidation. PMID- 22450124 TI - The anti-proliferative effects of a palm oil-derived product and its mode of actions in human malignant melanoma MeWo cells. AB - Melanoma incidence and mortality have risen dramatically in recent years. No effective treatment for metastatic melanoma exists; hence currently, an intense effort for new drug evaluation is being carried out. In this study, we investigated the effects of a palm oil-derived nanopolymer called Bio-12 against human malignant melanoma. The nanopolymers of Bio-12 are lipid esters derived from a range of fatty acids of palm oil. Our study aims to identify the anti proliferative properties of Bio-12 against human malignant melanoma cell line (MeWo) and to elucidate the mode of actions whereby Bio-12 brings about cell death. Bio-12 significantly inhibited the growth of MeWo cells in a concentration and time- dependent manner with a median inhibitory concentration (IC50) value of 1/25 dilution after 72 h but was ineffective on human normal skin fibroblasts (CCD-1059sk). We further investigated the mode of actions of Bio-12 on MeWo cells. Cell cycle flow cytometry demonstrated that MeWo cells treated with increasing concentrations of Bio-12 resulted in S-phase arrest, accompanied by the detection of sub-G1 content, indicative of apoptotic cell death. Induction of apoptosis was further confirmed via caspase (substrate) cleavage assay which showed induction of early apoptosis in MeWo cells. In addition, DNA strand breaks which are terminal event in apoptosis were evident through increase of TUNEL positive cells and formation of a characteristic DNA ladder on agarose gel electrophoresis. Moreover, treatment of MeWo cells with Bio-12 induced significant increase in lactate dehydrogenase (LDH) activity. These results show that Bio-12 possesses the ability to suppress proliferation of human malignant melanoma MeWo cells and this suppression is at least partly attributed to the initiation of the S-phase arrest, apoptosis and necrosis, suggesting that it is indeed worth for further investigations. PMID- 22450125 TI - Vascular disease. Corticosteroid therapy improves outcomes for Japanese children with Kawasaki disease. PMID- 22450127 TI - Pyrazolopyrimidines as dual Akt/p70S6K inhibitors. AB - Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development. PMID- 22450126 TI - Novel biomarkers in chronic heart failure. AB - Understanding of chronic heart failure (HF) has progressed from a syndrome of disordered hemodynamics caused by alterations in the structure of the heart to one that involves intertwined molecular pathways in disarray. Accordingly, the assessment and treatment of patients with chronic HF has shifted from a focus on hemodynamics to modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers of disease could provide a unique window into the pathophysiology of chronic HF, potentially improving our ability to predict adverse outcomes, provide novel drug targets, and even help gauge therapeutic efficacy. The more 'traditional' biomarkers such as cardiac troponin, natriuretic peptides, and C-reactive protein have been studied in large cohorts of patients with chronic HF and have relatively established clinical applications. In this Review, we summarize the properties, clinical data, and potential applications of some emerging biomarkers that could uniquely indicate the level of biomechanical stretch, inflammation, ventricular remodeling, myocardial injury, and renal dysfunction that occurs in chronic HF. We will also discuss the potential role for these biomarkers within a multimarker-based strategy that could, in the future, lead to better care for these patients. PMID- 22450128 TI - Design and synthesis of 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H quinolin-2-ones as VEGFR-2 kinase inhibitors. AB - A series of 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-quinolin-2 ones have been identified as a new class of VEGFR-2 kinase inhibitors. A variety of (4,5,6,7-tetrahydro-imidazo[5,4-c]pyridin-2-yl)-acetic acid ethyl esters were synthesized, and their VEGFR-2 inhibitory activity was evaluated. Described herein are the preparation of the series and the effects of the compounds on VEGFR-2 kinase activity. PMID- 22450129 TI - Melanogenesis inhibitory bisabolane-type sesquiterpenoids from the roots of Angelica koreana. AB - Bioactivity-guided isolation of the methanolic extract of the roots of Angelica koreana led to the isolation of four new bisabolane-type sesquiterpenoids, osterivolones A-D (1-4) together with four known compounds, bisabolangelone (5), decursinol angelate (6), psoralen (7), and falcarindiol (8). Their structures were elucidated on the basis of spectroscopic data interpretation, especially 2D NMR spectra such as HMQC, HMBC, and NOESY. All compounds were evaluated for their inhibitory effects of the melanogenesis against alpha-melanocyte stimulating hormone (alpha-MSH)-activated B16 melanoma cells. PMID- 22450130 TI - Design and synthesis of potent, isoxazole-containing renin inhibitors. AB - The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential. PMID- 22450131 TI - A new pancreatic lipase inhibitor from Broussonetia kanzinoki. AB - A new phenolic compound, broussonone A (1) were isolated from the stem barks of Broussonetia kanzinoki (Moraceae), together with two diphenylpropanes, broussonin A (2), broussonin B (3), two flavans, 7,4'-dihydroxyflavan (4), 3',7-dihydroxy-4' methoxyflavan (5), and two flavones, 3,7-dihydroxy-4'-methoxyflavone (6), 3,7,3' trihydroxy-4'-methoxyflavone (7). Compound 1 showed noncompetitive inhibitory activity on pancreatic lipase with an IC(50) of 28.4 MUM. In addition, compounds 1-5 significantly inhibited adipocyte differentiation in 3T3-L1 cells as measured fat accumulation using Oil Red O assay. PMID- 22450132 TI - Design and synthesis of thiourea derivatives containing a benzo[5,6]cyclohepta[1,2-b]pyridine moiety as potential antitumor and anti inflammatory agents. AB - Thiourea derivatives (6a-e) were developed and screened for antitumor and anti inflammatory activity. Most of the compounds exhibited growth inhibitory effects comparable to 5-fluorouracil in vitro against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. They also showed stronger anti inflammatory activity than ibuprofen in vivo in the xylene-induced ear swelling assay in mice. PMID- 22450133 TI - Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists. AB - Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model. PMID- 22450134 TI - Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as P glycoprotein-mediated multidrug resistance reversal agents. AB - A series of substituted dibenzo[c,e]azepine-5-ones (7a-h) were synthesized and evaluated as P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal agents. The most potent compound 7h could significantly and selectively enhance the chemo-sensitivity of drug-resistant K562/A02 cells to the cytotoxic effect of adriamycin (ADR) in a dose-dependent manner. Further studies indicated that 7h could markedly increase intracellular accumulation of both rhodamine 123 and ADR in K562/A02 cells and inhibit their efflux from the cells. And 7h had little effect on the levels of P-gp mRNA and protein in K562/A02 cells. These results suggest that the anti-MDR effect of 7h might be attributed to the inhibition of drug efflux function of P-gp, leading to the increased drug accumulation in K562/A02 cells, and thus the compound could be served as a lead for developing P gp-mediated MDR reversal agents. PMID- 22450136 TI - P-N bond protein phosphatases. AB - The current work briefly reviews what is currently known about protein phosphorylation on arginine, lysine and histidine residues, where PN bonds are formed, and the protein kinases that catalyze these reactions. Relatively little is understood about protein arginine and lysine kinases and the role of phosphorylation of these residues in cellular systems. Protein histidine phosphorylation and the two-component histidine kinases play important roles in cellular signaling systems in bacteria, plants and fungi. Their roles in vertebrates are much less well researched and there are no protein kinases similar to the two-component histidine kinases. The main focus of the review however, is to present current knowledge of the characterization, mechanisms of action and biological roles of the phosphatases that catalyze the hydrolysis of these phosphoamino acids. Very little is known about protein phosphoarginine and phospholysine phosphatases, although their existence is well documented. Some of these phosphatases exhibit very broad specificity in terms of which phosphoamino acids are substrates, however there appear to be one or two quite specific protein phospholysine and phosphoarginine phosphatases. Similarly, there are phosphatases with broad substrate specificities that catalyze the hydrolysis of phosphohistidine in protein substrates, including the serine/threonine phosphatases 1, 2A and 2C. However there are two, more specific, protein phosphohistidine phosphatases that have been well characterized and for which structures are available, SixA is a phosphatase associated with two-component histidine kinase signaling in bacteria, and the other is found in a number of organisms, including mammals. This article is part of a Special Issue entitled: Chemistry and mechanism of phosphatases, diesterases and triesterases. PMID- 22450137 TI - A method for determining alkaline phosphatase activity in marine phytoplankton using spectrofluorometry. AB - A method for determining relative percent intensity alkaline phosphatase activity (APA) using enzyme labeled fluorescence coupled with spectrofluorometry is presented. Compared to traditional microscopy and flow cytometry, we increase statistical power and reduce sample-handling issues. Combined with a biological standard, our method can quantify APA of natural plankton assemblages. PMID- 22450138 TI - Targeted gene engineering in Clostridium cellulolyticum H10 without methylation. AB - Genetic engineering of Clostridium cellulolyticum has been developed slowly compared with that of other clostridial species, and one of the major reasons might be the restriction and modification (RM) system which degrades foreign DNA. Here, a putative MspI endonuclease gene, ccel2866, was inactivated by a ClosTron based gene disruption method. The resulting C. cellulolyticum mutant H10DeltamspI lost the MspI endonuclease activity and can accept unmethylated DNA efficiently. Following that, an oxygen-independent green fluorescence protein gene was introduced into H10DeltamspI without methylation, generating a convenient reporter system to evaluate the expression of heterologous protein in C. cellulolyticum by green fluorescence. To further demonstrate the efficiency of the H10DeltamspI, double mutants H10DeltamspIDeltaldh and H10DeltamspIDeltaack were constructed by disrupting lactate dehydrogenase gene ccel2485 and acetate kinase gene ccel2136 in H10DeltamspI, respectively, without DNA methylation, and the stability of the double mutation was confirmed after the 100th generation. The mutant H10DeltamspI constructed here can be used as a platform for further targeted gene manipulation conveniently and efficiently. It will greatly facilitate the metabolic engineering of C. cellulolyticum aiming at faster cellulose degradation and higher biofuel production at the molecular level. PMID- 22450139 TI - Growth of Yersinia enterocolitica and Y. pseudotuberculosis in Yersinia selective enrichment broth according to Ossmer. AB - The growth of Yersinia enterocolitica and Yersinia pseudotuberculosis in Yersinia enrichment broth according to Ossmer (YSEO) was investigated. Y. enterocolitica reached a higher concentration than Y. pseudotuberculosis but both always exceeded 10(6)CFU/ml. The medium may be useful for the detection of both species in foods. PMID- 22450141 TI - [Chronic stress and epigenetics. Relation between academic sciences and theology]. AB - The author gives a short account on the principles of Selye's stress theory, and discusses similarities and dissimilarities of acute and chronic stress. Both the external, and the internal environment, as well as the psycho-mental status are involved in the notion of the environment. Basic principles of epigenetics are reviewed: interaction between environment and genes, neuroendocrine and enzymatic mechanisms involved in silencing and activation of genes, notions of phenotypic plasticity, and epigenetic reprogramming are discussed. Epigenetic mechanisms of interrelation between pathological clinical states (diseases) and the characteristic phenotypes, causative role of psycho-mental status in evoking pathological somatic alterations, and the potential therapeutic consequences are briefly discussed. The etiological role of chronic, civilization stress in producing the worldwide increment of cardiovascular morbidity is cited, argumentation and criticism of the current therapeutical practice is discussed. The author concludes that recent advances in epigenetic knowledge seem to solve the controversy between the academic and theological sciences. PMID- 22450142 TI - [Leukemia- and lymphoma-associated flow cytometric, cytogenetic, and molecular genetic aberrations in healthy individuals]. AB - Most leukemia and lymphoma cases are characterized by specific flow cytometric, cytogenetic and molecular genetic aberrations, which can also be detected in healthy individuals in some cases. The authors review the literature concerning monoclonal B-cell lymphocytosis, and the occurrence of chromosomal translocations t(14;18) and t(11;14), NPM-ALK fusion gene, JAK2 V617F mutation, BCR-ABL1 fusion gene, ETV6-RUNX1(TEL-AML1), MLL-AF4 and PML-RARA fusion gene in healthy individuals. At present, we do not know the importance of these aberrations. From the authors review it is evident that this phenomenon has both theoretical and practical (diagnostic, prognostic, and therapeutic) significance. PMID- 22450143 TI - [The effect of early immunosuppressive therapy on the rate of resections performed in patients with Chron's disease, in Veszprem county, Hungary, a population-based cohort study]. AB - Medical therapy for Crohn's disease has changed significantly over the past 20 years with the increasing use of immunosuppressants. In contrast, surgery rates are still high and evidence about the the changes in the outcome of Crohn's disease over the past decades is scarce. AIMS: The objective of this study was to analyze the evolution of the surgical rates and medical therapy in the population based Veszprem county database. METHODS: Data of 506 Crohn's disease patients were analyzed (age at diagnosis: 31.5 years, SD: 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. The study population was divided into three groups based on the year of diagnosis (cohort A: 1977-1989, cohort B: 1990-1998 and cohort C: 1999-2008). RESULTS: Overall azathioprine, systemic steroid, and biological (only available after 1998) exposure was 45.8, 68.6, and 9.5%, respectively. The 1 and 5-year probabilities of azathioprine use were 3.2 and 6.2% in cohort A, 11.4 and 29.9% in cohort B, and 34.8 and 46.2% in cohort C. In multivariate analysis, decade of diagnosis (P<0.001), age at onset (P = 0.008), disease behavior at diagnosis (P<0.001), and need for systemic steroids (P<0.001) were significantly associated with the time to initiation of azathioprine therapy. Early azathioprine use was significantly associated with the time to intestinal surgery in Crohn's disease patients; in a multivariate Cox analysis (HR: 0.43, 95% confidence interval (CI): 0.28-0.65) and after matching on propensity scores for azathioprine use (HR: 0.42,95% CI:0.26 0.67). CONCLUSIONS: This population-based inception cohort showed that reduction in surgical rates was independently associated with increased and earlier azathioprine use. PMID- 22450144 TI - [Chylothorax as a complication of coronary artery bypass grafting operation]. AB - The authors present the case of a 72-year-old woman who underwent coronary bypass grafting. Left sided chylothorax due to accidental dissection of a thoracic duct branch developed 2 months after sternotomy. As conservative therapy has failed, surgical pleurodesis was performed successfully. Chylothorax is a rare and underestimated complication of coronary bypass grafting. The worldwide increasing number of coronary artery bypass grafting surgeries makes it important to pay attention to this condition. Thus diagnosis of the chyle is relatively easy by its high chylomicron and triglyceride content, but identification of the etiology and its treatment is sometimes challenging for the physician. The treatment of chylothorax is usually conservative. The main goal is to keep the volume of the chyle under control. The number of surgical interventions because of chylothorax is increasing due to an increase of iatrogenic etiology. PMID- 22450145 TI - [Dr. Laszlo Csipo (1925-2002)]. PMID- 22450146 TI - Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies. AB - Glutathione S-transferases (GSTs) are members of a multigene family of isoenzymes that are important in the control of oxidative stress and in phase II metabolism. Acting non-enzymically, GSTs can modulate signalling pathways of cell proliferation, cell differentiation and apoptosis. Using a molecular epidemiology approach, we have investigated a potential involvement of GSTs in DNA damage processing, specifically the modulation of DNA repair in a group of 388 healthy adult volunteers; 239 with at least 5 years of occupational exposure to asbestos, stone wool or glass fibre, and 149 reference subjects. We measured DNA damage in lymphocytes using the comet assay (alkaline single cell gel electrophoresis): strand breaks (SBs) and alkali-labile sites, oxidised pyrimidines with endonuclease III, and oxidised purines with formamidopyrimidine DNA glycosylase. We also measured GST activity in erythrocytes, and the capacity for base excision repair (BER) in a lymphocyte extract. Polymorphisms in genes encoding three GST isoenzymes were determined, namely deletion of GSTM1 and GSTT1 and single nucleotide polymorphism Ile105Val in GSTP1. Consumption of vegetables and wine correlated negatively with DNA damage and modulated BER. GST activity correlated with oxidised bases and with BER capacity, and differed depending on polymorphisms in GSTP1, GSTT1 and GSTM1. A significantly lower BER rate was associated with the homozygous GSTT1 deletion in all asbestos site subjects and in the corresponding reference group. Multifactorial analysis revealed effects of sex and exposure in GSTP1 Ile/Val heterozygotes but not in Ile/Ile homozygotes. These variants affected also SBs levels, mainly by interactions of GSTP1 genotype with exposure, with sex, and with smoking habit; and by an interaction between sex and smoking. Our results show that GST polymorphisms and GST activity can apparently influence DNA stability and repair of oxidised bases, suggesting a potential new role for these proteins in DNA damage processing via DNA damage signalling. PMID- 22450147 TI - Resection of acquired mucosal web in Crohn disease. PMID- 22450148 TI - Larynx preservation. AB - PURPOSE OF REVIEW: Organ preservation, in particular larynx preservation, is a major challenge that has been evaluated during the past 3 decades. This review took in consideration the most recently published articles on this topic. RECENT FINDINGS: There are no new data on this topic but mainly confirming data. Most of the reports underscored that there was still a place for upfront surgery (either partial or total laryngectomy). Nonsurgical approaches are radiotherapy alone or chemotherapy-based protocols with either induction or concomitant chemotherapy added to radiotherapy (with conventional or accelerated fractionation). Different authors underscored that daily practice must follow carefully the selection of patients and monitoring of treatment when applying protocols evaluated in randomized clinical trials. SUMMARY: Larynx preservation is an undisputable advance in larynx cancer management. For early diseases, either surgery (open or endoscopic) or irradiation may control the disease and preserve the larynx function. For advanced cases, chemotherapy-based protocols have been validated, but the best protocol is still to be defined. Importantly some cases still require upfront total laryngectomy. A multidisciplinary approach for decision making is mandatory, whatever the stage. PMID- 22450149 TI - Active surveillance for prostate cancer: past, present and future. AB - PURPOSE OF REVIEW: This article reviews recent developments in the use of active surveillance for localized prostate cancer. RECENT FINDINGS: The treatment of localized prostate cancer continues to be a major challenge for urologic oncologists. Screening with prostate-specific antigen has resulted in increased numbers of low-risk prostate cancers being detected. Aggressive whole-gland therapy with surgery, or radiation therapy is associated with potentially life altering treatment-related side effects such as urinary incontinence, bowel toxicity and erectile dysfunction. The goal of active surveillance is to avoid or delay the adverse events associated with prostate cancer therapy while still allowing for curative intervention in the future, if needed. SUMMARY: Active surveillance is a reasonable treatment option for many men with low-risk, and some men with intermediate-risk, prostate cancer. Additional research is needed to determine the optimal active surveillance inclusion criteria, monitoring schedule, and treatment triggers. It is hoped that advances in prostate imaging, biomarkers, and focal therapy will foster greater use of active surveillance in appropriately selected men to optimize quality-of-life without compromising cancer outcomes. PMID- 22450150 TI - Rectal cancer: state of the art in 2012. AB - PURPOSE OF REVIEW: To discuss the recent developments of multimodal treatment for patients with local advanced rectal cancer, including incorporation of new chemotherapeutic and targeted agents, and the optimal sequence and timing of treatment components. RECENT FINDINGS: Five randomized trials have been completed to determine whether the addition of oxaliplatin to preoperative, fluorouracil based chemoradiotherapy (CRT) offers an advantage compared to single-agent fluorouracil CRT. Early results from the ACCORD 12, STAR-01, and NSAPB R-04 trials did not confirm a significant improvement of early efficacy endpoints with the addition of oxaliplatin, whereas the German CAO/ARO/AIO-04 did. Most of the phase II trials incorporating cetuximab into CRT reported disappointingly low rates of pathologic complete response (pCR); the combination of CRT with VEGF inhibition showed encouraging pCR rates; however, it was associated with increased surgical complications. Novel clinical trials address the role of induction chemotherapy, of delayed, minimal or omitted surgery following CRT, or the omission of radiotherapy for selected patients. SUMMARY: At this time, the use of oxaliplatin or targeted agents as component of multimodality treatment for rectal cancer outside of a clinical trial is not recommended. The inclusion of different treatment options, according to tumor stage, location, imaging features, and response, will render the multimodal treatment approach of rectal cancer more risk-adapted. PMID- 22450151 TI - Low-level laser therapy in the prevention and treatment of cancer therapy-induced mucositis: 2012 state of the art based on literature review and meta-analysis. AB - PURPOSE OF REVIEW: To discuss the promising state of the art low-level laser therapy (LLLT) for preventive and therapeutic usage in oral mucositis due to cancer therapy. RECENT FINDINGS: Photomedicine using LLLT is very effective with intraoral and extraoral devices in the management of oral mucositis, based on several studies including randomized control studies. A systematic review identified 33 relevant articles that were subjected to meta-analysis based on which laser parameters in routine practice are being defined. Meta-analysis showed that LLLT reduced risk of oral mucositis with relative risk (RR) 2.45 [confidence interval (CI) 1.85-3.18], reduced duration, severity of oral mucositis and reduced number of days with oral mucositis (4.38 days, P = 0.0009). RR was similar between the red (630-670 nm) and infrared (780-830 nm) LLLT. Pain relieving effect based on the Cohen scale was at 1.22 (CI 0.19-2.25). SUMMARY: No adverse side effects of LLLT were reported; hence, we recommend red or infrared LLLT with diode output between 10-100 mW, dose of 2-3 J/cm2/cm2 for prophylaxis and 4 J/cm2 (maximum limit) for therapeutic effect, application on single spot rather than scanning motion. Lesions must be evaluated by a trained clinician and therapy should be repeated daily or every other day or a minimum of three times per week until resolution. There is moderate-to-strong evidence in favor of LLLT at optimal doses as a well tolerated, relatively inexpensive intervention for cancer therapy-induced oral mucositis. It is envisaged that LLLT will soon become part of routine oral supportive care in cancer. PMID- 22450152 TI - Glycerol accumulation in edema formation following diffuse traumatic brain injury. AB - Traumatic brain injury (TBI) induces brain edema via water and glycerol transport channels, called aquaporins (AQPs). The passage of glycerol across brain cellular compartments has been shown during edema. Using a modified impact/head acceleration rodent model of diffuse TBI, we assessed the role of hypoxia inducible factor (HIF)-1alpha in regulating AQP9 expression and glycerol accumulation during the edema formation. Adult (400-425 g) male Sprague-Dawley rats received a closed head injury with a weight drop (450 g, 2-m height) and were allowed to survive up to 48 hours. Some rat groups were administered 2 methoxyestradiol (2ME2, a HIF-1alpha inhibitor) 30 minutes after injury and were euthanized at 4 and 24 hours after injury. Brain edema was measured directly by water content, and glycerol concentration was determined by the Cayman Glycerol Assay. HIF-1alpha and AQP9 protein levels were assessed by Western immunoblotting. This study demonstrated a significant (P<0.05) increase in brain water content at 4-48 hours following impact. Cerebral glycerol was significantly (P<0.05) up-regulated at as early as 1 hour and remained at high levels for up to 48 hours. Similarly, significant (P<0.05) increases in HIF-1alpha and AQP9 protein levels were found at 1 hour and up to 48 hours after injury. Compared to untreated but injured rats, inhibition of HIF-1alpha by 2ME2 significantly (P<0.05) reduced the TBI-induced AQP9 up-regulation. This reduction was temporally associated with significant (P<0.05) decreases in both edema and glycerol accumulation. The data suggested an associated induction of HIF-1alpha, AQP9, and extracellular glycerol accumulation in edema formation following diffuse TBI. The implication of HIF-1alpha and AQP9 underlying TBI-induced edema formation offers possibilities for novel TBI therapies. PMID- 22450153 TI - Relationship of perfluorooctanoic acid exposure to pregnancy outcome based on birth records in the mid-Ohio Valley. AB - BACKGROUND: Perfluorooctanoic acid (PFOA) is a potential cause of adverse pregnancy outcomes, but previous studies have been limited by low exposures and small study size. OBJECTIVES: Using birth certificate information, we examined the relation between estimated PFOA exposure and birth outcomes in an area of West Virginia and Ohio whose drinking water was contaminated by a chemical plant. METHODS: Births in the study area from 1990 through 2004 were examined to generate case groups of stillbirth (n = 106), pregnancy-induced hypertension (n = 224), preterm birth (n = 3,613), term low birth weight (n = 918), term small-for gestational-age (SGA) (n = 353), and a continuous measure of birth weight among a sample of term births (n = 4,534). A 10% sample of term births >= 2,500 g were selected as a source of controls (n = 3,616). Historical estimates of serum PFOA were derived from a previously developed fate and transport model. In a second study, we examined 4,547 area births linked to a survey with residential history data. RESULTS: In the analysis based only on birth records, we found no consistent evidence of an association between estimated PFOA exposure and stillbirth, pregnancy-induced hypertension, preterm birth, or indices of fetal growth. In the analysis of birth records linked to the survey, PFOA was unrelated to pregnancy-induced hypertension or preterm birth but showed some suggestion of an association with early preterm birth. Measures of growth restriction showed weak and inconsistent associations with PFOA. CONCLUSIONS: Based on the analysis using the health survey, these results provide little support for an effect of PFOA exposure on most pregnancy outcomes, except for early preterm birth and possibly fetal growth restriction. PMID- 22450154 TI - In vivo up-regulation of the unfolded protein response after hypoxia. AB - BACKGROUND: Low oxygen (O2) availability, a condition called hypoxia, has different and profound consequences in tissues and organs. Besides the hypoxia inducible response, mammalian cells induce a coordinated cytoprotective pathway called Unfolded Protein Response (UPR). We studied the molecular basis of UPR and apoptosis in animal models exposed to different hypoxic stresses and assessed the ability of liver and myocardium to respond to low oxygen by activating different arms of the UPR according to the severity of the insults in a tissue specific manner. METHODS: We assessed the levels of several UPR markers in hypoxic animals by Real Time PCR and Western blotting. RESULTS: While the hepatocytes activate the apoptotic pathway mediated, in part, by CHOP and p-JNK, we could not detect an UPR-dependent apoptosis in myocytes. Moreover, severe hypoxia results in ATF4 translation, and induction of CHOP and GADD34 transcripts in liver, by contrast in the myocardium, the ATF4-CHOP-GADD34 signaling pathway is not detectably activated. GENERAL SIGNIFICANCE: Comparison of several UPR markers in liver and myocardium enabled to underscore the ability of hepatocytes and myocites to selectively activate and fine tune the UPR signaling pathway during hypoxia in vivo. PMID- 22450155 TI - Cytotoxic effects of copper overload on human-derived lung and liver cells in culture. AB - BACKGROUND: Copper (Cu) is an essential trace metal used as a catalytic cofactor for many enzymes. However, it can have nocive effects when it participates in the Fenton reaction, producing reactive oxygen species (ROS). Excess Cu is present in the plasma of patients with diseases in which cell survival is crucial. In order to investigate the effect of Cu overload on the induction of cellular damage we chose two human cell lines derived from liver (HepG2) and lung (A-549) as representative cells exposed to exogenous (polluted air) and/or endogenous (systemic) Cu overload. METHODS: We studied ROS production using thiobarbituric acid reactive substances (TBARS) and fluorimetric measurements with dichlorofluorescein, cell viability by the trypan dye exclusion test, the methyltetrazolium (MTT) and lactate dehydrogenase leakage (LDH) assays, various cytotoxic indexes, and caspasa-3 and calpain-dependent activation as the main signals involved in the apoptosis pathway. RESULTS: Cu overload induces cell death by a differential activation of calpains (m- and MU-) and caspase-3, and modifies various proliferative indexes in a cell-type and concentration-dependent manner. The involvement of these two protease systems and the response of the two main Cu homoestatic proteins ceruloplasmin and metallothioneins are specific to each cell type. We demonstrated that Cu can trigger cell death by activation of specific protease systems and modify various proliferative indexes in a cell-type and concentration-dependent manner. GENERAL SIGNIFICANCE: These findings contribute to understanding the diverse effects of Cu overload on the pathogenesis of human diseases like cancer, cirrhosis and degenerative disorders. PMID- 22450156 TI - The road to nuclear receptors of thyroid hormone. AB - BACKGROUND: Early studies on the mechanism of action of thyroid hormone (TH) measured changes in enzyme activities following the addition of l-thyroxine (T4) and 3, 3', 5-triiodothyronine (T3) to tissue extracts and purified enzymes. SCOPE OF REVIEW: As techniques for isolation of mitochondria, ribosomes, nuclei and chromatin, were increasingly refined, it became possible to study complex cellular processes, such as oxidative phosphorylation, protein synthesis, transcription and chromosomal structure. Uncoupling of oxidative phosphorylation and direct action on protein synthesis as mechanisms of action of TH, proposed in the 1950s and 1960s, were found to be untenable as mechanisms of physiological action because of inappropriate experimental conditions. MAJOR CONCLUSIONS: Several findings in the 1960s and 1970s, mainly 1) that near-physiological doses of T3 stimulated transcription measured in vivo or in nuclei isolated from tissues of rats and frog tadpoles, 2) the inhibition of hormone action by inhibitors of transcription and 3) the rapid and almost identical kinetics of accumulation of labelled hormone and RNA synthesis in target cell nuclei, pointed to the cell nucleus as a major site of its action. The application of technologies of recombinant DNA, gene cloning and DNA sequencing in the mid-1980s allowed the identification and understanding of the structure and function of nuclear receptors of TH. GENERAL SIGNIFICANCE: This review traces the road leading to the nuclear receptors of thyroid hormone, thus explaining how the hormone influences gene expression. It also illustrates the importance of how new concepts originate from the progression of technological innovations. This article is part of a Special Issue entitled Thyroid hormone signalling. PMID- 22450157 TI - Galectin-3 endocytosis by carbohydrate independent and dependent pathways in different macrophage like cell types. AB - BACKGROUND: Galectin-3 (the Mac-2 antigen) is abundantly expressed in both macrophage like cells and certain non-macrophage cells. We have studied endocytosis of galectin-3 as one important step relevant for its function, and compared it between variants of a macrophage like cell line, and non-macrophage cells. METHODS: Endocytosis of galectin-3 was observed by fluorescence microscopy and measured by flow cytometry. The endocytosis mechanism was analysed using galectin-3 mutants, galectin-3 inhibitors and endocytic pathways inhibitors in the human leukaemia THP-1 cell line differentiated into naive (M0), classical (M1) or alternatively activated (M2) macrophage like cells, and the non macrophage cell lines HFL-1 fibroblasts and SKBR3 breast carcinoma. RESULTS: Galectin-3 endocytosis in non-macrophage cells and M2 cells was blocked by lactose and a potent galectin-3 inhibitor TD139, and also by the R186S mutation in the galectin-3 carbohydrate recognition domain (CRD). In M1 cells galectin-3 endocytosis could be inhibited only by chlorpromazine and by interference with the non-CRD N-terminal part of galectin-3. In all the cell types galectin-3 entered early endosomes within 5-10 min, to be subsequently targeted mainly to non-degradative vesicles, where it remained even after 24 h. CONCLUSIONS: Galectin-3 endocytosis in M1 cells is receptor mediated and carbohydrate independent, while in M2 cells it is CRD mediated, although the non-CRD galectin 3 domain is also involved. General significance The demonstration that galectin-3 endocytosis in M1 macrophages is carbohydrate independent and different from M2 macrophages and non-macrophage cells, suggests novel, immunologically significant interactions between phagocytic cells, galectin-3 and its ligands. PMID- 22450158 TI - The views of patients with severe chronic obstructive pulmonary disease on advance care planning: a qualitative study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide and there are concerns that end-of-life care for these patients is inadequate. Advance care planning is encouraged, with the hope that it will improve communication and avoid unwanted interventions, which have been particular concerns; in practice, these discussions rarely occur. We have little knowledge of the views of patients with COPD on advance care planning. Understanding this could help integrate advance care planning into the routine management of patients with COPD. AIM: To explore the views of people with severe COPD about advance care planning. DESIGN: Qualitative design, with data collection incorporating audio recorded semi-structured interviews. Analysis followed a grounded theory approach. SETTING/PARTICIPANTS: Patients with severe COPD (n =10, Gold Standards Framework criteria) were recruited from primary and secondary care settings. RESULTS: Participants felt they had not been given enough information about their diagnosis and prognosis, and were keen for more discussion with healthcare professionals. They wanted more involvement in decisions about their treatment when those decisions were required. Participants were happy to discuss their general views about future care, but felt uncomfortable with the traditional model of binding 'advance directives'. CONCLUSIONS: Considering advance care planning as a repeated process of discussion of prognosis, concerns and probable preferences for care would be more useful than encouraging binding advance decisions. Further research should assess the effectiveness of this approach. Local coordination of who is responsible for information provision is needed, and greater involvement of patients with COPD in management decisions as they arise. PMID- 22450159 TI - Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: a systematic review. AB - BACKGROUND: Cancer cachexia is a devastating syndrome of advanced malignancy which negatively impacts on patients' morbidity, mortality and quality of life. Chronic inflammation is a key characteristic of cancer cachexia. Therefore, non steroidal anti-inflammatory drugs (NSAIDs) may be able to break the cycle of cachexia. AIM: To systematically review the literature on the use of NSAIDs for the treatment of cachexia in advanced cancer patients. DESIGN: All titles retrieved through searching were downloaded to a reference management database, duplicates were removed and the remaining citations were checked for eligibility. Full copies of all eligible articles were obtained and reviewed. DATA SOURCES: Electronic searches (from inception up to 09/2011) included CINAHL, MEDLINE, EMBASE, and Web of Science. Reference lists from reviewed articles, trial registers and abstracts from relevant conferences were searched. Eligibility criteria were (a) Randomised Controlled Trial; (b) participants were adults with cancer with weight loss or a clinical diagnosis of cachexia; (c) administration of oral NSAIDs. RESULTS: Four studies were included. These studies provided some evidence of positive therapeutic effect on quality of life, performance status, inflammatory markers, weight gain and survival, but there was insufficient evidence demonstrated for their widespread use in practice. CONCLUSIONS: Insufficient studies have been performed to allow a conclusion to be formed with regard to the effectiveness of NSAIDs in the treatment of cachexia in advanced cancer. Major challenges in this patient cohort include the lack of uniformity of inclusion criteria across studies and the frailty of the patients recruited. PMID- 22450160 TI - Development of a Carer Support Needs Assessment Tool (CSNAT) for end-of-life care practice at home: a qualitative study. AB - BACKGROUND: Current end-of-life care policy and guidance recognises the important contribution of family carers, recommending that their needs should be assessed to support them in their caring role. How regular carer assessment is to be achieved is unclear, particularly because there is no evidence-based tool for directly assessing carers' support needs that is suitable for use in end-of-life home care practice. AIMS: To obtain carers' perspectives of key aspects of support needed during provision of end-of-life care at home and to develop a carer support needs assessment tool suitable for use in everyday practice. DESIGN: Qualitative using focus groups and telephone interviews. Thematic analysis uses a framework approach. SETTING/PARTICIPANTS: 75 adult bereaved carers who were family members/friends of patients referred to five Hospice at Home services in the UK. RESULTS: Carers' needs fell into two distinct groupings of key support areas or 'domains': support to enable them to provide care for their relative and more direct personal support for themselves. Many aspects of supportive input were common across domains, for example, anticipatory information, explanations or being included in the care process. Therefore, the tool was designed as a screening measure, to identify support needs requiring further detailed assessment. CONCLUSIONS: The Carer Support Needs Assessment Tool (CSNAT) is an evidence-based direct measure of carers' support needs in 14 domains. It is short but comprehensive in approach and thus suitable for both end of-life care research and practice. Further work has been undertaken to test its psychometric properties. PMID- 22450161 TI - Recombinant expression, in vitro refolding, and biophysical characterization of the N-terminal domain of T1R3 taste receptor. AB - The sweet taste receptor is a heterodimeric receptor composed of the T1R2 and T1R3 subunits, while T1R1 and T1R3 assemble to form the umami taste receptor. T1R receptors belong to the family of class C G-protein coupled receptors (GPCRs). In addition to a transmembrane heptahelical domain, class C GPCRs have a large extracellular N-terminal domain (NTD), which is the primary ligand-binding site. The T1R2 and T1R1 subunits have been shown to be responsible for ligand binding, via their NTDs. However, little is known about the contribution of T1R3-NTD to receptor functions. To enable biophysical characterization, we overexpressed the human NTD of T1R3 (hT1R3-NTD) using Escherichia coli in the form of inclusion bodies. Using a fractional factorial screen coupled to a functional assay, conditions were determined for the refolding of hT1R3-NTD. Far-UV circular dichroism spectroscopic studies revealed that hT1R3-NTD was well refolded. Using size-exclusion chromatography, we found that the refolded protein behaves as a dimer. Ligand binding quantified by tryptophan fluorescence quenching and microcalorimetry showed that hT1R3-NTD is functional and capable of binding sucralose with an affinity in the millimolar range. This study also provides a strategy to produce functional hT1R3-NTD by heterologous expression in E. coli; this is a prerequisite for structural determination and functional analysis of ligand-binding regions of other class C GPCRs. PMID- 22450162 TI - Expression and purification of bioactive high-purity human S100A6 in Escherichia coli. AB - S100A6, as a member of S100 protein family, have biological functions in cell proliferation, differentiation, morphology, cytoskeletal organization and apoptosis. In the last three decades, S100A6 has been caught more and more attention. Here, we introduced a simple and efficient method for producing high purity recombinant human S100A6 from Escherichia coli culture with low level of endotoxin. We further demonstrated its biological activities for triggering SH SY5Y cells apoptosis in vitro. These results can facilitate the study of physiological and pathological roles of S100A6 and other members of S100 family proteins. PMID- 22450163 TI - High-level expression of Falcipain-2 in Escherichia coli by codon optimization and auto-induction. AB - Falcipain-2, the major cysteine hemoglobinase from the human malaria parasite Plasmodium falciparum, is critical for parasite development and is considered a promising chemotherapeutic target. In order to facilitate the high-throughput screening of Falcipain-2 inhibitors from natural sources, we developed an economic and highly-productive overexpression system in Escherichia coli using a codon-optimized proFalcipain-2 construct. Very high expression levels (35-55% of total host proteins) were observed when proFalcaipain-2 expression was induced with 1mM isopropyl-1-thio-beta-D-galactopyranoside (IPTG) in several E. coli strains, with the highest level observed for BL21(DE3). A lower expression (~40% of total host proteins) was observed when BL21(DE3) was grown in ZYM-5052 auto induction medium, containing 0.2% lactose as inducer. However, the culture grew to notably higher cellular density, increasing ~1.5 times the overall yield of the system when compared with conventional IPTG-induction. Although several conditions were modified to achieve the expression of soluble and active Falcipain-2, the enzyme was mainly obtained in the form of insoluble aggregates. After purification and refolding, ~50 mg of active enzyme were obtained per liter of culture at low cost using a regular incubator shaker, and recombinant Falcipain-2 exhibited structural and functional characteristics very similar to the natural counterpart. Due to its versatility and simplicity, this strategy can be straightforwardly adapted to other proteins from Plasmodium species or any other organism with an AT-rich genome. PMID- 22450164 TI - Molecular cloning, expression, and characterization of a Ca2+-dependent nuclease of Arabidopsis thaliana. AB - A gene encoding a Ca(2+)-dependent nuclease (AtCaN2) consisting of 226 amino acids from Arabidopsis thaliana was isolated. The AtCaN2 gene was expressed in Escherichia coli as a His fusion protein. The His-AtCaN2 fusion protein was purified by affinity chromatography using a Ni-NTA column. Western blot analysis using an anti-His antibody showed that the His-AtCaN2 fusion protein was not degraded. The nuclease activity of the His-AtCaN2 fusion protein was highest at 37 degrees C, required a neutral or weakly-alkaline environment, and was stimulated by Ca(2+) and Mg(2+), but inhibited by Zn(2+) and high concentration of Mn(2+). PMID- 22450165 TI - Modelling cyanobacteria: from metabolism to integrative models of phototrophic growth. AB - Cyanobacteria are phototrophic microorganisms of global importance and have recently attracted increasing attention due to their capability to convert sunlight and atmospheric CO(2) directly into organic compounds, including carbon based biofuels. The utilization of cyanobacteria as a biological chassis to generate third-generation biofuels would greatly benefit from an increased understanding of cyanobacterial metabolism and its interplay with other cellular processes. In this respect, metabolic modelling has been proposed as a way to overcome the traditional trial and error methodology that is often employed to introduce novel pathways. In particular, flux balance analysis and related methods have proved to be powerful tools to investigate the organization of large scale metabolic networks-with the prospect of predicting modifications that are likely to increase the yield of a desired product and thereby to streamline the experimental progress and avoid futile avenues. This contribution seeks to describe the utilization of metabolic modelling as a research tool to understand the metabolism and phototrophic growth of cyanobacteria. The focus of the contribution is on a mathematical description of the metabolic network of Synechocystis sp. PCC 6803 and its analysis using constraint-based methods. A particular challenge is to integrate the description of the metabolic network with other cellular processes, such as the circadian clock, the photosynthetic light reactions, carbon concentration mechanism, and transcriptional regulation aiming at a predictive model of a cyanobacterium in silico. PMID- 22450166 TI - Evidence for the presence of functional lipid rafts in immune cells of ectothermic organisms. AB - The role of lipid rafts in non-mammalian leukocytes has been scarcely investigated. We performed biochemical and functional analysis of lipid rafts in fish leukocytes. Fish Flotillin-1 and a fish GM1-like molecule (fGM1-L) were found in low density detergent-resistant membranes (LD-DRM) in goldfish macrophages and catfish B lymphocytes, similarly to mammals. The presence of flotillin-1 and fGM1-L in LD-DRM was sensitive to increased detergent concentrations, and cholesterol extraction. Confocal microscopy analysis of flotillin-1 and fGM1-L in fish leukocytes showed a distinctive punctuated staining pattern, suggestive of pre-existing rafts. Confocal microscopy analysis of macrophages showed that the membrane of phagosomes containing serum-opsonized zymosan was enriched in fGM1-L, and zymosan phagocytosis was reduced after cholesterol extraction. The presence of flotillin-1 and fGM1-L in LD-DRM, the microscopic evidence of flotillin-1 and fGM1-L on fish macrophages and B-cells, and the sensitivity of phagocytosis to cholesterol extraction, indicate that lipid rafts are biochemically and functionally similar in leukocytes from fish and mammals. PMID- 22450167 TI - Transcriptomic analysis of Ruditapes philippinarum hemocytes reveals cytoskeleton disruption after in vitro Vibrio tapetis challenge. AB - The Manila clam, Ruditapes philippinarum, is an economically-important, commercial shellfish; harvests are diminished in some European waters by a pathogenic bacterium, Vibrio tapetis, that causes Brown Ring disease. To identify molecular characteristics associated with susceptibility or resistance to Brown Ring disease, Suppression Subtractive Hybridization (SSH) analyzes were performed to construct cDNA libraries enriched in up- or down-regulated transcripts from clam immune cells, hemocytes, after a 3-h in vitro challenge with cultured V. tapetis. Nine hundred and ninety eight sequences from the two libraries were sequenced, and an in silico analysis identified 235 unique genes. BLAST and "Gene ontology" classification analyzes revealed that 60.4% of the Expressed Sequence Tags (ESTs) have high similarities with genes involved in various physiological functions, such as immunity, apoptosis and cytoskeleton organization; whereas, 39.6% remain unidentified. From the 235 unique genes, we selected 22 candidates based upon physiological function and redundancy in the libraries. Then, Real Time PCR analysis identified 3 genes related to cytoskeleton organization showing significant variation in expression attributable to V. tapetis exposure. Disruption in regulation of these genes is consistent with the etiologic agent of Brown Ring disease in Manila clams. PMID- 22450168 TI - Engineering antibodies by yeast display. AB - Since its first application to antibody engineering 15 years ago, yeast display technology has been developed into a highly potent tool for both affinity maturing lead molecules and isolating novel antibodies and antibody-like species. Robust approaches to the creation of diversity, construction of yeast libraries, and library screening or selection have been elaborated, improving the quality of engineered molecules and certainty of success in an antibody engineering campaign and positioning yeast display as one of the premier antibody engineering technologies currently in use. Here, we summarize the history of antibody engineering by yeast surface display, approaches used in its application, and a number of examples highlighting the utility of this method for antibody engineering. PMID- 22450169 TI - Cofilin weakly interacts with 14-3-3 and therefore can only indirectly participate in regulation of cell motility by small heat shock protein HspB6 (Hsp20). AB - It has been previously reported that phosphorylated cofilin interacted with 14-3 3zeta protein to generate a sub-micromolar K(d) binary complex. Here we challenge this hypothesis by analyzing the direct association of recombinant cofilin with 14-3-3zeta using different in vitro biochemical methods. Phosphorylated cofilin at high concentration binds to 14-3-3 immobilized on nitrocellulose, however no complex formation was detected by means of native gel electrophoresis or chemical crosslinking. Intact dimeric or mutant monomeric 14-3-3 was unable to form stable complexes with phosphorylated or unphosphorylated cofilin detected by size exclusion chromatography. In co-sedimentation assay 14-3-3 did not affect interaction of cofilin with F-actin. The data of native gel electrophoresis indicate that 14-3-3 did not affect interaction of cofilin with G-actin. Thus, cofilin only weakly interacts with 14-3-3 and therefore cannot directly compete with phosphorylated small heat shock protein HspB6 for its binding to 14-3-3. It is hypothesized that phosphorylated HspB6 might affect interaction of 14-3-3 with protein phosphatases (and/or protein kinases) involved in dephosphorylation (or phosphorylation) of cofilin and by this means regulate cofilin-dependent reorganization of cytoskeleton. PMID- 22450170 TI - Modulation of the reactivity of the thiol of human serum albumin and its sulfenic derivative by fatty acids. AB - The single cysteine residue of human serum albumin (HSA-SH) is the most abundant plasma thiol. HSA transports fatty acids (FA), a cargo that increases under conditions of diabetes, exercise or adrenergic stimulation. The stearic acid-HSA (5/1) complex reacted sixfold faster than FA-free HSA at pH 7.4 with the disulfide 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) and twofold faster with hydrogen peroxide and peroxynitrite. The apparent pK(a) of HSA-SH decreased from 7.9+/-0.1 to 7.4+/-0.1. Exposure to H(2)O(2) (2mM, 5min, 37 degrees C) yielded 0.29+/-0.04mol of sulfenic acid (HSA-SOH) per mole of FA-bound HSA. The reactivity of HSA-SOH with low molecular weight thiols increased ~threefold in the presence of FA. The enhanced reactivity of the albumin thiol at neutral pH upon FA binding can be rationalized by considering that the corresponding conformational changes that increase thiol exposure both increase the availability of the thiolate due to a lower apparent pK(a) and also loosen steric constraints for reactions. Since situations that increase circulating FA are associated with oxidative stress, this increased reactivity of HSA-SH could assist in oxidant removal. PMID- 22450171 TI - Amphetamine-induced rotation and L-DOPA-induced dyskinesia in the rat 6-OHDA model: a correlation study. AB - The present study investigated whether the rotation rate induced by amphetamine in 6-OHDA-lesioned rats was predictive of development of L-DOPA-induced dyskinesia (LID) and success of the lesion procedure in our experimental settings. We collected data from 312 6-OHDA-lesioned rats (from different sets of experiments). Rats were subjected to the amphetamine-induced rotation test (2.5mg/kg) and chronically treated with L-DOPA (6 mg/kg) to establish dyskinesia. A poor correlation was present between amphetamine-induced rotation and LID. Moreover, no correlation was found between amphetamine-induced rotation and tyrosine hydroxylase (TH) positive cell number in the lesioned substantia nigra pars compacta, while there was a weak correlation between the percentage of TH positive cell number and LID. These results indicate that the amphetamine-induced rotation test is a poor predictor of the 6-OHDA-lesion success, as well as of the development of LID at the dose of amphetamine used here. Our data also suggest that all rats with amphetamine-induced rotation >= 3 turns/min should be included in dyskinesia studies, as they showed the same propensity to develop dyskinesia. Moreover, SERT expression levels suggest that reduced striatal and pallidal serotonin innervation might have contributed to the lower dyskinesia levels observed in a subset of amphetamine-responsive rats. PMID- 22450172 TI - Accountability in international disaster response. PMID- 22450173 TI - Comparative trial of a web-based tool to improve the quality of care provided to older adults in residency clinics: modest success and a tough road ahead. AB - PURPOSE: To determine whether residency programs can use a multicomponent, Web based quality improvement tool to improve the care of older adults. METHOD: The authors conducted an exploratory, cluster-randomized, comparative before-after trial of the Care of the Vulnerable Elderly Practice Improvement Module in the ambulatory clinics of 46 internal medicine and family medicine residency programs, 2006-2008. The main outcomes were the deltas between pre- and post performance on the Assessing Care of the Vulnerable Elderly (ACOVE) quality measures. RESULTS: Of the 46 programs initially selected for the study, 37 (80%) provided both baseline and follow-up data. Performance on all 10 ACOVE measures was poor at baseline (range 8.6%-33.6%). Intervention clinics most frequently chose for improvement fall-risk screening and documentation of end-of-life preferences. The change in the percentage of patients screened for fall risk for the intervention clinics that targeted this measure was significantly greater than the change observed by the control clinics (+23.3% versus +9.7%, P = .003, odds ratio [OR] = 2.0; 95% confidence interval [CI]: 1.25-3.75), as was the difference observed for documentation of preference for life-sustaining care (+16.4% versus +2.8%, P = .002, OR = 6.3; 95% CI: 2.0-19.6) and surrogate decision maker (+14.3% versus +2.8%, P = .003, OR = 6.8; 95% CI: 1.9-24.4). CONCLUSIONS: A multicomponent, Web-based, quality improvement tool can help residency programs improve care for older adults, but much work remains for improving the state of care for this population in training settings. PMID- 22450174 TI - Reflection in/and writing: pedagogy and practice in medical education. AB - During the past decade, "reflection" and "reflective writing" have become familiar terms and practices in medical education. The authors of this article argue that the use of the terms requires more thoughtfulness and precision, particularly because medical educators ask students to do so much reflection and reflective writing. First, the authors discuss John Dewey's thoughts on the elements of reflection. Then the authors turn the discussion to composition studies in an effort to form a more robust conception of reflective writing. In particular, they examine what the discipline of composition studies refers to as the writing process. Next, they offer two approaches to teaching composition: the expressivist orientation and the critical/cultural studies orientation. The authors examine the vigorous debate over how to respond to reflective writing, and, finally, they offer a set of recommendations for incorporating reflection and reflective writing into the medical curriculum. PMID- 22450175 TI - Predictors of workplace satisfaction for U.S. medical school faculty in an era of change and challenge. AB - PURPOSE: To examine the current state of satisfaction with the academic medicine workplace among U.S. medical school faculty and the workplace factors that have the greatest influence on global satisfaction. METHOD: The authors used data from the 2009 administration of a medical school faculty job satisfaction survey and used descriptive statistics and chi analyses to assess levels of overall satisfaction within faculty subgroups. Multiple regressions used the mean scores of the 18 survey dimensions and demographic variables to predict three global satisfaction measures. RESULTS: The survey was completed by 9,638 full-time faculty from 23 U.S. medical schools. Respondents were mostly satisfied on global satisfaction measures including satisfaction with their department (6,506/9,128; 71.3%) and medical school (5,796/9,124; 63.5%) and whether they would again choose to work at their medical school (5,968/8,506; 70.2%). The survey dimensions predicted global satisfaction well, with the final models explaining 51% to 67% of the variance in the dependent measures. Predictors across models include organization, governance, and transparency; focus of mission; recruitment and retention effectiveness; department relationships; workplace culture; and nature of work. CONCLUSIONS: Despite the relatively unpredictable environmental challenges facing medical schools today, leaders have opportunities to influence and improve the workplace satisfaction of their faculty. Examples of opportunities include fostering a culture characterized by open communication and occasions for faculty input, and remaining vigilant regarding factors contributing to faculty burnout. Understanding what drives faculty satisfaction is crucial for medical schools as they continue to seek excellence in all missions and recruit and retain high-quality faculty. PMID- 22450176 TI - Perspective: Integrating research into surgical residency education: lessons learned from orthopaedic surgery. AB - Orthopaedic research has advanced tremendously in parallel with accelerated progress in medical science. Possession of a fundamental understanding of basic and clinical science has become more essential than previously for orthopaedic surgeons to be able to translate advances in research into clinical practice. The number of medical graduates with prior education in scientific research who choose to pursue careers in orthopaedic surgery is small. Therefore, it is important that a core of research education be included during residency training to ensure the continued advancement of the clinical practice of orthopaedics. The authors examine some of the challenges to a comprehensive research experience during residency, including deficient priority, inadequate institutional infrastructure, financial strain on residency budgets, restricted time, and an insufficient number of mentors to encourage and guide residents to become clinician-scientists. They also present some strategies to overcome these challenges, including development and expansion of residency programs with clinician-scientist pathways, promotion of financial sources, and enhancement of opportunities for residents to interact with mentors who can serve as role models. Successful integration of research education into residency programs will stimulate future orthopaedic surgeons to develop the critical skills to lead musculoskeletal research, comprehend related discoveries, and translate them into patient care. Lessons learned from incorporating research training within orthopaedic residency programs will have broad application across medical specialties-in both primary and subspecialty patient care. PMID- 22450177 TI - Prevalence of bipolar disorder and schizophrenia in Houston Outreach Medicine, Education, and Social Services (HOMES) Clinic patients: implications for student managed clinics for underserved populations. AB - PURPOSE: Psychiatric conditions require aggressive management that is challenging to provide in free clinics. The purpose of this study was to determine the prevalence of certain mental illnesses and comorbid conditions among the patients of a student-managed free clinic for the homeless. METHOD: The authors conducted a retrospective analysis of the records of patients who visited the student-run Houston Outreach Medicine, Education, and Social Services (HOMES) Clinic from May 2007 through May 2008. They assessed the prevalence of bipolar disorder and schizophrenia among patients. They compared demographics, health insurance status, comorbid medical conditions, and social habit data of patients with these mental illnesses with those of other clinic patients. RESULTS: Of 286 patients (74.5% male, mean age 45.8 years), 25 (8.7%) had a diagnosis of schizophrenia and 45 (15.7%) had bipolar disorder. Compared with other clinic patients, patients with bipolar disorder or schizophrenia were less likely to be male (P < .0001) and were more likely to have publicly funded insurance (P = .024). They were also more likely to have certain comorbid conditions, including asthma (P = .0004), seizures (P = .0007), kidney disease (P = .01), and heart disease (P = .02). CONCLUSIONS: The high prevalence of these mental illnesses combined with the increased burden of medical comorbidity among HOMES Clinic patients has implications for student-managed free clinics, which often operate on limited budgets. Strategies for providing care for these patients in this setting include integrated care, street medicine, and case management. PMID- 22450178 TI - Physician-scientists in Japan: attrition, retention, and implications for the future. AB - PURPOSE: To investigate career trends for physician-scientists in Japan. METHOD: The authors analyzed 1996-2008 biennial census survey data from Japan's national physician registry to examine trends over time in the numbers and proportion of physician-scientists by sex and years since registration. They also analyzed the transition of registered physicians into and out of the physician-scientist field across two sets of two consecutive surveys (1996-1998 and 2006-2008). RESULTS: The number of physician-scientists between 1996 and 2008 was stable, with a low of 4,893 and a high of 5,325. The number of younger physician-scientists (those registered 0-4 years at the time of the surveys) declined sharply, however, from 828 in 1996 to 253 in 2008. The number of female physician-scientists increased from 528 in 1996 to 746 in 2008. Across the two survey periods, about 30% of physician-scientists left the career path, but this attrition was offset by about the same number of new individuals entering the field. CONCLUSIONS: Although the total number of physician-scientists was relatively unchanged during the period studied, it is essential that educators and policy makers develop approaches to address underlying demographic changes to ensure an adequate age- and gender balanced supply of physician-scientists in the future. PMID- 22450179 TI - Perspective: Resident physician wellness: a new hope. AB - Residency training is a challenging period in a physician's career owing to a multitude of stressors perhaps not previously encountered. In some cases, these stressors may culminate in a state of burnout. In response, much has been written about the issues of personal wellness during residency training. Recently, duty hours reform has been the major focus of addressing resident wellness; however, this intervention has established little benefit and has created unintended negative consequences. Alternatively, an emerging solution may be the implementation of resident wellness programs into residency training. Such programs are defined by a combination of active and passive initiatives targeting the various domains of physical, mental, social, and intellectual wellness. In contrast to duty hours reform, resident wellness programs are generally free from controversy and have been shown to improve resident wellness and enhance empathy.This article highlights the salient causes of burnout as it applies to present-day resident physicians and the patient care they provide. Moreover, in the wake of the controversy surrounding duty hours reform, a novel approach to resident wellness involving structured resident wellness programs is discussed. Specifically included are the fundamental components of a wellness program, the advantages held over duty hours reform, methods to evaluate program efficacy, and the current evidence to support these initiatives. Formal wellness curricula, including an evaluative process, should be an integral component of physician training. These programs represent a new hope in the solution to the long-debated issue of burnout and wellness during residency training. PMID- 22450180 TI - First-year residents who began their graduate medical education in 2009-2010 and found their positions within and outside the NRMP match. AB - PURPOSE: Analysts who assess trends in medical specialty choice often use statistics published by the National Resident Matching Program (NRMP), but a substantial minority of new residents find their positions outside of the NRMP. Rule changes to be implemented by the NRMP in 2013 may have a substantial impact on this behavior.The author quantified and characterized residents who found their positions outside of the NRMP. Using available data, the author was able to distinguish those who were unsuccessful in the NRMP from those who did not register and those who registered but failed to enter a rank order list of preferred programs. METHOD: NRMP data on applicants in 2009 (n = 36,971) were combined with data from the national resident census contained in the GMETrack system on residents who began their graduate medical education in 2009-2010 (n = 25,432). Residents were classified into categories based on their participation in the NRMP and their success in matching to a position, and by the type of medical school from which they graduated. RESULTS: Applicants who matched in the NRMP were 79.8% of new residents in first-year residency positions (n = 20,287). An additional 5.2% (n = 1,325) participated in the NRMP but were unsuccessful in matching. Aside from a small number of military residents, the remaining 13.7% (n = 3,488) found positions without participating in the NRMP Match. CONCLUSIONS: Workforce studies that rely on NRMP statistics alone to establish national trends are seriously deficient. PMID- 22450181 TI - Aging Q3: an initiative to improve internal medicine residents' geriatrics knowledge, skills, and clinical performance. AB - A growing number of older adults coupled with a limited number of physicians trained in geriatrics presents a major challenge to ensuring quality medical care for this population. Innovations to incorporate geriatrics education into internal medicine residency programs are needed. To meet this need, in 2009, faculty at the Medical University of South Carolina developed Aging Q(3)-Quality Education, Quality Care, and Quality of Life. This multicomponent initiative recognizes the need for improved geriatrics educational tools and faculty development as well as systems changes to improve the knowledge and clinical performance of residents. To achieve these goals, faculty employ multiple intervention strategies, including lectures, rounds, academic detailing, visual cues, and electronic medical record prompts and decision support. The authors present examples from specific projects, based on care areas including vision screening, fall prevention, and caring for patients with dementia, all of which are based on the Assessing Care of Vulnerable Elders quality indicators. The authors describe the principles driving the design, implementation, and evaluation of the Aging Q(3) program. They present data from multiple sources that illustrate the effectiveness of the interventions to meet the knowledge, skill level, and behavior goals. The authors also address major challenges, including the maintenance of the teaching and modeling interventions over time within the context of demanding primary care and inpatient settings. This organized, evidence-based approach to quality improvement in resident education, as well as faculty leadership development, holds promise for successfully incorporating geriatrics education into internal medicine residencies. PMID- 22450182 TI - Perspective: Organizational professionalism: relevant competencies and behaviors. AB - The professionalism behaviors of physicians have been extensively discussed and defined; however, the professionalism behaviors of health care organizations have not been systemically categorized or described. Defining organizational professionalism is important because the behaviors of a health care organization may substantially impact the behaviors of physicians and others within the organization as well as other institutions and the larger community. In this article, the authors discuss the following competencies of organizational professionalism, derived from ethical values: service, respect, fairness, integrity, accountability, mindfulness, and self-motivation. How nonprofit health care organizations can translate these competencies into behaviors is described. For example, incorporating metrics of population health into assessments of corporate success may increase collaboration among regional health care organizations while also benefiting the community. The unique responsibilities of leadership to model these competencies, promote them in the community, and develop relevant organizational strategies are clarified. These obligations elevate the importance of the executive leadership's capacity for self-reflection and the governing boards' responsibility for mapping operational activities to organizational mission. Lastly, the authors consider how medical organizations are currently addressing professionalism challenges. In an environment made turbulent by regulatory change and financial constraints, achieving proficiency in professionalism competencies can assist nonprofit health care organizations to promote population health and the well-being of their workforces. PMID- 22450183 TI - The unintended consequences of clarity: reviewing the actions of the Liaison Committee on Medical Education before and after the reformatting of accreditation standards. AB - PURPOSE: To determine the frequency of severe action decisions made by the Liaison Committee on Medical Education (LCME) in two time periods and to speculate about contributing factors for any change. METHOD: Two study periods were reviewed. Study Period 1 (1996-2000) was before a 2002 reformatting of the standards; Study Period 2 (2004-2009) was after that reformatting. The frequency of severe action decisions and patterns of noncompliance leading to those decisions in both periods were analyzed. RESULTS: There were more severe action decisions during Study Period 2 than Study Period 1, with a notable increase in the number of recommendations for probation. Study Period 1 had substantially more noncompliance with standards within the Institutional Setting and Educational Resource categories, whereas Study Period 2 had substantially more noncompliance within the Educational Program and Medical Student categories. CONCLUSIONS: The 2002 reformatting of the standards enhanced the clarity of each standard and connected previously existing annotations to their standards. As a result of the reformatting, all documents and communications to schools were directly tied to specific standards. This has allowed the LCME to more easily identify areas of chronic noncompliance and to improve survey team training. The shift in patterns of standards out of compliance in the more recent time period is consistent with the effect of the reformatting. There may be other contributing factors for the increase in severe action decisions, but it is clear that the reformatting of standards has improved the LCME's ability to monitor medical education programs. PMID- 22450184 TI - Perspective: a practical approach to defining professional practice gaps for continuing medical education. AB - The Accreditation Council for Continuing Medical Education mandates that continuing medical education (CME) be developed around professional practice gaps. Accordingly, CME course directors must identify the intended learners, assess learners' needs, identify gaps in knowledge, and evaluate their CME activities. Writing gap statements is challenging for CME course directors because there is not a universally accepted format for writing these statements. The authors describe a practical approach to defining gaps for CME accreditation, which involves four steps indicated by the mnemonic LASO (learner, assessment, standard, outcomes): (1) define the learner population's characteristics, (2) create a learning needs assessment, (3) determine if the standard is met, and (4) state educational outcome for the CME activity. Based on this model, the difference between the practice standard and the current practice represents the gap in practice. The LASO approach has assisted in making CME content learner centered, relevant, and measurable at the authors' institution. The authors anticipate that LASO will be able to provide all CME course directors with a practical approach to defining educational gaps for CME accreditation. PMID- 22450185 TI - The Donald W. Reynolds Consortium for Faculty Development to Advance Geriatrics Education (FD~AGE): a model for dissemination of subspecialty educational expertise. AB - PURPOSE: Most U.S. medical schools and training programs lack sufficient faculty expertise in geriatrics to train future physicians to care for the growing population of older adults. Thus, to reach clinician-educators at institutions and programs that have limited resources for enhancing geriatrics curricula, the Donald W. Reynolds Foundation launched the Faculty Development to Advance Geriatrics Education (FD~AGE) program. This consortium of four medical schools disseminates expertise in geriatrics education through support and training of clinician-educators. The authors conducted this study to measure the effects of FD~AGE. METHOD: Program leaders developed a three-pronged strategy to meet program goals: FD~AGE offers (1) advanced fellowships in clinical education for geriatricians who have completed clinical training, (2) mini-fellowships and intensive courses for faculty in geriatrics, teaching skills, and curriculum development, and (3) on-site consultations to assist institutions with reviewing and redesigning geriatrics education programs. FD~AGE evaluators tracked the number and type of participants and conducted interviews and follow-up surveys to gauge effects on learners and institutions. RESULTS: Over six years (2004-2010), FD~AGE trained 82 fellows as clinician-educators, hosted 899 faculty scholars in mini-fellowships and intensive courses, and conducted 65 site visits. Participants taught thousands of students, developed innovative curricula, and assumed leadership roles. Participants cited as especially important to program success expanded knowledge, improved teaching skills, mentoring, and advocacy. CONCLUSIONS: The FD~AGE program represents a unique model for extending concentrated expertise in geriatrics education to a broad group of faculty and institutions to accelerate progress in training future physicians. PMID- 22450186 TI - The crimson care collaborative: a student-faculty initiative to increase medical students' early exposure to primary care. AB - The current shortage of primary care physicians (PCPs), particularly as more individuals obtain health insurance and seek primary care services, is a growing national concern. The Crimson Care Collaborative (CCC) is a joint student-faculty initiative in post-health-care-reform Massachusetts that was started with the explicit goal of attracting medical students to primary care careers. It fills a niche for student-run clinics, providing evening access to primary care services for patients without a PCP and urgent care services for patients of a Massachusetts General Hospital-affiliated internal medicine clinic, with the aim of decreasing emergency department use in both groups. Unlike other student-run clinics, CCC is integrated into the mainstream health care structure of an existing primary care clinic and, because of universal health insurance coverage in Massachusetts, can bill for its services. In addition to the clinical services offered, the student-run research team evaluates the quality of care and the patients' experiences at the clinic. This article describes the creation and development of CCC, including a brief overview of clinic operations, social services, research, laboratory services, student and patient education programs, and finance. In the wake of the Patient Protection and Affordable Care Act of 2010, CCC is an example of how students can aid the transition to universal health care in the United States and how medical schools can expose students early in their training to primary care and clinic operations. PMID- 22450187 TI - The rise and fall of the American Jewish hospital. AB - American Jewish hospitals were founded, starting in 1854, to serve indigent Jews, to respond to anti-Semitism by creating opportunities for graduate medical education (GME) and medical practice, to provide culturally sensitive care to observant Jews, and to fulfill a religious commitment to healing. Jewish hospitals were governed, administered, staffed, and philanthropically supported predominantly by Jewish communities.In this essay, the author describes the origins of American Jewish hospitals, the purposes they were designed to serve, and why they are disappearing. He estimates that approximately 113 Jewish hospitals were founded in the history of the United States and that there are now about 22 left, some of which are Jewish in name only. Jewish hospitals have been disappearing as a result of the economic pressures facing all community hospitals, a decline in anti-Semitism, open access to GME positions and hospital privileges, the general acceptance of Jews in the American mainstream, and a loss of Jewish community philanthropy. PMID- 22450188 TI - North American medical schools' experience with and approaches to the needs of students with physical and sensory disabilities. AB - PURPOSE: To determine the nature and frequency of impairments and related underlying conditions of medical students with physical and sensory disabilities (PSDs), and to assess medical schools' use of relevant publications in setting admission criteria and developing appropriate accommodations. METHOD: A 25-item survey addressed schools' experiences with students known to have PSDs and their related policies and practices. The survey instrument was directed to student affairs deans at all 163 accredited American and Canadian medical schools. The authors limited the survey to consideration of PSDs, excluding psychiatric, cognitive, and learning disabilities. RESULTS: Eighty-six schools (52.8%) responded, representing an estimated 83,327 students enrolled between 2001 and 2010. Of these students, 0.56% had PSDs at matriculation and 0.42% at graduation. Although 81% of respondents were familiar with published guidelines for technical standards, 71% used locally derived institutional guidelines for the admission of disabled applicants. The most commonly reported accommodations for students with PSDs included extra time to complete tasks/exams (n = 62), ramps, lifts, or accessible entrances (n = 43), and dictated/audio-recorded lectures (n = 40). All responding schools required students' demonstration of physical examination skills; requirements for other technical skills, with or without accommodations, varied considerably. CONCLUSIONS: The matriculation and graduation rates of medical students with PSDs remain low. The most frequent accommodations reported were among those required of any academic or clinical setting by the Americans with Disabilities Act. There is a lack of consensus regarding technical standards for admission, suggesting a need to reexamine this critical issue. PMID- 22450189 TI - Educational outcomes of the Harvard Medical School-Cambridge integrated clerkship: a way forward for medical education. AB - PURPOSE: The authors report data from the Harvard Medical School-Cambridge Integrated Clerkship (CIC), a model of medical education in which students' entire third year consists of a longitudinal, integrated curriculum. The authors compare the knowledge, skills, and attitudes of students completing the CIC with those of students completing traditional third-year clerkships. METHOD: The authors compared 27 students completing the first three years of the CIC (2004 2007) with 45 students completing clerkships at other Harvard teaching hospitals during the same period. At baseline, no significant between-group differences existed (Medical College Admission Test and Step 1 scores, second-year objective structured clinical examination [OSCE] performance, attitudes toward patient centered care, and plans for future practice) in any year. The authors compared students' National Board of Medical Examiners Subject and Step 2 Clinical Knowledge scores, OSCE performance, perceptions of the learning environment, and attitudes toward patient-centeredness. RESULTS: CIC students performed as well as or better than their traditionally trained peers on measures of content knowledge and clinical skills. CIC students expressed higher satisfaction with the learning environment, more confidence in dealing with numerous domains of patient care, and a stronger sense of patient-centeredness. CONCLUSIONS: CIC students are at least as well as and in several ways better prepared than their peers. CIC students also demonstrate richer perspectives on the course of illness, more insight into social determinants of illness and recovery, and increased commitment to patients. These data suggest that longitudinal integrated clerkships offer students important intellectual, professional, and personal benefits. PMID- 22450194 TI - Breast cancer: Aromatase inhibitors--bone health assessment is crucial. PMID- 22450195 TI - Endothelium-derived relaxing factor-mediated vasodilation in mouse mesenteric vascular beds. AB - The endothelium in rat mesenteric vascular beds has been demonstrated to regulate vascular tone by releasing mainly endothelium-derived hyperpolarizing factor (EDHF), which is involved in the activation of K(+) channels and gap-junctions. However, it is unclear whether the endothelial system in mouse resistance arteries contributes to regulation of the vascular tone. The present study was designed to investigate the role of the endothelium using acetylcholine and A23187 (Ca(2+) ionophore) in mesenteric vascular beds isolated from male C57BL/6 mice and perfused with Krebs solution to measure perfusion pressure. In preparations with active tone produced by methoxamine in the presence of guanethidine, injections of acetylcholine, A23187, and sodium nitroprusside (SNP) caused a concentration-dependent decrease in perfusion pressure due to vasodilation. The vasodilator responses to acetylcholine and A23187, but not SNP, were abolished by endothelium dysfunction and significantly inhibited by N(omega) nitro-L-arginine methyl ester (nitric oxide synthase inhibitor) and tetraethylammonium (K(+)-channel inhibitor) but not glibenclamide (ATP-sensitive K(+)-channel inhibitor). Indomethacin (cyclooxygenase inhibitor) significantly blunted only A23187-induced vasodilation, while 18alpha-glycyrrhetinic acid (gap junction inhibitor) attenuated only acetylcholine-induced vasodilation. These results suggest that the endothelium in mouse mesenteric arteries regulates vascular tone by prostanoids, EDHF, and partially by nitric oxide, different from the endothelium of rat mesenteric arteries. PMID- 22450196 TI - Involvement of hypothalamic periventricular GABAergic nerves in the central pressor response to clonidine in freely-moving conscious rats. AB - Microinjection of the alpha(2)-adrenoceptor agonist clonidine into the hypothalamic periventricular nuclei (PVN) induces the pressor response associated with bradycardia in freely-moving conscious rats. This study investigated the involvement of gamma-aminobutyric acid nerves (GABAergic nerves) and glutamatergic nerves in the cardiovascular response to microinjection of clonidine in the PVN. Male Wistar rats were chronically implanted with a microinjection cannula into the PVN and an arterial catheter into the abdominal aorta through the femoral artery. Blood pressure and heart rate were measured under a conscious unrestrained state. PVN injection of clonidine induced a dose dependent pressor response concomitant with bradycardia. PVN pretreatment with GABA, muscimol (GABA(A)-receptor agonist), or bicuculline (GABA(A)-receptor antagonist) significantly inhibited the pressor response to PVN-injected clonidine without affecting bradycardia. PVN pretreatment with baclofen (GABA(B) receptor agonist), 2-hydroxysaclofen (GABA(B)-receptor antagonist), or kynurenic acid (non-selective NMDA-type glutamate-receptor and ionotropic glutamate receptor antagonist) did not affect the pressor response to PVN-injected clonidine. These results suggest that clonidine induces a pressor response by stimulating the presynaptic alpha(2)-adrenoceptor of GABAergic nerves in the PVN, thereby inhibiting GABAergic nerve activity. PMID- 22450197 TI - Sex differences in brain activation to emotional stimuli: a meta-analysis of neuroimaging studies. AB - Substantial sex differences in emotional responses and perception have been reported in previous psychological and psychophysiological studies. For example, women have been found to respond more strongly to negative emotional stimuli, a sex difference that has been linked to an increased risk of depression and anxiety disorders. The extent to which such sex differences are reflected in corresponding differences in regional brain activation remains a largely unresolved issue, however, in part because relatively few neuroimaging studies have addressed this issue. Here, by conducting a quantitative meta-analysis of neuroimaging studies, we were able to substantially increase statistical power to detect sex differences relative to prior studies, by combining emotion studies which explicitly examined sex differences with the much larger number of studies that examined only women or men. We used an activation likelihood estimation approach to characterize sex differences in the likelihood of regional brain activation elicited by emotional stimuli relative to non-emotional stimuli. We examined sex differences separately for negative and positive emotions, in addition to examining all emotions combined. Sex differences varied markedly between negative and positive emotion studies. The majority of sex differences favoring women were observed for negative emotion, whereas the majority of the sex differences favoring men were observed for positive emotion. This valence specificity was particularly evident for the amygdala. For negative emotion, women exhibited greater activation than men in the left amygdala, as well as in other regions including the left thalamus, hypothalamus, mammillary bodies, left caudate, and medial prefrontal cortex. In contrast, for positive emotion, men exhibited greater activation than women in the left amygdala, as well as greater activation in other regions including the bilateral inferior frontal gyrus and right fusiform gyrus. These meta-analysis findings indicate that the amygdala, a key region for emotion processing, exhibits valence-dependent sex differences in activation to emotional stimuli. The greater left amygdala response to negative emotion for women accords with previous reports that women respond more strongly to negative emotional stimuli, as well as with hypothesized links between increased neurobiological reactivity to negative emotion and increased prevalence of depression and anxiety disorders in women. The finding of greater left amygdala activation for positive emotional stimuli in men suggests that greater amygdala responses reported previously for men for specific types of positive stimuli may also extend to positive stimuli more generally. In summary, this study extends efforts to characterize sex differences in brain activation during emotion processing by providing the largest and most comprehensive quantitative meta-analysis to date, and for the first time examining sex differences as a function of positive vs. negative emotional valence. The current findings highlight the importance of considering sex as a potential factor modulating emotional processing and its underlying neural mechanisms, and more broadly, the need to consider individual differences in understanding the neurobiology of emotion. PMID- 22450198 TI - Impact of tDCS on performance and learning of target detection: interaction with stimulus characteristics and experimental design. AB - We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits)-Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (beta). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed. PMID- 22450199 TI - Allergens from Fusarium solani identified by immunoblotting in asthma patients In Iran. AB - We extracted Fusarium solani antigens to evaluate specific anti-F. solani IgE in fifty-one patients with asthma (33 men and 18 women) and in 22 non-atopic healthy subjects (15 men and 7 women). F. solani strains were cultured in Sabouraud glucose agar and subjected to cell disruption using the freeze-and-thaw method. The obtained cytoplasmic extracts were analysed using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Sensitisation to F. solani antigens has been evaluated in asthmatic patients using the immunoblotting assay. The SDS-PAGE identified 29 protein bands in the cytoplasmic extracts of F. solani isolates, with molecular weights ranging from 24 kDa to 112 kDa. Immunoblotting detected specific anti-F. solani IgE antibody in all asthma patients, but not in the control group. The predominant reactive allergens in patients corresponded to the bands with molecular weights of 24 kDa, 58.5 kDa, 64.5 kDa, 69 kDa, 72 kDa, and 97 kDa. Our results suggest that various allergenic components of F. solani may produce symptoms of asthma in susceptible individuals and they call for further research. PMID- 22450200 TI - Effects of myosmine on antioxidative defence in rat liver. AB - Myosmine [3-(1-pyrrolin-2-yl) pyridine] is an alkaloid structurally similar to nicotine, which is known to induce oxidative stress. In this study we investigated the effects of myosmine on enzymatic and non-enzymatic antioxidative defence in rat liver. Wistar rats received a single i.p. injection of 19 mg kg-1 of myosmine and an oral dose of 190 mg kg-1 by gavage. Nicotine was used as a positive control. Through either route of administration, myosmine altered the hepatic function by decreasing the levels of reduced glutathione, superoxide dismutase, and glutathione peroxidase activities on one hand and by increasing malondialdehyde, catalase, and glutathione reductase activity on the other. Compared to control, both routes caused significant lipid peroxidation in the liver and altered hepatic enzymatic and non-enzymatic antioxidative defences. The pro-oxidant effects of myosmine were comparable with those of nicotine. PMID- 22450201 TI - Cytotoxic effects of imidazolium ionic liquids on fish and human cell lines. AB - Ionic liquids bring a promise of a wide range of "green" applications that could replace conventional volatile solvents. However, before these applications become large-scale, their toxicity needs to be investigated in order to predict the impact on human health and environment. In this study we assessed the cytotoxicity of imidazolium ionic liquids (in the concentrations between 0.1 mmol L-1 and 10 mmol L-1) in the ovarian fish cell line CCO and the human tumour cell line HeLa using the MTT cell viability assay. Our results showed that the most cytotoxic ionic liquid was 1-n-butyl-3-methylimidazolium bis(trifluoro methylsulphonyl)imide, [BMIM][Tf2N], followed by 1-n-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4], 1-n-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], and 1,3-dimethylimidazolium hexafluorophosphate [MMIM][PF6]. Generally, the effects were concentration-dependent. They also depended on the type of anion and the n-alkyl chain length. The comparison between the fish CCO and human HeLa cell lines suggests that CCO cells provide a good biological system for initial toxicity testing of ionic liquids that could replace in vivo bioassays. PMID- 22450202 TI - Boat pressure washing wastewater treatment with calcium oxide and/or ferric chloride. AB - The aim of this study was to investigate the efficiency of (1) chemical precipitation by calcium oxide, (2) coagulation/flocculation by ferric chloride (FC), and (3) the combination these two methods in reducing the toxicity of wastewater generated by boat pressure washing. All three methods gave satisfactory results in the removal of colour, turbidity, Cr, Fe, Cu, Zn, and Pb. The concentrations of heavy metals were lowered below national limits with 1 g of CaO, 2.54 mg of Fe3+ in the form of FeCl3x6H2O, and the combination of 0.25 g of CaO and 5.08 mg of Fe3+ per 50 mL of wastewater. Both CaO (1.50 g per 50 mL of wastewater) and FC proved efficient, but their combination yielded a significantly better performance: 99.41 %, 100.00 %, 97.87 %, 99.09 %, 99.90 %, 99.46 % and 98.33 % for colour, turbidity, Cr, Fe, Cu, Zn, and Pb respectively. For colour, Cr, Cu, Zn, and Pb removal efficiencies increased in the following order: FC0.05). Neutralization of FGF-23 offers a new approach to reduce phosphate requirements of farmed animals and may provide a new means to reduce phosphate pollution related to animal farming. PMID- 22450331 TI - Therapeutic angiogenesis using genetically engineered human endothelial cells. AB - Cell therapy holds promise as a method for the treatment of ischemic disease. However, one significant challenge to the efficacy of cell therapy is poor cell survival in vivo. Here we describe a non-viral, gene therapy approach to improve the survival and engraftment of cells transplanted into ischemic tissue. We have developed biodegradable poly(beta-amino esters) (PBAE) nanoparticles as vehicles to genetically modify human umbilical vein endothelial cells (HUVECs) with vascular endothelial growth factor (VEGF). VEGF transfection using these nanoparticles significantly enhanced VEGF expression in HUVECs, compared with a commercially-available transfection reagent. Transfection resulted in the upregulation of survival factors, and improved viability under simulated ischemic conditions. In a mouse model of hindlimb ischemia, VEGF nanoparticle transfection promoted engraftment of HUVECs into mouse vasculature as well as survival of transplanted HUVECs in ischemic tissues, leading to improved angiogenesis and ischemic limb salvage. This study demonstrates that biodegradable polymer nanoparticles may provide a safe and effective method for genetic engineering of endothelial cells to enhance therapeutic angiogenesis. PMID- 22450332 TI - Post-translational regulated and hypoxia-responsible VEGF plasmid for efficient secretion. AB - Gene therapy using angiogenic genes has emerged as a potentially viable alternative treatment strategy for myocardial ischemia. Non-specific expression of angiogenic genes, however, may result in side effects, including the growth of occult tumors. Regulation of gene expression may help to avoid the occurrence of these side effects. In this study, a plasmid expressing vascular endothelial growth factor (VEGF) was constructed with an oxygen dependent degradation (ODD) domain and a secretion signal peptide (SP) in order to stabilize the VEGF protein and facilitate the secretion of VEGF protein, specifically under hypoxic conditions. We found that this plasmid, pbeta-SP-ODD-VEGF, expresses the SP-ODD VEGF protein at increased levels under hypoxic conditions compared to normoxic conditions. Since the size of the ODD domain is almost the same as that of VEGF, the ODD-VEGF fusion protein may have lower secretion efficiency. To address this issue, a furin recognition site was located between the ODD domain and the VEGF site to facilitate elimination of the SP-ODD domain from the fusion protein before its secretion. This optimizes the likelihood that the VEGF secreted from the target cells will be wild-type VEGF. Treatment with a furin inhibitor reduced the secretion efficiency of the VEGF, indicating that furin digestion increases the secretion of VEGF. The secreted wild-type VEGF facilitated the growth of endothelial cells more efficiently under hypoxic conditions than normoxic conditions. These results suggest that this plasmid, pbeta-SP-ODD-VEGF, warrants further study as a more efficient form of hypoxia-inducible gene therapy for the treatment of myocardial ischemia. PMID- 22450333 TI - The influence of ACE genotype on cardiovascular fitness of moderately active young men. AB - BACKGROUND: The angiotensin I-converting enzyme gene (ACE gene) has been broadly studied as for cardiorespiratory fitness phenotypes, but the association of the ACE genotype to middle-distance running has been poorly investigated. OBJECTIVE: This study investigated the possible influence of Angiotensin-Converting Enzyme (ACE) genotype (I/D) on cardiovascular fitness and middle-distance running performance of Brazilian young males. The validity of VO(2max) to predict the ACE genotype was also analyzed. METHODS: A homogeneous group of moderately active young males were evaluated in a 1,600 m running track test (V1600m; m.min(-1)) and in an incremental treadmill test for VO(2max) determination. Subsequently, the actual and the predicted [(0.177*V1600m) + 8.101] VO(2max) were compared to ACE genotypes. RESULTS: The VO(2max) and V1600m recorded for DD, ID and II genotypes were 45.6 (1.8); 51.9 (0.8) and 54.4 (1.0) mL.kg(-1).min(-1) and 211.2 (8.3); 249.1 (4.3) and 258.6 (5.4) m.min(-1) respectively, and were significantly lower for DD carriers (p< 0.05). The actual and predicted VO(2max) did not differ from each other despite ACE genotype, but the agreement between actual and estimated VO(2max) methods was lower for the DD genotype. CONCLUSION: It was concluded that there is a possible association between ACE genotype, cardiovascular fitness and middle-distance running performance of moderately active young males and that the accuracy of VO(2max) prediction may also depend on the ACE genotype of the participants. PMID- 22450334 TI - Left ventricular diastolic function in morbidly obese patients in the preoperative for bariatric surgery. AB - BACKGROUND: Obesity is a chronic and multifactorial disease, associated with increased cardiovascular risk, especially diastolic heart failure. OBJECTIVE: To evaluate left ventricular diastolic function in morbidly obese patients in the pre-operative for bariatric surgery, correlating it with cardiovascular risk factors and heart structure. METHODS: This is a cross-sectional study with 132 patients eligible for bariatric surgery submitted to transthoracic echocardiography assessment and of cardiovascular risk factors, as follows: 97 women (73.5%), mean age 38.5 +/- 10.5 years and BMI of 43.7 +/- 7.2 kg / m(2). Patients were divided into three groups: 61 with normal diastolic function, 24 with mild diastolic dysfunction and 47 with moderate/severe diastolic dysfunction, of which 41 with moderate diastolic dysfunction (pseudonormal pattern) and six with severe diastolic dysfunction (restrictive pattern). RESULTS: Hypertension, age and gender were different in the groups with diastolic dysfunction. Groups with dysfunction had higher left atrial diameter, left ventricular diameter, left atrial volume in four and two chambers, left atrial volume index and left ventricular mass index corrected for body surface area and height. CONCLUSION: The high frequency of left ventricular diastolic dysfunction in the preclinical phase in morbidly obese patients justifies the need for careful echocardiographic assessment, aiming at identifying individuals at higher risk, so that early intervention measures can be carried out. PMID- 22450335 TI - Is abnormal adrenergic activation associated with abnormal Heart Rate Recovery? AB - BACKGROUND: Heart Rate Recovery (HRR) reflects the capacity of the cardiovascular system to reverse the vagal withdrawal caused by exercise. Scintigraphy with metaiodobenzylguanidine (I(123) MIBG) evaluates innervation and cardiac adrenergic activation. The association of these two methods is not well established. OBJECTIVE: To evaluate the association between HRR and washout rate (WO) of I(123) MIBG in patients with heart failure (HF). METHODS: Twenty-five patients with ejection fraction < 45% underwent exercise testing, and analysis of the variation of HRR from the 1st to the 8th minute after exertion. Submitted to I(123) MIBG, they were separated into groups by WO: G1) <27% and G2) >= 27%. For the statistical analysis Mann-Whitney's U test and Spearman's correlation coefficient were used. RESULTS: G2 showed a slower variation of HRR: 1st minute: G1: 21.5 (16.12 to 26.87) vs. G2: 11.00 (8.5 to 13.5) bpm, p = 0.001; 2nd minute: G1: 34 (29-39) vs. G2: 20 (14 - 26) bpm, p = 0.001; 3rd minute: G1: 46 (37.8 - 54.1) vs. G2: 30 (22 - 38) bpm, p = 0.005; 5th minute: G1: 51.5 (42 - 61) vs. G2: 39 (31.5 to 46.5) bpm, p = 0.013, and in the 8th minute: G1: 54.5 (46.5 - 62.5) vs. G2: 43 (34 - 52) bpm, p = 0.037. HRR in the 1st (r = -0.555, p = 0.004), and in the 2nd minute (r = -0.550, p = 0.004) were negatively correlated with WO. CONCLUSION: Patients with high HF and WO showed an abnormal HRR compared with patients with normal WO. These findings suggest that adrenergic activation may influence the HRR. PMID- 22450336 TI - Feasibility of mitral valve surgery using minimal extracorporeal circulation. AB - AIM: Using minimal extracorporeal circulation (MECC) in isolated coronary artery bypass grafting or aortic valve replacement has been proven to be safe, feasible and superior compared to standard cardiopulmonary bypass (CPB) in terms of postoperative complications, total hospital stay and blood product transfusions. This feasibility study evaluates the clinical outcomes of mitral valve surgery performed with MECC. METHODS: From March 2006 to January 2011, seventy-five patients who underwent mitral valve surgery performed with MECC (n=75) in our institution were retrospectively evaluated. Demographic characteristics, operative data and clinical outcomes were collected in a prospectively designed database. RESULTS: The mean age was 68.8 +/- 10.2 years with a EuroSCORE of 7.0 +/- 2.3. Thirty-seven patients had a moderate left ventricular function (with a range of 30-40%). All patients except two had severe mitral valve incompetence (MI). Surgery was successful in all procedures. The mean duration of surgery was 210 +/- 44 min (range 118-356 min). The mean CPB time was 128 +/- 30 (range 67 249) min. The cross-clamp time was 99 +/- 26 (range 48-205) min. There were no intraoperative perfusion problems or airlocks reported. The mean intensive care unit (ICU) length of stay was two days. Subsequent analysis showed a first postoperative haemoglobin value of 9.4 g/dL +/- 1.7. There were no peroperative neurological complications. One patient developed an ischaemic cerebrovascular accident (CVA) on the forth postoperative day due to inadequate anticoagulation. Other postoperative complications included eight patients with pneumonia, one superficial wound infection, temporary renal insufficiency in two patients and four patients needed re-exploration for excessive postoperative leakage. Overall in-hospital mortality was four percent. CONCLUSION: Our results show, for the first time, that isolated or combined mitral valve surgery using MECC is feasible and safe. PMID- 22450339 TI - A single gene deletion on 4q28.3: PCDH18--a new candidate gene for intellectual disability? AB - We report a boy with severe developmental delay, seizures, microcephaly, hypoplastic corpus callosum, internal hydrocephalus and dysmorphic features (narrow forehead, round face, deep-set eyes, blue sclerae, large and prominent ears, nose with anteverted nares, thin upper lip, small and wide-spaced teeth, hyperextensibility of the elbows, wrists, and fingers, fingertip pads, broad hallux, sacral dimple), carrying a 1.53 Mb interstitial deletion at 4q28.3. The deletion was detected by Agilent 105K oligo-array genome hybridization and involves the genomic region between 137,417,338 and 138,947,282 base pairs on chromosome 4 (NCBI build 36). The alteration was inherited from a healthy mother and contains a single gene, PCDH18 which encodes a cadherin-related neuronal receptor thought to play a role in the establishment and function of cell-cell connections in the brain. Thus, haploinsufficiency of this gene may contribute to altered brain development and associated malformations. We found that this deletion is a private inherited copy number variation that is associated with specific clinical findings in our patient and propose the PCDH18 gene as a possible candidate gene for intellectual disability. PMID- 22450340 TI - Magnesium sulfate suppresses L-type calcium currents on the basilar artery smooth muscle cells in rabbits. AB - OBJECTIVES: Although magnesium is a well-known treatment for vasospasm following subarachnoid hemorrhage, its mechanism of action for cerebral vascular relaxation is not clear. In addition, it is known that L-type calcium (Ca(2+)) channels play a pivotal role in smooth muscle contraction. To investigate the role of L-type Ca(2+) channels in the magnesium-induced relaxation of basilar smooth muscle cells, we examined the effect of magnesium sulfate on L-type Ca(2+) currents using freshly isolated smooth muscle cells from rabbit basilar arteries. METHOD: Rabbits were anesthetized with ketamine (50 mg/kg) with xylazine (25 mg/kg) and exsanguinated. Smooth muscle cells were isolated from rabbit basilar arteries by enzyme treatment. Cells were stored at 4 degrees C before use. Whole-cell patch clamp technique was used to identify L-type Ca(2+) currents, using the potassium channel blocker, cesium chloride, and nimodipine and Bay K8644 as a blocker and activator of L-type Ca(2+) channels, respectively. RESULTS: Inward currents induced by step pulses were significantly reduced by nimodipine (n = 5, P<0.05) and increased by Bay K8644 (n = 5, P<0.05). The L-type Ca(2+) currents (122+/ 14.0 pA, n = 12) were significantly reduced by the application of 5 mM magnesium sulfate (28+/-4 pA, n = 12, P<0.05). The inward currents enhanced by Bay K8644 were further suppressed by the application of magnesium sulfate. DISCUSSION: These results demonstrate that L-type Ca(2+) channels are functionally expressed in rabbit basilar smooth muscle cells and suggest that L-type Ca(2+) channels may play a pivotal role for magnesium-induced relaxation. PMID- 22450341 TI - Adiponectin: regulation of its production and its role in human diseases. AB - Adiponectin is a white and brown adipose tissue hormone, also known as gelatin binding protein-28 (GBP28), AdipoQ, adipocyte complement-related protein (ACRP30), or apM1. Adiponectin circulates in the bloodstream in trimeric, hexameric, and high-molecular-mass species, while different forms of adiponectin have been found to play distinct roles in the balance of energy homoeostasis. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2, and T-cadherin. AdipoR1 is expressed abundantly in muscle, whereas AdipoR2 is predominantly expressed in the liver. Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states. In this review we present the current findings regarding the regulation of its production and several new findings pertaining to its biological effects. Adiponectin enhances AMPK and the PPARalpha pathway in the liver and skeletal muscle. Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. Adiponectin has been reported to exert an antiatherosclerotic effect. It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers. In this study, we present ample evidence that adiponectin mediates multiple molecular pathways. We therefore support the concept that it shows distinct potential for being of therapeutic value in the treatment of obesity related diseases, ranging from metabolic syndrome to malignancies. PMID- 22450342 TI - Pathogenesis of vascular complications in Cushing's syndrome. AB - Chronic exposure to high glucocorticoid levels in Cushing's syndrome (CS) is often associated with alterations in the hemostatic system and the expression of prothrombotic phenotypes. Increased frequency of both atherothrombotic and venous thromboembolic events (VTE) has been reported in patients with CS. In general, cardiovascular complications in these patients cause a five-fold increase in mortality compared to the normal population. Although numerous abnormalities in the hemostatic system have been detected in patients with CS, the underlying mechanisms of the prothrombotic state are not fully elucidated. High levels of factor VIII and von Willebrand factor, with evidence of enhanced thrombin generation and decreased fibrinolytic activity, have been documented in several studies. However, it is not clear to what extent these changes contribute to the shift of hemostatic balance towards the hypercoagulable state and expression of thrombophilic phenotypes. Thrombosis is usually a multicausal disease, and all three components of the so-called Virchow triad, namely 1) vascular abnormalities and endothelial dysfunction, 2) hypercoagulability and 3) stasis, may play a variable role in the pathogenesis of the prothrombotic state in CS patients. Larger studies are needed to establish strategies for prevention of cardiovascular complications in patients with Cushing's syndrome. PMID- 22450343 TI - Syndromes of impaired ion handling in the distal nephron: pseudohypoaldosteronism and familial hyperkalemic hypertension. AB - The distal nephron, which is the site of the micro-regulation of water absorption and ion handling in the kidneys, is under the control of aldosterone. Impairment of the mineralocorticoid signal transduction pathway results in resistance to the action of aldosterone and of mineralocorticoids in general. Herein, we review two syndromes in which ion handling in the distal nephron is impaired: pseudohypoaldosteronism (PHA) and familial hyperkalemic hypertension (FHH). PHA is a rare inherited syndrome characterized by mineralocorticoid resistance, which leads to salt loss, hypotension, hyperkalemia and metabolic acidosis. There are two types of this syndrome: a renal (autosomal dominant) type due to mutations of the mineralocorticoid receptor (MR), and a systemic (autosomal recessive) type due to mutations of the epithelial sodium channel (ENaC). There is also a transient form of PHA, which may be due to urinary tract infections, obstructive uropathy or several medications. FHH is a rare autosomal dominant syndrome, characterized by salt retention, hypertension, hyperkalemia and metabolic acidosis. In FHH, mutations of WNK (with-no-lysine kinase) 4 and 1 alter the activity of several ion transportation systems in the distal nephron. The study of the pathophysiology of PHA and FHH greatly elucidated our understanding of the renin-angiotensin-aldosterone system function and ion handling in the distal nephron. The physiological role of the distal nephron and the pathophysiology of diseases in which the renal tubule is implicated may hence be better understood and, based on this understanding, new drugs can be developed. PMID- 22450344 TI - Thyroid hormonal responses to intensive interval versus steady-state endurance exercise sessions. AB - OBJECTIVE: To compare the thyroid hormonal responses to high-intensity interval exercise (IE) and steady-state endurance exercise (SEE) in highly trained males (n=15). DESIGN: The IE session consisted of repeated periods of 90-seconds treadmill running at 100-110% VO(2max) and 90-seconds active recovery at 40% VO(2max) for 42-47 minutes. The SEE session was a 45-minute run at 60-65% VO(2max). Total work output was equal for each session. A 45-minute supine rest control session (CON) was also performed. Pre-session (PRE), immediate post session (POST), and 12-hours post-session (12POST) blood samples were collected and used to determine free (f) T4, fT3, reverse (r) T3, and cortisol levels. RESULTS: All PRE hormone levels were within clinical norms and did not differ significantly between sessions. All POST IE and SEE hormone levels were significantly elevated compared to POST CON (p<0.001). At 12POST, no significant differences between CON and SEE hormonal levels were observed; however, fT3 was significantly reduced and rT3 was significantly elevated in 12POST IE compared to 12POST SEE and CON (p=0.022). For IE, at 12POST a negative correlation (r(s) = 0.70, p<0.004) was found between fT3 and rT3.Also, for IE, a positive correlation (r(s) = 0.74, p<0.002) between cortisol POST and rT3 12POST was noted, and a negative correlation (r(s) = -0.72, p<0.003) between cortisol POST and fT3 12POST. CONCLUSION: IE results in a suppressed peripheral conversion of T4 to T3 implying that a longer recovery period is necessary for hormonal levels to return to normal following IE compared to SEE. These findings are useful in the implementation of training regimens relative to recovery needs and prevention of over-reaching-overtraining. PMID- 22450345 TI - Growth velocity and final height in elite female rhythmic and artistic gymnasts. AB - PURPOSE: The aim of this study was to determine the impact of intensive training on adult final height in elite female rhythmic and artistic gymnasts. METHODS: The study included 215 rhythmic gymnasts (RG) and 113 artistic gymnasts (AG). RESULTS: AG were below the 50th percentile, while RG were taller than average. Final adult height was lower than target height in AG, while in RG, it exceeded target height. AG started training earlier than RG (p<0.001) and reported lower intensity of training (p<0.001). RG were taller than AG, with higher target height, greater Delta final height-target height and lower body fat and BMI (p<0.001). Using multiple regression analysis, the main factors influencing final height were weight SDS (p<0.001), target height SDS (p<0.001) and age of menarche (p<0.001) for RG, and weight SDS (p<0.001) and target height SDS (p<0.001) for AG. CONCLUSION: In both elite female RG and AG, genetic predisposition to final height was not disrupted and remained the main force of growth. Although in elite RG genetic predisposition for growth was fully preserved, in elite female AG final adult height falls shorter than genetically determined target height, though within the standard error of prediction. PMID- 22450346 TI - The rs10830963 variant of melatonin receptor MTNR1B is associated with increased risk for gestational diabetes mellitus in a Greek population. AB - OBJECTIVE: To investigate the association between Gestational Diabetes Mellitus (GDM) and the variants rs10830963 and rs1387153 in the MTNR1B locus in a sample of the Greek population. DESIGN: One hundred seventy-five unrelated pregnant Greek women (77 with GDM and 98 non-diabetic control subjects) were enrolled and the SNaPshot method was employed in order to investigate the association between GDM and the variants rs10830963 and rs1387153 in the MTNR1B locus. Pregnant women were screened for GDM at the 26th week with the 75 g glucose oral glucose tolerance test according to the American Diabetes Association criteria. RESULTS: The GG genotype and the G-allele of the rs10830963 (C/G) variant was found to be positively associated with a significantly increased risk for GDM (p = 0.047 and p = 0.012, respectively). No differences in fasting glucose and insulin levels were found between GDM patients with and without the studied variants. The MTNR1B locus (rs10830963 C/G) seems to predispose for GDM in Greek pregnant women. CONCLUSIONS: Our study confirms the association of GDM with the rs10830963 (C/G) variant in a sample of the Greek population. Population based whole genome screening studies and larger studies with detailed phenotypic data in patients with GDM are needed to address the clinical significance of this finding. PMID- 22450347 TI - Plasma von Willebrand factor antigen levels are elevated in the classic phenotypes of polycystic ovary syndrome. AB - OBJECTIVE: We aimed to assess plasma Von Willebrand factor (vWF) levels in women with polycystic ovary syndrome (PCOS) and to compare these levels among the different PCOS phenotypes. DESIGN: We studied 140 women with PCOS and 40 age and body mass index (BMI)- matched healthy women (control group). RESULTS: Plasma vWF antigen levels were higher in women with PCOS than in controls (p=0.017). Plasma vWF antigen levels were also higher in patients with phenotypes 1 [i.e. with anovulation (ANOV), biochemical hyperandrogenemia or clinical manifestations of hyperandrogenemia (HA) and polycystic ovaries (PCO)] and 2 (i.e. with ANOV and HA but without PCO) than in controls (p=0.017). In contrast, plasma vWF antigen levels did not differ between controls and patients with phenotypes 3 (i.e. with HA and PCO but without ANOV) and 4 (i.e. with ANOV and PCO but without HA) or between patients with phenotypes 1 and 2 and patients with phenotypes 3 and 4. When overweight/obese and normal weight subjects were analyzed separately, plasma vWF antigen levels did not differ between patients with PCOS (regardless of phenotype) and controls. CONCLUSIONS: Plasma vWF levels are elevated in women with PCOS. This increase appears to be more pronounced in women with phenotypes 1 and 2 of PCOS. Given the association between vWF levels and increased incidence of cardiovascular events, the evaluation of vWF levels in women with PCOS might be helpful for cardiovascular risk stratification, but prospective studies are needed to support this hypothesis. PMID- 22450348 TI - Epidemiology of type 1 diabetes mellitus in Cyprus: rising incidence at the dawn of the 21st century. AB - OBJECTIVE: The incidence of Type 1 diabetes mellitus (T1DM) in Greek-Cypriot children aged less than 15 years between 1990 and 2009 was examined along with gender differences concerning the age of onset and the seasonal variation at manifestation of the disease. DESIGN: All newly diagnosed cases of T1DM in children less than 15 years old were registered with the capture-recapture method from 1990 until 2009. RESULTS: The overall mean annual incidence during these 20 years is 12.46 per 100,000. A comparison of the incidence between the two decades (1990-1999 vs 2000-2009) indicated a rising trend, from 10.80 per 100,000 person years during the first decade to 14.44 per 100,000 person-years during the second decade. There was an overall male predominance (M/F: 1.05), which is in agreement with the male predominance in the population less than 15 years of age, except for the group who manifested T1DM at ages 10-15 years where females prevail. The percentage of children who developed T1DM at ages 0-5 years in the total T1DM population increased in the second decade (26.4% vs 19.0%), and significantly more children were diagnosed during the cold months as opposed to the warm months (p<0.001). CONCLUSION: The incidence of T1DM in Cyprus is rising. The identification of causative environmental factors will theoretically explain this phenomenon and new preventive strategies can therefore potentially be developed. PMID- 22450349 TI - Atypical, invasive, recurring Crooke cell adenoma of the pituitary. AB - We report the case of a 49-year-old woman presenting with Cushing disease and visual disturbance. An atypical, aggressive, invasive pituitary tumor regrew despite several surgeries. Detailed morphologic investigation by histology, immunohistochemistry and electron microscopy documented a Crooke cell adenoma, a rare form of ACTH-producing pituitary tumor. Recognition of such adenomas is of importance given their aggressive behavior and tendency to recur. More studies are needed to explain the pathobiology of this not invariably functional pituitary adenoma. PMID- 22450350 TI - Escitalopram-induced subclinical hypothyroidism. A case report. AB - Several conditions and drugs induce subclinical hypothyroidism. We report a case of asymptomatic and reversible subclinical hypothyroidism in a 48-year old woman with minor depressive disorder receiving therapy with escitalopram 20 mg daily for six months. PMID- 22450351 TI - Non tumoral hyperserotoninaemia responsive to octreotide due to dual polymorphism in UGT1A1 and UGT1A6. AB - Gilbert's syndrome is a common inherited metabolic disorder, caused by genetic aberration in the enzyme UDP-glucuronosyl-transferase 1A1 that leads to reduced glucuronidation of bilirubin. Recent advances in molecular genetics have frequently reported the concurrence of dual genetic polymorphisms in UDP glucuronosyl-transferases 1A6 and 1A1 in patients with Gilbert's syndrome, leading to defective glucuronidation of bilirubin, as well as several other endogenous and exogenous substrates, such as serotonin. We present a case of Gilbert's syndrome with severe persistent hyperserotoninaemia, mimicking carcinoid syndrome, due to dual polymorphisms in UDP-glucuronosyl-transferases 1A1 and 1A6. The patient was treated with a long-acting somatostatin analogue (octreotide) for 8 months, resulting in a significant reduction in serum serotonin levels and immediate relief of the symptomatology, followed by a long term remission. The frequent occurrence of hyperserotoninaemia in Gilbert's syndrome may contribute, at least partly, to the nonspecific symptomatology commonly seen in these patients and should be promptly evaluated. PMID- 22450352 TI - Aretaeus of Cappadocia and the first description of diabetes. AB - The name Aretaeus of Cappadocia has been linked with diabetes more than that of any other physician of antiquity, his texts forming a sophisticated synthesis of the previous knowledge on this disease copiously supplemented by his own observations. Gifted with a unique faculty for observing pathologic phenomena, he was able to elaborate upon earlier texts enriching them with his own original findings and numerous thoughtful reflections. Among the many diseases he dealt with, Aretaeus has bequeathed to us an outstandingly vivid and accurate description of diabetes. PMID- 22450353 TI - [The personalized health care process in oncosexology: a new health care offer in the service of both patients and health carers]. AB - The sexual problematic linked to both cancers and their treatments remains underestimated by health carers especially since patients dare not speak about it. The oncosexology is a new offer of health care responding to an epidemiological reality, a strong demand, a care quality process and a societal demand of ethical, technical and humanist medicine. It aims at conciliating the oncological and quality of life objectives because sexual health belongs to oncological care and quality of life belongs to well-being for a majority of people/couple. By comparison to the pain situation of 20 years ago, a proactive politics is necessary to change the individual level to a collective one by modifying the attitudes of patients and... health carers, that is, by breaking the silence, by legitimating the demand and by allowing all the actors to be open about it. The optimal strategy for actualizing the "software" of physicians, who are the main factor of resistance, consists in simplifying and professionalizing the oncosexology by responding to the needs for information and offer visibility for all, and training for the most sensitized or involved carers. The term oncosexology should not shock. This new competence in supportive care corrects a real inequality of access to health care and fits in with a medical humanism by promoting a more personalized approach as much initially as in follow-up: a) to inform about sexual risks and sequels is an ethical and legal duty, b) the therapeutic strategy may be influenced by the iatrogenic sexual risk, which is frequently treatment-dependant, c) the impact and demand evolve throughout the health care process, d) multidisciplinary solutions exist according to the demand and its simple or complex nature, e) the impact is often positive for the patient/couple. PMID- 22450354 TI - Congenital heart disease affects cerebral size but not brain growth. AB - Infants with congenital heart disease (CHD) have delayed brain maturation and alterations in brain volume. Brain metrics is a simple measurement technique that can be used to evaluate brain growth. This study used brain metrics to test the hypothesis that alterations in brain size persist at 3 months of age and that infants with CHD have slower rates of brain growth than control infants. Fifty seven infants with CHD underwent serial brain magnetic resonance imaging (MRI). To evaluate brain growth across the first 3 months of life, brain metrics were undertaken using 19 tissue and fluid spaces shown on MRIs performed before surgery and again at 3 months of age. Before surgery, infants with CHD have smaller frontal, parietal, cerebellar, and brain stem measures (p < 0.001). At 3 months of age, alterations persisted in all measures except the cerebellum. There was no difference between control and CHD infants in brain growth. However, the cerebellum trended toward greater growth in infants with CHD. Somatic growth was the primary factor that related to brain growth. Presence of focal white matter lesions before and after surgery did not relate to alterations in brain size or growth. Although infants with CHD have persistent alterations in brain size at 3 months of age, rates of brain growth are similar to that of healthy term infants. Somatic growth was the primary predictor of brain growth, emphasizing the importance of optimal weight gain in this population. PMID- 22450355 TI - Variations in the number of CCL3L1 gene copies and Kawasaki disease in Korean children. AB - High-dose intravenous immunoglobulin (IVIG) therapy is the highly effective and standard treatment for Kawasaki disease (KD). However, ~20 % of KD patients have persistent fever or recurrence of fever after the initial IVIG treatment, which increases the risk for coronary artery lesions (CALs). Furthermore, the mechanism of IVIG resistance in KD patients still is unknown. The number of CC chemokine ligand 3-like 1 (CCL3L1) gene copies is reported to be associated with KD and IVIG resistance in Japanese patients. In addition, the authors observed significant upregulation of the CCL3L1 gene expression after in vitro immunoglobulin treatment in B cell lines derived from KD patients. Therefore, this study of 459 KD patients and 496 healthy control subjects tested whether the number of CCL3L1 gene copies is associated with a risk of KD, CALs, and/or IVIG resistance in Korean KD patients. However, the number of CCL3L1 gene copies was not associated with KD (P = 0.18), CAL formation (P = 0.062), or the IVIG resistance (P = 0.90). Therefore, the results indicate that the number of CCL3L1 gene copies does not have a role in susceptibility to KD or CALs nor with IVIG resistance in Korean KD patients. PMID- 22450356 TI - Psychopathology: genetics and the stress-vulnerability hypothesis. PMID- 22450357 TI - Phylogenetics and genetic diversity of the Cotesia flavipes complex of parasitoid wasps (Hymenoptera: Braconidae), biological control agents of lepidopteran stemborers. AB - The Cotesia flavipes complex of parasitoid wasps (Hymenoptera: Braconidae) are economically important for the biological control of lepidopteran stemboring pests associated with gramineous crops. Some members of the complex successfully parasitize numerous stemborer pest species, however certain geographic populations have demonstrated variation in the range of hosts that they parasitize. In addition, the morphology of the complex is highly conserved and considerable confusion surrounds the identity of species and host-associated biotypes. We generated nucleotide sequence data for two mtDNA genes (COI, 16S) and three anonymous nuclear loci (CfBN, CfCN, CfEN) for the C. flavipes complex. To analyze genetic variation and relationships among populations we used (1) concatenated mtDNA and nDNA data, (2) a nDNA multilocus network approach, and (3) two species tree inference methods, i.e. Bayesian estimation of species trees (BEST) and Bayesian inference of species trees from multilocus data with (*)BEAST. All phylogenetic analyses provide strong support for monophyly of the complex and the presence of at least four species, C. chilonis (from China and Japan), C. sesamiae (from Africa), C. flavipes (originating from the Indo-Asia region but introduced into Africa and the New World), and C. nonagriae (from Australia and Papua New Guinea). Haplotype diversity of geographic populations relates to historical biogeographic barriers and biological control introductions, and reflects previous reports of ecological variation in these species. Strong discordance was found between the mitochondrial and nuclear markers in the Papua New Guinea haplotypes, which may be an outcome of hybridization and introgression of C. flavipes and C. nonagriae. The position of Cotesia flavipes from Japan was not well supported in any analysis and was the sister taxon to C. nonagriae (mtDNA, (*)BEAST), C. flavipes (nDNA) or C. flavipes+C. nonagriae (BEST) and, may represent a cryptic species. The concatenated five gene phylogenetic analyses did not support the overall separation and monophyly of clades associated with different host species, although some clades did show specific host associations, possibly due to localized host availability, rather than host specificity. Our results provide a framework for assessing whether distinct lineages represent cryptic species, and for examining parasitoid-host evolution and compatibility more generally. Given the limitations of morphological based identification for members of this complex, molecular identification is recommended prior to any biological control introductions. PMID- 22450358 TI - Investigating the affective component of pain: no startle modulation by tonic heat pain in startle responsive individuals. AB - BACKGROUND: Experimental tonic pain has been assumed to equal clinical pain by triggering sizeable affective responses. A psycho-physiological indicator of defensive affective-motivational responses is the startle reflex. However, earlier studies have not provided unequivocal evidence for a potentiation of the startle reflex during tonic contact heat pain. OBJECTIVES: The demonstration of modulating effects of pain on the startle reflex might require very intense tonic stimulation and investigation of subjects, who are particularly sensitive to startle potentiation by threatening cues. METHOD: We investigated a sample of healthy subjects (N=20), who had shown pronounced startle amplitude potentiation in response to attack pictures. Noxious stimulation was provided by hand immersion into a hot water bath, which is a tonic pain model known for intense and summated stimulation. Modulation of the startle reflex was attempted by use of two stimulation intensities (42 degrees C, 46 degrees C) and one control condition (no stimulation). RESULTS: Even in these favorable conditions, we did not observe startle potentiation under painful stimulation in comparison to non painful conditions although subjects reported to be experiencing moderate to high pain. CONCLUSIONS: Our findings indicate that tonic heat pain does not trigger defensive affective-motivational responses as measured by the startle reflex when it is applied in a predictable and thus non-threatening fashion. Future research should investigate the effects of manipulations of threat on startle responses to painful stimulation. PMID- 22450359 TI - [PARP inhibitors and breast cancer: update and perspectives]. AB - Poly(ADP-ribose) polymerase (PARP) family has become a promising therapeutic target in various malignancies including breast cancer. When homologous recombination repair is deficient, as it is observed in BRCA1/2-mutated tumor models, inhibition of PARP was shown to induce massive and selective tumor cell death (the so-called "synthetic lethality"). In breast cancer, PARP inhibitors have been developed as single-agent in BRCA1/2-mutated tumors or in combination with chemotherapy. Recently, a randomized phase III clinical trial failed to demonstrate any survival improvement by combining the iPARP iniparib to chemotherapy in triple-negative metastatic breast cancer patients. This emphasizes the need for future development of this class of compounds to resolve critical issues such as optimal schedule of administration and association to other anticancer treatments, as well as identification of pertinent biomarkers predictive for efficacy. PMID- 22450360 TI - Two novel CTNS mutations in cystinosis patients in Thailand. AB - Cystinosis is an autosomal recessive disorder characterized by defective transport of cystine across the lysosomal membrane and resulting in renal, ophthalmic, and other organ abnormalities. Mutations in the CTNS gene cause a deficiency of the transport protein, cystinosin. We performed mutation analysis of CTNS in six cystinosis patients from four families in Thailand. Using PCR sequencing of the entire coding regions, we identified all eight mutant alleles, including two mutations, p.G309D and p.Q284X, that have not been previously reported. This study expands the mutational and population spectrum of nephropathic cystinosis. PMID- 22450361 TI - Identification of a new phospholipase D in Carica papaya latex. AB - Phospholipase D (PLD) is a lipolytic enzyme involved in signal transduction, vesicle trafficking and membrane metabolism. It catalyzes the hydrolysis and transphosphatidylation of glycerophospholipids at the terminal phosphodiester bond. The presence of a PLD in the latex of Carica papaya (CpPLD1) was demonstrated by transphosphatidylation of phosphatidylcholine (PtdCho) in the presence of 2% ethanol. Although the protein could not be purified to homogeneity due to its presence in high molecular mass aggregates, a protein band was separated by SDS-PAGE after SDS/chloroform-methanol/TCA-acetone extraction of the latex insoluble fraction. This material was digested with trypsin and the amino acid sequences of the tryptic peptides were determined by micro-LC/ESI/MS/MS. These sequences were used to identify a partial cDNA (723 bp) from expressed sequence tags (ESTs) of C. papaya. Based upon EST sequences, a full-length gene was identified in the genome of C. papaya, with an open reading frame of 2424 bp encoding a protein of 808 amino acid residues, with a theoretical molecular mass of 92.05 kDa. From sequence analysis, CpPLD1 was identified as a PLD belonging to the plant phosphatidylcholine phosphatidohydrolase family. PMID- 22450362 TI - Identification of two novel mutations in the first Sicilian APECED patient with no R203X mutation in AIRE gene and review of Italian APECED genotypes. AB - Aims of the present study are: 1) to report an additional Sicilian patient with autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), whose genotypic features are original, in that she is the first APECED patient with three coexisting mutations of Autoimmune Regulator (AIRE) gene, two of which had never been reported to date; 2) to review the genotypic epidemiology of APECED in Italy, in order to underline the great genetic heterogeneity of this disorder in Italian patients. Both the novel mutations of our new patient, named S107C and Q108fs respectively, were detected on exon 3 and were inherited by the mother, whereas the third one (T16M) was inherited by the father. Phenotypically, the present case is quite characteristic, in that she exhibited a classical clinical picture, with no original features. CONCLUSIONS: a) this is the seventh Sicilian APECED patient identified to date, and the first one with no R203X mutation; b) our data confirm that distribution of mutations may considerably vary according to different geographical distribution, within the same country, thus suggesting a potential founder effect. PMID- 22450363 TI - Molecular evolution of zebrafish dnmt3 genes and thermal plasticity of their expression during embryonic development. AB - DNA reprogramming by DNA (cytosine-5)-methyltransferases (dnmts) after fertilisation is a dynamic mechanism that is essential for early development. Amongst the three types of dnmt genes in vertebrates, dnmt3 is the one involved in de novo methylation and comprises three related genes, termed dnmt3a, dnmt3b and dnmt3L in mammals. Zebrafish (Danio rerio) has six dnmt3 paralogues, which have hitherto been termed dnmt3 to dnmt8. Bayesian inference of phylogeny and synteny analysis revealed that dnmt6 and dnmt8 are in fact duplicated dnmt3a genes, whereas the other paralogues are closely related to dnmt3b. Hence, we propose a revised nomenclature that more accurately reflects the relationship amongst zebrafish dnmt3 genes. Both dnmt3a genes were ubiquitously expressed in adult tissues, whilst the various dnmt3b paralogues were differentially expressed, with notably high expression levels in the gonads. The influence of embryonic temperature on dnmt3 expression was investigated, since it is known to have a significant impact in early development and a long-term effect on growth in some teleost species. Embryos were incubated at 23, 27 or 31 degrees C and samples collected at six developmental stages from blastula until protruding mouth. Dnmt3 expression during early development was remarkably dynamic. In particular, mRNA levels of the two dnmt3a genes showed a marked increase throughout development and several significant differences in dnmt3a and dnmt3b transcript levels were found between temperatures at the same developmental point. Taken together, our data indicate that dnmt3 paralogues are diverging and that dnmt3a and dnmt3b may play different roles in thermal epigenetic regulation of gene expression during early development. PMID- 22450364 TI - Characterization of a gene encoding prohibitin in silkworm, Bombyx mori. AB - BACKGROUND: Prohibitin (PHB) is an evolutionarily conserved multifunctional protein with ubiquitous expression. However, its molecular roles are largely unknown. METHODS: To better understand the function of prohibitin protein in silkworm (BmPHB), its coding sequence was isolated from a cDNA library of silkworm pupae. An His-tagged BmPHB fusion protein was expressed in Escherichia coli Rosetta (DE3) and purified with affinity and reversed-phase chromatography. Purified rBmPHB was used to generate anti-BmPHB polyclonal antibody. The subcellular localization of BmPHB was analysed by immunohistochemistry. RESULTS: BmPHB gene has an ORF of 825 bp, encoding a predicted peptide with 274 amino acid residues. Immunostaining indicate that prohibitin is expressed in nucleus and predominately in cytoplasm. Western blot analyses indicated that, in the fifth instar larva, BmPHB was expressed descendingly in gonad, malpighian tubule, trachea, fatty body, intestine, and head. However, no expression was detected in larva's silk gland and epidermis. In addition, BmPHB was expressed in the nascent egg, larva and pupa, but not in the moth. CONCLUSIONS: The expression of BmPHB gene presents differential characteristic in different stage and tissues. It may play important roles in the development of silkworm. GENERAL SIGNIFICANCE: Studies on prohibitin have been still restricted to a few specific insects and insect cell lines such as Drosophila, Acyrthosiphon pisum and mosquito cell lines, not yet in silkworm. This is a first characterization of prohibitin in silkworm, B. mori. PMID- 22450365 TI - Characterization of V1R receptor (ora) genes in Lake Victoria cichlids. AB - Although olfaction could play a crucial role in underwater habitats by allowing fish to sense a variety of nonvolatile chemical signals, the importance of olfaction in species-rich cichlids is still controversial. In particular, examining whether cichlids rely on olfaction for reproduction is of primary interest to understand the mechanisms of speciation. In the present study, we explored the V1R (also known as ora) genes, which are believed to encode reproductive pheromone receptors in fish, in the genomes of Lake Victoria cichlids. By screening a bacterial artificial chromosome library, we identified all six intact V1R genes (V1R1 to V1R6) that have been reported in other teleost fish. Furthermore, RT-PCR and in situ hybridization analyses showed that all of the V1R genes were expressed in the olfactory epithelium, indicating that these receptors are functional in cichlids. These observations indicate that cichlids use V1R-mediated olfaction in some ways for their social behaviors. PMID- 22450366 TI - Dilation of both pancreatic duct and the common bile duct on computed tomography and magnetic resonance imaging scans in patients with or without obstructive jaundice. AB - OBJECTIVES: "Double-duct sign" (strictures in both common bile duct [CBD] and pancreatic duct [PD] with proximal dilation) on endoscopic retrograde cholangiopancreatography is considered suggestive of pancreatic malignancy. Dilation of CBD and PD is frequently noted on computed tomography/magnetic resonance imaging scans, sometimes found incidentally in patients without jaundice. The prevalence of malignancy in these patients is not established. METHODS: In this retrospective analysis, consecutive patients who underwent endoscopic ultrasound (EUS) at a tertiary care hospital from 2002 to 2006 for suspected pancreatic malignancy and had double-duct sign on imaging were included. We evaluated (1) prevalence of malignancy in patients with or without obstructive jaundice and (2) performance characteristics of EUS-fine-needle aspiration (FNA) in diagnosing malignancy in this setting. RESULTS: A final diagnosis of pancreatic malignancy was made in 142 (85.5%) of 166 patients with and 4 (5.9%) of 68 without obstructive jaundice (P < 0.005). The accuracy of EUS FNA for diagnosing malignancy in patients with or without obstructive jaundice was 92.8% versus 98.5%. CONCLUSIONS: Dilation of both PD and CBD on computed tomography/magnetic resonance imaging scans is suggestive of pancreatic malignancy. The prevalence of malignancy, however, is markedly lower in patients without obstructive jaundice but is clinically significant and merits further diagnostic evaluation. Endoscopic ultrasound-FNA is highly accurate for diagnosing malignancy in this setting. PMID- 22450367 TI - Synergizing genomic analysis with biological knowledge to identify and validate novel genes in pancreatic development. AB - OBJECTIVE: This study investigated the utility of advanced computational techniques to large-scale genome-based data to identify novel genes that govern murine pancreatic development. METHODS: An expression data set for mouse pancreatic development was complemented with high-throughput data analyzer to identify and prioritize novel genes. Quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to validate selected genes. RESULTS: Four new genes whose roles in the development of murine pancreas have not previously been established were identified: cystathionine beta synthase (Cbs), Meis homeobox 1, growth factor independent 1, and aldehyde dehydrogenase 18 family, member A1. Their temporal expression during development was documented. Cbs was localized in the cytoplasm of the tip cells of the epithelial chords of the undifferentiated progenitor cells at E12.5 and was coexpressed with the pancreatic and duodenal homeobox 1 and pancreas-specific transcription factor, 1a-positive cells. In the adult pancreas, Cbs was localized primarily within the acinar compartment. CONCLUSIONS: In silico analysis of high throughput microarray data in combination with background knowledge about genes provides an additional reliable method of identifying novel genes. To our knowledge, the expression and localization of Cbs have not been previously documented during mouse pancreatic development. PMID- 22450368 TI - SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma. AB - OBJECTIVES: This study aimed to assess the role of SLC5A8 expression in the survival of pancreatic cancer. METHODS: We determined SLC5A8 expression in pancreatic ductal adenocarcinoma and adjacent non-neoplastic pancreas (NNP) obtained from 110 patients who underwent pancreatectomy. Formalin-fixed paraffin embedded core sections in a tissue microarray were immunostained using polyclonal anti-SLC5A8 antibody, and a semiquantitative measure of SLC5A8 expression was determined. RESULTS: SLC5A8 expression was low in 56% (62/110) of pancreatic cancers as compared to NNP that had low expression in only 9% (10/107) of specimens (P < 0.0001). All cells expressing SLC5A8 did so in the cytoplasm, whether they are neoplastic or not. Nuclear expression of SLC5A8 occurred in 38% (42/110) of cancers, but it was uncommon in NNP (7%, 8/107) (P < 0.0001). Kaplan Meier estimates showed that survival in patients whose cancers had low SLC5A8 expression, and/or nuclear expression, was significantly worse than in patients whose cancers had none of these abnormalities (P = 0.02). For the 88 patients whose cancers had abnormal SLC5A8 expression, median survival was 1.4 years, as compared to 3.9 years in patients whose cancers both expressed high levels of SLC5A8 and lacked nuclear expression. CONCLUSIONS: SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma. PMID- 22450369 TI - Infliximab enhances the therapeutic effectiveness of octreotide on acute necrotizing pancreatitis in rat model. AB - OBJECTIVES: To investigate the synergistic activity of infliximab to the therapeutic effectiveness of octreotide in a rat model of acute necrotizing pancreatitis (ANP). METHODS: Forty Sprague-Dawley rats were randomly divided into sham-operated group (SO), ANP group (ANP), octreotide group (OG), infliximab group (IG), and combination group (CG) (n = 8 in each group). The ANP model was induced by biliopancreatic duct injection with 4.5% of sodium taurocholate solution. Rats of the OG, IG, and CG were given a tail vein injection of octreotide (10 MUg/kg), infliximab (8 mg/kg), and infliximab (8 mg/kg), respectively, combined with octreotide (10 MUg/kg) at 6 hours after modeling. All rats in each group were killed at 24 hours after modeling. Serum biochemical indicator and partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) of rats were determined. Pathological severity score of organs were evaluated. RESULTS: The serum biochemical indicator and organs' pathology score of OG , IG, and CG were obviously lower than those in the ANP group, and those in the CG were the lowest (P < 0.05). The PaO2/FiO2 levels in the OG, IG, and CG were significantly higher than that in the ANP group (P < 0.05). CONCLUSION: Infliximab could significantly lower the serum biochemical indicator, improve organs' function, and enhance the therapeutic effectiveness of octreotide on ANP. PMID- 22450370 TI - Longitudinal brain volumetric changes during one year in non-elderly healthy adults: a voxel-based morphometry study. AB - Previous cross-sectional magnetic resonance imaging (MRI) studies of healthy aging in young adults have indicated the presence of significant inverse correlations between age and gray matter volumes, although not homogeneously across all brain regions. However, such cross-sectional studies have important limitations and there is a scarcity of detailed longitudinal MRI studies with repeated measures obtained in the same individuals in order to investigate regional gray matter changes during short periods of time in non-elderly healthy adults. In the present study, 52 healthy young adults aged 18 to 50 years (27 males and 25 females) were followed with repeated MRI acquisitions over approximately 15 months. Gray matter volumes were compared between the two times using voxel-based morphometry, with the prediction that volume changes would be detectable in the frontal lobe, temporal neocortex and hippocampus. Voxel-wise analyses showed significant (P < 0.05, family-wise error corrected) relative volume reductions of gray matter in two small foci located in the right orbitofrontal cortex and left hippocampus. Separate comparisons for males and females showed bilateral gray matter relative reductions in the orbitofrontal cortex over time only in males. We conclude that, in non-elderly healthy adults, subtle gray matter volume alterations are detectable after short periods of time. This underscores the dynamic nature of gray matter changes in the brain during adult life, with regional volume reductions being detectable in brain regions that are relevant to cognitive and emotional processes. PMID- 22450371 TI - The influence of stress on fear memory processes. AB - It is well recognized that stressful experiences promote robust emotional memories, which are well remembered. The amygdaloid complex, principally the basolateral complex (BLA), plays a pivotal role in fear memory and in the modulation of stress-induced emotional responses. A large number of reports have revealed that GABAergic interneurons provide a powerful inhibitory control of the activity of projecting glutamatergic neurons in the BLA. Indeed, a reduced GABAergic control in the BLA is essential for the stress-induced influence on the emergence of associative fear memory and on the generation of long-term potentiation (LTP) in BLA neurons. The extracellular signal-regulated kinase (ERK) subfamily of the mitogen-activated protein kinase (MAPK) signaling pathway in the BLA plays a central role in the consolidation process and synaptic plasticity. In support of the view that stress facilitates long-term fear memory, stressed animals exhibited a phospho-ERK2 (pERK2) increase in the BLA, suggesting the involvement of this mechanism in the promoting influence of threatening stimuli on the consolidation fear memory. Moreover, the occurrence of reactivation-induced lability is prevented when fear memory is encoded under intense stressful conditions since the memory trace remains immune to disruption after recall in previously stressed animals. Thus, the underlying mechanism in retrieval-induced instability seems not to be functional in memories formed under stress. All these findings are indicative that stress influences both the consolidation and reconsolidation fear memory processes. Thus, it seems reasonable to propose that the emotional state generated by an environmental challenge critically modulates the formation and maintenance of long-term fear memory. PMID- 22450372 TI - Estrous cycle and stress: influence of progesterone on the female brain. AB - The female brain operates in a constantly changing chemical milieu caused by cyclical changes in gonadal hormones during the estrous cycle (menstrual cycle in women). Such hormones are highly lipophilic and pass readily from the plasma to the brain where they can influence neuronal function. It is becoming clear that the rapid reduction in peripheral circulating progesterone, which occurs during the late diestrous phase of the cycle, can trigger a withdrawal-like response, in which changes in GABA(A) receptor expression render hyper-responsive certain brain areas involved in processing responses to stressful stimuli. The periaqueductal gray matter (PAG) is recognised as an important region for integrating anxiety/defence responses. Withdrawal from progesterone, via actions of its neuroactive metabolite allopregnanolone, triggers up-regulation of extrasynaptic GABA(A) receptors on GABAergic neurons in the PAG. As a consequence, ongoing GABAergic tone on the output cells decreases, leading to an increase in functional excitability of the circuitry and enhanced responsiveness to stressful stimuli during the late diestrous phase. These changes during late diestrus could be prevented by short-term neurosteroid administration, timed to produce a more gradual fall in the peripheral concentration of allopregnanolone than the rapid decrease that occurs naturally, thus removing the trigger for the central withdrawal response. PMID- 22450373 TI - Contrasting effects of nitric oxide and corticotropin- releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice. AB - The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N (cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6 trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino) N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of N(omega)-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure. PMID- 22450374 TI - What ethologically based models have taught us about the neural systems underlying fear and anxiety. AB - Classical Pavlovian fear conditioning to painful stimuli has provided the generally accepted view of a core system centered in the central amygdala to organize fear responses. Ethologically based models using other sources of threat likely to be expected in a natural environment, such as predators or aggressive dominant conspecifics, have challenged this concept of a unitary core circuit for fear processing. We discuss here what the ethologically based models have told us about the neural systems organizing fear responses. We explored the concept that parallel paths process different classes of threats, and that these different paths influence distinct regions in the periaqueductal gray - a critical element for the organization of all kinds of fear responses. Despite this parallel processing of different kinds of threats, we have discussed an interesting emerging view that common cortical-hippocampal-amygdalar paths seem to be engaged in fear conditioning to painful stimuli, to predators and, perhaps, to aggressive dominant conspecifics as well. Overall, the aim of this review is to bring into focus a more global and comprehensive view of the systems organizing fear responses. PMID- 22450375 TI - Neural regulation of the stress response: glucocorticoid feedback mechanisms. AB - The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback 'switch', control of the stress response requires a wide-reaching feedback 'network' that coordinates HPA activity to suit the overall needs of multiple body systems. PMID- 22450376 TI - Participation of the NO/cGMP/K+ATP pathway in the antinociception induced by Walker tumor bearing in rats. AB - Implantation of Walker 256 tumor decreases acute systemic inflammation in rats. Inflammatory hyperalgesia is one of the most important events of acute inflammation. The L-arginine/NO/cGMP/K(+)ATP pathway has been proposed as the mechanism of peripheral antinociception mediated by several drugs and physical exercise. The objective of this study was to investigate a possible involvement of the NO/cGMP/K(+)ATP pathway in antinociception induced in Walker 256 tumor bearing male Wistar rats (180-220 g). The groups consisted of 5-6 animals. Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. Walker tumor (4th and 7th day post-implantation) reduced prostaglandin E(2)- (PGE(2), 400 ng/paw; 50 uL; intraplantar injection) and carrageenan-induced hypernociception (500 ug/paw; 100 uL; intraplantar injection). Walker tumor-induced analgesia was reversed (99.3% for carrageenan and 77.2% for PGE(2)) by a selective inhibitor of nitric oxide synthase (L-NAME; 90 mg/kg, ip) and L-arginine (200 mg/kg, ip), which prevented (80% for carrageenan and 65% for PGE(2)) the effect of L-NAME. Treatment with the soluble guanylyl cyclase inhibitor ODQ (100% for carrageenan and 95% for PGE(2); 8 ug/paw) and the ATP-sensitive K(+) channel (KATP) blocker glibenclamide (87.5% for carrageenan and 100% for PGE(2); 160 ug/paw) reversed the antinociceptive effect of tumor bearing in a statistically significant manner (P < 0.05). The present study confirmed an intrinsic peripheral antinociceptive effect of Walker tumor bearing in rats. This antinociceptive effect seemed to be mediated by activation of the NO/cGMP pathway followed by the opening of KATP channels. PMID- 22450377 TI - A road map for the development of community systems (CoSy) biology. AB - Microbial interactions are essential for all global geochemical cycles and have an important role in human health and disease. Although we possess general knowledge about the major processes within a microbial community, we are presently unable to decipher what role individual microorganisms have and how their individual actions influence others in the community. We also have limited knowledge with which to predict the effects of microbial interactions and community composition on the environment and vice versa. In this Opinion article, we describe how community systems (CoSy) biology will enable us to decode these complex relationships and will therefore improve our understanding of individual members of the community and the modes of interactions in which they engage. PMID- 22450378 TI - Cellular microbiology: Ironing out Hfq regulation. PMID- 22450380 TI - A personal view on systems medicine and the emergence of proactive P4 medicine: predictive, preventive, personalized and participatory. AB - Systems biology and the digital revolution are together transforming healthcare to a proactive P4 medicine that is predictive, preventive, personalized and participatory. Systems biology - holistic, global and integrative in approach - has given rise to systems medicine, a systems approach to health and disease. Systems medicine promises to (1) provide deep insights into disease mechanisms, (2) make blood a diagnostic window for viewing health and disease for the individual, (3) stratify complex diseases into their distinct subtypes for a impedance match against proper drugs, (4) provide new approaches to drug target discovery and (5) generate metrics for assessing wellness. P4 medicine, the clinical face of systems medicine, has two major objectives: to quantify wellness and to demystify disease. Patients and consumers will be a major driver in the realization of P4 medicine through their participation in medically oriented social networks directed at improving their own healthcare. P4 medicine has striking implications for society - including the ability to turn around the ever escalating costs of healthcare. The challenge in bringing P4 medicine to patients and consumers is twofold: first, inventing the strategies and technologies that will enable P4 medicine and second, dealing with the impact of P4 medicine on society - including key ethical, social, legal, regulatory, and economic issues. Managing the societal problems will pose the most significant challenges. Strategic partnerships of a variety of types will be necessary to bring P4 medicine to patients. PMID- 22450379 TI - New insights into bacterial adaptation through in vivo and in silico experimental evolution. AB - Microbiology research has recently undergone major developments that have led to great progress towards obtaining an integrated view of microbial cell function. Microbial genetics, high-throughput technologies and systems biology have all provided an improved understanding of the structure and function of bacterial genomes and cellular networks. However, integrated evolutionary perspectives are needed to relate the dynamics of adaptive changes to the phenotypic and genotypic landscapes of living organisms. Here, we review evolution experiments, carried out both in vivo with microorganisms and in silico with artificial organisms, that have provided insights into bacterial adaptation and emphasize the potential of bacterial regulatory networks to evolve. PMID- 22450381 TI - Diffusion-weighted imaging with relative signal intensity statistical thresholding for delineating prostate cancer tumors. AB - PURPOSE: We assessed the utility of diffusion-weighted imaging (DWI) with relative signal intensity (rSI) statistical thresholding for delineating prostate cancer tumors. MATERIALS AND METHODS: Seventeen patients with prostate cancer underwent DWI before total prostatectomy. We measured standard deviation (SD) of the signal intensity (SI) of the lesser pelvic space at DWI, created rSI maps, displaying signal intensities with SDs of only > +3, > +3.5, > +4, or > +5, and assessed correlation between the proportion of cancerous area on the 4 different rSI maps and that on pathological slices. RESULTS: We could detect prostate cancer on rSI maps for all cases with SD > +3, but not 2 cases with SD > +3.5, five with SD > +4, and eight with SD > +5. The correlation coefficients (R) between the proportion of cancerous area on pathological examination and rSI maps were 0.7464 for SD > +3 (P = 0.0006); 0.6469 for SD > +3.5 (P = 0.0050); 0.6459 for SD > +4 (P = 0.0051), and 0.4540 for SD > +5 (P = 0.0671). CONCLUSION: DWI based rSI mapping may be used to delineate the extent of prostate cancer. We achieved best correlation between ratio of cancerous area of the lesser pelvic space on pathological examination and on rSI map using a threshold with SD > +3 of the SI. PMID- 22450382 TI - Whole-heart 3D late gadolinium-enhanced MR imaging: investigation of optimal scan parameters and clinical usefulness. AB - PURPOSE: Whole-heart 3-dimensional (3D) late-gadolinium-enhanced magnetic resonance (MR) imaging (WH-LGE) uses respiratory gating combined with acquisition of 3D data for the entire heart in a single scan, which permits reconstruction of any plane with high resolution. We investigated the optimal scan parameters and compared WH-LGE with the conventional scanning method. MATERIALS AND METHODS: We employed inversion recovery 3D fast field echo using a 1.5-tesla system and scan parameters: repetition time (TR), 6.6 ms; echo time (TE), 2.5 ms; number of segments, 2; parallel imaging factor, 1.8; matrix size, 128 * 256; field of view (FOV), 320 * 320 mm; and acquisition slice thickness, 3 mm (reconstruction slice thickness, 1.5 mm). Five healthy volunteers underwent scanning during free breathing with real-time motion correction, from which we determined optimal scan parameters. We then used those parameters to scan 25 patients with myocardial infarction to compare scan time and image quality between the WH-LGE and conventional 3D breath-holding methods (slice thickness, 10 mm; matrix size, 128 * 256). RESULTS: Results in volunteers showed optimal scan parameters of 12 degrees flip angle, fat suppression turned off in combination, and interleaved ordering. In clinical cases, scan times did not differ significantly. Sharpness of the margins of normal myocardium at the apex of the heart and contrast between enhanced and nonenhanced myocardium improved significantly with WH-LGE. CONCLUSION: WH-LGE yields high resolution images during free breathing and is considered useful for accurately estimating the area and transmural extent of myocardial infarction. PMID- 22450383 TI - Effective performance of T(1)-weighted FLAIR Imaging with BLADE in pediatric brains. AB - PURPOSE: In magnetic resonance imaging of the brain, BLADE is used to compensate for head motion. The technique focuses mainly on acquisition of T(2)-weighted or contrast-enhanced T(1)-weighted images in adults; its utility for nonenhanced T(1)-weighted imaging in children is not well established. We compared the quality of T(1)-weighted fluid-attenuated inversion recovery brain imaging with BLADE (T(1)-FLAIR-BLADE) to that of conventional spin-echo T(1)-weighted imaging (T(1)-SE) in pediatric patients who cannot stay still during MR imaging. MATERIALS AND METHODS: Our investigation included a volunteer study and a retrospective clinical study. Six healthy adult volunteers underwent scanning to compare the contrast of T(1)-SE, T(1)-weighted fluid-attenuated inversion recovery imaging (T(1)-FLAIR), and T(1)-FLAIR-BLADE at both 1.5 and 3 tesla. Comparison was based on scores assigned independently by 2 blinded observers and by calculated contrast-to-noise ratio. The clinical study included 20 children who underwent both T(1)-SE and T(1)-FLAIR-BLADE at either 1.5 (n = 9) or 3 T (n = 11). On each sequence, 2 blinded observers independently scored visualization of the cerebral gyri and contrast between gray and white matter. We compared scores between sequences separately for 1.5 and 3T using Wilcoxon signed-rank tests. RESULTS: At both 1.5 and 3T, contrast was better using T(1)-FLAIR and T(1)-FLAIR BLADE than T(1)-SE in volunteers, and overall scores were significantly higher with T(1)-FLAIR-BLADE (P < 0.05) than T(1)-SE in the clinical study. CONCLUSION: T(1)-FLAIR-BLADE may be superior to T(1)-SE in demonstrating brain structures in children who cannot stay still and may be used to supplement or replace T(1)-SE when T(1)-SE is insufficient for patient motion. PMID- 22450384 TI - Effects of image distortion correction on voxel-based morphometry. AB - PURPOSE: We aimed to show that correcting image distortion significantly affects brain volumetry using voxel-based morphometry (VBM) and to assess whether the processing of distortion correction reduces system dependency. MATERIALS AND METHODS: We obtained contiguous sagittal T(1)-weighted images of the brain from 22 healthy participants using 1.5- and 3-tesla magnetic resonance (MR) scanners, preprocessed images using Statistical Parametric Mapping 5, and tested the relation between distortion correction and brain volume using VBM. RESULTS: Local brain volume significantly increased or decreased on corrected images compared with uncorrected images. In addition, the method used to correct image distortion for gradient nonlinearity produced fewer volumetric errors from MR system variation. CONCLUSION: This is the first VBM study to show more precise volumetry using VBM with corrected images. These results indicate that multi-scanner or multi-site imaging trials require correction for distortion induced by gradient nonlinearity. PMID- 22450385 TI - Ytterbium-based PARACEST agent: feasibility of CEST imaging on a clinical MR scanner. AB - PURPOSE: We investigated the feasibility of performing chemical exchange saturation transfer (CEST) imaging using ytterbium-based paramagnetic CEST (PARACEST) agents on a clinical magnetic resonance (MR) scanner. MATERIALS AND METHODS: We prepared solutions of 3 different ytterbium-based PARACEST agents at concentrations of 5, 10, 20, and 50 mM at a pH of 7.4 and at a concentration of 50 mM at pHs of 3.0, 5.0, 7.4, and 9.5. We acquired images with a turbo spin echo technique using a quadrature head coil and a clinical 3.0-tesla MR system in accordance with the safety limits of the specific absorption rate (SAR). We acquired CEST images with presaturation offset frequencies from -5,000 Hz (-39.1 ppm) to 5,000 Hz (39.1 ppm) with an interval of 500 Hz (3.9 ppm) for each condition. We repeated each scan 3 times and then calculated the mean and standard deviations of the magnitude of the CEST effect at different concentrations and pH values for each agent. We used one-way analysis of variance and Tukey's honestly significant difference post hoc test to compare mean values of the magnitude of the CEST effect obtained at different concentrations and pH values. P < 0.05 was considered significant. RESULTS: PARACEST agents showed a strong CEST effect at their specific presaturation offset frequencies. For each agent, the CEST effect showed significant concentration dependency (P < 0.05), increasing with agent concentration, and significant pH dependency (P < 0.05), with strong effect near physiological pH. CONCLUSION: CEST imaging using ytterbium-based PARACEST agents might be feasible on a clinical MR scanner with further modifications, such as adjustments of the presaturation radiofrequency pulse and imaging protocols. PMID- 22450386 TI - Visualization of endolymphatic hydrops in Meniere's disease after single-dose intravenous gadolinium-based contrast medium: timing of optimal enhancement. AB - PURPOSE: Visualization of endolymphatic hydrops (EH) in patients with Meniere's disease (MD) is now possible by heavily T(2)-weighted 3-dimensional fluid attenuated inversion recovery (hT(2)W-3D-FLAIR) obtained 4 hours after intravenous (IV) administration of single dose gadolinium-based contrast medium (GBCM). Although maximum enhancement has been reported 4 hours after contrast administration in healthy volunteers, the timing of optimal enhancement in patients with MD is not reported. We investigated if that optimal timing is earlier or later than 4 hours. MATERIALS AND METHODS: We evaluated 10 consecutive patients with suspected MD whom we randomly divided into 2 groups. We obtained hT(2)W-3D-FLAIR before GBCM administration and 10 min, 3.5 hours, and 4 hours after GBCM administration in Group A and before and 10 min, 4 hours, and 4.5 hours after GBCM administration in Group B. We compared signal intensity ratio (SIR) values of the perilymph and pons between 3.5 and 4 hours in Group A and between 4 and 4.5 hours in Group B and evaluated grades of EH at 3.5 and 4 hours in Group A and at 4 and 4.5 hours in Group B. RESULTS: SIR values did not differ significantly between 3.5 and 4 hours in Group A and between 4 and 4.5 hours in Group B. However, SIR values at 4 hours were significantly higher in Group A than Group B. Grades of EH agreed between 3.5 and 4 hours in Group A and between 4 and 4.5 hours in Group B. CONCLUSION: The optimal timing of contrast enhancement in patients with suspected MD remains unclear, but evaluation of EH may be possible from 3.5 to 4.5 hours after contrast administration. PMID- 22450387 TI - Evaluation of concanavalin A-induced acute liver injury in rats using an empirical mathematical model and dynamic contrast-enhanced MR imaging with Gd-EOB DTPA. AB - PURPOSE: We evaluated concanavalin A (Con A)-induced acute hepatic injury in rats using an empirical mathematical model (EMM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). MATERIALS AND METHODS: We allocated 18 rats into 3 groups of six each and intravenously injected them with either 10 mg/kg body weight (BW) of Con A (Con A [10] group), 20 mg/kg BW of Con A (Con A [20] group), or a single dose of of saline (4 mL/kg BW, normal control group). We performed the DCE-MRI studies using Gd-EOB-DTPA (0.025 mmol Gd/kg; 0.1 mL/kg BW) as the contrast agent 24 hours after injection of Con A or saline. We then sampled blood, measured serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and calculated the rate of contrast uptake (alpha), rate of contrast washout (beta), area under the curve (AUC), time to maximum relative enhancement (RE) (T(max)), and elimination half-life of RE (T(1/2)) from the time signal intensity curves using the EMM. RESULTS: beta values were significantly smaller in the Con A (10) and Con A (20) groups than the control group, but alpha did not differ significantly among the 3 groups. The AUC value was significantly greater in the Con A (10) group than controls, and the T(max) and T(1/2) values were significantly greater in the Con A (20) group than controls. The beta, T(max), and T(1/2) values correlated significantly with AST and ALT. CONCLUSION: In conclusion, the EMM is useful for evaluating Con A-induced acute hepatic injury using DCE-MRI with Gd-EOB-DTPA. PMID- 22450388 TI - Central high signal in inflammatory swollen lymph nodes on SPIO-enhanced interstitial MR lymphograms: a mimic of lymph node metastasis. PMID- 22450389 TI - MR imaging of focal medullary sponge kidney: case report. AB - We present a case of focal medullary sponge kidney (MSK) that mimicked a renal tumor. Evaluation of a patient with history of macrohematuria revealed a left renal mass of 3-cm diameter. T(1)-weighted magnetic resonance (MR) images revealed a mass of mixed intensity protruding toward the renal sinus. On fat saturated T(2)-weighted MR images, the lesion's remarkable hyperintensity suggested the presence of an aggregation of tiny cysts. On diffusion-weighted MR images, the mass also demonstrated high intensity, and its apparent diffusion coefficient was partly decreased (1.12 * 10(-3) mm(2)/s). On computed tomography, precontrast images revealed no calcification in the mass. Although slight enhancement was seen in the corticomedullary phase, thick and dense streaks of contrast radiating peripherally were identified in the mass in the excretory phase. Focal MSK was diagnosed. We discuss the potential of MR imaging for diagnosing focal MSK. PMID- 22450390 TI - Diffusion-weighted imaging of a malignant brenner tumor. AB - Microscopically, ovarian malignant Brenner tumor shows components of malignant transitional cell tumor intermixed with benign and borderline elements. We report a case of this tumor with components that transition from benign to malignant on diffusion-weighted images (DWI) and in histologic findings. The benign component showed low signal intensity on T(2)-weighted images, whereas the malignant component showed high signal intensity on T(2)-weighted images and high signal intensity on DWI with low apparent diffusion coefficient (ADC) value. PMID- 22450391 TI - Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives? AB - PURPOSE OF REVIEW: Axial spondyloarthritis (SpA) - including ankylosing spondylitis (AS) - is a frequent chronic inflammatory disease that affects mainly the axial skeleton. There is evidence that NSAIDs and tumor necrosis factor (TNF) alpha blockers are efficacious, but not all patients achieve remission or a major clinical response. A variety of new drug classes have been investigated during the last years for the treatment of patients with AS in whom TNF blockers have failed or are contraindicated. RECENT FINDINGS: Data for abatacept, anakinra, apremilast, bisphosphonates, rituximab, secukinumab, sulfasalazine, thalidomide and tocilizumab were found. All studies had problems with design and methodology. SUMMARY: Although some trends for efficacy were seen, there is at present insufficient evidence to support a recommendation for any of these compounds. So far, none of these new drugs has been shown to reach response rates compared to TNF-blockers. PMID- 22450392 TI - Innovative antifibrotic therapies in systemic sclerosis. AB - PURPOSE OF REVIEW: Fibrosis is a key feature of systemic sclerosis (SSc) and arises from excessive release of collagens by pathologically activated fibroblasts. Affecting the skin and many internal organs, fibrosis represents a major cause for the high morbidity and mortality in SSc. So far, effective therapies to treat fibrosis in SSc and other fibrotic diseases are not available in clinical routine. Nevertheless, promising antifibrotic agents are emerging from translational studies with some having already entered clinical trials. RECENT FINDINGS: In this review, we focus on recent advances in the development of antifibrotic treatment strategies in SSc. We have selected for targeted therapeutic approaches that have proven high efficacy and tolerability in preclinical fibrosis models of SSc and/or are already in clinical evaluation. Applying these criteria, we discuss a large repertory of candidate antifibrotic therapies that block inflammatory pathways, inhibit profibrotic growth factors, modulate epigenetic signaling, and interfere with morphogenic pathways. SUMMARY: Many antifibrotic candidate therapies have proven efficacy and tolerability in preclinical models of SSc. So far, early clinical studies have tested only few of these agents. Besides discovering novel molecular treatment strategies, SSc research will now have to translate its findings into clinical practice. PMID- 22450393 TI - How to assess treatment efficacy in Sjogren's syndrome? AB - PURPOSE OF REVIEW: This article critically reviews the current views and discusses the future challenges with regard to assessing disease progression and disease activity in Sjogren's syndrome, as a decrease of disease progression and activity is what an effective Sjogren's syndrome therapy aims for. This topic has recently gained renewed attention as targeted treatment modalities have become available in primary Sjogren's syndrome, while the lack of well established outcome parameters interferes with a straightforward comparison of the outcomes of the various trials. RECENT FINDINGS: Recent advances in how to assess changes in disease progression and activity objectively (via repeated biopsies of salivary glands, sialometry, sialochemistry, biomarkers, secretion and composition of tears, EULAR Sjogren's Syndrome Disease Activity Index: ESSDAI) and subjectively (EULAR Sjogren's Syndrome Patient Related Index: ESSPRI) have opened new ways to reliably assess the outcome of a particular treatment. SUMMARY: Newly applied tools are instrumental, both for clinical research and clinical practice, in reliably judging and comparing the value of well established and newly developed therapies in Sjogren's syndrome. PMID- 22450394 TI - How to screen for axial spondyloarthritis in primary care? AB - PURPOSE OF REVIEW: There is a major delay of several years between first symptoms and making a diagnosis in patients with axial spondyloarthritis. A strategy for earlier diagnosis is urgently needed, for which efficient referral parameters applicable in primary care are an important part. Published studies on referral programs are reviewed and their relevance for daily clinical practice is discussed. RESULTS: Several referral investigations have been performed in several countries using the symptom of 'inflammatory back pain' (IBP) alone or in combination with other referral parameters. All studies performed resulted in a good and acceptable percentage of an axial SpA diagnosis in between 29 and 58%. A set of rather simple parameters (IBP and/or HLA-B27 positivity and/or sacroiliitis on imaging) performed better than IBP alone and is easier to use than more complicated referral strategies. SUMMARY: Referral strategies to screen for axial SpA patients in primary care are available, are effective and should be applied more regularly. PMID- 22450395 TI - The obesity paradox in chronic disease: facts and numbers. AB - Body size, particularly large, is a matter of concern among the lay public. Whether this is justified depends upon the state of health and should be judged individually. For patients with established chronic disease, there is sufficient evidence to support the benefits of large body size, i.e., the obesity paradox. This uniform finding is shared over a variety of cardiovascular, pulmonary, and renal diseases and is counterintuitive to the current concepts on ideal body weight. The scientific community has to increase the awareness about differences for optimal body size in health and disease. Simultaneously, clinicians have to be aware about body weight dynamics implications and should interpret the changes in the context of an underlying disease in order to implement the best available management. PMID- 22450396 TI - Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. AB - BACKGROUND & AIMS: The adequacy of monitoring HBeAg-negative patients based on ALT activity is controversial and current guidelines favor liver biopsy in HBeAg negative cases with normal ALT and HBV DNA >2000 IU/ml. We systematically reviewed all the available histological data on HBeAg-negative patients with persistently normal ALT (PNALT) to determine the prevalence of significant liver disease and its associating factors. METHODS: Literature search to identify studies with adult HBeAg-negative patients who had PNALT as defined by the authors, a minimum follow-up of 1 year and histological data. Traditional cut-off values of normal ALT were used in all studies. The definitions of PNALT were considered as acceptable or good if there were >=3 ALT determinations at unspecified intervals during 6-12 months or predefined intervals during >=12 month periods, respectively. RESULTS: Six studies including 335 patients met our inclusion criteria. Of these, four studies with 246 patients had good or acceptable definitions of PNALT. In the latter four studies, more than minimal (usually mild) necro-inflammatory activity was observed in 10% and more than mild fibrosis in 8% of all patients (moderate fibrosis: 7%, severe fibrosis: 1%, cirrhosis: 0%), and in 3% and 5% of patients with HBV DNA <=20,000 IU/ml, respectively. CONCLUSIONS: Histologically significant liver disease is rare in HBeAg-negative patients with PNALT based on stringent criteria and serum HBV DNA <=20,000 IU/ml. Such cases can be considered as true inactive HBV carriers, who require neither liver biopsy nor immediate therapy but continued follow-up. PMID- 22450397 TI - [Qualitative research in collective health: overview and challenges]. AB - This article provides an overview of the nuclear themes in the debate about the qualitative health research approach in the Brazilian scientific context and more specifically in the public health field. The author begins by defining some central concepts in the analysis conducted. Then, combining the literature on the subject with her academic praxis, she examines the current status of this research tradition, highlighting an extensive set of challenges. The discussion focuses on each challenge, moving between the different epistemic, ethical and operational planes in relation to the scientific status of this approach to public health. Considering various questions and based on empirical examples, analysis shows that, despite the expansion observed in qualitative research and its contributions to public health, this approach still faces many challenges before consolidating its status. The situation demands investments in dialogue with the other approaches which form the core area. Despite these challenges, the paper concludes by pointing to the possibility of new pacts in the public health field in order to incorporate innovations to address the diversity and complexity of this field. PMID- 22450399 TI - [Teaching and learning the science of qualitative research in the health area]. AB - Qualitative research constitutes a necessary perspective of knowledge within the field of health services. Healthcare always occurs in complex contexts and its enhancement requires research methodologies that address this complexity. Nevertheless, the knowledge and use of qualitative research in health services is still very limited. Among the different factors that affect its development, the teaching and learning of qualitative research proves to be fundamental, even beyond undergraduate education. Healthcare professionals and health services present certain specific aspects that must be considered in the design and development of the teaching and learning of qualitative research. Based on an eight-year online training experience with Primary Healthcare professionals, the main challenges are indentified and discussed. PMID- 22450400 TI - [Ethical dilemmas in fieldwork: forgotten issues in qualitative health research in Iberoamerica]. AB - This paper explores some ethical dilemmas faced while doing fieldwork. Ethical norms are not enough to appraise the relationship between researchers and participants; a reflexivity practice is needed to understand the dilemmas aroused during this process. Here four issues faced during fieldwork are presented. The academic social time usually defines the schedule of fieldwork; hence, the researcher may decide to follow the academic schedule or to arrange a different schedule with informants. Researchers usually decide which part of their identity will be disclosed for introducing themselves to the informants; but may also decide to hide who really he/she is. Researchers may cope with the dilemma to disclose their private life to informants during the fieldwork. Researchers also may decide to behave according to academic cultural norms of reciprocity or according to the cultural norms of participants. Finally, a reflexivity movement should be developed in Iberoamerica to define an agenda on ethical issues and to develop decolonizing strategies to debate these ethical dilemmas. PMID- 22450401 TI - [Sampling in qualitative research: basic principles and some controversies]. AB - This paper presents the rationale for the choice of participants in qualitative research in contrast with that of probability sampling principles in epidemiological research. For a better understanding of the differences, concepts of nomothetic and ideographic generalizability, as well as those of transferability and reflexivity, are proposed, Fundamentals of the main types of sampling commonly used in qualitative research, and the meaning of the concept of saturation are mentioned. Finally, some reflections on the controversies that have arisen in recent years on various paradigmatic perspectives from which to conduct qualitative research, their possibilities of combination with epidemiological research, and some implications for the study of health issues are presented. PMID- 22450402 TI - [Qualitative analysis: theory, steps and reliability]. AB - This essay seeks to conduct in-depth analysis of qualitative research, based on benchmark authors and the author's own experience. The hypothesis is that in order for an analysis to be considered reliable, it needs to be based on structuring terms of qualitative research, namely the verbs 'comprehend' and 'interpret', and the nouns 'experience', 'common sense' and 'social action'. The 10 steps begin with the construction of the scientific object by its inclusion on the national and international agenda; the development of tools that make the theoretical concepts tangible; conducting field work that involves the researcher empathetically with the participants in the use of various techniques and approaches, making it possible to build relationships, observations and a narrative with perspective. Finally, the author deals with the analysis proper, showing how the object, which has already been studied in all the previous steps, should become a second-order construct, in which the logic of the actors in their diversity and not merely their speech predominates. The final report must be a theoretic, contextual, concise and clear narrative. PMID- 22450403 TI - [Field work, narrative and knowledge production in contemporary ethnographic research: a contribution to the field of health]. AB - In this article I reflect on the peculiarities of contemporary ethnographic research, highlighting some challenges inherent to this process. The discussion focuses in particular on the following aspects: the limits imposed by the clear reduction in immersion time in the field; the challenges in learning about ethnographic work, either in the process of observation or interaction in the field, or in the task of textual production; issues of an epistemological and ethical nature that deserve particular attention on the part of practitioners of the ethnographic approach and the scientific community in general. It is especially appropriate to foster debate around the ethnographic method, addressing its peculiarities, operational complexity and potential as a tool for knowledge production, in the sphere of health/public health, bearing in mind the marked increase of this approach in this field. PMID- 22450404 TI - [Cartography of healthcare for pregnant women]. AB - This work uses cartography as a method for mapping the trajectory of primary healthcare provided to pregnant women. The scope of the study comprises 9 Basic Healthcare Units located in the city of Juazeiro do Norte in the State of Ceara. In all, fifteen women in the 37th to 39th week of pregnancy were selected. Interviews were conducted with these women during the period from January to June 2010. The cartographic findings were depicted in stages in the flowchart, which exposed lacunas in prenatal healthcare, such as the low number of oncotic cytology exams conducted and the lack of educational counseling. Nevertheless, in the interviews, a significant number of pregnant women expressed satisfaction with the prenatal care provided. The good relationships developed between the healthcare professionals and the pregnant women were the main reason that led them to continue the treatment. This fact reinforces the importance of dialogue between these two actors for the success of prenatal healthcare. PMID- 22450405 TI - [Innovation in mental health from the perspective of users: a community movement in the Northeast of Brazil]. AB - This study, originating from a multidimensional analysis on the innovation category in a Community Mental Health Movement of Bom Jardim (Fortaleza, Brazil) that examines subjective and psychosocial dimensions, seeks to examine to what extent the work developed by this movement is effectively an innovative model in mental healthcare from the perspective of users of this service. The methodology adopted was a qualitative case study method based on a critical-interpretive approach employing techniques such as in-depth interviews associated with focus groups. The categorization of the discursive material was conducted using a model based on the four main dimensions of psychiatric reform, namely conceptual, technical, legal and socio-cultural aspects. The results reveal the following: an emphasis on the individual rather than focusing on the sickness; care as the basis for purposeful actions; the co-production of genuine dialogue with multiple stakeholders, and the construction of autonomy emphasizing individual potential. In conclusion, it can be said that healthcare practices developed by the Movement involve deconstructing the traditional model of mental healthcare, permitting new forms of citizenship, thereby contributing to deinstitutionalization. PMID- 22450406 TI - [Matrixing support as an instrument of primary healthcare in mental health: multiple views and devices for resolution]. AB - The scope of this paper is to analyze the articulation of the mental health services between the teams of the Family Health Strategy and Psychosocial Care Center by the matrixing process with emphasis on comprehensive care and case resolution. The subjects included 32 users and 22 family members attended in the matrixing in mental health, 46 health professionals from the Family Health Strategy and 15 from the Psychosocial Care Centers in two cities in the state of Ceara. It is a study of a qualitative nature based on critical hermeneutics. As dictated by the results, the integration of mental health services in Primary Healthcare establishes innovative approaches for shared psychosocial care between staff, family members and users. The matrixing activities in mental health ensure broadened access and diversification of healthcare to achieve comprehensive care. Case resolution is defined by the acknowledgement of the social conditions of demand by the teams and overcoming medication-based health practices. PMID- 22450407 TI - Child feeding practices and household food insecurity among low-income mothers in Buenos Aires, Argentina. AB - This qualitative study of low-income mothers in Buenos Aires, Argentina, examines the influence of socio-economic conditions, organizational structures, family relationships, and food insecurity on child feeding practices and weight status. Thirty-eight mothers of preschool children living in urban Buenos Aires participated in four focus group discussions. The results indicated that many mothers were aware that obesity may be detrimental to the child's health, but most of them are unclear about the specific consequences. Maternal employment, family pressures, food insecurity and financial worries seem to influence child feeding practices. These findings have important implications for developing strategies for nutritional assistance that could benefit the health of children and provide opportunities for educational programs that are directed to nutritional awareness in Buenos Aires, Argentina. The right to eat regularly and properly is an obligation of the State and must be implemented taking into account the notion of food sovereignty and respecting the importance of preserving the culture and eating habits of a country and its diverse population groups. PMID- 22450408 TI - [Identity of the deaf and interventions in health from the perspective of a community of sign language users]. AB - The biomedical view sees deafness as a physiological loss of audition and the deaf as individuals with an organic abnormality to be corrected; healthcare interventions support this perception. This study sought to understand deafness from the standpoint of the deaf, in order to identify elements for public policies addressed to them in the context of the ethical dimension of care. The research adopted the qualitative approach (focus groups) and 9 members of a deaf community in Fortaleza (Ceara-Brazil), all fluent in Brazilian Sign Language LIBRAS, took part. The results show deafness is perceived as a way of being based on day-to-day experiences of visual interaction with nature and society, giving the deaf a different identity in terms of culture (being deaf) and linguistics (LIBRAS). Some public policies for oral training and technological interventions, like cochlear implants, are seen as a setback by the deaf, as it negates their status in the world and involves a loss of identity for the deaf. It is necessary to consider the deaf from a socio-historic, symbolic and cultural standpoint where different discourses co-exist, over and above the physiological dimension. PMID- 22450409 TI - [Life cannot consist of dreams alone: reflections on advertising and a healthy diet]. AB - In this essay we present some thoughts on advertising and a healthy diet in the contemporary world, where consumption plays a highly relevant role. We seek to emphasize two aspects, among many others yet to be explored in the scientific literature in the food and nutritional field: the hegemony of the biomedical paradigm and the fragmentation of human life when advertising campaigns associate food with the idea of a healthy diet. We believe that we cannot merely live through advertisements in which our desires are triggered constantly and where the world is only dreams and the main goal is to sell more and earn more, even using some strategies for dissemination of biomedical and nutritional information. In our opinion, the merger between diet and health, i.e. a healthy diet, must involve enlightenment of the individual including information on quality in the context of social life in order to achieve the ideal of happiness. Individuals whose identities are fully formed both in dreams and reality can boldly seek knowledge and think about themselves in the world context, as well as zeal for their diet and health. PMID- 22450410 TI - [Quality of food: perceptions of 'Bolsa Familia' program participants]. AB - INTRODUCTION: This study deals with perceptions of beneficiaries of the 'Bolsa Familia' Program, in Curitiba, southern Brazil, about their feeding habits. OBJECTIVE: To understand the perceptions of participants of the 'Bolsa Familia' Program on the quality of their food. METHOD: A qualitative study based on the critical-interpretive tradition, which used individual interviews as a technique for gathering empirical data from the informants. The study included 38 individuals, members of families included in the program. The discursive content was recorded on digital media and, thereafter, transcribed and analyzed. RESULTS: After categorization, three main themes emerged: a description of food, quality of food, and feelings and experiences of individuals enrolled in the program. CONCLUSION: the acknowledgement of social vulnerability and consequent feeding habit insecurity to which such groups are subject was the main finding, as well as feelings of resignation. PMID- 22450411 TI - [Parameters and paradigms for meta-evaluation: an exploratory and reflective review]. AB - The evaluation of an evaluation is not a mere play on words or simply an investigation into the person who evaluates the evaluation. It is far more than that. It is about how to evaluate the diverse components of the evaluation process and the evaluators per se. In this paper, we discuss some promising possibilities for meta-evaluation in the field of evaluation of programs and services. These include fostering interaction between theoretical and practical production in fieldwork and supporting the definition of methods and strategies in a sector imbued with political interests and a profusion of methodological possibilities, and promoting ethical and scientific rigor in the evaluation practices. We conclude this exploratory and reflective review by raising some historical and political questions related to evaluation and meta-evaluation of programs and services and by criticizing the universalist and egalitarian pretensions contained in some evaluation approaches. PMID- 22450412 TI - [Quality of life of women recovering from breast cancer after being subjected to mastectomies compared with those who had conservative surgery: a review of the literature]. AB - This study reviews the literature on the quality of life (QoL) of women with breast cancer who have been subjected to mastectomy, compared with those who had conservative surgery. Eight random controlled trials were selected. The studies were compared with respect to the moment quality of life was assessed (whether during or after treatment for breast cancer), the measurement tools of quality of life used, and also the methodology and results achieved. The results of four studies suggest a stronger negative impact in the QoL of mastectomized women; the other four studies showed no difference between the groups in terms of QoL. Objective measurements of quality of life may help identify potentially critical situations of daily life and assist in planning actions to promote health among women who have been subjected to breast cancer surgery. PMID- 22450413 TI - [Self-evaluation of posture by elderly people with or without thoracic kyphosis]. AB - This article lists the differences between self-perception of body posture among the elderly suffering from postural alterations or not, in order to ascertain whether self-evaluation of posture can lead to preventive measures. Eighteen cases from the elderly population participated in the EPIDOSO project at UNIFESP and were subjected to postural evaluation. Postures were photographed and copies given to the participants and their subsequent comments were analyzed by the qualitative method. The narratives were taped and cataloguedusingthe technique of theoretical axial and selective coding from the perspective of symbolic interactionism. A passive attitude was identified among the elderly in relation to postural alterations. There is a distortion of body image by those with postural deviation. Participants with adequate spinal alignment were more conscious about body posture and the importance of this being assimilated in the phases prior to aging. The adoption of postural self-care seems to occur in the earlier stages of aging and preventive measures should be implemented at this stage. Lack of concern about posture is linked to the concept of the elderly regarding the notion that aging is, in itself, the accumulation of inevitably simultaneous or successive dysfunctions. PMID- 22450414 TI - [Quality of life in elderly people that have suffered falls: integrative literature review]. AB - An Integrative Literature Review was conducted in order to evaluate the scientific knowledge produced regarding quality of life of the elderly who have suffered falls. Published articles between 1999 and 2009 were selected from the LILACS, CINAHL and MEDLINE databases, and the following search words in Portuguese, English and Spanish were used: quality of life, the elderly and accidents involving falls. Nine articles met the inclusion criteria. It was revealed that falls are frequent among the elderly, and especially the elderly with more intrinsic risk factors and who have suffered falls are those who are more afraid and more prone to fall again. They also reported physical, mental and emotional impairments, body pains and environmental problems. It was revealed that programs to prevent falling can improve the quality of life of the elderly over time. It was clear that there are knowledge gaps, especially a low level of national scientific output, especially by nurses and the predominance of descriptive studies, with low levels of data. We suggest that health professionals conduct research into interventions to prevent falls that can be used in clinical practice in improving the quality of life of the elderly. PMID- 22450415 TI - [Gender and work: the experience of providers of health services to indigenous women from Guerrero y Oaxaca]. AB - The scope of this paper was to identify the role of gender for women as workers, through the perception and discourse of health service providers at the 'Health Centers for Indigenous Women' ("Casas de Salud de las Mujeres Indigenas") in Ometepec, Guerrero and Matias Romero, Oaxaca, Mexico. It is a qualitative study, based on a secondary analysis of the interviews conducted as part of the "Rescatando la experiencia de la Casa de la Mujer Indigena: sistematizacion y evaluacion del proceso" project. A strong sense of the value of work and a strong commitment towards the community were identified. Guilt appears as the result of tension between work outside the home and the responsibilities as mothers and wives. The possibility of helping other women is a source of gratification that dissipates these conflicts; prestige and recognition are added to the benefits of their role. The labor experience of female workers in the "Casas de Salud de las Mujeres Indigenas" of Matias Romero, Oaxaca and Ometepec, Guerrero, described in this paper, reveals that it has very specific characteristics, which are difficult to replicate in other regions of the country. In future studies it is necessary to consider the different contexts of vulnerability. PMID- 22450416 TI - [Gender and perceived quality of life: research with professors from the health area]. AB - The rapid process of change in the global economy in recent years and the organization of labor have influenced gender relations in the teaching profession. These transformations have been disadvantageous for women, leaving them in a situation of occupational overload. The scope of this study was to analyze the working conditions of female teachers in higher education in the health education area in the city of Vitoria, State Espirito Santo, and their implications on health and quality of life. This is qualitative research into data gathered from interviews upon which Bardin content analysis was also employed. This technique revealed three categories: leisure, rest and health; sense of loss of social and family interaction; and perceived quality of life. The results show that insufficient leisure time may lead to sleep disturbances predisposing the individual to psychic illness; overwork; significant alterations in labor organization compromising social and family interaction with repercussions on health and quality of life. The work performed by female professors in the health area contributes to the onset of illness, with pejorative effects on their family, love, social, environmental and professional lives, with consequent loss of quality of life. PMID- 22450417 TI - Prevalence of overweight and obesity in elderly people from Vitoria-ES, Brazil. AB - The scope of this study was to estimate the prevalence of overweight and obesity and its association with socio-economic status in a sample of non institutionalized elderly people from Vitoria-ES, Brazil. This was a cross sectional survey with a sample of 882 elderly people aged 60 and over. Obesity and overweight were assessed using the body mass index (BMI) and waist circumference (WC). All subjects answered a personal and socio-demographic questionnaire in relation to age, gender, marital status, physical activity, number of children, chronic diseases and smoking. Associations between categorical variables were tested using chi-square analysis with a 5% significance level. The prevalence of overweight and obesity was high (41.8% and 23.4%, respectively) and 50.7% of the elderly had a substantially increased waist circumference. About 4.3% of the individuals had diabetes, 50.4% had hypertension and 14.9% were found to have both diseases. It was observed that both the BMI and WC were significant associated (p<0.05) with sex, marital status, the presence of diseases and with cigarette smoking. PMID- 22450418 TI - [Indicators of the pharmaceutical care service at the University of Southern Santa Catarina]. AB - Pharmaceutical Care has represented a new clinical practice for pharmacists. This study aims to show the indicators of the Pharmaceutical Care Service at the University of Southern Santa Catarina. Documentary analysis of pharmaceutical records of 58 patients was conducted between September 2007 and March 2008 to identify the indicators. Most patients were women (77.6%), with a mean age of 54 years. Average number of health problems per patient was 4.6 in the first visit and 4.3 in the last one. The most widely used drug classes were cardiovascular (30.2%) and nervous system (27.5%). On average, 2.7 drug-related problems per patient were detected, the most common being those related to effectiveness and safety. Of the problems identified, 82.2% were classified as preventable and 63.7% as manifested. Pharmaceutical interventions registered 79.0% of acceptance, of which 78.9% had positive results. On average, there were 2.6 patient-related needs, especially regarding questions about drug therapy (30.4%), which were positively answered in 84.8% of cases. These indicators show that the pharmaceutical care service is very active in promoting health education. PMID- 22450419 TI - [Health assessment and economic assessment in health: introduction to the debate on the points of intersection]. AB - The study aims to infer the existence of a continuum between Health Assessment and Economic Assessment in Health, by highlighting points of intersection of these forms of appraisal. To achieve this, a review of the theoretical foundations, methods and approaches of both forms of assessment was conducted. It was based on the theoretical model of health evaluation as reported by Hartz et al and economic assessment in health approaches reported by Brouwer et al. It was seen that there is a continuum between the theoretical model of evaluative research and the extrawelfarist approach for economic assessment in health, and between the normative theoretical model for health assessment and the welfarist approaches for economic assessment in health. However, in practice the assessment is still conducted using the normative theoretical model and with a welfarist approach. PMID- 22450420 TI - [Interpersonal relations between health professional and pregnant adolescents: distances and approaches of integral and humanized care]. AB - This study presents an analysis of relations between health professionals and pregnant adolescents in the installations of the prenatal care program of a public hospital in Rio de Janeiro. It involves qualitative research based on an interpretive approach, with comprehensiveness and humanization of care in relationship dimensions as a theoretical benchmark. Based on two predefined themes - the interaction between subjects and educational dimension of health practices - 22 individual and group care sessions were observed, with the participation of 31 pregnant adolescents, 5 professionals and 2 nutrition interns. The interpretation of the data using content analysis created five categories. The results show the negative effect of the predominance of the biomedical dimension in the perception of health professionals about psychosocial and cultural aspects of teenage pregnancy. There was a failure to utilize the care session as a privileged space for the construction of collective and individual significance about pregnancy and teenage motherhood, albeit in the context studied there are professionals who are aware of the need for a broader view regarding the needs of pregnant adolescent. PMID- 22450421 TI - [The construction of collective portfolios in traditional curriculums: an innovative approach in teaching-learning]. AB - Education to promote health has traditionally been based on knowledge transmission methodologies. However, the current scenario calls for the training of professionals with a critical-reflective profile, who are able to work in teams. We present the report of an innovative experience using the construction of collective portfolios as instruments of learning, changing attitudes and training of undergraduates, in a traditional subject-based curriculum structure context. It is a descriptive exploratory study, with a qualitative-quantitative approach, based on analysis of collective portfolios (n=9), built by Health Policy students, together with an open questionnaire to students who attended the course (n=58) and also the staging of focus groups (n=3). The use of collective portfolios mobilized students in critical and reflective thinking on Brazilian health policy - the Unified Health System - broadening the concept on the health disease process and practices related to health services, prioritizing teamwork and the active search for knowledge building, stressing the exercise of otherness, resilience and empowerment. PMID- 22450422 TI - [Epidemiological intelligence as a model of organization in health]. AB - The concept of epidemiological intelligence, as a construction of information societies, goes beyond monitoring a list of diseases and the ability to elicit rapid responses. The concept should consider the complexity of the definition of epidemiology in the identification of this object of study without being limited to a set of actions in a single government sector. The activities of epidemiological intelligence include risk assessment, strategies for prevention and protection, subsystems of information, crisis management rooms, geographical analysis, etc. This concept contributes to the understanding of policies in health, in multisectorial and geopolitical dimensions, as regards the organization of services around public health emergencies, primary healthcare, as well as disasters. The activities of epidemiological intelligence should not be restricted to scientific research, but the researchers must beware of threats to public health. Lalonde's model enabled consideration of epidemiological intelligence as a way to restructure policies and share resources by creating communities of intelligence, whose purpose is primarily to deal with public health emergencies and disasters. PMID- 22450425 TI - Mitochondrial complex I deficiency and ATP/ADP ratio in lymphocytes of amyotrophic lateral sclerosis patients. AB - OBJECTIVES: Several lines of evidence suggest that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress, and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. This study was performed to assess the mitochondrial respiratory chain dysfunction and cellular energy index (ATP/ADP ratio) in lymphocytes of ALS patients. METHODS: In this study, activity of mitochondrial respiratory chain complex I (measured as NADH ferricyanide reductase) and both intracellular ATP and ADP measurements were performed on lymphocytes of ALS patients (n = 14) and control subjects (n = 26). Then, ATP/ADP ratio was calculated. RESULTS: Our finding showed that in patients compared with controls, complex I activity and intracellular ATP were significantly reduced (P = 0.001) and intracellular ADP content was increased (P<0.005) and ATP/ADP ratio subsequently was decreased and also we found strong correlation between complex I activity and intracellular ATP content and strong reverse correlation between complex I activity and intracellular ADP content in the patients with ALS (r(2) = 0.90). DISCUSSION: This study suggests that complex I deficiency and both reduction in intracellular ATP and increase in intracellular ADP content may be involved in the progression and pathogenesis of ALS. PMID- 22450426 TI - Pulmonary hypertension: chapters of innovation and tribulation. AB - As can be seen by the mounting literature, there has been immense progress in the field of pulmonary hypertension (PH) over the last three decades, illustrated by several important milestones including improved understanding of disease pathogenesis, new classifications of disease, advances in screening and diagnostic techniques, and new rules for staging and follow-up, which have subsequently led to improvements in patient outcomes. The objectives of this manuscript are to not only highlight these very recent advances but also point out areas of deficiencies or gaps in our knowledge that may serve a focal point for future discussion and investigation. PMID- 22450427 TI - High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis. AB - AIMS: High-throughput metabolite quantification holds promise for cardiovascular risk assessment. Here, we evaluated whether metabolite quantification by nuclear magnetic resonance (NMR) improves prediction of subclinical atherosclerosis in comparison to conventional lipid testing. METHODS AND RESULTS: Circulating lipids, lipoprotein subclasses, and small molecules were assayed by NMR for 1595 individuals aged 24-39 years from the population-based Cardiovascular Risk in Young Finns Study. Carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, was measured in 2001 and 2007. Baseline conventional risk factors and systemic metabolites were used to predict 6-year incidence of high IMT (>= 90 th percentile) or plaque. The best prediction of high intima-media thickness was achieved when total and HDL cholesterol were replaced by NMR determined LDL cholesterol and medium HDL, docosahexaenoic acid, and tyrosine in prediction models with risk factors from the Framingham risk score. The extended prediction model improved risk stratification beyond established risk factors alone; area under the receiver operating characteristic curve 0.764 vs. 0.737, P =0.02, and net reclassification index 17.6%, P =0.0008. Higher docosahexaenoic acid levels were associated with decreased risk for incident high IMT (odds ratio: 0.74; 95% confidence interval: 0.67-0.98; P = 0.007). Tyrosine (1.33; 1.10 1.60; P = 0.003) and glutamine (1.38; 1.13-1.68; P = 0.001) levels were associated with 6-year incident high IMT independent of lipid measures. Furthermore, these amino acids were cross-sectionally associated with carotid IMT and the presence of angiographically ascertained coronary artery disease in independent populations. CONCLUSION: High-throughput metabolite quantification, with new systemic biomarkers, improved risk stratification for subclinical atherosclerosis in comparison to conventional lipids and could potentially be useful for early cardiovascular risk assessment. PMID- 22450428 TI - Effect of aliskiren treatment on endothelium-dependent vasodilation and aortic stiffness in essential hypertensive patients. AB - AIMS: Aliskiren is a new oral non-peptide renin inhibitor. Its effects on vascular function in human hypertension are unknown. We assessed whether aliskiren may improve peripheral endothelial function and arterial stiffness in essential hypertensive patients (EH), when compared with the angiotensin converting enzyme-inhibitor ramipril. METHODS AND RESULTS: Fifty EH received treatment with aliskiren (150-300 mg/daily) or ramipril (5-10 mg/daily) for 12 weeks, according to a randomized, open with blind endpoints, parallel group design. We studied the forearm blood flow (straingauge plethysmography) response to intrabrachial acetylcholine, repeated under the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4 MUmol/min), or the antioxidant ascorbic acid (8 mg/100 mL/min). Carotid-to-femoral pulse wave velocity (PWV), central blood pressure and augmentation index (AIx) were obtained by applanation tonometry. Brachial blood pressure was similarly normalized by aliskiren (from 149/94 to 136/86 mmHg) and ramipril (from 148/92 to 135/85 mmHg), as well as central blood pressure. Aliskiren increased (P < 0.001) the vasodilation to acetylcholine and restored the inhibitory effect of l-NMMA on acetylcholine. Ascorbic acid, which at baseline potentiated the response to acetylcholine, no longer improved endothelium-dependent relaxation after aliskiren treatment. In contrast, ramipril failed to affect the response to acetylcholine, the lacking inhibitory effect of l-NMMA, or the potentiating effect of ascorbic acid. Pulse wave velocity was significantly (P < 0.05) and similarly reduced by both drugs. Aliskiren induced a significantly (P < 0.05) greater AIx reduction than ramipril. CONCLUSION: Aliskiren increased nitric oxide availability in the forearm resistance arterioles of EH, an effect probably determined by an antioxidant activity, which can also contribute to improved peripheral wave reflection. PMID- 22450429 TI - The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. AB - AIMS: Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. METHODS AND RESULTS: A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. CONCLUSION: No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov number, NCT00050817. PMID- 22450430 TI - AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. AB - AIMS: Dysregulation of the bone morphogenetic protein receptor type 2 (BMPR2) is a hallmark feature that has been described in several forms of pulmonary hypertension. We recently identified the microRNA miR-20a within a highly conserved pathway as a regulator of the expression of BMPR2. To address the pathophysiological relevance of this pathway in vivo, we employed antagomiR-20a and investigated whether specific inhibition of miR-20a could restore functional levels of BMPR2 and, in turn, might prevent pulmonary arterial vascular remodelling. METHODS AND RESULTS: For specific inhibition of miR-20a, cholesterol modified RNA oligonucleotides (antagomiR-20a) were synthesized. The experiments in mice were performed by using the hypoxia-induced mouse model for pulmonary hypertension and animal tissues were analysed for right ventricular hypertrophy and pulmonary arterial vascular remodelling. Treatment with antagomiR-20a enhanced the expression levels of BMPR2 in lung tissues; moreover, antagomiR-20a significantly reduced wall thickness and luminal occlusion of small pulmonary arteries and reduced right ventricular hypertrophy. To assess BMPR2 signalling and proliferation, we performed in vitro experiments with human pulmonary arterial smooth muscle cells (HPASMCs). Transfection of HPASMCs with antagomiR 20a resulted in activation of downstream targets of BMPR2 showing increased activation of Id-1 and Id-2. Proliferation of HPASMCs was found to be reduced upon transfection with antagomiR-20a. CONCLUSION: This is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling. PMID- 22450431 TI - Maternity exclusion with a very high autosomal STRs kinship index. AB - This paper reports a maternity testing case to assess the biological relationship between a woman and the boy she was adopting. For all 46 tested autosomal STR loci, the adopting woman and the boy shared at least one allele at each locus, which supported that the woman could be the biological mother of the boy. The pairwise kinship indices (KIs) were calculated for various identity-by-descent distributions. Motherson was the most likely relationship with a very high KI (i.e., 6.91E+08) based on 35 independent autosomal STR loci, but KIs of other pairwise relationships (e.g., aunt-nephew, full sib, etc.) were also high. Further testing of X-STRs and mtDNA excluded the maternity relationship between woman and boy, in which 13 out of 20 X-STR loci were inconsistent and 18 nucleotide mismatches were observed at hypervariable regions I and II of the mtDNA. However, a more distant relationship (e.g., aunt-nephew) cannot be excluded. This case reinforces that possible false identifications can occur in kinship analysis cases yielding very high KIs. PMID- 22450432 TI - [Co(x)Cu(1-x)(DDOP)(OH2)(NO3)](NO3): hydrogen bond-driven distortion of cobalt(II) by solid solution 'network mismatch'. AB - Late-first row transition metal nitrate complexes of the tetradentate N-donor ligand cis-3,5-bis[(2-pyridinyleneamino]-trans-hydroxycyclohexane (DDOP) adopt a mono-cationic [M(DDOP)(H(2)O)(NO(3))](+) structure (M = Co, 1; Cu, 2; Zn, 3) in which the DDOP ligand occupies the equatorial plane. The complexes are essentially isostructural and isomorphous, allowing the Co(II) and Cu(II) complexes to co-crystallize in mixed-metal solid solutions with the formula [Co(x)Cu(1-x)(DDOP)(NO(3))(H(2)O)](NO(3)), where x = 0.4 (4), 0.1 (5), and 0.7 (6). For 4, structural and magnetochemical analysis indicate that the geometry of the octahedral Co(II) complex distorts to match that of the dominant Jahn-Teller distorted Cu(II) center. Magnetic susceptibility data of octahedral Co(II) are sensitive to ligand geometry distortions and have been analyzed accordingly, comparing 4 to the reference systems 1 and 2. Bond valence calculations have been used to estimate the relative stabilities of the six hydrogen bonded networks, suggesting that the stretching of the Co(II) coordination sphere 4 in is assisted by adoption of the most stable hydrogen bonded network; but that in 6 this is overcome by a higher loading of Co. This family of complexes therefore represent predictable metal-based tectons which can help probe the influence of secondary non-covalent interactions over metal coordination geometries and properties. PMID- 22450433 TI - Evaluation of carotid intima-media thickness, a marker of subclinical atherosclerosis, in children with cerebral palsy. AB - BACKGROUND: Respiratory and cardiovascular diseases are the most common causes of death in children with cerebral palsy. OBJECTIVE: To evaluate sonographic carotid intima-media thickness, an early marker of atherosclerosis, in children with cerebral palsy and in healthy controls. MATERIALS AND METHODS: One hundred children with cerebral palsy (65 boys), mean age 6.2 (SD, 2.1) years, and 35 age matched and sex-matched healthy controls were included. Common carotid artery intima-media thickness was measured sonographically. Differences between patients and controls were evaluated with an independent samples t-test. RESULTS: Age, sex distribution and levels of serum lipids were comparable between patients and controls. Average, right and left carotid artery intima-media were thicker in patients compared with controls (mean +/- SD, 0.61 +/- 0.13 mm vs 0.40 +/- 0.03 mm; 0.61 +/- 0.14 mm vs 0.40 +/- 0.03 mm; 0.61 +/- 0.13 mm vs 0.40 +/- 0.03 mm, respectively; all P < 0.001). CONCLUSION: Carotid intima-media is sonographically thicker in children with cerebral palsy compared with healthy controls, which may express an increased risk of atherosclerotic diseases. PMID- 22450434 TI - New target in kidney fibrosis identified by systems approach. PMID- 22450438 TI - Increasing the pool of deceased donor organs for kidney transplantation. AB - Expanding the pool of available deceased donor kidneys is critical for improving the outcomes of prospective and current renal transplant candidates. A number of interventions have been proposed that may increase the pool of donors in the US. However, these interventions have variable levels of empirical evidence supporting their potential beneficial impact. Proposed interventions include the instigation of policies for presumed donor consent, the expansion of donor registration, increased quality oversight of transplant providers, financial incentives for donors, increased reimbursement for higher risk donors, alterations in organ allocation policies and distribution, and the selective use of donors with potential or known risk for disease transmission. Many of these interventions have contentious elements that may have delayed or impeded their implementation; however, these options should be considered in the context of the diminishing prognoses for prospective transplant patients, given the increasing scarcity of donor organs relative to the population need. In this Review, we outline the proposed interventions and briefly discuss salient issues that characterize the debates concerning their implementation and effectiveness. Ultimately, any intervention must be based on the best evidence available, with consideration of numerous stakeholders and in conjunction with a careful evaluation of long-term and potential unintended consequences. PMID- 22450439 TI - Obesity and mortality on dialysis--does age matter? AB - The association between obesity and mortality has been observed to be paradoxical in persons on dialysis. Hoogeveen et al. examined whether the association between obesity and mortality on dialysis differed by age in participants in the NECOSAD2 study. PMID- 22450441 TI - Diagnostic challenges in chronic antibody-mediated rejection. AB - Measurement of glomerular and peritubular capillaritis in kidney transplant biopsy samples identifies allograft dysfunction associated with alloantibodies. Sis et al. show that this technique has a higher sensitivity but lower specificity than the current diagnostic criteria using peritubular capillary C4d deposition, and that capillaritis is an independent predictor of progression to graft failure. PMID- 22450442 TI - Pycnidione, a fungus-derived agent, induces cell cycle arrest and apoptosis in A549 human lung cancer cells. AB - Pycnidione, a small tropolone first isolated from the fermented broth of Theissenia rogersii 92031201, exhibits antitumor activities through an undefined mechanism. The present study evaluated the effects and mechanisms of pycnidione on the growth and death of A549 human lung cancer cells. Pycnidione significantly inhibited the proliferation of A549 cells in a concentration-dependent manner, with a 50% growth inhibition (GI(50)) value of approximately 9.3nM at 48h. Pycnidione significantly decreased the expression of cyclins D1 and E and induced G(1)-phase cell cycle arrest and a subsequent increase in the sub-G(1) phase population. Pycnidione also markedly reduced the expression of survivin and activated caspase-8 and -3, increased reactive oxygen species (ROS) generation, caused the collapse of the mitochondrial membrane potential (MMP), and enhanced PAI-1 production, thus triggering apoptosis in the A549 cells. Taken together, pycnidione exerts anti-proliferative effects on human lung cancer cells through the induction of cell cycle arrest and apoptosis. Therefore, testing of its effects in vivo is warranted to evaluate its potential as a therapeutic agent against lung cancer. PMID- 22450443 TI - Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. AB - Thymoquinone (TQ) is the major active compound derived from Nigella sativa. Our aim of this work was to evaluate the antioxidant and antiarthritic activity of TQ in Wistar rat by collagen induced arthritis (CIA). TQ was administered at a dose of 5mgkg(-1) body weight once daily for 21days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1beta, IL-6, TNF-alpha, IL-10, IFN-gamma and PGE(2)) and histological studies in joints. TQ was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of TQ resulted in significantly reduced the levels of pro-inflammatory mediators (IL-1beta, IL-6, TNF-alpha, IFN-gamma and PGE(2)) and increased level of IL-10. The protective effects of TQ against RA were also evident from the decrease in arthritis scoring and bone histology. In conclusion, the fact that TQ abolished a number of factors known to be involved in RA pathogenesis indicates that the administration of thymoquinone may have potential value in the treatment of inflammatory disease. PMID- 22450444 TI - Effects of bacterial and presystemic nitroreductase metabolism of 2-chloro-5 nitro-N-phenylbenzamide on its mutagenicity and bioavailability. AB - 2-Chloro-5-nitro-N-phenylbenzamide (GW9662), a potent irreversible PPAR-gamma antagonist, has shown promise as a cancer chemopreventive agent and is undergoing preclinical evaluations. Studies were initiated to assess its bacterial mutagenicity and pharmacokinetic profile in two animal species prior to subchronic oral toxicity evaluations and the results are reported here. GW9662 was mutagenic in both TA98 and TA100 bacterial strains with and without metabolic activation but was negative in the nitroreductase-deficient strains (TA98NR and TA100NR) also with and without metabolic activation, indicating that GW9662 mutagenicity is dependent on nitroreduction. The mutagenic activity was predominantly via a base-substitution mechanism. Following oral dosing in rats and dogs, the parent compound, GW9662, was virtually absent from plasma samples, but there was chromatographic evidence for the presence of metabolites in the plasma as a result of oral dosing. Metabolite identification studies showed that an amine metabolite ACPB (5-amino-2-chloro-N-phenylbenzamide), a product of nitro reduction, was the predominant species exhibiting large and persistent plasma levels. Thus systemic circulation of GW9662 has been attained largely in the form of its reduced metabolite, probably a product of gut bacterial metabolism. GW9662 was detectable in plasma of rats and dogs after intravenous dose albeit at low concentrations. Pharmacokinetic analysis following intravenous dosing in rats showed a rapid clearance and an extensive tissue distribution which could have accounted for the very low plasma levels. Of note, the amine metabolite was absent following intravenous dosing in both rats and dogs, confirming it being a product of presystemic metabolism. The potential utility of GW9662 as a chemopreventive agent, especially as an Estrogen Receptor-alpha (ER-alpha) inducer in an otherwise ER-alpha negative breast tissue, is of great interest. However, the results shown here suggest that additional animal toxicological and bioavailability studies are required to establish a role of GW9662 as a chemopreventive agent. PMID- 22450445 TI - Involvement of neuropathy target esterase in tri-ortho-cresyl phosphate-induced testicular spermatogenesis failure and growth inhibition of spermatogonial stem cells in mice. AB - Tri-ortho-cresyl phosphate (TOCP) has been widely used in industry and reported to induce delayed neurotoxicity in humans and animals. In addition, it is known to have a deleterious effect on the male reproductive system in animals, but the precise mechanism is yet to be elucidated. The present study shows that TOCP could disrupt the seminiferous epithelium in the mouse testis and decrease the sperm density in the epididymis in a dose-dependent manner. Neuropathy target esterase (NTE) was shown to exist in mouse spermatogenic cells, including spermatogonial stem cells and to be significantly inhibited by TOCP. Likewise, saligenin cyclic-o-tolyl phosphate (SCOTP), an activated metabolite of TOCP, markedly inhibited NTE activity in spermatogonial stem cells. Both inhibition of NTE activity by SCOTP and knockdown of NTE by shRNA remarkably inhibited cell proliferation. These results point to a role of NTE in regulating proliferation of mouse spermatogonial stem cells and provide a novel insight into the mechanism by which TOCP diminishes on the sperm number in the mouse testis. PMID- 22450446 TI - Potentials and mechanisms of genotoxicity of six pharmaceuticals frequently detected in freshwater environment. AB - Genotoxic potentials and the mechanisms of six pharmaceuticals, which are frequently detected in surface water worldwide, were investigated using isogenic chicken DT40 mutant cell lines. These pharmaceuticals include erythromycin, sulfamethazine, sulfathiazole, chlortetracycline, oxytetracycline, and diclofenac. The genotoxic effects of these pharmaceuticals were determined based on growth kinetics of several mutant cell lines. Genotoxic chemicals were expected to decrease the growth kinetics in at least one of the mutants more significantly than DNA-repair-proficient wild-type cells. The test pharmaceuticals sensitized the cells deficient in homologous recombination (HR) repair (RAD54-/-), nucleotide excision repair (XPA-/), or translesion DNA synthesis (REV3-/-), suggesting that these pharmaceuticals may induce bulky adducts covalently bound to duplex DNA, like ultraviolet (UV) light. Genotoxicity was confirmed again by analyzing chromosome aberrations (CAs) and gamma-H2AX foci in both wild-type and the susceptible mutants (i.e., RAD54-/- and XPA-/) following the exposure to all the test pharmaceuticals except for erythromycin. The data indicate that these pharmaceuticals induce the DNA damages that stall DNA replication, leading to chromosomal breaks as well as translesion DNA synthesis mediated mutagenesis in DT40 cells. PMID- 22450447 TI - Verification of posterior hyaloid status during pars plana vitrectomy, after preoperative evaluation on optical coherence tomography. AB - BACKGROUND: The purpose of the study is to establish the accuracy of optical coherence tomography (OCT) in visualizing the presence or absence of vitreopapillary adhesion. METHODS: This is a prospective, interventional case series based at Calderdale Royal Hospital and Huddersfield Royal Infirmary, both district general hospitals in the United Kingdom. Fifty consecutive eyes of 50 patients listed for vitrectomy surgery that showed media clear enough to enable adequate visualization of the fundus were included. All patients underwent assessment of posterior hyaloid status by OCT imaging of the optic disk. All OCT images were assessed by two observers, and preoperative OCT data were compared with intraoperative observations. Statistical analysis was performed using the Cohen kappa coefficient to measure the interrater agreement. RESULTS: There was 100% agreement between Observer 1 and 2. Cohen kappa was 0.95 and (95% confidence interval, 0.84-1.05) for agreement between preoperative OCT and intraoperative findings. CONCLUSION: Optical coherence tomography imaging can accurately visualize the vitreopapillary interface. Our results show a strong correlation between OCT and intraoperative findings. The presence of a posterior vitreous detachment would be useful knowledge to the vitreoretinal surgeon in planning surgery and weighing up the risk of developing certain conditions. PMID- 22450448 TI - Outpatient penicillin use after negative skin testing and drug challenge in a pediatric population. AB - The practice of elective penicillin skin testing could be compromised by the fact that patients, their parents, or their physicians remain reluctant to reuse penicillin-class antibiotics (PCAs) despite a negative evaluation by an allergist. This study addresses reuse of PCAs in a pediatric population after negative penicillin skin testing and drug challenge and factors associated with its reluctance. All children evaluated for a history of penicillin allergy at the CHU Sainte-Justine Allergy Clinic between January 1998 and June 2000 with negative skin testing and drug challenge were included in the study. A telephone survey was conducted between May and October 2002 to assess the perception of the initial reaction by the parents, subsequent use of antibiotics, and antibiotic related adverse reactions. Among the 200 children selected, parents of 170 (85%) children completed the survey. Since the allergist evaluation, 130 (76%) children had received antibiotics. PCA was used in 59 (45%) children. Parents of 24 (18%) children refused PCAs because they still feared an adverse reaction. They were more likely to have been very frightened by their child's allergic reaction than other parents whose children had used PCAs (p = 0.008). Although elective penicillin skin testing is useful and safe in the pediatric population, a significant proportion of parents still refuse PCAs even though they are needed. Identification of parents that were very frightened by their children's allergic reactions and additional reassurance could improve this situation. PMID- 22450449 TI - Routine administration of a single dose of cisplatin >= 75 mg/m2 after short hydration in an outpatient lung-cancer clinic. AB - BACKGROUND: Cisplatin is a pivotal drug in combined chemotherapy for non-small cell and small-cell lung cancers (NSCLC or SCLC), but its renal toxicity limits its use. Current guidelines recommend 24 h hydration: thus hospitalization is required. The aim of this retrospective study was to confirm the safety of short hydration before giving an intermediate-to-high dose of cisplatin in an outpatient clinic. PATIENTS AND METHODS: Patients eligible had NSCLC or SCLC and were being treated with a chemotherapy regimen that included cisplatin >= 75 mg/m(2). They were given the same short hydration protocol for 1 day. Nephrotoxicity was defined as >= grade 1 according to NCIC common toxicity criteria. Predictive factors for nephrotoxicity were analyzed. RESULTS: Three hundred and fifty-seven consecutive patients (median age 58 years, range: 25-81) were reviewed. Twenty-one patients (6%) had >= grade 1 nephrotoxicity and all except one had grade 1 toxicity according to NCIC criteria for common toxicity (SC < 1,5 N). Predictive factors independently associated with nephrotoxicity included associated co-morbid conditions (hypertension, diabetes, heart disease) (OR = 4.97 CI 95% [1.8-13.7] P = 0.002), initial serum creatinine >= 100 MUmol/L (OR = 8.3 CI 95% [2.55-27.4] P = 0.0005), and dose cycle of cisplatin >= 100 mg/m(2) (OR = 10.8 CI 95% [3.6-32.5] P < 0.0001). CONCLUSION: Rapid outpatient administration of a single dose of cisplatin at >= 75 mg/m(2) is feasible without a high risk of nephrotoxicity. PMID- 22450451 TI - Low-grade brain tumours and seizures. PMID- 22450452 TI - Improving the diagnostic accuracy in parkinsonism: a three-pronged approach. AB - Separating Parkinson's disease from the various causes of atypical parkinsonism (AP) is a common and clinically relevant challenge in clinical practice. Distinguishing between the different causes of AP is even more difficult. Here the authors discuss a systematic, clinically based and three-pronged approach that can assist clinicians in establishing the correct diagnosis in the consulting room. The three consecutive steps include: (1) to verify that the clinical syndrome truly represents parkinsonism (hypokinetic-rigid syndrome); (2) to search systematically for 'red flags' (alarm signs that may signal the presence of AP); and (3) to integrate these two steps, as a basis for a narrow differential diagnosis and a guide for further ancillary tests. PMID- 22450453 TI - Seizures after head injury. PMID- 22450454 TI - New diagnostic criteria for Alzheimer's disease and mild cognitive impairment for the practical neurologist. AB - Four articles in the journal Alzheimer's and Dementia in 2011 describe new criteria for Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD), as well as the underlying rationale for them. The new criteria also include preclinical AD criteria but these are intended purely for research purposes. The new criteria emphasise that the AD pathophysiological process starts years and perhaps decades before clinical symptoms, and that biomarkers can detect amyloid beta deposition and the effects of neurodegeneration in the brain. The criteria are recommendations based upon consensus meetings and will require future validation. Nonetheless, the authors believe that they are immediately helpful to the practising clinician, providing more accurate and specific guidelines for the diagnosis of AD dementia and MCI due to AD. As new diagnostic tools and treatments for AD become available, diagnoses using these criteria will enable patients with AD dementia, MCI due to AD and eventually preclinical AD to receive the best possible care. PMID- 22450455 TI - Teaching clinical neurology. PMID- 22450456 TI - Seeing optic neuritis through myopic eyes. PMID- 22450457 TI - SUDEP discussions with patients and families. AB - SUDEP is clearly a very important issue. Patients and their representatives (and in Scotland our legal system) would like consistency and clarity in how this information is conveyed. It behooves us to find a way to pass on our concerns in a way that acknowledges the needs, fears and circumstances of each individual patient and, where appropriate,of their family or carers. I think it is unreasonable to insist on not changing our practice. Emphasising and promoting measures that increase safety and reduce risk can only be to patients' benefit, no matter the terminology used. PMID- 22450458 TI - Comment on 'SUDEP discussions with patients and families'. PMID- 22450459 TI - SNAPs, CMAPs and F-waves: nerve conduction studies for the uninitiated. PMID- 22450460 TI - Encephalopathy in a 45-year-old woman: presented at the Advanced Clinical Neurology Course, Edinburgh 2010. PMID- 22450461 TI - Neuro-Sweet's disease. AB - Sweet's syndrome, or acute febrile neutrophilic dermatosis, is a multisystem, inflammatory disease characterised by tender skin lesions and neutrophilic infiltration of various organs, including the nervous system. A rare condition, neuro-Sweet's can present with a wide variety of neurological symptoms dependent on the region of the CNS affected. Here we present a case of neuro-Sweet's disease in association with Crohn's disease. PMID- 22450462 TI - Listeria rhomboencephalitis. PMID- 22450463 TI - Letter from Libya. PMID- 22450464 TI - End of the bed (end of the video) diagnosis. PMID- 22450465 TI - The term 'generalised' in EEG reports: too much ambiguity? PMID- 22450466 TI - Novel antimicrobial peptides isolated from the skin secretions of Hainan odorous frog, Odorrana hainanensis. AB - Long time geographical isolation of Hainan Island from the China continent has resulted in appearance of many novel frog species. As one of them, Hainan odorous frog, Odorrana hainanensis possesses some special antimicrobial peptides distinct from those found in other Odorrana. In this study, three antimicrobial peptides have been purified and characterized from the skin secretion of O. hainanensis. With the similarity to the temporin family, two peptides are characterized by amidated C-terminals, so they are named as temporin-HN1 (AILTTLANWARKFL-NH(2)) and temporin-HN2 (NILNTIINLAKKIL-NH(2)). The third antimicrobial peptide belongs to the brevinin-1 family which is widely distributed in Eurasian ranids, and thus, it is named as brevinin-1HN1 (FLPLIASLAANFVPKIFCKITKKC). Furthermore, after sequencing 68 clones, eight cDNAs encoding antimicrobial peptide precursors were cloned from the skin-derived cDNA library of O. hainanensis. These eight cDNAs can encode seven mature antimicrobial peptides including the above three, as well as brevinin-1V, brevinin-2HS2, odorranain-A6, and odorranain-B1. Twelve different species of microorganisms were chosen, including Gram-positive, Gram-negative and fungi, to test the antimicrobial activities of temporin-HN1, temporin-HN2, brevinin-1HN1, brevinin-1V, and brevinin-2HS2. The result shows that, in addition to their activities against Gram-positive bacteria, temporin-HN1 and temporin-HN2 also possess activities against some Gram-negative bacteria and fungi. However, the two antimicrobial peptides, brevinin-1HN1 and brevinin-1V of the brevinin-1 family have stronger antimicrobial activities than temporin-HN1 and temporin-HN2 of the temporin family. Brevinin-1HN1 possesses activity against Staphylococcus aureus (ATCC25923), Rhodococcus rhodochrous X15, and Slime mould 090223 at the concentration of 1.2 MUM. PMID- 22450467 TI - Dipeptidyl-peptidase IV inhibitory activity of peptides derived from tuna cooking juice hydrolysates. AB - The in vitro DPP-IV inhibitory activity of isolated peptides from of tuna cooking juice hydrolyzed by Protease XXIII (PR) and orientase (OR) was determined. The results showed that the peptide fractions with the molecular weight over 1,422 Da possessed the greatest DPP-IV inhibitory activity. The amino acid sequences of the three peptides isolated from PR and OR hydrolysates were identified by MALDI TOF/TOF MS/MS, and they were Pro-Gly-Val-Gly-Gly-Pro-Leu-Gly-Pro-Ile-Gly-Pro-Cys Tyr-Glu (1412.7 Da), Cys-Ala-Tyr-Gln-Trp-Gln-Arg-Pro-Val-Asp-Arg-Ile-Arg (1690.8 Da) and Pro-Ala-Cys-Gly-Gly-Phe-Try-Ile-Ser-Gly-Arg-Pro-Gly (1304.6 Da), while they showed the dose-dependent inhibition effect of DPP-IV with IC(50) values of 116.1, 78.0 and 96.4 MUM, respectively. In vitro simulated gastrointestinal digestion retained or even improved the DPP-IV inhibitory activities of the three peptides. The results suggest that tuna cooking juice would be a good precursor of DPP-IV inhibitor, and the DPP-IV inhibitory peptides can successfully passed through the digestive tract. PMID- 22450468 TI - Substance P stimulates Growth Hormone (GH) and GH-Releasing Hormone (GHRH) secretions through tachykinin NK2 receptors in sheep. AB - Substance P is ubiquitous undecapeptide belonging to the tachykinins family. It has been found in the hypothalamus and is involved in the hypothalamo-hypophysial axis in several mammals, including human. Previous studies have shown that substance P increases GH secretions in rats and human. In this study, we have shown that intravenously infused substance P in sheep caused an increased level of Growth Hormone (GH) and GH-Releasing Hormone (GHRH), and decreased Somatotropin Release Inhibiting Hormone (SRIH) secretions. GH was obtained from peripheral blood. GHRH and SRIH were directly collected from hypophysial portal blood, using a trans-nasal surgery technique in a vigil sheep that allowed accessing to hypothalamo-hypophysial portal vessels. Hormones assays were performed by radioimmunoassay (RIA). Moreover, we showed that substance P-induced GH and GHRH secretion appears to be mediated by NK2 tachykinin receptors, since it is specifically blocked by a non peptidic tachykinin NK2 receptor antagonist (SR48968, Sanofi, Montpellier, France) whereas a non peptidic tachykinin NK1 antagonist (SR140333, Sanofi, Montpellier, France) failed to modify GH and GHRH hormones secretions. PMID- 22450469 TI - On-bead tryptic proteolysis: an attractive procedure for LC-MS/MS analysis of the Drosophila caspase 8 protein complex during immune response against bacteria. AB - This study aims to characterize the immune response against bacteria in Drosophila melanogaster. Obtaining a description of the in vivo state of protein complexes requires their isolation as a snapshot of physiological conditions before their identification. Affinity purification with streptavidin-biotin system is widely used to address this issue. However, because of the extraordinary stability of the interaction between streptavidin and biotin, the release of biotin-labeled bait remains a challenge. We transfected Drosophila cells with a DNA construct encoding a biotin-tagged Dredd protein (ortholog of caspase 8). After affinity purification, different strategies were evaluated, and proteins analyzed by LC-MS/MS mass spectrometry. The on-bead digestion allowed the identification of more proteins associated to the Dredd complex than different protocols using competitive or acid elution. A functional assay showed that a large part of the proteins specifically identified in the Dredd sample are functionally involved in the activation of the Imd pathway. These proteins are immune response proteins (BG4, Q9VP57), stress response proteins (HSP7C, Q9VXQ5), structural proteins (TBB1, CP190), a protein biosynthesis protein (Q9W1B9) and an antioxidant system protein (SODC). Our results clearly show that on-bead digestion of proteins is an attractive procedure for the study of protein complexes by mass spectrometry. This article is part of a Special Issue entitled: Translational Proteomics. PMID- 22450470 TI - Global proteome survey of protocatechuate- and glucose-grown Corynebacterium glutamicum reveals multiple physiological differences. AB - Corynebacterium glutamicum can utilize various monocyclic aromatic carbon sources, including protocatechuate, which is catabolized via the beta-ketoadipate pathway. In order to obtain a global survey of occurring physiological adaptations on the proteome level, cytoplasmic and membrane fraction from cells grown on protocatechuate or glucose as sole carbon and energy source were compared. Shotgun proteomics and relative protein quantification with metabolic isotope labeling and spectral counting were employed. Altogether, 139 proteins were found to change their abundance during growth on protocatechuate. A general adaptation of energy metabolism to meet increased energy production by oxidative phosphorylation and a stress response occurred. Adjustments of carbon and amino acid metabolism in the cytoplasmic and membrane proteome were indicative of a starvation response. The different regulation of porins and cell wall biosynthesis proteins suggests a change in its architecture upon assimilation of the aromatic carbon source. Some of the observed changes could be explained by an involvement of the GlxR and McbR regulons. PMID- 22450471 TI - From the edge of oblivion: the dance between intrinsic neuronal currents and neuronal connectivity. PMID- 22450472 TI - High tidal volumes in mechanically ventilated patients increase organ dysfunction after cardiac surgery. AB - BACKGROUND: High tidal volumes in patients with acute respiratory distress syndrome and acute lung injury lead to ventilator-induced lung injury and increased mortality. We evaluated the impact of tidal volumes on cardiac surgery outcomes. METHODS: We examined prospectively recorded data from 3,434 consecutive adult patients who underwent cardiac surgery. Three groups of patients were defined based on the tidal volume delivered on arrival at the intensive care unit: (1) low: below 10, (2) traditional: 10-12, and (3) high: more than 12 ml/kg of predicted body weight. We assessed risk factors for three types of organ failure (prolonged mechanical ventilation, hemodynamic instability, and renal failure) and a prolonged stay in the intensive care unit. RESULTS: The mean tidal volume/actual weight was 9.2 ml/kg, and the tidal volume/predicted body weight was 11.5 ml/kg. Low, traditional, and high tidal volumes were used in 724 (21.1%), 1567 (45.6%), and 1,143 patients (33.3%), respectively. Independent risks factors for high tidal volumes were body mass index of 30 or more (odds ratio [OR] 6.25; CI: 5.26-7.42; P < 0.001) and female sex (OR 4.33; CI: 3.64 5.15; P < 0.001). In the multivariate analysis, high and traditional tidal volumes were independent risk factors for organ failure, multiple organ failure, and prolonged stay in the intensive care unit. Organ failures were associated with increased intensive care unit stay, hospital mortality, and long-term mortality. CONCLUSION: Tidal volumes of more than 10 ml/kg are risk factors for organ failure and prolonged intensive care unit stay after cardiac surgery. Women and obese patients are particularly at risk of being ventilated with injurious tidal volumes. PMID- 22450473 TI - Cardiac anesthesiologist: the friend of the heart. PMID- 22450475 TI - A massive upper abdominal tumor: an unusual mechanism of atelectasis and cardiac tamponade. PMID- 22450476 TI - Development of a population pharmacokinetic model for parecoxib and its active metabolite valdecoxib after parenteral parecoxib administration in children. AB - BACKGROUND: Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. METHODS: Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. RESULTS: A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. CONCLUSIONS: The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h. PMID- 22450477 TI - The guidelines for awake craniotomy guidelines committee of the Japan awake surgery conference. PMID- 22450478 TI - Noninvasive determination of speech dominance by single magnetic stimulation of the bilateral hand motor cortex. AB - Magnetic stimulation of the hand area of the motor cortex in both hemispheres was performed at rest and during reading aloud to observe modulated facilitation of hand muscle motor potentials in 6 right-handed patients, with supratentorial lesions but no motor impairment or aphasia, who had undergone the Wada test to determine speech dominance, showing that 5 were left hemisphere dominant and one was bilateral hemisphere dominant. Motor potentials were facilitated during reading aloud in only the right hand in 3 patients, all left hemisphere dominant, greater in the right hand in one, left hemisphere dominant, and greater in the left hand in one patient, bilateral hemisphere dominant. Based on these results we defined a laterality index which was consistent with the Wada test results. Magnetic stimulation may prove useful for determining cerebral dominance, as our method correlates well with the Wada test, and is safe, convenient, and inexpensive. PMID- 22450479 TI - Are there excitability changes in the hand motor cortex during speech in left handed subjects? AB - Hemispheric dominance was investigated in left-handed subjects using single transcranial magnetic stimulation to assess the possible effect of forced change in the dominant hand. Single transcranial magnetic stimuli were delivered randomly over the hand area of the left or right motor cortex of 8 Japanese self declared left-handed adult volunteers. Electromyographic responses were recorded in the relaxed first dorsal interosseous muscle while the subjects read aloud. Laterality quotient calculated by the Edinburgh Inventory ranged from -100 to 5.26 and laterality index calculated from motor evoked potentials ranged from 86.2 to 38.8. There was no significant correlation between laterality quotient and laterality index. Mean data values across all 8 subjects indicated significant increases only in the left hand. Our ratio analysis of facilitation of the hand motor potentials showed that 2 each of the 8 self-declared left handers were right- and left-hand dominant and the other 4 were bilateral-hand dominant. Speech dominancy was localized primarily in the right cerebral hemisphere in left-handed subjects, but some individuals exhibited bilateral or left dominance, possibly attributable to the forced change of hand preference for writing in childhood. Our findings suggest changes in the connections between the speech and hand motor areas. PMID- 22450480 TI - Improvement and impairment in cognitive function after carotid endarterectomy: comparison of objective and subjective assessments. AB - Objective and subjective assessments of postoperative improvement and impairment in cognition were prospectively compared in patients who underwent carotid endarterectomy (CEA). Each patient underwent subjective cognitive assessment by a neurosurgeon and the patient's next of kin, and neuropsychological testing consisting of five test scores within 7 days before surgery and between 1 and 2 months after surgery. Of 213 patients studied, 24 (11%), 166 (78%), and 23 (11%) patients were defined as having subjectively improved, unchanged, and impaired cognition, respectively, following surgery. In all neuropsychological tests, differences in test scores between the two tests (postoperative test score - preoperative test score) significantly differentiated patients with subjectively improved, unchanged, and impaired cognition after surgery. Receiver operating characteristic analysis showed that the cut-off point for the differences in neuropsychological test scores in detecting subjective improvement and impairment in cognition after surgery was identical to mean +2 standard deviations (SDs) and mean -2 SDs, respectively, of the control value obtained from normal subjects. Of 27 patients with differences in neuropsychological test scores more than the upper cut-off point and 26 patients with differences in neuropsychological test scores less than the lower cut-off point in one or more neuropsychological tests, 24 (89%) and 23 (88%) exhibited subjectively improved and impaired cognition, respectively, after surgery. The present study indicates that neuropsychological test scores reflect the subjective assessment of postoperative change in cognition, and can detect subjective improvement and impairment in cognition after CEA using the optimal cut-off points for the test scores. PMID- 22450481 TI - Ischemic events due to intraoperative microemboli developing in the cerebral hemisphere contralateral to carotid endarterectomy in a patient with preoperative cerebral hemodynamic impairment. AB - A 74-year-old man with a history of asymptomatic right internal carotid artery (ICA) occlusion experienced amaurosis fugax in the left eye. Angiography showed left cervical ICA stenosis in addition to right cervical ICA occlusion. The right anterior and middle cerebral artery (MCA) territories were perfused from the left ICA via the anterior communicating artery. Brain perfusion single-photon emission computed tomography revealed reduced cerebral blood flow and reduced cerebrovascular reactivity to acetazolamide only in the right cerebral hemisphere. The patient underwent left carotid endarterectomy (CEA). Transcranial Doppler monitoring showed microembolic signals in the left MCA during dissection of the left ICA, but intraoperative monitoring suggested absence of global hypoperfusion or ischemia in the bilateral cerebral hemispheres during left ICA clamping. Transient and slight motor weakness of the left upper extremity was noted on recovery from anesthesia. Diffusion-weighted magnetic resonance imaging demonstrated the development of new spotty ischemic lesions only in the right cerebral hemisphere. The present case suggests that intraoperative cerebral embolism causing postoperative neurological deficits can develop exclusively in the cerebral hemisphere contralateral to CEA if the hemisphere has preoperative hemodynamic impairment and collateral circulation via the anterior communicating artery from the ICA ipsilateral to CEA. PMID- 22450482 TI - Usefulness of ultrasonography with a burr-hole transducer during surgery through a burr hole. AB - Ultrasonography has become a common method for evaluation of the central nervous system. We present our experience with ultrasonography monitoring with a burr hole transducer for investigation of intracranial lesions. Common indications for this technique included guidance for placement of catheters, localization of masses, aspiration of cystic lesion, and confirmation of removal. Postoperative computed tomography (CT) was obtained to corroborate the appropriate procedures performed under ultrasonography guidance. Intraoperative ultrasonography provided immediate real-time information about the anatomy and pathological location of lesions. Postoperative CT findings were consistent with intraoperative ultrasonography findings. No procedure-related complication was noted and problems were minimal. Intraoperative ultrasonography using a burr-hole transducer has proved to be useful in burr-hole surgery. PMID- 22450483 TI - To the editor. PMID- 22450485 TI - Intracellular calcium movements during excitation-contraction coupling in mammalian slow-twitch and fast-twitch muscle fibers. AB - In skeletal muscle fibers, action potentials elicit contractions by releasing calcium ions (Ca(2+)) from the sarcoplasmic reticulum. Experiments on individual mouse muscle fibers micro-injected with a rapidly responding fluorescent Ca(2+) indicator dye reveal that the amount of Ca(2+) released is three- to fourfold larger in fast-twitch fibers than in slow-twitch fibers, and the proportion of the released Ca(2+) that binds to troponin to activate contraction is substantially smaller. PMID- 22450486 TI - Tuning the tetraethylammonium sensitivity of potassium channel Kcv by subunit combination. AB - Tetraethylammonium (TEA) is a potassium (K(+)) channel inhibitor that has been extensively used as a molecular probe to explore the structure of channels' ion pathway. In this study, we identified that Leu70 of the virus-encoded potassium channel Kcv is a key amino acid that plays an important role in regulating the channel's TEA sensitivity. Site-directed mutagenesis of Leu70 can change the TEA sensitivity by 1,000-fold from ~100 uM to ~100 mM. Because no compelling trends exist to explain this amino acid's specific interaction with TEA, the role of Leu70 at the binding site is likely to ensure an optimal conformation of the extracellular mouth that confers high TEA affinity. We further assembled the subunits of mutant and wt-Kcv into a series of heterotetramers. The differences in these heterochannels suggest that all of the four subunits in a Kcv channel additively participate in the TEA binding, and each of the four residues at the binding site independently contributes an equal binding energy. We therefore can present a series of mutant/wild-type tetramer combinations that can probe TEA over three orders of magnitude in concentration. This study may give insight into the mechanism for the interaction between the potassium channel and its inhibitor. PMID- 22450487 TI - Scorpion beta-toxin interference with NaV channel voltage sensor gives rise to excitatory and depressant modes. AB - Scorpion beta toxins, peptides of ~70 residues, specifically target voltage-gated sodium (Na(V)) channels to cause use-dependent subthreshold channel openings via a voltage-sensor trapping mechanism. This excitatory action is often overlaid by a not yet understood depressant mode in which Na(V) channel activity is inhibited. Here, we analyzed these two modes of gating modification by beta-toxin Tz1 from Tityus zulianus on heterologously expressed Na(V)1.4 and Na(V)1.5 channels using the whole cell patch-clamp method. Tz1 facilitated the opening of Na(V)1.4 in a use-dependent manner and inhibited channel opening with a reversed use dependence. In contrast, the opening of Na(V)1.5 was exclusively inhibited without noticeable use dependence. Using chimeras of Na(V)1.4 and Na(V)1.5 channels, we demonstrated that gating modification by Tz1 depends on the specific structure of the voltage sensor in domain 2. Although residue G658 in Na(V)1.4 promotes the use-dependent transitions between Tz1 modification phenotypes, the equivalent residue in Na(V)1.5, N803, abolishes them. Gating charge neutralizations in the Na(V)1.4 domain 2 voltage sensor identified arginine residues at positions 663 and 669 as crucial for the outward and inward movement of this sensor, respectively. Our data support a model in which Tz1 can stabilize two conformations of the domain 2 voltage sensor: a preactivated outward position leading to Na(V) channels that open at subthreshold potentials, and a deactivated inward position preventing channels from opening. The results are best explained by a two-state voltage-sensor trapping model in that bound scorpion beta toxin slows the activation as well as the deactivation kinetics of the voltage sensor in domain 2. PMID- 22450488 TI - Availability of added sugars in Brazil: distribution, food sources and time trends. AB - OBJECTIVE: To describe the regional and socio-economic distribution of consumption of added sugar in Brazil in 2002/03, particularly products, sources of sugar and trends in the past 15 years. METHODS: The study used data from Household Budget Surveys since the 1980s about the type and quantity of food and beverages bought by Brazilian families. Different indicators were analyzed: % of sugar calories over the total diet energy and caloric % of table sugar fractions and sugar added to processed food/ sugar calories of diet. RESULTS: In 2002/03, of the total energy available for consumption, 16.7% came from added sugar in all regional and socio-economic strata. The table sugar/ sugar added to processed food ratio was inversely proportional to increase in income. Although this proportion fell in the past 15 years, sugar added to processed food doubled, especially in terms of consumption of soft drinks and cookies. CONCLUSIONS: Brazilians consume more sugar than the recommended levels determined by the WHO and the sources of consumption of sugar have changed significantly. PMID- 22450489 TI - Mental performance of very low birth weight preterm infants: assessment of stability in the first two years of life and factors associated with mental performance. AB - The aim of this study was to investigate the stability of mental performance of very low birth weight premature infants during the first two years of life, and to identify factors associated with mental performance.The study included 109 children. The Mental Scale of Bayley Scales of Infant Development - Second Edition was administered at 6, 12 and 18-24 months of corrected age. The stability of the scores between assessments was verified by the analysis of variance for repeated measures.The association of the major social and neonatal characteristics with mental development was confirmed using multivariate analysis by linear regression, considering the following outcomes: mental development indices at 6 months, 12 months and between 18-24 months of corrected age. The mean Mental Developmental Index (MDI) was 83.4 (SD: 12.4) at 6 months, 86.4 (SD: 13.9) at 12 months, and 73.4 (SD: 14.5) at 18-24 months. A significant decrease in the mental developmental index (13 points) at 18-24 month corrected age was observed. The Mental development index did not show stability during the first two years of life in this population of preterm infants, except for children with neonatal pneumonia whose performance was unsatisfactory in all assessments. Among the risk factors investigated only male gender and neonatal pneumonia were associated with outcomes. PMID- 22450490 TI - Occupational accidents among mototaxi drivers. AB - The use of motorcycles as a means of work has contributed to the increase in traffic accidents, in particular, mototaxi accidents. The aim of this study was to estimate and characterize the incidence of occupational accidents among the mototaxis registered in Feira de Santana, BA. This is a cross-sectional study with descriptive and census data. Of the 300 professionals registered at the Municipal Transportation Service, 267 professionals were interviewed through a structured questionnaire. Then, a descriptive analysis was conducted and the incidence of accidents was estimated based on the variables studied. Relative risks were calculated and statistical significance was determined using the chi square test and Fisher's exact test, considering p < 0.05. Logistic regression was used in order to perform simultaneous adjustment of variables. Occupational accidents were observed in 10.5% of mototaxis. There were mainly minor injuries (48.7%), 27% of them requiring leaves of absence from work. There was an association between the days of work per week, fatigue in lower limbs and musculoskeletal complaints, and accidents. Knowledge of the working conditions and accidents involved in this activity can be of great importance for the adoption of traffic education policies, and to help prevent accidents by improving the working conditions and lives of these professionals. PMID- 22450491 TI - [Head and neck cancer: health related quality of life assessment considering clinical and epidemiological perspectives]. AB - The importance of oncology diseases as a cause of morbidity and mortality is increasing worldwide, and their social impact is being recognized due to economic and social costs involved in prevention, treatment and rehabilitation. Head and neck cancer is one of the six most prevalent neoplasms worldwide, with an estimated 900,000 new cases diagnosed annually. Regardless of tumor site, deterioration of basic functions affecting head and neck areas are perceived and affect patients' lives. Appropriate cancer registration may provide a better analysis of health-related quality of life outcomes. In this study, 380 head and neck cancer patients were evaluated. The study showed that women have lower overall Quality of Life results. It also emphasizes the importance of early diagnosis, which often relates to stages with better prognosis and better Quality of Life outcomes. The study concluded that tumor location has an impact on Quality of Life self-perception. Values of Health Related Quality of Life should be analyzed along with socio-demographic and clinical variables in order to better understand the epidemiology, pathogenesis, and prevention of Head and Neck Cancer. PMID- 22450492 TI - [Prevalence and factors associated with negative health perception by the Brazilian elderly]. AB - OBJECTIVE: To analyze the factors associated with negative health perception in older Brazilians. METHODS: Population study of a cross-sectional sample, conducted in 2009 in three cities of Brazil. The stratified simple random sample consisted of 909 adults between 60 and 91 years of age. A gross and multivariate analysis by estimated prevalence rate (PR) using Poisson regression with calculation of adjusted prevalence ratios, p < 0.05 was performed to identify factors associated with negative perception of health (NPH). RESULTS: The prevalence of NPH was 49.6%. After the multivariate association, a certain association for men with older age PR = 1.03 (Cl = 1.01 to 1.06), risk of malnutrition PR = 1.66 (CI = 1.13 to 2.43) and disability PR = 1.79 (CI = 1.21 to 1.77) was observed. For women, the association was with taking more than two medications PR = 1.41 (CI = 1.13 to 2.52), hypertension PR = 1.52 (CI = 1.43 to 1.97) and functional disability PR = 1.36 (CI = 1.13 to 1.86). CONCLUSIONS: Nearly half of the elderly have NHP, therefore preventive actions that decrease drug use and encourage behaviors toward better nutritional conditions should be tied to public policies in order to promote the functional independence and well being of the elderly. PMID- 22450493 TI - Construction of the discourse on dengue fever in the media. AB - The aim of this paper was to understand how the media in the state of Pernambuco portrays dengue fever, a disease that is affecting more and more Brazilians. Taking the explosive epidemic of 2002 as the starting point, we tried to understand the effects of meaning produced by the press in a comparative discourse strategy analysis used in 2002, 2004, 2006 and 2008. We selected 291 articles and notes published in the Jornal do Commercio (Recife-Brazil), on the situation of this viral disease in the state of Pernambuco in the four years. We also analysed dengue fever surveillance reports published by the health department of Pernambuco. To complement discourse analysis, we proposed the construction of a medialogy diagram, a graphic representation that tries to establish a relationship between newspaper texts and number cases of dengue reported. Results indicate that media coverage generally followed the development of dengue fever cases, with more news published during the epidemic periods and showing the appeal of the illness as a mass media phenomenon despite its risk to the Brazilian people. PMID- 22450494 TI - [Quality of life of people living with HIV/AIDS and its relationship with CD4+ lymphocytes, viral load and time of diagnosis]. AB - Quality of life (QOL) has accompanied the treatment of AIDS patients, along with pharmacological innovations that have allowed patients to live longer and maintain their well-being. The present study aimed at evaluating the QOL of these patients and correlate it with clinical and laboratory data. The study included 205 patients with HIV/AIDS, who answered the WHOQOL-120-HIV; and whose socio demographic data, clinical and laboratory findings were collected. The average age was 40.59 +/- 11.81 years; CD4+ lymphocyte count, 397.9 +/- 232.84 mm3; and years of diagnosis of HIV, 5.23 +/- 3.94. Viral load was <50 copies/ml in 115 patients; 50 to 10.000 in 61; and above 10.000 copies in 29 patients. Domains achieved satisfactory average scores, and the best were the psychological (14.5 +/- 2.7), followed by social relationships (13.7 +/- 2.2), physical (12.7 +/- 3.5), independence (12.6 +/- 2.5), personal beliefs (12.4 +/- 2.4), and environment (12.4 +/- 1.8). The best scores on pain, pleasure, social support, physical environment, and personal belief facets were observed for those with higher CD4 levels (p < 0.05). The best scores for the finance, leisure, concerns about the future, overall QOL, and perceived health facets were observed for patients with viral load <50 (p < 0.05). The highest rates for energy, fatigue, sexual activity, information, transportation, symptoms, care, and concerns about the future facets were seen in patients with less time of diagnosis (p < 0.05). HIV/AIDS patients in the study had an intermediate QOL correlating to CD4 levels, VL, and time of diagnosis. PMID- 22450495 TI - [Micronutrient consumption and overweight: is there a relationship?]. AB - INTRODUCTION: In past decades, the growth in obesity has been associated with changes in the lifestyle of the population, including comprehensive dietary changes, especially in the intake of micronutrients. OBJECTIVE: To describe micronutrient intake and review its consequences on nutritional status. METHODS: A literature review was performed covering domestic and international articles published over the past 11 years, on the SciELO, LILACS, MEDLINE and governmental databases, using descriptors such as "micronutrients", "food consumption", "excess weight", "health", "nutritional status" in Portuguese and in English. RESULTS: Micronutrient intake deficiency is a global health problem, affecting about 2 billion people and seems to be associated with an increased risk for non communicable diseases and disorders, including obesity. Insufficient intake of vitamin A favors overweight by altering thyroid metabolism, while vitamin C is related to the synthesis of carnitine and fat oxidation; vitamin D favors the control of satiety and energy expenditure. As for minerals, calcium helps the regulation of thermogenesis and lipogenesis / lipolysis, and zinc is involved in regulating insulin and leptin. CONCLUSION: The promotion of healthy eating habits through educational practices is necessary for greater public awareness of the implications of micronutrient intake on nutritional status, and should be included in Public Health strategies in order to control obesity and its complications. PMID- 22450496 TI - [Sample size and costs estimate in epidemiological survey of dental caries]. AB - This study aimed to analyze how the prevalence and the distribution of dental caries influence the sample size in epidemiological surveys, and how much are the costs. Secondary data of oral health surveys in 12-year-old schoolchildren from Bauru in 1976, 1984, 1990, 1994, and 2001, and from Piracicaba in 2001 and 2005 were studied. Sample sizes were estimated taking into account the mean DMFT and standard deviation of each survey, establishing sampling errors of 1%, 2%, 5%, and 10%. Costs were estimated considering permanent material, consumption material and human resources. The sample size in both towns needed to be increased, ranging from 119 in 1976 to 1,118 in 2001 in Bauru, and from 954 in 2001 to 1,252 in 2005 in Piracicaba, when a sampling error of 10% was considered. The cost of dental caries surveys was verified considering different sampling errors. This cost depends on how acceptable is the margin of difference between the true mean and the one found in the survey. In conclusion, the reduction in the prevalence of dental caries has determined the need for increase in sample size and in costs for conducting the surveys. PMID- 22450497 TI - Digital inclusion and functional capacity of older adults living in Florianopolis, Santa Catarina, Brazil (EpiFloripa 2009-2010). AB - OBJECTIVE: To study the relationship between digital inclusion, represented by the exchange of online messages, and functional capacity of older adults living in Florianopolis, Santa Catarina, Brazil. METHODS: Data were from EpiFloripa Idoso, a cross-sectional household-based survey conducted between 2009 and 2010 with older adults (60+ years). Functional capacity was represented by the inability / difficulty to perform basic / instrumental activities of daily living, and formed the outcome variable called functional dependence. The main independent variable was self-reported ability to send and receive online messages using the computer. Prevalence ratios (PR) and 95% confidence intervals (95%CI) were estimated with multivariable Poisson regression models. RESULTS: The sample consisted of 1,656 older adults between 60 and 102 years old with a mean age of 70.39 years (SD = 7.79). Older adults who could send and receive online messages without difficulty demonstrated a significant lower prevalence of moderate / severe functional dependence (PR = 0.61; 95%CI: 0.40 - 0.94) after adjustment for demographic, socioeconomic, health and behavioral factors. CONCLUSIONS: The exchange of online messages has a strong association with functional independence. The causality of this association cannot be determined. Studies support the hypothesis that the exchange of online messages and functional independence have a bidirectional, additive and synergistic association. Longitudinal studies could elucidate the mechanisms involved in this association, in order to support digital inclusion policies for older adults, and to identify the profile of older adults who would benefit the most from digital inclusion. PMID- 22450498 TI - Prevalence and characteristics of women with induced abortion--Favela Mexico 70, Sao Vicente-Sao Paulo. AB - In Brazil, abortion is among the leading causes of maternal mortality. Research has shown that abortion is practiced clandestinely by women of all social classes, but has unequal consequences depending on social inclusion, producing risks to poor women. Although the issue has been widely explored in the past 20 years, there is a lack of data about low-income women. Thus, the present study aims to estimate the prevalence of women with induced abortion. Women from a population-based household survey in low-income sectors of Sao Vicente, Sao Paulo were recruited. Women of childbearing age from 15 to 49 years were eligible. The evaluation of the prevalence ratios for women with induced abortion was performed by using generalized linear models, with Poisson log-link function and robust variance to approximate the binomial. The most frequent variables that influenced reporting of abortion were: "always accept this practice" (95% CI 2.98-11.02), followed by "not having a child born alive" (95% CI 1.35-19.78), having "two to five live births" (95% CI 1.42-14.40), "having 'six or more live births" (95% CI 1.35-19.78), "age at interview" (95% CI 1.01-1.07) and "income" < R$ 484.97' (95% CI 1.04-2.96). A widespread campaign about the practice of abortion, which can raise awareness among women in favor of the cause, especially among those in low income strata is necessary to prevent unnecessary deaths. PMID- 22450499 TI - [Quality of mortality information in a diabetes cohort--State of Rio de Janeiro, 2000 to 2003]. AB - OBJECTIVE: The aim of this study was to demonstrate the quality of the National Mortality Information System (SIM) in a special cohort of inpatients submitted to lower limb amputation (LLA) as a result of diabetes mellitus (DM), and compare the mortality pattern by causes for the cohort and for the population base of the State of Rio de Janeiro, from 2000 to 2003. METHODS: Data were generated from the linkage of the National Hospital Admittance Authorization-SIH-SUS (2000) and SIM (2000-2003) databases. Individuals under 30 years were excluded from the study, and deaths due to violent causes were also excluded in order to analyze the mention of DM as cause of death. Analyses of causes of death were conducted both in the cohort and the population base. Quality markers of SIM in the cohort were the frequency of mention of diabetes mellitus in the death certificate and the proportion of deaths classified as non-specific causes of death, and non-specific causes of death in the population base. RESULTS: 38.0% in the special cohort (n = 977) died during the four years following LLA as a result of diabetes mellitus (DM), and 49.1% of these deaths occurred during the first year. Endocrine, nutritional metabolic (41.5%), and cardiovascular diseases (28.5%), and non specific causes of death (8.1%) were the main underlying causes of death (UC). DM was mentioned as UC for 41.0%, as a sequential cause for 1.6%, and as contributive cause for 10.0%, among the other natural underlying causes of death besides DM on death certificates. Non-specific underlying causes of death accounted for 11.8% of death certificates in the population base. CONCLUSIONS: The high risk of death, the causes of death and the underreporting of DM on death certificates of adults with diabetes were similar to other population-based mortality studies. In the special cohort, the quality of the causes of death on certificates was considered bad. The improvement in the reliability of cause-of death depends on the ability of physicians to register, and of healthcare facilities to codify correctly the causes of death on death certificates. The method (linkage of data and multiple causes of death) applied in this study to qualify death information was efficient and effective. PMID- 22450500 TI - [Pre-pregnancy nutritional status, maternal weight gain, prenatal care, and adverse perinatal outcomes among adolescent mothers]. AB - OBJECTIVE: To identify the association between pre-gestational nutritional status, maternal weight gain, and prenatal care with low birth weight (LBW) and prematurity outcomes in infants of adolescent mothers. METHODS: Cross-sectional study with 542 pairs of adolescent mothers and their children attending a public maternity hospital in Rio de Janeiro. Data were collected from medical records. To determine the association between independent variables and the outcomes studied, odds ratio (OR) and a 95% confidence interval (CI) were estimated RESULTS: With respect to pre-pregnancy nutritional status of adolescents, 87% had normal weight, 1% were underweight, 10% were overweight, and 2% obese. Inadequate total gestational weight gain (72%) exceeded adequacy (28%). Birth weight was favored with greater gestational weight gain, and reduced with late onset of prenatal care. The comparison between the low birth weight and normal birth weight groups revealed significant differences between variable means: interval between the past pregnancy and current pregnancy (p = 0.022), pre-gestational weight (p = 0.018); pre-gestational body mass index (p < 0.001), and total gestational weight gain (p = 0.047). The odds of LBW (OR 2.70, 95% CI 1.45 to 5.06) and prematurity (OR 5.82, 95% CI 3.10 to 10.92) fell when the adolescent received six or more prenatal visits. CONCLUSION: Birth weight was associated with inter-gestational interval, pre-pregnancy weight and body mass index before pregnancy. The minimum frequency of six prenatal care visits was a protective factor against LBW and prematurity. PMID- 22450501 TI - Burnout syndrome among dental students. AB - The burnout syndrome is characterized by professional exhaustion and has been reported in college students. The aim of this study was to estimate the prevalence of Burnout Syndrome among dentistry students from a public university, and its relationship to socio-demographic characteristics. All students (n = 300) were invited to participate. We used the Maslach Burnout Inventory-Student Version (MBI-SS). We carried out an analysis of the MBI-SS' psychometric properties. Multivariate Analysis of Variance (MANOVA) was performed, followed by Analysis of Variance (ANOVA) and Tukey's post-hoc tests to compare the mean scores of burnout dimensions. Of the 235 participants, 72.8% were women and the mean age was 21.0 +/- 1.8 years. The MBI-SS was reliable and valid. Of the students, 17.0% had Burnout Syndrome. There was a significant relation between Burnout Syndrome and a student's performance during the course (F = 4.433, p < 0.001), medication intake because of studies (F = 7.721, p < 0.001), and the thought of dropping the course (F = 16.168, p < 0.001). The students most affected were those with poor performance, those who took medication because of studies, and those with thoughts of dropping the course. We concluded that the prevalence of the syndrome among dentistry students was high, with a significant relation between the syndrome and a student's academic performance, use of medication because of studies, and thoughts of dropping the course. PMID- 22450502 TI - [Intra-family violence: health workers' practice in Sao Joaquim do Monte, Pernambuco, Brazil]. AB - The objective of the study was to verify the association between assistance, referral and reporting of Intra-family Violence/ IFV against pregnant adolescents, and the socio-demographic characteristics of 84 professionals of the Family Health Program/FHP in the agreste region of Pernambuco. The study is part of a multicenter, cross sectional research, carried out from October 2008 to April 2009. A structured questionnaire related to the various types of violence (psychological, physical or sexual) and validated for Brazil was used. Sociodemographic variables and professional experience in assisting cases of IFV were added to the instrument: identification of types, care, referral, and notification. The analysis of results showed a large number of professionals that had never identified a case of violence (72%). Among the 23 who provided care to cases of violence, there was a majority of psychological (86.9%), followed by physical (60.8%), and sexual (43.5%) cases. Only eight professionals (34.8%) referred the adolescents to the Tutelary Council, Police Office and/or Public Prosecutor's Office. The analysis of association with care and reporting found older age (p = 0.018; IC(95) 1.31-17.1) and having children (p = 0.039; IC(95) 0.04-17.1) as statistically significant. On the other hand, a borderline association was found with work in an urban area and higher education. There was no association with sex, marriage status and years of work variables. The authors concluded that, despite the 'invisibleness' of IFV, the analysis of actions developed at the FHP represented an approximation to this complex and multifaceted phenomenon and the possibility of critical thinking on its different ways of social understanding. PMID- 22450503 TI - [Computerized tomography utilization for stroke inpatients in the Brazilian Health System]. AB - Stroke is a leading reason for hospitalization in the Brazilian Health System. Computerized tomography has been indicated as the main diagnostic method to define stroke treatment. The aim of this paper was to evaluate the utilization of computerized tomography in hospitalizations due to stroke. The source of data was the Brazilian hospital information system. The study population comprised adult stroke inpatients in Brazil in the Brazilian Health System, between April 2006 and December 2007. Data analysis was descriptive for stroke and for each separate subgroup. Of the 328,087 stroke inpatients, 73.5% had not done a computerized tomography scan. Among hospitalizations that underwent a computed tomography scan, 22.3% had access to one test, and only 4.2% had two tests. Besides underuse, the computed tomography scans performed did not improve the encoding of the disease subgroup. PMID- 22450504 TI - Diarrhea in children and sanitation and housing conditions in periurban areas in the city of Guarulhos, SP. AB - A cross-sectional study was carried out to identify the association between diarrhea in 0-2 year-old children and children's characteristics, access to sanitation and housing conditions in a periurban area served by the Family Health Program, in the city of Guarulhos, SP. Data were obtained from FHP registration forms. Multiple logistic regression showed interaction for Housing*Sewage (other materials and non collected wastewater, p < 0.001), age group (4-9 months old, p = 0.054; 10 months and older, p = 0.008) as risk factors for diarrhea. Information collected by the Family Health Program could be an excellent tool to identify populations with poor housing and sanitation conditions at locations where sanitation indicators are not efficient to identify populations living at risk. PMID- 22450505 TI - [Validity and reproducibility of a physical activity questionnaire for adolescents: adapting the Self-Administered Physical Activity Checklist]. AB - OBJECTIVES: To evaluate test-retest reproducibility and the validity of a physical activity questionnaire for adolescents (adapted from Self-Administered Physical Activity Checklist). METHODS: The test-retest reproducibility analysis was completed by 239 adolescents (average age 16 years, SD = 1.2; 56.4% female), and the validity analysis by 70 adolescents (average age 15.7 years, SD = 1.2; 55.7% female). All adolescents were high school students in Joao Pessoa, PB, in Northeastern Brazil, in 2009. The test-retest reproducibility was determined by repeated evaluations with one week interval between them. Validity of the physical activity questionnaire was assessed by comparing the results of the questionnaire with those of four 24-hour recalls (reference method). RESULTS: The test-retest reproducibility was high (intraclass correlation coefficient: ICC = 0.88; 95%CI: 0.84 - 0.91), and the agreement was moderate for physical activity classified in two groups (< 300 min/week vs. > 300 min/week; kappa coefficient: k = 0.52). Spearman correlation coefficient comparing the questionnaire data with those of four 24-hour recalls (reference method) was moderate (rho = 0.62; p < 0001). The agreement between these measures (questionnaire and 24-hours recalls) for physical activity classified in two groups was moderate (k = 0.59). CONCLUSIONS: The physical activity questionnaire showed high reproducibility, and moderate validity, and therefore, its use is recommended for assessing adolescents' physical activity level. PMID- 22450506 TI - Malnutrition among children under 60 months of age in two cities of the state of Acre, Brazil: prevalence and associated factors. AB - OBJECTIVE: To investigate the prevalence of malnutrition and associated factors in children under the age of 60 months in two cities in the state of Acre, Brazil. METHODS: A population-based cross-sectional study was carried out with 667 children living in urban areas of the cities of Acrelandia and Assis Brasil. The prevalence of malnutrition was calculated by height for age (stunting) and weight for height (W/H) indexes, which were calculated with a cutoff point of -2 for Z scores as determined by the 2006 World Health Organization child growth standards. A structured questionnaire was used to gather information on socioeconomic conditions, access to services and child care, birth weight and morbidity. Poisson regression was used to identify the factors associated with child malnutrition. RESULTS: The prevalence of height-for-age and weight-for height deficit was 9.9% and 4.1%, respectively. The factors associated with height-for-age deficit were low household wealth index (prevalence ratio [PR]: 1.74; 95% confidence interval [95% CI]: 0.95-3.18); having an illiterate father or stepfather (PR: 1.82; 95% CI: 1.01-3.27); having 2 or more younger siblings (PR: 2.88; 95% CI: 1.45-5.72); biological mother not living in the home (PR: 2.63; 95% CI: 1.32-5.24); and exposure to open wastewater near the home environment (PR: 2.46; 95% CI: 1.51-4.00). "Low weight at birth" was the only factor associated with weight-for-height deficit (PR: 2.91; CI95%: 1.16-7.24). CONCLUSIONS: In the cities studied, malnutrition in children under 60 months is an important public health problem, and is associated with indicators of social inequality, access to health services and biological mother not living in the home. PMID- 22450507 TI - Spatial distribution of tuberculosis and relationship with living conditions in an urban area of Campina Grande--2004 to 2007. AB - This research aimed to study the spatial distribution of tuberculosis and its relationship with living conditions in the urban area of the city of Campina Grande in the period from 2004 until 2007. It is an ecologic study which used the city's neighborhood distribution; demographic, social and economic data from year 2000 census; and the new cases of tuberculosis reported to the Disease and Reporting Information System. Georeferencing was done for the cases of tuberculosis, and disease incidence was calculated by neighborhood. Rates were softened and the Global Moran Index was calculated. Social-economic data were grouped in quartiles according to the Life Condition Index, calculating the incidence of TB in each stratum of living conditions. The results showed that the spatial distribution of tuberculosis in the city is not uniform. Grouping neighborhoods according to the Life Conditions Index revealed social differences that can justify the occurrence of higher incidence rates in the most socially and economically vulnerable regions. The best living condition stratum presented a high incidence possibly due to the underreporting of the cases of tuberculosis caused mainly by the centralization of disease control services. We hope that this study may help outline control strategies for the city of Campina Grande, from the perspective of health promotion, for a disease so socially determined, as is the case of TB. PMID- 22450509 TI - Neuromuscular disease: Muscular dystrophy--something new on God's green earth? PMID- 22450508 TI - Sex-related factors in multiple sclerosis susceptibility and progression. AB - The pathogenesis of multiple sclerosis (MS) involves complex interactions between genetic susceptibility and environmental triggers. Clinical observations suggest that the study of sex differences might provide important insight into mechanisms of pathogenesis and progression of the disease in patients. MS occurs more frequently in women than in men, indicating that sex-related factors have an effect on an individual's susceptibility to developing the condition. These factors include hormonal, genetic and environmental influences, as well as gene environment interactions and epigenetic mechanisms. Interestingly, women do not have a poorer prognosis than men with MS despite a higher incidence of the disease and more-robust immune responses, which suggests a mechanism of resilience. Furthermore, the state of pregnancy has a substantial effect on disease activity, characterized by a reduction in relapse rates during the third trimester but an increased relapse rate in the postpartum period. However, pregnancy has little effect on long-term disability in women with MS. The unravelling of the mechanisms underlying these clinical observations in the laboratory and application of the results to the clinical setting is a unique and potentially fruitful strategy to develop novel therapeutic approaches for MS. PMID- 22450510 TI - Molecular analysis of bacterial microbiota associated with oysters (Crassostrea gigas and Crassostrea corteziensis) in different growth phases at two cultivation sites. AB - Microbiota presumably plays an essential role in inhibiting pathogen colonization and in the maintenance of health in oysters, but limited data exist concerning their different growth phases and conditions. We analyzed the bacterial microbiota composition of two commercial oysters: Crassostrea gigas and Crassostrea corteziensis. Differences in microbiota were assayed in three growth phases: post-larvae at the hatchery, juvenile, and adult at two grow-out cultivation sites. Variations in the microbiota were assessed by PCR analysis of the 16S rRNA gene in DNA extracted from depurated oysters. Restriction fragment length polymorphism (RFLP) profiles were studied using Dice's similarity coefficient (Cs) and statistical principal component analysis (PCA). The microbiota composition was determined by sequencing temperature gradient gel electrophoresis (TGGE) bands. The RFLP analysis of post-larvae revealed homology in the microbiota of both oyster species (Cs > 88 %). Dice and PCA analyses of C. corteziensis but not C. gigas showed differences in the microbiota according to the cultivation sites. The sequencing analysis revealed low bacterial diversity (primarily beta-Proteobacteria, Firmicutes, and Spirochaetes), with Burkholderia cepacia being the most abundant bacteria in both oyster species. This study provides the first description of the microbiota in C. corteziensis, which was shown to be influenced by cultivation site conditions. During early growth, we observed that B. cepacia colonized and remained strongly associated with the two oysters, probably in a symbiotic host-bacteria relationship. This association was maintained in the three growth phases and was not altered by environmental conditions or the management of the oysters at the grow-out site. PMID- 22450511 TI - A vigorous specialized microbial food web in the suboxic waters of a shallow subtropical coastal lagoon. AB - To examine the extent of the microbial food web in suboxic waters of a shallow subtropical coastal lagoon, the density and biomass of bacteria and protozooplankton were quantified under different dissolved oxygen (DO) levels. In addition, bottom waters of a stratified site were compared with bottom waters of a homogeneous site under periods of high and low biological oxygen production/consumption in the lagoon. At the stratified site, microbial biomass decreased with oxygen decline, from oxia to suboxia, with a recovery of the initial total biomass after a 20-day period of persistent suboxia. A peak in density and biomass of purple sulfur bacteria (PSB) (90 MUg C L(-1)) occurred in the suboxic waters 20 days prior to the peak in biomass of ciliates >50 MUm (Loxophyllum sp. of 150 MUm) (160 MUg C L(-1)), demonstrating a top down biomass control. Ciliates >50 MUm were positively correlated with PSB and bacteriochlorophyll a (photosynthetic pigment of PSB). Total protozoan biomass reached 430 MUg C L(-1) in the suboxic waters of the stratified site, with ciliates >50 MUm accounting for 90% of the total ciliate biomass and of 55 % of biomass of protozoa. At the homogeneous site, total protozoan biomass was only 66 MUg C L(-1), where flagellates and ciliates <25 MUm were the dominant microorganisms. Therefore, as light is available for primary producers in the bottom waters of shallow stratified coastal lagoons or estuaries, one can expect that high primary production of PSB may favor a specialized microbial food web composed by larger microorganisms, accessible to zooplankton that tolerate low DO levels. PMID- 22450512 TI - Distribution patterns of Wolbachia endosymbionts in the closely related flower bugs of the genus Orius: implications for coevolution and horizontal transfer. AB - Vertical transmission is the primary route of the endosymbiont Wolbachia for its own spread among invertebrate hosts, but horizontal transmission between different hosts is believed to have occurred multiple times. However, it is not well known how Wolbachia commonly spread among closely related hosts. We focused on the closely related species of the minute pirate bugs belonging to the genus Orius, which are important biological control agents in agricultural crops because they are the most useful natural enemy of various tiny pests, such as thrips. Here, we examined five Orius species (Orius sauteri, Orius nagaii, Orius minutus, Orius strigicollis, and Orius tantillus) from eight geographic localities in Japan for Wolbachia infection. Two distinct strains, wOus1 and wOus2, were detected based on Wolbachia surface protein (wsp) gene sequencing. Furthermore, multilocus sequence typing revealed that each of the strains comprised two variants that differed in a single nucleotide. The overall distribution patterns of the two Wolbachia strains were found to differ among host species: prevalent double infection with wOus1 and wOus2 in O. strigicollis; fixation of single infection with wOus2 in O. nagaii; occurrence of single infection with wOus1 in O. sauteri; prevalence of single infection with wOus1 in O. minutus with an exception in a single population; and lack of Wolbachia infection in O. tantillus. Such differences in the distribution patterns of Wolbachia may reflect the evolutionary history of Wolbachia infection among Orius species and/or ecological and physiological differences among the Orius species that determine the invasiveness and maintenance of the two Wolbachia strains. PMID- 22450513 TI - Measuring retinal sensitivity with the microperimeter in patients with diabetes. AB - PURPOSE: To evaluate the retinal sensitivity and fixation characteristics in participants with diabetes mellitus, using the microperimeter (MP-1) and to correlate the MP-1 values with the severity of diabetic retinopathy (DR). METHODS: We performed complete ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, indirect ophthalmoscopy, and microperimetry (central 20 degrees of macula) on 210 eyes of 160 participants. Participants included healthy individuals, individuals with diabetes but no retinopathy, and individuals with different stages of DR. RESULTS: The mean age of participants was (mean +/- SD) 49.83 +/- 7.43 years for healthy individuals, 53.20 +/- 5.7 years for participants with diabetes but no retinopathy, and 55.39 +/- 7.81 years for participants with DR. Retinal sensitivity was significantly (P = 0.001) decreased with severity of DR. The mean foveal sensitivity (retinal sensitivity in the central 2 degrees ) was 16.68 +/- 2.13 dB in healthy individuals, 14.73 +/ 3.64 dB in participants with diabetes but no DR, and 11.60 +/- 5.76 dB in participants with DR. There was significant loss of retinal sensitivity in participants with diabetes but no retinopathy when compared with healthy individuals. Participants with severe nonproliferative DR showed more significant loss of retinal sensitivity in the central 20 degrees than those with other stages of DR. CONCLUSION: The MP-1 is a useful tool to quantify retinal sensitivity in DR. Using the MP-1, we can detect early loss of retinal sensitivity in patients with diabetes but no retinopathy. Patients with severe nonproliferative DR will have less retinal sensitivity than those with other stages of DR. Scotoma mapping using the MP-1 provides details of functional vision in patients with DR. PMID- 22450514 TI - Use of lutein and zeaxanthin alone or combined with Brilliant Blue to identify intraocular structures intraoperatively. AB - PURPOSE: To determine whether a natural dye solution based on lutein and zeaxanthin alone or combined with Brilliant Blue stains and facilitates peeling of intraocular membranes in human eyes. METHODS: In this study of 60 cadaveric eyes, open-sky vitrectomy including posterior hyaloid detachment was performed. Different lutein and zeaxanthin concentrations (0.01-20%) were tested alone or combined with different Brilliant Blue concentrations (0.0125-0.025%) in the corneal endothelium, corneal epithelium, anterior and posterior capsule, vitreous cavity through the macula including the posterior hyaloid, and internal limiting membrane. The various dye solutions were in contact with the intraocular membranes for <1 minute and then were removed by mechanical aspiration or membrane peeling initiated and completed with intraocular forceps. The specimens were examined by light and electron transmission microscopy. RESULTS: Contact between lutein and zeaxanthin and the retinal, lens, and vitreous surface resulted in orange and greenish staining of the intraocular membranes, which facilitated surgical steps in all eyes. Lutein and zeaxanthin alone was useful for vitreous identification and lutein and zeaxanthin combined with Brilliant Blue had strong affinity for internal limiting membrane and anterior capsule. Light microscopy confirmed internal limiting membrane removal in all eyes tested. No dye solutions remained in the eyes after the membrane removal. CONCLUSION: A natural dye solution based on lutein and zeaxanthin alone or combined with Brilliant Blue efficiently stained the anterior capsule, vitreous, and internal limiting membrane in human cadaveric eyes and may be a useful tool for vitreoretinal or cataract surgery. PMID- 22450515 TI - Site-directed modification of the adenylation domain of the fusaricidin nonribosomal peptide synthetase for enhanced production of fusaricidin analogs. AB - Fusaricidins produced by Paenibacillus polymyxa DBB1709 are lipopeptide antibiotics active against fungi and Gram-positive bacteria. The cyclic hexapeptide structures of fusaricidins are synthesized by fusaricidin synthetase, a non-ribosomal peptide synthetase. The adenylation domain of the third module (FusA-A3) can recruit L: -Tyr, L: -Val, L: -Ile, L: -allo-Ile, or L: -Phe, which diversifies the fusaricidin structures. Since the L: -Phe-incorporated fusaricidin analog (LI-F07) exhibits more potent antimicrobial activity than other analogs, we modified a specificity-conferring sequence in the substrate binding pocket of FusA-A3 to direct the enhanced production of LI-F07. Base on comparison to the adenylation domain of gramicidin S synthetase 1 and tyrocidine synthetase 1, both of which mainly activate L: -Phe, six mutant strains with altered FusA-A3 were generated using site-directed mutagenesis. M3 (I239W, I299V), M5 (I299V, G322A, V330I), and M6 (S239W, I299V, G322A, V330I) mutants produced significantly more LI-F07 than the wild-type strain. PMID- 22450516 TI - [Use of ambulatory blood pressure measurement in primary care in Iceland]. AB - OBJECTIVE: To study the use of ambulatory blood pressure measurement (ABPM) in primary care in Iceland. MATERIAL AND METHODS: All patients who had ABPM done during the period from 1st of June 2008 till 31st of May 2010 at three health care centers comprised the study group. Medical records of these patients were examined and information about previous diagnosis of hypertension, cardiovascular disease, diabetes, obesity, smoking habits and drug prescriptions along with results of blood pressure measurements were registrated. RESULTS: A total of 205 ABPM were done during the study period. Mean age of the patients was 54 years +/ 15.1, the youngest being 18 and the oldest 87 years old. The study group comprised 119 (58%) women and 86 men (42%). The ABPM was done as a part of follow up of hypertension in 112 (55%) cases, but among 93 patients it was used as an aid in the diagnosis of hypertension. The study showed that 88 (41%) were defined as dippers. The ABPM did not result in a change of treatment in 14% of cases, among 19% of subjects antihypertensive treatment was initiated whereas 16% did not require any treatment; in 6% of cases the antihypertensive treatment was reduced while in 13% it was necessary to increase the treatment. CONCLUSION: We conclude that ABPM is a very useful tool in primary care settings, both to improve diagnosis and the treatment of hypertension. PMID- 22450517 TI - [Diagnosis and management of hypertension]. PMID- 22450518 TI - [The traceability of implants in surgery]. PMID- 22450519 TI - [Negative pressure wound therapy in Iceland - indication and outcome]. AB - INTRODUCTION: Negative pressure wound therapy (NPWT) is a recent therapeutic option in wound healing, where a vacuum source is used to create sub-atmospheric pressure in the wound bed with airtight dressings. The aims were to study the indications for the use of NPWT in a whole country and evaluate the outcome of treatment. MATERIAL AND METHODS: This was a retrospective study that included all patients that were treated with NPWT in Iceland between January and December 2008. Information on indication, duration and outcome of treatment was collected from patient charts. Factors that are known to affect wound healing, such as diabetes, smoking and age, were also registered. RESULTS: During the 12 month study period a total of 65 NPWT-treatments were given to 56 patients; 35 (63%) males and 21 (37%) females, with an average age of 62 yrs (range; 8 - 93). The indications for treatment were: wound infection (40%), promotion of wound healing (42%) and keeping cavities open (19%). The lower limbs (26%) and chest area (25%) were the most common sites for treatment. Six patients died during the treatment period, none of them due to complications related to NPWT, and these patients were excluded from analysis of wound healing. In the other 59 treatments, 40 wounds (68%) healed successfully, but healing was incomplete in 19. Treatment related complications were recorded in 19 (32%) cases; wound pain (12%) and skin problems (11%) being the most common ones. CONCLUSION: NPWT has been used considerably in Iceland, especially for infected surgical wounds and chronic wounds. In two thirds of cases a complete wound healing was achieved, which must be regarded as a favorable outcome. PMID- 22450520 TI - [Diagnosis and treatment of hair pulling- and skin picking disorder]. AB - Hair pulling disorder (HPD; trichotillomania) is characterized by recurrent pulling of hair from the scalp, eyebrows or other parts of the body. Skin picking disorder (SPD) is closely related to HPD and involves re-current picking of the skin. Even though both HPD and SPD are relatively common and potentially severe disorders, health professionals typically know little about them. In the present article, we describe the clinical characteristics of these problems and provide diagnostic guidelines. We also discuss main treatment approaches (drug treatments and behavior therapy) and review research on their efficacy. Results show that behavior therapy (habit reversal) has consistently been shown to be effective, SSRIs seem not to work, but preliminary data suggest that other drugs (e.g. N acetylcysteine) may benefit some patients. PMID- 22450521 TI - [Neonatal vomiting. Diagnosis: intestinal malrotation]. PMID- 22450522 TI - Timing and duration of sleep and meals in obese and normal weight women. Association with increase blood pressure. AB - The aim was to evaluate the efficiency and duration of sleep and meals in normal weight and obese women and the impact of these factors on metabolic syndrome (MetS) variables. The study was conducted in 70 women, normal-weight women (n=20) and obese women (n=50). Anthropometric variables, plasma glucose, lipids and ghrelin concentrations were determined. Blood pressure measurement was performed before lunch and before dinner for a week on alternate days. Subjects were instructed to keep a sleep and feeding diary. In general, obese women displayed longer and a significantly higher number of awakenings per week than normal weight women and a higher duration of naps. Sleep efficiency was significantly lower in obese women. The higher intake in energy in the obese women was due to snacking differences. Moreover, higher sleep efficiency was correlated with a decrease in the diastolic blood pressure evening/morning ratio. Interestingly, among normal-weight women, visceral fat increased with the number of awakenings while plasma ghrelin was inversely correlated with meal duration (P=0.027). In conclusion, obese women had lower sleep efficiency, ate more quickly and spent more time eating and sleeping during the daytime hours than normal-weight women. Of note, sleep efficiency was associated with MetS features. Further interventions in obesity could include educating patients in food timing and in healthier sleep-hygiene practices, helping them to modify bad sleep habits. PMID- 22450523 TI - Top down modulation of attention to food cues via working memory. AB - Attentional biases towards food cues may be linked to the development of obesity. The present study investigated the mechanisms underlying attentional biases to food cues by assessing the role of top down influences, such as working memory (WM). We assessed whether attention in normal-weight, sated participants was drawn to food items specifically when that food item was held in WM. Twenty-three participants (15 f/8 m, age 23.4+/-5 year, BMI 23.5+/-4 kg/m(2)) took part in a laboratory based study assessing reaction times to food and non-food stimuli. Participants were presented with an initial cue stimulus to either hold in WM or to merely attend to, and then searched for the target (a circle) in a two-item display. On valid trials the target was flanked by a picture matching the cue, on neutral trials the display did not contain a picture matching the cue, and on invalid trials the distractor (a square) was flanked by a picture matching the cue. Cues were food, cars or stationery items. We observed that, relative to the effects with non-food stimuli, food items in WM strongly affected attention when the memorised cue re-appeared in the search display. In particular there was an enhanced response on valid trials, when the re-appearance of the memorised cue coincided with the search target. There were no effects of cue category on attentional guidance when the cues were merely attended to but not held in WM. These data point towards food having a strong effect on top-down guidance of search from working memory, and suggest a mechanism whereby individuals who are preoccupied with thoughts of food, for example obese individuals, show facilitated detection of food cues in the environment. PMID- 22450524 TI - Expression of complement components and regulators by different subtypes of bone marrow-derived macrophages. AB - Under inflammatory conditions, macrophages can differentiate into different functional subtypes. We show that bone marrow-derived macrophages constitutively express different levels of various complement-related genes. The relative expression levels are C1qb > Crry > CFH > C3 > C1r > CFB > DAF1 > CD59a > C2 > C1INH > C1s > C4. Upon activation, the expression of C1r, C1s, C3, C2, CFB, and C1INH was up-regulated, and CFH, CD59a, and DAF1, down-regulated in M1 (induced by interferon-gamma + lipopolysaccharides (LPS)) and M2b (induced by immune complex + LPS) macrophages. The expression of C4 and CFH was slightly up regulated in interleukin (IL)-10-induced M2c macrophages. Complement gene expression in IL-4-induced M2a macrophages was weakly down-regulated as compared to resting M0 macrophages. Higher levels of C3, C1INH, and CFB but lower levels of CFH expression in M1 and M2b macrophage suggests that they may be involved in the alternative pathway of complement activation during inflammation. PMID- 22450525 TI - [Is there a benefit to continue pap smear screening for cervical cancer after 65 years of age? A retrospective study on 53,644 women]. AB - BACKGROUND: One third of cervical cancers are discovered after age 65. French guidelines allow women to cease having cervical pap smears at age 65, providing they have had a minimum of two consecutive negative smears. AIM: To study the frequency of pathological smears in the group of women aged over 65 with a normal and sufficient cytological follow-up, according to the guidelines. To analyze the smear results and the former follow-up of this population to determine whether there is an interest to continue the smear screening after age 65. METHODS: This is a retrospective multicenter study based on collecting data from three pathology laboratories of the region Rhone-Alpes. We study a population of women 65 and older with smears that have been made between 2004 and 2008. RESULTS: Precancerous lesions and cervical cancer can be discovered after age 65 despite an adequate former follow-up. The rate of these women for having a pathological smear is 14,20/00, including 1,20/00 with cytological abnormalities in favour of cancer. CONCLUSION: These results show that there is interest to continue the smear tests after age 65 at least, while considering medical and financial issues of a reasonable screening strategy. PMID- 22450526 TI - Evaluating retinal toxicity of a new heavy intraocular dye, using a model of perfused and isolated retinal cultures of bovine and human origin. AB - BACKGROUND: Dyes such as brilliant blue (BBG) are used during vitreoretinal surgery to visualize anatomical structures. By adding deuterium oxide (D2O), surgeons have tried to create a dye mixture heavier than water to facilitate staining of the inner limiting membrane (ILM) without prior fluid-air exchange. This study investigated the effect of 0.4 ml BBG (Fluoron, Ulm, Germany) mixed with 0.13 ml/ml D2O and D2O on retinal function of a pseudo in vivo model using bovine and human whole mount cultures. METHODS: Bovine and human retinas were superfused, and the electroretinogram (ERG) was recorded. BBG with 0.13 ml/ml D2O and D2O were applied epiretinally, different staining periods (10, 30, 60 and 120 s) were tested, and ERG recovery was monitored. 1 mM aspartate was added to the nutrient solution to examine the photoreceptor reaction. RESULTS: Reductions of the a- and b-wave amplitudes were found directly after exposure with BBG with 0.13 ml/ml D2O and with D2O in all test series. These effects on the electroretinogram were rapidly and completely reversible within the recovery time for all exposure times. ERG amplitudes measured after dye application at the end of the washout did not differ significantly from those recorded before staining. CONCLUSIONS: The clinically used mixture of BBG/D2O seems to be safe for clinical use. Staining periods of more than 120 seconds were not tested. PMID- 22450527 TI - Factors predisposing to consecutive esotropia after surgery to correct intermittent exotropia. AB - BACKGROUND: To investigate the incidence of and factors predisposing to consecutive esotropia after intermittent exotropia surgery, and to prevent the onset of consecutive esotropia. METHODS: We retrospectively surveyed 226 patients who had been followed up for more than 1 year after surgery for intermittent exotropia conducted between February 2005 and September 2010. Consecutive esotropia was defined as an esotropia of at least 10 prism diopters (PD) at distance or near at least once in 2 weeks after surgery. Presumed risk factors for consecutive esotropia were analyzed. Gender, age at surgery, average binocular spherical equivalent, anisometropia, high myopia, amblyopia, preoperative angle of deviation, vertical deviation, A-V pattern strabismus, exotropia type, type of surgery, stereopsis, and suppression were investigated to evaluate factors influencing the onset of consecutive esotropia. RESULTS: Consecutive esotropia occurred in 22 patients (9.7 %). Significant correlations with occurrence of the condition were found with high myopia (P = 0.013), amblyopia (P = 0.047), preoperative angle of deviation of 25-40 PD at distance (P = 0.016), deviation at distance - deviation at near > 10 PD (P = 0.041), lateral incomitance (P = 0.007), tenacious proximal convergence fusion type (P = 0.001), unilateral lateral rectus muscle recession and medial rectus muscle resection (P = 0.001). CONCLUSIONS: High myopia, amblyopia, and lateral incomitance were predisposing factors for consecutive esotropia. Furthermore, the preoperative angle of deviation at distance, differences between the angle of deviation at near and at distance, the type of intermittent exotropia, and the type of surgery affected the incidence of consecutive esotropia. More attention must be paid to patients with such factors. PMID- 22450528 TI - A prospective observational evaluation of an anatomically guided, logically formulated airway measure to predict difficult laryngoscopy. AB - CONTEXT: Difficulty during tracheal intubation is the most common cause of serious adverse respiratory events for patients undergoing anaesthesia. Current traditional bedside predictors of difficult laryngoscopy have poor sensitivity. A simple method to accurately predict difficult laryngoscopy could greatly improve patient safety. OBJECTIVES: This study examined a novel bedside predictor of difficult laryngoscopy that calculates a ratio of measurements directly affecting the ability to achieve the necessary line of vision (NLV) from the larynx to the operator (NLV ratio). DESIGN: This was a prospective observational study. SETTING: A single tertiary care surgical centre. PATIENTS: We enrolled 2046 patients scheduled for elective surgery under general anaesthesia with anticipated tracheal intubation. INTERVENTION: Prior to surgery, patients had their NLV ratio and standard airway measures recorded. The anaesthesiologist who performed the intubation was blind to the airway assessment and recorded the best view of the larynx according to the Cormack and Lehane scale. Difficult laryngoscopy was defined as a grade 3 or 4 view. MAIN OUTCOME MEASURE: The main outcome measure was the sensitivity and specificity of the NLV ratio measurement for predicting difficult laryngoscopy. RESULTS: Receiver operating characteristics curve analysis of the NLV ratio revealed an optimal sensitivity of only 41% and specificity of 77%. CONCLUSION: Although our novel measurement performed similarly to traditional bedside predictors of difficult laryngoscopy, the sensitivity was too low for the test to be clinically useful. Numerous factors which may be very difficult to predict at the bedside probably contributed to the poor performance of this novel measurement. PMID- 22450529 TI - Potentially toxic concentrations in blood of total ropivacaine after bilateral transversus abdominis plane blocks; a pharmacokinetic study. AB - CONTEXT: Elevated blood levels of lidocaine and ropivacaine have been described after transversus abdominis plane (TAP) block. OBJECTIVE: To investigate the pharmacokinetic profile of ropivacaine after bilateral TAP blocks. DESIGN: Prospective observational pharmacokinetic study. SETTING: University teaching hospital in Copenhagen, Denmark. PATIENTS: Twenty-one adult patients presenting for abdominopelvic surgery with bilateral TAP blocks were enrolled. PROCEDURES: Ultrasound-guided TAP blocks with bilateral injections of 20 ml ropivacaine 0.5% w/v (total dose 200 mg). Blood was sampled at 0, 10, 30 and 60 min after TAP blocks. MEASURES: Total and free peak blood concentrations (Cmax) of ropivacaine. RESULTS: Data were analysed from N = 18 patients. The median dose of ropivacaine was 2.7 mg kg(-1) (range: 1.9-4.2 mg kg(-1)). Median total ropivacaine concentrations were 1.0, 1.6 and 1.7 MUg ml(-1) at 10, 30 and 60 min, respectively. Six patients (33%) had Cmax values above 2.2 MUg ml(-1) and the highest concentration measured was 5.1 MUg ml(-1). One patient had a 33% drop in mean arterial blood pressure. CONCLUSION: TAP blocks with bilateral injections of 20 ml ropivacaine 0.5% w/v gave rise to potentially toxic peak blood concentrations of total ropivacaine in one-third of the patients. PMID- 22450530 TI - Total hip arthroplasty and perioperative oral carbohydrate treatment: a randomised, double-blind, controlled trial. AB - CONTEXT: Perioperative oral carbohydrate intake is beneficial to general surgery patients. Total hip arthroplasty is a common surgical procedure, and even a moderate improvement in patient outcome could have a significant effect on the resources needed for these patients. However, few studies have focused on the effects of carbohydrate intake on orthopaedic patients. OBJECTIVE: The purpose of this study was to investigate if perioperative oral carbohydrate intake alters the postoperative course for patients undergoing total hip arthroplasty. The primary hypothesis was that pain scores would be lower in patients treated with carbohydrate. DESIGN: A randomised, double-blind, controlled trial. SETTING: This study was carried out between September 2009 and April 2011 at a district Swedish hospital that specialises in orthopaedic surgery. PATIENTS: Sixty ASA physical status I-III patients scheduled for elective total hip arthroplasty were included. Exclusion criteria were obesity, diabetes, prior hip surgery to the same hip, ongoing infection, immunological deficiency or age less than 50 or more than 80 years. INTERVENTIONS: Patients were given 400 ml of either an oral 12.5% carbohydrate solution or a placebo beverage (flavoured water) 1.5 h before and 2 h after surgery. MAIN OUTCOME MEASURES: Visual analogue scales were used to score six discomfort parameters. RESULTS: Immediately prior to surgery, the carbohydrate-treated patients were less hungry (median score 9.5 vs. 22 mm) and experienced less nausea (0 vs. 1.5 mm) (P< 0.05). Postoperatively, patients in the carbohydrate group experienced less pain at 12, 16 and 20 h (median scores 20, 30 and 34 vs. 7, 5 and 0 mm; P<0.05). CONCLUSION: This study shows that there is limited benefit from administering oral carbohydrate prior to total hip arthroplasty. PMID- 22450531 TI - The efficacy of continuous infusion of low dose dexmedetomidine for postoperative patients recovering in general wards. PMID- 22450532 TI - Obesity is not a risk factor for patients undergoing spinal surgery. PMID- 22450533 TI - Case report: use of thienopyridines in a patient with acquired idiopathic thrombotic thrombocytopenic purpura. AB - Thienopyridines are commonly used anti-platelet drugs that may be associated with the development of secondary, drug-induced thrombotic thrombocytopenic purpura (TTP), a rare but potentially life threatening condition. We report the case of a 70 year-old man with a history of recurrent idiopathic TTP episodes who was treated with clopidogrel and then ticlopidine for thromboprophylaxis after percutaneous coronary intervention. Treatment was successful with no signs of TTP recurrence. Platelet counts and ADAMTS13 activity levels remained normal for months after the initiation of anti-platelet therapy, with no reappearance of anti-ADAMTS13 autoantibodies. This report demonstrates that thienopyridines do not necessarily induce TTP in patients with a history of TTP who are in disease remission. PMID- 22450534 TI - Two distinct pathways for essential metabolic precursors for isoprenoid biosynthesis. AB - Isoprenoids are a diverse group of molecules found in all organisms, where they perform such important biological functions as hormone signaling (e.g., steroids) in mammals, antioxidation (e.g., carotenoids) in plants, electron transport (e.g., ubiquinone), and cell wall biosynthesis intermediates in bacteria. All isoprenoids are synthesized by the consecutive condensation of the five-carbon monomer isopentenyl diphosphate (IPP) to its isomer, dimethylallyl diphosphate (DMAPP). The biosynthetic pathway for the formation of IPP from acetyl-CoA (i.e., the mevalonate pathway) had been established mainly in mice and the budding yeast Saccharomyces cerevisiae. Curiously, most prokaryotic microorganisms lack homologs of the genes in the mevalonate pathway, even though IPP and DMAPP are essential for isoprenoid biosynthesis in bacteria. This observation provided an impetus to search for an alternative pathway to synthesize IPP and DMAPP, ultimately leading to the discovery of the mevalonate-independent 2-C-methyl-D erythritol 4-phosphate pathway. This review article focuses on our significant contributions to a comprehensive understanding of the biosynthesis of IPP and DMAPP. PMID- 22450535 TI - Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting. AB - Tumor and inflammation have many common features. One hallmark of both is enhanced vascular permeability, which is mediated by various factors including bradykinin, nitric oxide (NO), peroxynitrite, prostaglandins etc. A unique characteristic of tumors, however, is defective vascular anatomy. The enhanced vascular permeability in tumors is also distinctive in that extravasated macromolecules are not readily cleared. We utilized the enhanced permeability and retention (EPR) effect of tumors for tumor selective delivery of macromolecular drugs. Consequently, such drugs, nanoparticles or lipid particles, when injected intravenously, selectively accumulate in tumor tissues and remain there for long periods. The EPR effect of tumor tissue is frequently inhomogeneous and the heterogeneity of the EPR effect may reduce the tumor delivery of macromolecular drugs. Therefore, we developed methods to augment the EPR effect without inducing adverse effects for instance raising the systemic blood pressure by infusing angiotensin II during arterial injection of SMANCS/Lipiodol. This method was validated in clinical setting. Further, benefits of utilization of NO-releasing agent such as nitroglycerin or angiotensin-converting enzyme (ACE) inhibitors were demonstrated. The EPR effect is thus now widely accepted as the most basic mechanism for tumor-selective targeting of macromolecular drugs, or so-called nanomedicine. PMID- 22450536 TI - Role of the transcription factor Bcl11b in development and lymphomagenesis. AB - Bcl11b is a lineage-specific transcription factor expressed in various cell types and its expression is important for development of T cells, neurons and others. On the other hand, Bcl11b is a haploinsufficient tumor suppressor and loss of a Bcl11b allele provides susceptibility to mouse thymic lymphoma and human T-cell acute lymphoblastic leukemia. Although there are many transcription factors affecting both cell differentiation and cancer development, Bcl11b has several unique properties. This review describes phenotypes given by loss of Bcl11b and roles of Bcl11b in cell proliferation, differentiation and apoptosis, taking tissue development and lymphomagenesis into consideration. PMID- 22450537 TI - Health-promoting effects of green tea. AB - Green tea is manufactured from the leaves of the plant Camellia sinensis Theaceae and has been regarded to possess anti-cancer, anti-obesity, anti-atherosclerotic, anti-diabetic, anti-bacterial, and anti-viral effects. Many of the beneficial effects of green tea are related to the activities of (-)-epigallocatechin gallate (EGCG), a major component of green tea catechins. For about 20 years, we have engaged in studies to reveal the biological activities and action mechanisms of green tea and EGCG. This review summarizes several lines of evidence to indicate the health-promoting properties of green tea mainly based on our own experimental findings. PMID- 22450538 TI - Functional cDNA expression cloning: pushing it to the limit. AB - The 1970s and the following decade are the era of the birth and early development of recombinant DNA technologies, which have entirely revolutionized the modern life science by providing tools that enable us to know the structures of genes and genomes and to dissect their components and understand their functions at the molecular and submolecular levels. One major objective of the life sciences is to achieve molecular and chemical understandings of the functions of genes and their encoded proteins, which are responsible for the manifestation of all biological phenomena in organisms. In the early 1980s, I developed, together with Paul Berg, a new technique that enables the cloning of full-length complementary DNAs (cDNAs) on the basis of their functional expression in a given cell of interest. I review the development, application and future implications in the life sciences of this gene-cloning technique. PMID- 22450539 TI - Triple resonance for a three-level system of a chiral molecule. AB - A new spectroscopic method of triple resonance is proposed for studying chirality of a molecule of C1 symmetry. Each enantiomer of such a molecule is of mixed parity and thus exhibits all three a-, b-, and c-types of rotational spectra. The present study concludes, by using time-dependent perturbation theory, that the transition probability between two of the three rotational levels under triple resonance differs for different enantiomer. This result can thus be of some significance for enantiomer differentiation. PMID- 22450540 TI - Ursodeoxycholic acid treatment in a rat model of cancer cachexia. AB - BACKGROUND: Cancer cachexia is characterized by loss of both adipose and skeletal muscle tissue and by an increased production of proinflammatory cytokines. Ursodeoxycholic acid (UDCA), a bile acid used for centuries in the treatment of liver disease, is known to confer anti-inflammatory and anti-apoptotic effects as well as beneficial effects on mitochondrial integrity and cell signaling. We hypothesized that UDCA ameliorates the wasting process in the Yoshida hepatoma tumor model. In addition, we sought to establish if UDCA exerts beneficial effects on survival in this model. METHODS AND RESULTS: Forty-seven male rats were inoculated intraperitoneally with 10(8) Yoshida hepatoma AH-130 cells and treated with placebo or one of two different doses of UDCA, 25 or 100 mg/kg daily. Body weight, body composition, and activity indicators were measured over the course of study up to day 16. UDCA treatment had no effect on tumor growth, loss of body weight, and loss of fat mass. Compared with placebo, low-dose UDCA improved tissue loss in the lung (p = 0.022) and tended to reduce tissue loss in brown adipocytes (p = 0.06), gastrocnemius muscle (p = 0.06), extensor digitorum longus muscle (p = 0.09), and soleus muscle (p = 0.07). Compared with placebo, high-dose UDCA tended to reduce the loss of lean body mass (p = 0.06), lung tissue (p = 0.1), white adipose tissue (p = 0.11), and gastrocnemius muscle (p = 0.11). The activity and food intake were not altered in tumor-bearing rats by either dose of UDCA. Both doses tended to decrease the mortality rate in tumor bearing rats, (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.17-1.04; p = 0.061 for low-dose UDCA; HR, 0.44; 95% CI, 0.18-1.05; p = 0.065 for high-dose UDCA). CONCLUSION: UDCA treatment in the Yoshida hepatoma model showed a trend towards attenuation of tissue loss in animals with progressive weight loss in cancer cachexia. Tumor growth and activity indicators were not altered. Both doses of UDCA tended to reduce the mortality rates in tumor-bearing animals. Larger studies with longer follow-up are required to verify these findings. PMID- 22450541 TI - Electrocatalytic oxidation of alcohols by a carbon-supported Rh porphyrin. AB - A Rh porphyrin on carbon black was shown to catalyze the electro-oxidation of several aliphatic alcohols (ethanol, 1-propanol, and 2-propanol) and benzyl alcohols. The overpotentials for alcohol oxidation were very low. The reaction mechanism and substrate specificity are discussed. PMID- 22450542 TI - Congenital cholesteatoma and cochlear implantation: Implications for management. AB - INTRODUCTION: Cholesteatoma is an uncommon condition that has occasionally been associated with cochlear implantation (CI). Cases of secondary acquired cholesteatoma have been described, in which intra-operative breech of the posterior canal wall is thought to be a contributing factor. Primary acquired cholesteatoma is not typically associated with congenital sensorineural hearing loss (SNHL) or CI in children. Congenital cholesteatoma is a rarer entity yet with an incidence in the literature of 2-4% of all cholesteatomas. We present lessons learned from our experience of congenital cholesteatoma in CI candidates. METHODS: Retrospective reviews of departmental CI and cholesteatoma databases in a tertiary/quaternary pediatric center were conducted. Cases of congenital cholesteatoma were identified. The proportion of congenital cholesteatoma cases in CI candidates was compared with number of acquired cholesteatoma. Optimum management of congenital cholesteatoma in CI candidates was reviewed. RESULTS: In our pediatric CI population, 2/794 patients (0.25%) were recognized as having a congenital cholesteatoma during their evaluation for CI. No cases of primary acquired cholesteatoma were identified in this population at presentation or at follow up to 18 years. DISCUSSION: The 0.25% incidence of congenital cholesteatoma in our population of CI patients is higher than expected of this rare condition. It is surprisingly common given the absence of any cases of primary acquired cholesteatoma, which is considerably more common even in the pediatric population. Both patients likely had an inherited form of hearing loss and a genetic contribution to the presence of congenital cholesteatoma cannot be excluded. The presence of congenital cholesteatoma has implications for the algorithm currently employed for the assessment of CI. We consider that surgery should be staged to ensure complete removal of the cholesteatoma before implantation. Thus bilateral CI should be provided sequentially rather than simultaneously in the presence of unilateral cholesteatoma. PMID- 22450543 TI - Prothrombin complex concentrate (Octaplex): a Portuguese experience in 1152 patients. AB - In emergency/clinical practice it is often necessary to restore the balance of blood coagulation: the rapid reversal of oral anticoagulant therapy (OAT) is crucial in cases of serious acute bleeding and emergency surgery in patients with high international normalized ratios (INRs). Coagulation can be normalized via the application of haemostatic products, including fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs). Guidelines recommend PCCs for the reversal of OAT in preference to FFP in patients with major/life-threatening bleeding and high INRs. Advantages of PCCs include: minimal disruption to haemostasis, rapid administration and fast onset of action. One such PCC is Octaplex which is available in many countries, including Portugal. The aim of this retrospective, observational, multicentre study was to assess the clinical applications and efficacy (via reduction in INR after treatment) of Octaplex. Over the 4-year study period, 1194 infusions of Octaplex were administered in 1152 patients (69.2% for reversal of OAT, 17.3% for liver dysfunction, 10.2% for uncontrolled bleeding). The mean patient age was 64 years and the mean dose of Octaplex was 20.37 +/- 7.00 IU/kg. Overall, Octaplex treatment was associated with a significant reduction in INR (P < 0.0001). In 95% of all treatment episodes, only one dose of Octaplex was required. No adverse drug reactions or thromboembolic events were reported. Octaplex effectively and significantly reduces INR values in patients requiring the restoration of blood coagulation. It effectively reverses the effect of OAT and was efficacious in the majority of bleeding episodes in patients with liver dysfunction. PMID- 22450544 TI - Discard first tube for coagulation testing. AB - Tissue thromboplastin may contaminate the first tube sample due to the trauma of the venipuncture, and therefore, affect the accuracy of coagulation testing. This practice was stopped by Clinical and Laboratory Standards Institute after several studies. However, most of the studies have verified these conclusions and refuted the need for a discard tube when drawing samples for coagulation tests in healthy groups. The purpose of our study was to evaluate the clinical importance of discarding a tube for prothrombin time (PT) determinations on large samples with international normalized ratio (INR) values between and over targeted therapeutic range. Patients receiving oral anticoagulation therapy (OAT) managed by our cardiology service were selected for this study. Tube 1 was always treated as the discard tube. Tube 2 was allocated to be analyzed along with the tube 1 for coagulation tests. Individual values were grouped into four cohorts according to the INR range. The ranges were as follows: less than 2.0, 2.1-3.0, 3.1-4.5 and more. Three hundred and seventy-six samples were drawn for PT/INR and activated partial thromboplastin time testing. We found statistically significant differences between tube 1 and tube 2 (P < 0.05), and satisfactory correlation coefficients were obtained by linear regression analysis (0.86 or greater in all cases). This study consisted of a high number of samples. Our data suggest that drawing a discard tube is still necessary for coagulation testing. Consideration should be given to revising the international guidelines related to the necessity of a discard tube for repeated evaluation of coagulation tests especially receiving long-term OAT. PMID- 22450545 TI - The condensed MCMDM-1 VWD bleeding questionnaire as a predictor of bleeding disorders in women with unexplained menorrhagia. AB - Menorrhagia is a common clinical problem and is unexplained in more than 50% of women. Many studies have suggested that underlying bleeding disorders are prevalent in menorrhagic women. However, the assessment and quantifying of hemorrhagic symptoms are still limited and not widely used. Thirty women aged 11 31 years with a clinical diagnosis of unexplained menorrhagia were investigated to assess the diagnostic utility of the condensed MCMDM-1VWD bleeding questionnaire as a predictive of bleeding disorders in these women. In addition to administration of the questionnaire, comprehensive hemostatic testing was performed to all women. The incidence of inherited bleeding disorders among this group was 66.6% (20/30). Eight patients had von Willebrand disease (VWD) and seven had possible Glanzmann's thrombasthenia. Rare bleeding disorders including hemophilia A carrier, Afibrinogenemia, Factor V deficiency and combined factor V and factor VIII deficiency were also identified. The receiver operator characteristic analysis of the condensed MCMDM-1 VWD bleeding questionnaire in menorrhagic women showed that the cutoff, sensitivity, specificity, positive and negative predictive values were 3.5, 85, 90, 89 and 86%, respectively. Bleeding score was strongly correlated to bleeding time in women with possible Glanzmann's thrombasthenia. In VWD, a significant inverse correlation between the bleeding score and the VW factor levels was detected with a significant increase of bleeding score in type III VWD compared with type I. Bleeding disorders are common in women with unexplained menorrhagia and the condensed MCMDM-1VWD bleeding questionnaire can distinguish between menorrhagic women with and without bleeding disorders and help assess their severity. PMID- 22450546 TI - Laboratory diagnostic approach of the parents-children relationship in differentiating low-level von Willebrand factor from mild type 1 von Willebrand disease. AB - The present study aimed to evaluate the parent-child relationship in differentiating between unaffected healthy individuals and those with von Willebrand disease (VWD). This study was performed on 15 children between the ages of 5 and 15 years and parents with personal and familial evidence of bleeding. Diagnosis of VWD as considered 'low von Willebrand factor (VWF) level or mild type 1 VWD' in the following children: those with low VWF levels (VWF:RCo and VWF:Ag between 30 and 50 U/dl), at least one bleeding symptom and a family member with at least one bleeding symptom. Laboratory values in the parents of families 1-7 were VWF:Ag 65-90, VWF:RCo 54-87, and FVIII:C 74-110, versus VWF:Ag 33-47, VWF:RCo 30-42, and FVIII:C 36-67 in their children. The normal laboratory values in the parents of families 1-7 suggested that their children would probably have low VWF levels. Our findings are that VWF levels are increasing with age. Laboratory values in the parents of families 8-15 were VWF:Ag 30-59, VWF:RCo 32-55, and FVIII:C 44-66, versus VWF:Ag 32-48, VWF:RCo 30-54, and FVIII:C 38-55 in their children. The laboratory values in the children from families 8-15 were close to the minimum range of normal or below normal, which suggested that it was possible that the parents and children in families 8-15 could be diagnosed as having mild type 1 VWD. The present study's findings show that comparison of the VWF levels in parents and their children may be helpful in differentiating children with low VWF levels and mild type 1 VWD from children that only have low VWF levels. PMID- 22450547 TI - Endobronchial adenoid cystic carcinoma complicated with pneumothorax. PMID- 22450548 TI - Computational chemistry calculations of stability for bismuth nanotubes, fullerene-like structures and hydrogen-containing nanostructures. AB - Using molecular mechanics (MM+), semi-empirical (PM6) and density functional theory (DFT) (B3LYP) methods we characterized bismuth nanotubes. In addition, we predicted the bismuth clusters {Bi(20)(C(5V)), Bi(24)(C(6v)), Bi(28)(C(1)), B(32)(D(3H)), Bi(60)(C(I))} and calculated their conductor properties. PMID- 22450549 TI - TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover. AB - OBJECTIVE: Patients with endogenous Cushing's Syndrome (CS), as long-time treated patients with exogenous glucocorticoids (GCs), have severe systemic manifestations including secondary osteoporosis and low-energy fractures. The aim of the present study was to investigate the functional role of TXNIP in bone with focus on osteoblast (OB) differentiation and OB-mediated osteoclast activity and function in vitro. DESIGN AND METHODS: Nine bone biopsies from CS before and after surgical treatment were screened for expressional candidate genes. Microarray analyses revealed that the gene encoding TXNIP ranked among the most upregulated genes. Subsequent in vitro and in vivo studies were performed. RESULTS: We found that TXNIP gene in bone is downregulated in CS following surgical treatment. Furthermore, our in vivo data indicate novel associations between thioredoxin and TXNIP. Our in vitro studies showed that silencing TXNIP in OBs was followed by increased differentiation and expression and secretion of osteocalcin as well as enhanced activity of alkaline phosphatase. Moreover, treating osteoclasts with silenced TXNIP OB media showed an increased osteoclast activity. CONCLUSIONS: TXNIP expression in bone is highly regulated during the treatment of active CS, and by GC in bone cells in vitro. Our data indicate that TXNIP may mediate some of the detrimental effects of GC on OB function as well as modulate OB-mediated osteoclastogenesis by regulating the OPG/RANKL ratio. PMID- 22450550 TI - Concurrent FOXP3- and CTLA4-associated genetic predisposition and skewed X chromosome inactivation in an autoimmune disease-prone family. AB - CLTA4 is relevant for FOXP3(+)Treg cells, and the link between skewed X chromosome inactivation (XCI) and autoimmunity is recognized. The observation of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome and multiorgan endocrine autoimmune phenomena in various members of one family, associated with a CTLA4 polymorphism and skewed XCI, provides an in vivo model of how mechanisms of immune dysregulation may cooperate. PMID- 22450551 TI - Hypoxia-driven pathways in bone development, regeneration and disease. AB - Adaptation to hypoxia is a critical cellular event both in pathological settings, such as cancer and ischaemia, and in normal development and differentiation. Oxygen is thought to be not only an indispensable metabolic substrate for a variety of in vivo enzymatic reactions, including mitochondrial respiration, but also a key regulatory signal in tissue development and homeostasis by controlling a specific genetic program. Hypoxia-inducible transcription factors (HIFs) HIF-1 and HIF-2 are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Genetically altered mice have been used to identify important roles for HIF-1 and HIF-2 as well as vascular endothelial growth factor (VEGF)-a potent angiogenic factor and a downstream target of the HIF pathway-in the regulation of skeletal development, bone homeostasis and haematopoiesis. In this Review, we summarize the current knowledge of HIF signalling in cartilage, bone and blood, and pay particular attention to the complex relationship between HIF and VEGF in these tissues revealed by data from research using animal models. The study of these models expands our understanding of the cell autonomous, paracrine and autocrine effects that mediate the homeostatic responses downstream of HIFs and VEGF. PMID- 22450552 TI - Diagnosis and classification in spondyloarthritis: identifying a chameleon. AB - Spondyloarthritis (SpA) defines a group of interrelated diseases, including ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, enteropathic-related spondylitis and arthritis, and undifferentiated SpA. The clinical presentation of SpA is heterogeneous, and no single shared distinguishing feature exists for the conditions comprising SpA; in daily practice, diagnosis is usually made on the basis of a combination of symptoms, the findings of physical examination, imaging and laboratory investigations. Several classification criteria have been developed for AS and SpA, which are useful in a research setting but cannot be automatically applied to the diagnosis of individual patients. Currently, MRI is the most sensitive imaging modality available for detection of sacroiliitis, often enabling detection of axial inflammation long before structural lesions are observed radiographically, thus facilitating early diagnosis of axial SpA. However, MRI will never capture all facets of SpA and the expert opinion of a rheumatologist will remain the crucial step in recognition of this disease. In this Review, we discuss diagnosis and classification of AS and SpA, and highlight how MRI might facilitate both processes. PMID- 22450553 TI - Advances and challenges in imaging in juvenile idiopathic arthritis. AB - Imaging assessments of the joints of children with juvenile idiopathic arthritis (JIA) are challenging, owing to the unique features of the growing skeleton. Traditionally, imaging studies in childhood arthritis have been based on conventional radiography. However, in the past few years, interest in the use of MRI and ultrasonography has increased. As a result, imaging has become a main area of clinical and research investigation in paediatric rheumatology. The chief advance in the field of conventional radiography has been the development and validation of paediatric scoring systems for the assessment of radiographic progression. Several studies have shown that MRI provides a precise quantification of synovitis in children with JIA. Furthermore, a high frequency of bone marrow oedema and bone erosions has been found early in the disease course. Ultrasonography has been proven to be superior to clinical examination in detecting synovitis, tenosynovitis and enthesitis. A high frequency of subclinical synovitis has been demonstrated in patients with JIA who have clinically inactive disease using both MRI and ultrasonography. However, more information from healthy children is needed to enable differentiation of the bone and cartilage abnormalities that reflect damage from those that are part of normal development using MRI or ultrasonography. This Review provides a summary of the current information on conventional radiography, ultrasonography and MRI in JIA and highlights the advantages and limitations of each imaging modality. PMID- 22450554 TI - Bone: Two Notches in osteoclastogenesis. PMID- 22450555 TI - Experimental arthritis: Targeting EGFR to fight synovitis. PMID- 22450556 TI - Type 2 diabetic patients and their offspring show altered parameters of iron status, oxidative stress and genes related to mitochondrial activity. AB - Type 2 diabetes (T2D) is directly related to alterations in iron status, oxidative stress and decreased mitochondrial activity, but the possible interaction of these parameters among T2D patients and their offspring is unclear. The whole study included 301 subjects: 77 T2D patients and one of their offspring and 51 control subjects with one of their offspring. The offspring were older than 20 years old. We measured parameters of iron status (serum iron, ferritin and transferrin receptor), diabetes (pre and post-prandial glucose, insulin, lipids), oxidative stress (Heme oxygenase activity, TBARS, SOD, GSH, Vitamin E), as well as the expression of genes in blood leukocytes related to mitochondrial apopotosis (mitofusin and Bcl/Bax ratios). The offspring of T2D patients had increased levels of serum ferritin (P < 0.01) and lower transferrin receptor (P < 0.008); higher insulin (P < 0.03) and total and LDL cholesterol; higher heme oxygenase and SOD activities increased TBARS and lower GSH; decreased mitofusin and Bcl/Bax expression ratios compared to offspring of normal subjects. These results suggest that the offspring of T2D patients could have an increased metabolic risk of develop a cardiovascular disease mediated by oxidative stress and iron status. PMID- 22450557 TI - Reaction of N=W(O(t)Bu)3 with sigma3lambda5-phosphoranes. The [2 + 2] cycloaddition across the W=N triple bond results in the first representative of an inorganic four-membered metallacycle with conjugated endo- and exocyclic double bonds. AB - The reactions of N=W(O(t)Bu)(3) with the low-coordinate phosphorus compounds (Me(3)Si)(2)NP(NSiMe(3))(2) (I) and (Me(3)Si)(2)NPS(N(t)Bu) (II) were studied. Quantum chemical calculations were used to determine why Mo- and W-containing compounds with the same composition have different molecular structures. PMID- 22450558 TI - Six-month visual outcome after pars plana vitrectomy in proliferative diabetic retinopathy with or without a single preoperative injection of intravitreal bevacizumab. AB - The purpose of this study is to evaluate the effect of a single preoperative injection of intravitreal bevacizumab (IVB) on visual outcome in patients undergoing pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). Retrospective chart review of patients who underwent PPV for PDR and followed for at least 6 months after surgery. Patients who received a single IVB injection (1.25 mg in 0.05 ml) preoperatively were assigned to group A. Those who did not receive IVB were assigned to group B. The primary outcome measure was visual outcome at 6-month follow-up. The secondary outcomes were postoperative complications. At 6 months, visual acuity improved by at least 0.3 logMAR units in 70 (74.5 %) of the 94 eyes in group A versus 46 (52.9 %) of the 87 eyes in group B (p = 0.002). Postoperative vitreous hemorrhage occurred significantly less frequently in group A (6 eyes, 6.4 %) than in group B (14 eyes, 16.1 %; p = 0.037). The incidence of other postoperative complications did not differ significantly between the two groups. Preoperative use of bevacizumab improved the 6-month visual outcome in patients undergoing PPV for PDR and significantly reduced the occurrence of postoperative vitreous hemorrhage. PMID- 22450559 TI - Ocular findings in human immunodeficiency virus patients in Washington, DC. AB - The purpose of the study was to determine the prevalence of ocular diseases in human immunodeficiency virus (HIV) patients in Washington, DC in the era of highly active antiretroviral therapy (HAART). This was a cross-sectional study of patients with HIV who were seen by the ophthalmology consultation service between September 2003 and May 2011 at a single academic institution in Washington, DC. Medical history and ophthalmic findings were reviewed. Patients with complete laboratory data dated within 3 months of their presenting eye examination were included. Descriptive statistics were performed. The records of 151 patients were included in the final analysis. All patients had complete laboratory data dated within 3 months of their presenting eye examination. Sixty-eight (45 %) patients and fifty-eight (50 %) of those with a diagnosis of acquired immune deficiency syndrome (AIDS) were diagnosed with an HIV-related ophthalmic disease. The leading anterior segment disease was herpes zoster ophthalmicus and the leading posterior segment disease was HIV retinopathy. Of the 151 included patients, 78 (52 %) were receiving HAART at the time of the examination. Thirty-one (42 %) of those not receiving HAART were diagnosed with an HIV-related ophthalmic disease. In this study, we find that the overall prevalence of ocular disease has decreased since the introduction of HAART. However, HIV patients continue to be predisposed to developing ophthalmic disease at higher rates than the general population. Visual dysfunction remains an important source of morbidity in HIV patients, particularly in those with AIDS. Measures for improvement include increased communication between infectious disease specialists and ophthalmologists to ensure adherence to HAART and routine eye examinations. PMID- 22450560 TI - Candida interface keratitis following deep anterior lamellar keratoplasty. AB - The purpose is to report a case of Candida interface infection after deep anterior lamellar keratoplasty (DALK). A 23-year-old female patient underwent DALK surgery in the left eye for keratoconus. Four weeks after the surgery, she presented with asymptomatic white-cream colored deposits at the graft-host interface. Epithelial ingrowth was our first possible diagnosis because there were no symptoms or signs of inflammation. However, progression of the lesion under steroid treatment and the appearance of inflammation signs after tapering the steroid treatment raised suspicion of fungal keratitis. Anterior segment optical coherence tomography (OCT), ultrasound biomicroscopy, confocal microscopy and microbiologic examinations of the cornea were performed to evaluate the lesion. Anterior segment OCT and ultrasound biomicroscopy confirmed the lesion to be at the interface. The confocal scan disclosed hyper-reflective deposits and surrounding inflammatory cells but there were no hyphae-like structures. While taking a specimen from the lesion, the Descemet's membrane ruptured so a penetrating keratoplasty was performed. The microbiologic examination revealed Candida infection. Candida interface keratitis is a rare infection seen after DALK. The asymptomatic clinical picture and the similarity to epithelial ingrowth may postpone the diagnosis and consequently the treatment. Therefore, in cases of interface deposits seen after lamellar surgery, one should consider Candida interface keratitis. PMID- 22450561 TI - Evaluation of conservative management of high-grade cervical squamous intraepithelial lesion. AB - OBJECTIVE: To assess the association between conservative management of high grade cervical squamous intraepithelial lesions and recurrence rates and age groups. METHODS: Cross-sectional, retrospective, analytical observational study of 509 women (aged 15 to 76) with abnormal Pap smears attending a public reference center in the city of Maringa, southern Brazil, from 1996 to 2006. Data was collected from medical records, and the variables definitive diagnosis, type of treatment provided, occurrence of high-grade cervical squamous intraepithelial lesions and recurrence were studied. Pearson's chi-square test and Fisher's exact test were used in the statistical analyses. RESULTS: There were 168 cases of cervical high-grade cervical squamous intraepithelial lesions, of these, 31 were treated with cold-knife conization, 104 loop electrosurgical excision procedure, 9 hysterectomy and 24 conservative treatment (i.e., clinical and cytological follow-up or cervical electrocoagulation). A total of 8 (33.3%) women receiving conservative and 10 (6.9%) receiving non-conservative management had recurrent disease and this difference was statistically significant (p=0.0009), PR = 4.8 (95%CI 2.11;10.93). Three (30.0%) women among those undergoing clinical and cytological follow-up and five 5 (35.7%) among those submitted to cervical electrocoagulation had recurrent disease within three years, but the difference was not significant (p=0.5611). Recurrent rates in those younger and older than 30 were 13.8% (7 women) and 12.2% (11 women) (p = 0.9955). CONCLUSIONS: Age is not a predictor of disease recurrence. Conservative treatment is only recommended in exceptional situations due to its high recurrence rates. Careful cytological and colposcopic follow-up is required for three years when most recurrences occur. PMID- 22450562 TI - Stressful working conditions and poor self-rated health among financial services employees. AB - OBJECTIVE: To assess the association between exposure to adverse psychosocial working conditions and poor self-rated health among bank employees. METHODS: A cross-sectional study including a sample of 2,054 employees of a government bank was conducted in 2008. Self-rated health was assessed by a single question: "In general, would you say your health is (...)." Exposure to adverse psychosocial working conditions was evaluated by the effort-reward imbalance model and the demand-control model. Information on other independent variables was obtained through a self-administered semi-structured questionnaire. A multiple logistic regression analysis was performed and odds ratio calculated to assess independent associations between adverse psychosocial working conditions and poor self-rated health. RESULTS: The overall prevalence of poor self-rated health was 9%, with no significant gender difference. Exposure to high demand and low control environment at work was associated with poor self-rated health. Employees with high effort-reward imbalance and overcommitment also reported poor self-rated health, with a dose-response relationship. Social support at work was inversely related to poor self-rated health, with a dose-response relationship. CONCLUSIONS: Exposure to adverse psychosocial work factors assessed based on the effort-reward imbalance model and the demand-control model is independently associated with poor self-rated health among the workers studied. PMID- 22450563 TI - Use of accelerometry to measure physical activity in adults and the elderly. AB - OBJECTIVE: To review the use of accelerometry as an objective measure of physical activity in adults and elderly people. METHODS: A systematic review of studies on the use of accelerometty as an objective measure to assess physical activity in adults were examined in PubMed Central, Web of Knowledge, EBSCO and Medline databases from March 29 to April 15, 2010. The following keywords were used: "accelerometry," "accelerometer," "physical activity," "PA," "patterns," "levels," "adults," "older adults," and "elderly," either alone or in combination using "AND" or "OR." The reference lists of the articles retrieved were examined to capture any other potentially relevant article. Of 899 studies initially identified, only 18 were fully reviewed, and their outcome measures abstracted and analyzed. RESULTS: Eleven studies were conducted in North America (United States), five in Europe, one in Africa (Cameroon) and one in Australia. Very few enrolled older people, and only one study reported the season or time of year when data was collected. The articles selected had different methods, analyses, and results, which prevented comparison between studies. CONCLUSIONS: There is a need to standardize study methods for data reporting to allow comparisons of results across studies and monitor changes in populations. These data can help design more adequate strategies for monitoring and promotion of physical activity. PMID- 22450564 TI - Accumulated behavioral risk factors for cardiovascular diseases in Southern Brazil. AB - OBJECTIVE: To estimate the prevalence of, and identify factors associated with, accumulated risky behavior relating to cardiovascular diseases among adults. METHODS: This was a population-based cross-sectional study on a representative sample of 2732 adults of both sexes in Pelotas, Southern Brazil, in 2010. The behavioral risk factors investigated were: smoking; leisure-time physical inactivity; habitual consumption of visible fat in meat; and daily consumption of processed meats, red meat and whole milk. The study outcome was the accumulated behavioral risk factors score, ranging from zero to three: no behavioral risk factor for cardiovascular diseases or exposure to 1, 2 or > 3 behavioral risk factors. Multinomial logistic regression was performed to evaluate the adjusted effect of individual characteristics on behavioral risk factors accumulation, taking individuals without any of these factors as the reference category. RESULTS: Physical inactivity was the most prevalent risk factor (75.6%), followed by habitual consumption of visible fat in meat (52.3%). Two thirds of the population presented two or more behavioral risk factors. Combined physical inactivity and habitual consumption of visible fat in meat was observed in 17.5% of the sample; and combined physical inactivity, habitual consumption of visible fat in meat and smoking in 6.7%. The odds ratios for accumulation of two or more risk factors were higher among men and were inversely associated with a national economic indicator. CONCLUSIONS: There was a high accumulation of behavioral risk factors for cardiovascular diseases among the study population. Public interventions with the capacity to prevent simultaneous occurrence of these factors are needed. PMID- 22450565 TI - Skin exposure to deodorants/antiperspirants in aerosol form. AB - Many cosmetic products are available in spray form. Even though the principal targets of these products are the skin and hair, spraying leads to the partitioning of the product between the target and the surrounding air. In the previous COLIPA study (Hall et al., 2007) the daily use of deodorant/antiperspirant (Deo/AP) in spray form was quantified in terms of the amount of product dispensed from the spray can, without specifically quantifying the product fraction reaching the skin during use. Results of the present study provide this additional information, necessary for a reliable safety assessment of sprayed Deo/AP products. In a novel experimental approach the information obtained from real-life movement analysis (automated motion imaging) of volunteers using their own products was integrated with the aerosol cloud sampling data obtained from the same products, leading to the computation of the product deposited on the skin. The 90th percentile values, expressed as percent deposition relative to the can weight loss after spraying, are 23.5% and 11.4% for ethanol-based and non-ethanol-based products, respectively. Additionally, the study has generated data on the skin area covered by the products, spray duration time, spray angle and spray distance from the skin. PMID- 22450566 TI - Effect of vanillin and ethyl vanillin on cytochrome P450 activity in vitro and in vivo. AB - Food safety is of extreme importance to human health. Vanillin and ethyl vanillin are the widely used food additives and spices in foods, beverages, cosmetics and drugs. The objective of the present work was to evaluate the impact of vanillin and ethyl vanillin on the activities of CYP2C9, CYP2E1, CYP3A4, CYP2B6 and CYP1A2 in human liver microsomes (HLM) in vitro, and impact on the activities of CYP1A2, CYP2C, CYP3A and CYP2E1 in rat liver microsomes (RLM) in vivo. The in vitro results demonstrated that vanillin and ethyl vanillin had no significant effect on the activity of five human CYP450 enzymes with concentration ranged from 8 to 128 MUM. However, after rats were orally administered vanillin or ethyl vanillin once a day for seven consecutive days, CYP2E1 activity was increased and CYP1A2 activity was decreased in RLM. The in vivo results revealed that drug interaction between vanillin/ethyl vanillin and the CYP2E1/CYP1A2-metabolizing drugs might be possible, and also suggested that the application of the above additives in foods and drugs should not be unlimited so as to avoid the adverse interaction. PMID- 22450567 TI - Fragrance material review on 2-hexylidene cyclopentanone. AB - A toxicologic and dermatologic review of 2-hexylidene cyclopentanone when used as a fragrance ingredient is presented. 2-Hexylidene cyclopentanone is a member of the fragrance structural group ketones alkyl cyclic. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-hexylidene cyclopentanone were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, photoallergy, toxicokinetics, repeated dose, and genotoxicity data. A safety assessment of the entire ketones alkyl cyclic will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones alkyl cyclic in fragrances. PMID- 22450568 TI - Reversible clustering of magnetic nanobiocatalysts for high-performance biocatalysis and easy catalyst recycling. AB - Reversible clusters of nanobiocatalysts are developed via non-covalent interaction among enzyme-bound iron oxide magnetic nanoparticles. Dissociation of the clusters by shaking during biotransformation enables high catalytic performance, and re-clustering by stopping shaking after reaction allows for easy magnetic separation. The novel concept is demonstrated with alcohol dehydrogenase RDR for the enantioselective reduction of 7-methoxy-2-tetralone. PMID- 22450569 TI - Codon-optimized glucoamylase sGAI of Aspergillus awamori improves starch utilization in an industrial yeast. AB - The development of a yeast that converts raw starch to ethanol in one step (called consolidated bioprocessing) could yield large cost reductions in the bioethanol industry. The aim of this study was to develop an efficient amylolytic Saccharomyces cerevisiae strain suitable for industrial bioethanol production. A native and codon-optimized variant of the Aspergillus awamori glucoamylase gene were expressed in the S. cerevisiae Y294 laboratory strain. Codon optimization resulted to be effective and the synthetic sequence sGAI was then delta integrated into a S. cerevisiae strain with promising industrial fermentative traits. The mitotically stable recombinant strains showed high enzymatic capabilities both on soluble and raw starch (2425 and 1140 nkat/g dry cell weight, respectively). On raw corn starch, the engineered yeasts exhibited improved fermentative performance with an ethanol yield of 0.42 (g/g), corresponding to 75 % of the theoretical maximum yield. PMID- 22450570 TI - Voluntary and involuntary attention vary as a function of impulsivity. AB - In the present study we examined, first, whether voluntary and involuntary attention manifest differently in people who differ in impulsivity (measured with the Barratt Impulsivity Scale). For Experiment 1, we used the spatial cueing task with informative and noninformative spatial cues to probe voluntary and involuntary attention, respectively. We found that participants with high impulsivity scores exhibited larger involuntary attention effects, whereas participants with low impulsivity scores exhibited larger voluntary attention effects. For Experiment 2, we used the correlated-flanker task to determine whether the differences between groups in Experiment 1 were due to high-impulsive participants being less sensitive to the display contingencies or to high impulsive participants having a greater spread of spatial attention. Surprisingly, high-impulsive participants showed a greater sensitivity to contingencies in the environment (correlated-flanker effect). Our results illustrate one situation in which involuntary attention associated with high impulsivity can play a useful role. PMID- 22450571 TI - Shaping bursting by electrical coupling and noise. AB - Gap-junctional coupling is an important way of communication between neurons and other excitable cells. Strong electrical coupling synchronizes activity across cell ensembles. Surprisingly, in the presence of noise synchronous oscillations generated by an electrically coupled network may differ qualitatively from the oscillations produced by uncoupled individual cells forming the network. A prominent example of such behavior is the synchronized bursting in islets of Langerhans formed by pancreatic beta-cells, which in isolation are known to exhibit irregular spiking (Sherman and Rinzel, Biophys J 54:411-425, 1988; Sherman and Rinzel, Biophys J 59:547-559, 1991). At the heart of this intriguing phenomenon lies denoising, a remarkable ability of electrical coupling to diminish the effects of noise acting on individual cells. In this paper, building on an earlier analysis of denoising in networks of integrate-and-fire neurons (Medvedev, Neural Comput 21 (11):3057-3078, 2009) and our recent study of spontaneous activity in a closely related model of the Locus Coeruleus network (Medvedev and Zhuravytska, The geometry of spontaneous spiking in neuronal networks, submitted, 2012), we derive quantitative estimates characterizing denoising in electrically coupled networks of conductance-based models of square wave bursting cells. Our analysis reveals the interplay of the intrinsic properties of the individual cells and network topology and their respective contributions to this important effect. In particular, we show that networks on graphs with large algebraic connectivity (Fiedler, Czech Math J 23(98):298-305, 1973) or small total effective resistance (Bollobas, Modern graph theory, Graduate Texts in Mathematics, vol. 184, Springer, New York, 1998) are better equipped for implementing denoising. As a by-product of the analysis of denoising, we analytically estimate the rate with which trajectories converge to the synchronization subspace and the stability of the latter to random perturbations. These estimates reveal the role of the network topology in synchronization. The analysis is complemented by numerical simulations of electrically coupled conductance-based networks. Taken together, these results explain the mechanisms underlying synchronization and denoising in an important class of biological models. PMID- 22450572 TI - [Lymphoid diseases:Overview]. PMID- 22450573 TI - [Malignant lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma)]. PMID- 22450574 TI - [Multiple myeloma]. PMID- 22450575 TI - [Acute lymphoblastic leukemia and chronic lymphocytic leukemia in adults]. PMID- 22450576 TI - [Disorders of platelets, blood coagulation, fibrinolysis--Overview]. PMID- 22450577 TI - [Idiopathic thrombocytopenic purpura (ITP)]. PMID- 22450578 TI - [Thrombotic thrombocytopenic purpura]. PMID- 22450579 TI - [Disseminated intravascular coagulation]. PMID- 22450580 TI - [Markov decision analysis on post-remission therapies in patients with acute myeloid leukemia in the first remission]. PMID- 22450581 TI - [Sustained complete molecular remission after cessation of imatinib mesylate treatment in a patient with relapsed chronic myelogenous leukemia after allogeneic stem cell transplantation]. AB - We present a case with sustained complete molecular response (CMR) after cessation of two months of imatinib mesylate (IM) treatment for chronic myelogenous leukemia (CML) relapsed after allogeneic stem cell transplantation (Allo-SCT). A 30-year-old previously healthy woman was seen in a clinic because of left abdominal discomfort. Splenomegaly and increased leukocytes with Philadelphia chromosome led to the diagnosis of CML in the accelerated phase. She received four months of IM treatment followed by allo-SCT from her HLA-matched sibling. She achieved and maintained CMR without developing acute GVHD for six months, when hematologic relapse occurred. While reducing the immunosuppressant, she received IM; however, it was discontinued two months later due to myelosuppression. Even after the termination of IM, the positivity of chimeric BCR-ABL gene detected by FISH analysis in peripheral blood continued to decrease. The molecular analysis of bone marrow one year after allo-PBSCT revealed CMR lasting for more than two years after cessation of IM. IM may possibly enhance the graft-versus-leukemia effects by reducing tumor burden in cases relapsed after allo-SCT. PMID- 22450582 TI - [B-cell acute lymphoblastic leukemia developed 5 years after autologous stem cell transplantation for multiple myeloma]. AB - A 61-year-old female was diagnosed with multiple myeloma (MM) in 2001. After treatment with chemotherapy containing alkylating agents and thalidomide, she underwent autologous stem cell transplantation in 2003, with high-dose melphalan as a conditioning regimen. Thalidomide was also given after the transplant from July 2003 to November 2005 for residual disease and she remained in partial remission. In October 2008, she developed pancytopenia. Bone marrow examination confirmed the diagnosis of acute B lymphoblastic leukemia (B-ALL). We performed IgH gene rearrangement studies on genomic DNA which revealed the MM, and ALL seemed to be derived from different clones. The development of MM and ALL in the same patient is a very rare event. Further accumulation of the cases to understand the mechanism underlying this event is warranted. PMID- 22450583 TI - [Aplastic anemia complicated with ulcerative colitis]. AB - A 37-year-old female who presented with pancytopenia in April 2008 was diagnosed with aplastic anemia stage 2 with a normal karyotype. She had a PNH phenotype in her red blood cells (RBC) and granulocytes, and HLA DR15. Her aplastic anemia was deteriorated from stage 2 to stage 3, and she required periodic RBC transfusions. Four months after cyclosporine therapy, the pancytopenia improved and she did not need RBC transfusion. However, three months thereafter, she again required RBC transfusions after developing severe ulcerative colitis. Although mesalazine and steroid pulse therapy improved her ulcerative colitis, her transfusion dependency persisted. Eleven months after the diagnosis of aplastic anemia, equine anti thymocyte globulin (ATG) and cyclosporine were administered, but no hematological improvement was obtained. Six months after the administration of ATG and cyclosporine, transformation to refractory cytopenia with multilineage dysplasia (RCMD) with 7-monosomy was observed. An allogeneic bone marrow transplant (BMT) from a HLA-identical sibling was performed 23 months after the diagnosis of aplastic anemia. Complete remission of both the aplastic anemia and ulcerative colitis was obtained without medication. Although the relationship between aplastic anemia and ulcerative colitis remains unclear, immunological abnormalities might be involved in the pathogenesis of both disorders because she had PNH phenotype in RBC and HLA DR15 and because allogeneic BMT improved both disorders. PMID- 22450584 TI - [Early relapse in the central nervous system-after achieving complete response in primary vaginal lymphoma]. AB - A 76-year-old woman presented with vaginal bleeding and discharge in September 2009. She was admitted to our hospital because a tumor of 5 cm in diameter was found in the vagina in a nearby clinic. She was diagnosed with primary vaginal diffuse large B-cell lymphoma (DLBCL) on biopsy of the tumor because CT, MRI and FDG-PET showed no area of lymphomatous involvement other than the vagina and direct involvement into the bladder. She achieved complete response (CR) after chemotherapy followed by localized radiation therapy, but she had a relapse in the central nervous system (CNS) two months after CR. A study of 57 reported cases of primary vaginal lymphoma suggested that the most common histologic type was DLBCL, and most of patients were in a localized stage and responded well to combination of chemotherapy and radiation therapy. To date, two cases of primary vaginal lymphoma with a relapse in the CNS have been reported. We presumed that direct involvement into the bladder of vaginal lymphoma contributed to the relapse in the CNS in this case. PMID- 22450585 TI - [Successful treatment for thrombotic microangiopathy with recombinant human soluble thrombomodulin after umbilical cord blood transplantation]. AB - A 1-year-old girl with familial hemophagocytic lymphohistiocytosis underwent umbilical cord blood transplantation. On day 24, she developed renal failure, jaundice and hemolytic anemia, and we diagnosed transplantation-associated thrombotic microangiopathy (TMA). Despite discontinuation of tacrolimus, her condition became even worse. From day 25, we started to administer recombinant human soluble thrombomodulin (rTM). According to the recommendation of the pharmaceutical company, a dose reduction from 380 to 130 IU/kg/day in patients with renal failure, we administered rTM at the reduced dose during the first 2 days. Because the reduced dose was not effective, we administered rTM at the standard dose from day 27. Surprisingly, she began to recover from TMA on the next day, and we continued to administer rTM until day 109. She is alive without evidence of disease eighteen months after transplantation. Adverse events of rTM were severe gastrointestinal hemorrhage and hemorrhagic cystitis, and it was necessary to control hemorrhage by interruption of administration. This case report suggests that rTM may be effective for TMA. Moreover, alteration in the dosage schedule seems to be required according to the condition of patients. Further studies are needed to evaluate the effectiveness and an optimal dose of rTM as a treatment for TMA. PMID- 22450586 TI - [Clinical evaluation of three elderly cases with acquired hemophilia A]. AB - In this paper we report our clinical investigation of three cases with acquired hemophilia A treated in our department. These patients were all elderly males (79, 77, and 68 years old), and presented with subcutaneous bleeding, a prolonged activated partial thromboplastin time (APTT), and anemia. On the basis of these findings as well as decreased factor VIII activities (0.9~3.1%) and the presence of factor VIII inhibitors (57.1~173 BU/ml), we made a diagnosis of acquired hemophilia A. In cases 1 and 2, a recombinant activated factor VII was used to achieve hemostasis. The factor VIII inhibitor disappeared with prednisolone (PSL) alone in case 1 and a combination of PSL and cyclophosphamide in case 2. In case 3, treatment involving five courses of weekly rituximab (RTX) reduced the activity of factor III inhibitor to 3.5 BU/ml (and subsequently to zero). During this time, the patient achieved hemostasis without using a specific hemostatic agent, and was again referred to the previous hospital for the treatment of hepatocellular carcinoma. Although PSL is often chosen as a first-line therapy to suppress the production of factor VIII inhibitor, which may cause acquired hemophilia A, RTX may be another therapeutic option in some patients. PMID- 22450587 TI - [Sustained remission of blastic plasmacytoid dendritic cell neoplasm with ABVD chemotherapy]. AB - Blastic plasmacytoid dendritic cell neoplasm is a rare but clinically aggressive tumor known to be derived from the precursors of plasmacytoid dendritic cells with frequent cutaneous involvement. Though the majority of patients initially respond to multi-agent chemotherapy, most cases without hemopoietic stem cell transplantation relapse within a year. We describe a case of a 71-year-old man with a dark-purple subcutaneous nodule (5*3 cm) under his right auricle. Histologic examination of the excisional biopsy specimen revealed a diffuse proliferation of blast cells with irregular nuclei, fine chromatin and one to several small nucleoli in the dermis extending to the subcutaneous soft tissues. The tumor cells expressed CD123, CD56, CD4, CD7, LCA, and TdT but not CD3, CD20, CD79a, CD10, CD68, CD163, myeloperoxidase (MPO), or naphthol-ASD-chloroacetate (ASD-Ch) esterase. A diagnosis of blastic plasmacytoid dendritic cell neoplasm was made. He did not have any other lesions except for the solitary skin nodule. He had refractory cytopenia with multilineage dysplasia (RCMD) and renal dysfunction. It was difficult for him to receive hemopoietic stem cell transplantation because of his advanced age and renal dysfunction. We had previously experienced successful treatment with ABVD chemotherapy for interdigitating dendritic cell sarcoma after ineffective CHOP chemotherapy. The plasmacytoid dendritic cell is one of the precursor cells of the interdigitating dendritic cell. Therefore we tried to apply ABVD therapy to him. The first course of ABVD induced complete remission. Although the therapies were reduced and postponed because of various complications, he is now in complete remission that has lasted for 21 months. Although previously not reported, ABVD therapy is useful for patients with blastic plasmacytoid dendritic cell neoplasm who cannot receive hemopoietic stem cell transplantation. PMID- 22450588 TI - [Follicular lymphoma showing long-term false positive results by FDG-PET after rituximab-containing chemotherapy]. AB - We report a patient with follicular lymphoma who had false positive results on 18 fluorodeoxyglucose positron emission tomography (FDG-PET) tests for more than six months due to inflammatory reactions continuing over a long period of time after chemotherapy with rituximab. Although FDG-PET has advantages over other imaging methods when used for the evaluation of the response to chemotherapy and detection of recurrence, attention should be paid to the possibility of false positive results due to such inflammatory conditions, especially when rituximab is administered. Biopsy of the FDG-uptake lesions is strongly recommended if recurrence is suspected. PMID- 22450589 TI - Drinking behaviors of elite male runners during marathon competition. AB - OBJECTIVE: To describe the drinking behaviors of elite male marathon runners during major city marathons. DESIGN: Retrospective analysis of drinking behaviors. SETTING: Institutional. PARTICIPANTS: Ten (9 winners and 1 second position) male marathon runners during 13 major city marathons. MAIN OUTCOME MEASURES: Total drinking durations and fluid intake rates during major city marathons. RESULTS: The ambient conditions during the 13 studied marathon races were 15.3 degrees C +/- 8.6 degrees C and 59% +/- 17% relative humidity; average marathon competition time was 02:06:31 +/- 00:01:08 (hours:minutes:seconds). Total drinking duration during these races was 25.5 +/- 15.0 seconds (range, 1.6 50.7 seconds) equating to an extrapolated fluid intake rate of 0.55 +/- 0.34 L/h (range, 0.03-1.09 L/h). No significant correlations were found between total drink duration, fluid intake (rate and total), running speed, and ambient temperature. Estimated body mass (BM) loss based on calculated sweat rates and rates of fluid ingestion was 8.8% +/- 2.1% (range, 6.6%-11.7%). Measurements of the winner in the 2009 Dubai marathon revealed a BM loss of 9.8%. CONCLUSIONS: The most successful runners, during major city marathons, drink fluids ad libitum for less than approximately 60 seconds at an extrapolated fluid ingestion rate of 0.55 +/- 0.34 L/h and comparable to the current American College of Sports Medicine's recommendations of 0.4-0.8 L/h. Nevertheless, these elite runners do not seem to maintain their BM within current recommended ranges of 2%-3%. PMID- 22450590 TI - The epidemiology of severe and catastrophic injuries in BASE jumping. AB - OBJECTIVE: To report the demographic characteristics, injury rate, severity, and morbidity in BASE jumping. DESIGN: Cross-sectional survey. SETTING: BASE jumping group meetings from 2006 to 2010. PARTICIPANTS: Heterogenic group of 102 International BASE jumpers. ASSESSMENT OF RISK FACTORS: Injuries reported as function of jumps made, jumping days, age, experience, and sex. MAIN OUTCOME MEASURES: Incidence, severity, and type of injuries. RESULTS: Responses from 68 subjects were available for analysis. The median number of jumps was estimated at 286 per respondent. The median time respondents had participated in BASE jumping was 5.8 years. There were 39 reported severe injuries sustained by 29 different jumpers. Nineteen thousand four hundred ninety-seven jumps were reported, resulting in 2 severe injuries per 1000 jumps (0.2% severe injury rate) or 2.6 severe injuries per 1000 jumping days. Forty-nine respondents (72%) had witnessed the death or serious injury of other participants in the sport. Twenty-four accidents (61%) involved the lower limbs, 8 (20%) the back/spine, 7 (18%) the chest wall, and 5 (13%) were a head injury. The mean Abbreviated Injury Score was 3.2 (range, 2-5). Fifteen (52%) of the 29 injured jumpers required 20 acute surgical interventions, which were mostly orthopedic related. There was a significant correlation between number of jumps made and injuries sustained (P < 0.05). CONCLUSIONS: BASE jumpers have an average of 1 severe injury for every 500 jumps. Most active BASE jumpers have witnessed death or severe injury of a participant and have experienced a "close call" incident. PMID- 22450591 TI - Immediate effects of kinesiotaping on quadriceps muscle strength: a single blind, placebo-controlled crossover trial. AB - OBJECTIVE: To investigate the immediate effects on maximal muscle strength of kinesiotaping (KT) applied to the dominant quadriceps of healthy subjects. DESIGN: Single-blind, placebo-controlled crossover trial. SETTING: "Salvatore Maugeri" Foundation. PARTICIPANTS: With ethical approval and informed consent, a convenience sample of 36 healthy volunteers were recruited. Two subjects did not complete the sessions and were excluded from the analysis. INTERVENTIONS: Subjects were tested across 3 different sessions, randomly receiving 2 experimental KT conditions applied with the aim of enhancing and inhibiting muscle strength and a sham KT application. MAIN OUTCOME MEASURES: Quadriceps muscle strength was measured by means of an isokinetic maximal test performed at 60 and 180 degrees per second. Two secondary outcome measures were performed: the single-leg triple hop for distance to measure limb performance and the Global Rating of Change Scale (GRCS) to calculate agreement between KT application and subjective perception of strength. RESULTS: Compared with baseline, none of the 3 taping conditions showed a significant change in muscle strength and performance (all P > 0.05). Effect size was very low under all conditions (<=0.08). Very few subjects showed an individual change greater than the minimal detectable change. Global Rating of Change Scale scores demonstrated low to moderate agreement with the type of KT applied, but some placebo effects were reported independently of condition. CONCLUSIONS: Our findings indicated no significant effect in the maximal quadriceps strength immediately after the application of inhibition, facilitation, or sham KT. These results do not support the use of KT applied in this way to change maximal muscle strength in healthy people. PMID- 22450592 TI - Significance of deep T-wave inversions in an asymptomatic athlete with a family history of sudden death: addendum--full sporting disqualification. PMID- 22450593 TI - Longitudinal changes in the lower extremity functional scale after anterior cruciate ligament reconstructive surgery. AB - OBJECTIVE: To describe the pattern of change in lower extremity physical function status as measured by the Lower Extremity Functional Scale (LEFS) during the first 16 weeks after anterior cruciate ligament (ACL) reconstructive surgery and illustrate how this information can be applied in clinical practice to assist with goal setting and the evaluation of patient outcomes. The secondary objective is to estimate the test-retest reliability of the LEFS in this population. DESIGN: Prospective cohort, observational. SETTING: Physiotherapy private practice. PATIENTS: Forty-seven participants underwent ACL reconstructive surgery and were initially recruited. Two participants were excluded from the analysis, resulting in 45 participants (28 men, mean age 29.4 years; 17 women, mean age 29.0 years). INTERVENTIONS: Participants underwent a rehabilitation protocol. MAIN OUTCOME MEASURES: Participants completed the LEFS at each visit from their initial physiotherapy session to 16 weeks postsurgery. A nonlinear model of change was developed, which related LEFS scores to weeks postsurgery. Test-retest reliability was examined between the seventh and ninth weeks using intraclass correlation coefficients (ICC2,1) and standard error of measurement (SEM). RESULTS: The nonlinear model demonstrated rapid improvements in LEFS scores within the first 7 to 8 weeks with a gradual tapering of this improvement. At 16 weeks, the predicted LEFS score was 63 out of a maximum score of 80. The LEFS demonstrated excellent test-retest reliability in this population (ICC2,1 = 0.90, SEM = 3.7). CONCLUSIONS: This study provides a description of postsurgical change in functional status for patients after ACL reconstructive surgery that can assist clinicians in developing clinical goals. CLINICAL RELEVANCE: A rapid improvement in lower extremity physical function is demonstrated in the first 7 to 8 weeks after ACL reconstructive surgery with a tapering of this improvement after 8 weeks. PMID- 22450594 TI - Jet lag and travel fatigue: a comprehensive management plan for sport medicine physicians and high-performance support teams. AB - The impact of transcontinental travel and high-volume travel on athletes can result in physiologic disturbances and a complicated set of physical symptoms. Jet lag and travel fatigue have been identified by athletes, athletic trainers, coaches, and physicians as important but challenging problems that could benefit from practical solutions. Currently, there is a culture of disregard and lack of knowledge regarding the negative effects of jet lag and travel fatigue on the athlete's well-being and performance. In addition, the key physiologic metric (determination of the human circadian phase) that guides jet lag treatment interventions is elusive and thus limits evidence-based therapeutic advice. A better understanding of preflight, in-flight, and postflight management options, such as use of melatonin or the judicious application of sedatives, is important for the sports clinician to help athletes limit fatigue symptoms and maintain optimal performance. The purpose of this article was to provide a practical applied method of implementing a travel management program for athletic teams. PMID- 22450595 TI - Accelerated renal allograft failure due to monoclonal gammopathy of undetermined significance. PMID- 22450596 TI - Rescue kidney paired donation as emergency salvage for failed desensitization. PMID- 22450597 TI - Pharmacokinetic interaction between tacrolimus and amlodipine in a renal transplant child. PMID- 22450598 TI - Case report: Multidrug-resistant cytomegalovirus in a modified multivisceral transplant recipient. PMID- 22450599 TI - Assessment of psychopathic traits in an incarcerated adolescent sample: a methodological comparison. AB - Analyses of convergent validity and group assignment using self-report, caregiver report and interview-based measures of adolescent psychopathy were conducted in a sample of 160 incarcerated adolescents. Results reveal significant convergent validity between caregiver-report measures of adolescent psychopathy, significant convergent validity between self-report measures of adolescent psychopathy and an interviewer rating scale, but not between the caregiver-report measures and their corresponding self-report measures nor between the caregiver-report measures and the interviewer rating scale. Analyses of group assignment were also poorer than expected among all the measures with none evidencing significant agreement with the expert-rated device (Hare Psychopathy Checklist-Youth Version; PCL-YV), the most common forensic instrument used in clinical practice. Part of the poor agreement may be related to the poor psychometric performance of the callous unemotional subscale of most of these measures and the low response rates from caregivers (N = 35). These findings suggest that the measures do not provide an interchangeable assessment of callous-unemotional traits and suggest that further refinement of the measurement of callous-unemotional traits in youth may be warranted. PMID- 22450600 TI - Folding kinetics of a polymer. AB - We present the results of computer simulations giving a kinetic insight into the liquid-to-solid transition of a homopolymer chain with short-range interactions. By calculating the absolute rates in each direction of the transition, using molecular dynamics employing the forward flux sampling scheme, we provide the phase diagram based on purely kinetic data, and compare it with the results from Monte Carlo simulations. Additionally, we present and discuss a remarkably simple and general relation between the polymer topology and the folding pathway, and show that the eigenvalue spectrum of a matrix defined by non-bonded contacts (the Laplacian matrix) provides an insight into the nonequilibrium ensembles of these trajectories. In particular, the Laplacian matrix seems to identify a large fraction of configurations on the folding pathway at the free energy maximum that have a very low probability of reaching the crystallized state. This implies that the eigenvalues of this matrix may be suitable additional reaction coordinates to describe the folding transition of chain molecules. PMID- 22450601 TI - Re-examination of 'Einige Beitrage zur Theorie der Zahnregulierung' (Some contributions to the theory of the regulation of teeth) published in 1904-1905 by Carl Sandstedt. AB - The original histological investigation that forms the basis of our present understanding of tooth movement was carried out on dogs by the Swedish dentist Carl Sandstedt at the Karolinska Institute, Stockholm. His findings were published in 1901 as a monograph in Swedish, and shortly after his death in 1904, as three articles in German entitled 'Einige Beitrage zur Theorie der Zahnregulierung'. Sandstedt observed that the bone was deposited on the alveolar wall of the tension side with both heavy and light forces, new bone spicules following the orientation of the periodontal fibres. On the pressure side, with light forces, osteoclasts resorbed the surface of the alveolar bone, but heavy forces compressed the periodontal ligament resulting in hyalinization--the formation of localized cell-free areas. At these sites, bone removal resulted from undermining resorption by osteoclasts from adjacent marrow spaces. He also observed root resorption and commented on the centre of rotation of the teeth. No English version of Sandstedt's research has ever been published, and in view of its importance, one of us (DB) has translated his three articles from the original German. The aim was to persuade an orthodontic journal to publish the articles in full--however, weighing-in at 21,000 words, the impracticality of this plan soon became clear. We concluded that excerpts from the text plus commentary would be the most practical solution. Where possible and without materially changing the intended meaning, we have translated the German text into something resembling contemporary English, accompanied by the original 16 figures. PMID- 22450602 TI - When (and how) to surgically treat asymptomatic renal stones. AB - Asymptomatic renal stones are identified in 8-10% of screened populations. With the increasing utilization of CT, the number of patients seeking urologic care for incidentally diagnosed renal calculi is likely to increase. Such patients present an important management dilemma: differentiating those to treat surgically from those who can be safely observed. Observational studies have revealed that approximately 50% of asymptomatic stones will progress, but most will not require surgery. Stones >15 mm in diamater and located in the renal pelvis are at highest risk of progression. Although no guidelines exist for the optimal monitoring regimen for asymptomatic stones, follow-up studies may include serum creatinine, plain radiography, ultrasonography, and CT. Shock wave lithotripsy (SWL) does not seem to offer significant benefit over observation for asymptomatic calyceal stones. Percutaneous nephrolithotomy does improve stone free rates compared to SWL or observation. Additional research is needed to characterize the role of ureteroscopic management of asymptomatic renal stones. PMID- 22450603 TI - Surgery: are we likely to see more of LESS in urological surgery? PMID- 22450604 TI - The hemodynamic approach to evaluating adolescent varicocele. AB - During adolescence, the risk of developing a varicocele increases. Prevalence is less than 1% in boys aged younger than 10 years, but approaches that of the general adult population (about 15%) during puberty. For adolescent males with varicoceles, surgical risk factors have not yet been clearly delineated and clinical severity correlates poorly with prognosis. Fortunately, the widespread use of Doppler ultrasonography is transforming the diagnostic work-up for this demographic. A continuous reflux detected by color Doppler ultrasound (CDUS) is thought to have a negative prognostic value and evidence suggests that a peak retrograde flow above 38 cm per second is a powerful predictor of lack of spontaneous improvement in adolescent patients with >= 20% asymmetry between testes. CDUS also enables the detection of varicocele resulting from reflux in the deferential vein adjunctive to a refluxing internal spermatic vein; a causality that accounts for approximately 15% of cases. In addition to a diagnostic role, hemodynamic parameters can be used to predict the risk of persistence or worsening asymmetry. Although further studies are necessary to validate single parameters, it seems that the more severe the reflux, the greater the likelihood that the patient will develop testicular asymmetry. PMID- 22450605 TI - Kidney cancer: safety and efficacy demonstrated for novel bipolar radiofrequency ablation system. PMID- 22450606 TI - Bladder cancer: a noninvasive multi-analyte assay for triaging patients. PMID- 22450607 TI - Bladder hypocontractility--extending the indication for LDDM. PMID- 22450608 TI - Neuroanatomy of dopamine: reward and addiction. PMID- 22450609 TI - The neuropsychiatry of vitamin B12 deficiency in elderly patients. AB - Vitamin B12 deficiency is a common cause of neuropsychiatric symptoms in elderly persons. Malabsorption accounts for the majority of cases. Vitamin B12 deficiency has been associated with neurologic, cognitive, psychotic, and mood symptoms, as well as treatment-resistance. Clinician awareness should be raised to accurately diagnose and treat early deficiencies to prevent irreversible structural brain damage, because current practice can be ineffective at identifying cases leading to neuropsychiatric sequelae. This clinical review focuses on important aspects of the recognition and treatment of vitamin B12 deficiency and neuropsychiatric manifestations of this preventable illness in elderly patients. PMID- 22450610 TI - Impulse-control disorders in gilles de la tourette syndrome. AB - Impulse-control disorders (ICDs) are more common in clinic populations with Gilles de la Tourette syndrome (GTS) than in the general population. The clinical phenomenology of ICDs differ between men with GTS (who tend to be externally impulsive) and women with GTS (who tend to be internally impulsive). This article reviews the relevant literature to-date on impulsivity in GTS, with special focus on intermittent, explosive disorder, self-injurious behavior, trichotillomania, and impulsive-compulsive sexual behavior. The medical and legal community should be aware of the full spectrum of organically-based behaviors that may predispose patients with GTS to unwanted legal disciplinary action. PMID- 22450611 TI - Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease. AB - Deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson's disease (PD) improves motor functioning but has variable effects on mood. Little is known about the relationship between electrode contact location and mood response. The authors identified the anatomical location of electrode contacts and measured mood response to stimulation with the Visual Analog Scale in 24 STN DBS PD patients. Participants reported greater positive mood and decreased anxiety and apathy with bilateral and unilateral stimulation. Left DBS improved mood more than right DBS. Right DBS-induced increase in positive mood was related to more medial and dorsal contact locations. These results highlight the functional heterogeneity of the STN. PMID- 22450612 TI - Getting Past "g": testing a new model of dementing processes in persons without dementia. AB - The cognitive correlates of functional status are essential to dementia case finding. The authors have used structural-equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., delta) from the variance that is unrelated to a dementing process (i.e., g'). Together, g' and delta comprise Spearman's "g." Although delta represents only a small fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g'. In this analysis, the authors test whether delta can predict future cognitive decline in persons clinically without dementia at baseline. These results have implications for the clinical assessment of dementia and suggest that functional status should assume a more important role. PMID- 22450613 TI - Comparison of personality characteristics on the bear-fedio inventory between patients with epilepsy and those with non-epileptic seizures. AB - This study used the Bear-Fedio Personality Inventory (BFI) to compare 41 individuals with temporal lobe epilepsy (TLE) and 37 with psychogenic non epileptic seizures (NES). Both groups exhibited similar elevations on the BFI, although TLE individuals show greater endorsement of at least one hypergraphia symptom, as compared with those with NES. The correlates of the BFI with demographic and seizure characteristics differed between the groups. These results argue against a specific TLE personality syndrome and suggest that personality characteristics may be related to the experience of having repeated seizures, rather than the specific underlying pathophysiology of temporal lobe epilepsy. PMID- 22450614 TI - Longitudinal evaluation of neuropsychiatric symptoms in Huntington's disease. AB - A group of 111 patients with Huntington's disease (HD) underwent a minimum of three annual neuropsychiatric assessments, using the Problem Behaviors Assessment for Huntington's Disease (PBA-HD). Longitudinal prevalence of neuropsychiatric symptoms was notably higher than baseline prevalence, suggesting that previous studies may have underestimated the extent of this clinical problem. Moreover, apathy, irritability, and depression were each associated with distinct longitudinal profiles. Apathy progressed over time and across disease stages. Irritability also increased significantly, but only in early stages of HD. Depression did not increase significantly at any stage of disease. The neuropsychiatric syndrome of apathy appears to be intrinsic to the evolution and progression of HD. PMID- 22450615 TI - Sustained attention deficits among HIV-positive individuals with comorbid bipolar disorder. AB - Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD-), using the Conners' Continuous Performance Test II (CPT-II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT-II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD- participants. When examining CPT-II performance over the six study blocks, both HIV+/BD+ and HIV+/BD- participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT-II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD- participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT-II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes. PMID- 22450616 TI - Cognitive performance related to HIV-1-infected monocytes. AB - The effect that HIV type 1 (HIV) has on neurocognition is a dynamic process whereby peripheral events are likely involved in setting the stage for clinical findings. In spite of antiretroviral therapy (ART), patients continue to be at risk for HIV-associated neurocognitive disorders (HAND), which might be related to persistence of inflammation. In a yearly assessment of HIV DNA levels in activated monocytes, increased HIV DNA copies were found in patients with persistent HAND. Furthermore, activated monocytes from patients with high HIV DNA copies secreted more inflammatory cytokines. Since these activated monocytes traffic to the CNS and enter the brain, they may contribute to an inflammatory environment in the CNS that leads to HAND. PMID- 22450617 TI - Obsessive-compulsive-spectrum symptoms in patients with focal dystonia, hemifacial spasm, and healthy subjects. AB - This study is aimed at investigating obsessive-compulsive disorder (OCD) in three groups of patients matched for age and gender; namely, focal dystonia (FD), hemifacial spasm (HFS), and healthy-control subjects (HC). All subjects were investigated with the Structured Clinical Interview for DSM-I, the Hospital Anxiety and Depression Scale, the Symptom Checklist-90, the Yale-Brown Obsessive Compulsive Scale, and the Structured Clinical Interview for Obsessive-Compulsive Spectrum Self-Report, Lifetime Version (SCI-OBS-SR-LT). The prevalence of OCD was significantly higher in both FD and HFS than in HC participants. On the SCI-OBS, HFS patients showed higher scores than FD or HC for "contamination" and "aggressiveness." Despite the different pathophysiology, OCD is highly represented in both FD and HFS, with different thematic content characterizing the two conditions. PMID- 22450618 TI - Motor functioning in autistic spectrum disorders: a preliminary analysis. AB - The study sought to identify differences in motor functioning between autism and Asperger syndrome while also assessing the diagnostic contribution of such assessment. A sample of 16 individuals with autism and 10 with Asperger syndrome completed the Dean-Woodcock Sensory-Motor Battery, and outcomes were compared. Significant differences were found in measures of cerebellar functioning, favoring Asperger subjects. Deficits in coordination, ambulation, and the Romberg test were associated with both disorders. On the basis of motor outcomes alone, 100% were accurately differentiated. Findings support the idea that motor dysfunction is a core feature of these presentations and demonstrated the utility of motor assessment in diagnostic practice. PMID- 22450619 TI - Symptom profile and etiology of delirium in a referral population in northern india: factor analysis of the DRS-R98. AB - Delirium is understudied in developing countries, where there tends to be a lower proportion of older persons and comorbid dementia. The authors assessed 100 consecutive cases of DSM-IV delirium (patients' mean age: 44.4 [standard deviation: 19.4] years; mean DRS-R98 score: 25.6 [3.6]) referred to an adult Consultation-Liaison Psychiatry service in Northern India. Disturbances of attention, orientation, visuospatial ability, and sleep disturbance were the most frequent symptoms, followed by language, thought-process abnormality, and motor agitation. A three-factor solution was identified, representing domains for cognition, higher-order thinking, and circadian rhythm/psychosis. These domains can guide studies addressing the relationship between symptom profile, therapeutic needs, and outcomes and are consistent with core domains previously identified in other countries. PMID- 22450620 TI - Underlying neurobiology and clinical correlates of mania status after subthalamic nucleus deep brain stimulation in Parkinson's disease: a review of the literature. AB - Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson's disease (PD). The authors review the current literature to identify the clinical correlates associated with subthalamic nucleus (STN) DBS induced hypomania/mania in PD patients. Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male sex, and/or early-onset PD. STN DBS induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanisms of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight toward development of future DBS mood stabilization therapies. PMID- 22450621 TI - Can computerized cognitive tests assist in the clinical diagnosis of attention deficit hyperactivity disorder? AB - A group of 34 children and adolescents suspected of having attention-deficit hyperactivity disorder were referred for a computerized evaluation that included sustained attention, working memory, planning, and set-shifting. Although only sustained attention had reasonable specificity, all tests had questionable contribution to the diagnostic evaluation. PMID- 22450625 TI - Cerebral amyloid angiopathy-related inflammation: a treatable cause of rapidly progressive dementia. PMID- 22450626 TI - Bipolar disorder co-occurring with periodic paralysis: a case report. PMID- 22450627 TI - Demonstration of uniparental-isodisomy on chromosome 22q11.2 in a patient with childhood schizophrenia and facial dysmorphology by whole-genome analysis. PMID- 22450628 TI - Dystonia as a presenting feature of alcohol withdrawal. PMID- 22450629 TI - Good response to clonidine in tourette syndrome associated with chromosomal translocation involving the IMMP2L gene. PMID- 22450630 TI - Levocarnitine-induced hypophosphatemia in a hemodialysis patient with acute valproic acid toxicity. PMID- 22450631 TI - Psychosis in a patient with silent vascular brain lesions. PMID- 22450632 TI - Delusional misidentification syndrome: right-hemisphere findings on SPECT. PMID- 22450633 TI - Successful treatment of olfactory reference syndrome with paroxetine. PMID- 22450634 TI - Mental practice: a psychotherapy to improve action-selection in obsessive compulsive disorder. PMID- 22450635 TI - Asterixis (flapping tremors) as an outcome of complex psychotropic drug interaction. PMID- 22450636 TI - Auditory hallucinations as the only presenting symptom of right-parietal spontaneous hemorrhage: FDG-PET evidence of corpus callosum hyperactivity. PMID- 22450637 TI - Combined delusional misidentification syndrome in a patient with Parkinson's disease. PMID- 22450638 TI - Eating disorder in type 1 diabetes can be unmasked by information technology. PMID- 22450639 TI - Levomepromazine-induced retrograde ejaculation. PMID- 22450640 TI - NeuroQuant(r) revealed hippocampal atrophy in a patient with traumatic brain injury. PMID- 22450641 TI - Open-lip schizencephaly associated with bipolar disorder in a young man exposed in utero to the chernobyl disaster. PMID- 22450642 TI - Serotonin toxicity in aripiprazole augmentation. PMID- 22450643 TI - Successful use of quetiapine in two successive pregnancies. PMID- 22450644 TI - 17 years of treatment-resistant mutism in non-catatonic, childhood-onset schizophrenia: a rare case report. PMID- 22450645 TI - Comorbid multiple sclerosis and TDP-43 proteinopathy in a gulf war sea captain. PMID- 22450646 TI - Late onset of psychotic symptoms in a patient with cavum septum pellucidum and cavum vergae. PMID- 22450647 TI - Psychotic episode during steroid therapy in hashimoto encephalopathy. PMID- 22450648 TI - Sertraline-induced hyponatremia and seizures in old age. PMID- 22450649 TI - Successful treatment of benzodiazepine-resistant malignant catatonia with electroconvulsive therapy. PMID- 22450650 TI - A case of auditory hallucinations due to cerumen-induced transient hearing loss, successfully treated with cerumenolysis, in a patient with a major depressive episode. PMID- 22450651 TI - Effectiveness of clozapine in treating severe tardive dystonia and associated pyosis. PMID- 22450652 TI - Dandy walker variant with treatment-resistant bipolar disorder. PMID- 22450653 TI - Impairment of affective theory of mind in corticobasal degeneration. PMID- 22450654 TI - Intubation in a case of psychogenic, non-epileptic status epilepticus. PMID- 22450655 TI - Progressive non-fluent aphasia in a bilingual subject: relative preservation of "mother tongue". PMID- 22450656 TI - A lithography-free procedure for fabricating three-dimensional microchannels using hydrogel molds. AB - We present a lithography-free procedure for fabricating intrinsically three dimensional smooth-walled microchannels within poly(dimethylsiloxane) (PDMS) elastomer using hydrogel molds. In the fabrication process, small pieces of agarose gel ("wires" or "chips") are embedded in uncured PDMS composite, arranged in the shape of the desired microchannels, and used as molds to form the microchannels. The point of the process is that molds for creating junctions of microchannels such as T-junctions or cross-junctions can be robustly formed by simply grafting gel wires in uncured PDMS composite without using adhesive agents. The technical advantage of this method is that three-dimensional microstructures such as microchannels with circular cross sections, three dimensionally arranged junctions or interchanges of microchannels can be flexibly designed and fabricated with a straightforward procedure without the need for any specialized equipment or layer-by-layer assemblage processes. This method provides a low-cost, green procedure for fabricating microfluidic devices and promises to make microfluidic processes more accessible and easy to implement in a variety of scientific fields. PMID- 22450657 TI - Life signs in "dead" patients. PMID- 22450658 TI - Effects of bone marrow mesenchymal stem cells in a rat model of myocardial infarction. AB - AIM: Infusion of bone marrow mesenchymal stem cells (MSCs) improves myocardial function following myocardial infarction (MI). The mechanisms, however, remain controversial. This study was to investigate changes of MSCs in vivo after administration into myocardial infarcted rats. Our hypothesis was that MSCs might differentiate into contractile myocytes and improve myocardial function in vivo. METHODS: MI was induced in 21 Sprague-Dawley rats by ligation of the left anterior descending artery. One week after ligation, 18 rats were randomized to receive MSCs labeled with PKH26 in a phosphate buffer solution (PBS) by direct injection into the infarcted myocardium. The remaining 3 rats received PBS alone as placebo. An additional 3 non-ligated rats served as a normal group to obtain normal myocytes. RESULTS: Every week for 6 weeks, hearts from 3 rats injected with MSCs were harvested to observe single cardiomyocytes. Although each week numerous round MSCs were found in the hearts of animals treated with MSCs, beating cardiomyocyte-like cells labeled with PKH26 were observed at the sixth week. The contractility of cardiomyocyte-like cells was the same to that of the unlabeled contractile native cardiomyocytes at the sixth week and that of the normal group (10.71+/-1.59 vs. 11.09+/-3.42 vs. 11.21+/-2.16, p>0.05). The contractility of cardiomyocyte-like cells was greater than cells both from the first week (10.71+/-1.59 vs. 7.37+/-3.47, p<0.01) and the second week (10.71+/ 1.59 vs. 8.08+/-3.11, p<0.05) which was associated with significantly increased ejection fraction. CONCLUSIONS: MSCs can differentiate into beating cardiomyocytes in a rat model of MI and improve myocardial function. PMID- 22450659 TI - miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1. AB - SPHK1 expression is elevated in gastric cancer and is associated with shorter survival times for patients. However, the molecular mechanism of SPHK1 up regulation in gastric cancer remains unclear. In the present study, we report that miR-124 down-regulated SPHK1 expression by directly targeting its 3' untranslated region (3'-UTR) and that miR-124 expression was inversely correlated with SPHK1 expression in gastric cancer samples. Furthermore, we demonstrated that, similar to the effect of silencing SPHK1, up-regulation of miR-124 markedly inhibited proliferation and tumourigenicity of gastric cancer cells both in vitro and in vivo. This was found to be mechanistically associated with induction of cyclin-dependent kinase inhibitors p21$^{{?rm Cip1}}$ and p27$^{{?rm Kip1}}$, enhancement of the transcriptional activity of FOXO1 and suppression of AKT activity. Moreover, we showed that the re-introduction of SPHK1 (without the 3' UTR), but not with the 3'-UTR, could abrogate the miR-124-mediated induction of p21$^{{?rm Cip1}}$ and p27$^{{?rm Kip1}}$, as well as rescue the miR-124-induced proliferation inhibition. Together, these results suggest that miR-124 has an important role in the suppression of gastric cancer and presents a novel mechanism of miRNA-mediated SPHK1 expression in cancer cells. PMID- 22450660 TI - Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, L-DOPA, and curcumin: metal binding as a general antioxidant mechanism. AB - Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing interest in metal-neurotransmitter interactions. Catecholamine (dopamine, epinephrine, and norepinephrine) and amino acid (glycine, glutamate, and 4-aminobutyrate) neurotransmitters are antioxidants also known to bind metal ions. To investigate the role of metal binding as an antioxidant mechanism for these neurotransmitters, L-dihydroxyphenylalanine (L DOPA), and curcumin, their abilities to prevent iron- and copper-mediated DNA damage were quantified, cyclic voltammetry was used to determine the relationship between their redox potentials and DNA damage prevention, and UV-vis studies were conducted to determine iron and copper binding as well as iron oxidation rates. In contrast to amino acid neurotransmitters, catecholamine neurotransmitters, L DOPA, and curcumin prevent significant iron-mediated DNA damage (IC(50) values of 3.2 to 18 MUM) and are electrochemically active. However, glycine and glutamate are more effective at preventing copper-mediated DNA damage (IC(50) values of 35 and 12.9 MUM, respectively) than L-DOPA, the only catecholamine to prevent this damage (IC(50) = 73 MUM). This metal-mediated DNA damage prevention is directly related to the metal-binding behaviour of these compounds. When bound to iron or copper, the catecholamines, amino acids, and curcumin significantly shift iron oxidation potentials and stabilize Fe(3+) over Fe(2+) and Cu(2+) over Cu(+), a factor that may prevent metal redox cycling in vivo. These results highlight the disparate antioxidant activities of neurotransmitters, drugs, and supplements and highlight the importance of considering metal binding when identifying antioxidants to treat and prevent neurodegenerative disorders. PMID- 22450661 TI - The use of FDG-PET/CT in extranodal Rosai-Dorfman disease of bone. AB - We report the case of a 41-year-old man with extranodal Rosai-Dorfman disease (RDD), presenting with clinically detectable bone involvement only. The use of FDG-PET/CT in the diagnosis of RDD is discussed. PMID- 22450662 TI - [Structural analyses of unknown red dyes detected in dried strawberry]. AB - We examined two unknown red dyes (designated as red dyes "A" and "B") from a dried strawberry package with a label that indicated the presence of food red No. 40 (R40). Red dye "A" was identified as trisodium 3-hydroxy-4-[(2'-methoxy-5' methyl-4'-sulfonatophenyl)azo]-2,7-naphthalenedisulfonate (CSA-R) by HPLC, UV-VIS spectra and MS spectra. This compound is one of the four reported subsidiary colors of R40. Detailed analyses of red dye "B" by MS and NMR demonstrated that its structure was disodium 3-hydroxy-4-[(2'-methoxy-5'-methyl-4' sulfonatophenyl)azo]-2-naphthalenesulfonate. Red dye "B" is a structural isomer of R40, that has not been reported previously. Our results suggest that the two minor red dyes were subsidiary colors contained in R40, which had been added to the dried strawberries. PMID- 22450663 TI - [Comparative analyses of allergens between landlocked and anadromous species of masu salmon Oncorhynchus masou masou]. AB - Although the difference in allergenicity between landlocked and anadromous salmon is little understood, only anadromous salmon are recommended to be labeled in the current allergen labeling system. This study was designed to examine the allergenic potency of landlocked species (yamame) and anadromous species (sakuramasu) of masu salmon Oncorhynchus masou masou, with special reference to parvalbumin, a known major fish allergen. Analysis of the heated extracts by SDS PAGE suggested that yamame contains parvalbumin in the muscle at considerably higher levels, as compared with sakuramasu. In accordance with this, the parvalbumin content in the muscle of yamame (1.8-7.8 mg/g), determined by visible light ELISA, was significantly higher than that of sakuramasu (0.28-0.52 mg/g). Furthermore, fluorescence ELISA experiments showed that the heated extract from yamame reacts with serum from fish-allergic patients more strongly than that from sakuramasu. Three parvalbumin isoforms (PA-I, -II and -III) were individually purified from yamame and sakuramasu by gel filtration and reverse-phase HPLC. Based on the retention times in reverse-phase HPLC and the molecular weights estimated by MALDI/TOF-MS, PA-I, -II and -III from yamame were judged to be identical with PA-I, -II and -III from sakuramasu, respectively. Taken together, our data indicate that landlocked masu salmon (yamame) is more allergenic than anadromous salmon (sakuramasu). PMID- 22450664 TI - [LC-MS analysis of commercial sodium stearoyl lactylate components]. AB - The components of commercial sodium stearoyl lactylate (SSL), purchased in Japan, were determined and identified using thin layer chromatography (TLC) and liquid chromatography with mass spectroscopy (LC-MS). Stearoyl lactate (SL) and stearoyl 2-lactylate (SLL) were purified using TLC and silica gel chromatography to obtain standards. The results show that SSL consisted of lactic acid (8.4%), stearic acid (15%), SL (57%), and SLL (13%). The total amounts of free lactic acid, lactic acid derived from SL and lactic acid derived from SLL were determined using LC-MS. The mean value was approximately equal to that determined using the JECFA method. This is the first study to determine and identify the components of SSL purchased in Japan, using TLC and LC-MS. PMID- 22450665 TI - [Survey of plasticizers in polyvinyl chloride toys]. AB - Plasticizers in 101 samples of polyvinyl chloride (PVC) toys on the Japanese market were surveyed. No phthalates were detected in designated toys, though bis(2-ethylhexyl)phthalate, diisononyl phthalate, diisobutyl phthalate, dibutyl phthalate, diisodecyl phthalate and benzyl butyl phthalate were detected in more than half of other toys. 2,2,4-Tributyl-1,3-pentanediol diisobutylate, o-acetyl tributyl citrate, adipates and diacetyl lauroyl glycerol, which are alternative plasticizers to phthalates, were detected. The results of structural analysis confirmed the presence of di(2-ethylhexyl)terephthalate, tributyl citrate, diisononyl 1,2-cyclohexanedicarboxylate and neopentyl glycol esters; these have not previonsly been reported in Japan. There appears to be a shift in plasticizers used for designated toys from phthalates to new plasticizers, and the number of different plasticizers is increasing. PMID- 22450666 TI - [Test method of methanol content in detergent]. AB - A test method of methanol content in detergent using a headspace-GC method was established. A 1 g aliquot of test sample was mixed with 0.4 mg of 2-propanol and made up to 20 mL with water. Then, 5 mL of test solution was placed in a headspace vial. The vial was sealed and incubated for 30 min at 60 degrees C, then the headspace gas was analyzed by GC-FID. The recovery from spiked 1 mg/g of methanol was 95.6-100.6%. The determination limit was 0.1 mg/g. Using this method, the methanol content in 14 kinds of detergents was quantified. Methanol was detected from two detergents at the levels of 0.13 and 0.27 mg/g. PMID- 22450667 TI - Transfer profile of orally and intramuscularly administered tetrodotoxin to artificial hybrid specimens of the pufferfish Takifugu rubripes and Takifugu porphyreus. AB - Tetrodotoxin (TTX) was administered to artificially hybridized specimens of the pufferfish Takifugu rubripes and Takifugu porphyreus to investigate toxin accumulation in hybrids and TTX transfer/accumulation profiles in the pufferfish body. In test fish administered TTX-containing feed homogenate at a dose of ~400 MU/fish by oral gavage using a syringe (OGA group), the toxin content (MU/g tissue) of the digestive tract rapidly decreased and that of the liver increased from 1 to 24 h after administration. From 24 to 120 h, the toxin content of the liver decreased gradually, and the toxin appeared in the skin. On the other hand, intramuscularly administered TTX (400 MU/fish) was rapidly transferred to the liver and skin via the blood, and only a little toxin remained in the muscle even at 1 h (IMA group). The total amount of toxin remaining in the whole body (% of administered toxin) was 31-45% in the OGA group, and 42-74% in the IMA group; the scores in the OGA group were generally lower than those in the IMA group. In both OGA and IMA groups, the greatest amount of toxin accumulated in the liver (23 52%) after 8 h, followed by the skin (11-21%) after 72 h. The TTX administration experiment, especially using the oral gavage administration method, revealed that skins and livers of 'torama' pufferfish hybrid are endowed with TTX-accumulating ability, but the muscles are not, and that TTX taken up from toxic feed to the pufferfish body is transferred first to the liver and then to the skin via the blood. PMID- 22450668 TI - [Application of DNA extraction kit, 'GM quicker' for detection of genetically modified soybeans]. AB - Several DNA extraction methods have been officially introduced to detect genetically modified soybeans, but the choice of DNA extraction kits depend on the nature of the samples, such as grains or processed foods. To overcome this disadvantage, we examined whether the GM quicker kit is available for both grains and processed foods. We compared GM quicker with four approved DNA extraction kits in respect of DNA purity, copy numbers of lectin gene, and working time. We found that the DNA quality of GM quicker was superior to that of the other kits for grains, and the procedure was faster. However, in the case of processed foods, GM quicker was not superior to the other kits. We therefore investigated an unapproved GM quicker 3 kit, which is available for DNA extraction from processed foods, such as tofu and boiled soybeans. The GM quicker 3 kit provided good DNA quality from both grains and processed foods, so we made a minor modification of the GM quicker-based protocol that was suitable for processed foods, using GM quicker and its reagents. The modified method enhanced the performance of GM quicker with processed foods. We believe that GM quicker with the modified protocol is an excellent tool to obtain high-quality DNA from grains and processed foods for detection of genetically modified soybeans. PMID- 22450669 TI - [Development and performance evaluation of a GC-FPD method for quantification of ethephon in feeds]. AB - An analytical method of ethephon in feeds by GC-FPD was developed. Ethephon was extracted with ethyl acetate-hydrochloric acid (100 : 1) from feed samples. The extract was treated with added trimethylsilyldiazomethane in acetone-acetic acid (99 : 1) and this methylation procedure was repeated three times. Methylated ethephon was cleaned up on a graphitized carbon mini-column and a silicagel mini column, and determined by GC-FPD. A method performance study in 7 laboratories was conducted with three kinds of samples spiked with ethephon at 10 mg/kg, 1 mg/kg and 0.5 mg/kg. The recovery of ethephon ranged from 81.8% to 90.8% (the reproducibility standard deviation (RSDr) were within 11%) and HorRat values were 0.58 to 0.94. The limit of detection (S/N?3) and the limit of quantitation (S/N?10) of ethephon in samples except hay were 0.02 mg/kg and 0.05 mg/kg, respectively. In the case of hay, the corresponding values were 0.2 mg/kg and 0.5 mg/kg, respectively. PMID- 22450670 TI - [Improvement of 2-mercaptoimidazoline analysis in rubber products containing chlorine]. AB - An improved analysis method for 2-mercaptoimidazoline in rubber products containing chlorine was developed. 2-Mercaptoimidazoline (20 ug/mL) is detected by means of TLC with two developing solvents in the official method. But, this method is not quantitative. Instead, we employed HPLC using water-methanol (9 : 1) as the mobile phase. This procedure decreased interfering peaks, and the quantitation limit was 2 ug/mL of standard solution. 2-Mercaptoimidazoline was confirmed by GC-MS (5 ug/mL) and LC/MS (1 ug/mL) in the scan mode. For preparation of test solution, a soaking extraction method, in which 20 mL of methanol was added to the sample and allowed to stand overnight at about 40 degrees C, was used. This gave similar values to the Soxhlet extraction method (official method) and was more convenient. The results indicate that our procedure is suitable for analysis of 2-mercaptoimidazoline. When 2 mercaptoimidazoline is detected, it is confirmed by either GC/MS or LC/MS. PMID- 22450671 TI - [Aluminium content in foods with aluminium-containing food additives]. AB - The aluminium (Al) content of 105 samples, including bakery products made with baking powder, agricultural products and seafoods treated with alum, was investigated. The amounts of Al detected were as follows (limit of quantification: 0.01 mg/g): 0.01-0.37 mg/g in 26 of 57 bakery products, 0.22-0.57 mg/g in 3 of 6 powder mixes, 0.01-0.05 mg/g in all three agricultural products examined, 0.03-0.90 mg/g in 4 of 6 seafood samples, 0.01-0.03 mg/g in 3 of 11 samples of instant noodles, 0.04-0.14 mg/g in 3 of 4 samples of vermicelli, 0.01 mg/g in 1 of 16 soybean products, but none in soybeans. Amounts equivalent to the PTWI of a 16 kg infant were detected in two samples of bakery products, two samples of powder mixes and one sample of salted jellyfish, if each sample was taken once a week. These results suggest that certain foods, depending on the product and the intake, might exceed the PTWI of children, especially infants. PMID- 22450672 TI - [Validation study on a method for multiresidue analysis of pesticides in vegetables and fruits with supercritical fluid extraction]. AB - Supercritical fluid extraction (SFE) was applied to extraction of pesticides from vegetables and fruits. Residues were extracted from homogenized samples mixed with water-absorbent polymer with supercritical carbon dioxide in a stainless steel tube, followed by elution with acetone. Co-extractives were removed by means of mini-column clean-up. Measurement was performed by GC-MS/MS. Calibration was achieved by preparing matrix-matched calibration standards to counteract matrix effects. With the Japanese method validation guideline as a reference, the method was assessed in 5 agricultural products spiked with 334 pesticides at 0.01 and 0.1 ug/g. Compounds at each level were extracted from 2 samples on 5 separate days. The trueness of the method for 189 pesticides in all samples was 70-120%, and the repeatability and within-run reproducibility were also consistent with the guideline. The trueness of the method for the other 71 pesticides was in the range of 50-70%, though the repeatability and within-run reproducibility were satisfactory. This method is available as a multiresidue analysis method for vegetables and fruits. PMID- 22450673 TI - Activin B is produced early in antral follicular development and suppresses thecal androgen production. AB - Little is known about the role of activin B during folliculogenesis. This study investigated the expression levels of activin/inhibin subunits (betaA, betaB, and alpha), steroid enzyme, and gonadotrophin receptors in theca (TC) and granulosa cells (GC) by QPCR and activin A and B and inhibin A protein levels in follicular fluid (FF) of developing sheep follicles during estrus and anestrus. The effect of activin B on androgen production from primary TC cultures in vitro was also assessed. During folliculogenesis, in anestrus and estrus, FF activin B concentrations and thecal and GC activin betaB mRNA levels decreased as follicle diameter increased from 1-3 to >6 mm regardless of estrogenic status. Estrogenic preovulatory follicles had reduced concentrations of FF activins B and A, and TC and GCs expressed higher levels of activin betaA mRNA at 3-4 mm, and TCs more inhibin alpha mRNA at >4 mm stages of development compared with nonestrogenic follicles. Activin B decreased androstenedione production from primary TCs in vitro, an effect blocked by inhibin A. Thus, sheep follicles 1-3 mm in diameter contained high FF levels of activin B, which decreased as the follicle size increased, and, like activin A, suppressed thecal androgen production in vitro, an effect blocked by inhibin. Furthermore, the theca of large estrogenic follicles expressed high levels of inhibin alpha and activin betaA mRNA suggesting local thecal derived inhibin A production. This would inhibit the negative effects of thecal activins B and A ensuring maximum androgen production for enhanced estradiol production by the preovulatory follicle(s). PMID- 22450674 TI - Sperm transport and retention at the fertilization site is orchestrated by a chemical guidance and oviduct movement. AB - In mammals, only a few spermatozoa arrive at the fertilization site. During the last step in the journey to the egg, apart from their self-propulsion, spermatozoa may be assisted by oviduct movement and/or a guidance mechanism. The proportion of rabbit spermatozoa that arrive at the fertilization site was determined under in vivo conditions, in which either the ovulation products (secreting chemoattractants) and/or the oviduct movement (causing the displacement of the oviductal fluid) was inhibited. When only one of these components was inhibited, sperm transport to the fertilization site was partially reduced. However, when both the ovulation products and the oviduct movement were inhibited, almost no spermatozoa arrived at the fertilization site. The results suggest that spermatozoa are transported to and retained at the fertilization site by the combined action of a chemical guidance and the oviduct movement. A working model is proposed to explain how these two mechanisms may operate to transport spermatozoa to the fertilization site, probably as an evolutionary adaptation to maximize the chance of fertilizing an egg. PMID- 22450676 TI - The proximate determinants of educational homogamy: the effects of first marriage, marital dissolution, remarriage, and educational upgrading. AB - This paper adapts the population balancing equation to develop a framework for studying the proximate determinants of educational homogamy. Using data from the National Longitudinal Survey of Youth on a cohort of women born between 1957 and 1964, we decompose the odds of homogamy in prevailing marriages into four proximate determinants: (1) first marriages, (2) first and later marital dissolutions, (3) remarriages, and (4) educational attainment after marriage. The odds of homogamy among new first marriages are lower than among prevailing marriages, but not because of selective marital dissolution, remarriage, and educational attainment after marriage, as has been speculated. Prevailing marriages are more likely to be educationally homogamous than new first marriages because of the accumulation of homogamous first marriages in the stock of marriages. First marriages overwhelmingly account for the odds of homogamy in prevailing marriages in this cohort. Marital dissolutions, remarriages, and educational upgrades after marriage have relatively small and offsetting effects. Our results suggest that, despite the high prevalence of divorce, remarriage, and continued schooling after marriage in the United States, the key to understanding trends in educational homogamy lies primarily in variation in assortative mating into first marriage. PMID- 22450675 TI - The specialized roles of immature and mature dendritic cells in antigen cross presentation. AB - Exogenous antigen cross-presentation is integral to the stimulation of cytotoxic T-lymphocytes against viruses and tumors. Central to this process are dendritic cells (DCs), which specialize in cross-presentation. DCs may be considered to exist in two radically different states of activation, generally referred to as immature and mature. In each of these states, the cell has a series of separate and specialized abilities for the induction of T-cell immunity. In the immature state, the DC is adept in surveying the periphery, acquiring and storing antigen, but has a limited capacity for direct T-cell activation. During a brief and defined window of time following DC stimulation, nearly every aspect of antigen handling changes, as it transitions from an entity focused on protein preservation to one capable of efficient cross-presentation. It is this time period and the underlying molecular mechanisms active here, which form the core of our studies on cross-presentation. PMID- 22450677 TI - Relationship between wood color parameters measured by the CIELab system and extractive and phenol content in Acacia mangium and Vochysia guatemalensis from fast-growth plantations. AB - The heterogeneity of color distribution between sapwood and heartwood limits the market for wood from fast-growth plantations of tropical species. Wood color is associated with wood extractives contents. This study presents the relationship between wood color parameters measured by the CIELab color system and total amount of extractives and phenolic-type extractives in ethanol-toluene and hot water extracts of wood from two fast-growth plantation species. The results demonstrated that the difference in sapwood and hardwood color in Vochysia guatemalensis and Acacia mangium is caused by lower concentrations of extractives in sapwood of both species. Additionally, variations in total extractive and phenolic content have different effects on the color parameters (L*, a* and b*) of both species studied. In Vochysia guatemalensis wood, parameter L* decreases as total extractive and phenolic content increases; however, parameter a* increases as the content of extractives and phenols increases. In Acacia mangium, the amount of phenols showed no relationship with the color parameters. The ethanol-toluene total extractive content, however, shows a relationship with several color parameters. An increase in the content of total extractives in water and ethanol-toluene increases parameter a*, but decreases parameter L*. PMID- 22450678 TI - In vitro antimicrobial and antioxidant activities of ethanolic extract of lyophilized mycelium of Pleurotus ostreatus PQMZ91109. AB - The antioxidant and antimicrobial potential of the ethanolic extract of Pleurotus ostreatus PQMZ91109 mycelium was determined based on inorganic and organic nitrogen sources in the culture medium. The presence of ammonium sulfate resulted in a greater accumulation of bioactive compounds compared with the organic ones. This finding was also confirmed by the low values of the ascertained EC(50) and minimum inhibitory concentration (MICs). Among the organic sources, peptone followed by corn extract, led to a more important radical-scavenging activity. The extracts selectively inhibited the tested strains, mainly the two of the genus Candida, at an MIC value of 1.25 mg/mL. The antioxidant potential was evaluated by the inhibition capacity of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, beta-carotene-linoleic acid, which is the reducing power. In addition, the quantity of the compounds with antioxidant effects confirmed the data obtained, they being present in the extracts. PMID- 22450679 TI - The feasibility of enzyme targeted activation for amino acid/dipeptide monoester prodrugs of floxuridine; cathepsin D as a potential targeted enzyme. AB - The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5'-amino acid/dipeptide monoester floxuridine prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of prodrugs was evaluated. All prodrugs exhibited the range of 3.0 105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5'-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5'-O-L-phenylalanyl-L-tyrosylfloxuridine and 5'-O L-phenylalanyl-L-glycylfloxuridine compared to the other tested prodrugs. The wide range of growth inhibitory effect by floxuridine prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enzymes. In conclusion, it is feasible to design prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5'-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine prodrugs. PMID- 22450680 TI - Coupling of nanoporous chromium, aluminium-containing silicates with an ionic liquid for the transformation of glucose into 5-(hydroxymethyl)-2-furaldehyde. AB - Micro/mesoporous chromium, aluminium-containing silicates of the type TUD-1 (Al TUD-1, Cr-TUD-1, CrAl-TUD-1) and zeolite BEA, Cr-BEA, and related composites BEA/TUD-1 and Cr-BEA/TUD-1, were prepared, characterised, and tested as solid acids coupled with the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([bmim]Cl) as solvent, in the transformation of D-glucose into 5-(hydroxymethyl) 2-furaldehyde (Hmf), at 120 degrees C. The chromium-containing catalytic systems lead to considerably higher Hmf yields in comparison to the related systems without chromium. The IL is a favourable solvent for this target reaction (in terms of Hmf yields reached) compared to water or dimethylsulfoxide. A detailed study on the stabilities of the nanoporous solid acids in the IL medium is presented. PMID- 22450681 TI - Analysis of organic volatile flavor compounds in fermented stinky tofu using SPME with different fiber coatings. AB - The organic volatile flavor compounds in fermented stinky tofu (FST) were studied using SPME-GC/MS. A total of 39 volatile compounds were identified, including nine esters, seven alcohols, five alkenes, four sulfides, three heterocycles, three carboxylic acids, three ketones, two aldehydes, one phenol, one amine and one ether. These compounds were determined by MS, and conformed by comparison of the retention times of the separated constituents with those of authentic samples and by comparison of retention indexes (RIs) of separated constituents with the RIs reported in the literature. The predominant volatile compound in FST was indole, followed by dimethyl trisulfide, phenol, dimethyl disulfide and dimethyl tetrasulfide. In order to find a better extraction time, the extraction times was optimized for each type of SPME fiber; the results show that the best extraction time for Carboxen/PDMS is 60 min, for PDMS/DVB 30 min, for DVB/CAR/PDMS 60 min and for PDMS 75 min. Of the four fibers used in this work, Carboxen/PDMS is found to be the most suitable to extract the organic volatile flavor compounds in fermented stinky tofu. PMID- 22450682 TI - Extracts of Lycoris aurea induce apoptosis in murine sarcoma S180 cells. AB - Lycoris species have been known since long ago as a multi-utility ethnomedicinal herbal in China. It has been reported to exhibit a number of properties such as anticancer, neuroprotective, and antibacterial activities. In the present study, the anticancer efficacy of dichloromethane extracts of Lycoris aurea (DELA), was evaluated both in vivo and in vitro using murine sarcoma 180 cells. To evaluate the effects of DELA on apoptotic cell death, flow cytometry and Western blotting were performed. DELA demonstrated promising inhibition effects on sarcoma 180 cells in vitro and a 53.49% inhibitory rate on cancer cells in vivo. DELA treatment increased thymus indices and spleen indices in vivo, indicating that it reduced tumours, but did not damage the main immune organs. The DELA-evoked increase in apoptotic cell death was accompanied by occurrence of cleaved caspase 3 and decreases in the ratio of Bcl-2/Bax. Further purification and LCMS analysis showed DELA contained homolycorine, 2alpha-hydroxyoduline, oduline, hippeastrine, 2alpha-hydroxy-6-O- methyloduline, and 2alpha-methoxy-6-O-methyloduline. These results indicate that DELA exerted its anticancer effects, at least in part, by inducing cancer cell apoptosis and thus can be considered as a potential candidate agent for treatment of cancer. PMID- 22450683 TI - Xanthatin induces cell cycle arrest at G2/M checkpoint and apoptosis via disrupting NF-kappaB pathway in A549 non-small-cell lung cancer cells. AB - Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancer cells, yet little is known about its anticancer mechanism. In this study, we demonstrated that xanthatin had obvious dose-/time dependent cytotoxicity against the human non-small-cell lung cancer (NSCLC) cell line A549. Flow cytometry analysis showed xanthatin induced cell cycle arrest at G2/M phase. Xanthatin also had pro-apoptotic effects on A549 cells as evidenced by Hoechst 33258 staining and annexin V-FITC staining. Mechanistic data revealed that xanthatin downregulated Chk1, Chk2, and phosphorylation of CDC2, which contributed to the cell cycle arrest. Xathatin also increased total p53 protein levels, decreased Bcl-2/Bax ratio and expression of the downstream factors procaspase-9 and procaspase-3, which triggered the intrinsic apoptosis pathway. Furthermore, xanthatin blocked phosphorylation of NF-kappaB (p65) and IkappaBa, which might also contribute to its pro-apoptotic effects on A549 cells. Xanthatin also inhibited TNFa induced NF-kappaB (p65) translocation. We conclude that xanthatin displays significant antitumor effects through cell cycle arrest and apoptosis induction in A549 cells. These effects were associated with intrinsic apoptosis pathway and disrupted NF-kappaB signaling. These results suggested that xanthatin may have therapeutic potential against NSCLC. PMID- 22450684 TI - Determination of rutin in cigarette tobacco, filters, mainstream smoke and burned ash of different branded cigarettes by high performance liquid chromatography. AB - Tobacco consists of at least 3,800 chemical constituents. Among them, rutin is an important polyphenolic secondary metabolite in tobacco, which has positive actions such as antiallergic, anti-inflammatory and vasoactive, antitumor, antibacterial, antiviral and anti-protozoal properties. A high performance liquid chromatography method was used to analyze rutin in tobacco and filters, mainstream smoke, and burned ash of ten varieties of cigarettes made in China. The chromatographic analysis was performed on a Hypersil ODS2 column with a gradient elution of acetonitrile and water at a flow rate of 1.0 mL/min. Detection was carried out at 350 nm using a photodiode array detector. The calibration curves for the determination of analytes showed good linearity over the investigated ranges (R2 > 0.9998). Precision and reproducibility were evaluated by six replicated analyses, and the R.S.D. values were less than 0.59% and 1.53%. The recoveries were between 98.47 and 100.84%. Under the optimized conditions, namely 45 mL/g of solvent to solid ratio, 30 min of extraction time and 200 W of ultrasound power, the concentrations of rutin in tobacco and filter, mainstream smoke, burned ash of different brands cigarettes were 10.20-63.98, 0.10-0.32, 0.06-0.16 and 0 MUg/per cigarette, respectively. PMID- 22450685 TI - Enhancement of palmarumycin C12 and C13 production in liquid culture of the endophytic fungus Berkleasmium sp. Dzf12 by oligosaccharides from its host plant Dioscorea zingiberensis. AB - Three crude oligosaccharides were respectively prepared by acid hydrolysis of three polysaccharides, which were water-extracted polysaccharide (WEP), sodium hydroxide-extracted polysaccharide (SEP) and acid-extracted polysaccharide (AEP) from the rhizomes of Dioscorea zingiberensis. Among the three oligosaccharides, the crude oligosaccharide prepared by acid hydrolysis of WEP was found to be the most efficient elicitor to enhance the production of palmarumycins C(12) and C(13) in liquid culture of endophytic fungus Berkleasmium sp. Dzf12. When OW was applied to the medium at 300 mg/L on day 3 of culture, the maximal yields of palmarumycin C(12) (87.96 mg/L) and palmarumycin C(13) (422.28 mg/L) were achieved on day 15 of culture, which were 9.83 and 3.24-fold in comparison with those (8.95 and 130.43 mg/L) of control, respectively. The results indicate that addition of the oligosaccharides from the host plant D. zingiberensis should be an effective strategy for enhancing production of palmarumycins C(12) and C(13) in liquid culture of endophytic fungus Berkleasmium sp. Dzf12. PMID- 22450686 TI - Not being able to see the muscle for the fat. PMID- 22450687 TI - Extracellular HIV-1 Tat induces human beta-defensin-2 production via NF-kappaB/AP 1 dependent pathways in human B cells. AB - Defensins, a family of antimicrobial peptides, are one of the first lines of host defense. Human beta-defensins (hBD) such as hBD-2 and -3 have anti-HIV activity. Previous studies have shown that HIV-1 virion can induce the expression of hBD, although the exact components of HIV-1 virion that are responsible for hBD expression have not yet been elucidated. In this study, we examined the effect of HIV-1 Tat on the expression of hBD in B cells. Stimulation of B cells with HIV-1 Tat protein significantly increased the mRNA and protein levels of hBD-2. HIV-1 Tat also induced the activation of a reporter gene for hBD-2 in a dose-dependent manner in B cells. Pretreatment of B cells with a JNK inhibitor suppressed HIV-1 Tat-induced hBD-2 expression. Pretreatment of B cells with AP-1 inhibitors or NF kappaB inhibitors led to a decrease in HIV-1 Tat-induced protein and mRNA expression of hBD-2. Taken together, our results indicate that HIV-1 Tat can up regulate the expression of hBD-2 via JNK-NF-kappaB/AP-1-dependent pathways in human B cells. PMID- 22450688 TI - Prostaglandin E2 blocks menadione-induced apoptosis through the Ras/Raf/Erk signaling pathway in promonocytic leukemia cell lines. AB - Altered oxidative stress has long been observed in cancer cells, and this biochemical property of cancer cells represents a specific vulnerability that can be exploited for therapeutic benefit. The major role of an elevated oxidative stress for the efficacy of molecular targeted drugs is under investigation. Menadione is considered an attractive model for the study of oxidative stress, which can induce apoptosis in human leukemia HL-60 cell lines. Prostaglandin E(2) (PGE(2)) via its receptors not only promotes cell survival but also reverses apoptosis and promotes cancer progression. Here, we present evidence for the biological role of PGE(2) as a protective agent of oxidative stress-induced apoptosis in monocytic cells. Pretreatment of HL-60 cells with PGE(2) markedly ameliorated the menadione-induced apoptosis and inhibited the degradation of PARP and lamin B. The EP(2) receptor antagonist AH6809 abrogated the inhibitory effect of PGE(2), suggesting the role of the EP(2)/cAMP system. The PKA inhibitor H89 also reversed apoptosis and decreased the PKA activity that was elevated 10-fold by PGE(2). The treatment of HL-60 cells with NAC or zinc chloride showed a similar protective effect as with PGE(2) on menadione-treated cells. Furthermore, PGE(2) activated the Ras/Raf/MEK pathway, which in turn initiated ERK activation, and ultimately protected menadione-induced apoptosis. These results imply that PGE(2) via cell survival pathways may protect oxidative stress-induced apoptosis in monocytic cells. This study warrants further pre-clinical investigation as well as application towards leukemia clinics. PMID- 22450689 TI - Identification of tobacco proteins associated with the stem-loop 1 RNAs of Potato virus X. AB - Potato virus X (PVX) contains five viral proteins as well as cis-acting elements like stem-loop 1 (SL1) RNAs at the 5' region. SL1 RNAs are involved in PVX RNA replication, encapsidation, translation, and cell-to-cell movement. In this study, we performed two-dimensional electrophoresis Northwestern blot analysis and matrix-assisted laser desorption ionization time of flight mass spectrometry and identified 24 tobacco proteins that interact with SL1 RNAs. Interestingly, one-third of the identified host proteins have been shown to interact with many plant viral proteins. In addition, we demonstrated that PVX capsid protein can bind to both SL1(+/-) RNAs. We further selected three Nicotiana benthamiana proteins including NbMPB2Cb, NbMBF1, and NbCPIP2a, to confirm results of Northwestern blot analysis. Electrophoretic mobility shift assay showed that NbMPB2Cb and NbMBF1 bind to both SL1(+/-) RNAs in vitro. In contrast, NbCPIP2a interacts only SL1(+) RNA. Taken together, we provide a list of host proteins interacting with PVX SL1 RNAs, which would be good candidates for the study of viral RNA-host protein interaction. PMID- 22450690 TI - Monomeric and dimeric models of ERK2 in conjunction with studies on cellular localization, nuclear translocation, and in vitro analysis. AB - Extracellular signal-regulated protein kinase 2 (ERK2) plays many vital roles in cellular signal regulation. Phosphorylation of ERK2 leads to propagation and execution of various extracellular stimuli, which influence cellular responses to stress. The final response of the ERK2 signaling pathway is determined by localization and duration of active ERK2 at specific target cell compartments through protein-protein interactions of ERK2 with various cytoplasmic and nuclear substrates, scaffold proteins, and anchoring counterparts. In this respect, dimerization of phosphorylated ERK2 has been suggested to be a part of crucial regulating mechanism in various protein-protein interactions. After the report of putative dimeric structure of active ERK2 (Canagarajah et al., 1997), dimeric model was employed to explain many in vivo and in vitro experimental results. But more recently, many reports have been presented questioning the validity of dimer hypothesis of active ERK2. In this review, we summarize the various in vitro and in vivo studies concerning the Monomeric or the dimeric forms of ERK2 and the validity of the dimer hypothesis. PMID- 22450691 TI - Compartmentalization of vertebrate optic neuroephithelium: external cues and transcription factors. AB - The vertebrate eye is a laterally extended structure of the forebrain. It develops through a series of events, including specification and regionalization of the anterior neural plate, evagination of the optic vesicle (OV), and development of three distinct optic structures: the neural retina (NR), optic stalk (OS), and retinal pigment epithelium (RPE). Various external signals that act on the optic neuroepithelium in a spatial- and temporal-specific manner control the fates of OV subdomains by inducing localized expression of key transcription factors. Investigating the mechanisms underlying compartmentalization of these distinct optic neuroepithelium-derived tissues is therefore not only important from the standpoint of accounting for vertebrate eye morphogenesis, it is also helpful for understanding the fundamental basis of fate determination of other neuroectoderm- derived tissues. This review focuses on the molecular signatures of OV subdomains and the external factors that direct the development of tissues originating from the OV. PMID- 22450692 TI - On the nondifferential misclassification of a binary confounder. AB - Consider a study with binary exposure, outcome, and confounder, where the confounder is nondifferentially misclassified. Epidemiologists have long accepted the unproven but oft-cited result that, if the confounder is binary, then odds ratios, risk ratios, and risk differences that control for the mismeasured confounder will lie between the crude and the true measures. In this paper, we provide an analytic proof of the result in the absence of a qualitative interaction between treatment and confounder, and we demonstrate via counterexample that the result need not hold when there is such a qualitative interaction. We also present an analytic proof of the result for the effect of treatment among the treated and describe extensions to measures conditional on or standardized over other covariates. PMID- 22450693 TI - Premature birth and age at onset of puberty. AB - BACKGROUND: Premature birth is associated with poor metabolic health in both sexes, potentially via earlier pubertal timing. METHODS: We examined the associations of gestational age and premature birth (< 37 weeks gestation) with age at onset of puberty (Tanner stage II for breast or genitalia development). We used interval-censored survival analyses in 3963 boys and 3403 girls (93% follow up) in a population-representative Chinese birth cohort, "Children of 1997," comprising 88% of births in Hong Kong in April and May 1997. We also examined whether the associations varied with sex or with height or body mass index (BMI) at 7 years. RESULTS: Premature girls reached puberty about 4 months later than girls with >= 41 weeks' gestation (time ratio = 1.04 [95% confidence interval = 1.01-1.06]), adjusted for mother' age of menarche, mother's place of birth, and smoking during pregnancy. Gestational age was not associated with onset of puberty in boys (test for interaction by sex, P < 0.01). None of these associations was altered by adjustment for socioeconomic position or varied with childhood height or BMI. CONCLUSIONS: Premature birth was not related to earlier onset of puberty; instead, premature girls had later onset of puberty. Thus, the association between premature birth and subsequent cardiovascular risk is probably not mediated through the timing of pubertal onset. It is unclear whether onset, duration, or tempo of puberty is more relevant to the detrimental consequences of early puberty. Further studies investigating intrauterine, infant, and childhood influences on the duration and tempo of puberty may help unravel the early origins of cardiovascular diseases. PMID- 22450694 TI - PM mass concentration and PM oxidative potential in relation to carotid intima media thickness. AB - BACKGROUND: There is limited evidence on whether particulate matter (PM) can augment the progression of atherosclerosis; furthermore, the specific attributes of PM responsible for health effects are unclear. We developed models to predict exposure to PM <10 MUm (PM10) and also to predict a measure of oxidative potential (the capacity of particles to induce oxidative damage). Our objectives were (1) to estimate the association between PM10 and carotid intima-media thickness, a measure of subclinical atherosclerosis, and (2) to compare this association with that of PM10 weighted by its oxidative potential (PM10*OP). METHODS: Analysis was based on 2348 participants of the Whitehall II cohort of British civil servants who had intima-media thickness measured between 2003 and 2005 and lived in Greater London. Weekly PM10 and PM10*OP were predicted at each participant's residence. Primary exposure metrics were defined as PM10 and PM10*OP averaged over the year before scan. We estimated associations between exposure metrics and intima-media thickness using generalized linear regression models. RESULTS: An interquartile range increase (5.2 MUgm(-3)) in PM10 was associated with a 5.0% (95% confidence interval = 1.9% to 8.3%) increase in intima-media thickness after covariate adjustment. The association for an interquartile range change in PM10*OP (1.5 m(-3)) was weaker: 1.2% (0.2% to 2.2%). CONCLUSIONS: These findings support a relationship between PM exposure and atherosclerosis. PM weighted by this particular measure of oxidative potential was not more predictive of the extent of atherosclerosis than PM mass concentration. PMID- 22450695 TI - Completion potentials of sufficient component causes. AB - Many epidemiologists are familiar with Rothman's sufficient component cause model. In this paper, I propose a new index for this model, the completion potential index I show that, with proper assumptions (monotonicity, independent competing causes, proportional hazards), completion potentials for various classes of sufficient causes are estimable from routine epidemiologic data (cohort, case-control or time-to-event data). I discuss the advantage of the completion potential index over indices of rate ratio, rate difference, causal pie weight, population attributable fraction, and attributable fraction within the exposed population. Hypothetical and real data examples are used. The completion potential index proposed here allows better characterization of complex interactive effects of multiple monotonic risk factors. PMID- 22450696 TI - Imaging the molecular channel in acetaldehyde photodissociation: roaming and transition state mechanisms. AB - The roaming dynamics in the photodissociation of acetaldehyde is studied through the first absorption band, in the wavelength interval ranging from 230 nm to 325 nm. Using a combination of the velocity-map imaging technique and rotational resonance enhanced multiphoton ionization (REMPI) spectroscopy of the CO fragment, the branching ratio between the canonical transition state and roaming dissociation mechanisms is obtained at each of the photolysis wavelengths studied. Upon one photon absorption, the molecule is excited to the first singlet excited S(1) state, which, depending on the excitation wavelength, either converts back to highly vibrationally excited ground S(0) state or undergoes intersystem crossing to the first excited triplet T(1) state, from where the molecule can dissociate over two main channels: the radical (CH(3) + HCO) and the molecular (CO + CH(4)) channels. Three dynamical regions are characterized: in the red edge of the absorption band, at excitation energies below the T(1) barrier, the ratio of the roaming dissociation channel increases, largely surpassing the transition state contribution. As the excitation wavelength is increased, the roaming propensity decreases reaching a minimum at wavelengths ~308 nm. Towards the blue edge, at 230 nm, an upper limit of ~50% has been estimated for the contribution of the roaming channel. The experimental results are interpreted in terms of the interaction between the different potential energy surfaces involved by means of ab initio stationary points and intrinsic reaction coordinate paths calculations. PMID- 22450697 TI - Rational use of oxygen in medical disease and anesthesia. AB - PURPOSE OF REVIEW: Supplemental oxygen is often administered during anesthesia and in critical illness to treat hypoxia, but high oxygen concentrations are also given for a number of other reasons such as prevention of surgical site infection (SSI). The decision to use supplemental oxygen is, however, controversial, because of large heterogeneity in the reported results and emerging reports of side-effects. The aim of this article is to review the recent findings regarding benefits and harms of oxygen therapy in anesthesia and acute medical conditions. RECENT FINDINGS: Large randomized trials have not found significant reductions in SSI with 80% oxygen during and after abdominal surgery and cesarean section. There is no documented benefit of hyperbaric oxygen treatment for acute ischemic stroke, and there is emerging data to suggest increased mortality with normobaric supplemental oxygen for myocardial infarction without heart failure. Survival and neurologic outcome seem to be adversely affected by hyperoxia in patients with return of spontaneous circulation after cardiac arrest. SUMMARY: The benefits of supplemental oxygen are not yet confirmed, and new findings suggest that potential side-effects should be considered if the inspired oxygen concentration is increased above what is needed to maintain normal arterial oxygen saturation. PMID- 22450698 TI - Anesthesia in patients with cancer disorders. AB - PURPOSE OF REVIEW: Along with the increasing population of elderly people in developed countries, anesthesiologists have increasing opportunities to anesthetize cancer patients in their routine work. However, no guideline of anesthesia procedures for cancer patients is available even though guidelines of operative procedures have been formulated for different types of cancer. This review provides recent findings related to the optimal choice of anesthetics and adequate anesthesia management for cancer patients. RECENT FINDINGS: The intrinsic weapon fighting cancer cells is competent immune cells, particularly CD4+ T helper 1-type cells, CD8+ cytotoxic T cells, and natural killer cells. However, surgical inflammation, some anesthetics, and inadvertent anesthesia management suppress these effector cells and induce suppressive immune cells, which render cancer patients susceptible to tumor recurrence and metastasis after surgery. SUMMARY: Accumulated basic and clinical data suggest that total intravenous anesthesia with propofol, cyclooxygenase antagonists, and regional anesthesia can decrease negative consequences associated with perioperative immunosuppression. Volatile anesthesia, systemic morphine administration, unnecessary blood transfusions, intraoperative hypoxia, hypotension, hypothermia, and hyperglycemia should be avoided. PMID- 22450699 TI - Anesthetic considerations for the patient with liver disease. AB - PURPOSE OF REVIEW: An increasing number of patients requiring surgery are presenting with chronic or end stage liver disease. The management of these patients demands anesthesiologists with in-depth knowledge of the consequences of hepatic dysfunction, the effects on other organs, the risk of surgery, and the impact of anesthesia. RECENT FINDINGS: Chronic or end stage liver disease is associated with an increased risk of perioperative morbidity and mortality. It is essential to preoperatively assess possible hepatic encephalopathy, pleural effusions, hepatopulmonary syndrome, hepatopulmonary hypertension, hepatorenal syndrome, cirrhotic cardiomyopathy, and coagulation disorders. The application of two scoring systems, that is, Child-Turcotte-Pugh and model for end stage liver disease, helps to estimate the risk of surgery. The use of propofol is superior to benzodiazepines as intravenous narcotics. Although enflurane and halothane are discouraged for maintenance of anesthesia, all modern volatile anesthetics appear comparable with respect to outcome. Fentanyl, sufentanil, and remifentanil as opioids and cis-atracurium for relaxation may be the best choices in liver insufficency. Regional anesthesia is valuable for postoperative pain management. SUMMARY: Current studies have employed different anesthetic approaches in the preoperative and intraoperative management in order to improve outcomes of patients with liver disease. PMID- 22450700 TI - Effect of 15-lipoxygenase metabolites on angiogenesis: 15(S)-HPETE is angiostatic and 15(S)-HETE is angiogenic. AB - OBJECTIVE: 15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE] and 15(S) hydroperoxyeicosatetraenoic acid [15(S)-HPETE] are the products of arachidonic acid formed in the 15-lipoxygenase pathway. They have opposing effects on the inflammatory process. The present study was designed to examine the role of these metabolites on angiogenesis, which is critically associated with inflammatory conditions. METHODS: Chick chorio-allantoic membrane (CAM), rat aortic rings and human umbilical vein endothelial cells (HUVECs) in culture were used to study the effect of 15(S)-HETE and 15(S)-HPETE on angiogenesis. Biochemical markers of angiogenesis were analysed by ELISA. RESULTS: 15(S)-HETE increased vessel density in chick CAM, induced sprouting in rat aortic rings and increased endothelial cell-cell contact and formation of tubular network-like structures in HUVECs. Furthermore, it up-regulated the expression of CD31, E-selectin and vascular endothelial growth factor (VEGF) in HUVECs, indicating its pro-angiogenic effect. 15(S)-HPETE, on the other hand, decreased vessel density in chick CAM, down regulated the expression of E-selectin (<35 %), VEGF (<90 %) and CD31 (<50 %) and did not produce sprouting in aortic rings, suggesting an anti-angiogenic property. 15(S)-HETE-mediated up-regulation of CD 31 and VEGF was reversed by treatment with 15(S)-HPETE. CONCLUSION: These results indicate the divergent effects of hydroxy and hydroperoxy products of 15-LOX on angiogenesis, highlighting the role of these products in the co-dependence of inflammation and angiogenesis. PMID- 22450701 TI - A doubly 2,6-pyridylene-bridged porphyrin-perylene-porphyrin triad. AB - A doubly 2,6-pyridylene-bridged porphyrin-perylene-porphyrin triad was synthesized via Suzuki-Miyaura cross coupling reaction, which captures a tetrakis(3-pyridyl)porphyrin guest in a 2 : 1 manner to form a supramolecular complex that undergoes photo-induced electron transfer. PMID- 22450702 TI - Brief report: the relationship between visual acuity, the embedded figures test and systemizing in autism spectrum disorders. AB - Enhanced performance upon the Embedded Figures Test (EFT) in individuals with autism spectrum disorder (ASD) has informed psychological theories of the non social aspects that characterise ASD. The Extreme Male Brain theory of autism proposes that enhanced visual acuity underpins greater attention to detail (assessed by the EFT) which is a prerequisite for Systemizing. To date, however, no study has empirically examined these relationships. 13 males with ASD and 13 male controls were assessed upon tasks argued to reflect these levels of processing. The ASD group were found to have significantly greater visual acuity, EFT performance and Systemizing ability than the control group. However, regression analysis revealed that the strongest relationship was between visual acuity and EFT performance. PMID- 22450703 TI - "Who said that?" Matching of low- and high-intensity emotional prosody to facial expressions by adolescents with ASD. AB - Data on emotion processing by individuals with ASD suggest both intact abilities and significant deficits. Signal intensity may be a contributing factor to this discrepancy. We presented low- and high-intensity emotional stimuli in a face voice matching task to 22 adolescents with ASD and 22 typically developing (TD) peers. Participants heard semantically neutral sentences with happy, surprised, angry, and sad prosody presented at two intensity levels (low, high) and matched them to emotional faces. The facial expression choice was either across- or within-valence. Both groups were less accurate for low-intensity emotions, but the ASD participants' accuracy levels dropped off more sharply. ASD participants were significantly less accurate than their TD peers for trials involving low intensity emotions and within-valence face contrasts. PMID- 22450704 TI - Transplantation of adipose tissue-derived stem cells overexpressing heme oxygenase-1 improves functions and remodeling of infarcted myocardium in rabbits. AB - Adipose tissue-derived stem cells (ADSCs) are a promising source of autologous stem cells that are used for regeneration and repair of infracted heart. However, the efficiency of their transplantation is under debate. One of the possible reasons for marginal improvement in ADSCs transplantation is the significant cell death rate of implanted cells after being grafted into injured heart. Therefore, overcoming the poor survival rate of implanted cells may improve stem cell therapy. Due to limited improvement concerning direct stem cell therapy, gene-transfer methods are used to enhance cellular cardiomyoplasty efficacy. Heme oxygenase-1 (HO-1) can provide various types of cells with protection against oxidative injury and apoptosis. However, exact effects of autologous ADSCs combined with HO-1 on cardiac performance remains unknown. In this study, rabbits were treated with ADSCs transduced with HO-1 (HO-1-ADSCs), treated with non-transduced ADSCs, or injected with phosphate buffered saline 14 days after experimental myocardial infarction was induced, when autologous ADSCs were obtained simultaneously. Four weeks after injection, echocardiography showed significant improvements for cardiac functions and left ventricular dimensions in HO-1-ADSCs-treated animals. Structural consequences of transplantation were determined by detailed histological analysis, which showed differentiation of HO-1-ADSCs to cardiomyocyte-like tissues and lumen-like structure organizations. Apart from improvement in angiogenesis and scar areas, more connexin 43-positive gap junction and greater tyrosine hydroxylase-positive cardiac sympathetic nerves sprouting were observed in the HO-1-ADSCs-treated group compared with ADSCs group. These data suggest that the transplantation of autologous ADSCs combined with HO-1 transduction is a feasible and efficacious method for improving infarcted myocardium. PMID- 22450705 TI - Structural features and cytotoxicity of amyloid oligomers: implications in Alzheimer's disease and other diseases with amyloid deposits. AB - Amyloid diseases display the presence, in targeted tissues and organs, of fibrillar deposits of specific peptides or proteins. Increasing efforts are presently spent in investigating the structural features and the structure toxicity relation of the soluble oligomeric precursors arising in the path of fibrillization as well as the importance of surfaces as triggers of protein misfolding and aggregation and as possible responsible for amyloid polymorphism. Presently, it is recognized that the unstable, heterogeneous pre-fibrillar aggregates are the main responsible for amyloid toxicity. Conversely, mature fibrils are considered stable, harmless reservoirs of toxic species, although direct fibril toxicity has been reported. Recent studies show that mature fibrils grown at various conditions can display different structural features, stabilities and tendency to disassemble with leak of toxic oligomers. Fibril polymorphism can result from protein aggregation at differing conditions populating misfolded monomers and oligomers with distinct conformational characteristics. Recent research has started to unravel oligomer structural and biophysical features and their relation to cytotoxicity. Increasing information supports the notion that oligomer-membrane interaction, disruption of membrane integrity and cell impairment results from both oligomer and membrane biophysical features; accordingly, the formation of the oligomer-membrane complex, often the first step of amyloid toxicity, can be the result of the interplay of these events. This view can help explaining the variable vulnerability of different cell types to the same amyloids and the lack of relation between amyloid load and severity of clinical symptoms; it also stresses the importance, for cell/tissue impairment, of the presence of fibrils conformers of reduced stability as a possible source of oligomers resulting from leakage possibly favored by the interaction with suitable macromolecular/lipid surfaces or by other environmental conditions. PMID- 22450706 TI - Cerebral markers of the serotonergic system in rat models of obesity and after Roux-en-Y gastric bypass. AB - Food intake and body weight are regulated by a complex system of neural and hormonal signals, of which the anorexigenic neurotransmitter serotonin (5 hydroxytryptamine or 5-HT) is central. In this study, rat models of obesity and weight loss intervention were compared with regard to several 5-HT markers. Using receptor autoradiography, brain regional-densities of the serotonin transporter (SERT) and the 5-HT(2A) and 5-HT(4) receptors were measured in (i) selectively bred polygenic diet-induced obese (pgDIO) rats, (ii) outbred DIO rats, and (iii) Roux-en-Y gastric bypass (RYGB)-operated rats. pgDIO rats had higher 5-HT(4) and 5-HT(2A) receptor binding and lower SERT binding when compared to polygenic diet resistant (pgDR) rats. The most pronounced difference between pgDIO and pgDR rats was observed in the nucleus accumbens shell (NAcS), a brain region regulating reward aspects of feeding. No differences were found in the 5-HT markers between DIO rats, chow-fed control rats, and DIO rats experiencing a weight loss. The 5 HT markers were also similar in RYGB and sham-operated rats except for a downregulation of 5-HT(2A) receptors in the NAcS. The higher receptor and lower SERT binding in pgDIO as compared to pgDR rats corresponds to what is reported in overweight humans and suggests that the dysfunctions of the 5-HT system associated with overeating or propensity to become overweight are polygenically determined. Our results support that the obesity-prone rat model has high translational value and suggests that susceptibility to develop obesity is associated with changed 5-HT tone in the brain that may also regulate hedonic aspects of feeding. PMID- 22450707 TI - Drugs for tuberculosis. AB - RECOMMENDATIONS: The standard treatment for latent tuberculosis is nine months of isoniazid taken daily, or twice weekly under direct observation by a healthcare worker. Taking isoniazid and rifapentine once weekly for 12 weeks under direct observation is an alternative for patients >12 years old. Initial therapy for patients with active or suspected tuberculosis should include isoniazid, rifampin,pyrazinamide and ethambutol until susceptibility is known. In patients with drug-susceptible pulmonary tuberculosis, the continuation phase of treatment should be a combination of isoniazid and either rifampin or rifapentine, taken for 4 or 7 months depending on risk factors. Confirmed multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis should be treated with directly observed therapy in collaboration with a clinician familiar with management of these conditions. Treatment must include at least 4 drugs to which the organism is susceptible; the duration of therapy should usually be 18-24 months. Directly observed therapy by a healthcare worker should be offered to all patients with active tuberculosis to minimize treatment failure, relapse and the emergence of drug resistance. PMID- 22450708 TI - Sleep-related migraine occurrence increases with aging. AB - A preferential occurrence of attacks at night-time or during early morning is documented in migraine without aura, suggesting a relationship between migraine and sleep and an impairment of circadian rhythms. The objective of this study was to verify the occurrence of sleep-related migraine in a large sample of migraineurs divided in different age groups and to evaluate the possible role of physiological variables (i.e., aging, gender) and comorbidities (i.e., psychiatric diseases). 734 patients (519 women and 215 males), aged 21-70 years, fulfilling IHS criteria (2004) for migraine without aura, were enrolled. The population was divided into five groups according to decades of life and it was evaluated the percentage of sleep-related migraine (at least 75% migraine attacks occurring during night sleep and/or upon awakening) in the different age groups. Headache clinical diary, Pittsburgh Sleep Quality Index and Beck Depression Inventory were also used. The preferential emergence of attacks during night sleep and/or upon awakening progressively increased with aging, without gender predilection; the percentage of patients with sleep-related migraine was: 16% between 20 and 30 years, 27% between 31 and 40 years, 38% between 41 and 50 years, 45% between 51 and 60 years, and 58% between 61 and 70 years, respectively. Poor sleep quality and depression did not account for night-time and/or awakening migraine collocation. These data suggest the main role of aging in order to favor nocturnal/early morning emergence of migraine without aura and support the hypothesis of an involvement of impaired chronobiological mechanisms and sleep regulation. PMID- 22450709 TI - Evaluation of serum oxidant/antioxidant balance in multiple sclerosis. AB - The total oxidative status (TOS)/total anti-oxidative status (TAS) ratio can provide information on an individual's absolute oxidative stress index (OSI). We investigated the alterations in the oxidant-antioxidant balance by measuring the oxidant parameters OSI, TOS, and malondialdehyde (MDA) together with the antioxidant parameters such as TAS, and superoxide dismutase (SOD) in patients with relapsing remitting multiple sclerosis (MS). To our knowledge, this is the first study to evaluate OSI in patients with relapsing remitting MS. 35 ambulatory patients with relapsing-remitting MS (35.8 +/- 8.7 years) and 32 age- and activity-matched healthy control subjects (35.1 +/- 3.7 years) that participated in the study. Serum TAS and TOS levels were determined using new automated methods. MS patients had higher concentrations of MDA (151.5 +/- 51.1 vs. 111.3 +/- 27.4 nmol/g protein, respectively; p < 0.001), TOS (148.1 +/- 162.5 vs. 48.3 +/- 46.4 mmol H(2)O(2) Equiv./g protein, respectively; p = 0.002), OSI (21124 +/- 32543 vs. 5294 +/- 5562, respectively; p = 0.008), and SOD (4.5 +/- 0.7 vs. 3.4 +/- 0.6 U/L, respectively; p < 0.001) compared with healthy controls. On the other hand, MS patients had lower concentrations of NO (12.3 +/- 6.9 vs. 17.4 +/- 2.5 MUmol/g protein, respectively; p < 0.001) and TAS (0.82 +/- 0.27 vs. 0.26 +/- 0.15, respectively; p = 0.011) compared with healthy controls. In conclusion, these findings indicate that the oxidative stress plays an important role in the pathogenesis of MS. PMID- 22450710 TI - Relationships between edema degree and clinical and biochemical parameters in posterior reversible encephalopathy syndrome: a preliminary study. AB - The objective of the study was to investigate the associations between the degree of edema with the clinical and biochemical parameters such as serum lactate dehydrogenase (LDH), albumin (ALB) in posterior reversible encephalopathy syndrome (PRES) patients. Forty-nine patients with typical clinical symptoms and characteristic MR imaging findings of PRES were included in this study. Lactate dehydrogenase and ALB were analyzed with the immunoluminometric assays. Fluid attenuated inversion recovery images were used to evaluate the distribution of the extent or severity of vasogenic edema by two observers. Correlation analysis between the scores of brain edema and the blood pressures, clinical conditions and biochemical parameters was performed. No significant difference of brain edema score was found between patients with eclampsia, chronic renal failure and other clinical condition (P > 0.05). Both mean arterial pressures and LDH level were moderately correlated with the scores of brain edema distribution (Spearman's rho test, r = 0.405 and 0.497, respectively, P < 0.01). Serum ALB level was not correlated with the scores of brain edema distribution (P > 0.05). Larger and more diffuse lesions may be predicted by higher LDH level and blood pressure. The overall severity of the systemic process might be predicted by the degree of edema expression in PRES. PMID- 22450711 TI - Self-tolerance in multiple sclerosis. AB - During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naive regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons beta and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56(bright) natural killer cells. PMID- 22450712 TI - E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma. AB - E2F-1 is a transcription factor involved in DNA synthesis and repair, cell proliferation, and apoptosis. Hyposphorylated pRb represses E2F-1 action in early G1 phase, while in late G1, pRb hyperphosphorylation leads to E2F-1 release and activation. In vitro studies have shown that E2F-1 may act either as oncogene or as tumor suppressor gene. We evaluated immunohistochemical expression of E2F-1 protein in chronic viral liver disease and hepatocellular carcinoma (HCC) and correlated this with clinicopathological parameters, cell proliferation, apoptosis, and the expression of E2F-1-regulators, pRb, and phospho-pRb (Ser795). In liver biopsies from 30 patients with chronic viral hepatitis, including 22 with cirrhosis without HCC, and 57 with cirrhosis with HCC, E2F-1 expression was assessed by immunohistochemistry. In chronic hepatitis and cirrhosis, hepatocytes and cholangiocytes demonstrated mild cytoplasmic and/or nuclear membrane E2F-1 immunostaining. In contrast, all HCC (100 %) showed strong nuclear E2F-1 immunostaining, with or without membrane accentuation, while a minority demonstrated additional moderate cytoplasmic immunostaining. Abnormally low pRb and phospho-pRb expression was seen in 70 % and 67.9 % of HCC, respectively. In HCC, nuclear E2F-1 expression was inversely correlated with phospho-pRb expression (p = 0.001) and positively related to tumor apoptotic index (p = 0.025). No significant correlation was found between E2F-1 expression and patient demographics, HCC etiology, tumor grade, pRb, p53 expression, or cell proliferation. In conclusion, we show that the increased expression of E2F-1 protein in human HCC is correlated with enhanced tumor cell apoptosis supporting a pro-apoptotic role of E2F-1 in human HCC. PMID- 22450713 TI - Lysosomal delivery of therapeutic enzymes in cell models of Fabry disease. AB - The success of enzymatic replacement in Gaucher disease has stimulated development of targeted protein replacement for other lysosomal disorders, including Anderson-Fabry disease, which causes fatal cardiac, cerebrovascular and renal injury: deficiency of lysosomal alpha-Galactosidase A induces accumulation of glycosphingolipids. Endothelial cell storage was the primary endpoint in a clinical trial that led to market authorization. Two alpha-Galactosidase A preparations are licensed worldwide, but fatal outcomes persist, with storage remaining in many tissues. We compare mechanisms of uptake of alpha Galactosidase A into cells relevant to Fabry disease, in order to investigate if the enzyme is targeted to the lysosomes in a mannose-6-phosphate receptor dependent fashion, as generally believed. alpha -Galactosidase A uptake was examined in fibroblasts, four different endothelial cell models, and hepatic cells in vitro. Uptake of europium-labeled human alpha -Galactosidase A was measured by time-resolved fluorescence. Ligand-specific uptake was quantified in inhibitor studies. Targeting to the lysosome was determined by precipitation and by confocal microscopy. The quantity and location of cation-independent mannose-6 phosphate receptors in the different cell models were investigated using confocal microscopy. Uptake and delivery of alpha -Galactosidase A to lysosomes in fibroblasts is mediated by the canonical mannose-6-phosphate receptor pathway, but in endothelial cells in vitro this mechanism does not operate. Moreover, this observation is supported by a striking paucity of expression of cation independent mannose-6-phosphate receptors on the plasma membrane of the four endothelial cell models and by little delivery of enzyme to lysosomes, when compared with fibroblasts. If these observations are confirmed in vivo, alternative mechanisms will be needed to explain the ready clearance of storage from endothelial cells in patients undergoing enzyme replacement therapy. PMID- 22450714 TI - Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes. AB - Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a 'best practice' for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches. PMID- 22450716 TI - Highly reactive meso-like positions of dipyrihexaphyrin. AB - The meso-like position of a pyridine-containing porphyrin analogue structurally related to amethyrin was found to be highly reactive to undergo addition of alcohols, amines and hydrogen cyanide at room temperature under neutral conditions. PMID- 22450718 TI - Genetics of ion-channel disorders. AB - PURPOSE OF REVIEW: In this article, we summarize the main features of the most common inherited channelopathies, focusing on the findings that advanced the field in the last few years. RECENT FINDINGS: The progress in genetics prompted the discovery of several new genes associated with ion-channel disorders, elucidating new molecular pathways and new arrhythmogenic mechanisms. The diffusion and availability of genetic screening gave a new relevance to the application of genetics not only for diagnosis, but also for risk assessment and therapeutic decisions. As a consequence, the present challenge in the field is represented by the need to use genetic data to develop personalized clinical approaches. SUMMARY: Over a few years, the field of inherited arrhythmogenic diseases has rapidly expanded, thus reshaping clinical management for these conditions. It is now clear that to handle these patients a specialized expertise is needed, able to translate the discoveries derived from basic science studies into the clinical care of the patients. PMID- 22450717 TI - Tetraspanins and cell membrane tubular structures. AB - Tetraspanins regulate a variety of cellular functions. However, the general cellular mechanisms by which tetraspanins regulate these functions remain poorly understood. In this article we collected the observations that tetraspanins regulate the formation and/or development of various tubular structures of cell membrane. Because tetraspanins and their associated proteins (1) are localized at the tubular structures, such as the microvilli, adhesion zipper, foot processes, and penetration peg, and/or (2) regulate the morphogenesis of these membrane tubular structures, tetraspanins probably modulate various cellular functions through these membrane tubular structures. Some tetraspanins inhibit membrane tubule formation and/or extension, while others promote them. We predict that tetraspanins regulate the formation and/or development of various membrane tubular structures: (1) microvilli or nanovilli at the plasma membranes free of cell and matrix contacts, (2) membrane tubules at the plasma membrane of cell matrix and cell-cell interfaces, and (3) membrane tubules at the intracellular membrane compartments. These different membrane tubular structures likely share a common morphogenetic mechanism that involves tetraspanins. Tetraspanins probably regulate the morphogenesis of membrane tubular structures by altering (1) the biophysical properties of the cell membrane such as curvature and/or (2) the membrane connections of cytoskeleton. Since membrane tubular structures are associated with cell functions such as adhesion, migration, and intercellular communication, in all of which tetraspanins are involved, the differential effects of tetraspanins on membrane tubular structures likely lead to the functional difference of tetraspanins. PMID- 22450719 TI - Pulmonary hypertension in heart failure with preserved left ventricular ejection fraction: diagnosis and management. AB - PURPOSE OF REVIEW: To clarify the importance of pulmonary hypertension in the diagnosis and treatment of heart failure with preserved ejection fraction (HFpEF). RECENT FINDINGS: Pulmonary hypertension is frequently present in HFpEF because of both elevated pulmonary venous pressure and some element of pulmonary vasoconstriction. HFpEF may be the most common cause of pulmonary hypertension in the elderly. The noninvasive detection of pulmonary hypertension can distinguish patients with HFpEF from those with diastolic dysfunction without heart failure. Pulmonary hypertension may be an important target for treatment of HFpEF. Phosphodiesterase-5 inhibitors are a promising method to treat pulmonary hypertension because of HFpEF. SUMMARY: Pulmonary hypertension is an important contributor to the pathophysiology of HFpEF, can be used to recognize HFpEF and may be an important target for therapy. PMID- 22450720 TI - Contemporary management of pericardial diseases. AB - PURPOSE OF REVIEW: Pericardial diseases are relatively common in clinical practice, either as isolated disease or as manifestation of a systemic disorder. The aim of the present study is to review more recent updates on their contemporary management. RECENT FINDINGS: The cause of pericardial diseases is varied according to the epidemiologic background, patient population, and clinical setting. Most cases remain idiopathic, and empiric anti-inflammatory therapy should be considered as first-line therapy in most cases with the possible adjunct of colchicine in the setting of inflammatory pericardial diseases, especially relapsing or not responding to first-line drugs. A triage has been proposed to select high-risk cases requiring admission and specific cause search. The prognosis of pericardial diseases is essentially determined by the cause. The most feared complication is constriction, the risk of which is higher in bacterial forms, intermediate for postpericardiotomy syndromes and systemic inflammatory diseases, low for viral and idiopathic cases. Chronic constriction has a definite surgical therapy, whereas transient cases should be recognized and may be reversible with empirical anti-inflammatory therapy. SUMMARY: Contemporary management of pericardial diseases is largely empirical, although first clinical trials and new studies on diagnostic modalities and prognosis of pericardial diseases are bringing the contemporary management of pericardial diseases along a more evidence-based road. Integrated cardiovascular imaging is required for optimal management of the patient with suspected pericardial disease. PMID- 22450721 TI - Elements of 'missing heritability'. AB - PURPOSE OF REVIEW: To discuss the basis of 'missing heritability', which has emerged as an enigma in the post-genome-wide association studies (GWAS) era. RECENT FINDINGS: Alleles identified through GWAS account for a relatively small fraction of heritability of the complex phenotypes. Accordingly, a significant part of heritability of the complex traits remains unaccounted for ('missing heritability'). Recent findings offer several explanations, including overestimation of heritability of the complex traits and underestimation of the effects of alleles identified through GWAS. In addition, yet-to-be identified common as well as rare alleles might in part explain the 'missing heritability'. Moreover, gene-gene (epistasis) and gene-environmental interactions might explain another fraction of heritability of complex traits. Moreover, transgenerational epigenetic changes, regulated in part by microRNAs, might also contribute to the 'missing heritability'. SUMMARY: The new findings suggest a multifarious nature of the 'missing heritability'. The findings de-emphasize the focus on delineating the basis of 'missing heritability' and shift the focus to elucidation of the molecular mechanisms by which genomic and genetic factors govern the pathogenesis of the complex phenotypes. PMID- 22450723 TI - Renal angiomyolipoma with coexistent hemorrhagic aneurysm formation and fatty thrombus in inferior vena cava: a rare presentation. AB - Angiomyolipoma (AML) is known as the most common benign mesenchymal tumor of kidney. Usually AMLs present as benign lesions without local invasion or complication. However, few cases of renal AML have been reported with complications such as tumor thrombus extension into inferior vena cava (IVC) or hemorrhagic aneurysm formation. We report a complicated case of renal AML with CT and angiography evidence of hemorrhagic aneurysm formation and IVC thrombus, treated by a combination of selective arterial embolization, radical nephrectomy and thrombectomy. Radiologists and clinicians should be aware that AMLs could have such aggressive behaviors. PMID- 22450724 TI - Patient-controlled sedation for ERCP: a randomized double-blind comparison of alfentanil and remifentanil. AB - BACKGROUND AND STUDY AIMS: Self-administration of a propofol and opioid mixture by patients (patient-controlled sedation, PCS) could offer a practical alternative for individual sedation during endoscopic retrograde cholangiopancreatography (ERCP). However, what would be the most suitable sedative mixture for PCS is unknown. The aim of this study was to compare remifentanil and alfentanil in the PCS during ERCP. PATIENTS AND METHODS: Eighty one patients undergoing elective ERCP received PCS with propofol and opioid in three different regimens. The concentrations of opioids in the sedative mixture were 0.02 mg/mL in the remifentanil group (R) and 0.04 mg/mL and 0.08 mg/mL in the alfentanil 1 (A1) and alfentanil 2 (A2) groups, respectively. The infusion pump was adjusted to deliver a 1 mL single dose with zero lockout time. We considered PCS as successful if no procedure interruption due to sedation-related complications occurred or if additional propofol was not needed. The consumption of propofol was registered, and sedation levels and vital signs were monitored. Endoscopist and patient satisfaction with sedation were assessed using structured questionnaires. RESULTS: The consumption (SD) of propofol was 177 (105)mg in group R, 197 (88) mg in group A1 and 162 (70)mg in group A2. PCS was successful in 74 /81 (91 %) of sedations, without differences between the groups in terms of propofol consumption, sedation success rate, sedation levels, vital signs, postprocedural pain, and endoscopist and patient satisfaction. Respiratory depression and nausea were observed more frequently with remifentanil than with alfentanil (P < 0.05). CONCLUSIONS: PCS is an acceptable method of sedation for ERCP. The combination of propofol and alfentanil should be recommended because a remifentanil - propofol mixture depresses spontaneous respiration more and produces nausea more frequently. PMID- 22450725 TI - New cross-linking quinoline and quinolone derivatives for sensitive fluorescent labeling. AB - A variety of contemporary analytical platforms, utilized in technical and biological applications, take advantage of labeling the objects of interest with fluorescent tracers-compounds that can be easily and sensitively detected. Here we describe the synthesis of new fluorescent quinoline and quinolone compounds, whose light emission can be conveniently tuned by simple structural modifications. Some of these compounds can be used as sensitizers for lanthanide emission in design of highly sensitive luminescent probes. In addition, we also describe simple efficient derivatization reactions that allow introduction of amine- or click-reactive cross-linking groups into the fluorophores. The reactivity of synthesized compounds was confirmed in reactions with low molecular weight nucleophiles, or alkynes, as well as with click-reactive DNA oligonucleotide containing synthetically introduced alkyne groups. These reactive derivatives can be used for covalent attachment of the fluorophores to various biomolecules of interest including nucleic acids, proteins, living cells and small cellular metabolites. Obtained compounds are characterized using NMR, steady-state fluorescence spectroscopy as well as UV absorption spectroscopy. PMID- 22450726 TI - Synthesis of 1,8-naphthyridines and their application in the development of anionic fluorogenic chemosensors. AB - Two 1,8-naphthyridines were synthesized and found to be fluorescent in solution. These compounds were studied in the presence of Cu(+) and Cu(2+) ions and it was verified that the metal causes the quenching of their fluorescence emission, due to the formation of complexes between the naphthyridine and the metal. A displacement assay was carried out in a DMSO-water mixture with the addition of various anions to the solutions of the complexes, and it was observed that these systems have a high capacity to selectively detect cyanide. PMID- 22450727 TI - Highly selective and sensitive chemosensor for Hg2+ based on the naphthalimide fluorophore. AB - A new OFF-ON fluorescent chemosensor (H1) composed of a naphthalimide fluorophore and a 6-[(quinolin-8-yloxy)methyl]pyridin-2-ylmethanamine receptor has been synthesized and characterized by infra-red, (1)H NMR, (13)C NMR and mass spectrometry. The developed chemosensor H1 exhibited good turn-on and reversible responses toward Hg(2+), with excellent selectivity and sensitivity, in a neutral buffered aqueous solution. Other common metal ions did not interfere with the fluorescence-enhancement response to Hg(2+). Furthermore, the chemosensor H1, at a concentration of 10 MUM, showed a rapid and linear response toward Hg(2+) in the concentration range 0-10 MUM. On addition of 10 MUM Hg(2+), the fluorescence intensity of H1 was enhanced about 4-fold. The detection limit was calculated to be 63 nM. The association constant was 1.11 * 10(5) M(-1). The fluorescence quantum yield and lifetime of H1/Hg(2+) were 0.42 and 3.83 ns, respectively. PMID- 22450728 TI - Sorption and desorption of PVA-pyrene chains in and out of agarose Gel. AB - In situ steady-state fluorescence (SSF) measurement technique was applied to investigation of pyrene labeled Poly(vinyl alcohol) (PVA-Py) molecules diffusion in and out of agarose gels. Gel samples with four different concentration of agarose were prepared. PVA-Py was synthesized by "click" chemistry method and dissolved in water to use in diffusion experiments. The results were analyzed by using Fickian type diffusion model, and it was found that sorption and desorption processes of PVA-Py molecules in and out of agarose gel have two distinct regions for short and long diffusion times. Sorption and desorption coefficients were measured and it was seen that the diffusion rates were much larger at short times and at lower agarose concentrations. PMID- 22450729 TI - N,N,N,N-tetradentate macrocyclic ligand based selective fluorescent sensor for zinc (II). AB - N,N,N,N-tetradentate macrocyclic ligand (L) has been synthesized by the condensation of benzil and semicarbazide and characterized. On excitation by light of wavelength 350 nm, L exhibited a fluorescent peak at lambda(max) = 454 nm, which showed ca 6 times enhancement in intensity with a blue shift on interaction with Zn(2+). L has been found to act as a selective fluorescent sensor for zinc(2+) ion over a host of other metal ions such as- Cd(2+), Pb(2+), Hg(2+), Ca(2+), Fe(2+), Na(2+), Co(2+), Mn(2+), Cu(2+) and Ni(2+), in 1:1 CH(3)OH:H(2)O. A 1:1 complex formation between L and Zn(2+) was proved. The enhancement in the fluorescence could be explained on the basis of Photo induced electron transfer (PET) mechanism with log beta = 1.86. PMID- 22450730 TI - Protective effect of Chresta martii extract against indomethacin-induced gastric lesions in mice. AB - Chresta martii (Asteraceae) is a plant found in the Xingo region (semi-arid area) in Northeastearn Brazil, and is recognized by the local population as a traditional herb used to treat gastric diseases. This is the first report of the chemical composition, acute toxicity, and gastroprotective effect in mice of the hydroalcoholic extract (HAE) from the aerial parts (leaves and flowers) of Chresta martii. Animals received HAE doses from 10 to 2000 mg/kg, i.p. or 50 to 3000 mg/kg, p.o.) and were observed over 48 h for toxicity signs and mortality; sub-chronic toxicity was evaluated through 14 days treatment with once-daily HAE doses (400 mg/kg, p.o.). The gastroprotective effect of HAE was demonstrated on the indomethacin-induced gastric ulcer model after the administration of extracts. Data comparison of ulcer index averages between saline and HAE (100 or 400 mg/kg, p.o.) groups showed significant (P < 0.01) inhibition (71.73 and 76.72 %, respectively) of indomethacin-induced gastric lesions. Histological analyses showed significant (P < 0.05) inhibition of leukocyte migration in HAE-treated groups. A fingerprint of the HAE obtained by HPLC/UV/MS analysis showed major peaks characteristic of sesquiterpene lactones. Compound 1 was isolated and elucidated as a new natural product. Its capacity to prevent leukocyte chemotaxis was demonstrated in vitro, corroborating the pharmacological effects observed for C. martii HAE. PMID- 22450731 TI - Comment on Sirtuin 1 in skeletal muscle of cachectic tumour-bearing rats. PMID- 22450732 TI - Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. AB - OBJECTIVES: Clostridium difficile infection (CDI) has increased to epidemic proportions over the past 15 years, and recurrence rates of 30-65% with failure to respond to multiple courses of antimicrobials are common. The aim of this study was to report the efficacy of fecal microbiota transplantation (FMT) in patients with recurrent CDI in five geographically disparate medical centers across the United States. METHODS: A multicenter long-term follow-up study was performed on the use of FMT for recurrent CDI. We were able to contact 77 of 94 eligible patients who had colonoscopic FMT for recurrent CDI >= 3 months before. Respondents completed a 36-item questionnaire via mail and/or phone that solicited pre-FMT, post-FMT, and donor data. Study outcomes included primary cure rate (resolution of symptoms without recurrence within 90 days of FMT) and secondary cure rate (resolution of symptoms after one further course of vancomycin with or without repeat FMT). RESULTS: Seventy-three percent of patients were women and the average age was 65 years. The long-term follow-up period ranged from 3 to 68 months between FMT and data collection (mean: 17 months). The majority of patients were living independently at the time of FMT; however, 40% were ill enough to be hospitalized, homebound, or living in a skilled nursing facility. Spouses and partners accounted for 60% of donors and 27% were either first-degree relatives or otherwise related to the patient. The average symptom duration before FMT was 11 months and patients had failed an average of five conventional antimicrobial regimens; nonetheless, 74% of patients had resolution of their diarrhea in <= 3 days. Diarrhea resolved in 82% and improved in 17% of patients within an average of 5 days after FMT. The primary cure rate was 91%. Seven patients either failed to respond or experienced early CDI recurrence (<= 90 days) after FMT. Four of these patients were successfully treated with vancomycin with or without probiotics; two patients were treated unsuccessfully with vancomycin, but subsequent FMT was successful; one patient was not treated and died in hospice care of unclear cause. The secondary cure rate was 98%. All late recurrences of CDI occurred in the setting of antimicrobial therapy for treatment of infections unrelated to C. difficile. In all, 53% of patients stated they would have FMT as their preferred first treatment option if CDI were to recur. While no definite adverse effects of FMT were noted, two patients had improvement in a pre-existing medical condition and four patients developed diseases of potential interest after FMT. CONCLUSIONS: FMT is a rational, durable, safe, and acceptable treatment option for patients with recurrent CDI. PMID- 22450733 TI - Bartonella vinsonii subsp. berkhoffii and Bartonella henselae as potential causes of proliferative vascular diseases in animals. AB - Bartonella species are highly fastidious, vector borne, zoonotic bacteria that cause persistent intraerythrocytic bacteremia and endotheliotropic infection in reservoir and incidental hosts. Based upon prior in vitro research, three Bartonella sp., B. bacilliformis, B. henselae, and B. quintana can induce proliferation of endothelial cells, and each species has been associated with in vivo formation of vasoproliferative tumors in human patients. In this study, we report the molecular detection of B. vinsonii subsp. berkhoffii, B. henselae, B. koehlerae, or DNA of two of these Bartonella species simultaneously in vasoproliferative hemangiopericytomas from a dog, a horse, and a red wolf and in systemic reactive angioendotheliomatosis lesions from cats and a steer. In addition, we provide documentation that B. vinsonii subsp. berkhoffii infections induce activation of hypoxia inducible factor-1 and production of vascular endothelial growth factor, thereby providing mechanistic evidence as to how these bacteria could contribute to the development of vasoproliferative lesions. Based upon these results, we suggest that a fourth species, B. vinsonii subsp. berkhoffii, should be added to the list of bartonellae that can induce vasoproliferative lesions and that infection with one or more Bartonella sp. may contribute to the pathogenesis of systemic reactive angioendotheliomatosis and hemangiopericytomas in animals. PMID- 22450734 TI - A multi-target real-time PCR assay for rapid identification of meningitis associated microorganisms. AB - A central nervous system (CNS) infection, such as meningitis, is a serious and life-threatening condition. Bacterial meningitis can be severe and may result in brain damage, disability or even death. Rapid diagnosis of CNS infections and identification of the pathogenic microorganisms are needed to improve the patient outcome. Bacterial culture of a patient's cerebrospinal fluid (CSF) is currently considered the "gold standard" for diagnosing bacterial meningitis. From the CSF cultures researchers can assess the in vitro susceptibility of the causative microorganism to determine the best antibiotic treatment. However, many of the culture assays, such as microscopy and the latex agglutination test are not sensitive. To enhance pathogen detection in CSF samples we developed a multi target real-time PCR assay that can rapidly identify six different microorganisms: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Streptococcus agalactiae, Listeria monocytogenes and Cryptococcus neoformans. In this study we applied this PCR analysis to 296 CSF samples from patients who were suspected of having meningitis. Of the 296 samples that were examined, 59 samples were positive according to the CSF culture and/or molecular assays. Forty-six CSF samples were positive for both the CSF culture and our real time PCR assay, while 13 samples were positive for the real-time PCR but negative for the traditional assays. This discrepancy may have been caused by the fact that these samples were collected from 23 patients who were treated with antimicrobials before CSF sampling. PMID- 22450735 TI - Baseline human papillomavirus infection, high vaginal parity, and their interaction on cervical cancer risks after a follow-up of more than 10 years. AB - OBJECTIVES: Human papillomavirus (HPV) has been recognized as a major factor for cervical cancer causation. Other factors, relating to reproduction, are also important. This study aims to disentangle the roles of baseline HPV infection, high vaginal parity (defined as having >=4 vaginal deliveries), and the interaction between the two in predicting cervical cancer risk. METHODS: The authors apply a newly developed causal-pie modeling technique to analyze a cohort of more than 10,000 women conducted in Taiwan with more than 10 years of follow up. The rate ratios adjusted by age and menopausal status were further modeled by an additive Poisson regression with non-negative parameters. The index of causal pie weight (CPW) was calculated to indicate the proportion of cervical cancer cases attributable to a particular class of causal pies. RESULTS: It was found that the CPWs are 36.3 % for baseline HPV infection, 35.6 % for baseline HPV infection and high vaginal parity, and 28.1 % for other factors. CONCLUSIONS: A causal-pie modeling based on a women cohort in Taiwan successfully disentangles the roles of virus factors and reproductive factors at study entry, independently or interactively, on subsequent cervical cancer risk. PMID- 22450736 TI - Obesity and the incidence of skin cancer in US Caucasians. AB - BACKGROUND: Limited information is available on the potential link between obesity and either melanoma or non-melanoma skin cancers. OBJECTIVE: To conduct a prospective study to examine the association between obesity and the risk of both melanoma and non-melanoma skin cancers. METHODS: Using pooled data from two large national cohorts in the US, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we prospectively examined the incidence of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) among participants grouped according to body mass index (BMI). RESULTS: Compared to participants with an updated BMI in the normal range, those with a BMI in the obese range had a 32 % lower risk of developing SCC, and those with a BMI in the morbidly obese category had a 37 % lower risk of developing SCC. The decrease in SCC risk was limited to women. Compared to participants with a BMI in the normal range, those with a BMI in the obese range had a 19 % lower risk of developing BCC, and those with a BMI in the morbidly obese category had a 29 % lower risk of developing BCC. The risk of developing melanoma did not statistically differ by BMI grouping. The results were similar using BMI measurements obtained 10 years prior to the diagnosis of skin cancer. CONCLUSION: Obesity appears to be inversely associated with the development of non-melanoma skin cancers. Obesity is most likely a surrogate marker for lack of chronic sun exposure, which is a risk factor for non-melanoma skin cancers. PMID- 22450737 TI - Association of colorectal adenoma with components of metabolic syndrome. AB - PURPOSE: Recently, some studies have shown that diabetes mellitus and metabolic syndrome increase the risk of colorectal neoplasms. Although the mechanism is not known, those have been proposed to contribute to this phenomenon, including insulin resistance, oxidative stress, and adipokine production. The objective of this study was to assess the association between metabolic risk factors and colorectal neoplasm. METHODS: Study participants visited the National Cancer Center, Korea, for screening (2007-2009). A total of 1,771 diagnosed adenoma patients and 4,667 polyp-free controls were included. The association between risk factors and colorectal neoplasm was evaluated using logistic regression models. RESULTS: High waist circumference, blood pressure, and serum triglyceride levels were associated with an increased risk of colorectal adenoma. Metabolic syndrome (MS) was associated with an increased risk of adenoma (OR = 1.44, 95 % CI = 1.23-1.70). The association between MS and colorectal adenoma was observed regardless of advanced/low-risk adenoma, and multiplicity. MS affected right colon adenomas (OR = 1.50, 95 % CI = 1.22-1.85), left colon adenomas (OR = 1.36, 95 % CI = 1.05-1.76), and adenomas in multiple anatomical locations (OR = 1.59, 95 % CI = 1.19-2.12), but was not associated with rectum. CONCLUSION: Central obesity, triglyceride level, and MS are risk factors for colorectal adenoma including advanced adenoma and multiplicity. PMID- 22450738 TI - Racial and ethnic disparities in survival of US children with acute lymphoblastic leukemia: evidence from the SEER database 1988-2008. AB - PURPOSE: Prior studies have shown poorer survival from childhood acute lymphoblastic leukemia (ALL) among some minorities compared to non-Hispanic whites (NHW). Here, we examine whether these survival disparities have persisted and to see whether they also exist for Asian and Hispanic subgroups. METHODS: Using data from the US National Cancer Institute's Surveillance, Epidemiology and End Results program from 1988 to 2008, we compared all natural-cause survival for children aged 19 years or under diagnosed with ALL using Cox proportional hazards models adjusted for age, diagnosis year, gender and disease immunophenotype. RESULTS: Black, Hispanic and Native American children continue to have significantly poorer survival than NHW. Unlike previous studies, we found that Asian Americans also had significantly worse survival. Among Asian subgroups, Vietnamese (relative risk [RR] = 2.44, 95 % CI = 1.50-3.97) and Filipinos (RR = 1.64, 95 % CI = (1.13-2.38) had significantly poorer survival, while other East Asian groups, except Chinese, had non-significantly worse survival. Most Hispanic subgroups had RRs around 2. CONCLUSION: Previously observed poorer prognosis for childhood ALL for some minority groups appears to be shared by most Asians as well. Further research is needed to find explanations for the poorer survival of minority children with ALL and possible treatment implications. PMID- 22450740 TI - Underestimation of Clostridium difficile infection among clinicians: an international survey. AB - The objective of this investigation was to document clinicians' awareness regarding the incidence and severity of Clostridium difficile-associated diarrhea (CDAD). An international electronic survey was conducted among corresponding authors of articles indexed by PubMed and published during the last 10 years in 'Core Clinical Journals'. A total of 1,163 clinicians answered (response rate 59%); most of the responses were submitted from North America (54.6%), Europe (32.2%), and Asia/Pacific (11.6%). Only 2.2% of the participants answered correctly all four questions, while 14.1% answered all questions incorrectly. Regarding each question, 10.8% of the participants correctly estimated current CDAD treatment failure or recurrence rates to be around 40%, 33.4% correctly estimated the ratio of antibiotic-associated colitis attributed to C. difficile to be around 60%, 72.7% correctly responded that almost all antibiotics are associated with CDAD, and 41.7% correctly responded that any patient is at risk for CDAD. Almost half (44.4%) of the respondents considered CDAD to be underestimated. Participants from North America scored higher than those from Europe or Asia/Pacific (p < 0.001). Participants considering CDAD to be overestimated (3.4%) had the lowest mean score of correct answers. Among a clinically diverse international sample of physicians with academic expertise, there was an inadequate level of awareness of the magnitude and clinical importance of CDAD. PMID- 22450741 TI - Molecular fingerprinting of Staphylococcus aureus isolated from patients with osteomyelitis in Argentina and clonal distribution of the cap5(8) genes and of other selected virulence genes. AB - The molecular fingerprinting of a collection of 94 Staphylococcus aureus isolates from patients with osteomyelitis in Argentina was performed. Twenty-three SmaI pulsed-field gel electrophoresis (PFGE) types and 37 spa types were identified. The isolates were assigned to 23 sequence types (STs). The proportion of methicillin-resistant S. aureus (MRSA) isolates was significantly higher among cap5 S. aureus (35/61) compared with cap8 S. aureus (8/33) isolates (p = 0.0025). Twenty-four of the 94 isolates carried the lukS-PV/lukF-PV genes, which were significantly associated to cap5 [(23/38) compared with cap8 S. aureus isolates (1/32) (p = 0.0001)]. Forty of the 94 isolates carried genes of the egc locus (seg/sei). The distribution of seg/sei genes among isolates was related to certain clones. Isolates of the four agr types were found in the S. aureus collection. Whereas agr I isolates were evenly distributed among cap5 and cap8 S. aureus isolates (32/61 and 14/33, respectively), the agr II group was composed of 29 cap5 S. aureus isolates and agr III was composed of 16 cap8 S. aureus isolates. Two clones originally associated to animals (ST 188, 7 isolates and ST 1796, 5 isolates) were associated with chronic osteomyelitis and lack of capsular polysaccharide (CP) production. Loss of CP production remains the single factor among those investigated that is associated with chronic osteomyelitis. PMID- 22450742 TI - Therapeutic hypothermia following resuscitation. AB - PURPOSE OF REVIEW: The 2010 Cardiopulmonary Resuscitation (CPR) Guidelines recommended therapeutic hypothermia for postcardiac arrest syndrome as a beneficial and effective treatment. However, the optimal temperature, method, onset, duration and rewarming rate, and therapeutic window remain unknown. RECENT FINDINGS: Recent animal studies have shown that the sooner cooling is initiated after cardiac arrest, the better the outcome. Induction of hypothermia during cardiac arrest before return of spontaneous circulation (ROSC) (intra-arrest cooling) enhances its efficacy. In 2010, the Pre-ROSC IntraNasal Cooling Effectiveness (PRINCE) study and our clinical study of intra-arrest cooling concluded that intra-arrest cooling before ROSC was likely to have neurological benefits while protecting the myocardium for patients with out-of-hospital cardiac arrest. SUMMARY: One of the most significant advances in CPR treatment in the past decade is therapeutic hypothermia. Although post-ROSC cooling has been shown to improve neurological outcome for patients with out-of-hospital cardiac arrest, intra-arrest cooling during CPR is likely to protect the myocardium from reperfusion injury and enhance neurological benefits. PMID- 22450743 TI - Advanced life support and mechanical ventilation. AB - PURPOSE OF REVIEW: Artificial ventilation is one of the best known resuscitation procedures. It is generally accepted that there must be oxygen delivery to vital organs during cardiac arrest and resuscitation in order to prevent irreversible damage, but there is an increasing number of ventilation concepts for resuscitation. Traditional and alternative methods of ventilation are reviewed. RECENT FINDINGS: The need for positive-pressure ventilation during resuscitation as an essential gold standard might be overestimated at least in the first minutes of cardiopulmonary resuscitation (CPR). The co-founders of the concept of cardiocerebral resuscitation could show positive effects of a sole passive oxygenation at the beginning of advanced life support (ALS). Research was published on continuous positive airway pressure (CPAP) ventilation as well as on CPAP plus pressure support ventilation. In addition to positive-pressure ventilation, the use of an impedance threshold device, partly in addition with active compression-decompression CPR, was investigated in both experimental and clinical settings. None of these methods alone could be proven to improve the outcome of cardiac arrest. The role of high oxygen concentration during CPR also remains unclear. SUMMARY: Positive-pressure ventilation with pure oxygen remains, in clinical practice, the gold standard in ALS. Further research should focus on the role of passive oxygenation during early ALS. The concentration of oxygen needed during resuscitation has to be defined and alternative ventilation patterns, regarding the impact of CPR, should be investigated. PMID- 22450744 TI - p14(ARF) inhibits the growth of lung adenocarcinoma cells harbouring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway. AB - Epidermal growth factor receptor (EGFR) stimulates proliferative and survival signals. Activating mutations of EGFR are involved in the aetiology and maintenance of the malignant phenotype of lung tumours. We previously described the frequent association of these mutations with the decreased expression of the p14(ARF) tumour suppressor, another common feature of lung cancer. Based on these data, we postulated that p14(ARF) could protect cells against untimely or excessive mitotic signals induced by mutant EGFR. In this study, we demonstrate that p14(ARF) promotes apoptosis in lung tumour cells harbouring the EGFR L858R mutation through the accumulation of phosphorylated signal transducer and activator of transcription 3 (STAT3) on Tyr 705 residue, which leads to Bcl-2 downregulation. Using siRNA against PTP-RT, the phosphatase that specifically targets Tyr 705 residue, we show that accumulation of pSTAT3-Tyr705 promotes EGFR L858R mutant cell death, thereby confirming the existence of a STAT3-dependent pro-apoptotic pathway in these cells. Finally, we show that the expression of the EGFR L858R mutant represses p14(ARF) expression and inhibits STAT3/Bcl-2 signalling. These results identify a novel link between the p14(ARF) and EGFR pathways and suggest that EGFR L858R counteracts the pro-apoptotic function of p14(ARF) by downregulating its expression to promote carcinogenesis. PMID- 22450745 TI - Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer. AB - The small GTPase Ral is known to be highly activated in several human cancers, such as bladder, colon and pancreas cancers. It is reported that activated Ral is involved in cell proliferation, migration and metastasis of bladder cancer. This protein is activated by Ral guanine nucleotide exchange factors (RalGEFs) and inactivated by Ral GTPase-activating proteins (RalGAPs), the latter of which consist of heterodimers containing a catalytic alpha1 or alpha2 subunit and a common beta subunit. In Ras-driven cancers, such as pancreas and colon cancers, constitutively active Ras mutant activates Ral through interaction with RalGEFs, which contain the Ras association domain. However, little is known with regard to the mechanism that governs aberrant activation of Ral in bladder cancer, in which Ras mutations are relatively infrequent. Here, we show that Ral was highly activated in invasive bladder cancer cells due to reduced expression of RalGAPalpha2, the dominant catalytic subunit in bladder, rather than increased expression of RalGEFs. Exogenous expression of wild-type RalGAPalpha2 in KU7 bladder cancer cells with invasive phenotype, but not mutant RalGAPalpha2-N1742K lacking RalGAP activity, resulted in attenuated cell migration in vitro and lung metastasis in vivo. Furthermore, genetic ablation of Ralgapa2 promoted tumor invasion in a chemically-induced murine bladder cancer model. Importantly, immunohistochemical analysis of human bladder cancer specimens revealed that lower expression of RalGAPalpha2 was associated with advanced clinical stage and poor survival of patients. Collectively, these results are highly indicative that attenuated expression of RalGAPalpha2 leads to disease progression of bladder cancer through enhancement of Ral activity. PMID- 22450746 TI - Autocrine IL-1beta-TRAF6 signalling promotes squamous cell carcinoma invasion through paracrine TNFalpha signalling to carcinoma-associated fibroblasts. AB - The invasion of squamous cell carcinoma (SCC) is a significant cause of morbidity and mortality. Here, we identify an E3 ligase, Traf6 and a de-ubiquitinating enzyme, Cezanne/ZA20D1, as important regulators of this process in organotypic models. Traf6 can promote the formation of Cdc42-dependent F-actin microspikes. Furthermore, Traf6 has a key role in autocrine interleukin-1beta signalling in SCC cells, which in turn is required to drive the expression of tumour necrosis factor alpha (TNFalpha). TNFalpha acts in a paracrine manner to increase the invasion-promoting potential of carcinoma-associated fibroblasts (CAFs). Exogenous TNFalpha signalling can restore invasion in cells depleted of Traf6. In conclusion, Traf6 has two important roles in SCC invasion: it promotes cell intrinsic Cdc42-dependent regulation of the actin cytoskeleton and enables production of the paracrine signal, TNFalpha, that enhances the activity of CAFs. PMID- 22450747 TI - Disrupting the PIKE-A/Akt interaction inhibits glioblastoma cell survival, migration, invasion and colony formation. AB - The cyclin-dependent kinase 4 (CDK4) amplicon is frequently amplified in numerous human cancers including gliomas. PIKE-A, a proto-oncogene that is one of the important components of the CDK4 amplicon, binds to and enhances the kinase activity of Akt, thereby promoting cancer progression. To define the roles of the PIKE-A/Akt interaction in glioblastoma multiform (GBM) progression, we used biochemical protein/protein interaction (PPI) assays and live cell fluorescence based protein complementation assays to search for small peptide antagonist from these proteins that were able to block their interaction. Here, we show that disruption of the interaction between PIKE-A and Akt by the small peptides significantly reduces glioblastoma cell proliferation, colony formation, migration and invasion. Disruption of PIKE-A/Akt association potently suppressed GBM cell proliferation and sensitized the cells to two clinical drugs that are currently used to treat GBM. Interestingly, GBM cells containing the CDK4 amplicon were more responsive to the inhibition of the PIKE-A/Akt interaction than GBM cells lacking this amplicon. Taken together, our findings provide proof of-principle that blocking a PPI that is essential for cancer progression provides a valuable strategy for therapeutic discovery. PMID- 22450748 TI - P21-activated kinase 4 (PAK4) is required for metaphase spindle positioning and anchoring. AB - The oncogenic kinase PAK4 was recently found to be involved in the regulation of the G1 phase and the G2/M transition of the cell cycle. We have also identified that PAK4 regulates Ran GTPase activity during mitosis. Here, we show that after entering mitosis, PAK4-depleted cells maintain a prolonged metaphase-like state. In these cells, chromosome congression to the metaphase plate occurs with normal kinetics but is followed by an extended period during which membrane blebbing and spindle rotation are observed. These bipolar PAK4-depleted metaphase-like spindles have a defective astral microtubule (MT) network and are not centered in the cell but are in close contact with the cell cortex. As the metaphase-like state persists, centrosome fragmentation occurs, chromosomes scatter from the metaphase plate and move toward the spindle poles with an active spindle assembly checkpoint, a phenotype that is reminiscent of cohesion fatigue. PAK4 also regulates the acto-myosin cytoskeleton and we report that PAK4 depletion results in the induction of cortical membrane blebbing during prometaphase arrest. However, we show that membrane blebs, which are strongly enriched in phospho cofilin, are not responsible for the poor anchoring of the spindle. As PAK4 depletion interferes with the localization of components of the dynein/dynactin complexes at the kinetochores and on the astral MTs, we propose that loss of PAK4 could induce a change in the activities of motor proteins. PMID- 22450749 TI - SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. AB - In our previous study, we found that blockade of SDF-1/CXCR4 signaling inhibits pancreatic cancer cell migration and invasion in vitro. However, the mechanism governing the downstream regulation of SDF-1/CXCR4-mediated invasion remains unclear. Here we report the role of SDF-1/CXCR4 in pancreatic cancer and the possible mechanism of SDF-1/CXCR4-mediated pancreatic cancer invasion. We show that there is a cross-talk between SDF-1/CXCR4 axis and non-canonical Hedgehog (Hh) pathway in pancreatic cancer. Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4-positive pancreatic cancer invasion, epithelial-mesenchymal transition (EMT) process and activates the non-canonical Hh pathway. Moreover, we also demonstrate that the invasion of a pancreatic cancer and EMT resulting from the activation of SDF-1/CXCR4 axis is effectively inhibited by Smoothened (SMO) inhibitor cyclopamine and siRNA specific to Gli-1. Collectively, these data demonstrate that SDF-1/CXCR4 modulates the non-canonical Hh pathway by increasing the transcription of SMO in a ligand-independent manner. Taken together, SDF-1/CXCR4 axis may represent a promising therapeutic target to prevent pancreatic cancer progression. PMID- 22450750 TI - How to treat CML patients in the tyrosine kinase inhibitors era? From imatinib standard dose to second generation drugs front-line: unmet needs, pitfalls and advantages. AB - Imatinib has revolutionized treatment strategies for chronic myeloid leukemia patients: long-term overall survival was reported to be up to 80% at 8 years of follow-up in respondent patients. Despite the straightforward results obtained, it has been estimated a failure rate per year of 2-4%. Several attempts to improve response have been made with high-dose of imatinib and with combination of standard dose with interferon, but both failed to ameliorate cytogenetic and molecular responses and long-term event-free and overall survival and no advantages were reported in high-risk patients. The introduction of second generation tyrosine kinase inhibitors in clinical practice allowed to rescue more than 50% of patients resistant or intolerant to imatinib. Both dasatinib and nilotinib were tested as single agent in first-line and then tested against imatinib standard dose: the results of phases II and III trials showed early and maintained complete cytogenetic response, rapid reduction of molecular burden and significant reduction of progression rate. At the present time, after FDA approval of both agents in first-line, several points of discussion are still unresolved. PMID- 22450751 TI - Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers. AB - The prognosis of pancreatic cancer is extremely poor, mainly because of its aggressive biological behavior and late onset of symptoms for clinical diagnosis; these impose limitations on therapeutic intervention. Deeper genomic sequencing analyses of pancreatic cancers revealed 12 core pathways and a long duration, nearly 20 years from initiation to distant metastases. This evidence will offer a broader aspect and time window of opportunity for early detection, thus preventing deaths from this cruel cancer. Epigenetic biomarkers can be utilized for assessing cancer risk, early detection, and predicting prognosis and therapeutic responses. In this review, we briefly summarize relevant issues associated with pancreatic cancer progression and recent advances in epigenetic biomarkers such as DNA methylation, miRNAs, satellite repeats, and histone modifications for early diagnosis. PMID- 22450752 TI - Acquisition of an enhanced aggressive phenotype in human lung cancer cells selected by suboptimal doses of cisplatin following cell deattachment and reattachment. AB - Chemotherapy is one major approach for treating non-small cell lung carcinoma (NSCLC). However, the progression-free survival rate depends on whether there is tumor metastasis after drug treatment. The biological behavior for its characteristics remains to be clarified. Here, we treated A549 and H1299 NSCLC cell lines with cisplatin, doxorubicin and gemcitabine at the IC(50) dose. Most attached cells were surviving cells (A549-A and H1299-A), whereas only a small portion of detached cells survived and reattached to tissue culture plates (A549 R and H1299-R) for further growth. Using cisplatin, a series of H1299 sublines (H1299-R2~H1299-R5) were also generated by the same selection procedure. Drug treatment increased the migratory ability of A549-R and H1299-R cells. A serial selection could enhance the invasiveness of cells. Cisplatin treatment inhibited the adhesion ability of H1299-R cells compared with their H1299 and H1299-A counterparts. H1299-R cells exhibited increased drug resistance to cisplatin and increased expression of ABCG2, CD133 and CD44. Compared with mice subcutaneously injected with H1299 cells, mice subcutaneously injected with H1299-R cells showed an increase in the number of metastatic lung nodules. We conclude that H1299-R cells selected by suboptimal doses of cisplatin following detachment from and reattachment to the tissue culture plate acquire an enhanced malignant phenotype. Therefore, they provide a more faithful lung cancer model associated with biological aggressiveness for studying clinically recurrent cancers after chemotherapy. PMID- 22450753 TI - The clinical value of non-curative resection followed by chemotherapy for incurable gastric cancer. AB - BACKGROUND: The clinical value of a non-curative resection for gastric cancer is still controversial. We analyzed the clinical outcomes of patients who underwent non-curative gastric resection. METHODS: Data from a total of 178 patients who underwent non-curative resection for advanced gastric cancer at Seoul St. Mary's hospital were reviewed. Factors related to the incurability were classified as peritoneal metastasis (P), liver metastasis (H), extra-abdominal metastasis (X), direct adjacent organ invasion that was unresectable (T). The clinicopathologic data, survival, and quality of life of patients were evaluated. RESULTS: The overall median survival time was 12.1 months, and that for the patients with gastrectomy with chemotherapy was 14.3 months. Operation-related complications occurred in 20 patients (11.2 %). Five patients (2.8 %) died of postoperative complications within 30 days, and 43 patients (24.2 %) had symptoms and signs of gastric outlet obstruction or uncontrolled bleeding. The mean duration of postoperative hospital stay was 15.9 days for those symptomatic patients, and the symptom-relieved period was 8.6 months. CONCLUSIONS: There might be a role for non-curative resection followed by chemotherapy for incurable gastric cancer, in terms of survival, and this treatment approach should be carefully considered because of the high mortality rate associated with the disease. A large, randomized, prospective study is warranted to prove the benefit of non-curative resection in patients with incurable gastric cancer. PMID- 22450754 TI - Preoperative pancreas CT/MRI characteristics predict fistula rate after pancreaticoduodenectomy. AB - BACKGROUND: Pancreatic fistula (PF) is considered to be the main cause of morbidity after pancreaticoduodenectomy (PD). A recent study from our institution suggested the risk for pancreatic fistula after distal pancreatectomy to be closely related to the pancreatic remnant volume (PRV). The hypothesis was formulated that after PD the PRV is an important determinant of the risk for PF formation. METHOD: All patients undergoing PD between September 2007 and November 2010 at the Karolinska University Hospital Stockholm were included. Preoperative multidetector computed tomography (CT) or magnetic resonance imaging (MRI) was used to calculate the PRV and the pancreatic duct width (PDW) at the alleged resection line. RESULTS: A total of 182 patients (median age 67 years) undergoing PD were included. The diagnosis was malignant in 144 patients (79.1 %) and benign in 38 (20.9 %). Pancreatic fistula defined according to the International Study Group on Pancreatic Fistula (ISGPF) criteria was diagnosed in 37 patients (20.3 %). The median PRV was 35.2 cm(3) and the median PDW was 3.9 mm. In a univariate analysis a large calculated volume of the pancreatic remnant increased the subsequent risk of PF (odds ratio [OR], 3.71; 95% confidence interval [95% CI], 1.58-8.71; P < 0.01), as did a small duct width (OR, 8.46; 95% CI, 3.11-23.04; P < 0.01). According to the multivariate analysis, the size of the pancreatic remnant and the width of the pancreatic duct maintained their impact on leakage risk. CONCLUSIONS: A large pancreatic volume and small pancreatic duct increase the risk of PF. Preoperative CT and/or MRI therefore are useful in predicting fistula formation before pancreaticoduodenectomy. PMID- 22450755 TI - A highly sensitive two-photon fluorescent probe for mitochondrial zinc ions in living tissue. AB - We report a highly sensitive two-photon probe (SZn2-Mito) which shows a 70-fold two-photon excited fluorescence enhancement in response to Zn(2+) and can selectively detect mitochondrial Zn(2+) in a rat hippocampal slice at a depth of 100-200 MUm by using two-photon microscopy. PMID- 22450756 TI - More often striatal myelinolysis than pontine? A consecutive series of patients with osmotic demyelination syndrome. AB - INTRODUCTION: Osmotic demyelination syndrome (ODS) is increasingly recognized to involve extrapontine locations in addition to the better-known central pontine myelinolysis. AIMS: This study describes clinical and radiological features of consecutive patients with ODS detected over 1 year. METHODS: Patients fulfilling clinical and radiological criteria for ODS were prospectively enrolled and were followed with serial assessments during hospital stay and up to 253 days after discharge. RESULTS: Eight patients (five females) aged 24-89 years were enrolled, comprising 0.06% of all admissions to the general medical and neurology services. All had preceding hyponatraemia and hypokalaemia of various aetiologies. One patient developed ODS after postpartum pituitary haemorrhage, which has been reported only rarely. Sodium levels were corrected at maximal rates exceeding 8 mmol/l/day. Neurological symptoms attributed to ODS began 3-15 days after clinical improvement following sodium correction in four patients; the remainder did not show any intervening lucent interval. Fifty per cent were stuporous at admission, 50% had seizures, 62.5% had symmetric parkinsonism, and 75% had prominent primitive reflexes. Stretch reflexes were absent in 25% and normal or brisk in the remainder. Magnetic resonance imaging (MRI) showed symmetric striatal lesions in all patients, with concomitant pontine involvement in only 25%. Four patients had poor outcomes (modified Rankin score >3), with prognosis dependent on the presence of severe systemic illness, liver dysfunction, encephalopathy, seizures, and degree of disability upon discharge from hospital. Patients with parkinsonism responded to dopaminergic therapy, with chorea, dystonia, and depression as later developments. This series is remarkable for the high incidence of extrapontine lesions, much more common than pontine involvement. PMID- 22450757 TI - LocARNA-P: accurate boundary prediction and improved detection of structural RNAs. AB - Current genomic screens for noncoding RNAs (ncRNAs) predict a large number of genomic regions containing potential structural ncRNAs. The analysis of these data requires highly accurate prediction of ncRNA boundaries and discrimination of promising candidate ncRNAs from weak predictions. Existing methods struggle with these goals because they rely on sequence-based multiple sequence alignments, which regularly misalign RNA structure and therefore do not support identification of structural similarities. To overcome this limitation, we compute columnwise and global reliabilities of alignments based on sequence and structure similarity; we refer to these structure-based alignment reliabilities as STARs. The columnwise STARs of alignments, or STAR profiles, provide a versatile tool for the manual and automatic analysis of ncRNAs. In particular, we improve the boundary prediction of the widely used ncRNA gene finder RNAz by a factor of 3 from a median deviation of 47 to 13 nt. Post-processing RNAz predictions, LocARNA-P's STAR score allows much stronger discrimination between true- and false-positive predictions than RNAz's own evaluation. The improved accuracy, in this scenario increased from AUC 0.71 to AUC 0.87, significantly reduces the cost of successive analysis steps. The ready-to-use software tool LocARNA-P produces structure-based multiple RNA alignments with associated columnwise STARs and predicts ncRNA boundaries. We provide additional results, a web server for LocARNA/LocARNA-P, and the software package, including documentation and a pipeline for refining screens for structural ncRNA, at http://www.bioinf.uni-freiburg.de/Supplements/LocARNA-P/. PMID- 22450758 TI - Both Sm-domain and C-terminal extension of Lsm1 are important for the RNA-binding activity of the Lsm1-7-Pat1 complex. AB - Lsm proteins are a ubiquitous family of proteins characterized by the Sm-domain. They exist as hexa- or heptameric RNA-binding complexes and carry out RNA-related functions. The Sm-domain is thought to be sufficient for the RNA-binding activity of these proteins. The highly conserved eukaryotic Lsm1 through Lsm7 proteins are part of the cytoplasmic Lsm1-7-Pat1 complex, which is an activator of decapping in the conserved 5'-3' mRNA decay pathway. This complex also protects mRNA 3' ends from trimming in vivo. Purified Lsm1-7-Pat1 complex is able to bind RNA in vitro and exhibits a unique binding preference for oligoadenylated RNA (over polyadenylated and unadenylated RNA). Lsm1 is a key subunit that determines the RNA-binding properties of this complex. The normal RNA-binding activity of this complex is crucial for mRNA decay and 3'-end protection in vivo and requires the intact Sm-domain of Lsm1. Here, we show that though necessary, the Sm-domain of Lsm1 is not sufficient for the normal RNA-binding ability of the Lsm1-7-Pat1 complex. Deletion of the C-terminal domain (CTD) of Lsm1 (while keeping the Sm domain intact) impairs mRNA decay in vivo and results in Lsm1-7-Pat1 complexes that are severely impaired in RNA binding in vitro. Interestingly, the mRNA decay and 3'-end protection defects of such CTD-truncated lsm1 mutants could be suppressed in trans by overexpression of the CTD polypeptide. Thus, unlike most Sm-like proteins, Lsm1 uniquely requires both its Sm-domain and CTD for its normal RNA-binding function. PMID- 22450759 TI - Thermodynamic characterization of the Saccharomyces cerevisiae telomerase RNA pseudoknot domain in vitro. AB - Recent structural and functional characterization of the pseudoknot in the Saccharomyces cerevisiae telomerase RNA (TLC1) has demonstrated that tertiary structure is present, similar to that previously described for the human and Kluyveromyces lactis telomerase RNAs. In order to biophysically characterize the identified pseudoknot secondary and tertiary structures, UV-monitored thermal denaturation experiments, nuclear magnetic resonance spectroscopy, and native gel electrophoresis were used to investigate various potential conformations in the pseudoknot domain in vitro, in the absence of the telomerase protein. Here, we demonstrate that alternative secondary structures are not mutually exclusive in the S. cerevisiae telomerase RNA, tertiary structure contributes 1.5 kcal mol(-1) to the stability of the pseudoknot (~ half the stability observed for the human telomerase pseudoknot), and identify additional base pairs in the 3' pseudoknot stem near the helical junction. In addition, sequence conservation in an adjacent overlapping hairpin appears to prevent dimerization and alternative conformations in the context of the entire pseudoknot-containing region. Thus, this work provides a detailed in vitro characterization of the thermodynamic features of the S. cerevisiae TLC1 pseudoknot region for comparison with other telomerase RNA pseudoknots. PMID- 22450760 TI - Pri-miR-17-92a transcript folds into a tertiary structure and autoregulates its processing. AB - MicroRNAs control gene expression either by RNA transcript degradation or translational repression. Expressions of miRNAs are highly regulated in tissues, disruption of which leads to disease. How this regulation is achieved and maintained is still largely unknown. MiRNAs that reside on clustered or polycistronic transcripts represent a more complex case where individual miRNAs from a cluster are processed with different efficiencies despite being cotranscribed. To shed light on the regulatory mechanisms that might be operating in these cases, we considered the long polycistronic primary miRNA transcript pri miR-17-92a that contains six miRNAs with diverse functions. The six miRNA domains on this cluster are differentially processed to produce varying amounts of resultant mature miRNAs in different tissues. How this is achieved is not known. We show, using various biochemical and biophysical methods coupled with mutational studies, that pri-miR-17-92a adopts a specific three-dimensional architecture that poses a kinetic barrier to its own processing. This tertiary structure could create suboptimal protein recognition sites on the pri-miRNA cluster due to higher-order structure formation. PMID- 22450761 TI - [Combination therapy for epilepsy]. AB - Use of Monotherapy is acknowledged as the standard anticonvulsant therapy although no more than about 65% of patients become seizure-free with a single antiepileptic drug. Therefore, up to 50% of patients with epilepsy are treated at least intermittently with more than one antiepileptic drug. The percentage of patients achieving complete seizure control with combination therapy after ineffective monotherapy is small. Monotherapy and combination therapy are not always contrary to each other; many anticonvulsants have different modes of action and are effectively a combination therapy in one drug. Combinations of anticonvulsants with differing mechanisms of action are called "rational polypharmacy". A superior efficacy of these combinations over combinations of anticonvulsants with identical or similar mechanisms of action have not been proved by randomised trials. Add-on trials with lacosamide and the combination of lamotrigine and valproic acid, however, suggest a superior tolerability and/or efficacy of combinations with differing mechanisms of action. Treatment with drug combinations should take into account, above all, efficacy and safety, interactions, and costs of each antiepileptic drug as well as comorbidity. PMID- 22450762 TI - [Primary amelanotic meningeal melanomatosis]. AB - Primary melanocytic lesions of the central nervous system are rare. The spread of melanoma cells primarily into the meningeal layers is referred to as meningeal melanomatosis. A few case reports about either intracranial or intraspinal primary meningeal melanoma were published in the past. The amelanotic variation of primary melanoma in the central nervous system is a very rare event and so far no cases of primary amelanotic meningeal melanomatosis have been described in the current literature. We present a case with combined multiple intracranial and intraspinal primary malignant amelanotic melanomas. PMID- 22450763 TI - Cellular apoptosis susceptibility (chromosome segregation 1-like, CSE1L) gene is a key regulator of apoptosis, migration and invasion in colorectal cancer. AB - Cellular apoptosis susceptibility (chromosome segregation 1-like, CSE1L) gene maps to chromosomal region 20q13.13, a region frequently amplified in solid tumours. In this study, we investigated the roles played by CSE1L in colorectal cancer by examining CSE1L expression and clinico-pathological parameters in colorectal cancer and investigating the effect of CSE1L on the viability, adhesion and migration of colorectal cancer cells. RT-PCR showed that CSE1L mRNA was over-expressed in colorectal cancer. CSE1L depletion by knock-down with CSE1L specific siRNA significantly reduced viability in HCT116 cells (p = 0.004) and SW480 cells (p = 0.003) whilst significantly increasing the proportion of apoptotic HCT116 cells (p < 0.001) and SW480 cells (p < 0.001). Furthermore, CSE1L depletion significantly reduced the adhesive capacity of HCT116 (p = 0.003) and SW480 cells (p = 0.004). Analysis by qRT-PCR following CSE1L siRNA treatment of HCT116 and SW480 cells showed significant modulation of key apoptotic (p53, p73 and BAK) and adhesive (E-cadherin, Ep-CAM and ICAM-1) molecules. Immunohistochemistry of a colorectal cancer tissue microarray showed that CSE1L had a significantly increased level in colorectal cancer compared to normal colorectal epithelium (p < 0.001). There were significant decreases in both nuclear (p = 0.006) and cytoplasmic (p = 0.003) staining of CSE1L in tumours with lymph node metastasis (stage 3 tumours) compared with lymph node-negative tumours (stage 1 and 2 tumours). In lymph node-negative patients, poor survival was associated with increased CSE1L cytoplasmic expression (p = 0.042). These results indicate that CSE1L is associated with viability and apoptosis, cellular adhesion and invasion, thus implicating CSE1L in the progression of colorectal cancer. PMID- 22450764 TI - Simultaneous cerebrospinal fluid otorrhea and rhinorrhea as a cause of recurrent meningitis in a patient with cochlear dysplasia. AB - Inner ear dysplasia is a rare cause of cerebrospinal fluid otorhinorrhea and presents in a variety of ways, ranging from asymptomatic to recurrent bacterial meningitis. We describe a 6-year-old boy who presented with clear watery nasal discharge and recurrent bacterial meningitis. Magnetic resonance cisternogram showed cerebrospinal fluid leak through the cribriform plate of ethmoid. High resolution computed tomographic scan of temporal bones confirmed the diagnosis of cochlear dysplasia, with cerebrospinal fluid leak coming through a defect near the oval window and through the eustachian tube orifice into the nose. Surgical closure of the defects was performed successfully. CONCLUSION: Recurrent meningitis in a child should be investigated for inner ear malformations. Awareness of this condition, a high index of suspicion and early imaging can prevent complications and give excellent results in these children. PMID- 22450765 TI - The absence of insulin resistance in metabolic syndrome definition leads to underdiagnosing of metabolic risk in obese patients. AB - This study explores in a group of obese children and adolescents aged 10 to 16 years, the prevalence of metabolic syndrome (MS) according to the criteria of International Diabetes Federation (IDF). In addition, the prevalence of insulin resistance (IR) was investigated to find correlations between MS and IR. IDF definition was compared to a modified WHO definition. A total of 159 obese patients (74 male and 85 female; median age 12.7 years) were included in the study. Anthropometric measurements, blood pressure, and serum fasting lipids were evaluated. An oral glucose tolerance test (OGTT) was performed, and serum glucose and insulin levels were measured at 0, 30, 60, 90, and 120 min. Homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), fasting glucose/insulin ratio (FGIR), Matsuda index, and total insulin levels during OGTT were calculated. For the IR diagnosis, we used cutoff values described in previous publications (HOMA-IR of >3.16, QUICKI of <0.357, FGIR of <7, and/or the sum of insulin levels during OGTT of >300 mIU/mL). MS prevalence, defined according to IDF criteria, was 34.6 %. Using the IDF definition, there was no statistically significant difference for the surrogate IR indices between patients with or without MS (QUICKI, 94.5 vs. 83.7 %), FGIR (81.1 vs. 78.8 %), HOMA-IR (70.9 vs. 63.5 %), and total insulin levels during OGTT (61.8 vs. 51.9 %). The Matsuda index values, the prevalence of fasting hyperinsulinemia, and impaired glucose tolerance were also similar in these two groups. In conclusion, IR was prominent in obese patients with and without MS. IDF definition of MS fails to discover individuals with IR, unless it is specifically investigated. PMID- 22450766 TI - Antioxidant sestrin-2 redistribution to neuronal soma in human immunodeficiency virus-associated neurocognitive disorders. AB - Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1 infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer's disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronal-soma predominance (S; P < 0.0001, Chi-square test for linear trend). Among HIV cases showing the NS or S pattern, HAND cases were preferentially associated with the S pattern (n = 10 of 20) compared to cognitively intact cases (n = 1 of 11; P = 0.047, Fisher's exact test). In AD brains, sestrin-2 immunoreactivity was mostly intense in the neuropil and co-localized with phospho-Tau immunoreactivity in a subset of neurofibrillary lesions. Phospho-Tau-immunoreactive neurofibrillary lesions were rare in HIV cases and their occurrence was not associated with HAND. Levels of isocortical 8-hydroxy-deoxyguanosine (marker of nucleic acid oxidation) immunoreactivity were not significantly altered in HAND cases compared to cognitively intact HIV cases. In conclusion, the sestrin-2 immunoreactivity redistribution to neuronal soma in HAND suggests unique involvement of sestrin-2 in the pathophysiology of HAND, which is different from the role of sestrin-2 in AD pathogenesis. Alternatively, the difference in sestrin-2 immunoreactivity distribution between HAND and AD may be related to different degrees of severity or stages of oxidative stress. PMID- 22450767 TI - Dead certain: confidence and conservatism predict aggression in simulated international crisis decision-making. AB - Evolutionary psychologists have suggested that confidence and conservatism promoted aggression in our ancestral past, and that this may have been an adaptive strategy given the prevailing costs and benefits of conflict. However, in modern environments, where the costs and benefits of conflict can be very different owing to the involvement of mass armies, sophisticated technology, and remote leadership, evolved tendencies toward high levels of confidence and conservatism may continue to be a contributory cause of aggression despite leading to greater costs and fewer benefits. The purpose of this paper is to test whether confidence and conservatism are indeed associated with greater levels of aggression-in an explicitly political domain. We present the results of an experiment examining people's levels of aggression in response to hypothetical international crises (a hostage crisis, a counter-insurgency campaign, and a coup). Levels of aggression (which range from concession to negotiation to military attack) were significantly predicted by subjects' (1) confidence that their chosen policy would succeed, (2) score on a liberal-conservative scale, (3) political party affiliation, and (4) preference for the use of military force in real-world U.S. policy toward Iraq and Iran. We discuss the possible adaptive and maladaptive implications of confidence and conservatism for the prospects of war and peace in the modern world. PMID- 22450768 TI - Synthesis and characterization of four new thallium(I) tetrazole supramolecular compounds with various secondary interactions; new precursors for thallium(III) oxide nano-particles. AB - Four new thallium(I) coordination polymers, [TlBt](n) (1) (Hbt = 5 phenyltetrazole), [TlBbt] (2) (Hbbt = 5-(4-bromobenzyl)tetrazole), [Tl(2)Bdt](n) (3) (H(2)bdt = 5,5'-benzene-1,4-diylbistetrazole), [Tl(2)Pht.H(2)O](n) and [TlBet] (4), (Hbet = 5-(benzyl)tetrazole) have been synthesized and characterized. The single-crystal X-ray data shows that, in compounds 1-3, the coordination sphere of the Tl(I) ion is the same and it is surrounded with six tetrazolate rings. In compound 4, one thallium atom has three interactions with tetrazolate groups and close Tl(I)...pi (aromatic) contacts with the phenyl ring. Furthermore, in all cases the single-crystal X-ray data show the same stereo chemical activity of the valence shell electron lone pair of Tl(I). There is a strong Tl(I)...Tl(I) interaction in one dimension in compounds 1 and 3. All these four compounds have been used as new precursors for the preparation of thallium(III) oxide nano-particles through a simple calcination method. Thallium(III) oxide was characterized by powder XRD diffraction and the morphology of nano particles characterized by scanning electron microscope (SEM). PMID- 22450770 TI - Establishment and characterization of novel gastric signet-ring cell and non signet-ring cell poorly differentiated adenocarcinoma cell lines with low and high malignant potential. AB - BACKGROUND: Poorly differentiated signet-ring cell carcinoma (SRCC) and non signet-ring cell carcinoma (NSRCC) are prevalent histological subtypes of gastric cancers with distinct morphological features. To date, however, the molecular basis of their growth, differentiation, and metastasis still remains unclear, because of the limitation of available cell lines. METHODS: In the present study, we established novel SRCC and NSRCC cell lines (designated GPM-2 and GPM-1) derived from the ascites of two individual gastric cancer patients with peritoneal metastasis. RESULTS: Immunohistochemical and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that GPM-2 cells showed both gastric and intestinal differentiation phenotypes (E cadherin+/MUC5AC+/MUC6+/Villin+), and formed xenografted tumors with typical SRCC histology in nude mice. In contrast, GPM-1 cells only weakly expressed differentiation markers, showing a phenotype of E-cadherin(low)+/MUC2-/MUC5AC /Villin(low)+. Characteristically, GPM-2 cells were found to highly express both membrane-bound mucin (MUC1/MUC4) and secreted mucin glycoproteins (MUC5AC/MUC6), whose expression is regulated by an epigenetic mechanism such as histone acetylation. GPM-2 cells also secreted a large amount of sTn antigen into the culture medium. These mucin profiles of GPM-2 cells are distinct from those of conventional SRCC cell lines (KATO III and HSC-39), which preferentially express intestinal MUC2/MUC4 as well as sLe(x) and sLe(A) antigens. In addition, GPM-2 cells showed a slow growth rate, and a lower metastatic potential than GPM-1 cells. CONCLUSIONS: These results indicate that the cells of the new SRCC line, GPM-2 cells, are more differentiated and less aggressive than NSRCC-type GPM-1 cells, and would thus offer an excellent model for understanding the molecular mechanism underlying the growth, differentiation, and mucin production of an SRCC gastric cancer cell line. PMID- 22450771 TI - [Medicinal or instrumental (corrected) therapy of renal artery stenosis?]. AB - Arteriosclerotic renal artery stenosis (RAS) has an increased incidence in patients with cardiovascular risk factors. Clinically RAS presents in some patients as secondary, sometimes resistant arterial hypertension and in others as chronic renal insufficiency, sometimes with acute renal failure and in a third group both symptoms are observed. Doppler ultrasound plays a central role in the diagnosis of RAS. Therapeutically, it is important to identify hemodynamically relevant RAS before interventional therapy is initiated. The therapy of RAS has been under intensive debate since the publication of randomized controlled trials (RCT) which showed that only a subset of RAS can be successfully treated by interventional therapy. Since then the medicinal therapy of RAS has gained more and more impact. The following questions are raised: which forms of RAS can be treated by which therapy? What is the best medicinal therapy to treat RAS? What substances are recommended? PMID- 22450772 TI - [Dynamic left ventricular outflow tract obstruction in pulmonary embolism]. AB - Left ventricular hypertrophy, dehydration, sepsis, vasodilatation, excessive sympathetic stimulation, pericardial tamponade and surgical treatment of the atrioventricular valve are known causes of left ventricular outflow tract (LVOT) obstruction. We report the rare case of a patient who developed dynamic LVOT obstruction as a complication of acute pulmonary embolism. PMID- 22450773 TI - Late effects of a perinatal exposure to a 16 PAH mixture: Increase of anxiety related behaviours and decrease of regional brain metabolism in adult male rats. AB - Polycyclic Aromatic Hydrocarbons (PAHs) are ubiquitous pollutants originated from incomplete combustion processes. Ingestion of contaminated food is the main route of exposure for humans. These molecules are able to cross the placental barrier and are also found in breast milk. Since PAHs are neurotoxic agents, the potential adverse effects of a perinatal exposure of the developing brain is a key issue for public health especially concerning PAH mixture. In this study, female rats were exposed trough diet to a mixture of 16 PAHs, at doses of 2 MUg/kg/day or 200 MUg/kg/day during gestation and 1.5 MUg/kg/day or 150 MUg/kg/day during breast-feeding period. To assess late neurotoxic effects in male offsprings, behavioural and cognitive tests were carried out and histochemical analyses using cytochrome oxidase as a cerebral metabolism marker were performed on adult animals. Results showed that anxiety-related behaviours significantly increased in exposed animals, but there was no significant alteration of motor activity and learning and memory abilities. Several brain areas of the limbic system showed a neuronal hypometabolism in exposed animals. This work highlights that exposure to PAHs at early stages of brain development can cause later troubles on behaviour and that PAHs are able to partly alter the central nervous system metabolism on adulthood. PMID- 22450774 TI - Current understanding of placental fatty acid transport. AB - PURPOSE OF REVIEW: The amount and activity of placental enzymes, receptors, and transport proteins will determine the extent of lipid transfer to the fetus that strongly contributes to fetal fat accretion. RECENT FINDINGS: Several studies have shown an association between the percentage of maternal plasma docosahexaenoic acid during gestation and the development of cognitive functions in the neonate. The functionality of the placenta could affect neonatal adiposity and fetal levels of long-chain polyunsaturated fatty acids in the offspring. SUMMARY: Both in-vitro and human in-vivo studies using labeled fatty acids (FAs) reported a preferential placental-fetal transfer of long-chain polyunsaturated fatty acids, although the mechanisms are still uncertain. The placenta uptakes the maternal circulating nonesterified fatty acids (NEFAs) and FAs released by maternal lipoprotein lipase and endothelial lipase. These NEFAs enter the cell through passive diffusion or by membrane carrier proteins. NEFAs bind to cytosolic fatty-acid-binding proteins to interact with subcellular organelles, including the endoplasmic reticulum, mitochondria, lipid droplets and peroxisomes. Knowledge about FA metabolism and adaptations in response to obesity or diabetes in human placenta is more limited, and contradictory results are available in their influence on placental lipases and carriers. PMID- 22450775 TI - Malnutrition, fatigue, frailty, vulnerability, sarcopenia and cachexia: overlap of clinical features. AB - PURPOSE OF REVIEW: Malnutrition, fatigue, frailty, vulnerability, sarcopenia and cachexia all phenotypically present with the same features because they are subject to the operation of similar mechanistic factors. However, the conditions referred to above differ by which mechanism dominates the cause of the clinical condition. This review discusses the overlap and differences, which distinguish as well as unite these different conditions and allow a rationale for treatment. RECENT FINDINGS: In the continuum of malnutrition, cachexia, sarcopenia and frailty the recent activities focus on two areas. The first is a better understanding of the mechanisms of cachexia and sarcopenia and frailty. In particular, the differential effects of cytokines on muscle and on the hypothalamic system. The effects of inactivity promoting the loss of body mass in cachexia and sarcopenia as well as the positive effects of exercise. The second is the development of a synthesis of available literature to develop consensus documents about the definition, causes, diagnosis and treatment of cachexia, sarcopenia and frailty. SUMMARY: Loss of body tissues resulting in wasting is a common phenotype for several different conditions which can be caused by a combination of reduced food intake, excessive requirements, altered metabolism, sepsis, trauma, ageing and inactivity. They have been referred to loosely as malnutrition but in not all will respond to simply providing nutrients. In this review the common features and the differences as they relate to cause and response to treatment are discussed. PMID- 22450776 TI - Enucleation of painful blind eye for refractory intraocular lymphoma after dose limiting chemotherapy and radiotherapy. PMID- 22450777 TI - Preventive effect of embelin from embelia ribes on lipid metabolism and oxidative stress in high-fat diet-induced obesity in rats. AB - A high-fat diet (HFD) results in hyperlipidemia and an increase in oxidative stress. The purpose of this study was to investigate the preventive effect of embelin against hyperlipidemia and oxidative stress in HFD-induced obesity in rats. Male Wistar rats aged 12 weeks (150-200 g) were fed with an HFD for a period of 28 days to induce experimental obesity. HFD-induced obese rats were treated with embelin (50 mg/kg) or orlistat (10 mg/kg) for 21 days. A range of parameters were tested including body weight gain, body mass index (BMI), blood pressure, visceral fat pad weights, serum levels of glucose, insulin, leptin, apolipoprotein B (ApoB), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hepatic thiobarbituric acid-reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Twenty-one days of embelin (50 mg/kg) treatment produced effects similar to orlistat in reducing body weight gain, blood pressure, visceral fat pad weight, serum lipid levels, as well as coronary artery risk and atherogenic indices of HFD-fed rats. Embelin treatment also lowered the serum levels of glucose by 24.77 %, insulin by 35.03 %, and leptin by 43.39 %. Furthermore, embelin treatment significantly (p < 0.01) decreased the hepatic TBARS levels, while increasing the SOD, CAT, and GSH levels in obese rats. The present study indicated the preventive effect of embelin in HFD-induced obesity and its related complications. Embelin could be valuable in the development of new drug therapies to prevent obesity, hyperlipidemia, and oxidative stress. PMID- 22450778 TI - Small-molecule photovoltaics based on functionalized squaraine donor blends. AB - Two squaraine (SQ) donor molecules with different absorption bands are blended together for better coverage of the solar spectrum. The blend SQ device shows a significant improvement compared with single SQ donor devices. By applying a solvent annealing process and a compound buffer layer, a power-conversion efficiency of 5.9 +/- 0.3% is achieved under 1 sun illumination. PMID- 22450779 TI - Thiazolidinedione drugs promote onset, alter characteristics, and increase mortality of ischemic ventricular fibrillation in pigs. AB - PURPOSE: Despite favorable metabolic and vascular effects, thiazolidinedione (TZD) drugs have not convincingly reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (K(ATP)) channels in pigs. In this study, we investigated whether TZDs affect onset, spectral characteristics, and mortality of ischemic ventricular fibrillation (VF) and whether such effects are recapitulated by a non-selective K(ATP) blocker (glyburide) or a mitochondrial K(ATP) blocker (5-hydroxydecanoate). METHODS: A total of 121 anesthetized pigs were pre-treated with TZD (pioglitazone or rosiglitazone, 1 mg/kg IV, resulting in clinically relevant plasma concentrations), glyburide (1 mg/kg IV), 5-hydroxydecanoate (5 mg/kg IV) or inert vehicle. Ischemia was produced by occlusion of the left anterior descending coronary artery. In a subset of pigs treated with rosiglitazone or vehicle, ischemic preconditioning was performed. RESULTS: VF developed in all but 6 pigs. In non-preconditioned pigs, onset of VF occurred sooner with pioglitazone (11+/-3 min, p<0.05) or rosiglitazone (14+/-3 min, p=0.06) than with vehicle (20+/-2 min). Defibrillation of VF was successful in 44% of pigs treated with vehicle, compared with 0% with pioglitazone (p=0.057) and 33% with rosiglitazone (NS). After ischemic preconditioning, defibrillation was successful in 62% of pigs treated with vehicle, compared with 26% treated with rosiglitazone (p=0.03). TZDs attenuated slowing of conduction due to ischemia and shifted ECG power spectra during VF toward higher frequencies. All effects of TZDs were recapitulated by glyburide, but not by 5-hydroxydecanoate, supporting an interaction of TZDs with the sarcolemmal K(ATP) channel. CONCLUSION: In a porcine model, TZDs promote onset and increase mortality of ischemic VF, associated with alterations of conduction and VF spectral characteristics. Similar effects in a clinical setting might adversely impact cardiovascular mortality. PMID- 22450780 TI - Photochemical cycloaddition on the pore surface of a porous coordination polymer impacts the sorption behavior. AB - Photochemical [2+2] cycloaddition reactions in a two-dimensional interdigitated porous crystalline framework proceed in a single-crystal-to-single-crystal manner, and one-dimensional channels show structural changes that have a significant impact on the CO(2) sorption. PMID- 22450781 TI - Lack of microRNA-101 causes E-cadherin functional deregulation through EZH2 up regulation in intestinal gastric cancer. AB - E-cadherin expression disruption is commonly observed in metastatic epithelial cancers and is a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression/function of pivotal cancer-related genes, we characterized and dissected a pathway that causes E-cadherin dysfunction via loss of microRNA-101 and up-regulation of EZH2 expression in GC. MicroRNA microarray expression profiling and array-CGH were used to reinforce miR-101 involvement in GC. By using quantitative real-time PCR and quantitative SNaPshot genomic PCR, we confirmed that miR-101 was significantly down-regulated in GC (p < 0.0089) in comparison with normal gastric mucosas and, at least in 65% of the GC cases analysed, this down-regulation was caused by deletions and/or microdeletions at miR-101 genomic loci. Moreover, around 40% of cases showing miR-101 down-regulation displayed concomitant EZH2 over-expression (at the RNA and protein levels), which, in turn, was associated with loss/aberrant expression of E-cadherin. Interestingly, this occurred preferentially in intestinal-type GCs, retaining allele(s) untargeted by classical CDH1-inactivating mechanisms. We also demonstrated that miR-101 gain of function or direct inhibition of EZH2 in Kato III GC cells led to a strong depletion of endogenous EZH2 and consequent rescue of E-cadherin membranous localization, mimicking results obtained in clinical GC samples. In conclusion, we show that deletions and/or microdeletions at both miR-101 genomic loci cause mature miR-101 down-regulation, subsequent EZH2 over-expression and E-cadherin dysfunction, specifically in intestinal-type GC. PMID- 22450782 TI - Isolation of surfactant-resistant pseudomonads from the estuarine surface microlayer. AB - Bioremediation efforts often rely on the application of surfactants to enhance hydrocarbon bioavailability. However, synthetic surfactants can sometimes be toxic to degrading microorganisms, thus reducing the clearance rate of the pollutant. Therefore, surfactant-resistant bacteria can be an important tool for bioremediation efforts of hydrophobic pollutants, circumventing the toxicity of synthetic surfactants that often delay microbial bioremediation of these contaminants. In this study, we screened a natural surfactant-rich compartment, the estuarine surface microlayer (SML), for cultivable surfactant-resistant bacteria using selective cultures of sodium dodecyl sulfate (SDS) and cetyl trimethylammonium bromide (CTAB). Resistance to surfactants was evaluated by colony counts in solid media amended with critical micelle concentrations (CMC) of either surfactants, in comparison with non-amended controls. Selective cultures for surfactant-resistant bacteria were prepared in mineral medium also containing CMC concentrations of either CTAB or SDS. The surfactantresistant isolates obtained were tested by PCR for the Pseudomonas genus marker gacA gene and for the naphthalene-dioxygenase-encoding gene ndo. Isolates were also screened for biosurfactant production by the atomized oil assay. A high proportion of culturable bacterioneuston was tolerant to CMC concentrations of SDS or CTAB. The gacA-targeted PCR revealed that 64% of the isolates were Pseudomonads. Biosurfactant production in solid medium was detected in 9.4% of tested isolates, all affiliated with genus Pseudomonas. This study shows that the SML is a potential source of surfactant-resistant and biosurfactant-producing bacteria in which Pseudomonads emerge as a relevant group. PMID- 22450783 TI - Biochemical characterization of recombinant L-asparaginase (AnsA) from Rhizobium etli, a member of an increasing rhizobial-type family of L-asparaginases. AB - We report the expression, purification, and characterization of L-asparaginase (AnsA) from Rhizobium etli. The enzyme was purified to homogeneity in a single step procedure involving affinity chromatography, and the kinetic parameters K(m), V(max), and k(cat) for L-asparagine were determined. The enzymatic activity in the presence of a number of substrates and metal ions was investigated. The molecular mass of the enzyme was 47 kDa by SDS-PAGE. The enzyme showed a maximal activity at 50 degrees C, but the optimal temperature of activity was 37 degrees C. It also showed maximal and optimal activities at pH 9.0. The values of K(m), V(max), k(cat), and k(cat)/K(m) were 8.9 +/- 0.967 * 10-3 M, 128 +/- 2.8 U/mg protein, 106 +/- 2 s-1, and 1.2 +/- 0.105 * 104 M-1s-1, respectively. The L asparaginase activity was reduced in the presence of Mn2+, Zn2+, Ca2+, and Mg2+ metal ions for about 52% to 31%. In addition, we found that NH4+, L-Asp, D-Asn, and beta-aspartyl-hydroxamate in the reaction buffer reduced the activity of the enzyme, whereas L-Gln did not modify its enzymatic activity. This is the first report on the expression and characterization of the L-asparaginase (AnsA) from R. etli. Phylogenetic analysis of asparaginases reveals an increasing group of known sequences of the Rhizobialtype asparaginase II family. PMID- 22450784 TI - Molecular profiling of rhizosphere bacterial communities associated with Prosopis juliflora and Parthenium hysterophorus. AB - Prosopis juliflora and Parthenium hysterophorus are the two arid, exotic weeds of India that are characterized by distinct, profuse growth even in nutritionally poor soils and environmentally stressed conditions. Owing to the exceptional growth nature of these two plants, they are believed to harbor some novel bacterial communities with wide adaptability in their rhizosphere. Hence, in the present study, the bacterial communities associated with the rhizosphere of Prosopis and Parthenium were characterized by clonal 16S rRNA gene sequence analysis. The culturable microbial counts in the rhizosphere of these two plants were higher than bulk soils, possibly influenced by the root exudates of these two plants. The phylogenetic analysis of V1_V2 domains of the 16S rRNA gene indicated a wider range of bacterial communities present in the rhizosphere of these two plants than in bulk soils and the predominant genera included Acidobacteria, Gammaproteobacteria, and Bacteriodetes in the rhizosphere of Prosopis, and Acidobacteria, Betaproteobacteria, and Nitrospirae in the Parthenium rhizosphere. The diversity of bacterial communities was more pronounced in the Parthenium rhizosphere than in the Prosopis rhizosphere. This culture-independent bacterial analysis offered extensive possibilities of unraveling novel microbes in the rhizospheres of Prosopis and Parthenium with genes for diverse functions, which could be exploited for nutrient transformation and stress tolerance in cultivated crops. PMID- 22450785 TI - Ramlibacter ginsenosidimutans sp. nov., with ginsenoside-converting activity. AB - A novel beta-proteobacterium, designated BXN5-27(T), was isolated from soil of a ginseng field of Baekdu Mountain in China, and was characterized using a polyphasic approach. The strain was Gram-staining-negative, aerobic, motile, non spore-forming, and rod shaped. Strain BXN5-27(T) exhibited beta-glucosidase activity that was responsible for its ability to transform ginsenoside Rb1 (one of the dominant active components of ginseng) to compound Rd. Phylogenetic analysis based on 16S rRNA gene sequences showed that this strain belonged to the family Comamonadaceae; it was most closely related to Ramlibacter henchirensis TMB834(T) and Ramlibacter tataouinensis TTB310(T) (96.4% and 96.3% similarity, respectively). The G+C content of the genomic DNA was 68.1%. The major menaquinone was Q-8. The major fatty acids were C16:0, summed feature 4 (comprising C16:1 omega7c and/or iso-C15:0 2OH), and C17:0 cyclo. Genomic and chemotaxonomic data supported the affiliation of strain BXN5-27(T) to the genus Ramlibacter. However, physiological and biochemical tests differentiated it phenotypically from the other established species of Ramlibacter. Therefore, the isolate represents a novel species, for which the name Ramlibacter ginsenosidimutans sp. nov. is proposed, with the type strain being BXN5-27(T) (= DSM 23480(T) = LMG 24525(T) = KCTC 22276(T)). PMID- 22450786 TI - Attenuated secretion of the thermostable xylanase xynB from Pichia pastoris using synthesized sequences optimized from the preferred codon usage in yeast. AB - Xylanase has been used extensively in the industrial and agricultural fields. However, the low-yield production of xylanase from native species cannot meet the increasing demand of the market. Therefore, improving the heterologous expression of xylanase through basic gene optimization may help to overcome the shortage. In this study, we synthesized a high-GC-content native sequence of the thermostable xylanase gene xynB from Streptomyces olivaceoviridis A1 and, also designed a slightly AT-biased sequence with codons completely optimized to be favorable to Pichia pastoris. The comparison of the sequences' expression efficiencies in P. pastoris X33 was determined through the detection of single-copy-number integrants, which were quantified using qPCR. Surprisingly, the high GC content did not appear to be detrimental to the heterologous expression of xynB in yeast, whereas the optimized sequence, with its extremely skewed codon usage, exhibited more abundant accumulation of synthesized recombinant proteins in the yeast cell, but an approximately 30% reduction of the secretion level, deduced from the enzymatic activity assay. In this study, we developed a more accurate method for comparing the expression levels of individual yeast transformants. Moreover, our results provide a practical example for further investigation of what constitutes a rational design strategy for a heterologously expressed and secreted protein. PMID- 22450787 TI - Elucidation of antifungal metabolites produced by Pseudomonas aurantiaca IB5-10 with broad-spectrum antifungal activity. AB - Antifungal metabolites were isolated from a culture of Pseudomonas aurantiaca IB5 10. Chemical structures of the metabolites were elucidated as phenazine-1 carboxylic acid (PCA; 1), 2-hydroxyphenazine (2-OH-PHZ; 2), and cyclo-(L-Pro-L Val; 3), respectively, based on spectroscopic methods. Among them, 3 was isolated for the first time from this strain. The antifungal activities of 1-3 were evaluated against a variety of plant pathogens. To the best of our knowledge, the antifungal activities of 3 against plant fungal pathogens have been evaluated for the first time in this work. PCA (1) showed the most potent antifungal activities against Phytophthora capsici, Rhizoctonia solani AG-1(IA), and Pythium ultimum with MICs (microgram/ml) of less than 1.0, 1.3, and 2.0, respectively. On the other hand, 2-OH-PHZ (2) showed potent antifungal activity against R. solani AG 1(IA) with the MIC (microgram/ml) of 2.0, whereas it showed moderate antifungal activity against P. ultimum with the MIC (microgram/ml) of 50.0. In addition, 3 showed antifungal activity against only R. solani AG- 1(IA). PMID- 22450788 TI - Cloning, high-level expression, purification, and properties of a novel endo-beta 1,4-mannanase from Bacillus subtilis G1 in Pichia pastoris. AB - A novel gene coding for an endo-beta-1,4-mannanase (manA) from Bacillus subtilis strain G1 was cloned and overexpressed in P. pastoris GS115, and the enzyme was purified and characterized. The manA gene consisted of an open reading frame of 1,092 nucleotides, encoding a 364-aa protein, with a predicted molecular mass of 41 kDa. The beta-mannanase showed an identity of 90.2-92.9% (< or =95%) with the corresponding amino acid sequences from B. subtilis strains deposited in GenBank. The purified beta- mannanase was a monomeric protein on SDS-PAGE with a specific activity of 2,718 U/mg and identified by MALDITOF mass spectrometry. The recombinant beta-mannanase had an optimum temperature of 45 degrees C and optimum pH of 6.5. The enzyme was stable at temperatures up to 50 degrees C (for 8 h) and in the pH range of 5-9. EDTA and most tested metal ions showed a slightly to an obviously inhibitory effect on enzyme activity, whereas metal ions (Hg2+, Pb2+, and Co2+) substantially inhibited the recombinant beta-mannanase. The chemical additives including detergents (Triton X- 100, Tween 20, and SDS) and organic solvents (methanol, ethanol, n-butanol, and acetone) decreased the enzyme activity, and especially no enzyme activity was observed by addition of SDS at the concentrations of 0.25-1.0% (w/v) or n-butanol at the concentrations of 20 30% (v/v). These results suggested that the beta-mannanase expressed in P. pastoris could potentially be used as an additive in the feed for monogastric animals. PMID- 22450789 TI - Characterization of new antihypertensive angiotensin I-converting enzyme inhibitory peptides from Korean traditional rice wine. AB - This study describes the characterization of a new angiotensin I-converting enzyme (ACE) inhibitory peptide from a Korean traditional rice wine. After purification of the ACE inhibitor peptides with ultrafiltration, Sephadex G-25 column chromatography, and successively C18 and SCX solid-phase extraction, reverse-phase HPLC, and size exculsion chromatography, two types of the purified ACE inhibitors with IC50 values of 0.34 mg/ml and 1.23 mg/ml were finally obtained. The two purified ACE inhibitors (F-1 and F-2) were found to have two kinds of novel oligopeptides, showing very little similarity to other ACE inhibitory peptide sequences. The amino acid sequences of the two purified oligopeptides were found to be Gln- Phe-Tyr-Ala-Val (F-1) and Ala-Gly-Pro-Val-Leu Leu (F-2), and their molecular masses were estimated to be 468.7 Da (F-1) and 357.7 Da (F-2), respectively. They all showed a clear antihypertensive effect on spontaneously hypertensive rats at a dosage of 500 mg/kg. PMID- 22450790 TI - Kinetics of a cloned special ginsenosidase hydrolyzing 3-O-glucoside of multi protopanaxadiol-type ginsenosides, named ginsenosidase type III. AB - In this paper, the kinetics of a cloned special glucosidase, named ginsenosidase type III hydrolyzing 3-O-glucoside of multi-protopanaxadiol (PPD)-type ginsenosides, were investigated. The gene (bgpA) encoding this enzyme was cloned from a Terrabacter ginsenosidimutans strain and then expressed in E. coli cells. Ginsenosidase type III was able to hydrolyze 3-O-glucoside of multi-PPD-type ginsenosides. For instance, it was able to hydrolyze the 3-O-beta-D-(1-->2) glucopyranosyl of Rb1 to gypenoside XVII, and then to further hydrolyze the 3-O beta-D-glucopyranosyl of gypenoside XVII to gypenoside LXXV. Similarly, the enzyme could hydrolyze the glucopyranosyls linked to the 3-O- position of Rb2, Rc, Rd, Rb3, and Rg3. With a larger enzyme reaction Km value, there was a slower enzyme reaction speed; and the larger the enzyme reaction Vmax value, the faster the enzyme reaction speed was. The Km values from small to large were 3.85 mM for Rc, 4.08 mM for Rb1, 8.85 mM for Rb3, 9.09 mM for Rb2, 9.70 mM for Rg3(S), 11.4 mM for Rd and 12.9 mM for F2; and Vmax value from large to small was 23.2 mM/h for Rc, 16.6 mM/h for Rb1, 14.6 mM/h for Rb3, 14.3 mM/h for Rb2, 1.81mM/h for Rg3(S), 1.40 mM/h for Rd, and 0.41 mM/h for F2. According to the Vmax and Km values of the ginsenosidase type III, the hydrolysis speed of these substrates by the enzyme was Rc>Rb1>Rb3>Rb2>Rg3(S)>Rd>F2 in order. PMID- 22450791 TI - Characterization of zinc-solubilizing Bacillus isolates and their potential to influence zinc assimilation in soybean seeds. AB - One hundred thirty-four putative Bacillus isolates were recovered from soybean rhizosphere soils of Nimar region to select effective zinc solubilizers for increased assimilation of zinc (Zn) in soybean seeds. These isolates were screened in vitro for zinc-solubilization ability on Tris-minimal agar medium supplemented separately with 0.1% zinc in the form of zinc oxide, zinc phosphate, and zinc carbonate. Of all, 9 isolates and a reference Bacillus cereus ATCC 13061 were characterized and identified as Bacillus species based on Gram-positive reaction, endospore-forming cells, and the presence of iso-C15:0 and anteiso C15:0 as predominant fatty acids. On plate assay, two isolates KHBD-6 and KHBAR-1 showed a greater diameter of solubilization halo and colony diameter on all the three zinc compounds. The isolates KHBD-6, KHBAR-1, BDSD-2-2C, and KHTH-4-1 and the reference strain ATCC 13061 had higher soluble zinc concentration in liquid medium supplemented with zinc phosphate and zinc carbonate compounds as compared with the other isolates and uninoculated control. Evaluation under microcosm conditions showed that inoculation of isolates KHBD-6 (57.34 MUg/g), KHBAR-1 (55.67 MUg/g), and strain ATCC 13061 (53.10 MUg/g) significantly increased the Zn concentration in soybean seeds as compared with the other isolates and uninoculated control (47.14 MUg/g). This study suggests the occurrence of zinc solubilizing Bacillus in soils of Nimar region and isolates KHBD-6 and KHBAR-1 were found to be promising zinc solubilizers for increased assimilation of Zn in soybean seeds. PMID- 22450792 TI - Microbial community analysis of a methane-oxidizing biofilm using ribosomal tag pyrosequencing. AB - Current ecological knowledge of methanotrophic biofilms is incomplete, although they have been broadly studied in biotechnological processes. Four individual DNA samples were prepared from a methanotrophic biofilm, and a multiplex 16S rDNA pyrosequencing was performed. A complete library (before being de-multiplexed) contained 33,639 sequences (average length, 415 nt). Interestingly, methanotrophs were not dominant, only making up 23% of the community. Methylosinus, Methylomonas, and Methylosarcina were the dominant methanotrophs. Type II methanotrophs were more abundant than type I (56 vs. 44%), but less richer and diverse. Dominant non-methanotrophic genera included Hydrogenophaga, Flavobacterium, and Hyphomicrobium. The library was de-multiplexed into four libraries, with different sequencing efforts (3,915-20,133 sequences). Sorrenson abundance similarity results showed that the four libraries were almost identical (indices > 0.97), and phylogenetic comparisons using UniFrac test and P-test revealed the same results. It was demonstrated that the pyrosequencing was highly reproducible. These survey results can provide an insight into the management and/or manipulation of methanotrophic biofilms. PMID- 22450793 TI - Mcl-PHAs produced by Pseudomonas sp. Gl01 using fed-batch cultivation with waste rapeseed oil as carbon source. AB - The present study describes medium-chain-length polyhydroxyalkanoates (mcl-PHAs) production by the Pseudomonas Gl01 strain isolated from mixed microbial communities utilized for PHAs synthesis. A two-step fedbatch fermentation was conducted with glucose and waste rapeseed oil as the main carbon source for obtaining cell growth and mcl-PHAs accumulation, respectively. The results show that the Pseudomonas Gl01 strain is capable of growing and accumulating mcl-PHAs using a waste oily carbon source. The biomass value reached 3.0 g/l of CDW with 20% of PHAs content within 48 h of cultivation. The polymer was purified from lyophilized cells and analyzed by gas chromatography (GC). The results revealed that the monomeric composition of the obtained polyesters depended on the available substrate. When glucose was used in the growth phase, 3 hydroxyundecanoate and 3- hydroxydodecanoate were found in the polymer composition, whereas in the PHAs-accumulating stage, the Pseudomonas Gl01 strain synthesized mcl-PHAs consisting mainly of 3- hydroxyoctanoate and 3 hydroxydecanoate. The transcriptional analysis using reverse-transcription real time PCR reaction revealed that the phaC1 gene could be transcribed simultaneously to the phaZ gene. PMID- 22450794 TI - Organotin compounds act as inhibitor of transcriptional activation with human estrogen receptor. AB - In aquatic invertebrates, particularly marine gastropods, organotin compounds induce irreversible sexual abnormality in females, which is termed imposex, at very low concentrations. Organotin compounds are agonists for nuclear receptors such as RXRs and PPARgamma. However, the imposex phenomenon has not been reported to act as an antagonist on estrogen receptors in other species, including vertebrates and invertebrates. In order to gain insights into the antagonistic activity of organotin compounds on estrogen receptors (ERs), we examined the inhibitive effect of these compounds on estradiol-dependent beta-galactosidase activity using the yeast two-hybrid detection system consisting of a combination of the human estrogen receptor (hERbeta) ligand-binding domain and the co activator steroid receptor co-activator-1 (SRC1). Tributyltin-hydroxide (TBT-OH) and triphenyltin-chlorine (TPT-Cl) exhibited an inhibitive effect on E2-dependent transcriptional activity, similar to antagonistic chemicals such as 4 hydroxytamoxifen (OHT) or ICI 182,780, at a very low concentration of 10-14 M TBT or 10-10 M TPT, respectively. The yeast growth and transcriptional activity with transcriptional factor GAL4 did not exhibit any effect at the tested concentration of TBT or TPT. Moreover, the yeast two-hybrid system using the interaction between p53 and the T antigen of SV40 large did not describe any effect at the tested concentration of OHT or ICI 182,780. However, the interaction between p53 and T antigen was inhibited at a TBT or TPT concentration of 10-9 M, respectively. These results indicate that TBT and TPT act as inhibitors of ER-dependent reporter gene transcriptional activation and of the interaction between hERbeta LBD and the co-activator SRC1 in the yeast two-hybrid system. Consequently, our data could partly explain the occurrence of organotin compound-induced imposex on the endocrine system of mammals, including humans. PMID- 22450795 TI - Application of alkaliphilic biofilm-forming bacteria to improve compressive strength of cement-sand mortar. AB - The application of microorganisms in the field of construction material is rapidly increasing worldwide; however, almost all studies that were investigated were bacterial sources with mineral-producing activity and not with organic substances. The difference in the efficiency of using bacteria as an organic agent is that it could improve the durability of cement material. This study aimed to assess the use of biofilm-forming microorganisms as binding agents to increase the compressive strength of cement-sand material. We isolated 13 alkaliphilic biofilmforming bacteria (ABB) from a cement tetrapod block in the West Sea, Korea. Using 16S RNA sequence analysis, the ABB were partially identified as Bacillus algicola KNUC501 and Exiguobacterium marinum KNUC513. KNUC513 was selected for further study following analysis of pH and biofilm formation. Cement-sand mortar cubes containing KNUC513 exhibited greater compressive strength than mineral-forming bacteria (Sporosarcina pasteurii and Arthrobacter crystallopoietes KNUC403). To determine the biofilm effect, Dnase I was used to suppress the biofilm formation of KNUC513. Field emission scanning electron microscopy image revealed the direct involvement of organic-inorganic substance in cement-sand mortar. PMID- 22450796 TI - Cloning, expression, and characterization of endoglucanase gene egIV from Trichoderma viride AS 3.3711. AB - Endoglucanase gene egIV was cloned from Trichoderma viride AS 3.3711, an important cellulose-producing fungus, by using an RT-PCR protocol. The egIV cDNA is 1,297 bp in length and contains a 1,035 bp open reading frame encoding a 344 amino acid protein with an estimated molecular mass of 35.5 kDa and isoelectronic point (pI) of 5.29. The expression of gene egIV in T. viride AS 3.3711 could be induced by sucrose, corn straw, carboxymethylcellulose (CMC), or microcrystalline cellulose, but especially by CMC. The transcripts of egIV were regulated under these substrates, but the expression level of the egIV gene could be inhibited by glucose and fructose. Three recombinant vectors, pYES2-xegIV, pYES2Malpha-egIV, and pYES2Malpha-xegIV, were constructed to express the egIV gene in Saccharomyces cerevisiae H158. The CMCase activity of yeast transformants IpYES2Malpha-xegIV was higher than that of transformant IpYES2-xegIV or IpYES2Malpha-egIV, with the highest activity of 0.13 U/ml at induction for 48 h, illustrating that the modified egIV gene could enhance CMCase activity and that MFalpha signal peptide from S. cerevisiae could regulate exogenous gene expression more effectively in S. cerevisiae. The recombinant EGIV enzyme was stable at pH 3.5 to 7.5 and temperature of 35 degrees C to 65 degrees C. The optimal reaction condition for EGIV enzyme activity was at the temperature of 55 degrees C, pH of 5.0, 0.75 mM Ba2+, and using CMC as substrate. Under these conditions, the highest activity of EGIV enzyme in transformant IpYES2Malpha-xegIV was 0.18 U/ml. These properties would provide technical parameters for utilizing cellulose in industrial bioethanol production. PMID- 22450797 TI - Effects of pH and carbon sources on biohydrogen production by co-culture of Clostridium butyricum and Rhodobacter sphaeroides. AB - To improve the hydrogen yield from biological fermentation of organic wastewater, a co-culture system of dark- and photo-fermentation bacteria was investigated. In a pureculture system of the dark-fermentation bacterium Clostridium butyricum, a pH of 6.25 was found to be optimal, resulting in a hydrogen production rate of 18.7 ml-H2/l/h. On the other hand, the photosynthetic bacterium Rhodobacter sphaeroides could produce the most hydrogen at 1.81 mol-H2/mol-glucose at pH 7.0. The maximum specific growth rate of R. sphaeroides was determined to be 2.93 h-1 when acetic acid was used as the carbon source, a result that was significantly higher than that obtained using either glucose or a mixture of volatile fatty acids (VFAs). Acetic acid best supported R. sphaeroides cell growth but not hydrogen production. In the co-culture system with glucose, hydrogen could be steadily produced without any lag phase. There were distinguishable inflection points in a plot of accumulated hydrogen over time, resulting from the dynamic production or consumption of VFAs by the interaction between the dark- and photofermentation bacteria. Lastly, the hydrogen production rate of a repeated fed-batch run was 15.9 ml-H2/l/h, which was achievable in a sustainable manner. PMID- 22450798 TI - Induction of defense response against Rhizoctonia solani in cucumber plants by endophytic bacterium Bacillus thuringiensis GS1. AB - An endophytic bacterium, Bacillus thuringiensis GS1, was isolated from bracken (Pteridium aquilinum) and found to have maximal production of chitinase (4.3 units/ml) at 5 days after culture. This study investigated the ability of B. thuringiensis GS1 to induce resistance to Rhizoctonia solani KACC 40111 (RS) in cucumber plants. Chitinase activity was greatest in RS-treated plants at 4 days. beta-1,3- Glucanase activity was highest in GS1-treated plants at 5 days. Guaiacol peroxidase (GPOD) activity increased continuously in all treated plants for 5 days. Ascorbate peroxidase (APX) activity in RS-treated plants was increased 1.5-fold compared with the control at 4 days. Polyphenol oxidase (PPO) activity in RS-treated plants was increased 1.5-fold compared with the control at 3 days. At 5 days after treatment, activity staining revealed three bands with chitinase activity (Ch1, Ch2, and Ch3) on SDSPAGE of cucumber plants treated with GS1+RS, whereas only one band was observed for RS-treated plants (Ch2). One GPOD isozyme (Gp1) was also observed in response to treatment with RS and GS1+RS at 4 days. One APX band (Ap2) was present on the native-PAGE gel of the control, and GS1- and GS1+RS-treated plants at 1 day. PPO bands (Po1 and Po2) from RS- and GS1+RS-treated plants were stronger than in the control and GS1-treated plants upon native-PAGE at 5 days. Taken together, these results indicate that the induction of PR proteins and defense-related enzymes by B. thuringiensis GS1 might have suppressed the damping-off caused by R. solani KACC 40111 in cucumber plants. PMID- 22450799 TI - Improved immune response to recombinant influenza nucleoprotein formulated with ISCOMATRIX. AB - Current influenza vaccines elicit antibodies effective against homologous strains, but new strategies are urgently needed for protection against emerging epidemic or pandemic strains. Although influenza vaccine candidates based on the viral nucleoprotein (NP) or matrix protein do not elicit sterilizing immunity, they have the advantage of inducing immunity that may cover a larger number of viral strains. In this study, recombinant NP produced in Escherichia coli was purified and formulated in combination with the adjuvant ISCOMATRIX. This formulation increased a NP-specific immunity in mice, with a Th1 profile, and may constitute a promising low-cost influenza vaccine candidate, with ability to stimulate humoral and cellular immune responses.. PMID- 22450800 TI - Bupleurum falcatum prevents depression and anxiety-like behaviors in rats exposed to repeated restraint stress. AB - Previous studies have demonstrated that repeated restraint stress in rodents produces increases in depression and anxietylike behaviors and alters the expression of corticotrophinreleasing factor (CRF) in the hypothalamus. The current study focused on the impact of Bupleurum falcatum (BF) extract administration on repeated restraint stress-induced behavioral responses using the forced swimming test (FST) and elevated plus maze (EPM) test. Immunohistochemical examinations of tyrosine hydroxylase (TH) expression in rat brain were also conducted. Male rats received daily doses of 20, 50, or 100 mg/kg (i.p.) BF extract for 15 days, 30 min prior to restraint stress (4 h/day). Hypothalamicpituitary- adrenal axis activation in response to repeated restraint stress was confirmed base on serum corticosterone levels and CRF expression in the hypothalamus. Animals that were pre-treated with BF extract displayed significantly reduced immobility in the FST and increased open-arm exploration in the EPM test in comparison with controls. BF also blocked the increase in TH expression in the locus coeruleus of treated rats that experienced restraint stress. Together, these results demonstrate that BF extract administration prior to restraint stress significantly reduces depression and anxiety-like behaviors, possibly through central adrenergic mechanisms, and they suggest a role for BF extract in the treatment of depression and anxiety disorders. PMID- 22450801 TI - Cancer-specific induction of adenoviral E1A expression by group I intron-based trans-splicing ribozyme. AB - In this study, we describe a novel approach to achieve replicative selectivity of conditionally replicative adenovirus that is based upon trans-splicing ribozyme mediated replacement of cancer-specific RNAs. We developed a specific ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to induce adenoviral E1A gene expression selectively in cancer cells that express the RNA. Western blot analysis showed that the ribozyme highly selectively triggered E1A expression in hTERT-expressing cancer cells. RT-PCR and sequencing analysis indicated that the ribozyme-mediated E1A induction was caused via a high fidelity trans-splicing reaction with the targeted residue in the hTERTexpressing cells. Moreover, reporter activity under the control of an E1A-dependent E3 promoter was highly transactivated in hTERT-expressing cancer cells. Therefore, adenovirus containing the hTERT RNA-targeting transsplicing ribozyme would be a promising anticancer agent through selective replication in cancer cells and thus specific destruction of the infected cells. PMID- 22450802 TI - Induction of type I IFNs by intracellular DNA-sensing pathways. AB - A successful antimicrobial immune response involves the coordinate action of cells and soluble factors, with the cytokine family of type I interferons (IFNs) having a central role. Type I IFNs are not only crucial in conferring immediate antimicrobial, most importantly antiviral effects, but they also have an essential role in bridging the innate with the adaptive immune response. Therefore, production of these key cytokines must be tightly controlled. To this effect the host has evolved a set of pattern recognition receptors (PRRs) that reliably and specifically detect the presence of microbial pathogens before mounting an IFN response. Most PRR pathways that are known to induce type I IFNs are triggered upon recognition of nucleic acids. This mode of sensing is not straightforward, as large amounts of RNA and DNA are also present within the host. Nevertheless, in some cases distinct molecular features that are present within foreign nucleic acids but absent in endogenous nucleic acids, allow the host to reliably discriminate between 'self' and 'non-self'. At the same time, compartmentalization of PRRs within subcellular organelles that are usually devoid of host nucleic acids, but are sites of pathogen localization, is another principle that enables the host to distinguish self from non-self. The latter mode of sensing applies to the detection of microbial DNA within the cytoplasm, a compartment in which host DNAs are usually not present. Despite the past years' tremendous progress in the field of innate immunity, our understanding of cytoplasmic DNA sensing mechanisms is only beginning to form/take form. In this review, we outline the recent advancements in the elucidation of intracellular DNA-sensing pathways and discuss the future directions of this emerging field. PMID- 22450803 TI - Conventional dendritic cells may be ideal targets for vaccine strategies in the aged. PMID- 22450804 TI - Lyn but not Fyn kinase controls IgG-mediated systemic anaphylaxis. AB - Anaphylaxis is a rapid, life-threatening hypersensitivity reaction. Until recently, it was mainly attributed to histamine released by mast cells activated by allergen crosslinking (XL) of FcepsilonRI-bound allergen-specific IgE. However, recent reports established that anaphylaxis could also be triggered by basophil, macrophage, and neutrophil secretion of platelet-activating factor subsequent to FcgammaR stimulation by IgG/Ag complexes. We have investigated the contribution of Fyn and Lyn tyrosine kinases to FcgammaRIIb and FcgammaRIII signaling in the context of IgG-mediated passive systemic anaphylaxis (PSA). We found that mast cell IgG XL induced Fyn, Lyn, Akt, Erk, p38, and JNK phosphorylation. Additionally, IgG XL of mast cells, basophils, and macrophages resulted in Fyn- and Lyn-regulated mediator release in vitro. FcgammaR-mediated activation was enhanced in Lyn-deficient (knockout [KO]) cells, but decreased in Fyn KO cells, compared with wild-type cells. More importantly, Lyn KO mice displayed significantly exacerbated PSA features whereas no change was observed for Fyn KO mice, compared with wild-type littermates. Intriguingly, we establish that mast cells account for most serum histamine in IgG-induced PSA. Taken together, our findings establish pivotal roles for Fyn and Lyn in the regulation of PSA and highlight their unsuspected functions in IgG-mediated pathologies. PMID- 22450805 TI - Cellular interactions of synovial fluid gammadelta T cells in juvenile idiopathic arthritis. AB - The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of gammadelta T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vgamma9(+)Vdelta2(+) (Vgamma9(+)) T cells, in JIA. We found that as opposed to CD4(+) T cells, equally high percentages (~35%) of Vgamma9(+) T cells in SF and peripheral blood (PB) produced TNF-alpha and IFN-gamma. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vgamma9Jgamma1.2(+) T cells, similarly amplified cytokine secretion by SF and PB Vgamma9(+) T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vgamma9(+) T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vgamma9(+) T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4(+)CD25(+)FOXP3(+) cells (regulatory T cells). Furthermore, coculture with the Vgamma9(+) T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vgamma9(+) T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation. PMID- 22450806 TI - Control of transplant tolerance and intragraft regulatory T cell localization by myeloid-derived suppressor cells and CCL5. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that are believed to inhibit immune responses in the contexts of cancer and organ transplantation, in association with regulatory T cells (Treg). However, the way in which MDSC cooperate with Treg remains elusive. In this study, we used DNA microarrays to analyze gene expression in blood-derived MDSC from rat recipients of kidney allografts. We found CCL5 (Rantes), a chemotactic C C motif 5 chemokine, to be strongly downregulated after treatment with a tolerizing regimen. The amount of CCL5 protein was also lower in the plasma of tolerant recipients, whereas intragraft CCL5 was unchanged. Because CCL5 is chemotactic for Treg, we hypothesized that a gradient of CCL5 between the graft and peripheral blood might contribute to the intragraft localization of Treg in tolerant animals. To test this hypothesis, we treated tolerant rat recipients of kidney allografts with recombinant rat CCL5 to restore normal plasma concentrations. This led to a strong reduction in intragraft Treg monitored by immunohistofluorescence and by quantitative real-time PCR measurement of Foxp3 mRNA. Ultimately, this treatment led to an increase in serum creatinine concentrations and to kidney graft rejection after about a month. The kidney function of syngeneic grafts was not affected by a similar administration of CCL5. These data highlight the contribution of MDSC to the establishment of a graft-to-periphery CCL5 gradient in tolerant kidney allograft recipients, which controls recruitment of Treg to the graft where they likely contribute to maintaining tolerance. PMID- 22450807 TI - Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis. AB - Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF kappaB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN beta and STAT1-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STAT1-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STAT1-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase-3). LPS-induced lung injury was attenuated in STAT1 knockout mice. In addition, LPS and IFN-beta induced apoptosis was absent in cultured cells lacking STAT1, and, unlike in wild type cells, a permissive effect of rapamycin was not observed. In contrast to its effect on STAT1, rapamycin inhibited NF-kappaB activation in vivo and reduced selected markers of inflammation (i.e., neutrophils in the bronchoalveolar lavage fluid, TNF-alpha). Therefore, although it inhibits NF-kappaB and neutrophilic inflammation, rapamycin augments LPS-induced lung injury and apoptosis in a mechanism that involves STAT1 and the induction of STAT1-dependent apoptosis genes. PMID- 22450808 TI - Purinergic receptors are required for HIV-1 infection of primary human macrophages. AB - Macrophages play a significant role in HIV infection, viral rebound, and the development of AIDS. However, the function of host proteins in viral replication is incompletely characterized in macrophages. Purinergic receptors P2X and P2Y are major components of the macrophage immune response to pathogens, inflammation, and cellular damage. We demonstrate that these receptors are necessary for HIV infection of primary human macrophages. Inhibition of purinergic receptors results in a significant reduction in HIV replication in macrophages. This inhibition is independent of viral strain and is dose dependent. We also identify that P2X(1), P2X(7), and P2Y(1) receptors are involved in viral replication. We show that P2X(1), but not P2X(7) or P2Y(1), is necessary for HIV entry into macrophages. We demonstrate that interaction of the HIV surface protein gp120 with macrophages stimulates an increase in ATP release. Thus, we propose that HIV's binding to macrophages triggers a local release of ATP that stimulates purinergic receptors and facilitates HIV entry and subsequent stages of viral replication. Our data implicate a novel role for a family of host proteins in HIV replication in macrophages and suggest new therapeutic targets to reduce the devastating consequences of HIV infection and AIDS. PMID- 22450809 TI - Requirement for diverse TCR specificities determines regulatory T cell activity in a mouse model of autoimmune arthritis. AB - CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are required to restrain the immune system from mounting an autoaggressive systemic inflammatory response, but why their activity can prevent (or allow) organ-specific autoimmunity remains poorly understood. We have examined how TCR specificity contributes to Treg activity using a mouse model of spontaneous autoimmune arthritis, in which CD4(+) T cells expressing a clonotypic TCR induce disease by an IL-17-dependent mechanism. Administration of polyclonal Tregs suppressed Th17 cell formation and prevented arthritis development; notably, Tregs expressing the clonotypic TCR did not. These clonotypic Tregs exerted Ag-specific suppression of effector CD4(+) T cells using the clonotypic TCR in vivo, but failed to mediate bystander suppression and did not prevent Th17 cells using nonclonotypic TCRs from accumulating in joint-draining lymph nodes of arthritic mice. These studies indicate that the availability of Tregs with diverse TCR specificities can be crucial to their activity in autoimmune arthritis. PMID- 22450810 TI - CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation. AB - Germinal center (GC) B cells and T follicular helper (T(FH)) cells interact in the production of high-affinity long-lived plasma cells (PCs) and memory B cells, although the mechanisms regulating the formation of these long-lived populations remain unclear. Because CD80 is one of the few markers shared by human and murine memory B cells, we investigated its role in the development of GCs, memory cells, and PCs. In CD80-deficient mice, fewer long-lived PCs were generated upon immunization compared with that in B6 controls. In concert, the absence of CD80 resulted in an increase in apoptotic GC B cells during the contraction phase of the GC. CD80(-/-) mice had fewer T(FH) cells compared with that of B6, and residual T(FH) cells failed to mature, with decreased ICOS and PD-1 expression and decreased synthesis of IL-21 mRNA. Mixed bone marrow chimeras demonstrated a B cell-intrinsic requirement for CD80 expression for normal T(FH) cell and PC development. Therefore, B cell expression of CD80 plays a critical role in regulating B-T interactions in both early and late GC responses. This, in turn, results in impaired ability to produce long-lived PCs. These data provide new insights into the development of GCs and Ab-forming cells and the functions of CD80 in humoral immunity. PMID- 22450811 TI - Resolvin E2 formation and impact in inflammation resolution. AB - Acute inflammation and its resolution are essential processes for tissue protection and homeostasis. In this context, specialized proresolving mediators derived from polyunsaturated fatty acids are of interest. In this study, we report that resolvin E2 (RvE2) from eicosapentaenoic acid is endogenously produced during self-limited murine peritonitis in both the initiation and resolution phases. RvE2 (1-10 nM) carries potent leukocyte-directed actions that include: 1) regulating chemotaxis of human neutrophils; and 2) enhancing phagocytosis and anti-inflammatory cytokine production. These actions appear to be mediated by leukocyte G-protein-coupled receptors as preparation of labeled RvE2 gave direct evidence for specific binding of radiolabeled RvE2 to neutrophils (K(d) 24.7 +/- 10.1 nM) and resolvin E1 activation of recombinant G protein-coupled receptors was assessed. In addition to the murine inflammatory milieu, RvE2 was also identified in plasma from healthy human subjects. RvE2 rapidly downregulated surface expression of human leukocyte integrins in whole blood and dampened responses to platelet-activating factor. Together, these results indicate that RvE2 can stimulate host-protective actions throughout initiation and resolution in the innate inflammatory responses. PMID- 22450812 TI - CD70-driven costimulation induces survival or Fas-mediated apoptosis of T cells depending on antigenic load. AB - Apoptosis plays an essential role in the removal of activated CD8 T cells that are no longer required during or postinfection. The Bim-dependent intrinsic pathway of apoptosis removes effector CD8 T cells upon clearance of viral infection, which is driven by withdrawal of growth factors. Binding of Fas ligand to Fas mediates activation-induced T cell death in vitro and cooperates with Bim to eliminate CD8 T cells during chronic infection in vivo, but it is less clear how this pathway of apoptosis is initiated. In this study, we show that the costimulatory TNFR CD27 provides a dual trigger that can enhance survival of CD8 T cells, but also removal of activated CD8 T cells through Fas-driven apoptosis. Using in vitro stimulation assays of murine T cells with cognate peptide, we show that CD27 increases T cell survival after stimulation with low doses of Ag, whereas CD27 induces Fas-driven T cell apoptosis after stimulation with high doses of Ag. In vivo, the impact of constitutive CD70-driven stimulation on the accumulation of memory and effector CD8 T cells is limited by Fas-driven apoptosis. Furthermore, introduction of CD70 signaling during acute infection with influenza virus induces Fas-dependent elimination of influenza-specific CD8 T cells. These findings suggest that CD27 suppresses its costimulatory effects on T cell survival through activation of Fas-driven T cell apoptosis to maintain T cell homeostasis during infection. PMID- 22450813 TI - The mammalian actin-binding protein 1 is critical for spreading and intraluminal crawling of neutrophils under flow conditions. AB - Recently, the mammalian actin-binding protein 1 (mAbp1; Hip-55, SH3P7, debrin like protein) was identified as a novel component of the beta(2) integrin mediated signaling cascade during complement-mediated phagocytosis and firm adhesion of polymorphonuclear neutrophils (PMN) under physiological shear stress conditions. In this study, we found that the genetic ablation of mAbp1 severely compromised not only the induction of adhesion, but also subsequent spreading of leukocytes to the endothelium as assessed by intravital microscopy of inflamed vessels of the cremaster muscle of mice. In vitro studies using murine PMN confirmed that mAbp1 was required for beta(2) integrin-mediated spreading under shear stress conditions, whereas mAbp1 was dispensable for spreading under static conditions. Upon beta(2) integrin-mediated adhesion and chemotactic migration of human neutrophil-like differentiated HL-60 cells, mAbp1 was enriched at the leading edge of the polarized cell. Total internal reflection fluorescence microscopy revealed that mAbp1 formed propagating waves toward the front of the lamellipodium, which are characteristic for dynamic reorganization of the cytoskeleton. Accordingly, binding of mAbp1 to actin was increased upon beta(2) integrin-mediated adhesion, as shown by coimmunoprecipitation experiments. However, chemotactic migration under static conditions was unaffected in the absence of mAbp1. In contrast, the downregulation of mAbp1 by RNA interference technique in neutrophil-like differentiated HL-60 cells or the genetic ablation of mAbp1 in leukocytes led to defective migration under flow conditions in vitro and in inflamed cremaster muscle venules in the situation in vivo. In conclusion, mAbp1 is of fundamental importance for spreading and migration under shear stress conditions, which are critical prerequisites for efficient PMN extravasation during inflammation. PMID- 22450814 TI - Distinct effects of saracatinib on memory CD8+ T cell differentiation. AB - Immunologic memory involving CD8(+) T cells is a hallmark of an adaptive Ag specific immune response and constitutes a critical component of protective immunity. Designing approaches that enhance long-term T cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the Ag-specific T cell response has led to new approaches that target the magnitude and quality of the memory T cell response. In this article, we show that T cells from TCR transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases--priming, expansion, contraction, and memory--of an Ag-specific T cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62L(high)/CD44(high) central memory CD8(+) T cells and IFN gamma production but suppressed immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases but were accompanied by Akt-mammalian target of rapamycin suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune potentiating effects on CD8(+) T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine. PMID- 22450815 TI - Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. AB - BACKGROUND: Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation. METHODS: The aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor bearing animals analyzing changes in muscle proteolysis and in quality of life. RESULTS: Administration of sActRIIB resulted in an improvement in body and muscle weights. Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force. CONCLUSIONS: These results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia. PMID- 22450816 TI - Consensus clustering based on a new Probabilistic Rand Index with application to subtopic retrieval. AB - We introduce a probabilistic version of the well-known Rand Index (RI) for measuring the similarity between two partitions, called Probabilistic Rand Index (PRI), in which agreements and disagreements at the object-pair level are weighted according to the probability of their occurring by chance. We then cast consensus clustering as an optimization problem of the PRI value between a target partition and a set of given partitions, experimenting with a simple and very efficient stochastic optimization algorithm. Remarkable performance gains over input partitions as well as over existing related methods are demonstrated through a range of applications, including a new use of consensus clustering to improve subtopic retrieval. PMID- 22450817 TI - Estimating information from image colors: an application to digital cameras and natural scenes. AB - The colors present in an image of a scene provide information about its constituent elements. But the amount of information depends on the imaging conditions and on how information is calculated. This work had two aims. The first was to derive explicitly estimators of the information available and the information retrieved from the color values at each point in images of a scene under different illuminations. The second was to apply these estimators to simulations of images obtained with five sets of sensors used in digital cameras and with the cone photoreceptors of the human eye. Estimates were obtained for 50 hyperspectral images of natural scenes under daylight illuminants with correlated color temperatures 4,000, 6,500, and 25,000 K. Depending on the sensor set, the mean estimated information available across images with the largest illumination difference varied from 15.5 to 18.0 bits and the mean estimated information retrieved after optimal linear processing varied from 13.2 to 15.5 bits (each about 85 percent of the corresponding information available). With the best sensor set, 390 percent more points could be identified per scene than with the worst. Capturing scene information from image colors depends crucially on the choice of camera sensors. PMID- 22450818 TI - On detection of multiple object instances using Hough transforms. AB - Hough transform-based methods for detecting multiple objects use nonmaxima suppression or mode seeking to locate and distinguish peaks in Hough images. Such postprocessing requires the tuning of many parameters and is often fragile, especially when objects are located spatially close to each other. In this paper, we develop a new probabilistic framework for object detection which is related to the Hough transform. It shares the simplicity and wide applicability of the Hough transform but, at the same time, bypasses the problem of multiple peak identification in Hough images and permits detection of multiple objects without invoking nonmaximum suppression heuristics. Our experiments demonstrate that this method results in a significant improvement in detection accuracy both for the classical task of straight line detection and for a more modern category-level (pedestrian) detection problem. PMID- 22450819 TI - Probabilistic tracking of affine-invariant anisotropic regions. AB - Despite a wide range of feature detectors developed in the computer vision community over the years, direct application of these techniques to surgical navigation has shown significant difficulties due to the paucity of reliable salient features coupled with free--form tissue deformation and changing visual appearance of surgical scenes. The aim of this paper is to propose a novel probabilistic framework to track affine-invariant anisotropic regions under contrastingly different visual appearances during Minimally Invasive Surgery (MIS). The theoretical background of the affine-invariant anisotropic feature detector is presented and a real-time implementation exploiting the computational power of the GPU is proposed. An Extended Kalman Filter (EKF) parameterization scheme is used to adaptively adjust the optimal templates of the detected regions, enabling accurate identification and matching of the tracked features. For effective tracking verification, spatial context and region similarity have also been incorporated. They are used to boost the prediction of the EKF and recover potential tracking failure due to drift or false positives. The proposed framework is compared to the existing methods and their respective performance is evaluated with in vivo video sequences recorded from robotic-assisted MIS procedures, as well as real-world scenes. PMID- 22450820 TI - A Closed-Form Solution to Retinex with Nonlocal Texture Constraints. AB - We propose a method for intrinsic image decomposition based on retinex theory and texture analysis. While most previous methods approach this problem by analyzing local gradient properties, our technique additionally identifies distant pixels with the same reflectance through texture analysis, and uses these nonlocal reflectance constraints to significantly reduce ambiguity in decomposition. We formulate the decomposition problem as the minimization of a quadratic function which incorporates both the retinex constraint and our nonlocal texture constraint. This optimization can be solved in closed form with the standard conjugate gradient algorithm. Extensive experimentation with comparisons to previous techniques validate our method in terms of both decomposition accuracy and runtime efficiency. PMID- 22450821 TI - WORDGRAPH: Keyword-in-Context Visualization for NETSPEAK's Wildcard Search. AB - The WORDGRAPH helps writers in visually choosing phrases while writing a text. It checks for the commonness of phrases and allows for the retrieval of alternatives by means of wildcard queries. To support such queries, we implement a scalable retrieval engine, which returns high-quality results within milliseconds using a probabilistic retrieval strategy. The results are displayed as WORDGRAPH visualization or as a textual list. The graphical interface provides an effective means for interactive exploration of search results using filter techniques, query expansion, and navigation. Our observations indicate that, of three investigated retrieval tasks, the textual interface is sufficient for the phrase verification task, wherein both interfaces support context-sensitive word choice, and the WORDGRAPH best supports the exploration of a phrase's context or the underlying corpus. Our user study confirms these observations and shows that WORDGRAPH is generally the preferred interface over the textual result list for queries containing multiple wildcards. PMID- 22450822 TI - Image-Based Remodeling. AB - Imagining what a proposed home remodel might look like without actually performing it is challenging. We present an image-based remodeling methodology that allows real-time photorealistic visualization during both the modeling and remodeling process of a home interior. Large-scale edits, like removing a wall or enlarging a window, are performed easily and in real time, with realistic results. Our interface supports the creation of concise, parameterized, and constrained geometry, as well as remodeling directly from within the photographs. Real-time texturing of modified geometry is made possible by precomputing view dependent textures for all faces that are potentially visible to each original camera viewpoint, blending multiple viewpoints and hole-filling when necessary. The resulting textures are stored and accessed efficiently enabling intuitive real-time realistic visualization, modeling, and editing of the building interior. PMID- 22450823 TI - Using Patterns to Encode Color Information for Dichromats. AB - Color is one of the most common ways to convey information in visualization applications. Color vision deficiency (CVD) affects approximately 200 million individuals worldwide and considerably degrades their performance in understanding such contents by creating red-green or blue-yellow ambiguities. While several content-specific methods have been proposed to resolve these ambiguities, they cannot achieve this effectively in many situations for contents with a large variety of colors. More importantly, they cannot facilitate color identification. We propose a technique for using patterns to encode color information for individuals with CVD, in particular for dichromats. We present the first content-independent method to overlay patterns on colored visualization contents that not only minimizes ambiguities but also allows color identification. Further, since overlaying patterns does not compromise the underlying original colors, it does not hamper the perception of normal trichromats. We validated our method with two user studies: one including 11 subjects with CVD and 19 normal trichromats, and focused on images that use colors to represent multiple categories; and another one including 16 subjects with CVD and 22 normal trichromats, which considered a broader set of images. Our results show that overlaying patterns significantly improves the performance of dichromats in several color-based visualization tasks, making their performance almost similar to normal trichromats'. More interestingly, the patterns augment color information in a positive manner, allowing normal trichromats to perform with greater accuracy. PMID- 22450824 TI - Evaluation of Interactive Visualization on Mobile Computing Platforms for Selection of Deep Brain Stimulation Parameters. AB - In recent years, there has been significant growth in the use of patient-specific models to predict the effects of neuromodulation therapies such as deep brain stimulation (DBS). However, translating these models from a research environment to the everyday clinical workflow has been a challenge, primarily due to the complexity of the models and the expertise required in specialized visualization software. In this paper, we deploy the interactive visualization system ImageVis3D Mobile, which has been designed for mobile computing devices such as the iPhone or iPad, in an evaluation environment to visualize models of Parkinson's disease patients who received DBS therapy. Selection of DBS settings is a significant clinical challenge that requires repeated revisions to achieve optimal therapeutic response, and is often performed without any visual representation of the stimulation system in the patient. We used ImageVis3D Mobile to provide models to movement disorders clinicians and asked them to use the software to determine: 1) which of the four DBS electrode contacts they would select for therapy; and 2) what stimulation settings they would choose. We compared the stimulation protocol chosen from the software versus the stimulation protocol that was chosen via clinical practice (independent of the study). Lastly, we compared the amount of time required to reach these settings using the software versus the time required through standard practice. We found that the stimulation settings chosen using ImageVis3D Mobile were similar to those used in standard of care, but were selected in drastically less time. We show how our visualization system, available directly at the point of care on a device familiar to the clinician, can be used to guide clinical decision making for selection of DBS settings. In our view, the positive impact of the system could also translate to areas other than DBS. PMID- 22450825 TI - Thyroid remnant ablation using 1,110 MBq of I-131 after total thyroidectomy: regulatory considerations on release of patients after unsealed radioiodine therapy. AB - OBJECTIVES: This study was undertaken to measure the radiation exposure level of caregivers following outpatient NaI (I-131) 1,110 MBq therapy for remnant thyroid ablation after total thyroidectomy in patients with differentiated thyroid cancer, and to evaluate the influence of activities of daily living on radiation exposure level, with the goal of proposing an optimum method of I-131 therapy. METHODS: The study included 37 patients with differentiated thyroid cancer, who had undergone total thyroidectomy and received outpatient based remnant thyroid ablation using NaI (I-131) 1,110 MBq, who were satisfying the following requirements: (1) patients who have no evidence of distant metastases, (2) whose living environments were appropriate for outpatient I-131 (1,110 MBq) therapy, and (3) patients who gave written informed consent. The dose rate at a distance of 1 m from the body surface of the patient at the moment of release was measured using survey meters of the GM type or ionization chamber type. The dose level for the caregiver was measured with a personal dosimeter in all cases. RESULTS: The dose rate at a distance of 1 m from the patient's body surface 1 h after I-131 administration was in the range of 29-115 MUSv/h (mean 63.8 MUSv/h). The 7-day cumulative effective dose of caregivers was 0.11 +/- 0.08 mSv, on an average, in 34 dosimeters. In 31 of 34 dosimeters, cumulative effective dose of caregivers was below 0.2 mSv. Dose levels exceeding 0.2 mSv were recorded in 3 cases (0.21, 0.35 and 0.43 mSv in one case each). These results suggest that the exposure level of family members (caregiver and others) was minimal and is lower than the radiation levels affecting human environments. CONCLUSION: Outpatient-based remnant thyroid ablation with I-131 (1,110 MBq) performed after total thyroidectomy in patients with differentiated thyroid cancer is safe if applied in accordance with the appropriate supervision and guidance by experts with certain qualifications. PMID- 22450826 TI - Dosimetric evaluation of nanotargeted (188)Re-liposome with the MIRDOSE3 and OLINDA/EXM programs. AB - OBJECTIVE: The OLINDA/EXM computer code was created as a replacement for the widely used MIRDOSE3 code for radiation dosimetry in nuclear medicine. A dosimetric analysis with these codes was performed to evaluate nanoliposomes as carriers of radionuclides ((188)Re-liposomes) in colon carcinoma-bearing mice. METHODS: Pharmacokinetic data for (188)Re-N, N-bis (2-mercaptoethyl)-N',N' diethylethylenediamine ((188)Re-BMEDA) and (188)Re-liposome were obtained for estimation of absorbed doses in normal organs. Radiation dose estimates for normal tissues were calculated using the MIRDOSE3 and OLINDA/EXM programs for a colon carcinoma solid tumor mouse model. RESULTS: Mean absorbed doses derived from(188)Re-BMEDA and (188)Re-liposome in normal tissues were generally similar as calculated by MIRDOSE3 and OLINDA/EXM programs. One notable exception to this was red marrow, wherein MIRDOSE3 resulted in higher absorbed doses than OLINDA/EXM (1.53- and 1.60-fold for (188)Re-BMEDA and (188)Re-liposome, respectively). CONCLUSIONS: MIRDOSE3 and OLINDA have very similar residence times and organ doses. Bone marrow doses were estimated by designating cortical bone rather than bone marrow as a source organ. The bone marrow doses calculated by MIRDOSE3 are higher than those by OLINDA. If the bone marrow is designated as a source organ, the doses estimated by MIRDOSE3 and OLINDA programs will be very similar. PMID- 22450827 TI - Using GPUs for the exact alignment of short-read genetic sequences by means of the Burrows-Wheeler transform. AB - General Purpose Graphic Processing Units (GPGPUs) constitute an inexpensive resource for computing-intensive applications that could exploit an intrinsic fine-grain parallelism. This paper presents the design and implementation in GPGPUs of an exact alignment tool for nucleotide sequences based on the Burrows Wheeler Transform. We compare this algorithm with state-of-the-art implementations of the same algorithm over standard CPUs, and considering the same conditions in terms of I/O. Excluding disk transfers, the implementation of the algorithm in GPUs shows a speedup larger than 12, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximizing memory locality and ensuring a symmetric access to the data. The paper describes the behavior of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory. PMID- 22450828 TI - Interaction between 2',4-dihydroxychalcone and the N, f, e conformers of bovine serum albumin: influence of temperature and ionic strength. AB - UV-Vis spectroscopy was used to study the interaction between the 2',4- dihydroxychalcone, flavonoid which is known to have anti-tumor activity in vitro, and others biological properties, and the N, F and E conformers of bovine serum albumin at different ionic strengths and temperatures. The Klotz model was found to be adequate to determine the constants and number of binding sites. The reaction was found to be exothermic and spontaneous. The number of binding sites decreases and the reaction is more exergonic along with the increase in ionic strength and the conformational change of N to E. The reactions were necessarily hydrophobic and followed by a process of ionic character. PMID- 22450829 TI - Effect of glucose on the lactoferrin's conformation and its effect on MC 3T3-E1 cell proliferation. AB - The objective of this research was to investigate the influence of glucose on bovine lactoferrin's (LF) conformation, thermodynamic stability and osteoblastic cell proliferation. The conformation and thermodynamic stability of LF was detected by spectroscopic and differential scanning calorimetry (DSC). The osteoblastic cell proliferation of LF at physiological concentrations (100 MUg/ml) was measured by BrdU incorporation. The binding constant between glucose and LF is KSV = 5 * 10(-3), and Tyr residues of LF were located in a more hydrophobic environment, while Trp residues were located in a more hydrophilic environment. LF with glucose had increased alpha-helix and beta-sheet contents by 6 and 14 %, respectively. It showed a two-step denaturation of LF. There was a gradual changs in the denaturation temperature and the calorimetric enthalpies (DeltaHcal) with a growing concentration of glucose. It has also revealed that glucose dose dependently reduced the ability of LF to increase MC 3T3-E1 cell proliferation. Increasing the binding with glucose, LF might cause to change its native state, which reduced the stimulation activity of osteoblasts cell proliferation. PMID- 22450830 TI - [Pharmacoeconomic evaluation of combination therapy with dutasteride and alpha1 blocker for treatment of benign prostatic hyperplasia in Japan]. AB - The cost-effectiveness of combination therapy with an alpha1 blocker and dutasteride in benign prostatic hyperplasia (BPH) was analyzed in comparison with alpha1 blocker monotherapy. A Markov model with seven health states related to BPH was constructed with 4-year and 10-year time horizons and from the entire payers perspective. The transition probabilities among different health states input into the model were mainly derived from CombAT Study data, while cost parameters were estimated from a clinical database including DPC claims. Effectiveness was defined as quality adjusted life year (QALY). The cost effectiveness of combination therapy was assessed by the incremental cost effectiveness ratio (ICER) threshold (6 to 7 million Japanese yen (JPY)/QALY gained). For a base-case analysis, combination therapy produced an incremental effectiveness versus monotherapy of 0.050 and 0.097 QALYs at 4 years and 10 years, respectively, while the concomitant incremental costs were estimated to be 257,172 and 579,908 JPY, respectively. The ICERs for combination therapy versus monotherapy calculated at 4 years and 10 years were 5,119,007 and 5,974,495 JPY/QALY gained, respectively, both below the acceptable ICER threshold. Sensitivity analyses revealed that the ICER tended to decrease with greater BPH severity. These findings suggest that combination therapy with an alpha1 blocker and dutasteride would be more cost-effective in BPH than alpha1 blocker monotherapy and more efficient in moderate-to-severe BPH. PMID- 22450831 TI - [Experience in the treatment with recombinant thrombomodulin on disseminated intravascular coagulation with severe urinary tract infection]. AB - Severe urinary tract infection occasionally causes urosepsis and disseminated intravascular coagulation (DIC). We experienced six cases of DIC with severe urinary tract infection from July 2009 to January 2011. Patients comprised two men and four women, ranging in age from 67-84 years old. In all cases, urinary tract infection was caused by pyelonephritis. The results of analysis of bacterial culture from blood and urine revealed E. faecalis in 2 cases, E. coli in 1 case, P. mirabilis in 1 case and Candida tripicalis in 1 case. Percutaneous nephrostomy in 1 case and ureteral stent indwelling in 3 cases and ureteral stent exchange in 2 cases were used for the drainage of the origin of infection. Under the diagnosis of DIC, the administration of antibiotics and anti-DIC treatment with recombinant thrombomodulin (rTM) were performed. rTM isa new drug for the treatment of DIC. rTM binds to thrombin to inactivate coagulation, and the thrombinrTM complex activates protein C to form activated protein C. Therefore, rTM actsasa negative feedback regulator of blood coagulation. Treatment with rTM improved in 5 of the 6 patients. PMID- 22450832 TI - [A case of retroperitoneal angioleiomyoma resected by laparoscopy]. AB - A retroperitoneal angioleiomyoma was incidentally detected in a 56-year-old woman during an examination of cardiovascular disease, and referred to the department of urology. Computed tomography (CT) showed a solid tumor approximately 3 cm in diameter, enhanced heterogeneously adjacent to the right adrenal and renal vein on magnetic resonance imaging the tumor showed a low intensity in the T1-weighted image and high intensity in T2-weighted image. These radiographic findings suggested a retroperitoneal tumor such as paraganglioma, angioma. Furthermore, because she was a carrier of Human Adult T Cell Leukemia Virus-I (HTLV-I) this tumor was suspected to have relevance to malignant lymphoma. We performed laparoscopic surgical excision of the tumor. Pathlogical diagnosis was an angioleiomyoma. Angioleiomyoma is a rare type of leiomyoma originating from smooth muscle and containing thick-walled vessels. Only a few cases of retroperitoneal angioleiomyoma have been reported. PMID- 22450833 TI - [A case of retroperitoneal liposarcoma with inflammatory pseudotumor]. AB - A 54-year-old man presented with pollakiuria and dysuria. Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) showed a retroperitoneal tumor 10 cm in diameter. Pathological examination of a transrectal biopsy specimen obtained from the patient revealed the presence of an inflammatory myofibroblastic tumor (IMT). The patient underwent surgical resection of the tumor. Histopathologically, the tumor was composed of 3 parts : the largest part was compatible with an inflammatory pseudotumor: the second part, well-differentiated liposarcoma: and the third part, a myxoid liposarcoma. He has been followed up for 14 months ; but there was no evidence of local recurrence of the tumor. We believe that the inflammatory pseudotumor complicated in repairing the inflammation arising from the liposarcoma. PMID- 22450834 TI - [A case of Bellini collecting duct carcinoma with hypercalcemia in a young adult]. AB - A 25-year-old man presented to a local clinic with right flank pain and gross hematuria. Computed tomography revealed the right renal tumor and he was referred to our hospital. Laparoscopic radical nephrectomy was performed and diagnosis of Bellini collecting duct carcinoma was made pathologically. Adjuvant therapy with interferon-alpha, followed by a gemcitabine and cisplatin-based regimen of chemotherapy was performed, but the disease progressed. Sunitinib was started 14 months after the operation. After one course of sunitinib, mental status was altered due to hypercalcemia (serum calcium level was 18.6 mg/dl and PTH-rP was 3.7 pmol/l). Level of consciousness recovered along with decreasing serum calcium level, but he died of multiple organ dysfunction 17 months after the operation. Autopsy showed liver, bone, lymph node, mediastinum and left adrenal tumor metastases. PMID- 22450835 TI - [Laparoscopic pyelolithotomy in a horseshoe kidney]. AB - A 66-year-old woman had a 22 mm right kidney stone accompanied with a horseshoe kidney. The size of this stone had been increasing gradually from 7 mm to 22 mm during the past 5 years. Although apparent pelviuretic junction stenosis could not be identified by intravenous urography, external pelvis was dilated in both kidneys. Complete excretion of fragmented stones by extracorporeal shockwave lithotripsy seemed to be difficult because impaired urinary passage from the renal pelvis to the ureter was suspected. Percutaneous nephrolithotomy was also difficult due to malrotation of the pelvic-caliceal system and possible interposition of bowel loops between kidney and abdominal wall. Therefore, we chose laparoscopic pyelolithotomy. This procedure made it possible to remove the stone completely with minimum invasiveness. We assume that laparoscopic pyelolithotomy is a safe and effective approach for renal pelvic stone in case of horseshoe kidney. PMID- 22450836 TI - [Renal carcinoid tumor: a case report]. AB - A right renal tumor was incidentally found in a 38-year-old woman by annual medical check up. She visited our hospital for further examination and treatment. She did not show typical symptoms of carcinoid. A computed tomography (CT) revealed a calcified solid tumor in the upper portion of the right kidney. The tumor was 6.0 cm in diameter and was not enhanced in either early or late phase. There was no evidence of extrarenal invasion or distant metastasis. Based on a clinical diagnosis of stage 1 renal cell carcinoma, laparoscopic nephrectomy was performed. The pathological diagnosis was renal carcinoid tumor. The tumor had trabecular and ribbon-like structures with a thin fibrovascular stroma. Immunohistochemicaliy, the tumor cells stained positive for chromogranin A, synaptophisin and CD56. The cell proliferation rate was estimated to be under 1% with Ki67 staining. To find the primary lesion, we performed upper and lower gastric endoscopy and chest computed tomography, but could not find any/other carcinoid tumors. At 1-year follow up, she had no evidence of local recurrence or metastasis. PMID- 22450837 TI - [Renal salt wasting syndrome induced by Cisplatin: a case report]. AB - A 69-year-old woman diagnosed with a urinary carcinoma was admitted to the hospital for chemotherapy consisting of cisplatin (CDDP) and gemcitabine. Two days after administration of CDDP, she complained of general fatigue. The total urine volume was 5, 500 ml/day. Three days after she received CDDP, her serum sodium level decreased to 118 mEq/l, leading to disturbed consciousness. After the intravenous administration of saline, her serum sodium levels recovered to the normal value (137 mEq/l) without any complications. The diagnosis of renal salt-wasting syndrome was made on the basis of hyponatremia, high urinary sodium excretion and increased urinary output. PMID- 22450838 TI - [A case of plasmacytoid urothelial carcinoma of the bladder: rapid progression after transurethral resection]. AB - An 85-year-old man complained of macroscopic hematuria and painful urination. Cytoscopy revealed a non-papillary tumor at the bladder neck extending to the trigone. Abdominal computed tomography revealed thickening of the bladder wall in the same area but did not reveal lymph node swelling. Urinary cytology was class IIIb. We conducted a transurethral resection of the bladder tumor (TURBT) after which a histopathological examination showed urothelial carcinoma, G3, INFgamma, pT2. From 6 days after TURBT, severe fever persisted despite the administration of various antibiotics and his general condition deteriorated. He died of acute myocardial infarction at 37 days after TURBT. Histopathological examination at autopsy revealed extensive urothelial carcinoma, a plasmacytoid variant, of the bladder which had invaded into the entire body including the lungs, liver, kidneys, adrenal glands, and veins, although tumor cells were not identified in lymph nodes. We review the literature and report this rare case of urothelial carcinoma, a plasmacytoid variant, of the bladder. PMID- 22450839 TI - [Solitary fibrous tumor of the urinary bladder: a case report]. AB - A 41-year-old woman with an incidental tumor of the urinary bladder was referred to our hospital. Computed tomography and magnetic resonance imaging showed a tumor in the urinary bladder wall with expansive growth. Under the suspicion of leiomyoma, we performed transurethral resection of the tumor. Pathological examination of tumor specimens revealed patternless arrangements of spindle cells. Immunochemical analysis revealed tumor cells positive for CD34 and bcl-2. The final diagnosis was a solitary fibrous tumor. PMID- 22450840 TI - [A case of late recurrence of urothelial carcinoma in an ileal conduit after radical cystectomy and ileal conduit diversion for bladder cancer]. AB - Recurrence of urothelial cancer in an ileal conduit after radical cystectomy is rare. A 79-year-old man suffered bladder cancer (UC cTisN0M0 G2>3) and underwent total cystectomy with ileal conduit. He had recurrence of the right renal pelvis carcinoma 6 years after the total cystectomy, and was treated by right radical nephroureterectomy (pT3 G2=3). The patient had another episode of recurrence in the ileal conduit 13 years after the initial operation. The entire ileal conduit (UC, G3, ew (-)) was resected and left cutaneous ureterostomy was performed. This case suggests that long-term follow-up is necessary after radical cystectomy and ileal conduit for urinary diversion. PMID- 22450841 TI - [A case of tuberculous epididymitis after Bacillus Calmette-Guerin intravesical instillation therapy for bladder cancer]. AB - A 65-year-old male had undergone transurethral resection of bladder tumor (TUR Bt) four times for recurrent bladder cancer, and each histopathological examination revealed non-invasive urothelial carcinoma, pTa, G2. To prevent further recurrence, he received eight weekly intravesical instillations of Bacillus Calmette-Guerin (BCG). Four months after the BCG therapy, he underwent cystoscopy. One week after the cystoscopy, he developed a painful and swollen left scrotum. Treatment with levofloxacin for acute epididymitis reduced the scrotal pain initially, but the pain increased and 3 months later, a fistula with suppurative discharge appeared at the bottom of the scrotum. A smear of the discharge revealed Gaffky 2, and a culture showed tubercle bacillus. Incisional drainage of the abscess and anti-tuberculosis chemotherapy for 2 months to treat tuberculous epididymitis was not completely effective. We performed a left orchiectomy with resection of the infected scrotal skin. Histopathological examination showed tuberculous epididymitis consisting of a caseating granuloma with epithelioid cells and Langhans giant cells. He received anti-tuberculosis chemotherapy for 4 months postoperatively and had no sign of recurrence 1 year postoperatively. PMID- 22450842 TI - [Leiomyosarcoma of the scrotum]. AB - A 31-year-old man visited another hospital with a chief complaint of a solid mass in the left scrotum. The diagnosis was a skin cancer of the scrotum, and he was referred to our hospital. We performed surgical resection of the mass, left testis, and bilateral superfical inguinal nodes. Histopathological findings revealed leiomyosarcoma of the scrotum. He is free of disease at 16 months after the operation. PMID- 22450843 TI - The iPad as a mobile device for CT display and interpretation: diagnostic accuracy for identification of pulmonary embolism. AB - Recent software developments enable interactive, real-time axial, 2D and 3D CT display on an iPad by cloud computing from a server for remote rendering. The purpose of this study was to compare radiologists' interpretative performance on the iPad to interpretation on the conventional picture archive and communication system (PACS). Fifty de-identified contrast-enhanced CT exams performed for suspected pulmonary embolism were compiled as an educational tool to prepare our residents for night call. Two junior radiology attendings blindly interpreted the cases twice, one reader used the PACS first, and the other interpreted on the iPad first. After an interval of at least 2 weeks, the cases were reinterpreted in different order using the other display technique. Sensitivity, specificity, and accuracy for identification of pulmonary embolism were compared for each interpretation method. Pulmonary embolism was present in 25 patients, ranging from main pulmonary artery to subsegmental thrombi. Both readers interpreted 98 % of cases correctly regardless of display platform. There was no significant difference in sensitivity (98 vs 100 %, p = 1.0), specificity (98 vs 96 %, p = 1.0), or accuracy (98 vs 98 %, p = 1.0) for interpretation with the iPad vs the PACS, respectively. CT interpretation on an iPad enabled accurate identification of pulmonary embolism, equivalent to display on the PACS. This mobile device has the potential to expand radiologists' availability for consultation and expedite emergency patient management. PMID- 22450844 TI - Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro. AB - BACKGROUND: The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated. METHODS: PC 3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin beta subtypes, integrin-dependent signaling, as well as cell cycle regulating proteins, were analyzed by western blots. RESULTS: ZA dose dependently reduced tumor-cell growth but did not impair tumor-endothelium and tumor-matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated beta1-integrin in PC-3 and diminished beta4 integrin in PC-3 and DU-145 cells. CONCLUSIONS: ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall. PMID- 22450845 TI - Studies on the establishment of a co-culture system of lung stage Schistosoma japonicum with host cells. AB - Due to their role in eliciting protective Th1 cell-mediated immune responses in definitive hosts lung stage schistosomula are in the focus of intensive research. In vitro culture approaches in the past exhibited significant differences in gene expression profiles between lung stage schistosomula isolated from hosts and those cultured conventionally. Therefore, new approaches to culture schistosomula are of broad interest. In the present study, co-culture systems of schistosomula of Schistosoma japonicum and different vertebrate host cells were tested. Among these, human hepatic venous endothelial cells (ED25) turned out to be very suitable and interesting feeder cells. Compared with controls cultured in vitro or co-cultured with other cells, schistosomula co-cultured with ED25 cells shared more similarities in morphology and tegumental structures with schistosomula directly obtained from infected mice as microscopically determined. According to results from a suppression subtractive hybridization approach to compare transcriptional differences of co-cultured and host group or control group parasites, four candidate transcripts encoding cathepsin L precursor, heat shock protein 70, glyceraldehyde 3-phosphate dehydrogenase, and programmed cell death protein 10 were shown to be differently expressed among the three groups by real time PCR. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis finally confirmed not only congruent protein patterns but also interesting differences among the compared schistosomula groups. The co-culture system between schistosomula of S. japonicum and ED25 cells established in the present study improved existing cultivation attempts. Although some differences to host derived schistosomula were still observed, co-culture with ED25 cells positively influenced parasite morphology and gene expression in a more host-like manner. PMID- 22450846 TI - "Fluidic batteries" as low-cost sources of power in paper-based microfluidic devices. AB - This communication describes the first paper-based microfluidic device that is capable of generating its own power when a sample is added to the device. The microfluidic device contains galvanic cells (that we term "fluidic batteries") integrated directly into the microfluidic channels, which provides a direct link between a power source and an analytical function within the device. This capability is demonstrated using an example device that simultaneously powers a surface-mount UV LED and conducts an on-chip fluorescence assay. PMID- 22450847 TI - Prosthetic component segmentation with blur compensation: a fast method for 3D fluoroscopy. AB - A new method for prosthetic component segmentation from fluoroscopic images is presented. The hybrid approach we propose combines diffusion filtering, region growing and level-set techniques without exploiting any a priori knowledge of the analyzed geometry. The method was evaluated on a synthetic dataset including 270 images of knee and hip prosthesis merged to real fluoroscopic data simulating different conditions of blurring and illumination gradient. The performance of the method was assessed by comparing estimated contours to references using different metrics. Results showed that the segmentation procedure is fast, accurate, independent on the operator as well as on the specific geometrical characteristics of the prosthetic component, and able to compensate for amount of blurring and illumination gradient. Importantly, the method allows a strong reduction of required user interaction time when compared to traditional segmentation techniques. Its effectiveness and robustness in different image conditions, together with simplicity and fast implementation, make this prosthetic component segmentation procedure promising and suitable for multiple clinical applications including assessment of in vivo joint kinematics in a variety of cases. PMID- 22450848 TI - Strain-gradient effect on energy bands in bent ZnO microwires. AB - The table of contents image illustrates the strain-gradient effect on the optical electronic properties in a bent ZnO microwire, with a much stronger red-shift on the outer tensile side than a blue-shift on the inner compressive side. The low temperature cathodoluminescence cross-sectional scanning spectra on the strain neutral middle-plane are highlighted by thicker black lines, which clearly shows a strain-gradient induced red-shift. PMID- 22450849 TI - Response to 'More fuel in the obesity paradox debate': fatness, fitness, stiffness and blood pressure. PMID- 22450850 TI - Neural and humoral changes associated with the adjustable gastric band: insights from a rodent model. AB - BACKGROUND: Bariatric surgical procedures, including the laparoscopic adjustable gastric band (LAGB), are currently the only effective treatments for morbid obesity, however, there is no clear understanding of the mechanisms underpinning the efficacy of LAGB. The aim of this study is to examine changes in activation of the sensory neuronal pathways and levels of circulating gut hormones associated with inflation of an AGB. DESIGN AND RESULTS: The trajectory within the central nervous system of polysynaptic projections of sensory neurons innervating the stomach was determined using the transsynaptically transported herpes simplex virus (HSV). Populations of HSV-infected neurons were present in the brainstem, hypothalamus and cortical regions associated with energy balance. An elevation of Fos protein was present within the nucleus of the solitary tract, a region of the brainstem involved in the control of food intake, following acute and chronic band inflation. Two approaches were used to test (1) the impact of inflation of the band alone (on a standard caloric background) or (2) the impact of a standard caloric meal (on the background of the inflated band) on circulating gut hormones. Importantly, there was a significant elevation of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) following oral gavage of a liquid meal in animals with pre-inflated bands. There was no impact of inflation of the band alone on circulating GLP-1, PYY or ghrelin in animals on a standard caloric background. CONCLUSION: These data are consistent with the notion that the LAGB exerts its effects on satiety, reduced food intake and reduced body weight by the modulation of both neural and hormonal responses with the latter involving an elevation of meal-related levels of GLP-1 and PYY. These data are contrary to the view that the surgery is purely 'restrictive'. PMID- 22450851 TI - More fuel in the obesity paradox debate. PMID- 22450852 TI - 'Do I care?' Young adults' recalled experiences of early adolescent overweight and obesity: a qualitative study. AB - OBJECTIVE: Individual behaviour change to reduce obesity requires awareness of, and concern about, weight. This paper therefore describes how young adults, known to have been overweight or obese during early adolescence, recalled early adolescent weight-related awareness and concerns. Associations between recalled concerns and weight-, health- and peer-related survey responses collected during adolescence are also examined. DESIGN: Qualitative semi-structured interviews with young adults; data compared with responses to self-report questionnaires obtained in adolescence. PARTICIPANTS: A total of 35 participants, purposively sub-sampled at age 24 from a longitudinal study of a school year cohort, previously surveyed at ages 11, 13 and 15. Physical measures during previous surveys allowed identification of participants with a body mass index (BMI) indicative of overweight or obesity (based on British 1990 growth reference) during early adolescence. Overall, 26 had been obese, of whom 11 had BMI?99.6th centile, whereas 9 had been overweight (BMI=95th-97.9th centile). MEASURES: Qualitative interview responses describing teenage life, with prompts for school , social- and health-related concerns. Early adolescent self-report questionnaire data on weight-worries, self-esteem, friends and victimisation (closed questions). RESULTS: Most, but not all recalled having been aware of their overweight. None referred to themselves as having been obese. None recalled weight-related health worries. Recollection of early adolescent obesity varied from major concerns impacting on much of an individual's life to almost no concern, with little relation to actual severity of overweight. Recalled concerns were not clearly patterned by gender, but young adult males recalling concerns had previously reported more worries about weight, lower self-esteem, fewer friends and more victimisation in early adolescence; no such pattern was seen among females. CONCLUSION: The popular image of the unhappy overweight teenager was not borne out. Many obese adolescents, although well aware of their overweight recalled neither major dissatisfaction nor concern. Weight-reduction behaviours are unlikely in such circumstances. PMID- 22450853 TI - Maternal high-fat diet impacts endothelial function in nonhuman primate offspring. AB - OBJECTIVE: The link between maternal under-nutrition and cardiovascular disease (CVD) in the offspring later in life is well recognized, but the impact of maternal over-nutrition on the offspring's cardiovascular function and subsequent risk for CVD later in life remains unclear. Here, we investigated the impact of maternal exposure to a high-fat/calorie diet (HFD) during pregnancy and early postnatal period on endothelial function of the offspring in a nonhuman primate model. METHODS: Offspring, naturally born to either a control (CTR) diet (14% fat calories) or a HFD (36% fat calories) consumption dam, were breast-fed until weaning at about 8 months of age. After weaning, the offspring were either maintained on the same diet (CTR/CTR, HFD/HFD), or underwent a diet switch (CTR/HFD, HFD/CTR). Blood samples and arterial tissues were collected at necropsy when the animals were about 13 months of age. RESULTS: HFD/HFD juveniles displayed an increased plasma insulin level and glucose-stimulated insulin secretion in comparison with CTR/CTR. In abdominal aorta, but not the renal artery, acetylcholine-induced vasorelaxation was decreased remarkably for HFD/HFD juveniles compared with CTR/CTR. HFD/HFD animals also showed a thicker intima wall and an abnormal vascular-morphology, concurrent with elevated expression levels of several markers related to vascular inflammation and fibrinolytic function. Diet-switching animals (HFD/CTR and CTR/HFD) displayed modest damage on the abdominal vessel. CONCLUSION: Our data indicate that maternal HFD exposure impairs offspring's endothelial function. Both early programming events and postweaning diet contribute to the abnormalities that could be reversed partially by diet intervention. PMID- 22450854 TI - Body mass index across midlife and cognitive change in late life. AB - BACKGROUND: High midlife body mass index (BMI) has been linked to a greater risk of dementia in late life, but few have studied the effect of BMI across midlife on cognitive abilities and cognitive change in a dementia-free sample. METHODS: We investigated the association between BMI, measured twice across midlife (mean age 40 and 61 years, respectively), and cognitive change in four domains across two decades in the Swedish Adoption/Twin Study of Aging. RESULTS: Latent growth curve models fitted to data from 657 non-demented participants showed that persons who were overweight/obese in early midlife had significantly lower cognitive performance across domains in late life and significantly steeper decline in perceptual speed, adjusting for cardio-metabolic factors. Both underweight and overweight/obesity in late midlife were associated with lower cognitive abilities in late life. However, the association between underweight and low cognitive abilities did not remain significant when weight decline between early and late midlife was controlled for. CONCLUSION: There is a negative effect on cognitive abilities later in life related to being overweight/obese across midlife. Moreover, weight decline across midlife rather than low weight in late midlife per se was associated with low cognitive abilities. Weight patterns across midlife may be prodromal markers of late life cognitive health. PMID- 22450855 TI - Physician weight loss advice and patient weight loss behavior change: a literature review and meta-analysis of survey data. AB - Primary care providers (PCPs) can empower their patients to make health-promoting behavior changes. Many guidelines recommend that PCPs counsel overweight and obese patients about weight loss, yet few studies examine the impact of provider weight loss counseling on actual changes in patient behavior. We performed a systematic review and meta-analysis of published studies of survey data examining provider weight loss counseling and its association with changes in patient weight loss behavior. We reviewed the published literature using keywords related to weight loss advice. We used meta-analytic techniques to compute and aggregate effect sizes for the meta-analysis. We also tested variables that had the potential to moderate the responses. A total of 32 studies met criteria for the literature review. Of these, 12 were appropriate for the meta-analysis. Most studies demonstrated a positive effect of provider weight loss advice on patient weight loss behavior. In random effects meta-analysis, the overall mean weighted effect size for patient weight loss efforts was odds ratio (OR)=3.85 (95% confidence interval (CI) 2.71, 5.49; P<0.01), indicating a statistically significant impact of weight loss advice. There was no significant difference in the effectiveness of advice in studies using obese patients alone versus mixed samples (obese alone OR=3.44, 95% CI 2.37, 5.00; mixed sample OR=3.98, 95% CI 2.53, 6.26, P=0.63). PCP advice on weight loss appears to have a significant impact on patient attempts to change behaviors related to their weight. Providers should address weight loss with their overweight and obese patients. PMID- 22450856 TI - Stress, coping, and circadian disruption among women awaiting breast cancer surgery. AB - BACKGROUND: Psychological distress and coping related to a breast cancer diagnosis can profoundly affect psychological adjustment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for early mortality in metastatic colorectal and breast cancers, respectively. PURPOSE: This study aims to explore the relationships of cancer specific distress and avoidant coping with rest/activity and cortisol rhythm disruption in the period between diagnosis and breast cancer surgery. METHODS: Fifty-seven presurgical breast cancer patients provided daily self-reports of cancer-specific distress and avoidant coping as well as actigraphic and salivary cortisol data. RESULTS: Distress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsistent rhythms). Patients with disrupted rest/activity cycles had flattened diurnal cortisol rhythms. CONCLUSIONS: Maladaptive psychological responses to breast cancer diagnosis were associated with disruption of circadian rest/activity rhythms. Given that circadian cycles regulate tumor growth, we need greater understanding of possible psychosocial effects in cancer-related circadian disruption. PMID- 22450857 TI - Gas sorption and luminescence properties of a terbium(III)-phosphine oxide coordination material with two-dimensional pore topology. AB - The structure, stability, gas sorption properties and luminescence behaviour of a new lanthanide-phosphine oxide coordination material are reported. The polymer PCM-15 is based on Tb(III) and tris(p-carboxylated) triphenylphosphine oxide and has a 5,5-connected net topology. It exhibits an infinite three-dimensional structure that incorporates an open, two-dimensional pore structure. The material is thermally robust and remains crystalline under high vacuum at 150 degrees C. When desolvated, the solid has a CO(2) BET surface area of 1187 m(2) g(-1) and shows the highest reported uptake of both O(2) and H(2) at 77 K and 1 bar for a lanthanide-based coordination polymer. Isolated Tb(III) centres in the as synthesized polymer exhibit moderate photoluminescence. However, upon removal of coordinated OH(2) ligands, the luminescence intensity was found to approximately double; this process was reversible. Thus, the Tb(III) centre was used as a probe to detect directly the desolvation and resolvation of the polymer. PMID- 22450859 TI - Probability of success of breeding strategies for improving pro-vitamin A content in maize. AB - Biofortification for pro-vitamin A content (pVAC) of modern maize inbreds and hybrids is a feasible way to deal with vitamin A deficiency in rural areas in developing countries. The objective of this study was to evaluate the probability of success of breeding strategies when transferring the high pVAC present in donors to elite modern-adapted lines. For this purpose, a genetic model was built based on previous genetic studies, and different selection schemes including phenotypic selection (PS) and marker-assisted selection (MAS) were simulated and compared. MAS for simultaneously selecting all pVAC genes and a combined scheme for selecting two major pVAC genes by MAS followed by ultra performance liquid chromatography screening for the remaining genetic variation on pVAC were identified as being most effective and cost-efficient. The two schemes have 83.7 and 84.8% probabilities of achieving a predefined breeding target on pVAC and adaptation in one breeding cycle under the current breeding scale. When the breeding scale is increased by making 50% more crosses, the probability values could reach 94.8 and 95.1% for the two schemes. Under fixed resources, larger early generation populations with fewer crosses had similar breeding efficiency to smaller early generation populations with more crosses. Breeding on a larger scale was more efficient both genetically and economically. The approach presented in this study could be used as a general way in quantifying probability of success and comparing different breeding schemes in other breeding programs. PMID- 22450858 TI - Illicit use of androgens and other hormones: recent advances. AB - PURPOSE OF REVIEW: To summarize recent advances in studies of illicit use of androgens and other hormones. RECENT FINDINGS: Androgens and other appearance enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. SUMMARY: Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern. PMID- 22450860 TI - The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone. AB - Fibrous dysplasia (FD) is characterized by the replacement of normal bone with abnormal fibro-osseous tissue. This disorder is due to activating missense mutations in the GNAS gene and resultant over-production of cAMP. However, the signalling pathways that contribute to FD pathogenesis remain unknown. In the current study, bone marrow stromal cells (BMSCs) carrying GNAS R201H mutation were isolated from lesion site of FD patients. cAMP accumulation, enhanced proliferation and impaired osteogenesis potential were observed. Two cell models, BMSCs treated with excess exogenous cAMP and BMSCs infected with lentivirus GNAS R201H, were established to model the pathological conditions of FD and used to investigate its pathogenesis. The results suggest that the CREB-Smad6-Runx2 axis is involved in osteogenesis dysfunction of BMSCs with the FD phenotype. We confirmed the results in FD lesion-derived BMSCs and observed that the impaired osteogenesis potential of BMSCs infected with lentivirus GNAS (R201H) was recovered in vitro through modulation of the CREB-Smad6-Runx2 axis. This study provides useful insight into the signalling pathways involved in the FD phenotype and facilitates dissection of the molecular pathogenesis of FD and testing of novel therapies. PMID- 22450861 TI - Percutaneous valve replacement in a young adult for radiation-induced aortic stenosis. AB - A 46-year-old woman known with relapsing Hodgkin's lymphoma diagnosed at age 5, treated with repeated cycles of radiotherapy and chemotherapy, presented with severe symptomatic radiation-induced aortic stenosis. She also had other late sequelae of radiotherapy including thyroid cancer, mediastinal fribrosis and left pulmonary fibrosis with severe restrictive lung disease and a newly diagnosed renal carcinoma. Due to the prohibitively high surgical risk and need for urgent treatment, she underwent successful transcatheter aortic valve replacement with transfemoral implantation of a 23 mm Edwards SAPIEN-XT prosthesis, which was performed without valvuloplasty of the noncalcified fibrotic valve. The final result was excellent with reduction of the transaortic gradient and no residual aortic regurgitation. PMID- 22450862 TI - Does long-lasting sports practice increase the risk of atrial fibrillation in healthy middle-aged men? Weak suggestions, no objective evidence. AB - BACKGROUND: Some authors have suggested that sports activity can increase the risk of atrial fibrillation in healthy middle-aged men. Therefore, sport activity, although it prevents coronary artery disease, might be the cause of a potentially dangerous arrhythmia. METHODS: To verify this assumption, we critically analyzed the current literature including original articles, reviews and meta-analyses. RESULTS AND CONCLUSIONS: All published articles showed several limitations. The data provided by published studies support the following conclusions: the incidence of atrial fibrillation in sporting middle-aged men is rare (<0.5% per year); a possible facilitating effect on atrial fibrillation is limited to vigorous endurance exercise, not to less vigorous sports; there are no convincing data to demonstrate that sport itself may be the cause of atrial fibrillation in healthy middle-aged men; and a facilitating effect of long lasting sport cannot be excluded in middle-aged individuals with cardiovascular disorders. Nevertheless, the beneficial effects of exercise should offset this supposed risk, which, albeit increased, remains low. PMID- 22450863 TI - Association of sleep apnea with coronary slow-flow phenomenon. AB - BACKGROUND: Both obstructive sleep apnea (OSA) and coronary slow-flow phenomenon (CSFP) are known to share similar etiopathogenic mechanisms, such as chronic sympathetic activation, upregulation of inflammatory pathways, oxidative stress and, finally, endothelial dysfunction. OBJECTIVE: We evaluated whether there is an association between OSA and coronary flow rates. METHOD: We retrospectively reviewed medical records of all patients who underwent diagnostic nocturnal polysomnography for suspected OSA. Those who had coronary angiography performed within the same year of polysomnography were divided into two main groups: those with (group 1) and without (group 2) OSA; also, angiographic coronary TIMI (thrombolysis in myocardial infarction) frame counts (TFC) were compared between the groups. Patients with coronary arterial stenosis and angiograms with inadequate filling of the coronary arteries or visualization of the distal landmarks for frame counting were excluded from the study. RESULTS: There was a statistically significant difference between the groups regarding TFCs. We found a significant positive correlation between mean TFC and apnea-hypopnea index (r=0.611, P<0.001). CONCLUSION: The current study demonstrated that sleep apnea impairs coronary flow rates and is associated with CSFP. PMID- 22450864 TI - A case of crossing coronary arteries. AB - We present the case of a patient in whom coronary angiography, performed due to severe calcific aortic stenosis, revealed crossing between the left anterior descending artery and the first diagonal branch. There is only a single report presenting this particular coronary anatomy, whereas this is the eleventh case of crossing coronary arteries ever reported. The clinical implications of this variant coronary anatomy with regard to diagnostic angiography and selection of revascularization procedures are briefly discussed. PMID- 22450865 TI - Large coronary aneurysm following laser angioplasty of the left anterior descending coronary artery. AB - Coronary aneurysm is a rare complication after coronary excimer laser angioplasty. A 45-year-old woman underwent laser angioplasty and bare metal direct stenting of the proximal segment of the left anterior descending artery (LAD); after 3 months, angiographic follow-up showed significant ostial stenosis of the LAD with a large sacciform aneurysm and diffuse intrastent restenosis. PMID- 22450866 TI - Prognostic value of QRS fragmentation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. AB - CONTEXT: QRS fragmentation, including epsilon potentials, terminal activation delay and prolonged S wave upstroke, has been recently described as a diagnostic criterion of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Whether QRS fragmentation is a marker of recurrent ventricular tachycardia, primary ventricular fibrillation, implantable cardioverter defibrillator (ICD) discharge and sudden cardiac death in these patients is unknown. RESULTS: Three hundred and thirty-five patients (167 men, mean age 46.3 +/- 14.6 years) with ARVC/D according to International Society and Federation of Cardiology/European Society of Cardiology (ISFC/ESC) criteria were analyzed retrospectively. Patients with complete and incomplete right bundle branch block were excluded from the analysis. At 6.3 +/- 3.1 years mean follow-up, seven patients (0.02%) had died suddenly, 39 patients (0.13%) experienced recurrent ventricular tachycardia, 32 patients (0.1%) presented with primary ventricular fibrillation and 30 patients (0.1%) had recurrent ICD discharges. QRS fragmentation was significantly associated with arrhythmic events (P < 0.0000001 for the endpoint of sudden cardiac death, P < 0.01 for recurrent ventricular tachycardia, P < 0.0001 for primary ventricular fibrillation and P < 0.001 for recurrent ICD discharges, respectively). CONCLUSION: QRS fragmentation predicts arrhythmic events in patients with ARVC/D. Further, properly designed prospective studies are warranted to confirm these findings. PMID- 22450867 TI - Minimally aggressive treatment of spontaneous coronary artery dissections. AB - Spontaneous coronary artery dissection--the separation of the coronary artery wall layers caused by an intramural hematoma--frequently causes an acute coronary syndrome (ACS) and sudden cardiac death. The diagnosis is made at angiography by the 'tram-track' appearance of the contrast media in the true and false lumina, separated by a radiolucent intimal flap. Here we report two cases of spontaneous coronary artery dissection-related ACS managed with minimally aggressive treatment. PMID- 22450868 TI - Weight is an independent predictor of vascular injury in healthy volunteers with aspartate allele. AB - BACKGROUND: Endothelial dysfunction and carotid intima-media thickeness (IMT) are currently considered key early events in atherogenesis and markers of arterial damage. We investigated whether endothelial nitric oxide synthase (eNOS) glutamate (Glu)298-aspartate (Asp) polymorphism may influence the vascular response to weight, as measured by BMI, in young, healthy individuals. METHODS: One hundred young (30.6 +/- 5.9 years) healthy individuals, without concomitant traditional cardiovascular risk factors took part in the study. Brachial artery endothelial function was assessed by vascular response to reactive hyperemia [flow-mediated dilation (FMD) and sublingual nitroglycerin (GTN)-mediated dilation] using high-resolution ultrasound. Carotid IMT was also measured. RESULTS: Participants were grouped as Glu-homozygotes (n = 38) and Asp-carriers (n = 62). On univariate analysis, a higher response to GTN was associated with lower brachial baseline diameter (P < 0.001) and increasing value of high-density lipoprotein cholesterol (P = 0.04) in Asp-carriers, but not in Glu-homozygotes. Higher FMD correlated with lower brachial baseline diameter (P < 0.001), BMI (P = 0.03) and SBP (P = 0.03) in the Asp-carriers, but not in Glu-homozygotes. Higher IMT showed a similar Asp-genotype-dependent association with higher BMI (P = 0.001), SBP (P = 0.006) and DBP (P = 0.001). In individuals with Asp-alleles, the multivariate analysis showed that BMI was the only independent predictor of IMT. CONCLUSION: Weight is independently associated with impaired arterial structure in healthy and genetically predisposed young individuals. The allelic variation (Asp298) of the eNOS gene polymorphism makes individuals vulnerable to the impact of weight on the development of atherosclerosis. PMID- 22450869 TI - Food deserts and nutritional risk in Paraguay. AB - OBJECTIVES: The purpose of this case study in San Lorenzo, Paraguay is to identify a food desert in a developing context and to test if food deserts shape residential obesity risk. This article reviews some of the debate surrounding whether food deserts really exist; and, if so, what are the dietary implications of living in a food desert. METHODS: The research is an exploratory/explanatory design. The author mapped the downtown food retail district and the neighborhood food environment to identify what stores/markets. The author assessed each type of food store using an adapted version of the Nutrition Environment Measure Survey for Stores (NEMS-S) for Paraguay. Body mass index and household characteristics were collected with 68 households in a small neighborhood; and, the author matched the NEMS-S scores to the store reported by households as their primary grocery store for regression tests. RESULTS: The results suggest that a tradeoff exists in the local food environment between food stores which negatively impact obesity risk for local residents. Exposure to this tradeoff appears to worsen as people live longer in the food desert. Thus, the results support the location of a food desert finding in Paraguay. CONCLUSIONS: The underlying factors of a food desert extend beyond food access to focus on the issues of justice. A way to improve upon future research to build scholarship on the relationship between deprivation and obesity requires that sample sizes are either large or representative of the population and that the research should be based on multiple neighborhood and city sites. PMID- 22450870 TI - Cell-autonomous enhancement of glutamate-uptake by female astrocytes. AB - Since gonadal female hormones act on and protect neurons, it is well known that the female brain is less vulnerable to stroke or other brain insults than the male brain. Although glial functions have been shown to affect the vulnerability of the brain, little is known if such a sex difference exists in glia, much less the mechanism that might cause gender-dependent differences in glial functions. In this study, we show that in vitro astrocytes obtained from either female or male pups show a gonadal hormone-independent phenotype that could explain the gender-dependent vulnerability of the brain. Female spinal astrocytes cleared more glutamate by GLAST than male ones. In addition, motoneurons seeded on female spinal astrocytes were less vulnerable to glutamate than those seeded on male ones. It is suggested that female astrocytes uptake more glutamate and reveal a stronger neuroprotective effect against glutamate than male ones. It should be noted that such an effect was independent of gonadal female hormones, suggesting that astrocytes have cell-autonomous regulatory mechanisms by which they transform themselves into appropriate phenotypes. PMID- 22450871 TI - Rhes: a GTP-binding protein integral to striatal physiology and pathology. AB - Rhes, the Ras Homolog Enriched in Striatum, is a GTP-binding protein whose gene was discovered during a screen for mRNAs preferentially expressed in rodent striatum. This 266 amino acid protein is intermediate in size between small Ras like GTP-binding proteins and alpha-subunits of heterotrimeric G proteins. It is most closely related to another Ras-like GTP-binding protein termed Dexras1 or AGS1. Although subsequent studies have shown that the rhes gene is expressed in other brain areas in addition to striatum, the striatal expression level is relatively high, and Rhes protein is likely to play a vital role in striatal physiology and pathology. Indeed, it has recently been shown to interact with the Huntingtin protein and play a pivotal role in the selective vulnerability of striatum in Huntington's disease (HD). Not surprisingly, Rhes can interact with multiple proteins to affect striatal physiology at multiple levels. Functional studies have indicated that Rhes plays a role in signaling by striatal G protein coupled receptors (GPCR), although the details of the mechanism remain to be determined. Rhes has been shown to bind to both alpha- and beta-subunits of heterotrimeric G proteins and to affect signaling by both Gi/o- and Gs/olf coupled receptors. In this context, Rhes can be classified as a member of the family of accessory proteins to GPCR signaling. With documented effects in dopamine- and opioid-mediated behaviors, an interaction with thyroid hormone systems and a role in HD pathology, Rhes is emerging as an important protein in striatal physiology and pathology. PMID- 22450872 TI - Klippel-Feil syndrome in a boy exposed inadvertently to cyclophosphamide during pregnancy: a case report. AB - BACKGROUND: Cyclophosphamide (CPA) is an alkylating agent widely used as an immunosuppressive agent in the treatment of several autoimmune diseases, including systemic lupus erythematosus. Its teratogenic effect has been well studied in different experimental mammalian and non-mammalian animal models. In humans, 11 cases of CPA teratogenesis have been documented. CASE: We present a case of a patient with Klippel-Feil syndrome inadvertently exposed to CPA and prednisone in utero during the first trimester. CONCLUSIONS This case of possible cyclophosphamide embryopathy provides evidence of teratogenesis as an etiologic agent in developmental field defects such as Klippel-Feil syndrome. PMID- 22450874 TI - Solvent-dependent amplification of chirality in assemblies of porphyrin trimers based on benzene tricarboxamide. AB - Self-assembling achiral and chiral porphyrin trimers based on benzene tricarboxamide exhibit amplification of chirality only in solvents in which the assemblies are dynamic enough to rearrange their constituting components. PMID- 22450873 TI - Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17 demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors. AB - PURPOSE: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. METHODS: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC(0-24 h), using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. RESULTS: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC(0-24 h) for the median dose of 36 mg/m(2) was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC(0-24 h) considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. CONCLUSIONS: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy. PMID- 22450875 TI - Phosphino imidazoles and imidazolium salts for Suzuki C-C coupling reactions. AB - The consecutive syntheses of imidazoles 1-(4-X-C(6)H(4))-4,5-R(2)-(c)C(3)HN(2) (3a, X = Br, R = H; 3b, X = I, R = Me; 3c, X = H, R = Me; 5, X = Fc, R = H; 7, X = C=CFc, R = H; 9, X = C(6)H(5), R = Me; Fc = Fe(eta(5)-C(5)H(4))(eta(5) C(5)H(5))), phosphino imidazoles 1-(4-X-C(6)H(4))-2-PR'(2)-4,5-R(2)-(c)C(3)N(2) (11a-k; X = Br, I, Fc, FcC=C, Ph; R = H, Me; R' = Ph, (c)C(6)H(11), (c)C(4)H(3)O), imidazolium salts [1-(4-X-C(6)H(4))-3-R''-4,5-R(2)-(c)C(3)HN(2)]I (16a; X = Br, R = H, R'' = n-Bu; 16b, X = Br, R = H, R'' = n-C(8)H(17); 16c, X = I, R = Me, R'' = n-C(8)H(17), 16d, X = H, R = Me, R'' = n-C(8)H(17)) and phosphino imidazolium salts [1-C(6)H(5)-2-PR'(2)-3-n-C(8)H(17)-4,5-Me(2) (c)C(3)N(2)]PF(6) (17a, R' = C(6)H(5); 17b, R' = (c)C(6)H(11)) or [1-(4 P(C(6)H(5))(2)-C(6)H(4))-3-n-C(8)H(17)-4,5-Me(2)-(c)C(3)HN(2)]PF(6), (20) and their selenium derivatives 1-(4-X-C(6)H(4))-2-P([double bond, length as m dash]Se)R'(2)-4,5-R(2)-(c)C(3)N(2) (11a-Se-f-Se; X = Br, I; R = H, Me; R' = C(6)H(5), (c)C(6)H(11), (c)C(4)H(3)O) are reported. The structures of 11a-Se and [(1-(4-Br-C(6)H(4))-(c)C(3)H(2)N(2)-3-n-Bu)(2)PdI(2)] (19) in the solid state were determined. Cyclovoltammetric measurements were performed with the ferrocenyl-containing molecules 5 and 7 showing reversible redox events at E(0) = 0.108 V (DeltaE(p) = 0.114 V) (5) and E(0) = 0.183 V (DeltaE(p) = 0.102 V) (7) indicating that 7 is more difficult to oxidise. Imidazole oxidation does not occur up to 1.3 V in dichloromethane using [(n-Bu)(4)N][B(C(6)F(5))(4)] as supporting electrolyte, whereas an irreversible reduction is observed between 1.2 - -1.5 V. The phosphino imidazoles 11a-k and the imidazolium salts 17a,b and 20, respectively, were applied in the Suzuki C-C cross-coupling of 2-bromo toluene with phenylboronic acid applying [Pd(OAc)(2)] as palladium source. Depending on the electronic character of 11a-k, 17a,b and 20 the catalytic performance of the in situ generated catalytic active species can be predicted. As assumed, more electron-rich phosphines with their higher donor capability show higher activity and productivity. Additionally, 11e was applied in the coupling of 4-chloro toluene with phenylboronic acid showing an excellent catalytic performance when compared to catalysts used by Fu, Beller and Buchwald. Furthermore, 11e is eligible for the synthesis of sterically hindered biaryls under mild reaction conditions. C-C Coupling reactions with the phosphino imidazolium salts 17b and 20 in ionic liquids [BMIM][PF(6)] and [BDMIM][BF(4)] were performed, showing less activity than in common organic solvents. PMID- 22450876 TI - Efficacy of micafungin in empirical therapy of deep mycosis in surgically ill patients. AB - Micafungin (MCFG), an echinocandin antifungal agent, exhibits antifungal activity against Candida albicans and non-albicans Candida. The fungicidal activity of MCFG against clinical isolates of Candida species was investigated, and the clinical efficacy of MCFG in therapy of deep mycosis in surgery was studied using the AKOTT algorithm. The minimum inhibitory concentration and minimum fungicidal concentration values of fluconazole were <=0.06-4 and >64 MUg/ml, respectively, for each strain, whereas these values of MCFG were 0.008-0.5 and 0.016-1 MUg/ml, suggesting that MCFG provided superior fungicidal ability against Candida albicans and non-albicans Candida. The subjects were separated into two groups: group A consisted of 20 subjects with both persisting fever refractory to broad spectrum antibiotics and positive reaction to beta-D-glucan test, and group B consisted of 20 subjects with either of those conditions. The overall response was evaluated as "effective" in 17 patients (85%) and 20 patients (100%) in groups A and B, respectively. In total, response was evaluated as "effective" in 37 patients (92.5%) and "ineffective" in 3 patients (7.5%). These findings suggest that MCFG administration should be used as empirical therapy for deep mycosis in surgically ill patients as it was shown to be an effective antifungal drug lacking serious adverse effects. PMID- 22450877 TI - An inadequate dose of ribavirin is related to virological relapse by chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin. AB - The aim of this large-scale analysis was to assess the effect of 48-week pegylated interferon (PEG-IFN) alpha-2b and ribavirin (RBV) therapy on virological relapse by patients infected with hepatitis C virus (HCV) genotype 1. The relationship between virological relapse and the dose of PEG-IFNalpha-2b and RBV was investigated in 619 patients who had once cleared HCV RNA during PEG IFNalpha-2b and RBV treatment for 48 weeks. The overall virological relapse rate was 34.1% (211 of 619). The relapse rate was 59.5% (22 of 37) for patients who received <6 mg/kg/day of RBV, even if a sufficient dose of PEG-IFNalpha-2b (>=1.5 MUg/kg/day) was received. In contrast, the relapse rate was 28.1% (16 of 57) for patients who received >=12 mg/kg/day of RBV, irrespective of the PEG-IFNalpha-2b dose. The relapse rates were significantly increased with the reduction of the RBV dose for both PEG-IFNalpha-2b doses of >=1.2 and <1.2 MUg/kg/week (P < 0.0001 and P = 0.0006, respectively). Moreover, the relapse rate was 41.2% (35 of 85) for patients with an early virological response (EVR) who received <6 mg/kg/day of RBV. The relapse rates were significantly increased with the reduction of the RBV dose in both those patients with an EVR and those with a late virological response (P = 0.0006 and P = 0.0088, respectively). To summarize, for HCV genotype 1 patients treated with PEG-IFNalpha-2b and RBV, the virological relapse of HCV was RBV dose-dependent, irrespective of the dose of PEG-IFNalpha or the effect of early viral kinetics. PMID- 22450878 TI - Preventive effect of ginsenoid on chronic bacterial prostatitis. AB - Empirical antibiotic therapy is the preferred primary treatment modality for chronic bacterial prostatitis (CBP). However, this method of treatment has a low success rate and long-term therapy may result in complications and the appearance of resistant strains. Therefore a new alternative method for the prevention of CBP is necessary. There are several reports that ginsenoid has a preventive effect on urinary tract infection (UTI). To evaluate the preventive effect of ginsenoid on CBP compared to conventional antibiotics, we carried out an experiment in a rat model of the disease. Four groups of adult male Wistar rats were treated with the following medications: (1) control (no medication), (2) ciprofloxacin, (3) ginsenoid, and (4) ciprofloxacin/ginsenoid. All medications were given for 4 weeks, and then we created a CBP model in the animals by injecting an Escherichia coli Z17 (O2:K1;H(-)) suspension into the prostatic urethra. After 4 weeks, results of microbiological cultures of prostate and urine samples, as well as histological findings of the prostate in each group were analyzed. The microbiological cultures of the prostate samples demonstrated reduced bacterial growth in all experimental groups compared with the control group. Histopathological examination showed a significantly decreased rate of infiltration of inflammatory cells into prostatic tissue and decreased interstitial fibrosis in the ginsenoid group compared with the control group. Inhibition of prostate infection was greater in the group receiving both ginsenoid and antibiotic than in the single-medication groups. Although the findings of this study suggest a preventive effect of ginsenoid, preventive methods for CBP are still controversial. PMID- 22450879 TI - Innovative sensitizer DiPBI outperforms PCBM. AB - A new photorefractive (PR) material sensitized with a novel functional unit DiPBI is prepared based on the guest/host approach. This unique mixture exhibits strong absorption in the whole range of visible light. Moreover, the photorefractive performance as well as PR speed is improved by far compared to the widely used sensitizer PCBM. PMID- 22450880 TI - A case of primary cutaneous anaplastic large cell lymphoma with prominent epidermotropism. AB - Primary cutaneous anaplastic large cell lymphoma (PCALCL) is defined as anaplastic large cell lymphoma localized to the skin without extracutaneous involvement at the time of diagnosis. Histologically, PCALCL is characterized by a dense nodular infiltrate of large lymphocytes, extending into the deep dermis or subcutis. Epidermotropism is sometimes, but not frequently, seen. We herein report a case of PCALCL with prominent epidermotropism. A 63-year-old Japanese woman was referred to our hospital with a red nodule and indurated erythema in 1997. Histological findings of a skin biopsy specimen from a red nodule were typical of PCALCL, however, biopsy specimens from indurated erythema showed remarkable epidermotropism. Tumor cells were positive for CD4, and CD30, but negative for CD3 and CD8. She was diagnosed with PCALCL. In 2007, skin biopsy was performed again, which showed large atypical lymphocytes in the upper dermis with mild epidermotropism. Tumor cells expressed in both CC chemokine receptor 4 and CXC chemokine receptor 3, which may explain prominent epidermotropism in this case. PMID- 22450881 TI - Language switching in the production of phrases. AB - The language switching task has provided a useful insight into how bilinguals produce language. So far, however, the studies using this method have been limited to lexical access. The present study provides empirical evidence on language switching in the production of simple grammar structures. In the reported experiment, Polish-English unbalanced bilinguals switched between their L1 and L2 while describing pictures of ongoing and completed actions with simple SV progressive and perfective phrases. The results show asymmetrical switching costs for progressive phrases and symmetrical switching costs with reversed dominance for perfective phrases. These findings parallel those obtained in tasks requiring the production of single words, although the present study is the first in which the same bilingual participants display different patterns of switching costs depending on the characteristics of utterances they produce. These results can be explained using recently developed models of bilingual language control. PMID- 22450882 TI - Measurement error in estimates of sprint velocity from a laser displacement measurement device. AB - This study aimed to determine the measurement error associated with estimates of velocity from a laser-based device during different phases of a maximal athletic sprint. Laser-based displacement data were obtained from 10 sprinters completing a total of 89 sprints and were fitted with a fifth-order polynomial function which was differentiated to obtain instantaneous velocity data. These velocity estimates were compared against criterion high-speed video velocities at either 1, 5, 10, 30 or 50 m using a Bland-Altman analysis to assess bias and random error. Bias was highest at 1 m (+ 0.41 m/s) and tended to decrease as the measurement distance increased, with values less than + 0.10 m/s at 30 and 50 m. Random error was more consistent between distances, and reached a minimum value (+/-0.11 m/s) at 10 m. Laser devices offer a potentially useful time-efficient tool for assessing between-subject or between-session performance from the mid acceleration and maximum velocity phases (i. e., at 10 m and beyond), although only differences exceeding 0.22-0.30 m/s should be considered genuine. However, laser data should not be used during the first 5 m of a sprint, and are likely of limited use for assessing within-subject variation in performance during a single session. PMID- 22450883 TI - An evidence-based review on the influence of aging with a spinal cord injury on subjective quality of life. AB - STUDY DESIGN: Systematic review. OBJECTIVES: To identify changes in subjective quality of life (QoL) as one ages with a spinal cord injury (SCI). SETTING: Vancouver, Canada. METHODS: Electronic databases were searched for studies reporting on age-related QoL changes over time. Data from relevant studies were transcribed into data extraction forms and analyzed by years post injury (YPI) and chronologic age. Each study was assigned a level of evidence based on a modified Sackett scale. RESULTS: In all, 21 studies, each with a low level of evidence, were included for review. The results indicated that regardless of chronologic age, individuals with relatively new SCI have the potential to improve their QoL. Among individuals with advanced YPI, overall QoL is consistently reported as good or excellent over time, however, with variations in different QoL domains. CONCLUSION: The QoL of individuals aging with a SCI has the potential to improve, and remain high and stable over time. As the identified studies provide low levels of evidence, more longitudinal research with greater methodological and measurement rigor is needed to corroborate the findings and conclusions of this review. PMID- 22450884 TI - International Spinal Cord Injury Quality of Life Basic Data Set. AB - STUDY DESIGN: Survey of expert opinion, feedback, and development of final consensus. OBJECTIVE: Present the background, purpose, development process and results for the International Spinal Cord Injury (SCI) Quality of Life (QoL) Basic Data Set. SETTING: International. METHODS: A committee of experts was established to select and define data elements to be included in an International SCI QoL Basic Data Set. A draft data set was developed and disseminated to appropriate organizations for comment. All suggested revisions were considered, and a final version of the QoL data set was completed. RESULTS: The QoL data set consists of 3 variables: ratings of satisfaction with general quality of life, satisfaction with physical health, and satisfaction with psychological health. All variables are rated on a scale ranging from 0 (completely dissatisfied) to 10 (completely satisfied). CONCLUSION: Collection of the International SCI QoL Basic Data Set variables should be a part of all future studies of SCI QoL to facilitate comparison of results across published studies from around the world. Additional standardized instruments to assess other aspects of QoL can be administered based on the purpose of a particular study. PMID- 22450885 TI - Self-efficacy and self-esteem as predictors of participation in spinal cord injury--an ICF-based study. AB - STUDY DESIGN: A multi-centre cross-sectional study. OBJECTIVE: To examine the relationship of self-efficacy and self-esteem with participation of persons with spinal cord injury (SCI) from a comprehensive bio-psycho-social perspective, based on the conceptual framework of the International Classification of Functioning, Disability and Health (ICF). SETTING: Community-dwelling participants, <5 years post discharge, recruited through three SCI rehabilitation centers in Switzerland. METHODS: Data were collected by means of standardized self-report questionnaires sent to the eligible participants by postal mail. The questionnaires covered the different components of the ICF's bio-psycho-social model, namely health conditions, body functions, participation, environmental and personal factors. Bivariate correlations and multivariate linear regression analyses with participation as the dependent variable have been conducted. RESULTS: In all, 102 persons with SCI answered the survey, response rate 25.9%. Self-esteem (r=0.61) and self-efficacy (r=0.54) correlated highly with participation and were the strongest correlates of participation. They were stronger correlates of participation than symptoms of anxiety, depressive symptoms, pain, health conditions, social support, coping styles or sense of coherence. Participation seemed to be independent of gender, age, level or completeness of injury. Self-efficacy and self-esteem explained together with time since discharge and years of education 48% of the variance in participation adjusting for health condition, depressive symptoms, pain interference and social support. CONCLUSION: Considering self-efficacy and self-esteem within the comprehensive framework of the ICF can contribute to a better understanding of functioning, disability and health in SCI, which in turn may facilitate the development of interventions to support the persons' adjustment and reintegration. PMID- 22450886 TI - How much equipment is prescribed for people with spinal cord injury in Australia, do they use it and are they satisfied 1 year later? AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the amount and type of equipment prescribed to aid mobility and self-care for patients with spinal cord injuries (SCI) in Australia and to determine how frequently the equipment is used 1 year later and whether patients are satisfied with it. METHODS: A consecutive series of 61 patients admitted for rehabilitation to two Sydney SCI units were recruited. All mobility and self-care equipment worth more than $AU50 prescribed by therapists before patients' discharge was recorded. This included wheelchairs, commodes, shower chairs, hoists, electric beds, pressure relieving cushions, bed mattresses, slideboards, walking aids, orthoses, electrical stimulation systems and other pieces of notable exercise equipment. Patients were interviewed 1 year later and asked about each piece of equipment they had been prescribed. Specifically, they were asked about how frequently they had used each piece of equipment and whether they were satisfied with it. Data were analysed using descriptive statistics. RESULTS: Three hundred and fourteen pieces of equipment, including 68 wheelchairs, were prescribed for the 61 patients. Most of the equipment (226/314) was used more than 20 times in the 2 months preceding the 1-year review. Most patients were satisfied or highly satisfied with the majority of equipment prescribed, although patients were very dissatisfied or only partly dissatisfied with 18/314 pieces of equipment. DISCUSSION: Patients were generally satisfied with the equipment they were prescribed. There was a small amount of equipment prescribed that was not used 1 year later or with which patients were dissatisfied. PMID- 22450887 TI - State of the Science Conference in Spinal Cord Injury Rehabilitation 2011: introduction. PMID- 22450888 TI - Incidence and predictors of contracture after spinal cord injury--a prospective cohort study. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: To determine incidence of contracture and develop prediction models to identify patients susceptible to contracture after spinal cord injury. SETTING: Two Sydney spinal cord injury units. METHODS: A total of 92 consecutive patients with acute spinal cord injury were assessed within 35 days of injury and 1 year later. Incidence of contracture at 1 year was measured in all major appendicular joints by categorizing range of motion on a 4-point scale (0-no contracture to 3-severe contracture), and in the wrist, elbow, hip and ankle by measuring range of motion at standardized torque. Multivariate models were developed to predict contracture at 1 year using age, neurological status, spasticity, pain and limb fracture recorded at the time of injury. RESULTS: At 1 year, 66% of participants developed at least one contracture (defined as >=1 point deterioration on the 4-point scale). Incidence of contracture at each joint was: shoulder 43%, elbow and forearm 33%, wrist and hand 41%, hip 32%, knee 11% and ankle 40%. Incidence of contracture determined by standardized torque measures of range (defined as loss of >=10 degrees) was: elbow 27%, wrist 26%, hip 23% and ankle 25%. Prediction models were statistically significant but lacked sufficient predictive accuracy to be clinically useful (R(2)<=31%). CONCLUSION: The incidence of contracture in major joints 1 year after spinal cord injury ranges from 11-43%. The ankle, wrist and shoulder are most commonly affected. It is difficult to accurately predict those susceptible to contracture soon after injury. PMID- 22450889 TI - Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience. AB - AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC 95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies. PMID- 22450890 TI - Soluble CD163: a biomarker linking macrophages and insulin resistance. AB - AIMS/HYPOTHESIS: Soluble CD163 (sCD163) was recently identified as a strong risk marker for developing type 2 diabetes. We hypothesised that sCD163 independently associates with insulin resistance. METHODS: This cross-sectional study includes 234 participants: 96 with type 2 diabetes, 34 with impaired glucose tolerance (IGT) and 104 with normal glucose tolerance (NGT), matched for sex and BMI. Glucose-lowering medication was paused for 1 week before plasma samples were obtained for determination of sCD163 and other inflammatory and metabolic variables. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Concentrations of sCD163 were 1.95 mg/l (0.63-6.97) in individuals with type 2 diabetes, 1.64 mg/l (0.58-4.19) in those with IGT, and 1.48 mg/l (0.48-4.11) (median [range]) in those with NGT (p < 0.0001). In univariate analyses, sCD163 correlated significantly with HOMA-IR (R = 0.44), insulin (R = 0.41), glucose (R = 0.30), triacylglycerol (R = 0.29) and HDL-cholesterol (R = -0.34) (all p < 0.0001). All but glucose remained significant when adjusting for age, sex, BMI and glycaemic group. In univariate regression analyses, HOMA-IR was associated with sCD163, C-reactive protein (CRP), TNF-alpha and IL-6 (all p <= 0.0001). An increase of 50% in sCD163 resulted in an estimated increase in HOMA-IR of 36% (95% CI 26, 48; p < 0.0001). In multiple linear regression analyses, sCD163 (p = 0.001) and CRP (p = 0.01) remained independent predictors of HOMA-IR, whereas TNF-alpha and IL-6 did not. CONCLUSIONS/INTERPRETATION: Macrophage-specific sCD163 was strongly associated with insulin resistance independently of TNF-alpha and other predictors. Moreover, sCD163 was associated with well-known variables of the metabolic syndrome. PMID- 22450891 TI - Keratins: markers and modulators of liver disease. AB - PURPOSE OF REVIEW: Keratins are a subgroup of intermediate filaments expressed in the epithelia. Keratins emerged as important tissue-protecting genes and keratin variants cause/predispose to development of more than 50 human disorders. Our review focuses on the importance of keratins in context of liver disease. RECENT FINDINGS: K8/K18 variants are found in approximately 4% of white population and predispose to development and adverse outcome of multiple liver diseases. K8/K18 are major constituents of Mallory-Denk bodies, that is inclusions found in alcoholic and nonalcoholic steatohepatitis (NASH) and dysregulated keratin expression, K8 hyperphosphorylation, misfolding and crosslinking via transglutaminase 2 facilitate aggregate formation. Necrosis-generated and apoptosis-generated keratin serum fragments are emerging as important noninvasive markers of multiple liver diseases, particularly NASH. Keratins are established markers of tumor origin and in hepatocellular carcinoma, K19 expression is associated with poor prognosis. SUMMARY: Keratins are established tumor markers and are widely used as noninvasive markers of liver injury. In addition, the data that have become available in recent years have greatly advanced our understanding of keratins as modifiers of liver disease development. PMID- 22450892 TI - Animal models of biliary tract injury. AB - PURPOSE OF REVIEW: Cholestatic liver diseases with bile duct injury and biliary fibrosis account for a significant percentage of patients with end-stage liver disease and undergoing liver transplantation. A number of different animal models have been established and have added substantially to our understanding of the molecular mechanisms underlying this group of chronic liver diseases. In the present review, we discuss recent findings and new insight derived from different animal models of biliary tract injury and fibrosis. RECENT FINDINGS: Cholangiocytes do not undergo epithelial to mesenchymal transition and do not contribute to the pool of biliary fibroblasts involved in extracellular matrix deposition. Rather cholangiocytes can acquire a reactive phenotype activating fibrogenesis through secretion of proinflammatory and profibrogenic mediators. Bile acid homeostasis is controlled by a gut-liver axis playing a crucial role in the adaptive response to bile duct injury and cholestasis. The nuclear factor kappa B and hedgehog signaling pathways play a critical role in cholestatic liver injury and the emergence of liver cancer. Nuclear receptors are key mediators of adaptive response mechanisms in cholestasis and potential therapeutical targets. SUMMARY: Recent progress and mechanistic insights from mouse models have added to our understanding of the molecular mechanisms underlying cholestatic liver and biliary tract injury and pointed to new therapeutic options. PMID- 22450893 TI - Drug-induced liver injury. AB - PURPOSE OF REVIEW: Drug-induced liver injury (DILI) remains an important disease in clinical practice. It is difficult to predict, diagnose and manage. Studies in the peer-reviewed literature in the last 2 years, focusing on the diagnosis, prediction and management of DILI will be reviewed. RECENT FINDINGS: Antibiotics remain the most common drug causing DILI in the United States and Europe. Expert opinion may still be the better method of diagnosing DILI compared with an objective tool such as the Roussel-Uclaf Causality Assessment Method. Hepatitis E represents an alternative diagnosis to some cases of presumed drug hepatotoxicity. There is ongoing research into the genetics of the pathophysiology and susceptibility of DILI. A genome-wide association study confirmed the association between human leukocyte antigen (HLA) class II and susceptibility to coamoxiclav (amoxicillin-clavulanic acid) induced DILI. There is new information on the protective effect of HLA-DRB1*07 family of alleles. MicroRNAs are a potential marker of DILI. Keratin variants may predict outcome of acute liver failure. N-acetylcysteine may be protective against DILI while taking antituberculosis medication. SUMMARY: Recent findings in the genetics of pathophysiology and susceptibility of DILI can help with predicting and avoiding DILI in clinical practice and provide the foundation for ongoing research. PMID- 22450894 TI - New advances in chronic hepatitis B. AB - PURPOSE OF REVIEW: This article reviews recent developments in the evaluation and treatment of chronic hepatitis B (CHB) based on articles published between December 2010 and January 2012. RECENT FINDINGS: The majority of patients infected with CHB have not been diagnosed and most at-risk individuals have not been immunized. Progression to cirrhosis depends on hepatitis B virus (HBV) genotype, hepatitis B e antigen (HBeAg) presence, persistently high levels of HBV DNA, and elevated alanine aminotransferase, although hepatitis B surface antigen (HBsAg) kinetics may help predict natural history and antiviral response. Antiviral resistance limits the success of nucleos(t)ide analogs and agents such as entecavir and tenofovir with high potency and high genetic barrier to resistance are considered first-line therapy. Specialized treatment of CHB in pregnancy, coinfection, decompensated cirrhosis, and posttransplant is safe and effective. SUMMARY: The complications of CHB can now be avoided and reversed with potent antiviral suppression of HBV DNA. For now, treatment is long-term and further studies are needed to discern whether sequential or combination therapy may be superior to current monotherapy for certain patients. Increased awareness should improve screening resulting in more frequent treatment and immunization of at-risk individuals toward eventual CHB eradication. PMID- 22450895 TI - The aryl hydrocarbon receptor in inflammatory bowel disease: linking the environment to disease pathogenesis. AB - PURPOSE OF REVIEW: The aryl hydrocarbon receptor (AhR), a transcription factor activated by a large number of environmental agents, modulates the activity of immune and nonimmune cells in the gut, and may represent an important link between the environment and the immune perturbations which underlie the pathogenesis of inflammatory bowel disease. This review will summarize the current knowledge of the role of AhR in regulation of intestinal immune homeostasis and inflammation. RECENT FINDINGS: Activation of AhR by dietary ligands is necessary for the maintenance or expansion of innate immune cells in the gut, such as intraepithelial lymphocytes (IELs) and interleukin (IL)-22 producing lymphoid cells (ILC22). AhR-deficient mice lack IELs, have reduced number of ILC22 cells, and are more susceptible to bacterial infections and experimental colitis. In animal models, AhR activators inhibit proinflammatory cytokine synthesis and attenuate colitis by a pathway that involves IL-22. Analysis of AhR in the human gut reveals that intestinal T cells and natural killer cells isolated from Crohn's disease patients express low levels of AhR and respond to AhR ligands by downregulating inflammatory cytokines and upregulating IL-22. SUMMARY: These novel findings may help explain how environmental factors may regulate mucosal immune responses. PMID- 22450896 TI - High-grade dysplasia and intramucosal adenocarcinoma in Barrett's esophagus: the role of endoscopic eradication therapy. AB - PURPOSE OF REVIEW: Endoscopic eradication therapy is considered a well tolerated and effective alternative to esophagectomy for a select patient population with high-grade Barrett's esophagus and intramucosal adenocarcinoma. This review highlights the available eradication techniques (resection and ablation) with emphasis on factors that influence the choice of therapy. RECENT FINDINGS: Long term follow-up of patients treated with endoscopic eradication therapies demonstrates high rates of complete remission of dysplasia and intestinal metaplasia with overall survival comparable to patients treated surgically. Cohort studies also report that recurrence following successful ablation occurs in a significant proportion of patients, making careful surveillance an indispensable component following successful endoscopic therapy. Endoscopic eradication therapy is also effective for the treatment of recurrent dysplasia and intestinal metaplasia. Ablative therapies may lead to buried metaplasia in a small proportion of patients. The long-term clinical implications of buried metaplasia are unclear. SUMMARY: Patients undergoing endoscopic eradication therapy should be enrolled in a comprehensive surveillance and staging program that offers both resection and ablative techniques. Complete remission of dysplasia and intestinal metaplasia can be achieved in the vast majority of patients undergoing endoscopic therapy. Surveillance should continue after treatment with close monitoring for recurrent dysplasia. PMID- 22450897 TI - The biliary HCO(3)(-) umbrella: experimental evidence revisited. AB - PURPOSE OF REVIEW: To critically review most recent experimental evidence for the protective action of biliary HCO(3)(-) secretion against bile acid-induced bile duct damage and development of fibrosing cholangiopathy in humans and experimental animals. RECENT FINDINGS: Studies in human cholangiocytes in vitro indicate that a biliary HCO(3)(-) umbrella protects against bile acid-induced cholangiocyte damage and apoptosis in humans. The Cl(-)/HCO(3)(-) exchanger, AE2, and an intact biliary glycocalyx appear crucial for its stability. Related studies with experimental animal models in vivo have to be interpreted with caution as humans and mice differ not only with regard to bile salt pool, but also their expression patterns of transport proteins and signalling molecules. SUMMARY: Adequate biliary HCO(3)(-) secretion may protect against bile salt induced cholangiopathies. Future therapeutic strategies in biliary diseases will aim at stabilizing the biliary HCO(3)(-) umbrella. PMID- 22450898 TI - Update in liver transplantation. AB - PURPOSE OF REVIEW: Successful transplant outcomes require optimal patient selection and timing. This review will update clinicians with current status and challenges in liver transplantation. Currently, the major limitation facing liver transplant centers is the shortage of organs. The limited availability of organs has led to long waiting periods for liver transplantation and consequently many patients become seriously ill or die while on the waiting list. RECENT FINDINGS: This has major implications in the selection of patients, as well as the timing of transplant, for optimal use of these scarce organs. Indications and contraindications have changed slightly over the years and will be reviewed in this article. SUMMARY: Timing for transplantation has changed more dramatically in the recent years because major changes to organ allocation systems have been undertaken to provide clinicians with a better way to prioritize patients for liver transplant. PMID- 22450899 TI - Post-ERCP pancreatitis: review of current preventive strategies. AB - PURPOSE OF REVIEW: This article reviews the most recent literature with significant findings pertaining to the prevention of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. RECENT FINDINGS: Despite several promising reports of pharmacologic agents that have demonstrated the efficacy for prophylaxis against post-ERCP pancreatitis such as nonsteroidal anti-inflammatory drugs and secretin, there are currently no universally accepted agents for use in high-risk patients. The greatest reductions in the incidence of post-ERCP pancreatitis in high-risk patients have been demonstrated through advancements in endoscopic techniques such as pancreatic duct stenting and dye-free guidewire cannulation. SUMMARY: Pancreatitis requiring hospitalization is the most common complication of ERCP. Numerous pharmaceutical and procedure related interventions have been studied in attempts to prevent this complication; however, morbidity associated with ERCP remains significant. The most effective methods for preventing post-ERCP pancreatitis are careful patient selection and identification of risk factors prior to procedure. PMID- 22450900 TI - Eosinophilic esophagitis: diagnostic tests and criteria. AB - PURPOSE OF REVIEW: To present the clinical, endoscopic, and histologic features of eosinophilic esophagitis (EoE), review the current diagnostic guidelines for EoE, and present an approach for diagnosis of EoE. It will also highlight selected techniques that are under development that may be useful in the future for diagnosis of EoE. RECENT FINDINGS: Recently updated guidelines emphasize that EoE is a clinicopathologic condition. Specifically, three criteria must be met to diagnose EoE: clinical symptoms of esophageal dysfunction; an esophageal biopsy with a maximum eosinophil count of at least 15 eosinophils per high-power microscopy field, with few exceptions; and exclusion of other possible causes of esophageal eosinophilia, including proton-pump inhibitor responsive esophageal eosinophilia (PPI-REE). A PPI trial is typically required both to assess for PPI REE and to evaluate for the presence of concomitant gastroesophageal reflux disease. SUMMARY: EoE is a chronic, immune-mediated disorder. Because no single symptom, endoscopic finding, or histopathologic feature is pathognomonic, diagnosis can be challenging. In the future, symptom scores, tissue or serum biomarkers, and genetic testing may play a role in diagnosis, but these methods have yet to be validated and are not yet recommended for routine clinical use. PMID- 22450901 TI - Impact of Centers for Medicare & Medicaid Services national coverage determination on erythropoiesis-stimulating agent and transfusion use in chemotherapy-treated cancer patients. AB - PURPOSE: In July 2007, the Centers for Medicare & Medicaid Services released a national coverage determination (NCD) for erythropoiesis-stimulating agent (ESA) use in cancer patients, mandating payment restrictions likely to reduce ESA use and possibly increase red blood cell transfusions. We aimed to quantify ESA and transfusion use pre-NCD and post-NCD. METHODS: Medicare 5% sample data, 2005 2007, were used. Patients were 66 years or older, had lung, breast, or colorectal cancer or lymphomas, and initiated chemotherapy in pre-NCD and post-NCD periods (September-November 2006, September-November 2007). ESA use and transfusions were identified from claims. Differences in proportions of patients using ESAs and receiving transfusions pre-NCD and post-NCD were evaluated using logistic regression; differences in transfusion event rates were evaluated using a Poisson model. RESULTS: The pre-NCD cohort included 1897 patients and the post-NCD cohort 1877. In the pre-NCD cohort, 31% of patients had lung cancer, 29% lymphoma, 20% colorectal cancer, and 20% breast cancer; distribution was similar in the post NCD cohort. Overall, ESA use decreased from 35.0% pre-NCD to 15.2% post-NCD. Transfusion use increased from 9.3% to 10.4%, and transfusion event rates from 19.0 to 21.8 per 100 patient-quarters. Results adjusted for baseline characteristics and comorbid conditions were similar. ESA use reduction achieved statistical significance; transfusion use and rate increases did not. CONCLUSIONS: ESA use decreased sharply post-NCD. This was accompanied by an estimated 1.1% (95% confidence interval -0.8% to 3.0%) absolute increase in transfusion use. PMID- 22450902 TI - Nano-hydroxyapatite particles induce apoptosis on MC3T3-E1 cells and tissue cells in SD rats. AB - While the advantages of nanomaterials are being increasingly recognized, their potential toxicity is drawing more and more attention and concern. In this study, we explore the toxicity mechanism of 20-30 nm rod-shaped hydroxyapatite (HA) nanoparticles in vitro and in vivo. The nanoparticles were prepared by precipitation and characterized by IR, XRD and TEM. Concentrations of 0 MUg mL( 1), 10 MUg mL(-1), 100 MUg mL(-1), 1 mg mL(-1), and 10 mg mL(-1) were applied to the MC3T3-E1 cells for viability (MTT-test). Based on the characteristic differences of the two methods of cell death, the morphological features of the MC3T3-E1 cell line co-cultured with nano-hydroxyapatite (n-HA) (10 mg mL(-1)) for 24 h were also observed by TEM. Furthermore, important serum biochemical markers and histopathological examinations were used to evaluate the potential toxicological effect of n-HA on the major organs of SD rats injected intraperitoneally with n-HA (33.3 mg kg(-1) body weight). In the results, we found cell growth inhibition and apoptosis in MC3T3-E1 cells co-cultured with n HA. Moreover, apoptosis but not necrosis was illustrated in liver and renal tissue by using histopathology slices and serum biochemical markers. It suggests that apoptosis may be the possible mechanism of n-HA toxicity and provides a better understanding of the biocompatibility of nanomaterials applied in human bone repair. PMID- 22450903 TI - Factors affecting the local control of stereotactic body radiotherapy for lung tumors including primary lung cancer and metastatic lung tumors. AB - PURPOSE: To identify factors affecting local control of stereotactic body radiotherapy (SBRT) for lung tumors including primary lung cancer and metastatic lung tumors. MATERIALS AND METHODS: Between June 2006 and June 2009, 159 lung tumors in 144 patients (primary lung cancer, 128; metastatic lung tumor, 31) were treated with SBRT with 48-60 Gy (mean 50.1 Gy) in 4-5 fractions. Higher doses were given to larger tumors and metastatic tumors in principle. Assessed factors were age, gender, tumor origin (primary vs. metastatic), histological subtype, tumor size, tumor appearance (solid vs. ground glass opacity), maximum standardized uptake value of positron emission tomography using (18)F-fluoro-2 deoxy-D: -glucose, and SBRT doses. RESULTS: Follow-up time was 1-60 months (median 18 months). The 1-, 2-, and 3-year local failure-free rates of all lesions were 90, 80, and 77 %, respectively. On univariate analysis, metastatic tumors (p < 0.0001), solid tumors (p = 0.0246), and higher SBRT doses (p = 0.0334) were the statistically significant unfavorable factors for local control. On multivariate analysis, only tumor origin was statistically significant (p = 0.0027). The 2-year local failure-free rates of primary lung cancer and metastatic lung tumors were 87 and 50 %, respectively. CONCLUSIONS: A metastatic tumor was the only independently significant unfavorable factor for local control after SBRT. PMID- 22450904 TI - Evaluation of associative effects of total mixed ration for dairy cattle using in vitro gas production and different rumen inocula. AB - BACKGROUND: Current feed evaluation systems for dairy cattle assume that nutritive values of feed components can be added, but do not take into account possible interactions among feed components. The main objective of this study was to investigate associative effects on in vitro gas production from total mixed ration (TMR), based on grass silage and cereal concentrate, and separate TMR components. TMR was incubated with inocula of free rumen liquid (FRL) and particle-associated rumen liquid (PAL) for 48 h and donor cows were fed TMRs with three different particle sizes to evaluate their influence on associative effects. RESULTS: Associative effects on gas production largely occurred at 2 and 4 h of incubation and dissipated with time of incubation. Incubation of TMR with PAL increased (P < 0.01) gas production compared to FRL at all incubation times; however, associative effects were not different between rumen inocula. Dietary particle size affected associative effects on gas production when TMR was incubated with FRL (P < 0.05) compared to PAL, particularly at early hours of incubation. CONCLUSIONS: Associative effects at early incubation hours emphasise that summing the nutritive values of feedstuffs may underestimate fermentation intensity of TMR which may have implications for prediction of ruminal fermentation yield. PMID- 22450905 TI - Association between MTHFR polymorphisms and orofacial clefts risk: a meta analysis. AB - BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta-analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06-1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05-1.76). CONCLUSIONS This meta-analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations. PMID- 22450906 TI - A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin. AB - Oxaliplatin is effective in advanced colorectal cancer and is known to have relatively few side effects, such as hemolysis and renal toxicity. We report a case of acute kidney injury (AKI) after treatment with a combination of oxaliplatin, folinic acid and 5-fluorouracil or capecitabine. The patient developed acute renal failure, hemolytic anemia and thrombocytopenia after the 34th course of chemotherapy including oxaliplatin. A positive direct antiglobulin test and detection of immunoglobulin G and complement C3b and C3d on erythrocytes suggested the diagnosis of immune-related severe intravascular hemolytic anemia. She was successfully treated and recovered using plasma exchange, corticosteroids and hemodialysis therapy. Only seven other cases of AKI associated with oxaliplatin use have been reported to date. As in this case, acute hemolysis due to autoimmune mechanisms and subsequent AKI occurred suddenly after frequent use of oxaliplatin in four of those cases. We should be aware that oxaliplatin may cause sudden life-threatening hemolysis by drug-induced antibodies and subsequent AKI, even though oxaliplatin is frequently administered without side effects. This represents the first case report of AKI-related hemolysis due to oxaliplatin in Japan. PMID- 22450907 TI - Emphysematous cyst infection in autosomal dominant polycystic kidney disease. PMID- 22450908 TI - Design rule of nanostructures in light-emitting diodes for complete elimination of total internal reflection. AB - Cone-shaped nanostructures with controllable side-wall angle are success- fully fabricated with a SiO(2) nanosphere lithography (NSL) etching mask. Vertical LEDs with cone-shaped nanostructures with a 24.1 degrees side-wall angle provide 6% more light output power compared to those using hexagonal pyramids formed by photochemical etching. This achievement is attributed to effective elimination of total internal reflection by angle-controlled nanostructures. PMID- 22450910 TI - Expression and role of receptor 1 for orexins in seminiferous tubules of rat testis. AB - Orexins (OxA and OxB) and their receptors (Ox1R and Ox2R), originally detected in the hypothalamus, have also been localized in multiple cerebral areas and peripheral organs. Thus, in addition to their central function in the regulation of food intake, arterial blood pressure, heart rate, sleep/wake cycle, sexual behaviour, arousal, and hypothalamic/hypophyseal axis, these neuropeptides may exert a local action in various peripheral organs and tissues. Emerging evidence suggests a main role of OxA and its highly specific receptor Ox1R in the male genital tract of mammals. We previously demonstrated OxA localization in Sertoli cells and spermatids of rat testis. Here, we show positive stainings of Ox1R in developing spermatocytes, and spermatids of rat testis by immunohistochemistry. The expression of Ox1R mRNA and the protein in the tissue was also established by reverse-transcription polymerase chain reaction and Western blotting respectively. The addition of OxA to fresh testis slices significantly increased testosterone (T) secretion which, conversely, was inhibited by Mullerian inhibiting substance (MIS). The sequential treatment of testis samples with the two substances highlighted an antagonizing activity of OxA versus MIS in regulating T levels. Furthermore, the stimulating effect on T production by OxA was prevented by the addition of the selective Ox1R inhibitor SB-408124. Overall, our findings suggest that locally secreted OxA interacting with Ox1R activates signals which antagonize MIS action in the control of T levels in mammalian testis. PMID- 22450911 TI - VAMP8/endobrevin is a critical factor for the homotypic granule growth in pancreatic acinar cells. AB - The delivery of newly-formed secretory content to the granule inventory occurs through direct fusion of recently formed granules and mature granules. The introduction of knockout mice allowed us to investigate the characteristics of the delivery process and to determine the core protein machinery required for granule growth. The SNARE machinery mediates membrane fusion and is essential for the granule lifecycle. In the current work, we use VAMP8 knockout mice to show that the SNARE machinery plays a critical role in the process of granule homotypic fusion. Consistent with this, the mutated mouse pancreatic acinar secretory granules are significantly smaller compared to the control group, demonstrating few granule profiles that might be the result of homotypic fusion. PMID- 22450909 TI - Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases. AB - In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-beta3 (TGFbeta3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies. PMID- 22450912 TI - [Malaria epidemiology in Bitlis from 1998 to 2008]. AB - OBJECTIVE: Malaria is still an important public health problem both in Turkey and the world. In this investigation, the records of patients with malaria that had been detected by the Health Directorship of Bitlis between 1998 and 2008 were examined. METHODS: The retrospective study was performed on data from the Provincial Health Directory. During this 11-year period, a total of 86,951 blood samples were taken by active and pasive surveillance. Thin and thick blood smears stained with Giemsa were examined by immersion objective under microscope. RESULTS: A total of 659 (0.75%) malaria cases were detected. Of these cases, 368 (55.84%) were male and 291 (44.16%) female. It was also observed that the positive cases were found mostly between 1998-2000 and showed an increase between May-September and an important decrease from 2001. Out of the 659 cases of malaria, 599 (90.9%) cases were indigenous, 60 (9.1%) cases were imported and in all cases the determinant was Plasmodium vivax. CONCLUSION: It is hoped that, with this study, the data will contribute to the epidemiology of malaria and its prevention in Bitlis. PMID- 22450913 TI - [Evaluation of malaria cases in Antalya between 2001 and 2011]. AB - OBJECTIVE: Malaria is a mosquito-borne infectious disease that is transmitted by female Anopheles mosquitoes to humans when an infected mosquito bites a person. In this research, we examined the epidemiology of malaria using the data provided by the Malaria Control Unit of the Infectious Disease Divison of Antalya Health Directory, from the years 2001 to 2011. METHODS: The cases were evaluated according to age groups, gender, months and parasite species. RESULTS: During this period, a total of 131.989 blood samples were evaluated and 66 malaria cases (0.0005%) were reported, and the highest rate of cases occurred during September. Seventy-four percent (49) of malaria cases were male, 26% (17 cases) were female. The species of malaria parasites were recorded in 86% of cases, of which Plasmodium vivax was the most common (57 cases), with P. falciparum accounting for 14% of cases (9 cases). All P. falciparum cases were found to be imported cases coming to Antalya from other countries. Most of the malaria cases (78.8%) were 15 years old and over. CONCLUSION: We belived that our resarch contributes to the epidemiology of malaria and its prevention in Antalya region. PMID- 22450914 TI - [Survey of Theileria annulata and Theileria buffeli/orientalis complex in cattle in the Kirsehir region using multiplex-PCR]. AB - OBJECTIVE: To investigate the presence of T. annulata and T. buffeli/orientalis complex in the blood of 172 cattle selected from 9 different regions of Kirsehir. METHODS: Genes for the merozoite surface antigen (Tams 1) and the major piroplasm surface protein (MPSP) were amplified with multiplex- PCR for T. annulata and T. buffeli/orientalis, respectively. RESULTS: By multiplex-PCR examination 4 (2.32%) samples were positive for T. annulata whereas none of the samples were positive for T. buffeli/orientalis complex. CONCLUSION: In this study, it is concluded that simultaneous diagnosis of Theileria species by using multiplex-PCR is more practical than the investigation of species individually by using classical PCR. We also believe that a more accurate epidemiological data is achieved with the use of moleculer diagnosis methods such as multiplex-PCR, which eliminates the disadvantages of the traditional methods used in the diagnosis of parasitic diseases. PMID- 22450915 TI - [Five year surveillance of Entamoeba histolytica and Giardia antigen of stool samples by ELISA method]. AB - OBJECTIVE: The aim of this study is to show the ratio of detection of distribution of E. histolytica ve Giardia in the fecal samples of the patients with diarrhoea complaints admitted to the hospitals and medical centers of our instution between June 2004 and June 2009. METHODS: In our study, the patient samples were analyzed by E. histolytica antigen ELISA (Cellabs, Entamoeba Celisa Path, Brookvale, NSW Australia) kit and by Giardia antigen (Ridascreen, R Biopharm AG, Darmstadt, Germany). Further, fecal cultures were performed and the presence of leukocytes and erythrocytes and Entamoeba and Giardia trophozoite and cysts were also examined. RESULTS: During this time in 539 of the 10305 patients (5.2%) Entamoeba histolytica (E. histolytica) and in 343 of 3100 patients (11.1%) Giardia specific antigens were detected. In the microscopical examination Entamoeba cysts were detected in 3% of the E. histolytica antigen positively detected patients and in 2% of the E. histolytica antigen negatively detected patients. Giardia cysts were detected in only 10% of the Giardia antigen positively detected patients. CONCLUSION: Continuous training of personnel is planned. The physicians were informed and trained to order antigen detection tests along with the direct microscopic examinations in fecal samples to provide the best diagnosis. PMID- 22450916 TI - [The distribution of intestinal parasites detected in the Uludag University Medical Faculty Hospital between 2009-2010]. AB - OBJECTIVE: Intestinal parasite infection is still an important public health problem. In this study, patients with various gastrointestinal system complaints presenting at various clinics of the Uludag University Medical Faculty, between 2009-2010 were investigated for intestinal parasites. METHODS: All fecal samples were examined with the formol ethyl acetate sedimentation method for helminth ova and protozoan cysts. For the diagnosis of coccidian protozoa, the modified Ehrlich-Ziehl-Neelsen was used. Trichrome staining was also performed in ambiguous cases. The cellophane tape method was used to detect Enterobius vermicularis egg. The prevalence of intestinal parasites was evaluated with respect to age, gender and the months in which cases were seen. RESULTS: One or more parasites were found in 195 of the 2686 stool samples. The overall prevalence of intestinal parasitic infection rate was 7.3%, and of these patients, 57.95% were female and 42.05% male. Predominant parasites were Giardia intestinalis 3.23%, followed by Entamoeba coli 2.34%, Entamoeba histolytica 0.59%, and Strongyloides stercoralis 0.44%. Enterobius vermicularis eggs were detected by the cellophane tape method in 80 (12.08%) out of 622 patients. The proportion of individuals infected with one parasite was 85.4%, two parasites 12.6%, and three parasites 2.0%. The age group 10-19 years had the highest prevalence of parasites and was predominantly infected with G. Intestinalis (p < 0.001). CONCLUSION: The results of this study emphasized that, even in the Bursa Province with a relatively high level of social hygiene, intestinal parasitic infections are still an important public health problem. PMID- 22450917 TI - [Chewing lice species (Phthiraptera: Ischnocera) found on blackbirds (Turdus merula): new records from Turkey]. AB - OBJECTIVE: This study was conducted to detect the chewing lice species on the blackbirds shot (Turdus merula) in Yesilyurt village, Canakkale METHODS: Four Blackbirds (Turdus merula) shot by a hunter were examined for lice in Yesilyurt village, Canakkale. The lice specimens collected on the Blackbirds were preserved in alcohol 70%, transparented in KOH 10% and mounted on the slides in Canada balsam. RESULTS: The lice specimens were identified as Ricinus elongatus (Olfers, 1816) and Brueelia merulensis (Denny, 1842) on microscopical examination. CONCLUSION: In this study, R. elongatus and B. merulensis are recorded for the first time in Turkey. PMID- 22450918 TI - [Occurence of the hindgut ciliates Paraisotricha colpoidea and P. minuta (Ciliophora: Paraisotrichidae) in horses in Turkey]. AB - OBJECTIVE: The aim of this study was to determine the cytological features of 2 endocommensal ciliates, P. colpoidea and P. minuta belonging to genus Paraisotricha found in the hindgut of 15 Turk rahvan and 15 English and Arabic horses from Izmir, compare the morphological characters of species with their original descriptions and previous reports and discuss the similarities and differences. METHODS: The cytological features of two endocommensal ciliates were investigated with the pyridinated silver carbonate impregnation and silver nitrate impregnation techniques at the level of light microscopy. RESULTS: Specimens from our horses were found to be similar to the original descriptions on the basis of cytological features, morphological characters and biometric data. CONCLUSION: We have concluded that the geographical variation and feeding habits of the host animals are important for evaluating the biometric data of species. PMID- 22450919 TI - [Retrospective evaluation of the alveolar echinococcosis cases between 1980-2010 in Erciyes University Hospital]. AB - OBJECTIVE: Alveolar echinococcosis is an uncommon parasitic disesae confined to the Northern Hemisphere. There is limited data regarding the incidence of the disease in Kayseri. METHODS: Clinicopathologic features of the cases with the diagnosis of alveolar echinococcosis reviewed between 1980-2010. RESULTS: Twenty nine cases of alveolar echinococcosis were found. There were no significant distribution differences during the study period. 28 of the 29 cases were localised in the liver, whereas one case was localised in the omentum. Sixteen of the 29 cases were male (55%) and 13 were female (45%). The age distribution of these cases varied between 33 and 80. Thirteen cases resided in Kayseri, 2 cases resided in Erzurum, 1 each case resided in Adana, Ardahan, Kars, Nigde, Nevsehir and Yozgat. We could not obtain information from the remaining 8 cases. Abdominal pain was the main symptom in 8 cases, jaundice in 2 cases and fatigue and fever in one case on admission. One case was detected incidentally. All of the cases were diagnosed by histologic examination. CONCLUSION: The data about the alveolar echinococcosis is limited due to its low prevelance. Alveolar echinococcosis cases were detected in Kayseri with a lower incidence than in the East Anatolian region. This report will add data about the incidence of the alveolar echinococcosis. PMID- 22450920 TI - Enterobius vermicularis: a rare cause of appendicitis. AB - OBJECTIVE: Although appendicitis is one of the most common causes of emergency surgery, parasites are rarely found associated with inflammation of the appendix. The aim of this study is to establish the prevalence of Enterobius vermicularis in surgically removed appendices, as well as to determine its possible role in the pathogenesis of appendicitis. METHODS: A retrospective analysis of all the appendices removed during the last 20 years at a tertiary university hospital. Appendices removed during the course of another intra-abdominal procedure were excluded from the study. RESULTS: All 1085 surgical specimens removed from patients with clinical appendicitis were evaluated. Enterobius vermicularis was found in seven appendices (0.65%) with clinical symptoms of appendicitis. The parasite was most frequently identified in appendices without pathological changes (6/117). There was no case of chronic appendicitis presenting E. vermicularis infestation, while the parasite was rarely related to histological changes of acute appendicitis (1/901). CONCLUSION: The results suggest that the presence of E. vermicularis in the appendix might cause appendiceal pain (colic), but can rarely be associated with pathologic findings of acute appendicitis. PMID- 22450921 TI - [Two cases of rare cerebral hydatid cyst]. AB - Hydatid cyst disease (Echinococcosis) is a parasitic illness that is rarely located in the brain. Primary cerebral hydatid cyst disease is rarely seen. We report here rare two cases presenting with sixth cranial nerve palsy with increased intracranial pressure syndrome due to primary cerebral hydatid cyst. A 5-year-old female and a 13-year-old boy complained of headache, strabismus, nausea, and vomiting. Neurological examination revealed sixth nerve palsy and papilloedema. The diagnosis was cerebral hydatid cyst disease and was confirmed with radiological and pathological investigations. Both cases were operated on. The cysts were removed without rupture, and therapy was completed with albendazole for a period of six months. They were symptom-free during the follow up period. In conclusion, cerebral hydatid cyst disease should be kept in mind in the differential diagnosis of increased intracranial pressure syndrome. PMID- 22450922 TI - [Ruptured pulmonary hydatid cyst: a case report]. AB - Hydatid cyst (HD), a very common disease in the world, is often transmitted to humans through dog feces. HD is especially common in countries where agriculture and animal husbandry is prevalent. HD is caused by Echinococcus granulosus. The clinic course of HD usually features settling in the liver and lungs. Lung involvement with chest pain, cough, shortness of breath can cause non specific symptoms such as fever and hemoptysis. Diagnostic interventions for HD include chest X-ray tomography, and physical examination. Although the treatment options of HD vary according to the clinical findings of the patients, the primary treatment may be considered as surgery. The most frequently applied methods of surgical treatment are cystectomy and capitonnage. Medical treatment is usually warranted for complicated cases, including the patients with multiple and unresectable lesions, patients who refuse surgery and the patients who cannot tolerate surgery. Treatment with albendazole and its derivatives are used. In this case report, we present a child with primary complaints of cough, chest pain, dyspnea, fatigue and fever who was latterly diagnosed with lung HD. PMID- 22450923 TI - [Incidentally diagnosed liver and right iliac muscle hydatid disease]. AB - Hydatid cyst disease is localized in the liver and lungs in most of the cases, but also can exist throughout the body. In this article, we present a 20-year-old male patient who was diagnosed with hydatid cyst of the liver and iliac muscle, who presented because of respiratory problems. Especially in endemic areas, in patients who are detected as having hydatid cyst in the liver, systemic examinations must be cattied out and investigated regarding any involvement of other organs. PMID- 22450924 TI - [Urogenital myiasis caused by Psychoda albipennis]. AB - Myiasis cases are often encountered in humans, especially in tropical and subtropical regions. Urogenital myiasis is one of the facultative myiasis cases that may be seen in humans. Psychoda albipennis is an insect species that causes urogential myiasis in humans Adults of this species, belongs to the Psychodidae subfamily, lives especially in humid toilets and domestic bathrooms. This case, presented as urogenital myiasis caused by P. albipennis in a fifteen year old male. The person, who was a student, was living in the city center reported to have passed five-six larvae for three months. The patient had normal urinalysis, stool microscopy and urine culture. Larvae were examined under a microscope and were identified as fourth period larvae of P. albipennis. Therefore, it should not be forgotten that P. albipennis may be an agent in urogenital myiasis. PMID- 22450925 TI - A case of traumatic myiasis in a domestic rabbit (Oryctolagus cuniculus) caused by Lucilia sericata. AB - Lucilia sericata is one of the factors resulting in facultative traumatic myiasis in animals and humans. L. sericata threatens human health and leads to significant economic losses in animal industry by leading to serious parasitic infestations. A three month old female rabbit was presented to the clinics of the Veterinary Faculty of Dicle University for the treatment of the wound located on the left carpal joint. The examination revealed that the wound was infested with larvae. The microscopic inspection of the larvae collected from the rabbit showed that they were the third instar larvae of L. sericata. PMID- 22450926 TI - Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. AB - We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (P trend ?0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in the RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA. PMID- 22450927 TI - Evolution of the immune system at geological and local scales. AB - PURPOSE OF REVIEW: This review will contest the idea that the adaptive immune system of mammals represents an evolutionary advance which superseded the less evolved, innate immune system of invertebrates. General conclusions about the evolution of immune systems will be applied to current infectious diseases of humans common in conditions of poverty. RECENT FINDINGS: Many invertebrates have mechanisms for diversifying the repertoire of receptors specific for pathogen associated molecules. The lamprey uses true genetic rearrangement to produce a repertoire comparable to that of our antibody-based system. Both adaptive immune systems may have evolved independently from an efficient, pre-existing, lymphocyte-based, innate immune system, the importance of which has only recently been described in mammals.Genetic variation in human populations is associated with susceptibility and resistance to infectious diseases. Specifically, human leucocyte antigen and natural killer receptor alleles are associated with susceptibility or resistance to HIV. However, the extent to which these will exert long-term selective pressure is unclear. SUMMARY: Human pathogens do to exert selective pressures on the immune system, but these are unlikely to do more than change allele frequencies in the short term. In the long term, pathogen driven evolution seems to promote expansion of recognition repertoire in adaptive and innate immune systems. PMID- 22450928 TI - The history and future of the Urologic Oncology Study Group (UOSG) of the Japan Clinical Oncology Group (JCOG). AB - The Urologic Oncology Study Group (UOSG) of the Japan Clinical Oncology Group was founded in 2001. At the beginning, 41 collaborative institutions participated, and the first group representative was Kenichi Tobisu, from the Shizuoka Cancer Center. In the last 10 years, three JCOG studies have been conducted. In two of them, patient registration has been closed and they are now in the follow-up period. The third study has just started registration in 2011. At present, we have not yet completed the final data analyses in any of the studies. In the meantime, however, we have performed a few retrospective analyses by collecting clinical data from each of the participating institutions, and the results were published as important Japanese data. All the activities of the investigation were supported by the Health and Labor Sciences Research Grants for Clinical Research in Japan. The UOSG encountered great difficulties in planning the prospective study, completing the sophisticated protocol and recruiting the expected number of patients. It usually took a longer time than expected to achieve the final goal. This was probably due to insufficient experience in conducting sophisticated protocol studies and immaturity in managing a study group. Now, the UOSG consists of 38 institutions and is gradually overcoming these problems. In 2011, the UOSG changed its group representative to Yoshiyuki Kakehi from Kagawa University and continues to strive to meet the challenge of becoming a more active group. In this review, we provide an overview of the history and achievements of the UOSG over the past 10 years, along with a list of participating institutions. PMID- 22450929 TI - Efficacy and safety of gemcitabine-docetaxel combination therapy for recurrent or refractory high-grade osteosarcoma in China: a retrospective study of 18 patients. AB - OBJECTIVE: In this study, we describe experiences with gemcitabine-docetaxel combination therapy as salvage treatment for Chinese patients with recurrent or refractory high-grade osteosarcoma. METHODS: We retrospectively reviewed the medical records of 18 patients with recurrent or refractory high-grade osteosarcoma who had undergone gemcitabine-docetaxel combination treatment as salvage chemotherapy. Gemcitabine at 675 mg/m(2) was administered on Days 1 and 8, and docetaxel at 75-100 mg/m(2) was administered on Day 8. The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. RESULTS: The patients (ages 12-57 years) received a total of 44 cycles of chemotherapy (median: 2 courses; range: 2 6 courses). The overall response rate was 5.6% and the disease control rate was 22.3%, with one partial response and three patients with stable disease. The median time to progression and overall survival time were 2 months (range: 2-6 months) and 8 months (range: 3-21 months), respectively. Major severe toxicities were hematologic toxicities, including Grade 3 or 4 anemia (9.1%), leucopenia (29.5%) and thrombocytopenia (18.1%) in total cycles; mild toxicities included Grade 1 or 2 nausea and vomiting (31.8%), fatigue (38.6%) and alopecia (20.5%). There were no treatment-related deaths. CONCLUSIONS: In the current study, gemcitabine-docetaxel combination therapy at this dosage and schedule was found to be well tolerated and marginally effective, which could be considered as salvage therapy for patients with recurrent or refractory high-grade osteosarcoma. PMID- 22450930 TI - Apocrine carcinoma as triple-negative breast cancer: novel definition of apocrine type carcinoma as estrogen/progesterone receptor-negative and androgen receptor positive invasive ductal carcinoma. AB - OBJECTIVE: Apocrine carcinoma, a subtype of invasive ductal carcinoma of the breast, expresses androgen receptor (AR), but often lacks estrogen receptor (ER) and progesterone receptor (PgR). In the present study, the author immunohistochemically defined apocrine-type carcinoma as ER-/PgR-/AR+ invasive ductal carcinoma and analyzed the significance of apocrine-type carcinoma as triple-negative breast cancer. METHODS: Four hundred and forty breast cancers from 429 cases were immunostained for estrogen receptor, progesterone receptor, androgen receptor, human epidermal growth factor receptor type 2 (HER2), p53, Ki 67 and epidermal growth factor receptor. The lesions included 58 in situ malignancies (including 13 apocrine-type lesions) and 325 invasive ductal carcinomas (including 44 apocrine type). RESULTS: Of 91 estrogen receptor negative invasive ductal carcinomas, 44 (48%) belonged to apocrine-type carcinoma, and overexpression of human epidermal growth factor receptor type 2 and p53 was observed in 23 (52%) and 33 (75%), respectively. Histologically, 22 (50%) were categorized as classical apocrine carcinoma. Among 281 non-apocrine invasive ductal carcinomas, 30 (11%) were quadruple-negative (ER-/PgR-/AR-/HER2-) and 17 (6%) were hormone receptor-negative and human epidermal growth factor receptor type 2-overexpressed. Invasive ductal carcinomas in the triple-negative breast cancer category (n= 51) were divided into triple-negative, androgen receptor-positive (apocrine, n= 21) and quadruple-negative (non-apocrine, n= 30). p53 overexpression was more often seen in the apocrine-type triple-negative breast cancer (18/21 = 86%) than in the non-apocrine type (14/30 = 46%) (P< 0.05). Ki-67 labeling was significantly higher in the non-apocrine type (58%) than in the apocrine type (37%) (P< 0.01). Epidermal growth factor receptor is consistently expressed in triple-negative breast cancers (16/16 = 100% in apocrine and 18/20 = 90% in non-apocrine). CONCLUSIONS: Androgen receptor should be added to immunohistochemical panels, since apocrine-type invasive ductal carcinoma, resembling basal-like phenotypes, may show clinical behaviors different from the basal-like triple-negative breast cancer. PMID- 22450931 TI - Genotypic differences in zinc efficiency of Chinese maize evaluated in a pot experiment. AB - BACKGROUND: Zinc (Zn) deficiency, a major problem limiting crop production worldwide, is common on calcareous soils of China. Using such a Zn-deficient soil supplied adequately with plant mineral nutrients, with or without Zn, 30 Chinese maize genotypes were grown for 30 days in a greenhouse pot experiment and assessed for Zn efficiency (ZE), measured as relative biomass under Zn-limiting compared with non-limiting conditions. RESULTS: Substantial variation in tolerance to low Zn nutritional status was observed within the maize genotypes. Tolerant genotypes did not show Zn deficiency symptoms at the studied early seedling growth, and there was a well-defined relationship between shoot dry matter and the ZE trait. ZE values ranged on average from 45 to 100% for shoot dry weight. Under low available soil Zn conditions, shoot and root dry weights, shoot Zn concentration and content, leaf superoxide dismutase (SOD) activity, leaf area and plant height were all correlated with ZE. Shoot Zn and phosphorus (P) concentrations were negatively correlated. CONCLUSION: Three genotypes (L55 * 178, L114 * 178 and Zhongnong 99) were identified as highly Zn-efficient and three (L53 * 178, L105 * 178 and L99 * 178) as very low in ZE. This selection allows further work to evaluate ZE based on grain yield and grain Zn concentration, including field experiments likely to benefit farmers producing maize on Chinese soils low in available Zn. PMID- 22450932 TI - Child and adolescent affective and behavioral distress and elevated adult body mass index. AB - Obesity rates throughout the world have risen rapidly in recent decades, and are now a leading cause of morbidity and mortality. Several studies indicate that behavioral and affective distress in childhood may be linked to elevated adult body mass index (BMI). The present study utilizes data from a 20-year longitudinal study to examine the relations between symptoms of conduct disorder, attention-deficit/hyperactivity disorder, and depression during late childhood and mid-adolescence and BMI during emerging adulthood. Data were analyzed using multiple regression. Results suggest that childhood and adolescent problems may influence adult BMI through direct impacts on adolescent overweight, a condition which then persists into adulthood. PMID- 22450933 TI - Strong supramolecular binding of Li(+)@C60 with sulfonated meso tetraphenylporphyrins and long-lived photoinduced charge separation. AB - A supramolecular binding occurred between lithium ion encapsulated [60]fullerene (Li(+)@C(60)) and sulfonated tetraphenylporphyrins ([MTPPS](4-) M = H(2) and Zn) in a benzonitrile solution. Photoexcitation of Li(+)@C(60)/[MTPPS](4-) results in formation of a long-lived charge-separated state by photoinduced electron transfer. PMID- 22450935 TI - First "more," then "less". PMID- 22450936 TI - Sitting time and all-cause mortality risk in 222 497 Australian adults. AB - BACKGROUND: Prolonged sitting is considered detrimental to health, but evidence regarding the independent relationship of total sitting time with all-cause mortality is limited. This study aimed to determine the independent relationship of sitting time with all-cause mortality. METHODS: We linked prospective questionnaire data from 222 497 individuals 45 years or older from the 45 and Up Study to mortality data from the New South Wales Registry of Births, Deaths, and Marriages (Australia) from February 1, 2006, through December 31, 2010. Cox proportional hazards models examined all-cause mortality in relation to sitting time, adjusting for potential confounders that included sex, age, education, urban/rural residence, physical activity, body mass index, smoking status, self rated health, and disability. RESULTS: During 621 695 person-years of follow-up (mean follow-up, 2.8 years), 5405 deaths were registered. All-cause mortality hazard ratios were 1.02 (95% CI, 0.95-1.09), 1.15 (1.06-1.25), and 1.40 (1.27 1.55) for 4 to less than 8, 8 to less than 11, and 11 or more h/d of sitting, respectively, compared with less than 4 h/d, adjusting for physical activity and other confounders. The population-attributable fraction for sitting was 6.9%. The association between sitting and all-cause mortality appeared consistent across the sexes, age groups, body mass index categories, and physical activity levels and across healthy participants compared with participants with preexisting cardiovascular disease or diabetes mellitus. CONCLUSIONS: Prolonged sitting is a risk factor for all-cause mortality, independent of physical activity. Public health programs should focus on reducing sitting time in addition to increasing physical activity levels. PMID- 22450937 TI - New exercise prescription: don't just sit there: stand up and move more, more often. PMID- 22450938 TI - Treatment of mild to moderate sinusitis. AB - BACKGROUND: The National Physicians Alliance (NPA)-initiated a project titled "Promoting Good Stewardship in Clinical Practice" to develop a list of the "Top 5" activities in primary care, where changes in practice could lead simultaneously to higher quality care and better use of finite clinical resources. The treatment of acute mild to moderate sinusitis was selected for the "Top 5" list because it is a common clinical problem. Evidence supports avoiding antibiotics early in the course of the illness, and doing so could markedly reduce costs. METHODS: We reviewed the results of meta-analyses of randomized controlled trials published in the past 10 years comparing antibiotic treatment with placebo and summarized the evidence regarding the benefits, harms, and costs of antibiotic treatment of acute mild to moderate sinusitis. RESULTS: Sinusitis is one of the most common diagnoses in primary care, accounting for 20 million visits annually in the United States and 15% to 21% of annual antibiotic prescriptions. In randomized controlled trials, cure or improvement 7 to 15 days after beginning treatment was statistically significantly more common among patients assigned to antibiotics compared with placebo, but the differences were small, ranging from a 7% to 14% higher rate of improvement with antibiotics. The rate of complications and recurrence did not differ between those treated with antibiotics and placebo. Adverse effects, primarily diarrhea, were 80% more common in the antibiotic compared with the placebo groups. In addition to adverse effects, overuse of antibiotics can also harm population health by increasing rates of antibiotic resistance CONCLUSIONS: Antibiotics should not be prescribed for mild to moderate sinusitis within the first week of the illness. Avoiding antibiotics for acute sinusitis could reduce antibiotic adverse effects, antibiotic resistance, and the cost of health care. PMID- 22450939 TI - "So that's why they didn't get better!". PMID- 22450940 TI - Fatal lung toxic effects related to dronedarone use. PMID- 22450941 TI - Dronedarone use and fatal lung toxic effects? PMID- 22450942 TI - Bridging the chasm: effect of health information exchange on volume of laboratory testing. PMID- 22450943 TI - Association between more frequent chocolate consumption and lower body mass index. PMID- 22450944 TI - What is a modest public health impact? PMID- 22450945 TI - Nontargeted HIV screening in emergency departments. PMID- 22450946 TI - Cardiovascular risk evaluation tools specific to population with diabetes. PMID- 22450947 TI - The patient-centered medical home: friend or foe? PMID- 22450948 TI - First agreement analysis and day-to-day comparison of pharyngeal pH monitoring with pH/impedance monitoring in patients with suspected laryngopharyngeal reflux. AB - OBJECTIVE: Diagnosis of laryngopharyngeal reflux (LPR) is still challenging. Recently a diagnostic device for pH values in the aerosolized environment of the pharynx has been introduced (Dx-pH). We evaluated results of Dx-pH with objective criteria of pH/impedance monitoring (MII) and subjective reflux scoring systems and assessed day-to-day variability. DESIGN: This study makes use of a prospective single-center trial. Thirty patients with suspected LPR were analyzed. Upper endoscopic examination, manometry, phoniatric examination, and reflux scores were assessed. Dx-pH was performed on two consecutive days, first in combination with MII and second as single measurement. Thereafter, proton pump inhibitor (PPI) trial was performed. Patients were interviewed about symptom relief after 3 months. RESULTS: There were considerable differences between MII and results on Dx-pH: day 1 (agreement 11 out of 30, kappa 0.137) and day 2 (agreement 14 out of 30, kappa 0.036). Statistically significant differences were detected correlating all single reflux episodes (n = 453) of Dx-pH with MII and vice versa. Furthermore acidic reflux episodes did not result in pH drops of the pharynx. There was a fair agreement between Dx-pH measurements on subsequent days. After follow-up, 3 out of 18 patients with pathological Dx-pH results reported positive response to PPIs, in contrast to 5 out of 6 patients with pathological MII. CONCLUSION: According to our data, acid pharyngeal pH levels detected with Dx-pH are not related to GERD and acid esophageal reflux episodes do not result in pharyngeal pH alterations. Hence, present etiology of LPR needs to be reconsidered since neither mixed nor gas reflux events result in pharyngeal pH alteration. Other acid-producing or retaining factors should be taken into account. PMID- 22450949 TI - How i do it: per-oral endoscopic myotomy (POEM). AB - INTRODUCTION: Laparoscopic Heller myotomy has become the therapy of choice for achalasia. In the last three years, clinical experience with a novel approach to this disease, Per-Oral Endoscopic Myotomy (POEM), has grown. METHODS: Herein, we describe the technical steps in the POEM procedure. CONCLUSION: In our experience, the method appears to be a safe alternative to standard laparoscopic Heller myotomy, but further assessment is needed to understand long-term outcomes. PMID- 22450950 TI - Genomic analysis of pterostilbene predicts its antiproliferative effects against pancreatic cancer in vitro and in vivo. AB - BACKGROUND: To investigate the inhibitory role of pterostilbene in pancreatic cancer, we conducted a genomic analysis of pterostilbene-treated pancreatic cancer cells. We also investigated the effect of pterostilbene upon the carcinogenic markers, manganese superoxide dismutase, cytochrome C, Smac/DIABLO, and STAT3 phosphorylation in vitro. The antiproliferative effects of pterostilbene were further evaluated in an in vivo model. METHODS: Pancreatic cancer cells were treated with pterostilbene and evaluated with DNA microarray analysis. Pterostilbene-treated cells were analyzed for cytochrome C, Smac/DIABLO, manganese superoxide dismutase (MnSOD)/antioxidant activity, and STAT3 phosphorylation using ELISA. Data were statistically analyzed using ANOVA. Pterostilbene was then administered to nude mice for 8 weeks, and tumor growth rates were recorded and statistically analyzed. RESULTS: Microarray analysis of pterostilbene-treated cells revealed upregulation of pro-apoptosis genes. In vitro, pterostilbene treatment altered levels of phosphorylated STAT3, MnSOD/antioxidant activity, cytochrome C, and Smac/DIABLO. In nude mice, oral pterostilbene inhibited tumor growth rates. CONCLUSION: Pterostilbene alters gene expression in pancreatic cancer and increases the antiproliferative markers cytochrome C, Smac/DIABLO, and MnSOD/antioxidant activity. It was also shown to inhibit phosphorylated STAT3, a marker of accelerated tumorigenesis, and decrease pancreatic tumor growth in vivo. Further studies are warranted to elucidate the effects of pterostilbene in humans. PMID- 22450951 TI - Total mesorectal excision--does the choice of dissection technique have an impact on pelvic autonomic nerve preservation? AB - BACKGROUND: The aim of this experimental study was to assess the quality of pelvic autonomic nerve preservation of different dissection techniques. MATERIAL AND METHODS: Twelve pigs underwent low anterior rectal resection (LARR) with scissors, ultracision, monopolar diathermy, and waterjet, each in three animals. Assessment of pelvic autonomic nerve preservation was carried out by stimulation of the pelvic splanchnic nerves under electromyography of the internal anal sphincter (IAS). Neurostimulation was performed bilaterally after posterior dissection, after complete mesorectal dissection, and after rectal resection. RESULTS: Stimulation resulted in significantly increased amplitudes of the time based electromyographic signal of the IAS, confirming nerve preservation. The stimulation results after complete mesorectal dissection showed comparable median amplitude increases for dissection with scissors (10.34 MUV (interquartile range [IQR], 5.58; 14.74)) and ultracision (9.79 MUV (IQR, 7.63; 11.6)). Lower amplitude increases were observed for monopolar diathermy (4.47 MUV (IQR, 2.52; 10.46)) and waterjet (0.61 MUV (IQR, 0.07; 2.11)) (p = 0.038). All animals undergoing dissection with scissors, ultracision, and monopolar diathermy had bilateral positive results. Of three animals undergoing LARR with waterjet, one had bilateral positive results. Two had unilateral negative results, indicating incomplete nerve preservation. CONCLUSION: Scissors, ultracision, and monopolar diathermy might have comparable nerve-sparing potentials and differed from waterjet. PMID- 22450952 TI - Splenic injury during colonoscopy--a complication that warrants urgent attention. AB - INTRODUCTION: Colonoscopy is a safe procedure that is performed routinely worldwide. There is, however, a small but significant risk of splenic injury that is often under-recognized. Due to a lack of awareness about this injury, the diagnosis may be delayed, which can lead to an increased risk of morbidity as well as mortality. This paper presents a comprehensive review of the medical literature on colonoscopy-associated splenic injury and describes the clinical presentation and management of this rare but potentially life-threatening complication. MATERIALS AND METHODS: A comprehensive literature search identified 102 patients worldwide, including patients from our experience, with splenic injury during colonoscopy. A meta-regression analysis was completed using a mixed generalized linear model for repeated measures to identify risk factors for this rare complication. RESULTS: A total of 75 articles were identified and 102 patients were studied. The majority of the papers were in English (92 %). Only 23.4 % of patients (26/102) were reported prior to the year 2000. Among the patients reported after the year 2000, the majority (84.2 %, 64/76) were reported after 2005. There were more females (76.5 %), median age was 65 years (range, 29 90 years), and most of the colonoscopies were performed without difficulty (66.6 %). Nearly 67 % of patients presented within 24 h of colonoscopy with complaints ranging from abdominal pain to dizziness. The most common symptom was left upper quadrant pain (58 %), and CT scan was found to be the most sensitive tool for diagnosis. Seventy-three patients underwent operative intervention; 96 % of these were treated with splenectomy. Hemoglobin drop of more than 3 gm/dL was identified as the only significant predictor of operative intervention. The overall mortality rate was 5 %. CONCLUSION: Splenic injury during colonoscopy is rare; however, it is associated with significant morbidity and mortality. Splenic injury warrants a high degree of clinical suspicion critical to prompt diagnosis, and early surgical consultation is warranted. PMID- 22450953 TI - Comprehensive analysis of variables affecting delayed gastric emptying following pancreaticoduodenectomy. AB - INTRODUCTION: Delayed gastric emptying (DGE) occurs commonly following pancreaticoduodenectomy (PD), and criteria for its clinical diagnosis have recently been standardized by an international consensus group. We evaluated 24 operative and peri-operative variables to assess which were independent risk factors for DGE development. Secondarily, we also examined DGE incidence over time and evaluated the consensus guidelines' ability to diagnose DGE in patients with complicated post-operative courses. METHODS: A prospective, single-surgeon database of 235 patients undergoing PD at an academic tertiary center was retrospectively reviewed and DGE was assessed per published guidelines. RESULTS: DGE occurred in 42 patients overall (17.9 %), with incidence falling from 30.0 to 9.1% during the study period. Post-operative abscess, pancreatic fistula formation, pulmonary comorbidity, and increased intraoperative blood loss were found to be independent risk factors (p<0.05) for DGE on multivariate analysis. Changes in operative technique, such as pylorus preservation, did not associate with DGE. In a separate analysis, when patients with confounding post-operative events such as re-intubation or re-laparotomy were excluded, DGE incidence was 11.9 %. CONCLUSIONS: Perturbation of the operative bed by a secondary complication seems to be the dominant risk for DGE development. The consensus guidelines for DGE diagnosis, while indispensable, may overestimate DGE incidence. PMID- 22450954 TI - Initial experience of robotic gastrectomy and comparison with open and laparoscopic gastrectomy for gastric cancer. AB - BACKGROUND: Robotic gastrectomy has become more popular in the treatment of gastric cancer, especially in Asian countries. Until now, few studies have compared robotic surgery with open or laparoscopic surgery for gastric cancer patients. METHODS: Data were prospectively collected between January 2006 and February 2012. A total of 689 patients underwent curative resection of adenocarcinoma of the stomach. Patients were separated into three groups according to the different surgical approaches used (586 open, 64 laparoscopic, and 39 robotic). The clinicopathological characteristics and surgical outcomes of the three groups were compared. RESULTS: The open group was associated with a larger tumor size, more D2 dissection, more advanced tumor stage, and more blood loss than the groups treated with laparoscopic and robotic methods. Robotic gastrectomy was associated with female predominance, less blood loss, shorter hospital stay, and longer operative time than open and laparoscopic gastrectomy. The retrieved lymph node numbers were similar between the open and robotic groups. Postoperative morbidity rates were similar among the three groups. In terms of the learning curve of robotic gastrectomy, operative time and docking time were significantly reduced in the recent robotic group (n=14) compared to the initial robotic group (n=25). CONCLUSION: Robotic gastrectomy could achieve extended lymph node dissection similar to open surgery. Our results showed a significant learning curve effect in the initial 25 cases of the robotic group. PMID- 22450955 TI - Intramural colonic splenosis: a rare case of lower gastrointestinal bleeding. AB - BACKGROUND: A 41-year-old man had left upper quadrant abdominal pain, constipation, and melena. About 6 years previously, he received a single gunshot wound to the abdomen, which required partial gastrectomy and small bowel resection. He subsequently developed bleeding gastric varices for which he underwent a splenectomy 2 years before the current admission. DISCUSSION: A CT scan identified a 6.5 * 2.5 cm left upper quadrant mass. Upper endoscopy was unremarkable, but on colonoscopy, a 3-cm polypoid mass partially obstructed the descending colon. A left hemicolectomy was performed with a primary colonic anastomosis and incidental appendectomy. The mass involved the muscularis of the colon and caused ulceration of the mucosa was ectopic hyperplasic splenic tissue, indicating intramural colonic splenosis. We hypothesize that after the patient's splenectomy, a colonic focus of heterotrophic spleen became hyperplastic and led to a clinically apparent lesion. PMID- 22450956 TI - Arthroscopy of the fetlock joint of the dromedary camel. AB - OBJECTIVES: To describe a technique for arthroscopy of the fetlock joint of the dromedary camel, and the problems that could occur during and after arthroscopy. METHODS: Seven animals (4 cadaveric limbs and 3 living camels) were used in this study. Two dorsal arthroscopic portals (lateral and medial) and one palmaro lateral portal were used. Distension of the joint capsule was effected by injecting Ringer's lactate solution into the joint cavity. Landmarks for the dorsal arthroscopic portals were located at the centre of the groove bounded by the lateral branch of the suspensory ligament and the large metacarpus at a point 1 cm proximal to the joint. The palmaro-lateral portal was located in a triangular area between the branch of the suspensory ligament, the large metacarpus, and the sesamoid bone, with insertion of the arthroscope in a 45 degrees joint flexion angle. RESULTS: Arthroscopy of the fetlock joint via the dorso-lateral portal allowed examination of the distal end of the large metacarpus and the proximal end of the first phalanx of the fourth digit. Arthroscopy via a dorso-medial approach allowed examination of the distal end of the large metacarpus and the proximal end of the first phalanx and the distal end of the third digit. The palmaro-lateral portal allowed examination of the sesamoid bones, the synovial membrane, and the synovial villi. The main complications recorded during arthroscopy were iatrogenic articular surface injury as well as obstruction of vision with the synovial villi. CLINICAL SIGNIFICANCE: This is the first work to describe the normal arthroscopy of the fetlock joint in the dromedary camel, the arthroscopic portals, and the complications that could occur during and after arthroscopy. Further studies are required for diagnosis of pathological changes in the fetlock joint of the dromedary camel and for arthroscopy of other joints in the dromedary camel. PMID- 22450957 TI - Sialoadhesin in recognition of self and non-self. AB - The immune system is tightly regulated to maintain an appropriate balance between immune activation and tolerance. Macrophages play a key role in this process since they express many pathogen recognition molecules as well as receptors for 'self'. Sialoadhesin is a major macrophage receptor that specifically recognizes sialic acid, an abundant component of host glycoconjugates but which can also be found on several human pathogens. In recent years, several studies have demonstrated that sialoadhesin can contribute to the uptake and processing of sialylated pathogens as well as playing an important role in regulating inflammatory and autoimmune responses via recognition of self. PMID- 22450958 TI - Among children with food allergy, do sociodemographic factors and healthcare use differ by severity? AB - Among children with food allergy, we aim to describe differences in allergy severity by sociodemographic characteristics and potential differences in healthcare characteristics according to food allergy severity. Using the 2007 National Survey of Children's Health, we identified children with food allergies based on parental report (n = 4,657). Food allergic children were classified by the severity of their food allergy, as either mild (n = 2,333) or moderate/severe (n = 2,285). Using logistic regression, we estimated the odds of having moderate/severe versus mild food allergy by sociodemographic characteristics and the odds of having selected healthcare characteristics by food allergy severity. Among children with food allergy, those who were older (ages 6 through 17 years) and those who had siblings were more likely to have moderate/severe allergy compared to their younger and only-child counterparts. There were no significant differences in severity by other sociodemographic characteristics. Children with a moderate/severe food allergy were more likely to report use of an Individual Education Plan (OR = 1.88 [1.31, 2.70]) and to have seen a specialist than those with mild food allergy. Among younger children with food allergy, those with moderate/severe food allergy were more likely to require more services than is usual compared with those with mild allergy. Associations between allergy severity and health care-related variables did not differ significantly by race/ethnicity, income level, or maternal education. We report few differences in allergy severity by sociodemographic characteristics of food allergic children. In addition, we found that associations between allergy severity and use of health related services did not differ significantly by race/ethnicity or poverty status among children with food allergy. Given the importance of food allergy as an emerging public health issue, further research to confirm these findings would be useful. PMID- 22450959 TI - Medical regulation and health outcomes: the effect of the physician examination requirement. AB - This article investigates the effect on health outcomes of the regulation prohibiting physicians from prescribing drugs without a prior physical examination. This requirement could improve health by reducing illegal access to prescription drugs. However, it reduces access to health care by making it more difficult for patients and physicians to use many forms of telemedicine. Thus, this regulation generates a trade-off between access and safety. Using matching techniques, we find that the physician examination requirement leads to an increase of 1% in mortality rates from disease, the equivalent of 8.5 more deaths per 100,000 people, and a decrease of 6.7% in injury mortality, the equivalent of 2.5 deaths per 100,000 people. The magnitude of these effects is larger in rural areas and in areas with low physician density and is accompanied by an 18% increase in the number of days lost each month to illness. PMID- 22450960 TI - Persistent organic pollutants (PCBs and DDTs) in European conger eel, Conger conger L., from the Ionian Sea (Mediterranean Sea). AB - The present study provides novel data regarding levels of polychlorinated biphenyls (PCBs) and organochlorine pesticides (DDTs) in muscle tissue of European conger eel (Conger conger) from Ionian Sea (Mediterranean Sea). The mean concentration of PCBs (891 ng g(-1) lipid weight) was higher than those of DDTs (543 ng g(-1) lipid weight). PCB pattern was dominated by higher chlorinated congeners (hexa-CBs: 69.3 %, penta-CBs: 17.2 %, hepta-CBs: 13.3 %). Regarding DDT pattern, p,p'-DDE was prevalent in all samples (85.5 %), suggesting no recent DDT input. The total 2,3,7,8-TCDD toxic equivalent (TEQs) of coplanar PCBs, including mono-and non-ortho congeners was 0.41 pg g(-1) wet weight (29.92 pg g(-1) lipid weight). The PCB and DDT levels, as well as TEQ concentrations were lower than most of the corresponding published data for fish from Mediterranean and non Mediterranean regions, probably reflecting a moderately contaminated area. PMID- 22450961 TI - Evaluation of heavy metals and polycyclic aromatic hydrocarbons (PAHs) in Mullus barbatus from Sicily Channel and risk-based consumption limits. AB - Our study is a preliminary step to evaluate water contamination of the Mediterranean Sea surrounding Lampedusa island and health risks for fish consumers. We analyzed muscle tissue of Mullus barbatus specimens to detect metals and polycyclic aromatic hydrocarbons (PAHs). Results show the following average concentrations of heavy metals: Pb 0.035, Cd 0.001, Hg 0.027, Cr 0.524, As 27.01, Cu 0.433, Co 0.013, Ni 0.042, Se 0.487, V 0.072, U 0.055 and Zn 3.360 ppm. PAHs ranged from 0.250 to 13.16 ppb. A possible risk to human health was determined based on consumption limits data and the content of total PAHs in fillets of this species. PMID- 22450964 TI - Researchers use bloodspots to identify genetic hearing loss: study indicates testing scenario has potential. PMID- 22450965 TI - Autism testing service includes telephone counseling: bypasses initial genetics exam. PMID- 22450967 TI - The aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria. AB - Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an ever-increasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria. PMID- 22450968 TI - Meropenem-clavulanic acid shows activity against Mycobacterium tuberculosis in vivo. AB - The carbapenems imipenem and meropenem in combination with clavulanic acid reduced the bacterial burden in Mycobacterium tuberculosis-infected macrophages by 2 logs over 6 days. Despite poor stability in solution and a short half-life in rodents, treatment of chronically infected mice revealed significant reductions of bacterial burden in the lungs and spleens. Our results show that meropenem has activity in two in vivo systems, but stability and pharmacokinetics of long-term administration will offer significant challenges to clinical evaluation. PMID- 22450969 TI - Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. AB - The failure of raltegravir (RAL) is generally associated with the selection of mutations at integrase position Y143, Q148, or N155. However, a relatively high proportion of failures occurs in the absence of these changes. Here, we report the phenotypic susceptibilities to RAL and elvitegravir (EVG) for a large group of HIV-infected patients failing on RAL-containing regimens. Plasma from HIV infected individuals failing on RAL-containing regimens underwent genotypic and phenotypic resistance testing (Antivirogram v2.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2.5 (interquartile range [IQR], 2.1 to 3.1). Fourteen samples from patients with RAL failures showed diminished RAL susceptibility, with a median FC of 38.5 (IQR, 10.8 to 103.2). Primary integrase resistance mutations were found in 11 of these samples, displaying a median FC of 68.5 (IQR, 23.5 to 134.3). The remaining 3 samples showed a median FC of 2.5 (IQR, 2 to 2.7). EVG susceptibility was diminished in 19/40 samples from patients with RAL failures (median FC, 7.71 [IQR, 2.48 to 99.93]). Cross-resistance between RAL and EVG was high (R(2) = 0.8; P < 0.001), with drug susceptibility being more frequently reduced for EVG than for RAL (44.3% versus 24.6%; P = 0.035). Susceptibility to RAL and EVG is rarely affected in the absence of primary integrase resistance mutations. There is broad cross-resistance between RAL and EVG, which should preclude their sequential use. Resistance to EVG seems to be more frequent and might be more influenced by integrase variability. PMID- 22450970 TI - Molecular characterization of multidrug-resistant Mycobacterium tuberculosis isolated in Nepal. AB - Despite the fact that Nepal is one of the first countries globally to introduce multidrug-resistant tuberculosis (MDR-TB) case management, the number of MDR-TB cases is continuing to rise in Nepal. Rapid molecular tests applicable in this setting to identify resistant organisms would be an effective tool in reversing this trend. To develop such tools, information about the frequency and distribution of mutations that are associated with phenotypic drug resistance in Mycobacterium tuberculosis is required. In the present study, we investigated the prevalence of mutations in rpoB and katG genes and the inhA promoter region in 158 M. tuberculosis isolates (109 phenotypically MDR and 49 non-MDR isolates collected in Nepal) by DNA sequencing. Mutations affecting the 81-bp rifampin (RIF) resistance-determining region (RRDR) of rpoB were identified in 106 of 109 (97.3%) RIF-resistant isolates. Codons 531, 526, and 516 were the most commonly affected, at percentages of 58.7, 15.6, and 15.6%, respectively. Of 113 isoniazid (INH)-resistant isolates, 99 (87.6%) had mutations in the katG gene, with Ser315Thr being the most prevalent (81.4%) substitution. Mutations in the inhA promoter region were detected in 14 (12.4%) INH-resistant isolates. The results from this study provide an overview of the current situation of RIF and INH resistance in M. tuberculosis in Nepal and can serve as a basis for developing or improving rapid molecular tests to monitor drug-resistant strains in this country. PMID- 22450971 TI - Divalent metals and pH alter raltegravir disposition in vitro. AB - Raltegravir shows marked pharmacokinetic variability in patients, with gastrointestinal pH and divalent-metal binding being potential factors. We investigated raltegravir solubility, lipophilicity, pK(a), and permeativity in vitro to elucidate known interactions with omeprazole, antacids, and food, all of which increase gastric pH. Solubility of raltegravir was determined at pH 1 to 8. Lipophilicity of raltegravir was determined using octanol-water partition. Raltegravir pK(a) was determined using UV spectroscopy. The effects of pH, metal salts, and omeprazole on the cellular permeativity of raltegravir were determined using Caco-2 monolayers. Cellular accumulation studies were used to determine the effect of interplay between pH and ABCB1 transport on raltegravir accumulation. Samples were analyzed using liquid chromatography-tandem mass spectroscopy (LC MS/MS) or scintillation counting. Raltegravir at 10 mM was partly insoluble at pH 6.6 and below. Raltegravir lipophilicity was pH dependent and was reduced as pH was increased from 5 to 9. The pK(a) of raltegravir was 6.7. Raltegravir cellular permeativity was heavily influenced by changes in extracellular pH, where apical to-basolateral permeativity was reduced 9-fold (P < 0.05) when apical pH was increased from 5 to 8.5. Raltegravir cellular permeativity was also reduced in the presence of magnesium and calcium. Omeprazole did not alter raltegravir cellular permeativity. Cellular accumulation of raltegravir was increased independently by inhibiting ABCB1 and by lowering extracellular pH from pH 8 to 5. Gastrointestinal pH and polyvalent metals can potentially alter the pharmacokinetic properties of raltegravir, and these data provide an explanation for the variability in raltegravir exposure in patients. The evaluation of how divalent-metal-containing products, such as multivitamins, that do not affect gastric pH alter raltegravir pharmacokinetics in patients is now justified. PMID- 22450972 TI - Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses. AB - The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a beta-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose limiting toxicity was identified. PMID- 22450973 TI - Scaling adult doses of antifungal and antibacterial agents to children. AB - My general pharmacokinetic scaling theory is discussed for the important matter of determining pediatric dosing for existing and new therapeutic drugs when optimal, or near-optimal, dosing for adults is known. The basis for the scaling is the requirement of a time-scaled likeness of the free-drug concentration time histories of children and adults. Broad categories of single and periodic dosing are considered. The former involves the scaling of dosage, and the latter involves both the dosage and schedule. The validity of the scaling relations is demonstrated by using measurements from previously reported clinical trials with adults and children (with ages generally 1 year or older) for the relatively new antifungal agent caspofungin and for the relatively new antibacterial agent linezolid. Standard pharmacodynamic effectiveness criteria are shown to be satisfied for the scaled dosage and schedule for children to the same extent that they are for the referenced adult. Consideration of scaling from adults to children is discussed for the case of new agents where no pediatric data are available and needed parameters are determined from in vitro measurements and preclinical animal data. A connection is also made between the allometric representation of clearance data and the dosing formulas. Limitations of the scaling results for infants because of growth and maturational matters are discussed. The general conclusion from this work is that the scaling theory does indeed have application to pediatric dosing for children, for both confirmation and refinement of present practice and guidance in pediatric treatment with new therapeutic agents. PMID- 22450974 TI - Safety and tolerability of voriconazole in patients with baseline renal insufficiency and candidemia. AB - Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole. PMID- 22450975 TI - Characterization of multidrug-resistant Salmonella enterica serovar heidelberg from a ground turkey-associated outbreak in the United States in 2011. PMID- 22450976 TI - Involvement of the lon protease in the SOS response triggered by ciprofloxacin in Pseudomonas aeruginosa PAO1. AB - Pseudomonas aeruginosa PAO1 lon mutants have phenotypes of deficiencies in cell division, swarming, twitching, and biofilm formation as well as a phenotype of ciprofloxacin supersusceptibility. In this study, we demonstrated that a lon mutant was also supersensitive to the DNA-damaging agent UV light. To understand the influence of lon in causing these phenotypes, global gene expression was characterized by performing microarrays on the lon mutant and the PAO1 wild type grown in the presence of subinhibitory concentrations of ciprofloxacin. This revealed major differences in the expression of genes involved in the SOS response and DNA repair. Real-time quantitative PCR confirmed that these genes were highly upregulated upon ciprofloxacin exposure in the wild type but were significantly less induced in the lon mutant, indicating that Lon modulates the SOS response and consequentially ciprofloxacin susceptibility. As the known Lon target SulA is a member of the SOS response regulon, the influence of mutating or overexpressing this gene, and the negative regulator of the SOS response, LexA, was examined. Overexpression of lexA had no effect on the Lon-related phenotypes, but sulA overexpression recapitulated certain lon mutant phenotypes, including altered motility and cell division, indicating that Lon regulates these phenotypes through SulA. However, sulA overexpression did not affect ciprofloxacin susceptibility or biofilm formation, indicating that these properties were independently determined. Lon protease was also demonstrated to strongly influence RecA protein accumulation in the presence of ciprofloxacin. A model of DNA repair involving the Lon protease is proposed. PMID- 22450977 TI - Class A carbapenemase FPH-1 from Francisella philomiragia. AB - FPH-1 is a new class A carbapenemase from Francisella philomiragia. It produces high-level resistance to penicillins and the narrow-spectrum cephalosporin cephalothin and hydrolyzes these beta-lactam antibiotics with catalytic efficiencies of 10(6) to 10(7) M(-1) s(-1). When expressed in Escherichia coli, the enzyme confers resistance to clavulanic acid, tazobactam, and sulbactam and has K(i) values of 7.5, 4, and 220 MUM, respectively, against these inhibitors. FPH-1 increases the MIC of the monobactam aztreonam 256-fold and the MIC of the broad-spectrum cephalosporin ceftazidime 128-fold, while the MIC of cefoxitin remains unchanged. MICs of the carbapenem antibiotics imipenem, meropenem, doripenem, and ertapenem are elevated 8-, 8-, 16-, and 64-fold, respectively, against an E. coli JM83 strain producing the FPH-1 carbapenemase. The catalytic efficiencies of the enzyme against carbapenems are in the range of 10(4) to 10(5) M(-1) s(-1). FPH-1 is 77% identical to the FTU-1 beta-lactamase from Francisella tularensis and has low amino acid sequence identity with other class A beta lactamases. Together with FTU-1, FPH-1 constitutes a new branch of the prolific and ever-expanding class A beta-lactamase tree. PMID- 22450978 TI - Native valve endocarditis caused by Corynebacterium striatum with heterogeneous high-level daptomycin resistance: collateral damage from daptomycin therapy? AB - We describe a patient who developed Corynebacterium striatum native valve endocarditis after receiving two 6-week courses of daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. The organism exhibited in vitro heteroresistance to daptomycin, with two subpopulations showing daptomycin susceptibility (MIC of <= 0.094 MUg/ml) and high-level resistance to daptomycin (MIC of >= 256 MUg/ml). The selection of daptomycin-resistant Gram-positive skin flora with the potential of causing invasive disease may be a concern during prolonged courses of daptomycin. PMID- 22450979 TI - Multidrug-resistant Proteus mirabilis bloodstream infections: risk factors and outcomes. AB - Our aims were to identify (i) risk factors associated with the acquisition of multidrug-resistant (MDR, to 3 or more classes of antimicrobials) Proteus mirabilis isolates responsible for bloodstream infections (BSIs) and (ii) the impact on mortality of such infections. Risk factors for acquiring MDR P. mirabilis BSIs were investigated in a case-case-control study; those associated with mortality were assessed by comparing survivors and nonsurvivors in a cohort study. The population consisted of 99 adult inpatients with P. mirabilis BSIs identified by our laboratory over an 11-year period (1999 to 2009), 36 (33.3%) of which were caused by MDR strains, and the overall 21-day mortality rate was 30.3%. Acquisition of an MDR strain was independently associated with admission from a long-term care facility (odds ratio [OR], 9.78; 95% confidence interval [CI], 1.94 to 49.16), previous therapy with fluoroquinolones (OR, 5.52; 95% CI, 1.30 to 23.43) or oxyimino-cephalosporins (OR, 4.72; 95% CI, 1.31 to 16.99), urinary catheterization (OR, 3.89; 95% CI, 1.50 to 10.09), and previous hospitalization (OR, 2.68; 95% CI, 10.4 to 6.89). Patients with MDR P. mirabilis BSIs received inadequate initial antimicrobial therapy (IIAT, i.e., treatment with drugs to which the isolate displayed in vitro resistance) more frequently than those with non-MDR infections; they also had increased mortality and (for survivors) longer post-BSI-onset hospital stays. In multivariate regression analysis, 21-day mortality was associated with septic shock at BSI onset (OR, 12.97; 95% CI, 32.2 to 52.23), P. mirabilis isolates that were MDR (OR, 6.62; 95% CI, 16.4 to 26.68), and IIAT (OR, 9.85; 95% CI, 26.7 to 36.25), the only modifiable risk factor of the 3. These findings can potentially improve clinicians' ability to identify P. mirabilis BSIs likely to be MDR, thereby reducing the risk of IIAT--a major risk factor for mortality in these cases--and facilitating the prompt implementation of appropriate infection control measures. PMID- 22450980 TI - Dissemination of pCT-like IncK plasmids harboring CTX-M-14 extended-spectrum beta lactamase among clinical Escherichia coli isolates in the United Kingdom. AB - IncK plasmids encoding CTX-M-14 extended-spectrum beta-lactamase (ESBL) and highly related to plasmid pCT were detected in 13 of 67 (19%) human clinical isolates of Escherichia coli with a group 9 CTX-M-type ESBL from the United Kingdom and in 2 quality assurance isolates. None of these E. coli strains was related to the cattle strain from which pCT was originally characterized. PMID- 22450981 TI - Preclinical monitoring of drug association in experimental chemotherapy of Chagas' disease by a new HPLC-UV method. AB - A combination of drugs in experimental chemotherapy of Chagas' disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (C(max)) and an increase of 2.66-fold in the volume of distribution (V) and 7.5-fold in the elimination half-life (t(1/2beta)) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0 infinity)), time to maximum concentration of drug in serum (T(max)), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole against Trypanosoma cruzi in vivo. PMID- 22450982 TI - NDM-1-producing Klebsiella pneumoniae resistant to colistin in a French community patient without history of foreign travel. AB - A carbapenem-resistant Klebsiella pneumoniae strain, Kp5196, was responsible for an uncomplicated cystitis in a patient living at home and without history of foreign travel. This isolate produced the metallocarbapenemase NDM-1 and was resistant to all antibiotics except tetracyclines and colistin. The K. pneumoniae strain belonged to sequence type ST15, and bla(NDM-1) was carried by a nontypeable conjugative plasmid. Two months later, a similar ST15 isolate, Kp5241, was present in the patient but was additionally colistin resistant. PMID- 22450983 TI - Multiplex real-time PCR for detection of an epidemic KPC-producing Klebsiella pneumoniae ST258 clone. AB - We describe a multiplex real-time PCR assay capable of identifying both the epidemic Klebsiella pneumoniae ST258 clone and bla(KPC) carbapenemase genes in a single reaction. The assay displayed excellent sensitivity (100%) and specificity (100%) for identification of ST258 clone and bla(KPC) in a collection of 75 K. pneumoniae isolates comprising 41 sequence types. Our results suggest that this assay is an effective tool for surveillance of this clone among carbapenem resistant K. pneumoniae clinical isolates. PMID- 22450984 TI - Kinetic analysis of Enterococcus faecium L,D-transpeptidase inactivation by carbapenems. AB - Bypass of classical penicillin-binding proteins by the L,D-transpeptidase of Enterococcus faecium (Ldt(fm)) leads to high-level ampicillin resistance in E. faecium mutants, whereas carbapenems remain the lone highly active beta-lactams. Kinetics of Ldt(fm) inactivation was determined for four commercial carbapenems and a derivative obtained by introducing a minimal ethyl group at position 2. We show that the bulky side chains of commercial carbapenems have both positive and negative effects in preventing hydrolysis of the acyl enzyme and impairing drug binding. PMID- 22450985 TI - Membrane-active action mode of polybia-CP, a novel antimicrobial peptide isolated from the venom of Polybia paulista. AB - The extensive use of antibiotics in medicine, the food industry, and agriculture has resulted in the frequent emergence of multidrug-resistant bacteria, which creates an urgent need for new antibiotics. It is now widely recognized that antimicrobial peptides (AMPs) could play a promising role in fighting multidrug resistant bacteria. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and studied its action mode of antibacterial activity. Our results revealed that polybia-CP has potent antibacterial activity against both Gram-positive and Gram negative bacteria. The results from both the real bacterial membrane and the in vitro model membrane showed that polybia-CP is membrane active and that its action target is the membrane of bacteria. It is difficult for bacteria to develop resistance to polybia-CP, which may thus offer a new strategy for defending against resistant bacteria in medicine and the food and farming industries. PMID- 22450986 TI - Correlative time-resolved fluorescence microscopy to assess antibiotic diffusion reaction in biofilms. AB - The failure of antibiotics to inactivate in vivo pathogens organized in biofilms has been shown to trigger chronic infections. In addition to mechanisms involving specific genetic or physiological cell properties, antibiotic sorption and/or reaction with biofilm components may lessen the antibiotic bioavailability and consequently decrease their efficiency. To assess locally and accurately the antibiotic diffusion-reaction, we used for the first time a set of advanced fluorescence microscopic tools (fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and fluorescence lifetime imaging) that offer a spatiotemporal resolution not available with the commonly used time-lapse confocal imaging method. This set of techniques was used to characterize the dynamics of fluorescently labeled vancomycin in biofilms formed by two Staphylococcus aureus human isolates. We demonstrate that, at therapeutic concentrations of vancomycin, the biofilm matrix was not an obstacle to the diffusion-reaction of the antibiotic that can reach all cells through the biostructure. PMID- 22450987 TI - The relative contributions of physical structure and cell density to the antibiotic susceptibility of bacteria in biofilms. AB - For many bacterial infections, noninherited mechanisms of resistance are responsible for extending the term of treatment and in some cases precluding its success. Among the most important of these noninherited mechanisms of resistance is the ability of bacteria to form biofilms. There is compelling evidence that bacteria within biofilms are more refractory to antibiotics than are planktonic cells. Not so clear, however, is the extent to which this resistance can be attributed to the structure of biofilms rather than the physiology and density of bacteria within them. To explore the contribution of the structure of biofilms to resistance in a quantitative way, we developed an assay that compares the antibiotic sensitivity of bacteria in biofilms to cells mechanically released from these structures. Our method, which we apply to Escherichia coli and Staphylococcus aureus each with antibiotics of five classes, controls for the density and physiological state of the treated bacteria. For most of the antibiotics tested, the bacteria in biofilms were no more resistant than the corresponding populations of planktonic cells of similar density. Our results, however, suggest that killing by gentamicin, streptomycin, and colistin is profoundly inhibited by the structure of biofilms; these drugs are substantially more effective in killing bacteria released from biofilms than cells within these structures. PMID- 22450988 TI - Efficacy of ceftobiprole Medocaril against Enterococcus faecalis in a murine urinary tract infection model. AB - We evaluated ceftobiprole against the well-characterized Enterococcus faecalis strain OG1RF (with and without the beta-lactamase [Bla] plasmid pBEM10) in a murine urinary tract infection (UTI) model. Ceftobiprole was equally effective for Bla(+) and Bla(-) OG1 strains, while ampicillin was moderately to markedly (depending on the inoculum) less effective against Bla(+) than Bla(-) OG1 strains. These data illustrate an in vivo effect on ampicillin of Bla production by E. faecalis and the stability and efficacy of ceftobiprole in experimental UTI. PMID- 22450989 TI - Binder-free LiCoO2/carbon nanotube cathodes for high-performance lithium ion batteries. AB - Binder-free LiCoO(2) -SACNT cathodes with excellent flexibility and conductivity are obtained by constructing a continuous three-dimensional super-aligned carbon nanotube (SACNT) framework with embedded LiCoO(2) particles. These binder-free cathodes display much better cycling stability, greater rate performance, and higher energy density than classical cathodes with binder. Various functional binder-free SACNT composites can be mass produced by the ultrasonication and co deposition method described in this paper. PMID- 22450991 TI - Planarian regeneration: a classic topic claiming new attention. PMID- 22450992 TI - Evolutionary history of the Tricladida and the Platyhelminthes: an up-to-date phylogenetic and systematic account. AB - Within the free-living platyhelminths, the triclads, or planarians, are the best known group, largely as a result of long-standing and intensive research on regeneration, pattern formation and Hox gene expression. However, the group's evolutionary history has been long debated, with controversies ranging from their phyletic structure and position within the Metazoa to the relationships among species within the Tricladida. Over the the last decade, with the advent of molecular phylogenies, some of these issues have begun to be resolved. Here, we present an up-to-date summary of the main phylogenetic changes and novelties with some comments on their evolutionary implications. The phylum has been split into two groups, and the position of the main group (the Rhabdithophora and the Catenulida), close to the Annelida and the Mollusca within the Lophotrochozoa, is now clear. Their internal relationships, although not totally resolved, have been clarified. Tricladida systematics has also experienced a revolution since the implementation of molecular data. The terrestrial planarians have been demonstrated to have emerged from one of the freshwater families, giving a different view of their evolution and greatly altering their classification. The use of molecular data is also facilitating the identification of Tricladida species by DNA barcoding, allowing better knowledge of their distribution and genetic diversity. Finally, molecular phylogenetic and phylogeographical analyses, taking advantage of recent data, are beginning to give a clear picture of the recent history of the Dugesia and Schmidtea species in the Mediterranean. PMID- 22450993 TI - Planarian embryology in the era of comparative developmental biology. AB - During the last decade, the field of evolutionary developmental biology (evo devo) has emerged as a major research discipline in modern biology and an essential approach to understanding evolutionary relationships in the animal kingdom. At the same time, planarians have become a useful and important model with which to address basic questions regarding the molecular and cellular basis of regeneration, tissue repair and stem cells in adult organisms. Nevertheless, little attention has been paid to their embryonic development, even though this provides a unique opportunity for studying how molecular developmental mechanisms are re-deployed during adult regeneration or the independent losses of spiral cleavage that took place in different lophotrochozoan lineages. In this paper, we review the most relevant works on planarian embryos from a historical point of view. In doing so, we highlight the questions that have recurrently intrigued researchers, most of which remain unanswered. Finally, we present a comprehensive scenario for planarian embryogenesis in an attempt to provide a testable hypothesis that will help to bridge the gap between this divergent mode of development, the ancestral canonical spiral cleavage, and adult planarian regeneration. PMID- 22450994 TI - The past and present of planarians--an interview with Vittorio Gremigni. Interview by Alessandra Salvetti and Leonardo Rossi. AB - Vittorio Gremigni is a scientific leader in the field of planarian biology with a very long historical perspective. By using electron microscopy, he contributed to the reconstruction of the phylogenesis of free living "Turbellaria", and he pioneered the study of the origin of blastema cells by using chromosomal markers. In this interview, Professor Gremigni describes the steps that moved his career towards the planarian field, the main scientific achievements he obtained and the changes that are taking place in the field. He also discusses recent progress and unanswered questions on planarian neoblasts and regeneration. PMID- 22450995 TI - Wnt signaling in planarians: new answers to old questions. AB - Wnts are secreted glycoproteins involved in a broad range of essential cell functions, including proliferation, migration and cell-fate determination. Recent years have seen substantial research effort invested in elucidating the role of the Wnt signaling pathway in planarians, flatworms with incredible regenerative capacities. In this review, we summarize current knowledge on the role of canonical (beta-catenin-dependent) and non-canonical (beta-catenin-independent) Wnt signaling in planarians, not only during regeneration, but also during normal homeostasis. We also describe some of the preliminary data that has been obtained regarding the role of these pathways during embryogenesis. Models are proposed to integrate the different results which have been obtained to date and highlight those questions that still remain to be answered. PMID- 22450996 TI - Small RNA pathways in Schmidtea mediterranea. AB - Planarians are bilaterally symmetrical fresh water organisms capable of regenerating body parts from small fragments following bodily injury. Planarians possess a specialized population of pluripotent cells called neoblasts, which are responsible for their unique regenerative ability. The study of planarian stem cell biology and regeneration has traditionally focused on the transcription factors and proteins that regulate signal transduction pathways. New evidence shows that small RNA molecules are important players in stem cell function and regeneration, yet little is known about the exact nature of their regulatory roles during the regenerative process. In this review, we discuss biogenesis of microRNAs and piwiRNAs and their functional role in key developmental pathways in vertebrates and invertebrates with an emphasis on recent studies on planarian small RNA pathways. PMID- 22450997 TI - Comprehensive gene expression analyses in pluripotent stem cells of a planarian, Dugesia japonica. AB - The neoblasts are the only somatic stem cells in planarians possessing pluripotency, and can give rise to all types of cells, including germline cells. Recently, accumulated knowledge about the transcriptome and expression dynamics of various pluripotent somatic stem cells has provided important opportunities to understand not only fundamental mechanisms of pluripotency, but also stemness across species at the molecular level. The neoblasts can easily be eliminated by radiation. Also, by using fluorescence activated cell sorting (FACS), we can purify and collect many neoblasts, enabling identification of neoblast-related genes by comparison of the gene expression level among intact and X-ray irradiated animals, and purified neoblasts. In order to find such genes, here we employed the high coverage expression profiling (HiCEP) method, which enables us to observe and compare genome-wide gene expression levels between different samples without advance sequence information, in the planarian D. japonica as a model organism of pluripotent stem cell research. We compared expression levels of ~17,000 peaks corresponding to independent genes among different samples, and obtained 102 peaks as candidates. Expression analysis of genes identified from those peaks by in situ hybridization revealed that at least 42 genes were expressed in the neoblasts and in neoblast-related cells that had a different distribution pattern in the body than neoblasts. Also, single-cell PCR analysis of those genes revealed heterogeneous expression of some genes in the neoblast population. Thus, using multidimensional gene expression analyses, we were able to obtain a valuable data set of neoblast-related genes and their expression patterns. PMID- 22450998 TI - Global irradiation effects, stem cell genes and rare transcripts in the planarian transcriptome. AB - Stem cells are the closest relatives of the totipotent primordial cell, which is able to spawn millions of daughter cells and hundreds of cell types in multicellular organisms. Stem cells are involved in tissue homeostasis and regeneration, and may play a major role in cancer development. Among animals, planarians host a model stem cell type, called the neoblast, which essentially confers immortality. Gaining insights into the global transcriptional landscape of these exceptional cells takes an unprecedented turn with the advent of Next Generation Sequencing methods. Two Digital Gene Expression transcriptomes of Schmidtea mediterranea planarians, with or without neoblasts lost through irradiation, were produced and analyzed. Twenty one bp NlaIII tags were mapped to transcripts in the Schmidtea and Dugesia taxids. Differential representation of tags in normal versus irradiated animals reflects differential gene expression. Canonical and non-canonical tags were included in the analysis, and comparative studies with human orthologs were conducted. Transcripts fell into 3 categories: invariant (including housekeeping genes), absent in irradiated animals (potential neoblast-specific genes, IRDOWN) and induced in irradiated animals (potential cellular stress response, IRUP). Different mRNA variants and gene family members were recovered. In the IR-DOWN class, almost all of the neoblast-specific genes previously described were found. In irradiated animals, a larger number of genes were induced rather than lost. A significant fraction of IRUP genes behaved as if transcript versions of different lengths were produced. Several novel potential neoblast-specific genes have been identified that varied in relative abundance, including highly conserved as well as novel proteins without predicted orthologs. Evidence for a large body of antisense transcripts, for example regulated antisense for the Smed-piwil1 gene, and evidence for RNA shortening in irradiated animals is presented. Novel neoblast-specific candidates include a peroxiredoxin protein that appears to be preferentially expressed in human embryonic stem cells. PMID- 22450999 TI - Heterogeneity of planarian stem cells in the S/G2/M phase. AB - The planarian adult stem cell (pASC) population has a specific molecular signature and can be easily visualized and isolated by flow cytometry. However, the lack of antibodies against specific surface markers for planarian cells prevents a deeper analysis of specific cell populations. Here, if we describe the results of the immunoscreening of pASC plasma membrane proteins (PMPs). A novel papain-based method for planarian cell dissociation enabling both high yield and improved cell viability was used to generate single cell preparations for PMP purification. PMPs were used for intraperitoneal immunization of mice and thus about 1000 hybridoma clones were generated and screened. Supernatants collected from the hybridoma clones were first screened by ELISA and then by live immuno staining. About half of these supernatants stained all the planarian cells, whereas the other half specifically labeled a subfraction thereof. A detailed analysis of two hybridoma supernatants revealed that large subfractions of the X1, X2 and Xin populations differentially express specific membrane markers. Quantitative PCR data disclosed a correlation between the immunostaining results and the expression of markers of the early and late progeny, also for those pASCs in the S/G2/M phase of the cell cycle (X1 population). Thus, about two thirds of the cycling pASCs showed a specific membrane signature coupled with the expression of markers hitherto considered to be restricted to differentiating, post-mitotic progeny. In summary, a library of 66 monoclonal antibodies against planarian PMPs was generated. The analysis of two of the clones generated revealed that a subset of cells of the X1 population expresses early and late progeny markers, which might indicate that these cells are committed while still proliferating. The findings demonstrate the usefulness of our PMP antibody library for planarian research. PMID- 22451000 TI - Stem cell protection mechanisms in planarians: the role of some heat shock genes. AB - Planarians contain a large population of stem cells, named neoblasts, and use these for continuous turnover of all cell types. In addition, thanks to the amazing flexibility of these cells, planarians respond well to the effects of stressful situations, for example activating regeneration after trauma. How neoblasts respond to stress and support continuous proliferation, maintaining long-term stability, is still an open question. Heat shock proteins (HSPs) are a complex protein family with key roles in maintaining protein homeostasis, as well as in apoptosis and growth-related processes. We recently characterized some planarian homologs of hsp genes that are highly expressed in mammalian stem cells, and observed that some of them are critical for neoblast survival/maintenance. The results of these studies support the notion that some HSPs play crucial roles in the modulation of pathways regulating stem cell activity, regeneration and tissue repair. In this review we compare the evidence available for planarian hsp genes and focus on questions emerging from these results. PMID- 22451001 TI - Stem cells and neural signalling: the case of neoblast recruitment and plasticity in low dose X-ray treated planarians. AB - Planarians (Platyhelminthes) possess an abundant population of adult stem cells, the neoblasts, capable to give rise to both somatic and germ cells. Although neoblasts share similar morphological features, several pieces of evidence suggest that they constitute a heterogeneous population of cells with distinct ultrastructural and molecular features. We found that in planarians treated with low X-ray doses (5 Gy), only a few neoblasts survive. Among these cells, those located close to the nervous system activate an intense proliferation program and migrate to reconstitute the whole complex neoblast population. This phenomenon is inhibited by the substance P receptor antagonist spantide, and accompanied by the up-regulation of a number of genes implicated in neuronal signalling and plasticity, suggesting that signals of neural origin modulate neoblast proliferation and/or migration. Here, we review these findings and the literature available on the influence of the nervous system on stem cell activity, both in planarians and vertebrates, and we propose 5 Gy-treated planarians as a unique model system to study the influence of neural signalling on stem cell biology. PMID- 22451002 TI - Regeneration of neuronal cell types in Schmidtea mediterranea: an immunohistochemical and expression study. AB - Freshwater planarians are unique in their ability to regenerate a complete Central Nervous System (CNS) from almost any small piece of their body in just a few days. The planarian CNS contains a pair of anterior cephalic ganglia lying on top of two ventral nerve cords that extend along the length of the animal. Studies of planarian CNS regeneration have generally used pan-neural markers, which provide only a general overview of the process. Nevertheless, some reports have started to characterize the genes that are required for this process. In this study, to obtain a more detailed description of planarian neural regeneration, we monitored the regeneration of neuronal populations specifically labelled with antibodies against serotonin, allatostatin, neuropeptide F, GYRFamide and FMRFamide. We also characterized the regeneration of dopaminergic and octopaminergic cell populations by in situ hybridization. Finally, we characterized the expression pattern of a set of receptors for neurotransmitters, neuropeptides and hormones that are suggested to play a role in the regeneration process itself. Together, these data provide a more detailed description of the cellular events occurring during anterior and posterior CNS regeneration in planarians and provide the foundations for future mechanistic studies into the regeneration process in this important model system. PMID- 22451003 TI - Inhibitory Smads and bone morphogenetic protein (BMP) modulate anterior photoreceptor cell number during planarian eye regeneration. AB - Planarians represent an excellent model to study the processes of body axis and organ re-specification during regeneration. Previous studies have revealed a conserved role for the bone morphogenetic protein (BMP) pathway and its intracellular mediators Smad1/5/8 and Smad4 in planarian dorsoventral (DV) axis re-establishment. In an attempt to gain further insight into the role of this signalling pathway in planarians, we have isolated and functionally characte rized the inhibitory Smads (I-Smads) in Schmidtea mediterranea. Two I-Smad homologues have been identified: Smed-smad6/7-1 and Smed-smad6/7-2. Expression of smad6/7-1 was detected in the parenchyma, while smad6/7-2 was found to be ex pressed in the central nervous system and the eyes. Neither single smad6/7-1 and smad6/7-2 nor double smad6/7-1,-2 silencing gave rise to any apparent disruption of the DV axis. However, both regenerating and intact smad6/7-2 (RNAi) planarians showed defects in eye morphogenesis and displayed small, rounded eyes that lacked the anterior subpopulation of photoreceptor cells. The number of pigment cells was also reduced in these animals at later stages of regeneration. In contrast, after low doses of Smed-bmp(RNAi), planarians regenerated larger eyes in which the anterior subpopulation of photoreceptor cells was expanded. Our results suggest that Smed-smad6/7-2 and Smed-bmp control the re-specification and maintenance of anterior photoreceptor cell number in S. mediterranea. PMID- 22451004 TI - The Dr-nanos gene is essential for germ cell specification in the planarian Dugesia ryukyuensis. AB - Homologs of nanos are required for the formation and maintenance of germline stem cell (GSC) systems and for gametogenesis in many metazoans. Planarians can change their reproductive mode seasonally, alternating between asexual and sexual reproduction; they develop and maintain their somatic stem cells (SSCs) and GCSs from pluripotent stem cells known as neoblasts. We isolated a nanos homolog, Dr nanos, from the expressed sequence tags (ESTs) of the sexualized form of Dugesia ryukyuensis. We examined the expression of Dr-nanos in asexual and sexualized planarians by in situ hybridization and analyzed its function using RNA interference (RNAi) together with a planarian sexualization assay. A nanos homolog, Dr-nanos, was identified in the planarian D. ryukyuensis. Dr-nanos expression was observed in the ovarian primordial cells of the asexual worms. This expression increased in proportion to sexualization and was localized in the early germline cells of the ovaries and testes. In X-ray-irradiated worms, the expression of Dr-nanos decreased to a large extent, indicating that Dr-nanos is expressed in some subpopulations of stem cells, especially in GSCs. During the sexualization process, worms in which Dr-nanos was knocked down by RNAi exhibited decreased numbers of oogonia in the ovaries and failed to develop testes, whereas the somatic sexual organs were not affected. We conclude that Dr-nanos is essential for the development of germ cells in the ovaries and testes and may have a function in the early stages of germ cell specification, but not in the development of somatic sexual organs. PMID- 22451005 TI - The planarian P2X homolog in the regulation of asexual reproduction. AB - The growth in size of freshwater planarians in response to nutrient intake is limited by the eventual separation of tail and body fragments in a process called fission. The resulting tail fragment regenerates the entire body as an artificially amputated tail fragment would do, and the body fragment regenerates a tail, resulting in two whole planarians. This regenerative ability is supported by pluripotent somatic stem cells, called neoblasts, which are distributed throughout almost the entire body of the planarian. Neoblasts are the only planarian cells with the ability to continuously proliferate and give rise to all types of cells during regeneration, asexual reproduction, homeostasis, and growth. In order to investigate the molecular characteristics of neoblasts, we conducted an extensive search for neoblast-specific genes using the High Coverage Expression Profiling (HiCEP) method, and tested the function of the resulting candidates by RNAi. Disruption of the expression of one candidate gene, DjP2X-A (Dugesia japonica membrane protein P2X homologue), resulted in a unique phenotype. DjP2X-A RNAi leads to an increase of fission events upon feeding. We confirmed by immunohistochemistry that DjP2X-A is a membrane protein, and elucidated its role in regulating neoblast proliferation, thereby explaining its unique phenotype. We found that DjP2X-A decreases the burst of neoblast proliferation that normally occurs after feeding. We also found that DjP2X-A is required for normal proliferation in starved animals. We propose that DjP2X-A modulates stem cell proliferation in response to the nutritional condition. PMID- 22451006 TI - Physiological and molecular characterisation of cadmium stress in Schmidtea mediterranea. AB - The planarian Schmidtea mediterranea is a well-studied model organism for developmental research, because of its stem cell system. This characteristic also provides a unique opportunity to study stress management and the effect of stress on stem cells. In this study, we characterised the stress signature at different levels of biological organization. The carcinogenic metal cadmium was used as a model chemical stressor. We focused on stem cell activity and its interaction with other known stress parameters. Here, we have found that S. mediterranea is able to cope with high internal levels of cadmium. At endpoints such as size and mobility, cadmium-related stress effects were detected but all of these responses were transient. Correspondingly, cadmium exposure led to an elevated mitotic activity of the neoblasts, at the same time points when the other responses disappeared. At the molecular level, we observed redox-related responses that can be linked with both repair as well as proliferation mechanisms. Together, our results suggest that these animals have a high plasticity. The induction of stem cell activity may underlie this 'restoring' effect, although a carcinogenic outcome after longer exposure times cannot be excluded. PMID- 22451007 TI - Planarians in pharmacology: parthenolide is a specific behavioral antagonist of cocaine in the planarian Girardia tigrina. AB - Planarians are traditional animal models in developmental and regeneration biology. Recently, these organisms are arising as vertebrate-relevant animal models in neuropharmacology. Using an adaptation of published behavioral protocols, we have described the alleviation of cocaine-induced planarian seizure like movements (pSLM) by a naturally-occurring sesquiterpene lactone, parthenolide. Interestingly, parthenolide does not prevent the expression of pSLM induced by amphetamines; in vertebrates, amphetamines interact with the same protein target as cocaine. Parthenolide is also unable to prevent pSLM elicited by the cholinergic com-pounds nicotine and cytisine or by the glutamatergic agents L- or D- glutamic acid or NMDA. Thus, we conclude that parthenolide is a specific anti-cocaine agent in this experimental organism. PMID- 22451008 TI - Catalytic methanolysis of hydrazine borane: a new and efficient hydrogen generation system under mild conditions. AB - Safe and efficient hydrogen storage is a major obstacle for using hydrogen as an energy carrier. Therefore, intensive efforts have been focused on the development of new materials for chemical hydrogen storage. Of particular importance, hydrazine borane (N(2)H(4)BH(3)) is emerging as one of the most promising solid hydrogen carriers due to its high gravimetric hydrogen storage capacity (15.4 wt%) and low molecular weight. Herein, we report metal catalyzed methanolysis of hydrazine borane (N(2)H(4)BH(3), HB) as a fast hydrogen generation system under mild conditions. When trace amounts of nickel(ii) chloride (NiCl(2)) is added to the methanol solution of hydrazine borane ([HB]/[Ni] >= 200) the reaction solution releases 3 equiv. of H(2) with a rate of 24 mol H(2) (mol Ni min)(-1) at room temperature. The results reported here also includes (i) identification of the reaction products by using ATR-IR, DP-MS, (1)H and (11)B NMR spectroscopic techniques and the establishment of the reaction stoichiometry, (ii) investigation of the effect of substrate and catalyst concentrations on the hydrogen generation rate to determine the rate law for the catalytic methanolysis of hydrazine borane, (iii) determination of the activation parameters (E(a), DeltaH(#), and DeltaS(#)) for the catalytic methanolysis of hydrazine borane by using the temperature dependent rate data of the hydrogen generation. PMID- 22451009 TI - Ugi reaction-assisted rapid assembly of affinity-based probes against potential protein tyrosine phosphatases. AB - The multi-component Ugi reaction has been employed to assemble a small library of affinity-based probes (AfBPs) that target potential protein tyrosine phosphatases. The probes showed good labelling of PTP1B and MptpB, and were subsequently used to label endogenous PTP1B in MCF-7 cell lysates. PMID- 22451010 TI - Development of an in vivo experimental model for percutaneous vertebroplasty in sheep. AB - INTRODUCTION: Several studies have described 'open' approach techniques for cementation of sheep and goat vertebrae; however, no percutaneous technique has been developed so far for use in non-primates. The aim of this study was to develop an animal model for percutaneous vertebroplasty under clinical conditions. METHODS: In a pilot study with dissected cadaveric ovine vertebrae, the technique and instruments as well as the optimal needle position were determined. In an in vivo animal study using 33 lumbar vertebrae of 11 sheep, a percutaneous vertebroplasty was performed under general anaesthesia. Needle position and cement volume were evaluated from high resolution, quantitative computed tomography imaging. RESULTS: The percutaneous technique for vertebroplasty was applicable to the vertebral bodies (L1 to L5) of the ovine lumbar spine without any related adverse effects for the animals. The procedure showed a steep learning curve represented by the reduction of the distance between the actual and planned needle positioning (7.2 mm to 3.7 mm; median value) and shorter surgery times (21.3 min to 15.0 min, average) with progression of the study. CONCLUSION: The described technique is feasible and repeatable under clinical conditions. This is the first percutaneous vertebroplasty technique for non-primates and we conclude that the sheep is a valid animal model to investigate the effects of cement augmentation in vivo. PMID- 22451011 TI - Local adaptation in adult feeding preference and juvenile performance in the generalist herbivore Idotea balthica. AB - Populations can respond to environmental heterogeneity by genetic adaptation to local conditions. Evidence for local adaptation in herbivores with relatively broad host breadth is scarce, either because generalists rarely locally adapt or because fewer studies have tested for local adaptation. The marine isopod Idotea balthica, a small (<3 cm) generalist herbivore common to estuaries of the northwestern Atlantic, is found on multiple macroalgae and sea grasses north of 42 degrees N, while more southerly populations utilize sea grass-dominated and macroalgal-poor habitats. Feeding preference assays revealed a latitudinal shift in preference hierarchy that mirrors this geographic variation in host availability. Northern populations have higher feeding preference for fresh and freeze-dried tissue of the brown macroalga Fucus vesiculosus and consumed more of its water-soluble and lipophilic extracts relative to southern populations. In contrast, southern populations have a relatively higher preference for the green macroalga Ulva linza and sea grass Zostera marina. The rank of hosts in feeding assays exhibited by northern adults (Fucus = Ulva > Zostera) and southern adults (Ulva > Fucus > Zostera) closely mirrored ranking of juvenile growth rates, suggesting that preference and performance are strongly correlated across these macrophytes. Several of our assays included isopods that had parents reared under uniform laboratory conditions, indicating that geographic differences are genetically mediated and unlikely to reflect phenotypic plasticity or maternal effects. Local adaptation in host use traits may be common in broadly distributed, generalist herbivores in marine and terrestrial systems, and will manifest itself as local shifts in the preference ranking of hosts. PMID- 22451012 TI - Variation of electrochemical capacitor performance with Room Temperature Ionic Liquid electrolyte viscosity and ion size. AB - The use of Room Temperature Ionic Liquid (RTIL) electrolytes promises to improve the energy density of Electrochemical Capacitors (ECs) by allowing for operation at higher voltages. RTIL electrolytes 1-ethyl-3-methylimidazolium tetrafluoroborate (EMImBF(4)), 1-ethyl-3-methylimidazolium dicyanamide (EMImN(CN)(2)), 1,2-dimethyl-3-propylimidazolium bis(trifluoromethylsulfonyl)imide (DMPImTFSI), and 1-butyl-3-methylpyrrolidinium tris(pentafluoroethyl)trifluorophosphate (BMPyFAP) were studied. Tetraethylammonium tetrafluoroborate 1 molar solution in anhydrous propylene carbonate (Et(4)NBF(4)-PC 1M) was studied for comparison purposes. Carbon was produced from phenolic resin activated in CO(2). The porosity of the carbon samples were characterised by N(2) adsorption-desorption at 77 K and the relevant electrochemical behaviour was characterised by galvanostatic charge-discharge, electrochemical impedance spectroscopy and cyclic voltammetry. The highest operating voltage of 3.5 V was obtained for BMPyFAP, whilst the best capacitive performance was obtained for EMImBF(4). The maximum energy density increased to 70 Wh kg(-1) (carbon) for RTIL EMImBF(4) from 35 Wh kg(-1)(carbon) for the organic electrolyte Et(4)NBF(4)-PC 1M. It was found that the performance of the RTIL electrolytes could be related to the IL viscosity and ion size whilst the electrolyte equivalent series resistances produced a linear relationship with viscosity. It was found that the capacitance performance of the RTIL electrolytes followed the order EMImBF(4) > DMPImTFSI > BMPyFAP > EMImN(CN)(2). The electrolyte and equivalent series resistance were in the order EMImN(CN)(2) < EMImBF(4) < DMPImTFSI < BMPyFAP. PMID- 22451015 TI - Evaluation of language concordant, patient-centered drug label instructions. AB - BACKGROUND: Despite federal laws requiring language access in healthcare settings, most US pharmacies are unable to provide prescription (Rx) medication instructions to limited English proficient (LEP) patients in their native language. OBJECTIVE: To evaluate the efficacy of health literacy-informed, multilingual Rx instructions (the ConcordantRx instructions) to improve Rx understanding, regimen dosing and regimen consolidation in comparison to standard, language-concordant Rx instructions. DESIGN: Randomized, experimental evaluation. PARTICIPANTS: Two hundred and two LEP adults speaking five non English languages (Chinese, Korean, Russian, Spanish, Vietnamese), recruited from nine clinics and community organizations in San Francisco and Chicago. INTERVENTION: Subjects were randomized to review Rx bottles with either ConcordantRx or standard instructions. MAIN MEASURES: Proper demonstration of common prescription label instructions for single and multi-drug medication regimens. Regimen consolidation was assessed by determining how many times per day subjects would take medicine for a multi-drug regimen. KEY RESULTS: Subjects receiving the ConcordantRx instructions demonstrated significantly greater Rx understanding, regimen dosing and regimen consolidation in comparison to those receiving standard instructions (incidence rate ratio [IRR]: 1.25, 95 % confidence interval [CI]: 1.06-1.48; P= 0.007 for Rx understanding, IRR: 1.19, 95 % CI: 1.03-1.39; P= 0.02 for regimen dosing and IRR: 0.76, 95 % CI: 0.64-0.90; P= 0.001 for regimen consolidation). In most cases, instruction type was the sole, independent predictor of outcomes in multivariate models controlling for relevant covariates. CONCLUSIONS: There is a need for standardized, multilingual Rx instructions that can be implemented in pharmacy practices to promote safe medication use among LEP patients. The ConcordantRx instructions represent an important step towards achieving this goal. PMID- 22451016 TI - A physiologically based pharmacokinetic model of mitoxantrone in mice and scale up to humans: a semi-mechanistic model incorporating DNA and protein binding. AB - We conducted a pharmacokinetic (PK) study of mitoxantrone (Novantrone(r)), a clinically well-established anticancer agent, in mice and developed a mechanism based PBPK (physiologically based pharmacokinetic) model to describe its disposition. Mitoxantrone concentrations in plasma and six organs (lung, heart, liver, kidney, spleen, and brain) were determined after a 5 mg/kg i.v. dose. We evaluated three different PBPK models in order to characterize our experimental data: model 1 containing Kp values, model 2 incorporating a deep binding compartment, and model 3 incorporating binding of mitoxantrone to DNA and protein. Among the three models, only model 3 with DNA and protein binding captured all the experimental data well. The estimated binding affinity for DNA (K (DNA)) and protein (K (macro)) were 0.0013 and 1.44 MUM, respectively. Predicted plasma and tissue AUC values differed from observed values by <19 %, except for heart (60 %). Model 3 was further used to simulate plasma mitoxantrone concentrations in humans for a 12-mg/m(2) dose, using human physiological parameters. The simulated results generally agreed with the observed time course of mitoxantrone plasma concentrations in patients after a standard dose of 12 mg/m(2). In summary, we reported for the first time a mechanism-based PBPK model of mitoxantrone incorporating macromolecule binding which may have clinical applicability in optimizing clinical therapy. Since mitoxantrone is a substrate of the efflux transporters ABCG2 and ABCB1, the incorporation of efflux transporters may also be necessary to characterize the data obtained in low-dose studies. PMID- 22451017 TI - Perinatal depression screening in healthy start: an evaluation of the acceptability of technical assistance consultation. AB - In 2001, Healthy Start was required to screen for maternal depression. To support this mandate, technical assistance (TA) consultations were provided to eleven programs. Participant evaluations assessed TA recipients' views, a foundational level of program evaluation. Staff evaluated TA presentations immediately; and directors assessed its helpfulness in a 6-month and a 5-year follow-up. Staff believed their knowledge increased significantly; the majority rated TA presentations as "useful" to "very useful." Most directors rated TA as "useful" or "very useful" in achieving TA goals, reported having "few" or "no" obstacles in screening, and rated staff as "willing" or "very willing" to screen. A range of educational programs have been developed to assist the implementation of maternal depression screening. The current evaluation indicates that diverse types of programs held positive views of TA consultation and believed it was effective. The success of the method argues for further development. PMID- 22451018 TI - The impact of psychiatric disorders on employment: results from a national survey (NESARC). AB - In this study we examine the longitudinal effects of psychiatric and substance use disorders on employment, in an employed population. The sample included respondents to the National epidemiologic survey on alcohol related conditions (NESARC) who were employed at Wave 1 (N=22,407). Bivariate and multivariable analyses were conducted examining the associations between 12-month and new onset 12-month psychiatric diagnoses at Wave 1 and employment status at Wave 2. Past year and new onset 12-month depression, 12-month bipolar, new onset 12-month drug abuse, and 12-month and new onset 12-month drug dependence were associated with a decreased odds of being employed at Wave 2. This study suggests that it would be beneficial for employers to support their employees in participating in mental health treatment. Additionally, understanding how psychiatric disorders influence employment over the life course might inform the development of preemptive interventions to treat mental health symptoms. PMID- 22451019 TI - The G protein-coupled oestrogen receptor 1 agonist G-1 disrupts endothelial cell microtubule structure in a receptor-independent manner. AB - The G protein-coupled oestrogen receptor GPER1, also known as GPR30, has been implicated in oestrogen signalling, but the physiological importance of GPER1 is not fully understood. The GPER1 agonist G-1 has become an important tool to assess GPER1-mediated cellular effects. Here, we report that this substance, besides acting via GPER1, affects the microtubule network in endothelial cells. Treatment with G-1 (3 MUM) for 24 h reduced DNA synthesis by about 60 % in mouse microvascular endothelial bEnd.3 cells. Treatment with 3 MUM G-1 prevented outgrowth of primary endothelial cells from mouse aortic explants embedded in Matrigel. Treatment with G-1 (0.3-3 MUM) for 24 h disrupted bEnd.3 cell and HUVEC microtubule structure in a concentration-dependent manner as assessed by laser scanning confocal immunofluorescence microscopy. G-1-induced (3 MUM) disruption of microtubule was observed also after acute (3 and 6 h) treatment and in the presence of the protein synthesis inhibitor cycloheximide. Disruption of microtubules by 3 MUM G-1 was observed in aortic smooth muscle cells obtained from both GPER1 knockout and wild-type mice, suggesting that G-1 influences microtubules through a mechanism independent of GPER1. G-1 dose dependently (10 50 MUM) stimulated microtubule assembly in vitro. On the other hand, microtubules appeared normal in the presence of 10-50 MUM G-1 as determined by electron microscopy. We suggest that G-1-promoted endothelial cell anti-proliferation is due in part to alteration of microtubule organization through a mechanism independent of GPER1. This G-1-promoted mechanism may be used to block unwanted endothelial cell proliferation and angiogenesis such as that observed in, e.g. cancer. PMID- 22451020 TI - The effect of various disease-modifying anti-rheumatic drugs on the suppressive function of CD4+CD25+ regulatory T cells. AB - Accumulating evidence suggests that defects in the function of CD4(+)CD25(+) regulatory T cells (Tregs) are important in immune-mediated diseases such as rheumatoid arthritis. Here, we investigated the effects of various disease modifying anti-rheumatic drugs (DMARDs) on Treg function. Tregs and CD4(+)CD25(-) effector T cells (Teffs) were isolated from peripheral blood mononuclear cells obtained from healthy adults. Isolated Tregs were cultured with the DMARDs methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF), or infliximab (INF). We found that each DMARD had a different effect on Treg function. SSZ and LEF inhibited the anti-proliferative function of Tregs on cocultured Teffs and reduced Treg expression of Foxp3 mRNA, whereas MTX and INF did not. PMID- 22451021 TI - Non-invasive electromagnetic field therapy produces rapid and substantial pain reduction in early knee osteoarthritis: a randomized double-blind pilot study. AB - This study examined whether a non-thermal, non-invasive, pulsed electromagnetic field (PEMF), known to modulate the calmodulin (CaM)-dependent nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway, could reduce pain in early knee OA. This randomized, placebo-controlled, double-blind pilot clinical study enrolled 34 patients. Patient selection required initial VAS >=4, 2 h of standing activity per day, and no recent interventions such as cortisone injections or surgery. Results showed VAS pain score decreased in the active cohort by 50 +/- 11% versus baseline starting at day 1 and persisting to day 42 (P < 0.001). There was no significant decrease in VAS versus baseline at any time point in the sham cohort (P = 0.227). The overall decrease in mean VAS score for the active cohort was nearly threefold that of the sham cohort (P < 0.001). The results suggest that non-thermal, non-invasive PEMF therapy can have a significant and rapid impact on pain from early knee OA and that larger clinical trials are warranted. PMID- 22451022 TI - L-carnitine enhances extracellular matrix synthesis in human primary chondrocytes. AB - Osteoarthritis (OA) is one of the most common degenerative joint disease for which there is no cure. It is treated mainly with non-steroidal anti-inflammatory drugs to control the symptoms and some supplements, such as glucosamine and chondroitin sulphate in order to obtain structure-modifying effects. Aim of this study is to investigate the effects of L-carnitine, a molecule with a role in cellular energy metabolism, on extracellular matrix synthesis in human primary chondrocytes (HPCs). Dose-dependent effect of L-carnitine on cartilage matrix production, cell proliferation and ATP synthesis was examined by incubating HPCs with various amounts of molecule in monolayer (2D) and in hydromatrix scaffold (3D). L-Carnitine affected extracellular matrix synthesis in 3D in a dose dependent manner; moreover, L-carnitine was very effective to stimulate cell proliferation and to induce ATP synthesis, mainly in 3D culture condition. In conclusion, L-carnitine enhances cartilage matrix glycosaminoglycan component production and cell proliferation, suggesting that this molecule could be useful in the treatment of pathologies where extracellular matrix is degraded, such as OA. To our knowledge, this is the first study where the effects of L-carnitine are evaluated in HPCs. PMID- 22451023 TI - IRAK1 rs3027898 C/A polymorphism is associated with risk of rheumatoid arthritis. AB - IRAK1 and miR-499 play an important role in the etiology of rheumatoid arthritis. Few studies to date have focused on the influence of the IRAK1 rs3027898 C/A and hsa-mir-499 rs3746444 T/C polymorphisms in the susceptibility of the Chinese population to rheumatoid arthritis. We hypothesized that these polymorphisms may contribute to rheumatoid arthritis susceptibility. We studied IRAK1 rs3027898 C/A and hsa-mir-499 rs3746444 T/C gene polymorphisms in 214 rheumatoid arthritis cases and 478 controls in a Chinese population. Genotyping was performed by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). When the IRAK1 rs3027898 CC homozygote genotype was used as the reference group, the AA genotype was associated with significantly increased risk of rheumatoid arthritis (odds ratio (OR) = 1.91, 95 % confidence interval (CI) = 1.12-3.26, p = 0.017). A significantly increased risk of RA associated with the IRAK1 rs3027898 AA genotype was more evident among females, younger patients, CRP negative patients and both anti-CCP positive and negative patients compared with the IRAK1 rs3027898 CC/CA genotypes. The hsa-mir-499 rs3746444 T/C single nucleotide polymorphism (SNP) was not significantly associated with the risk for rheumatoid arthritis. Our findings suggest that the functional SNP IRAK1 rs3027898 C/A variant allele is associated with the development of rheumatoid arthritis. However, the hsa-mir-499 rs3746444 T/C polymorphism may not be associated with susceptibility to rheumatoid arthritis. PMID- 22451024 TI - Inhibitory effects of simvastatin on migration and invasion of rheumatoid fibroblast-like synoviocytes by preventing geranylgeranylation of RhoA. AB - To investigate the effect of simvastatin on the migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and its cellular signal mechanisms, FLS from active RA patients were stimulated with 3 % FBS or GM-CSF in the presence or absence of simvastatin. Cells migration and invasion in vitro were measured by the Boyden chamber method. RhoA activity was assessed by a pull-down assay. Matrix metalloproteinases-2 (MMP-2) activity was evaluated by zymography. Simvastatin inhibits FBS- or GM-CSF-induced migration in a dose-dependent manner by RA FLS, and this inhibitory effect is independent of cell apoptosis. We also found that simvastatin suppressed in vitro invasion, adhesion, MMP-2 activity, cytoskeletal reorganization and RhoA activation. Furthermore, mevalonate or GGPP treatment reversed the inhibitory effect of simvastatin not only on migration and invasion in vitro but also on RhoA activation, and inhibition of RhoA by specific siRNA transfection reduced migration, adhesion and invasion of RA FLS. This study shows that simvastatin reduces RA FLS migration and invasion through the prevention of protein geranylgeranylation and RhoA activation. These findings provide a novel evidence that statin may be benefit for preventing RA arthritic destruction, and also indicate that RhoA may be a new target for the modulation of RA FLS migration and invasion. PMID- 22451025 TI - Relationship between sonographic parameters and YKL-40 levels in rheumatoid arthritis. AB - YKL-40, also known as human cartilage glycoprotein 39, is a member of the "mammalian chitinase-like proteins" family without chitinase activity. Increased serum concentrations are associated with inflammatory processes and several types of cancer. In this study, we evaluated YKL-40 levels in serum and synovial fluid of patients with rheumatoid arthritis in comparison with the ultrasonographic findings. YKL-40 levels were measured by enzyme-linked immunosorbent assay in 25 patients with active rheumatoid arthritis and in 40 healthy subjects. B mode and power Doppler were performed to determine synovial thickening and vascularization. Serum YKL-40 level in patients was significantly higher than the concentration in healthy controls (P < 0.01). In patients with rheumatoid arthritis, the level of the glycoprotein in synovial fluid was remarkably elevated compared to the serum level (P = 0.003). The B mode and power Doppler scores correlated to YKL-40 in serum and synovial fluid (P = 0.07). Serum YKL-40 levels were related positively to serum markers of inflammation such as C reactive protein (P = 0.004) and erythrocyte sedimentation rate (P = 0.003). This study is the first to demonstrate a relationship between YKL-40 levels and ultrasonographic examinations in Bulgarian patients with rheumatoid arthritis. The findings suggest that YKL-40 might be implicated in the pathogenesis of the disease and could indicate the level of joint inflammation. PMID- 22451026 TI - Prevalence and significance of the MEFV gene mutations in childhood Henoch Schonlein purpura without FMF symptoms. AB - Familial Mediterranean fever (FMF) has been reported more frequently in patients presenting with Henoch-Schonlein purpura (HSP) than in the general population. But, there is no clear knowledge about MEFV mutations in patients with HSP. We investigated the prevalence of MEFV mutations in children with HSP and without FMF whether these mutations have any effect on the disease course or complications. A total of 76 children with HSP who had no typical symptoms of FMF were screened for the mutations in exon 2 and exon 10 of the MEFV gene. Eleven of 76 patients (14.4 %) were heterozygous (E148Q in 5, M694V in 4, M680I in 1, E148V in 1), 5 (6.6 %) were homozygous (M694V/M694V in 4, V726A/V726A in 1), and 2 (2.6 %) were compound heterozygous (E148Q/M694V mutations in 1 and L110P/E148Q mutations in 1). Altogether, 7 patients carried 2 mutated MEFV alleles (9.2 %), which was higher than that observed in the general Turkish population (1 %). No significant differences in joint, gastrointestinal, renal involvement, or subcutaneous edema, and also acute phase reactants including leukocyte count, erythrocyte sedimentation rate, and serum C-reactive protein concentration were found between the groups. The prevalence of the two allele-MEFV mutations in patients with HSP was found higher than that of the general population. However, it seems that MEFV gene mutations may not have any effect on the clinical presentation of HSP. PMID- 22451027 TI - Rheumatoid arthritis prevalence, incidence, and mortality rates: a nationwide population study in Taiwan. AB - There are few nationwide population studies on the epidemiology of rheumatoid arthritis (RA). Here, we present the epidemiologic features and mortality rates of RA in Taiwan. The catastrophic illness registry of the Taiwan National Health Insurance Research Database and the National Death Registry of Taiwan were used to estimate the incidence and prevalence of RA and its associated mortality rates. All-cause and cause-specific standardized mortality ratios (SMRs) were calculated and compared to the corresponding ratios of the general population in 2002. The study comprised 15,967 incident RA cases (3,562 men; 12,405 women) occurring from 2002 through 2007. The annual incidence of RA was 15.8 cases (men, 10.1; women, 41.0) per 100,000 population. The period prevalence was 97.5 cases (men, 37.4; women, 159.5) per 100,000 population. During 67,010 person-years of follow-up, 985 deaths (372 men; 613 women) were identified, and this corresponded to a crude mortality rate of 14.7 deaths (men, 25.0; women, 11.8) per 1,000 person-years. Compared to female patients, male patients had a higher risk for mortality (log-rank test, p < 0.001). RA patients had an SMR of 1.25 (95 % confidence interval [CI], 1.18-1.33) for all-cause mortality. Compared to the general population, RA patients of both genders in this cohort had a significantly higher risk of mortality from infection (SMR, 2.49) and gastrointestinal diseases (SMR, 1.76). RA incidence and prevalence were higher in women than in men. Mortality was higher in men than in women. Compared to the general population, RA patients had a higher risk of death, particularly from infection and gastrointestinal diseases. PMID- 22451028 TI - Dry cough is a frequent manifestation of giant cell arteritis. AB - Physicians need to be familiar with the typical manifestations of giant cell arteritis. However, the challenge lies in recognizing atypical cases that lack the more specific manifestations or reflect vasculitis in less frequently involved territories. Among atypical clinical manifestations, dry cough has been reported in recent years. The literature contains sporadic reports mainly single case report. The objective of this study was to determine the frequency of dry cough in patients with giant cell arteritis. Clinical data were collected from 88 patients with giant cell arteritis. Relationships between dry cough and other clinical manifestations or biological data were analyzed. Dry cough of recent appearance was found at initial presentation of giant cell arteritis in 12 patients (13.6%). In 2 cases, dry cough was isolated. The 2 patients sought attention because of chronic dry cough associated with inflammation of unknown origin. In 10 cases, dry cough was associated with typical clinical manifestations of giant cell arteritis. A correlation was found between inflammatory biomarkers and presence of dry cough. The mean CRP was 153.8 mg/l (SD 85.1) in patients with dry cough and 94 mg/l (SD 72.2) in patients without dry cough (p = 0.0131). We conclude that the diagnosis of giant cell arteritis should always be considered in an elderly patient with an unexplained elevation of inflammatory markers and chronic dry cough. Dry cough in giant cell arteritis was not correlated with other clinical manifestations of this vasculitis, including pulmonary manifestations, but was correlated with inflammatory biomarkers. PMID- 22451029 TI - Catch me if you can: a national survey of rheumatologists and obstetricians on the use of DMARDs during pregnancy. AB - The use of disease-modifying anti-rheumatic drugs and biological therapy is variable throughout pregnancy. This questionnaire-based study was undertaken to explore and compare the current practice amongst rheumatologists and obstetricians across the UK, regarding the use of drugs during pregnancy. A questionnaire was devised to address issues regarding individual drugs used during preconception, pregnancy and lactation. Members of the British Society of Rheumatology, Midlands Rheumatology Society and the British Maternal Fetal Medicine Society were emailed. Results were analysed by the online survey software and Fisher's exact testing. Our results show differences between rheumatologists and obstetricians. A total of 500 members of each society were emailed. There were 102 (20 %) versus 33 (7 %) respondents. With regard to medication, in relation to advice given before conception, hydroxychloroquine 80 versus 61 % continue, 19 versus 15 % discontinue (p = 1.0); sulphasalazine 59 versus 70 % continue, 41 versus 6 % discontinue (p = 0.002); azathioprine 62 versus 58 % continue, 36 versus 21 % discontinue (p = 0.37); methotrexate 0 versus 3 % continue, 100 versus 76 % discontinue (p = 0.2); leflunomide 0 versus 0 % continue, 98 versus 42 % discontinue (p = 1.0); anti-TNF therapy 7 versus 15 % continue, 54 versus 54 % discontinue (p = 0.05); and rituximab 2 versus 12 % continue, 95 versus 52 % (p = 0.01) would discontinue prior to conception. This survey is the first of its nature amongst rheumatologists and obstetricians. Most would give advice to continue with sulphasalazine, azathioprine and stop methotrexate and leflunomide. We observed no uniform practice and therefore recommend guidelines. PMID- 22451030 TI - A rare form of SLE: pseudo-pseudo meigs syndrome and hydrocephalus. PMID- 22451031 TI - Right or left hand: is this the real problem of Pontormo's Halberdier? PMID- 22451032 TI - Interleukin-6 and cytochrome-P450, reason for concern? AB - Interleukin 6 (IL-6) plays a central role in the immunopathogenesis of rheumatoid arthritis (RA) and tocilizumab [TCZ] (an anti-IL-6 receptor antibody) has been shown to be effective in the treatment of the condition. As up-regulation of IL-6 reduces the activity of cytochrome P450 (CYP) enzymes, blockade of this cytokine may enhance CYP function. This may lead to reduced bioavailability of CYP metabolized drugs. Due to the increasing use of TCZ, we undertook a systematic literature review to explore such interactions. Our search was conducted in MEDLINE, EMBASE, Web of Science, FDA and EMEA websites for in vitro and in vivo studies, clinical trials and reviews mentioning TCZ and CYP on the basis of the title and abstract. Appropriate articles were further screened based on full-text review to select only those reporting IL-6, TCZ and their potential interaction with CYP-metabolized drugs. Two in vitro studies showed that TCZ-reversed IL-6 induced reduction of CYP isozymes. CYP3A4 mRNA expression was most reduced by IL 6 followed by CYP2C9 and CYP2C19. This change was prevented with TCZ. Three clinical studies investigated the interaction showing simvastatin (CYP3A4 substrate) bioavailability reduced by TCZ and omeprazole bioavailability was decreased by TCZ-induced CYP2C19 activity. The bioavailability of dextromethorphan (CYP2D6 and CYP3A4 substrates) was shown to be unaffected by TCZ treatment. The observed increase in CYP isozyme activity by TCZ is of clinical relevance as the bioavailability of the CYP isozyme substrates were decreased in vivo. As CYP3A4 is the isozyme responsible for the largest proportion of drug metabolism, it is probable that the bioavailability of other drugs may be reduced by TCZ. Thus, clinicians should exercise caution when co-prescribing TCZ and CYP metabolized drugs. More studies are required to investigate this interaction further. PMID- 22451033 TI - Prevalence of cervical human papillomavirus infection in women with systemic lupus erythematosus. AB - Genital infection by human papillomavirus (HPV) tends to occur more frequently in patients with conditions associated with immune suppression. Systemic lupus erythematosus (SLE) is an immunological disorder characterized by generalized inflammation and a number of clinical manifestations and circulating autoantibodies. The aim of the present study was to determine the prevalence of genital HPV infection among female SLE patients. Women diagnosed with SLE based on American College of Rheumatology classification criteria followed at rheumatology outpatient clinic of the Escola Bahiana de Medicina e Saude Publica, Salvador, Brazil, were included in the study. As a comparison group, clinically healthy women who were attending the gynecology outpatient clinic for routine examination at the same institution were recruited. Testing for cervical HPV infection was performed using the nested polymerase chain reaction technique. Eighty-eight female SLE patients (mean age, 41.4 +/- 11.6 years) and seventy healthy female subjects (control group) were studied. The prevalence of HPV infection was 80.7 % (71/88) in the SLE group and 35.7 % (25/70) in the control group (p < 0.0001). After adjustment of the variables (early sexual activity, number of partners and obstetric history), the odds ratio (OR) for genital HPV infection in women with SLE was 7.2 (95 % CI, 2.9 to 17.8; p = 0.0001). The use of immunosuppressive drugs was not associated with a higher prevalence of HPV infection. This study demonstrated that SLE patients have a higher prevalence of genital HPV infection, even when exposed to less potential risk factors for the virus. PMID- 22451034 TI - Posterior ischemic optic neuropathy in a patient with granulomatosis with polyangiitis (Wegener's). PMID- 22451035 TI - Presentation of psoriatic arthritis in the literature: a twenty-year bibliometric evaluation. AB - Psoriatic arthritis is an inflammatory arthritis disabling patients with psoriasis. Bibliometric studies are tools for evaluating scientific productions in different countries, universities as well as publications related to a special topic. We aimed to perform a scientometric study to evaluate articles published under "Psoriatic arthritis" topic and also attempted to compare publications of different authors, countries, universities, and journals related to this topic. Study was performed on all articles published between 1989 and 2009. The ISI web of science was our main source. Two key words, "Psoriatic arthritis" and "Psoriatic arthropathy," were used to conduct search. Original articles were subject of further evaluation. A whole number of 3,727 article was result of our search. From this number, 1,961 (52.6 %) were original articles. Whole original articles were cited 38,613 times with average citations per item of 19.69. Gladman DD was the most popular author in this field. Articles were mostly in English (91.3 %). USA was the leading country in producing article under this topic with 463 (23.6 %) publications. University of Toronto was the first rank institution while publishing 125 (6.4 %) articles. More than half of articles were published under "Rheumatology" subject. "Journal of Rheumatology," "Annals of the Rheumatic Diseases," and "Arthritis and Rheumatism" were three journals with highest number of articles on this topic. There has been growing interest in psoriatic arthritis subject during these two decades. Between countries, institutions and journals; USA, university of Toronto, "Journal of Rheumatology," "Annals of The Rheumatic Diseases," and "Arthritis and Rheumatism" have special contributions to body of literature published under this topic, respectively. PMID- 22451036 TI - Fear of recurrence among head and neck cancer survivors: longitudinal trends. AB - BACKGROUND: Fear of recurrence (FoR) following head and neck cancer (HNC) treatment is a major patient concern but is infrequently discussed in outpatient settings and may cause significant detrimental effect on patient psychological well-being. AIM: The aim of this paper is to determine longitudinal trends and predictors of significant FoR. METHOD: Prospective data collection was obtained in 189 post-treatment HNC patients with 456 clinic attendances from October 2008 to January 2011. All patients completed Patient Concerns Inventory (PCI), University of Washington Quality of Life Questionnaire version 4 and the FoR questionnaires using a combination of paper and touch-screen technology. RESULTS: The prevalence of significant FoR was 35%, which was stable longitudinally. Logistic regression-delineated predictors of significant FoR were young age (<65 years), anxiety/mood and patient-reported FoR. Conventional prognostic factors including standard clinicopathological factors, treatment modality and length of follow-up did not predict significant FoR. Over time, 20% of patients reported significant FoR intermittently, whereas 30% experienced it consistently. The remaining 50% did not experience significant FoR. DISCUSSION: Patient-related characteristics were more important than clinicopathological prognostic factors in predicting significant FoR, potentially creating a mismatch between the doctors' perception of patient's experience of FoR with what patients may experience. In the long term, FoR is expressed across a spectrum extending from 'normal' FoR to persistent significant FoR with an intermediate category of intermittent significant FoR. Those patients experiencing intermittent and consistent levels of significant FoR may benefit from psychological support. This study confirmed that self-reported screening FoR using the PCI is a valuable tool in identifying significant FoR. PMID- 22451038 TI - Intake levels of dietary long-chain PUFAs modify the association between genetic variation in FADS and LDL-C. AB - Polymorphisms of the FA desaturase (FADS) gene cluster have been associated with LDL, HDL, and triglyceride concentrations. Because FADS converts alpha-linolenic acid (ALA) and linoleic acid into PUFAs, we investigated the interaction between different PUFA intakes and the FADS polymorphism rs174547 (T>C) on fasting blood lipid and lipoprotein concentrations. We included 4,635 individuals (60% females, 45-68 years) from the Swedish population-based Malmo Diet and Cancer cohort. Dietary intakes were assessed by a modified diet history method including 7-day registration of cooked meals. The C-allele of rs174547 was associated with lower LDL concentration (P = 0.03). We observed significant interaction between rs174547 and long-chain omega-3 PUFA intakes on LDL (P = 0.01); the C-allele was only associated with lower LDL among individuals in the lowest tertile of long chain omega-3 PUFA intakes (P < 0.001). In addition, significant interaction was observed between rs174547 and the ratio of ALA and linoleic FA intakes on HDL (P = 0.03). However, no significant associations between the C-allele and HDL were detected within the intake tertiles of the ratio. Our findings suggest that dietary intake levels of different PUFAs modify the associated effect of genetic variation in FADS on LDL and HDL. PMID- 22451039 TI - Nanocomposite "superhighways" by solution assembly of semiconductor nanostructures with ligand-functionalized conjugated polymers. AB - Poly(3-hexyl thiophene) containing chain-end thiols or phosphonic acids is crystallized to yield nanowires with the functional groups at the wire edges. CdSe quantum dots and nanorods associate with these fibrils, leading to 'superhighways' that consist of alternating parallel lanes of conjugated polymer and CdSe. PMID- 22451041 TI - Efficient energy transfer via the cyanide bridge in dinuclear complexes containing Ru(II) polypyridine moieties. AB - We report the synthesis, structure and properties of the cyanide-bridged dinuclear complex ions [Ru(L)(bpy)(MU-NC)M(CN)(5)](2-/-) (L = tpy, 2,2';6',2'' terpyridine, or tpm, tris(1-pyrazolyl)methane, bpy = 2,2'-bipyridine, M = Fe(II), Fe(III), Cr(III)) and the related monomers [Ru(L)(bpy)X](2+) (X = CN(-) and NCS( )). All the monomeric compounds are weak MLCT emitters (lambda = 650-715 nm, phi ~ 10(-4)). In the Fe(II) and Cr(III) dinuclear systems, the cyanide bridge promotes efficient energy transfer between the Ru-centered MLCT state and a Fe(II)- or Cr(III)-centered d-d state, which results either in a complete quenching of luminescence or in a narrow red emission (lambda ~ 820 nm, phi ~ 10( 3)) respectively. In the case of Fe(III) dinuclear systems, an electron transfer quenching process is also likely to occur. PMID- 22451042 TI - The poetry of reproduction: the role of LEAFY in Arabidopsis thaliana flower formation. AB - For successful reproduction, angiosperms must form fertile flowers at the appropriate positions and at the appropriate times. The reproductive transition is especially important for monocarpic plants that only flower once. In the model annual plant Arabidopsis thaliana, this transition is controlled through regulation of a group of genes termed floral meristem identity genes, of which LEAFY (LFY) is arguably the most important. LFY orthologs are found throughout land plants and are essential for angiosperm reproduction. These genes have also been implicated in reproductive development in gymnosperms. LFY encodes a plant specific transcription factor that can act as either an activator or repressor depending on context, including what co-factors it is interacting with. It controls multiple aspects of floral morphogenesis, including phyllotaxis, organ number, organ identity and determinacy. Much progress has been made in elucidating the molecular mechanisms through which LFY and its orthologs contribute to a precise switch to flowering. We discuss the current state of knowledge in Arabidopsis, with an emphasis on known target genes and co-factors of LFY. PMID- 22451043 TI - The Hydra model - a model for what? AB - The introductory personal remarks refer to my motivations for choosing research projects, and for moving from physics to molecular biology and then to development, with Hydra as a model system. Historically, Trembley's discovery of Hydra regeneration in 1744 was the beginning of developmental biology as we understand it, with passionate debates about preformation versus de novo generation, mechanisms versus organisms. In fact, seemingly conflicting bottom-up and top-down concepts are both required in combination to understand development. In modern terms, this means analysing the molecules involved, as well as searching for physical principles underlying development within systems of molecules, cells and tissues. During the last decade, molecular biology has provided surprising and impressive evidence that the same types of molecules and molecular systems are involved in pattern formation in a wide range of organisms, including coelenterates like Hydra, and thus appear to have been "invented" early in evolution. Likewise, the features of certain systems, especially those of developmental regulation, are found in many different organisms. This includes the generation of spatial structures by the interplay of self-enhancing activation and "lateral" inhibitory effects of wider range, which is a main topic of my essay. Hydra regeneration is a particularly clear model for the formation of defined patterns within initially near-uniform tissues. In conclusion, this essay emphasizes the analysis of development in terms of physical laws, including the application of mathematics, and insists that Hydra was, and will continue to be, a rewarding model for understanding general features of embryogenesis and regeneration. PMID- 22451044 TI - Modeling pattern formation in hydra: a route to understanding essential steps in development. AB - Modeling of pattern formation in hydra has revealed basic mechanisms that underlie the reproducible generation of complex and self-regulating patterns. Organizing regions can be generated by a local self-enhancing reaction that is coupled with an inhibitory effect of longer range. Such reactions enable pattern formation even in an initially almost homogeneous assembly of cells. A long ranging feedback of the organizer onto the competence to perform the pattern forming reaction stabilizes the polar axial pattern during growth and allows for regeneration with preserved polarity. Hypostome formation is assumed to be under the control of two positive feedback loops in which Wnt3 is a common element. In addition to the well-established loop employing beta-catenin, a second cell-local loop is involved, possibly with Brachyury as an additional component. This model accounts for the different expression patterns of beta-catenin and Wnt3. Wnt molecules are proposed to play a dual role, functioning as activators and, after processing, as inhibitors. Since Wnt genes code for complete pattern-forming systems, gene duplication and diversification lead to a family of genes whose expression regions have a precise relation to each other. Tentacle formation is an example of positioning a second pattern-forming system by medium-ranging activation and local exclusion exerted by the primary system. A model for bud formation suggests that a transient pre-bud signal is involved that initiates the formation of the foot of the bud, close to the normal foot, as well as close to the bud tip. Many dynamic regulations, as observed in classical and molecular observations, are reproduced in computer simulations. A case is made that hydra can be regarded as a living fossil, documenting an evolutionary early axis formation before trunk formation and bilaterality were invented. Animated simulations are available in the supplementary information accompanying this paper. PMID- 22451046 TI - Chiral electrokinetic chromatography-electrospray ionization-mass spectrometry using a double junction interface. AB - A double junction interface was utilized to preserve separation efficiency and alleviate ion suppression from sulfated beta-cyclodextrin (S-beta-CD) in electrokinetic chromatography-electrospray ionization-mass spectrometry. The utility of the approach was demonstrated by chiral EKC-MS analysis of dihydroxyphenylalanine and methyldihydroxyphenylalanine enantiomers using either low concentration (counter-migration mode; 0.1% S-beta-CD) or high concentration (carrier mode; 2% S-beta-CD). In the counter-migration mode, S-beta-CD anions were supplied continuously from the junction reservoir to the separation column so that the effective separation length was preserved. This interface is especially useful under carrier mode in which high concentration of S-beta-CD will migrate toward the ESI source. With the use of the double junction interface, the S-beta-CD exited the separation column will remain in the junction reservoir, whereas the analyte will flow toward the ESI source through a connecting column. As a result, no ion suppression was observed and the sensitivity was improved significantly. PMID- 22451047 TI - Evaluation of a sheathless nanospray interface based on a porous tip sprayer for CE-ESI-MS coupling. AB - The hyphenation of capillary electrophoresis (CE) with mass spectrometry (MS) is a powerful method to obtain high efficient, sensitive, and selective analyses. The successful coupling with electrospray ionization (ESI) source requires closed electric circuits for both the CE separation and the ESI processes. A wide range of interfaces has been proposed to satisfy this requirement. Among them, the new high sensitivity porous sprayer based on a porous tip achieves the electric connection by inserting the capillary outlet made of a porous material into an ESI needle filled with a conductive liquid and independently grounded. This device is compatible with the minute flow rates exhibited in CE and therefore makes possible the use of a nano-electrospray behavior. In this work, this interface was evaluated for hyphenating a CE with a single quadrupole MS instrument for low molecular weight analytes. Investigations aimed at highlighting the most influent parameters thanks to a design of experiments, reaching the best performance in terms of sensitivity and stability. MS signal intensities of various pharmaceutical compounds (e.g. amphetamines, beta blockers) emphasized high sensitivity and efficiency, while repeatability, expressed as relative standard deviation of corrected heights and areas, was suitable for quantitative purposes (<5%). PMID- 22451048 TI - Alignment of laser-induced fluorescence and mass spectrometric detection traces using electrophoretic mobility scaling in CE-LIF-MS of labeled N-glycans. AB - The combination of optical detection techniques like photometry (UV) or laser induced fluorescence (LIF) with mass spectrometry for capillary electrophoresis offers advantages, both for later use of stand-alone CE-UV or CE-LIF systems and for combined CE-UV-MS or CE-LIF-MS analysis. Faster method development is enabled, the identification of analytes is facilitated, and it allows christian the optical detection scheme to be used for more precise quantification. However, shortcomings of current methodology and equipment hindered the broader use of such detection combinations mainly due to the long distance between the detection points (at least 20 cm). Large shifts in migration times and changes in resolution are visible between the detection traces hindering their straightforward comparison. We present here novel equipment for a robust coupling of CE-LIF-MS with the shortest possible distance between detection points (12 cm) determined by the length of the electrospray needle. In addition, we encourage the use of a normalization of detection traces using a scale of effective electrophoretic mobility to obtain the same x-scale for both detection traces. As an example, the proposed methodology is applied to a mixture of labeled as well as non-labeled N-glycans. PMID- 22451049 TI - Performance of different separation methods interfaced in the same MS-reflection TOF detector: a comparison of performance between CE versus HPLC for biomarker analysis. AB - One of the aims in the field of proteomics is the identification of a protein or polypeptide, or a range of these compounds, that could provide pre-symptomatic indication of the onset of a disease. A number of analytical techniques have been employed to try and achieve this end. These techniques have been applied to the complete range of body fluids and tissues that are readily available from clinical studies. Of these sample sources, the urinary low molecular weight peptidome has been shown to reflect changes in the health status of the individual. The alterations that occur in the polypeptide make up of urine, which reflect changes in biological status, are known as biomarkers. To be able to determine these changes no single technique has emerged that can cope with detecting the large number of peptides present and quantifying them over the wide concentration range they exist in. In this investigation, we made use of a single reflectron time of flight (RTOF)-MS analyser to which we first connected a CE system and then a nanoflow HPLC. Two pooled male and female standard urine samples were compared on these systems. Both techniques had similar results in terms of number of peptides detected and the mass range the peptides were detected over. The major differences in terms of biomarker research were the ability in CE to calibrate the migration time of the peptides to allow comparison between samples. In addition, CE was shown not to suffer from carry over from previous samples as was seen in the LC analysis. PMID- 22451050 TI - In-depth performance investigation of a nano-LC gradient generator. AB - An innovative approach for nano-liquid chromatography (LC) gradient generation is presented. This system represents an optimized and refined version of a prototype proposed by the authors a few years ago: the current version is characterized by a new configuration that guarantees complete automation and easier operation. The core of the system is an electronically controlled, multiposition valve that hosts six loops, filled with different mobile phase compositions of increasing strength. A conventional flow rate of water is reduced at nano-scale through a split device to push the content of the on-line loop into the column. No mixing occurs between solvents inside the loops, due to the low flow rate and the reduced loop diameter. Valve actuation allows the selection of the on-line loop to obtain the solvent gradient. The evaluation of the system performance takes into account gradient accuracy, precision, delay time, shape (linear, convex, or concave), and organic solvent consumption. Results highlight the reliability and the competitiveness of the system, especially in terms of accuracy and precision. A comparison between the described system and a conventional split-based one demonstrates that the new approach reduces the solvent consumption by about 40 times, improving green chromatography and cutting laboratory costs. PMID- 22451051 TI - Implementation of a design of experiments to study the influence of the background electrolyte on separation and detection in non-aqueous capillary electrophoresis-mass spectrometry. AB - Non-aqueous capillary electrophoresis (NACE) background electrolytes are most often composed of a mixture of methanol and acetonitrile (ACN) with soluble ammonium salts added as electrolyte. In this study on NACE-MS, we used a mixture of glacial acetic acid and ACN giving rise to an acidic background electrolyte (BGE) with a very low dielectric constant. Impressive changes in selectivity and resolution were observed for structurally closely related indole alkaloids including diastereomers upon addition of ammonium formate as electrolyte and upon variation of the solvent ratio. In order to obtain best separation and MS detection conditions and to reveal the influence of the parameters of the BGE on separation and detection and vice versa of the MS parameters on separation, an optimization strategy was employed using a design of experiments in a central composite design with response surface methodology. It was proven that at high electroosmotic flow conditions capillary electrophoretic separations and thus optimization can be realized without interference from the coupling to an MS system. Several significantly interacting parameters were revealed, which are not accessible with classical univariate optimization approaches. With this optimization, alkaloid mixtures from a plant extract of Mitragyna speciosa, containing a large number of diastereomeric compounds were successfully separated. PMID- 22451052 TI - Analysis of drugs of forensic interest with capillary zone electrophoresis/time of-flight mass spectrometry based on the use of non-volatile buffers. AB - The present work is aimed at investigating the influence of the background electrolyte composition and concentration on the separation efficiency and resolution and mass spectrometric detection of illicit drugs in a capillary zone electrophoresis-electrospray ionization-time of flight mass spectrometry (CZE-ESI TOF MS) system. The effect of phosphate, borate and Tris buffers on the separation and mass spectrometry response of a mixture of 3,4 methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, methadone, cocaine, morphine, codeine and 6-monoacetylmorphine was studied, in comparison with a reference ammonium formate separation buffer. Inorganic non-volatile borate and Tris buffers proved hardly suitable for capillary electrophoresis-mass spectrometry (CE-MS) analysis, but quite unexpectedly ammonium phosphate buffers showed good separation and ionization performances for all the analytes tested. Applications of this method to real samples of hair from drug addicts are also provided. PMID- 22451053 TI - Capillary electrophoresis coupled to electrospray mass spectrometry through a coaxial sheath flow interface and semi-permanent phospholipid coating for the determination of oligosaccharides labeled with 1-aminopyrene-3,6,8-trisulfonic acid. AB - For the first time, a semi-permanent phospholipid coating is utilized in capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS). Although phospholipids in free solution are generally avoided in ESI, they did not interfere with the detection of linear and branched oligosaccharides using ESI operated in negative mode. The CE and ESI were coupled using a coaxial sheath flow interface. The separation was operated in reversed polarity and the electroosmotic flow was effectively suppressed by the phospholipid coating. The method was characterized with linear oligosaccharides and used to monitor the enzymatic hydrolysis of maltooligosaccharides with alpha-amyloglucosidase. Branched oligosaccharides were separated and detected with the system. The enzyme beta1-4 galactosidase was used to distinguish branched isomeric oligosaccharides derived from asialofetuin. PMID- 22451054 TI - An optimized electrochemistry-liquid chromatography-mass spectrometry method for studying guanosine oxidation. AB - Oxidative stress can disrupt the integrity of genetic material. Due to its importance in the pathogenesis of different kinds of disease, including neurodegenerative disease, cardiovascular disease and cancer, major efforts are put into the elucidation of mechanisms involved. Herein, the combination of electrochemistry/liquid chromatography/mass spectrometry (EC/LC/MS) is presented as convenient, fast and simple method to study nucleic acids oxidation. Guanosine was selected as test compound. 8-Hydroxyguanosine and (guanosine-H)(2) were identified as primary oxidation products. Oxidation was accomplished in an electrochemical thin-layer cell integrated in the flow path of the autosampler of the chromatographic system. The reaction mixture was separated and mass analyzed by LC/MS. The use of LC was found to be particularly beneficial to resolve isobaric oxidation products. Another advantage of the setup used was the ability to decouple the electrochemical cell and the electrospray ionization source from each other eliminating any kind of cell potential interaction. Separation of EC from LC/MS, furthermore, facilitates method optimization. Experimental parameters were optimized for both techniques independently. Highest yields and best detectability of oxidation products were obtained with 10 mM ammonium formate at physiological pH delivered at a flow rate of 2.5-5 MUL/min through the electrochemical cell. PMID- 22451055 TI - Capillary electrophoretic methods in the development of metal-based therapeutics and diagnostics: new methodology and applications. AB - In recent years, capillary electrophoresis (CE) has matured to a standard method in medicinal inorganic chemistry. More and more steps of the drug discovery process are followed by CE. However, not only the number of applications has steadily increased but also the variety of used methodology has significantly broadened and, as compared to a few years ago, a wider scope of separation modes and hyphenated systems has been used. Herein, a summary of the newly utilized CE methods and their applications in metallodrug research in the timeframe 2006-2011 is presented, following related reviews from 2003 and 2007 (Electrophoresis, 2003, 24, 2023-2037; Electrophoresis 2007, 28, 3436-3446). Areas covered include impurity profiling, quality control of pharmaceutical formulations, lipophilicity estimation, interactions between metallodrugs and proteins or nucleotides, and characterization and also quantification of metabolites in biological matrices and real-world samples. PMID- 22451056 TI - Microfluidic chip-based liquid chromatography coupled to mass spectrometry for determination of small molecules in bioanalytical applications. AB - The development and integration of microfabricated liquid chromatography (LC) microchips have increased dramatically in the last decade due to the needs of enhanced sensitivity and rapid analysis as well as the rising concern on reducing environmental impacts of chemicals used in various types of chemical and biochemical analyses. Recent development of microfluidic chip-based LC mass spectrometry (chip-based LC-MS) has played an important role in proteomic research for high throughput analysis. To date, the use of chip-based LC-MS for determination of small molecules, such as biomarkers, active pharmaceutical ingredients (APIs), and drugs of abuse and their metabolites, in clinical and pharmaceutical applications has not been thoroughly investigated. This mini review summarizes the utilization of commercial chip-based LC-MS systems for determination of small molecules in bioanalytical applications, including drug metabolites and disease/tumor-associated biomarkers in clinical samples as well as adsorption, distribution, metabolism, and excretion studies of APIs in drug discovery and development. The different types of commercial chip-based interfaces for LC-MS analysis are discussed first and followed by applications of chip-based LC-MS on biological samples as well as the comparison with other LC-MS techniques. PMID- 22451057 TI - Development of a capillary electrophoresis-mass spectrometry method for the determination of rivastigmine in human plasma--optimization of the limits of detection and quantitation. AB - A capillary zone electrophoresis-electrospray ionization-mass spectrometry (CZE ESI-MS) method was developed for the analysis of the acetylcholinesterase inhibitor rivastigmine. Several electrophoretic and ESI-MS parameters were investigated in order to improve sensitivity. These parameters were categorized in three areas: (i) background electrolyte (BGE) parameters, (ii) sheath liquid parameters, and (iii) spray chamber parameters. The optimized results were obtained by using 40-mM ammonium acetate at pH 9 as BGE, a sheath liquid of 1% acetic acid in water:MeOH (50:50 v/v) at a flow rate of 10 MUL/min, and a drying gas flow rate that was set at 6 L/min and at a temperature of 200 degrees C. These parameters provided limit of detection and limit of quantitation of 2.8 ng/mL and 8.4 ng/mL, respectively. The optimal CZE-ESI-MS conditions were applied to a plasma sample obtained from an Alzheimer's disease patient following rivastigmine patch administration, and the mean (+/-standard deviation) plasma concentration was estimated to be 14.6 (+/-1.7) ng/mL. Several sample preparation procedures were examined, and solid-phase extraction using a C18 cartridge proved to be the most effective procedure, since higher sensitivity and recovery were obtained. In addition, precision was evaluated based on migration time and peak area in plasma, and the relative standard deviations were in the range of 0.10 0.16% and 0.62-9.0%, respectively. PMID- 22451058 TI - Simultaneous analysis of cocaine and its metabolites in urine by capillary electrophoresis-electrospray mass spectrometry using a pressurized liquid junction nanoflow interface. AB - A new method for the simultaneous separation of cocaine and four metabolites in urine by CE-ESI-MS via a pressurized nanoliquid junction interface was developed. The resolution of cocaine, cocaethylene, benzoylecgonine, norcocaine, and ecgonine methyl ester was achieved in a polyvinyl-alcohol-coated capillary with 75 MUm id * 50 cm total length, using a 15 mM ammonium formate electrolyte solution (pH 9.5) in less than 15 min. In addition, to enhance sensitivity, a field-amplified sample injection (FASI) was evaluated in terms of injection time and sample solvent composition. The limits of detection achieved with the FASI method ranged from 1.5 to 10 ng/mL for all the compounds. The detection of the studied compounds was performed using an ion-trap mass spectrometer in a positive ionization mode. A mixture of methanol:water (80:20 v/v) containing 0.1% v/v of formic acid was employed as spray liquid and delivered at ~200 nL/min. Under optimal CE-MS conditions, linearity was assessed in the concentration range of interest for all analytes with correlation coefficients r2 >= 0.9913. Intra- and inter-day precision provided a relative standard deviation lower than 1.54% for migration times and lower than 12.15% for peak areas. Finally, urine samples, spiked with the standard mixture, were extracted using a solid-phase extraction procedure and injected under FASI conditions, providing recoveries from 80% to 94% for all analytes. PMID- 22451059 TI - Poly(glycidyl methacrylate-divinylbenzene) based immobilized pH gradient capillary isoelectric focusing coupling with MALDI mass spectrometry for enhanced neuropeptide analysis. AB - Herein, we report an immobilized pH gradient (IPG) capillary isoelectric focusing matrix-assisted laser desorption/ionization mass spectrometry (CIEF-MALDI MS) platform designed for the separation of complex neuropeptides. This platform features a poly(glycidyl methacrylate-divinylbenzene) (GMA-DVB)-based monolithic column for CIEF separation. Different from regular CIEF, carrier ampholytes are preimmobilized on the monolithic surface instead of being added to the sample. An off-line coupling of IPG-CIEF to MALDI MS has been established. Comparison with regular CIEF and optimizations are performed with bovine serum albumin tryptic peptides and extracted neuropeptide mixtures from crustacean Callinectes sapidus. It has been demonstrated that the separation of complex peptide mixtures in neutral and basic pH ranges can be achieved in less than 10 min with comparable separation efficiency with regular CIEF, while the MS signal is significantly enhanced when employing IPG-CIEF. Enhanced neuropeptide detection is also observed after coupling IPG-CIEF with MALDI MS. PMID- 22451060 TI - A neurosteroid analogue photolabeling reagent labels the colchicine-binding site on tubulin: a mass spectrometric analysis. AB - Previous studies have shown that the neurosteroid analogue, 6-Azi-pregnanolone (6 AziP), photolabels voltage-dependent anion channels and proteins of approximately 55 kDa in rat brain membranes. The present study used two-dimensional electrophoresis and nanoelectrospray ionization ion-trap mass spectrometry (nano ESI-MS) to identify the 55 kDa proteins (isoelectric point 4.8) as isoforms of beta-tubulin. This identification was confirmed by immunoblot and immunoprecipitation of photolabeled protein with anti-beta-tubulin antibody and by the demonstration that 6-AziP photolabels purified bovine brain tubulin in a concentration-dependent pattern. To identify the photolabeling sites, purified bovine brain tubulin was photolabeled with 6-AziP, digested with trypsin, and analyzed by matrix-assisted laser desorption/ionization MS (MALDI). A 6-AziP adduct of TAVCDIPPR(m/z = 1287.77), a beta-tubulin specific peptide, was detected by MALDI. High-resolution liquid chromatography-MS/MS analysis identified that 6 AziP was covalently bound to cysteine 354 (Cys-354), previously identified as a colchicine-binding site. 6-AziP photolabeling was inhibited by 2 methoxyestradiol, an endogenous derivative of estradiol thought to bind to the colchicine site. Structural modeling predicted that neurosteroids could dock in this colchicine site at the interface between alpha- and beta-tubulin with the photolabeling group of 6-AziP positioned proximate to Cys-354. PMID- 22451061 TI - Comparative proteomic profiling of human lung adenocarcinoma cells (CL 1-0) expressing miR-372. AB - Lung cancer is a common malignancy and has a poor overall prognosis. Widespread metastasis is a common phenomenon in non-small cell lung cancer (NSCLC). It has been demonstrated that cancer relapse and survival can be predicted by the presence of a five-microRNA (miRNA) signature independent of stage or histologic type in NSCLC patients. Among the five miRNAs in the signature, miR-372 has been shown to play a significant role in metastasis and in the development of human testicular germ cell tumors. In addition, there is evidence that miR-372 posttranscriptionally downregulates large tumor suppressor, homolog 2 (Lats2), resulting in tumorigenesis and proliferation. To further investigate the cellular mechanisms involved in miR-372-induced silencing, we conducted a comparative proteomic analysis of NSCLC CL 1-0 cells expressing miRNA-372 and/or vector only by using two-dimensional gel electrophoresis (2DE), two-dimensional difference gel electrophoresis (2D-DIGE), and LC/MS/MS. Proteins identified as being up- or downregulated were further classified according to their biological functions. Many of the proteins identified in our study may be potential diagnostic biomarkers of NSCLC, particularly phosphorylated eIF4A-I. PMID- 22451062 TI - A hyphenated microLC-Q-TOF-MS platform for exosomal lipidomics investigations: application to RCC urinary exosomes. AB - Urinary exosomes are released from every renal epithelial cell type facing the urinary space and therefore, they may carry molecular markers of renal dysfunction and structural injury. Here, we present a hyphenated microLC-Q-TOF-MS platform for lipidomics studies applied to investigate the urinary exosome lipid repertoire. Lipids were separated by reversed-phase chromatography using a linear gradient of formic acid 0.2% and tetrahydrofuran, in 40 min of analysis. Features (m/z with associated own retention time) were extracted by MarkerLynx(TM) (Waters) and processed, demonstrating good analytical performance in terms of repeatability and mass accuracy of the microLC Q-TOF MS platform. In particular, a stable retention time (RSD less than 4%) and relative intensity (RSD from 2.9% to 11%) were observed. Moreover, the method takes advantages by the use of a lock spray interface (Waters) that allows readjusting the m/z data after acquisition, obtaining inaccuracy below 6 ppm in measuring the m/z value of the reference compound during chromatographic run. The method was employed in a preliminary application to perform comparative analysis from healthy control subjects and renal cell carcinoma (RCC) patients, in order to possibly highlight differences in lipid composition to be exploited as potential tumor biomarker. Differential lipid composition in RCC urinary exosomes was achieved and tentatively identified by accurate mass, providing a preliminary indication of a relationship between lipid composition of urinary exosomes and RCC disease. Among the total features significantly different in RCC exosomes, the ion at m/z 502.3 was taken as an example for molecular confirmation by MS/MS fragmentation analysis. PMID- 22451063 TI - A simple and robust LC-MS/MS method for quantification of free 3-nitrotyrosine in human plasma from patients receiving on-pump CABG surgery. AB - We have developed a simple, sensitive, and robust liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to determine free 3 nitrotyrosine concentrations in human plasma of patients receiving on-pump coronary artery bypass grafting surgery. A one-step solid-phase extraction protocol was optimized to enrich the analyte at low nanomolar concentrations. The processed samples were analyzed by LC-MS/MS with a 2.1 * 100 mm Kinetex PFP column and a triple quadrupole mass spectrometer. The method was validated for 3 nitrotyrosine concentrations close to real patient plasma levels. The relative standard deviations or relative errors of the intraday and interday determinations were all within 10%. Limit of detection and limit of quantitation were determined to be 0.034 nM and 0.112 nM, respectively, while lower limit of quantitation was below 0.625 nM. No deterioration of the column performance was noticed after running a large number of patient samples. The results showed that the 3-nitrotyrosine concentrations in coronary sinus plasma samples were elevated after cardiopulmonary bypass (CPB) procedure. The pre-CPB and post-CPB concentrations of 3-nitrotyrosine in patient plasmas were 1.494 +/- 0.107 nM and 2.167 +/- 0.177 nM (mean +/- SEM), respectively. Application of this method to more patients in clinical studies may help validate 3-nitrotyrosine as a meaningful biomarker for nitrosative stress and link patient characteristics, clinical outcomes, and cardioprotective treatments to endogenous nitrosative stress levels. PMID- 22451064 TI - Sensitive and fast determination of Sudan dyes in chili powder by partial-filling micellar electrokinetic chromatography-tandem mass spectrometry. AB - A fast and sensitive method for the simultaneous determination of Sudan dyes (I, II, III, and IV) in food samples was developed for the first time using partial filling micellar electrokinectic chromatography-mass spectrometry (MEKC-MS). The use of MEKC was essential to achieve the separation of these neutral analytes, while the partial filling technique was necessary to avoid the contamination of the ion source with non-volatile micelles. MEKC separation and MS detection conditions were optimized in order to achieve a fast, efficient, and sensitive separation of the four dyes. Filling 25% of the capillary with an MEKC solution containing 40 mM ammonium bicarbonate, 25 mM SDS, and 32.5% (v/v) acetonitrile, a baseline separation of the four azo-dyes was obtained in 10 min. Tandem MS was investigated in order to improve the sensitivity and selectivity of the analysis. Limits of detection (LOD) values 5, 8, 15, and 29 times better were obtained for Sudan III, I, II, and IV, respectively, using partial filling MEKC-MS/MS instead of partial filling MEKC-MS. Under optimized conditions, LOD from 0.05 to 0.2 MUg/mL were obtained. The suitability of the developed method was demonstrated through the fast and sensitive determination of Sudan I, II, III, and IV in spiked chilli powder samples. This determination could not be achieved by MEKC-UV due to the existence of several interfering compounds from the matrix. PMID- 22451065 TI - Investigation of antibacterial phytochemicals in the bark and leaves of Ficus coronata by high-performance liquid chromatography-electrospray ionization-ion trap mass spectrometry (HPLC-ESI-MS(n) ) and ESI-MS(n). AB - The ethyl acetate extracts of the bark and leaves of Ficus coronata were separated by column chromatography and the resulting fractions tested for their bioactivity toward methicillin-resistant-Staphylococcus aureus (MRSA) and M. luteus. The bioactive column chromatography fractions were further separated by preparative thin layer chromatography (TLC) and the resulting bands investigated by high-performance liquid chromatography-electrospray ionization-ion trap mass spectrometry (HPLC-ESI-MS(n) ) and ESI-MS(n) . The resulting retention times, molecular masses, their fragmentation patterns, and the chemnet database (www.chemnetbase.com) were then used in the dereplication process by structural elucidation of some of the compounds when compared with known structures of natural origin. Some molecular masses and the corresponding fragmentations were found that did not correlate with any known compounds thus revealing potentially novel natural products that could be investigated on a larger scale and could ultimately find application as new drugs against MRSA and other multidrug resistant microorganisms. Structures are also proposed for known compounds that have not been previously reported for F. coronata. PMID- 22451066 TI - Simultaneous determination of components released from dental composite resins in human saliva by liquid chromatography/multiple-stage ion trap mass spectrometry. AB - Dental composite resins are widely used for fixing teeth; however, the monomers used in dental composite resins have been found to be cytotoxic and genotoxic, namely triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA), and bisphenol A glycol dimethacrylate (Bis-GMA). In this study, we incubated dental composite resins with human saliva for demonstrating the released monomers and biodegradation products. A simple saliva sample dilution method without purification or derivatization was used for quantification. We found that liquid chromatography coupled with multiple-stage ion trap mass spectrometry (LC-MS(n) ) operated in selected reaction monitoring (SRM) mode was able to separate the three monomers within 10 min. The calibration curves were linear (R2 >0.996) over a wide range for each monomer in saliva: TEGDMA, 5-500 ppb; UDMA, 5-100 ppb, and Bis-GMA, 5-700 ppb. Furthermore, several biodegradation products were discovered with data-dependent MS/MS scan techniques. Although TEGMA degradation products have previously been reported, we identified two previously unknown UDMA degradation products. The LC-MS/MS method developed in this study was able to successfully quantify monomers and their principal biodegradation products from dental composite resins in human saliva. PMID- 22451067 TI - Analysis of iron-phytosiderophore complexes in soil related samples: LC-ESI-MS/MS versus CE-MS. AB - Phytosiderophores (PS) form stable complexes with various transition metals. These ligands are exuded by the roots of graminacous plants as a mechanism for mobilizing and acquiring soil iron. To investigate iron mobilization and transport, a novel LC method in combination with ESI-MS/MS for the determination of three Fe(III)-complexes with mugineic acid (MA), 2'-epi-MA and 2' deoxymugineic acid (DMA) has been developed. Liquid chromatographic separation was realized using a silica-based mixed-mode reversed phase/weak-anion exchange type stationary phase and a 50 mM ammonium acetate buffer, pH 6.5. Baseline separation of the two complex diastereomers Fe(III)-MA and Fe(III)-epi-MA could be achieved. ESI-MS/MS detection allowed for simultaneous quantification of the complexes and the free ligands. Limits of detection were determined to be 0.001 and 0.05 MUM for DMA and Fe(III)-DMA, respectively. The analytical figures of merit of the novel method were evaluated and compared with a CE-ESI-MS method that we had published earlier. The LC-ESI-MS/MS method has been successfully applied to real samples derived from preliminary extraction experiments. PMID- 22451068 TI - CE-ESI-MS separation of divalent organic and inorganic anions using a tricationic complexing reagent. AB - A tricationic ion-pairing reagent, 1,3,5-1-butyl-3-methyl-1H-imidazol-3-ium-2,4,6 trimethylbenzene, was used to form complexes with doubly charged anions for their subsequent analysis by capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS) in the positive-ion mode. This methodology offers the advantages of greater versatility and sensitivity relative to direct detection of the anions in negative-ion mode, and it can be realized by a number of possible complexation strategies, including pre-column, on-column, and post-column modes. Three model anions, sulfate [SO42-], thiosulfate [TSFA, S2O32-], and benzenedisulfonate [BZDS, C6H4(SO3)22-], were amenable to complexation with the tricationic reagent, yielding singly charged cations with greater mass-to-charge (m/z) ratios than the native analytes. By utilizing optimized parameters obtained through previous work with dicationic reagents and singly charged anions, including the CE separation buffer composition and pH, the concentration of the dicationic reagent, the mode of complexation, the nebulizing gas pressure, and the sheath liquid composition, it was possible to develop a robust CE-ESI-MS method appropriate for the analysis of divalent anions in a mixture. PMID- 22451071 TI - Early hearing detection and intervention: parent experiences with the diagnostic hearing assessment. AB - PURPOSE: The aim of this study was to investigate parent experiences with the infant diagnostic hearing evaluation process. METHOD: This study used a cross sectional survey design. Surveys were distributed via parent support organizations in December 2009 to parents of children with hearing loss. A total of 416 completed surveys were received from 43 states. RESULTS: The median age of diagnosis of hearing loss has decreased over time from 11 months of age to 2 months. For babies born between 2006 and 2009, the most frequently reported challenge to obtaining a diagnostic hearing evaluation by 3 months of age was a delay in appointment availability (36%). Just >¼ (27%) of parents reported that they did not feel comfortable in knowing what they needed to do next after talking with the audiologist at the time their child was diagnosed with hearing loss. CONCLUSION: Significant progress has been made over the past 2 decades in reducing the age of hearing loss identification. However, many parents in this study experienced challenges that resulted in delays that exceeded Joint Committee on Infant Hearing (2007) recommendations of diagnosis by 3 months of age. The parent-reported experiences provide valuable information about areas that need further investigation to improve the early hearing detection and intervention process for children with hearing loss. PMID- 22451072 TI - Chemoselective reduction of nitrobenzenes to aminobenzenes having reducible groups by a titanium(IV) oxide photocatalyst under gas- and metal-free conditions. AB - m-Nitrovinylbenzene was chemoselectively reduced to m-aminovinylbenzene in a suspension of a TiO(2) photocatalyst in the presence of a hole scavenger at room temperature under atmospheric pressure without the use of a precious metal or reducing gas, and nitrobenzenes having other reducible groups were also chemoselectively reduced to corresponding aminobenzenes. PMID- 22451073 TI - Age- and gender-dependent values of skeletal muscle mass in healthy children and adolescents. AB - BACKGROUND: Skeletal muscle mass (SMM) can be extracted from whole-body scans obtained by X-ray-based dual-photon absorptiometry (DXA). There is a need to establish expected age-dependent values for children and adolescents. METHODS: Appendicular lean tissue mass (ALM) was extracted from whole-body DXA scans in 140 healthy children and adolescents (68 females and 72 males). Whole-body SMM was calculated from ALM using equations developed by Kim et al. (Am J Clin Nutr 84:1014-1020, 2006). Age-dependent patterns of increase in SMM were derived by fitting SMM values to equations that consisted of the sum of two logistic expressions, one accounting for SMM changes during growth and the other for SMM changes during puberty. Normal ranges were defined so that 95% of the SMM values were included. The reproducibility of SMM measurements was obtained from whole body DXA scans repeated on three occasions in each of a separate group of 32 normal children with repositioning between scans. RESULTS: Normal ranges are presented as equations describing the age-dependent pattern of increase in SMM as well as population standard deviations that increased steadily with age. For 15 children below age 10, SMM reproducibility (95% CI) was 149 g (119-199 g) while for 17 children and adolescents over age 10, reproducibility was 170 g (138-223 g). CONCLUSION: DXA-based measurements of SMM in children and adolescents are reproducible and can be expressed in terms of age-dependent Z scores. PMID- 22451074 TI - Preparation and confinement effect of a heterogeneous 9-amino-9-deoxy-epi cinchonidine organocatalyst for asymmetric aldol addition in aqueous medium. AB - A series of novel porous zirconium phosphonate-supported 9-amino-9-deoxy-epi cinchonidines of general formulae Zr(OH)(4-2x)(O(3)PR)(x).nH(2)O and Zr(HPO(4))(2 x)(O(3)PR)(x).nH(2)O with the different arm chain lengths (n = 2-6) and mean diameters of approximately 20-40 nm have been prepared as heterogeneous organocatalysts. The different microtextures of zirconium phosphonates were also obtained by using template guest molecules, such as Et(3)N, NaH(2)PO(4) and sodium dodecyl benzene sulfonate. In the heterogeneous asymmetric aldol addition of p-nitrobenzaldehyde to cyclohexanone, excellent catalytic properties were achieved, especially in an aqueous medium. After completing the reaction, those zirconium phosphonate-supported 9-amino-9-deoxy-epi-cinchonidine organocatalysts could be readily recovered in quantitative yield by centrifugation or filtration, and reused for five consecutive runs without significant loss in catalytic performance. In particular, due to the steric confinement effect of the inorganic backbone, the single different configuration among possible four stereo-isomers in aldol adducts were favorably obtained, respectively depending on the interaction between the o-, m- or p-position of nitrobenzaldehyde and the backbone, which was never observed in homogeneous aldol addition. PMID- 22451075 TI - Increasing batch-to-batch reproducibility of CHO-cell cultures using a model predictive control approach. AB - By means of a model predictive control strategy it was possible to ensure a high batch-to-batch reproducibility in animal cell (CHO-cell) suspensions cultured for a recombinant therapeutic protein (EPO) production. The general control objective was derived by identifying an optimal specific growth rate taking productivity, protein quality and process controllability into account. This goal was approached indirectly by controlling the oxygen mass consumed by the cells which is related to specific biomass growth rate and cell concentration profile by manipulating the glutamine feed rate. Process knowledge represented by a classical model was incorporated into the model predictive control algorithm. The controller was employed in several cultivation experiments. During these cultivations, the model parameters were adapted after each sampling event to cope with changes in the process' dynamics. The ability to predict the state variables, particularly for the oxygen consumption, led to only moderate changes in the desired optimal operational trajectories. Hence, nearly identical oxygen consumption profiles, cell and protein titers as well as sialylation patterns were obtained for all cultivation runs. PMID- 22451076 TI - Advanced microscale bioreactor system: a representative scale-down model for bench-top bioreactors. AB - In recent years, several automated scale-down bioreactor systems have been developed to increase efficiency in cell culture process development. ambrTM is an automated workstation that provides individual monitoring and control of culture dissolved oxygen and pH in single-use, stirred-tank bioreactors at a working volume of 10-15 mL. To evaluate the ambrTM system, we compared the performance of four recombinant Chinese hamster ovary cell lines in a fed-batch process in parallel ambrTM, 2-L bench-top bioreactors, and shake flasks. Cultures in ambrTM matched 2-L bioreactors in controlling the environment (temperature, dissolved oxygen, and pH) and in culture performance (growth, viability, glucose, lactate, Na(+), osmolality, titer, and product quality). However, cultures in shake flasks did not show comparable performance to the ambrTM and 2-L bioreactors. PMID- 22451077 TI - Formation of aerobic granules by Mg2+ and Al3+ augmentation in sequencing batch airlift reactor at low temperature. AB - Aerobic granules technology (AGS) was difficult to cultivate at low temperature, and the treatment efficiency of domestic sewage was remarkably low because of low temperature, which greatly limits its development and application. AGS formation time significantly decreased for 43 days by adding 19.0 mg/L Mg(2+) and 21.0 mg/L Al(3+), moreover, AGS possessed better simultaneously chemical oxygen demand, NH(4) (+)-N, TP removal efficiencies at low temperature, which the respective removal efficiencies were 85.6, 88.8, and 91.9%. The content of total polysaccharides was 8.23 mg/gMLSS as well as the content of total protein was 8.52 mg/gMLSS, consequently, the total proteins/total polysaccharides ratio was 1.04, which the relatively high protein content induced by Mg(2+) and Al(3+) presented an essential feature for AGS formation. In addition, the affinity among Mg(2+), Al(3+) and -OH may drive the stretching vibration of -OH band which led to the infrared motion of functional groups in AGS and accelerate AGS formation as well. PMID- 22451078 TI - Comparison of various pretreatment methods for biohydrogen production from cornstalk. AB - To establish high-efficiency pretreatments of cornstalk (CS) for hydrogen fermentative production, various pretreatment strategies have been investigated and contrasted in this work. Five pretreatment methods, including acid-soaking pretreatment, base-soaking pretreatment, high-temperature-assisted acid pretreatment, high-temperature-assisted base pretreatment and ultrasonic-assisted acid pretreatment (UAP), were performed on CS. The results showed that UAP significantly promoted the hydrogen production by CS compared with other pretreatments. The optimum UAP process, pretreating substrate with ultrasonication in 2.0% sulfuric acid solution for 1.5 h at the liquid-solid ratio of 20:1, obtained the maximum specific hydrogen accumulation of 142.59 mL g(-1)-CS and an average hydrogen production rate of 17.03 mL g(-1)-CS h(-1). Furthermore, the scanning electron microscope analysis of CS samples supports the hydrogen production results as well. The present work demonstrates that UAP is an efficient and practical CS pretreatment for hydrogen production from agricultural waste straws. PMID- 22451079 TI - Utilization of Jatropha deoiled seed cake for production of cellulases under solid-state fermentation. AB - Toxic waste generated by Jatropha seed cake after utilization of biodiesel on one hand has stimulated the need to develop new technologies to treat the waste and on the other, forced us to reevaluate the efficient utilization of its nutritive potential for production of various high-value compounds and its conversion to non-toxic forms which could be used as animal feed stock. In this study, Jatropha seed cake was used for production of cellulases by new isolate of Thermoascus aurantiacus under solid-state fermentation. The interaction of nitrogen source concentration, moisture ratio, initial pH of the medium and inoculum size was investigated and modelled using response surface methodology (RSM) using Box Behnken Design (BBD). Under optimized conditions endo-beta-1,4-glucanase, beta glucosidase and filter paper activities were found to be 124.44, 28.86, 4.87 U/g of substrate, respectively. Characterization of endo-beta-1,4-glucanase, beta glucosidase was done after partial purification by ammonium sulfate fractionation followed by desalting. The endo-beta-1,4-glucanase and beta-glucosidase showed maximum activity at 70 degrees C and pH 4. Saccharification studies performed with different lignocellulosic substrates showed that sugar cane bagasse was most susceptible to enzymatic hydrolysis. The study suggests that Jatropha seed cake can be used as a viable nutrient source for cellulase production without any pretreatment under solid-state fermentation by T. aurantiacus. PMID- 22451080 TI - Cross-linking of horseradish peroxidase adsorbed on polycationic films: utilization for direct dye degradation. AB - Horseradish peroxidase (HRP) was immobilized on the polyaniline (PANI) grafted polyacrylonitrile (PAN) films. The maximum HRP immobilization capacity of the PAN g-PANI-3 film was 221 MUg/cm(2). The HRP-immobilized PAN-g-PANI-3 film retained 79 % of the activity of the same quantity free enzyme. The HRP-immobilized PAN-g PANI-3 film was operated for the decolorization of two different benzidine-based dyes in the presence of hydrogen peroxide. The maximum decolorization grade was obtained at pH 6.0 for both dyes. The HRP-immobilized PAN-g-PANI-3 film was very effective for removal of Direct Blue-53 compared to Direct Black-38 from aqueous solutions. The immobilized HRP exhibited high resistance to proteolysis by trypsin compared to the free counterpart. Immobilized HRP preserved 83 % of its original activity even after 8 weeks of storage at 4 degrees C, while the free enzyme lost its initial activity after 3 weeks of storage period. PMID- 22451081 TI - Optimization of process parameters by response surface methodology and kinetic modeling for batch production of canthaxanthin by Dietzia maris NIT-D (accession number: HM151403). AB - Dietzia maris NIT-D, a canthaxanthin producer, was isolated during routine screening of pigment-producing bacteria. Response surface methodology was applied for statistical designing of process parameters for biomass and canthaxanthin production. The effects of four process parameters (considered as independent variables), namely temperature (10-30 degrees C), pH (4.75-5.75), shaker speed (75-135 rpm) and percentage inoculum (0.5-2.5 %) on the biomass and canthaxanthin yield (considered as dependent variables) were studied. As much as 122 mg L(-1) of canthaxanthin was obtained when Dietzia maris NIT-D was incubated for 120 h at 25 degrees C and 120 rpm, initial pH and percentage inoculum being 5.5 and 2 % respectively. The pigment yield is the highest reported till date, with Dietzia maris as the test organism. The maximum biomass yield was 7.39 g L(-1) under optimized process parameters. The predicted values were also verified by validation experiments in 5-day fermentation. Different mathematical models were used to describe growth and production, considering the effect of glucose in batch mode. The kinetic constants were calculated by fitting the experimental data to the models. Cell growth was inhibited beyond a glucose concentration of 15 g L(-1). Andrews' model gave the best fit with a R (2) value of 0.9993. During the exponential growth phase, the specific growth rate was found to remain fairly constant with respect to time. There was no inhibitory effect due to intracellular product accumulation for all concentrations of glucose. This observation is the first of its kind, as previous studies have reported that increasing accumulation of intracellular carotenoid exerts greater degree of inhibition on growth. PMID- 22451082 TI - Development and validation of a measurement tool to assess perceptions of palliative care. AB - OBJECTIVES: Understanding patient's perceptions about palliative care is necessary to make an effective referral. The aim was to develop and validate a measure of patient perceptions. METHODS: Items were generated through patient, family caregiver and health professional interviews. The Perceptions of Palliative Care Instrument (PPCI) was administered to 85 patients with advanced cancer (AC). A subset (n = 39) completed it 7 days later. Participants also completed the Palliative Care Outcome Scale (POS), the Edmonton Symptom Assessment Scale (ESAS) and the Distress Thermometer (DT) for validation purposes. RESULTS: Factor analysis revealed four domains (positive and negative emotional and cognitive reactions to palliative care, emotional and practical palliative care needs and perceptions of health) and eight subscales with factor loadings for all items above 0.51, explaining 61-81% of the total variance. Reliability analyses revealed high internal consistency (Cronbach's alpha coefficients >0.76). Intraclass correlation coefficients showed moderate to strong correlations between time points indicating stability over time. All POS items correlated with two or more dimensions of the PPCI (all r > 0.30); ESAS total distress correlated positively with the palliative care needs domain and the DT with needs and perceived burden (all r > 0.30). CONCLUSIONS: The PPCI is a four-factor, 37-item measure that assesses perceptions of palliative care held by patients with AC. The measure has good internal consistency, test-retest reliability and convergent validity. PMID- 22451084 TI - [Newborn screening as a predictive genetic test: principles and challenges]. AB - Universal newborn screening for a range of mostly inherited metabolic and endocrine disorders, started in mid-1960ies, is a success story of preventive medicine. New technological advances particularly in the last 10-15 years have led to an expansion of newborn screening in many countries. This has allowed introduction of sometimes life-saving preventive measures in more children, but it has also become more obvious that screening may not be prudent for all conditions in which it is technically feasible. The present article provides criteria that have been used or discussed for the inclusion of "new" disorders in newborn screening programs, and highlights exemplary metabolic disorders that illustrate imminent challenges. In order to secure long-term acceptance of universal newborn screening within the society, its aims and contents should be determined through a transparent decision finding process. This may best be achieved through the establishment of a representative newborn screening advisory board. PMID- 22451085 TI - [Does the duration of confinement of criminally responsible mentally disordered offenders (S 21/2 StGB) play a role in the development of a functional psychosyndrome? - A pupillometric investigation]. AB - BACKGROUND: Pupillometry is a non-invasive investigation based on the concept that pupillary reagibility depends on a number of specific sensory, mental and emotional variables. By means of the receptor test based on the topical application of the cholinergic antagonist tropicamide cognitive deficits can be evaluated. The present study focuses on the question whether the receptor test is able to differentiate criminally responsible mentally disordered offenders (S 21/2 StGB) with different durations of confinement concerning the presence of a functional psychosyndrome, as defined by Grunberger. METHODS: Four groups of offenders with different durations of confinement (group A: confinement 0-2 years, n = 26, X = 33; group B: 2-5 years, n = 29, X = 34; group C: 5-10 years, n = 6, X = 36; group D: >10 years, n = 10, X = 43) were investigated by means of a computer-assisted TV pupillometer. After a baseline measurement 0.01% tropicamide was instilled into the eye. The second measurement was conducted 20 min after the first, the 3rd and 4th measurements in intervals of 20 min. RESULTS: The groups with a longer duration of confinement showed a reduced activation and vigilance and increased fatigability as compared with the groups of shorter confinement. In the receptor test the group that had been imprisoned for 0-2 years showed more cognitive deficits than those imprisoned for >=5 years. CONCLUSIONS: Evaluation of activation, fatigability and vigilance indicates that the duration of confinement plays a role in the development of a functional psychosyndrome. The results of the receptor test, in which the group with a longer duration of confinement showed less pronounced cognitive deficits and no significant changes of the tropicamide effect over time, suggest that in this group a dose change might be required to make the cognitive deficits evident. PMID- 22451087 TI - Effects of maternal separation and methamphetamine exposure on protein expression in the nucleus accumbens shell and core. AB - Early life adversity has been suggested to predispose an individual to later drug abuse. The core and shell sub-regions of the nucleus accumbens are differentially affected by both stressors and methamphetamine. This study aimed to characterize and quantify methamphetamine-induced protein expression in the shell and core of the nucleus accumbens in animals exposed to maternal separation during early development. Isobaric tagging (iTRAQ) which enables simultaneous identification and quantification of peptides with tandem mass spectrometry (MS/MS) was used. We found that maternal separation altered more proteins involved in structure and redox regulation in the shell than in the core of the nucleus accumbens, and that maternal separation and methamphetamine had differential effects on signaling proteins in the shell and core. Compared to maternal separation or methamphetamine alone, the maternal separation/methamphetamine combination altered more proteins involved in energy metabolism, redox regulatory processes and neurotrophic proteins. Methamphetamine treatment of rats subjected to maternal separation caused a reduction of cytoskeletal proteins in the shell and altered cytoskeletal, signaling, energy metabolism and redox proteins in the core. Comparison of maternal separation/methamphetamine to methamphetamine alone resulted in decreased cytoskeletal proteins in both the shell and core and increased neurotrophic proteins in the core. This study confirms that both early life stress and methamphetamine differentially affect the shell and core of the nucleus accumbens and demonstrates that the combination of early life adversity and later methamphetamine use results in more proteins being affected in the nucleus accumbens than either treatment alone. PMID- 22451088 TI - Primary flexor enthesopathy of the canine elbow: imaging and arthroscopic findings in eight dogs with discrete radiographic changes. AB - OBJECTIVE: To describe the radiographic, ultrasonographic, computed tomography (CT), magnetic resonance imaging (MRI), and arthroscopic findings in eight dogs with elbow lameness caused by primary flexor enthesopathy. STUDY DESIGN: Clinical study. ANIMALS: Eight client-owned dogs. METHODS: In all dogs, lameness was localized to the elbow by clinical examination. Radiographic examination, ultrasound, CT and MRI were performed prior to arthroscopy. In seven dogs, surgical treatment and subsequent histopathology were performed. RESULTS: Primary enthesopathy of the medial epicondyle was diagnosed in eight dogs (13 joints) by combining the minimal radiographic changes with specific ultrasonographic, CT, MRI and arthroscopic findings at the medial epicondyle. In all joints, any other pathology could be excluded. Histopathology of the affected tissue revealed degeneration and metaplasia in the flexor muscles. CONCLUSIONS: Primary flexor enthesopathy at the medial epicondyle is an unrecognized condition and is a possible cause of elbow lameness in the dog. Diagnosis is based on specific imaging and arthroscopic findings. CLINICAL RELEVANCE: The most important cause of elbow lameness in dogs is medial coronoid disease. Often this condition presents with minimal radiographic and arthroscopic changes. In these cases, primary enthesopathy of the medial epicondyle should be considered as a differential diagnosis, in order to make the correct treatment decision. PMID- 22451089 TI - Reference gene selection for qPCR in Ammopiptanthus mongolicus under abiotic stresses and expression analysis of seven ROS-scavenging enzyme genes. AB - Ammopiptanthus mongolicus, the only evergreen broadleaf shrub endemic to the northwest desert of China, is a valuable species for plant abiotic stress research. No report has so far described the selection of reference genes to get stringent normalization for qPCR in A. mongolicus. This work identified reliable reference genes for normalization of qPCR data in A. mongolicus under abiotic stresses from 14 reference gene candidates (UBQ, Tub1, Tub2, Abc1, Ubc1, Ubc2, Ubc4, Ubc5, eIF1, eIF2, eIF3, eIF4, EF1, EF2), and used the most suitable combination of reference genes to normalize the expression profiles of seven ROS scavenging enzyme genes (AmSOD, AmAPX, AmGPX, AmCAT, AmGLR, AmPrx, and AmTrx). We set a series of 22 experimental samples covering the control and different time points under cold, dry, salt, and heat stresses. According to geNorm and NormFinder, the combination of eIF1 and eIF3 was best for accurate normalization across all the treatments, confirmed by normalizing qPCR data with AmHsp90. In contrast, these data show that Tub1, Abc1, and EF1 are not suitable reference gene candidates. After being normalized against eIF1 and eIF3, the seven ROS scavenging enzyme genes exhibited differentially up- or down-regulated expression patterns. AmSOD and AmGPX were up-regulated by all four treatments, indicating that they may participate in an anti-oxidative mechanism under abiotic stresses in A. mongolicus. AmCAT exhibited a much higher expression level than AmAPX, AmPrx, and AmGPX, suggesting a principle role in detoxifying excessive H2O2. AmSOD, AmGPX and AmAPX showing the most abundant transcripts under heat, AmCAT and AmGLR under drought, and AmPrx under salt, were observed. Expression patterns of the seven ROS-scavenging enzyme genes suggest different antioxidant protection roles of these genes under abiotic stresses. These results are valuable for future research on gene expression and abiotic stress tolerance in A. mongolicus. PMID- 22451091 TI - Non-rigid calcium phosphate cement containing hydrogel microbeads and absorbable fibres seeded with umbilical cord stem cells for bone engineering. AB - The need for bone repair has increased as the population ages. Non-rigid calcium phosphate scaffolds could provide compliance for micro-motions within the tissues and yet have load-supporting strength. The objectives of this study were to: (a) develop a non-rigid calcium phosphate cement (CPC) with microbeads and fibre reinforcement; and (b) investigate human umbilical cord mesenchymal stem cell (hUCMSC) proliferation, osteodifferentiation and mineralization on non-rigid CPC for the first time. Non-rigid CPC was fabricated by adding extra tetracalcium phosphate in the traditional CPC and by incorporating chitosan, absorbable fibres and hydrogel microbeads. The non-rigid CPC-microbead scaffold possessed a strain at-failure of 10.7%, much higher than the traditional CPC's strain of 0.05% which is typical for brittle bioceramics. Flexural strength of non-rigid CPC-microbead was 4-fold that of rigid CPC-microbead scaffold, while work-of-fracture (toughness) was increased by 20-fold. The strength of non-rigid CPC-microbead fibre scaffold matched that of cancellous bone. hUCMSCs on non-rigid CPC proliferated from 100 cells/mm(2) at 1 day to 600 cells/mm(2) at 8 days. Alkaline phosphatase, osteocalcin and collagen gene expressions of hUCMSCs were greatly increased, and the cells synthesized bone minerals. hUCMSCs on non-rigid CPC microbead-fibre constructs had higher bone markers and more mineralization than those on rigid CPC controls. In conclusion, this study developed the first non rigid, in situ-setting calcium phosphate-microbead-fibre scaffold with a strain at-failure exceeding 10%. hUCMSCs showed excellent proliferation, osteodifferentiation and mineralization on non-rigid CPC scaffold. The novel non rigid CPC-hUCMSC construct with good strength, high strain-at-failure and toughness, as well as superior stem cell proliferation, osteodifferentiation and mineralization, is promising for load-bearing bone regeneration applications. PMID- 22451092 TI - Effects of diphenyl diselenide on depressive-like behavior in ovariectomized mice submitted to subchronic stress: involvement of the serotonergic system. AB - RATIONALE: The transition to menopause is associated with an increased risk of depressed mood. OBJECTIVES: This study was conducted to investigate whether diphenyl diselenide [(PhSe)2] treatment could reduce the effects of postmenopausal depression-like behavior in ovariectomized female mice submitted to subchronic stress exposure. METHODS: Mice were divided into four groups: sham, (PhSe)2, ovariectomy (OVX), and OVX + (PhSe)2. Animals were ovariectomized/sham operated and subjected to stress session once a day for 7 days from the fifth to the 11th day after OVX. The behavioral tests (open field, tail suspension (TST), and forced swimming (FST)) were performed on the 14th day after OVX. Mice were treated orally once a day with vehicle (canola oil, 10 ml/kg) or (PhSe)2 (10 mg/kg; 10 ml/kg) 30 min before being exposed to subchronic stress, or from the 11th to the 14th day. Paroxetine (8 mg/kg i.p.) and pargyline (30 mg/kg i.p.) were used as positive controls. The involvement of serotonergic receptor subtypes in the antidepressant-like effect of (PhSe)2 was assessed in the FST using WAY 100635 (0.1 mg/kg s.c.), ritanserin (1 mg/kg i.p.), and ondansetron (1 mg/kg i.p.) as serotonergic antagonists. Monoamine oxidase (MAO) A and B activities were also determined. RESULTS: The prolongation of immobility time in TST and FST in OVX mice submitted to subchronic stress was prevented by (PhSe)2 treatment. Ritanserin and ondansetron blocked the antidepressive-like effect of (PhSe)2, suggesting the involvement of 5-HT(2A/2C) and 5-HT3 receptor subtypes. Both paroxetine and pargyline were effective in reducing the immobility time of stressed OVX mice in the FST. No alterations in locomotor activity were observed. Although (PhSe)2 had inhibited in vitro MAO-A and MAO-B activities, none of the groups presented alterations neither in ex vivo MAO-A nor in MAO-B activity. CONCLUSIONS: (PhSe)2 treatment could influence mood and behavior, indicating a promising role of this organoselenium compound in the management of postmenopausal depressive symptoms. PMID- 22451093 TI - Effects of naltrexone on alcohol drinking patterns and extinction of alcohol seeking in baboons. AB - RATIONALE: Understanding naltrexone's effect on motivation to drink and pattern of drinking is important for better treatment outcomes and for comparison with novel medications. OBJECTIVES: Naltrexone's effects on number and pattern of seeking, self-administration, and extinction responses were evaluated in two groups of baboons trained under a three-component chained schedule of reinforcement (CSR). METHODS: Alcohol (4 % w/v; n = 4; alcohol group) or a preferred nonalcoholic beverage (n = 4; control group) was available for self administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). Naltrexone (0.32-3.2 mg/kg) and saline were administered before drinking and component 2 extinction sessions. RESULTS: Acute doses of naltrexone significantly decreased total self-administration responses (p < 0.01), intake volume (p < 0.001), and grams per kilogram of alcohol (p < 0.01) in the alcohol group only. Pattern of drinking did not change, but the number of drinks during the initial drinking bout was decreased significantly by naltrexone for both groups (p < 0.05). During within-session extinction tests, acute naltrexone significantly decreased time to reach extinction (p < 0.01) and number of seeking responses (p < 0.05), particularly early in the extinction period in the alcohol group only. When administered chronically, naltrexone did not decrease progressive ratio breaking points to gain access to alcohol, but dose dependently reduced alcohol self-administration (p < 0.05) by decreasing the magnitude of the initial drinking bout. CONCLUSIONS: The results support clinical observations that naltrexone may be most effective at reducing self-administration in the context of ongoing alcohol availability and may reduce motivation to drink in the presence of alcohol-related cues. PMID- 22451094 TI - A selective reversible monoamine oxidase B inhibitor in smoking cessation: effects on its own and in association with transdermal nicotine patch. AB - RATIONALE: Monoamine oxidase B (MAO-B) activity is reduced in smokers. A MAO-B inhibitor alone or co-administered with nicotine may mimic the effects of smoking and be a candidate drug for smoking cessation. OBJECTIVE: This study aims to determine the efficacy and safety of EVT302, a selective reversible MAO-B inhibitor, alone and on top of nicotine patch (NP) in smoking cessation. METHODS: This was a randomised, double blind, placebo-controlled phase II, multicentre trial. Smokers (>=10 cigarettes/day) received either EVT302 (N = 145) or placebo (N = 145), or EVT302 (N = 61) or placebo (N = 61) on top of open label NP 21 mg/day for 8 weeks. The main comparison was between EVT302 and placebo without NP. The primary outcome measure was end-of-treatment 4-week continuous abstinence rate (CAR). SECONDARY OUTCOME MEASURES: point prevalence abstinence rate, saliva cotinine concentrations in the groups without NP, urge to smoke, nicotine withdrawal symptoms and assessment of subjective effects of cigarettes. RESULTS: The 4-week CAR was 15.2 % in the placebo, 17.2 % in the EVT302, 26.8 % in the NP + placebo and 32.8 % in the NP + EVT302 groups, respectively. There was no difference between EVT302 and placebo either alone (adjusted OR: 1.45, 95 % CI: 0.65-3.26) or when co-administered with NP. No statistically significant difference occurred for the secondary outcome measures. CONCLUSIONS: The selective, reversible MAO-B inhibitor EVT302 was not superior to placebo in helping smokers quit, in line with data with selegiline and confirms that MAO-B inhibitors are not effective in smoking cessation. Co-administration of NP does not provide a supplementary benefit. PMID- 22451095 TI - Clinical outcome of low- and high-risk malignant colorectal polyps: results of a population-based study and meta-analysis of the available literature. AB - Some histological features of malignant polyps have been used to classify patients into low- and high-risk groups. This study proposed to evaluate the impact of this classification on the clinical outcome of patients with malignant polyps. Through the Colorectal Cancer Registry, 105 patients with endoscopically removed malignant polyps were selected. The presence of one of the following histological features defined malignant polyps as high-risk: infiltrated resection-margin, poorly differentiated carcinoma, lymphatic/vascular invasion and tumour budding and depth of submucosal invasion. Available literature was reviewed by applying a similar classification. Most of the malignant polyps were pedunculated and were localized in the left colon. Fifty-five malignant polyps were classified as low-risk lesions and 50 as high-risk. None of the patients at low-risk died of colorectal cancer. Of the patients at high-risk, three died of cancer; all three cases showed lymphatic/vascular invasion. Review of the literature reveals that an unfavourable clinical outcome is significantly more prevalent in the high-risk compared with the low-risk group (p > 0.005). Moreover, all histological risk factors show a specific predictive value of clinical adverse outcome. Our study and the pooled data analysis confirmed the usefulness of the subdivision into low- and high-risk malignant polyps for management of patients with endoscopically removed colorectal carcinoma. PMID- 22451097 TI - Nanoemulsion composite microgels for orthogonal encapsulation and release. PMID- 22451098 TI - Characterization of chromatin domains by 3D fluorescence microscopy: An automated methodology for quantitative analysis and nuclei screening. AB - Fluorescence microscopy has provided a route to qualitatively analyze features of nuclear structures and chromatin domains with increasing resolution. However, it is becoming increasingly important to develop tools for quantitative analysis. Here, we present an automated method to quantitatively determine the enrichment of several endogenous factors, immunostained in pericentric heterochromatin domains in mouse cells. We show that this method permits an unbiased characterization of changes in the enrichment of several factors with statistical significance from a large number of nuclei. Furthermore, the nuclei can be sorted according to the enrichment value of these factors. This method should prove useful to monitor events related to changes in the amount, rather than the presence or absence, of any factor. By adapting a few parameters, it could be extended to other nuclear structures and the benefit of using available software will permit its use in many biological labs. PMID- 22451100 TI - The varieties of human dignity: a logical and conceptual analysis. AB - The word 'dignity' is used in a variety of ways in bioethics, and this ambiguity has led some to argue that the term must be expunged from the bioethical lexicon. Such a judgment is far too hasty, however. In this article, the various uses of the word are classified into three serviceable categories: intrinsic, attributed, and inflorescent dignity. It is then demonstrated that, logically and linguistically, the attributed and inflorescent meanings of the word presuppose the intrinsic meaning. Thus, one cannot conclude that these meanings are arbitrary and unrelated. This categorization and logical and linguistic analysis helps to unravel what seem to be contradictions in discourse about dignity and bioethics, and provides a hierarchy of meaning that has potential normative implications. PMID- 22451101 TI - Biological sources and sinks of nitrous oxide and strategies to mitigate emissions. AB - Nitrous oxide (N(2)O) is a powerful atmospheric greenhouse gas and cause of ozone layer depletion. Global emissions continue to rise. More than two-thirds of these emissions arise from bacterial and fungal denitrification and nitrification processes in soils, largely as a result of the application of nitrogenous fertilizers. This article summarizes the outcomes of an interdisciplinary meeting, 'Nitrous oxide (N(2)O) the forgotten greenhouse gas', held at the Kavli Royal Society International Centre, from 23 to 24 May 2011. It provides an introduction and background to the nature of the problem, and summarizes the conclusions reached regarding the biological sources and sinks of N(2)O in oceans, soils and wastewaters, and discusses the genetic regulation and molecular details of the enzymes responsible. Techniques for providing global and local N(2)O budgets are discussed. The findings of the meeting are drawn together in a review of strategies for mitigating N(2)O emissions, under three headings, namely: (i) managing soil chemistry and microbiology, (ii) engineering crop plants to fix nitrogen, and (iii) sustainable agricultural intensification. PMID- 22451102 TI - The role of N2O derived from crop-based biofuels, and from agriculture in general, in Earth's climate. AB - In earlier work, we compared the amount of newly fixed nitrogen (N, as synthetic fertilizer and biologically fixed N) entering agricultural systems globally to the total emission of nitrous oxide (N(2)O). We obtained an N(2)O emission factor (EF) of 3-5%, and applied it to biofuel production. For 'first-generation' biofuels, e.g. biodiesel from rapeseed and bioethanol from corn (maize), that require N fertilizer, N(2)O from biofuel production could cause (depending on N uptake efficiency) as much or more global warming as that avoided by replacement of fossil fuel by the biofuel. Our subsequent calculations in a follow-up paper, using published life cycle analysis (LCA) models, led to broadly similar conclusions. The N(2)O EF applies to agricultural crops in general, not just to biofuel crops, and has made possible a top-down estimate of global emissions from agriculture. Independent modelling by another group using bottom-up IPCC inventory methodology has shown good agreement at the global scale with our top down estimate. Work by Davidson showed that the rate of accumulation of N(2)O in the atmosphere in the late nineteenth and twentieth centuries was greater than that predicted from agricultural inputs limited to fertilizer N and biologically fixed N (Davidson, E. A. 2009 Nat. Geosci. 2, 659-662.). However, by also including soil organic N mineralized following land-use change and NO(x) deposited from the atmosphere in our estimates of the reactive N entering the agricultural cycle, we have now obtained a good fit between the observed atmospheric N(2)O concentrations from 1860 to 2000 and those calculated on the basis of a 4 per cent EF for the reactive N. PMID- 22451099 TI - Cognitive domains that predict time to diagnosis in prodromal Huntington disease. AB - BACKGROUND: Prodromal Huntington's disease (prHD) is associated with a myriad of cognitive changes but the domains that best predict time to clinical diagnosis have not been studied. This is a notable gap because some domains may be more sensitive to cognitive decline, which would inform clinical trials. OBJECTIVES: The present study sought to characterise cognitive domains underlying a large test battery and for the first time, evaluate their ability to predict time to diagnosis. METHODS: Participants included gene negative and gene positive prHD participants who were enrolled in the PREDICT-HD study. The CAG-age product (CAP) score was the measure of an individual's genetic signature. A factor analysis of 18 tests was performed to identify sets of measures or latent factors that elucidated core constructs of tests. Factor scores were then fit to a survival model to evaluate their ability to predict time to diagnosis. RESULTS: Six factors were identified: (1) speed/inhibition, (2) verbal working memory, (3) motor planning/speed, (4) attention-information integration, (5) sensory perceptual processing and (6) verbal learning/memory. Factor scores were sensitive to worsening of cognitive functioning in prHD, typically more so than performances on individual tests comprising the factors. Only the motor planning/speed and sensory-perceptual processing factors predicted time to diagnosis, after controlling for CAP scores and motor symptoms. Conclusions The results suggest that motor planning/speed and sensory-perceptual processing are important markers of disease prognosis. The findings also have implications for using composite indices of cognition in preventive Huntington's disease trials where they may be more sensitive than individual tests. PMID- 22451103 TI - UK emissions of the greenhouse gas nitrous oxide. AB - Signatories of the Kyoto Protocol are obliged to submit annual accounts of their anthropogenic greenhouse gas emissions, which include nitrous oxide (N(2)O). Emissions from the sectors industry (3.8 Gg), energy (14.4 Gg), agriculture (86.8 Gg), wastewater (4.4 Gg), land use, land-use change and forestry (2.1 Gg) can be calculated by multiplying activity data (i.e. amount of fertilizer applied, animal numbers) with simple emission factors (Tier 1 approach), which are generally applied across wide geographical regions. The agricultural sector is the largest anthropogenic source of N(2)O in many countries and responsible for 75 per cent of UK N(2)O emissions. Microbial N(2)O production in nitrogen fertilized soils (27.6 Gg), nitrogen-enriched waters (24.2 Gg) and manure storage systems (6.4 Gg) dominate agricultural emission budgets. For the agricultural sector, the Tier 1 emission factor approach is too simplistic to reflect local variations in climate, ecosystems and management, and is unable to take into account some of the mitigation strategies applied. This paper reviews deviations of observed emissions from those calculated using the simple emission factor approach for all anthropogenic sectors, briefly discusses the need to adopt specific emission factors that reflect regional variability in climate, soil type and management, and explains how bottom-up emission inventories can be verified by top-down modelling. PMID- 22451104 TI - Fungal denitrification and nitric oxide reductase cytochrome P450nor. AB - We have shown that many fungi (eukaryotes) exhibit distinct denitrifying activities, although occurrence of denitrification was previously thought to be restricted to bacteria (prokaryotes), and have characterized the fungal denitrification system. It comprises NirK (copper-containing nitrite reductase) and P450nor (a cytochrome P450 nitric oxide (NO) reductase (Nor)) to reduce nitrite to nitrous oxide (N(2)O). The system is localized in mitochondria functioning during anaerobic respiration. Some fungal systems further contain and use dissimilatory and assimilatory nitrate reductases to denitrify nitrate. Phylogenetic analysis of nirK genes showed that the fungal-denitrifying system has the same ancestor as the bacterial counterpart and suggested a possibility of its proto-mitochondrial origin. By contrast, fungi that have acquired a P450 from bacteria by horizontal transfer of the gene, modulated its function to give a Nor activity replacing the original Nor with P450nor. P450nor receives electrons directly from nicotinamide adenine dinucleotide to reduce NO to N(2)O. The mechanism of this unprecedented electron transfer has been extensively studied and thoroughly elucidated. Fungal denitrification is often accompanied by a unique phenomenon, co-denitrification, in which a hybrid N(2) or N(2)O species is formed upon the combination of nitrogen atoms of nitrite with a nitrogen donor (amines and imines). Possible involvement of NirK and P450nor is suggested. PMID- 22451105 TI - Structural basis for nitrous oxide generation by bacterial nitric oxide reductases. AB - The crystal structure of the bacterial nitric oxide reductase (cNOR) from Pseudomonas aeruginosa is reported. Its overall structure is similar to those of the main subunit of aerobic and micro-aerobic cytochrome oxidases (COXs), in agreement with the hypothesis that all these enzymes are members of the haem copper oxidase superfamily. However, substantial structural differences between cNOR and COX are observed in the catalytic centre and the delivery pathway of the catalytic protons, which should be reflected in functional differences between these respiratory enzymes. On the basis of the cNOR structure, we propose a possible reaction mechanism of nitric oxide reduction to nitrous oxide as a working hypothesis. PMID- 22451106 TI - Biochemical characterization of the purple form of Marinobacter hydrocarbonoclasticus nitrous oxide reductase. AB - Nitrous oxide reductase (N(2)OR) catalyses the final step of the denitrification pathway-the reduction of nitrous oxide to nitrogen. The catalytic centre (CuZ) is a unique tetranuclear copper centre bridged by inorganic sulphur in a tetrahedron arrangement that can have different oxidation states. Previously, Marinobacter hydrocarbonoclasticus N(2)OR was isolated with the CuZ centre as CuZ*, in the [1Cu(2+) : 3Cu(+)] redox state, which is redox inert and requires prolonged incubation under reductive conditions to be activated. In this work, we report, for the first time, the isolation of N(2)OR from M. hydrocarbonoclasticus in the 'purple' form, in which the CuZ centre is in the oxidized [2Cu(2+) : 2Cu(+)] redox state and is redox active. This form of the enzyme was isolated in the presence of oxygen from a microaerobic culture in the presence of nitrate and also from a strictly anaerobic culture. The purple form of the enzyme was biochemically characterized and was shown to be a redox active species, although it is still catalytically non-competent, as its specific activity is lower than that of the activated fully reduced enzyme and comparable with that of the enzyme with the CuZ centre in either the [1Cu(2+) : 3Cu(+)] redox state or in the redox inactive CuZ* state. PMID- 22451107 TI - Nitrous oxide production and consumption: regulation of gene expression by gas sensitive transcription factors. AB - Several biochemical mechanisms contribute to the biological generation of nitrous oxide (N(2)O). N(2)O generating enzymes include the respiratory nitric oxide (NO) reductase, an enzyme from the flavo-diiron family, and flavohaemoglobin. On the other hand, there is only one enzyme that is known to use N(2)O as a substrate, which is the respiratory N(2)O reductase typically found in bacteria capable of denitrification (the respiratory reduction of nitrate and nitrite to dinitrogen). This article will briefly review the properties of the enzymes that make and consume N(2)O, together with the accessory proteins that have roles in the assembly and maturation of those enzymes. The expression of the genes encoding the enzymes that produce and consume N(2)O is regulated by environmental signals (typically oxygen and NO) acting through regulatory proteins, which, either directly or indirectly, control the frequency of transcription initiation. The roles and mechanisms of these proteins, and the structures of the regulatory networks in which they participate will also be reviewed. PMID- 22451108 TI - Regulation of denitrification at the cellular level: a clue to the understanding of N2O emissions from soils. AB - Denitrifying prokaryotes use NO(x) as terminal electron acceptors in response to oxygen depletion. The process emits a mixture of NO, N(2)O and N(2), depending on the relative activity of the enzymes catalysing the stepwise reduction of NO(3)( ) to N(2)O and finally to N(2). Cultured denitrifying prokaryotes show characteristic transient accumulation of NO(2)(-), NO and N(2)O during transition from oxic to anoxic respiration, when tested under standardized conditions, but this character appears unrelated to phylogeny. Thus, although the denitrifying community of soils may differ in their propensity to emit N(2)O, it may be difficult to predict such characteristics by analysis of the community composition. A common feature of strains tested in our laboratory is that the relative amounts of N(2)O produced (N(2)O/(N(2)+N(2)O) product ratio) is correlated with acidity, apparently owing to interference with the assembly of the enzyme N(2)O reductase. The same phenomenon was demonstrated for soils and microbial communities extracted from soils. Liming could be a way to reduce N(2)O emissions, but needs verification by field experiments. More sophisticated ways to reduce emissions may emerge in the future as we learn more about the regulation of denitrification at the cellular level. PMID- 22451110 TI - Global oceanic production of nitrous oxide. AB - We use transient time distributions calculated from tracer data together with in situ measurements of nitrous oxide (N(2)O) to estimate the concentration of biologically produced N(2)O and N(2)O production rates in the ocean on a global scale. Our approach to estimate the N(2)O production rates integrates the effects of potentially varying production and decomposition mechanisms along the transport path of a water mass. We estimate that the oceanic N(2)O production is dominated by nitrification with a contribution of only approximately 7 per cent by denitrification. This indicates that previously used approaches have overestimated the contribution by denitrification. Shelf areas may account for only a negligible fraction of the global production; however, estuarine sources and coastal upwelling of N(2)O are not taken into account in our study. The largest amount of subsurface N(2)O is produced in the upper 500 m of the water column. The estimated global annual subsurface N(2)O production ranges from 3.1 +/- 0.9 to 3.4 +/- 0.9 Tg N yr(-1). This is in agreement with estimates of the global N(2)O emissions to the atmosphere and indicates that a N(2)O source in the mixed layer is unlikely. The potential future development of the oceanic N(2)O source in view of the ongoing changes of the ocean environment (deoxygenation, warming, eutrophication and acidification) is discussed. PMID- 22451109 TI - Impacts of nitrogen application rates on the activity and diversity of denitrifying bacteria in the Broadbalk Wheat Experiment. AB - Bacterial denitrification results in the loss of fertilizer nitrogen and greenhouse gas emissions as nitrous oxides, but ecological factors in soil influencing denitrifier communities are not well understood, impeding the potential for mitigation by land management. Communities vary in the relative abundance of the alternative dissimilatory nitrite reductase genes nirK and nirS, and the nitrous oxide reductase gene nosZ; however, the significance for nitrous oxide emissions is unclear. We assessed the influence of different long-term fertilization and cultivation treatments in a 160-year-old field experiment, comparing the potential for denitrification by soil samples with the size and diversity of their denitrifier communities. Denitrification potential was much higher in soil from an area left to develop from arable into woodland than from a farmyard manure-fertilized arable treatment, which in turn was significantly higher than inorganic nitrogen-fertilized and unfertilized arable plots. This correlated with abundance of nirK but not nirS, the least abundant of the genes tested in all soils, showing an inverse relationship with nirK. Most genetic variation was seen in nirK, where sequences resolved into separate groups according to soil treatment. We conclude that bacteria containing nirK are most probably responsible for the increased denitrification potential associated with nitrogen and organic carbon in this soil. PMID- 22451111 TI - Stratospheric ozone depletion due to nitrous oxide: influences of other gases. AB - The effects of anthropogenic emissions of nitrous oxide (N(2)O), carbon dioxide (CO(2)), methane (CH(4)) and the halocarbons on stratospheric ozone (O(3)) over the twentieth and twenty-first centuries are isolated using a chemical model of the stratosphere. The future evolution of ozone will depend on each of these gases, with N(2)O and CO(2) probably playing the dominant roles as halocarbons return towards pre-industrial levels. There are nonlinear interactions between these gases that preclude unambiguously separating their effect on ozone. For example, the CH(4) increase during the twentieth century reduced the ozone losses owing to halocarbon increases, and the N(2)O chemical destruction of O(3) is buffered by CO(2) thermal effects in the middle stratosphere (by approx. 20% for the IPCC A1B/WMO A1 scenario over the time period 1900-2100). Nonetheless, N(2)O is expected to continue to be the largest anthropogenic emission of an O(3) destroying compound in the foreseeable future. Reductions in anthropogenic N(2)O emissions provide a larger opportunity for reduction in future O(3) depletion than any of the remaining uncontrolled halocarbon emissions. It is also shown that 1980 levels of O(3) were affected by halocarbons, N(2)O, CO(2) and CH(4), and thus may not be a good choice of a benchmark of O(3) recovery. PMID- 22451112 TI - Nitrous oxide emissions from wastewater treatment processes. AB - Nitrous oxide (N(2)O) emissions from wastewater treatment plants vary substantially between plants, ranging from negligible to substantial (a few per cent of the total nitrogen load), probably because of different designs and operational conditions. In general, plants that achieve high levels of nitrogen removal emit less N(2)O, indicating that no compromise is required between high water quality and lower N(2)O emissions. N(2)O emissions primarily occur in aerated zones/compartments/periods owing to active stripping, and ammonia oxidizing bacteria, rather than heterotrophic denitrifiers, are the main contributors. However, the detailed mechanisms remain to be fully elucidated, despite strong evidence suggesting that both nitrifier denitrification and the chemical breakdown of intermediates of hydroxylamine oxidation are probably involved. With increased understanding of the fundamental reactions responsible for N(2)O production in wastewater treatment systems and the conditions that stimulate their occurrence, reduction of N(2)O emissions from wastewater treatment systems through improved plant design and operation will be achieved in the near future. PMID- 22451113 TI - Social cognitive influences on physical activity participation in long-term breast cancer survivors. AB - BACKGROUND: Although physical activity is beneficial for breast cancer survivors, the majority do not meet public health physical activity recommendations. The purpose of this study was to test a social cognitive theory model of physical activity behavior in a sample of long-term breast cancer survivors using both self-report and objective measures of physical activity. METHODS: Participants (N = 1527) completed measures of physical activity, self-efficacy, goals, outcome expectations, fatigue, and social support at baseline and 6-month follow-up. A subsample (n = 370) was randomly selected to wear an accelerometer. It was hypothesized that self-efficacy directly and indirectly influences physical activity through goals, social support, fatigue, and outcome expectations. Relationships were examined using panel analysis within a covariance modeling framework. RESULTS: The hypothesized model provided a good model-data fit (chi(2) = 1168.73, df = 271, p = <0.001, CFI = 0.96, SRMR = 0.04) in the full sample when controlling for covariates. At baseline, self-efficacy directly and indirectly, via goals, outcome expectations, and social support, influenced physical activity. These relationships were also supported across time. Additionally, the hypothesized model was supported in the subsample with accelerometer data (chi2 = 656.88, df = 330, p < 0.001, CFI = 0.95, SRMR = 0.05). CONCLUSIONS: This study validates a social cognitive model for understanding physical activity behavior in long-term breast cancer survivors. Future studies should be designed to replicate this model in other breast cancer survivor populations, and the findings should be applied to the development of future physical activity programs and studies for this population. PMID- 22451114 TI - HAX-1 promotes the chemoresistance, invasion, and tumorigenicity of esophageal squamous carcinoma cells. AB - BACKGROUND: HAX-1 is an anti-apoptotic factor and regulates the expression of DNA pol beta. Interestingly, DNA polymerase pol beta is overexpressed in esophageal squamous cell carcinoma (ESCC). However, the functional role of HAX-1 in ESCC remains unclear. AIMS: To investigate the role of HAX-1 in chemoresistance, invasion, and tumorigenicity of ESCC. METHODS: Lentivirus-mediated overexpression or knockdown of HAX-1 was employed to establish ESCC EC9706 cell lines that expressed HAX-1 at different levels. The biological behaviors of these engineered cells were characterized in vitro and in vivo using a xenograft nude mice model. In addition, HAX-1 and pol beta expression in the tumor tissues was detected by RT-PCR and immunohistochemistry. RESULTS: HAX-1 overexpression promoted cell proliferation and resistance against cisplatin, increased cell invasion and suppressed apoptosis along with increased pol beta expression. Conversely, HAX-1 knockdown inhibited the malignant phenotypes of EC9706 cells. The xenograft nude mice model demonstrated that HAX-1 overexpression or depletion led to increased or decreased tumor growth in vivo, respectively. Furthermore, a positive correlation of HAX-1 and pol beta expression in the tumor tissues was observed. CONCLUSIONS: HAX-1 promotes the proliferation, chemoresistance, invasion, and tumorigenicity of ESCC, and this is correlated with increased poly beta expression. HAX-1 may represent a potential target to overcome the resistance and metastasis of ESCC. PMID- 22451115 TI - Gastrointestinal manifestations of Henoch-Schoenlein purpura. PMID- 22451116 TI - CD30 ligand/CD30 interaction is involved in pathogenesis of inflammatory bowel disease. AB - BACKGROUND AND AIMS: Although CD30 has long been recognized as an important marker in many lymphomas of diverse origin, and as an activation molecule on B and T cells, its primary function has remained obscure. Soluble CD30 (sCD30) is released from CD30 on the cell membrane by enzymatic cleavage. This study investigated the role of CD30 ligand (CD30L)/CD30 signals in intestinal mucosal damage. METHODS: Serum sCD30 in patients with ulcerative colitis (UC) and Crohn's disease (CD) and healthy individuals was assessed. A model of enteritis induced by anti-CD3 monoclonal antibody injection was studied in wild-type mice and in CD30L knockout mice. RESULTS: Increased sCD30 was observed in UC and CD patients, and the level was correlated with disease activity in both conditions. In a murine model of enteritis, histological intestinal damage was significantly reduced in CD30L knockout mice with decreased Th1 and Th17 cytokine levels. Moreover, blocking of CD30L/CD30 signals by CD30-immunoglobulin (CD30-Ig) resulted in reduced inflammation. CONCLUSIONS: Increased sCD30 expression correlating with disease activity suggested that CD30L/CD30 signals play an important role in pathogenesis of UC and CD. CD30L/CD30 pathway acts as an accelerator of enteritis in a murine disease model. Successful blockade of enteritis by CD30-Ig suggests a potential tool for future therapy of inflammatory bowel diseases. PMID- 22451117 TI - Hypovitaminosis D in adults with inflammatory bowel disease: potential role of ethnicity. AB - BACKGROUND: Although vitamin D deficiency occurs in inflammatory bowel disease (IBD), it is currently unclear to what extent ethnicity affects vitamin D levels. Our aim was therefore to determine the ethnic variation in serum 25 hydroxyvitamin D status and its association with disease severity in adults with IBD. METHODS: We conducted a prospective cohort study in ambulatory care IBD patients. Clinical disease severity was assessed through validated questionnaires. Serum 25-hydroxyvitamin D levels were used for vitamin D status. C-reactive protein (CRP), ferritin and hemoglobin (Hgb) levels were correlated with serum 25-hydroxyvitamin D levels. RESULTS: Sixty ulcerative colitis (UC) and forty Crohn's disease (CD) patients were enrolled comprising 65 % Caucasians and 29 % South Asians. However, South Asians had consistently lower average serum 25 hydroxyvitamin D levels (All 44.8 +/- 18.1 nmol/L, UC 48.2 +/- 18.3 nmol/L, CD 24.3 +/- 13.3 nmol/L). Hypovitaminosis D was found in 39 % of All, 36.7 % of UC and 42.5 % of CD patients. A significantly higher proportion of South Asians were vitamin D deficient when compared to Caucasians in All and CD groups (58.6 % vs. 30.8 %, p = 0.01 and 85.7 % vs. 32.3 %, p < 0.01, respectively). CONCLUSIONS: A significantly higher percentage of South Asians had hypovitaminosis D when compared to Caucasians. Disease severity trended towards an inverse relationship with vitamin D status in all South Asian and Caucasian CD patients, although most patients in this study had only mild to moderate disease. We suggest that vitamin D supplementation should be considered in all adult IBD patients. PMID- 22451118 TI - Impedance pH confirms the relationship between GERD and BMI. AB - BACKGROUND: During the last 20 years the prevalence of both gastroesophageal reflux disease (GERD) and obesity has been increasing in the United States. The pathophysiology of GERD is multifactorial and its relationship with obesity is still not well understood. AIM: To evaluate the association between BMI and GERD as detected by multichannel intraluminal impedance-pH (MII-pH) monitoring. METHODS: Retrospective review of 122 consecutive MII-pH studies of adult patients while on PPI therapy. Patients were divided into normal (BMI < 25), overweight (BMI >= 25 and <30) and obese (BMI >= 30). Reflux episodes were classified as acid reflux (AR), nonacid reflux (NAR), and total number of reflux episodes, as detected by MII-pH. We evaluated the symptoms associated with reflux by using the symptom index (SI). We also assessed the number of reflux episodes during recumbency and compared them in the different BMI groups. RESULTS: The total number of reflux episodes and NAR episodes increased significantly as BMI increased. There was no significant difference between groups in AR. Similarly, during recumbency, total number of reflux episodes increased significantly when BMI increased. For symptoms associated with reflux, SI was more likely to be positive in the obese group. CONCLUSIONS: This study shows a clear association between increased reflux as detected by MII-pH and higher BMI. Obesity not only increases the likelihood of reflux events, as shown in previous studies, but also makes it more likely that symptoms reported during MII-pH studies are actually due to MII detected reflux. PMID- 22451119 TI - Effect of Boswellia serrata on antioxidant status in an experimental model of colitis rats induced by acetic acid. AB - AIM OF THE STUDY: To evaluate the antioxidant effect of an extract of the plant Boswellia serrata in an experimental model of acute ulcerative colitis induced by administration of acetic acid (AA) in rats. MATERIALS AND METHODS: The extract of B. serrata (34.2 mg/kg/day) was administered orally by gavage for 2 days before and after induction of colitis with AA diluted to 4 % and in a volume of 4 ml. RESULTS: The anal sphincter pressure in the groups treated with B. serrata showed a significant increase compared to the colitis group (P < 0.001). Histological analysis of treated animals showed less edema with preservation of mucosal crypts. Lipid peroxidation showed a significant decrease in the treated groups compared to the colitis group (P < 0.001). The superoxide dismutase (SOD) enzyme activity showed a significant reduction in the treated groups compared to the colitis group (P < 0.001), the glutathione peroxidase (GPx) significantly increased in the treated groups compared to colitis group (P < 0.05), and the same was the result for enzyme activity glutathione (GSH; P < 0.05). CONCLUSIONS: The extract of B. serrata has active antioxidant substances that exert protective effects in acute experimental colitis. PMID- 22451120 TI - Sorafenib for treatment of hepatocellular carcinoma: a systematic review. AB - BACKGROUND: Sorafenib, a drug that inhibits Raf serine/threonine kinases mediating cell proliferation and receptor tyrosine kinases involved in angiogenesis, is approved for treatment of advanced hepatocellular carcinoma. AIMS: To explore the efficacy and safety of sorafenib for treating advanced HCC, and to identify clinical factors that might affect that efficacy and safety. METHODS: We conducted a systematic review using the PRISMA guidelines to identify prospective studies on sorafenib used alone or in combination with systemic and/or loco regional anti-tumor therapy for treating advanced HCC. RESULTS: We identified 21 prospective trials of sorafenib treatment alone (7) or combined with other treatment (14). In randomized, placebo-controlled trials, sorafenib prolonged overall survival by 2.3-2.8 months, extended the time to tumor progression by 1.4-2.7 months, and increased disease control by 11-19 %. OS and DCRs were lowest for studies with the highest percentage of hepatitis B patients. Most studies reported major side effects (diarrhea, fatigue, and hand-foot syndrome) in <15 % of patients, with greater incidence in patients with advanced cirrhosis and those treated with sorafenib in combination with 5-FU drugs. CONCLUSIONS: Treatment with sorafenib results in statistically significant, but clinically modest, improvements in OS, TTP, and DCR. For patients with hepatitis B, response seems to be poorer than for those with hepatitis C. The frequency of hand-foot syndrome seems to be higher when sorafenib is used in advanced cirrhosis and is combined with 5-FU drugs. It is not clear that sorafenib combined with other treatments is more effective than sorafenib alone. PMID- 22451121 TI - A water-jet videoendoscope may reduce operation time of endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND: One of the problems with endoscopic submucosal dissection (ESD) for early gastric cancer is that it prolongs procedure time considerably. AIM: The purpose of this study was to investigate whether a videoendoscope with water-jet function shortened the time of ESD for early gastric cancer. METHODS: A total of 82 early gastric cancers that were intramucosal, differentiated-type adenocarcinoma <=2 cm, without ulcer or scar, in 75 consecutive patients were investigated. Three supervised resident endoscopists participated as operators. After stratification by the operator and tumor location, the lesions were randomly assigned to the water-jet videoendoscope or a conventional videoendoscope groups. An insulated tipped knife was used for the ESD procedure. Total operation time was evaluated as a primary endpoint. RESULTS: The median (25 75th percentile) total operation time for the water-jet videoendoscope group was 51 (33-87) minutes, which was shorter than the 62 (43-88) minutes for the conventional videoendoscope, but it did not reach significance (P = 0.201). Multivariate analysis revealed that the water-jet videoendoscope (OR 3.0, P = 0.046), tumor size <=14 mm (OR 3.2, P = 0.040) and antral tumor (OR 4.5, P = 0.046) were significantly associated with short (<=60 min) operation time. CONCLUSIONS: The water-jet videoendoscope may reduce operation time of ESD for early gastric cancer, compared with conventional videoendoscope. A large-scale multicenter trial is warranted to clarify the efficacy of the water-jet videoendoscope for gastric ESD. PMID- 22451122 TI - Performance of the fecal immunochemical test is not decreased by high ambient temperature in the rapid return system. AB - BACKGROUND: Hemoglobin concentration of fecal immunochemical test may be decreased at high ambient temperature, and fecal samples in FIT may be exposed to high ambient temperature. AIMS: The aim of this study was to determine whether a high ambient temperature on the day of screening may decrease the performance of FITs in population-based screening. METHODS: We performed FITs for asymptomatic participants aged 50 years or older. Fecal hemoglobin concentration, the probability of a positive FIT and a detection rate of colorectal neoplasms were compared between low (<10.0 degrees C) and high (>=25.0 degrees C) temperature groups. RESULTS: The FIT results for 8,316 participants were analyzed. The mean log(10) Hb concentration in the low temperature group was significantly higher than those in the high temperature group (0.36 vs. 0.25 ng/ml, p = 0.000). Regression analysis showed that an increase in temperature of 1 degrees C reduced the probability of a positive FIT by 3.1 %. However, we found no differences between the two groups in the FIT positive rate and detection rate of colorectal neoplasms. In multivariate analysis, high ambient temperature was not a significant risk factor for either the positive FIT result or the detection of colorectal neoplasms. CONCLUSIONS: Potential instability of fecal hemoglobin at high ambient temperatures should be considered; however, its influence on performance of FIT may be attenuated by the short exposure time of fecal samples to high ambient temperature (i.e., rapid return system). PMID- 22451123 TI - Corneal displacement during tonometry with a noncontact tonometer. AB - PURPOSE: To measure the extent of corneal displacement during the early phase of tonometry using a noncontact tonometer and to determine the factors that affect the extent of the displacement. METHODS: The cornea was photographed in profile by use of a high-speed camera during tonometry with a noncontact tonometer. The frame rate of the camera was 5,000 frames/s. The extent of the displacement of the central corneal area at 13.2 ms after application of the air puff was measured in 115 healthy volunteers. The factors that affected the extent of the corneal displacement were determined by stepwise multiple linear regression analysis. RESULTS: The subjects' age, sex, intraocular pressure (IOP), central corneal thickness, anterior chamber depth, and axial length were selected by the stepwise method. The results of the multiple linear regression analysis showed that subjects with low IOP, of older age, and of male sex had significantly greater displacement of the central cornea. CONCLUSIONS: High-speed photography can be used to evaluate the degree of corneal displacement during tonometry with a noncontact tonometer. The amount of corneal displacement is affected by the individual's IOP, age, and sex. PMID- 22451125 TI - [Amino acids in cerebrospinal fluid and plasma: its usefulness in the study of neuropaediatric diseases]. AB - INTRODUCTION: Studying the amino acids in cerebrospinal fluid (CSF) is essential in the diagnosis of some neurological diseases and is an important aid in the diagnosis of others. No research has been published in the literature to prove the physiological relationship between the values of amino acids in CSF and plasma in the paediatric population. AIM: To define a set of ratios for amino acids in plasma and CSF in the paediatric population that can be used in daily clinical practice. PATIENTS AND METHODS: The aminograms in plasma and CSF of 105 patients with ages between 0 and 12 months were collected and analysed retrospectively. Aminograms with amino acid values that are considered to be normal according to the reference values of our laboratory were included in the sample. The quantitative analysis of amino acids was performed using high resolution liquid chromatography and statistical analysis with the software application SPSS 19.0. RESULTS: The mean values, range and standard deviation of the amino acid concentrations in plasma and CSF, together with the CSF/plasma ratios, are reported. Significant correlations were found from 0.6 onwards between different neutral amino acids, above all in those with smaller molecular weights (Thr, Ser, Gly and Ala). CONCLUSIONS: The existence of significant correlations between the different neutral amino acids supports the idea that they share the same transporters in the blood-brain barrier. Standardising the amino acid ratios will make it possible to increase sensitivity in the detection of pathological values in plasma and CSF, to further knowledge of the pathophysiology of neurological diseases and perhaps to describe new aminoacidopathies. PMID- 22451124 TI - [Epidemiology of the subtypes of stroke in hospitalised patients attended by neurologists: results of the EPICES registry (I)]. AB - INTRODUCTION: Hospital-based population studies are a good way to determinate the number and features of strokes that occur in a given society. The major stroke subtypes have different patterns of incidence and outcome, for that reason information on the natural history of stroke subtypes is essential. AIM: To determine the incidence of the stroke subtypes and the prevalence of the major risk factors in the Spanish population. PATIENTS AND METHODS: EPICES is an observational, multicenter and prospective study. Methodology includes systematic review of consecutive medical records of hospitalized stroke patients in neurological care. 6,197 patients were included during the period April 2008 and January 2009. 3,544 (57.2%) were men. Mean age was 71.4 +/- 12.8 years. RESULTS: Intracerebral haemorrhage was diagnosed in 771 patients (12.4%) and ischemic stroke in 5,426 (87.6%). 1,543 (28.4%) were classified as large-artery atherosclerosis, cardioembolic 1,424 (26.2%), small-vessel occlusion 1,202 (22.5%), undetermined etiology 1,125 (20.7%). Stroke of other uncommon origin was founded in 132 (2.4%). Hypertension is the most common risk factor in both ischemic stroke (67%) and intracerebral haemorrhage (69.1%). The different types of ischemic and hemorrhagic stroke showed differences in risk factors prevalence. CONCLUSIONS: The overall distribution of stroke subtypes are not significantly different from those of most Western countries. The frequency of vascular risk factors differs between stroke subtypes. Hypertension remains the most important modifiable risk factor. PMID- 22451126 TI - [Clinical and demographic characteristics of the cases of dementia diagnosed in the Health District of Girona throughout the period 2007-2010: data from the Girona Dementia Registry (ReDeGi)]. AB - INTRODUCTION: The Girona Dementia Registry (ReDeGi, from Spanish: Registro de Demencias de Girona) is a population-based epidemiological surveillance mechanism that registers the cases of dementia diagnosed by the reference centres in the Girona Health District. AIM: To report on the frequency of the diagnoses and their clinical and sociodemographic characteristics, as well as to compare differences depending on the different subtypes of dementia. PATIENTS AND METHODS: The method used consisted in a consecutive standardised register of the diagnoses involving dementia in specialised procedures in the Girona Health District between 2007 and 2010. RESULTS: A total of 2814 cases were registered, which represents a clinical incidence of 6.6 cases per 1000 persons/year. Of this total number, 69.2% were primary degenerative dementias, 18.9% were dementias secondary to a vascular pathology, 5.4% were other secondary dementias and 6.5% were non-specific dementias. The mean age was 79.2 +/- 7.6 years (range: 33-99 years) and 59.3% were females. The mean time elapsed since the onset of symptoms and clinical diagnosis was 2.5 +/- 1.7 years. The mean score on the Blessed dementia scale was 7.7 +/- 4.5 points and in the minimental test it was 17.6 +/- 5.4 points. A family history of dementia was present in 26.6% of cases and 69.6% presented one or more cardiovascular risk factors. In 60.6% of cases they were cases of mild dementia, 28.5% were moderate and 10.9% were severe cases. CONCLUSIONS: The epidemiological surveillance activity carried out by the ReDeGi throughout the period 2007-2010 has made it possible to record information that is extremely valuable for the planning and management of health care resources. PMID- 22451127 TI - [Characterisation of pain in patients with carpal tunnel syndrome according to electromyographic severity criteria]. AB - INTRODUCTION: The symptoms of carpal tunnel syndrome (CTS) vary greatly and can depend on the severity of the clinical symptoms. AIMS: To characterise the description and self-perception of pain in a sample of patients with CTS and to determine whether that perception of pain differs among the patients on the basis of electrodiagnostic severity criteria. PATIENTS AND METHODS: The sample consisted of 92 females with CTS, who were classified as having mild, moderate or severe CTS, bearing in mind electrodiagnostic criteria. Different instruments were used in the study: a numerical scale (0-10) to evaluate the intensity of the pain, the McGill questionnaire to classify the descriptors that represent the quality of the pain, and the Boston questionnaire for assessing symptom severity and disability. RESULTS: The most representative descriptors were the presence of tingling (92%), heaviness (67%) and a feeling of swelling (64%). The women with mild CTS showed a longer history of pain than those with moderate and severe CTS (p < 0.05). There were no significant differences among the intensity of the pain, the disability questionnaire and most of the descriptors on the McGill questionnaire between the different groups of mild, moderate or severe CTS. The women with severe CTS described the pain as being periodic, repetitive and terribly unpleasant more often than those with mild or moderate CTS (p < 0.05). CONCLUSIONS: The presence of tingling and the feeling of heaviness are the most prevalent symptoms of CTS. There are no great differences in the quality of the pain among cases of mild, moderate or severe CTS. PMID- 22451128 TI - [Change of treatment in patients with multiple sclerosis and its consequences in clinical practice]. AB - INTRODUCTION: Thirty per cent of patients with multiple sclerosis (MS) present a suboptimal response to treatment in the first few years. The real impact of the change of treatment has still not been well established. AIMS: To describe our clinical practice with regard to the change of treatment in MS patients with a suboptimal response and to analyse their progress depending on our therapeutic decisions. PATIENTS AND METHODS: The study is observation-based and retrospective. The sample was made up of patients with relapsing-remitting MS and at least one event after establishing immunomodulatory treatment. Both the intention to change treatment and the delays until the actual change took place were taken into account. The theoretical consequences of these strategies were measured by the changes in the expected curve of the Multiple Sclerosis Severity Scale (MSSS). RESULTS: A comparison of those who changed immunomodulator with those that did not showed that 64.3% versus 35.3%, respectively, improved on the expected curve of the MSSS (p > 0.05). Patients who improved the expected curve of the MSSS had changed treatment before those who did not improve (1.9 months versus 6 months), although the differences were not significant. The mean time that elapsed between taking the decision to change and actually changing the treatment was 2.70 +/- 3.55 months. CONCLUSIONS: Despite limitations due to the size of the sample, the patients with a suboptimal response who changed treatment early could benefit from an improvement in their expected progression on the MSSS. PMID- 22451129 TI - [Fast and spectacular clinical response to plasmapheresis in a paediatric case of anti-NMDA encephalitis]. AB - INTRODUCTION: Autoimmune encephalitis against N-methyl-D-aspartate (NMDA) receptors is being diagnosed more and more frequently in the paediatric age. It should be suspected in children with psychiatric symptoms, encephalopathy, abnormal movements or epileptic seizures. Paraneoplastic cases are less frequent than in adults. CASE REPORT: We report the case of a boy, 2.5 years of age, with subacute encephalopathic signs and symptoms and epileptic seizures followed by behaviour disorders, neurological regression, dyskinesias and insomnia. Results of a cerebrospinal fluid study were normal, the magnetic resonance scan of the head revealed a focal periventricular lesion and diffuse leptomeningeal uptake; moreover, the serial electroencephalograms showed high-amplitude delta activity interspersed with generalised intercritical epileptiform activity. The patient was given empirical treatment with high doses of corticoids and intravenous immunoglobulins with no response. After showing up positive for antibodies against the NMDA receptor, plasmapheresis was begun, which led to his swift and spectacular recovery. After more than 18 months' follow-up, his sequelae are limited to mild behavioural and language alterations. He has had no relapses and has not needed any kind of maintenance treatment. CONCLUSIONS: Anti-NMDA encephalitis is a treatable disorder and, sometimes, the first evidence of an underlying neoplasia, which makes its early recognition and treatment essential. Treatment of the non-paraneoplastic forms are based on immunotherapy: glucocorticoids, intravenous immunoglobulins, plasmapheresis and immunosuppressants. Plasmapheresis can bring about a fast, spectacular improvement. PMID- 22451130 TI - [Orthostatic tremor: an enigmatic condition]. AB - INTRODUCTION: Orthostatic tremor is a rare kind of tremor which is clinically characterised by a feeling of instability or being about to fall that is experienced on standing up, which disappears or improves on walking and is absent when sitting or lying down. AIM: To shed light on the main features of this tremor syndrome. DEVELOPMENT: First, its clinical spectrum is defined, with emphasis on the key characteristics that enable us to make an initial approximation to its syndromes. Then the main neurophysiological features that make up the electromyographic profile of orthostatic tremor are described. Finally, the pathophysiological hypotheses regarding the genesis of this kind of tremor are addressed and the therapeutic options currently available are described. CONCLUSIONS: The convergence of all the data reviewed provides a complete, critical analysis of this enigmatic motor disorder, thus allowing a rigorous approach to its main characteristics, which makes both its clinical recognition and its therapeutic management easier. PMID- 22451131 TI - [Electroencephalographic normal variants or with uncertain significance]. AB - Electroencephalography is an important tool in the diagnosis of primary or secondary disorders of central nervous system, epilepsy is one of the most important. Sometimes normal electroencephalographic activity simulates epileptiform activity. This activity does not have pathological value and is considered a variant of normal brain activity. The main groups based on the classification proposed by Blum and Cervone are: rhythmic patterns; epileptiform patterns; lambda waves, and age dependent changes. These changes are frequently seen during drowsiness, sleep and during activation maneuvers and more common in children and adolescents. The aim of this review is to present the most important characteristics of each of these variants, in order to prevent them being confused with abnormal brain activity. PMID- 22451132 TI - [Spontaneous intracranial hypotension syndrome: importance of magnetic resonance findings]. PMID- 22451133 TI - [Budget impact analysis of the first-line treatment of relapsing remitting multiple sclerosis in Spain]. PMID- 22451135 TI - Biomechanical comparison of strategies to adjust axial stiffness of a hybrid fixator. AB - OBJECTIVES: To evaluate strategies for increasing the axial stiffness of a hybrid external bone fixator. MATERIALS AND METHODS: Type Ia hybrid fixators, consisting of a uniplanar linear component connected to a circular ring, were tested in displacement controlled loading in axial compression. The basic hybrid construct was modified to explore strategies considered to increase fixator stiffness including: decreasing ring diameter, increasing ring thickness, adding pins to the ring fixation, and adding struts between the ring and vertical post components of the device. Stiffness in the initial phase of loading was compared between the groups. RESULTS: The addition of a single diagonal bar between the ring and linear connecting rail did not significantly improve the stiffness of constructs. However, the addition of two half-pins to the ring, the addition of two struts between the ring and linear connecting rail, or decreasing the internal ring diameter from 115 to 85 mm progressively increased the stiffness of the frame. The most effective strategy consisted of increasing the thickness of the ring from 6 to 12 mm, thereby increasing the stiffness of the control frame by 335%. CLINICAL SIGNIFICANCE: Modulating the ring thickness, adding two struts between the ring and linear connecting rail, and reducing the ring diameter appear to be the most effective, simple, and clinically versatile ways to increase axial stiffness, most likely due to their impact on reducing ring bending. PMID- 22451136 TI - Characterization of the human papillomavirus (HPV) integration sites into genital cancers. AB - Oncogenic HPVs have been found frequently integrated into human genome of invasive cancers and chromosomal localization has been extensively investigated in cervical carcinoma. Few studies have analyzed the HPV integration loci in other genital cancers. We have characterized the integration sites of HPV16 in invasive penile carcinoma by means of Alu-HPV-based PCR. Nucleotide sequence analysis of viral-human DNA junctions showed that HPV integration occurred in one case within the chromosome 8q21.3 region, in which the FAM92A1 gene is mapped, and in the second case inside the chromosome 16p13.3, within the intronic region of TRAP1 gene. These results confirm previous observations, summarized in a systematic review of the literature, on the HPV integration events in gene loci relevant to cancer pathogenesis. PMID- 22451137 TI - Major effect of retinal short-chain dehydrogenase reductase (RDHE2) on bovine fat colour. AB - Beef with yellow fat is considered undesirable by consumers in most European and Asian markets. beta-Carotene is the major carotenoid deposited in the adipose tissue and milk fat of cattle (Bos taurus), which can result in the yellowness. The effects of retinal short-chain dehydrogenase reductase (RDHE2) and beta, beta carotene 9',10-dioxygenase (BCO2) were considered jointly as major candidate genes for causing the yellow fat colour, based on their genomic locations in the fat colour quantitative trait loci (QTL) and their roles in the metabolism of beta-carotene. In a secondary pathway, BCO2 cleaves beta-carotene into retinoic acid, the most potent form of vitamin A. RDHE2 converts trans-retinol to trans retinal, a less active form of vitamin A. We evaluated the effects of two amino acid variants of the RDHE2 gene (V6A and V33A) along with a mutation in the BCO2 gene that results in a stop codon (W80X) in seven cattle populations. The RDHE2 V6A genotype affected several fat colour traits but the size of the effect varied in the populations studied. The genotype effect of the RDHE2 V33A variant was observed only in New Zealand samples of unknown breed. In general, the individual effects of RDHE2 V6A and V33A SNPs genotypes were greater in the random New Zealand samples than in samples from pedigreed Jersey-Limousin backcross progeny, accounting for 8-17 % of the variance in one population. Epistasis between the BCO2 W80X and RDHE2 variants was observed, and in some populations this explained more of the variation than the effects of the individual RDHE2 variants. PMID- 22451138 TI - Essential requirements of information technology for primary care. PMID- 22451139 TI - Drug-related problem in children with chronic kidney disease. AB - Drug therapies in the management of chronic kidney disease (CKD) are complex and specialised and have a high potential for drug-related problem (DRP). In adult CKD populations, the identification and resolution of DRP has been shown to have beneficial effects on disease management, adherence and knowledge of treatment, patient's quality of life, hospitalisation rate and length of stay and cost to the healthcare system. The focus of this article is the review of published studies on DRP in children with CKD. There is a lack of information on the epidemiology of DRP in this patient group, and research in this area is therefore needed to better understand and manage DRP in children with CKD. PMID- 22451140 TI - Synergistic effect of scaffold composition and dynamic culturing environment in multilayered systems for bone tissue engineering. AB - Bone extracellular matrix (ECM) is composed of mineralized collagen fibrils which support biological apatite nucleation that participates in bone outstanding properties. Understanding and mimicking bone morphological and physiological parameters at a biological scale is a major challenge in tissue engineering scaffolding. Using emergent (nano)technologies scaffold designing may be critically improved, enabling highly functional tissue substitutes for bone applications. This study aims to develop novel biodegradable composite scaffolds of tricalcium phosphate (TCPs) and electrospun nanofibers of poly(epsilon caprolactone) (PCL), combining TCPs osteoconductivity with PCL biocompatibility and elasticity, mimicking bone structure and composition. We hypothesized that scaffolds with such structure/composition would stimulate the proliferation and differentiation of bone marrow stromal cells (BMSCs) towards the osteogenic phenotype. Composite scaffolds, developed by electrospining using consecutive stacked layers of PCL and TCPs, were characterized by FTIR spectroscopy, X-Ray diffraction and scanning electronic microscopy. Cellular behavior was assessed in goat BMSCs seeded onto composite scaffolds and cultured in static or dynamic conditions, using basal or osteogenic media during 7, 14 or 21 days. Cellular proliferation was quantified and osteogenic differentiation confirmed by alkaline phosphatase activity, alizarin red staining and immunocytochemistry for osteocalcin and collagen I. Results suggest that PCL-TCP scaffolds provide a 3D support for gBMSCs proliferation and osteogenic differentiation with production of ECM. TCPs positively stimulate the osteogenic process, especially under dynamic conditions, where PCL-TCP scaffolds are sufficient to promote osteogenic differentiation even in basal medium conditions. The enhancement of the osteogenic potential in dynamic conditions evidences the synergistic effect of scaffold composition and dynamic stimulation in gBMSCs osteogenic differentiation. PMID- 22451141 TI - Trends in and perspectives on extracorporeal membrane oxygenation for severe adult respiratory failure. AB - Various approaches such as ventilator management involving lung-protective ventilation, corticosteroids, prone positioning, and nitric oxide have failed to maintain sufficient lung oxygenation or appropriate ventilation competence in very severe acute respiratory distress syndrome (ARDS). Extracorporeal membrane oxygenation (ECMO) has been aggressively introduced for such patients, although in only a few institutions. The clinical usefulness of ECMO in a large-scale multicenter study (CESAR trial, 2009) and continued development/improvement of ECMO devices have facilitated performance of ECMO, with further increase in the number of institutions adopting ECMO therapy. Clinical usefulness of ECMO was documented in many cases of severe ARDS secondary to influenza A (H1N1) 2009 infection. ECMO requires establishment of an appropriate management system to minimize fatal complications (e.g., hemorrhage), which requires a multidisciplinary team. This, in combination with a new technique, interventional lung assist, will further extend the indications for ECMO. ECMO can be expected to gain importance as a respiratory support technique. PMID- 22451142 TI - Outcomes and long-term quality of life of patients with severe left ventricular dysfunction who underwent coronary artery bypass surgery. AB - PURPOSE: The aim of this study was to identify determinants of long-term results after coronary artery bypass surgery (CABG) in group of Iranian patients with systolic left ventricular (LV) dysfunction. METHODS: Reduced LV function was defined as an LV ejection fraction of <30%. Using our surgery database, we randomly selected 110 patients with EF < 30% and the same number of patients with EF >= 30% for whom demographic and clinical characteristics as well as in hospital postoperative outcomes were available. Followup data were completed for 94 patients with EF < 30% (85.5%) and 101 patients with EF >= 30% (91.8%). Longterm results of the operation and the patients' quality of life were assessed for a mean follow-up period of 29.4 +/- 11.0 months. RESULTS: In-hospital mortality and follow-up survival rates had no statistically differences in the low and normal EF groups (2.2% vs. 1.1% and 86.0% vs. 93.6%, respectively). Long term surgical morbidity occurred in 43.6% of patients with severe LV dysfunction and in 38.6% of normal EF patients; it was considered similar for the two groups. Family history of coronary artery disease, New York Heart Association class IV, and moderate mitral insufficiency were the main predictors of long-term morbidity. Regarding the quality-of-life assessment, patients with severe LV dysfunction attained significantly lower levels of social activities. CONCLUSION: Patients with severe LV dysfunction in comparison with those with normal LV function had similar 3-year survival rates and long-term complications. To improve survival following CABG in patients with severe LV dysfunction, mitral valve repair/replacement at the time of the initial operation should be considered. PMID- 22451143 TI - Survival and quality of life of octogenarians who underwent mechanical valve replacement at a younger age. AB - PURPOSE: Mechanical valve replacement is associated with complications, however, there is little information on the quality of life (QOL) of octogenarians who had undergone mechanical valve replacement at a relatively younger age. We examined survival, valve-related events, and the QOL of octogenarians who had undergone mechanical valve replacement. METHODS: A total of 56 octogenarians who underwent mechanical valve replacement between 1969 and 1997 (age at the time of surgery, 65.6 +/- 6.7 years), completed a questionnaire on survival, valve-related events, and QOL (basic activities of daily living, instrumental activities of daily living, mental health). RESULTS: The mean follow-up was 12.4 +/- 6.6 years, and the cumulative follow-up period was 642.4 patient-years. Six valve-related deaths (0.9%/patient-year) were registered during the follow-up. Furthermore, 11 valve related events (1.8%/patient-year) were recorded. The mean age of the 21 survivors was 82.9 +/- 1.8 years, and 19 of the survivors lived at home. Their QOL was excellent. CONCLUSION: The valve-related deaths and events in octogenarians who had previously undergone mechanical valve replacement at a younger age were within acceptable limits. The QOL was similar to that of octogenarians described in previous studies. PMID- 22451144 TI - Propensity analysis of outcome in coronary artery bypass graft surgery patients >75 years old. AB - PURPOSE: We looked at the complications and hospital resources of an elderly population undergoing first-time isolated coronary artery bypass graft surgery (CABG) in comparison to a younger counterpart for a propensity matched cohort. METHODS: A retrospective analysis of prospectively collected data was conducted on 2804 CABG patients. Two age groups, >75 years and <=75 years, were generated. Potential differences in demographic, baseline, preoperative, and intraoperative characteristics were investigated. A propensity score based on these differences was calculated and used to create a matched set of patients. Major postoperative complications were recorded, and data on indicators of resource utilization were collected. RESULTS: In all, 311 (11.1%) patients were identified as >75 years of age. The observed complication rate was significantly higher in overall, pulmonary, cardiac, renal, gastrointestinal (GI), neurological, infective, and mortality categories (P < 0.0001). Observed hospital resource utilization was significant in the elderly group in terms of initial stay in the intensive care unit (ICU) and ICU readmission (P < 0.05) and in all preoperative, postoperative, cardiac surgery, and total hospital stays (P < 0.001). However, after propensity matching to 311 patients <=75 years, the overall postoperative complication rate maintained its significance (P < 0.0001), in addition to atrial fibrillation and neurological, renal, and GI complications (P < 0.05). Elderly patients required longer duration of ventilation postoperatively and longer postoperative stay, cardiac surgery stay, and total hospital stay; and they maintained a higher surgical mortality rate (6.1% vs. 2.6%) (P < 0.05). CONCLUSION: Elderly patients undergoing CABG had significantly higher rates of postoperative complications. Their prolonged hospital stay and consequently higher resources utilization need to be adequately highlighted to heath care officials and appropriately addressed. PMID- 22451145 TI - Isolated dissecting aneurysm of the brachiocephalic artery associated with contained rupture. AB - A 79-year-old man with no history of trauma complained of a sudden onset of headache and backache. Computed tomography showed an isolated dissecting aneurysm 4 cm in diameter associated with contained rupture at the takeoff region of the brachiocephalic artery. Surgery was performed on an emergent basis. The proximal aortic arch was successfully replaced using antegrade selective cerebral perfusion. The patient was easily weaned from cardiopulmonary bypass and recovered uneventfully. PMID- 22451146 TI - Combined aortic valve replacement and coronary artery bypass grafting for a calcified ascending aorta. AB - Although a severely calcified ascending aorta is encountered infrequently, it presents formidable problems during cardiac surgery. We describe a case of severe aortic valve stenosis and coronary artery disease combined with a severely calcified ascending aorta. The patient was an 80-year-old man with a calcified ascending aorta. He successfully underwent an aortic valve replacement and a single coronary artery bypass graft (CABG) using a saphenous vein graft with the proximal end connected on a Dacron patch, which was used for aortoplasty of the calcified plate along the aortotomy. These procedures were performed under moderate hypothermia with aortic clamping. This patch aortoplasty can be a useful alternative in cases that require aortotomy and proximal anastomoses of a CABG on a calcified ascending aorta. PMID- 22451147 TI - Surgical resection and reconstruction for a giant cell tumor of the anterior rib. AB - Giant cell tumors (GCTs) are rare neoplasms, most commonly arising in the metaphysis/epiphysis of long bones. They consist of multinucleated giant cells with surrounding spindle-shaped mononuclear stromal cells. GCTs rarely appear in the ribs. We report a case of a GCT originating from the anterior arc of the fourth rib in a 31-year-old man who presented with a progressively growing thoracic mass in the left anterior chest wall. Thoracotomy involving en bloc resection of the chest wall and tumor and a reconstruction of the chest wall were performed. PMID- 22451148 TI - Intrathoracic ganglioneuroma surrounding left vertebral and subclavian arteries successfully resected by modified trapdoor thoracotomy. AB - Neurogenic tumors are derived from tissue of the neural crest. Most of the mediastinal neurogenic tumors occur in the posterior compartment. Extension to the cervical area and the surrounding major arteries is rare. We report a patient with a ganglioneuroma arising from the brachial plexus, extending into the cervical region, and surrounding the left vertebral and subclavian arteries. The patient underwent successful resection by modified trapdoor thoracotomy. PMID- 22451149 TI - cT1aN0M0 lung adenocarcinoma treated with left S9+10 segmentectomy followed by completion lobectomy for a solitary metastasis (isolated tumor cells) in the neighboring segmental lymph node. AB - A 47-year-old woman with a lung adenocarcinoma of 1.3 cm located in the left S9+10 was treated by S9+10 segmentectomy with sentinel node (SN) identification using radioisotopes. During segmentectomy, frozen section of the segmental nodes at S9+10 and S6, identified as SNs, did not show metastasis; however, postoperative immunohistochemical staining with cytokeratin revealed isolated tumor cells in the segmental node at S6. None of the other dissected nodes, including the hilar, interlobar, and mediastinal nodes, showed metastasis, even with immunohistochemical staining. Completion lobectomy was conducted 6 days after segmentectomy, and the resected specimens did not show further metastasis. The final pathological diagnosis was adenocarcinoma with pT1aN0(i+)M0 stage A. The present case was indicative of the importance of dissecting the segmental lymph node located not only at the tumor-bearing segment but also at the neighboring segment, especially the one located between the primary tumor and the lobar bronchi. PMID- 22451150 TI - Anastomosis of left to right superior vena cava for repair of unroofed coronary sinus. AB - Left superior vena cava (LSVC) draining into the left atrium is a rare congenital cardiac complex. It may appear as an isolated anomaly or as part of more complex cardiac anomalies. Intraatrial rerouting techniques have been the most common approaches to correcting LSVC drainage into the left atrium in patients without a connecting vein. Although these techniques have proved reliable and successful, there are cases in which extracardiac methods for managing this form of anomalous systemic drainage may be preferable. In the present report, we describe an extracardiac approach to the correction of LSVC draining into the left atrium. PMID- 22451151 TI - Aortic arch occlusion technique using a balloon during open proximal anastomosis. AB - We report a new aortic arch occlusion technique with a balloon for distal aortic arch repair via left thoracotomy using an open proximal method. Distal aortic arch repair via left thoracotomy sometimes causes brain infarction and perioperative myocardial infarction. That is because air or debris enters into coronary arteries and cervical branches and the left ventricle. Occlusion of the aortic arch using a balloon can prevent such perioperative complications. PMID- 22451152 TI - Bronchoplasty with continuous sutures for non-small-cell lung cancer. AB - Bronchoplasty is sometimes performed in patients with compromised lung function to preserve functional lung parenchyma. Although the bronchial anastomosis was generally performed with interrupted sutures, we applied it with continuous sutures by using monofilament absorbable material in two patients with non-small cell lung cancers to obtain a good operative view and shorten the operating time. These patients recovered uneventfully with good healing of the bronchial anastomosis. Bronchial anastomosis with continuous sutures is considered a useful technique. PMID- 22451154 TI - Magnetic transport, mixing and release of cargo with tailored nanoliter droplets. PMID- 22451153 TI - Identification and characterization of genes related to the development of breast muscles in Pekin duck. AB - Pekin Duck is world-famous for its fast growth, but its breast muscle development is later and breast muscle content is lower compared with other muscular ducks. Therefore, it is very important to discover the genetic mechanism between breast muscle development and relative gene expression in Pekin duck. In current study, the genes which have relationships with breast muscle development were identified by suppression subtractive hybridization. A total of 403 positive clones were sequenced and 257 unigenes were obtained. The expression of 23 genes were analyzed in the breast muscle of 2-, 4-, 6-, 8- week old Pekin ducks. The results showed that unknown clone A233, C83 and C99 showed descending tendency as age increased; KBTBD10, HSPA8, MYL1, ZFP622, MARCH4, Nexilin, FABP4 and MUSTN1 had high expression levels at 6 weeks old; WAC, NT5C3, HSP90AA1, MRPL33, KLF6, TSNAX, CDC42EP3, HSPA4, TRAK1, NR2F2, HAUS1 and IGF1 had high expression levels at 8 weeks and showed ascending tendency as age increased. Expression of these 23 genes were also analyzed in breast muscle, leg muscle, heart, kidney, liver, muscular stomach and sebum cutaneum in 4-8-week old Pekin duck and results showed that most of these genes had high expression in breast muscle, leg muscle and heart. PMID- 22451155 TI - Associations between cognitive impairment in advanced cancer patients and psychiatric disorders in their caregivers. AB - OBJECTIVE: This study examined whether cognitive impairment in advanced cancer patients is associated with a heightened frequency of psychiatric disorders in their primary caregivers. METHODS: Three hundred fifty-six patient-caregiver dyads were interviewed and administered the Short Portable Mental Status Questionnaire and the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition approximately 3.4 months before the patient's death. The Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition was administered to caregivers again approximately 6 months after the patient's death. RESULTS: Forty six (12.9%) patients displayed signs of mild cognitive impairment at the baseline interview. After adjustment for relevant confounders, patient cognitive impairment was significantly associated with caregiver pre-loss major depressive disorder [OR 6.88 (95% CI 1.32-35.92); p = 0.02], without associated increases in suicidality. There were no significant associations between patient cognitive impairment and caregiver pre-loss generalized anxiety disorder, posttraumatic stress disorder, panic disorder, or grief. Likewise, there were no significant associations between patient cognitive impairment and caregiver post-loss psychiatric disorders, but caregivers of cognitively impaired patients appeared to be less satisfied with the patient's manner of death (p = 0.01). CONCLUSIONS: Caregivers of cognitively impaired advanced cancer patients appear at heightened risk of major depression that resolves after the patient's death. Further study with a larger sample and more sensitive longitudinal cognitive measures is indicated. PMID- 22451157 TI - Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally bioavailable cytotoxic and vascular-disrupting agent. AB - PURPOSE: CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. EXPERIMENTAL DESIGN: We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: A total of 56 doses were administered to 21 patients over 8 dose levels (15-164 mg/m(2)). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11 fold dose range. At doses of 84 mg/m(2) and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour K(trans) in some patients. CONCLUSIONS: CYT997 is orally bioavailable. The 118 mg/m(2) dose level should be used to guide dosing in future studies. PMID- 22451158 TI - The wide-angle point spread function of the human eye reconstructed by a new optical method. AB - The point spread function (PSF) of the human eye spans over a wide angular distribution where the central part is associated mostly to optical aberrations while the peripheral zones are associated to light scattering. There is a plethora of optical methods for the direct and indirect measurements of the central part of the PSF as a result of monochromatic and polychromatic aberrations. The impact of the spatial characteristics of this central part of the PSF on the retinal image quality and visual function has been extensively analyzed and documented both by optical and psychophysical methods. However, the more peripheral areas of the PSF in the living human eye, ranging from about 1 to 10 degrees of eccentricity, have been investigated only psychophysically. We report here a new optical method for the accurate reconstruction of the wide angle PSF in the living human eye up to 8 degrees. The methodology consists of projecting disks of uniform radiance on the retina, recording the images after reflection and double pass through the eye's optics and performing a proper analysis of the images. Examples of application of the technique in real eyes with different amount of scatter artificially induced are presented. This procedure allows the direct, accurate, and in vivo measurement of the effect of intraocular scattering and may be a step toward the comprehensive optical evaluation of the optics of the living human eye. PMID- 22451159 TI - Plasma amyloid-beta as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. AB - BACKGROUND: Preclinical prediction of Alzheimer disease (AD) is important and critical to effective intervention. Plasma levels of amyloid-beta (Abeta) peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods, and sample size, making it difficult to readily interpret the overall data. OBJECTIVE: To conduct a systematic review and meta-analysis of relevant prospective studies to determine whether plasma amyloid-beta levels may predict development of dementia, AD, and cognitive decline. DESIGN: We searched prospective studies published between 1995 and 2011 indexed in the MEDLINE, EMBASE, and PsycINFO databases. Selected studies included those measuring at least 1 relevant plasma amyloid-beta species (Abeta(40), Abeta(42), or Abeta(42):Abeta(40) ratio) and reporting an effect estimate for dementia, AD, or cognitive change. MAIN OUTCOME MEASURES: Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were used to generate summary risk ratios and 95% confidence intervals comparing the bottom vs top quantiles for each plasma measure. RESULTS: Thirteen studies with a total of 10 303 subjects met inclusion criteria for meta-analysis. Lower Abeta(42):Abeta(40) ratios were significantly associated with development of AD (summary risk ratio, 1.60; 95% CI, 1.04-2.46; P = .03) and dementia (risk ratio, 1.67; 95% CI, 1.02-2.75; P = .04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants' age, sex distribution, the study's follow-up time, or year of publication. Plasma levels of Abeta(40) and Abeta(42) alone were not significantly associated with either outcome. CONCLUSIONS: Overall, the literature indicates that plasma Abeta(42):Abeta(40) ratios predict development of AD and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid-beta levels as a preclinical biomarker. PMID- 22451160 TI - 4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations. AB - OBJECTIVE: To report a novel clinical and genetic presentation of a patient with 4H syndrome, which is a recently described leukodystrophy syndrome characterized by ataxia, hypomyelination, hypodontia, and hypogonadotropic hypogonadism. DESIGN: Case report. SETTING: University teaching hospital. PATIENT: A 20-year old male patient with 4H syndrome. RESULTS: The patient was found to have delayed tooth eruption and a late-onset growth hormone deficiency without overt growth failure. He was a compound heterozygote for the novel missense mutations R1005H and A1331T of POLR3A, which codes for the largest subunit of RNA polymerase III. CONCLUSION: This is the first report of this type of leukodystrophy from southeastern Europe, which suggests that POLR3A mutations should be suspected in patients with hypomyelination and various central nervous system-based endocrine abnormalities. PMID- 22451161 TI - Autoantibodies in the patient with drug-resistant epilepsy: are we missing a treatable etiology? PMID- 22451163 TI - An unusual case of lower leg weakness. PMID- 22451162 TI - Autoimmune epilepsy: clinical characteristics and response to immunotherapy. AB - OBJECTIVE: To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. DESIGN: Observational, retrospective case series. SETTING: Mayo Clinic Health System. PATIENTS: Thirty-two patients with an exclusive (n=11) or predominant (n=21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more antiepileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response- mediator protein 5 in 6%; and Ma2, N-methyl-D aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. INTERVENTION: Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. MAIN OUTCOME MEASURE: Seizure frequency. RESULTS: After a median interval of 17 months (range, 3-72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody-positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody-positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone. CONCLUSION: When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome. PMID- 22451164 TI - Preparation and application of steeps of tea as new simulations of urine for the performance testing programme of 14C. AB - (14)C is one of the radionuclides for which the Canadian Nuclear Safety Commission has developed performance testing programmes (PTPs). During the PTP exercises, clients receive samples of natural urine containing spiked radionuclides, for testing. In these programmes, urine has disadvantages. These include (1) slow collection times from donors, (2) unpleasant smell and (3) potential to transmit diseases. To assist in solving some of these problems, the Canadian National Calibration Reference Centre for Bioassay and In Vivo Monitoring has conducted research with tea solutions, to find simpler, safer and more readily available alternatives to urine. This paper provides a new technique by which steeps of black tea have been successfully prepared for the (14)C PTP. The results of tea solutions compared well with those of urine. It was concluded that tea steeps, of which the spectroscopic and colour quenching properties have been adjusted, do provide appropriate urine simulations, suitable for use in PTPs. PMID- 22451165 TI - Occurrence of Vibrio cholerae in municipal and natural waters and incidence of cholera in Azerbaijan. AB - Cholera, a waterborne disease caused by Vibrio cholerae, is an autochthonous member of the aquatic environment and predominantly reported from developing countries. Technical reports and proceedings were reviewed to determine the relationship between occurrence of V. cholerae in natural waters, including sources of municipal water, and cases of cholera in Azerbaijan. Water samples collected from different environmental sources from 1970 to 1998 were tested for V. cholerae and 0.73% (864/117,893) were positive. The results showed that in April of each year, when the air temperature rose by approximately 5 degrees C, V. cholerae could be isolated. With each increase in air temperature, 6-8 weeks after, impact on cases of cholera was recorded. The incidence of cholera peaked when the air temperature reached >25 degrees C during the month of September. It is concluded that a distinct seasonality in cholera incidence exists in Azerbaijan, with increased occurrence during warmer months. PMID- 22451166 TI - Is there such thing as a parasite free lunch? The direct and indirect consequences of eating invasive prey. AB - As the number of invasive species increases globally, more and more native predators are reported to shift their diet toward invasive prey. The consequences of such diet shifts for the health of populations of native predators are poorly studied, but diet shifts are expected to have important parasitological and immunological consequences, ultimately affecting predator fitness. We reviewed evidence that diet shifts from native to invasive prey can alter parasite exposure directly and also indirectly affect immune functions via changes in condition and contaminant exposure. We highlight relevant conceptual and methodological tools that should be used for the design of experiments aimed at exploring important links between invasive prey and parasitism, contaminants and fitness of their native predators. PMID- 22451167 TI - Computerized measurements of radiographic anatomical parameters of the elbow joint in Bernese Mountain Dogs. AB - OBJECTIVE: Comparison of two methods for evaluation of anatomical parameters of elbow joints in Bernese Mountain Dogs. STUDY DESIGN: Radiographic analysis. ANIMALS: Nine hundred and thirty-one radiographs of elbow joints from 305 Bernese Mountain Dogs. MATERIAL AND METHODS: The angles OL, PA, RA and UL were measured according to the Mues method and the Radius of the humeral condyle, Opening angle beta, Quotient Q and Ae, Area X, Step 1 and Step 2 according to the Viehmann method. The radiographs were divided according to their angle of flexion into five groups: 0-30 degrees , 31-60 degrees , 61-90 degrees , 91-120 degrees and >120 degrees . The difference and the correlation between measured values and the elbow dysplasia (ED) score was calculated and compared. RESULTS: The average values of angle OL, PA and RA, Area X, Step 1 and Step 2 were significantly different within the different elbow flexion angle groups. The values of Opening angle beta, Quotients Q and Ae as well as Radius of the humeral condyle varied independently from the degree of the elbow flexion on the radiograph. The angles OL, PA and RA and the Radius of the humeral condyle, the Opening angle beta, the Quotients Q and Ae, Step 1 and Step 2 correlated with the ED score. CONCLUSION: In contrast to the method of Mues, the majority of the measured parameters of the method of Viehmann were not influenced by the degree of flexion of the elbow joint and correlated with the ED score. CLINICAL RELEVANCE: The method of Viehmann warrants consideration for the evaluation of radiographs of elbow joints in the Bernese Mountain Dog for ED. PMID- 22451168 TI - Standardized ex vivo comparison of different upper urinary tract biopsy devices: impact on ureterorenoscopes and tissue quality. AB - OBJECTIVES: To evaluate the influence of different biopsy forcipes on the deflection, irrigant flow, and optical characteristics of flexible ureterorenoscopes and to assess tissue quality for histopathologic evaluation in an ex vivo setting. MATERIALS AND METHODS: The following five different biopsy forcipes were compared: Olympus (FB-56D-1; diameter 5Fr.), R. Wolf (829.601; 3Fr.), Karl Storz Medical (11275ZE; 3Fr.), Boston Scientific (Piranha; 505-160; 3 Fr.), and Cook BIGopsy (115CM; 2.4 Fr.). The devices were tested in 3 different ureterorenoscopes: Storz 11278 VU (Flex-X(2)), Storz 11278 V (Flex-X(C)), and Wolf Cobra (7326071/-6). Tissue samples were obtained from porcine upper urinary tracts. RESULTS: Baseline irrigation flow rates with empty channels were significantly higher in the Wolf Cobra than in Storz ureterorenoscopes (30.5 vs. 23 and 21 ml/min). The BIGopsy forceps allowed for higher flow rates in both Storz ureterorenoscopes (2.2 and 1.3, respectively) when compared to the other devices (0.5 and 0.6 ml/min). The Storz and Wolf biopsy forcipes resulted in the highest impairment of the deflection angle. In all 3 ureterorenoscopes, flow rates and deflection angle were least impaired by the BIGopsy. However, BIGopsy compromised the field of view (20 % reduction vs. 12 % by others). The largest sample of renal pelvis and ureter biopsies was obtained with BIGopsy and Storz((r)) forcipes, respectively. The extent of artifacts and denuded urothelium were comparable in all samples. CONCLUSIONS: The various biopsy devices showed different impacts on irrigation flow, deflection, and field of view. The Cook BIGopsy best retains irrigation flow in single-channel flexible ureterorenoscopes and deflection. However, a smaller field of view may complicate handling and tissue acquisition. PMID- 22451169 TI - Effects of different ventilation strategies on lung injury in newborn rabbits. AB - BACKGROUND: The results from experimental and clinical studies have shown that mechanical ventilation (MV) and/or hyperoxia may aggravate a pre-existing lung injury, or even cause lung injury in healthy lungs, despite the fact that it might be the only life-saving intervention available to a patient. The present study was designed to investigate the roles of MV and hyperoxia in the pathogenesis of lung injury. METHODS: Newborn New Zealand white rabbits were randomly assigned to an unventilated air control group or to one of the 2 * 3 * 3 ventilation strategies using a factorial design. The experimental groups were assigned different fractions of inspired oxygen (FiO(2)), peak inspiratory pressures (PIP), and respiratory times (RT). The lung wet-to-dry ratio (W/D), lung histopathology scores, and cells in the bronchoalveolar lavage fluid (BALF) were analyzed for each group. The apoptosis levels were studied by immunohistochemistry and a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: Different ventilation regimes induced alterations in microvascular permeability, differential histopathological grading, WBC and/or neutrophil and/or lymphocyte influx, and apoptosis levels; moreover, there were significant correlations and interaction effects between these indices. CONCLUSIONS: Our data demonstrate that different ventilation regimes can induce lung injury and that the interaction effects of the FiO(2), the PIP and the RT may play crucial roles in the pathogenesis of lung injury. PMID- 22451170 TI - Chain-length-identification strategy in zinc polyphosphate glasses by means of XPS and ToF-SIMS. AB - The surface chemistry of amorphous zinc polyphosphates of different compositions (ranging from zinc metaphosphate to zinc orthophosphate) has been investigated by means of X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary-ion mass spectroscopy (ToF-SIMS). The identification of the chain length of zinc polyphosphates by XPS was on the basis of the integrated intensity ratio of the bridging (P-O-P) and nonbridging (P = O and P-O-M) oxygen peaks used for fitting the oxygen 1s signal, the shift of the P 2p(3/2) signal towards lower binding energies and the modified Auger parameter towards higher values as the zinc content increases. The discrimination of the polyphosphate chain lengths was also achieved by ToF-SIMS, by comparing the intensities of selected characteristic phosphate fragments. Both techniques appear to be suitable for the investigation of polyphosphate glasses in applications such as tribology, where there is a need to identify the chain length present in the outermost monolayer of the film. Fourier-transform infrared (FT-IR) spectroscopy was used to characterize the bulk compounds. The FT-IR studies showed that long-chain structures linked through P-O P bonds predominate in the metaphosphate composition, while when the zinc content is increased, the chains become shorter, ultimately being replaced by PO(4) monomers in the orthophosphate composition. PMID- 22451171 TI - Single-molecule emulsion PCR in microfluidic droplets. AB - The application of microfluidic droplet PCR for single-molecule amplification and analysis has recently been extensively studied. Microfluidic droplet technology has the advantages of compartmentalizing reactions into discrete volumes, performing highly parallel reactions in monodisperse droplets, reducing cross contamination between droplets, eliminating PCR bias and nonspecific amplification, as well as enabling fast amplification with rapid thermocycling. Here, we have reviewed the important technical breakthroughs of microfluidic droplet PCR in the past five years and their applications to single-molecule amplification and analysis, such as high-throughput screening, next generation DNA sequencing, and quantitative detection of rare mutations. Although the utilization of microfluidic droplet single-molecule PCR is still in the early stages, its great potential has already been demonstrated and will provide novel solutions to today's biomedical engineering challenges in single-molecule amplification and analysis. PMID- 22451172 TI - Highly efficient precipitation of phosphoproteins using trivalent europium, terbium, and erbium ions. AB - This study describes a highly efficient method for the selective precipitation of phosphoproteins by trivalent europium, terbium, and erbium metal ions. These metal cations belong to the group of lanthanides and are known to be hard acceptors with an overwhelming preference for oxygen-containing anions such as phosphates to which they form very tight ionic bonds. The method could be successfully applied to specifically precipitate phosphoproteins from complex samples including milk and egg white by forming solid metal-protein complexes. Owing to the low solubility product of the investigated lanthanide salts, the produced metal-protein complexes showed high stability. The protein pellets were extensively washed to remove nonphosphorylated proteins and contaminants. For the analysis of proteins the pellets were first dissolved in 30 % formic acid and subjected to matrix-assisted laser desorption/ionization-time of flight (MALDI TOF) MS. For peptide mass-fingerprint analysis the precipitated phosphoproteins were enzymatically digested using microwave-assisted digestion. The method was found to be highly specific for the isolation and purification of phosphoproteins. Protein quantification was performed by colorimetric detection of total precipitated phosphoproteins and revealed more than 95 % protein recovery for each lanthanide salt. PMID- 22451173 TI - An insight into iTRAQ: where do we stand now? AB - The iTRAQ (isobaric tags for relative and absolute quantification) technique is widely employed in proteomic workflows requiring relative quantification. Here, we review the iTRAQ literature; in particular, we focus on iTRAQ usage in relation to other commonly used quantitative techniques e.g. stable isotope labelling in culture (SILAC), label-free methods and selected reaction monitoring (SRM). As a result, we identify several issues arising with respect to iTRAQ. Perhaps frustratingly, iTRAQ's attractiveness has been undermined by a number of technical and analytical limitations: it may not be truly quantitative, as the changes in abundance reported will generally be underestimated. We discuss weaknesses and strengths of iTRAQ as a methodology for relative quantification in the light of this and other technical issues. We focus on technical developments targeted at iTRAQ accuracy and precision, use of 4-plex over 8-plex reagents and application of iTRAQ to post-translational modification (PTM) workflows. We also discuss iTRAQ in relation to label-free approaches, to which iTRAQ is losing ground. PMID- 22451174 TI - Development of surface plasmon resonance-based sensor for detection of silver nanoparticles in food and the environment. AB - Silver nanoparticles are recognized as effective antimicrobial agents and have been implemented in various consumer products including washing machines, refrigerators, clothing, medical devices, and food packaging. Alongside the silver nanoparticles benefits, their novel properties have raised concerns about possible adverse effects on biological systems. To protect consumer's health and the environment, efficient monitoring of silver nanoparticles needs to be established. Here, we present the development of human metallothionein (MT) based surface plasmon resonance (SPR) sensor for rapid detection of nanosilver. Incorporation of human metallothionein 1A to the sensor surface enables screening for potentially biologically active silver nanoparticles at parts per billion sensitivity. Other protein ligands were also tested for binding capacity of the nanosilver and were found to be inferior to the metallothionein. The biosensor has been characterized in terms of selectivity and sensitivity towards different types of silver nanoparticles and applied in measurements of real-life samples such as fresh vegetables and river water. Our findings suggest that human MT1 based SPR sensor has the potential to be utilized as a routine screening method for silver nanoparticles, that can provide rapid and automated analysis dedicated to environmental and food safety monitoring. PMID- 22451175 TI - Investigations on the influence of different grinding procedures on measured ethyl glucuronide concentrations in hair determined with an optimized and validated LC-MS/MS method. AB - Ethyl glucuronide (EtG) analysis in hair is a suitable method for the retrospective determination of previous alcohol consumption. According to the German guidelines, EtG abstinence is improbable at c(EtG) > 7 pg/mg in the proximal 3 cm of scalp hair. The chromatography of the routinely used liquid chromatography-tandem mass spectrometry procedure was optimized by replacing the stationary phase. To simplify sample preparation, two different mills were tested, and an optimized grinding process was developed. The new method was successfully validated according to the guidelines of the German Society of Toxicological and Forensic Chemistry. Despite a simple extraction procedure without any cleaning steps, a very high sensitivity (limit of detection, 1.7 pg/mg; limit of quantitation, 2.3 pg/mg) could be achieved. Competitive analysis showed significantly higher EtG concentrations in pulverized versus cut hair samples. The strong impact of sample preparation on the determined EtG concentrations suggests the introduction of a standardized sample preparation method to produce comparable results. PMID- 22451176 TI - Determination of trehalose-6-phosphate in Arabidopsis thaliana seedlings by hydrophilic-interaction liquid chromatography-mass spectrometry. AB - A hydrophilic-interaction chromatography (HILIC) method coupled to electrospray ionization mass spectrometry (ESI-MS) was developed for the determination of trehalose-6-phophate (Tre6P) in Arabidopsis thaliana seedlings. The method was optimized for MS detection and separation of Tre6P from its isomers, such as sucrose-6-phosphate, by testing eluent pH, type of organic solvent and alkalinizer, and gradient conditions. Tre6P could be resolved from matrix components within 28 min by using a water-acetonitrile gradient (0.2 ml/min) at pH 12 with piperidine as alkalinizer. The method was validated for concentrations between 25 and 4,000 nM Tre6P in A. thaliana seedling extracts. Seedlings were extracted with consecutive liquid-liquid and solid-phase extractions, and analyzed with HILIC-MS. Obtained accuracy (80-120 %) and precision (<24 %) demonstrated the suitability of HILIC-MS for determining Tre6P level variations in plants. The limit of detection (LOD) was 3.5 nM Tre6P in extracts corresponding to 4.1 pmol.g(-1) fresh plant weight (FW). This is a considerable improvement with respect to anion-exchange chromatography (AEC)-MS (40 nM) and capillary electrophoresis-MS (80 nM). Furthermore, HILIC-MS analysis times were shorter than with AEC-MS (30 and 60 min, respectively). The applicability of the HILIC-MS method was demonstrated by the analysis of extracts from seedlings grown on medium containing 100 mM sorbitol or trehalose, resulting in mean Tre6P concentrations of 0.2 and 1.9 nmol.g(-1) FW, respectively. Similar concentrations were found with AEC-MS. HILIC-MS was also evaluated at a high flow rate (2.0 ml/min). This high-speed method resolved the Suc6P and Tre6P peaks within 3 min yielding a detection limit of 1.3 nM Tre6P. PMID- 22451177 TI - Combination of sugar analysis and stable isotope ratio mass spectrometry to detect the use of artificial sugars in royal jelly production. AB - The effects of feeding bees artificial sugars and/or proteins on the sugar compositions and (13)C isotopic measurements of royal jellies (RJs) were evaluated. The sugars fed to the bees were two C4 sugars (cane sugar and maize hydrolysate), two C3 sugars (sugar beet, cereal starch hydrolysate), and honey. The proteins fed to them were pollen, soybean, and yeast powder proteins. To evaluate the influence of the sugar and/or protein feeding over time, samples were collected during six consecutive harvests. (13)C isotopic ratio measurements of natural RJs gave values of around -25 0/00, which were also seen for RJs obtained when the bees were fed honey or C3 sugars. However, the RJs obtained when the bees were fed cane sugar or corn hydrolysate (regardless of whether they were also fed proteins) gave values of up to -17 0/00. Sugar content analysis revealed that the composition of maltose, maltotriose, sucrose, and erlose varied significantly over time in accordance with the composition of the syrup fed to the bees. When corn and cereal starch hydrolysates were fed to the bees, the maltose and maltotriose contents of the RJs increased up to 5.0 and 1.3 %, respectively, compared to the levels seen in authentic samples (i.e., samples obtained when the bees were fed natural food: honey and pollen) that were inferior to 0.2% and not detected, respectively. The sucrose and erlose contents of natural RJs were around 0.2 %, whereas those in RJs obtained when the bees were fed cane or beet sugar were as much as 4.0 and 1.3 %, respectively. The combination of sugar analysis and (13)C isotopic ratio measurements represents a very efficient analytical methodology for detecting (from early harvests onward) the use of C4 and C3 artificial sugars in the production of RJ. PMID- 22451178 TI - Cardiometabolic risk factors and acute kidney injury based on urinary neutrophil gelatinase associated lipocalin (NGALu) in acute coronary syndrome patients. AB - AIM: to analyze the association between cardiometabolic risk factors and acute kidney injury (AKI) based on urinary neutrophil gelatinase associated lipocalin (NGALu) in patients with acute coronary syndrome (ACS). METHODS: a cross sectional study was conducted on the ACS patients who were admitted to the Emergency Room in Hasan Sadikin Hospital. Urinary samples were obtained at the time of the arrival and considered AKI if the urinary NGAL level 150 ng/ml. The cardiometabolic risk factors were in accord with the IDF criteria for MetS. RESULTS: there were 60 subjects that consisted of 39 men (65%) and 21 women (35%) and the average of was 58.47 (SD 9.9) years. There were 30 subjects (50%) considered AKI based on NGAL level. There were two significant CMR risk factors associated with AKI; blood pressure (hypertension) and HDL (p 0.05). HDL being the most significant cardiometabolic factor (p=0.037; OR 5.137 (95% CI 1.102 23.95)). The number of factors was also associated with the incidence of AKI; the more factors existed in a person the greater the incidence of AKI (p=0.03). CONCLUSION: blood pressure and HDL were cardiometabolic risk factors associated with AKI in ACS patients. The more cardiometabolic factors existed in a person the greater the incidence of AKI. PMID- 22451179 TI - Primary hormonal treatment in localized and locally advanced prostate cancer: effectiveness and survival predictive factors. AB - AIM: to evaluate the effectiveness of primary hormonal treatment on localized and locally advanced prostate cancer, including the analysis on the survival predictive factors. METHODS: patients with localized (T1,T2N0M0) and locally advanced (T3, T4N0M0) prostate cancer who had received primary hormonal treatment between January 1995 and December 2009 were evaluated retrospectively based on their specific medical records at Department of Urology in Cipto Mangunkusumo Hospital (RSCM) and Dharmais Cancer Hospital (RSKD). RESULTS: about 79 (29.9%) of 264 patients with localized and advanced local prostate cancer received primary hormonal treatment. In the localized prostate cancer group, mean survival was 58.3 months (range: 1.87-170.78) and 5-year survival was 77.3%; while in locally advanced prostate cancer patients, mean survival was 40.87 months (range 7.29 115.29) and 5-year survival was only 22.7%. Hemoglobin level was a significant clinical parameter of survival predictive factors for both localized and locally advanced prostate cancer groups. The lower the hemoglobin level, the survival will be shorter. CONCLUSION: there were no significant differences between mean survival and 5-year survival rate, between localized and locally advanced prostate cancer patients who had received primary hormonal treatment. Hemoglobin level is survival predictive factors for localized and locally advanced prostate cancer patients. PMID- 22451180 TI - Effect of metformin and pioglitazone treatment on cardiovascular risk profile in polycystic ovary syndrome. AB - AIM: to compare the effectiveness of metformin and pioglitazone in ameliorating insulin resistance and cardiovascular risk factors in women with polycystic ovary syndrome (PCOS). METHODS: this study was a randomized clinical trial to compare treatment with metformin and pioglitozone. Fifty two women with PCOS aged 20-45 years were randomly allocated to one of the two treatment groups. All patients underwent clinical and biochemical evaluation and analyses involving these measures which consisted of repeated measures MANOVA using the pre- and post intervention fasting blood sugar (FBS), lipid profiles, body mass index (BMI), serum insulin in two groups. RESULTS: weight and BMI were significantly decreased in metformin group but not in case of pioglitazone. FBS, serum triglycerides, total cholesterol were all reduced significantly by both metfomin and pioglitazone. Insulin resistance measured by homeostasis model assessment (HOMA) method was significantly decreased in both treatment groups (P<0.05). There were no significant differences between treatments in most of variables except BMI. CONCLUSION: these results suggest pioglitazone is as effective as metformin in improving insulin sensitivity and some cardiovascular risk biomarkers but it has no significant effect on reducing BMI and body weight. PMID- 22451181 TI - Reversin increase the plasticity of bone marrow-derived mesenchymal stem cell for generation of cardiomyocyte in vitro. AB - AIM: to speed up transdifferentiation of bone marrow-derived stem cells into cardiomyocyte in vitro by inducing dedifferentiation of bone marrow-derived mesenchymal stem cell, before induction by 5-aza-2'-deoxycytidine into cardiomyocyte. METHODS: two-three months old 2.5 kg weight adult male New Zealanad Rabbits were anesthezied with ether, thigh bones were excised, and bone marrow cells were obtained by aspiration. RESULTS: in our experiments after 1 week of mesenchymal stem cell cultures, 20 nM reversin was given to induce dediferentiation and after 24 hours exposure with 9MUM 5-aza-2-deoxycytidine, early phase of cardiomyocyte differentiation appeared as cultured cell were strongly positive for GATA-4 and weakly positive for MLC-2alpha, although beating cardiomyocyte has not yet appeared at the end of experiment. These experiments also showed a marked CD34+ and c-kit+ gene expression on RT-PCR examination. CONCLUSION: reversine increase plasticity of bone marrow-derived mesenchymal stem cell to generate cardiomyocyte after 5-aza-2'-deoxycytidine induction. CD34+ and c-kit+ may be a marker for cardiomyocyte progenitor cells. PMID- 22451182 TI - Efficacy and safety of pioglitazone in type 2 diabetes mellitus: a postmarketing observational study. AB - AIM: to assess the effectiveness and safety profile of pioglitazone in Indonesian type 2 diabetic patients. METHODS: type 2 diabetic patients, naive or under oral antidiabetics, with uncontrolled fasting (FBG) or postprandial blood glucose (PPBG) were enrolled from September 2009 to December 2010 from 23 cities in Indonesia. Pioglitazone (Actos(r)) 15 mg or 30 mg daily was prescribed by the physician and performed observation for 12 weeks. Body weight (BW), body mass index (BMI), FBG and PPBG were measured every 4 weeks and serum transaminase (SGPT) was measured at the beginning and at the end of the study. Changes from baseline to each visit were analyzed using Wilcoxon-test. RESULTS: 190 patients (92 male and 98 female) aged 56.3 (28-80) years were included. Mean FBG decreased from 191.8 mg/dL at baseline to 155.9; 141.0; and 127.3 mg/dL, at week 4, 8, and 12, respectively (p<0.001). Mean PPBG decreased from 267.3 mg/dL at baseline to 209.7; 188.2; and 174.9 at week 4, 8, and 12, respectively (p<0.001). BW slightly increased from 67.3 (range: 40-98) kg at baseline to 67.7 (42.0-98.5) and 67.8 (43.0-99.0) kg at weeks 8 and 12, respectively (p<0.001) and BMI increased from 25.6 (16.2-38.6) kg/m2 at baseline to 25.7 (17.0-36.3) and 25.7 (17.4-36.6) kg/m2 at weeks 8 and 12, respectively (p<0.001). SGPT values were not significantly changed (35.6U/L at baseline and 35.5U/L at week 12, p=0.93). CONCLUSION: Pioglitazone is effective in controlling blood glucose, without harmful effect on the liver. However, there was a slight but statistically significant increase in body weight, that mandates the precaution when using this drug in patients with heart failure or other conditions with water retention. PMID- 22451183 TI - Prevalence of hepatic steatosis in chronic hepatitis B patients and its association with disease severity. AB - AIM: to know the prevalence of liver steatosis in chronic hepatitis B (CHB) patients and evaluate whether its presence was associated with a more progressive disease. METHODS: a cross-sectional study was conducted in Cipto Mangunkusumo and Medistra Hospitals, Jakarta on CHB patients between 2007 and 2009. Data on patients' demography, anthropometry, liver function test and hepatitis B serology were collected. Hepatic steatosis was assessed by liver biopsy and graded as mild (<33%), moderate (33-66%) or severe (>66%). Fibrosis stage and necroinflammatory activity were assessed according to the METAVIR system. RESULTS: one-hundred and seventy four patients were enrolled; 99 (56.9%) among them were men. Patients' mean age was 39.9 +/- 10.69 years. About 56% of cases were HBeAg negative. The prevalence of liver steatosis was 29.9%. Patients with liver steatosis had significantly higher body mass index (25.1 +/- 3.3 vs. 22.7 +/- 3.33 kg/m2, p<0.001) and waist circumference (88.3 vs. 79.0 cm; p<0.001). No association between liver steatosis and HBeAg status (p=0.736). There were no differences of log HBV-DNA levels (5.72 +/- 1.993 vs. 6.07 +/- 2.077; p=0.675) and liver stiffness (8.3 +/- 6.28 vs. 9.5 +/- 10.18 kPa) between patients with and without liver steatosis. The presence of significant fibrosis (61.5% vs. 69.7%; p=0.295) and necroinflammation (63.5% vs. 65.6%; p=0.789) was not differed between patients with and without liver steatosis. CONCLUSION: liver steatosis was found in 30% of chronic hepatitis B patients. Its presence was mostly associated with central obesity. Unlike chronic hepatitis C, liver steatosis in chronic hepatitis B was not related to a more progressive disease. PMID- 22451184 TI - NM23HI as marker of metastasis in invasive ductal breast cancer. AB - AIM: to examine the presence of metastasis marker in various histological malignancies of ductal breast carcinoma using NM23HI protein. METHODS: paraffin blocks were obtained from 97 patients with invasive breast ductal cancer with 1, 2, 3 grade of malignancy from 2000 to early 2006 in several hospitals in Jakarta and Bandung. Examination began with histophatologic examination of eosin hematoxylin slides to diagnose the case of invasive ductal cancer and to get the data on the degree of histologic malignancy, metastasis or non-metastasis cases. It then continued to immunohistochemistry examination of NM23HI, and cytokeratin. RESULTS: subjects were 29-75 years old with the mean of 48.19 years; most subjects were 40-45 years old with malignancy grade 1 numbering 18.56%; grade 2, 45.36%; and grade 3, 36.1%. Ninety seven paraffin blocks were examined from 2000 to 2006. There was a significant relationship between NM23HI expression in primary tumor with the possibility of inhibition of invasion and metastasis 11 times of those of negative expression of NM23HI. The ROC curve showed that NM23HI expression was strongly correlated (r=0.816) sensitive and specific as metastasis marker. NM23HI expression did not show significant relationship with histologic degree of invasive ductal carcinoma. CONCLUSION: NM23HI expressions can be used as invasion and metastasis markers, but cannot be used as markers for the degree of histologic malignancy of invasive ductal cancer. PMID- 22451185 TI - Risk factors for depressive symptom changes in Indonesian geriatric outpatient. AB - AIM: to determine risk factors for depressive symptom changes in geriatric outpatients. METHODS: a prospective cohort study was conducted on 106 geriatric outpatients at Integrated Geriatric Clinic Cipto Mangunkusumo Hospital, Jakarta in 2010. A structured questionnaire was applied to obtain independent variable such as age, sex, educational level, chronic diseases (diabetes mellitus, chronic kidney diseases, hypertension, dyslipidemia, and osteoarthritis), functional status (WHO-Unescap score), nutritional status (body mass index), health related quality of life (Eq5D score), hospitalization within 6 months, and total calorie intake. Depressive symptom as dependent variable was assessed using Geriatric Depression Scale. The association between aforementioned various factors with depressive symptom changes were analyzed using multiple logistic regression analysis. RESULTS: most of subjects were women (63.2%), aged 70 years old and older (71.0%) and had hypertension (82.1%). There were 22.6% subjects with increase in GDS score during 6-month follow-up. Bivariable analysis showed that diabetes mellitus and chronic kidney diseases were significantly associated with depressive symptom changes. Multiple logistic regression showed that variable which independently associated with depressive symptom changes was uncontrolled chronic kidney disease (OR 3.390; 95% CI 1.07-10.76. CONCLUSION: uncontrolled chronic kidney disease is risk factor for depressive symptom changes in geriatric outpatients. PMID- 22451186 TI - Appendico-cutaneous fistula presenting as a large wound: a rare phenomenon-brief review. AB - Appendicular inflammation can present as a discharging fistula on the abdominal wall. We are reporting a rare case of appendico - cutaneous fistula presenting as a large wound over the right iliac region. A 60 year old female reported to the emergency with a large wound and slough on right side of the abdomen. The thin shinning serous discharge from the wound revealed actinomycosis on microbiology. Patient was successfully treated conservatively with the help of percutaneous drainage and antibiotics. On follow-up of 3 months, patient is doing well and is asymptomatic. Acute appendicitis is considered one of the elementals of general surgical disease processes, yet its presentation often confounds its diagnosis by most surgeons. Its presentation as abscess in the abdominal wall and groin is a rare clinical entity. Because of insidious onset and subtle clinical signs of resulting abscess, the diagnosis of such cases is often delayed. USG and Contrast enhanced computed tomography are important part of investigations to make diagnose and helps in the treatment. PMID- 22451187 TI - Acute pancreatitis in dengue hemorrhagic fever. AB - We reported a case of acute pancreatitis as the complication of dengue hemorrhagic fever (DHF). This complication can cause more severe fatal condition, and difficulties in treatment, although it is rare. Dengue hemorrhagic fever (DHF) is one of the endemic diseases and often come as an outbreak event in South East Asia including Indonesia. Dengue hemorrhagic fever (DHF) is a global public health problem, because until now there has been no medicine to eradicate the dengue virus, no dengue vaccine and difficult to eradicate the mosquitoes as the contagious vector. Diagnosis and treatment of acute pancreatitis as early as possible is important to improve the patient's condition and survival. The patient was a 59 year old male and had been treated conservatively. The patient was admitted to the hospital, oral fasting until the fourth day, given parenteral nutrition, antibiotic and other intravenous medicines. Initial oral liquid diet was given on the fifth day of hospitalization and changed gradually according to the condition. The patient was then improved and discharged from the hospital. PMID- 22451188 TI - Adult bone marrow stem cells in cartilage therapy. AB - Cartilage defect rarely heals spontaneously since cartilage tissue is poorly vascularized and the lesion usually does not penetrate to subchondral bone, and hence it does not have access to progenitor cells of bone marrow. Severe cartilage damage may lead to osteoarthritis (OA). Current surgical and non surgical therapeutic interventions in OA are limited to symptom relief and/or repair of focal lesion, and later a total knee replacement is still necessary. Cell therapy with chondrocyte implantation requires healthy cartilage for donor of the cells. Adult mesenchymal stem cells (MSCs) have the ability to differentiate into chondrogenic lineage. They can readily be isolated from bone marrow as well as many other adult tissues and have an extensive proliferation capacity. Therefore, MSCs may offer a great potential to be developed as an alternative for cell-based articular cartilage therapy. PMID- 22451189 TI - Streptokinase induced purpura-like lesions. PMID- 22451190 TI - Current status of phase I clinical trials in Asia: an academic perspectives. AB - Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries. PMID- 22451191 TI - National consensus on geriatric immunization 2011. AB - As the growth of elderly population increases, the number of geriatric patients who may demand health care services is also increasing since the elderly are more vulnerable to various conditions of acute illnesses. Upper respiratory tract infections are the leading cause of death and the most significant cause that impairs quality of life in the elderly. Upper respiratory tract infections and influenza are common in the elderly and may develop into pneumonia. Considering the high morbidity and mortality rates related to pneumonia in the elderly, it is important to have prevention strategies. A delay in diagnosis due to non-specific signs and symptoms of pneumonia in the elderly has demanded greater concern on the importance of pneumonia prevention strategies. Influenza and pneumonia impair quality of life in the elderly, resulted in decreased functional status (ADL scores) during infection and recovery period. With increasing antibiotic resistance, the management may be complicated as it may lead to conditions that reduce quality of life and cause high mortality rate. Therefore, immunization is very important as the prevention strategy against influenza and or pneumonia, reducing the incidence as well as the complication. The consensus has been made in order to provide immunization against influenza and pneumonia for elderly population in Indonesia. It is expected that by 2025, about 60% of the elderly in Indonesia would have immunization against influenza and 50% of them would have immunization against pneumonia annually. PMID- 22451192 TI - Organic semiconducting single crystals as next generation of low-cost, room temperature electrical X-ray detectors. AB - Direct, solid-state X-ray detectors based on organic single crystals are shown to operate at room temperature, in air, and at voltages as low as a few volts, delivering a stable and reproducible linear response to increasing X-ray dose rates, with notable radiation hardness and resistance to aging. All-organic and optically transparent devices are reported. PMID- 22451193 TI - Epigenetics, asthma, and allergic diseases: a review of the latest advancements. AB - Environmental epigenetic regulation in asthma and allergic disease is an exciting area that has gained a great deal of scientific momentum in recent years. Environmental exposures, including prenatal maternal smoking, have been associated with asthma-related outcomes that may be explained by epigenetic regulation. In addition, several known allergy and asthma genes have been found to be susceptible to epigenetic regulation. We review the latest experimental and translational studies that have been published this past year in several areas, including 1) characterization of environmental asthma triggers that induce epigenetic changes, 2) characterization of allergic immune and regulatory pathways important to asthma that undergo epigenetic regulation, 3) evidence of active epigenetic regulation in asthma experimental models and the production of asthma biomarkers, 4) evidence of transmission of an asthma-related phenotype across multiple generations, and 5) "pharmaco-epigenetics." The field has certainly advanced significantly in the past year. PMID- 22451194 TI - Refining endpoints in brain tumor clinical trials. AB - As targeted therapies advance treatment for brain tumors, standard clinical trial endpoints of survival, progression free survival and radiographic response have become insufficient to capture clinical benefit. Brain cancer is a malignancy with neurodegenerative features. In this setting prolongation of life and/or radiographic stability are less clinically meaningful if neurocognitive function substantially declines. Hence evaluation of new therapeutic strategies should routinely include periodic assessment of neurocognitive function. PMID- 22451195 TI - Effects of sequential chemotherapy of FOLFIRI/FOLFOX on the endocrine axes of ACTH-cortisol and renin-angiotensin-aldosterone. AB - The chemotherapies of FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) and FOLFIRI (folinic acid + 5-fluorouracil + irinotecan) are effective for a variety of malignant tumors. In particular, the sequential chemotherapy of FOLFOX/FOLFIRI has become the preferred post-operational treatment approach for gastrointestinal cancer and an important palliative care program for advanced cancer. However, the sequential chemotherapy of FOLFOX/FOLFIRI showed severe side effects due to the fact that the toxicity of the drugs can be enhanced by each other. Here, we report the dynamic changes in the activities of serum ACTH, cortisol, renin, angiotensin, and aldosterone in patients following multiple cycles of FOLFOX/FOLFIRI sequential chemotherapy. We found that the sequential chemotherapy might cause damage to the activities of the endocrine cells and/or the sympathetic nerve, and alter endocrine function, specifically the ACTH-cortisol and renin-angiotensin-aldosterone axes. PMID- 22451196 TI - Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain. AB - Antipsychotic drugs act on the dopaminergic system (first-generation antipsychotics, FGA), but some also directly affect serotonergic function (second generation antipsychotics, SGA) in the brain. Short and long-term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single-dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic-induced rCBF changes and brain alterations in schizophrenia. PMID- 22451197 TI - Coelomic fluid: a complimentary biological medium to assess sub-lethal endosulfan exposure using 1H NMR-based earthworm metabolomics. AB - Endosulfan is an environmentally persistent pesticide and has been shown to be genotoxic, neurotoxic and carcinogenic to surrounding organisms. Earthworms are widely used in environmental metabolomic studies to assess soil ecotoxicity. Previous nuclear magnetic resonance (NMR)-based metabolomic studies have analyzed earthworm tissue extracts after exposure to endosulfan and identified some key metabolic indicators that can be used as biomarkers of stress. However, some metabolites may have been masked due to overlap with other metabolites in the tissue extract. Therefore, in this study, the coelomic fluid (CF) and the tissue extract of the earthworm, Eisenia fetida, were both investigated using 1H NMR based metabolomics to analyze their metabolic profile in response to endosulfan exposure at three sub-lethal (below LC50) concentrations. Principal component analysis determined the earthworm CF and earthworm tissue extract to both have significant separation between the exposed and control at the two highest sub lethal endosulfan exposures (1.0 and 2.0 MUg cm-2). Alanine, glycine, malate, alpha-ketoglutarate, succinate, betaine, myo-inositol, lactate and spermidine in the earthworm CF and alanine, glutamine, fumarate, glutamate, maltose, melibiose, ATP and lactate in earthworm tissue extract were all detected as having significant fluctuations after endosulfan exposure. An increase in ATP production was detected by the increase activity in the citric acid cycle and by anaerobic metabolism. A significant decrease in the polyamine, spermidine after endosulfan exposure describes an apoptotic mode of protection which correlates to a previous endosulfan exposure study where DNA damage has been reported. This study highlights that earthworm CF is a complementary biological medium to tissue extracts and can be helpful to better understand the toxic mode of action of contaminants at sub-lethal levels in the environment. PMID- 22451198 TI - Re-engineering of pathogenic aquaporin 4-specific antibodies as molecular decoys to treat neuromyelitis optica. PMID- 22451199 TI - Evolving role of biomarkers in acute cerebrovascular disease. AB - The development of a clinically validated biomarker of acute cerebral ischemia would have the potential to facilitate the use of time-sensitive reperfusion strategies, allow for individualization of patient care by predicting relative risk of hemorrhage and volume of penumbral tissue, and add valuable prognostic information for patients presenting with acute stroke. Additionally, a stroke biomarker might benefit early stage clinical research by serving as a surrogate measure of ischemic injury. Although at present there are no clinically validated biomarkers of acute stroke, previous studies have focused on markers associated with different components of the ischemic cascade, including microglial activation, inflammation, oxidative stress, neuronal injury, hemostasis, and endothelial dysfunction. Evolving technologies have provided high throughput approaches to investigate potential gene and protein signatures, and methods to measure newly discovered markers of cell death and immune responses. Prior to defining the clinical utility of stroke biomarkers, it is critical to understand the inherent limitations of a biomarker-based approach and define its potential value for providing adjunctive diagnostic and prognostic information. The identification and validation of a clinically relevant biomarker, or panel of markers, of stroke will ultimately require incorporation of both stringent research design and assessment in the clinical context in which the marker will be used. PMID- 22451200 TI - Evidence-based path to newborn screening for Duchenne muscular dystrophy. AB - OBJECTIVE: Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing. METHODS: A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification. RESULTS: DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels>2,000U/l. In 3 newborns with CK>2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP. INTERPRETATION: A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations. PMID- 22451201 TI - Optic radiation tractography and vision in anterior temporal lobe resection. AB - OBJECTIVE: Anterior temporal lobe resection (ATLR) is an effective treatment for refractory temporal lobe epilepsy but may result in a contralateral superior visual field deficit (VFD) that precludes driving in the seizure-free patient. Diffusion tensor imaging (DTI) tractography can delineate the optic radiation preoperatively and stratify risk. It would be advantageous to incorporate display of tracts into interventional magnetic resonance imaging (MRI) to guide surgery. METHODS: We studied 20 patients undergoing ATLR. Structural MRI scans, DTI, and visual fields were acquired before and 3 to 12 months following surgery. Tractography of the optic radiation was performed on preoperative images and propagated onto postoperative images. The anteroposterior extent of the damage to Meyer's loop was determined, and visual loss was quantified using Goldmann perimetry. RESULTS: Twelve patients (60%) suffered a VFD (10-92% of upper quadrant; median, 39%). Image registration took <3 minutes and predicted that Meyer's loop was 4.4 to 18.7mm anterior to the resection margin in these patients, but 0.0 to 17.6mm behind the resection margin in the 8 patients without VFD. The extent of damage to Meyer's loop significantly correlated with the degree of VFD and explained 65% of the variance in this measure. INTERPRETATION: The optic radiation can be accurately delineated by tractography and propagated onto postoperative images. The technique is fast enough to propagate accurate preoperative tractography onto intraoperative scans acquired during neurosurgery, with the potential to reduce the risk of VFD. PMID- 22451202 TI - Distinct hyperexcitability mechanisms underlie fast ripples and epileptic spikes. AB - OBJECTIVE: In partial epilepsies, interictal epileptic spikes (IESs) and fast ripples (FRs) represent clinically relevant biomarkers characteristic of epileptogenic networks. However, their specific significance and the pathophysiological changes leading to either FRs or IESs remain elusive. The objective of this study was to analyze the conditions in which hyperexcitable networks can generate either IESs or FRs and to reveal shared or distinct mechanisms that underlie both types of events. METHODS: This study is the first to comparatively analyze mechanisms that induce either IESs or FRs using an approach that combines computational modeling and experimental data (in vivo and in vitro). A detailed CA1 hippocampal network model is introduced. A parameter sensitivity analysis was conducted to determine which model parameters (cell related and network related) allow the most accurate simulation of FRs and IESs. RESULTS: Our model indicates that although FRs and IESs share certain common mechanisms (shifted gamma-aminobutyric acid [GABA]A reversal potential, altered synaptic transmission), there are also critical differences in terms of number of pyramidal cells involved (small vs large), spatial distribution of hyperexcitable pyramidal cells (clustered vs uniform), and firing patterns (weakly vs highly synchronized). In vitro experiments verified that subtle changes in GABAergic and glutamatergic transmission favor either FRs or IESs, as predicted by the model. INTERPRETATION: This study provides insights into the interpretation of 2 interictal markers observed in intracerebral electroencephalographic data. Depending on the degree and spatiotemporal features of hyperexcitability, not only IESs or FRs are generated but also transitions between both types of events. PMID- 22451203 TI - Dihydropyridine calcium channel blockers and the progression of parkinsonism. AB - OBJECTIVE: A study was undertaken to test the association between dihydropyridine calcium channel blocker use and the time to important milestones of disease progression among patients with parkinsonism. METHODS: Data were obtained from Ontario's health care administrative databases. Within a cohort of hypertensive individuals older than 65 years who developed parkinsonism, we examined the effect of the length of exposure to less brain-penetrant dihydropyridines (amlodipine) and more brain-penetrant dihydropyridines (eg, nifedipine, felodipine) on parkinsonism milestones as measured by time to requiring drug treatment for parkinsonism, nursing home admission, and death. RESULTS: Among 4,733 hypertensive individuals with parkinsonism, longer treatment with any dihydropyridine was associated with a decreased risk of each of the 3 outcomes. There was no difference, however, between amlodipine (adjusted hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.42-0.50 for initiation of drug treatment; HR, 0.68; 95% CI, 0.63-0.73 for application for nursing home admission; and HR, 0.75; 95% CI, 0.70-0.80 for death) and nonamlodipine dihydropyridines (adjusted HRs [95% CIs], 0.45 [0.39-0.53], 0.74 [0.67-0.81], and 0.74 [0.64-0.85] for the 3 milestones, respectively). INTERPRETATION: We found no specific beneficial effect of treatment with brain-penetrant dihydropyridines on delaying parkinsonism progression milestones. Dihydropyridine calcium channel blockers are unlikely to have a clinically significant effect on the course of parkinsonism, particularly Parkinson disease, in the doses used to treat hypertension. PMID- 22451205 TI - Neuron deficit in the white matter and subplate in periventricular leukomalacia. AB - OBJECTIVE: The cellular basis of cognitive abnormalities in preterm infants with periventricular leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons that are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls. METHODS: We used a computer-based method for the determination of the density of microtubule-associated protein 2 immunolabeled neurons in the ventricular/subventricular region, periventricular white matter, central white matter, and subplate region in PVL cases and controls. RESULTS: There were 5 subtypes of subcortical neurons: granular, unipolar, bipolar, inverted pyramidal, and multipolar. The neuronal density of the granular neurons in each of the 4 regions was 54 to 80% lower (p<=0.01) in the PVL cases (n=15) compared to controls adjusted for age and postmortem interval (n=10). The overall densities of unipolar, bipolar, multipolar, and inverted pyramidal neurons did not differ significantly between the PVL cases and controls. No granular neurons expressed markers of neuronal and glial immaturity (Tuj1, doublecortin, or NG2). INTERPRETATION: These data suggest that quantitative deficits in susceptible granular neurons occur in the white matter distant from periventricular foci, including the subplate region, in PVL, and may contribute to abnormal cortical formation and cognitive dysfunction in preterm survivors. PMID- 22451206 TI - Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol. AB - OBJECTIVE: To test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory-predominant polyradiculoneuropathy among swine abattoir employees in the Midwestern United States. METHODS: Mice were exposed intranasally, 5 days per week, to liquefied brain tissue. Serum from exposed mice, patients, and unaffected abattoir employees were analyzed for clinically pertinent neural autoantibodies. RESULTS: Patients, coworkers, and mice exposed to liquefied brain tissue had an autoantibody profile dominated by neural cation channel immunoglobulin Gs (IgGs). The most compelling link between patients and exposed mice was magnetic resonance imaging (MRI) evidence of grossly swollen spinal nerve roots. Autoantibody responses in patients and mice were dose-dependent and declined after antigen exposure ceased. Autoantibodies detected most frequently, and at high levels, bound to detergent-solubilized macromolecular complexes containing neuronal voltage-gated potassium channels ligated with a high affinity Kv1 channel antagonist, 125I-alpha-dendrotoxin. Exposed mice exhibited a behavioral phenotype consistent with potassium channel dysfunction recognized in drosophila with mutant ("shaker") channels: reduced sensitivity to isoflurane-induced anesthesia. Pathological and electrophysiological findings in patients supported peripheral nerve hyperexcitability over destructive axonal loss. The pain-predominant symptoms were consistent with sensory nerve hyperexcitability. INTERPRETATION: Our observations establish that inhaled neural antigens readily induce neurological autoimmunity and identify voltage-gated potassium channel complexes as a major immunogen. PMID- 22451207 TI - Gain of glycosylation: a new pathomechanism of myelin protein zero mutations. AB - We report the first case of a missense mutation in MPZ causing a gain of glycosylation in myelin protein zero, the main protein of peripheral nervous system myelin. The patient was affected by a severe demyelinating neuropathy caused by a missense mutation, D32N, that created a new glycosylation sequence. We confirmed that the mutant protein is hyperglycosylated, is partially retained into the Golgi apparatus in vitro, and disrupts intercellular adhesion. By sequential experiments, we demonstrated that hyperglycosylation is the main mechanism of this mutation. Gain of glycosylation is a new mechanism in Charcot Marie-Tooth type 1B. PMID- 22451208 TI - Regarding the beautiful and ethereal neurological exam. PMID- 22451209 TI - The neurological examination: a misplaced research priority? PMID- 22451210 TI - Infarct growth with and without intravenous thrombolysis in acute ischemic stroke. PMID- 22451212 TI - What statistics cannot tell us about the neurological examination. PMID- 22451213 TI - The neurological exam: striking a nerve. PMID- 22451214 TI - Medical device conflict of interest in the CCSVI debate. PMID- 22451215 TI - Fewer jobs available for new PhDs. PMID- 22451204 TI - Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. AB - OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3*10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5*10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2*10(-9)/rs11248060; T: OR=1.35; p=2.0*10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2*10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5*10(-8) Combined Sample) (N370; OR=3.08; p=7*10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5*10(-5) Discovery Sample; p=1.52*10(-7) Replication sample; p=2*10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA. PMID- 22451217 TI - Profile of eicosanoids in breath condensate in asthma and COPD. AB - The collection of exhaled breath condensates (EBC) is a noninvasive method for obtaining samples from the lungs. Eicosanoids are lipid mediators implicated in the asthmatic inflammatory response. The objective of our study was to investigate whether the profile of eicosanoid lipid mediators in EBC can characterize the inflammation in asthma and chronic obstructive pulmonary disease (COPD). EBC samples were collected from 22 healthy controls (C), 25 mild intermittent asthmatics (MIA), 20 with moderate to severe asthma (MSA) and 20 with moderate to severe COPD. EBC samples were analyzed by unique tandem mass spectrometry that allows the quantification of up to 25 eicosanoid mediators simultaneously. No differences were found between MIA and C. Subjects with MSA and COPD had higher levels of 6-keto, PGE2, LTB4, 11-12 EET and AA, while lower levels of LXA4, 11DHyTxB2, 11HETE and 8,9EET, when compared to MSA and C (p < 0.05). Our study shows that the analysis of EBC through mass spectrometry is mixed and has a similar response in MSA and COPD when compared to MIA and controls. PMID- 22451218 TI - Long-term effect of apatite on ectomycorrhizal growth and community structure. AB - Ectomycorrhizal (ECM) fungi are efficient at taking up phosphorus (P) from mineral sources, such as apatite, which are not easily available to the host trees. Since ECM fungal species differ in P uptake rates, it can be expected that the composition of the ECM fungal community will change upon exposure to apatite, provided that the P transfer is rewarded by more carbon being transferred to the fungal symbiont. Control and apatite-amended mesh bags were buried in pairs in the humus layer of a P-poor Norway spruce forest. The ECM fungal community that colonized these bags was analyzed by DNA extraction, PCR amplification of the internal transcribed spacer (ITS) region, cloning, and random sequencing. Fungal biomass was estimated by ergosterol analysis. No change in the ECM fungal community structure was seen after 5 years of apatite exposure, although the fungal biomass increased threefold upon apatite amendment. Our results indicate that host trees enhance carbon allocation to ECM fungi colonizing P sources in P poor forests but the lack of change in the composition of the ECM fungal community suggests that P transfer rates were similar among the species. Alternatively, higher P transfer among certain species was not rewarded with higher carbon transfer from the host. PMID- 22451219 TI - Mid-thigh cortical bone structural parameters, muscle mass and strength, and association with lower limb fractures in older men and women (AGES-Reykjavik Study). AB - In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained <10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns. PMID- 22451220 TI - No association between dietary vitamin K intake and fracture risk in chinese community-dwelling older men and women: a prospective study. AB - Data on the association between dietary vitamin K intake and fracture risk are limited among Chinese. This study examined such an association in community dwelling elderly in Hong Kong. We present data from 2,944 subjects (1,605 men, 1,339 women) who participated in a prospective cohort study. Baseline dietary intakes of energy, protein, calcium, vitamin D, and vitamin K were assessed using a food-frequency questionnaire. Data on incident hip fracture and nonvertebral fracture during a median of 6.9 follow-up years were collected from a hospital database. Cox regression analyses were performed with adjustments for age, education attainment, smoking status, alcohol use, body mass index, hip bone mineral density, physical activity, use of calcium supplement, and energy adjusted nutrient intakes. There were 29 (1.8 %) men and 19 (1.4 %) women with incident hip fractures and 97 (6.0 %) men and 88 (6.6 %) women with nonvertebral fractures. The median (interquartile range) of dietary vitamin K intake was 241.8 (157.5-360.8) and 238.9 (162.4-343.6) MUg/day in men and women, respectively. Similar dietary vitamin K intakes were observed between subjects with hip or nonvertebral fractures and subjects without hip or nonvertebral fractures. In both men and women, dietary vitamin K intake was not associated with fracture risks at all measured sites in either crude or adjusted models. In Chinese community-dwelling elderly, hip or nonvertebral fracture risk was not associated with dietary vitamin K intake. The high dietary vitamin K intake of the studied group may have limited the ability to detect the association between vitamin K intake and fracture risk. PMID- 22451221 TI - Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. AB - Osteoporotic fracture healing is critical to clinical outcome in terms of functional recovery, morbidity, and quality of life. Osteoporosis treatments may affect bone repair, so insights into their impact on fracture healing are important. We reviewed the current evidence for an impact of osteoporosis treatments on bone repair. Treatment with bisphosphonate in experimental models is associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. Experimental data for denosumab and raloxifene suggest no negative implications for bone repair. The extensive experimental results for teriparatide indicate increased callus formation, improved biomechanical strength, and greater external callus volume and total bone mineral content and density. Case reports and a randomized trial have produced mixed results but are consistent with a positive impact of teriparatide on clinical fracture healing. Studies with strontium ranelate in models of fracture healing indicate that it is associated with improved bone microstructure, callus volume, and biomechanical properties. Finally, there is experimental evidence for a beneficial effect of some of the agents currently being developed for osteoporosis, notably sclerostin antibody and DKK1 antibody. There is currently no evidence that osteoporosis treatments are detrimental for bone repair and some promising experimental evidence for positive effects on healing, notably for agents with a bone-forming mode of action, which may translate into therapeutic applications. PMID- 22451222 TI - Recent advances in osteogenesis imperfecta. AB - "Osteogenesis imperfecta" is a term used to describe a group of genetic disorders of variable phenotype usually defined by recurrent fractures, low bone mass, and skeletal fragility. Most cases are associated with mutations in one of the type I collagen genes, but in recent years several other forms have been identified with recessive inheritance. In most instances the latter result from mutations in genes encoding proteins involved in type I collagen's complex posttranslational modification or in genes regulating bone matrix homeostasis. This article reviews the recent discoveries and an approach to classification and diagnosis. Bisphosphonates are widely used in patients with osteogenesis imperfecta, but some important questions about their optimal usage, their utility in children and adults with milder phenotypes, and their potential adverse effects are not yet resolved. PMID- 22451223 TI - Respiratory management strategies for Duchenne muscular dystrophy: practice variation amongst Canadian sub-specialists. AB - PURPOSE: Respiratory management of Duchenne muscular dystrophy (DMD) is not well studied and may vary across centers and practitioners. Our objective was to describe and compare the respiratory management practices of Canadian Pediatric Respirologists and Neuromuscular specialists for children with DMD. METHODS: A web-based survey was sent to all 56 practicing Canadian Pediatric Respirologists and to all 24 members of the Canadian Pediatric Neuromuscular Group (CPNG) who follow children with neuromuscular diseases. The survey included 28 questions about timing and indications for respiratory consultation, sleep disordered breathing (SDB) assessments, and treatments. RESULTS: Thirty eight (68%) pediatric respirologists and 17 (71%) CPNG members responded. Respirologists provide initial consultation after a patient's first admission to hospital with respiratory complications (14/38, 37%) and when symptoms of SDB are present (14/38, 37%). Half of the CPNG members request initial Respirology consultation at the time of DMD diagnosis. Both groups request routine pulmonary function tests. Ninety-six percent of respirologists use maximal inspiratory (MIP) and expiratory pressures (MEP) to assess respiratory muscle strength, whereas 82% of CPNG members additionally use peak cough flow. Assessment for SDB is requested by both groups when pulmonary function is abnormal or patients are symptomatic. Respirologists favor polysomnography, whereas CPNG members use overnight pulse oximetry. Nocturnal non-invasive ventilation and lung volume recruitment (LVR) are used in a minority of patients. CONCLUSIONS: Respirologists and CPNG members provide similar respiratory management of DMD patients, but differ in timing of consultation and choice of tests for pulmonary function and SDB. Canadian practices differ from the American Thoracic Society and Centre for Disease Control guidelines. PMID- 22451224 TI - Stretchable light-emitting electrochemical cells using an elastomeric emissive material. AB - Dispersing an ionic transition metal complex into an elastomeric matrix enables the fabrication of intrinsically stretchable light-emitting devices that possess large emission areas (~175 mm(2)) and tolerate linear strains up to 27% and repetitive cycles of 15% strain. This work demonstrates the suitability of this approach to new applications in conformable lighting that require uniform, diffuse light emission over large areas. PMID- 22451225 TI - Synthesis of NAC capped near infrared-emitting CdTeS alloyed quantum dots and application for in vivo early tumor imaging. AB - The synthesis of water-soluble near-infrared (NIR)-emitting quantum dots (QDs) has recently received extensive attention for non-invasive detection of biological information in living subjects. Highly fluorescent CdTeS alloyed QDs for biological application are introduced in this paper. QDs were synthesized by a hydrothermal method and coated with N-acetyl-l-cysteine (NAC) as both bioactive ligand and sulfur source for biocompatibility and biological stability. The optical properties, morphology and structure of CdTeS alloyed QDs were characterized. The in vitro and in vivo toxicity was intensively investigated. Furthermore, the dynamics and bio-distribution of CdTeS alloyed QDs on living mice were studied. To explore biomedical application, folate-polyethylene glycol (FA-PEG) was used to decorate the CdTeS alloyed QDs (FP-CdTeS QDs) for targeted imaging of tumors over-expressing the folate receptor (FR). The tumor targeting capability of FP-CdTeS QDs on tumor bearing nude mice was demonstrated. The results showed that the prepared CdTeS QDs have excellent optical properties and low toxicity, which makes them an ideal inorganic material for biomedical imaging. In addition, the folate-PEG conjugated NIR-QDs displayed good biocompatibility as well as excellent sensitivity and specificity for optical imaging of tumors which can extend the application of CdTeS QDs. PMID- 22451226 TI - Z-ligustilide potentiates the cytotoxicity of dopamine in rat dopaminergic PC12 cells. AB - Dopamine toxicity is an ongoing controversy surrounding the use of levadopa (L Dopa) in the therapy of Parkinson's disease. The initial objective of this study was to investigate the potential of neuroprotective botanicals such as Z ligustilide in reducing the cytotoxicity of dopamine. We surprisingly found that Z-ligustilide potentiated dopamine toxicity in a dopaminergic cell specific manner. Using rat dopaminergic cell line PC12 as a model, we demonstrated that dopamine and Z-ligustilide in combination profoundly induced cell death, although these drugs alone, to a lesser extent, affected the cell viability in a concentration-dependent manner. The synergistic cytotoxicity of dopamine and Z ligustilide is likely mediated via apoptosis, characterized by DNA fragmentation and chromatin shrinking after 12 h incubation. By measuring the intracellular reactive oxygen species (ROS) and reduced glutathione (GSH), Z-ligustilide and dopamine in combination dramatically enhanced the ROS formation and further depleted reduced GSH, whereas these drugs alone showed much less activity. Importantly, the synergistic cytotoxicity of dopamine and Z-ligustilide could be largely prevented by thiol-containing antioxidant N-acetylcysteine and GSH other than vitamin C and Trolox. Since the cytotoxicity of Z-ligustilide was not reported previously, the results of this study should raise public concerns over the potential risk associated with the combined use of herbal medicines containing Z-ligustilide with L-Dopa in the therapy of Parkinson's disease. PMID- 22451227 TI - Signaling and regulatory functions of bioactive sphingolipids as therapeutic targets in multiple sclerosis. AB - Spingolipids (SLs) are an important component of central nervous system (CNS) myelin sheaths and affect the viability of brain cells (oligodendrocytes, neurons and astrocytes) that is determined by signaling mediated by bioactive sphingoids (lyso-SLs). Recent studies indicate that two lipids, ceramide and sphingosine 1 phosphate (S1P), are particularly involved in many human diseases including the autoimmune inflammatory demyelination of multiple sclerosis (MS). In this review we: (1) Discuss possible sources of ceramide in CNS; (2) Summarize the features of the metabolism of S1P and its downstream signaling through G-protein-coupled receptors; (3) Link perturbations in bioactive SLs metabolism to MS neurodegeneration and (4) Compile ceramide and S1P relationships to this process. In addition, we described recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod) as well as proposed intervention to specify critical SL levels that tilt balances of apoptotic/active ceramide versus anti apoptotic/inactive dihydroceramide that may offer a novel and important therapeutic approach to MS. PMID- 22451228 TI - Racial, socioeconomic, and demographic disparities in access to fertility preservation in young women diagnosed with cancer. AB - BACKGROUND: This study seeks to examine the relation between sociodemographic characteristics and the utilization of fertility preservation services in reproductive age women diagnosed with cancer. METHODS: A total of 1041 women diagnosed with cancer between the ages of 18 and 40 years responded to a retrospective survey on demographic information and reproductive health history. Five cancer types were included: leukemia, Hodgkin disease, non-Hodgkin lymphoma, breast cancer, and gastrointestinal cancer. Nine hundred eighteen women reported treatment with potential to affect fertility (chemotherapy, pelvic radiation, pelvic surgery, or bone marrow transplant). Student t test, linear regression, and multivariate logistic regression were used where appropriate to determine the relation between sociodemographic characteristics and the odds of using fertility preservation services. RESULTS: Sixty-one percent of women were counseled on the risk of cancer treatment to fertility by the oncology team. Overall, 4% of women pursued fertility preservation. In multivariate analysis, women who had not attained a bachelor's degree (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9) were less likely to be counseled. Trends also suggested possible disparities in access to fertility preservation with age older than 35 years (OR, 0.1; 95% CI, 0.0-1.4) or previous children (OR, 0.3; 95% CI, 0.1-1.1) at diagnosis. Disparities in access to fertility preservation based on ethnicity and sexual orientation were also observed. CONCLUSIONS: Sociodemographic health disparities likely affect access to fertility preservation services. Although awareness of fertility preservation has improved in the past decade, an unmet need remains for reproductive health counseling and fertility preservation in reproductive age women diagnosed with cancer. PMID- 22451229 TI - Ventral stabilization and facetectomy in a Great Dane with wobbler syndrome due to cervical spinal canal stenosis. AB - This report describes the management of clinically significant, single level cervical spinal canal stenosis associated with articular facet hypertrophy in a three-year-old Great Dane dog, by combined surgical decompression and spinal stabilization. Spinal column stabilization was achieved by ventral application of two String of Pearls locking plates and subsequent decompression was accomplished by unilateral facetectomy. The six-month postoperative reassessment examination confirmed satisfactory clinical outcome with a complete return to normal activity, resolution of neurological deficits and maintenance of implant positioning. PMID- 22451230 TI - A novel salvage approach for pedicle axial flap--free-ization of pedicle internal mammary artery perforator flap. AB - A pedicle flap with distal segment compromise is classically managed by allowing tissue demarcation, debridement of non-viable tissue, and local tissue manipulation to achieve wound closure. When aggressive debridement leaves insufficient tissue for defect coverage, the original flap is often discarded. We present a case of distal necrosis of a pedicle internal mammary artery perforator flap for cheek reconstruction. The flap, which was rendered too small after debridement for defect coverage in its pedicle form, was converted to a free flap. The technical details of such conversion and potential feasibility of applying this conversion to other compromised pedicle flaps are discussed. We hypothesized that the principle of "free-ization" can be applied effectively for salvage of other failing pedicle flaps with axial blood supply. PMID- 22451231 TI - Anesthetic management and renal function in pediatric patients undergoing cytoreductive surgery with continuous hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin. AB - BACKGROUND: Extensive tumor implants secondary to sarcoma, sarcomatosis, or mesothelioma in children is rare. We conducted the first phase 1 trial of escalating doses of cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) in children with sarcomatosis. The most devastating complication of cisplatin therapy is nephrotoxicity. Here we present the anesthetic management and analysis of the impact of intraoperative fluid management on the incidence of renal failure. METHODS: Of the 10 patients under 18 years of age who underwent HIPEC in the context of our phase 1 trial, six patients were under the age of 10 years. We reviewed the anesthetic management, intraoperative fluid and blood administration, and postoperative renal function in these patients. RESULTS: The average age and weight were 6 years and 20.9 kg, respectively. To avoid renal toxicity, urine output was maintained at an average of 3 ml/kg/h. Crystalloid and colloid were transfused at an average rate of 9 ml/kg/h. Percentage increase in creatinine postoperatively varied from 33 to 500 %. Volume of fluid administered did not correlate with percentage increase in creatinine. All patients had a temporary increase in their serum creatinine, but none required dialysis. CONCLUSIONS: Fluid administration at an average rate of 9 ml/kg/h was required to maintain satisfactory urine output. This rate of intraoperative fluid administration is similar to what is provided to adult HIPEC patients. There was no significant correlation in the volume or type of fluid delivered and the increase in serum creatinine. More studies are needed to determine optimal fluid management in children undergoing HIPEC with cisplatin. PMID- 22451232 TI - The impact of obesity on breast cancer: a retrospective review. AB - BACKGROUND: Obesity has been linked to many adverse health consequences, including breast cancer; however, the impact on clinical presentation, tumor characteristics, and survival outcomes has yet to be clearly defined. METHODS: Retrospective review of a prospectively collected database of patients treated at a single institution for invasive breast cancer from 2000-2008 comparing two groups: nonobese (body mass index of <30) and obese (body mass index of >= 30) patients. Continuous variables, categorical variables, and survival data were analyzed. RESULTS: Of 1352 total patients, 76% were classified as nonobese and 24% were obese. When comparing age, obese patients presented less frequently than nonobese patients <50 years old (10% vs. 90%), and when comparing patients >50 years old (18% vs. 82%, P = 0.0019). Obese patients were more likely to present with disease detected by imaging when compared to nonobese patients (67% vs. 56%, P = 0.0006). Obese patients had larger tumors (1.7 cm vs. 1.4 cm, P < 0.001) and higher rates of lymph node (LN) metastases (31% vs. 25%, P = 0.026). On multivariate analysis, obesity was associated with nonpalpable tumors, larger tumors, a higher incidence of LN metastasis, lower incidence of Her2 positivity, lower incidence of multifocality, and less likely to undergo reconstruction after mastectomy. CONCLUSIONS: Obese patients clinically present at older ages with mammographically detected breast cancer at more advanced stages than nonobese patients. Strategies to encourage screening among the obese patient population are important. PMID- 22451233 TI - Outcome of pure mucinous breast carcinoma compared to infiltrating ductal carcinoma: a population-based study from China. AB - PURPOSE: Pure mucinous breast carcinoma (PMBC) is a rare pathologic finding. Few studies have addressed the biologic features of PMBC and prognostic factors among patients with this disease. We performed a study to compare PMBC and invasive ductal carcinoma (IDC) by means of a large database to reliably assess the biologic phenotype and clinical behavior of PMBC. METHODS: A total of 2,511 patients who met the inclusion criteria were identified from 1999 to 2010; 2,202 patients had pure IDC and 309 had PMBC. Clinical and biologic features, overall survival, and recurrence/metastasis-free survival (RFS) were compared for both groups. RESULTS: PMBC had favorable characteristics including smaller size, lower rates of lymph node positivity, lower stage, higher expression of hormone receptors, and less HER2 overexpression. Patients with PMBC had better 10-year RFS (71 %) than patients with IDC (64 %). Multivariate analysis revealed that node status and tumor, node, metastasis system (TNM) stage were statistically significant prognostic factors for survival. RFS curves stratified for node status revealed a highly significant difference between node negative and node positive patients. Additionally, patients with PMBC underwent breast-conserving surgery (BCS) more frequently than patients with IDC, and the 5-year overall survival rate of the BCS group was not significantly different from the total mastectomy group. CONCLUSIONS: PMBC in Chinese women showed less aggressive behavior and had a better prognosis than IDC, and this favorable outcome was maintained after 10 years. Node status and TNM stage appeared to be the most significant predictors of worse prognosis. BCS should be preferred over mastectomy in the treatment of early-stage PMBC. PMID- 22451234 TI - Clinical significance of promoter hypermethylation of ERbeta and RARbeta2 in tumor and serum DNA in Indian breast cancer patients. AB - PURPOSE: To determine concordance of promoter hypermethylation of ERbeta (estrogen receptor beta) and RARbeta2 (retinoic acid receptor beta2) in tumor and circulating DNA of Indian breast cancer patients and their association with clinicopathologic parameters and disease prognosis. METHODS: ERbeta and RARbeta2 methylation was analyzed by methylation-specific PCR in the tumors and circulating DNA of 100 patients with invasive ductal breast carcinoma. Promoter hypermethylation was associated with the expression of the encoded protein in tumors by immunohistochemistry, and their prognostic utility was explored in a follow-up study. RESULTS: Significant correlation was observed between promoter hypermethylation of ERbeta (r = + 0.77; p <= 0.001) and RARbeta2 (r = + 0.85; p <= 0.001) in tumors and paired sera. No association was found between ERbeta and RARbeta2 promoter hypermethylation and loss of protein expression. Kaplan-Meier survival curve showed loss of ERbeta expression, and RARbeta2 promoter hypermethylation was associated with poor overall survival (OS) (p = 0.03, p = 0.001). Breast cancer patients showing concurrent hypermethylation of ERbeta and RARbeta2 had a significantly shorter median OS (p = 0.02), underscoring that hypermethylation of these two genes may serve as an adverse prognosticator for breast carcinoma. CONCLUSIONS: Methylation status of ERbeta and RARbeta2 in serum could potentially be used to predict invasive ductal breast carcinoma. Furthermore, concurrent ERbeta and RARbeta2 methylation as well as loss of ERbeta expression may serve as a good prognostic marker. PMID- 22451235 TI - Hospital and medical care days in pancreatic cancer. AB - BACKGROUND: Little is known about resource utilization (number of days in the hospital or medical care) between diagnosis and death in patients with pancreatic cancer. METHODS: Using Surveillance, Epidemiology, and End Results (SEER) Medicare linked data, we identified 25,476 patients with pancreatic cancer (1992 2005). Hospital and medical care days per person-month from the time of diagnosis were described, stratified by stage, treatment, and survival duration. RESULTS: Hospital/medical care days vary by length of survival and treatment strategy in patients with pancreatic cancer. For all stages, patients were in the hospital a mean of 6.4 days and received medical care a total of 9.0 days in the first month after diagnosis, decreasing to 1.7 and 3.7 days per month, respectively, by the end of the first year. Hospital/medical care days per month of life were higher in patients with shorter survival but increased sharply at the end of life in all patients, regardless of duration of survival. In patients with locoregional disease, resection was associated with a higher number of hospital/medical care days during the first 4 months after diagnosis, but fewer at the end of the first year. For distant disease, hospital days were similar but days in medical care were higher for patients receiving chemotherapy, increasing especially at the end of life. CONCLUSIONS: This study is the first to quantify hospital/medical care days in patients with pancreatic cancer by stage, treatment, and survival. This information will provide realistic expectations and allow for treatment decisions based on patient preferences. PMID- 22451236 TI - Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome. AB - BACKGROUND: The interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer has arbitrarily been set at 6-8 weeks. However, tumor regression is variable. This study aimed to evaluate whether the interval between neoadjuvant therapy and surgery had an impact on pathologic response and on surgical and oncologic outcome. METHODS: A total of 356 consecutive patients with clinical stage II and III rectal adenocarcinoma were identified. Median age was 63 years, and 65 % were men. All patients received neoadjuvant chemoradiotherapy (45 Gy) with a continuous infusion of 5-fluorouracil. Data on neoadjuvant-surgery interval, type of surgery, pathology, postoperative complications, length of hospital stay, disease recurrence, and survival were reviewed. Patients were divided into two groups according to the interval between neoadjuvant therapy and surgery: <= 7 weeks (short interval, n = 201) and >7 weeks (long interval, n = 155). RESULTS: The complete pathologic response rate was 21 %. It was significantly higher after a longer interval (28 %) than after a shorter interval (16 %, p = 0.006). A longer interval did not affect morbidity or length of hospital stay. After a median follow-up of 4.9 years, the 5-year cancer-specific survival rate was 83 % in the short-interval group versus 91 % in the long interval group (p = 0.046), and the free-from-recurrence rate was 73 versus 83 %, respectively (p = 0.026). CONCLUSIONS: In this retrospective analysis, there seems to be an association between a longer interval after neoadjuvant chemoradiotherapy and complete pathologic response without affecting postoperative morbidity and length of hospital stay, and with no detrimental effect on oncologic outcome. PMID- 22451237 TI - Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features, treatment modalities, and prognosis. AB - BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer that has rarely been reported in large-scale clinical studies. The aim of this study was to clarify the clinical features, treatment modalities, and prognosis of cHCC-CC. METHODS: Included in this study were 113 patients who were histologically diagnosed as having Allen type C cHCC-CC, 103 of whom received liver resection, 6 transarterial chemoembolization treatment, 3 radiofrequency ablation, and 1 palliative supportive treatment. Clinicopathologic features and prognosis of 103 cHCC-CC patients after liver resection were compared with those of 6,679 patients with hepatocellular carcinoma (HCC) and 386 patients with intrahepatic cholangiocarcinoma (ICC) who underwent liver resection during the same period. RESULTS: The proportion of cHCC-CC in primary liver cancers was 1.5 %. The 103 cases of cHCC-CC were characterized by male predominance, infection with hepatitis virus or presence of liver cirrhosis, and elevated alfa-fetoprotein findings similar to HCC. However, serum CA19-9 elevation, incomplete capsules, and lymph node involvement were similar to ICC. The 1-, 3-, and 5-year overall survival rates after liver resection were 73.9, 41.4, and 36.4 %, respectively, for patients with cHCC-CC versus 77.5, 53.3, and 41.4 % for HCC patients, and 58.0, 29.1, and 22.3 % for ICC patients (chi(2) = 137.5, P < 0.001). Tumor, node, metastasis system stage (hazard ratio 1.27, 95 % confidence interval 1.08-1.49, P = 0.003) and radical liver resection (hazard ratio 0.31, 95 % confidence interval 0.14-0.68, P = 0.004) were independent prognostic factors for overall survival. CONCLUSIONS: cHCC-CC has biological behavior and prognosis that are intermediate between HCC and ICC. Radical liver resection can provide a better outcome for this uncommon malignancy. PMID- 22451238 TI - Evidence-based medicine and the selection of lipid-lowering therapy in type 2 diabetes. PMID- 22451239 TI - Association between bone mineral density and type 2 diabetes mellitus: a meta analysis of observational studies. AB - Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm(2)) between diabetic and non diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross sectional, cohort or case-control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA(1C) were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM. PMID- 22451240 TI - Threat as a feature in visual semantic object memory. AB - Threatening stimuli have been found to modulate visual processes related to perception and attention. The present functional magnetic resonance imaging (fMRI) study investigated whether threat modulates visual object recognition of man-made and naturally occurring categories of stimuli. Compared with nonthreatening pictures, threatening pictures of real items elicited larger fMRI BOLD signal changes in medial visual cortices extending inferiorly into the temporo-occipital (TO) "what" pathways. This region elicited greater signal changes for threatening items compared to nonthreatening from both the natural occurring and man-made stimulus supraordinate categories, demonstrating a featural component to these visual processing areas. Two additional loci of signal changes within more lateral inferior TO areas (bilateral BA18 and 19 as well as the right ventral temporal lobe) were detected for a category-feature interaction, with stronger responses to man-made (category) threatening (feature) stimuli than to natural threats. The findings are discussed in terms of visual recognition of processing efficiently or rapidly groups of items that confer an advantage for survival. PMID- 22451241 TI - Spirometry and forced oscillations in the detection of airway hyperreactivity in asthmatic children. AB - BACKGROUND: Provocation tests are routinely used to detect airway hyperreactivity (AH) in the diagnosis of asthma. We compared the sensitivities of the forced oscillation technique (FOT) and spirometry in the detection of AH in asthmatic children. METHODS: FOT and spirometry were performed in 20 asthmatic children (aged 5-18 years) following aerosolized histamine and methacholine at an interval of 2 weeks. The respiratory system input impedance was measured by FOT; the resistance at 6 Hz (R(6) ), the average resistance between 4 and 24 Hz, the area under the reactance curve (AX) and the resonant frequency were extracted from these recordings. Spirometry was used to obtain forced expiratory volumes and flow parameters. RESULTS: Following provocation with the two agonists, the FOT detected the airway response as early as spirometry. When the greater variability of the impedance parameters was taken into account, the two methods were observed to have similar sensitivities. Among the lung function parameters studied, AX and R(6) were the most sensitive for the demonstration of AH. CONCLUSIONS: Our findings demonstrate that FOT is as suitable as spirometry for the measurement of bronchoconstriction and thus it may be considered for the detection of AH in asthmatic children. Since its application requires minimal cooperation, this approach imposes less stress and may be particularly favorable in the diagnosis of asthma at a young age. PMID- 22451242 TI - Facile synthesis of concave decahedra enclosed by high-index facets and truncated decahedra with a large size. AB - Nanostructures with concave surfaces are not common, and their synthesis is still challenging. In this paper, we have successfully synthesized two kinds of five fold-twinned Au decahedra and dodecagonal plates by changing the reaction conditions. 40 high-index {221} facets were observed in the concave decahedron. The truncated decahedral gold nanocrystals (NCs) with a large size of 250-350 nm were obtained for the first time, which breaks the assumption that the truncated five-fold-twinned Au nanoparticles (NPs) can only be obtained with a size below 5 nm. The growth mechanism and the evolution process of the gold nanostructures were discussed. This work provides a facile way to synthesize concave decahedra, truncated decahedra and dodecagonal plates with controlled nanostructures. PMID- 22451243 TI - Dielectric properties of rat embryo and foetus as a function of gestation. AB - The dielectric properties of rat embryos/foetuses have been acquired at several stages of gestation at 37 degrees C and in the frequency range of 40 MHz-20 GHz. Measurements were carried out on homogenized tissues, as trial experiments did not show any systematic difference between the dielectric data of intact and homogenized tissues at microwave frequencies. The results showed that dielectric properties of the foetus are generally higher than adult muscle and brain. The measured data also showed some decline for both permittivity and conductivity as the foetus grew from 18 to 20 days old; however, these changes were not statistically significant. Data were also collected for placenta and amniotic fluid which were in good agreement with those recently obtained from human tissues. Finally, tabulated numerical dielectric data for rat foetal tissues are presented for a wide range of medical and telecommunication frequencies. PMID- 22451244 TI - Absorption of different oral dosage forms of oxycodone in the elderly: a cross over clinical trial in patients undergoing cystoscopy. AB - PURPOSE: To characterize the pharmacokinetics (PK) of oxycodone following intravenous injection and administration of three oral dosage forms (solution, capsule, and controlled-release tablet) in elderly patients (age 76-89 years) undergoing cystoscopy. METHODS: This was an open, randomized study with two sequences and two visits in 15 elderly patients. The patients were given intravenous injection (over 10 min) of 5 mg of oxycodone hydrochloride trihydrate. Oxycodone hydrochloride (5 mg in all forms) was orally administered as a solution, a capsule, and a controlled-release tablet. Venous blood samples were collected up to 17 h after oxycodone administration. Population PK parameters were calculated with NONMEM VI 2.0. For intravenous injection we calculated clearance, volume of distribution at steady state, and the half-life of elimination, and for oral dosage forms also the absolute bioavailability. RESULTS: Clearance of the intravenous injections was 28.9 L/h; the volume of distribution at steady state and the half-life of elimination were 186 L and 5.2 h, respectively. The absolute bioavailability of oxycodone was 59 % from oral solutions, 64 % from capsules, and 55 % from controlled-release tablets. CONCLUSIONS: Our results indicate that, in the elderly, the bioavailability of the three different oral dosage forms of oxycodone is fairly similar. PMID- 22451245 TI - Tuning solid state luminescent properties in a hydrogen bonding-directed supramolecular assembly of bis-cyclometalated iridium(III) ethylenediamine complexes. AB - Synthesis, crystal structural determination and photophysical properties of a series of heteroleptic cationic cyclometalated iridium(III) derivatives of general formula [(ppy)(2)Ir(en)]X (X = ClO(4)(-) (1), PF(6)(-) (2), Cl(-) (3), BPh(4)(-) (4)), are described. The assembly of the common molecular building block allows to get highly luminescent crystalline materials or to assemble poorly luminescent supramolecular channelled architectures, for which the additional contribution of oxygen quenching effects has been observed. Moreover, the high reproducibility of the preparations of the crystalline materials in their specific crystalline phases, makes the control of the supramolecular organization of photo-active iridium(III) complexes within the crystalline structures a useful synthetic procedure for the construction of highly luminescent materials. PMID- 22451246 TI - Effects and action mechanisms of Korean pear (Pyrus pyrifolia cv. Shingo) on alcohol detoxification. AB - Korean pear (Pyrus pyrifolia cv. Shingo) has been used as a traditional medicine for alleviating alcohol hangover. However, scientific evidence for its effectiveness or mechanism is not clearly established. To investigate its mechanism of alcohol detoxification, both in vitro and in vivo studies were performed with an aldehyde dehydrogenase 2 (ALDH2) alternated animal model. The pear extract (10 mL/kg bw) was administered to Aldh2 normal (C57BL/6) and deficient (Aldh2 -/-) male mice. After 30 min, ethanol (1 g or 2 g/kg bw) was administered to the mice via gavage. Levels of alcohol and acetaldehyde in blood were quantified by GC/MS. First, it was observed that the pears stimulated both alcohol dehydrogenase (ADH) and ALDH activities by 2~3- and 1.3-fold in in vitro studies, respectively. Second, mouse PK data (AUC(infinity) and C(max) ) showed that the pear extract decreased the alcohol level in blood regardless of ALDH2 genotype. Third, the pear increased the acetaldehyde level in blood in Aldh2 deficient mice but not in Aldh2 normal mice. Therefore, the consistent in vitro and in vivo data suggest that Korean pears stimulate the two key alcohol metabolizing enzymes. These stimulations could be the main mechanism of the Korean pear for alcohol detoxification. Finally, the results suggest that polymorphisms of human ALDH2 could bring out individual variations in the effects of Korean pear on alcohol detoxification. PMID- 22451247 TI - Prevention of gastric stasis by omentum patching after living donor left hepatectomy. AB - Among 137 living liver donors who underwent partial hepatectomy between August 1997 and November 2010, 58 donated the left lobe of their liver, with or without the caudate lobe. Gastric stasis developed after surgery in 4 (7 %) of these 58 donors (Fig. 1); possibly because of dislocation of the stomach after hepatectomy and adhesion between the stomach and the cut surface of the liver. This complication is specific to left hepatectomy [1] and although not life threatening, it is symptomatic and requires endoscopic or surgical intervention. We describe our surgical technic designed to prevent this complication. Fig. 1 Gastric stasis after living donor left hepatectomy. Fluorescent imaging study shows an enlarged stomach with no passage of radiofluorescence through the pylorus. PMID- 22451248 TI - Novel surfactants with diglutamic acid polar head group: drug solubilization and toxicity studies. AB - PURPOSE: Novel surfactants made of diglutamic acid (DG) polar head linked to lithocholic, arachidonic, linoleic or stearic acids were designed for drug solubilization. METHODS: Surfactants 3-D conformer and packing parameter were determined by molecular modelling and self-assembling properties by pyrene fluorescence measurements. Cytotoxicity was assessed on Human Umbilical Vein Endothelial Cells (HUVEC) and haemolyitic activity on rat red blood cells. Drug solubilization was quantified and its interaction with hydrophobic moieties was characterized using differential scanning calorimetry and X-ray diffraction. Self organisation of stearoyl-DG was observed by cryogenic transmission electron microscopy. Toxicity after repeated injections of stearoyl-DG was investigated in Wistar rats. RESULTS: DG-based surfactants self-assemble into water and their critical micellar concentrations are comprised between 200 and 920 MUg/mL. Cytotoxicity and haemolysis were lower than for polysorbate 80. At best, stearoyl DG solubilized the drug up to 22% (w/w). Solid-state characterization evidenced drug/lipid interactions leading to the formation of a new complex. Stearoyl-DG formed spherical micelles of 20 nm, as predicted by packing parameter calculation. However, it induced a possible liver toxicity after intravenous administration in rats. CONCLUSIONS: Among the surfactants tested, stearoyl-DG is the more efficient for drug solubilization but its use is limited by its possible liver toxicity. PMID- 22451249 TI - Combination therapy of antiandrogen and XIAP inhibitor for treating advanced prostate cancer. AB - PURPOSE: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. METHODS: CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. RESULTS: CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC(50) for CBDIV17 was ~ 12 MUM and ~ 21 MUM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC(50) of ~ 46 MUM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. CONCLUSIONS: Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer. PMID- 22451250 TI - Near-infrared image-guided delivery and controlled release using optimized thermosensitive liposomes. AB - PURPOSE: To engineer optimized near-infrared (NIR) active thermosensitive liposomes to potentially achieve image-guided delivery of chemotherapeutic agents. METHODS: Thermosensitive liposomes were surface-coated with either polyethylene glycol or dextran. Differential scanning calorimetry and calcein release studies were conducted to optimize liposomal release, and flow cytometry was employed to determine the in vitro macrophage uptake of liposomes. Indocyanine green (ICG) was encapsulated as the NIR dye to evaluate the in vivo biodistribution in tumor-bearing mice. RESULTS: The optimized thermosensitive liposome formulation consists of DPPC, SoyPC, and cholesterol in the 100:50:30 molar ratio. Liposomes with dextran and polyethylene glycol demonstrated similar thermal release properties; however in vitro macrophage uptake was greater with dextran. Non-invasive in vivo NIR imaging showed tumor accumulation of liposomes with both coatings, and ex vivo NIR imaging correlated well with actual ICG concentrations in various organs of healthy mice. CONCLUSIONS: The optimized thermosensitive liposome formulation demonstrated stability at 37 degrees C and efficient burst release at 40 and 42 degrees C. Dextran exhibited potential for application as a surface coating in thermosensitive liposome formulations. In vivo studies suggest that liposomal encapsulation of ICG permits reliable, real time monitoring of liposome biodistribution through non-invasive NIR imaging. PMID- 22451252 TI - Functional heartburn: definition and management strategies. AB - Functional heartburn (FH) is a functional gastro-intestinal disorder characterized by symptoms of heartburn not related to gastro-esophageal reflux. The absence of evidence of reflux-related symptoms relies on absence of esophagitis at endoscopy (including biopsies to exclude eosinophilic esophagitis), a normal esophageal acid exposure during esophageal pH-monitoring together with a negative symptom-reflux association analysis and an unsatisfactory response to proton pump inhibitor therapy. Addition of impedance measurement to pH-monitoring is likely to increase the number of patients with recognized reflux-related symptoms. The pathophysiology of functional heartburn remains largely unknown but involves disturbed esophageal perception and psychological factors such as depression, anxiety and somatization. The treatment of FH remains largely empirical and an individual approach is therefore recommended. The clinician should provide reassurance and refrain from performing too many invasive tests or therapeutic procedures. The use of pain modulators is recommended by most experts despite the lack of appropriate clinical trials to support it. PMID- 22451253 TI - Anti-tumoural effects of PlgK1-5 are directly linked to reduced ICAM expression, resulting in hepatoma cell apoptosis. AB - PURPOSE: Angiostatin and angiostatin-like molecules are known as anti-angiogenic factors, which inhibit endothelial cell functions resulting in reduced tumour growth. Recent data indicate that these molecules, especially PlgK1-5, directly affect tumour cells, which could explain the strong anti-tumoural effects of PlgK1-5. Therefore, we have analysed whether PlgK1-5 alters tumour cell functions and expression levels of cell adhesion molecules in murine and human hepatoma cells in vitro and in vivo. METHODS: First, effects on tumour growth, proliferation and apoptosis were investigated in vivo in a subcutaneous tumour model. In vitro, effects of PlgK1-5 on tumour cell apoptosis, clonal expansion, migration, corresponding ICAM expression and intracellular signal transduction in murine Hepa129 and human HuH7 hepatoma cells have been analysed. RESULTS: In vivo, subcutaneous tumour growth was reduced by 75% in PlgK1-5-treated animals compared to the controls. This was accompanied by increased tumour cell apoptosis (up to 33%) and decreased tumour cell proliferation (by up to 21%). In vitro, PlgK1-5 induced apoptosis in hepatoma cells, corresponding to increased caspase-8 cleavage and reduced AKT phosphorylation. Migration and clonal expansion was also diminished in PlgK1-5-treated Hepa129, corresponding to decreased ICAM expression levels. CONCLUSIONS: Here, we show that PlgK1-5 directly affects tumour cells by decreasing cell adhesion resulting-at least partly-in apoptosis. This is mediated by altered intracellular signal transduction and by activation of the caspase cascade. These findings further underscore the potential therapeutic role of PlgK1-5 in the treatment of HCC. PMID- 22451254 TI - Ostomy function after abdominoperineal resection--a clinical and patient evaluation. AB - PURPOSE: Abdominoperineal resection (APR) for rectal cancer results in a permanent colostomy. As a consequence of a recent change in operative technique from standard (S-APR) to extralevator resection (E-APR), the perineal part of the procedure is now performed with the patient in a prone jackknife position. The impact of this change on stoma function is unknown. The aim was to determine stoma-related complications and the individual patient experience of a stoma. METHODS: Consecutive patients with rectal cancer operated on with APR in one institution in 2004 to 2009 were included. Recurrent cancer, palliative procedures, pre-existing stoma and patients not alive at the start of the study were excluded. Data were collected from hospital records and the national colorectal cancer registry. A questionnaire was sent out to patients. The median follow-up was 44 months (13-84) after primary surgery. RESULTS: Ninety-six patients were alive in February 2011. Seventy seven agreed to participate. Sixty nine patients (90 %) returned the questionnaire. Stoma necrosis was more common for E-APR, 34 % vs. 10 %, but bandaging problems and low stoma height were more common for S-APR. There were no differences in the patients' experience of stoma function. In all, 35 % of the patients felt dirty and unclean, but 90 % felt that they had a full life and could engage in leisure activities of their choice. CONCLUSIONS: This exploratory study indicates no difference in stoma function after 1 year between S-APR and E-APR. Over 90 % of the patients accept their stoma, but our study indicates that more information and support for patients are warranted. PMID- 22451255 TI - Management of synchronous rectal and prostate cancer. AB - PURPOSE: Although well described, there is limited published data related to management on the coexistence of prostate and rectal cancer. The aim of this study was to describe a single institution's experience with this and propose a treatment algorithm based on the best available evidence. METHODS: From 2000 to 2011, a retrospective review of institutional databases was performed to identify patients with synchronous prostate and rectal cancers where the rectal cancer lay in the lower two thirds of the rectum. Operative and non-operative outcomes were analysed and a management algorithm is proposed. RESULTS: Twelve patients with prostate and rectal cancer were identified. Three were metachronous diagnoses (>3 month time interval) and nine were synchronous diagnoses. In the synchronous group, four had metastatic disease at presentation and were treated symptomatically, while five were treated with curative intent. Treatment included pelvic radiotherapy (74 Gy) followed by pelvic exenteration (three) and watchful waiting for rectal cancer (one). The remaining patient had a prostatectomy, long course chemoradiotherapy and anterior resection. There were no operative mortalities and acceptable morbidity. Three remain alive with two patients disease-free. CONCLUSIONS: Synchronous detection of prostate cancer and cancer of the lower two thirds of the rectum is uncommon, but likely to increase with rigorous preoperative staging of rectal cancer and increased awareness of the potential for synchronous disease. Treatment must be individualized based on the stage of the individual cancers taking into account the options for both cancers including EBRT (both), surgery (both), hormonal therapy (prostate), surgery (both) and watchful waiting (both). PMID- 22451256 TI - 2011 Rita Schaffer lecture: nanoparticles for intracellular nucleic acid delivery. AB - Nanoparticles are a promising technology for delivery of new types of therapeutics. A polymer library approach has allowed engineering of polymeric particles that are particularly effective for the delivery of DNA and siRNA to human cells. Certain chemical structural motifs, degradable linkages, hydrophobicity, and biophysical properties are key for successful intracellular delivery. Small differences to biomaterial structure, and especially the type of degradable linkage in the polymers, can be critical for successful delivery of siRNA vs. DNA. Furthermore, subtle changes to biomaterial structure can facilitate cell-type gene delivery specificity between human brain cancer cells and healthy cells as well as between human retinal endothelial cells and epithelial cells. These polymeric nanoparticles are effective for nucleic acid delivery in a broad range of human cell types and have applications to regenerative medicine, ophthalmology, and cancer among many other biomedical research areas. PMID- 22451257 TI - The development of novel biodegradable bifurcation stents for the sustainable release of anti-proliferative sirolimus. AB - In this report, a balloon-expandable, biodegradable, drug-eluting bifurcation stent (DEBS) that provides a sustainable release of anti-proliferative sirolimus was developed. Biodegradable bifurcation stents, made of polycaprolactone, were first manufactured by injection molding and hot spot welding techniques. Various properties of the fabricated stents, including compression strengths, collapse pressures, and flow pattern in a circulation test, were characterized. The experimental results showed that biodegradable bifurcation stents exhibited comparable mechanical properties with those of metallic stents and superior flow behavior to that of metallic bifurcation stents deployed via the T And small Protrusion approach. Polylactide-polyglycolide (PLGA) copolymer and sirolimus were then dissolved in acetonitrile and coated onto the surface of the stents by a spray coating device. An elution method and a high performance liquid chromatography analysis were utilized to examine the in vitro release characteristics of sirolimus. Biodegradable bifurcation stents released high concentrations of sirolimus for more than 6 weeks, and the total period of drug release could be prolonged by increasing the drug loading of the PLGA/sirolimus coating layers. In addition, the eluted drug could effectively inhibit the proliferation of smooth muscle cells. The developed DEBS in this study may provide a promising strategy for the treatment of cardiovascular bifurcation lesions. PMID- 22451258 TI - Deep brain stimulation in Huntington's disease: A 4-year follow-up case report. PMID- 22451259 TI - "Feeling" others' painful actions: the sensorimotor integration of pain and action information. AB - Sensorimotor regions of the brain have been implicated in simulation processes such as action understanding and empathy, but their functional role in these processes remains unspecified. We used functional magnetic resonance imaging (fMRI) to demonstrate that postcentral sensorimotor cortex integrates action and object information to derive the sensory outcomes of observed hand-object interactions. When subjects viewed others' hands grasping or withdrawing from objects that were either painful or nonpainful, distinct sensorimotor subregions emerged as showing preferential responses to different aspects of the stimuli: object information (noxious vs. innocuous), action information (grasps vs. withdrawals), and painful action outcomes (painful grasps vs. all other conditions). Activation in the latter region correlated with subjects' ratings of how painful each object would be to touch and their previous experience with the object. Viewing others' painful grasps also biased behavioral responses to actual tactile stimulation, a novel effect not seen for auditory control stimuli. Somatosensory cortices, including primary somatosensory areas 1/3b and 2 and parietal area PF, may therefore subserve somatomotor simulation processes by integrating action and object information to anticipate the sensory consequences of observed hand-object interactions. PMID- 22451260 TI - Cognitive functioning in children and adults with nonsyndromal cleft lip and/or palate: a meta-analysis. AB - OBJECTIVE: To provide a meta-analysis of research that has examined the cognitive functioning of children and adults with cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). METHODS: Data from 29 studies, which compared persons with a cleft to a control group on tests of cognitive functioning, were analyzed. The data were obtained from 1,546 persons with cleft and 279,805 controls. RESULTS: Participants with a cleft performed significantly worse on 7 cognitive domains. However, the only moderate and significant deficit, which was based on nonheterogeneous study findings and not subject to publication bias, was in the language domain. CL, CP, and CLP were all associated with cognitive impairments, although the profiles for the groups differed. CONCLUSIONS: Cross-sectional studies suggest that persons with clefts experience poorer cognitive functioning across a range of domains, although large-scale longitudinal studies are needed to more definitively differentiate outcomes by cleft type. PMID- 22451261 TI - Does the Brief Symptom Inventory-18 case rule apply in adult survivors of childhood cancer? Comparison with the Symptom Checklist-90. AB - OBJECTIVE: Screening for psychological distress is an important tool for improving survivors' access to psychosocial care. The Brief Symptom Inventory-18 (BSI-18) has been widely used to identify psychological distress in cancer survivors, but few studies have reported on its validity. This study evaluated validity of the BSI-18 by comparing it to the Symptom Checklist-90 (SCL-90). METHODS: Concordance of cases identified by the BSI-18 and SCL-90 was examined in a sample of 193 adult survivors of childhood cancer. RESULTS: Receiver operating characteristics analysis showed strong diagnostic utility of the BSI-18 (area under curve = 0.922). However, the standard BSI-18 case-rule demonstrated low sensitivity (45.2%) against the SCL-90. An alternative case-rule showed better results; sensitivity (87.10%), specificity (83.33%). CONCLUSIONS: The BSI-18 is a useful measure for evaluating distress in adult survivors of childhood cancers; however, the standard BSI-18 case-rule has not been validated for this population, and an alternative case rule should be considered. PMID- 22451262 TI - On the uncertainties of photon mass energy-absorption coefficients and their ratios for radiation dosimetry. AB - A systematic analysis of the available data has been carried out for mass energy absorption coefficients and their ratios for air, graphite and water for photon energies between 1 keV and 2 MeV, using representative kilovoltage x-ray spectra for mammography and diagnostic radiology below 100 kV, and for 192Ir and 60Co gamma-ray spectra. The aim of this work was to establish 'an envelope of uncertainty' based on the spread of the available data. Type A uncertainties were determined from the results of Monte Carlo (MC) calculations with the PENELOPE and EGSnrc systems, yielding mean values for u(en)/rho with a given statistical standard uncertainty. Type B estimates were based on two groupings. The first grouping consisted of MC calculations based on a similar implementation but using different data and/or approximations. The second grouping was formed by various datasets, obtained by different authors or methods using the same or different basic data, and with different implementations (analytical, MC-based, or a combination of the two); these datasets were the compilations of NIST, Hubbell, Johns-Cunningham, Attix and Higgins, plus MC calculations with PENELOPE and EGSnrc. The combined standard uncertainty, u(c), for the u(en)/rho values for the mammography x-ray spectra is 2.5%, decreasing gradually to 1.6% for kilovoltage x ray spectra up to 100 kV. For 60Co and 192Ir, u(c) is approximately 0.1%. The Type B uncertainty analysis for the ratios of u(en)/rho values includes four methods of analysis and concludes that for the present data the assumption that the data interval represents 95% confidence limits is a good compromise. For the mammography x-ray spectra, the combined standard uncertainties of (u(en)/rho)(graphite,air) and (u(en)/rho)(graphite,water) are 1.5%, and 0.5% for (u(en)/rho)(water,air), decreasing gradually down to u(c) = 0.1% for the three u(en)/rho ratios for the gamma-ray spectra. The present estimates are shown to coincide well with those of Hubbell (1977 Rad. Res. 70 58-81), except for the lowest energy range (radiodiagnostic) where it is concluded that current databases and their systematic analysis represent an improvement over the older Hubbell estimations. The results for (u(en)/rho)(graphite,air) for the gamma-ray dosimetry range are moderately higher than those of Seltzer and Bergstrom (2005 private communication). PMID- 22451263 TI - Lung function in young adults with congenital diaphragmatic hernia; a longitudinal evaluation. AB - BACKGROUND: Survival rates of patients with congenital diaphragmatic hernia (CDH) have improved to up to 80%. Little is known about long-term consequences of the disease and its treatment. We evaluated lung function and respiratory symptoms longitudinally in a previously studied cohort of CDH patients and age-matched non CDH patients who underwent similar neonatal intensive care treatment. STUDY DESIGN: We tested 27 young adults [mean (SD) age: 26.8 years (2.9)] with CDH and 30 non-CDH patients. Dynamic and static lung volumes, midexpiratory flows, and diffusion capacity were expressed as mean (SD) standard deviation scores. Prevalence of respiratory symptoms was evaluated with the European Community Respiratory Health Survey. RESULTS: All data are expressed as mean (SD). FEF(25 75) in CDH patients had slightly deteriorated since childhood (CDH: -0.7 (1.4) vs. -1.6 (1.5), P < 0.001; non-CDH patients: 0.2 (1.4) vs. -0.3 (1.6), P = 0.038, ns). Diffusion capacity decreased in both groups (CDH: DL(CO) c 0.2 (1.1) vs. 1.5 (1.1), P <0.001; non-CDH: DL(CO) c 0.1 (0.4) vs. -1.1 (1.1), P < 0.001). Lung volumes were normal in both groups. The prevalence of asthma was higher than in the normal population (27.6% in patients and 30% in controls, P < 0.001). CONCLUSIONS: Airflow obstruction and diffusion capacity deteriorated mildly from childhood into adulthood in survivors of CDH. The improved survival of patients with more severe forms of diaphragmatic hernia calls for long-term follow-up of lung function. PMID- 22451265 TI - Antioxidant/antibacterial activities of a topical phytopharmaceutical formulation containing a standardized extract of Baccharis incarum, an extremophile plant species from Argentine Puna. AB - The antimicrobial and antioxidant activities of standardized extracts of Baccharis incarum in 60 degrees and 80 degrees ethanol and of a phytopharmaceutical formulation obtained from them were measured. Baccharis tinctures showed antimicrobial activity against clinically isolated antibiotic resistant Staphylococcus aureus and Enterococcus faecalis, with MIC values of 40 80 ug GAE/mL. Both tinctures exhibited ABTS(?+) scavenging activity with SC(50) values between 1.6 and 4.0 ug GAE/mL. The tinctures were not genotoxic in the Salmonella assay. For this reason, the tincture in 60 degrees ethanol was incorporated into a topical pharmaceutical formulation (Hydrogel/ Carbopol(r) 934). The phytopharmaceutical formulation also showed antibacterial and antioxidant activities in the in vitro assays. The hydrogel showed microbiological, chemical, physical and functional stability during storage at room temperature. Studies that measure drug release as a determination of bioavailability were also carried out using the Franz diffusion cell (FC). The results demonstrated the release of two bioactive compounds (chlorogenic acid and 4',5-dihydroxy-3',3,6,7,8-pentamethoxyflavone) from the phytotherapic preparation in HPLC studies of FC receptor solution. In consequence, the phytopreparation applied topically could be used to treat skin and soft tissue infection produced by methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus faecalis and opens new opportunities for the use of active natural ingredients in the cosmeceutical field as antiacne and antioxidant. PMID- 22451266 TI - Climate change, land use conflicts, predation and ecological degradation as challenges for reindeer husbandry in northern Europe: what do we really know after half a century of research? AB - Reindeer grazing has been entitled as ecological keystone in arctic-alpine landscapes. In addition, reindeer husbandry is tightly connected to the identity of the indigenous Sami people in northern Europe. Nowadays, reindeer husbandry is challenged in several ways, of which pasture degradation, climate change, conflicting land uses and predation are the most important. Research on reindeer related topics has been conducted for more than half a century and this review illuminates whether or not research is capable to match these challenges. Despite its high quality, traditional reindeer-related research is functionally isolated within the various disciplines. The meshwork of ecology, socio-economy, culture and politics, however, in which reindeer husbandry is embedded by various interactions, will remain unclear and difficult to manage, if actors and relationships are kept separate. We propose some targets for new integrative research approaches that incorporate traditional knowledge and focus on the entire human-ecological system 'reindeer husbandry' to develop solutions for its challenges. PMID- 22451267 TI - Inhibition of alpha-SMA by the ectodomain of FGFR2c attenuates lung fibrosis. AB - The soluble ectodomain of fibroblast growth factor receptor-IIIc (sFGFR2c) is able to bind to fibroblast growth factor (FGF) ligands and block the activation of the FGF-signaling pathway. In this study, sFGFR2c inhibited lung fibrosis dramatically in vitro and in vivo. The upregulation of alpha-smooth muscle actin (alpha-SMA) in fibroblasts by transforming growth factor-beta1 (TGF-beta1) is an important step in the process of lung fibrosis, in which FGF-2, released by TGF beta1, is involved. sFGFR2c inhibited alpha-SMA induction by TGF-beta1 via both the extracellular signal-regulated kinase 1/2 (ERK1/2) and Smad3 pathways in primary mouse lung fibroblasts and the proliferation of mouse lung fibroblasts. In a mouse model of bleomycin (BLM)-induced lung fibrosis, mice were treated with sFGFR2c from d 3 or d 10 to 31 after BLM administration. Then we used hematoxylin and eosin staining, Masson staining and immunohistochemical staining to evaluate the inhibitory effects of sFGFR2c on lung fibrosis. The treatment with sFGFR2c resulted in significant attenuation of the lung fibrosis score and collagen deposition. The expression levels of alpha-SMA, p-FGFRs, p-ERK1/2 and p-Smad3 in the lungs of sFGFR2c-treated mice were markedly lower. sFGFR2c may have potential for the treatment of lung fibrosis as an FGF-2 antagonist. PMID- 22451268 TI - Implication of AMP-activated protein kinase in transient receptor potential vanilloid type 1-mediated activation of endothelial nitric oxide synthase. AB - We investigated whether AMP-activated protein kinase (AMPK), a multi-functional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in Matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E deficient (ApoE(-/-)) mice was abrogated in TRPV1-deficient ApoE(-/-) mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis. PMID- 22451269 TI - CpGassoc: an R function for analysis of DNA methylation microarray data. AB - SUMMARY: With the increasing availability of high-density methylation microarrays, there has been growing interest in analysis of DNA methylation data. We have developed CpGassoc, an R package that can efficiently perform the statistical analysis needed for increasingly large methylation datasets. CpGassoc is a modular, expandable package with functions to perform rapid analyses of DNA methylation data via fixed or mixed effects models, to perform basic quality control, to carry out permutation tests, and to display results via an array of publication-quality plots. AVAILABILITY AND IMPLEMENTATION: CpGassoc is implemented in R and is freely available at http://genetics.emory.edu/conneely; we are in the process of submitting it to CRAN. PMID- 22451270 TI - ADMIT: a toolbox for guaranteed model invalidation, estimation and qualitative quantitative modeling. AB - SUMMARY: Often competing hypotheses for biochemical networks exist in the form of different mathematical models with unknown parameters. Considering available experimental data, it is then desired to reject model hypotheses that are inconsistent with the data, or to estimate the unknown parameters. However, these tasks are complicated because experimental data are typically sparse, uncertain, and are frequently only available in form of qualitative if-then observations. ADMIT (Analysis, Design and Model Invalidation Toolbox) is a MatLab(TM)-based tool for guaranteed model invalidation, state and parameter estimation. The toolbox allows the integration of quantitative measurement data, a priori knowledge of parameters and states, and qualitative information on the dynamic or steady-state behavior. A constraint satisfaction problem is automatically generated and algorithms are implemented for solving the desired estimation, invalidation or analysis tasks. The implemented methods built on convex relaxation and optimization and therefore provide guaranteed estimation results and certificates for invalidity. AVAILABILITY: ADMIT, tutorials and illustrative examples are available free of charge for non-commercial use at http://ifatwww.et.uni-magdeburg.de/syst/ADMIT/ PMID- 22451271 TI - 1001 Proteomes: a functional proteomics portal for the analysis of Arabidopsis thaliana accessions. AB - MOTIVATION: The sequencing of over a thousand natural strains of the model plant Arabidopsis thaliana is producing unparalleled information at the genetic level for plant researchers. To enable the rapid exploitation of these data for functional proteomics studies, we have created a resource for the visualization of protein information and proteomic datasets for sequenced natural strains of A. thaliana. RESULTS: The 1001 Proteomes portal can be used to visualize amino acid substitutions or non-synonymous single-nucleotide polymorphisms in individual proteins of A. thaliana based on the reference genome Col-0. We have used the available processed sequence information to analyze the conservation of known residues subject to protein phosphorylation among these natural strains. The substitution of amino acids in A. thaliana natural strains is heavily constrained and is likely a result of the conservation of functional attributes within proteins. At a practical level, we demonstrate that this information can be used to clarify ambiguously defined phosphorylation sites from phosphoproteomic studies. Protein sets of available natural variants are available for download to enable proteomic studies on these accessions. Together this information can be used to uncover the possible roles of specific amino acids in determining the structure and function of proteins in the model plant A. thaliana. An online portal to enable the community to exploit these data can be accessed at http://1001proteomes.masc-proteomics.org/ PMID- 22451272 TI - Differences in cortico-striatal-cerebellar activation during working memory in syndromal and nonsyndromal children with prenatal alcohol exposure. AB - Although children with heavy prenatal alcohol exposure may exhibit the distinctive facial dysmorphology seen in full or partial fetal alcohol syndrome (FAS/PFAS), many lack that dysmorphology. This study examined the functional organization of working memory in the brain in three groups of children-those meeting diagnostic criteria for FAS or PFAS, heavily exposed (HE) nonsyndromal children, and healthy controls. A verbal n-back task (1-back and 0-back) was administered to 47 children (17 with FAS/PFAS, 13 HE, and 17 controls) during fMRI. Intra-group one-sample t-tests were used to identify activity regions of interest central to verbal working memory including the dorsal prefrontal cortex (dPFC), inferior frontal gyrus, caudate/putamen, parietal cortex, and cerebellar Crus I/lobule VI and lobule VIIB-IX. Whereas groups did not differ in task sensitivity, fMRI analyses suggested different patterns of sub-network recruitment across groups. Controls primarily recruited left inferior frontal gyrus (Broca's area). By contrast, HE primarily recruited an extensive set of fronto-striatal regions, including left dPFC and left caudate, and the FAS/PFAS group relied primarily on two cerebellar subregions and parietal cortex. This study is, to our knowledge, the first to demonstrate differential recruitment of critical brain regions that subserve basic function in children with different fetal alcohol spectrum disorders compared to controls. The distinct activation patterns seen in the two exposed groups may be related to substantial differences in alcohol dose/occasion to which these groups were exposed in utero. PMID- 22451273 TI - On GxxxG in N-terminal stretches of type-1 VDAC/porin: critical in vertebrate apoptosis, missing in plants. PMID- 22451274 TI - L-Glutamine regulates amino acid utilization by intestinal bacteria. AB - Catabolism of amino acids (AA) by intestinal bacteria greatly affects their bioavailability in the systemic circulation and the health of animals and humans. This study tests the novel hypothesis that L-glutamine regulates AA utilization by luminal bacteria of the small intestine. Pure bacterial strains (Streptococcus sp., Escherichia coli and Klebsiella sp.) and mixed bacterial cultures derived from the jejunum or ileum of pigs were cultured in the presence of 0-5 mM L glutamine under anaerobic conditions. After 3 h of incubation, samples were taken for the determination of AA utilization. Results showed concentration-dependent increases in the utilization of glutamine in parallel with the increased conversion of glutamine into glutamate in all the bacteria. Complete utilization of asparagine, aspartate and serine was observed in pure bacterial strains after the 3-h incubation. The addition of glutamine reduced the net utilization of asparagine by both jejunal and ileal mixed bacteria. Net utilization of lysine, leucine, valine, ornithine and serine by jejunal or ileal mixed bacteria decreased with the addition of glutamine in a concentration-dependent manner. Collectively, glutamine dynamically modulates the bacterial metabolism of the arginine family of AA as well as the serine and aspartate families of AA and reduced the catabolism of most AA (including nutritionally essential and nonessential AA) in jejunal or ileal mixed bacteria. The beneficial effects of glutamine on gut nutrition and health may involve initiation of the signaling pathways related to AA metabolism in the luminal bacteria of the small intestine. PMID- 22451275 TI - Carnosine enhances diabetic wound healing in the db/db mouse model of type 2 diabetes. AB - Diabetes mellitus (DM) is a progressive disorder with severe late complications. Normal wound healing involves a series of complex and well-orchestrated molecular events dictated by multiple factors. In diabetes, wound healing is grossly impaired due to defective, and dysregulated cellular and molecular events at all phases of wound healing resulting in chronic wounds that fail to heal. Carnosine, a dipeptide of alanine and histidine and an endogenous antioxidant is documented to accelerate healing of wounds and ulcers. However, not much is known about its role in wound healing in diabetes. Therefore, we studied the effect of carnosine in wound healing in db/db mice, a mice model of Type 2 DM. Six millimeter circular wounds were made in db/db mice and analyzed for wound healing every other day. Carnosine (100 mg/kg) was injected (I.P.) every day and also applied locally. Treatment with carnosine enhanced wound healing significantly, and wound tissue analysis showed increased expression of growth factors and cytokines genes involved in wound healing. In vitro studies with human dermal fibroblasts and microvascular-endothelial cells showed that carnosine increases cell viability in presence of high glucose. These effects, in addition to its known role as an antioxidant and a precursor for histamine synthesis, provide evidence for a possible therapeutic use of carnosine in diabetic wound healing. PMID- 22451276 TI - Design of a highly potent inhibitory peptide acting as a competitive inhibitor of HMG-CoA reductase. AB - This study presents a design of a highly potent and competitive inhibitory peptide for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). HMGR is the major regulatory enzyme of cholesterol biosynthesis and the target enzyme of many investigations aimed at lowering the rate of cholesterol biosynthesis. In previous studies, the two hypocholesterolemic peptides (LPYP and IAVPGEVA) were isolated and identified from soy protein. Based on these peptide sequences, a number of peptides were designed previously by using the correlation between the conformational flexibility and bioactivity. The design method that was applied in previous studies was slightly modified for the purpose of the current research and 12 new peptides were designed and synthesized. Among all peptides, SFGYVAE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (K (i)) of 12 +/- 0.4 nM. This is an overall 14,500-fold increase in inhibitory activity compared to the first isolated LPYP peptide from soybeans. Conformational data support a conformation of the designed peptides close to the bioactive conformation of the previously synthesized active peptides. PMID- 22451278 TI - [Morbidity replaces mortality: an ethical dilemma in the care of premature babies at the limits of viability]. PMID- 22451279 TI - [Treatment of dehydration due to gastroenteritis. Epitaph for gavage or star over?]. PMID- 22451280 TI - [Inappropriate use of antibiotics in pediatrics]. PMID- 22451281 TI - [History of paediatric cardiology and the Committee on Cardiology of Sociedad Argentina de Pediatria: progress and challenges]. PMID- 22451282 TI - [Newborn ventilation: comparison between a T-piece resuscitator and self-infating bags in a neonatal preterm simulator]. AB - INTRODUCTION: Although the provision of effective assisted ventilation is the most effective intervention in delivery room resuscitation of depressed newborn infants, there is still limited evidence about which is the optimal device to deliver positive pressure ventilation (PPV). OBJECTIVE: To compare the accuracy of pressures and ventilation rate (VR) delivered to a neonatal simulator with three devices: 240 ml and 450 ml self-infating bags (SIB) and a T-piece resuscitator, and to evaluate the variability in terms of providers' experience. MATERIAL AND METHODS: 76 health care providers divided in two groups according to experience were asked to provide positive pressure ventilation to a neonatal simulator through a facial mask or an endotracheal tube with three ventilating devices: a T-piece resuscitator, a 240 ml and a 450 ml self-infating bags. Participants used each combination of device and interface randomly on 2 consecutive occasions. Mean and maximum PIP and respiratory rate were recorded. Statistical analyses were performed using two-factor analysis of variance for repeated measures. RESULT: SIB 240 and 450 were similar in the mean target peak inspiratory pressure (PIP) but both were significantly different (p < 0.001) from T-piece, although all values were close to the target. Mean VR was over the target for all the devices (p < 0.001). The highest difference found was 7 +/- 1.7 breaths/minute with the 240 ml bag when compared with the T-piece using a mask. Experienced operators were closer than novice operators to target VR, regardless of the device or interface. CONCLUSION: The accuracy for the devices was comparable in the variables measured regardless operator's experience. Overall, the T-piece provided lower PIP while both SIB, higher than the target. The VR was over the target for all the devices. Both SIB and novice participants were associated with higher VR. The intraoperator consistency was comparable in the variables measured with all devices. PMID- 22451283 TI - [Parents' satisfaction in a single pediatric intensive care unit]. PMID- 22451284 TI - [Prevalence of anemia in infants under the age of 6 months being treated at a primary care setting in the city of La Plata, Argentina]. PMID- 22451285 TI - [Grandmothers, concepts and perceptions in caring for their grandchildren: qualitative study in a population from the Italian Hospital of Buenos Aires]. AB - Grandparents are an important source in caring of grandchildren. In the world literature there are several contradictions regarding the positive, negative or no effects on the health of the grandparents by taking care of grandchildren. The aim of this study is to explore the concepts and perceptions of grandmothers, belonging to an insured population from the Italian Hospital of Buenos Aires, while caring for their grand-children. Method. Exploratory and descriptive study that used qualitative techniques for compiling the information. We made two focal groups with grandmothers aged 50-75 years old, who take care of their grandchildren at least 9 hours per week. Altogether 13 women took part, achieving the saturation of the speech. Transcription, analysis and triangulation of information was carried out from obtained data. Results. Maternal grandmothers are the most called. The purpose is to help the family while parents are at work. Being grandmother care-giver seems to be an implicit duty and an established thought, where the family is considered the best way of taking care of children. The majority agreed that taking care of a grandchild constitutes a very rewarding and even pleasant act, although it was also observed that those who spent more day hours taking care of their grand-children or that were living together with them, experiment stress, claims for lack of recognition, sensation of overcharge and depletions, and reported a worse health condition. Conclusion. Caring for grandchildren provides satisfaction, feelings of vitality and dynamism. On the negative side, can lead to stress, lack of personal time, health problems and confict with parents. PMID- 22451286 TI - [Regulation of gene expression: how do epigenetic mechanisms work]. AB - Cell phenotype does not only depend on the nucleotide sequence, but is determined by those genes that are expressed and those that are not. One way to regulate this gene expression pattern is by modifying the chromatin structure via diverse epigenetic mechanisms. In the present article we present the most important epigenetic mechanisms: deoxyribonucleic acid methylation, histone post translational modifications, non-coding ribonucleic acid mediated gene-silencing, ATP-dependent chromatin remodeling, and Polycomb and Trithorax group proteins. PMID- 22451287 TI - [Promoting healthy food habits in children. What happens to the pediatrician?]. PMID- 22451288 TI - [Childhood tuberculosis. How to diagnose it?]. AB - Tuberculosis is one of the conditions with higher incidence worldwide. Infection occurs when Mycobacterium enters the body, and its progression to disease occurs when immune, nutritional and vaccination status are altered. The diagnosis in children is based on elements such as contact history, tuberculin test, chest radiograph and microbiological finding of the bacillus, so these criteria will help us to make an early diagnosis and treatment, breaking the life cycle of M. tuberculosis, preventing an increase in morbidity and mortality in a community. PMID- 22451289 TI - [Congenital nasal obstruction due to choanal atresia: case series]. AB - Nasal obstruction in neonates is a potential fatal condition because of their exclusive nasal breathing. The most common congenital causes include choanal atresia, dermoid cyst, glioma and encephalocele. Choanal atresia is the most common congenital nasal anomaly. When bilateral, it presents with respiratory distress at birth. Unilateral atresia is manifested by respiratory failure and unilateral rhinorrhea, and may go along unnoticed. Diagnosis is suspected in the absence of airfow in the nasal cavity and for the inability to advance a nasogastric tube. Diagnosis is confirmed by endoscopic examination and computed tomography. The definitive treatment is surgical, and there are different techniques and surgical approaches. We describe our experience with 7 patients with this disease, successfully treated by transnasal endoscopic technique. PMID- 22451290 TI - [Participation of one children hospital residents in scientific and training activities of Sociedad Argentina de Pediatria]. AB - The Sociedad Argentina de Pediatria, SAP (Argentine Society of Pediatrics) offers courses and scientific activities for pediatricians and residents. We evaluated the participation of Pedro de Elizalde Hospital residents in the scientific and training activities of SAP and assessed the trend of participation throughout the residency; 107 residents were surveyed; 48% were members, and the participation increased significantly throughout the residence (p <0.01). None of the surveyed residents were part of any association; 84% did not know the "Pediatricians in Training Group"; 49% participated in continued training programs, with a growing tendency to participation through-out the residency (p <0.01); 80% considered that the SAP is a friendly entity. We concluded that participation of residents in the SAP is scarce during the first two years of training, and that it shows a growth in the senior residents' group. Encouraging the interest of first and second year residents in the activities is necessary. PMID- 22451291 TI - [Guidelines for planning consensus]. PMID- 22451292 TI - [Description of a case presented in the previous issue: congenital tuberculosis]. PMID- 22451294 TI - [Childhood cutaneous granular cell tumor: case report]. AB - Granular cell tumors (GCT) are benign neoplasms of distinctive differentiation when observed by light microscopy, which are characterized by the presence of cells with abundant granular eosinophilic cytoplasm. Reports in children are extremely rare. An 11-year-old male patient presented with a nodule after six months of evolution, which progressively increased in size, asymptomatic, localized on the back. Exploration revealed an oval nodule, 1.5 cm in diameter, movile, nonadherent, and painless. Histological study revealed a non-encapsulated tumorous lesion formed by large cells, organized in clusters, of abundant cytoplasm containing eosinophilic granules and small, centrally located nuclei. Immunohistochemical study demonstrated the presence of S100. Treatment indicated was local conservative surgical excision. We emphasize the need to biopsy persistent ulcerated solitary nodules, for diagnostic accuracy, highlighting the importance of histopathology because clinical diagnosis is difficult and almost never we think about it, unless the tumor arises on the tongue. PMID- 22451295 TI - [Idiopathic gastric rupture in toddler: case report]. AB - Idiopathic gastric rupture is rare in children. Most of them occur in newborn. The authors report the case of a 2-year-old female toddler with no significant medical records. Clinical picture began 48 h before with abdominal pain, nausea and vomiting. She was admitted to the Emergency Room in poor general condition, with abdominal distension and rebound tenderness. Laparotomy was performed immediately show-ing multiple perforations in the posterior wall of the stomach. Partial gastrectomy was performed. Afterwards, she was admitted to ICU in shock. She received mechanical ventilation, intravenous fluid administration (260 ml/kg in 12 h), vasoactive support and antibacterial therapy (cefotaxime and metronidazole). Laboratory showed leukopenia and thrombocytopenia. Etiological study was entirely negative for toxic and drug consumption. Collagen disease was ruled out and serum level of gastrin was normal. Her post operative course was characterized by persistent fever caused by left subphrenic collection (positive culture for Candida galabrata). Peritoneal lavage via laparotomy and percutaneous drainage of the residual collections were performed. She completed 3 weeks of antibacterial and antifungal therapies with adequate outcome. Her follow-up in 12 months was uneventful. PMID- 22451296 TI - [Cystic lymphatic malformation of the pancreas in a 13-month-old child]. AB - Lymphatic malformations--previously called "lymphangiomas"--emerge due to an abnormal development of the lymphatic channels, with obstruction of the lymph flow and formation of lymphatic cysts. These cystic masses are frequently located in the neck and axillary region (95%). A pancreatic localization is extremely rare in children. Pancreatic lymphatic malformations should be distinguished from other cystic pancreatic masses. For those located in the head of the pancreas, a pancreaticoduodenectomy is proposed. We report the case of a 13-month-old child with a lymphatic malformation on the pancreas head, resected through a pancreaticoduodenectomy. A persistent chylous drainage followed, causing immunitary impairment and an overwhelming sepsis. A non surgical approach to this lesion is discussed, and a literature review is made. PMID- 22451297 TI - [Syncope in the debut of a mediastinal mass]. AB - Pediatric syncope accounts for 3% of the consultations in emergency department. It is frequent in pediatrics, particularly in teenager girls between 15 and 19 years old, and up to a 25% of them have suffered from a syncopal episode. Most causes are benign, but the aim in its initial evaluation is ruling out those which mean any danger. Heart disease can lead to syncope in a 10-28% of cases. A detailed medical history and an exhaustive exploration are enough to rule out organic pathology in most situations. We present the case of a diffuse large B cell lymphoma located in the mediastinum diagnosed after repetitive syncopal episodes. PMID- 22451298 TI - [Sepsis by Leuconostoc spp. in a healthy infant]. AB - Leuconostoc genus, belonging to the lactic acid bacteria group, are Gram-positive bacteria intrinsically resistant to vancomycin, broad distributed in nature and widely used in the food industry. Traditionally considered safe for humans, has recently been implicated in various diseases in susceptible individuals, increasingly isolated and with a broad profile of pathogenicity, and it is now classified as an emerging opportunistic pathogen. Children are particularly vulnerable, especially premature babies and those suffering from severe digestive pathology. The way of entry to the human organism has not been studied in depth. The most frequent are the altered intestine and the skin through loss of barrier integrity. Also are described contamination of parenteral and enteral nutrition, especially associated with the use of gastric tubes. Anecdotal cases reported in immunocompetent patients without underlying disease and no use of external devices have occurred in infants, as the case presented here. PMID- 22451299 TI - Resveratrol and its synthetic derivatives exert opposite effects on mesothelial cell-dependent angiogenesis via modulating secretion of VEGF and IL-8/CXCL8. AB - We examined the effect of resveratrol (RVT) and its two derivatives (3,3',4,4' tetrahydroxy-trans-stilbene and 3,3',4,4',5,5'-hexahydroxy-trans-stilbene) on human peritoneal mesothelial cell (HPMC)-dependent angiogenesis in vitro. To this end, angiogenic activity of endothelial cells (HUVEC, HMVEC, and HMEC-1) was monitored upon their exposure to conditioned medium (CM) from young and senescent HPMCs treated with stilbenes or to stilbenes themselves. Results showed that proliferation and migration of endothelial cells were inhibited in response to indirect (HPMC-dependent) or direct RVT activity. This effect was associated with decreased secretion of VEGF and IL-8/CXCL8 by HPMCs treated with RVT, which confirmed the experiments with recombinant forms of these angiogenic agents. Angiogenic activity of endothelial cells treated with CM from HPMCs exposed to RVT analogues was more effective. Improved migration was particularly evident in cells exposed to CM from senescent HPMCs. Upon direct treatment, RVT derivatives stimulated proliferation (but not migration) of HUVECs, and failed to affect the behaviour of HMVEC and HMEC-1 cells. These compounds stimulated production of VEGF and IL-8/CXCL8 by HPMCs. Studies with neutralizing antibodies against angiogenic factors revealed that augmented angiogenic reactions of endothelial cells exposed to CM from HPMC treated with RVT analogues were related to enhanced production of VEGF and IL-8/CXCL8. Collectively, these findings indicate that RVT and its synthetic analogues divergently alter the secretion of the angiogenic factors by HPMCs, and thus modulate HPMC-dependent angiogenic responses in the opposite directions. This may have implications for the attempts of practical employment of the stilbenes for treatment of pathologies proceeding with abnormal vascularisation of the peritoneal tissue. PMID- 22451300 TI - Lung abscess due to non-tuberculous, non-Mycobacterium fortuitum in a neonate. AB - Although Mycobacterium fortuitum (MF) is a non-tuberculous mycobacterium that rarely causes disease, there are reported cases of pneumonia, lung abscess, and empyema in subjects with predisposing lung disease. We report a neonate, without predisposing disease or risk factors, who manifested pneumonia and lung abscess. The patient was initially treated with amoxicillin-clavulanic acid and gentamycin, and subsequently with piperazilin, tazobactam, and vancomycin when there was no improvement. Pleural nodules were detected on computed tomography, and microbiology revealed MF in the absence of other pathogens and a week later the organism was identified in culture as MF, confirmed on four separate samples. The MF was sensitive to amikacin and clarithromycin and the patient was continued on oral clarithromycin for two more weeks until full recovery. To our knowledge, this is the first reported case of MF abscess in a neonate. MF should be sought in similar patients, especially when microbiology fails to detect the usual pathogens, and when the clinical picture is unclear. PMID- 22451301 TI - Mouse models of spinocerebellar ataxia type 3 (Machado-Joseph disease). AB - Machado-Joseph disease, also called spinocerebellar ataxia type 3 (MJD/SCA3), is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a pathological polyglutamine stretch (mutant ataxin-3). Seven transgenic mouse models expressing full-length human mutant ataxin-3 throughout the brain have been generated and are compared in this review. They vary in the corresponding transgenic DNA constructs with differences that include the encoded human ataxin 3 isoform(s), number of polyglutamine(s), and the promoter driving transgene expression. The behaviors/signs evaluated in most models are body weight, balance/coordination, locomotor activity, gait, limb position, and age at death. The pathology analyzed includes presence of neuronal intranuclear inclusions, and qualitative evidence of neurodegeneration. On the basis of striking similarities in age-range of detection and number of behavior/sign abnormalities and pathology, all but 1 mouse model could be readily sorted into groups with high, intermediate, and low severity of phenotype. Stereological analysis of neurodegeneration was performed in the same brain regions in 2 mouse models; the corresponding results are consistent with the classification of the mouse models. PMID- 22451302 TI - Pachastrissamine from Pachastrissa sp. inhibits melanoma cell growth by dual inhibition of Cdk2 and ERK-mediated FOXO3 downregulation. AB - Melanoma cells are relatively resistant to apoptosis compared with other tumor cell types, and thus, chemotherapy, radiotherapy and immunotherapy are not effective in treating melanoma. Pachastrissamine (PA) exhibits cytotoxic activity and promotes apoptosis in several cancer cells. However, its specific molecular mechanisms have not been characterized fully. This study investigated the antimelanoma effect of PA, an anhydrophytosphingosine derived from marine sponge, and its underlying molecular mechanisms. The data demonstrated that treatment with PA inhibited the phosphorylation of ERK and subsequent ERK-mediated FOXO3 phosphorylation in melanoma cells. Interestingly, PA did not inhibit AKT-mediated FOXO3 phosphorylation. Therefore, it appears that PA-induced apoptosis results from the inhibition of ERK. Furthermore, intravenous administration of PA was found to suppress melanoma cell growth in a C57BL6 mouse without causing side effects. Additionally, PA inhibited the production of Cdk2, which is involved in cell cycle regulation. Taken together, inhibition of melanoma cell growth by PA is a result of the inhibition of ERK-mediated FOXO3 downregulation and decreased Cdk2 levels. The results of this study imply that dual inhibition of the ERK pathway and cell cycle progression could be an effective approach to control the growth of melanoma cells. PMID- 22451304 TI - [Myelopoiesis and bone marrow function in elderly tumor patients]. AB - According to a model described by Balducci, the human myelopoietic stem cell reserve shows a shift from the reproductive to the proliferative pool corresponding to higher immunological demands resulting from the breakdown of infection defences. Every "hematopoietic stress," i.e., sepsis and/or cytoreductive chemotherapy, leads to a reduction of myelopoietic stem cells in the elderly in contrast to an increase in younger individuals. These changes are relevant starting at the age of 70 years and show a reduced compensation capacity in the aged organism. In addition, the function of the effector cells, i.e., the granulocytes and especially their phagocytic capacity, as well as the balance between stimulating and inhibiting cytokines are compromised. A significant influence on leukopenia and febrile septicemia has been shown for several comorbidities, especially chronic inflammation. The prophylactic use of myelopoietic growth factors is, therefore, recommended for the elderly when there is an expected risk for hematotoxicity grade III or IV. However, prognostic tests to predict the individual risk of hematotoxicity and septicemia are lacking. PMID- 22451305 TI - [Editorial]. PMID- 22451306 TI - ["Atypical" anemia in a geriatric patient]. AB - A gastroenterologic examination was performed on an 83-year-old woman due to unexplained anemia; however, no bleeding site could be identified. Because of the advanced age of the patient, no further diagnostic efforts were made and iron deficiency anemia was suspected. After 3 weeks, an emergency laparotomy was performed for acute diffuse peritonitis, which was diagnosed as perforation of the jejunum by a wooden foreign body. After extraction of the foreign body and closure of the perforation in the small intestine, healing proceeded without complications. PMID- 22451307 TI - Pyruvate prevents the inhibition of the long-term potentiation induced by amyloid beta through protein phosphatase 2A inactivation. AB - Amyloid-beta (Abeta) oligomers are derived from proteolytic cleavage of amyloid beta protein precursor and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. Pyruvate has a protective effect against Abeta-induced neuronal cell death in hippocampal slice cultures. However, whether pyruvate also has a protective effect against the inhibition of neuronal plasticity induced by Abeta remains to be elucidated. This study examined the effect of pyruvate on the Abeta-induced inhibition of LTP in the rat hippocampus. We found that pyruvate prevented the Abeta-induced inhibition of LTP as strong as fostriecin, a specific protein phosphatase 2A (PP2A) inhibitor. Pyruvate prevented the Abeta block of Ca(2+)/calmodulin dependent protein kinase 2 (CaMK2) autophosphorylation and the Abeta-induced PP2A activation. Pyruvate, but not lactate, decreased reactive oxygen species levels in CA1 slices exposed to Abeta. We propose that pyruvate could prevent the Abeta-induced inhibition of LTP by the re-autophosphorylation of CaMK2 through PP2A inactivation. The reduction of reactive oxygen species production is considered to be the upstream mechanism of this observed pyruvate protection. PMID- 22451308 TI - Overexpression of human wild-type amyloid-beta protein precursor decreases the iron content and increases the oxidative stress of neuroblastoma SH-SY5Y cells. AB - The accumulation of amyloid-beta protein precursor (AbetaPP) is related to the pathogenesis of Alzheimer's disease (AD); however, the underlying mechanism is still unclear. The abnormal interactions of AbetaPP with metal ions such as iron are implicated in the process of oxidative stress in AD brains. In this study, we found that the overexpression of wild-type human AbetaPP695 decreased the iron content and increased the oxidative stress in neuroblastoma SH-SY5Y cells. The catalase activity of stably transfected cells overexpressing wild-type AbetaPP695 (AbetaPP cells) was significantly lower than that of the control cells. Intracellular reactive oxygen species (ROS) generation and calcium levels significantly increased in AbetaPP cells compared to control cells. The mitochondrial membrane potential of AbetaPP cells was significantly lower than that of the control cells. Moreover, iron treatment decreased ROS and calcium levels and increased cell viability of AbetaPP cells. The iron deficiency in AbetaPP cells may contribute to the pathogenesis of AD. PMID- 22451310 TI - Three subsystems of the inferior parietal cortex are differently affected in mild cognitive impairment. AB - The Inferior parietal cortex (IPC), including the intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus (SG), plays an important role in episodic memory, and is considered to be one of the specific neuroimaging markers in predicting the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, it is still unclear whether the connectivity of the IPC is impaired in MCI patients. In the present study, we used resting state fMRI to examine the functional connectivity of the three subdivisions of the IPC in MCI patients after controlling the impact of regional grey matter atrophy. It was found that, using IPS, AG, and SG as seeds of functional connectivity, three canonical functional networks could be correspondingly traced, i.e., executive control network (ECN), default mode network (DMN), and salience network (SN), and the three networks are differently altered in MCI patients. In contrast to the healthy controls, it was found that in MCI patients: 1) AG connectivity was significantly reduced within the DMN; 2) IPS showed decreased connectivity with the right inferior frontal gyrus while showing increased connectivity with the left frontal regions within the ECN; and 3) SG displayed decreased connectivity with a distribution of regions including the frontal and parietal regions, and increased connectivity with some sub-cortical areas within the SN. Moreover, the connectivity within the three networks was correlated with episodic memory and general cognitive impairment in MCI patients. These results extend well beyond the DMN, and further suggest that MCI is associated with alteration of large scale functional brain networks. PMID- 22451309 TI - Antemortem pulse pressure elevation predicts cerebrovascular disease in autopsy confirmed Alzheimer's disease. AB - Elevated pulse pressure (PP) is associated with cognitive decline and increased risk of Alzheimer's disease (AD) in older adults, although the mechanisms behind these associations remain unclear. To address this question, we examined whether antemortem late-life PP elevation predicted vascular or AD pathology in autopsy confirmed AD patients. Sixty-five elderly patients (mean age 74.2 years) clinically diagnosed with possible or probable AD underwent neuropsychological testing and blood pressure examinations. Postmortem histopathological measures of cerebrovascular disease (CVD) and AD neuropathology were later obtained on these same patients. We expected that antemortem PP elevation, but not standard blood pressure measures such as systolic or diastolic blood pressure, would predict the autopsy-based presence of CVD, and possibly AD pathology, in elderly AD patients. Results demonstrated that antemortem PP elevation was associated with the presence and severity of CVD at autopsy. For every 5 mmHg increase in antemortem PP there was an estimated 36% increase in the odds of having CVD at autopsy. Additionally, PP accounted for 12% of variance in CVD severity. No significant associations were present for cerebral amyloid angiopathy or Braak and Braak staging of the severity of AD pathology. Other standard blood pressure measures also did not significantly predict neuropathology. The association between antemortem PP and CVD at autopsy suggests that in older adults with AD, PP elevation may increase the risk of CVD. These findings may have treatment implications since some antihypertensive medications specifically address the pulsatile component of blood pressure (e.g., renin-angiotensin system inhibitors, calcium channel blockers). PMID- 22451311 TI - Pesticides induce spatial memory deficits with synaptic impairments and an imbalanced tau phosphorylation in rats. AB - Pesticides are widely used in agriculture, and epidemiological studies suggest that pesticide exposure is a risk factor for Alzheimer's disease (AD), but the mechanisms are elusive. Here, we studied the effects of pesticide exposure on the cognitive ability and the underlying mechanisms in rats. Deltamethrin and carbofuran were administered respectively into the rats once a day for 28 days by gavage. We found that pesticide exposure induced spatial learning and memory deficits with a simultaneous decrease of N-methyl-D-aspartate receptor 1, synaptophysin, and synapsin I, all of which are memory-related synaptic proteins. Pesticide exposure also induced tau hyperphosphorylation at multiple AD-related phosphorylation sites with activation of glycogen synthase kinase-3beta and inhibition of protein phosphatase-2A. Additionally, neuron loss in the hippocampus and cortex was observed upon administration of the pesticides. These results indicate that the pesticides exposure could induce AD-like pathology and cognitive abnormality in rats. PMID- 22451312 TI - Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex. AB - Evidence supports a role for epigenetic mechanisms in the pathogenesis of late onset Alzheimer's disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-beta protein precursor post translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets. PMID- 22451313 TI - AbetaPP intracellular C-terminal domain function is related to its degradation processes. AB - The amyloid-beta protein precursor (AbetaPP) can be processed by either the amyloidogenic or the non-amyloidogenic pathway; both pathways lead to release of the AbetaPP intracellular C-terminal domain (AICD). AICD involvement in signal transduction within Fe65/Tip60 complex is one of the most discussed mechanisms, and different models have been hypothesized to explain the role of AICD within this complex. The analysis of these models in relation to the degradation processes highlights the discrepancy among AICD localization, function, and degradation, leading to the hypothesis that a signaling mechanism may exist which allows AbetaPP proteolysis to generate either a transcriptionally active fragment or an inactive one with different involvement of proteasome and IDE (insulin degrading enzyme). Our work aimed to analyze the functional role of AICD within the Fe65/Tip60 complex considering the AICD degradation processes. Our data suggest a correlation between the role of AICD in gene regulation and its removal operated by proteasome activity. Moreover, treatments with IDE inhibitor underlined the presence of an alternative mechanism involved in AICD removal when the latter is not exerting nuclear activity, thus providing clearer support for the existence of at least two mechanisms as previously suggested. PMID- 22451314 TI - A butyrolactone derivative 3BDO alleviates memory deficits and reduces amyloid beta deposition in an AbetaPP/PS1 transgenic mouse model. AB - Excessive extracellular deposition of amyloid- peptide (Abeta) in the brain is the pathological hallmark of Alzheimer's disease (AD). Cumulative evidence indicates that autophagy is involved in the metabolism of Abeta and pathogenesis of AD. However, the molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. We recently found that long-term treatment with a butyrolactone derivative 3-benzyl-5-((2 nitrophenoxy) methyl)-dihydrofuran- 2(3 H)-one (3BDO) increased levels of insulin degrading enzyme and neprilysin, suppressed autophagy via an mTOR pathway, lowered levels of Abeta, and prevented AD-like cognitive deficits in the AbetaPP/PS1 double transgenic mouse model. Therefore, our findings suggest that 3BDO may be beneficial in the prevention and treatment of AD. PMID- 22451315 TI - Validation of a latent variable representing the dementing process. AB - The cognitive correlates of functional status are essential to dementia case finding. Nevertheless, cognitive performance is a generally weak predictor of functional outcomes. We have employed structural equation models to explicitly distinguish functional status, and therefore "dementia-relevant" variance in cognitive task performance (i.e., delta) from the variance that is unrelated to a dementing process (i.e., g'). Together, g' + delta encompass Spearman's g. Although delta represents only a small fraction of the total variance in cognitive task performance, it is more strongly associated with dementia status than is g'. In this study, we validate delta in a well characterized Alzheimer's disease cohort, the Texas Alzheimer's Research and Care Consortium. Our approach results in "error free" continuous variables. This suggests that delta can serve as a dementia specific endophenotype. As a result, future studies may be able to associate delta with inflammatory and genetic biomarkers. PMID- 22451316 TI - Toward a brain-computer interface for Alzheimer's disease patients by combining classical conditioning and brain state classification. AB - Brain-computer interfaces (BCIs) provide alternative methods for communicating and acting on the world, since messages or commands are conveyed from the brain to an external device without using the normal output pathways of peripheral nerves and muscles. Alzheimer's disease (AD) patients in the most advanced stages, who have lost the ability to communicate verbally, could benefit from a BCI that may allow them to convey basic thoughts (e.g., "yes" and "no") and emotions. There is currently no report of such research, mostly because the cognitive deficits in AD patients pose serious limitations to the use of traditional BCIs, which are normally based on instrumental learning and require users to self-regulate their brain activation. Recent studies suggest that not only self-regulated brain signals, but also involuntary signals, for instance related to emotional states, may provide useful information about the user, opening up the path for so-called "affective BCIs". These interfaces do not necessarily require users to actively perform a cognitive task, and may therefore be used with patients who are cognitively challenged. In the present hypothesis paper, we propose a paradigm shift from instrumental learning to classical conditioning, with the aim of discriminating "yes" and "no" thoughts after associating them to positive and negative emotional stimuli respectively. This would represent a first step in the development of a BCI that could be used by AD patients, lending a new direction not only for communication, but also for rehabilitation and diagnosis. PMID- 22451317 TI - Lipid lowering agents, cognitive decline, and dementia: the three-city study. AB - The aim of this prospective cohort study was to evaluate the effects of lipid lowering agent (LLA) intake on cognitive function in 6,830 community-dwelling elderly persons. Cognitive performance (global cognitive functioning, visual memory, verbal fluency, psychomotor speed, and executive function), clinical diagnosis of dementia, and fibrate and statin use, were evaluated at baseline, and 2, 4, and 7 year follow-up. Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics, mental and physical health including vascular risk factors, and genetic vulnerability (apolipoprotein E and cholesteryl ester transfer protein). For women but not men, fibrate use was specifically associated with an increased risk over 7 years of decline in visual memory only (HR = 1.29, 95% CI = 1.09-1.54, p = 0.004), and did not increase risk for incident dementia. This association was independent of genetic vulnerability related to apolipoprotein E and cholesteryl exchange transfer protein polymorphisms and occurred only in women with higher low density lipoprotein (LDL)-cholesterol levels and treated with fibrate (HR = 1.39, 95% CI = 1.08-1.79, p = 0.01) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment. For both genders, no significant associations were found between statins (irrespective of their lipophilicity) and either cognitive decline or dementia incidence. This prospective study, adjusting for multiple confounders, found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia, but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory. PMID- 22451318 TI - CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AbetaPP/PS1 mice. AB - The present study shows that chronic administration of the cannabinoid receptor type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AbetaPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-beta (Abeta) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of Abeta42 oligomers in primary cultures of cortical neurons, and reverses Abeta induced dephosphorylation of glycogen synthase kinase-3beta (GSK3beta) in vitro and in vivo. Reduced activity of GSK3beta in ACEA-treated mice is further supported by the reduced amount of phospho-tau (Thr181) in neuritic processes around Abeta plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of Abeta plaques and decreased expression of the pro inflammatory cytokine interferon-gamma in astrocytes when compared with age matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3beta inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-gamma. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease. PMID- 22451319 TI - Proton and phosphorus magnetic resonance spectroscopy of a mouse model of Alzheimer's disease. AB - The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. In addition, the recent development of high-field animal scanners enables the measurement of brain metabolites that cannot be reliably quantified at lower magnetic fields. In this report, we studied a new transgenic mouse model of AD, the 5xFAD model, by in vivo proton and phosphorus MR spectroscopy. This model, which is characterized by an early-onset and a robust amyloid pathology, developed changes in the neurochemical profile, which are typical in the human disease, i.e., an increase in myo-inositol and a decrease in N-acetylaspartate concentrations, as early as in the 40th week of age. In addition, a significant decrease in the gamma aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 * FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD. PMID- 22451320 TI - Changes in brain volume and cognition in a randomized trial of exercise and social interaction in a community-based sample of non-demented Chinese elders. AB - Physical exercise has been shown to increase brain volume and improve cognition in randomized trials of non-demented elderly. Although greater social engagement was found to reduce dementia risk in observational studies, randomized trials of social interventions have not been reported. A representative sample of 120 elderly from Shanghai, China was randomized to four groups (Tai Chi, Walking, Social Interaction, No Intervention) for 40 weeks. Two MRIs were obtained, one before the intervention period, the other after. A neuropsychological battery was administered at baseline, 20 weeks, and 40 weeks. Comparison of changes in brain volumes in intervention groups with the No Intervention group were assessed by t tests. Time-intervention group interactions for neuropsychological measures were evaluated with repeated-measures mixed models. Compared to the No Intervention group, significant increases in brain volume were seen in the Tai Chi and Social Intervention groups (p < 0.05). Improvements also were observed in several neuropsychological measures in the Tai Chi group, including the Mattis Dementia Rating Scale score (p = 0.004), the Trailmaking Test A (p = 0.002) and B (p = 0.0002), the Auditory Verbal Learning Test (p = 0.009), and verbal fluency for animals (p = 0.01). The Social Interaction group showed improvement on some, but fewer neuropsychological indices. No differences were observed between the Walking and No Intervention groups. The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise (Tai Chi). In addition, intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements. PMID- 22451321 TI - Hippocampal membrane-associated p75NTR levels are increased in Alzheimer's disease. AB - The pan-specific p75 neurotrophin receptor (p75(NTR)) is believed to play an important role in the pathogenesis of Alzheimer's disease (AD). It is involved in mediating amyloid-beta (Abeta) toxicity and stimulating amyloidogenesis. In addition, we have recently shown that stimulating cultured SH-SY5Y human neuroblastoma cells with Abeta(42) increases the level of membrane-associated p75(NTR) and that Abeta(42)-accumation in two strains of transgenic AD model mice is accompanied by an increased level of hippocampal membrane-associated p75(NTR) (Chakravarthy et al. J Alzheimers Dis 19, 915-925, 2010). This raised an important question whether accumulating Abeta(42) in human AD is also accompanied by an increased hippocampal membrane-associated p75(NTR). In this study, using polyclonal and monoclonal antibodies against the p75(NTR) receptor's intra- and extracellular domains, we show that indeed the mean level of membrane-associated p75(NTR) in the hippocampal formation is significantly higher (~two-fold, p < 0.03) in human AD brains than in identical samples of hippocampal formation in age-matched non-AD human brains. The possible relation of this elevated hippocampal p75(NTR) to AD cognitive decline is discussed. PMID- 22451322 TI - Neuronal cell cycle re-entry markers are altered in the senescence accelerated mouse P8 (SAMP8). AB - Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer's disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3beta, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, cyclin D1, cyclin E, Cdk2, cyclin B, pR, and E2F1 were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease. PMID- 22451323 TI - Antioxidant enzymatic activities in Alzheimer's disease: the relationship to acetylcholinesterase inhibitors. AB - The mode of action of acetylcholinesterase inhibitors (AChEIs) in Alzheimer's disease (AD) is mainly by potentiating neuronal transmission. Animal studies have also consistently described a role for AChEIs in enhancement of antioxidants and attenuation of oxidative stress. The influence of AChEIs on blood antioxidants in AD patients has not been established before. Furthermore, AChEI treatment, or lack of it, may have contributed to the inconsistent antioxidant data reported by other studies so far. Here we sought to investigate the potential modulation effect of AChEIs on blood antioxidants in AD patients. Catalase (CAT) and glutathione reductase (GR) activities were analyzed in 25 drug naive patients (Group A), 43 patients receiving AChEIs (Group B) and 34 cognitively unimpaired controls (Group C). A statistically significant difference for CAT and GR was observed between the two AD groups (A and B) when compared to the control group C (KW-H = 36.530, p < 0.001; post hoc tests p < 0.001 and KW-H = 37.814, p < 0.001; post hoc tests p < 0.001, respectively). In contrast, CAT and GR activities did not differ significantly between the two AD groups, and were not influenced by AChEI treatment. Hence, these results do not replicate the extensively reported data from animal studies and question whether AChEI efficacy in AD is mediated by processes beyond neuron to neuron enhancement of transmission. Studies assessing a wider range of oxidative/inflammatory markers taking into account type, dosage, and treatment duration of the various acetylcholinesterase inhibitors are now needed. PMID- 22451324 TI - New evidence of mitochondria dysfunction in the female Alzheimer's disease brain: deficiency of estrogen receptor-beta. AB - Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor beta (ERbeta) in neuronal mitochondrial (mtERbeta) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERbeta is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERbeta, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERbeta expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERbeta in AD-related mitochondrial dysfunction, using ERbetaKO mice as a model, we found that lack of ERbeta enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Abeta peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERbeta expression in the human brain and the deficiency of mtERbeta in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERbetaKO mice demonstrated that ERbeta depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERbeta depletion impairs mitochondrial function in mice, and reduction of brain mtERbeta may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women. PMID- 22451325 TI - Antithrombotic therapy for stroke prevention in patients with heart failure. AB - OPINION STATEMENT: Congestive heart failure (CHF) is associated with an increased risk of stroke mainly due stasis leading to increased risk of thrombus formation in the left ventricle and subsequent cerebral embolism. CHF patients are also at increased risk of atrial fibrillation (AF) that also leads to cerebral embolism. Aggressive medical management to prevent cardiac decompensation and maintain sinus rhythm is indicated in CHF patients. All patients with CHF and AF should be anticoagulated with warfarin or one of the newer oral anticoagulants. There is no clear indication for anticoagulation in CHF patients due to ischemic cardiomyopathy who are in sinus rhythm. Based on data from the WARCEF study (see below), those patients with CHF due to non-ischemic etiologies who are in sinus rhythm and have a left ventricular ejection fraction (LVEF) less than 30 % to 35 % may benefit from warfarin for the reduction of ischemic stroke risk, but warfarin does not increase survival. Whether warfarin is particularly beneficial for CHF patients who have a prior history of stroke or transient ischemic attack (TIA) is unknown. If, however, there is high enough suspicion that the stroke was of cardioembolic origin in patients with low LVEF, then anticoagulation would possibly be a reasonable option for prevention of recurrent stroke or TIA. Warfarin is indicated for stroke prophylaxis among those CHF patients who have an implanted mechanical device. The role of newer anticoagulants in patients with CHF who do not have AF is unknown at this time. Theoretically, there should be no reason against using these agents in place of warfarin in selected patients, particularly those with highly variable International Normalized Ratios (INR) in the context of warfarin therapy, but the newer anticoagulants have not yet been studied among CHF patients without concomitant AF. PMID- 22451326 TI - Assessment of metal status in drainage canal water and their bioaccumulation in Oreochromis niloticus fish in relation to human health. AB - The purpose of this study was to assess metal concentrations (Al, Cd, Pb, Hg and Ni) in Sabal drainage canal (Al-Menoufiya Province, River Nile Delta, Egypt) water as well as their accumulation in some selected organs (skin, muscles and kidneys) of Oreochromis niloticus fish to evaluate their hazard levels in relation to the maximum residual limits for human consumption. Drainage canal water was found to be heavily polluted with metals which far exceeded the permissible limits. It was found that metals accumulated in organs of O. niloticus in concentrations higher than those of canal water. Kidneys of O. niloticus contained the highest concentrations of the detected metals, while skin appeared to be the least preferred site for the bioaccumulation of metals as the lowest metals concentrations were detected in this tissue. The present study shows that fish organs contained high levels of metals exceeding the permissible limits values. Metals in muscle of fish were higher than the maximum permissible concentrations for human consumption. Thus, consuming fish caught from drainage canals is harmful to the consumers. PMID- 22451327 TI - The association between use of non-injection drug implements and hepatitis C virus antibody status in homeless and marginally housed persons in San Francisco. AB - BACKGROUND: Up to 17,000 persons in the USA became infected with hepatitis C virus (HCV) in 2007, and many cases have unknown transmission routes. To date research on transmission of HCV via shared implements used to snort or smoke non injection drugs has been inconclusive. METHODS: We tested stored sera for HCV antibodies (anti-HCV) in a large population-based study of homeless and marginally housed persons in San Francisco. We examined the association between sharing implements used for snorting and smoking drugs and anti-HCV while controlling for sociodemographic variables in those who denied ever injecting drugs (n = 430). We also examined the association of anti-HCV status with history of incarceration, tattoo and piercing history, sexual history and alcohol consumption. RESULTS: Seventeen percent of our sample was anti-HCV positive. We found no statistically significant associations with sharing implements used to smoke or snort drugs with anti-HCV status in our various multivariate models. There was a statistically significant negative association between ever snorting cocaine and anti-HCV status (adjusted odds ratio: 0.39; 95% confidence interval: 0.21-0.73). There were no other statistically significant associations with any other measured covariates in multivariate analyses. CONCLUSIONS: Our findings suggest that sharing implements to snort or smoke drugs is not a significant risk factor for anti-HCV-positive status. PMID- 22451328 TI - A crucial role for the cortico-striato-cortical loop in the pathogenesis of stroke-related neurogenic stuttering. AB - Neurogenic stuttering is an acquired speech disorder characterized by the occurrence of stuttering-like dysfluencies following brain damage. Because the onset of stuttering in these patients is associated with brain lesions, this condition provides a unique opportunity to study the neural processes underlying speech dysfluencies. Lesion localizations of 20 stroke subjects with neurogenic stuttering and 17 control subjects were compared using voxel-based lesion symptom mapping. The results showed nine left-hemisphere areas associated with the presence of neurogenic stuttering. These areas were largely overlapping with the cortico-basal ganglia-cortical network comprising the inferior frontal cortex, superior temporal cortex, intraparietal cortex, basal ganglia, and their white matter interconnections through the superior longitudinal fasciculus and internal capsule. These results indicated that stroke-induced neurogenic stuttering is not associated with neural dysfunction in one specific brain area but can occur following one or more lesion throughout the cortico-basal ganglia-cortical network. It is suggested that the onset of neurogenic stuttering in stroke subjects results from a disintegration of neural functions necessary for fluent speech. PMID- 22451329 TI - A longitudinal study of postpartum depressive symptoms: multilevel growth curve analyses of emotion regulation strategies, breastfeeding self-efficacy, and social support. AB - Postpartum depression is a serious health issue affecting as many as 10-15 % of postpartum women. This longitudinal study aimed to explore how psychological variables such as cognitive emotion regulation strategies, breastfeeding self efficacy (BSE), and dimensions of social support predicted postpartum depressive symptoms (Edinburgh Postnatal Depression Scale). The data were collected with web based survey questionnaires between May 2008 and December 2009, in a sample of 737 new mothers. The same questionnaire was surveyed at three points in time: 6 weeks, 3 months, and 6 months postpartum. Data were analyzed using multilevel modeling (level 1, time points; level 2, person). Results showed that BSE, certain cognitive emotion regulation strategies, perceived available support, and need for support predicted the rate of postpartum depressive symptoms. Only breastfeeding self-efficacy predicted change in postpartum depressive symptoms. This study illustrates the importance of psychological variables with regard to postpartum depressive symptoms. Implications for preventative efforts are discussed. PMID- 22451330 TI - The neuropathology of genetic Parkinson's disease. AB - Pathological data from autopsies genotyped for Parkinson's disease (PD)-related mutations in alpha-synuclein, Parkin, PINK1, DJ1, LRRK2, and glucocerebrosidase have accumulated in recent years. The aim of this review is to systematically review all pathological reports of mutation carriers and to identify pathological patterns and gaps in the currently available data. A systematic review of the English literature was done using the terms "Parkinson's disease," "brain pathology," "autopsy," the specific gene nomenclature, and any combination of the above. Most studies included reports of convenience samples: either cases that were preidentified as mutation carriers before autopsy or screens of Lewy body brain banks. Nineteen autopsies of alpha-synuclein mutation carriers, 49 of LRRK2 mutation carriers, nine of Parkin mutation carriers, one of a PINK1 mutation carrier, and 86 of glucocerebrosidase mutation carriers were identified. Most autopsies of alpha-synuclein, LRRK2 G2019S, and glucocerebrosidase mutation carriers demonstrated Lewy body pathology, as opposed to Parkin and LRRK2 non G2019S mutation carriers. However, there was a marked variability in pathological findings, even among carriers of identical mutations. Pathological data from DJ1 mutation carriers, nonmanifesting mutation carriers (e.g., of LRRK2 mutations), and carriers of a single Parkin mutation were lacking. In gathering together all studies of PD autopsies with an identified genetic risk, this review highlights the wealth of information generated as well as shortcomings in the available data. In particular, there is a need for larger, unbiased pathological studies. Differential association of Lewy pathology with specific mutations may reflect heterogeneity in pathogenic mechanisms among the different PD-related genes. PMID- 22451331 TI - Effects of Bixa orellana L. seeds on hyperlipidemia. AB - Bixa orellana L., urucum, or urucu, a native tropical tree of Central and South American rain forests is used to treat various diseases in popular medicine. In Ceara, Northeast of Brazil, the seeds of urucum have been used for the treatment of high lipid blood levels. The present study investigated the effects of the aqueous extract from Bixa orellana seeds (AEBO) in mice with hyperlipidemia induced by tyloxapol, fructose and ethanol. In hyperlipidemia induced by Triton WR1339, 400 and 800 mg/kg AEBO reduced triglycerides (TG) serum levels at 24 h and 48 h. In the study of hypertriglyceridemia induced by fructose, AEBO in doses of 400 mg/kg and 800 mg/kg reduced TG levels by 48.2% and 48.7%, respectively. Finally, the ethanol experimental model with 400 mg/kg AEBO promoted a reduction of 33.6% of TG levels, while the 800 mg/kg concentration reduced hypertriglyceridemia in 62.2%. In conclusion, the aqueous extract of the seeds of Bixa orellana was capable of reversing the hypertriglyceridemia induced by Triton, fructose and ethanol, demonstrating a hypolipidemic effect. However, further studies are necessary to discover the precise mechanism of action. PMID- 22451332 TI - Macrophage migration inhibitory factor gene polymorphisms and plasma levels in children with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is associated with increased risk for cardiovascular and metabolic dysfunction in both adults and children. In adults with OSA, serum levels of macrophage migration inhibitory factor (MIF) are elevated. Therefore, we assessed plasma MIF levels and MIF allelic variant frequencies in children with and without OSA (NOSA). METHODS: A total of 614 consecutive children ages 5-8 years were recruited. Children were divided into those with OSA and NOSA based on the apnea-hypopnea index (AHI). In addition to lipid profile, hsCRP, and fasting insulin and glucose levels, plasma MIF levels were assayed using ELISA, and 28 single nucleotide polymorphisms (SNPs) covering the region were genotyped. Linkage disequilibrium and haplotype blocks were analyzed using Haploview version 4.2 software. RESULTS: Morning plasma MIF levels were increased in children with OSA. Of the 28 SNPs tested, the frequency of rs10433310 minor allele was significantly decreased in OSA. This SNP was also associated with reduced fasting insulin and hsCRP levels in OSA. The minor allele frequency of all other 27 SNPs was similar in OSA and NOSA groups. CONCLUSIONS: Childhood OSA is associated with higher plasma MIF, hsCRP, and fasting insulin levels that promote cardiometabolic risk, and the MIF gene SNP rs10433310 may account for some of the variance in such risk. PMID- 22451333 TI - Selective detection of peptide-oligonucleotide heteroconjugates utilizing capillary HPLC-ICPMS. AB - A method for the selective detection and quantification of peptide:oligonucleotide heteroconjugates, such as those generated by protein:nucleic acid cross-links, using capillary reversed-phase high performance liquid chromatography (cap-RPHPLC) coupled with inductively coupled plasma mass spectrometry detection (ICPMS) is described. The selective detection of phosphorus as (31)P(+), the only natural isotope, in peptide-oligonucleotide heteroconjugates is enabled by the elemental detection capabilities of the ICPMS. Mobile phase conditions that allow separation of heteroconjugates while maintaining ICPMS compatibility were investigated. We found that trifluoroacetic acid (TFA) mobile phases, used in conventional peptide separations, and hexafluoroisopropanol/triethylamine (HFIP/TEA) mobile phases, used in conventional oligonucleotide separations, both are compatible with ICPMS and enable heteroconjugate separation. The TFA-based separations yielded limits of detection (LOD) of ~40 ppb phosphorus, which is nearly seven times lower than the LOD for HFIP/TEA-based separations. Using the TFA mobile phase, 1-2 pmol of a model heteroconjugate were routinely separated and detected by this optimized capLC-ICPMS method. PMID- 22451334 TI - Quantitative analysis of polymer additives with MALDI-TOF MS using an internal standard approach. AB - MALDI-TOF MS is used for the qualitative analysis of seven different polymer additives directly from the polymer without tedious sample pretreatment. Additionally, by using a solid sample preparation technique, which avoids the concentration gradient problems known to occur with dried droplets and by adding tetraphenylporphyrine as an internal standard to the matrix, it is possible to perform quantitative analysis of additives directly from the polymer sample. Calibration curves for Tinuvin 770, Tinuvin 622, Irganox 1024, Irganox 1010, Irgafos 168, and Chimassorb 944 are presented, showing coefficients of determination between 0.911 and 0.990. PMID- 22451335 TI - Few insurance-based differences in upper extremity elective surgery rates after healthcare reform. AB - BACKGROUND: Before the US Patient Protection and Affordable Care Act of 2010, there were documented insurance-based disparities in access to orthopaedic surgeons and care of orthopaedic conditions. While Massachusetts passed healthcare reform in 2007 with many similar provisions, it is unknown whether the disparities were present during the period of the law's enactment. QUESTIONS/PURPOSES: We asked whether differences in rates of surgery between patients with novel government-subsidized healthcare plans and other forms of insurance, and between uninsured and insured patients, were similar after institution of the Massachusetts reform laws. METHODS: We identified 7577 patients diagnosed with upper extremity injuries between January 1, 2007 and October 1, 2010. From an institutional administrative database, we extracted demographics, insurance status, and plan of care. Insurance categories included government-subsidized healthcare plan (Commonwealth Care), private insurance, workers compensation, military-related (TriCare), Medicare, Medicaid (MassHealth), non-Commonwealth Care, and other insured and uninsured. After adjusting for age, gender, and diagnosis, we compared the proportions of patients who underwent elective surgery. RESULTS: Of 7577 patients, 1685 (22%) underwent elective upper extremity surgery. The adjusted rates of surgery were similar across most insurance categories, with higher rates in the workers compensation and TriCare categories compared with Commonwealth Care. Uninsured patients were as likely to undergo surgery as insured patients. CONCLUSION: In a population with near-universal health insurance, a government-run health insurance exchange, and novel, government-subsidized, managed care plans, we found few insurance based differences in rates of elective upper extremity orthopaedic surgery in a cohort of patients after healthcare reform. PMID- 22451336 TI - Better function for fusions versus above-the-knee amputations for recurrent periprosthetic knee infection. AB - BACKGROUND: Treatment of chronic periprosthetic joint infections (PJIs) after TKA is limited to fusions, above-the-knee amputations (AKAs), revision TKA, and antibiotic suppression and is often based on the patient's medical condition. However, when both fusion and AKA are options, it is important to compare these two procedures with regard to function. QUESTIONS/PURPOSES: Do patients receiving a knee fusion for PJI after TKA have better function compared to patients receiving an AKA? METHODS: We retrospectively reviewed patients who were eligible for either fusion or AKA after PJI TKA. Thirty-seven patients underwent a fusion for PJIs after TKA between 1999 and 2010. Nine patients died postoperatively and eight patients were lost to followup, leaving 20 patients. Patients completed a specialized questionnaire about their fusion, and functional capability was assessed by the SF-12. We compared fusions to a previously published group of six patients who underwent AKA for recurrent PJI after TKA. RESULTS: For patients with fusion, community ambulators increased from five to 10 and nonambulators decreased from three to one. For patients with AKA, nonambulatory patients increased from zero to two, and community ambulators decreased from four to one. The SF-12 physical component summary measurements were higher for fusions (51) than for AKAs (26). The mental component summary was also higher in fusions (60) than in AKAs (44). Seventy percent of patients indicated they would undergo a fusion again instead of undergoing an amputation if they were presented with both options after undergoing their operation. CONCLUSIONS: Patients receiving knee fusions for treating recurrent PJIs after TKA have better function and ambulatory status compared to patients receiving AKA. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 22451337 TI - Do joint registries report true rates of hip dislocation? AB - BACKGROUND: Despite advances in primary THA, dislocation remains a common complication. In New Zealand (NZ), dislocations are reported to the National Joint Registry (NJR) only when prosthetic components are revised in the treatment of a dislocation. Closed reductions of dislocated hips are not recorded by the NJR. QUESTIONS/PURPOSES: We compared the true dislocation rate for patients receiving primary THA in the Wellington region with the rate reported by the NZ NJR for the same group of patients. METHODS: The NZ NJR identified 570 patients undergoing primary THA from January 1, 2008, to December 31, 2009, with addresses in the Wellington region. The mean age was 67.5 years (range, 27-96 years). The minimum followup was 2 years (mean, 3 years; range, 2-4 years). RESULTS: Six patients required revision of at least one component for dislocation. There was 100% agreement between the hospital database and the NJR. Using the NJR criteria of revision of any component as an end point, the dislocation rate in the Wellington region after primary THA was 1.05%. The hospital database identified a further eight patients who presented with a dislocation of their primary THA and underwent a closed reduction. These patients were not recorded by the NJR. The true rate of all dislocations, which includes closed reductions, was 2.46%. CONCLUSIONS: This article documents the discrepancy between the NZ NJR reported rate of revision for dislocation and the true rate of dislocation in primary THA. We recommend documentation of all dislocations by NJR in their database to allow more accurate comparisons between centers and research outcomes. LEVEL OF EVIDENCE: Level IV, clinical research study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22451338 TI - Extent of tibiofemoral osteoarthritis before knee arthroplasty: multicenter data from the osteoarthritis initiative. AB - BACKGROUND: Knee arthroplasty traditionally is recommended for persons with substantial disability and disabling pain attributable to moderate or severe osteoarthritis (OA). Pain and functional status after arthroplasty may be influenced by the extent of knee OA before surgery and recent evidence suggests persons with less severe knee OA before undergoing TKA have greater pain levels and worse function than persons with more severe knee OA. QUESTIONS/PURPOSES: We determined the proportion of patients undergoing knee arthroplasty who had less than moderate knee OA before surgery and who had either a radiographically normal medial or lateral joint space before surgery. METHODS: One hundred sixteen persons in the Osteoarthritis Initiative underwent knee arthroplasty during a 3 year period. Ninety-seven of the 116 patients (84%) had radiographs available less than 1 year before surgery and were included. We used Z-tests to determine whether the proportion of patients with a modified Kellgren-Lawrence (KL) grade of 3 or higher differed from literature-based estimates. In addition, we described the proportion of patients with medial and lateral joint space narrowing. RESULTS: The proportion of patients with a modified KL grade of 3 or higher was 0.81 (95% CI, 0.73-0.89) and was less than the 0.95 estimated population proportion. Of the patients who underwent knee arthroplasty, 85% (82 of 97 knee arthroplasties) had at least one tibiofemoral joint compartment that had no joint space narrowing. One in six patients with OA who underwent knee arthroplasty had a KL grade of 2 or lower. CONCLUSIONS: Variation in the extent of tibiofemoral OA in patients preparing for joint arthroplasty is greater than previously described. A greater percentage of patients undergoing knee arthroplasty may be at risk for increased pain and poorer function than previously assumed after surgery because of less severe knee OA before surgery. LEVEL OF EVIDENCE: Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22451339 TI - Enhanced resting-state oscillations in schizophrenia are associated with decreased synchronization during inattentional blindness. AB - Patients suffering from schizophrenia have been characterized by an apparent lack of theta (around 6 Hz) and gamma (>40 Hz) brain oscillatory activity during task execution. The neurocognitive reasons for these abnormal synchronization patterns, however, remain elusive. Recording the electroencephalogramm (EEG) during a selective visual attention task, the current study investigates whether abnormal brain oscillatory resting-state activity in the theta band might account for a lack of task-related brain oscillatory activity in schizophrenia. EEGs were recorded from 26 patients with schizophrenia and 26 healthy matched controls during rest and during the execution of a selective visual attention task, in which an unexpected object (monkey) appeared on the screen. On a behavioral level, patients were less likely to report perceiving the unexpected event than controls. Controls showed a stronger increase in task-related theta power than patients in prefrontal, parietal, and occipital brain regions. Task-related theta power change differed between patients who perceived, and patients who did not perceive the unexpected event. Moreover, patients showed higher levels of theta power during rest than controls, whereas the absolute theta power values during the selective attention task did not differ between groups. These results suggest that the failure to increase oscillatory activity during a cognitive task can be accounted for by abnormally high oscillatory activity in a resting state. This finding has important implications for future studies examining abnormal brain oscillatory activity in schizophrenia, which usually treat resting-state activity as a baseline for task-related activity. PMID- 22451340 TI - Involvement of FGF9/16/20 subfamily in female germ cell development of the Nile tilapia, Oreochromis niloticus. AB - Fibroblast growth factors (FGFs) have been proved to participate in a wide variety of processes, including growth, differentiation, cell proliferation, migration, sex determination and sex differentiation. The roles of FGF9/16/20 subfamily members in the gonadal development of teleost fish have not yet been reported. Three FGFs (16, 20a and 20b) of the FGF9/16/20 subfamily were cloned from the Nile tilapia by RT-PCR and RACE. Phylogenetic, bioinformatic and syntenic analyses demonstrated that these cloned FGFs are genuine FGF16, 20a and 20b. Our analyses further supported the non-existence of FGF9 ortholog and the existence of two FGF20 paralogs in teleost genomes. Tissue distribution analysis by RT-PCR demonstrated that FGF16 was expressed in a wide range of tissues including the testis and ovary, FGF20b in the brain, pituitary, intestine and ovary, but not in the testis, while FGF20a in the brain, pituitary and spleen, but not in the gonad. These results were consistent with the Northern blot analysis. The expression profiles of FGF16 and FGF20b during normal and sex reversed gonadal development were investigated by real-time PCR. Both showed much higher expression in the XX ovary and 17 beta-estradiol induced XY ovary compared with the XY testis and fadrozole and tamoxifen induced XX testis, with the highest in both sexes at 120 dah. Strong signals of FGF16 and FGF20b were detected in phase II oocytes by in situ hybridization. These data suggest that FGF9/16/20 subfamily is involved in the early oocyte development of the female. PMID- 22451341 TI - Fullerene and omega-3 and omega-6 fatty acids on fish brain antioxidant status. AB - The carbon nanomaterial fullerene (C(60)) can act as anti or pro-oxidant. The aim of this study was to evaluate, in cell suspensions of carp brains (Cyprinus carpio, Cyprinidae), the effect of C(60) after a pre-treatment with polyunsaturated fatty acid (PUFAs) such as omega-3 (docosahexaenoic acid, DHA) and omega-6 (linoleic acid, LA). Assays consisted of a pre-treatment with PUFA (48 h) and then exposure to C(60) (2 h). Cell viability and total anti-oxidant capacity did not differ (p > 0.05). A reduction (p < 0.05) was observed in reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) concentration in fish brain cells pre-exposed with PUFA groups and then exposed or not with C(60). An antioxidant effect of C(60) was evident since in control group (cells not pre-exposed to PUFA), a significant (p < 0.05) reduction of intracellular ROS concentration was observed, although this reduction was not enough to reduce the TBARS levels. Cysteine levels presented a reduction (p < 0.05) in all groups exposed to C(60). For glutathione (GSH), an increase (p < 0.05) was registered in cells exposed to C(60) without PUFAs pre-treatment and in the C(60) group pre-treated with DHA. Overall C(60) appears to play an antioxidant role that is modulated by PUFA, taking into account its effects on intracellular ROS concentration and MDA levels. Results also suggest that C(60) influences GSH synthesis, as showed for the augmented levels of this antioxidant and also for the lowering of the intracellular cysteine concentration. PMID- 22451342 TI - Fully automatic CAD design of the occlusal morphology of partial crowns compared to dental technicians' design. AB - OBJECTIVES: The aim of this study was to compare the occlusal morphology of partial crown reconstructions made by dental technicians with reconstructions made by a fully automatic software process (biogeneric tooth model) in relation to the original natural tooth shape. MATERIAL AND METHODS: Stone replicas of natural teeth were measured three-dimensionally before preparing inlay and onlay cavities for ceramic restorations (n = 5). For each preparation, five reconstructions (in total n = 25) were made by five dental technicians. Additionally, reconstructions were calculated automatically by a software based on the biogeneric tooth model (Cerec 3D). In order to compare the two different kinds of reconstruction, an objective metrical similarity measure (shape similarity value, SSV) based on calculated volumes between compared datasets was used. RESULTS: In 22 of 25 cases, the reconstructions made by the CAD software were closer to the original situation than the reconstructions made by the technicians. Mean average SSV of reconstructions made by the technicians (310.2 +/- 78.8 MUm) was significantly higher (p < 0.05) than mean SSV of CAD reconstructions (biogeneric model) (222.0 +/- 47.7 MUm). CONCLUSIONS: In the design of naturally shaped occlusal inlay/onlay surfaces, a fully automatic CAD system can be at least as good as conventional wax-ups by dental technicians. CLINICAL RELEVANCE: The adjustment of a dental restoration to fit the morphology of surrounding tooth structures, still presents challenges for the dentist. PMID- 22451343 TI - The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells. AB - MHC class I (MHC-I) molecules are ubiquitously expressed on the cells of an organism. Study of the regulation of these molecules in normal and disease conditions is important. In tumour cells, the expression of MHC-I molecules is very frequently lost, allowing these cells to evade the immune response. Cancers of different histology have shown total loss of MHC-I molecule expression, due to a coordinated transcriptional down-regulation of various antigen-processing machinery (APM) components and/or MHC-I heavy chains. The mechanisms responsible for these alterations remain unclear. We determined the possible genes involved by comparing MHC-I-positive with MHC-I-negative murine metastases derived from the same fibrosarcoma tumour clone. MHC-I-negative metastases showed transcriptional down-regulation of APM and MHC-I heavy chains. The use of microarrays and subtraction cDNA libraries revealed four candidate genes responsible for this alteration, but two of them were ruled out by real-time RT PCR analyses. The other two genes, AP-2alpha and Fhit tumour suppressors, were studied by using siRNA to silence their expression in a MHC-I-positive metastatic cell line. AP-2alpha inhibition did not modify transcriptional expression of APM components or MHC-I heavy chains or surface expression of MHC-I. In contrast, silencing of the Fhit gene produced the transcriptional down-regulation of APM components and MHC-I heavy chains and decreased MHC-I surface expression. Moreover, transfection of Fhit in MHC-I-negative tumour cell lines restored MHC-I cell surface expression. These data indicate that defects in Fhit expression may promote MHC-I down-regulation in cancer cells and allow escape from immunosurveillance(#). PMID- 22451344 TI - Quality of life and self-stigma in individuals with schizophrenia. AB - Recent mental illness stigma research has almost exclusively studied community and family responses to the stigmas of mental illness. Too little has been done to understand the current subjective experience of psychiatric patients. Our study explores the influence of self-stigma on the quality of life of mentally disabled people. Participating in the survey were 100 people diagnosed with schizophrenia. Using Ritsher's internalized stigma of mental illness scale, which incorporates alienation, stereotype endorsement, discrimination experience, social withdrawal, and social resistance subscales, along with the standard SF 12, helped us evaluate the subjective experience of mental illness stigma. According to our survey data, self-stigma correlates negatively with all of the quality of life measures except the Internalized Stigma of Mental Illness subscale's 'stigma resistance', which did not correlate significantly. Improved stigma resistance requires an understanding of one's sociocultural background and a strong social network to provide the sense of comfort and security that enables a fulfilling life. PMID- 22451345 TI - Differential activation in the primary motor cortex during individual digit movement in focal hand dystonia vs. healthy. AB - PURPOSE: The pathophysiology of focal hand dystonia (FHD) is not clearly understood. Previous studies have reported increased and decreased cortical activity associated with motor tasks. The aim of this study was to investigate blood oxygen level dependent (BOLD) signal changes in functional magnetic resonance imaging within the hand area of primary motor cortex during cued movement of individual digits. METHODS: Eight healthy individuals and five individuals with right hand FHD participated. Beta weight contrasts were examined within the hand area of the motor cortex. RESULTS: In both groups, BOLD signal changes in the hemisphere contralateral to the moving hand were greater in the left hemisphere than the right. Between groups, no difference was found during control of the left hand, but a significant difference was seen during right hand movement; specifically, individuals with dystonia showed increased contralateral and decreased ipsilateral cortical response associated with the affected hand as compared to healthy individuals. This suggests a similar, albeit exaggerated pattern of activation in individuals with FHD on the affected side. CONCLUSIONS: These results suggest different levels of ipsilateral and contralateral activation between healthy and dystonic individuals but also show a relative difference between symptomatic and asymptomatic control within the patient population. PMID- 22451346 TI - Neuroplasticity-based computerized cognitive remediation for geriatric depression. AB - OBJECTIVE: This article describes a novel treatment model designed to target specific neurocognitive deficits in geriatric depression with neuroplasticity based computerized cognitive remediation (NBCCR). METHOD: The recent National Institute of Mental Health (NIMH) report "From Discovery to Cure" calls for studies focusing on mechanisms of treatment response with the goal of arriving at new interventions for those who do not respond to existing treatments. We describe the process that led to the identification of specific executive deficits and their underlying neurobiology, as well as the rationale for targeting these symptoms as a part of a strategy intended to improve both executive dysfunction and depression. We then propose a strategy for further research in this emerging area. RESULTS AND CONCLUSIONS: Despite significant developments, conventional antidepressant treatments leave many older adults still depressed and suffering. Psychotherapy may be effective in some depressed elders, although a recent review concluded that none of the available treatment studies meets stringent criteria for efficacy in the acute treatment of geriatric depression. Appropriately developed and targeted NBCCR, has the potential to serve as a novel treatment intervention for geriatric depression. Pathophysiological changes associated with executive dysfunction may be an appropriate target for NBCCR. Examining both behavioral changes and indices of structural integrity and functional change of networks related to cognitive and emotional regulation may lead to a novel treatment and elucidate the role of specific cerebral networks in geriatric depression. PMID- 22451347 TI - The anxiolytic potential and psychotropic side effects of an echinacea preparation in laboratory animals and healthy volunteers. AB - We investigated the toxicity, psychotropic side effects and anxiolytic potential of an Echinacea angustifolia extract that produced promising effects in laboratory tests performed earlier. Rats were studied in the elevated plus-maze, conditioned fear, open-field, object recognition and conditioned place preference tests. Toxicity was studied in rats after intragastric administration. The preparation decreased anxiety in the elevated plus-maze and ameliorated contextual conditioned fear. No lethality or behavioural signs of discomfort were noticed in rats treated with 1000 and 3000 mg/kg Echinacea angustifolia. The extract was without effect in tests of locomotion (open-field), memory (object recognition) and rewarding potential (conditioned place preference) within a wide dose range. A pharmacological formulation based on the same E. angustifolia extract was tested in human subjects. One or two tablets per day were administered for 1 week to healthy volunteers scoring high on the State-Trait Anxiety Inventory (STAI). The tablets contained 20 mg of the plant extract. Data were collected using a structured self-assessment diary technique. The high dose (2 tablets per day) decreased STAI scores within 3 days in human subjects, an effect that remained stable for the duration of the treatment (7 days) and for the 2 weeks that followed treatment. The lower dose (1 tablet per day) did not affect anxiety significantly. PMID- 22451348 TI - A reconstructed human epidermal keratinization culture model to characterize ceramide metabolism in the stratum corneum. AB - To examine factors that regulate ceramide production during keratinization of the human stratum corneum (SC), we developed a reconstructed human epidermal keratinization model in which a fresh layer of SC is newly formed within 1 week. Addition of the UDP-glucose: ceramide glucosyltransferase inhibitor 1-phenyl-2 decanoylamino-3-morpholino-1-propanol significantly diminished SC ceramide levels (expressed as ug/mg protein) with decreased glucosylceramide levels. Desipramine hydrochloride, an inhibitor of sphingomyelinase, also significantly reduced SC ceramide levels. Similarly, conduritol B epoxide, an inhibitor of beta glucocerebrosidase, significantly down-regulated SC ceramide levels and significantly increased glucosylceramide levels. These results indicate the reliability of this model to elucidate ceramide synthesis regulating factors. Using this model, we assessed the effects of the inflammatory cytokine interleukin-1alpha (IL-1alpha), several bioactive sphingolipids and all-trans retinoic acid (RA) on ceramide levels in the SC. Whereas treatment with IL-1alpha (at 10 nM) significantly down-regulated ceramide levels, treatment with sphingosylphosphorylcholine (at 50 uM) or sphingosine-1-phosphate (at 10 or 20 uM) distinctly up-regulated ceramide levels. Interestingly, RA (at low as 10 nM) significantly up-regulated ceramide levels without affecting the formation of the SC or levels of keratinization-related proteins in the epidermis. The increased levels of ceramide were accompanied by a significantly increased secretion of granulocyte-macrophage colony-stimulating factor as well as by a significantly down-regulated expression of acid-ceramidase at both the gene and protein levels. Taken together, our results underscore the superiority of this reconstructed human epidermal keratinization model to analyze factors that regulate ceramide synthesis, especially in human SC. PMID- 22451349 TI - Neural substrates of individual differences in human fear learning: evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data. AB - To provide insight into individual differences in fear learning, we examined the emotional and cognitive expressions of discriminative fear conditioning in direct relation to its neural substrates. Contrary to previous behavioral-neural (fMRI) research on fear learning--in which the emotional expression of fear was generally indexed by skin conductance--we used fear-potentiated startle, a more reliable and specific index of fear. While we obtained concurrent fear potentiated startle, neuroimaging (fMRI), and US-expectancy data, healthy participants underwent a fear-conditioning paradigm in which one of two conditioned stimuli (CS(+) but not CS(-)) was paired with a shock (unconditioned stimulus [US]). Fear learning was evident from the differential expressions of fear (CS(+) > CS(-)) at both the behavioral level (startle potentiation and US expectancy) and the neural level (in amygdala, anterior cingulate cortex, hippocampus, and insula). We examined individual differences in discriminative fear conditioning by classifying participants (as conditionable vs. unconditionable) according to whether they showed successful differential startle potentiation. This revealed that the individual differences in the emotional expression of discriminative fear learning (startle potentiation) were reflected in differential amygdala activation, regardless of the cognitive expression of fear learning (CS-US contingency or hippocampal activation). Our study provides the first evidence for the potential of examining startle potentiation in concurrent fMRI research on fear learning. PMID- 22451350 TI - Axenic cultures of Nitrosomonas europaea and Nitrobacter winogradskyi in autotrophic conditions: a new protocol for kinetic studies. AB - As a part of a natural biological N-cycle, nitrification is one of the steps included in the conception of artificial ecosystems designed for extraterrestrial life support systems (LSS) such as Micro-Ecological Life Support System Alternative (MELiSSA) project, which is the LSS project of the European Space Agency. Nitrification in aerobic environments is carried out by two groups of bacteria in a two-step process. The ammonia-oxidizing bacteria (Nitrosomonas europaea) realize the oxidation of ammonia to nitrite, and the nitrite-oxidizing bacteria (Nitrobacter winogradskyi), the oxidation of nitrite to nitrate. In both cases, the bacteria achieve these oxidations to obtain an energy and reductant source for their growth and maintenance. Furthermore, both groups also use CO2 predominantly as their carbon source. They are typically found together in ecosystems, and consequently, nitrite accumulation is rare. Due to the necessity of modeling accurately conversion yields and transformation rates to achieve a complete modeling of MELiSSA, the present study focuses on the experimental determination of nitrogen to biomass conversion yields. Kinetic and mass balance studies for axenic cultures of Nitrosomonas europaea and Nitrobacter winogradskyi in autotrophic conditions are performed. The follow-up of these cultures is done using flow cytometry for assessing biomass concentrations and ionic chromatography for ammonium, nitrite, and nitrate concentrations. A linear correlation is observed between cell count and optical density (OD) measurement (within a 10 % accuracy) validating OD measurements for an on-line estimation of biomass quantity even at very low biomass concentrations. The conversion between cell count and biomass concentration has been determined: 7.1 * 1012 cells g dry matter (DM)-1 for Nitrobacter and 6.3 * 1012 cells g DM-1 for Nitrosomonas. Nitrogen substrates and products are assessed redundantly showing excellent agreement for mass balance purposes and conversion yields determination. Although the dominant phenomena are the oxidation of NH4+ into nitrite (0.95 mol mol N-1 for Nitrosomonas europaea within an accuracy of 3 %) and nitrite into nitrate (0.975 mol mol N-1 for Nitrobacter winogradskyi within an accuracy of 2 %), the Nitrosomonas europaea conversion yield is estimated to be 0.42 g DM mol N-1, and Nitrobacter winogradskyi conversion yield is estimated to be 0.27 g DM mol N-1. The growth rates of both strains appear to be dominated by the oxygen transfer into the experimental setups. PMID- 22451351 TI - Depressive symptoms and their impact on health-seeking behaviors in newly diagnosed HIV-infected patients in Durban, South Africa. AB - We evaluated the prevalence and correlates of depressive symptoms prior to HIV diagnosis and determined the effect of these symptoms on seeking HIV care at an urban and rural clinic in Durban, South Africa. Adults were administered a questionnaire which included the 5-item Mental Health Index (MHI-5) before HIV testing. We determined the depressive symptoms among HIV-infected subjects. Of 1,545 newly-diagnosed HIV-infected subjects, 55% had depressive symptoms by MHI-5 score. Enrolling at the urban clinic and decreasing functional activity score were associated with depressive symptoms. Subjects with depressive symptoms who were referred for HIV testing by a healthcare provider were less likely to obtain a CD4 count than those without depressive symptoms who self-referred for testing. Depressive symptoms were common among newly-diagnosed HIV-infected participants and impacted CD4 uptake. Depression screening at the time of HIV diagnosis is critical for improving linkage to mental health and HIV services in South Africa. PMID- 22451352 TI - Adaptive evolution of Xa21 homologs in Gramineae. AB - The XA21 protein has broad spectrum resistance against Xanthomonas oryzae pv. oryzae. Although Xa21-mediated immunity is well characterized, little is known about the origin and evolutionary history of this gene in grasses. Therefore, we analyzed all Xa21 gene homologs in eight whole-genome sequenced rice lines, as well as in four gramineous genomes, rice, Brachypodium, sorghum and maize; using Arabidopsis Xa21 homologs as outgroups, 17, 7, 7 and 3 Xa21 homologs were detected in these four grasses, respectively. Synteny and phylogenetic analysis showed that frequent gene translocation, duplication and/or loss, have occurred at Xa21 homologous loci, suggesting that they have undergone or are undergoing rapid generation of copy number variations. Within the rice species, the high level of nucleotide diversity between Xa21-like orthologs showed a strong association with the presence/absence haplotypes, suggesting that the genetic structure of rice lines plays an important role in the variations between these Xa21-like orthologs. Strongly positive selection was detected in the core region of the leucine-rich repeat domains of the Xa21 subclade among the rice lines, indicating that the rapid gene diversification of Xa21 homologs may be a strategy for a given species to adapt to the changing spectrum of species-specific pathogens. PMID- 22451353 TI - Perceptual plasticity is mediated by connectivity changes of the medial thalamic nucleus. AB - It is well known that the threshold for somatosensory perception may adapt to different inputs. Recent studies suggest the presence of a modulating effect of somatosensory inputs on the spinal dorsal horn. However, the effects of somatosensory inputs on cerebral processing and, in particular, on the functional and effective connectivity of the somatosensory brain network, are poorly understood. In this study, we investigated the longitudinal impact of somatosensory stimuli on the resting-state functional connectivity and effective connectivity of the somatosensory brain network. We performed resting-state functional magnetic resonance imaging (fMRI) in 12 healthy subjects before and after unilateral electrical median nerve stimulation. We combined this analysis with a psychophysiological examination of changes of the perception threshold. We found that the unilateral median nerve stimulation increased the perception thresholds bilaterally and increased the resting-state functional and effective connectivity between most cortical areas of the somatosensory network. The major finding, however, was a decreased resting-state functional connectivity between both secondary somatosensory cortices and the bilateral medial nuclear complex of the thalamus. This decreased connectivity was correlated with increased perception thresholds. These findings emphasize the importance of the medial thalamic nucleus for the perceptual awareness of somatosensory stimuli. PMID- 22451354 TI - Neurocognitive functioning in early-onset and late-onset older patients with euthymic bipolar disorder. AB - OBJECTIVE: Most neurocognitive studies have not taken into account the fact that older patients with bipolar disorder (BD) are a heterogeneous population. The main goal of this study was to compare neurocognitive performance and extrapyramidal symptoms in older patients with early-onset BD (EO-BD) and late onset BD (LO-BD). METHODS: Euthymic older patients with EO-BD (n = 20), LO-BD (n = 20), and healthy controls (n = 20) were evaluated with traditional clinical instruments and measures of exposure to psychotropic drugs, as well as extrapyramidal symptoms. All subjects completed an extensive neuropsychological battery. RESULTS: Patients with EO-BD showed poorer performance than healthy controls in two measures of verbal memory and two measures of executive functions, whereas patients with LO-BD exhibited lower performance scores than healthy controls in almost all of the measures assessed. Impairments in the LO-BD group included even neurocognitive domains typically spared in mixed-age patients. Additionally, there was a trend toward displaying higher extrapyramidal symptoms in the LO-BD group compared with both EO-BD and healthy control groups. In both patient groups, psychosocial functioning was related with executive dysfunction and extrapyramidal symptoms. CONCLUSIONS: Patients with LO-BD may have more extensive and severe cognitive impairments, as well as higher vulnerability to extrapyramidal symptoms, compared with patients with EO-BD. Cognitive-motor disturbances may help to explain impairments in daily functioning among older patients with EO-BD and LO-BD during remission. PMID- 22451355 TI - Antiproliferative and antiangiogenic properties of horse chestnut extract. AB - This study was designed to examine the in vitro antiproliferative effect of the horse chestnut extract (HCE) on cancer cell lines. Furthermore, we have investigated the in vitro effect of HCE on some angiogenic events by using human umbilical vein endothelial cells. The cell proliferation was evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and anchorage independent growth by colony-forming assay. To understand the growth inhibitory effects, carcinoma cell lines (Jurkat, CEM, HeLa, and MCF-7) were treated with various concentrations of HCE. Incubation of Jurkat, CEM, HeLa, and MCF-7 cancer cells with HCE at 125 ug/mL for 72 h caused 93.7%, 32.3%, 20.4% and 40.4% reduction in cell survival. Colony-forming assay also confirmed growth-inhibitory effects of the compound studied. In HeLa HCE-treated cells, we found a significant increase in cells having sub-G(0) /G(1) DNA content which is considered to be a marker of apoptotic cell death. Apoptosis was also further confirmed by DNA fragmentation analysis.Furthermore, HCE inhibited migration of human umbilical vein endothelial cells as well as decreased secretion of matrix metalloproteinase and vascular endothelial growth factor.In conclusion, the present study has assessed the in vitro antiproliferative/antiangiogenic potential of HCE. These results generate a rationale for in vivo efficacy studies with horse chestnut in preclinical cancer models. PMID- 22451356 TI - Micro total bioassay system for oral drugs: evaluation of gastrointestinal degradation, intestinal absorption, hepatic metabolism, and bioactivity. AB - A micro total bioassay system that mimics physiological processes was developed as a means of evaluating orally administered drugs. A new feature accounting for gastrointestinal digestion was added to the previous system, which consists of microintestine, microliver, and target components. The artificial micro gastrointestinal tract employs synthetic digestive juices. The system could correctly assay the overall digestive properties of ingested anticancer agents, i.e., the stability during digestive processes, as well as intestinal absorption, hepatic metabolism, and bioactivity toward target cells. PMID- 22451357 TI - Direct drug metabolism monitoring in a live single hepatic cell by video mass spectrometry. AB - The metabolism of anti-breast cancer drug, tamoxifen, in a single human hepatocellular carcinoma cell, HepG2, was directly monitored by a video-mass spectroscope. The cytoplasm, a vacuole or nucleus of the cell was directly sucked by a nano-spray tip under a video-microscope, and then was introduced into a mass spectrometer. Unchanged drug molecules were found in cytoplasm and a vacuole, but the metabolites were only found in the cytoplasm. This direct detection of drug metabolites in a live single cell is useful for speedy drug metabolism monitoring. PMID- 22451358 TI - Polyoxyethylene as the stationary phase in ion chromatography. AB - The present article reviews the use of polyethylene glycol (PEG) or polyoxyethylene (POE) as the stationary phase for the separation of inorganic anions in ion chromatography and discusses about the retention mechanisms involved in the separation of anions on the novel stationary phases. PEG permanently coated on a hydrophobic stationary phase retained anions in the partition mode and allowed us to use high-concentration eluents because the retention of anions increased with increasing eluent concentration for most of the eluents. This situation was convenient to determine trace anions contained in seawater samples without any disturbance due to matrices. Chemically bonded POE stationary phases retained not only anions but also cations. Anions were retained in the ion-exchange mode, although POE chains possess no ion exchange sites. The retention behavior suggested that eluent cations could be trapped among multiple POE chains via ion-dipole interaction, and that the trapped cations worked as the anion-exchange sites. Anions could be separated using crown ether, i.e., cyclic POE, as the eluent additive with a hydrophobic stationary phase, where analyte anions were retained via electrostatic interaction with the eluent cation trapped on the crown ether. PMID- 22451359 TI - Validation of a stability-indicating RP-LC method for the assessment of recombinant human interleukin-11 and its correlation with bioassay. AB - A stability-indicating reversed-phase liquid chromatography (RP-LC) method was validated for the assessment of recombinant human interleukin-11 (rhIL-11), based on the ICH guidelines. The method was carried out on a Jupiter C(4) column (250 mm * 4.6 mm i.d.), maintained at 25 degrees C. The mobile phase A consisted of 0.1% trifluoroacetic acid (TFA) and the mobile phase B was acetonitrile with 0.1% TFA, run at a flow rate of 1 mL/min, and using a photodiode array (PDA) detection at 214 nm. Separation was obtained with a retention time of 27.6 min, and was linear over the concentration range of 1-200 ug/mL (r(2) = 0.9995). Specificity was established in degradation studies, which also showed that there was no interference of the excipients. The accuracy was 100.22% with bias lower than 1.25%. Moreover, the in vitro cytotoxicity test of the degraded products showed non-significant differences (p > 0.05). The method was applied to the assessment of rhIL-11 and related proteins in biopharmaceutical dosage forms, and the results were correlated to those of a bioassay. PMID- 22451360 TI - Isolation of selenoprotein-P and determination of Se concentration incorporated in proteins in human and mouse plasma by tandem heparin affinity and size exclusion column HPLC-ICPMS. AB - Sel-P is considered to be the most important selenoprotein for evaluating the selenium (Se) status in the body. To isolate and determine Sel-P in plasma, we have developed an analytical method combining heparin affinity (AF) and size exclusion column (SEC) high-performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). We used this method to validate the adsorption efficiency of selenoproteins on a heparin AF column, and to then determine the Se concentrations incorporated in proteins in human and mouse plasma. The adsorption efficiency of Sel-P on a heparin column was more than 90% for both human and mouse plasma. Tandem AF and SEC separation proved to be useful for determining the Se concentrations incorporated in Sel-P in mouse plasma, but not in human plasma, because of nonspecific adsorption of plasma extracellular glutathione peroxidase (eGPx) and albumin on the heparin AF column. Ultimately, we used the tandem AF and SEC separation method for mouse plasma and SEC separation alone for human plasma. The Se concentration incorporated in selenoproteins determined by our method showed good agreements with the total Se concentration determined following acid digestion. PMID- 22451361 TI - Selective determination of trace iron in different oxidation states in natural water by flow injection-solid phase spectrometry. AB - A novel method for the selective determination of Fe(II) and Fe(III) in water using 2-nitroso-5-[N-n-propyl-N-(3-sulfopropyl)amino]phenol (PSAP) was developed. QAE-Sephadex anion exchanger packed in a flow-through cell was used as a medium not only for both the concentration and the spectrophotometric measurements of the Fe-PSAP complex, but also for reduction of the Fe(III)-PSAP complex. The PSAP complex of Fe(II) or Fe(III) was strongly adsorbed on the anion exchanger in a weakly acidic to weakly basic region, but the Fe(III) complex was readily and completely reduced to the Fe(II) complex only in a neutral to weakly alkaline region in the solid phase. These properties were utilized to determine the Fe(II) and total Fe concentration without the addition of any reducing agent. The detection limits (3sigma) were 0.18 ng for Fe(II) and 0.18 ng for total Fe using a 3.2-cm(3) sample solution. The present method is applicable to the determination of dissolved iron species present at ug dm(-3) levels in natural water samples. PMID- 22451362 TI - Application of pressure-assisted electrokinetic injection-tandem mass spectrometry in the determination of perchlorate in water and soil samples. AB - A new method for the determination of perchlorate in water and soil samples using on-line enrichment in a capillary zone electrophoresis-mass spectrometry is presented. The target analytes in the sample solutions were introduced into the capillary column by pressure-assisted electrokinetic injection (PAEKI) with the simultaneous application of -18 kV and +50 mbar external pressure to the sample vial at the capillary inlet for 4 min. The injected sample zone was flushed out with a running buffer and analyzed by a tandem mass spectrometer in a negative selected reaction monitoring mode. The influence of the matrix in both water and soil samples was eliminated by a clean-up step by passing the sample through Ba/Ag/H cartridges. The method showed good linearity in the dynamic range of 20 to 1000 ng/L, and achieved a detection limit of 18.7 ng/L for water samples and 3.3 ng/g for soil samples, respectively. The recovery of perchlorate in spiked samples, at three different levels, ranged over 79-127%. The method reproducibility was found to be 11% RSD for water samples and 7% RSD for soil samples. Perchlorate was found in 25 out of 28 water samples analyzed, with the levels ranging from 19.8 to 192 ng/L, and was not detected in the 10 soil samples analyzed. PMID- 22451363 TI - A novel, universal and sensitive lateral-flow based method for the detection of multiple bacterial contamination in platelet concentrations. AB - In the present study, we aimed to develop a nucleic acid lateral-flow method for the rapid and sensitive detection of multiple bacteria that contaminate platelet concentrations (PCs). Polymerase chain reaction (PCR) amplicons were produced by a set of board-range primers that recognize the conserved region of bacteria 16S rDNA, followed by hybridization with both an FITC (fluorescein isothiocyanate) labelled probe and biotin-labelled probe, and then a nucleic acid lateral-flow dipstick (LFD) assay. The LFD accurately identified 7 species of bacteria, but had no cross-reactivity with human genomic DNA. The limit of detection (LOD) of the LFD assay was as low as 10(1) copies/uL of 16S rDNA for plasmid. In the case of spiked PCs without enrichment, the detection limit of LFD for K. pneumonia was 5 CFU/mL, 6.5 * 10(4) CFU/mL for the S. epidermidis and 35 CFU/mL for P. aeruginosa. PMID- 22451364 TI - Substoichiometric isotope dilution mass spectrometry of boron by the ion-pair extraction with halogenated salicyl alcohol derivatives and a quaternary ammonium salt. AB - Novel salicyl alcohol derivatives (H(2)X(n)sal), 5-bromo-, 3,5-dibromo-, and 3,5 diiodosalicyl alcohol which were abbreviated to H(2)Brsal, H(2)Br(2)sal, and H(2)I(2)sal, respectively, were synthesized and used for the selective extraction of boric acid. Boric acid was extracted with each H(2)X(n)sal into chlorobenzene containing trioctylmethylammonium chloride (TOMACl) as an ion-pair complex, TOMA.B(X(n)sal)(2), at a different pH range. The extraction constant (K(ex)) of boric acid was determined by the equilibrium analyses including the formation of hydrogen-bonded complex of each H(2)X(n)sal with TOMACl in the organic phase. The K(ex) values obtained by salicyl alcohol (H(2)sal) and its derivatives were decreased in the order of H(2)I(2)sal >= H(2)Br(2)sal > H(2)Brsal > H(2)sal. The most powerful extractant, H(2)I(2)sal, was employed for the substoichiometric extraction of boric acid, which was extracted at pH 5 - 9 with a substoichiometric amount of TOMACl in the presence of an excess of H(2)I(2)sal. The present substoichiometric separation method combined with the stable isotope dilution analysis using inductively coupled plasma mass spectrometry (ICP-MS) could be successfully applied to the determination of boron in a reference material of high-analysis compound fertilizer (FAMIC-A-08) without any correction as to the isotopic abundance. PMID- 22451365 TI - Voltammetric sensing of phosphoproteins using a gallium(III) acetylacetonate modified carbon paste electrode. AB - The voltammetric detection of phosphoproteins was developed using a gallium(III) acetylacetonate-modified carbon paste electrode. Because phosphate groups of the protein interacted with the gallium(III) ion, the protein was accumulated on the electrode surface. A hexaammine ruthenium(III) ion, which combined with the functional groups, was used to monitor the interaction. When phosvitin and hexaammine ruthenium(III) ions were incubated in 0.1 M acetate buffer (pH 3.2), a reduction peak of hexaammine ruthenium(III) ion at the electrode decreased as the concentration of the protein increased. In contrast, an increase in the peak current was observed with a plain carbon paste electrode. These results were caused by a competitive reaction of the phosphate groups with the hexaammine ruthenium(III) and gallium(III) ions. In the presence of alpha-, beta- and kappa caseins, the electrode response decreased due to the order of the numbers of phosphate groups. This method could be applied to the sensing of phosphoproteins at the 10(-10) M level. PMID- 22451366 TI - Mechanistic study on the electrochemical reduction of 9,10-anthraquinone in the presence of hydrogen-bond and proton donating additives. AB - The electrochemical reduction of 9,10-anthraquinone (AQ) was investigated in CH(3)CN in both the absence and presence of the hydrogen-bond and proton donating additives, CH(3)OH, CH(CF(3))(2)OH, phenol, 4-methoxyphenol, 4-cyanophenol, 2,4,6 trichlorophenol, and benzoic acid (BA). Three clearly different types of electrochemical behavior were observed with increasing concentrations of the additives, and were simulated to analyze the reaction mechanisms. Type I was observed for weakly interacting additives, such as CH(3)OH, characterized by positive shifts of the two well-separated reduction waves, corresponding to the formation of AQ(*-) and AQ(2-), with no loss of reversibility. The second wave shifted more strongly, and finally merged with the first. These behaviors are explained by the association of AQ(2-) with the additives via strong hydrogen bonding. Type II is attributed to a reduction mechanism involving quantitative formation of strong hydrogen-bonded complexes of AQ(2-) with additives, such as CH(CF(3))(2)OH, phenol and 4-methoxyphenol, showing a reversible or quasireversible two-electron reduction wave with increasing concentrations of the additives. The behavior of Type III, observed in the presence of strongly interacting additives, such as 2,4,6-trichlorophenol and BA, is characterized by a voltammogram composed of the 2-electorn cathodic and the broad anodic waves without keeping reversibility, facilitated by proton transfer in the hydrogen bonded complexes, AQ(*-)-BA and AQ(2-)-BA. The effects of hydrogen-bonding and protonation on the electrochemistry of AQ have been systematically demonstrated in terms of the potentials and reaction pathways of the various species, which appear in quinone-hydroquinone systems. PMID- 22451367 TI - Enhanced electrochemiluminescence employed for the selective detection of methyl parathion based on a zirconia nanoparticle film modified electrode. AB - A simple, rapid and sensitive electrochemiluminescence (ECL) sensor was proposed for direct measurements of methyl parathion (MP) based on the strong affinity of a nano zirconia particles (ZrO(2) NPs) modified film on the electrode to the phosphoric group. ZrO(2) NPs, which could provide a larger absorption area to immobilize organophosphorus, was firstly modified on the glassy carbon electrode surface to prepare the proposed ECL sensor (ZrO(2)/GC). Subsequently, the ZrO(2)/GC electrode was scanned from -0.8 to +0.6 V to obtain the background signal at 0.44 V in a luminol/KCl solution. Then, a certain concentration of MP was added to an aqueous solution for 240 s, which was absorbed onto the ZrO(2)/GC electrode surface. Moreover, the MP absorbed on the surface of the ZrO(2)/GC electrode enhanced the ECL signal of luminol in the luminol/KCl solution, which increased with the concentration of MP. As a result, a novel ECL sensor was obtained in a luminol/KCl solution. The MP was determined in the range of from 3.8 * 10(-11) to 3.8 * 10(-6) mol L(-1), with a low detection limit of 1.27 * 10( 11) mol L(-1) (S/N = 3). The proposed ECL sensor performance for MP detection will open a new field in the application of rapid and screen detection of ultra trace amounts of organ phosphorus pesticides (OPs) of vegetables used in farm markets. PMID- 22451368 TI - Ligand-modified multi-walled carbon nanotubes for potentiometric detection of silver. AB - Three novel hybrid materials have been synthesized by ligands: N-(2-vinylsulfanyl ethylidene)-benzene-1,2-dimine (SBD), N-pyridin-2-ylmethylene-benzene-1,2-dimine (NBD) and N-furan-2-ylmethylene-benzene-1,2-dimine (OBD), covalently linking to multi-walled carbon nanotubes (MWCNTs). These MWCNT hybrid materials were used both as ionophores and as ion-to-electron transducers to construct Ag(+) carbon paste electrodes. The resulting electrodes show higher selectivity to Ag(+) than other cations tested. Among the three electrodes, the electrode based on SBD-g MWCNTs with optimum composition shows the best performance to Ag(+). It exhibits an excellent Nernstian response to Ag(+) in the concentration range from 8.8 * 10(-8) to 1.0 * 10(-1) M with a detection limit of 6.3 * 10(-8) M, and it can also be used over a wide pH range of 3.0-8.0 with a quick response time of 5 s. The response mechanism of the proposed electrode was also investigated by using AC impedance and UV-vis spectroscopy techniques. PMID- 22451369 TI - Modified indirect hard modeling for non-invasive Raman measurements containing surface interference. AB - Non-invasive Raman spectroscopy has been used in an increasing number of applications in recent years. However, in situations where surface signal is excessive, the acquired spectrum of probed sample suffers from surface interference in either conventional backscattering Raman or specially designed Raman methods. A computational method for Raman spectral recovery is required. Strong overlapping of Raman bands and intense fluorescence are the main obstacles that hinder the spectral recovery. In this paper, we present a modified version of an indirect hard modeling algorithm to extract the true Raman spectrum of the probed sample in a two-layer system. The proposed algorithm requires two spectra. By an iterative stepwise optimization, it models one spectrum as a combination of a scaling of the other spectrum, a polynomial baseline and the Raman peaks of the probed sample. It addresses the issue of Raman bands overlapping as well as intense fluorescence interference. The performance of the algorithm is evaluated on experimental Raman spectra. Comparative studies show that the proposed algorithm provides better results for Raman spectral recovery. PMID- 22451370 TI - Evaluation of electrodeposited gold nanostructures for applications in QCM sensing. AB - The electrodeposition of gold nanostructures increases the surface area of a biosensor, which brings an enhancement of the sensitivity by increasing the amount of analyte binding to the surface. To evaluate the relationship among the surface structure, the area and the analyte binding, we quantitatively analyzed them for quartz crystal microbalance (QCM) sensing by scanning electron microscopy and cyclic voltammetry measurements. The results indicate a several times increase of analyte bindings, and also the limitation of the sensing performance. PMID- 22451371 TI - Desorption/ionization efficiency of peptides containing disulfide bonds in matrix assisted laser desorption/ionization mass spectrometry. AB - In order to elucidate the role of desorption/ionization efficiency of peptides in MALDI-MS, we focused on peptides with disulfide bonds, which form a rigid tertiary structure. We synthesized seven sets of peptides with one disulfide bond (oxytocin, somatostatin, [Arg(8)]-vasopressin, [Arg(8)]-vasotocin, cortistatin, melanin-concentrating hormone, urotensin II-related peptide) and five sets of peptides with two disulfide bonds (tertiapin, alpha-conotoxin GI, alpha-conotoxin ImI, alpha-conotoxin MI and alpha-conotoxin SI). Each peptide set consisted of three peptides: the oxidized form (S-S type), the reduced form (SH type), and an internal standard peptide in which all cysteine residues were substituted with alanine residues. In the case of urotensin II-related peptide, tertiapin, alpha-conotoxin ImI and alpha-conotoxin MI, the reduced form showed higher desorption/ionization efficiency than the oxidized form. In contrast, the other peptides revealed higher desorption/ionization efficiency in the oxidized form relative to the reduced form. These results imply that a rigid structure of peptides formed by disulfide bonds does not correlate with desorption/ionization efficiency in MALDI-MS. PMID- 22451372 TI - Potential applicability of MALDI-MS for low-molecular-weight pesticide determination. AB - The application of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) for pesticide analysis was demonstrated. Fifteen pesticides were chosen as the model pesticides and twenty-six MALDI matrices were screened for the most suitable matrix. Under the optimized conditions, the obtained limits of detections were lower than the maximum residue limit values stated with 12 pesticides out of 15 tested. The proposed methodology showed a good analytical performance in terms of rapid, good sensitivity and high throughput of the method as an alternative method for pesticide residues evaluation. PMID- 22451373 TI - Separation and determination of process-related impurities of erlotinib using reverse-phase HPLC with a photo-diode array detector. AB - A simple and rapid reverse-phase high-performance liquid chromatographic (HPLC) method for the simultaneous separation and determination of erlotinib and its process-related impurities in bulk drugs has been developed. Five process-related impurities of erlotinib have been separated on an Inerstsil ODS-3V (C18) column and detected at 254 nm using a photo diode array (PDA). This HPLC method was successfully applied to the analysis of erlotinib bulk drug. The recoveries of erlotinib and process-related impurities were in the range of 92.86-106.23%, and found to be specific, precise and reliable for the determination of unreacted raw materials, intermediates in the reaction mixtures and bulk drugs. PMID- 22451374 TI - A test of Rescorla and Wagner's (1972) prediction of nonlinear effects in contingency learning. AB - According to most theories, in a simple contingency learning situation, excitatory learning occurs when the probability of the unconditioned stimulus in the presence of the conditioned stimulus (p(1)) is higher than the probability of the unconditioned stimulus in the absence of the conditioned stimulus (p(2)). In Rescorla and Wagner's (1972) model, this prediction varies, depending on the parameters used. In the following experiments, we evaluated whether the difference between p(1) and p(2) that is required to produce excitatory conditioning is the same, independent of the specific value of p(1), or whether this difference varies proportionally to p(1)'s value. To do so, an appetitive procedure of Pavlovian conditioning with rats was used. In four experiments, we compared different levels of contingency (low, medium and high) and found that the difference between p(1) and p(2) that is required to produce excitatory conditioning increases when the value of p(1) is higher. The possibility of analyzing contingency learning as a discrimination between p(1) and p(2) is also discussed. PMID- 22451375 TI - Forms of selenium affect its transport, uptake and glutathione peroxidase activity in the Caco-2 cell model. AB - The experiment was designed to investigate the effect of selenium (Se) chemical forms (sodium selenite, selenium nanoparticle [nano-Se] and selenomethionine) on the transport, uptake and glutathione peroxidase (GSH-Px) activity in the Caco-2 cell model. The transport and uptake of different forms of Se (0.1 MUmol l(-1)) across the Caco-2 cell monolayer were carried out in two directions (apical [AP] to basolateral [BL] and BL to AP) for 2 h, respectively, and the apparent permeability coefficient (P(app)), transport efficiency and uptake efficiency were all calculated. In the present study, the transport and uptake of three forms of Se were time-dependent both in AP to BL and BL to AP directions. By the end of 2 h, the transport efficiencies of selenomethionine and nano-Se were higher than that of sodium selenite (P<0.05). The highest uptake efficiency (P<0.05) was observed in cells treated with nano-Se and significant difference (P<0.05) was also observed between the cells incubated with sodium selenite and selenomethionine. As for the P(app), sodium selenite (P<0.05) had the lowest values compared with that of selenomethionine and nano-Se, in both AP-BL and BL AP. However, no significant differences were observed in GSH-Px activities. These results indicated that the efficiency of Se in the Caco-2 cells varied with its chemical forms, which might be associated with the differences in Se transport and uptake. PMID- 22451376 TI - Prenatal exposure to arsenic and its effects on fetal development in the general population of Dalian. AB - To evaluate prenatal exposure to arsenic in the general population and its effects on birth size, we conducted a cross-sectional study in Dalian, China. Arsenic concentration in maternal and cord blood was detected by inductively coupled plasma-mass spectrometry and its effects on birth size were analyzed by multivariate analysis and multiple linear regression analysis. Arsenic concentrations in cord blood were significantly lower than those in maternal blood. A significant positive correlation was shown between maternal and cord blood arsenic concentrations. Maternal arsenic concentration was negatively associated with birth weight, height and chest circumference, and fetal arsenic concentration was negatively associated with head circumference. Our results indicate that arsenic exposure at environmental levels in uterus may pose adverse effects on fetal development. PMID- 22451377 TI - Cortical habituation deficit in tinnitus sufferers: contingent negative variation as an indicator of duration of the disease. AB - Cortical attention and habituation parameters are altered in patients suffering from tinnitus. The aim of the study was to quantify cortical attention and habituation parameters in tinnitus patients by recording the contingent negative variation (CNV) response and to correlate amplitudes of different CNV parameters with duration of disease. Twenty patients suffering from tinnitus (median: 44 years) and twenty age- and sex-matched healthy controls (median: 41 years) were tested by a CNV paradigm. We recorded overall CNV, initial CNV, and terminal CNV and calculated habituation slopes. All CNV parameters were Spearman-correlated with individual duration of disease. Highly significant between groups differences emerged in total (tinnitus: -8.4 uV vs. controls: -3.8 uV), initial ( 11.2 vs. -6.0 uV), and terminal CNV (-11.9 vs. -6.5 uV) demonstrating higher negative amplitudes in tinnitus patients. Habituation differed in total and terminal CNV, indicating missing habituation in tinnitus patients. Overall CNV (rho = -.365) and initial CNV (rho = -.529) showed a medium Spearman correlation with duration of disease. We conclude that the correlation between duration of tinnitus and the initial CNV amplitudes indicates an altered state of cortical excitability that can also be observed in more negative CNV-amplitudes in tinnitus patients. We assume that this state indicates a chronicity process in tinnitus disease. PMID- 22451378 TI - Racemisation of N-Fmoc phenylglycine under mild microwave-SPPS and conventional stepwise SPPS conditions: attempts to develop strategies for overcoming this. AB - We have been engaged in the microwave-solid phase peptide synthesis (SPPS) synthesis of the phenylglycine (Phg)-containing pentapeptide H-Ala-Val-Pro-Phg Tyr-NH(2) (1) previously demonstrated to bind to the so-called BIR3 domain of the anti-apoptotic protein XIAP. Analysis of the target peptide by a combination of RP-HPLC, ESI-MS, and NMR revealed the presence of two diastereoisomers arising out of the racemisation of the Phg residue, with the percentage of the LLLDL component assessed as 49%. We performed the synthesis of peptide (1) using different microwave and conventional stepwise SPPS conditions in attempts to reduce the level of racemisation of the Phg residue and to determine at which part of the synthetic cycle the epimerization had occurred. We determined that racemisation occurred mainly during the Fmoc-group removal and, to a much lesser extent, during activation/coupling of the Fmoc-Phg-OH residue. We were able to obtain the desired peptide with a 71% diastereomeric purity (29% LLLDL as impurity) by utilizing microwave-assisted SPPS at 50 degrees C and power 22 Watts, when the triazine-derived coupling reagent DMTMM-BF(4) was used, together with NMM as an activator base, for the incorporation of this residue and 20% piperidine as an Fmoc-deprotection base. In contrast, the phenylalanine analogue of the above peptide, H-Ala-Val-Pro-Phe-Tyr-NH(2) (2), was always obtained as a single diastereoisomer by using a range of standard coupling and deprotection conditions. Our findings suggest that the racemisation of Fmoc-Phg-OH, under both microwave-SPPS and stepwise conventional SPPS syntheses conditions, is very facile but can be limited through the use of the above stated conditions. PMID- 22451379 TI - Bithiophene imide and benzodithiophene copolymers for efficient inverted polymer solar cells. AB - Bithiophene imide (BTI) and benzodithiophene (BDT) copolymers are synthesized for application in organic photovoltaic (OPV) cells. The electron deficiency of the BTI units leads to polymers with a low-lying HOMOs (~-5.6 eV). Inverted solar cells are fabricated to investigate the OPV performance of the BTI-based polymers and achieve power conversion efficiencies up to 5.5%, with substantial V(oc)s above 0.9 V which are among the highest V(oc)s reported to date for polymer/PCBM solar cells. The results indicate that the BTI is a promising building block for constructing polymer donors for OPV applications. PMID- 22451380 TI - Effects of Ilex latifolia and Camellia sinensis on cholesterol and circulating immune complexes in rats fed with a high-cholesterol diet. AB - Hypercholesterolaemia is one of the risk factors for atherosclerosis and subsequent cardiovascular disease. Here, we investigated the effects of dietary supplementation with Ilex latifolia or green tea (Camellia sinensis) on the levels of plasma total cholesterol, high-density lipoprotein cholesterol and circulating immune complexes in Sprague Dawley rats fed with a high-cholesterol diet. We demonstrated that daily administration by gavage of I. latifolia or C. sinensis at doses of 1.0 or 2.0 g/kg body weight for 30 days resulted in a significant decrease in plasma total cholesterol levels and circulating immune complexes and an increase in high-density lipoprotein cholesterol in rats fed with a high-cholesterol diet compared with levels in the high-cholesterol diet control group. C. sinensis was more effective than I. latifolia. I. latifolia and C. sinensis could be used as food supplements to protect against the development of hypercholesterolaemia. PMID- 22451381 TI - Relation between the rheological properties and the swallowing characteristics of vegetable juices fortified with carrot puree. AB - The relation between the rheological properties and the swallowing characteristics of vegetable juices fortified with 0-30.0% carrot puree (CP) was evaluated. The apparent viscosity of vegetable juices increased with increasing CP concentrations, and a increases in yield stress were observed at and above 17.5% CP. In a sensory evaluation, texture perceived in the oral cavity varied as between vegetable juices with >17.5% CP and those with <12.5% CP. The maximum velocity in the pharyngeal region was classified into three same-quality subgroups: vegetable juices with 0-12.5% CP, with 10.0-25.0% CP, and with 17.5 30.0% CP. It significantly decreased with increasing CP concentrations. PMID- 22451382 TI - Expression analysis of Arabidopsis thaliana small secreted protein genes. AB - Small proteins secreted to the extracellular matrix in plants regulate many physiological activities, including pathogen response, material transport, and morphogenesis, but the functions of most small secreted proteins have not been elucidated except for some well-known small secreted proteins. To predict the functions and physiological roles of unidentified small secreted proteins, information on their expression patterns is valuable. Here, we report expression analysis of Arabidopsis thaliana small secreted protein (ATSP) genes that encode proteins possessing a signal peptide at N-terminal, and protein sizes were less than 100 amino acid residues. By promoter:reporter experiments, we examined the expression of 122 ATSPs, including 47 unannotated ATSPs that do not have any discernable motifs, in tissues and at the cellular level in Arabidopsis seedlings, and floral organs. As a result, 79 ATSP genes were expressed in various regions of the seedlings, and 37 ATSP genes were specifically expressed. PMID- 22451383 TI - Identification of amino acid residues essential for onion lachrymatory factor synthase activity. AB - Lachrymatory factor synthase (LFS), an enzyme essential for the synthesis of the onion lachrymatory factor (propanethial S-oxide), was identified in 2002. This was the first reported enzyme involved in the production of thioaldehyde S-oxides via an intra-molecular H(+) substitution reaction, and we therefore attempted to identify the catalytic amino acid residues of LFS as the first step in elucidating the unique catalytic reaction mechanism of this enzyme. A comparison of the LFS cDNA sequences among lachrymatory Allium plants, a deletion analysis and site-directed mutagenesis enabled us to identify two amino acids (Arg71 and Glu88) that were indispensable to the LFS activity. Homology modeling was performed for LFS/23-169 on the basis of the template structure of a pyrabactin resistance 1-like protein (PYL) which had been selected from a BLASTP search on SWISS-MODEL against LFS/23-169. We identified in the modeled structure of LFS a pocket corresponding to the ligand-binding site in PYL, and Arg71 and Glu88 were located in this pocket. PMID- 22451384 TI - Functional analysis of the C-terminal region of gamma-glutamyl kinase of Saccharomyces cerevisiae. AB - gamma-Glutamyl kinase (GK) is the rate-limiting enzyme in proline synthesis in microorganisms. Most microbial GKs contain an N-terminal kinase domain and a C terminal pseudouridine synthase and archaeosine transglycosylase (PUA) domain. In contrast, higher eukaryotes possess a bifunctional Delta(1)-pyrroline-5 carboxylate synthetase, which consists of a PUA-free GK domain and a gamma glutamyl phosphate reductase (GPR) domain. Here, to examine the role of the C terminal region, including the PUA domain of Saccharomyces cerevisiae GK, we constructed a variety of truncated yeast GK and GK/GPR fusion proteins from which the C-terminal region was deleted. A complementation test in Escherichia coli and S. cerevisiae and enzymatic analysis of recombinant proteins revealed that a 67 residue linker sequence between a 255-residue kinase domain and a 106-residue PUA domain is essential for GK activity. It also appeared that 67 or more residues of the C-terminal region, not the PUA domain itself, are required for the full display of GK activity. Further, the GK/GPR fusion protein was functional in E. coli, but decreased stability and Mg-binding ability as compared to wild-type GK. These results suggest that the C-terminal region of S. cerevisiae GK is involved in the folding and/or the stability of the kinase domain. PMID- 22451385 TI - Effects of lotus root (the edible rhizome of Nelumbo nucifera) on the deveolopment of non-alcoholic fatty liver disease in obese diabetic db/db mice. AB - Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialized countries. The discovery of food components that would ameliorate NAFLD is therefore of interest. Lotus root, the edible rhizome of Nelumbo nucifera, contains a high level of polyphenolic compounds, and several health-promoting properties of lotus root have been reported. The present study examines whether dietary lotus root powder can protect db/db mice from hepatic injury. After 3 weeks of feeding, the hepatomegaly, hepatic triglyceride accumulation, and elevated hepatic injury markers in the serum were markedly alleviated in the Lotus diet-fed db/db mice relative to the control mice. These effects were partly attributable to suppression of the lipogenic enzyme activities and mRNA expression by the Lotus diet. The serum levels of adiponectin, which has been reported to have a protective effect against NAFLD, were significantly higher in the Lotus group than in the Control group of the db/db mice. Moreover, the hepatic expression of such inflammatory genes as tumor necrosis factor-alpha and monocyte chemoattractant protein-1 were markedly suppressed by the Lotus diet. We speculate that the development and progression of NAFLD were prevented by suppressing the expression of lipogenic and inflammatory genes as a result of the higher serum adioponectin level in the Lotus diet-fed db/db mice. PMID- 22451386 TI - Effects of ionic substances on the adsorption of egg white proteins to a stainless steel surface. AB - The surface fouling of food processing equipment by proteins was studied by investigating the adsorption of egg white proteins to the surface of stainless steel (SS) at pH 7.4 and 30 degrees C, and particularly the effects of different types of ionic substances. Ovalbumin and ovomucoid, acidic egg white proteins, were less adsorbed in the presence of phosphate (P(i)), a multivalent anion, than in the presence of HEPES, an amphoteric ion. On the other hand, lysozyme, a basic egg white protein, was more adsorbed in the presence of P(i) than in the presence of HEPES. Citrate as another multivalent anion and taurine as another amphoteric ion affected the respective adsorption of those egg white proteins similarly to P(i) and HEPES. The adsorption of an egg white protein to an SS surface therefore depended on the combination of the type of protein and the effective charge of the coexisting ionic substance. This behaviour can be well explained by assuming that a small ionic substance precedes a protein in attaching to an SS surface, resulting in an alteration to the effective surface charge. Pretreating SS with a P(i) buffer lowered the amount of ovalbumin adsorbed with the HEPES buffer, demonstrating that P(i) can attach to and remain on the SS surface to affect the subsequent protein adsorption. PMID- 22451387 TI - Amelioration of the progression of an atopic dermatitis-like skin lesion by silk peptide and identification of functional peptides. AB - The efficacy of silk peptide in treatment of atopic dermatitis was examined in a picryl chloride-induced atopic dermatitis model in NC/Nga mice. Silk peptide ameliorated the development of atopic dermatitis by lowering the serum IgE concentration. Treatment of cultured spleen cells with silk peptide reduced IgE production by enhancing the production of IFN-gamma and reducing the level of IL 4. The functional peptides in the silk peptide were identified as mixture of GAGA sequences containing peptides by mass spectrometry and in vitro assay. Our findings indicate that silk peptide exerts an effect on atopic dermatitis by modulating the Th1/Th2 balance. PMID- 22451388 TI - Introducing site-specific glycosylation using protein engineering techniques reduces the immunogenicity of beta-lactoglobulin. AB - To reduce the immunogenicity of beta-lactoglobulin (BLG), we prepared wild-type bovine BLG variant A (wt) and three site-specifically glycosylated BLGs (D28N, D137N/A139S, and P153A), and expressed them in the methylotrophic yeast Pichia pastoris by fusion of the cDNA to the sequence coding for the alpha-factor signal peptide from Saccharomyces cerevisiae. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicated that the glycosylated BLGs were conjugated with a ~4 kDa high-mannose chain. Each glycosylated BLG retained ~80% of the retinol-binding activity of BLG. Structural analyses by intrinsic fluorescence, CD spectra, and ELISA with monoclonal antibodies indicated that the surface structure was slightly changed by using protein engineering techniques, but that the site-specifically glycosylated BLGs were covered by high-mannose chains without substantial disruption of wt conformation. Antibody responses to the glycosylated BLGs tended to be weaker in BALB/c, C57BL/6, and C3H/He mice. We conclude that site-specific glycosylation is an effective method to reduce the immunogenicity of BLG, and that masking of epitopes by high-mannose chains is effective to reduce immunogenicity. PMID- 22451389 TI - Relationship between ATM and ribosomal protein S6 revealed by the chemical inhibition of Ser/Thr protein phosphatase type 1. AB - The optimal cellular responses to DNA damage are modulated by kinase and phosphatase. The ataxia telangiectasia mutated (ATM) is a Ser/Thr kinase which is the core of the DNA damage signaling apparatus. The Ser/Thr protein phosphatase type 1 (PP1) inhibitor, tautomycetin (TC) and an antibody to the phospho-(S/T)Q sites of the ATM substrate were used to identify the common substrates for PP1 and ATM in regulating the pathway for DNA damage response. Ribosomal protein S6 (RPS6) was first identified as a substrate for PP1 and ATM. The phosphorylation at Ser247 of RPS6 was then significantly decreased by PP1-mediated dephosphorylation immediately after UV irradiation. These results suggest that PP1 specifically dephosphorylated RPS6 at phospho-Ser247 in vivo. In response to DNA damage, ATM activity was finally required for the phosphorylation of RPS6 at Ser247. We propose from these results a novel mechanism for modulating the RPS6 function by PP1 and ATM which regulates cell growth and survival in response to DNA-damage stimuli. PMID- 22451390 TI - Survival of the aerobic denitrifier Pseudomonas stutzeri strain TR2 during co culture with activated sludge under denitrifying conditions. AB - The aerobic denitrifier Pseudomonas stutzeri TR2 (strain TR2) has the potential to reduce nitrous oxide emissions during the wastewater treatment process. In this application, it is important to find the best competitive survival conditions for strain TR2 in complex ecosystems. To that end, we examined co cultures of strain TR2 with activated sludge via five passage cultures in a medium derived from treated piggery wastewater that contained a high concentration of ammonium. The results are as follows: (i) The medium supported the proliferation of strain TR2 (P. stutzeri strains) under denitrifying conditions. (ii) Nitrite was a better denitrification substrate than nitrate for TR2 survival. (iii) Strain TR2 also demonstrated strong survival even under aerobic conditions. This suggests that strain TR2 is effectively augmented to the wastewater treatment process, aiding in ammonium-nitrogen removal and reducing nitrous oxide production with a partial nitrification technique in which nitrite accumulates. PMID- 22451391 TI - Immunostimulatory activity of polysaccharides isolated from Caulerpa lentillifera on macrophage cells. AB - Polysaccharides were extracted from Caulerpa lentillifera by treating with water and then purified by size-exclusion chromatography. The purified polysaccharides, termed SP1, were found to be sulfated xylogalactans with a molecular mass of more than 100 kDa. Adding SP1 to murine macrophage RAW 264.7 cells increased the production of nitric oxide (NO) in a dose-dependent manner. NO was found by immunoblotting and RT-PCR analyses to be synthesized by an inducible NO synthase. SP1 caused the degradation of IkappaB-alpha and the nuclear translocation of nuclear factor (NF)-kappaB subunit p65 in macrophage cells. SP1 also increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). These results demonstrate that SP1 activated macrophage cells via both the NF-kappaB and p38 MAPK signaling pathways. Moreover, SP1 increased the expression of various genes encoding cytokines, and the phagocytic activity of macrophage cells. These combined results show that SP1 immunostimulated the activity of macrophage cells. PMID- 22451392 TI - Genetic and biochemical characterization of the Pseudoalteromonas tetraodonis alkaline kappa-carrageenase. AB - An alkaline kappa-carrageenase, Cgk-K142, was found in the culture broth of a deep-sea bacterium, Pseudoalteromonas tetraodonis JAM-K142. A gene for the enzyme was cloned and expressed. Purified recombinant Cgk-K142 (rCgk-K142) showed an optimal pH of about 8.8 in glycine-NaOH buffer at 30 degrees C and of about 8.0 in MOPS buffer at 50 degrees C. The optimal temperature for the enzyme was 55 degrees C at pH 8.0. rCgk-K142 was unstable, but lambda- and iota-carrageenans, non-degradative substrate homologs, extensively enhanced its stability. The nucleotide sequence of the gene for Cgk-K142 comprised 1,194 bp, and the deduced amino acid sequence (397 amino acids) showed a high level of similarity to the kappa-carrageenase of P. carrageenovora, with 94% identity. Another gene for a kappa-carrageenase-like protein was found downstream of the gene for Cgk-K142. The nucleotide sequence of that gene consisted of 966 bp (321 amino acids), and it showed the highest similarity, at 64% identity, to protein CgkB of P. carrageenovora, which has been reported as an incomplete 57-amino acid sequence. PMID- 22451393 TI - Chimeric yeast G-protein alpha subunit harboring a 37-residue C-terminal gustducin-specific sequence is functional in Saccharomyces cerevisiae. AB - Despite many recent studies of G-protein-coupled receptor (GPCR) structures, it is not yet well understood how these receptors activate G proteins. The GPCR assay using baker's yeast, Saccharomyces cerevisiae, is an effective experimental model for the characterization of GPCR-Galpha interactions. Here, using the yeast endogenous Galpha protein (Gpa1p) as template, we constructed various chimeric Galpha proteins with a region that is considered to be necessary for interaction with mammalian receptors. The signaling assay using the yeast pheromone receptor revealed that the chimeric Galpha protein harboring 37 gustducin-specific amino acid residues at its C-terminus (GPA1/gust37) maintained functionality in yeast. In contrast, GPA1/gust44, a variant routinely used in mammalian experimental systems, was not functional. PMID- 22451394 TI - Heterologous expression and functional characterization of a novel chitinase from the chitinolytic bacterium Chitiniphilus shinanonensis. AB - Chitiniphilus shinanonensis strain SAY3(T) is a chitinolytic bacterium isolated from moat water of Ueda Castle in Nagano Prefecture, Japan. Fifteen genes encoding putative chitinolytic enzymes (chiA-chiO) have been isolated from this bacterium. Five of these constitute a single operon (chiCDEFG). The open reading frames of chiC, chiD, chiE, and chiG show sequence similarity to family 18 chitinases, while chiF encodes a polypeptide with two chitin-binding domains but no catalytic domain. Each of the five genes was successfully expressed in Escherichia coli, and the resulting recombinant proteins were characterized. Four of the recombinant proteins (ChiC, ChiD, ChiE, and ChiG) exhibited endo-type chitinase activity toward chitinous substrates, while ChiF showed no chitinolytic activity. In contrast to most endo-type chitinases, which mainly produce a dimer of N-acetyl-D-glucosamine (GlcNAc) as final product, ChiG completely split the GlcNAc dimer into GlcNAc monomers, indicating that it is a novel chitinase. PMID- 22451395 TI - The use of mammalian cultured cells loaded with a fluorescent dye shows specific membrane penetration of undissociated acetic acid. AB - Acetic acid induces unique physiological responses in mammalian cells. Our previous study found that fura-2-loaded human embryonic kidney (HEK) 293T cells showed a robust intracellular fluorescence response immediately after stimulation with acetic acid, and no such response in the case of citric acid. In the present study, we aimed to identify the unique characteristics of acetic acid responsible for this phenomenon. We found that one such feature is its hydrophobicity. We also discovered that acetic acid induces cell responses by intracellular acidification. Of the components of acetic acid in solution (protons, acetate ions, and undissociated acetic acid), undissociated acetic acid might be the functional unit that penetrates the lipid bilayer of cell membranes to acidify the intracellular environment, thereby inducing cell responses. The method used in this study might be convenient in evaluating the intracellular acidification of cultured cells by acids in the external environment. PMID- 22451396 TI - Mutational analysis of a CBM family 5 chitin-binding domain of an alkaline chitinase from Bacillus sp. J813. AB - Chitinase J from alkaliphilic Bacillus sp. J813 comprises a glycoside hydrolase (GH) family 18 catalytic domain (CatD), a fibronectin type III like domain, and a carbohydrate-binding module (CBM) family 5 chitin-binding domain (ChBD). It has been suggested that the ChBD binds to insoluble chitin and enhances its degradation by the CatD. To investigate the roles of two aromatic residues (Trp541 and Trp542), which are exposed on the surface of the ChBD, mutational analysis was performed. Single and double mutations of the two aromatic residues decreased binding and hydrolyzing abilities toward insoluble chitin. This result suggests that the ChBD binds to chitin by hydrophobic interactions via two surface-exposed aromatic residues. However, the double mutant, which has no such aromatic residue, bound to chitin at pH 5.2, probably by electrostatic interactions. Moreover, the ChBD bound to insoluble chitosan by electrostatic interactions. PMID- 22451397 TI - Isoliquiritigenin isolated from licorice Glycyrrhiza uralensis prevents 6 hydroxydopamine-induced apoptosis in dopaminergic neurons. AB - Licorice (Glycyrrhiza uralensis) is a medicinal herb containing various bioactive components implicated in antioxidative, anti-inflammatory, antiviral, and neuroprotective effects, but the effects of licorice against Parkinson's disease (PD)-related dopaminergic cell death have not been studied. In this study, we investigated the protective effects of isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in a dopaminergic cell line, SN4741. ISL (1 uM) significantly attenuated 6-OHDA (50 uM)-induced reactive oxygen species (ROS) and nitric oxide (NO) generation and apoptotic cell death. ISL pretreatment effectively suppressed 6-OHDA-mediated upregulation of Bax, p-c-Jun N-terminal kinase (JNK), p-p38 mitogen-activated protein (MAP) kinase, cytochrome c release, and caspase 3 activation. In addition, ISL significantly attenuated 6-OHDA-induced Bcl-2, brain-derived neurotrophic factor (BDNF), and mitochondrial membrane potential (MMP) reduction. Pharmacological inhibitors of the phosphatidylinositol 3-kinase (PI3K) Akt/protein kinase B (PKB) pathway reversed ISL-mediated neuroprotection against 6-OHDA toxicity in SN4741 cells. These results provide the first evidence that ISL can protect dopaminergic cells under oxidative stress conditions by regulating the apoptotic process. PMID- 22451398 TI - An unusual spliced variant of DELLA protein, a negative regulator of gibberellin signaling, in lettuce. AB - DELLA proteins are negative regulators of the signaling of gibberellin (GA), a phytohormone regulating plant growth. DELLA degradation is triggered by its interaction with GID1, a soluble GA receptor, in the presence of bioactive GA. We isolated cDNA from a spliced variant of LsDELLA1 mRNA in lettuce, and named it LsDELLA1sv. It was deduced that LsDELLA1sv encodes truncated LsDELLA1, which has DELLA and VHYNP motifs at the N terminus but lacks part of the C-terminal GRAS domain. The recombinant LsDELLA1sv protein interacted with both Arabidopsis GID1 and lettuce GID1s in the presence of GA. A yeast two-hybrid assay suggested that LsDELLA1sv interacted with LsDELLA1. The ratio of LsDELLA1sv to LsDELLA1 transcripts was higher in flower samples at the late reproductive stage and seed samples (dry seeds and imbibed seeds) than in the other organ samples examined. This study suggests that LsDELLA1sv is a possible modulator of GA signaling in lettuce. PMID- 22451399 TI - Structural characteristics and evolution of a novel venom phospholipase A2 gene from Protobothrops flavoviridis. AB - A novel phospholipase A(2) (PLA(2)) gene, named PfPLA 6, was found in a 6,328-bp NIS-1(5')-a segment in the Protobothrops flavoviridis (Habu, Crotalinae) genome. A comparison of the aligned nucleotide sequences of Viperidae (Viperinae and Crotalinae) venom PLA(2) genes, including PfPLA 6, revealed the deletion of a 12 bp segment called S1EX 1 and a 55-bp segment called S2EX 1 in exon 1 and the interposition of a 219-bp segment called SINT 2 (SINE) in intron 2. A classification of Viperidae PLA(2) genes based on these structural modes indicated that the A-type genes (without SINE), including PfPLA 6, are evolutionarily ancestral to the B-type (Viperinae) and C-type (Crotalinae) PLA(2) genes (both with SINE). Since PfPLA 6 is a pseudogene, an active prototype of PfPLA 6 can be assumed to be the ancestral PLA(2) gene. Putative evolutionary processes from this A-type prototype PLA(2) gene to descendent PLA(2) genes are discussed. PMID- 22451400 TI - Molecular and catalytic properties of monoacetylphloroglucinol acetyltransferase from Pseudomonas sp. YGJ3. AB - Monoacetylphloroglucinol (MAPG) acetyltransferase, catalyzing the conversion of MAPG to 2,4-diacetylphloroglucinol (DAPG), was purified from Pseudomonas sp. YGJ3 grown without Cl(-). Cl(-) and pyoluteorin repressed expression of the enzyme. SDS-polyacrylamide gel electrophoresis showed that the purified enzyme (M(r)=330 kDa) was composed of three subunits of 17, 38, and 43 kDa, and protein sequencing identified these as PhlB, PhlA, and PhlC respectively. The enzyme catalyzed the reversible disproportionation of 2 moles of MAPG to phloroglucinol (PG) and DAPG. The equilibrium constant K (=[DAPG][PG]/[MAPG](2)) was estimated to be about 1.0 at 25 degrees C. A KpnI 20-kb DNA fragment was cloned from the genomic DNA of strain YGJ3, and a 12,598-bp long DNA region containing the phl gene cluster phlACBDEFGHI was sequenced. PCR cloning and expression of the phl genes in Escherichia coli confirmed that expression of phlACB genes produced MAPG ATase. PMID- 22451401 TI - Molecular and catalytic properties of 2,4'-dihydroxyacetophenone dioxygenase from Burkholderia sp. AZ11. AB - The gene dad encoding 2,4'-dihydroxyacetophenone (DHAP) dioxygenase was cloned from Burkholderia sp. AZ11. The initiation codon GTG was converted to ATG for high-level expression of the enzyme in Escherichia coli. The enzyme was moderately thermostable, and the recombinant enzyme was briefly purified. The enzyme (M(r)=90 kDa) was a homotetramer with a subunit M(r) of 23 kDa. It contained 1.69 mol of non-heme iron, and had a dark gray color. On anaerobic incubation of it with DHAP, the absorption at around 400 nm increased due to the formation of an enzyme-DHAP complex. Multiple sequence alignment suggested that His77, His79, His115, and Glu96 in the cupin fold were possible metal ligands. The apparent K(m) for DHAP and the apparent V(max) were estimated to be 1.60 uM and 6.28 umol/min/mg respectively. 2-Hydroxyacetophenone was a poor substrate. CuCl(2) and HgCl(2) strongly inhibited the enzyme, while FeSO(4) weakly activated it. PMID- 22451402 TI - Absorption of the indigestible disaccharide, beta-1,4-mannobiose, from coconut by the rat portal vein. AB - The intestinal absorption of beta-1,4-mannobiose by rats was investigated. Mannobiose was detected in the portal vein plasma by matrix-assisted laser desorption ionization/time of flight mass spectrometry after its administration to rats. The presence of mannobiose in the rat plasma was confirmed by an experiment using beta-mannosidase. These results indicate that mannobiose was directly absorbed through the intestines even without being hydrolyzed. PMID- 22451403 TI - Distribution of pink-pigmented facultative methylotrophs on leaves of vegetables. AB - The distribution of pink-pigmented facultative methylotrophs (PPFMs) on the leaves of various vegetables was studied. All kinds of vegetable leaves tested gave pink-pigmented colonies on agar plates containing methanol as sole carbon source. The numbers of PPFMs on the leaves, colony-forming units (CFU)/g of fresh leaves, differed among the plants, although they were planted and grown at the same farm. Commercial green perilla, Perilla frutescens viridis (Makino) Makino, gave the highest counts of PPFMs (2.0-4.1*10(7) CFU/g) of all the commercial vegetable leaves tested, amounting to 15% of total microbes on the leaves. The PPFMs isolated from seeds of two varieties of perilla, the red and green varieties, exhibited high sequence similarity as to the 16S rRNA gene to two different Methylobacterium species, M. fujisawaense DSM5686(T) and M. radiotolerans JCM2831(T) respectively, suggesting that there is specific interaction between perilla and the PPFMs. PMID- 22451404 TI - Evaluation of the antiviral activity of a green tea solution as a hand-wash disinfectant. AB - Based on the broad-spectrum antiviral effect of green tea catechins, we established an experimental skin contact model for influenza virus transmission and evaluated the use of a green tea solution as a first-hand disinfectant. The infectivity of the virus on the skin cell layer became obsolete when washed with the green tea solution. The skin contact model could be applied to develop non pharmaceutical intervention measures for reducing human transmission of the influenza virus. PMID- 22451405 TI - Two-dimensional protein separation by the HPLC system with a monolithic column. AB - A two-dimensional high-performance liquid chromatography (2D-HPLC) system for protein separation was developed using an ion-exchange column in the first dimension and a reversed-phase monolithic column in the second dimension. The system demonstrated efficient separation of proteins in comparison with conventional systems. For proteomic analysis, proteins extracted from the cell surface of the yeast were separated by 2D-HPLC and evaluated. PMID- 22451406 TI - Gene expression and characterization of a third type of dye-linked L-proline dehydrogenase from the aerobic hyperthermophilic archaeon, Aeropyrum pernix. AB - A third novel type of dye-linked L-proline dehydrogenase (LPDH) has recently been found in the hyperthermophilic archaeon, Pyrobaculum calidifontis, by Satomura et al. The gene encoding the enzyme homologue was identified in the aerobic hyperthermophilic archaeon, Aeropyrum pernix. The gene was successfully expressed in Escherichia coli, and the product was purified to homogeneity and characterized. The expressed enzyme was highly thermostable LPDH having a molecular mass of about 88 kDa and a homodimeric structure. The preferred substrate for the enzyme was L-proline with 2,6-dichloroindophenol (DCIP) as the electron acceptor. However, the enzyme did not utilize ferricyanide as the electron acceptor, in contrast to all other known LPDHs. The electrochemical determination of L-proline at concentrations from 0 to 0.7 mM was achieved by using A. pernix LPDH. A phylogenetic analysis revealed A. pernix LPDH to be clustered with the third type of LPDHs, and to be clearly separated from the clusters of previously known heterooligomeric LPDHs. PMID- 22451407 TI - Separation and identification of rice prolamins by two-dimensional gel electrophoresis and amino acid sequencing. AB - There are difficulties in detecting and separating rice prolamin polypeptides by 2D-PAGE analysis because prolamin polypeptides are insoluble, and the amino acid sequences show high homology among them. In this study, we improved the prolamin extraction method and the 2D-PAGE procedure, and succeeded in separating prolamin polypeptide species by 2D-PAGE and in identifying major prolamin polypeptide sequences. PMID- 22451408 TI - Sudachitin, a polymethoxyflavone from Citrus sudachi, suppresses lipopolysaccharide-induced inflammatory responses in mouse macrophage-like RAW264 cells. AB - Although some polymethoxyflavones possess several important biological properties, including neuroprotective, anticancer, and anti-inflammatory ones, sudachitin, a polymethoxyflavone from Citrus sudachi, has been little studied. In this study, we found that sudachitin inhibited nitric oxide production by suppressing the expression of inducible nitric oxide synthase in lipopolysaccharide-stimulated macrophages, indicating that sudachitin has an anti inflammatory effect. PMID- 22451409 TI - The smallest active fragment of microtubule-associated protein 4 and its interaction with microtubules in phosphate buffer. AB - To analyze the interaction between microtubule-associated protein (MAP) 4 and microtubules physicochemically, a MAP4 active site fragment was designed for nuclear magnetic resonance (NMR) use. The fragment was bacterially expressed and purified to homogeneity. The buffer conditions for NMR were optimized to support microtubule assembly. The fragment was found to bind to microtubules under the optimized buffer conditions. PMID- 22451410 TI - Stereoselective synthesis of a protected form of (6R,7E,9S,10R,12Z)-6,9,10 trihydroxy-7,12-hexadecadienoic acid. AB - The protected stereoisomer of a trihydroxy unsaturated fatty acid, which could be employed as a potential nigricanoside alpha-chain building block, was synthesized by using Evans asymmetric alkylation, Sharpless kinetic resolution, and diastereoselective reduction as the key steps. PMID- 22451411 TI - Membrane topology and functional analysis of Methylobacillus sp. 12S genes epsF and epsG, encoding polysaccharide chain-length determining proteins. AB - The EpsF and EpsG of the methanol-assimilating bacterium Methylobacillus sp. 12S are involved in the synthesis of a high molecular weight exopolysaccharide, methanolan. These proteins share homology with chain-length determiners in other polysaccharide-producing bacteria. The N- and C-termini of EpsF were found to locate to the cytoplasm, and EpsF was predicted to have two transmembrane regions. EpsG showed both ATPase and autophosphorylation activities. PMID- 22451412 TI - Overexpression of the (R)-specific enoyl-CoA hydratase gene from Pseudomonas chlororaphis HS21 in Pseudomonas strains for the biosynthesis of polyhydroxyalkanoates of altered monomer composition. AB - The (R)-specific enoyl-CoA hydratase gene (phaJ(HS21)) from Pseudomonas chlororaphis HS21 was overexpressed in various Pseudomonas strains, alone and in combination with the polyhydroxyalkanoate synthase gene (phaC(HS21)), for the biosynthesis of polyhydroxyalkanoates (PHAs) of altered monomer composition. Recombinant Pseudomonas strains harboring phaC(HS21) and phaJ(HS21) generated saturated and unsaturated monomers of C12-C14 in their PHAs. In particular, the level of the 3-hydroxytetradecenoate monomer in recombinant P. chlororaphis HS21 increased by approximately 260%. PhaJ(HS21) is expected to be useful in the biosynthesis of PHAs consisting of unusual monomer units. PMID- 22451413 TI - Inhibitory effects of methylglyoxal on light-induced stomatal opening and inward K+ channel activity in Arabidopsis. AB - Methylglyoxal (MG) is a reactive aldehyde derived by glycolysis. In Arabidopsis, MG inhibited light-induced stomatal opening in a dose-dependent manner. It significantly inhibited both inward-rectifying potassium (K(in)) channels in guard-cell protoplasts and an Arabidopsis K(in) channel, KAT1, heterologously expressed in Xenopus oocytes. Thus it appears that MG inhibition of stomatal opening involves MG inhibition of K(+) influx into guard cells. PMID- 22451414 TI - Microbial fucoidan degradation by Luteolibacter algae H18 with deacetylation. AB - A bacterial strain that assimilates fucoidan from Cladosiphon okamuranus as sole carbon source was isolated as Luteolibacter algae H-18. It was found that it degraded fucoidan by intracellular enzymes, and that the degradation reactions were catalyzed by multiple enzymes. One enzyme, designated fraction B, was established to exhibit the deacetylation reaction of fucoidan. Other enzyme(s), designated fraction A, catalyzed the reaction(s) lowering the molecular weight of fucoidan. PMID- 22451415 TI - Overexpression of the transcription activator Msn2 enhances the fermentation ability of industrial baker's yeast in frozen dough. AB - We constructed a self-cloning diploid baker's yeast strain that overexpressed the transcription activator Msn2. It showed higher tolerance to freeze-thaw stress and higher intracellular trehalose level than observed in the wild-type strain. Overexpression of Msn2 also enhanced the fermentation ability of baker's yeast cells in frozen dough. Hence, Msn2-overexpressing baker's yeast should be useful in frozen-dough baking. PMID- 22451416 TI - Soy peptides enhance heterologous membrane protein productivity during the exponential growth phase of Saccharomyces cerevisiae. AB - In this study, the production of eight G protein-coupled receptors by Saccharomyces cerevisiae was compared using two types of media, one of which contained soy peptides and the other free amino acids. Yeast cell growth improved in the medium with soy peptides, and the expression levels of six of the receptors increased during the exponential phase by an average of 2.3-fold as against the free amino acid-based medium. The enhancement of protein expression by soy peptides can be explained by alleviation of metabolite stress due to amino acid source depletion caused by heterologous protein expression. PMID- 22451418 TI - Optimization of flow-sensitive alternating inversion recovery (FAIR) for perfusion functional MRI of rodent brain. AB - Arterial spin labeling (ASL) MRI provides a noninvasive method to image perfusion, and has been applied to map neural activation in the brain. Although pulsed labeling methods have been widely used in humans, continuous ASL with a dedicated neck labeling coil is still the preferred method in rodent brain functional MRI (fMRI) to maximize the sensitivity and allow multislice acquisition. However, the additional hardware is not readily available and hence its application is limited. In this study, flow-sensitive alternating inversion recovery (FAIR) pulsed ASL was optimized for fMRI of rat brain. A practical challenge of FAIR is the suboptimal global inversion by the transmit coil of limited dimensions, which results in low effective labeling. By using a large volume transmit coil and proper positioning to optimize the body coverage, the perfusion signal was increased by 38.3% compared with positioning the brain at the isocenter. An additional 53.3% gain in signal was achieved using optimized repetition and inversion times compared with a long TR. Under electrical stimulation to the forepaws, a perfusion activation signal change of 63.7 +/- 6.3% can be reliably detected in the primary somatosensory cortices using single slice or multislice echo planar imaging at 9.4 T. This demonstrates the potential of using pulsed ASL for multislice perfusion fMRI in functional and pharmacological applications in rat brain. PMID- 22451417 TI - Peripheral blood stem cells: phenotypic diversity and potential clinical applications. AB - A small proportion of cells in peripheral blood are actually pluripotent stem cells. These peripheral blood stem cells (PBSCs) are thought to be heterogeneous and could be exploited for a variety of clinical applications. The exact number of distinct populations is unknown. It is likely that individual PBSC populations detected by different experimental strategies are similar or overlapping but have been assigned different names. In this mini review, we divide PBSCs into seven groups: hematopoietic stem cells (HSCs), CD34- stem cells, CD14+ stem cells, mesenchymal stem cells (MSCs), very small embryonic-like (VSEL) stem cells, endothelial progenitor cells (EPCs), and other pluripotent stem cells. We review the major characteristics of these stem/progenitor cell populations and their potential applications in ophthalmology. PMID- 22451419 TI - Automated measurement of spontaneous pain-associated limb movement and drug efficacy evaluation in a rat model of neuropathic pain. AB - BACKGROUND: The withdrawal response elicited by a nociceptive stimulus, i.e., evoked pain measure, is commonly used as an efficacy endpoint in neuropathic pain animal models. It, however, has several limitations, which highlight the importance of examining spontaneous pain. The present study describes an automated method for measuring spontaneous pain behaviour in a rat model of neuropathic pain caused by chronic constriction injury (CCI) of sciatic nerve. METHODS: After CCI surgery, a small magnet was implanted into the operated limb. The rat was placed in a test chamber that was surrounded by wire coil. Limb movements, including lifting/guarding, flinching/shaking, licking and walking in the operated limb, caused changes in the electromagnetic field, including a change in voltage and transformed into a signal via an amplifier. RESULTS: CCI rats consistently showed more frequent limb movement than sham rats. There was no significant correlation between the frequency of spontaneous pain behaviour and the evoked pain symptoms. Treatment with duloxetine (30 mg/kg p.o.) and amitriptyline (30 and 100 mg/kg p.o.) significantly reduced this frequency. Pregabalin at 30 mg/kg p.o. tended to reduce the frequency, and diclofenac up to 10 mg/kg p.o. had no effect. CONCLUSION: A non-subjective automated method for measuring spontaneous pain behaviour in an animal model of neuropathic pain was established. It is expected that the current system will greatly enhance the analysis of spontaneous pain-related behaviour, which is a predominant symptom in patients with neuropathic pain. The current system may also be valuable in the screening of potential analgesic treatments. PMID- 22451420 TI - Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. AB - Deletion of Runx1 in adult mice produces a myeloproliferative phenotype. We now find that Runx1 gene deletion increases marrow monocyte while reducing granulocyte progenitors and that exogenous RUNX1 rescues granulopoiesis. Deletion of Runx1 reduces Cebpa mRNA in lineage-negative marrow cells and in granulocyte monocyte progenitors or common myeloid progenitors. Pu.1 mRNA is also decreased, but to a lesser extent. We also transduced marrow with dominant-inhibitory RUNX1a. As with Runx1 gene deletion, RUNX1a expands lineage-Sca-1+c-kit+ and myeloid cells, increased monocyte CFUs relative to granulocyte CFUs, and reduced Cebpa mRNA. Runx1 binds a conserved site in the Cebpa promoter and binds 4 sites in a conserved 450-bp region located at +37 kb; mutation of the enhancer sites reduces activity 6-fold in 32Dcl3 myeloid cells. Endogenous Runx1 binds the promoter and putative +37 kb enhancer as assessed by ChIP, and RUNX1-ER rapidly induces Cebpa mRNA in these cells, even in cycloheximide, consistent with direct gene regulation. The +37 kb region contains strong H3K4me1 histone modification and p300-binding, as often seen with enhancers. Finally, exogenous C/EBPalpha increases granulocyte relative to monocyte progenitors in Runx1-deleted marrow cells. Diminished CEBPA transcription and consequent impairment of myeloid differentiation may contribute to leukemic transformation in acute myeloid leukemia cases associated with decreased RUNX1 activity. PMID- 22451421 TI - Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. AB - Congenital factor XIII (FXIII) deficiency is a rare, autosomal-recessive disorder, with most patients having an A-subunit (FXIII-A) deficiency. Patients experience life-threatening bleeds, impaired wound healing, and spontaneous abortions. In many countries, only plasma or cryoprecipitate treatments are available, but these carry a risk for allergic reactions and infection with blood borne pathogens. The present study was a multinational, open-label, single-arm, phase 3 prophylaxis trial evaluating the efficacy and safety of a novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency. Forty-one patients >= 6 years of age (mean, 26.4; range, 7-60) with congenital FXIII-A subunit deficiency were enrolled. Throughout the rFXIII prophylaxis, only 5 bleeding episodes (all trauma induced) in 4 patients were treated with FXIII containing products. The crude mean bleeding rate was significantly lower than the historic bleeding rate (0.138 vs 2.91 bleeds/patient/year, respectively) for on-demand treatment. Transient, non-neutralizing, low-titer anti-rFXIII Abs developed in 4 patients, none of whom experienced allergic reactions, any bleeds requiring treatment, or changes in FXIII pharmacokinetics during the trial or follow-up. These non-neutralizing Abs declined below detection limits in all 4 patients despite further exposure to rFXIII or other FXIII-containing products. We conclude that rFXIII is safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency. This study is registered at http://www..clinicaltrials.gov as number NCT00713648. PMID- 22451422 TI - Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. AB - The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM. PMID- 22451423 TI - Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. AB - This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38 80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6% 41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704. PMID- 22451424 TI - Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). AB - Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation. PMID- 22451425 TI - The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice. AB - The miR-17-92 cluster and its 6 encoded miRNAs are frequently amplified and aberrantly expressed in various malignancies. This study demonstrates that retroviral-mediated miR-17-92 overexpression promotes expansion of multipotent hematopoietic progenitors in mice. Cell lines derived from these miR-17-92 overexpressing mice are capable of myeloid and lymphoid lineage differentiation, and recapitulate the normal lymphoid phenotype when transplanted to nonobese diabetic/severe combined immunodeficiency mice. However, overexpression of individual miRNAs from this locus, miR-19a or miR-92a, results in B-cell hyperplasia and erythroleukemia, respectively. Coexpression of another member of this cluster miR-17, with miR-92a, abrogates miR-92a-induced erythroleukemogenesis. Accordingly, we identified several novel miR-92a and miR 17 target genes regulating erythroid survival and proliferation, including p53. Expression of this critical target results in marked growth inhibition of miR-92a erythroleukemic cells. In both murine and human leukemias, p53 inactivation contributed to the selective overexpression of oncogenic miR-92a and miR-19a, and down-regulation of tumor-suppressive miR-17. This miR-17-92 expression signature was also detected in p53- B-cell chronic lymphocytic leukemia patients displaying an aggressive clinical phenotype. These results revealed that imbalanced miR-17 92 expression, also mediated by p53, directly transforms the hematopoietic compartment. Thus examination of such miRNA expression signatures should aid in the diagnosis and treatment of cancers displaying miR-17-92 gene amplification. PMID- 22451426 TI - Progression in smoldering Waldenstrom macroglobulinemia: long-term results. AB - The purpose of this study was to define the risk of progression and survival of patients with smoldering Waldenstrom macroglobulinemia (SWM). SWM is defined clinically as having a serum monoclonal IgM protein>=3 g/dL and/or>=10% bone marrow lymphoplasmacytic infiltration but no evidence of end-organ damage (anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly). We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of SWM between 1974 and 1995. During 285 cumulative person-years of follow-up of the 48 patients with SWM (median, 15.4 years), 34 (71%) progressed to symptomatic Waldenstrom macroglobulinemia (WM) requiring treatment, one to primary amyloidosis, and one to lymphoma (total, 75%). The cumulative probability of progression to symptomatic WM, amyloidosis, or lymphoma was 6% at 1 year, 39% at 3 years, 59% at 5 years, and 68% at 10 years. The major risk factors for progression were percentage of lymphoplasmacytic cells in the bone marrow, size of the serum M spike, and the hemoglobin value. Patients with SWM should be followed and not treated until symptomatic WM develops. Treatment on a clinical trial for those at greatest risk of progression should be considered. PMID- 22451427 TI - Antibacterial peptides "bacteriocins": an overview of their diverse characteristics and applications. AB - Bacteriocins are ribosomally synthesized antibacterial peptides produced by bacteria that inhibit the growth of similar or closely related bacterial strains. A number of bacteriocins from a wide variety of bacteria have been discovered, and their diverse structures have been reported. Growing evidence suggests that bacteriocins have diverse structures, modes of action, mechanisms of biosynthesis and self-immunity, and gene regulation. Bacteriocins are considered as an attractive compound in food and pharmaceutical industries to prevent food spoilage and pathogenic bacterial growth. Furthermore, elucidation of their biosynthesis has led to the use of bacteriocin-controlled gene-expression systems and the biosynthetic enzymes of lantibiotics, a class of bacteriocins, as tools to design novel peptides. In this review, we summarize and discuss currently known information on bacteriocins produced by Gram-positive bacteria and their applications. PMID- 22451428 TI - Capture of influenza viruses and prevention of their infection by coral mineral powder (sango mineral powder). AB - The anti-influenza virus activity of fossilized marine coral powder (sango mineral powder, SMP) was studied. SMP is composed in terms of mass of around 25 % of calcium and 10 % of magnesium, respectively, principally as dolomite (CaMg(CO(3))(2)) but not as calcium oxide (CaO) or magnesium oxide (MgO). By mixing the influenza virus with SMP, the infectivity of the virus substantially decreased and there was more than a 10(4) reduction on the 3rd d of infection. The antiviral effect was observed against all the type A and B strains of the influenza virus examined including the H1N1 2009 pandemic and H5N1 avian viruses. The surface structure of SMP was highly porous and the anti-influenza activity was explained by the adsorption of the viral particles onto its surface. The binding of viruses to SMP was strong and stable in the physiological condition, and the attached viruses detached only in the presence of a high concentration of phosphate. This was similar to the binding of protein to hydroxyapatite, suggesting an ionic interaction between SMP and the viral proteins. SMP maintained its activity to capture influenza viruses even after being immobilized on a non-woven textile. SMP would be useful as a practical anti-influenza tool especially in preparation for the next pandemic virus. PMID- 22451429 TI - The antimicrobial activity, toxicity and antimicrobial mechanism of a new type of tris(alkylphenyl)sulfonium. AB - The antimicrobial activity, toxicity and antimicrobial mechanism of a new type of tris(4-alkylphenyl)sulfonium which has sterically bulky alkyl substituents (bTAPS), were estimated and compared with those of other sulfoniums which we reported previously. Concerning tris {4-(iso-propyl)phenyl}sulfonium (bTAPS-iso3) and tris{4-(tert-butyl)phenyl}sulfonium (bTAPS-tert4), the antimicrobial activity of these compounds tended to be lower than both tri(n-alkyl)sulfoniums (TASs) and tris{4-(n-alkylphenyl)}sulfoniums (TAPSs) at similar ClogP values. However, the activities of tris{4-(cyclohexyl)phenyl}sulfonium (bTAPS-cyclo6) were clearly higher than those of TAS and were almost similar to those of TAPS at similar ClogP values. The mutagenicities of tested bTAPSs were judged to be all negative. Both the acute oral toxicity strength and the acute skin irritation/corrosion toxicity strength tended to follow the order of TAPSs > bTAPSs > TASs. However, only the acute skin irritation/corrosion toxicity strength of bTAPS-cyclo6 was almost as low as that of TAS which has a similar ClogP value to bTAPS-cyclo6. Because bTAPS-cyclo6 has both high antimicrobial activity and low toxicity, this compound might become to be an alternative antimicrobial compound to relatively hazardous antimicrobials which have been widely used in many fields. PMID- 22451430 TI - Antimicrobial action of a unique phosphorus-adsorbent additive for resin, and the mechanism of its antimicrobial effect. AB - We found that an additive for a resin, which was comprised of collagen and aluminum (Al), showed a strong and stable antibacterial effect against various bacterium under certain conditions. We tried to clarify its mechanism of action, and investigated optimum conditions for its effects. This additive (Al cross linked collagen powder: Al-COL) absorbed phosphorus in LB medium, gradually released aluminum in the phosphorus-reduced LB medium, and exhibited a bactericidal effect. Allophane was very suitable as the control subject, because it did not release Al in the medium, decreased phosphorus levels in the medium, and the phosphorus decrease led to a reduction in bacterial growth, though not to a bactericidal effect. On the other hand, the addition of Al to the phosphorus reduced solution led to a bactericidal effect. These results suggested that Al can exert a strong antibacterial effect in the absence of phosphorus. This phenomenon was confirmed using film-shaped test items mixed with Al-COL powder. Furthermore, the reduction of phosphorus also synergistically led to the enhancement of the antibacterial effect of silver (Ag). The phosphorous absorption promoted the antibacterial action of Al and Ag, and Al, which has seldom been used as an antimicrobial agent, is available as an antibacterial agent in the absence of phosphorus. PMID- 22451431 TI - Virucidal activity of alcohol-based hand rub disinfectants. AB - We investigated the virucidal activity of commercially available alcohol-based hand rub products against coxsackievirus A7, B5, feline calicivirus F9, and human adenovirus type 3, type 7, type 8 using susceptible cell lines, Vero cells, CRFK cells, and A549 cells. Fifteen tested hand rub products were ethanol (EtOH) for disinfection (Japanese Pharmacopoeia Grade), two EtOH-based products, one povidone iode-containing product, one alkyldiaminoethylglycine hydrochloride containing product, six benzalkonium chloride (BAK)-containing products, and four chlorohexidine gluconate (CHG)-containing products. Some active ingredients (BAK, benzetonium chloride, and CHG) were diluted with EtOH to make 0.5% and 0.2% solutions. Virus inactivation rates were calculated after contact with each hand rub product for 10 or 60 seconds. Of the hand rub products tested, only the povidone iode-based product showed antiviral activity superior to that of EtOH against all the strains. EtOH solutions of active ingredients (0.2% and 0.5%) also showed decreased antiviral activity. In conclusion, antiviral activity of all the commercially available alcohol-based hand rub products except that containing povidone idode was dependent on their active ingredients. The povidone idode-containing hand rub product kept its effectiveness even after the dilution with EtOH. Although alcohol-based hand rub products are convenient and suitable for the control of some microbes, they are not generally recommended for the control of viral infections. PMID- 22451432 TI - Bacterial diversity associated with the rotifer Brachionus plicatilis sp. complex determined by culture-dependent and -independent methods. AB - The bacterial communities associated with rotifers (Brachionus plicatilis sp. complex) and their culture water were determined using culture-dependent and independent methods (16S rRNA gene clone library). The bacterial communities determined by the culture-independent method were more diverse than those determined by the culture-dependent method. Although the culture-dependent method indicated the bacterial community of rotifers was relatively similar to that of the culture water, 16S rRNA gene clone library analyses revealed a great difference between the two microbiotas. Our results suggest that most bacteria associated with rotifers are not easily cultured using conventional methods, and that the microbiota of rotifers do not correspond with that of the culture water completely. PMID- 22451433 TI - Manifestation of carrier relaxation through the manifold of localized states in PCDTBT:PC60BM bulk heterojunction material: the role of PC84BM traps on the carrier transport. AB - The transport and relaxation of photogenerated carriers in a bulk heterojunction (BHJ) material made of a blend of PCDTBT and PC(60) BM are studied as a function of the concentration of PC(84)BM impurities. For low concentrations of PC(84)BM, the increasing activation energy with delay time indicates transport dominated by trap-limited carrier drift while the photocarriers relax through a manifold of disorder-induced localized states near the band edge. In the BHJ material with high concentration of PC(84)BM, transport is dominated by carrier hopping within the PC(84)BM impurity band. PMID- 22451434 TI - Lactate flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II. AB - Rapid exchange of metabolites between different cell types is crucial for energy homeostasis of the brain. Besides glucose, lactate is a major metabolite in the brain and is primarily produced in astrocytes. In the present study, we report that carbonic anhydrase 2 (CAII) enhances both influx and efflux of lactate in mouse cerebellar astrocytes. The augmentation of lactate transport is independent of the enzyme's catalytic activity, but requires direct binding of CAII to the C terminal of the monocarboxylate transporter MCT1, one of the major lactate/proton cotransporters in astrocytes and most tissues. By employing its intramolecular proton shuttle, CAII, bound to MCT1, can act as a 'proton collecting antenna' for the transporter, suppressing the formation of proton microdomains at the transporter-pore and thereby enhancing lactate flux. By this mechanism CAII could enhance transfer of lactate between astrocytes and neurons and thus provide the neurons with an increased supply of energy substrate. PMID- 22451435 TI - Distinct contributions by ionotropic purinoceptor subtypes to ATP-evoked calcium signals in mouse parotid acinar cells. AB - There is emerging consensus that P2X4 and P2X7 ionotropic purinoceptors (P2X4R and P2X7R) are critical players in regulating [Ca2+]i dynamics and fluid secretion in the salivary gland. In contrast, details regarding their compartmentalization and selective activation, contributions to the spatiotemporal properties of intracellular signals and roles in regulating protein exocytosis and ion channel activity have remained largely undefined. To address these concerns, we profiled mouse parotid acinar cells using live-cell imaging to follow the spatial and temporal features of ATP-evoked Ca2+ dynamics and exocytotic activity. Selective activation of P2X7Rs revealed an apical-to basal [Ca2+]i signal that initiated at the sub-luminal border and propagated with a wave speed estimated at 17.3 +/- 4.3 MUm s-1 (n =6). The evoked Ca2+ spike consisted of Ca2+ influx and Ca2+-induced Ca2+ release from intracellular Ca2+ channels. In contrast, selective activation of P2X4Rs induced a Ca2+ signal that initiated basally and propagated toward the lumen with a wave speed of 4.3 +/- 0.2 MUm s-1 (n =8) that was largely independent of intracellular Ca2+ channel blockade. Consistent with these observations, P2X7R expression was enriched in the sub-luminal regions of acinar cells while P2X4R appeared localized to basal areas. In addition, we showed that P2X4R and P2X7R activation evokes exocytosis in parotid acinar cells. Our studies also demonstrate that the P2X4R-mediated [Ca2+]i rise and subsequent protein exocytosis was enhanced by ivermectin (IVR). Thus, in addition to furthering our understanding of salivary gland physiology, this study identifies P2X4R as a potential target for treatment of salivary hypofunction diseases. PMID- 22451436 TI - Bleaching of mouse rods: microspectrophotometry and suction-electrode recording. AB - When a substantial fraction of rhodopsin in a rod photoreceptor is exposed to bright light, the rod is desensitized by a process known as bleaching adaptation. Experiments on isolated photoreceptors in amphibians have revealed many of the features of bleaching adaptation, but such experiments have not so far been possible in mammals. We now describe a method for making microspectrophotometric measurements of pigment concentration and suction-electrode recording of electrical responses over a wide range of bleaching exposures from isolated mouse rods or pieces of mouse retina. We show that if pigment is bleached at a low rate in the presence of bovine serum albumin (BSA), and intermediate photoproducts are allowed to decay, mouse rods are stably desensitized; subsequent treatment with exogenous 11-cis retinal results in pigment regeneration and substantial recovery of sensitivity to the dark-adapted value. Stably bleached wild-type (WT) rods show a decrease in circulating current and acceleration of the time course of decay, much as in steady background light; similar effects are seen in guanylyl cyclase-activating protein knockout (GCAPs(-/-)) rods, indicating that regulation of guanylyl cyclase is not necessary for at least a part of the adaptation produced by bleaching. Our experiments demonstrate that in mammalian rods, as in amphibian rods, steady-state desensitization after bleaching is produced by two components: (1) a reduction in the probability of photon absorption produced by a decrease in rhodopsin concentration; and (2) an equivalent background light whose intensity is proportional to the fraction of bleached pigment, and which adapts the rod like real background light. These two mechanisms together fully account for the 'log-linear' relationship in mammalian retina between sensitivity and per cent bleach, which can be measured in the steady state following exposure to bright light. Our methods will now make possible an examination of bleaching adaptation and pigment regeneration in mouse animal lines with mutations or other alterations in the proteins of transduction. PMID- 22451437 TI - Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. AB - Leucine is a nutrient regulator of muscle protein synthesis by activating mTOR and possibly other proteins in this pathway. The purpose of this study was to examine the role of leucine in the regulation of human myofibrillar protein synthesis (MPS). Twenty-four males completed an acute bout of unilateral resistance exercise prior to consuming either: a dose (25 g) of whey protein (WHEY); 6.25 g whey protein with total leucine equivalent to WHEY (LEU); or 6.25 g whey protein with total essential amino acids (EAAs) equivalent to WHEY for all EAAs except leucine (EAA-LEU). Measures of MPS, signalling through mTOR, and amino acid transporter (AAT) mRNA abundance were made while fasted (FAST), and following feeding under rested (FED) and post-exercise (EX-FED) conditions. Leucinaemia was equivalent between WHEY and LEU and elevated compared to EAA-LEU (P=0.001). MPS was increased above FAST at 1-3 h post-exercise in both FED (P <0.001) and EX-FED (P <0.001) conditions with no treatment effect.At 3-5 h, only WHEY remained significantly elevated above FAST in EX-FED(WHEY 184% vs. LEU 55% and EAA-LEU 35%; P =0.036). AAT mRNA abundance was increased above FAST after feeding and exercise with no effect of leucinaemia. In summary, a low dose of whey protein supplemented with leucine or all other essential amino acids was as effective as a complete protein (WHEY) in stimulating postprandial MPS; however only WHEY was able to sustain increased rates of MPS post-exercise and may therefore be most suited to increase exercise-induced muscle protein accretion. PMID- 22451438 TI - Mechanisms of VIP-induced inhibition of the lymphatic vessel pump. AB - Lymphatic vessels serve as a route by which interstitial fluid, protein and other macromolecules are returned to the blood circulation and immune cells and antigens gain access to lymph nodes. Lymph flow is an active process promoted by rhythmical contraction-relaxation events occurring in the collecting lymphatic vessels. This lymphatic pumping is an intrinsic property of the lymphatic muscles in the vessel wall and consequent to action potentials. Compromised lymphatic pumping may affect lymph and immune cell transport, an action which could be particularly detrimental during inflammation. Importantly, many inflammatory mediators alter lymphatic pumping. Vasoactive intestinal peptide (VIP) is a neuro and immuno-modulator thought to be released by nerve terminals and immune cells in close proximity to lymphatic vessels. We demonstrated the presence of the peptide in lymphatic vessels and in the lymph and examined the effects of VIP on mesenteric collecting lymphatic vessels of the guinea pig using pharmacological bioassays, intracellular microelectrode electrophysiology, immunofluorescence and quantitative real-time PCR. We showed that VIP alters lymphatic pumping by decreasing the frequency of lymphatic contractions and hyperpolarizing the lymphatic muscle membrane potential in a concentration-dependent manner. Our data further suggest that these effects are mainly mediated by stimulation of the VIP receptor VPAC2 located on the lymphatic muscle and the downstream involvement of protein kinase A (PKA) and ATP-sensitive K+ (KATP) channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes. PMID- 22451439 TI - Elevated uric acid, the metabolic syndrome and cardiovascular disease: cause, consequence, or just a not so innocent bystander? AB - For more than 200 years initially seen as a cause of gout, speaking in a politically correct 21st century term, a disease of the rich and very well nourished people, many experimental and epidemiological studies have associated increased levels of serum uric acid (UA) with the classical components of the metabolic syndrome (MS), type 2 diabetes, and cardiovascular disease [1]. This association with components of the MS is seen even in children and adolescents [2]. The topic of increased UA concentrations, its consequences or associations is getting more important nowadays due to the increments in the prevalence of obesity and the MS in both developed and developing countries. PMID- 22451440 TI - Early, intensified home-based exercise after total hip replacement--a pilot study. AB - BACKGROUND AND PURPOSE: Despite a successful surgical procedure, deficits in muscle strength and physical function are documented 1-2 years after total hip replacement (THR). There is a lack of evidence concerning which rehabilitation strategy is the most effective after THR. The purpose of this pilot study was to investigate the feasibility of an early-initiated intensified, home-based training regime and to form the basis of future studies with regard to exercises, outcome measures and power calculations. METHODS: The trial is a single-blinded, cluster-randomized controlled trial performed at an orthopaedic physiotherapy department in a public hospital in Denmark. A consecutive sample of 46 patients undergoing primary THR surgery for osteoarthritis between September 2008 and January 2009 was included. Forty-four patients completed the trial (96% follow up). Participants were randomly assigned to an intervention group (IG, n = 23) receiving 12 weeks of intensified exercises (e.g. rubber band resistance) or a control group (CG, n = 21) receiving standard rehabilitation exercises without external resistance. The outcome measurements were maximal gait speed, isometric hip abductor muscle strength, one-legged stance, health-related quality of life (EuroQol-5 Dimensions), patient satisfaction, and patient-evaluated function, stiffness and pain (Western and Ontario McMasters University Osteoarthritis Index). RESULTS: There were significant increases in both groups in all the measurements during the 12 weeks of exercises. All participants in the IG were satisfied or very satisfied with the exercises compared with 85% in the CG (P = 0.095). In the IG, four participants (17.4%) had difficulties when performing the intensified exercises at home. Hip abduction strength was significantly weaker in the leg operated compared with the leg not operated on after the intervention in both groups (P < 0.01). CONCLUSION: This pilot study indicates that the majority of THR patients tolerated early-initiated intensified exercises without additional pain and with high patient satisfaction. It seems that some of the patients need supervision to perform intensified exercises. PMID- 22451441 TI - High-performance energy-storage architectures from carbon nanotubes and nanocrystal building blocks. AB - High-performance energy-storage architectures are fabricated by forming conformal coatings of active nanocrystal building blocks on preformed carbon nanotube conductive scaffolds for lithium ion electrodes. This unique structure offers effective pathways for charge transport, high active-material loading, structure robustness, and flexibility. This general approach enables the fabrication of a new family of high-performance architectures for energy storage and many other applications. PMID- 22451442 TI - Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13 C NMR. AB - The activity of specific enzyme-catalyzed reactions may be detected in vivo by (13) C NMR of hyperpolarized (HP) substrates. The signals from HP substrates and products, acquired over time, have been fitted to a number of different mathematical models to determine fluxes, but these models have not been critically compared. In this study, two-pool and three-pool first-order models were constructed to measure flux through lactate dehydrogenase in isolated glioblastoma cells by NMR detection of lactate and pyruvate following the addition of HP [1-(13) C]pyruvate. Mass spectrometry (MS) was used to independently monitor (13) C enrichment in intra- and extracellular lactate. Six models were evaluated using time-dependent pyruvate C2 and lactate C1 HP NMR data acquired by the use of selective excitation pulses, plus (13) C enrichment data from intracellular and extracellular lactate measured by MS. A three-pool bidirectional model provided the most accurate description of pyruvate metabolism in these cells. With computed values for T(1) of pyruvate and lactate, as well as the effect of pulsing, the initial flux through lactate dehydrogenase was well determined by both the two-pool bidirectional and unidirectional models when only HP data were available. The three-pool model was necessary to fit the combined data from both MS and HP, but the simpler two-pool exchange model was sufficient to determine the (13) C lactate concentration when the lactate appearance was measured only by HP. PMID- 22451444 TI - The Turkish Society of Cardiology--towards the 50th anniversary: dedication to continuous progress in cardiovascular health through education, training and research. PMID- 22451446 TI - Off-pump coronary artery bypass grafting--the current state. AB - The optimal strategy for coronary revascularization remains controversial. Currently, most surgical revascularizations are performed with the use of cardiopulmonary bypass (ONCAB), yet over the past 20 years off-pump coronary artery bypass grafting (OPCAB) has been increasingly used because of the increased awareness of the deleterious effects of cardiopulmonary bypass (CPB) and aortic manipulation. Small, prospective, randomized controlled trials have lacked sufficient sample size to demonstrate differences in early and long-term outcomes. Larger observational studies that are better powered to statistically compare outcomes have shown more favorable in-hospital outcomes and equivalent long-term outcomes with OPCAB and ONCAB. The benefits of OPCAB techniques may be more apparent for patients at high risk for complications associated with CPB and aortic manipulation. Recent studies have demonstrated improved outcomes in higher risk patients undergoing OPCAB, as well as improved neurological outcomes. The purpose of this review is to outline the recent literature comparing OPCAB with ONCAB, and to demonstrate efficacy of OPCAB as a useful technique for coronary revascularization. PMID- 22451445 TI - Novel functional risk factors for the prediction of cardiovascular events in vulnerable patients following acute coronary syndrome. AB - Over the years there has been considerable improvement in the clinical outcomes of patients treated for acute coronary syndrome (ACS). Despite a significant reduction in acute mortality, a large percentage of patients post ACS continue to experience adverse cardiovascular (CV) events, with high long-term mortality rates and overall suboptimal medical management. Long-term risk prediction tools rely on traditional CV risk factors and are developed and validated in specific populations. Established CV risk factors, however, only explain half or fewer of CV events. These risk models may thus not be optimal in determining individual risk for long-term adverse outcomes or in helping to identify individual patients who do not respond to therapy. Identifying the specific plaque characteristics associated with increased likelihood for thrombotic complications and rapid progression has led to the concept of the vulnerable plaque. Recently, "vulnerable myocardium" (ie, myocardium that is prone to myocardial ischemia and fatal arrhythmia) has been shown to play an important role in outcome. Both vulnerable plaque and vulnerable myocardium are associated with functional vascular abnormalities, such as endothelial dysfunction, which are considered a key event in the initiation, progression and complications of coronary artery disease. Endothelial dysfunction may serve as an underlying unifying mechanism that would independently predict long-term outcome in patients with ACS undergoing revascularization. PMID- 22451447 TI - Catheter ablation of tachyarrhythmias from the aortic sinuses of Valsalva--when and how? AB - The aortic root is at the center of the heart. Each of the aortic sinuses of Valsalva, positioned at the base of the aortic root, is in contact with the atrial myocardium and/or ventricular myocardium at their bases, which enables mapping and ablating of some ventricular arrhythmias with an outflow tract origin and supraventricular tachycardias (ie, atrial tachycardia, accessory pathways) from the aortic sinuses of Valsalva. These arrhythmias have characteristic electrocardiographic findings associated with their origins, and almost all are difficult to ablate from an atrial or ventricular endocardial site. Site-specific and potential complications, such as a coronary artery occlusion or atrioventricular block, can occur with catheter ablation at the aortic sinuses of Valsalva. Therefore, accurate diagnosis and proper ablation at the aortic sinuses of Valsalva are required for a cure. This review describes the anatomic features of the aortic sinuses of Valsalva and focuses on the diagnosis and radiofrequency catheter ablation of arrhythmias that can be ablated from this site. (Circ J 2012; 76: 791-800). PMID- 22451448 TI - Qualitative plaque stabilization but not quantitative plaque regression. PMID- 22451450 TI - Superiority of long-acting to short-acting loop diuretics in the treatment of congestive heart failure. AB - BACKGROUND: Diuretics are the most prescribed drug in heart failure (HF) patients. However, clinical evidence about their long-term effects is lacking. The purpose of this study was to compare the therapeutic effects of furosemide and azosemide, a short- and long-acting loop diuretic, respectively, in patients with chronic heart failure (CHF). METHODS AND RESULTS: In this multicenter, prospective, randomized, open, blinded endpoint trial, we compared the effects of azosemide and furosemide in patients with CHF and New York Heart Association class II or III symptoms. 320 patients (160 patients in each group, mean age 71 years) were followed up for a minimum of 2 years. The primary endpoint was a composite of cardiovascular death or unplanned admission to hospital for congestive HF. During a median follow-up of 35.2 months, the primary endpoint occurred in 23 patients in the azosemide group and in 34 patients in the furosemide group (hazard ratio [HR], 0.55, 95% confidence interval [CI] 0.32 0.95: P=0.03). Among the secondary endpoints, unplanned admission to hospital for congestive HF or a need for modification of the treatment for HF were also reduced in the azosemide group compared with the furosemide group (HR, 0.60, 95%CI 0.36-0.99: P=0.048). CONCLUSIONS: Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admission to hospital for congestive HF. PMID- 22451449 TI - Reverse vessel remodeling but not coronary plaque regression could predict future cardiovascular events in ACS patients with intensive statin therapy--the extended JAPAN-ACS study. AB - BACKGROUND: The JAPAN-ACS study demonstrated that statins significantly reduced coronary plaque volume in patients with acute coronary syndrome (ACS). The clinical implications of plaque regression for clinical outcomes in ACS patients has not been established. The Extended JAPAN-ACS study was conducted to evaluate the relationship between coronary plaque regression and long-term clinical outcome, and to explore the factors associated with cardiovascular events. METHODS AND RESULTS: Patients with intravascular ultrasound (IVUS) data at both enrollment and follow-up in the JAPAN-ACS study were enrolled and observed for at least 3 years. Patients were divided into lesser and greater coronary plaque regression groups. The primary endpoint was defined as a composite of the following events: cardiovascular death, nonfatal myocardial infarction, nonfatal cerebral infarction, and unstable angina. The median value of the percent change in plaque volume, 18.0%, was used as a cutoff point. There were 4 primary events (3.4%) in the lesser regression group, and 2 events (1.7%) in the greater regression group (P=0.4). Cumulative secondary cardiovascular events did not differ between the 2 groups. Multivariate analysis identified the high-density lipoprotein cholesterol (HDL-C) at baseline and the % change of the external elastic membrane volume as independent risk factors of cardiovascular events. CONCLUSIONS: Coronary plaque regression induced by an intensive statin regimen did not predict future cardiovascular events in ACS patients. Rather, the baseline HDL-C level and reverse vessel remodeling might serve as predictors for cardiovascular events. PMID- 22451451 TI - Effects of valsartan on fibrinolysis in hypertensive patients with metabolic syndrome. AB - BACKGROUND: The purpose of this study was to analyze the effect of valsartan on abnormal adipocyte metabolism and prothrombotic state in hypertensive patients with metabolic syndrome (MetS). METHODS AND RESULTS: We conducted a multicenter, prospective, randomized, parallel-group controlled trial in 150 hypertensive patients with MetS. They were randomly assigned to receive either 80-160 mg valsartan per day (valsartan group, n=79) or other conventional treatment without a renin-angiotensin system (RAS) inhibitor (non-RAS inhibitor group, n=71). After 1 year, there were no significant differences between the 2 groups in the changes in systolic and diastolic blood pressures (valsartan: 153+/-15/86+/-15 to 138+/ 16/77+/-12 mmHg; non-RAS inhibitor: 150+/-14/82+/-15 to 137+/-15/76+/-10 mmHg). There was a significant difference in the change in the levels of plasminogen activator inhibitor-1 (PAI-1) between the 2 groups after 1 year (valsartan: 3.7+/ 3.2 ng/ml; non-RAS inhibitor: 5.8+/-3.3 ng/ml, P=0.04). There was no significant difference between groups in the change in the concentration of adiponectin after 1 year (valsartan: 0.3+/-0.4 ug/ml; non-RAS inhibitor: 0.9+/-0.4 ug/ml, P=0.22). The animal study showed aortic PAI-1 protein expression was reduced in double knockout mice of angiotensin II type 1a receptor and apolipoprotein E (apoE) compared with the apoE knockout mice. CONCLUSIONS: Valsartan reduced plasma PAI-1 levels compared to non-RAS inhibitor in hypertensive patients with MetS, which suggests it may be useful for improving fibrinolytic function. PMID- 22451452 TI - Distribution of first-detected atrial fibrillation patients without structural heart diseases in symptom classifications. AB - BACKGROUND: The characteristics and prognosis of patients with first-detected atrial fibrillation (AF) in Japan remain unclear. METHODS AND RESULTS: First detected AF patients without structural heart disease (n=289) were reviewed with regard to 2 symptom classifications (CCS-SAF and EHRA). In both classifications, asymptomatic patients comprised ~40% of the patients, and patients in the most symptomatic class (~6%) had peculiar characteristics and poor prognosis. In other symptomatic classes, symptoms affected the treatment strategy without a significant difference in the patients' backgrounds and prognosis. CONCLUSIONS: This is the first report to describe the distribution, characteristics and outcomes of first-detected AF patients according to symptom classifications. PMID- 22451453 TI - Conducting metallopolymers as precursors to fabricate palladium nanoparticle/polymer hybrids for oxygen reduction. AB - The novel conducting metallopolymer [N,N'-((2,2'-dimethyl)propyl)bis(5-(2,2' bithiophene-5-yl)salcylideniminato-palladium(II)](n) prepared by electropolymerization provides a polymer matrix in which the palladium metal centers are evenly distributed. The metal centers embedded directly in the conducting metallopolymer backbone serve as seed points for size-controlled palladium nanoparticle (NP) growth of 3.8 to 4.9 nm NPs within the conducting metallopolymer film. The palladium NP/conducting metallopolymer hybrid material has demonstrated electrocatalytic behavior toward oxygen reduction with peak current densities around 400 MUA/cm(2) in acidic aqueous conditions. These results demonstrate a promising new method for the production of electrocatalytically active hybrid materials. PMID- 22451454 TI - Comments on 'Application of an adaptive design to a randomized phase II selection trial in gastric cancer: a report of the study design' by Satoshi Morita and Junichi Sakamoto. Pharmaceutical Statistics. AB - In this commentary, we show that the treatment selection probabilities in Morita and Sakamoto [1] could be different if safety information is considered. PMID- 22451455 TI - Endovenous laser ablation with and without high ligation compared with high ligation and stripping in the treatment of great saphenous varicose veins: initial results of a multicentre randomized controlled trial. AB - OBJECTIVES: To compare reflux recurrences at the saphenofemoral junction after endovenous laser ablation (EVLA) with or without high ligation with high ligation and stripping (HL/ST) of the great saphenous vein (GSV) in patients with varicosity of the GSV. Design Multicentre, randomized, three-arm, parallel trial. Material and Methods Patients with varicosity of the GSV were randomized to one of three groups: HL/ST, laser ablation (980 nm) or a combination of laser ablation with high ligation (EVLA/HL). Patients were examined clinically and by ultrasound pre- and postoperatively and after two months. The primary endpoint of this ongoing study is the inguinal venous reflux (IVR) in the proximal section of the GSV after two years. We present data after two months. Secondary endpoints include postoperative ecchymosis, pain or discomfort, saphenous syndrome. Groups were compared by chi-squared test. RESULTS: A total of 449 patients were randomized; mean age 48 years and 71.2% were women. Postoperative ecchymosis developed among 69.2% in the HL/ST group, in 50.4% of the EVLA group and in 50.3% of the EVLA/HL group (P = 0.0007). Postoperative pain after one day occurred in 32.7% in the HL/ST group. Discomfort occurred after surgery in 37.3% in the EVLA group, and in 50.0% in the EVLA/HL group (P = 0.0069). Early postoperative nervus saphenous syndrome developed in 0.6% in the HL/ST group, in 3.7% in the EVLA group and in 6.1% in the EVLA/HL group (P = 0.0341). After two months, IVR persisted in 38 cases (8.5%) in the laser group, in 10 (2.2%) in the EVLA/HL group and none in the HL/ST group (P = 0.6800). CONCLUSIONS: After two months IVR was more often seen in both EVLA groups compared with the HL/ST group. There were significantly more postoperative ecchymosis in the HL/ST. Postoperative pain occurred significantly more often in the EVLA/HL group. Peri- and postoperative data showed significant differences between the three groups. For definitive results concerning the primary endpoint of IVR the later follow-up has to be waited for. PMID- 22451456 TI - Foot-sparing postoperative compression bandage: a possible alternative to the traditional bandage. AB - OBJECTIVES: To verify whether a foot-sparing bandage is effective for patients who have undergone varicose vein surgery, being in the C2 class, having a normal deep venous system and actively walking. METHODS: Ninety consecutive lower legs meeting the inclusion criteria underwent treatment with an inelastic foot-sparing bandage. Patient's satisfaction, efficacy and local effects were systematically documented. RESULTS: The bandage was well tolerated and highly effective. Four of the first 20 cases experienced a slight morning oedema of the foot, which disappeared while walking. Thus, in the remaining cases we covered the foot and distal limb with a custom short tubular-shaped 'sock' providing 10 mmHg compression, only during the first 24 hours. CONCLUSION: The foot-sparing inelastic bandage is effective, cheap and tolerated by well-selected patients who have undergone varicose vein surgery. PMID- 22451457 TI - Compression hosiery for occupational leg symptoms and leg volume: a randomized crossover trial in a cohort of hairdressers. AB - OBJECTIVE: Occupational leg symptoms are highly prevalent in the general population and impair the psychic state of health. We investigated hairdressers, a cohort exposed to prolonged standing during work, in a randomized crossover trial. We hypothesized that hairdressers wearing low-strength compression hosiery would benefit from less leg volume increase and discomfort. METHODS: One hundred and eight hairdressers were randomized to wear medical compression stockings (MCS; 15-20 mmHg) in a crossover study. The effect of MCS on symptoms and on lower leg volume was compared with no compression treatment. Symptoms were assessed with a comprehensive questionnaire, categorized using factor analysis with varimax rotation and correlated with leg volume changes. RESULTS: Wearing MCS reduced the symptom score for pain and feelings of swelling (range 0-4) by an average of 0.22 (12%, P < 0.001). Sleep disturbance, feeling of unattractive legs and depressiveness improved with MCS compared with no MCS. Subjects initially obliged to refrain from wearing stockings showed a significant decrease of pain and feelings of swelling as well (by 0.10 [6%], P = 0.015). Wearing MCS was associated with a decrease of lower leg volume by an average of 19 mL (P < 0.001), with preference in older hairdressers (P < 0.001). The effects of wearing MCS on symptoms and on leg volume were not correlated with each other. CONCLUSIONS: Individuals working in a standing profession experience leg pain, feelings of swelling, heaviness and various other disturbing feelings. These symptoms can be alleviated by wearing low-strength MCS. PMID- 22451458 TI - Primary tibial vein aneurysm: a source of pulmonary emboli. AB - OBJECTIVE: To describe a case of a rare type of venous aneurysm (posterior tibial) with associated pulmonary embolus. We will discuss options and considerations germane to the diagnostic evaluation and possible interventions for this challenging clinical scenario. METHODS: Case presentation and literature review. RESULTS: A 36-year-old man presented to an outside hospital with a three day history of left calf pain, acute shortness of breath and syncope elicited by exercise. Work-up demonstrated a pulmonary embolus and a posterior tibial venous aneurysm with mural thrombus. The patient presented to us 18 months later with persistent calf pain seeking an alternative to recommendations of lifelong anticoagulation. The patient was treated with surgical resection of the venous aneurysm with subsequent discontinuation of his anticoagulation. There were no surgical or thrombotic complications of this treatment course and the patient's discomfort improved. CONCLUSION: Primary aneurysms of the tibial veins as a cause of pulmonary emboli are rare. A review of the literature suggests that anticoagulation alone does not provide effective amelioration of thromboembolic risk from lower extremity venous aneurysms. We have reported a case of successful surgical treatment of a posterior tibial venous aneurysm and recommend that surgical correction be strongly considered for accessible venous aneurysms. PMID- 22451459 TI - Prevalence, risk and aggravating factors of chronic venous disease: an epidemiological survey of the general population of Greece. AB - INTRODUCTION: Chronic venous disease (CVD) is a common disease all over the world, mainly in Western Europe and the USA. AIM: To evaluate the prevalence of CVD in the Greek general population and the characteristics of CVD. MATERIALS AND METHODS: The study sample included 1500 individuals, 15-64 years of age, who were citizens of Athens, Thessaloniki, or one of five Greek cities with more than 10,000 in the population. The sample was selected by a stratified, multistage, random sampling procedure based on the Greek Census 2001. Questionnaires were completed for each individual by personal interview. RESULTS: From 1500 individuals, 224 (14.9%) had symptoms and/or signs of CVD, 9.6% were men and 20.1% were women. The highest percentage of presenting CVD symptoms was among 45 54-year-olds (23.4%) and 55-64-year-olds (27%). The symptoms that were mostly mentioned among sufferers were 58% achy legs, 37.4% swollen legs and 25.3% heavy legs, whereas the frequent signs were broken capillaries - telangiectasia (19.2%) and varicose veins (14.8%). About 62.9% with CVD had an obese body mass index (BMI > 25). The prevalence of CVD in patients with prolonged standing hours at work (4+ hours) was 20.8%. The symptoms of CVD were worse during the summer period only in 26.8% of the patients whereas in 50.8% during all the year. Regarding quality of life, more than 40% of the patients had either health or cosmetic problems. Sufferers mentioned that they took first advice from physicians (28%), or from friends and relatives (27%) or from pharmacists (26%). CONCLUSION: This is a real whole-population study of Greece - a Mediterranean country that provides important and remarkable data on the epidemiology of CVD and highlights that we need improvement of relations within the triangle constituted by physicians, patients and disease. PMID- 22451460 TI - Catheter-directed foam sclerotherapy for insufficiency of the great saphenous vein: occlusion rates and patient satisfaction after one year. AB - OBJECTIVES: This study aims to describe a technique for catheter-directed foam sclerotherapy (CDS) of great saphenous vein (GSV) insufficiency and report occlusion rate and patient satisfaction after a single treatment. METHODS: About 100 patients were included. The GSV was accessed at knee level. With the method of Tessari 10 mL sclerosant foam was made (2 mL 3% polidocanol and 8 mL air) and delivered along the GSV while the catheter was withdrawn. At two weeks and at one year after treatment the patients were evaluated. RESULTS: CDS was successfully performed in 94 of the 100 patients. After one year, 84% of the patients were satisfied. Seventy percent of the GSV were completely occluded, 14% were partly occluded and 15% were recanalized. No serious side-effects occurred. CONCLUSIONS: CDS is safe. Patient satisfaction is very satisfying and the occlusion rate is promising after a single treatment. Repeated treatments and technical development may achieve higher occlusion rates. PMID- 22451461 TI - Using ICD-9 codes to establish prevalence of malformations in newborn infants. AB - BACKGROUND The International Classification of Disease (ICD-9) codes are used to identify, after discharge, diagnoses from a review of the medical record and provide the basis for reimbursement. These codes have been used to establish the prevalence of malformations and to assess potential teratogens. We have analyzed the accuracy of codes 740 to 759.9 to identify newborn infants with malformations. METHODS: The diagnoses and ICD-9 codes in the medical records of 1000 consecutive live-born and stillborn infants were compared to the information provided in the medical records of those infants. RESULTS: One hundred twenty seven of the 1000 infants had ICD-9 codes between 740 and 759.9. 67 (52.8%) of the codes identified minor features, such as birth marks and minor anomalies. Twenty-three (18.1%) of the codes designated a malformation and were correct. Two types of errors were identified in another 33 infants (26%) whose codes designated a malformation: either the pediatricians' notes described a less severe finding or the fact that there was no such abnormality. In addition, four malformed infants were missed in pregnancies that were either terminated electively or stillborn, as they did not have medical records. CONCLUSION: The ICD-9 codes 740 to 759.9 identified accurately some infants (18%) with malformations, but identified incorrectly many others. The accuracy of the coding for identifying malformations would be improved if (1) the findings of the examining pediatricians were considered; (2) normal features of prematurity, such as patent foramen ovale and patent ductus arteriosus, were not considered malformations; (3) minor physical features were not assigned ICD-9 codes within the 740 to 759.9 sequence. PMID- 22451462 TI - [Cadherin-induced remodeling of the synaptic junction]. PMID- 22451463 TI - [Reelin dysfunction in neuropsychiatric diseases and its potential as a drug target]. PMID- 22451464 TI - [Development of NSAID-induced small intestinal lesions - pathogenic role of COX inhibition]. PMID- 22451465 TI - [Future prospects for the relationship between pharmacological studies and good laboratory practice]. PMID- 22451466 TI - [Development of unapproved drugs-- current status in Japan]. PMID- 22451467 TI - [Preclinical and clinical data of the synthetic Xa inhibitor fondaparinux (Arixtra((r)))]. PMID- 22451468 TI - The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. AB - This review focuses on cardiovascular protective effects of insulin-like growth factor (IGF)-1, provides a landscape of molecular mechanisms involved in cardiovascular alterations in patients and animal models with congenital and adult-onset IGF-1 deficiency, and explores the link between age-related IGF-1 deficiency and the molecular, cellular, and functional changes that occur in the cardiovascular system during aging. Microvascular protection conferred by endocrine and paracrine IGF-1 signaling, its implications for the pathophysiology of cardiac failure and vascular cognitive impairment, and the role of impaired cellular stress resistance in cardiovascular aging considered here are based on emerging knowledge of the effects of IGF-1 on Nrf2-driven antioxidant response. PMID- 22451469 TI - Fatigability in osteoarthritis: effects of an activity bout on subsequent symptoms and activity. AB - BACKGROUND: Older adults with osteoarthritis (OA) are more likely to experience increased fatigue following bouts of physical activity than those without OA. The highly "fatigable" nature of this population is problematic as it has been linked to OA severity and decreased function. This study examined the effects of engaging in standardized lab-based physical tasks on subsequent fatigue, pain, and activity in older adults with OA. METHODS: Thirty-five older adults with OA performed lab-based tasks (sweeping, grocery shopping, and walking) in 15-minute circuits until they felt too fatigued to continue. Fatigue and pain were self reported (0-10 scale) following each circuit and at set intervals during a 4-day baseline (pretask) and a 5-day posttask home period. Activity was tracked via wrist-worn accelerometer. Multilevel modeling was used to examine levels and patterns of fatigue, pain, and activity across the study period. RESULTS: The lab based tasks altered subsequent levels and patterns of fatigue and activity but had no effects on pain. Compared with baseline, on the day of the lab-based tasks, fatigue was higher and more stable, and activity was significantly lower and dropped steadily toward evening. Activity returned to baseline levels and patterns by the day following the lab-based tasks while fatigue was lower for 3 days following task performance. CONCLUSIONS: Among older adults with OA, a bout of standardized physical activity resulted in increased fatigue and reduced activity, but effects were short-lived. Future studies will need to identify factors that differentiate people who are particularly fatigable in order to target interventions. PMID- 22451470 TI - Total and abdominal adiposity are associated with inflammation in older adults using a factor analysis approach. AB - BACKGROUND: Obesity-related increases in multiple inflammatory markers may contribute to the persistent subclinical inflammation common with advancing age. However, it is unclear if a specific combination of markers reflects the underlying inflammatory state. We used factor analysis to identify inflammatory factor(s) and examine their associations with adiposity in older adults at risk for disability. METHODS: Adiponectin, CRP, IL-1ra, IL-1sRII, IL-2sRalpha, IL-6, IL-6sR, IL-8, IL-15, sTNFRI, sTNFRII, and TNF-alpha were measured in 179 participants from the Lifestyle Interventions and Independence for Elders Pilot (Mean +/- SD age 77 +/- 4 years, 76% white, 70% women). Body mass index, waist circumference, and total fat mass were assessed by anthropometry and dual-energy x-ray absorptiometry. RESULTS: IL-2sRalpha, sTNFRI, and sTNFRII loaded highest on the first factor (factor 1). CRP, IL-1ra, and IL-6 loaded highest on the second factor (factor 2). Factor 2, but not factor 1, was positively associated with 1 SD increments in waist circumference (beta = 0.160 +/- 0.057, p = .005), body mass index (beta = 0.132 +/- 0.053, p = .01), and total fat mass (beta = 0.126 +/ 0.053, p = .02) after adjusting for age, gender, race/ethnicity, site, smoking, anti-inflammatory medications, comorbidity index, health-related quality of life, and physical function. These associations remained significant after further adjustment for grip strength, but only waist circumference remained associated with inflammation after adjusting for total lean mass. There were no significant interactions between adiposity and muscle mass or strength for either factor. CONCLUSIONS: Greater total and abdominal adiposity are associated with higher levels of an inflammatory factor related to CRP, IL-1ra, and IL-6 in older adults, which may provide a clinically useful measure of inflammation in this population. PMID- 22451471 TI - Age-related increase in food spilling by laboratory mice may lead to significant overestimation of actual food consumption: implications for studies on dietary restriction, metabolism, and dose calculations. AB - It is widely accepted that food consumption in humans declines with advanced age; however, data from mice remain controversial. Based on our previous observation that mice spill a considerable amount of food while eating, we hypothesized that increased food spillage in old mice masks actual food intake. To investigate whether mice exhibit age-associated declines in food consumption, we evaluated the actual food consumption of C57BL/6 mice at various ages by measuring both the amount of food in the food receptacle and the amount dropped to the cage bottom during feeding. We found that old mice dropped significantly more food (36% +/- 8%) than young mice (18% +/- 5%), which led to overestimations of food consumption, particularly in old mice. Although actual food consumption decreased in very old mice, food intake per body weight did not significantly change. These findings suggest that caution should be taken to accurately quantify food consumption by aged animals. PMID- 22451472 TI - Expression and function of multidrug resistance protein 1 and multidrug resistance-associated protein 1 in lung dendritic cells from aging mice. AB - Multidrug resistance protein 1 and multidrug resistance-associated protein 1 are transporters that efflux diverse xenobiotics from cells. We investigated changes in the expression and activity of multidrug resistance protein 1 and multidrug resistance-associated protein 1 in highly purified lung dendritic cells (LDCs) during aging using magnetic and flow cytometric cell sorting. Multidrug resistance protein 1 blockade by the specific inhibitor reduced the percentage of rhodamine 123(low) cells in LDCs from aged mice (54.8% +/- 2.6% to 13.2% +/- 2.5%, p < .01). The difference in the proportions of rhodamine 123(low) cells in aged LDCs was more apparent than that in LDCs from young mice (p < .05). The multidrug resistance-associated protein 1-specific inhibitor reduced the percentage of Fluo-3(low) cells in aged LDCs (60.8% +/- 5.3% to 25.8% +/- 7.5%, p < .01). The difference in the proportions of Fluo-3(low) cells in aged LDCs was smaller than that in young LDCs (p < .05). These data showed that LDCs from aged mice exhibited multidrug resistance protein 1- and multidrug resistance associated protein 1-mediated efflux and that the age-associated changes differed according to transporters. PMID- 22451473 TI - Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. AB - The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. We report here on the results of lifelong treatment of mice, beginning at 4 months of age, with each of five agents, that is, green tea extract (GTE), curcumin, oxaloacetic acid, medium-chain triglyceride oil, and resveratrol, on the life span of genetically heterogeneous mice. Each agent was administered beginning at 4 months of age. None of these five agents had a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested, although a secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only. PMID- 22451475 TI - Structure of the CENP-A nucleosome and its implications for centromeric chromatin architecture. AB - Centromeres are dictated by the epigenetic inheritance of the centromeric nucleosome containing the centromere-specific histone H3 variant, CENP-A. The structure of the CENP-A nucleosome has been considered to be the fundamental architecture of the centromeric chromatin. Controversy exists in the literature regarding the CENP-A nucleosome structures, with octasome, hemisome, compact octasome, hexasome, and tetrasome models being reported. Some of these CENP-A nucleosome models may correspond to transient intermediates for the assembly of the mature CENP-A nucleosome; however, their significances are still unclear. Therefore, the structure of the mature CENP-A nucleosome has been eagerly awaited. We reconstituted the human CENP-A nucleosome with its cognate centromeric DNA fragment, and determined its crystal structure. In this review, we describe the structure and the physical properties of the CENP-A nucleosome, and discuss their implications for centromeric chromatin architecture. PMID- 22451474 TI - The role of androgens and estrogens on healthy aging and longevity. AB - Aging is associated with a loss of sex hormone in both men (andropause) and women (menopause). In men, reductions in testosterone can trigger declines in muscle mass, bone mass, and in physical function. In women, the impact of the loss of sex hormones, such as estradiol, on bone is well elucidated, but evidence is limited on whether the loss of estradiol negatively affects muscle mass and physical function. However, deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons. Thus, consideration should be given as to whether targeted hormone replacement therapies may prove effective at treating clinical conditions, such as age related sarcopenia, cancer cachexia, and/or acute or chronic illnesses. If initiated carefully in the appropriate clinical population, hormone replacement therapies in men and women may prevent and reverse muscle and bone loss and functional declines and perhaps promote healthy aging and longevity. PMID- 22451476 TI - The Bacillus subtilis essential gene dgkB is dispensable in mutants with defective lipoteichoic acid synthesis. AB - The dgkB gene is essential for the growth of Bacillus subtilis. It encodes a diacylglycerol (DG) kinase that converts DG to phosphatidic acid to reintroduce it into the phospholipid synthesis pathway. Repression of the dgkB gene placed under a regulatable promoter causes accumulation of DG and leads to lethality. DG is formed as a byproduct of the synthesis of lipoteichoic acid (LTA), a polyanionic component of the cell envelope. B. subtilis synthesizes LTA by polymerizing the glycerophosphate moiety of phosphatidylglycerol (PG) onto a glucolipid membrane anchor, and releasing the DG moiety of PG. B. subtilis has four genes homologous to Staphylococcus aureus ltaS, which encodes LTA synthase. Disruption of either or both of two genes, yflE and yfnI, whose products show higher homology with S. aureus LtaS among the four homologues, suppressed the lethality caused by dgkB repression. In cells with dgkB repression, DG was accumulated to 43 +/- 3% of total lipids, about three times the content of wild type cells (13 +/- 1%). Disruption of yfnI in the dgkB-repressed cells reduced the DG content to 15 +/- 2%, but yflE-disruption did not (42 +/- 1%); this was probably due to efficient LTA synthesis by YfnI in the yflE-disrupted cells. Further introduction of a disrupted allele of ugtP, encoding glucolipid synthase that consumes DG as a substrate, partially lowered the colony forming capacity in strains with yflE-disruption. A disrupted dgkB allele was successfully introduced into strains disrupted for either or both of yflE and yfnI, indicating that the essential gene dgkB is dispensable in mutants defective in LTA synthesis. PMID- 22451477 TI - Effectiveness of physical activity promotion based in primary care: systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVES: To determine whether trials of physical activity promotion based in primary care show sustained effects on physical activity or fitness in sedentary adults, and whether exercise referral interventions are more effective than other interventions. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, CINAHL, PsycINFO, EMBASE, SPORTDiscus, Centre for Reviews and Dissemination, the Cochrane Library, and article reference lists. REVIEW METHODS: Review of randomised controlled trials of physical activity promotion in sedentary adults recruited in primary care, with minimum follow-up of 12 months, reporting physical activity or fitness (or both) as outcomes, and using intention to treat analyses. Two reviewers independently assessed studies for inclusion, appraised risk of bias, and extracted data. Pooled effect sizes were calculated using a random effects model. RESULTS: We included 15 trials (n=8745). Most interventions took place in primary care, included health professionals in delivery, and involved advice or counselling given face to face or by phone (or both) on multiple occasions. Only three trials investigated exercise referral. In 13 trials presenting self reported physical activity, we saw small to medium positive intervention effects at 12 months (odds ratio 1.42, 95% confidence interval 1.17 to 1.73; standardised mean difference 0.25, 0.11 to 0.38). The number needed to treat with an intervention for one additional sedentary adult to meet internationally recommended levels of activity at 12 months was 12 (7 to 33). In four trials reporting cardiorespiratory fitness, a medium positive effect at 12 months was non-significant (standardised mean difference 0.51, -0.18 to 1.20). Three trials of exercise referral found small non-significant effects on self reported physical activity at 12 months (odds ratio 1.38; 0.98 to 1.95; standardised mean difference 0.20, -0.21 to 0.61). CONCLUSIONS: Promotion of physical activity to sedentary adults recruited in primary care significantly increases physical activity levels at 12 months, as measured by self report. We found insufficient evidence to recommend exercise referral schemes over advice or counselling interventions. Primary care commissioners should consider these findings while awaiting further trial evaluation of exercise referral schemes and other primary care interventions, with longer follow-up and use of objective measures of outcome. PMID- 22451478 TI - Investigating the pregnant woman exposed to a child with a rash. PMID- 22451479 TI - Health secretary is accused of demanding "politically driven" raids on abortion clinics. PMID- 22451480 TI - France and Japan increase support for Global Fund; a new leader is appointed. PMID- 22451481 TI - Does context matter in evaluations of stigmatized individuals? An fMRI study. AB - The manner in which disparate affective responses shape attitudes toward other individuals has received a great deal of attention in neuroscience research. However, the malleability of these affective responses remains largely unexplored. The perceived controllability of a stigma (whether or not the bearer of the stigma is perceived as being responsible for his or her condition) has been found to polarize behavioral affective responses to that stigma. The current study uses functional magnetic resonance imaging to identify the neural correlates underlying the evaluation of stigmatized individuals (people who are homeless) when perceptions of the controllability of their condition are altered. Results demonstrated that perceivers engaged neural networks implicated in inferring intentionality (e.g. the medial prefrontal cortex) when they evaluated a homeless individual who was described as being responsible for becoming homeless. Conversely, neural networks associated with resolving strong affective responses (e.g. insula) were engaged when evaluating a homeless individual who was described as not being responsible for becoming homeless. PMID- 22451482 TI - Self-determined, but not non-self-determined, motivation predicts activations in the anterior insular cortex: an fMRI study of personal agency. AB - Neuroscientific studies on agency focus rather exclusively on the notion of who initiates and regulates actions, not on the notion of why the person does. The present study focused on the latter to investigate two different reasons underlying personal agency. Using event-related functional magnetic resonance imaging, we scanned 16 healthy human subjects while they imagined the enactment of volitional, agentic behavior on the same task but either for a self-determined and intrinsically motivated reason or for a non-self-determined and extrinsically motivated reason. Results showed that the anterior insular cortex (AIC), known to be related to the sense of agency, was more activated during self-determined behavior while the angular gyrus, known to be related to the sense of loss of agency, was more activated during non-self-determined behavior. Furthermore, AIC activities during self-determined behavior correlated highly with participants' self-reported intrinsic satisfactions. We conclude that self-determined behavior is more agentic than is non-self-determined behavior and that personal agency arises only during self-determined, intrinsically motivated action. PMID- 22451483 TI - Both younger and older adults have difficulty updating emotional memories. AB - OBJECTIVE: The main purpose of the study was to examine whether emotion impairs associative memory for previously seen items in older adults, as previously observed in younger adults. METHOD: Thirty-two younger adults and 32 older adults participated. The experiment consisted of 2 parts. In Part 1, participants learned picture-object associations for negative and neutral pictures. In Part 2, they learned picture-location associations for negative and neutral pictures; half of these pictures were seen in Part 1 whereas the other half were new. The dependent measure was how many locations of negative versus neutral items in the new versus old categories participants remembered in Part 2. RESULTS: Both groups had more difficulty learning the locations of old negative pictures than of new negative pictures. However, this pattern was not observed for neutral items. DISCUSSION: Despite the fact that older adults showed overall decline in associative memory, the impairing effect of emotion on updating associative memory was similar between younger and older adults. PMID- 22451484 TI - Associations of openness and conscientiousness with walking speed decline: findings from the Health, Aging, and Body Composition Study. AB - OBJECTIVES: The objective of this study was to explore the associations between openness to experience and conscientiousness, two dimensions of the five-factor model of personality, and usual gait speed and gait speed decline. METHOD: Baseline analyses were conducted on 907 men and women aged 71-82 years participating in the Cognitive Vitality substudy of the Health, Aging, and Body Composition study. The longitudinal analytic sample consisted of 740 participants who had walking speed assessed 3 years later. RESULTS: At baseline, gait speed averaged 1.2 m/s, and an average decline of 5% over the 3-year follow-up period was observed. Higher conscientiousness was associated with faster initial walking speed and less decline in walking speed over the study period, independent of sociodemographic characteristics. Lifestyle factors and disease status appear to play a role in the baseline but not the longitudinal association between conscientiousness and gait speed. Openness was not associated with either initial or decline in gait speed. DISCUSSION: These findings extend the body of evidence suggesting a protective association between conscientiousness and physical function to performance-based assessment of gait speed. Future studies are needed to confirm these associations and to explore mechanisms that underlie the conscientiousness mobility connection in aging adults. PMID- 22451485 TI - Inhibition of Mcl-1 promotes senescence in cancer cells: implications for preventing tumor growth and chemotherapy resistance. AB - Although senescence in oncogenesis has been widely studied, little is known regarding the role of this process in chemotherapy resistance. Thus, from the standpoint of enhancing and improving cancer therapy, a better understanding of the molecular machinery involved in chemotherapy-related senescence is paramount. We show for the first time that Mcl-1, a Bcl-2 family member, plays an important role in preventing chemotherapy-induced senescence (CIS). Overexpression of Mcl-1 in p53+ cell lines inhibits CIS. Conversely, downregulation of Mcl-1 makes cells sensitive to CIS. Surprisingly, downregulation of Mcl-1 in p53- cells restored CIS to similar levels as p53+ cells. In all cases where senescence can be induced, we observed increased p21 expression. Moreover, we show that the domain of Mcl-1 responsible for its antisenescent effects is distinct from that known to confer its antiapoptotic qualities. In vivo we observe that downregulation of Mcl 1 can almost retard tumor growth regardless of p53 status, while overexpression of Mcl-1 in p53+ cells conferred resistance to CIS and promoted tumor outgrowth. In summary, our data reveal that Mcl-1 can inhibit CIS in both a p53-dependent and -independent manner in vitro and in vivo and that this Mcl-1-mediated inhibition can enhance tumor growth in vivo. PMID- 22451486 TI - Analysis of chromatin dynamics during glucocorticoid receptor activation. AB - Steroid hormone receptors initiate a genetic program tightly regulated by the chromatin environment of the responsive regions. Using the glucocorticoid receptor (GR) as a model factor for transcriptional initiation, we classified chromatin structure through formaldehyde-assisted isolation of regulatory elements (FAIRE). We looked at dynamic changes in FAIRE signals during GR activation specifically at regions of receptor interaction. We found a distribution of GR-responsive regions with diverse responses to activation and chromatin modulation. The majority of GR binding regions demonstrate increases in FAIRE signal in response to ligand. However, the majority GR-responsive regions shared a similar FAIRE signal in the basal chromatin state, suggesting a common chromatin structure for GR recruitment. Supporting this notion, global FAIRE sequencing (seq) data indicated an enrichment of signal surrounding the GR binding site prior to activation. Brg-1 knockdown showed response element specific effects of ATPase-dependent chromatin remodeling. FAIRE induction was universally decreased by Brg-1 depletion, but to varying degrees in a target specific manner. Taken together, these data suggest classes of nuclear receptor response regions that react to activation through different chromatin regulatory events and identify a chromatin structure that classifies the majority of response elements tested. PMID- 22451487 TI - Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. AB - It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to alphaKlotho, betaKlotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on betaKlotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR. PMID- 22451488 TI - Hydrophobic motif phosphorylation coordinates activity and polar localization of the Neurospora crassa nuclear Dbf2-related kinase COT1. AB - Nuclear Dbf2p-related (NDR) kinases and associated proteins are recognized as a conserved network that regulates eukaryotic cell polarity. NDR kinases require association with MOB adaptor proteins and phosphorylation of two conserved residues in the activation segment and hydrophobic motif for activity and function. We demonstrate that the Neurospora crassa NDR kinase COT1 forms inactive dimers via a conserved N-terminal extension, which is also required for the interaction of the kinase with MOB2 to generate heterocomplexes with basal activity. Basal kinase activity also requires autophosphorylation of the COT1 MOB2 complex in the activation segment, while hydrophobic motif phosphorylation of COT1 by the germinal center kinase POD6 fully activates COT1 through induction of a conformational change. Hydrophobic motif phosphorylation is also required for plasma membrane association of the COT1-MOB2 complex. MOB2 further restricts the membrane-associated kinase complex to the hyphal apex to promote polar cell growth. These data support an integrated mechanism of NDR kinase regulation in vivo, in which kinase activation and cellular localization of COT1 are coordinated by dual phosphorylation and interaction with MOB2. PMID- 22451489 TI - Cyclin-dependent kinase 8 regulates mitotic commitment in fission yeast. AB - Temporal changes in transcription programs are coupled to control of cell growth and division. We here report that Mediator, a conserved coregulator of eukaryotic transcription, is part of a regulatory pathway that controls mitotic entry in fission yeast. The Mediator subunit cyclin-dependent kinase 8 (Cdk8) phosphorylates the forkhead 2 (Fkh2) protein in a periodic manner that coincides with gene activation during mitosis. Phosphorylation prevents degradation of the Fkh2 transcription factor by the proteasome, thus ensuring cell cycle-dependent variations in Fkh2 levels. Interestingly, Cdk8-dependent phosphorylation of Fkh2 controls mitotic entry, and mitotic entry is delayed by inactivation of the Cdk8 kinase activity or mutations replacing the phosphorylated serine residues of Fkh2. In addition, mutations in Fkh2, which mimic protein phosphorylation, lead to premature mitotic entry. Therefore, Fkh2 regulates not only the onset of mitotic transcription but also the correct timing of mitotic entry via effects on the Wee1 kinase. Our findings thus establish a new pathway linking the Mediator complex to control of mitotic transcription and regulation of mitotic entry in fission yeast. PMID- 22451490 TI - A dual role for the dREAM/MMB complex in the regulation of differentiation specific E2F/RB target genes. AB - E2F and RB proteins regulate the expression of genes involved in cell cycle progression, apoptosis, differentiation, and development. Recent studies indicate that they function as part of an evolutionarily conserved multiprotein complex termed dREAM/DREAM/LINC. Here we characterize the role of the Drosophila complex, dREAM, in the regulation of differentiation-specific E2F target genes in actively proliferating cells. These genes are regulated differently from cell cycle related E2F targets, they do not depend on E2F activation, and E2F/RB repression is maintained throughout the cell cycle. In proliferating cells, their repression is dependent on dREAM. We find that dREAM plays a dual role in their regulation. First, it is required for the stability of the repressive dE2F2/RBF complexes at their promoters during S phase. Second, we find that dREAM is indispensable for both transcriptional repression mechanisms employed at these genes. PMID- 22451491 TI - Rapid cytoplasmic turnover of yeast ribosomes in response to rapamycin inhibition of TOR. AB - The target of rapamycin (TOR) pathway is the central regulator of cell growth in eukaryotes. Inhibition of TOR by rapamycin elicits changes in translation attributed mainly to altered translation initiation and repression of the synthesis of new ribosomes. Using quantitative analysis of rRNA, we found that the number of existing ribosomes present in a Saccharomyces cerevisiae culture during growth in rich medium rapidly decreases by 40 to 60% when the cells are treated with rapamycin. This process is not appreciably affected by a suppression of autophagy, previously implicated in degradation of ribosomes in eukaryotes upon starvation. Yeast cells deficient in the exosome function or lacking its cytoplasmic Ski cofactors show an abnormal pattern of rRNA degradation, particularly in the large ribosomal subunit, and accumulate rRNA fragments after rapamycin treatment and during diauxic shift. The exosome and Ski proteins are thus important for processing of rRNA decay intermediates, although they are probably not responsible for initiating rRNA decay. The role of cytoplasmic nucleases in rapamycin-induced rRNA degradation suggests mechanistic parallels of this process to nutrient-controlled ribosome turnover in prokaryotes. We propose that ribosome content is regulated dynamically in eukaryotes by TOR through both ribosome synthesis and the cytoplasmic turnover of mature ribosomes. PMID- 22451492 TI - De novo mutation in schizophrenia. AB - Several studies in the last 5 years have shown that newly arising (de novo) mutations contribute to the genetics of schizophrenia (SZ). This will replenish genetic variants removed by natural selection and could, in part, explain why SZ prevalence has remained stable in the general population despite low fecundity. The strongest evidence to date for the association between SZ and de novo mutation comes from studies of de novo copy number variation (CNV), where the rate of de novo CNV mutation is shown to be increased in cases when compared with controls, and genes disrupted by these mutations are enriched for those encoding proteins involved in synaptic function and development. Previous estimates have shown high levels of negative selection operating against SZ associated CNVs, and we provide an updated estimate of these levels of selection using the most recently published data. Recent studies involving next-generation sequencing technology have provided preliminary evidence that de novo single-nucleotide mutations might also increase risk of SZ. However, these are very small in scale, and the results can only be considered as preliminary. PMID- 22451493 TI - Neural substrates of empathic accuracy in people with schizophrenia. AB - INTRODUCTION: Empathic deficits in schizophrenia may lead to social dysfunction, but previous studies of schizophrenia have not modeled empathy through paradigms that (1) present participants with naturalistic social stimuli and (2) link brain activity to "accuracy" about inferring other's emotional states. This study addressed this gap by investigating the neural correlates of empathic accuracy (EA) in schizophrenia. METHODS: Fifteen schizophrenia patients and 15 controls were scanned while continuously rating the affective state of another person shown in a series of videos (ie, targets). These ratings were compared with targets' own self-rated affect, and EA was defined as the correlation between participants' ratings and targets' self-ratings. Targets' self-reported emotional expressivity also was measured. We searched for brain regions whose activity tracked parametrically with (1) perceivers' EA and (2) targets' expressivity. RESULTS: Patients showed reduced EA compared with controls. The left precuneus, left middle frontal gyrus, and bilateral thalamus were significantly more correlated with EA in controls compared with patients. High expressivity in targets was associated with better EA in controls but not in patients. High expressivity was associated with increased brain activity in a large set of regions in controls (eg, fusiform gyrus, medial prefrontal cortex) but not in patients. DISCUSSION: These results use a naturalistic performance measure to confirm that schizophrenic patients demonstrate impaired ability to understand others' internal states. They provide novel evidence about a potential mechanism for this impairment: schizophrenic patients failed to capitalize on targets' emotional expressivity and also demonstrate reduced neural sensitivity to targets' affective cues. PMID- 22451494 TI - Towards a reliable animal model of migraine. AB - The pharmaceutical industry shows a decreasing interest in the development of drugs for migraine. One of the reasons for this could be the lack of reliable animal models for studying the effect of acute and prophylactic migraine drugs. The infusion of glyceryl trinitrate (GTN) is the best validated and most studied human migraine model. Several attempts have been made to transfer this model to animals. The different variants of this model are discussed as well as other recent models. PMID- 22451495 TI - Screening trial of blood test for lung cancer is set to start in Scotland. PMID- 22451496 TI - Controversial allergy doctor admits faults in her treatment of a patient with lead poisoning. PMID- 22451497 TI - Europe's health systems can survive economic squeeze, conference hears. PMID- 22451498 TI - Health campaigners attack government plans to remove calories from foods as "token gestures". PMID- 22451499 TI - Just 4% of young women treated for cancer take up fertility preservation services. PMID- 22451500 TI - Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. AB - RAD51C was defined by Meindl et al. in 2010 as a high-risk gene involved in hereditary breast and ovarian cancers. Although this role seems to be clear, nowadays there is controversy about the indication of including the gene in routine clinical genetic testing, due to the lower prevalence or the absence of mutations found in subsequent studies. Here, we present the results of a comprehensive mutational screening of the RAD51C gene in a large series of 785 Spanish breast and/or ovarian cancer families, which, in contrast to the various subsequent studies published to date, includes the functional characterization of suspicious missense variants as reported in the initial study. We have detected 1.3% mutations of RAD51C in breast and ovarian cancer families, while mutations in breast cancer only families seem to be very rare. More than half of the deleterious variants detected were of missense type, which highlights their significance in the gene, and suggest that RAD51C mutations may have been so far partially disregarded and their prevalence underestimated due to the lack of functional complementation assays. Our results provide new evidences, suggesting that the genetic testing of RAD51C should be considered for inclusion into the clinical setting, at least for breast and ovarian cancer families, and encourage re-evaluating its role incorporating functional assays. PMID- 22451501 TI - Use of a predictive model derived from in vivo endophenotype measurements to demonstrate associations with a complex locus, CYP2A6. AB - This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes made comparisons by dividing subjects into broad categories based on assumptions that simplify the range of function of different CYP2A6 alleles, their numerous possible diplotype combinations and non-additive allele effects. A predictive model that translates CYP2A6 diplotype into a single continuous variable was previously derived from an in vivo metabolism experiment in 189 European Americans. Here, we apply this model to assess associations between genotype, inferred nicotine metabolism and smoking behaviors in larger samples without direct nicotine metabolism measurements. CYP2A6 genotype is not associated with nicotine dependence, as defined by the Fagerstrom Test of Nicotine Dependence, demonstrating that cigarettes smoked per day (CPD) and nicotine dependence have distinct genetic correlates. The predicted metric is significantly associated with CPD among African Americans and European American dependent smokers. Individual slow metabolizing genotypes are associated with lower CPD, but the predicted metric is the best predictor of CPD. Furthermore, optimizing the predictive model by including additional CYP2A6 alleles improves the fit of the model in an independent data set and provides a novel method of predicting the functional impact of alleles without direct metabolism measurements. Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms are the result of synthetic associations. PMID- 22451502 TI - CD147 regulates apoptosis in mouse spermatocytes but not spermatogonia. AB - BACKGROUND: Spermatogenesis is maintained by a dynamic balance between germ cell proliferation and apoptosis. Previous study has demonstrated that CD147 knockout mice are infertile with arrested germ cells. However, the question of whether and how CD147 may be involved in the apoptotic process during spermatogenesis remains elusive. The aim of this study was to evaluate the role of CD147 in the regulation of germ cell apoptosis in mice. METHODS: CD147 function was blocked by anti-CD147 antibody in GC-1 (immortalized spermatogonia) and GC-2 (immortalized spermatocytes) cell lines and in testicular germ cells in vivo. Testes size and weight were examined after injection of anti-CD147 antibody into the seminiferous tubules of severe combined immunodeficiency mice. Germ cell apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and levels of p53 and two effectors, caspase 3 and poly ADP-ribose polymerase (PARP), using western blots. RESULTS: The size and weight of the CD147 immunodepleted testes were decreased compared with that in control testes (P < 0.001). The TUNEL assay showed an increase in the number of apoptotic spermatocytes (P < 0.001 versus control) but not spermatogonia in Stages XI-XII of CD147-immunodepleted testes. In addition, in vitro experiments demonstrated that CD147 immunodepletion induced an increase in apoptosis in GC-2 cells (P < 0.001 versus control) but had no effect on GC-1 cells. Moreover, deprivation of CD147 induced apoptosis in spermatocytes through a p53-independent mechanism, which led to caspase 3 and PARP activation. CONCLUSIONS: We have demonstrated that immunodepletion of CD147 induces p53-independent apoptosis in mouse spermatocytes but not spermatogonia. PMID- 22451503 TI - Hormonal and molecular characterization of follicular fluid, cumulus cells and oocytes from pre-ovulatory follicles in stimulated and unstimulated cycles. AB - BACKGROUND: The use of ovarian stimulation, to stimulate a multi-follicular response for assisted reproduction treatments, may force the production of oocytes from follicles that do not reach optimal maturation, possibly yielding oocytes that are not fully competent. The present study aimed to define the follicular environment and oocyte competence of unstimulated pre-ovulatory follicles, to compare it with that of similar-sized stimulated follicles. For this purpose, we analyzed the follicular hormonal milieu, the oocyte meiotic spindle, the embryo development and the cumulus cells gene expression (GE) profiles. METHODS AND RESULTS: The study population was divided in two groups: (i) 42 oocyte donors undergoing unstimulated cycles and (ii) 18 oocyte donors undergoing controlled ovarian stimulation cycles (COS). Follicular fluid was analyzed to quantify the concentrations of estradiol (E2), progesterone (P), FSH, LH, testosterone (T) and androstendione (Delta4). T was higher in the COS group, while Delta4, E2 and LH were significantly higher in unstimulated cycles. The cumulus oophorus cells (CC) surrounding the oocyte were removed and their GE profiles were analyzed with microarrays. There were 18 differentially expressed genes in CC: 7 were up-regulated and 11 were down-regulated in the COS cycles. The microarray was validated by qRT-PCR. The analysis of spindle structure revealed no significant differences between the groups, except for the parameter of length which presented differences. The fertilization ability and embryo morphology on Days 2, 3 and 4 did not show any significant differences between groups. CONCLUSIONS: The use of ovarian stimulation induces changes in the follicular fluid and in CC GE that may affect immune processes, meiosis and ovulation pathways. Although these differences do not seem to relate to early stage embryo morphology, the implications of some of the molecules, especially ALDH1A2, CTSL and ZNF33B at the CC level, deserve to be addressed in future studies. PMID- 22451504 TI - Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity. AB - Rhombencephalosynapsis is a midline brain malformation characterized by missing cerebellar vermis with apparent fusion of the cerebellar hemispheres. Rhombencephalosynapsis can be seen in isolation or together with other central nervous system and extra-central nervous system malformations. Gomez-Lopez Hernandez syndrome combines rhombencephalosynapsis with parietal/temporal alopecia and sometimes trigeminal anaesthesia, towering skull shape and dysmorphic features. Rhombencephalosynapsis can also be seen in patients with features of vertebral anomalies, anal atresia, cardiovascular anomalies, trachea oesophageal fistula, renal anomalies, limb defects (VACTERL) association. Based on a comprehensive evaluation of neuroimaging findings in 42 patients with rhombencephalosynapsis, we propose a spectrum of severity, ranging from mild (the partial absence of nodulus, anterior and posterior vermis), to moderate (the absence of posterior vermis with some anterior vermis and nodulus present), to severe (the absence of posterior and anterior vermis with some nodulus present), to complete (the absence of the entire vermis including nodulus). We demonstrate that the severity of rhombencephalosynapsis correlates with fusion of the tonsils, as well as midbrain abnormalities including aqueductal stenosis and midline fusion of the tectum. Rhombencephalosynapsis is also associated with multiple forebrain abnormalities including absent olfactory bulbs, dysgenesis of the corpus callosum, absent septum pellucidum and, in rare patients, atypical forms of holoprosencephaly. The frequent association between rhombencephalosynapsis and aqueductal stenosis prompted us to evaluate brain magnetic resonance images in other patients with aqueductal stenosis at our institution, and remarkably, we identified rhombencephalosynapsis in 9%. Strikingly, subjects with more severe rhombencephalosynapsis have more severely abnormal neurodevelopmental outcome, as do subjects with holoprosencephaly and patients with VACTERL features. In summary, our data provide improved diagnostic and prognostic information, and support disruption of dorsal-ventral patterning as a mechanism underlying rhombencephalosynapsis. PMID- 22451505 TI - Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination. AB - Mutations in dynamin 2 (DNM2) lead to dominant intermediate Charcot-Marie-Tooth neuropathy type B, while a different set of DNM2 mutations cause autosomal dominant centronuclear myopathy. In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot-Marie-Tooth neuropathy type B versus autosomal dominant centronuclear myopathy. We used tissue derived from Dnm2-deficient mice to establish an appropriate peripheral nerve model and found that dominant intermediate Charcot-Marie-Tooth neuropathy type B-associated dynamin 2 mutants, but not autosomal dominant centronuclear myopathy mutants, impaired myelination. In contrast to autosomal dominant centronuclear myopathy mutants, Schwann cells and neurons from the peripheral nervous system expressing dominant intermediate Charcot-Marie-Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination is strictly dependent on Dnm2 and clathrin-mediated endocytosis function. Thus, we propose that altered endocytosis is a major contributing factor to the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B. PMID- 22451506 TI - Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies. AB - Central catecholamine deficiency characterizes alpha-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 +/- 0.09 (SEM), 1.00 +/- 0.09, 1.32 +/- 0.12 nmol/l] than controls (2.15 +/- 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 +/- 0.44, 7.75 +/- 0.42, 5.82 +/- 0.65 nmol/l) than controls (11.0 +/- 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenylacetic acid seems to provide a sensitive means to identify even early Parkinson's disease. PMID- 22451507 TI - Shaping quality: the use of performance polygons for multidimensional presentation and interpretation of qualitative performance data. AB - BACKGROUND: Measuring outcomes and quality in anaesthesia is challenging. In the UK, there is increased focus on these as a result of changes in Department of Health strategy and the imminent introduction of mandatory revalidation for all doctors. A definition of quality may differ according to the observer's standpoint and numerous performance measures may contribute to overall quality. Patients, surgeons, anaesthetic assistants, recovery nurses, managers, and anaesthetic peers are each likely to have their own perspective on 'anaesthetic quality' and would perhaps suggest different metrics to measure it. Speed, efficiency, cost, interpersonal skills, complication rates, patient recorded outcome measures, and satisfaction are all valid as quality measures, but none alone captures anaesthetic quality. Performance data are frequently presented as single-dimension measurements (e.g. pain, postoperative nausea and vomiting, patient satisfaction), but this does not address the fact that two or more domains may be closely related (e.g. use of regional anaesthesia and quality of analgesia) or in opposition (e.g. use of regional anaesthesia and speed). METHODS: We introduce the concept of a 'performance polygon' as a tool to represent multidimensional performance assessment. This method of data presentation encourages balanced appraisal of anaesthetic quality. RESULTS: Performance polygons may be used to compare individual performance with peers, published outcome norms, trends in performance over time, to explore aspects of team performance and potentially capture data that are required for medical revalidation. CONCLUSIONS: Performance polygons enable easy comparison with any relevant data set and are a visual tool that potentially has wider applications in healthcare quality improvement. PMID- 22451508 TI - Comparison of three ADHD screening instruments in college students of varying cognitive ability. AB - OBJECTIVE: To assess three of the better known screeners for Attention Deficit/Hyperactive Disorder (ADHD) and review the relationship between ADHD and cognitive ability. METHOD: The three ADHD screeners were administered to 111 college students enrolled in a college Introductory Psychology class, on whom ACT scores and total course performance were also available. As a measure of cognitive ability, the Wonderlic Personnel Test (Wonderlic, Inc., 2000) was also administered. Furthermore, self-report data were available from participants who had been diagnosed with ADHD. The three screeners were the Adult ADHD Self-Report Scale (ASRS) (Kessler et al., 2005), the Conners' Adult ADHD Rating Scale-Self Report: Long Version (CAARS) (Conners, Erhardt, & Sparrow, 1999), and the Brown ADD Scales (Brown, 1996). RESULTS: The results are discussed in terms of the scales' reliability, as well as their relationship to academic aptitude, class performance, and their ability to identify self-reported ADHD diagnoses. CONCLUSION: All three screeners exhibited acceptable reliability levels. Criterion validity was demonstrated by the relationship between the CAARS's inattention subscale and self-reported cases of ADHD. Criterion validity was also seen in the relationship found between the CAARS's hyperactivity/restlessness subscale and the total course performance even after controlling for cognitive ability. Contrary to past research cognitive ability exhibited a weak but significant relationship with a few screeners and screener subscales. PMID- 22451509 TI - Strategy Selection in ADHD Characteristics Children: A Study in Arithmetic. AB - Objective: It has been argued that ADHD characteristics children have difficulties in selecting the best strategy when they accomplish cognitive tasks. The detrimental influence of these poor strategy skills may be crucial for several aspects of academic achievement such as mathematical learning. Method: Fourth- and fifth-grade children with ADHD symptoms and matched controls were asked to select the better of two rounding strategies in a computational estimation task (i.e., finding the best estimate of two-digit addition problems). Results: (a) Both control and ADHD children correctly executed a selected strategy, (b) ADHD children selected the best strategy less often than controls, (c) ADHD took more time to estimate sums of two-digit addition problems and provided poorer estimates, and (d) different factors predicted best strategy selections in each group. Conclusion: These findings have important implications for further understanding the sources of differences in cognitive performance between ADHD and control children. (J. of Att. Dis. 2012; XX(X) 1-XX). PMID- 22451510 TI - Catechol-o-methyltransferase gene and executive function in children with ADHD. AB - OBJECTIVE: To examine the association between functional haplotypes in the catechol-o-methyltransferase (COMT) gene and ADHD diagnosis, and executive function (EF) in children with ADHD. METHOD: COMT single nucleotide polymorphism (SNPs; rs6269, rs4633, rs4818, and rs4680) were genotyped in 445 ADHD children. EF was assessed using Wisconsin Card Sorting Test (WCST), Tower of London, and self-ordered pointing task. COMT haplotypes were tested for association using family-based association testing (fBAT) and quantitative trait analyses. RESULTS: fBAT analysis showed no association between COMT alleles/haplotypes and ADHD diagnosis and EF parameters. Using ANCOVA in the Caucasian only sample, significant associations between COMT haplotypes, and WCST indices were observed. However, after correction for multipletesting, the only significant effect observed was between rs6269 and the number of categories completed (a measure of concept formation ability) on the WCST, F(1,285) = 8.92, p = .003. CONCLUSION: These results tentatively implicate COMT gene in modulating EF in children with ADHD. PMID- 22451511 TI - The SDF-1/CXCR4 axis in stem cell preconditioning. AB - We review the pivotal role of the stromal derived factor (SDF)-1 chemokine in tissue ischaemia and how it orchestrates the rapid revascularization of injured, ischaemic, and regenerating tissues via the CXC chemokine receptors CXCR4 and CXCR7. Furthermore, we discuss the effects of preconditioning (PC), which is a well-known protective phenomenon for tissue ischaemia. The positive effect of both hypoxic and acidic PC on progenitor cell therapeutic potential is reviewed, while stressing the role of the SDF-1/CXCR4 axis in this process. PMID- 22451512 TI - Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation. AB - AIMS: Binge drinking often triggers compromised myocardial contractile function while activating AMP-activated protein kinase (AMPK). Given the role of AMPK in the initiation of autophagy through the mammalian target of rapamycin complex 1 (mTORC1) and Unc51-like kinase (ULK1), this study was designed to examine the impact of AMPK deficiency on cardiac function and the mechanism involved with a focus on autophagy following an acute ethanol challenge. METHODS AND RESULTS: Wild-type (WT) and transgenic mice overexpressing a kinase-dead (KD) alpha2 isoform (K45R mutation) of AMPK were challenged with ethanol. Glucose tolerance, echocardiography, Langendorff heart and cardiomyocyte contractile function, autophagy, and autophagic signalling including AMPK, acetyl-CoA carboxylase (ACC), mTOR, the mTORC1-associated protein Raptor, and ULK1 were examined. Ethanol exposure triggered glucose intolerance and compromised cardiac contraction accompanied by increased phosphorylation of AMPK and ACC as well as autophagosome accumulation (increased LC3II and p62), the effects of which were attenuated or mitigated by AMPK deficiency or inhibition. Ethanol dampened and stimulated, respectively, the phosphorylation of mTOR and Raptor, the effects of which were abolished by AMPK deficiency. ULK1 phosphorylation at Ser(757) and Ser(777) was down-regulated and up-regulated, respectively, by ethanol, the effect of which was nullified by AMPK deficiency or inhibition. Moreover, the ethanol challenge enhanced LC3 puncta in H9c2 cells and promoted cardiac contractile dysfunction, and these effects were ablated by the inhibition of autophagy or AMPK. Lysosomal inhibition failed to accentuate ethanol-induced increases in LC3II and p62. CONCLUSION: In summary, these data suggest that ethanol exposure may trigger myocardial dysfunction through a mechanism associated with AMPK-mTORC1-ULK1-mediated autophagy. PMID- 22451513 TI - Physiological and pathological role of the ubiquitin-proteasome system in the vascular smooth muscle cell. AB - Vascular smooth muscle cell (VSMC) plasticity implies a capacity for rapid change and adaptability through processes requiring protein turnover. The ubiquitin proteasome system (UPS) is at the core of protein turnover as the main pathway for the degradation of proteins related to cell-cycle regulation, signalling, apoptosis, and differentiation. This review briefly addresses some structural UPS aspects under the perspective of VSMC (patho)biology. The UPS loss-of-function promotes direct cell effects and many indirect effects related to the adaptation to apoptosis/survival signalling, oxidative stress, and endoplasmic reticulum stress. The UPS regulates redox homeostasis and is redox-regulated. Also, the UPS closely interacts with endoplasmic reticulum (ER) homeostasis as the effector of un/misfolded protein degradation, and ER stress is strongly involved in atherosclerosis. Inhibition of cell cycle-controlling ubiquitin ligases or the proteasome reduces VSMC proliferation and prevents modulation of their synthetic phenotype. Proteasome inhibition also strongly promotes VSMC apoptosis and reduces neointima. In atherosclerosis models, proteasome inhibitors display vasculoprotective effects and reduce inflammation. However, worsening of atherosclerosis or vascular dysfunction has also been reported. Proteasome inhibitors sensitize VSMC to increased ER stress-mediated cell death and suppress unfolded protein response signalling. Taken together, these observations show that the UPS has powerful effects in the control of VSMC phenotype and survival signalling. However, more profound knowledge of mechanisms is needed in order to render the UPS an operational therapeutic target. PMID- 22451514 TI - Nasopharyngeal colonization elicits antibody responses to staphylococcal and pneumococcal proteins that are not associated with a reduced risk of subsequent carriage. AB - Knowledge of the immunological correlates of Staphylococcus aureus and Streptococcus pneumoniae colonization is required for the search for future protein vaccines. We evaluated natural antibody levels against pneumococcal and staphylococcal proteins in relation to previous bacterial colonization with both pathogens. In a randomized controlled trial, nasopharyngeal samples were obtained from children at 1.5, 6, 12, 18, and 24 months and cultured for S. aureus and S. pneumoniae. Approximately 50% of the children were PCV7 vaccinated. Serum IgG against 18 pneumococcal and 40 staphylococcal proteins was semiquantified by Luminex technology from 111 12 month olds and 158 24 month olds. Previous culture proven S. aureus colonization was associated with higher IgG levels against 6/40 staphylococcal proteins (ClfB, ClfA, Efb, CHIPS, LukD, and LukF [P <= 0.001]) compared to noncarriers. Previous pneumococcal colonization was associated with increased IgG levels against 12/18 pneumococcal proteins compared to noncarriers (P <= 0.003). Increasing age was associated with higher levels of antibodies to most pneumococcal proteins and lower levels of antibodies to over half the staphylococcal proteins, reflecting natural colonization dynamics. Anti-S. pneumoniae and anti-S. aureus protein antibodies at the age of 12 months were not negatively correlated with subsequent colonization with the homologous species in the following year and did not differ between PCV7-vaccinated and nonvaccinated children. Colonization with S. aureus and S. pneumoniae induces serum IgG against many proteins, predominantly proteins with immune-modulating functions, irrespective of PCV7 vaccination. None of them appeared to be protective against new acquisition with both pathogens, possibly due to the polymorphic nature of those proteins in the circulating bacterial population. PMID- 22451515 TI - L-ficolin and capsular polysaccharide-specific IgG in cord serum contribute synergistically to opsonophagocytic killing of serotype III and V group B streptococci. AB - Group B streptococci (GBS; Streptococcus agalactiae) are the most common cause of neonatal sepsis and meningitis. Serotype-specific IgG antibody is known to protect neonates against GBS infections by promoting opsonophagocytosis. The L ficolin-mediated lectin pathway of the complement is also a potential mechanism for opsonization of GBS, because L-ficolin activates the complement after binding to serotype Ib, III, V, VI, and VIII GBS. In the present study, we investigated how L-ficolin and serotype-specific IgG in cord sera contribute to opsonophagocytic killing of GBS. Neither L-ficolin nor serotype-specific IgG concentrations correlated with C3b deposition on serotype Ib and VI GBS, suggesting L-ficolin- and serotype-specific IgG-independent mechanisms of complement activation. The percentage of serotype VIII GBS killed was high regardless of the concentration of L-ficolin and IgG. In contrast, L-ficolin and serotype-specific IgG can each initiate C3b deposition on serotype III and V GBS and promote phagocytosis by polymorphonuclear leukocytes, but L-ficolin and serotype-specific IgG together promote opsonophagocytic killing to a greater extent than does either alone in vitro. This synergy was observed when serotype III-specific IgG concentrations were between 1 and 6 MUg/ml and when serotype V specific IgG concentrations were between 2 and 5 MUg/ml. Concentrations of serotype III-specific IgG in cord blood above 7 MUg/ml are considered protective for neonates colonized with GBS, but most neonates with IgG levels of less than 7 MUg/ml do not develop GBS infections. The data presented here suggest that L ficolin enhances opsonophagocytosis of serotype III and V GBS when serotype specific IgG alone is suboptimal for protection. PMID- 22451516 TI - The type II secretion system and its ubiquitous lipoprotein substrate, SslE, are required for biofilm formation and virulence of enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli (EPEC) is a major cause of diarrhea in infants in developing countries. We have identified a functional type II secretion system (T2SS) in EPEC that is homologous to the pathway responsible for the secretion of heat-labile enterotoxin by enterotoxigenic E. coli. The wild-type EPEC T2SS was able to secrete a heat-labile enterotoxin reporter, but an isogenic T2SS mutant could not. We showed that the major substrate of the T2SS in EPEC is SslE, an outer membrane lipoprotein (formerly known as YghJ), and that a functional T2SS is essential for biofilm formation by EPEC. T2SS and SslE mutants were arrested at the microcolony stage of biofilm formation, suggesting that the T2SS is involved in the development of mature biofilms and that SslE is a dominant effector of biofilm development. Moreover, the T2SS was required for virulence, as infection of rabbits with a rabbit-specific EPEC strain carrying a mutation in either the T2SS or SslE resulted in significantly reduced intestinal colonization and milder disease. PMID- 22451517 TI - Development of a single-gene, signature-tag-based approach in combination with alanine mutagenesis to identify listeriolysin O residues critical for the in vivo survival of Listeria monocytogenes. AB - Listeriolysin O (LLO) is a pore-forming toxin of the cholesterol-dependent cytolysin (CDC) family and a primary virulence factor of the intracellular pathogen Listeria monocytogenes. LLO mediates rupture of phagosomal membranes, thereby releasing bacteria into the growth-permissive host cell cytosol. Several unique features of LLO allow its activity to be precisely regulated in order to facilitate phagosomal escape, intracellular growth, and cell-to-cell spread. To improve our understanding of the multifaceted contribution of LLO to the pathogenesis of L. monocytogenes, we developed a screen that combined saturation mutagenesis and signature tags, termed in vivo analysis by saturation mutagenesis and signature tags (IVASS). We generated a library of LLO mutant strains, each harboring a single amino acid substitution and a signature tag, by using the previously described pPL2 integration vector. The signature tags acted as molecular barcodes, enabling high-throughput, parallel analysis of 40 mutants in a single animal and identification of attenuated mutants by negative selection. Using the IVASS technique we were able to screen over 90% of the 505 amino acids present in LLO and identified 60 attenuated mutants. Of these, 39 LLO residues were previously uncharacterized and potentially revealed novel functions of the toxin during infection. The mutants that were subsequently analyzed in vivo each conferred a 2- to 4-orders of magnitude loss in virulence compared to wild type, thereby validating the screening methods. Phenotypic analysis of the LLO mutant library using common in vitro techniques suggested that the functional contributions of some residues could only have been revealed through in vivo analysis. PMID- 22451518 TI - Myeloid-derived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous Gr1(+) CD11b(+) population of immature cells containing granulocytic and monocytic progenitors, which expand under nearly all inflammatory conditions and are potent repressors of T-cell responses. Studies of MDSCs during inflammatory responses, including sepsis, suggest they can protect or injure. Here, we investigated MDSCs during early and late sepsis. To do this, we used our published murine model of cecal ligation and puncture (CLP)-induced polymicrobial sepsis, which transitions from an early proinflammatory phase to a late anti-inflammatory and immunosuppressive phase. We confirmed that Gr1(+) CD11b(+) MDSCs gradually increase after CLP, reaching ~88% of the bone marrow myeloid series in late sepsis. Adoptive transfer of early (day 3) MDSCs from septic mice into naive mice after CLP increased proinflammatory cytokine production, decreased peritoneal bacterial growth, and increased early mortality. Conversely, transfer of late (day 12) MDSCs from septic mice had the opposite effects. Early and late MDSCs studied ex vivo also differed in their inflammatory phenotypes. Early MDSCs expressed nitric oxide and proinflammatory cytokines, whereas late MDSCs expressed arginase activity and anti-inflammatory interleukin 10 (IL-10) and transforming growth factor beta (TGF beta). Late MDSCs had more immature CD31(+) myeloid progenitors and, when treated ex vivo with granulocyte-macrophage colony-stimulating factor (GM-CSF), generated fewer macrophages and dendritic cells than early MDSCs. We conclude that as the sepsis inflammatory process progresses, the heterogeneous MDSCs shift to a more immature state and from being proinflammatory to anti-inflammatory. PMID- 22451519 TI - Control of Entamoeba histolytica adherence involves metallosurface protease 1, an M8 family surface metalloprotease with homology to leishmanolysin. AB - Invasive amebiasis due to Entamoeba histolytica infection is an important cause of morbidity in developing countries. The E. histolytica genome contains two homologues to the metalloprotease leishmanolysin gene, Entamoeba histolytica MSP 1 (EhMSP-1) and EhMSP-2, while the commensal ameba Entamoeba dispar has lost EhMSP-1. In this study, we sought to characterize E. histolytica metallosurface protease 1 (EhMSP-1). Using immunoprecipitation and a model substrate, we found that EhMSP-1 was a functional metalloprotease. Confocal microscopy and flow cytometry revealed that EhMSP-1 localized to the cell surface and revealed the existence of distinct, nonclonal trophozoite populations with high and low EhMSP 1 surface abundance that became synchronized following serum starvation. Phenotypic assays were performed after silencing EhMSP-1. Adherence of EhMSP-1 deficient trophozoites to tissue culture cell monolayers was more than five times greater than that of control amebas, but surface staining of several antigens, including the galactose adherence lectin, was unchanged. EhMSP-1 silencing similarly increased adherence to both viable and apoptotic Jurkat lymphocytes. Tissue culture cell monolayer destruction was reduced by EhMSP-1 silencing, although it was blocked almost completely by inhibiting cysteine proteases. Consistent with a primary defect in regulation of amebic adherence, EhMSP-1 silencing also resulted in reduced mobility on tissue culture cell monolayers and in increased phagocytosis. In conclusion, EhMSP-1 was shown to be a surface metalloprotease involved in regulation of amebic adherence, with additional effects on cell motility, cell monolayer destruction, and phagocytosis. PMID- 22451520 TI - Impact of mosquito bites on asexual parasite density and gametocyte prevalence in asymptomatic chronic Plasmodium falciparum infections and correlation with IgE and IgG titers. AB - An immunomodulatory role of arthropod saliva has been well documented, but evidence for an effect on Plasmodium sp. infectiousness remains controversial. Mosquito saliva may orient the immune response toward a Th2 profile, thereby priming a Th2 response against subsequent antigens, including Plasmodium. Orientation toward a Th1 versus a Th2 profile promotes IgG and IgE proliferation, respectively, where the former is crucial for the development of an efficient antiparasite immune response. Here we assessed the direct effect of mosquito bites on the density of Plasmodium falciparum asexual parasites and the prevalence of gametocytes in chronic, asymptomatic infections in a longitudinal cohort study of seasonal transmission. We additionally correlated these parasitological measures with IgE and IgG antiparasite and anti-salivary gland extract titers. The mosquito biting density was positively correlated with the asexual parasite density but not asexual parasite prevalence and was negatively correlated with gametocyte prevalence. Individual anti-salivary gland IgE titers were also negatively correlated with gametocyte carriage and were strongly positively correlated with antiparasite IgE titers, consistent with the hypothesis that mosquito bites predispose individuals to develop an IgE antiparasite response. We provide evidence that mosquito bites have an impact on asymptomatic infections and differentially so for the production of asexual and sexual parasites. An increased research focus on the immunological impact of mosquito bites during asymptomatic infections is warranted, to establish whether strategies targeting the immune response to saliva can reduce the duration of infection and the onward transmission of the parasite. PMID- 22451521 TI - Aggregatibacter actinomycetemcomitans infection enhances apoptosis in vivo through a caspase-3-dependent mechanism in experimental periodontitis. AB - The purpose of this study was to test the hypothesis that diabetes aggravates periodontal destruction induced by Aggregatibacter actinomycetemcomitans infection. Thirty-eight diabetic and 33 normal rats were inoculated with A. actinomycetemcomitans and euthanized at baseline and at 4, 5, and 6 weeks after inoculation. Bone loss and the infiltration of polymorphonuclear leukocytes (PMNs) in gingival epithelium were measured in hematoxylin-eosin-stained sections. The induction of tumor necrosis factor alpha (TNF-alpha) was evaluated by immunohistochemistry and of apoptotic cells by a TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay. After A. actinomycetemcomitans infection, the bone loss in diabetic rats was 1.7-fold and the PMN infiltration 1.6-fold higher than in normoglycemic rats (P < 0.05). The induction of TNF-alpha was 1.5-fold higher and of apoptotic cells was up to 3 fold higher in diabetic versus normoglycemic rats (P < 0.05). Treatment with a caspase-3 inhibitor significantly blocked noninflammatory cell apoptosis induced by A. actinomycetemcomitans infection in gingival epithelium and connective tissue (P < 0.05). These results provide new insight into how diabetes aggravates A. actinomycetemcomitans-induced periodontal destruction in rats by significantly increasing the inflammatory response, leading to increased bone loss and enhancing apoptosis of gingival epithelial and connective tissue cells through a caspase-3-dependent mechanism. Antibiotics had a more pronounced effect on many of these parameters in diabetic than in normoglycemic rats, suggesting a deficiency in the capacity of diabetic animals to resist infection. PMID- 22451522 TI - FlaA proteins in Leptospira interrogans are essential for motility and virulence but are not required for formation of the flagellum sheath. AB - Spirochetes have periplasmic flagella composed of a core surrounded by a sheath. The pathogen Leptospira interrogans has four flaB (proposed core subunit) and two flaA (proposed sheath subunit) genes. The flaA genes are organized in a locus with flaA2 immediately upstream of flaA1. In this study, flaA1 and flaA2 mutants were constructed by transposon mutagenesis. Both mutants still produced periplasmic flagella. The flaA1 mutant did not produce FlaA1 but continued to produce FlaA2 and retained normal morphology and virulence in a hamster model of infection but had reduced motility. The flaA2 mutant did not produce either the FlaA1 or the FlaA2 protein. Cells of the flaA2 mutant lacked the distinctive hook shaped ends associated with L. interrogans and lacked translational motility in liquid and semisolid media. These observations were confirmed with a second, independent flaA2 mutant. The flaA2 mutant failed to cause disease in animal models of acute infection. Despite lacking FlaA proteins, the flagella of the flaA2 mutant were of the same thickness as wild-type flagella, as measured by electron microscopy, and exhibited a normal flagellum sheath, indicating that FlaA proteins are not essential for the synthesis of the flagellum sheath, as observed for other spirochetes. This study shows that FlaA subunits contribute to leptospiral translational motility, cellular shape, and virulence. PMID- 22451523 TI - Functional differences and interactions between the Escherichia coli type III secretion system effectors NleH1 and NleH2. AB - The human pathogens enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC), as well as the related mouse pathogen Citrobacter rodentium, utilize a type III secretion system (T3SS) to inject multiple effector proteins into host cells. The E. coli O157:H7 strain EDL933 carries two copies of non-locus of enterocyte effacement (LEE)-encoded protein H, designated NleH1 and NleH2, both of which bind to the human ribosomal protein S3 (RPS3), a subunit of NF-kappaB transcriptional complexes. In this study, we describe significant functional differences between NleH1 and NleH2 in their ability to regulate the host NF kappaB pathway. We show that the EHEC and EPEC NleH effectors are functionally equivalent in their ability to affect RPS3 nuclear translocation. NleH1, but not NleH2, inhibited NF-kappaB activity without altering the kinetics of IkappaBalpha phosphorylation/degradation. We also determined that the class I PSD-95/Disc Large/ZO-1 (PDZ)-binding domain of NleH was important for its activity in the NF kappaB pathway. In addition to binding RPS3, we found that NleH1 and NleH2 are able to bind to each other in vitro and in vivo, suggesting an additional mechanism by which the E. coli NleH effectors may regulate the extent and duration of NF-kappaB activation after their T3SS-dependent translocation. We also performed mouse infection experiments and established that mouse mortality and Citrobacter colonization were reduced in mice infected with DeltanleH. Complementing DeltanleH with NleH1 restored Citrobacter virulence and colonization to wild-type levels, whereas complementing with NleH2 reduced them. Taken together, our data show that NleH1 and NleH2 have pronounced functional differences in their ability to alter host transcriptional responses to bacterial infection. PMID- 22451524 TI - IbeA and OmpA of Escherichia coli K1 exploit Rac1 activation for invasion of human brain microvascular endothelial cells. AB - Meningitis-causing Escherichia coli K1 internalization of the blood-brain barrier is required for penetration into the brain, but the host-microbial interactions involved in E. coli entry of the blood-brain barrier remain incompletely understood. We show here that a meningitis-causing E. coli K1 strain RS218 activates Rac1 (GTP-Rac1) of human brain microvascular endothelial cells (HBMEC) in a time-dependent manner. Both activation and bacterial invasion were significantly inhibited in the presence of a Rac1 inhibitor. We further showed that the guanine nucleotide exchange factor Vav2, not beta-Pix, was involved in E. coli K1-mediated Rac1 activation. Since activated STAT3 is known to bind GTP Rac1, the relationship between STAT3 and Rac1 was examined in E. coli K1 invasion of HBMEC. Downregulation of STAT3 resulted in significantly decreased E. coli invasion compared to control HBMEC, as well as a corresponding decrease in GTP Rac1, suggesting that Rac1 activation in response to E. coli is under the control of STAT3. More importantly, two E. coli determinants contributing to HBMEC invasion, IbeA and OmpA, were shown to affect both Rac1 activation and their association with STAT3. These findings demonstrate for the first time that specific E. coli determinants regulate a novel mechanism of STAT3 cross talk with Rac1 in E. coli K1 invasion of HBMEC. PMID- 22451525 TI - Olfactory detectability of L-amino acids in the European honeybee (Apis mellifera). AB - The honeybee is one of several insect model systems for the study of olfaction, yet our knowledge regarding the spectrum of odorants detectable by Apis mellifera is limited. One class of odorants that has never been tested so far are the amino acids, which are important constituents of floral nectar. Using the proboscis extension response paradigm, we assessed whether the odor of amino acids is detectable for honeybees and determined olfactory detection thresholds for those amino acids that were detectable. We found that honeybees are able to detect the odor of 5 of the 20 proteinogenic amino acids when presented at a concentration of 50 or 100 mM. Median olfactory detection thresholds for these 5 amino acids were 12.5 mM with L-tyrosine and L-cysteine, 50 mM with L-tryptophan and L asparagine, and 100 mM with L-proline. All detection thresholds were much higher than reported concentrations of amino acids in floral nectars. We conclude that in the foraging and feeding context, honeybees are likely to detect amino acids through taste rather than olfaction. Across-species comparisons of the detectability of and sensitivity to amino acids suggest that the number of functional genes coding for olfactory receptors may affect both a species' sensitivity for odorants and the breadth of its spectrum of detectable odorants. PMID- 22451526 TI - Amiloride-sensitive and amiloride-insensitive responses to NaCl + acid mixtures in hamster chorda tympani nerve. AB - Component signaling in taste mixtures containing both beneficial and dangerous chemicals depends on peripheral processing. Unidirectional mixture suppression of chorda tympani (CT) nerve responses to sucrose by quinine and acid is documented for golden hamsters (Mesocricetus auratus). To investigate mixtures of NaCl and acids, we recorded multifiber responses to 50 mM NaCl, 1 and 3 mM citric acid and acetic acid, 250 MUM citric acid, 20 mM acetic acid, and all binary combinations of each acid with NaCl (with and without 30 MUM amiloride added). By blocking epithelial Na(+) channels, amiloride treatment separated amiloride-sensitive NaCl specific responses from amiloride-insensitive electrolyte-generalist responses, which encompass all of the CT response to the acids as well as responses to NaCl. Like CT sucrose responses, the amiloride-sensitive NaCl responses were suppressed by as much as 50% by citric acid (P = 0.001). The amiloride-insensitive electrolyte-generalist responses to NaCl + acid mixtures approximated the sum of NaCl and acid component responses. Thus, although NaCl-specific responses to NaCl were weakened in NaCl-acid mixtures, electrolyte-generalist responses to acid and NaCl, which tastes KCl-like, were transmitted undiminished in intensity to the central nervous system. The 2 distinct CT pathways are consistent with known rodent behavioral discriminations. PMID- 22451527 TI - Theory-guided selection of discrimination measures for racial/ ethnic health disparities research among older adults. AB - OBJECTIVE: Discrimination may contribute to health disparities among older adults. Existing measures of perceived discrimination have provided important insights but may have limitations when used in studies of older adults. This article illustrates the process of assessing the appropriateness of existing measures for theory-based research on perceived discrimination and health. METHOD: First, we describe three theoretical frameworks that are relevant to the study of perceived discrimination and health-stress-process models, life course models, and the Public Health Critical Race (PHCR) praxis. We then review four widely-used measures of discrimination, comparing their content and describing how well they address key aspects of each framework, and discussing potential areas of modification. DISCUSSION: Using theory to guide measure selection can help improve understanding of how perceived discrimination may contribute to racial/ethnic health disparities among older adults. PMID- 22451528 TI - Dynapenic abdominal obesity and metabolic risk factors in adults 50 years of age and older. AB - OBJECTIVES: To investigate the additive effect of dynapenia and abdominal obesity on metabolic risk factors in older adults. METHOD: A total of 3,007 men and women from the National Health and Nutrition Examination Survey (NHANES) study were categorized as follows: (a) non-dynapenic/non-abdominally obese (N-DYN/N-AO), (b) dynapenic/non-abdominally obese (DYN/N-AO), (c) non-dynapenic/abdominally obese (N-DYN/AO), (d) dynapenic/ abdominally obese (DYN/AO) based on waist circumference (WC) and leg muscle strength tertiles. Dependent variables were lipids, glucose, blood pressure, and other chronic conditions. RESULTS: The DYN/AO group had lower plasma HDL-chol and higher triglyceride and glucose levels than N-DYN/N-AO and DYN/N-AO groups (all p <= .01). Higher plasma triglyceride was observed in the DYN/AO group compared with N-DYN/AO group (p <= .01). The odds of having metabolic syndrome, cardiovascular diseases, and type II diabetes were higher in DYN/AO compared with DYN/N-AO and N-DYN/N-AO. CONCLUSION: DYN/AO older adults might be at greater risk of metabolic alterations than those displaying dynapenia alone or those with neither abdominal obesity nor dynapenia. PMID- 22451529 TI - Multiple routes to B-cell memory. AB - B-cell memory describes the populations of cells that provide long-term humoral immunity: long-lived antibody-secreting plasma cells that reside mainly in the bone marrow and memory B cells. Interestingly, the memory B-cell population is heterogenous, although the importance of this heterogeneity has been unclear. Recent studies have investigated the formation and function of memory in different settings. In particular, T-independent memory-like cells and T dependent (TD) IgM memory B cells qualitatively differ from canonical TD class switched memory B cells; however, these studies suggest that IgM memory cells preserve the memory population over long periods of time. These subsets are evocative of the evolution of the humoral immune response, with memory-like cells appearing before acquisition of germinal centers, suggesting that there are multiple pathways to producing B-cell memory. PMID- 22451530 TI - Macrocephaly-capillary malformation syndrome in a newborn with tetralogy of fallot and sagittal sinus thrombosis. AB - Macrocephaly-capillary malformation syndrome is characterized by cutaneous vascular malformations with associated anomalies as macrocephaly, macrosomia, hemihypertrophy, hypotonia, developmental delay, lax joints, loose skin, polysyndactyly, and neuroimaging abnormalities. We present a newborn with a prenatal diagnosis of macrosomia and tetralogy of Fallot. He also had macrocephaly; a high forehead; capillary hemangioma on the forehead, upper lip, and philtrum; generalized loose skin; postaxial polydactyly of both hands and feet, with neuroimaging findings of polymicrogyria and thrombosis in sagittal sinus and sinus rectus. His condition was diagnosed as macrocephaly-capillary malformation syndrome in the neonatal period and he died suddenly during sleep at 6 months of age. The clinical course in this syndrome is not as benign as was previously thought. Careful follow-up of these patients with particular emphasis on neuroradiologic and cardiologic evaluation might help decrease the risk of sudden death and to improve long-term outcome. PMID- 22451531 TI - Quantification of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet detector (HPLC-UV): application to pharmacokinetic studies in 28 healthy Korean subjects. AB - Nimesulide is a selective COX-2 inhibitor that is as effective as the classical non-acidic nonsteroidal anti-inflammatory drugs in the relief of various pain and inflammatory conditions, but is better tolerated with lower incidences of adverse effects than other drugs. After oral dose of 100 mg nimesulide to western subjects, a mean maximal concentration (C(max)) of 2.86 ~ 6.5 ug/mL was reached at 1.22 ~ 2.75 h and mean t(1/2beta) of 1.8 ~ 4.74 h. This study developed a robust method for quantification of nimesulide for the pharmacokinetics and suitability of its dosage in Korea and compared its suitability with other racial populations. Nimesulide and internal standard were extracted from acidified samples with methyl tert-butyl ether and analyzed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The 28 healthy volunteers took 2 tablets of 100 mg nimesulide and blood concentrations were analyzed during the 24 h post dose. Several pharmacokinetic parameters were represented: AUC(0 infinity) = 113.0 mg-h/mL, C(max) = 12.06 mg/mL, time for maximal concentrations (T(max)) = 3.19 h and t(1/2beta) = 4.51 h. These were different from those of western populations as follows: AUC was 14.5% and C(max) was 28% that of of Korean subjects and T(max) and t(1/2beta) were also different. The validated HPLC UV method was successfully applied for the pharmacokinetic studies of nimesulide in Korean subjects. Because the pharmacokinetics of nimesulide were different from western populations, its dosage regimen needs to be adjusted for Koreans. PMID- 22451532 TI - Simultaneous determination of nine related substances in p-phthalic acid residue by RP-HPLC. AB - A high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is established for the simultaneous determination of p-phthalic acid, benzoic acid, 4-carboxybenzaldehyde, m-phthalic acid, o-phthalic acid, phthalide, o-toluic acid, m-toluic acid and p-toluic acid in the residue generated during the production of p-phthalic acid (PPA). On a narrow-diameter reversed-phase C18 column, gradient elution is applied with a methanol-water-ammonium acetate-acetic acid buffer (100 mmol/L, pH 4.70) as mobile phase at a flow rate of 0.2 mL/min, and detection is operated by UV absorption at a wavelength of 254 nm. Under the conditions, these nine relative compounds, including organic acids, are well separated. The detection limits (S/N = 3) are 0.05 ug/mL-0.20 ug/mL, and the correlation coefficients of standard curves are between 0.99995 and 0.99999. Relative standard deviations for analyses of real samples are below 5.3%, and recoveries of these determined compounds ranges from 90.0 to 104.9%. The method, which provides accurate and reliable results, can effectively guide the recycling and reutilization of organic acids and related substances in PPA residue. PMID- 22451533 TI - Posterior insular molecular changes in myofascial pain. AB - Temporomandibular disorders (TMD) include craniocervical pain conditions with unclear etiologies. Central changes are suspected; however, few neuroimaging studies of TMD exist. Single-voxel proton magnetic resonance spectroscopy ((1)H MRS) was used before and after pressure-pain testing to assess glutamate (Glu), glutamine (Gln), N-acetylaspartate (NAA), and choline (Cho) levels in the right and left posterior insulae of 11 individuals with myofascial TMD and 11 matched control individuals. Glu levels were significantly lower in all individuals after pain testing. Among those with TMD, left-insular Gln levels were related to reported pain, left posterior insular NAA and Cho levels were significantly higher at baseline than in control individuals, and NAA levels were significantly correlated with pain-symptom duration, suggesting adaptive changes. The results suggest that significant central cellular and molecular changes can occur in individuals with TMD. PMID- 22451534 TI - Personalized tumor response assessment in the era of molecular medicine: cancer specific and therapy-specific response criteria to complement pitfalls of RECIST. AB - OBJECTIVE: The purpose of this article is to review cancer- and therapy-specific tumor response assessment criteria used in clinical trials and in practice, with illustrative case examples, and to discuss future directions toward "personalized" tumor response assessment. CONCLUSION: Although Response Evaluation Criteria in Solid Tumors will remain as the primary generalized criteria for response assessment, newer cancer- and therapy-specific criteria will play an important role in providing state-of-the-art response assessment of tumor following molecular targeted therapy and will contribute to personalized cancer care in the era of molecular medicine. PMID- 22451535 TI - Introduction to digital medical image management: departmental concerns. AB - OBJECTIVE: The objective of this article is to provide an overview of the considerations that are faced when a film-based imaging department transitions to a filmless practice. Both departmental and enterprise issues will be discussed in the context of a single geographically confined campus. CONCLUSION: A successful transition to a filmless practice results from applying imaging informatics principles and using established standard, appropriate change management practices, all coordinated by a team of representative stakeholders. PMID- 22451536 TI - The application of x-rays in radiology: from difficult and dangerous to simple and safe. AB - OBJECTIVE: This article will provide an assessment of the application of x-rays in the early days of radiology, which is an excellent way to come to value the convenience and safety of modern x-ray systems. CONCLUSION: The gas tubes that were originally applied for x-ray production were very unstable because of variations in the tube's vacuum. In an effort to understand some of the problems of these tubes and the high occupational exposure that was indirectly caused by the tubes' erratic behavior, we measured x-ray output rates as a function of the gas pressure inside the tube. The pressure range for the optimal production of x rays, using an original Ruhmkorff inductor as a high-voltage generator, was found to be narrow. With the vacuum changing over time, this might explain the many photographs from the first years of radiology with operators watching their unshielded tube, either with bare eyes or with a fluoroscope, and their own hand as a test object. This practice often led to severe damage of the hands and to many early deaths due to cancer. Today, after a century of technologic development of x-ray tubes and associated equipment, the total average effective dose of workers in radiology can be close to natural background levels. PMID- 22451537 TI - JPEG2000 compression of CT images used for measuring coronary artery calcification score: assessment of optimal compression threshold. AB - OBJECTIVE: The purpose of our study was to assess the acceptable compression threshold for JPEG2000 compression of CT images used for measuring coronary artery calcification scores (CACS) in terms of variability. MATERIALS AND METHODS: In a retrospective review, 80 patients who had undergone CT for determination of the CACS were compiled in four subsets (20 scans each) according to CACS: 0, subset A; > 0 to >= 100, subset B; > 100 to <= 400, subset C; and > 400, subset D. Each scan was compressed using eight compression ratios (CRs). We measured the CACS on all 720 CT scans (80 original and 640 compressed scans). For each compressed scan, the variability in CACS was evaluated by comparing with the CACS of the corresponding original CT scan. RESULTS: For each subset and each CR, we determined whether the upper limit of the one-sided 95% CI of the variability in CACS exceeded 5%. The variability in CACS tended to increase as the CR increased and tended to decrease in the order of increasing CACSs at each CR (i.e., subset B > subset C > subset D). With 5% as the limit of variability, acceptable compression CRs were between 20:1 and 25:1 for subset B; between 40:1 and 60:1 for subset C; and > 100:1 for subset D. CONCLUSION: A level of 20:1 could be a potentially acceptable threshold for JPEG2000 compression of CT images used for measuring CACS, with 5% of the variability in CACS as the acceptable limit of variability. PMID- 22451538 TI - Emerging trends in the volume and format of outside examinations submitted for secondary interpretation. AB - OBJECTIVE: The purpose of this article is to describe the trends of secondary interpretations, including the total volume and format of cases. MATERIALS AND METHODS: This retrospective study involved all outside neuroradiology examinations submitted for secondary interpretation from November 2006 through December 2010. This practice utilizes consistent criteria and includes all images that cover the brain, neck, and spine. For each month, the total number of outside examinations and their format (i.e., hard-copy film, DICOM CD-ROM, or non DICOM CD-ROM) were recorded. RESULTS: There was no significant change in the volume of cases (1043 +/- 131 cases/month; p = 0.46, two-sided Student t test). There was a significant decrease in the volume of hard-copy films submitted, with the mean number of examinations submitted per month on hard-copy film declining from 297 in 2007 to 57 in 2010 (p < 0.0001, Student t test). This decrease was mirrored by an increase in the mean number of cases submitted on CD-ROM (753 cases/month in 2007 and 1036 cases/month in 2010; p < 0.0001). Although most were submitted in DICOM format, there was almost a doubling of the volume of cases submitted on non-DICOM CD-ROM (mean number of non-DICOM CD-ROMs, nine cases/month in 2007 and 17 cases/month in 2010; p < 0.001). CONCLUSION: There has been a significant decrease in the number of hard-copy films submitted for secondary interpretation. There has been almost a doubling of the volume of cases submitted in non-DICOM formats, which is unfortunate, given the many advantages of the internationally derived DICOM standard, including ease of archiving, standardized display, efficient review, improved interpretation, and quality of patient care. PMID- 22451539 TI - Automatic selective removal of embedded patient information from image content of DICOM files. AB - OBJECTIVE: Patient data may appear as burned-in text on the image content of DICOM image files, which is commonly seen in ultrasound images and some secondarily scanned images. The purpose of this article is to discuss the removal of such information, which can be cumbersome and demands human intervention. CONCLUSION: This article presents a computerized scheme that automatically removes patient data from the image content by finding burned-in texts that match information in the DICOM header, thus cleaning the entire DICOM image file while preserving other useful labels. PMID- 22451540 TI - The new era of radiology teaching files. AB - OBJECTIVE: In this article, we describe how we constructed a radiology teaching file that simulates real-life scenarios and discuss some of the advantages it affords. CONCLUSION: Using OsiriX imaging software and iWork Pages, we have created a HIPAA-compliant interstitial lung disease radiology teaching resource that allows the user to navigate through the complete dataset of images for each patient. Integrated within the file is a navigation tool that allows the user to access the patient's clinical report, imaging reports, pulmonary function tests, and pathology report simultaneously. To our knowledge, this is the first teaching file of its kind. PMID- 22451541 TI - Imaging of pregnant and lactating patients: part 1, evidence-based review and recommendations. AB - OBJECTIVE: The objectives of this article are to discuss the current evidence based recommendations regarding radiation dose concerns, the use of iodinated and gadolinium-based contrast agents, and the comparative advantages of multimodality imaging (ultrasound, CT, and MRI) during pregnancy and lactation. We also discuss the use of imaging to evaluate pregnant trauma patients. CONCLUSION: Maternal and fetal radiation exposure and dose are affected by gestational age, anatomic site, modality, and technique. The use of iodinated and gadolinium-based contrast agents during pregnancy and lactation has not been well studied in human subjects. Imaging should be used to evaluate pregnant trauma patients only when the benefits outweigh the risks. PMID- 22451542 TI - Imaging of pregnant and lactating patients: part 2, evidence-based review and recommendations. AB - OBJECTIVE: The objectives of this article are to discuss the current evidence based recommendations regarding the use of diagnostic imaging in the evaluation of pulmonary embolism, appendicitis, urolithiasis, and cholelithiasis during pregnancy. CONCLUSION: Diagnostic imaging should be performed during pregnancy only with an understanding of the maternal and fetal risks and benefits, the comparative advantages of different modalities, and the unique anatomic and physiologic issues associated with pregnancy. PMID- 22451543 TI - Clinical significance of lung nodules reported on abdominal CT. AB - OBJECTIVE: The objective of our study was to identify the significance of lung nodules reported on abdominal CT. MATERIALS AND METHODS: Abdominal CT reports from a 1-year period were reviewed for the terms "nodule," "nodular," or "mass" in reference to the lung bases. Patients with prior chest or abdominal CT examinations were excluded; the study population included patients with an initial abdominal CT study and at least one follow-up chest or abdominal CT examination. Two thoracic radiologists characterized nodules in consensus. Radiology and clinical records were reviewed for nodule growth and clinical diagnoses. RESULTS: The term "nodule," "nodular," or "mass" in reference to the lung bases was reported in 364 of 12,287 abdominal CT studies (3%). Of 125 patients with no prior CT examination, 42 had undergone follow-up chest CT, abdominal CT, or both. Common imaging indications included abdominal pain (13/42, 31%) and preexisting malignancy (n = 7, 16.7%). Regardless of the indication for imaging, 16 (38.1%) had malignancy that was known (n = 13) or newly diagnosed (n = 3) on the initial abdominal CT. Three of 42 patients (7.1%) had malignant nodules representing metastatic disease: Nodule growth was seen in one patient with preexisting colon cancer, one patient with newly diagnosed metastatic pancreatic cancer, and a third with known bladder cancer. The latter patient had suspected lung metastases that were confirmed on chest CT 1 day later. Three of the 16 patients (18.8%) with preexisting or newly diagnosed cancer had malignant nodules. No malignant nodules were identified without such history. Six patients (14.3%) had an infection. CONCLUSION: Lung nodules incidentally detected on abdominal CT were rarely malignant and were seen only in the setting of an underlying abdominal malignancy. Knowledge of such history is of critical importance to both the clinician and the radiologist. Dedicated chest CT is most useful when assessing pulmonary nodules in patients with localized malignancy. PMID- 22451544 TI - Mean bronchial wall attenuation value in chronic obstructive pulmonary disease: comparison with standard bronchial parameters and correlation with function. AB - OBJECTIVE: The objective of our study was to evaluate bronchial wall attenuation values quantified using CT in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Ninety patients (81 men, nine women; age range, 21 80 years; mean age, 56 years) underwent CT and pulmonary function tests (PFTs). Bronchial wall attenuation value, wall area, and lumen area were averaged over four segmental bronchi in control subjects (n = 30), smokers with COPD (n = 30), and smokers without COPD (n = 30). The bronchial wall thickness, wall area-to lumen area ratio, and wall area-to-total area ratio were computed. The extent of emphysema was measured as the percentage of area with an attenuation of less than -950 HU. Parameters were compared among groups and were correlated with PFT results. Receiver operating characteristic curves were obtained for each parameter and areas under the curve were compared. Variables responsible for changes in wall attenuation values and those accounting for obstructive indexes were assessed using multiple regressions. RESULTS: The wall attenuation value was the only parameter discriminating between each pair of groups (mean +/- SD, -293 +/- 71 HU in COPD patients, -387 +/- 70 HU in smokers, and -457 +/- 69 HU in control subjects). The area under the curve of the wall attenuation value was greater than that of any other CT bronchial parameter to separate smokers from COPD patients. Wall attenuation value correlated with PFT results and was influenced by the wall area-to-lumen area ratio. The wall attenuation value, extent of emphysema, and standard bronchial parameters independently influenced obstructive indexes. CONCLUSION: The bronchial wall attenuation value is a powerful index for assessing tobacco-related bronchial wall changes in patients with COPD. PMID- 22451545 TI - Intraindividual comparison of gadobutrol and gadopentetate dimeglumine for detection of myocardial late enhancement in cardiac MRI. AB - OBJECTIVE: Gadobutrol is an extracellular macrocyclic gadolinium chelate recently introduced in MRI, and it has already been used for cardiac late enhancement imaging; however, until now it has never been compared with gadopentetate dimeglumine. The purpose of our study was to compare 0.1 mmol/kg gadobutrol to 0.2 mmol/kg gadopentetate dimeglumine for the detection of myocardial late enhancement in the same group of patients. SUBJECTS AND METHODS: This was an exploratory single-blind parallel group study comparing gadobutrol (0.1 mmol/kg) to gadopentetate dimeglumine (0.2 mmol/kg) in 20 adult patients scheduled for cardiac late enhancement MRI with gadopentetate dimeglumine and whose MR images showed late enhancement. MR images were acquired at 10, 15, and 20 minutes after peripheral injection of gadobutrol by using a 3D turbo field echo inversion recovery T1-weighted sequence. Volume and percentage of late enhancement, number of involved segments, late enhancement localization and pattern, and late enhancement signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between contrast agents. RESULTS: Late enhancement was not significantly different with gadobutrol and gadopentetate dimeglumine both in terms of total volume of myocardium (mean +/- SD, 37.8 +/- 56.1 and 35.1 +/- 46.7 cm(3), respectively; p = 0.33) and percentage of myocardial wall involvement (22.5% +/- 19.1% and 22.0% +/- 17.2%, respectively; p = 0.67). The number of segments involved was not different (138 with gadobutrol vs 134 with gadopentetate dimeglumine). Furthermore, SNR and CNR were not different (gadopentetate dimeglumine, 123.8 +/- 82.9 and gadobutrol, 117.2 +/- 88.6, p = 0.58 and gadopentetate dimeglumine, 96.2 +/- 68.9 and gadobutrol, 88.4 +/- 72.9, p = 0.53, respectively). CONCLUSION: A single dose of gadobutrol seems to be as effective as a double dose of gadopentetate dimeglumine for the detection of late enhancement. PMID- 22451546 TI - Initial assessment of dual-energy CT in patients with gallstones or bile duct stones: can virtual nonenhanced images replace true nonenhanced images? AB - OBJECTIVE: The purpose of our study was to investigate whether virtual nonenhanced images can replace true nonenhanced images for the evaluation of biliary stones and to compare two virtual nonenhanced images obtained from dual energy data sets during the late arterial phase (LAP) and portal venous phase (PVP) with true nonenhanced images. MATERIALS AND METHODS: One hundred patients with gallstones (n = 77) or bile duct stones (n = 23) who had undergone dual source dual-energy CT (using 80kVp and 140kVp with the ratio of dose partitioning, 1:1.3), were included. The CT numbers for the stone, liver, and bile; stone size; and image noise were assessed for each image set. The conspicuity and size of the stones, image quality, and acceptability of the virtual nonenhanced images as a replacement for true nonenhanced images were assessed. RESULTS: Virtual nonenhanced images from both LAP (VNE(LAP)) and PVP showed lower CT numbers for the stone and smaller stone size than did true nonenhanced images (p < 0.05). VNE(LAP) images failed to show stones in 16 patients (16%) with relatively radiolucent bile duct stones (< 78 HU) or small gallstones (< 9 mm(2), < 1.7 mm). There was no difference between the two virtual nonenhanced image sets except for the contrast-to-noise ratio of stone to bile and the image noise (CT numbers for the stone, liver, and muscle; stone size; and contrast-to-noise ratio of stone to liver, p = 1; the CT number for the bile, p = 0.1618; and effective dose, p = 0.7478). VNE(LAP) images were considered acceptable as a replacement for true nonenhanced images in 89% and 90% by reviewers 1 and 2, respectively. CONCLUSION: Virtual nonenhanced images allow the detection of biliary stones with moderate accuracy, irrespective of the dual energy contrast-enhanced phase. The detection of gallbladder stones of 9 mm(2) or smaller and of relatively radiolucent bile duct stones of 78 HU or lower is limited. PMID- 22451547 TI - Congenital cystic lesions of the biliary tree. AB - OBJECTIVE: The purpose of this essay is to illustrate the imaging findings of congenital cystic lesions of the biliary tract. CONCLUSION: Congenital cystic lesions of the biliary tract include ductal plate malformations and choledochal cysts and can be recognized with characteristic imaging findings and basic knowledge of the embryologic development of the biliary tree. PMID- 22451548 TI - Inadvertent ingestion of wire bristles from a grill cleaning brush: radiologic detection of unsuspected foreign bodies. AB - OBJECTIVE: We report acute onset of either odynophagia or abdominal pain immediately after ingestion of grilled meat in six patients presenting between May 1, 2009, and November 18, 2010. In all six patients, radiologic studies revealed a linear metallic foreign body. Careful history revealed cleaning of the grill with a metallic brush immediately before cooking in all six cases. CONCLUSION: Physicians should be aware of this potential hazard to facilitate accurate and timely diagnosis. PMID- 22451549 TI - Characterization of adrenal nodules with dual-energy CT: can virtual unenhanced attenuation values replace true unenhanced attenuation values? AB - OBJECTIVE: The purpose of our study was to investigate whether virtual unenhanced adrenal nodule attenuation values can replace true noncontrast attenuation values. MATERIALS AND METHODS: Twenty-three incidentally discovered adrenal nodules (19 adenomas and four metastases) were identified in 19 patients (11 men and eight women; mean age, 65 years; age range, 38-84 years) who underwent unenhanced single-energy CT followed by contrast-enhanced dual-energy CT on the same scanner. A virtual unenhanced imaging dataset was generated from each dual energy CT dataset. CT attenuation of each adrenal nodule was measured at the same location on virtual unenhanced images and true unenhanced images by three radiologists and mean values compared using the Student t test. Correlation between virtual unenhanced and true unenhanced values was determined using linear regression analysis. The mean difference and percentage of diagnostic agreement were also determined. Interreader variability was assessed using the intraclass correlation coefficient (ICC). RESULTS: The mean +/- SD attenuation values for virtual unenhanced images and true unenhanced images were 14.7 +/- 15.1 HU and 12.9 +/- 13.4 HU, respectively (p = 0.2). Strong positive correlation was observed between virtual unenhanced images and true unenhanced images (R = 0.83 0.87). The mean difference between virtual unenhanced images and true unenhanced images was 1.8 +/- 1.7 HU. Diagnostic agreement between virtual unenhanced images and true unenhanced images was 83-91% for three radiologists. No malignant nodules were misclassified as benign on virtual unenhanced images. The ICC was 0.88 and 0.96 for virtual unenhanced images and true unenhanced images, respectively, indicating high interreader agreement. CONCLUSION: Virtual unenhanced and true unenhanced attenuation measurements of adrenal nodules were not significantly different and showed strongly positive linear correlation. This finding resulted in substantial diagnostic agreement between virtual unenhanced images and true unenhanced images for distinguishing benign from malignant nodules. PMID- 22451550 TI - Centrally infiltrating renal masses on CT: differentiating intrarenal transitional cell carcinoma from centrally located renal cell carcinoma. AB - OBJECTIVE: The objective of our study was to retrospectively determine the accuracy of CT for differentiating intrarenal transitional cell carcinoma (TCC) from centrally located renal cell carcinoma (RCC) and to define the most discriminating diagnostic CT features. MATERIALS AND METHODS: CT studies of 98 pathologically proven central renal tumors (64 centrally located RCCs and 34 intrarenal TCCs) seen over 5 years at three university hospitals were reviewed by five specialty-trained radiologists who were blinded to the final diagnosis. Multiple CT features and global impression were graded on a 4-point score. The sensitivity and specificity of each feature and of global assessment were calculated and compared using receiver operating characteristic (ROC) analysis. Interobserver agreement (kappa values) was also calculated for each parameter. RESULTS: All five readers recognized intrarenal TCCs with a high diagnostic accuracy (sensitivity, 90%; specificity, 90%; area under ROC curve [AUC], 0.80 0.95 for global assessment) with moderate-to-excellent interobserver agreement (kappa = 0.72-1). Six CT features were most diagnostically specific for identifying intrarenal TCCs: tumor centered within the collecting system; focal filling defect in the pelvicalyceal system; preserved renal shape; absence of cystic or necrotic change; homogeneous tumor enhancement; and tumor extension toward the ureteropelvic junction (sensitivity, 68-82%; specificity, 79-89%; AUC, 0.75-0.84). There was moderate-to-good agreement among the readers over all these features (kappa = 0.44-0.69). CONCLUSION: Intrarenal TCC can be recognized with a high accuracy on CT; global impression showed the best diagnostic performance. A solid, homogeneously enhancing mass that is centered on the collecting system and extends toward the ureteropelvic junction combined with a focal pelvicalyceal filling defect and preserved renal outline is more likely to be an intrarenal TCC than a centrally located RCC. PMID- 22451551 TI - Masters of radiology panel discussion: maintaining maintenance of certification in the field of radiology. PMID- 22451552 TI - Association of hospital characteristics and diagnosis with the repeat use of CT and MRI: a nationwide population-based study in an Asian country. AB - OBJECTIVE: The objective of our study was to assess the association of hospital characteristics and diagnosis with repeated utilization of CT and MRI using the nationwide population-based Taiwan National Health Insurance database. MATERIALS AND METHODS: All CT and MR examinations for all health care services-including inpatient, outpatient, and emergency services-performed during 2004 and 2005 were identified. Logistic regression using generalized estimating equations was used for multivariate analysis to explore the relationships between hospital characteristics, diagnosis, and the use of CT and MRI repeated within 90 days. RESULTS: A total of 2,152,292 patients underwent CT and MR examinations during the study period, and 21.5% of those patients underwent repeat scanning within 90 days. The medical center had the highest rate of repeat scanning (24.9%) followed by the regional hospital (20.4%) and community hospital (13%). Repeat CT or MRI was most commonly performed of patients with a malignancy (31.8%), a neurologic disorder (24.0%), or a brain or spinal injury (25.3%). CONCLUSION: Our study shows that repeat use of CT and MRI within 90 days is high and is related to both diagnosis and hospital characteristics. Although the Taiwanese experience might not apply to all countries, this knowledge should aid in the review of health care policies so that guidelines for repeat scanning may be tailored to the different levels of hospitals (medical centers, 25%; regional hospital, 20%; community hospital, 13%) and to different diseases (malignant neoplasms, 32%; neurologic disorders and brain, neck, or spinal injury, 25%; other entities, 20%) to achieve maximum efficiency within a limited health care budget. PMID- 22451553 TI - Growth of carotid artery duplex ultrasound among Medicare beneficiaries (2000 2007). AB - OBJECTIVE: Although intervention in asymptomatic carotid artery stenosis remains controversial, most carotid interventions are performed in asymptomatic individuals. Carotid duplex ultrasound is the diagnostic test that precedes more than 90% of carotid interventions. In terms of economic incentives, providers who perform carotid artery revascularization may experience synergy if they also provide carotid duplex ultrasound, because the diagnostic service is reimbursed and also can lead to referrals for revascularization procedures. To test the hypothesis that providers of revascularization services are incentivized to increase utilization of carotid duplex ultrasound, we compared the utilization of carotid duplex ultrasound among Medicare beneficiaries by three specialties that perform revascularization for carotid stenosis (interventional radiology, vascular surgery, and cardiology) with one that usually does not (diagnostic radiology). MATERIALS AND METHODS: We analyzed 100% of procedure-specific claims submitted to Medicare by the four specialties during 2000, 2002, 2004, 2005, 2006, and 2007. Only professional and global components of services approved by Medicare were included. Compounded annual growth rates were used to compare utilization by different specialties. RESULTS: Utilization by diagnostic radiology increased at a compound annual growth rate of 1% during 2000-2007. Interventional radiology and vascular surgery experienced higher compound annual growth rates of 3% and 6%, respectively. Utilization by cardiology increased at a rate 11 times that of diagnostic radiology, translating into an additional 960 procedures per 100,000 Medicare beneficiaries by cardiology in 2007 than in 2000. CONCLUSION: Medicare beneficiaries are increasingly being tested for carotid artery stenosis, especially by specialties that perform revascularization for carotid stenosis. The health benefits of this practice are uncertain. PMID- 22451554 TI - Bisphosphonate-related femoral periosteal stress reactions: scoring system based on radiographic and MRI findings. AB - OBJECTIVE: The purpose of this study was to review the radiographic and MRI findings of bisphosphonate-related femoral periosteal stress reactions to propose a scoring system for predicting symptoms and fracture risk. MATERIALS AND METHODS: A retrospective study included patients undergoing long-term bisphosphonate therapy who had radiographic evidence of focal femoral periosteal thickening on radiographs and MR images. There were 43 femoral periosteal stress reactions in 33 patients; eight patients underwent MRI. Radiographs and MR images were evaluated for focal cortical thickening (periosteal and endosteal), bone edema, focal cortical abnormalities (radiolucency, striations, cavities), and dreaded black line. The radiographic score (derived with statistical methods) and simple scores (simple radiographic, MRI, and combined scores) were compared with symptoms and fracture outcome. RESULTS: Logistic regression analysis showed an association between radiographic dreaded black line and symptoms (odds ratio, 68.0). Kaplan-Meier and Cox regression analyses showed radiographic dreaded black line (p < 0.0005; hazard ratio, 27.3) and focal cortical radiolucency (p = 0.011; hazard ratio, 6.8) were independent predictors of fracture. The survival score derived from Cox regression coefficients showed good separation of high- and low risk groups. Mann-Whitney tests showed an association between MRI and combined scores and symptoms (p = 0.036, p = 0.036). The area under the receiver operating characteristic curve suggested better association with symptoms for MRI and combined scores than for simple radiographic scores (1.00, 1.00, 0.93). CONCLUSION: In bisphosphonate-related femoral periosteal stress reactions, radiographic dreaded black line and MRI and combined scores were associated with symptoms, and radiographic survival score was predictive of fracture risk. The relation between MRI and combined scores and fracture was not statistically significant. PMID- 22451555 TI - Validation of MRI classification system for tibial stress injuries. AB - OBJECTIVE: The purpose of our study was to compare an MRI classification system for tibial stress injuries with semiquantitative MR features of injury severity and clinical outcome. MATERIALS AND METHODS: Two musculoskeletal radiologists retrospectively reviewed in consensus the MR findings of 142 tibial stress injuries to quantify the degree of periosteal and bone marrow edema and grade the injuries using the Fredericson classification system (grade 1 = periosteal edema only, grade 2 = bone marrow edema visible on T2-weighted images, grade 3 = bone marrow edema visible on T1-weighted and T2-weighted images, grade 4a = multiple focal areas of intracortical signal abnormality, and grade 4b = linear areas of intracortical signal abnormality). Kruskal-Wallis tests were used to determine the relationship between the grade of stress injury and the degree of periosteal and bone marrow edema and the time to return to sports activity. RESULTS: Grade 4b injuries had significantly (p < 0.002) more severe and grade 1 injuries less severe periosteal and bone marrow edema than grades 2, 3, and 4a injuries. Grade 4b injuries had significantly (p < 0.002) longer time and grade 1 injuries shorter time to return to sports activity than grades 2, 3, and 4a injuries. There was no significant difference (p = 0.06-0.79) among grades 2, 3, and 4a injuries in the degree of periosteal and bone marrow edema and the time to return to sports activity. CONCLUSION: Grades 2, 3, and 4a stress injuries had similar degrees of periosteal and bone marrow edema and similar time to return to sports activity, which suggests that these three grades can be combined into a single category in an abbreviated Fredericson classification system. PMID- 22451556 TI - The bright rim sign on MRI for anterior talofibular ligament injury with arthroscopic correlation. AB - OBJECTIVE: The purpose of this article is to determine whether bright rim lesions on MRI are a marker for anterior talofibular ligament injury. MATERIALS AND METHODS: The study included 34 patients who had an ankle injury and underwent arthroscopic surgery. All patients underwent 3-T MRI for the diagnosis of anterior talofibular ligament injury. If MRI revealed nonvisualization of the ligament, ligament discontinuity, and unusual ligament thickening (criterion 1) or the bright rim sign (criterion 2), the injury was considered to be a ligament disruption. After MRI, ankle arthroscopy was performed in all patients for a definitive diagnosis. RESULTS: Arthroscopy showed anterior talofibular ligament disruption in 33 patients. When the MRI diagnosis was based on criterion 1, anterior talofibular ligament disruption was diagnosed with a sensitivity of 60.6 66.7% and an accuracy of 58.8-67.6%. When the MRI diagnosis was based on both criteria 1 and 2, anterior talofibular ligament disruption was diagnosed with a sensitivity of 90.9-97.0% and an accuracy of 88.2-94.1%. By adding criterion 2 to the diagnosis, the sensitivity for anterior talofibular ligament injury was increased significantly (p < 0.01), and 8-12 additional patients with anterior talofibular ligament injury were diagnosed, most of whom exhibited a partial tear of the anterior talofibular ligament on arthroscopy. The interobserver agreement rate for the presence of anterior talofibular ligament disruption using criterion 1, both criteria, and the bright rim sign was fair to excellent. CONCLUSION: A cortical defect with bright dotlike or curvilinear high-signal-intensity lesions on T2-weighted MRI may be an additional morphologic feature to increase the diagnostic performance of detecting anterior talofibular ligament injuries, including those with partial tears. PMID- 22451557 TI - Contribution of the BRAF mutation analysis in calcified thyroid nodules. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic contribution of BRAF(V600E) mutation analysis from the fine-needle aspiration (FNA) specimens of calcified thyroid nodules. SUBJECTS AND METHODS: From January 2008 to December 2008, 139 patients with 139 calcified thyroid nodules prospectively underwent BRAF(V600E) mutation analysis and ultrasound-guided FNA. At ultrasound, the patterns of calcification were classified into microcalcification, macrocalcification, and rim calcification. The performance of FNA alone then FNA plus BRAF(V600E) mutation analysis for the diagnosis of calcified thyroid nodules was compared on the basis of surgery, repeated FNA, or imaging follow-up for at least 1 year. RESULTS: Of 139 calcified nodules, 92 (66%) malignancies were detected, which included 91 papillary thyroid carcinomas and one follicular thyroid carcinoma. The malignant rates based on calcification type were 80% (63 of 79) for microcalcifications, 59% (19 of 32) for macrocalcifications, and 36% (10 of 28) for rim calcifications. The BRAF(V600E) mutation was identified in 50% of all nodules and in five (25%) of 20 nodules with indeterminate or nondiagnostic cytology. Adding BRAF(V600E) mutation analysis to FNA compared with FNA alone improved the negative predictive value of 83.9 to 92.2% (p = 0.034) but not the sensitivity, specificity, positive predictive value, and accuracy. CONCLUSION: The BRAF(V600E) mutation analysis from FNA specimens for calcified thyroid nodules may be performed for a greater negative predictive value and unveil the malignancy in 25% of indeterminate or nondiagnostic cytology. PMID- 22451558 TI - Interobserver agreement and intraobserver reproducibility in thyroid ultrasound elastography. AB - OBJECTIVE: The objective of this study was to evaluate interobserver agreement and intraobserver reproducibility in thyroid ultrasound elastography. SUBJECTS AND METHODS: Fifty-six patients (56 nodules) were enrolled for this prospective study between December 2010 and March 2011. All patients were scheduled for thyroid surgery because their nodules had been found by fine-needle aspiration biopsies to be malignant, suspicious for malignancy, or follicular/Hurthle cell neoplasm. On each patient, three endocrinologists performed ultrasound elastography examinations using a commercial ultrasound machine. No external compression with the transducer was applied because pulsation from the carotid artery was used. Each endocrinologist repeated an elastography examination on the same thyroid nodule. An elasticity contrast index, which quantifies the local strain contrast within a nodule, was interactively determined after a nodule's boundary was delineated by the endocrinologist. A large elasticity contrast index value indicates an increased probability of the nodule being malignant. Pearson correlation coefficient was used to evaluate the interobserver and intraobserver agreement in the measured elasticity contrast index values, and p values < 0.05 were considered statistically significant. RESULTS: Significant interobserver and intraobserver agreement was found in thyroid ultrasound elastography. Pearson correlation coefficients between two observers were 0.79 (observers 1 and 2, p < 0.01), 0.77 (observers 1 and 3, p < 0.01), and 0.73 (observers 2 and 3, p < 0.01). Pearson correlation coefficients for intraobserver agreement were 0.87 (p < 0.01), 0.73 (p < 0.01), and 0.84 (p < 0.01) for observers 1, 2 and 3, respectively. CONCLUSION: Good interobserver and intraobserver agreement exists in thyroid ultrasound elastography. Compared with external compression elastography, we found that thyroid elastography with intrinsic compression can produce reliable results. PMID- 22451559 TI - PET/CT in the management of patients with stage IIIC and IV metastatic melanoma considered candidates for surgery: evaluation of the additive value after conventional imaging. AB - OBJECTIVE: The purpose of this article is to determine how often unexpected (18)F FDG PET/CT findings result in a change in management for patients with stage IV and clinically evident stage III melanoma with resectable disease according to conventional imaging. SUBJECTS AND METHODS: Thirty-two patients with oligometastatic stage IV and clinically evident stage III melanoma were identified by surgical oncologists according to the results of conventional imaging, which included contrast-enhanced CT of the chest, abdomen, and pelvis and MRI of the brain. The surgical plan included resection of known metastases or isolated limb perfusion with chemotherapy. Thirty-three FDG PET/CT scans were performed within 36 days of their contrast-enhanced CT. The impact of PET/CT was defined as the percentage of cases in which a change in the surgical plan resulted from the unanticipated PET/CT findings. RESULTS: PET/CT revealed unexpected melanoma metastases in 12% of scans (4/33). As a result, the surgery was canceled for two patients, and the planned approach was altered for another two patients to address the unexpected sites. In 6% of scans (2/33), the unexpected metastases were detected in the extremities, which were not included in conventional imaging. Three scans (9%) showed false-positive FDG-avid findings that proved to be benign by subsequent stability or resolution with no therapy. CONCLUSION: In patients with surgically treatable metastatic melanoma, FDG PET/CT can detect unexpected metastases that are missed or not imaged with conventional imaging, and can be considered as part of preoperative workup. PMID- 22451560 TI - The depiction of brown adipose tissue is related to disease status in pediatric patients with lymphoma. AB - OBJECTIVE: The objective of our study was to determine whether the depiction of brown adipose tissue (BAT) in PET/CT studies of pediatric patients with lymphoma is related to disease status. MATERIALS AND METHODS: The PET/CT studies of 31 pediatric patients (17 boys and 14 girls) with Hodgkin or non-Hodgkin lymphoma were reviewed, and the prevalence of metabolically active BAT at diagnosis and the prevalence of BAT when there was no evidence of disease were compared. RESULTS: The percentage of PET/CT studies depicting BAT was greater when there was no evidence of disease than at diagnosis (10% vs 77%, respectively; p < 0.001). The McNemar test indicated a strong inverse correlation between the presence of disease and the presence of BAT (p < 0.001). This correlation was noted when all subjects were examined together and when subjects with Hodgkin lymphoma and those with non-Hodgkin lymphoma were analyzed separately (p < 0.001 and < 0.05, respectively). When baseline and follow-up PET/CT scans for all patients were analyzed for the presence of BAT using conditional logistic regression, both the season when the study was performed and disease status independently predicted BAT: The winter months positively predicted BAT and the presence of lymphoma was negatively correlated with the depiction of BAT on PET/CT. Age, sex, treatment, and weight did not provide additional information when added to the model. CONCLUSION: The knowledge that BAT is a predictor of disease status should contribute to the correct analysis of PET/CT studies in children with lymphoma. PMID- 22451561 TI - Preoperative percutaneous transhepatic portal vein embolization with ethanol injection. AB - OBJECTIVE: The purpose of this article is to evaluate the feasibility and efficacy of preoperative percutaneous transhepatic portal vein embolization with ethanol injection. MATERIALS AND METHODS: We retrospectively evaluated 143 patients who underwent percutaneous transhepatic portal vein embolization. Hypertrophy of the future liver remnant was assessed by comparing the volumetric data obtained from CT image data before and after percutaneous transhepatic portal vein embolization. The evaluation of effectiveness was based on changes in the absolute volume of the future liver remnant and the ratio of the future liver remnant to the total estimated liver volume. RESULTS: Ten of 143 patients (7.0%) underwent additional embolization because of recanalization and insufficient hypertrophy of the future liver remnant. The mean increase in the ratio of the future liver remnant was 33.6% (p < 0.0001), and the mean ratio of future liver remnant to total estimated liver volume increased from 34.9% to 45.7% (p < 0.0001). Although most of the patients complained of pain after ethanol injection, they were gradually relieved of pain in a few minutes by conservative treatment. Fever (38-39 degrees C) was reported after 47 of 151 (31.1%) percutaneous transhepatic portal vein embolization sessions and was resolved within a few days. Transient elevation of the liver transaminases was observed after the procedures and resolved within about a week. Major complications occurred in nine of 151 (6%) percutaneous transhepatic portal vein embolization sessions, but no patients developed hepatic insufficiency or severe complications precluding successful resection. One hundred twenty patients underwent hepatic resection, and two patients developed hepatic failure after surgery. CONCLUSION: Preoperative percutaneous transhepatic portal vein embolization with ethanol is a feasible and effective procedure to obtain hypertrophy of the future liver remnant for preventing hepatic failure after hepatectomy. PMID- 22451562 TI - Safety and optimal management of hepatic arterial infusion chemotherapy after pancreatectomy for pancreatobiliary cancer. AB - OBJECTIVE: The purpose of this study was to assess the safety of hepatic arterial infusion (HAI) chemotherapy after pancreatectomy for pancreatobiliary cancer. MATERIALS AND METHODS: The study subjects comprised 51 patients treated with HAI chemotherapy after pancreatectomy: 31 patients had undergone pancreaticoduodenectomy or total pancreatectomy and 20 patients had undergone distal pancreatectomy. HAI chemotherapy was performed for the prevention of liver metastasis in 42 patients and for the treatment of metastases in nine patients. HAI chemotherapy consisted of 5-fluorouracil administered at 1000 mg/m(2)/wk. After each cycle of chemotherapy, the patency of the hepatic artery and complications were evaluated using digital subtraction angiography and CT arteriography via the catheter-port system. RESULTS: Placement of the catheter port system was successful in all patients. Hepatic arterial occlusion and severe asymptomatic hepatic artery stenosis were observed in one patient (2%) and 10 patients (19.6%), respectively. The hepatic arterial patency rate tended to be lower in the group who underwent pancreaticoduodenectomy or total pancreatectomy (71%) than in the group who underwent distal pancreatectomy (90%), although the difference was not significant (p = 0.107). Four asymptomatic patients with hepatic artery stenosis restarted HAI chemotherapy after a 4-week withdrawal of treatment. In three patients (5.9%), all of whom had undergone pancreaticoduodenectomy, liver abscess or biloma developed synchronously with asymptomatic hepatic artery stenosis. All three cases were cured by percutaneous abscess drainage or conservative management. The tumor response rate in the treatment of liver metastases was 44.4%. The hepatic recurrence rate with adjuvant therapy was 7.1%. CONCLUSION: Our findings suggest that HAI chemotherapy after pancreatectomy is feasible and tolerable, although caution is required particularly after pancreaticoduodenectomy or after total pancreatectomy. PMID- 22451563 TI - Image quality, contrast enhancement, and radiation dose of ECG-triggered high pitch CT versus non-ECG-triggered standard-pitch CT of the thoracoabdominal aorta. AB - OBJECTIVE: We sought to compare image quality, contrast enhancement, and radiation dose in patients undergoing ECG-triggered high-pitch helical CT or non ECG-synchronized helical CT of the thoracoabdominal aorta. MATERIALS AND METHODS: We retrospectively assessed data from 101 consecutive patients (81 men, 20 women; mean age, 71 +/- 11 [SD] years) undergoing clinically indicated CT angiography (CTA) of the thoracoabdominal aorta on a dual-source scanner using either the ECG triggered high-pitch helical mode (group 1, n = 52) or non-ECG-synchronized standard-pitch helical mode (group 2, n = 49) during the arterial phase. Two independent readers assessed image quality, noise, and contrast enhancement throughout the thoracoabdominal aorta. Scanner-reported dose-length product values were used to estimate effective dose values. RESULTS: Image quality at the root-proximal ascending level was higher in group 1 (mean +/- SD, 2.81 +/- 0.40) than in group 2 (1.22 +/- 0.47; p < 0.0001), with similar quality for both groups noted at other levels. Group 1 scans displayed higher image noise at all levels. The groups received a similar volume of contrast material (p = 0.77), and similar percentages of cases with acceptable contrast enhancement (> 250 HU) were noted in the two groups. The estimated radiation burden was significantly lower in group 1 (mean +/- SD, 5.4 +/- 1.8 mSv) than in group 2 (14.4 +/- 5.1 mSv; p < 0.0001). CONCLUSION: Imaging of the thoracoabdominal aorta with ECG-triggered high-pitch CTA provides higher quality images of the aortic root and ascending aorta with sufficient contrast enhancement and decreased estimated radiation dose compared with non-ECG-synchronized standard-pitch helical CT. PMID- 22451564 TI - Aortoiliac CT angiography for planning transcutaneous aortic valve implantation: aortic root anatomy and frequency of clinically significant incidental findings. AB - OBJECTIVE: The purpose of this article is to assess aortic root and iliofemoral vessel anatomy and the frequency of clinically significant incidental findings on aortoiliac CT angiography (CTA) performed for planning of transcutaneous aortic valve implantation. MATERIALS AND METHODS: Aortoiliac CTA studies of 207 patients scheduled for transcutaneous aortic valve implantation were analyzed. Anatomic dimensions relevant to the interventional procedure, including diameter of the aortic annulus and sinus of Valsalva, distance between aortic annulus and coronary ostia, coronary leaflet length, left ventricular outflow tract diameter, and vessel diameter of iliac arteries, were analyzed. Clinically significant incidental findings were recorded. RESULTS: The mean (+/- SD) maximum and minimum diameters of the aortic annulus were 29 +/- 3.9 mm and 23.5 +/- 4.1 mm, respectively. The mean distances between aortic annulus and the ostium of the left and right coronary artery were 13.5 +/- 3.2 mm and 14.8 +/- 3.9 mm, respectively. The mean maximum and minimum diameters of the left ventricular outflow tract were 27 +/- 4 mm and 1.9 +/- 4 mm, respectively. The mean diameter of the sinus of Valsalva was 33.4 +/- 5.1 mm. The mean diameters of the right and left external iliac artery were 8 +/- 1 and 8 +/- 2 mm, respectively. Almost half the patients (101/207) had clinically significant incidental findings, including noncalcified pulmonary nodules larger than 8 mm (n = 7), pulmonary embolism (n = 3), or aortic aneurysm (n = 12). CONCLUSION: Aortoiliac CTA provides relevant information on aortic root and iliofemoral vessel anatomy for preinterventional planning. CTA reveals clinically significant incidental findings in a high number of patients considered for transcutaneous aortic valve implantation, which may have a significant impact on patient selection. PMID- 22451565 TI - Comparison of digital flat-panel detector and conventional angiography machines: evaluation of stent detection rates, visibility scores, and dose-area products. AB - OBJECTIVE: The objective of this study was to compare the performance and radiation doses of a flat-panel detector (FPD) angiography machine with an image intensifier (II) angiography machine. MATERIALS AND METHODS: Images of four nitinol stents (Sinus-SuperFlex, SMART, Luminexx, and Zilver stents) in a phantom of a human pelvis were acquired on an FPD system (Axiom Artis) and an II system (Fluorospot TOP) using the following modes: spot-film, continuous fluoroscopy (4, 7.5, 15, and 30 pulses/s), and three amplification modes. Objective stent detection rates and subjective radiopacity scores (scale: 0 [not visible] to 4 [excellent visibility]) were calculated. The radiation doses evaluated by the respective machines were compared. RESULTS: Over all modes and stents, the mean objective correct stent detection rates and mean subjective radiopacity scores were 89.49% and 1.81, respectively, for the Axiom Artis and 91.00% and 2.26 for the Fluorospot TOP. The stent detection rates over all modes for the SMART and Luminexx stents were better using the Axiom Artis machine (97.61% vs 93.55% and 98.28% vs 90.41%, respectively) and those for the Sinus-SuperFlex and Zilver stents were better using the Fluorospot TOP machine (90.83% vs 83.56% and 89.29% vs 80.50%). The subjective radiopacity scores of stent visibility were worse for the Axiom Artis than the Fluorospot TOP for all stents except the Luminexx stent (mean score, 2.34 vs 2.21, respectively). The objective stent detection rates and subjective radiopacity scores improved using the spot-film mode and with raising amplification, whereas increases in the fluoroscopy pulsing frequency did not improve stent detection rates or radiopacity scores for either machine. The radiation doses at continuous fluoroscopy were approximately 90% higher for the Axiom Artis than for the Fluorospot TOP (2.60 vs 1.41 MUGy/m(2) at 30 pulses/s, respectively). CONCLUSION: The objective correct stent detection rates were similar for both machines with differences in detection for the respective stents. The subjective radiopacity scores were almost always better for the Fluorospot TOP machine. Also, the Axiom Artis machine generated approximately 90% higher radiation doses in fluoroscopy. For both machines, using a higher fluoroscopy pulsing frequency had no positive effect on objective correct stent detection rates or subjective radiopacity scores. PMID- 22451566 TI - Intimal tears in thoracic aortic dissection: appearance on MDCT with virtual angioscopy. AB - OBJECTIVE: The location, number, size, and configuration of intimal tears in aortic dissection have important therapeutic and prognostic implications. Planning of procedures to treat complications of aortic dissection may require precise delineation of the intimal tears. The purpose of this article is to illustrate the ability of MDCT using multiplanar image reformatting and virtual angioscopy to depict the location and appearance of intimal tears and fenestrations within dissection flaps in cases of thoracic aortic dissection. CONCLUSION: MDCT with virtual angioscopy can depict the configuration of intimal tears in cases of thoracic aortic dissection, which may facilitate therapeutic planning. PMID- 22451567 TI - Using the BI-RADS lexicon in a restrictive form of double reading as a strategy for minimizing screening mammography recall rates. AB - OBJECTIVE: The purpose of this article is to determine the potential reduction in screening recall rates by strictly following standardized BI-RADS lexicon for lesions seen on screening mammography. MATERIALS AND METHODS: Of 3084 consecutive mammograms performed at our screening facilities, 345 women with 437 lesions were recalled for additional imaging and constituted our study population. Three radiologists retrospectively classified lesions using the standard BI-RADS lexicon and assigned each to one of four groups: group A, the finding met criteria for recall by the BI-RADS lexicon; group B, the finding did not meet strict BI-RADS criteria for recall but was sufficiently indeterminate to warrant recall by the majority of the study panel; group C, the finding was classifiable by the BI-RADS lexicon but was not recalled because it was benign or stable; and group D, the questioned finding was not considered an abnormality by our study panel. Recall rates and the cancer detection rate were determined. The adjusted recall rate was calculated for lesions considered appropriate for recall (group A), and the reduction in the recall rate was determined. RESULTS: Nineteen malignancies were detected in our recalled population, for a cancer detection rate of 0.65%. All 19 malignancies were lesions considered appropriate for recall (group A). If only group A lesions had been recalled, the recall rate would have decreased from 11.4% to 6.2%, representing a 46% reduction in recalls without affecting the cancer detection rate. CONCLUSION: Using the BI-RADS lexicon as a decision-making aid may help adjust thresholds for recalling indeterminate or suspicious lesions and reduce recall rates from screening mammography. PMID- 22451568 TI - Association between time spent interpreting, level of confidence, and accuracy of screening mammography. AB - OBJECTIVE: The objective of this study was to examine the effect of time spent viewing images and level of confidence on a screening mammography test set on interpretive performance. MATERIALS AND METHODS: Radiologists from six mammography registries participated in this study and were randomized to interpret one of four test sets and complete 12 survey questions. Each test set had 109 cases of digitized four-view screening screen-film mammograms with prior comparison screening views. Viewing time for each case was defined as the cumulative time spent viewing all mammographic images before recording which visible feature, if any, was the "most significant finding." Log-linear regression fit via the generalized estimating equation was used to test the effect of viewing time and level of confidence in the interpretation on test set sensitivity and false-positive rate. RESULTS: One hundred nineteen radiologists completed a test set and contributed data on 11,484 interpretations. The radiologists spent more time viewing cases that had significant findings or cases for which they had less confidence in their interpretation. Each additional minute of viewing time increased the probability of a true-positive interpretation among cancer cases by 1.12 (95% CI, 1.06-1.19; p < 0.001) regardless of confidence in the assessment. Among the radiologists who were very confident in their assessment, each additional minute of viewing time increased the adjusted risk of a false-positive interpretation among noncancer cases by 1.42 (95% CI, 1.21-1.68), and this viewing-time effect diminished with decreasing confidence. CONCLUSION: Longer interpretation times and higher levels of confidence in an interpretation are both associated with higher sensitivity and false-positive rates in mammography screening. PMID- 22451569 TI - Breast calcifications: the focal group. PMID- 22451570 TI - Accountability in professionalism. PMID- 22451571 TI - Radiation dose management: part 1, minimizing radiation dose in CT-guided procedures. AB - OBJECTIVE: The purpose of this article is to discuss radiation dose during CT guided interventions and to explain how radiologists can modify technical factors to minimize radiation doses. Scanner-displayed indexes of radiation exposure that are available during the procedure will be defined to increase awareness about CT radiation dose reduction during interventional procedures. CONCLUSION: CT-guided fluoroscopic procedures are safe and effective methods of directed intervention; however, the increasing use of medical radiation is an important consideration. The appropriate use of imaging with an acceptable risk must be considered in every case. During CT-guided interventions, scanner parameters that can be used as a guide for effective dose management, including the CT dose index and dose length product, are readily displayed. These parameters can be adjusted by modifying the longitudinal scan length, number of scans, and tube current exposure time product (milliampere * second [mAs]). A team approach to radiation dose reduction will work the best. PMID- 22451572 TI - Radiation dose management: part 2, estimating fetal radiation risk from CT during pregnancy. AB - OBJECTIVE: The purpose of this article is to review fetal radiation doses and associated risks resulting from CT performed during pregnancy. The scanning parameters that influence dose and the techniques for estimating and reducing dose are explained. CONCLUSION: Fetal radiation doses for CT examinations in which the fetus is not directly imaged-for example, head or chest CT-are minimal and need not figure in the risk-benefit analysis to perform the examination. In contrast, radiation dose should be considered with abdominopelvic CT because the fetus is likely to be exposed directly to the scanning beam. Safe implementation of CT in this setting requires an understanding of the factors influencing radiation dose. With this knowledge, when a risk-benefit analysis in a given clinical situation favors imaging using CT, the radiologist need not withhold or delay the examination and can achieve diagnostic-quality images while reducing radiation exposure. PMID- 22451573 TI - 3-T high-resolution MR neurography of sciatic neuropathy. AB - OBJECTIVE: The sciatic nerve may normally exhibit mild T2 hyperintensity in MR neurography (MRN) images, rendering assessment of sciatic neuropathy difficult. The purpose of this case-control study was to evaluate whether a quantitative and qualitative analysis of the sciatic nerves and regional skeletal muscles increases the accuracy of MRN in detecting sciatic neuropathy. MATERIALS AND METHODS: We retrospectively reviewed the MRN studies of the pelvis and thighs of 34 subjects (12 men and 22 women; mean [+/- SD] age, 50 +/- 15 years), of which 17 had a final diagnosis of sciatic neuropathy according to electrodiagnostic or surgical confirmation, and 17 had no evidence of sciatic neuropathy and served as control subjects. On each side, the sciatic nerves were evaluated for signal intensity (SI), size, course, and fascicular shape, whereas the regional skeletal muscles were evaluated for edema, fatty replacement, and atrophy. In addition, the nerve-to-vessel SI ratio was registered for each side at the same time and 8 months later. RESULTS: The sciatic nerves of the abnormal sides exhibited higher nerve-to-vessel SI ratios and higher incidences of T2 hyperintensity, enlargement, and abnormal fascicular shape compared to the nerves of the normal sides. The regional muscles of the abnormal sides demonstrated a higher grade of fatty infiltration and higher frequencies of edema and atrophy. A cutoff value of nerve-to-vessel SI ratio of 0.89 exhibited high sensitivity and specificity in predicting sciatic neuropathy. Calculation of the nerve-to-vessel SI ratio demonstrated excellent inter- and intraobserver reliability. CONCLUSION: Both qualitative and quantitative criteria should be used to suggest the MRN diagnosis of sciatic neuropathy. PMID- 22451574 TI - The diagnostic accuracy of radiographs in Lisfranc injury and the potential value of a craniocaudal projection. AB - OBJECTIVE: The purpose of this study is to determine the diagnostic accuracy of radiographs in the diagnosis of Lisfranc injury. In addition, a foot phantom was investigated to determine the optimum degree of craniocaudal angulation on the anteroposterior radiograph to best show the joint. The angle of the joint in patients with midfoot injury was investigated to determine the optimum degree of craniocaudal angulation. MATERIALS AND METHODS: Sixty patients examined by CT had their radiographs evaluated independently and by consensus opinion by two observers, and the diagnostic performance was calculated using CT as the reference standard. A foot phantom was radiographed with varying degrees of craniocaudal angulation, and the radiograph that best revealed the joint was determined. This was compared with the angle of the joint as measured on CT. The angle of the joint in all 60 patients was measured on CT. RESULTS: The radiographs correctly identified 31 of the 45 cases (68.9%) of Lisfranc injury, with a positive predictive value of 84.4%, a negative predictive value of 53.3%, a sensitivity of 84.4%, and a specificity of 53.3%. Twenty degrees of craniocaudal angulation best showed the second tarsal-metatarsal joint of the phantom, and this correlated with a 20 degrees angle measured by CT. The mean (+/- SD) angle of the joint in the patients was 28.9 degrees +/- 5.7 degrees . CONCLUSION: Conventional radiographs miss a significant number of cases of Lisfranc injury. Craniocaudal angulation can better show the joint, and an angle of 28.9 degrees is likely to optimally visualize the joint in the majority of patients. PMID- 22451575 TI - Ultraselective arterial embolization of vasa recta using 1.7-French microcatheter with small-sized detachable coils in acute colonic hemorrhage after failed endoscopic treatment. AB - OBJECTIVE: The purpose of this article is to document our experiences with ultraselective arterial embolization to manage acute colonic hemorrhage using a 1.7-French microcatheter with small-sized detachable coils and to discuss the feasibility and clinical efficacy of this new technique. CONCLUSION: We achieved technical success in all four patients with the sole use of short-segment embolization of the long branch of the vasa recta. Our findings suggest that this technique is useful for embolization in cases of colonic hemorrhage. PMID- 22451576 TI - Background parenchymal enhancement on breast MRI: impact on diagnostic performance. AB - OBJECTIVE: Breast density is documented to reduce sensitivity and specificity of mammography. However, little is known regarding the effect of normal background parenchymal enhancement on accuracy of breast MRI. The purpose of this study was to evaluate the effect of background parenchymal enhancement on MRI diagnostic performance. MATERIALS AND METHODS: A review of our established MRI data identified all women undergoing breast MRI from March 1, 2006, through June 30, 2007. Prospectively reported background parenchymal enhancement categories of minimal, mild, moderate, or marked (anticipated BI-RADS MRI lexicon definitions) and assessments were extracted from the database for each patient. Outcomes were determined by pathologic analysis, imaging, and linkage with the regional tumor registry with a minimum of 24 months of follow-up. Patients were dichotomized into categories of minimal or mild versus moderate or marked background parenchymal enhancement. Associations with patient age, abnormal interpretation rate, positive biopsy rate, cancer yield, sensitivity, and specificity were compared using chi-square and z score tests. RESULTS: The study cohort included 736 women. Moderate or marked background parenchymal enhancement was significantly more frequent among patients younger than 50 years compared with those 50 years old and older (39.7% vs 18.9%; p < 0.0001). Moderate or marked background parenchymal enhancement was also associated with a higher abnormal interpretation rate compared with minimal or mild background parenchymal enhancement (30.5% vs 23.3%; p = 0.046). Positive biopsy rate, cancer yield, sensitivity, and specificity were not significantly different according to background parenchymal enhancement category. CONCLUSION: Increased background parenchymal enhancement on breast MRI is associated with younger patient age and higher abnormal interpretation rate. However, it is not related to significant differences in positive biopsy rate, cancer yield, sensitivity, or specificity of MRI. PMID- 22451577 TI - Incidence of ovarian maldescent in women with mullerian duct anomalies: evaluation by MRI. AB - OBJECTIVE: The objective of our study was to evaluate the incidence of ovarian mal-descent in patients with and in those without mullerian duct anomalies. MATERIALS AND METHODS: Multiplanar MRI examinations of patients with (n = 65) and those without (n = 64) congenital uterine anomalies were evaluated for ovarian size, position, follicle count, and associated renal anomalies. Patients who were pregnant, had known prior pelvic surgery, or had large uterine leiomyomas were excluded. Two criteria were used to determine ovarian malposition: Was the upper pole of the ovary above the pelvic brim, as defined by the pubic symphysis-sacral promontory line, or was the upper pole of the ovary at or above the iliac artery bifurcation? RESULTS: The mullerian duct anomalies identified in the study group included hypoplasia, unicornuate, didelphys, bicornuate, and septate uterus. Ovarian maldescent was identified in 12 of 65 women with uterine anomalies (17%) as compared with two of 64 women with normal uterine anatomy (3%) using the criterion of the ovarian pole being above the iliac bifurcation. Among the women with mullerian duct anomalies, only three of 29 with septate uterus (10%) had ovarian maldescent compared with the remaining nine of 36 women with other anomalies (25%). Ovarian size did not vary significantly between the two groups. Follicle count was increased in women with mullerian duct anomalies. Renal anomalies were present in 16 of 65 patients, five of whom had concomitant ovarian maldescent. CONCLUSION: The incidence of ovarian maldescent is increased in patients with mullerian duct anomalies, with the highest association seen in those with didelphys, unicornuate, or bicornuate uterus. PMID- 22451578 TI - Imaging features of primary breast sarcoma. AB - OBJECTIVE: This purpose of this study is to describe the imaging findings in patients who presented with a diagnosis of primary breast sarcoma. MATERIALS AND METHODS: A search was performed of the pathology database at a single institution for patients with a histopathologic diagnosis of primary breast sarcoma or pure sarcomatoid carcinoma and who underwent preoperative mammography, sonography, or MRI. Patients with malignant phyllodes tumors were excluded. The imaging studies were retrospectively reviewed using the American College of Radiology BI-RADS lexicon. We documented clinical presentation, histopathologic characteristics, axillary nodal status, and the presence of distant metastases. RESULTS: Twenty four women were included in the study; their mean age was 56 years (range, 21-86 years), and the mean tumor size was 6.1 cm (range, 0.9-15 cm). Only one tumor was identified in each patient. The predominant mammographic finding was a noncalcified oval mass with indistinct (9/14 [64%]) margins. Sonography most commonly revealed an oval (19/22 [86%]) solid mass with indistinct margins (17/22 [77%]). The masses were frequently hypoechoic (18/21 [86%]) and hypervascular (17/20 [85%]) and had posterior acoustic enhancement (13/21 [62%]). MRI showed a round or oval T2-hyperintense mass with irregular margins in four of five (80%) patients, and inhomogeneous enhancement was most common (3/4 [75%]). CONCLUSION: Primary breast sarcoma has imaging features that are not typically seen in infiltrating ductal carcinoma. A large oval hypervascular mass with indistinct margins should raise the suspicion for a primary breast sarcoma and prompt biopsy. PMID- 22451579 TI - Reporting images for tube or catheter placement. PMID- 22451580 TI - Storing unread radiologic images on PACS. PMID- 22451581 TI - Intraoperative ultrasound of the liver. PMID- 22451582 TI - Double-edged sword of the new cancer therapeutics. PMID- 22451583 TI - Application of geographic modeling techniques to quantify spatial access to health services before and after an acute cardiac event: the Cardiac Accessibility and Remoteness Index for Australia (ARIA) project. AB - BACKGROUND: Access to cardiac services is essential for appropriate implementation of evidence-based therapies to improve outcomes. The Cardiac Accessibility and Remoteness Index for Australia (Cardiac ARIA) aimed to derive an objective, geographic measure reflecting access to cardiac services. METHODS AND RESULTS: An expert panel defined an evidence-based clinical pathway. Using Geographic Information Systems (GIS), the team developed a numeric/alphabetic index at 2 points along the continuum of care. The acute category (numeric) measured the time from the emergency call to arrival at an appropriate medical facility via road ambulance. The aftercare category (alphabetic) measured access to 4 basic services (family doctor, pharmacy, cardiac rehabilitation, and pathology services) when a patient returned to his or her community. The numeric index ranged from 1 (access to principal referral center with cardiac catheterization service <=1 hour) to 8 (no ambulance service, >3 hours to medical facility, air transport required). The alphabetic index ranged from A (all 4 services available within a 1-hour drive-time) to E (no services available within 1 hour). The panel found that 13.9 million Australians (71%) resided within Cardiac ARIA 1A locations (hospital with cardiac catheterization laboratory and all aftercare within 1 hour). Those outside Cardiac 1A were overrepresented by people >65 years of age (32%) and indigenous people (60%). CONCLUSIONS: The Cardiac ARIA index demonstrated substantial inequity in access to cardiac services in Australia. This methodology can be used to inform cardiology health service planning and could be applied to other common disease states within other regions of the world. PMID- 22451584 TI - Pulmonary arterial hypertension in patients treated by dasatinib. AB - BACKGROUND: The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. METHODS AND RESULTS: This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (<=20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. CONCLUSIONS: Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib. PMID- 22451585 TI - Interval arthrometric comparison of anterior cruciate ligament reconstruction using bone-patellar tendon-bone autograft versus allograft: do grafts attenuate within the first year postoperatively? AB - BACKGROUND: There is little information regarding the incremental changes in the postoperative laxity of patellar tendon (PT) autografts versus allografts in anterior cruciate ligament (ACL) reconstruction. HYPOTHESES: (1) There would be no significant increase in laxity between 6 weeks and 1 year postoperatively with PT autografts or allografts, (2) there would be no significant difference in laxity between PT autografts and allografts, (3) there would not be a significant difference in laxity between nonirradiated and low dose-irradiated PT allograft tissues, and (4) the physical examination findings would correlate with the instrumented laxity outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective review of 238 ACL-deficient patients who underwent single-incision endoscopic ACL reconstruction with a PT autograft (n = 132) or allograft (n = 106; 58 irradiated and 48 nonirradiated) from a single surgeon was made looking at data from preoperatively and from 6 weeks to 1 year postoperatively. The objective measurements of ligament integrity included range of motion, Lachman test, pivot-shift test, and KT-1000 arthrometer instrumented laxity examination. Failure was defined as arthrometric side-to-side differences (maximum manual difference) >=3 mm or a positive pivot shift. Statistical significance was defined as P < .05. RESULTS: There were no differences in postoperative examination findings or instrumented laxity between PT autografts and allografts (irradiated or nonirradiated) in either subgroup. The postoperative improvement based on the Lachman examination, pivot-shift test, and arthrometric data in all study groups was significant (P < .001) in 98% (autograft: n = 130; allograft: n = 104) of patients, and arthrometric failure correlated with failure by physical examination. There was no significant change in graft laxity, as measured by KT-1000 arthrometer, from 6 weeks to 1 year postoperatively for 98% of patients. Finally, there was no statistical correlation in instrumented laxity results for either the autograft or allograft group with reference to age, gender, concurrent meniscectomy, meniscal repairs, interval to surgery, postoperative patellar pain, time to surgery, or irradiated versus nonirradiated allograft. CONCLUSION: Laxity is not increased after the initial 6 weeks for either PT allograft or autograft constructs during the first postoperative year. There was no correlation between age, gender, concomitant injury, interval to surgery, or radiation of the graft with instrumented laxity results. Furthermore, our arthrometric data paralleled our clinical findings of stability at follow-up. PMID- 22451591 TI - Manipulation of hyperbaric lidocaine using a weak magnetic field: a pilot study. AB - High spinal block is a potentially fatal complication of spinal anesthesia, with an incidence of 0.6 per 1000. Current prevention strategies include decreasing the dose of local anesthetic drug and altering patient positioning such that the location of hyperbaric anesthetic drugs in the neuraxis can be manipulated by gravity. Incorporation of a ferrofluid into a local anesthetic solution, combined with application of an external magnetic field in an in vitro spine model, allowed control of position of a solution of ferrofluid, dye, and local anesthetic against gravity, suggesting an additional mechanism by which anesthesia providers may prevent high spinal block. PMID- 22451592 TI - The effects of peptide and lipid endocannabinoids on arthritic pain at the spinal level. AB - BACKGROUND: Hemopressin, a nonapeptide (PVNFKFLSH: HP) derived from the alpha chain of hemoglobin was shown to interact specifically with brain cannabinoid CB(1) receptors. Therefore, it seems to be the only peptide structure with cannabinoid activities. Our goal in this study was to further characterize this peptide and to clarify the antinociceptive potency of the polyunsaturated fatty acid derivates, 2-arachidonoyl-glycerol (2-AG) and anandamide, by investigating their effects on mechanical allodynia at the spinal level. METHODS: HP was prepared on solid phase by in situ neutralization. After chronic intrathecal catheterization, mechanical hypersensitivity was produced in male Wistar rats by injection of carrageenan (300 MUg/30 MUL) into the tibiotarsal joint of one of the hind legs. Three hours after carrageenan administration, the ligands were administered intrathecally. The mechanical threshold was assessed using a dynamic aesthesiometer. RESULTS: 2-AG (1-200 MUg) and anandamide (10-200 MUg) decreased carrageenan-induced mechanical allodynia in a dose-dependent manner, whereas HP had no antinociceptive effect in a wide dose range (0.3-30 MUg). The effect of 2 AG was prevented by the CB(1) receptor antagonist AM 251, but not by the CB(2) antagonist SSR144528-2. HP (3 and 30 MUg) also inhibited the effect of 2-AG. None of the ligands influenced the degree of edema. CONCLUSIONS: HP posttreatment had no effect on mechanical allodynia, whereas spinally injected 2-AG and anandamide were potent drugs. PMID- 22451593 TI - Off-label use of medications in children undergoing sedation and anesthesia. AB - BACKGROUND: Many drugs used for anesthesia and analgesia in children are administered "off-label." We undertook an audit of drugs commonly used for pediatric anesthesia to determine which drugs have United States Food and Drug Administration (FDA) labeling for pediatric use, which drugs are age-restricted, and which have no labeling for pediatric use. METHODS: We identified drugs administered during anesthesia to pediatric patients from the operating room pharmacy. FDA approval and indications were determined by using the Thomson Micromedex(r) online database. Drugs without FDA approval for pediatric use were further examined for strength of evidence and strength of recommendation for their listed indications in the database. We then examined the rate of off-label drug administration to patients younger than the age of 18 years between July 1, 2010, and August 31, 2011. RESULTS: One hundred six drugs were identified. Thirty six (34%) were not FDA-labeled for use in any pediatric age group, 40 (38%) were FDA-labeled for use in all pediatric age groups, and 30 (28%) were FDA-labeled for use in only specific age groups. Drugs were administered off-label in 73.4% of cases. Of those not labeled for any pediatric age group, some were among the most commonly used drugs in pediatric anesthesia, including neostigmine, hydromorphone, and dopamine. CONCLUSIONS: Many drugs used for children during anesthesia continue to lack FDA labeling for pediatric use. Off-label use of these drugs is an accepted practice that is considered superior to the alternative of withholding needed medications. Studies are still needed to determine the safety and efficacy of drugs that lack FDA labeling for this vulnerable patient population. PMID- 22451594 TI - Acute kidney injury after lung resection surgery: incidence and perioperative risk factors. AB - BACKGROUND: Postoperative acute kidney injury (AKI) is associated with increased perioperative morbidity and mortality in a variety of surgical settings, but has not been well studied after lung resection surgery. In the present study, we defined the incidence of postoperative AKI, identified risk factors, and clarified the relationship between postoperative AKI and outcome in patients undergoing lung resection surgery. METHODS: A retrospective, observational study of patients who underwent lung resection surgery between January 2006 and March 2010 in a tertiary care academic center was conducted. Postoperative AKI was diagnosed within 72 hours after surgery based on the Acute Kidney Injury Network creatinine criteria. Logistic regression was used to model the association between perioperative factors and the risk of AKI within 72 hours after surgery. The relationship between postoperative AKI and patient outcome including mortality, days in hospital, and the requirement of reintubation was investigated. RESULTS: A total of 1129 patients (pneumonectomy n = 71, bilobectomy n = 30, lobectomy n = 580, segmentectomy n = 35, wedge resection/bullectomy n = 413) were included in the final analysis. Patients were an average of 61 years (SD 15) and 50% were female. AKI was diagnosed in 67 patients (5.9%) based on Acute Kidney Injury Network criteria (stage 1, n = 59; stage 2, n = 8; and stage 3, n = 0) within 72 hours after surgery, and only 1 patient required renal replacement therapy. Multivariate analysis demonstrated an independent association between postoperative AKI and hypertension (adjusted odds ratio [OR] 2.0, 95% confidence interval [CI]: 1.1-3.8), peripheral vascular disease (OR 4.4, 95% CI: 1.8-10), estimated glomerular filtration rate (OR 0.8, 95% CI: 0.69-0.93), preoperative use of angiotensin II receptor blockers (OR 2.2, 95% CI: 1.1-4.4), intraoperative hydroxyethyl starch administration (OR 1.5, 95% CI: 1.1-2.1), and thoracoscopic (versus open) procedures (OR 0.37, 95% CI: 0.15 0.90). Development of AKI was associated with increased rates of tracheal reintubation (12% vs 2%, P < 0.001), postoperative mechanical ventilation (15% vs 3%, P < 0.001), and prolonged hospital length of stay (10 vs 8 days, P < 0.001). There was no difference in mortality between the 2 groups (3% vs 1%, P = 0.12). CONCLUSIONS: Preoperative risk factors for AKI after lung resection surgery overlap with those established for other surgical procedures. Perioperative management seems to influence the risk of AKI after lung resection; in particular, the use of synthetic colloids may increase the risk, whereas thoracoscopic procedures may decrease the risk of AKI. Early postoperative AKI is associated with respiratory complications and prolonged hospitalization. PMID- 22451595 TI - Ventilation of neck breathers undergoing a diagnostic procedure or surgery. AB - Receiving sedation while undergoing a diagnostic procedure or general anesthesia for surgery is challenging for neck breathers including laryngectomees. Unfortunately, most medical personnel including nurses, medical technicians, surgeons, and anesthesiologists caring for laryngectomees before, during, and after surgery are not familiar with their unique anatomy, how they speak, and how to manage their airways during and after the operation. Methods to improve the care are discussed. Educating medical personnel about these issues can improve the care of neck breathers. PMID- 22451596 TI - Hemodynamic stability after intraarterial injection of verapamil for cerebral vasospasm. AB - BACKGROUND: Vasospasm after subarachnoid hemorrhage is a common and potentially life-threatening complication. Treatment of vasospasm may include intraarterial (IA) injections of verapamil into the cerebral vasculature. Clinical experience suggests that the average patient experiences an acute reduction in systemic blood pressure after IA verapamil. Our study objective was to (1) identify the effects of IA injection of verapamil on mean arterial blood pressure (MAP) and heart rate (HR) in patients with cerebral vasospasm and (2) determine the effect of verapamil dose on change in MAP and HR. We hypothesized that (1) selective IA injection of verapamil for treatment of cerebral vasospasm is associated with a reduction in MAP and an increase in HR and (2) the change in MAP and HR are linearly related to the dose of verapamil administered. METHODS: We prospectively studied subjects with vasospasm scheduled for cerebral angiography with possible IA injection of verapamil. All subjects were given a general anesthetic. Invasive arterial blood pressure and HR were monitored continuously and recorded at 10 second intervals throughout the procedure. We identified the lowest MAP and highest HR before and after verapamil injection. The association between IA verapamil and change in MAP and HR was determined using repeated-measures multivariate regression analysis, adjusting for potential confounding factors (weight, preoperative vasopressor use, and preinjection MAP). Data are reported as adjusted coefficients and 95% confidence intervals (CI). RESULTS: We included 20 subjects who underwent a total of 46 injections of IA verapamil. On the basis of our multivariate model, on average, each 5 mg of IA verapamil was associated with a 3.5 mm Hg reduction in MAP (95% CI -5.0 to -2.0, P < 0.001). HR was not significantly altered by IA verapamil on both unadjusted and adjusted analyses (nonsignificant increase of 0.4 beats per minute for each 5 mg of IA verapamil, 95% CI -1.6 to 2.4, P = 0.70). CONCLUSIONS: Under general anesthesia, injection of IA verapamil into cerebral arteries reduces MAP but does not change HR in the average patient. Further research is required to determine the clinical significance of these results. PMID- 22451597 TI - Acute normovolemic hemodilution can aggravate neurological injury after spinal cord ischemia in rats. AB - BACKGROUND: Acute normovolemic hemodilution (ANH) is currently performed during thoracoabdominal aortic surgery. However, the effects of ANH on spinal cord ischemic injury are currently unknown. Because hemodilution below a certain level of hematocrit (Hct) aggravates the neurological damage after cerebral ischemia, we hypothesized that ANH may increase neurological damage after spinal cord ischemia. The aim of these experiments was to determine the effects of ANH on spinal cord ischemic injury. METHODS: Thirty male Sprague-Dawley rats were randomly assigned to 1 of the following 3 groups: no hemodilution (group C), target Hct level of 30% (group HD30), and target Hct level of 25% (group HD25). ANH was performed upon withdrawal of blood and simultaneous replacement with the same volume with hydroxyethyl starch. Spinal cord ischemia and reperfusion were induced by using a balloon-tipped catheter placed in the descending thoracic aorta, and changes in mean arterial blood pressure were recorded. Neurological function of the hindlimbs was evaluated for 7 days and recorded using a motor deficit score (MDS) (0 = normal; 5 = complete paraplegia). The number of motor neurons within the spinal cord was counted after final MDS evaluation. RESULTS: Group HD25 developed hypotension during the latter part of the ANH procedure. Group C and group HD30 experienced 3 minutes of reperfusion hypotension, whereas 6 minutes of hypotension was observed in group HD25. Two rats in group HD25 died during the experimental period. Seven days after reperfusion, the MDS of group C, group HD30, and group HD25 was 1.0 (0.5-2.0), 1.0 (0.5-2.0), and 4.0 (2.8-4.2) (median [95% confidence interval]), respectively. Group HD25 showed significantly higher MDS compared with group C (corrected P = 0.0018; 95% CI for median difference = 1.0-3.5). Motor neuron numbers in the anterior horns of group C, group HD30, and group HD25 were 26.5 (25.0-27.5), 23.5 (22.0-26.5), and 12.5 (8.4 16.6) (median [95% CI]), respectively. Motor neuron numbers of group HD25 were significantly lower than those of group C (corrected P < 0.0001; 95% CI for median difference = 9.0-18.0). CONCLUSION: The results of the present study indicate that intraoperative ANH to an Hct of 25%, combined with coincident hypotension, caused a delayed recovery of baseline mean arterial blood pressure during the reperfusion period and aggravated neurological outcome after spinal cord ischemia. PMID- 22451598 TI - How the timberline formed: altitudinal changes in stand structure and dynamics around the timberline in central Japan. AB - BACKGROUND AND AIMS: Altitudinal timberlines are thought to move upward by global warming, a crucial topic in ecology. Tall tree species (the conifer Abies mariesii and the deciduous broad-leaved Betula ermanii) dominate the sub-alpine zone between 1600 and 2500 m a.s.l., the timberline, on Mount Norikura in central Japan. Dwarf pine Pinus pumila dominates above the timberline to near the summit (3026 m a.s.l.). This study evaluated how the timberline formed on Mount Norikura by examining altitudinal changes in stand structure and dynamics around the timberline. METHODS: One hundred and twenty-five plots of 10 m * 10 m were established around the timberline (2350-2600 m a.s.l.). Trunk diameter growth rate during 6 years was examined for A. mariesii, B. ermanii and P. pumila. Mortality during this period and mechanical damage scars on the trunks and branches due to strong wind and snow were examined for A. mariesii only. KEY RESULTS: The density, maximum trunk height and diameter of A. mariesii in plots decreased with altitude. The maximum trunk height of B. ermanii decreased with altitude, but density and maximum trunk diameter did not decrease. In contrast, the density of P. pumila abruptly increased from around the timberline. A strong negative correlation was found between the densities of P. pumila and tall tree species, indicating their interspecific competition. Trunk diameter growth rates of A. mariesii and B. ermanii did not decrease with altitude, suggesting that these two tall tree species can grow at the timberline. The ratio of trees with mechanical damage scars increased with altitude for A. mariesii, a tendency more conspicuous for larger trees. The mortality of larger A. mariesii was also greater at higher altitude. Tall tree species may not increase their trunk height and survive around the timberline because of mechanical damage. CONCLUSIONS: This study suggests that the altitudinal location of the timberline is mainly affected by mechanical damage due to strong wind and snow rather than by growth limitation due to low temperature. Therefore, the timberline would not move upward even under global warming if these growth and mortality characteristics do not change for a long time. PMID- 22451599 TI - The cyanogenic syndrome in rubber tree Hevea brasiliensis: tissue-damage dependent activation of linamarase and hydroxynitrile lyase accelerates hydrogen cyanide release. AB - BACKGROUND AND AIMS: The release of hydrogen cyanide (HCN) from injured plant tissue affects multiple ecological interactions. Plant-derived HCN can act as a defence against herbivores and also plays an important role in plant-pathogen interactions. Crucial for activity as a feeding deterrent is the amount of HCN generated per unit time, referred to as cyanogenic capacity (HCNc). Strong intraspecific variation in HCNc has been observed among cyanogenic plants. This variation, in addition to genotypic variability (e.g. in Trifolium repens), can result from modifications in the expression level of the enzymes involved in either cyanogenic precursor formation or HCN release (as seen in Sorghum bicolor and Phaseolus lunatus). Thus, a modification or modulation of HCNc in reaction to the environment can only be achieved from one to the next generation when under genetic control and within days or hours when transcriptional regulations are involved. In the present study, it is shown that in rubber tree (Hevea brasiliensis) HCNc is modulated by post-translational activity regulation of the key enzymes for cyanide release. METHODS: Linamarase (LIN) and hydroxynitrile lyase (HNL) activity was determined by colorimetric assays utilizing dissociation of the substrates p-nitrophenyl-beta-d-glucopyranoside and acetone cyanohydrin, respectively. KEY RESULTS: In rubber tree leaves, LIN and HNL show up to ten-fold increased activity in response to tissue damage. This enzyme activation occurs within seconds and results in accelerated HCN formation. It is restricted to the damaged leaf area and depends on the severity of tissue damage. CONCLUSIONS: LIN and HNL activation (in contrast to genetic and transcriptional regulations) allows an immediate, local and damage type-dependent modulation of the cyanogenic response. Accordingly, this post-translational activation plays a decisive role in the defence of H. brasiliensis against herbivores as well as pathogens and may allow more flexible reactions in response to these different antagonists. PMID- 22451600 TI - Interactions between exotic invasive plants and soil microbes in the rhizosphere suggest that 'everything is not everywhere'. AB - BACKGROUND: The study of soil biota in the context of exotic plant invasions has led to an explosion in our understanding of the ecological roles of many different groups of microbes that function in roots or at the root-soil interface. Part of this progress has been the emergence of two biogeographic patterns involving invasive plants and soil microbes. First, in their non-native ranges invasive plants commonly interact differently with the same soil microbes than native plants. Second, in their native ranges, plants that are invasive elsewhere commonly interact functionally with soil microbes differently in their home ranges than they do in their non-native ranges. These studies pose a challenge to a long-held paradigm about microbial biogeography - the idea that microbes are not limited by dispersal and are thus free from the basic taxonomic, biogeographical and evolutionary framework that characterizes all other life on Earth. As an analogy, the global distribution of animals that function as carnivores does not negate the fascinating evolutionary biogeographic patterns of carnivores. Other challenges to this notion come from new measurements of genetic differences among microbes across geographic boundaries, which also suggest that meaningful biogeographic patterns exist for microorganisms. SCOPE AND CONCLUSIONS: We expand this discussion of whether or not 'everything is everywhere' by using the inherently biogeographic context of plant invasions by reviewing the literature on interactions among invasive plants and the microorganisms in the rhizosphere. We find that these interactions can be delineated at multiple scales: from individual plants to continents. Thus the microbes that regulate major aspects of plant biology do not appear to be exempt from the fundamental evolutionary processes of geographical isolation and natural selection. At the important scales of taxonomy, ecotype and ecosystem functions, the fundamental ecology of invaders and soil microbes indicates that everything might not be everywhere. PMID- 22451601 TI - Extreme phenotypic variation in Cetraria aculeata (lichenized Ascomycota): adaptation or incidental modification? AB - BACKGROUND AND AIMS: Phenotypic variability is a successful strategy in lichens for colonizing different habitats. Vagrancy has been reported as a specific adaptation for lichens living in steppe habitats around the world. Among the facultatively vagrant species, the cosmopolitan Cetraria aculeata apparently forms extremely modified vagrant thalli in steppe habitats of Central Spain. The aim of this study was to investigate whether these changes are phenotypic plasticity (a single genotype producing different phenotypes), by characterizing the anatomical and ultrastructural changes observed in vagrant morphs, and measuring differences in ecophysiological performance. METHODS: Specimens of vagrant and attached populations of C. aculeata were collected on the steppes of Central Spain. The fungal internal transcribed spacer (ITS), glyceraldehyde-3 phosphate dehydrogenase (GPD) and the large sub-unit of the mitochondrial ribosomal DNA (mtLSUm), and the algal ITS and actin were studied within a population genetics framework. Semi-thin and ultrathin sections were analysed by means of optical, scanning electron and transmission electron microscopy. Gas exchange and chlorophyll fluorescence were used to compare the physiological performance of both morphs. KEY RESULTS AND CONCLUSIONS: Vagrant and attached morphs share multilocus haplotypes which may indicate that they belong to the same species in spite of their completely different anatomy. However, differentiation tests suggested that vagrant specimens do not represent a random sub-set of the surrounding population. The morphological differences were related to anatomical and ultrastructural differences. Large intercalary growth rates of thalli after the loss of the basal-apical thallus polarity may be the cause of the increased growth shown by vagrant specimens. The anatomical and morphological changes lead to greater duration of ecophysiological activity in vagrant specimens. Although the anatomical and physiological changes could be chance effects, the genetic differentiation between vagrant and attached sub-populations and the higher biomass of the former show fitness effects and adaptation to dry environmental conditions in steppe habitats. PMID- 22451602 TI - Invasive aspergillosis: a severe infection in juvenile systemic lupus erythematosus patients. AB - Infections are an important cause of morbidity and mortality in juvenile systemic lupus erythematosus (JSLE). Among them, invasive aspergillosis (IA), which is usually related to immunosuppressed patients, has been rarely reported in JSLE. From 1983 to 2011, 5604 patients were followed at our institution and 283 (5%) met the American College of Rheumatology (ACR) classification criteria for SLE. Six (2.1%) of our JSLE patients had IA. One of them was previously reported and five will be described herein. Four of them were female. The median age at JSLE diagnosis was 12 years (8-16) and the median interval between diagnosis of JSLE and IA was 6 months (1-38). All had pulmonary involvement and three of them had systemic involvement. The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was 19 (7-22). Diagnosis of IA was performed by isolation of Aspergillus spp., two in bronchoalveolar lavage culture and by way of autopsy in the others. All of them were treated with corticosteroids and/or immunosuppressive drugs at IA diagnosis (azathioprine and/or intravenous cyclophosphamide). They all required treatment in the pediatric intensive care unit with mechanical ventilation and antifungal therapy (fluconazole, amphotericin B, itraconazole and/or voriconazole); nonetheless, none of them survived. In conclusion, this was the first report that evaluated the prevalence of IA in a large population of JSLE patients from a tertiary pediatric hospital, and clearly showed the severity of the outcome, especially in patients with active disease and treated with immunosuppressive agents. This study reinforces the importance of early diagnosis and treatment with certain antifungals, especially in critically ill patients. PMID- 22451603 TI - Clinicopathological insights into lupus nephritis in South Africans: a study of 251 patients. AB - There are few published studies on biopsy proven lupus nephritis (LN) from sub Sahara Africa, mainly due to lack of expertise and pathology back-up for performing and interpreting renal biopsies in many centres. The purpose of this study was to document factors associated with biopsy proven LN and to determine clinical and laboratory models that best predict proliferative LN in South Africans. Of the 251 patients studied, 84.1% were females and 79.3% were of mixed ancestry. There were more observed cases of proliferative LN (63%) than non proliferative LN. Factors associated with proliferative LN were male gender (p = 0.049), haematuria on dipstix (p < 0.0001), proteinuria on dipstix (p = 0.042), low serum albumin (p = 0.032), low complement C3 (p < 0.0001), low complement C4 (p = 0.009) and positive double-stranded DNA (p = 0.039). Using four models designed from various combinations of the factors associated with proliferative LN, the specificity and positive predictive values were highest for the model that combined gender (male), presence of dipstix haematuria and proteinuria, hypoalbuminaemia, low C3 and low C4 and positive double-stranded DNA (100% respectively). Further study is recommended to identify the value of using these demographic and laboratory parameters in identifying patients with proliferative LN in resource limited centres where the performance of a biopsy is not possible. PMID- 22451604 TI - Lupus nephritis is more severe in children and adolescents than in older adults. AB - OBJECTIVE: To evaluate clinicopathological features and treatment response in patients with lupus nephritis (LN), comparing the childhood- and late-onset forms of the disease. METHODS: We retrospectively analyzed clinical presentation, treatment and evolution in patients diagnosed with LN by renal biopsy between 1999 and 2008. Patients were grouped by age-<=18 years (n = 23); and >=50 years (n = 13)-and were followed for the first year of treatment. RESULTS: The baseline features of the childhood- and late-onset groups, respectively, were as follows: mean age, 15 +/- 2 and 54 +/- 5 years; female gender, 87% and 92%; hypertension, 87% and 77%; Systemic Lupus Erythematosus Disease Activity Index, 29 +/- 9 and 17 +/- 7 (p = 0.002); estimated glomerular filtration rate (eGFR), 86 +/- 66 and 70 +/- 18 ml/min; concurrent SLE/LN diagnosis, 90% and 15% (p < 0.001); crescents on biopsy, 74% and 30% (p = 0.02); activity index on biopsy, 4.8 +/- 2.6 and 3.3 +/- 1.9 (p = 0.10); and interstitial fibrosis (>10%), 39% and 61% (p = 0.08). Treatment consisted mainly of methylprednisolone, prednisone and intravenous cyclophosphamide, average cumulative doses being similar between the groups. After 12 months of treatment, the eGFR in the younger and older patients was 116 +/- 62 and 78 +/- 20 ml/min, respectively (p = 0.005). Three of the younger patients progressed to dialysis at 12 months, compared with none of the older patients. CONCLUSION: Childhood-onset LN seems to be more severe than is late onset LN. PMID- 22451605 TI - Role for cysteine protease cathepsins in heart disease: focus on biology and mechanisms with clinical implication. PMID- 22451606 TI - Sudden death from genetic and acquired cardiomyopathies. PMID- 22451607 TI - Progress for stroke prevention with atrial fibrillation: emergence of alternative oral anticoagulants. PMID- 22451608 TI - Reverse Takotsubo cardiomyopathy associated with the consumption of an energy drink. PMID- 22451609 TI - Spontaneous intrastent dissection: late neointimal separation within a bare metal stent causing acute coronary syndrome. PMID- 22451610 TI - Bridging anticoagulation: is it needed when warfarin is interrupted around the time of a surgery or procedure? PMID- 22451611 TI - Concealed metastatic lung carcinoma presenting as acute coronary syndrome with progressive conduction abnormalities. PMID- 22451612 TI - Long-term survivor with pulmonary veno-occlusive disease. PMID- 22451614 TI - Letter by Espinoza regarding article, "Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia". PMID- 22451615 TI - Letter by Winkler et al regarding article, "Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia". PMID- 22451616 TI - The effect of adult HIFA waiver expansions on insurance coverage of children. AB - This article evaluates the effect of the Health Insurance Flexibility and Accountability (HIFA) demonstrations on uninsurance rates among children. HIFA could increase the probability that children would have health insurance either by directly enrolling a child into a HIFA program or by creating a "spillover" effect from adults onto children by making parents of children already eligible for public programs eligible for HIFA. Data were drawn from the Current Population Survey from 2000 to 2007. The estimation approach was a probit model using a difference-in-differences approach. The authors find that the HIFA wavier demonstrations had no measureable effect on the uninsurance rate among children, either through direct eligibility or through a "spillover" effect from parental eligibility. This suggests that public programs that integrate family insurance coverage into a single structure are likely to be more effective at reducing the rate of uninsurance than different programs for different members of the same family. PMID- 22451617 TI - The role of cognitive and learning theories in supporting successful EHR system implementation training: a qualitative study. AB - Given persistent barriers to effective electronic health record (EHR) system implementation and use, the authors investigated implementation training practices in six organizations reputed to have ambulatory care EHR system implementation "best practices." Using the lenses of social cognitive and adult learning theories, they explored themes related to EHR implementation training using qualitative data collected through 43 key informant interviews and 6 physician focus groups conducted between February 2009 and December 2010. The authors found consistent evidence that training practices across the six organizations known for exemplary implementations were congruent with the tenets of these theoretical frameworks and highlight seven best practices for training. The authors' analyses suggest that effective training programs must move beyond technical approaches and incorporate social and cultural factors to make a difference in implementation success. Taking these findings into account may increase the likelihood of successful EHR implementation, thereby helping organizations meet "meaningful use" requirements for EHR systems. PMID- 22451618 TI - The impact of the Medicaid/CHIP expansions on children: a synthesis of the evidence. AB - This article reviews findings from 38 rigorous studies published in the peer reviewed literature of the impact of the Medicaid/Children's Health Insurance Program (CHIP) expansions on children. There is strong evidence for increases in enrollment in public programs and reductions in uninsurance following eligibility expansions. Medicaid enrollment continued to increase during the CHIP era (a "spillover effect"). Evidence for improved access to and use of services, particularly for dental care, is also very strong. There are fewer studies of health status impacts, and the evidence is mixed. There is a very wide range in the size of effects estimated in the studies reviewed because of the methods used and the populations studied. The review identifies several important research gaps on this topic, particularly the small number of studies of the effects on health status. Both research methods and findings from the child expansions can provide insights for evaluating the coming expansions for adults under the Affordable Care Act. PMID- 22451620 TI - In search of a real "targeted" therapy for thyroid cancer. AB - Over the past 5 years, patients with progressive radioactive iodine-refractory thyroid cancer have responded to "targeted" multikinase inhibitors, which inhibit angiogenesis and not the tumor cell. Here, selumetinib targets the mitogen activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the (V600E)BRAF mutation. PMID- 22451619 TI - Abiraterone in prostate cancer: a new angle to an old problem. AB - Abiraterone acetate is an orally administered potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17), which is essential for synthesis of testosterone from cholesterol. Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer, residual androgens may still be detected in patients treated with luteinizing hormone-releasing hormone agonists or antagonists. Treatment with abiraterone results in rapid, and complete, inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself. An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo-controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate-resistant prostate cancer previously treated with docetaxel chemotherapy. Abiraterone's efficacy shows the importance of androgen signaling in patients with castrate-resistant metastatic disease, with additional confirmation from recent studies of other novel agents such as MDV3100, an androgen receptor signaling inhibitor. These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops, how to best sequence therapy, and how to optimize combinations with other emerging novel agents. PMID- 22451621 TI - Clinical measurement of von Willebrand factor by fluorescence correlation spectroscopy. AB - BACKGROUND: Identification of von Willebrand factor (vWF) abnormalities in a variety of conditions is hampered by the limitations of currently available diagnostic tests. Although direct multimer visualization by immunoelectrophoresis is a commonly used method, it is impractical as a routine clinical test. In this study, we used a biophysical analysis tool, fluorescence correlation spectroscopy (FCS), to measure vWF distributions. The goals were to develop a method that is quicker and simpler than vWF gel electrophoresis and to evaluate the potential of FCS as a clinical diagnostic technique. METHODS: We analyzed plasma from 12 patients with type 1 von Willebrand disease (vWD), 14 patients with type 2 vWD, and 10 healthy controls using a fluctuation-based immunoassay approach. RESULTS: FCS enabled identification and proper classification of type 1 and type 2 vWD, producing quantitative results that correspond to qualitative gel multimer patterns. FCS required minimal sample preparation and only a 5-min analysis time. CONCLUSIONS: This study represents the first implementation of FCS for clinical diagnostics directly on human plasma. The technique shows potential for further vWF studies and as a generally applicable laboratory test method. PMID- 22451622 TI - Digital PCR analysis of maternal plasma for noninvasive detection of sickle cell anemia. AB - BACKGROUND: Cell-free fetal DNA (cffDNA) constitutes approximately 10% of the cell-free DNA in maternal plasma and is a suitable source of fetal genetic material for noninvasive prenatal diagnosis (NIPD). The objective of this study was to determine the feasibility of using digital PCR for NIPD in pregnancies at risk of sickle cell anemia. METHODS: Minor-groove binder (MGB) TaqMan probes were designed to discriminate between wild-type hemoglobin A and mutant (hemoglobin S) alleles encoded by the HBB (hemoglobin, beta) gene in cffDNA isolated from maternal plasma samples obtained from pregnancies at risk of sickle cell anemia. The fractional fetal DNA concentration was assessed in male-bearing pregnancies with a digital PCR assay for the Y chromosome-specific marker DYS14. In pregnancies with a female fetus, a panel of biallelic insertion/deletion polymorphism (indel) markers was developed for the quantification of the fetal DNA fraction. We used digital real-time PCR to analyze the dosage of the variant encoding hemoglobin S relative to that encoding wild-type hemoglobin A. RESULTS: The sickle cell genotype was correctly determined in 82% (37 of 45) of male fetuses and 75% (15 of 20) of female fetuses. Mutation status was determined correctly in 100% of the cases (25 samples) with fractional fetal DNA concentrations >7%. The panel of indels was informative in 65% of the female bearing pregnancies. CONCLUSIONS: Digital PCR can be used to determine the genotype of fetuses at risk for sickle cell anemia. Optimization of the fractional fetal DNA concentration is essential. More-informative indel markers are needed for this assay's comprehensive use in cases of a female fetus. PMID- 22451623 TI - "The things we make, make us". PMID- 22451624 TI - The possibilities with paradexity. AB - This manuscript explores Howard's concept of paradexity: a convergence of paradox and complexity. Emerging paradigms of paradexity are explored including the emotional economy, sense making, time expansion, and communities of interest. Parse's theory of humanbecoming is presented as a theoretical basis to guide nursing in transcending the challenges of paradexity and cocreating a futuristic role for nursing. PMID- 22451625 TI - Trust-mistrust: a dimension of being professional. PMID- 22451626 TI - Trust-mistrust: conflicts of interest and nurse research. AB - Professional nurses have special obligations and responsibilities to society, especially in choices regarding participating in and utilizing and promoting nurse research as evidence for practice. Potential conflicts of interest are ever present and may interfere with healthcare recipients' desires and wishes. The author of this research column begins a discussion of potential conflicts of interest in nurse research that may have an impact on the confirmability of research findings. PMID- 22451627 TI - Teaching-learning in community: the metaphor of nurse as guest. AB - Metaphors are creative learning devices that may illustrate novel and different meanings in teaching-learning situations. In this column, the author discusses possible meanings of the metaphor of nurse as guest in nurse-community relationships from a humanbecoming theoretical lens. Humanbecoming teaching learning essences, paradoxes, and processes are used to illustrate potential ethical meanings and implications for nurse practice. PMID- 22451628 TI - Exploring creativity in teaching-learning. PMID- 22451629 TI - Humanbecoming and practice: fairness-unfairness. AB - In this column a synthetic definition of fairness-unfairness is followed by a situation study involving an exchange between two undergraduate nursing students and their professor. A series of situations unfolds in which the students encounter a refugee and her family as they enter the American healthcare system. Students share their impressions of fairness-unfairness in this family's experiences. The professor interacts with the students to demonstrate the humanbecoming way of being with persons while bearing witness to the choices made in living out their values. PMID- 22451630 TI - Illumination of Parse's theory of humanbecoming: modern literature as situation study. AB - The theory of humanbecoming can be illuminated through utilizing popular literature as a situation study. The living experience of Morrie Schwartz as related in Tuesdays with Morrie, serves as exemplar for lingering presence, the emerging now, and the three themes of meaning, rhythmicity, and transcendence. This exemplar formed the basis for an educational session for graduate nursing students in a nursing theory course. The response to this teaching methodology suggests popular literature can be used successfully in teaching nursing theory. PMID- 22451631 TI - Humanbecoming theory in practice: a case for theory-guided nurse practitioner education. AB - The age-old battle of what to include in nursing education continues. Now this battle extends itself into nurse practitioner education with a slightly different twist. Abandoning nursing theory-guided education for the medical model leaves nurse practitioner education flat. In this author's academic experience, nursing theory was included in the curriculum. The exemplar presented is testament to the distinction and significance of including nursing theory-guided education. The unique difference between nurse practitioners and physicians is the use of theory in practice. PMID- 22451632 TI - Discipline-specific knowledge: time for clarity. PMID- 22451633 TI - The future of nursing: how important is discipline-specific knowledge? A conversation with Jacqueline Fawcett. Interview by Dr. Janie Butts and Dr. Karen Rich. AB - Nurses have long attempted to secure a unique identity for the profession. Many scholars are now promoting an interdisciplinary framework for nursing practice. Fawcett is convinced that interdisciplinary practice poses a danger for nursing to lose its identity and that interdisciplinary practice cannot be successful if members of each discipline do not understand the conceptual models, practice, and research of their own discipline. Dr. Janie Butts and Dr. Karen Rich interviewed Dr. Jacqueline Fawcett about her views related to discipline-specific knowledge and nursing's future. The authors conclude that Fawcett's scientific foundation gives nursing the solidarity and power necessary to determine the unique internal goods of its practice. PMID- 22451634 TI - Making a meaningful contribution to nursing theory. AB - The value of being a part of a network of theoretically like-minded individuals for a small group of nurse scholars, namely Richard Cowling, Howard Butcher and William Cody, is here discussed. The like-mindedness in this case is what has been described by some as an angular view of nursing or the simultaneity paradigm. An underlying theme is that joy-sorrow often arises in living the isolation and connectedness of a career in nursing that includes a commitment to scholarship. PMID- 22451635 TI - A preliminary evaluation of the Well-Being Picture Scale-Children's Version (WPS CV) in a sample of fourth and fifth graders. AB - In this paper the authors report the development and preliminary evaluation of the Rogerian-based Well-Being Picture Scale-Children's Version in a sample of 19 fourth and fifth grade students. Data was collected in conjunction with a larger study that examined childhood overweight and depression, and other measurements in the data set included the Child Depression Inventory. Scores on the Child Depression Inventory indicated that 20% of the children in the study were at risk for depression. A significant statistical inverse correlation (p < .05) was found between the post-test scores on the Well-Being Picture Scale-Children's Version and the Child Depression Inventory indicating that as depression scores increase well-being scores decrease. PMID- 22451636 TI - Development and psychometric assessment of the Presence of Nursing Scale. AB - Nursing presence has been conceptualized in the literature. However, no instrument has been developed to measure it. The purpose of this study was to develop a scale to measure patients' perceptions of nursing presence and to examine its psychometric properties. A conceptual definition of nursing presence was operationalized and integrated into the 25-item Presence of Nursing Scale and tested on 330 hospitalized patients. Reliability and validity of the Presence of Nursing Scale were supported when tested with this sample. The study represents the first time the phenomenon of nursing presence has been measured. PMID- 22451637 TI - Health economics and informatics: the gap-fit of current healthcare and Parse practice. AB - The provision of healthcare is a major global preoccupation and there is a continuing challenge due to a growing demand with finite resources. The tensions at play mean that people and their quality of life, which ought to be the main value considered, can be given lower priority than aspects of health economics and informatics. In this paper the authors demystify the economics and informatics of healthcare, and challenge policy makers and project managers to put nursing care in the fore in their decision-making. As an illustration of the non-negotiable patient-centric values Parse's contributions to nursing are suggested. PMID- 22451638 TI - Dilemmas of international collaborative nursing partnerships. PMID- 22451639 TI - Nursing in Malawi: nursing theory in the movement to professionalize nursing. AB - Nursing in Malawi has been predominately a technical trade and only recently has begun the transition to a profession with autonomy and advanced degree preparation. Nursing theories provide a framework for the evolution of nursing to an independent profession. Theories provide a means for the articulation of the nursing role to other members of the healthcare team including consumers. Healthcare and human needs are basic and the guidance provided by nursing theories, including Nightingale's, gives language and structure to the education of nurses as the profession moves into advanced practice in a developing country. PMID- 22451640 TI - Fairness and justice as dimensions of leading-following. PMID- 22451641 TI - Fairness and justice in leading-following: opportunities to foster integrity in the first 100 days. AB - Fairness and justice in living the art of leading-following are explored from the perspective of the humanbecoming school of thought. In particular, fairness and justice are considered in light of the ideas of fostering integrity, being just, and trusting the process. PMID- 22451642 TI - Instead of reconceptualizing the nursing process let's re-name it. AB - The discipline of nursing embraces the unitary-transformative paradigm and its theories that focus on nursing with attention to the language of humanbecoming, holism, relationship, authentic presence, caring, ethical interaction, complexity, pattern, energy, and recognition. In hospital nursing practice the medical paradigm is more prevalent and focuses on regulatory compliance, the standardization of technical language of the electronic health record, and the implementation of evidence-based practice initiatives for patient safety and quality improvement. Nursing and nursing theories are considered a moral enterprise; they involve seeking the good or caring for patients, others, and complex systems. With the continued influence of the medical paradigm, the questions for nursing are: what kind of good does nursing want to promote, and what unique contribution to patient care do nurses provide through their language, theories, and practice? A new mnemonic of Recognizing, Connecting, Partnering, and Reflecting is proposed. PMID- 22451643 TI - Thoughts about evidence-based nursing practice. AB - This paper is an essay about evidence-based nursing practice, with an emphasis on evidence in the form of various types of theories developed by various modes of inquiry. The essay is the second in a series written to acknowledge the 25th anniversary of the founding of Nursing Science Quarterly. PMID- 22451646 TI - Plant programmed cell death caused by an autoactive form of Prf is suppressed by co-expression of the Prf LRR domain. AB - In tomato, the NBARC-LRR resistance (R) protein Prf acts in concert with the Pto or Fen kinase to determine immunity against Pseudomonas syringae pv. tomato (Pst). Prf-mediated defense signaling is initiated by the recognition of two sequence-unrelated Pst-secreted effector proteins, AvrPto and AvrPtoB, by tomato Pto or Fen. Prf detects these interactions and activates signaling leading to host defense responses including localized programmed cell death (PCD) that is associated with the arrest of Pst growth. We found that Prf variants with single amino acid substitutions at D1416 in the IHD motif (isoleucine-histidine-aspartic acid) in the NBARC domain cause effector-independent PCD when transiently expressed in leaves of Nicotiana benthamiana, suggesting D1416 plays an important role in activation of Prf. The N-terminal region of Prf (NPrf) and the LRR domain are required for this autoactive Prf cell death signaling but dispensable for accumulation of the Prf(D1416V) protein. Significantly, co-expression of the Prf LRR but not NPrf, with Prf(D1416V), AvrPto/Pto, AvrPtoB/Pto, an autoactive form of Pto (Pto(Y207D)), or Fen completely suppresses PCD. However, the Prf LRR does not interfere with PCD caused by Rpi-blb1(D475V), a distinct R protein-mediated PCD signaling event, or that caused by overexpression of MAPKKKalpha, a protein acting downstream of Prf. Furthermore, we found the Prf(D1416V) protein is unable to accumulate in plant cells when co-expressed with the Prf LRR domain, likely explaining the cell death suppression. The mechanism for the LRR-induced degradation of Prf(D1416V) is unknown but may involve interference in the intramolecular interactions of Prf or to binding of the unattached LRR to other host proteins that are needed for Prf stability. PMID- 22451647 TI - Plant genes related to gibberellin biosynthesis and signaling are differentially regulated during the early stages of AM fungal interactions. PMID- 22451648 TI - Ultrafast excited-state deactivation of flavins bound to dodecin. AB - Dodecins, a group of flavin-binding proteins with a dodecameric quaternary structure, are able to incorporate two flavins within each of their six identical binding pockets building an aromatic tetrade with two tryptophan residues. Dodecin from the archaeal Halobacterium salinarum is a riboflavin storage device. We demonstrate that unwanted side reactions induced by reactive riboflavin species and degradation of riboflavin are avoided by ultrafast depopulation of the reactive excited state of riboflavin. Intriguingly, in this process, the staggered riboflavin dimers do not interact in ground and photoexcited states. Rather, within the tetrade assembly, each riboflavin is kept under the control of the respective adjacent tryptophan, which suggests that the stacked arrangement is a matter of optimizing the flavin load. We further identify an electron transfer in combination with a proton transfer as a central element of the effective excited state depopulation mechanism. Structural and functional comparisons of the archaeal dodecin with bacterial homologs reveal diverging evolution. Bacterial dodecins bind the flavin FMN instead of riboflavin and exhibit a clearly different binding pocket design with inverse incorporations of flavin dimers. The different adoption of flavin changes photochemical properties, making bacterial dodecin a comparably less efficient quencher of flavins. This supports a functional role different for bacterial and archaeal dodecins. PMID- 22451649 TI - The role of ERp44 in maturation of serotonin transporter protein. AB - In heterologous and endogenous expression systems, we studied the role of ERp44 and its complex partner endoplasmic reticulum (ER) oxidase 1-alpha (Ero1-Lalpha) in mechanisms regulating disulfide bond formation for serotonin transporter (SERT), an oligomeric glycoprotein. ERp44 is an ER lumenal chaperone protein that favors the maturation of disulfide-linked oligomeric proteins. ERp44 plays a critical role in the release of proteins from the ER via binding to Ero1-Lalpha. Mutation in the thioredoxin-like domain hampers the association of ERp44C29S with SERT, which has three Cys residues (Cys-200, Cys-209, and Cys-109) on the second external loop. We further explored the role of the protein chaperones through shRNA knockdown experiments for ERp44 and Ero1-Lalpha. Those efforts resulted in increased SERT localization to the plasma membrane but decreased serotonin (5-HT) uptake rates, indicating the importance of the ERp44 retention mechanism in the proper maturation of SERT proteins. These data were strongly supported with the data received from the N-biotinylaminoethyl methanethiosulfonate (MTSEA-biotin) labeling of SERT on ERp44 shRNA cells. MTSEA-biotin only interacts with the free Cys residues from the external phase of the plasma membrane. Interestingly, it appears that Cys-200 and Cys-209 of SERT in ERp44-silenced cells are accessible to labeling by MTSEA-biotin. However, in the control cells, these Cys residues are occupied and produced less labeling with MTSEA-biotin. Furthermore, ERp44 preferentially associated with SERT mutants (C200S, C209S, and C109A) when compared with wild type. These interactions with the chaperone may reflect the inability of Cys-200 and Cys-209 SERT mutants to form a disulfide bond and self association as evidenced by immunoprecipitation assays. Based on these collective findings, we hypothesize that ERp44 together with Ero1-Lalpha plays an important role in disulfide formation of SERT, which may be a prerequisite step for the assembly of SERT molecules in oligomeric form. PMID- 22451650 TI - Ca2+-activated nucleotidase 1, a novel target gene for the transcriptional repressor DREAM (downstream regulatory element antagonist modulator), is involved in protein folding and degradation. AB - DREAM is a Ca(2+)-dependent transcriptional repressor highly expressed in neuronal cells. A number of genes have already been identified as the target of its regulation. Targeted analysis performed on cerebella from transgenic mice expressing a dominant active DREAM mutant (daDREAM) showed a drastic reduction of the amount of transcript of Ca(2+)-activated nucleotidase 1 (CANT1), an endoplasmic reticulum (ER)-Golgi resident Ca(2+)-dependent nucleoside diphosphatase that has been suggested to have a role in glucosylation reactions related to the quality control of proteins in the ER and the Golgi apparatus. CANT1 down-regulation was also found in neuroblastoma SH-SY5Y cells stably overexpressing wild type (wt) DREAM or daDREAM, thus providing a simple cell model to investigate the protein maturation pathway. Pulse-chase experiments demonstrated that the down-regulation of CANT1 is associated with reduced protein secretion and increased degradation rates. Importantly, overexpression of wtDREAM or daDREAM augmented the expression of the EDEM1 gene, which encodes a key component of the ER-associated degradation pathway, suggesting an alternative pathway to enhanced protein degradation. Restoring CANT1 levels in neuroblastoma clones recovered the phenotype, thus confirming a key role of CANT1, and of the regulation of its gene by DREAM, in the control of protein synthesis and degradation. PMID- 22451651 TI - Response to copper stress in Streptomyces lividans extends beyond genes under direct control of a copper-sensitive operon repressor protein (CsoR). AB - A copper-sensitive operon repressor protein (CsoR) has been identified in Streptomyces lividans (CsoR(Sl)) and found to regulate copper homeostasis with attomolar affinity for Cu(I). Solution studies reveal apo- and Cu(I)-CsoR(Sl) to be a tetramer assembly, and a 1.7-A resolution crystal structure of apo-CsoR(Sl) reveals that a significant conformational change is necessary to enable Cu(I) binding. In silico prediction of the CsoR regulon was confirmed in vitro (EMSA) and in vivo (RNA-seq), which highlighted that next to the csoR gene itself, the regulon consists of two Cu(I) efflux systems involving a CopZ-like copper metallochaperone protein and a CopA P(1)-type ATPase. Although deletion of csoR has only minor effects on S. lividans development when grown under high copper concentrations, mutations of the Cu(I) ligands decrease tolerance to copper as a result of the Cu(I)-CsoR mutants failing to disengage from the DNA targets, thus inhibiting the derepression of the regulon. RNA-seq experiments carried out on samples incubated with exogenous copper and a DeltacsoR strain showed that the set of genes responding to copper stress is much wider than anticipated and largely extends beyond genes targeted by CsoR. This suggests more control levels are operating and directing other regulons in copper homeostasis beside the CsoR regulon. PMID- 22451652 TI - The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. AB - Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study. PMID- 22451653 TI - Siglec-15 protein regulates formation of functional osteoclasts in concert with DNAX-activating protein of 12 kDa (DAP12). AB - Osteoclasts are multinucleated giant cells that reside in osseous tissues and resorb bone. Signaling mediated by receptor activator of nuclear factor (NF) kappaB (RANK) and its ligand leads to the nuclear factor of activated T cells 2/c1 (NFAT2 or NFATc1) expression, a critical step in the formation of functional osteoclasts. In addition, adaptor proteins harboring immunoreceptor tyrosine based activation motifs, such as DNAX-activating protein of 12 kDa (DAP12), play essential roles. In this study, we identified the gene encoding the lectin Siglec 15 as NFAT2-inducible, and we found that the protein product links RANK ligand RANK-NFAT2 and DAP12 signaling in mouse osteoclasts. Both the recognition of sialylated glycans by the Siglec-15 V-set domain and the association with DAP12 through its Lys-272 are essential for its function. When Siglec-15 expression was knocked down, fewer multinucleated cells developed, and those that did were morphologically contracted with disordered actin-ring structures. These changes were accompanied by significantly reduced bone resorption. Siglec-15 formed complexes with Syk through DAP12 in response to vitronectin. Furthermore, chimeric molecules consisting of the extracellular and transmembrane regions of Siglec-15 with a K272A mutation and the cytoplasmic region of DAP12 significantly restored bone resorption in cells with knocked down Siglec-15 expression. Together, these results suggested that the Siglec-15-DAP12-Syk-signaling cascade plays a critical role in functional osteoclast formation. PMID- 22451654 TI - Hyaluronidase 1 and beta-hexosaminidase have redundant functions in hyaluronan and chondroitin sulfate degradation. AB - Hyaluronan (HA), a member of the glycosaminoglycan (GAG) family, is a critical component of the extracellular matrix. A model for HA degradation that invokes the activity of both hyaluronidases and exoglycosidases has been advanced. However, no in vivo studies have been done to determine the extent to which these enzymes contribute to HA breakdown. Herein, we used mouse models to investigate the contributions of the endoglycosidase HYAL1 and the exoglycosidase beta hexosaminidase to the lysosomal degradation of HA. We employed histochemistry and fluorophore-assisted carbohydrate electrophoresis to determine the degree of HA accumulation in mice deficient in one or both enzyme activities. Global HA accumulation was present in mice deficient in both enzymes, with the highest levels found in the lymph node and liver. Chondroitin, a GAG similar in structure to HA, also broadly accumulated in mice deficient in both enzymes. Accumulation of chondroitin sulfate derivatives was detected in mice deficient in both enzymes, as well as in beta-hexosaminidase-deficient mice, indicating that both enzymes play a significant role in chondroitin sulfate breakdown. Extensive accumulation of HA and chondroitin when both enzymes are lacking was not observed in mice deficient in only one of these enzymes, suggesting that HYAL1 and beta hexosaminidase are functionally redundant in HA and chondroitin breakdown. Furthermore, accumulation of sulfated chondroitin in tissues provides in vivo evidence that both HYAL1 and beta-hexosaminidase cleave chondroitin sulfate, but it is a preferred substrate for beta-hexosaminidase. These studies provide in vivo evidence to support and extend existing knowledge of GAG breakdown. PMID- 22451655 TI - Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation. AB - S100 proteins have been implicated in tumorigenesis and metastasis. As a member of S100 proteins, the role of S100A14 in carcinogenesis has not been fully understood. Here, we showed that ectopic overexpression of S100A14 promotes motility and invasiveness of esophageal squamous cell carcinoma cells. We investigated the underlying mechanisms and found that the expression of matrix metalloproteinase (MMP)-2 is obviously increased after S100A14 gene overexpression. Inhibition of MMP2 by a specific MMP2 inhibitor at least partly reversed the invasive phenotype of cells overexpressing S100A14. By serendipity, we found that S100A14 could affect p53 transactivity and stability. Thus, we further investigated whether the effect of MMP2 by S100A14 is dependent on p53. A series of biochemical assays showed that S100A14 requires functional p53 to affect MMP2 transcription, and p53 potently transrepresses the expression of MMP2. Finally, RT-quantitative PCR analysis of human breast cancer specimens showed a significant correlation between S100A14 mRNA expression and MMP2 mRNA expression in cases with wild-type p53 but not in cases with mutant p53. Collectively, our data strongly suggest that S100A14 promotes cell motility and invasiveness by regulating the expression and function of MMP2 in a p53-dependent manner. PMID- 22451656 TI - Roles of N-acetylglucosaminyltransferase III in epithelial-to-mesenchymal transition induced by transforming growth factor beta1 (TGF-beta1) in epithelial cell lines. AB - The epithelial-to-mesenchymal transition (EMT) plays crucial roles in embryonic development, wound healing, tissue repair, and cancer progression. Results of this study show how transforming growth factor beta1 (TGF-beta1) down-regulates expression of N-acetylglucosaminyltransferase III (GnT-III) during EMT-like changes. Treatment with TGF-beta1 resulted in a decrease in E-cadherin expression and GnT-III expression, as well as its product, the bisected N-glycans, which was confirmed by erythro-agglutinating phytohemagglutinin lectin blot and HPLC analysis in human MCF-10A and mouse GE11 cells. In contrast with GnT-III, the expression of N-acetylglucosaminyltransferase V was slightly enhanced by TGF beta1 treatment. Changes in the N-glycan patterns on alpha3beta1 integrin, one of the target proteins for GnT-III, were also confirmed by lectin blot analysis. To understand the roles of GnT-III expression in EMT-like changes, the MCF-10A cell was stably transfected with GnT-III. It is of particular interest that overexpression of GnT-III influenced EMT-like changes induced by TGF-beta1, which was confirmed by cell morphological changes of phase contrast, immunochemical staining patterns of E-cadherin, and actin. In addition, GnT-III modified E cadherin, which served to prolong E-cadherin turnover on the cell surface examined by biotinylation and pulse-chase experiments. GnT-III expression consistently inhibited beta-catenin translocation from cell-cell contact into the cytoplasm and nucleus. Furthermore, the transwell assay showed that GnT-III expression suppressed TGF-beta1-induced cell motility. Taken together, these observations are the first to clearly demonstrate that GnT-III affects cell properties, which in turn influence EMT-like changes, and to explain a molecular mechanism for the inhibitory effects of GnT-III on cancer metastasis. PMID- 22451657 TI - Engulfment protein GULP is regulator of transforming growth factor-beta response in ovarian cells. AB - Transforming growth factor beta (TGF-beta) is a key regulatory molecule with pleiotropic effects on cell growth, migration, and invasion. As a result, impairment of proper TGF-beta signaling is central to tumorigenesis and metastasis. The TGF-beta receptor V (TGFBRV or LRP1) has been shown to be responsible for TGF-beta-mediated cell growth inhibition in Chinese hamster ovary (CHO) cells. The LRP1 adapter protein GULP mediates internalization of the various LRP1-specific ligands, and we hypothesize that GULP acts as a novel regulator of TGF-beta signaling in ovarian cells. CHO cells that overexpress exogenous GULP (FL) demonstrate enhancement in growth inhibition, migration, and invasion from TGF-beta treatment, whereas cells that lack GULP (AS) show impairment of growth inhibition and decreased migration and invasion. The enhanced TGF-beta response in FL cells was confirmed by a prolonged TGF-beta induced SMAD3 phosphorylation, whereas a shortening of the phosphorylation event is observed in AS cells. Mechanistically, the presence of GULP retains the TGF beta in a signaling-competent early endosome for enhanced signaling. To address this mechanism in a physiological setting, TGF-beta insensitive ovarian adenocarcinoma cells (HEY) have a very low GULP expression level, similar to the observation made in a wide selection of human ovarian adenocarcinomas. Transfection of GULP into the HEY cells restored the TGF-beta responsiveness, as measured by SMAD3 phosphorylation and impairment of cell growth. Because GULP expression positively regulates TGF-beta signaling leading to growth inhibition, this may represent an attractive target to achieve TGF-beta responsiveness in ovarian cells. PMID- 22451658 TI - Overexpression of hyaluronan-binding protein 1 (HABP1/p32/gC1qR) in HepG2 cells leads to increased hyaluronan synthesis and cell proliferation by up-regulation of cyclin D1 in AKT-dependent pathway. AB - Overexpression of the mature form of hyaluronan-binding protein 1 (HABP1/gC1qR/p32), a ubiquitous multifunctional protein involved in cellular signaling, in normal murine fibroblast cells leads to enhanced generation of reactive oxygen species (ROS), mitochondrial dysfunction, and ultimately apoptosis with the release of cytochrome c. In the present study, human liver cancer cell line HepG2, having high intracellular antioxidant levels was chosen for stable overexpression of HABP1. The stable transformant of HepG2, overexpressing HABP1 does not lead to ROS generation, cellular stress, and apoptosis, rather it induced enhanced cell growth and proliferation over longer periods. Phenotypic changes in the stable transformant were associated with the increased "HA pool," formation of the "HA cable" structure, up-regulation of HA synthase-2, and CD44, a receptor for HA. Enhanced cell survival was further supported by activation of MAP kinase and AKT-mediated cell survival pathways, which leads to an increase in CYCLIN D1 promoter activity. Compared with its parent counterpart HepG2, the stable transformant showed enhanced tumorigenicity as evident by its sustained growth in low serum conditions, formation of the HA cable structure, increased anchorage-independent growth, and cell-cell adhesion. This study suggests that overexpression of HABP1 in HepG2 cells leads to enhanced cell survival and tumorigenicity by activating HA-mediated cell survival pathways. PMID- 22451659 TI - Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1alpha activity in hypoxia. AB - Adaptive response to hypoxia in nucleus pulposus cells of the intervertebral disc is regulated by the hypoxia-inducible factors, HIF-1alpha and HIF-2alpha. Moreover, oxygen-dependent turnover of HIF-1alpha in these cells is controlled by the prolyl-4-hydroxylase domain (PHD) family of proteins. Whether HIF homologues control expression of PHDs and whether PHDs control hypoxia-inducible factor (HIF) turnover and/or activity under hypoxia is not known. Here, we show that in nucleus pulposus cells, hypoxia robustly induces PHD3 expression and, to a lesser extent, of PHD2 and PHD1. Reporter analysis shows that the hypoxic induction of the PHD2 promoter is HIF-1alpha dependent, whereas PHD3 promoter/enhancer activity is dependent on both HIF-1alpha and HIF-2alpha. Lentiviral delivery of HIF-1alpha, ShHIF-1alpha, and ShHIF-1beta confirmed these observations. Noteworthy, HIF-1alpha maintains basal expression of PHD1 in hypoxia at the posttranscriptional level. Finally, loss of function studies using lentiviral transduction of ShPHDs clearly shows that even at 1% O(2), PHD2 selectively degrades HIF-1alpha. In contrast, in hypoxia, PHD3 enhances HIF-1alpha transcriptional activity without affecting protein levels. To correlate these observations with disc disease, a condition characterized by tissue vascularization, we analyzed human tissues. Increased PHD1 mRNA expression but decreased PHD2 and PHD3 expression is observed in degenerate tissues. Interestingly, the hypoxic responsiveness of all the PHDs is maintained in isolated nucleus pulposus cells regardless of the disease state. We propose that PHD2 and PHD3 can be used as a biomarker of tissue oxygenation in the disc and that, as such, it may have important clinical implications. PMID- 22451660 TI - Conjugated fatty acid synthesis: residues 111 and 115 influence product partitioning of Momordica charantia conjugase. AB - Conjugated linolenic acids (CLNs), 18:3 Delta(9,11,13), lack the methylene groups found between the double bonds of linolenic acid (18:3 Delta(9,12,15)). CLNs are produced by conjugase enzymes that are homologs of the oleate desaturases FAD2. The goal of this study was to map the domain(s) within the Momordica charantia conjugase (FADX) responsible for CLN formation. To achieve this, a series of Momordica FADX-Arabidopsis FAD2 chimeras were expressed in the Arabidopsis fad3fae1 mutant, and the transformed seeds were analyzed for the accumulation of CLN. These experiments identified helix 2 and the first histidine box as a determinant of conjugase product partitioning into punicic acid (18:3 Delta(9cis,11trans,13cis)) or alpha-eleostearic acid (18:3 Delta(9cis,11trans,13trans)). This was confirmed by analysis of a FADX mutant containing six substitutions in which the sequence of helix 2 and first histidine box was converted to that of FAD2. Each of the six FAD2 substitutions was individually converted back to the FADX equivalent identifying residues 111 and 115, adjacent to the first histidine box, as key determinants of conjugase product partitioning. Additionally, expression of FADX G111V and FADX G111V/D115E resulted in an approximate doubling of eleostearic acid accumulation to 20.4% and 21.2%, respectively, compared with 9.9% upon expression of the native Momordica FADX. Like the Momordica conjugase, FADX G111V and FADX D115E produced predominantly alpha-eleostearic acid and little punicic acid, but the FADX G111V/D115E double mutant produced approximately equal amounts of alpha eleostearic acid and its isomer, punicic acid, implicating an interactive effect of residues 111 and 115 in punicic acid formation. PMID- 22451661 TI - Cathepsins L and Z are critical in degrading polyglutamine-containing proteins within lysosomes. AB - In neurodegenerative diseases caused by extended polyglutamine (polyQ) sequences in proteins, aggregation-prone polyQ proteins accumulate in intraneuronal inclusions. PolyQ proteins can be degraded by lysosomes or proteasomes. Proteasomes are unable to hydrolyze polyQ repeat sequences, and during breakdown of polyQ proteins, they release polyQ repeat fragments for degradation by other cellular enzymes. This study was undertaken to identify the responsible proteases. Lysosomal extracts (unlike cytosolic enzymes) were found to rapidly hydrolyze polyQ sequences in peptides, proteins, or insoluble aggregates. Using specific inhibitors against lysosomal proteases, enzyme-deficient extracts, and pure cathepsins, we identified cathepsins L and Z as the lysosomal cysteine proteases that digest polyQ proteins and peptides. RNAi for cathepsins L and Z in different cell lines and adult mouse muscles confirmed that they are critical in degrading polyQ proteins (expanded huntingtin exon 1) but not other types of aggregation-prone proteins (e.g. mutant SOD1). Therefore, the activities of these two lysosomal cysteine proteases are important in host defense against toxic accumulation of polyQ proteins. PMID- 22451662 TI - Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac dysfunction and myocyte apoptosis. AB - Decreases in cardiac Na/K-ATPase have been documented in patients with heart failure. Reduction of Na/K-ATPase alpha1 also contributes to the deficiency in cardiac contractility in animal models. Our previous studies demonstrate that reduction of cellular Na/K-ATPase causes cell growth inhibition and cell death in renal proximal tubule cells. To test whether reduction of Na/K-ATPase in combination with increased cardiotonic steroids causes cardiac myocyte death and cardiac dysfunction, we examined heart function in Na/K-ATPase alpha1 heterozygote knock-out mice (alpha1(+/-)) in comparison to wild type (WT) littermates after infusion of marinobufagenin (MBG). Adult cardiac myocytes were also isolated from both WT and alpha1(+/-) mice for in vitro experiments. The results demonstrated that MBG infusion increased myocyte apoptosis and induced significant left ventricle dilation in alpha1(+/-) mice but not in their WT littermates. Mechanistically, it was found that in WT myocytes MBG activated the Src/Akt/mTOR signaling pathway, which further increased phosphorylation of ribosome S6 kinase (S6K) and BAD (Bcl-2-associated death promoter) and protected cells from apoptosis. In alpha1(+/-) myocytes, the basal level of phospho-BAD is higher compared with WT myocytes, but MBG failed to induce further activation of the mTOR pathway. Reduction of Na/K-ATPase also caused the activation of caspase 9 but not caspase 8 in these cells. Using cultures of neonatal cardiac myocytes, we demonstrated that inhibition of the mTOR pathway by rapamycin also enabled MBG to activate caspase 9 and induce myocyte apoptosis. PMID- 22451663 TI - Plasminogen is a complement inhibitor. AB - Plasminogen is a 92-kDa single chain glycoprotein that circulates in plasma as a zymogen and when converted to proteolytically active plasmin dissolves preformed fibrin clots and extracellular matrix components. Here, we characterize the role of plasmin(ogen) in the complement cascade. Plasminogen binds the central complement protein C3, the C3 cleavage products C3b and C3d, and C5. Plasminogen binds to C3, C3b, C3d, and C5 via lysine residues, and the interaction is ionic strength-dependent. Plasminogen and Factor H bind C3b; however, the two proteins bind to different sites and do not compete for binding. Plasminogen affects complement action in multiple ways. Plasminogen enhanced Factor I-mediated C3b degradation in the presence of the cofactor Factor H. Plasminogen when activated to plasmin inhibited complement as demonstrated by hemolytic assays using either rabbit or sheep erythrocytes. Similarly, plasmin either in the fluid phase or attached to surfaces inhibited complement that was activated via the alternative and classical pathways and cleaved C3b to fragments of 68, 40, 30, and 17 kDa. The C3b fragments generated by plasmin differ in size from those generated by the complement protease Factor I, suggesting that plasmin-mediated C3b cleavage fragments lack effector function. Plasmin also cleaved C5 to products of 65, 50, 30, and 25 kDa. Thus, plasmin(ogen) regulates both complement and coagulation, the two central cascade systems of a vertebrate organism. This complement inhibitory activity of plasmin provides a new explanation why pathogenic microbes utilize plasmin(ogen) for immune evasion and tissue penetration. PMID- 22451664 TI - Tamm-Horsfall protein regulates circulating and renal cytokines by affecting glomerular filtration rate and acting as a urinary cytokine trap. AB - Although few organ systems play a more important role than the kidneys in cytokine catabolism, the mechanism(s) regulating this pivotal physiological function and how its deficiency affects systemic cytokine homeostasis remain unclear. Here we show that elimination of Tamm-Horsfall protein (THP) expression from mouse kidneys caused a marked elevation of circulating IFN-gamma, IL1alpha, TNF-alpha, IL6, CXCL1, and IL13. Accompanying this were enlarged spleens with prominent white-pulp macrophage infiltration. Lipopolysaccharide (LPS) exacerbated the increase of serum cytokines without a corresponding increase in their urinary excretion in THP knock-out (KO) mice. This, along with the rise of serum cystatin C and the reduced inulin and creatinine clearance from the circulation, suggested that diminished glomerular filtration may contribute to reduced cytokine clearance in THP KO mice both at the baseline and under stress. Unlike wild-type mice where renal and urinary cytokines formed specific in vivo complexes with THP, this "trapping" effect was absent in THP KO mice, thus explaining why cytokine signaling pathways were activated in renal epithelial cells in such mice. Our study provides new evidence implicating an important role of THP in influencing cytokine clearance and acting as a decoy receptor for urinary cytokines. Based on these and other data, we present a unifying model that underscores the role of THP as a major regulator of renal and systemic immunity. PMID- 22451665 TI - Calmodulin and S100A1 protein interact with N terminus of TRPM3 channel. AB - Transient receptor potential melastatin 3 ion channel (TRPM3) belongs to the TRP family of cation-permeable ion channels involved in many important biological functions such as pain transduction, thermosensation, and mechanoregulation. The channel was reported to play an important role in Ca(2+) homeostasis, but its gating mechanisms, functions, and regulation are still under research. Utilizing biophysical and biochemical methods, we characterized two independent domains, Ala-35-Lys-124 and His-291-Gly-382, on the TRPM3 N terminus, responsible for interactions with the Ca(2+)-binding proteins calmodulin (CaM) and S100A1. We identified several positively charged residues within these domains as having a crucial impact on CaM/S100A1 binding. The data also suggest that the interaction is calcium-dependent. We also performed competition assays, which suggested that CaM and S100A1 are able to compete for the same binding sites within the TRPM3 N terminus. This is the first time that such an interaction has been shown for TRP family members. PMID- 22451666 TI - The Syk-binding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation. AB - B cell receptor (BCR)-mediated antigen (Ag) processing and presentation lead to B cell-T cell interactions, which support affinity maturation and immunoglobulin class switching. These interactions are supported by generation of peptide-MHC class II complexes in multivesicular body-like MIIC compartments of B cells. Previous studies have shown that trafficking of Ag.BCR complexes to MVB-like MIIC occurs via an ubiquitin-dependent pathway and that ubiquitination of Ag.BCR complexes occurs by an Src family kinase signaling-dependent mechanism that is restricted to lipid raft-resident Ag.BCR complexes. This study establishes that downstream Syk-dependent BCR signaling is also required for BCR ubiquitination and BCR-mediated antigen processing and presentation. Knockdown studies reveal that of the two known Syk-binding E3 ubiquitin ligases c-Cbl and Cbl-b, only c Cbl appears to have a central role in BCR ubiquitination, trafficking to MIIC, and ubiquitin-dependent BCR-mediated antigen processing and presentation. These results establish the novel role for Syk signaling and the Syk-binding ubiquitin ligase c-Cbl in the BCR-mediated processing and presentation of cognate antigen and define one mechanism by which antigen-induced BCR ubiquitination is modulated to impact the initiation and maturation of the humoral immune response. PMID- 22451667 TI - Opiate antagonist prevents MU- and delta-opiate receptor dimerization to facilitate ability of agonist to control ethanol-altered natural killer cell functions and mammary tumor growth. AB - In the natural killer (NK) cells, delta-opiate receptor (DOR) and MU-opioid receptor (MOR) interact in a feedback manner to regulate cytolytic function with an unknown mechanism. Using RNK16 cells, a rat NK cell line, we show that MOR and DOR monomer and dimer proteins existed in these cells and that chronic treatment with a receptor antagonist reduced protein levels of the targeted receptor but increased levels of opposing receptor monomer and homodimer. The opposing receptor-enhancing effects of MOR and DOR antagonists were abolished following receptor gene knockdown by siRNA. Ethanol treatment increased MOR and DOR heterodimers while it decreased the cellular levels of MOR and DOR monomers and homodimers. The opioid receptor homodimerization was associated with an increased receptor binding, and heterodimerization was associated with a decreased receptor binding and the production of cytotoxic factors. Similarly, in vivo, opioid receptor dimerization, ligand binding of receptors, and cell function in immune cells were promoted by chronic treatment with an opiate antagonist but suppressed by chronic ethanol feeding. Additionally, a combined treatment of an MOR antagonist and a DOR agonist was able to reverse the immune suppressive effect of ethanol and reduce the growth and progression of mammary tumors in rats. These data identify a role of receptor dimerization in the mechanism of DOR and MOR feedback interaction in NK cells, and they further elucidate the potential for the use of a combined opioid antagonist and agonist therapy for the treatment of immune incompetence and cancer and alcohol-related diseases. PMID- 22451668 TI - Two neonatal diabetes mutations on transmembrane helix 15 of SUR1 increase affinity for ATP and ADP at nucleotide binding domain 2. AB - K(ATP) channels, (SUR1/Kir6.2)(4) (sulfonylurea receptor type 1/potassium inward rectifier type 6.2) respond to the metabolic state of pancreatic beta-cells, modulating membrane potential and insulin exocytosis. Mutations in both subunits cause neonatal diabetes by overactivating the pore. Hyperactive channels fail to close appropriately with increased glucose metabolism; thus, beta-cell hyperpolarization limits insulin release. K(ATP) channels are inhibited by ATP binding to the Kir6.2 pore and stimulated, via an uncertain mechanism, by magnesium nucleotides at SUR1. Glibenclamide (GBC), a sulfonylurea, was used as a conformational probe to compare nucleotide action on wild type versus Q1178R and R1182Q SUR1 mutants. GBC binds with high affinity to aporeceptors, presumably in the inward facing ATP-binding cassette configuration; MgATP reduces binding affinity via a shift to the outward facing conformation. To determine nucleotide affinities under equilibrium, non-hydrolytic conditions, Mg(2+) was eliminated. A four-state equilibrium model describes the allosteric linkage. The K(D) for ATP(4 ) is ~1 versus 12 mM, Q1178R versus wild type, respectively. The linkage constant is ~10, implying that outward facing conformations bind GBC with a lower affinity, 9-10 nM for Q1178R. Thus, nucleotides cannot completely inhibit GBC binding. Binding of channel openers is reported to require ATP hydrolysis, but diazoxide, a SUR1-selective agonist, concentration-dependently augments ATP(4-) action. An eight-state model describes linkage between diazoxide and ATP(4-) binding; diazoxide markedly increases the affinity of Q1178R for ATP(4-) and ATP(4-) augments diazoxide binding. NBD2, but not NBD1, has a higher affinity for ATP (and ADP) in mutant versus wild type (with or without Mg(2+)). Thus, the mutants spend more time in nucleotide-bound conformations, with reduced affinity for GBC, that activate the pore. PMID- 22451669 TI - Thematic minireview series on results from the ENCODE Project: Integrative global analyses of regulatory regions in the human genome. PMID- 22451670 TI - Substrate transport activation is mediated through second periplasmic loop of transmembrane protein MalF in maltose transport complex of Escherichia coli. AB - In a recent study we described the second periplasmic loop P2 of the transmembrane protein MalF (MalF-P2) of the maltose ATP-binding cassette transporter (MalFGK(2)-E) as an important element in the recognition of substrate by the maltose-binding protein MalE. In this study, we focus on MalE and find that MalE undergoes a structural rearrangement after addition of MalF-P2. Analysis of residual dipolar couplings (RDCs) shows that binding of MalF-P2 induces a semiopen state of MalE in the presence and absence of maltose, whereas maltose is retained in the binding pocket. These data are in agreement with paramagnetic relaxation enhancement experiments. After addition of MalF-P2, an increased solvent accessibility for residues in the vicinity of the maltose binding site of MalE is observed. MalF-P2 is thus not only responsible for substrate recognition, but also directly involved in activation of substrate transport. The observation that substrate-bound and substrate-free MalE in the presence of MalF-P2 adopts a similar semiopen state hints at the origin of the futile ATP hydrolysis of MalFGK(2)-E. PMID- 22451671 TI - Conditional mutagenesis of a novel choline kinase demonstrates plasticity of phosphatidylcholine biogenesis and gene expression in Toxoplasma gondii. AB - The obligate intracellular and promiscuous protozoan parasite Toxoplasma gondii needs an extensive membrane biogenesis that must be satisfied irrespective of its host-cell milieu. We show that the synthesis of the major lipid in T. gondii, phosphatidylcholine (PtdCho), is initiated by a novel choline kinase (TgCK). Full length (~70-kDa) TgCK displayed a low affinity for choline (K(m) ~0.77 mM) and harbors a unique N-terminal hydrophobic peptide that is required for the formation of enzyme oligomers in the parasite cytosol but not for activity. Conditional mutagenesis of the TgCK gene in T. gondii attenuated the protein level by ~60%, which was abolished in the off state of the mutant (Deltatgck(i)). Unexpectedly, the mutant was not impaired in its growth and exhibited a normal PtdCho biogenesis. The parasite compensated for the loss of full-length TgCK by two potential 53- and 44-kDa isoforms expressed through a cryptic promoter identified within exon 1. TgCK-Exon1 alone was sufficient in driving the expression of GFP in E. coli. The presence of a cryptic promoter correlated with the persistent enzyme activity, PtdCho synthesis, and susceptibility of T. gondii to a choline analog, dimethylethanolamine. Quite notably, the mutant displayed a regular growth in the off state despite a 35% decline in PtdCho content and lipid synthesis, suggesting a compositional flexibility in the membranes of the parasite. The observed plasticity of gene expression and membrane biogenesis can ensure a faithful replication and adaptation of T. gondii in disparate host or nutrient environments. PMID- 22451672 TI - Mapping targetable sites on human telomerase RNA pseudoknot/template domain using 2'-OMe RNA-interacting polynucleotide (RIPtide) microarrays. AB - Most cellular RNAs engage in intrastrand base-pairing that gives rise to complex three-dimensional folds. This self-pairing presents an impediment toward binding of the RNA by nucleic acid-based ligands. An important step in the discovery of RNA-targeting ligands is therefore to identify those regions in a folded RNA that are accessible toward the nucleic acid-based ligand. Because the folding of RNA targets can involve interactions between nonadjacent regions and employ both Watson-Crick and non-Watson-Crick base-pairing, screening of candidate binder ensembles is typically necessary. Microarray-based screening approaches have shown great promise in this regard and have suggested that achieving complete sequence coverage would be a valuable attribute of a next generation system. Here, we report a custom microarray displaying a library of RNA-interacting polynucleotides comprising all possible 2'-OMe RNA sequences from 4- to 8 nucleotides in length. We demonstrate the utility of this array in identifying RNA-interacting polynucleotides that bind tightly and specifically to the highly conserved, functionally essential template/pseudoknot domain of human telomerase RNA and that inhibit telomerase function in vitro. PMID- 22451673 TI - 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthases, naturally fragile enzymes specifically stabilized by nucleotide binding. AB - Activated sulfate in the form of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) is needed for all sulfation reactions in eukaryotes with implications for the build up of extracellular matrices, retroviral infection, protein modification, and steroid metabolism. In metazoans, PAPS is produced by bifunctional PAPS synthases (PAPSS). A major question in the field is why two human protein isoforms, PAPSS1 and -S2, are required that cannot complement for each other. We provide evidence that these two proteins differ markedly in their stability as observed by unfolding monitored by intrinsic tryptophan fluorescence as well as circular dichroism spectroscopy. At 37 degrees C, the half-life for unfolding of PAPSS2 is in the range of minutes, whereas PAPSS1 remains structurally intact. In the presence of their natural ligand, the nucleotide adenosine 5'-phosphosulfate (APS), PAPS synthase proteins are stabilized. Invertebrates only possess one PAPS synthase enzyme that we classified as PAPSS2-type by sequence-based machine learning techniques. To test this prediction, we cloned and expressed the PPS-1 protein from the roundworm Caenorhabditis elegans and also subjected this protein to thermal unfolding. With respect to thermal unfolding and the stabilization by APS, PPS-1 behaved like the unstable human PAPSS2 protein suggesting that the less stable protein is evolutionarily older. Finally, APS binding more than doubled the half-life for unfolding of PAPSS2 at physiological temperatures and effectively prevented its aggregation on a time scale of days. We propose that protein stability is a major contributing factor for PAPS availability that has not as yet been considered. Moreover, naturally occurring changes in APS concentrations may be sensed by changes in the conformation of PAPSS2. PMID- 22451674 TI - Loss of caveolin-1 impairs retinal function due to disturbance of subretinal microenvironment. AB - Caveolin-1 (Cav-1), an integral component of caveolar membrane domains, is expressed in several retinal cell types, including photoreceptors, retinal vascular endothelial cells, Muller glia, and retinal pigment epithelium (RPE) cells. Recent evidence links Cav-1 to ocular diseases, including autoimmune uveitis, diabetic retinopathy, and primary open angle glaucoma, but its role in normal vision is largely undetermined. In this report, we show that ablation of Cav-1 results in reduced inner and outer retinal function as measured, in vivo, by electroretinography and manganese-enhanced MRI. Somewhat surprisingly, dark current and light sensitivity were normal in individual rods (recorded with suction electrode methods) from Cav-1 knock-out (KO) mice. Although photoreceptor function was largely normal, in vitro, the apparent K(+) affinity of the RPE expressed alpha1-Na(+)/K(+)-ATPase was decreased in Cav-1 KO mice. Cav-1 KO retinas also displayed unusually tight adhesion with the RPE, which could be resolved by brief treatment with hyperosmotic medium, suggesting alterations in outer retinal fluid homeostasis. Collectively, these findings demonstrate that reduced retinal function resulting from Cav-1 ablation is not photoreceptor intrinsic but rather involves impaired subretinal and/or RPE ion/fluid homeostasis. PMID- 22451675 TI - 1,3-1,4-alpha-L-fucosynthase that specifically introduces Lewis a/x antigens into type-1/2 chains. AB - alpha-L-fucosyl residues attached at the non-reducing ends of glycoconjugates constitute histo-blood group antigens Lewis (Le) and ABO and play fundamental roles in various biological processes. Therefore, establishing a method for synthesizing the antigens is important for functional glycomics studies. However, regiospecific synthesis of glycosyl linkages, especially alpha-L-fucosyl linkages, is quite difficult to control both by chemists and enzymologists. Here, we generated an alpha-L-fucosynthase that specifically introduces Le(a) and Le(x) antigens into the type-1 and type-2 chains, respectively; i.e. the enzyme specifically accepts the disaccharide structures (Galbeta1-3/4GlcNAc) at the non reducing ends and attaches a Fuc residue via an alpha-(1,4/3)-linkage to the GlcNAc. X-ray crystallographic studies revealed the structural basis of this strict regio- and acceptor specificity, which includes the induced fit movement of the catalytically important residues, and the difference between the active site structures of 1,3-1,4-alpha-L-fucosidase (EC 3.2.1.111) and alpha-L fucosidase (EC 3.2.1.51) in glycoside hydrolase family 29. The glycosynthase developed in this study should serve as a potentially powerful tool to specifically introduce the Le(a/x) epitopes onto labile glycoconjugates including glycoproteins. Mining glycosidases with strict specificity may represent the most efficient route to the specific synthesis of glycosidic bonds. PMID- 22451676 TI - TRPC1 protein channel is major regulator of epidermal growth factor receptor signaling. AB - TRP channels have been associated with cell proliferation and aggressiveness in several cancers. In particular, TRPC1 regulates cell proliferation and motility, two processes underlying cancer progression. We and others have described the mechanisms of TRPC1-dependent cell migration. However, the involvement of TRPC1 in cell proliferation remains unexplained. In this study, we show that siRNA mediated TRPC1 depletion in non small cell lung carcinoma cell lines induced G(0)/G(1) cell cycle arrest resulting in dramatic decrease in cell growth. The expression of cyclins D1 and D3 was reduced after TRPC1 knockdown, pointing out the role of TRPC1 in G(1)/S transition. This was associated with a decreased phosphorylation and activation of EGFR and with a subsequent disruption of PI3K/Akt and MAPK downstream pathways. Stimulation of EGFR by its natural ligand, EGF, induced Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry through TRPC1. Ca(2+) entry through TRPC1 conversely activated EGFR, suggesting that TRPC1 is a component of a Ca(2+)-dependent amplification of EGF-dependent cell proliferation. PMID- 22451677 TI - Signals in APOBEC3F N-terminal and C-terminal deaminase domains each contribute to encapsidation in HIV-1 virions and are both required for HIV-1 restriction. AB - Human cytidine deaminases APOBEC3F (A3F) and APOBEC3G (A3G) inhibit human immunodeficiency virus type-1 (HIV-1) replication. In the absence of HIV-1 Vif, A3F and/or A3G are incorporated into assembling virions and exert antiviral functions in subsequently infected target cells. Encapsidation of A3F or A3G within the protease-matured virion core following their incorporation into virions is hypothesized to be important for the antiviral function of these proteins. In this report, we demonstrated that A3F was quantitatively encapsidated in the mature virion core. In distinct contrast, A3G was distributed both within and outside of the virion core. Analysis of a series of A3F-A3G chimeras comprised of exchanged N- and C-terminal deaminase domains identified a 14 amino acid segment in the A3F C-terminal deaminase domain that contributed to preferential encapsidation and anti-HIV activity. Amino acid residue L306 in this C-terminal segment was determined to be necessary, but not sufficient, for these effects. Amino acid residue W126 in the N-terminal deaminase domain was determined also to contribute to preferential encapsidation and antiviral activity of A3F. Analysis of the A3F (W126A L306A) double mutant revealed that both residues are required for full anti-HIV function. The results reported here advance our understanding of the mechanisms of A3F virion encapsidation and antiviral function and may lead to innovative strategies to inhibit HIV-1 replication. PMID- 22451678 TI - Membrane-bound trafficking regulates nuclear transport of integral epidermal growth factor receptor (EGFR) and ErbB-2. AB - Nuclear localization of multiple receptor-tyrosine kinases (RTKs), such as EGF receptor (EGFR), ErbB-2, FGF receptor (FGFR), and many others, has been reported by several groups. We previously showed that cell surface EGFR is trafficked to the nucleus through a retrograde pathway from the Golgi to the endoplasmic reticulum (ER) and that EGFR is then translocated to the inner nuclear membrane (INM) through the INTERNET (integral trafficking from the ER to the nuclear envelope transport) pathway. However, the nuclear trafficking mechanisms of other membrane RTKs, apart from EGFR, remain unclear. The purpose of this study was to compare the nuclear transport of EGFR family proteins with that of FGFR-1. Interestingly, we found that digitonin permeabilization, which selectively releases soluble nuclear transporters from the cytoplasm and has been shown to inhibit nuclear transport of FGFR-1, had no effects on EGFR nuclear transport, raising the possibility that EGFR and FGFR-1 use different pathways to be translocated into the nucleus. Using the subnuclear fractionation assay, we further demonstrated that biotinylated cell surface ErbB-2, but not FGFR-1, is targeted to the INM, associating with Sec61beta in the INM, similar to the nuclear trafficking of EGFR. Thus, ErbB-2, but not FGFR-1, shows a similar trafficking pathway to EGFR for translocation to the nucleus, indicating that at least two different pathways of nuclear transport exist for cell surface receptors. This finding provides a new direction for investigating the trafficking mechanisms of various nuclear RTKs. PMID- 22451679 TI - Transforming growth factor-beta1 regulates Cdk5 activity in primary sensory neurons. AB - In addition to many important roles for Cdk5 in brain development and synaptic function, we reported previously that Cdk5 regulates inflammatory pain signaling, partly through phosphorylation of transient receptor potential vanilloid 1 (TRPV1), an important Na(+)/Ca(2+) channel expressed in primary nociceptive afferent nerves. Because TGF-beta regulates inflammatory processes and its receptor is expressed in TRPV1-positive afferents, we studied the cross-talk between these two pathways in sensory neurons during experimental peripheral inflammation. We demonstrate that TGF-beta1 increases transcription and protein levels of the Cdk5 co-activator p35 through ERK1/2, resulting in an increase in Cdk5 activity in rat B104 neuroblastoma cells. Additionally, TGF-beta1 enhances the capsaicin-induced Ca(2+) influx in cultured primary neurons from dorsal root ganglia (DRG). Importantly, Cdk5 activity was reduced in the trigeminal ganglia and DRG of 14-day-old TGF-beta1 knock-out mice, resulting in reduced Cdk5 dependent phosphorylation of TRPV1. The decreased Cdk5 activity is associated with attenuated thermal hyperalgesia in TGF-beta1 receptor conditional knock-out mice, where TGF-beta signaling is significantly reduced in trigeminal ganglia and DRG. Collectively, our results indicate that active cross-talk between the TGF beta and Cdk5 pathways contributes to inflammatory pain signaling. PMID- 22451680 TI - Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells. AB - Neutral ceramidase (NCDase) is considered to be a critical enzyme for controlling the turnover of ceramide, an important bioactive lipid, which determines cell's fate. All-trans retinoic acid (ATRA) has been reported to induce neuronal differentiation and cell-cycle arrest [Lopez-Carballo, Moreno, Masia, Perez, and Barettino (Activation of the phosphatidylinositol 3-kinase/Akt signalling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. J Biol Chem 2002:277:25297-304.)]. In this study, we observed that ATRA-induced cellular ceramide accumulation, cell-growth arrest and differentiation accompanied with down-regulation of NCDase in SH-SY5Y cells, without a decrease in sphingosine or sphingosine 1-phosphate. We examined whether the down-regulation of NCDase was involved in the increase in ceramide and cell differentiation. ATRA was found to down-regulate mRNA, protein and the enzyme activity of NCDase. Interestingly, GATA-2 was also decreased with ATRA treatment, and experiments using its expression vector and siRNA and chromatin immunoprecipitation assay demonstrated GATA-2 acted as transcription-factor of NCDase gene expression. By establishing stable transfectants with decreased NCDase expression and activity, we clarified the significance of NCDase down regulation for ATRA-induced neuronal differentiation. Those sub-clones showed both increased cellular ceramide and reduced cell growth as well as neuronal differentiation phenotypes. These results demonstrate that down-regulation of NCDase through ATRA-induced GATA-2 decrease plays an important role in induction of ceramide accumulation and neuronal differentiation in SH-SY5Y cells. PMID- 22451681 TI - Repair of oxidative DNA damage is delayed in the Ser326Cys polymorphic variant of the base excision repair protein OGG1. AB - Gene-environment interactions influence an individual's risk of disease development. A common human 8-oxoguanine DNA glycosylase 1 (OGG1) variant, Cys326 hOGG1, has been associated with increased cancer risk. Evidence suggests that this is due to reduced repair ability, particularly under oxidising conditions but the underlying mechanism is poorly understood. Oxidising conditions may arise due to internal cellular processes, such as inflammation or external chemical or radiation exposure. To investigate wild-type and variant OGG1 regulation and activity under oxidising conditions, we generated mOgg1 (-/-) null mouse embryonic fibroblasts cells stably expressing Ser326- and Cys326-hOGG1 and measured activity, gene expression, protein expression and localisation following treatment with the glutathione-depleting compound L-buthionine-S-sulfoximine (BSO). Assessment of OGG1 activity using a 7,8-dihydro-8-oxodeoxyguanine (8-oxo dG) containing molecular beacon demonstrated that the activity of both Ser326- and Cys326-hOGG1 was increased following oxidative treatment but with different kinetics. Peak activity of Ser326-hOGG1 occurred 12 h prior to that of Cys326 hOGG1. In both variants, the increased activity was not associated with any gene expression or protein increase or change in protein localisation. These findings suggest that up-regulation of OGG1 activity in response to BSO-induced oxidative stress is via post-transcriptional regulation and provide further evidence for impaired Cys326-hOGG1 repair ability under conditions of oxidative stress. This may have important implications for increased mutation frequency resulting from increased oxidative stress in individuals homozygous for the Cys326 hOGG1 allele. PMID- 22451682 TI - Structure and mechanical properties of the ribosomal L1 stalk three-way junction. AB - The L1 stalk is a key mobile element of the large ribosomal subunit which interacts with tRNA during translocation. Here, we investigate the structure and mechanical properties of the rRNA H76/H75/H79 three-way junction at the base of the L1 stalk from four different prokaryotic organisms. We propose a coarse grained elastic model and parameterize it using large-scale atomistic molecular dynamics simulations. Global properties of the junction are well described by a model in which the H76 helix is represented by a straight, isotropically flexible elastic rod, while the junction core is represented by an isotropically flexible spherical hinge. Both the core and the helix contribute substantially to the overall H76 bending fluctuations. The presence of wobble pairs in H76 does not induce any increased flexibility or anisotropy to the helix. The half-closed conformation of the L1 stalk seems to be accessible by thermal fluctuations of the junction itself, without any long-range allosteric effects. Bending fluctuations of H76 with a bulge introduced in it suggest a rationale for the precise position of the bulge in eukaryotes. Our elastic model can be generalized to other RNA junctions found in biological systems or in nanotechnology. PMID- 22451683 TI - Tongue hyperpigmentation during hepatitis C treatment. PMID- 22451684 TI - The church of cryopreservation. PMID- 22451685 TI - The writer is in. PMID- 22451686 TI - Diagnostic accuracy of case-finding questions to identify perinatal depression. AB - BACKGROUND: Guidelines for perinatal mental health care recommend the use of two case-finding questions about depressed feelings and loss of interest in activities, despite the absence of validation studies in this context. We examined the diagnostic accuracy of these questions and of a third question about the need for help asked of women receiving perinatal care. METHODS: We evaluated self-reported responses to two case-finding questions against an interviewer assessed diagnostic standard (DSM-IV criteria for major depressive disorder) among 152 women receiving antenatal care at 26-28 weeks' gestation and postnatal care at 5-13 weeks after delivery. Among women who answered "yes" to either question, we assessed the usefulness of asking a third question about the need for help. We calculated sensitivity, specificity and likelihood ratios for the two case-finding questions and for the added question about the need for help. RESULTS: Antenatally, the two case-finding questions had a sensitivity of 100% (95% confidence interval [CI] 77%-100%), a specificity of 68% (95% CI 58%-76%), a positive likelihood ratio of 3.03 (95% CI 2.28-4.02) and a negative likelihood ratio of 0.041 (95% CI 0.003-0.63) in identifying perinatal depression. Postnatal results were similar. Among the women who screened positive antenatally, the additional question about the need for help had a sensitivity of 58% (95% CI 38% 76%), a specificity of 91% (95% CI 78%-97%), a positive likelihood ratio of 6.86 (95% CI 2.16-21.7) and a negative likelihood ratio of 0.45 (95% CI 0.25-0.80), with lower sensitivity and higher specificity postnatally. INTERPRETATION: Negative responses to both of the case-finding questions showed acceptable accuracy for ruling out perinatal depression. For positive responses, the use of a third question about the need for help improved specificity and the ability to rule in depression. PMID- 22451687 TI - Age, sex, location ... sperm count? PMID- 22451688 TI - Status quo wait times. PMID- 22451689 TI - Five things to know about...: contrast-enhanced ultrasonography. PMID- 22451691 TI - Predisposed to risk but not change. PMID- 22451692 TI - Oxycodone class action lawsuit filed. PMID- 22451693 TI - Consent requirements for pelvic examinations performed for training purposes. PMID- 22451694 TI - Crystal structure of alpha5beta1 integrin ectodomain: atomic details of the fibronectin receptor. AB - Integrin alpha5beta1 is a major cellular receptor for the extracellular matrix protein fibronectin and plays a fundamental role during mammalian development. A crystal structure of the alpha5beta1 integrin headpiece fragment bound by an allosteric inhibitory antibody was determined at a 2.9-A resolution both in the absence and presence of a ligand peptide containing the Arg-Gly-Asp (RGD) sequence. The antibody-bound beta1 chain accommodated the RGD ligand with very limited structural changes, which may represent the initial step of cell adhesion mediated by nonactivated integrins. Furthermore, a molecular dynamics simulation pointed to an important role for Ca(2+) in the conformational coupling between the ligand-binding site and the rest of the molecule. The RGD-binding pocket is situated at the center of a trenchlike exposed surface on the top face of alpha5beta1 devoid of glycosylation sites. The structure also enabled the precise prediction of the acceptor residue for the auxiliary synergy site of fibronectin on the alpha5 subunit, which was experimentally confirmed by mutagenesis and kinetic binding assays. PMID- 22451695 TI - Nucleophosmin/B23 activates Aurora A at the centrosome through phosphorylation of serine 89. AB - Aurora A (AurA) is a major mitotic protein kinase involved in centrosome maturation and spindle assembly. Nucleophosmin/B23 (NPM) is a pleiotropic nucleolar protein involved in a variety of cellular processes including centrosome maturation. In the present study, we report that NPM is a strong activator of AurA kinase activity. NPM and AurA coimmunoprecipitate and colocalize to centrosomes in G2 phase, where AurA becomes active. In contrast with previously characterized AurA activators, NPM does not trigger autophosphorylation of AurA on threonine 288. NPM induces phosphorylation of AurA on serine 89, and this phosphorylation is necessary for activation of AurA. These data were confirmed in vivo, as depletion of NPM by ribonucleic acid interference eliminated phosphorylation of CDC25B on S353 at the centrosome, indicating a local loss of AurA activity. Our data demonstrate that NPM is a strong activator of AurA kinase activity at the centrosome and support a novel mechanism of activation for AurA. PMID- 22451696 TI - A link between mitotic entry and membrane growth suggests a novel model for cell size control. AB - Addition of new membrane to the cell surface by membrane trafficking is necessary for cell growth. In this paper, we report that blocking membrane traffic causes a mitotic checkpoint arrest via Wee1-dependent inhibitory phosphorylation of Cdk1. Checkpoint signals are relayed by the Rho1 GTPase, protein kinase C (Pkc1), and a specific form of protein phosphatase 2A (PP2A(Cdc55)). Signaling via this pathway is dependent on membrane traffic and appears to increase gradually during polar bud growth. We hypothesize that delivery of vesicles to the site of bud growth generates a signal that is proportional to the extent of polarized membrane growth and that the strength of the signal is read by downstream components to determine when sufficient growth has occurred for initiation of mitosis. Growth dependent signaling could explain how membrane growth is integrated with cell cycle progression. It could also control both cell size and morphogenesis, thereby reconciling divergent models for mitotic checkpoint function. PMID- 22451697 TI - Netrin instructs synaptic vesicle clustering through Rac GTPase, MIG-10, and the actin cytoskeleton. AB - Netrin is a chemotrophic factor known to regulate a number of neurodevelopmental processes, including cell migration, axon guidance, and synaptogenesis. Although the role of Netrin in synaptogenesis is conserved throughout evolution, the mechanisms by which it instructs synapse assembly are not understood. Here we identify a mechanism by which the Netrin receptor UNC-40/DCC instructs synaptic vesicle clustering in vivo. UNC-40 localized to presynaptic regions in response to Netrin. We show that UNC-40 interacted with CED-5/DOCK180 and instructed CED-5 presynaptic localization. CED-5 in turn signaled through CED-10/Rac1 and MIG 10/Lamellipodin to organize the actin cytoskeleton in presynaptic regions. Localization of this signaling pathway to presynaptic regions was necessary for synaptic vesicle clustering during synapse assembly but not for the subcellular localization of active zone proteins. Thus, vesicle clustering and localization of active zone proteins are instructed by separate pathways downstream of Netrin. Our data indicate that signaling modules known to organize the actin cytoskeleton during guidance can be co-opted to instruct synaptic vesicle clustering. PMID- 22451698 TI - Autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell. AB - Apoptotic cell degradation is a fundamental process for organism development, and impaired clearance causes inflammatory or autoimmune disease. Although autophagy genes were reported to be essential for exposing the engulfment signal on apoptotic cells, their roles in phagocytes for apoptotic cell removal are not well understood. In this paper, we develop live-cell imaging techniques to study apoptotic cell clearance in the Caenorhabditis elegans Q neuroblast lineage. We show that the autophagy proteins LGG-1/LC3, ATG-18, and EPG-5 were sequentially recruited to internalized apoptotic Q cells in the phagocyte. In atg-18 or epg-5 mutants, apoptotic Q cells were internalized but not properly degraded; this phenotype was fully rescued by the expression of autophagy genes in the phagocyte. Time-lapse analysis of autophagy mutants revealed that recruitment of the small guanosine triphosphatases RAB-5 and RAB-7 to the phagosome and the formation of phagolysosome were all significantly delayed. Thus, autophagy genes act within the phagocyte to promote apoptotic cell degradation. PMID- 22451699 TI - A comprehensive assessment of repaglinide metabolic pathways: impact of choice of in vitro system and relative enzyme contribution to in vitro clearance. AB - Repaglinide is presently recommended by the U.S. Food and Drug Administration as a clinical CYP2C8 probe, yet current in vitro and clinical data are inconsistent concerning the role of this enzyme in repaglinide elimination. The aim of the current study was to perform a comprehensive investigation of repaglinide metabolic pathways and assess their contribution to the overall clearance. Formation of four repaglinide metabolites was characterized using in vitro systems with differential complexity. Full kinetic profiles for the formation of M1, M2, M4, and repaglinide glucuronide were obtained in pooled cryopreserved human hepatocytes, human liver microsomes, human S9 fractions, and recombinant cytochrome P450 enzymes. Distinct differences in clearance ratios were observed between CYP3A4 and CYP2C8 for M1 and M4 formation, resulting in a 60-fold M1/M4 ratio in recombinant (r) CYP3A4, in contrast to 0.05 in rCYP2C8. Unbound K(m) values were within 2-fold for each metabolite across all in vitro systems investigated. A major system difference was seen in clearances for the formation of M2, which is suggested to be a main metabolite of repaglinide in vivo. An approximately 7-fold higher unbound intrinsic clearance was observed in hepatocytes and S9 fractions in comparison to microsomes; the involvement of aldehyde dehydrogenase in M2 formation was shown for the first time. This systematic analysis revealed a comparable in vitro contribution from CYP2C8 and CYP3A4 to the metabolism of repaglinide (<50%), whereas the contribution of glucuronidation ranged from 2 to 20%, depending on the in vitro system used. The repaglinide M4 metabolic pathway is proposed as a specific CYP2C8 probe for the assessment of drug-drug interactions. PMID- 22451700 TI - In vitro evaluation of the interaction potential of irosustat with drug metabolizing enzymes. AB - Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 MUM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 MUM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane. PMID- 22451701 TI - Accuracy and usefulness of the HEDIS childhood immunization measures. AB - OBJECTIVE: With the use of Centers for Disease Control and Prevention (CDC) immunization recommendations as the gold standard, our objectives were to measure the accuracy ("is this child up-to-date on immunizations?") and usefulness ("is this child due for catch-up immunizations?") of the Healthcare Effectiveness Data and Information Set (HEDIS) childhood immunization measures. METHODS: For children aged 24 to 35 months from the 2009 National Immunization Survey, we assessed the accuracy and usefulness of the HEDIS childhood immunization measures for 6 individual immunizations and a composite. RESULTS: A total of 12 096 children met all inclusion criteria and composed the study sample. The HEDIS measures had >90% accuracy when compared with the CDC gold standard for each of the 6 immunizations (range, 94.3%-99.7%) and the composite (93.8%). The HEDIS measure was least accurate for hepatitis B and pneumococcal conjugate immunizations. The proportion of children for which the HEDIS measure yielded a nonuseful result (ie, an incorrect answer to the question, "is this child due for catch-up immunization?") ranged from 0.33% (varicella) to 5.96% (pneumococcal conjugate). The most important predictor of HEDIS measure accuracy and usefulness was the CDC-recommended number of immunizations due at age 2 years; children with zero or all immunizations due were the most likely to be correctly classified. CONCLUSIONS: HEDIS childhood immunization measures are, on the whole, accurate and useful. Certain immunizations (eg, hepatitis B, pneumococcal conjugate) and children (eg, those with a single overdue immunization), however, are more prone to HEDIS misclassification. PMID- 22451702 TI - The national Perinatal Hepatitis B Prevention Program, 1994-2008. AB - OBJECTIVE: To determine the trends and outcomes of the national Perinatal Hepatitis B Prevention Program (PHBPP) for infants born from 1994 to 2008. METHODS: PHBPPs in state and city public health jurisdictions annually submitted program outcome reports to the Centers for Disease Control and Prevention. The annual number of births to hepatitis B surface antigen (HBsAg)-positive women was estimated and used to evaluate the percentage of PHBPP-identified HBsAg-positive pregnant women. PHBPP reports were used to assess program objectives achieved, and infant outcomes by 12 to 24 months of age. RESULTS: From 1994 to 2008, the estimated number of annual births to HBsAg-positive women increased from 19 208 to 25 600 (P < .001). The annual number of PHBPP-managed infants increased (P < .001), comprising 40.8% to 50.5% of the estimated number. On average, 94.4% of PHBPP-managed infants received hepatitis B immunoglobulin and hepatitis B vaccine within 1 day of birth. The percentage of infants who completed the vaccine series by age 12 months decreased from 86.0% to 77.7% (P = .004), but the percentage who received postvaccination testing increased from 25.1% to 56.0% (P < .001). Incidence of chronic hepatitis B virus infection among tested infants decreased from 2.1% in 1999 to 0.8% in 2008 (P = .001). CONCLUSIONS: The PHBPP achieved substantial progress in preventing perinatal hepatitis B virus infection in the United States, despite an increasing number of at-risk infants. Significant gaps remain in identifying HBsAg-positive pregnant women, and completing management and assessment of their infants to ensure prevention of perinatal hepatitis B virus transmission. PMID- 22451703 TI - Risk factor changes for sudden infant death syndrome after initiation of Back-to Sleep campaign. AB - OBJECTIVE: To test the hypothesis that the profile of sudden infant death syndrome (SIDS) changed after the Back-to-Sleep (BTS) campaign initiation, document prevalence and patterns of multiple risks, and determine the age profile of risk factors. METHODS: The San Diego SIDS/Sudden Unexplained Death in Childhood Research Project recorded risk factors for 568 SIDS deaths from 1991 to 2008 based upon standardized death scene investigations and autopsies. Risks were divided into intrinsic (eg, male gender) and extrinsic (eg, prone sleep). RESULTS: Between 1991-1993 and 1996-2008, the percentage of SIDS infants found prone decreased from 84.0% to 48.5% (P < .001), bed-sharing increased from 19.2% to 37.9% (P < .001), especially among infants <2 months (29.0% vs 63.8%), prematurity rate increased from 20.0% to 29.0% (P = .05), whereas symptoms of upper respiratory tract infection decreased from 46.6% to 24.8% (P < .001). Ninety-nine percent of SIDS infants had at least 1 risk factor, 57% had at least 2 extrinsic and 1 intrinsic risk factor, and only 5% had no extrinsic risk. The average number of risks per SIDS infant did not change after initiation of the BTS campaign. CONCLUSIONS: SIDS infants in the BTS era show more variation in risk factors. There was a consistently high prevalence of both intrinsic and especially extrinsic risks both before and during the Back-to-Sleep era. Risk reduction campaigns emphasizing the importance of avoiding multiple and simultaneous SIDS risks are essential to prevent SIDS, including among infants who may already be vulnerable. PMID- 22451704 TI - Pharmacy communication to adolescents and their physicians regarding access to emergency contraception. AB - OBJECTIVE: Emergency contraception (EC) is an effective pregnancy prevention strategy. EC is available without a prescription to those aged 17 years or older. The objective of this study was to assess the accuracy of information provided to adolescents and their physicians when they telephone pharmacies to inquire about EC. METHODS: By using standardized scripts, female callers telephoned 943 pharmacies in 5 US cities posing as 17-year-old adolescents or as physicians calling on behalf of their 17-year-old patients. McNemar tests were used to compare outcomes between adolescent and physician callers. RESULTS: Seven hundred fifty-nine pharmacies (80%) indicated to adolescent callers, and 766 (81%) to physician callers, that EC was available on the day of the call. However, 145 pharmacies (19%) incorrectly told the adolescent callers that it would be impossible to obtain EC under any circumstances, compared with 23 pharmacies (3%) for physician callers. Pharmacies conveyed the correct age to dispense EC without a prescription in 431 adolescent calls (57%) and 466 physician calls (61%). Compared with physician callers, adolescent callers were put on hold more often (54% vs 26%) and spoke to self-identified pharmacists less often (3% vs 12%, P < .0001). When EC was not available, 36% and 33% of pharmacies called by adolescents and physicians respectively offered no additional suggestions on how to obtain it. CONCLUSIONS: Most pharmacies report having EC in stock. However, misinformation regarding who can take EC, and at what age it is available without a prescription, is common. Such misinformation may create barriers to timely access. PMID- 22451705 TI - Medical staff appointment and delineation of pediatric privileges in hospitals. AB - The review and verification of credentials and the granting of clinical privileges are required of every hospital to ensure that members of the medical staff are competent and qualified to provide specified levels of patient care. The credentialing process involves the following: (1) assessment of the professional and personal background of each practitioner seeking privileges; (2) assignment of privileges appropriate for the clinician's training and experience; (3) ongoing monitoring of the professional activities of each staff member; and (4) periodic reappointment to the medical staff on the basis of objectively measured performance. We examine the essential elements of a credentials review for initial and renewed medical staff appointments along with suggested criteria for the delineation of clinical privileges. Sample forms for the delineation of privileges can be found on the American Academy of Pediatrics Committee on Hospital Care Web site (http://www.aap.org/visit/cmte19.htm). Because of differences among individual hospitals, no 1 method for credentialing is universally applicable. The medical staff of each hospital must, therefore, establish its own process based on the general principles reviewed in this report. The issues of medical staff membership and credentialing have become very complex, and institutions and medical staffs are vulnerable to legal action. Consequently, it is advisable for hospitals and medical staffs to obtain expert legal advice when medical staff bylaws are constructed or revised. PMID- 22451706 TI - Mental health difficulties in children with developmental coordination disorder. AB - OBJECTIVE: To explore the associations between probable developmental coordination disorder (DCD) defined at age 7 years and mental health difficulties at age 9 to 10 years. METHODS: We analyzed of prospectively collected data (N = 6902) from the Avon Longitudinal Study of Parents and Children. "Probable" DCD was defined by using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria as those children below the 15th centile of the Avon Longitudinal Study of Parents and Children Coordination Test, with functional limitations in activities of daily living or handwriting, excluding children with neurologic difficulties or an IQ <70. Mental health was measured by using the child-reported Short Moods and Feelings Questionnaire and the parent reported Strengths and Difficulties Questionnaire. Multiple logistic regression models, with the use of multiple imputation to account for missing data, assessed the associations between probable DCD and mental health difficulties. Adjustments were made for environmental confounding factors, and potential mediating factors such as verbal IQ, associated developmental traits, bullying, self-esteem, and friendships. RESULTS: Children with probable DCD (N = 346) had an increased odds of self-reported depression, odds ratio: 2.08 (95% confidence interval: 1.36 3.19) and parent-reported mental health difficulties odds ratio: 4.23 (95% confidence interval: 3.10-5.77). The odds of mental health difficulties significantly decreased after accounting for verbal IQ, social communication, bullying, and self-esteem. CONCLUSIONS: Children with probable DCD had an increased risk of mental health difficulties that, in part, were mediated through associated developmental difficulties, low verbal IQ, poor self-esteem, and bullying. Prevention and treatment of mental health difficulties should be a key element of intervention for children with DCD. PMID- 22451707 TI - Novel modeling of reference values of cardiovascular risk factors in children aged 7 to 20 years. AB - BACKGROUND AND OBJECTIVE: Most of the cardiovascular risk factors strongly associated with obesity and overweight vary with age and gender. However, few reference values are available for healthy European children. Our objective was to establish pediatric reference ranges for waist circumference, systolic and diastolic blood pressures, fasting lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), glucose, and insulin. METHODS: A representative sample of 1976 healthy French individuals (1004 female participants and 972 male participants) aged 7 to 20 years was used to obtain age- and gender-specific normal ranges for each of the above-listed cardiovascular risk factors, based on the Royston and Wright method. RESULTS: Mean waist circumference increased with age in both genders and was slightly higher in males than in females. Whereas systolic blood pressure increased gradually with age, with the increase being steeper in males than in females, no gender effect was found for diastolic blood pressure, which was therefore modeled after pooling males and females. Total cholesterol, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride values varied little with age and gender. Glucose and insulin levels revealed pubertal peaks, which were sharper in females than in males, reflecting the normal insulin resistance during puberty. CONCLUSIONS: These ranges can be used as references for European children to monitor cardiovascular risk factors and to plan interventions and education programs. PMID- 22451708 TI - Epidemiology and diagnosis of health care-associated infections in the NICU. AB - Health care-associated infections in the NICU are a major clinical problem resulting in increased morbidity and mortality, prolonged length of hospital stays, and increased medical costs. Neonates are at high risk for health care associated infections because of impaired host defense mechanisms, limited amounts of protective endogenous flora on skin and mucosal surfaces at time of birth, reduced barrier function of neonatal skin, the use of invasive procedures and devices, and frequent exposure to broad-spectrum antibiotics. This statement will review the epidemiology and diagnosis of health care-associated infections in newborn infants. PMID- 22451711 TI - Immune status in very preterm neonates. AB - OBJECTIVES: Preterm neonates are at increased risk of sepsis compared with those born at term. We investigated immune status at birth and early neonatal life in very preterm neonates and its association with short-term outcomes. METHODS: Prospective observational study conducted at a university hospital recruiting 113 preterm neonates (23-32 weeks) and 78 controls. Monocyte major histocompatibility complex (MHC) class II expression, serum, and ex vivo lipopolysaccharide stimulated levels of six cytokines (tumor necrosis factor alpha, interleukin (IL) 1beta, IL-6, IL-8, IL-10, and IL-12p70) were measured in umbilical cord blood and over the first 7 days. The presence of neonatal sepsis and histologic chorioamnionitis was recorded. RESULTS: Prematurity (preterm labor and preterm premature rupture of membranes cohorts), neonatal sepsis, and histologic chorioamnionitis were associated with significant reduction in monocyte MHC class II expression. Neonates who had evidence of subsequent protracted sepsis had low levels of MHC class II expression at birth. Serial monocyte MHC class II expression revealed a fall by day 2, in all preterm neonates, with the degree being influenced by both prematurity and sepsis, and incomplete recovery by day 7, suggesting immunoparalysis in preterm premature rupture of membranes and preterm labor cohorts. Whole blood lipopolysaccharide stimulation assay showed significantly lower tumor necrosis factor alpha, values in preterm neonates who subsequently developed sepsis indicating a degree of immunoparalysis. CONCLUSIONS: Our data support the concept that fetal exposure to inflammation before preterm delivery leads to subsequent endotoxin hyporesponsiveness (immunoparalysis), which increases the risk of subsequent sepsis and associated organ dysfunction. PMID- 22451712 TI - Strategies for prevention of health care-associated infections in the NICU. AB - Health care-associated infections in the NICU result in increased morbidity and mortality, prolonged lengths of stay, and increased medical costs. Neonates are at high risk of acquiring health care-associated infections because of impaired host-defense mechanisms, limited amounts of protective endogenous flora on skin and mucosal surfaces at time of birth, reduced barrier function of their skin, use of invasive procedures and devices, and frequent exposure to broad-spectrum antibiotic agents. This clinical report reviews management and prevention of health care-associated infections in newborn infants. PMID- 22451713 TI - Pediatric sudden cardiac arrest. AB - Pediatric sudden cardiac arrest (SCA), which can cause sudden cardiac death if not treated within minutes, has a profound effect on everyone: children, parents, family members, communities, and health care providers. Preventing the tragedy of pediatric SCA, defined as the abrupt and unexpected loss of heart function, remains a concern to all. The goal of this statement is to increase the knowledge of pediatricians (including primary care providers and specialists) of the incidence of pediatric SCA, the spectrum of causes of pediatric SCA, disease specific presentations, the role of patient and family screening, the rapidly evolving role of genetic testing, and finally, important aspects of secondary SCA prevention. This statement is not intended to address sudden infant death syndrome or sudden unexplained death syndrome, nor will specific treatment of individual cardiac conditions be discussed. This statement has been endorsed by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society. PMID- 22451714 TI - Motor coordination and psychosocial correlates in a normative adolescent sample. AB - OBJECTIVES: Previous research has revealed an important relationship between motor coordination difficulties and internalizing problems such as anxiety and depressive symptoms. However, further research is needed to understand the potential mediating factors in this relationship. The aim of the current study was to examine whether the association between motor coordination and emotional functioning is mediated by self-perceptions in a normative sample of adolescents. METHODS: Participants included 93 adolescents aged 12 to 16 years. The Movement Assessment Battery for Children-2 provided 2 indicators of motor coordination; the Mood and Feelings Questionnaire and Spence Children's Anxiety Scale provided 2 indicators of emotional functioning; and the Self-Description Questionnaire--II provided 6 indicators for self-perceived competence. RESULTS: Structural equation modeling revealed that motor coordination affects emotional functioning via self perceptions. CONCLUSIONS: These results suggest that the relationship between motor coordination and emotional functioning in adolescents from a normative sample may be understood in terms of a mechanism by which motor coordination has an indirect impact on emotional outcomes through various self-perception domains. These findings have important implications for increasing awareness and developing appropriate treatment programs for motor coordination and emotional difficulties. PMID- 22451715 TI - The pitfalls of transgenic selection and new roles of AtHXK1: a high level of AtHXK1 expression uncouples hexokinase1-dependent sugar signaling from exogenous sugar. PMID- 22451716 TI - Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. AB - Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibalpha and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features. PMID- 22451717 TI - Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection. AB - The development of AIDS in chronic HIV/simian immunodeficiency virus (SIV) infection has been closely linked to progressive failure of CD4(+) memory T cell (T(M)) homeostasis. CD4(+) naive T cells (T(N)) also decline in these infections, but their contribution to disease progression is less clear. We assessed the role of CD4(+) T(N) in SIV pathogenesis using rhesus macaques (RMs) selectively and permanently depleted of CD4(+) T(N) before SIV infection. CD4(+) T(N)-depleted and CD4(+) T(N)-repleted RMs were created by subjecting juvenile RMs to thymectomy versus sham surgery, respectively, followed by total CD4(+) T cell depletion and recovery from this depletion. Although thymectomized and sham treated RMs manifested comparable CD4(+) T(M) recovery, only sham-treated RMs reconstituted CD4(+) T(N). CD4(+) T(N)-depleted RMs responded to SIVmac239 infection with markedly attenuated SIV-specific CD4(+) T cell responses, delayed SIVenv-specific Ab responses, and reduced SIV-specific CD8(+) T cell responses. However, CD4(+) T(N)-depleted and -repleted groups showed similar levels of SIV replication. Moreover, CD4(+) T(N) deficiency had no significant effect on CD4(+) T(M) homeostasis (either on or off anti-retroviral therapy) or disease progression. These data demonstrate that the CD4(+) T(N) compartment is dispensable for CD4(+) T(M) homeostasis in progressive SIV infection, and they confirm that CD4(+) T(M) comprise a homeostatically independent compartment that is intrinsically capable of self-renewal. PMID- 22451718 TI - Transglutaminase is essential for IgA nephropathy development acting through IgA receptors. AB - IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA-soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1-sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89-TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1-sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1-sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease. PMID- 22451719 TI - The ATPase activity of MLH1 is required to orchestrate DNA double-strand breaks and end processing during class switch recombination. AB - Antibody diversification through somatic hypermutation (SHM) and class switch recombination (CSR) are similarly initiated in B cells with the generation of U:G mismatches by activation-induced cytidine deaminase but differ in their subsequent mutagenic consequences. Although SHM relies on the generation of nondeleterious point mutations, CSR depends on the production of DNA double strand breaks (DSBs) and their adequate recombination through nonhomologous end joining (NHEJ). MLH1, an ATPase member of the mismatch repair (MMR) machinery, is emerging as a likely regulator of whether a U:G mismatch progresses toward mutation or DSB formation. We conducted experiments on cancer modeled ATPase deficient MLH1G67R knockin mice to determine the function that the ATPase domain of MLH1 mediates in SHM and CSR. Mlh1(GR/GR) mice displayed a significant decrease in CSR, mainly attributed to a reduction in the generation of DSBs and diminished accumulation of 53BP1 at the immunoglobulin switch regions. However, SHM was normal in these mice, which distinguishes MLH1 from upstream members of the MMR pathway and suggests a very specific role of its ATPase-dependent functions during CSR. In addition, we show that the residual switching events still taking place in Mlh1(GR/GR) mice display unique features, suggesting a role for the ATPase activity of MLH1 beyond the activation of the endonuclease functions of its MMR partner PMS2. A preference for switch junctions with longer microhomologies in Mlh1(GR/GR) mice suggests that through its ATPase activity, MLH1 also has an impact in DNA end processing, favoring canonical NHEJ downstream of the DSB. Collectively, our study shows that the ATPase domain of MLH1 is important to transmit the CSR signaling cascade both upstream and downstream of the generation of DSBs. PMID- 22451720 TI - Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33. AB - Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33 dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential. PMID- 22451721 TI - Contrasting physiological effects of partial root zone drying in field-grown grapevine (Vitis vinifera L. cv. Monastrell) according to total soil water availability. AB - Different spatial distributions of soil moisture were imposed on field-grown grapevines by applying the same irrigation volumes to the entire (DI; deficit irrigation) or part of the (PRD; partial root zone drying) root zone. Five treatments were applied: controls irrigated at 60% ETc (crop evapotranspiration) for the whole season (308 mm year(-1)); DI-1 and PRD-1 that received the same irrigation as controls before fruit set, 30% ETc from fruit set to harvest and 45% ETc post-harvest (192 mm year(-1)); and DI-2 and PRD-2 that were the same, except that 15% ETc was applied from fruit set to harvest (142 mm year(-1)). Compared with DI-1, PRD-1 maintained higher leaf area post-veraison and increased root water uptake, whole-plant hydraulic conductance, leaf transpiration, stomatal conductance, and photosynthesis, but decreased intrinsic gas exchange efficiency without causing differences in leaf xylem abscisic acid (ABA) concentration. Compared with DI-2, PRD-2 increased leaf xylem ABA concentration and decreased root water uptake, whole-plant hydraulic conductance, leaf transpiration, stomatal conductance, and photosynthesis, mainly at the beginning of PRD cycles. Distinctive PRD effects (e.g. greater stomatal closure) depended on the volumetric soil water content of the wet root zone, as predicted from a model of root-to-shoot ABA signalling. PMID- 22451722 TI - Hypoxia induces H2O2 production and activates antioxidant defence system in grapevine buds through mediation of H2O2 and ethylene. AB - Paradoxically, in eukaryotic cells, hydrogen peroxide (H(2)O(2)) accumulates in response to oxygen deprivation (hypoxia). The source of H(2)O(2) under hypoxia varies according to the species, organs, and tissue. In non-photosynthetic tissues, H(2)O(2) is mainly produced by activation of NAD(P)H-oxidases or by disruption of the mitochondrial electron transport chain (m-ETC). This study showed that hypoxia, and inhibitors of respiration like potassium cyanide (KCN) and sodium nitroprusside (SNP), trigger the production of H(2)O(2) in grapevine buds. However, diphenyleneiodonium, an inhibitor of NAD(P)H-oxidase, did not reduce the H(2)O(2) levels induced by KCN, suggesting that, under respiratory stress, H(2)O(2) is mainly produced by disruption of the m-ETC. On the other hand, gamma-aminobutyric acid (GABA), a metabolite that in plants alleviates oxidative stress by activating antioxidant enzymes, reduced significantly the levels of H(2)O(2) induced by KCN and, surprisingly, repressed the expression of genes encoding antioxidant enzymes such as ASCORBATE PEROXIDASE (VvAPX), GLUTATHIONE PEROXIDASE (VvGLPX), SUPEROXIDE DISMUTASE (VvSOD), and one of the CATALASE isoforms (VvCAT1), while VvCAT2 was upregulated. In contrast to GABA, hypoxia, H(2)O(2), and ethylene increased dramatically the expression of genes encoding antioxidant enzymes and enzymes of the alternative respiratory pathway such as ALTERNATIVE NADH-DEHYDROGENASES (VvaNDs) and ALTERNATIVE OXIDASES (VvAOXs). Hence, it is concluded that H(2)O(2) production is stimulated by respiratory stress in grapevine buds, that H(2)O(2) and ethylene act as signalling molecules and activate genes related to the antioxidant defence system, and finally that GABA reduces H(2)O(2) levels by up-regulating the expression of VvCAT2. PMID- 22451723 TI - Modulation of ethylene responses by OsRTH1 overexpression reveals the biological significance of ethylene in rice seedling growth and development. AB - Overexpression of Arabidopsis Reversion-To-ethylene Sensitivity1 (RTE1) results in whole-plant ethylene insensitivity dependent on the ethylene receptor gene Ethylene Response1 (ETR1). However, overexpression of the tomato RTE1 homologue Green Ripe (GR) delays fruit ripening but does not confer whole-plant ethylene insensitivity. It was decided to investigate whether aspects of ethylene-induced growth and development of the monocotyledonous model plant rice could be modulated by rice RTE1 homologues (OsRTH genes). Results from a cross-species complementation test in Arabidopsis showed that OsRTH1 overexpression complemented the rte1-2 loss-of-function mutation and conferred whole-plant ethylene insensitivity in an ETR1-dependent manner. In contrast, OsRTH2 and OsRTH3 overexpression did not complement rte1-2 or confer ethylene insensitivity. In rice, OsRTH1 overexpression substantially prevented ethylene-induced alterations in growth and development, including leaf senescence, seedling leaf elongation and development, coleoptile elongation or curvature, and adventitious root development. Results of subcellular localizations of OsRTHs, each fused with the green fluorescent protein, in onion epidermal cells suggested that the three OsRTHs were predominantly localized to the Golgi. OsRTH1 may be an RTE1 orthologue of rice and modulate rice ethylene responses. The possible roles of auxins and gibberellins in the ethylene-induced alterations in growth were evaluated and the biological significance of ethylene in the early stage of rice seedling growth is discussed. PMID- 22451724 TI - Different effect of cadmium and copper on H+-ATPase activity in plasma membrane vesicles from Cucumis sativus roots. AB - The effect of heavy metals on plasma membrane (PM) H(+)-ATPase (EC 3.6.3.14) activity in cucumber (Cucumis sativus) roots was studied. The aim of this work was to explain the mechanism of modification of the PM H(+)-ATPase activity in plants subjected to heavy metals. Plants were treated with 10 MUM Cd or Cu for 6 d. After 3 d exposure to the heavy metals, some of the plants were transferred to control conditions for a further 3 d (3/3 plants). The activity of PM H(+)-ATPase was found to be increased in plants treated with heavy metals. The highest activity measured as proton transport was observed in 3/3 plants. Estimation of transcript levels of C. sativus PM H(+)-ATPase in roots indicated that the action of Cd, but not Cu, affected the gene expression level. Transcript levels of C. sativus PM H(+)-ATPase (CsHA2, CsHA3, CsHA4, CsHA8, and CsHA9) genes increased in roots treated with Cd. Moreover, Western blot analysis with antibody against phosphothreonine and 14-3-3 protein indicated that increased activity of PM H(+) ATPase under heavy-metal stress resulted from phosphorylation of the enzyme. It was found that Cu markedly increased the activity of catalase and ascorbate peroxidase and reduced the level of H(2)O(2) in cucumber roots. In contrast, Cd did not affect these parameters. These results indicate that Cd and Cu can, in different ways, lead to modification of PM H(+)-ATPase activity. Additionally, it was observed that treatment of plants with heavy metals led to an increased level of heat-shock proteins in the tissues. This suggests that the plants had started adaptive processes to survive adverse conditions, and increased PM H(+)-ATPase activity could further enhance the repair processes in heavy-metal-stressed plants. PMID- 22451725 TI - Synchronously developing collet hairs in Arabidopsis thaliana provide an easily accessible system for studying nuclear movement and endoreduplication. AB - Early Arabidopsis thaliana seedling growth includes the highly synchronous development of hairs from every epidermal cell of the collet (the root-hypocotyl transition zone). The dynamics of collet hair growth, and accompanying nuclear movement and endoreduplication, were followed using a combination of different fluorescent probes for time-lapse imaging and flow cytometry. Using laser scanning confocal microscopy on the double-transgenic Arabidopsis hybrid line NLS GFP-GUS * YPM, there appeared to be a correlation between nuclear position and the cell tip during growth of the collet hair cells, as occurs in asynchronously developing root hairs. However, disruption of nuclear movement in the growing collet hairs using low concentrations of cytoskeletal inhibitors demonstrated that nuclear positioning close to the tip of the cell is not essential for tip directed growth of the hair. Nuclear DNA content increases from 4C to 16C during development of the collet hairs. Following cessation of growth, nuclei moved to the base of the hairs and then their movement became asynchronous and limited. Co visualization of RFP-highlighted prevacuolar vesicles and GFP-labelled nuclei showed that, whereas small vesicles allowed unimpeded nuclear movement within the hair, transient stops and directional reversals coincided with the presence of larger vesicles in close proximity to the nucleus. Arabidopsis collet hairs provide a robust, easily accessible, naturally synchronized population of single tip-growing cells that can be used as a model cell type for studying nuclear movement and endoreduplication. PMID- 22451726 TI - Comparative Genomics and Evolution of Molybdenum Utilization. AB - The trace element molybdenum (Mo) is the catalytic component of important enzymes involved in global nitrogen, sulfur, and carbon metabolism in both prokaryotes and eukaryotes. With the exception of nitrogenase, Mo is complexed by a pterin compound thus forming the biologically active molybdenum cofactor (Moco) at the catalytic sites of molybdoenzymes. The physiological roles and biochemical functions of many molybdoenzymes have been characterized. However, our understanding of the occurrence and evolution of Mo utilization is limited. This article focuses on recent advances in comparative genomics of Mo utilization in the three domains of life. We begin with a brief introduction of Mo transport systems, the Moco biosynthesis pathway, the role of posttranslational modifications, and enzymes that utilize Mo. Then, we proceed to recent computational and comparative genomics studies of Mo utilization, including a discussion on novel Moco-binding proteins that contain the C-terminal domain of the Moco sulfurase and that are suggested to represent a new family of molybdoenzymes. As most molybdoenzymes need additional cofactors for their catalytic activity, we also discuss interactions between Mo metabolism and other trace elements and finish with an analysis of factors that may influence evolution of Mo utilization. PMID- 22451727 TI - Anti-apoptotic effects of SERPIN B3 and B4 via STAT6 activation in macrophages after infection with Toxoplasma gondii. AB - Toxoplasma gondii penetrates all kinds of nucleated eukaryotic cells but modulates host cells differently for its intracellular survival. In a previous study, we found out that serine protease inhibitors B3 and B4 (SERPIN B3/B4 because of their very high homology) were significantly induced in THP-1-derived macrophages infected with T. gondii through activation of STAT6. In this study, to evaluate the effects of the induced SERPIN B3/B4 on the apoptosis of T. gondii infected THP-1 cells, we designed and tested various small interfering (si-) RNAs of SERPIN B3 or B4 in staurosporine-induced apoptosis of THP-1 cells. Anti apoptotic characteristics of THP-1 cells after infection with T. gondii disappeared when SERPIN B3/B4 were knock-downed with gene specific si-RNAs transfected into THP-1 cells as detected by the cleaved caspase 3, poly-ADP ribose polymerase and DNA fragmentation. This anti-apoptotic effect was confirmed in SERPIN B3/B4 overexpressed HeLa cells. We also investigated whether inhibition of STAT6 affects the function of SERPIN B3/B4, and vice versa. Inhibition of SERPIN B3/B4 did not influence STAT6 expression but SERPIN B3/B4 expression was inhibited by STAT6 si-RNA transfection, which confirmed that SERPIN B3/B4 was induced under the control of STAT6 activation. These results suggest that T. gondii induces SERPIN B3/B4 expression via STAT6 activation to inhibit the apoptosis of infected THP-1 cells for longer survival of the intracellular parasites themselves. PMID- 22451728 TI - Gene expression profiles in genetically different mice infected with Toxoplasma gondii: ALDH1A2, BEX2, EGR2, CCL3 and PLAU. AB - Toxoplasma gondii can modulate host cell gene expression; however, determining gene expression levels in intermediate hosts after T. gondii infection is not known much. We selected 5 genes (ALDH1A2, BEX2, CCL3, EGR2 and PLAU) and compared the mRNA expression levels in the spleen, liver, lung and small intestine of genetically different mice infected with T. gondii. ALDH1A2 mRNA expressions of both mouse strains were markedly increased at day 1-4 postinfection (PI) and then decreased, and its expressions in the spleen and lung were significantly higher in C57BL/6 mice than those of BALB/c mice. BEX2 and CCR3 mRNA expressions of both mouse strains were significantly increased from day 7 PI and peaked at day 15-30 PI (P<0.05), especially high in the spleen liver or small intestine of C57BL/6 mice. EGR2 and PLAU mRNA expressions of both mouse strains were significantly increased after infection, especially high in the spleen and liver. However, their expression patterns were varied depending on the tissue and mouse strain. Taken together, T. gondii-susceptible C57BL/6 mice expressed higher levels of these 5 genes than did T. gondii-resistant BALB/c mice, particularly in the spleen and liver. And ALDH1A2 and PLAU expressions were increased acutely, whereas BEX2, CCL3 and EGR2 expressions were increased lately. Thus, these demonstrate that host genetic factors exert a strong impact on the expression of these 5 genes and their expression patterns were varied depending on the gene or tissue. PMID- 22451729 TI - A recombinant Plasmodium vivax apical membrane antigen-1 to detect human infection in Iran. AB - In Iran, Plasmodium vivax is responsible for more than 80% of the infected cases of malaria per year. Control interventions for vivax malaria in humans rely mainly on developed diagnostic methods. Recombinant P. vivax apical membrane antigen-1 (rPvAMA-1) has been reported to achieve designing rapid, sensitive, and specific molecular diagnosis. This study aimed to perform isolation and expression of a rPvAMA-1, derived from Iranian patients residing in an endemic area. Then, the diagnostic efficiency of the characterized Iranian PvAMA-1 was assessed using an indirect ELISA method. For this purpose, a partial region of AMA-1 gene was amplified, cloned, and expressed in pET32a plasmid. The recombinant His-tagged protein was purified and used to coat the ELISA plate. Antibody detection was assessed by indirect ELISA using rPvAMA-1. The validity of the ELISA method for detection of anti-P. vivax antibodies in the field was compared to light microscopy on 84 confirmed P. vivax patients and compared to 84 non-P. vivax infected individuals. The ELISA cut-off value was calculated as the mean+2SD of OD values of the people living in malaria endemic areas from a south part of Iran. We found a cut-off point of OD=0.311 that showed the best correlation between the sera confirmed with P. vivax infection and healthy control sera. A sensitivity of 81.0% and specificity of 84.5% were found at this cut off titer. A good degree of statistical agreement was found between ELISA using rPvAMA-1 and light microscopy (0.827) by Kappa analysis. PMID- 22451730 TI - Transmission of Toxocara canis via ingestion of raw cow liver: a cross-sectional study in healthy adults. AB - The aim of this study is to ascertain the relationship between ingestion of raw cow liver and Toxocara canis infection. A total of 150 apparently healthy adults were divided into 2 groups; 1 group consisted of 86 adults with positive results of Toxocara ELISA, and the other group of 64 adults with negative results. One researcher collected the history of ingestion of raw cow liver within 1 year and recent history of keeping dogs. Among 86 seropositive adults for T. canis, 68 (79.1%) had a recent history of ingestion of raw cow liver. Multivariate statistical analysis showed that a recent ingestion of raw cow liver and keeping dogs were related to an increased risk of toxocariasis (odds ratios, 4.4 and 3.7; and 95% confidence intervals, 1.9-10.2 and 1.2-11.6, respectively). A recent history of ingestion of raw cow liver and keeping dogs was significantly associated with toxocariasis. PMID- 22451731 TI - T regulatory cell responses to immunization with a soluble egg antigen in Schistosoma mansoni-infected mice. AB - The aim of the study is to characterize the phenotypes of CD4(+) CD25(+) T regulatory cells within the liver granulomas and association with both Foxp-3 gene expression and splenic cytokines. Naive C57BL/6 mice were intravenously injected with multiple doses of the soluble egg antigen (SEA) 7 days before cercarial infection. The immunized and infected control groups were sacrificed 8 and 16 weeks post-infection (PI). Histopathology, parasitological parameters, splenic phenotypes for T regulatory cells, the FOXP-3 expression in hepatic granuloma using real-time PCR, and the associated splenic cytokines were studied. Histopathological examination of the liver revealed remarkable increase in degenerated ova within hepatic granuloma which decreased in diameter at weeks 8 and 16 PI (P<0.01). The percentage of T regulatory cells (CD4(+) CD25(+)) increased significantly (P<0.01) in the immunized group compared to the infected control at weeks 8 and 16 PI. The FOXP-3 expression in hepatic granulomas increased from 10 at week 8 to 30 fold at week 16 PI in the infected control group. However, its expression in the immunized group showed an increase from 30 at week 8 to 70 fold at week 16 PI. The splenic cytokine levels of pro inflammatory cytokines, IFN-gamma, IL-4, and TNF-alpha, showed significant decreases (P<0.05) compared to the infected control group. In conclusion, the magnitude and phenotype of the egg-induced effects on T helper responses were found to be controlled by a parallel response within the T regulatory population which provides protection in worm parasite-induced immunopathology. PMID- 22451732 TI - Fasciola gigantica fatty acid binding protein (FABP) as a prophylactic agent against Schistosoma mansoni infection in CD1 mice. AB - Although schistosomicidal drugs and other control measures exist, the advent of an efficacious vaccine remains the most potentially powerful means for controlling this disease. In this study, native fatty acid binding protein (FABP) from Fasciola gigantica was purified from the adult worm's crude extract by saturation with ammonium sulphate followed by separation on DEAE-Sephadex A-50 anion exchange chromatography and gel filtration using Sephacryl HR-100, respectively. CD1 mice were immunized with the purified, native F. gigantica FABP in Freund's adjuvant and challenged subcutaneously with 120 Schistosoma mansoni cercariae. Immunization of CD1 mice with F. gigantica FABP has induced heterologous protection against S. mansoni, evidenced by the significant reduction in mean worm burden (72.3%), liver and intestinal egg counts (81.3% and 80.8%, respectively), and hepatic granuloma counts (42%). Also, it elicited mixed IgG(1)/IgG(2b) immune responses with predominant IgG1 isotype, suggesting that native F. gigantica FABP is mediated by a mixed Th1/Th2 response. However, it failed to induce any significant differences in the oogram pattern or in the mean granuloma diameter. This indicated that native F. gigantica FABP could be a promising vaccine candidate against S. mansoni infection. PMID- 22451733 TI - Protective role of purified cysteine proteinases against Fasciola gigantica infection in experimental animals. AB - Fascioliasis is one of the public health problems in the world. Cysteine proteinases (CP) released by Fasciola gigantica play a key role in parasite feeding, migration through host tissues, and in immune evasion. There has been some evidence from several parasite systems that proteinases might have potential as protective antigens against parasitic infections. Cysteine proteinases were purified and tested in vaccine trials of sheep infected with the liver fluke. Multiple doses (2 mg of CP in Freund's adjuvant followed by 3 booster doses 1 mg each at 4 week intervals) were injected intramuscularly into sheep 1 week prior to infect orally with 300 F. gigantica metacercariae. All the sheep were humanely slaughtered 12 weeks after the first immunization. Changes in the worm burden, ova count, and humoral and cellular responses were evaluated. Significant reduction was observed in the worm burden (56.9%), bile egg count (70.7%), and fecel egg count (75.2%). Immunization with CP was also found to be associated with increases of total IgG, IgG(1), and IgG(2) (P<0.05). Data showed that the serum cytokine levels of pro-inflammatory cytokines, IL-12, IFN-gamma, and TNF alpha, revealed significant decreases (P<0.05). However, the anti-inflammatory cytokine levels, IL-10, TGF-beta, and IL-6, showed significant increases (P<0.05). In conclusion, it has been found that CP released by F. gigantica are highly important candidates for a vaccine antigen because of their role in the fluke biology and host-parasite relationships. PMID- 22451734 TI - Scolicidal effects of Olea europaea and Satureja khuzestanica extracts on protoscolices of hydatid cysts. AB - Treatment of hydatid disease is mainly surgical, with medical treatment being reserved as a coadjuvant treatment. Use of effective scolicidal agents during surgery of cystic echinococcosis is essential to reduce the recurrence rate. The goal of this study was to evaluate the in vitro scolicidal effects of hydroalcoholic extracts of Satureja khuzestanica leaves and aqueous extracts of Olea europaea leaves on hydatid cyst protoscolices. Echinococcus granulosus protoscolices were collected from the liver of sheep infected with the hydatid cyst. Various concentrations of plant extracts were used in different exposure times for viability assay of protoscolices. Among the olive leaf extracts tested, 0.1% and 0.01% concentrations had strong scolicidal effects in 120 min. S. khuzestanica 0.1% had very strong scolicidal effects in 30, 60, and 120 min of exposure times and the mortality rate decreased with the lower concentration. The finding have shown that the scolicidal activity of S. khuzestanica against cystic echinococosis protoscolices were more effective, while the O. europaea extract showed less effects. PMID- 22451735 TI - Opportunistic parasites among immunosuppressed children in Minia District, Egypt. AB - A total of 450 stool samples were collected from inpatient and outpatient clinics of Pediatric Department, Minia University Hospital, Minia District, Egypt. Two groups of patients were studied, including 200 immunosuppressed and 250 immunocompetent children. Stool samples were subjected to wet saline and iodine mounts. A concentration technique (formol-ether sedimentation method) was carried out for stool samples diagnosed negative by wet saline and iodine mounts. Samples were stained by 2 different methods; acid fast stain (modified Ziehl-Neelsen stain) and Giemsa stain. Total 188 cases (94%) were diagnosed positive for parasitic infections among immunosuppressed children, whereas 150 cases (60%) were positive in immunocompetent children (P<0.0001). The most common protozoan infection in immunosuppressed group was Cryptosporidium parvum (60.2%), followed by Blastocystis hominis (12.1%), Isospora belli (9.7%), and Cyclospora caytenensis (7.8%). On the other hand, Entamoeba histolytica (24.6%) and Giardia lamblia (17.6%) were more common than other protozoans in immunocompetent children. PMID- 22451736 TI - Congenital neosporosis in goats from the State of Minas Gerais, Brazil. AB - Congenital Neospora caninum infection was diagnosed in two Saanen goat kids from two distinct herds with a history of abortion and weak newborn goat kids in the Southern region of the State of Minas Gerais, Brazil. The first kid was weak at birth, had difficulty to rise and was unable to nurse. Gross lesions of porencephaly and hydrocephalus ex vacuo were seen. Multifocal necrosis, gliosis and non-supurative encephalitis were observed in the brain. Several parasitic cysts with a thick wall that reacted strongly only with polyclonal antiserum to Neospora caninum were seen in the cerebral cortex, brain stem and cerebellum. The second kid was born from a Neospora caninum seropositive mother that aborted in the last pregnancy. It was born without clinical signs. The diagnosis of neosporosis was based on antibody titer of 1:800 to N. caninum by indirect fluorescence antibody test obtained from blood collected before the goat kid ingested the colostrum and Neospora caninum DNA was detected by polymerase chain reaction and sequenced from placenta. This is the first report of neosporosis in goats in the southeast region of Brazil. PMID- 22451737 TI - Trichuris vulpis (Froelich, 1789) infection in a child: a case report. AB - We present a human infection with the canine whipworm, Trichuris vulpis, in a child suffering from rhinitis with a diagnosis of rhinitis. T. vulpis eggs resemble those of T. trichiura but they can be differentiated based on their morphological features and egg size, using micrometry with an ocular micrometer. T. vulpis eggs measured an average of 90 um by 44 um (range 86-99 um by 38-47 um). Prevalence of hookworms (28.1%), Toxocara canis (11.8%), and Trichuris vulpis (3.5%) was found in 292 fecal samples of dogs collected at the peri domicile, which showed that the risk of infection was not only fortuitous. The treatment of canine whipworm infections is similar to that of T. trichiura infection. We recommend differentiation of the 2 species for their epidemiological and prevention implications. PMID- 22451738 TI - Imported intraocular gnathostomiasis with subretinal tracks confirmed by western blot assay. AB - We report a case of intraocular gnathostomiasis diagnosed by western blot assay in a patient with subretinal tracks. A 15-year-old male patient complained of blurred vision in the right eye, lasting for 2 weeks. Eight months earlier, he had traveled to Vietnam for 1 week and ate raw wild boar meat and lobster. His best-corrected visual acuity was 20/20 in both eyes and anterior chamber examination revealed no abnormalities. Fundus examination showed subretinal tracks in the right eye. Fluorescein angiography and indocyanine green angiography showed linear hyperfluorescence of the subretinal lesion observed on fundus in the right eye. Ultrasound examination revealed no abnormalities. Blood tests indicated mild eosinophilia (7.5%), and there was no abnormality found by systemic examinations. Two years later, the patient visited our department again for ophthalmologic evaluation. Visual acuity remained 20/20 in both eyes and the subretinal tracks in the right eye had not changed since the previous examination. Serologic examination was performed to provide a more accurate diagnosis, and the patient's serum reacted strongly to the Gnathostoma nipponicum antigen by western blot assay, which led to a diagnosis of intraocular gnathostomiasis. This is the first reported case of intraocular gnathostomiasis with subretinal tracks confirmed serologically using western blot in Korea. PMID- 22451739 TI - Cat flea infestation in a hospital: a case report. AB - Cat flea bite in humans results in extremely pruritic skin lesions. It has been reported to occur among those living in domiciliary accommodation. However, nosocomial infestation with cat flea has not been reported. We hereby report a case of nosocomial infestation of cat flea in a hospital facility. Identification of the parasite, its appropriate eradication, and adequate medical management of the patients resulted in a satisfactory outcome. PMID- 22451740 TI - Effects of kimchi extract and temperature on embryostasis of Ascaris suum eggs. AB - To determine the effects of kimchi extracts at different temperatures on larval development, Ascaris suum eggs were mixed with soluble part of 7 different brands of commercially available kimchi and preserved at either 5C or 25C for up to 60 days. A. suum eggs incubated at 25C showed marked differences in larval development between kimchi extract and control group. While all eggs in the control group completed embryonation by day 21, only 30% of the eggs in the kimchi extract group became embryonated by day 36 and about 25% never became larvated even at day 60. At 5C, however, none of the eggs showed larval development regardless of the incubation period or type of mixture group. To determine the survival rate of A. suum eggs that showed no embryonation after being preserved at 5C, eggs preserved in kimchi extracts for 14, 28, and 60 at 5C were re-incubated at 25C for 3 weeks in distilled water. While all eggs in the control group became larvated, eggs in the kimchi extract group showed differences in their embryonation rates by the incubation period; 87.4 % and 41.7% of the eggs became embryonated after being refrigerated for 14 days and 28 days, respectively. When refrigerated for 60 days, however, no eggs mixed in kimchi extract showed larval development. Our results indicate that embryogenesis of A. suum eggs in kimchi extract was affected by duration of refrigeration, and that all eggs stopped larval development completely in kimchi kept at 5C for up to 60 days. PMID- 22451741 TI - Depressed neuronal growth associated protein (GAP)-43 expression in the small intestines of mice experimentally infected with Neodiplostomum seoulense. AB - Neodiplostomum seoulense (Digenea: Neodiplostomidae) is an intestinal trematode that can cause severe mucosal pathology in the small intestines of mice and even mortality of the infected mice within 28 days after infection. We observed neuronal growth associated protein-43 (GAP-43) expression in the myenteric plexus of the small intestinal wall of N. seoulense-infected mice until day 35 post infection (PI). BALB/c mice were infected with 200 or 500 N. seoulense metacercariae isolated from naturally infected snakes and were killed every 7 days for immunohistochemical demonstration of GAP-43 in the small intestines. N. seoulense-infected mice showed remarkable dilatation of intestinal loops compared with control mice through days 7-28 PI. Conversely, GAP-43 expression in the mucosal myenteric plexus was markedly (P<0.05) reduced in the small intestines of N. seoulense-infected mice during days 7-28 PI and was slightly normalized at day 35 PI. From this study, it is evident that neuronal damage occurs in the intestinal mucosa of N. seoulense-infected mice. However, the correlation between intestinal pathology, including the loop dilatation, and depressed GAP-43 expression remains to be elucidated. PMID- 22451742 TI - APPLICATIONS OF MULTICOMPONENT ASSEMBLY PROCESSES TO THE FACILE SYNTHESES OF DIVERSELY FUNCTIONALIZED NITROGEN HETEROCYCLES. AB - Several multicomponent assembly processes have been developed for the synthesis of intermediates that may be elaborated by a variety of cyclizations to generate a diverse array of highly functionalized heterocycles from readily-available starting materials. The overall approach enables the efficient preparation of libraries of small molecules derived from fused, privileged scaffolds. PMID- 22451743 TI - Acculturation and Post-Migration Stress in Middle-Aged Chinese Immigrant Women in Philadelphia: Variation between the Fujianese and the non-Fujianese women. AB - The experience of acculturation in Chinese immigrant women from the rural coastal province of Fujian has not been well studied despite of their growing numbers in American cities. This exploratory study is an attempt to examine the experience of acculturation and post-migration stress in Fujianese immigrant women as compared to those from other parts of China. The study is based on a convenience sample 240 Fujianese and 162 non-Fujianese Chinese immigrant women living in Philadelphia.Results from bivariate analyses showed that the variation in demographic characteristics between Fujianese and non-Fujianese women was marginal; that all Chinese women in this study reported experiencing a unidimensional process of acculturation and a domain-generic model of acculturation; and that the Fujianese women showed a higher level of post migration stress than the non-Fujianese women. In multiple regression controlling for demographic characteristics and including all the women in our sample, more acculturated women reported a higher level of post-migration stress. However, separate multiple regression analyses for Fujianese and non-Fujianese women revealed a different pattern of post-migration stress models. The findings suggest the importance of further research to understand acculturation and post migration stress among Fujianese immigrant women. PMID- 22451745 TI - Infection in AIDS. PMID- 22451744 TI - Occupational HIV infection: Can we talk? PMID- 22451746 TI - Clinical significance and characterization of AZT-resistant strains of HIV-1. AB - A number of laboratories have now independently confirmed that zidovudine (AZT) resistant strains of human immunodeficiency virus type 1 (HIV-1) may be isolated from patients undergoing prolonged therapy with this drug. In certain instances, such drug-resistant viral isolates have been obtained from patients with clinical acquired immune deficiency syndrome (aids), while in others, isolation of drug resistant strains has been achieved in the case of HIV seropositive, asymptomatic subjects. Most of the evidence points to a series of mutations within the polymerase gene of HIV-1, which encodes viral reverse transcriptase, as being responsible for development of the drug-resistant phenotype. It further appears that over 50% of patients treated with AZT for periods longer than six months are likely to yield drug-resistant strains of HIV-1 in their circulation. Furthermore, the development of drug resistance soon after initiation of AZT therapy may potentially be correlated with the likelihood of AZT treatment failure. In several instances, cross resistance has been observed between AZT and other nucleosides being considered for potential therapy of HIV-1-associated disease. PMID- 22451747 TI - Pneumocystis carinii: A review of an important opportunistic pathogen in AIDS. AB - Since the first report of human infection with Pneumocystis carinii in 1942, cases of pneumonia due to this opportunistic pathogen have become increasingly common. Animal studies and clinical observations show that a significant depletion or dysfunction of T helper lymphocytes predisposes to clinical disease. Individuals with damaged T helper cells secondary to malignancies (eg, Hodgkin's lymphoma), drugs (eg, cyclosporine, steroids), or certain infections (eg, human immunodeficiency virus) are at particular risk. Serological studies suggest that disease is most often secondary to the reactivation of an asymptomatic infection, usually acquired during childhood. Increasing shortness of breath, a nonproductive cough and hypoxia often preceded by several weeks of lethargy, fever and weight loss are the classical features of P carinii pneumonia in acquired immune deficiency syndrome. Bronchoalveolar lavage is usually the optimal diagnostic test. Immunofluorescent staining on liquified sputum induced by nebulized saline appears to be a promising and noninvasive test. Early empiric therapy with trimethoprim-sulphamethoxazole (trimethoprim 5 mg-sulphamethoxazole 25 mg/kg/day every 6 h) or intravenous pentamidine (4 mg/kg/day) for 21 days is usually effective, but infection is not eradicated, and clinical disease is likely to recur. Prophylaxis using aerosolized pentamidine reduces the risk of pulmonary disease but can predispose to extrapulmonary infection. Improved in vitro and in vivo models of human pneumocystis infection would significantly increase understanding of the molecular biology of the organism, the pathogenesis of disease, and the optimal therapeutic regimens. PMID- 22451748 TI - Mycobacterial infections in AIDS. AB - Tuberculosis (TB) remains uniquely important among acquired immune deficiency syndrome (AIDS)-associated opportunistic infections: it presents the greatest public health hazard worldwide, is the most readily curable, and is largely preventable with existing means. Given the expanding pool of human immunodeficiency virus (HIV) seropositive persons, particularly in developing nations where Mycobacterium tuberculosis remains a leading health problem, one can expect a continued rise in TB cases during the 1990s. Global efforts to eliminate TB are now inextricably entwined with the effectiveness of measures to curtail the HIV epidemic. Mycobacterium avium complex infection, currently an intractable late complication of aids, may increase in clinical importance as success in managing other opportunistic infections and HIV disease itself improves. Understanding of the pathogenesis and management of mycobacterial diseases should increase rapidly given the renewed research spurred on by the advent of HIV. PMID- 22451749 TI - Heterosexual transmission of human immunodeficiency virus infection - Strategies for prevention. AB - In Canada, over 90% of the acquired immune deficiency syndrome cases diagnosed so far have been acquired sexually, with an increasing proportion made up of heterosexual contacts of high risk individuals. In multiple studies, the transmission rate among steady heterosexual partners of infected individuals has been variable. It is likely that complex biological and epidemiological interactions exist between human immunodeficiency virus (HIV) and sexually transmitted diseases with respect to transmission and disease. Other important determinants in transmission of infection may relate to the virus itself. The importance of sexual practices other than vaginal intercourse (such as anal intercourse) in the heterosexual transmission of HIV has not been well studied. The major approach to the control of HIV-associated disease remains the control of primary infection. Sexual practices which are the major epidemiological determinants of HIV transmission can be successfully modified by appropriate educational interventions. The promotion of condom use must form a special part of these interventions. Results of ongoing trials should be available prior to the formulation of recommendations for the use of spermicides. Targeted education programs may allow us to make better use of our resources in a more efficient way. In Canada, groups that could be reached by such programs include: prostitutes and their clients; men and women attending sexually transmitted disease clinics; sexually active women attending family planning clinics; and children and adolescents who are becoming sexually active. PMID- 22451750 TI - Establishing goals, techniques and priorities for national communicable disease surveillance. PMID- 22451751 TI - Quality control assessment of Canadian laboratories testing for Lyme disease. AB - In June 1990 a quality control assessment was undertaken of Canadian public health laboratories testing for antibodies to Borrelia burgdorferi, the etiological agent of Lyme disease. Twenty sera were distributed to nine laboratories, including 12 obtained from patients in Lyme endemic areas and presumed to be serological positives, and eight prescreened negative controls. Seventeen serological reports were submitted, comprising nine enzyme-linked immunosorbent assays (elisa), six immunofluorescent assays and two Western blot assessments. Antibodies were detected in 11 of the 12 sera which had been presumed to be positive. Assuming 11 positive sera had been submitted, the test sensitivities varied from 88.9 to 100% by elisa, and 54.5 to 90.1% by immunofluorescent assay. Specificities were 100% for all but one elisa and one immunofluorescent assay assessment. The results indicate a satisfactory performance by elisa but a need for upgrading or replacement of some immunofluorescent assay tests. PMID- 22451752 TI - CJID: Volume 3. PMID- 22451753 TI - Pediatric immunization for the 1990s. PMID- 22451754 TI - Current issues and perspectives: Prevention of central venous catheter infections. PMID- 22451755 TI - Neonatal rectal colonization with Malassezia furfur. AB - Malassezia furfur and Candida albicans are fungal pathogens which have been recognized with increasing frequency as agents of mortality and serious morbidity in neonatal intensive care unit patients. A longitudinal study of oral, rectal and umbilical colonization by these organisms of newborns admitted to a neonatal intensive care unit within 24 h of birth was undertaken. Of 71 infants followed for a minimum of 10 days, 24 were colonized with M furfur and 12 with C albicans during the first 10 days of life. The lower gastrointestinal tract was found to be the most common colonization site for both organisms. Statistically significant (P<0.05) inverse associations were demonstrated between gestational age and risk of colonization with either organism at any site, and between birthweight or gestational age and risk of rectal colonization with either organism. Antibiotics were associated with a relative risk colonization of 4.06 (P=0.06) with either organism at any site. It is concluded that M furfur and C albicans are common colonizing organisms in a neonatal intensive care unit setting and are most frequently harboured in the lower gastrointestinal tract. M furfur, recently implicated as a systemic pathogen in this population, has not been previously recognized as a gastrointestinal commensal organism. The relationship between colonization and invasive fungal disease, and potential roles for preventive strategies, remain to be elucidated. PMID- 22451756 TI - Cotrimoxazole-resistant Escherichia coli bacteremia in neutropenic patients at a regional oncology hospital. AB - In a regional oncology hospital using cotrimoxazole (trimethoprim sulphamethoxazole) prophylaxis during chemotherapy-induced neutropenia, a single strain of Escherichia coli (indole negative) caused 15 of 27 episodes of Gram negative rod bacteremia in 1987, and four of 32 such episodes in 1988. This biotype had not been recovered in 1986. Investigations during this 'outbreak' of bacteremias revealed enteric colonization with this strain of E coli in 37% of patients on leukemia or bone marrow transplant wards and in several staff members in July 1987. In 1988, 11 of 32 Gram-negative rod bacteremias were secondary to other strains of indole positive E coli of several different biotypes and plasmid profiles. Indole negative strains all exhibited low level trimethoprim resistance, whereas indole positive strains which subsequently appeared exhibited high level trimethoprim resistance. Failure of cotrimoxazole prophylaxis was initially due to the clonal dissemination of a single strain of E coli within the institution, with the subsequent appearance of multiple E coli strains with probable differing genetic bases for their resistance. PMID- 22451757 TI - Clinical features fail to distinguish respiratory infections caused by Branhamella catarrhalis from those caused by Haemophilus influenzae. AB - Branhamella catarrhalis is being isolated with increasing frequency from patients with symptoms and signs of respiratory tract infection. Records of 77 patients were reviewed to define the spectrum of respiratory illness and to compare clinical and laboratory features with those of respiratory infection due to Haemophilus influenzae. Both B catarrhalis and H influenzae caused respiratory infection predominantly in elderly males with underlying heart or lung disease. There were no clinical or laboratory features aside from sputum Gram stain and culture which differentiated the two groups. Although fewer than one-half of each group received antibiotics, no patient developed progressive respiratory disease. PMID- 22451758 TI - Comparative evaluation of seven commercial tests for detection of heterophile antibody in infectious mononucleosis. AB - Detection of heterophile antibodies in infectious mononucleosis is the most rapid and cost-effective method for confirming the clinical diagnosis of the disease. This study compared seven commercial test kits (the Oxoid Infectious Mononucleosis Kit [Oxoid Ltd], Immunoscan Im-Latex [Baxter Travenol], Mono-Latex [Wampole Laboratories], Monospot and Im Screen Test [Ortho Diagnostics], Immunoscan Im-RBC Test [Baxter Travenol], and Infectious Mononucleosis Test [NCS Diagnostics]) to the Davidsohn differential test. All of the kits were shown to be acceptable for use, with specificities and sensitivities greater than 96.5% and 95.5%, respectively. PMID- 22451759 TI - Antibody to hepatitis C virus in risk groups in Canada. AB - The prevalence of antibodies against hepatitis C virus (HCV) was studied in hemophiliacs, hemodialysis patients, intravenous drug abusers, female prisoners, homosexuals, individuals with no markers of recent hepatitis A or B virus infections and normal individuals (federal public servants), by an enzyme immunoassay (Ortho Diagnostic Systems Inc). Repeat positive samples were further tested by recombinant immunoblot assay (riba) HCV (Chiron Corp, California). The number of samples positive for antibodies to HCV (anti-HCV) was higher with enzyme immunoassay than by riba HCV in most cases. A high prevalence of anti-HCV was detected in hemophiliacs by both enzyme immunoassay (68.8%) and riba HCV (53.7%). Among intravenous drug abusers and female prisoners the prevalence rates for anti-HCV were 42.8% and 29.8%, respectively, by riba HCV; the results with enzyme immunoassay were only slightly higher. The prevalence rate was also high by both tests (54.2%) in hemodialysis patients' sera taken during 1980-82, when many cases of non-A,non-B hepatitis were suspected in this group. In contrast, only 14.1% of sera taken during 1990 were positive by riba HCV. In individuals with no markers of recent hepatitis A or B infections, 13.4% were positive by enzyme immunoassay, whereas only 4.5% were reactive by riba HCV. The lowest prevalence was seen in homosexuals (2.3%) and normal individuals (1.2%) by riba HCV. These results indicate a high prevalence of anti-HCV in high risk groups tested in Canada. PMID- 22451760 TI - De novo subgaleal abscess. AB - The authors report a case of spontaneous subgaleal abscess formation in a 62-year old woman without antecedent trauma or injury. She presented with occipital scalp pain and swelling which rapidly became generalized two days following recovery from an upper respiratory infection. Diagnosis was based on radiological examination and aspiration of the subgaleal space, which yielded a purulent exudate with a pure growth of Streptococcus pyogenes. Initial management with incision, drainage and parenteral antimicrobial therapy was not successful. Operative exploration of the subgaleal space revealed extensive necrosis of the galea aponeurotica, and bone curettings revealed microscopic evidence compatible with osteomyelitis. Management with debridement and excision of all necrotic tissue plus prolonged parenteral antimicrobials was successful. Subgaleal abscess formation without an overlying wound or previous trauma has not been reported previously. PMID- 22451761 TI - Praziquantel failure in the treatment of Fasciola hepatica. AB - A case of human fascioliasis is presented in which the patient remained symptomatic after treatment with praziquantel and other agents but eventually responded to bithionol. The difficulties in finding an efficacious and tolerable drug therapy for this condition are reviewed with reference to the life cycle and pathogenesis of the parasite. It is concluded that while bithionol remains the current drug of choice, triclabendazole may play a dominant role in the near future. PMID- 22451762 TI - Thrombotic thrombocytopenic purpura associated with the acquired immune deficiency syndrome. AB - A bisexual male presented with acute thrombotic thrombocytopenic purpura (TTP) in association with established acquired immune deficiency syndrome. The patient had classic clinical and laboratory findings of TTP and responded well to plasmapheresis therapy. Previously reported cases of TTP in association with human immunodeficiency virus (HIV) infection are briefly reviewed. Basic concepts in the pathogenesis of TTP are examined in reference to HIV infection. PMID- 22451763 TI - Sexually transmitted disease control. PMID- 22451764 TI - Response to "Treatment guidelines for nosocomial pneumonia: Agreeing to disagree". PMID- 22451765 TI - The changing face of childhood meningitis. PMID- 22451766 TI - Systemic antifungal drugs: Are we making any progress? PMID- 22451767 TI - A prospective comparison of Porta-sonic and Fisoneb ultrasonic nebulizers for administering aerosol pentamidine. AB - OBJECTIVE: To report patient acceptability and overall therapeutic effectiveness of two different ultrasonic nebulizers, Fisoneb and Porta-sonic, for the administration of aerosol pentamidine for Pneumocysitis carinii prophylaxis in human immunodeficiency virus (hiv)-infected individuals. DESIGN: Prospective assessment of a random subgroup of 174 individuals from an inception cohort of 1093 patients attending a central aerosol pentamidine treatment centre in Toronto, Ontario. METHODS: One hundred and seventy-four patients who had been receiving aerosolized pentamidine for more than 10 weeks using Fisoneb at 60 mg every two weeks were switched to Porta-sonic. Subjective evaluation included three standard 10 cm visual analogue scales rating cough/wheeze, aftertaste and overall preference. The individuals were also asked to compare the duration of time spent on the aerosol treatments. Objective evaluation included spirometry performed immediately before and 15 mins after pentamidine administration. Prospective surveillance of the entire cohort was preformed to record and document episodes of breakthrough P carinii pneumonia. RESULTS: Porta-sonic was the overall preferred nebulizer in 82% of patients. Less time was spent on aerosol treatment using the Porta-sonic nebulizer compared with the Fisoneb in 66% of patients. The Porta-sonic nebulizer system produced less aftertaste compared with Fisoneb. Both nebulizers produced significant but modest reduction in flow rates. During the study period there was no statistically significant difference in the rates of breakthrough P carinii pneumonia between the two groups. A total of 91 episodes occurred, at a rate of 0.5 episodes per patient month on Porta-sonic compared with 0.7 episodes per patient-month on Fisoneb (P=0.2536). DISCUSSION: Aerosol pentamidine remains the proven second-line prophylaxis against P carinii pneumonia in hiv/aids for those intolerant to trimethoprim-sulphamethoxazole. Cough, bronchospasm and poor taste are side effects that may limit patient tolerance and acceptability. The results of this study show that the Porta-sonic nebulizer system significantly reduces some of these side effects and increases patient preference. CONCLUSION: This study suggests that Porta-sonic, the newer nebulizer system, with more ideal in vitro characteristics may become a favoured device in clinical practice. PMID- 22451768 TI - What do parents learn by reading a DPT vaccine information form? AB - OBJECTIVE: Information forms are commonly used to inform parents about childhood vaccination. This study assessed the knowledge of mothers about pertussis and pertussis vaccine before and after reading a form about diphtheria-pertussis tetanus (dpt) vaccine. DESIGN: A test was administered to mothers before and after the first vaccination of their infant. By random allocation, one-half of the mothers received the form (study group) in addition to the routine counselling by a public health nurse given to the others (control group). SETTING: Public health immunization clinics in suburban Vancouver, British Columbia. SUBJECTS: One hundred and fifty-one mothers who were scheduled to bring their infant for the first dpt immunization were recruited, of whom 145 (96%) completed the study. INTERVENTIONS: A test consisting of 20 true/false questions was administered by telephone two weeks before and two weeks after the first dpt vaccination. Additional data about sources of vaccine information, maternal education, number of children and maternal age were obtained. OUTCOME MEASURES: Mean scores and mean change in scores on test. RESULTS: The mean changes in scores between tests 1 and 2 in study and control groups were +22.2% and +6.9%, respectively, on the disease-related questions (P<0.001) and +14.6% and +10.7%, respectively, on the vaccine-related questions (P=0.16). The forms were considered to be very useful by the mothers and clearly enabled them to score higher on a test of their knowledge of pertussis and pertussis vaccine. CONCLUSIONS: Reading a dpt vaccine form enabled mothers to improve their knowledge of pertussis and pertussis vaccine. PMID- 22451769 TI - Evaluation of Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) in Canadian infants. AB - OBJECTIVE: To assess adverse effects and immune responses with a three-dose series of Haemophilus influenzae type b meningococcal protein conjugate (PedvaxHIB or Hib.OMP) vaccine, including any immunological response alterations from concurrent administration with routine vaccines for infants. DESIGN: Randomized, controlled trial with treatment group crossover for dose 3. SETTING: Two public health units near Vancouver. PARTICIPANTS: One hundred and ten healthy infants eight to 14 weeks old were enrolled; 105 completed the study (95%). INTERVENTIONS: All participants received two doses of diphtheria-pertussis tetanus (dpt) vaccine (at two and four months of age) and one dose of measles mumps-rubella (mmr) vaccine at 12 months. In each instance, Hib.OMP was given either concurrently in another limb or after a delay of two weeks (after dpt) or four weeks (after mmr). MAIN OUTCOME MEASURES: Adverse effects, particularly fever and local erythema, were monitored by parents for 72 h after each dose of Hib.OMP vaccine. Five blood samples were taken at prescribed intervals to assess responses to each dose of Hib.OMP and to selected other vaccine antigens. MAIN RESULTS: Follow-up was obtained after all 322 doses of Hib.OMP. Local adverse effects were infrequent and mild: 13% had redness, 17% tenderness. Systemic effects in those given Hib.OMP alone included fever in 8%, irritability in 29%. Anti-polyribose-ribitol phosphate (prp) responses to Hib.OMP were not impaired by coadministration with dpt or mmr vaccines, nor were tetanus or diphtheria antitoxin levels or rubella or measles response rates affected. After two doses of Hib.OMP, 92% were seropositive and 64% had greater than 1.0 MUg/mL of anti prp. After three doses, 100% were seropositive and 82% exceeded 1.0 MUg/mL. CONCLUSION: Hib.OMP vaccine was well tolerated, immunogenic and compatible with vaccines routinely given to infants in Canada. PMID- 22451770 TI - Tunga penetrans acquired while traveling in Africa. AB - Three cases of tungiasis acquired in the course of travel are briefly described, and the biology of the jigger flea, Tunga penetrans, is reviewed. PMID- 22451771 TI - Diagnosis of cellulitis in patients infected with the human immunodeficiency virus. AB - A prospective microbiological evaluation of cellulitis in 22 patients infected with the human immunodeficiency virus was performed. Patients with helper lymphocyte counts of less than 200 cells/mm(3) had a greater frequency of positive cultures. The most frequently isolated pathogens were Staphylococcus aureus and Streptococcus pyogenes, and initial antibiotic therapy should cover these Gram-positive cocci. PMID- 22451772 TI - Intercontinental spread of a highly transmissible clone of Pseudomonas cepacia proved by multilocus enzyme electrophoresis and ribotyping. PMID- 22451773 TI - Comparative study of three different BACTEC culture media for the detection of bacteremia in ambulatory and hospitalized children. AB - To compare the yield of two aerobic and an anaerobic BACTEC blood culture media in detecting bacteremia in ambulatory and hospitalized care settings at a children's hospital, a prospective cohort study was completed. Over an 18-month period, equal blood volumes (minimum of 1 mL/bottle) were inoculated into a three bottle culture set including aerobic BACTEC NR 6A, aerobic BACTEC PEDS Plus and anaerobic NR 7A broths. Chart reviews were completed on all children with bacteremia to determine whether the isolate was clinically significant based on predefined criteria. Among 5328 evaluable blood culture sets, 323 clinically significant organisms (110 from ambulatory and 213 from hospitalized children) were isolated. Most Streptococcus pneumoniae, Haemophilus species, and Neisseria or Moraxella species were recovered from children attending the emergency department or out-patient clinics. Important isolates in hospitalized children included most of the staphylococci and Enterobacteriaceae, and all group D enterococci, Gram-negative nonfermentative bacilli and all Candida species. Overall, significantly more isolates were detected only in the anaerobic bottle from ambulatory children (P<0.0001), including 13 of 54 (24%) patients with S pneumoniae bacteremias presenting to the emergency department. This study indicated that different BACTEC blood culture media combinations are needed in ambulatory and hospitalized pediatric care settings to ensure the optimal recovery of all types of isolates. Whereas aerobic blood culture bottles are adequate for detection of bacteremia in hospitalized children, the common occurrence of fastidious organisms mandates the need for a combined aerobic/anaerobic culture set in ambulatory pediatric care settings. PMID- 22451774 TI - Diagnosis. PMID- 22451775 TI - Current practices of adjunctive therapy for pertussis at six Canadian tertiary care pediatric hospitals. AB - OBJECTIVE: To document initial investigations and treatment used in the management of children hospitalized with pertussis. DESIGN: Retrospective chart review encompassing admissions from January 1, 1991 to June 1, 1995. SETTING: Six Canadian pediatric hospitals representing about 39% of the pediatric tertiary care beds in Canada. PATIENTS: Four hundred and forty children who met the inclusion criterion of a primary admitting diagnosis of pertussis and who did not meet the exclusion criterion of nosocomially acquired pertussis or a prior admission for pertussis during the study period. MAIN RESULTS: Most patients had cultures positive for Bordetella pertussis, although the proportion of positive tests varied widely among hospitals. Erythromycin was the most commonly used medication; however, only 47% of children received the recommended dosage. Salbutamol and corticosteroids were used most often in patients with reactive airways disease. Younger children and those with reactive airways disease had longer lengths of stay in hospital. CONCLUSIONS: Pertussis treatment varied widely among the six hospitals studied, and was often not consistent with current Canadian recommendations. The results will allow practitioners to place their practices in a national perspective and provide a baseline for further studies. PMID- 22451776 TI - Utility of bronchoscopy with bronchoalveolar lavage in diagnosing pulmonary infection in hospitalized patients with underlying malignancy. AB - OBJECTIVES: To evaluate the clinical utility of bronchoscopy with bronchoalveolar lavage (BAL) for diagnosing pulmonary infection in patients with underlying malignancy and to evaluate the impact of positive microbiology results on antimicrobial therapy. DESIGN: Retrospective chart review. SETTING: University affiliated downtown teaching hospital in Toronto. PATIENT POPULATION: All patients who underwent bronchoscopy with BAL from November 1990 to September 1992. RESULTS: One hundred and thirty-nine BALs were performed, of which 82 (59%) were positive for microorganisms. These 82 charts were reviewed. The main underlying diagnosis was hemotogenous malignancy (70 of 82). Primary indiction for bronchoscopy was the presence of pulmonary symptoms with or without radiographic abnormality. Common organisms identified were fungi (n=50), primarily Candida albicans and cytomegalovirus (CMV) (27), and 16 'usual' pathogens. Less common were herpes simplex virus (six), Pneumoncystis carinii pneumonia (PCP) (four), Legionella pneumoniae and Mycoplasma pneumoniae (one each). Eighty-seven per cent of patients were on broad spectrum antibiotics at the time of bronchoscopy. Although antiibiotic therapy was altered postbronchoscopy in 47 of the 82 cases, only 26 instances could be directly attributed to the results of BAL. Pathogens that commonly initiated specific therapy were CMV (16 of 27) and PCP (three of four). Diagnostic yield was highest in allogenic bone marrow transplant recipients (BMT). They comprised only 49% (40 of 82) of the cases but accounted for 85% (22 of 26) of those whose therapy was directly altered by the results of BAL. Of these 22 cases, 20 were attributed to the isolation of CMV. CONCLUSIONS: The overall raw diagnostic yield from bronchoscopy with BAL was high at 59%. Of those with positive BAL cultures, a change in antimicrobial management occurred in 32% of cases. In a patient poulation with underlying hematogenous malignancy, particularly BMT recipients, bronchoscopy with BAL is useful for a specfic diagnosis of pulmonary infection. PMID- 22451777 TI - T lymphocyte immunity in host defence against Chlamydia trachomatis and its implication for vaccine development. AB - Chlamydia trachomatis is an obligate intracellular bacterial pathogen that causes several significant human infectious diseases, including trachoma, urethritis, cervicitis and salpingitis, and is an important cofactor for transmission of human immunodeficiency virus. Until very recently, over three decades of research effort aimed at developing a C trachomatis vaccine had failed, due mainly to the lack of a precise understanding of the mechanisms for protective immunity. Although most studies concerning protective immunity to C trachomatis have focused on humoral immune responses, recent studies have clearly shown that T helper-1 (Th1)-like CD4 T cell-mediated immune responses play the dominant role in protective immunity. These studies suggest a paradigm for chlamydial immunity and pathology based on the concept of heterogeneity (Th1/Th2) in CD4 T cell immune responses. This concept for chlamydial immunity offers a rational template on which to base renewed efforts for development of a chlamydial vaccine that targets the induction of cell-mediated Th1 immune responses. PMID- 22451778 TI - Frontal osteomyelitis (Pott's puffy tumour) associated with Pasteurella multocida A case report and review of the literature. AB - A 58-year-old woman presented with progressive midforehead swelling and erythema with frontal headache. Investigations revealed erosion of the anterior wall of the frontal sinus with subgaleal abscess formation, establishing a diagnosis of Pott's puffy tumour. Pasteurella multocida was isolated in pure growth from an aspirate of the abscess. P multocida is a rare cause of sinusitis. It is isolated from the respiratory tract of asymptomatic individuals and, more commonly, patients with chronic respiratory conditions. Although a cause of osteomyelitis associated with animal bites or scratches, P multocida has not previously been implicated as a cause of frontal osteomyelitis or Pott's puffy tumour. A review of reported cases of Pott's puffy tumour, including clinical presentation, microbiology, treatment and outcome, is provided. PMID- 22451779 TI - Laboratory restructuring and service support for infection control programs. PMID- 22451780 TI - New distributional data on Oxysternon pteroderum Nevinson, 1892 (Scarabaeidae, Scarabaeinae,Phanaeini) and its possible implications in conservation. AB - New distributional data are reported on the rare phanaeine dung beetle, Oxysternon pteroderum Nevinson, 1892, based on five specimens recently collected between 1985 and 2010. Before the present study, Oxysternun pteroderum had been reported solely from the super-moist Atlantic coastal forests of southeastern Brazil. We now believe that the distribution of Oxysternun pteroderum follows the riparian areas of large rivers connected to the super-moist forest ecosystem. PMID- 22451781 TI - The ochodaeidae of Argentina (coleoptera, scarabaeoidea). AB - The Ochodaeidae (Coleoptera: Scarabaeoidea) of Argentina are revised. Previously, two species of Ochodaeinae were known from the country, both in the genus Parochodaeus Nikolajev: Parochodaeus campsognathus (Arrow) and Parochodaeus cornutus (Ohaus). An additional 7 species of Parochodaeus from Argentina are described here as new. In addition, Gauchodaeus patagonicus, new genus and new species in the subfamilyChaetocanthinae, is described. This is the first record of the subfamily Chaetocanthinae in South America. Redescriptions, diagnoses, and maps are provided for each species. We also provide a key to genera and a key to species of Parochodaeus of Argentina. With this work, the number of ochodaeid species known from Argentina is increased from 2 to 10. PMID- 22451782 TI - First record of the cicada genus Semia Matsumura (Hemiptera, Cicadidae) from Vietnam, with the description of one new species and a key to species. AB - The first record of the genus Semia Matsumura (Cicadidae: Cicadinae, Cicadini) from Vietnam is presented. One new species, Semia spinosasp. n., is described from southern Vietnam. Photos of the adult, illustrations of the male genitalia, a distribution map and biological data are provided. A key to the species of Semia based on the male adults is also given. PMID- 22451783 TI - A new species of the cicada genus Cicadatra Kolenati, 1857 (Hemiptera, Cicadidae) from Pakistan with a key to the known species of Pakistani Cicadatra. AB - A new species of cicada, Cicadatra ziaraticasp. n., is described from Pakistan. Male genitalia, timbal and opercula are described and illustrated as important diagnostic characters. Biological notes are also provided. A key to the known Cicadatra of Pakistan is provided. PMID- 22451784 TI - Perapion connexum (Schilsky, 1902) (Coleoptera, Apionidae) in Central Europe, a case of plant expansion chase. AB - Perapion connexum (Schilsky) is recorded for the first time from Hungary and Kyrgyzstan, and new distribution data from Ukraine and Russia are provided. Preliminary placements of this weevil in faunal checklists for Poland and Slovakia are here documented with detailed data. Its occurrence in Austria based on older evidence, is discussed. The neophytic and invasive in Central Europe sorrel Rumex confertus Willd. is confirmed to be its unique host plant in Poland. Morphology of the newcoming weevil is described and illustrated, and the key to all Central European species of Perapion is presented. PMID- 22451785 TI - Terrestrial slugs (Gastropoda, Pulmonata) in the NATURA 2000 areas of Cyprus island. AB - Terrestrial slugs of the Island of Cyprus were recently studied in the framework of a study of the whole terrestrial malacofauna of the island. The present work was carried out in the Natura 2000 conservation areas of the island in 155 sampling sites over three years (2004-2007). Museum collections as well as literature references were included. In total six species are present in the Natura 2000 areas of the island, belonging to three families: Limacidae, Agriolimacidae and Milacidae. One of the species, Milax riedeli, is a new record for the island. The distribution of the species across the island and in the surrounding areas is discussed. PMID- 22451786 TI - New records and a new species of chewing lice (Phthiraptera, Amblycera, Ischnocera) found on Columbidae (Columbiformes) in Pakistan. AB - The chewing lice (Phthiraptera) of Columbidae (Columbiformes) from Pakistan are studied. Six species of chewing lice with new host records are recorded and one new species of the genus Colpocephalum is described from Columba livia in the Karachi region. All the columbid chewing lice from Pakistan are keyed out and the new species is illustrated and compared with the closest allied species. PMID- 22451787 TI - Three new species of Potamothrix (Oligochaeta, Naididae, Tubificinae) from Fuxian Lake, the deepest lake of Yunnan Province, Southwest China. AB - Three new species of Potamothrix Vejdovsky & Mrazek, 1902 (Oligochaeta: Tubificinae), Potamothrix praeprostatussp. n., Potamothrix paramoldaviensissp. n. and Potamothrix parabedotisp. n., are reported from Fuxian Lake of Yunnan Province, Southwest China. Potamothrix praeprostatusdiffers from its allies by its prostate glands joining atria in its proximal to middle portion, and spermathecal chaetae. Potamothrix paramoldaviensis is distinguishable from its allies by having penial chaeta but no penes, and differs from Potamothrix moldaviensisby its homogenous atrium. Potamothrix parabedoti is distinctive in the position of its reproductive organs, and differs from Potamothrix bedoti by its homogenous atrium. Hitherto, 34 freshwater oligochaete species have been recorded in Yunnan Province, including nine endemic species from the plateau lakes. PMID- 22451788 TI - Darwininitium - a new fully pseudosigmurethrous orthurethran genus from Nepal (Gastropoda, Pulmonata, Cerastidae). AB - A new genus and species of pseudosigmurethrous orthurethran pulmonate of the family Cerastidae, Darwininitium shiwalikianumgen. n. and sp. n. is described from the Lesser Himalaya of Nepal. It represents the first record of an orthurethran with a fully developed pseudosigmurethrous pallial system, having a completely closed secondary ureteric system. Biogeographically this new taxon provides a significant range extension for the family north of the previously known distribution range. PMID- 22451789 TI - Loxosceles niedeguidonae (Araneae, Sicariidae) a new species of brown spider from Brazilian semi-arid region. AB - A new species of recluse spider, Loxosceles niedeguidonaesp. n., is described from the Parque Nacional Serra da Capivara, State of Piaui, Brazil. This is the first endemic species described from Brazilian semi-arid environment. The species is included in gaucho group of Gertsch (1967) due to its spermathecal shape and is considered close to Loxosceles chapadensis Bertani, Fukushima & Nagahama, 2010 by the unusual long male palpal tibia, a character not common for species of this group. An updated key for Loxosceles species of gaucho group is presented. PMID- 22451790 TI - Katatopygia gen. n., a monophyletic branch segregated from Boletina (Diptera, Mycetophilidae). AB - The genus Katatopygiagen. n. is proposed for the Boletina erythropyga/punctus group that was first introduced by Garrett (1924, 1925) and currently comprises eight described species. Molecular studies have strongly indicated that this group forms a monophyletic sister-group to a clade consisting of all other Boletina, Coelosia and Gnoriste, and its monophyly is supported by morphological data as well. The new genus includes the following species: Katatopygia antoma (Garrett, 1924), comb. n., Katatopygia antica (Garrett, 1924), comb. n., Katatopygia erythropyga (Holmgren, 1883), comb. n.,Katatopygia hissarica (Zaitzev & Polevoi, 2002), comb. n., Katatopygia magna (Garrett, 1925), comb. n., Katatopygia laticauda (Saigusa, 1968), comb. n., Katatopygia neoerythropyga (Zaitzev & Polevoi, 2002), comb. n. andKatatopygia sahlbergi (Lundstrom, 1906), comb. n., all transferred from Boletina. Katatopygia sahlbergi is found to be a senior synonym of Boletina punctus Garrett, 1925, syn. n. A phylogeny based on morphological data and using parsimony analysis yielded four most parsimonious trees where the new genus is retrieved as monophyletic with high support. Katatopygia neoerythropyga is found to be the sister-taxon to all other species that form two clades, one with Katatopygia sahlbergi-like species and one with Katatopygia erythropyga-like species. A key to males of Katatopygia is provided. PMID- 22451791 TI - A new species of Hedgpethia (Arthropoda, Pycnogonida, Colossendeidae) from southwestern Japan. AB - We describe Hedgpethia spinosasp. n. based on a single male specimen obtained from 197-207 m depth, south of Yaku Island, Kagoshima Prefecture, Japan. Among 15 previously known congeners, the new species resembles Hedgpethia bicornis (Losina Losinsky & Turpaeva, 1958), Hedgpethia chitinosa (Hilton, 1943), and probably Hedgpethia brevitarsis (Losina-Losinsky & Turpaeva, 1958), in having a mid-dorsal tubercle on the posterior rim on each trunk segment. The new species, however, is distinguishable from those by a pair of horns on the anterior margin of the cephalic segment, spines on the first coxae, and denticulate spines on the strigilis. The new species represents the fifth member of the genus so far known from Japanese waters, in addition to Hedgpethia brevitarsis (Losina-Losinsky & Turpaeva, 1958), Hedgpethia chitinosa (Hilton, 1943), Hedgpethia dofleini (Loman, 1911), and Hedgpethia elongata Takahashi, Dick & Mawatari, 2007. PMID- 22451792 TI - Two new species of Pselaphodes Westwood and new record of Taiwanophodes minor Hlavac from South China (Coleoptera, Staphylinidae, Pselaphinae). AB - Two new species, Pselaphodes linae Yin & Li, sp. n. (Hainan, Fujian) and Pselaphodes shii Yin & Li, sp. n. (Hainan) are described from South China. Taiwanophodes minor Hlavac is reported from outside Taiwan for the first time. Illustrations of major diagnostic features are provided for all treated taxa. The latest key to Chinese Pselaphodes is modified to include the new species. PMID- 22451793 TI - Salvage Treatment of Local Recurrence in Esthesioneuroblastoma: A Meta-analysis. AB - Esthesioneuroblastoma has a local recurrence rate of ~30%, but no standard regimen for salvage of local recurrence has been established. We report data from 678 patients from series published since 1990, with a risk reduction analysis of salvage with surgery, radiation, or combined surgery and radiation therapy. We found a 28.5% rate of local recurrence after treatment, and a 42.6% rate of successful salvage with surgery, radiation, or combined treatment. The odds ratio for successful salvage, defined as disease-free survival for at least 1 year, was not significantly different for combined surgery and radiation versus surgery alone or radiation alone or for surgery alone versus radiation alone. The salvage odds ratio for combined surgery and radiation therapy versus radiation therapy alone, 3.5, approached, but did not reach statistical significance. This study reveals a reasonable rate of successful salvage of local esthesioneuroblastoma recurrence using surgery, radiation, or combined surgery and radiation. PMID- 22451794 TI - Outcomes of Direct Facial-to-Hypoglossal Neurorrhaphy with Parotid Release. AB - Lesions of the temporal bone and cerebellopontine angle and their management can result in facial nerve paralysis. When the nerve deficit is not amenable to primary end-to-end repair or interpositional grafting, nerve transposition can be used to accomplish the goals of restoring facial tone, symmetry, and voluntary movement. The most widely used nerve transposition is the hypoglossal-facial nerve anastamosis, of which there are several technical variations. Previously we described a technique of single end-to-side anastamosis using intratemporal facial nerve mobilization and parotid release. This study further characterizes the results of this technique with a larger patient cohort and longer-term follow up. The design of this study is a retrospective chart review and the setting is an academic tertiary care referral center. Twenty-one patients with facial nerve paralysis from proximal nerve injury at the cerebellopontine angle underwent facial-hypoglossal neurorraphy with parotid release. Outcomes were assessed using the Repaired Facial Nerve Recovery Scale, questionnaires, and patient photographs. Of the 21 patients, 18 were successfully reinnervated to a score of a B or C on the recovery scale, which equates to good oral and ocular sphincter closure with minimal mass movement. The mean duration of paralysis between injury and repair was 12.1 months (range 0 to 36 months) with a mean follow-up of 55 months. There were no cases of hemiglossal atrophy, paralysis, or subjective dysfunction. Direct facial-hypoglossal neurorrhaphy with parotid release achieved a functional reinnervation and good clinical outcome in the majority of patients, with minimal lingual morbidity. This technique is a viable option for facial reanimation and should be strongly considered as a surgical option for the paralyzed face. PMID- 22451795 TI - Endoscopic transcranial and intracranial resection: case series and design of a perioperative management protocol. AB - Purely endoscopic resections of transcranial/intracranial pathology represent an exciting minimally invasive option for some patients. There is an abundance of literature on surgical techniques, though very little deals with perioperative management, which is critical for good outcomes. We present a detailed case review and a perioperative management protocol with specific reference to skull base and neuroanatomy. We performed a retrospective chart review and analysis of outcomes and complications by approach and design and prospective employment of a perioperative management protocol in a major tertiary care referral hospital. We included patients undergoing endoscopic skull base approaches by the two senior surgeons from September 2005 to April 2009, selecting of transcranial/intracranial cases for detailed review. Our main outcome measures included perioperative morbidity, mortality, and complications; degree of resection; recurrence rate; and survival. Fifteen patients met study criteria. No perioperative mortality occurred. There were two major and four minor complications. Mean follow-up was 15 months; 11/13 patients with malignancies had no evidence of disease. A perioperative management protocol was designed from these data and has resulted in decreased lumbar drainage and increased fluid/electrolyte monitoring. Endoscopic transcranial/intracranial anterior skull base surgery is both safe and effective when a complete understanding of the surgery and perioperative management is achieved. PMID- 22451796 TI - Accessing the basilar artery apex: is the temporopolar transcavernous route an anatomically advantageous alternative? AB - The restricted operative field, difficulty of obtaining proximal vascular control, and close relationship to important anatomic structures limit approaches to basilar apex aneurysms. We used a cadaveric model to compare three surgical transcavernous routes to the basilar apex in the neutral configuration. Five cadaveric heads were dissected and analyzed. Working areas and length of exposure provided by the transcavernous (TC) approach via pterional, orbitozygomatic, and temporopolar (TP) routes were measured along with assessment of anatomic variation for the basilar apex region. In the pterional TC and orbitozygomatic TC approaches, the mean length of exposure of the basilar artery measured 6.9 and 7.2 mm, respectively (p = NS). The mean length of exposure in a TP TC approach increased to 9.3 mm (p < 0.05). Compared with the pterional and orbitozygomatic approaches, the TP TC approach provided a larger peribasilar area of exposure ipsilaterally and contralaterally (p < 0.05). The multiplanar working area related to the TP TC approach was 77.7 and 69.5% wider than for the pterional TC and orbitozygomatic TC, respectively. For a basilar apex in the neutral position, the TP TC approach may be advantageous, providing a wider working area for the basilar apex region, improving maneuverability for clip application, fine visualization of perforators, and better proximal control. PMID- 22451797 TI - The puzzling olfactory groove schwannoma: a systematic review. AB - We systematically reviewed the literature concerning the anterior cranial fossa schwannomas to understand their pathogenesis, determine their origin, and standardize the terminology. We performed a MEDLINE, EMBASE, and Science Citation Index Expanded search of the literature; age, gender, clinical presentation, presence or absence of hyposmia, radiological features, and apparent origin were analyzed and tabulated. Cases in a context of neurofibromatosis and nasal schwannomas with intracranial extension were not included. Age varied between 14 and 63 years (mean = 30.9). There were 22 male and 11 female patients. The clinical presentation included seizures (n = 15), headache (n = 16), visual deficits (n = 7), cognitive disturbances (n = 3), and rhinorrhea (n = 1). Hyposmia was present in 14 cases, absent in 13 cases (39.3%), and unreported in five. Homogeneous and heterogeneous contrast enhancement was observed in 14 and 15 cases, respectively. The region of the olfactory groove was the probable site in 96.5%. Olfactory tract could be identified in 39.3%. The most probable origin is the meningeal branches of trigeminal nerve or anterior ethmoidal nerves. Thus, olfactory groove schwannoma would better describe its origin and pathogenesis and should be the term preferentially used to name it. PMID- 22451798 TI - Evaluation of the prognostic indicators of giant intracranial aneurysms. AB - The indicators of poor outcome in giant intracranial aneurysms have been the subject of several studies in the literature. We conducted a retrospective analysis to evaluate the predictors of poor outcome in giant intracranial aneurysms. We studied consecutive cases with aneurysms admitted over a 9-year period in our institution. All the aneurysms were treated with clipping. Patient demographics, clinical profile, and aneurysm characteristics were evaluated in a multivariate analysis as probable indicators of Glasgow Outcome Scale (GOS) score. The outcome of the aneurysms (GOS score) was compared with the remaining non-giant aneurysms. A total of 41 giant and 348 non-giant aneurysms were identified in our series. In the multivariate analysis, the indicators of poor outcome were identified as poor clinical grade (p < 0.0004), intraoperative rupture (p < 0.007), and posterior circulation of the aneurysms (p < 0.01). Non giant aneurysms had a better outcome compared with the giant aneurysms (p < 0.01). Giant aneurysms impose a relatively higher risk of morbidity and mortality to the patients. The predictors of the postsurgical outcome of the giant aneurysms include the clinical condition of the patient, location of the aneurysm, and intraoperative rupture. PMID- 22451799 TI - Primary closure of a cerebrospinal fluid fistula by nonpenetrating titanium clips in endoscopic endonasal transsphenoidal surgery: technical note. AB - Postoperative cerebrospinal fluid (CSF) leakage is one of the most common and aggravating complications in transsphenoidal surgery. Although primary closure of the fistula would be the most desirable solution for an intraoperatively encountered CSF leak, it is difficult to achieve in such a deep and narrow operative field. In this article, the authors report endonasal endoscopic applications of no-penetrating titanium clips to repair a CSF fistula following tumor removal. The AnastoClip Vessel Closure System (VCS; LeMaitre Vascular, Boston, MA) was used for closure of a CSF fistula in endonasal transsphenoidal surgery. In all four patients, CSF leakage was successfully obliterated primarily with two to five clips. There was no postoperative CSF rhinorrhea or complications related to the use of the VCS. Metal artifact by the clips on postoperative images was tolerable. Primary closure of the fistula using the VCS was an effective strategy to prevent postoperative CSF leakage in transsphenoidal surgery. Future application can be expanded to reconstruction of the skull base dura via endonasal skull base approaches. PMID- 22451800 TI - A new look at an old canal. AB - Attempts to explain abducens vulnerability have centered around the petroclival segment of its pathway in the skull base, in particular, its relations to the Dorello's canal and the petrosphenoidal ligament of Gruber. This study aims to contribute to the definition of the Dorello's canal and to the understanding of abducens vulnerability from an evolutionary perspective. The petroclival region and the Dorello's canal in particular were examined in a sample of 86 primate skulls. The sample contains 20 Pan troglodytes (common chimpanzee), 35 Gorilla gorilla, 20 Pongo pygmaeus (orangoutan), and 11 Hylobates moloch (gibbon) skulls. Distance between the petrous apex and tip of the posterior clinoid process was measured using a 10-mm scale that was inserted into the endocranium. Complete absence of the Gruber ligament and an uninterrupted osseous circumference of the Dorello's canal (foramen) was demonstrated in all nonhuman primate species. Whatever the reason for the morphological difference between the human and ape Dorello's canal, it is without a doubt suggestive of the source of vulnerability of the abducens nerve, as the ligament of Gruber, unique to the human configuration, renders the contents of the Dorello's canal susceptible to compression against the cranial base. PMID- 22451801 TI - Should initial surveillance of vestibular schwannoma be abandoned? AB - Early diagnosis of vestibular schwannoma (VS) has increased in recent years because of increased longevity and availability of magnetic resonance imaging (MRI). Initial conservative radiological surveillance is often requested by patients and physicians to establish whether these tumors are growing before embarking on intervention. Initial observation of at least 1 year in all small VS was therefore recommended by some authors. We evaluated our prospective skull base database of VSs that were managed with initial radiological surveillance to establish when this policy should be abandoned and what predicts future growth. Fifty-four consecutive patients with VS in our institution who were managed by initial yearly MRI scanning were studied. The MRI data were collected prospectively and analyzed by Kodak CareStream viewing software where VS maximum diameters in three perpendicular planes and volume were calculated. One patient was excluded from the analysis as he had only one MRI follow-up. The median age of the 53 patients was 59 years (range, 26 to 86 years), 25 were males and 28 were females, and 33 were under 65 years of age; 18 VSs were extracanalicular, 18 were intracanalicular, and 17 extended both inside and outside the canal; 21 VSs were 1.2 cm(3) or less, 22 were 1.2 to 4 cm(3), and the rest were >4 cm(3). Using volumetric analysis, 29.72% of conservatively managed VS grew by at least 2 mm per year, and 70.82% did not grow in 5 years. Age, gender, symptoms, and side did not predict future growth. However, growth in the first year was a strong predictor of future growth (p < 0.001) and initial volume was also a strong predictor of future growth (p < 0.05). Twenty-nine percent of observed VSs grew by at least 2 mm per year in the first 5 years of surveillance. As the growth rate is slow, initial radiological surveillance is justified in elderly patients and patients with small VSs and nonserviceable hearing. Growth in the first year was a strong predictor of future growth. The reported treatment effect should be interpreted in the light of 70.24% of VSs that either shrink or do not change in the first 5 years. PMID- 22451802 TI - Morphometric measurements of the anterior skull base for endoscopic transoral and transnasal approaches. AB - The objective of this study is to determine the bony limits of the transnasal and transoral approaches to the anterior skull base. The data we present are meant to assist surgeons in preoperative planning for lesions of the sella, clivus, foramen magnum, and odontoid. Using precise measurements undertaken on 41 high resolution computed tomography scans from patients at the University of Pennsylvania without any history of sinus or sellar pathology, we sought to define the bony limits of transoral and transnasal approaches. Direct measurements and calculated angles were used to assess the dimensions of the anterior skull base. Using our measurements, a transnasal approach can reach an average of 22.5 mm below the plane of the hard palate to the body of C2, and a transoral route can reach 38 mm above the basion along the length of the clivus. Analysis of variance demonstrated no significant differences when subjects were grouped based on race or gender. The measurements outlined within this article help to define the relative dimensions necessary for adapted transoral and transnasal skull base surgeries. PMID- 22451803 TI - Intraoperative transillumination to determine the extent of frontal sinus in subcranial approach to anterior skull base. AB - We sought to determine the extent of the frontal sinus by intraoperative transillumination through the superomedial orbital wall in a subcranial approach to the anterior skull base. After raising a bicoronal flap, the frontal sinus was transilluminated through the superomedial orbital wall with a fiber-optic light source, delineating the extent of the frontal sinus. The frontal sinus boundary was marked with a marker pen. A frontal sinus anterior wall osteotomy was performed with a sagittal saw, staying within the confines of the frontal sinus marking. A bone flap was removed, and the posterior wall was drilled out. The remaining procedure was performed in a standard fashion. At the end of the procedure, the bone flap was fixed with a titanium plate. A total of 58 patients had undergone craniofacial resection from January 2004 to December 2007. In 13 patients, a subcranial approach was employed using the transillumination technique. Transillumination was successful in delineating the frontal sinus periphery in all 13 patients. Intraoperative transillumination of the frontal sinus through the superomedial orbital wall is a simple and effective method to delineate the frontal sinus periphery in a subcranial approach to the anterior skull base. PMID- 22451804 TI - Vestibular schwannoma in patients with sudden sensorineural hearing loss. AB - Sudden sensorineural hearing loss (SSNHL) has several etiologies. It may be a presenting symptom of vestibular schwannoma (VS). This study aimed to establish the incidence of VS in patients with SSNHL, and we report several unusual cases among these patients. We reviewed retrospectively the charts and magnetic resonance imaging (MRI) findings of all adult patients who presented with SSNHL between 2002 and 2008. We utilized three-dimensional fast imaging with steady state acquisition temporal MRI as a screening method. Of the 295 patients with SSNHL, VS was found in 12 (4%). All patients had intrameatal or small to medium sized tumors. There were three cases with SSNHL in one ear and an incidental finding of intracanalicular VS in the contralateral ear. There were four cases of VS that showed good recovery from SSNHL with corticosteroid treatment. There were two cases that mimicked labyrinthitis with hearing loss and vertigo. A greater number of cases than expected of VS were detected in patients with SSNHL, as a result of increasing widespread use of MRI. Various unusual findings in these patients were identified. MRI would seem to be mandatory in all cases of SSNHL. PMID- 22451805 TI - Feasibility of a robotic surgical approach to reconstruct the skull base. AB - The role of robotic surgery in the skull base is evolving and represents the natural progression toward maximizing surgical resections in confined spaces without compromising oncological principles. In this study, we describe the novel application of robotic surgery to the repair of dural defects in the skull base. A transmaxillary-transantral approach to the nasal cavity was performed bilaterally in a cadaveric model. Repair of the skull base defect was undertaken robotically. In this technical report, we demonstrate the feasibility of a suture based technique for surgical reconstruction of the skull base with robotic assistance in a cadaveric model. In all cases, suture repair of dural defects was successfully performed with robotic-assisted technique. Although preliminary in nature, this study suggests that traditional suture techniques can be implemented in a confined surgical site with the use of robotic technology. PMID- 22451806 TI - Endoscopic anterior skull base surgery: intraoperative considerations of the crista galli. AB - We sought to measure the anatomic dimensions of the crista galli in a consecutive series of patients undergoing the endoscopic transcribriform approach for anterior skull base tumors at a tertiary academic university hospital. We performed a retrospective chart review of patients undergoing purely endoscopic transcribriform surgery for sinonasal and skull base lesions. Main outcome measures included radiological dimensions of the crista galli. A total of 12 patients were identified and treated by the senior authors at the University of Pennsylvania. The average crista galli dimensions were 12.7 +/- 2.4 mm (anterior posterior) and 12.9 +/- 2.5 mm (cranial-caudal dimension). Knowledge of the dimensions of the crista galli is important in preoperative planning for both instrumentation and access. PMID- 22451807 TI - Risk of incisional recurrence after midface and anterior skull base surgery in sinonasal malignancies. AB - We sought to determine the risk of tumor incisional recurrence in patients receiving surgery and postoperative radiation therapy for locally advanced sinonasal malignancies. Medical records for 70 patients newly diagnosed with nonmetastatic American Joint Committee on Cancer stage II to stage IV sinonasal malignancies between 1991 and 2003 were retrospectively reviewed. Patient demographics and tumor variables were recorded. All patients underwent upfront surgical resection with postoperative three-dimensional conformal proton beam radiotherapy. Recurrence and survival-related outcomes were recorded. Two patients with squamous cell carcinoma had pathologically confirmed tumor recurrence at the incision site. The actuarial risk of incisional recurrence for the entire group at 1 year was 3%. One of the two patients had a maxillary sinus tumor and developed isolated skin recurrence along the transfacial incision. The other patient with an ethmoid sinus tumor developed isolated dural recurrence along the craniotomy incision. Both patients underwent multiple courses of salvage surgery and radiation therapy. One was successfully salvaged locally but developed distant metastases and the other died of local recurrence. Tumor seeding following transfacial and craniotomy surgery can occur, especially for squamous cell carcinoma. Sound oncological surgical technique, even when utilizing these difficult surgical approaches, is important to minimize incisional recurrence. PMID- 22451808 TI - Nasoseptal flap closure of traumatic cerebrospinal fluid leaks. AB - The vascularized nasoseptal flap has become a principal reconstructive technique for the closure of endonasal skull base surgery defects. Despite its potential utility, there has been no report describing the use of the modern nasoseptal flap to repair traumatic cerebrospinal fluid (CSF) leaks and documenting the outcomes of this application. Specific concerns in skull base trauma include septal trauma with disruption of the flap pedicle, multiple leak sites, and issues surrounding persistent leaks after traumatic craniotomy. We performed a retrospective case series review of 14 patients who underwent nasoseptal flap closure of traumatic CSF leaks in a tertiary academic hospital. Main outcome measures include analysis of clinical outcome data. Defect etiology was motor vehicle collision in eight patients (57%), prior sinus surgery in four (29%), and assault in two (14%). At the time of nasoseptal flap repair, four patients had failed prior avascular grafts and two had previously undergone craniotomies for repair. Follow-up data were available for all patients (mean, 10 months). The overall success rate was 100% (no leaks), with 100% defect coverage. The nasoseptal flap is a versatile and reliable local reconstructive technique for ventral base traumatic defects, with a 100% CSF leak repair rate in this series. PMID- 22451809 TI - Fundus obliteration and facial nerve outcome in vestibular schwannoma surgery. AB - The major objectives in vestibular schwannoma (VS) surgery have evolved from reducing mortality to functional preservation of the facial nerve and hearing. Absence of fluid between the lateral end of the VS and the internal auditory canal fundus on magnetic resonance imaging (MRI) appeared to have a negative influence on hearing outcome. Our goal was to study the prognostic significance of fundus obliteration on facial nerve function after VS surgery in patients with clinically normal facial function. We performed a retrospective review in a tertiary referral neurotology unit or 110 consecutive patients with a surgically removed VS and normal preoperative facial nerve function. Facial nerve function was evaluated at 1 month and 1 year by using the House-Brackmann (HB) scale and correlated to fundus obliteration on MRI. Facial nerve function was intact preoperatively in 114 of 123 patients (92.7%). We noticed a statistically significant difference and worse short-term outcome when the fundus was obliterated: 29.7% had HB 3 or more versus 13.0% if no fundus obliteration was seen. This statistically significant difference disappeared at 1 year. Fundus obliteration has a negative prognostic influence on short-term facial nerve function after VS surgery in patients with clinically normal facial function preoperatively. PMID- 22451810 TI - Secondary skull base malignancies in survivors of retinoblastoma: the memorial sloan kettering cancer center experience. AB - We report the pathology and outcome of secondary skull base tumors in patients previously treated with external beam radiation for retinoblastoma (Rb). Rb patients are at increased risk of second head and neck primary malignancies due to early radiation exposure during treatment and loss of RB1 protein in genetic carriers. An institutional database was reviewed for patients with retinoblastoma who had previously received radiation therapy and subsequently developed skull base tumors. Seventeen patients met the selection criteria. The median age of Rb diagnosis was 12 months. Thirteen cases underwent enucleation in addition to radiation therapy as part of initial Rb treatment. A median of 19 years elapsed between the diagnosis of Rb and diagnosis of skull base malignancy. The most common tumors were osteogenic sarcoma (39%) and leiomyosarcoma (22%). Eleven (71%) patients received postoperative chemotherapy, and 7 (41%) received postoperative radiotherapy. Three (24%) patients underwent salvage surgery for recurrent disease. Five-year survival was 68%, and 10-year survival was 51% by Kaplan-Meier analysis. Secondary malignancy in Rb patients is a well-defined event. The use of surgery with appropriate adjuvant therapy was associated with a 51% 10-year survival in this study population. PMID- 22451811 TI - A Vascular Catastrophe during Endonasal Surgery: An Endoscopic Sheep Model. AB - Internal carotid artery (ICA) injury is a dramatic complication of endonasal skull base approaches with massive bleeding. This study aims to design an animal model of ICA injury during endonasal skull base surgery. Eight sheep underwent ICA isolation followed by arterial pressure monitoring and placement of a rapid infuser. The Sinus Model Otorhino Neuro Trainer (Pro Delphus, Pernambuco, Brazil) nasal model was then modified. A novel posterior sphenoid wall was created, allowing the artery to be placed within and fixed to the model in a watertight fashion. A diamond-tipped bur allowed surgical exposure of the carotid artery. A standardized injury was created endoscopically. The "two-surgeon technique" allowed local packing measures to be performed. Outcome measures were mean arterial pressure (MAP) following injury, resuscitation fluid volume, survival time, and total blood loss. Mean preinjury weight was 51.8 +/- 4.59 kg. All baseline hematologic parameters fell within normal limits. The mean preinjury and postinjury MAP was 65.7 +/- 9.3 mm Hg versus 39.1 +/- 6.9 mm Hg, respectively. The mean survival time was 50.25 +/- 17.89 minutes, with mean resuscitation fluid volume of 10.89 +/- 2.40 L and mean blood loss of 4943 +/- 1089 mL. This model replicates the endoscopic surgical field of an ICA injury, with the potential to train endoscopic skull base teams in the skills require to manage an ICA injury. PMID- 22451812 TI - Microsurgical Maneuvers under Side-Viewing Endoscope in the Treatment of Skull Base Lesions. AB - The objective of the present study is to elucidate the feasibility of surgical maneuvers under the side-viewing endoscope during skull base tumor removal. The study focused on 51 patients who underwent tumor removal with the assistance of a side-viewing endoscope. The side-viewing endoscope enabled visualization and removal of residual tumors obscured by the skull base bone, cranial nerves, and other vital structures after a microscopic procedure. If the surgical field is surrounded by the dura or skull base tissue, not only curettage of a tumor but also semisharp dissection and bipolar coagulation are shown to be feasible. In the subarachnoid space, however, the primary feasible surgical maneuver was suctioning of the tumor. The extent of skull base resection could be reduced in 25 cases and additional tumor removal became possible in 47 cases. Application of the side-viewing endoscope enabled removal of the tumor compartment, the exposure of which has conventionally required an extensive skull base resection. This technique is a promising option for the treatment of skull base tumors. PMID- 22451813 TI - Dural opening/removal for combined petrosal approach: technical note. AB - Detailed descriptions of stepwise dural opening/removal for combined petrosal approach are presented. Following maximum bone work, the first dural incision was made along the undersurface of the temporal lobe parallel to the superior petrosal sinus. Posterior extension of the dural incision was made in a curved fashion, keeping away from the transverse-sigmoid junction and taking care to preserve the vein of Labbe. A second incision was made perpendicular to the first incision. After sectioning the superior petrosal sinus around the porus trigeminus, the incision was extended toward the posterior fossa dura in the middle fossa region. The tentorium was incised toward the incisura at a point just posterior to the entrance of the trochlear nerve. A third incision was made longitudinally between the superior petrosal sinus and the jugular bulb. A final incision was initiated perpendicular to the third incision in the presigmoid region and extended parallel to the superior petrosal sinus connecting the second incision. The dural complex consisting of the temporal lobe dura, the posterior fossa dura, and the freed tentorium could then be removed. In addition to extensive bone resection, our strategic cranial base dural opening/removal can yield true advantages for the combined petrosal approach. PMID- 22451814 TI - Endoscopic resection of solitary fibrous tumors of the nose and paranasal sinuses. AB - Solitary fibrous tumors (SFTs) are uncommon neoplasms of mesenchymal origin that were first described as primary spindle-cell tumors of the pleura in 1931. Since then, infrequent case reports of extrapleural SFTs have been described including various subsites within the head and neck. Based on a review of the literature and a description of the endoscopic treatment of three patients with SFTs of the nasal cavity and ethmoid sinuses, the challenges associated with the management of sinonasal SFTs are discussed. Successful endoscopic resection was performed at a tertiary referral rhinology practice within a university center in three cases of sinonasal SFTs with no evidence of recurrence at 26, 35, and 49 months following resection. Summarized are the common presenting symptoms, appropriate diagnostic workup, and indicative computed tomography and magnetic resonance imaging appearance of SFTs. Further discussed are the challenge associated with accurate histological and immunohistochemical diagnosis, the difficulty in assessing the aggressiveness and malignant potential of these lesions, and the appropriate treatment and follow-up duration that these neoplasms require. PMID- 22451815 TI - On "malignant transformation of acoustic neuroma/vestibular schwannoma 10 years after gamma knife stereotactic radiosurgery" (skull base 2010;20:381-388). PMID- 22451816 TI - Unilateral endoscopic approach for repair of frontal sinus cerebrospinal fluid leak. AB - Cerebrospinal fluid (CSF) leak closure remains one of the most difficult surgeries for skull base surgeons, particularly with frontal sinus involvement. Technological advances in endoscopic surgery increasingly allow for less morbid approaches to the frontal sinus. We describe a series of patients who underwent endoscopic frontal sinus CSF leak repair utilizing a unilateral approach, to evaluate the utility and outcomes of this method. We performed a retrospective review of four cases in tertiary care centers. Participants included patients with CSF leak involving the frontal sinus. Main outcome measures included cessation of CSF leak and frontal sinus patency. Three patients were closed on the first surgical attempt; one with a communicating hydrocephalus required a revision procedure. Leak etiologies included prior craniotomy for frontal sinus mucopyocele, spontaneous meningoencephalocele, erosion due to mucormycosis, and prior endoscopic sinus surgery. The frontal sinus remained patent in three of four patients. No patients have evidence of a leak at a minimum of 1 year after surgery. The repair of frontal sinus CSF leaks is possible in specific cases with an endoscopic unilateral approach in leaks with multiple etiologies. Surgeons should consider this approach when selecting the appropriate procedure for repair of frontal sinus CSF leaks. PMID- 22451817 TI - When is posterolateral orbitotomy useful in a pterional craniotomy? A morphometric study. AB - Adding posterolateral orbitotomy to pterional craniotomy allows greater exposure of the anterolateral skull base. However, there is a paucity of literature quantifying the relative benefit of adding posterolateral orbitotomy for various surgical targets. Our study is a step to address this issue. We performed dissections of five cadaveric heads (10 sides). The anterior communicating artery (A-Com) complex, posterior chiasm (anterior third ventricular region), ipsilateral optic canal, and ipsilateral supraclinoid internal carotid artery (ICA) bifurcation were chosen as targets. A pterional craniotomy was performed and the targets were morphometrically analyzed. Subsequently, posterolateral orbitotomy was done and analysis repeated. The field of view and measurements quantifying the angle of attack were compared. Addition of orbitotomy to pterional craniotomy increased the angle of exposure to ICA bifurcation, anterior third ventricular region, and A-Com complex by average of 15%, 29%, and 50%, respectively. Our study shows the addition of a posterolateral orbitotomy to the pterional craniotomy improves the angle of attack to the anterior third ventricular region and the A-Com complex, thus supporting the use of orbitopterional craniotomy for suprasellar lesions extending into anteroinferior third ventricle and A-Com aneurysms that point superiorly/posteriorly. PMID- 22451818 TI - Concomitant chemoradiotherapy as a standard treatment for squamous cell carcinoma of the temporal bone. AB - We sought to characterize the effectiveness of concomitant chemoradiotherapy (CCRT) for patients with squamous cell carcinoma of the temporal bone. We performed a retrospective chart review of 14 patients with cancer of the temporal bone who were provided initial treatment in our hospital from December 2001 to November 2008. Four patients with stage I tumors were treated by radiation therapy alone or with oral administration of S1. One patient with a stage II tumor was treated by radiation therapy concomitant with low dose docetaxel. Nine patients with stage IV tumors were treated by CCRT using the TPF regimen (docetaxel, cisplatin, and 5-fluorouracil). As an initial treatment, all patients but one were treated by radiation therapy with or without chemotherapy. Grade 4 adverse events of patients who received CCRT using the TPF regimen involved the leukopenia in one patient and the neutropenia in two patients. Local recurrences were observed in three patients including two patients with T4 tumors. Five-year disease-specific survival rates for all patients and for patients with T4 tumors were 78% and 67%, respectively. CCRT using the TPF regimen is safe and effective as the first treatment for patients with cancer of the temporal bone. PMID- 22451819 TI - The "agnes fast" craniotomy: the modified pterional (osteoplastic) craniotomy. AB - The "Agnes Fast" craniotomy is a fast and simple way of performing the pterional craniotomy while preserving the temporalis muscle, together with its fascia and bony attachment. Using this technique, the surgeon need not divide the temporalis muscle, separate it from its bony attachment, or perform an interfacial dissection. With a little practice, this craniotomy can be performed in less than 5 minutes and is highly recommended in emergent settings. The modified pterional craniotomy was performed in 10 cadaveric specimens, preserving the temporalis muscle with its attachment. An interfascial dissection was not performed while exposing the frontozygomatic process. The exposure gained, the length of the procedure, and the ease of application were recorded for all heads studied. In all heads studied, the Agnes Fast craniotomy was performed, with complete preservation of the temporalis muscle and its attachments. This procedure was performed quickly, with complete preservation of the fascial nerve and its branches. The muscle was put back in its natural place following the craniotomy. The Agnes Fast craniotomy offers a fast way of performing a pterional craniotomy while preserving the temporalis muscle, with its blood supply, neural innervation, bony attachment, and fascia intact. Replacing the muscle is also fast and simple and involves placement of two CranioFix (Aesculap, Inc., Center Valley, PA) holders to the bone, with no suture material. This approach does not limit the exposure gained and offers the same exposure as the "usual" pterional craniotomy. PMID- 22451820 TI - Surgical ablation and free flap reconstruction in children with malignant head and neck tumors. AB - We assessed the feasibility and safety of free flap reconstruction in children undergoing extensive surgical excision of malignant head and neck tumors. We performed a retrospective review in a tertiary referral center of all patients aged 18 years or younger who underwent free flap reconstruction following resection of malignant head and neck tumors at our institution. Main outcome measures included complications at the primary and donor sites, functional and esthetic outcome, and tumor control. Eight of the 237 (3.4%) free flap reconstructions were performed on children. All tumors were malignant sarcomas. Ablative surgery was via a transfacial (n = 4) or a combined approach (n = 4). Transferred free flaps were the rectus abdominis (n = 3), gracilis (n = 3), fibula (n = 1), and anterolateral thigh (n = 1). The mean follow-up was 25.5 months. The overall early and late complication rates were 50% and 25%, respectively. There were no flap losses and no donor site complications. Functional outcome, including mastication, deglutition, and speech, was satisfactory. Local tumor control rate at last follow-up was 87.5%. Free flap reconstruction is an efficient and relatively safe technique for reconstructing surgical defects of the head and neck in children undergoing extensive surgery for malignant disease. PMID- 22451821 TI - Outcomes after surgical resection of head and neck paragangliomas: a review of 61 patients. AB - We reviewed the postoperative functional outcome following surgical resection of paragangliomas in patients with and without preoperative cranial nerve dysfunction. Patients who underwent surgical resections of head and neck paragangliomas were reviewed with functional outcomes defined as feeding tube and/or tracheostomy dependence, need for vocal cord medialization, and incidence of cerebral vascular accidents as primary end points. Secondary end points included pre- and postoperative function of lower cranial nerves and the impact of this dysfunction on long-term functional status. Sixty-one patients were identified: 27 with carotid paraganglioma (CP), 21 with jugular paraganglioma (JP), 8 with tympanic paragangliomas, 4 with vagal paragangliomas (VPs), and 1 with aortopulmonary paraganglioma. Following resection, 8 patients were feeding tube dependent, 14 patients required vocal cord medialization, 2 patients suffered strokes, but no patients required tracheostomy tubes. Twenty percent of patients (4/20) with JP and postoperative cranial neuropathies were feeding tube dependent, and 80% of patients (4/5) with CP and postoperative cranial nerve dysfunction were feeding tube dependent. Cranial nerve deficits were more common in patients with JP relative to those with CP. However, when cranial nerve dysfunction was present, our patients with CP had a higher incidence of temporary feeding tube dependence. Overall, 98% of patients were able to resume oral nutrition. PMID- 22451822 TI - Surgical approaches to facial nerve deficits. AB - The facial nerve is one of the most commonly injured cranial nerves. Once injured, the effects on form, function, and psyche are profound. We review the anatomy of the facial nerve from the brain stem to its terminal branches. We also discuss the physical exam findings of facial nerve injury at various levels. Finally, we describe various reconstructive options for reanimating the face and restoring both form and function. PMID- 22451823 TI - Endoscopy-assisted iliotibial tract harvesting for skull base reconstruction: feasibility on a cadaveric model. AB - During the last years, multiple methods and a wide set of materials for skull base reconstruction have been described. In our experience, the ideal graft for duraplasty is the iliotibial tract due to its favorable characteristics in terms of thickness, pliability, and strength. In this report, we show the iliotibial tract-harvesting technique under endoscopic guidance with a minimally invasive approach using a cadaveric model. Two longitudinal incisions of 1 cm each were made at 4 cm down a line drawn between the anterior-superior iliac spine and the lateral margin of patella at the extremities of the middle third of the thigh. By using a set of instruments for endoscopic face-lifting, the graft was easily set up and harvested. The endoscopic approach is associated with less visible scars, but longer operative time in comparison with open traditional procedure. The pros and cons in terms of morbidity need to be evaluated by further studies on actual cases. PMID- 22451824 TI - Use of Hemostatic Matrix for Hemostasis of the Cavernous Sinus during Endoscopic Endonasal Pituitary and Suprasellar Tumor Surgery. AB - The endoscopic endonasal approach offers a wide, panoramic exposure of the sellar floor, planum, and clivus. The ability to expose fully the tumor margins, through lateral extension of cavernous sinuses, increases the exposure and ability to resect the tumor but increases the risk of bleeding. The authors describe achieving hemostasis using a hemostatic matrix, FloSeal (Baxter Biosciences, Vienna, Austria) sealant, during endoscopic endonasal tumor removal, specifically for pituitary and suprasellar tumors. Thirty-nine cases (33 pituitary adenomas, 4 craniopharyngiomas, 1 clival plasmacytoma, and 1 planum meningioma) are described using this technique. FloSeal was injected directly to the site of bleeding, and a cottonoid was used for further tamponade, immediately achieving hemostasis with no hemorrhagic complications in any of the patients. Surgery could be immediately pursued without any delay. This simple nuance can be used as a safe method in cavernous sinus hemostasis during endoscopic endonasal surgery and may decrease operative time. PMID- 22451825 TI - Accuracy of Surgeon's Estimation of Sella Margins during Endoscopic Surgery for Pituitary Adenomas: Verification Using Neuronavigation. AB - We assessed the accuracy of a surgeon's localization of sella margins during endoscopic transsphenoidal surgery for pituitary adenomas, as verified using a neuronavigational system, and we identify types of pathology in which neuronavigation is of most benefit. We performed a prospective cohort study of 32 consecutive patients undergoing image-guided endoscopic transsphenoidal surgery for pituitary adenomas. We assessed the margin of error in the surgeon's localization of the superior and inferior margins of the sella and the lateral margins as determined by the medial border of left and right carotid arteries, using a magnetic resonance-based neuronavigational system. The overall mean error of localization of sella margins by the surgeon was 4.5 +/- 3 mm. Localization of the inferior sella margin was more accurate (3.1 +/- 2 mm mean error) compared with localization of the left (4.8 +/- 3 mm) or right carotid arteries (4.6 +/- 3 mm). Giant adenomas (> 2.5 cm), more invasive adenomas (Hardy grade IV), and those with parasellar extension (Hardy grades D and E) were associated with larger errors in localization of the carotid arteries. There was no significant difference when stratifying for recurrent surgery, nostril of approach, and sella morphology. During endoscopic transsphenoidal surgery, the margin of error in the surgeon's estimation of the sella margins for adenomas less than 2.5 cm located predominantly within the sella is relatively small. The margin of error increases for giant adenomas, with greater invasiveness and parasellar spread, and the use of neuronavigation can be especially useful in such cases. PMID- 22451826 TI - Feasibility of proton beam therapy for chordoma and chondrosarcoma of the skull base. AB - We explored the general feasibility of proton beam therapy for chordoma and chondrosarcoma of the skull base. Clinical records and treatment-planning data of patients with the pathological diagnosis of chordoma or chondrosarcoma were examined. Proton beam therapy was administered for gross tumor mass as well as microscopic residual disease after surgery. The prescribed dose was determined to maximize the coverage of the target and to not exceed predefined constraints for the organs at risk. Eight cases of chordoma and eight cases of chondrosarcoma were enrolled. The median tumor volume was 40 cm(3) (range, 7 to 546 cm(3)). The prescribed dose ranged from 50 to 70 Gy (relative biological effectiveness [RBE]), with a median of 63 Gy RBE. The median follow-up duration was 42 months (range 9 to 80 months). The overall survival rate was 100%, and the local control rate at 3 years of chordoma and chondrosarcoma were 100% and 86%. None of the patients developed radiation-induced optic neuropathy, brain stem injury, or other severe toxicity. Proton beam therapy is generally feasible for both chordoma and chondrosarcoma of the skull base, with excellent local control and survival rates. PMID- 22451827 TI - Evaluation of Three Cases Using a Novel Titanium Mesh System-Skull-Fit with Orbital Wall (Skull-Fit WOW)-For Cranial Base Reconstructions. AB - Cranial base reconstructions associated with tumor resections around the orbital wall often require that both the upper and lateral orbital walls be reconstructed during a single procedure. Previously, we used titanium mesh plates that were preoperatively fabricated based on three-dimensional models. Although these plates are precise and do not increase the probability of infection, we still had to use autologous bones to reconstruct the orbital walls. Recently, we developed a new titanium mesh plate-called Skull-Fit((r))-with orbital wall (Skull-Fit WOW((r))), enabling us to reconstruct the cranial base and orbital walls without bone grafts. Here, we report on three reconstruction cases in which the novel titanium mesh-orbital wall system was used. In all three cases, the customized titanium mesh system performed satisfactorily with little, if any, complications. PMID- 22451828 TI - Secondary trigeminal neuralgia in cerebellopontine angle tumors. AB - The analysis of the treatment results in patients with cerebellopontine angle (CPA) tumors, manifested as trigeminal neuralgia (TN). During the 10-year period from 1998 to 2008, 14 patients with verified CPA tumors that had the typical manifestations of TN were operated on at our hospital (5.8% from all patients with TN who underwent surgery). In nine cases the epidermoid was identified; three patients had meningioma, one patient had acoustic neurinoma, and one patient had lipoma. The follow-up of all patients lasted at least 12 months. The intraoperative assessment identified the three variants of relationship between the tumors and neurovascular structures: (1) tumor grows around the trigeminal nerve; (2) the tumor causes compression and displacement of the trigeminal nerve; and (3) tumor presses the arterial vessel to the trigeminal nerve by moving the vessel or nerve. For six patients, with removal of tumor a microvascular decompression of the trigeminal nerve was performed. Complete pain relief was achieved in 12 patients (86%). TN is an expectative symptom of CPA tumors. The most frequent cause of secondary TN of CPA tumors is epidermoid. All patients with manifestations of TN should undergo the magnetic resonance imaging for early diagnosis of CPA tumor. PMID- 22451829 TI - Expectant management of vestibular schwannoma: a retrospective multivariate analysis of tumor growth and outcome. AB - We conducted a retrospective observational study to assess the consequences of conservative management of vestibular schwannoma (VS). Data were collected from tertiary neuro-otological referral units in United Kingdom. The study included 59 patients who were managed conservatively with radiological diagnosis of VS. The main outcome measures were growth rate and rate of failure of conservative management. Multivariate analysis sought correlation between tumor growth and (i) demographic features, (ii) tumor characteristics. The mean tumor growth was 0.66 mm/y. 11 patients (19%) required intervention. Mean time to intervention was 37 months with two notable late "failures" occurring at 75 and 84 months. Tumors extending into the cerebellopontine angle (CPA) grew significantly faster than intracanalicular tumors (p = 0.0045). No association was found between growth rate and age, sex, tumor laterality, facial nerve function, and grade of hearing loss. Conservative management is acceptable for a subset of patients. Tumors extending into the CPA at diagnosis grow significantly faster than intracanalicular tumors. No growth within 5 years of surveillance does not guarantee a continued indolent growth pattern; surveillance must therefore continue. PMID- 22451830 TI - Osseointegrated implant applications in cosmetic and functional skull base rehabilitation. AB - This study discusses the indications, outcomes, and complications in patients that underwent osseointegrated implantation for skull base rehabilitation. We conducted a retrospective review of eight patients with skull base defects who had undergone implantation of a facial prosthetic retention device +/- bone anchored hearing aid at a tertiary academic referral center. Descriptive analysis of applications, techniques, outcomes, and complications were reviewed. The majority of patients were males (n = 6) with previously diagnosed skull base malignancy (n = 5) with an average age of 46 (range, 14 to 77). All patients received an implanted facial prosthetic device either for an aural (n = 7) or orbital (n = 1) prosthesis. There were only two complications that included infection (n = 1) and implant extrusion (n = 1). Osseointegrated implantation of abutments for anchoring prosthetic devices in patients for skull base rehabilitation provides an excellent cosmetic option with minimal complications. PMID- 22451831 TI - Fibrin Sealant Injection: An Aid to Reduce Venous Bleeding during Jugular Bulb and Sigmoid Sinus Dissection in Glomus Jugulare (Jugulotympanic Paraganglioma) Surgery. AB - Glomus jugulare (jugulotympanic paraganglioma) surgery requires tumor dissection in the region of the jugular bulb, upper internal jugular vein, and sigmoid sinus. Despite ligation or external compression of the sigmoid sinus proximally and ligation of the internal jugular vein distally, troublesome venous bleeding can arise from the inferior petrosal sinus or condylar veins at the medial wall of the jugular bulb. Excessive packing in this area can place the integrity of the lower cranial nerves at risk. We report a technique in which Tisseel((r)) fibrin sealant is injected into the ligated sigmoid sinus and internal jugular vein. This forms an internal cast around the tumor in the sigmoid-jugular complex and helps seal the inferior petrosal sinus and condylar veins. This allows for safer dissection with reduced venous bleeding. Our experience in five cases has shown this technique to be effective. PMID- 22451832 TI - Long-term follow-up of microvascular decompression for trigeminal neuralgia. AB - We conducted a study to evaluate the follow-up characteristics of patients with trigeminal neuralgia (TN) and to evaluate the factors affecting long-term outcome of microvascular decompression (MVD) in TN. Between 1983 and 2003, 156 patients with TN treated with MVD by 4 neurosurgeons at University Medical Centre Groningen/the Netherlands were evaluated. Baseline data from operative outcome were evaluated using univariate and multivariate analysis. The group consisted of 156 patients with TN: 90 females and 66 males with a median follow-up period of 9.7 years. The average age of initial symptoms was 51 years. The average duration of symptoms was 58 months. Postoperative 22 patients had a facial hyperpathia or hyperesthesia. Postoperatively, 137 patients had immediate relief. Postoperatively 1 year, 140 patients still had a good outcome of the operation. Twenty-seven patients with good immediate postoperative results had recurrent pain. From the group of patients with typical TN, 82% had good long-term results after operation. Patients with typical TN and immediate postoperative remission, in univariate analysis, had significantly more often an excellent/good postoperative outcome. Immediate postoperative remission is an independent predictive factor for a good long-term outcome. The long-term results of MVD in majority of patients were good with no mortalities and no major morbidities. Patients with typical TN had better long-term outcomes and less recurrence. PMID- 22451833 TI - Repositioning of Cranial Bone Flaps Cut with a Diamond-Coated Threadwire Saw: 5 Year Experience with Cosmetic Cranioplasty without Fixation Devices. AB - Artificial fixation systems for cranial bone flaps have problems related to their materials and designs. We developed an alternative technique for supratentorial craniotomy that employs a diamond-coated threadwire saw (diamond T-saw), originally developed for spinal surgery, and reduces the bone gap for fitted bone flap fixation. The study subjects were 77 adults undergoing elective supratentorial craniotomy. After placing a burr hole at each corner of the craniotomy, we performed osteotomy between adjacent burr holes to approximately one-third of the length of the osteotomy with a craniotome; this leaves a bony bridge at each corner. The diamond T-saw was introduced between adjacent burr holes through the epidural space and a bridge was cut with reciprocating strokes. On closure, the bridge firmly supports the flap and only sutures are needed for fixation. Successful bone flap fixation was obtained in all followed-up cases. There were no technique-related complications such as dural laceration, flap displacement, or resorption. Our method is ideal for bone cuts in cosmetic cranioplasty; it is easy, safe, and inexpensive and avoids the need for flap fixation with artificial devices. PMID- 22451834 TI - Petrous carotid exposure with eustachian tube preservation: a morphometric elucidation. AB - Inadvertent injury to eustachian tube leading to cerebrospinal fluid rhinorrhea is a known complication associated with drilling of Glasscock's triangle to expose the horizontal petrous internal carotid artery (ICA) for management of difficult tumors (especially malignant) or aneurysms at the cranial base. Contrary to the usual approach, we hypothesize that a "medial-to-lateral" approach to Glasscock's triangle drilling will minimize eustachian tube injury. Four formalin-fixed human cadaveric heads were dissected, and underwent appropriate morphometric analysis; yielding a total of eight datasets. The diameter of the horizontal petrous ICA exposed was 4.7 +/- 0.9 mm (range, 3.8 to 5.6 mm).The mean distance from the medial carotid wall midpoint to the medial most point on the eustachian tube was 6.35 +/- 0.58 mm (range, 5.4 to 7.1 mm), yielding a "safety zone" for eustachian tube, ranging 0.2 to 1.9 mm lateral to the lateral carotid wall. With the medial-to-lateral approach, the eustachian tube remained preserved in all the specimens. The results of our study provide a practical, consistent, and safe method of maximizing horizontal petrous carotid artery exposure while minimizing the eustachian tube injury. PMID- 22451835 TI - Endoscopic endonasal infrasellar approach to the sellar and suprasellar regions: technical note. AB - We report a technical variation of the endoscopic endonasal approach to the sellar and suprasellar regions which relies on the use of a 45-degree angled endoscope. The so-called "infrasellar approach" aims at excising lesions situated within the intermediate and posterior lobes of the pituitary gland without damaging the anterior lobe, thus potentially minimizing endocrinological morbidity. In this regard the endoscopic infrasellar approach might be advantageous in selected cases when compared with the traditional transsphenoidal approach with the microscope. We describe the technique and illustrate it with representative clinical cases. PMID- 22451836 TI - DengueTools: innovative tools and strategies for the surveillance and control of dengue. AB - Dengue fever is a mosquito-borne viral disease estimated to cause about 230 million infections worldwide every year, of which 25,000 are fatal. Global incidence has risen rapidly in recent decades with some 3.6 billion people, over half of the world's population, now at risk, mainly in urban centres of the tropics and subtropics. Demographic and societal changes, in particular urbanization, globalization, and increased international travel, are major contributors to the rise in incidence and geographic expansion of dengue infections. Major research gaps continue to hamper the control of dengue. The European Commission launched a call under the 7th Framework Programme with the title of 'Comprehensive control of Dengue fever under changing climatic conditions'. Fourteen partners from several countries in Europe, Asia, and South America formed a consortium named 'DengueTools' to respond to the call to achieve better diagnosis, surveillance, prevention, and predictive models and improve our understanding of the spread of dengue to previously uninfected regions (including Europe) in the context of globalization and climate change.The consortium comprises 12 work packages to address a set of research questions in three areas:Research area 1: Develop a comprehensive early warning and surveillance system that has predictive capability for epidemic dengue and benefits from novel tools for laboratory diagnosis and vector monitoring.Research area 2: Develop novel strategies to prevent dengue in children.Research area 3: Understand and predict the risk of global spread of dengue, in particular the risk of introduction and establishment in Europe, within the context of parameters of vectorial capacity, global mobility, and climate change.In this paper, we report on the rationale and specific study objectives of 'DengueTools'. DengueTools is funded under the Health theme of the Seventh Framework Programme of the European Community, Grant Agreement Number: 282589 Dengue Tools. PMID- 22451837 TI - RNA interference: a promising approach for the treatment of viral hepatitis. PMID- 22451838 TI - Intravenous drug use and hepatitis C virus in iran. PMID- 22451839 TI - Association of hepatitis C virus with insulin resistance: evidences from animal studies and clinical studies. AB - CONTEXT: HCV infection is strongly associated with development of insulin resistance and type-2 diabetes, however molecular mechanism of these associations is not known. The aim of this review was to conduct a comprehensive literature search to understand the nature of the association between hepatitis C virus (HCV) infection and insulin resistance (IR). We also explored the role of HCV core protein and NS5a in modulating the course of the insulin-signaling pathway. EVIDENCE ACQUISITIONS: We searched Directory of Open Access Journals (DOAJ) Google Scholar, Pubmed (NLM), LISTA (EBSCO), Web of Science (TS and PakMediNet). RESULTS: Emerging evidence suggests an association between HCV infection and carotid/coronary vascular disease. IR appears to be a dominant underlying cause of accelerated atherosclerosis in patients with chronic hepatitis C (CHC). HCV can induce IR directly through the stimulation of SOCS3 and PPA2, and both of these molecules have been shown to inhibit interferon-alpha signaling. Improvement of insulin sensitivity may increase the response rate to antiviral treatment and prevent IR complications, including vascular diseases. The results of several clinical trials that have used insulin sensitizers (metformin and PPAR gamma agonists) have been inconclusive. CONCLUSIONS: Beside the association between HCV and IR, the published data also have showed the possible association of HCV core and NS5A protein with IR. PMID- 22451840 TI - Factors Correlated With Hepatitis C and B Virus Infections Among Injecting Drug Users in Tehran, IR Iran. AB - BACKGROUND: In Iran, the number of injecting drug users (IDUs) has increased in recent years. The rates of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections among IDUs are reportedly high. OBJECTIVES: The purpose of this study was to assess factors correlated with HCV and HBV infections among IDUs in Tehran. PATIENTS AND METHODS: A cross-sectional study included 899 IDUs recruited from the community, drug treatment centers, and drop-in-centers. The study involved interviews conducted using an adapted version of the WHO Drug Injection Study Phase II (Version 2b) questionnaire and blood testing for the HCV antibody, hepatitis B surface antigen, and hepatitis B core antibody. A logistic regression model was used to identify independent factors correlated with HCV and HBV infections. RESULTS: HCV infection was found to be primarily associated with female gender [odds ratio (OR) 5.0, 95% confidence interval (CI) 2.0-10.0)], unmarried status (OR 2.9, 95% CI 1.9-4.4), drug use for more than 10 years (OR 2.7, 95% CI 1.8-3.9), drug injection frequency of more than once per day (OR 2.6, 95% CI 1.6-4.2), history of imprisonment (OR 2.5, 95% CI 1.6-4.0)], and a history of shared injection needles in prison (OR 2.3, 95% CI 1.5-3.6). HBV infection was mainly correlated with a history of imprisonment (OR 1.9, 95% CI 1.4-2.7) and drug use for more than 10 years (OR 1.4, 95% CI 1.1-1.9). CONCLUSIONS: Because a considerable number of IDUs in Iran are receiving reduction services, tailoring services for prevention of hepatitis infection are necessary. PMID- 22451841 TI - Safety and effectiveness of blind percutaneous liver biopsy: analysis of 1412 procedures. AB - BACKGROUND: Percutaneous liver biopsy is one of the most important and widely used methods for diagnosing chronic liver diseases; however, controversies related to the potential risk of complications and patient discomfort still exist. OBJECTIVES: The objective of this study was to evaluate the safety and success rate of blind percutaneous liver biopsy. PATIENTS AND METHODS: We conducted a retrospective analysis of 1412 blind percutaneous thick-needle liver biopsies performed during 1977-2000 at a single center on 1110 patients, using archived medical data of the center. RESULTS: The overall success rate of obtaining a liver sample with this method was 95.3%. Of all the samples assessed, 91.7% were determined to be fully representative for an evaluation by the pathologist. Complications occurred in 259 procedures (18.3%). While no fatalities associated with liver biopsy were noted, 9 serious complications (0.64%) directly related to biopsies were reported. Pain was the most common complication (15.3%). Significantly more complications (pain and vasovagal reactions) were reported in females (22.1%) than in males (16.1%) (P = 0.005). The rate of complications was significantly correlated with the stage of fibrosis (P = 0.027), i.e. the higher the fibrosis stage, the higher the complication rate. Previous surgical procedures involving the abdominal cavity or thorax influenced the effectiveness of liver biopsy (P = 0.017). Less operator experience was significantly associated with a higher rate of procedure failure (P = 0.002). Statistical significance of the relationship between individual operator efficiency and complication rate (P = 0.000) and that between individual operator efficiency and biopsy failure rate (P = 0.002) was observed. CONCLUSIONS: Blind percutaneous liver biopsy is a safe and effective invasive procedure, despite the fact that noninvasive fibrosis assessment methods are currently widely available and used instead of histological evaluation. Complications risk and failure rate are low if indications and contraindications are considered carefully and the biopsy is performed by a skilled and experienced operator. Certain groups of patients may benefit from an image-guided procedure to improve its effectiveness. PMID- 22451842 TI - The Effect of GBV-C Infection on CD4 Count and Viral Loads in Patients Infected With HIV. AB - BACKGROUND: The picture that has emerged from studies investigating HIV infected people with GBV-C viremia is that they have lower plasma HIV viral loads in comparison with HIV-positive people who did not have the GBV-C viremia. OBJECTIVES: Since GBV-C HIV coinfection has not been studied in Iran, we have designed a survey to study the outcomes of GBV-C infection on HIV infected individuals. PATIENTS AND METHODS: We analyzed 78 serum samples from HIV-positive patients in Tehran. The HIV positive statue was confirmed by Western blot in our laboratory. Next we detected GBV-C RNA by RT nested-PCR and divided our patient into GBV-C positive and GBV-C negative groups. The final step was measuring the CD4 count and HIV viral load and comparing the means of the CD4 count and HIV viral load in HIV-infected individuals in the GBV-C positive and GBV-C negative groups. RESULTS: We detected GBV-C RNA in 15 patients out of 78. The mean CD4 count was 607.13 compared to 415.87 in the GBV-C negative group and the difference was significant (P = 0.005). In contrast to the CD4 count there was no significant difference in HIV viral loads between HIV infected individuals in the GBV-C positive and GBV-C negative groups. CONCLUSION: Although there was no significant difference in the mean of the HIV viral load between the GBV-C positive and GBV-C negative groups, the significantly higher CD4 mean in the GBV C positive group compared with the GBV-C negative group suggests a beneficial effect of this coinfection. PMID- 22451843 TI - Pediatric autoimmune hepatitis in a patient who presented with erythema nodosum: a case report. AB - BACKGROUND: Autoimmune hepatitis (AIH) is a form of chronic hepatitis with unclear causative factors and is characterized by immunological and auto immunological manifestations. Several extrahepatic manifestations, such as other autoimmune disorders, are associated with AIH. AIH with dermatological conditions as the initial manifestation is rare. We report the case of AIH in which erythema nodosum (EN) was the first manifestation. CASE PRESENTATION: An 8-year-old girl with several persistent dermatological lesions was referred to our hospital several months ago. Her skin had nodular, painful, dry, and erythematous lesions, predominantly on the extensor areas of both the legs, with some erythematous patches on her face. Physical examination revealed that she had hepatosplenomegaly as well. Skin biopsy indicated EN. The results of the laboratory tests showed increased levels of several liver enzymes. The patient's International Autoimmune Hepatitis Group (IAIHG) score was a definite indicator of AIH. The results of liver biopsy indicated AIH. Other causes of EN and abnormal liver function were ruled out. The only obvious cause of skin lesions was chronic inflammation due to an autoimmune response. The patient was treated for AIH, and her skin lesions along with other signs and symptoms resolved. CONCLUSIONS: AIH can present with protean clinical manifestations, and is thus associated with the risk of delayed diagnosis. Dermatological manifestations, including EN, could indicate a serious disease, and further investigation might be required. AIH should be considered as the possible diagnosis in such cases. PMID- 22451844 TI - Hepatitis C virus infection trends in Italy. PMID- 22451845 TI - HFE Gene Mutations in Cryptogenic Cirrhosis Patients. PMID- 22451846 TI - Author's Reply: HFE Gene Mutations (C282Y and H63D) in a Group of Patients With Cryptogenic Cirrhosis. PMID- 22451847 TI - Common dietary supplements for cognitive health. AB - Advancing age is a major risk factor for cognitive impairment and dementia. Currently, there are no effective preventive strategies for cognitive decline. Since physicians have no drug therapies to offer, patients and families may turn to complementary and alternative medicine to preserve cognition. Dietary supplements are one of the most common forms of complementary and alternative medicine that patients use and although limited, evidence for their potential interactions with other treatments has been documented. Considering the insufficient evidence for their efficacy, potential for interaction with other therapies and costs to patients, physicians should be aware of the use of dietary supplements among their patients so that they can advise their patients on the potential benefits and harms. PMID- 22451848 TI - The need for co-ordinated studies for obesity-related problems like diabetes mellitus in Libyan population. PMID- 22451849 TI - The impact of anti-diabetic drugs on colorectal cancer risk in a large cohort of women with diabetes. PMID- 22451850 TI - Transforming growth factor-beta and smooth muscle differentiation. AB - Transforming growth factor (TGF)-beta family members are multifunctional cytokines regulating diverse cellular functions such as growth, adhesion, migration, apoptosis, and differentiation. TGF-betas elicit their effects via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knockout mouse models for the different components of the TGF-beta signaling pathway have revealed their critical roles in smooth muscle cell (SMC) differentiation. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular disorders such as aorta aneurysm and congenital heart diseases due to SMC defects. In this review, the current understanding of TGF-beta function in SMC differentiation is highlighted, and the role of TGF-beta signaling in SMC-related diseases is discussed. PMID- 22451851 TI - Biochemical analysis of the interactions of IQGAP1 C-terminal domain with CDC42. AB - AIM: To understand the interaction of human IQGAP1 and CDC42, especially the effects of phosphorylation and a cancer-associated mutation. METHODS: Recombinant CDC42 and a novel C-terminal fragment of IQGAP1 were expressed in, and purified from, Escherichia coli. Site directed mutagenesis was used to create coding sequences for three phosphomimicking variants (S1441E, S1443D and S1441E/S1443D) and to recapitulate a cancer-associated mutation (M1231I). These variant proteins were also expressed and purified. Protein-protein crosslinking using 1-Ethyl-3-(3 dimethylaminopropyl)carbodiimide was used to investigate interactions between the C-terminal fragment and CDC42. These interactions were quantified using surface plasmon resonance measurements. Molecular modelling was employed to make predictions about changes to the structure and flexibility of the protein which occur in the cancer-associated variant. RESULTS: The novel, C-terminal region of human IQGAP1 (residues 877-1558) is soluble following expression and purification. It is also capable of binding to CDC42, as judged by crosslinking experiments. Interaction appears to be strongest in the presence of added GTP. The three phosphomimicking mutants had different affinities for CDC42. S1441E had an approximately 200-fold reduction in affinity compared to wild type. This was caused largely by a dramatic reduction in the association rate constant. In contrast, both S1443D and the double variant S1441E/S1443D had similar affinities to the wild type. The cancer-associated variant, M1231I, also had a similar affinity to wild type. However, in the case of this variant, both the association and dissociation rate constants were reduced approximately 10-fold. Molecular modelling of the M1231I variant, based on the published crystal structure of part of the C-terminal region, revealed no gross structural changes compared to wild type (root mean square deviation of 0.564 A over 5556 equivalent atoms). However, predictions of the flexibility of the polypeptide backbone suggested that some regions of the variant protein had greatly increased rigidity compared to wild type. One such region is a loop linking the proposed CDC42 binding site with the helix containing the altered residue. It is suggested that this increase in rigidity is responsible for the observed changes in association and dissociation rate constants. CONCLUSION: The consequences of introducing negative charge at Ser-1441 or Ser-1443 in IQGAP1 are different. The cancer-associated variant M1231I exerts its effects partly by rigidifying the protein. PMID- 22451852 TI - Management dilemmas in patients with mechanical heart valves and warfarin-induced major bleeding. AB - Management of warfarin-induced major bleeding in patients with mechanical heart valves is challenging. There is vast controversy and confusion in the type of treatment required to reverse anticoagulation and stop bleeding as well as the ideal time to restart warfarin therapy safely without recurrence of bleeding and/or thromboembolism. Presently, the treatments available to reverse warfarin induced bleeding are vitamin K, fresh frozen plasma, prothrombin complex concentrates and recombinant activated factor VIIa. Currently, vitamin K and fresh frozen plasma are the recommended treatments in patients with mechanical heart valves and warfarin-induced major bleeding. The safe use of prothrombin complex concentrates and recombinant activated factor VIIa in patients with mechanical heart valves is controversial and needs well-designed clinical studies. With regard to restarting anticoagulation in patients with warfarin induced major bleeding and mechanical heart valves, the safe period varies from 7 14 d after the onset of bleeding for patients with intracranial bleed and 48-72 h for patients with extra-cranial bleed. In this review article, we present relevant literature about these controversies and suggest recommendations for management of patients with warfarin-induced bleeding and a mechanical heart valve. Furthermore, there is an urgent need for separate specific guidelines from major associations/ professional societies with regard to mechanical heart valves and warfarin-induced bleeding. PMID- 22451853 TI - Acupuncture for paroxysmal and persistent atrial fibrillation: An effective non pharmacological tool? AB - In Traditional Chinese Medicine, stimulation of the Neiguan spot has been utilized to treat palpitations and symptoms related to different cardiovascular diseases. We evaluated whether acupuncture might exert an antiarrhythmic effect on patients with paroxysmal or persistent atrial fibrillation (AF). Two sets of data are reviewed. The first included patients with persistent AF who underwent electrical cardioversion to restore sinus rhythm. The second included patients with symptomatic paroxysmal AF. All subjects had normal ventricular function. Acupuncture treatment consisted of 10 acupuncture sessions on a once a week basis with puncturing of the Neiguan, Shenmen and Xinshu spots. In patients with persistent AF, the recurrence rate after acupuncture treatment was similar to that observed in patients on amiodarone, but significantly smaller than that measured after sham acupuncture treatment or in the absence of any antiarrhythmic drugs. In a small group of patients with paroxysmal AF, acupuncture resulted in a significant reduction in the number and duration of symptomatic AF episodes. In conclusion, we observed that acupuncture of the Neiguan spot was associated with an antiarrhythmic effect, which was evident in patients with both persistent and paroxysmal AF. These preliminary data, observed in 2 small groups of AF patients, need to be validated in a larger population but strongly suggest that acupuncture may be an effective non-invasive and safe antiarrhythmic tool in the management of these patients. PMID- 22451854 TI - Short-term outcomes in heart failure patients with chronic obstructive pulmonary disease in the community. AB - AIM: To establish the short term outcomes of heart failure (HF) patients in the community who have concurrent chronic obstructive pulmonary disease (COPD). METHODS: We evaluated 783 patients (27.2%) with left ventricular systolic dysfunction under the care of a regional nurse-led community HF team between June 2007 and June 2010 through a database analysis. RESULTS: One hundred and one patients (12.9%) also had a diagnosis of COPD; 94% of patients were treated with loop diuretics, 83% with angiotensin converting enzyme inhibitors, 74% with beta blockers; 10.6% with bronchodilators; and 42% with aldosterone antagonists. The mean age of the patients was 77.9 +/- 5.7 years; 43% were female and mean New York Heart Association class was 2.3 +/- 0.6. The mean follow-up was 28.2 +/- 2.9 mo. beta-blocker utilization was markedly lower in patients receiving bronchodilators compared with those not taking bronchodilators (overall 21.7% vs 81%, P < 0.001). The 24-mo survival was 93% in patients with HF alone and 89% in those with both comorbidities (P = not significant). The presence of COPD was associated with increased risk of HF hospitalization [hazard ratio (HR): 1.56; 95% CI: 1.4-2.1; P < 0.001] and major adverse cardiovascular events (HR: 1.23; 95% CI: 1.03-1.75; P < 0.001). CONCLUSION: COPD is a common comorbidity in ambulatory HF patients in the community and is a powerful predictor of worsening HF. It does not however appear to affect short-term mortality in ambulatory HF patients. PMID- 22451855 TI - Management of chronic heart failure: Role of home echocardiography in monitoring care programs. AB - AIM: To identify a possible role of home echocardiography for monitoring chronic heart failure (CHF) patients. METHODS: We prospectively investigated 118 patients hospitalized during the last year for CHF who could not easily reach the pertaining District Healthcare Center. The patients were followed up with 2 home management programs: one including clinical and electrocardiographic evaluations and also periodic home echocardiographic examinations (group A), the other including clinical and electrocardiographic evaluations only (group B). RESULTS: At the end of the 18-mo follow-up no signi-ficant differences were observed between the 2 groups as regards the primary endpoint: rehospitalization occurred in 4 patients of the group A and in 6 patients of the group B; major cardiovascular events occurred in 2 and in 3 patients, respectively. No significant differences were observed with respect to the secondary endpoints: one vascular event appeared in both the groups, 3 cardiovascular deaths occurred in group A and 2 in group B. No significant differences were observed between the 2 groups as regards the composite endpoint of death plus hospitalization. CONCLUSION: Home echocardiography for monitoring of CHF patients does not improve the cardiovascular endpoints. In our CHF patients, a low incidence of vascular events was observed. PMID- 22451856 TI - A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome. AB - AIM: To test the efficacy of a proprietary nutraceutical combination in reducing insulin resistance associated with the metabolic syndrome (MetS). METHODS: Sixty four patients with MetS followed at a tertiary outpatient clinic were randomly assigned to receive either placebo or a proprietary nutraceutical combination (AP) consisting of berberine, policosanol and red yeast rice, in a prospective, double-blind, placebo-controlled study. Evaluations were performed at baseline and after 18 wk of treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) index was the primary outcome measure. Secondary endpoints included lipid panel, blood glucose and insulin fasting, after a standard mixed meal and after an oral glucose tolerance test (OGTT), flow-mediated dilation (FMD), and waist circumference. RESULTS: Fifty nine patients completed the study, 2 withdrew because of adverse effects. After 18 wk there was a significant reduction in the HOMA-IR index in the AP group compared with placebo (DeltaHOMA respectively -0.6 +/- 1.2 vs 0.4 +/- 1.9; P < 0.05). Total and low density lipoprotein cholesterol also significantly decreased in the treatment arm compared with placebo (Deltalow density lipoprotein cholesterol -0.82 +/- 0.68 vs -0.13 +/- 0.55 mmol/L; P < 0.001), while triglycerides, high density lipoprotein cholesterol, and the OGTT were not affected. In addition, there were significant reductions in blood glucose and insulin after the standard mixed meal, as well as an increase in FMD (DeltaFMD 1.9 +/- 4.2 vs 0 +/- 1.9 %; P < 0.05) and a significant reduction in arterial systolic blood pressure in the AP arm. CONCLUSION: This short-term study shows that AP has relevant beneficial effects on insulin resistance and many other components of MetS. PMID- 22451857 TI - Brugada electrocardiographic pattern induced by fever. AB - Brugada syndrome is a major cause of sudden death in young adults. Fever has been described to induce a Brugada-type electrocardiogram in asymptomatic patients with a negative family history, to disclose Brugada syndrome and to increase the risk of death and induce T wave alternans in patients with diagnosed Brugada syndrome. Risk stratification is challenging and demands a careful evaluation. Here we present 2 case reports and review the literature. PMID- 22451858 TI - Severe mitral annular calcification in rheumatic heart disease: A rare presentation. AB - Severe mitral annular calcification (MAC) is frequently seen in patients with advanced age and chronic kidney disease, but it is rare in rheumatic heart disease (RHD). We hereby report a case of 45-year-old female with chronic RHD, who had severe MAC and mitral regurgitation. Fluoroscopy revealed a "crown"-like severe calcification of the mitral annulus. Autopsy of the heart revealed a calcified posterior mitral annulus, fused commissures, and calcified nodules at the atrial aspect of the mitral valve. PMID- 22451859 TI - Revision of subjects of the Korean Optometrist Licensing Examination suggested by optometrists. PMID- 22451860 TI - Importance of social pharmacy education in Libyan pharmacy schools: perspectives from pharmacy practitioners. AB - The present study aims to explore the perceptions among pharmacy practitioners in Libya on the importance of social pharmacy education. A qualitative methodology was employed to conduct this study. Using a purposive sampling technique, a total of ten Libyan registered pharmacists were interviewed. Based on the content analysis of the interviews, two major themes emerged, namely the understanding of social pharmacy education and the need for incorporating social pharmacy courses into the pharmacy education curriculum. The majority of the respondents knew about the concept. Of those that had no prior knowledge of this term, half of them expressed interest in knowing more about it. There was a positive perception of introducing social pharmacy into the undergraduate curricula among the respondents, and they believed that it is necessary for future pharmacists to know about social pharmacy components. The findings from the pharmacy practitioners' evaluation suggest the need to incorporate social pharmacy courses into the curricula of all pharmacy schools in Libya. PMID- 22451861 TI - Infection of specific strains of Streptococcus mutans, oral bacteria, confers a risk of ulcerative colitis. AB - Although oral bacteria-associated systemic diseases have been reported, association between Streptococcus mutans, pathogen of dental caries, and ulcerative colitis (UC) has not been reported. We investigated the effect of various S. mutans strains on dextran sodium sulfate (DSS)-induced mouse colitis. Administration of TW295, the specific strain of S. mutans, caused aggravation of colitis; the standard strain, MT8148 did not. Localization of TW295 in hepatocytes in liver was observed. Increased expression of interferon-gamma in liver was also noted, indicating that the liver is target organ for the specific strain of S. mutans-mediated aggravation of colitis. The detection frequency of the specific strains in UC patients was significantly higher than in healthy subjects. Administration of the specific strains of S. mutans isolated from patients caused aggravation of colitis. Infection with highly-virulent specific types of S. mutans might be a potential risk factor in the aggravation of UC. PMID- 22451862 TI - Lipids induce expression of serum-responsive transmembrane kinase EhTMKB1-9 in an early branching eukaryote Entamoeba histolytica. AB - Mechanisms underlying the initiation of proliferative response are known only for a few organisms, and are not understood for the medically important organisms including Entamoeba histolytica. The trans membrane kinase EhTMKB1-9 of E. histolytica is one of the early indicators of proliferation and its' expression is regulated by serum, one of the components necessary for cellular proliferation in vitro. In this study we show that bovine serum albumin (BSA) can induce EhTMKB1-9 expression in place of serum, and that both follow the same mechanism. Both serum and BSA use the same promoter element and the activation process is initiated through a PI3 kinase-mediated pathway. We further show that BSA activates EhTMKB1-9 due to the lipids associated with it and that unsaturated fatty acids are responsible for activation. These results suggest that lipid molecules are ligand(s) for initiation of a signaling system that stimulates EhTMKB1-9 expression. PMID- 22451863 TI - Roles of residues in the interface of transient protein-protein complexes before complexation. AB - Transient protein-protein interactions play crucial roles in all facets of cellular physiology. Here, using an analysis on known 3-D structures of transient protein-protein complexes, their corresponding uncomplexed forms and energy calculations we seek to understand the roles of protein-protein interfacial residues in the unbound forms. We show that there are conformationally near invariant and evolutionarily conserved interfacial residues which are rigid and they account for ~65% of the core interface. Interestingly, some of these residues contribute significantly to the stabilization of the interface structure in the uncomplexed form. Such residues have strong energetic basis to perform dual roles of stabilizing the structure of the uncomplexed form as well as the complex once formed while they maintain their rigid nature throughout. This feature is evolutionarily well conserved at both the structural and sequence levels. We believe this analysis has general bearing in the prediction of interfaces and understanding molecular recognition. PMID- 22451864 TI - Effect of prenatal hypobaric hypoxia on glutamatergic signal transduction in rat brain. AB - Ca(2+)-mediated signal transduction of group I metabotropic glutamate receptors (ImGluR) was studied in the brain of young (15 days) and old rats (90 days) exposed to severe hypobaric hypoxia on gestation days 14-16. Changes in the concentration of bound intracellular Ca(2+) (Ca(2+) response) were evaluated after repeated application of a selective ImGluR agonist 3,5 dihydroxyphenylglycine (DHPG) to cultured brain slices. Primary application of DHPG for 2 min induced a negative Ca(2+) response in slices from 15-day-old intact animals, while repeated application caused a positive response. In slices from 90-day-old control animals, both responses were negative. In slices from rats of both age groups subjected to severe prenatal hypobaric hypoxia, both responses were mainly positive, but short-term negative components were present in adult animals. Our results suggest that severe hypobaric hypoxia changes the balance between the two constitutive signal pathways triggered by ImGluR (inosine triphosphate and diacylglycerol pathways). This procedure is followed by the increased influx of extracellular Ca(2+) (as compared to Ca(2+) release from the intracellular stores). This imbalance is particularly pronounced at the early stage of ontogeny. PMID- 22451865 TI - Physiology of adaptation of first-year students to studies at higher educational institutions. AB - Changes in anthropometric and hematological values and parameters of cardiovascular function indicated sufficiently effective adaptation of first-year students to studies at higher educational institutions. On the other hand, a certain strain of the physiological optimum caused by examination stress was found in the students. PMID- 22451866 TI - Opposite effect of ATP on contraction force of tonic and phasic skeletal muscles in frogs. AB - Experiments in vitro showed that ATP and adenosine equally suppressed contractions of frog m. sartorius, which belongs to the phasic type muscles. Adenosine receptors antagonist 8-SPT abolished the effect of adenosine, but did not change the effect of ATP. This fact proves the independence of signaling pathways of these purines. ATP produced an opposite effect on the tonic muscle m. cruralis and increased the force of its contraction. Adenosine produced an inhibitory effect on the force of m. cruralis contration. In this case, 8-SPT also eliminated the effect of adenosine, but did not change the effect of ATP. The potentiating effect of ATP was blocked by suramin, a nonselective antagonist of P2 receptors, which attests to their involvement into the effects of this purine. The opposite effects of purinergic regulation reflect fundamental differences in functional organization of phasic and tonic muscular systems. It was hypothesized that the increase in contraction force under the effect of ATP is a mechanism providing maitenance of the contracted state of tonic muscle without appreciable metabolic costs. PMID- 22451867 TI - Changes in phospholipid composition of cardiomyocyte plasma membranes during hemorrhagic shock. AB - Changes in the phospholipid composition of cardiomyocyte plasma membranes during hemorrhagic shock suggest that disturbances in phosphatidylethanolamine metabolism serve as one of the major factors for myocardial alteration in shock. Depletion of membrane phosphatidylcholine causes destruction of cardiomyocytes. The enhanced breakdown of membrane sphingomyelin at the late stage of hemorrhagic shock is considered as a mechanism, which induces apoptosis in cardiomyocytes and Ca(2+) accumulation in these cells. A simultaneous increase in the content of membrane phosphatidylserine is the mechanism of activation of opioid receptors, which plays a compensatory role. PMID- 22451868 TI - Correction of microcirculatory disturbances with terahertz electromagnetic radiation at nitric oxide frequencies in albino rats under conditions of acute stress. AB - Terahertz electromagnetic irradiation at frequencies corresponding to NO molecular emission and absorption spectrum 150.176-150.664 GHz corrects disturbances in peripheral circulation typical of acute stress reaction in rats during acute immobilization stress. PMID- 22451869 TI - Effect of hypoxic preconditioning on free radical processes in tissues of rats with different resistance to hypoxia. AB - We studied the effect of single hypoxic preconditioning exposure (hypobaric hypoxia, 5000 m, 60 min) on free radical processes, glutathione system, and antioxidant defense enzymes in tissues of rats with different resistance to acute hypoxia. The intensity of free radical processes was shown to increase or decrease on day 1 after hypoxic preconditioning. These changes were tissue specific and opposite in animals with genetically determined differences in the resistance to hypoxia. Hypoxic preconditioning contributes to the immediate resistance. The effect was more pronounced in low resistant animals, who did not exhibit signs of oxidative stress in tissues during the early posthypoxic period. By contrast, hypoxic preconditioning was followed by activation of free radical processes in tissues of highly resistant animals. These rats were characterized by low ability for the development of immediate resistance. Activation of free radical processes in the early period of adaptation (first hours after hypoxic preconditioning) does not play a role in the induction of immediate adaptive mechanisms for hypoxia. PMID- 22451870 TI - Effect of unilateral inactivation of brain hemispheres on hypoxic resistance in mice. AB - The effects of unilateral cortical spreading depression on the resistance to acute hypoxia with hypercapnia were studied in male SHR mice. The life-span of mice with active right hemisphere was significantly longer than that of intact, but not of sham-operated (active control) animals. Mice with active left hemisphere differed significantly from intact and active control animals. It seems that the right hemisphere supports the optimal level of resistance to hypoxia with hypercapnia, while the left hemisphere performs the "antihypoxic" function. Additional analysis found no differences between the hemispheres in mice with low hypoxic resistance. The differences between the hemispheres increased with increasing the resistance to hypoxia. PMID- 22451871 TI - Threefold exposure to moderate hypobaric hypoxia decreases the expression of Cu,Zn-superoxide dismutase in some regions of rat hippocampus. AB - The effect of moderate hypobaric hypoxia on the expression of a peptide antioxidant Cu,Zn-superoxide dismutase in rat hippocampal neurons was evaluated in an immunocytochemical study. The expression of Cu,Zn-superoxide dismutase decreased significantly in the dorsal hippocampus (CA1 and CA2) and tended to decrease in ventral regions (CA3 and dentate gyrus) by the 24th hour after 3-fold exposure to hypoxia. PMID- 22451872 TI - Role of antibodies to neuronal alpha7-acetylcholine receptors in myasthenia. AB - The role of antibodies to a fragment of neuronal acetylcholine receptor was studied by EIA in patients with myasthenia. Antibody levels were significantly higher in patients with generalized myasthenia. Enzyme immunoassay of antibodies by the reaction with acetylcholine receptor fragment can serve as an additional method for studies of autoimmune myasthenia pathogenesis. PMID- 22451873 TI - Hemodynamic disturbances and activation of lipid peroxidation in the pathogenesis of acute myocardial injury induced by propranolol in toxic doses. AB - We studied the dose-dependent cardiotoxic effect of propranolol. Intraperitoneal injection of propranolol in doses of 1 and 2 mg/100 g body weight produced a potent effect on central hemodynamics and myocardial contractility, impaired diastolic relaxation, and caused damage to cardiomyocyte membranes due to activation of free radical oxidation. PMID- 22451874 TI - Effect of angiotensin-converting enzyme inhibitor quadropril on dynamic parameters of vascular tone under conditions of NO synthesis blockade in normotensive and spontaneously hypertensive rats. AB - The role of NO in the mechanism of quadropril modulation of the flow-dependent vasodilation was examined in normotensive (Wistar) and spontaneously hypertensive (SHR) rats. The abdominal aorta was cannulated and autoperfused at different volume rates to obtain the pressure-flow curves. In the first experimental series, the blood flow-pressure dependence was measured before and after intravenous injection of quadropril (1 mg/kg). In the next series, this dependence was obtained before and after injection of NO-synthase inhibitor L-NNA (10 mg/kg) and quadropril, respectively. Quadropril potentiated vasodilation caused by an increase in perfusion volume rate in both normo- and hypertensive rats and stabilized intravascular pressure. Inhibition of NO synthesis elevated hydraulic resistance and decreased stability of intravascular pressure in normo- and hypertensive rats. In normotensive rats, these changes were promoted by a decrease in vascular distensibility. Under these conditions, quadropril pronouncedly potentiated the flow-dependent vasodilation only in SHR rats, which was revealed methodically by an increase in perfusion rate in the posterior quarter of the body. Thus, in SHR rats the quadropril-potentiated vasodilation in response to increased perfusion rate does not depend on NO synthesis. PMID- 22451875 TI - Effect of alloxan on spontaneous lipolysis and glutathione system in isolated rat adipocytes. AB - In vitro experiments on cultured adipocytes from epididymal adipose tissue showed that addition of alloxan (0.5-10.0 mmol/liter) to the incubation medium induced the development of oxidative stress accompanied by an increase in the concentration of reactive oxygen species, TBA-reactive substances, and lipid hydroperoxides in cells. The redox state of adipocytes changed significantly under these conditions, which was associated with a decrease in the amount of reduced tripeptide, an increase in the content of glutathione disulfide, and a decrease in the reduced/oxidized glutathione ratio. The development of oxidative stress in adipocytes was accompanied by activation of spontaneous lipolysis, which probably plays an important role in the mechanisms of insulin resistance. PMID- 22451876 TI - Effects of long-term microgravitation exposure on cell respiration of the rat musculus soleus fibers. AB - Cell respiration of the m. soleus fibers was studied in Wistar rats treated with succinic acid and exposed to microgravitation for 35 days. The results indicated that respiration rates during utilization of endogenous and exogenous substrates and the maximum respiration rate decreased in animals subjected to microgravitation without succinate treatment. The respiration rate during utilization of exogenous substrate did not increase in comparison with that on endogenous substrates. Succinic acid prevented the decrease in respiration rate on endogenous substrates and the maximum respiration rate. On the other hand, the respiration rate on exogenous substrates was reduced in vivarium control rats receiving succinate in comparison with intact control group. That could indicate changed efficiency of complex I of the respiratory chain due to reciprocal regulation of the tricarbonic acid cycle. PMID- 22451877 TI - Adaptive responses of individual tissue structures of rat gingival mucosa to exposure to low-intensity 890-nm laser irradiation. AB - Adaptive reactions develop in rat gingival mucosa 1 min after single exposure to low-intensity 890-nm laser: the number of mast cells, degree and index of their degranulation, the diameter of blood vessels and their total area considerably increased. These parameters returned to normal after 1 day, while on days 3-7 they were below the control. PMID- 22451878 TI - Modulation of the blood-stimulating effect of immobilized granulocyte colony stimulating factor by immobilized hyaluronidase. AB - We evaluated whether immobilized hyaluronidase can modify the hematotropic effect of immobilized granulocyte CSF (G-CSF). The preparation of immobilized hyaluronidase (50 arb. units per mouse) potentiated the specific effect of immobilized G-CSF on granulomonocytopoiesis. The preparation was shown to facilitate the indirect effect of immobilized G-CSF on hemopoiesis (stimulation of the erythroid and lymphoid hemopoietic stems). These changes were accompanied by an increase in functional activity of hemopoietic precursor cells, secretion of humoral factors by bone marrow myelokaryocytes, and concentration of hemopoietins in the serum. PMID- 22451879 TI - Permeability of the blood-brain barrier for dilept and its active metabolite. AB - Experiments on rats with measurements by HPLC-MS/MS showed that antipsychotic preparation dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) administered per os in doses of 40 and 200 mg/kg crossed the blood-brain barrier and was detected in rat brain (unchanged drug and its active metabolite N-caproyl-L-prolyl-L tyrosine). The brain/plasma distribution coefficient for dilept was 2.0, for metabolite 0.5. No dose-concentration relationship was found, presumably because of the high dose of the drug transported from the blood to the brain not only by free diffusion, but also with participation of active carriers, whose number was limited. PMID- 22451880 TI - Correction of furosemide-induced magnesium deficiency with different stereoisomers of organic magnesium salts: a comparative study. AB - We compared the efficiency of different stereoisomers of organic magnesium salts (Mg DL-, Mg D-, and Mg L-aspartate and Mg L- and Mg DL-glutamate) after oral administration under conditions of furosemide-induced magnesium deficiency. The time to complete compensation of erythrocyte magnesium level was 5 days for Mg L aspartate, 10 and 8 days for Mg L-glutamate and Mg D-aspartate, respectively, and 11 days for Mg DL-aspartate and Mg DL-glutamate. These findings attest to better bioavailability of Mg complex with L-stereoisomer of aspartate in comparison with DL and D-stereoisomers and stereoisomers of Mg glutamate. PMID- 22451881 TI - Anxiolytic activity of tenoten and diazepam depends on conditions in Vogel conflict test. AB - We compared two modifications of Vogel conflict test and assessed anxyolitic activity of two drugs: diazepam (benzodiazepine anxiolitic) and tenoten (ultra low doses of antibodies to S-100 protein) in both modifications of the test. It was found that the intensity of anxiolitic effect of the drugs depends on the conditions of Vogel test. PMID- 22451882 TI - Cytotoxic effect of paclitaxel incorporated in nanoparticles based on lactic and glycolic acid copolymer. AB - Paclitaxel dosage form on nanoparticles of 200-300 nm based on lactic and glycolic acid copolymer was obtained by the co-precipitation method. The possibility of controlled release of paclitaxel at pH 7.4 for 24 h was studied in vitro. Studies on Jurkat/WT human T-lymphoblastic leukemia cells showed that incorporation of paclitaxel in the nanoparticles led to a 4-fold increase of its cytotoxicity (6.8*10(-6) M) in comparison with paclitaxel solution. The efficiency of compositions containing polysorbate-80 was comparable to that of non-modified nanoparticles containing paclitaxel. PMID- 22451883 TI - Subpopulation composition and activation of T lymphocytes during coculturing with mesenchymal stromal cells in medium with different O(2) content. AB - The concentration of O(2) during coculturing practically did not affect the subpopulation composition of T lymphocytes (CD3(+)/CD4(+), CD3(+)/CD8(+), CD3(+)/CD16(+)/CD56(+) T cells) under conditions of PHA-induced activation. Coculturing with mesenchymal stromal cells (MSC) led to a significant decrease in the ratio of lymphocytes carrying activation markers (CD3(+)/CD25(+) and CD3(+)/HLA-DR(+)) and increase in the number of CD3(+)/CD16(+)/CD56(+) T cells. The percent of activated HLA-DR(+) T cells in a heterotypic culture with MSC at 5% O(2) was much lower than that observed under normal conditions of culturing (20% O(2)). Our results suggest that antigen presentation by T lymphocytes due to HLA-DR expression can be reduced in the target tissues at low concentration of O(2), while the interaction between allogeneic MSC probably contributes to more significant inhibition of the immune response. PMID- 22451884 TI - Expression of a recombinant extracellular fragment of human vascular endothelial growth factor receptor VEGFR1 in E. coli. AB - Human vascular endothelium growth factor receptor VEGFR1 is a type III fms-like tyrosine kinase with weakly pronounced tyrosine kinase function. The second and third IgG-like domains of the extracellular part of VEGFR1 act as "traps" for VEGF and are prospective candidates for antiangiogenic therapy of VEGF-dependent tumors. cDNA encoding extracellular Ig-like domains 2, 3, 4 of VEGFR1 was cloned in expressing vectors pET28a, pET32a, and pQE60. The recombinant protein was expressed in E. coli cells and purified by metal affinity chromatography. An expressing construction and a superproducer strain were created, allowing the production of high amounts of recombinant VEGFR1 extracellular fragment, needed for experimental in vivo antiangiogenic therapy. PMID- 22451885 TI - Role sympathetic autonomic nervous system in the regulation of immune response during myasthenia. AB - In 12 patients with myasthenia, the content of beta(2)-adrenoreceptors on the cell surface and activity of intracellular lymphocytic enzymes were determined by EIA and biochemical methods, respectively. In comparison with the normal, these patients demonstrated pronounced elevation in the content of beta(2) adrenoreceptors and significant changes in activity of lymphocytic enzymes. In 10 of 12 patients, administration of the agonists to beta(2)-adrenoreceptors resulted in health improvement accompanied by normalization of EMG and immunobiochemical indices. Our findings suggest that intra- and intercellular signaling pathways and their modification can serve as potential targets for the therapy. PMID- 22451886 TI - Immune response during activation of pre- and postsynaptic serotonin 5-HT(1A) receptors in C57Bl/6J mice at various stages of a depression-like state. AB - The development of a depression-like state in C57Bl/6J mice with repeated defeat experience (10 and 20 days) was accompanied by inhibition of the immune response (evaluated from the number of IgM antibody-producing cells). Activation of postsynaptic 5-HT(1A) receptors with a selective agonist 8-OH-DPAT (1.0 mg/kg) in these animals had no effect on the immune reaction. In mice without the experience of confrontations, stimulation of postsynaptic receptors caused a decrease in the number of IgM antibody-producing cells at the peak of the immune response induced by sheep erythrocytes (5*10(8) cells). However, the count of these cells remained unchanged in mice with a depression-like state (irrespective of the stage of disorder). Activation of presynaptic 5-HT(1A) receptors with 8-OH DPAT (0.1 mg/kg) in control animals and mice with 10-day defeat experience was followed by immune stimulation. These changes were not observed in mice with a depression-like state caused by 20-day social stress. PMID- 22451887 TI - Matrix metalloproteinases 2, 7, and 9 in tumors and sera of patients with breast cancer. AB - Enzyme immunoassay showed that the content of matrix metalloproteinases (MMP) 2 and 7 in tumors was higher than in the adjacent histologically intact tissue in 91 and 76% patients with breast cancer, respectively, while MMP-9 levels in the tumor and intact tissue were virtually the same. Serum concentrations of MMP-2 and MMP-7 did not correlate with their levels in the tumors, were within the normal range, and virtually did not decrease after removal of the primary tumor. Serum levels of MMP-9 in patients were significantly lower than in the control and increased after surgery in 85% patients. No clear-cut relationship between the studied parameters and clinical morphological prognostic factors of breast cancer was detected. PMID- 22451888 TI - Melatonin and metformin inhibit skin carcinogenesis and lipid peroxidation induced by benz(a)pyrene in female mice. AB - Outbred female SHR mice (n=200) were divided at random into 4 groups, 50 per group. Benz(a)pyrene solution in acetone was applied onto a skin site on the back during 26 weeks. In parallel, the animals received melatonin, metformin, or both. Melatonin, metformin, and their combination promoted significant reduction of the number and size of skin tumors. In mice receiving no therapy, benz(a)pyrene applications increased the concentrations of malonic dialdehyde in the serum and skin tumor tissue in comparison with the concentrations in the sera and skin of intact mice. Melatonin, metformin, and their combination normalized LPO level. PMID- 22451889 TI - Peptide geroprotector from the pituitary gland inhibits rapid aging of elderly people: results of 15-year follow-up. AB - The paper presents the results of randomized comparative study of the efficiency of peptide geroprotector from the pituitary gland in elderly patients with rapidly aging cardiovascular system. Over three years 39 coronary patients received, in addition to basic therapy, regular courses of epithalamin (peptide drug), while 40 coronary patients (control group) received basic therapy alone. Long-term treatment with epithalamin (6 courses over 3 years) decelerated aging of the cardiovascular system, prevented age-associated impairment of physical endurance, normalized circadian rhythm of melatonin production and carbohydrate and lipid metabolism. A significantly lower mortality in the group of patients treated with epithalamin in parallel with basic therapy also indicated a geroprotective effect of the peptide preparation from the pineal gland. PMID- 22451890 TI - Blood level of osteonectin in stenosing atherosclerosis and calcinosis of coronary arteries. AB - Blood levels of stem cell marker proteins CD34 and osteonectin were studied in male patients with coronary atherosclerosis by direct biomagnetic separation of proteins with magnetic microspheres using the PureProteome Protein A and Protein G Magnetic Beads proteomic technology. High concentration of osteonectin in the blood was detected, particularly in men with stenosing atherosclerosis and coronary artery calcinosis. Blood osteonectin concentration correlated significantly with some key biomarkers of atherosclerosis and with stenosing atherosclerosis and calcinosis of coronary arteries. The results indicate that osteonectin as a marker of stromal stem cells with osteogenic potential presumably plays an important role in atherogenesis and can serve as a new biomarker of stenosing atherosclerosis and calcinosis of coronary arteries. PMID- 22451891 TI - Dynamics of hepatocyte proliferation in regenerating fetal rat liver. AB - We studied hepatocyte proliferation in the regenerating liver of 17-day fetuses of outbred albino rats. The animals were sacrificed every 3 h over 2 days after resection of 20% liver. The number of mitoses beyond the zone of injury increased sharply 12 and 24 h after resection. The hepatocyte mitotic index in the perifocal zone did not surpass the mitotic index in regions distant from the focus of injury during any of the studied periods. No circadian rhythm of hepatocyte mitotic activity was detected for resected or intact fetal liver. The injury caused virtually no changes in hepatocyte mitosis phase ratio in the operated compared to intact liver, which attested to stable course of mitosis. The weight of fetal liver recovered at the expense of enhanced mitotic activity of hepatocytes in the entire liver. PMID- 22451892 TI - Simple method of specimen preparation for scanning electron microscopy. AB - We compared conventional method for specimen (cell cultures, tissue specimens) preparation for scanning electron microscopy and a method without sputtering and critical-point drying. OTO-method (osmium-thiocarbohydrazide-osmium) with sample impregnation with hexamethyldisilazane followed by air drying was used as an alternative method. Excellent preservation of surface ultrastructures and electrical conductivity was proved. The method is easy to use and does not require additional costs for equipment. PMID- 22451893 TI - Label-free fluorescent assays based on aptamer-target recognition. AB - Label-free fluorescent assays were developed based on the competition of intramolecular DNA hybridization and aptamer-target binding. Using small molecule adenosine triphosphate (ATP) and biomacro-molecule thrombin as model targets, our design was proved to be a general method with good sensitivity and high selectivity. PMID- 22451894 TI - Pendant amine bases speed up proton transfers to metals by splitting the barriers. AB - By using density functional theory on [FeFe]-hydrogenase mimics we deconvolute the function of pendant amine bases in proton transfer to and from the metal center. By dividing the high free energy barrier into one high enthalpy-low entropy barrier and one with a low enthalpy-high entropy, a lower free energy barrier is reached. PMID- 22451895 TI - Inter-chain acyl transfer reaction in a peptide six-helical bundle: a chemical method for regulating the interaction between peptides or proteins. AB - An inter-helical acyl transfer specifically occurred between the C-and N-peptides of HIV gp41 after assembly of the six-helical bundle (6HB), forming an inter helical covalent bond that greatly enhanced 6HB stability. In the reaction, the C peptide was modified as an acyl donor, and the N-peptide served as an acyl acceptor. PMID- 22451897 TI - Molecular MRI enables early and sensitive detection of brain metastases. AB - Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 * 10(5) cells) than those volumes detectable clinically (10(7)-10(8) cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients. PMID- 22451898 TI - Evidence for a Peierls phase-transition in a three-dimensional multiple charge density waves solid. AB - The effect of dimensionality on materials properties has become strikingly evident with the recent discovery of graphene. Charge ordering phenomena can be induced in one dimension by periodic distortions of a material's crystal structure, termed Peierls ordering transition. Charge-density waves can also be induced in solids by strong coulomb repulsion between carriers, and at the extreme limit, Wigner predicted that crystallization itself can be induced in an electrons gas in free space close to the absolute zero of temperature. Similar phenomena are observed also in higher dimensions, but the microscopic description of the corresponding phase transition is often controversial, and remains an open field of research for fundamental physics. Here, we photoinduce the melting of the charge ordering in a complex three-dimensional solid and monitor the consequent charge redistribution by probing the optical response over a broad spectral range with ultrashort laser pulses. Although the photoinduced electronic temperature far exceeds the critical value, the charge-density wave is preserved until the lattice is sufficiently distorted to induce the phase transition. Combining this result with ab initio electronic structure calculations, we identified the Peierls origin of multiple charge-density waves in a three dimensional system for the first time. PMID- 22451899 TI - Single-molecule observation of helix staggering, sliding, and coiled coil misfolding. AB - The biological functions of coiled coils generally depend on efficient folding and perfect pairing of their alpha-helices. Dynamic changes in the helical registry that lead to staggered helices have only been proposed for a few special systems and not found in generic coiled coils. Here, we report our observations of multiple staggered helical structures of two canonical coiled coils. The partially folded structures are formed predominantly by coiled coil misfolding and occasionally by helix sliding. Using high-resolution optical tweezers, we characterized their energies and transition kinetics at a single-molecule level. The staggered states occur less than 2% of the time and about 0.1% of the time at zero force. We conclude that dynamic changes in helical registry may be a general property of coiled coils. Our findings should have broad and unique implications in functions and dysfunctions of proteins containing coiled coils. PMID- 22451900 TI - Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates. AB - Our understanding of the molecular control of many disease pathologies requires the identification of direct substrates targeted by specific protein kinases. Here we describe an integrated proteomic strategy, termed kinase assay linked with phosphoproteomics, which combines a sensitive kinase reaction with endogenous kinase-dependent phosphoproteomics to identify direct substrates of protein kinases. The unique in vitro kinase reaction is carried out in a highly efficient manner using a pool of peptides derived directly from cellular kinase substrates and then dephosphorylated as substrate candidates. The resulting newly phosphorylated peptides are then isolated and identified by mass spectrometry. A further comparison of these in vitro phosphorylated peptides with phosphopeptides derived from endogenous proteins isolated from cells in which the kinase is either active or inhibited reveals new candidate protein substrates. The kinase assay linked with phosphoproteomics strategy was applied to identify unique substrates of spleen tyrosine kinase (Syk), a protein-tyrosine kinase with duel properties of an oncogene and a tumor suppressor in distinctive cell types. We identified 64 and 23 direct substrates of Syk specific to B cells and breast cancer cells, respectively. Both known and unique substrates, including multiple centrosomal substrates for Syk, were identified, supporting a unique mechanism that Syk negatively affects cell division through its centrosomal kinase activity. PMID- 22451901 TI - Buckling-induced encapsulation of structured elastic shells under pressure. AB - We introduce a class of continuum shell structures, the Buckliball, which undergoes a structural transformation induced by buckling under pressure loading. The geometry of the Buckliball comprises a spherical shell patterned with a regular array of circular voids. In order for the pattern transformation to be induced by buckling, the possible number and arrangement of these voids are found to be restricted to five specific configurations. Below a critical internal pressure, the narrow ligaments between the voids buckle, leading to a cooperative buckling cascade of the skeleton of the ball. This ligament buckling leads to closure of the voids and a reduction of the total volume of the shell by up to 54%, while remaining spherical, thereby opening the possibility of encapsulation. We use a combination of precision desktop-scale experiments, finite element simulations, and scaling analyses to explore the underlying mechanics of these foldable structures, finding excellent qualitative and quantitative agreement. Given that this folding mechanism is induced by a mechanical instability, our Buckliball opens the possibility for reversible encapsulation, over a wide range of length scales. PMID- 22451902 TI - Resolving the complex role of enzyme conformational dynamics in catalytic function. AB - Despite growing evidence suggesting the importance of enzyme conformational dynamics (ECD) in catalysis, a consensus on how precisely ECD influences the chemical step and reaction rates is yet to be reached. Here, we characterize ECD in Cyclophilin A, a well-studied peptidyl-prolyl cis-trans isomerase, using normal and accelerated, atomistic molecular dynamics simulations. Kinetics and free energy landscape of the isomerization reaction in solution and enzyme are explored in unconstrained simulations by allowing significantly lower torsional barriers, but in no way compromising the atomistic description of the system or the explicit solvent. We reveal that the reaction dynamics is intricately coupled to enzymatic motions that span multiple timescales and the enzyme modes are selected based on the energy barrier of the chemical step. We show that Kramers' rate theory can be used to present a clear rationale of how ECD affects the reaction dynamics and catalytic rates. The effects of ECD can be incorporated into the effective diffusion coefficient, which we estimate to be about ten times slower in enzyme than in solution. ECD thereby alters the preexponential factor, effectively impeding the rate enhancement. From our analyses, the trend observed for lower torsional barriers can be extrapolated to actual isomerization barriers, allowing successful prediction of the speedup in rates in the presence of CypA, which is in notable agreement with experimental estimates. Our results further reaffirm transition state stabilization as the main effect in enhancing chemical rates and provide a unified view of ECD's role in catalysis from an atomistic perspective. PMID- 22451903 TI - Nonprocessive [2 + 2]e- off-loading reductase domains from mycobacterial nonribosomal peptide synthetases. AB - In mycobacteria, polyketide synthases and nonribosomal peptide synthetases (NRPSs) produce complex lipidic metabolites by using a thio-template mechanism of catalysis. In this study, we demonstrate that off-loading reductase (R) domain of mycobacterial NRPSs performs two consecutive [2 + 2]e(-) reductions to release thioester-bound lipopeptides as corresponding alcohols, using a nonprocessive mechanism of catalysis. The first crystal structure of an R domain from Mycobacterium tuberculosis NRPS provides strong support to this mechanistic model and suggests that the displacement of intermediate would be required for cofactor recycling. We show that 4e(-) reductases produce alcohols through a committed aldehyde intermediate, and the reduction of this intermediate is at least 10 times more efficient than the thioester-substrate. Structural and biochemical studies also provide evidence for the conformational changes associated with the reductive cycle. Further, we show that the large substrate-binding pocket with a hydrophobic platform accounts for the remarkable substrate promiscuity of these domains. Our studies present an elegant example of the recruitment of a canonical short-chain dehydrogenase/reductase family member as an off-loading domain in the context of assembly-line enzymology. PMID- 22451904 TI - Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1). AB - Calcium influx through the Ca(2+) release-activated Ca(2+) (CRAC) channel is an essential process in many types of cells. Upon store depletion, the calcium sensor in the endoplasmic reticulum, STIM1, activates Orai1, a CRAC channel in the plasma membrane. We have determined the structures of SOAR from Homo sapiens (hSOAR), which is part of STIM1 and is capable of constitutively activating Orai1, and the entire coiled coil region of STIM1 from Caenorhabditis elegans (ceSTIM1-CCR) in an inactive state. Our studies reveal that the formation of a SOAR dimer is necessary to activate the Orai1 channel. Mutations that disrupt SOAR dimerization or remove the cluster of positive residues abolish STIM1 activation of Orai1. We identified a possible inhibitory helix within the structure of ceSTIM1-CCR that tightly interacts with SOAR. Functional studies suggest that the inhibitory helix may keep the C-terminus of STIM1 in an inactive state. Our data allowed us to propose a model for STIM1 activation. PMID- 22451905 TI - RNA binding and RNA remodeling activities of the half-a-tetratricopeptide (HAT) protein HCF107 underlie its effects on gene expression. AB - The half-a-tetratricopeptide repeat (HAT) motif is a helical repeat motif found in proteins that influence various aspects of RNA metabolism, including rRNA biogenesis, RNA splicing, and polyadenylation. This functional association with RNA suggested that HAT repeat tracts might bind RNA. However, RNA binding activity has not been reported for any HAT repeat tract, and recent literature has emphasized a protein binding role. In this study, we show that a chloroplast localized HAT protein, HCF107, is a sequence-specific RNA binding protein. HCF107 consists of 11 tandem HAT repeats and short flanking regions that are also predicted to form helical hairpins. The minimal HCF107 binding site spans ~11 nt, consistent with the possibility that HAT repeats bind RNA through a modular one repeat-1 nt mechanism. Binding of HCF107 to its native RNA ligand in the psbH 5' UTR remodels local RNA structure and protects the adjacent RNA from exonucleases in vitro. These activities can account for the RNA stabilizing, RNA processing, and translational activation functions attributed to HCF107 based on genetic data. We suggest that analogous activities contribute to the functions of HAT domains found in ribonucleoprotein complexes in the nuclear-cytosolic compartment. PMID- 22451906 TI - miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes. AB - Human inducible nitric oxide synthase (hiNOS) gene expression is regulated by transcriptional and posttranscriptional mechanisms. The purpose of this study was to determine whether specific microRNA (miRNA) directly regulate hiNOS gene expression. Sequence analysis of the 496-bp hiNOS 3'-untranslated region (3'-UTR) revealed five putative miR-939 binding sites. The hiNOS 3'-UTR conferred significant posttranscriptional blockade of luciferase activity in human A549, HCT8, and HeLa cells. The hiNOS 3'-UTR also exerted basal and cytokine-stimulated posttranscriptional repression in an orientation-dependent manner. Functional studies demonstrated that transfection of miR-939 into primary human hepatocytes (HCs) significantly inhibited cytokine-induced NO synthesis in a dose-dependent manner that was abrogated by a specific miR-939 inhibitor. MiR-939 (but not other miRNAs) abolished cytokine-stimulated hiNOS protein in human HC, but had no effect on hiNOS mRNA levels. Site-directed mutagenesis of miR-939 bindings sites at +99 or +112 bp in the hiNOS 3'-UTR increased reporter gene expression. Furthermore, intact miR-939 binding sites at +99 or +112 positions were required for posttranscriptional suppression by miR-939. Cytokine stimulation directly increased miR-939 levels in human HC. Transfection of miR-939 inhibitor (antisense miR-939) enhanced cytokine-induced hiNOS protein and increased NO synthesis in vitro in human HC. Finally, cytokine or LPS injection in vivo in mice increased hepatic miR-939 levels. Taken together, these data identify that miR-939 directly regulates hiNOS gene expression by binding in the 3'-UTR to produce a translational blockade. These findings suggest dual regulation of iNOS gene expression where cytokines induce iNOS transcription and also increase miR 939, leading to translational inhibition in a check-and-balance system. PMID- 22451907 TI - Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter. AB - Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylation-deficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases. PMID- 22451908 TI - Cyanobacteria produce a high variety of hepatotoxic peptides in lichen symbiosis. AB - Lichens are symbiotic associations between fungi and photosynthetic algae or cyanobacteria. Microcystins are potent toxins that are responsible for the poisoning of both humans and animals. These toxins are mainly associated with aquatic cyanobacterial blooms, but here we show that the cyanobacterial symbionts of terrestrial lichens from all over the world commonly produce microcystins. We screened 803 lichen specimens from five different continents for cyanobacterial toxins by amplifying a part of the gene cluster encoding the enzyme complex responsible for microcystin production and detecting toxins directly from lichen thalli. We found either the biosynthetic genes for making microcystins or the toxin itself in 12% of all analyzed lichen specimens. A plethora of different microcystins was found with over 50 chemical variants, and many of the variants detected have only rarely been reported from free-living cyanobacteria. In addition, high amounts of nodularin, up to 60 MUg g(-1), were detected from some lichen thalli. This microcystin analog and potent hepatotoxin has previously been known only from the aquatic bloom-forming genus Nodularia. Our results demonstrate that the production of cyanobacterial hepatotoxins in lichen symbiosis is a global phenomenon and occurs in many different lichen lineages. The very high genetic diversity of the mcyE gene and the chemical diversity of microcystins suggest that lichen symbioses may have been an important environment for diversification of these cyanobacteria. PMID- 22451909 TI - Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. AB - Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening. PMID- 22451910 TI - An essential bacterial-type cardiolipin synthase mediates cardiolipin formation in a eukaryote. AB - Cardiolipin is important for bacterial and mitochondrial stability and function. The final step in cardiolipin biosynthesis is catalyzed by cardiolipin synthase and differs mechanistically between prokaryotes and eukaryotes. To study the importance of cardiolipin synthesis for mitochondrial integrity, membrane protein complex formation, and cell proliferation in the human and animal pathogenic protozoan parasite, Trypanosoma brucei, we generated conditional cardiolipin synthase-knockout parasites. We found that cardiolipin formation in T. brucei procyclic forms is catalyzed by a bacterial-type cardiolipin synthase, providing experimental evidence for a prokaryotic-type cardiolipin synthase in a eukaryotic organism. Ablation of enzyme expression resulted in inhibition of de novo cardiolipin synthesis, reduction in cellular cardiolipin levels, alterations in mitochondrial morphology and function, and parasite death in culture. By using immunofluorescence microscopy and blue-native gel electrophoresis, cardiolipin synthase was shown to colocalize with inner mitochondrial membrane proteins and to be part of a large protein complex. During depletion of cardiolipin synthase, the levels of cytochrome oxidase subunit IV and cytochrome c1, reflecting mitochondrial respiratory complexes IV and III, respectively, decreased progressively. PMID- 22451911 TI - U7 small nuclear ribonucleoprotein represses histone gene transcription in cell cycle-arrested cells. AB - Histone gene expression is tightly coordinated with DNA replication, as it is activated at the onset of S phase and suppressed at the end of S phase. Replication-dependent histone gene expression is precisely controlled at both transcriptional and posttranscriptional levels. U7 small nuclear ribonucleoprotein (U7 snRNP) is involved in the 3'-end processing of nonpolyadenylated histone mRNAs, which is required for S phase-specific gene expression. The present study reports a unique function of U7 snRNP in the repression of histone gene transcription under cell cycle-arrested conditions. Elimination of U7 snRNA with an antisense oligonucleotide in HeLa cells as well as in nontransformed human lung fibroblasts resulted in elevated levels of replication-dependent H1, H2A, H2B, H3, and H4 histone mRNAs but not of replication-independent H3F3B histone mRNA. An analogous effect was observed upon depletion of Lsm10, a component of the U7 snRNP-specific Sm ring, with siRNA. Pulse-chase experiments revealed that U7 snRNP acts to repress transcription without remarkably altering mRNA stability. Mass spectrometric analysis of the captured U7 snRNP from HeLa cell extracts identified heterogeneous nuclear (hn)RNP UL1 as a U7 snRNP interaction partner. Further knockdown and overexpression experiments revealed that hnRNP UL1 is responsible for U7 snRNP dependent transcriptional repression of replication-dependent histone genes. Chromatin immunoprecipitation confirmed that hnRNP UL1 is recruited to the histone gene locus only when U7 snRNP is present. These findings support a unique mechanism of snRNP-mediated transcriptional control that restricts histone synthesis to S phase, thereby preventing the potentially toxic effects of histone synthesis at other times in the cell cycle. PMID- 22451912 TI - PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas. AB - Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (~40%) and/or mutations disrupting autoregulation (~16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6 associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas. PMID- 22451913 TI - The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. AB - CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPalpha, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies. PMID- 22451914 TI - Optimal portfolio design to reduce climate-related conservation uncertainty in the Prairie Pothole Region. AB - Climate change is likely to alter the spatial distributions of species and habitat types but the nature of such change is uncertain. Thus, climate change makes it difficult to implement standard conservation planning paradigms. Previous work has suggested some approaches to cope with such uncertainty but has not harnessed all of the benefits of risk diversification. We adapt Modern Portfolio Theory (MPT) to optimal spatial targeting of conservation activity, using wetland habitat conservation in the Prairie Pothole Region (PPR) as an example. This approach finds the allocations of conservation activity among subregions of the planning area that maximize the expected conservation returns for a given level of uncertainty or minimize uncertainty for a given expected level of returns. We find that using MPT instead of simple diversification in the PPR can achieve a value of the conservation objective per dollar spent that is 15% higher for the same level of risk. MPT-based portfolios can also have 21% less uncertainty over benefits or 6% greater expected benefits than the current portfolio of PPR conservation. Total benefits from conservation investment are higher if returns are defined in terms of benefit-cost ratios rather than benefits alone. MPT-guided diversification can work to reduce the climate-change induced uncertainty of future ecosystem-service benefits from many land policy and investment initiatives, especially when outcomes are negatively correlated between subregions of a planning area. PMID- 22451915 TI - Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation. AB - Exposure and/or sensitivity to stress have been implicated as conferring risk for development of Alzheimer's disease (AD). Although the basis for such a link remains unclear, we previously reported differential involvement of corticotropin releasing factor receptor (CRFR) 1 and 2 in acute stress-induced tau phosphorylation (tau-P) and solubility in the hippocampus. Here we examined the role of CRFRs in tau-P induced by repeated stress and the structural manifestations of altered tau solubility. Robust tau-P responses were seen in WT and CRFR2 null mice exposed to repeated stress, which were sustained at even 24 h after the final stress exposure. A portion of phosphorylated tau in these mice was sequestered in detergent-soluble cellular fractions. In contrast, CRFR1 and CRFR double-KO mice did not exhibit repeated stress-induced alterations in tau-P or solubility. Similarly, treatment with CRFR1 antagonist attenuated repeated stress-induced tau-P. Using histochemical approaches in a transgenic CRFR1 reporter mouse line, we found substantial overlap between hippocampal CRFR1 expression and cells positive for phosphorylated tau after exposure to repeated stress. Ultrastructural analysis of negatively stained extracts from WT and CRFR2 null mice identified globular aggregates that displayed positive immunogold labeling for tau-P, as well as conformational changes in tau (MC1) seen in early AD. Given that repeated stress exposure results in chronic increases in hippocampal tau-P and its sequestration in an insoluble (and potentially prepathogenic) form, our data may define a link between stress and an AD-related pathogenic mechanism. PMID- 22451916 TI - Action potential propagation in transverse-axial tubular system is impaired in heart failure. AB - The plasma membrane of cardiac myocytes presents complex invaginations known as the transverse-axial tubular system (TATS). Despite TATS's crucial role in excitation-contraction coupling and morphological alterations found in pathological settings, TATS's electrical activity has never been directly investigated in remodeled tubular networks. Here we develop an ultrafast random access multiphoton microscope that, in combination with a customly synthesized voltage-sensitive dye, is used to simultaneously measure action potentials (APs) at multiple sites within the sarcolemma with submillisecond temporal and submicrometer spatial resolution in real time. We find that the tight electrical coupling between different sarcolemmal domains is guaranteed only within an intact tubular system. In fact, acute detachment by osmotic shock of most tubules from the surface sarcolemma prevents AP propagation not only in the disconnected tubules, but also in some of the tubules that remain connected with the surface. This indicates that a structural disorganization of the tubular system worsens the electrical coupling between the TATS and the surface. The pathological implications of this finding are investigated in failing hearts. We find that AP propagation into the pathologically remodeled TATS frequently fails and may be followed by local spontaneous electrical activity. Our findings provide insight on the relationship between abnormal TATS and asynchronous calcium release, a major determinant of cardiac contractile dysfunction and arrhythmias. PMID- 22451917 TI - Hierarchical clustering of brain activity during human nonrapid eye movement sleep. AB - Consciousness is reduced during nonrapid eye movement (NREM) sleep due to changes in brain function that are still poorly understood. Here, we tested the hypothesis that impaired consciousness during NREM sleep is associated with an increased modularity of brain activity. Cerebral connectivity was quantified in resting-state functional magnetic resonance imaging times series acquired in 13 healthy volunteers during wakefulness and NREM sleep. The analysis revealed a modification of the hierarchical organization of large-scale networks into smaller independent modules during NREM sleep, independently from EEG markers of the slow oscillation. Such modifications in brain connectivity, possibly driven by sleep ultraslow oscillations, could hinder the brain's ability to integrate information and account for decreased consciousness during NREM sleep. PMID- 22451918 TI - Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability. AB - Mutations in Drosophila merry-go-round (mgr) have been known for over two decades to lead to circular mitotic figures and loss of meiotic spindle integrity. However, the identity of its gene product has remained undiscovered. We now show that mgr encodes the Prefoldin subunit counterpart of human von Hippel Lindau binding-protein 1. Depletion of Mgr from cultured cells also leads to formation of monopolar and abnormal spindles and centrosome loss. These phenotypes are associated with reductions of tubulin levels in both mgr flies and mgr RNAi treated cultured cells. Moreover, mgr spindle defects can be phenocopied by depleting beta-tubulin, suggesting Mgr function is required for tubulin stability. Instability of beta-tubulin in the mgr larval brain is less pronounced than in either mgr testes or in cultured cells. However, expression of transgenic beta-tubulin in the larval brain leads to increased tubulin instability, indicating that Prefoldin might only be required when tubulins are synthesized at high levels. Mgr interacts with Drosophila von Hippel Lindau protein (Vhl). Both proteins interact with unpolymerized tubulins, suggesting they cooperate in regulating tubulin functions. Accordingly, codepletion of Vhl with Mgr gives partial rescue of tubulin instability, monopolar spindle formation, and loss of centrosomes, leading us to propose a requirement for Vhl to promote degradation of incorrectly folded tubulin in the absence of functional Prefoldin. Thus, Vhl may play a pivotal role: promoting microtubule stabilization when tubulins are correctly folded by Prefoldin and tubulin destruction when they are not. PMID- 22451919 TI - Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. AB - Antibodies against CD47, which block tumor cell CD47 interactions with macrophage signal regulatory protein-alpha, have been shown to decrease tumor size in hematological and epithelial tumor models by interfering with the protection from phagocytosis by macrophages that intact CD47 bestows upon tumor cells. Leiomyosarcoma (LMS) is a tumor of smooth muscle that can express varying levels of colony-stimulating factor-1 (CSF1), the expression of which correlates with the numbers of tumor-associated macrophages (TAMs) that are found in these tumors. We have previously shown that the presence of TAMs in LMS is associated with poor clinical outcome and the overall effect of TAMs in LMS therefore appears to be protumorigenic. However, the use of inhibitory antibodies against CD47 offers an opportunity to turn TAMs against LMS cells by allowing the phagocytic behavior of resident macrophages to predominate. Here we show that interference with CD47 increases phagocytosis of two human LMS cell lines, LMS04 and LMS05, in vitro. In addition, treatment of mice bearing subcutaneous LMS04 and LMS05 tumors with a novel, humanized anti-CD47 antibody resulted in significant reductions in tumor size. Mice bearing LMS04 tumors develop large numbers of lymph node and lung metastases. In a unique model for neoadjuvant treatment, mice were treated with anti-CD47 antibody starting 1 wk before resection of established primary tumors and subsequently showed a striking decrease in the size and number of metastases. These data suggest that treatment with anti-CD47 antibodies not only reduces primary tumor size but can also be used to inhibit the development of, or to eliminate, metastatic disease. PMID- 22451920 TI - Dichotomous effects of VEGF-A on adipose tissue dysfunction. AB - Obese fat pads are frequently undervascularized and hypoxic, leading to increased fibrosis, inflammation, and ultimately insulin resistance. We hypothesized that VEGF-A-induced stimulation of angiogenesis enables sustained and sufficient oxygen and nutrient exchange during fat mass expansion, thereby improving adipose tissue function. Using a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpression model, we demonstrate that the local up-regulation of VEGF-A in adipocytes improves vascularization and causes a "browning" of white adipose tissue (AT), with massive up-regulation of UCP1 and PGC1alpha. This is associated with an increase in energy expenditure and resistance to high fat diet-mediated metabolic insults. Similarly, inhibition of VEGF-A-induced activation of VEGFR2 during the early phase of high fat diet-induced weight gain, causes aggravated systemic insulin resistance. However, the same VEGF-A-VEGFR2 blockade in ob/ob mice leads to a reduced body-weight gain, an improvement in insulin sensitivity, a decrease in inflammatory factors, and increased incidence of adipocyte death. The consequences of modulation of angiogenic activity are therefore context dependent. Proangiogenic activity during adipose tissue expansion is beneficial, associated with potent protective effects on metabolism, whereas antiangiogenic action in the context of preexisting adipose tissue dysfunction leads to improvements in metabolism, an effect likely mediated by the ablation of dysfunctional proinflammatory adipocytes. PMID- 22451921 TI - Histone H3R17me2a mark recruits human RNA polymerase-associated factor 1 complex to activate transcription. AB - The histone coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for a number of transcription factors, including nuclear receptors. Although CARM1 and its asymmetrically deposited dimethylation at histone H3 arginine 17 (H3R17me2a) are associated with transcription activation, the mechanism by which CARM1 activates transcription remains unclear. Using an unbiased biochemical approach, we discovered that the transcription elongation associated PAF1 complex (PAF1c) directly interacts with H3R17me2a. PAF1c binds to histone H3 tails harboring dimethylation at R17 in CARM1-methylated histone octamers. Knockdown of either PAF1c subunits or CARM1 affected transcription of CARM1-regulated, estrogen-responsive genes. Furthermore, either CARM1 knockdown or CARM1 enzyme-deficient mutant knockin resulted in decreased H3R17me2a accompanied by the reduction of PAF1c occupancy at the proximal promoter estrogen responsive elements. In contrast, PAF1c knockdown elicited no effects on H3R17me2a but reduced the H3K4me3 level at estrogen-responsive elements. These observations suggest that, apart from PAF1c's established roles in directing histone modifications, PAF1c acts as an arginine methyl histone effector that is recruited to promoters and activates a subset of genes, including targets of estrogen signaling. PMID- 22451922 TI - Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. AB - MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca(2+) it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. The MUC2-N aggregates were dissolved by removing Ca(2+) and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion. PMID- 22451923 TI - Mutagenesis of pairwise combinations of histone amino-terminal tails reveals functional redundancy in budding yeast. AB - A large body of literature provides compelling evidence for the role of evolutionarily conserved core histone residues in various biological processes. However, site-directed mutagenesis of individual residues that are known to be sites of posttranslational modifications often does not result in clear phenotypic defects. In some cases, the combination of multiple mutations can give rise to stronger phenotypes, implying functional redundancy between distinct residues on histones. Here, we examined the "histone redundancy hypothesis" by characterizing double deletion of all pairwise combinations of amino-terminal tails (N-tails) from the four core histones encoded in budding yeast. First, we found that multiple lysine residues on the N-tails of both H2A and H4 are redundantly involved in cell viability. Second, simultaneous deletion of N-tails from H2A and H3 leads to a severe growth defect, which is correlated with perturbed gross chromatin structure in the mutant cells. Finally, by combining point mutations on H3 with deletion of the H2A N-tail, we revealed a redundant role for lysine 4 on H3 and the H2A N-tail in hydroxyurea-mediated response. Altogether, these data suggest that the N-tails of core histones share previously unrecognized, potentially redundant functions that, in some cases are different from those of the widely accepted H2A/H2B and H3/H4 dimer pairs. PMID- 22451924 TI - Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation. AB - To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apc(min/+) genetic background. Here, we show that Apc(min/+)/Tpl2(-/-) mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2(-/-) mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2. The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and inflammation increased progressively with time. The rate of increase of both, however, was more rapid in Apc(min/+)/Tpl2(-/-) mice, suggesting that the positive feedback initiated by inflammatory signals originating in developing polyps is more robust in these mice. This may be because these mice have a higher intestinal polyp burden as a result of the enhancement of tumor initiation. PMID- 22451925 TI - Induced fit on heme binding to the Pseudomonas aeruginosa cytoplasmic protein (PhuS) drives interaction with heme oxygenase (HemO). AB - Iron, an essential nutrient with limited bioavailability, requires specialized cellular mechanisms for uptake. Although iron uptake into the cytoplasm in the form of heme has been well characterized in many bacteria, the subsequent trafficking is poorly understood. The cytoplasmic heme-binding proteins belong to a structurally related family thought to have evolved as "induced fit" ligand binding macromolecules. One member, Pseudomonas aeruginosa cytoplasmic protein (PhuS), has previously been shown to be important for delivering heme to the iron regulated heme oxygenase (HemO). Spectroscopic investigations of the holo-PhuS complex revealed a dynamic heme environment with overlapping but distinct heme binding sites with alternative coordinating heme ligands, His-209 or His-212. In the present work we establish a mechanism for how heme is transferred from PhuS to its partner, HemO. Using surface plasmon resonance and isothermal titration calorimetry, we have discovered that holo-PhuS, but not apo-PhuS, forms a 1:1 complex with HemO. Sedimentation velocity and limited proteolysis experiments suggest that heme binding to PhuS induces a conformational rearrangement that drives the protein interaction with HemO. Hydrodynamic analysis reveals that the holo-PhuS displays a more expanded hydrodynamic envelope compared with apo-PhuS, and we propose that this conformational change drives the interaction with HemO. We further demonstrate that replacement of His-212 by Ala disrupts the interaction of holo-PhuS with HemO; in contrast, the His-209-Ala variant can still complex with HemO, albeit more weakly. Together, the present studies reveal a mechanism that couples a heme-dependent conformational switch in PhuS to protein-protein interaction, the subsequent free energy of which drives heme release to HemO. PMID- 22451926 TI - CHD3 protein recognizes and regulates methylated histone H3 lysines 4 and 27 over a subset of targets in the rice genome. AB - Histone lysine methylation is an important component of the epigenetic system demarcating transcriptionally active and inactive chromatin domains. It is of primary importance in understanding how different histone lysine methylation marks and a specific combination of them are read and interpreted by chromatin proteins to regulate gene expression. In this paper, we report that the rice CHD3 protein CHR729 that was required for many aspects of plant development can interact with dimethylated histone H3 lysine 4 (H3K4me2, a mark associated with moderately expressed or repressed genes) and with trimethylated histone H3 lysine 27 (H3K27me3, a mark associated with repressed genes), respectively, through the chromodomains and the plant homeodomain (PHD) finger of the protein. A mutation or down-regulation of the gene provoked a decrease of H3K27me3 and H3K4me3 (a mark associated with active genes). Genome-wide analysis revealed that H3K27me3 and H3K4me3, respectively, were lost from about 56 and 23% of marked loci, which correspond mostly to under-expressed or repressed genes. In the mutant, a higher than-expected proportion of down-regulated genes lost H3K4me3, among which many encode DNA-binding transcription factors. These results suggest that the rice CHD3 protein is a bifunctional chromatin regulator able to recognize and modulate H3K4 and H3K27 methylation over repressed or tissue-specific genes, which may be associated with regulation of a gene transcription program of plant development. PMID- 22451927 TI - Role of the translationally controlled tumor protein in DNA damage sensing and repair. AB - The translationally controlled tumor protein (TCTP) is essential for survival by mechanisms that as yet are incompletely defined. Here we describe an important role of TCTP in response to DNA damage. Upon exposure of normal human cells to low-dose gamma rays, the TCTP protein level was greatly increased, with a significant enrichment in nuclei. TCTP up-regulation occurred in a manner dependent on ataxia-telangiectasia mutated (ATM) kinase and the DNA-dependent protein kinase and was associated with protective effects against DNA damage. In chromatin of irradiated cells, coimmunoprecipitation experiments showed that TCTP forms a complex with ATM and gammaH2A.X, in agreement with its distinct localization with the foci of the DNA damage-marker proteins gammaH2A.X, 53BP1, and P-ATM. In cells lacking TCTP, repair of chromosomal damage induced by gamma rays was compromised significantly. TCTP also was shown to interact with p53 and the DNA-binding subunits, Ku70 and Ku80, of DNA-dependent protein kinase. TCTP knockdown led to decreased levels of Ku70 and Ku80 in nuclei of irradiated cells and attenuated their DNA-binding activity. It also attenuated the radiation induced G(1) delay but prolonged the G(2) delay. TCTP therefore may play a critical role in maintaining genomic integrity in response to DNA-damaging agents. PMID- 22451928 TI - Designing orthogonal signaling pathways: how to fit in with the surroundings. PMID- 22451929 TI - Decade-long bacterial community dynamics in cystic fibrosis airways. AB - The structure and dynamics of bacterial communities in the airways of persons with cystic fibrosis (CF) remain largely unknown. We characterized the bacterial communities in 126 sputum samples representing serial collections spanning 8-9 y from six age-matched male CF patients. Sputum DNA was analyzed by bar-coded pyrosequencing of the V3-V5 hypervariable region of the 16S rRNA gene, defining 662 operational taxonomic units (OTUs) from >633,000 sequences. Bacterial community diversity decreased significantly over time in patients with typically progressive lung disease but remained relatively stable in patients with a mild lung disease phenotype. Antibiotic use, rather than patient age or lung function, was the primary driver of decreasing diversity. Interpatient variability in community structure exceeded intrapatient variability in serial samples. Antibiotic treatment was associated with pronounced shifts in community structure, but communities showed both short- and long-term resilience after antibiotic perturbation. There was a positive correlation between OTU occurrence and relative abundance, with a small number of persistent OTUs accounting for the greatest abundance. Significant changes in community structure, diversity, or total bacterial density at the time of pulmonary exacerbation were not observed. Despite decreasing community diversity in patients with progressive disease, total bacterial density remained relatively stable over time. These findings show the critical relationship between airway bacterial community structure, disease stage, and clinical state at the time of sample collection. These features are the key parameters with which to assess the complex ecology of the CF airway. PMID- 22451930 TI - Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating. AB - Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerstrom Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score >= 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia. PMID- 22451931 TI - Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis. AB - During apoptosis, hundreds of proteins are cleaved by caspases, most of them by the executioner caspase-3. However, caspase-7, which shares the same substrate primary sequence preference as caspase-3, is better at cleaving poly(ADP ribose) polymerase 1 (PARP) and Hsp90 cochaperone p23, despite a lower intrinsic activity. Here, we identified key lysine residues (K(38)KKK) within the N terminal domain of caspase-7 as critical elements for the efficient proteolysis of these two substrates. Caspase-7's N-terminal domain binds PARP and improves its cleavage by a chimeric caspase-3 by ~30-fold. Cellular expression of caspase 7 lacking the critical lysine residues resulted in less-efficient PARP and p23 cleavage compared with cells expressing the wild-type peptidase. We further showed, using a series of caspase chimeras, the positioning of p23 on the enzyme providing us with a mechanistic insight into the binding of the exosite. In summary, we have uncovered a role for the N-terminal domain (NTD) and the N terminal peptide of caspase-7 in promoting key substrate proteolysis. PMID- 22451933 TI - Sex, puberty, and the timing of sleep EEG measured adolescent brain maturation. AB - The steep adolescent decline in the slow wave (delta, 1-4 Hz) electroencephalogram (EEG) of nonrapid eye movement (NREM) sleep is a dramatic maturational change in brain electrophysiology thought to be driven by cortical synaptic pruning. A perennial question is whether this change in brain electrophysiology is related to sexual maturation. Applying Gompertz growth models to longitudinal data spanning ages 9-18 y, we found that the timing of the delta decline was significantly (P < 0.0001) linked to timing of pubertal maturation. This timing relation remained significant when sex differences in the timing of the delta decline were statistically controlled. Sex differences and the relation to the timing of puberty jointly explained 67% of the between subject variance in the timing of the delta decline. These data provide a demonstration of a temporal relation between puberty and an electrophysiological marker of adolescent brain development. They can guide research into whether the neuroendocrine events of puberty are mechanistically linked to cortical maturation or whether, instead, the two maturational processes are parallel but independent programs of human ontogenesis. PMID- 22451932 TI - Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. AB - The HIV-1 envelope (Env) spike (gp120(3)/gp41(3)) undergoes considerable structural rearrangements to mediate virus entry into cells and to evade the host immune response. Engagement of CD4, the primary human receptor, fixes a particular conformation and primes Env for entry. The CD4-bound state, however, is prone to spontaneous inactivation and susceptible to antibody neutralization. How does unliganded HIV-1 maintain CD4-binding capacity and regulate transitions to the CD4-bound state? To define this mechanistically, we determined crystal structures of unliganded core gp120 from HIV-1 clades B, C, and E. Notably, all of these unliganded HIV-1 structures resembled the CD4-bound state. Conformational fixation with ligand selection and thermodynamic analysis of full length and core gp120 interactions revealed that the tendency of HIV-1 gp120 to adopt the CD4-bound conformation was restrained by the V1/V2- and V3-variable loops. In parallel, we determined the structure of core gp120 in complex with the small molecule, NBD-556, which specifically recognizes the CD4-bound conformation of gp120. Neutralization by NBD-556 indicated that Env spikes on primary isolates rarely assume the CD4-bound conformation spontaneously, although they could do so when quaternary restraints were loosened. Together, the results suggest that the CD4-bound conformation represents a "ground state" for the gp120 core, with variable loop and quaternary interactions restraining unliganded gp120 from "snapping" into this conformation. A mechanism of control involving deformations in unliganded structure from a functionally critical state (e.g., the CD4-bound state) provides advantages in terms of HIV-1 Env structural diversity and resistance to antibodies and inhibitors, while maintaining elements essential for entry. PMID- 22451934 TI - Ni(II) coordination to mixed sites modulates DNA binding of HpNikR via a long range effect. AB - Helicobacter pylori NikR (HpNikR) is a nickel-dependent transcription factor that regulates multiple genes in the H. pylori pathogen. There are conflicting data regarding the locations of the Ni(II) sites and the role of Ni(II) coordination in DNA recognition. Herein, we report crystal structures of (i) the metal-binding domain (MBD) of HpNikR (3.08 A) and (ii) a mutant, H74A (2.04 A), designed to disrupt native Ni(II) coordination. In the MBD structure, four nickel ions are coordinated to two different types of nickel sites (4-coordinate, square planar, and 5/6-coordinate, square pyramidal/octahedral). In the H74A structure, all four nickel ions are coordinated to 4-coordinate square-planar sites. DNA-binding studies reveal tighter binding for target DNA sequences for holo-HpNikR compared with the affinities of Ni(II) reconstituted apo-HpNikR and H74A for these same DNA targets, supporting a role for Ni(II) coordination to 5/6 sites in DNA recognition. Small-angle X-ray scattering studies of holo-HpNikR and H74A reveal a high degree of conformational flexibility centered at the DNA-binding domains of H74A, which is consistent with disorder observed in the crystal structure of the protein. A model of DNA recognition by HpNikR is proposed in which Ni(II) coordination to specific sites in the MBD have a long-range effect on the flexibility of the DNA-binding domains and, consequently, the DNA recognition properties. PMID- 22451935 TI - Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1. AB - To ensure genome stability, DNA must be replicated once and only once during each cell cycle. Cdt1 is tightly regulated to make sure that cells do not rereplicate their DNA. Multiple regulatory mechanisms operate to ensure degradation of Cdt1 in S phase. However, little is known about the positive regulators of Cdt1 under physiological conditions. Here we identify FOXO3 as a binding partner of Cdt1. FOXO3 forms a protein complex with Cdt1, which in turn blocks its interaction with DDB1 and PCNA. Conversely, FOXO3 depletion facilitated the proteolysis of Cdt1 in unperturbed cells. Intriguingly, FOXO3 deficiency resulted in impaired S phase entry and reduced cell proliferation. We provide data that FOXO3 knockdown mimics Cdt1 down-regulation and affects G1/S transitions. Our results demonstrate a unique role of FOXO3 in binding to Cdt1 and maintaining its level required for cell cycle progression. PMID- 22451936 TI - Loss of DNA methylation affects the recombination landscape in Arabidopsis. AB - During sexual reproduction, one-half of the genetic material is deposited in gametes, and a complete set of chromosomes is restored upon fertilization. Reduction of the genetic information before gametogenesis occurs in meiosis, when cross-overs (COs) between homologous chromosomes secure an exchange of their genetic information. COs are not evenly distributed along chromosomes and are suppressed in chromosomal regions encompassing compact, hypermethylated centromeric and pericentromeric DNA. Therefore, it was postulated that DNA hypermethylation is inhibitory to COs. Here, when analyzing meiotic recombination in mutant plants with hypomethylated DNA, we observed unexpected and counterintuitive effects of DNA methylation losses on CO distribution. Recombination was further promoted in the hypomethylated chromosome arms while it was inhibited in heterochromatic regions encompassing pericentromeric DNA. Importantly, the total number of COs was not affected, implying that loss of DNA methylation led to a global redistribution of COs along chromosomes. To determine by which mechanisms altered levels of DNA methylation influence recombination- whether directly in cis or indirectly in trans by changing expression of genes encoding recombination components--we analyzed CO distribution in wild-type lines with randomly scattered and well-mapped hypomethylated chromosomal segments. The results of these experiments, supported by expression profiling data, suggest that DNA methylation affects meiotic recombination in cis. Because DNA methylation exhibits significant variation even within a single species, our results imply that it may influence the evolution of plant genomes through the control of meiotic recombination. PMID- 22451937 TI - Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. AB - AcrAB-TolC is the major efflux protein complex in Escherichia coli extruding a vast variety of antimicrobial agents from the cell. The inner membrane component AcrB is a homotrimer, and it has been postulated that the monomers cycle consecutively through three conformational stages designated loose (L), tight (T), and open (O) in a concerted fashion. Binding of drugs has been shown at a periplasmic deep binding pocket in the T conformation. The initial drug-binding step and transport toward this drug-binding site has been elusive thus far. Here we report high resolution structures (1.9-2.25 A) of AcrB/designed ankyrin repeat protein (DARPin) complexes with bound minocycline or doxorubicin. In the AcrB/doxorubicin cocrystal structure, binding of three doxorubicin molecules is apparent, with one doxorubicin molecule bound in the deep binding pocket of the T monomer and two doxorubicin molecules in a stacked sandwich arrangement in an access pocket at the lateral periplasmic cleft of the L monomer. This access pocket is separated from the deep binding pocket apparent in the T monomer by a switch-loop. The localization and conformational flexibility of this loop seems to be important for large substrates, because a G616N AcrB variant deficient in macrolide transport exhibits an altered conformation within this loop region. Transport seems to be a stepwise process of initial drug uptake in the access pocket of the L monomer and subsequent accommodation of the drug in the deep binding pocket during the L to T transition to the internal deep binding pocket of the T monomer. PMID- 22451938 TI - Mixotrophic basis of Atlantic oligotrophic ecosystems. AB - Oligotrophic subtropical gyres are the largest oceanic ecosystems, covering >40% of the Earth's surface. Unicellular cyanobacteria and the smallest algae (plastidic protists) dominate CO(2) fixation in these ecosystems, competing for dissolved inorganic nutrients. Here we present direct evidence from the surface mixed layer of the subtropical gyres and adjacent equatorial and temperate regions of the Atlantic Ocean, collected on three Atlantic Meridional Transect cruises on consecutive years, that bacterioplankton are fed on by plastidic and aplastidic protists at comparable rates. Rates of bacterivory were similar in the light and dark. Furthermore, because of their higher abundance, it is the plastidic protists, rather than the aplastidic forms, that control bacterivory in these waters. These findings change our basic understanding of food web function in the open ocean, because plastidic protists should now be considered as the main bacterivores as well as the main CO(2) fixers in the oligotrophic gyres. PMID- 22451939 TI - Superoxide dismutase is dispensable for normal animal lifespan. AB - Reactive oxygen species (ROS) are toxic oxygen-containing molecules that can damage multiple components of the cell and have been proposed to be the primary cause of aging. The antioxidant enzyme superoxide dismutase (SOD) is the only eukaryotic enzyme capable of detoxifying superoxide, one type of ROS. The fact that SOD is present in all aerobic organisms raises the question as to whether SOD is absolutely required for animal life and whether the loss of SOD activity will result in decreased lifespan. Here we use the genetic model organism Caenorhabditis elegans to generate an animal that completely lacks SOD activity (sod-12345 worms). We show that sod-12345 worms are viable and exhibit a normal lifespan, despite markedly increased sensitivity to multiple stresses. This is in stark contrast to what is observed in other genetic model organisms where the loss of a single sod gene can result in severely decreased survival. Investigating the mechanism underlying the normal lifespan of sod-12345 worms reveals that their longevity results from a balance between the prosurvival signaling and the toxicity of superoxide. Overall, our results demonstrate that SOD activity is dispensable for normal animal lifespan but is required to survive acute stresses. Moreover, our findings indicate that maintaining normal stress resistance is not crucial to the rate of aging. PMID- 22451940 TI - Interaction with plant transcription factors can mediate nuclear import of phytochrome B. AB - Phytochromes (phy) are red/far-red-absorbing photoreceptors that regulate the adaption of plant growth and development to changes in ambient light conditions. The nuclear transport of the phytochromes upon light activation is regarded as a key step in phytochrome signaling. Although nuclear import of phyA is regulated by the transport facilitators far red elongated hypocotyl 1 (FHY1) and fhy1-like, an intrinsic nuclear localization signal was proposed to be involved in the nuclear accumulation of phyB. We recently showed that nuclear import of phytochromes can be analyzed in a cell-free system consisting of isolated nuclei of the unicellular green algae Acetabularia acetabulum. We now show that this system is also versatile to elucidate the mechanism of the nuclear transport of phyB. We tested the nuclear transport characteristics of full-length phyB as well as N- and C-terminal phyB fragments in vitro and showed that the nuclear import of phyB can be facilitated by phytochrome-interacting factor 3 (PIF3). In vivo measurements of phyB nuclear accumulation in the absence of PIF1, -3, -4, and -5 indicate that these PIFs are the major transport facilitators during the first hours of deetiolation. Under prolonged irradiations additional factors might be responsible for phyB nuclear transport in the plant. PMID- 22451941 TI - Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF kappaB. AB - Ductal growth of the mammary gland occurs in two distinct stages. The first round of branching morphogenesis occurs during embryogenesis, and the second round commences at the onset of puberty. Currently, relatively little is known about the genetic networks that control the initial phases of ductal expansion, which, unlike pubertal development, proceeds independent of hormonal input in female mice. Here we identify NF-kappaB downstream of the TNF-like ligand ectodysplasin (Eda) as a unique regulator of embryonic and prepubertal ductal morphogenesis. Loss of Eda, or inhibition of NF-kappaB, led to smaller ductal trees with fewer branches. On the other hand, overexpression of Eda caused a dramatic NF-kappaB dependent phenotype in both female and male mice characterized by precocious and highly increased ductal growth and branching that correlated with enhanced cell proliferation. We have identified several putative transcriptional target genes of Eda/NF-kappaB, including PTHrP, Wnt10a, and Wnt10b, as well as Egf family ligands amphiregulin and epigen. We developed a mammary bud culture system that allowed us to manipulate mammary development ex vivo and found that recombinant PTHrP, Wnt3A, and Egf family ligands stimulate embryonic branching morphogenesis, suggesting that these pathways may cooperatively mediate the effects of Eda. PMID- 22451942 TI - Disclosing the in vivo organization of a viral histone-like protein in Bacillus subtilis mediated by its capacity to recognize the viral genome. AB - Organization of replicating prokaryotic genomes requires architectural elements that, similarly to eukaryotic systems, induce topological changes such as DNA supercoiling. Bacteriophage 29 protein p6 has been described as a histone-like protein that compacts the viral genome by forming a nucleoprotein complex and plays a key role in the initiation of protein-primed DNA replication. In this work, we analyze the subcellular localization of protein p6 by immunofluorescence microscopy and show that, at early infection stages, it localizes in a peripheral helix-like configuration. Later, at middle infection stages, protein p6 is recruited to the bacterial nucleoid. This migrating process is shown to depend on the synthesis of components of the 29 DNA replication machinery (i.e., terminal protein and DNA polymerase) needed for the replication of viral DNA, which is required to recruit the bulk of protein p6. Importantly, the double-stranded DNA binding capacity of protein p6 is essential for its relocalization at the nucleoid. Altogether, the results disclose the in vivo organization of a viral histone-like protein in bacteria. PMID- 22451943 TI - Evidence for elevated mutation rates in low-quality genotypes. AB - The deleterious mutation rate plays a key role in a number of important topics in biology, from mating system evolution to human health. Despite this broad significance, the nature and causes of variation in mutation rate are poorly understood, especially in multicellular organisms. We test whether genetic quality, the presence or absence of deleterious alleles, affects the mutation rate in Drosophila melanogaster by using a modified mutation accumulation approach. We find evidence that genotypes constructed to carry deleterious "treatment" alleles on one chromosome during mutation accumulation experience an elevated mutation rate on a different chromosome. Further, this elevation is correlated with the effect of the treatment alleles on phenotypic condition, measured as body mass. Treatment alleles that reduce mass by 10% cause a doubling in the rate of mutational decline. Our results show that mutation rates are sensitive to genetic stress, such that individuals with low-quality genotypes will produce offspring of even lower genetic quality, in a mutational positive feedback loop. This type of variation in mutation rate is expected to alter a variety of predictions based on mutation load theory and accelerate adaptation to new environments. Positive mutational feedback could affect human health by increasing the rate of germline mutation, and possibly somatic mutation, in individuals of poor health because of genetic or environmental stress. PMID- 22451944 TI - Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. AB - Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing interspecies differences in the transcriptional responses of primary human and mouse macrophages to the Toll-like receptor (TLR) 4 agonist lipopolysaccharide (LPS). By using a custom platform permitting cross species interrogation coupled with deep sequencing of mRNA 5' ends, we identified extensive divergence in LPS-regulated orthologous gene expression between humans and mice (24% of orthologues were identified as "divergently regulated"). We further demonstrate concordant regulation of human-specific LPS target genes in primary pig macrophages. Divergently regulated orthologues were enriched for genes encoding cellular "inputs" such as cell surface receptors (e.g., TLR6, IL 7Ralpha) and functional "outputs" such as inflammatory cytokines/chemokines (e.g., CCL20, CXCL13). Conversely, intracellular signaling components linking inputs to outputs were typically concordantly regulated. Functional consequences of divergent gene regulation were confirmed by showing LPS pretreatment boosts subsequent TLR6 responses in mouse but not human macrophages, in keeping with mouse-specific TLR6 induction. Divergently regulated genes were associated with a large dynamic range of gene expression, and specific promoter architectural features (TATA box enrichment, CpG island depletion). Surprisingly, regulatory divergence was also associated with enhanced interspecies promoter conservation. Thus, the genes controlled by complex, highly conserved promoters that facilitate dynamic regulation are also the most susceptible to evolutionary change. PMID- 22451945 TI - Posttranslational modifications of Rab GTPases help their insertion into membranes. PMID- 22451946 TI - Angiogenesis and the tumor space-time continuum. PMID- 22451947 TI - Krypton red laser photocoagulation of the ocular fundus. 1982. AB - The theoretical rationale, the histopathologic evidence, and the preliminary clinical studies related to krypton red laser (KRL) photocoagulation of the ocular fundus are reviewed. The authors report on their experience with currently available laser systems using this wavelength (647.1 nm) for photocoagulation of retinal vascular proliferative diseases and chorioretinal diseases associated with exudative manifestations. A histopathologic and clinical comparison of argon blue-green laser (ABGL), the pure argon green laser (AGL), and the krypton yellow laser (KYL), with reference to photocoagulation treatment of the ocular fundus is also discussed. PMID- 22451948 TI - Idiopathic polypoidal choroidal vasculopathy (IPCV). 1990. AB - Eleven patients, 40 to 71 years old, had a choroidal vasculopathy that led to hemorrhagic and exudative macular degeneration. The patients had peculiar polypoidal, subretinal, vascular lesions associated with serous and hemorrhagic detachments of the retinal pigment epithelium. This macular disorder, which we have named idiopathic polypoidal choroidal vasculopathy (IPCV), appears to represent a distinct entity that differs clinically and demograph-ically from age related macular degeneration (AMD) and other macular diseases associated with subretinal neovascularization. Recognition of this condition is important because it may have specific risk factors, natural course, and management considerations that differ from those of age-related macular degeneration PMID- 22451949 TI - Solar retinopathy: a photobiologic and geophysical analysis. 1989. AB - A series of young adult patients developed solar retinopathy during sun exposure over a two-day period in a particular region of the United States during March of 1986. Evaluation of the photobiological and geophysical parameters involved in solar retinitis are presented. A multifactorial pathogenesis is proposed. Of interest, a possible increase in terrestrial ultra-violet B radiation secondary to a localized relatively low ozone column during the days involved may have contributed to the retinal damage. Recommendations for protection from solar retinitis are noted. PMID- 22451950 TI - Retinoschisis associated with optic nerve pits. 1988. AB - Stereoscopic transparencies studied with magnification and projection suggest that the retinal elevation that communicates with optic pits is frequently a schisislike separation of the internal layers of retina. Thirteen of 15 eyes with optic pits and maculopathy fit the schisis pattern. Separation of the outer layers of the retina is a secondary phenomenon that starts in the macula. PMID- 22451951 TI - Digital indocyanine green videoangiography and choroidal neovascularization. 1992. AB - This report describes a new system for digital indocyanine green videoangiography (ICGV) that provides enhanced imaging of the choroidal circulation. This newly assembled system was used to study a consecutive series of 129 patients with exudative age-related macular degeneration (AMD), and ill-defined or occult choroidal neovascularization (CNV). Overall, 39% of the patients in this study with occult CNV could be reclassified as having well-delineated or so-called classic CNV by virtue of the additional findings provided by ICGV. In this series, ICGV was particularly useful in identifying occult CNV in eyes with a large, serous pigment epithelial detachment (PED) and in eyes with recurrent CNV after previous laser photocoagulation treatment. Some of these patients were selected for laser photocoagulation of the abnormal choroidal vessels in order to evaluate the feasibility of this form of treatment on the basis of combined clinical, fluorescein angiographic, and ICGV findings. The results of this study suggest that ICGV is an important adjunct in the evaluation, classification, and laser treatment of patients with occult CNV secondary to AMD. PMID- 22451952 TI - Indocyanine green angiography-guided photodynamic therapy for treatment of chronic central serous chorioretinopathy: a pilot study. 2003. AB - BACKGROUND: Most patients with central serous chorioretinopathy (CSC) have spontaneous resolution of exudative macular detachments and a good visual prognosis. Patients with CSC have a primary choroidal hyperpermeability problem evident as multifocal areas of hyperpermeability during indocyanine green (ICG) angiography. A small percentage of patients develop chronic or progressive disease with widespread decompensation of the retinal pigment epithelium and severe vision loss. There is no known treatment for this variant of the disorder. PURPOSE: To study ICG-guided photodynamic therapy (PDT) with verteporfin as a potential treatment for patients with chronic CSC. METHODS: Twenty eyes of 15 patients were studied with fluorescein angiography, optical coherence tomography, and ICG angiography to diagnose the maculopathy, monitor the detachments, and localize the choroidal hyperpermeability of the disorder. PDT with ICG guidance was applied to areas of choroidal hyperpermeability, and the patients were observed to determine the anatomic and functional outcomes. RESULTS: Photodynamic therapy guided by ICG was associated with complete resolution of exudative macular detachments in 12 patients and incomplete resolution in the remaining eight eyes. The vision improved in six eyes and remained unchanged in 14 eyes during a mean follow-up of 6.8 months. Six weeks after treatment, the mean visual acuity improved by 0.55 lines, an amount that was marginally significant. There was a significant inverse correlation between the baseline visual acuity and the amount of improvement in acuity at 6 weeks. No patient had any treatment-related side effects. CONCLUSIONS: Indocyanine green angiography-guided PDT with verteporfin seems to aid in the resolution of exudative detachments in patients with chronic CSC. This treatment was associated with a rapid reduction in subretinal fluid and improvement in visual acuity. Although the follow-up time and number of patients in this pilot study were limited, the encouraging results and lack of complications suggest that further study is indicated. PMID- 22451953 TI - Retinal angiomatous proliferation in age-related macular degeneration. 2001. AB - BACKGROUND: It is known that choroidal neovascularization (CNV) in age-related macular degeneration (ARMD) may erode through the retinal pigment epithelium, infiltrate the neurosensory retina, and communicate with the retinal circulation in what has been referred to as a retinal-choroidal anastomosis (RCA). This is extremely common in the end stage of disciform disease. In recent years, the reverse also seems to be possible, as angiomatous proliferation originates from the retina and extends posteriorly into the subretinal space, eventually communicating in some cases with choroidal new vessels. This form of neovascular ARMD, termed retinal angiomatous proliferation (RAP) in this article, can be confused with CNV. PURPOSE: The purpose of this article is 1) to review the clinical and angiographic characteristics of a series of patients with RAP and 2) to propose a theoretical sequence of events that accounts for the neovascularized process. METHODS: In this retrospective clinical and angiographic analysis, 143 eyes with RAP (108 patients) were reviewed and classified based on their vasogenic nature and course. Clinical biomicroscopic examination, fluorescein angiography, and indocyanine green angiography were used to evaluate patients. RESULTS: The results of this series suggest that angiomatous proliferation within the retina is the first manifestation of the vasogenic process in this form of neovascular ARMD. Dilated retinal vessels and pre-, intra-, and subretinal hemorrhages and exudate evolve, surrounding the angiomatous proliferation as the process extends into the deep retina and subretinal space. One or more dilated compensatory retinal vessels perfuse and drain the neovascularization, sometimes forming a retinal-retinal anastomosis. Fluorescein angiography in these patients usually revealed indistinct staining simulating occult CNV. Indocyanine green angiography was useful to make an accurate diagnosis in most cases. It revealed a focal area of intense hyperfluorescence corresponding to the neovascularization ("hot spot") and other characteristic findings. Based on understanding of the nature and progression of the neovascularized process, patients with RAP were classified into three vasogenic stages. Stage I involved proliferation of intraretinal capillaries originating from the deep retinal complex (intraretinal neovascularization [IRN]). Stage II was determined by growth of the retinal vessels into the subretinal space (subretinal neovascularization [SRN]). Stage III occurred when CNV could clearly be determined clinically or angiographically. A vascularized pigment epithelial detachment and RCA were inconsistent features of this stage. CONCLUSIONS: Retinal angiomatous proliferation appears to be a distinct subgroup of neovascular ARMD. It may present in one of three vasogenic stages: IRN, SRN, or CNV. Whereas ICG angiography is helpful in diagnosing RAP and in documenting the stage of the neovascularized process, it is frequently difficult to determine the precise nature and location of the new vessel formation. It is important for clinicians to recognize the vasogenic potential and the associated manifestations of this peculiar form of neovascular ARMD so that a proper diagnosis can be made, and when possible, an appropriate management administered. PMID- 22451954 TI - Idiopathic macular telangiectasia. 2006. AB - OBJECTIVES: To review the frequency and nature of idiopathic macular telangiectasia and to classify the disorders based on new clinical and imaging observations. METHODS: A combined retrospective and prospective analysis of newly diagnosed patients seen over a period of 3 years. Patients were identified based on the Gass-Blodi classification and were studied with biomicroscopy, fluorescein angiography, and optical coherence tomography. RESULTS: Ten patients associated with aneurysmal telangiectasia (Gass-Blodi group 1) and 26 patients with perifoveal telangiectasia (Gass-Blodi group 2) were recruited. None with occlusive telangiectasia (Gass-Blodi group 3) were identified. New observations based on clinical, fluorescein angiographic, and optical coherence tomographic findings were made. CONCLUSIONS: Our series was similar to that in the Gass-Blodi study in terms of frequency. New observations in groups 1 and 2 have expanded our knowledge of the clinical spectrum of these disorders. A simplified classification termed idiopathic macular telangiectasia with 2 distinct types (type I, or aneurysmal telangiectasia, and type II, or perifoveal telangiectasia) was proposed to produce a better understanding of the entities and to enhance teaching and research. The third type, occlusive telangiectasia, has been omitted from our classification based on its rarity and presence of capillary nonperfusion rather than macular telangiectasia as the primary abnormality. PMID- 22451955 TI - Treatment of polypoidal choroidal vasculopathy with photodynamic therapy. 2002. AB - PURPOSE: To study the effects of photodynamic therapy using verteporfin in the treatment of patients with subfoveal polypoidal choroidal vasculopathy (PCV). METHODS: A retrospective chart review of 16 consecutive patients with subfoveal PCV treated with photodynamic therapy using verteporfin was performed. RESULTS: The mean age of the patients involved was 70.5 years. The mean follow-up time was 12 months. The visual acuity improved in 9 (56.3 %), remained the same in 5 (31.3 %), and decreased in 2 (12.5 %). The mean change in visual acuity was an improvement of 2.38 lines, a difference that was highly significant (P = 0.004). The change in visual acuity was negatively correlated with increasing age. The final visual acuity was positively correlated with initial acuity and negatively correlated with age. These results were confirmed by multiple linear regression. No patient had any lasting complication from the treatment. CONCLUSIONS: Subfoveal PCV has no proven method of treatment. Although the follow-up time and the number of patients in this pilot study were limited, the encouraging results and lack of complications suggest that further study is indicated. PMID- 22451956 TI - Type A behavior and central serous chorioretinopathy. PMID- 22451957 TI - A classification of abnormal fundus fluorescence. 1971. PMID- 22451958 TI - Recurrent subretinal neovascularization. 1987. PMID- 22451959 TI - Unilateral acute idiopathic maculopathy. 1991. AB - This is a report of nine patients who experienced sudden, severe, unilateral central vision loss following a flulike illness. Each patient had an exudative detachment of the macula. All patients experienced a spontaneous resolution of the acute macular manifestations with near-complete recovery of vision. A characteristic "bull's-eye" appearance in the macula persisted. The acute manifestations of the disorder did not recur in any of the patients during the period of follow-up. The constellation of findings was suggestive of an inflammatory disease of the retinal pigment epithelium, but a specific causative agent could not be identified. The acute clinical and angiographic features, the natural course, and the residual pigment epithelial derangement were not consistent with any previously described disorder. PMID- 22451960 TI - Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy. 1984. AB - Twenty-five patients with central serous pigment epitheliopathy (CSP), also known as central serous chorioretinopathy, have been observed to have inferior hemispheric retinal pigment epithelial atrophic tracts, presumptive of antecedent retinal detachments. Five of these patients were noted to have clinically discernible, dependent peripheral retinal detachments. The clinical and fluorescein angiographic features of these patients are reviewed. Alterations in the retina, the retinal pigment epithelium (RPE) and the choroid are also described. They include the commonly associated manifestations of CSP such as RPE leaks and macular detachment as well as some newly recognized disturbances such as retinal capillary dilatation (telangiectasia), retinal capillary leakage, retinal lipid deposition, cystoid macular edema, choriocapillaris atrophy, choroidal neovascularization and disciform scarring. PMID- 22451961 TI - Primary cutaneous cryptococcosis in immunocompetent hosts. PMID- 22451962 TI - UK researcher wins 2012 Gairdner Global Health Award. PMID- 22451963 TI - 2012 Gairdner International Awards go to US scientists. PMID- 22451964 TI - Can social protection improve tuberculosis control? PMID- 22451965 TI - Estonia lauded for tuberculosis control efforts. PMID- 22451966 TI - Remembering my sister Rosalind Franklin. PMID- 22451967 TI - What is wrong with Medicare? Comment. PMID- 22451968 TI - Whats wrong with Medicare? Comment. PMID- 22451969 TI - Whats wrong with Medicare? Comment. PMID- 22451970 TI - Oncogene silencing by systemic delivery of lipid nanoparticle. PMID- 22451971 TI - Sheddable PEG for deshielding siRNA nanoparticles in the tumor acid microenvironment. PMID- 22451972 TI - A to X: the problem of categorisation of drugs in pregnancy - an Australian perspective. Comment. PMID- 22451973 TI - From the Australian Commission on Safety and Quality in Health Care. PMID- 22451974 TI - Recommended immunization schedules for persons aged 0 through 18 Years - United States, 2012. PMID- 22451975 TI - Retraction. An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. PMID- 22451976 TI - [Interview -- sports injuries -- prevention is better than cure]. PMID- 22451977 TI - [Youth forum -- give something to the young ear]. PMID- 22451978 TI - [Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis]. PMID- 22451979 TI - [A systematic review of the treatment of acute fractures of the scaphoid]. PMID- 22451980 TI - [Published evidence relevant to the diagnosis of impingement syndrome of the shoulder]. PMID- 22451981 TI - [Can patients really participate in sport after high tibial osteotomy?]. PMID- 22451982 TI - [Spontaneous closure of idiopathic macular hole (presentation of 4 cases)]. AB - PURPOSE: To describe the cases of spontaneous closure of idiopathic macular hole. MATERIAL AND METHOD: OCT findings were retrospectively searched for cases of macular hole closure. Based on the corresponding documentation it was checked, if they were idiopathic macular holes and if the closure was spontaneous. RESULTS: The authors present two cases of macular hole closures in phase IB, in one of which the closed hole reopened again in full thickness after 15 months. In further two cases of the phase II, one hole closed after posterior vitreous detachment after cataract surgery and once quite spontaneously. CONCLUSION: Four cases of spontaneous closure of idiopathic macular hole were documented by three ophthalmology departments during the period of nearly four years. Based on this result we suppose that this process is not as rare, as stated in the literature. PMID- 22451983 TI - Not "Simply Mrs. Warren": Eliza Warren Francis (1810-1900) and the "Ladies' Treasury". PMID- 22451984 TI - Nonself help: how immunology might reframe the Enlightenment. AB - The classical immunological paradigm is predicated on the body's ability to recognize and eliminate "nonself." However, the "self-nonself" model has yet to facilitate any resolution of the field's major concerns, and may thus prove to be of limited use. Merely discarding it is no solution, as the juxtaposition of "self" and "nonself" persists in research, in clinical settings, and in everyday practice despite the best efforts of theoretical immunologists. Instead, the very conception of "selfhood" may prove to be key. Replacing immunology's prior and persistent "self" with less static concepts derived from non-Western contexts not only resolves immunology's famous paradoxes but also offers a new and more accurate model that allows immunology to reframe what may become an outmoded Enlightenment construct of "self." In such a new paradigm, immunology's well known system of protection and defense is replaced with a view in which nonself becomes less the body's enemy than its primary mechanism for the creative assimilation of difference. This incorporative model-in which the "immune system" functions more as a search engine than as an expeller of difference-both resolves outstanding paradoxes, and complies more accurately with contemporary knowledge and research practice. PMID- 22451985 TI - On hunger and child mortality in India. AB - Despite accelerated growth there is pervasive hunger, child undernutrition and mortality in India. Our analysis focuses on their determinants. Raising living standards alone will not reduce hunger and undernutrition. Reduction of rural/urban disparities, income inequality, consumer price stabilization, and mothers' literacy all have roles of varying importance in different nutrition indicators. Somewhat surprisingly, public distribution system (PDS) do not have a significant effect on any of them. Generally, child undernutrition and mortality rise with poverty. Our analysis confirms that media exposure triggers public action, and helps avert child undernutrition and mortality. Drastic reduction of economic inequality is in fact key to averting child mortality, conditional upon a drastic reordering of social and economic arrangements. PMID- 22451986 TI - Rural income transfer programs and rural household food security in Ethiopia. AB - Based on household food security surveys conducted in Ethiopia, this study seeks to understand the roles and limitations of income transfer projects as determinants of households' food security. By covering the Food-For-Work Programs (FFWPs) and the Productive Safety Net Programs (PSNPs), the study shows that these programs served as temporary safety nets for food availability, but they were limited in boosting the dietary diversity of households and their coping strategies. Households which participated in the programs increased their supply of food as a temporary buffer to seasonal asset depletion. However, participation in the programs was marred by inclusion error (food-secure households were included) and exclusion error (food-insecure households were excluded). Income transfer projects alone were not robust determinants of household food security. Rather, socio-demographic variables of education and family size as well as agricultural input of land size were found to be significant in accounting for changes in households' food security. The programs in the research sites were funded through foreign aid, and the findings of the study imply the need to reexamine the approaches adopted by bilateral donors in allocating aid to Ethiopia. At the same time the study underscores the need to improve domestic policy framework in terms of engendering rural local institutional participation in project management. PMID- 22451987 TI - [National recommendations for the treatment of pharyngotonsillitis are valid]. PMID- 22451988 TI - [Motherhood and abortion in the experience of immigrant women in Milan]. PMID- 22451989 TI - [Statistics on foreigners and penal justice]. PMID- 22451990 TI - [Foreign students and cultural integration programs in Italy]. PMID- 22451991 TI - [Immigrant housing and labor in Milan during the 1990's]. PMID- 22451993 TI - [Decentralization or fragmentation? Reflections on urban land reform in Mexico]. PMID- 22451994 TI - [Public housing in Parma during two decades of Fascism]. PMID- 22451995 TI - [Property formalization and guided land development in Lima and Trujillo, Peru]. PMID- 22451996 TI - [Regional plans in the construction of contemporary Italian urban studies: comparing two experiences]. PMID- 22451997 TI - Who owns the information in the medical record? Copyright issues. AB - As part of every private healthcare practice and healthcare facility, documentation of patients' healthcare, diagnoses and treatment are an ongoing requirement with legal connotations. The question that may arise is whether copyright can subsist in patient medical records, and if so, what benefit may arise from ownership of such copyright. PMID- 22451998 TI - Designing health insurance exchanges: key decisions. AB - A cornerstone of health care reform is the establishment of state-level insurance exchanges where individuals and small businesses can purchase health insurance in an online marketplace. States are required to develop an exchange by 2014, or participate in a federal one. The exchanges will help people without employer sponsored insurance find and choose a health plan to meet their needs. This Issue Brief reviews the experience of Massachusetts in developing a health insurance exchange and offers policymakers guidance on key features and likely consumer responses. PMID- 22451999 TI - ''Buddy system'' of peer mentors may help control diabetes. AB - Type 2 diabetes is more prevalent and severe among African Americans. Even within the Veterans Health Administration, which is thought to have minimized barriers in access to care, racial disparities in glucose control and outcomes persist. This Issue Brief summarizes work testing two novel interventions--one-on-one peer mentoring (a "buddy system") and financial incentives--designed to help patients with consistently poor diabetes control achieve better results. In this case, a telephone buddy makes a big difference. PMID- 22452000 TI - [The 1835-37 cholera epidemic: the vulnerability of Italian cities]. PMID- 22452001 TI - [The legalization of favelas in Brazil: problems and prospects]. PMID- 22452002 TI - [The regularization of informal settlements in the metropolitan areas of Latin America: between chronicle and history]. PMID- 22452003 TI - [The regularization of the low-cost housing in Mexico]. PMID- 22452004 TI - [Regularization policies in Buenos Aires, Argentina: between euphoria and frustration]. PMID- 22452006 TI - [Udine 1836: a hospital for those suffering from cholera]. PMID- 22452007 TI - [Udine and the 1836 cholera epidemics]. PMID- 22452008 TI - [Urban woodlands: the Astroni woods from the crown to the National Veterans' Agency, 18th-20th centuries]. PMID- 22452009 TI - [Childhood and youth as periods of life in the thinking of J. A. Comenius]. PMID- 22452010 TI - [Demographic dynamics and socioeconomic structures in Italy]. PMID- 22452011 TI - [Quaker women in the 17th century]. PMID- 22452012 TI - [Italian working women and men in the first half of the 20th century]. PMID- 22452013 TI - [Medical skill in the juridical experience of common law]. PMID- 22452014 TI - [The Inquisition in Siena: the witchcraft trials, 1580-1721]. PMID- 22452015 TI - [Physicians and confessors: medicine of the body and medicine of the soul]. PMID- 22452016 TI - [Therapeutic practices, medico-legal skills: new approaches to the history of medicine]. PMID- 22452017 TI - Health reform: special report. Health reform turns two: after passage of the Affordable Care Act, the work--and the criticisms--persist. AB - NCSL tracks state actions on federal health reform closely. You can learn more about federal regulations, state legislation, Medicaid, insurance reform and more at www.ncsl.org/healthreform. Several NCSL health staff contributed to this package of stories related to the two-year anniversary of the Affordable Care Act. Contributors: Exchanges: job no. 1--Martha Salazar. Big changes for insurers -Richard Cauchi. Sharp divisions persist over law's future--Richard Cauchi. Transforming Medicaid--Melissa Hansen. States decided essential benefits--Richard Cauchi. PREVENTION: more than an ounce--Amy Winerfeld. Help wanted: doctors and nurses--Laura Tobler. PMID- 22452018 TI - [Renunciation, peace, pardon: pacification rituals in the early modern era]. PMID- 22452019 TI - [Sentiments and documents]. PMID- 22452020 TI - [The purge of women school teachers during Francoism]. PMID- 22452021 TI - [State, rural society, and technological innovation in agriculture: changes around 1900]. PMID- 22452022 TI - [Seasonal fluctuations and integration of markets in Santander and Castile during the first half of the 19th century]. PMID- 22452023 TI - [An original approach to immigration in times of crisis: plans for Franco Spanish demographic symbiosis in the 1930's]. PMID- 22452024 TI - Everyday crime, native mendacity and the cultural psychology of justice in colonial India. PMID- 22452025 TI - ERISA failures and the erosion of workers' rights: the urgent need to protect private & public workers' pension and benefits. AB - On March 11, 2011, Governor Scott Walker of Wisconsin signed into law a bill that eliminated most collective bargaining rights for the state's public-sector workers. Many other cash-strapped states followed Wisconsin's lead and introduced or enacted similar restraints on the rights of their workers. Thousands of public workers, whose only means of protecting their rights rested in their ability to collectively bargain, suddenly found their retirement benefits in jeopardy. This truth highlighted the lack of protections for public worker benefits similar to those of the private sector. However, the Employee Retirement Income Security Act, enacted for that purpose, has failed to secure these benefits. This article seeks to provide a broad overview of the crisis facing the pension and benefits system in the United States and offers some possible solutions. More importantly, the goal is to spur discourse on the urgent need to protect the benefits of all workers, public and private. PMID- 22452026 TI - Fallen men: representations of male impotence in Britain. PMID- 22452027 TI - Time is money: outpatient waiting times and health insurance choices of elderly veterans in the United states. PMID- 22452028 TI - [Suggestion by a resident to overcome the crisis in surgical practice--overcoming the generational gap]. PMID- 22452029 TI - [Current critical status of surgical practice and steps to remedy the situation]. PMID- 22452030 TI - [To remedy surgical practice that is at a crisis: suggestion by a surgical practitioner]. PMID- 22452031 TI - [Remedy for the crisis in surgical practice? Three prescriptions to save the hospital surgical staff]. PMID- 22452032 TI - [Technological certification by the Japanese Society of Endoscopy]. PMID- 22452033 TI - [Toward the establishment of a surgical no fault system--what can the legislative body do?]. PMID- 22452035 TI - [Technology required of surgeons specializing in the digestive system and their evaluation]. PMID- 22452034 TI - [Hepato-biliary and pancreatic surgery of high technical difficulty and its technological evaluation]. PMID- 22452036 TI - [Technological level of surgeons specializing in the respiratory tract and methods to evaluate their technical proficiency]. PMID- 22452037 TI - [Technology of cardiovascular surgeons and its evaluation: solutions for its problems proposed by the management and their implementation]. PMID- 22452038 TI - [Technology acknowledgement and scores given for health insurance coverage: a viewpoint of the Surgical Insurance Alliance]. PMID- 22452039 TI - [Keypoints in clinical statistics fo research design of clinical research]. PMID- 22452040 TI - [Statistical keypoints in designing clinical research]. PMID- 22452041 TI - [Promotion, control and data management in clinical trials]. PMID- 22452043 TI - [On revision of the "Ethical Guidelines Concerning Clinical Research"]. PMID- 22452044 TI - [Clinical trials on lung cancers]. PMID- 22452045 TI - [Clinical research on pancreatic cancer--Japanese and Wakayama experiences]. PMID- 22452046 TI - [EM and EM703 suppress inflammatory cytokines formation by human respiratory epithelial cells provoked by diesel exhaust particles]. PMID- 22452047 TI - [Action of EM900 on mucus secretion by the respiratory epithelial cells]. PMID- 22452048 TI - [The effects of macrolides (EM900, clarithromycin and azithromycin) on IL-17 induced IL-8 production by airway epithelial cells]. PMID- 22452050 TI - [Suppression of endotoxic shock by macrolide derivative, EM900, and the mechanism involved in the process]. PMID- 22452051 TI - [Efficacy of EM900: summary of discussion]. PMID- 22452052 TI - [Clinical aspect of Mycobacterium avium complex disease of the lung]. PMID- 22452053 TI - [Immuno-adjuvants for the treatment of MAC infection]. PMID- 22452054 TI - [Analysis of inflammatory substances associated with intracellular amplification of Mycobacterium avium BEAS-2B cells and suppressive effects of clarithromycin]. PMID- 22452055 TI - [Anti-bacterial and anti-inflammatory actions of clarithromycin against Haemophilus influenzae that has infiltrated the respiratory epithelial cells]. PMID- 22452056 TI - [Analysis of airway secretion caused by Chlamydophila pneumoniae and the suppressive effects brought about macrolide antibacterial agents]. PMID- 22452057 TI - [14-membered ring macrolides exaggerate IL-10 expression stimulated by LPS]. PMID- 22452058 TI - [Analysis of the mechanism involved in the effects of erythromycin in suppressing the development of pseudomembranous colitis]. PMID- 22452059 TI - ["Quantitative cardiotocography"--clinical practice guideline]. AB - INTRODUCTION: The "quantitative cardiotocography" method provides important information about the condition of the fetus during labor, non-invasively and in real time. Since the forecast pH-results are being updated every 5 (five) minutes, significant differences in the readings for pH can be observed. In certain cases this can hamper the evaluation of fetal condition and lead to contradictions. Such inconveniences can be easily avoided by using the arithmetic average value of the last 6 forecast results for pH, generated by the quantitative cardiotocography software. Another inconvenience of the "quantitative cardiotocography" method lies in the fact that the components involved in the formation of CTG-score seem to be unequal in terms of potential for evaluating the fetal condition. Based on that, we believe that clinical practice guideline is needed. We developed such guideline based on two main criteria: the arithmetic average value over the last 6 (six) pH estimates; which components of the CTG-score are involved in the formation of the pH forecast readings. MATERIAL AND METHODS: Our previous studies demonstrated that in 85% of all cases, the actual pH value of the newborn was in the range of -0037/+0046 from the average arithmetic value of the last six (6) pH estimates before the delivery. Based on this variability in the pH forecast results we defined three groups of findings--normal (pH 7.350 to 7.237), suspect (pH of 7.237 to 7.137) and abnormal (pH < 7.137). In another study, we differentiated several varieties of CTG-score (with very high, high, satisfactory and low predictive value), depending on the observed deviations between forecast and actual pH results. RESULTS: pH forecast results should always be assessed together with the composition of the CTG-score. This can be achieved by using the presented clinical guideline, which also contains recommendations for adopting specific obstetric behavior, based on the "quantitative cardiotocography" readings. CONCLUSION: In future studies we will investigate if it is possible the presented clinical practice guideline to replace fetal blood sampling for intrapartal assessment of the fetal condition. Further clinical studies will clarify whether the use of this clinical guideline could lead to a reduction in the incidence of metabolic acidosis in newborns or change the percentage of operative deliveries compared with the cases where classical indirect cardiotocography was used. PMID- 22452060 TI - [Frequency of multiple pregnancy]. AB - OBJECTIVES: The aim of this research was to find out the frequency and tendency of multiple pregnancy. Study design. There are used retrospective and prospective comparative analysis. The study includes 51162 births, 960 twins, 39 triplets and 1 quadruplets. RESULTS: The number of multiple pregnancy in 1994 was 44, but in 2009 it was 152. The frequency of twins increased from 1.18% in the beginning of the observed period to 3.62% in the end of the period. The frequency of triplets chanced from 0.06% to 0.34%. We determined that the number of twins increased 3 times and the number of triplets - 6 times. In the beginning of the researched period in 2005, the frequency of twin pregnancy shows a tendency of smooth increase, while form 2006 there is a significant and rapid increase. The frequency of the triplet's births shows relative stability from 1996 till 2006, while from 2007 till now there is a progressive increase in it too. CONCLUSIONS: There is a significant increase in the frequency of the multiple preganancies, observed in twins as well as in triplets. There is a stable tendency of increasing, which has the following characteristics smooth growth in the beginning of the period and rapid expand in the last years. The problem of the increasing frequency of the multiple pregnancies and the following up complications must be the aim of our future research and discussion. PMID- 22452061 TI - [Our experience with management of inherited thrombophilia during pregnancy. Preliminary report]. AB - It has become clear in the recent years that inherited thrombophilias (IT) are associated with serious abnormalities during pregnancy. This includes miscarriage, still birth, placental abruption, praeclamcspia and intrauterine fetal growth restriction. The aim of this study is to share our experience in the field. MATERIALS AND METHODS: 38 patients with medical history of abnormal pregnancies (miscarriage, still birth, placental abruption, praeclamcspia and intrauterine fetal growth reastriction). They were all tested for the following gene alterations: V Laidon-R506Q/phiVL-R506Q/, protrombin G/A 20210 /Pi pG/A20210/, Plasminogen activator inhibitor- PAI- 4G/4G/PAI 4G/5G/). IT were diagnosed in 24 patients. They were all treated by: Aspirin 75 mg form prior to conception and low molecular Heparin after detection of fetal heart movement. Due to the observed NRDS in some of the newborns, the low molecular heparin intake was discontinued 30 days prior to expected delivery. RESULTS: keeping up to the therapeutic scheme, 70% (17) of women with IT gave birth to a term baby, and 30% (7)-to a preterm one, all pregnancies were successful. Amongst the patients with medical history of miscarriage, 72% were diagnosed with IT and 87.5% of them gave birth to a term newborn as a result of the anticoagulant treatment. CONCLUSIONS: Undiagnosed IT is a common cause of adverse pregnancy outcome. Uninterrupted anticoagulant treatment of these patients is very successful. The whole pregnancy should be followed up closely. Due to the higher risk of respiratory complications in the infants, delivery should be performed in a specialized hospital with neonatology department, capable of newborn resuscitation. PMID- 22452062 TI - [Our experience with management of inherited thrombophilia during pregnancy. Preliminary report]. AB - The physiologic mechanism that results in the occurrence of premenstrual syndrome (PMS) is not well understood. OBJECTIVE: Effective treatment in premenstrual syndrome with vitex agnus castus--femicur N in adolescent girls. [corrected]. MATERIAL AND METHODS: We have investigated 45 adolescent girls 14-16 years old for a 3 years period from march 2009 to march 2011. The first group of 23 girls were prescribed Femicur N 4 mg once daily for 3 month--90 capsules per course. The second group of 22 girls were given 40 mg of the study drug (Femicur N) twice a day, from the 19th day of the first day of the cycle for 10 days 3 month as the dose is 60 capsules per course. RESULTS: Our investigation showed that therapy with VAC-Femicur N in adolescents suffering from PMS was effective and the results were good. From 45 girls 20 girls (44.4%) were without any complaints and 13 girls (28.8%) had reduction of all premenstrual symptoms. In both groups premenstrual mastodynia in 13 girls (28.8%) has disappeard and with 4 girls (8.8%) complaints were redused. PMID- 22452063 TI - [Complications in gynecologic laparoscopic surgery--retrospective and prospective study]. AB - Laparoscopic surgery is a surgical approach with proven advantages in the contemporary treatment of gynaecological diseases. It is applied with proven results in oncologic patients in order to respect certain rules. Mini-invasive approach has less complication and therefore is widely recommended. In this respect, the constantly increasing interest in this surgery and additional training and education. Risk factors must be taken into consideration and patients should be informed about possible complications during surgery. PMID- 22452064 TI - [Content of iron, copper and zinc in plasma of women with leiomyoma of the uterus]. AB - The aim of this investigation was to determine the plasma iron, copper and zinc concentration in group of 22 women with leiomyoma of the uterus (group A) and control group of 25 women (group B). The plasma iron and copper concentrations were significantly decreased in group A compared to the group B. No significantly difference was observed between plasma copper concentration of the groups A and B. PMID- 22452065 TI - [Epidural analgesia for vaginal delivery. Influence over the delivery, fetal presentation, the method of delivery and lactation]. AB - Epidural anaesthesia is the most efficient and widespread in developed countries method of pain reduction. The effects of epidural analgesia over uterine activity, duration of first, second and third period of labor, frequency of operative delivery--vaginal and abdominal, as like as its effects of breastfeeding are established in this review. PMID- 22452066 TI - [Ultrasound markers for Down syndrome]. AB - Trisomy 21 (Down syndrome) is the most common chromosomal abnormality. Sonographic findings in fetuses with Down syndrome include both structural abnormalities and nonstructural abnormalities or "markers." These markers are known as "soft markers" of aneuploidy. These markers are nonspecific, often transient. The most commonly studied soft markers of aneuploidy include a thickened nuchal fold, long bones shortening, mild fetal pyelectasis, echogenic bowel, echogenic intracardiac focus, FMF angle > 90 degrees, pathologic velocity of Ductus venosus and choroid plexus cyst. PMID- 22452067 TI - [Spontaneous pneumothorax during pregnancy--a case report]. AB - Authors present a case of spontaneous pneumothorax, which developed twice during the pregnancy of a lady, who delivered at term by a Cesarian section. Spontaneous pneumothorax is an extremely rare complication in pregnancy. The etiology of this condition is variable and previous broncho-pulmonary pathology is often found. Spontaneous pneumothorax may occur in any time during the pregnancy period. Early detection and prompt diagnosis of this condition are important for the prevention of some severe complications. The diagnostic and therapeutic methods used in pregnancy do not differ essentially to those used in non-pregnant patients. Delivery in such women can be performed per viasnaturales, with effortless bearing period, as well as per a Cesarian section, according to the severity and current condition of this complication. PMID- 22452068 TI - [Endometrial cancer, turned out to be an endometroid ovarian cancer stage II]. AB - 43 years old female patients endometrial biopsy diagnosis shows highly differentiated adenocarcinoma. Because of this result she underwent total hysterectomy two weeks later, and the new hystology result is: highly differentiated endometroid ovarian carcinoma. PMID- 22452069 TI - [Activity of oral lactoferrin into systematic iron homeostasis in pregnant women suffering from iron deficiency and iron deficiency anemia]. PMID- 22452070 TI - Ultrafast laser control of electron dynamics in atoms, molecules and solids. AB - Exploiting coherence properties of laser light together with quantum mechanical matter interferences in order to steer a chemical reaction into a pre-defined target channel is the basis of coherent control. The increasing availability of laser sources operating on the time scale of molecular dynamics, i.e. the femtosecond regime, and the increasing capabilities of shaping light in terms of amplitude, phase and polarization also on the time scale of molecular dynamics brought the temporal aspect of this field to the fore. Since the last Faraday Discussion (Faraday Discussion 113, Stereochemistry and control in molecular reaction dynamics) devoted to this topic more than a decade ago a tremendous cross-fertilization to neighbouring "quantum technology disciplines" in terms of experimental techniques and theoretical developments has occurred. Examples are NMR, quantum information, ultracold molecules, nonlinear spectroscopy and microscopy and extreme nonlinear optics including attosecond-science. As pointed out by the organizers, this meeting brings us back to chemistry and aims to assess recent progress in our general understanding of coherence and control in chemistry and to define new avenues for the future. To that end we will in the Introductory lecture first shortly review some aspects of coherent control. This will not be fully comprehensive and is mainly meant to give some background to current experimental efforts of our research group in controlling (coherent) electronic excitations with tailored light fields. Examples and perspectives for the latter will be given. PMID- 22452071 TI - Coherently-controlled two-dimensional spectroscopy: evidence for phase induced long-lived memory effects. AB - Using low-intensity phase-shaped excitation pulses we used two-dimensional (2D) electronic spectroscopy to follow the time dependence of the coherent correlations imposed on a solvated organic dye (Rhodamine 101 in methanol) at room temperature. Shaping of the excitation pulses strongly affects both the real and imaginary parts of the 2D-spectra, especially at small waiting times. In particular, the periodic phase modulation of the excitation pulses appears as a two-dimensional grid-like modulation in the correlation spectrum corresponding to the waiting time T = 0. By increasing the waiting time, this modulation quickly disappears in omega(t) space. However, it is still present in w, space even at very long waiting times (> or = 80 ps) where the inhomogeneous broadening is significantly reduced, and reaches its stationary value of approximately 16%. The resonant nature of this induced modulation at long waiting time allows us to conclude that phase shaping of the excitation induces a long-lived memory in solvated organic dyes that is associated with coherent population transfer. PMID- 22452072 TI - Electronic energy transfer in model photosynthetic systems: Markovian vs. non Markovian dynamics. AB - A simple numerical algorithm for solving the non-Markovian master equation in the second Born approximation is developed and used to propagate the traditional dimer system that models electronic energy transfer in photosynthetic systems. Specifically, the coupled integro-differential equations for the reduced density matrix are solved by an efficient auxiliary function method in both the energy and site representations. In addition to giving exact results to this order, the approach allows us to access the range of the reorganization energy and decay rates of the phonon auto-correlation function for which the Markovian Redfield theory and the second-order approximation is useful. For example, the use of Redfield theory for lambda > 10 cm(-1) in Fenna-Mathews-Olson (FMO) type systems is shown to be fundamentally inaccurate. PMID- 22452073 TI - Coherent control of single molecules at room temperature. AB - The detection of individual molecules allows to unwrap the inhomogeneously broadened ensemble and reveal the spatial disorder and temporal dynamics of single entities. During 20 years of increasing sophistication this approach has provided valuable insights into biomolecular interactions, cellular processes, polymer dynamics, etc. Unfortunately the detection of fluorescence, i.e. incoherent spontaneous emission, has essentially kept the time resolution of the single molecule approach out of the range of ultrafast coherent processes. In parallel coherent control of quantum interferences has developed as a powerful method to study and actively steer ultrafast molecular interactions and energy conversion processes. However the degree of coherent control that can be reached in ensembles is restricted, due to the intrinsic inhomogeneity of the synchronized subset. Clearly the only way to overcome spatio-temporal disorder and achieve key control is by addressing individual units: coherent control of single molecules. Here we report the observation and manipulation of vibrational wave-packet interference in individual molecules at ambient conditions. We show that adapting the time and phase distribution of the optical excitation field to the dynamics of each molecule results in a superior degree of control compared to the ensemble approach. Phase reversal does invert the molecular response, confirming the control of quantum coherence. Time-phase maps show a rich diversity in excited state dynamics between different, yet chemically identical, molecules. The presented approach is promising for single-unit coherent control in multichromophoric systems. Especially the role of coherence in the energy transfer of single antenna complexes under physiological conditions is subject of great attention. Now the role of energy disorder and variation in coupling strength can be explored, beyond the inhomogeneously broadened ensemble. PMID- 22452074 TI - Exploring the role of phase modulation on photoluminescence yield. AB - We report an investigation to elucidate the mechanisms of control in phase sensitive experiments in two molecular systems. A first inspection of optimization procedures yields the same experimental result: increase in the emission efficiency upon excitation by a phase modulated pulse in a two-photon transition. More detailed studies, which include power dependence, spectral response, one and two color pump-probe and pump-pump experiments show that while for one chromophore phase modulation leads to spectral matching between the two photon cross section and the second order power spectrum for the other it provides a tool to manipulate the wavepacket dynamics in the excited state. PMID- 22452075 TI - Extracting dynamics of excitonic coherences in congested spectra of photosynthetic light harvesting antenna complexes. AB - We present an analysis of dephasing rates for multiple zero-quantum electronic coherences in the Fenna-Matthew-Olson (FMO) pigment-protein complex using two dimensional electronic spectroscopy. We employ the linear prediction Z-transform to determine both the frequency and decay rates of 8 individually assigned exciton-exciton coherences. Despite congestion in the spectra, we can isolate multiple crosspeaks signals and analyze their dephasing rates. A nontrivial relationship exists between the excitons and the bath determining the lifetimes of different exciton-exciton coherences. We propose that the correlations that protect long-lived electronic coherence may yield microscopic knowledge regarding the structure of the protein bath surrounding the chromophores. PMID- 22452076 TI - Multiconfigurational Ehrenfest approach to quantum coherent dynamics in large molecular systems. AB - This article briefly describes recently developed Multiconfigurational Ehrenfest dynamics method to simulate quantum dynamics in systems with many degrees of freedom. The central idea is to guide the trajectories of basis wave functions by means of the Ehrenfest trajectories. The amplitudes of guided basis functions are coupled through a system of linear equations. The approach has been applied to simulations of nonadiabatic dynamics in Spin-Boson model and in pyrazine molecule. A new application to nonadiabatic dynamics in 24D model of pyrazine, where good spectrum for is obtained with the basis of only 34 basis Ehrenfest configurations is reported. This application provides the ground for future fully quantum direct dynamics. Another new application to the model of sticking to the surface described by the System-Bath Hamiltonian is presented to demonstrate the broadness of the approach, which can be applied to both electronically adiabatic and nonadiabatic dynamics. For all applications the results are in good agreement with those of MCTDH, which is very difficult to achieve with other trajectory based methods. Therefore MCE can serve as a starting point for future use with "on the fly" direct dynamics. MCE provides an efficient fully quantum method capable of catching coherent dynamics in multidimentional systems, which is a necessary step for developing and understanding coherent control in realistic quantum systems. PMID- 22452077 TI - The influence of the optical pulse shape on excited state dynamics in provitamin D3. AB - Broadband visible transient absorption spectroscopy was used to characterize the excited state population of 7-dehydrocholesterol (provitamin D3, DHC) following excitation by UV pulses with systematically varied linear chirp. These experiments demonstrate that the phase of the excitation pulse can modify the observed excited state decay. The results suggest that coherent mechanisms involving multiple interfering pathways may be exploited to control branching between excited state pathways and manipulate product formation. PMID- 22452078 TI - Wavepacket and potential reconstruction by four-wave mixing spectroscopy: preliminary application to polyatomic molecules. AB - We have recently shown how the excited-state wavepacket of a polyatomic molecule can be completely reconstructed from resonant coherent anti-Stokes Raman spectroscopy [Avisar and Tannor, Phys. Rev. Lett., 2011, 106, 170405]. The method assumes knowledge of the ground-state potential but not of any excited-state potential, however the latter can be computed once the excited-state wavepacket is known. The formulation applies to dissociative as well as bound excited potentials. We demonstrate the method on the Li2 molecule with its bound first excited-state as well as with a model dissociative excited state potential. Preliminary results are shown for a model two-dimensional molecular system. The calculations assume constant transition dipole moment (Condon approximation), delta-pulse excitation and a single excited-state potential, but we discuss the implications of removing these assumptions. PMID- 22452079 TI - Entanglement in interference-based quantum control: the wave function is not enough. AB - We analyze the way entanglement affects features of interference-based quantum control. We show that quantum interferences vanishes in several cases in the process of extracting probabilities from wave functions. As an example, we discuss the loss of quantum interferences when tracing over number states of the radiation field. We also consider the way in which controllability is reduced when tracing over an entire manifold of states whose cumulative probability we wish to control. Finally, we show that it is impossible to control the relative populations of degenerate states (occurring, e.g., in dissociation and chemical reactions) when the relevant transition amplitude is factorizeable, i.e., when it can be written as a product of a purely classical field-dependent part and a purely materialdependent part. Differences between entanglement and non factorizability of amplitudes are emphasized. PMID- 22452080 TI - Searching for pathways involving dressed states in optimal control theory. AB - Selective population of dressed states has been proposed as an alternative control pathway in molecular reaction dynamics [Wollenhaupt et al., J. Photochem. Photobiol. A: Chem., 2006, 180, 248]. In this article we investigate if, and under which conditions, this strong field pathway is included in the search space of optimal control theory. For our calculations we used the proposed example of the potassium dimer, in which the different target states can be reached via dressed states by resonant transition. Especially, we investigate whether the optimization algorithm is able to find the route involving the dressed states although the target state lies out of resonance in the bare state picture. PMID- 22452081 TI - Photoelectron photoion coincidence imaging of ultrafast control in multichannel molecular dynamics. AB - The control of multichannel ionic fragmentation dynamics in CF3I is studied by femtosecond pulse shaping and velocity map photoelectron photoion coincidence imaging. When CF3I is photoexcited with femtosecond laser pulses around 540 nm there are two major ions observed in the time-of-flight mass spectrum, the parent CF3I+ ion and the CF3+ fragment ion. In this first study we focussed on the influence of LCD-shaped laser pulses on the molecular dynamics. The three dimensional recoil distribution of electrons and ions were imaged in coincidence using a single time-of-flight delay line detector. By fast switching of the voltages on the various velocity map ion lenses after detection of the electron, both the electron and the coincident ion are measured with the same imaging detector. These results demonstrate that a significant simplification of a photoelectron-photoion coincidence imaging apparatus is in principle possible using switched lens voltages. It is observed that shaped laser fields like chirped pulses, double pulses, and multiple pulses can enhance the CF3+CF3I+ ratio by up to 100%. The total energetics of the dynamics is revealed by analysis of the coincident photoelectron spectra and the kinetic energy of the CF3+ and I fragments. Both the parent CF3I+ and the CF3+ fragment result from a five-photon excitation process. The fragments are formed with very low kinetic energy. The photoelectron spectra and CF3+/CF3I+ ratio vary with the center wavelength of the shaped laser pulses. An optimal enhancement of the CF3+/CF3I+ ratio by about 60% is observed for the double pulse excitation when the pulses are spaced 60 fs apart. We propose that the control mechanism is determined by dynamics on neutral excited states and we discuss the results in relation to the location of electronically excited (Rydberg) states of CF3I. PMID- 22452082 TI - A general control mechanism of energy flow in the excited state of polyenic biochromophores. AB - Quantum dynamics in photobiology is a highly controversial subject of modern research. In particular, the role of low-frequency vibrational coherence of biochromophores has been intensely discussed. Coherent control of polyenic chromophores, like carotenoids and retinoids, has been showing that the manipulation of such low frequency coherences may play a crucial role in the evolution of excited population and therefore in the efficiency of photosynthesis. However, no precise control mechanism has been derived. In order to clarify this open question, we combined quantum dynamical modelling with a sensitive experimental technique, namely Pump-Degenerate Four Wave Mixing (Pump DFWM). In this work we investigate in detail the internal conversion channel of beta-carotene, an important polyenic chromophore, under multipulse excitation and focus on the role of the non-adiabatic coupling between excited-state potentials and the internal energy loss. Our control mechanism is based on the interference between wavepackets in the excited state, which leads to a transient evolution of the vibrational population dependent on the relative phase between excitation sub pulses. Such a transient evolution can affect the branching ratio between competing channels in the excited state. Therefore, our results are able to rationalize pulse shapes found in a whole class of coherent control experiments involving polyenic biochromophores, like in light harvesting complexes and in bacteriorhodopsin. PMID- 22452083 TI - Coherent control of vibrational transitions: discriminating molecules in mixtures. AB - Identifying complex molecules often entails detection of multiple vibrational resonances, especially in the case of mixtures. Phase shaping of broadband pump and probe pulses allows for the coherent superposition of several resonances, such that specific molecules can be detected directly and with high selectivity. Our particular implementation of coherent anti-Stokes Raman scattering (CARS) spectroscopy and imaging employs broadband pump and probe fields in combination with a narrowband Stokes field. We describe our approach for combining spectral phase shaping and closed-loop optimization strategies to perform chemically selective microscopy. To predict the optimal excitation profile we employ evolutionary algorithms that use the vibrational phase responses of five distinct molecules with overlapping resonances and investigate the effect of phase instability on the optimization. We have recently shown that modified polynomials and orthogonal rational functions can give rise to improved contours for CARS fitness landscapes. Now, by considering the landscapes associated with different basis sets, we introduce two figures of merit to quantitatively rank basis functions in terms of their "appropriateness" for modeling nonlinear phase-shaped processes. PMID- 22452084 TI - Coherent control of the motion of complex molecules and the coupling to internal state dynamics. AB - We discuss coherent control of the centre of mass motion of complex molecules by de Broglie interferometry. We describe an experiment to couple the dynamics of internal state population of complex molecules to their centre of mass motion. We discuss how this can be used to probe state population and transition, especially the photo-switching of flourinated di-azobenzene molecules between their cis- and trans-configuration. We propose an experiment to photo-isomerise complex di azobenzene molecules in the gas-phase, including the selective detection of molecules in different conformations. In addition we discuss possible ways of optimising the conformation detection through cooling, and optical techiques. PMID- 22452085 TI - Combining dissociative ionization pump-probe spectroscopy and ab initio calculations to interpret dynamics and control through conical intersections. AB - Nonadiabatic processes play an important role in molecular dynamics, and understanding these processes better can help interpret and guide control over molecules. We are using high level electronic structure calculations in combination with intense, shaped, ultrafast laser pulses to study excited state dynamics in the nucleic acid bases, cytosine and uracil. These molecules have very short excited state lifetimes as they relax radiationless through conical intersections after absorption of UV radiation. The presence of more than one relaxation pathway provides the possibility to control which pathway can be involved in the dynamics. In our approach the molecules were excited using ultrafast laser pulses in the deep UV and then probed with strong field near infrared pulses which ionize and dissociate the molecules. Key to this approach is the fact that different fragments exhibit different dynamics and we can correlate these fragments, and their associated dynamics, to the various pathways involved in the neutral dynamics. Multiconfigurational electronic structure methods were used to calculate potential energy surfaces of the neutral and ionic states involved in the dynamics. Calculating mechanisms for fragmentation in the ion enables us to relate specific fragments to different neutral pathways, and use them as signatures to follow the dynamics. Possibilities for control are also discussed. PMID- 22452086 TI - Nonadiabatic ab initio molecular dynamics including spin-orbit coupling and laser fields. AB - Nonadiabatic ab initio molecular dynamics (MD) including spin-orbit coupling (SOC) and laser fields is investigated as a general tool for studies of excited state processes. Up to now, SOCs are not included in standard ab initio MD packages. Therefore, transitions to triplet states cannot be treated in a straightforward way. Nevertheless, triplet states play an important role in a large variety of systems and can now be treated within the given framework. The laser interaction is treated on a non-perturbative level that allows nonlinear effects like strong Stark shifts to be considered. As MD allows for the handling of many atoms, the interplay between triplet and singlet states of large molecular systems will be accessible. In order to test the method, IBr is taken as a model system, where SOC plays a crucial role for the shape of the potential curves and thus the dynamics. Moreover, the influence of the nonresonant dynamic Stark effect is considered. The latter is capable of controlling reaction barriers by electric fields in time-reversible conditions, and thus a control laser using this effect acts like a photonic catalyst. In the IBr molecule, the branching ratio at an avoided crossing, which arises from SOC, can be influenced. PMID- 22452087 TI - Dynamic Stark control: model studies based on the photodissociation of IBr. AB - The Stark effect is produced when a static field alters molecular states. When the field applied is time dependent, the process is known as the dynamic Stark effect. Of particular interest for the control of molecular dynamics is the Non Resonant Dynamic Stark Effect (NRDSE), in which the time dependent field is unable to effect a one-photon excitation. The intermediate strength laser pulse instead shapes the potential energy surfaces (PES) and so guides the evolution of the system. A prototype control scheme uses the NRDSE to change the topography of PES in regions where they intersect, thus providing control over photochemistry. Following earlier experimental work, in this paper we study the NRDSE on a new 3 state model of the IBr molecule to gain insight into the mechanism of control at the avoided crossing that governs the branching ratio of the photodissociation. PMID- 22452088 TI - From molecular control to quantum technology with the dynamic Stark effect. AB - The non-resonant dynamic Stark effect is a powerful and general way of manipulating ultrafast processes in atoms, molecules, and solids with exquisite precision. We discuss the physics behind this effect, and demonstrate its efficacy as a method of control in a variety of systems. These applications range from the control of molecular rotational dynamics to the manipulation of chemical reaction dynamics, and from the suppression of vacuum fluctuation effects in coherent preparation of matter, to the dynamic generation of bandwidth for storage of broadband quantum states of light. PMID- 22452089 TI - Controlled redistribution of vibrational population by few-cycle strong-field laser pulses. AB - The use of strong-field (i.e. intensities in excess of 10(13) Wcm(-2)) few-cycle ultrafast (durations of 10 femtoseconds or less) laser pulses to create, manipulate and image vibrational wavepackets is investigated. Quasi-classical modelling of the initial superposition through tunnel ionization, wavepacket modification by nonadiabatically altering the nuclear environment via the transition dipole and the Stark effect, and measuring the control outcome by fragmenting the molecule is detailed. The influence of the laser intensity on strong-field ultrafast wavepacket control is discussed in detail: by modifying the distribution of laser intensities imaged, we show that focal conditions can be created that give preference to this three-pulse technique above processes induced by the pulses alone. An experimental demonstration is presented, and the nuclear dynamics inferred by the quasi-classical model discussed. Finally, we present the results of a systematic investigation of a dual-control pulse scheme, indicating that single vibrational states should be observable with high fidelity, and the populated state defined by varying the arrival time of the two control pulses. The relevance of such strong-field coherent control methods to the manipulation of electron localization and attosecond science is discussed. PMID- 22452090 TI - Control of coherent excitation of neon in the extreme ultraviolet regime. AB - Coherent excitation of a superposition of Rydberg states in neon by the 13th harmonic of an intense 804 nm pulse and the formation of a wave packet is reported. Pump-probe experiments are performed, where the 3d-manifold of the 2p6- >2p5 (2P3/2) 3d [1/2]1- and 2p6-->2p5 (2P3/2) 3d [3/2]1-transitions are excited by an extreme ultraviolet (XUV) radiation pulse, which is centered at 20.05 eV photon energy. The temporal evolution of the excited state population is probed by ionization with a time-delayed 804 nm pulse. Control of coherent transient excitation and wave packet dynamics in the XUV-regime is demonstrated, where the spectral phase of the 13th harmonic is used as a control parameter. Modulation of the phase is achieved by propagation of the XUV-pulse through neon of variable gas density. The experimental results indicate that phase-shaped high-order harmonics can be used to control fundamental coherent excitation processes in the XUV-regime. PMID- 22452091 TI - Optical manipulation of coherent phonons in superconducting YBa2Cu3O7-delta thin films. AB - The coherent phonons of YBa2Cu3O7-delta are believed to be strongly coupled to its superconductivity. Controlling the phonons below its transition temperature, therefore, may serve as a promising scheme of the control of superconductivity. Here we demonstrate optical manipulation of the Ba-O and Cu-O vibrations in a thin-film YBa2Cu3O7-delta below its transition temperature using a pair of femtosecond laser pulses. The interpulse delay is tuned to integral and half integral multiples of the oscillation period of a specific phonon mode (Ba-O or Cu-O vibration) to enhance and suppress its amplitude, respectively. PMID- 22452092 TI - Femtosecond coherent control of thermal photoassociation of magnesium atoms. AB - We investigate femtosecond photoassociation of thermally hot atoms in the gas phase and its coherent control. In the photoassociation process, formation of a chemical bond is facilitated by light in a free-to-bound optical transition. Here, we study free-to-bound photoassociation of a diatomic molecule induced by femtosecond pulses exciting a pair of scattering atoms interacting via the van der-Waals-type electronic ground state potential into bound levels of an electronically excited state. The thermal gas of reactants is at temperatures in the range of hundreds of degrees. Despite this incoherent initial state, rotational and vibrational coherences are observed in the probing of the created Mg2 molecules. PMID- 22452093 TI - A perspective on controlling quantum phenomena. AB - Controlling dynamical processes at the atomic and molecular scales with laser radiation has been a long-standing dream. The Faraday Discussion presented a cross section of the current experimental and theoretical advances as well as the challenges for the field. This paper summarizes the current status of controlling quantum dynamics phenomena and provides a perspective on the future. PMID- 22452094 TI - [From research on occupational tumors to interventional prevention: use of the OCCAM method at the ASL in Como]. AB - In the framework of "Occupational Cancers" project of the Lombardy Region, estimates of cancer risk by site and by economic activity for the incidence period 2001-2004 have been produced in the Local Health Unit of Como. Using these estimates a set of cancer cases with possible occupational origin has been determined. This has been carried out using the OCCAM approach, a case control study where incident cases are identified by hospital discharge records, controls are sampled from health population files and occupational histories are obtained by automatic link with social security archives. This has been integrated with the knowledge of firms and the workers' awareness of other cancer cases in the workforce of the same firms. Among 45 cases with potential occupational origin, 24 were established as due to occupation. These cases were referred for compensation. Moreover, carcinogenic risks still present in some firms were identified and appropriate interventions were carried out. PMID- 22452095 TI - [Environmental monitoring of volatile organic compounds and metallic elements in two analysis laboratories]. AB - Environmental monitoring of volatile organic compounds (VOCs) in analytical chemistry laboratories is somewhat tricky because exposure levels are highly variable and the number of toxic compounds, often used in combination, may be very high. This study was designed to evaluate airborne levels of VOCs and metallic elements associated to inhalable dusts in two Italian labs. The airborne levels of VOCs and elements fell well below the occupational exposure limit values recorded in the Italian law (D.lgs. 81/2008, Allegato XXXVIII) and the TLV TWA from the list of American Conference of Governmental Industrial Hygienists. The determination of measurable levels of toxic and potentially carcinogenic compounds in office rooms may be of interest for personnel not specifically engaged to handle chemicals. PMID- 22452096 TI - [Accidents and headache]. AB - Work accidents are a major cause of morbidity and mortality by creating a loss not only for the individual affected but also for society given the high number of absences from work that follows. Many have been efforts since the early 60 'to minimize the number of accidents but, although it is known a steady downward trend in recent years, in Italy in 2010 there were still 775,000 cases of accidents and 980 deaths. The study examined a population of 192 persons injured of which 41 have proven to be headache and data collected showed that the frequency of headache among the workers who suffer an injury is equal to 26.2%. Finally, it is conceivable that the reduction of attention, "disability" or the effect induced headache post-pharmacological risk factors are important in causing accidents at work and would therefore be appropriate to continue the study recorded the presence/absence of headache at the time of the event accidents. PMID- 22452097 TI - [Work capacity perceived by nurses: descriptive study]. AB - Perceived work ability is the worker perception of his/her job performances. There are many factors involved in this perception: individual characteristics (such as health status, motivation, and attitudes), job characteristics (such as technological resources, physical and mental demands) and working climate (such as job organization and leadership styles). The promotion of a good work ability could decrease the premature loss of workers and could help them in facing job demands and stress. In the health care settings the risk to perceive a low work ability could be higher due to nurses' shortage. The main aim of this pilot study was to measure the perceived work ability among nurses in order to find the work ability predictors. 78 nurses were recruited and had filled the Work Ability Index (WAI). The main work ability predictors found were: age over 45 years (OR=4,56; IC 95% 1,14 to 19,14), working years over 15 (OR=3,18; IC 95% 1,09 to 9,45) and more than 3 diseases (OR=25,00; IC95% 3,17 to 531,90). These results give useful information to health care managers in order to improve human resources management strategies and to find solutions about nurses' shortage and aging workforce. PMID- 22452098 TI - [Assessing work-related stress: an Italian adaptation of the HSE Management Standards Work-Related Stress Indicator Tool]. AB - The aim of this paper is to present a preliminary validation of an Italian adaptation of the HSE Management Standards Work-Related Stress Indicator Tool (IT), an instrument for assessing work-related stress at the organizational level, originally developed in Britain by the Health and Safety Executive. A scale that assesses the physical work environment has been added to the original version of the IT. 190 employees of the University of Trieste have been enrolled in the study. A confirmatory analysis showed a satisfactory fit of the eight factors structure of the instrument. Further psychometric analysis showed adequate internal consistency of the IT scales and good criterion validity, as evidenced by the correlations with self-perception of stress, work satisfaction and motivation. In conclusion, the Indicator Tool proved to be a valid and reliable instrument for the assessment of work-related stress at the organizational level, and it is also compatible with the instructions provided by the Ministry of Labour and Social Policy (Circular letter 18/11/2010). PMID- 22452099 TI - [Work-related stress and mobbing: case series and gender differences]. AB - The attention of international agencies and scientific community on mobbing (bullying) and work-related stress is increasing. However, research on gender differences and etiologic agents is still limited. This study describes the gender differences found in victims of mobbing and work-related stress in an Italian case series. Between 2001 and 2009, at the Occupational Medicine Unit of our Institution we examined 345 outpatients (197 women and 148 men) for suspected psychopathological work-related problems. After interdisciplinary diagnostic evaluation, the diagnosis of "mobbing syndrome" was formulated, according to international criteria (ICD-I0 and DSM-IV), in a minority of cases: 35 subjects. In the other workers, we found pre-existing psychiatric conditions (not related to work), or altered relationships dynamics with the colleagues. Significant gender differences emerged among people with "mobbing syndrome": there was a high prevalence of women (65%), with medium to high level of education; the most affected age group was between 34 and 45 years; several occupations were involved, with a clear preponderance of office workers. Women are mostly harassed for personal aspects related to emotional and relational factors; men for the content of their work. The knowledge of the phenomenon is an essential prerogative to contrast mobbing; this can be realized, at a preventive level, only through effective information and training for workers and employers, who have the legal obligation to preserve the integrity of the mental and physical status of their employees during the work. PMID- 22452100 TI - [Active research on occupational diseases caused by biomechanical overload in construction: experience at the ASL of Bergamo]. AB - The analysis of the national and international literature reveals a prevalence of around 20% of work-related musculoskeletal disorders in construction workers over 40 years of age. The chronic-degenerative disease in the muscular-skeletal system is important not only for the number of reported cases, but also for the seriousness of the symptoms, which are one of the main causes of evaluations of limited work-suability and unfitness for work. The aim of this study is to improve the quality of the diagnosis of occupational musculoskeletal illnesses and to ensure that the occupational physicians identify such disease, as prescribed by the Italian legislation about safety and health in workplaces. The research involved 57 construction companies located in the Bergamo's province, which employ, in aggregate, 833 workers. A sample of 479 workers, 40, or more, years old (403 Italians and 76 foreigners) was analysed. It was found out that 152 workers had some musculoskeletal disorders but only for 5 of them an occupational disease was already reported. It was necessary to ask the occupational physician for further clinical investigation for 60 employees, which revealed 29 new musculoskeletal occupational diseases in 19 workers. At the end of the study a total of 34 musculoskeletal occupational diseases were diagnosed in 22 workers: it was 4, 6% of the total sample investigated (n. 479) and 14% of those who already had problems (no 152). The results confirm the under-reporting of occupational musculoskeletal diseases in construction workers. The active research is a useful tool for the purposes of verifying the level of health surveillance carried out by occupational physicians. In fact the study highlighted that physicians seem not to be inclined to require additional clinical investigations and not always report occupational diseases. PMID- 22452101 TI - [microRNAs as biological indicators of environmental and occupational exposure to asbestos]. AB - Malignant mesothelioma is an aggressive cancer refractory to current therapies, the incidence of which is expected to rise in the next decades. Exposure to asbestos is a well known risk factor, as InternationalAgency for Research and Cancer (IARC) classified this compound as group I (carcinogenic to humans). The lack of tumor biomarkers for diagnosis and medical survey plays a fundamental role for the development of a universally accepted therapeutic approach. In this review we evaluated the mechanism of asbestos carcinogenesis by analyzing activated oncogenes, genetic predisposition, and SV40 infection as cofactors. Therefore, interest has focused on microRNAs, 19-25 nucleotide-long single stranded RNAs that negatively regulate gene expression by modulating translational efficiency of target genes involved in numerous cellular processes including development, differentiation, proliferation, apoptosis, and stress response. The analysis revealed a differential expression of miRNAs between mesothelioma and mesothelial cells, suggesting their potential role as oncogenes or tumor suppressor genes in mesothelioma oncogenesis. We have also investigated the role of polymorphism in the etiology and pathogenesis of mesothelioma, in order to evaluate the association between disease linked to asbestos exposure andgenetic variability. The identification of dysregulated miRNAs or frequent genetic polymorphisms as potential diagnostic biomarkers or as prognostic factors for malignant mesothelioma could facilitate the surveillance procedure of subjects exposed to asbestos. PMID- 22452102 TI - [Particulate matter and atmospheric pollutants exposure for outdoor workers in the Muggia area (Trieste, Italy)]. AB - Urban air pollution originates from traffic, heating and industrial activities and it exposes several categories of workers to noxious chemicals; in recent years various surveys have been carried on taxi drivers, bus drivers, policemen, newspaper kiosks, fuel station workers and general population, for assessing exposure to main contaminants, benzene and PAHs in particular. AIM: defining a specific sampling strategy for collecting an experimental data base for the assessment of potential population exposure to atmospheric particulate matter in the Muggia area (Trieste, North-East Italy). MATERIALS AND METHODS: A sample of 14 urban police officers working mainly on the roads and potentially subject to occupational exposure has been analyzed, as well as a sample of the municipal administrative personnel (13 people) working in indoor environments during the same sampling periods. Exposure has been monitored by personal samplers and high volume environmental samples; urinary levels of 1 OH-pyrene and creatinine were collected for each participant at the end of each sampling period. RESULTS: PAHs analyses provided diagnostic ratios for identification of the sources of pollution. In general experimental BaP values stay below the environmental target value, with satisfactory agreement between environmental and personal monitoring. Levels of urinary 1 OH-pyrene for administrative personnel was detected always below the background value (0.089 micromoles/mole creatinine), while they are above the background and below the attention value for most of urban police officers. CONCLUSIONS: Municipal police officers participating to the present study, while belonging to one of the categories of people most exposed to outdoor PM, do not show any worrying exposure to the considered chemicals associated to their occupational activity, in comparison to other factors, possibly associated to personal lifestyles. PMID- 22452103 TI - [Six years of appeals against the judgements expressed by occupational physicians and received by ASL 3 Genovese]. AB - We illustrate the results of an historic analysis about the appeals against the judgements expressed by occupational physicians in the territory of ASL3 "Genovese": S.C. PSAL of the ASL3 "Genovese" is the vigilance committee of the local health unit of Genoa. The data have been analyzed for the last six years of activity, from 2005 to 2010 (159 appeals). The analysis of the characteristics of: applicants, duties, occupational risks and results of the appeals contributed for a best knowledge of a procedure for a judgment that involves two important rights of working people: health (safety) and work. This analysis is also most useful for occupational physicians and for the health units interested in surveillance activity. PMID- 22452104 TI - [WMSDs in supermarket cashiers]. AB - High prevalence of Cumulative Trauma Disorders (CTD) of shoulder and wristle among supermarket cashiers have been reported by several studies. To evaluate CTD prevalence in a group of supermarket cashiers in Pisa area is the aim of this study. Standardized Questionnaire and clinical examination have been performed in 128 female supermarket cashiers. In subjects having Symptoms and Signs, Elettroneurography and Echography have been performed. 54 subjects had Paresthesias and performed elettroneurography: 44 (34,4%) had Median nerve impairment at the wrist and among them 37 cases were bilateral; 15 had Ulnar nerve impairment (11,7%), among them 8 were bilateral. Moreover we have performed the echographies in all the 25 subjects with a positive medical examination of the shoulder and they all (19,5% del totale) showed a rotator cuff tendinosis. 25 subjects with CTD (44,6%) showed a comorbidity. An index called BiCo considering both bilaterality and comorbility has been calculated. The percentage of CTD is much more elevated than in general population and many workers present comorbility and bilaterality: a strategy for primary prevention improving ergonomy and information is needed. PMID- 22452105 TI - [Metabolic syndrome and shift work: study of the relationship in workers of a chemical plant]. AB - Metabolic syndrome is defined by several metabolic factors, related to one another, which induce atherosclerotic pathology. These factors are: visceral obesity, atherogenic dyslipidemia, high blood pressure, hyperglycemia, proinflammatory and prothrombotic state. Shift work is known to be related to a series of organic changes, including increased cardiovascular risk independent factors. The aim of our study is to assess if shift work might be a cofactor inducing metabolic syndrome. 119 workers of a chemical industry have been examinated and been divided in two groups: shift workers and daytime workers. We checked if workers were affected by metabolic syndrome, following the ATP III criteria. The results have been statistically compared. The prevalence of metabolic syndrome is significantly higher in night shift workers comparing to other workers. Among night shift workers metabolic syndrome was found in 28 out of 77 (36,36%); in daytime workers the syndrome was observed in 8 workers out of 42 (19,05%) (DR: 2, 43; 95% CI 0,99 - 5,98; p=0,049). This difference is stronger when only over 40 years old subjects were considered. Our results show an association between metabolic syndrome and night shift work. It is therefore necessary, as primary health safety measure, to verify the presence of metabolic syndrome in night shift workers. All aspects of the syndrome should be studied to prevent disease and its clinical complications. The primary prevention activity should be based on specific information and education programs, particulary aimed at learning about a correct lifestyle. PMID- 22452106 TI - Effect of therapeutic horseback riding on balance and gait of people with multiple sclerosis. AB - BACKGROUND: Exercise therapy is an important part of symptomatic and supportive treatment in patients with multiple sclerosis (PwMS). According to the literature, equine-assisted therapies--such as therapeutic horseback riding (THR) and hippotherapy (HT)--are exercise therapies that can have positive physical effects on coordination, muscle tone, postural alignment, stiffness/flexibility, endurance and strength, correcting abnormal movement patterns and improving gait and balance. While HT is known to have a positive effect on balance in PwMS, data about THR are limited. OBJECTIVE: The aim of the present work was to determine the effect of THR on the balance and gait of ambulatory PwMS. METHODS: Twenty seven PwMS were included in the study. Patients were divided into two groups: 12 underwent THR and 15 traditional physiotherapy (for both groups, two series of 10 weekly sessions were performed). Before and after the study period, the following outcome measures were applied: Extended Disability Status Scale (EDSS), Barthel Index, Tinetti Performance-Oriented Mobility Assessment (POMA). In addition, patients of the THR group underwent a gait analysis to assess spatiotemporal gait parameters and ground reaction forces. RESULTS: The THR group showed a significant improvement in POMA scores (p<0.005) and two gait parameters: stride time (p<0.04) and ground reaction forces (p<0.01). No statistically significant change was found in the control group. CONCLUSION: The results of the study show that THR can improve balance and gait of ambulatory PwMS. Findings are preliminary, but promising and in line with the recent literature. PMID- 22452107 TI - Top ten tech trends 2012. A time of exhilaration and anxiety. PMID- 22452108 TI - Performance imperatives. PMID- 22452109 TI - Population health management and readmissions. PMID- 22452111 TI - Bridging the care transition gap. PMID- 22452110 TI - Turning healthcare's business model inside out. PMID- 22452112 TI - Second-generation clinical decision support. PMID- 22452113 TI - Year of the CISO. PMID- 22452114 TI - Private HIEs on the upswing. PMID- 22452115 TI - Imaging informatics and the enterprise. PMID- 22452116 TI - The BYOD revolution. PMID- 22452117 TI - The game changer. PMID- 22452118 TI - Getting analytical. AB - How one physician group manages revenue and reimbursements around highly complex legal issues. PMID- 22452119 TI - The diabetes dashboard: when physician time is money. PMID- 22452121 TI - PACS in the cloud--plus teleradiology. PMID- 22452120 TI - Perioperative suite ripe for IT investment. PMID- 22452122 TI - ePrescribing: lost in transmission. PMID- 22452123 TI - Building a successful (remote) team. PMID- 22452124 TI - [Estimated orphans]. PMID- 22452125 TI - [Special characteristics of antibiotic therapy in the elderly]. AB - The ever-increasing proportion of elderly people in the general population represents physicians and pharmacists with new challenges. Older people suffer more frequently than younger persons from bacterial diseases, and they have a higher tendency to develop more severe or progressive forms of these illnesses. Bacterial diseases of the urinary tract, respiratory tract, skin and soft tissues are especially common in old age. In general, most antibacterial agents are also promising agents for the therapy of bacterial diseases in the elderly. Prior to initiating therapy, however, the modified organ functions of the elderly have to be considered carefully. Depending on the individual and the antibacterial agent, a dose adjustment may be necessary. To reduce the high mortality rate characteristic for many infectious diseases in the elderly, antibacterial therapy ought to be carefully calculated and initiated as quickly as possible. It has to be born in mind that some side effects of antibiotics are more common and more severe in old age. Since older people often take several drugs simultaneously, the probability for the occurrence of side effects and drug interactions in this population is greatly increased. Significant compliance problems may also arise. PMID- 22452126 TI - [Medication review for dementia patients]. AB - Due to demographic changes we are faced with several challenges as an increasing prevalence of dementia patients. We report on a medication review of a patient with Alzheimer's disease as well as Lewy body dementia. The intake of risperidone was interrupted instead of a dose reduction which was recommended by the psychiatrist to improve mobility. As an adverse event the patient developed serious psychiatric symptoms which were treated in an acute care facility. We discussed several alternative treatment options (pipamperon, melperon, haloperidol, risperidone, clozapine, olanzapine, aripiprazol, and quetiapin) in a case conference. Due to a short half life period and insignificant anticholinergic effects we decided to choose quetiapin. Despite a small number of taken drugs we identified several potential drug related problems which were solved in a multipartite health care professional team. PMID- 22452127 TI - [Chronic pancreatitis]. PMID- 22452128 TI - [Renin angiotensin system inhibitors: too much of a good thing can be dangerous]. PMID- 22452129 TI - [Renal amyloidosis]. AB - Amyloidosis is defined as the extracellular deposition of proteins that have the capacity to form beta-pleated sheets and become insoluble. More than 17 types of amyloidosis have been described. Systemic light chain amyloid (AL) and AA amyloid (secondary to chronic inflammatory process) are by far the most frequent forms of amyloidosis. In these systemic forms, organs involved are the kidneys, the heart and the gastrointestinal tract in AL amyloidosis. The diagnostic can be established only by tissue biopsy. Treatment of primary amyloidosis (AL) aims at suppressing the responsible clone whereas treatment of secondary amyloidosis relies on controlling the underlying inflammatory process. Prognosis is globally poor and depends on the extend of organs involvement particularly cardiac and renal. The prognosis is even worse in patients requiring dialysis. PMID- 22452130 TI - [What reasonable applications for regional citrate anticoagulation in renal replacement therapy?]. AB - Regional citrate anticoagulation of the extracorporeal circuits (CRA) experienced considerable growth over the past decade. This development is partly explained by the significant progresses made in the field of bioengineering. These allow a secure administration of citrate, while an increasing availability of ionized calcium measurement at the bedside allows reactivity in monitoring the treatment. An increasing severity of the medical condition of patients requiring blood purification treatment gives more contrast to the profile of patient who may benefit from a CRA. If some methods of renal replacement therapy are well suited to this mode of anticoagulation, others are, to date, only at the stage of development and are applied under close medical supervision. PMID- 22452131 TI - [Sleep disorders in patients with chronic renal insufficiency]. AB - Sleep disorders, especially insomnia, daytime sleepiness, sleep apnea syndrome and restless legs syndrome are very frequently encountered in patients with chronic renal failure whether or not they undergo renal replacement therapy. The causes of sleep disorders are multifactorial and not only linked to the renal disease itself, but also to its treatment and its associated psychosocial factors. This article discusses the prevalence and physiopathology of the most frequently encountered sleep disorders in chronic renal failure patients, and highlights the actually available therapeutic options. PMID- 22452132 TI - [Is the use of vitamin K antagonists harmful in patients with CDK?]. AB - As chronic kidney disease (CKD) is a contraindication to the use of the new anticoagulants, the vitamin K antagonists (VKA) are still valid in patients with CKD, though their use may be harmful. During overanticoagulation, some patients can develop acute kidney injury (AKI), especially those with CKD, by obstruction of the renal tubules and Bowman's spaces by erythrocytes. In addition, VKA increase atherogenesis through vitamin K deficiency, which is essential for the carboxylation of proteins that inhibit calcification of vessels. Eventually, hemodialysed patients under VKA have an increased risk of stroke, especially those over 75 years of age. Therefore anticoagulation with VKA in patients with CKD should be carefully implemented and its monitoring more frequent than in non CKD patients. PMID- 22452133 TI - [Proteinuria: pathophysiology and clinical implications]. AB - Pathological proteinuria is a sign of renal disease, either tubular or glomerular. Proteinuria is considered as a major renal and cardiovascular risk factor Screening, and quantification of proteinuria is part of the care of chronic kidney disease (CKD) patients, but also of high renal risk patients and high cardiovascular risk patients. CKD is now classified according to estimated GFR and proteinuria to improve prediction of adverse events. in this article, we summarize the pathophysiology of proteinuria, its clinical qualification and implications. PMID- 22452134 TI - [Diabetic nephropathy: an update]. AB - Diabetes has a constantly growing prevalence and leads to a number of complications such as diabetic nephropathy. A systematic screening and an adapted management are needed to limit the renal and also the cardiovascular complications linked to diabetic nephropathy. An adequate glycemic and tensional control and control of proteinuria are the priority in the care of diabetic nephropathy. Other aspects such as phospho-calcium balance, lipid panel or lifestyle changes are also important and therefore a multidisciplinary approach is essential. A better understanding of the physiopathology may lead to even more effective treatments in the future. We resume in this article the actual management of a patient suffering from diabetic nephropathy and the future treatment perspectives. PMID- 22452135 TI - [Anosognosia]. PMID- 22452136 TI - [Alzheimer disease: the temptation coming from off-label use]. PMID- 22452137 TI - [When physicians practiced war against ovaries]. PMID- 22452138 TI - [The helmet: this enemy that wants to be good to cyclists]. PMID- 22452139 TI - [Discomfort in data]. PMID- 22452140 TI - Pastoral counseling has received increasing public and professional attention. PMID- 22452141 TI - Research report: a grounded theory description of pastoral counseling. AB - Historically, clerical paradigms of ordained ministry have defined pastoral counseling. However, these fail to describe pastoral counselors in the complex social, theological and medical contexts in which they now work. This study asks the question: How do pastoral counselors in clinical practice describe what is uniquely "pastoral" about the counseling they offer clients? Grounded theory was used to propose a preliminary description and an intermediate theory of how pastoral counselors interpret "pastoral." Eighty-five pastoral counselors were selected for the study over a four year period using criteria to assure maximum variation. Interviews and pastoral identity statements were collected and coded, and theoretical models were organized using NVIVO, a computer assisted qualitative design and analysis software (CAQDAS) package. Results suggest that pastoral counselors share some common ideas regarding "pastoral identity" and clinical practice. How pastoral counselors interpret "pastoral" is highly context sensitive and varies widely. PMID- 22452142 TI - Seminarian attitudes toward counseling. AB - This paper examines whether seminarians are interested in referring parishioners to pastoral counselors or prefer handling commingled psychological and spiritual problems through counseling parishioners themselves. Research results revealed openness toward referral and also a strong interest in counseling persons themselves. Forms of collaboration other than referral were also examined, and seminarians indicated openness to using consultation, training, and personal therapeutic support. Implications for church-psychology collaboration, generally, are discussed. Areas for further research are recommended. PMID- 22452143 TI - Clergy referral of suicidal individuals: a qualitative study. AB - In a national study, 25% of help-seekers contacted clergy; suicidal behavior was one of the significant predictors for making contact. Clergy have been found to refer 10% of help-seekers to mental health providers. This qualitative study explored the referral practices of 15 northeastern Mainline and Evangelical Protestant clergy when contacted by suicidal individuals; all referred to mental health providers. Participants reported low confidence with risk identification and provided moving examples of pastoral care. PMID- 22452144 TI - Using movies in pastoral counseling. AB - This article uses a case study of a bereaved woman to illustrate the potential benefits of using movies as an adjunctive therapy in pastoral counseling. The article also references the literature on bibliotherapy and cinematherapy while summarizing relevant findings from studies for the use of movies in clinical practice. This article offers both suggestions and cautions for practitioners. At this time, research suggests that a considered therapeutic use of movies can be beneficial for personal growth. PMID- 22452145 TI - Process theology's relevance for older survivors of domestic violence. AB - Pastoral work with survivors of domestic violence may reveal theological struggles. Understandings of scripture that reinforce a sense of powerlessness and alienation from God may contribute to an impaired relationship and limit resources for healing. One framework for re-imaging a relationship with God is process theology. This framework was applied to a case study for one survivor. The application resulted in a line of inquiry that may assist survivors in their healing process. PMID- 22452146 TI - Professional boundary violations and mentalizing in the clergy. AB - Increasing attention has been focused on mental health problems of clergy in light of long work hours, extraordinary demands, and diversity of tasks. In this communication we report findings from the psychiatric evaluation of 70 Episcopal priests. We describe psychiatric diagnoses, but our focus is on two common themes that emerged: difficulties maintaining professional boundaries and problems with mentalizing, i.e., imagining the impact of their behavior and words on others. Recommendations for education and prevention are addressed. PMID- 22452147 TI - Just who do you think you are? Self-care and the resident. PMID- 22452148 TI - Hoary wisdom. PMID- 22452149 TI - A pilot study of spirituality and inpatient rehabilitation outcomes in persons with spinal cord dysfunction and severe neurological illnesses. AB - This prospective, observational pilot study was conducted on an academic inpatient rehabilitation unit. Ninety-three persons with spinal cord dysfunction or severe neurological illness participated. All completed admission surveys; 46 completed surveys six months after discharge. The aims were to describe admission and post-discharge spirituality and associations between spirituality and rehabilitation outcomes. At admission, participants reported spirituality similar to that of other samples of medical patients. After discharge, frequency of private spiritual practices increased and spiritual and existential well-being decreased. No significant associations were detected between spirituality and rehabilitation outcomes. Findings suggest the importance of spirituality to the participants and future research with a larger sample and modifications to the methodology. PMID- 22452150 TI - Celibacy and male psycho-sexual development. AB - Counselors and psychologists would benefit from a nuanced appreciation of Catholic sexual morality when working with human development issues among those who adhere to Church teaching. This focus is especially so among those preparing for a life of stable celibate chastity. Appreciation of the differences between boys and men and girls and women in the processes of psycho-sexual maturation is important. This article addresses these issues with a focus on celibacy and male psycho-sexual development in young men of Catholic commitment. PMID- 22452151 TI - A survey of clergy practices associated with premarital financial counseling. AB - The purpose of this exploratory study was to gain an understanding of the state of clergy-led premarital financial counseling. Clergy respondents (n = 223) indicated that they often include a financial component in their formal premarital counseling. The most frequently discussed financial topics are budgeting, managing debt and credit, and saving. The most frequently cited obstacles to providing premarital financial counseling are lack of time and lack of subject matter expertise. PMID- 22452152 TI - Pastoral care professionals in health and mental health care: recognizing classic and newer versions of ageism. AB - Pastoral care professionals are cognizant of many forms of prejudice and discrimination in society and health care environments. Ageism is perhaps the least likely to be challenged as prejudice or discrimination. Ageist perception is suspicious of the health and cognitive ability of older persons; without consideration of emotional, spiritual, or social abilities. While positive and negative ageist attributions are culturally abundant, new and subtle versions of ageism offer convincing guidance about personal responsibility for health status and insist on personal social engagement. Older persons who are not free of disease or disability may be viewed as culpable for their failure to age well. Additionally, elders may be expected to maintain social involvement; especially through volunteerism. Elders who are unable or unwilling to engage in volunteerism may be viewed as selfish or irresponsible. If individuals are held responsible for their health as they age, then services and reimbursement for service may be limited to evidence-based medical interventions that result in complete recovery rather than life-quality improvement and only for "worthy" individuals. This paper seeks to heighten the awareness of pastoral care professionals to common ageist themes found in health and mental care service delivery. PMID- 22452153 TI - Richard Clarke Cabot, M.D., a unitarian critique. AB - This article is written to correct a historical impression about Richard C. Cabot, one of the founders of Clinical Pastoral Education (CPE). Contrary to the popular understanding that he was a typical Unitarian, the author posits that even though Cabot may have been a typical liberal, in his theology, he was an atypical Unitarian. This article places Cabot in his family and historical contexts, his involvement in CPE, and comments on his theology, noting how this differed from the prevailing Unitarian theology of his day. PMID- 22452154 TI - A shepherd's journey--final CPE reflection. PMID- 22452155 TI - Eyes. PMID- 22452156 TI - Today I was a queer chaplain. PMID- 22452157 TI - Fetal lung maturity testing: what labs need to know now. PMID- 22452159 TI - Challenges in hemoglobinopathy testing. PMID- 22452158 TI - Improving diagnosis and clinical management of pre-eclampsia. PMID- 22452160 TI - High multiplex quantitative PCR: what is needed right now. PMID- 22452161 TI - Issues to consider when hiring. PMID- 22452162 TI - Vitamin D: how much is enough, too much, or too little? PMID- 22452163 TI - Vitamin D status assessment: a clinical perspective. PMID- 22452164 TI - Connecting your LIS and EHR. PMID- 22452165 TI - Investing in EMR interfaces for outreach growth. PMID- 22452166 TI - The middleware revolution: bridging automation gaps in laboratory processes. PMID- 22452167 TI - The coming "sepsis boom..." and the available but underutilized diagnostic tools that could avert it. PMID- 22452168 TI - Giving patients direct access to their test results. PMID- 22452169 TI - Accumetrics looks to the future of platelet function analysis. PMID- 22452170 TI - [Fracture of clavicle in newborns, an attempt to make prognostic factors]. AB - The most common bone fracture of the newborn is that of the clavicle - frequency 0.2-3.5% of all births, according to various literature sources. The most common cause of this complication perinatally determining the weight of the newborn and the skills of those who manage second stage of labour Purpose of the study was the establishment of prognostic factors for fracture of the clavicle regardless of the way of delivery. MATERIAL AND METHODS: The study was retrospective for the period January 2005 to June 2010 and includes 38 infants with fracture of the clavicle in spontaneous and operative vaginal deliveries, as well as caesarean sections. There were examined the following factors: age, parity and maternal weight, fetal weigh and length duration of pregnancy, experience of managing labour. RESULTS: The incidence of fracture of the clavicle during the study was 0.26%, calculated to the total number of births. Eight fractures are of newborn delivered by caesarean section, 6 by vacuum extractor and 24 by normal vaginal deliveries with episiotomy mostly. The average weight of infants with fractures was 3767 gr 3 fractures are accompanied by brachial plexus paresis, and 2 were complicated with shoulder dystocia. CONCLUSIONS: It was not found statistically significant prognostic value of most of the indicators studied. Fracture of the clavicle most often dependent on the weight of the newborn and the technique of managing labour without the consequence of shoulder dystocia. PMID- 22452171 TI - [The efficacy of topical application of bionect (hialuronic acid) in wound treatment after cesarean section]. AB - Hyaluronic acid is an important component of the extracellular matrix and has a crucial role in wound healing by stimulation of neutrophil migration, fibroblast proliferation and neoangiogenesis. OBJECTIVE: To study the efficacy of topical application of Bionect (Hialuronic Acid Sodium Sal 0.2%t) in wound treatment after cesarean section. RESULTS: The incidence of edema, infiltration, exudation and superficial blood collections was significantly lower in cases of Bionect application. The results in patients, treated with Bionect makes it a reasonable wound treatment option. PMID- 22452172 TI - [Comparative study of pathological Doppler and non-stress test in IUGR]. AB - The aim of the study was to evaluate the timing of delivery and the relationship between pathological Doppler ultrasonography and NST in IUGR fetuses. The prospective study included 84 fetuses with ultrasound diagnosis of IUGR and 100 fetuses of normal pregnancy The study group underwent Doppler velocimetry study of UA, MCA, DV and UV twice weekly, AFI twice weekly and NST daily. Apgar score, need of intubation, RDS, IVH, days of NICU hospitalization were available and related to neonatal outcome. Patients were stratified into groups: Preeclampsia with IUGR (Group 1) and IUGR only (group 2). In the group 1 the stillbirth was 3/44 (6,8%), in the group 2 the stillbirth was 8/40 (20%). Sensitivity for NST was 60%, and for Doppler velocimetry of DV was 71%. Specificity for NST was 87%, and for Doppler velocimetry of DV was 90%, respectively. Doppler changes occur first in chronic hypoxia while abnormal NST represent late stage of fetal compromise. PMID- 22452173 TI - [Myoinositol--alternative treatment of insulin resistance in adolescents]. AB - Myo-inostitol is a part of inositolphosphoglycan (IPG) mediators, which are known as putative mediators of insulin. One of the theories for insulin resistance is any deficiency in Myo-inositol. Presumably a substitution therapy with exogenous Myo-inositol could be effective for treatment of insulin resistance and PCOS. This is well established in women in reproductive age, but there is insufficient data for adolescence. PMID- 22452174 TI - [Susceptibility to antibiotics of microorganisms related with recurrent bacterial vaginosis]. AB - There are presented data of sensitivity to a range of antibiotics of the main microorganisms related with the problem "recurrent bacterial vaginosis". G. vaginalis are sensitive in 34% to metronidazole, and 82% to clindamycin. Atopobium spp. and HP/+/Lactobacillus spp. are resistant to metronidazole and sensitive to clindamycin. PMID- 22452175 TI - [Prevention of cerebral palcy during pregnancy and delivery]. AB - Cerebral palsy is a disease causing significant medical, emotional, financial and social difficulties for the patient and his family, medical staff and society. In this review we tried to figure out the possibilities for prevention of cerebral palsy during pregnancy and delivery. It have been discussed the strict followup of pregnancy, early prenatal diagnosis and termination of pregnancy with congenital anomalies of the fetus, detection and treatment of intrauterine infections, management in multiple pregnancies, prevention of prematurity. Use of antenatal magnesium also plays a role in the prevention of cerebral palsy. In this review are discussed fetal asphyxia and the role of caesarean section. We present briefly the modem terminology and clinical picture of various types and forms of cerebral palsy, and organization in the diagnosis, treatment and rehabilitation of children with specific impairment in the development of motor function and cerebral palsy. PMID- 22452176 TI - [Annexins as a new thrombotic factors]. AB - This review retraces the current state of knowledge on Annexin A2 and A5 functions causing thrombophilia. Thrombophilia is multifactorial inherited hypercoagulable state, promoted by multiple gen-gen and gen-environmental factors. Abnormalities of placenta in intervillous spacies and horion vessels are discussed as venous thrombosis. The cause of adverse pregnancy outcome is still unknown, etiological up to 50% of cases. Understanding of function of sequence variations in potencial risk factors annexins A2 and A5 could precise estimation of individual risk and should guide the adequate prophylaxis among pregnant women. PMID- 22452177 TI - [Insulin resistance in preeclampsia]. AB - Contemporary scientific data show that there is a link between insulin resistance and preeclampsia. Many features of the insulin resistance syndrome are common with this condition. These include hypertension, hyperinsulinemia, glucose intolerance, obesity and lipid abnormalities. The women with preeclampsia are more insulin resistant than those with normal pregnancy. The surrogate markers of insulin resistance like leptin, TNF-alpha, tissue plasminogen activator, SHBG etc are also changed in preeclampsia. Whether these changes are connected with etiology or with the pathogenesis of preeclampsia is still not clear. PMID- 22452178 TI - [Cornual heterotopic pregnancy: a case report]. AB - Heterotopic pregnancy is the simultaneous development of an intrauterine pregnancy and ectopic pregnancy. We report a rare case of corneal heterotopic pregnancy at 9 weeks of amenorrhoea in a 30-year-old woman, after IVF. Because of the massive intraabdominal hemorrhage laparotomy was performed. Cornual resection and suture was performed and intrauterine pregnancy was evacuated. Doctors must be alert to the fact that confirming an intrauterine pregnancy does not exclude the coexistence of an ectopic pregnancy, particularly after IVF. PMID- 22452179 TI - Gynevac-a vaccine, containing lactobacillus for therapy and prevention of bacterial vaginosis and related diseases. AB - Bacterial vaginosis is a frequently encountered infection nowadays. Evidence based data suggest, that it can cause serious co-morbidity with HIV and HPV infection, as also postoperative complications, sterility, miscarriage and preterm delivery. Prophylactic immunization with Gynevac, a Hungarian patented vaccine with 5 inactivated strains of Lactobacilli might be a good alternative for prevention of the abovementioned complications. PMID- 22452180 TI - [Air pollutant emissions of aircraft in China in recent 30 years]. AB - Although aircrafts are of great importance in transportation in China, there has been rare study on air pollutant emissions of aircrafts until now. Based on the annually statistical data collected by the Statistic Center of Civil Aviation of China, using the emission factor method derived from fuel consumption, the air pollutant emissions of aircrafts during 1980-2009 were calculated, and their emission intensities and dynamic characteristics were analyzed. The results show that the emissions of SO2, CO, NO(x) and HC from aircrafts of China Civil Aviation increased from 0.31 thousand, 1.89 thousand, 2.25 thousand and 3.14 thousand tons in 1980 to 11.83 thousand, 72.98 thousand, 87.05 thousand and 121.59 thousand tons in 2009, indicating a increase of 0.397 thousand, 2.45 thousand, 2.92 thousand and 4.08 thousand tons per year, respectively. The emission intensities of SO2, CO, NO(x) and HC decreased significantly from 0.624, 3.806, 4.53 and 6.322 g x (t x km)(-1) in 1980 to 0.275, 1.697, 2.025 and 2.828 g x (t x km)(-1) in 2009, respectively. SO2, CO, NO(x) emissions of aircrafts of China Civil Aviation accounted very little of each total emissions in China, and the air pollutant emissions from aircrafts of China Civil Aviation was less than those from other industries in China. PMID- 22452181 TI - [Study on the in-situ measurement of atmospheric CH4 and CO by GC-FID method at the Shangdianzi GAW regional station]. AB - In-situ GC-FID system for atmospheric CH4 and CO mixing ratio measurements at the Shangdianzi (SDZ) GAW regional station in Beijing was designed and optimized in 2009 based on a comparable system at the Waliguan GAW global station in Qinhai. Results from this study indicate that the system's precisions for CH4 and CO are higher than 0.03% and 0.45% respectively, which can meet the quality target on background greenhouse gas observations by the World Meteorology Organization's Global Atmosphere Watch (WMO/GAW) program. The selection method of working standards for this system was established: two working standards (WH for the high concentration and WL for the low concentration) were selected, the concentrations of CH4 and CO in these two standards can cover the ambient mixing ratios of CH4 (2 007.1 x 10(-9) and 1 809.5 x 10(-9)) and CO (405.6 x 10(-9) and 123.8 x 10( 9)), an injection sequence was programmed so that the two standards were analyzed alternatively for every three runs. The measurement accuracies are high, as shown by the standard deviations less than 1.7 x 10(-9) and 1 x 10(-9), for CH4 and CO, respectively. This method has been applied to in-situ measurement of atmospheric CH4 and CO in North China. PMID- 22452182 TI - [Reconstructed ambient light extinction coefficient and its contribution factors in Beijing in January, 2010]. AB - Aerosol samples for PM2.5 were collected from 1st January to 31st January 2010, in Beijing. The concentrations of organic carbon, elemental carbon, water solubile ions and soil elements of all particle samples were determined by thermal/optical carbon analyzer, ion chromatography and X-ray fluorescence spectrometer, respectively. The scattering coefficients (b(sp)), absorbing coefficients (b(ap)) and meteorological parameters for this period were also measured. Ambient light extinction coefficients were reconstructed by IMPROVE formula and were compared with measured light extinction coefficients. The results showed that the average mass concentration of PM2.5 was (144.3 +/- 89.1) microg x m(-3) during campaigning period. The average values of measured b(ap), b(sp) and extinction coefficient (b(ext)) were (67.4 +/- 54.3), (328.5 +/- 353.8) and (395.9 +/- 405.2) Mm(-1), respectively. IMPROVE formula is suitable for source apportionment of light extinction coefficient in campaign period. The average value of calculated b'(ext) was (611 +/- 503) Mm(-1) in January, 2010. The major contributors to ambient light extinction coefficients included (NH4) 2SO4 (24.6%), NH4NO3 (11.6%), OM (45.5%), EC (11.9%) and FS (6.4%), respectively. PMID- 22452183 TI - [Atmospheric deposition of polychlorinated naphthalenes in Dongjiang River basin of Guangdong Province]. AB - Atmospheric deposition of polychlorinated naphthalenes (PCNs) was investigated at 11 sites in Dongjiang River basin of Guangdong Province during the winter (January and February) and summer (July and August) of 2010 to assess the effect of PCNs on those areas. The average daily deposition fluxes of total PCNs was 828 pg x (m2 x d)(-1), and the corresponding TEQ was 0.14 pg x (m2 x d)(-1). Based on these values, the presumed average annual deposition value of sigma PCNs was 8.5 kg for Dongjiang River basin within Guangdong province, while the corresponding TEQ was 1.3 g. Spatially, the average daily deposition fluxes of PCNs in Guangzhou and Dongguan were much higher than that in Huizhou, and the fluxes were higher in urban areas than those in rural areas. Seasonally, the fluxes were generally higher in summer than those in winter. Tri-CNs dominated the deposition fluxes in all samples and contributed to more than 50% of total PCNs. In addition, higher contents of high chlorinated PCNs (penta-CNs to octa-CN) were found in Guangzhou and Dongguan in comparison with Huizhou. Combustion and other sources may both contribute to the PCNs emission in the Dongjiang River basin. Combustion related source may be the main contributor of PCNs in Dongguan; while non-combustion related source may dominate the contribution to the site of Guangzhou. PMID- 22452184 TI - [Metabolic characteristics of air microbial communities from sandstorm source areas of the Taklamakan desert]. AB - The aim was to compare the characteristics and the differences in carbon catabolic diversity of air samples collected from five locations that around the edge of Taklamakan desert. The characteristics and the differences of carbon metabolic profiles were detected by using the BIOLOG micro plate (BIOLOG EcoPlate). The results showed that the average well color development (AWCD) curve of all five samples did not reach clear saturation during the incubation time (10 days), but differences among them were significant. The highest AWCD value appeared in Shache and the lowest was in Hotan, which were 0.24 and 0.1, respectively. Carbon utilization showed that all samples exhibited high level of polymer, carbohydrates, amino acids and carboxylic acid; however, amine and the phenol compound were the lowest. Principal components analysis (PCA) indicated that twenty categories of carbon significantly related to PC1 and twelve categories for PC2. Hierarchical cluster analysis showed these five areas could be divided into 2 clusters: (1) Hotan, Pishan, (2) Shache, Luntai, Ulugqat. Canonical correspondence analysis (CCA) showed that those community functional diversities were highly affected by some environmental factors, such as wind speed, altitude, humidity. Further investigation by correlation analysis revealed that the microbial communities using single carbon source were significantly affected by abiotic factors, such as the utilization of beta-methyl-D-glucoside, D-galacturonic acid and putrescine had significantly positive correlation (P < 0.05) with latitude; 2-hydroxy benzoic acid and alpha-D-lactose significantly related to wind speed (P < 0.05); and D-glucosaminic acid was positive with air pressure, but it negatively correlated with altitude (P < 0.05). In conclusion,the carbon sources provided by BIOLOG EcoPlate were utilized slowly by air microbial communities; and the characteristics of the air community carbon catabolic along the edge of the Taklamakan desert revealed regional feature, which may be affected by environmental factors. PMID- 22452185 TI - [Mechanisms of UV photodegradation on performance of a subsequent biofilter treating gaseous chlorobenzene]. AB - To provide insight into effects of UV pretreatment on a subsequent biofilters, the mechanisms of UV pretreatment on biofilter performance were further studied. Results showed that gaseous chlorobenzene UV photodegradation products resulted in a pH decrease from 6-8 to 4-7 in filter bed. Ozone produced by UV photodegradation changed the physical properties of biofilm by reducing biofilm thickness and oxidizing surface part of the extra-cellular polymer substance, which promoted the oxygen, nutrient and pollutant transfer to biofilm. The reduction of biofilm thickness further resulted in the improvement of filter bed's physical properties by providing a higher specific surface area of 880 m x m(-3) compared with the value of 784 m2 x m(-3) without UV pretreatment. PMID- 22452186 TI - [Distribution of dissolved organic carbon in the Bohai Sea and Yellow Sea in spring]. AB - Based on the data from cruises that carried out in the Yellow Sea and Bohai Sea from April to May, 2010, the horizontal distribution of DOC was studied. And the influencing factors were preliminary discussed. The results showed that the concentration of DOC in the Yellow Sea and Bohai Sea ranged from 0.96 to 4.71 mg x L(-1) in spring and the average content was 2.27 mg x L(-1). In horizontal distribution, the highest DOC content appeared in the coastal zones both in the south and the north and it tended to decrease toward the offshore in central section on the whole. The highest DOC value was in the nearshore in the western of Bohai Sea and eastern of Shandong Peninsula which was mainly affected by the terrestrial inputs and the offshore current, especially in the nearshore of the western of Bohai Sea, the highest DOC content was 4.71 mg x L(-1). The second highest DOC value was in the Northeast of Yangtze River Estuary which was mainly affected by the Yangtze River Diluted Water (YRDW). However, the low DOC content was mainly found in open seas in the central of the South Yellow Sea, and the DOC value was lower than 1.50 mg x L(-1). PMID- 22452187 TI - [Research on the mercury species in Jiaozhou Bay in spring]. AB - In April 2010, seawater samples collected every twenty minutes in the Jiaozhou Bay were separated and determined in-situ and indoor to study mercury speciation and its daily variation and to further understand the end-result and effect of mercury on offshore environment. Results showed that dissolved element mercury (DEM) concentration of seawater ranged from 38.2 pg x L(-1) to 156 pg x L(-1), with an average value of 97.5 pg x L(-1). The highest and the lowest value appeared at around 13:00 and 17:30 respectively under the influence of tide and light intensity. DEM concentration gradually declined with depth. DEM of surface sea primarily derived from photoreduction of bivalent mercury. Dissolved mercury (DHg) concentrations ranged from 7.32 ng x L(-1) to 49.1 ng x L(-1) (average value was 13.9 ng x L(-1)), from 4.39 ng x L(-1) to 19.3 ng x L(-1) (average value was 7.94 ng x L(-1)) for dissolved reactive mercury (RHg). The maximum peaks of DHg and RHg all appeared around 13:00, due to dirty seawater carried by tidal movement in the lowest tide. The variation trend with depth of RHg and DHg concentrations was similar at different time. Under the influence of the light and water temperature, the ratio of RHg to DHg was higher in the surface water. RHg accounted for 62% of DHg, so the mercury had relatively high activity and biological availability, and contributed to the form of DEM. The methylmercury concentration was low, with an average value of 0.30 ng x L(-1), and some samples were lower than the detection limit. PMID- 22452188 TI - [Geochemistry of surface and ground water in the Lijang basin, Northwest Yunnan]. AB - The study focused on the chemical element compositions of river water and groundwater in Lijiang Basin. Water samples were collected in Baishui, Sanshu, Geji and Shuhe rivers in Lijiang Basin to analyze pH, conductivity and ion concentration, in order to understand the contributions of anthropogenic activities and rock weathering to river solutes. The results show that all water samples are mildly alkaline and are rich in Ca2+ and HCO3-, which account for 54.8 and 92.4 percentage of total ion concentration respectively. Obvious variations have been perceived during monsoon and westward wind season. The ion concentration of river water is lower than that of groundwater. With decreasing elevation, the ion concentrations are found to increase considerably in the study region. According to source study of major ions, water chemistry is mainly influenced by precipitation rock weathering and dissolving processes. In addition, precipitation is an important factor in monsoon seasons whereas the anthropogenic inputs have lead to light pollution on water in residential district. PMID- 22452189 TI - [Variations in depth and chemistry of groundwater in interval of water delivery at the lower Tarim River]. AB - Variations in groundwater depth and groundwater chemistry influenced by ecological water delivery in the lower Tarim River result in ecological changes. Based on the monitoring data during March, 2007 to September, 2009, the changes of both depths and chemistry of groundwater were studied. It is found that the depth of groundwater at the upper section of lower reaches increased, the major ions, such as Cl-, Na+, showed an increased change. The variations in groundwater depth in groundwater at middle section of lower Tarim River increased, and the concentrations of the major ions showed an opposite trend after the 11th water delivery. At lower section, the depths of groundwater decreased from August, 2008 till September, 2009. At the same time, the major ions in groundwater increased gradually. The groundwater depth and groundwater chemistry far away from the watercourse had a complex change. PMID- 22452190 TI - [Simulation on contamination forecast and control of groundwater in a certain hazardous waste landfill]. AB - On the basis of site investigation and data collection of a certain hazardous waste landfill, the groundwater flow and solute transport coupled models were established by applying Visual Modflow software, which was used to conduct a numerical simulation that forecast the transport process of Cr6+ in groundwater and the effects of three control measures (ground-harden, leakage-proof barriers and drainage ditches) of contaminants transport after leachate leakage happened in impermeable layer of the landfill. The results show that the contamination plume of Cr6+ transports with groundwater flow direction, the contamination rang would reach the pool's boundary in 10 years, and the distance of contamination transport is 1 450 m. But the diffusion range of contamination plume would not be obviously expanded between 10 and 20 years. While the ground is hardened, the contamination plume would not reach the pool's boundary in 20 years. When the leakage-proof barrier is set in the bottom of water table aquifer, the concentration of Cr6+ is higher than that the leakage-proof barrier is unset, but the result is just opposite when setting the leakage-proof barrier in the bottom of underlying aquifer. The range of contamination plume is effectively controlled by setting drainage ditches that water discharge is 2 642 m3 x d(-1), which makes the monitoring wells would not be contaminated in 20 years. Moreover, combining the ground-harden with drainage ditches can get the best effect in controlling contaminants diffusion, and meanwhile, the drainage ditches' daily discharge is reduced to 1 878 m3 x d(-1). Therefore, it is suggested that the control measure combining the ground-harden with drainage ditches should apply to prevent contamination diffusion in groundwater when leachate leakage have happened in impermeable layer of the landfill. PMID- 22452191 TI - [Research on evaluation of water quality of Beijing urban stormwater runoff]. AB - The natural rainwater and stormwater runoff samples from three underlying surfaces (rooftop, campus road and ring road) were sampled and analyzed from July to October, 2010 in Beijing. Eight rainfall events were collected totally and thirteen water quality parameters were measured in each event. Grey relationship analysis and principal component analysis were applied to assess composite water quality and identify the main pollution sources of stormwater runoff. The results show that the composite water quality of ring road runoff is mostly polluted, and then is rooftop runoff, campus road runoff and rainwater, respectively. The composite water quality of ring road runoff is inferior to V class of surface water, while rooftop runoff, campus road runoff and rainwater are in II class of surface water. The mean concentration of TN and NH4(+)-N in rainwater and runoff is 5.49-11.75 mg x L(-1) and 2.90-5.67 mg x L(-1), respectively, indicating that rainwater and runoff are polluted by nitrogen (N). Two potential pollution sources are identified in ring road runoff: (1) P, SS and organic pollutant are possibly related to debris which is from vehicle tyre and material of ring road; (2) N and dissolved metal have relations with automobile exhaust emissions and bulk deposition. PMID- 22452192 TI - [Characterization and source apportionment of pollutants in urban roadway runoff in Chongqing]. AB - By investigating surface runoff from urban roadway in Chongqing, we assessed the characteristics of surface runoff pollution and the effect of rainfall intensity and antecedent dry weather period on water quality. Using multivariate statistical analysis of data of runoff quality, potential pollutants discharged from urban roadway runoff were identified. The results show that the roadway runoff has high levels of COD, TP and TN, the EMC were 60.83-208.03 mg x L(-1), 0.47-1.01 mg x L(-1) and 2.07-5.00 mg x L(-1) respectively, being the main pollutants; The peaks of pollutant concentration are ahead of or synchronous with the peak of runoff volume; the peaks of pollutant concentrations are mostly occurred within 10 minutes of rainfall. The heavy metal concentrations fluctuate dentately during runoff proceeding. Two potential pollution sources to urban roadway runoff apportioned by using principal component analysis are: vehicle's traffic loss and atmospheric dry and wet deposition, and municipal wastes. PMID- 22452193 TI - [Applied study of the submerged macrophytes bed-immobilized bacteria in drinking water restoration]. AB - The effect of submerged macrophytes bed-immobilized bacteria technology which applied in drinking water restoration was studied. Ammonifying bacteria, nitrobacteria, nitrosobacteria and denitrifying bacteria which isolated from Taihu Labe was immobilized to the porous carries, combined with the submerged macrophytes bed technology, we applied the new equipment in water restoration of gonghu bay, this equipment has good ability to resist storm, the denitrifying bacteria number increased from 5.4 x 10(2)-2.7 x 10(3) to 3.9 x 10(5)-9.1 x 10(5), N2O flux of experimental plot was 3-24 microg x (m2 x h)(-1), it's more than the contrast group obviously, TN concentration reduced 19% - 74%, while NO3- concentration reduced 24% -81% after the equipment running a period of time; The experimental data of 120 days showed that this technology is suitable for drinking water restoration, as it can control eutrophication. PMID- 22452194 TI - [Catalytic hydrodechlorination of 2,4-dichlorophenol over Pd/TiO2]. AB - Pd/TiO2 catalysts were prepared by the deposition-precipitation and impregnation methods, and were further characterized by TEM, XRD and ICP-AES. The liquid catalytic hydrodechlorination of 2,4-dichlorophenol over the catalysts was investigated. It is demonstrated that despite catalyst prepared by deposition precipitation method exhibits higher activity than that synthesized from impregnation method, both catalysts show good performance in hydrodechlorination process. When initial concentration of the reactant was 3.11 mmol x L(-1), pH was 12 and amount of catalyst used was 50 mg, hydrodechlorination of 2,4 dichlorophenol was completed within 45 min. Acidic condition facilitates hydrodechlorination process. The initial activity was not significantly influenced when the amount of catalyst used varied between 15-80 mg, which proves that mass transport limitation exerts little impact on hydrodechlorination reaction. Finally, the initial activity sharply enhanced with the increase of initial concentration of 2,4-dichlorophenol when the concentration was in the range of 0.62-3.11 mmo x L(-1) while it almost remained constant with further increasing the initial concentration. Therefore, the catalytic hydrodechlorination of 2,4-dichlorophenol over Pd/TiO2-DP follows the Langumuir Hinshelwood model, indicating that the catalytic hydrodechlorination is controlled by 2,4-dichlorophenol adsorption. PMID- 22452195 TI - [Effects of pH value on the adsorption and degradation of 2, 4-DCP by nanoscale zero-valent iron]. AB - To evaluate the effect of pH on the degradation of 2,4-DCP by zero-valent iron nanoparticles (with the particle size of 30-40 nm in diameter) samples were taken for TEM, SEM-EDX, and ICP-OES analysis and investigated on the particle morphology changes and 2,4-DCP removal under different pH conditions. It is shown that iron nanoparticles agglomerate from individual particles and tiny clusters into massive aggregate assemblies with their surfaces oxidized and coated by the needle-like rotten iron oxide products (FeOOH) in the degradation process, which will block up a further reaction of 2,4-DCP dechlorination, while the low pH value condition in acidic system can effectively suppress particles aggregation and the surface oxidation, although iron loss in the solid phase is somehow inevitable. Large quantity of Fe2+ ions soaked out from iron nanoparticles significantly promote 2,4-DCP removal by reduction, and the solution pH tends to go up in the reaction process. Acidic conditions facilitate 2,4-DCP dechlorination, and the removal efficiency became higher with the pH reduced, in which 90% of 2,4-DCP removal is reached in 24 h under the pH value of 3. PMID- 22452196 TI - [Inactivation of the chlorine-resistant bacteria isolated from the drinking water distribution system]. AB - Inactivation experiments of seven strains of chlorine-resistant bacteria, isolated from a drinking water distribution system, were conducted with four kinds of disinfectants. All the bacteria showed high resistance to chlorine, especially for Mycobacterium mucogenicum. The CT value of 99.9% inactivation for M. mucogenicum, Sphingomonas sanguinis and Methylobacterium were 120 mg x (L x min)(-1), 7 mg x (L x min)(-1) and 4 mg x (L x min)(-1), respectively. The results of inactivation experiments showed that chlorine dioxide and potassium monopersulfate could inactive 5 lg of M. mucogenicum within 30 min, which showed significantly higher efficiency than free chlorine and monochloramine. Free chlorine was less effective because the disinfectant decayed very quickly. Chloramination needed higher concentration to meet the disinfection requirements. The verified dosage of disinfectants, which could effectively inactivate 99.9% of the highly chlorine-resistant M. mucogenicum within 1 h, were 3.0 mg/L monochloramine, 1.0 mg/L chlorine dioxide (as Cl2), and 1.0 mg/L potassium monopersulfate (as Cl2). It was suggested that the water treatment plants increase the concentration of monochloramine or apply chlorine dioxide intermittently to control the disinfectant-resistant bacteria. PMID- 22452197 TI - [Risk assessment of the farmland and water contamination with the livestock manure in Anhui province]. AB - Basing on the data of livestock in 2001-2009 in Anhui province, the farmland pollution loading and water equal standard pollution loading of livestock manure were calculated utilizing the discharge rate of livestock manure. In addition, the risk assessment was evaluated on the livestock pollution in farmland and water bodies in this province. The industrial production of animal manure of this industry in 2008-2009 in Anhui amounted to 0.67 billion tons, and the averaged farmland loading of livestock manure, N, and P were 16.2 t x hm(-2), 83.8 kg x hm(-2), and 34.5 kg x hm(-2), respectively. The overall averaged risk constant of livestock manure loading in farmland was 0.36 (approximately risk level I). As to the water bodies, the averaged equal standard pollution loading was 7.03. However, significant differences were observed for the farmland and water contamination with livestock manure in different areas of Anhui, suggesting that some areas might receive much higher doses than the averaged amounts. The contamination weakened comparing with that in 2001-2002. But there was a trend of increase for P pollution. According to the information in 2008-2009, the farmland and water bodies in the areas of Hefei, Suzhou, and Bengbu still borne the livestock manure contamination. Results of this work provide some useful information for the water and farmland environmental protection in Huaihe river basin in Anhui province. PMID- 22452198 TI - [Analysis of membrane fouling genesis in nanofiltration process for advanced treatment of dyeing and finishing wastewater]. AB - In order to investigate the types and genesis of membrane fouling of nanofiltration desalination system treating dyeing and finishing wastewater of cotton knit textile, comprehensive analysis, using ICP-AES, SEM-EDX, FTIR, TGA, high optical microscope and XRF, was carried out based on tests of influent water quality, and tests of the membrane fouling states of different processes and tests of membrane cleaning. The results showed that the types of membrane fouling included inorganic fouling, organic fouling and microbial fouling. The mass percents of bound water, organic substance and inorganic substance of dry foulants, dried at 105 degrees C, were 8.2%, 41.0% and 50.8% respectively. Ferric salt was the most serious inorganic fouling salt, and the main functional groups, found from organic foulants, were -OH, -CH and -C =C. Several kinds of protozoa were found from the membrane foulants as well as metazoan. The analysis of short term and long-term membrane fouling indicated that it need a long time cumulative effect for the formation of organic fouling and microbial fouling. The results of NF cleaning tests showed that the mainly reason lead to the decline of membrane flux were organic fouling and microbial fouling, which took 53.3%. PMID- 22452199 TI - [Experimental research on combined water and air backwashing reactor technology for biological activated carbon]. AB - To proper control the backwashing process of biological activated carbon (BAC) reactor and improve the overall operation performance, the evaluative indexes such as backwashing wastewater turbidity, organic pollutants removal rate of pre and post-backwashing, and the variation of biomass and biological activity in carbon column are used to compare and analyze the effect of three different combined water and air backwashing methods on the operation of BAC reactor. The result shows that intermittent combined water and air backwashing method is most suitable to BAC reactor. The biological activaty obviously increases by 62.5% after intermittent combined water and air backwashing process. While, the biological activaty using the backwashing method of air plus water and the backwashing method of water and air compounded plus water washing increases by 55.6%, 38.5%, respectively. After backwashing 308h, the reactor recovered to its normal function after intermittent combined water and air backwashing process with the removal rate of UV254 reaching to 60.0%. The fulvic-like fluorescence peak of backwashing water are very weak, and are characterized by low-excitation wavelength tryptophan like (peak S) and high excitation wavelength of tryptophan (peak T), which are caused by the microbial debris washed down. The three dimensional fluorescence spectra also show that microbial fragments are easy to be washed clean with intermittent combined water and air backwashing. PMID- 22452200 TI - [Impacts of pH and surfactants on adsorption behaviors of norfloxacin on marine sediments]. AB - The adsorption behaviors of norfloxacin (NOR) on marine sediments at different pH values and in the presence of four different surfactants were systematically investigated by a batch equilibrium method. The results indicated that Freundlich adsorption isotherms fitted the adsorption behavior of NOR on marine sediments very well at different pH values. The Freundlich constant K(F) and the equilibrium adsorption amount of NOR reduced with the increase of pH values, and the minimum appeared at pH 8.10. The results suggested that cation exchange was the main adsorption mechanism of NOR at pH 6.01, while Van der Waals' force, hydrophobic effects, electrostatic force were the major adsorption mechanism of NOR on marine sediments at pH 8.10. The adsorption process fitted well with pseudo-second-order kinetic equations with the addition of surfactants. Our study also indicated that the addition of surfactants had the significant influence on the saturated adsorption amount of adsorption of NOR. The equilibrium adsorption amount (Q(e)) of NOR exhibited the following sequence: Q(e) (Tween80) < Q(e) (Tween20) soybean straw char > peanut straw char > rice hull char. This order is generally consistent with the amount of negative charge and specific surface area of these biochars. While methylene blue was mainly adsorbed specifically by the biochars, because the adsorption of methylene blue increased with the increase of ionic strength and the adsorption led to the shift of zeta potential of biochar particles to positive value direction. Langmuir equation fitted the adsorption isotherms well and can be used to describe the adsorption behaviors of methylene blue by the biochars. The maximum adsorption capacity of methylene blue predicted by langmuir equation was 196.1, 169.5, 129.9 and 89.3 mmol x kg(-1) for rice straw char, soybean straw char, peanut straw char and rice hull char, respectively. Leaching experiments show that rice hull char of 156 g can remove methylene blue from 30 L water containing 0.3 mmol x L(-1) of methylene blue completely and the cumulative amount of methylene blue absorbed by the biochar reaches 57.7 mmol x kg(-1). The biochars can be used as efficient adsorbents to remove methylene blue from waste water of dye. PMID- 22452203 TI - [Adsorption and desorption of dyes by waste-polymer-derived activated carbons]. AB - Mesoporous activated carbons with high surface area were prepared from three waste polymers, i. e., tire rubber, polyvinyl chloride (PVC) and polyethyleneterephtalate (PET), by KOH activation. The adsorption/desorption characteristics of dyes (methylene blue and methyl orange) on the carbons were studied. The effects of pH, ionic strength and surface surfactants in the solution on the dye adsorption were also investigated. The results indicated that the carbons derived from PVC and PET exhibited high surface area of 2 666 and 2 831 m2 x g(-1). Their mesopore volume were as high as 1.06 and 1.30 cm3 g(-1), respectively. 98.5% and 97.0% of methylene blue and methyl orange were removed in 15 min by PVC carbon, and that of 99.5% and 95.0% for PET carbon. The Langmuir maximum adsorption capacity to these dyes was more than 2 mmol x g(-1), much higher than that of commercial activated carbon F400. Compared with Freundlich model, the adsorption data was fitted better by Langmiur model, indicating monolayer coverage on the carbons. The adsorption was highly dependent on solution pH, ionic strength and concentration of surface surfactants. The activated carbons exhibited higher adsorption to methylene blue than that of methyl orange, and it was very hard for both of the dyes to be desorbed. The observation in this study demonstrated that activated carbons derived from polymer waste could be effective adsorbents for the treatment of wastewater with dyes. PMID- 22452204 TI - [Study on the sorption behavior of tetracycline onto activated sludge]. AB - The batch sorption methods were employed to investigate the sorption behavior of tetracycline (TC) on the activated sludge. It was shown that the mixed liquor suspended solids (MLSS) and the initial concentration of TC had great impacts on equilibrium time, adsorption capacity and adsorption rate. Compared with pseudo first-order model, pseudo second-order model showed the better agreement. At 10, 25 degrees C, the Langmuir model was the best isotherm to describe the experimental data for adsorption of TC on activated sludge, and the maximum adsorption capacities were 31.14, 70.95 mg x g(-1) respectively; at 40 degrees C, the linear isotherm confirmed the agreement. The data were also modeled by D-R isotherm to determine the type of adsorption. At 10 degrees C (E was 9.13 kJ x mol(-1)), the dominant type was physical, and at 40 degrees C (E was 7.07 kJ x mol(-1)), the dominant type was chemical. With the temperature increasing, the adsorption capacity increased. Ion exchange is one mechanism for adsorption of TC on activated sludge. When the initial concentrations of TC were 5, 10, 20 mg x L( 1), with the Na+ concentration increasing from 0 mol x L(-1) to 0.1 mol x L(-1), the adsorption capacities decreased by 15.32%, 15.00%, 20.12% respectively. The maximum adsorption capacity was got at pH 6 when pH varied from 5 to 10. PMID- 22452205 TI - [In situ experimental research on natural attenuation of oil pollutants in a gas station]. AB - The natural attenuation rules of oil pollutants are investigated by carrying out a field experiment in a gas station in Beijing, using a set of soil gas sampling and monitoring device designed independently. The samples of soil gas were collected in the field and tested to examine the content of O2, CO2 and VOCs in the unsaturated zone. The results show that after 381 days' natural attenuation, the concentration of the contaminants at the polluted point deceased by 99.2%, while the ratio of BTEX to TVOC decreased from 17.0% to 12.1%. Moreover, the content of O2 decreased while that of CO2 grew as the soil depth increases at G3 point. Further theoretical analysis indicated that: (1) The test results of first step experiment show that there was a certain level of contamination in G3 area. And after 381 days' natural attenuation, the content of the BTEX at G3 point fell below the environmental standard level, which means the control measures could be removed. (2) The origin of the contamination was proved as short-term sources, and no long-term sources of leakage existed. (3) An effective removal of contaminants in the soil was found under the influence of the natural attenuation. This method could be applied in long-term monitoring for similar contaminated sites. (4) The test of O2and CO2 contents was proved to be an effective approach to determine if the aerobic degradation happens. PMID- 22452206 TI - [Influence and assessment of biochar on the bioavailability of chlorobenzenes in soil]. AB - A laboratory experiment was conducted to study the influence of biochar on the residues of chlorobenzenes (CBs) in soil. Two treatments as the control and the addition of 1% wheat straw biochar were designed. Three chemical extractions as butanol, HPCD and Tenax extractions and earthworm accumulation were used to assess the changes of the bioavailability of CBs in soil. The results showed that the residues of HCB, PeCB and 1,2,4,5-TeCB in the control were 29.87%, 18.02% and 5.16% after 4 months incubation, however, the residues of HCB, PeCB and 1,2,4,5 TeCB in biochar amended soil were 68.25%, 61.32% and 58.02%, respectively, indicating that biochar amendment would inhibit the dissipation of CBs in soil. Butanol, HPCD and Tenax extraction as well as earthworm accumulation results demonstrated that the bioavailability of CBs in soil was significantly affected by biochar amendment (P < 0.05). With aging time increase, the biochar amendment significantly lowered the bioavailability of CBs. The extraction ratios differed among different chemical extraction methods. The extraction ratio was HCB > PeCB > 1,2,4,5-TeCB for butanol and Tenax extraction, while 1,2,4,5-TeCB > PeCB > HCB for HPCD extraction. The bioaccumulation factor of CBs by earthworm was significantly lower in biochar amended soil compared to the control (P < 0.05). This study showed that the biochar could reduce the bioavailability of organic pollutants, however, the high residues of the pollutants in soil showed potential environmental risk. PMID- 22452207 TI - [Control for MUCT process operation using nitrate concentration in the secondary anoxic zone]. AB - The feasibility of the control for MUCT process operation using nitrate concentration in the secondary anoxic zone were investigated by using simulative domestic sewage, in which the influent chemical oxygen demand concentration was stabilized at (290 +/- 10) mg x L(-1), the influent total nitrogen (TN) concentration was stabilized at (55 +/- 0.5) mg x L(-1), the influent total phosphorus (TP) concentration was stabilized at (7.0 +/- 0.5) mg x L(-1). The nitrate concentration in the secondary anoxic zone was changed to compare the effluent total nitrogen and total phosphorus concentration. The results indicated that, effluent total nitrogen and total phosphorus concentration significantly were affected by S(NO3-), controlling nitrate recirculation flow keeping SNO3- in 2.5 mg x L(-1) can realize MUCT process as the optimal control for nitrogen and phosphorus removal. The TP and NO3(-) -N mass balances were performed around each zone and settling tank based on the averaged TP and TN concentrations for each nitrate concentration in the secondary anoxic zone, which was indicated that S(NO3-) is a key factor determining the mass of phosphorus which is released in anaerobic zone, mass of phosphorus uptake in the secondary anoxic zone, and mass of NO3(-) -N which is denitrified in the first and secondary anoxic zone. PMID- 22452208 TI - [Modeling formation of aerobic granule and influence of hydrodynamic shear forces on granule diameter]. AB - A one-dimension aerobic granule mathematical model was established, basing on mathematical biofilm model and activated sludge model. The model was used to simulate simple aerobic granule process such as nutrients removal, granule diameter evolution, cycle performance as well as depth profiles of DO and biomass. The effluent NH4(+) -N concentration decreased as the modeling processed. The simulation effluent NO3(-)-N concentration decreased to 3 mg x L( 1) as the granules grew. While the granule diameter increased from 1.1 mm on day 30 to 2.5 mm on day 100, the TN removal efficiency increased from less than 10% to 91%. The denitrification capacity was believed to enhance because the anoxic zone would be enlarged with the increasing granule diameter. The simultaneous nitrification and denitrification occurred inside the big aerobic granules. The oxygen permeating depth increased with the consumption of substrate. It was about 100-200 microm at the beginning of the aeration phase, and it turned to near 800 microm at the end of reaction. The autotrophs (AOB and NOB) were mostly located at the out layer where the DO concentration was high. The heterotrophic bacteria were distributed through the whole granule. As hydrodynamic shear coefficient k(de) increased from 0.25 (m x d)(-1) to 5 (m x d)(-1), the granule diameter under steady state decreased form 3.5 mm to 1.8 mm. The granule size under the dynamic steady-state decreased with the increasing hydrodynamic shear force. The granule size could be controlled by adjusting aeration intensity. PMID- 22452209 TI - [Effect of different sludge retention time (SRT) on municipal sewage sludge bioleaching continuous plug flow reaction system]. AB - A plug-flow bio-reactor of 700 L working volume for sludge bioleaching was used in this study. The reactor was divided into six sections along the direction of the sludge movement. Fourteen days of continuous operation of sludge bioleaching with different sludge retention time (SRT) under the condition of 1.2 m3 x h(-1) aeration amount and 4 g x L(-1) of microbial nutritional substance was conducted. During sludge bioleaching, the dynamic changes of pH, DO, dewaterability (specific resistance to filtration, SRF) of sewage sludge in different sections were investigated in the present study. The results showed that sludge pH were maintained at 5.00, 3.00, 2.90, 2.70, 2.60 and 2.40 from section 1 to section 6 and the SRF of sludge was drastically decreased from initial 0.64 x 10(13) m x kg(-1) to the final 0.33 x 10(13) m x kg(-1) when bioleaching system reached stable at hour 72 with SRT 2.5d. In addition, the sludge pH were maintained at 5.10, 4.10, 3.20, 2.90, 2.70 and 2.60, the DO value were 0.43, 1.47, 3.29, 4.76, 5.75 and 5.88 mg x L(-1) from section 1 to section 6, and the SRF of sludge was drastically decreased from initial 0.56 x 10(13) to the final 0.20 x 10(13) m x kg(-1) when bioleaching system reached stable at hour 120 with SRT 2 d. The pH value was increased to 3.00 at section 6 at hour 48 h with SRT 1.25 d. The bioleaching system imbalanced in this operation conditions because of the utilization efficiency of microbial nutritional substance by Acidibacillus spp. was decreased. The longer sludge retention time, the easier bioleaching system reached stable. 2 d could be used as the optimum sludge retention time in engineering application. The bioleached sludge was collected and dewatered by plate-and-frame filter press to the moisture content of dewatered sludge cake under 60%. This study would provide the necessary data to the engineering application on municipal sewage sludge bioleaching. PMID- 22452210 TI - [Biological phosphorus removal in intermittent aerated biological filter]. AB - Under intermittent aerated and continuous fed operation where the biofilm system was subjected to alternated anaerobic/aerobic condition, the effect of influent volatile fatty acids (VFAs) concentrations, operation cycle and backwash on the biological phosphorus removal performance of the biofilter was studied. In the experiment, synthetic domestic wastewater was used, and the influent velocity was 5 L x h(-1) with gas versus liquid ratio of 8:1 and hydraulic retention time (HRT) of 1.3 h, resulting in average COD, ammonium and phosphorus load of 4.7, 0.41 and 0.095 g x (L x d) (-1) respectively. Results show that, (1) effective release and uptake of phosphorus was achieved in a operation cycle; (2) when influent VFAs was 100 mg x L(-1) (calculated by COD value) and operation cycle was 6 h the filter performed best in phosphorus removal, the phosphorus loading removal rate can be as much as 0.059 g x (L x d)(-1) at the aerated phase with those of COD and ammonium being 3.8 g x (L x d)(-1) and 0.28 g x (L x d)(-1) respectively, and with average effluent phosphorus, COD and ammonium concentrations being 1.8, 43.6 and 8.7 mg x L(-1), which shows nitrogen loss also happened; (3) the pause of backwash decreased the phosphorus removal performance rapidly with the removal efficiency lower than 40% in two days, but the consequent daily backwash operation gave a short improvement on the phosphorus removal, which disappeared in another two days. Thus, it is shown that biological phosphorus removal achieved with better phosphorus loading removal performance in the biofilter under intermittent aerated and continuous fed operation, and that sufficient and stable influent VFAs concentration, proper operation cycle, and more frequent backwash favored the performance. PMID- 22452211 TI - [Methane production by anaerobic co-digestion of chicken manure and Spartina alterniflora residue after producing methane]. AB - The characteristics of Spartina alterniflora residue after producing methane (SAR) digested alone and co-digestion of various proportions of chicken manure and SAR were investigated by batch model at 35 degrees C +/- 1 degrees C. The initial total solid (TS) loading of all treatments was 8.0%. The results indicated that there was still some biogas produced by SAR with TS biogas yield of 107.25 mL x g(-1) and average methane content of 76.92%. The cellulose crystallinity of re-digested SAR was destructed by anaerobic microorganisms, and the destruction rate was 5.55%. Co-digestion meliorated the environment where microorganisms lived in and increased the cumulative biogas yield. When the ratio of chicken manure to SAR was 4 : 1, the cumulative biogas yield was highest while the cumulative biogas yield of T1 (the rate of chicken manure to SAR is 5 : 0 based on TS), T3-T6 (the rate of chicken manure to SAR are 3 : 2, 2 : 3, 1 :4 and 0 : 5 based on TS, respectively) were 61.31%, 62.09%, 52.15%, 39.74% and 31.67% of it. The anaerobic fermentation type of co-digestion is mix acid type fermentation. Co-digested with chicken manure promoted the destruction of cellulous crystallinity by 1.13% - 21.61% and especially when the rate of chicken manure to SAR was 4 : 1. PMID- 22452212 TI - [Uncertainty analysis for evaluating methane emissions from municipal solid waste landfill in Beijing]. AB - In order to improve the accurate evaluation of CH4 emissions from municipal solid waste landfill in Beijing, FOD-model and Monte Carlo method were conducted. Based on local data, national data and experts' experience, the uncertainty of FOD model and parameters' sensitivity analysis were identified. And we quantified effect of various parameters on model output. The results showed that 95% probability distribution range of CH4 emission from landfill was (11.8-19.76) x 10(4) t x a(-1) in Beijing. The mean value was 15.58 x 10(4)t x a(-1) with uncertainty range of -24.26% - 26.83%. Among all the parameters MCF (after 2000) showed the greatest impact on landfill CH4 emission in 2008, and its contribution to the uncertainty of emission result was 41.4%. This research can improve the assessment accuracy and quality on CH4 emission from municipal solid waste landfill in Beijing, as providing scientific basis to improve the landfill greenhouse gas inventory and data collection. PMID- 22452213 TI - [Electricity generation of surplus sludge microbial fuel cells enhanced by additional enzyme]. AB - In this paper the feasibility of enhanced electricity generation of microbial fuel cell fed surplus sludge by additional enzymes (neutral protease and alpha amylase) was discussed. The effect of dosage of additional enzyme on characteristics of electricity generation of the surplus sludge microbial fuel cell (SSMFC) and the reduction of surplus sludge were investigated. The results indicated that the maximum output power destiny of the group of experiment was higher than that of control under the same condition. Moreover, the maximum output power density, coulomb efficiency, efficiency of reducing TCOD, efficiency of reducing TSS and efficiency of reducing VSS reached up to 507 W x m(-2) (700 mW x m(-2)), 3.98% (5.11%), 88.31% (94.09%), 83.18% (98.02%) and 89.03% (98.80%) respectively for protease (alpha-amylase) at the dosage of 10 mg x g(-1). This study demonstrated that additional enzyme greatly enhanced the electricity generation of MFC with simultaneous accomplishments of sludge treatment, providing a novel approach for the practical application of microbial fuel cell. PMID- 22452214 TI - [Construction of electrochemiluminescence system for harmful algae detection]. AB - To develop a new technique, Electrochemiluminescence-Molecular Probe (ECL-MP), for harmful algae detection, a highly sensitive electrochemiluminescence (ECL) detection system was set up based on the principle of ECL and related literature. The optimization tests were carried out, including the impact of voltage and current, the concentration of tripropylamine (TPrA) and the pH of phosphate buffer (PBS). The determination limit of Ru (bpy)3Cl2 x 6H2O was 10(-11) mol x L( 1) and the detection range was from 10(-9) - 10(-5) mol x L(-1) as well as the detection amount of substance was in the range from 0.4 pmol-4 nmol in the optimal reaction conditions with voltage of 1.0 V, current of 1.0 mA, TPrA concentration of 1.5 mol x L(-1) and pH of 7.4. It was proved by facts that this ECL analyzer was stable and highly sensitive, which was helpful in establishment of ECL-MP. PMID- 22452215 TI - [Mechanism of the inhibitory action of allelochemical dibutyl phthalate on algae Gymnodinium breve]. AB - The aim of this study was to investigate the mechanism of inhibitory action of dibutyl phthalate (DBP) on red tide algae Gymnodinium breve. The effects of DBP on malonaldehyde, subcellular structure and superoxide dismutase (SOD) isoforms were investigated. The results showed that MDA accumulated in the algae cell under DBP exposure, and for the 3 mg x L(-1) DBP treated algae culture a peak value of 0.34 micromol x (10(9) cells) (-1) occurred at 72 h, which was about 2. 3 times than that of the control. TEM pictures showed the disruption of DBP on the subcellular structure of G. breve. A morphological phenomenon appeared that the algae cell was commonly found small tubules or apical parts around the cell membrane, and almost all normal cell organelles were indistinguishable finally. The activity of CuZn-SOD (main cytoplast located isoform with little in cloroplast) under DBP exposure was higher than that of the control, and no significant difference was observed on Fe-SOD (chloroplast located isoform) activity, but for the Mn-SOD (mitochondrial isoform), the activity was significantly inhibited. These results indicated that DBP might inhibit the algae growth from the plasma membrane and the mitochondria, resulting in oxidative damage in algae cell and a final death. This paper will give a theoretical support to the practical usage of the allelochemical on red tide algae. PMID- 22452216 TI - [Toxic effects of nano-TiO2 on Gymnodinium breve]. AB - In order to reveal the toxicity and mechanism of nano-TiO2 on algae, the inhibition effect, enzyme activity, oxygen free radicals of nano-TiO2 on the growth of G. breve were investigated. The results showed that G. breve was inhibited by nano-TiO2, and the 72 h-EC50 was 9.7 mg x L(-1). With the increasing concentration of nano-titanium dioxide, the activities of SOD decrease significantly (P < 0.05). The content of hydrogen peroxide radicals and the activities of CAT increase significantly (P < 0.05), and the content of superoxide anion shows the increasing trend. The content of hydrogen peroxide radicals was 0.083 U x mL(-1) in 0 mg x L(-1) nano-TiO2 suspension while that was 1.1 U x mL(-1) in control after 48 h. Through the study of 20 mg x L(-1) nano titanium dioxide on G. breve at different times, the activities of SOD and CAT, the content of MDA are consistent, which the highest values is achieved at the exposure time of 12 hours and the lowest value is found at the exposure time of 48 hours. The content of hydroxyl radical increased significantly at the exposure time of 48 hours. The activity of SOD was 0.14 U x (10(7) cell x min)(-1) in G. breve at 12 h which was ten times higher than that at 48 h. PMID- 22452217 TI - [Spatial distribution of three endocrine disrupting chemicals in sediments of the Suzhou Creek and their environmental risks]. AB - Three environmental endocrine disrupting chemicals (EDCs), named nonylphenol (NP), octylphenol (4-t-OP) and bisphenol A (BPA), in sediments of the Suzhou Creek and its branches were detected using gas chromatography-mass spectrometry (GC-MS) method. The results showed that the concentration of three chemicals varied greatly from site to site, which ranged from < 1.0-5 800, < 0.10-39 and 0.90-180 microg x kg(-1), respectively. In general, the accumulation of pollutants in sediments closely related to the intensity of anthropogenic activities: the concentration of three chemicals in sediments of municipal section of the creek are significantly higher than those in the sections of suburb of Shanghai city and Jiangsu province; the chemical concentrations in sediments of branches are significantly higher than those of the main stream of the creek. Significant correlations between each two of the three chemicals in sediments were observed, implying their similar source provenance. Taking nonylphenol as an example, the environmental risks of the EDCs in sediments were assessed. The result indicated that this chemical in the entire creek except the Wujiagang Bridge point had posed potential toxic risks to ecological system. Therefore, more countermeasures should be taken to prevent EDCs from entering the creek. PMID- 22452218 TI - [Level, distribution, and source identification of polychlorinated naphthalenes in surface agricultural soils from an electronic waste recycling area]. AB - The concentration of 46 polychlorinated naphthalenes (PCNs) in the agricultural soils from Luqiao was analyzed by GC-NCI-MS. The objectives of this study were to investigate the contents, spatial distribution and sources of PCNs. The total concentrations of PCNs (sigma PCNs) in soil samples were in the range of 0.062 to 2.92 ng x g(-1), with a mean of 0.630 ng x g(-1). Tetra-CNs and penta-CNs were the predominant homologues in most of the samples, accounting for 18.4% - 88.8% and 8.40% - 53.1%, with average values of 46.7% and 30.7%, respectively, followed by tri-CNs, accounting for 0 - 47.3%, with a mean of 10.6%. Cluster analysis and combustion marker analysis showed that the sampling sites were mainly polluted by Halowax 1014 and Halowax 1013, also possibly polluted by PCBs mixtures and e waste combustion process. Compared to other studies, the PCNs concentration in this study was at a medium level. PMID- 22452219 TI - [Heavy metal pollution in street dusts from different functional zones of Luoyang City and its potential ecological risk]. AB - The concentrations of heavy metals (Cu, Zn, Pb, Cr, Cd) in street dusts were investigated in six different functional zones of Luoyang City, i.e., urban-rural continuum, urban artery, industrial district, urban green space, residential district, and business district. The pollution levels and potential ecological risk of heavy metals were assessed by the methods of potential ecological risk index suggested by Hakanson. The results showed that heavy metal concentrations in street dusts from different functional zones of Luoyang City were all higher than soil background values in Henan, with average concentrations of Zn (1019.75 mg x kg(-1)) > Cr (401.63 mg x kg(-1)) > Cu (240.94 mg x kg(-1)) > Pb (176.04 mg x kg(-1)) > Cd (2.33 mg x kg(-1)). Cd was the most seriously polluted metal in all functional zones, and the average pollution index (Cf(i)) reached 35.84, following by Zn (16.32) > Cu (12.05) > Pb (7.90) > Cr (6.36). Heavy metal concentrations and pollution levels varied greatly in different functional zones, and industrial zone had the highest total contents and the heaviest pollution. The integrated potential ecological risk index (RI) in different functional zones all reached very strong levels, with an order of industrial district (1709.51) > urban green space (1581.50) > business district (1 297.45) > residential district (1 111.25) > urban artery (889.97) > urban-rural continuum (641.39). Among the surveyed heavy metals, Cd accounted for the major potential ecological risk, and the average potential ecological risk index (Er(i)) reached 1075.16 (extremely strong risk level) in all six functional zones. The average Er(i) of Cu and Pb reached 60.23 and 40.77 respectively, belonging to moderate risk level, while Zn (16.32) and Cr (12.71) only reached slight risk level. A reduction in industrial and traffic pollution might be the key measure to decrease the heavy metal pollution and potential risk in street dusts. PMID- 22452220 TI - [Soil contamination and assessment of heavy metals of Xiangjiang River Basin]. AB - The contents of heavy metals (As, Cd, Cu, Zn, Ni and Pb) in soils from Xiangjiang River Basin, Hunan Province, China, were analyzed by toxicity characteristic leaching procedure (TCLP) and Nemrow method. Results showed that the total contents of As, Cd, Cu, Zn, Ni and Pb were 4.25-549.67, 0.13-76.84, 11.49-281.69, 7.75-7234.81, 5.50-56.65 and 8.60-2084.81 mg x kg(-1), respectively, and the available contents of As, Cd, Cu, Zn, Ni and Pb extracted by TCLP were 0.02 10.97, 0.06-28.41, 0.04-72.29, 0.59-1 152.32, 0.07-10. 65 and 0.17-1 165.58 mg x kg(-1). The contents of available heavy metals extracted by TCLP correlated with total contents of heavy metals. Moreover, the pollution index Nemrow method showed that 72 samples at safety level, alert level, light pollution level, medium pollution level and heavy pollution level ratios were 60.52%, 11.33%, 5.65%, 4.22% and 18.38% separately, illustrating that pollution of heavy metals in soil samples of Xiangjiang River Basin is serious. PMID- 22452221 TI - [Characteristics of heavy metals in soil profile and pore water around Hechi antimony-lead smelter, Guangxi, China]. AB - In the area around an antimony-lead smelter, soil and soil water samples were collected from different soil profiles in vegetable field, uncultivated field and wood field. The distribution and migration of heavy metals in soil profile were investigated. In soil, Sb, Pb, Cu and Cd are found to accumulate in the topsoil layer, and decrease rapidly with the depth. However, Sb, Pb, and As appear to accumulate below 60 cm. Sb and As show a much stronger affinity to the pore water than Pb. In consequence, different soil utilization types lead to different effects of heavy metals migration in soil profile. Furthermore, Sb and As show a higher potential to migrate along the soil profile than that of Pb. In addition, the high content of heavy metals in the topsoil may be absorbed by crops post to desorption in soil water, and possibly form a threat to human health. PMID- 22452222 TI - [Speciation transformation and behavior of arsenic in soils under anoxic conditions]. AB - The soil of 0-100 cm depth was collected from the wastewater-irrigated farmland in Zhangshi, Shenyang and was amended with low concentration of arsenic. Microbial-mediated speciation transformation and environmental behavior of arsenic were investigated with and without addition of sulfate. The results showed that without addition of sulfate, arsenate was significantly reduced and released into soil solution after eight days of anaerobic incubation. Above 70% of arsenic presented as arsenite. More arsenic was released from the soil of 20 40 cm depth with arsenite and total arsenicconcentration of 892.8 microg x L(-1) and 1 240.6 microg x L(-1) respectively. Compared with abiotic control, the amount of arsenic dissolved in hydrochloric acid decreased greatly in each layer of soil, moreover, almost all of arsenic was reduced to arsenite. Ferric iron was also significantly reduced to ferrous and released into soil solution simultaneously. The concentration of ferrous iron in soil solution was above 40 mg x L(-1) in solution and was 9.0-13.4 g x kg(-1) in soil solid. Above 50% of the iron dissolved in hydrochloric acid was presented as ferrous. This indicates that microbial reduction leads to reductive dissolution of iron oxides and transformation of mineral configuration in soil solid. The release of arsenic and iron was notably suppressed after addition of 10 mmol x L(-1) sulfate, with the concentration reduced by 50%. The amount of HCl-dissolvable arsenic in soil solid decreased by 50%, compared to the treatment without sulfate addition, which probably due to precipitation of arsenic sulfide. It is obvious that microbial reduction leads to reduction and release of arsenic when sulfate is absent. In the presence of sulfate, microbes may transform mobile arsenic into more stable species. Formation of arsenic sulfide mineral was probably the mechanism for arsenic fixation in soil by microbes. PMID- 22452223 TI - [Remediation of chromium (VI) contaminated soils using permeable reactive composite electrodes technology]. AB - Electrokinetic transport processes have been shown to have potential for the effective removal of heavy metals from soils. However, pH changes near the anode and cathode limit their widespread application in the remediation of contaminated soils. Permeable reactive composite electrodes (PRCE) were made by attaching reactive materials such as Fe(0) and zeolite to the electrodes, and the effects of the composite electrodes on pH control, chromium removal efficiency and Cr speciation changes were studied in the electrokinetic remediation process of Cr( VI) contaminated soil. Composite electrodes consisting of permeable reactive materials gave better pH control and Cr removal efficiency compared to traditional electrodes, and a Fe(0) + zeolite reactive layer in the anode exhibited the best performance compared to zeolite or Fe(0) alone. After 5 days of electrokinetic remediation with a DC voltage of 2 V x cm(-1), the Fe(0) + zeolite reactive layer lowered the pH fluctuation, maintained the soil pH in the range of 5.5 to 8.5, raised the Cr(VI) removal efficiency up to 97% in any soil section, produced lower Cr(III) residues, enhanced the amount of Cr retention up to 8 and 1.8 times respectively, and transformed 98% of the Cr(VI) into lower toxicity Cr(III). This study provides a theoretical basis for the exploitation of permeable reactive composite electrodes which are a practical option for future applications. PMID- 22452224 TI - [Determination and characterization on the capacity of humic acid for the reduction of divalent mercury]. AB - Reduction capacity (RC) has been recognized as an important parameter for evaluating the redox role of humic acid (HA). Thus, for understanding the capacity of HA for the reduction of mercury (Hg2+), chemical reduction capacity (CRC), microbial reduction capacity (MRC) and native reduction capacity (NRC) for mercury reduction by three types of HAs extracted from various sources (SH, TJ and JY) were measured respectively, following the pre-treatment of the HA samples by saturated hydrogen oscillation, soil solution incubation and the control (without any pretreatment). Three electron acceptors including mercuric chloride (HgCl2), mercuric nitrate [Hg(NO3)3] and ferric citrate (FeCit) as a reference were adapted respectively based on the Fe3+ reduction method. The principal results indicated that: (1) the capacity of HA for the reduction of Hg was significantly affected by various electron acceptors, with the RC values obtained under FeCit condition were all greatly higher than those in the conditions of Hg(NO3)2 and HgCl2, which suggested that the RC obtained using Fe3+ reduction method could exaggerate the actual capacity of HA for the reduction of Hg2+; (2) significant differences existed for the reduction capacity of Hg2+ by different HAs, with those of JY were the highest, which were (0.95 +/- 0.03) mmol(c) x mol( 1) (NRC), (5.95 +/- 0.63) mmol(c) x mol(-1) (CRC) and (6.26 +/- 0.51) mmol(c) x mol(-1) (MRC) respectively; (3) HA in solution forms had approximately 100% - 691.67% higher reduction capacity than those as solid forms. Meanwhile, through comparison of the differences among three RC indices, higher CRC and MRC values than NRC were observed, but no significant difference between CRC and MRC was concluded. Thus, CRC may not be applicable to comprehensively represent the real reduction capacity of HA for Hg reduction under microbial condition. PMID- 22452225 TI - [Effect of Zn(II) on microbial activity in anaerobic acid mine drainage treatment system with biomass as carbon source]. AB - In this study, with rape straw as carbon source, anaerobic batch experiments were executed to investigate the effect of Zn (II) on the activity of sulphate reducing bacteria (SRB) in the microbial treatment of simulative acid mine drainage (AMD). The results showed that during the 60 experimental days, when initial Zn2+ concentrations were in the range of 73.7 to 196.8 mg x L(-1), SRB had high culturalbility. At the end of these experiments, pH values rose from initial 5.0 to neutral, about 96% of sulphate was reduced and the concentrations of Zn2+ reduced to 0.05 mg x L(-1). The results of Tessier sequential extraction, field emission scanning electron microscope (FE-SEM) and X-ray diffraction(XRD) showed that Zn was found to be fixed through forming organic and sulphide (mainly sphalerite) compounds. For the experiment with high Zn2+ concentration (262.97 mg x L(-1)), at the end of experiments, pH values dropped from initial 5.0 to 4.0, only 27% of sulphate was only reduced and the concentrations of Zn2+ kept in high range (25 mg x L(-1)), the activity of SRB significantly inhibited. This study indicated that: (1) Rape straw can be used as slow-release carbon source for long term anaerobic AMD treatment; (2) Rape straw can decrease the toxicity of Zn2+ to SRB through adsorption; (3) In anaerobic AMD treatment system, Zn can be fixed by sulphide minerals with mediation of SRB. PMID- 22452226 TI - [Diversity of culturable butane-oxidizing bacteria in oil and gas field soil]. AB - Butane-oxidizing bacteria in soil sample sites from Puguang gas field in Sichuan province and Jianghan oil field in Hubei province were isolated and 16S rRNA gene sequence and phylogenetic analysis were applied. The differences of number and phylogenetic position and population diversity of hydrocarbon-oxidizing bacteria in different environment were investigated. The results show that 25 strains of butane-oxidizing bacteria were isolated. Based on sequencing of 16S rRNA gene, the species of bacteria in two samples are classified into 3 phyla including Firmicutes, Actinobacteria and Proteobacteria. The community structure of butane oxidizing bacteria isolated from two oil samples is simple, both of them contain 4 genus including Bacillus, Pseudomonas, Rhodococcus and Arthrobacter. Strains in the genus of Ochrobactrum and Mycobacterium were only isolated from Puguang gas field. The number and population diversity of butane-oxidizing bacteria in Puguang gas field was more than those in Jianghan oil field. PMID- 22452227 TI - [Microbial community structure analysis of unexploited oil and gas fields by PCR DGGE]. AB - Microbial communities of different depths (30, 60, 100, 150, 200cm) from the unexploited oilfield, gas field and control area were studied by PCR-DGGE and sequencing methods. The objectives of this study were to understand the microbial distribution in the regions of unexploited oil and gas fields, and to investigate the potential microbial indicators of oil and gas resources. The results showed that the Dice coefficients between different depths were very low (26-69.9). The microbial communities in the soil of 150 cm and 200 cm depth had greater richness (S > or = 19), diversity (H > or = 2.69) and evenness (E > or = 0. 90). The results of sequencing demonstrated that the bands from oilfield were mainly grouped into alpha-Proteobacteria, gamma-Proteobacteria, Actinobacteria, Acidobacteria with the predominance of gamma-Proteobacteria (75%). Most of the bands were related to oil-associated and hydrocarbon degrading bacteria, such as Methylophaga and Alcanivorax. While the gas field had alpha, beta, gamma, delta Proteobacteria and Bacteroidetes, and gamma-Proteobacteria accounted for only 24%. More strains showed relativity to methanotrophs, such as Methylocystaceae. Thus, 150 cm and 200 cm were more suitable as the oil-gas exploration sampling depth. Methylocystaceae may act as potential indicators for gas resources, Methylophaga and Alcanivorax for oil. PMID- 22452228 TI - [Community diversity of bacteria and arbuscular mycorrhizal fungi in the rhizosphere of eight plants in Liudaogou watershed on the Loess Plateau China]. AB - Terminal restriction fragment length polymorphism (T-RFLP) was used to examine the community diversity of bacteria and arbuscular mycorrhizal fungi (AMF) and their interrelation in the rhizosphere of 8 plants in the Liudaogou watershed in Shenmu County. The objective was to obtain diversity indices and provide theoretical basis for ecological restoration. Results showed significant variations in the species and abundances of rhizospheric bacteria and AMF associated with 8 plants. Among these, the Shannon diversity index of rhizospheric bacteria was the highest for Robinia pseudoacacia (4.01) and the lowest for Salix babylonica (2.18), whereas the Shannon diversity index of rhizospheric AMF was the highest for Populus simonii (2.07) and the lowest for Hippophae rhamnoides (1.21). Cluster analysis and redundancy analysis indicated a significant difference in associated microbial community structure, while the similarity among community diversity of rhizospheric bacteria and AMF associated with specific plants was also found. There was a significant correlation between diversity indices of bacteria and AMF (P < 0.01). Associated microbial community diversity was influenced primarily by organic matter and total nitrogen content. Our work demonstrated strong impacts of plant species and rhizospheric environment on associated microbial community structure. Due to the high diversity indices of rhizospheric bacteria and AMF, R. pseudoacacia was considered to be a pioneer plant species for vegetation restoration in the Liudaogou watershed. PMID- 22452229 TI - [Dynamics of degradation of oxytetracycline of pig and chicken manures in soil and mechanism investigation]. AB - Simulated indoor incubation experiment was carried out to explore the degradation dynamics of oxytetracycline (OTC) from different manures and the mechanisms were investigated as well. The results suggested that manures accelerated OTC entering soil and degrading period, and resembled the L-type curves. Both degradation rate and degradation percentage were significantly different for different antibiotics with different concentration (P < 0.05). At day 180, the OTC degradation percentage of chicken feces was higher than that of pig feces, and the highest degradation percentage reached to 85.4% and 92.3% respectively. The half-lives of chicken and pig manures were 26.98 d, 31.32 d respectively. Degradation percentage was negatively correlated with the amount of manures used and positively correlated with incubation time (v = A + Blnt, r > 0.96). At day 50, the photo-degradation and micro-degradation accounted for 20.03% and 3.16% of total reduction. 25.05% decreased in photo degradation and 2.50% increased in microbiological degradation. It is indicated that the degradation effects to OTC from pig manures was superior to chicken manures, photo decomposing played an important role in the process of degradation and indigenous soil microorganisms only had a little effect on it. With the extension of incubation time, microbiological decomposing became better, but photo decomposing became weaker. PMID- 22452230 TI - [Influence of impurities on waste plastics pyrolysis: products and emissions]. AB - The study is aimed to evaluate the impact of impurities like food waste, paper, textile and especially soil on the pyrolysis of waste plastics. For this purpose, emissions, gas and liquid products from pyrolysis of waste plastics and impurities were studied, as well as the transfer of element N, Cl, S from the substrates to the pyrolysis products. It was found that the presence of food waste would reduce the heat value of pyrolysis oil to 27 MJ/kg and increase the moisture in the liquid products, therefore the food residue should be removed from waste plastics; and the soil, enhance the waste plastics' pyrolysis by improving the quality of gas and oil products. The presence of food residue, textile and paper leaded to higher gas emissions. PMID- 22452231 TI - The role of cytological evaluation of pleural fluid in diagnosing malignant mesothelioma. AB - Malignant mesothelioma is the most significant pleural tumour and it can be divided into three types: epithelial, sarcomatoid and biphasic mesothelioma. The most significant clinical manifestation of this tumour is pleural effusion. This paper was aimed at determining the role of cytological evaluation of pleural fluid in the diagnosis of malignant mesothelioma. This retrospective study included 33 medical records of patients with pleural malignant mesothelioma referred to the Institute for Lung Diseases of Vojvodina, in Sremska Kamenica in the period from 2004 to 2009. In 24 out of 33 patients, x-rays confirmed pleural effusion, thoracentesis was performed and specimens of effusion were cytologically examined at the Department of Pathology of the Institute for Lung Diseases of Vojvodina. Forty-nine cytological examinations were done. Only 2 of the first specimens were positive for malignant cells and 6 were suspicious. In repeated cytological examinations, 5 out of 6 initially suspicious specimens were positive for malignant cells, and the remaining 1 was negative. To sum up, 7 of 49 cytological examinations were positive and the sensitivity of our cytological study for the diagnosis of malignancy was 29%. Due to the low sensitivity of the cytological examinations, it has been recommended to perform biopsy of the pleura for definitive diagnosis in every patient with clinical symptoms and suspicious radiography. PMID- 22452232 TI - Hemorrhagic complications of thrombolytic therapy. AB - Stroke is the most frequent neurological disorder, and the most common cause of severe disability compared to other diseases. Recombinant tissue plasminogen activator (rt-PA) is the only approved specific therapy for acute ischemic stroke. Hemorrhage is a significant complication of thrombolytic treatment. This study, which included a hundred patients (52 male and 48 female), was aimed at assessing the safety according to our experience with 100 thrombolytic treatments for stroke. The death rate related to hemorrhage after thrombolysis was 3%. The frequency of hemorrhagic events (hemorrhagic infarctions type 1 and 2, parenchymal hematomas type 1 and 2) was 16%. The study results have shown that the intravenous recombinant tissue plasminogen activator (rt-PA) therapy is safe. PMID- 22452233 TI - [Effect of a tight necktie on intraocular pressure]. AB - INTRODUCTION: Any factor causing constriction of the neck may lead to an increase in intraocular pressure. A tight necktie may result in increasing intraocular pressure, which could lead to an erroneous diagnosis and treatment of ocular hypertension or even glaucoma. This study was aimed at evaluating the effect of a tight necktie on intraocular pressure measurement using Goldmann applanation tonometry. MATERIAL AND METHODS: This study included forty eyes of 20 patients with primary open angle glaucoma and 20 healthy controls (all male). Intraocular pressure was measured without a necktie, 3 minutes after placing a tight necktie and 3 minutes after loosening it. Student's t-test was used to analyze the data between two groups. The intraocular pressure measurements were subjected to paired t-test. The va lue p < 0.05 was considered statistically significant. A possible correlation between the age of subjects and intraocular pressure values was analyzed using linear regression (Pearson). RESULTS: A statistically significant difference was found in intraocular pressure readings in all three measurements between two tested groups (p < 0.05). When analyzed within groups, statistical significance in intraocular pressure readings was found after loosening the necktie (< 0.05). No correlation between the age of subjects and increased intraocular pressure was found in either tested group of subjects after the necktie had been tightened (r2 = 0.006, p = 0.70 for primary open angle patients, r2 = 0.07, p = 0. 22 for healthy controls). CONCLUSION: Wearing a tight necktie for a limited period of time during the day could be considered as a possible risk factor for glaucoma development. PMID- 22452234 TI - Left ventricular diastolic dysfunction in patients with metabolic syndrome. AB - Metabolic syndrome (MetS), which is a cluster of medical disorders, is common and it is associated with increased cardiovascular morbidity and mortality. The aim of this study was to evaluate the relationship between characteristics of metabolic syndrome and the grade of diastolic dysfunction. The study included 72 patients (29 male and 43 female), who had central obesity and at least two of the other four characteristics of metabolic syndrome according to IDF (International Diabetes Federation) criteria. The exclusion criteria were age above 65, impaired systolic function (left ventricular ejection fraction < 55%) atrial fibrillation, valvular and pericardial heart disease. Diastolic function was determined according to the criteria of the American Society of Echocardiography. There was a positive correlation between the number of characteristics of metabolic syndrome and the diastolic dysfunction grade (p < 0.0001). The positive correlation was found between the grade of diastolic dysfunction and the waist circumference (p < 0.0001), arterial hypertension (p < 0.001). pared glucose tolerance/diabetes (P = 0.0063), and hypertriglyceridemia (p = 0.0262). A low level of high-density lipoprotein did not show a statistically significant correlation. The presence of metabolic syndrome is associated with the presence of diastolic dysfunction. The grade of diastolic dysfunction is dependent on the number of coexisting characteristics of metabolic syndrome. Arterial hypertension, central obesity, hyperglycemia and hypertriglyceridemia showed a significant correlation with the degree of diastolic dysfunction. PMID- 22452235 TI - [Differences in the outcome of disease between patients diagnosed with 1st and recurrent stroke after two years of monitoring]. AB - INTRODUCTION: A stroke is the most common neurological disorder, and the most common cause of severe disability. The aim of this study was to establish the incidence and recurrence of the stroke among the population of the Doljevac district, as well as the differences in the outcome of disease between the patients diagnosed with the first and recurrent stroke. MATERIAL AND METHODS: A prospective examination was carried out, and the study included all patients with the first and recurrent stroke in the territory of the Doljevac district (population, 19529) in the period from 2004 to 2008, after two years of monitoring. RESULTS: During the observed period, the total number of the affected people was 380, of whom 182 (47.89%) were males, and 198 (52.10%) were females. The overall standardized incidence rate of the stroke was 270.20, and with recurrences--42.03. Among the patients with the first stroke, we recorded a higher number of survivals (Chi2 = 3.99; p = 0.04) and patients with recurrences in a one-year period (Chi2 = 5.29; p = 0.02), as well as in a two-year period (Chi2 = 7.72; p = 0.00) since the beginning of the disease. Among the patients with recurrences, we recorded a higher demand for medical help in home healthcare environment (Chi2 = 4.97; p = 0.02), and the higher one-month (Chi2 = 12.09; p = 0.00), and one-year lethality (Chi2 = 9.03; p = 0.00). Among the patients with recurrences, there were no differences in the diagnosis of the first and recurrent stroke (p > 0.05). CONCLUSION: This study showed that there were no statistical differences in the incidence between the first and recurrent stroke between the sexes (p > 0.05). Among the patients with the first stroke, we recorded a higher tendency for survival, and frequent cases of recurrence, and among those with recurrences, the rate of mortality was higher. PMID- 22452236 TI - [Costs of anesthetics and other drugs in anesthesia]. AB - INTRODUCTION: Drugs are real and transparent costs of treatment, which are subject to constant monitoring and changes. The study was aimed at measuring and analyzing consumption of anesthetics and other drugs in anesthesia in the Clinical Centre of Serbia. MATERIAL AND METHODS: This paper is part of a five year (2005-2009), academic, pharmacoeconomic retrospective-prospective study (the 4th phase). We calculated the costs of anesthetics and other drugs in all anesthetized patients at the Institute of Anesthesia and Reanimation, Clinical Center of Serbia in 2006. The data, obtained from the Clinical Centre of Serbia Database, were analyzed by descriptive statistical methods using computer program Microsoft Office Excel 2003 and the Statistical Package for the Social Sciences (SPSS) for Windows. RESULTS: The amount of money spent for the application of 33,187 general and 16,394 local anesthesia and 20,614 anesthesiology procedures was 83,322,046.36 RSD (Euros 1,054,705.4), which was 5.93% of the funds allocated for all drugs used at the Clinical Center of Serbia. Of the total fund for drugs, 57.8% was spent for anesthetics (local anesthetics 1.20%) and muscle relaxants, whereas 42.2% was spent for other drugs in anesthesia. The highest amount was spent at the Emergency Center (35.8%), then at the Cardio-surgery (11.9%) and the Neurosurgery (10.9%) because of the large number and length of surgical interventions. CONCLUSION: There is no space for rationalizing the costs of anesthetics and other drugs in anesthesia. PMID- 22452237 TI - [Idiopathic scoliosis]. AB - INTRODUCTION: Idiopathic scoliosis is a structural and lateral curvature of the spine for which a currently recognizable cause has not been found and there is no basic evidence for physical and radiographic pathology. COMPLICATIONS: Scoliosis could be a cause of the back pain, deformities, respiratory and cardiology problems. There is a higher risk for decreasing of bone mineral density. DIAGNOSIS AND MANAGEMENT: Physical examination, radiography and stereophotogrametry are used in diagnostics of idiopathic scoliosis. The management of idiopathic scoliosis can be conservative or operative. The main forms of conservative management are: therapy exercises, electrical stimulation and spinal orthosis. The primary aim of scoliosis management is to stop curvature progression. The improvement of pulmonary function (vital capacity) and treatment of pain are also of major importance. THE GUIDELINES FOR CONSERVATIVE MANAGEMENT OF SCOLIOSIS: The International Society on Scoliosis Orthopaedic and Rehabilitation Treatment gave the guidelines for conservative management of scoliosis. Conservative management of scoliosis includes: a) Lyonaise, Side Shift, Dobosiewicz, Schroth and other kinesitherapy methods, b) scoliosis intensive rehabilitation which appears to be effective with respect to many signs and symptoms of scoliosis and with respect to impeding curvature progression and c) brace treatment, which has been found to be effective in preventing curvature progression and thus in altering the natural history of idiopathic scoliosis. CONCLUSION: The International Society has given the standards for kinesitherapy, intensive rehabilitation and spinal orthosis in clinical practice and clinical investigations. Surgical procedures can improve curves in the frontal plane, but have important limitations in maintaining fixation and achieving correction in other planes. PMID- 22452238 TI - Obturator approach in the surgical treatment of stress urinary incontinence using tension-free transvaginal tape. AB - The study reviews the surgical treatment results of urinary stress incontinence in the group of 51 female patients, in whom the tension-free transvaginal tape was placed beneath the middle part of urethra using obturator approach during the period from 2005 to 2009. The method of surgery applied in all patients was obturator approach ("inside-out" method sec. de Leval), using a synthetic tension free transvaginal prolen tape. After the sub-urethral tunnel had been created by scissors, the obturator membrane was perforated, then the placement of wing guides followed, through which helical needles with synthetic tape were brought to the skin. The following complications were observed in 8 (15.7%) patients: erosion of tape in 2 (3.9%), urine retention in 2 (3.9%), bleeding from the site of incision in 1 (1.9%) and transitory leg pain in 3 (5.8%) cases. Two years after the surgery, 43 (84.3%) patients were dry, 4 (7.8%) patients showed a significant improvement, while the recurrence was recorded in 4 (7.8%) operated patients. PMID- 22452239 TI - [Hierarchy of evidence in interpretation of clinical significance of drug interactions]. AB - INTRODUCTION: Since drug interactions may result in serious adverse effects or failure of therapy, it is of huge importance that health professionals base their decisions about drug prescription, dispensing and administration on reliable research evidence, taking into account the hierarchy of data sources for evaluation. CLINICAL SIGNIFICANCE OF POTENTIAL INTERACTIONS--INFORMATION SOURCES: The sources of data regarding drug interactions are numerous, beginning with various drug reference books. However, they are far from uniformity in the way of choosing and presenting putative clinically relevant interactions. CLINICAL SIGNIFICANCE OF POTENTIAL INTERACTIONS--INTERPRETATION OF INFORMATION: The difficulties in interpretation of drug interactions are illustrated through the analysis of a published example involving assessment made by two different groups of health professionals. SYSTEMATIC EVALUATION OF DRUG--DRUG INTERACTION: The potential for interactions is mainly investigated before marketing a drug. Generally, the in vitro, followed by in vivo studies are to be performed. The major metabolic pathways involved in the metabolism of a new molecular entity, as well as the potential of induction of human enzymes involved in drug metabolism are to be examined. In the field of interaction research it is possible to make use of the population pharmacokinetic studies as well as of the pharmacodynamic assessment, and also the post-registration monitoring of the reported adverse reactions and other literature data. CONCLUSION: In vitro and in vivo drug metabolism and transport studies should be conducted to elucidate the mechanisms and potential for drug-drug interactions. The assessment of their clinical significance should be based on well-defined and validated exposure-response data. PMID- 22452240 TI - [Importance of haemovigilance and reports on transfusion reaction in blood component therapy]. AB - INTRODUCTION: Application of blood and blood components throughout decades is very successful and mostly safe procedure in patients' therapy. However, it may lead to unfavourable effects, such as transfusion reactions. MATERIAL AND METHODS: In the period from 2000 to 2009, 180 transfusion reactions were reported at the Department of Clinical Transfusion of the Service for Blood Transfusion of Vojvodina in Novi Sad. The aetiology of transfusion reactions was determined by examining pre-transfusion and post-transfusion sample of patient's blood and by examining the unit of blood component that induced reaction. RESULTS: Out of 180 reported transfusion reactions, 98 (54.4%) were febrile non-haemolytic transfusion reactions, 69 (38.3%) allergic reactions and 2 (1.11%) haemolytic reactions. Blood components that caused most of transfusion reactions were erythrocytes (62.4%), fresh frozen plasma (11.2%) and platelets (14.4%). All patients underwent multiple transfusions. DISCUSSION: The fact that only 0.13% transfusion reactions were reported, compared with data from literature (2-15%), points to the lack of regular reporting of transfusion reactions, as well as the fact that there is only one report of delayed transfusion reaction. CONCLUSIONS: To improve and make blood transfusion safer it is necessary to respect all pre transfusion procedures, constant follow up of blood transfusion must be done and patients with diagnosed non-haemolytic transfusion reaction should be given leukocyte reduced blood components. PMID- 22452241 TI - Functional hearing results in patients with otosclerosis before and after stapedotomy. AB - Surgical treatment of otosclerosis with stapedotomy leads to the improvement of subjective and objective problems in patients with otosclerosis. A prospective study included patients who had been treated surgically at the Department for Ear, Nose and Throat in Novi Sad in the period from September 2006 to September 2007. On the basis of the appropriate diagnostic procedures, 33 patients were diagnosed with otosclerosis. Functional hearing was assessed before and after surgery by means of pure tone audiometry. The comparison of functional results before and after surgery revealed no changes in pure tone average of bone conduction threshold (average hearing threshold for hearing range), whereas pure tone average of air conduction and pure tone average of the gap showed statistically significant improvement. The results of this study demonstrated the applicability of stapedotomy as a method for successful management of otosclerosis. This way of examination offers a new perspective on patients' health, which should be defined as a physical, psychosocial and social well being, and not only the absence of a disease itself. PMID- 22452242 TI - Acute osteomyelitis and septic arthritis of the shoulder in premature neonates- report of two cases. AB - Acute hematogenous osteomyelitis and septic arthritis are pyogenic infections of bone and joint, respectively. At the youngest age, they usually occur at the same time--hence the common name "osteoarthritis". When it comes to neonates, osteoarthritis is an infrequent finding, but it can give a permanent disability and can be even fatal unless early recognized and adequately and promptly treated. An early diagnosis is rather challenging because the signs and symptoms of this disease are subtle and/or nonspecific. The therapy involves a combination of intravenous antimicrobial therapy in high doses and of sufficient duration, with a mandatory decompression of affected joint by needle aspiration or artrhrotomy. The aim of this paper is to present two premature newborns with rare localization of osteoarthritis - the humerus and shoulder joint, as well as to point to the modern diagnostic and therapeutic approach to this disease. PMID- 22452243 TI - [Pathohistological changes in fetuses with cystic fibrosis]. AB - INTRODUCTION: Cystic fibrosis or mucoviscidosis is a genetically caused disease. The intensity of disease and histopathological changes grow throughout the life. According to the literature, pathological changes characteristic of cystic fibrosis become noticeable around the sixth month of life. CASE REPORT: After amniocentesis of a 5-lunar month-old fetus had been done, which confirmed cystic fibrosis, the Ethics Commission approved the preterm labor. The autopsy and histopathological analysis demonstrated the existence of typical histopathological changes in the pancreas and intestines. DISCUSSION: In the late fetal period or during the period around the delivery, cystic fibrosis is usually manifested as meconial cap with or without obstruction of the intestinal lumen. Morphological changes in the exocrine glands usually develop only after birth. In this case, the existence of meconial obstruction, as well as the typical acidofil content in the secretory ducts and acini of the pancreas was confirmed, which is unusual for the fetal age of five months. PMID- 22452244 TI - [Acute pancreatitis in children]. AB - INTRODUCTION: Acute pancreatitis in children is mostly due to abdominal trauma, diseases or congenital anomalies of the biliary-pancreatic tree. Both exogenous and endogenous functions of the gland could be disturbed by various levels of damage. CLINICAL FINDING AND DIAGNOSTICS: Acute abdominal pain, gastrointestinal signs and general deterioration are the main clinical findings. The examination can be completed by blood and urine tests of amylase, electrolytes level, and the C-reactive protein. In addition to these tests, ultrasound, computed tomography and endoscopy are required as well. THERAPEUTIC METHODS: The therapy of choice is non-operative treatment using medicaments to control the pain, decrease the pancreatic activity and prevent further complications. If the conservative treatment fails, the surgical approach is necessary: drainage, resections, by pass procedures, etc. CONCLUSION: Acute pancreatitis is a very serious disease in childhood. Clinical experience and rational approach are very important in the diagnostic and therapeutic methods. PMID- 22452245 TI - [Historical review of congenital foot deformity treatment]. AB - INTRODUCTION: There is still no good solution for the treatment of all the forms of clubfoot. HISTORY OF THE TREATMENT IN THE WORLD: The first written description of the treatment of this deformity was given by Hippocrates. In the Middle Ages, Galenus, Celsus and Averroe only reviewed the lessons of Hippocrates's principles. The first description of orthopedic prosthetic for the treatment of clubfoot was published in "Opera Chirurgica" by Amboise Perea in 1575. In 1796, Bruckner wrote the first monography about clubfoot. The biggest contribution to the modern way of treating clubfoot was given by Abel Mix Phelebs, who described the medial "release" in 1890. Since 1980 an advantage has been given to early non operative treatment. The progressive operative approach (use of "release procedures") was introduced. THE HISTORY OF TREATMENT IN OUR COUNTRY: The first procedures were performed by D. Jovcic and S. Stojanovic in Belgrade in 1937. In the period from 1960 to 1970, more and more orthopedic and pediatric surgeons became interested in clubfoot treatment. In 1970 one of the main topics of the 5th Congress of Orthopedics and Traumatology in Belgrade was "Foot Surgery". Many specialists from Belgrade were engaged in clubfoot treatment: D. Rakic, S. Rajic, S. Popovic, L. Stojanovic among pediatricians, and B. Radulovic, P. Klisic among orthopedic surgeons, as well as R. Brdar, Z. Vukasinovic and G. Cobeljic with their assistants. In Novi Sad, in 1967, D. Pajic began diagnosis and treatment of clubfoot. Very soon D. Pajic became a symbol of clubfoot treatment followed by hardworking assistants L. Petkovic and V. Tomasevic. CONCLUSION: The treatment of clubfoot is still controversial and continues to be one of the most interesting fields in pediatric orthopedics. PMID- 22452246 TI - Atmospheric fate of methacrolein. 1. Peroxy radical isomerization following addition of OH and O2. AB - Peroxy radicals formed by addition of OH and O(2) to the olefinic carbon atoms in methacrolein react with NO to form methacrolein hydroxy nitrate and hydroxyacetone. We observe that the ratio of these two compounds, however, unexpectedly decreases as the lifetime of the peroxy radical increases. We propose that this results from an isomerization involving the 1,4-H-shift of the aldehydic hydrogen atom to the peroxy group. The inferred rate (0.5 +/- 0.3 s(-1) at T = 296 K) is consistent with estimates obtained from the potential energy surface determined by high level quantum calculations. The product, a hydroxy hydroperoxy carbonyl radical, decomposes rapidly, producing hydroxyacetone and re forming OH. Simulations using a global chemical transport model suggest that most of the methacrolein hydroxy peroxy radicals formed in the atmosphere undergo isomerization and decomposition. PMID- 22452247 TI - Adverse effects of long-term right ventricular apical pacing and identification of patients at risk of atrial fibrillation and heart failure. AB - In patients needing a pacemaker (PM) for bradycardia indications, the amount of right ventricular (RV) apical pacing has been correlated with atrial fibrillation (AFib) and heart failure (HF) in both DDD and VVI mode. RV pacing was linked with left ventricular (LV) dyssynchrony in almost 50% of patients with PM implantation and atrioventricular (AV) node ablation for AFib. In patients with normal systolic function needing a PM, apical RV pacing resulted in LV ejection fraction (LVEF) reduction. These negative effects were prevented by cardiac resynchronization therapy (CRT). Algorithms favoring physiological AV conduction are possible useful tools able to maintain both atrial and ventricular support and limit RV pacing. However, when chronic RV pacing cannot be avoided, it appears necessary to reconsider the cut-off value of basic LVEF for CRT. In HF patients, RV pacing can induce greater LV dyssynchrony, enhanced by underlying conduction diseases. In this context, a more deleterious effect of RV pacing in implantable cardioverter-defibrillator (ICD) patients with low LVEF can be expected. In some major ICD trials, DDD mode was correlated with increased mortality/HF. This negative impact was attributed to unnecessary RV pacing >40 50%, virtually absent in VVI-40 mode. However, some data suggest that avoiding RV pacing may also not be the best option for patients requiring an ICD. In patients with impaired LV function, AV synchrony should therefore be ensured. The best pacing mode in ICD patients with HF should be defined on an individual basis. PMID- 22452248 TI - Performance of isobaric and isotopic labeling in quantitative plant proteomics. AB - Mass spectrometry has become indispensable for peptide and protein quantification in proteomics studies. When proteomics technologies are applied to understand the biology of plants, two-dimensional gel electrophoresis is still the prevalent method for protein fractionation, identification, and quantitation. In the present work, we have used LC-MS to compare an isotopic (ICPL) and isobaric (iTRAQ) chemical labeling technique to quantify proteins in the endosperm of Ricinus communis seeds at three developmental stages (IV, VI, and X). Endosperm proteins of each stage were trypsin-digested in-solution, and the same amount of peptides was labeled with ICPL and iTRAQ tags in two orders (forward and reverse). Each sample was submitted to nanoLC coupled to an LTQ-Orbitrap high resolution mass spectrometer. Comparing labeling performance, iTRAQ was able to label 99.8% of all identified unique peptides, while 94.1% were labeled by ICPL. After statistical analysis, it was possible to quantify 309 (ICPL) and 321 (iTRAQ) proteins, from which 95 are specific to ICPL, 107 to iTRAQ, and 214 common to both labeling strategies. We noted that the iTRAQ quantification could be influenced by the tag. Even though the efficiency of the iTRAQ and ICPL in protein quantification depends on several parameters, both labeling methods were able to successfully quantify proteins present in the endosperm of castor bean during seed development and, when combined, increase the number of quantified proteins. PMID- 22452249 TI - Combining label-free technologies: discovery in strength. PMID- 22452251 TI - 'Large Meets Small': connecting the bioanalytical community around peptide and protein bioanalysis with LC-MS(/MS). AB - This conference report provides an overview of the discussions at the 2nd European Bioanalysis Forum (EBF) Focus Meeting 'Large Meets Small' held on 20 and 21 June 2011 in Brussels. The meeting discussed scientific progress in the bioanalysis of peptides and proteins with MS-based techniques. Bioanalytical experts in ligand-binding assays (LBAs) and MS from industry and academia presented at the meeting or joined the discussion. The conference hosted sessions on technology developments, validation requirements, cutting edge (bio)analytical approaches for both proteins and peptides and discussions on the analytical challenge presented by the metabolism of peptides or proteins. The engagement of the scientists as well as the bioanalytical challenges identified were real: by shifting peptide or protein analysis from the LBAs laboratory into the LC-MS laboratory, the bioanalytical scientist is moving into partially uncharted territory. The conference delegates strongly shared the feeling that success in overcoming the challenges of peptide and protein bioanalysis will require further integration of the expertise of LBAs and LC-MS/MS experts. PMID- 22452252 TI - 'Less is More': defining modern bioanalysis. AB - The 4th Open Symposium of the European Bioanalytical Forum entitled 'Less is More' was held on 16-18 November 2011 at the Hesperia Tower Hotel, Barcelona, Spain. More than 50 interesting presentations were delivered covering areas with interest for the small- and large-molecule community - biomarker validation; regulations, including an update on new and emerging guidelines and on Global harmonization; technology updates; incurred sample stability; microdosing; dried blood spots and microsampling; challenges of 'free' and 'total' macromolecule quantification; stability issues in ligand binding assays or anomalous results. In excess of 450 delegates from more than 170 institutes and companies (industry, regulators and academia) from all global regions participated in the open and stimulating discussions. This manuscript provides an overview of the highlights discussed at the meeting. PMID- 22452253 TI - Advances in metabolic profiling. AB - The main topics of this conference were based around new technologies and applications of metabolomics in healthcare, bioscience and environmental applications. There were sessions themed on 'Novel Approaches and Technology in Metabolomics', 'Disease in Metabolomics', 'Data Processing and Functional Metabolomics', and 'Plant and Environmental Metabolomics'. Analytical methodologies favored included targeted metabolite analysis (LC-MS/MS, GC-MS), global metabolite analysis (LC-accurate mass, direct injection MS) and NMR. PMID- 22452254 TI - Commentary on the history and quantitative nature of filter paper used in blood collection devices. PMID- 22452255 TI - Letter to the Editor: Response to: Commentary on the history and quantitative nature of filter paper used in blood collection devices. PMID- 22452256 TI - Recommendations on the interpretation of the new European Medicines Agency Guideline on Bioanalytical Method Validation by Global CRO Council for Bioanalysis (GCC). PMID- 22452257 TI - Capillary microsampling of 25 ul blood for the determination of toxicokinetic parameters in regulatory studies in animals. AB - BACKGROUND: Capillary microsampling (CMS) is a new technique for simplified collection, handling and analysis of small, exact volumes of liquid matrices. CMS was compared with conventional large volume sampling, in toxicology studies in rat and dog. RESULTS: Bioanalytical validation data were well within acceptance limits. Toxicokinetic (TK) parameters from microsampling were in agreement with data from conventional volume sampling. Clinical pathology parameters in rats measured 2 days after repeated microsampling were not affected when compared with rats not sampled. CONCLUSION: The fast collection and simple handling of small, exact volumes of liquid blood makes the CMS technique generic and flexible, as well as easily implemented and automated. Presented data support that TK measurements can be performed in main study rats, instead of dosing additional satellite animals only for TK sampling, giving both a higher scientific value and a substantial reduction of animal numbers in preclinical development. PMID- 22452258 TI - Analytical bias between species caused by matrix effects in quantitative analysis of a small-molecule pharmaceutical candidate in plasma. AB - BACKGROUND: Suppression or enhancement of MS ionization, particularly evident when electrospray is used as the source of ions, has been widely discussed. METHODS: An assay for a small-molecule pharmaceutical in dog plasma between 1-300 ng/ml was validated with a mean bias across the calibration range of 5.0%. When the calibration sample matrix was substituted for human plasma, the mean bias across the range increased to 29.1%. A study of bias originating as a result of matrix effects, arising from endogenous glycerophosphocholine species, in plasma sources is discussed. CONCLUSION: A simple strategy to assess the potential of any unmitigated matrix effect to bias quantitative analysis by nonequivalent ionization induction or suppression is evaluated. PMID- 22452259 TI - Quantitation of polypeptides (glucagon and salmon calcitonin) in plasma samples by 'high resolution' on a triple quadrupole mass spectrometer. AB - BACKGROUND: Bioanalysis of large molecules can be challenging on LC-MS/MS due to multiply charged and endogenous interferences. While high sensitivity triple quadrupole systems (QqQ) have been commercialized recently, high-resolution MS (HRMS) systems are also available. HRMS provides alternative analysis methods, but more costly and with sensitivity lower than MRM on QqQ. RESULTS: QqQ is generally operated at unit resolution; however, newer systems are able to practically tune to 'high resolution'. Therefore, the advantages of both higher sensitivity of MRM on QqQ and better specificity on HRMS can possibly be combined on a QqQ to meet bioanalysis needs. Glucagon and salmon calcitonin were successfully quantified in high-resolution with fast cycle time on AB Sciex TripleQuadTM 5500. LLOQ (S/N) was increased and interferences reduced. CONCLUSION: For large molecules, the bioanalysis methods developed using high resolution on the QqQ are validated and used in preclinical and clinical studies. PMID- 22452260 TI - Influence of DNA-dye complex stability on separation resolution in microchip electrophoresis. AB - BACKGROUND: Different markers have been used to label DNA for sample detection in gel electrophoresis. Intercalating dyes, (e.g., YOYO) have been widely used to label DNA for sample detection, because they do not require the use of radioisotopes, covalent attachment or enzyme reactions. The labeling of DNA fragments can be achieved by simply mixing solutions of the intercalating dye and DNA sample. However, the separation quality of DNA labeled with intercalating dyes is greatly influenced by the buffer used, which affects the DNA-dye complex stability. RESULTS: In this study, we investigated the effects of DNA-dye complex stability on separation resolution of dsDNA migrating in a photopolymerized polyacrylamide gel by measuring mobility and dispersion coefficients on a microfluidic chip and comparing predicted separation resolution under different dye and buffer conditions. CONCLUSION: We found that a buffer containing tetrapentylammonium (NPe(4)(+)) yielded better separation resolution than the frequently used TBE buffer on our microchip electrophoresis system. PMID- 22452261 TI - A case study on Sema3E-Fc aggregation and assay-dependent differences in quantitation. AB - BACKGROUND: In evaluating the serum concentrations in mice of a Sema3E IgG1 Fc fusion protein, a possible antitumor agent, two ELISAs were developed: a generic assay detecting only the Fc portion of the therapeutic and a specific receptor binding assay detecting intact protein. RESULTS: An unexpected discrepancy was observed in the measured in vivo serum concentrations, with the generic ELISA yielding higher concentrations than the specific ELISA. Size-exclusion HPLC and SDS-PAGE analysis of in vitro serum stability samples revealed extensive aggregation of Sema3E-Fc. The generic assay recovered more Sema3E-Fc in the presence of aggregates than the specific assay. CONCLUSION: Biophysical characterization combined with immunochemical analysis was key to elucidating not only the nature of the protein instability, but also the cause for the assay discrepancy. PMID- 22452262 TI - Pharmacokinetics, bioavailability and metabolism of rhaponticin in rat plasma by UHPLC-Q-TOF/MS and UHPLC-DAD-MSn. AB - BACKGROUND: Rhaponticin (Rheum L.) demonstrates a variety of pharmacological activities, including antitumor, antithrombotic and antioxidant effect. However, there is no information describing the pharmacokinetics, bioavailability and metabolism of rhaponticin after intravenous administration. RESULTS: UHPLC-Q TOF/MS and UHPLC-multistage tandem MS methods were developed for the pharmacokinetics, bioavailability and metabolism of rhaponticin in rats. The metabolite of rhaponticin, rhapontigenin, a potent inhibitor of cytochrome P450, was confirmed by UHPLC-multistage tandem MS. The plasma profile of rhaponticin and rhapontigenin was determined by UHPLC-Q-TOF/MS. The results showed that rhaponticin was rapidly distributed and eliminated from rat plasma. The absolute oral bioavailability of rhaponticin was calculated to be 0.03%. The plasma concentrations of rhapontigenin rapidly increased and gradually eliminated after intravenous administration. CONCLUSION: The present pharmacokinetics, bioavailability and metabolism studies of rhaponticin will provide helpful information for development of suitable dosage forms and clinical references on rational administration. PMID- 22452263 TI - Recent advances in liquid microextraction techniques coupled with MS for determination of small-molecule drugs in biological samples. AB - Sample preparation is an important and necessary step in a measurement process for isolation and concentration of desired components from complex matrices. It is the most time-consuming and error-prone step in analytical methodology, greatly affecting quality and quantity of analytical data. During the past 15 years, solvent microextraction techniques have been introduced as alternatives to conventional sample preparation methods, such as liquid-liquid extraction and solid-phase extraction. These novel methodologies, which have proved to be extremely simple, low-cost and virtually solvent-free sample-preparation techniques provide a high degree of selectivity, sample cleanup and enrichment. The aim of the present review is to explore recent analytical applications of solvent microextraction techniques for quantification of drugs in biological samples, with particular focus on the methods involving MS as a detection system. PMID- 22452264 TI - Tissue sample preparation in bioanalytical assays. AB - Analytical quantitation of compounds in tissue has become a more prevalent addition to biological sample analysis in recent times. This increase will most certainly continue to bring the question of proper analytical method validation to the forefront of discussion. Thoughtful design of sample homogenization, analyte fortification and extraction can ensure a successful analysis. This review presents current trends in tissue sample preparation by harvesting, homogenization techniques, as well as concerns for calibrator and QC preparation. Strategies for consideration and resolution of common pitfalls in method development, for example stability issues and control biomatrices in endogenous analysis, are also presented. PMID- 22452265 TI - In memory of Niklas Lindegardh. PMID- 22452266 TI - Enhancing surface plasmon detection using template-stripped gold nanoslit arrays on plastic films. AB - Nanostructure-based sensors are capable of sensitive and label-free detection for biomedical applications. However, high-throughput and low-cost fabrication techniques are the main issues which should be addressed. In this study, chip based nanostructures for intensity-sensitive detection were fabricated and tested using a thermal-annealing-assisted template-stripping method. Large-area uniform nanoslit arrays with a 500 nm period and various slit widths, from 30 to 165 nm, were made on plastic films. A transverse magnetic-polarized wave in these gold nanostructures generated sharp and asymmetric Fano resonances in transmission spectra. The full width at half-maximum bandwidth decreased with the decrease of the slit width. The narrowest bandwidth was smaller than 10 nm. Compared to nanoslit arrays on glass substrates using electron-beam lithography, the proposed chip has a higher intensity sensitivity up to 10367%/RIU (refractive index unit) and reaches a figure of merit up to 55. The higher intensity sensitivity for the template-stripped nanostructure is attributed to a smoother gold surface and larger grain sizes on the plastic film, which reduces the surface plasmon propagation loss. PMID- 22452267 TI - Analysis of diffusion-controlled stochastic events of iridium oxide single nanoparticle collisions by scanning electrochemical microscopy. AB - We investigated the electrochemical detection of single iridium oxide nanoparticle (IrO(x) NP) collisions at the NaBH(4)-treated Pt ultramicroelectrode (UME) in a scanning electrochemical microscope (SECM) over an insulating surface. The NP collision events were monitored by observing the electrocatalytic water oxidation reaction at potentials where it does not take place on the Pt UME. These collisions occurred stochastically, resulting in a transient response ("blip") for each collision. The frequency of the collisions is proportional to the flux of NPs to the UME tip, and thus equivalent to the SECM current. A plot of collision frequency versus distance followed the theoretical approach curve behavior for negative feedback for a high concentration of mediator, demonstrating that the collisions were diffusion-controlled and that single particle measurements of mass transport are equivalent to ensemble ones. When the SECM was operated with a Pt substrate at the same potential as the tip, the behavior followed that expected of the shielding mode. These studies and additional ones result in a model where the IrO(x) NP collision on the Pt UME is adsorptive, with oxygen produced by the catalyzed water oxidation causing a current decay. This results in a blip current response, with the current decay diminished in the presence of the oxygen scavenger, sulfite ion. Random walk and theoretical bulk simulations agreed with the proposed mechanism of IrO(x) NP collision, adsorption, and subsequent deactivation. PMID- 22452268 TI - Quantitative structure-activity relationship analysis of human neutrophil elastase inhibitors using shuffling classification and regression trees and adaptive neuro-fuzzy inference systems. AB - The purpose of this study was to develop quantitative structure-activity relationship models for N-benzoylindazole derivatives as inhibitors of human neutrophil elastase. These models were developed with the aid of classification and regression trees (CART) and an adaptive neuro-fuzzy inference system (ANFIS) combined with a shuffling cross-validation technique using interpretable descriptors. More than one hundred meaningful descriptors, representing various structural characteristics for all 51 N-benzoylindazole derivatives in the data set, were calculated and used as the original variables for shuffling CART modelling. Five descriptors of average Wiener index, Kier benzene-likeliness index, subpolarity parameter, average shape profile index of order 2 and folding degree index selected by the shuffling CART technique have been used as inputs of the ANFIS for prediction of inhibition behaviour of N-benzoylindazole derivatives. The results of the developed shuffling CART-ANFIS model compared to other techniques, such as genetic algorithm (GA)-partial least square (PLS)-ANFIS and stepwise multiple linear regression (MLR)-ANFIS, are promising and descriptive. The satisfactory results r2p = 0.845, Q2(LOO) = 0.861, r2(L25%O) = 0.829, RMSE(LOO) = 0.305 and RMSE(L25%O) = 0.336) demonstrate that shuffling CART-ANFIS models present the relationship between human neutrophil elastase inhibitor activity and molecular descriptors, and they yield predictions in excellent agreement with the experimental values. PMID- 22452269 TI - Quality of life following liver transplantation in patients with liver metastases from colorectal carcinoma. AB - PURPOSE: To study quality of life (QoL) in patients with liver metastases from colorectal carcinoma (CRC) following liver transplantation (Ltx). METHODS: Ten patients participated in a prospective explorative pilot study. Inclusion criteria were nonresectable liver-only metastases determined by CT/MRI-, PET/CT- scans and colonoscopy, and ECOG 0-1. Primary outcome was QoL assessed by the EORTC-C30 questionnaires at baseline, and at 3, 6 and 12 months after Ltx. RESULTS: The patients' age ranged from 50 to 63 years. Nine of 10 patients were observed for 12 months. One patient did not return the form at 6 months and died shortly after because of recurrence of the malignant disease. Compared to baseline, Ltx resulted in sustained excellent global health status scale (score of 100) in one patient, improved scores in 4 and unchanged scores in 3 patients at 12 months. The majority of the patients also reported good functional scores at follow-ups. Although two patients had marked symptoms both before and after Ltx, the patients in general reported low levels of pain and fatigue before and after surgery. CONCLUSION: The present study indicates that CRC patients with liver-only metastases who receive Ltx have good QoL and have mostly minor symptoms the first year after Ltx. PMID- 22452270 TI - Associations of the lower urinary tract symptoms with the lifestyle, prostate volume, and metabolic syndrome in the elderly males. AB - This study aimed to evaluate the influence of the lifestyle, prostate volume (PV), and metabolic syndrome (MS) on lower urinary tract symptoms (LUTS) in the elderly males. A total of 764 men aged greater than 40 years were enrolled. Their severities of LUTS were assessed by the International Prostate Symptom Score questionnaire, while their MS was diagnosed according to the criteria developed by the National Cholesterol Education Program Adult Treatment Panel III. Lifestyle factors, PV, and components of MS were compared between no/mild and moderate/severe LUTS groups. In univariate analysis, age, cigarette smoking, alcohol consumption, physical activity, and PV significantly correlated with the severity of LUTS, but the presence or any components of MS did not. Results of multivariate analysis showed that aging, cigarette smoking, lack of regular exercise, and larger PV were independent predictors for moderate/severe LUTS. Notably, the risk factors for LUTS was influenced by the presence of MS. PV may play a role in determining the severity of LUTS for men without MS, while physical activity was the critical factor for men with MS. It was suggested that healthy lifestyle would be beneficial to lessen the severity of LUTS in the elderly males. PMID- 22452271 TI - Effect of sample storage time on detection of hybridization signals in Checkerboard DNA-DNA hybridization. AB - Long-term sample storage can affect the intensity of the hybridization signals provided by molecular diagnostic methods that use chemiluminescent detection. The aim of this study was to evaluate the effect of different storage times on the hybridization signals of 13 bacterial species detected by the Checkerboard DNA DNA hybridization method using whole-genomic DNA probes. Ninety-six subgingival biofilm samples were collected from 36 healthy subjects, and the intensity of hybridization signals was evaluated at 4 different time periods: (1) immediately after collecting (n = 24) and (2) after storage at -20 degrees C for 6 months (n = 24), (3) for 12 months (n = 24), and (4) for 24 months (n = 24). The intensity of hybridization signals obtained from groups 1 and 2 were significantly higher than in the other groups (p < 0.001). No differences were found between groups 1 and 2 (p > 0.05). The Checkerboard DNA-DNA hybridization method was suitable to detect hybridization signals from all groups evaluated, and the intensity of signals decreased significantly after long periods of sample storage. PMID- 22452272 TI - A comparison between child psychiatric outpatients with AD/HD and anxiety/depression. AB - BACKGROUND: Studies have shown that children with attention-deficit/hyperactivity disorder (AD/HD) have a lower quality of life (QoL), and lower school and psychosocial functioning than healthy children. AIMS: This is the first study to compare these domains and child competence between children with AD/HD- and anxiety/depression-related problems and healthy children using data from multiple informants. METHOD: Children were matched by age and sex, resulting in two clinical groups consisting of 62 children with AD/HD-related problems, 49 children with anxiety/depression-related problems and a reference group of 65 healthy schoolchildren. The Inventory of Life Quality for Children and Adolescents (parent and child report), the Child Behaviour Checklist (parent report), the Teacher's Report Form and the Children's Global Assessment Scale (therapist evaluation) were used. Differences between group means were analysed by t-tests and analysis of variance. RESULTS: The AD/HD group reported a significantly higher QoL than did the Anxiety/Depression group. However, no significant differences in QoL were found between the two clinical groups by parent proxy report. The AD/HD group reported a significantly higher QoL than shown by parent proxy evaluation. According to parent and teacher reports, both clinical groups showed significantly lower school functioning than the group of healthy children. Further, the AD/HD group showed significantly lower school functioning and total competence than the Anxiety/Depression group. CONCLUSION: To obtain a full clinical picture of subgroups of patients with AD/HD- and anxiety/depression-related problems referred to child mental health outpatient treatment, clinicians should always use multiple informants to evaluate symptoms/problems, functioning and QoL. PMID- 22452273 TI - Impact of transfusion of autologous 7- versus 42-day-old AS-3 red blood cells on tissue oxygenation and the microcirculation in healthy volunteers. AB - BACKGROUND: Stored red blood cells (RBCs) accumulate biochemical and biophysical changes. Maximum storage duration is based on acceptable in vitro characteristics and 24-hour survival, but not RBC function. Relatively little is known about the impact of RBC storage duration on oxygenation and the microcirculation. STUDY DESIGN AND METHODS: Eight healthy subjects donated a double RBC apheresis, which were prestorage leukoreduced and processed in AS-3. Subjects were transfused 1 unit of RBCs at 7 and 42 days after blood collection. Measurements of percentage of tissue oxygenation in the thenar eminence muscle (StO2) and brain (SctO2) were recorded with Food and Drug Administration-cleared noninvasive devices. Sublingual microvascular blood flow (microcirculatory flow index [MFI]) was quantified before and after RBC transfusion using a video microscope. Raw electronic data for all measurements were analyzed by a blinded observer at a core laboratory. RESULTS: The only pre- versus posttransfusion change observed in measurements of SctO2, StO2, or MFI was a very small increase in SctO2, from 70.4 to 71.8 (means, p=0.032) at 7 days. There was no significant difference in the amount of pre-post change at 7 days versus 42 days for any of the measures. CONCLUSION: Transfusion of 1 unit of 42-day-stored RBCs to healthy subjects has no overt detrimental effect on tissue oxygenation or the microcirculation assessed by clinically available monitors. PMID- 22452274 TI - The El-Tal El-Kebir story: an example of social accountability from Egypt. AB - BACKGROUND: In 1985, the Faculty of Medicine at Suez Canal University responded to a request from the people of El-Tal El-Kebir, a district in Ismailia Governorate, Egypt, to assist them in addressing their poor health statistics. After an initial visit, the team realized that any long-term solution in dealing with and improving their community health problems needed a true inter-sectoral collaborative approach, with the involvement of other sectors such as agriculture, veterinary medicine, and education. The team also realized that establishing a true partnership with the community as well as the local governmental agencies was indispensible in order to maintain any long-term effects. AIMS: In this article, we will describe how the medical school mobilized other sectors to improve the community health. METHODS: The methodology adopted during this example of providing community outreach services was concordant with the principles of social accountability, which was later described by the World Health Organization. RESULTS: Our multi-sectoral team has established several projects for enhancing community participation in solving their own health problems. CONCLUSION: Medical schools can lead a community development project in collaboration with the community. PMID- 22452275 TI - Patient-centredness from education to practice: the 'lived' impact of communication skills training. AB - BACKGROUND: Although communication skills training (CST) enhances patient-centred skills and attitudes, the literature indicates a problematic transfer of these from education into practice. AIM: We explored 'lived' experiences of medical students and doctors to gain a better understanding of the impact of CST on patient-centredness in the transition to real practice. METHODS: From a phenomenological perspective, we conducted 15 interviews and 11 focus groups with 4-9 participants/group (n = 67) at two universities and carried out constant comparative analysis. RESULTS: The gap between education and practice is the central phenomenon. Although CST raises students' communication awareness and self-efficacy in an 'ideal' context, this paradoxically seems to jeopardize their ability to bridge the gulf. In addition, CST does not come to grips with students' attitudes. However, CST appears to be successful in equipping students with long-lasting 'handles'. Yet students need more support to mould the provided 'ideal' models into their own unique style of context-specific patient-centred behaviour. This implies: raising students' awareness of own attitudes and communication styles, offering a more realistic training ground, integrating CST with clinical experience and translating the primary-care-rooted concept of patient-centredness into various specialization contexts. CONCLUSION: CST could raise its impact by supporting students' recycling processes towards a personal style of context-sensitive patient-centredness. PMID- 22452276 TI - Social mapping: a potential teaching tool in public health. AB - BACKGROUND: Mapping is a fundamental way of displaying spatial human cognition. It is a rapid technique of summarising and presenting large amount of information. Social map is a technique that finds use as a participatory rural appraisal tool. AIM: To evaluate the feasibility of using social mapping as a public health teaching tool. METHODS: A resident doctor posted in the Urban Health Training Centre was assigned to do social mapping of an urban resettlement colony. The area was first divided into segments. The mapping was done by people residing in each segment and compiled with the assistance of the resident doctor. RESULTS: Social mapping helped the student acquire various cognitive, affective and psychomotor skills. It also helped in understanding the geographical area, people, language, cultural practices, social networks and interactions. It trained the student in using rapid appraisal techniques, cartography, effective and succinct summarising and presentation of data of social relevance. The different language and cultural background of the community was the main challenge encountered. CONCLUSION: Social mapping is an excellent learning and a very practical teaching tool in public health, especially when the researcher/health care provider has little knowledge about his/her field practice area. PMID- 22452277 TI - Twelve tips for constructing problem-based learning cases. AB - BACKGROUND: One of the key elements for introducing a problem-based learning (PBL) programme is constructing good PBL cases. Good cases should reflect the educational principles of PBL including (a) integration of basic and clinical sciences together with professionalism and psychosocial components, (b) encouragement of discussion of cognitive domains such as identification of problems, generation of hypotheses, construction of an enquiry plan, weighing evidence for and against each hypothesis, interpretation of findings, construction of mechanisms, using evidence to refine the hypothesis and construction of a management plan, (c) encouragement of discussion of cases in small groups with an emphasis on student-centred learning, (d) promotion of collaborative learning and contribution of students to the case discussion and (e) encouragement of teamwork and self-directed learning strategies. AIMS AND METHODS: Despite the importance of construction of good PBL cases to the success of a PBL programme, the art of construction of these cases is understudied or described in the literature. Based on our experience in PBL and evidence from literature, we described 12 tips for constructing good PBL cases. RESULTS AND CONCLUSIONS: Constructing good PBL cases is an art that necessitates teamwork and input from several different disciplines. Cases should be constructed using a template reflecting the educational objectives of the programme. This approach will ensure optimum learning outcomes and consistency in the design and delivery of cases. PMID- 22452278 TI - Aspects of clinical skills test demanded by the public for the national medical licensure examination in Japan. PMID- 22452279 TI - Medical school places: distribution and availability of places in the UK. PMID- 22452280 TI - Evaluation drives curriculum. PMID- 22452281 TI - How we equip undergraduates with prioritisation skills using simulated teaching scenarios. AB - BACKGROUND: Goldacre et al. [Goldacre MJ, Lambert T, Evans J, Turner G. 2003. PRHO views' on whether their experience at medical school prepared them well for their jobs: National questionnaire survey. BMJ 326 (1):1011-1012.] undertook a study which showed that 40% of undergraduates felt under prepared for work by their undergraduate curriculum. Illing et al. [Illing J et al. 2008. A GMC report: Submitted to GMC.] demonstrated that one of four key areas, for which they felt least prepared, was prioritisation of tasks in the clinical setting. AIM: To equip undergraduates about to become Foundation year 1 with the prioritisation skills along with others highlighted by Illing in a very real yet safe environment. METHODS: We devised a simulated teaching session 'an evening on call'. Each individual student had a 45 min session, held on mock wards where they were given a handover task list, and like a de facto on call would be paged by the wards at varying intervals. Tasks ranged from prescribing night sedation, interpretation of ECG and blood results to dealing with acute gastrointestinal bleeds. At the end of the session each student was given feedback on their prioritisation and patient management by an experienced medic. RESULTS: Feedback from students rate this as one of the best ways to learn as they have responsibility for patients in a very safe yet real environment. They felt better prepared for the job they were about to do. CONCLUSION: Simulated teaching is a relatively easy yet effective way to teach prioritisation and other skills. We hope that our method is self-explanatory and could be adapted for other teaching groups or material. PMID- 22452282 TI - Effectiveness of a programme design for the development of competence in solving clinical problems. AB - BACKGROUND: To apply what has been learned theoretically in a clinical context is for many students a major challenge. In order to ease their transition into practice, a training programme was developed, focusing on learning to solve clinical problems. AIMS: The programme is designed for veterinary medicine students in the preclinical phase with already a sound theoretical base in biomedical and clinical sciences. The design is based on the engagement in learning and work processes derived from clinical practice and exposure to a large variety of real and paper-based cases. This article addresses the effectiveness of this programme design. METHOD: Programme effectiveness was defined in terms of the progress made by the students. This progress was established using methodological triangulation of the results from student questionnaires, performance observations and (pre and post) assessment. RESULTS: On all dimensions of effectiveness, the results consistently showed that the programme was perceived as effective and led to improved performances in solving clinical problems and better solutions in the assessment. The students' progress was substantial. CONCLUSIONS: At preclinical level, a course design based on the work processes in clinical practice and a mixture of real and paper-based patients is effective in enhancing problem-solving competence. PMID- 22452283 TI - Twelve tips for designing and implementing a structured rater training in OSCEs. AB - BACKGROUND: Observation, rating, and grading are parts of the routine of the faculty when in contact with medical students. Most interestingly, there is a dearth of proper instructions on rater training for objective structured clinical examinations (OSCEs) in medical education literature. AIMS: We assembled 12 tips for implementing a structured rater training program. To highlight these tips, we provided examples of our implementation of rater training for an OSCE in 2009. METHODS: We developed a tailored rater training program by compiling information from medical education and other related research disciplines. RESULTS: The structured rater training at hand proved feasible, and the acceptance rate of this training by examiners was high. PMID- 22452284 TI - Teaching social scientific methods to medical undergraduates: a challenge worth facing. PMID- 22452285 TI - Delivering free healthcare to rural Central Appalachia population: the case of the Health Wagon. AB - Central Appalachia residents present unique healthcare challenges. This vulnerable population faces poor health status and low access to health care. 'The Health Wagon' was established to innovatively enhance access to health care for the poor and marginalized rural population of Central Appalachia. This article describes the operations of the Health Wagon, a full mobile medical clinic, in delivering free health care to those in rural Southwest Virginia in Central Appalachia. The Health Wagon provides a wide range of comprehensive healthcare services, such as acute and chronic disease management, laboratory and diagnostic services, medication assistance, dental and eye care and specialty clinics for marginalized, poor and disenfranchised patients living in the mountains of that region. In 2009, a total of 157 clinics were provided and 2900 patients were seen (3165 patient encounters) in addition to 268 telemedicine specialty consultations at no cost to the patients. The work of the Health Wagon has broken down a financial barrier to healthcare access and offers unique and profound opportunities to improve health and expand health care in rural Central Appalachia. PMID- 22452286 TI - pH-dependent inhibition of native GABA(A) receptors by HEPES. AB - BACKGROUND AND PURPOSE: Artificial buffers such as HEPES are extensively used to control extracellular pH (pH(e) ) to investigate the effect of H(+) ions on GABA(A) receptor function. EXPERIMENTAL APPROACH: In neurones cultured from spinal cord dorsal horn (DH), dorsal root ganglia (DRG) and cerebellar granule cells (GC) of neonatal rats, we studied the effect of pH(e) on currents induced by GABA(A) receptor agonists, controlling pH(e) with HCO(3) (-) or different concentrations of HEPES. KEY RESULTS: Changing HEPES concentration from 1 to 20 mM at constant pH(e) strongly inhibited the currents induced by submaximal GABA applications, but not those induced by glycine or glutamate, on DH, DRG or GC neurones, increasing twofold the EC(50) for GABA in DH neurones and GC. Submaximal GABA(A) receptor-mediated currents were also inhibited by piperazine N,N'-bis(2-ethanesulfonic acid) (PIPES), 3-(N-morpholino)propanesulfonic acid, tris(hydroxymethyl)aminomethane or imidazole. PIPES and HEPES, both piperazine derivatives, similarly inhibited GABA(A) receptors, whereas the other buffers had weaker effects and 2-(N-morpholino)ethanesulfonic acid had no effect. HEPES induced inhibition of submaximal GABA(A) receptor-mediated currents was unaffected by diethylpyrocarbonate, a histidine-modifying reagent. HEPES-induced inhibition of GABA(A) receptors was independent of membrane potential, HCO(3) (-) and intracellular Cl(-) concentration and was not modified by flumazenil, which blocks the benzodiazepine binding site. However, it strongly depended on pH(e) . CONCLUSIONS AND IMPLICATIONS: Inhibition of GABA(A) receptors by HEPES depended on pH(e) , leading to an apparent H(+) -induced inhibition of DH GABA(A) receptors, unrelated to the pH sensitivity of these receptors in both low and physiological buffering conditions, suggesting that protonated HEPES caused this inhibition. PMID- 22452287 TI - Quantum rod-sensitized solar cell: nanocrystal shape effect on the photovoltaic properties. AB - The effect of the shape of nanocrystal sensitizers in photoelectrochemical cells is reported. CdSe quantum rods of different dimensions were effectively deposited rapidly by electrophoresis onto mesoporous TiO(2) electrodes and compared with quantum dots. Photovoltaic efficiency values of up to 2.7% were measured for the QRSSC, notably high values for TiO(2) solar cells with ex situ synthesized nanoparticle sensitizers. The quantum rod-based solar cells exhibit a red shift of the electron injection onset and charge recombination is significantly suppressed compared to dot sensitizers. The improved photoelectrochemical characteristics of the quantum rods over the dots as sensitizers is assigned to the elongated shape, allowing the build-up of a dipole moment along the rod that leads to a downward shift of the TiO(2) energy bands relative to the quantum rods, leading to improved charge injection. PMID- 22452288 TI - A randomized study of defibrillator lead implantations in the right ventricular mid-septum versus the apex: the SEPTAL study. AB - INTRODUCTION: The study was designed to evaluate the feasibility and performance of right ventricular (RV) mid-septal versus apical implantable defibrillator (ICD) lead placement. METHODS AND RESULTS: SEPTAL is a randomized, noninferiority trial, which randomly assigned patients to implantation of ICD leads in the RV mid-septum versus apex, with a primary objective of comparing the implant success rate of implant at each site, based on strict electrical predefined criteria. We also compared the (1) pacing lead characteristics, (2) rates of appropriate and inappropriate ICD therapies, and (3) all-cause mortality between the 2 sites at 1 year. The trial enrolled 215 patients (mean age = 59.7 +/- 12.4 years, mean LVEF = 34.0 +/- 14.2%, 84.2% men), of whom 148 (68.8%) presented with ischemic heart disease. The ICD indication was primary prevention in 117 patients (54.4%). The lead was successfully implanted in 96/107 patients (89.7%) assigned to the RV mid septum, and in 99/108 (91.7%) assigned to the apex (ns). The 1-year rate of lead related adverse events was similar in both groups. A total of 8 first inappropriate ICD therapies (7.9%) were delivered in the RV mid-septal group, versus 8 (7.8%) in the apical group (ns), while first appropriate therapies were delivered to 22 (21.4%) and 24 patients (23.8%), respectively (ns). All-cause mortality was 7.9% in the RV mid-septal versus 2.9% in the RV apical group (ns). CONCLUSION: This study confirmed the technical feasibility and noninferior performance of ICD leads implanted in the RV mid-septum versus the apex. PMID- 22452289 TI - Symptomatic intradialytic hypotension and mortality: an opinionated review. AB - The unchanging rate of symptomatic hypotension that attends maintenance hemodialysis and its link to sodium/volume overload are explored. Correlations between interdialytic weight gain, ultrafiltration rate, hypertension, and mortality are found to be strong. Suggestions/opinions for correcting this unfortunate clinical reality are offered. PMID- 22452290 TI - Xenobiotic-induced liver injury and fibrosis. AB - INTRODUCTION: Many different drugs and xenobiotics (chemical compounds foreign to an organism) can injure the bile duct epithelium and cause inflammatory bile duct diseases (cholangiopathies) ranging from transient cholestasis to vanishing bile duct syndrome, sclerosing cholangitis with development of biliary fibrosis and cirrhosis. Animal models of xenobiotic-induced liver injury have provided major mechanistic insights into the molecular mechanisms of xenobiotic-induced cholangiopathies and biliary fibrosis including primary biliary cirrhosis and primary sclerosing cholangitis. AREAS COVERED: In this review, the authors discuss the basic principles of xenobiotic-induced liver and bile duct injury and biliary fibrosis with emphasis on animal models. A PubMed search was performed using the search terms "xenobiotic," "liver injury," "cholestasis," and "biliary fibrosis." Reference lists of retrieved articles were also searched for relevant literature. EXPERT OPINION: Xenobiotic-induced cholangiopathies are underestimated and frequently overlooked medical conditions due to their often transient nature. However, biliary disease may progress to vanishing bile duct syndrome, biliary fibrosis, and cirrhosis. Moreover, xenobiotics may prime the liver for subsequent liver disease by other agents and may also contribute to the development of hepatobiliary cancer though interaction with resident stem cells. PMID- 22452291 TI - Validity of intraoperative gross examination of myometrial invasion in patients with endometrial cancer: a meta-analysis. AB - OBJECTIVE: The current recommended endometrial cancer surgical treatment is abdominal extrafascial total hysterectomy with bilateral salpingo-oophorectomy followed by pelvic lymphadenectomy if >50% myometrial invasion is estimated by intraoperative gross examination (IGE). This meta-analysis aims to quantify evidence regarding the validity/predictive value of IGE staging compared with final histology. DESIGN: Meta-analysis of studies published until October 2011. SETTING: Systematic search, according to PRISMA guidelines, of the six major medical literature databases - Medline, Scopus, EMBASE, Google Scholar, Ovid, Cochrane. POPULATION: Sixteen eligible studies including 2567 endometrial cancer patients. METHODS: Pooled sensitivity/specificity, accuracy, negative/positive predictive value (NPV/PPV) and diagnostic odds ratio (DOR) of IGE were calculated and the summary receiver operator characteristic (sROC) curve was constructed. A meta-regression analysis was used to explore the role of potential modifiers of sensitivity and specificity. MAIN OUTCOME MEASURES: Pooled diagnostic measures of IGE indices. Results. Sixteen studies (15 retrospective, one prospective) meeting the inclusion criteria were qualitatively analyzed. Pooled IGE estimates were: sensitivity = 0.75 (95%CI: 0.72-0.78), specificity = 0.92 (95%CI 0.90-0.94), accuracy = 0.87 (95%CI 0.86-0.88), NPV = 0.89 (95%CI 0.87-0.92), PPV = 0.80 (95%CI 0.76-0.84) and DOR = 36.9 (95%CI 28.7-47.4). No significant modifiers were identified for sensitivity or specificity. CONCLUSIONS: The synthesized measures presented here for the first time showed that accuracy, sensitivity and specificity of IGE were 87, 75 and 92%, respectively, which indicates that IGE is useful for estimating depth of myometrial invasion and staging of endometrial cancer in clinical practice. The degree to which the relatively low values of some of its performance indicators could be improved remains to be elucidated in order for the values to be comparable with those from frozen section biopsies. PMID- 22452292 TI - The extent and nature of alcohol advertising on Australian television. AB - INTRODUCTION AND AIMS: Current alcohol guidelines in Australia recommend minimising alcohol consumption, especially among minors. This study investigated (i) the extent to which children and the general population are exposed to television advertisements that endorse alcohol consumption and (ii) the themes used in these advertisements. DESIGN AND METHODS: A content analysis was conducted on alcohol advertisements aired over two months in major Australian cities. The advertisements were coded according to the products that were promoted, the themes that were employed, and the time of exposure. Advertising placement expenditure was also captured. RESULTS: In total, 2810 alcohol advertisements were aired, representing one in 10 beverage advertisements. Advertisement placement expenditure for alcohol products in the five cities over the two months was $15.8 million. Around half of all alcohol advertisements appeared during children's popular viewing times. The most common themes used were humour, friendship/mateship and value for money. DISCUSSION AND CONCLUSIONS: Children and adults are regularly exposed to advertisements that depict alcohol consumption as fun, social and inexpensive. Such messages may reinforce existing alcohol-related cultural norms that prevent many Australians from meeting current intake guidelines. PMID- 22452294 TI - Atmospheric fate of methacrolein. 2. Formation of lactone and implications for organic aerosol production. AB - We investigate the oxidation of methacryloylperoxy nitrate (MPAN) and methacrylicperoxy acid (MPAA) by the hydroxyl radical (OH) theoretically, using both density functional theory [B3LYP] and explicitly correlated coupled cluster theory [CCSD(T)-F12]. These two compounds are produced following the abstraction of a hydrogen atom from methacrolein (MACR) by the OH radical. We use a RRKM master equation analysis to estimate that the oxidation of MPAN leads to formation of hydroxymethyl-methyl-alpha-lactone (HMML) in high yield. HMML production follows a low potential energy path from both MPAN and MPAA following addition of OH (via elimination of the NO(3) and OH from MPAN and MPAA, respectively). We suggest that the subsequent heterogeneous phase chemistry of HMML may be the route to formation of 2-methylglyceric acid, a common component of organic aerosol produced in the oxidation of methacrolein. Oxidation of acrolein, a photo-oxidation product from 1,3-butadiene, is found to follow a similar route generating hydroxymethyl-alpha-lactone (HML). PMID- 22452296 TI - Recent advances in the synthesis and application of layered double hydroxide (LDH) nanosheets. PMID- 22452295 TI - Clinical epidemiology, management and outcome of acute coronary syndromes in the Italian network on acute coronary syndromes (IN-ACS Outcome study). AB - BACKGROUND: The Italian network on acute coronary syndromes outcome (IN-ACS Outcome) study is a nationwide observational, multicenter study with the aim to describe clinical epidemiology, management, 30-days and one-year outcomes of ACS in Italy. METHODS: All consecutive patients admitted for ACS to 38 hospitals, between December 2005 and February 2007, were enrolled in the study. Patient in hospital details and follow-up data at 30-days and one-year were collected using a web-based CRF and stored in a central database. RESULTS: A total of 6045 patients (age 68 +/- 13 years) were enrolled: 2313 patients (38.3%) had ST elevation myocardial infarction (STEMI) and 3732 (61.7%) patients had NSTE-ACS. Primary PCI was performed in 1085 (46.9%) STEMI patients, thrombolysis in 590 (25.5%) patients, whereas 638 (27.6%) patients were not reperfused. Among patients with NSTE-ACS, coronary angiography was performed in 2797 (75%) patients, PCI in 1797 (48.2%) patients and CABG in 213 (5.7%) patients. Thirty days and one-year mortality rates were 5.8% and 9.8%, in STEMI patients and 3.1% and 8.6%, in NSTE-ACS patients. CONCLUSIONS: The IN-ACS Outcome study showed that the management of ACS is still suboptimal. Although 30-days mortality is low, the one-year mortality is still substantial. PMID- 22452297 TI - High stability of thermoresponsive polymer-brush-grafted silica beads as chromatography matrices. AB - Thermo-responsive chromatography matrices with three types of graft architecture were prepared, and their separation performance and stability for continuous use were investigated. Poly(N-isopropylacrylamide)(PIPAAm) hydrogel-modified silica beads were prepared by a radical polymerization through modified 4,4'-azobis(4 cyanovaleric acid) and N,N'-methylenebisacrylamide. Dense PIPAAm brush-grafted silica beads and dense poly(N-tert-Butylacrylamide (tBAAm)-b-IPAAm) brush-grafted silica beads were prepared through a surface-initiated atom transfer radical polymerization (ATRP) using CuCl/CuCl(2)/ Tris(2-(N,N-dimethylamino)ethyl)amine (Me(6)TREN) as an ATRP catalytic system and 2-propanol as a reaction solvent. Dense PIPAAm brush-grafted silica beads exhibited the highest separation performance because of their strong hydrophobic interaction between the densely grafted well-defined PIPAAm brush on silica-bead surfaces and analytes. Using an alkaline mobile phase, dense themoresponsive polymer brushes, especially having a hydrophobic basal layer, exhibited a high stability for continuous use, because polymer brush on the silica bead surfaces prevented the access of water to silica surface, leading to the hydrolysis of silica and cleavage of grafted polymers. Thus, the precisely modulating graft configuration of thermoresponsive polymers provided chromatography matrices with a high separation efficiency and stability for continuous use, resulting in elongating the longevity of chromatographic column. PMID- 22452298 TI - Theoretical perspectives of male sexual abuse: conceptualization of a case study. AB - The purpose of this article is to demonstrate the traumatic impact that sexual abuse can have on a young male's development by addressing mediating dispositions that can render a child vulnerable to the effects of sexual abuse. Consideration is given to three different theoretical perspectives that are not exclusive to male victims but shed light on the impact that sexual abuse can have on the development of a young boy. These perspectives include early family relationships and attachment theory, developmental psychopathology, and trauma theory. These theoretical lenses provide a conceptual understanding into why some victims are vulnerable to the effects of sexual abuse. Each theoretical view is applied to a case study of an adolescent male with a history of early trauma and sexual abuse. Clinical implications are discussed. PMID- 22452299 TI - Shame and guilt in men exposed to childhood sexual abuse: a qualitative investigation. AB - This study examined the experiences of shame and guilt in adult males sexually abused as children. Seven participants attending a service for male sexual abuse completed measures of shame, guilt, dissociation, and childhood trauma history and subsequently participated in a focus group. All participants experienced childhood sexual abuse in the "severe" range and showed elevated scores for shame, guilt, and dissociation. Four superordinate themes with associated subordinate themes emerged: (a) self-as-shame (foundations of self-as-shame, fear of exposure, temporary antidote: connection), (b) pervasiveness and power of doubt and denial (from others, from self, consequences of incredulity), (c) uncontrollability (of problems after disclosure, of rage, of intrusions and emotional pain), and (d) dissociation. Results are discussed with reference to the existing literature and the emerging "self-as-shame" construct, which appeared to encapsulate participants' view of themselves. PMID- 22452300 TI - Father-daughter incest: data from an anonymous computerized survey. AB - Retrospective data were entered anonymously by 1,521 adult women using computer assisted self-interview. Nineteen were classified as victims of father-daughter incest, and 241 were classified as victims of sexual abuse by an adult other than their father before reaching 18 years of age. The remaining 1,261 served as controls. Incest victims were more likely than controls to endorse feeling damaged, psychologically injured, estranged from one or both parents, and shamed by others when they tried to open up about their experience. They had been eroticized early on by the incest experience, and it interfered with their adult sexuality. Incest victims experienced coitus earlier than controls and after reaching age 18 had more sex partners and were more likely to have casual sex outside their primary relationship and engage in sex for money than controls. They also had worse scores on scales measuring depression, sexual satisfaction, and communication about sex than controls. PMID- 22452304 TI - What Poole and Wolfe (2009) actually said: a comment on Everson and Faller (2012). AB - Everson and Faller's (2012) article on the significance of sexualized behavior in child sexual abuse assessments critiques a chapter by Poole and Wolfe (2009), but their objections assumed conclusions and practice implications that were not contained in that chapter. In this comment, I reiterate the value of educating adults about normative sexual and nonsexual behavior that could be misconstrued as symptoms of sexual abuse in some children, review key points from the chapter, and point out that Everson and Faller's critique supports the chapter's take-home messages (i.e., the importance of gathering information from multiple sources and the need to test alternative hypotheses for concerning behavior, consider the overall context of individual cases, and obtain independent verification of evidence). PMID- 22452305 TI - Comment on Cross, Fine, Jones, and Walsh (2012): Good therapeutic services- therapeutic advocacy and forensic neutrality. AB - Cross, Fine, Jones, and Walsh (2012 ) provided a thoughtful review and critique of a book chapter describing the interview process at Child Advocacy Centers. They observed some of the ways that concerns raised in that chapter are being addressed and described revised guidelines that further clarify issues. Ongoing research and examination of the important processes carried on by child advocacy centers and the role fulfilled by mental health professionals in the investigation of child sexual abuse contributes positively to service delivery. PMID- 22452306 TI - Comment on Cross, Fine, Jones, and Walsh (2012): Do mental health professionals who serve on/with child advocacy centers experience role conflict? AB - Cross, Fine, Jones, and Walsh's (2012 ) article "Mental health professionals in children's advocacy centers: is there role conflict?" challenges two recent publications' criticisms that child advocacy centers create role conflict for mental health professionals and explains how child advocacy centers actually work, describing the different roles for mental health professionals who participate in them. This commentary points out that more precise data would have helped to specifically address the critics' concerns. Furthermore, professional ethics and licensure issues may have served as an additional but unacknowledged check on the "spillover effect" that the critics have alleged comes with being associated with prosecution. This commentary also highlights three main strengths of the Cross and colleagues' article. PMID- 22452307 TI - Comment on Cross, Fine, Jones, and Walsh (2012): we are now on the same page. AB - Role conflict has been an issue in the intervention of child abuse cases since the beginning of the alliance drawn between the legal and mental health professions. In child abuse cases, clearly defined roles will prevent an attack on the process, thereby providing successful interventions to protect children. The child advocacy center concept is one of the best ways to meld the two professional functions into a cohesive approach to those interventions. PMID- 22452310 TI - Quantum statistics of surface plasmon polaritons in metallic stripe waveguides. AB - Heralded single surface plasmon polaritons are excited using photons generated via spontaneous parametric down conversion. The mean excitation rates, intensity correlations, and Fock state populations are studied. The observed dependence of the second-order coherence in our experiment is consistent with a linear uncorrelated Markovian environment in the quantum regime. Our results provide important information about the effect of loss for assessing the potential of plasmonic waveguides for future nanophotonic circuitry in the quantum regime. PMID- 22452311 TI - Trends in hypertension prevalence (1990-2005) and mean blood pressure (1975-2005) in Portugal: a systematic review. AB - AIMS: We aimed to describe the temporal trends of the mean blood pressure and prevalence of hypertension in studies that evaluated Portuguese adults. METHODS: Pubmed was searched and 42 eligible studies were identified. Reference screening and data extraction were conducted independently by two researchers. We fitted linear regression models to compute ecological estimates of hypertension prevalence and mean blood pressure, adjusting for sex, age and significant interaction terms. RESULTS: Between 1990 and 2005, the prevalence of hypertension defined as blood pressure >= 140/90 mmHg and/or drug treatment remained approximately constant in young adults and decreased in middle-aged and older adults, whereas the prevalence of self-reported hypertension increased 0.4% per year (95% confidence interval 0.1-0.7) overall. Between 1975 and 2005, mean systolic and diastolic blood pressures decreased in middle-aged and older adults, reaching a 32-mmHg decrease in systolic blood pressure among women at average age 70. CONCLUSION: The trends in the last decades show a decrease in blood pressure levels, probably attributable to increasing awareness and a higher treatment proportion. Although this absolute trend in blood pressure parallels the observed in other high income European countries, Portugal maintains its position above the mean levels in other Western settings. PMID- 22452312 TI - Endophytic fungi associated with leaves of Betulaceae in Japan. AB - Diversity and species composition of endophytic fungi on leaves of 11 tree species in Betulaceae were studied, with reference to climatic, tree species, and seasonal variations. A total of 186 fungal isolates were obtained from 190 leaves collected in a subalpine forest, a cool temperate forest, and a subtropical forest in Japan, and were divided into 46 operational taxonomic units (OTUs) according to the base sequences of D1-D2 region of large subunit rDNA. The 2 most frequent OTUs were Muscodor sp. and Nemania sp. in Xylariaceae, followed by Gnomonia sp., Glomerella acutata , Apiosporopsis sp., Asteroma sp., and Cladosporium cladosporioides . The similarities of OTU composition in endophytic fungal assemblages on leaves of Betulaceae were generally low among the forests of different climatic regions. Fungal OTU compositions were relatively similar between 2 Betula species in the subalpine forest, whereas 7 tree species in the cool temperate forest were divided into 3 groups according to the similarity of endophytic fungal assemblages on the leaves, with 4 Carpinus species assigned into 2 of the 3 groups. The similarity of endophytic fungal assemblages between August and October was relatively high in the subalpine forest, whereas the seasonal changes were generally greater (i.e., the similarities among sampling dates were lower) in the cool temperate forest. PMID- 22452313 TI - A rest period does not affect in vitro storage properties in apheresis platelets collected from the buffy coat layer. AB - BACKGROUND: A previous study demonstrated that several in vitro storage properties of apheresis platelets (PLTs) that are isolated by sedimentation against the collection container and subsequently resuspended can benefit from a rest period before continuous agitation. This study examines whether the in vitro storage properties of apheresis PLTs isolated by collection from the buffy coat layer benefit from a rest period before agitation. STUDY DESIGN AND METHODS: Freshly collected apheresis PLTs (Trima, GambroBCT) were divided into five 60-mL aliquots. One aliquot was immediately placed on a flat-bed agitator; the other aliquots were held on a laboratory bench for 1, 2, 4, and 6 hours before continuous agitation. Samples were obtained on Days 1, 5, and 7 for standard in vitro PLT assays. The experiment was repeated 12 times. RESULTS: For each sampling day, no significant differences were observed in aliquots held with or without a rest period for any of the following PLT properties: PLT content, mean PLT volume, pH, pCO2, bicarbonate, glucose, lactate, hypotonic shock response, extent of shape change, aggregation, morphology, CD62P, CD63, and CD42b. Although regression analysis identified several in vitro properties whose mean levels appeared to improve with increasing length of the rest period, maximum differences in mean levels were small (<6%). CONCLUSION: The in vitro storage properties of Trima apheresis PLTs isolated from the buffy coat layer do not benefit from a rest period. PMID- 22452314 TI - Newborn feeding behaviour depressed by intrapartum oxytocin: a pilot study. AB - AIM: To investigate the effect intrapartum oxytocin administration can have on Primitive Neonatal Reflexes. The secondary objective was to observe the influence of intrapartum oxytocin may have on breastfeeding. METHODS: Twenty healthy primiparae with a single gestation at term were included. To assess Primitive Neonatal Reflexes, video film was taken during an experimental situation designed to elicit Primitive Neonatal Reflexes. Three independent observers blinded to the oxytocin dose that had been administered coded the Primitive Neonatal Reflexes. Data regarding breastfeeding were collected by telephone at 3 months. RESULTS: Medium oxytocin dose was 1931.9 +/- 1754.4 mUI. A Kappa index >0.75 was obtained for four Primitive Neonatal Reflexes: swallow, jaw jerk, suck and gazing. A negative association was found between oxytocin dose and sucking (p = 0.03). At 3 months of life, women exclusively breastfeeding (63.1%) had received a significantly lower average dose of oxytocin than those not exclusively breastfeeding (36.8%) (p = 0.04). CONCLUSION: In this pilot study, intrapartum exogenous oxytocin seems to disturb sucking and breastfeeding duration. Further studies are required to confirm these results and to ascertain whether there could be other effects of intrapartum oxytocin on newborn behaviour. PMID- 22452315 TI - Bacillus anthracis protease InhA regulates BslA-mediated adhesion in human endothelial cells. AB - To achieve widespread dissemination in the host, Bacillus anthracis cells regulate their attachment to host endothelium during infection. Previous studies identified BslA (Bacillus anthracis S-layer Protein A), a virulence factor of B. anthracis, as necessary and sufficient for adhesion of vegetative cells to human endothelial cells. While some factors have been identified, bacteria-specific contributions to BslA mediated adhesion remain unclear. Using the attenuated vaccine Sterne 7702 strain of B. anthracis, we tested the hypothesis that InhA (immune inhibitor A), a B. anthracis protease, regulates BslA levels affecting the bacteria's ability to bind to endothelium. To test this, a combination of inhA mutant and complementation analysis in adhesion and invasion assays, Western blot and InhA inhibitor assays were employed. Results show InhA downregulates BslA activity reducing B. anthracis adhesion and invasion in human brain endothelial cells. BslA protein levels in DeltainhA bacteria were significantly higher than wild-type and complemented strains showing InhA levels and BslA expression are inversely related. BslA was sensitive to purified InhA degradation in a concentration- and time-dependent manner. Taken together these data support the role of InhA regulation of BslA-mediated vegetative cell adhesion and invasion. PMID- 22452316 TI - No free lunch and benchmarks. AB - We extend previous results concerning black box search algorithms, presenting new theoretical tools related to no free lunch (NFL) where functions are restricted to some benchmark (that need not be permutation closed), algorithms are restricted to some collection (that need not be permutation closed) or limited to some number of steps, or the performance measure is given. Minimax distinctions are considered from a geometric perspective, and basic results on performance matching are also presented. PMID- 22452317 TI - Role of H(2)O(2) in hypertension, renin-angiotensin system activation and renal medullary disfunction caused by angiotensin II. AB - BACKGROUND AND PURPOSE: Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H(2) O(2) ) contribute to hypertension. We examined whether H(2) O(2) mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II). EXPERIMENTAL APPROACH: Ang II (200 ng.kg(-1) .min(-1) ) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U.kg(-1) .day(-1) ) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H(2) O(2) , angiotensin AT(1) receptor and Nox4 expression and nuclear factor-kappaB (NF-kappaB) activation were evaluated in the kidney. Plasma and urinary H(2) O(2) and angiotensinogen were also measured. KEY RESULTS: Ang II increased H(2) O(2) , AT(1) receptor and Nox4 expression and NF kappaB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H(2) O(2) levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT(1) receptors and Nox4 in Ang II-infused rats. Renal medullary NF-kappaB activation was correlated with local H(2) O(2) levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen. CONCLUSIONS AND IMPLICATIONS: The renal medulla is a major target for Ang II-induced redox dysfunction. H(2) O(2) appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H(2) O(2) levels may provide future grounds for the treatment of hypertension. PMID- 22452318 TI - Analysis of van der Waals surface area properties for human ether-a-go-go-related gene blocking activity: computational study on structurally diverse compounds. AB - In the present investigation, a computational analysis was performed on a data set comprised of human ether-a-go-go-related gene (hERG) blockers (triethanolamine, 1,3-thiazol-2-yl and tetrasubstituted imidazoline derivatives) in order to investigate the structural features required to reduce the hERG induced cardiotoxicity problems in an early stage of drug discovery. The results derived from the quantitative structure-activity relationship (QSAR) analysis showed that the volume, surface area and shape descriptors (vsurf_) contributed significantly in all the models. This reveals that the hydrogen-bonding and hydrophilicity properties (vsurf_HB1, vsurf_CW4 and a_acc) on the van der Waals (vdW) surface of the molecule is negatively contributed for the hERG blocking activity and the hydrophobic property (vsurf_D6) and the total polar volume (vsurf_Wp2) on the vdW surface of the molecule are favourable for the activity. Further, the pharmacophore analysis also shows that the Aro/Hyd/Acc contour is one of the important biophore sites for the hERG blocking activity. This suggests that the presence of aromatic, hydrophobic and hydrogen-bonding groups in the molecules is favourable for interaction. In comparison with our earlier works (explaining the role of topological and hydrophobicity properties for the hERG blocking activity), these studies provided additional information on the importance of vdW surface area properties for the hERG blocking activity. These results can be used with other molecular modelling studies for the design of novel molecules that are free of cardiotoxicity. PMID- 22452319 TI - Curtin-Hammett paradigm for stereocontrol in organocatalysis by diarylprolinol ether catalysts. AB - Detailed mechanistic study of two reactions catalyzed by diarylprolinol ether catalysts, the conjugate addition of aldehydes to nitro-olefins and the alpha chlorination of aldehydes, leads to the proposal that the stereochemical outcome in these cases is not determined by the transition state of the step in which the stereogenic center is formed from enamine attack on the electrophile but instead is correlated with the relative stability and reactivity of diastereomeric intermediates downstream in the catalytic cycle. This combination of kinetic and thermodynamic factors illustrates a remarkable Curtin-Hammett scenario that can result in either an enhancement or an erosion of the selectivity that would be predicted by the transition state for enamine attack on the electrophile. Evidence is offered to suggest that this concept may represent a general phenomenon for pyrrolidine-based catalysts lacking an acidic directing proton. Implications for catalyst and reaction design are discussed. PMID- 22452320 TI - Cost-effectiveness of extending the coverage of water supply fluoridation for the prevention of dental caries in Australia. AB - OBJECTIVE: Fluoride was first added to the Australian water supply in 1953, and by 2003, 69% of Australia's population was receiving the minimum recommended dose. Extending coverage of fluoridation to all remaining communities of at least 1000 people is a key strategy of Australia's National Oral Health Plan 2004-2013. We evaluate the cost-effectiveness of this strategy from an Australian health sector perspective. METHODS: Health gains from the prevention of caries in the Australian population are modelled over the average 15-year lifespan of a treatment plant. Taking capital and on-going operational costs of fluoridation into account, as well as costs of caries treatment, we determine the dollars per disability-adjusted life years (DALY) averted from extending coverage of fluoridation to all large (>= 1000 people) and small (<1000 people) communities in Australia. RESULTS: Extending coverage of fluoridation to all communities of at least 1000 people will lead to improved population health (3700 DALYs, 95% uncertainty interval: 2200-5700 DALYs), with a dominant cost-effectiveness ratio and 100% probability of cost-savings. Extending coverage to smaller communities leads to 60% more health gains, but is not cost-effective, with a median cost effectiveness ratio of A$92 000/DALY and only 10% probability of being under a cost-effectiveness threshold of A$50 000/DALY. CONCLUSIONS: Extension of fluoridation coverage under the National Oral Health Plan is highly recommended, but given the substantial dental health disparities and inequalities in access to dental care that currently exist for more regional and remote communities, there may be good justification for extending coverage to include all Australians, regardless of where they live, despite less favourable cost-effectiveness. PMID- 22452321 TI - Correlation between sex hormone levels and obesity in the elderly male. AB - OBJECTIVE: To investigate the levels of sex hormones and androgen receptor (AR) in elderly male patients and to explore a possible correlation with obesity. METHODS: The cross-sectional study included 314 Elderly males (age >= 65 year). Of these subjects, 104 were healthy (age range 65-92 year; mean 71.38 +/- 5.154 year), 74 were obese (65-87 year; 71.32 +/- 4.74 year), and 111 were overweight (65-85 year; 71.43 +/- 5.03 year). The following parameters were measured: total testosterone (TT), free testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone, follicle stimulating hormone and AR. RESULTS: (i) The levels of TT and SHBG in the obesity group were significantly lower than those in non-obese subjects. (ii) Body mass index (BMI) negatively correlated with TT and SHBG. (iii) Multiple regression analysis revealed that TT (beta: -0.230; p = 0.045) and SHBG (beta: -0.163; p = 0.02) were statistically correlated with BMI. CONCLUSION: Testosterone levels in the obese population were significantly lower than in the non-obese population and there is a significant association between testosterone levels and the extent of obesity. PMID- 22452322 TI - Identification of the slow conduction zone in a macroreentry circuit of verapamil sensitive idiopathic left ventricular tachycardia using electroanatomic mapping. AB - BACKGROUND: Although idiopathic left ventricular tachycardia (ILVT) has been shown to possess a slow conduction zone (SCZ), the details of the electrophysiological and anatomic aspects are still not well understood. OBJECTIVE: We hypothesized that the SCZ can be identified using a 3-dimensional electroanatomic (EA) mapping system. METHODS: Ten patients with ILVT were mapped using a 3-dimensional electroanatomic (EA) mapping system. After a 3-dimensional endocardial geometry of the left ventricular was created, the conduction system with left Purkinje potential (PP) and the SCZ with diastolic potential (DP) in LV were mapped during sinus rhythm (SR) and ventricular tachycardia (VT) and were tagged as special landmarks in the geometry. The electrophysiological and anatomic aspects of it were investigated. RESULTS: EA mapping during SR and VT was successfully performed in 7 patients, during VT in 3 patients. The SCZ with DPs located at the inferoposterior septum was found in 7 patients during SR and all patients during VT. The length of the SCZ was 25.2 +/- 2.3 mm with conduction velocity 0.08 +/- 0.01 m/s. No differences in these parameters were found between patients during SR and VT (P > 0.05). An area with PP was found within the posterior septum. A crossover junction area with DP and PP was found in 7 patients during SR and VT. This area with DP and PP during SR coincided or were in proximity to such area during VT and radiofrequency ablation targeting the site within the area abolished VT in all patients. CONCLUSION: The ILVT substrate within the junction area of the SCZ and the posterior fascicular can be identified and can be used to guide the ablation of ILVT. PMID- 22452323 TI - Admission and stay in psychiatric hospitals in northern Norway among Sami and a control group: a registry-based study. AB - BACKGROUND: The aim of this study was analyze the admission and inpatient stay at psychiatric hospital in northern Norway among people from the Sami-speaking municipalities (Sami group) and a control group (non-Sami group). Are they treated equally? METHODS: All admissions and inpatient stay from the administration area of the Sami language law (eight municipalities) was matched with a control group of 11 municipalities. All adult patients treated during the 2-year time period 2009-2010 and registered by the Norwegian Patient Registry (NPR) were included in the study. Population data as of 2009 was accessed from Statistics Norway. The admission rate and the days in hospital (DiH) rate per 10,000 inhabitants/year were set as 1.0. RESULTS: Both study groups had a significantly higher admission and DiH-rate than northern Norwegians in general. The median annual admission rate/10,000 inhabitants was 284 (Sami) and 307 (non Sami), respectively (P = 0.23). Whereas there were no difference between groups with regard to DiH/10,000 inhabitants/year (P = 0.24), the males of the Sami group spent significantly fewer DiH when any form of coercion was used (RR = 0.41). CONCLUSIONS: Sami did not experience significantly more or fewer admissions (voluntary and compulsory) to psychiatric hospitals than the control group. There were significant intergroup variations in both groups. PMID- 22452324 TI - Rational design of plasmonic nanostructures for biomolecular detection: interplay between theory and experiments. AB - In this work, we report a simple strategy to obtain ultrasensitive SERS nanostructures by self-assembly and bioconjugation of Au nanospheres (NSs). Homodimer aggregates with an interparticle gap of around 8 nm are generated in aqueous dispersions by the highly specific molecular recognition of biotinylated Au NSs to streptavidin (STV), while random Au NS aggregates with a gap of 5 nm are formed in the absence of STV due to hydrogen bonding among biotinylated NSs. Both types of aggregates depict SERS analytical enhancement factors (AEF) of around 10(7) and the capability to detect biotin concentrations lower than 1 * 10(-12) M. Quite interesting, the AEF for an external analyte, Rhodamine 6G (RH6G), using the dimer aggregates is 1 order of magnitude greater (10(5)) than using random aggregates (around 10(4)). The dependence on the wavelength and the differences of the AEF for Au random aggregates and dimers are rationalized with rigorous electrodynamic simulations. The dimers obtained afford a new type of an in situ self-calibrated and reliable SERS substrate where biotinylated molecules can selectively be "trapped" by STV and located in the nanogap enhanced plasmonic field. Using this concept, powerful molecular-recognition-based SERS assays can be carried out. The capability of the dimeric structures for analytical applications is demonstrated using SPR spectroscopy to detect biotinylated immunoglobulin G at very low concentrations. PMID- 22452325 TI - Pre-existing root cementum may promote cementoblast differentiation of human periodontal ligament cells. AB - OBJECTIVES: To observe whether preserved healthy cementum could promote differentiation of human periodontal ligament cells to cementoblasts. MATERIALS AND METHODS: Symmetrical root slices from each healthy premolar were distributed into either the control group (cementum removed) or test group (cementum preserved). After isolation and characterization, human periodontal ligament cells were inoculated onto root slices for 7 days co-culture. Two slices per group were studied for cell morphology by scanning electronic microscopy. Twenty three slices were detected for expression of cementum attachment protein and cementum protein 23, two putative cementoblast markers, by real-time polymerase chain reaction. Twenty slices were transplanted into nude mice and analysed using histology and immunohistochemistry for osteopontin and bone sialoprotein expression after 8 weeks. RESULTS: Cells of the test group had smoother fibroblast morphology and higher cementum protein 23 and cementum attachment protein expression than those of the control group (P < 0.01). In the test group, 14 root slices revealed cementum-like matrix formation resting on old cementum; no splits were observed between newly formed matrix and old cementum. In the control group, 17 specimens had fibrous tissue formation along the root surface and varying width of splits could be seen between new fibrous tissue and dentine surface. Only three specimens demonstrated presence of newly formed thin cementum like matrix. Newly formed cementum-like matrix was positive for osteopontin and bone sialoprotein. CONCLUSIONS: The results demonstrate that healthy root cementum may promote differentiation of human periodontal ligament cells towards cementoblasts. PMID- 22452326 TI - Does targeted pre-load optimisation by stroke volume variation attenuate a reduction in cardiac output in the prone position. AB - The prone position can reduce cardiac output by up to 25% due to reduced preload. We hypothesised that preload optimisation targeted to stroke volume variation before turning prone might alleviate this. A supine threshold stroke volume variation of 14% in a preliminary study identified patients whose cardiac outputs would decline when turned prone. In 45 patients, cardiac output declined only in the group whose supine stroke volume variation was high (mean (SD) 5.1 (2.0) to 3.9 (1.9) l.min(-1) ; p < 0.001), but not in patients in whom it was low, or in those in whom stroke volume variation was high, but who received volume preload (p = 0.525 and 0.941, respectively). We conclude that targeted preload optimisation using a supine stroke volume variation value < 14% is effective in preventing falls in cardiac output induced by the prone position. PMID- 22452327 TI - Charles Bonnet syndrome: a literature review into diagnostic criteria, treatment and implications for nursing practice. AB - Charles Bonnet syndrome is a disease of vision which may be mistakenly identified as manifestations of psychosis and consequently be treated by psychiatrists and mental health nurses rather than ophthalmologists. This literature review considers current understanding of the syndrome, its treatment and the role of mental health nurses. The two main findings of the review are that despite a long recognition of the syndrome, diagnostic criteria are not established and that there is no recognized evidence-based medical treatment. As well as this, two novel treatments which may offer future benefits are discussed. Current best practice is identified as identifying the condition and providing reassurance and education, a role that mental health nurses that are aware of Charles Bonnet syndrome can fulfil perhaps better than any other discipline. PMID- 22452328 TI - Radiofrequency and cryoablation therapies for supraventricular arrhythmias in the young: five-year review of efficacies. AB - BACKGROUND: Cryoablation (Cryo) has augmented radiofrequency (RF) as the ablation energy choice for most supraventricular tachycardias (SVT). Although initial acute results and more recent, but limited, 3-36-month follow-up studies have been reported, more longer follow-up information is required to determine actual efficacy. METHODS: Data from patients with structurally normal hearts who underwent reentrant forms of SVT ablation at our institution from January 2005 to December 2009 were reviewed. These included demographics, clinical and electrophysiologic findings, and ablative energies used. Following apparent acute success, all patients were then reevaluated for any potential recurrences of SVT or preexcitation up to 5 years later. RESULTS: A total of 155 patients (83 male) were reviewed (mean age 13.4 +/- 3.7 years). Ablations were predominantly right sided (75%). Atrioventricular reciprocating tachycardia was seen in 74% and atrioventricular node reciprocating tachycardia (AVNRT) in 17% of patients. For concerns of atrioventricular node integrity, Cryo +/- RF was user-preferred for anteroseptal accessory fiber locations and AVNRT. Acute success rate was 98% and chronic 83.2% over the next 5 years. Among patients with accessory pathways, recurrence was pathway number and location dependent: significantly higher (P < 0.05) if they were right anterior-anteroseptal, multiple, or with a broad distribution pattern. There were no significant differences in recurrence rates with use of RF or its combination with Cryo. CONCLUSION: Radiofrequency ablation and Cryo are both effective therapies for pediatric patients. Although use of Cryo with RF in combination may enhance safety while affording comparable success, risk of recurrence still persists in the current era among patients depending on accessory pathways connection location and characteristics. PMID- 22452330 TI - Measurement of H2O broadening of O2 A-band transitions and implications for atmospheric remote sensing. AB - We present laboratory measurements of H(2)O-broadened (16)O(2) A-band (b(1)Sigma(g)(+) <- X(3)Sigma(g)(-)(0,0)) absorption spectra acquired with a laser-based photoacoustic spectroscopy method. This absorption band is widely used in a variety of high-precision atmospheric remote sensing applications. We report H(2)O broadening parameters for six of the strongest transitions in this band, and we show that these measured values are nominally 1.5-2 times greater than the corresponding air-broadening parameters. Simulations of atmospheric transmission spectra in the O(2) A-band that incorporate our measured H(2)O broadening parameters indicate that H(2)O present at concentrations typically found in the Earth's atmosphere can influence the column-integrated transmission relative to the dry air case. Further, because of spatial and seasonal variations in humidity, failure to account for the enhanced H(2)O pressure broadening effects can lead to concomitant biases in atmospheric O(2) A-band retrievals of quantities such as surface pressure and path length in greenhouse gas retrievals. PMID- 22452331 TI - Surface reactivity and cell responses to chrysotile asbestos nanofibers. AB - High aspect-ratio nanomaterials (HARNs) have recently attracted great attention from nanotoxicologists because of their similarity to asbestos. However, the actual risk associated with the exposure to nanosized asbestos, which escapes most regulations worldwide, is still unknown. Nanometric fibers of chrysotile asbestos have been prepared from two natural sources to investigate whether nanosize may modulate asbestos toxicity and gain insight on the hazard posed by naturally occurring asbestos, which may be defined as HARNs because of their dimensions. Power ultrasound was used to obtain nanofibers from two different chrysotile specimens, one from the dismissed asbestos mine in Balangero (Italian Western Alps) and the other from a serpentine outcrop in the Italian Central Alps. Electron microscopy, X-ray diffraction, and fluorescence spectroscopy revealed that the procedure does not affect mineralogical and chemical composition. Surface reactions related to oxidative stress, free radical generation, bioavailability of iron, and antioxidant depletion, revealed a consistent reduction in reactivity upon reduction in size. When tested on A549 human epithelial cells, the pristine but not the nanosized fibers proved cytotoxic (LDH release), induced NO production, and caused lipid peroxidation. However, nanofibers still induced some toxicity relevant oxidative stress activity (ROS production) in a dose-dependent fashion. The reduction in length and a lack of poorly coordinated bioavailable iron in nanochrysotile may explain this behavior. The present study provides a one-step procedure for the preparation of a homogeneous batch of natural asbestos nanofibers and shows how a well-known toxic material might not necessarily become more toxic than its micrometric counterpart when reduced to the nanoscale. PMID- 22452332 TI - Rh2(S-biTISP)2-catalyzed asymmetric functionalization of indoles and pyrroles with vinylcarbenoids. AB - Asymmetric functionalization of N-heterocycles by vinylcarbenoids in the presence of catalytic amounts of Rh(2)(S-biTISP)(2) has been successfully developed. This bridged dirhodium catalyst not only selectively enforces the reaction to occur at the vinylogous position of the carbenoid but also affords high levels of asymmetric induction. PMID- 22452333 TI - Characteristics of emodin on modulating the contractility of jejunal smooth muscle. AB - Emodin is traditionally used as a laxative and is found to increase or decrease the contractility of intestinal smooth muscle in low doses and high doses, respectively. In this study, we propose that bidirectional regulation (BR) on the contractility of jejunal smooth muscle (CJSM) is inducible by emodin in the absence of control by the central nervous system. The results indicated that emodin-induced BR had the following characteristics. A stimulatory effect on CJSM was induced by emodin at 7 low contractile states, and an inhibitory effect was induced on CJSM at 7 high contractile states. Emodin-induced BR on myosin phosphorylation was also observed. BR was not observed in the presence of tetrodotoxin, suggesting that enteric nervous system is required for producing BR. The stimulatory effect of emodin on CJSM was abolished by atropine and diphenhydramine, respectively, suggesting that BR was correlated with cholinergic and histamine system while jejunal smooth muscle was at low contractile state. The inhibitory effect of emodin on CJSM was abolished by phentolamine, propranolol, and L-NG-nitroarginine (L-NNA), respectively, suggesting that BR was related to adrenergic hyperactivity and with a nitric oxide relaxing mechanism while jejunal smooth muscle was in a high contractile state. The exact mechanism, however, needs further investigation. PMID- 22452334 TI - Left atrial enlargement: a prevalent marker of hypertensive heart disease. PMID- 22452335 TI - Identification of a novel skin penetration enhancement peptide by phage display peptide library screening. AB - Skin is an important site for local or systemic application of drugs. However, a majority of drugs have poor permeability through the skin's topmost layer, stratum corneum (SC). The aim of this study was to identify safe and smaller peptides that could enhance the skin penetration of drug molecules. By screening phage display peptide library, we have identified a T2 peptide (LVGVFH), which enhanced the penetration of bacteriophages (~800 nm long bacterial viruses) across porcine and mouse skin. Pretreating the skin with synthetic T2 peptide at pH 4.5 resulted in significant penetration enhancement of hydrophilic drug 5 fluorouracil (5-FU) across skin. FTIR spectroscopy showed that the T2 peptide interacted with skin lipids to enhance the skin penetration. Pretreating the skin with T2 peptide enhanced the partitioning of small molecules with different lipophilicities (5-FU, fluorescein isothiocyanate, and rhodamine 123 hydrochloride) into skin. Fluorescence studies showed that T2 peptide enhanced the diffusion of these molecules into intercellular lipids of SC and thus enhanced the penetration into the skin. Histidine at the c-terminus of T2 peptide was identified to be critical for the skin penetration enhancement. T2 peptide interacted with skin lipids to cause skin penetration enhancement. The study identified a novel, safe, and noninvasive peptide to improve the skin penetration of drugs without chemical conjugation. PMID- 22452336 TI - The small GTPases Rab9A and Rab23 function at distinct steps in autophagy during Group A Streptococcus infection. AB - Autophagy mediates the degradation of cytoplasmic contents in the lysosome and plays a significant role in immunity. Here we identified the small GTPases Rab9A and Rab23 as novel autophagy regulators during Group A streptococcus (GAS) infection. Rab9A was recruited to GAS-containing autophagosome-like vacuoles (GcAVs) after autophagosomal maturation and its activity was required for GcAV enlargement and eventual lysosomal fusion. GcAV enlargement appeared to be related to homotypic fusion of GcAVs with Rab9A. Rab23 was recruited to GAS capturing forming autophagosomes. Knockdown of Rab23 expression decreased both LC3- and Atg5-positive GAS formation and caused the accumulation of LC3-positive structures that did not associate with intracellular GAS. It was suggested, therefore, that Rab23 is required for GcAV formation and is involved in GAS targeting of autophagic vacuoles. Furthermore, knockdown of Rab9A or Rab23 expression impaired the degradation of intracellular GAS. Therefore, our data reveal that the Rab9A and Rab23 GTPases play crucial roles in autophagy of GAS. However, neither Rab9A nor Rab23 were localized to starvation-induced autophagosomes. Not only Rab9A but also Rab23 was dispensable for starvation induced autophagosome formation. These findings demonstrate that specific Rab proteins function at distinct steps during autophagy in response to GAS infection. PMID- 22452337 TI - Why we still need randomized trials to compare effectiveness. PMID- 22452338 TI - Comparative effectiveness of revascularization strategies. AB - BACKGROUND: Questions persist concerning the comparative effectiveness of percutaneous coronary intervention (PCI) and coronary-artery bypass grafting (CABG). The American College of Cardiology Foundation (ACCF) and the Society of Thoracic Surgeons (STS) collaborated to compare the rates of long-term survival after PCI and CABG. METHODS: We linked the ACCF National Cardiovascular Data Registry and the STS Adult Cardiac Surgery Database to claims data from the Centers for Medicare and Medicaid Services for the years 2004 through 2008. Outcomes were compared with the use of propensity scores and inverse-probability weighting adjustment to reduce treatment-selection bias. RESULTS: Among patients 65 years of age or older who had two-vessel or three-vessel coronary artery disease without acute myocardial infarction, 86,244 underwent CABG and 103,549 underwent PCI. The median follow-up period was 2.67 years. At 1 year, there was no significant difference in adjusted mortality between the groups (6.24% in the CABG group as compared with 6.55% in the PCI group; risk ratio, 0.95; 95% confidence interval [CI], 0.90 to 1.00). At 4 years, there was lower mortality with CABG than with PCI (16.4% vs. 20.8%; risk ratio, 0.79; 95% CI, 0.76 to 0.82). Similar results were noted in multiple subgroups and with the use of several different analytic methods. Residual confounding was assessed by means of a sensitivity analysis. CONCLUSIONS: In this observational study, we found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was a long-term survival advantage among patients who underwent CABG as compared with patients who underwent PCI. (Funded by the National Heart, Lung, and Blood Institute.). PMID- 22452339 TI - Gut hormones: the future of obesity treatment? AB - Obesity is a major worldwide health problem. The treatment options are severely limited. The development of novel anti-obesity drugs is fraught with efficacy and safety issues. Consequently, several investigational anti-obesity drugs have failed to gain marketing approval in recent years. Anorectic gut hormones offer a potentially safe and viable option for the treatment of obesity. The prospective utility of gut hormones has improved drastically in recent years with the development of longer acting analogues. Additionally, specific combinations of gut hormones have been demonstrated to have additive anorectic effects. This article reviews the current stage of anti-obesity drugs in development, focusing on gut hormone-based therapies. PMID- 22452340 TI - Vitalization of porous polyethylene (Medpor(r)) with chondrocytes promotes early implant vascularization and incorporation into the host tissue. AB - Porous polyethylene (Medpor((r))) is frequently used in craniofacial reconstructive surgery. The successful incorporation of this alloplastic biomaterial depends on adequate vascularization. Here, we analyzed whether the early vascularization of porous polyethylene can be accelerated by vitalization with human chondrocytes. For this purpose, small polyethylene samples were coated with platelet-rich plasma (PRP) or a suspension of PRP and human chondrocytes. Uncoated polyethylene samples served as controls. Subsequently, the samples were implanted into the dorsal skinfold chamber of CD-1 nude mice to repetitively analyze their vascularization and biocompatibility by means of intravital fluorescence microscopy. PRP-chondrocyte-coated polyethylene exhibited an accelerated and improved vascularization when compared with the other two groups. This was indicated by a significantly higher functional capillary density of the microvascular network developing around the implants. Moreover, a leukocyte endothelial cell interaction was found in a physiological range at the implantation site of all three groups, demonstrating that the vitalization with PRP and chondrocytes did not affect the good biocompatibility of the alloplastic material. Additional histological, immunohistochemical, and in situ hybridization analyses revealed that the chondrocytes formed a bioprotective tissue layer, which prevented the accumulation of macrophages and foreign body giant cells on the polyethylene surface. These findings clearly indicate that vitalization of polyethylene with chondrocytes promotes early implant vascularization and incorporation into the host tissue and, thus, may be a promising approach that prevents postoperative complications such as implant extrusion, migration, and infection. PMID- 22452341 TI - Asynchronous master-slave parallelization of differential evolution for multi objective optimization. AB - In this paper, we present AMS-DEMO, an asynchronous master-slave implementation of DEMO, an evolutionary algorithm for multi-objective optimization. AMS-DEMO was designed for solving time-intensive problems efficiently on both homogeneous and heterogeneous parallel computer architectures. The algorithm is used as a test case for the asynchronous master-slave parallelization of multi-objective optimization that has not yet been thoroughly investigated. Selection lag is identified as the key property of the parallelization method, which explains how its behavior depends on the type of computer architecture and the number of processors. It is arrived at analytically and from the empirical results. AMS DEMO is tested on a benchmark problem and a time-intensive industrial optimization problem, on homogeneous and heterogeneous parallel setups, providing performance results for the algorithm and an insight into the parallelization method. A comparison is also performed between AMS-DEMO and generational master slave DEMO to demonstrate how the asynchronous parallelization method enhances the algorithm and what benefits it brings compared to the synchronous method. PMID- 22452342 TI - Distinct roles of trauma and transfusion in induction of immune modulation after injury. AB - BACKGROUND: Trauma and transfusion can both alter immunity, and while transfusions are common among traumatically injured patients, few studies have examined their combined effects on immunity. STUDY DESIGN AND METHODS: We tracked the plasma levels of 41 immunomodulatory proteins in 56 trauma patients from time of injury up to 1 year later. In addition, a murine model was developed to distinguish between the effects of transfusion and underlying injury and blood loss. RESULTS: Thirty-one of the proteins had a significant change over time after traumatic injury, with a mixed early response that was predominantly anti inflammatory followed by a later increase in proteins involved in wound healing and homeostasis. Results from the murine model revealed similar cytokine responses to humans. In mice, trauma and hemorrhage caused early perturbations in a number of the pro- and anti-inflammatory mediators measured, and transfusion blunted early elevations in interleukin (IL)-6, IL-10, matrix metalloproteinase 9, and interferon-gamma. Transfusion caused or exacerbated changes in monocyte chemotactic protein-1, IL-1alpha, IL-5, IL-15, and soluble E-selectin. Finally, trauma and hemorrhage alone increased CXCL1 and IL-13. CONCLUSIONS: This work provides a detailed characterization of the major shift in the immunologic environment in response to trauma and transfusion and clarifies which immune mediators are affected by trauma and hemorrhage and which by transfusion. PMID- 22452343 TI - Rate-dependent and site-specific conduction block at the posterior right atrium and drug effects evaluated using a noncontact mapping system in patients with typical atrial flutter. AB - INTRODUCTION: Conduction block in the posterior right atrium (RA) plays an important role in perpetuating atrial flutter (AFL). Although conduction blocks have functional properties, it is not clear how the block line changes with the pacing rate, pacing site, and administration of antiarrhythmic drugs. METHODS AND RESULTS: Forty patients with typical AFL were enrolled. Pacing (110, 170, 230 ppm) from the coronary sinus ostium (CSo) and low lateral RA was performed. After 1 mg/kg pilsicainide (pure sodium channel blockade) administration, the pacing protocol was repeated. Conduction block was assessed based on a color-coded isopotential map and 20 points of virtual unipolar electrograms in the posterior RA using noncontact mapping. Block line proportion was defined as the percentage of length of the block line between the superior and inferior vena cava. The pacing rate-dependent extension of the block proportion was significant during pacing from both sides (pacing from the CSo: 59 +/- 17% at 110 ppm, 69 +/- 16% at 230 ppm, P < 0.05; pacing from the low lateral RA: 43 +/- 19% at 110 ppm, 55 +/- 22% at 230 ppm, P < 0.05). The block line was significantly longer during CSo pacing than during low lateral RA pacing at each rate (all P < 0.05). After pilsicainide administration, the block line extended further. CONCLUSION: In addition to pacing rate-dependent and site-dependent changes in the block line, pilsicainide further extended the block line length. This phenomenon explains the clinical observation that counterclockwise AFL occurs more frequently than clockwise AFL, and the mechanism of class IC AFL. PMID- 22452344 TI - The use of Bayesian nonlinear regression techniques for the modelling of the retention behaviour of volatile components of Artemisia species. AB - The main aim of this work was to assess the ability of Bayesian multivariate adaptive regression splines (BMARS) and Bayesian radial basis function (BRBF) techniques for modelling the gas chromatographic retention indices of volatile components of Artemisia species. A diverse set of molecular descriptors was calculated and used as descriptor pool for modelling the retention indices. The ability of BMARS and BRBF techniques was explored for the selection of the most relevant descriptors and proper basis functions for modelling. The results revealed that BRBF technique is more reproducible than BMARS for modelling the retention indices and can be used as a method for variable selection and modelling in quantitative structure-property relationship (QSPR) studies. It is also concluded that the Markov chain Monte Carlo (MCMC) search engine, implemented in BRBF algorithm, is a suitable method for selecting the most important features from a vast number of them. The values of correlation between the calculated retention indices and the experimental ones for the training and prediction sets (0.935 and 0.902, respectively) revealed the prediction power of the BRBF model in estimating the retention index of volatile components of Artemisia species. PMID- 22452345 TI - Use of plethysmographic variability index derived from the Massimo((r)) pulse oximeter to predict fluid or preload responsiveness: a systematic review and meta analysis. AB - This systematic review and meta-analysis assessed the accuracy of plethysmographic variability index derived from the Massimo((r)) pulse oximeter to predict preload responsiveness in peri-operative and critically ill patients. A total of 10 studies were retrieved from the literature, involving 328 patients who met the selection criteria. Overall, the diagnostic odds ratio (16.0; 95% CI 5-48) and area under the summary receiver operating characteristic curve (0.87; 95% CI 0.78-0.95) for plethysmographic variability index to predict fluid or preload responsiveness was very good, but significant heterogeneity existed. This could be explained by a lower accuracy of plethysmographic variability index in spontaneously breathing or paediatric patients and those studies that used pre load challenges other than colloid fluid. The results indicate specific directions for future studies. PMID- 22452346 TI - Mitochondrial F(0) F(1) -ATP synthase is a molecular target of 3-iodothyronamine, an endogenous metabolite of thyroid hormone. AB - BACKGROUND AND PURPOSE: 3-iodothyronamine (T1AM) is a metabolite of thyroid hormone acting as a signalling molecule via non-genomic effectors and can reach intracellular targets. Because of the importance of mitochondrial F(0) F(1) -ATP synthase as a drug target, here we evaluated interactions of T1AM with this enzyme. EXPERIMENTAL APPROACH: Kinetic analyses were performed on F(0) F(1) -ATP synthase in sub-mitochondrial particles and soluble F(1) -ATPase. Activity assays and immunodetection of the inhibitor protein IF(1) were used and combined with molecular docking analyses. Effects of T1AM on H9c2 cardiomyocytes were measured by in situ respirometric analysis. KEY RESULTS: T1AM was a non-competitive inhibitor of F(0) F(1) -ATP synthase whose binding was mutually exclusive with that of the inhibitors IF(1) and aurovertin B. Both kinetic and docking analyses were consistent with two different binding sites for T1AM. At low nanomolar concentrations, T1AM bound to a high-affinity region most likely located within the IF(1) binding site, causing IF(1) release. At higher concentrations, T1AM bound to a low affinity-region probably located within the aurovertin binding cavity and inhibited enzyme activity. Low nanomolar concentrations of T1AM increased ADP-stimulated mitochondrial respiration in cardiomyocytes, indicating activation of F(0) F(1) -ATP synthase consistent with displacement of endogenous IF(1,) , reinforcing the in vitro results. CONCLUSIONS AND IMPLICATIONS: Effects of T1AM on F(0) F(1) -ATP synthase were twofold: IF(1) displacement and enzyme inhibition. By targeting F(0) F(1) -ATP synthase within mitochondria, T1AM might affect cell bioenergetics with a positive effect on mitochondrial energy production at low, endogenous, concentrations. T1AM putative binding locations overlapping with IF(1) and aurovertin binding sites are described. PMID- 22452347 TI - Interrogation of global active site occupancy of a fungal iterative polyketide synthase reveals strategies for maintaining biosynthetic fidelity. AB - Nonreducing iterative polyketide synthases (NR-PKSs) are responsible for assembling the core of fungal aromatic natural products with diverse biological properties. Despite recent advances in the field, many mechanistic details of polyketide assembly by these megasynthases remain unknown. To expand our understanding of substrate loading, polyketide elongation, cyclization, and product release, active site occupancy and product output were explored by Fourier transform mass spectrometry using the norsolorinic acid anthrone producing polyketide synthase, PksA, from the aflatoxin biosynthetic pathway in Aspergillus parasiticus. Here we report the simultaneous observation of covalent intermediates from all catalytic domains of PksA from in vitro reconstitution reactions. The data provide snapshots of iterative catalysis and reveal an underappreciated editing function for the C-terminal thioesterase domain beyond its recently established synthetic role in Claisen/Dieckmann cyclization and product release. The specificity of thioesterase catalyzed hydrolysis was explored using biosynthetically relevant protein-bound and small molecule acyl substrates and demonstrated activity against hexanoyl and acetyl, but not malonyl. Processivity of polyketide extension was supported by the inability of a nonhydrolyzable malonyl analog to trap products of intermediate chain lengths and by the detection of only fully extended species observed covalently bound to, and as the predominant products released by, PksA. High occupancy of the malonyl transacylase domain and fast relative rate of malonyl transfer compared to starter unit transfer indicate that rapid loading of extension units onto the carrier domain facilitates efficient chain extension in a manner kinetically favorable to ultimate product formation. PMID- 22452348 TI - Questionnaire survey of cardiologists' knowledge, attitudes, and guideline application of implantable cardioverter defibrillator therapy. AB - INTRODUCTION: There are little data on cardiologists' knowledge and application of current implantable cardioverter defibrillator (ICD) guidelines, attitudes to risk, and how these may influence ICD prescription. METHODS: A questionnaire survey was sent to UK cardiologists to test their knowledge and application of ICD guidelines and their estimate of the clinical benefits gained in different clinical scenarios. They were questioned on the minimum absolute risk reduction (ARR) required to justify an ICD implant and factors that influenced their decision making. RESULTS: Sixty responses from 23 implanters and 37 nonimplanters were obtained. Eighty-three percent implanters and 43% nonimplanters were fully aware of UK ICD National Institute of Clinical Excellence guidelines. Only 7% responders had a screening program to identify primary prevention (PP) candidates. Although the mean estimate of ARR in PP scenarios was similar to trial data, the range of estimates was very wide. The benefit in secondary prevention (SP) scenarios was overestimated by both implanters and nonimplanters. Three-year ARR believed to justify PP and SP ICDs were heavily influenced by patients' age but in patients <80 years, age was compatible with trial results. Implanters and nonimplanters correctly applied guidelines in SP scenarios with younger patients but often withheld an ICD in elderly patients. Correct application did not correlate with full awareness of guidelines. CONCLUSION: Lack of knowledge of guidelines (particularly in nonimplanters), failure of nonimplanters to offer ICDs to appropriate PP patients, age bias, and a lack of screening programs appear to be the greatest barriers to uptake of ICDs in the United Kingdom, rather than financial concerns. PMID- 22452349 TI - In silico discovery and virtual screening of multi-target inhibitors for proteins in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (MTB) is the principal pathogen which causes tuberculosis (TB), a disease that remains as one of the most alarming health problems worldwide. An active area for the search of new anti-TB therapies is concerned with the use of computational approaches based on Chemoinformatics and/or Bioinformatics toward the discovery of new and potent anti-TB agents. These approaches consider only small series of structurally related compounds and the studies are generally realized for only one target like a protein. This fact constitutes an important limitation. The present work is an effort to overcome this problem. We introduce here the first chemo-bioinformatic approach by developing a multi-target (mt) QSAR discriminant model, for the in silico design and virtual screening of anti-TB agents against six proteins in MTB. The mt-QSAR model was developed by employing a large and heterogeneous database of compounds and substructural descriptors. The model correctly classified more than 90% of active and inactive compounds in both, training and prediction series. Some fragments were extracted from the molecules and their contributions to anti-TB activity through inhibition of the six proteins, were calculated. Several fragments were identified as responsible for anti-TB activity and new molecular entities were designed from those fragments with positive contributions, being suggested as possible anti-TB agents. PMID- 22452350 TI - Generalized anomeric effect on N-alkyl-amino cation affinities: a G2(+)M investigation. AB - The gas-phase N-alkyl-amino-cation affinities (NAACA) of archetypal anionic main group element hydrides across the Periodic Table have been investigated by means of a modified G2(+) scheme. The reactions studied include R(2)NB -> R(2)N(+) + B( ) (R = H, Me; B = XH(n), n = 0-3; X = F, Cl, Br, O, S, Se, N, P, As, C, Si, Ge). Our calculations indicate that the reasonable linear correlations between NAACA and proton affinities (PA) only exist within the Period 2 anions, including H(3)C(-), H(2)N(-), HO(-), and F(-), or the anions within Periods 3-4 in the Periodic Table, which is significantly different from the alkyl cation affinities, where there is a reasonable correlation between the computed alkyl cation affinity and PA values of the set of anionic main-group element hydrides. The interesting differences can be ascribed to the generalized anomeric effect induced by n(N) -> sigma*(X-H) negative hyperconjugation found in R(2)NXH(n), with central atom X belonging to Groups 14-16 (X = O, S, Se, N, P, As, C, Si, Ge). PMID- 22452351 TI - Programmable light-controlled shape changes in layered polymer nanocomposites. AB - We present soft, layered nanocomposites that exhibit controlled swelling anisotropy and spatially specific shape reconfigurations in response to light irradiation. The use of gold nanoparticles grafted with a temperature-responsive polymer (poly(N-isopropylacrylamide), PNIPAM) with layer-by-layer (LbL) assembly allowed placement of plasmonic structures within specific regions in the film, while exposure to light caused localized material deswelling by a photothermal mechanism. By layering PNIPAM-grafted gold nanoparticles in between nonresponsive polymer stacks, we have achieved zero Poisson's ratio materials that exhibit reversible, light-induced unidirectional shape changes. In addition, we report rheological properties of these LbL assemblies in their equilibrium swollen states. Moreover, incorporation of dissimilar plasmonic nanostructures (solid gold nanoparticles and nanoshells) within different material strata enabled controlled shrinkage of specific regions of hydrogels at specific excitation wavelengths. The approach is applicable to a wide range of metal nanoparticles and temperature-responsive polymers and affords many advanced build-in options useful in optically manipulated functional devices, including precise control of plasmonic layer thickness, tunability of shape variations to the excitation wavelength, and programmable spatial control of optical response. PMID- 22452352 TI - Up-regulation of Anxa2 gene promotes proliferation and invasion of breast cancer MCF-7 cells. AB - OBJECTIVE: The metastatic ability of breast cancer cells with chemoresistant properties is higher when compared to that of their parental wild-type cells. Expression of AnnexinA2 (Anxa2), a 36-kDa calcium-dependent phospholipid binding protein, is increased in metastatic tumours and has been found to be associated with the phenotype of drug resistance and metastasis. MATERIALS AND METHODS AND RESULTS: In the present study, we found that up-regulation of Anxa2 correlates with enhanced migration and invasion ability of MCF-7 breast cancer cells both in vitro and in vivo. Western blot analysis revealed that exposure to chemotherapeutic drugs may induce elevated expression of Anxa2. In addition, our data have shown that Anxa2 might influence proliferation, migration and invasion of MCF-7 cells by increasing expression of c-myc and cyclin D1 via activation of Erk1/2 signalling pathways. CONCLUSION: Our findings suggest that up-regulation of Anxa2 may play an important role in modulating proliferation and invasion of breast cancer MCF-7 cells through regulation of many relevant downstream target genes. PMID- 22452356 TI - Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. AB - BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP] ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). PMID- 22452357 TI - Peroxynitrite has potent pulmonary vasodilator activity in the rat. AB - Peroxynitrite (PN) worsens pathological conditions associated with oxidative stress. However, beneficial effects have also been reported. PN has been shown to demonstrate vasodilator as well as vasoconstrictor properties that are dependent upon the experimental conditions and the vascular bed studied. PN-induced vascular smooth muscle relaxation may involve the formation of nitric oxide (NO) donors. The present results show that PN has significant vasodilator activity in the pulmonary and systemic vascular beds, and that responses to PN were not attenuated by L-penicillamine (L-PEN), a PN scavenger, whereas responses to sodium nitroprusside (SNP) were decreased. PN had a small inhibitory effect on decreases in arterial pressure in response to the NO donors diethylammonium (Z)-1 (N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) and S-nitrosoglutathione (GSNO). PN partially reversed hypoxic pulmonary vasoconstriction. PN responses were attenuated by the soluble guanylate cyclase (sGC) inhibitor, 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and responses to PN and the PN precursor, 3-morpholinosydnonimine (SIN-1), were different. These data show that PN has potent pulmonary vasodilator activity in the rat, and provide evidence that a PN interaction with S-nitrosothiols is not the major mechanism mediating the response. These data suggest that responses to PN are mediated by the activation of sGC, and that PN has a small inhibitory effect on NO responses. PMID- 22452358 TI - A European approach to categorizing medicines for fitness to drive: outcomes of the DRUID project. AB - AIMS: To illustrate (i) the criteria and the development of the DRUID categorization system, (ii) the number of medicines that have currently been categorized, (iii) the added value of the DRUID categorization system and (iv) the next steps in the implementation of the DRUID system. METHODS: The development of the DRUID categorization system was based on several criteria. The following steps were considered: (i) conditions of use of the medicine, (ii) pharmacodynamic and pharmacokinetic data, (iii) pharmacovigilance data, including prevalence of undesirable effects, (iv) experimental and epidemiological data, (v) additional data derived from the patient information leaflet, existing categorization systems and (vi) final categorization. DRUID proposed four tiered categories for medicines and driving. RESULTS: In total, 3054 medicines were reviewed and over 1541 medicines were categorized (the rest were no longer on the EU market). Nearly half of the 1541 medicines were categorized 0 (no or negligible influence on fitness to drive), about 26% were placed in category I (minor influence on fitness to drive) and 17% were categorized as II or III (moderate or severe influence on fitness to drive). CONCLUSIONS: The current DRUID categorization system established and defined standardized and harmonized criteria to categorize commonly used medications, based on their influence on fitness to drive. Further efforts are needed to implement the DRUID categorization system at a European level and further activities should be undertaken in order to reinforce the awareness of health care professionals and patients on the effects of medicines on fitness to drive. PMID- 22452360 TI - 4-Methoxybenzyloxymethyl group, a racemization-resistant protecting group for cysteine in Fmoc solid phase peptide synthesis. AB - The 4-methoxybenzyloxymethyl (MBom) group was introduced for sulfhydryl protection of Cys in combination with Fmoc chemistry. The MBom group proved to substantially suppress racemization of Cys during its incorporation mediated by phosphonium or uronium reagents. Furthermore, this group was found to significantly reduce racemization of the C-terminal Cys linked to a hydroxyl resin during repetitive base treatment, in comparison with the usually used trityl (Trt) and acetamidomethyl (Acm) groups. PMID- 22452359 TI - Antiretroviral use in Italian children with perinatal HIV infection over a 14 year period. AB - BACKGROUND: Information on the use of new antiretroviral drugs in children in the real setting of clinical fields is largely unknown. METHODS: Data from 2554 combined antiretroviral therapy (cART) regimens administered to 911 children enrolled in the Italian Register for HIV infection in children, between 1996 and 2009, were analysed. Factors potentially associated with undetectable viral load and immunological response to cART were explored by Cox regression analysis. RESULTS: Proportion of protease inhibitor (PI)-based regimens significantly decreased from 88.0% to 51.2% and 54.9%, while proportion on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens increased from 4.5% to 38.8% and 40.2% in 1996-1999, 2000-2004 and 2005-2009, respectively (p < 0.0001). Significant change in the use of each antiretroviral drug occurred over the time periods (p < 0.0001). Factors independently associated with virological and immunological success were as follows: later calendar periods, younger age at regimen (only for virological success) and higher CD4(+) T-lymphocyte percentage at baseline. Use of unboosted PI was associated with lower adjusted hazard ratio (aHR) of virological or immunological success with respect to NNRTI- and boosted PI-based regimens, with no difference among these two latter types. CONCLUSION: Use of new generation antiretroviral drugs in Italian HIV-infected children is increasing. No different viro-immunological outcomes between NNRTI- and boosted PI-based cART were observed. PMID- 22452361 TI - Heat-labile enterotoxin-induced activation of NF-kappaB and MAPK pathways in intestinal epithelial cells impacts enterotoxigenic Escherichia coli (ETEC) adherence. AB - Enterotoxigenic Escherichia coli (ETEC) causes human morbidity and mortality in developing nations and is an emerging threat to food safety in developed nations. The ETEC heat-labile enterotoxin (LT) not only causes diarrheal disease by deregulating host adenylate cyclase, but also enhances ETEC adherence to intestinal epithelial cells. The mechanism governing this LT pro-adherence phenotype is unclear. Here we investigated intestinal epithelial cell signal transduction pathways activated by ETEC and quantified the relative importance of these host pathways to LT-induced ETEC adherence. We show that ETEC activates both NF-kappaB and mitogen-activated protein kinase signalling pathways through mechanisms that are primarily dependent upon LT. LT-induced NF-kappaB activation depends upon the cAMP-dependent activation of the Ras-like GTPase Rap1 but is independent of protein kinase A (PKA). By using inhibitors of these pathways, we demonstrate that inhibiting the p38 mitogen-activated protein kinase prevents LT from increasing ETEC adherence. By contrast, the LT pro-adherence phenotype appears unrelated to both LT-induced Rap1 activity and to subsequent NF-kappaB activation. We speculate that LT may alter host signal transduction to induce the presentation of ligands for ETEC adhesins in such a way that promotes ETEC adherence. Our findings provide insight into previously unexplored functions of LT and their relative importance to ETEC virulence. PMID- 22452362 TI - Preclinical evaluation of biomarkers for response monitoring to the MET inhibitor BAY-853474. AB - CONTEXT: The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models. OBJECTIVE: For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models. RESULTS: We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies. CONCLUSION: IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring. PMID- 22452363 TI - Efficacy and safety of peripheral blood stem cell mobilization and collection: a single-center experience in 190 allogeneic donors. AB - BACKGROUND: In the past two decades peripheral blood stem cells (PBSCs) have increasingly replaced marrow as stem cells source for allogeneic transplantation. The PBSC donation initially applied only to related donors; later, due to the safety of the procedure, it was extended to unrelated donors. STUDY DESIGN AND METHODS: We have retrospectively collected data regarding mobilization, collection, and short- and long-term follow-up of 190 consecutive donors, 174 related and 16 unrelated. All donors followed a standard protocol for mobilization and underwent at least one PBSC collection. Follow-up in related donors was performed every 4 months in the first year and then annually, with no time limits, while unrelated donors were monitored for 10 years. RESULTS: All 190 donors completed the established mobilization protocol. The mobilizing capacity was significantly greater in males and in donors less than 60 years old. No case of major toxicity by granulocyte-colony-stimulating factor was found, nor thromboembolic events. The total dose of CD34+/recipient (median 5.8*10(6)/kg recipient/body weight) was statistically correlated with age, CD34+ before and after mobilization, and collection efficiency. Compliance to follow-up was 66%, with a significant difference between related and unrelated (63% vs. 100%, p=0.03). During follow-up no significant abnormalities in hematologic variables or hematologic malignancies were reported. CONCLUSION: Our study allowed us to define the PBSC donation as "a safe procedure for the donors," with short- and long-term effects limited to a small percentage of donors and "effective for the recipient," due to the dose of collected CD34+, adequate for transplantation in almost all recipients. PMID- 22452364 TI - Dissemination of behavioural activation for depression to mental health nurses: training evaluation and benchmarked clinical outcomes. AB - Depression causes significant distress, disability and cost within the UK. Behavioural activation (BA) is an effective single-strand psychological approach which may lend itself to brief training programmes for a wide range of clinical staff. No previous research has directly examined outcomes of such dissemination. A 5-day training course for 10 primary care mental health workers aiming to increase knowledge and clinical skills in BA was evaluated using the Training Acceptability Rating Scale. Depression symptom level data collected in a randomized controlled trial using trainees were then compared to results from meta-analysis of studies using experienced therapists. BA training was highly acceptable to trainees (94.4%, SD 6%). The combined effect size of BA was unchanged by the addition of the results of this evaluation to those of studies using specialist therapists. BA offers a promising psychological intervention for depression that appears suitable for delivery by mental health nurses following brief training. PMID- 22452365 TI - DNA immunization against proacrosin impairs fertility in male mice. AB - PROBLEM: Evaluation of proacrosin/acrosin ability to induce an immune response in male mice after genetic immunization and assessment of animal fertility. METHOD OF STUDY: Mice received 50 MUg per animal of a plasmid containing the human proacrosin cDNA (pSF2-Acro) (control: empty plasmid, pSF2). The humoral response was evaluated by ELISA and immunocytochemistry. In vivo fertility was assessed by mating immunized males with control females. The effect of antibodies upon Ca(+2) ionophore-induced acrosomal exocytosis (AE) and in vitro sperm-zona pellucida (ZP) binding was also studied. RESULTS: pSF2-Acro-immunized mice developed high levels of specific antibodies (P < 0.05) that recognized the sperm acrosomal cap. The number of fertile mice was lower (P = 0.027) in pSF2-Acro-immunized animals than in controls. Litter size was smaller (P < 0.05) in the pSF2-Acro group compared with controls. A negative correlation (P < 0.05) between antibody levels and litter size was found. Antiproacrosin/acrosin antibodies inhibited sperm-ZP binding (P < 0.0001) and Ca(+2)-ionophore-induced AE (P < 0.05). CONCLUSION: DNA immunization against proacrosin elicits an immune response in male mice associated with abnormal sperm functions and reduced fertility. PMID- 22452366 TI - Impact of donor histology on survival following liver transplantation for chronic hepatitis C virus infection: a Scandinavian single-center experience. AB - OBJECTIVE: Survival following liver transplantation for hepatitis C virus (HCV) infection is affected by several factors. The aims of this single-center study were to evaluate survival from 1992 to 2006 in HCV-infected liver transplant recipients and to identify factors influencing patient and graft survival, with particular focus on donor liver histopathology. MATERIAL AND METHODS: Survival among 84 patients transplanted for HCV-related liver disease at the Sahlgrenska University Hospital during the above period was evaluated. Median follow-up time was 57 months (range 28-87). A perioperative liver biopsy from the donor liver graft was available in 68 cases. Biopsies were assessed for fibrosis, necroinflammatory activity, and degree of steatosis. Patient and graft survival according to relevant factors including donor histopathology were analyzed by Kaplan-Meier analysis. RESULTS: We found an association between donor liver fibrosis and patient survival (p = 0.016) as well as between graft survival and portal inflammation in the donor liver (p = 0.026). Both these associations remained significant in multivariate analysis (p = 0.007 and 0.017 respectively). Moreover, recipient age over 60 was found predictive of patient survival and repeated steroid boluses or steroid-resistant rejection of graft survival. Donor age was high throughout the study period. CONCLUSION: Histopathological features, especially portal inflammation and stage of fibrosis, in the donor liver may deleteriously affect graft and patient survival following HCV-related liver transplantation. Thus, pretransplant evaluation of donor histopathology may be of value in the selection of donors for transplantation of HCV-positive individuals, especially among donors older than 60 years. PMID- 22452367 TI - The impact of pre-operative focused transthoracic echocardiography in emergency non-cardiac surgery patients with known or risk of cardiac disease. AB - This prospective observational study investigated the effect of focused transthoracic echocardiography in 99 patients who had suspected cardiac disease or were >= 65 years old, and were scheduled for emergency non-cardiac surgery. The treating anaesthetist completed a diagnosis and management plan before and after transthoracic echocardiography, which was performed by an independent operator. Clinical examination rated cardiac disease present in 75%; the remainder were asymptomatic. The cardiac diagnosis was changed in 67% and the management plan in 44% of patients after echocardiography. Cardiac disease was identified by echocardiography in 64% of patients, which led to a step-up of treatment in 36% (4% delay for cardiology referral, 2% altered surgery, 4% intensive care and 26% intra-operative haemodynamic management changes). Absence of cardiac disease in 36% resulted in a step-down of treatment in 8% (no referral 3%, intensive care 1% or haemodynamic treatment 4%). Pre-operative focused transthoracic echocardiography in patients admitted for emergency surgery and with known cardiac disease or suspected to be at risk of cardiac disease frequently alters diagnosis and management. PMID- 22452368 TI - Engineering of bone using porous calcium phosphate cement and bone marrow stromal cells for maxillary sinus augmentation with simultaneous implant placement in goats. AB - The aim of this study was to explore the effects of maxillary sinus floor elevation and simultaneous dental implantation with a tissue-engineered bone complex of calcium phosphate cement (CPC) scaffolds combined with bone marrow stromal cells (BMSCs). A large animal goat model is used with the tissue engineering method. Eighteen bilateral maxillary sinus of nine goats were randomly allocated into three groups; the CPC/BMSC complex (n=6) was used to elevate maxillary sinus floor with a simultaneous implant placement; the effects were compared with those treated with CPC alone (n=6) or autogenous bone (n=6). After a healing period of 3 months, sequential triad-color fluorescence labeling, micro-CT, as well as histological and histomorphometric analyses indicated that the tissue-engineered BMSC/CPC complex could promote earlier bone formation and mineralization, and maximally maintain the volume and height of the augmented maxillary sinus. By comparison, CPC-alone or autogenous bone achieved less bone formation and later mineralization. Besides, the average bone-implant contact value reflecting the osseointegration was 35.63%+/-9.42% in the BMSCs/CPC group, significantly higher than 22.47%+/-4.28% in the CPC-alone group or 28.26%+/-8.03% in the autogenous bone group. In conclusion, CPC serves as a potential substrate for BMSCs for the maxillary sinus floor augmentation and simultaneous implantation. The tissue-engineered bone might enhance the stability of implants and thus be of great significance to achieve improved quality to restore the oral function in clinic. PMID- 22452370 TI - Association of thrombophilia and polycystic ovarian syndrome in women with history of recurrent pregnancy loss. AB - PURPOSE: To evaluate the prevalence of thrombophilic disorders in polycystic ovarian syndrome (PCOS) women with history of recurrent pregnancy loss (RPL). MATERIALS AND METHODS: This study was carried out in 184 women with history of RPL, of which 92 of them were diagnosed with PCOS and 92 patients were without known PCOS. The prevalence of thrombophilic disorders was compared between the two mentioned groups. RESULTS: According to the findings, 70.7% of PCOS women with history of RPL had thrombophilic disorders. The prevalence of protein C deficiency was significantly higher in PCOS group compared to the non-PCOS group (21.7% vs. 10.9%, p = 0.04). There was a trend toward higher prevalence of protein S deficiency in PCOS group compared to the control group, but the difference did not reach statistical significance (23.9% vs. 13%, p = 0.05). The prevalence of other thrombophilic disorders such as antithrombin III deficiency, homocysteine elevation, antiphospholipid antibody and Factor V Leiden was comparable between groups. CONCLUSION: The prevalence of thrombophilic disorders was more common in PCOS women than the normal group. The protein C deficiency is associated with PCOS in women with history of RPL. There was a trend toward higher prevalence of protein S deficiency in PCOS women, which needs further study. PMID- 22452371 TI - Prediction of segmental lean mass using anthropometric variables in young adults. AB - The aim of the present study was to develop and cross-validate anthropometrical prediction equations for segmental lean tissue mass (SLM). One hundred and seventeen young healthy Caucasians (67 men and 50 women; mean age: 31.9 +/- 10.0 years; Body Mass Index: 24.3 +/- 3.2 kg . m(-2)) were included. Body mass (BM), stretch stature (SS), 14 circumferences (CC), 13 skinfolds (SF) and 4 bone breadths (BB) were used as anthropometric measurements. Segmental lean mass of both arms, trunk and both legs were measured by dual energy X-ray absorptiometry as the criterion method. Three prediction equations for SLM were developed as follows: arms = 40.394(BM) + 169.836(CCarm-tensed) + 399.162(CCwrist) - 85.414(SFtriceps) - 39.790(SFbiceps) - 7289.190, where Adj.R (2) = 0.97, P < 0.001, and standard error of estimate (SEE) = 355 g;trunk = 181.530(BM) + 155.037(SS) + 534.818(CCneck) + 175.638(CCchest) - 88.359(SFchest) - 147.232(SFsupraspinale) - 46522.165, where Adj.R(2) = 0.97, P < 0.001, and SEE = 1077g; and legs = 55.838(BM) + 88.356(SS) + 235.579(CCmid-thigh) + 278.595(CCcalf) + 288.984(CCankle) - 84.954(SFfront-thigh) - 53.009(SFmedial calf) - 28522.241, where Adj.R (2) = 0.96, P < 0.001, and SEE = 724 g. Cross validation statistics showed no significant differences (P < 0.05) between observed and predicted SLM. Root mean squared errors were smallest for arms (362 g), followed by legs (820 g) and trunk (1477 g). These new prediction equations allow an accurate estimation of segmental lean mass in groups of young adults, but estimation errors of 8 to 14% can occur in certain individuals. PMID- 22452372 TI - Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus - insights into its mechanisms of action. AB - A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARgamma activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARgamma activity, such as obesity and atherosclerosis. LINKED ARTICLE: This article is a commentary on Lin et al., pp. 2212-2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x. PMID- 22452373 TI - Persistent atrial fibrillation is associated with a poor prognosis in patients with atrioventricular block and dual-chamber pacemaker. AB - BACKGROUND: The prognostic significance of development of persistent atrial fibrillation (AF) in patients with atrioventricular (AV) block and dual chamber (DDD) pacemakers has not been separately investigated. We sought to determine whether persistent AF influences clinical outcome in these patients. METHODS: Three hundred-eight consecutive patients with second- or third-degree AV block and implanted a DDD pacemaker were followed for 36 +/- 20 months and retrospectively divided into two groups. Thirty-four patients who developed persistent AF formed persistent AF group, and 278 patients who remained free of this arrhythmia control group. Clinical and outcome data of the two groups were compared. The primary outcome was cardiovascular death. RESULTS: The primary outcome occurred more often among the patients in the persistent AF group (6.8% per year) than among those in the control group (2.9% per year; P = 0.028). This difference was primarily because of higher rate of heart failure-related deaths in the persistent AF group (P = 0.009). Secondary outcomes, hospitalization for heart failure and paroxysmal AF episode >=5 minutes, occurred also more often among the patients in the persistent AF group (P = 0.008 and P < 0.001, respectively), although the risk of nonfatal stroke was similar in both groups (P = 0.628). CONCLUSION: In patients with second- or third-degree AV block and DDD pacemaker, the development of persistent AF is associated with an increased risk of cardiovascular death and heart failure. PMID- 22452375 TI - Current status of pharmacotherapy against metastatic renal cell carcinoma in Japan. AB - So far, metastatic renal cell carcinoma has been one of the most treatment resistant cancers. The extensive use of cytokines, such as interferon-alpha and interleukin-2, were carried out for metastatic renal cell carcinoma. However, significant advances in understanding the molecular mechanisms underlying renal cell carcinoma have led to the development of molecular target-based drugs, which were desperately awaited for a long time, and now two types of molecular target based drugs are available. Two vascular endothelial growth factor receptor tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors have been approved and available in Japan. The molecular target-based drugs have unique and characteristic adverse events, whose profile are not well understood in Japanese patients, because most of the clinical trials were carried out in Europe and America. In contrast, immunotherapy is being reconsidered in the selection of more appropriate patients or as a combined treatment form with other drugs, because of few complete responses obtained and unexpected adverse events by molecular targeted treatments. We have several molecular targeted-drugs available at present and will have more, and we will actually use these drugs in various clinical settings, such as the presurgical setting, the adjuvant setting, sequential administration and combined administration, in addition to cytokines. Therefore, we need more elaborate studies to obtain the optimal treatment methods to maximize the effect of such agents to extend overall survival while maintaining quality of life of metastatic renal cell carcinoma patients. In this article, we reviewed the issues related to the current status of pharmacotherapy available for metastatic renal cell carcinoma. PMID- 22452376 TI - Editorial comment to poorly differentiated neuroendocrine carcinoma of the seminal vesicle. PMID- 22452377 TI - The 7th American Urological Association and the Japanese Urological Association international affiliate society meeting. PMID- 22452378 TI - Cell targeting peptide conjugation to siRNA polyplexes for effective gene silencing in cardiomyocytes. AB - To deliver siRNA specifically to cardiomyocytes with a high transfection efficiency, primary cardiomyocyte-targeting (PCM) and/or cell-penetrating (Tat) peptides were incorporated into the siRNA. With the addition of plasmid DNA, these peptide-conjugated siRNAs were able to form compact and stable nanosized polyplex particles with bioreducible poly(CBA-DAH). The peptide-modified siRNA polyplexes enhanced the cellular uptake and the gene-silencing capacity of the siRNA in cardiomyocytes without significant immunogenicity or cytotoxicity. These findings demonstrate that the cell-targeting peptide and/or cell-penetrating peptide conjugation of siRNA may be a potentially important strategy for cell specific gene therapy in gene-mediated disease states. PMID- 22452379 TI - An appeal to medical journal editors: the need for a full description of laboratory methods and specimen handling in clinical study reports. PMID- 22452380 TI - Dimeric 1,3-phenylene-bis(piperazinyl benzimidazole)s: synthesis and structure activity investigations on their binding with human telomeric G-quadruplex DNA and telomerase inhibition properties. AB - Ligand-induced stabilization of G-quadruplex structures formed by the human telomeric DNA is an active area of research. The compounds which stabilize the G quadruplexes often lead to telomerase inhibition. Herein we present the results of interaction of new monomeric and dimeric ligands having 1,3-phenylene bis(piperazinyl benzimidazole) unit with G-quadruplex DNA (G4DNA) formed by human telomeric repeat d[(G(3)T(2)A)(3)G(3)]. These ligands efficiently stabilize the preformed G4DNA in the presence of 100 mM monovalent alkali metal ions. Also, the G4DNA formed in the presence of low concentrations of ligands in 100 mM K(+) adopts a highly stable parallel-stranded conformation. The G-quadruplexes formed in the presence of the dimeric compound are more stable than that induced by the corresponding monomeric counterpart. The dimeric ligands having oligo-oxyethylene spacers provide much higher stability to the preformed G4DNA and also exert significantly higher telomerase inhibition activity. Computational aspects have also been discussed. PMID- 22452381 TI - Compared outcomes of very preterm infants born in 2000 and 2005. AB - AIM: To compare neonatal and 2-year outcomes in very premature infants born 5 years apart. METHODS: Prospective observational study of infants born before 33 weeks' gestation in 2000 or 2005 admitted to a neonatal intensive care unit in France. We collected perinatal data and evaluated motor, cognitive, neurosensory and behavioural outcomes at 2 years of age. RESULTS: We included 170 infants in 2000 and 173 in 2005. The significant differences in neonatal outcomes were decreases in postnatal corticosteroid use and in percentage of infants with head circumference below the 3rd percentile on days 7 (25% vs. 13%) and 30 (30% vs. 17%). At 2 years of age, rates of follow-up were 87% in 2000 and 94% in 2005. The cerebral palsy rate was 6% in both cohorts. The overall rate of motor disabilities diminished from 30% (41/137) to 18% (26/142), and the rate of mild motor disabilities decreased from 24% to 12%. Rates of cognitive, behavioural and neurosensorial impairments were similar. CONCLUSION: Between 2000 and 2005, motor impairments at 2 years of age diminished in very preterm children (but not cerebral palsy rates). We observed a reduced use of postnatal corticosteroids and a decreased percentage of neonates with head circumference below the third percentile. PMID- 22452382 TI - New reconstructive technologies after decompressive craniectomy in traumatic brain injury: the role of three-dimensional titanium mesh. AB - Functional and aesthetic reconstruction after wide decompressive craniectomy directly correlates with subsequent quality of life. Advancements in the development of biomaterials have now made three-dimensional (3-D) titanium mesh a new option for the repair of skull defects after craniectomy. The purpose of this study was to review aesthetic and surgical outcomes and complications of patients who had skull defects repaired with 3-D titanium mesh. The records of 40 adult patients (31 unilateral craniectomies and 9 bilateral craniectomies) who underwent a computer-assisted designed titanium mesh implant at a university hospital from January 2008 to January 2010 were retrospectively reviewed. Aesthetic outcomes, cranial nerve V and VII function, and complications (hardware extrusions, meningitis, osteomyelitis, brain abscess, and pneumocephalus) were evaluated. The craniofacial symmetry, implant stability, and functional outcomes were excellent for all patients. No patients had trigeminal or facial dysfunction. All had excellent cosmetic results as measured by post-reduction radiographs and personal and family perceptions of the forehead contour. Two patients had delayed wound healing and subsequent subclinical wound infections, which resolved after treatment with antibiotics for 2 weeks. Craniofacial skeletal reconstruction with 3-D titanium mesh results in excellent forehead contour and cosmesis, and subsequently a better quality of life with few complications. Titanium mesh reconstruction offers a favorable alternative to other graft materials in the repair of large skull defects. PMID- 22452383 TI - Advanced cancer patients' self-assessed physical and emotional problems on admission and discharge from hospital general wards--a questionnaire study. AB - Most cancer patients receiving life-prolonging or palliative treatment are offered non-specialist palliative services. There is a lack of knowledge about their problem profile. The aim of this article is to describe the incidence of patient-reported physical and emotional problems on admission and discharge from general hospital wards and health staff's reported intervention. A prospective study was undertaken over 12 months, where advanced cancer patients completed a patient questionnaire, EORTC QLQ C15-PAL, on admission (n= 97) and discharge (n= 46). The incidences of the problems were dichotomised in intensity categories. The average number of 'clinically relevant problems' on admission was 5 (SD 2) and on discharge 4 (SD 2). A Wilcoxon signed rank test showed significant change in mean score for six out of nine problem areas, but the majority of the patients did not move to the lower intensity category. The highest concurrence was between patient-reported problems and reported intervention for physical function, pain, constipation and loss of appetite. Palliative cancer patients' self-reported problem profile on admission and discharge from hospital has not previously been described and the results indicate a need to focus on improvements to palliative services and for a special service for pain and constipation that could prevent some admissions. PMID- 22452384 TI - Developing standards of care for HIV prevention research in developing countries - a case study of 10 research centers in Eastern and Southern Africa. AB - Standards of care provided to volunteers in HIV prevention research in developing countries are evolving. Inconsistency in standards, particularly within a research network highlights the need to balance volunteers' health and wellness with the efficient conduct of research. Ten research centers (RC's) in East and Southern Africa affiliated with the International AIDS Vaccine Initiative (IAVI) were studied using a mixed methods approach to understand variations, similarities and gaps in services provided, recipients of services, referral systems, and barriers to referral uptake. These data were then used to develop expected standards across the 10 RCs. Findings indicated that RCs consistently provided HIV risk reduction and family planning (FP) counseling, male condoms, management of sexually transmitted infections, CD-4 counts, and general medical care to volunteers and non-research volunteers. Services that were less consistently provided on-site included: female condoms, adult male circumcision (AMC), antiretroviral therapy (ART) and post-exposure prophylaxis (PEP) in case of rape. The FP options provided on-site varied, with few providing implants, intrauterine devices, tubal ligation, and vasectomy. Most RCs had established referral systems for ART, AMC, PEP, and FP, but few had referral points for psychosocial services. Few RCs had comprehensive guidelines on referrals other than those related to adverse events. Findings indicate that the greatest challenges for referral uptake were transportation and health care costs, poor quality and inconsistency of services at some referral points. Few RCs covered the cost of referrals for non-study related adverse events. A collaborative process between IAVI and the RCs was undertaken to reach consensus on expected standards of care. A set of required and recommended services to be provided on site or by referral was developed. In developing such standards, we tried to balance scientific priorities, equity, contextual realities, community expectations, and cost-effectiveness. PMID- 22452385 TI - The status of pharmacometrics in pregnancy: highlights from the 3(rd) American conference on pharmacometrics. AB - Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy. PMID- 22452386 TI - The diversity of microsporidia in parasitic copepods (Caligidae: Siphonostomatoida) in the Northeast Pacific Ocean with description of Facilispora margolisi n. g., n. sp. and a new Family Facilisporidae n. fam. AB - Three distinct microsporidia were identified from parasitic copepods in the northeast Pacific Ocean. Sequencing and phylogenetic analysis of a partial small subunit ribosomal RNA gene (SSU rDNA) sequence identified a genetically distinct variety of Desmozoon lepeophtherii from Lepeophtheirus salmonis on cultured Atlantic salmon Salmo salar, and this was confirmed by transmission electron microscopy. Phylogenetic analysis resolved the SSU rDNA sequence of the second organism in a unique lineage that was most similar to microsporidia from marine and brackish water crustaceans. The second occurred in L. salmonis on Atlantic, sockeye Oncorhynchus nerka, chum O. keta and coho O. kisutch salmon, in Lepeophtheirus cuneifer on Atlantic salmon, and in Lepeophtheirus parviventris on Irish Lord Hemilepidotus hemilepidotus. Replication occurred by binary fission during merogony and sporogony, diplokarya were not present, and all stages were in contact with host cell cytoplasm. This parasite was identified as Facilispora margolisi n. g., n. sp. and accommodated within a new family, the Facilisporidae n. fam. The third, from Lepeophtheirus hospitalis on starry flounder Platichthys stellatus, was recognized only from its unique, but clearly microsporidian SSU rDNA sequence. Phylogenetic analysis placed this organism within the clade of microsporidia from crustaceans. PMID- 22452387 TI - Mapping the excited states of single hexa-peri-benzocoronene oligomers. AB - Electronic states of a molecule are usually analyzed via their decomposition in linear superposition of multielectronic Slater determinants built up from monoelectronics molecular orbitals. It is generally believed that a scanning tunneling microscope (STM) is able to map those molecular orbitals. Using a low temperature ultrahigh vacuum (LT-UHV) STM, the dI/dV conductance maps of large single hexabenzocoronene (HBC) monomer, dimer, trimer, and tetramer molecules were recorded. We demonstrate that the attribution of a tunnel electronic resonance to a peculiar pi molecular orbital of the molecule (or sigma intermonomer chemical bond) in the STM junction is inappropriate. With an STM weak-measurement-like procedure, a dI/dV resonance results from the conductance contribution of many molecular states whose superposition makes it difficult to reconstruct an apparent molecular orbital electron probability density map. PMID- 22452388 TI - Impact of Mano a Mano-Mujer, an HIV prevention intervention, on depressive symptoms among Chilean women. AB - Worldwide, and in Chile, the number of women living with HIV is increasing. Depression is considered a factor that interferes with HIV prevention. Depression may reach 41% among low-income Chilean women. Depressed people are less willing to participate in behaviours that protect them against HIV. The aim of this study is to analyze the impact of Mano a Mano-Mujer (MM-M), and HIV prevention intervention, on depressive symptoms among Chilean women. A quasi-experimental design was used for this study. The research was conducted in Santiago, Chile; a total of 400 women participated in the study (intervention group, n=182; control group, n=218). The intervention was guided by the social-cognitive model and the primary health care model. The intervention consists of six 2-h sessions delivered in small groups. Sessions covered: HIV prevention, depression, partner's communication, and substance abuse. Face-to-face interviews were conducted at baseline and at 3-month follow-up. Chilean women who participated in MM-M significantly decreased, at 3 months follow up, their reported depressive symptoms. MM-M provided significant benefits for women's depression symptoms. In this study nurses participated as leaders for the screening of depressive symptoms and as facilitators of community interventions. PMID- 22452389 TI - Expression of cysteine protease cathepsin L is increased in endometrial cancer and correlates with expression of growth regulatory genes. AB - Proteases contribute to tumor invasion and metastasis by degrading basement membranes and extracellular matrix (ECM). In this study, we compared gene expression levels of two proteases, cysteine protease Cathepsin L2 (CTSL2) and matrix metalloproteinase MMP11, in human endometrium and endometrial cancer. Our data demonstrate CTSL2 transcript levels to be strongly elevated in endometrial cancer, particularly in G3 tumors. Furthermore, we observed a highly significant positive correlation of CTSL2 with expression of growth regulatory genes Ki-67, cyclin B1, MYBL2, p21/WAF, and HER2 receptor tyrosine kinase. Our data suggest that CTSL2 might be involved in progression of endometrial cancer. PMID- 22452390 TI - Removal of microbial multi-species biofilms from the paper industry by enzymatic treatments. AB - This study aimed to characterize biofilms from the paper industry and evaluate the effectiveness of enzymatic treatments in reducing them. The extracellular polymeric substances (EPS) extracted from six industrial biofilms were studied. EPS were mainly proteins, the protein to polysaccharide ratio ranging from 1.3 to 8.6 depending on where the sampling point was situated in the paper making process. Eight hydrolytic enzymes were screened on a 24-h multi-species biofilm. The enzymes were tested at various concentrations and contact durations. Glycosidases and lipases were inefficient or only slightly efficient for biofilm reduction, while proteases were more efficient: after treatment for 24 h with pepsin, Alcalase(r) or Savinase(r), the removal exceeded 80%. Savinase(r) appeared to be the most adequate for industrial conditions and was tested on an industrial biofilm sample. This enzyme led to a significant release of proteins from the EPS matrix, indicating its potential efficiency on an industrial scale. PMID- 22452391 TI - Dependence of the initial adhesion of biofilm forming Pseudomonas putida mt2 on physico-chemical material properties. AB - Bacterial adhesion is strongly dependent on the physico-chemical properties of materials and plays a fundamental role in the development of a growing biofilm. Selected materials were characterized with respect to their physico-chemical surface properties. The different materials, glass and several polymer foils, showed a stepwise range of surface tensions (gamma(s)) between 10.3 and 44.7 mN m(-1). Measured zeta potential values were in the range between -74.8 and -28.3 mV. The initial bacterial adhesion parameter q(max) was found to vary between 6.6 * 10(6) and 28.1 * 10(6) cm(-2). By correlation of the initial adhesions kinetic parameters with the surface tension data, the optimal conditions for the immobilization of Pseudomonas putida mt2 were found to be at a surface tension of 24.7 mN m(-1). Both higher and lower surface tensions lead to a smaller number of adherent cells per unit surface area. Higher energy surfaces, commonly termed hydrophilic, could constrain bacterial adhesion because of their more highly ordered water structure (exclusion zone) close to the surface. At low energy surfaces, commonly referred to as hydrophobic, cell adhesion is inhibited due to a thin, less dense zone (depletion layer or clathrate structure) close to the surface. Correlation of q (max) with zeta potential results in a linear relationship. Since P. putida carries weak negative charges, a measurable repulsive effect can be assumed on negative surfaces. PMID- 22452392 TI - Spectrophotometric color measurement for early detection and monitoring of greening on granite buildings. AB - This paper addresses the detection and monitoring of the development of epilithic phototrophic biofilms on the granite facade of an institutional building in Santiago de Compostela (NW Spain), and reports a case study of preventive conservation. The results provide a basis for establishing criteria for the early detection of phototrophic colonization (greening) and for monitoring its development on granite buildings by the use of color changes recorded with a portable spectrophotometer and represented in the CIELAB color space. The results show that parameter b* (associated with changes of yellowness-blueness) provides the earliest indication of colonization and varies most over time, so that it is most important in determining the total color change. The limit of perception of the greening on a granite surface was also established in a psycho-physical experiment, as Deltab*: +0.59 CIELAB units that correspond, in the present study, to 6.3 MUg of biomass dry weight cm(-2) and (8.43 +/- 0.24) * 10(-3) MUg of extracted chlorophyll a cm(-2). PMID- 22452393 TI - Artificial structures influence fouling on habitat-forming kelps. AB - The addition of artificial structures along urbanised shorelines is a global phenomenon. Such modifications of habitats have important consequences to the abundance of fouling organisms on primary substrata, but the influence on fouling of habitat-formers living on these structures is poorly understood. Fouling of habitat-forming kelps Ecklonia radiata on pier-pilings was compared to that on rocky reefs at three locations in Sydney Harbour. Kelps on pilings supported different assemblages of bryozoans from those on reefs. The abundances of bryozoans on kelps, in particular of the non-indigenous species Membranipora membranacea, were significantly greater on pilings. Differences were consistent in time and space. This indicates that the addition of artificial structures also affects fouling on secondary biogenic substrata, altering biodiversity and potentially facilitating the introduction and dispersal of non-indigenous epibiota. Understanding the processes that cause these patterns is necessary to allow sensible predictions about ecological effects of built structures. PMID- 22452394 TI - Lipid acquisition by intracellular Chlamydiae. AB - Chlamydia species are obligate intracellular pathogens that are important causes of human genital tract, ocular and respiratory infections. The bacteria replicate within a specialized membrane-bound compartment termed the inclusion and require host-derived lipids for intracellular growth and development. Emerging evidence indicates that Chlamydia has evolved clever strategies to fulfil its lipid needs by interacting with multiple host cell compartments and redirecting trafficking pathways to its intracellular niche. In this review, we highlight recent findings that have significantly expanded our understanding of how Chlamydia exploit lipid trafficking pathways to ensure the survival of this important human pathogen. PMID- 22452395 TI - Bifunctional compounds for controlling metal-mediated aggregation of the abeta42 peptide. AB - Abnormal interactions of Cu and Zn ions with the amyloid beta (Abeta) peptide are proposed to play an important role in the pathogenesis of Alzheimer's disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu(2+) and Zn(2+) and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Abeta species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Abeta(42) peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Abeta(42) oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Abeta(42) peptide-in contrast to the Abeta(40) peptide-the previously employed strategy of inhibiting Abeta aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Abeta(42) oligomers. PMID- 22452396 TI - Total synthesis of (-)-herbindoles A, B, and C via transition-metal-catalyzed intramolecular [2 + 2 + 2] cyclization between ynamide and diynes. AB - The total syntheses of (-)-herbindoles A, B, and C as naturally occurring forms were accomplished for the first time through transition-metal-catalyzed intramolecular [2 + 2 + 2] cyclization between ynamide and diynes. This strategy provided a highly efficient synthetic route to all three herbindoles from an identical indoline derivative as a common intermediate. PMID- 22452398 TI - Homozygous CYP17A1 mutation (H373L) identified in a 46,XX female with combined 17alpha-hydroxylase/17,20-lyase deficiency. AB - BACKGROUND: Defects in cytochrome P450c17 are uncommon forms of congenital adrenal hyperplasia caused by CYP17A1 mutations. An H373L mutation in the CYP17A1 gene has been identified in Japanese and Chinese patients. This mutation impairs 17alpha-hydroxylase and 17,20-lyase activity. CASE: A 23-year-old Korean female (46,XX) presented with absent spontaneous puberty and hypertension. Hormonal findings were consistent with combined 17alpha-hydroxylase/17,20-lyase deficiency. Very high levels of progesterone and 11-deoxycorticosterone were detected, coincident with normal 17-hydroxysteroid levels. Plasma levels of dehydroepiandrosterone, androstenedione and testosterone were extremely low. Mutation analysis of the CYP17A1 gene identified a homozygous missense mutation changing His (CAC) to Leu (CTC) at codon 373. This mutation is known to completely abolish both 17alpha-hydroxylase and 17,20-lyase activity. The patient's nonconsanguineous parents were heterozygous for this mutation. Of note, her serum steroid levels indicated decreased, but still present, 17alpha hydroxylase activity in vivo. CONCLUSION: We detected a homozygous H373L mutation in a patient with combined 17alpha-hydroxylase/17,20-lyase deficiency. Our findings demonstrate minimally preserved 17alpha-hydroxylase activity in vivo and contribute to our knowledge of the regional prevalence of this mutation in Northeast Asia. PMID- 22452399 TI - Polymorphism of the complement 5 gene and cardiovascular outcome in patients with atherosclerosis. AB - BACKGROUND: Humoral mediators of inflammation, in particular the complement system, have been described to play an important role in atherogenesis. Previously, we found a single-nucleotide polymorphism (SNP) in the complement 5 gene (C5 rs17611, A>G) independently associated with stroke. Up to now, the impact of C5 rs17611 on the progression of atherosclerosis and cardiovascular outcome in patients with asymptomatic atherosclerosis was unclear. MATERIALS AND METHODS: We investigated C5 rs17611 in a cohort of 1065 consecutive patients with asymptomatic carotid atherosclerosis. All patients were prospectively followed for the progression of carotid atherosclerosis and the development of a first major cardiovascular event (MACE), respectively. RESULTS: Three hundred and thirty-seven patients (31.6%) experienced a MACE during a median follow-up of 3.0 years. The homozygous GG genotype of the C5 rs17611 was significantly associated with adverse cardiovascular outcome (adjusted HR: 1.36 [95% CI, 1.07-1.73]; P = 0.01). After stratification for sex, C5 rs17611 CC was found to be an independent risk factor for MACE in men (HR 1.50 [95% CI, 1.12-1.83]). No association of C5 rs17611 with progression of carotid stenosis, observed in 93 (8.7%) patients, was detectable. Performance of ELISA indicated a significant association of the C5 rs17611 variant with C5a plasma levels. CONCLUSION: The C5 rs17611 GG genotype is associated with increased C5a plasma levels and represents a risk factor for adverse cardiovascular outcome in male patients with carotid atherosclerosis. PMID- 22452401 TI - In vivo cleavage rate of a dextran-bound magnetic resonance imaging contrast agent: preparation and intravascular pharmacokinetic characteristics in the rabbit. AB - Earlier described dextran-based contrast agents for magnetic resonance imaging (MRI) comprising the gadolinium chelate diethylenetriamine pentaacetic acid (GdDTPA, 1) have shown significantly shorter in vivo contrast duration in rat than what would be expected from the initial average molecular weight (Mw) of the dextran fraction (71.4 kD). To investigate this further, four dextran fractions with given initial average molecular weight (Mw) of 10.4, 41.0, 71.4 and 580 kD were used as starting material to prepare products 2-5 where one of the carboxylic acid functionalities in GdDTPA was used as a direct covalent ester linker to hydroxyl groups in dextrans. A fifth derivative (6) was an amide-ester bound beta-alanine-DTPAGd conjugate with dextran having Mw 71.4 kD. The reference compound GdDTPA (1) and gadoliniumlabelled dextran derivatives 2-6 were injected intravenously in rabbits. Pharmacokinetic parameters showed that when GdDTPA is ester-bound directly to dextran hydroxyls, the cleavage rates of 2-5 were only moderately dependent on the molecular weights of the dextrans, having blood pool half-lives comparable to the low-molecular reference compound (t 1/2,beta 0.3 - 0.5 hrs.). Presence of a beta-alanine spacer in 6 prolonged the plasma half-life t 1/2,beta to 6.9 hours, rendering a blood residence time suitable for blood pool slow release of GdDTPA. Biological cleavage regenerates the clinically acceptable carrier dextran and the beta-alanine derivative of GdDTPA, pointing at a clinically acceptable product class for blood-pool contrast in MRI. PMID- 22452402 TI - Active targeting strategies for anticancer drug nanocarriers. AB - Chemotherapy at present remains the main form of treatment for cancer, though there is no clinically available antineoplastic drug that acts selectively on the tumor mass. For this reason, the scientific research is focused towards the development of novel cancer therapies and drug delivery strategies, like drug targeting, that would enhance the therapeutic efficacy of drugs while reducing their side toxicity. This review describes tree types of nanoparticles used in active targeting for cancer treatment: liposomes, lipid and polymer nanoparticles, and micelles. The opportunities and challenges achieved by the proposed strategies of active targeting have been highlighted, as well as the necessity to conciliate the targeting efficiency of drug nanocarriers with their longevity in the bloodstream. PMID- 22452403 TI - An insight to osmotic drug delivery. AB - In a typical therapeutic regimen the drug dose and the dosing interval are optimized to maintain drug concentration within the therapeutic window, thus ensuring efficacy while minimizing toxic effects. For many decades treatment of acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. The immediate release conventional dosage form does not provide the proper plasma concentration of drug for prolonged period. This results in the development of various controlled drug delivery system. Among which the osmotic drug delivery systems (ODDS) are gaining importance as these systems deliver the drug at specific time as per the path physiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. They work on the principle of osmotic pressure for controlling the delivery of the drug. Osmotic drug delivery systems with their versatility and their highly predictable drug release rates offer various biomedical advantages when given parenterally like reduced dose, targeting of site, avoiding gastrointestinal stability, hepatic bypass of drug molecule and follows zero order kinetics. Osmosis is an aristocratic phenomenon that seizes the attention for its exploitation in zero-order drug delivery systems. The release of the drug is independent of pH and physiological factors of the GIT to a large extent. Optimizing semi-permeable membrane characteristics and osmotic agent can modulate delivery of drug from the system. This review highlights the theoretical concept of drug delivery, history, types of oral osmotic drug delivery systems, factors affecting the drug delivery system, advantages and disadvantages of this delivery system, theoretical aspects, applications, and the marketed status. PMID- 22452404 TI - In vitro drug permeation enhancement potential of aloe gel materials. AB - Aloe vera gel previously showed the ability to increase the bioavailability of vitamins and to enhance the in vitro transport of a macromolecular drug across intestinal epithelial cell monolayers. The purpose of this study is to investigate the potential of other species of aloe to act as drug absorption enhancement agents. The effect of gel materials from three South African aloes; Aloe ferox, A. marlothii and A. speciosa on the transepithelial electrical resistance and permeability of atenolol across excised intestinal tissue of the rat as well as the transport of FITC-dextran across Caco-2 cell monolayers was investigated. The aloe gel materials exhibited the ability to statistically significantly reduce the transepithelial electrical resistance of excised rat intestinal tissue but did not significantly increase the transport of atenolol across this in vitro tissue model at the concentrations tested. At least one concentration of each aloe gel material enhanced the transport of FITC-dextran statistically significantly across Caco-2 cell monolayers. The aloe gel materials showed potential to act as drug absorption enhancing agents across intestinal epithelia. The absorption enhancement effect was dependent on the type of in vitro model and type of drug was investigated. PMID- 22452405 TI - Synthesis and characterization of carboxymethyl chitosan hydrogel: application as pH-sensitive delivery for nateglinide. AB - In current research, chitosan was reacted with mono-chloroacetic acid under alkaline condition to prepare carboxymethyl chitosan (CMCTs). The degree of substitution (Ds) on prepared CMCTs was found to be 0.68. CMCTs was used as a potential carrier for pH specific delivery of nateglinide after crosslinked using glutaraldehyde in presence of nateglinide. The average molecular weight and degree of deacetylation (DD) of chitosan were found to be 3.5x104 Da and 84.6% respectively. High yield (82%) and loading of drug (75%) were found in the developed hydrogel formulations. pH responsive swelling behavior of prepared hydrogels was checked using different pH values (1.2, 6.8 and 7.4). The study indicated very less swelling at pH 1.2 (for first 2 h) and quick swelling at pH 6.8 (for next 3 h) followed by linear swelling at pH 7.4 (for next 7 h) with slight increase. In vitro release profile of hydrogels showed biphasic release pattern dependent on swelling behavior. The release pattern was found to be non fickian diffusion kinetics at higher pH. FTIR, 1H-NMR, DSC and p-XRD studies were carried out to confirm the formation of CMCTs, drug entrapment and its possible interaction in formulations. These studies revealed that no chemical change was found in nateglinide during preparation of hydrogel formulations. Scanning Electron Microscopy (SEM) was used to study the surface morphology of prepared hydrogels before and after dissolution which revealed pores formation after dissolution. PMID- 22452406 TI - Bioactive diopside (CaMgSi(2)O(6)) as a drug delivery carrier - a review. AB - The bone infections are the most divesting complications confronted by the physicians and patients. The antibiotic loaded bone cements, such as synthetic ceramics and natural ceramics were accepted for bone infections. The currently available bone cements were not accepted due to the lack of mechanical strength, porosity and quick degradation rate etc. The major aim of this review is to discuss about several different synthetic methods used to prepare the bioactive diopside (CaMgSi(2)O(6)) and its applications in ceramic drug delivery systems for controlled and targeted delivery. It has been reported from various research articles, diopside was mainly used for bone tissue regeneration, dentistry, orthopedics and enzyme delivery matrices with different formulations. Compared to other bioceramics diopside is preferable due to its biocompatibility and high mechanical strength. PMID- 22452407 TI - Controlled release of insulin in blood from strontium-substituted carbonate apatite complexes. AB - Diabetes mellitus is a chronic disease accompanied by a multitude of problems worldwide with subcutaneously administered insulin being the most common therapy currently. Controlledrelease insulin is assumed to be of high importance for long term glycaemic control by reducing the number of daily injections. Long-acting insulin also mimics the basal insulin levels in normal individuals that may be lacking in diabetic patients. Nanoparticles of carbonate apatite as established for efficient intracellular transport of DNA and siRNA have the potential to be used for sustained release of insulin as responsive nano-carriers. The flexibility in the synthesis of the particles over a wide range of pHs with eventual adjustment of pH-dependent particle dissolution and the manageable variability of particle-integrity by incorporating selective ions into the apatite structure are the promising features that could help in the development of sustained release formulations for insulin. In particular strontium incorporated carbonate apatite particles were formulated and compared with those of unsubstituted apatite in the context of insulin binding and subsequent release kinetics in DMEM, simulated buffer and finally human blood over a period of 20 hours. Clearly, the former demonstated to have a stronger electrostatic affinity towards the acidic insulin molecules and facilitate to some extent sustained release of insulin by preventing the initial burst effect at physiological pH in comparison with the latter. Thus, our findings suggest that optimization of the carbonate apatite particle composition and structure would serve to design an ideal insulin nano-carrier with a controlled release profile. PMID- 22452408 TI - Comparative studies of lamivudine-zidovudine nanoparticles for the selective uptake by macrophages. AB - The present study investigates the specific drug targeting of anti retroviral drugs, such as lamivudine and zidovudine, after intraperitoneal (i.p) injection by incorporation into polymeric nanoparticles (PNs) and solid lipid nanoparticles (SLNs). Our results showed that Glyceryl Monosterate-Poloxamer 188 SLNs (average diameter of 522.466 nm) showed slow drug release rates (63.18% of lamivudine and 62.37% of zidovudine were released in 12 hrs) among all the SLN formulations. For Poly lactic-co-glycolic acid (PLGA)-Poloxamer 188 PNs (average diameter of 70.348 nm), there were faster release rates of both lamivudine and zidovudine (97% and 94.06%, respectively, in 12 hrs). Tissue distribution studies were carried out in mice and concentrations of drugs in different organs were determined using high performance liquid chromatography (HPLC) after i.p. administration. Glyceryl Monosterate-Poloxamer 188 SLNs and PLGA-Poloxamer 188 PNs showed increase in the distribution of lamivudine and zidovudine to liver and spleen when compared to the drugs in solution. Also, Glyceryl Monosterate-P 188 SLNs showed higher concentration of drugs in RES organs than PLGA-P 188 PNs. PMID- 22452409 TI - Effect of bioimpedance body composition analysis on function of implanted cardiac devices. AB - BACKGROUND: It is routinely recommended that patients with pacemakers, implantable cardioverter defibrillators (ICD), and cardiac resynchronization therapy-defibrillators (CRT-D) avoid bioelectrical impedance analysis (BIA)--a commonly used method to estimate body composition--because of the concern for the potential for BIA interference with pacemaker or ICD function. However, the prevalence of such interference is not known. OBJECTIVE: Assess for incidence of interference between BIA and ICD or CRT-D devices. METHODS AND RESULTS: Twenty patients with heart failure and cardiac implanted electronic devices (50% ICD, 50% CRT-D) underwent BIA during real-time device interrogation to detect interference. Study patients were 90% male, with mean age 54 +/- 14 years, and mean LVEF 23 +/- 11%. Devices from all four leading cardiac device manufacturers were included. Device therapies were temporarily disabled to prevent inappropriate shocks. During body composition testing using BIA, no evidence of interference with ICD function was seen in any patient, including no telemetry disruption, no oversensing on any lead, and no patient symptoms. CONCLUSIONS: Despite the manufacturers' recommendation to avoid BIA in patients with ICDs, this study showed no evidence of any interference in 20 patients. Bioimpedance analysis might be safe in such patients, but further confirmatory studies are required. PMID- 22452410 TI - Late onset renal failure and nephrotic syndrome after autologous stem cell transplant for Al amyloidosis. AB - We present a patient with AL amyloidosis who had an autologous stem cell transplant (ASCT) over 9 years ago. She has since then developed slowly progressive renal insufficiency and the nephrotic syndrome. Hematologic evaluation has failed to identify recurrent disease and a renal biopsy demonstrated extensive amyloid deposition and substantial glomerulosclerosis. We suggest that the patient has chronic glomerulosclerosis as a consequence of renal damage associated with her disease process and her treatment. PMID- 22452411 TI - 99mTc-labeled RGD-BBN peptide for small-animal SPECT/CT of lung carcinoma. AB - We recently designed and synthesized a Glu-c(RGDyK)-bombesin (RGD-BBN) heterodimeric peptide exhibiting a dual integrin alpha(v)beta(3) and gastrin releasing peptide receptor (GRPR) targeting property. In this study, we investigated whether (99m)Tc-labeled RGD-BBN peptide could be used for the noninvasive detection of lung carcinoma by using small-animal single-photon emission computed tomography (SPECT)/CT. RGD-BBN peptide was conjugated with 6 hydrazinonicotinyl (HYNIC) and then radiolabeled with (99m)Tc using tricine and TPPTS as the coligands (TPPTS = trisodium triphenylphosphine-3,3',3" trisulfonate). The biodistribution, planar gamma imaging, and small-animal SPECT/CT studies of (99m)Tc-HYNIC(tricine)(TPPTS)-RGD-BBN ((99m)Tc-RGD-BBN) were performed in C57/BL6 mice bearing Lewis lung carcinoma (LLC) or bearing both inflammation and LLC. HYNIC-RGD-BBN possessed a dual integrin alpha(v)beta(3) and GRPR binding capacity. (99m)Tc-RGD-BBN was prepared with a high radiochemical purity (>98%), and it exhibited specific tumor imaging with high contrast to the contralateral background. (99m)Tc-RGD-BBN was superior to (18)F-FDG for distinguishing lung carcinoma from inflammation. The uptake of (99m)Tc-RGD-BBN in LLC xenografts was 2.69 +/- 0.66% ID/g at 1 h postinjection (p.i.) and was decreased to 1.99 +/- 0.61% ID/g at 2 h p.i. The inflammation uptake of (99m)Tc RGD-BBN was 1.20 +/- 0.32% ID/g at 1 h and 0.56 +/- 0.17% ID/g at 2 h p.i., respectively. High pancreas uptake (25.76 +/- 5.49%ID/g and 19.56 +/- 6.78% ID/g at 1 and 2 h p.i., respectively) was also found due to the high GRPR expression of this organ. Small-animal SPECT/CT using (99m)Tc-RGD-BBN can specifically detect the LLC pulmonary metastases. Our results suggested that SPECT/CT with (99m)Tc-RGD-BBN would provide an effective approach for the noninvasive detection of lung cancer. PMID- 22452412 TI - Structure-activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter P glycoprotein. AB - The drug efflux pump P-glycoprotein (P-gp) has been shown to promote multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. Here we synthesized and tested a series of benzophenone derivatives structurally analogous to propafenone-type inhibitors of P-gp. Some of the compounds showed ligand efficiency and lipophilic efficiency (LipE) values in the range of compounds which entered clinical trials as MDR modulators. Interestingly, although lipophilicity plays a dominant role for P-gp inhibitors, all compounds investigated showed LipE values below the threshold for promising drug candidates. Docking studies of selected analogues into a homology model of P glycoprotein suggest that benzophenones show an interaction pattern similar to that previously identified for propafenone-type inhibitors. PMID- 22452413 TI - Effects of hypothermia on NSE and S-100 protein levels in CSF in neonates following hypoxic/ischaemic brain damage. AB - AIM: The aim of the study was to evaluate the effects of hypothermia on neuron specific enolase (NSE) and S-100 protein levels in cerebrospinal fluid (CSF) in neonates with hypoxic/ischaemic encephalopathy (HIE). METHODS: Fifty-one enrolled neonates with HIE were divided into two groups: hypothermia (n = 23) and control (n = 28). NSE and S-100 protein were measured with immunoradiometric assays. Amino acid neurotransmitters were also measured by reversed-phase high performance liquid chromatography. Neurodevelopmental assessments were performed at 3 and 12 months of age. RESULTS: Neuron-specific enolase and S-100 levels were lower, and neurodevelopment outcome was better in the hypothermia group compared with the control group. Among the infants who received hypothermia, CSF NSE and S 100 were significantly higher in those who developed severe neurological impairment (mental development index or physical development index <70). There were no significant differences between the two groups in amino acid neurotransmitters. CONCLUSION: These results indicated that hypothermia was associated with decreased CSF NSE and S-100 level and correlated with neurodevelopmental outcome in infants with HIE. PMID- 22452414 TI - Redescription of Rhizodomus tagatzi (Ciliophora: Spirotrichea: Tintinnida), based on morphology and small subunit ribosomal RNA gene sequence. AB - Herein, we redescribe a tintinnid ciliate that is most commonly known as Tintinnopsis corniger Hada, 1964; but it has been described several times with different names, specifically Tintinnopsis nudicauda Paulmier, 1997 and Rhizodomus tagatzi Strelkow & Wirketis, 1950. Neotype material was collected from the water column of the coastal saline Lake Faro, a meromictic basin connected to the Straits of Messina, Central Mediterranean. The Lake Faro population is characterized by a hyaline or sparsely agglomerated lorica, which made it possible to observe in detail the basal layer structure, usually concealed by abundant incrusting particles. Along with an improved description of the lorica, we provide novel information, such as the general zooid morphology, the ciliary pattern, and the small subunit rRNA (SSU rRNA) gene sequence. Our phylogenetic analysis, based on the SSU rRNA, groups this species with Tintinnopsis radix, while the first taxonomic study designated it as R. tagatzi, introducing a new genus due to peculiarities in lorica morphology. We conclude that the species should be known as R. tagatzi, the senior synonym for the species. However, we do not transfer any other species to this genus, despite strong molecular similarities. Although it is obvious that the genus Tintinnopsis is in need of a thorough revision, current molecular and cytological information for this genus is too sparse, and the type species has not yet been redescribed with modern methods. PMID- 22452416 TI - Evaluation of Candida albicans adhesion and biofilm formation on a denture base acrylic resin containing silver nanoparticles. AB - AIM: This study firstly evaluated the activity of a silver nanoparticle (AgNPs) solution against Candida albicans and then the effect of incorporation of AgNPs into a denture base acrylic resin on the material's hydrophobicity, C. albicans adhesion and biofilm formation. METHODS AND RESULTS: The AgNPs solution was synthesized by chemical reduction and characterized. Minimum inhibitory (MIC) and minimum fungicidal (MFC) concentrations for planktonic cells and sessile cells (MFCs) of the AgNPs solution against C. albicans were determined. Specimens (n = 360) of silver-incorporated acrylic resin at concentrations of 1000, 750, 500, 250 and 30 ppm were also prepared and stored in PBS for 0, 7, 90 and 180 days. Control was acrylic resin without AgNPs (0 ppm). After the storage periods, contact angles were measured and the specimens were used for C. albicans adherence (37 degrees C; 90 min; n = 9) and biofilm formation (37 degrees C; 48 h; n = 9) by XTT reduction assay. MIC, MFC and MFCs values were 3.98, 15.63 and 1000 ppm, respectively. Incorporation of AgNPs reduced the hydrophobicity of the resin. No effect on adherence and biofilm formation was observed. At 90 and 180 days of storage, there was significant increase in adherence and biofilm formation. CONCLUSIONS: Although the AgNPs solution had antifungal activity, no effect on C. albicans adherence and biofilm formation was observed after its incorporation into a denture base resin. SIGNIFICANCE AND IMPACT OF THE STUDY: The synthesized AgNPs solution is a promising antifungal agent, warranting investigations of more efficient methods of incorporation into denture base resins. PMID- 22452415 TI - Review: a critical evaluation of arguments opposing male circumcision for HIV prevention in developed countries. AB - A potential impediment to evidence-based policy development on medical male circumcision (MC) for HIV prevention in all countries worldwide is the uncritical acceptance by some of arguments used by opponents of this procedure. Here we evaluate recent opinion-pieces of 13 individuals opposed to MC. We find that these statements misrepresent good studies, selectively cite references, some containing fallacious information, and draw erroneous conclusions. In marked contrast, the scientific evidence shows MC to be a simple, low-risk procedure with very little or no adverse long-term effect on sexual function, sensitivity, sensation during arousal or overall satisfaction. Unscientific arguments have been recently used to drive ballot measures aimed at banning MC of minors in the USA, eliminate insurance coverage for medical MC for low-income families, and threaten large fines and incarceration for health care providers. Medical MC is a preventative health measure akin to immunisation, given its protective effect against HIV infection, genital cancers and various other conditions. Protection afforded by neonatal MC against a diversity of common medical conditions starts in infancy with urinary tract infections and extends throughout life. Besides protection in adulthood against acquiring HIV, MC also reduces morbidity and mortality from multiple other sexually transmitted infections (STIs) and genital cancers in men and their female sexual partners. It is estimated that over their lifetime one-third of uncircumcised males will suffer at least one foreskin related medical condition. The scientific evidence indicates that medical MC is safe and effective. Its favourable risk/benefit ratio and cost/benefit support the advantages of medical MC. PMID- 22452417 TI - The role of self-injury in the organisation of behaviour. AB - BACKGROUND: Self-injuring acts are among the most dramatic behaviours exhibited by human beings. There is no known single cause and there is no universally agreed upon treatment. Sophisticated sequential and temporal analysis of behaviour has provided alternative descriptions of self-injury that provide new insights into its initiation and maintenance. METHOD: Forty hours of observations for each of 32 participants were collected in a contiguous 2-week period. Twenty categories of behavioural and environmental events were recorded electronically that captured the precise time each observation occurred. Temporal behavioural/environmental patterns associated with self-injurious events were revealed with a method (t-patterns; THEME) for detecting non-linear, real-time patterns. RESULTS: Results indicated that acts of self-injury contributed both to more patterns and to more complex patterns. Moreover, self-injury left its imprint on the organisation of behaviour even when counts of self-injury were expelled from the continuous record. CONCLUSIONS: Behaviour of participants was organised in a more diverse array of patterns when self-injurious behaviour was present. Self-injuring acts may function as singular points, increasing coherence within self-organising patterns of behaviour. PMID- 22452418 TI - Bilateral hemicraniectomy in non-penetrating traumatic brain injury. AB - Traumatic brain injury is a heterogeneous entity that encompasses both surgical and non-surgical conditions. Surgery may be indicated with traumatic lesions such as hemorrhage, fractures, or malignant cerebral edema. However, the neurological exam may be clouded by the effects of medications administered in the field, systemic injuries, and inaccuracies in hyperacute prognostication. Typically, neurological injury is considered irreversible if diffuse loss of grey/white matter differentiation or if brainstem hemorrhage (Duret hemorrhage) exists. We aim to characterize a cohort of patients undergoing bilateral hemicraniectomy for severe traumatic brain injury. A retrospective consecutive cohort of adult patients undergoing craniectomy for trauma was established between the dates of January 2008 and November 2011. The primary outcome of the study was in-hospital mortality. Secondary outcomes were ICU length of stay, surgical complications, and Glasgow Outcome Score at most recent follow-up. During the study period, 210 patients undergoing craniectomy for traumatic mass-occupying lesion (epidural hematoma, subdural hematoma, or parenchymal contusion) were analyzed. Of those, 9 met study criteria. In-hospital mortality was 67% (6 of 9 patients). The average ICU length of stay was 12 days. The GOS score was 3 in surviving patients. Bilateral hemicraniectomy is a heroic intervention for patients with severe TBI, but can be a life-saving procedure. PMID- 22452420 TI - Clinical value of whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of metastatic bladder cancer. AB - OBJECTIVES: To investigate the value of whole-body fluorine-18 2-fluoro-2-deoxy-D glucose positron emission tomography/computed tomography for the detection of metastatic bladder cancer. METHODS: From December 2006 to August 2010, 60 bladder cancer patients (median age 60.5 years old, range 32-96) underwent whole body positron emission tomography/computed tomography positron emission tomography/computed tomography. The diagnostic accuracy was assessed by performing both organ-based and patient-based analyses. Identified lesions were further studied by biopsy or clinically followed for at least 6 months. RESULTS: One hundred and thirty-four suspicious lesions were identified. Among them, 4 primary cancers (2 pancreatic cancers, 1 colonic and 1 nasopharyngeal cancer) were incidentally detected, and the patients could be treated on time. For the remaining 130 lesions, positron emission tomography/computed tomography detected 118 true positive lesions (sensitivity = 95.9%). On the patient-based analysis, the overall sensitivity and specificity resulted to be 87.1% and 89.7%, respectively. There was no difference of sensitivity and specificity in patients with or without adjuvant treatment in terms of detection of metastatic sites by positron emission tomography/computed tomography. Compared with conventional imaging modality, positron emission tomography/computed tomography correctly changed the management in 15 patients (25.0%). CONCLUSIONS: Positron emission tomography/computed tomography has excellent sensitivity and specificity in the detection of metastatic bladder cancer and it provides additional diagnostic information compared to standard imaging techniques. PMID- 22452421 TI - Current practices on sheep and beef farms in New Zealand for depriving sheep of feed prior to transport for slaughter. AB - AIM: To assess current practices on sheep and beef farms that deprive sheep of feed prior to transport to facilitate effluent management and processing at slaughter. METHODS: A national telephone survey of 122 sheep and 346 sheep and beef farmers was conducted in March and April 2010. They were asked how long sheep were held off green feed prior to transport and why, what environment the sheep were held in, and if that period ever varied. RESULTS: Of the 468 respondents, 303 (65%) removed their sheep from green feed 3-12 h before transport for slaughter, with longer periods reported in the South than North Island. The main reasons given were to reduce the volume of effluent for transport operators (n=174), to prevent wool staining during transport (n=173), and that sheep were better suited to load and travel empty (n=171). Water was provided during feed deprivation by 313 farmers. The period of food deprivation could be altered in response to requirements of transporters and processors, the weather, and by the class of stock involved, although 115/468 (25%) farmers stated that they never changed their normal protocol. CONCLUSIONS: Amongst survey respondents, common practices compared favourably with recommendations to reduce effluent during transportation. Previous studies have investigated the effects of fasting lambs whilst in lairage prior to slaughter and focussed on carcass quality such as carcass weight and tenderness. Changes in liveweight and gastrointestinal tract contents suggest feed deprivation reduces the risk of defaecation and urination contributing to the accumulation of effluent during transport and of carcass contamination during processing. However, the point at which that risk is acceptable to transport and processing is unclear. Fasting results in physiological changes indicative of altered metabolism but it is not clear when those changes are indicative of adaptation to food deprivation or metabolic depletion and compromised welfare. There may be opportunities to improve the logistics of livestock preparation, transport and processing. PMID- 22452422 TI - An experimental and computational analysis of primary cilia deflection under fluid flow. AB - In this study we have developed a novel model of the deflection of primary cilia experiencing fluid flow accounting for phenomena not previously considered. Specifically, we developed a large rotation formulation that accounts for rotation at the base of the cilium, the initial shape of the cilium and fluid drag at high deflection angles. We utilised this model to analyse full 3D data sets of primary cilia deflecting under fluid flow acquired with high-speed confocal microscopy. We found a wide variety of previously unreported bending shapes and behaviours. We also analysed post-flow relaxation patterns. Results from our combined experimental and theoretical approach suggest that the average flexural rigidity of primary cilia might be higher than previously reported (Schwartz et al. 1997, Am J Physiol. 272(1 Pt 2):F132-F138). In addition our findings indicate that the mechanics of primary cilia are richly varied and mechanisms may exist to alter their mechanical behaviour. PMID- 22452423 TI - Streptococcus pneumoniae urinary antigen test and acute exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Streptococcus pneumoniae is one of the most common bacteria identified in sputum obtained from subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). PURPOSE: To examine the urinary pneumococcal antigen test in subjects admitted with AECOPD and subjects with COPD, and to evaluate its relationship with AECOPD. METHODS: Urine samples from 82 subjects with AECOPD involved in 122 consecutive hospitalizations were tested. Additionally, 196 consecutive subjects with stable COPD were tested a total of 607 times at intervals greater than 6 months. RESULTS: Pneumococcal antigen was positive in 14 (17.1%) out of all 82 subjects first hospitalized with AECOPD. It was positive in 7 (20.6%) out of the 34 subjects with pneumonic exacerbations of COPD, and in 7 (14.6%) out of the 48 subjects with non-pneumonic exacerbations of COPD. Two subjects with non-pneumonic S. pneumoniae-related AECOPD were identified, and they both tested positive. A total of 607 urinary antigen tests were performed on stable COPD subjects, and 16 (2.6%) specimens were positive. Colonization by S. pneumoniae was found in the sputum of only 25% of the COPD subjects with positive urinary pneumococcal antigen test results. CONCLUSION: The results of the pneumococcal urinary antigen test were similar for AECOPD subjects with and without pneumonia. This test may be a useful method for preventing the under-diagnosis of S. pneumoniae-related exacerbations of COPD. The detection of pneumococcal antigen in the urine is not related to the persistent colonization of the respiratory mucosa by S. pneumoniae. PMID- 22452424 TI - Allocation of carbon to fine root compounds and their residence times in a boreal forest depend on root size class and season. AB - Fine roots play a key role in the forest carbon balance, but their carbon dynamics remain largely unknown. We pulse labelled 50 m(2) patches of young boreal forest by exposure to (13)CO(2) in early and late summer. Labelled photosynthates were traced into carbon compounds of < 1 and 1-3 mm diameter roots (fine roots), and into bulk tissue of these and first-order roots (root tips). Root tips were the most strongly labelled size class. Carbon allocation to all size classes was higher in late than in early summer; mean residence times (MRTs) in starch increased from 4 to 11 months. In structural compounds, MRTs were 0.8 yr in tips and 1.8 yr in fine roots. The MRT of carbon in sugars was in the range of days. Functional differences within the fine root population were indicated by carbon allocation patterns and residence times. Pronounced allocation of recent carbon and higher turnover rates in tips are associated with their role in nutrient and water acquisition. In fine roots, longer MRTs but high allocation to sugars and starch reflect their role in structural support and storage. Accounting for heterogeneity in carbon residence times will improve and most probably reduce the estimates of fine root production. PMID- 22452425 TI - Acentric nonlinear optical 2,4-dihydroxyl hydrazone isomorphic crystals with large linear, nonlinear optical susceptibilities and hyperpolarizability. AB - A systematic ab initio study of the linear, nonlinear optical susceptibilities, and hyperpolarizability of noncentrosymmetric-monoclinic 2,4-dihydroxyl hydrazone isomorphic crystals (DHNPH) within density functional theory in the local density approximation (LDA), general gradient approximation (GGA), the Engel-Vosko generalized gradient approximation (EV-GGA) and modified Becke-Johnson potential (mBJ) has been performed. The complex dielectric susceptibility dispersion, its zero-frequency limit and the birefringence are studied. Using scissors' corrected mBJ we find a large uniaxial dielectric anisotropy (-0.56) resulting in a significant birefringence (0.61). We also find that 2,4- DHNPH possess large second harmonic generation. The calculated second order susceptibility tensor components for the static limit |chi(111)(2)(0)| and |chi(111)(2)(omega)| at lambda=1.9 MUm (0.651 eV) and at lambda = 1.064 MUm (1.165 eV) are 53, 91, and 209 pm/V, respectively. A remarkable finding, applying the scissors' correction has a profound effect on value, magnitude and sign of chi(ijk)(2)(omega). In additional we have calculated the microscopic hyperpolarizability, beta(111), vector component along the principal dipole moment directions for the dominant component. We find that the value of beta(111) equal to 47* 10(-30) esu, in good agreement with the measured value (48.2* 10(-30) esu). PMID- 22452426 TI - African Pygmies, what's behind a name? PMID- 22452427 TI - Changing language, remaining pygmy. AB - In this article I am illustrating the linguistic diversity of African Pygmy populations in order to better address their anthropological diversity and history. I am also introducing a new method, based on the analysis of specialized vocabulary, to reconstruct the substratum of some languages they speak. I show that Pygmy identity is not based on their languages, which have often been borrowed from neighboring non-Pygmy farmer communities with whom each Pygmy group is linked. Understanding the nature of this partnership, quite variable in history, is essential to addressing Pygmy languages, identity, and history. Finally, I show that only a multidisciplinary approach is likely to push forward the understanding of African Pygmy societies as genetic, archeological, anthropological, and ethnological evidence suggest. PMID- 22452428 TI - A craniometric perspective on the transition to agriculture in Europe. AB - Debates surrounding the nature of the Neolithic demographic transition in Europe have historically centered on two opposing models: a "demic" diffusion model whereby incoming farmers from the Near East and Anatolia effectively replaced or completely assimilated indigenous Mesolithic foraging communities, and an "indigenist" model resting on the assumption that ideas relating to agriculture and animal domestication diffused from the Near East but with little or no gene flow. The extreme versions of these dichotomous models were heavily contested primarily on the basis of archeological and modern genetic data. However, in recent years a growing acceptance has arisen of the likelihood that both processes were ongoing throughout the Neolithic transition and that a more complex, regional approach is required to fully understand the change from a foraging to a primarily agricultural mode of subsistence in Europe. Craniometric data were particularly useful for testing these more complex scenarios, as they can reliably be employed as a proxy for the genetic relationships among Mesolithic and Neolithic populations. In contrast, modern genetic data assume that modern European populations accurately reflect the genetic structure of Europe at the time of the Neolithic transition, while ancient DNA data are still not geographically or temporally detailed enough to test continent-wide processes. Here, with particular emphasis on the role of craniometric analyses, we review the current state of knowledge regarding the cultural and biological nature of the Neolithic transition in Europe. PMID- 22452429 TI - Warfarin pharmacogenetics: polymorphisms of the CYP2C9, CYP4F2, and VKORC1 loci in a genetically admixed Omani population. AB - This is the first study to evaluate the spectrum and prevalence of dose predictive genetic polymorphisms of the CYP2C9, CYP4F2 and VKORC1 loci together, in a geographically defined, ethnically admixed healthy adult Omani population sharing common lifestyle/environmental factors. Since the present-day Omani population is the result of an admixture of Caucasian, African and Asian ancestries, we compared the pharmacogenetic profile of these three loci in this population. Interestingly, the Omani pharmacogenetic profile, in terms of allele and genotype distribution, has values that are intermediate between Caucasians and African Americans, the African admixture further substantiated by the presence of the CYP2C9*8 allele. However, limitations and usefulness of such comparisons warrant caution, as the data from pharmacogenetic literature do not always represent bona fide population categories. Furthermore, definition of study population based on microgeographical scale would be more appropriate in pharmacogenetic research rather than the flawed racial, ethnic, or social categorizations since pharmacogenetic variation is clinal, and genetic influences will be further altered by lifestyle and environmental factors. PMID- 22452430 TI - The Y-chromosome C3* star-cluster attributed to Genghis Khan's descendants is present at high frequency in the Kerey clan from Kazakhstan. AB - To verify the possibility that the Y-chromosome C3* star-cluster attributed to Genghis Khan and his patrilineal descendants is relatively frequent in the Kereys, who are the dominant clan in Kazakhstan and in Central Asia as a whole, polymorphism of the Y-chromosome was studied in Kazakhs, represented mostly by members of the Kerey clan. The Kereys showed the highest frequency (76.5%) of individuals carrying the Y-chromosome variant known as C3* star-cluster ascribed to the descendants of Genghis Khan. C3* star-cluster haplotypes were found in two subclans, Abakh-Kereys and Ashmaily-Kereys, diverged about 20-22 generations ago according to the historical data. Median network of the Kerey star-cluster haplotypes at 17 STR loci displays a bipartite structure, with two subclusters defined by the only difference at the DYS448 locus. Noteworthy is a strong correspondence of these subclusters with the Kerey subclans affiliation. The data obtained suggest that the Kerey clan appears to be the largest known clan in the world descending from a common Y-chromosome ancestor. Possible ways of Genghis Khan's relationship to the Kereys are discussed. PMID- 22452432 TI - A randomized trial of methotrexate vs. azathioprine for severe atopic eczema: a critical appraisal. AB - AIM: Schram et al. aimed to compare the efficacy and safety of methotrexate vs. azathioprine in adults with severe atopic eczema. SETTING AND DESIGN: This single blind, parallel-group (ratio 1 : 1), randomized controlled trial was conducted in a secondary care setting in the Netherlands between July 2009 and December 2010. STUDY EXPOSURE: Patients with severe atopic eczema were randomly assigned in a 1 : 1 ratio to receive either methotrexate (10-22.5 mg weekly) or azathioprine (1.5 2.5 mg kg(-1) daily) for 12 weeks, followed by a 12-week follow-up period. OUTCOMES: The outcome measures comprised various eczema severity measures including: SCORing of Atopic Dermatitis index (SCORAD); Investigator Global Assessment (IGA); Patient Global Assessment (PGA); Eczema Area and Severity Index (EASI); and Patient-Oriented Eczema Measurement (POEM). Further outcomes included a visual analogue scale of itch and sleeplessness; Skindex-17; serum levels of thymus and activation-regulated chemokine; quantity of topical corticosteroids used; and the number of courses of rescue medication (oral prednisolone) used. PRIMARY OUTCOME MEASURE: The primary outcome was the mean change in SCORAD after 12 weeks of treatment. RESULTS: Forty-five patients were screened and 42 of these were included in the trial. At week 12, patients in the methotrexate group had a mean +/- SD relative reduction in SCORAD of 42 +/- 18% compared with 39 +/- 25% in the azathioprine group (P = 0.52). Proportions of patients achieving at least mild disease and reductions in impact on quality of life and symptoms were similar in both groups at weeks 12 and 24. No statistically significant differences were found in the number and severity of adverse events. Abnormalities in blood count were more common in the azathioprine group but no serious adverse events occurred in either group. CONCLUSIONS: Schram et al. conclude that both methotrexate and azathioprine achieved clinically relevant improvement and were safe in the short term. They also conclude that both treatments are appropriate treatment options for severe atopic eczema in adult populations. PMID- 22452434 TI - Commentary: are methotrexate and azathioprine really equivalent for treating severe atopic eczema? PMID- 22452435 TI - Melanoma of the hand and foot: a distinct clinical variant of cutaneous melanoma. PMID- 22452436 TI - Frontalis-based island pedicle flaps for the single-stage repair of large defects on the forehead and frontal scalp. PMID- 22452437 TI - Patterns of sun protection for young children: do we deliver the right sun protection messages? PMID- 22452438 TI - New topical drug development in atopic dermatitis: a place for hope. PMID- 22452439 TI - Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. AB - Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by alpha-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of alpha-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources. PMID- 22452441 TI - Biotic and abiotic interactions in aquatic microcosms determine fate and toxicity of Ag nanoparticles. Part 1. Aggregation and dissolution. AB - To better understand their fate and toxicity in aquatic environments, we compared the aggregation and dissolution behavior of gum arabic (GA) and polyvinylpyrrolidone (PVP) coated Ag nanoparticles (NPs) in aquatic microcosms. There were four microcosm types: surface water; water and sediment; water and aquatic plants; or water, sediment, and aquatic plants. Dissolution and aggregation behavior of AgNPs were examined using ultracentrifugation, ultrafiltration, and asymmetrical flow field flow fractionation coupled to ultraviolet-visible spectroscopy, dynamic and static laser light scattering, and inductively coupled plasma mass spectrometry. Plants released dissolved organic matter (DOM) into the water column either through active or passive processes in response to Ag exposure. This organic matter fraction readily bound Ag ions. The plant-derived DOM had the effect of stabilizing PVP-AgNPs as primary particles, but caused GA-AgNPs to be removed from the water column, likely by dissolution and binding of released Ag ions on sediment and plant surfaces. The destabilization of the GA-AgNPs also corresponded with X-ray absorption near edge spectroscopy results which suggest that 22-28% of the particulate Ag was associated with thiols and 5-14% was present as oxides. The results highlight the potential complexities of nanomaterial behavior in response to biotic and abiotic modifications in ecosystems, and may help to explain differences in toxicity of Ag observed in realistic exposure media compared to simplified laboratory exposures. PMID- 22452442 TI - Asymmetric hydrovinylation of 1-vinylcycloalkenes. Reagent control of regio- and stereoselectivity. AB - 1-Vinylcycloalkenes undergo highly regio- and enantioselective (>98% ee) 1,4 hydrovinylation (HV) when treated with ethylene (1 atm) at room temperature in the presence of [(S,S)-2,4-bis-diphenylphosphinopentane (BDPP)]CoCl(2) (0.05 equiv) and methylaluminoxane. The minor 1,2-HV products, seen only in 1 vinylcyclohexene (~15%) and 1-vinylcycloheptene (2%), are formed as racemic mixtures. The corresponding Ni(II)-catalyzed HV reactions of these substrates give mostly the 1,2-adducts. Racemic 4-tert-butyl-1-vinylcyclohexene, when treated with Co[(S,S)-(BDPP)]Cl(2) and ethylene, undergoes a rare enantiodivergent reaction giving two diastereomers each in >98% ee. PMID- 22452443 TI - Structural modification on the Lys linker enhanced tumor to kidney uptake ratios of 99mTc-labeled RGD-conjugated alpha-MSH hybrid peptides. AB - The purpose of this study was to examine whether the structural modification on the positively charged Lys linker could reduce the kidney uptake of (99m)Tc labeled Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (alpha MSH) hybrid peptides. The RGD motif {cyclic(Arg-Gly-Asp-D-Tyr-Asp)} was coupled to [Cys(3,4,10), D-Phe(7), Arg(11)]alpha-MSH(3-13) {(Arg(11))CCMSH} through a neutral glycine linker to eliminate the positively charged amino side chain of the Lys linker or without a linker to delete the Lys linker. The receptor binding affinity of RGD-Gly-(Arg(11))CCMSH and RGD-(Arg(11))CCMSH was determined in B16/F1 melanoma cells. The melanoma targeting and imaging properties of (99m)Tc RGD-Gly-(Arg(11))CCMSH and (99m)Tc-RGD-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The structural modification on the Lys linker retained a low nanomolar receptor binding affinity of RGD-Gly-(Arg(11))CCMSH and RGD (Arg(11))CCMSH (1.5 and 1.0 nM, respectively). The structural modification on the Lys linker dramatically decreased the renal uptake of (99m)Tc-RGD-Gly (Arg(11))CCMSH and (99m)Tc-RGD-(Arg(11))CCMSH by 79% and 77% at 4 h postinjection compared to (99m)Tc-RGD-Lys-(Arg(11))CCMSH. (99m)Tc-RGD-(Arg(11))CCMSH displayed a higher melanoma uptake (16.12 +/- 3.09% ID/g) than (99m)Tc-RGD-Gly (Arg(11))CCMSH (11.50 +/- 1.01% ID/g) at 2 postinjection. The tumor uptake of (99m)Tc-RGD-(Arg(11))CCMSH was 1.4 times the tumor uptake of (99m)Tc-RGD-Gly (Arg(11))CCMSH at 2 postinjection. A dramatically enhanced tumor-to-kidney uptake ratio of (99m)Tc-RGD-(Arg(11))CCMSH suggests that (188)Re-RGD-(Arg(11))CCMSH may behave in a similar fashion warranting future evaluation for melanoma treatment. PMID- 22452444 TI - Tailor-made magnetic Fe3O4@mTiO2 microspheres with a tunable mesoporous anatase shell for highly selective and effective enrichment of phosphopeptides. AB - Selective enrichment of phosphoproteins or phosphopeptides from complex mixtures is essential for MS-based phosphoproteomics, but still remains a challenge. In this article, we described an unprecedented approach to synthesize magnetic mesoporous Fe(3)O(4)@mTiO(2) microspheres with a well-defined core/shell structure, a pure and highly crystalline TiO(2) layer, high specific surface area (167.1 m(2)/g), large pore volume (0.45 cm(3)/g), appropriate and tunable pore size (8.6-16.4 nm), and high magnetic susceptibility. We investigated the applicability of Fe(3)O(4)@mTiO(2) microspheres in a study of the selective enrichment of phosphopeptides. The experiment results demonstrated that the Fe(3)O(4)@mTiO(2) possessed remarkable selectivity for phosphopeptides even at a very low molar ratio of phosphopeptides/non-phosphopeptides (1:1000), large enrichment capacity (as high as 225 mg/g, over 10 times as that of the Fe(3)O(4)@TiO(2) microspheres), extreme sensitivity (the detection limit was at the fmol level), excellent speed (the enrichment can be completed in less than 5 min), and high recovery of phosphopeptides (as high as 93%). In addition, the high magnetic susceptibility allowed convenient separation of the target peptides by magnetic separation. These outstanding features give the Fe(3)O(4)@mTiO(2) composite microspheres high benefit for mass spectrometric analysis of phosphopeptides. PMID- 22452445 TI - Evaluation of two commonly used temporary skin dressings for the treatment of acute partial-thickness wounds in rats. AB - OBJECTIVES: There is a broad range of expensive temporary wound dressings that promise better results in wound management. The aim of this study was to compare two commonly used temporary dressings for the treatment of partial-thickness wounds in a rat model. METHODS: Forty-two partial thickness wounds were created on the back of Lewis rats and treated with the dressings; control wounds remained without treatment. Wound size was determined daily by measuring the scabbed area. Three months after the wounds were created, skin elasticity was measured and a histologic evaluation was performed. RESULTS: Wound appearance in the animals in the treated groups did not differ significantly. Wound closure was slower in the control group than in the dressing groups. There was no histologic evidence of inflammation and no suggestion of epidermal changes in any group. CONCLUSION: Using both skin dressings, we observed satisfying results without any significant differences. Because of rising health care expenses, cost should play an essential role in the clinical application of these dressings. PMID- 22452446 TI - The reliability of sensitive information provided by injecting drug users in a clinical setting: clinician-administered versus audio computer-assisted self interviewing (ACASI). AB - Research with injecting drug users (IDUs) suggests greater willingness to report sensitive and stigmatised behaviour via audio computer-assisted self-interviewing (ACASI) methods than during face-to-face interviews (FFIs); however, previous studies were limited in verifying this within the same individuals at the same time point. This study examines the relative willingness of IDUs to report sensitive information via ACASI and during a face-to-face clinical assessment administered in health services for IDUs. During recruitment for a randomised controlled trial undertaken at two IDU-targeted health services, assessments were undertaken as per clinical protocols, followed by referral of eligible clients to the trial, in which baseline self-report data were collected via ACASI. Five questions about sensitive injecting and sexual risk behaviours were administered to participants during both clinical interviews and baseline research data collection. "Percentage agreement" determined the magnitude of concordance/discordance in responses across interview methods, while tests appropriate to data format assessed the statistical significance of this variation. Results for all five variables suggest that, relative to ACASI, FFI elicited responses that may be perceived as more socially desirable. Discordance was statistically significant for four of the five variables examined. Participants who reported a history of sex work were more likely to provide discordant responses to at least one socially sensitive item. In health services for IDUs, information collection via ACASI may elicit more reliable and valid responses than FFI. Adoption of a universal precautionary approach to complement individually tailored assessment of and advice regarding health risk behaviours for IDUs may address this issue. PMID- 22452447 TI - Organic/Metallic nanohybrids based on amphiphilic dumbbell-shaped dendrimers. AB - In this study, we synthesized a series of amphiphilic dumbbell-shaped dendrimers through the addition reactions of a hydrophilic poly(oxyalkylene) with hydrophobic dendrons based on 4-isocyanate-4'-(3,3-dimethyl-2,4-dioxo azetidine)diphenylmethane with different numbers of branching generations. The addition reaction of azetidine-2,4-diones of dendrons to amines of poly(oxyalkylene) was proceeded by stirring the reactants in dry tetrahydrofuran (THF) under nitrogen at 60 degrees C. In aqueous media, the dumbbell-shaped dendrimers self-assembled into micelles with their hydrophobic dendrons in the core and their hydrophilic poly(oxyalkylene) segments forming loops in the corona shell. Employing the unique self-assembled micelle structures as templates for subsequent chemical reduction of the Ag(+) ions, we generated new types of organic/metallic [silver nanoparticle (AgNP)] nanohybrid clusters. The long poly(oxyalkylene) loops that extended into the aqueous phase complexed with the Ag(+) ions, providing the suspension with steric stabilization to prevent the AgNPs from collision and flocculation. After reduction, the AgNPs were present in a homogeneous distribution in the round dendrimer micelle-stabilized nanoclusters. The diameter of each AgNP was less than 10 nm; the diameter of each round nanocluster was in the range of 50-200 nm. The encapsulation efficiency of the AgNPs in micelles was about 54-69% for the dumbbell-shaped dendrimer based organic/AgNP nanohybrid. PMID- 22452448 TI - Cost effectiveness of prostacyclins in pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is considered an orphan disease. Prostacyclins are the keystone for PAH treatment. Choosing between the three available prostacyclin therapies could be complicated because there are no comparison studies, so the final decision must be driven by factors such as efficacy, administration route, safety profile and economic aspects. OBJECTIVE: This study provides a cost-effectiveness and cost-utility comparison of initiating prostacyclin therapy with three different treatment alternatives (inhaled iloprost [ILO], intravenous epoprostenol [EPO] and subcutaneous treprostinil [TRE]) for patients with PAH. The goal of this work is to help physicians with their therapeutic decision-making. METHODS: A Markov model was built to simulate a patient cohort with class III PAH according to the classification of the New York Heart Association (NYHA). Four health states corresponding with the NYHA classes plus death were allowed for patients in the model. Changing the treatment was possible when patients worsened from functional class III to IV. The time horizon was 3 years, allowing patients to transition between health states on a 12-week cycle basis. The study perspective was that of the National Health System (NHS) [only direct medical costs were included]. Unitary costs were obtained from the Drug Catalogue and e-Salud Database in 2009 and are given in euros (?). Data on health resources and treatment pathways were informed by a four-member expert panel. Efficacy was obtained from pivotal clinical trials of ILO, EPO and TRE, the latter used in Spain as a foreign medication. Utilities for each health state were obtained from the literature. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs). Costs and effects were discounted at a 3% rate. To check for the robustness of the results, sensitivity analyses were performed. RESULTS: At the end of the 3 years, in the base case of the deterministic analysis, initiating prostacyclin therapy with iloprost was the less costly strategy (?132,840), followed by treprostinil (?359,869) and epoprostenol (?429,775). Epoprostenol has shown the best efficacy results with 2.73 LYG and 1.78 QALY, followed by iloprost (2.69 LYG and 1.74 QALY) and treprostinil (2.69 LYG and 1.73 QALY). Incremental cost-effectiveness ratios (ICER) and cost-utility ratios (ICUR) of epoprostenol versus iloprost and treprostinil were much above the ?30,000 per LYG or QALY threshold commonly used in Spain. Iloprost was dominant compared with treprostinil. In the probabilistic analysis, epoprostenol, when compared with iloprost, was a dominant strategy in 15% of the simulations, but it was not a cost-effective option in 83% of the cases. When compared with treprostinil, epoprostenol was dominant in 43% of the simulations. Iloprost was dominant compared with treprostinil in 45% of the cases and it was a cost-effective alternative in 39% of the simulations. CONCLUSIONS: Initiating prostacyclin treatment with iloprost in patients with PAH, functional class III of the NYHA, is the less costly alternative for the NHS in Spain, with a good efficacy profile when compared with the other alternatives. PMID- 22452449 TI - Challenging symptoms in children with rare life-limiting conditions: findings from a prospective diary and interview study with families. AB - AIM: The aim was to describe the nature, frequency, severity and management challenges of symptoms in children with two rare life-limiting conditions [Mucopolysaccharide (MPS) and Batten disease]. METHODS: This was an embedded mixed-method study set in the UK between 2009 and 2011. Twenty-six children from 23 families took part. Seventeen children had an MPS condition [MPS III (Sanfilippo) n = 15; MPS I (Hurler) n = 1; MPS IVA (Morquio); n = 1]. Nine children had Batten disease. Prospective data relating to symptoms were collected over 8 weeks using a symptom diary, and qualitative retrospective interviews with families were conducted. Main outcome measures included frequency, severity rating and identification of most challenging symptoms to manage. RESULTS: The most common and severe symptoms in MPS III were agitation, repetitive behaviours, hyperactivity and disturbed sleep, and in Batten disease were agitation, joint stiffness, secretions, and disturbed sleep. The data highlighted the high prevalence of behavioural symptoms. Distress caused to families by symptoms was not related simply to their occurrence, but to difficulty in management, likelihood of control and extent to which they signalled disease progression and decline. CONCLUSION: In challenging contrast to the dominant biomedical framing of these rare conditions it was behavioural symptoms, rather than the physical ones, that families documented as most frequent, severe and challenging to manage. The diary developed for this study has potential use in aiding parents and clinicians to document and communicate concerns about symptoms. PMID- 22452450 TI - Neutrophil-to-lymphocyte ratio as a predictor of worsening renal function in diabetic patients (3-year follow-up study). AB - BACKGROUND: Previous studies have demonstrated the role of inflammation in diabetic nephropathy (DN). Neutrophil to lymphocyte ratio (NLR) rather than other white cell parameters was found to be a useful inflammatory marker to predict adverse outcomes in medical and surgical conditions. Nevertheless, the value of NLR in predicting DN has not been elucidated. METHOD: An observational study included 338 diabetic patients, who were followed at our clinic between 2007 and 2009. We arranged our patients into tertiles according to their 2007 NLR. The primary outcome was continuous decrease of GFR >12 mL/min between 2007 and 2009 with the last GFR <60 mL/min. RESULT: The lowest NLR tertile had fewer patients (2.7%) with primary outcome (i.e., worsening renal function) compared with middle and highest NLR tertiles, which had more patients with primary outcomes (8.7% and 11.5%, respectively) with a significant p-value 0.0164. When other potential confounders were individually analyzed with NLR tertile, the NLR tertiles remained a significant predictor of poor GFR outcome in the presence of other variables (hemoglobin A1C, systolic blood pressure, diastolic blood pressure, age, and congestive heart failure with p-values 0.018, 0.019, 0.017, 0.033, and 0.022, respectively). CONCLUSION: NLR predicted the worsening of the renal function in diabetic patients. Further studies are needed to confirm this result. PMID- 22452451 TI - Does family history of alcohol problems influence college and university drinking or substance use? A meta-analytical review. AB - AIMS: Family history of alcohol use problems is a reliable determinant of alcohol use and problems in the population at large, but findings are inconsistent when this issue is examined in college and university students. No quantitative summary of this literature has been reported to date. The purpose of this study was to conduct a meta-analysis on the effects of family history on substance use and abuse in college and university students. METHODS: A two-group contrast meta analysis was conducted to evaluate the differences in substance use and abuse between family history-positive and -negative students pursuing higher education. The studies that contributed data to this meta-analysis were conducted in five countries, with the majority of studies from the United States. A total of 65 published papers (53 samples) contributed data from 89 766 participants attending university or college. Effect sizes were coded for alcohol consumption, problems and use disorder symptoms, as well as other illegal drug use and abuse. Two independent coders calculated effect sizes and coded descriptive content about the papers, and discrepancies were reconciled. Family history was used as the grouping variable. RESULTS: Family history had a minimal effect on alcohol consumption, with stronger effects on alcohol consequences (Cohen's d: 0.21 0.25), alcohol use disorder symptoms (Cohen's d: 0.24) and other drug involvement (Cohen's d: 0.37-0.86). CONCLUSIONS: Relative to students without a family history of alcohol problems, students with positive family histories do not drink more, but may be at greater risk for difficulties with alcohol and drugs. PMID- 22452452 TI - Sex differences in the clearance of CYP3A4 substrates: exploring possible reasons for the substrate dependency and lack of consensus. AB - Sex differences in the clearance of substrates of Cytochrome P4503A (CYP3A4) have been reported frequently although there has been no consensus on reasons for variation in observations amongst drugs which are seemingly all dependent on this enzyme for their metabolism. Moreover, these observations could not be replicated in all studies even when investigating the same drugs. Differing study designs and inadequate power to identify the sex differences may explain the conflicting reports. The aim of the current study was to use in vitro data on a number of CYP3A4 substrates to develop mechanistic population pharmacokinetic models which are capable of integrating various attributes of drugs and estimating the statistical power of in vivo studies designed to discern sex differences in the clearance of CYP3A4 substrates. Midazolam, triazolam, alprazolam, nifedipine and zolpidem were selected as test substrates. These compounds are predominantly metabolized by CYP3A4, unaffected by p-glycoprotein and have abundant clinical studies which can be used for validation purposes. Simulated apparent clearance, obtained by use of the Simcyp(r) Population-based Simulator and in vitro in vivo extrapolation (IVIVE) techniques, was compared in males and females after correcting for weight (CL/wt) in 1560 trials. Results suggested that about 105 subjects per study are required for an 80% probability of identifying a higher CL/wt in females with alprazolam, while the corresponding numbers for a similar power were 120, about 150 and 300 for nifedipine, triazolam and oral midazolam, respectively. The results were consistent with outcomes in published clinical studies and support the view that many of the published studies have inadequate power to detect these sex differences in drug clearance, thereby contributing to the lack of consensus on this subject. PMID- 22452453 TI - Physiologically-based pharmacokinetic (PBPK) models for assessing the kinetics of xenobiotics during pregnancy: achievements and shortcomings. AB - The physiological changes that occur in the maternal body and the placental foetal unit during pregnancy influence the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics. These include drugs that are prescribed for therapeutic reasons or chemicals to which women are exposed unintentionally from the surrounding environment. The pregnancy physiologically-based pharmacokinetic (p-PBPK) models developed for theoretical assessment of the kinetics of xenobiotics during pregnancy should take into account all the dynamic changes of the maternal and embryonic/foetal physiological functions. A number of p-PBPK models have been reported for pregnant animals and humans in the past 3 decades which have mainly been applied in the risk assessment of various environmental chemicals. The purpose of this review is to critically evaluate the current state of the art in p-PBPK modelling and to recommend potential steps that could be taken to improve model development and its application particularly in drug discovery and development for pregnant women, with potential implications for optimal drug treatment in pregnancy. The pregnancy-induced changes in physiology and pharmacokinetics, including metabolism, are reviewed to illustrate the basic alterations essential for pregnancy model development. A systemic search of the literature for existing p-PBPK models is carried out and the model structures, governing equations, methods of modelling growth, model validation/verification as well as model applications are highlighted. This review discusses benefits and limitations of the reported p-PBPK models so far and suggests areas for model improvement. The need for establishing databases on the system-related (biological, anatomical and physiological) and drug-related (physiochemical, affinity to enzymes and transpoorters) parameters for healthy and unhealthy pregnancies is particularly emphasized. PMID- 22452454 TI - Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO). AB - ECMO support is an established life saving therapy for potentially reversible respiratory and/or cardiac failure. Improvement of outcome depends on effective treatment of the primary diagnosis and complications. Adequate drug therapy is important in reaching these goals. Pharmacokinetic and pharmacodynamic data in neonates and older children on ECMO are sparse. Most studies show altered volume of distribution and clearance for the drugs studied. This article gives an overview of the available PK and PD studies in neonates and children on ECMO, suggests possible mechanisms of altered PK and PD and identifies areas of interest for further research. PMID- 22452455 TI - Ontogeny of hepatic glucuronidation; methods and results. AB - The onset and maturation, or so-called ontogeny, of hepatic glucuronidation is important for the clearance of a number of drugs in children. The current review discusses methods for studying the ontogeny of liver enzyme systems and specifically focuses on the results obtained with these methods for uridine 5' diphosphate glucuronosyltransferases (UGTs). The number of contributing components in the biological system increases in going from mRNA transcription, to enzyme expression, in vitro enzyme activity, and in vivo glucuronidation clearance. This may result in different conclusions on UGT ontogeny when different methods are used. Various metrics to quantify glucuronidation activity, like linear or allometric scaling based on bodyweight, further disperse the conclusions on UGT ontogeny. Generally, it can be concluded that the onset of UGT expression and activity occurs after 20 weeks of gestation with a boost in expression and activity occurring in the first weeks of life. Maturation rates vary between the UGTs, but may well extend beyond the age of two years. Compared to adults, absolute doses of drugs eliminated via glucuronidation should be reduced in children. However, since the UGT isoenzymes mature differently, since substrate specificities are overlapping and since many external factors influence drug glucuronidation, it is not possible to derive general dosing recommendations for the pediatric population for these drugs. This can be improved by obtaining system specific information on each UGT isoenzyme on the basis of validated in vivo models that describe the ontogeny of glucuronidation and the influence of other patient characteristics like genetic polymorphisms and co-morbidities on the (intrinsic) clearance of isoenzyme specific probe drugs. PMID- 22452456 TI - Growing up with midazolam in the neonatal and pediatric intensive care. AB - A variety of developmental changes is of influence on the pharmacokinetics and pharmacodynamics of midazolam in neonatal and pediatric intensive care patients. However, dosing regimens in children are based upon rather empirical extrapolations from the dosing regimens in adults. Based on current available studies it appears that with the rising of age, the pharmacokinetics of intravenously administered midazolam alter, resulting in a shorter half-life due to a higher hepatic clearance in older children as compared to newborn. Also, with the rising of age, the pharmacodynamics of intravenously administered midazolam may alter due to a decrease in density of receptors, possibly leading to a decreased clinical response. These findings implicate opposite effects and it is uncertain which of these effects are predominant. In conclusion, there is a large interindividual variability in the response to midazolam in children, which may be caused by differences in pharmacokinetics and pharmacodynamics. Both are subject to considerable developmental changes. It remains remarkable that high quality evidence to support the use of midazolam for continuous sedation in the neonatal and pediatric intensive care setting is lacking. PMID- 22452457 TI - Pharmacokinetic considerations of perinatal antiretroviral therapy. AB - Antiretroviral therapy (ART) in pregnant women represents a unique combination of therapy and prophylaxis of HIV infection. Until the global epidemic of HIV and the discovery of efficient prevention of perinatal transmission through ART, the world has not witnessed a pharmacologic intervention of such a scale during pregnancy and delivery. The use of ART in pregnancy creates unique challenges in delivering therapeutic agents, targeting the HIV virus in both the pregnant woman and her unborn child, throughout dramatic changes in their physiologic state. With an increased complexity of perinatal ART and the introduction of novel agents into clinical practice, a better understanding of the pharmacokinetics (PK) and pharmacodynamics of ARV drugs is crucial for the safe and most effective use of ARV drugs in women during pregnancy and infants in the first months of life. While PK studies are already difficult to perform during pregnancy, they are particularly challenging in women with HIV infection due to multiple social, economic and cultural constrains. In this paper we provide an overview of published studies of ART disposition during pregnancy, labor, breastfeeding and in the newborn infant after delivery. PMID- 22452458 TI - Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation. AB - There have been an increasing number of clinical studies investigating the relationship between interindividual genetic variability and the safety and efficacy of opioid analgesics. Despite the widespread use of opioids in pregnant and lactating women for the treatment of acute pain, few studies have investigated the interplay of genetic factors and pregnancy-related physiological alterations in relation to opioid metabolism and response. Some interesting avenues of research require further pursuit- including evidence of cytochrome P450 2D6 (CYP2D6) induction during pregnancy and its effect on the generation of the active opioid metabolites morphine, oxymorphone, O-desmethyltramadol, and hydromorphone following the administration of codeine, oxycodone, tramadol, and hydrocodone respectively. Studies investigating the duration of maternal CYP2D6 induction after delivery are also needed to shed light on genotype to phenotype correlations in breastfeeding mothers using opioid analgesics in the postpartum period. PMID- 22452459 TI - Drug metabolism in pediatrics, pregnancy and lactation. PMID- 22452460 TI - A comparison of methods used to extract bacterial DNA from raw milk and raw milk cheese. AB - AIMS: In this study, we compare seven different methods which have been designed or modified to extract total DNA from raw milk and raw milk cheese with a view to its subsequent use for the PCR of bacterial DNA. MATERIALS AND RESULTS: Seven extraction methods were employed to extract total DNA from these foods, and their relative success with respect to the yield and purity of the DNA isolated, and its quality as a template for downstream PCR, was compared. Although all of the methods were successful with respect to the extraction of DNA naturally present in cheese, they varied in their relative ability to extract DNA from milk. However, when milk was spiked with a representative Gram-positive (Listeria monocytogenes EGDe) or Gram-negative (Salmonella enterica serovar Typhimurium LT2) bacterium, it was established that all methods successfully extracted DNA which was suitable for subsequent detection by PCR. CONCLUSIONS: Of the seven approaches, the PowerFoodTM Microbial DNA Isolation kit (MoBio Laboratories Inc.) was found to most consistently extract highly concentrated and pure DNA with a view to its subsequent use for PCR-based amplification and also facilitated accurate detection by real-time quantitative PCR. SIGNIFICANCE AND IMPACT OF THE STUDY: Accurately assessing the bacterial composition of milk and cheese is of great importance to the dairy industry. Increasingly, DNA-based technologies are being employed to provide an accurate assessment of this microbiota. However, these approaches are dependent on our ability to extract DNA of sufficient yield and purity. This study compares a number of different options and highlights the relative success of these approaches. We also highlight the success of one method to extract DNA from different microbial populations as well as DNA which is suitable for real-time PCR of microbes of interest, a challenge often encountered by the food industry. PMID- 22452461 TI - Influences of brain tissue poroelastic constants on intracranial pressure (ICP) during constant-rate infusion. AB - A 3D finite element (FE) model has been developed to study the mean intracranial pressure (ICP) response during constant-rate infusion using linear poroelasticity. Due to the uncertainties in the poroelastic constants for brain tissue, the influence of each of the main parameters on the transient ICP infusion curve was studied. As a prerequisite for transient analysis, steady state simulations were performed first. The simulated steady-state pressure distribution in the brain tissue for a normal cerebrospinal fluid (CSF) circulation system showed good correlation with experiments from the literature. Furthermore, steady-state ICP closely followed the infusion experiments at different infusion rates. The verified steady-state models then served as a baseline for the subsequent transient models. For transient analysis, the simulated ICP shows a similar tendency to that found in the experiments, however, different values of the poroelastic constants have a significant effect on the infusion curve. The influence of the main poroelastic parameters including the Biot coefficient alpha, Skempton coefficient B, drained Young's modulus E, Poisson's ratio nu, permeability kappa, CSF absorption conductance C(b) and external venous pressure p(b) was studied to investigate the influence on the pressure response. It was found that the value of the specific storage term S(epsilon) is the dominant factor that influences the infusion curve, and the drained Young's modulus E was identified as the dominant parameter second to S(epsilon). Based on the simulated infusion curves from the FE model, artificial neural network (ANN) was used to find an optimised parameter set that best fit the experimental curve. The infusion curves from both the FE simulation and using ANN confirmed the limitation of linear poroelasticity in modelling the transient constant-rate infusion. PMID- 22452462 TI - Duty-free: the non-obligatory nature of preimplantation genetic diagnosis. PMID- 22452463 TI - The case for a parental duty to use preimplantation genetic diagnosis for medical benefit. AB - This article explores the possibility that there is a parental duty to use preimplantation genetic diagnosis (PGD) for the medical benefit of future children. Using one genetic disorder as a paradigmatic example, we find that such a duty can be supported in some situations on both ethical and legal grounds. Our analysis shows that an ethical case in favor of this position can be made when potential parents are aware that a possible future child is at substantial risk of inheriting a serious genetic condition. We further argue that a legal case for a duty to use PGD for medical benefit can be made in situations in which potential parents have chosen to conceive through in vitro fertilization and know that any children conceived are at substantial risk of having a serious genetic condition. PMID- 22452464 TI - In favor of PGD: the moral duty to avoid harm argument. PMID- 22452465 TI - A parental duty to use PGD: more than we bargained for? PMID- 22452466 TI - A wrongful case for parental tort liability. PMID- 22452467 TI - The harms of a duty: misapplication of the best interest standard. PMID- 22452468 TI - Moral duty in the use of preimplantation genetic diagnosis. PMID- 22452469 TI - A duty to use IVF? PMID- 22452470 TI - A duty to discriminate? PMID- 22452471 TI - Revisiting the non-identity problem and the virtues of parenthood. PMID- 22452472 TI - More mud, less crystal? Ambivalence, disability, and PGD. PMID- 22452473 TI - The ethics of PGD: what about the physician? PMID- 22452474 TI - Acting in the best interest of a child does not mean choosing the "best" child. PMID- 22452475 TI - Swabbing students: should universities be allowed to facilitate educational DNA testing? AB - Recognizing the profound need for greater patient and provider familiarity with personalized genomic medicine, many university instructors are including personalized genotyping as part of their curricula. During seminars and lectures students run polymerase chain reactions on their own DNA or evaluate their experiences using direct-to-consumer genetic testing services subsidized by the university. By testing for genes that may influence behavioral or health-related traits, however, such as alcohol tolerance and cancer susceptibility, certain universities have stirred debate on the ethical concerns raised by educational genotyping. Considering the potential for psychosocial harm and medically relevant outcomes, how far should university-facilitated DNA testing be permitted to go? The analysis here distinguishes among these learning initiatives and critiques their approaches to the ethical concerns raised by educational genotyping. PMID- 22452476 TI - Assessing the pedagogical goals of self-testing in evaluating the consultation needs of different student populations. PMID- 22452477 TI - Personalized genomic educational testing: what do the undergrads think? PMID- 22452478 TI - Introducing personal genomics to college athletes: potentials and pitfalls. PMID- 22452479 TI - The professor really wants me to do my homework: conflicts of interest in educational research. PMID- 22452481 TI - Editorial comment from Dr Ishizuka to periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: report of three initial cases. PMID- 22452482 TI - Endothelial progenitor cells promote astrogliosis following spinal cord injury through Jagged1-dependent Notch signaling. AB - Interactions between endothelial and neural stem cells are believed to play a critical role in the kinetics of neural stem cells in the central nervous system. Here we demonstrate that endothelial progenitor cells promote the repair of injured spinal cord through the induction of Notch-dependent astrogliosis and vascular regulation. The transplantation of Jagged1(+/+) endothelial progenitor cells, but not Jagged1(-/-) endothelial progenitor cells, increased the number of reactive astrocytes during the acute phase, and improved functional recovery following spinal cord injury. Expression of the Notch effector Hes5 was upregulated in the injured spinal cord after Jagged1(+/+) endothelial progenitor cell transplantation. Furthermore, we found that the Notch ligand Delta-like-1 was highly expressed in Jagged1(-/-) endothelial progenitor cells. Transplantation of Delta-like-1, as well as Jagged1-overexpressing 3T3 cells, revealed that only Jagged1-overexpressing 3T3 stromal cells enhanced astrogliosis following spinal cord injury. In addition, Jagged1(+/+) endothelial progenitor cells exhibited not only dramatic pro-angiogenic effects, but also morphologically abnormal vessel stabilization, compared with Jagged1(-/ )endothelial progenitor cells in injured spinal cord. Thus, transplanted endothelial progenitor cells promote astrogliosis, vascular regulation, and spinal cord regeneration through activation of Jagged1-Notch signaling. PMID- 22452483 TI - Efficacy of Ageratum conyzoides on tissue repair and collagen formation in rats. AB - BACKGROUND: Wound healing occurs as a fundamental response to tissue injury. Several natural products have been shown to accelerate the healing process. AIM: To observe the efficacy of topical administration of an ethanolic extract of Ageratum conyzoides on cutaneous wound healing in rats. METHODS: An ethanolic extract of A. conyzoides was prepared, and its wound-healing efficacy on rats was studied. An open excision wound was made on the back of each rat, and 200 MUL (40 mg/kg body weight) of the A. conyzoides extract was applied topically once daily to the treated wounds. The control wounds were treated with 200 MUL of 50% ethanol. The wound tissues formed were removed at 4, 8 and 12 days after wounding, and biochemical parameters such as DNA, total protein, total collagen, hexosamine and uronic acid were estimated. The extent of epithelialization and the tensile strength of the wounded tissues were also measured. RESULTS: The A. conyzoides extract increased cellular proliferation and collagen synthesis. Wounds treated with the extract were found to heal much faster, based on the improved rates of epithelialization and wound contraction, and on the histopathological results. A 40% increase in the tensile strength of the treated tissue was seen. CONCLUSIONS: Topical application of A. conyzoides accelerates the rate of wound healing. PMID- 22452484 TI - Seasonal partitioning of growth into biomass and area expansion in a cephalolichen and a cyanolichen of the old forest genus Lobaria. AB - Growth in two old forest lichens was studied to evaluate how temporal (seasonal) and spatial (aspect-wise) partitioning of biomass and area growth respond to seasonal changes in light and climate. We monitored relative growth rates during annual courses in the cephalolichen Lobaria pulmonaria and the cyanolichen Lobaria scrobiculata transplanted in boreal clear-cut to five fixed aspects in winter, spring, summer, and autumn. For each annual set, growth was quantified in January-March, April-June, July-September and October-December. Mean biomass and area increased in all seasons, but growth was highest in July-September. Mass growth did not follow area increment during a year. As a result, mass per area (specific thallus mass (STM)) declined (L. scrobiculata) or stayed constant (L. pulmonaria) in the dark, humid October-December season, whereas it strongly increased in the dry, sunny April-June season. Aspect influenced growth in species-specific ways. Seasonality in biomass growth mainly followed light availability, whereas area growth was strongest during humid seasons. The substantial STM changes across seasons, species, and aspects can be explained as passive responses to seasonal climate. However, as STM, according to the literature, is a driver of water storage, recorded changes probably improve fitness by prolonging hydration in places or during times with high evaporative demands. PMID- 22452485 TI - Solid-state spectroscopic characterization of alpha-chitins deacetylated in homogeneous solutions. AB - Synthesis and spectroscopic characterization of alpha-chitins exhibiting degrees of acetylation (DA) between 0.5 and 1 were reported. Crab shell alpha-chitin consisting of microfibrils with a width of less than 1 MUm was regenerated from or alkaline deacetylated in 30% aqueous NaOH solution. After the deacetylation in homogeneous solution, the DA of alpha-chitins decreased steadily with prolonged deacetylation times from 1 to 0.54. The native microfibrils of starting alpha chitin were destroyed, while aggregates or sheets were formed depending on the DA of chitins. According to WAXD measurements, deacetylated chitins with DA lower than 0.76 have different crystalline structures than starting alpha-chitin. Furthermore, FT Raman spectroscopy demonstrated a novel rapid method to determine the DA of chitin with correlation coefficients greater than 0.99. On the basis of the FT Raman signals ascribed to the amide groups, the amount of hydrogen bonds linked to C?O groups decreased strongly with lower DA and the relationship between them was presented. PMID- 22452486 TI - Retene emission from residential solid fuels in China and evaluation of retene as a unique marker for soft wood combustion. AB - Retene (1-methyl-7-isopropylphenanthrene) is often used as a marker for softwood combustion and for polycyclic aromatic hydrocarbon (PAH) source apportionment. The emission factors of retene (EF(RET)s) from 11 crop residues, 27 firewood fuels, and 5 coals were measured using traditional rural Chinese stoves. Retene was measured in combustion emissions from all of the residential fuels tested and EF(RET)s varied significantly among the fuels due to the differences in fuel properties and combustion conditions. EF(RET)s for pine (0.34 +/- 0.08 mg/kg) and larch (0.29 +/- 0.22 mg/kg) were significantly higher than those of other wood types, including fir and cypress (0.081 +/- 0.058 mg/kg). However, EF(RET)s for crop residues varied from 0.048 +/- 0.008 to 0.37 +/- 0.14 mg/kg and were not significantly lower than those for softwood (0.074 +/- 0.026 to 0.34 +/- 0.08 mg/kg). The EF(RET)s for coal were very high and ranged from 2.2 +/- 1.5 (anthracite briquette) to 187 +/- 113 mg/kg (raw bituminous chunk). EF(RET) was positively correlated with EFs of coemitted particulate matter (EF(PM)) and phenanthrene (EF(PHE)) for crop residue and coal, but not for wood. In addition, the ratios of EF(PHE)/EF(RET) and EF(PM)/EF(RET) for coals were much lower than those for crop residues and wood. These data suggest that retene is not a unique PAH marker for softwood combustion and that coal combustion, in particular, should be taken into account when retene is used for PAH source apportionment. PMID- 22452487 TI - Relationship between skin parameters (darkness or thickness) and photoreaction of Chinese Han skin. AB - BACKGROUND: Skin pigmentation and the stratum corneum are the two primary natural factors that protect against UV damage. Although several classification systems exist to quantify the ability of the skin to protect itself from damaging UV radiation, few reports have assessed skin parameters and photoreaction in persons of Han Chinese descent. AIMS: To understand the relationship between skin darkness, skin thickness, and photoreaction in Chinese Han subjects. METHODS: Thirty-one subjects were exposed to UVA and UVB. Minimal persistent pigment darkening dose (MPPD) and minimal erythema dose (MED) were obtained. Before the UV irradiation, the test sites were measured by the Mexameter MX 16, Chromameter CR400, and Skin B-ultrasonic to determine skin color and thickness>. Using the ratio of J(MPPD)/J(MED), we classified the subjects into four energy skin phototypes (ESPTs) and the skin parameters for each of these groups were analyzed. RESULTS: Skin color and skin thickness were significantly different among the ESPTs. There was also a significant positive correlation between skin group and the skin color and thickness parameters (b*, melanin index [MI], thickness). As the ESPTs increased from ESPT A to ESPT D, the mean dose to achieve MED increased, while the MPPD decreased. CONCLUSION: As the ESPTs increased from type A to type D, there was a proclivity to tan rather than burn. Similarly, the skin became darker and thicker as the phototype increased from A to D. PMID- 22452488 TI - HIV seroconversion and prevalence rates in heterosexual discordant couples in China: a systematic review and meta-analysis. AB - This study aims to systematically review published literature on heterosexual transmission among HIV discordant couples in China. We conducted a systematic review and random-effects meta-analysis of 32 published articles in both Chinese and English. The summarized overall HIV seroconversion rate among discordant couples in China is 1.2 per 100 person-years (95% CI 0.9-1.7/100 PY). The overall estimate for HIV prevalence through heterosexual transmission in discordant couples is 11.5% (95% CI 8.2%-15.2%) in China. In a stratified meta-analysis by region, Henan province showed an HIV seroconversion rate of 0.9/100 PY (95% CI 0.6-1.2/100 PY) and an HIV prevalence rate of 3.9% (95% CI 2.5-5.7%). Yunnan province showed an HIV seroconversion rate of 1.7/100 PY (95% CI 1.2-2.3/100 PY) and an HIV prevalence rate of 17.0% (95% CI 13.7-20.6%). Other provinces collectively showed a HIV seroconversion rate of 3.9/100 PY (95% CI 1.0-8.7/100 PY) and an HIV prevalence rate of 21.5% (95% CI 9.6-36.5%). In a stratified meta analysis by time, the subgroup from 1994 to 2004 had a seroconversion rate of 3.9/100 PY (95% CI 1.0-8.7/100 PY) and the subgroup from 2005 to 2011 had a seroconversion rate of 1.1/100 PY (95% CI 0.8-1.5/100 PY). These data show that China's free national HIV prevention and treatment program has been successful at limiting transmission in discordant couples. Because heterosexual transmission is now the dominant method of HIV transmission in China, it is important to understand seroconversion and prevalence rates in discordant couples to develop more effective prevention and treatment programs. PMID- 22452489 TI - First observation of diffusion-limited plant root phosphorus uptake from nutrient solution. AB - Diffusion towards the root surface has recently been shown to control the uptake of metal ions from solutions. The uptake flux of phosphorus (P) from solutions often approaches the maximal diffusion flux at low external concentrations, suggesting diffusion-controlled uptake also for P. Potential diffusion limitation in P uptake from nutrient solutions was investigated by measuring P uptake of Brassica napus from solutions using P-loaded Al(2) O(3) nanoparticles as mobile P buffer. At constant, low free phosphate concentration, plant P uptake increased up to eightfold and that of passive, diffusion-based samplers up to 40-fold. This study represents the first experimental evidence of diffusion-limited P uptake by plant roots from nutrient solution. The Michaelis constant of the free phosphate ion obtained in unbuffered solutions (K(m) = 10.4 umol L(-1) ) was 20-fold larger than in the buffered system (K(m) ~0.5 umol L(-1) ), indicating that K(m) s determined in unbuffered solutions do not represent the transporter affinity. Increases in the P uptake efficiency of plants by increasing the carrier affinity are therefore unlikely, while increased root surface area or exudation of P solubilizing compounds are more likely to enhance P uptake. Furthermore, our results highlight the important role natural nanoparticles may have in plant P nutrition. PMID- 22452490 TI - State cuts put colleges in precarious situation. PMID- 22452491 TI - Comparison of glomerular filtration rate determined by use of single-slice dynamic computed tomography and scintigraphy in cats. AB - OBJECTIVE: To compare estimation of glomerular filtration rate determined via conventional methods (ie, scintigraphy and plasma clearance of technetium Tc 99m pentetate) and dynamic single-slice computed tomography (CT). ANIMALS: 8 healthy adult cats. PROCEDURES: Scintigraphy, plasma clearance testing, and dynamic CT were performed on each cat on the same day; order of examinations was randomized. Separate observers performed GFR calculations for scintigraphy, plasma clearance testing, or dynamic CT. Methods were compared via Bland-Altman plots and considered interchangeable and acceptable when the 95% limits of agreement (mean difference between methods +/- 1.96 SD of the differences) were <= 0.7 mL/min/kg. RESULTS: Global GFR differed < 0.7 mL/min/kg in 5 of 8 cats when comparing plasma clearance testing and dynamic CT; the limits of agreement were 1.4 and -1.7 mL/min/kg. The mean +/- SD difference was -0.2 +/- 0.8 mL/min/kg, and the maximum difference was 1.6 mL/min/kg. The mean +/- SD difference (absolute value) for percentage filtration by individual kidneys was 2.4 +/- 10.5% when comparing scintigraphy and dynamic CT; the maximum difference was 20%, and the limits of agreement were 18% and 23% (absolute value). CONCLUSIONS AND CLINICAL RELEVANCE: GFR estimation via dynamic CT exceeded the definition for acceptable clinical use, compared with results for conventional methods, which was likely attributable to sample size and preventable technical complications. Because 5 of 8 cats had comparable values between methods, further investigation of dynamic CT in a larger sample population with a wide range of GFR values should be performed. PMID- 22452492 TI - Evaluation of a midazolam-ketamine-xylazine infusion for total intravenous anesthesia in horses. AB - OBJECTIVE: To evaluate the use of midazolam, ketamine, and xylazine for total IV anesthesia (TIVA) in horses. ANIMALS: 6 healthy Thoroughbred mares. PROCEDURES: Horses were sedated with xylazine (1.0 mg/kg, IV). Anesthesia was induced with midazolam (0.1 mg/kg, IV) followed by ketamine (2.2 mg/kg, IV) and was maintained with an IV infusion of midazolam (0.002 mg/kg/min), ketamine (0.03 mg/kg/min), and xylazine (0.016 mg/kg/min). Horses underwent surgical manipulation and injection of the palmar digital nerves; duration of the infusion was 60 minutes. Additional ketamine (0.2 to 0.4 mg/kg, IV) was administered if a horse moved its head or limbs during procedures. Cardiopulmonary and arterial blood variables were measured prior to anesthesia; at 10, 20, 30, 45, and 60 minutes during infusion; and 10 minutes after horses stood during recovery. Recovery quality was assessed by use of a numeric (1 to 10) scale with 1 as an optimal score. RESULTS: Anesthesia was produced for 70 minutes after induction; supplemental ketamine administration was required in 4 horses. Heart rate, respiratory rate, arterial blood pressures, and cardiac output remained similar to preanesthetic values throughout TIVA. Arterial partial pressure of oxygen and oxygen saturation of arterial hemoglobin were significantly decreased from preanesthetic values throughout anesthesia; oxygen delivery was significantly decreased at 10- to 30 minute time points. Each horse stood on its first attempt, and median recovery score was 2. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam, ketamine, and xylazine in combination produced TIVA in horses. Further studies to investigate various dosages for midazolam and ketamine or the substitution of other alpha(2) adrenoceptor for xylazine are warranted. PMID- 22452493 TI - Comparison of the analgesic efficacy of oral ABT-116 administration with that of transmucosal buprenorphine administration in dogs. AB - OBJECTIVE: To evaluate the analgesic efficacy of ABT-116, a transient receptor potential cation channel vanilloid subfamily V member 1 antagonist, and compare it with that of buprenorphine by measurement of mechanical and thermal nociceptive thresholds in dogs. ANIMALS: Six 7- to 8-month-old dogs (3 males and 3 females). PROCEDURES: In a crossover study design, all dogs received ABT-116 (30 mg/kg, PO) and buprenorphine (0.03 mg/kg, orotransmucosally), with each treatment separated by 1 week. Physiologic variables were recorded prior to and 1, 6, and 24 hours after drug administration. Thermal (thoracic) and mechanical (dorsolateral aspect of the radius [proximal] and dorsopalmar aspect of the forefoot [distal]) nociceptive thresholds were assessed prior to (baseline) and 15 minutes and 1, 2, 4, 6, 12, 18, and 24 hours after treatment. RESULTS: Buprenorphine administration resulted in higher overall thermal and proximal mechanical nociceptive thresholds, compared with ABT-116. Distal mechanical nociceptive thresholds after treatment were higher than baseline values for both treatments, but the magnitude of change was greater for buprenorphine at 1 hour after administration. Whereas HR and RR sporadically differed from baseline values after ABT-116 administration, rectal temperature increased from a baseline value of 39 +/- 0.2 degrees C (mean +/- SD) to a peak of 40.6 +/- 0.2 degrees C at 6 hours. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs without inflammation or nerve injury, PO administration of ABT-116 did not consistently result in an increase in nociceptive thresholds. However, clinically relevant increases in rectal temperature were identified after ABT-116 administration. PMID- 22452494 TI - Effect of kennel noise on hearing in dogs. AB - OBJECTIVE: To evaluate the degree of noise to which kenneled dogs were exposed in 2 typical kennels and to determine whether a measurable change in hearing might have developed as a result of exposure to this noise. ANIMALS: 14 dogs temporarily housed in 2 kennel environments. PROCEDURES: Noise levels were measured for a 6-month period in one environment (veterinary technical college kennel) and for 3 months in another (animal shelter). Auditory brainstem response testing was performed on dogs in the veterinary kennel 48 hours and 3 and 6 months after arrival. Temporal changes in the lowest detectable response levels for wave V were analyzed. RESULTS: Acoustic analysis of the kennel environments revealed equivalent sound level values ranging between 100 and 108 dB sound pressure level for the 2 kennels. At the end of 6 months, all 14 dogs that underwent hearing tests had a measured change in hearing. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the noise assessments indicated levels that are damaging to the human auditory system. Such levels could be considered dangerous for kenneled dogs as well, particularly given the demonstrated hearing loss in dogs housed in the veterinary kennel for a prolonged period. Noise abatement strategies should be a standard part of kennel design and operation when such kennels are intended for long-term housing of dogs. PMID- 22452495 TI - Clinical, behavioral, and pulmonary changes in calves following inoculation with Mycoplasma bovis. AB - OBJECTIVE: To characterize clinical and behavioral changes in calves following inoculation with Mycoplasma bovis and evaluate relationships between those changes and pulmonary disease. ANIMALS: 22 healthy Holstein steers. PROCEDURES: 20 calves were inoculated intranasally with < 10(8) CFU or > 10(9) CFU of M bovis. Calves were assigned a clinical illness score (CIS) on a scale of 1 through 4 twice daily on the basis of severity of cough, labored breathing, and lethargy. For each calf, distance traveled and time spent near the waterer, feed bunk, or shelter were determined via a remote location monitoring device. Calves were euthanized and necropsied 22 days after inoculation. RESULTS: 13 calves became clinically ill after challenge inoculation; 3 calves were euthanized within 20 days. Among all calves, consolidation was evident in 0% to 79.9% of the lungs; extent of lung consolidation did not differ between the challenge dose groups. Distance traveled and percentages of time spent in proximity to the feed bunk and shelter were associated with CIS; calves with more severe disease traveled less distance and spent less time at the feed bunk and more time in the shelter. Distance traveled by calves was negatively associated with extent of lung consolidation (< or >= 10% of lungs affected); this effect was modified by trial day. CONCLUSIONS AND CLINICAL RELEVANCE: Following inoculation with M bovis, calf behavior patterns were associated with both CIS and severity of pulmonary disease. Use of behavior monitoring systems may aid in recognition of respiratory tract disease in calves. PMID- 22452496 TI - Histologic and histomorphometric evaluation of midcarpal joint defects in Thoroughbreds raised with and without early conditioning exercise. AB - OBJECTIVE: To describe and measure histologic features of midcarpal joint cartilage defects in Thoroughbreds and evaluate the influence of early conditioning exercise on defect development. SAMPLE: 24 midcarpal joints from twelve 18-month-old Thoroughbreds. PROCEDURES: Midcarpal joints from 12 horses (6 exercised spontaneously at pasture only and 6 given additional conditioning exercise beginning at a mean age of 3 weeks were evaluated. Gross cartilage defects were assessed histologically. Third and radial carpal bones were categorized with regard to the presence or absence of calcified cartilage (CC) abnormalities at the dorsoproximal and dorsodistal articular surfaces, respectively; histomorphometric assessment and statistical analysis were conducted for the third carpal bone. RESULTS: Number and severity of defects did not appear different between exercise groups. Nine third or radial carpal bones had thickened CC with microcracks, matrix and osteochondral junction changes, and increased vascularity, without histologic changes in the hyaline cartilage. Third carpal bones with CC abnormalities had significantly thicker CC (452 vs 228 MUm) than did those without CC abnormalities in the evaluated region. However, in the same region, there were no significant differences in hyaline cartilage thickness (681 vs 603 MUm), vascular channel area in the subchondral bone (624,894 vs 490,320 MUm(2)), or number of vascular channels (15.9 vs 18.0). CONCLUSIONS AND CLINICAL RELEVANCE: Early exercise did not appear to influence the distribution or severity of cartilage defects in the midcarpal joint. Calcified cartilage abnormalities beneath the undisrupted hyaline cartilage in the dorsoproximal aspect of the third carpal bone may represent the first changes in the pathogenesis of midcarpal osteochondral disease. PMID- 22452497 TI - Changes in heart rate, heart rate variability, and atrioventricular block during withholding of food in Thoroughbreds. AB - OBJECTIVE: To determine whether withholding of food affects autonomic nervous system balance by analysis of heart rate (HR), HR variability (HRV), and frequency of second-degree atrioventricular block in horses. ANIMALS: 5 healthy Thoroughbreds. PROCEDURES: For two 24-hour periods in a crossover study, food was withheld from horses or horses were maintained on their regular feeding schedule (control conditions) in their stalls and Holter monitor ECG recordings were obtained. The ECGs were analyzed by use of fast-Fourier transformation, and power spectrum densities were calculated for low-frequency (0.01 to 0.07 Hz) and high frequency (0.07 to 0.6 Hz) variations in HR. Serum cortisol and plasma ACTH, norepinephrine, and glucose concentrations were measured at predetermined time points. RESULTS: Withholding of food resulted in significantly lower HR and more frequent second-degree atrioventricular block (the frequency of which was inversely related to the HR), compared with findings for control conditions. Circadian rhythms were similar during food-withholding and control conditions; peak HR was detected from 7:00 pm to 8:00 pm, and the lowest HR was detected in the early morning. During food-withholding conditions, the low-frequency and high frequency components of HRV were significantly higher, and the low-frequency-to high-frequency ratio was lower than during control conditions. Serum cortisol concentration was higher and plasma glucose concentration was lower at 6:00 pm in horses when food was withheld, compared with findings during control conditions. CONCLUSIONS AND CLINICAL RELEVANCE: Indices of HRV seemed to be sensitive to changes in autonomic nervous activity and may be useful as clinical indices of the neuroendocrine response to stressors in horses. PMID- 22452498 TI - Changes in heart rate and heart rate variability during transportation of horses by road and air. AB - OBJECTIVE: To determine the influence of transportation by road and air on heart rate (HR) and HR variability (HRV) in horses. Animals-6 healthy horses. PROCEDURES: ECG recordings were obtained from horses before (quarantine with stall rest [Q]; 24 hours) and during a journey that included transportation by road (RT; 4.5 hours), waiting on the ground in an air stall (W; 5.5 hours), and transportation by air (AT; 11 hours); HR was determined, and HRV indices of autonomic nervous activity (low-frequency [LF; 0.01 to 0.07 Hz] and high frequency [HF; 0.07 to 0.6 Hz] power) were calculated. RESULTS: Mean +/- SD HRs during Q, RT, W, and AT were 38.9 +/- 1.5 beats/min, 41.7 +/- 5.6 beats/min, 41.5 +/- 4.3 beats/min, and 48.8 +/- 5.6 beats/min, respectively; HR during AT was significantly higher than HR during Q. The LF power was significantly higher during Q (3,454 +/- 1,087 milliseconds(2)) and AT (3,101 +/- 567 milliseconds(2)) than it was during RT (1,824 +/- 432 milliseconds(2)) and W (2,072 +/- 616 milliseconds(2)). During Q, RT, W, and AT, neither HF powers (range, 509 to 927 milliseconds(2)) nor LF:HF ratios (range, 4.1 to 6.2) differed significantly. The HR during RT was highly correlated with LF power (R(2) = 0.979), and HR during AT was moderately correlated with the LF:HF ratio (R(2) = 0.477). CONCLUSIONS AND CLINICAL RELEVANCE: In horses, HR and HRV indices during RT and AT differed, suggesting that exposure to different stressors results in different autonomic nervous influences on HR. PMID- 22452499 TI - Effect of head and neck position on intrathoracic pressure and arterial blood gas values in Dutch Warmblood riding horses during moderate exercise. AB - OBJECTIVE: To evaluate the effect of various head and neck positions on intrathoracic pressure and arterial oxygenation during exercise in horses. ANIMALS: 7 healthy Dutch Warmblood riding horses. PROCEDURES: The horses were evaluated with the head and neck in the following predefined positions: position 1, free and unrestrained; position 2, neck raised with the bridge of the nose aligned vertically; position 4, neck lowered and extremely flexed with the nose pointing toward the pectoral muscles; position 5, neck raised and extended with the bridge of the nose in front of a vertical line perpendicular to the ground surface; and position 7, neck lowered and flexed with the nose pointing towards the carpus. The standard exercise protocol consisted of trotting for 10 minutes, cantering for 4 minutes, trotting again for 5 minutes, and walking for 5 minutes. An esophageal balloon catheter was used to indirectly measure intrathoracic pressure. Arterial blood samples were obtained for measurement of Pao(2), Paco(2), and arterial oxygen saturation. RESULTS: Compared with when horses were in the unrestrained position, inspiratory intrathoracic pressure became more negative during the first trot (all positions), canter and second trot (position 4), and walk (positions 4 and 5). Compared with when horses were in position 1, intrathoracic pressure difference increased in positions 4, 2, 7, and 5; Pao(2) increased in position 5; and arterial oxygen saturation increased in positions 4 and 7. CONCLUSIONS AND CLINICAL RELEVANCE: Position 4 was particularly influential on intrathoracic pressure during exercise in horses. The effects detected may have been caused by a dynamic upper airway obstruction and may be more profound in horses with upper airway disease. PMID- 22452500 TI - Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs. AB - OBJECTIVE: To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs. ANIMALS: 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs. PROCEDURES: The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index. Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured and dual energy x-ray absorptiometry was performed to evaluate body composition. RESULTS: Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations as well as abdominal fat content were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged. CONCLUSIONS AND CLINICAL RELEVANCE: Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications. PMID- 22452501 TI - Bioavailability of a novel midazolam gel after intranasal administration in dogs. AB - OBJECTIVE: To compare the pharmacokinetics of a novel bioadhesive gel formulation of midazolam after intranasal (IN) administration with that of midazolam solution after IN, IV, and rectal administration to dogs. ANIMALS: 10 (5 males and 5 females) healthy adult Beagles. PROCEDURES: Dogs were assigned to 4 treatment groups for a crossover study design. Initially, midazolam solution (5 mg/mL) was administered (0.2 mg/kg) IV to group 1, rectally to group 2, and IN to group 3; a 0.4% hydroxypropyl methylcellulose midazolam gel formulation (50 mg/mL) was administered (0.2 mg/kg, IN) to group 4. Each dog received all 4 treatments; there was a 7-day washout period between subsequent treatments. Blood samples were collected before and after midazolam administration. Plasma concentration of midazolam was determined by use of high-performance liquid chromatography. RESULTS: The peak plasma concentration after IN administration of the gel formulation was significantly higher than that after IN and rectal administration of the solution. Mean +/- SD time to peak concentration was 11.70 +/- 2.63 minutes (gel IN), 17.50 +/- 2.64 minutes (solution IN), and 39 +/- 14.49 minutes (solution rectally). Mean bioavailability of midazolam was 70.4% (gel IN), 52.0% (solution IN), and 49.0% (solution rectally). Bioavailability after IN administration of the gel formulation was significantly higher than that after IN and rectal administration of the solution. CONCLUSIONS AND CLINICAL RELEVANCE: IN administration of midazolam gel was superior to both IN and rectal administration of midazolam solution with respect to peak plasma concentration and bioavailability. PMID- 22452502 TI - Effect of optical defocus on performance of dogs involved in field trial competition. AB - OBJECTIVE: To measure the effect of induced myopia on field trial performance in dogs. ANIMALS: 7 Labrador Retrievers and 1 Chesapeake Bay Retriever trained in field trial competition. PROCEDURES: Dogs were commanded to retrieve targets at 137.2 m (150 yards). Each dog participated in 3 trials while their eyes were fitted with 0- (plano), +1.50-, or +3.00-diopter (D) contact lenses, applied in random order. Retrieval times were measured objectively, and dog performances were evaluated subjectively by masked judges. RESULTS: Retrieval times were significantly faster with plano lenses than with +1.50- or +3.00-D lenses, but there were no significant differences in times between +1.50- and +3.00-D lenses. Masked judges assigned the best performance scores to dogs with plano lenses and the lowest scores to dogs fitted with +3.00-D lenses. CONCLUSIONS AND CLINICAL RELEVANCE: Even mild myopic defocusing had a significant negative impact on both the subjective and objective assessments of dogs' performances. Dogs with demanding visual tasks or signs of visual deterioration should be evaluated retinoscopically to determine the refractive state because they may have ametropia. PMID- 22452503 TI - Fluorophotometric determination of aqueous humor flow rates in red-tailed hawks (Buteo jamaicensis). AB - OBJECTIVE: To determine aqueous humor flow rate (AHFR) in an avian species by use of anterior segment fluorophotometry. ANIMALS: 9 healthy red-tailed hawks (Buteo jamaicensis; 4 males and 5 females) that ranged from 8 months to 8 years of age. PROCEDURES: A protocol was developed for fluorophotometric determination of AHFR. Topical administration of 10% fluorescein was used to load the corneas, and corneal and aqueous humor fluorescein concentrations were measured approximately 5, 6.5, and 8 hours later. Concentration-versus-time plots were generated, and slopes and cornea-to-aqueous humor concentration ratios from these plots were used to manually calculate flow rates. RESULTS: Mean +/- SD AHFRs for the right eye, left eye, and both eyes were 3.17 +/- 1.36 MUL/min (range, 1.67 to 6.21 MUL/min), 2.86 +/- 0.88 MUL/min (range, 2.04 to 4.30 MUL/min), and 2.90 +/- 0.90 MUL/min (range, 1.67 to 4.42 MUL/min), respectively. The AHFRs were similar for right and left eyes. These flow rates represented a mean aqueous humor transfer coefficient of 0.0082/min, which is similar to that of mammalian species. CONCLUSIONS AND CLINICAL RELEVANCE: The AHFR in red-tailed hawks was similar to that of most mammalian species, and the fractional egress was almost identical to that of other species. This information will allow a greater understanding of aqueous humor flow in avian eyes, which is crucial when evaluating diseases that affect avian eyes as well as medications that alter aqueous humor flow. PMID- 22452504 TI - Dose determination of fondaparinux in healthy cats. AB - OBJECTIVE: To establish practical doses and administration frequencies of fondaparinux for cats that would approximate human therapeutic peak and trough plasma anti-factor Xa activities for thromboprophylaxis (TP) and thrombosis treatment (TT) protocols. ANIMALS: 6 healthy adult purpose-bred cats. PROCEDURES: Dosage protocols for TP and TT were selected on the basis of a single compartment pharmacokinetic model incorporating data from humans but modified to account for the higher body weight-normalized cardiac output of cats. Fondaparinux was administered at 0.06 mg/kg, SC, every 12 hours (TP) for 7 days in one session, and 0.20 mg/kg, SC, every 12 hours (TT) for 7 days in another, with a minimum of 1 week separating the sessions. Plasma anti-factor Xa activity was measured before fondaparinux administration (day 1) and at 2 (peak) and 12 (trough) hours after drug administration on days 1 and 7. Platelet aggregation and thromobelastographic (TEG) parameters were also measured 2 hours after drug administration on day 7. RESULTS: Peak plasma anti-factor Xa activities on day 7 for TP (median, 0.59 mg/L; range, 0.36 to 0.77 mg/L) and TT (median, 1.66 mg/L; range, 1.52 to 2.00 mg/L) protocols were within therapeutic ranges for humans. However, only the TP protocol achieved trough anti-factor Xa activity considered therapeutic in humans (median, 0.19 mg/L; range, 0.00 to 0.37 mg/L) on day 7. There were significant changes in the TEG parameters at peak for the TT protocol, suggesting a hypocoagulable state. No significant changes in platelet aggregation were evident for either protocol. CONCLUSIONS AND CLINICAL RELEVANCE: A fondaparinux dosage of 0.06 or 0.20 mg/kg, SC, every 12 hours, was sufficient to achieve a peak plasma anti-factor Xa activity in cats that has been deemed therapeutic in humans. This study provided preliminary data necessary to perform fondaparinux dose-determination and clinical efficacy studies. PMID- 22452505 TI - Pharmacokinetics, efficacy, and adverse effects of selamectin following topical administration in flea-infested rabbits. AB - OBJECTIVE: To determine pharmacokinetics, efficacy, and adverse effects of topically administered selamectin in flea-infested rabbits. ANIMALS: 18 healthy 5 month-old New Zealand White rabbits. PROCEDURES: On day 0, rabbits (n = 6/group) received topically applied selamectin at doses of 10 or 20 mg/kg or received no treatment. Each rabbit was infested with 50 fleas (Ctenocephalides felis) on days -1, 7, and 14. Live and dead flea counts were performed on days 2, 9, and 16, and treatment efficacy was calculated. Blood samples were collected prior to drug administration and at 6 and 12 hours and 1, 2, 3, 5, 7, 10, 14, 21, and 28 days after treatment for determination of plasma selamectin concentrations via high performance liquid chromatography with mass spectrometry. Pharmacokinetic parameters were determined. RESULTS: On day 2, efficacy of selamectin against flea populations of rabbits in the 10 and 20 mg/kg treatment groups was 91.3% and 97.1%, respectively, but by day 9, these values decreased to 37.7% and 74.2%, respectively. Mean terminal half-life and maximum plasma concentrations of selamectin were 0.93 days and 91.7 ng/mL, respectively, for rabbits in the 10 mg/kg group and 0.97 days and 304.2 ng/mL, respectively, for rabbits in the 20 mg/kg group. No adverse effects were detected. CONCLUSIONS AND CLINICAL RELEVANCE: Selamectin was rapidly absorbed transdermally and was rapidly eliminated in rabbits. Results suggested that topical administration at a dosage of 20 mg/kg every 7 days is efficacious for treatment of flea infestation in rabbits. Further studies are needed to assess long-term safety in rabbits following repeated applications. PMID- 22452506 TI - Evaluation of the onset of protection induced by a modified-live virus vaccine in calves challenge inoculated with type 1b bovine viral diarrhea virus. AB - OBJECTIVE: To evaluate onset of protection induced by modified-live virus (MLV) bovine viral diarrhea virus (BVDV) vaccine administered 7, 5, or 3 days before inoculation with type 1b BVDV (strain NY-1). Animals-40 calves. PROCEDURES: Calves were assigned to 4 groups: an unvaccinated control group or groups vaccinated with MLV vaccine containing BVDV types 1a and 2 at 7, 5, or 3 days, before inoculation with NY-1 BVDV. Blood samples were collected for leukocyte counts, serum virus neutralization, and virus isolation (VI); nasal swab specimens (NSSs) were obtained for VI, and rectal temperatures were monitored for 14 days after inoculation. RESULTS: No significant differences in leukocyte counts or rectal temperatures were detected after BVDV inoculation in vaccinated calves. Vaccinated calves had reduced viremia and viral shedding after inoculation, compared with results for unvaccinated calves. On day 5 after inoculation, a higher proportion of calves vaccinated 3 days before inoculation had positive VI from NSSs, compared with NSS VI results for calves vaccinated 5 and 7 days before inoculation. Unvaccinated calves had leukopenia on days 3, 5, and 6 and had higher rectal temperatures on days 7 and 8 after inoculation, compared with temperatures before inoculation. All unvaccinated calves had >= 1 positive VI result from NSSs 3 to 11 days after inoculation, and 4 became viremic. CONCLUSIONS AND CLINICAL RELEVANCE: MLV BVDV vaccine prevented fever, viremia, and leukopenia in calves challenge inoculated with NY-1 BVDV. A high proportion of calves vaccinated 3 days before inoculation shed BVDV after inoculation. PMID- 22452509 TI - Multiresponsive polymer conetworks capable of responding to changes in pH, temperature, and magnetic field: synthesis, characterization, and evaluation of their ability for controlled uptake and release of solutes. AB - This study deals with the preparation of novel multiresponsive (magnetoresponsive, thermoresponsive and pH-responsive) nanocomposite conetworks consisting of oleic acid-coated magnetite nanoparticles (OA.Fe(3)O(4)), hydrophilic/thermoresponsive hexa(ethylene glycol) methyl ether methacrylate (HEGMA), hydrophobic/metal binding 2-(acetoacetoxy)ethyl methacrylate (AEMA), and pH-responsive/thermoresponsive N-diethylaminoethyl methacrylate (DEAEMA) and 2 (dimethylamino)ethyl methacrylate (DMAEMA) moieties. Conventional free radical copolymerization was employed for the synthesis of random conetworks in the absence and presence of preformed OA.Fe(3)O(4). Further, in characterization of these materials in regards to their swelling behavior in organic and aqueous solvents, thermal/thermoresponsive properties, and composition, assessment of their magnetic characteristics disclosed tunable superparamagnetic behavior. These systems were also evaluated toward their ability to adsorb and release a solute (benzoic acid) in a controlled manner upon varying the pH. PMID- 22452510 TI - Subterranean microbial populations metabolize hydrogen and acetate under in situ conditions in granitic groundwater at 450 m depth in the Aspo Hard Rock Laboratory, Sweden. AB - Pressure-resistant circulating systems were constructed to enable the investigation of attached and unattached microbial populations under in situ pressure (2.5 MPa), diversity, dissolved gas and chemistry conditions. Three parallel flow cell cabinets were configured to allow observation of the effect on microbial metabolic activity of adding 3 mM hydrogen or 2.4 mM acetate, compared with an untreated control. Hydrogen addition reduced the generation time fourfold to 2 weeks, doubled the sulphide production rate and increased acetate production by approximately 50%. The acetate addition induced acetate consumption. The studied subterranean microbial processes appeared to proceed very slowly in terms of volume and time, although the results suggest that individual cells could be very active. Lytic bacteriophages are hypothesized to have caused this contradictive observation. Phages may consequently significantly reduce the rates of subterranean microbial processes. Furthermore, the results suggest that hydrogen from corroding underground constructions could induce significant local microbial activity and that the low concentrations of hydrogen often observed in pristine subterranean environments may support slow but sustainable microbial activity in deep groundwater. PMID- 22452511 TI - Clinical evaluation of a microwave device for treating axillary hyperhidrosis. AB - BACKGROUND: A third-generation microwave-based device has been developed to treat axillary hyperhidrosis by selectively heating the interface between the skin and underlying fat where the sweat glands reside. MATERIALS AND METHODS: Thirty-one (31) adults with primary axillary hyperhidrosis were enrolled. All subjects had one to three procedure sessions over a 6-month period to treat both axillae fully. Efficacy was assessed using the Hyperhidrosis Disease Severity Scale (HDSS), gravimetric weight of sweat, and the Dermatologic Life Quality Index (DLQI), a dermatology-specific quality-of-life scale. Subject safety was assessed at each visit. Subjects were followed for 12 months after all procedure sessions were complete. RESULTS: At the 12-month follow-up visit, 90.3% had HDSS scores of 1 or 2, 90.3% had at least a 50% reduction in axillary sweat from baseline, and 85.2% had a reduction of at least 5 points on the DLQI. All subjects experienced transient effects in the treatment area such as swelling, discomfort, and numbness. The most common adverse event (12 subjects) was the presence of altered sensation in the skin of the arm that resolved in all subjects. CONCLUSION: The device tested provided efficacious and durable treatment for axillary hyperhidrosis. PMID- 22452512 TI - Model of a six immunoglobulin-like domain fragment of filamin A (16-21) built using residual dipolar couplings. AB - Filamins are actin-binding proteins that participate in a wide range of cell functions, including cell morphology, locomotion, membrane protein localization, and intracellular signaling. The three filamin isoforms found in humans, filamins A, B, and C, are highly homologous, and their roles are partly complementary. In addition to actin, filamins interact with dozens of other proteins that have roles as membrane receptors and channels, enzymes, signaling intermediates, and transcription factors. Filamins are composed of an N-terminal actin-binding domain and 24 filamin-type immunoglobulin-like domains (FLN) that form tail-to tail dimers with their C-terminal FLN domain. Many of the filamin interactions including those for glycoprotein Ibalpha and integrins have been mapped to the region comprising FLN domains 16-21. Traditionally, FLN domains have been viewed as independent folding units, arranged in a linear chain joined with flexible linkers. Recent structural findings have shown that consecutive FLNs form more intricate superstructures. The crystal structure of filamin A domains 19-21 (FLNa19-21) revealed that domains 20 and 21 fold together and that the domain interaction can be autoregulatory. The solution structure of domains 18-19 showed a similar domain interaction, whereas domain pair 16-17 has a completely different domain packing mode. In this study, we characterize the domain organization of the FLNa domain sextet 16-21 using NMR spectroscopy. A structure model of this 60-kDa protein has been built using residual dipolar coupling restraints. RDCs and (15)N relaxation data have been used to characterize interdomain motions. PMID- 22452513 TI - Self-assembly of flexible beta-strands into immobile amyloid-like beta-sheets in membranes as revealed by solid-state 19F NMR. AB - The cationic peptide [KIGAKI](3) was designed as an amphiphilic beta-strand and serves as a model for beta-sheet aggregation in membranes. Here, we have characterized its molecular conformation, membrane alignment, and dynamic behavior using solid-state (19)F NMR. A detailed structure analysis of selectively (19)F-labeled peptides was carried out in oriented DMPC bilayers. It showed a concentration-dependent transition from monomeric beta-strands to oligomeric beta-sheets. In both states, the rigid (19)F-labeled side chains project straight into the lipid bilayer but they experience very different mobilities. At low peptide-to-lipid ratios <=1:400, monomeric [KIGAKI](3) swims around freely on the membrane surface and undergoes considerable motional averaging, with essentially uncoupled phi/psi torsion angles. The flexibility of the peptide backbone in this 2D plane is reminiscent of intrinsically unstructured proteins in 3D. At high concentrations, [KIGAKI](3) self-assembles into immobilized beta-sheets, which are untwisted and lie flat on the membrane surface as amyloid-like fibrils. This is the first time the transition of monomeric beta-strands into oligomeric beta-sheets has been characterized by solid-state NMR in lipid bilayers. It promises to be a valuable approach for studying membrane-induced amyloid formation of many other, clinically relevant peptide systems. PMID- 22452514 TI - The role of AMPKalpha in high-glucose-induced dysfunction of cultured rat mesangial cells. AB - AIM: Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is known as a mammalian cell energy sensor, which could regulate cellular energy metabolism via sensing the alterations of energy balance, such as oversupply or lack of glucose and fatty acid. Recent studies have suggested that AMPK could also regulate many other biological processes, including cell cycling, inflammation, protein synthesis, and so on. In this study, AMPK signaling in high-glucose induced dysfunction of mesangial cells (MCs) was investigated. METHODS: Established rat glomerular MCs were treated under normal glucose (5.6 mM glucose) or high-glucose conditions (30 mM glucose). mRNA levels of AMPK subunits were detected by reverse transcriptase-polymerase chain reaction. Expressions of AMPKalpha, phosphorylated AMPKalpha (p-AMPKalpha), phosphorylated acetyl-CoA carboxylase (p-ACC), and collagen IV were measured by Western blot. RESULTS: Under high-glucose conditions, AMPKalpha protein expression and mRNA levels were significantly decreased. High-glucose treatment also induced a notable decrease in p-AMPKalpha and p-ACC expression. AMPKalpha activation by 5-aminoimidazole-4 carboxamide-1-beta-d-ribofuranoside (AICAR) effectively ameliorated high-glucose induced dysfunction of MCs, including cell proliferation, cell-cycle progression, and collagen IV production. CONCLUSION: High glucose impaired AMPKalpha in its expression and activity; AICAR significantly ameliorated high-glucose-induced proliferation of MCs and collagen IV production, indicating a role of AMPKalpha in high-glucose-induced dysfunction of MCs. PMID- 22452515 TI - Psychiatric Advance Directives as a complex and multistage intervention: a realist systematic review. AB - Psychiatric Advance Directives (PADs) are documents that allow users with severe and chronic mental illnesses to notify their treatment preferences for future crisis relapses and to appoint a surrogate decision-maker for a period of incompetence. Despite many supposed clinical and organisational benefits, their take-up rate has remained very low and their clinical evaluation has given contradictory results for organisational outcomes. Intermediary results are available, however, which rely on different theoretical views about how PADs are supposed to work. We carried out a realist systematic review that considered the PAD as a multistage intervention including the definition of the document, its completion and its access and honouring. We identified the theoretical frameworks underlying this kind of intervention and examined the available evidence that supported or contradicted the expectations at each stage of the intervention. Forty-seven references were retrieved, ranging from 1996 to 2009. Three frameworks underlie a PAD intervention: enhancement of the autonomy of the user, improvement of the therapeutic alliance and integration of care through partnership working. Although designed in the first place with a view to sustaining the user's autonomy, results indicate that the intervention is more efficient within a therapeutic alliance framework. Moreover, much is known about the completion process and the content of the document, but very little about its access and honouring. The mixture of expectations makes the purpose of PADs unclear, for example, crisis relapse prevention or management, advance planning of long-term or emergency care, or reduction in the resort to coercion. This may explain their low take-up rates. Hence, frameworks and purpose have to be clarified. The shape of the whole intervention at each stage relies on such clarification. More research is needed, particularly on the later stages of the intervention, as the evidence for how PADs should be implemented is still incomplete. PMID- 22452516 TI - SCORTEN and impaired renal function related to mortality of toxic epidermal necrolysis syndrome patients in the Asian population. AB - BACKGROUND: Toxic epidermal necrolysis syndrome (TEN) is a rare, life threatening, drug-related skin reaction with a high mortality rate. To date, only a few studies with insufficient sample sizes have been conducted to analyse SCORTEN in Asian populations with TEN. OBJECTIVE: To analyse SCORTEN and other related factors that affect TEN patients in Taiwan. METHODS: A retrospective review of medical records of 101 patients with TEN from 1992 to 2009. RESULTS: There were 62 cases of adverse reactions to a single medication and 39 cases of idiopathic reaction, from multiple medications, or infectious pathogens, of 101 TEN patients. Of the seven individual SCORTEN parameters, only associate malignancy, detached or compromised body surface area >10%, serum urea and bicarbonate were statistically significant in the multivariate analysis. Factors such as 1.5 times baseline serum creatinine levels, urine output of less than 0.5 mL/kg for 6 h and acute renal failure were connected with subsequent mortality. CONCLUSION: The SCORTEN score is effective in predicting the outcome in Taiwanese TEN patients. A number of factors are predictors of mortality. In our study, we determine renal insufficiency and failure to be a marker for predicting a poor outcome. PMID- 22452517 TI - Can a partial volume edge effect reduction algorithm improve the repeatability of subject-specific finite element models of femurs obtained from CT data? AB - The reliability of patient-specific finite element (FE) modelling is dependent on the ability to provide repeatable analyses. Differences of inter-operator generated grids can produce variability in strain and stress readings at a desired location, which are magnified at the surface of the model as a result of the partial volume edge effects (PVEEs). In this study, a new approach is introduced based on an in-house developed algorithm which adjusts the location of the model's surface nodes to a consistent predefined threshold Hounsfield unit value. Three cadaveric human femora specimens were CT scanned, and surface models were created after a semi-automatic segmentation by three different experienced operators. A FE analysis was conducted for each model, with and without applying the surface-adjustment algorithm (a total of 18 models), implementing identical boundary conditions. Maximum principal strain and stress and spatial coordinates were probed at six equivalent surface nodes from the six generated models for each of the three specimens at locations commonly utilised for experimental strain guage measurement validation. A Wilcoxon signed-ranks test was conducted to determine inter-operator variability and the impact of the PVEE-adjustment algorithm. The average inter-operator difference in stress values was significantly reduced after applying the adjustment algorithm (before: 3.32 +/- 4.35 MPa, after: 1.47 +/- 1.77 MPa, p = 0.025). Strain values were found to be less sensitive to inter-operative variability (p = 0.286). In summary, the new approach as presented in this study may provide a means to improve the repeatability of subject-specific FE models of bone obtained from CT data. PMID- 22452518 TI - Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3- morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo. AB - Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7 dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2 yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c. PMID- 22452519 TI - A novel pathway of photoinduced decomposition of sphingolipids. AB - A possibility of a novel photodestruction process has been shown for sphingolipids and their low-molecular analogues, including the stage of Norrish Type-I decomposition of excited molecules of the starting compounds followed by fragmentation of nitrogen-centered radicals via rupture of the C-C and O-H bonds. Realization of such transformation during photolysis of ceramide, sphingomyelin and galactocerebroside results in formation of 2-hexadecenal, which possess a wide spectrum of biological activity. PMID- 22452520 TI - The chronic prostatitis/chronic pelvic pain syndrome and pain catastrophizing: a vicious combination. AB - OBJECTIVE: This study aimed to evaluate the presence and importance of pain catastrophizing among men diagnosed with chronic abacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS) in a routine clinical setting. MATERIAL AND METHODS: 61 men, mean age 46 +/- 11 years, with a mean CP/CPPS history of 11 +/- 11 years, completed the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), Short-Form McGill Pain Questionnaire (SF-MPQ) and Coping Strategies Questionnaire (CSQ) to evaluate pain catastrophizing, and the International Index of Erectile Function (IIEF-5). They were also scored according to the UPOINT system. RESULTS: The patients' mean scores were: IEEF-5 17.6 +/- 7.3, NIH-CPSI pain subscale 11.1 +/- 4.4, quality of life question 2.7 +/- 1.6, quality of life impact subscale 6.9 +/- 2.7 and CSQ catastrophizing score 15.3 +/- 9.1. Patients with a high tendency for catastrophizing (CSQ score >=20) (28%) had higher UPOINT and pain scores, worse quality of life and quality of life impact, but did not stand out regarding voiding dysfunction and ejaculatory pain. CONCLUSIONS: Two distinctly different cohorts could be identified: a smaller cohort with a high degree of catastrophizing, severe pain and poor quality of life, and a larger one with a low degree of catastrophizing, less severe pain and moderately reduced quality of life. It is important in clinical practice to distinguish between the two groups since they require different therapeutic approaches. PMID- 22452521 TI - Body fat, abdominal fat and body fat distribution related to cardiovascular risk factors in prepubertal children. AB - AIM: We analysed whether total body fat (TBF), abdominal fat and body fat distribution are associated with higher composite risk factor scores for cardiovascular disease (CVD) in young children. METHODS: Cross-sectional study of 238 children aged 8-11 years. TBF and abdominal fat mass (AFM) were measured by Dual-Energy X-Ray Absorptiometry. TBF was expressed as a percentage of body weight (BF%). Body fat distribution was calculated as AFM/TBF. Maximal oxygen uptake (VO(2PEAK) ), systolic and diastolic blood pressure (SBP, DBP), and resting heart rate (RHR) were measured. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated. Left atrial diameter (LA) was measured, and left ventricular mass (LVM) and relative wall thickness (RWT) were calculated. Z scores were calculated. Sum of z-scores for SBP, DBP, MAP, PP, RHR, LVM, LA, RWT and -VO(2PEAK) was calculated in boys and girls, separately, and used as composite risk factor score. RESULTS: Pearson correlations between ln BF%, ln AFM and AFM/TBF versus composite risk factor score for boys were r = 0.56, r = 0.59 and r = 0.48, all p < 0.001, and for girls r = 0.45, r = 0.50 and r = 0.48, all p < 0.001. CONCLUSION: Total body fat, abdominal fat and body fat distribution were all associated with higher composite risk factor scores for CVD in young children. PMID- 22452522 TI - Microsatellite markers within the alpha-globin gene cluster for robust preimplantation genetic diagnosis of severe alpha-thalassemia syndromes in Mediterranean populations. AB - In this study we report the development of a generic protocol for preimplantation genetic diagnosis (PGD) of severe alpha-thalassemia (alpha-thal) syndromes in alpha-thal carrier couples of Mediterranean origin. The in silico identification and design of primers for multiplex analysis of short tandem repeats (STRs), was followed by the optimization of polymerase chain reaction (PCR) conditions for multiplexed STR analysis within the alpha-globin gene cluster (16p3.3) and subsequent optimization and validation of a single-cell multiplex reaction including the selected STRs. Three simple dinucleotide repeats were selected based on their rate of heterozygosity, multiplex PCR efficiency and product size, and location within the alpha-globin gene cluster. The multiplex PCR was optimized in single lymphocytes with PCR efficiency ranging from 92.5 to 98% and an allele drop-out (ADO) rate of 0 to 9.0% for the three loci. The optimized method was applied in two clinical PGD cycles and genotypes were achieved in 17 out of 18 blastomeres (94%). Transfer of unaffected embryos led to a singleton pregnancy in one of the two couples. The triplex PCR validated for Greek and Cypriot populations is a robust generic method for alpha-thal PGD. PMID- 22452523 TI - Load-bearing capacity of fiber reinforced fixed composite bridges. AB - OBJECTIVE: The aim of this study was to evaluate the reinforcing effect of differently oriented fibers on the load-bearing capacity of three-unit fixed dental prostheses (FDPs). MATERIALS AND METHODS: Forty-eight composite FDPs were fabricated. Specimens were divided into eight groups (n = 6/group; codes 1-8). Groups 1 and 5 were plain restorative composites (Grandio and Z100) without fiber reinforcement, groups 2 and 6 were reinforced with a continuous unidirectional fiber substructure, groups 3 and 7 were reinforced with a continuous bidirectional fiber and groups 4 and 8 were reinforced with a continuous bidirectional fiber substructure and continuous unidirectional fiber. FDPs were polymerized incrementally with a handheld light curing unit for 40 s and statically loaded until final fracture. RESULTS: Kruskal-Wallis analysis revealed that all groups had significantly different load-bearing capacities. Group 4 showed the highest mean load-bearing capacity and Group 7 the lowest. CONCLUSION: The results of this study suggest that continuous unidirectional fiber increased the mechanical properties of composite FDPs and bidirectional reinforcement slowed crack propagation on abutments. PMID- 22452524 TI - Poor achievement of guidelines-recommended targets in type 2 diabetes: findings from a contemporary prospective cohort study. AB - AIMS: To prospectively evaluate diabetes management in the primary care setting and explore factors related to guideline-recommended triple target achievement [blood pressure (BP) <= 130/80 mmHg, A1C <= 7% and low-density lipoprotein (LDL) cholesterol < 2.5 mmol/l]. METHODS: Baseline, 6 and 12 month data on clinical and laboratory parameters were measured in 3002 patients with type 2 diabetes enrolled as part of a prospective quality enhancement research initiative in Canada. A generalised estimating equation model was fitted to assess variables associated with triple target achievement. RESULTS: At baseline, 54%, 53% and 64% of patients, respectively, had BP, A1C and LDL-cholesterol at target; all three goals were met by 19% of patients. The percentage of individuals achieving these targets significantly increased during the study [60%, 57%, 76% and 26%, respectively, at the final visit, p < 0.0001 except for A1C, p = 0.27]. A much smaller proportion of patients had adequate control during the entire study period [30%, 39%, 53% and 7%, respectively]. In multivariable analysis, women, patients younger than 65 years and patients of Afro-Canadian origin were less likely to achieve the triple target. DISCUSSION: As part of a quality enhancement research initiative, we observed important improvements in the attainment of guidelines-recommended targets in patients with type 2 diabetes followed for a 12 month period in the primary care setting; however, many individuals still failed to achieve and especially maintain optimal goals for therapy, particularly the triple target. Results of the multivariable analysis reinforce the need to address barriers to improve diabetes care, particularly in more susceptible groups. PMID- 22452526 TI - The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis. AB - BACKGROUND: The role of antidepressants in the management of fibromyalgia syndrome (FMS) still needs to be determined. OBJECTIVE: The objective of this study was to provide a quantitative analysis (meta-analysis) of the efficacy and harms of antidepressants in the management of adult FMS patients. DATA SOURCES: The data sources used were the databases MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials (until December 30, 2010), the reference lists of included articles, and the websites of the US National Institutes of Health (NIH) and the Pharmaceutical Research and Manufacturers of America (PhRMA). STUDY SELECTION: Studies with a randomized controlled trial (RCT) design comparing any types of antidepressants with pharmacological placebo or head-to-head comparisons of different types of antidepressants in FMS patients were included. RCTs in which antidepressants were combined with any other defined treatment or antidepressants were tested against anything but drug placebo were excluded. Patients diagnosed with FMS according to predefined criteria of any age were included. To be included, studies had to assess at least one key domain of FMS (pain, sleep, fatigue, health-related quality of life [HRQOL]) as outcomes of efficacy and report total treatment discontinuation rates and/or dropout rates due to adverse events as outcomes for harms. DATA EXTRACTION: Data were extracted according to protocols of previous systematic reviews on antidepressants in FMS. Methodology quality was assessed by the van Tulder score. DATA SYNTHESIS: Standardized mean differences (SMD) were calculated for continuous outcomes by means and standard deviations and relative risks (RR) for 30% pain reduction and total dropout rate for comparisons of antidepressants with placebo. Examination of the combined results was performed by a random effects model. We used Cohen's categories to evaluate the magnitude of the effect size, calculated by SMD. Heterogeneity was tested by the I2 statistic. Thirty-five studies were included in the meta-analysis. The SMDs of serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) on pain, sleep, fatigue, depression and HRQOL were significant. Based on Cohen's categories, the effect size on pain was small and the ones on sleep, fatigue, depression and HRQOL were not substantial. 1481/3528 (42.0%) patients with SNRIs and 737/2304 (32.0%) patients with placebo reported a 30% pain reduction (number needed to treat [NNT] 10.0; 95% CI 8.00, 13.4; I2 = 4%). The RR of dropouts due to adverse events was 1.83 (95% CI 1.53, 2.18; I2 = 33%). The SMDs of selective serotonin reuptake inhibitors (SSRIs) on pain, sleep, depression and HRQOL were significant. Based on Cohen's categories, the effect sizes on pain, depression and HRQOL were small and the one on sleep not substantial. 72/198 (36.4%) patients with SSRIs and 40/194 (20.6%) patients with placebo reported a 30% pain reduction (NNT 6.3; 95% CI 4.1, 14.1). The RR of dropouts due to adverse events was 1.60 (95% CI 0.84, 3.04; I2 = 0%). The SMDs of tricyclic antidepressants (TCAs) on pain, sleep, fatigue and HRQOL were significant. Based on Cohen's categories, the effect sizes on pain and sleep were moderate and the ones on fatigue and HRQOL were small. 140/290 (48.3%) patients with TCAs and 70/252 (27.8%) patients with placebo reported a 30% pain reduction (NNT 4.9; 95% CI 3.5, 8.0). The RR of dropouts due to adverse events was 0.84 (95% CI 0.46, 1.52; I2 = 0%). CONCLUSIONS: The TCA amitriptyline and the SNRIs duloxetine and milnacipran are first-line options for the treatment of FMS patients. Physicians and patients should be realistic about the potential benefits of antidepressants in FMS. A small number of patients experience a substantial symptom relief with no or minor adverse effects. However, a remarkable number of patients dropout of therapy because of intolerable adverse effects or experience only a small relief of symptoms, which does not outweigh the adverse effects. PMID- 22452525 TI - Role of ghrelin in the pathophysiology of eating disorders: implications for pharmacotherapy. AB - Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs. PMID- 22452527 TI - Pharmacological revascularization of acute ischaemic stroke: focus on challenges and novel strategies. AB - The only currently approved treatment for acute ischaemic stroke (AIS) is alteplase, a thrombolytic agent given intravenously (IV) within 4.5 hours of symptom onset, in an attempt to reopen occluded intracerebral arteries. However, no more than 5% of all AIS patients receive IV alteplase, mainly because of too long symptom-onset-to-hospital intervals. Moreover, this strategy is effective for less than half of the patients treated within the therapeutic window. Early recanalization is the most powerful prognostic factor, and novel drugs or therapeutic strategies are primarily aimed at improving alteplase efficacy to rapidly and safely reopen the occluded arteries. Because IV alteplase-resistant thrombi are those with the largest clot burden, responsible for the most devastating brain-tissue infarctions, development of novel approved AIS therapies is an urgent priority. At present, in the absence of controlled trials, no valid recommendations can be made. However, the most promising emerging strategy is a combination of standard or low-dose IV alteplase with an intra-arterial (IA) procedure, including additional endovascular thrombolytic and/or mechanical clot retrieval. Notably, results of open trials using the IA route had relatively disappointing clinical outcomes, despite remarkable arterial recanalization rates. Controlled trials are urgently needed to evaluate strategies including an IA route. In addition, logistic and cost constraints will likely limit their routine use, even in industrialized countries. Combining of another IV drug and IV alteplase is a far less studied option, although much easier to implement. Add on IV drugs could be an antiplatelet glycoprotein (GP) IIb/IIIa receptor antagonist, a direct thrombin inhibitor or a second thrombolytic agent, e.g. tenecteplase. However, neuroimaging to measure the clot burden and infarction size will probably be necessary to predict IV alteplase failure and the subsequent use of these eventual additional therapies. PMID- 22452528 TI - Cost effectiveness of lacosamide in the adjunctive treatment of patients with refractory focal epilepsy in Belgium. AB - OBJECTIVES: Lacosamide is an anti-epileptic drug, indicated as adjunctive therapy for patients with focal seizures with or without secondary generalization. This study aims to assess the cost effectiveness of standard anti-epileptic drug therapy plus lacosamide 300 mg/day compared with standard therapy alone from the perspective of the Belgian healthcare payer. METHODS: The treatment pathway of a hypothetical cohort of 1000 patients over 2 years was simulated using a decision tree. Data about health state probabilities, seizure frequency and utility values were taken from lacosamide trials or from the literature. Effectiveness measures included the number of seizures avoided and the number of quality-adjusted life years gained. Unit costs were taken from national references. Resource use was estimated by a panel of eight neurologists with extensive experience in epilepsy. The price year was 2008. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Over a 24-month period, standard anti-epileptic drug therapy plus lacosamide led to a reduction of seven seizures, an increase of 0.038 quality-adjusted life-years and a cost decrease of &U20AC;3619 per patient compared with standard therapy alone. Using a willingness to pay of &U20AC;30 000 per quality-adjusted life-year, the net monetary benefit of standard anti epileptic drug therapy plus lacosamide amounted to &U20AC;4754. The probability of standard anti-epileptic drug therapy plus lacosamide being cost effective was 97.3%, 99.8%, 99.9% and 100% at 6, 12 , 18 and 24 months, respectively. CONCLUSION: In patients with difficult-to-treat epilepsy, standard anti-epileptic drug therapy plus lacosamide appears to be a cost-effective option in Belgium. PMID- 22452529 TI - Ziprasidone and the corrected QT interval: a comprehensive summary of clinical data. AB - BACKGROUND: Prolongation of the corrected QT interval (QTc) is understood to be a predictor of risk for ventricular arrhythmia; consequently, data on QTc effects of drugs are used by regulatory bodies to evaluate potential safety risks. Clinical pharmacology studies in adults receiving oral ziprasidone demonstrated a dose-dependent mean increase (4.5-19.5 milliseconds [ms]) in QTc over the range of 40-160 mg/d with a small incremental increase (22.5 ms) at 320 mg/d. In a comparative study of ziprasidone versus five antipsychotics, the mean QTc increase at steady state maximum concentration (C(max)) for ziprasidone was 15.9 ms. Accordingly, the effects of ziprasidone on QTc were studied in phase II-IV randomized controlled trials (RCTs). OBJECTIVE: The objective of this study was to provide clinicians and clinical researchers with a comprehensive analysis of QTc changes associated with ziprasidone based on data from Pfizer-sponsored phase II-IV RCTs in schizophrenia or bipolar disorder patients, safety reports and post marketing surveillance. METHODS: The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone: (i) post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies; (ii) post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults; (iii) post hoc analyses from phase II IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects; (iv) cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia; (v) a large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18 154 subjects with schizophrenia (the only previously reported results included here); and (vi) cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007. RESULTS: A total of 4306 adults received ziprasidone in placebo- and active-comparator phase II-IV RCTs and had evaluable QTc data. One subject reached a QTc >=480 ms; 33 (0.8%) had a QTc >=450 ms. QTc prolongation >=30 ms was observed in 389 subjects (9.0%); >=60 ms in 30 (0.7%); and >=75 ms in 12 (0.3%). In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (+/- 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (+/- 20.6) ms. Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects. A scatter plot of QTc prolongation against baseline QTc showed QTc prolongation >=60 ms exclusively in adult subjects with a baseline QTc <=400 ms. The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6 ms for each 100 ng/mL increase in ziprasidone concentration. The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use. Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs. CONCLUSIONS: These analyses provide the first comprehensive summary of QTc changes associated with ziprasidone based on Pfizer-sponsored phase II-IV RCTs, safety reports and post marketing surveillance. The results of the analyses of pooled data from phase II IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation >=60 ms (<1.0%) and rare observation of QTc >=480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post-marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder. PMID- 22452530 TI - Implicit acquisition of grammars with crossed and nested non-adjacent dependencies: investigating the push-down stack model. AB - A recent hypothesis in empirical brain research on language is that the fundamental difference between animal and human communication systems is captured by the distinction between finite-state and more complex phrase-structure grammars, such as context-free and context-sensitive grammars. However, the relevance of this distinction for the study of language as a neurobiological system has been questioned and it has been suggested that a more relevant and partly analogous distinction is that between non-adjacent and adjacent dependencies. Online memory resources are central to the processing of non adjacent dependencies as information has to be maintained across intervening material. One proposal is that an external memory device in the form of a limited push-down stack is used to process non-adjacent dependencies. We tested this hypothesis in an artificial grammar learning paradigm where subjects acquired non adjacent dependencies implicitly. Generally, we found no qualitative differences between the acquisition of non-adjacent dependencies and adjacent dependencies. This suggests that although the acquisition of non-adjacent dependencies requires more exposure to the acquisition material, it utilizes the same mechanisms used for acquiring adjacent dependencies. We challenge the push-down stack model further by testing its processing predictions for nested and crossed multiple non adjacent dependencies. The push-down stack model is partly supported by the results, and we suggest that stack-like properties are some among many natural properties characterizing the underlying neurophysiological mechanisms that implement the online memory resources used in language and structured sequence processing. PMID- 22452531 TI - Evaluation of cytotoxicity and up-regulation of gelatinases in fibroblast cells by three root repair materials. AB - AIM: To investigate the effects of root repair materials on the cytotoxicity and gelatinolytic activity of matrix metalloproteinases (MMPs) in 3T3 fibroblasts. METHODOLOGY: Fibroblasts (3T3, 3 * 10(5) cells per well) were incubated with elutes of calcium hydroxide (Biodinamica, Ibipora, PR, Brazil), EndoBinder (Binderware, Sao Carlos, SP, Brazil) and mineral trioxide aggregate (MTA) (Angelus, Londrina, PR, Brazil) for 24 h. The cytotoxicity of all root repair materials was determined using the MTT assay. Supernatants of cell cultures incubated with materials were collected after 24 h to determine the levels of MMP 2 and MMP-9 gelatinolytic activity by gelatin zymography. Data were analysed using anova and Tukey's test. RESULTS: Cells secreted MMP-2 after 24 h with calcium hydroxide inducing significantly greater MMP-2 expression in relation to the control and the other root repair materials (P < 0.05). The cytotoxicity results revealed that there was no significant difference in the cell viability of MTA, EndoBinder and the control group. However, there was a significantly reduced cell viability of 3T3 fibroblasts in association with calcium hydroxide (P < 0.05). CONCLUSIONS: Calcium hydroxide was associated with significantly less cell viability when compared with EndoBinder and MTA. All materials had gelatinolytic activity for MMP-2 with calcium hydroxide being associated with the greatest activity. PMID- 22452532 TI - Exploring the solid-liquid phase change of an adapted Dzugutov model using generalized replica exchange method. AB - The generalized replica exchange method (gREM) is applied to simulate a solid liquid phase change in an adapted Dzugutov model system. The idea of gREM is to incorporate the merit of sampling from a generalized ensemble into the replica exchange paradigm. The generalized ensemble weights are determined from effective temperatures tailored for this system, through an inverse mapping strategy. The ordered and disordered phases are smoothly joined together through a succession of unimodal energy distributions, providing a continuous transformation from an isotropic liquid into an amorphous solid phase under the given condition. The phase change temperature is determined by evaluation of various thermodynamic and structural order parameters. The increasing tendency for icosahedral local order under cooling is quantified using bond order parameters. The ergodic measure is used to demonstrate the advantage of gREM over the traditional temperature-based REM in sampling the phase change region. PMID- 22452533 TI - Study on transformation of natural organic matter in source water during chlorination and its chlorinated products using ultrahigh resolution mass spectrometry. AB - Natural organic matter (NOM) can affect the performance of water treatment processes, and serves as a main precursor for the formation of disinfection byproduct (DBPs) during chlorination. To minimize such undesirable effects, a better understanding of its structural information and reactivity toward chlorine is necessary. In this study, electrospray ionization coupled to Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS) was used to study the molecular composition of NOM in source water. More than four thousand NOM components were resolved in the sample. NOM molecules with a low degree of oxidation (low O/C ratio) were found to be more reactive toward chlorine than those with high O/C ratio. Totally, 659 one-chlorine containing products and 348 two-chlorine containing products were detected in the chlorinated sample at a high confidence level. The chlorinated products can be arranged into series, which indicate they were originated from precursor compounds in series related by the replacement of CH(4) against oxygen. Of the 1007 chlorine-containing products observed in this study, only 7 molecular formulas can be found in previous studies, showing the distinct difference from previous studies. This study explored the reactivity of NOM toward chlorine on a molecular level, which was previously explained on the level of whole mixtures or fractions of NOM, and the identified chlorinated products may contribute to our knowledge of the unknown total organic halide (TOX). PMID- 22452534 TI - Image guided navigation by intraoperative CT scan for cochlear implantation. AB - INTRODUCTION: For successful cochlear implantation in difficult ears, image guided navigation systems can help identify surgical landmarks or confirm the surgeon's anatomical knowledge. In this pilot case study, exact navigation based on intraoperative CT scanning was investigated and helped confirm important and necessary landmarks, such as the facial nerve, cochlea and intracochlear structures, and at least adequate placement of a straight electrode array. MATERIAL AND METHODS: Intraoperative imaging was performed on a 40-slice sliding gantry CT scanner (Siemens SOMATOM Sensation 40 Open) with an expanded gantry bore (82 cm). Raw image data were reconstructed with a slice thickness and increment of 0.6 mm and were imported to a frameless infrared-based navigation station (BrainLAB VectorVision Sky). In a preoperative accuracy and feasibility study, a phantom skull was scanned and registered five times by the navigation system. Based on the encouraging results, the system was then applied to a male patient with post-traumatic sensorineural hearing loss. The intraoperative target positioning error was measured by a "blinded" colleague who defined the distance of the pointer from different sections of the facial nerve without seeing the intraoperative field. RESULTS: The average deviation in the phantom skull was 0.91 mm (SD 0.27 mm) on the mastoid, 1.01 mm (SD 0.21 mm) on the round window, and 0.9 mm (SD 0.18 mm) on the inner ear canal. Surgery could be performed without major complications. The distance of the pointer from the facial nerve could be defined exactly using navigation in ten measurements. The cochleostomy and electrode insertion were performed with the aid of navigation. After insertion, direct intraoperative control of the electrode position was achieved by means of a low-dose CT scan. Two months postoperatively, the patient had a satisfactory open-set speech understanding of 85%. CONCLUSION: With the use of intraoperative acquisition of CT images (or digital volume tomography devices) and automatic volumetric registration for navigation, surgical precision can be improved, thereby allowing successful cochlear implant surgery in patients with complex malformations or who have undergone multiple previous ear surgeries and consequently lack anatomical landmarks. Our study clearly shows that this high technology combination is superior to other registration methods in terms of accuracy and precision. Further investigations should aim at developing automatic segmentation and applications for minimally invasive surgery of the lateral skull base. PMID- 22452535 TI - Lattice defect-enhanced hydrogen production in nanostructured hematite-based photoelectrochemical device. AB - Nanostructured hematite photoanodes have been intensively studied in photoelectrochemical (PEC) water splitting for sustainable hydrogen production. Whereas many previous efforts have been focused on doping elements in nanostructured hematite (alpha-Fe(2)O(3)), we herein demonstrated an alternative approach to enhance the PEC performance by exploiting intrinsic nanostructuring properties of hematite. We found that the introduction of lattice defects effectively decreased the flatband potential and increased the charge transport mobility of nanostructured hematite, hence enhance the light harvest for more efficient hydrogen production via PEC. The nanostructured hematite photoanodes with lattice defects yielded water-splitting photocurrent density of 1.2 mA/cm(2) at 1.6 V vs reversible hydrogen electrode (RHE), which excelled defect-free ones by approximately 1.5 folds. This study thus provides a new strategy for finely tuning properties of nanostructured hematite photoanodes and enhancing the water splitting ability of PEC. PMID- 22452536 TI - New device technologies for subcutaneous fat biopsy. AB - PURPOSE: Subcutaneous fat biopsy is useful for the evaluation of amyloidosis, environmental contaminants, lipid metabolism, genetic studies and diabetes research. The present study examined new technologies for fat biopsy. METHODS: Subcutaneous fat biopsy in 10 high-risk individuals was randomized to (i) a 10 ml reciprocating procedure device (RPD) mechanical syringe or (ii) a 60 ml vacuum syringe. Outcome measures included pain by the 10 cm Visual Analogue Pain Scale (VAS), adequacy of biopsied tissue, complications and diagnosis. The operator's ability to control syringes was quantitatively measured by the linear displacement method. RESULTS: Both syringes permitted facile aspiration of subcutaneous fat with adequate sample without complications. The mechanical and the vacuum syringes enhanced control of the needle compared to conventional syringes, reducing unintended forward penetration by 75% (3.6 +/- 0.5 mm) and 87% (12.0 +/- 1.4 mm), respectively (p < 0.0001). Free adipose cells were obtained in abundance as well as columnar biopsies containing intact blood vessels and connective tissue septa permitting precise microhistological examination. One case of primary AL amyloidosis (kappa light chain disease) was diagnosed in each group. CONCLUSIONS: Subcutaneous fat biopsy by needle aspiration can be facilely achieved with new aspiration syringe technologies with improved needle control and enhanced patient safety. PMID- 22452537 TI - Spatio-temporal patterns of microbial communities in a hydrologically dynamic pristine aquifer. AB - Seasonal patterns of groundwater and sediment microbial communities were explored in a hydrologically dynamic alpine oligotrophic porous aquifer, characterized by pronounced groundwater table fluctuations. Rising of the groundwater level in consequence of snow melting water recharge was accompanied by a dramatic drop of bacterial Shannon diversity in groundwater from H' = 3.22 +/- 0.28 in autumn and winter to H' = 1.31 +/- 0.35 in spring and summer, evaluated based on T-RFLP community fingerprinting. Elevated numbers of bacteria in groundwater in autumn followed nutrient inputs via recharge from summer rains and correlated well with highest concentrations of assimilable organic carbon. Sterile sediments incubated to groundwater in monitoring wells were readily colonized reaching maximum cell densities within 2 months, followed by a consecutive but delayed increase and leveling-off of bacterial diversity. After 1 year of incubation, the initially sterile sediments exhibited a similar number of bacteria and Shannon diversity when compared to vital sediment from a nearby river incubated in parallel. The river bed sediment microbial communities hardly changed in composition, diversity, and cell numbers during 1 year of exposure to groundwater. Summing up, the seasonal hydrological dynamics were found to induce considerable dynamics of microbial communities suspended in groundwater, while sediment communities seem unaffected and stable in terms of biomass and diversity. PMID- 22452538 TI - Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis. AB - The epithelial-to-mesenchymal transition (EMT) is a developmental programme that regulates embryonic morphogenesis and involves significant morphological and molecular changes in cells. Experimental models have revealed that EMT also contributes to various malignant features of cancer cells, including motile, invasive, anti-apoptotic and stem-like phenotypes. Clinically, correlative studies have indicated that mesenchymal-like features of tumour cells are associated with poor tumour differentiation as well as worse patient prognosis. Nevertheless, due to its transitory nature, demonstration of an actual occurrence of EMT during human carcinogenesis is challenging, and most of the evidence to date has been limited to breast and colorectal cancers. However, recent studies suggest that EMT may occur during lung cancer development, although such evidence is still limited. We propose three approaches for obtaining direct evidence of EMT in human cancers and use these criteria to review the available data. We suggest that multiple intrinsic and extrinsic factors cooperatively induce EMT in lung cancer. Intrinsic factors include oncogenic genetic changes such as mutant K RAS. Extrinsic factors are associated with a tumour microenvironment that is inflammatory and hypoxic. The induction of EMT is primarily mediated by various EMT-inducing transcription factors that suppress E-cadherin expression, including SLUG and ZEB1. miR-200 family expression can reverse EMT by suppressing EMT- inducing transcription factors. Obviously, more data demonstrating the clinical relevance of EMT in lung cancer are required, and further elucidation of how EMT is regulated in lung cancer will enable us to develop novel therapeutics that specifically target molecules with critical roles in EMT. PMID- 22452540 TI - Coupled motion in proteins revealed by pressure perturbation. AB - The cooperative nature of protein substructure and internal motion is a critical aspect of their functional competence about which little is known experimentally. NMR relaxation is used here to monitor the effects of high pressure on fast internal motion in the protein ubiquitin. In contrast to the main chain, the motions of the methyl-bearing side chains have a large and variable pressure dependence. Within the core, this pressure sensitivity correlates with the magnitude of motion at ambient pressure. Spatial clustering of the dynamic response to applied hydrostatic pressure is also seen, indicating localized cooperativity of motion on the sub-nanosecond time scale and suggesting regions of variable compressibility. These and other features indicate that the native ensemble contains a significant fraction of members with characteristics ascribed to the recently postulated "dry molten globule". The accompanying variable side chain conformational entropy helps complete our view of the thermodynamic architecture underlying protein stability, folding, and function. PMID- 22452541 TI - Oral health locus of control in a Swedish adolescent population. AB - OBJECTIVE: The aim was to test and evaluate the psychometric properties of the Oral Health Locus of Control (OHLoC) instrument and its relation to dental anxiety, self-efficacy and self-perceived oral health among Swedish adolescents. MATERIALS AND METHODS: A random sample of 758 (63% of 1208 invited) 19-year-old individuals in three residential areas in western Sweden (two rural, one urban) answered a set of questionnaires prior to a dental examination. RESULTS: The face and content validity of the OHLoC was deemed good in pilot interviews with individuals of the target age. Explorative factor analysis verified the dimensions of the OHLoC sub-scales (internal, external, chance locus of control) with loadings from 0.503 - 0.812, explaining 54.6% of the variance. Construct validity was confirmed in relation to two other psychometric scales, on dental anxiety (DAS) and on general self-efficacy (GSE), with correlations in the expected directions. In multivariate logistic regression analyses, the internal sub-scale displayed the most consistent statistically significant associations with self-perceived oral health, also when accounting for gender, demography and health behavior. There were no significant differences between genders on the OHLoC, but females scored statistically significantly higher on the DAS (p = 0.005) and lower on the GSE (p = 0.021) than males. CONCLUSIONS: The Swedish version of the OHLoC appears to have acceptable psychometric properties for use in an adolescent population. PMID- 22452542 TI - Analysis and design of photobioreactors for microalgae production II: experimental validation of a radiation field simulator based on a Monte Carlo algorithm. AB - In a previous study, we developed a methodology to assess the intrinsic optical properties governing the radiation field in algae suspensions. With these properties at our disposal, a Monte Carlo simulation program is developed and used in this study as a predictive autonomous program applied to the simulation of experiments that reproduce the common illumination conditions that are found in processes of large scale production of microalgae, especially when using open ponds such as raceway ponds. The simulation module is validated by comparing the results of experimental measurements made on artificially illuminated algal suspension with those predicted by the Monte Carlo program. This experiment deals with a situation that resembles that of an open pond or that of a raceway pond, except for the fact that for convenience, the experimental arrangement appears as if those reactors were turned upside down. It serves the purpose of assessing to what extent the scattering phenomena are important for the prediction of the spatial distribution of the radiant energy density. The simulation module developed can be applied to compute the local energy density inside photobioreactors with the goal to optimize its design and their operating conditions. PMID- 22452543 TI - The influence of uncemented femoral stem length and design on its primary stability: a finite element analysis. AB - One of the crucial factors for short- and long-term clinical success of total hip arthroplasty cementless implants is primary stability. Indeed, motion at the bone implant interface above 40 MUm leads to partial bone ingrowth, while motion exceeding 150 MUm completely inhibits bone ingrowth. The aim of this study was to investigate the effect of two cementless femoral stem designs with different lengths on the primary stability. A finite element model of a composite Sawbones((r)) fourth generation, implanted with five lengths of the straight prosthesis design and four lengths of the curved prosthesis design, was loaded with hip joint and abductor forces representing two physiological activities: fast walking and stair climbing. We found that reducing the straight stem length from 146 to 54 mm increased the average micromotion from 17 to 52 MUm during fast walking, while the peak value increased from 42 to 104 MUm. With the curved stem, reducing length from 105 to 54 mm increased the average micromotion from 10 to 29 MUm, while the peak value increased from 37 to 101 MUm. Similar findings are obtained for stair climbing for both stems. Although the present study showed that femoral stem length as well as stem design directly influences its primary stability, for the two femoral stems tested, length could be reduced substantially without compromising the primary stability. With the aim of minimising surgical invasiveness, newer femoral stem design and currently well performing stems might be used with a reduced length without compromising primary stability and hence, long-term survivorship. PMID- 22452544 TI - Development and validation of the shy bladder scale. AB - Paruresis, characterized by the difficulty or inability to urinate in a variety of social contexts, is a scientifically under-studied phenomenon. One reason for this state of affairs is the paucity of reliable and valid measures for assessing this problem. The present article attempted to address this limitation by investigating the psychometric properties and validity of a new measure of paruresis: the Shy Bladder Scale (SBS). In two undergraduate samples, the SBS demonstrated excellent internal consistency and a stable factor structure assessing difficulty urinating in public, impairment and distress, and paruresis related fear of negative evaluation. Undergraduate students evidenced very low levels of paruresis-related concerns. In contrast, SBS scores were markedly elevated among individuals recruited from an online support network who appeared to meet diagnostic criteria for paruresis-specific social phobia. Our findings highlight the SBS's potential utility as a measure of paruresis in clinical and research contexts. PMID- 22452545 TI - Pain associated with the chronic pelvic pain syndrome is strongly related to the ambient temperature. AB - OBJECTIVE: There are indications suggesting that the pain associated with the chronic pelvic pain syndrome (CPPS) may be related to cold. The purpose of the present study was to evaluate how the symptom intensity reported by the patient relates to the time of the year in a temperate climate, i.e. to the ambient temperature and to weather changes. MATERIAL AND METHODS: Thirty-one patients, mean age 51 years (range 35-66 years), with CPPS for 17 +/- 10 years (3-42 years) were asked to complete a set of questionnaires including questions concerning how they experienced their symptom intensity during the different seasons using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire. RESULTS: The total NIH-CPSI score was 22.2 +/- 8.2. There was a highly marked relationship between season and pain intensity as reported by the informants: it was experienced to be three times more intense during the winter months. All subjects reported that a temperature drop was associated with deterioration. CONCLUSION: The strong relationship between the ambient temperature, a drop in temperature and the pain experienced by men with CPPS confirms the association between cold and symptom intensity in the Scandinavian countries, where the seasonal temperature variation spans a long range and the winters are long. The cause of this relationship is still to be established. Muscular spasm/stiffness is a possibility that remains to be explored. PMID- 22452546 TI - Mechanisms and urodynamic effects of a potent and selective EP4 receptor antagonist, MF191, on cyclophosphamide and prostaglandin E2-induced bladder overactivity in rats. AB - OBJECTIVE: To investigate the mechanisms and urodynamic effects of a potent and selective prostaglandin E(2) (PGE(2)) receptor subtype 4 (EP4) antagonist, MF191, on cyclophosphamide (CYP) or PGE(2)-induced bladder overactivity in rats. MATERIALS AND METHODS: Experimental and control rats were injected with CYP (200 mg/kg i.p.) or saline on day 1. Continuous cystometrogram (CMGs) were performed on day 3. In group 1, MF191 (vehicle 0.1 and 1 mg/kg) was given i.v. The bladder was then harvested for histology and immunohistochemistry. Some bladders were harvested for analysis of EP4 expression by Western blotting without a CMG study. In group 2, MF191 (vehicle 10 nM, and 100 nM) was continuously infused into the bladder. In group 3, bladder overactivity was induced by intravesical instillation of PGE(2) (200 uM) and vehicle or MF191 (1 mg/kg) was given i.v. RESULTS: CYP induced bladder inflammation, overactivity and EP4 upregulation. The CYP effects were suppressed by MF191 (1 mg/kg i.v.; intercontraction interval [ICI]: 39.4% increase, and reduced inflammatory cells infiltration, and EP4 expression). Intravesical instillation of MF191 (100 nM) suppressed CYP-induced bladder overactivity (ICI: 71.8% increase). PGE(2)-induced bladder overactivity was suppressed by MF191 (ICI: 43.2% increase). MF191 had no significant effects on other CMG variables or on control rats. CONCLUSIONS: MF191 might affect the bladder urothelium and inflammatory cells and suppresses CYP- or PGE(2)-induced bladder overactivity. Systemic or intravesical MF191 administration for the treatment of overactive bladder merits clinical study. PMID- 22452547 TI - Quantitative molecular and culture analyses of bacterial elimination in oval shaped root canals by a single-file instrumentation technique. AB - AIM: Bacterial reduction in oval-shaped root canals by a single-instrument technique was compared ex vivo with a conventional nickel-titanium rotary technique. Data obtained from two quantification methods, quantitative real-time polymerase chain reaction (qPCR) and culture, were also compared. METHODOLOGY: Oval-shaped canals of extracted teeth contaminated with Enterococcus faecalis were instrumented using either a single Reciproc instrument or the BioRaCe instrument series. Bacteriological samples were taken before (S1) and after instrumentation (S2). Bacterial quantification was performed using qPCR and culture. RESULTS: Intragroup analysis showed that both protocols promoted a highly significant bacterial reduction (P < 0.001). Intergroup analysis (S2 samples) showed no significant differences between the two instrumentation systems (P > 0.05). As for the quantification methods, qPCR revealed significantly higher counts of E. faecalis in S1 than culture (P < 0.05), but no significant differences occurred for S2 (P > 0.05). CONCLUSION: The single-file technique was comparable with the conventional technique in oval-shaped canals provided the width of apical preparation, volume of irrigants and duration of irrigation are kept similar. No significant difference was observed for qPCR and culture in post-instrumentation samples, indicating that both methods can be reliably used for studies of antibacterial effectiveness. PMID- 22452548 TI - Increased risks of parkinsonism in the 3 years after chronic renal failure. AB - AIMS: Movement disorders are one of the central nervous system complications in uremic patients. Asterixis, multifocal myoclonus, and restless leg syndrome are well-documented in this category. Acute parkinsonism, however, is only reported in rare series with a small number of cases. In this study, we investigated the risk for parkinsonism during a 3-year follow-up period after a diagnosis of uremia. METHODS: The Longitudinal Health Insurance Database in Taiwan was utilised. We identified a total of 2862 patients who had visited ambulatory care centers with a diagnosis of chronic renal failure between 1999 and 2001 as the study cohort. We further randomly selected 14,310 enrollees matched with the study cohort in terms of gender, age, and year of their index visit for comparison. Each patient was individually tracked for 3 years to identify the occurrence of parkinsonism. Stratified Cox proportional hazard regressions (stratified by age and gender) were performed for analyses. RESULTS: We found the annual incidence rates of parkinsonism to be 1.2% and 0.6% in the uremic and non uremic groups, respectively. Furthermore, uremic patients were more vulnerable to developing parkinsonism with a 1.81-fold higher risk [95%CI = (1.21-2.71)] than the non-uremic group after adjusting for diabetes mellitus, which did not augment the risk. CONCLUSIONS: The importance of raising awareness regarding the early symptoms of parkinsonism among patients with uremia is tied to its early identification, with timely aggressive dialysis being able to apply to slow the progression of the disease and its symptoms. Further study is warranted to elucidate the pathophysiology of uremic parkinsonism. PMID- 22452549 TI - Implementation of new Healthy Conversation Skills to support lifestyle changes - what helps and what hinders? Experiences of Sure Start Children's Centre staff. AB - Effective communication is necessary for good relationships between healthcare practitioners and clients. This study examined barriers and facilitators to implementing new communication skills. One hundred and ten Sure Start Children's Centre staff attended one of 13 follow-up workshops in Southampton, UK between May 2009 and February 2011 to reflect on the use of new skills following a training course in communication, reflection and problem-solving. Barriers and facilitators were assessed with an adapted Problematic Experiences of Therapy scale (PETS). Staff reported frequency of skill use, and described what made it more difficult or easier to use the skills. Complete data were available for 101 trainees. The PETS indicated that staff had confidence in using the skills, but felt that there were practical barriers to using them, such as lack of time. Skills were used less often when staff perceived parents not to be engaging with them (Spearman's correlation r(s) = -0.42, P < 0.001), when staff felt less confident to use the skills (r(s) = -0.37, P < 0.001) and when there were more practical barriers (r(s) = -0.37, P < 0.001). In support of findings from the PETS, content analysis of free text responses suggested that the main barrier was a perceived lack of time to implement new skills. Facilitators included seeing the benefits of using the skills, finding opportunities and having good relationships with parents. Understanding the range of barriers and facilitators to implementation is essential when developing training to facilitate ongoing support and sustain skill use. Special attention should be given to exploring trainees' perceptions of time, to be able to address this significant barrier to skill implementation. Staff training requires a multi-faceted approach to address the range of perceived barriers. PMID- 22452550 TI - Pathogenesis of transthyretin amyloidosis. AB - Current dogma for transthyretin (TTR) pathogenesis is that mutations in TTR alter its structure such that the tetramer becomes unstable and prone to release of monomer which then becomes the putative building block of the fibril. This hypothesis is supported by thermodynamic data showing decreased stability of mutant TTR tetrameric proteins and accelerated fibril formation under acidic conditions in vitro. There are, however, a number of questions that are not readily answered by this simplistic model of a very complex disease. Worrisome questions still to be answered include: 1. If the monomer is the precursor of the fibril, why do fibril deposits contain large amounts of wild-type TTR and not just variant? 2. If destabilized tetramers can form fibrils in vitro, why do we consistently find partial proteolysis of fibril subunit proteins? If enzymatic proteolysis is a required step in fibril formation, are the findings of in vitro fibril formation relevant to the true pathogenesis? 3. With some TTR mutations (e.g. 122DeltaVal), it would appear that very little TTR is present in the blood (probably due to degradation prior to hepatic secretion). Enough mutant TTR circulates to the heart and nerves to cause pathology but, if the mutant only serves to initiate fibril deposition, why are not the deposits mainly wild-type TTR?4. Since mutated TTR is present from birth, why is TTR amyloidosis of such delayed onset? What is the role of aging factors?5. Do the variations in biochemical analyses of heart and nerve versus choroid and leptomeningeal fibrils tell us something about pathogenesis? These are questions we need to address. Do not expect quick and easy answers. Hopefully, they will generate thought and discussion. PMID- 22452551 TI - Social cognitive factors and perceived social influences that improve adolescent eHealth literacy. AB - While adolescents are increasingly using the Internet for health information, little research has been done to assess and improve their "eHealth literacy"-the abilities to find, evaluate, and apply online health information. This study examines the extent to which adolescents' levels of eHealth literacy can be improved by known determinants such as social cognitive factors and perceived social influences, either independently or jointly. Among 182 middle-schoolers, an eHealth literacy intervention was carried out. It involved qualitative and quantitative baseline research, three online training sessions, and a postintervention survey. According to hierarchical regression model results, social cognitive factors of outcome expectations and involvement, but not health motivation, significantly improved eHealth literacy, and all the perceived social influence variables significantly improved eHealth literacy. However, no joint effect of social cognitive factors and perceived social influences was found. In light of these findings, educators need to make eHealth literacy programs personally relevant to adolescents and reinforce local social norms about the importance of seeking health information online. PMID- 22452552 TI - Vibrational optical activity of cysteine in aqueous solution: a comparison of theoretical and experimental spectra. AB - Raman, Raman optical activity (ROA), infrared (IR), and vibrational circular dichroism (VCD) spectra of cysteine in aqueous solution have been measured and calculated by means of density functional theory. The influence of aqueous environment on the spectra of cysteine has been simulated by means of implicit (polarizable continuum model) and explicit (molecular dynamics, solute-solvent clusters) methods. The results indicate that, while PCM reproduces some of the features of the spectra, the best description is rendered by the microsolvation model (solute-solvent clusters). The shape of the bands is in some cases more correctly reproduced by MD, but their intensities and positions are not, since these simulations are hampered by the standard force field being parametrized for conformations of peptides rather than isolated amino acids. The calculated ROA spectra have been used to extract conformational ratios from the experimental spectra, and again, the best results (as verified by simulations of other spectra) have been obtained when using the microsolvation model. This procedure renders three zwitterion conformers dominating the spectra of hydrated cysteine, of conformational ratios of 35, 33, and 24%, respectively. PMID- 22452553 TI - Pigmented epithelioid melanocytoma developed in a patient with Becker nevus syndrome. PMID- 22452554 TI - Behavioral choice-related neuronal activity in monkey primary somatosensory cortex in a haptic delay task. AB - The neuronal activity in the primary somatosensory cortex was collected when monkeys performed a haptic-haptic DMS task. We found that, in trials with correct task performance, a substantial number of cells showed significant differential neural activity only when the monkeys had to make a choice between two different haptic objects. Such a difference in neural activity was significantly reduced in incorrect response trials. However, very few cells showed the choice-only differential neural activity in monkeys who performed a control task that was identical to the haptic-haptic task but did not require the animal to either actively memorize the sample or make a choice between two objects at the end of a trial. From these results, we infer that the differential activity recorded from cells in the primary somatosensory cortex in correct performance reflects the neural process of behavioral choice, and therefore, it is a neural correlate of decision-making when the animal has to make a haptic choice. PMID- 22452555 TI - Nonspatial cueing of tactile STM causes shift of spatial attention. AB - The focus of attention can be flexibly altered in mnemonic representations of past sensory events. We investigated the neural mechanisms of selection in tactile STM by applying vibrotactile sample stimuli of different intensities to both hands, followed by a symmetrically shaped visual retro-cue. The retro-cue indicated whether the weak or strong sample was relevant for subsequent comparison with a single tactile test stimulus. Locations of tactile stimuli were randomized, and the required response did not depend upon the spatial relation between cued sample and test stimulus. Selection between spatially segregated items in tactile STM was mirrored in lateralized activity following visual retro cues (N2pc) and influenced encoding of task-irrelevant tactile probe stimuli (N140). Our findings support four major conclusions. First, retrospective selection results in transient shifts of spatial attention. Second, retrospective selection is functionally dissociable from attention-based rehearsal of locations. Third, selection mechanisms are linked across processing stages, as attention shifts in STM influence encoding of sensory signals. Fourth, selection in tactile STM recruits attentional control mechanisms that are, at least partially, supramodal. PMID- 22452556 TI - A meta-analysis of functional neuroimaging studies of self- and other judgments reveals a spatial gradient for mentalizing in medial prefrontal cortex. AB - The distinction between processes used to perceive and understand the self and others has received considerable attention in psychology and neuroscience. Brain findings highlight a role for various regions, in particular the medial PFC (mPFC), in supporting judgments about both the self and others. We performed a meta-analysis of 107 neuroimaging studies of self- and other-related judgments using multilevel kernel density analysis [Kober, H., & Wager, T. D. Meta-analyses of neuroimaging data. Wiley Interdisciplinary Reviews, 1, 293-300, 2010]. We sought to determine what brain regions are reliably involved in each judgment type and, in particular, what the spatial and functional organization of mPFC is with respect to them. Relative to nonmentalizing judgments, both self- and other judgments were associated with activity in mPFC, ranging from ventral to dorsal extents, as well as common activation of the left TPJ and posterior cingulate. A direct comparison between self- and other judgments revealed that ventral mPFC as well as left ventrolateral PFC and left insula were more frequently activated by self-related judgments, whereas dorsal mPFC, in addition to bilateral TPJ and cuneus, was more frequently activated by other-related judgments. Logistic regression analyses revealed that ventral and dorsal mPFC lay at opposite ends of a functional gradient: The z coordinates reported in individual studies predicted whether the study involved self- or other-related judgments, which were associated with increasingly ventral or dorsal portions of mPFC, respectively. These results argue for a distributed rather than localizationist account of mPFC organization and support an emerging view on the functional heterogeneity of mPFC. PMID- 22452557 TI - The context-object-manipulation triad: cross talk during action perception revealed by fMRI. AB - To recognize an action, an observer exploits information about the applied manipulation, the involved objects, and the context where the action occurs. Context, object, and manipulation information are hence expected to be tightly coupled in a triadic relationship (the COM triad hereafter). The current fMRI study investigated the hemodynamic signatures of reciprocal modulation in the COM triad. Participants watched short video clips of pantomime actions, that is, actions performed with inappropriate objects, taking place at compatible or incompatible contexts. The usage of pantomime actions enabled the disentanglement of the neural substrates of context-manipulation (CM) and context-object (CO) associations. There were trials in which (1) both manipulation and objects, (2) only manipulation, (3) only objects, or (4) neither manipulation nor objects were compatible with the context. CM compatibility effects were found in an action related network comprising ventral premotor cortex, SMA, left anterior intraparietal sulcus, and bilateral occipito-temporal cortex. Conversely, CO compatibility effects were found bilaterally in lateral occipital complex. These effects interacted in subregions of the lateral occipital complex. An overlap of CM and CO effects was observed in the occipito-temporal cortex and the dorsal attention network, that is, superior frontal sulcus/dorsal premotor cortex and superior parietal lobe. Results indicate that contextual information is integrated into the analysis of actions. Manipulation and object information is linked by contextual associations as a function of co-occurrence in specific contexts. Activation of either CM or CO associations shifts attention to either action- or object-related relevant information. PMID- 22452558 TI - Neural correlates of people's hypercorrection of their false beliefs. AB - Despite the intuition that strongly held beliefs are particularly difficult to change, the data on error correction indicate that general information errors that people commit with a high degree of belief are especially easy to correct. This finding is called the hypercorrection effect. The hypothesis was tested that the reason for hypercorrection stems from enhanced attention and encoding that results from a metacognitive mismatch between the person's confidence in their responses and the true answer. This experiment, which is the first to use imaging to investigate the hypercorrection effect, provided support for this hypothesis, showing that both metacognitive mismatch conditions-that in which high confidence accompanies a wrong answer and that in which low confidence accompanies a correct answer-revealed anterior cingulate and medial frontal gyrus activations. Only in the high confidence error condition, however, was an error that conflicted with the true answer mentally present. And only the high confidence error condition yielded activations in the right TPJ and the right dorsolateral pFC. These activations suggested that, during the correction process after error commission, people (1) were entertaining both the false belief as well as the true belief (as in theory of mind tasks, which also manifest the right TPJ activation) and (2) may have been suppressing the unwanted, incorrect information that they had, themselves, produced (as in think/no-think tasks, which also manifest dorsolateral pFC activation). These error-specific processes as well as enhanced attention because of metacognitive mismatch appear to be implicated. PMID- 22452559 TI - Nicotine effects on brain function during a visual oddball task: a comparison between conventional and EEG-informed fMRI analysis. AB - In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), that is, single-trial P3 ERP parameters, in the analysis of fMRI responses can detect activation that is not apparent with conventional fMRI data modeling strategies [Warbrick, T., Mobascher, A., Brinkmeyer, J., Musso, F., Richter, N., Stoecker, T., et al. Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task. Neuroimage, 47, 1532-1544, 2009]. Given that P3 is modulated by nicotine, including P3 parameters in the fMRI analysis might provide additional information about nicotine effects on brain function. A 1-mg nasal nicotine spray (0.5 mg each nostril) or placebo (pepper) spray was administered in a double-blind, placebo-controlled, within-subject, randomized, cross-over design. Simultaneous EEG-fMRI and behavioral data were recorded from 19 current smokers in response to an oddball-type visual choice RT task. Conventional general linear model analysis and single-trial P3 amplitude informed general linear model analysis of the fMRI data were performed. Comparing the nicotine with the placebo condition, reduced RTs in the nicotine condition were related to decreased BOLD responses in the conventional analysis encompassing the superior parietal lobule, the precuneus, and the lateral occipital cortex. On the other hand, reduced RTs were related to increased BOLD responses in the precentral and postcentral gyri, and ACC in the EEG-informed fMRI analysis. Our results show how integrated analyses of simultaneous EEG-fMRI data can be used to detect nicotine effects that would not have been revealed through conventional analysis of either measure in isolation. This emphasizes the significance of applying multimodal imaging methods to pharmacoimaging. PMID- 22452560 TI - Rules rule! Brain activity dissociates the representations of stimulus contingencies with varying levels of complexity. AB - The significance of stimuli is linked not only to their nature but also to the sequential structure in which they are embedded, which gives rise to contingency rules. Humans have an extraordinary ability to extract and exploit these rules, as exemplified by the role of grammar and syntax in language. To study the brain representations of contingency rules, we recorded ERPs and event-related optical signal (EROS; which uses near-infrared light to measure the optical changes associated with neuronal responses). We used sequences of high- and low-frequency tones varying according to three contingency rules, which were orthogonally manipulated and differed in processing requirements: A Single Repetition rule required only template matching, a Local Probability rule required relating a stimulus to its context, and a Global Probability rule could be derived through template matching or with reference to the global sequence context. ERP activity at 200-300 msec was related to the Single Repetition and Global Probability rules (reflecting access to representations based on template matching), whereas longer latency activity (300-450 msec) was related to the Local Probability and Global Probability rules (reflecting access to representations incorporating contextual information). EROS responses with corresponding latencies indicated that the earlier activity involved the superior temporal gyrus, whereas later responses involved a fronto-parietal network. This suggests that the brain can simultaneously hold different models of stimulus contingencies at different levels of the information processing system according to their processing requirements, as indicated by the latency and location of the corresponding brain activity. PMID- 22452561 TI - Paying attention through eye movements: a computational investigation of the premotor theory of spatial attention. AB - Growing evidence indicates that planning eye movements and orienting visuospatial attention share overlapping brain mechanisms. A tight link between endogenous attention and eye movements is maintained by the premotor theory, in contrast to other accounts that postulate the existence of specific attention mechanisms that modulate the activity of information processing systems. The strong assumption of equivalence between attention and eye movements, however, is challenged by demonstrations that human observers are able to keep attention on a specific location while moving the eyes elsewhere. Here we investigate whether a recurrent model of saccadic planning can account for attentional effects without requiring additional or specific mechanisms separate from the circuits that perform sensorimotor transformations for eye movements. The model builds on the basis function approach and includes a circuit that performs spatial remapping using an "internal forward model" of how visual inputs are modified as a result of saccadic movements. Simulations show that the latter circuit is crucial to account for dissociations between attention and eye movements that may be invoked to disprove the premotor theory. The model provides new insights into how spatial remapping may be implemented in parietal cortex and offers a computational framework for recent proposals that link visual stability with remapping of attention pointers. PMID- 22452562 TI - A sensorimotor network for the bodily self. AB - Neuroscientists and philosophers, among others, have long questioned the contribution of bodily experience to the constitution of self-consciousness. Contemporary research answers this question by focusing on the notions of sense of agency and/or sense of ownership. Recently, however, it has been proposed that the bodily self might also be rooted in bodily motor experience, that is, in the experience of oneself as instantiating a bodily structure that enables a specific range of actions. In the current fMRI study, we tested this hypothesis by making participants undergo a hand laterality judgment task, which is known to be solved by simulating a motor rotation of one's own hand. The stimulus to be judged was either the participant's own hand or the hand of a stranger. We used this task to investigate whether mental rotation of pictures depicting one's own hands leads to a different activation of the sensorimotor areas as compared with the mental rotation of pictures depicting another's hand. We revealed a neural network for the general representation of the bodily self encompassing the SMA and pre-SMA, the anterior insula, and the occipital cortex, bilaterally. Crucially, the representation of one's own dominant hand turned out to be primarily confined to the left premotor cortex. Our data seem to support the existence of a sense of bodily self encased within the sensorimotor system. We propose that such a sensorimotor representation of the bodily self might help us to differentiate our own body from that of others. PMID- 22452563 TI - A benefit-risk assessment of dapoxetine in the treatment of premature ejaculation. AB - Premature ejaculation (PE) is considered to be the most common sexual problem affecting men, despite the likelihood that it is under-diagnosed. It is a complex condition with many physical and psychological components, making management complicated. It is important to develop treatments for PE as it adversely affects quality of life for individuals and partners. Dapoxetine is a short-acting selective serotonin reuptake inhibitor (SSRI) that has been developed principally for the treatment of PE. It is considered more suitable for the treatment of PE than other SSRIs as it can be used as an 'on demand' treatment to be taken a few hours before an expected sexual encounter, reducing the possibility of adverse effects. Dapoxetine may represent a breakthrough in the treatment of PE as it is the first drug to be licensed for this indication. This review attempts to present a balanced benefit-risk assessment of dapoxetine by examining the evidence from phase III clinical trials, focusing on its efficacy in prolonging intravaginal ejaculatory latency time (IELT), patient sexual satisfaction and safety in patients with PE. The benefits and risks of other therapies that are used to treat PE off-licence are also reviewed. There has only been one study to date that directly compares dapoxetine to another therapy, paroxetine, for this indication. It was found that dapoxetine is most effective at a dose of 60 mg in increasing IELT compared with placebo. All studies have also found that dapoxetine is well tolerated as an 'on-demand' therapy and with continual dosing; however, there are little data regarding possible long-term adverse effects. Findings of the dapoxetine development programme demonstrated that dapoxetine is associated with vasovagal-mediated (neurocardiogenic) syncope. No other associated significant cardiovascular adverse events were identified. Further research is needed to directly compare dapoxetine with other therapies and to investigate the outcomes of dapoxetine used in conjunction with behavioural therapies, and other non-pharmaceutical therapies. PMID- 22452564 TI - Soluble receptor for advanced glycation end products (sRAGE) is present at high concentrations in the lungs of children and varies with age and the pattern of lung inflammation. AB - BACKGROUND AND OBJECTIVE: The soluble receptor for advanced glycation end products (sRAGE) plays an important role in inflammation. Few studies have looked at sRAGE levels in human lungs, and there is no information in children. Therefore, this study aimed to compare bronchoalveolar lavage fluid (BALF) and plasma sRAGE concentrations in children in relation to age and inflammation. METHODS: BAL was performed in 76 children, and BALF and plasma sRAGE levels were determined by enzyme-linked immunosorbent assay. RESULTS: sRAGE levels were fourfold higher in BALF than in plasma (P < 0.001). BALF sRAGE was inversely proportional to age (r = -0.333, P = 0.008) and serum immunoglobulin A (r = 0.283, P = 0.028). Plasma sRAGE showed a positive correlation to the percentage of BAL macrophages and negative correlation to the percentage of neutrophils and lymphocytes (P < 0.05). Multivariate linear regression analysis identified that the percentage of BAL lymphocytes and neutrophils were significant independent predictors of plasma sRAGE levels, while age and the percentage of BAL macrophages independently predicted BALF sRAGE levels. CONCLUSIONS: In children, sRAGE is present at higher concentrations in the lung compared with blood. It appears that sRAGE varies with age, and hence future studies of sRAGE in paediatric lung disease require age matching. The significant relationship between sRAGE and lung inflammation warrants further research. PMID- 22452565 TI - Body phosphorus mobilization and deposition during lactation in dairy cows. AB - Dairy cow bone phosphorus (P) mobilization and deposition and their influence on P requirements were studied over the lactation cycle. Thirty Holsteins received a common diet during the dry period and one of the following three dietary treatments that varied in P percentage during the subsequent lactation (44 weeks): (i) 0.36 throughout (constant P, 0.36-0.36-0.36), (ii) 0.36 for 30 weeks then 0.29 for 14 weeks (P changed once, 0.36-0.36-0.29), and (iii) 0.43 for 10 weeks, 0.36 for 20 weeks, and 0.29 for 14 weeks (P changed twice, 0.43-0.36 0.29). Six P balance studies were conducted during the experiment, including one during the dry period and five along lactation, based on P intake, faecal P, urinary P and milk P, when appropriate. Blood samples were taken during balance to analyse bone formation (osteocalcin) and resorption (pyridinoline) marker concentrations and rib biopsies performed to determine bone P content. Phosphorus balance was negative during weeks -4 to -1 relative to lactation for all groups and remained negative for cows fed 0.36% P during weeks 1-5, but showed a positive value for cows that received 0.43% P. The balance was close to zero for all groups at weeks 19-23 and showed a clear retention during weeks 38-42; by the end of lactation, cows re-stored most of the P mobilized earlier. The pattern in P balance was consistent with changes in blood bone metabolism marker concentrations, rib bone P content, and faecal and urinary P concentrations over the experiment, indicating that cows, irrespective of the dietary P treatments received, mobilized P from bone during the late dry period when fed a low-Ca diet and early lactation, and re-stored P in late lactation. This dynamic of P metabolism can have important implications for dietary P requirements and ration formulations. PMID- 22452567 TI - Coordination chemistry of 4-methyl-2,6,7-trioxa-1-phosphabicyclo[2,2,1]heptane: preparation and characterization of Ru(II) complexes. AB - The complexes TpRu[P(OCH(2))(2)(OCCH(3)](PPh(3))Cl (2) [Tp = hydridotris(pyrazolyl)borate; P(OCH(2))(2)(OCCH(3)) (1) = (4-methyl-2,6,7-trioxa 1-phosphabicyclo[2,2,1]heptane] and TpRu(L)(PPh(3))Cl [L = P(OCH(2))(3)CEt (3), PMe(3) (4) or P(OMe)(3) (5)], (eta(6)-C(6)H(6))Ru(L)Cl(2) [L = PPh(3) (6), P(OMe)(3) (7), PMe(3) (8), P(OCH(2))(3)CEt (9), CO (10) or P(OCH(2))(2)(OCCH(3)) (11)] and (eta(6)-p-cymene)Ru(L)Cl(2) [L = P(OCH(2))(3)CEt (12), P(OCH(2))(2)(OCCH(3))P(OCH(2))(2)(OCCH(3)) (13), P(OMe)(3) (14) or PPh(3) (15)] have been synthesized, isolated, and characterized by NMR spectroscopy, cyclic voltammetry, mass spectrometry, and, for some complexes, single crystal X-ray diffraction. Data from cyclic voltammetry and solid-state structures have been used to compare the properties of (1) with other phosphorus-based ligands as well as carbon monoxide. Data from the solid-state structures of Ru(II) complexes show that P(OCH(2))(2)(OCCH(3)) has a cone angle of 104 degrees . Cyclic voltammetry data reveal that the Ru(II) complexes bearing P(OCH(2))(2)(OCCH(3)) have more positive Ru(III/II) redox potentials than analogous complexes with the other phosphorus ligands; however, the Ru(III/II) potential for (eta(6) C(6)H(6))Ru[P(OCH(2))(2)(OCCH(3))]Cl(2) is more negative compared to the Ru(III/II) potential for the CO complex (eta(6)-C(6)H(6))Ru(CO)Cl(2). For the Ru(II) complexes studied herein, these data are consistent with the overall donor ability of 1 being less than other common phosphines (e.g., PMe(3) or PPh(3)) or phosphites [e.g., P(OCH(2))(3)CEt or P(OMe)(3)] but greater than carbon monoxide. PMID- 22452568 TI - Structure-based design of novel benzoxazinorifamycins with potent binding affinity to wild-type and rifampin-resistant mutant Mycobacterium tuberculosis RNA polymerases. AB - By utilization of three-dimensional structure information of rifamycins bound to RNA polymerase (RNAP) and the human pregnane X receptor (hPXR), representative examples (2b-d) of a novel subclass of benzoxazinorifamycins have been synthesized. Relative to rifalazil (2a), these analogues generally display superior affinity toward wild-type and Rif-resistant mutants of the Mycobacterium tuberculosis RNAP but lowered antitubercular activity in cell culture under both aerobic and anaerobic conditions. Lowered affinity toward hPXR for some of the analogues is also observed, suggesting a potential for reduced Cyp450 induction activity. Mouse and human microsomal studies of analogue 2b show it to have excellent metabolic stability. Mouse pharmacokinetics in plasma and lung show accumulation of 2b but with a half-life suggesting nonoptimal pharmacokinetics. These studies demonstrate proof of principle for this subclass of rifamycins and support further expansion of structure-activity relationships (SARs) toward uncovering analogues with development potential. PMID- 22452569 TI - Traveling Time of a translating ribosome along messenger RNA monitored directly on a quartz crystal microbalance. AB - During translation, the biosynthesis of polypeptides is dynamically regulated. The translation rate along messenger RNA (mRNA), which is dependent on the codon, structure, and sequence, is not always constant. However, methods for measuring the duration required for polypeptide elongation on an mRNA of interest have not been developed. In this work, we used a quartz crystal microbalance (QCM) technique to monitor mRNA translation in an Escherichia coli cell-free translation system in real time. This method permitted us to evaluate the translation of proteins of interest fused upstream of a streptavidin-binding peptide (SBP) fusion protein. The translation of mRNA encoding the SBP fusion protein alone was observed as a mass increase on a streptavidin-modified QCM plate. Addition of the protein of interest resulted in a delay in the mass change corresponding to the traveling time of the ribosome along the coding region of the protein of interest. With this technique, the lengths of coding sequences, codon usages, influences of unique sequences, and various protein-coding sequences were evaluated. The results showed that the traveling time of the translating ribosome depends on the length of the coding region translated but is also affected by the sequence itself. Differences in the time lags for various proteins imply that mRNA coding sequences may regulate gene expression. PMID- 22452570 TI - Pellet layering: scale-up considerations using different kinds of processing equipment. AB - OBJECTIVE: In this study an aqueous suspension of poorly water-soluble HCT (hydrochlorothiazide) was layered on small spherical starter cores with a drug content in the final pellets of 30%. The aim was to compare different kinds of processing equipment (Wurster fluid-bed, CPS rotor fluid-bed and drum coater) in view of process efficiency, process duration and feasibility to scale-up. RESULTS: In a pilot scale drum coater, it was possible to achieve the desired LE (layering efficiency) and yield specifications (both >95%), but the process duration was at least 202 min. In the small scale Wurster fluid-bed machine, it was possible to reduce the process time for an optimized process from 67 min to 41 min. However, the acceleration of the process led to an increase of agglomerates and the same process took at least 114 min in the scale-up experiments. A small scale CPS rotor processor with a cone-shaped disc was superior to the conventional planar rotor disc design, regarding yield and agglomerates. This rotor process was both, fast and highly efficient (yield: 98.4%; LE: 99.3%). The high quality of the process was also observed for the pilot scale batches, in which neither considerable losses of drug (LE >= 98.6%) nor formation of agglomerates occurred. The absolute spray rate in this pilot scale process was 85 kg/h. CONCLUSION: Best results were achieved with the CPS rotor technology. With a duration of 29 min (small scale) and 44 min (pilot scale) it was the fastest option to produce layered pellets. PMID- 22452571 TI - Contrasting trends in distribution of four major planktonic betaproteobacterial groups along a pH gradient of epilimnia of 72 freshwater habitats. AB - The distribution and abundance of Betaproteobacteria and three of its genera - Limnohabitans (R-BT065 lineage), Polynucleobacter (including subclusters Polynucleobacter necessarius and Polynucleobacter acidiphobus/Polynucleobacter difficilis), and Methylophilus - across the epilimnia of 72 limnologically diverse freshwater habitats were investigated using fluorescence in situ hybridization. Moreover, seasonal development of Betaproteobacteria subgroups along the longitudinal axis of a reservoir was followed. Betaproteobacteria comprised on average 29.1%, Polynucleobacter 11.6%, P. necessarius 10.1%, P. acidiphobus/difficilis 0.5%, Limnohabitans 8.9%, and Methylophilus 0.9% of total bacterioplankton cells in the investigated habitats. Polynucleobacter necessarius and Limnohabitans coexisted in the majority of habitats but showed contrasting abundance patterns along the pH gradient of habitats (pH, 3.8-8.5). The observed distribution patterns could theoretically be explained by different preferences for substrate sources, that is, substances of humic origin in acidic waters and algal-derived substances in alkaline waters. However, substrate utilization patterns observed in laboratory experiments indicate no coherent group-specific differences in substrate preferences. Interestingly, similar distribution patterns were revealed for Limnohabitans and P. acidiphobus/difficilis, suggesting similar ecological adaptations of these distantly related taxa. Our findings further emphasize that at least two taxa of freshwater Betaproteobacteria represent ecologically diversified groups. Investigations at higher phylogenetic resolution are required for obtaining further insights into their ecology. PMID- 22452572 TI - Inkjet-printed lines with well-defined morphologies and low electrical resistance on repellent pore-structured polyimide films. AB - Polyimide films are the most promising substrates for use in printed electronics because of their high thermal stability. However, the high wettability of polyimide films by conductive inks often produces thin inkjet-printed lines with splashed and wavy boundaries, resulting in high electrical resistance of the lines. To overcome these disadvantages, we fabricated repellent pore structures composed of polyamideimide with high thermal stability on a polyimide film. Using this film, the inkjet-printed line thickness was increased without penetration of silver nanoparticles into the pore structures, thus resulting in very sharp edges without any splashing. This was because the repellent treatment restricted the spreading of the silver nanoparticles into the pore structures and the pore structures prevented ink splashing upon impact on the film. As a result, the electrical resistance of these lines decreased to one-fifth that of the lines on the pristine polyimide film. The inkjet printing of conductive inks onto repellent pore structures would contribute to the future of printed electronics because this technique enables printing closely packed line patterns while maintaining high conductivity within a limited space. PMID- 22452573 TI - Oral health, sense of coherence and dental anxiety among middle-aged women. AB - AIMS: The specific aims of this investigation were to analyze the relationship between sense of coherence (SOC), dental anxiety (DA) and oral health status among middle-aged women, measured both subjectively and objectively and adjusted for socioeconomic status (SES). MATERIALS AND METHODS: Randomly selected women, 38 (n = 206) and 50 (n = 287) years of age, were included in a cross-sectional health examination. The participants underwent a series of examination stages, including a clinical and dental radiographic examination. The women responded to questionnaires concerning SES, oral health, DA and SOC. RESULTS: The number of teeth was significantly related to SOC, where more missing teeth revealed a lower SOC level among 50-year-olds. The variables of caries, apical periodontitis and filled surfaces were not statistically significantly associated with SOC. However, the self-reported measure of oral health was associated with SOC in both age groups. High DA was significantly related to self-perceived poor oral health regardless of age. Individuals with high DA also had fewer teeth, more filled surfaces and more approximal caries. The multivariate models showed that higher SOC levels were associated with better oral health, as estimated by objective or subjective measures, while the inverse results were seen for DA. Thus, individuals reporting high DA were more likely to have fewer teeth and poor perceived oral health, taking SES into account. CONCLUSIONS: Sense of coherence and dental anxiety are psychological aspects with respect to health- and risk factors of oral health. PMID- 22452574 TI - Formation of organic nanoparticles by electrospinning of volatile microemulsions. AB - This study presents a method for one-step formation of poly(ethylene oxide) nanofibers incorporating nanoparticles of a poorly water-soluble compound. Using the new method reported here, nanofiber-nanoparticle composites are fabricated in one step by electrospinning of an oil-in-water microemulsion, in which a model material, propylparaben, has been dissolved within the volatile dispersed phase in the presence of a high-molecular-weight polymer. The approach is based on nanoscale confinement to the dispersed phase of an oil-in-water microemulsion with a volatile oil phase, in which the poorly water-soluble materials are dissolved. Thus, when the thermodynamically stable oil-in-water microemulsion is combined with the rapid evaporation of solvent inherent in the electrospinning process, the droplets are converted into organic nanoparticles embedded within a polymeric nanofiber. In addition to possessing process simplicity, this method exhibits a very high percentage of nanoparticle loading with desirable active material properties. Specifically, the diameter of the nanofibers is in the range of 60-185 nm, and propylparaben exists within the nanofiber as nanocrystals of 30 120 nm. These dimensions suggest that the nanofiber-nanocrystal composites could serve as a delivery system for water-insoluble materials. PMID- 22452575 TI - Aluminum stress response in rice: effects on membrane lipid composition and expression of lipid biosynthesis genes. AB - The presence of aluminum (Al) in acidic soils is a major abiotic stress limiting the production of cultivated plants. Cell membranes are the main targets of environmental stresses and there is growing evidence for the involvement of membrane lipids in plant adaptation. The aim of this study was to evaluate the mid-long effects of Al on membrane lipid content and composition in the roots and shoots of rice plants grown under hydroponic conditions. Four rice cultivars were compared: two acknowledged as Al-resistant (Koshihikari) and Al-sensitive (Kasalath), respectively, and two Vietnamese cultivars, OM6073 and OM1490. Al treatment inhibited root and shoot growth in the sensitive cultivars and the observed changes in root and shoot lipid and fatty acid composition revealed patterns associated with Al sensitivity: larger decreases in lipid content and decreases in fatty acid unsaturation. In the roots, phospholipids, and particularly phosphatidylcholine (PC), decreased dramatically in the susceptible cultivars whereas the amount of lipid classes remained unchanged in the tolerant ones. In the shoots, the glycolipids monogalactosyldiacylglycerol and digalactosyldiacylglycerol as well as PC were mostly affected by Al treatment in the susceptible varieties. mRNA accumulation corresponding to genes coding for galactolipid synthases, enzymes of the PC and phosphatidylethanolamine biosynthetic pathways and fatty acid desaturases correlated well with changes in lipid contents in roots and partly explained lipid changes in leaves. The results suggested that the capacity to maintain the proper functioning of some lipid biosynthetic activities and hence the stability of lipid composition may help the rice plant to withstand Al stress. PMID- 22452576 TI - An intact RNA interference pathway is required for expression of the mutant wing phenotype of vg(21-3), a P-element-induced allele of the vestigial gene in Drosophila. AB - We have determined that two P elements, P[21-3] and P[21r36], residing in the 5' UTR of the vestigial wing gene, encode functional repressors in eye tissue. However, neither element fits a previous categorization of repressor-making elements as Type I or II. Both elements encode polypeptides that are shorter than the canonical elements they most closely resemble. DNA sequencing reveals that P[21r36] encodes an intact THAP domain that is missing in the P[21] element, which does not encode a functional repressor. Recovery of P[21-3] at sites other than vestigial (where it causes the wing mutant, vg(21-3)) reveals that the element can make repressor in wing tissue of sufficient activity to repress the mutant phenotype of vg(21-3). Why the P[21-3] element fails to produce repressor when located at vestigial may be explained by our observation that three different mutants in the RNA interference pathway cause a partial reversion of vg(21-3). We speculate that the vg and P-initiated transcripts that arise at the vg locus in the vg(21-3) mutant trigger an RNA interference response that results in the mutual degradation of both transcripts. PMID- 22452577 TI - Vasectomy reversal with ultrasonography-guided spermatic cord block. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Vasectomy reversal is often performed in general or neuraxial anaesthesia. Even though the site of vasectomy reversal is easily amenable to regional/local anaesthesia, spermatic cord blocks are rarely applied because of their risk of vascular damage within the spermatic cord. Recently, we described the technique of ultrasonography (US)-guided spermatic cord block for scrotal surgery, which, thanks to the US guidance, at the same time avoids the risk of vascular damage of blindly performed injections and the risks of general and neuraxial anaesthesia. Vasectomy reversal can easily be done in regional anaesthesia with the newly described technique of US-guided spermatic cord block without the risks of vascular damage by a blindly performed injection and the risks of standard general and neuraxial anaesthesia. In addition, this technique grants long-lasting postoperative pain relief and patients recover more quickly. Microsurgical conditions are excellent and patient satisfaction is high. Thanks to these advantages, more patients undergoing vasectomy reversal might avoid general or neuraxial anaesthesia. OBJECTIVE: * To assess the success rate, microsurgical conditions, postoperative recovery, complications and patient satisfaction of ultrasonography (US)-guided spermatic cord block in patients undergoing microscopic vasectomy reversal and to compare them to a control group with general or neuraxial anaesthesia. PATIENTS AND METHODS: * The present study comprised a prospective series of 10 consecutive patients undergoing US-guided spermatic cord block for microscopic vasectomy reversal. * The cohort was compared with 10 patients in a historical control group with general or neuraxial anaesthesia. RESULTS: * Nineteen of 20 (95%) blocks were successful, defined as no pain >3 on the Visual Analogue Scale (VAS), no additional analgesics and/or no conversion to general anaesthesia. Median pain was 0 on the VAS (range 0-5). Additional analgesics were requested in one (5%) block, and there was no conversion to general anaesthesia. * Microsurgical conditions were excellent. * In the spermatic cord block vs general/neuraxial anaesthesia groups, median times (range) between surgery and first postoperative analgesics, alimentation, mobilization and hospital discharge were 12 (2-14) vs 3 (1-6), 1 (0.25-3) vs 4 (3 6), 2 (1-3) vs 6 (3-10), and 4 (3-11) vs 8.5 (6-22) h, respectively. * No complications were reported after the spermatic cord block. * Patient satisfaction was excellent. CONCLUSIONS: * US-guided spermatic cord block for microscopic vasectomy reversal is highly successful and provides long-lasting perioperative analgesia. * Times to alimentation, mobilization and hospital discharge are shorter under US-guided spermatic cord block than under general/neuraxial anaesthesia. * Additional anaesthetic pain management might, however, be required unexpectedly with US-guided spermatic cord block. PMID- 22452578 TI - Critical role of truncated alpha-synuclein and aggregates in Parkinson's disease and incidental Lewy body disease. AB - The role of Lewy bodies, Lewy neurites and alpha-synuclein (alphaSYN) in the pathophysiology and diagnosis of Parkinson's disease (PD) is unclear. We used postmortem human tissue, a panel of antibodies (Abs) and confocal microscopy to examine the three-dimensional neurochemical anatomy of the nigrostriatal system. Abs were specific to truncated (talphaSYN), phosphorylated and full-length alphaSYN. The findings demonstrate the critical role of talphaSYN in initiating aggregation, a role for other forms of alphaSYN in aggregate expansion, a reason for the wide variety of proteins present in different aggregates, an explanation for the laminar appearance of aggregates described historically using different methods, the existence of proximal greater than distal aggregation in the vulnerable nigrostriatal pathway, the independent transport of different forms of alphaSYN as cargo along axons and a possible sequence for the formation of Lewy bodies. Findings differed between incidental Lewy body disease and PD only quantitatively. These findings have implications for understanding the pathogenesis and treatment of PD. PMID- 22452579 TI - Liver transplantation for a pediatric patient with hemophilia B. AB - Hemophilia exposes patients to greater risks of bleeding complications during the perioperative period. However, there are no current protocols for factor replacement during LT. We herein describe a case of pediatric living donor LDLT performed for a patient with hemophilia B using perioperative short-term factor replacement. A 4-yr-old female patient with an extrahepatic portosystemic shunt and asymptomatic hemophilia B (factor IX activity 18.7%) underwent an ABO compatible LDLT using a left lobe graft. The bleeding volume was 2980 mL. Freeze dried human blood coagulation factor IX concentrate (Novact M, Kaketsuken, Japan) was administered at the induction of anesthesia and at the end of LDLT by bolus infusion (80 U/kg) and was continued by bolus infusion (40 U/kg) on POD 1, 2, 3, and 4. On POD 1, 5, 8, and 12, the factor IX plasma levels were 34.5%, 64.9%, 43.5%, and 53.1%, respectively. The postoperative course was uneventful, and the patient is currently doing well at 2.5 yr after LDLT. Factor concentrate should be administered at the induction of anesthesia and at the end of LT by bolus infusion, and thereafter be continued for a few days after LT by bolus infusion. PMID- 22452580 TI - Folic acid supplement use is the most significant predictor of folate concentrations in Canadian women of childbearing age. AB - One-fifth of Canadian women of childbearing age (WCBA) have red blood cell (RBC) folate concentrations below those considered optimal for neural tube defect risk reduction (>=906 nmol.L(-1)). Determinants of optimal concentrations have not been examined in a nationally representative sample of Canadian WCBA since food fortification with folic acid was implemented. This study explored correlates of optimal RBC folate concentrations and characteristics of folic acid supplement users in a sample of Canadian WCBA. RBC folate concentrations from the 2007-2009 Canadian Health Measures Survey were assessed in women aged 15 to 45 years (n = 1162). Sociodemographic, behavioural, and clinical determinants of RBC folate >=906 nmol.L(-1) were examined using univariate and separate multiple logistic regression models that controlled for age and household income. t tests were used to study differences between folic acid supplement users and nonusers. WCBA not taking folic acid supplements were less likely to achieve a RBC folate concentration >=906 nmol.L(-1) compared with folic acid supplement users (odds ratio, 0.47; 95% confidence interval, 0.24, 0.92). Twenty-five percent of WCBA reported folic acid supplement use, and there was a higher percentage of folic acid supplement users in the highest income group. Folic acid supplement users were also more frequent consumers of supplemental vitamin B(12) and of fruit and vegetables (>3 times per day). Folic acid supplement use was the most significant predictor of WCBA achieving optimal RBC folate concentrations. These results indicate a need for targeted strategies to improve compliance with folic acid supplement recommendations among WCBA. PMID- 22452581 TI - A simple model predicts experimental folding rates and a hub-like topology. AB - A simple model is presented that describes general features of protein folding, in good agreement with experimental results and detailed all-atom simulations. Starting from microscopic physics, and with no free parameters, this model predicts that protein folding occurs remarkably quickly because native-like states are kinetic hubs. A hub-like network arises naturally out of microscopic physical concerns, specifically the kinetic longevity of native contacts during a search of globular conformations. The model predicts folding times scaling as tau(f) ~ e(xiN) in the number of residues, but because the model shows xi is small, the folding times are much faster than Levinthal's approximation. Importantly, the folding time scale is found to be small due to the topology and structure of the network. We show explicitly how our model agrees with generic experimental features of the folding process, including the scaling of tau(f) with N, two-state thermodynamics, a sharp peak in C(V), and native-state fluctuations. PMID- 22452582 TI - HPV vaccine information in the blogosphere: how positive and negative blogs influence vaccine-related risk perceptions, attitudes, and behavioral intentions. AB - This research examines the impact of exposure to online blogs about the human papillomavirus (HPV) vaccine on vaccine-related risk perceptions, attitudes, and behavioral intentions. In a controlled experiment (N = 341), college students were exposed to either a negative blog post about the HPV vaccine or a positive one. Compared to the control group, participants who had viewed the negative blog perceived the vaccine as less safe, held more negative attitudes toward the vaccine, and had reduced intentions to receive the vaccine. In contrast, exposure to the positive blog did not alter any vaccine-related risk perceptions, attitudes, or intentions. Implications of the findings for online vaccine risk communication are discussed. PMID- 22452583 TI - Long-term experience with surgical treatment of selected patients with bladder pain syndrome/interstitial cystitis. AB - OBJECTIVE: The role of major surgery in patients with bladder pain syndrome/interstitial cystitis (BPS/IC) is not fully established. This report presents a single-institution experience with major surgery in patients with disabling BPS/IC where conservative treatment had failed. MATERIAL AND METHODS: Forty-one patients (34 women, seven men) with BPS/IC refractory to conservative treatment underwent major surgery from 1983 to 2004. Surgical approach was determined on a case-by-case basis. Postoperative pain and satisfaction were assessed by a questionnaire. RESULTS: Cystectomy was the primary procedure in five patients. The remaining 36 patients were primarily operated on with subtotal cystectomy and bladder augmentation (n = 16) or supravesical urinary diversion with intact bladder (n = 20). Thirteen of these patients were later operated on with cystectomy due to persisting pain 12 (6-146) months after the primary procedure. The questionnaire was answered by 38 of 41 patients after a median follow-up of 66 (6-238) months. In total, 28 patients (74%) were free of pain, and 26 patients (68%) were satisfied with the end result. There was no difference in reported pain between cystectomized and non-cystectomized patients. When comparing patients who reported pain at follow-up with those who did not report pain, preoperative length of symptoms was significantly increased, with 12.1 compared to 5.4 years (p = 0.02). CONCLUSIONS: Major surgery is associated with good symptom relief in strictly selected patients with disabling BPS/IC, where conservative treatment has failed. Extended preoperative duration of symptoms may be a predictor for persisting pain after major surgery for BPS/IC. PMID- 22452584 TI - Case of aggressive angiomyxoma of the vulva. PMID- 22452585 TI - Impaired brain growth and neurodevelopment in preterm infants with posthaemorrhagic ventricular dilatation. AB - AIM: To correlate volumetric magnetic resonance imaging at term with neurodevelopmental outcome at 2 years in infants with posthaemorrhagic ventricular dilatation. Preterm infants with posthaemorrhagic ventricular dilatation have high risk of disabilities, but the range is wide and predicting severity of motor and mental disability is difficult. METHODS: Twenty-five preterm infants with posthaemorrhagic ventricular dilatation had cerebral magnetic resonance imaging at term age. Total and regional brain volumes were calculated using a manual segmentation technique. Bayley Scales of Infant Development II were assessed at 2 years post-term. Developmental Quotients (DQ) were calculated from Developmental Age Equivalent scores. RESULTS: Total cerebral volume, excluding ventricles, correlated positively with Motor (r = 0.7, p < 0.0001) and Mental DQ (r = 0.4, p = 0.02). Only three of 16 infants with cerebral volume <336 cm(3) were ambulant at 2 years. Cerebellar volumes correlated strongly with Motor DQ (r = 0.6, p = 0.002) but only with Mental DQ after adjustment. Thalamic volumes correlated strongly with Motor DQ (r = 0.7, p = 0.0002). CONCLUSION: Brain growth is significantly impaired in posthaemorrhagic ventricular dilatation. Volumetric measurements at term of total cerebral and cerebellar volume may have a role in predicting severity of disability. PMID- 22452586 TI - Dialysis-dependent changes in ventricular repolarization. AB - BACKGROUND: Epidemiological data suggest increased risk of sudden death during and immediately after hemodialysis. Microvolt T-wave alternans (mTWA) is an electrocardiogram (ECG) measure of abnormal ventricular repolarization, which can be used in sudden death risk stratification. The aim of this study was to determine whether mTWA measurements during dialysis indicate abnormal repolarization as a potential trigger to dialysis associated arrhythmias. METHODS: Forty-eight-hour, 12-lead Holter ECG recordings were taken on a cohort of maintenance hemodialysis patients. Modified moving average mTWA was examined for 48 hours from the start of dialysis. Predialysis biochemistry was taken and echocardiography was performed on a nondialysis day. RESULTS: Nineteen patients were analyzed (age 61 +/- 14 years, time on dialysis 2.7 +/- 2 years). mTWA increased during dialysis (P < 0.01) but returned to baseline 2 hours postdialysis (first hour mTWA = 10.1 +/- 4.5MUV, final hour mTWA = 12.2 +/- 3.7MUV, postdialysis mTWA = 10.3 +/- 2.7MUV, P = 0.015). The change in mTWA did not correlate with serum biochemistry or echocardiographic measurements of left ventricular mass and function. Peak mTWA and frequency of spikes in mTWA >= 65MUV were not more common during dialysis compared to other times. Patients who showed greater frequency of spikes >=65MUV or increase in hourly mean mTWA during dialysis did not have a worse cardiovascular outcome over a mean follow-up of 2.6 years. CONCLUSIONS: Though there were subtle changes in mTWA during dialysis, there was no association with mTWA abnormalities previously shown to be associated with worse outcome. The presence of abnormal mTWA did not correlate with outcome. PMID- 22452587 TI - Colonization of native Andean grasses by arbuscular mycorrhizal fungi in Puna: a matter of altitude, host photosynthetic pathway and host life cycles. AB - The relationships of altitude, host life cycle (annual or perennial) and photosynthetic pathway (C(3) or C(4) ) with arbuscular mycorrhiza (AM) root colonization were analysed in 35 species of Andean grasses. The study area is located in north-western Argentina along altitudinal sites within the Puna biogeographical region. Twenty-one sites from 3320 to 4314 m were sampled. Thirty five grasses were collected, and the AM root colonization was quantified. We used multivariate analyses to test emerging patterns in these species by considering the plant traits and variables of AM colonization. Pearson's correlations were carried out to evaluate the specific relationships between some variables. Most grasses were associated with AM, but the colonization percentages were low in both C(3) and C(4) grasses. Nevertheless, the AM root colonization clearly decreased as the altitude increased. This distinctive pattern among different species was also observed between some of the populations of the same species sampled throughout the sites. An inverse relationship between altitude and AM colonization was found in this Southern Hemisphere Andean system. The effect of altitude on AM colonization seems to be more related to the grasses' photosynthetic pathway than to life cycles. This study represents the first report for this biogeographical region. PMID- 22452588 TI - Successful reduced-intensity umbilical cord blood transplant for fulminant hemophagocytic syndrome in an adult with pre-existing rheumatoid arthritis and autoimmune hemolytic anemia. PMID- 22452589 TI - Incidence of transient single metaphase chromosomal abnormalities identified by routine metaphase cytogenetics in bone marrow specimens. PMID- 22452590 TI - Parenthood in patients with acute promyelocytic leukemia after treatment with arsenic trioxide: a case series. AB - Arsenic trioxide, believed to be a carcinogen and a teratogen, has found its niche in the treatment of acute promyelocytic leukemia (APL). APL is a disease affecting young patients. Post-treatment fertility and outcome of pregnancy are always a concern in a disease with high cure rates. We report a case series of six patients who were treated successfully for APL with arsenic trioxide and who parented at least one healthy offspring after completing their treatment. PMID- 22452591 TI - Special delivery: getting radiation to the target in diffuse large B-cell lymphoma. PMID- 22452592 TI - Monoclonal B-lymphocytosis: reflections and definitions. PMID- 22452593 TI - Highly enhanced electrocatalytic oxygen reduction performance observed in bimetallic palladium-based nanowires prepared under ambient, surfactantless conditions. AB - We have employed an ambient, template-based technique that is simple, efficient, and surfactantless to generate a series of bimetallic Pd(1-x)Au(x) and Pd(1 x)Pt(x) nanowires with control over composition and size. Our as-prepared nanowires maintain significantly enhanced activity toward oxygen reduction as compared with commercial Pt nanoparticles and other 1D nanostructures, as a result of their homogeneous alloyed structure. Specifically, Pd(9)Au and Pd(4)Pt nanowires possess oxygen reduction reaction (ORR) activities of 0.49 and 0.79 mA/cm(2), respectively, which are larger than the analogous value for commercial Pt nanoparticles (0.21 mA/cm(2)). In addition, core-shell Pt~Pd(9)Au nanowires have been prepared by electrodepositing a Pt monolayer shell and the corresponding specific, platinum mass, and platinum group metal mass activities were found to be 0.95 mA/cm(2), 2.08 A/mg(Pt), and 0.16 A/mg(PGM), respectively. The increased activity and catalytic performance is accompanied by improved durability toward ORR. PMID- 22452594 TI - The radiation bystander effect and its potential implications for human health. AB - A long-held dogma in radiation biology has been that the biological effects of exposure to ionizing radiation occur as a result of damage in directly irradiated cells and that no effect would occur in neighboring unirradiated cells. This paradigm has been frequently challenged by reports of radiation effects in unirradiated or 'bystander' cells receiving signals from directly irradiated cells, an issue that may have substantial impact on radiation risk assessment and development of radiation-based therapies. Radiation-induced bystander effects have been shown in single-cell systems in vitro for an array of cancer relevant endpoints, and may trigger damage in more complex 3-D tissue systems. They may be mediated by soluble factors released by irradiated cells into the extracellular environment and/or by the passage of mediator molecules through gap-junction intercellular communication. To date, evidence that radiation-associated bystander or abscopal responses are effectual in vivo has been limited, but new data suggest that they may significantly affect tumor development in susceptible mouse models. Further understanding of how the signal/s is transmitted to unirradiated cells and tissues and how it provokes long-range and significant responses is crucial. By summarizing the existing evidence of radiation induced bystander-like effects in various systems with emphasis on in vivo findings, we will discuss the potential mechanisms involved in these observations and how effects in bystander cells contribute to uncertainties in assessing cancer risks associated with radiation exposure. PMID- 22452595 TI - How to write research papers and grants: 2011 Asian Pacific Society for Respirology Annual Scientific Meeting Postgraduate Session. AB - This review article summarizes the content of a series of interrelated workshop presentations from the Annual Scientific Meeting of the Asian Pacific Society of Respirology held in Shanghai in November, 2011. The article describes tips and strategies for writing research papers and research grant applications and includes discussion of: the role of pulmonologists in research; the debates around the use of the journal impact factor; tips for writing manuscripts and publishing research in high-impact journals; how journals assess manuscripts and the most common reasons editors reject manuscripts; how to write grant applications and what grant panels look for in successful proposals; and how to undertake research in resource-limited countries. PMID- 22452596 TI - Short bowel syndrome in children: current and potential therapies. AB - Short bowel syndrome (SBS) reflects a state of malabsorption that occurs due to loss of a significant portion of the small bowel. The pathophysiology of SBS is determined largely by the process of adaptation, which is the innate attempt by the remnant portions of the intestine to increase fluid and nutrient reabsorption. In recent years, emphasis has been placed on intestinal rehabilitation with multidisciplinary teams as a comprehensive approach to the management of patients with SBS. In our institution, the multidisciplinary team members include pediatric gastroenterologists, pediatric surgeons, pediatric dieticians, physical therapists, occupational therapists, neonatologists (especially for patients still under their care), transplant surgeons, transplant coordinators and social workers. Parenteral nutrition plays a significant role in the management of SBS, but its use is associated with many potential complications, including cholestatic liver disease. Fish oil-based lipid emulsions have shown promise in their ability to reverse and also prevent the development of cholestasis in these patients. Clinical trials have shown that growth factors and other trophic hormones facilitate the process of adaptation. The most significant impact has been shown with the use of glucagon-like peptide 2 and its analog (teduglutide). Surgical interventions remain an important part of the management of SBS to facilitate adaptation and treat complications. Intestinal transplantation is a last resort option when the process of adaptation is unsuccessful. This review article is intended to provide an overview of the conventional and emerging therapies for pediatric SBS. PMID- 22452597 TI - Oxygen concentration and cysteamine supplementation during in vitro production of buffalo (Bubalus bubalis) embryos affect mRNA expression of BCL-2, BCL-XL, MCL-1, BAX and BID. AB - This study examined the effects of O(2) concentration (5% vs 20%) during in vitro maturation (IVM), fertilization (IVF) and culture (IVC) or supplementation of IVM and IVC media with cysteamine (50 and 100 MUm, respectively; IVM, IVF and IVC carried out in 20% O(2)), on blastocyst rate and relative mRNA abundance of some apoptosis-related genes measured by real-time qPCR in immature and in vitro matured buffalo oocytes and in embryos at 2-, 4-, 8- to 16-cell, morula and blastocyst stages. The blastocyst rate was significantly higher (p < 0.05) while the percentage of TUNEL-positive cells was significantly lower (p < 0.05) under 5% O(2) than that under 20% O(2). The mRNA expression of anti-apoptotic genes BCL 2 and MCL-1 was significantly higher (p < 0.05) and that of pro-apoptotic genes BAX and BID was lower (p < 0.05) under 5% O(2) than that under 20% O(2) concentration at many embryonic stages. Following cysteamine supplementation, the blastocyst rate and the relative mRNA abundance of BCL-XL and MCL-1 was significantly higher (p < 0.05) and that of BAX but not BID was lower (p < 0.05) at many stages of embryonic development, although it did not affect the percentage of TUNEL positive cells in the blastocysts significantly. The mRNA expression pattern of these genes during embryonic development was different in 5% vs 20% O(2) groups and in cysteamine supplemented vs controls. At the 8- to 16 cell stage, where developmental block occurs in buffalo, the relative mRNA abundance of BCL-2 and MCL-1 was highest under 5% O(2) concentration and that of BAX and BID was highest (p < 0.05) under 20% O(2) concentration. These results suggest that one of the mechanisms through which beneficial effects of low O(2) concentration and cysteamine supplementation are mediated during in vitro embryo production is through an increase in the expression of anti-apoptotic and a decrease in the expression of pro-apoptotic genes. PMID- 22452598 TI - Chemical composition and in vitro schistosomicidal activity of the essential oil from the flowers of Bidens sulphurea (Asteraceae). AB - In this study, the chemical composition and the in vitro schistosomicidal properties of the essential oil obtained from Bidens sulphurea flowers (Bs-EO) were investigated. Its major constituents were identified as being 2,6-di-tert butyl-4-methylphenol (44.98%), germacrene D (33.70%) and beta-caryophyllene (10.23%). Bs-EO at 100 ug mL(-1) caused death of all the adult worms and promoted separation of the couple pairs into individual male and female within 48 h, besides leading to a significant decrease in the motility of the parasites. This oil was also responsible for a remarkable reduction in the number of eggs and the percentage of developed eggs produced by adult worms. These results suggest that the Bs-EO can be considered a promising source for the development of new schistosomicidal agents. PMID- 22452599 TI - Influence of second coordination sphere hydroxyl groups on the reactivity of copper(I) complexes. AB - We report the enhanced reactivity of hydroxyl substituted CuN(3)(+) derivatives, where N(3) = tris(picolinyl)methane (tripic) and related derivatives, upon deprotonation of the O-H functionality. The work capitalizes on new methodology for incorporating hydroxyl groups into the second coordination sphere of copper centers. The key synthetic methodology relies on Pd-catalyzed coupling reactions of dilithiated 6-methyl-2-pyridone with bromopyridyl derivatives. These building blocks allow the preparation of tridentate N(3) ligands with OH and OMe substituents flanking the fourth coordination site of a tetrahedral complex. Coupling of these tridendate ligands gives the corresponding hydroxy- and methoxy functionalized bistripodal ligands. [Cu[bis(2-methylpyrid-6-yl)(2-hydroxypyrid-6 yl)methane](NCMe)](+) ([Cu(2H)(NCMe)](+)) oxidizes readily in air to afford the mixed valence Cu(1.5) dimer ([Cu(2)(2)(2)](+)). Formation of [Cu(2)(2)(2)](+) is accelerated in the presence of base and can be reversed with a combination of decamethylferrocene and acid. The reactivity of [Cu(2H)(NCMe)](+) with dioxygen requires deprotonation of the hydroxyl substituent: neither [Cu(tripic)(NCMe)](+) nor the methoxy-derivatives displayed comparable reactivity. A related mixed valence dimer formed upon oxidation of the dicopper(I) complex of a tetrahydroxy bis(tridentate) ligand, [Cu(2)(6H(4))(NCMe)(2)](2+). The dicopper(I) complex of the analogous tetramethoxy N(6)-ligand, [Cu(2)(5)(NCMe)(2)](2+), instead reversibly binds O(2). Deprotonation of [Cu(2H)(CO)](+) and [Cu(2H)(NCMe)](+) afforded the neutral derivatives Cu(2)(CO) and Cu(2)(2)(2), respectively. The dicopper(I) derivative Cu(2)(2)(2) can be reoxidized, reprotonated, and carbonylated. The silver(I) complex, [Ag(2H)(NCMe)]BF(4), forms an analogous neutral dimer (Ag(2)(2)(2)) upon deprotonation of the hydroxyl group. The structures of ligand 2H, [Cu(2)(5)(NCMe)(2)](+), [Cu(2)(2)(2)](+), [Cu(2)(6H(2))](+), [Ag(2H)(NCMe)]BF(4), and Ag(2)(2)(2) were confirmed by single crystal X-ray diffraction. PMID- 22452600 TI - Effects of salt stress on the structure and function of the photosynthetic apparatus in Cucumis sativus and its protection by exogenous putrescine. AB - With the objective to clarify the physiological significance of polyamines (PAs) in the photosynthetic apparatus, the present study investigated the effects of salt stress with and without foliar application of putrescine (Put) on the structure and function of the photosynthetic apparatus in cucumber. Salt stress at 75 mM NaCl for 7 days resulted in a severe reduction of photosynthesis. The fast chlorophyll afluorescence transient analysis showed that salt stress inhibited the maximum quantum yield of PSII photochemistry (F(v)/F(m)), mainly due to damage at the receptor side of PSII. In addition, salt stress decreased the density of active reaction centers and the structure performance. The microscopic analysis revealed that salt stress-induced destruction of the chloroplast envelope and increased the number of plastoglobuli along with aberrations in thylakoid membranes. Besides, salt stress caused a decrease in the content of endogenous PAs, conjugated and bound forms of spermidine and spermine in particular, in thylakoid membranes. However, applications of 8 mM Put alleviated the salt stress-mediated decrease in net photosynthetic rates (Pn) and actual efficiency of PSII(Phi(PSII)). Put increased PAs in thylakoid membranes and overcame the damaging effects of salt stress on the structure and function of the photosynthetic apparatus in salt-stressed plant leaves. Put application to control plants neither increased PAs in thylakoid membranes nor affected photosynthesis. These results indicate that PAs in chloroplasts play crucial roles in protecting the thylakoid membranes against the deleterious influences of salt stress. In addition, the present results point to the probability that the salt-induced dysfunction of photosynthesis is largely attributable to the loss of PAs in the photosynthetic apparatus. PMID- 22452601 TI - Dissolution enhancement of poorly water-soluble APIs processed by hot-melt extrusion using hydrophilic polymers. AB - The aim of this study was to investigate the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) processed by hot-melt extrusion (HME). Indomethacin (INM) and famotidine (FMT) were selected as model active substances while polyvinyl caprolactam graft copolymer, soluplus (SOL) and vinylpyrrolidone-vinyl acetate copolymer grades, Kollidon VA64 (VA64) and Plasdone S630 (S630) were used as hydrophilic polymeric carriers. For the purpose of the study, drug-polymer binary blends at various ratios were processed by a Randcastle single screw extruder. The physicochemical properties and the morphology of the extrudates were evaluated through X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Increased drug loadings of up to 40% were achieved in the extruded formulations for both drugs. INM and FMT exhibited strong plasticization effects with increasing concentrations and were found to be molecularly dispersed within the polymer blends. The in vitro dissolution studies showed increased INM/FMT release rates for all formulations compared to that of pure APIs alone. PMID- 22452602 TI - Efficacy of montelukast as added therapy in patients with chronic idiopathic urticaria. AB - Chronic idiopathic urticaria is a common skin disorder characterized by recurrent appearance of wheals and/or angioedema for more than 6 weeks without an identifiable cause. Consensus guidelines suggest use of leukotriene receptor antagonists (montelukast or zafirlukast) in patients whose urticaria is resistant to antihistamines. Our objectives were (1) document the efficacy of montelukast in our patients, and (2) evaluate whether any clinical features or available laboratory investigations were associated with a response to montelukast. Patients who received montelukast between the years 2008-2011 (4-year period) were retrospectively identified from clinic letters. Clinical features and laboratory investigations were collected and analyzed. The primary end point was adequate control of disease without the need for systemic steroid therapy. 25 patients (10 males and 15 females; median age, 33 years; age range, 13-66 years) with an average duration of urticaria at 3.8 years received montelukast 10mg daily. 12 patients (48%) were better on montelukast with combined anti-H1 and anti-H2 therapy, with no statistical significance between median age and duration of urticaria between males and females. In 11 patients, montelukast had no effect and in 2 patients the urticaria worsened after montelukast was started. 15 patients had peripheral blood basopenia of which 5 patients responded to montelukast. Two patients had positive antinuclear antibody, 3 thyroid peroxidase antibodies and 4 with positive basophil histamine release. All 20 patients who had complement C3 and C4 levels done were within normal limits. Four of 6 patients (67%) with positive specific IgE responded to montelukast and combined anti-H1/H2 therapy. Almost half of our patients with chronic urticaria responded to montelukast and combined anti-H1 and anti-H2 therapy. We were unable to identify any clinical features or laboratory markers that were associated with a response to montelukast. Further studies are required to understand the failure of response of leukotriene inhibition in urticaria. PMID- 22452603 TI - Antagonizing IL-6 in ankylosing spondylitis: a short review. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disorder with predilection for the axial skeleton, leading to progressive restricted mobility and deformity of the spine. The fundamental mechanism involves autoimmunity orchestrated by T cells. Similar to other rheumatic diseases, the complex interplay of cytokines such as tumour necrosis factor alpha, interleukin-6 (IL 6) and interleukin-10 (IL 10) has been implicated in the pathogenesis of the disease. Despite extensive research over the past decades, the treatment options for AS, are limited. Non steroidal antiinflammatory drugs are the first line of therapy, whereas anti TNF drugs are administered for refractory cases which fail to respond to the treatment. There have been conflicting views on the correlation of IL 6 with disease activity in AS. As such, the debate on the role of anti IL6 in AS is still ongoing. Anti IL 6 such as tocilizumab and siltuximab have proven efficacy based on the large randomized controlled trials. The Food and Drug Administration (FDA) has approved these drugs for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis. Researchers have adventurously experimented anti IL 6 therapy in AS but the conclusions made were not consolidated into international guidelines or consensus statement for clinical practice. In the present review, we explore the role of anti IL6 in the treatment of AS based on the cumulative evidence over recent years. PMID- 22452604 TI - Probiotic multistrain treatment may eradicate Helicobacter pylori from the stomach of dyspeptics: a placebo-controlled pilot study. AB - Probiotics survive in gastric environment competing with H. pylori. We studied probiotic "multistrain" administration in dyspeptics with H. pylori (placebo controlled study). Forty patients with H. pylori (urea breath test - UBT - and IgG) were treated for 10 days with a mixture of 8 species of probiotics. Control group represented by 40 positive subjects received placebo. A second UBT and H. pylori stool antigen (HpSA) detection were performed after 1 month. Patients who remained infected were treated with triple therapy undergoing another UBT after 30 days. A second line therapy was administered in remaining positive patients. STATISTICS: Fisher's exact probability and Student's t tests. Thirteen out of 40 patients using probiotics became negative, while controls remained positive, irrespectively of the initial UBT delta value. No difference in the eradication rates between the two groups was found (68%-71%). After second line therapy two patients remained positive. An adequate supplementation with probiotics might eradicate H. pylori. PMID- 22452605 TI - Inhaled KMUP-1 Prevents Allergic Pulmonary Vascular Inflammation and Remodeling via NO and Suppressed MMP-9 and ICAM-1/VCAM-1. AB - AIMS: This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA) sensitized and - challenged peri-bronchial vascular inflammation and remodeling in mice. METHODS AND RESULTS: After short-term KMUP-1 (1-5 mM, 30 min) nebulization and L-NAME (12 mM, 15 min)- pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases-9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intraperitoneal OVA on day 1 and day 8, challenged with OVA nebulization and treated with KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NOmetabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP 1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri bronchiolar regions. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1. CONCLUSIONS: Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease. PMID- 22452606 TI - Treatment of Guillain-Barre syndrome: a review. AB - Guillain-Barre syndrome is a frequently post-infectious, autoimmune acute inflammatory polyradiculoneuropathy affecting all age groups. It typically results in rapid-onset weakness symmetrically affecting proximal and distal muscles. Cranial muscles are not infrequently affected and respiratory muscle weakness requiring mechanical ventilation occurs in 25% of cases. The incidence is around 1-2 per 100,000/year. Various clinical, electrophysiological and immunological subtypes are described. Plasma exchanges (PE) and intravenous immunoglobulins (IVIg) represent the main treatment options. PE were shown to be effective on rate of recovery in randomized trials. Subsequently further trials have demonstrated the equivalence of IVIg. IVIg are frequently the preferred option for practical reasons. Treatment can result in reversible clinical fluctuations which need to be readily recognized. Although number of PE appears to be optimally of 4, except in mildly affected patients where only 2 may suffice, the dosage of IVIg conventionally administered (2 g/kg) may be sub optimal in some patients. This may relate to a relationship between IVIg pharmacokinetics and clinical outcome. Studies are under way to evaluate the usefulness of a second IVIg course in severely-affected GBS patients. There is no evidence for use of corticosteroids in GBS. Both IVIg and PE are costly and despite their use and established effectiveness, there is still a need for new treatments to lessen disability. Further research is warranted in optimizing currently available therapies as well as finding others to effectively improve the management of this potentially devastating condition. PMID- 22452607 TI - Bone marrow niches for hematopoietic stem cells and immune cells. AB - In mammals, hematopoietic stem cells (HSCs), which give rise to all blood cells and their progenies, including immune cells are controlled by special microenvironments, termed niches in the bone marrow during homeostasis and infection. However, the identity, nature and function of these niches remain unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (termed endosteal niche). However, recent studies suggest that only a small number of HSCs reside in the endosteal niche. In contrast, many HSCs are shown to be in contact with endothelial cells in the marrow. In addition, recent studies suggest that primitive mesenchymal cells, including CXCL12-abundant reticular (CAR) cells and Nestin-expressing cells, which have the ability to differentiate into adipocytes as well as osteoblasts act as niches for HSCs. Here we review candidate niches for HSCs in the bone marrow controlling hematopoiesis and chronic inflammation. PMID- 22452608 TI - A Method for Fabrication of Implant-Supported Fixed Partial Dentures. AB - Abstract When restoring a partially edentulous arch with an implant-supported fixed partial denture, the optimal fit and function of the final restoration depend on the fabrication of an accurate impression and the registration of the interocclusal relationship. The present case report presents a method for the fabrication of impressions and the registration of the interocclusal relationship for implant-supported partial dentures. The described method allows the accurate transfer of the implant position and the registration of the interocclusal relationship using transfer key and electroformed gold copings. The key and copings were used to transfer the intraoral implant position to the cast, to position the abutments intraorally, and to facilitate the fabrication of the final partial denture. PMID- 22452609 TI - The HALO submaximal treadmill protocol to measure cardiorespiratory fitness in obese children and youth: a proof of principle study. AB - Many limitations exist with completing cardiorespiratory fitness testing in obese children. The aim of this study was to determine if the new Healthy Active Living and Obesity Research Group's (HALO's) submaximal cardiorespiratory fitness testing protocol for obese children and youth provides a comparable estimate of peak oxygen uptake to that measured using validated maximal and submaximal, equation-based protocols in the obese pediatric population. A group of obese children (n = 21; all >=95th body mass index percentile; aged 10-17 years) completed 3 exercise testing protocols. Testing was completed as part of an ongoing cohort study and 2 submaximal cardiorespiratory fitness tests were completed, in randomized order, during a second visit. Significant correlations were found between observed peak oxygen uptake (mL.min(-1)) and predicted peak oxygen uptake for both the HALO (r = 0.75, p = 0.001) and Nemeth (r = 0.66, p = 0.001) submaximal protocols. A similar correlation was found, after accounting for body mass, between measured and predicted HALO peak oxygen uptake (mL.kg( 1).min(-1)) values (r = 0.54, p = 0.01). HALO predicted peak oxygen uptake values showed a significant correlation when plotted against the measured values (r = 0.99). A Bland-Altman analysis found agreement between the maximal and HALO submaximal protocols (mean bias = -201.75 mL.min(-1)). The significant relationships found between estimates of peak oxygen uptake from the HALO submaximal protocol and measures of peak oxygen uptake during maximal cardiorespiratory testing support the use of the HALO submaximal protocol as a valid measure to estimate maximal cardiorespiratory fitness within the obese pediatric population. Given the proof of principle goal of this study, future research in the obese, pediatric population is encouraged to confirm the generalizability of the protocol. PMID- 22452610 TI - Effect of training load on simulated team sport match performance. AB - This study examined the effect of training load on running performance and plasma markers of anaerobic metabolism, muscle damage, and inflammation during a simulated team sport match performance. Seven team sport athletes (maximal oxygen uptake, 47.6 +/- 4.2 mL.kg(-1).min(-1)) completed a 60-min simulated team sport match before and after either 4 days of HIGH or LOW training loads. Venous blood samples were taken pre-match, immediately post-match, and 2 h post-match for interlukin-6, monocyte chemoattractant protein-1 (MCP-1), creatine kinase (CK), lactate dehydrogenase, C-reactive protein, xanthine oxidase (XO), and hypoxanthine. Following HIGH training load, sprint velocity decreased (p < 0.001) and total distance covered was reduced (HIGH 5495 +/- 670 m, LOW 5608 +/- 674 m, p = 0.02) was observed during the simulated match protocol compared with the LOW match simulation. Decreased performance capacity was accompanied by a significant increase in serum CK concentration (HIGH 290 +/- 62 U.L(-1), LOW 199 +/- 33 U.L( 1), p = 0.005). The HIGH training also resulted in a decreased post-match hypoxanthine and MCP-1 and an increase in XO concentration 2 h post-match. Four days of increased training load reduced running performance during the match simulation and altered the metabolic and inflammatory response to high-intensity intermittent exercise. PMID- 22452611 TI - Unconventional microarray design reveals the response to obesity is largely tissue specific: analysis of common and divergent responses to diet-induced obesity in insulin-sensitive tissues. AB - Obesity is a chronic condition involving the excessive accumulation of adipose tissue that adversely affects all systems in the body. The aim of the present study was to employ an unbiased, genome-wide assessment of transcript abundance in order to identify common gene expression pathways within insulin-sensitive tissues in response to dietary-induced diabetes. Following 20 weeks of chow or high-fat feeding (60% kcal), age-matched mice underwent a euglycemic hyperinsulinemic clamp to assess insulin sensitivity. High-fat-fed animals were obese and highly insulin resistant, disposing of ~75% less glucose compared with their chow-fed counterparts. Tissues were collected, and gene expression was examined by microarray in 4 tissues known to exhibit obesity-related metabolic disturbances: white adipose tissue, skeletal muscle, liver, and heart. A total of 463 genes were differentially expressed between diets. Analysis of individual tissues showed skeletal muscle to exhibit the largest number of differentially expressed genes (191) in response to high-fat feeding, followed by adipose tissue (169), liver (115), and heart (65). Analyses revealed that the response of individual genes to obesity is distinct and largely tissue specific, with less than 10% of transcripts being shared among tissues. Although transcripts are largely tissue specific, a systems approach shows numerous commonly activated pathways, including those involved in signal transduction, inflammation, oxidative stress, substrate transport, and metabolism. This suggests a coordinated attempt by tissues to limit metabolic perturbations occurring in early-stage obesity. Many identified genes were associated with a variety of disorders, thereby serving as potential links between obesity and its related health risks. PMID- 22452612 TI - N-O bond homolysis of an iron(II) TEMPO complex yields an iron(III) oxo intermediate. AB - The reaction of TEMPO with the iron(I) synthon PhB(MesIm)(3)Fe(COE) leads to formation of the kappa(1)-TEMPO complex PhB(MesIm)(3)Fe(TEMPO). Structural and spectroscopic data establish the complex contains divalent iron bound to a nitroxido anion and is isoelectronic to an iron(II) peroxo complex. Thermolysis of the complex results in N-O bond homolysis, leading to the formation of an iron(III) oxo intermediate. The oxo intermediate is active in oxygen atom transfer reactions and can be trapped by the triphenylmethyl radical to give the iron(II) alkoxo complex PhB(MesIm)(3)Fe(OCPh(3)). PMID- 22452613 TI - Short oligonucleotides aligned in stretched humid matrix: secondary DNA structure in poly(vinyl alcohol) environment. AB - We report that short, synthetic, double- as well as single-stranded DNA can be aligned in stretched humid poly(vinyl alcohol) (PVA) matrix, and the secondary structure (nucleobase orientation) can be characterized with linear dichroism (LD) spectroscopy. Oligonucleotides of lengths varying between 10 (3.4 nm) and 60 bases (20.4 nm) were investigated with respect to structural properties in the gel-like polymer environment. The DNA conformation as a function of relative humidity reveals a strong dependence of helical structure of DNA on PVA hydration level, results of relevance for nanotechnical studies of DNA-based supramolecular systems. Also, the PVA gel could provide possibilities to test models for nucleic acid interactions and distribution in cell contexts, including structural stability of genetic material in the cell and PVA-packaging for gene delivery. A method by which duplex oligonucleotides, with sequences designed to provide specific binding sites, become amenable to polarized-light spectroscopy opens up new possibilities for studying structure in DNA complexes with small adduct molecules as well as proteins. PMID- 22452614 TI - Measuring adherence to medications: are complex methods superior to simple ones? PMID- 22452615 TI - Vasovasostomy and predictors of vasal patency: a systematic review. AB - About 3-6% of vasectomized men requested vasectomy reversal, for various reasons. Vasal patency (VP) is an important surrogate outcome of vasectomy reversal. This article reviews the impact of surgical skills, surgical approaches, intraoperative vasal fluid characteristics and the length of obstructive interval on VP. Based on the best available evidence, the rate of patency is related to the operative frequency of the surgeons, with better results obtained by surgeons who perform the operations at least 10 times annually. Microsurgical vasovasostomy is the preferred technique for durable good results. One-layer vasovasostomy and two-layer vasovasostomy seem to be equal with regard to VP. The rate of patency following vasovasostomy in the convoluted vas and vasovasostomy in the straight vas is comparable. The patency rate is high in men with clear intraoperative vasal fluid in at least one vas. VP is still high among patients with a long obstructive interval. In conclusion, surgical skills and intraoperative vasal fluid characteristics are the most important predictors of VP. Postoperative semen quality and the age of the female partner determine the chance of spontaneous conception in these couples. PMID- 22452616 TI - Pharmacologic and nonpharmacologic therapies for stroke prevention in nonvalvular atrial fibrillation. AB - Thromboembolism is the crucial cause of ischemic stroke in patients with atrial fibrillation (AF). Anticoagulation therapy with vitamin K antagonists, such as warfarin, have been proven to be effective for stroke prevention in AF. Nonetheless, the use of warfarin may be limited due to increased risk of bleeding, the potential interaction with multiple foods and drugs, and the need for routine coagulation monitoring. Over the last decade anticoagulants, such as dabigatran and rivaroxaban, have been developed and have shown superiority compared to warfarin for preventing stroke in patients with nonvalvular AF in large randomized trials. In addition, on account of the risk of thrombus formation in the left atrial appendage (LAA), many nonpharmacologic approaches have been developed to reduce stroke risk in patients with AF who are not candidates for anticoagulant therapy. Surgical, epicardial, and endovascular techniques for LAA closure are being investigated currently. Both novel pharmacotherapy and nonpharmacologic approaches for stroke prevention will be detailed in this review. PMID- 22452617 TI - Association of maturation period blood pressure with dialysis access patency. AB - Problematic dialysis vascular access is a major health issue. The purpose of this study was to evaluate for potentially modifiable factors associated with access patency, particularly, the association of early postoperative, or maturation period, blood pressure with patency. A retrospective review was performed of patients who had undergone placement of an arteriovenous fistula or graft. Demographic, operative, and postoperative factors were evaluated for possible association with access primary patency using univariate and multivariate Cox regression analyses. Seventy-three patients over a 3-year review period were examined. Overall analysis showed a significant association of absence of peripheral vascular disease, aspirin use, and absence of previous permanent dialysis access with higher primary patency rates. Fistula subgroup analysis showed that higher blood pressure during the maturation period relative to preoperative blood pressure was associated with lower patency rates. For grafts, race was significantly associated with patency, with blacks having higher patency rates than whites. Multiple clinical factors were found to have a significant association with dialysis access primary patency. The finding of an association of maturation period blood pressure with fistula patency suggests that the maturation period environment, specifically hemodynamics during this time, may play an important role in dialysis access patency. PMID- 22452618 TI - Photodegradation effects on the emission properties of an amplifying poly(9,9 dioctylfluorene) active waveguide operating in air. AB - We investigated the effects of photodegradation on the emission properties of a poly(9,9-dioctylfluorene) (PF8) active waveguide operating in air. We demonstrate that the PF8 degradation results in an unexpected wavelength dependent intensity variation, with an intensity enhancement of the PF8 0-0 line, an exponential decrease of the amplified spontaneous emission (ASE) intensity stronger than the one expected due to exciton quenching and a weak intensity quenching in the green emission range. We ascribe these results to the PF8 exciton quenching and keto defect formation due to photodegradation, affecting not only the exciton densities but also the waveguide losses, reducing the intrinsic PF8 self absorption and increasing the keto defect absorption. PMID- 22452619 TI - Chronic urinary retention in men: how we define it, and how does it affect treatment outcome. AB - What's known on the subject? and What does the study add? Chronic urinary retention (CUR) is a poorly defined entity, as the key element of definition, significant postvoid residual urine volume (PVR), has not a worldwide and moreover evidenced-based definition. There is no agreement on which is the threshold value to define a significant PVR and different society produced guidelines with different thresholds ranging from 300 mL to 1000 mL. Diagnosis is difficult, and management has not been defined yet. There is a lack of studies on the best management of these patients, as this group of patients has always been considered at high risk of failure. Only one study compares conservative with the surgical management but it is not a randomised controlled trail. This review offers a systematic appraisal of the most recent publications on CUR. It indicates the absence of a real worldwide agreed definition, as the two keys element of it are not satisfactorily defined yet: significant PVR, is suffering from a lack of evidenced-based definition, and percussable or palpable bladder is a very nebulous concept as it is not a criteria of certainty as different individual variables affect it. This has an important effect on management which is not structured. Most of the trials involving benign prostatic hyperplasia treatments (either medical or surgical) tend to exclude this group of patients, which is a clinically important group, comprising up to a quarter of men undergoing TURP in the UK. Urinary retention describes a bladder that does not empty completely or does not empty at all. Historically, urinary retention has been classified as either acute or chronic the latter is generally classified as high pressure or low pressure according to the bladder filling pressure on urodynamic. A MEDLINE(r) search for articles written in English and published before January 2010 was done using a list of terms related to urinary retention: 'urinary retention', 'chronic urinary retention' and 'PVR'. Chronic urinary retention (CUR) is defined by the International Continence Society as 'a non painful bladder, which remains palpable or percussable after the patient has passed urine'. Abrams was the first to choose a residual urine volume >300 mL to define CUR as he considered it the minimum volume at which the bladder becomes palpable suprapubically. The UK National Institute for Health and Clinical Excellence lower urinary tract symptoms (LUTS) guidelines define CUR as a postvoid residual urine volume (PVR) of >1000 mL. No studies have specifically addressed the problem of quantifying the minimum amount of urine present in the bladder to define CUR. Nor did we find any publications objectively assessing at what amount of urine a bladder can be palpable. The ability to feel a bladder may rely on variables (i.e. medical skills and patient habitus). There is a marked variability of PVR, so the test should be repeated to improve precision. As defining CUR is difficult, structured management is challenging. Nearly all prospective trials exclude men with CUR from analysis, possibly anticipating a poor outcome and a high risk of complications. However, men with CUR are a clinically important group, comprising up to 25% of men undergoing transurethral resection of the prostate. Definition of CUR is imprecise and arbitrary. Most studies seem to describe the condition as either a PVR of >300 mL in men who are voiding, or >1000 mL in men who are unable to void. This confusion leads to an inability to design and interpret studies; indeed most prospective trials simply exclude these patients. There is a clear need for internationally accepted definitions of retention to allow both treatment and reporting of outcomes in men with LUTS, and for such definitions to be used by all investigators in future trials. PMID- 22452620 TI - Randomised clinical trial: enteral nutrition does not improve the long-term outcome of alcoholic cirrhotic patients with jaundice. AB - BACKGROUND: Malnutrition and jaundice are independent prognostic factors in cirrhosis. AIM: To assess the impact of enteral nutrition on the survival of alcoholic cirrhotic patients with jaundice but without acute alcoholic hepatitis. METHODS: The study was a multicentre prospective randomised controlled trial comparing effects of enteral nutrition vs. a symptomatic support in patients with alcoholic cirrhosis and jaundice (bilirubin >=51 umol/L) but without severe acute alcoholic hepatitis. A total of 99 patients were randomised to receive either the conventional symptomatic treatment (55 patients) or the symptomatic support associated with 35 kcal/Kg/day of enteral nutrition during 4 weeks followed by an oral nutritional support during 2 months (44 patients). Randomisation was stratified on nutritional status. One-year survival curves were compared using the Kaplan-Meier method and Logrank test. RESULTS: Populations in both arms were similar. One-year survival was similar in the overall population (27/44 patients (61.4%) in the enteral nutrition arm vs. 36/55 (65.5%) in the control arm; Logrank P = 0.60) and in the subgroup suffering from malnutrition [18/29 patients (62.1%) in the enteral nutrition arm vs. 20/32 (62.5%) in the control arm; Logrank P = 0.99]. There was no statistical difference for bilirubin, prothrombin rate, Child-Pugh score, albumin or nutritional assessment. Complications during treatment (bleeding, encephalopathy, infection) occurred in 23% of patients in the enteral nutrition group (10/44) vs. 16% (9/55) of the control patients (P = 0.59). CONCLUSION: Enteral nutrition does not improve the survival and hepatic or nutritional parameters of cirrhotic patients with jaundice. PMID- 22452621 TI - Can the early condition at admission of a high-risk infant aid in the prediction of mortality and poor neurodevelopmental outcome? A population study in Australia. AB - AIM: The aim of this article was to evaluate the Revised Clinical Risk Index for Babies' (CRIB-II) severity of illness score as a predictor of moderate to severe functional disability (FD) in very premature infants. METHODS: Population study of infants born <29 weeks' gestation cared for in all Neonatal Intensive Care Unit in New South Wales and the Australian Capital Territory between 1998 and 2003. FD at 2-3 years corrected age was defined as developmental delay (quotient < 2 standard deviation), non-ambulatory cerebral palsy (needing aids to walk), blindness (acuity <6/60 in better eye) or deafness (hearing aids). Sensitivity and specificity of CRIB-II scores to predict FD were performed by receiver operating characteristic curve analysis. RESULTS: Of study population of 2210, 480 (21.7%) died before hospital discharge. Among 1328 infants assessed, 217 (16.3%) had FD, 109 (8.2%) developmental delay, 75 (5.6%) cerebral palsy and 54 (4.1%) blindness or deafness. CRIB-II performed significantly better than gestation or birthweight (BW) alone in predicting mortality (area under the curve (AUC) +/- standard error 0.83 +/- 0.01, vs. 0.78 +/- 0.01 and 0.76 +/- 0.01, respectively). CRIB-II scores were significantly higher in FD than non-FD children (11.9 +/- 2.9 vs. 10.1 +/- 2.6), but the AUC for CRIB-II (0.68 +/- 0.02) did not significantly differ from that of gestation (0.65 +/- 0.02) and BW (0.65 +/- 0.02). CONCLUSION: CRIB-II improved prediction of mortality but did not perform better than gestational age or BW in predicting FD. We would caution clinicians against using the infant's condition at admission to predict long-term outcome. PMID- 22452622 TI - Standardization and characterization of antigens for the diagnosis of aspergillosis. AB - The aim of this study was to develop and characterize antigens for the diagnosis of aspergillosis. Nine strains of Aspergillus species Aspergillus fumigatus , Aspergillus flavus , and Aspergillus niger were grown in Sabouraud and Smith broth to produce exoantigens. The antigens were tested by immunodiffusion against sera from patients with aspergillosis and other systemic mycoses. The protein fraction of the antigens was detected by SDS-PAGE; Western blot and representative bands were assessed by mass spectrometry coupled to a nano Acquity UltraPerformance LC and analyzed by the Mascot search engine. Concurrently, all sera were tested with Platelia Aspergillus EIA. The most reactive antigens to sera from patients infected by A. fumigatus were produced by A. fumigatus MG2 Sabouraud and pooled A. fumigatus Sabouraud samples, both with a sensitivity of 93% and specificity of 100% and 97%, respectively. Aspergillus niger and A. flavus antigens were reactive against A. niger and A. flavus sera, each one with a sensitivity and specificity of 100%. Two proteins, probably responsible for antigenic activity, beta-glucosidase in A. fumigatus and alpha-amylase in A. niger were attained. The commercial kit had a specificity of 22%, sensitivity of 100%, positive predictive value of 48%, and negative predictive value of 100%. The antigens produced showed high sensitivity and specificity and can be exploited for diagnostics of aspergilloma. PMID- 22452623 TI - Malignant melanoma arising from an NRAS-mutated medium-sized congenital melanocytic nevus. PMID- 22452625 TI - Non-centrosymmetric coordination polymer with a highly hindered octahedral copper center bridged by mandelate. AB - A novel chiral coordination polymer, [Cu(C(6)H(5)CH(OH)COO)(MU C(6)H(5)CH(OH)COO)] (1-L and 1-D), was synthesized through a reaction of copper acetate with L-mandelic acid at room temperature. Although previously reported copper mandelate prepared by hydrothermal reaction was a centrosymmetric coordination polymer because of the racemization of mandelic acid, the current coordination polymer shows noncentrosymmetry and a completely different structure from that previously reported. The X-ray crystallography for 1-L revealed that the copper center of the compound showed a highly distorted octahedral structure bridged by a chiral mandelate ligand in the unusual coordination mode to construct a one-dimensional (1D) zigzag chain structure. These 1D chains interdigitated each other to give a layered structure as a result of the formation of multiple aromatic interactions and hydrogen bonds between hydroxyl and carboxylate moieties at mandelate ligands. The coordination polymer 1-L belongs to the noncentrosymmetric space group of C2 to show piezoelectric properties and second harmonic generation (SHG) activity. PMID- 22452626 TI - Molecular physiology and breeding at the crossroads of cold hardiness improvement. AB - Alfalfa (Medicago sativa L.) is a major forage legume grown extensively worldwide with important agronomic and environmental attributes. Insufficient cold hardiness is a major impediment to its reliable production in northern climates. Improvement of freezing tolerance using conventional breeding approaches is slowed by the quantitative nature of inheritance and strong interactions with the environment. The development of gene-based markers would facilitate the identification of genotypes with superior stress tolerance. Successive cycles of recurrent selection were applied using an indoor screening method to develop populations with significantly higher tolerance to freezing (TF). Bulk segregant analysis of heterogeneous TF populations identified DNA variations that are progressively enriched in frequency in response to selection. Polymorphisms resulting from intragenic variations within a dehydrin gene were identified and could potentially lead to the development of robust selection tools. Our results illustrate the benefits of feedback interactions between germplasm development programs and molecular physiology for a deeper understanding of the molecular and genetic bases of cold hardiness. PMID- 22452627 TI - Benefits for me or risks for others: a cross-culture investigation of the effects of message frames and cultural appeals. AB - This study examined the effects of message frames when they were culturally tailored. Focusing on one aspect of culture-individualism and collectivism-the study discovered some similar patterns across cultures: The effect of message framing in motivating preventive behaviors could be moderated by the cultural values embedded in the messages. Messages focusing on individualistic gains and collectivistic losses successfully increased people's intention to adopt preventive behaviors. Practical and theoretical implications are discussed. PMID- 22452628 TI - Bovine OPU-derived oocytes can be matured in vitro for 16-28 h with similar developmental capacity. AB - The aim of this study was to determine the optimal maturation culture period of ovum pick up (OPU)-derived cumulus oocytes complexes (COCs) in relation to their developmental capacity. Embryo production, embryo cryotolerance, post-transfer embryonic survival and calf characteristics such as gestation length, birthweight and sex ratio were investigated. This retrospective study covers the analyses of ovum pick up -in vitro production and calving results from a commercial programme that took place between March 1994 and September 2004. Donors were both heifers (of which approximately 90% pregnant) and cows (of which approximately 10% pregnant). Embryo production analyses were based on 7800 OPU sessions conducted from January 1995 until January 1999. Analyses of calving rate were based on 13 468 embryo transfers performed during January 1995 until May 2002. Analyses on calf characteristics were based on 2162 calves born between March 1994 and September 2004. The in vitro maturation culture period ranged from 16 to 28 h. The mean production rate of transferable embryos was 16.5% (1.2 embryos per OPU session). Length of maturation culture period did not affect the production of transferable embryos. Mean calving rate was 40.9% and 38.7% for fresh and frozen/thawed embryos, respectively. Calving rate was not affected by the maturation culture period. Mean birthweight, gestation length and proportion of male calves were 46 kg, 281.9 days and 52.8%, respectively. Maturation culture period did not affect these variables. In conclusion, this study shows that the in vitro maturation culture period within the range of 16-28 h does not affect in vitro embryo production, embryo cryotolerance, post-transfer embryonic survival and calf characteristics, suggesting that all COC batches collected by OPU on the same day, can be fertilized in one IVF session without a significant loss in the production from oocyte to calf. PMID- 22452631 TI - Banking on brains: insights of brain donor relatives and friends from an experiential perspective. AB - Brain donation is critical to understand the pathological causes of neurodegenerative diseases. Increasing levels of donation requires an understanding of those factors that both encourage and deter donation. At present, there are few studies of how people understand, feel and decide about brain donation for scientific research. This qualitative experiential study contributes to the growing literature on brain donation through its specific focus on how the donation process is experienced from the perspectives of family members and friends. Nineteen semi-structured interviews were analysed using a phenomenologically informed thematic analysis. Four themes were derived from the analysis, three of which are described in detail: Making the decision to donate; a personal perspective on the donation process; the significance of the brain; beliefs about brain donation. In particular, the thematic analysis highlights the variation of individual decision making and the emotions and reasons underpinning such decisions. Key conclusions include the importance of integrated practice amongst relevant healthcare professionals as well as the need for supportive and informed communication. Also, in light of the finding that the brain assumed no special significance for most participants, the value of the distinction between brain donation for research purposes and organ transplantation is questioned. PMID- 22452632 TI - Structured community-based inpatient rehabilitation of older patients is better than standard primary health care rehabilitation: an open comparative study. AB - PURPOSE: To compare the outcome of multi-disciplinary, structured rehabilitation of older patients in a district inpatient rehabilitation centre (Model 1) versus standard primary health care rehabilitation (Model 2). METHOD: Open, prospective, comparative observational study. Totally 302 patients, 202 in Model 1 and 100 in Model 2, aged >= 65 years, with stroke, osteoarthritis, hip fracture or other chronic diseases, considered to have a rehabilitation potential. Referred from district hospital, nursing- or own homes. OUTCOMES: Primary: Sunnaas ADL Index (SI). Secondary: Umeaa Life Satisfaction Checklist (LSC). Cognitive (MMSE), emotional (SCL-10) and marital status, residence, length of rehabilitation and hours/week care services. Follow-up 3 months after end of rehabilitation. RESULTS: Patients in Model 1 improved and persisted 1.9 points higher in SI (CI (1.0, 2.8), p < 0.001) compared to Model 2, with 2.4 weeks shorter rehabilitation (CI (1.6, 3.1), p < 0.001). LSC indicated similar satisfaction within both models. Fewer Model 1 patients received home care services >3 h/week (OR = 0.6 CI (0.4, 0.8), p = 0.002). Cognitive status predicted the SI gain positively, and level of care services negatively, in both models. CONCLUSIONS: Disabled older patients increase their independency significantly more within shorter time upon structured, multi-disciplinary rehabilitation in a district inpatient centre compared to standard primary health care rehabilitation. [Box: see text]. PMID- 22452633 TI - The impact of co-morbidity burden on preference-based health-related quality of life in the United States. AB - BACKGROUND: Many statistical analyses, clinical trials and cost-utility analyses designed to measure the impact of a particular disease on utility scores often overlook the important influence of co-morbidity burden. OBJECTIVES: This study aims to examine the impact of co-morbidity burden on EQ-5D index scores in a nationally representative sample of the US. METHODS: The pooled 2001 and 2003 Medical Expenditure Panel Survey was used. The total number of chronic conditions for each individual was calculated based on Clinical Classification Categories codes. Spline regression was used to identify nonlinear age effects: individuals were separated into four quartiles based on age. Censored least absolute deviation was used to regress EQ-5D index scores on age and chronic co-morbidity, controlling for income, gender, race, ethnicity, education, physical activity and smoking status. Interactions between age and chronic conditions were also explored. RESULTS: The coefficients for chronic co-morbidities were highly statistically significant with large magnitudes for those with two or more chronic conditions (coefficient two chronic conditions=-0.16; coefficient nine chronic conditions=-0.28). After controlling for chronic co-morbidities and other confounders, age was not statistically significant except for those aged>58 years and the magnitude of this coefficient was very small (coefficient aged>58 years= 0.0006). The interactions between age and chronic co-morbidity were significant, but the deleterious impact of their interaction was largely dominated by the existence and number of chronic conditions. CONCLUSIONS: Chronic conditions have a significant deleterious impact on EQ-5D index scores that is much more pronounced than age and other sociodemographic and behavioural characteristics. Future analyses and cost-utility models should incorporate the impact of multiple morbidity. PMID- 22452634 TI - Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction. AB - AIMS: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. RESULTS: Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD(+)-dependent deacetylase in the production of this chemokine. INNOVATION: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction. CONCLUSIONS: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice. PMID- 22452635 TI - Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance. AB - OBJECTIVE: The aim of this study was to explore whether vascular density and tumour cell proliferation are related to the risk of prostate cancer death in patients managed by watchful waiting. MATERIAL AND METHODS: From a consecutive series of men diagnosed with prostate cancer at transurethral resection in 1975 1990, tissue microarrays (TMAs) were constructed. A majority of men had no metastases at diagnosis and were followed by watchful waiting (n = 295). The TMAs were stained for Ki67, endoglin and factor VIII-related antigen (vWf). RESULTS: In univariate Cox analyses, increased Ki67 index, endoglin vascular density and vWf vascular density were associated with shorter cancer-specific survival. Ki67 index and endoglin vascular density added independent prognostic information to clinical stage, estimated tumour size and Gleason score (GS) in multivariate Cox analysis. In GS 6 tumours, high Ki67 index and high endoglin vascular density identified patients with poor outcome. After 15 years of follow-up not a single man out of 34 men with low staining for both markers (35% of all GS 6 tumours) had died of prostate cancer, in contrast to 15 prostate cancer deaths among the remaining 63 men with GS 6 tumours (65% cumulative risk of prostate cancer death). vWf vascular density in benign areas was a prognostic marker in GS 6 and 7 tumours. CONCLUSIONS: Men with GS 6 tumours with both low Ki67 index and endoglin vascular density staining scores have a low risk of progression. Additional studies are needed to test whether these two markers can be applied to core biopsies to select patients suitable for surveillance. PMID- 22452636 TI - Surface plasmon mapping of dumbbell-shaped gold nanorods: the effect of silver coating. AB - We report on the identification of surface plasmons in individual gold dumbbell shaped nanoparticles (AuDBs), as well as AuDBs coated with silver. We use spatially resolved electron energy-loss spectroscopy in a scanning electron microscope, which allows us to map plasmon-energy and intensity spatial distributions. Two dominant plasmon resonances are experimentally resolved in both AuDBs and silver-coated AuDBs. The intensity of these features is peaked either at the tips or at the sides of the nanoparticles. We present boundary element method simulations in good agreement with the experiment, allowing us to elucidate the nature of such modes. While the lower-energy, tip-focused plasmon is of longitudinal character for all dumbbells under consideration, the second side-bound plasmon has a more involved symmetry, starting as a longitudinal quadrupole in homogeneous AuDBs and picking up transversal components when silver coating is added. The longitudinal dipolar mode energy is found to blue-shift upon coating with silver. We find that the substrate produces sizable shifts in the plasmons of silver-coated AuDBs. Our analysis portraits a complex plasmonic scenario in metal nanoparticles coated with silver, including a transition from the original homogeneous gold dumbbell plasmons to the modes of homogeneous silver rods. We believe that these findings can have potential application to plasmon engineering. PMID- 22452637 TI - Crystallization, melting, and structure of water nanoparticles at atmospherically relevant temperatures. AB - Water nanoparticles play an important role in atmospheric processes, yet their equilibrium and nonequilibrium liquid-ice phase transitions and the structures they form on freezing are not yet fully elucidated. Here we use molecular dynamics simulations with the mW water model to investigate the nonequilibrium freezing and equilibrium melting of water nanoparticles with radii R between 1 and 4.7 nm and the structure of the ice formed by crystallization at temperatures between 150 and 200 K. The ice crystallized in the particles is a hybrid form of ice I with stacked layers of the cubic and hexagonal ice polymorphs in a ratio approximately 2:1. The ratio of cubic ice to hexagonal ice is insensitive to the radius of the water particle and is comparable to that found in simulations of bulk water around the same temperature. Heating frozen particles that contain multiple crystallites leads to Ostwald ripening and annealing of the ice structures, accompanied by an increase in the amount of ice at the expense of the liquid water, before the particles finally melt from the hybrid ice I to liquid, without a transition to hexagonal ice. The melting temperatures T(m) of the nanoparticles are not affected by the ratio of cubic to hexagonal layers in the crystal. T(m) of the ice particles decreases from 255 to 170 K with the particle size and is well described by the Gibbs-Thomson equation, T(m)(R) = T(m)(bulk) - K(GT)/(R - d), with constant K(GT) = 82 +/- 5 K.nm and a premelted liquid of width d = 0.26 +/- 0.05 nm, about one monolayer. The freezing temperatures also decrease with the particles' radii. These results are important for understanding the composition, freezing, and melting properties of ice and liquid water particles under atmospheric conditions. PMID- 22452638 TI - Preexisting venous calcification prior to dialysis vascular access surgery. AB - Vascular calcification is present in arterial vessels used for dialysis vascular access creation prior to surgical creation. Calcification in the veins used to create a new vascular access has not previously been documented. The objective of this study was to describe the prevalence of venous calcification in samples collected at the time of vascular access creation. Sixty-seven vein samples were studied. A von Kossa stain was performed to quantify calcification. A semi quantitative scoring system from 0 to 4+ was used to quantify the percentage positive area for calcification as a fraction of total area (0: 0; 1+: 1-10%; 2+: 11-25%; 3+: 26-50%; 4+: >50% positive). Twenty-two of 67 (33%) samples showed evidence of venous calcification. Histologic examination showed varying degrees of calcification within each cell layer. Among the subset of patients with calcification, 4/22 (18%), 19/22 (86%), 22/22 (100%), and 7/22 (32%) had calcification present within the endothelium, intima, media, and adventitia, respectively. The mean semi-quantitative scores of the 22 samples with calcification were 0.18 +/- 0.08, 1.2 +/- 0.14, 1.6 +/- 0.13, and 0.36 +/- 0.12 for the endothelium, intima, media, and adventitia, respectively. Our results demonstrate that vascular calcification is present within veins used to create new dialysis vascular access, and located predominately within the neointimal and medial layers. PMID- 22452639 TI - Budd-Chiari syndrome in children and outcome after liver transplant. AB - BCS is a rare form of portal hypertension in children. The authors describe two cases of BCS with differing presentations. Case 1: Previously healthy four-yr-old girl. BCS was diagnosed during the course of an episode of acute gastroenteritis with dehydration. Despite conservative therapy for two months, the condition was progressive resulting in liver failure leading ultimately to LT. Molecular studies showed that she was heterozygous for the Factor (F) V Leiden. At follow up, six yr post-LT (two yr without anticoagulation therapy), no thromboembolic/bleeding events were apparent. Case 2: Three-yr-old boy with IgA deficiency and liver disease. Following a febrile episode, he developed fulminant liver failure requiring urgent LT from a living donor (father). Molecular studies disclosed MTHFR C677T homozygosity and FV Leiden heterozygosity. The father was homozygous for the MTHFR mutation. Three months post-LT, persistent graft dysfunction was associated with stenosis of the IVC, which improved upon stent placement. He received dipyridamole and aspirin for five yr, after which time dipyridamole was discontinued. Evidence is sparse on the follow-up of BCS cases with liver transplant. The authors discuss their findings, particularly the need for long-term anticoagulation. PMID- 22452640 TI - Interaction network of the 14-3-3 protein in the ancient protozoan parasite Giardia duodenalis. AB - 14-3-3s are phosphoserine/phosphotreonine binding proteins that play pivotal roles as regulators of multiple cellular processes in eukaryotes. The flagellated protozoan parasite Giardia duodenalis, the causing agent of giardiasis, is a valuable simplified eukaryotic model. A single 14-3-3 isoform (g14-3-3) is expressed in Giardia, and it is directly involved in the differentiation of the parasite into cyst. To define the overall functions of g14-3-3, the protein interactome has been investigated. A transgenic G. duodenalis strain was engineered to express a FLAG-tagged g14-3-3 under its own promoter. Affinity chromatography coupled with tandem mass spectrometry analysis have been used to purify and identify FLAG-g14-3-3-associated proteins from trophozoites and encysting parasites. A total of 314 putative g14-3-3 interaction partners were identified, including proteins involved in several pathways. Some interactions seemed to be peculiar of one specific stage, while others were shared among the different stages. Furthermore, the interaction of g14-3-3 with the giardial homologue of the CDC7 protein kinase (gCDC7) was characterized, leading to the identification of a multiprotein complex containing not only g14-3-3 and gCDC7 but also a newly identified and highly divergent homologue of DBF4, the putative regulatory subunit of gCDC7. The relevance of g14-3-3 interactions in G. duodenalis biology was discussed. PMID- 22452641 TI - Formation of lysine-derived oxidation products and loss of tryptophan during processing of porcine patties with added avocado byproducts. AB - The effects of the addition of avocado oil and a phenolic-rich avocado peel extract on protein oxidation were studied in porcine patties subjected to cooking and chilled storage. Protein oxidation was assessed by means of tryptophan loss and the formation of specific lysine oxidation products, such as alpha aminoadipic semialdehyde (AAS), alpha-aminoadipic acid (AAA), and Schiff bases. In the present paper, quantitative data of AAA are reported for the first time on a food matrix. The addition of the avocado extract inhibited the formation of AAS, AAA, and Schiff bases in patties during cooking and subsequent chilled storage. The antioxidant effect may respond to the protecting effect of phenolic compounds, mainly procyanidins, found on the avocado extract. Apparently, the combination of both strategies (back-fat replacement and addition of avocado extract) does not lead to an enhanced advantage on the oxidative stability of the product. The novel methodologies used in the present study enable a better comprehension of the mechanisms and consequences of protein oxidation in food systems. PMID- 22452643 TI - Reentrant ventricular outflow tract tachycardia arising from focal scar detected by delayed enhancement magnetic resonance imaging. AB - A 58-year-old man was referred to our emergency room with hemodynamically unstable sustained ventricular tachycardia (VT). The morphology of the VT exhibited a left bundle branch block and inferior axis deviation. He had no past history of cardiovascular disease. Echocardiography, cardiac catheterization, cardiac biopsy, gallium scintigram, myocardial scintigram, T1,T2-weighted magnetic resonance imaging (MRI), and gadolinium-enhanced cine MRI did not detect any structural heart disease or abnormal cardiac function. However, delayed enhancement MRI (DE-MRI) detected a focal intramural scar within the septal ventricular outflow tract. An electrophysiological study revealed a sustained VT with several morphologies and the entrainment phenomenon. Radiofrequency catheter ablation to the site corresponding to the focal scar detected by DE-MRI successfully eliminated the VT. PMID- 22452644 TI - Synthesis, crystal structure, chemical bonding, and physical properties of the ternary Na/Mg stannide Na2MgSn. AB - A ternary stannide of sodium and magnesium, Na(2)MgSn, was synthesized from the elements, and the crystal structure was determined by single-crystal X-ray diffraction. The compound crystallizes in the Li(2)CuAs structure type (hexagonal, P6(3)/mmc, Z = 2, a = 5.0486(11) A, c = 10.095(2) A), and its structure is built up of two-dimensional honeycomb layers of (2)(infinity)[(MgSn)(2-)] stacked along the c-axis, with Na atoms as "space fillers". First-principles computations at various levels of density functional theory (DFT) verify that the most stable configuration is the one in which Na and Mg atoms occupy the 4f and 2b sites, respectively, and thus DFT provides a necessary complement to X-ray structural elucidation. Our computations also predict that Na(2)MgSn must be a semiconductor with a small band gap. In accord with these predictions, the electrical resistivity measured for a polycrystalline sample of Na(2)MgSn is 9.6-10.4 mOmega cm in the range of 90-635 K, and the Seebeck coefficient decreases from +390 MUV K(-1) (at 300 K) to +150 MUV K(-1) (at 430 K). PMID- 22452645 TI - Detection of microcystin-producing Microcystis in Guanqiao Lake using a sandwich hybridization assay. AB - Based on sequence analyses of the mcyJ gene from Microcystis strains, a probe pair TJF and TJR was designed and a sandwich hybridization assay (SHA) was established to quantitatively detect microcystin-producing Microcystis. Through BLAST and cyanobacterial culture tests, TJF and TJR were demonstrated to be specific for microcystin-producing Microcystis. A calibration curve for the SHA was established, and the lowest detected concentration was 100 cells.mL(-1). Laboratory cultures and field samples from Guanqiao Lake were analyzed with both the SHA and microscopy. The cell number of microcystin-producing Microcystis and that of total Microcystis were compared. The biotic and abiotic components of the samples were of little disturbance to the SHA. In this study, a SHA was established to detect Microcystis, providing an alternative to PCR-ELISA and real time PCR technology. PMID- 22452646 TI - Adenotonsillar disease. AB - Adenotonsillar disease (adenoiditis and recurrent tonsillitis) is a prevalent otolaryngologic disorder aetiologically based on chronic inflammation triggered by a persistent bacterial infection. These bacteria, mostly Staphylococcus aureus, Haemophilus sp., and Streptococcus sp., persist predominantly intracellular and within mucosal biofilms. The recurrent or chronic inflammation of the adenoids and faucial tonsils leads to chronic activation of the cell mediated and humoral immune response, resulting in hypertrophy of the lymphoid tonsillar tissue. This hypertrophic tissue is the cause for the prominent clinical symptoms: obstruction of the upper airways, snoring, and sleep apnea for adenoiditis or sore throat, dysphagia and halitosis for recurrent tonsillitis. Treatment strategies should target the persisting bacteria within their biofilm or intracellular shelter. Macrolide antibiotics like clarithromycin are able to modulate the immune system and to interfere in bacterial signaling within biofilms. Clindamycin, quinupristin-dalfopristin, and oritavancin are intracellular high active compounds. Surgical removal of the hypertrophic tissue by modern procedures like laser tonsil ablation, eliminates not only a mechanical obstacle of the airways, it removes also the basis for the aetiologic cause, the "biofilm carrier". This review summarizes the role of bacterial persistence in mucosal biofilms for the aetiology, diagnosis and treatment of adenotonsillar disease and relevant patents. PMID- 22452647 TI - Clinical and pathological features of primary renal synovial sarcoma: analysis of 64 cases from 11 years of medical literature. AB - OBJECTIVE: To describe, for the first time, the clinical characteristics of primary renal synovial sarcoma (SS) and to examine the association of histological features with the expression of immunohistochemical markers. PATIENTS AND METHODS: We collated published data on all cases of primary renal SS, from its first description in 2000 to September 2011. Data on clinical and pathological characteristics were extracted and used to create a database. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method with Rothman's 95% confidence intervals (CIs) and compared across the groups using the log-rank test. The associations between tumour extension and histological features were evaluated using the non parametric Spearman rank test. A chi-squared test was used to assess the differences between groups. RESULTS: In the overall cohort, the median OS was 48 months (95% CI, 14.1-81.9). Cox analysis showed that the risk of death at diagnosis was greatly increased in patients with metastatic disease compared with those with non-metastatic disease (hazard ratio [HR]: 343.9, 95% CI, 2.8-42,000; P= 0.017). The median DFS was 33.0 months (95% CI, 16.8-49.2), and patients who develop metastatic disease have a very poor prognosis with a median survival of 6 months (95% CI, 5.1-6.9). Microscopic features were monophasic, biphasic and poorly differentiated synovial sarcoma in 76, 16 and 8% of patients, respectively. Significant differences in expression of immunohistochemical markers or genetic mutation were found between different subtypes. CONCLUSIONS: Despite its retrospective nature, this study shows that renal SS comprises different histological subtypes, which are characterized by specific immunohistochemical stains and by specific translocations. When diagnosed at metastatic stage, the prognosis was very poor compared with that for non metastatic disease, even though one out of three patients with non-metastatic disease had disease relapse. Cooperative efforts and publication of cases with adequate follow-up are necessary to better define prognosis and therapeutic strategies for this rare disease. PMID- 22452648 TI - Graphene-based frequency tripler. AB - Graphene has captured the imagination of researchers worldwide as an ideal two dimensional material with exceptional electrical transport properties. The high electron and hole mobility quickly inspired scientists to search for electronic applications that require high-performance channel materials. However, the absence of a bandgap in graphene immediately revealed itself in terms of ambipolar device characteristics and the nonexistence of a device off-state. The question is: How can the superior electronic properties of graphene be harvested while dealing appropriately with its unique characteristics rather than enforcing conventional device concepts? Here, we report a novel device idea, a graphene based frequency tripler, an application that employs an innovative electrostatic doping approach and exploits the unique ambipolar behavior of graphene. PMID- 22452649 TI - Metal-mediated DNA base pairing: alternatives to hydrogen-bonded Watson-Crick base pairs. AB - With its capacity to store and transfer the genetic information within a sequence of monomers, DNA forms its central role in chemical evolution through replication and amplification. This elegant behavior is largely based on highly specific molecular recognition between nucleobases through the specific hydrogen bonds in the Watson-Crick base pairing system. While the native base pairs have been amazingly sophisticated through the long history of evolution, synthetic chemists have devoted considerable efforts to create alternative base pairing systems in recent decades. Most of these new systems were designed based on the shape complementarity of the pairs or the rearrangement of hydrogen-bonding patterns. We wondered whether metal coordination could serve as an alternative driving force for DNA base pairing and why hydrogen bonding was selected on Earth in the course of molecular evolution. Therefore, we envisioned an alternative design strategy: we replaced hydrogen bonding with another important scheme in biological systems, metal-coordination bonding. In this Account, we provide an overview of the chemistry of metal-mediated base pairing including basic concepts, molecular design, characteristic structures and properties, and possible applications of DNA-based molecular systems. We describe several examples of artificial metal-mediated base pairs, such as Cu(2+)-mediated hydroxypyridone base pair, H-Cu(2+)-H (where H denotes a hydroxypyridone-bearing nucleoside), developed by us and other researchers. To design the metallo-base pairs we carefully chose appropriate combinations of ligand-bearing nucleosides and metal ions. As expected from their stronger bonding through metal coordination, DNA duplexes possessing metallo-base pairs exhibited higher thermal stability than natural hydrogen-bonded DNAs. Furthermore, we could also use metal mediated base pairs to construct or induce other high-order structures. These features could lead to metal-responsive functional DNA molecules such as artificial DNAzymes and DNA machines. In addition, the metallo-base pairing system is a powerful tool for the construction of homogeneous and heterogeneous metal arrays, which can lead to DNA-based nanomaterials such as electronic wires and magnetic devices. Recently researchers have investigated these systems as enzyme replacements, which may offer an additional contribution to chemical biology and synthetic biology through the expansion of the genetic alphabet. PMID- 22452650 TI - Poisson cluster analysis of cardiac arrest incidence in Columbus, Ohio. AB - BACKGROUND: Scarce resources in disease prevention and emergency medical services (EMS) need to be focused on high-risk areas of out-of-hospital cardiac arrest (OHCA). OBJECTIVE: Cluster analysis using geographic information systems (GISs) was used to find these high-risk areas and test potential predictive variables. METHODS: This was a retrospective cohort analysis of EMS-treated adults with OHCAs occurring in Columbus, Ohio, from April 1, 2004, through March 31, 2009. The OHCAs were aggregated to census tracts and incidence rates were calculated based on their adult populations. Poisson cluster analysis determined significant clusters of high-risk census tracts. Both census tract-level and case-level characteristics were tested for association with high-risk areas by multivariate logistic regression. RESULTS: A total of 2,037 eligible OHCAs occurred within the city limits during the study period. The mean incidence rate was 0.85 OHCAs/1,000 population/year. There were five significant geographic clusters with 76 high risk census tracts out of the total of 245 census tracts. In the case-level analysis, being in a high-risk cluster was associated with a slightly younger age (-3 years, adjusted odds ratio [OR] 0.99, 95% confidence interval [CI] 0.99 1.00), not being white, non-Hispanic (OR 0.54, 95% CI 0.45-0.64), cardiac arrest occurring at home (OR 1.53, 95% CI 1.23-1.71), and not receiving bystander cardiopulmonary resuscitation (CPR) (OR 0.77, 95% CI 0.62-0.96), but with higher survival to hospital discharge (OR 1.78, 95% CI 1.30-2.46). In the census tract level analysis, high-risk census tracts were also associated with a slightly lower average age (-0.1 years, OR 1.14, 95% CI 1.06-1.22) and a lower proportion of white, non-Hispanic patients (-0.298, OR 0.04, 95% CI 0.01-0.19), but also a lower proportion of high-school graduates (-0.184, OR 0.00, 95% CI 0.00-0.00). CONCLUSIONS: This analysis identified high-risk census tracts and associated census tract-level and case-level characteristics that can be used to target public education efforts to prevent OHCA and to mitigate its occurrence with CPR and automated external defibrillator training. In addition, EMS resources can be redeployed to minimize response times to these census tracts. PMID- 22452651 TI - Blood pressure response to angiotensin II is enhanced in obese Zucker rats and is attributed to an aldosterone-dependent mechanism. AB - BACKGROUND AND PURPOSE: Plasma aldosterone levels correlate positively with obesity, suggesting a link between the hypertension associated with obesity and increased mineralocorticoid levels. We tested the hypothesis that aldosterone is involved in the BP response to angiotensin II (AngII) in obese rats. EXPERIMENTAL APPROACH: Lean (LZR) and obese (OZR) Zucker rats were treated with AngII (9 ug.h( 1) ; 4 weeks), and BP and plasma AngII and aldosterone were determined. KEY RESULTS: Chronic AngII increased the BP in OZR markedly more so than in LZR. Plasma AngII levels in LZR and OZR were similar after AngII treatment. The AngII stimulated a rise in plasma aldosterone that was sixfold more in OZR than in LZR. The thickness of the zona glomerulosa of the adrenal glands was selectively increased by AngII in OZR. Adrenal mRNA levels of CYP11B2 aldosterone synthase and the AT(1B) receptor were selectively increased in AngII-treated OZR. The BP response to chronic AngII stimulation was diminished in OZR after adrenalectomy when plasma aldosterone was absent. Acute bolus injections of AngII did not increase the BP response or aldosterone release in OZR. CONCLUSIONS AND IMPLICATIONS: The AngII-induced BP response is enhanced in obesity and this is associated with a specific increase in circulating aldosterone. Due to the AngII induced growth of the zona glomerulosa in OZR, the AT(1B) receptors and aldosterone synthase may be selectively enhanced in obesity under concomitant AngII stimulation, increasing the adrenal synthesis of aldosterone. Our results confirm functionally that aldosterone plays a major role in obesity-related hypertension. PMID- 22452652 TI - Meta-analysis: the use of carbon dioxide insufflation vs. room air insufflation for gastrointestinal endoscopy. AB - BACKGROUND: Carbon dioxide (CO(2)) insufflation has been proposed as an alternative to air insufflation to distend the lumen in gastrointestinal (GI) endoscopy. AIM: To perform a systematic review with meta-analysis of randomised controlled trials (RCTs) in which CO(2) insufflation was compared with room air insufflation in GI endoscopy. METHODS: Electronic and manual searches were combined to search RCTs. After methodological quality assessment and data extraction, the efficacy and safety of CO(2) insufflation were systematically assessed. RESULTS: Twenty-one RCTs [13 on colonoscopy, four on endoscopic retrograde cholangiopancreatography (ERCP), two on double-balloon enteroscopy (DBE), one on oesophagogastroduodenoscopy, and one on flexible sigmoidoscopy] were identified. For colonoscopy, CO(2) insufflation resulted lower postprocedural pain intensity, and increased the proportion of patient without pain at 1 h (RR: 1.84, 95% CI: 1.37-2.47) and 6 h (RR: 1.28; 95% CI: 1.14-1.44) postprocedure. For ERCP, the pain-releasing effect of CO(2) insufflation was not obvious (SMD: -1.48, 95% CI: -3.56, 0.59). CO(2) insufflation revealed no consistent advantages in the RCTs of DBE, but was shown as safe as air insufflation in oesophagus/stomach endoscopic submucosal dissection in one study. pCO(2) level showed no significant variation during these procedures. CONCLUSIONS: Compared with air insufflation, CO(2) insufflation during colonoscopy causes lower postprocedural pain and bowel distension without significant pCO(2) variation. More RCTs are needed to assess its advantages in other GI endoscopic procedures. PMID- 22452653 TI - Olanzapine-induced limb edema simulating episodic angioedema with eosinophilia. PMID- 22452654 TI - Preventing transfusion-transmitted babesiosis: preliminary experience of the first laboratory-based blood donor screening program. AB - BACKGROUND: Babesiosis is the most common transfusion-transmitted infection reported to the Food and Drug Administration (FDA). We developed and implemented the first laboratory-based blood donor screening program for Babesia microti to help reduce and prevent transfusion-transmitted babesiosis (TTB) and report results for the initial year. STUDY DESIGN AND METHODS: Selective B. microti donor screening was performed using real-time polymerase chain reaction (PCR) and indirect immunofluorescence assay (IFA) to reduce the incidence of TTB in neonates and pediatric sickle cell and thalassemia patients under an FDA-approved investigational new drug application. We compared the reports of TTB in these patients in the first 12 months of the study with those of patients who received unscreened blood from 2005 to 2010. RESULTS: There were 2113 units tested with 2086 negative results, 26 positive IFA results (1.23%), and one indeterminate PCR result (0.05%). No reported case of TTB occurred with any B. microti-screened unit transfused to the targeted patients (0/787 units) or to any patient who received the screened units (0/2086 units). Before screening, there were seven cases of TTB in neonates, sickle cell, and thalassemia patients from 6500 unscreened units (one case/929 units) and 24 cases in the total transfused population from 496,545 units distributed (one case/20,686 units). CONCLUSION: Implementation of B. microti IFA and PCR screening is compatible with blood center operations to provide tested units. While the results after 1 year are not powered to demonstrate a change in the rate of TTB after testing, they are encouraging. PMID- 22452655 TI - Lateralized reward-related visual discrimination in the avian entopallium. AB - In humans and many other animals, the two cerebral hemispheres are partly specialized for different functions. However, knowledge about the neuronal basis of lateralization is mostly lacking. The visual system of birds is an excellent model in which to investigate hemispheric asymmetries as birds show a pronounced left hemispheric advantage in the discrimination of various visual objects. In addition, visual input crosses at the optic chiasm and thus testing of each hemisphere is easily accomplished. We aimed to find a neuronal correlate for three hallmarks of visual lateralization in pigeons: first, the animals learn faster with the right eye-left hemisphere; second, they reach higher performance levels under this condition; third, visually guided behavior is mostly under left hemisphere control. To this end, we recorded from the left and right forebrain entopallium while the animals performed a colour discrimination task. We found that, even before learning, left entopallial neurons were more responsive to visual stimulation. Subsequent discrimination acquisition recruited more neuronal responses in the left entopallium and these cells showed a higher degree of differentiation between the rewarded and the unrewarded stimulus. Thus, differential left-right responses are already present, albeit to a modest degree, before learning. As soon as some cues are associated with reward, however, this asymmetry increases substantially and the higher discrimination ratio of the left hemispheric tectofugal pathway would not only contribute to a higher performance of this hemisphere but could thereby also result in a left hemispheric dominance over downstream motor structures via reward-associated feedback systems. PMID- 22452656 TI - Structure of PA1221, a nonribosomal peptide synthetase containing adenylation and peptidyl carrier protein domains. AB - Many bacteria use large modular enzymes for the synthesis of polyketide and peptide natural products. These multidomain enzymes contain integrated carrier domains that deliver bound substrates to multiple catalytic domains, requiring coordination of these chemical steps. Nonribosomal peptide synthetases (NRPSs) load amino acids onto carrier domains through the activity of an upstream adenylation domain. Our lab recently determined the structure of an engineered two-domain NRPS containing fused adenylation and carrier domains. This structure adopted a domain-swapped dimer that illustrated the interface between these two domains. To continue our investigation, we now examine PA1221, a natural two domain protein from Pseudomonas aeruginosa. We have determined the amino acid specificity of this new enzyme and used domain specific mutations to demonstrate that loading the downstream carrier domain within a single protein molecule occurs more quickly than loading of a nonfused carrier domain intermolecularly. Finally, we have determined crystal structures of both apo- and holo-PA1221 proteins, the latter using a valine-adenosine vinylsulfonamide inhibitor that traps the adenylation domain-carrier domain interaction. The protein adopts an interface similar to that seen with the prior adenylation domain-carrier protein construct. A comparison of these structures with previous structures of multidomain NRPSs suggests that a large conformational change within the NRPS adenylation domains guides the carrier domain into the active site for thioester formation. PMID- 22452657 TI - Structure-activity relationships delineate how the maize pathogen Cochliobolus heterostrophus uses aromatic compounds as signals and metabolites. AB - The necrotrophic maize pathogen Cochliobolus heterostrophus senses plant-derived phenolic compounds, which promote nuclear retention of the redox-sensitive transcription factor ChAP1 and alter gene expression. The intradiol dioxygenase gene CCHD1 is strongly upregulated by coumaric and caffeic acids. Plant phenolics are potential nutrients but some of them are damaging compounds that need to be detoxified. Using coumaric acid as an inducer (16 to 160 MUM), we demonstrated the rapid and simultaneous upregulation of most of the beta-ketoadipate pathway genes in C. heterostrophus. A cchd1 deletion mutant provided genetic evidence that protocatechuic acid is an intermediate in catabolism of a wide range of aromatic acids. Aromatics catabolism was slowed for compounds showing toxicity, and this was strongly correlated with nuclear retention of GFP-ChAP1. The activity of a structure series of compounds showed complementary requirements for upregulation of CCHD1 and for ChAP1 nuclear retention. Thus, there is an inverse correlation between the ability to metabolize a compound and the stress response (ChAP1 nuclear retention) that it causes. The ability to metabolize phenolics and to respond to them as signals should be an advantage to plant pathogens and may explain the presence of at least two response pathways detecting these compounds. PMID- 22452658 TI - Hierarchical virtual screening: identification of potential high-affinity and selective beta(3)-adrenergic receptor agonists. AB - The hierarchical virtual screening (HVS) study, consisting of pharmacophore modelling, docking and VS of the generated focussed virtual library, has been carried out to identify novel high-affinity and selective beta(3)-adrenergic receptor (beta-AR) agonists. The best pharmacophore model, comprising one H-bond donor, two hydrophobes, one positive ionizable and one negative ionizable feature, was developed based on a training set of 51 beta(3)-AR agonists using the pharmacophore generation protocol implemented in Discovery Studio. The model was further validated with the test set, external set and ability of the pharmacophoric features to complement the active site amino acids of the homology modelled beta(3)-AR developed using MODELLER software. The focussed virtual library was generated using the structure-based insights gained from our earlier reported comprehensive study focussing on the structural basis of beta-AR subtype selectivity of representative agonists and antagonists. The HVS with the sequential use of the best pharmacophore model and homology modelled beta(3)-AR in the screening of the generated focussed library has led to the identification of potential virtual leads as novel high-affinity and selective beta(3)-AR agonists. PMID- 22452659 TI - Copolythiophene-derived colorimetric and fluorometric sensor for visually supersensitive determination of lipopolysaccharide. AB - 3-Phenylthiophene-based water-soluble copolythiophenes (CPT1) were designed for colorimetric and fluorometric detection of lipopolysaccharide (LPS). The sensor (CPT1-C) shows a high selectivity to LPS in the presence of other negatively charged bioanalytes as well an extreme sensitivity with the detection limit at picomolar level, which is the lowest ever achieved among all synthetic LPS sensors available thus far. Significantly, the sensing interaction can be apparently observed by the naked eyes, which presents a great advantage for its practical applications. The appealing performance of sensor was demonstrated to originate from the multiple electrostatic and hydrophobic cooperative interactions, synergetic with signal amplification via the conformational change of the 3-phenylthiophene-based copolymer main chain. As a straightforward application, CPT1-C is capable of rapidly discriminating the Gram-negative bacteria (with LPS in the membrane) from Gram-positive bacteria (without LPS). PMID- 22452660 TI - Quercetin attenuates TNF-induced inflammation in hepatic cells by inhibiting the NF-kappaB pathway. AB - The dietary flavonoid quercetin is an antioxidant that possesses antiinflammatory and anticarcinogenic properties and may modulate signaling pathways. Inflammation is considered to play a pivotal role in carcinogenesis by triggering activation of transcription factors such as nuclear factor kappa B (NF-kappaB), functionally dependent on cellular redox status. This study aims to investigate the antiinflammatory effect of quercetin and its role on the NF-kappaB pathway, and cyclooxygenase-2 (COX-2) and mitogen-activated protein kinases modulation in a human hepatoma cell line (HepG2). Quercetin alone did not modify any of the parameters analyzed but protected cells against activation of the NF-kappaB route induced by tumor necrosis factor-alpha. This inhibitory effect of quercetin was mediated, at least in part, by extracellular regulated kinase, c-jun amino terminal kinase, and reactive oxygen species, and it was accompanied by reduced COX-2 levels. These observations suggest that quercetin may contribute as an antiinflammatory agent in the liver and provide evidences about its role in the prevention of diseases associated with inflammation, including cancer. PMID- 22452661 TI - Recent advances in drug delivery strategies for treatment of ovarian cancer. AB - INTRODUCTION: Ovarian cancer is associated with the highest mortality rate of all gynecological malignancies, due in part to inadequate treatment strategies and the asymptomatic nature of the disease. Current standard of care includes surgery and systemic chemotherapy. However, this approach can result in toxicities and eventual disease relapse, due to the emergence of multidrug resistance. Drug delivery systems (DDS) have shown promise in overcoming many of the limitations facing conventional treatment regimens. AREAS COVERED: This review provides an overview of recent advances in DDS strategies for the treatment ovarian cancers. Nano-sized systems, including nanoparticles, micelles, liposomes and drug conjugates; microspheres; implants and injectable depots are discussed. The advantages, limitations and clinical potential of these strategies are also outlined. EXPERT OPINION: Nano-sized DDS enable passive targeting to tumors due to their size, and further improvements in tumor localization can be made using targeting moieties. Microspheres, implants and injectable depots have been investigated for peritoneal localized and sustained therapy. Overall, the benefits of using DDS for ovarian cancer therapy include higher drug levels at the diseased site, circumvention of drug resistance mechanisms, minimization of non-specific toxicities, improvements in solubility of poorly soluble drugs and elimination of toxicities associated with conventionally used pharmaceutical excipients. PMID- 22452662 TI - Involvement of oxidative stress and mitogen-activated protein kinase signaling pathways in heat stress-induced injury in the rat small intestine. AB - Extreme heat stress-induced gastrointestinal injury and dysfunction may occur during summer. We investigated possible mechanisms of heat stress-induced damage in the small intestine using male Sprague-Dawley rats subjected to 2 h of heat stress (40 degrees C, 60% relative humidity) daily for 10 consecutive days. Rats were killed at specific times immediately following heat treatment to determine: morphological changes by optical and electron microscopy; intestinal permeability using fluorescein isothiocyanate-dextran; production of reactive oxygen species (ROS), malondialdehyde (MDA), and activities of superoxide-dismutase and glutathione-peroxidase by specific assays; phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) by immunocytochemistry and western-blot analysis. The rat intestinal epithelial cell line (IEC-6) and specific MAPK inhibitors were used for in vitro investigation of effects of activation of MAPKs by heat stress. Heat stress caused marked morphological damage to the small intestine and significantly increased intestinal permeability. Heat stress increased ROS and MDA production, and significantly reduced anti-oxidase activity. MAPK activity in small intestine was increased by heat stress. In vitro, heat stress caused damage and apoptosis in IEC-6 cells; inhibition of ERK1/2 activation (by U0126) exacerbated these effects, which were attenuated by inhibition of JNK (by SP600125) and p38 (by SB203580) activation. Hence, heat stress caused severe small intestine injury, increased oxidative stress, and activated MAPK signaling pathways. The in vitro studies indicated that ERK1/2 activation is anti-apoptotic, and JNK and p38 activation are pro-apoptotic in heat stressed intestinal epithelial cells. PMID- 22452663 TI - Cardiopulmonary exercise testing in cancer rehabilitation: a systematic review. AB - This systematic review aims to get insight into the feasibility of cardiopulmonary exercise testing (CPET) in patients with cancer prior to a physical exercise programme. We will focus on quality (defined as the adherence to international guidelines for methods of CPET) and safety of CPET. Furthermore, we compare the peak oxygen uptake (.VO(2peak)) values of patients with cancer with reference values for healthy persons to put these values into a clinical perspective. A computer aided search with 'cardiopulmonary exercise testing' and 'cancer' using MEDLINE, EMBASE, Pedro, CINAHL(r) and SPORTDiscusTM was carried out. We included studies in which CPET with continuous gas exchange analysis has been performed prior to a physical exercise programme in adults with cancer. Twenty studies describing 1158 patients were eligible. Reported adherence to international recommendations for CPET varied per item. In most studies, the methods of CPET were not reported in detail. Adverse events occurred in 1% of patients. The percentage .VO(2peak) of reference values for healthy persons varied between 65% and 89% for tests before treatment, between 74% and 96% for tests during treatment and between 52% and 117% for tests after treatment. Our results suggest that CPET is feasible and seems to be safe for patients with cancer prior to a physical exercise programme. We recommend that standard reporting and quality guidelines should be followed for CPET methods. The decreased .VO(2peak) values of patients with cancer indicate that physical exercise should be implemented in their standard care. PMID- 22452664 TI - Cardiac catheterization in the dialysis population in 2012: we know more, but much remains unknown. AB - Chronic kidney disease is now widely accepted as an independent risk factor for coronary disease and the dialysis population may represent the highest risk subgroup. Among all dialysis patients, a cardiac cause of mortality has been estimated at 40%. In addition, prior studies have demonstrated that when cardiac catheterization is obtained in a consecutive series of asymptomatic diabetic patients on dialysis the rates of coronary disease can approach 50%. However, the ability to define the problem continues to be greater than the ability to treat or prevent it. Coronary revascularization strategies have limitations in the general population which are amplified in the dialysis population. The ability to accurately diagnose an acute coronary syndrome is more difficult, clinical outcomes have a smaller margin of benefit, and technical challenges result in higher complication rates. Recent data demonstrate an inverse relationship between glomerular filtration rate and the risk of presenting with an acute myocardial infarction rather than unstable angina suggesting that patients with CKD may have a unique pathophysiologic profile that is more prone to plaque rupture. However, these "vulnerable" plaques typically are associated with stenoses <50% prior to rupture and are thus poor targets for revascularization and perhaps best treated with medical therapy. Although the benefits of revascularization may continue to outweigh the risks in the context of acute coronary syndromes, preventive strategies would have to overcome the lower margin of benefit and higher complication rates. PMID- 22452665 TI - Strain-level typing and identification of bacteria using mass spectrometry-based proteomics. AB - Because of the alarming expansion in the diversity and occurrence of bacteria displaying virulence and resistance to antimicrobial agents, it is increasingly important to be able to detect these microorganisms and to differentiate and identify closely related species, as well as different strains of a given species. In this study, a mass spectrometry proteomics approach is applied, exploiting lipid-based protein immobilization (LPI), wherein intact bacterial cells are bound, via membrane-gold interactions, within a FlowCell. The bound cells are subjected to enzymatic digestion for the generation of peptides, which are subsequently identified, using LC-MS. Following database matching, strain specific peptides are used for subspecies-level discrimination. The method is shown to enable a reliable typing and identification of closely related strains of the same bacterial species, herein illustrated for Helicobacter pylori . PMID- 22452666 TI - Interfering with hepatitis C virus assembly in vitro using affinity peptides directed towards core protein. AB - Viral assembly is a crucial key step in the life cycle of every virus. In the case of Hepatitis C virus (HCV), the core protein is the only structural protein to interact directly with the viral genomic RNA. Purified recombinant core protein is able to self-assemble in vitro into nucleocapsid-like particles upon addition of a structured RNA, providing a robust assay with which to study HCV assembly. Inhibition of self-assembly of the C170 core protein (first 170 amino acids) was tested using short peptides derived from the HCV core, from HCV NS5A protein, and from diverse proteins (p21 and p73) known to interact with HCV core protein. Interestingly, peptides derived from the core were the best inhibitors. These peptides are derived from regions of the core predicted to be involved in the interaction between core subunits during viral assembly. We also demonstrated that a peptide derived from the C-terminal end of NS5A protein moderately inhibits the assembly process. PMID- 22452667 TI - Insecticide residues in pollen and nectar of a cucurbit crop and their potential exposure to pollinators. AB - Neonicotinoids are systemic insecticides widely used on many pollinated agricultural crops, and increasing evidence indicates that they move to some extent into pollen and nectar. This study measured levels of neonicotinoid residues in pollen and nectar from a pumpkin crop treated with formulated products containing imidacloprid, dinotefuran, and thiamethoxam using different timings and application methods. Environmental conditions have a significant effect on overall residue levels; nectar residues were 73.5-88.8% less than pollen residues, and metabolites accounted for 15.5-27.2% of the total residue amounts. Foliar-applied treatments and chemigated insecticides applied through drip irrigation during flowering resulted in the highest residues of parent insecticide and metabolites, which may reach average levels up to 122 ng/g in pollen and 17.6 ng/g in nectar. The lowest levels of residues were detected in treatment regimens involving applications of insecticides at planting, as either seed dressing, bedding tray drench, or transplant water treatment. PMID- 22452668 TI - Oral lactoferrin treatment resolves amoebic intracecal infection in C3H/HeJ mice. AB - Entamoeba histolytica is a protozoan parasite that causes amoebiasis, an illness that affects many people around the world. We have previously reported that lactoferrin is able to kill E. histolytica in in vitro cultures. The aim of the present study was to evaluate the therapeutic effect of orally administered bovine lactoferrin in the control of intestinal amoebiasis of susceptible C3H/HeJ mice. The results showed that 20 mg lactoferrin/kg orally administered each day for 1 week was able to eliminate the infection in 63% of the mice, since neither trophozoites nor evidence of epithelial damage and (or) swelling were found in tissue sections of the cecum. The rest of the treated animals (37%) showed a decrease in trophozoite numbers and mucus secreted to the lumen, as compared with untreated and infected mice (p < 0.05). By immunohistochemistry, the profile of secreted cytokines in the cecum revealed that infected but untreated animals showed a mixed Th1/regulatory cytokines profile, whereas the cecum of mice treated (cured) showed a Th2 cytokine profile (IL-4) and expression of the multifunctional IL-6. In addition, cytokines and increasing cecal production of total IgA antibodies were found associated with little inflammation and disease control observed in the cecum of lactoferrin-treated animals. These results suggest that oral administration of lactoferrin can control intestinal amoebic infection probably by killing amoebas or favoring their removal and reestablish the antiinflammatory intestinal environment. PMID- 22452669 TI - Stone area and volume are correlated with operative time for cystolithotripsy for bladder calculi using a holmium: yttrium garnet laser. AB - OBJECTIVE: This study investigated the correlation between the operation time and the stone size as determined by multiple modalities and the computed tomography (CT) densities of bladder calculi using holmium: yttrium garnet (Ho:YAG) laser lithotripsy. MATERIAL AND METHODS: A total of 68 patients underwent cystolithotripsy from March 2010 to October 2011. Thirty-six of these patients underwent cystolithotripsy using a Ho:YAG laser for bladder calculi by a single surgeon. The stone size was assessed by six modalities: sum of the stones' diameters: stone burden; maximum stone's diameter; number of stones; sum of the area using axial CT; sum of area using kidney-ureter-bladder (KUB) films; and volume using CT. In addition, the stone's CT density was measured by: the mean CT density of the maximum stone's whole area; maximum CT density of the maximum stone's whole area; and mean CT density of the maximum stone's center area. Correlations between the operation time and the stone size and the stone CT density were assessed. RESULTS: A total of 36 patients (30 male and six female) who underwent cystolithotripsy using a Ho:YAG laser for bladder calculi were enrolled in this study. Spearman correlation showed that the area and volume were strongly correlated with the operative time. The multipliers between the stone size and stone CT density showed no advantages based on the stone area or volume alone. CONCLUSION: The area and volume of the stones correlated more closely with the operation time than the stone burden for bladder calculi lithotripsy using a Ho:YAG laser. PMID- 22452670 TI - Interactions between a left ventricular assist device and implantable cardioverter-defibrillator. AB - Left ventricular assist devices (LVADs) are approved for both a bridge to cardiac transplantation as well as for destination therapy. Most patients with LVADs have implantable cardioverter-defibrillators (ICDs) and several interactions between LVADs and ICDs have been reported. In the present case, we describe an interaction of an approved LVAD with remote telemetry of a previously implanted Sorin ICD (Sorin Group, Milan, Italy) that could not be resolved with standard shielding techniques. PMID- 22452671 TI - High-throughput transformation of colloidal polymer spheres to discs simply via magnetic stirring of their dispersions. AB - In this article, we have successfully demonstrated the high-throughput production of colloidal discs via magnetic stirring of aqueous dispersions of monodisperse, sulfate-stabilized polystyrene (PS) spheres in the presence of a good organic solvent. The organic solvent could be water-miscible, such as tetrahydrofuran, or water-immiscible, such as chloroform. Water-immiscible organic solvents were mixed into aqueous dispersions of PS spheres in the presence of sodium dodecyl sulfate. The geometry of the resulting discs could be easily adjusted by the magnetic stirring time and speed, the stirring bar weight, and the amount of organic solvent. Our strategy is simple, scalable, and hardly dependent on the nature of the organic solvent and the PS sphere diameter; PS spheres with diameters ranging from 200 nm to 5 MUm were deformed into discs with almost 100% yield. When organic solutions of fluorescent dyes and nanoparticles were used instead of pure organic solvents for PS sphere liquefaction, fluorescent discs were obtained, underlining the effective, efficient encapsulation of the fluorescent substance in the discs. PMID- 22452672 TI - A direct synthesis of allenes by a traceless Petasis reaction. AB - A one-pot synthesis of allenes by the 2-nitrobenzenesulfonylhydrazide-mediated coupling of hydroxyaldehydes or ketones with alkynyl trifluoroborate salts is reported. This mild process involves in situ formation of a sulfonylhydrazone that reacts with alkynyl trifluoroborates to generate a transient propargylic hydrazide species. Decomposition of this unstable hydrazide via an intermediate monoalkyldiazine produces the allene products through an alkene walk mechanism. PMID- 22452673 TI - ZrFe, a sextuply-bonded diatomic transition metal? AB - Diatomic ZrFe has been spectroscopically investigated for the first time, with the optical spectrum recorded in the range from 13890 cm(-1) to 18870 cm(-1). In the region from 13890 to 17500 cm(-1), a single exceptionally weak vibrational progression is found. Band origins, excited state vibrational frequencies and anharmonicities, excited state lifetimes, and the ground state vibrational interval, DeltaG"(1/2), are reported for the five most abundant isotopomers. For the most abundant species, (90)Zr(56)Fe (47.2%), these values are: T(0) = 13931.9(1.2) cm(-1), omega'(e) = 325.05(54) cm(-1), omega'(e)x'(e) = 1.589(40) cm(-1), and DeltaG"(1/2) = 452.2 cm(-1). Rotationally resolved studies have revealed ground and excited state rotational constants and Omega values, bond lengths and rotation-vibration constants, giving B(0)" = 0.138786(30) cm(-1) and r(0)" = 1.87685(20) A for (90)Zr(56)Fe. The ground state and all observed excited states have Omega = 0. On the basis of the short bond length, the ground state of ZrFe is assigned as a nominally sextuply bonded (1)Sigma(+) (Omega = 0(+)) state deriving from the 1sigma(2)1pi(4)2sigma(2)1delta(4) electronic configuration. Above 18000 cm(-1), the spectrum becomes much more intense and congested, indicating the onset of electronically allowed transitions in this region. PMID- 22452674 TI - Can we eliminate noninducibility by programmed stimulation as an endpoint for ventricular tachycardia ablation in patients with structural heart disease? PMID- 22452675 TI - Nitrogen-doped multiwall carbon nanotubes for lithium storage with extremely high capacity. AB - The increasing demands on high performance energy storage systems have raised a new class of devices, so-called lithium ion capacitors (LICs). As its name says, LIC is an intermediate system between lithium ion batteries and supercapacitors, designed for taking advantages of both types of energy storage systems. Herein, as a quest to improve the Li storage capability compared to that of other existing carbon nanomaterials, we have developed extrinsically defective multiwall carbon nanotubes by nitrogen-doping. Nitrogen-doped carbon nanotubes contain wall defects through which lithium ions can diffuse so as to occupy a large portion of the interwall space as storage regions. Furthermore, when integrated with 3 nm nickel oxide nanoparticles for a further capacity boost, nitrogen doping enables unprecedented cell performance by engaging anomalous electrochemical phenomena such as nanoparticles division into even smaller ones, their agglomeration-free diffusion between nitrogen-doped sites as well as capacity rise with cycles. The final cells exhibit a capacity as high as 3500 mAh/g, a cycle life of greater than 10,000 times, and a discharge rate capability of 1.5 min while retaining a capacity of 350 mAh/g. PMID- 22452676 TI - Probable drug-drug interaction leading to serotonin syndrome in a patient treated with concomitant buspirone and linezolid in the setting of therapeutic hypothermia. AB - WHAT IS KNOWN AND OBJECTIVE: Serotonin syndrome can be a rare but life threatening condition that is commonly the result of a drug-drug interaction causing excessive serotonin activity. The symptoms associated with serotonin syndrome can include hyperthermia, mental status changes, autonomic hyperactivity and neuromuscular abnormalities, all of which can be concealed in the critically ill patient owing to concomitant therapies. The objective of this case report is to describe a probable drug-drug interaction between buspirone and linezolid, and to highlight the potential confounding effects of hypothermia in this case. CASE SUMMARY: We present a case of a 28-year-old man who potentially developed serotonin syndrome after coadministration of buspirone and linezolid while being therapeutically cooled for traumatic brain injury. The patient developed hyperthermia, hypertension and tachycardia when buspirone and linezolid were administered concomitantly for 2 days. Symptoms resolved within 24 h after discontinuation of both medications. WHAT IS NEW AND CONCLUSIONS: Caution should be used in patients receiving multiple serotonergic agents in addition to therapeutic hypothermia. The use of therapeutic hypothermia may mask the symptoms associated with serotonin syndrome, thus delaying the diagnosis and treatment of this potentially deadly condition. If a patient requires the combination of such medications, close monitoring for the symptoms of serotonin syndrome is warranted. PMID- 22452677 TI - Primary angle-closure glaucoma is a multifactorial disease. PMID- 22452678 TI - Diabetic macular oedema in 2011: what are the options for refractory cystic oedema? PMID- 22452679 TI - Eye health service access and utilization in the National Indigenous Eye Health Survey. AB - BACKGROUND: To determine access to and utilization of eye health services for indigenous Australians. DESIGN: A national, stratified, random cluster sample was drawn from 30 communities across Australia that each included about 300 indigenous people. PARTICIPANTS: A total of 1189 indigenous adults aged 40 and above were examined, representing 79% of the target population. METHODS: Eye health services data including nature and availability of facilities and workforce supply were collected for comparison with eye health prevalence data. The data were collected in 2008. MAIN OUTCOME MEASURES: Low vision prevalence and coverage rate for distance refractive correction. RESULTS: The full-time equivalent availability of an optometrist working in an Aboriginal Medical Service was significantly associated with both a decrease in the prevalence of low vision (t = -2.41, P = 0.02) and an increase in the coverage rate for distance refractive correction (t = 2.99, P = 0.006). These associations were not replicated when comparing availability of private or hospital-based optometry in each community. Regional eye health coordinators appeared to provide an improved utilization of Aboriginal Health Services and therefore improved access to Aboriginal medical service optometry. CONCLUSIONS: Eye health services for indigenous Australians need to be provided in culturally appropriate facilities with clear links to the indigenous community to optimize access to care and reduce the prevalence of vision impairment. The adequate provision of accessible eye care services is an important component in 'closing the gap' in vision loss for indigenous Australians. PMID- 22452680 TI - Prevalence of pterygium in indigenous Australians within central Australia: the Central Australian Ocular Health Study. AB - BACKGROUND: To determine the prevalence of pterygium within the indigenous Australian population living in central Australia. DESIGN: Clinic-based cross sectional study. PARTICIPANTS: A total of 1884 individuals living in one of 30 remote communities within the statistical local area of 'Central Australia'. This equated to 36% of those aged >=20 years and 67% of those aged >=40 years within this district. METHODS: PARTICIPANTS aged 20 years or over were recruited as they presented to the eye clinic at each remote community. Slit-lamp examination was performed, and the presence of a pterygium or evidence of previous pterygium surgery was recorded. MAIN OUTCOME MEASURES: The prevalence of a pterygium in one or both eyes is presented. RESULTS: Pterygium was present in one or both eyes of 9.3% of individuals aged 40 years or older. Right and left eyes were affected equally (chi(2) = 0.19; P = 0.91). There was a significant association between the presence of a pterygium and age (t = 3.99; P < 0.0001). There was no association with gender (chi(2) = 1.06; P = 0.30). CONCLUSION: Pterygium was present in a significantly higher proportion of indigenous Australians compared with non-indigenous Australians. This is similar to previous findings of the National Trachoma and Eye Health Program and may be due to a difference in proportion of hours spent outdoors and consequent exposure to ultraviolet radiation. PMID- 22452681 TI - Distribution and associations of intraocular pressure in indigenous Australians within central Australia: the Central Australian Ocular Health Study. AB - PURPOSE: To determine the distribution and associations of intraocular pressure (IOP) among the indigenous Australian population living in central Australia. DESIGN: Clinic-based cross-sectional study. PARTICIPANTS: 1884 individuals living in one of 30 remote communities within the statistical local area of 'Central Australia'. This equated to 36% of those aged >=20 years and 67% of those aged >=40 years within this district. METHODS: Participants aged 20 years or over were recruited as they presented to the eye clinic at each remote community. Of those recruited into the study, 1060 underwent IOP measurement using either a Perkins tonometer (Haag-Streit, Koeniz, Switzerland) or an ICare tonometer (Tiolat Oy, Helsinki, Finland) depending on the availability of equipment. Central corneal thickness (CCT) was also measured using ultrasound pachymetry. MAIN OUTCOME MEASURES: The distribution and associations of IOP from the right eye of each participant is presented. RESULTS: Mean IOP was 12.8 mmHg (SD 3.2 mmHg) and CCT was 512 um (SD 36 um). IOP was strongly associated with CCT (r(2) = 0.14, t = 3.87; P < 0.0001), showing an increase of 0.4 mmHg with every 10 um increase in CCT. Furthermore, IOP was strongly associated with age, decreasing by 1.9 mmHg for every decade increase in age, but only for eyes with a CCT above the mean. CONCLUSION: IOP of indigenous Australians is lower than any other racial group previously published. This may relate to the low CCT readings found among this population. Clinicians will need to bear this in mind when examining indigenous Australians and make appropriate allowances for the measured IOP. PMID- 22452682 TI - Vogt-Koyanagi-Harada disease presenting as acute angle closure glaucoma at onset. AB - BACKGROUND: To investigate the clinical features of Vogt-Koyanagi-Harada (VKH) disease presenting as acute angle closure glaucoma at onset. DESIGN: Retrospective non-comparative case series. PARTICIPANTS: Four hundred and eighty six VKH patients seen from February 2001 to March 2010. METHODS: The history and clinical findings of all patients were reviewed. Auxiliary examinations, including ultrasound biomicroscopy, fundus fluorescein angiography and optical coherence tomography, were performed in certain cases. Corticosteroids with or without cyclosporine A were used to treat these patients. MAIN OUTCOME MEASURE: Patients' demographics, clinical presentation and auxiliary examination findings. RESULTS: Eight out of 486 VKH patients were misdiagnosed as acute angle closure glaucoma. The mean age of these eight patients was 55.6 years. Six patients were female. The mean intraocular pressure (IOP) at disease onset was 32.9 mmHg. All of these patients had a shallow anterior chamber and a narrow or closed angle at their first visit. The complaints of these patients were mostly headache and sudden decreased vision in both eyes. Alterations shown on ultrasound biomicroscopy included detachment of the ciliary body and peripheral choroid. The increased IOP did not respond to anti-glaucoma therapy, but resolved following treatment with corticosteroids. The eye of one patient was enucleated after failed trabeculectomies prior to referral to our uveitis centre. CONCLUSION: VKH disease presenting with a bilateral increased IOP mostly occurs in older women. The strikingly decreased visual acuity associated with mild to moderate increased IOP is a clue to the diagnosis. The increased IOP responded well to corticosteroids but not to anti-glaucoma treatment. PMID- 22452683 TI - Outcome of repeat trabeculectomies. AB - BACKGROUND: To determine the success of repeat trabeculectomy augmented with mitomycin C in a cohort of patients who had undergone previously failed trabeculectomy surgery. DESIGN: A consecutive cohort series of patients. PARTICIPANTS: Fifty patients undergoing augmented trabeculectomy surgery following a previously failed trabeculectomy and at least 12 months' follow up. METHODS: All patients had demographic and clinical data collected at the time of surgery and at all subsequent follow-up visits. MAIN OUTCOME MEASURES: Visual field progression, loss of visual acuity, intraocular pressure (IOP) control. RESULTS: The mean follow up was 36.7 months. Forty-one patients (82%) achieved an IOP <=21 mmHg (with >=20% reduction of preoperative IOP) and >=6 mmHg on no additional glaucoma treatment at 12 months' follow up. Forty-four patients (88%) achieved a qualified success with the same criteria at 1 year. The median logMAR acuity preoperative was unchanged after surgery; however, 11 patients (22%) lost >=2 Snellen lines during follow up. There was no significant change in mean deviation during the follow-up period. CONCLUSIONS: Repeating trabeculectomy augmented with mitomycin C is an effective method of controlling IOP and preventing further visual deterioration in the majority of patients treated. However, visual loss was seen in a significant proportion of patients. PMID- 22452684 TI - A1/A2 polymorphism of the glycoprotein IIIa gene and diabetic retinopathy in Caucasians with type 2 diabetes. AB - BACKGROUND: A PlA1/A2 polymorphism of glycoprotein IIIa is known to be involved in the pathogenesis of arterial thrombosis, myocardial infarction, stroke and type 2 diabetes, but there is no evidence of association with diabetic retinopathy. The aim of this study was to examine the role of the PlA1/A2 polymorphism of the glycoprotein IIIa gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes. DESIGN: Cross-sectional case control study. PARTICIPANTS: Totally 222 patients with diabetic retinopathy and 120 diabetic subjects without clinical signs of diabetic retinopathy from the Eye Clinic, University Medical Centre Ljubljana were enrolled in the study. METHODS: Fundus examination and blood biochemical analysis were performed. The polymerase chain reaction and restriction fragment length polymorphism were used. MAIN OUTCOME MEASURES: The total cholesterol, triglyceride, high-density lipoprotein levels, fasting blood glucose and HbA(1c) were measured, and the genotypes of the PlA1/A2 polymorphism were determined. RESULTS: Patients with diabetic retinopathy had earlier onset, longer duration of type 2 diabetes and a higher incidence of insulin therapy compared to the diabetic patients without diabetic retinopathy. A significantly lower frequency of the A2A2 genotype of glycoprotein IIIa was found in diabetic patients with retinopathy compared to those without retinopathy (odds ratio = 0.49, 95% confidence interval = 0.28-0.89; P = 0.018). CONCLUSIONS: The A2A2 genotype of the glycoprotein IIIa polymorphism was associated with lower risk for diabetic retinopathy in Caucasians with type 2 diabetes. Further studies are needed to elucidate its protective role in the development of diabetic retinopathy in Caucasians. PMID- 22452685 TI - Intravitreal triamcinolone acetonide versus combined intravitreal bevacizumab and dexamethasone in diffuse diabetic macular oedema. AB - BACKGROUND: To compare the efficacy of a single injection of combined intravitreal dexamethasone and bevacizumab (Avastin) with that of intravitreal triamcinolone acetonide in eyes with diffuse cystoid diabetic macular oedema. DESIGN: Prospective, non-randomized, masked, interventional case series. PARTICIPANTS: Twenty-four eyes of 24 subjects with centre-involved diabetic macular oedema extending over two disc-areas with predominant cystic changes on spectral domain optical coherence tomography were selected. METHODS: Ten phakic and two pseudophakic, ocular hypertensive eyes received intravitreal dexamethasone and bevacizumab as against 12 pseudophakic, normotensive eyes that received intravitreal triamcinolone acetonide. MAIN OUTCOME MEASURES: Change in central macular volume on spectral domain optical coherence tomography and best corrected visual acuity were measured at 6-week follow-up. RESULTS: Baseline data were matched in both groups. Post-injection central macular volume (7.46 +/- 0.73 mm(3)) was significantly lower (P < 0.001) in the intravitreal triamcinolone acetonide group when compared with its pre-injection central macular volume (9.11 +/- 1.0 mm(3)) or when compared with the post-injection central macular volume (P = 0.02) of the intravitreal dexamethasone and bevacizumab group (8.42 +/- 1.18 mm(3)). However, post-injection best-corrected visual acuity between the intravitreal triamcinolone acetonide (0.65 +/- 0.15 logMAR) and the intravitreal dexamethasone and bevacizumab groups (0.685 +/- 0.15 logMAR) was not significantly different (P = 0.06) at 6 weeks. No significant correlation was noted between change in central macular volume and change in best-corrected visual acuity (r = 0.35, P = 0.07) from the pooled data of both the groups. A fair correlation was noted between change in central macular volume and pre injection central macular volume (r = 0.55, P = 0.005). CONCLUSIONS: Intravitreal triamcinolone acetonide may be more effective than intravitreal dexamethasone and bevacizumab in reducing macular volume in patients with diffuse cystoid diabetic macular oedema. A significant reduction in macular volume does not necessarily translate into a correspondingly significant improvement in best-corrected visual acuity. PMID- 22452686 TI - Diabetic eye disease among adults in Fiji with previously undiagnosed diabetes. AB - BACKGROUND: To determine the prevalence and severity of diabetic eye disease among adults aged >=40 years with unrecognized diabetes in Fiji. DESIGN: Population-based cross-sectional survey using multistage cluster random sampling. PARTICIPANTS: 1381 (=73.0% participation). METHODS: Interview-based questionnaire; visual acuity measured; dilated ocular examination performed; glycosylated haemoglobin (HbA1c) concentration determined. MAIN OUTCOME MEASURES: Prevalence and grade of diabetic retinopathy/maculopathy. RESULTS: Sample prevalence of diabetes was 44.8% (95%CI 42.2-47.5%), with 63.4% (95%CI 59.5 67.1%) previously undiagnosed (384/606). Predictors of undiagnosed compared with previously diagnosed diabetes were female gender (P = 0.001), rural residence (P = 0.049) and not having a relative with known diabetes (P < 0.001). Twenty-two retinae of participants with previously undiagnosed diabetes were unexaminable (predominantly cataract). Of the remaining 746 eyes, 3.5% (95%CI 2.4-5.1%) had diabetic retinopathy/maculopathy, 1 (0.1%) had proliferative retinopathy and 4 (0.5%) had active significant maculopathy. Of eyes with diabetic disease, two (7.7%, 95%CI 1.0-25.3%) had diabetes-related vision impairment (3/60; 6/60). Sixteen previously undiagnosed participants (4.2%, 95%CI 2.5-6.7%) had diabetic disease evident in at least one eye: for four (all Melanesian women aged >50 years), this was vision-threatening (1.0%; 95%CI 0.3-2.8). Mean HbA1c (10.7 +/- 2.6%) of participants undiagnosed and with diabetes eye disease was higher (P < 0.001) than that of those undiagnosed and without. CONCLUSIONS: The prevalence of diabetic eye disease was low among this cohort, but where present, severe vision threatening retinopathy/maculopathy was relatively common. If diabetic eye disease is to be avoided or ameliorated in Fiji, then community awareness of and access to diabetes diagnostic services must improve, particularly for women and rural dwellers. PMID- 22452687 TI - Multifocal outer retinopathy in a patient with multifocal inner choroidopathy. PMID- 22452688 TI - Novel use of positron emission tomography/computed tomography in the diagnosis of infected porous orbital implant. PMID- 22452689 TI - Choroidal metastasis from primary pulmonary leiomyosarcoma. PMID- 22452690 TI - Diagnosis and clinical course of epithelial ingrowth after Descemet-stripping automated endothelial keratoplasty followed by in vivo confocal microscopy. PMID- 22452691 TI - Spontaneous bleb formation. PMID- 22452692 TI - Retained metallic foreign bodies after phacoemulsification. PMID- 22452693 TI - Retained releasable suture causing infectious keratitis following trabeculectomy. PMID- 22452694 TI - Syphilitic retinitis and uveitis. PMID- 22452695 TI - Myopic macular hole. PMID- 22452697 TI - Optic disc area and correlation with central corneal thickness, corneal hysteresis and ocular pulse amplitude in glaucoma patients and controls: comment. PMID- 22452699 TI - Bevacizumab: not as good with more adverse reactions? Response. PMID- 22452701 TI - Excessively high soluble Klotho in patients with acromegaly. AB - OBJECTIVES: Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy. PATIENTS AND DESIGN: We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women/15 men, age 28-76 years) before and after transsphenoidal surgery. RESULTS: Soluble Klotho levels were excessively high at baseline (mean +/- SEM, 4.2 +/- 0.7 ng mL( 1) ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 +/- 5.2 to 2.6 +/- 0.6 MUg L(-1) , P <0.0001, and from 588 +/- 35 to 193 +/- 12 MUg L(-1) , P < 0.001, 0.0001, respectively). Creatinine increased from 71 +/- 3 to 80 +/- 3 MUmol L(-1) (P < 0.001), and phosphate decreased from 1.37 +/- 0.04 to 1.06 +/- 0.02 mmol L(-1) (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 +/- 0.1 ng mL(-1) , P < 0.0001). CONCLUSIONS: This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly. PMID- 22452702 TI - Application of parahydrogen induced polarization techniques in NMR spectroscopy and imaging. AB - Magnetic resonance provides a versatile platform that allows scientists to examine many different types of phenomena. However, the sensitivity of both NMR spectroscopy and MRI is low because the detected signal strength depends on the population difference that exists between the probed nuclear spin states in a magnetic field. This population difference increases with the strength of the interacting magnetic field and decreases with measurement temperature. In contrast, hyperpolarization methods that chemically introduce parahydrogen (a spin isomer of hydrogen with antiparallel spins that form a singlet) based on the traditional parahydrogen induced polarization (PHIP) approach tackle this sensitivity problem with dramatic results. In recent years, the potential of this method for MRI has been recognized, and its impact on medical diagnosis is starting to be realized. In this Account, we describe the use of parahydrogen to hyperpolarize a suitable substrate. This process normally involves the introduction of a molecule of parahydrogen into a target to create large population differences between nuclear spin states. The reaction of parahydrogen breaks the original magnetic symmetry and overcomes the selection rules that prevent both NMR observation and parahydrogen/orthohydrogen interconversion, yielding access to the normally invisible hyperpolarization associated with parahydrogen. Therefore the NMR or MRI measurement delivers a marked increase in the detected signal strength over the normal Boltzmann-population derived result. Consequently, measurements can be made which would otherwise be impossible. This approach was pioneered by Weitekamp, Bargon, and Eisenberg, in the late 1980s. Since 1993, we have used this technique in York to study reaction mechanisms and to characterize normally invisible inorganic species. We also describe signal amplification by reversible exchange (SABRE), an alternative route to sensitize molecules without directly incorporating a molecule of parahydrogen. This approach widens the applicability of PHIP methods and the range of materials that can be hyperpolarized. In this Account we describe our parahydrogen studies in York over the last 20 years and place them in a wider context. We describe the characterization of organometallic reaction intermediates including those involved in catalytic reactions, either with or without hydride ligands. The collection of spectroscopic and kinetic data with rapid inverse detection methods has proved to be particularly informative. We can see enhanced signals for the organic products of catalytic reactions that are linked directly to the catalytic intermediates that form them. This method can therefore prove unequivocally that a specific metal complex is involved in a catalytic cycle, thus pinpointing the true route to catalysis. Studies where a pure nuclear spin state is detected show that it is possible to detect all of the analyte molecules present in a sample using NMR. In addition, we describe methods that achieve the selective detection of these enhanced signals, when set against a strong NMR background such as that of water. PMID- 22452703 TI - Editorial comment: Chronic urinary retention in men: can we define it, and does it affect treatment outcome. PMID- 22452704 TI - Myocardial beta(2) -adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure. AB - BACKGROUND AND PURPOSE: We investigated whether beta(2) -adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. EXPERIMENTAL APPROACH: We explored the angiogenic effects of beta(2) -adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral mediated beta(2) -adrenoceptor overexpression was obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to beta(2) adrenoceptor -/- mice undergoing MI. KEY RESULTS: Transgenes were robustly expressed in the LV at 2 weeks post-gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac beta(2) -adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad beta(2) -adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, beta(2) -adrenoceptor overexpression was associated with a markedly increased capillary and arteriolar length density and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac beta(2) adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro angiogenic pathway. In beta(2) -adrenoceptor-/- mice, we found a ~25% reduction in cardiac capillary density compared with beta(2) -adrenoceptor+/+ mice. The lack of beta(2) -adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls. CONCLUSIONS AND IMPLICATION: beta(2) -Adrenoceptors play an important role in the regulation of the angiogenic response in HF. The activation of VEGF/PKB/eNOS pathway seems to be strongly involved in this mechanism. PMID- 22452705 TI - In situ nondestructive sediment characterization and resuspendability evaluation of concentrated aqueous paliperidone palmitate suspensions in prefilled syringes by low-field one-dimensional pulsed-field gradient NMR profilometry. AB - This work aims to demonstrate the usefulness of a low-field one-dimensional pulsed-field gradient NMR (1D pfg NMR) profilometry technique to enable in situ nondestructive sediment characterization and resuspendability quantification of concentrated prefilled injectable suspensions. Aqueous paliperidone palmitate suspensions were used as model samples and low-intensity centrifugation was evaluated as a long-term gravity simulation approach. The low-field 1D pfg NMR technique allowed a detection zone of 2.5 cm in height for water content measurement of syringe samples using a Teflon syringe holder. Thus, the sediment compactness could be deduced from its water content. Quantitative evaluation of resuspendability was realized by front tracking of the NMR profile signals, which yielded the exponential sediment volume decay constant as a resuspendability quantification parameter. The study shows that both active ingredient particle size distribution and storage temperature had significant effects on the sedimentation rate and the resuspendability of the suspensions. The centrifugation method proved to be useful as a long-term gravity simulation and screening method, although the results should be interpreted with caution due to its higher acceleration and compression force imposed on the active ingredient particles. PMID- 22452706 TI - Interaction of deoxyhemoglobin with the cytoplasmic domain of murine erythrocyte band 3. AB - The partial pressure of oxygen constitutes an important factor in the regulation of human erythrocyte physiology, including control of cell volume, membrane structure, and glucose metabolism. Because band 3 is thought to be involved in all three processes and because binding of hemoglobin (Hb) to the cytoplasmic domain of band 3 (cdb3) is strongly oxygen-dependent, the possibility that the reversible association of deoxyhemoglobin (deoxyHb) with cdb3 might constitute an O(2)-dependent sensor that mediates O(2)-regulated changes in erythrocyte properties arises. While several lines of evidence support this hypothesis, a major opposing argument lies in the fact that the deoxyHb binding sequence on human cdb3 is not conserved. Moreover, no effect of O(2) pressure on Hb-band 3 interactions has ever been demonstrated in another species. To explore whether band 3-Hb interactions might be widely involved in O(2)-dependent regulation of erythrocyte physiology, we undertook characterization of the effect of O(2) on band 3-Hb interactions in the mouse. We report here that murine band 3 binds deoxyHb with significantly greater affinity than oxyHb, despite the lack of significant homology within the deoxyHb binding sequence. We further map the deoxyHb binding site on murine band 3 and show that deletion of the site eliminates deoxyHb binding. Finally, we identify mutations in murine cdb3 that either enhance or eliminate its affinity for murine deoxyHb. These data demonstrate that despite a lack of homology in the sequences of both murine band 3 and murine Hb, a strong oxygen-dependent association of the two proteins has been conserved. PMID- 22452707 TI - The Academic Support Process (ASP) website: helping preceptors develop resident learning plans and track progress. AB - BACKGROUND: At times, preceptors struggle with aspects of resident education. Many are looking for more support and faculty development in this area. AIMS: To address preceptors' needs for resources and provide a proactive framework for their teaching, the Academic Support Process (ASP) website was developed and evaluated. Preceptors' (N = 35) experiences using the ASP website, as well as their perceptions of its usefulness in supporting resident education, were identified. METHODS: The research comprised two phases: a self-directed workshop involving the creation of a web-based learning plan for a standardised scenario of a resident in difficulty followed by 3 months use of the ASP website with residents in their practice. Information on their experiences was solicited via surveys and focus group interviews. RESULTS: Findings revealed the ASP website enabled preceptors to find words for their concerns around resident competency, gave them a proactive teaching framework, expanded their arsenal of teaching strategies, and supported a customised approach for all learners along the performance spectrum. However, there were a number of challenges encountered by the preceptors that affected site use and buy in. CONCLUSIONS: Results are promising. Next steps involve developing a clear strategy for adoption. PMID- 22452708 TI - Editorial: focus on cardiovascular disease, diabetes and vessel fibrosis. PMID- 22452709 TI - A standard blood bank donation alters the thermal and cardiovascular responses during subsequent exercise. AB - BACKGROUND: The fear for adverse effects of blood donation on subsequent exercise may prevent physically active people from donating. We studied the impact of a standard blood bank donation (i.e., 450-mL blood withdrawal) on the thermoregulatory and cardiovascular responses to prolonged exercise in the heat. STUDY DESIGN AND METHODS: Eight moderately trained, heat-acclimated males cycled for 1 hour at 60% in a hot environment (34.9+/-0.6 degrees C) on four occasions: 1) 2 days before blood donation (CON), 2) 2 hours after donation (DON), 3) 2 days after donation (2 DAYS), and 4) 7 days after donation (7 DAYS). RESULTS: Two thirds of the blood volume withdrawn was endogenously restored before exercise in the DON trial (p<0.05). DON started with increased preexercise rectal temperature (TRE; 0.42+/-0.1 degrees C above CON; p<0.05), which resulted in high levels of hyperthermia (i.e., 39.0+/-0.2 degrees C) after 1 hour of exercise. Skin temperature (34.5+/-0.1 degrees C) and sweat rate (1.15+/-0.1 L/h) were not affected by DON. However, DON lowered the skin blood flow:TRE relationship and elevated heart rate (HR) above CON (12+/-4 beats/min; p<0.05) maintaining cardiac output. After 2 DAYS, TRE and HR were restored to CON levels while cardiac output increased above CON (6%; p<0.05) in association with reduced hemoglobin concentration (i.e., peak hemodilution). CONCLUSION: A blood bank donation increases preexercise TRE. Subsequent exercise in a hot environment results in high levels of hyperthermia and HR. These thermoregulatory and cardiovascular perturbations observed during exercise disappear 2 days after donation. PMID- 22452710 TI - 4D-QSAR study of HEPT derivatives by electron conformational-genetic algorithm method. AB - In this work, the EC-GA method, a hybrid 4D-QSAR approach that combines the electron conformational (EC) and genetic algorithm optimization (GA) methods, was applied in order to explain pharmacophore (Pha) and predict anti-HIV-1 activity by studying 115 compounds in the class of 1-[(2-hydroxyethoxy)-methyl]-6 (phenylthio) thymine (HEPT) derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs). The series of NNRTIs were partitioned into four training and test sets from which corresponding quantitative structure-activity relationship (QSAR) models were constructed. Analysis of the four QSAR models suggests that the three models generated from the training and test sets used in previous works yielded comparable results with those of previous studies. Model 4, the data set of which was partitioned randomly into two training and test sets with 11 descriptors, including electronical and geometrical parameters, showed good statistics both in the regression (r2(training) )= 0.867, r2test = 0.923) and cross-validation (q (2) = 0.811, q2(ext1) = 0.909, q2(ext2) = 0.909) for the training set of 80 compounds and the test set of 27 compounds. The prediction of the anti-HIV-1 activity of HEPT compounds by means of the EC-GA method allowed for a quantitatively consistent QSAR model. In addition, eight novel compounds never tested experimentally have been designed theoretically using model 4. PMID- 22452711 TI - Sudden cardiac death in dialysis: do current guidelines for implantable cardioverter defibrillator therapy apply to patients with end-stage kidney disease? AB - Arrhythmic mechanisms account for one in four deaths in end-stage kidney disease. Large-scale randomized controlled trials have demonstrated a mortality benefit from implantable cardioverter defibrillator therapy in carefully selected patient groups at high risk for sudden cardiac death. Unfortunately, patients with end stage kidney disease were systematically excluded from these trials. Consequently, the applicability of American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines on implantable cardioverter defibrillator therapy to dialysis patients remains uncertain. Observational data suggest that secondary preventative implantable cardioverter defibrillator therapy following resuscitated cardiac arrest prolongs the lives of dialysis patients. This intervention may also offer a survival advantage as a primary preventative strategy in end-stage kidney disease. However, competing risk from co-morbidity can negate any perceived benefit. Device-related complications also negatively impact outcome. The recommendation that primary preventative device implantation be reserved for patients with severely impaired left ventricular function may be excessively restrictive in this high-risk population. Trials of implantable cardioverter defibrillator therapy that include dialysis patients are required to validate existing device eligibility criteria in this unique population. Novel indications for this intervention in dialysis patients should also be identified. PMID- 22452712 TI - Initial assessment of impact of adenovirus type 4 and type 7 vaccine on febrile respiratory illness and virus transmission in military basic trainees, March 2012. AB - After a 12-year hiatus, military recruit training centers resumed administration of adenovirus type 4 and type 7 vaccine, live, oral (adenovirus vaccine) to trainees beginning in October of 2011. Subsequently, rates of febrile respiratory illnesses (FRI) and adenovirus isolations markedly declined. These findings are consistent with those of a placebo-controlled efficacy trial conducted prior to the vaccine's licensure by the U.S. Food and Drug Administration. Continued surveillance will clarify the longer term impact of vaccine use. PMID- 22452713 TI - Surveillance snapshot: adenovirus among U.S. military recruit trainees. PMID- 22452714 TI - Case report: Chest pain in service members following smallpox vaccination. PMID- 22452715 TI - Predictive value of surveillance case definitions of Guillain-Barre Syndrome in vaccine safety assessment. PMID- 22452716 TI - Mental health diagnoses during the year prior to schizophrenia, U.S. Armed Forces, 2001-2010. AB - Identification of military members in the prodromal phase of schizophrenia may lead to earlier treatment and allow non-urgent transition away from military duties. This report documents the incidence of schizophrenia in the U.S. military and summarizes mental health diagnoses during the year prior to initial clinical diagnoses schizophrenia. During 2001-2010, 3,000 service members met the case definition of schizophrenia (incidence rate: 21 per 100,000 person-years). Rates declined with increasing age. Of those diagnosed with schizophrenia, 71% had at least one mental health-related medical encounter during the preceding 12 months; 51% received at least one antecedent diagnosis of paranoia. The findings may inform a model to predict the likelihood and timing of clinical manifestations of schizophrenia among U.S. military members. PMID- 22452717 TI - Update: heat injuries, active component, U.S. Armed Forces, 2011. AB - In 2011, the number of service members treated for heat stroke (n=362) was higher than the number in 2010, but lower than the numbers in 2007-2009. Incidence rates of heat stroke were highest among males, service members in combat-specific occupations, in the Marine Corps and Army, and among those younger than 20 years of age. The number of service members treated for "other heat injuries" was higher in 2011 (n=2,652) than in any of the four prior years; however, there were fewer hospitalizations for "other heat injuries" in 2011 than in recent prior years. In contrast to heat stroke, the incidence rate of "other heat injuries" was higher among females than males and the rate among enlisted members was more than twice that of officers. PMID- 22452718 TI - Update: Exertional rhabdomyolysis, active component, U.S. Armed Forces, 2011. AB - In 2011, there were 435 incident episodes of rhabdomyolysis likely due to physical exertion and/or heat stress ("exertional rhabdomyolysis") among U.S. service members. The annual rates of exertional rhabdomyolysis nearly doubled from 2007 to 2011. The highest incidence rates occurred in males, black, non Hispanics, service members younger than 20 years of age and in the Marine Corps and Army. Most cases were diagnosed at installations that support basic combat/recruit training centers or major Army and Marine Corps combat units. Medical care providers should consider exertional rhabdomyolysis in the differential diagnosis when service members -- particularly recruits -- present with muscular pain, swelling, limited range of motion, or the excretion of dark urine possibly due to myoglobinuria after strenuous physical activity, particularly in hot, humid weather. PMID- 22452719 TI - Update: Exertional hyponatremia, active component, U.S. Armed Forces, 1999-2011. AB - From 1999 through 2011, there were 1,329 incident diagnoses of exertional hyponatremia among active component members. In 2011, there were more incident cases (n=183) than in any other year of the period and more than three-times as many cases as in 1999 (n=57). Crude incidence rates of exertional hyponatremia were highest among females, Marines, and those in the youngest and oldest age groups. The increased incidence in the U.S. military overall reflects sharply increasing rates in the Marine Corps and slight increases in the other services, particularly since 2005. Service members (particularly trainees and women) and their supervisors must be vigilant for early signs of heat-related illnesses and must be knowledgeable of the dangers of excessive water consumption and the prescribed limits for water intake during prolonged physical activity--e.g., field training exercises, personal fitness training, recreational activities--in hot, humid weather. PMID- 22452720 TI - Quantitation of femtomolar protein levels via direct readout with the electrochemical proximity assay. AB - We have developed a separation-free, electrochemical assay format with direct readout that is amenable to highly sensitive and selective quantitation of a wide variety of target proteins. Our first generation of the electrochemical proximity assay (ECPA) is composed of two thrombin aptamers which form a cooperative complex only in the presence of target molecules, moving a methylene blue (MB) conjugated oligonucleotide close to a gold electrode. Without washing steps, electrical current is increased in proportion to the concentration of a specific target protein. By employing a DNA-based experimental model with the aptamer system, we show that addition of a short DNA competitor can reduce background current of the MB peak to baseline levels. As such, the detection limit of aptamer-based ECPA for human thrombin was 50 pM via direct readout. The dual probe nature of ECPA gave high selectivity and 93% recovery of signal from 2.5 nM thrombin in 2% bovine serum albumin (BSA). To greatly improve the flexibility of ECPA, we then proved the system functional with antibody-oligonucleotide conjugates as probes; the insulin detection limit was 128 fM with a dynamic range of over 4 orders of magnitude in concentration, again with high assay selectivity. ECPA thus allows separation-free, highly sensitive, and highly selective protein detection with a direct electrochemical readout. This method is extremely flexible, capable of detecting a wide variety of protein targets, and is amenable to point-of-care protein measurement, since any target with two aptamers or antibodies could be assayed via direct electrochemical readout. PMID- 22452721 TI - Synthetic RGDS peptide attenuates mechanical ventilation-induced lung injury in rats. AB - Pulmonary inflammation is the key pathological presentation of mechanical ventilation-induced lung injury (VILI), and synthetic RGDS peptide has been suggested to attenuate pulmonary inflammation. The present study aimed to determine whether RGDS peptide has protective effects on VILI. Rats received 4 hours of high tidal volume mechanical ventilation with or without pretreatment with RGDS. Rats that were kept on spontaneous respiration served as controls. At the end of 4 hours, rats that received 4 hours of mechanical ventilation exhibited serious pulmonary pathological changes, more polymorphonulear and mononuclear leukocyte recruitment, more tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) production, higher total protein contents in the bronchoalveolar lavage fluids (BALFs) and more lung phosphorylation of integrin beta3 and nuclear factor-kappaB inhibitor (I-kappaB), and increased NF-kappaB p65 binding activity than did the control group. Administration of RGDS peptide tended to significantly inhibit all these changes induced by mechanical ventilation. These results suggested that RGDS pretreatment might improve VILI in rats by attenuating inflammatory cascade related to integrin alphaVbeta3 and NF kappaB. PMID- 22452722 TI - Vitamin D deficiency is widespread in cancer patients and correlates with advanced stage disease: a community oncology experience. AB - The purpose of this study was to correlate serum vitamin D levels with potential clinical variables and to determine the extent of vitamin D deficiency in a large, outpatient oncology practice. One hundred ninety-five consecutive patients referred for consultation at a community radiation oncology center from October 8, 2008 to March 17, 2010 had vitamin D levels ordered. Patients who were deficient in vitamin D were treated with replacement therapy. Demographic and medical data were collected prospectively and subsequently analyzed. Pretreatment baseline patient and tumor characteristics were evaluated with respect to vitamin D concentrations. One hundred and sixty patients were analyzed. A total of 74% of patients had 25-hydroxyvitamin D concentrations considered either deficient (<20 ng/mL) or suboptimal (20-30 ng/mL). Replacement therapy raised serum vitamin D levels by an average of 15 ng/mL (95% CI = 11-18, P < 0.01). Lower than median serum vitamin D levels were associated with stage III disease in univariate analysis [OR = 2.6 (95% CI = 1.1-6.2), p = 0.04] as well as multivariate analysis adjusted for age, sex, body mass index, and season of draw [OR = 3.3 (95% CI = 1.1-9.7), P = 0.03]. Three-quarters of patients in our series had suboptimal or deficient circulating concentrations of 25-hydroxyvitamin D. Low serum vitamin D levels, independent of age, sex, and body mass index, predicted advanced stage disease. PMID- 22452723 TI - Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach. AB - BACKGROUND: The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis. METHODS: A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction. KEY RESULTS: The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal-air interface, forming a 'secretion layer' in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 +/- 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%. CONCLUSIONS & INFERENCES: The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric 'acid pocket'. PMID- 22452724 TI - RNA-Seq analysis uncovers transcriptomic variations between morphologically similar in vivo- and in vitro-derived bovine blastocysts. AB - BACKGROUND: A valuable tool for both research and industry, in vitro fertilization (IVF) has applications range from gamete selection and preservation of traits to cloning. Although IVF has achieved worldwide use, with approximately 339,685 bovine embryos transferred in 2010 alone, there are still continuing difficulties with efficiency. It is rare to have more than 40% of fertilized in vitro cattle oocytes reach blastocyst stage by day 8 of culture, and pregnancy rates are reported as less than 45% for in vitro produced embryos. To investigate potential influences in-vitro fertilization (IVF) has on embryonic development, this study compares in vivo- and in vitro-derived bovine blastocysts at a similar stage and quality grade (expanded, excellent quality) to determine the degree of transcriptomic variation beyond morphology using RNA-Seq. RESULTS: A total of 26,906,451 and 38,184,547 fragments were sequenced for in vitro and in vivo embryo pools, respectively. We detected expression for a total of 17,634 genes, with 793 genes showing differential expression between the two embryo populations with false discovery rate (FDR) < 0.05. There were also 395 novel transcribed units found, of which 45 were differentially expressed (FDR < 0.05). In addition, 4,800 genes showed evidence of alternative splicing, with 873 genes displaying differential alternative splicing between the two pools (FDR < 0.05). Using GO enrichment analysis, multiple biological pathways were found to be significantly enriched for differentially expressed genes (FDR < 0.01), including cholesterol and sterol synthesis, system development, and cell differentiation. CONCLUSIONS: Thus, our results support that IVF may influence at the transcriptomic level and that morphology is limited in full characterization of bovine preimplantation embryos. PMID- 22452725 TI - To the editor. PMID- 22452726 TI - From nano to micro: synthesis and optical properties of homogeneous spheroidal gold particles and their superlattices. AB - Iodide ions have been used as an additive to fabricate homogeneous gold spheres with a la carte dimensions, ranging from the nano- (50 nm) to the microscale (ca. 1 MUm). Due to the high uniformity and surface functionalization of the produced materials, they undergo spontaneous assembly into organized superlattices upon solvent drying. Thus, optical properties of the particles including localized surface plasmon resonances and surface enhanced Raman scattering (SERS) response, both in solution and organized into superlattices, are also reported. PMID- 22452727 TI - Seroprevalence of tularemia in rural Azerbaijan. AB - A representative, two-stage probability sampling design was used to select 40 villages in northern Azerbaijan with populations of <500 people to screen for evidence of prior infection with Francisella tularensis. Informed consent was provided, and samples were obtained from 796 volunteers and tested for the presence of immunoglobulin G antibodies using enzyme-linked immunosorbent assay. F. tularensis seropositivity was prevalent (15.5% of volunteers), but there was minimal reporting of signs and symptoms consistent with clinical tularemia, suggesting that mild or asymptomatic infection commonly occurs. Frequently seeing rodents around the home was a risk factor for seropositivity (POR = 1.6, p = 0.03), controlling for age and gender. Geospatial analysis identified associations between village-level tularemia prevalence and suitable tick habitats, annual rainfall, precipitation in the driest quarter, and altitude. This study contributes to the growing understanding of the geographic distribution of tularemia and provides further information on the climatic and landscape conditions that increased the potential for exposure to this pathogen. The potential occurrence of asymptomatic or mild F. tularensis infection warrants further study. PMID- 22452728 TI - Applications of calcium and its supplement derived from marine organisms. AB - Calcium, being an essential mineral with many important and diversified functions, plays an important role in the health and well being of the human. Marine organisms serve as an alternate source for calcium. Calcium has to be solubilized in the body in order to have the maximum benefits. The increased solubility of calcium from diet contributes to calcium absorption and bioavailability in the body. In this paper, we report various marine sources of calcium, solubilizing the calcium to improve the bioavailability and the applications of calcium as an important mineral in controlling different diseases. PMID- 22452729 TI - Is authentication of regional and traditional food made of meat possible? AB - Authentication of regional and traditional food made of meat poses a significant challenge. It continues to be a very difficult task which requires employment of quite advanced analytical techniques. These products, despite a similar process of manufacturing, differ in taste and aroma. This happens due to the use of special breeds of animals, the application of appropriate feeding regimes as well as the effect of the place and climate. In order to perform correct identification of geographical origin, a good solution is to determine both stable isotopes as well as trace elements. It is essential to collect detailed meteorological and geochemical data and information about farming practices and to compare them with the obtained results. In a majority of cases, the performed identification is confined to species and the determination of the animal breed is very limited. In the case of individual breeds a comparative analysis of SNPs appears to present the highest potential, especially genes affecting the coat color of animals may serve as markers. Experiments confirm that genes responsible for pigmentation underwent mutations in individual breeds. Authentication on the basis of the manufacturing process appears to be easier to realize than tracing geographical origins. PMID- 22452730 TI - Implication of conjugated linoleic acid (CLA) in human health. AB - Conjugated linoleic acid (CLA) has drawn significant attention in the last two decades for its variety of biologically beneficial effects. CLA reduces body fat, cardiovascular diseases and cancer, and modulates immune and inflammatory responses as well as improves bone mass. It has been suggested that the overall effects of CLA are the results of interactions between two major isomers, cis 9,trans-11 and trans-10,cis-12. This review will primarily focus on current CLA publications involving humans, which are also summarized in the tables. Along with a number of beneficial effects of CLA, there are safety considerations for CLA supplementation in humans, which include effects on liver functions, milk fat depression, glucose metabolism, and oxidative stresses. PMID- 22452731 TI - The impact of salt reduction in bread: a review. AB - The dietary intake of sodium chloride has increased considerably over the last few decades due to changes in the human diet. This higher intake has been linked to a number of diseases including hypertension and other cardiovascular diseases. Numerous international health agencies, as well as the food industry, have now recommended a salt intake level of about 5-6 g daily, approximately half the average current daily intake level. Cereal products, and in particular bread, are a major source of salt in the diet. Therefore, any reduction in the level of salt in bread would have a major impact on global health. However, salt is a critical ingredient in bread production, and its reduction can have a deleterious effect on the production process. This includes an impact on dough handling, as well as final bread quality characteristics, including shelf-life, bread volume, and sensory characteristics, all deviating from the expectations of bakers and consumers. This review describes the effect of salt reduction during bread production and the resulting problems, both technological and qualitative, as well as evaluating some techniques commonly used to replace sodium chloride. PMID- 22452732 TI - The 1,2-benzenedithiole-based cyclocondensation assay: a valuable tool for the measurement of chemopreventive isothiocyanates. AB - Many naturally occurring isothiocyanates (ITCs) show highly promising chemopreventive activities. Humans are commonly exposed to these compounds through the consumption of cruciferous vegetables which are the main source of dietary ITCs. Dietary ITCs may play an important role in cancer prevention and in the well-recognized cancer preventive activities of cruciferous vegetables. A generic analytical method, namely the 1,2-benzenedithiol-based cyclocondensation assay, was previously developed for quantitation of ITCs and their in vivo metabolites. This method has been widely used and has contributed greatly to research on chemoprevention by ITCs. In this article, the discovery and development of the cyclocondensation assay are recapitulated, and its sensitivity and specificity as well as its advantages and limitations are scrutinized. Moreover, detailed discussion is also provided to show how this assay has been used to advance our understanding of the cancer chemopreventive potential and the mechanism of action of ITCs. PMID- 22452733 TI - Edible films and coatings from whey proteins: a review on formulation, and on mechanical and bioactive properties. AB - The latest decade has witnessed joint efforts by the packaging and the food industries to reduce the amount of residues and wastes associated with food consumption. The recent increase in environmental awareness has also contributed toward development of edible packaging materials. Viable edible films and coatings have been successfully produced from whey proteins; their ability to serve other functions, viz. carrier of antimicrobials, antioxidants, or other nutraceuticals, without significantly compromising the desirable primary barrier and mechanical properties as packaging films, will add value for eventual commercial applications. These points are tackled in this review, in a critical manner. The supply of whey protein-based films and coatings, formulated to specifically address end-user needs, is also considered. PMID- 22452734 TI - Wheat aleurone: separation, composition, health aspects, and potential food use. AB - Over the last three decades substantial attention has been given to the role of dietary fiber in health and disease, in particular diabetes, cardiovascular disease, intestinal health, and some types of cancer. As a result the food industry started to add back fiber to refined foods and develop fiber rich foods. Scientists suggested that whole grain foods are superior to foods enriched with fibers obtained/synthesized using enzyme treatment, and thermal or chemical processing because the content of bioactive components and micronutrients in whole grain is more abundant. This triggered interest in how to isolate the micronutrient rich aleurone fiber fraction from wheat. Aleurone is a single cell layer at the inner site of the bran. It contains most of the minerals, vitamins, phenolic antioxidants, and lignans of the wheat grain. Novel milling and dry fractionation techniques have recently allowed for full-scale separation of aleurone cells from the other layers of wheat bran, yielding a fiber rich concentrate which potentially contains many of the "whole grain kernel bioactives," which recently have been used in a variety of studies. The present review highlights available data on aleurone isolation, composition, intestinal physiology, and its metabolism and potential health benefits as well as its use in food. PMID- 22452735 TI - Binge drinking trajectories from adolescence to young adulthood: the effects of peer social network. AB - This study investigates an association between social network characteristics and binge drinking from adolescence to young adulthood, utilizing National Longitudinal Study of Adolescent Health (n = 7,966) and employing social network and longitudinal analysis. Lower integration and socialization with alcohol-using peers had immediate risks of binge drinking during adolescence; however, over time, the effects of socialization with alcohol-using peers had the most dramatic reduction. The most prestigious adolescents had the highest longitudinal risks of binge drinking, although they had no immediate risk. Alcohol consumption-related interventions overlooking longitudinal dynamics of social networks may not effectively prevent adolescents from binge drinking in young adulthood. PMID- 22452736 TI - Marker residue determination of tritium-labeled ivermectin in the muscle of aquacultured largemouth bass, hybrid striped bass, and yellow perch following oral treatment. AB - The residue depletion profiles of tritium-labeled ivermectin and its metabolites in the muscle of aquacultured largemouth bass (LMB), hybrid striped bass (HSB), and yellow perch (YP) following oral treatment are reported. Fish were administered 3H-ivermectin at the dose level of 0.1 mg/kg body weight (7-9 MUCi) in a gel capsule via stomach tube. At each postdose withdrawal time, six fish of each species were sedated with buffered MS-222 and blood samples taken. Fish were then euthanized, and fillets with adhering skin (scales removed) and bile samples were collected. The muscle fillets were homogenized in dry ice to a fine powder. Aliquots of tissue, plasma, and bile were assayed for total radioactive residue (TRR). The homogenized muscle was extracted in acetonitrile or methanol followed by high-performance liquid chromatographic (HPLC) analysis to determine the presence of parent ivermectin and its potential metabolites. The highest TRR concentrations (ivermectin equivalents) of 53, 45, and 44 ng/g (ppb) were obtained on postdose day 1 for HSB, LMB, and YP, respectively. The TRR depleted most slowly in HSB to 25 ppb at day 91, followed by YP to 19 ppb at day 42 and then by LMB to 22 ppb at day 35. The total residue of ivermectin and its metabolites by HPLC analysis followed the same depletion pattern in the three species. Additionally, the depletion rate of TRR of 3H-ivermectin in the three species followed the pattern bile > plasma > muscle. The results further indicate that one of the polar metabolites of ivermectin could serve as a potential marker residue as an indication of use, rather than the parent ivermectin. PMID- 22452737 TI - Lamivudine plus adefovir vs. entecavir in HBeAg-positive hepatitis B with sequential treatment failure of lamivudine and adefovir. AB - BACKGROUND AND AIMS: Few studies have adequately examined the efficacy of lamivudine plus adefovir (LAM+ADV) combination therapy vs. entecavir (ETV) monotherapy in HBeAg-positive hepatitis B patients who fail to respond to sequential treatment with LAM and ADV. We compared directly the efficacy of LAM+ADV vs. ETV in such patients and assessed prognostic factors associated with a virologic response at month 12. METHODS: In total, 72 HBeAg-positive patients who showed resistance (n = 33) or a suboptimal virologic response (n = 39) to ADV monotherapy with resistance to LAM therapy underwent rescue therapy (31 LAM+ADV and 41 ETV). All patients were followed for at least 12 months. RESULTS: Following 12 months of treatment, in the LAM+ADV and ETV groups, a virologic response was observed in 7/31 (22.6%) and 8/41 (19.5%; P = 0.777) patients; ALT normalization occurred in 11/13 (84.6%) and 16/18 (88.9%; P = 0.566); HBeAg seroconversion in 1/31 (2.3%) and 4/41 (9.8%; P = 0.341) and a virologic breakthrough in 3/31 (9.0%) and 5/41 (12.1%; P = 0.452) respectively. Independent prognostic factors associated with a virologic response were the baseline HBV-DNA level (OR = 0.37; 95% CI 0.17-0.80; P = 0.011) and the duration of prior ADV monotherapy (OR = 0.89; 95% CI 0.83-0.95; P = 0.044). CONCLUSIONS: Neither LAM+ADV nor ETV was adequately effective in patients with sequential LAM and ADV treatment failure. Thus, when chronic hepatitis B patients show resistance or suboptimal response to ADV monotherapy, early modification of treatment should be considered. PMID- 22452738 TI - Recurrent widespread perineal erythema in a 2 1/2-year-old boy. PMID- 22452739 TI - Coaxial metal-silicide Ni2Si/C54-TiSi2 nanowires. AB - One-dimensional metal silicide nanowires are excellent candidates for interconnect and contact materials in future integrated circuits devices. Novel core-shell Ni(2)Si/C54-TiSi(2) nanowires, 2 MUm in length, were grown controllably via a solid-liquid-solid growth mechanism. Their interesting ferromagnetic behaviors and excellent electrical properties have been studied in detail. The coercivities (Hcs) of the core-shell Ni(2)Si/C54-TiSi(2) nanowires was determined to be 200 and 50 Oe at 4 and 300 K, respectively, and the resistivity was measured to be as low as 31 MUOmega-cm. The shift of the hysteresis loop with the temperature in zero field cooled (ZFC) and field cooled (FC) studies was found. ZFC and FC curves converge near room temperature at 314 K. The favorable ferromagnetic and electrical properties indicate that the unique core-shell nanowires can be used in penetrative ferromagnetic devices at room temperature simultaneously as a future interconnection in integrated circuits. PMID- 22452740 TI - Intact protoscolices and hooklets in cytospin preparation of intra-operative cyst fluid allow rapid confirmation of rare cerebral intraventricular hydatid infestation. PMID- 22452741 TI - Experimental investigation of the complete inner shell hydration energies of Ca2+: threshold collision-induced dissociation of Ca(2+)(H2O)x Complexes (x = 2 8). AB - The sequential bond energies of Ca(2+)(H(2)O)(x) complexes, where x = 1-8, are measured by threshold collision-induced dissociation (TCID) in a guided ion beam tandem mass spectrometer. From an electrospray ionization source that produces an initial distribution of Ca(2+)(H(2)O)(x) complexes where x = 6-8, complexes down to x = 2 are formed using an in-source fragmentation technique. Ca(2+)(H(2)O) cannot be formed in this source because charge separation into CaOH(+) and H(3)O(+) is a lower energy pathway than simple water loss from Ca(2+)(H(2)O)(2). The kinetic energy dependent cross sections for dissociation of Ca(2+)(H(2)O)(x) complexes, where x = 2-9, are examined over a wide energy range to monitor all dissociation products and are modeled to obtain 0 and 298 K binding energies. Analysis of both primary and secondary water molecule losses from each sized complex provides thermochemistry for the sequential hydration energies of Ca(2+) for x = 1-8 and the first experimental values for x = 1-4. Additionally, the thermodynamic onsets leading to the charge separation products from Ca(2+)(H(2)O)(2) and Ca(2+)(H(2)O)(3) are determined for the first time. Our experimental results for x = 1-6 agree well with previously calculated binding enthalpies as well as quantum chemical calculations performed here. Agreement for x = 1 is improved when the basis set on calcium includes core correlation. PMID- 22452742 TI - Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq. AB - BACKGROUND: Although G6PD deficiency is the most common genetically determined blood disorder among Iraqis, its molecular basis has only recently been studied among the Kurds in North Iraq, while studies focusing on Arabs in other parts of Iraq are still absent. METHODS: A total of 1810 apparently healthy adult male blood donors were randomly recruited from the national blood transfusion center in Baghdad. They were classified into G6PD deficient and non-deficient individuals based on the results of methemoglobin reduction test (MHRT), with confirmation of deficiency by subsequent enzyme assays. DNA from deficient individuals was studied using a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) for four deficient molecular variants, namely G6PD Mediterranean (563 C->T), Chatham (1003 G->A), A- (202 G->A) and Aures (143 T >C). A subset of those with the Mediterranean variant, were further investigated for the 1311 (C->T) silent mutation. RESULTS: G6PD deficiency was detected in 109 of the 1810 screened male individuals (6.0%). Among 101 G6PD deficient males molecularly studied, the Mediterranean mutation was detected in 75 cases (74.3%), G6PD Chatham in 5 cases (5.0%), G6PD A- in two cases (2.0%), and G6PD Aures in none. The 1311 silent mutation was detected in 48 out of the 51 G6PD deficient males with the Mediterranean variant studied (94.1%). CONCLUSIONS: Three polymorphic variants namely: the Mediterranean, Chatham and A-, constituted more than 80% of G6PD deficient variants among males in Baghdad. Iraq. This observation is to some extent comparable to other Asian Arab countries, neighboring Turkey and Iran. PMID- 22452743 TI - Allosteric activation of the phosphoinositide phosphatase Sac1 by anionic phospholipids. AB - Sac family phosphoinositide phosphatases comprise an evolutionarily conserved family of enzymes in eukaryotes. Our recently determined crystal structure of the Sac phosphatase domain of yeast Sac1, the founding member of the Sac family proteins, revealed a unique conformation of the catalytic P-loop and a large positively charged groove at the catalytic site. We now report a unique mechanism for the regulation of its phosphatase activity. Sac1 is an allosteric enzyme that can be activated by its product phosphatidylinositol or anionic phospholipid phosphatidylserine. The activation of Sac1 may involve conformational changes of the catalytic P-loop induced by direct binding with the regulatory anionic phospholipids in the large cationic catalytic groove. These findings highlight the fact that lipid composition of the substrate membrane plays an important role in the control of Sac1 function. PMID- 22452744 TI - Impact of a recent lead recall on utilization of implantable cardioverter defibrillators: data from the NCDR ICD RegistryTM. AB - INTRODUCTION: Underutilization of ICDs is well documented. It has been hypothesized that device recalls, and the resultant negative publicity, may contribute. METHODS AND RESULTS: To determine if the October 2007 recall of the Medtronic Fidelis lead was associated with a decrease in volume of ICD procedures in the United States, we analyzed data submitted to the ICD RegistryTM between July 2006 and December 2008. Time-series analyses were performed comparing actual and predicted implant volumes following the recall, using monthly data from July 2006 to September 2007 to establish a trend line. Observed data points falling outside the 95% CIs from the trend line were considered statistically significant. The study cohort includes 173,616 implantations in 658 hospitals. Before October 2007, an average of 5,952 devices, 4,910 for primary prevention, were implanted per month. Following the recall, the average monthly number of implants was modestly lower at 5,623 (P = 0.05), 4,601 for primary prevention (P = 0.01.) However, as volume was decreasing prior, in time-series analysis, the observed monthly implant volume for primary prevention devices differed from expected based on the trend line for only 1 month. The proportion of Medtronic implants declined from 51.1% in the 15 months prior to the recall to 45.8% in the 15 months of the recall or after (P < 0.01), falling outside the 95% CI of the trend line for 3 months in time-series analysis. CONCLUSIONS: A recent well publicized lead recall had minimal impact on ICD utilization either overall or for primary prevention. PMID- 22452745 TI - Activation of inflammatory responses in human U937 macrophages by particulate matter collected from dairy farms: an in vitro expression analysis of pro inflammatory markers. AB - BACKGROUND: The purpose of the present study was to investigate activation of inflammatory markers in human macrophages derived from the U937 cell line after exposure to particulate matter (PM) collected on dairy farms in California and to identify the most potent components of the PM. METHODS: PM from different dairies were collected and tested to induce an inflammatory response determined by the expression of various pro-inflammatory genes, such as Interleukin (IL)-8, in U937 derived macrophages. Gel shift and luciferase reporter assays were performed to examine the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and Toll-like-receptor 4 (TLR4). RESULTS: Macrophage exposure to PM derived from dairy farms significantly activated expression of pro inflammatory genes, including IL-8, cyclooxygenase 2 and Tumor necrosis factor alpha, which are hallmarks of inflammation. Acute phase proteins, such as serum amyloid A and IL-6, were also significantly upregulated in macrophages treated with PM from dairies. Coarse PM fractions demonstrated more pro-inflammatory activity on an equal-dose basis than fine PM. Urban PM collected from the same region as the dairy farms was associated with a lower concentration of endotoxin and produced significantly less IL-8 expression compared to PM collected on the dairy farms. CONCLUSION: The present study provides evidence that the endotoxin components of the particles collected on dairies play a major role in mediating an inflammatory response through activation of TLR4 and NF-kappaB signaling. PMID- 22452746 TI - Time perspective and environmental engagement: a meta-analysis. AB - Environmental issues entail both a social conflict (private vs. public interests) and a temporal conflict (short- vs. long-term interests). This paper focuses on the role temporal concerns play in influencing environmental engagement by quantitatively integrating results of studies that assessed the associations between time perspective and proenvironmental attitudes and behaviors. The meta analysis included a total of 19 independent samples and 6,301 participants from seven countries (Australia, Brazil, Germany, Mexico, New Zealand, Norway, and the United States). Results showed that the associations between time perspective and proenvironmental behaviors were higher than those for proenvironmental attitudes. Supporting predictions, the associations between future time perspective and proenvironmental behaviors were strong and nontrivial compared to those for the combined past-present time perspective. The findings indicate that future time perspective seems to play an important role in influencing individuals' attitudes and behaviors towards the environment. Implications of the findings for theory and practice are discussed. PMID- 22452747 TI - Butyrophenone on O-TiO2(110): one-dimensional motion in a weakly confined potential well. AB - We demonstrate the one-dimensional confinement of weakly bound butyrophenone molecules between strongly bound complexes formed via reaction with oxygen on TiO(2)(110). Butyrophenone weakly bound to Ti rows through the carbonyl oxygen diffuses freely in one dimension along the rows even at 55 K, persisting for many minutes before hopping out of the 1-D well. Quantitative analysis yields an estimate of the migration barrier of 0.11 eV and a frequency factor of 6.5 * 10(9) Hz. These studies demonstrate that weakly bound organic molecules can be confined on a surface by creating molecular barriers, potentially altering their assembly. PMID- 22452748 TI - Evaluation of thrombelastographic platelet-mapping in healthy cats. AB - BACKGROUND: Thrombelastography (TEG) permits analysis of clot formation but it is not specific for platelet activity. TEG PlateletMapping (TEG-PM) is a modification of TEG that uses adenosine diphosphate (ADP) and arachidonic acid (AA) as platelet agonists to define the contribution of platelets to clot formation. OBJECTIVES: The objectives of this study were to determine values for TEG-PM in healthy cats and the interassay variation of TEG-PM. METHODS: TEG-PM analysis was performed on blood specimens collected from 12 healthy cats and was repeated using a second blood specimen collected 2 hours later. Maximum amplitudes generated by thrombin (MA(thrombin)), fibrin (MA(fibrin)), ADP stimulated platelet activity (MA(ADP)), and AA-stimulated platelet activity (MA(AA)) were recorded. RESULTS: Mean +/- SD for MA(thrombin) was 51.1 +/- 8.5 mm, for MA(fibrin) was 32.3 +/- 17.7 mm, for MA(ADP) was 32.3 +/- 15.0 mm, and for MA(AA) was 24.5 +/- 12.2 mm. Mean MA(ADP) and MA(fibrin) were not significantly different, whereas mean MA(AA) was significantly lower than mean MA(fibrin). Results from the first and second specimens were not significantly different. Correlation between the first and second specimens was moderate for MA(thrombin), MA(fibrin), and MA(ADP), but was poor for MA(AA). A high degree of variability (coefficient of variation 47.7-60.0%) was observed for MA(fibrin), MA(ADP), and MA(AA). CONCLUSIONS: As MA(ADP) and MA(AA) (AA) were the same as or lower than MA(fibrin), a valid baseline to determine platelet-stimulated clot formation could not be established. Considerable interassay variation and wide intervals for MA(fibrin), MA(ADP), and MA(AA) values in this study indicate that TEG-PM should be used cautiously in feline patients. Several preanalytical factors should be examined in further detail. PMID- 22452749 TI - Primary squamous cell carcinoma of thyroid: a case report and review of literature. AB - BACKGROUND: Thyroid gland lacks squamous epithelium (except in some rare situations like embroyonic remnants or in inflammatory processes); for that reason the primary squamous cell carcinoma (SCC) of thyroid is extremely rare entity, seen only in less than 1% of all thyroid malignancies and is considered almost fatal. So, far, only few case reports have been published in literature. CASE PRESENTATION: Herein we present a 54 years old Saudi female with 3 months history of progressive neck swelling and hoarse voice, who was referred to us by her primary care physician as suspected case of anaplastic carcinoma of thyroid for radical external beam radiation therapy (EBRT). Fine Needle aspiration cytology (FNAC) revealed squamous cell carcinoma. Computed tomography (CT) neck showed 10 * 10 cm mass in left lobe of thyroid invading trachea and skin. Extensive staging work up ruled out the possibility of any primary site of SCC other than thyroid gland. Tumor was found unresectable and was referred to radiation oncology. She received palliative EBRT 30 Gy in 10 fractions. After completion of EBRT, there was progression of disease and patient died 3 months after completion of EBRT by airway compromise. CONCLUSION: Primary SCC of thyroid is rare and aggressive entity. FNAC is reliable and effective tool for immediate diagnosis. Surgery is a curative option, but it is not always possible as most of cases present as locally advanced with adjacent organs involvement. EBRT alone was found ineffective. Aggressive combined modality (debulking surgery, radiation and chemotherapy) shall be considered for such cases. PMID- 22452750 TI - Exercise may offset nicotine-induced injury in lung tissue: a preliminary histological study based on a rat model. AB - Nicotine appears to be the primary pharmacologic agent that causes smoking related pulmonary diseases. An understanding of the effect of nicotine on lungs is essential to develop interventions that can be used to counter smoking-related diseases. Further, it is shown that physical exercise may partially reverse smoking-induced pathological changes in experimental animals. Hence, this study focuses on the pathological changes in rat lung following nicotine administration and the role of exercise in reversing the nicotine-induced lung injury. This is a randomized controlled trial with 3 groups of rats. Control (CG), nicotine-exposed (NG), and nicotine-exposed and exercise group (NEG). Control group received no intervention. Both NG and NEG were given 1.5 mg/kg nicotine base, daily, subcutaneously, but NEG were also subjected to an intensive daily swimming protocol. The rats were sacrificed and the lung tissue was processed for light and transmission electron microscopic and immunohistochemical studies. Compared with the control group, the nicotine group showed enlargement and destruction of the alveolar septum, cellular hyperplasia and interstitial fibrosis, and interstitial mononuclear cell infiltration with increased intraluminal macrophages. There was only modest morphological change between the nicotine administered and nicotine and exercise groups. Expression of superoxide dismutase (SOD) and catalase showed a mild increase in the NEG, whereas glutathione peroxidase (GPX) showed mild and moderate increase in the expression in the NG and NEG, respectively. This study shows that nicotine induces substantial pathological changes in the lung and prolonged exercise may have some beneficial effects in partially reversing the nicotine-induced lung injury by inducing the expression of antioxidants. PMID- 22452751 TI - Biophysical properties of Na(v) 1.8/Na(v) 1.2 chimeras and inhibition by uO conotoxin MrVIB. AB - BACKGROUND AND PURPOSE: Voltage-gated sodium channels are expressed primarily in excitable cells and play a pivotal role in the initiation and propagation of action potentials. Nine subtypes of the pore-forming alpha-subunit have been identified, each with a distinct tissue distribution, biophysical properties and sensitivity to tetrodotoxin (TTX). Na(v) 1.8, a TTX-resistant (TTX-R) subtype, is selectively expressed in sensory neurons and plays a pathophysiological role in neuropathic pain. In comparison with TTX-sensitive (TTX-S) Na(v) alpha-subtypes in neurons, Na(v) 1.8 is most strongly inhibited by the uO-conotoxin MrVIB from Conus marmoreus. To determine which domain confers Na(v) 1.8 alpha-subunit its biophysical properties and MrVIB binding, we constructed various chimeric channels incorporating sequence from Na(v) 1.8 and the TTX-S Na(v) 1.2 using a domain exchange strategy. EXPERIMENTAL APPROACH: Wild-type and chimeric Na(v) channels were expressed in Xenopus oocytes, and depolarization-activated Na+ currents were recorded using the two-electrode voltage clamp technique. KEY RESULTS: MrVIB (1 uM) reduced Na(v) 1.2 current amplitude to 69 +/- 12%, whereas Na(v) 1.8 current was reduced to 31 +/- 3%, confirming that MrVIB has a binding preference for Na(v) 1.8. A similar reduction in Na+ current amplitude was observed when MrVIB was applied to chimeras containing the region extending from S6 segment of domain I through the S5-S6 linker of domain II of Na(v) 1.8. In contrast, MrVIB had only a small effect on Na+ current for chimeras containing the corresponding region of Na(v) 1.2. CONCLUSIONS AND IMPLICATIONS: Taken together, these results suggest that domain II of Na(v) 1.8 is an important determinant of MrVIB affinity, highlighting a region of the alpha-subunit that may allow further nociceptor-specific ligand targeting. PMID- 22452752 TI - Preparing medical students for clinical decision making: a pilot study exploring how students make decisions and the perceived impact of a clinical decision making teaching intervention. AB - BACKGROUND: Junior doctors are frequently faced with making difficult clinical decisions and previous studies have shown that they are unprepared for some aspects of clinical decision making. AIM: To explore medical students' feelings and strategies when responsible for making clinical decisions and to obtain students' views of the effectiveness of a clinical decision making teaching intervention. METHODS: A teaching intervention was developed, consisting of a clinical decision making tool, a tutorial and scenarios within a simulated ward environment. A total of 23 volunteer students participated in individual interviews immediately after their simulator sessions. The qualitative data from the interviews were analysed to identify emerging themes. RESULTS: Despite extended shadowing programmes, students feel unprepared for clinical decision making as FY1s, and lack effective decision making strategies. Experiencing complex decision making scenarios through individually orientated simulation results in students being subjectively more prepared for work as FY1s. CONCLUSION: Students continue to feel unprepared for the responsibility of clinical decision making. A teaching intervention, including simulated individual clinical scenarios, later in undergraduate training, appeared to be useful in improving medical students' decision making, specifically in relation to making a diagnosis, prioritising, asking for help and multi-tasking, but further work is required. PMID- 22452753 TI - Anti-inflammatory recombinant TSG-6 stabilizes the progression of focal retinal degeneration in a murine model. AB - BACKGROUND: Inflammatory responses are detected in the retina of patients with age-related macular degeneration and Ccl2-/-/Cx3cr1-/- mice on rd8 background,(Ccl2-/-/Cx3cr1-/- mice) a model that develops progressive age-related macular degeneration-like retinal lesions including focal photoreceptor degeneration, abnormal retinal pigment epithelium and A2E accumulation. Tumor necrosis factor-inducible gene 6 protein is an anti-inflammatory protein and has been shown to improve myocardial infarction outcome and chemically injured cornea in mice by suppressing inflammation. In this study, we evaluated the effect of an intravitreous injection of recombinant TSG-6 on the retinal lesions of Ccl2-/ /Cx3cr1-/- mice. METHODS: Recombinant TSG-6 (400 ng) was administered by intravitreous injection into the right eye of six-week-old Ccl2-/-/Cx3cr1-/- mice. Their left eye was injected with phosphate-buffered saline as a control. Funduscopic pictures were taken before injection and sequentially once a month after injection. The mice were killed two months after injection and the ocular histology examined. Retinal A2E, a major component of lipofuscin, was measured by high performance liquid chromatography. The microarray of ocular mRNA of 92 immunological genes was performed. The genes showing differentiated expression in microarray were further compared between the injected right eye and the contralateral (control) eye by [real-time quantitative reverse transcription polymerase chain reaction] qRT-PCR. RESULTS: The continuous monitoring of the fundus for two months showed a slower progression or alleviation of retinal lesions in the treated right eyes as compared with the untreated left eyes. Among 23 pairs of eyes, the lesion levels improved in 78.3%, stayed the same in 8.7% and progressed in 13.0%. Histology confirmed the clinical observation. Even though there was no difference in the level of A2E between the treated and the untreated eyes, microarray analysis of 92 immune genes showed that IL-17a was substantially decreased after the treatment. Expression of TNF-alpha showed a similar pattern to IL-17a. The results were consistent in duplicated arrays and confirmed by qRT-PCR. CONCLUSIONS: We concluded that intravitreous administration of recombinant TSG-6 might stabilize retinal lesions in Ccl2-/-/Cx3cr1-/- mice on rd8 background. Modulation of ocular immunological gene expressions, especially IL-17a, could be one of the mechanisms. PMID- 22452754 TI - Cognitive control deficits associated with antisocial personality disorder and psychopathy. AB - Antisociality has been linked to a variety of executive functioning deficits, including poor cognitive control. Surprisingly, cognitive control deficits are rarely found in psychopathic individuals, despite their notoriously severe and persistent antisocial behavior. In fact, primary (low-anxious) psychopathic individuals display superior performance on cognitive control-type tasks under certain circumstances. To clarify these seemingly contradictory findings, we administered a response competition (i.e., flanker) task to incarcerated offenders, who were assessed for Antisocial Personality Disorder (APD) symptoms and psychopathy. As hypothesized, APD related to poorer accuracy, especially on incongruent trials. Contrary to expectation, however, the same pattern of results was found in psychopathy. Additional analyses indicated that these effects of APD and psychopathy were associated with overlapping variance. The findings suggest that psychopathy and APD symptoms are both associated with deficits in cognitive control, and that this deficit relates to general antisociality as opposed to a specific antisocial syndrome. PMID- 22452755 TI - An investigation of experiential avoidance, emotion dysregulation, and distress tolerance in young adult outpatients with borderline personality disorder symptoms. AB - In this study we investigated 3 domains of emotional functioning--emotion dysregulation, distress tolerance, and experiential avoidance--in young adult outpatients with borderline personality disorder (BPD) symptoms. Participants were 40 young adult outpatients at a university counseling center who reported current suicidal ideation and met diagnostic criteria for BPD or experienced subthreshold BPD symptoms (i.e., met diagnostic criteria for 3 or 4 symptoms). Participants completed 3 self-report measures of emotional functioning experiential avoidance (Acceptance and Action Questionnaire-2; Bond et al., 2011; Hayes et al., 2004), emotion dysregulation (Difficulties in Emotion Regulation Scale; Gratz & Roemer, 2004), and distress tolerance (Distress Tolerance Scale; Simons & Gaher, 2005)-and a behavioral measure of distress tolerance (Paced Auditory Serial Addition Task-Computerized; Lejuez, Kahler, & Brown, 2003), in addition to self-report measures of depression and BPD symptom severity. Partial correlations demonstrated that both emotion dysregulation and experiential avoidance were significantly associated with BPD symptom severity after accounting for depression. However, neither the self-report nor behavioral measure of distress tolerance were related to BPD symptom severity. A regression analysis with emotion dysregulation and experiential avoidance as independent variables revealed that only experiential avoidance was significantly associated with BPD symptom severity after controlling for depression symptoms. The current findings suggest that experiential avoidance may be a central process in BPD symptom severity. Future research directions are discussed. PMID- 22452756 TI - Borderline personality disorder as a female phenotypic expression of psychopathy? AB - Evidence suggests that the combination of the interpersonal-affective (F1) and impulsive-antisocial (F2) features of psychopathy may be associated with borderline personality disorder (BPD), specifically among women (e.g., Coid, 1993; Hicks, Vaidyanathan, & Patrick, 2010). However, empirical research explicitly examining gendered relationships between BPD and psychopathy factors is lacking. To further inform this area of research, we investigated the hypothesis that the interplay between the two psychopathy factors is associated with BPD among women across two studies. Study 1 consisted of a college sample of 318 adults (51% women), and Study 2 consisted of a large sample of 488 female prisoners. The interpersonal-affective (F1) and impulsive-antisocial psychopathy (F2) scores, measured with self-report and clinician-rated indices, respectively, were entered as explanatory variables in regression analyses to investigate their unique contributions to BPD traits. Across two independent samples, results indicated that the interaction of high F1 and F2 psychopathy scores was associated with BPD in women. This association was found to be specific to women in Study 1. These results suggest that BPD and psychopathy, at least as they are measured by current instruments, overlap in women and, accordingly, may reflect gender-differentiated phenotypic expressions of similar dispositional vulnerabilities. PMID- 22452757 TI - Non-suicidal self-injury (NSSI) disorder: a preliminary study. AB - Non-suicidal self-injury (NSSI) disorder has been suggested for inclusion into the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, in preparation), yet there is concern that NSSI is primarily a function of high borderline personality disorder (BPD) symptoms. The purpose of this study was to examine the characteristics of NSSI disorder and compare it to BPD and other DSM Axis I diagnoses commonly seen in clinical practice to aid in the determination of whether NSSI should be considered a separate, valid diagnostic entity. Chart data were analyzed from the screening, intake, and termination information of 571 treatment-seeking patients in a general practice clinic. Patients were classified into one of three groups: NSSI without BPD, BPD (with and without NSSI) or a comparison condition for those who did not meet criteria for the first 2 groups. Participants in these 3 groups were compared on functioning at intake, psychopathology, and diagnostic co-occurrence. Results indicated important group differences regarding diagnostic co-occurrence rates, patient history of associated features, and impairment at intake. The NSSI group displayed similar levels of functional impairment as the BPD group, including on indices of suicidality. The BPD group reported increased experiences with abuse and fewer men relative to the NSSI group. Most in the NSSI group did not exhibit subthreshold BPD symptoms or personality disorder not otherwise specified. In conclusion, a potential NSSI disorder may be characterized by high levels of depressive symptoms, anxiety, suicidality, and low functioning relative to other Axis I diagnoses. PMID- 22452758 TI - Ruminative and mindful self-focused attention in borderline personality disorder. AB - The current study investigated the short-term effects of mindful and ruminative forms of self-focused attention on a behavioral measure of distress tolerance in individuals with borderline personality disorder (BPD) who had completed an angry mood induction. Participants included 40 individuals who met criteria for BPD and were currently involved in mental health treatment. Each completed an individual 1-hr session. Following an angry mood induction, each participant was randomly assigned to engage in ruminative or mindful self-focus for several minutes. All participants then completed the computerized Paced Auditory Serial Addition Test (PASAT-C), a behavioral measure of willingness to tolerate distress in the service of goal-directed behavior. The mindfulness group persisted significantly longer than the rumination group on the distress tolerance task and reported significantly lower levels of anger following the self-focus period. Results are consistent with previous studies in suggesting that distinct forms of self focused attention have distinct outcomes and that, for people with BPD, mindful self-observation is an adaptive alternative to rumination when feeling angry. PMID- 22452759 TI - Integrating competing dimensional models of personality: linking the SNAP, TCI, and NEO using Item Response Theory. AB - Mounting evidence suggests that several inventories assessing both normal personality and personality disorders measure common dimensional personality traits (i.e., Antagonism, Constraint, Emotional Instability, Extraversion, and Unconventionality), albeit providing unique information along the underlying trait continuum. We used Widiger and Simonsen's (2005) pantheoretical integrative model of dimensional personality assessment as a guide to create item pools. We then used Item Response Theory (IRT) to compare the assessment of these five personality traits across three established dimensional measures of personality: the Schedule for Nonadaptive and Adaptive Personality (SNAP), the Temperament and Character Inventory (TCI), and the Revised NEO Personality Inventory (NEO PI-R). We found that items from each inventory map onto these five common personality traits in predictable ways. The IRT analyses, however, documented considerable variability in the item and test information derived from each inventory. Our findings support the notion that the integration of multiple perspectives will provide greater information about personality while minimizing the weaknesses of any single instrument. PMID- 22452760 TI - Aversion and proneness to shame in self- and informant-reported personality disorder symptoms. AB - The present study examined the specificity and extent of relationships between shame and symptoms of five personality disorders (PDs), as they are apparent to both the self and others. Borderline, narcissistic, avoidant, dependent, and obsessive-compulsive PD symptoms were assessed in a sample of 367 undergraduates that evidenced a wide range of symptom levels (25.6% endorsed threshold or greater severity of symptoms on the Schedule of Nonadaptive and Adaptive Personality-2). Importantly, for both conceptual and methodological reasons, information about PD symptoms was also obtained from friends/family of 45.2% of the sample. Shame aversion (the tendency to perceive shame as a particularly painful and unwanted emotion) was assessed using the Shame-Aversive Reactions Questionnaire, and shame-proneness (the propensity to experience shame across situations) was assessed using the Test of Self-Conscious Affect-3. Shame aversion displayed the most consistent relationship with PD symptoms, being associated with self-reports of symptoms of all five PDs and informant-reports of symptoms of three PDs, over and above experiential avoidance, trait affect, and guilt. A significant Shame Aversion * Shame-Proneness interaction further revealed that shame-proneness was associated with symptoms of avoidant and dependent PDs among individuals with high but not low levels of shame aversion. Thus, these findings highlight shame aversion's specific importance in PD symptoms and suggest important future research directions. PMID- 22452761 TI - Addressing narcissistic personality features in the context of medical care: integrating diverse perspectives to inform clinical practice. AB - Narcissistic personality disorder (NPD) is characterized by an unrealistic need for admiration, lack of empathy toward others, and feelings of superiority. NPD presents a unique and significant challenge in clinical practice, particularly in medical settings with limited provider contact time, as health professionals treat individuals who often require excessive admiration and have competing treatment needs. This practice review highlights real case examples across three distinct medically oriented clinical settings (inpatient and outpatient behavioral medicine and a Level I trauma center) to demonstrate the difficult and compromising situations that providers face when treating patients with general medical conditions and comorbid narcissistic personality features. The main goal of this article is to discuss the various challenges and obstacles associated with these cases in medical settings and discuss some strategies that may prove successful. A second goal is to bridge diverse conceptualizations of narcissism/NPD through the discussion of theoretical and empirical perspectives that can inform understanding of the clinical examples. Despite differing perspectives regarding the underlying motivation of narcissistic behavior, this practice review highlights that these paradigms can be integrated when sharing the same ultimate goal: to improve delivery of care across medically oriented clinical settings for patients with narcissistic features. PMID- 22452762 TI - Psychopathic personality traits and environmental contexts: Differential correlates, gender differences, and genetic mediation. AB - Theorists have speculated that primary psychopathy (or Factor 1 affective interpersonal features) is prominently heritable whereas secondary psychopathy (or Factor 2 social deviance) is more environmentally determined. We tested this differential heritability hypothesis using a large adolescent twin sample. Trait based proxies of primary and secondary psychopathic tendencies were assessed using Multidimensional Personality Questionnaire (MPQ) estimates of Fearless Dominance and Impulsive Antisociality, respectively. The environmental contexts of family, school, peers, and stressful life events were assessed using multiple raters and methods. Consistent with prior research, MPQ Impulsive Antisociality was robustly associated with each environmental risk factor, and these associations were significantly greater than those for MPQ Fearless Dominance. However, MPQ Fearless Dominance and Impulsive Antisociality exhibited similar heritability, and genetic effects mediated the associations between MPQ Impulsive Antisociality and the environmental measures. Results were largely consistent across male and female twins. We conclude that gene-environment correlations rather than main effects of genes and environments account for the differential environmental correlates of primary and secondary psychopathy. PMID- 22452763 TI - Psychopathy-related differences in selective attention are captured by an early event-related potential. AB - According to the response modulation model, the poorly regulated behavior of psychopathic individuals reflects a problem reallocating attention to process peripheral information while engaged in goal-directed behavior (Patterson & Newman, 1993). We evaluated this tenet using male prisoners and an early event related potential component (P140) to index attentional processing. In all task conditions, participants viewed and categorized letter stimuli that could also be used to predict electric shocks. Instructions focused attention either on the threat-relevant dimension of the letters or an alternative, threat-irrelevant dimension. Offenders with high scores on Hare's (2003) Psychopathy Checklist Revised displayed a larger P140 under alternative versus threat conditions. Beyond demonstrating psychopathy-related differences in early attention, these findings suggest that psychopathic individuals find it easier to ignore threat related distractors when they are peripheral versus central to their goal directed behavior. PMID- 22452764 TI - An examination of the Psychopathic Personality Inventory's nomological network: a meta-analytic review. AB - Since its publication, the Psychopathic Personality Inventory and its revision (Lilienfeld & Andrews, 1996; Lilienfeld & Widows, 2005) have become increasingly popular such that it is now among the most frequently used self-report inventories for the assessment of psychopathy. The current meta-analysis examined the relations between the two PPI factors (factor 1: Fearless Dominance; factor 2: Self-Centered Impulsivity), as well as their relations with other validated measures of psychopathy, internalizing and externalizing forms of psychopathology, general personality traits, and antisocial personality disorder symptoms. Across 61 samples reported in 49 publications, we found support for the convergent and criterion validity of both PPI factor 2 and the PPI total score. Much weaker validation was found for PPI factor 1, which manifested limited convergent validity and a pattern of correlations with central criterion variables that was inconsistent with many conceptualizations of psychopathy. PMID- 22452765 TI - Is there adequate empirical justification for radically revising the personality disorders section for DSM-5? AB - The DSM-5 Personality and Personality Disorders (PDs) Work Group has recommended a reformulation of the PD section. In the present review I examined the empirical support for the Work Group's criticisms of the DSM-IV approach that were central to the justification for radically changing the diagnostic criteria. The Work Group indicated that comorbidity among the DSM-IV PDs is excessive, and to reduce comorbidity they recommended deleting five PDs. The studies they cited demonstrating high levels of comorbidity were of samples of psychiatric patients. A review of the epidemiological literature shows that comorbidity rates are much lower than in patient samples, and this challenges the proposition that high comorbidity is due to the diagnostic criteria. Moreover, the empirical support for the exclusion of some disorders over others is lacking. The Work Group noted that the diagnostic stability of the PDs is modest. However, modest levels of diagnostic stability may be largely attributable to methodological factors such test-retest unreliability, state effects, regression to the mean, and measurement error due to repeated assessments, rather than a reflection of inadequacies of the diagnostic system. Thus, modest stability is likely to be found in any approach toward diagnosing PDs. The present review therefore suggests that several of the core problems linked to the DSM-IV approach toward diagnosing PDs are more likely due to methodological factors than inadequacies of the criteria themselves. The Work Group's recommendation to delete five PDs is inconsistent with the explicit guidelines established for making revisions for DSM-5 which specify that for a disorder to be deleted there should be a thorough review of that disorder's clinical utility and validity. PMID- 22452766 TI - The clinical utility of the Five Factor Model of personality disorder. AB - Previous research has suggested that clinicians would be unable to recover DSM-IV TR personality disorder diagnoses on the basis of information provided by the Five Factor Model (FFM) of personality disorder. However, the prior research did not provide all of the information that would be available to a clinician when determining a personality disorder diagnosis; more specifically, the maladaptive personality traits associated with each FFM trait elevation. In the current study, 201 clinicians provided DSM-IV-TR personality disorder diagnoses on the basis of either the DSM-IV-TR criterion sets or the respective FFM maladaptive personality traits. Accuracy using the FFM maladaptive traits was much improved over the prior research and comparable to the accuracy obtained with the criterion sets. The clinicians also rated the FFM and the DSM-IV-TR as comparably useful for obtaining a DSM-IV-TR personality disorder diagnosis. PMID- 22452767 TI - Social anhedonia, but not positive schizotypy, is associated with poor affective control. AB - Emotion researchers have distinguished between automatic versus controlled processing of affective information. One previous study with a small sample size found that extreme levels of social anhedonia (SocAnh) in college students, which predicts future schizophrenia-spectrum disorders, is associated with problems in controlled affective processing on a primed evaluation task. The current study examined whether in a larger college student sample SocAnh but not elevated perceptual aberration/magical ideation (PerMag) was associated with poor controlled affective processing. On the primed evaluation task, primes and targets could be either affectively congruent or incongruent and participants judged the valence of targets. Previous research on this task has found that participants appear to use controlled processing in an attempt to counteract the influence of the prime in evaluating the target. In this study, compared to the PerMag (n = 48) and control groups (n = 338), people with extreme levels of social anhedonia (n = 62) exhibited increased affective interference as they were slower for incongruent than for congruent trials. In contrast, there were no differences between the PerMag and control groups. Overall, these results suggest that SocAnh, but not PerMag, is associated with poor controlled affective processing. PMID- 22452769 TI - Affective startle modulation in incarcerated women with borderline personality disorder features. AB - Affective startle modulation was assessed in a sample of Caucasian female offenders classified as exhibiting high levels of borderline personality disorder (BPD) features (n = 19) or low levels of BPD features (n = 43) using the Diagnostic Interview for Borderlines-Revised (DIB-R; Zanarini, Gunderson, Frankenburg, & Chauncey, 1989). Contrary to prediction, high-BPD feature participants did not show significantly greater startle blink magnitudes than controls while viewing unpleasant pictures at either a short (2 s) or long (4.5 s) probe time. High-BPD feature participants did show significant blink attenuation while viewing pleasant pictures at the short probe time. The role of attention and the relative specificity of the negative emotion-processing abnormalities exhibited by women with BPD are discussed. PMID- 22452770 TI - Changes in negative affect following pain (vs. nonpainful) stimulation in individuals with and without a history of nonsuicidal self-injury. AB - Theoretical models of nonsuicidal self-injury (NSSI; i.e., purposeful destruction of body tissue without suicidal intent) suggest that individuals engage in NSSI in order to regulate negative affect (NA). One limitation of the current research is that most studies using pain as a proxy of NSSI have failed to include a nonpainful stimuli control group. This study attempted to address this limitation by comparing the emotional response to painful (vs. nonpainful) heat stimulation in individuals with a history of NSSI (vs. no history of NSSI) following a negative mood induction. It was predicted that among individuals with a history of NSSI, pain would lead to larger reductions in NA than warm stimulation. Furthermore, it was predicted that this reduction would be larger than that of controls regardless of condition. The hypotheses received partial support, such that pain led to greater reductions in negative affect for individuals with a history of NSSI, but not compared to controls. Future research directions are discussed. PMID- 22452771 TI - Gender and factor-level interactions in psychopathy: implications for self directed violence risk and borderline personality disorder symptoms. AB - Women with antisocial and psychopathic traits have a more extensive history of self-directed violence, as well as borderline personality disorder (BPD) symptoms, than their male counterparts (Chapman, Specht, & Cellucci, 2005; Warren et al., 2003). To inform this area of research, we examined gender differences in the relationship between psychopathy factors and risk for self-directed violence, as measured by a history of suicidal ideation, self-harm, and suicide attempts, across 2 studies. In both studies, we found that the interaction of the interpersonal-affective (Factor 1) and impulsive-antisocial traits (Factor 2) of psychopathy, a combination considered to exemplify high psychopathy, was associated with ideation, self-harm, and suicide attempt histories specifically in women. In men, Factor 2 traits were associated with these risk indices for self-directed violence, regardless of Factor 1. In Study 2, we extended our analysis to examine whether BPD accounted for the relationship between psychopathy and self-directed violence differentially in women and men. Results suggested that BPD symptoms partially accounted for the effects of Factor 2 on self-directed violence (both self-harm and attempts) in both genders but fully accounted for Factor 1 protective effects only in men. These findings underscore the notion that the same psychopathic trait liabilities, at least as they are currently assessed, may confer risk for different forms of behavioral maladjustment in women versus men. PMID- 22452772 TI - Behavior genetics of personality disorders: informing classification and conceptualization in DSM-5. AB - Personality pathology is currently captured in the Diagnostic and Statistical Manual through 10 categorical personality disorder (PD) diagnoses grouped into three descriptive clusters. This classification system has been criticized by many for using discrete categories and arbitrary thresholds when making clinical decisions. To address these critiques, the DSM-5 Personality and Personality Disorders Work Group has put forth a proposal that significantly alters the structure and content of the DSM-IV PD section. If this DSM-5 Work Group has conducted its own systematic review of the empirical literature, this review has not been released or made widely available. As such, it is up to the psychology community at large to determine how well the suggested changes align with findings from extant PD research. The current article joins this effort by addressing the contribution of behavior genetic findings to the revision process for classification of PDs in DSM-5. First, we provide a brief review of the history of PD classification in the DSM. Next, we present an overview and rationale for each of the five major suggested changes to PD diagnoses. For each suggested change, we outline the available evidence from behavior genetics and interpretations of these findings. Finally, we offer a summary of considerations for PD classification as the DSM-5 moves forward. Review of the behavior genetics literature suggests that several features of the DSM-5 proposal, including the elimination of 4 PDs, merging clinical disorders and PDs on a single axis, and the implementation of a trait rating system, require significantly greater explication before a product is finalized. PMID- 22452773 TI - No sympathy for the devil: attributing psychopathic traits to capital murderers also predicts support for executing them. AB - Mental health evidence concerning antisocial and psychopathic traits appears to be introduced frequently in capital murder trials in the United States to argue that defendants are a "continuing threat" to society and thus worthy of execution. Using a simulation design, the present research examined how layperson perceptions of the psychopathic traits exhibited by a capital defendant would impact their attitudes about whether he should receive a death sentence. Across three studies (total N = 362), ratings of a defendant's perceived level of psychopathy strongly predicted support for executing him. The vast majority of the predictive utility was attributable to interpersonal and affective traits historically associated with psychopathy rather than traits associated with a criminal and socially deviant lifestyle. A defendant's perceived lack of remorse in particular was influential, although perceptions of grandiose self-worth and a manipulative interpersonal style also contributed incrementally to support for a death sentence. These results highlight how attributions regarding socially undesirable personality traits can have a pronounced negative impact on layperson attitudes toward persons who are perceived to exhibit these characteristics. PMID- 22452774 TI - Self- and informant-reported perspectives on symptoms of narcissistic personality disorder. AB - Because narcissistic individuals tend to have an inflated view of themselves and their abilities, the reliance on self-reported information in the assessment and diagnosis of narcissistic personality disorder (NPD) is problematic. Hence, the use of informants in the assessment of NPD may be necessary. In the current study we examined self- and informant-reported features of NPD using agreement, frequency, and discrepancy analyses. The results indicated that informants tended to report more NPD features than selves, and that there were either low or nonsignificant levels of self-informant agreement among the 9 NPD diagnostic criteria and its categorical diagnosis. Informants were increasingly more likely to report higher raw scores relative to selves, indicating that the discrepancy between self- and informant reports increases with the NPD scale. Informants also reported NPD features that selves often did not, suggesting that current prevalence estimates of NPD, which use only self-reported information, are most likely underestimates. These results highlight the importance of gathering informant-reported data in addition to self-reported data when assessing NPD. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 22452775 TI - The role of aberrant salience and self-concept clarity in psychotic-like experiences. AB - Most theories of psychotic-like experiences posit the involvement of cognitive mechanisms. The current research examined the relations between psychotic-like experiences and two cognitive mechanisms, high aberrant salience and low self concept clarity. In particular, we examined whether aberrant salience, or the incorrect assignment of importance to neutral stimuli, and low self-concept clarity interacted to predict psychotic-like experiences. The current research included three large samples (n = 667, 724, 744) of participants and oversampled for increased schizotypal personality traits. In all three studies, an interaction between aberrant salience and self-concept clarity was found such that participants with high aberrant salience and low self-concept clarity had the highest levels of psychotic-like experiences. In addition, aberrant salience and self-concept clarity interacted to predict a supplemental measure of delusions in Study 2. In Study 3, in contrast to low self-concept clarity, neuroticism did not interact with aberrant salience to predict psychotic-like experiences, suggesting that the relation between low self-concept clarity and psychosis may not be a result of neuroticism. Additionally, aberrant salience and self-concept clarity did not interact to predict two other SPD criteria, social anhedonia or trait paranoia, which suggests the interaction is specific to psychotic-like experiences. Overall, our results are consistent with several cognitive models of psychosis suggesting that aberrant salience and self-concept clarity might be important mechanisms in the occurrence of psychotic-like symptoms. PMID- 22452776 TI - Predicting domains and rates of change in borderline personality disorder. AB - What changes and how quickly these changes occur as a result of therapy in borderline personality disorder (BPD) is an important ongoing question. The features of BPD patients that are most predictive of rates of change in such patients remain largely unknown. Using the Cornell Personality Disorders Institute (CPDI) randomized controlled trial data, we sought to determine (a) the number and nature of broad domains underlying a large number of rate of change (slope) measures across many psychological, psychiatric, and psychosocial indexes, and (b) which baseline individual difference psychological features of the BPD patients correlated with these rate of change domains. We examined the latent structure of slope (rate of change) measures gleaned from individual growth curves for each subject, studied in multiwave perspective, on separate measures of anger, aggression, impulsivity, depression, global functioning, and social adjustment. Three broad domains of change rate could be discerned. These domains were reflected in factors that are described as (a) anger/aggression change ("aggressive dyscontrol"), (b) global functioning/social adjustment change ("social adjustment/self-acceptance"), and (c) anxiety/depression/impulsivity change ("conflict tolerance/behavioral control"). Factor scores were computed for each change domain and baseline measures of personality and psychodynamic features, selected a priori, were correlated with these factor scores. Multiple regression analyses revealed (a) baseline negative affectivity and aggression predicted the aggressive dyscontrol change domain, (b) baseline identity diffusion predicted the social adjustment/self-acceptance change domain, and (c) baseline social potency predicted the conflict tolerance/behavioral control change domain. These baseline predictors suggest potential research foci for understanding those aspects of BPD that change at comparable rates over time. PMID- 22452777 TI - Facets of psychopathy in relation to potentially traumatic events and posttraumatic stress disorder among female prisoners: the mediating role of borderline personality disorder traits. AB - Despite the high prevalence of trauma exposure in female prisoners, few studies have examined the link between psychopathy and posttraumatic stress disorder (PTSD)-or the potential mediating role of borderline personality disorder traits. Using a sample of incarcerated women, we identified differential associations across facets of psychopathy, as assessed via the Psychopathy Checklist-Revised (PCL-R; Hare, 2003), with potentially traumatic events (PTE) and symptoms of PTSD. Specifically, the Interpersonal and Affective facets were unrelated to both PTE and PTSD, while the Lifestyle and Antisocial facets were each associated with PTE and the Antisocial facet was uniquely associated with PTSD symptoms. Borderline personality disorder traits fully accounted for the association between the Antisocial facet and both PTE and PTSD, while the Lifestyle facet contributed incrementally to the prediction of PTE. The findings clarify linkages among psychopathy, trauma, PTSD, and borderline personality disorder traits, and extend our understanding of the clinical presentation of psychopathy in women. PMID- 22452778 TI - Where is multidimensional perfectionism in DSM-5? A question posed to the DSM-5 personality and personality disorders work group. AB - A radical reworking of Axis II has been proposed for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders whereby personality disorder categories will be replaced by a trait dimensional model of personality pathology. Perfectionism is specified as a lower order facet of Compulsivity within this proposed model. This marginalization of the perfectionism construct is inconsistent with the empirical literature that suggests that perfectionism is an important dimension of maladaptive personality in its own right, complete with its own set of more specific lower order facets. Further, perfectionism in the current proposed system is relevant only to the characterization of the obsessive compulsive personality disorder type, despite compelling empirical research that demonstrates that various dimensions of perfectionism are differentially associated with personality pathology of all kinds. The present article reviews existing research on the role of various dimensions of perfectionism in personality disorder, highlights these seemingly ignored areas of the perfectionism literature, and discusses the problems and consequences that will arise if perfectionism continues to be defined narrowly and is largely excluded from dimensional models of personality pathology. PMID- 22452779 TI - The relation between self-reported psychopathic traits and distorted response styles: a meta-analytic review. AB - A concern among researchers is that self-report measures may not be valid indicators of psychopathic traits due to the core features of psychopathy (e.g., lying, deception/manipulation). The current study addresses this issue by combining effects sizes from studies published on or before March 31, 2010 to examine the relation between scores of 3 widely used self-report psychopathy measures--the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996) and its revised version (PPI-R; Lilienfeld & Widows, 2005) and Levenson's Self-Report Psychopathy scale (LSRP; Levenson, Kiehl, & Fitzpatrick, 1995) and scores on measures assessing response style (i.e., faking good and faking bad). Effect sizes were obtained from 45 studies for total, Factor 1, and Factor 2 scores (faking good: k = 54, 55, and 55, respectively; faking bad: k = 51, 50, and 50, respectively). Based on a random effects model, a significant negative association was found between social desirability/faking good and both total (r(w) = -.11, p < .01) and F2 (r(w) = -.16, p < .01) scores, and moderation analyses suggested that effect sizes varied as a function of psychopathy scale and validity scale used. Significant positive associations were also found between faking bad and both total (r(w) = .27, p < .05) and F2 (r(w) = .32, p < .05) scores. Also, moderation analyses suggested that effect sizes varied as a function of study location, psychopathy scale, and validity scale. Despite several limitations (e.g., inclusion of only published studies, limited moderators, exclusion of other measures), the general findings temper concerns of positive response bias and underscore the validity of self-report psychopathy scales. PMID- 22452780 TI - What controls the distribution of tropical forest and savanna? AB - Forest and savanna biomes dominate the tropics, yet factors controlling their distribution remain poorly understood. Climate is clearly important, but extensive savannas in some high rainfall areas suggest a decoupling of climate and vegetation. In some situations edaphic factors are important, with forest often associated with high nutrient availability. Fire also plays a key role in limiting forest, with fire exclusion often causing a switch from savanna to forest. These observations can be captured by a broad conceptual model with two components: (1) forest and savanna are alternative stable states, maintained by tree cover-fire feedbacks, (2) the interaction between tree growth rates and fire frequency limits forest development; any factor that increases growth (e.g. elevated availability of water, nutrients, CO(2)), or decreases fire frequency, will favour canopy closure. This model is consistent with the range of environmental variables correlated with forest distribution, and with the current trend of forest expansion, likely driven by increasing CO(2) concentrations. Resolving the drivers of forest and savanna distribution has moved beyond simple correlative studies that are unlikely to establish ultimate causation. Experiments using Dynamic Global Vegetation Models, parameterised with measurements from each continent, provide an important tool for understanding the controls of these systems. PMID- 22452781 TI - Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT: a rebuttal. PMID- 22452782 TI - Quercetin increased the antiproliferative activity of green tea polyphenol (-) epigallocatechin gallate in prostate cancer cells. AB - We previously demonstrated that 50% of (-)-epigallocatechin gallate (EGCG) was present in methylated form (4"-MeEGCG) in human prostate tissue, which is less bioactive. We therefore investigated whether quercetin, a natural inhibitor of catechol-O-methyl transferase (COMT), will inhibit EGCG methylation leading to enhanced antiproliferative activity of EGCG in prostate cancer cells. Incubation with both quercetin and EGCG for 2 h increased the cellular concentrations of EGCG by 4- to 8-fold and 6- to 10-fold in androgen-independent PC-3 cells and androgen-dependent LNCaP cells, respectively. Concurrently, the percent of 4" MeEGCG in the total EGCG was decreased from 39% to 15% in PC-3 cells and from 61% to 38% in LNCaP cells. Quercetin and EGCG in combination synergistically inhibited cell proliferation, caused cell cycle arrest, and induced apoptosis in PC-3 cells. In LNCaP cells, EGCG and quercetin exhibited a stronger antiproliferative activity leading to an additive effect. The synergistic effect of these 2 agents in PC-3 cells could be based on the fact that EGCG primarily inhibited COMT activity, whereas quercetin reduced the amount of COMT protein. In summary, quercetin combined with EGCG in vitro demonstrated enhanced inhibition of cell proliferation by increasing the intracellular concentration of EGCG and decreasing EGCG methylation. PMID- 22452783 TI - A modelling-experimental approach reveals insulin receptor substrate (IRS) dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. AB - Mammalian target of rapamycin (mTOR) kinase responds to growth factors, nutrients and cellular energy status and is a central controller of cellular growth. mTOR exists in two multiprotein complexes that are embedded into a complex signalling network. Adenosine monophosphate-dependent kinase (AMPK) is activated by energy deprivation and shuts off adenosine 5'-triphosphate (ATP)-consuming anabolic processes, in part via the inactivation of mTORC1. Surprisingly, we observed that AMPK not only responds to energy deprivation but can also be activated by insulin, and is further induced in mTORC1-deficient cells. We have recently modelled the mTOR network, covering both mTOR complexes and their insulin and nutrient inputs. In the present study we extended the network by an AMPK module to generate the to date most comprehensive data-driven dynamic AMPK-mTOR network model. In order to define the intersection via which AMPK is activated by the insulin network, we compared simulations for six different hypothetical model structures to our observed AMPK dynamics. Hypotheses ranking suggested that the most probable intersection between insulin and AMPK was the insulin receptor substrate (IRS) and that the effects of canonical IRS downstream cues on AMPK would be mediated via an mTORC1-driven negative-feedback loop. We tested these predictions experimentally in multiple set-ups, where we inhibited or induced players along the insulin-mTORC1 signalling axis and observed AMPK induction or inhibition. We confirmed the identified model and therefore report a novel connection within the insulin-mTOR-AMPK network: we conclude that AMPK is positively regulated by IRS and can be inhibited via the negative-feedback loop. PMID- 22452784 TI - Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP. AB - We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen-ERalpha (oestrogen receptor alpha) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen ERalpha signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen induced transcriptional up-regulation as well as UPP (ubiquitin-proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERalpha target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen-ERalpha signalling and thus implicate ATBF1 in oestrogen dependent breast development and carcinogenesis. PMID- 22452785 TI - Banning retail tobacco sales: time to start the discussion. PMID- 22452786 TI - Significance of hanging total spine x-ray to estimate the indicative correction angle by brace wearing in idiopathic scoliosis patients. AB - BACKGROUND: Although most idiopathic scoliosis patients subject to conservative treatment in daily clinical practice, there have been no ideal methods to evaluate the spinal flexibility for the patients who are scheduled the brace treatment. The purpose of this study was to investigate the value of hanging total spine x-ray to estimate the indicative correction angle by brace wearing in idiopathic scoliosis patients. METHODS: One hundred seventy-six consecutive patients with idiopathic scoliosis who were newly prescribed the Osaka Medical College (OMC) brace were studied. The study included 14 boys and 162 girls with a mean age of 13 years and 1 month. The type of curves consisted of 62 thoracic, 23 thoracolumbar, 22 lumbar, 42 double major, 14 double thoracic, and 13 triple curve pattern. We compared the Cobb angles on initial brace wearing (BA) and in hanging position (HA). Of those, 108 patients who had main thoracic curves were selected and evaluated the corrective ability of OMC brace. These subjects were divided into three groups according to the relation between BA and HA (BA < HA group, BA = HA group, and BA > HA group), and then, maturity was compared among them. RESULTS: The average Cobb angle in upright position (UA) of all cases was 31.0 +/- 7.8 degrees . The average BA and HA of all cases were 20.3 +/- 9.5 degrees and 21.1 +/- 8.4 degrees , respectively. The average chronological age was lowest in BA < HA group. And also, maturity in BA < HA group was the lowest among each of them. The rate of BA < HA cases were decreased as the Risser stage of the patients were progressed. CONCLUSIONS: The use of hanging total spine x ray served as a useful tool to estimate the degree of correction possible curve within the OMC brace for main thoracic curve in idiopathic scoliosis. Maturity had some influence on the correlation between HA and BA. Namely, in immature patients, HA tended to be larger than BA. In contrast, in mature patients, HA had a tendency to be smaller than BA. With consideration for spinal flexibility based on maturity, in mature patients, larger BA than HA may be allowed. However, in immature patients, smaller BA than HA should be aimed. PMID- 22452787 TI - Liquid courage or liquid fear: alcohol intoxication and anxiety facilitate physical aggression. AB - Participants were 138 male social drinkers between 18 and 30 years of age from a university community in the southeastern United States in 2000. Trait and state anxiety was measured using the Trait Anxiety Inventory and the Facial Action Coding System, respectively. Participants consumed an alcoholic or nonalcoholic control beverage and completed a shock-based aggression task. Regression analysis indicated that alcohol-facilitated elevations in anxiety mediated the relation between alcohol consumption and aggression and that trait anxiety and physical provocation moderated this effect. Implications and limitations of this study are noted and future research directions are suggested. PMID- 22452788 TI - Relation of the three-component model of short form-36 scores to disease severity in chronic heart failure outpatients. PMID- 22452789 TI - Abnormal increase in urinary aquaporin-2 excretion in response to hypertonic saline in essential hypertension. AB - BACKGROUND: Dysregulation of the expression/shuttling of the aquaporin-2 water channel (AQP2) and the epithelial sodium channel (ENaC) in renal collecting duct principal cells has been found in animal models of hypertension. We tested whether a similar dysregulation exists in essential hypertension. METHODS: We measured urinary excretion of AQP2 and ENaC beta-subunit corrected for creatinine (u-AQP2(CR), u-ENaC(beta-CR)), prostaglandin E2 (u-PGE2) and cyclic AMP (u-cAMP), fractional sodium excretion (FE(Na)), free water clearance (C(H2O)), as well as plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (Ang II), aldosterone (Aldo), and atrial and brain natriuretic peptide (ANP, BNP) in 21 patients with essential hypertension and 20 normotensive controls during 24-h urine collection (baseline), and after hypertonic saline infusion on a 4-day high sodium (HS) diet (300 mmol sodium/day) and a 4-day low sodium (LS) diet (30 mmol sodium/day). RESULTS: At baseline, no differences in u-AQP2(CR) or u-ENaC(beta CR) were measured between patients and controls. U-AQP2(CR) increased significantly more after saline in patients than controls, whereas u-ENaC(beta CR) increased similarly. The saline caused exaggerated natriuretic increases in patients during HS intake. Neither baseline levels of u-PGE2, u-cAMP, AVP, PRC, Ang II, Aldo, ANP, and BNP nor changes after saline could explain the abnormal u AQP2(CR) response. CONCLUSIONS: No differences were found in u-AQP2(CR) and u ENaC(beta-CR) between patients and controls at baseline. However, in response to saline, u-AQP2(CR) was abnormally increased in patients, whereas the u-ENaC(beta CR) response was normal. The mechanism behind the abnormal AQP2 regulation is not clarified, but it does not seem to be AVP-dependent. Clinicaltrial.gov identifier: NCT00345124. PMID- 22452790 TI - Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender. AB - BACKGROUND: Cannabis use is associated with an earlier age at onset of psychotic illness. The aim of the present study was to examine whether this association is confounded by gender or other substance use in a large cohort of patients with a non-affective psychotic disorder. METHOD: In 785 patients with a non-affective psychotic disorder, regression analysis was used to investigate the independent effects of gender, cannabis use and other drug use on age at onset of first psychosis. RESULTS: Age at onset was 1.8 years earlier in cannabis users compared to non-users, controlling for gender and other possible confounders. Use of other drugs did not have an additional effect on age at onset when cannabis use was taken into account. In 63.5% of cannabis-using patients, age at most intense cannabis use preceded the age at onset of first psychosis. In males, the mean age at onset was 1.3 years lower than in females, controlling for cannabis use and other confounders. CONCLUSIONS: Cannabis use and gender are independently associated with an earlier onset of psychotic illness. Our findings also suggest that cannabis use may precipitate psychosis. More research is needed to clarify the neurobiological factors that make people vulnerable to this precipitating effect of cannabis. PMID- 22452791 TI - Identification of tristetraprolin as a factor that modulates the stability of the TAFI transcript through binding to the 3'-untranslated region. AB - BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen encoded by the human gene CPB2. TAFI constitutes a molecular link between coagulation and fibrinolysis, and between coagulation and inflammation. The 3'-untranslated region (UTR) of the human CPB2 mRNA plays a key role in regulating CPB2 mRNA abundance, but the exact mechanisms that mediate this regulation are largely unexplored. OBJECTIVES: To pinpoint cis-acting elements in the CPB2 3'-UTR that act as stability determinants and to identify protein factors binding to these sites. METHODS: We constructed a series of plasmids encoding mRNAs containing rabbit beta-globin sequences (as a reporter) fused to sequences of the CPB2 3'-UTR (encompassing 5' and internal deletions). These plasmids were transfected into HepG2 (human hepatoma) cells and the stability of the fusion transcripts measured. We performed a series of gel mobility shift analyses using RNA probes encompassing putative (in)stability elements. RESULTS: We identified one element conferring stability and three elements conferring instability. Supershift assays identified the protein bound to the site between the second and third polyadenylation sites as tristetraprolin (TTP). Mutation of the TTP site abolished TTP binding in gel mobility shift assays and also stabilized beta-globin/CPB2 fusion transcripts. TTP knockdown stabilized the fusion transcript containing the TTP site, but not a fusion transcript in which this site was mutated. CONCLUSIONS: Our findings are indicative of a role for TTP in constitutive, and perhaps regulated, control of CPB2 mRNA stability and hence abundance. PMID- 22452792 TI - Loss of HLTF function promotes intestinal carcinogenesis. AB - BACKGROUND: HLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown. RESULTS: To address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apcmin/+ mutant background, Hltf- deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf-/-/Apcmin/+ mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apcmin/+ mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased. CONCLUSION: Taken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer. PMID- 22452793 TI - Metal cation dependence of interactions with amino acids: bond energies of Cs+ to Gly, Pro, Ser, Thr, and Cys. AB - The interactions of cesium cations with five amino acids (AA) including glycine (Gly), proline (Pro), serine (Ser), threonine (Thr), and cysteine (Cys) are examined in detail. Experimentally, the bond dissociation energies (BDEs) are determined using threshold collision-induced dissociation of the Cs(+)(AA) complexes with xenon in a guided ion beam tandem mass spectrometer. Analyses of the energy-dependent cross sections include consideration of unimolecular decay rates, internal energy of the reactant ions, and multiple ion-neutral collisions. Bond dissociation energies (0 K) of 93.3 +/- 2.5, 107.9 +/- 4.6, 102.3 +/- 4.1, 105.4 +/- 4.3, and 96.8 +/- 4.2 kJ/mol are determined for complexes of Cs(+) with Gly, Pro, Ser, Thr, and Cys, respectively. Quantum chemical calculations are conducted at the B3LYP, B3P86, MP2(full), and M06 levels of theory with geometries and zero-point energies calculated at the B3LYP level using both HW*/6 311+G(2d,2p) and def2-TZVPPD basis sets. Results obtained using the former basis sets are systematically low compared to the experimental bond energies, whereas the latter basis sets show good agreement. For Cs(+)(Gly), theory predicts the ground-state conformer has the cesium cation binding to the carbonyl group of the carboxylic acid. For Cs(+)(Pro), the secondary nitrogen accepts the carboxylic acid hydrogen to form the zwitterionic structure, and the metal cation binds to both oxygens. Cs(+)(Ser), Cs(+)(Thr), and Cs(+)(Cys) are found to have tridentate binding at the MP2(full) level, whereas the density functional approaches slightly prefer bidentate binding of Cs(+) at the carboxylic acid moiety. Comparison of these results to those for the smaller alkali cations provides insight into the trends in binding affinities and structures associated with metal cation variations. PMID- 22452794 TI - The prognostic significance of p63 and Ki-67 expression in myoepithelial carcinoma. AB - BACKGROUND: Myoepithelial carcinoma is a rare tumour. The clinical and biological behaviours of these tumours are variable. Although many factors have been evaluated as potential prognostic indicators, including clinical stage, site and size of the tumour, high proliferative activity, extensive invasion into the surrounding tissue, perineural permeation, the abnormal presence of nuclear DNA content, and marked cellular pleomorphism, there are no definite histological features that clearly correlate with their behaviour. Thus, conclusions regarding prognostic factors and ideal treatment may emerge as the number of investigated myoepithelial carcinoma cases accumulate. METHODS: Using immunohistochemistry, expression levels of p63 and Ki-67 were determined in 16 myoepithelial carcinoma samples and correlated with clinicopathological characteristics and patient prognosis. RESULTS: p63 expression was detected in six of the myoepithelial carcinoma tissues (37.5%) and Ki-67 was detected in five (31.3%). In addition, p63 and Ki-67 expression levels were associated with myoepithelial carcinoma recurrence and metastasis. All six patients with p63-positive expression died due to disease or cardiovascular disease (mean survival time = 50.5 months), and p63 expression was statistically significant with respect to survival (P = 0.01). Four patients with Ki-67-positive expression died due to disease or cardiovascular disease (mean survival time = 44.0 months); however, there was no statistically significant difference between Ki-67 expression and survival (P = 0.24). CONCLUSIONS: Recurrence and metastasis in myoepithelial carcinomas are more frequent in p63-positive and Ki-67-positive EMCs, and poor prognosis is associated with overexpression of p63. PMID- 22452795 TI - Lateralized gap junctions in pulmonary hypertension: lost but not alone. PMID- 22452796 TI - Early repolarization: a sword in the haystack? PMID- 22452797 TI - Altered expression of testis-specific genes, piRNAs, and transposons in the silkworm ovary masculinized by a W chromosome mutation. AB - BACKGROUND: In the silkworm, Bombyx mori, femaleness is strongly controlled by the female-specific W chromosome. Originally, it was presumed that the W chromosome encodes female-determining gene(s), accordingly called Fem. However, to date, neither Fem nor any protein-coding gene has been identified from the W chromosome. Instead, the W chromosome is occupied with numerous transposon related sequences. Interestingly, the silkworm W chromosome is a source of female enriched PIWI-interacting RNAs (piRNAs). piRNAs are small RNAs of 23-30 nucleotides in length, which are required for controlling transposon activity in animal gonads. A recent study has identified a novel mutant silkworm line called KG, whose mutation in the W chromosome causes severe female masculinization. However, the molecular nature of KG line has not been well characterized yet. RESULTS: Here we molecularly characterize the KG line. Genomic PCR analyses using currently available W chromosome-specific PCR markers indicated that no large deletion existed in the KG W chromosome. Genetic analyses demonstrated that sib crosses within the KG line suppressed masculinization. Masculinization reactivated when crossing KG females with wild type males. Importantly, the KG ovaries exhibited a significantly abnormal transcriptome. First, the KG ovaries misexpressed testis-specific genes. Second, a set of female-enriched piRNAs was downregulated in the KG ovaries. Third, several transposons were overexpressed in the KG ovaries. CONCLUSIONS: Collectively, the mutation in the KG W chromosome causes broadly altered expression of testis-specific genes, piRNAs, and transposons. To our knowledge, this is the first study that describes a W chromosome mutant with such an intriguing phenotype. PMID- 22452798 TI - Double-blinded, placebo-controlled, randomized gene therapy using surgery for vector delivery. PMID- 22452799 TI - A hematopoietic contribution to microhemorrhage formation during antiviral CD8 T cell-initiated blood-brain barrier disruption. AB - BACKGROUND: The extent to which susceptibility to brain hemorrhage is derived from blood-derived factors or stromal tissue remains largely unknown. We have developed an inducible model of CD8 T cell-initiated blood-brain barrier (BBB) disruption using a variation of the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. This peptide-induced fatal syndrome (PIFS) model results in severe central nervous system (CNS) vascular permeability and death in the C57BL/6 mouse strain, but not in the 129 SvIm mouse strain, despite the two strains' having indistinguishable CD8 T-cell responses. Therefore, we hypothesize that hematopoietic factors contribute to susceptibility to brain hemorrhage, CNS vascular permeability and death following induction of PIFS. METHODS: PIFS was induced by intravenous injection of VP2121-130 peptide at 7 days post-TMEV infection. We then investigated brain inflammation, astrocyte activation, vascular permeability, functional deficit and microhemorrhage formation using T2*-weighted magnetic resonance imaging (MRI) in C57BL/6 and 129 SvIm mice. To investigate the contribution of hematopoietic cells in this model, hemorrhage-resistant 129 SvIm mice were reconstituted with C57BL/6 or autologous 129 SvIm bone marrow. Gadolinium-enhanced, T1-weighted MRI was used to visualize the extent of CNS vascular permeability after bone marrow transfer. RESULTS: C57BL/6 and 129 SvIm mice had similar inflammation in the CNS during acute infection. After administration of VP2121-130 peptide, however, C57BL/6 mice had increased astrocyte activation, CNS vascular permeability, microhemorrhage formation and functional deficits compared to 129 SvIm mice. The 129 SvIm mice reconstituted with C57BL/6 but not autologous bone marrow had increased microhemorrhage formation as measured by T2*-weighted MRI, exhibited a profound increase in CNS vascular permeability as measured by three-dimensional volumetric analysis of gadolinium-enhanced, T1-weighted MRI, and became moribund in this model system. CONCLUSION: C57BL/6 mice are highly susceptible to microhemorrhage formation, severe CNS vascular permeability and morbidity compared to the 129 SvIm mouse. This susceptibility is transferable with the bone marrow compartment, demonstrating that hematopoietic factors are responsible for the onset of brain microhemorrhage and vascular permeability in immune-mediated fatal BBB disruption. PMID- 22452800 TI - Hemocompatible poly(NIPAm-MBA-AMPS) colloidal nanoparticles as carriers of anti inflammatory cell penetrating peptides. AB - Anionic copolymer systems containing sulfated monomers have great potential for delivery of cationic therapeutics, but N-isopropylacrylamide (NIPAm) 2-acrylamido 2-methyl-1-propanesulfonic acid (AMPS) copolymer nanoparticles have seen limited characterization to date with regard to physical properties relevant to loading and release of therapeutics. Characterization of polymeric nanoparticles incorporating AMPS showed an increased size and decreased thermodynamic swelling ratios of AMPS containing particles as compared to NIPAm nanoparticles lacking AMPS. Particles with increasing AMPS addition showed an increased propensity for uniformity, intraparticle colloidal stability, and drug loading capacity. Peptide encapsulated in particles was shielded from peptide degradation in serum. Particles were shown not impede blood coagulation or to cause hemolysis. This study has demonstrated that AMPS incorporation into traditional NIPAm nanoparticles presents a tunable parameter for changing particle LCST, size, swelling ratio, zeta potential, and cationic peptide loading potential. This one pot synthesis results in a thermosensitive anionic nanoparticle system that is a potentially useful platform to deliver cationic cell penetrating peptides. PMID- 22452801 TI - Evaluation of derived Coulter red blood cell parameters for the assessment of iron deficiency in adults with congenital heart disease. AB - INTRODUCTION: The aim of our study was to evaluate derived red blood cell parameters in determining the presence of iron depletion and iron-deficient erythropoiesis, as states that precede iron deficiency anemia, in adults with congenital heart disease. METHODS: Eighty-eight adults who were diagnosed with congenital heart disease were divided into two groups (cyanotic and acyanotic). In both groups, congenital heart disease patients were then divided into three subgroups: with iron depletion, with iron-deficient erythropoiesis, and a control group. The following parameters were measured: complete blood count, reticulocytes, ferritin, soluble transferrin receptor, haptoglobin, lactate dehydrogenase, and calculated parameters: low hemoglobin density (LHD), red cell size factor (RSF), and microcytic anemia factor (MAF). RESULTS: Discriminant analysis indicated statistically significant differences in the first discriminant function: Function 1 - body iron, LHD, MAF, sTfR, and RSF (P < 0.001) in patients with acyanotic congenital heart disease and significant differences in both discriminant functions in patients with cyanotic congenital heart disease: Function 1 - body iron, soluble transferrin receptor, LHD, RSF, MAF, lactate dehydrogenase, and haptoglobin (P = 0.008) and Function 2 - reticulocytes (#), immature reticulocyte fraction and reticulocytes (%) (P = 0.049). CONCLUSIONS: Beside parameters that describe iron metabolism dynamics (body iron and soluble transferrin receptor), LHD, indicator of hypochromia, have the highest potential to differentiate and classify iron deficiency in patients with congenital heart disease. PMID- 22452802 TI - Characterization of transcriptional profiling of Kupffer cells during liver regeneration in rats. AB - KCs (Kupffer cells), as an important hepatic immunoregulatory cells, play a key role in LR (liver regeneration). Uncovering the transcriptional profiling of KCs after PH (partial hepatectomy) would likely clarify its implication in LR. Here, we isolated KCs by methods of Percoll density gradient centrifugation and immunomagnetic beads. Transcriptional profiles of KCs were monitored up to 168 h post-PH using microarray. By comparing the expression profile of KCs at 2-168 h post-PH with that of the control and applying the statistical and bioinformatics criteria, we found 1407 known and 927 unknown genes related to LR. K-means clustering analysis grouped these 1407 genes into robust 14 time-course clusters representing distinct patterns of regulation. Based on gene-set enrichment analysis, genes encoding products involved in cytokine signalling, inflammatory response and cell chaemotaxis were highly enriched in the cluster characterized by gradual up-regulation and then return; genes in defence response and immune response were enriched in clusters 'the general down-regulation during LR'; genes in fatty acid synthesis and sterol metabolism were preferentially distributed in the cluster 'gradual increase'; whereas genes in the categories 'lipid catabolism' and 'glycolysis' were enriched in cluster 'decrease at two intervals'. According to the above analysis, KCs were seemingly sensitive to operative stimulus; immune defence and detoxification function of KCs obviously dropped post-operatively; fatty acid synthesis were enhanced, whereas lipid catabolism and glycolysis were reduced after PH. This study provides a detailed in vivo gene expression profile of KCs, providing a framework to better understand the molecular mechanisms underlying the regeneration process at cellular level. PMID- 22452804 TI - The prevalence, risk factors and prognosis of aspirin resistance in elderly male patients with cardiovascular disease. AB - AIM: Aspirin resistance is recognized in different population. However, the prevalence and clinical events of aspirin resistance in elderly male patients with cardiovascular disease (CVD) have not been reported. METHODS: We enrolled 304 elderly male patients with CVD receiving daily aspirin therapy (>= 75 mg) more than 1 month. Platelet aggregation was measured by light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). The median follow-up time was 1.8 years. The primary outcome was the composite of death, myocardial infarction, unstable angina, stroke and transient ischemic attack. RESULTS: By LTA, 25 (8.2%) of elderly patients were aspirin resistant and 106 (34.9%) patients were semiresponders. According to TEG, 62 patients (20.4%) were found to be resistant to aspirin therapy. Of the 62 patients with aspirin resistance by TEG, 21 patients were aspirin resistant by LTA. Twenty-two of the 106 semiresponders by LTA were aspirin resistant by TEG. Patients with aspirin resistance or aspirin semiresponders were at increased risk of the composite outcome compared with aspirin-sensitive patients by LTA (18.3% vs 9.8%, Hazard ratio (HR) = 1.864, 95% confidence interval (CI): 1.046-3.324 p = 0.039). However, aspirin resistance was not associated with an increased risk of clinical vascular events compared to aspirin-sensitive patients by TEG (17.7% vs 10.9%, p = 0.452). In addition, Cox proportional hazard regression modeling demonstrated that aspirin resistance or semiresponders (HR = 3.050, 95% CI: 1.464-6.354, p = 0.003) and diabetes (HR = 2.055, 95% CI: 1.060-3.981, p = 0.033) were associated with major adverse long-term outcomes. CONCLUSIONS: Aspirin resistance or semiresponders, defined by LTA, are associated with an increased risk of adverse clinical events in elderly male patients with CVD. PMID- 22452803 TI - NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. AB - BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition. MATERIALS AND METHODS: We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual gammaH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well. RESULTS: Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of gammaH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor. CONCLUSIONS: The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy. PMID- 22452805 TI - BaySTDetect: detecting unusual temporal patterns in small area data via Bayesian model choice. AB - Space-time modeling of small area data is often used in epidemiology for mapping chronic disease rates and by government statistical agencies for producing local estimates of, for example, unemployment or crime rates. Although there is typically a general temporal trend, which affects all areas similarly, abrupt changes may occur in a particular area, e.g. due to emergence of localized predictors/risk factor(s) or impact of a new policy. Detection of areas with "unusual" temporal patterns is therefore important as a screening tool for further investigations. In this paper, we propose BaySTDetect, a novel detection method for short-time series of small area data using Bayesian model choice between two competing space-time models. The first model is a multiplicative decomposition of the area effect and the temporal effect, assuming one common temporal pattern across the whole study region. The second model estimates the time trends independently for each area. For each area, the posterior probability of belonging to the common trend model is calculated, which is then used to classify the local time trend as unusual or not. Crucial to any detection method, we provide a Bayesian estimate of the false discovery rate (FDR). A comprehensive simulation study has demonstrated the consistent good performance of BaySTDetect in detecting various realistic departure patterns in addition to estimating well the FDR. The proposed method is applied retrospectively to mortality data on chronic obstructive pulmonary disease (COPD) in England and Wales between 1990 and 1997 (a) to test a hypothesis that a government policy increased the diagnosis of COPD and (b) to perform surveillance. While results showed no evidence supporting the hypothesis regarding the policy, an identified unusual district (Tower Hamlets in inner London) was later recognized to have higher than national rates of hospital readmission and mortality due to COPD by the National Health Service, which initiated various local enhanced services to tackle the problem. Our method would have led to an early detection of this local health issue. PMID- 22452806 TI - Socio-demographic determinants of hearing impairment studied in 103,835 term babies. AB - BACKGROUND: Serious hearing problems appear in approximately one in 1000 newborns. In 2000, the Joint Committee on Infant Hearing defined a list of risk factors for neonatal hearing impairment relating to health, physical characteristics and family history. The aim of this study is to determine which personal, environmental and social factors are associated with the prevalence of congenital hearing impairment (CHI). METHODS: The entire population of 103,835 term newborns in Flanders, Belgium, was tested by a universal neonatal hearing screening (UNHS) programme using automated auditory brainstem responses (AABR). In the case of a positive result, a CHI diagnosis was verified in specialized referral centres. Socio-demographic risk factors were investigated across the entire population to study any relationship with CHI. RESULTS: The prevalence of bilateral CHI of 35 dB nHL (normal hearing level) or more was 0.87/1000 newborns. The sensitivity and specificity of the screening test were 94.02 and 99.96%, respectively. The socio-demographic factors of gender, birth order, birth length, feeding type, level of education and origin of the mother were found to be independent predictors of CHI. CONCLUSIONS: The socio-demographic factors found to be associated with CHI extend the list of classic risk factors as defined by the American Academy of Pediatrics (AAP). Assessment of these additional factors may alert the treating physician to the increased risk of newborn hearing impairment and urge the need for accurate follow-up. Moreover, this extended assessment may improve decision making in medical practice and screening policy. PMID- 22452807 TI - Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. AB - CONTEXT: Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration. OBJECTIVE: To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS). DESIGN, SETTING, AND PARTICIPANTS: Randomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS. INTERVENTION: Intravenous GIK solution (n = 411) or identical-appearing 5% glucose placebo (n = 460) administered by paramedics in the out-of-hospital setting and continued for 12 hours. MAIN OUTCOME MEASURES: The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation. RESULTS: There was no significant difference in the rate of progression to MI among patients who received GIK (n = 200; 48.7%) vs those who received placebo (n = 242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66-1.13; P = .28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40-1.29; P = .27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27-0.85; P = .01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40-1.38; P = .34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27-1.49; P = .29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18-0.82; P = .01). Serious adverse events occurred in 6.8% (n = 28) with GIK vs 8.9% (n = 41) with placebo (P = .26). CONCLUSIONS: Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00091507. PMID- 22452808 TI - Angels of mercy? The legal and professional implications of withdrawal of life sustaining treatment by nurses in England and Wales. AB - In circumstances where life-sustaining treatment appears merely to be drawing out the inevitable, it is usual practice for the healthcare team to withdraw aggressive life-sustaining measures, once agreement is reached with the patient and their family. Common law gives doctors several defences to allegations of criminality or malpractice in taking the key actions that withdraw treatment and result in the patient's death; however, the legal defensibility of nurses undertaking this role has not been explored. In the absence of a specific body of law related to nurses taking the actions that withdraw life-sustaining treatment, I discuss the probable legal response by considering parallel cases. Examining some of the circumstances in which doctors are allowed to take life, I argue that the legal dispensation by which doctors are permitted to perform these tasks rests largely on their identity as doctors rather than any distinctive feature of their activities themselves. This uniqueness means that medical law for nurses is quite distinct from that for doctors. While it may nevertheless give nurses practical exemption from the legal consequences of their actions in withdrawal, it depends upon a judicial view that nurses are instruments of doctors. This judicial position is at odds with nurses' professional responsibilities, which envisage them as independent professionals who are liable for their own actions, inviting potentially adverse consequences from their professional registrar. PMID- 22452809 TI - Depressed fathers' speech to their 3-month-old infants: a study of cognitive and mentalizing features in paternal speech. AB - BACKGROUND: Depression in fathers in the postnatal period is associated with an increased risk of child behaviour problems. A key potential pathway of risk transmission is exposure of the child to negative cognitions and affect in the context of early parenting. This study examines paternal speech during face-to face father-infant interactions at 3 months. METHOD: Currently depressed (n=19) and non-depressed (n=19) fathers were individually matched on age and education. Speech was coded for cognitive biases and mentalizing statements using a modified version of previous measures of maternal speech. Paternal depression was diagnosed using a structured psychiatric interview. RESULTS: Depression in fathers was associated with more speech focused on the paternal experience and less on the infants' experience. Depressed fathers' speech comprised more negative and critical utterances, compared with non-depressed fathers. CONCLUSIONS: Important differences emerge in the speech of fathers who experience depression. Examining negative cognitions in the speech of these fathers as early as 3 months may help in understanding children's risk in relation to paternal psychopathology. PMID- 22452810 TI - A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC TICs) exhibits similar aggressive phenotype to the human disease. AB - BACKGROUND: Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease- recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems. METHODS: To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis. RESULTS: We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC TICs) were significantly more effective at repopulating the mammary glands of naive female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A). CONCLUSIONS: Taken together, we have developed a TNBC-TICs model system based on the 4T1 cells which is a very useful metastasis model with the advantage of being able to be transplanted into immune competent recipients. Our data demonstrates that the TNBC-TICs model system could be a useful tool for studies on the pathogenesis and therapeutic treatment for TNBC. PMID- 22452811 TI - Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case control study. AB - BACKGROUND: The long-term outcome of pregnancy-related venous thrombosis (VT) is not known. OBJECTIVES: To assess predictors and long-term frequency of post thrombotic syndrome (PTS) after pregnancy-related VT. PATIENTS/METHODS: In 2006, 313 women with pregnancy-related VT during 1990-2003 and 353 controls answered a comprehensive questionnaire that included self-reported Villalta score as a measure of PTS. Cases were identified from 18 Norwegian hospitals using the Norwegian Patient Registry and the Medical Birth Registry of Norway. The latter was used to select as possible controls women who gave birth at the same time as a case. Thirty-nine patients and four controls were excluded because of VT outside the lower limbs/lungs or missing Villalta scores. Two hundred and four patients had DVT in the lower limb and 70 had pulmonary embolism (PE). The control group comprised 349 women naive for VT at the time of the index pregnancy. RESULTS: Forty-two per cent of cases with DVT in the lower limb, compared with 24% of cases with PE and 10% of controls, reported a Villalta score of >= 5. Severe PTS (Villalta score of >= 15) was reported among 7%, 4% and 1%. Proximal postnatal, but not antenatal, thrombosis was a strong predictor of PTS with an adjusted odds ratio of 6.3 (95% confidence interval, 2.0-19.8; P = 0.002). Daily smoking before the index pregnancy and age above 33 years at event were independent predictors for post-thrombotic syndrome. CONCLUSIONS: PTS is a common long-term complication after pregnancy-related DVT. Proximal postnatal thrombosis, smoking and higher age were independent predictors of the development of PTS. PMID- 22452812 TI - Phylogenetic and functional diversity of metagenomic libraries of phenol degrading sludge from petroleum refinery wastewater treatment system. AB - In petrochemical refinery wastewater treatment plants (WWTP), different concentrations of pollutant compounds are received daily in the influent stream, including significant amounts of phenolic compounds, creating propitious conditions for the development of particular microorganisms that can rapidly adapt to such environment. In the present work, the microbial sludge from a refinery WWTP was enriched for phenol, cloned into fosmid vectors and pyrosequenced. The fosmid libraries yielded 13,200 clones and a comprehensive bioinformatic analysis of the sequence data set revealed a complex and diverse bacterial community in the phenol degrading sludge. The phylogenetic analyses using MEGAN in combination with RDP classifier showed a massive predominance of Proteobacteria, represented mostly by the genera Diaphorobacter, Pseudomonas, Thauera and Comamonas. The functional classification of phenol degrading sludge sequence data set generated by MG-RAST showed the wide metabolic diversity of the microbial sludge, with a high percentage of genes involved in the aerobic and anaerobic degradation of phenol and derivatives. In addition, genes related to the metabolism of many other organic and xenobiotic compounds, such as toluene, biphenyl, naphthalene and benzoate, were found. Results gathered herein demonstrated that the phenol degrading sludge has complex phylogenetic and functional diversities, showing the potential of such community to degrade several pollutant compounds. This microbiota is likely to represent a rich resource of versatile and unknown enzymes which may be exploited for biotechnological processes such as bioremediation. PMID- 22452813 TI - Isolation and identification of a distinct strain of Culex Flavivirus from mosquitoes collected in Mainland China. AB - BACKGROUND: Culexflavivirus (CxFV) is an insect specific virus that has been isolated from Culexpipiens, Culexquinquefasciatus, Culextritaeniorhynchus and other Culex mosquitoes. It is a novel flavivirus isolated in Asia, North America, Central America and Africa. Phylogenetic analysis indicates that, based on the envelope gene (E gene) sequence, the worldwide CxFV strains can be divided into two genotypes. RESULT: A virus (SDDM06-11) was isolated from Culexpipiens collected in Shandong Province, China in 2006. The strain caused cytopathic effect (CPE) in Aedesalbopictus (C6/36) cells by 3 days post-infection and immunofluorescence assay (IFA) showed a reaction with Japanese encephalitis virus (JEV) polyclonal antibodies. Phylogenetic analysis of the E gene sequence showed CxFV formed two genotypes with the SDDM06-11 strain assigned to genotype 1. Analysis of the E gene nucleotide homology showed the virus possessed characteristic amino acids at specific sites. The nucleotide homology of the open reading frame (ORF) was 94.8%-95.1% between SDDM06-11 and isolates from Japan, Iowa and Texas, and 90.2%-90.5% between SDDM06-11 and isolates from Uganda and Mexico. CONCLUSION: In this paper we report the first isolation and identification of an isolate of CxFV in mainland China. Phylogenetic analysis indicates the isolate belongs to genotype 1. Our findings provide insight into the occurrence of CxFV in Culex mosquito populations and its distribution on a global scale. PMID- 22452814 TI - Fuzheng Huayu recipe prevents nutritional fibrosing steatohepatitis in mice. AB - BACKGROUND: Fuzheng Huayu recipe (FZHY), a compound of Chinese herbal medicine, was reported to improve liver function and fibrosis in patients with hepatitis B virus infection. However, its effect on nutritional fibrosing steatohepatitis is unclear. We aimed to elucidate the role and molecular mechanism of FZHY on this disorder in mice. METHODS: C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrosing steatohepatitis. FZHY and/or heme oxygenase-1 (HO-1) chemical inducer (hemin) were administered to mice, respectively. The effect of FZHY was assessed by comparing the severity of hepatic injury, levels of hepatic lipid peroxides, activation of hepatic stellate cells (HSCs) and the expression of oxidative stress, inflammatory and fibrogenic related genes. RESULTS: Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, necro-inflammation and fibrosis. Administration of FZHY or hemin significantly lowered serum levels of alanine aminotransferase, aspartate aminotransferase, reduced hepatic oxidative stress and ameliorated hepatic inflammation and fibrosis. An additive effect was observed in mice fed MCD supplemented with FZHY or/and hemin. These effects were associated with down-regulation of pro-oxidative stress gene cytochrome P450 2E1, up-regulation of anti-oxidative gene HO-1; suppression of pro-inflammation genes tumor necrosis factor alpha and interleukin-6; and inhibition of pro-fibrotic genes including alpha-smooth muscle actin, transforming growth factor beta 1, collagen type I (Col-1) and Col-3. CONCLUSIONS: Our study demonstrated the protective role of FZHY in ameliorating nutritional fibrosing steatohepatitis. The effect was mediated through regulating key genes related to oxidative stress, inflammation and fibrogenesis. PMID- 22452815 TI - Steroid-like signalling by interferons: making sense of specific gene activation by cytokines. AB - Many cytokines, hormones and growth factors use the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway for cell signalling and specific gene activation. In the classical model, ligand is said to interact solely with the receptor extracellular domain, which triggers JAK activation of STATs at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific gene activation. Given the limited number of STATs (seven) and the activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on IFNgamma (interferon gamma), we have shown that ligand, receptor and activated JAKs are involved in nuclear events that are associated with specific gene activation, where the receptor subunit IFNGR1 (IFNgamma receptor 1) functions as a transcription/co-transcription factor and the JAKs are involved in key epigenetic events. RTKs (receptor tyrosine kinases) such as EGFR [EGF (epidermal growth factor) receptor] and FGFR [FGF (fibroblast growth factor) receptor] also undergo nuclear translocation in association with their respective ligands. EGFR and FGFR, like IFNGR1, have been shown to function as transcription/co-transcription factors. The RTKs also regulate other kinases that have epigenetic effects. Our IFNgamma model, as well as the RTKs EGFR and FGFR, have similarities to that of steroid receptor signalling. These systems consist of ligand-receptor-co-activator complexes at the genes that they activate. The co activators consist of transcription factors and kinases, of which the latter play an important role in the associated epigenetics. It is our view that signalling by cytokines such as IFNgamma is but a variation of specific gene activation by steroid hormones. PMID- 22452816 TI - Virology and molecular pathogenesis of HPV (human papillomavirus)-associated oropharyngeal squamous cell carcinoma. AB - The current literature fully supports HPV (human papillomavirus)-associated OPSCC (oropharyngeal squamous cell carcinoma) as a unique clinical entity. It affects an unambiguous patient population with defined risk factors, has a genetic expression pattern more similar to cervical squamous cell carcinoma than non-HPV associated HNSCC (head and neck squamous cell carcinoma), and may warrant divergent clinical management compared with HNSCC associated with traditional risk factors. However, a detailed understanding of the molecular mechanisms driving these differences and the ability to exploit this knowledge to improve clinical management of OPSCC has not yet come to fruition. The present review summarizes the aetiology of HPV-positive (HPV+) OPSCC and provides a detailed overview of HPV virology and molecular pathogenesis relevant to infection of oropharyngeal tissues. Methods of detection and differential gene expression analyses are also summarized. Future research into mechanisms that mediate tropism of HPV to oropharyngeal tissues, improved detection strategies and the pathophysiological significance of altered gene and microRNA expression profiles is warranted. PMID- 22452818 TI - Mousing around with caspases and IAPs. AB - In a paper in this issue of the Biochemical Journal that questions the role of c IAP1 (cellular inhibitor of apoptosis 1) in inflammation, new results from the Duckett laboratory remind us of the importance of truly knowing the mice we depend on. It turns out that c-IAP1 is tightly linked to caspase 11 and cannot be segregated by recombination. This disturbing result implies that immune functions ascribed to c-IAP1 may be due to the caspase 11 mutation that is co-inherited with the locus. PMID- 22452819 TI - Microbial resource management of one-stage partial nitritation/anammox. AB - About 30 full-scale partial nitritation/anammox plants are established, treating mostly sewage sludge reject water, landfill leachate or food processing digestate. Although two-stage and one-stage processes each have their advantages, the one-stage configuration is mostly applied, termed here as oxygen-limited autotrophic nitrification/denitrification (OLAND), and is the focus of this review. The OLAND application domain is gradually expanding, with technical-scale plants on source-separated domestic wastewater, pre-treated manure and sewage, and liquors from organic waste bioenergy plants. A 'microbial resource management' (MRM) OLAND framework was elaborated, showing how the OLAND engineer/operator (1: input) can design/steer the microbial community (2: biocatalyst) to obtain optimal functionality (3: output). In the physicochemical toolbox (1), design guidelines are provided, as well as advantages of different reactor technologies. Particularly the desirable aeration regime, feeding regime and shear forces are not clear yet. The development of OLAND trickling filters, membrane bioreactors and systems with immobilized biomass is awaited. The biocatalyst box (2) considers 'Who': biodiversity and its dynamic patterns, 'What': physiology, and 'Where': architecture creating substrate gradients. Particularly community dynamics and extracellular polymeric substances (EPS) still require insights. Performant OLAND (3) comprises fast start-up (storage possibility; fast growth of anammox bacteria), process stability (endured biomass retention; stress resilience), reasonable overall costs, high nitrogen removal efficiency and a low environmental footprint. Three important OLAND challenges are elaborated in detailed frameworks, demonstrating how to maximize nitrogen removal efficiency, minimize NO and N(2)O emissions and obtain through OLAND a plant-wide net energy gain from sewage treatment. PMID- 22452820 TI - Comparative analysis of Mycobacterium and related Actinomycetes yields insight into the evolution of Mycobacterium tuberculosis pathogenesis. AB - BACKGROUND: The sequence of the pathogen Mycobacterium tuberculosis (Mtb) strain H37Rv has been available for over a decade, but the biology of the pathogen remains poorly understood. Genome sequences from other Mtb strains and closely related bacteria present an opportunity to apply the power of comparative genomics to understand the evolution of Mtb pathogenesis. We conducted a comparative analysis using 31 genomes from the Tuberculosis Database (TBDB.org), including 8 strains of Mtb and M. bovis, 11 additional Mycobacteria, 4 Corynebacteria, 2 Streptomyces, Rhodococcus jostii RHA1, Nocardia farcinia, Acidothermus cellulolyticus, Rhodobacter sphaeroides, Propionibacterium acnes, and Bifidobacterium longum. RESULTS: Our results highlight the functional importance of lipid metabolism and its regulation, and reveal variation between the evolutionary profiles of genes implicated in saturated and unsaturated fatty acid metabolism. It also suggests that DNA repair and molybdopterin cofactors are important in pathogenic Mycobacteria. By analyzing sequence conservation and gene expression data, we identify nearly 400 conserved noncoding regions. These include 37 predicted promoter regulatory motifs, of which 14 correspond to previously validated motifs, as well as 50 potential noncoding RNAs, of which we experimentally confirm the expression of four. CONCLUSIONS: Our analysis of protein evolution highlights gene families that are associated with the adaptation of environmental Mycobacteria to obligate pathogenesis. These families include fatty acid metabolism, DNA repair, and molybdopterin biosynthesis. Our analysis reinforces recent findings suggesting that small noncoding RNAs are more common in Mycobacteria than previously expected. Our data provide a foundation for understanding the genome and biology of Mtb in a comparative context, and are available online and through TBDB.org. PMID- 22452821 TI - A simple quality assurance test tool for the visual verification of light and radiation field congruent using electronic portal images device and computed radiography. AB - BACKGROUND: The radiation field on most megavoltage radiation therapy units are shown by a light field projected through the collimator by a light source mounted inside the collimator. The light field is traditionally used for patient alignment. Hence it is imperative that the light field is congruent with the radiation field. METHOD: A simple quality assurance tool has been designed for rapid and simple test of the light field and radiation field using electronic portal images device (EPID) or computed radiography (CR). We tested this QA tool using Varian PortalVision and Elekta iViewGT EPID systems and Kodak CR system. RESULTS: Both the single and double exposure techniques were evaluated, with double exposure technique providing a better visualization of the light-radiation field markers. The light and radiation congruency could be detected within 1 mm. This will satisfy the American Association of Physicists in Medicine task group report number 142 recommendation of 2 mm tolerance. CONCLUSION: The QA tool can be used with either an EPID or CR to provide a simple and rapid method to verify light and radiation field congruence. PMID- 22452822 TI - Terminal sterilization of BisGMA-TEGDMA thermoset materials and their bioactive surfaces by supercritical CO2. AB - The development of biomaterials endowed with bioactive features relies on a simultaneous insight into a proper terminal sterilization process. FDA recommendations on sterility of biomaterials are very strict: a sterility assurance level (SAL) of 10(-6) must be guaranteed for biomaterials to be used in human implants. In the present work, we have explored the potential of supercritical CO(2) (scCO(2)) in the presence of H(2)O(2) as a low-temperature sterilization process for thermoset materials and their bioactive surfaces. Different conditions allowing for terminal sterilization have been screened and a treatment time-amount of H(2)O(2) relationship proposed. The selected terminal sterilization conditions did not notably modify the mechanical properties of the thermoset nor of their fiber-reinforced composites. This was confirmed by MUCT analyses performed prior to and after the treatment. On the contrary, terminal sterilization in the presence of H(2)O(2) induced a slight decrease in the surface hardness. The treatment of the thermoset material with scCO(2) led to a reduction in the residual unreacted monomers content, as determined by means of high performance liquid chromatography (HPLC) analyses. Finally, it was found that a thermoset coated with a polysaccharide layer containing silver nanoparticles maintained a very high antimicrobial efficacy even after the scCO(2)-based terminal sterilization. PMID- 22452823 TI - Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. AB - BACKGROUND: Inhibitor development is influenced by several factors and the type of factor VIII (FVIII) products may play a role. OBJECTIVES: In order to explore such a role, we designed a cohort study whose novelty resides in the classification of products not only according to the source of FVIII (plasmatic, pd, or recombinant, r) but also to their degree of purity (expressed as specific activity). PATIENTS/METHODS: Treatment data up to inhibitor development or 150 exposure days were collected in 377 patients with hemophilia A. RESULTS: Inhibitors developed in 111 patients (29%; 96 high-responders, 25%). The cumulative incidence was progressively higher from patients treated with low/intermediate-purity pdFVIII compared with those treated with high-purity pd and rFVIII. The adjusted hazard ratio of inhibitor development was 4.9 with rFVIII and 2.0 with high-purity pdFVIII (95% CI, 2.9-8.3 and 1.1-4.0), taking as reference low/intermediate-purity pdFVIII. There was no difference in the frequency of inhibitor testing between treatment groups. Sensitivity analyses (in patients who never switched product type, previously untreated patients, those treated on-demand and those with high-risk F8 mutations) confirmed an increased inhibitor risk with rFVIII and high-purity pdFVIII. CONCLUSIONS: This study shows that the degree of purity of FVIII products influences inhibitor development independently from other risk factors, and emphasizes that differences exist within pdFVIII products. PMID- 22452824 TI - Meningoencephalitis associated with Carnobacterium maltaromaticum-like bacteria in stranded juvenile salmon sharks (Lamna ditropis). AB - Juvenile salmon sharks beach yearly along the California coast, primarily during late summer and early fall. Fresh, frozen, and formalin-fixed tissues from 19 stranded salmon sharks were collected for examination. Histopathology revealed meningitis or meningoencephalitis in 18 of 19 shark brains with intralesional bacteria observed in 6 of the affected brains. Bacterial culture of fresh or frozen brain, liver, and/or heart blood from 13 sharks yielded pure cultures characterized molecularly and/or biochemically as belonging to the genus Carnobacterium. The 16s ribosomal DNA sequence of 7 tissue isolates from 7 separate sharks was 99% homologous to C. maltaromaticum (GenBank FJ656722.1). Sequence of the large ribosomal DNA intergenic spacer region (ISR) was 97% homologous to C. maltaromaticum (AF374295.1). This is the first report of Carnobacterium infection in any shark species, and the authors posit that brain infection caused by Carnobacterium is a significant cause of morbidity and mortality in juvenile salmon sharks found stranded along the Pacific coast of California. PMID- 22452825 TI - Input frequency and lexical variability in phonological development: a survival analysis of word-initial cluster production. AB - Although it has been often hypothesized that children learn to produce new sound patterns first in frequently heard words, the available evidence in support of this claim is inconclusive. To re-examine this question, we conducted a survival analysis of word-initial consonant clusters produced by three children in the Providence Corpus (0 ; 11-4 ; 0). The analysis took account of several lexical factors in addition to lexical input frequency, including the age of first production, production frequency, neighborhood density and number of phonemes. The results showed that lexical input frequency was a significant predictor of the age at which the accuracy level of cluster production in each word first reached 80%. The magnitude of the frequency effect differed across cluster types. Our findings indicate that some of the between-word variance found in the development of sound production can indeed be attributed to the frequency of words in the child's ambient language. PMID- 22452826 TI - Heterologous expression of Oenococcus oeni malolactic enzyme in Lactobacillus plantarum for improved malolactic fermentation. AB - Lactobacillus plantarum is involved in a multitude of food related industrial fermentation processes including the malolactic fermentation (MLF) of wine. This work is the first report on a recombinant L. plantarum strain successfully conducting MLF. The malolactic enzyme (MLE) from Oenococcus oeni was cloned into the lactobacillal expression vector pSIP409 which is based on the sakacin P operon of Lactobacillus sakei and expressed in the host strain L. plantarum WCFS1. Both recombinant and wild-type L. plantarum strains were tested for MLF using a buffered malic acid solution in absence of glucose. Under the conditions with L-malic acid as the only energy source and in presence of Mn2+ and NAD+, the recombinant L. plantarum and the wild-type strain converted 85% (2.5 g/l) and 51% (1.5 g/l), respectively, of L-malic acid in 3.5 days. Furthermore, the recombinant L. plantarum cells converted in a modified wine 15% (0.4 g/l) of initial L-malic acid concentration in 2 days. In conclusion, recombinant L. plantarum cells expressing MLE accelerate the malolactic fermentation. PMID- 22452827 TI - UK ethnicity data collection for healthcare statistics: the South Asian perspective. AB - BACKGROUND: Ethnicity data collection has been proven to be important in health care but despite government initiatives remains incomplete and mostly un validated in the UK. Accurate self-reported ethnicity data would enable experts to assess inequalities in health and access to services and help to ensure resources are targeted appropriately. The aim of this paper is to explore the reasons for the observed gap in ethnicity data by examining the perceptions and experiences of healthy South Asian volunteers. South Asians are the largest ethnic minority group accounting for 50% of all ethnic minorities in the UK 2001 census. METHODS: Five focus groups, conducted by trained facilitators in the native language of each group, recruited 36 South Asian volunteers from local community centres and places of worship. The topic guide focused on five key areas:1) general opinions on the collection of ethnicity, 2) experiences of providing ethnicity information, 3) categories used in practice, 4) opinions of other indicators of ethnicity e.g. language, religion and culture and 5) views on how should this information be collected. The translated transcripts were analysed using a qualitative thematic approach. RESULTS: The findings of this Cancer Research UK commissioned study revealed that participants felt that accurate recording of ethnicity data was important in healthcare with several stating the increased prevalence of certain diseases in minority ethnic groups as an appropriate justification to improve this data. The overwhelming majority raised no objections to providing this data when the purpose of data collection is fully explained. CONCLUSIONS: This study confirmed that the collection of patients' ethnicity data is deemed important by potential patients but there remains uncertainty and unease as to how the data may be used. A common theme running through the focus groups was the willingness to provide these data, strongly accompanied by a desire to have more information with regard to its use. PMID- 22452828 TI - Evaluation of the immunogenicity of liposome encapsulated HVR1 and NS3 regions of genotype 3 HCV, either singly or in combination. AB - BACKGROUND: Hepatitis C virus displays a high rate of mutation and exists as a quasispecies in infected patients. In the absence of an effective universal vaccine, genotype-specific vaccine development represents an alternative. We have attempted to develop a genotype 3 based, liposome encapsulated HCV vaccine with hypervariable region-1 (HVR1) and non-structural region-3 (NS3) components. RESULTS: HCV RNA extracted from serum samples of 49 chronically infected patients was PCR amplified to obtain HVR1 region. These amplified products were cloned to obtain 20 clones per sample in order to identify the quasispecies pattern. The HVR1 consensus sequence, along with three variants was reverse transcribed to obtain peptides. The peptides were checked for immunoreactivity individually, as a pool or as a single peptide tetramer interspersed with four glycine residues. Anti-HCV positivity varied from 42.6% (tetramer) to 92.2% (variant-4) when 115 anti-HCV positive sera representing genotypes 1, 3, 4 and 6 were screened. All the 95 anti-HCV negatives were scored negative by all antigens. Mice were immunized with different liposome encapsulated or Al(OH)3 adjuvanted formulations of HVR1 variants and recombinant NS3 protein, and monitored for anti-HVR1 and anti-NS3 antibody titres, IgG isotypes and antigen specific cytokine levels. A balanced Th1/Th2 isotyping response with high antibody titres was observed in most of the liposome encapsulated antigen groups. The effect of liposomes and aluminium hydroxide on the expression of immune response genes was studied using Taqman Low Density Array. Both Th1 (IFN-gamma, Il18) and Th2 (Il4) genes were up regulated in the liposome encapsulated HVR1 variant pool-NS3 combination group. In-vitro binding of the virus to anti-HVR1 antibodies was demonstrated. CONCLUSION: The optimum immunogen was identified to be combination of peptides of HVR1 consensus sequence and its variants along with pNS3 encapsulated in liposomes, which could generate both cellular and humoral immune responses in mice deserving further evaluation in a suitable cell culture system/non-human primate model. PMID- 22452829 TI - Percutaneous treatment of patients with heart diseases: selection, guidance and follow-up. A review. AB - Aortic stenosis and mitral regurgitation, patent foramen ovale, interatrial septal defect, atrial fibrillation and perivalvular leak, are now amenable to percutaneous treatment. These percutaneous procedures require the use of Transthoracic (TTE), Transesophageal (TEE) and/or Intracardiac echocardiography (ICE). This paper provides an overview of the different percutaneous interventions, trying to provide a systematic and comprehensive approach for selection, guidance and follow-up of patients undergoing these procedures, illustrating the key role of 2D echocardiography. PMID- 22452830 TI - Relationships between body weight and milk yield during the early postpartum period and bull and technician and the reproductive performance of high producing dairy cows. AB - The aim of this study was to evaluate the effect of body weight (BW) change during the early postpartum period and BW on day 50 post partum on the subsequent expression of estrus and fertility at first insemination before day 90 post partum. The data were derived from 1036 postpartum cows reaching 90 days in milk. The following data were recorded for each animal: lactation number, daily milk production at day 50 post partum, calving date, days in milk at estrus and at AI, insemination date, insemination number, inseminating bull, AI technician and body weight at calving, at day 50 post partum and at AI. Of the 1036 cows registered, 817 (78.9%) showed first estrus before day 90 post partum and were inseminated. Using logistic regression procedures and based on the odds ratio a one unit (kg) increase in the daily milk production at day 50 post partum and a one unit (kg) decrease in the BW between calving and day 50 post partum were related to a 1.03 fold increase and a 0.97-fold decrease in the estrus expression rate before day 90 post partum, respectively. Of the 817 cows inseminated before day 90 post partum, 437 became pregnant (53.5%). A one unit increase in the BW at day 50 post partum produced a 1.003-fold increase in the early fertility rate. Pregnancy rate before day 90 was also influenced by the season at calving, bull providing semen and technician. In conclusion, the register of BW during the postpartum period may be a useful tool for evaluating the nutritional status and its relationship with the subsequent reproductive efficiency in dairy cows. PMID- 22452831 TI - Successful production of offspring using cryopreserved sperm via nonsurgical artificial insemination in rats. AB - In rats, artificial insemination (AI) is surgically performed as a general tool to obtain offspring using cryopreserved spermatozoa. Nonsurgical AI is a more desirable technology because it does not require any surgical procedures. However, there has never been a successful nonsurgical AI since frozen-thawed rat spermatozoa show low motility. We show here for the first time successful nonsurgical AI in rats using oxytocin treatment. Intraperitoneal injection of oxytocin (1/800 IU) immediately before nonsurgical AI significantly increased the number of sperm collected from the oviducts compared with that without oxytocin treatment. Therefore, to obtain pups, oxytocin was intraperitoneally injected into females mated with vasectomized males, and the rats were then used for nonsurgical AI. Seven of the 12 oxytocin-treated rats became pregnant after nonsurgical AI, and 37 pups were obtained. Only one rat (1/13) without oxytocin treatment was pregnant after nonsurgical AI, and only 1 pup was delivered. These results show success for the first time in obtaining offspring using frozen thawed rat spermatozoa via nonsurgical AI. Our results also suggest the possibility that oxytocin treatment is effective for improvement of nonsurgical AI even in other species. PMID- 22452832 TI - Ideal cardiovascular health in childhood and cardiometabolic outcomes in adulthood: the Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: The American Heart Association (AHA) defined a new concept, cardiovascular health, and determined metrics needed to monitor it over time as part of its 2020 Impact Goal definition. Ideal cardiovascular health is defined by the presence of both ideal health behaviors and ideal health factors. The applicability of this concept to a cohort of children and its relationship with cardiometabolic outcomes in adulthood has not been reported. METHODS AND RESULTS: The sample comprised 856 participants aged 12 to 18 years (mean age 15.0 years) from the Cardiovascular Risk in Young Finns Study cohort. Participants were followed up for 21 years since baseline (1986) and had data available concerning health factors and behaviors in childhood and cardiometabolic outcomes in adulthood (2007). The number of ideal cardiovascular health metrics present in childhood was associated with reduced risk of hypertension (odds ratio [95% confidence interval] 0.66 [0.52-0.85], P<0.001), metabolic syndrome (0.66 [0.52 0.77], P<0.001), high low-density lipoprotein cholesterol (0.66 [0.52-0.85], P=0.001), and high-risk carotid artery intima-media thickness (0.75 [0.60-0.94], P=0.01) in adulthood. All analyses were age and sex adjusted, and the results were not altered after additional adjustment with socioeconomic status. CONCLUSIONS: The number of ideal cardiovascular health metrics present in childhood predicts subsequent cardiometabolic health in adulthood. Our findings suggest that pursuit of ideal cardiovascular health in childhood is important to prevent cardiometabolic outcomes in adulthood. PMID- 22452833 TI - Ideal cardiovascular health: start young, finish strong. PMID- 22452834 TI - SO(2) protects the amino nitrogen metabolism of Saccharomyces cerevisiae under thermal stress. AB - Thermal stress conditions during alcoholic fermentation modify yeasts' plasma membrane since they become more hyperfluid, which results in a loss of bilayer integrity. In this study, the influence of elevated temperatures on nitrogen metabolism of a Saccharomyces cerevisiae strain was studied, as well as the effect of different concentrations of SO(2) on nitrogen metabolism under thermal stress conditions. The results obtained revealed that amino nitrogen consumption was lower in the fermentation sample subjected to thermal stress than in the control, and differences in amino acid consumption preferences were also detected, especially at the beginning of the fermentation. Under thermal stress conditions, among the three doses of SO(2) studied (0, 35, 70 mg l(-1) SO(2) ), the highest dose was observed to favour amino acid utilization during the fermentative process, whereas sugar consumption presented higher rates at medium doses. PMID- 22452835 TI - Effects of probiotics and antibiotics on the intestinal homeostasis in a computer controlled model of the large intestine. AB - BACKGROUND: Antibiotic associated diarrhea and Clostridium difficile infection are frequent complications of broad spectrum antibiotic therapy. Probiotic bacteria are used as therapeutic and preventive agents in these disorders, but the exact functional mechanisms and the mode of action are poorly understood. The effects of clindamycin and the probiotic mixture VSL#3 (containing the 8 bacterial strains Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei and Lactobacillus delbrueckii subsp. Bulgaricus) consecutively or in combination were investigated and compared to controls without therapy using a standardized human fecal microbiota in a computer-controlled in vitro model of large intestine. Microbial metabolites (short chain fatty acids, lactate, branched chain fatty acids, and ammonia) and the intestinal microbiota were analyzed. RESULTS: Compared to controls and combination therapy, short chain fatty acids and lactate, but also ammonia and branched chain fatty acids, were increased under probiotic therapy. The metabolic pattern under combined therapy with antibiotics and probiotics had the most beneficial and consistent effect on intestinal metabolic profiles. The intestinal microbiota showed a decrease in several indigenous bacterial groups under antibiotic therapy, there was no significant recovery of these groups when the antibiotic therapy was followed by administration of probiotics. Simultaneous application of anti- and probiotics had a stabilizing effect on the intestinal microbiota with increased bifidobacteria and lactobacilli. CONCLUSIONS: Administration of VSL#3 parallel with the clindamycin therapy had a beneficial and stabilizing effect on the intestinal metabolic homeostasis by decreasing toxic metabolites and protecting the endogenic microbiota from destruction. Probiotics could be a reasonable strategy in prevention of antibiotic associated disturbances of the intestinal homeostasis and disorders. PMID- 22452836 TI - The number of ophthalmologists in practice and training worldwide: a growing gap despite more than 200,000 practitioners. AB - BACKGROUND/AIMS: To assess the current number of ophthalmologists practicing worldwide in 2010 and to create a system for maintaining, collecting and improving the accuracy of data on ophthalmologists per population, ophthalmologists performing surgery, growth rate of the profession, and the number of residents in training. METHODS: Between March 2010 and April 2010, the International Council of Ophthalmology emailed a standardised survey of 12 questions to 213 global ophthalmic societies. Missing data and additional information were gathered from direct correspondences with ophthalmologist contacts. RESULTS: The total number of ophthalmologists reported was 204,909. Data are presented for 193 countries. Information was obtained from 67 countries on the number of ophthalmologists doing surgery, entering practice, leaving practice, rate of growth and resident training. CONCLUSION: The survey results show that despite over 200,000 ophthalmologists worldwide, there is currently a significant shortfall of ophthalmologists in developing countries. Furthermore, although the number of practitioners is increasing in developed countries, the population aged 60+ is growing at twice the rate of the profession. To meet this widening gap between need and supply, it is necessary to aggressively train eye care teams now to alleviate the current and anticipated deficit of ophthalmologists worldwide. PMID- 22452837 TI - An economic perspective on childhood obesity: recent findings on cost of illness and cost effectiveness of interventions. AB - OBJECTIVE: This review aims to put an economic perspective on childhood and adolescent obesity by providing an overview on the latest literature on obesity related costs and the cost effectiveness of interventions to prevent or manage the problem. METHODS: The review is based on a comprehensive PubMed/Medline search performed in October 2011. RESULTS: Findings on the economic burden of childhood obesity are inconclusive. Considering the different cost components and age groups, most but not all studies found excess health care costs for obese compared with normal-weight peers. The main limitations relate to short study periods and the strong focus on health care costs, neglecting other components of the economic burden of childhood obesity. The results of the economic evaluations of childhood and adolescent obesity programs support the expectation that preventive and management interventions with acceptable cost effectiveness do exist. Some interventions may even be cost saving. However, owing to the differences in various methodologic aspects, it is difficult to compare preventive and treatment approaches in their cost effectiveness or to determine the most cost-effective timing of preventive interventions during infancy and adolescence. CONCLUSION: To design effective public policies against the obesity epidemic, a better understanding and a more precise assessment of the health care costs and the broader economic burden are necessary but, critically, depend on the collection of additional longitudinal data. The economic evaluation of childhood obesity interventions poses various methodologic challenges, which should be addressed in future research to fully use the potential of economic evaluation as an aid to decision making. PMID- 22452838 TI - Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. AB - BACKGROUND: Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH). METHODS: Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected. RESULTS: We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype. CONCLUSION: This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling. PMID- 22452839 TI - Polystyrenesulfonate-catalyzed synthesis of novel pyrroles through Paal-Knorr reaction. AB - BACKGROUND: The classical Paal-Knorr reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful pyrrole derivatives. RESULTS: Polystyrenesulfonate catalyzed simple synthesis of substituted pyrroles following Paal-Knorr reaction has been accomplished with an excellent yield in aqueous solution. This method also produces pyrroles with multicyclic polyaromatic amines. CONCLUSIONS: The present procedure for the synthesis of N-polyaromatic substituted pyrroles will find application in the synthesis of potent biologically active molecules. PMID- 22452840 TI - A novel prospective three-dimensional analysis of nasolabial fold augmentation. AB - BACKGROUND: There are many products approved for aesthetic soft tissue augmentation. Despite this abundance, there is limited objective data regarding safety, longevity, and complication rates. Instead, most reports rely on subjective measures to report volume changes and outcomes, making product comparison difficult. OBJECTIVES: The authors developed and validated a mathematical model to prospectively calculate and analyze three-dimensional (3D) volumetric changes associated with nasolabial fold augmentation based on human acellular dermis. METHODS: Seven consecutive patients were included in this prospective review. The patients underwent nasolabial fold treatment with BellaDerm (Musculoskeletal Transplant Foundation, Edison, NJ), administered by a single surgeon. 3D photographs were obtained and analyzed with a novel mathematical model to determine absolute volumetric changes and objective longevity. RESULTS: Mean preoperative nasolabial fold volume was 0.17 mL. The mean one-, three-, and six-month postoperative fill volumes were 0.35, 0.19, and 0.07 mL, respectively. Fill volumes and contour changes returned to baseline by 24 weeks postoperatively in the majority of patients. CONCLUSIONS: The mathematical model utilized in this study provided prospective and objective data regarding longevity and volumetric changes associated with nasolabial fold augmentation. The analysis demonstrated minimal objective filler permanence beyond six months, with peak volume enhancement between one and three months. Adoption of objective 3D mathematical metrics into the assessment of soft tissue filler outcomes is critical to obtaining more accurate product-to-product comparisons. PMID- 22452841 TI - Comparison of five commonly-available, lidocaine-containing topical anesthetics and their effect on serum levels of lidocaine and its metabolite monoethylglycinexylidide (MEGX). AB - BACKGROUND: Topical anesthetics are commonly applied for a variety of indications. Several lidocaine-containing topical anesthetics are available for purchase over the counter (OTC). Recently, the authors' group has shown that there is great interindividual discrepancy in the manner in which lidocaine is absorbed and metabolized for even a single OTC product. OBJECTIVES: The authors compare five commonly-available lidocaine preparations and their levels of absorption when applied to the face. Three of the preparations are available OTC; two require prescriptions and were compounded in a pharmacy. METHODS: Twenty-five subjects enrolled in this Institutional Review Board-approved study were randomly assigned to one of five groups. The five topical anesthetics were LMX-4 (4% lidocaine; Biopelle/Ferndale Laboratories, Ferndale, Michigan), Topicaine (4% lidocaine; Ebsa Laboratories, Jupiter, Florida), 2.5% lidocaine/2.5% prilocaine (generic EMLA preparation; High Tech Pharmaceuticals, Amityville, New York), LET (4% lidocaine, 1:2000 epinephrine, and 0.5% tetracaine), and BLT (20% benzoncaine, 6% lidocaine, and 4% tetracaine). After a patch test for adverse reactions, the topical anesthetic was applied to each patient's face and neck and covered with an occlusive dressing for 60 minutes. Blood was drawn at 90, 120, 150, 240, and 480 minutes to measure serum levels of lidocaine and monoethylglycinexylidide (MEGX). RESULTS: The average age of the 17 women and eight men included in the study was 26 years (range, 22-62 years), and the average weight was 70.9 kg (range, 46.4-96.4 kg). The OTC preparations had the highest serum lidocaine and MEGX levels. Topicaine had the greatest serum levels of individual lidocaine absorption (0.808 ug/mL), followed by generic EMLA (0.72 ug/mL), LMX-4 (0.44 ug/mL), BLT (0.17 ug/mL), and LET (0.13 ug/mL). On average, Topicaine had the highest serum lidocaine and MEGX levels: 0.438 ug/mL and 0.0678 ug/mL, respectively. There were significant interindividual differences between the serum levels of MEGX and lidocaine in all groups except LET (P<.0001). There were significant differences between the 4% lidocaine-containing preparations (P=.0439); the 2.5% preparation had a greater absorption than the 4% lidocaine containing preparation and the 6% lidocaine preparation (P=.0016). There were three adverse reactions in patients who received OTC preparations, one of which resulted in postinflammatory hyperpigmentation. CONCLUSIONS: This study demonstrates that although topical anesthetics are considered safe, some individuals have unpredictably high absorption levels. This study also demonstrates that the concentration of lidocaine, the formulation of the drug, and the individual patient all have significant effects on serum levels of lidocaine. The authors recommend that even OTC topical anesthetics be used under the supervision of a healthcare professional to avoid adverse toxic effects and, in rare cases, death. LEVEL OF EVIDENCE: 2. PMID- 22452842 TI - Equivalent effects of topically-delivered adipose-derived stem cells and dermal fibroblasts in the ischemic rabbit ear model for chronic wounds. AB - BACKGROUND: Mesenchymal stem cells (MSC) have garnered considerable attention in plastic surgery. Via proliferation/differentiation or the elaboration of paracrine factors, MSC and their adipose-derived stem cell counterparts (ADSC) have been suggested to stimulate cutaneous wound healing. Previous reports have been limited by a lack of appropriate controls and the lack of a clinically relevant context or ability to extrapolate to human wound healing. OBJECTIVES: The authors qualitatively and quantitatively evaluate the ability of ADSC to improve wound healing in an ischemic variant of their well-established rabbit ear wound model. METHODS: To incorporate ischemia, a major pathophysiologic factor in human chronic wounds, into our model, two of the three main arteries to the rabbit ear were ligated before wounding. Green fluorescent protein (GFP)-labeled ADSC or rabbit dermal fibroblasts (RDF) were then applied to wounds and histologic parameters of healing quantified. RESULTS: At Postoperative Day (POD) 1, both cell types were present in a uniform distribution across wounds and positive for the proliferation marker Ki-67. By POD 7 and continuing through POD 10, ADSC and RDF contributed similarly to the accumulation of stratified "neogranulation" across the wound bed. No statistically-significant differences were observed between ADSC and RDF in terms of this positive effect on granulation (P=.2-.3 for comparison of mean granulation tissue gaps and areas). CONCLUSIONS: ADSC and RDF can be delivered topically to wounds, resulting in a high level of engraftment in the ischemic background. Cellular wound therapy holds promise for chronic wound healing as well as other antiscarring therapies, but further studies are warranted before full clinical translation. PMID- 22452843 TI - The regulation of mRNA stability in mammalian cells: 2.0. AB - Messenger RNA decay is an essential step in gene expression to set mRNA abundance in the cytoplasm. The binding of proteins and/or noncoding RNAs to specific recognition sequences or secondary structures within mRNAs dictates mRNA decay rates by recruiting specific enzyme complexes that perform the destruction processes. Often, the cell coordinates the degradation or stabilization of functional subsets of mRNAs encoding proteins collectively required for a biological process. As well, extrinsic or intrinsic stimuli activate signal transduction pathways that modify the mRNA decay machinery with consequent effects on decay rates and mRNA abundance. This review is an update to our 2001 Gene review on mRNA stability in mammalian cells, and we survey the enormous progress made over the past decade. PMID- 22452844 TI - Complete genome sequence of Bradyrhizobium sp. S23321: insights into symbiosis evolution in soil oligotrophs. AB - Bradyrhizobium sp. S23321 is an oligotrophic bacterium isolated from paddy field soil. Although S23321 is phylogenetically close to Bradyrhizobium japonicum USDA110, a legume symbiont, it is unable to induce root nodules in siratro, a legume often used for testing Nod factor-dependent nodulation. The genome of S23321 is a single circular chromosome, 7,231,841 bp in length, with an average GC content of 64.3%. The genome contains 6,898 potential protein-encoding genes, one set of rRNA genes, and 45 tRNA genes. Comparison of the genome structure between S23321 and USDA110 showed strong colinearity; however, the symbiosis islands present in USDA110 were absent in S23321, whose genome lacked a chaperonin gene cluster (groELS3) for symbiosis regulation found in USDA110. A comparison of sequences around the tRNA-Val gene strongly suggested that S23321 contains an ancestral-type genome that precedes the acquisition of a symbiosis island by horizontal gene transfer. Although S23321 contains a nif (nitrogen fixation) gene cluster, the organization, homology, and phylogeny of the genes in this cluster were more similar to those of photosynthetic bradyrhizobia ORS278 and BTAi1 than to those on the symbiosis island of USDA110. In addition, we found genes encoding a complete photosynthetic system, many ABC transporters for amino acids and oligopeptides, two types (polar and lateral) of flagella, multiple respiratory chains, and a system for lignin monomer catabolism in the S23321 genome. These features suggest that S23321 is able to adapt to a wide range of environments, probably including low-nutrient conditions, with multiple survival strategies in soil and rhizosphere. PMID- 22452845 TI - Two types of morphologically distinct fibers comprising Gallionella ferruginea twisted stalks. AB - Two morphologically distinct extracellular stalk fibers produced by Gallionella ferruginea were compared by electron microscopy and elemental analysis. The thick and fine-fiber stalks were different in structure on a micrometer scale and in the site on the mother cell to which they were attached, but on a nanometer scale they were similar in ultrastructure and in the elemental composition of their basic fiber matrix. PMID- 22452846 TI - Anxiety and depression amongst patients enrolled in a public sector antiretroviral treatment programme in South Africa: a cross-sectional study. AB - BACKGROUND: HIV/AIDS and depression are projected to be the two leading causes of disability by 2030. HIV/AIDS and anxiety/depression are interlinked. People suffering from depression may be more likely to engage in risky sexual behaviour, and therefore at greater risk of contracting HIV. An HIV + diagnosis may trigger symptoms of anxiety and depression, which may in turn result in risky sexual behaviour and the spread of HIV. This study explores correlates of anxiety and depression in patients enrolled in a public sector ART programme in South Africa. METHODS: Interviews were conducted with 716 patients initiating ART at twelve public health care facilities in the Free State. Symptoms of anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). An 8+ cut-off was used to identify possible cases of anxiety and depression. Multivariate logistic regression analysis, using STATA Version 11, was performed to identify correlates of anxiety and depression. RESULTS: The prevalence of symptoms of respectively anxiety and depression amongst this study population in the Free State was 30.6% and 25.4%. The multivariate logistic regression analyses identified five correlates of symptoms of anxiety and depression. Disruptive side effects (OR = 3.62, CI 1.95-6.74) and avoidant coping (OR = 1.42, CI 1.22-1.65) were associated with a greater number of symptoms of anxiety. Stigma was associated with an increase in symptoms of anxiety (OR = 1.14, CI 1.07-1.21) and of depression (OR = 1.13, CI 1.06-1.20), while being a widow (OR = 0.30, CI 0.13 0.69) and participating in a support group (OR = 0.21, CI 0.05-0.99) were associated with decreased symptoms of depression. CONCLUSIONS: The findings from the study provide valuable insights into the psychosocial aspects of the Free State public-sector ART programme. Combined with the literature on the intricate link between mental health problems and treatment outcomes our results emphasise firstly, the necessity that resources be allocated for both screening and treating mental health problems and, secondly, the need for interventions that will encourage support-group participation, address ART side effects, reduce maladaptive coping styles, and minimise the stigma associated with symptoms of anxiety and/or depression. PMID- 22452847 TI - Protein kinase A enhances lipopolysaccharide-induced IL-6, IL-8, and PGE2 production by human gingival fibroblasts. AB - OBJECTIVE: Periodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases. Interleukin (IL)-6, IL-8, and the chemical mediator prostaglandin E2 (PGE2) are known to play important roles in inflammatory responses and tissue degradation. Recently, we reported that the protein kinase A (PKA) inhibitor H-89 suppresses lipopolysaccharide (LPS)-induced IL-8 production by human gingival fibroblasts (HGFs). In the present study, the relevance of the PKA activity and two PKA-activating drugs, aminophylline and adrenaline, to LPS-induced inflammatory cytokines (IL-6 and IL-8) and PGE2 by HGFs were examined. METHODS: HGFs were treated with LPS from Porphyromonas gingivalis and H-89, the cAMP analog dibutyryl cyclic AMP (dbcAMP), aminophylline, or adrenaline. After 24 h, IL-6, IL-8, and PGE2 levels were evaluated by ELISA. RESULTS: H-89 did not affect LPS-induced IL-6 production, but suppressed IL-8 and PGE2 production. In contrast, dbcAMP significantly increased LPS-induced IL-6, IL-8, and PGE2 production. Up to 10 MUg/ml of aminophylline did not affect LPS-induced IL-6, IL 8, or PGE2 production, but they were significantly increased at 100 MUg/ml. Similarly, 0.01 MUg/ml of adrenaline did not affect LPS-induced IL-6, IL-8, or PGE2 production, but they were significantly increased at concentrations of 0.1 and 1 MUg/ml. In the absence of LPS, H-89, dbcAMP, aminophylline, and adrenaline had no relevance to IL-6, IL-8, or PGE2 production. CONCLUSION: These results suggest that the PKA pathway, and also PKA-activating drugs, enhance LPS-induced IL-6, IL-8, and PGE2 production by HGFs. However, aminophylline may not have an effect on the production of these molecules at concentrations used in clinical settings (8 to 20 MUg/ml in serum). These results suggest that aminophylline does not affect inflammatory responses in periodontal disease. PMID- 22452848 TI - Osteochondral tissue engineering: scaffolds, stem cells and applications. AB - Osteochondral tissue engineering has shown an increasing development to provide suitable strategies for the regeneration of damaged cartilage and underlying subchondral bone tissue. For reasons of the limitation in the capacity of articular cartilage to self-repair, it is essential to develop approaches based on suitable scaffolds made of appropriate engineered biomaterials. The combination of biodegradable polymers and bioactive ceramics in a variety of composite structures is promising in this area, whereby the fabrication methods, associated cells and signalling factors determine the success of the strategies. The objective of this review is to present and discuss approaches being proposed in osteochondral tissue engineering, which are focused on the application of various materials forming bilayered composite scaffolds, including polymers and ceramics, discussing the variety of scaffold designs and fabrication methods being developed. Additionally, cell sources and biological protein incorporation methods are discussed, addressing their interaction with scaffolds and highlighting the potential for creating a new generation of bilayered composite scaffolds that can mimic the native interfacial tissue properties, and are able to adapt to the biological environment. PMID- 22452849 TI - Changes in mild cognitive impairment and its subtypes as seen on diffusion tensor imaging. AB - BACKGROUND: Previous studies using diffusion tensor imaging (DTI) have observed microstructural abnormalities in white matter regions in both Alzheimer's disease and mild cognitive impairment (MCI). The aim of this work was to examine the abnormalities in white matter and subcortical regions of MCI and its subtypes in a large, community-dwelling older aged cohort. METHODS: A community-based sample of 396 individuals without dementia underwent medical assessment, neuropsychiatric testing, and neuroimaging. Of these, 158 subjects were classified as MCI and 238 as cognitively normal (controls) based on international MCI consensus criteria. Regional fractional anisotropy (FA) and mean diffusivity (MD) measures were calculated from the DTI and compared between groups. The false discovery rate correction was applied for multiple testing. RESULTS: Subjects with MCI did not have significant differences in FA compared with controls after correction for multiple testing, but had increased MD in the right putamen, right anterior limb of the internal capsule, genu and splenium of the corpus callosum, right posterior cingulate gyrus, left superior frontal gyrus, and right and left corona radiata. When compared with controls, changes in left anterior cingulate, left superior frontal gyrus, and right corona radiata were associated with amnestic MCI (aMCI), whereas changes in the right putamen, right anterior limb of the internal capsule, and the right corona radiata were associated with non amnestic MCI (naMCI). On logistic regression, the FA values in the left superior gyrus and MD values in the anterior cingulate distinguished aMCI from naMCI. CONCLUSIONS: MCI is associated with changes in white matter and subcortical regions as seen on DTI. Changes in some anterior brain regions distinguish aMCI from naMCI. PMID- 22452850 TI - Immune response to a potyvirus with exposed amino groups available for chemical conjugation. AB - BACKGROUND: The amino terminus of the tobacco etch virus (TEV) capsid protein is located on the external surface of infectious TEV particles, as proposed by previous studies and an in silico model. The epsilon amino groups on the exposed lysine residues are available for chemical conjugation to any given protein, and can thus act as antigen carriers. The availability of amino groups on the surfaces of TEV particles was determined and the immune response to TEV evaluated. RESULTS: Using a biotin-tagged molecule that reacts specifically with amino groups, we found that the TEV capsid protein has amino groups on its surface available for coupling to other molecules via crosslinkers. Intraperitoneal TEV was administered to female BALB/c mice, and both their humoral and cellular responses measured. Different IgG isotypes, particularly IgG2a, directed against TEV were induced. In a cell proliferation assay, only spleen cells from vaccinated mice that were stimulated in vitro with TEV showed significant proliferation of CD3+/CD4+ and CD3+/CD8+ subpopulations and secreted significant amounts of interferon gamma. CONCLUSIONS: TEV has surface amino groups that are available for chemical coupling. TEV induces both humoral and cellular responses when administered alone intraperitoneally to mice. Therefore, TEV should be evaluated as a vaccine adjuvant when chemically coupled to antigens of choice. PMID- 22452851 TI - Production of recombinant nonstructural 1 protein in Escherichia coli for early detection of Japanese encephalitis virus infection. AB - Japanese encephalitis is a major public health problem in South-East Asia and Western Pacific countries. The recombinant nonstructural 1 (rNS1) protein of Japanese encephalitis virus is a potential diagnostic as well as vaccine candidate. Developments of cost-effective and simple culture media as well as appropriate culture conditions are generally favourable for large-scale production of recombinant proteins. The effects of medium composition and cultivation conditions on the production of rNS1 protein were investigated in shake flask culture as well as batch cultivation of Escherichia coli. Further, the fed-batch process was also carried out for high cell density cultivation (HCDC) of E. coli expressing rNS1 protein. Isopropyl-beta-d-thiogalactopyranoside (IPTG) was used to induce the expression of rNS1 protein at ~ 13 g dry cell weight per litre of culture. The final dry cell weight after fed-batch cultivation was ~ 17 g l(-1) . The Inclusion bodies were isolated and purified through affinity chromatography to give a final product yield of ~ 142 mg l(-1) . The reactivity of purified protein was confirmed by Western blotting and Enzyme linked immunosorbent assay. These results show that rNS1 protein may be used as a diagnostic reagent or for further prophylactic studies. This approach of producing rNS1 protein in E. coli with high yield may also offer promising method for production of other viral recombinant proteins. PMID- 22452852 TI - A bZIP protein, VIP1, is a regulator of osmosensory signaling in Arabidopsis. AB - Abscisic acid is a stress-related phytohormone that has roles in dehydration and rehydration. In Arabidopsis (Arabidopsis thaliana), two genes that inactivate abscisic acid, CYP707A1 and CYP707A3, are rapidly up-regulated upon rehydration. The factors that regulate CYP707A1/3 are not well characterized. We expressed a bZIP protein, VIP1, as a green fluorescent protein fusion protein in Arabidopsis and found that the nuclear localization of VIP1 was enhanced within 10 min after rehydration. A yeast one-hybrid assay revealed that the amino-terminal region of VIP1 has transcriptional activation potential. In a transient reporter assay using Arabidopsis protoplasts, VIP1 enhanced the promoter activities of CYP707A1/3. In gel shift and chromatin immunoprecipitation analyses, VIP1 directly bound to DNA fragments of the CYP707A1/3 promoters. Transgenic plants expressing VIP1-green fluorescent protein were found to overexpress CYP707A1/3 mRNAs. The time course of nuclear-cytoplasmic shuttling of VIP1 was consistent with the time courses of the expression of CYP707A1/3. These results suggest that VIP1 functions as a regulator of osmosensory signaling in Arabidopsis. PMID- 22452853 TI - The CHD3 remodeler PICKLE associates with genes enriched for trimethylation of histone H3 lysine 27. AB - In Arabidopsis (Arabidopsis thaliana), the ATP-dependent chromatin remodeler PICKLE (PKL) determines expression of genes associated with developmental identity. PKL promotes the epigenetic mark trimethylation of histone H3 lysine 27 (H3K27me3) that facilitates repression of tissue-specific genes in plants. It has previously been proposed that PKL acts indirectly to promote H3K27me3 by promoting expression of the POLYCOMB REPRESSIVE COMPLEX2 complex that generates H3K27me3. We undertook expression and chromatin immunoprecipitation analyses to further characterize the contribution of PKL to gene expression and developmental identity. Our expression data support a critical and specific role for PKL in expression of H3K27me3-enriched loci but do not support a role for PKL in expression of POLYCOMB REPRESSIVE COMPLEX2. Moreover, our chromatin immunoprecipitation data reveal that PKL protein is present at the promoter region of multiple H3K27me3-enriched loci, indicating that PKL directly acts on these loci. In particular, we find that PKL is present at LEAFY COTYLEDON1 and LEAFY COTYLEDON2 during germination, which is when PKL acts to repress these master regulators of embryonic identity. Surprisingly, we also find that PKL is present at the promoters of actively transcribed genes that are ubiquitously expressed such as ACTIN7 and POLYUBIQUITIN10 that do not exhibit PKL-dependent expression. Taken together, our data contravene the previous model of PKL action and instead support a direct role for PKL in determining levels of H3K27me3 at repressed loci. Our data also raise the possibility that PKL facilitates a common chromatin remodeling process that is not restricted to H3K27me3-enriched regions. PMID- 22452854 TI - Xenobiotic- and jasmonic acid-inducible signal transduction pathways have become interdependent at the Arabidopsis CYP81D11 promoter. AB - Plants modify harmful substances through an inducible detoxification system. In Arabidopsis (Arabidopsis thaliana), chemical induction of the cytochrome P450 gene CYP81D11 and other genes linked to the detoxification program depends on class II TGA transcription factors. CYP81D11 expression is also induced by the phytohormone jasmonic acid (JA) through the established pathway requiring the JA receptor CORONATINE INSENSITIVE1 (COI1) and the JA-regulated transcription factor MYC2. Here, we report that the xenobiotic- and the JA-dependent signal cascades have become interdependent at the CYP81D11 promoter. On the one hand, MYC2 can only activate the expression of CYP81D11 when both the MYC2- and the TGA-binding sites are present in the promoter. On the other hand, the xenobiotic-regulated class II TGA transcription factors can only mediate maximal promoter activity if TGA and MYC2 binding motifs, MYC2, and the JA-isoleucine biosynthesis enzymes DDE2/AOS and JAR1 are functional. Since JA levels and degradation of JAZ1, a repressor of the JA response, are not affected by reactive chemicals, we hypothesize that basal JA signaling amplifies the response to chemical stress. Remarkably, stress-induced expression levels were 3-fold lower in coi1 than in the JA biosynthesis mutant dde2-2, [corrected] revealing that COI1 can contribute to the activation of the promoter in the absence of JA. Moreover, we show that deletion of the MYC2 binding motifs abolishes the JA responsiveness of the promoter but not the responsiveness to COI1. These findings suggest that yet unknown cis-element(s) can mediate COI1-dependent transcriptional activation in the absence of JA. PMID- 22452855 TI - Thioredoxin redox regulates ATPase activity of magnesium chelatase CHLI subunit and modulates redox-mediated signaling in tetrapyrrole biosynthesis and homeostasis of reactive oxygen species in pea plants. AB - The chloroplast thioredoxins (TRXs) function as messengers of redox signals from ferredoxin to target enzymes. In this work, we studied the regulatory impact of pea (Pisum sativum) TRX-F on the magnesium (Mg) chelatase CHLI subunit and the enzymatic activation of Mg chelatase in vitro and in vivo. In vitro, reduced TRX F activated the ATPase activity of pea CHLI and enhanced the activity of Mg chelatase reconstituted from the three recombinant subunits CHLI, CHLD, and CHLH in combination with the regulator protein GENOMES UNCOUPLED4 (GUN4). Yeast two hybrid and bimolecular fluorescence complementation assays demonstrated that TRX F physically interacts with CHLI but not with either of the other two subunits or GUN4. In vivo, virus-induced TRX-F gene silencing (VIGS-TRX-F) in pea plants did not result in an altered redox state of CHLI. However, simultaneous silencing of the pea TRX-F and TRX-M genes (VIGS-TRX-F/TRX-M) resulted in partially and fully oxidized CHLI in vivo. VIGS-TRX-F/TRX-M plants demonstrated a significant reduction in Mg chelatase activity and 5-aminolevulinic acid synthesizing capacity as well as reduced pigment content and lower photosynthetic capacity. These results suggest that, in vivo, TRX-M can compensate for a lack of TRX-F and that both TRXs act as important redox regulators of Mg chelatase. Furthermore, the silencing of TRX-F and TRX-M expression also affects gene expression in the tetrapyrrole biosynthesis pathway and leads to the accumulation of reactive oxygen species, which may also serve as an additional signal for the transcriptional regulation of photosynthesis-associated nuclear genes. PMID- 22452856 TI - Assessing the biosynthetic capabilities of secretory glands in Citrus peel. AB - Epithelial cells (ECs) lining the secretory cavities of Citrus peel have been hypothesized to be responsible for the synthesis of essential oil, but direct evidence for such a role is currently sparse. We used laser-capture microdissection and pressure catapulting to isolate ECs and parenchyma cells (as controls not synthesizing oil) from the peel of young grapefruit (Citrus * paradisi 'Duncan'), isolated RNA, and evaluated transcript patterns based on oligonucleotide microarrays. A Gene Ontology analysis of these data sets indicated an enrichment of genes involved in the biosynthesis of volatile terpenoids and nonvolatile phenylpropanoids in ECs (when compared with parenchyma cells), thus indicating a significant metabolic specialization in this cell type. The gene expression patterns in ECs were consistent with the accumulation of the major essential oil constituents (monoterpenes, prenylated coumarins, and polymethoxylated flavonoids). Morphometric analyses demonstrated that secretory cavities are formed early during fruit development, whereas the expansion of cavities, and thus oil accumulation, correlates with later stages of fruit expansion. Our studies have laid the methodological and experimental groundwork for a vastly improved knowledge of the as yet poorly understood processes controlling essential oil biosynthesis in Citrus peel. PMID- 22452857 TI - Clostridium difficile genotypes other than ribotype 078 that are prevalent among human, animal and environmental isolates. AB - BACKGROUND: Characterising the overlap of C. difficile genotypes in different reservoirs can improve our understanding of possible transmission routes of this pathogen. Most of the studies have focused on a comparison of the PCR ribotype 078 isolated from humans and animals. Here we describe for the first time a comparison of C. difficile genotypes isolated during longer time intervals from different sources including humans, animals and the non-hospital environment. RESULTS: Altogether 786 isolates from time interval 2008-2010 were grouped into 90 PCR ribotypes and eleven of them were shared among all host types and the environment. Ribotypes that were most common in humans were also present in water and different animals (014/020, 002, 029). Interestingly, non-toxigenic isolates were very common in the environment (30.8%) in comparison to humans (6.5%) and animals (7.7%). A high degree of similarity was observed for human and animal isolates with PFGE. In human isolates resistance to erithromycin, clindamycin and moxifloxacin was detected, while all animal isolates were susceptible to all antibiotics tested. CONCLUSION: Our results show that many other types in addition to PCR Ribotype 078 are shared between humans and animals and that the most prevalent genotypes in humans have the ability to survive also in the environment and several animal hosts. The genetic relatedness observed with PFGE suggests that transmission of given genotype from one reservoir to the other is likely to occur. PMID- 22452858 TI - The first case of Brucella canis in Sweden: background, case report and recommendations from a northern European perspective. AB - Infection with Brucella canis has been diagnosed in Sweden for the first time. It was diagnosed in a three-year-old breeding bitch with reproductive disturbances. Fifteen in-contact dogs were tested repeatedly and all of them were negative for B. canis. The source of infection could not be defined. The present article describes the case and the measures undertaken and gives a short review over B. canis. Recommendations on how to avoid the infection in non-endemic countries are given. PMID- 22452859 TI - [Determination of blood markers and inflammation in subjects with impaired glucose tolerance]. AB - OBJECTIVE: This study was designed to explore the presence of a prothrombotic state, fibrinolytic dysfunction and inflammation in impaired glucose tolerance subjects, by evaluating serum markers of thrombosis, fibrinolysis and inflammation. METHODS: In 48 consecutive adults, 25 patients with impaired glucose tolerance (nine men and 16 women, 50.0 +/- 9.2 years) were compared with 23 control subjects (six men and 17 women, 48.0 +/- 11 years). The markers of thrombotic activation used were D-dimer and fibrinogen. Fibrinolysis dysfunction was evaluated with plasminogen activator inhibitor 1 (PAI-1) and the inflammatory marker studied was hs-C reactive protein (hs-CRP). RESULTS: The markers of thrombotic state were significantly higher in patients with impaired glucose tolerance (IGT) than in controls: D dimer (489.6 +/- 277.3 vs. 345.8 +/- 158.9 ng/mL) (p< 0.01) and fibrinogen (317.7 +/- 32.1 vs. 266.7 +/- 25.4 mg/dL) (p < 0.0001). Fibrinolytic marker PAI-1 also differed significantly between the two study groups (66.4 +/- 30.7 vs. 35.5 +/- 31.0 ng/mL) (p < 0.006). However, hs CRP, as inflammation marker, (0.45 +/- 0.62 mg/dL vs. 0.38 +/- 0.47) did not differ significantly between the two study groups (<0.28). CONCLUSION: This result suggests the presence of a prothrombotic state with fibrinolytic dysfunction in subjects with impaired glucose tolerance. PMID- 22452860 TI - The TIMI risk score for STEMI predicts in-hospital mortality and adverse events in patients without cardiogenic shock undergoing primary angioplasty. AB - INTRODUCTION: Patients with ST elevation acute myocardial infarction (STEMI) comprise a heterogeneous population with respect to the risk for adverse events. Primary percutaneous coronary intervention (PCI) has shown to be better, mainly in high-risk patients. OBJECTIVE: The purpose of this study was to determine if the Thrombolysis in Myocardial Infarction (TIMI) risk score for STEMI applied to patients undergo primary PCI identifies a group of patients at high risk for adverse events. METHODS: We identified patients with STEMI without cardiogenic shock on admission, who were treated with primary PCI. The TIMI and CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) risk scores were calculated to determine their predictive value for in hospital mortality. Patients were divided into two groups according to their TIMI risk score, low risk being 0-4 points and high risk .5 points, and the frequency of adverse events was analyzed. RESULTS: We analyzed 572 patients with STEMI. The c-statistics predictive value of the TIMI risk score for mortality was 0.80 (p=0.0001) and the CADILLAC risk score was 0.83, (p=0.0001). Thirty-two percent of patients classified as high risk (TIMI .5) had a higher incidence of adverse events than the low-risk group: mortality 14.8% vs. 2.1%, (p=0.0001); heart failure 15.3% vs. 4.1%, (p=0.0001); development of cardiogenic shock 10.9% vs. 1.5%, (p=0.0001); ventricular arrhythmias 14.8% vs. 5.9%, (p=0.001); and no reflow phenomenon 22.4% vs. 13.6%, (p=0.01). CONCLUSIONS: The TIMI risk score for STEMI prior to primary PCI can predict in hospital mortality and identifies a group of high-risk patients who might develop adverse events. PMID- 22452861 TI - Clinical characteristics, process of care and outcomes among Mexican, Hispanic and non-Hispanic white patients presenting with non-ST elevation acute coronary syndromes: data from RENASICA and CRUSADE registries. AB - INTRODUCTION: Data regarding management characteristics of non-ST elevation acute coronary syndromes (NSTE ACS) in Mexican, Hispanic and Non- Hispanic white patients are scarce. METHODS: We sought to describe the clinical characteristics, process of care, and outcomes of Mexicans, Hispanics and non-Hispanic whites presenting with NSTE ACS at Mexican and US hospitals. We compared baseline characteristics, resource use, clinical practice guidelines (CPGs) compliance and in-hospital mortality among 3 453 Mexicans, 3 936 Hispanics and 90, 280 non Hispanic whites with NSTE ACS from the RENASICA and CRUSADE registries. RESULTS: Mexicans were younger with a different cardiovascular risk profile, fewer incidences of hypertension (p<0.001), hyperlipidemia (p<0.001), renal failure (p<0.001) and prior revascularization (p<0.001) but were more likely to be smoking compared with Hispanics and non-Hispanic white populations. Mexicans and Hispanics had a higher incidence of diabetes (p<0.001). At clinical presentation Mexican patients were more likely to have ST depression (p<0.001) but less likely to have left ventricular dysfunction (p<0.001) and troponin stratification (p<0.001). Regarding CPGs compliance, aspirin was used in 90% of patients in all groups, but clopidogrel or unfractionated or low-molecular weight heparin in 50% of patients or less. Mexican patients were less likely to receive glycoprotein IIb/IIIa inhibitors and revascularization. In spite of clinical differences and therapeutic trends, cardiovascular mortality was similar among all groups (Mexicans 4%, Hispanics 4% and non-Hispanic white 5%). In all groups of patients, a poor CPGs compliance was observed. CONCLUSIONS: In a post-hoc analysis, Mexican patients with NSTE ACS had a different cardiovascular risk factor profile and clinical presentation, and less intensive in - hospital treatment than Hispanic and non-Hispanic white patients. However, these differences do not appear to affect in - hospital mortality. PMID- 22452862 TI - Electrocardiographic pattern combined with echocardiographic wall motion abnormalities in stress related cardiomyopathies: clinical and pathophysiological insights. AB - We report five cases of stress related cardiomyopathies that occurred in post menopausal women (age range from 49 to 90) consecutively admitted to our Department in the last year in different clinical settings: typical anginal pain, carotid endarterectomy, pulmonary edema, cardiogenic shock, and severe asthenia. Apical left ventricular involvement was observed in three patients in conjunction with ECG mild ST segment elevation in anterior precordial leads resembling acute anterior myocardial infarction; isolated mid ventricular dysfunction was present in two patients in conjunction with ST segment depression in the anterior precordial leads. The ECG evolved showing T wave inversion in four cases and normalized in one. In all cases, blood chemistry showed mild elevation of CK-MB and TN. The observed wall motion abnormalities were reversible in four of five cases during hospital stay. Stress echocardiography was performed in two patients (dobutamine in the patient with persistent mid-ventricular hypokinesis, exercise in another case) and correctly predicted the absence of coronary artery disease. We conclude that wall motion analysis at echocardiography combined with ECG ST segment changes and serum markers of myocardial necrosis (CK-MB and TN) may allow recognition of stress cardiomyopathies in different clinical settings. Echo stress may be proposed in those patients in whom some suspicion of coronary artery disease persists. PMID- 22452863 TI - [Aortic intramural hematoma type B: images of an entity with different evolution pathways]. AB - The progress in noninvasive imaging techniques for aortic pathology, such as computed tomography (CT), magnetic resonance (MRI) and transesophageal echocardiography (TEE) have facilitated the diagnosis and management of patients with aortic intramural hematoma (IMH). Despite incomplete understanding of their natural history, it is known there is no significant difference between the IMH and classic aortic dissection (AD) on the incidence of major complication or death. In this article, we present images of patient with type B aortic hematoma and different outcomes in their natural evolution. PMID- 22452864 TI - [Percutaneous exclusion of traumatic abdominal aortic pseudoaneurysm from a brachial approach]. AB - Abdominal aortic pseudoaneurysm (AAP) is a rare lesion, although traumatic aortic injury is described as one of the main causes; both the rupture as the surgical treatment of the defect has high morbidity and mortality. Therefore, endovascular treatment either by chemical embolization or exclusion of defect with devices has emerged as an alternative treatment. However, there are risks such as occlusion of visceral vessels near the neck of the defect, embolization material or aortic rupture. Therefore, the choice of material and method of approach should be planned carefully in each case. We report a patient who ten years after abdominal wound firearm was diagnosed with AAP 17 x 13 cm, with short neck originated close to the ostium of the celiac trunk at an acute angle with the aortic axis. We perform the exclusion of the defect with a device designed for closing atrial septal defect from the left brachial access due to the angulation of the neck defect. There were no complications. At 72 hours was granted discharge. A month later, CT scan control showed the false aneurysm of equal size and no residual flow. The monitoring to date is five months and the patient remained asymptomatic. PMID- 22452865 TI - Multiplanar transesophageal echocardiography for the evaluation and percutaneous management of ostium secundum atrial septal defects in the adult. AB - The purpose of this paper is to review the usefulness of multiplanar transesophageal echocardiography before, during and after percutaneous transcatheter closure of secundum atrial septal defects. Transesophageal echocardiography imaging techniques,including their role in patient selection, procedural guidance and immediate assessment of technical success and complications are described and discussed in this review. Percutaneous transcatheter closure is indicated for ostium secundum atrial septal defects of less than 40 mm in maximal diameter. The defect must have a favorable anatomy, with adequate rims of at least 5 mm to anchor the prosthesis. Transesophageal echocardiography plays a critical role before the procedure in identifying potential candidates for percutaneous closure and to exclude those with unfavorable anatomy or associated lesions, which could not be addressed percutaneously. Transesophageal echocardiography is also important during the procedure to guide the deployment of the device. After device deployment, the echocardiographer must assess the device (integrity, position and stability), residual shunt, atrio-ventricular valve regurgitation, obstruction to systemic or venous return and pericardial effusion, in order to determine procedural success and diagnose immediate complications. PMID- 22452866 TI - [Management of acute pulmonary thromboembolism]. AB - Acute pulmonary embolism (APE) is considered a cardiovascular emergency and is one of the most important causes of morbidity and mortality in hospitalized patients. Pulmonary embolism diagnosis has to be made early in the course of the disease and its management installed immediately. Pulmonary embolism management includes hemodynamic support, anticoagulation, thrombolysis and embolectomy. We present an overview of the treatment of APE. PMID- 22452867 TI - [Chaos, complexity and cardiology]. AB - Science is an ever-changing discipline. Modern medical knowledge is based on science. Current medical paradigm is both linear and reductionist. There is a new general theory validated by computer's calculations named chaos and complexity theory. This new paradigm will probably have an impact on medical practice. Cardiovascular physiology may display fractal and/ or chaotic behavior. Computerized heart rhythm analyses enhanced our understanding of complex diseases otherwise not explainable by current linear-reductionist paradigms. Cases in point are diverse dysautonomia including orthostatic intolerance, cardiac X syndrome and fibromyalgia. Derived from this, new knowledge is a different diagnostic and therapeutic stance: scientific holism. PMID- 22452868 TI - Almanac 2011: Cardiomyopathies. The national society journals present selected research that has driven recent advances in clinical cardiology. PMID- 22452869 TI - [Evidence-based cardiology: practical applications from epidemiology. IV Cardiovascular risk prediction]. AB - Cardiovascular risk assessment in patients without established disease allows to match the intensity of risk factor modification to the underlying hazard for cardiovascular events. The cardiologist needs to know the characteristics of current risk prediction algorithms, their advantages and limitations. PMID- 22452870 TI - [Determination for preference of the terminal digit in arterial hypertension. Utopia in underdeveloped countries]. PMID- 22452871 TI - [In memoriam Rafael Mendez, M.D]. PMID- 22452872 TI - Prevalence and correlates of intimate partner violence among older Chinese couples in Hong Kong. AB - BACKGROUND: This study examined the prevalence and risk factors for intimate partner violence (IPV) among Chinese older couples in Hong Kong. METHODS: A population representative sample was surveyed. RESULTS: The prevalence of IPV in older adults was found to be quite high in the present study, with a lifetime prevalence ranging from 1.4% to 53.6%, and a past year prevalence ranging from 0.4% to 36.1% for various forms of aggression. Results of logistic regression analyses showed that older persons who were younger among this "older" group, who were not employed, who had a substance abuse problem, who had witnessed parental violence during their childhood, who had a criminal history, who had a low level of assertiveness, who had an anger management problem, who experienced a low level of social support and/or experienced stressful conditions, were all more likely to fall victims of IPV. CONCLUSION: It is suggested that IPV in older couples is a complex phenomenon that is closely intertwined with other forms of domestic violence, including spousal violence, child abuse, in-law conflicts, and elderly adult abuse. Thus, before we have more definitive and concrete evidence that IPV in older couples should definitively come under the category of elder abuse or IPV, it is advisable to treat it under its own separate category of family violence. PMID- 22452873 TI - Carrier-mediated gamma-aminobutyric acid transport across the basolateral membrane of human intestinal Caco-2 cell monolayers. AB - The aim of the present study was to investigate the transport of gamma aminobutyric acid (GABA) across the basolateral membrane of intestinal cells. The proton-coupled amino acid transporter, hPAT1, mediates the influx of GABA and GABA mimetic drug substances such as vigabatrin and gaboxadol and the anticancer prodrug delta-aminolevulinic acid across the apical membrane of small intestinal enterocytes. Little is however known about the basolateral transport of these substances. We investigated basolateral transport of GABA in mature Caco-2 cell monolayers using isotope studies. Here we report that, at least two transporters seem to be involved in the basolateral transport of GABA. The basolateral uptake consisted of a high-affinity system with a K(m) of 290 MUM and V(max) of 75 pmol cm(-2) min(-1) and a low affinity system with a K(m) of approximately 64 mM and V(max) of 1.6 nmol cm(-2) min(-1). The high-affinity transporter is Na(+) and Cl( ) dependent. The substrate specificity of the high-affinity transporter was further studied and Gly-Sar, Leucine, gaboxadol, sarcosine, lysine, betaine, 5 hydroxythryptophan, proline and glycine reduced the GABA uptake to approximately 44-70% of the GABA uptake in the absence of inhibitor. Other substances such as beta-alanine, GABA, 5-aminovaleric acid, taurine and delta-aminolevulinic acid reduced the basolateral GABA uptake to 6-25% of the uptake in the absence of inhibitor. Our results indicate that the distance between the charged amino- and acid-groups is particular important for inhibition of basolateral GABA uptake. Thus, there seems to be a partial substrate overlap between the basolateral GABA transporter and hPAT1, which may prove important for understanding drug interactions at the level of intestinal transport. PMID- 22452874 TI - Lessons from a one-year hospital-based surveillance of acute respiratory infections in Berlin- comparing case definitions to monitor influenza. AB - BACKGROUND: Surveillance of severe acute respiratory infections (SARI) in sentinel hospitals is recommended to estimate the burden of severe influenza cases. Therefore, we monitored patients admitted with respiratory infections (RI) in 9 Berlin hospitals from 7.12.2009 to 12.12.2010 according to different case definitions (CD) and determined the proportion of cases with influenza A(H1N1)pdm09 (pH1N1). We compared the sensitivity and specificity of CD for capturing pandemic pH1N1 cases. METHODS: We established an RI-surveillance restricted to adults aged <= 65 years within the framework of a pH1N1 vaccine effectiveness study, which required active identification of RI-cases. The hospital information-system was screened daily for newly admitted RI-patients. Nasopharyngeal swabs from consenting patients were tested by PCR for influenza virus subtypes. Four clinical CD were compared in terms of capturing pH1N1 positives among hospitalized RI-patients by applying sensitivity and specificity analyses. The broadest case definition (CD1) was used for inclusion of RI-cases; the narrowest case definition (CD4) was identical to the SARI case definition recommended by ECDC/WHO. RESULTS: Over the study period, we identified 1,025 RI cases, of which 283 (28%) met the ECDC/WHO SARI case definition. The percentage of SARI-cases among internal medicine admissions decreased from 3.2% (calendar week 50-2009) to 0.2% (week 25-2010). Of 354 patients tested by PCR, 20 (6%) were pH1N1-positive. Two case definitions narrower than CD1 but -in contrast to SARI- not requiring shortness of breath yielded the largest areas under the Receiver Operator-Curve. Heterogeneity of proportions of patients admitted with RI between hospitals was significant. CONCLUSIONS: Comprehensive surveillance of RI cases was feasible in a network of community hospitals. In most settings, several hospitals should be included to ensure representativeness. Although misclassification resulting from failure to obtain symptoms in the hospital information-system cannot be ruled out, a high proportion of hospitalized PCR positive pH1N1-patients (45%) did not fulfil the SARI case-definition that included shortness of breath or difficulty breathing. Thus, to assess influenza related disease burden in hospitals, broader, alternative case definitions should be considered. PMID- 22452875 TI - The Chinese version of the cardiac depression scale: Mokken scaling. AB - BACKGROUND: Myocardial infarction is a major cause of death and morbidity in many countries, including China. The aim of this study was to analyse a Mandarin Chinese translation of the Cardiac Depression Scale for a hierarchy of items according to the criteria of Mokken scaling. FINDINGS: Data from 438 Chinese participants who completed the Chinese translation of the Cardiac Depression Scale were analysed using the Mokken scaling procedure and the 'R' statistical programme using the diagnostics available in these programmes. Correlations between Mandarin Chinese items and Chinese translations of the Hospital Anxiety and Depression Scale and the Beck Depression Inventory were also analysed. Fifteen items from the Mandarin Chinese Cardiac Depression Scale were retained in a weak but reliable Mokken scale; invariant item ordering was evident but of low accuracy and the Mokken scaled items of the Chinese Cardiac Depression Scale correlated with the Hospital Anxiety and Depression Scale and the Beck Depression Inventory. CONCLUSIONS: Items from the Mandarin Chinese Cardiac Depression Scale form a Mokken scale and this offers further insight into how the items of the Cardiac Depression Scale relate to the measurement of depression in people with a myocardial infarction. PMID- 22452876 TI - Intestinal T-cell lymphoma with severe hypereosinophilic syndrome in a cat. AB - A Japanese domestic long-hair cat of about 8 years of age was presented with vomiting and hematochezia and was found to have significant hypereosinophilia. Bone marrow aspiration revealed moderate increases of eosinophilic lineages. Histopathological examination revealed mild eosinophilic and epitheliotropic T lymphocytic infiltrations in the duodenum. Although the cat remained asymptomatic with only prednisolone administration, the cat presented with hematemesis, weight loss, and severe anorexia 512 days after the initial presentation. Subsequently, gastrointestinal perforation developed, and the cat died on Day 536. Histopathological examination of autopsy specimens revealed mixed cellular infiltration including eosinophils and neoplastic lymphocytes in the intestinal lymph nodes, intestine, liver, spleen, and pancreas. Immunohistochemical examination supports a diagnosis of intestinal T-cell lymphoma with severe hypereosinophilic syndrome. PMID- 22452877 TI - Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet. AB - BACKGROUND: Rats fed a high-fat and high-sucrose (HF) diet develop hepatic steatosis and hyperlipidemia. There are several reports that a change in nutritional status affects hepatic levels of drug-metabolizing enzymes. Synthetic inulin is a dietary component that completely evades glucide digestion. Supplementing a HF diet with inulin ameliorates hypertriglycemia and hepatic steatosis, but not hypercholesterolemia. This study aimed at distinguishing the effects of synthetic inulin and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), which inhibit cholesterol biosynthesis. METHODS: We examined effects of co-treatment with synthetic inulin (5%) and fluvastatin (0, 4, and 8 mg/kg, per os) on body weight, epidydimal white adipose tissue weight, serum and hepatic lipid profiles, and hepatic cytochrome P450 (CYP) mRNA and protein profiles in rats fed a standard diet or a HF diet for 3 weeks. RESULTS: Treatment with the synthetic inulin (5%) or fluvastatin at 4 mg/kg (lethal dose in rats fed the HF diet, 8 mg/kg) ameliorated the elevation in hepatic triacylglycerol and total cholesterol levels in rats fed the HF diet. Whereas co-treatment with the inulin (5%) and fluvastatin (4 mg/kg) had a tendency to more strongly suppress the elevation in serum levels of very low density lipoprotein triacylglycerol than either treatment alone, no additive or synergistic effect was found in decrease in hepatic lipid levels. Hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein and methoxyresorufin O-demethylase and ethoxyresorufin O-deethylase activities were reduced in rats fed the HF diet. The synthetic inulin alleviated the reduction in hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein more strongly than fluvastatin, and no synergistic effects were observed on co treatment. Furthermore, hepatic levels of aryl hydrocarbon receptor mRNA were decreased in rats fed the HF diet and recovered to near normal values with the intake of dietary inulin, which correlated with change in CYP1A1/2. CONCLUSIONS: Dietary inulin alone was effective to prevent the development of hepatic steatosis, ameliorate nutritional effects, and alleviate the hepatic change in the expression of CYP1A1/2 and CYP2E1, while co-treatment with statin did not have additive or synergistic effects and statin may cause adverse effects in rats fed the HF diet. PMID- 22452878 TI - Cellular microRNA let-7c inhibits M1 protein expression of the H1N1 influenza A virus in infected human lung epithelial cells. AB - The influenza virus (IV) triggers a series of signalling events inside host cells and induces complex cellular responses. Studies have suggested that host factors play an essential role in IV replication. MicroRNAs (miRNAs) represent a class of small non-coding RNAs that target mRNAs, triggering either translation repression or RNA degradation. Emerging research suggests that host-derived cellular miRNAs are involved in mediating the host-IV interaction. Using miRNA microarrays, we identified several miRNAs aberrantly expressed in IV-infected human lung epithelial cells (A549). Specifically, miR-let-7c was highly up-regulated in IV infected A549 cells. PITA and miRanda database screening indicated that the let 7c seed sequence is a perfect complementary sequence match to the 3' untranslated region (UTR) of viral gene M1 (+) cRNA, but not to PB2 and PA. As detected by a luciferase reporter system, let-7c directly targeted the 3'-UTR of M1 (+) cRNA, but not PB2 and PA. To experimentally identify the function of cellular let-7c, precursor let-7c was transfected into A549 cells. Let-7c down-regulated IV M1 expression at both the (+) cRNA and protein levels. Furthermore, transfection with a let-7c inhibitor enhanced the expression of M1. Therefore, let-7c may reduce IV replication by degrading M1 (+) cRNA. This is the first report indicating that cellular miRNA regulates IV replication through the degradation of viral gene (+) cRNA by matching the 3'-UTR of the viral cRNA. These findings suggest that let-7c plays a role in protecting host cells from the virus in addition to its known cellular functions. PMID- 22452879 TI - Expression analysis of immune response genes in fish epithelial cells following ranavirus infection. AB - Ranaviruses (family Iridoviridae) are a growing threat to fish and amphibian populations worldwide. The immune response to ranavirus infection has been studied in amphibians, but little is known about the responses elicited in piscine hosts. In this study, the immune response and apoptosis induced by ranaviruses were investigated in fish epithelial cells. Epithelioma papulosum cyprini (EPC) cells were infected with four different viral isolates: epizootic haematopoietic necrosis virus (EHNV), frog virus 3 (FV3), European catfish virus (ECV) and doctor fish virus (DFV). Quantitative real-time PCR (qPCR) assays were developed to measure the mRNA expression of immune response genes during ranavirus infection. The target genes included tumour necrosis factor alpha (TNF alpha), interleukin-1beta (IL-1beta), beta2-microglobulin (beta2M), interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta). All ranaviruses elicited changes in immune gene expression. EHNV and FV3 caused a strong pro inflammatory response with an increase in the expression of both IL-1beta and TNF alpha, whereas ECV and DFV evoked transient up-regulation of regulatory cytokine TGF-beta. Additionally, all viral isolates induced increased beta2M expression as well as apoptosis in the EPC cells. Our results indicate that epithelial cells can serve as an in vitro model for studying the mechanisms of immune response in the piscine host in the first stages of ranavirus infection. PMID- 22452880 TI - Antiviral activity of FNC, 2'-deoxy-2'-beta-fluoro-4'-azidocytidine, against human and duck HBV replication. AB - BACKGROUND: New drugs are needed to combat HBV infection. We investigated the anti-HBV activity of the deoxycytidine analogue FNC, which has anticancer activity and has been found to inhibit HCV replication. METHODS: In this study, a human hepatoma HepG2.2.15 cell culture system and duck HBV (DHBV) infection model were used as the in vitro and in vivo models to evaluate the anti-HBV activity of FNC. RESULTS: In the cell model, FNC effectively suppressed the secretion of the HBV antigens in a dose-dependent manner, with 50% effective concentration values of 0.037 MUM for hepatitis B surface antigen and 0.044 MUM for hepatitis B e antigen on day 9. Consistent with the HBV antigen reduction, FNC also reduced the HBV DNA level by 92.31% and 93.90% intracellularly and extracellularly, respectively. DHBV DNA levels were markedly reduced after treatment with the FNC at 0.5, 1.0 and 2.0 mg/kg*day dosages. The inhibition rate of FNC at the dose of 2.0 mg/kg*day reached 91.68% and 81.96%, in duck serum and liver, respectively, on day 10. Furthermore, significant liver histology restoration after FNC treatment was observed, as evaluated by the histopathological analysis. CONCLUSIONS: FNC can evidently inhibit the replication of HBV in the HepG2.2.15 cell line in vitro and inhibits DHBV replication in ducks in vivo. It could be potentially developed into a new anti-HBV drug. PMID- 22452881 TI - Regional differences in self-reported screening, prevalence and management of cardiovascular risk factors in Switzerland. AB - BACKGROUND: In Switzerland, health policies are decided at the local level, but little is known regarding their impact on the screening and management of cardiovascular risk factors (CVRFs). We thus aimed at assessing geographical levels of CVRFs in Switzerland. METHODS: Swiss Health Survey for 2007 (N = 17,879). Seven administrative regions were defined: West (Leman), West-Central (Mittelland), Zurich, South (Ticino), North-West, East and Central Switzerland. Obesity, smoking, hypertension, dyslipidemia and diabetes prevalence, treatment and screening within the last 12 months were assessed by interview. RESULTS: After multivariate adjustment for age, gender, educational level, marital status and Swiss citizenship, no significant differences were found between regions regarding prevalence of obesity or current smoking. Similarly, no differences were found regarding hypertension screening and prevalence. Two thirds of subjects who had been told they had high blood pressure were treated, the lowest treatment rates being found in East Switzerland: odds-ratio and [95% confidence interval] 0.65 [0.50-0.85]. Screening for hypercholesterolemia was more frequently reported in French (Leman) and Italian (Ticino) speaking regions. Four out of ten participants who had been told they had high cholesterol levels were treated and the lowest treatment rates were found in German-speaking regions. Screening for diabetes was higher in Ticino (1.24 [1.09 - 1.42]). Six out of ten participants who had been told they had diabetes were treated, the lowest treatment rates were found for German-speaking regions. CONCLUSIONS: In Switzerland, cardiovascular risk factor screening and management differ between regions and these differences cannot be accounted for by differences in populations' characteristics. Management of most cardiovascular risk factors could be improved. PMID- 22452882 TI - Rapid determination of natural steroidal hormones in saliva for the clinical diagnoses. AB - BACKGROUND: Saliva samples are easily collectable and non-invasive, and the monitoring of natural steroidal hormones, such as estrone (E1), 17beta-estradiol (E2), estriol (E3), progesterone (P), and testosterone (T), in saliva has attracted much attention due to its numerous potential clinical and health related applications. Because E1, E2, E3, P and T are useful indicators in numerous clinical and health-related diagnoses, there is a need for simultaneous determination. RESULTS: A gas chromatography-mass spectrometric assay was developed for rapid simultaneous determination of E1, E2, E3, P and T in saliva for clinical diagnoses. Extraction was achieved with a liquid extraction using 3.0 mL of pentane. The extract was dried and silylated with N-methyl-N (trimethylsilyl) trifluoroacetamide/NH4I (100:2) under a catalysis of 1.5% dithioerythritol for 10 min at 90 degrees C. The accuracy of the analytes was in the range of 96% to 112% at concentrations of 0.05 and 0.10 MUg/L (5.0 and 10.0 MUg/L for E3), respectively, with relative standard deviations of less than 11%. The lowest quantification limits were from 0.002 to 0.6 MUg/L for 1.0 mL of saliva. CONCLUSION: Natural steroidal hormones were detected in the concentration ranges of nd to 0.2 MUg/L in human saliva. The salivary testosterone values in the patients with prostatic carcinoma were significantly lower than in normal males. The method may useful in numerous clinical and health-related diagnoses. PMID- 22452883 TI - Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin. AB - Although hyperactivated mTOR is well recognized as being pivotal to prostate cancer growth and progression, the underlying mechanisms by which it promotes such responses remain incompletely understood. Here, we show that rapamycin activates Smads 1 and 5 in human prostate cancer cells and tissues through blocking mTORC1 kinase. Small hairpin RNA-based gene silencing and gene overexpression approaches reveal that Smads 1 and 5 mediate, whereas Smad8 represses, rapamycin-induced cell death and expression of the bone morphogenetic protein (BMP) transcriptional target Id1 in human prostate cancer cell lines. Moreover, such phospho-Smad1/5-mediated rapamycin responses were blocked by LDN 193189 (a BMPRI kinase inhibitor) or Noggin (a BMP antagonist) in LNCaP prostate cancer cells. Likewise, the mTOR kinase inhibitors Ku-0063794 and WYE-354 each enhanced phosphorylation of Smad1/5. Intriguingly, silencing raptor alone enhanced, whereas silencing rictor repressed, the phosphorylation of Smad1/5, indicating that mTORC1 represses, whereas mTORC2 activates, BMP signaling. Immunohistochemical analysis showed increased levels of phospho-Smad1/5 concomitant with suppression of phospho-S6 and survivin levels in PC3 human prostate cancer xenografts in athymic mice administered rapamycin (intraperitoneally, 5 mg/kg/d, 2-6 days). Moreover, we show that compared with prostate tumor tissue from untreated patients, levels of phospho-Smad1/5 were significantly elevated in the prostate tumor tissue of patients with high-risk prostate cancer who received 8 weeks of the rapalog everolimus as part of a neoadjuvant clinical trial before undergoing local definitive therapy by radical prostatectomy. Taken together, our data implicate Smads 1, 5 and 8 as potential prognostic markers and therapeutic targets for mTOR inhibition therapy of prostate cancer. PMID- 22452884 TI - Biological functions of cytokeratin 18 in cancer. AB - The structural proteins cytokeratin 18 (CK18) and its coexpressed complementary partner CK8 are expressed in a variety of adult epithelial organs and may play a role in carcinogenesis. In this study, we focused on the biological functions of CK18, which is thought to modulate intracellular signaling and operates in conjunction with various related proteins. CK18 may affect carcinogenesis through several signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, Wnt, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways. CK18 acts as an identical target of Akt in the PI3K/Akt pathway and of ERK1/2 in the ERK MAPK pathway, and regulation of CK18 by Wnt is involved in Akt activation. Finally, we discuss the importance of gaining a more complete understanding of the expression of CK18 during carcinogenesis, and suggest potential clinical applications of that understanding. PMID- 22452885 TI - Influence of endodontic irrigants on resin sealer bond strength to radicular dentin. AB - The present study evaluated the influence of 2% chlorhexidine and 2.5% sodium hypochlorite on the resin sealer/dentin interface bond strength of AH Plus/gutta percha and Epiphany/Resilon. Seventy-two extracted bovine incisors were randomly distributed into 6 groups according to irrigant and sealers: G(S+AH)=physiologic saline solution+AH Plus/gutta-percha; G(S+Ep)=physiologic saline solution+Epiphany/Resilon; G(H+AH)=2.5% sodium hypochlorite (NaOCl)+AH Plus/gutta percha; G(H+Ep)=2.5% NaOCl+Epiphany/Resilon; G(C+AH)=2% chlorhexidine (CHX)+AH Plus/gutta-percha; and G(C+Ep)=2% CHX+Epiphany/Resilon. After 7 days at 37 degrees C and 100% humidity, the roots were cut transversally on the long axis of the tooth in 0.8 mm (+/-0.09)-thick slices; these slices were then subjected to the push-out test. Data were analyzed using a 2-way ANOVA and Tukey tests at 5% significance. The AH Plus/gutta-percha groups showed significantly higher bond strength than the Epiphany/Resilon groups, regardless of the irrigant used (p<0.001). Sodium hypochlorite adversely affected bond strength in the AH Plus group, whereas chlorhexidine did not influence the push-out bond strength of either sealer (p<0.05). Two percent chlorhexidine did not adversely affect the bond strength of the sealers, whereas 2.5% sodium hypochlorite solution damaged AH Plus/gutta-percha bond strength. PMID- 22452886 TI - Upper gastrointestinal tract cancers as double-cancers in elderly patients with oral squamous cell carcinoma. AB - Against a background of a rapidly aging society, the number of patients with oral cancers in Japan is increasing yearly. The number of double-cancers with oral cancer as the first malignancy is also reportedly on the rise. Esophageal and gastric cancers are the most common second malignancies. At our institution, our policy is to proactively perform upper gastrointestinal (GI) fiberscopy (GIF) in patients with oral cancer. In anticipation of a probable further increase in the number of patients with double-cancers consisting of oral and GI tract malignancies, we retrospectively analyzed the occurrence of upper GI tract cancers in patients with oral squamous cell carcinoma (OSCC). The cohort consisted of 171 patients in whom OSCC had been diagnosed and who had undergone upper GIF between March 1996 and August 2008. Multivariate analysis was performed. Upper GIF identified 8 patients (7 men, 1 woman, totaling 4.7% of 171 patients) with double-cancer in the upper GI tract. One patient had a triple malignancy consisting of oral, esophageal and gastric cancers. Seven patients had esophageal cancer, while two had gastric cancer. An age of over 65 years was significantly higher in patients with double-cancers including esophageal cancer than in patients without esophageal cancer (OR=10.454, 95% CI=1.143-95.621). None of the other analyzed patient factors (sex, smoking habit, drinking habit, site of OSCC, TNM classification, staging results) showed a significant difference. These results indicate that, when treating elderly patients with oral cancers, physicians need to devise suitable treatment plans which take into account the possibility of upper GI tract cancer, particularly esophageal cancer, as a double cancer. PMID- 22452887 TI - Lymphoepithelial cysts of oral mucosa: two cases in different regions. AB - Lymphoepithelial cyst of the oral cavity is a rare cystic lesion that presents as an asymptomatic, well-circumscribed, yellowish small submucosal nodule covered by normal overlying mucosa, usually located in the floor of the mouth or in the ventral or posterolateral surface of the tongue. Histopathological examination reveals a cyst lined by a stratified squamous epithelium surrounded by lymphoid tissue. In this paper, we report two cases of oral lymphoepithelial cyst, one on the anterior floor of the mouth and another on the posterior lateral tongue. In both cases, the patients were women aged approximately 50 years and the lesions were treated by local surgical excision, with no evidence of recurrence after 2 years of follow-up. PMID- 22452888 TI - A case of apical fenestration misdiagnosed as persistent apical periodontitis. AB - We report a case of apical fenestration misdiagnosed as persistent apical periodontitis. The patient was a 55-year-old woman who presented with persistent tooth pain at the right maxillary canine, despite repeated root canal treatment by a general practitioner. When the patient visited Tokyo Dental College Suidobashi Hospital, a CT examination was performed and apical fenestration diagnosed. The patient received an apicoectomy after which the symptoms disappeared. This suggests that dentists should consider the possibility of apical fenestration when examining patients with persistent tooth pain after repeated root canal treatment. PMID- 22452889 TI - Digital video image processing from dental operating microscope in endodontic treatment. AB - Recently, optical microscopes have been used in endodontic treatment, as they offer advantages in terms of magnification, illumination, and documentation. Documentation is particularly important in presenting images to patients, and can take the form of both still images and motion video. Although high-quality still images can be obtained using a 35-mm film or CCD camera, the quality of still images produced by a video camera is significantly lower. The purpose of this study was to determine the potential of RegiStax in obtaining high-quality still images from a continuous video stream from an optical microscope. Video was captured continuously and sections with the highest luminosity chosen for frame alignment and stacking using the RegiStax program. The resulting stacked images were subjected to wavelet transformation. The results indicate that high-quality images with a large depth of field could be obtained using this method. PMID- 22452890 TI - Prepulse facilitation of calcium channel current in osteoblasts. AB - Osteoblasts play a major role in bone formation. Osteoblasts employ intracellular Ca(2+) as a second messenger modulating hormonal responses and a cofactor for bone mineralization. Voltage-dependent Ca(2+) channels (VDCCs) are most commonly present in excitable cell membranes. They are also present at lower levels even in most nonexcitable cells too. In both types of cell, they mediate the influx of Ca(2+) in response to membrane depolarization. Prepulse facilitation is a phenomenon in which a long and strong depolarizing pulse induces a form of VDCC that exhibits an increased opening probability. We believe this to be the first study to demonstrate that strong depolarization prepulses both increase and decrease VDCCs in osteoblasts. PMID- 22452891 TI - Relationship between Eichner Index and number of present teeth. AB - The aim of this study was to determine the percentage of participants in each of the six Eichner Index groups by number of present teeth (PT). The data were obtained from a periodontal disease examination carried out under a health promotion law in a city located northeast of Tokyo, Japan, in 2005. Data from a total of 1,549 (524 male and 1,025 female) 60-year-old participants were analyzed in this study. Number of occlusal supports was counted by analyzing dental charts. The Eichner Index was used to group the participants into six groups based on distribution of occlusal support teeth. The percentage of patients in Group A with 24 PT was 31.4%; none in Group A had fewer than 19 PT. The percentage in Groups A, B1, and B2 with between 20 and 28 PT was above 50%; the number of participants in these groups with fewer than 20 PT decreased rapidly. Those with fewer than 16 PT were almost found in Groups B3, B4 and C. Only a few patients in Group C had between 10 and 14 PT; those with fewer than 9 PT were only found in Groups B4 or C. Based on these results, the Eichner Index category of a given participant can be estimated from number of PT. PMID- 22452892 TI - The STAMPEDE trial and celecoxib: how to adapt? PMID- 22452893 TI - A new generation of EGFR tyrosine-kinase inhibitors in NSCLC. PMID- 22452894 TI - Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. AB - BACKGROUND: Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). METHODS: Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0.92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. FINDINGS: 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0.94 (95% CI 0.74 1.20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43 58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. INTERPRETATION: Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. FUNDING: Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK). PMID- 22452895 TI - Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. AB - BACKGROUND: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. METHODS: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. FINDINGS: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). INTERPRETATION: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR mutation-positive NSCLC. FUNDING: Boehringer Ingelheim Inc. PMID- 22452896 TI - Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. AB - BACKGROUND: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. METHODS: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0 1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. FINDINGS: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10.8 months (95% CI 10.0-12.0) in the afatinib group and 12.0 months (10.2-14.3) in the placebo group (hazard ratio 1.08, 95% CI 0.86-1.35; p=0.74). Median progression-free survival was longer in the afatinib group (3.3 months, 95% CI 2.79-4.40) than it was in the placebo group (1.1 months, 0.95-1.68; hazard ratio 0.38, 95% CI 0.31-0.48; p<0.0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. INTERPRETATION: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. FUNDING: Boehringer Ingelheim Inc. PMID- 22452897 TI - Calcium affects on vascular endpoints. AB - Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research. PMID- 22452898 TI - The safety of sputum induction in adults with acute exacerbation of COPD. AB - INTRODUCTION: Induced sputum is a non-invasive method, and a useful tool to evaluate inflammatory cells and mediators in the airway lumen in the setting of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the inhalation of hypertonic saline solution to induce sputum may cause a bronchoconstrictive response, so it is important to evaluate the success and safety of sputum induction (SI). OBJECTIVES: The aims of this study were to assess the safety and efficacy of SI in adults with AECOPD. METHODS: Eighty-three AECOPD subjects and 26 healthy controls underwent a modified SI. The outcome measures included fall in lung function during induction and success of SI. RESULTS: Adults hospitalized with AECOPD had moderate to very severe airflow obstruction. SI was successful in over 80% of subjects. The percentage decrease in forced expiratory volume in 1s (FEV1 ) from baseline by the Global initiative for Chronic Obstructive Lung Disease (GOLD) category was median 1.2(interquartile range, 0.5-3.3)(GOLD II), 2.3(1.3-3.2)(GOLD III), 5.2(3.3-8.6)(GOLD IV) and 1.4(0.5-3.2)(control), respectively. A fall in FEV1 of >20% occurred in only one subject with AECOPD who was in GOLD category III. The decrease in percentage of FEV1 from baseline was greatest in the second stage of induction, and correlated with that of the final stage (r=0.589; P=0.01). The fall in FEV1 during induction increased with GOLD category (P<0.05). CONCLUSIONS: SI can be safely and successfully performed in patients with moderate to very severe chronic obstructive pulmonary disease who experience an exacerbation using this modified induction protocol. The early decrease in FEV1 can be used to predict the maximum fall. PMID- 22452899 TI - Control of intestinal bacterial proliferation in regulation of lifespan in Caenorhabditis elegans. AB - BACKGROUND: A powerful approach to understanding complex processes such as aging is to use model organisms amenable to genetic manipulation, and to seek relevant phenotypes to measure. Caenorhabditis elegans is particularly suited to studies of aging, since numerous single-gene mutations have been identified that affect its lifespan; it possesses an innate immune system employing evolutionarily conserved signaling pathways affecting longevity. As worms age, bacteria accumulate in the intestinal tract. However, quantitative relationships between worm genotype, lifespan, and intestinal lumen bacterial load have not been examined. We hypothesized that gut immunity is less efficient in older animals, leading to enhanced bacterial accumulation, reducing longevity. To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional marker of intestinal immunity. RESULTS: We show that as adult worms age, several C. elegans genotypes show diminished capacity to control intestinal bacterial accumulation. We provide evidence that intestinal bacterial load, regulated by gut immunity, is an important causative factor of lifespan determination; the effects are specified by bacterial strain, worm genotype, and biologic age, all acting in concert. CONCLUSIONS: In total, these studies focus attention on the worm intestine as a locus that influences longevity in the presence of an accumulating bacterial population. Further studies defining the interplay between bacterial species and host immunity in C. elegans may provide insights into the general mechanisms of aging and age-related diseases. PMID- 22452900 TI - Senescence determines the fate of activated rat pancreatic stellate cells. AB - In chronic pancreatitis (CP), persistent activation of pancreatic stellate cells (PSC) converts wound healing into a pathological process resulting in organ fibrosis. Here, we have analysed senescence as a novel mechanism involved in the termination of PSC activation and tissue repair. PSC senescence was first studied in vitro by establishing long-term cultures and by applying chemical triggers, using senescence-associated beta-Galactosidase (SA beta-Gal) as a surrogate marker. Subsequently, susceptibility of PSC to immune cell-mediated cytolysis was investigated employing cocultures. Using the model of dibutyltin dichloride induced CP in rats, appearance of senescent cells was monitored by immunohistochemistry and immunofluorescence, and correlated with the progression of tissue damage and repair, immune cell infiltration and fibrosis. The results indicated that long-term culture and exposure of PSC to stressors (doxorubicin, H(2) O(2) and staurosporine) induced senescence. Senescent PSC highly expressed CDKN1A/p21, mdm2 and interleukin (IL)-6, but displayed low levels of alpha-smooth muscle actin. Senescence increased the susceptibility of PSC to cytolysis. In CP, the number of senescent cells correlated with the severity of inflammation and the extension of fibrosis. Areas staining positive for SA beta-Gal overlapped with regions of fibrosis and dense infiltrates of immune cells. Furthermore, a close physical proximity of immune cells and activated PSC was observed. We conclude that inflammation, PSC activation and cellular senescence are timely coupled processes which take place in the same microenvironment of the inflamed pancreas. Lymphocytes may play a dual-specific role in pancreatic fibrogenesis, triggering both the initiation of wound healing by activating PSC, and its completion by killing senescent stellate cells. PMID- 22452901 TI - On the crisis of conscience. AB - OBJECTIVE: This paper examines the crisis of conscience as portrayed in the biblical story of Abraham and Isaac. CONCLUSION: The perspective of allegory allows intense emotion to be contained, and placed in a socio-cultural context, which may work against bloodshed. PMID- 22452902 TI - Culture, context and therapeutic processes: delivering a parent-child intervention in a remote Aboriginal community. AB - OBJECTIVE: Little is written about the process of delivering mainstream, evidence based therapeutic interventions for Aboriginal children and families in remote communities. Patterns of interaction between parents and children and expectations about parenting and professional roles and responsibilities vary across cultural contexts. This can be a challenging experience for professionals accustomed to work in urban settings. Language is only a part of cultural difference, and the outsider in a therapeutic group in an Aboriginal community is outside not only in language but also in access to community relationships and a place within those relationships. METHOD: This paper uses examples from Let's Start, a therapeutic parent-child intervention to describe the impact of distance, culture and relationships in a remote Aboriginal community, on the therapeutic framework, group processes and relationships. RESULTS: Cultural and contextual factors influence communication, relationships and group processes in a therapeutic group program for children and parents in a remote Aboriginal community. Group leaders from within and from outside the community, are likely to have complementary skills. CONCLUSIONS: Cultural and contextual factors influence communication, relationships and group processes in a therapeutic group program for children and parents in a remote Aboriginal community. Group leaders from within and from outside the community, are likely to have complementary skills. Program adaptation, evaluation and staff training and support need to take these factors into account to ensure cultural accessibility without loss of therapeutic fidelity and efficacy. PMID- 22452903 TI - Acute anterior compartment syndrome associated with psychogenic polydipsia. AB - OBJECTIVE: The aim of this paper is to describe the association of psychogenic polydipsia with anterior compartment syndrome. METHOD: Case report. RESULTS: A 31 year-old man with glucose-6-phosphate-dehydrogenase (G6PD) deficiency had a history of paranoid schizophrenia from age 16 complicated by the use of drugs. Four years after the initial diagnosis of schizophrenia, he developed psychogenic polydipsia. This was complicated by episodic severe acute hyponatraemia with seizures and, on one occasion, by generalized rhabdomyolysis. One episode of severe acute hyponatraemia with delirium led to anterior compartment syndrome in both legs. Delayed diagnosis and treatment led to extensive myonecrosis and permanent bilateral foot drop. For 6 years his polydipsia remained partially controlled in a locked psychiatric ward with limited leave, until his sudden death related to severe water intoxication. CONCLUSIONS: Anterior compartment syndrome is a rare event associated with psychogenic polydipsia. Psychiatrists, physicians and surgeons should be aware of the seriousness of anterior compartment syndrome and its potential to increase morbidity in patients with psychogenic polydipsia. PMID- 22452904 TI - Environmental factors associated with overweight among adults in Nigeria. AB - BACKGROUND: Understanding environmental factors related to obesity can inform interventions for the world wide obesity epidemic, yet no study has been conducted in this context in Africa. This study examined associations between neighbourhood environment variables and overweight in Nigerian adults. METHODS: A total of 1818 randomly selected residents (age: 20-65 years, 40% female, 31% overweight and 61.2% response) living in high and low socioeconomic (SES) neighbourhoods in Metropolitan Maiduguri, Nigeria, participated in a cross sectional study. Anthropometric measurements of height and weight and an interview-assisted self-reported measure of 16 items of perceived neighborhood environments were conducted. The primary outcome was overweight (body mass index [BMI] > or = 25 kg/m(2)) vs. normal weight (BMI = 18.5-24.9 kg/m(2)). RESULTS: After adjustment for sociodemographic variables, overweight was associated with distant access to commercial facilities (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02- 2.18), poor neighbourhood aesthetics (OR, 1.58; 95% CI, 1.16 2.09), perceiving garbage and offensive odours in the neighbourhood (OR, 1.41; 95% CI, 1.05-1.89) and feeling unsafe from crime at night (OR, 1.47; 95% CI, 1.13 1.91) and unsafe from traffic (OR, 1.56; 95% CI, 1.17-2.07) in the total sample. Significant interactions regarding overweight were found between gender and four environmental variables, with low residential density (OR, 1.39; 95% CI, 1.02 1.93) and poorly maintained pedestrian pathways (OR, 1.89; 95% CI, 1.13-3.17) associated with overweight in men only, and absence of beautiful things (OR, 2.23; 95% CI, 1.42-3.50) and high traffic making it unsafe to walk (OR, 2.39; 95% CI, 1.49-3.83) associated with overweight in women only. There were few significant interactions between environmental factors and neighborhood SES regarding overweight. CONCLUSION: Neighbourhood environment factors were associated with being overweight among Nigerian adults. These findings support previous reports in international literature, but should be replicated in other African studies before any firm conclusions can be drawn. PMID- 22452905 TI - The role of emotion in PTSD: two preliminary studies. AB - BACKGROUND: Two studies are presented that highlight the role of emotion in PTSD in which we examine what emotions in addition to anxiety may be present. AIMS: The first aim was to assess the overall emotion profile across the five basic emotions of anxiety, sadness, anger, disgust, and happiness in clients attending a stress clinic. A small pilot study was also carried out to see how the emotion profiles impacted on outcome for CBT. METHOD: In Study 1, 75 consecutive attenders at a trauma service who were diagnosed with PTSD were assessed with a number of measures that included the Basic Emotions Scale. RESULTS: The results showed that less than 50% of PTSD cases presented with anxiety as the primary emotion, with the remainder showing primary emotions of sadness, anger, or disgust rather than anxiety. A second pilot study involved the follow-up across exposure-based CBT of 20 of the participants from Study 1. CONCLUSIONS: The results suggest that anxiety-based PTSD is more likely to benefit from exposure than is non-anxiety based PTSD. Implications both for the classification and the treatment of PTSD are considered. PMID- 22452906 TI - What are the most revealing interview questions? PMID- 22452907 TI - Faculty empathy and the hidden curriculum. PMID- 22452909 TI - Additional ways to better reduce medical errors and adverse events. PMID- 22452911 TI - Toward a better understanding of the retention of physician-scientists in the career pipeline. PMID- 22452913 TI - Commentary: Lost in translation? How electronic health records structure communication, relationships, and meaning. AB - The media through which we communicate shape how we think, how we act, and who we are. Electronic health records (EHRs) may promote more effective, efficient, coordinated, safer care. Research is emerging, but more is needed to assess the effect of EHRs on communication, relationships, patients' trust, adherence, and health outcomes. The authors posit that EHRs introduce a "third party" into exam room interactions that competes with the patient for clinicians' attention, affects clinicians' capacity to be fully present, and alters the nature of communication, relationships, and physicians' sense of professional role. Screen driven communication inhibits patients' narratives and diminishes clinicians' responses to patients' cues about psychosocial issues and emotional concerns. Students, trainees, and clinicians can, however, learn to integrate EHRs into triadic exam room interactions to facilitate information sharing and shared decision making.Student exposure to EHRs is currently limited. Educators and researchers should implement curricula and assessment tools to help learners integrate EHRs into clinical interactions in ways that foster, rather than diminish, communication and relationships. Further, educators must prioritize the teaching and modeling of self-awareness and self-calibration, mindful presence, and compassion within such curricula to prevent these important qualities and skills from being lost in translation in the digital era. PMID- 22452914 TI - Artist's statement: #485 (Juliet's balcony series). PMID- 22452915 TI - PPQRST revisited. PMID- 22452917 TI - Medicine and the arts. Red Beard (1965) directed by Akira Kurosawa. Commentary. PMID- 22452918 TI - Reflections on the ideal physician. PMID- 22452919 TI - AM last page: A guide to research paradigms relevant to medical education. PMID- 22452920 TI - Identifying microRNA/mRNA dysregulations in ovarian cancer. AB - BACKGROUND: MicroRNAs are a class of noncoding RNA molecules that co-regulate the expression of multiple genes via mRNA transcript degradation or translation inhibition. Since they often target entire pathways, they may be better drug targets than genes or proteins. MicroRNAs are known to be dysregulated in many tumours and associated with aggressive or poor prognosis phenotypes. Since they regulate mRNA in a tissue specific manner, their functional mRNA targets are poorly understood. In previous work, we developed a method to identify direct mRNA targets of microRNA using patient matched microRNA/mRNA expression data using an anti-correlation signature. This method, applied to clear cell Renal Cell Carcinoma (ccRCC), revealed many new regulatory pathways compromised in ccRCC. In the present paper, we apply this method to identify dysregulated microRNA/mRNA mechanisms in ovarian cancer using data from The Cancer Genome Atlas (TCGA). METHODS: TCGA Microarray data was normalized and samples whose class labels (tumour or normal) were ambiguous with respect to consensus ensemble K-Means clustering were removed. Significantly anti-correlated and correlated genes/microRNA differentially expressed between tumour and normal samples were identified. TargetScan was used to identify gene targets of microRNA. RESULTS: We identified novel microRNA/mRNA mechanisms in ovarian cancer. For example, the expression level of RAD51AP1 was found to be strongly anti-correlated with the expression of hsa-miR-140-3p, which was significantly down-regulated in the tumour samples. The anti-correlation signature was present separately in the tumour and normal samples, suggesting a direct causal dysregulation of RAD51AP1 by hsa-miR-140-3p in the ovary. Other pairs of potentially biological relevance include: hsa-miR-145/E2F3, hsa-miR-139-5p/TOP2A, and hsa-miR-133a/GCLC. We also identified sets of positively correlated microRNA/mRNA pairs that are most likely result from indirect regulatory mechanisms. CONCLUSIONS: Our findings identify novel microRNA/mRNA relationships that can be verified experimentally. We identify both generic microRNA/mRNA regulation mechanisms in the ovary as well as specific microRNA/mRNA controls which are turned on or off in ovarian tumours. Our results suggest that the disease process uses specific mechanisms which may be significant for their utility as early detection biomarkers or in the development of microRNA therapies in treating ovarian cancers. The positively correlated microRNA/mRNA pairs suggest the existence of novel regulatory mechanisms that proceed via intermediate states (indirect regulation) in ovarian tumorigenesis. PMID- 22452921 TI - Phenotypic changes to the endogenous antigen-specific CD8+ T cell response correlates with the development and resolution of allergic airway disease. AB - The role of CD8(+) T cells in the pathogenesis of asthma remains controversial, as both pro- and anti-inflammatory functions have been suggested. This study was designed to examine the endogenous CD8(+) T cell response in a biphasic ovalbumin (OVA)-induced model of allergic airway disease (AAD) and its subsequent resolution with the development of local inhalational tolerance (LIT). We observed increases in OVA-specific CD8(+) T cell numbers in the local lung compartments (bronchoalveolar lavage, lung tissue, hilar lymph node) at AAD and LIT; systemic compartments (spleen, inguinal lymph node) displayed no such increases in CD8(+) T cell numbers. OVA-specific CD8(+) T cells appeared to exhibit plasticity both phenotypically and functionally. They possessed pro inflammatory characteristics at AAD, with high phenotypic expression of CD11a and increased functional expression of granzyme B and interferon-gamma. In contrast, at LIT they showed increased phenotypic expression of the inhibitory marker NKG2A and functionally did not produce granzyme B or interferon-gamma. In addition, in a discontinuous model the OVA-specific CD8(+) T cells could be recalled on re exposure to OVA, demonstrating memory. Finally, confocal microscopy results showed that OVA-specific CD8(+) T cells at AAD are associated with B cell aggregates in lung tissue. These B cell aggregates resembled tertiary ectopic lymphoid tissue and may thus provide a local environment for the salient cellular interactions that contribute to the development of LIT. PMID- 22452922 TI - Potential relevance of pre-operative quality of life questionnaires to identify candidates for surgical treatment of genital prolapse: a pilot study. AB - BACKGROUND: To evaluate prolapse-related symptoms, quality of life and sexuality of patients with validated questionnaires before and after surgery for genital prolapse and assess relevance of such an evaluation to select women for surgery. METHODS: From November 2009 to April 2010, 16 patients operated on for genital prolapse of grade greater than or equal to 2 (POP-Q classification) were evaluated prospectively by three questionnaires of quality of life Pelvic Floor Distress Inventory (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7) and Pelvic Organ Prolaps/Urinary Incontinence Sexual Questionnaire (PISQ-12). Data were collected the day before surgery and 6 weeks postoperatively. RESULTS: Eleven patients had laparoscopic surgery and five vaginal surgery. There was a significant decrease in pelvic heaviness, vaginal discomfort and urinary symptoms after surgery. The score of symptoms of prolapse, the PFDI-20 score was 98.5 preoperatively and 31.8 postoperatively (p < 0.0001). The score for quality of life, the PFIQ-7 score was 54.5 preoperatively and 7.4 postoperatively (p = 0.001). The score of sexuality, the PISQ-12 score was 35.3 preoperatively and 37.5 postoperatively (p = 0.1). Two of the 3 patients with a PFIQ 7 under or equal to 20 were not improved while all the women with a preoperative PFIQ-7 over 20 were improved after surgery. CONCLUSIONS: This study suggests that surgery improves quality of life of patients with genital prolapse. Quality of life questionnaires could help select good candidates for surgery. Further studies are required to determine threshold to standardize indications of surgery. PMID- 22452923 TI - Swine influenza virus infection dynamics in two pig farms; results of a longitudinal assessment. AB - In order to assess the dynamics of influenza virus infection in pigs, serological and virological follow-ups were conducted in two whole batches of pigs from two different farms (F1 and F2), from 3 weeks of age until market age. Anti-swine influenza virus (SIV) antibodies (measured by ELISA and hemagglutination inhibition) and nasal virus shedding (measured by RRT-PCR and isolation in embryonated chicken eggs and MDCK cells) were carried out periodically. SIV isolates were subtyped and hemagglutinin and neuraminidase genes were partially sequenced and analyzed phylogenetically. In F1, four waves of viral circulation were detected, and globally, 62/121 pigs (51.2%) were positive by RRT-PCR at least once. All F1 isolates corresponded to H1N1 subtype although hemagglutination inhibition results also revealed the presence of antibodies against H3N2. The first viral wave took place in the presence of colostral derived antibodies. Nine pigs were positive in two non-consecutive sampling weeks, with two of the animals being positive with the same isolate. Phylogenetic analyses showed that different H1N1 variants circulated in that farm. In F2, only one isolate, H1N2, was detected and all infections were concentrated in a very short period of time, as assumed for a classic influenza outbreak. These findings led us to propose that influenza virus infection in pigs might present different patterns, from an epidemic outbreak to an endemic form with different waves of infections with a lower incidence. PMID- 22452924 TI - Functional definition of the N450 event-related brain potential marker of conflict processing: a numerical stroop study. AB - BACKGROUND: Several conflict processing studies aimed to dissociate neuroimaging phenomena related to stimulus and response conflict processing. However, previous studies typically did not include a paradigm-independent measure of either stimulus or response conflict. Here we have combined electro-myography (EMG) with event-related brain potentials (ERPs) in order to determine whether a particularly robust marker of conflict processing, the N450 ERP effect usually related to the activity of the Anterior Cingulate Cortex (ACC), is related to stimulus- or to response-conflict processing. EMG provided paradigm-independent measure of response conflict. In a numerical Stroop paradigm participants compared pairs of digits and pressed a button on the side where they saw the larger digit. 50% of digit-pairs were preceded by an effective cue which provided accurate information about the required response. 50% of trials were preceded by a neutral cue which did not communicate the side of response. RESULTS: EMG showed that response conflict was significantly larger in neutrally than in effectively cued trials. The N450 was similar when response conflict was high and when it was low. CONCLUSIONS: We conclude that the N450 is related to stimulus or abstract, rather than to response conflict detection/resolution. Findings may enable timing ACC conflict effects. PMID- 22452925 TI - Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice. AB - Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice. PMID- 22452926 TI - Muscarinic receptors activity in the perirhinal cortex and hippocampus has differential involvement in the formation of recognition memory. AB - In this work we probed the effects of post-trial infusions of the muscarinic receptor antagonist scopolamine on object recognition memory formation. Scopolamine was infused bilaterally immediately after the sample phase in the perirhinal cortex or dorsal hippocampus and animals were tested for short-term (90 min) or long-term (24 h) memory. Results showed that scopolamine impaired short-term memory when injected in either the perirhinal cortex or hippocampus. Nevertheless, scopolamine disrupted long-term memory when administrated in the perirhinal cortex but not when applied in the hippocampus. Long-term memory was unaffected when scopolamine was infused 160 min after the sample phase or 90 min before test phase. Our data indicate that short-term recognition memory requires muscarinic receptors signaling in both the perirhinal cortex and hippocampus, whereas long-term recognition memory depends on muscarinic receptors in the perirhinal cortex but not hippocampus. These results support a differential involvement of muscarinic activity in these two medial temporal lobe structures in the formation of recognition memory. PMID- 22452927 TI - Occurrence of breast cancer subtypes in adolescent and young adult women. AB - INTRODUCTION: Breast cancers are increasingly recognized as heterogeneous based on expression of receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2). Triple-negative tumors (ER-/PR-/HER2-) have been reported to be more common among younger women, but occurrence of the spectrum of breast cancer subtypes in adolescent and young adult (AYA) women aged between 15 and 39 years is otherwise poorly understood. METHODS: Data regarding all 5,605 AYA breast cancers diagnosed in California during the period 2005 to 2009, including ER and PR status (referred to jointly as hormone receptor (HR) status) and HER2 status, was obtained from the population-based California Cancer Registry. Incidence rates were calculated by subtype (triple-negative; HR+/HER2-; HR+/HER2+; HR-/HER2+), and logistic regression was used to evaluate differences in subtype characteristics by age group. RESULTS: AYAs had higher proportions of HR+/HER2+, triple-negative and HR-/HER2+ breast cancer subtypes and higher proportions of patients of non-White race/ethnicity than did older women. AYAs also were more likely to be diagnosed with stage III/IV disease and high-grade tumors than were older women. Rates of HR+/HER2- and triple-negative subtypes in AYAs varied substantially by race/ethnicity. CONCLUSIONS: The distribution of breast cancer subtypes among AYAs varies from that observed in older women, and varies further by race/ethnicity. Observed subtype distributions may explain the poorer breast cancer survival previously observed among AYAs. PMID- 22452928 TI - Controlled human wood smoke exposure: oxidative stress, inflammation and microvascular function. AB - BACKGROUND: Exposure to wood smoke is associated with respiratory symptoms, whereas knowledge on systemic effects is limited. We investigated effects on systemic inflammation, oxidative stress and microvascular function (MVF) after controlled wood smoke exposure. METHODS: In a randomised, double-blinded, cross over study 20 non-smoking atopic subjects were exposed at rest to 14, 220, or 354 MUg/m3 of particles from a well-burning modern wood stove for 3 h in a climate controlled chamber with 2 week intervals. We investigated the level of oxidatively damaged DNA, inflammatory markers and adhesion molecules before and 0, 6 and 20 h after exposure. Six h after exposure we measured MVF non-invasively by digital peripheral artery tonometry following arm ischemia. RESULTS: The MVF score was unaltered after inhalation of clean air (1.58 +/- 0.07; mean +/- SEM), low (1.51 +/- 0.07) or high (1.61 +/- 0.09) concentrations of wood smoke particles in atopic subjects, whereas unexposed non-atopic subjects had higher score (1.91 +/- 0.09). The level of oxidatively damaged DNA, mRNA of ITGAL, CCL2, TNF, IL6, IL8, HMOX1, and OGG1 and surface marker molecules ICAM1, ITGAL and L selectin in peripheral blood mononuclear cells were not affected by inhalation of wood smoke particles. CONCLUSIONS: Exposure to wood smoke had no effect on markers of oxidative stress, DNA damage, cell adhesion, cytokines or MVF in atopic subjects. PMID- 22452929 TI - Causal tapestries for psychology and physics. AB - Archetypal dynamics is a formal approach to the modeling of information flow in complex systems used to study emergence. It is grounded in the Fundamental Triad of realisation (system), interpretation (archetype) and representation (formal model). Tapestries play a fundamental role in the framework of archetypal dynamics as a formal representational system. They represent information flow by means of multi layered, recursive, interlinked graphical structures that express both geometry (form or sign) and logic (semantics). This paper presents a detailed mathematical description of a specific tapestry model, the causal tapestry, selected for use in describing behaving systems such as appear in psychology and physics from the standpoint of Process Theory. Causal tapestries express an explicit Lorentz invariant transient now generated by means of a reality game. Observables are represented by tapestry informons while subjective or hidden components (for example intellectual and emotional processes) are incorporated into the reality game that determines the tapestry dynamics. As a specific example, we formulate a random graphical dynamical system using causal tapestries. PMID- 22452930 TI - Some critical aspects of fractality research. AB - Numerous empirical studies identified fractal noise in human behavior. According to the theory of Self Organized Criticality, long memory 1/f scaling is a signature of stable and adaptive complex dynamical systems. This article discusses the following aspects of fractality research: (a) generation of fractal noise in simulation studies; (b) quality of some popular estimators of fractal parameters; (c) measurement artifacts in cognitive performances. 36 time series obtained in response tasks experiments under three different task conditions serve as empirical basis. PMID- 22452931 TI - Gender consistency and flexibility: using dynamics to understand the relationship between gender and adjustment. AB - Controversy surrounds questions regarding the influence of being gender consistent (i.e., having and expressing gendered characteristics that are consistent with one's biological sex) versus being gender flexible (i.e., having and expressing gendered characteristics that vary from masculine to feminine as circumstances arise) on children's adjustment outcomes, such as self-esteem, positive emotion, or behavior problems. Whereas evidence supporting the consistency hypothesis is abundant, little support exists for the flexibility hypothesis. To shed new light on the flexibility hypothesis, we explored children's gendered behavior from a dynamical perspective that highlighted variability and flexibility in addition to employing a conventional approach that emphasized stability and consistency. Conventional mean-level analyses supported the consistency hypothesis by revealing that gender atypical behavior was related to greater maladjustment, and dynamical analyses supported the flexibility hypothesis by showing that flexibility of gendered behavior over time was related to positive adjustment. Integrated analyses showed that gender typical behavior was related to the adjustment of children who were behaviorally inflexible, but not for those who were flexible. These results provided a more comprehensive understanding of the relation between gendered behavior and adjustment in young children and illustrated for the first time the feasibility of applying dynamical analyses to the study of gendered behavior. PMID- 22452932 TI - The game of futsal as an adaptive process. AB - Some researchers have described team sports as complex, open, and hierarchical systems. This study aimed to investigate and describe how the game of futsal could be characterized as a dynamic adaptive process. One game, which included participation by two amateur teams, was analyzed by examining players' individual (space occupied, skills with and without ball) and collective actions (attacks and defenses). Data were collected through time-continuum notation, and were analyzed through frequencies and clustering, using trend analysis and multiple comparisons, and Ward's minimum variance method with Euclidean distance, respectively. Results revealed four attack patterns for each team, with four defense patterns for one (Blue), and seven for the other (Red), and they showed within-pattern variability. All were performed in an unpredictable manner, with no absolute correspondence between attacks and defenses. The futsal game as an adaptive process was characterized by changing intra- and inter patterns. PMID- 22452933 TI - Endogenously determined cycles: empirical evidence from livestock industries. AB - This paper applies the techniques of phase space reconstruction and recurrence quantification analysis to investigate U.S. livestock cycles in relation to recent literature on the business cycle. Results are presented for pork and cattle cycles, providing empirical evidence that the cycles themselves have slowly diminished. By comparing the evolution of production processes for the two livestock cycles we argue that the major cause for this moderation is largely endogenous. The analysis suggests that previous theoretical models relying solely on exogenous shocks to create cyclical patterns do not fully capture changes in system dynamics. Specifically, the biological constraint in livestock dynamics has become less significant while technology and information are relatively more significant. Concurrently, vertical integration of the supply chain may have improved inventory management, all resulting in a small, less deterministic, cyclical effect. PMID- 22452934 TI - Dentistry and molecular biology: a promising field for tooth agenesis management. AB - Tooth agenesis is the failure of tooth bud development, causing definitive absence of the tooth. It is the most common dental anomaly, affecting up to one quarter of the general population. The main cause is related to abnormal function of specific genes which play key roles during odontogenesis, particularly MSX1 and PAX9. MSX1 is a transcription factor highly expressed in the mesenchyme of developing tooth germs, whereas PAX9 is a transcription factor that shows a direct relationship with craniofacial development, particularly the formation of the palate and teeth. Despite the high frequency of tooth agenesis, there are as yet only a restricted number of mutations in MSX1 and PAX9 that have been associated with non-syndromic tooth agenesis. Thus, a deeper analysis of the gene networks underlying this anomaly is imperative. By means of a literature review based on Medline, PubMed, Lilacs, NCBI, and STRING, performed between 1991 and 2010 and focused on etiologically associated mutations, this work aimed to assess the latest advances in the genetic etiology of tooth agenesis and to offer an insight into how they can assist dental practice in the near future. A better knowledge of the genetic networks underlying tooth agenesis will lead to better treatment options and, perhaps, a tool for early diagnosis possibly related to DNA examination based on polymorphic variants. Such a test based on DNA analysis may be available to and accessible by clinicians, resulting in a more accurate diagnosis and allowing for a better approach to this anomaly. PMID- 22452935 TI - Fluoroquinolone-induced tendinopathy: etiology and preventive measures. AB - Tendinopathy is a serious health problem and its etiology is not fully elucidated. Among intrinsic and extrinsic predisposing factors of tendinopathy, the impact of therapeutic agents, especially fluoroquinolone (FQ) group antibiotics, is recently being recognized. FQs are potent bactericidal agents widely used in various infectious diseases, including community acquired pneumonia and bronchitis, chronic osteomyelitis, traveler's diarrhea, typhoid fever, shigellosis, chronic bacterial prostatitis, uncomplicated cervical and urethral gonorrhea and prophylaxis of anthrax. FQs have an acceptable tolerability range. However, many lines of evidence for developing tendinitis and tendon rupture during FQ use have resulted in the addition of a warning in patient information leaflets. FQ-induced tendinopathy presents a challenge for the clinician because healing response is poor due to low metabolic rate in mature tendon tissue and tendinopathy is more likely to develop in patients who are already at high risk, such as elderly, solid organ transplant recipients and concomitant corticosteroid users. FQs become photo-activated under exposure to ultraviolet light, and this process results in formation and accumulation of intracellular reactive oxygen species (ROS). The subsequent FQ-related oxidative stress disturbs mitochondrial functions, leading to apoptosis. ROS overproduction also has direct cytotoxic effects on extracellular matrix components. Understanding the mechanisms of the FQ-associated tendinopathy may enable designing safer therapeutic strategies, hence optimization of clinical response. In this review, we evaluate multi-factorial etiology of the FQ-induced tendinopathy and discuss proposed preventive measures such as antioxidant use and protection from natural sunlight and artificial ultraviolet exposure. PMID- 22452936 TI - Evaluation of local electric fields generated by transcranial direct current stimulation with an extracephalic reference electrode based on realistic 3D body modeling. AB - In this study, local electric field distributions generated by transcranial direct current stimulation (tDCS) with an extracephalic reference electrode were evaluated to address extracephalic tDCS safety issues. To this aim, we generated a numerical model of an adult male human upper body and applied the 3D finite element method to electric current conduction analysis. In our simulations, the active electrode was placed over the left primary motor cortex (M1) and the reference electrode was placed at six different locations: over the right temporal lobe, on the right supraorbital region, on the right deltoid, on the left deltoid, under the chin, and on the right buccinator muscle. The maximum current density and electric field intensity values in the brainstem generated by the extracephalic reference electrodes were comparable to, or even less than, those generated by the cephalic reference electrodes. These results suggest that extracephalic reference electrodes do not lead to unwanted modulation of the brainstem cardio-respiratory and autonomic centers, as indicated by recent experimental studies. The volume energy density was concentrated at the neck area by the use of deltoid reference electrodes, but was still smaller than that around the active electrode locations. In addition, the distributions of elicited cortical electric fields demonstrated that the use of extracephalic reference electrodes might allow for the robust prediction of cortical modulations with little dependence on the reference electrode locations. PMID- 22452937 TI - SHARPIN is a key regulator of immune and inflammatory responses. AB - Mice with spontaneous mutations in the Sharpin gene develop chronic proliferative dermatitis that is characterized by eosinophilic inflammation of the skin and other organs with increased expression of type 2 cytokines and dysregulated development of lymphoid tissues. The mutant mice share phenotypic features with human hypereosinophilic syndromes. The biological function of SHARPIN and how its absence leads to such a complex inflammatory phenotype in mice are poorly understood. However, recent studies identified SHARPIN as a novel modulator of immune and inflammatory responses. The emerging mechanistic model suggests that SHARPIN functions as an important adaptor component of the linear ubiquitin chain assembly complex that modulates activation of NF-kappaB signalling pathway, thereby regulating cell survival and apoptosis, cytokine production and development of lymphoid tissues. In this review, we will summarize the current understanding of the ubiquitin-dependent regulatory mechanisms involved in NF kappaB signalling, and incorporate the recently obtained molecular insights of SHARPIN into this pathway. Recent studies identified SHARPIN as an inhibitor of beta1-integrin activation and signalling, and this may be another mechanism by which SHARPIN regulates inflammation. Furthermore, the disrupted lymphoid organogenesis in SHARPIN-deficient mice suggests that SHARPIN-mediated NF-kappaB regulation is important for de novo development of lymphoid tissues. PMID- 22452938 TI - The perception of the neighborhood environment changes after participation in a pedometer based community intervention. AB - BACKGROUND: The aim of this study was to investigate whether the perception of the neighbourhood environment alters when changing the physical activity behaviour through a pedometer intervention. FINDINGS: The intervention was implemented for 15 weeks in a small village in Germany, and was based on the individual baseline activity level. Eighty-two inhabitants participated in the study and completed an environmental questionnaire before and after the intervention. Results showed that after the intervention the participants perceived a lower distance to local facilities, a higher availability of bike lanes and infrastructures, a better maintenance of infrastructure, a better network and a safer traffic situation. CONCLUSION: This suggests that a change in the levels of physical activity merges the levels of exposure to the environment which results in different environmental perceptions. PMID- 22452939 TI - Microarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clusters. AB - PURPOSE: Cancer stroma plays an important role in the progression of cancer. Although alterations in miRNA expression have been explored in various kinds of cancers, the expression of miRNAs in cancer stroma has not been explored in detail. EXPERIMENTAL DESIGN: Using a laser microdissection technique, we collected RNA samples specific for epithelium or stroma from 13 colorectal cancer tissues and four normal tissues, and miRNA microarray and gene expression microarray were carried out. The expression status of miRNAs was confirmed by reverse transcriptase PCR. Furthermore, we investigated whether miRNA expression status in stromal tissue could influence the clinicopathologic factors. RESULTS: Oncogenic miRNAs, including two miRNA clusters, miR-17-92a and miR-106b-25 cluster, were upregulated in cancer stromal tissues compared with normal stroma. Gene expression profiles from cDNA microarray analyses of the same stromal tissue samples revealed that putative targets of these miRNA clusters, predicted by Target Scan, such as TGFBR2, SMAD2, and BMP family genes, were significantly downregulated in cancer stromal tissue. Downregulated putative targets were also found to be involved in cytokine interaction and cellular adhesion. Importantly, expression of miR-25 and miR-92a in stromal tissues was associated with a variety of clinicopathologic factors. CONCLUSIONS: Oncogenic miRNAs were highly expressed in cancer stroma. Although further validation is required, the finding that stromal miRNA expression levels were associated with clinicopathologic factors suggests the possibility that miRNAs in cancer stroma are crucially involved in cancer progression. PMID- 22452940 TI - Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer. AB - PURPOSE: To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer. EXPERIMENTAL DESIGN: Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively. RESULTS: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26-0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26-0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively). CONCLUSIONS: JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma. PMID- 22452941 TI - Correlation of ERG expression and DNA methylation biomarkers with adverse clinicopathologic features of prostate cancer. AB - PURPOSE: Fusion of the TMPRSS2 gene with the ERG oncogene and aberrant DNA methylation patterns are commonly found in prostate cancer. The aim of this study was to analyze the relationship between ERG expression, DNA methylation of three biomarkers, and clinicopathologic features of prostate cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for ERG protein was conducted as a surrogate for TMPRSS2-ERG fusions. We analyzed methylation of CYP26A1, TBX15, and HOXD3 in 219 prostatectomy specimens by the quantitative MethyLight assay. DNA methylation was compared between ERG-positive and -negative cases and correlations of ERG and DNA methylation with clinicopathologic features were analyzed using chi(2), Spearman correlation, logistic regression, and Cox regression. RESULTS: ERG expression varied according to Gleason pattern (almost absent in pattern II, highest in pattern III, and lower in pattern IV/V) and showed a strong positive correlation with methylation levels of CYP26A1, TBX15, and HOXD3 (Spearman P < 0.005). TBX15 and HOXD3 methylation were significantly associated with pathologic stage, Gleason score, and Gleason pattern (P <= 0.015). In multivariate regression analysis, PSA, TBX15 high methylation, and HOXD3 high methylation were significantly associated with stage (P < 0.05), whereas ERG expression was negatively correlated with Gleason score (P = 0.003). In univariate time-to recurrence analysis, a combination of HOXD3/TBX15 high methylation predicted recurrence in ERG-positive and -negative cases (P < 0.05). CONCLUSIONS: CYP26A1, TBX15, and HOXD3 are methylation markers of prostate cancer associated with ERG expression and clinicopathologic variables, suggesting that incorporation of these markers may be useful in a pre- and posttreatment clinical setting. PMID- 22452942 TI - Pharmacokinetics and repolarization effects of intravenous and transdermal granisetron. AB - PURPOSE: The need for greater clarity about the effects of 5-HT(3) receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT(3) receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). EXPERIMENTAL DESIGN: In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. RESULTS: A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). CONCLUSION: GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. PMID- 22452943 TI - Survival of 1,181 patients in a phase I clinic: the MD Anderson Clinical Center for targeted therapy experience. AB - PURPOSE: To determine whether the Royal Marsden Hospital (RMH; London, UK) prognostic score for phase I patients can be validated in a large group of individuals seen in a different center and whether other prognostic variables are also relevant, we present an analysis of 1,181 patients treated in the MD Anderson Cancer Center (MDACC; Houston, TX) phase I clinic. EXPERIMENTAL DESIGN: Medical records of 1,181 consecutive patients who were treated on at least one trial in the phase I clinic were reviewed. RESULTS: The median age was 58 years and 50% were women. The median number of prior therapies was four and median survival 10 months [95% confidence interval (CI), 9.1-10.9 months]. Independent factors that predicted shorter survival in a multivariate Cox model and could be internally validated included RMH score of >1 (P < 0.0001; albumin <3.5 g/dL; lactate dehydrogenase >upper limit of normal, and >two sites of metastases), gastrointestinal tumor type (P < 0.0001), and Eastern Cooperative Oncology Group performance status >= 1 (P = 0.0004). The median survival was 24.0, 15.2, 8.4, 6.2, and 4.1 months for patients with 0, 1, 2, 3, and 4 or 5 of the above risk factors, respectively. CONCLUSION: The RMH score was validated in a large group of patients at MDACC. Internal validation of the independent prognostic factors for survival led to the development of the MDACC prognostic score, a modification of the RMH score that strengthens it. PMID- 22452944 TI - Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies. AB - PURPOSE: The mechanisms underlying muscle wasting in patients with cancer remain poorly understood, and consequently there remains an unmet clinical need for new biomarkers and treatment strategies. EXPERIMENTAL DESIGN: Microarrays were used to examine the transcriptome in single biopsies from healthy controls (n = 6) and in paired biopsies [pre-resection baseline (weight-loss 7%) and 8 month post resection follow-up (disease-free/weight-stable for previous 2 months)] from quadriceps muscle of patients with upper gastrointestinal cancer (UGIC; n = 12). RESULTS: Before surgery, 1,868 genes were regulated compared with follow-up (false discovery rate, 6%). Ontology analysis showed that regulated genes belonged to both anabolic and catabolic biologic processes with overwhelming downregulation in baseline samples. No literature-derived genes from preclinical cancer cachexia models showed higher expression in baseline muscle. Comparison with healthy control muscle (n = 6) revealed that despite differences in the transcriptome at baseline (941 genes regulated), the muscle of patients at follow up was similar to control muscle (2 genes regulated). Physical activity (step count per day) did not differ between the baseline and follow-up periods (P = 0.9), indicating that gene expression differences reflected the removal of the cancer rather than altered physical activity levels. Comparative gene expression analysis using exercise training signatures supported this interpretation. CONCLUSIONS: Metabolic and protein turnover-related pathways are suppressed in weight-losing patients with UGIC whereas removal of the cancer appears to facilitate a return to a healthy state, independent of changes in the level of physical activity. PMID- 22452945 TI - MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. AB - PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. DESIGN: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. PMID- 22452946 TI - Antitumor activity of Src inhibitor saracatinib (AZD-0530) in preclinical models of biliary tract carcinomas. AB - Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is, therefore, an urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the nonreceptor tyrosine kinase Src, observing promising antitumor effects of its small-molecule inhibitor saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from patients with BTC. Upon saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28, and TGBC1-TKB. The effect of saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G(0)-G(1) phase, and inhibited cell migration. At high concentrations (median dose from 2.26-6.99 MUmol/L), saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. Here, we provide a demonstration that the targeted inhibition of Src kinase by saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of saracatinib based clinical applications. PMID- 22452947 TI - Off-target function of the Sonic hedgehog inhibitor cyclopamine in mediating apoptosis via nitric oxide-dependent neutral sphingomyelinase 2/ceramide induction. AB - Sonic hedgehog (SHh) signaling is important in the pathogenesis of various human cancers, such as medulloblastomas, and it has been identified as a valid target for anticancer therapeutics. The SHh inhibitor cyclopamine induces apoptosis. The bioactive sphingolipid ceramide mediates cell death in response to various chemotherapeutic agents; however, ceramide's roles/mechanisms in cyclopamine induced apoptosis are unknown. Here, we report that cyclopamine mediates ceramide generation selectively via induction of neutral sphingomyelin phosphodiesterase 3, SMPD3 (nSMase2) in Daoy human medulloblastoma cells. Importantly, short interfering RNA-mediated knockdown of nSMase2 prevented cyclopamine-induced ceramide generation and protected Daoy cells from drug-induced apoptosis. Accordingly, ectopic wild-type N-SMase2 caused cell death, compared with controls, which express the catalytically inactive N-SMase2 mutant. Interestingly, knockdown of smoothened (Smo), a target protein for cyclopamine, or Gli1, a downstream signaling transcription factor of Smo, did not affect nSMase2. Mechanistically, our data showed that cyclopamine induced nSMase2 and cell death selectively via increased nitric oxide (NO) generation by neuronal nitric oxide synthase (n-NOS) induction, in Daoy medulloblastoma, and multiple other human cancer cell lines. Knockdown of n-NOS prevented nSMase2 induction and cell death in response to cyclopamine. Accordingly, N-SMase2 activity-deficient skin fibroblasts isolated from homozygous fro/fro (fragilitas ossium) mice exhibited resistance to NO-induced cell death. Thus, our data suggest a novel off target function of cyclopamine in inducing apoptosis, at least in part, by n NOS/NO-dependent induction of N-SMase2/ceramide axis, independent of Smo/Gli inhibition. PMID- 22452948 TI - Current situation of Leishmania infantum infection in shelter dogs in northern Spain. AB - BACKGROUND: Canine leishmaniosis (CanL) caused by Leishmania infantum is a widespread endemic disease in the Mediterranean basin, though, so far, the north of Spain has been considered a non-endemic area. The aim of the present study was to determine the prevalence of specific antibodies to L. infantum among stray dogs living in shelters in this area, and to evaluate the clinical status (both clinical signs and clinico-pathological abnormalities) of seropositive dogs. Besides L. infantum infection, the epidemiological role of variables like sex, breed and age was also assessed. METHODS: Over the year 2011 a cross-sectional study was conducted on a total of 418 stray dogs. A preliminary entomological survey was carried out using CDC-light traps. The chi-squared test was used to examine relationships between L. infantum seroprevalence and the remaining variables. RESULTS: The overall seroprevalence of L. infantum infection detected was 3% in the Cantabrian coast. In Orense the seroprevalence was 35.6%. In this latter region, the presence of sand fly, Phlebotomus perniciosus was also detected.In general, seropositivity for L. infantum was related to size (large breed dogs versus small) and age, with a significantly higher seroprevalence recorded in younger (0-3 years) and older dogs (> 7 years) than adult dogs. Clinical signs of CanL were observed in 41.3% of the seropositive dogs. The seropositivity for L. infantum infection associated with the presence of clinical signs and/or abnormal laboratory findings shows a prevalence of 4.5%. CONCLUSION: Our data provide new insight into the prevalence of CanL across northern Spain. The situation observed in Orense seems to be worsening compared to the few reports available, with figures being similar to those cited for known endemic areas of Spain. Besides, the presence of P. perniciosus in Orense points out to a risk of the spread of this zoonotic disease in this geographical area. These findings identify a need for an active search for the sand fly vectors of L. infantum across the entire northern spanish region including the rest of Galicia, Asturias, Cantabria and the Basque Country. PMID- 22452949 TI - Characterization of proximal pulmonary arterial cells from chronic thromboembolic pulmonary hypertension patients. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with proximal pulmonary artery obstruction and vascular remodeling. We hypothesized that pulmonary arterial smooth muscle (PASMC) and endothelial cells (PAEC) may actively contribute to remodeling of the proximal pulmonary vascular wall in CTEPH. Our present objective was to characterize PASMC and PAEC from large arteries of CTEPH patients and investigate their potential involvement in vascular remodeling. METHODS: Primary cultures of proximal PAEC and PASMC from patients with CTEPH, with non-thromboembolic pulmonary hypertension (PH) and lung donors have been established. PAEC and PASMC have been characterized by immunofluorescence using specific markers. Expression of smooth muscle specific markers within the pulmonary vascular wall has been studied by immunofluorescence and Western blotting. Mitogenic activity and migratory capacity of PASMC and PAEC have been investigated in vitro. RESULTS: PAEC express CD31 on their surface, von Willebrand factor in Weibel-Palade bodies and take up acetylated LDL. PASMC express various differentiation markers including alpha-smooth muscle actin (alpha-SMA), desmin and smooth muscle myosin heavy chain (SMMHC). In vascular tissue from CTEPH and non-thromboembolic PH patients, expression of alpha-SMA and desmin is down-regulated compared to lung donors; desmin expression is also down regulated in vascular tissue from CTEPH compared to non-thromboembolic PH patients. A low proportion of alpha-SMA positive cells express desmin and SMMHC in the neointima of proximal pulmonary arteries from CTEPH patients. Serum induced mitogenic activity of PAEC and PASMC, as well as migratory capacity of PASMC, were increased in CTEPH only. CONCLUSIONS: Modified proliferative and/or migratory responses of PASMC and PAEC in vitro, associated to a proliferative phenotype of PASMC suggest that PASMC and PAEC could contribute to proximal vascular remodeling in CTEPH. PMID- 22452950 TI - The arbuscular mycorrhizal status has an impact on the transcriptome profile and amino acid composition of tomato fruit. AB - BACKGROUND: Arbuscular mycorrhizal (AM) symbiosis is the most widespread association between plant roots and fungi in natural and agricultural ecosystems. This work investigated the influence of mycorrhization on the economically relevant part of the tomato plant, by analyzing its impact on the physiology of the fruit. To this aim, a combination of phenological observations, transcriptomics (Microarrays and qRT-PCR) and biochemical analyses was used to unravel the changes that occur on fruits from Micro-Tom tomato plants colonized by the AM fungus Glomus mosseae. RESULTS: Mycorrhization accelerated the flowering and fruit development and increased the fruit yield. Eleven transcripts were differentially regulated in the fruit upon mycorrhization, and the mycorrhiza-responsive genes resulted to be involved in nitrogen and carbohydrate metabolism as well as in regulation and signal transduction. Mycorrhization has increased the amino acid abundance in the fruit from mycorrhizal plants, with glutamine and asparagine being the most responsive amino acids. CONCLUSIONS: The obtained results offer novel data on the systemic changes that are induced by the establishment of AM symbiosis in the plant, and confirm the work hypothesis that AM fungi may extend their influence from the root to the fruit. PMID- 22452951 TI - Tricholemmoma and clear cell squamous cell carcinoma (associated with Bowen's disease): immunohistochemical profile in comparison to normal hair follicles. AB - There have been only a few reported comparative immunohistochemical studies of normal hair follicles and tricholemmomas. Clear cell squamous cell carcinomas (SCCs), which are derived from Bowen's disease, histopathologically mimic or are difficult to distinguish from tricholemmal carcinoma. The purpose of and methods used in the present study are as follows: (1) evaluation of whether the immunohistochemical profile (cytokeratin (CK)1, CK10, CK17, CD34, and D2-40) in normal hair follicles is retained in tricholemmomas (11 lesions); and (2) a study of the immunohistochemical profile of in situ or superficially invasive clear cell SCCs (associated with Bowen's disease) (10 lesions) to investigate the presence or absence of tricholemmal differentiation markers in these lesions. The present study demonstrated that (1) the immunohistochemical profile of the normal outer root sheath cells was generally retained in tricholemmomas; (2) in contrast to the D2-40 expression in tricholemmomas (only a peripheral pattern, which is similar to that in the normal outer root sheath), the CD34 expression in tricholemmomas represented in a diffuse pattern, a peripheral pattern, and a combined diffuse and peripheral pattern; (3) tricholemmomas are benign neoplasms with outer root sheath (below the isthmus) differentiation, which characteristically show upregulation of CD34 expression with some functionally similar conditions to the terminal hair follicles in the anagen phase; and (4) there is no clear immunohistochemical evidence of tricholemmal differentiation in clear cell SCC (associated with Bowen's disease). PMID- 22452952 TI - Histopathological periodic acid-schiff stains of nail clippings as a second-line diagnostic tool in onychomycosis. AB - The diagnosis of onychomycosis, using direct microscopy and fungal cultures, is often negative despite the presence of disease. Periodic acid-Schiff (PAS) staining of nail clippings, using histopathological processing, may be positive in these cases. It is not always clear, however, whether the fungal elements detected by PAS staining are pathogenic fungi or some are saprophytes. We aimed to study the efficacy of histopathological PAS staining of nail clippings as a second-line diagnostic tool in onychomycosis. The study included 100 consecutive cases in which direct microscopy and fungal cultures from suspected onychomycosis were negative on one occasion or more. The obtained nail clippings were processed for routine histology, stained with hematoxylin and eosin and PAS, and examined microscopically. Of the 100 cases, 38 (38%) showed positive fungal elements. As a result, 9 patients had sought and received oral antifungal therapy and all achieved complete clinical cure. The histological examination also revealed parakeratosis and globules of plasma, which were statistically significantly more common in the fungal infected nail samples. This may indicate an ongoing inflammatory process associated with onychomycosis. Neutrophils and bacteria were not statistically and significantly more common in the fungal infected nails. We conclude that as a second-line diagnostic tool, PAS stain of nail clippings increases markedly the diagnostic yield of onychomycosis and, consequently, the outcome of therapy. PMID- 22452953 TI - Histologic features of nail cosmetics. AB - Nail cosmetics and adornments are widely used in today's society. However, their histologic features are not well characterized. Routine histologic examination and polarization of nail plate specimens in our academic dermatopathology practice at the Hospital of the University of Pennsylvania revealed 3 distinct histologic patterns of nail cosmetics: a hyperpigmented pattern with diffuse fine granular material, a layered pattern with a single linear band of polarizable material, and a hyperpigmented pattern with larger granules containing flecks of polarizable material. In our experience, submitting clinicians rarely indicate the patient's use of nail polish or other enhancements. Recognition of the histologic features of nail cosmetics is important to prevent confusion with dermatoses affecting the nail unit, and it will help dermatopathologists render more accurate diagnoses. PMID- 22452954 TI - Current issues on the production and utilization of medium-calorific solid recovered fuel: a case study on SRF for the HOTDISC technology. AB - The HOTDISC technology allows the use of Solid Recovered Fuel (SRF) of a coarse grain size in cement rotary kilns. A suitable medium-calorific SRF is produced by mechanical treatment of mixed municipal and commercial waste that was previously used in fluidized bed incineration systems. Through a modification of the production process the quality of the SRF could be improved and its energetic utilization within a cement kiln with an integrated HOTDISC technology was realized. In course of a material flow analysis changes in quality and mass due to planned process changes were simulated on a theoretical basis. Due to a good agreement of the mass and quality prediction with the real data of the material flow analysis conducted after the system implementation it can be stated that by simulation beforehand the security in planning increases while the economic risk can be significantly reduced. Both the material flow analysis as well as practical operational experience confirms that the industrially produced HOTDISC SRF is applicable and can be produced from mixed municipal and commercial solid waste. An improvement in quality of the produced HOTDISC SRF can be shown by positive changes of essential parameters. From a waste management perspective the production and energetic utilization of HOTDISC SRF is reasonable by all means. This is shown by the conduction of an energy and CO2-balance. A growing international importance of the HOTDISC technology and the increased use of medium-calorific SRF are expected. PMID- 22452955 TI - Involvement of citizens in hazardous waste management and use of recycling centres in the city of Madrid (Spain). AB - In Spain, hazardous household waste management by citizens occurs via fixed recycling centres (FRC) and mobile recycling centres (MRC) which usually depend on local governments. This paper addresses a request by the Madrid City Council, in an attempt to improve the service it provides to the city of Madrid. The aim of the study involved analysing the information people possess in relation to hazardous waste and to the use of available equipment, and conducting a post evaluation of the effectiveness of an environmental communication campaign conducted by the Madrid City Council and aimed at providing awareness of the existence of new FRCs and MRCs. To this end, a questionnaire was conducted with 5644 inhabitants of the city of Madrid. Qualitative data was categorized using content analysis followed by chi-squared tests, considering some socio demographic characteristics of the sample, such as age or place of residence (district). Communication campaigns influenced citizen awareness of what constituted hazardous waste, of how to properly separate waste and of the existence of FRCs and MRCs. However, few citizens actually used FRCs or MRC (18% across four districts), a fact that might be related to a lack of knowledge of downstream waste treatment issues, or to self-limiting hindrances to householders, such as distance to recycling centres. It is recommended that future communication campaigns investigate householder needs and pre-conceptions in relation to recycling, as well as tailored education aimed at addressing the barriers, perceived or otherwise, facing citizens. PMID- 22452956 TI - Theoretical analysis of the kinetic performance of laboratory- and full-scale composting systems. AB - Composting research at laboratory-scale is critical for the development of optimized full-scale plants. Discrepancies between processes at laboratory-scale and full-scale systems have been investigated in terms of heat balances, but a kinetic analysis of this issue is still missing. In this study, the composting rate at laboratory-scale was, on average, between 1.9 and 5.7 times faster than in full-scale systems for a set of published studies using municipal solid waste, food waste or similar materials. Laboratory-scale performance and full-scale systems were limited to 71 and 46%, respectively, of their maximum potential due to poor management of environmental process conditions far from their optimum. The main limiting environmental factor was found to be moisture content, followed by temperature. Besides environmental factors, waste composition and particle size were identified as factors accounting for kinetic differences between laboratory- and full-scale systems. Overall, this study identifies those factors that affect the kinetics of the composting process most and revealed a significant margin for reducing process time in full-scale composting. PMID- 22452957 TI - Greenhouse gas emissions of different waste treatment options for sector-specific commercial and industrial waste in Germany. AB - This article investigates greenhouse gas (GHG) emissions from commercial and industrial (C&I) waste treatment considering five sector-specific waste compositions and four different treatment scenarios in Germany. Results show that the highest share of CO2-equivalent emissions can be avoided in each of the analysed industrial sectors if solid recovered fuel (SRF) is produced for co incineration in cement kilns. Across all industries, emissions of approximately 680 kg CO2-eq. Mg-1 C&I waste can be avoided on average under this scenario. The combustion of C&I waste in waste incineration plants without any previous mechanical treatment generates the lowest potential to avoid GHG emissions with a value of approximately 50 kg CO2-eq. Mg-1 C&I waste on average in all industries. If recyclables are sorted, this can save emissions of approximately 280 kg CO2 eq. Mg-1 C&I waste while the treatment in SRF power plants amounts to savings of approximately 210 kg CO2-eq. Mg-1 C&I waste. A comparison of the treatment scenarios of the waste from these five sectors shows that waste treatment of the craft sector leads to the lowest CO2-equivalent reduction rates of all scenarios. In contrast, the treatment of waste from catering sector leads to the highest CO2 equivalent reduction rates except for direct incineration in waste incineration plants. The sensitivity analysis of the different scenarios for this paper shows that the efficiency and the substitution factor of energy have a relevant influence on the result. Changes in the substitution factor of 10% can result in changes in emissions of approximately 55 to 75 kg CO2-eq. Mg-1 in waste incineration plants and approximately 90 kg CO2-eq. Mg-1 in the case of cement kilns. PMID- 22452958 TI - Proposal of a new model to improve the collection of small WEEE: a pilot project for the recovery and recycling of toys. AB - A new collection model was designed and tested in Catalonia (Spain) to foster the separate collection and recycling of electrical and electronic toys, with the participation of selected primary and secondary schools, as well as waste collection points and municipalities. This project approach is very original and important because small household WEEE has low rates of collection (16-21% WEEE within the EU or 5-7% WEEE in Spain) and no research on new approaches to enhance the collection of small WEEE is found in the literature. The project was successful in achieving enhanced toys collection and recycling rates, which went up from the national Spanish average of 0.5% toys before the project to 1.9 and 6% toys during the two project years, respectively. The environmental benefits of the campaign were calculated through a life-cycle approach, accounting for the avoided impact afforded by the reuse of the toys and the recycling of the valuable materials contained therein (such as metals, batteries and circuit boards) and subtracting the additional environmental burdens associated with the establishment of the collection campaign. PMID- 22452959 TI - Public-private sector partnership in household waste management as perceived by residents in south-west Nigeria. AB - In most developing countries public-private sector partnership is becoming increasingly applied in household waste management service delivery especially in urban areas to reduce cost and improve effectiveness. This paper reports a study of householders' perceptions of public-private sector partnership in provision of household waste management services in Ilorin, south-west Nigeria. A multistage random sampling technique was used to select 224 households for the study. The data generated from the survey were analysed using a binary logit model. The results show that most of the respondents were of the opinion that the public private partnership has not been able to improve household waste management services. Time taken to visit solid waste collection point, income and marital status negatively influenced their perceptions, while activities of sanitary inspectors, occupation and gender had positive influence. The public-private partnership will be more effective and sustainable if the public sector could pay more attention to performance monitoring and accountability. PMID- 22452960 TI - Suppressing effect of calcium-based waste on control of bromine flux during the pyrolysis of printed circuit boards. AB - The effect of calcium-based addition on the brominate flux during printed circuit board (PCB) pyrolysis was investigated. It was found that bromine (Br) can be effectively fixed in solid phase during PCB pyrolysis by adding calcium-based waste materials. Phenol and 4-ethylphenol are the major products of pyrolysis. When the two kinds of red mud were used as additive, their content was 85.25 and 84.81%, respectively, which was higher than others. The 2-bromophenol and 2-bromo 4-methyl-benzene are the main Br-containing pyrolysis volatiles. After adding calcium-based additive, these two volatiles were apparently reduced and only small amounts of 2-bromo-4-methyl-benzene were detected in the products, namely 0.71 and 0.86%, respectively for the two kinds of red mud. Hence, no matter from the perspective of product use or simple Br-fixing, the bromine in the three phase products can be effectively regulated and controlled by adding calcium based waste residue during PCB pyrolysis. Finally, the Br-fixing mechanism was analysed. As a result, when calcium-based waste materials were added to the PCB pyrolysis it made bromine fix easily in the resident yielding a byproduct that can be further used. PMID- 22452961 TI - Metals bioleaching from electronic waste by Chromobacterium violaceum and Pseudomonads sp. AB - These days, electronic waste needs to be taken into consideration due to its materials content, but due to the heterogeneity of the metals present, reprocessing of electronic waste is quite limited. The bioleaching of metals from electronic waste was investigated by using cyanogenic bacterial strains (Chromobacterium violaceum, Pseudomonas aeruginosa and Pseudomonas fluorescens). A two-step bioleaching process was followed under cyanide-forming conditions for maximum metals mobilization. Both single and mixed cultures of cyanogenic bacteria were able to mobilize metals from electronic waste with different efficiencies. In all the flasks in which high metal mobilizations were observed, the consequent biomass productions were also high. Pseudomonas aeruginosa was applied in the bioleaching process for the first time and this achieved its bioleaching ability of mobilization of metals from electronic waste. Chromobacterium violaceum as a single culture and a mixture of C. violaceum and P. aeruginosa exhibited maximum metal mobilization. Chromobacterium violaceum was capable of leaching more than 79, 69, 46, 9 and 7% of Cu, Au, Zn, Fe and Ag, respectively at an electronic waste concentration of 1% w/v. Moreover, the mixture of C. violaceum and P. aeruginosa exhibited metals leaching of more than 83, 73, 49, 13 and 8% of total Cu, Au, Zn, Fe, and Ag, respectively. Precious metals were mobilized through bioleaching which might be considered as an industrial application for recycling of electronic waste in the near future. PMID- 22452962 TI - A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. AB - INTRODUCTION: Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent. METHODS: To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls. RESULTS: In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 * 10-14). CONCLUSIONS: This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer. PMID- 22452963 TI - Brain functional connectivity during induced sadness in patients with obsessive compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with a range of emotional abnormalities linked to its defining symptoms, comorbid illnesses and cognitive deficits. The aim of this preliminary study was to examine functional changes in the brain that are associated with experimentally induced sad mood in patients with OCD compared with healthy controls in a frontolimbic circuit relevant to both OCD and mood regulation. METHODS: Participants underwent a validated sad mood induction procedure during functional magnetic resonance imaging. Analyses focused on mapping changes in the functional connectivity of the subgenual anterior cingulate cortex (ACC) within and between the 2 groups in response to successfully induced sadness. RESULTS: We enrolled 11 patients with OCD and 10 age-, sex- and IQ-matched controls in our study. Unlike controls, patients with OCD did not demonstrate predicted increases in functional connectivity between the subgenual ACC and other frontal regions during mood induction. Instead, patients demonstrated heightened connectivity between the subgenual ACC and ventral caudate/nucleus accumbens region and the hypothalamus. LIMITATIONS: Our study included a small, partially medicated patient cohort that precluded our ability to investigate sex or drug effects, evaluate behavioural differences between the groups and perform a whole-brain analysis. CONCLUSION: The ventral striatum and ventral frontal cortex were distinctly and differentially modulated in their connectivity with the subgenual ACC during the experience of sad mood in patients with OCD. These results suggest that, in patients with OCD, induced sadness appears to have provoked a primary subcortical component of the hypothesized "OCD circuit," which may offer insights into why OCD symptoms tend to develop and worsen during disturbed emotional states. PMID- 22452964 TI - Typical investigational medicinal products follow relatively uniform regulations in 10 European Clinical Research Infrastructures Network (ECRIN) countries. AB - BACKGROUND: In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe. METHODS: We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries. RESULTS: Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised. CONCLUSION: The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products. PMID- 22452965 TI - Absorption and metabolism of 4-hydroxyderricin and xanthoangelol after oral administration of Angelica keiskei (Ashitaba) extract in mice. AB - To investigate the absorption and metabolism of 4-hydroxyderricin and xanthoangelol, we established an analytical method based on liquid chromatography tandem mass spectrometry and measured these compounds in the plasma, urine, feces, liver, kidney, spleen, muscle and white adipose tissues of mice orally administered with Ashitaba extract (50-500mg/kg body weight). 4-Hydroxyderricin and xanthoangelol were quickly absorbed into the plasma, with time-to-maximum plasma concentrations of 2 and 0.5h for 4-hydroxyderricin and xanthoangelol, respectively. Although these compounds have similar structures, the total plasma concentration of 4-hydroxyderricin and its metabolites was approximately 4-fold greater than that of xanthoangelol and its metabolites at 24h. 4-Hydroxyderricin and xanthoangelol were mostly excreted in their aglycone forms and related metabolites (glucuronate and/or sulfate forms) in urine between 2 and 4h after oral administration of Ashitaba extract. On the other hand, these compounds were only excreted in their aglycone forms in feces. When tissue distribution of 4 hydroxyderricin and xanthoangelol was estimated 2h after administration of Ashitaba extract, both compounds were detected in all of the tissues assessed, mainly in their aglycone forms, except in the mesenteric adipose tissue. These results suggest that 4-hydroxyderricin and xanthoangelol are rapidly absorbed and distributed to various tissues. PMID- 22452966 TI - Improving arrival time identification in transient elastography. AB - In this paper, we improve the first step in the arrival time algorithm used for shear wave speed recovery in transient elastography. In transient elastography, a shear wave is initiated at the boundary and the interior displacement of the propagating shear wave is imaged with an ultrasound ultra-fast imaging system. The first step in the arrival time algorithm finds the arrival times of the shear wave by cross correlating displacement time traces (the time history of the displacement at a single point) with a reference time trace located near the shear wave source. The second step finds the shear wave speed from the arrival times. In performing the first step, we observe that the wave pulse decorrelates as it travels through the medium, which leads to inaccurate estimates of the arrival times and ultimately to blurring and artifacts in the shear wave speed image. In particular, wave 'spreading' accounts for much of this decorrelation. Here we remove most of the decorrelation by allowing the reference wave pulse to spread during the cross correlation. This dramatically improves the images obtained from arrival time identification. We illustrate the improvement of this method on phantom and in vivo data obtained from the laboratory of Mathias Fink at ESPCI, Paris. PMID- 22452967 TI - Provision and awareness for isoniazid preventive therapy among PLHIV in Addis Ababa, Ethiopia. AB - BACKGROUND: The risk of acquiring tuberculosis by People living with HIV (PLHIV) could significantly be reduced through provision of isoniazid preventive therapy (IPT). In Ethiopia, it is neither practiced well nor researched in depth. Our objective was to assess IPT provision and awareness among PLHIV in Addis Ababa City Administration. METHODS: Between February 2008 and May 2008, a cross sectional facility-based survey was conducted by exit interview of 406 PLHIV from six health facilities. The findings were analyzed and described in this report. RESULTS: The proportion of PLHIV ever had been provided with IPT were 74 of 231 TB free PLHIV (32.0%) and the proportion of having information about IPT among study participants was 29.8%. Females were about two times more informed about the provision of IPT in their health facilities than males [AOR (95%CI): 2.18 (1.31-3.61)]. CONCLUSIONS: We conclude that the practice of provision of IPT for PLHIV is high, but there is room for improvement. Provision of INH for TB free PLHIV has to be strengthened with better diagnostic facilities to certainly rule out active TB cases. PMID- 22452969 TI - Expanding the perspective of translational medicine: the value of observational data. AB - In 2003, the Journal of Translational Medicine was launched to foster the publication of high quality research in both "bench-to-bedside" as well as ex vivo human observation. In spite of the success of several large-scale observational studies, e.g. Framingham Heart Study, the opportunity to expand upon the ex vivo human observation has remained limited within the field of translational medicine. We believe that this presents a significant opportunity that merits consideration in both the planning and analysis of large scale observational studies and can contribute greatly to expanding our approaches in translational medicine. PMID- 22452968 TI - Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke. AB - Brain repair involves a compendium of natural mechanisms that are activated following stroke. From a therapeutic viewpoint, reparative therapies that encourage cerebral plasticity are needed. In the last years, it has been demonstrated that modulatory treatments for brain repair such as trophic factor- and stem cell-based therapies can promote neurogenesis, gliogenesis, oligodendrogenesis, synaptogenesis and angiogenesis, all of which having a beneficial impact on infarct volume, cell death and, finally, and most importantly, on the functional recovery. However, even when promising results have been obtained in a wide range of experimental animal models and conditions these preliminary results have not yet demonstrated their clinical efficacy. Here, we focus on brain repair modulatory treatments for ischaemic stroke, that use trophic factors, drugs with trophic effects and stem cell therapy. Important and still unanswered questions for translational research ranging from experimental animal models to recent and ongoing clinical trials are reviewed here. PMID- 22452970 TI - Occurrence and identification of risk areas of Ixodes ricinus-borne pathogens: a cost-effectiveness analysis in north-eastern Italy. AB - BACKGROUND: Ixodes ricinus, a competent vector of several pathogens, is the tick species most frequently reported to bite humans in Europe. The majority of human cases of Lyme borreliosis (LB) and tick-borne encephalitis (TBE) occur in the north-eastern region of Italy. The aims of this study were to detect the occurrence of endemic and emergent pathogens in north-eastern Italy using adult tick screening, and to identify areas at risk of pathogen transmission. Based on our results, different strategies for tick collection and pathogen screening and their relative costs were evaluated and discussed. METHODS: From 2006 to 2008 adult ticks were collected in 31 sites and molecularly screened for the detection of pathogens previously reported in the same area (i.e., LB agents, TBE virus, Anaplasma phagocytophilum, Rickettsia spp., Babesia spp., "Candidatus Neoehrlichia mikurensis"). Based on the results of this survey, three sampling strategies were evaluated a-posteriori, and the impact of each strategy on the final results and the overall cost reductions were analyzed. The strategies were as follows: tick collection throughout the year and testing of female ticks only (strategy A); collection from April to June and testing of all adult ticks (strategy B); collection from April to June and testing of female ticks only (strategy C). RESULTS: Eleven pathogens were detected in 77 out of 193 ticks collected in 14 sites. The most common microorganisms detected were Borrelia burgdorferi sensu lato (17.6%), Rickettsia helvetica (13.1%), and "Ca. N. mikurensis" (10.5%). Within the B. burgdorferi complex, four genotypes (i.e., B. valaisiana, B. garinii, B. afzelii, and B. burgdorferi sensu stricto) were found. Less prevalent pathogens included R. monacensis (3.7%), TBE virus (2.1%), A. phagocytophilum (1.5%), Bartonella spp. (1%), and Babesia EU1 (0.5%). Co infections by more than one pathogen were diagnosed in 22% of infected ticks. The prevalences of infection assessed using the three alternative strategies were in accordance with the initial results, with 13, 11, and 10 out of 14 sites showing occurrence of at least one pathogen, respectively. The strategies A, B, and C proposed herein would allow to reduce the original costs of sampling and laboratory analyses by one third, half, and two thirds, respectively. Strategy B was demonstrated to represent the most cost-effective choice, offering a substantial reduction of costs, as well as reliable results. CONCLUSIONS: Monitoring of tick-borne diseases is expensive, particularly in areas where several zoonotic pathogens co-occur. Cost-effectiveness studies can support the choice of the best monitoring strategy, which should take into account the ecology of the area under investigation, as well as the available budget. PMID- 22452971 TI - Newer fecal tests: opportunities for professionals in laboratory medicine. PMID- 22452972 TI - Perturbation of cytokinin and ethylene-signalling pathways explain the strong rooting phenotype exhibited by Arabidopsis expressing the Schizosaccharomyces pombe mitotic inducer, cdc25. AB - BACKGROUND: Entry into mitosis is regulated by cyclin dependent kinases that in turn are phosphoregulated. In most eukaryotes, phosphoregulation is through WEE1 kinase and CDC25 phosphatase. In higher plants a homologous CDC25 gene is unconfirmed and hence the mitotic inducer Schizosaccharomyces pombe (Sp) cdc25 has been used as a tool in transgenic plants to probe cell cycle function. Expression of Spcdc25 in tobacco BY-2 cells accelerates entry into mitosis and depletes cytokinins; in whole plants it stimulates lateral root production. Here we show, for the first time, that alterations to cytokinin and ethylene signaling explain the rooting phenotype elicited by Spcdc25 expression in Arabidopsis. RESULTS: Expressing Spcdc25 in Arabidopsis results in increased formation of lateral and adventitious roots, a reduction of primary root width and more isodiametric cells in the root apical meristem (RAM) compared with wild type. Furthermore it stimulates root morphogenesis from hypocotyls when cultured on two way grids of increasing auxin and cytokinin concentrations. Microarray analysis of seedling roots expressing Spcdc25 reveals that expression of 167 genes is changed by > 2-fold. As well as genes related to stress responses and defence, these include 19 genes related to transcriptional regulation and signaling. Amongst these was the up-regulation of genes associated with ethylene synthesis and signaling. Seedlings expressing Spcdc25 produced 2-fold more ethylene than WT and exhibited a significant reduction in hypocotyl length both in darkness or when exposed to 10 ppm ethylene. Furthermore in Spcdc25 expressing plants, the cytokinin receptor AHK3 was down-regulated, and endogenous levels of iPA were reduced whereas endogeous IAA concentrations in the roots increased. CONCLUSIONS: We suggest that the reduction in root width and change to a more isodiametric cell phenotype in the RAM in Spcdc25 expressing plants is a response to ethylene over-production. The increased rooting phenotype in Spcdc25 expressing plants is due to an increase in the ratio of endogenous auxin to cytokinin that is known to stimulate an increased rate of lateral root production. Overall, our data reveal important cross talk between cell division and plant growth regulators leading to developmental changes. PMID- 22452973 TI - Arm exercise training in chronic obstructive pulmonary disease: a randomised controlled trial. AB - The aim of this study was to compare the effects of arm endurance training, arm strength training, a combination of arm endurance and strength training, and no arm training on endurance arm exercise capacity. A randomised controlled trial was undertaken with chronic obstructive pulmonary disease subjects randomised into one of four groups to complete 8 weeks of training: (a) arm endurance training (endurance group) consisting of supported and unsupported arm exercises, (b) arm strength training (strength group) using weight machines, (c) a combination of arm endurance and arm strength training (combined group), or (d) no arm training (control group). The primary outcome measurement was endurance arm exercise capacity measured by an endurance arm crank test. Secondary outcomes included functional arm exercise capacity measured by the incremental unsupported arm exercise test and health-related quality of life. A total of 52 subjects were recruited and 38 (73%) completed the study. When comparing the arm endurance group to the control group, there was a significant increase in endurance time of 6 min (95% CI 2-10, p < 0.01) following the interventions. When comparing the combined group to each of the control, endurance and strength groups, there was a significantly greater reduction in dyspnoea and rate of perceived exertion at the end of the functional arm exercise test for the combined group following the interventions. The mode of training to be favoured to increase endurance arm exercise capacity is arm endurance training. However, combined arm endurance and strength training may also be very useful to reduce the symptoms during everyday arm tasks. PMID- 22452974 TI - Nonpharmacological interventions for managing respiratory symptoms in lung cancer. AB - Patients with lung cancer experience significant symptom burden, particularly symptoms of a respiratory nature. Such symptom burden can be distressing for patients and negatively impact their functional status and quality of life. The aim of this review is to evaluate studies of nonpharmacological and noninvasive interventions for the management of respiratory symptoms experienced by patients with lung cancer. In total, 13 studies met the inclusion criteria for this review and included 1383 participants of which 1296 were lung cancer patients. The most frequently assessed and reported symptom was breathlessness (n = 9 studies). Cough and haemoptysis were reported in one study. A variety of outcome measurement tools were used and a broad range of intervention strategies evaluated. Lack of consistency between studies impinged on the ability to combine studies. It is not possible to draw any firm conclusion as to the effectiveness of nonpharmacological interventions for the management of respiratory symptoms in lung cancer. Nonpharmacological interventions may well have an important role to play in the management of some of the respiratory symptoms (or combinations of respiratory symptoms), but more work of higher quality is necessary in the future. PMID- 22452975 TI - Ambulatory oxygen improves the effectiveness of pulmonary rehabilitation in selected patients with chronic obstructive pulmonary disease. AB - The effect of ambulatory oxygen use during pulmonary rehabilitation (PR) has not yet been clearly established, but many studies have shown benefit from oxygen acutely. Two small studies to date demonstrated no clear benefit when oxygen was used in patients who desaturated on exertion during a PR programme. One study showed the benefit of using oxygen during PR in patients who were normoxic at rest and desaturated to a minimum of 88% on exertion. We conducted a single blind, randomised controlled trial comparing PR undertaken either with or without ambulatory oxygen, in those with demonstrable benefit from oxygen at baseline. Subjects from three PR services were recruited who, during baseline assessment, desaturated by more than 4% and to less than 90% on exertion, and walked 10% or more further with ambulatory oxygen on endurance shuttle walk test. Patients were randomised to either room air or oxygen via portable cylinder, titrated to optimise pulse oxygen saturation but up to a maximum flow rate of 6 L/min. All patients then completed a twice weekly, 6- to 7-week PR programme. Data were analysed as per protocol. Totally 51 patients completed the study. At the end of PR, both groups improved with PR, with patients in the oxygen group demonstrating a highly statistically significantly greater mean improvement in endurance walking distance than the controls, 490 m (95% confidence interval 228-750; p <= 0.001), as well as clinically, although not statistically, significant changes in quality of life. The use of ambulatory oxygen during a 6- to 7-week PR programme greatly improved endurance walking distance in patients who desaturated on exertion with a positive acute response to ambulatory oxygen at baseline. PMID- 22452976 TI - Motivations for participating in a clinical trial on an avian influenza vaccine. AB - In this study we describe the sociodemographic characteristics of people participating in a clinical trial on the safety and immunogenicity of a H5N1 influenza vaccine and we identify the main motivations for joining it. PMID- 22452977 TI - Combination of roflumilast with a beta-2 adrenergic receptor agonist inhibits proinflammatory and profibrotic mediator release from human lung fibroblasts. AB - BACKGROUND: Small airway narrowing is an important pathology which impacts lung function in chronic obstructive pulmonary disease (COPD). The accumulation of fibroblasts and myofibroblasts contribute to inflammation, remodeling and fibrosis by production and release of mediators such as cytokines, profibrotic factors and extracellular matrix proteins. This study investigated the effects of the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting beta2 adrenergic agonist indacaterol, both approved therapeutics for COPD, on fibroblast functions that contribute to inflammation and airway fibrosis. METHODS: The effects of roflumilast and indacaterol treatment were characterized on transforming growth factor beta1 (TGFbeta1)-treated normal human lung fibroblasts (NHLF). NHLF were evaluated for expression of the profibrotic mediators endothelin-1 (ET-1) and connective tissue growth factor (CTGF), expression of the myofibroblast marker alpha smooth muscle actin, and fibronectin (FN) secretion. Tumor necrosis factor-alpha (TNF-alpha) was used to induce secretion of chemokine C-X-C motif ligand 10 (CXCL10), chemokine C-C motif ligand 5 (CCL5) and granulocyte macrophage colony-stimulating factor (GM-CSF) from NHLF and drug inhibition was assessed. RESULTS: Evaluation of roflumilast (1-10 MUM) showed no significant inhibition alone on TGFbeta1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN protein production, alpha smooth muscle expression, or TNF-alpha-induced secretion of CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF was shown with indacaterol treatment, and a submaximal concentration was chosen for combination studies. When indacaterol (0.1 nM) was added to roflumilast, significant inhibition was seen on all inflammatory and fibrotic mediators evaluated, which was superior to the inhibition seen with either drug alone. Roflumilast plus indacaterol combination treatment resulted in significantly elevated phosphorylation of the transcription factor cAMP response element-binding protein (CREB), an effect that was protein kinase A-dependent. Inhibition of protein kinase A was also found to reverse the inhibition of indacaterol and roflumilast on CTGF. CONCLUSIONS: These results demonstrate that addition of roflumilast to a LABA inhibits primary fibroblast/myofibroblast function and therapeutically this may impact lung fibroblast proinflammatory and profibrotic mediator release which contributes to small airway remodeling and airway obstruction in COPD. PMID- 22452978 TI - KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function. AB - Chromatin remodeling is fundamental for B-cell differentiation. In the present study, we explored the role of KAP1, the cofactor of KRAB-ZFP transcriptional repressors, in this process. B-lymphoid-specific Kap1-KO mice displayed reduced numbers of mature B cells, lower steady-state levels of Abs, and accelerated rates of decay of neutralizing Abs after viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an up-regulation of PTEN, the enzymatic counteractor of PIK3 signaling, and of genes encoding DNA-damage response factors, cell-cycle regulators, and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to several of these genes and controlled chromatin status at their promoters. Genome wide, KAP1 binding sites lacked active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. Our results therefore reveal the role of KRAB/KAP1-mediated epigenetic regulation in B-cell development and homeostasis. PMID- 22452979 TI - Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. AB - Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer. PMID- 22452980 TI - von Willebrand factor (VWF) propeptide binding to VWF D'D3 domain attenuates platelet activation and adhesion. AB - Noncovalent association between the von Willebrand factor (VWF) propeptide (VWFpp) and mature VWF aids N-terminal multimerization and protein compartmentalization in storage granules. This association is currently thought to dissipate after secretion into blood. In the present study, we examined this proposition by quantifying the affinity and kinetics of VWFpp binding to mature VWF using surface plasmon resonance and by developing novel anti-VWF D'D3 mAbs. Our results show that the only binding site for VWFpp in mature VWF is in its D'D3 domain. At pH 6.2 and 10mM Ca(2+), conditions mimicking intracellular compartments, VWFpp-VWF binding occurs with high affinity (K(D) = 0.2nM, k(off) = 8 * 10(-5) s(-1)). Significant, albeit weaker, binding (K(D) = 25nM, k(off) = 4 * 10(-3) s(-1)) occurs under physiologic conditions of pH 7.4 and 2.5mM Ca(2+). This interaction was also observed in human plasma (K(D) = 50nM). The addition of recombinant VWFpp in both flow-chamber-based platelet adhesion assays and viscometer-based shear-induced platelet aggregation and activation studies reduced platelet adhesion and activation partially. Anti-D'D3 mAb DD3.1, which blocks VWFpp binding to VWF-D'D3, also abrogated platelet adhesion, as shown by shear-induced platelet aggregation and activation studies. Our data demonstrate that VWFpp binding to mature VWF occurs in the circulation, which can regulate the hemostatic potential of VWF by reducing VWF binding to platelet GpIbalpha. PMID- 22452981 TI - Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. AB - Patients with heparin-induced thrombocytopenia (HIT) remain at risk for recurrent thromboembolic complications despite improvements in management. HIT is caused by antibodies that preferentially recognize ultralarge complexes (ULCs) of heparin and platelet factor 4 (PF4) tetramers. We demonstrated previously that a variant PF4(K50E) forms dimers but does not tetramerize or form ULCs. Here, we identified small molecules predicted to bind PF4 near the dimer-dimer interface and that interfere with PF4 tetramerization. Screening a library of small molecules in silico for binding at this site, we identified 4 compounds that inhibited tetramerization at micromolar concentrations, designated PF4 antagonists (PF4As). PF4As also inhibited formation of pathogenic ULCs, and 3 of these PF4As promoted the breakdown of preformed ULCs. To characterize the ability of PF4As to inhibit cellular activation, we developed a robust and reproducible assay that measures cellular activation by HIT antibodies via FcgammaRIIA using DT40 cells. PF4As inhibit FcgammaRIIA-dependent activation of DT40 cells by HIT antibodies as well as platelet activation, as measured by serotonin release. PF4As provide new tools to probe the pathophysiology of HIT. They also may provide insight into the development of novel, disease-specific therapeutics for the treatment of thromboembolic complications in HIT. PMID- 22452982 TI - Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions. AB - Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacologic and genetic evidence indicates that autophagy plays pleiotropic functions in cellular homeostasis, development, survival, and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by colony stimulating factor-1. We show here, using pharmacologic inhibitors, siRNA approaches, and Atg7-/- mice, that autophagy initiated by ULK1 is required for proper colony stimulating factor-1-driven differentiation of human and murine monocytes. We also unravel a role for autophagy in macrophage acquisition of phagocytic functions. Collectively, these findings highlight an unexpected and essential role of autophagy during monocyte differentiation and acquisition of macrophage functions. PMID- 22452983 TI - A DTI-based model for TMS using the independent impedance method with frequency dependent tissue parameters. AB - Accurate simulations on detailed realistic head models are necessary to gain a better understanding of the response to transcranial magnetic stimulation (TMS). Hitherto, head models with simplified geometries and constant isotropic material properties are often used, whereas some biological tissues have anisotropic characteristics which vary naturally with frequency. Moreover, most computational methods do not take the tissue permittivity into account. Therefore, we calculate the electromagnetic behaviour due to TMS in a head model with realistic geometry and where realistic dispersive anisotropic tissue properties are incorporated, based on T1-weighted and diffusion-weighted magnetic resonance images. This paper studies the impact of tissue anisotropy, permittivity and frequency dependence, using the anisotropic independent impedance method. The results show that anisotropy yields differences up to 32% and 19% of the maximum induced currents and electric field, respectively. Neglecting the permittivity values leads to a decrease of about 72% and 24% of the maximum currents and field, respectively. Implementing the dispersive effects of biological tissues results in a difference of 6% of the maximum currents. The cerebral voxels show limited sensitivity of the induced electric field to changes in conductivity and permittivity, whereas the field varies approximately linearly with frequency. These findings illustrate the importance of including each of the above parameters in the model and confirm the need for accuracy in the applied patient-specific method, which can be used in computer-assisted TMS. PMID- 22452984 TI - Faster sequencers, larger datasets, new challenges. AB - A report on the Advances in Genome Biology and Technology (AGBT) meeting, Marco Island, Florida, USA, 15-18 February 2012. PMID- 22452986 TI - Systematic review and validation of prediction rules for identifying children with serious infections in emergency departments and urgent-access primary care. AB - BACKGROUND: Although the vast majority of children with acute infections are managed at home, this is one of the most common problems encountered in children attending emergency departments (EDs) and primary care. Distinguishing children with serious infection from those with minor or self-limiting infection is difficult. This can result in misdiagnosis of children with serious infections, which results in a poorer health outcome, or a tendency to refer or admit children as a precaution; thus, inappropriately utilising secondary-care resources. OBJECTIVES: We systematically identified clinical features and laboratory tests which identify serious infection in children attending the ED and primary care. We also identified clinical prediction rules and validated those using existing data sets. DATA SOURCES: We searched MEDLINE, Medion, EMBASE, Cumulative Index to Nursing and Allied Health Literature and Database of Abstracts of Reviews of Effects in October 2008, with an update in June 2009, using search terms that included terms related to five components: serious infections, children, clinical history and examination, laboratory tests and ambulatory care settings. We also searched references of included studies, clinical content experts, and relevant National Institute for Health and Clinical Excellence guidelines to identify relevant studies. There were no language restrictions. Studies were eligible for inclusion if they were based in ambulatory settings in economically developed countries. REVIEW METHODS: Literature searching, selection and data extraction were carried out by two reviewers. We assessed quality using the quality assessment of diagnostic accuracy studies (QUADAS) instrument, and used spectrum bias and validity of the reference standard as exclusion criteria. We calculated the positive likelihood ratio (LR+) and negative likelihood ratio (LR-) of each feature along with the pre- and post-test probabilities of the outcome. Meta-analysis was performed using the bivariate method when appropriate. We externally validated clinical prediction rules identified from the systematic review using existing data from children attending ED or primary care. RESULTS: We identified 1939 articles, of which 35 were selected for inclusion in the review. There was only a single study from primary care; all others were performed in the ED. The quality of the included studies was modest. We also identified seven data sets (11,045 children) to use for external validation. The most useful clinical features for ruling in serious infection was parental or clinician overall concern that the illness was different from previous illnesses or that something was wrong. In low- or intermediate-prevalence settings, the presence of fever had some diagnostic value. Additional red flag features included cyanosis, poor peripheral circulation, rapid breathing, crackles on auscultation, diminished breath sounds, meningeal irritation, petechial rash, decreased consciousness and seizures. Procalcitonin (LR+ 1.75-2.96, LR- 0.08-0.35) and C-reactive protein (LR+ 2.53 3.79, LR- 0.25-0.61) were superior to white cell counts. The best performing clinical prediction rule was a five-stage decision tree rule, consisting of the physician's gut feeling, dyspnoea, temperature >= 40 degrees C, diarrhoea and age. It was able to decrease the likelihood of serious infections substantially, but on validation it provided good ruling out value only in low-to-intermediate prevalence settings (LR- 0.11-0.28). We also identified and validated the Yale Observation Scale and prediction rules for pneumonia, meningitis and gastroenteritis. LIMITATIONS: Only a single study was identified from primary care settings, therefore results may lack generalisability. CONCLUSIONS: Several clinical features are useful to increase or decrease the probability that a child has a serious infection. None is sufficient on its own to substantially raise or lower the risk of serious infection. Some are highly specific ('red flags'), so when present should prompt a more thorough or repeated assessment. C-reactive protein and procalcitonin demonstrate similar diagnostic characteristics and are both superior to white cell counts. However, even in children with a serious infection, red flags will occur infrequently, and their absence does not lower the risk. The diagnostic gap is currently filled by using clinical 'gut feeling' and diagnostic safety-netting, which are still not well defined. Although two prediction rules for serious infection and one for meningitis provided some diagnostic value, we do not recommend widespread implementation at this time. Future research is needed to identify predictors of serious infection in children in primary-care settings, to validate prediction rules more widely, and determine the added value of blood tests in primary-care settings. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22452985 TI - Estrogens need insulin-like growth factor I cooperation to exert their neuroprotective effects in post-menopausal women. AB - BACKGROUND: The abrupt fall in estrogens levels during the menopausal transition may connote an hormonal state predisposing to neurodegenerative disorders, e.g. Alzheimer's disease (AD). Reportedly, the neurotrophic activity of estrogen involves an interaction with IGF-I. AIM: To evaluate the leukocyte gene expression of progesterone receptor (PR-A/B) and interleukin 6 (IL-6), two parameters under the control of estrogens and involved in the pathogenesis of AD. SUBJECTS: The study was conducted in non-demented women divided into two groups according to their pre- or post-menopausal state; each group being further divided into two subgroups based on their circulating levels of IGF-I (normal or low). An additional sample of AD-affected women served as a comparison group. RESULTS: Estrogens maintained their full activity only when IGF-I levels were in the range of normalcy. On the contrary, if the concentrations of one or both hormones were reduced, estrogens were not anymore capable to control the gene expression of PR-A/B or IL-6. CONCLUSIONS: Before administering hormone-based replacement therapy, characterization of the somatotropic function should be performed in the early phase of the menopause. PMID- 22452987 TI - The structure of putative N-acetyl glutamate kinase from Thermus thermophilus reveals an intermediate active site conformation of the enzyme. AB - The de novo biosynthesis of arginine in microorganisms and plants is accomplished via several enzymatic steps. The enzyme N-acetyl glutamate kinase (NAGK) catalyzes the phosphorylation of the gamma-COO(-) group of N-acetyl-L-glutamate (NAG) by adenosine triphosphate (ATP) which is the second rate limiting step in arginine biosynthesis pathway. Here we report the crystal structure of putative N acetyl glutamate kinase (NAGK) from Thermus thermophilus HB8 (TtNAGK) determined at 1.92A resolution. The structural analysis of TtNAGK suggests that the dimeric quaternary state of the enzyme and arginine insensitive nature are similar to mesophilic Escherichia coli NAGK. These features are significantly different from its thermophilic homolog Thermatoga maritima NAGK which is hexameric and arginine sensitive. TtNAGK is devoid of its substrates but contains two sulfates at the active site. Very interestingly the active site of the enzyme adopts a conformation which is not completely open or closed and likely represents an intermediate stage in the catalytic cycle unlike its structural homologs, which all exist either in the open or closed conformation. Engineering arginine biosynthesis pathway enzymes for the production of l-arginine is an important industrial application. The structural comparison of TtNAGK with EcNAGK revealed the structural basis of thermostability of TtNAGK and this information could be very useful to generate mutants of NAGK with increased overall stability. PMID- 22452988 TI - Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function. AB - Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline-NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regulates AS and eNOS transcription to support NO production. Moreover, we show that insulin enhances NO production in response to physiological cues such as bradykinin. To translate these results to an in vivo model, we show that AS transcription is diminished in coronary endothelial cells isolated from rats with streptozotocin (STZ)-induced diabetes. Importantly, we demonstrate restoration of AS and eNOS transcription by insulin treatment in STZ diabetic rats, and show that this restoration was accompanied by improved endothelial function as measured by endothelium-dependent vasorelaxation. Overall, this report demonstrates, both in cell culture and whole animal studies, that insulin maintains vascular function, in part, through the maintenance of AS transcription, thus ensuring an adequate supply of arginine to maintain vascular endothelial response to physiological cues. PMID- 22452989 TI - Stress granules contribute to alpha-globin homeostasis in differentiating erythroid cells. AB - Hemoglobin is the major biosynthetic product of developing erythroid cells. Assembly of hemoglobin requires the balanced production of globin proteins and the oxygen-carrying heme moiety. The heme-regulated inhibitor kinase (HRI) participates in this process by phosphorylating eIF2alpha and inhibiting the translation of globin proteins when levels of free heme are limiting. HRI is also activated in erythroid cells subjected to oxidative stress. Phospho-eIF2alpha mediated translational repression induces the assembly of stress granules (SG), cytoplasmic foci that harbor untranslated mRNAs and promote the survival of cells subjected to adverse environmental conditions. We have found that differentiating erythroid, but not myelomonocytic or megakaryocytic, murine and human progenitor cells assemble SGs, in vitro and in vivo. Targeted knockdown of HRI or G3BP, a protein required for SG assembly, inhibits spontaneous and arsenite-induced assembly of SGs in erythroid progenitor cells. This is accompanied by reduced alpha-globin production and increased apoptosis suggesting that G3BP+ SGs facilitate the survival of developing erythroid cells. PMID- 22452990 TI - Prevalence of Dirofilaria immitis, Ehrlichia canis, Borrelia burgdorferi sensu lato, Anaplasma spp. and Leishmania infantum in apparently healthy and CVBD suspect dogs in Portugal--a national serological study. AB - BACKGROUND: Canine vector-borne diseases (CVBDs) are caused by a wide range of pathogens transmitted to dogs by arthropods including ticks and insects. Many CVBD-agents are of zoonotic concern, with dogs potentially serving as reservoirs and sentinels for human infections. The present study aimed at assessing the seroprevalence of infection with or exposure to Dirofilaria immitis, Ehrlichia canis, Borrelia burgdorferi sensu lato, Anaplasma spp. and Leishmania infantum in dogs in Portugal. METHODS: Based on 120 veterinary medical centres from all the regions of mainland and insular Portugal, 557 apparently healthy and 628 CVBD suspect dogs were sampled. Serum, plasma or whole blood was tested for qualitative detection of D. immitis antigen and antibodies to E. canis, B. burgdorferi s. l., Anaplasma spp. and L. infantum with two commercial in-clinic enzyme-linked immunosorbent assay kits. Odds ratios (OR) were calculated by logistic regression analysis to identify independent risk factors of exposure to the vector-borne agents. RESULTS: Total positivity levels to D. immitis, E. canis, B. burgdorferi, Anaplasma spp., L. infantum, one or more agents and mixed agents were 3.6%, 4.1%, 0.2%, 4.5%, 4.3%, 14.0% and 2.0% in the healthy group, and 8.9%, 16.4%, 0.5%, 9.2%, 25.2%, 46.3% and 11.6% in the clinically suspect group, respectively. Non-use of ectoparasiticides was a risk factor for positivity to one or more agents both in the apparently healthy (OR = 2.1) and CVBD-suspect (OR = 1.5) dogs. Seropositivity to L. infantum (OR = 7.6), E. canis (OR = 4.1) and D. immitis (OR = 2.4) were identified as risk factors for the presence of clinical signs compatible with CVBDs. Positivity to mixed agents was not found to be a risk factor for disease. CONCLUSIONS: Dogs in Portugal are at risk of becoming infected with vector-borne pathogens, some of which are of zoonotic concern. CVBDs should be considered by practitioners and prophylactic measures must be put in place to protect dogs and limit the risk of transmission of vector-borne agents to humans. This study is expected to give veterinary and public health authorities an increased awareness about CVBDs in Portugal and to serve as a reference for future investigations and control actions. PMID- 22452991 TI - Specific tagging of the egress-related osmiophilic bodies in the gametocytes of Plasmodium falciparum. AB - BACKGROUND: Gametocytes, the blood stages responsible for Plasmodium falciparum transmission, contain electron dense organelles, traditionally named osmiophilic bodies, that are believed to be involved in gamete egress from the host cell. In order to provide novel tools in the cellular and molecular studies of osmiophilic body biology, a P. falciparum transgenic line in which these organelles are specifically marked by a reporter protein was produced and characterized. METHODOLOGY: A P. falciparum transgenic line expressing an 80-residue N-terminal fragment of the osmiophilic body protein Pfg377 fused to the reporter protein DsRed, under the control of pfg377 upstream and downstream regulatory regions, was produced. RESULTS: The transgenic fusion protein is expressed at the appropriate time and stage of sexual differentiation and is trafficked to osmiophilic bodies as the endogenous Pfg377 protein. These results indicate that a relatively small N-terminal portion of Pfg377 is sufficient to target the DsRed reporter to the gametocyte osmiophilic bodies. CONCLUSIONS: This is the first identification of a P. falciparum aminoacid sequence able to mediate trafficking to such organelles. To fluorescently tag such poorly characterized organelles opens novel avenues in cellular and imaging studies on their biogenesis and on their role in gamete egress. PMID- 22452992 TI - Anticancer activities of genistein-topotecan combination in prostate cancer cells. AB - Prostate cancer is one of the leading causes of death in men aged 40 to 55. Genistein isoflavone (4', 5', 7-trihydroxyisoflavone) is a dietary phytochemical with demonstrated anti-tumour activities in a variety of cancers. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy drug, primarily used for secondary treatment of ovarian, cervical and small cell lung cancers. This study was to demonstrate the potential anticancer efficacy of genistein-topotecan combination in LNCaP prostate cancer cells and the mechanism of the combination treatment. The LNCaP cells were grown in complete RPMI medium, and cultured at 37 degrees C, 5% CO(2) for 24-48 hrs to achieve 70-90% confluency. The cells were treated with varying concentrations of genistein, topotecan and genistein topotecan combination and incubated for 24 hrs. The treated cells were assayed for (i) post-treatment sensitivity using MTT assay and DNA fragmentation, (ii) treatment-induced apoptosis using caspase-3 and -9 binding assays and (iii) treatment-induced ROS generation levels. The overall data indicated that (i) both genistein and topotecan induce cellular death in LNCaP cells, (ii) genistein topotecan combination was significantly more efficacious in reducing LNCaP cell viability compared with either genistein or topotecan alone, (iii) in all cases, cell death was primarily through apoptosis, via the activation of caspase-3 and 9, which are involved in the intrinsic pathway, (iv) ROS generation levels increased significantly with the genistein-topotecan combination treatment. Treatments involving genistein-topotecan combination may prove to be an attractive alternative phytotherapy or adjuvant therapy for prostate cancer. PMID- 22452993 TI - The Stanford Data Miner: a novel approach for integrating and exploring heterogeneous immunological data. AB - BACKGROUND: Systems-level approaches are increasingly common in both murine and human translational studies. These approaches employ multiple high information content assays. As a result, there is a need for tools to integrate heterogeneous types of laboratory and clinical/demographic data, and to allow the exploration of that data by aggregating and/or segregating results based on particular variables (e.g., mean cytokine levels by age and gender). METHODS: Here we describe the application of standard data warehousing tools to create a novel environment for user-driven upload, integration, and exploration of heterogeneous data. The system presented here currently supports flow cytometry and immunoassays performed in the Stanford Human Immune Monitoring Center, but could be applied more generally. RESULTS: Users upload assay results contained in platform-specific spreadsheets of a defined format, and clinical and demographic data in spreadsheets of flexible format. Users then map sample IDs to connect the assay results with the metadata. An OLAP (on-line analytical processing) data exploration interface allows filtering and display of various dimensions (e.g., Luminex analytes in rows, treatment group in columns, filtered on a particular study). Statistics such as mean, median, and N can be displayed. The views can be expanded or contracted to aggregate or segregate data at various levels. Individual-level data is accessible with a single click. The result is a user driven system that permits data integration and exploration in a variety of settings. We show how the system can be used to find gender-specific differences in serum cytokine levels, and compare them across experiments and assay types. CONCLUSIONS: We have used the tools and techniques of data warehousing, including open-source business intelligence software, to support investigator-driven data integration and mining of diverse immunological data. PMID- 22452994 TI - Quality of life of Chinese urban community residents: a psychometric study of the mainland Chinese version of the WHOQOL-BREF. AB - BACKGROUND: The short version of the World Health Organization's Quality of Life Instrument (WHOQOL-BREF) is widely validated and popularly used in assessing the subjective quality of life (QOL) of patients and the general public. We examined its psychometric properties in a large sample of community residents in mainland China. METHODS: The WHOQOL-BREF was administered to 1052 adult community residents in a major metropolitan city in southern China. The structural integrity of the 4-factor model in confirmatory factor analyses (CFA) and the relationship of QOL with demographic variables were examined. Validity was assessed using the known-group comparison (229 with vs. 823 without chronic illness), item-domain correlations, and CFA using the ML estimation in LISREL. RESULTS: Internal consistency reliability of the whole instrument (26 items) was 0.89, and the psychological, social, and environment domains had acceptable reliability (alpha = 0.76, 0.72, 0.78 respectively), while that of the physical domain was slightly lower (alpha = 0.67). The respective mean scores of these domains were 13.69, 14.11, 12.33 and 14.56. Item-domain correlations were much higher for corresponding domains than for non-corresponding domains, indicating good convergent validity. CFA provided a marginally acceptable fit to the a priori four-factor model when two matching content item pairs were allowed to be correlated; chi2 (244) = 1836, RMSEA = 0.088, NNFI = 0.898, CFI = 0.909. This factorial structure was shown to be equivalent between the participants with and without chronic illness. The differences in means between these two groups were significant but small in some domains; effect size = 0.55, 0.15, 0.18 in the physical, psychological, and social relationship domains respectively. Furthermore, males had significantly higher QOL scores than females in the psychological domain, while individuals with a younger age, higher income, and higher education levels also had significantly higher QOL. Compared with the international data, the Chinese in this study had relatively low QOL scores with about 5% of males and 16% of females being at risk for poor QOL. CONCLUSIONS: This study has provided psychometric properties of the WHOQOL-BREF as used in China and should definitely be useful for researchers who would like to use or further refine the instrument. PMID- 22452995 TI - An integrative probabilistic model for identification of structural variation in sequencing data. AB - Paired-end sequencing is a common approach for identifying structural variation (SV) in genomes. Discrepancies between the observed and expected alignments indicate potential SVs. Most SV detection algorithms use only one of the possible signals and ignore reads with multiple alignments. This results in reduced sensitivity to detect SVs, especially in repetitive regions. We introduce GASVPro, an algorithm combining both paired read and read depth signals into a probabilistic model which can analyze multiple alignments of reads. GASVPro outperforms existing methods with a 50-90% improvement in specificity on deletions and a 50% improvement on inversions. PMID- 22452996 TI - Hypoxia-inducible factor-2a is associated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma. AB - BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer mortality in women worldwide. Hypoxia is an important factor involved in the progression of solid tumors and has been associated with various indicators of tumor metabolism, angiogenesis and metastasis. But little is known about the contribution of Hypoxia-Inducible Factor-2a (HIF-2a) to the drug resistance and the clinicopathological characteristics in breast cancer. METHODS: Immunohistochemistry was employed on the tissue microarray paraffin sections of surgically removed samples from 196 invasive breast cancer patients with clinicopathological data. The correlations between the expression of HIF-2a and ABCG2 as well as other patients' clinicopathological data were investigated. RESULTS: The results showed that HIF-2a was expressed in different intensities and distributions in the tumor cells of the breast invasive ductal carcinoma. A positive staining for HIF-2a was defined as a brown staining observed mainly in the nucleus. A statistically significant correlation was demonstrated between HIF 2a expression and ABCG2 expression (p = 0.001), histology-grade (p = 0.029), and Ki67 (p = 0. 043) respectively. CONCLUSION: HIF-2a was correlated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma. HIF-2a could regulate ABCG2 in breast cancer cells, and could be a novel potential bio-marker to predict chemotherapy effectiveness. The hypoxia/HIF 2a/ABCG2 pathway could be a new mechanism of breast cancer multidrug-resistance. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/2965948166714795. PMID- 22452997 TI - Differential subcellular localization of DNA topoisomerase-1 isoforms and their roles during Caenorhabditis elegans development. AB - DNA topoisomerase-1 (TOP-1) resolves the topological problems associated with DNA replication, transcription and recombination by introducing temporary single strand breaks in the DNA. Caenorhabditis elegans TOP-1 has two isoforms, TOP 1alpha and TOP-1beta. TOP-1beta is broadly localized to the nuclei of many cells at all developmental stages and concentrated in nucleoli in embryo gut and oogenic cells. However, TOP-1alpha is specifically localized to centrosomes, neuronal cells, excretory cells and chromosomes of germ cells in embryonic and larval stages. Reporter gene analysis also shows that top-1 transcription is highly activated in several sensory neurons, speculating the possible role of TOP 1alpha in neuronal development. From RNA interference (RNAi) experiments, we demonstrated that C. elegans TOP-1 is required for chromosomal segregation, germline proliferation and gonadal migration, which are all correlated with the expression and activity of TOP-1. Therefore, our findings may provide an insight into a new role of TOP-1 in development of multicellular organisms. PMID- 22452998 TI - Progressive dry-core-wet-rim hydration trend in a nested-ring topology of protein binding interfaces. AB - BACKGROUND: Water is an integral part of protein complexes. It shapes protein binding sites by filling cavities and it bridges local contacts by hydrogen bonds. However, water molecules are usually not included in protein interface models in the past, and few distribution profiles of water molecules in protein binding interfaces are known. RESULTS: In this work, we use a tripartite protein water-protein interface model and a nested-ring atom re-organization method to detect hydration trends and patterns from an interface data set which involves immobilized interfacial water molecules. This data set consists of 206 obligate interfaces, 160 non-obligate interfaces, and 522 crystal packing contacts. The two types of biological interfaces are found to be drier than the crystal packing interfaces in our data, agreeable to a hydration pattern reported earlier although the previous definition of immobilized water is pure distance-based. The biological interfaces in our data set are also found to be subject to stronger water exclusion in their formation. To study the overall hydration trend in protein binding interfaces, atoms at the same burial level in each tripartite protein-water-protein interface are organized into a ring. The rings of an interface are then ordered with the core atoms placed at the middle of the structure to form a nested-ring topology. We find that water molecules on the rings of an interface are generally configured in a dry-core-wet-rim pattern with a progressive level-wise solvation towards to the rim of the interface. This solvation trend becomes even sharper when counterexamples are separated. CONCLUSIONS: Immobilized water molecules are regularly organized in protein binding interfaces and they should be carefully considered in the studies of protein hydration mechanisms. PMID- 22452999 TI - Impact of low levels of vascular endothelial growth factor after myocardial infarction on 6-month clinical outcome. Results from the Nagoya Acute Myocardial Infarction Study. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is induced by myocardial ischemia and is thought to facilitate cardiovascular repair after acute myocardial infarction (AMI). However, the association between the plasma VEGF levels and clinical outcome in AMI patients is unclear. METHODS AND RESULTS: We evaluated 879 AMI patients undergoing successful primary revascularization within 24h of symptom onset. The patients were classified into 3 groups according to tertiles of plasma VEGF levels at 7 days after the onset of AMI. Major adverse cardiovascular and cerebrovascular events (MACCE), defined as cardiac death, recurrent acute coronary syndrome, hospital readmission for heart failure, or stroke, were assessed during the 6-month follow-up period. The incidence of MACCE was the least frequent in the middle tertile. Compared to the middle tertile, patients in the low tertile were at a significantly higher risk for MACCE even after adjusting for baseline characteristics (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.18-6.06, P=0.019). An absence of statin treatment before onset and a younger age (HR 0.54, 0.87; 95%CI 0.33-0.90, 0.76-0.99; P=0.017, 0.037; respectively) were significantly associated with low VEGF. CONCLUSIONS: Low plasma VEGF levels at 7 days after the onset of AMI were associated with a significantly increased risk for MACCE during 6 months of follow-up. PMID- 22453000 TI - Identification of epsilonPKC targets during cardiac ischemic injury. AB - BACKGROUND: Epsilon-protein kinase C (epsilonPKC) protects the heart from ischemic injury. However, the mechanism(s) of epsilonPKC cardioprotection is still unclear. Identification of the epsilonPKC targets may aid in elucidating the epsilonPKC-mediated cardioprotective mechanisms. Previous studies, using epsilonPKC transgenic mice and difference in gel electrophoresis, identified proteins involved in glucose metabolism, the expression of which was modified by epsilonPKC. Those studies were accompanied by metabolomic analysis, suggesting that increased glucose oxidation may be responsible for the cardioprotective effect of epsilonPKC. Whether these epsilonPKC-mediated alterations were because of differences in protein expression or phosphorylation was not determined. METHODS AND RESULTS: In the present study, we used an epsilonPKC -specific activator peptide, psiepsilonRACK, combined with phosphoproteomics, to find epsilonPKC targets, and identified that the proteins whose phosphorylation was altered by selective activation of epsilonPKC were mostly mitochondrial proteins. Analysis of the mitochondrial phosphoproteome led to the identification of 55 spots, corresponding to 37 individual proteins, exclusively phosphorylated, in the presence of psiepsilonRACK. The majority of the proteins identified were involved in glucose and lipid metabolism, components of the respiratory chain as well as mitochondrial heat shock proteins. CONCLUSIONS: The protective effect of epsilonPKC during ischemia involves phosphorylation of several mitochondrial proteins involved in glucose and lipid metabolism and oxidative phosphorylation. Regulation of these metabolic pathways by epsilonPKC phosphorylation may lead to epsilonPKC-mediated cardioprotection induced by psiepsilonRACK. PMID- 22453001 TI - Coronary plaque characteristics in patients with mild chronic kidney disease. Analysis by 320-row area detector computed tomography. AB - BACKGROUND: The differences in the coronary plaque characteristics between patients with mild chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] 30-59 ml.min(-1) . 1.73 m(-2)) and those without CKD (eGFR >=60) by 320-row area detector computed tomography (CT) have not been studied. METHODS AND RESULTS: We enrolled 487 patients undergoing coronary CT angiography with suspected stable coronary artery disease (mean age: 66.6+/-10.8 years, 131 with mild CKD) and analyzed 6,352 segments. All coronary plaques were characterized for the presence of vessel remodeling, plaque consistency and the disposition of coronary calcification, and a plaque with positive vessel remodeling and/or low attenuation was defined as high risk. The number of diseased segments per patient was higher in mild CKD patients than in those without CKD (4.61+/-3.83 vs. 2.95+/ 3.11, P<0.0001). The prevalence of severe stenosis (>=70% luminal diameter) was significantly higher in cases of mild CKD than in no CKD (35.1% vs. 19.4%, P=0.0003), but there was no significant difference in the prevalence of high-risk plaque (13.0% vs. 9.8%, P=0.3189). CONCLUSIONS: The severity of coronary artery stenosis was higher in the patients with mild CKD, though there was no significant difference in the prevalence of high-risk plaque. We suggest that the high risk of coronary events in patients with CKD is related to the severity of stenosis rather than to the characteristics of plaque. PMID- 22453002 TI - Clinical usefulness of myocardial contrast echocardiography to detect stress induced cardiomyopathy in the emergency department. AB - BACKGROUND: The purpose of this study was to investigate the clinical usefulness of myocardial contrast echocardiography (MCE) to distinguish stress-induced cardiomyopathy (SCMP) from acute myocardial infarction (AMI) in the emergency department (ED). METHODS AND RESULTS: We investigated 51 patients (62+/-13 years, 29 women) who had suspected SCMP in the ED with acute chest pain and showed apical wall motion abnormality on 2-dimensional echocardiography. All patients were assessed by real-time MCE and the perfusion status and quantitative myocardial perfusion parameters were analyzed. After MCE, coronary angiography was performed within 24h. Of 51 patients, 27 had significant perfusion defects (group A) and 24 had preserved perfusion at the apex (group B) by MCE. In group A, 25 patients showed significant luminal stenosis in the left anterior descending artery (LAD) and 2 patients showed no critical luminal stenosis. In group B, 20 patients showed no luminal stenosis and 4 patients showed moderate LAD stenosis. Sensitivity, specificity, positive and negative predictive values of MCE for detection of SCMP were 91%, 86.2%, 83%, and 93%, respectively. Quantitative MCE parameters were significantly decreased in group A compared with group B. CONCLUSIONS: Myocardial perfusion measured by MCE is relatively preserved in patients with SCMP compared with those with AMI. Therefore, real time MCE may be a useful noninvasive diagnostic tool to distinguish SCMP from AMI in the ED. PMID- 22453003 TI - Early improvement in carotid plaque echogenicity by acarbose in patients with acute coronary syndromes. AB - BACKGROUND: The resolution of hyperglycemia is associated with suppression of in hospital cardiac complications in patients with acute coronary syndromes (ACS). This study evaluated carotid artery plaque echolucency using ultrasound in patients with ACS and type 2 diabetes mellitus (DM) to determine whether acarbose, an alpha-glucosidase inhibitor, may rapidly stabilize unstable atherosclerotic plaques. METHODS AND RESULTS: ACS patients with type 2 DM and carotid plaques (n=44) were randomly assigned to treatment with acarbose (150 or 300 mg/day, n=22) or a control group (no acarbose, n=22). Acarbose treatment was initiated within 5 days after the onset of ACS. Unstable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, and at 2 weeks, 1 and 6 months after the initiation of treatment. An increase in the IBS value reflected an increase in carotid plaque echogenicity. As results, the IBS value of echolucent carotid plaques showed a significant increase at 1 month and a further increase at 6 months after treatment in the acarbose group, but there was minimal change in the control group. The increase in IBS values was significantly correlated with a decrease in C-reactive protein levels. CONCLUSIONS: Acarbose rapidly improved carotid plaque echolucency within 1 month of therapy in patients with ACS and type 2 DM. PMID- 22453004 TI - Effect of direct renin inhibitor, aliskiren, on peripheral blood monocyte subsets and myocardial salvage in patients with primary acute myocardial infarction. AB - BACKGROUND: It remains unclear whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) have fully delivered the expected reduction in cardiovascular diseases. We investigated the effects of adding the direct renin inhibitor (DRI), aliskiren, to an ACEI or an ARB on monocyte subsets and myocardial salvage in patients with primary acute myocardial infarction (AMI). METHODS AND RESULTS: Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren combined with an ACEI or an ARB (DRI group). Two monocyte subsets (CD14(+)CD16(-) and CD14(+)CD16(+)) were measured by flow cytometry. The extent of myocardial salvage 7 days after AMI was evaluated by cardiac magnetic resonance imaging. Both plasma renin activity and aldosterone levels were significantly lower in the DRI group than in the non-DRI group. Peak levels of CD14(+)CD16(-) monocyte number and ratio were also significantly lower in the DRI group. The extent of myocardial salvage was significantly higher in the DRI group than in the non-DRI group (44.8 [41.2-53.1] vs. 36.0 [28.5-42.6], P=0.001). CONCLUSIONS: A DRI combined with an ACEI or an ARB can better improve the extent of myocardial salvage after AMI than an ACEI or an ARB alone in association with the decrease in circulating CD14(+)CD16(-) monocytes. PMID- 22453005 TI - Novel strategy to improve end-organ function with pulsatile cardiopulmonary bypass. PMID- 22453006 TI - Epidemiological evidence of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease in Japan. AB - Although epidemiological studies in the US and Europe have confirmed that type 2 diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD) events, evidence is limited in Japan. Earlier studies in Japan showed that hypertension has a major effect on atherosclerosis in relatively lean subjects, with type 2 DM contributing more to CVD events, because of a decline in blood pressure levels in both sexes and an increase in body mass index in men. Recent cohort studies in Japan using baseline assessments carried out during the 1990s have confirmed that type 2 DM is associated with an increased risk of coronary heart disease (CHD) and all types of stroke, except hemorrhagic stroke. In addition, the metabolic syndrome, a constellation of metabolic risk factors, was shown to predict CVD events in Japanese people, independent of the presence or absence of obesity. The strong association of type 2 DM with CHD (hazard ratio: 1.5-4) and ischemic stroke (hazard ratio: 2-4) events was confirmed in Japanese adults. Individuals with impaired glucose tolerance or impaired fasting glucose were also shown to have an increased risk of a CHD event, but not a stroke. PMID- 22453007 TI - Plaque-stabilizing statin therapy prior to percutaneous transluminal angioplasty and stenting. PMID- 22453009 TI - Expression of microRNA-122 contributes to apoptosis in H9C2 myocytes. AB - The microRNAs (miRNAs) can post-transcriptionally regulate gene expression and heart development. The Pax-8 gene knockout mice have apparent heart abnormalities. This study investigated the role of miRNAs in regulation of cardiac apoptosis and development in the knockout mice. MicroRNA microarrays demonstrated differential expression of microRNAs between Pax-8(-/-) and Pax 8(+/-) mice, confirmed by real-time PCR. The miR-122 was up-regulated by 1.92 folds in Pax-8(-/-) mice. There were ventricular septum defects in Pax-8(-/-) mice, and increased numbers of apoptotic cells in the left ventricular wall and interventricular septum in Pax-8(-/-) mice. In H9C2 myocytes, treatment with miR 122 mimics or miR-122 inhibitor affects the expression of CCK-8 and activity of Caspase-3. The miR-122 is up-regulated in the myocytes of Pax-8(-/-) mice and may participate in the apoptotic gene expression and pathogenesis of heart development defect. PMID- 22453010 TI - Special issue on melanoma. PMID- 22453011 TI - Molecular testing in melanoma. AB - Melanoma is the deadliest form of skin cancer and is increasing in incidence. Recent treatment advances have been made, but there remains a need for continued development of effective therapy options, as treatment rarely leads to cure. Many melanomas contain somatic mutations involved in tumor pathogenesis. Accurate identification of these mutations is necessary to stratify patients for the purpose of treatment and potential for clinical trials, given the absence or presence of a specific mutation. There are a number of techniques available that will identify genetic mutations and genomic aberrations present within melanoma tumor samples which are reviewed here. The type of mutation and sample number will drive selection of a given mutation detection strategy. The strengths and weaknesses, along with limitations, of the various methods will also be discussed. The discovery of somatic mutations integral in melanoma will increase our understanding of tumor pathogenesis and should facilitate identification of mutations relevant to clinical treatment decisions, advancing progress toward personalized medicine. PMID- 22453012 TI - Targeting mutant BRAF in melanoma: current status and future development of combination therapy strategies. AB - The discovery of activating BRAF mutations in ~50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. In this commentary, we review the latest research delineating the role of mutant BRAF in melanoma initiation and progression and discuss the remarkable 10-year journey leading up to the recent U.S. Food and Drug Administration approval of the small-molecule BRAF inhibitor vemurafenib. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. It is hoped that our evolving understanding of melanoma genetics and intracellular signaling coupled with a growing armamentarium of signal transduction inhibitors will lead to significant improvements in the level and durability of therapeutic response in metastatic melanoma. PMID- 22453013 TI - Targeting NRAS in melanoma. AB - Cutaneous melanomas have mutations in the NRAS GTPase in 15% of cases. Compared to melanomas with BRAF mutations, or melanomas "wild-type" for BRAF and NRAS, melanomas with NRAS mutations are more likely to be thicker tumors and to have a higher mitotic rate. Preclinical studies indicate that melanoma cells with NRAS mutations are dependent on NRAS for survival and proliferation, making NRAS an attractive therapeutic target in melanoma. However, to date, therapeutic strategies for NRAS mutant melanomas have not been realized. Promising strategies to target NRAS include targeting the membrane localization of NRAS or reducing expression through the use of therapeutic small interfering RNAs. Finally, use of inhibitors to target downstream signaling through mitogen-activated protein kinase kinase and phosphatidylinositol 3-OH kinase or AKT are now entering clinical trials, and if these combinations can be safely delivered at sufficient dose to inhibit the targets, there is significant potential to target NRAS mutant melanoma. PMID- 22453014 TI - Therapeutic implications of KIT in melanoma. AB - Melanoma is a heterogeneous disease representing distinct biologic and genetic subsets. Activating mutations in KIT have been discovered in a significant proportion of melanomas arising from acral, mucosal, and chronically sun-damaged sites and represent an important melanoma genetic subset. Initially, KIT was believed to function as a tumor suppressor, but additional research suggests that, in certain contexts, KIT functions as an oncogene. Therapeutic strategies targeting KIT with imatinib demonstrated remarkable efficacy in patients with gastrointestinal stromal tumors, but initial trials in melanoma were unsuccessful. Nevertheless, case reports continued to surface that demonstrated the remarkable efficacy of imatinib for patients with specific KIT genetic aberrations. Recently, trials of imatinib have selected patients with KIT genetic aberrations and have shown promising results. Current efforts are investigating additional agents that target KIT and testing KIT inhibitors in combination with other agents to improve the outcome for patients with this genetic subset of melanoma. PMID- 22453015 TI - The role of the PI3K-AKT pathway in melanoma. AB - The PI3K (phosphatidylinositol 3-kinase)-AKT pathway is one of the most important signaling networks in cancer. There is growing evidence that activation of this pathway plays a significant role in melanoma, frequently in the setting of concurrent activation of RAS-RAF-MEK-ERK signaling. This evidence includes the identification of genetic and epigenetic events that activate this pathway in melanoma cell lines and clinical specimens. In addition, functional experiments have demonstrated important roles for the PI3K-AKT pathway in both melanoma initiation and therapeutic resistance. The availability of many inhibitors against the PI3K-AKT pathway is rapidly leading to the development of trials that will ultimately determine its clinical significance in this disease. The rational development of such therapies will be facilitated by strategies that utilize the growing understanding of the complexity of the regulation and roles of this pathway. PMID- 22453016 TI - Metastatic uveal melanoma: biology and emerging treatments. AB - Uveal melanoma is the most common primary intraocular cancer in adults. Nearly half of primary uveal melanoma tumors metastasize, but there are currently no effective therapies for metastatic uveal melanoma. The recent discovery of mutations that underlie uveal melanoma metastasis, growth, and survival provide a key to the molecular understanding of this disease. Much work is now underway to leverage this knowledge to develop effective therapies. This review summarizes recently discovered molecular features of uveal melanoma and therapies being explored to capitalize on this knowledge. PMID- 22453017 TI - Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma. AB - Insight into the mechanisms of anti-tumor immunity has generated great enthusiasm for the treatment of patients with advanced melanoma. Particularly, negative regulators of the immune system, called immunologic checkpoints, have been found to play important roles in restraining otherwise effective anti-tumor immunologic responses. Therapies that target these negative regulator checkpoints, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 receptor (PD-1), have demonstrated promising clinical results. Treatment is generally well tolerated, but a novel spectrum of side effects, termed immune related adverse events, has been experienced. Unfortunately, not all patients respond to these therapies, and evaluation of biomarkers predictive of response is ongoing. Based on their unique mechanisms of action, radiographic assessment of response differs from methods traditionally applied to cytotoxic chemotherapy. We expect ongoing and future efforts combining agents that target immunologic checkpoints with other immunotherapeutic approaches, targeted therapy, chemotherapy, and radiotherapy may additionally be beneficial. PMID- 22453018 TI - Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. AB - Immunotherapy using autologous T cells has emerged to be a powerful treatment option for patients with metastatic melanoma. These include the adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs), T cells transduced with high affinity T cell receptors against major tumor antigens, and T cells transduced with chimeric antigen receptors composed of hybrid immunoglobulin light chains with endodomains of T-cell signaling molecules. Among these and other options for T-cell therapy, TILs together with high-dose interleukin 2 have had the longest clinical history with multiple clinical trials in centers across the world consistently demonstrating durable clinical response rates near 50% or more. A distinct advantage of TIL therapy making it still the T-cell therapy of choice is the broad nature of the T-cell recognition against both defined and undefined tumors antigens against all possible major histocompatibility complex, rather than the single specificity and limited major histocompatibility complex coverage of the newer T cell receptors and chimeric antigen receptor transduction technologies. In the past decade, significant inroads have been made in defining the phenotypes of T cells in TIL-mediating tumor regression. CD8+ T cells are emerging to be critical, although the exact subset of CD8+ T cells exhibiting the highest clinical activity in terms of memory and effector markers is still controversial. We present a model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long term tumor control in responding patients. Although TIL therapy has shown great potential to treat metastatic melanoma, a number of issues have emerged that need to be addressed to bring it more into the mainstream of melanoma care. First, we have a reached the point where a pivotal phase II or phase III trial is needed in an attempt to gain regulatory approval of TILs as standard of care. Second, improvements in how we expand TILs for therapy are needed that minimize the time the T cells are in culture and improve the memory and effector characteristics of the T cells for longer persistence and enhanced anti-tumor activity in vivo. Third, there is a critical need to identify surrogate and predictive biomarkers to better select suitable patients for TIL therapy to improve response rate and duration. Overall, the outlook for TIL therapy for melanoma is very bright. We predict that TILs will indeed emerge to become an approved treatment in the upcoming years through pivotal clinical trials. Moreover, new approaches combining TILs with targeted signaling pathway drugs, such as mutant B-RAF inhibitors, and synergistic immunomodulatory interventions enhancing T-cell costimulation and preventing negative regulation should further increase therapeutic efficacy and durable complete response rates. PMID- 22453019 TI - Surgery for distant melanoma metastasis. AB - Traditionally, distant metastatic melanoma has a poor prognosis owing to lack of efficacious, U.S. Food and Drug Administration-approved systemic therapy and the limited use of surgical resection as a therapeutic option. More recently, new biological therapies such as vemurafenib (Zelboraf) and ipilimumab (Yervoy) have shown strong promise and dramatically improved the landscape of stage IV melanoma therapy. Although there are numerous single-institution studies advocating the role for therapeutic surgical intervention, many remain skeptical of nonpalliative surgery for metastatic melanoma. Surgical resection of advanced melanoma has been proven to be effective as long as all disease is removed (R0). Patient selection is paramount. The combination of newer systemic therapies and surgical resection is currently under investigation. Understanding the tumor biology of melanoma and its mechanism of metastatic spread is essential to developing the most efficacious treatment strategy. PMID- 22453020 TI - Sentinel lymph node biopsy in melanoma. AB - The technique of lymphatic mapping and sentinel lymph node (SLN) biopsy for melanoma has emerged during the last 2 decades as a minimally invasive approach to evaluate regional lymph node basins in patients with intermediate- and high risk primary cutaneous melanoma and has changed our approach to the clinically negative lymph node basin in melanoma during the same period. This review focuses on preoperative assessment and operative strategies, pathologic evaluation of the SLN, issues related to regional lymph node basin control, and current clinical practice guidelines. Predictors of SLN status, the prognostic significance of the SLN, and areas of controversy are also discussed. PMID- 22453022 TI - Role of radiation therapy in cutaneous melanoma. AB - Radiotherapy plays a vital role in the management of primary cutaneous melanoma in definitive, adjuvant, and palliative settings. The indications for radiation therapy in melanoma are expanding on the basis of recent clinical trials. The advances of technology in delivering radiation therapy (stereotactic radiosurgery for brain metastasis, stereotactic body radiation therapy, and intensity modulated radiation therapy) and an increasing appreciation of melanoma radiobiology in particular mean that the role of radiation therapy will continue to expand in this disease. PMID- 22453021 TI - Adjuvant therapy for melanoma. AB - Estimates from the U.S. Surveillance, Epidemiology, and End Results registry suggest that melanoma incidence will reach 70,230 cases in 2011, of whom 8790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society.High-dose interferon-alpha-2b is the only agent approved for adjuvant therapy for melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However, toxicity affects compliance, and current research is focusing on biomarkers that may allow selection of patients with greater likelihood of response and exploring new agents either singly or in combination that may improve on the benefit of interferon.In this article, we review the data for the adjuvant therapy for malignant melanoma--focusing on the results obtained with various regimens testing the several formulations of interferon-alpha2 and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA 4 blockade and BRAF-inhibition, raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway. PMID- 22453023 TI - Treatment of melanoma brain metastases: a new paradigm. AB - Brain metastases occur commonly in patients with metastatic melanoma, are associated with a poor prognosis, and cause significant morbidity. Both surgery and stereotactic radiosurgery are used to control brain metastases and, in selected patients, improve survival. In those with extensive brain involvement, whole-brain radiotherapy can alleviate symptoms. Historically, systemic therapy has had little role to play in the management of melanoma brain metastases; however, early clinical trials of BRAF inhibitors have shown promising activity. This review examines the evidence for local and systemic treatments in the management of patients with melanoma brain metastases. We present a new treatment algorithm for melanoma patients with brain metastases, which integrates the evolving evidence for the use of BRAF inhibitors. PMID- 22453024 TI - Estradiol and raloxifene induce the proliferation of osteoblasts through G protein-coupled receptor GPR30. AB - BACKGROUND: Although G-protein-coupled receptor, GPR30, has been considered as a G-protein-coupled estrogen receptor, conflicting results have been reported and the function of GPR30 in bone remains unresolved. The aim of this study was to clarify the functional role of GPR30 in osteoblasts using its derived cell line. METHODS AND RESULTS: Immunohistochemical study revealed that GPR30 is expressed in human osteoblasts. Human fetal osteoblast cell lines, hFOB cells, which express GPR30 but lack estrogen receptor, were used for the in vitro experiments. Estradiol or raloxifene induced the proliferation of hFOB cells, which was accompanied by the activation of mitogen-activated protein (MAP) kinase. Those proliferative effects were completely abrogated by the transfection of GPR30 small interfering RNA, while the transfection alone did not affect the cell viability. CONCLUSION: GPR30 is required for the proliferation of hFOB cells induced by estradiol or raloxifene. This proliferative effect was at least partly mediated via MAP kinase activation. These findings revealed a novel function of GPR30 in osteoblasts and might lead to a better understanding of how estrogen and selective estrogen receptor modulators show their osteoprotective effects. PMID- 22453025 TI - Better learning through instructional science: a health literacy case study in "how to teach so learners can learn". AB - Health education and behavior change interventions typically pay little attention to the intervention's instructional foundation. Combining the fields of health literacy, cognitive psychology, and adult learning theory, this article provides an integrative scientific approach, called the BEAN (Better Education and iNnovation) model, to creating an instructional foundation based on how individuals acquire knowledge and skills. The article uses a case study example from an adult literacy center's health literacy class to explore how environmental factors and instructional strategies can be applied to health education and behavior change interventions. Data for this case study were derived through 20 hours of classroom observation and qualitative interviews with 21 adult education students and 3 instructors. Results provide practical examples of environmental factors and instructional strategies designed to facilitate learning, such as fostering autonomy, activating prior knowledge, and fostering perspective change. Results also describe the resulting health behavior changes of students attending the health literacy class, such as increased medication adherence and physical activity, improved nutritional habits, and increased question asking of health practitioners. This article serves as a first step to encouraging researchers and educators to consider the importance of drawing on cognitive psychology and theories of adult learning to create a scientifically based instructional foundation for health behavior change programs. Additionally, by drawing on the expertise of adult educators well versed in the science of instructional design, this article also demonstrates that the adult education classroom is an excellent setting for conducting health education and behavior change interventions. PMID- 22453026 TI - Dietary habits in women with recurrent idiopathic calcium nephrolithiasis. AB - BACKGROUND: Nutrition has been widely recognized to influence the risk of kidney stone formation. Therefore the aim of our study was to assess: a) whether usual diet of women with idiopathic calcium nephrolithiasis (ICN) living in Parma (Northern-Italy) is different compared to healthy controls, b) how their diet differs from Italian National guidelines and c) whether it is related to nephrolithiasis clinical course. METHODS: 143 women with recurrent ICN (mean age 43 +/- 13 ys) and 170 healthy women (mean age 42 +/- 11 ys) were enrolled. All women completed a food frequency questionnaire for the last 60-days and a 3-day dietary diary analysed with a dedicated software. RESULTS: Stone formers showed a higher consumption of sausages, ham, meat and sweets than healthy controls (43.1% vs 11.1%, 29.4% vs 13.9%, 21.6% vs 4.2%, 66.7% vs 18.1%, p < 0.001). The 3-day diary analysis showed an intake of calories, carbohydrates, lipids and non discretionary sodium about 10% higher than healthy controls (p < 0.001). Finally, after dividing the population into 3 age groups (<=30, 31-40, > 40 years), the differences described above were amplified in the class <=30 years, where nephrolithiasis presented a more serious course (shorter recurrence interval, greater stone-rate). In this age group the intake of fruit and vegetables was notably lower than guideline recommendations. CONCLUSIONS: We conclude that the usual diet of women with recurrent ICN is different from controls and characterized by low intake of fruits and vegetables and higher consumption of simple sugars and foods with high protein and salt content. This dietary imbalance could play a role in the ICN pathogenesis, especially in younger women. PMID- 22453027 TI - A refined estimate of the malaria burden in Niger. AB - BACKGROUND: The health authorities of Niger have implemented several malaria prevention and control programmes in recent years. These interventions broadly follow WHO guidelines and international recommendations and are based on interventions that have proved successful in other parts of Africa. Most performance indicators are satisfactory but, paradoxically, despite the mobilization of considerable human and financial resources, the malaria-fighting programme in Niger seems to have stalled, as it has not yet yielded the expected significant decrease in malaria burden. Indeed, the number of malaria cases reported by the National Health Information System has actually increased by a factor of five over the last decade, from about 600,000 in 2000 to about 3,000,000 in 2010. One of the weaknesses of the national reporting system is that the recording of malaria cases is still based on a presumptive diagnosis approach, which overestimates malaria incidence. METHODS: An extensive nationwide survey was carried out to determine by microscopy and RDT testing, the proportion of febrile patients consulting at health facilities for suspected malaria actually suffering from the disease, as a means of assessing the magnitude of this problem and obtaining a better estimate of malaria morbidity in Niger. RESULTS: In total, 12,576 febrile patients were included in this study; 57% of the slides analysed were positive for the malaria parasite during the rainy season, when transmission rates are high, and 9% of the slides analysed were positive during the dry season, when transmission rates are lower. The replacement of microscopy methods by rapid diagnostic tests resulted in an even lower rate of confirmation, with only 42% of cases testing positive during the rainy season, and 4% during the dry season. Fever alone has a low predictive value, with a low specificity and sensitivity. These data highlight the absolute necessity of confirming all reported malaria cases by biological diagnosis methods, to increase the accuracy of the malaria indicators used in monitoring and evaluation processes and to improve patient care in the more remote areas of Niger. This country extends over a large range of latitudes, resulting in the existence of three major bioclimatic zones determining vector distribution and endemicity. CONCLUSION: This survey showed that the number of cases of presumed malaria reported in health centres in Niger is largely overestimated. The results highlight inadequacies in the description of the malaria situation and disease risk in Niger, due to the over-diagnosis of malaria in patients with simple febrile illness. They point out the necessity of confirming all cases of suspected malaria by biological diagnosis methods and the need to take geographic constraints into account more effectively, to improve malaria control and to adapt the choice of diagnostic method to the epidemiological situation in the area concerned. Case confirmation will thus also require a change in behaviour, through the training of healthcare staff, the introduction of quality control, greater supervision of the integrated health centres, the implementation of good clinical practice and a general optimization of the use of available diagnostic methods. PMID- 22453028 TI - Design choices made by target users for a pay-for-performance program in primary care: an action research approach. AB - BACKGROUND: International interest in pay-for-performance (P4P) initiatives to improve quality of health care is growing. Current programs vary in the methods of performance measurement, appraisal and reimbursement. One may assume that involvement of health care professionals in the goal setting and methods of quality measurement and subsequent payment schemes may enhance their commitment to and motivation for P4P programs and therefore the impact of these programs. We developed a P4P program in which the target users were involved in decisions about the P4P methods. METHODS: For the development of the P4P program a framework was used which distinguished three main components: performance measurement, appraisal and reimbursement. Based on this framework design choices were discussed in two panels of target users using an adapted Delphi procedure. The target users were 65 general practices and two health insurance companies in the South of the Netherlands. RESULTS: Performance measurement was linked to the Dutch accreditation program based on three domains (clinical care, practice management and patient experience). The general practice was chosen as unit of assessment. Relative standards were set at the 25th percentile of group performance. The incentive for clinical care was set twice as high as the one for practice management and patient experience. Quality scores were to be calculated separately for all three domains, and for both the quality level and the improvement of performance. The incentive for quality level was set thrice as high as the one for the improvement of performance. For reimbursement, quality scores were divided into seven levels. A practice with a quality score in the lowest group was not supposed to receive a bonus. The additional payment grew proportionally for each extra group. The bonus aimed at was on average 5% to 10% of the practice income. CONCLUSIONS: Designing a P4P program for primary care with involvement of the target users gave us an insight into their motives, which can help others who need to discuss similar programs. The resulting program is in line with target users' views and assessments of relevance and applicability. This may enhance their commitment to the program as was indicated by the growing number of voluntary participants after a successfully performed field test during the procedure. The elements of our framework can be very helpful for others who are developing or evaluating a P4P program. PMID- 22453029 TI - Translational discoveries, personalized medicine, and living biobanks of the future. PMID- 22453030 TI - The emerging role of MIR-146A in the control of hematopoiesis, immune function and cancer. AB - MicroRNA (miRs) represent a class of small non-coding regulatory RNAs playing a major role in the control of gene expression by repressing protein synthesis at the post-transcriptional level. Studies carried out during the last years have shown that some miRNAs plays a key role in the control of normal and malignant hgematopoiesis. In this review we focus on recent progress in analyzing the functional role of miR-146a in the control of normal and malignant hematopoiesis. On the other hand, this miRNA has shown to impact in the control of innate immune responses. Finally, many recent studies indicate a deregulation of miR-146 in many solid tumors and gene knockout studies indicate a role for this miRNA as a tumor suppressor. PMID- 22453031 TI - Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. AB - BACKGROUND: Recently, it has been proposed that epigenetic variation may contribute to the risk of complex genetic diseases like cancer. We aimed to demonstrate that epigenetic changes in normal cells, collected years in advance of the first signs of morphological transformation, can predict the risk of such transformation. METHODS: We analyzed DNA methylation (DNAm) profiles of over 27,000 CpGs in cytologically normal cells of the uterine cervix from 152 women in a prospective nested case-control study. We used statistics based on differential variability to identify CpGs associated with the risk of transformation and a novel statistical algorithm called EVORA (Epigenetic Variable Outliers for Risk prediction Analysis) to make predictions. RESULTS: We observed many CpGs that were differentially variable between women who developed a non-invasive cervical neoplasia within 3 years of sample collection and those that remained disease free. These CpGs exhibited heterogeneous outlier methylation profiles and overlapped strongly with CpGs undergoing age-associated DNA methylation changes in normal tissue. Using EVORA, we demonstrate that the risk of cervical neoplasia can be predicted in blind test sets (AUC = 0.66 (0.58 to 0.75)), and that assessment of DNAm variability allows more reliable identification of risk associated CpGs than statistics based on differences in mean methylation levels. In independent data, EVORA showed high sensitivity and specificity to detect pre invasive neoplasia and cervical cancer (AUC = 0.93 (0.86 to 1) and AUC = 1, respectively). CONCLUSIONS: We demonstrate that the risk of neoplastic transformation can be predicted from DNA methylation profiles in the morphologically normal cell of origin of an epithelial cancer. Having profiled only 0.1% of CpGs in the human genome, studies of wider coverage are likely to yield improved predictive and diagnostic models with the accuracy needed for clinical application. TRIAL REGISTRATION: The ARTISTIC trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821. PMID- 22453032 TI - The gene expression profiles of canine mammary cancer cells grown with carcinoma associated fibroblasts (CAFs) as a co-culture in vitro. AB - BACKGROUND: It is supposed that fibroblasts present in tumour microenvironment increase cancer invasiveness and its ability to metastasize but the mechanisms have not been clearly defined yet. Thus, the current study was designed to assess changes in gene expression in five various cancer cell lines grown as a co culture with the carcinoma-associated fibroblasts (CAFs) in vitro. RESULTS: A carcinoma-associated fibroblast cell line was isolated from a canine mammary cancer. Then, a co-culture of cancer cells with the CAFs was established and maintained for 72 hrs. Having sorted the cells, a global gene expression in cancer cells using DNA microarrays was examined. The analysis revealed an up regulation of 100 genes and a down-regulation of 106 genes in the cancer cells grown as a co-culture with the CAFs in comparison to control conditions. The PANTHER binomial statistics tool was applied to determine statistically over manifested pathways (p < 0.05). Bulk of the up-regulated genes are involved in the adhesion, the angiogenesis, the epithelial-mesenchymal transition (EMT) and generally take part in the developmental processes. These results were further confirmed using real-time qPCR. Moreover, a wound-healing assay and growth characteristics on Matrigel matrix showed that CAFs increase cancer cell migration and matrix invasion. CONCLUSION: The results of the current study showed that the co-culturing of cancer cells and the CAFs caused significant changes to the cancer gene expression. The presence of the CAFs in a microenvironment of cancer cells promotes adhesion, angiogenesis and EMT. PMID- 22453033 TI - Evaluation of flavonoids and enterolactone in overnight urine as intake biomarkers of fruits, vegetables and beverages in the Inter99 cohort study using the method of triads. AB - Since collection of 24 h urine samples is very time consuming and difficult to obtain, epidemiological studies typically only obtain spot urine samples. The aim of the present study was to evaluate whether flavonoids and enterolactone in overnight urine could substitute flavonoids and enterolactone in 24 h urine as an alternative and more feasible biomarker of fruit, vegetable and beverage intake. A total of 191 individuals in the Inter99 cohort in Denmark completed the validation study. Concentrations of nine urinary flavonoid aglycones (quercetin, isorhamnetin, tamarixetin, kaempferol, hesperetin, naringenin, eriodictyol, phloretin and apigenin) and enterolactone were determined in overnight and 24 h urine samples, and their validity as biomarkers of fruit, vegetable and beverage intake was evaluated in relation to two independent reference methods (Inter99 FFQ data and plasma carotenoids) by using the method of triads. The intakes of fruit, juice, vegetables and tea reported in the FFQ were reflected by the flavonoid biomarker both in overnight and 24 h urine samples. Validity coefficients for the flavonoid biomarker in overnight urine ranged from 0.39 to 0.49, while the corresponding validity coefficients for the biomarker in 24 h urine ranged from 0.43 to 0.66. Although the validity coefficients were lower for overnight urine than for the 24 h urine flavonoid biomarker, they were still of acceptable magnitude. In conclusion, the results indicate that flavonoids and enterolactone in overnight urine samples may be used as a more feasible biomarker than 24 h urine for the assessment and validation of fruit, juice, vegetable and tea intakes in epidemiological studies. PMID- 22453034 TI - Estimating demographic parameters from large-scale population genomic data using Approximate Bayesian Computation. AB - BACKGROUND: The Approximate Bayesian Computation (ABC) approach has been used to infer demographic parameters for numerous species, including humans. However, most applications of ABC still use limited amounts of data, from a small number of loci, compared to the large amount of genome-wide population-genetic data which have become available in the last few years. RESULTS: We evaluated the performance of the ABC approach for three 'population divergence' models - similar to the 'isolation with migration' model - when the data consists of several hundred thousand SNPs typed for multiple individuals by simulating data from known demographic models. The ABC approach was used to infer demographic parameters of interest and we compared the inferred values to the true parameter values that was used to generate hypothetical "observed" data. For all three case models, the ABC approach inferred most demographic parameters quite well with narrow credible intervals, for example, population divergence times and past population sizes, but some parameters were more difficult to infer, such as population sizes at present and migration rates. We compared the ability of different summary statistics to infer demographic parameters, including haplotype and LD based statistics, and found that the accuracy of the parameter estimates can be improved by combining summary statistics that capture different parts of information in the data. Furthermore, our results suggest that poor choices of prior distributions can in some circumstances be detected using ABC. Finally, increasing the amount of data beyond some hundred loci will substantially improve the accuracy of many parameter estimates using ABC. CONCLUSIONS: We conclude that the ABC approach can accommodate realistic genome-wide population genetic data, which may be difficult to analyze with full likelihood approaches, and that the ABC can provide accurate and precise inference of demographic parameters from these data, suggesting that the ABC approach will be a useful tool for analyzing large genome-wide datasets. PMID- 22453035 TI - Traumatic dental injury among 12-year-old South Brazilian schoolchildren: prevalence, severity, and risk indicators. AB - An increasing prevalence of traumatic dental injury (TDI) has been reported in the last few decades. The aim of this study was to assess the prevalence and severity of TDI and its association with socio-demographics and physical characteristics in the anterior permanent teeth of 12-year-old Brazilian schoolchildren. A cross-sectional study was carried out in a population-based sample of 1528 subjects attending 33 public and nine private schools (response rate of 83.17%). A single calibrated examiner performed the clinical examinations at the schools and recorded the TDI index (Children's Dental Health Survey criteria), overjet and lip coverage. Height and weight were measured to calculate the body mass index (BMI). Parents/legal guardians answered a questionnaire containing socio-demographic questions. The relationships among TDI, socio demographic variables and physical characteristics were assessed by survey Poisson regression models. The prevalence of TDI was 34.79% (mild trauma = 24.37%; severe trauma = 10.43%). Male schoolchildren (RR = 1.41, 95% CI = 1.23 1.61, P = 0.002) and schoolchildren from low socioeconomic status (RR = 1.32, 95% CI = 1.07-1.64, P = 0.021) were more likely to present at least one tooth with TDI, whereas students attending 7th grade (advanced students) were less likely to experience TDI (RR = 0.59, 95% CI = 0.43-0.82, P = 0.012). Regarding the severity analysis, students of mid-high (RR = 1.46, 95% CI = 1.09-1.94, P = 0.022), mid low (RR = 1.68, 95% CI = 1.01-2.77, P = 0.045) and low (RR = 1.78, 95% CI = 1.11 2.85, P = 0.027) socioeconomic status were more likely to have mild trauma when compared with schoolchildren of high socioeconomic status. No significant association between severe trauma and socioeconomic status was observed. In conclusion, this study showed a high prevalence of TDI in 12-year-old Brazilian schoolchildren. Socio-demographic data and school achievement were associated with TDI. PMID- 22453036 TI - Effects of selenium supplementation on the natural course of autoimmune thyroiditis: a short review. AB - Selenium (Se) is an important element that exerts its effects on the selenoproteins. It is an essential component of the glutathione peroxidase enzymes, which have anti-oxidant and anti-inflammatory properties, and a component of iodothyronine selenodeiodinases, which catalyze the extrathyroid production of T3 from T4. Se is important to several aspects of thyroid homeostasis and may influence the natural course of thyroid diseases such as autoimmune thyroiditis (AIT). This review analyzes the effects of Se supplementation in patients with AIT, based on the studies published on this issue to date. PMID- 22453037 TI - [A case of posterior reversible encephalopathy syndrome occurring after anemia correction]. AB - A 53-year-old woman was admitted to our hospital with headache and convulsion. Advanced anemia with a Hb level of 3.5 g/dl had been detected about a month earlier, and it had been treated by iron administration to achieve a Hb level of 8.9 g/dl. The patient developed status epilepticus on admission. The blood pressure was elevated, and brain diffusion weighted imaging and fluid attenuated inversion recovery imaging revealed high intensity areas in the bilateral posterior and parietal lobes, right frontal lobe, and right basal ganglia. The cerebrospinal fluid protein was elevated. The convulsions settled after continuous infusion of thiamylal under mechanical ventilation. Subsequently, the patient became conscious, and the brain MRI abnormalities gradually disappeared. While a number of factors such as hypertension, medication and others have been reported as causes of posterior reversible encephalopathy syndrome (PRES), comparatively rapid anemia correction could also possibly precipitate PRES as like as this case. Thus anemia correction needs to be undertaken carefully. PMID- 22453038 TI - [Unusual visual impairments in a case of MPO-ANCA associated hypertrophic pachymeningitis]. AB - We report a 79-year-old man presenting MPO-ANCA associated hypertrophic pachymeningitis and bilateral visual impairment. Two years before, microscopic hematuria and positive MPO-ANCA were indicated, then oral steroids and cyclophosphamide were given as systemic vasculitis. On admission, lateral hemianopsia in the right visual field was documented. Some weeks after admission, he complained of a left-hand side headache, and the visual impairment of a right eye. Brain MRI detected thick dura matter with abnormal enhancement predominantly on the left side of the basal temporal lobe and a tumor-like lesion at the sphenoid sinus near the right cavernous sinus. Multiple scotomas in the left visual field were compatible with ischemic changes caused by MPO-ANCA related vasculitis. On the other hand, the hemianopsia in his right eye was related with a tumor-like lesion. The visual problems showed a favorable response to the steroid pulse therapy. ANCA-positive cases can demonstrate various symptoms including intra-/extra-cranial involvement. Thus, thorough clinical workup is needed to determine the actual site of the lesion when cranial nerve involvement is observed in MPO-ANCA positive hypertrophic pachymeningitis. PMID- 22453039 TI - [An autopsied case of progressive supranuclear palsy presenting with slow progression and unusually prolonged disease duration]. AB - A 55-year-old Japanese female with no family history of neurological disease showed gait disturbance with rigidity and resting tremor. She was initially diagnosed with Parkinson's disease, but neither laterality of symptoms nor levodopa benefit were observed. The parkinsonism and gait freezing progressed unusually slowly and she experienced frequent falls 17 years after the onset of symptoms. When neurologic examination revealed vertical gaze palsy, masked face, bradykinesia and dominant axial rigidity, the diagnosis was modified to progressive supranuclear palsy (PSP). Retrocollis, grasp reflex, and bilateral Babinski's sign developed, but resting tremor disappeared. Gastrostomy was performed 22 years after onset, after which she was still capable of walking with assistance. Tracheotomy was not performed. The patient died of an acute subarachnoid hemorrhage 24 years after onset at the age of 79. On autopsy, the brain weighed 1,050 g and showed frontal lobe atrophy. Coronal cerebral slices showed atrophy of the globus pallidus and subthalamic nucleus. Tegmental atrophy of the brainstem and depigmentation of the substantia nigra were observed. Neuropathologic examination showed severe neuron loss with gliosis in the globus pallidus, subthalamic nucleus, substantia nigra, and tegmentum of the brainstem. The Purkinje neuron layer and cerebellar dentate nucleus showed mild neuron loss. Globose-type neurofibrillary tangles were widespread, particularly in the globus pallidus, subthalamic nucleus, substantia nigra, nucleus of oculomotor nerve, locus ceruleus, and cerebellar dentate nucleus. Glial fibrillary tangles (coiled body and tuft-shaped astrocyte) and argyrophilic threads were also widespread, particularly in the frontal lobe and basal ganglia. Lewy bodies were not observed. Although, the pathologic findings were consistent with PSP, Gallyas positive and tau-positive structures were generally small in number. According to the clinicopathological findings, we speculate that this case showed a distinct subtype of PSP with a slowly progressive clinical course and generally mild tau deposition. PMID- 22453040 TI - [Paradoxical brain embolism mediated through a pulmonary arteriovenous malformation with hereditary hemorrhagic telangiectasia in a Japanese patient]. AB - We report a case of paradoxical brain embolism mediated through a pulmonary arteriovenous malformation (PAVM) with hereditary hemorrhagic telangiectasia (HHT). A 25-year-old right handed man was admitted to our hospital after sudden headache and visual field abnormality. In neurologic examinations, he had left superior-quadrantanopsia. Laboratory findings showed iron deficiency anemia. Diffusion weighted images disclosed a high-signal-intensity area in the right occipito-temporal lobe, and intraarterial digital subtraction cerebral angiography revealed occlusion of the right posterior cerebral artery. Transesophageal echocardiography revealed continuous right-to-left shunt. We confirmed his history of spontaneous recurrent epistaxis and the first-degree relatives with epistaxis or PAVM. A contrast enhanced CT scan of the chest revealed a PAVM. The diagnosis of paradoxical brain embolism mediated through the PAVM with HHT was, thus, established. The PAVM was occluded by using embolization coils successfully. In Asian countries, the prevalence of PAVM with HHT is thought to be lower than in European countries. We should carefully take medical and family histories, especially epistaxis, in a young stroke patient. PMID- 22453041 TI - [A case of successful treatment of brain and lung cryptococcosis caused by Cryptococcus gattii]. AB - We report the case of a 34-year-old woman with cerebral and pulmonary cryptococcosis. After surgery for uterine cervical cancer, chest CT scan indicated a solitary tumor. Cryptococcosis was detected by transbronchial lung biopsy, and brain MRI showed multiple tumors. We diagnosed the patient with cerebral and pulmonary cryptococcosis. Oral and intravenous antifungal treatments were not effective, and a disturbance of consciousness appeared. We began intraventricular antifungal treatment, and the symptoms improved, with a reduction in the size of multiple lesions. However, the size of the brain lesions increased, and we diagnosed late deterioration of cryptococcosis and corticosteroid response. Because of the refractory clinical course, we examined the Cryptococcus strains from the surgical resected pulmonary lesion and identified Cryptococcus gattii(VG I type). C. gattii occurs predominantly in apparently healthy hosts. An intracranial C. gattii infection is associated with neurological complications and delayed therapeutic response. If cerebral cryptococcosis responds slowly and relatively poorly to antifungal therapy, C. gattii should be considered. Aggressive therapy, including intraventricular therapy and corticosteroids therapy for cryptococcoma, is required. PMID- 22453042 TI - [Successful cyclosporine treatment in 2 patients with refractory CIDP, involving monitoring of both AUC(0-4h) and trough levels]. AB - Cyclosporine A (CYA) treatment has been reported to be probably useful for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) that is resistant to conventional treatment. Although several studies have shown that appropriate area under the concentration-time curve (AUC) monitoring of CYA levels results in improved outcomes for refractory nephrotic syndrome patients, the importance of using AUC analysis for CIDP remains unclear. In this study, we measured both trough and AUC from 0 to 4 h (AUC(0-4 h)) levels of CYA in 2 patients with CIDP and compared the findings for the clinical parameters. On the basis of the CYA dosing recommendations for patients with nephrotic syndrome, we used a CYA concentration of 150 ng/ml for the trough level and an AUC(0-4 h) value of 2,500 ng/(ml.h). Patient 1 showed a significant increase in grip strength and a prolonged remission period. Patient 2 showed improvement in the modified Rankin scale and manual muscle test (MMT) scores. Monitoring both AUC(0 4 h) and trough levels of CYA seems to be a better option than monitoring the trough level alone because it leads to improved estimation of the efficacy and safety of CYA treatment in the case of CIDP patients. PMID- 22453043 TI - [Hemicape-like sensory disturbance caused by cortical infarction in the postcentral gyrus]. AB - We report a case of a small cortical infarction in the postcentral gyrus that presented an isolated hemicape-like sensory disturbance. A 47-year-old man suddenly developed numbness and paresthesia in the left neck, shoulder, arm, and upper trunk. Examination revealed hypoesthesia to touch and pain in these areas along with a hemicape-like distribution. The sensitivity to cold and vibration was normal, and two-point discrimination and graphesthesia were preserved. The patient had a normal visual field, muscle strength, and reflexes, and there were no neuropsychological deficits. Magnetic resonance imaging (MRI) demonstrated a fresh, small cerebral infarction in the right postcentral gyrus, which was superior medial to the precentral knob. The area of infarction in this patient corresponds well with the area of the upper trunk, neck, head, shoulder, and arm in the sensory homunculus drawn by Penfield and Rassumussen. The spinal MRI was normal. Transesophageal echocardiography disclosed a patent foramen ovale with a right-to-left-shunt. The patient was diagnosed as having acute cerebral infarction, probably due to paradoxical embolism, and was treated with warfarin. A small localized infarct in the postcentral gyrus can present an isolated sensory disturbance with an atypical hemicape-like distribution. PMID- 22453044 TI - [A case of reversible cerebral vasoconstriction syndrome (RCVS) triggered by human placenta extract]. AB - We present a case of a female patient with reversible cerebral vasoconstriction syndrome (RCVS) arising after receiving subcutaneous injection of human placenta extract. A 44-year-old woman started taking human placenta extract with the aim of improving her menopausal symptoms, fatigue, and beauty. However, 18 days after taking human placenta extract, she had three episodes of thunderclap headache. Repeated cranial CT did not show subarachnoid hemorrhage; CSF examination showed neither xanthochromia nor inflammation. Brain diffusion weighted and FLAIR images were normal. However, magnetic resonance angiography showed multifocal segmental stenosis of the right middle cerebral artery and bilateral anterior cerebral arteries. Follow-up angiography, which performed 12 days after the oncet of thunderclap headache, revealed almost normalized flow in all cerebral arteries; we made a diagnosis of RCVS. She has had no symptoms and signs since the third attack of headache. The only identified etiologic factor was subcutaneous injection of human placenta extract started 18 days prior to onset. This is the first report of RCVS triggered by human placenta extract. PMID- 22453045 TI - [A case of POEMS syndrome associated with Waldenstrom's macroglobulinemia and treated with lenalidomide]. AB - This report deals with a 46-year-old male with Waldenstrom's macroglobulinemia (WM), who developed POEMS syndrome four years after diagnosis. The patient was diagnosed with WM, based on the presence of IgM-kappa type monoclonal (M) protein and infiltration of lymphoplasmacytic cells identified in bone marrow aspirates. Four years later, the patient presented with progressive weakness and paresthesia of the limb extremities, and he was admitted to our hospital. Physical and neurological examination on admission revealed polyneuropathy, hepatosplenomegaly, hypothyroidism, IgM-kappa M protein, leg edema, and cutaneous hyperpigmentation. He fulfilled the diagnostic criteria for POEMS syndrome. Laboratory tests showed normocytic normochromic anemia, elevated erythrocyte sedimentation rate, and increased levels of soluble IL-2 receptor, IL-6 and plasma vascular endothelial growth factor (VEGF). He was started on lenalidomide. After therapy, the leg edema and limb dysesthesia improved, and the VEGF level decreased from 608 pg/ml to 380 pg/ml. This is a very rare case of POEMS syndrome associated with WM, and is the first case treated with lenalidomide in Japan. VEGF presumably producted WM may be associated with development of POEMS syndrome. PMID- 22453046 TI - Cardiovascular risk assessment in the asymptomatic individual: a case-based approach. AB - Coronary artery disease remains the leading cause of mortality worldwide, and the identification of at-risk individuals represents a significant clinical challenge. In this review, a typical clinical case is presented, followed by a discussion of the cardiovascular risk assessment of such individuals. Specifically, the role of imaging modalities such as carotid intima-media thickness measurements and coronary artery calcium scoring is explored. Case resolution and recommendations are subsequently suggested. PMID- 22453047 TI - Clinical remission after stopping infliximab in Crohn's disease: is all that glitters true gold? PMID- 22453048 TI - The association between malnutrition and the incidence of malaria among young HIV infected and -uninfected Ugandan children: a prospective study. AB - BACKGROUND: In sub-Saharan Africa, malnutrition and malaria remain major causes of morbidity and mortality in young children. There are conflicting data as to whether malnutrition is associated with an increased or decreased risk of malaria. In addition, data are limited on the potential interaction between HIV infection and the association between malnutrition and the risk of malaria. METHODS: A cohort of 100 HIV-unexposed, 203 HIV-exposed (HIV negative children born to HIV-infected mothers) and 48 HIV-infected children aged 6 weeks to 1 year were recruited from an area of high malaria transmission intensity in rural Uganda and followed until the age of 2.5 years. All children were provided with insecticide-treated bed nets at enrolment and daily trimethoprim sulphamethoxazole prophylaxis (TS) was prescribed for HIV-exposed breastfeeding and HIV-infected children. Monthly routine assessments, including measurement of height and weight, were conducted at the study clinic. Nutritional outcomes including stunting (low height-for-age) and underweight (low weight-for-age), classified as mild (mean z-scores between -1 and -2 during follow-up) and moderate-severe (mean z-scores < -2 during follow-up) were considered. Malaria was diagnosed when a child presented with fever and a positive blood smear. The incidence of malaria was compared using negative binomial regression controlling for potential confounders with measures of association expressed as an incidence rate ratio (IRR). RESULTS: The overall incidence of malaria was 3.64 cases per person year. Mild stunting (IRR = 1.24, 95% CI 1.06-1.46, p = 0.008) and moderate severe stunting (IRR = 1.24, 95% CI 1.03-1.48, p = 0.02) were associated with a similarly increased incidence of malaria compared to non-stunted children. Being mildly underweight (IRR = 1.09, 95% CI 0.95-1.25, p = 0.24) and moderate-severe underweight (IRR = 1.12, 95% CI 0.86-1.46, p = 0.39) were not associated with a significant difference in the incidence of malaria compared to children who were not underweight. There were no significant interactions between HIV-infected, HIV exposed children taking TS and the associations between malnutrition and the incidence of malaria. CONCLUSIONS: Stunting, indicative of chronic malnutrition, was associated with an increased incidence of malaria among a cohort of HIV infected and -uninfected young children living in an area of high malaria transmission intensity. However, caution should be made when making causal inferences given the observational study design and inability to disentangle the temporal relationship between malnutrition and the incidence of malaria. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00527800. PMID- 22453049 TI - Tracking family medicine graduates. Where do they go, what services do they provide and whom do they see? AB - BACKGROUND: There are continued concerns over an adequate supply of family physicians (FPs) practicing in Canada. While most resource planning has focused on intake into postgraduate education, less information is available on what postgraduate medical training yields. We therefore undertook a study of Family Medicine (FM) graduates from the University of Toronto (U of T) to determine the type of information for physician resource planning that may come from tracking FM graduates using health administrative data. This study compared three cohorts of FM graduates over a 10 year period of time and it also compared FM graduates to all Ontario practicing FPs in 2005/06. The objectives for tracking the three cohorts of FM graduates were to: 1) describe where FM graduates practice in the province 2) examine the impact of a policy introduced to influence the distribution of new FM graduates in the province 3) describe the services provided by FM graduates and 4) compare workload measures. The objectives for the comparison of FM graduates to all practicing FPs in 2005/06 were to: 1) describe the patient population served by FM graduates, 2) compare workload of FM graduates to all practicing FPs. METHODS: The study cohort consisted of all U of T FM postgraduate trainees who started and completed their training between 1993 and 2003. This study was a descriptive record linkage study whereby postgraduate information for FM graduates was linked to provincial health administrative data. Comprehensiveness of care indicators and workload measures based on administrative data where determined for the study cohort. RESULTS: From 1993 to 2003 there were 857 University of Toronto FM graduates. While the majority of U of T FM graduates practice in Toronto or the surrounding Greater Toronto Area, there are FM graduates from U of T practicing in every region in Ontario, Canada. The proportion of FM graduates undertaking further emergency training had doubled from 3.6% to 7.8%. From 1993 to 2003, a higher proportion of the most recent FM graduates did hospital visits, emergency room care and a lower proportion undertook home visits. Male FM graduates appear to have had higher workloads compared with female FM graduates, though the difference between them was decreasing over time. A 1997 policy initiative to discount fees paid to new FPs practicing in areas deemed over supplied did result in a decrease in the proportion of FM graduates practicing in metropolitan areas. CONCLUSIONS: We were able to profile the practices of FM graduates using existing and routinely collected population-based health administrative data. Further work tracking FM graduates could be helpful for physician resource forecasting and in examining the impact of policies on family medicine practice. PMID- 22453050 TI - Towards real-time cardiovascular magnetic resonance guided transarterial CoreValve implantation: in vivo evaluation in swine. AB - BACKGROUND: Real-time cardiovascular magnetic resonance (rtCMR) is considered attractive for guiding TAVI. Owing to an unlimited scan plane orientation and an unsurpassed soft-tissue contrast with simultaneous device visualization, rtCMR is presumed to allow safe device navigation and to offer optimal orientation for precise axial positioning. We sought to evaluate the preclinical feasibility of rtCMR-guided transarterial aortic valve implatation (TAVI) using the nitinol based Medtronic CoreValve bioprosthesis. METHODS: rtCMR-guided transfemoral (n = 2) and transsubclavian (n = 6) TAVI was performed in 8 swine using the original CoreValve prosthesis and a modified, CMR-compatible delivery catheter without ferromagnetic components. RESULTS: rtCMR using TrueFISP sequences provided reliable imaging guidance during TAVI, which was successful in 6 swine. One transfemoral attempt failed due to unsuccessful aortic arch passage and one pericardial tamponade with subsequent death occurred as a result of ventricular perforation by the device tip due to an operating error, this complication being detected without delay by rtCMR. rtCMR allowed for a detailed, simultaneous visualization of the delivery system with the mounted stent-valve and the surrounding anatomy, resulting in improved visualization during navigation through the vasculature, passage of the aortic valve, and during placement and deployment of the stent-valve. Post-interventional success could be confirmed using ECG-triggered time-resolved cine-TrueFISP and flow-sensitive phase-contrast sequences. Intended valve position was confirmed by ex-vivo histology. CONCLUSIONS: Our study shows that rtCMR-guided TAVI using the commercial CoreValve prosthesis in conjunction with a modified delivery system is feasible in swine, allowing improved procedural guidance including immediate detection of complications and direct functional assessment with reduction of radiation and omission of contrast media. PMID- 22453051 TI - Up-regulation of hypoxia inducible factor-1alpha by cobalt chloride correlates with proliferation and apoptosis in PC-2 cells. AB - BACKGROUND: The exact mechanism of the effects of hypoxia on the proliferation and apoptosis in carcinoma cells is still conflicting. This study investigated the variation of hypoxia-inducible factor-1alpha(HIF-1alpha) expression and the apoptosis effect of hypoxia stimulated by cobalt chloride (CoCl(2)) in pancreatic cancer PC-2 cells. METHODS: PC-2 cells were cultured with different concentration (50-200 MUmol/L) of CoCl(2) after 24-120 hours to simulate hypoxia in vitro. The proliferation of PC-2 cells was examined by MTT assay. The cellular morphology of PC-2 cells were observed by light inverted microscope and transmission electron microscope(EM). The expression of HIF-1alpha on mRNA and protein level was measured by semi-quantitative RT-PCR and Western blot analysis. Apoptosis of PC-2 cells were demonstrated by flow cytometry with Annexin V-FITC/PI double staining. RESULTS: MTT assay showed that the proliferation of PC-2 cells were stimulated in the first 72 h, while after treated over 72 h, a dose- dependent inhibition of cell growth could be observed. By using transmission electron microscope, swollen chondrosomes, accumulated chromatin under the nuclear membrane and apoptosis bodies were observed. Flow cytometer(FCM) analysis showed the apoptosis rate was correlated with the dosage of CoCl(2). RT-PCR and Western blot analysis indicated that hypoxia could up-regulate the expression of HIF-1alpha on both mRNA and protein levels. CONCLUSION: Hypoxic microenvironment stimulated by CoCl(2) could effectively induce apoptosis and influence cell proliferation in PC-2 cells, the mechanism could be related to up-expression of HIF-1alpha. PMID- 22453052 TI - Effect of glucagon-like peptide 2 on hepatic, renal, and intestinal disposition of 1-chloro-2,4-dinitrobenzene. AB - The ability of the liver, small intestine, and kidney to synthesize and subsequently eliminate dinitrophenyl-S-glutathione (DNP-SG), a substrate for multidrug resistance-associated protein 2 (Mrp2), was assessed in rats treated with glucagon-like peptide 2 (GLP-2, 12 MUg/100 g b.wt. s.c. every 12 h for 5 consecutive days). An in vivo perfused jejunum model with simultaneous bile and urine collection was used. A single intravenous dose of 30 MUmol/kg b.wt. 1 chloro-2,4-dinitrobenzene (CDNB) was administered, and its conjugate, DNP-SG, and dinitrophenyl cysteinyl glycine (DNP-CG), resulting from the action of gamma glutamyltransferase on DNP-SG, were determined in bile, intestinal perfusate, and urine by high-performance liquid chromatography. Tissue content of DNP-SG was also assessed in liver, intestine, and kidneys. Biliary excretion of DNP-SG+DNP CG was decreased in GLP-2 rats with respect to controls. In contrast, their intestinal excretion was substantially increased, whereas urinary elimination was not affected. Western blot and real-time polymerase chain reaction studies revealed preserved levels of Mrp2 protein and mRNA in liver and renal cortex and a significant increase in intestine in response to GLP-2 treatment. Tissue content of DNP-SG detected 5 min after CDNB administration was decreased in liver, increased in intestine, and unchanged in kidney in GLP-2 versus control group, consistent with GLP-2-induced down-regulation of expression of glutathione transferase (GST) Mu in liver and up-regulation of GST-Alpha in intestine at both protein and mRNA levels. In conclusion, GLP-2 induced selective changes in hepatic and intestinal disposition of a common GST and Mrp2 substrate administered systemically that could be of pharmacological or toxicological relevance under therapeutic treatment conditions. PMID- 22453053 TI - A novel bead-based assay to detect specific antibody responses against Toxoplasma gondii and Trichinella spiralis simultaneously in sera of experimentally infected swine. AB - BACKGROUND: A novel, bead-based flow cytometric assay was developed for simultaneous determination of antibody responses against Toxoplasma gondii and Trichinella spiralis in pig serum. This high throughput screening assay could be an alternative for well known indirect tests like ELISA. One of the advantages of a bead-based assay over ELISA is the possibility to determine multiple specific antibody responses per single sample run facilitated by a series of antigens coupled to identifiable bead-levels. Furthermore, inclusion of a non-coupled bead level in the same run facilitates the determination of, and correction for non specific binding. The performance of this bead-based assay was compared to one T. spiralis and three T. gondii ELISAs. For this purpose, sera from T. gondii and T. spiralis experimentally infected pigs were used. With the experimental infection status as gold standard, the area under the curve, Youden Index, sensitivity and specificity were determined through receiver operator curve analysis. Marginal homogeneity and inter-rater agreement between bead-based assay and ELISAs were evaluated using McNemar's Test and Cohen's kappa, respectively. RESULTS: Results indicated that the areas under the curve of the bead-based assay were 0.911 and 0.885 for T. gondii and T. spiralis, respectively, while that of the T. gondii ELISAs ranged between 0.837 and 0.930 and the T. spiralis ELISA was 0.879. Bead based T. gondii assay had a sensitivity of 86% and specificity of 96%, while the ELISAs ranged between 64-84% and 93-99%, respectively. The bead-based T. spiralis assay had a sensitivity of 68% and specificity of 100% while the ELISA scored 72% and 95%, respectively. Marginal homogeneity was found between the T. gondii bead based test and one of the T. gondii ELISAs. Moreover, in this test combination and between T. spiralis bead-based assay and respective ELISA, an excellent inter rater agreement was found. When results of samples before expected seroconversion were removed from evaluation, notably higher test specifications were found. CONCLUSIONS: This new bead-based test, which detects T. gondii and T. spiralis antibodies simultaneously within each sample, can replace two indirect tests for the determination of respective antibodies separately, while performing equally well or better. PMID- 22453054 TI - Effect of a novel proteoglycan PTP1B inhibitor from Ganoderma lucidum on the amelioration of hyperglycaemia and dyslipidaemia in db/db mice. AB - Protein tyrosine phosphatase 1B (PTP1B) is implicated in the negative regulation of the insulin signalling pathway by dephosphorylating the insulin receptor (IR) and IR substrates. Ganoderma lucidum has traditionally been used for the treatment of diabetes in Chinese medicine; however, its anti-diabetic potency and mechanism in vivo is still unclear. Our previously published study reported a novel proteoglycan PTP1B inhibitor, named Fudan-Yueyang-Ganoderma lucidum (FYGL) from G. lucidum, with a half-maximal inhibitory concentration (IC50) value of 5.12 (sem 0.05) MUg/ml, a protein:polyglycan ratio of 17:77 and 78 % glucose in polysaccharide, and dominant amino acid residues of aspartic acid, glycine, glutamic acid, alanine, serine and threonine in protein. FYGL is capable of decreasing plasma glucose in streptozotocin-induced diabetic mice with a high safety of median lethal dose (LD50) of 6 g/kg. In the present study, C57BL/6 db/db diabetic mice were trialed further using FYGL as well as metformin for comparison. Oral treatment with FYGL in db/db diabetic mice for 4 weeks significantly (P < 0.01 or 0.05) decreased the fasting plasma glucose level, serum insulin concentration and the homeostasis model assessment of insulin resistance. FYGL also controlled the biochemistry indices relative to type 2 diabetes-accompanied lipidaemic disorders. Pharmacology research suggests that FYGL decreases the plasma glucose level by the mechanism of inhibiting PTP1B expression and activity, consequently, regulating the tyrosine phosphorylation level of the IR beta-subunit and the level of hepatic glycogen, thus resulting in the improvement of insulin sensitivity. Therefore, FYGL is promising as an insulin sensitiser for the therapy of type 2 diabetes and accompanied dyslipidaemia.